PMID- 29412668 TI - Total Synthesis of Ecumicin. AB - The first total synthesis of the potent anti-mycobacterial cyclic depsipeptide natural product ecumicin is described. Synthesis was achieved via a solid-phase strategy, incorporating the synthetic non-proteinogenic amino acids N-methyl-4 methoxy-l-tryptophan and threo-beta-hydroxy-l-phenylalanine into the growing linear peptide chain. The synthesis employed key on-resin esterification and dimethylation steps as well as a final macrolactamization between the unusual N methyl-4-methoxy-l-tryptophan unit and a bulky N-methyl-l-valine residue. The synthetic natural product possessed potent antimycobacterial activity against the virulent H37Rv strain of Mycobacterium tuberculosis (MIC90 = 312 nM). PMID- 29412669 TI - Modified Abietane Diterpenoids from Whole Plants of Selaginella moellendorffii. AB - A new modified abietane diterpenoid, (3S,4S,5R,10S)-18(4->3)-abeo-3,4,12,18 tetrahydroxy-8,11,13-abietatrien-7-one (1), and two novel dimers, selaginedorffones A (2) and B (3), featuring a new cyclohexene moiety that was biogenetically constructed from two modified abietane diterpenoids through a Diels-Alder reaction were obtained from a methanolic extract of Selaginella moellendorffii, a traditional Chinese herb. The structures of 1-3 were identified by a combination of NMR spectroscopic analysis and ECD calculations. In the present study, diterpenoids were identified from S. moellendorffii for the first time, which supports the presence of diterpene synthases in this plant. These three diterpenoids (1-3) were evaluated for their growth-inhibitory activities against several human cancer cell lines. Of these substances, selaginedorffone B (3) showed cytotoxicity against the MCF-7 human-breast-cancer-cell line (IC50 9.0 MUM). PMID- 29412670 TI - Understanding and Calibrating Density-Functional-Theory Calculations Describing the Energy and Spectroscopy of Defect Sites in Hexagonal Boron Nitride. AB - Defect states in 2-D materials present many possible uses but both experimental and computational characterization of their spectroscopic properties is difficult. We provide and compare results from 13 DFT and ab initio computational methods for up to 25 excited states of a paradigm system, the VNCB defect in hexagonal boron nitride (h-BN). Studied include: (i) potentially catastrophic effects for computational methods arising from the multireference nature of the closed-shell and open-shell states of the defect, which intrinsically involves broken chemical bonds, (ii) differing results from DFT and time-dependent DFT (TDDFT) calculations, (iii) comparison of cluster models to periodic-slab models of the defect, (iv) the starkly differing effects of nuclear relaxation on the various electronic states that control the widths of photoabsorption and photoemission spectra as broken bonds try to heal, (v) the effect of zero-point energy and entropy on free-energy differences, (vi) defect-localized and conduction/valence-band transition natures, and (vii) strategies needed to ensure that the lowest-energy state of a defect can be computationally identified. Averaged state-energy differences of 0.3 eV are found between CCSD(T) and MRCI energies, with thermal effects on free energies sometimes also being of this order. However, DFT-based methods can perform very poorly. Simple generalized gradient functionals like PBE fail at the most basic level and should never be applied to defect states. Hybrid functionals like HSE06 work very well for excitations within the triplet manifold of the defect, with an accuracy equivalent to or perhaps exceeding the accuracy of the ab initio methods used. However, HSE06 underestimates triplet-state energies by on average of 0.7 eV compared to closed-shell singlet states, while open-shell singlet states are predicted to be too low in energy by 1.0 eV. This leads to misassignment of the ground state of the VNCB defect. Long-range corrected functionals like CAM-B3LYP are shown to work much better and to represent the current entry level for DFT calculations on defects. As significant differences between cluster and periodic slab models are also found, the widespread implementation of such functionals in periodic codes is in urgent need. PMID- 29412671 TI - Phase Behavior of Co-Nonsolvent Systems: Poly( N-isopropylacrylamide) in Mixed Solvents of Water and Methanol. AB - Cloud points of poly( N-isopropylacrylamide) in aqueous mixed solvents, with methanol as the cosolvent, are experimentally measured for polymer concentrations varied up to as high as the weight fraction 0.25. They are shown to form closed loops on the ternary phase plane in the temperature region between 5 and 30 degrees C, and hence co-nonsolvency is complete. Miscibility loops shrink by cooling, or equivalently, they exhibit lower critical solution temperature behavior. For a fixed polymer concentration, there is a composition of the mixed solvent at which the cloud-point temperature takes the lowest value. This minimum cloud-point temperature composition of the mixed solvent turned out to be almost independent of the polymer concentration, at least within the measured dilute region below the weight fraction 0.25. On the basis of the assumption that the phase separation is closely related to the preferential adsorption of the solvents by hydrogen bonding, we employ a model solution of Flory-Huggins type, augmented with direct and cooperative polymer-solvent hydrogen bonds, to construct the ternary phase diagrams. Theoretical calculation of the spinodal curves is performed, and the results are compared with the obtained experimental cloud-point data. The effect of molecular volume of the cosolvent is also studied within the same theoretical framework. Possibility for a upper critical solution temperature co-nonsolvency to appear for cosolvents with larger molecular volume is discussed. PMID- 29412672 TI - Allosteric Modulators of Drug Targets Special Issue. PMID- 29412673 TI - What is Responsible for Atypical Dependence of the Rate of Amyloid Formation on Protein Concentration: Fibril-Catalyzed Initiation of New Fibrils or Competition with Oligomers? AB - An abnormal dependence of the rate of amyloid formation on protein concentration has been recently observed by Meisl et al. for Abeta40 peptides associated with Alzheimer's disease. To explain this effect, Meisl et al. proposed a novel mechanism of fibril growth: the fibril-catalyzed initiation of fibril formation. In this paper we offer an alternative explanation of the observed anomalous kinetics: formation of metastable oligomers competing with fibril formation by decreasing the concentration of the fibril-forming free monomers. Here we show that the oligomer sizes resulting from the anomalous dependence of the fibril growth rate on protein concentration are close to the sizes of oligomers observed by electron microscopy. PMID- 29412674 TI - Combination of Phospholipid Complex and Submicron Emulsion Techniques for Improving Oral Bioavailability and Therapeutic Efficacy of Water-Insoluble Drug. AB - Water-insoluble drugs cannot be absorbed effectively through the gastrointestinal tract due to insufficient solubility and often face the problems of low bioavailability and poor therapeutic efficacy. To overcome these biopharmaceutical challenges, lipid-based formulations were suggested and have been researched in recent years. In this study, we used atorvastatin as a model drug to prepare a phospholipid complex prodrug system to upgrade its lipophilicity and further developed a drug loaded submicron emulsion to improve its in vivo bioavailability. The mean particle size and zeta potential of submicron emulsion were 122.7 nm and -22.7 mV. Intestinal absorption of atorvastatin from submicron emulsion was significantly improved compared with free drug, and the absorption rate constant ( Ka) and apparent permeability coefficients ( Papp) increase 2.88-fold and 2.45-fold, respectively. After oral administration, the atorvastatin plasma concentration of the emulsion group was much higher than that of free drug and the area under the curve (AUC) reached to 4.033 mg/L.h (2.58-fold). In vivo pharmacodynamics results revealed that atorvastatin submicron emulsion showed excellent antihyperlipidemia efficacy by reducing the total cholesterol, triglyceride, and low density lipoprotein cholesterol (LDL-cholesterol) levels and simultaneously increasing the high density lipoprotein cholesterol (HDL-cholesterol) level in comparison with Lipitor. In conclusion, drug-phospholipid complex loaded submicron emulsion was a promising oral delivery system for improving in vivo absorption behavior and therapeutic efficacy for water-insoluble drugs. PMID- 29412675 TI - Direct Atomic-Scale Observation of Intermediate Pathways of Melting and Crystallization in Supported Bi Nanoparticles. AB - Uncovering the evolutional pathways of melting and crystallization atomically is critical to understanding complex microscopic mechanism of first-order phase transformation. We conduct in situ atomic-scale observations of melting and crystallization in supported Bi nanoparticles under heating and cooling within an aberration-corrected TEM. We provide direct evidence of the multiple intermediate state events in melting and crystallization. The melting of the supported nanocrystal involves the formation and migration of domain boundaries and dislocations due to the atomic rearrangement under heating, which occurs through a size-dependent multiple intermediate state. A critical size, which is key to inducing the transition pathway in melting from two to four barriers, is identified for the nanocrystal. In contrast, crystallization of a Bi droplet involves three stages. These findings demonstrate that the phase transformations cannot be viewed as a simple single barrier-crossing event but as a complex multiple intermediate state phenomenon, highlighting the importance of nonlocal behaviors. PMID- 29412676 TI - Nanoladder Cantilevers Made from Diamond and Silicon. AB - We present a "nanoladder" geometry that minimizes the mechanical dissipation of ultrasensitive cantilevers. A nanoladder cantilever consists of a lithographically patterned scaffold of rails and rungs with feature size ~100 nm. Compared to a rectangular beam of the same dimensions, the mass and spring constant of a nanoladder are each reduced by roughly 2 orders of magnitude. We demonstrate a low force noise of 158-42+62 zN and 190-33+42 zN in a 1 Hz bandwidth for devices made from silicon and diamond, respectively, measured at temperatures between 100-150 mK. As opposed to bottom-up mechanical resonators like nanowires or nanotubes, nanoladder cantilevers can be batch-fabricated using standard lithography, which is a critical factor for applications in scanning force microscopy. PMID- 29412677 TI - Gold(I)-Catalyzed Formation of Naphthalene/Acenaphthene Heterocyclic Acetals. AB - A gold-catalyzed addition/cyclization reaction to form 3-alkoxy benzo[de]isochromene derivatives was developed. All reactions, performed in mild conditions, exhibited high regioselectivity and good to excellent reaction yields. Additionally, optimized methodology was used in total synthesis of 2 phenylphenalenone, an alleged natural product found in Macropidia fuliginosa plant. PMID- 29412678 TI - Copper-Mediated Reactions of Nitriles with Nitromethanes: Aza-Henry Reactions and Nitrile Hydrations. AB - In this study, the first aza-Henry reaction of nitriles with nitromethane in a CuI/Cs2CO3/DBU system is described. The process was conveniently and directly used for the synthesis of beta-aminonitroalkenes 2a-x and tolerated aryl-, alkyl , hetaryl-, alkenyl-, and alkynylnitriles. The resulting aminonitroalkenes 2 could be successfully transformed to the corresponding 2-nitroacetophenones, 2 amino-1-halonitroalkenes, 2-alkylaminonitroalkenes, or 3-nitropyridines. In the presence of H2O, the aza-Henry reaction turned the reaction path to the nitrile hydration to exclusively yield the amides 3a-s. PMID- 29412679 TI - Rhodium-Catalyzed Insertion Reaction of PhP Group of Pentaphenylcyclopentaphosphine with Acyclic and Cyclic Disulfides. AB - Organophosphorus compounds with a phosphorus atom attached to a phenyl group and two organothio/organoseleno groups were synthesized using the rhodium-catalyzed insertion reaction of the PhP group of pentaphenylcyclopentaphosphine (PhP)5 with acyclic disulfides and diselenides. The method was applied to the synthesis of heterocyclic compounds containing the S-P-S group by the reaction of (PhP)5 and cyclic disulfides such as 1,2-dithietes, 1,2-dithiocane, 1,4,5-dithiopane, and 1,2-dithiolanes. PMID- 29412680 TI - Negative Differential Resistance Behavior of the Iron Storage Protein Ferritin. AB - Realization of useful nanometer length scale devices in which metalloproteins are junction-confined in a distinct molecular arrangement for generating practical electronic signals (e.g., in bioelectronic switch configuration) is elusive till date. This is mostly due to difficulties in observing an electronically appropriate signal (i.e., reproducible and controllable), when studied under junction-assembled condition. A useful "ON"-"OFF" behavior, based on the negative differential resistance (NDR) peak characteristics in the current-voltage response curves, acquired using metal-insulator-metal (MIM) configuration, has been observed only in the case of a few proteins, namely, azurin, cytochrome c, bacteriorhodopsin, so far. The case of NDR in ferritin, an iron storage protein having a semiconducting iron core consisting of few thousands of iron atoms connected in an oxide network, has not been studied in the MIM configuration where single (or a few) molecule(s) are junction-trapped, for example, as in the case of local probe configuration of scanning probe microscopy. The present study by scanning tunneling microscopy (STM), using the naturally occurring iron containing ferritin (human liver), as well as different iron-loaded ferritins, provides clear indication of the capability of ferritins to be NDR capable, at varying sweep conditions. As ferritin can be tailor-made in a structurally conserved manner, metal core-reconstituted ferritins, that is, Mn(III)-ferritin, Cu(II)-ferritin, and Ag-ferritin, were prepared. A correlation between the NDR peak signatures, as observed in the respective current-voltage response curves of these reconstituted ferritins, and the nature of the metal core is demonstrated. In support of our earlier proposition, here, we affirm that the ferritin protein behaves as a conductor-insulator (metal core-polypeptide shell) composite, where the overall electronic structure of the material can alter as a function of the nature of the conducting filler placed inside the insulated matrix. PMID- 29412681 TI - In Situ Salt Formation during Melt Extrusion for Improved Chemical Stability and Dissolution Performance of a Meloxicam-Copovidone Amorphous Solid Dispersion. AB - As the pipeline for poorly soluble compounds continues to grow, drug degradation during melt extrusion must be addressed. We present a novel method for stabilizing a thermally labile drug substance while preserving its physical stability and even improving its dissolution performance. In a previous study, we found that incorporating meglumine during extrusion of meloxicam results in chemical stabilization that cannot be achieved using process optimization alone. The purpose of this study is to understand the mechanism behind this stabilization and its impact on the performance of a meloxicam-Kollidon VA64 amorphous solid dispersion. The meloxicam concentration was maintained at 10% (w/w) for blends with and without meglumine. The optimal meglumine blend contained an equimolar amount of meloxicam to meglumine with the remainder consisting of Kollidon VA64. Both formulations were processed with optimized extrusion conditions and analyzed by HPLC for purity. Meglumine at a 1:1 molar ratio with meloxicam results in 100% purity of meloxicam after melt extrusion. Solid-state NMR revealed a proton transfer between the meloxicam and meglumine indicating an in situ salt formation. During non-sink dissolution, the meglumine ASD enables meloxicam to maintain supersaturatation (?50 times more than meloxicam free acid) for >7.25 h. The ASD without meglumine began precipitating 2.25 h following the pH shift. The ASDs were placed at 40 degrees C/75% RH for 6 months, and their stability was assessed. No significant chemical degradation, recrystallization, or significant moisture uptake was observed after six months' storage at 40 degrees C/75% RH. PMID- 29412682 TI - Pentaketide Ansamycin Microansamycins A-I from Micromonospora sp. Reveal Diverse Post-PKS Modifications. AB - Overexpression of the pathway-specific positive regulator gene mas13 activated the cryptic gene cluster mas, resulting in the isolation of nine novel pentaketide ansamycins, namely, microansamycins A-I (1-9). These results not only revealed a biosynthetic gene cluster of pentaketide ansamycins for the first time but also presented an unprecedented scenario of diverse post-PKS modifications in ansamycin biosynthesis. PMID- 29412683 TI - Diosmetin Induces Apoptosis of Acute Myeloid Leukemia Cells. AB - Acute myeloid leukemia is an aggressive disease with limited and nonselective therapeutic options. This study explored the bioactivity and cell death inducing mechanism of diosmetin, a novel compound identified in a nutraceutical screen to impart selective anti-AML activity. Diosmetin, a citrus flavone, induced apoptosis characterized by increases in caspases 8 and 3/7 and the death inducing cytokine TNFalpha. In fact, through protein and mRNA expression analysis, activity was shown to be dependent on expression of estrogen receptor (ER) beta. Treatment with diosmetin also delayed tumor growth in AML mouse xenografts. In summary, these studies highlight diosmetin as a novel therapeutic that induces apoptosis through estrogen receptor beta. PMID- 29412684 TI - Design Strategy for the Molecular Functionalization of Semiconductor Photoelectrodes: A Case Study of p-Si(111) Photocathodes for H2 Generation. AB - Functionalization of semiconductor photoelectrodes is actively pursued as an approach to improve the efficiency of photoelectrochemical reactions by modulating the semiconductor's barrier height, but the selection of molecules for functionalization remains largely empirical. We propose a simple but effective design strategy for the organic functionalization of photocathodes for high efficiency hydrogen generation based on first-principles density functional theory (DFT) calculations. The surface dipole of the functionalized photocathode determines its barrier height, which can be optimized to enhance charge separation at the semiconductor-electrolyte interface. Focusing on p-Si(111) photocathodes functionalized with different mixed aryl/methyl monolayers, we use DFT to systematically investigate the effect of - the presence and distribution of pi bonds, binding atom (the atom in the functional group that bonds with the Si surface), functional group length, and electrophilic substituent groups - on the surface dipole and charge rearrangement at the functionalized surface. We find that the most important factors affecting the surface dipole are the intrinsic molecular dipole moment of the organic moiety, the presence of electrophilic substituent groups, and the binding atom. Using these findings, a three-step design strategy is proposed for the experimental realization of high performing functionalized p-Si(111) photocathodes by maximizing the surface dipole. PMID- 29412685 TI - Can Elderly Lungs Cope with Urban Concentrations of Ground-Level Ozone? Experiences from a Large-Scale Multicenter Exposure Chamber Study. PMID- 29412687 TI - Lung Transplantation from Hepatitis C Viremic Donors to Uninfected Recipients. PMID- 29412686 TI - The common marmoset monkey: avenues for exploring the prenatal, placental, and postnatal mechanisms in developmental programming of pediatric obesity. AB - Animal models have been critical in building evidence that the prenatal experience and intrauterine environment are capable of exerting profound and permanent effects on metabolic health through developmental programming of obesity. However, despite physiological and evolutionary similarities, nonhuman primate models are relatively rare. The common marmoset monkey ( Callithrix jacchus) is a New World monkey that has been used as a biomedical model for well more than 50 years and has recently been framed as an appropriate model for exploring early-life impacts on later health and disease. The spontaneous, multifactorial, and early-life development of obesity in the common marmoset make it a valuable research model for advancing our knowledge about the role of the prenatal and placental mechanisms involved in developmental programming of obesity. This paper provides a brief overview of obesity in the common marmoset, followed by a discussion of marmoset reproduction and placental characteristics. We then discuss the occurrence and utility of variable intrauterine environments in developmental programming in marmosets. Evidence of developmental programming of obesity will be given, and finally, we put forward future directions and innovations for including the placenta in developmental programming of obesity in the common marmoset. PMID- 29412688 TI - Long-Acting beta-Agonist/Inhaled Corticosteroid in Patients with Chronic Obstructive Pulmonary Disease with Cardiovascular Disease or Risk: A Factorial Analysis of the SUMMIT Clinical Trial. PMID- 29412689 TI - Branched fibers from old fast-twitch dystrophic muscles are the sites of terminal damage in muscular dystrophy. AB - A striking pathological feature of dystrophinopathies is the presence of morphologically abnormal branched skeletal muscle fibers. The deterioration of muscle contractile function in Duchenne muscular dystrophy is accompanied by both an increase in number and complexity of these branched fibers. We propose that when number and complexity of branched fibers reaches a critical threshold, or "tipping point," the branches in and of themselves are the site of contraction induced rupture. In the present study, we use the dystrophic mdx mouse and littermate controls to study the prediseased dystrophic fast-twitch extensor digitorum longus (EDL) muscle at 2-3 wk, the peak myonecrotic phase at 6-9 wk, and finally, "old," at 58-112 wk. Using a combination of isolated muscle function contractile measurements coupled with single-fiber imaging and confocal microscope imaging of cleared whole muscles, we identified a distinct pathophysiology, acute fiber rupture at branch nodes, which occurs in "old" fast twitch EDL muscle approaching the end stage of the dystrophinopathy muscle disease, where the EDL muscles are entirely composed of complexed branched fibers. This evidence supports our concept of "tipping point" where the number and extent of fiber branching reach a level where the branching itself terminally compromises muscle function, irrespective of the absence of dystrophin. PMID- 29412691 TI - Lack of contribution of nitric oxide synthase to cholinergic vasodilation in murine renal afferent arterioles. AB - We have previously reported significant increases in neuronal nitric oxide synthase (NOS) immunostaining in renal arterioles of angiotensin type 1A receptor (AT1A) knockout mice, and in arterioles and macula densa cells of AT1A/AT1B knockout mice. The contribution of nitric oxide derived from endothelial and macula densa cells in the maintenance of afferent arteriolar tone and acetylcholine-induced vasodilation was functionally determined in kidneys of wild type, AT1A, and AT1A/AT1B knockout mice. Acetylcholine-induced changes in arteriolar diameters of in vitro blood-perfused juxtamedullary nephrons were measured during control conditions, in the presence of the nonspecific NOS inhibitor, Nomega-nitro-l-arginine methyl ester (NLA), or the highly selective neuronal NOS inhibitor, N5-(1-imino-3-butenyl)-l-ornithine (VNIO). Acetylcholine (0.1 mM) produced a significant vasoconstriction in afferent arterioles of AT1A/AT1B mice (-10.9 +/- 5.1%) and no changes in afferent arteriolar diameters of AT1A knockout mice. NLA (0.01-1 mM) or VNIO (0.01-1 MUM) induced significant dose-dependent vasoconstrictions (-19.8 +/- 4.0% 1 mM NLA; -7.8 +/- 3.5% 1 MUM VNIO) in afferent arterioles of kidneys of wild-type mice. VNIO had no effect on afferent arteriole diameters of AT1A knockout or AT1A/AT1B knockout mice, suggesting nonfunctional neuronal nitric oxide synthase. These data indicate that acetylcholine produces a significant renal afferent arteriole vasodilation independently of nitric oxide synthases in wild-type mice. AT1A receptors are essential for the manifestation of renal afferent arteriole responses to neuronal nitric oxide synthase-mediated nitric oxide release. PMID- 29412690 TI - Platelet procoagulant phenotype is modulated by a p38-MK2 axis that regulates RTN4/Nogo proximal to the endoplasmic reticulum: utility of pathway analysis. AB - Upon encountering physiological cues associated with damaged or inflamed endothelium, blood platelets set forth intracellular responses to ultimately support hemostatic plug formation and vascular repair. To gain insights into the molecular events underlying platelet function, we used a combination of interactome, pathway analysis, and other systems biology tools to analyze associations among proteins functionally modified by reversible phosphorylation upon platelet activation. While an interaction analysis mapped out a relative organization of intracellular mediators in platelet signaling, pathway analysis revealed directional signaling relations around protein kinase C (PKC) isoforms and mitogen-activated protein kinases (MAPKs) associated with platelet cytoskeletal dynamics, inflammatory responses, and hemostatic function. Pathway and causality analysis further suggested that platelets activate a specific p38 MK2 axis to phosphorylate RTN4 (reticulon-4, also known as Nogo), a Bcl-xl sequestration protein and critical regulator of endoplasmic reticulum (ER) physiology. In vitro, we find that platelets drive a p38-MK2-RTN4-Bcl-xl pathway associated with the regulation of the ER and platelet phosphatidylserine exposure. Together, our results support the use of pathway tools in the analysis of omics data sets as a means to help generate novel, mechanistic, and testable hypotheses for platelet studies while uncovering RTN4 as a putative regulator of platelet cell physiological responses. PMID- 29412692 TI - Peptide hormone relaxin: from bench to bedside. AB - The peptide hormone relaxin has numerous roles both within and independent of pregnancy and is often thought of as a "pleiotropic hormone." Relaxin targets several tissues throughout the body, and has many functions associated with extracellular matrix remodeling and the vasculature. This review considers the potential therapeutic applications of relaxin in cervical ripening, in vitro fertilization, preeclampsia, acute heart failure, ischemia-reperfusion, and cirrhosis. We first outline the animal models used in preclinical studies to progress relaxin into clinical trials and then discuss the findings from these studies. In many cases, the positive outcomes from preclinical animal studies were not replicated in human clinical trials. Therefore, the focus of this review is to evaluate the various animal models used to develop relaxin as a potential therapeutic and consider the limitations that must be addressed in future studies. These include the use of human relaxin in animals, duration of relaxin treatment, and the appropriateness of the clinical conditions being considered for relaxin therapy. PMID- 29412693 TI - Bronchiectasis: Phenotyping an Orphan Disease. PMID- 29412694 TI - Lateral Ankle Sprain in a Mouse Model: Lifelong Sensorimotor Dysfunction. AB - CONTEXT: Ankle sprains are the most common orthopaedic injury that occurs during sport and physical activity. Many individuals who sprain their ankles develop chronic ankle instability (CAI), a condition characterized by recurrent injury, decreased physical activity, and decreased quality of life. These residual impairments are believed to persist for the remainder of the patient's life, in part due to the link between CAI and posttraumatic ankle osteoarthritis. However, this belief remains speculative due to the lack of long-term prospective investigations. OBJECTIVE: To use a mouse model of mild (MILD) and severe (SEVERE) ankle sprains to quantify balance and locomotor adaptations across the lifespan. DESIGN: Cohort study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Fifty male mice (CBA/J) were randomly placed into a control (SHAM), MILD, or SEVERE group and housed individually. INTERVENTION(S): The MILD group underwent surgical transection of a single right hind-limb lateral ankle ligament, and the SEVERE group had 2 of the lateral ligaments transected. The SHAM group underwent a sham surgery during which no lateral ligaments were transected. MAIN OUTCOME MEASURE(S): After surgically inducing the ankle sprain, we measured balance and gait using a balance beam and footprint test before and every 6 weeks for 78 weeks. RESULTS: Age-related declines in balance but not stride length were exacerbated by an ankle sprain ( P < .001). Balance and stride lengths changed with age ( P < .001). Foot slips were worse in the SEVERE (4.32 +/- 0.98) and MILD (3.53 +/- 0.98) groups than in the SHAM group (2.16 +/- 0.99; P < .001). Right-limb stride length was shorter in the SEVERE group (6.45 cm +/- 0.41 cm) than in the SHAM group (6.87 cm +/- 0.40 cm; P = .04). CONCLUSIONS: Transecting the lateral ligaments of a mouse hind foot resulted in lifelong sensorimotor dysfunction. Declines starting at 42 weeks postinjury may have represented the onset of posttraumatic osteoarthritis. PMID- 29412695 TI - High Injury Burden in Elite Adolescent Athletes: A 52-Week Prospective Study. AB - CONTEXT: Our understanding of the injury burden in elite adolescent athletes in most sports is limited or unknown because of the lack of prospective, long-term injury studies. OBJECTIVE: To describe injury patterns in terms of type, location, prevalence and incidence, recurrence, and severity grade; time to first injury; and prevalence of illness in elite adolescent athletes and to compare differences in injury data by sex and sport type. DESIGN: Cohort study. SETTING: Fifteen national sports high schools in Sweden. PATIENTS OR OTHER PARTICIPANTS: Participants were 284 elite adolescent athletes (boys = 147, girls = 137; median age = 17 years; 25th-75th percentile range = 16-18 years) competing at a high national level for their age in athletics (track and field), cross-country skiing, downhill skiing, freestyle skiing, handball, orienteering, or ski orienteering. MAIN OUTCOME MEASURE(S): All athletes were monitored weekly over 52 weeks, using a validated online questionnaire to identify injury type, location, prevalence or incidence, and severity grade; time to first injury; and prevalence of illness. RESULTS: Among all athletes, 57.4% reported at least 1 new injury, whereas the 1-year injury prevalence was 91.6%. The overall injury incidence was 4.1/1000 hours of exposure to sport, and every week, on average, 3 of 10 (30.8%) elite adolescent athletes reported being injured. Of all injuries from which athletes recovered, 22.2% (n = 35) resulted in absence from normal training for at least 2 months. Female athletes reported higher ( P < .05) average weekly injury prevalence and substantial injury prevalence (injuries leading to a moderate or severe reduction in sport performance or participation or time loss) than male athletes. CONCLUSIONS: A considerable number of elite adolescent athletes were injured weekly, resulting in serious consequences for sport participation, training, or performance (or a combination of these). Appropriately designed interventions to prevent knee and foot injuries will target both the greatest number of injuries and the injuries with the most serious consequences in elite adolescent athletes. PMID- 29412696 TI - Involuntary care - capturing the experience of people with dementia in nursing homes. A concept mapping study. AB - OBJECTIVE: To avoid restraints and involuntary care caregivers should be aware if and how a patient resists care. This article focuses on behavioural expressions of people with severe dementia in nursing homes that are interpreted by their formal and informal caregivers as possible expressions of their experience of involuntary care. METHOD: Concept mapping was used, following five steps: (1) brainstorming, (2) rating, (3) sorting, (4) statistical analysis & visual representation and (5) interpretation. Specialists (n = 12), nurses (n = 23) and relatives (n = 13) participated in separate groups . RESULTS: The views generated are grouped into clusters of behaviour, presented in graphic charts for each of the respondent groups. The large variety of behavioural symptoms includes, in all groups, not only the more obvious and direct behavioural expressions like aggression, resistance and agitation, but also more subtle behaviour such as sorrow, general discomfort or discontent. CONCLUSION(S): In the interpretation of behavioural symptoms of people with severe dementia it is important to take into account the possibility of that person experiencing involuntary care. Increased awareness and understanding of the meaning and consequences of the behavioural expressions is an important step in improving dementia care by avoiding restraints and involuntary care to its maximum. PMID- 29412697 TI - miR-155 Affects Osteosarcoma MG-63 Cell Autophagy Induced by Adriamycin Through Regulating PTEN-PI3K/AKT/mTOR Signaling Pathway. AB - OBJECTIVE: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays a positive regulatory role on cell autophagy through inhibiting PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway. miR-155 plays a critical role in osteosarcoma occurrence and chemoresistance. Bioinformatics analysis revealed the targeted binding site between miR-155 and the 3'-UTR (untranslated region) of PTEN mRNA. This study investigated the role of miR-155 in regulating osteosarcoma cell autophagy, chemosensitivity to Adriamycin (ADM), and PTEN-PI3K/AKT/mTOR signaling pathway. MATERIALS AND METHODS: Dual luciferase reporter gene assay confirmed the relationship between miR-155 and PTEN. MG-63 cells and drug resistant MG-63/ADM cells were treated by ADM to compare miR-155, PTEN, p-AKT, p mTOR, and Beclin-1 expressions. Cell apoptosis was tested by flow cytometry. MG 63/ADM cells were divided into five groups, including anti-miR-NC, anti-miR-155, pSicoR-blank, pSicoR-PTEN, and anti-miR-155+pSicoR-PTEN group. RESULTS: miR-155 targeted suppressed PTEN expression. miR-155, p-AKT, and p-mTOR significantly increased, while PTEN and Beclin-1 obviously reduced in MG-63/ADM cells compared with MG-63 cells. ADM treatment markedly elevated miR-155, p-AKT, and p-mTOR expressions, whereas reduced PTEN level. Beclin-1 was slightly upregulated, and autophagy and apoptosis levels were low. Anti-miR-155 and/or pSicoR-PTEN significantly enhanced PTEN and Beclin-1 expressions, cell apoptosis, and autophagy induced by ADM and declined p-AKT and p-mTOR levels. CONCLUSIONS: miR 155 targeted suppressed PTEN expression, enhanced PI3K/AKT/mTOR signaling pathway, inhibited cell apoptosis and autophagy induced by ADM, and reduced sensitivity to ADM. PMID- 29412698 TI - Organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin. AB - The sodium-glucose cotransporter SGLT2 inhibitor empagliflozin (plasma protein binding ~88%) may reach its target in the brush border of the early proximal tubule by glomerular filtration and tubular secretion. Here we determined whether empagliflozin is secreted by renal tubules in mice and whether genetic knockout of the basolateral organic anion transporter 3 ( Oat3-/-) affects its tubular secretion or glucosuric effect. Renal clearance studies in wild-type (WT) mice showed that tubular secretion accounted for 50-70% of empagliflozin urinary excretion. Immunostaining indicated that SGLT2 and OAT3 localization partially overlapped in proximal tubule S1 and S2 segments. Glucosuria in metabolic cage studies was reduced in Oat3-/- vs. WT mice for acute empagliflozin doses of 1, 3, and 10 mg/kg, whereas 30 mg/kg induced similar maximal glucosuria in both genotypes. Chronic application of empagliflozin (~25 mg.kg-1 .day-1) in Oat3-/- mice was associated with lower urinary glucose-to-creatinine ratios despite maintaining slightly higher blood glucose levels than WT. On a whole kidney level, renal secretion of empagliflozin was largely unchanged in Oat3-/- mice. However, the absence of OAT3 attenuated the influence of empagliflozin on fractional glucose excretion; higher levels of plasma or filtered empagliflozin were needed to induce similar increases in fractional renal glucose excretion. We conclude that empagliflozin is excreted into the urine to similar extent by glomerular filtration and tubular secretion. The latter can occur largely independent of OAT3. However, OAT3 increases the glucosuric effect of empagliflozin, which may relate to the partial overlap of its localization with SGLT2 and thus OAT3-mediated tubular secretion of empagliflozin in the early proximal tubule. PMID- 29412699 TI - Identification of differential gene expression patterns in human arteries from patients with chronic kidney disease. AB - Uremia accelerates atherosclerosis, but little is known about affected pathways in human vasculature. This study aimed to identify differentially expressed arterial transcripts in patients with chronic kidney disease (CKD). Global mRNA expression was estimated by microarray hybridization in iliac arteries ( n = 14) from renal transplant recipients and compared with renal arteries from healthy living kidney donors ( n = 19) in study 1. Study 2 compared nonatherosclerotic internal mammary arteries (IMA) from five patients with elevated plasma creatinine levels and age- and sex-matched controls with normal creatinine levels. Western blotting and immunohistochemistry for selected proteins were performed on a subset of study 1 samples. Fifteen gene transcripts were significantly different between the two groups in study 1 [fold changes (FC) > 1.05 and false discovery rates (FDR) < 0.005]. Most upregulated mRNAs associated with cellular signaling, apoptosis, TNFalpha/NF-kappaB signaling, smooth muscle contraction, and 10 other pathways were significantly affected. To focus attention on genes from genuine vascular cells, which dominate in IMA, concordant deregulated genes in studies 1 and 2 were examined and included 23 downregulated and eight upregulated transcripts (settings in study 1: FC > 1.05 and FDR < 0.05; study 2: FC > 1.2 and P < 0.2). Selected deregulated gene products were investigated at the protein level, and whereas HIF3alpha confirmed mRNA upregulation, vimentin showed upregulation in contrast to the mRNA results. We conclude that arteries from CKD patients display change in relatively few sets of genes. Many were related to differentiated vascular smooth muscle cell phenotype. These identified genes may contribute to understanding the development of arterial injury among patients with CKD. PMID- 29412700 TI - Lineage tracing aged mouse kidneys shows lower number of cells of renin lineage and reduced responsiveness to RAAS inhibition. AB - Blocking the renin-angiotensin-aldosterone system (RAAS) remains a mainstay of therapy in hypertension and glomerular diseases. With the population aging, our understanding of renin-producing cells in kidneys with advanced age is more critical than ever. Accordingly, we administered tamoxifen to Ren1cCreERxRs tdTomato-R mice to permanently fate map cells of renin lineage (CoRL). The number of Td-tomato-labeled CoRL decreased significantly in aged mice (24 mo of age) compared with young mice (3.5 mo of age), as did renin mRNA levels. To determine whether aged CoRL responded less to RAAS blockade, enalapril and losartan were administered over 25 days following uninephrectomy in young and aged mice. The number of CoRL increased in young mice in response to enalapril and losartan. However, this was significantly lower in aged mice compared with young mice due to limited proliferation, but not recruitment. Gene expression analysis of laser captured CoRL showed a substantial increase in mRNA levels for proapoptotic and prosenescence genes, and an increase in a major prosenescence protein on immunostaining. These results show that CoRL are lower in aged mice and do not respond to RAAS inhibition to the same extent as young mice. PMID- 29412701 TI - The rise and fall of novel renal magnesium transporters. AB - Body Mg2+ balance is finely regulated in the distal convoluted tubule (DCT), where a tight interplay among transcellular reabsorption, mitochondrial exchange, and basolateral extrusion takes place. In the last decades, several research groups have aimed to identify the molecular players in these processes. A multitude of proteins have been proposed to function as Mg2+ transporter in eukaryotes based on phylogenetic analysis, differential gene expression, and overexpression studies. However, functional evidence for many of these proteins is lacking. The aim of this review is, therefore, to critically reconsider all putative Mg2+ transporters and put their presumed function in context of the renal handling of Mg2+. Sufficient experimental evidence exists to acknowledge transient receptor potential melastatin (TRPM) 6 and TRPM7, solute carrier family 41 (SLC41) A1 and SLC41A3, and mitochondrial RNA splicing 2 (MRS2) as Mg2+ transporters. TRPM6/7 facilitate Mg2+ influx, SLC41A1 mediates Mg2+ extrusion, and MRS2 and SLC41A3 are implicated in mitochondrial Mg2+ homeostasis. These proteins are highly expressed in the DCT. The function of cyclin M (CNNM) proteins is still under debate. For the other proposed Mg2+ transporters including Mg2+ transporter subtype 1 (MagT1), nonimprinted in Prader Willi/Angelman syndrome (NIPA), membrane Mg2+ transport (MMgT), Huntingtin interacting protein 14 (HIP14), and ATP13A4, functional evidence is limited, or functions alternative to Mg2+ transport have been suggested. Additional characterization of their Mg2+ transport proficiency should be provided before further claims about their role as Mg2+ transporter can be made. PMID- 29412702 TI - alpha-Ketoglutarate stimulates pendrin-dependent Cl- absorption in the mouse CCD through protein kinase C. AB - alpha-Ketoglutarate (alpha-KG) is a citric acid cycle intermediate and a glutamine catabolism product. It is also the natural ligand of 2-oxoglutarate receptor 1 (OXGR1), a Gq protein-coupled receptor expressed on the apical membrane of intercalated cells. In the cortical collecting duct (CCD), Cl /[Formula: see text] exchange increases upon alpha-KG binding to the OXGR1. To determine the signaling pathway(s) by which alpha-KG stimulates Cl- absorption, we examined alpha-KG-stimulated Cl- absorption in isolated perfused mouse CCDs. alpha-KG increased electroneutral Cl- absorption in CCDs from wild-type mice but had no effect on Cl- absorption in pendrin knockout mice. Because Gq protein coupled receptors activate PKC, we hypothesized that alpha-KG stimulates Cl- absorption through PKC. If so, PKC agonists should mimic, whereas PKC inhibitors should abolish, alpha-KG-stimulated Cl- absorption. Like alpha-KG, PKC agonist (phorbol-12,13-dibutyrate, 500 nM) application increased Cl- absorption in wild type but not in pendrin null CCDs. Moreover, PKC inhibitors (2.5 mM GF109203X and 20 nM calphostin C), Ca2+ chelators (BAPTA, 10-20 MUM), or PKC-alpha or -delta gene ablation eliminated alpha-KG-stimulated Cl- absorption. We have shown that STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) gene ablation increases urinary alpha-KG excretion, renal pendrin abundance, and CCD Cl- absorption. However, in SPAK null CCDs, Cl- absorption was not activated further by luminal alpha-KG application nor was Cl- absorption reduced with the PKC inhibitor GF109203 . Thus SPAK gene ablation likely acts through a PKC independent pathway to produce a chronic adaptive increase in pendrin function. In conclusion, alpha-KG stimulates pendrin-dependent Cl-/[Formula: see text] exchange through a mechanism dependent on PKC and Ca2+ that involves PKC-alpha and PKC-delta. PMID- 29412703 TI - A new low-nephron CKD model with hypertension, progressive decline of renal function, and enhanced inflammation in C57BL/6 mice. AB - Chronic kidney disease (CKD) is a major health issue in the US. The typical five sixths nephrectomy (typical 5/6 NX) is a widely used experimental CKD model. However, the typical 5/6 NX model is hypertensive in rats but strain dependent in mice. In particular, C57BL/6 mice with the typical 5/6 NX exhibits normal blood pressure and well-preserved renal function. The goal of the present study was to create a new hypertensive CKD model in C57BL/6 mice. We first characterized the vascular architecture originated from each renal artery branch by confocal laser scanning microscopy with fluorescent lectin. Then, a novel 5/6 NX-BL model was generated by uninephrectomy combined with 2/3 renal infarction via a ligation of upper renal artery branch on the contralateral kidney. Compared with 5/6 NX-C, the 5/6 NX-BL model exhibited elevated mean arterial pressure (137.6 +/- 13.9 vs. 104.7 +/- 8.2 mmHg), decreased glomerular filtration rate (82.9 +/- 19.2 vs. 125.0 +/- 13.9 ul/min) with a reciprocal increase in plasma creatinine (0.31 +/- 0.03 vs. 0.19 +/- 0.04 mg/dl), and significant renal injury as assessed by proteinuria, histology with light, and transmission electron microscopy. In addition, inflammatory status, as indicated by the level of proinflammatory cytokine TNFalpha and the leukocyte counts, was significantly upregulated in 5/6 NX-BL compared with the 5/6 NX-C. In summary, we developed a new hypertensive CKD model in C57BL/6 mice with 5/6 renal mass reduction by uninephrectomy and upper renal artery branch ligation on the contralateral kidney. This 5/6 NX-BL model exhibits an infarction zone-dependent hypertension and progressive deterioration of the renal function accompanied by enhanced inflammatory response. PMID- 29412704 TI - With no lysine kinase 4 modulates sodium potassium 2 chloride cotransporter activity in vivo. AB - With no lysine kinase 4 (WNK4) is essential to activate the thiazide-sensitive NaCl cotransporter (NCC) along the distal convoluted tubule, an effect central to the phenotype of familial hyperkalemic hypertension. Although effects on potassium and sodium channels along the connecting and collecting tubules have also been documented, WNK4 is typically believed to have little role in modulating sodium chloride reabsorption along the thick ascending limb of the loop of Henle. Yet wnk4-/- mice (knockout mice lacking WNK4) do not demonstrate the hypocalciuria typical of pure distal convoluted tubule dysfunction. Here, we tested the hypothesis that WNK4 also modulates bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) function along the thick ascending limb. We confirmed that w nk4-/- mice are hypokalemic and waste sodium chloride, but are also normocalciuric. Results from Western blots suggested that the phosphorylated forms of both NCC and NKCC2 were in lower abundance in wnk4-/- mice than in controls. This finding was confirmed by immunofluorescence microscopy. Although the initial response to furosemide was similar in wnk4-/- mice and controls, the response was lower in the knockout mice when reabsorption along the distal convoluted tubule was inhibited. Using HEK293 cells, we showed that WNK4 increases the abundance of phosphorylated NKCC2. More supporting evidence that WNK4 may modulate NKCC2 emerges from a mouse model of WNK4-mediated familial hyperkalemic hypertension in which more phosphorylated NKCC2 is present than in controls. These data indicate that WNK4, in addition to modulating NCC, also modulates NKCC2, contributing to its physiological function in vivo. PMID- 29412705 TI - Twelve-week combined resistance and aerobic training confers greater benefits than aerobic training alone in nondialysis CKD. AB - There is a growing consensus that patients with chronic kidney disease (CKD) should engage in regular exercise, but there is a lack of formal guidelines. In this report, we determined whether combined aerobic and resistance exercise would elicit superior physiological gains, in particular muscular strength, compared with aerobic training alone in nondialysis CKD. Nondialysis patients with CKD stages 3b-5 were randomly allocated to aerobic exercise {AE, n = 21; 9 men; median age 63 [interquartile range (IQR) 58-71] yr; median estimated glomerular filtration rate (eGFR) 24 (IQR 20-30) ml.min-1.1.73 m-2} or combined exercise [CE, n = 20, 9 men, median age 63 (IQR 51-69) yr, median eGFR 27 (IQR 22-32) ml.min-1.1.73 m-2], preceded by a 6-wk run-in control period. Patients then underwent 12 wk of supervised AE (treadmill, rowing, or cycling exercise) or CE training (as AE plus leg extension and leg press exercise) performed three times per week. Outcome assessments of knee extensor muscle strength, quadriceps muscle volume, exercise capacity, and central hemodynamics were performed at baseline, following the 6-wk control period, and at the end of the intervention. AE and CE resulted in significant increases in knee extensor strength of 16 +/- 19% (mean +/- SD; P = 0.001) and 48 +/- 37% ( P < 0.001), respectively, which were greater after CE ( P = 0.02). AE and CE resulted in 5 +/- 7% ( P = 0.04) and 9 +/- 7% ( P < 0.001) increases in quadriceps volume, respectively ( P < 0.001), which were greater after CE ( P = 0.01). Both AE and CE increased distance walked in the incremental shuttle walk test [28 +/- 44 m ( P = 0.01) and 32 +/- 45 m ( P = 0.01), respectively]. In nondialysis CKD, the addition of resistance exercise to aerobic exercise confers greater increases in muscle mass and strength than aerobic exercise alone. PMID- 29412706 TI - The Changing Nature of Work. PMID- 29412707 TI - A Healthy Public Cannot Abide Unhealthy And Unsafe Workplaces. PMID- 29412708 TI - Terrorism as Disease: Beware of Misleading Metaphors. PMID- 29412709 TI - Perron et al. Respond. PMID- 29412710 TI - Monforton Comments. PMID- 29412711 TI - Period Life Tables for Calculating Life Expectancy: Options to Assess and Minimize the Potential for Bias. PMID- 29412712 TI - Why Words Matter. PMID- 29412713 TI - Mortality Disparities in Racial/Ethnic Minority Groups in the Veterans Health Administration: An Evidence Review and Map. AB - BACKGROUND: Continued racial/ethnic health disparities were recently described as "the most serious and shameful health care issue of our time." Although the 2014 US Affordable Care Act-mandated national insurance coverage expansion has led to significant improvements in health care coverage and access, its effects on life expectancy are not yet known. The Veterans Health Administration (VHA), the largest US integrated health care system, has a sustained commitment to health equity that addresses all 3 stages of health disparities research: detection, understanding determinants, and reduction or elimination. Despite this, racial disparities still exist in the VHA across a wide range of clinical areas and service types. OBJECTIVES: To inform the health equity research agenda, we synthesized evidence on racial/ethnic mortality disparities in the VHA. SEARCH METHODS: Our research librarian searched MEDLINE and Cochrane Central Registry of Controlled Trials from October 2006 through February 2017 using terms for racial groups and disparities. SELECTION CRITERIA: We included studies if they compared mortality between any racial/ethnic minority and nonminority veteran groups or between different minority groups in the VHA (PROSPERO# CRD42015015974). We made study selection decisions on the basis of prespecified eligibility criteria. They were first made by 1 reviewer and checked by a second and disagreements were resolved by consensus (sequential review). DATA COLLECTION AND ANALYSIS: Two reviewers sequentially abstracted data on prespecified population, outcome, setting, and study design characteristics. Two reviewers sequentially graded the strength of evidence using prespecified criteria on the basis of 5 key domains: study limitations (study design and internal validity), consistency, directness, precision of the evidence, and reporting biases. We synthesized the evidence qualitatively by grouping studies first by racial/ethnic minority group and then by clinical area. For areas with multiple studies in the same population and outcome, we pooled their reported hazard ratios (HRs) using random effects models (StatsDirect version 2.8.0; StatsDirect Ltd., Altrincham, England). We created an evidence map using a bubble plot format to represent the evidence base in 5 dimensions: odds ratio or HR of mortality for racial/ethnic minority group versus Whites, clinical area, strength of evidence, statistical significance, and racial group. MAIN RESULTS: From 2840 citations, we included 25 studies. Studies were large (n >= 10 000) and involved nationally representative cohorts, and the majority were of fair quality. Most studies compared mortality between Black and White veterans and found similar or lower mortality for Black veterans. However, we found modest mortality disparities (HR or OR = 1.07, 1.52) for Black veterans with stage 4 chronic kidney disease, colon cancer, diabetes, HIV, rectal cancer, or stroke; for American Indian and Alaska Native veterans undergoing noncardiac major surgery; and for Hispanic veterans with HIV or traumatic brain injury (most low strength). AUTHOR'S CONCLUSIONS: Although the VHA's equal access health care system has reduced many racial/ethnic mortality disparities present in the private sector, our review identified mortality disparities that have persisted mainly for Black veterans in several clinical areas. However, because most mortality disparities were supported by single studies with imprecise findings, we could not draw strong conclusions about this evidence. More disparities research is needed for American Indian and Alaska Native, Asian, and Hispanic veterans overall and for more of the largest life expectancy gaps. Public Health Implications. Because of the relatively high prevalence of diabetes in Black veterans, further research to better understand and reduce this mortality disparity may be prioritized as having the greatest potential impact. However, other mortality disparities affect thousands of veterans and cannot be ignored. PMID- 29412715 TI - News From The Nation's Health. PMID- 29412714 TI - Unforgotten Biafra 50 Years Later. PMID- 29412717 TI - Causes and Causes of Causes of Population Health: A Public Health of Consequence, March 2018. PMID- 29412716 TI - The Key Role of Work in Population Health Inequities. PMID- 29412718 TI - Public Health Implications of Front-of-Package Labels. PMID- 29412719 TI - Fostering Interprofessional Education Through a Multidisciplinary, Community Based Pandemic Mass Vaccination Exercise. AB - We expanded health care services to economically disadvantaged individuals in an interprofessional, student-driven vaccination effort that also served as a pandemic planning drill. Health care professional students from colleges in and around Rockford, Illinois participated in implementing a mass vaccination event from 2011 to 2014 that targeted the underserved population. There was a 459% increase in total vaccinations administered to at-risk patients from year 1 to year 4. This interprofessional health care student-driven effort expanded medical service to disadvantaged individuals. PMID- 29412720 TI - Big Food's Opposition to the French Nutri-Score Front-of-Pack Labeling Warrants a Global Reaction. PMID- 29412721 TI - AJPH Global News. PMID- 29412722 TI - Durkin and Imm Respond. PMID- 29412723 TI - Autism and Socioeconomic Status-An Immune Link? PMID- 29412724 TI - Reducing Collateral Damage in Responses to the Opioid Crisis. PMID- 29412725 TI - Racial/Ethnic Variations in Mortality in the VA Health Care System. PMID- 29412726 TI - Disparities in Dental Health and Care: In Quest of Suitable Intervention Points. PMID- 29412727 TI - ERRATUM. PMID- 29412728 TI - Livingston et al. Respond. PMID- 29412729 TI - Population-Level Analyses Cannot Tell Us Anything About Individual-Level Marijuana-Opioid Substitution. PMID- 29412730 TI - Universal Care: The Force of an Idea. PMID- 29412731 TI - Veterans, Like Other Working- and Middle-Class Americans, Increasingly Rely on Public Health Programs. PMID- 29412734 TI - Chemically Defined Conditions Mediate an Efficient Induction of Mesodermal Lineage from Human Umbilical Cord- and Bone Marrow- Mesenchymal Stem Cells and Dental Pulp Pluripotent-Like Stem Cells. AB - The human umbilical cord Wharton's Jelly- and the bone marrow- mesenchymal stem cells (WJ-MSCs and BM-MSCs, respectively) and the newly identified dental pulp pluripotent-like stem cells (DPPSCs) are new sources for stem cells with prospective use in cell regeneration and therapy. These cells are self-renewable, can be differentiated into several lineages, and can potentiate the immune responses. We hypothesized that three-dimensional (3D) culture conditions and directed differentiation using specific signaling regulators will enhance an efficient generation of mesoderm (MD) lineage independent from the origin or source of the stem cells. For a period of 3-days, cell aggregates were generated in a serum-free media containing ascorbic acid, retinoic acid, and keratinocyte growth factor; sonic hedgehog and bone morphogenic protein-4 signaling were inhibited using small molecules. In all cell types used, the biochemical and molecular analysis revealed a time course-dependent induction of the mesodermal, but not endodermal or ectodermal makers. In this study, we utilized a novel and efficient serum-free protocol to differentiate WJ-MSCs, BM-MSCs, and DPPSCs into MD-cells. Successful development of an efficient differentiation protocol can further be utilized and expanded on to obtain MD- derivative cell lineages. PMID- 29412735 TI - Analysis of H19/Igf2 Methylation Status in the Sperm of Cloned Goats and Their Offspring. AB - The H19/insulin-like growth factor 2 (Igf2) gene plays vital roles during development, but their expression and methylation status have not been elucidated in male cloned animals. In this study, we investigated the methylation status of imprinting control region (ICR) and differentially methylated region (DMR) of the H19/Igf2 locus in the sperm and testes of naturally reproduced Saanen dairy goats (NG, control), transgenic cloned dairy goats (CG), and the first generation of mating the CGs with the female NGs (FG). Bisulfite sequencing polymerase chain reaction revealed that the H19 ICR was highly methylated in the sperm of all testing groups (97.07% +/- 0.47%, 93.73% +/- 0.85%, and 96.67% +/- 0.54%). Notably, the methylation level of H19 ICR was decreased in the testes of CG goats compared with that of NG goats (73.83% +/- 3.28% vs. 97.27% +/- 0.71%, p < 0.05), while the Igf2 DMR2 was highly methylated in the sperm of these three groups (89.57% +/- 1.74%, 87.23% +/- 1.11%, and 83.2% +/- 1.27%). However, the Igf2 DMR2 was abnormally hypomethylated in the testes of CG goats (27.33% +/- 1.005%, p < 0.001), and moderately methylated in FG goats (53.1% +/- 1.47%, p < 0.01) compared with that in NG goats (82.67% +/- 0.70%). Furthermore, we found significantly decreased expression of H19 (p < 0.01) and increased expression of Igf2 (p < 0.01) in CG goats. Thus, we infer that somatic cell nuclear transfer has clear effect on genomic imprinting in the testes, but not sperm of cloned goats. PMID- 29412736 TI - Epigenetic Alteration of Donor Cells with Histone Deacetylase Inhibitor m Carboxycinnamic Acid Bishydroxymide Improves the In Vitro Developmental Competence of Buffalo (Bubalus bubalis) Cloned Embryos. AB - Epigenetic reprogramming is an indispensable process during the course of mammalian development, but aberrant in cloned embryos. The aim of this study was to examine the effect of donor cell treatment with histone deacetylase (HDAC) inhibitor m-carboxycinnamic acid bishydroxymide (CBHA) on cloned embryo development and establish its optimal concentration. Different concentrations of CBHA (2.5, 5.0, 10.0, and 20.0 MUM) were used to treat buffalo adult fibroblast cells for 24 hours and effect on cell proliferation, gene expression, and histone modifications was analyzed. Based on these experiments, the best concentration was chosen to determine the effect of enhanced gene activation mark on developmental rates. Among the different concentrations, CBHA at higher concentration (20 MUM) shows the sign of apoptosis and stress as indicated by proliferation rate and gene expression data. CBHA treatment significantly decreased the activity of HDACs and increased the level of gene activation mark H3K9ac and H3K4me3, but could not alter the level of H3K27ac. Based on these experiments, 5 MUM CBHA was chosen for treatment of donor cells used for the production of cloned embryos. There was no significant difference in cleavage rate between the control and CBHA treatment group (98.5% +/- 1.5% vs. 99.0% +/- 1.0%), whereas, blastocyst rate markedly improved (46.65% +/- 1.94% vs. 57.18% +/ 2.68%). The level of H3K9ac and H3K27me3 did not differ significantly in cloned blastocyst produced from either control or CBHA-treated cells. Altogether, these results suggested that donor cell treatment with CBHA supports the reprogramming process and improves the cloned preimplantation development. PMID- 29412737 TI - High Pregnancy and Calving Rates with a Limited Number of Transferred Handmade Cloned Bovine Embryos. AB - A major obstacle of widespread commercial application of bovine somatic cell nuclear transfer is the low overall efficiency, that is, healthy calf-late pregnancy per transferred embryo rate. In this study, we report a series of experiments with a limited number of embryos created with handmade cloning (HMC) and transferred without or after open pulled straw vitrification. Embryo reconstruction was performed by using in vitro matured oocytes and adult ear skin fibroblasts. In two experiments, a total of 53 D7 blastocysts were developed from 188 reconstructed embryos. Fresh transfer of seven blastocysts into six recipients has resulted in three early pregnancies, two of them developed over 90 days and eventually resulted in healthy calves (33% offspring/transfer rate). In another two experiments, a total of 11 D7 blastocysts were obtained from 36 reconstructed embryos. Out of these, eight have reexpanded 18 hours after vitrification and warming. Transfer of these blastocysts into eight recipients has resulted in four early pregnancies and two live births; 25% offspring/transfer rate. These results indicate that low overall efficiency may not be an intrinsic feature of cattle cloning, and selection of the right procedures may help to overcome the actual limitations. PMID- 29412739 TI - MC1568 Enhances Histone Acetylation During Oocyte Meiosis and Improves Development of Somatic Cell Nuclear Transfer Embryos in Pig. AB - An increasing number of studies have revealed that histone deacetylase (HDAC) mediated histone deacetylation is important for mammalian oocyte development. However, nonselective HDAC inhibitors (HDACi) were applied in most studies; the precise functions of specific HDAC classes during meiosis are poorly defined. In this study, the class IIa-specific HDACi MC1568 was used to reveal a crucial role of class IIa HDACs in the regulation of histone deacetylation during porcine oocyte meiosis. Besides, the functions of HDACs and histone acetyltransferases in regulating the balance of histone acetylation/deacetylation were also confirmed during oocyte maturation. After the validation of nontoxicity of MC1568 in maturation rate, spindle morphology, and chromosome alignment, effects of MC1568 on developmental competence of porcine somatic cell nuclear transfer (SCNT) embryos were evaluated, and data indicated that treatment with 10 MUM MC1568 for 12 hours following electrical activation significantly enhanced the blastocyst rate and cell numbers. Moreover, results showed that optimal MC1568 treatment increased the H4K12 acetylation level in SCNT one cells and two cells. In addition, MC1568 treatment stimulated expression of the development-related genes OCT4, CDX2, SOX2, and NANOG in SCNT blastocysts. Collectively, our investigation uncovered a critical role of class IIa HDACs in the regulation of histone deacetylation during oocyte meiosis. Furthermore, for the first time, we showed that MC1568 can improve the in vitro development of porcine SCNT embryos. These findings provide an alternative HDACi for improving animal cloning efficiency and may shed more light on nuclear reprogramming. PMID- 29412738 TI - Reciprocity of Action of Increasing Oct4 and Repressing p53 in Transdifferentiation of Mouse Embryonic Fibroblasts into Cardiac Myocytes. AB - p53 is a barrier to somatic cell reprogramming. Deletion or transient suppression of p53 increases the efficiency of reprogramming of somatic cells into induced pluripotent stem cells. Whether p53 represents an obstacle to a similar process transdifferentiation of somatic cells is unknown. However, it is predicted that inhibition of p53 would promote transdifferentiation of fibroblasts into cardiomyocytes. In this study, the effect of p53 on the capacity of cardiogenic transdifferentiation is evaluated using p53 wild-type (p53+/+), p53 heterozygous mutant (p53+/-), and p53 homozygous mutant (p53-/-) mouse embryonic fibroblasts (MEFs). Repression of p53 in MEFs increases the expression level of mesoderm transcription factors Brachyury (T) and MESP1. The cardiac-specific markers, Myh6 (Myosin, Heavy Chain 6), Myh7 (Myosin, Heavy Chain 7), and cTnI (cardiac muscle troponin I), show elevated expression in p53+/- and p53-/- MEFs compared with wild-type MEFs, but cardiac muscle troponin T (cTnT) showed a lower expression level when p53 was inhibited. After induction to cardiac differentiation, cTnT expression increased and markers of endoderm and ectoderm decreased in p53+/- and p53-/- MEFs. The effect of an important reprogramming factor Oct4 on cardiac transdifferentiation was also evaluated in the allelic series of p53 MEFs. We found that overexpression of Oct4 significantly enhanced Mesp1, Tbx5, and Isl1 expression in p53+/+ and p53+/- MEFs. Oct4 also enhanced cTnT expression in all three cell lines, especially in p53+/- MEFs. Thus, inhibition of p53 expression and viral expression of Oct4 both promote transdifferentiation of MEFs into cardiomyocytes, establishing reciprocity of action in the process. PMID- 29412740 TI - Measles Virus Persistent Infection of Human Induced Pluripotent Stem Cells. AB - In this study, we found that the measles virus (MV) can infect human-induced pluripotent stem cells (hiPSCs). Wild-type MV strains generally use human signaling lymphocyte activation molecule (SLAM; CD150) as a cellular receptor, while vaccine strains such as the Edmonston strain can use both CD150 and CD46 as receptors. It is not yet known how early in the embryonal differentiation stages these receptors are expressed. We established two hiPSCs (BGU-iPSCs and EMF iPSCs) which express CD46 and CD150. Both cell types can be infected by MV to form persistent, noncytopathic cell lines that release infectious MV particles. Following MV persistent infection, BGU-iPSCs and EMF-iPSCs remain pluripotent and can differentiate in vitro into the three germ layers. This includes cells expressing the neuronal differentiation markers: NF68 and miRNA-124. Since the MV does not integrate into the cell's genome, it can be utilized as a vehicle to systematically introduce genes into iPSC, to dissect and to define factors regulating lineage differentiation. PMID- 29412742 TI - Cloning After Dolly. PMID- 29412741 TI - Pharmacologic Reprogramming Designed to Induce a Warburg Effect in Porcine Fetal Fibroblasts Alters Gene Expression and Quantities of Metabolites from Conditioned Media Without Increased Cell Proliferation. AB - The Warburg effect is a metabolic phenomenon characterized by increased glycolytic activity, decreased mitochondrial oxidative phosphorylation, and the production of lactate. This metabolic phenotype is characterized in rapidly proliferative cell types such as cancerous cells and embryonic stem cells. We hypothesized that a Warburg-like metabolism could be achieved in other cell types by treatment with pharmacological agents, which might, in turn, facilitate nuclear reprogramming. The aim of this study was to treat fibroblasts with CPI 613 and PS48 to induce a Warburg-like metabolic state. We demonstrate that treatment with both drugs altered the expression of 69 genes and changed the level of 21 metabolites in conditioned culture media, but did not induce higher proliferation compared to the control treatment. These results support a role for the reverse Warburg effect, whereby cancer cells induce cancer-associated fibroblast cells in the surrounding stroma to exhibit the metabolically characterized Warburg effect. Cancer-associated fibroblasts then produce and secrete metabolites such as pyruvate to supply the cancerous cells, thereby supporting tumor growth and metastasis. While anticipating an increase in the production of lactate and increased cellular proliferation, both hallmarks of the Warburg effect, we instead observed increased secretion of pyruvate without changes in proliferation. PMID- 29412744 TI - Correction to: Child Development and the Community Environment: Understanding Overweight across the Income Gradient Child Obes 2017;13(6):479-489; DOI: 10.1089/chi.2017.0025. PMID- 29412743 TI - Investigating Caesarean Section Birth as a Risk Factor for Childhood Overweight. AB - BACKGROUND: Caesarean section birth may be associated with overweight in childhood; however, findings to date have been inconsistent. This study explored the association of caesarean section vs. vaginal birth with childhood overweight in Vietnam. METHODS: This longitudinal cohort study explored the association of delivery mode with overweight, obesity, and overweight/or obesity at 8 years of age in children (n = 1937) across 20 sites in Vietnam, using Young Lives longitudinal cohort study data. Categories were defined using BMI z-scores in relationship to the World Health Organization (WHO) reference median: overweight >1 and <2 standard deviations (SD) above WHO reference median, obese >2 SD, and overweight/or obese >1 SD. Individual questionnaire data collected sociodemographic information and pregnancy/birth information through face-to-face interviews with mothers/caregivers. Anthropometric measurements for mother and child were collected at baseline and at 8 years for children. RESULTS: Adjusted multivariable logistic models revealed a twofold increase in odds at age 8 years of overweight [odds ratio (OR) = 1.8, 95% confidence interval (95% CI) 1.03-3.2, p = 0.039], obese (OR = 2.2, 95% CI 1.2-4.0, p = 0.014), or overweight/or obese (OR = 2.1, 95% CI 1.3-3.3, p = 0.002) for children born through caesarean section compared with vaginal birth. Children born through planned caesarean section (adjusted OR = 2.3, 95% CI 1.2-4.1, p < 0.001) and unplanned caesarean section (adjusted OR = 1.9, 95% CI 1.1-3.5, p = 0.03) had similar increased odds of overweight/or obesity compared with children born through vaginal birth. CONCLUSIONS: These findings suggest that there may be an association between caesarean section and childhood overweight even after adjustment for confounders. Further research is needed to explore the underlying mechanisms of this finding. PMID- 29412748 TI - Characterization of salivary gland tumours with diffusion tensor imaging. AB - OBJECTIVES: To characterize salivary glands tumours with diffusion tensor imaging. METHODS: This study was conducted upon 53 patients (aged 18-81 years: mean 37 years) with salivary gland tumours that underwent diffusion tensor imaging was obtained using a single-shot echoplanar imaging sequence with parallel imaging at 1.5 T scanner. 48 slices were obtained, with a thickness of 2.5 mm, with no gap and the total scan duration was 7-8 min. The fractional anisotropy (FA) and the mean diffusivity (MD) value of the salivary gland tumours was calculated and correlated with pathological findings. Image analysis was performed by one radiologist. The receiver operating characteristic curve was drawn to detect the cut-off point of FA and MD used to characterize salivary gland tumours. RESULTS: The mean FA and MD of malignant salivary gland tumours (n = 17) (0.41 +/- 0.07 and 0.89 +/- 0.15 * 10-3 mm2 s-1) was significantly different (p = 0.001) than that of benign tumours (n = 36) (0.19 +/- 0.07 and 1.28 +/- 0.42 * 10-3 mm2 s-1), respectively. Combined FA and MD used to differentiate malignant from benign tumours has an area under the curve (AUC) of 0.974, and an accuracy of 86%. There was a significant difference in FA between Warthin tumours and malignant tumours (p = 0.001). Selection FA of 0.35 to differentiate malignant tumours from Warthin tumours revealed AUC of 0.878 and an accuracy of 80%. There was a significant difference in FA and MD of malignant tumours and pleomorphic adenomas (p = 0.001). Combined FA and MD used to differentiate malignant tumours from pleomorphic adenomas revealed AUC of 0.993, and an accuracy of 93%. There was a significant difference in FA and MD of Warthin tumours and pleomorphic adenomas (p = 0.001). Combined FA and MD used to differentiate Warthin tumours from pleomorphic adenomas revealed AUC of 0.978, and an accuracy of 86%. CONCLUSIONS: Diffusion-weighed imaging is a promising non invasive method and it may be useful for the characterization and differentiation of benign and malignant salivary gland tumours. PMID- 29412753 TI - Comparison of Adult and Pediatric Surgeons: Insight into Simulation-Based Tools That May Improve Expertise Among Experts. AB - BACKGROUND: Laparoscopic models are increasingly recognized as important tools in surgical training. The purpose of this study was to compare pediatric and adult laparoscopic surgical skills, and gain insight into the upskilling in both groups. MATERIALS AND METHODS: Adult- and pediatric-sized laparoscopic simulators were fitted with custom-built motion tracking hardware and software. Participants were recruited at the Education Booth of the 2012 combined SAGES/IPEG meeting. They each performed 1 adult and 1 pediatric intracorporeal suturing task. Velocity, acceleration, and range were studied in all degrees of freedom available during laparoscopic surgery (pitch, yaw, roll, and surge). Participants were stratified by expertise based on the traditional metrics of self-reported caseloads. RESULTS: A total of 57 participants (15 novices, 7 intermediates, and 35 experts) were recruited. Experts had significantly higher extreme events in three of the four degrees of freedom when using the pediatric simulator than when using the adult simulator. Few significant differences were seen when comparing novice and intermediate performances on the adult versus pediatric simulator. Linear regression showed no difference between adult and pediatric experts tested on the adult or pediatric simulator. CONCLUSIONS: Experts were more challenged with the pediatric than with the adult suturing task. No difference was noted for overall averaged performance metrics comparing adult and pediatric experts suturing in adult versus pediatric simulators. As a participant's level of expertise improves, a model progressing from larger to smaller domains in the performance of defined laparoscopic tasks may, by virtue of its greater challenge, encourage psychomotor development. PMID- 29412760 TI - How Genomes Generate Animals: A View from Pasadena Genomic Control Process: Development and Evolution. PMID- 29412757 TI - Effects of triptolide on pharmacokinetics of fenofibrate in rats and its potential mechanism. AB - Triptolide and fenofibrate are often used together for the treatment of nephrotic syndrome in Chinese clinics. This study investigates the effects of triptolide on the pharmacokinetics of fenofibrate in rats and it potential mechanism. The pharmacokinetics of fenofibrate (20 mg/kg) with or without triptolide pretreatment (2 mg/kg/day for seven days) were investigated. Additionally, the inhibitory effects of triptolide on the metabolic stability of fenofibrate were investigated using rat liver microsome incubation systems. The results indicated that the Cmax (35.34 +/- 7.52 vs. 30.43 +/- 6.45 MUg/mL), t1/2 (6.17 +/- 1.15 vs. 4.90 +/- 0.82 h) and AUC(0-t) (468.12 +/- 35.84 vs. 416.35 +/- 32.68 mg h L-1) of fenofibric acid decreased significantly (p < .05). The Tmax of fenofibric acid increased significantly (p < .05) from 5.12 +/- 0.36 to 6.07 +/- 0.68 h. Additionally, the metabolic stability of fenofibrate was prolonged from 35.8 +/- 6.2 to 48.6 +/- 7.5 min (p < .05) with the pretreatment of triptolide. In conclusion, these results indicated that triptolide could affect the pharmacokinetics of fenofibric acid, possibly by inhibiting the metabolism of fenofibrate in rat liver when they were co-administered. PMID- 29412762 TI - Quantitative Live-Cell Confocal Imaging of 3D Spheroids in a High-Throughput Format. AB - Accurately predicting the human response to new compounds is critical to a wide variety of industries. Standard screening pipelines (including both in vitro and in vivo models) often lack predictive power. Three-dimensional (3D) culture systems of human cells, a more physiologically relevant platform, could provide a high-throughput, automated means to test the efficacy and/or toxicity of novel substances. However, the challenge of obtaining high-magnification, confocal z stacks of 3D spheroids and understanding their respective quantitative limitations must be overcome first. To address this challenge, we developed a method to form spheroids of reproducible size at precise spatial locations across a 96-well plate. Spheroids of variable radii were labeled with four different fluorescent dyes and imaged with a high-throughput confocal microscope. 3D renderings of the spheroid had a complex bowl-like appearance. We systematically analyzed these confocal z stacks to determine the depth of imaging and the effect of spheroid size and dyes on quantitation. Furthermore, we have shown that this loss of fluorescence can be addressed through the use of ratio imaging. Overall, understanding both the limitations of confocal imaging and the tools to correct for these limits is critical for developing accurate quantitative assays using 3D spheroids. PMID- 29412763 TI - Association Between Carotid Intima Media Thickness, Age, and Cardiovascular Risk Factors in Children and Adolescents. AB - BACKGROUND: Measures of carotid intima media thickness (cIMT) in adults are correlated with adiposity and the metabolic syndrome (MetS) and predict cardiovascular (CV) events. Relations in children are not as well studied. Our objective was to determine the relations of cIMT with body mass index (BMI) and CV risk score in children. METHODS: The study included 291 children (158 M/133 F) 6-18 years of age (140 aged 6-11/151 aged 12-18) with measurements of height, weight, waist circumference; fasting lipids, glucose, insulin, and cIMT. A CV risk cluster score was developed from sum of the z-scores of the five MetS components (waist circumference, blood pressure, serum triglycerides, high density lipoprotein cholesterol, and insulin). Partial Pearson correlation coefficients were adjusted for age, sex, and race. RESULTS: There was no significant age difference in cIMT from 6 to 18 years of age. BMI and CV risk score were significantly correlated (P < 0.0001), and both were correlated with cIMT (r = 0.14, P = 0.02 and r = 0.16, P = 0.006, respectively). Slight age related differences in associations of cIMT with CV risk score and BMI were explained by unusual values in a few children. CONCLUSIONS: These cross-sectional data in normal children show that cIMT was stable from childhood into adolescence. However, both BMI and CV risk score had small, but significant positive correlations with cIMT. Therefore, maintaining normal levels of adiposity and other risk variables may be useful in preventing early changes associated with preclinical atherosclerosis. PMID- 29412764 TI - Will Changes to Medicare Payment Rates Alter Hospice's Cost-Saving Ability? AB - BACKGROUND: On January 1, 2016, Medicare implemented a new "two-tiered" model for hospice services, with per diem rates increased for days 1 through 60, decreased for days 61 and greater, and service intensity add-on payments made retrospectively for the last seven days of life. OBJECTIVE: To estimate whether the Medicare hospice benefit's potential for cost savings will change as a result of the January 2016 change in payment structure. DESIGN: Analysis of decedents' claims records using propensity score matching, logistic regression, and sensitivity analysis. SETTING/SUBJECTS: All age-eligible Medicare decedents who received care and died in North Carolina in calendar years 2009 and 2010. MEASUREMENTS: Costs to Medicare for hospice and other healthcare services. RESULTS: Medicare costs were reduced from hospice election until death using both 2009-2010 and new 2016 payment structures and rates. Mean cost savings were $1,527 with actual payment rates, and would have been $2,105 with the new payment rates (p < 0.001). Cost savings were confirmed by reducing the number of days used for cost comparison by three days for those with hospice stays of at least four days ($4,318 using 2009-2010 rates, $3,138 for 2016 rates: p < 0.001). Cost savings were greater for males ($3,393) versus females ($1,051) and greatest in cancer ($6,706) followed by debility and failure to thrive ($5,636) and congestive heart failure ($1,309); dementia patients had higher costs (+$1,880) (p < 0.001). When adding 3 days to the comparison period, hospice increased costs to Medicare. CONCLUSIONS: Medicare savings could continue with the 2016 payment rate change. Cost savings were found for all primary diagnoses analyzed except dementia. PMID- 29412765 TI - Nomad Biosensors: A New Multiplexed Technology for the Screening of GPCR Ligands. AB - Nomad Technology (Innoprot [Innovative Technologies in Biological Systems], Derio, Spain), a novel tool for multiplexing high-throughput cell-based G protein coupled receptor (GPCR) assays, is described in this work. This new technology comprises a family of fluorescent biosensors called Nomad Biosensors that allow for the measurement of responses mediated by G proteins through their interactions with second-messenger transduction proteins. GPCRs are one of the largest protein families of receptors in eukaryotes, and their signaling mediates important physiological processes within cells. Thus, GPCRs are associated with a wide variety of diseases, and considered major targets in therapeutic research. Nomad constitutes a novel tool for unraveling the mechanism of GPCR signal transduction by simultaneously tracing different pathways. GPCR activation changes the structural folding of the biosensor and promotes its vesicularization, as well as an increase in the fluorescence intensity. Based on this technology, the MPXNomad cellular model was developed to discriminate between the Ca2+-mediated pathway and the cyclic adenosine monophosphate (cAMP) mediated pathway. To validate this model, endothelin receptor B (ETBR) was coexpressed into the MPXNomad cell line and assessed with a specific agonist, an antagonist, and a chemical library of compounds. Nomad Technology optimizes the identification of novel GPCR ligands and enables the testing of large numbers of compounds. PMID- 29412766 TI - Porcine Response to a Multidrug-Resistant Salmonella enterica serovar I 4,[5],12:i:- Outbreak Isolate. AB - Salmonella enterica serovar I 4,[5],12:i:- has emerged as a common nontyphoidal Salmonella serovar to cause human foodborne illness. An interesting trait of serovar I 4,[5],12:i:- is that it only expresses the fliC gene for bacterial motility (i.e., monophasic), while most Salmonella strains alternately express two flagellin genes (fliC and fljB). The goal of this study was to characterize the porcine response following inoculation with a multidrug-resistant (MDR) serovar I 4,[5],12:i:- isolate associated with a multistate pork outbreak to determine if the increased prevalence of serovar I 4,[5],12:i:- in swine is due to enhanced pathogenicity. Pigs were inoculated and subsequently evaluated for the ability of the isolate to colonize intestinal tissues, cause clinical symptoms, induce an immune response, and alter the fecal microbiota over a 7-day period. Pigs exhibited a significant increase in rectal temperature (fever) (p < 0.01) and fecal moisture content (diarrhea) (p < 0.05) at 2 days postinoculation (d.p.i.) compared with preinoculation (day 0). Serum analyses revealed significantly increased interferon-gamma (IFN-gamma) levels at 2 (p <= 0.0001) and 3 (p < 0.01) d.p.i. compared with day 0, and antibodies against Salmonella lipopolysaccharide (LPS) were present in all pigs by 7 d.p.i. Serovar I 4,[5],12:i:- colonized porcine intestinal tissues and was shed in the feces throughout the 7-day study. Analysis of the 16S rRNA gene sequences demonstrated that the fecal microbiota was significantly altered following MDR serovar I 4,[5],12:i:- inoculation, with the largest shift observed between 0 and 7 d.p.i. Our data indicate that the pork outbreak-associated MDR serovar I 4,[5],12:i:- isolate induced transient clinical disease in swine and perturbed the gastrointestinal microbial community. The porcine response to MDR serovar I 4,[5],12:i:- is similar to previous studies with virulent biphasic Salmonella enterica serovar Typhimurium, suggesting that the absence of fljB does not substantially alter acute colonization or pathogenesis in pigs. PMID- 29412767 TI - Beneficial Effects of Flavonoids Against Parkinson's Disease. AB - Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta and decreases in striatal dopamine levels. These changes led to several clinical symptoms: rigidity, resting tremor, and bradykinesia. Although the cause of PD remains unclear, it is widely accepted that oxidative stress, neuroinflammation, mitochondrial dysfunction, and insufficient support of neurotrophic factors are involved in the pathophysiology of the disease. However, novel regimens to prevent neurodegeneration and restore the degenerated nigrostriatal DA system are still required. In recent years, there has been a growing interest in naturally occurring phytochemicals, which are believed to reduce the risk of neurodegenerative diseases. This review provides an overview of the scientific literature concerning the preventive and protective roles of flavonoids, one of the largest families of phytochemicals, against PD. In addition to providing antioxidant and anti-inflammatory effects, flavonoids exhibit a neuroprotective effect by activating antiapoptotic pathways that target mitochondrial dysfunction and induce neurotrophic factors. This review suggests that flavonoids may be promising natural products for the prevention of PD and could potentially be utilized as therapeutic compounds against PD, even though there was no report showing that the treatment with flavonoids could restore the aberrant phenotypes of patients with PD. PMID- 29412768 TI - Oncology Clinical Pathways: Charting the Landscape of Pathway Providers. PMID- 29412769 TI - When Investment Meets Return. PMID- 29412770 TI - Two Cases of Hepatoblastoma in Young Adults. AB - Adult hepatoblastoma (AHB) is a rare liver tumor with a poor prognosis in adolescents and adults. This contrasts with hepatoblastoma in children and is not fully understood. Here we describe two adolescents with AHB who were treated in our hospital. Adolescents are likely to receive less intensive chemotherapy protocols and are treated in hospitals with less experience in pediatric oncology, resulting in poor outcome. More research is necessary for optimal treatment of AHB in adolescents. Adolescents with AHB should be referred to hospitals experienced in pediatric oncology and receive intensive chemotherapy, followed by hemihepatectomy. PMID- 29412771 TI - Human Papillomavirus Vaccine Awareness Among HIV-Positive Gay and Bisexual Men: A Qualitative Study. AB - PURPOSE: This study explores HIV-positive gay and bisexual men's (GBM) understanding of human papillomavirus (HPV) and the HPV vaccine. METHODS: Researchers conducted 15 in-depth interviews with HIV-positive GBM between the ages of 18-30 years old. RESULTS: Two participants had received a single dose of the HPV vaccine. Otherwise, the majority of participants had either never heard of the HPV vaccine or they perceived it as a resource for women only. Other commonly cited barriers to getting the vaccine included lack of provider recommendation to complete the vaccine series and vaccine costs. CONCLUSIONS: Future provider-driven interventions should focus on increasing HPV vaccine among age-eligible HIV-positive GBM. PMID- 29412772 TI - Physician Perspectives on Palliative Care for Children with Advanced Heart Disease: A Comparison between Pediatric Cardiology and Palliative Care Physicians. AB - BACKGROUND: While the importance of pediatric palliative care (PPC) for children with life-threatening illness is increasingly recognized, little is known about physicians' attitudes toward palliative care for children with heart disease. OBJECTIVE: To compare the perspectives of PPC physicians and pediatric cardiologists regarding palliative care in pediatric heart disease. DESIGN: Cross sectional web-based surveys. RESULTS: Responses from 183 pediatric cardiologists were compared to those of 49 PPC physicians (response rates 31% [183/589] and 28% [49/175], respectively). Forty-eight percent of PPC physicians and 63% of pediatric cardiologists agreed that availability of PPC is adequate (p = 0.028). The majority of both groups indicated that PPC consultation occurs "too late." Compared with pediatric cardiologists, PPC physicians reported greater competence in all areas of advance care planning, communication, and symptom management. PPC physicians more often described obstacles to PPC consultation as "many" or "numerous" (42% vs. 7%, p < 0.001). PPC physicians overestimated how much pediatric cardiologists worry about PPC introducing inconsistency in approach (60% vs. 11%, p < 0.001), perceive lack of added value from PPC (30% vs. 7%, p < 0.001), believe that PPC involvement will undermine parental hope (65% vs. 44%, p = 0.003), and perceive that PPC is poorly accepted by parents (53% vs. 27%, p < 0.001). CONCLUSIONS: There are significant differences between pediatric cardiologists and PPC physicians in perception of palliative care involvement and perceived barriers to PPC consultation. An intervention that targets communication and exchange of expertise between PPC and pediatric cardiology could improve care for children with heart disease. PMID- 29412774 TI - Examination of muscle composition and motor unit behavior of the first dorsal interosseous of normal and overweight children. AB - We examined differences between normal weight (NW) and overweight (OW) children aged 8-10 yr in strength, muscle composition, and motor unit (MU) behavior of the first dorsal interosseous. Ultrasonography was used to determine muscle cross sectional area (CSA), subcutaneous fat (sFAT), and echo intensity (EI). MU behavior was assessed during isometric muscle actions at 20% and 50% of maximal voluntary contraction (MVC) by analyzing electromyography amplitude (EMGRMS) and relationships between mean firing rates (MFR), recruitment thresholds (RT), and MU action potential amplitudes (MUAPsize) and durations (MUAPtime). The OW group had significantly greater EI than the NW group ( P = 0.002; NW, 47.99 +/- 6.01 AU; OW, 58.90 +/- 10.63 AU, where AU is arbitrary units) with no differences between groups for CSA ( P = 0.688) or MVC force ( P = 0.790). MUAPsize was larger for NW than OW in relation to RT ( P = 0.002) and for MUs expressing similar MFRs ( P = 0.011). There were no significant differences ( P = 0.279 0.969) between groups for slopes or y-intercepts from the MFR vs. RT relationships. MUAPtime was larger in OW ( P = 0.015) and EMGRMS was attenuated in OW compared with NW ( P = 0.034); however, there were no significant correlations ( P = 0.133-0.164, r = 0.270-0.291) between sFAT and EMGRMS. In a muscle that does not support body mass, the OW children had smaller MUAPsize as well as greater EI, although anatomical CSA was similar. This contradicts previous studies examining larger limb muscles. Despite evidence of smaller MUs, the OW children had similar isometric strength compared with NW children. NEW & NOTEWORTHY Ultrasound data and motor unit action potential sizes suggest that overweight children have poorer muscle composition and smaller motor units in the first dorsal interosseous than normal weight children. Evidence is presented that suggests differences in action potential size cannot be explained by differences in subcutaneous fat alone. PMID- 29412773 TI - Phrenic motor neuron loss in aged rats. AB - Sarcopenia is the age-related reduction of muscle mass and specific force. In previous studies, we found that sarcopenia of the diaphragm muscle (DIAm) is evident by 24 mo of age in both rats and mice and is associated with selective atrophy of type IIx and IIb muscle fibers and a decrease in maximum specific force. These fiber type-specific effects of sarcopenia resemble those induced by DIAm denervation, leading us to hypothesize that sarcopenia is due to an age related loss of phrenic motor neurons (PhMNs). To address this hypothesis, we determined the number of PhMNs in young (6 mo old) and old (24 mo old) Fischer 344 rats. Moreover, we determined age-related changes in the size of PhMNs, since larger PhMNs innervate type IIx and IIb DIAm fibers. The PhMN pool was retrogradely labeled and imaged with confocal microscopy to assess the number of PhMNs and the morphometry of PhMN soma and proximal dendrites. In older animals, there were 22% fewer PhMNs, a 19% decrease in somal surface area, and a 21% decrease in dendritic surface area compared with young Fischer 344 rats. The age associated loss of PhMNs involved predominantly larger PhMNs. These results are consistent with an age-related denervation of larger, more fatigable DIAm motor units, which are required primarily for high-force airway clearance behaviors. NEW & NOTEWORTHY Diaphragm muscle sarcopenia in rodent models is well described in the literature; however, the relationship between sarcopenia and frank phrenic motor neuron (MN) loss is unexplored in these models. We quantify a 22% loss of phrenic MNs in old (24 mo) compared with young (6 mo) Fischer 344 rats. We also report reductions in phrenic MN somal and proximal dendritic morphology that relate to decreased MN heterogeneity in old compared with young Fischer 344 rats. PMID- 29412775 TI - Opposing effects of 2-deoxy-d-glucose on interictal- and ictal-like activity when K+ currents and GABAA receptors are blocked in rat hippocampus in vitro. AB - The ketogenic diet (KD), a high-fat, carbohydrate-restricted diet, is used as an alternative treatment for drug-resistant epileptic patients. Evidence suggests that compromised glucose metabolism has a significant role in the anticonvulsant action of the KD; however, it is unclear what part of the glucose metabolism that is important. The present study investigates how selective alterations in glycolysis and oxidative phosphorylation influence epileptiform activity induced by blocking K+ currents and GABAA and NMDA receptors in the hippocampal slice preparation. Blocking glycolysis with the glucose derivative 2-deoxy-d-glucose (2 DG; 10 mM) gave a fast reduction of the frequency of interictal discharge (IED) consistent with findings in other in vitro models. However, this was followed by the induction of seizure-like discharges in area CA1 and CA3. Substituting glucose with sucrose (glucopenia) had effects similar to those of 2-DG, whereas substitution with l-lactate or pyruvate reduced the IED but had a less proconvulsant effect. Blockade of ATP-sensitive K+ channels, glycine or adenosine 1 receptors, or depletion of the endogenous anticonvulsant compound glutathione did not prevent the actions of 2-DG. Baclofen (2 MUM) reproduced the effect of 2 DG on IED activity. The proconvulsant effect of 2-DG could be reproduced by blocking the oxidative phosphorylation with the complex I toxin rotenone (4 MUM). The data suggest that inhibition of IED, induced by 2-DG and glucopenia, is a direct consequence of impairment of glycolysis, likely exerted via a decreased recurrent excitatory synaptic transmission in area CA3. The accompanying proconvulsant effect is caused by an excitatory mechanism, depending on impairment of oxidative phosphorylation. NEW & NOTEWORTHY This study reveals two opposing effects of 2-deoxy-d-glucose (2-DG) and glucopenia on in vitro epileptiform discharge observed during combined blockade of K+ currents and GABAA receptors. Interictal-like activity is inhibited by a mechanism that selectively depends on impairment of glycolysis and that results from a decrease in the strength of excitatory recurrent synaptic transmission in area CA3. In contrast, 2-DG and glucopenia facilitate ictal-like activity by an excitatory mechanism, depending on impairment of mitochondrial oxidative phosphorylation. PMID- 29412777 TI - Cardiac modulation of alpha motoneuron discharges. AB - Recordings of alpha motoneuron discharges from branches of the intercostal and abdominal nerves in anesthetized cats were analyzed for modulation during the cardiac cycle. Cardiac modulation was assessed by the construction of cross correlation histograms between the R-wave of the ECG and the largest amplitude efferent spikes. In all but two recordings (which were believed to have either no or few alpha spikes), the histograms showed relatively short duration peaks and/or troughs (widths at half amplitude 4-50 ms) at lags of 10-150 ms. These observations were deduced to result from activity in oligosynaptic pathways, probably from muscle spindle afferents, whose discharges are known to be synchronized to the cardiac pulse. The results suggest that onward transmission of the cardiac signal from thoracic muscle afferents (and possibly from other dynamically sensitive afferents) to other parts of the central nervous system is highly likely and that therefore these afferents could contribute to cardiac interoception. NEW & NOTEWORTHY It has been recognized since 1933 that muscle spindles respond to the cardiac pulse, but it is unknown whether this cardiac signal is transmitted to other levels in the nervous system. Here we show that a cardiac signal, likely arising from muscle spindles, is present in the efferent activities of thoracic and abdominal muscle nerves, suggesting probable onward transmission of this signal to higher levels and therefore that muscle spindles could contribute to cardiac interoception. PMID- 29412778 TI - The Long Noncoding RNA TP73-AS1 Interacted with miR-124 to Modulate Glioma Growth by Targeting Inhibitor of Apoptosis-Stimulating Protein of p53. AB - P73 antisense RNA 1T (non-protein coding), known as TP73-AS1 or PDAM, is a long noncoding RNA (lncRNA), which may regulate apoptosis by regulation of p53 dependent antiapoptotic genes. An abnormal change of TP73-AS1 expression was noticed in cancers. The effects of TP73-AS1 in brain glioma growth and the underlying mechanism remain unclear so far. In this study, the effect of TP73-AS1 in human brain glioma cell lines and clinical tumor samples was detected so as to reveal its role and function. In this study, TP73-AS1 was specifically upregulated in brain glioma cell lines and promoted glioma cell growth through targeting miR-124. TP73-AS1 knocking down suppressed human brain glioma cell proliferation, invasion, and metastasis in vitro. The inhibitory effect of TP73 AS1 knocking down on glioma cell proliferation and invasion could partly be restored by miR-124 inhibition. In addition, miR-124-dependent inhibitor of apoptosis-stimulating protein of p53 (iASPP) regulation was required in TP73-AS1 induced brain glioma cell growth. Data from this study revealed that TP73-AS1 inhibited the brain glioma growth and metastasis as a competing endogenous RNA (ceRNA) through miR-124-dependent iASPP regulation. In conclusion, we regarded TP73-AS1 as an oncogenic lncRNA promoting brain glioma proliferation and metastasis and a potential target for human brain glioma treatment. PMID- 29412779 TI - Can Work Be Required in the Medicaid Program? PMID- 29412776 TI - Fifty years of microneurography: learning the language of the peripheral sympathetic nervous system in humans. AB - As a primary component of homeostasis, the sympathetic nervous system enables rapid adjustments to stress through its ability to communicate messages among organs and cause targeted and graded end organ responses. Key in this communication model is the pattern of neural signals emanating from the central to peripheral components of the sympathetic nervous system. But what is the communication strategy employed in peripheral sympathetic nerve activity (SNA)? Can we develop and interpret the system of coding in SNA that improves our understanding of the neural control of the circulation? In 1968, Hagbarth and Vallbo (Hagbarth KE, Vallbo AB. Acta Physiol Scand 74: 96-108, 1968) reported the first use of microneurographic methods to record sympathetic discharges in peripheral nerves of conscious humans, allowing quantification of SNA at rest and sympathetic responsiveness to physiological stressors in health and disease. This technique also has enabled a growing investigation into the coding patterns within, and cardiovascular outcomes associated with, postganglionic SNA. This review outlines how results obtained by microneurographic means have improved our understanding of SNA outflow patterns at the action potential level, focusing on SNA directed toward skeletal muscle in conscious humans. PMID- 29412780 TI - Metastatic Prostate Cancer. PMID- 29412781 TI - Prognostic Model for Stratification of Radioresistant Nasopharynx Carcinoma to Curative Salvage Radiotherapy. AB - Purpose To investigate for a prognostic index (PI) to personalize recommendations for salvage intensity-modulated radiotherapy (IMRT) in patients with locally recurrent nasopharyngeal carcinoma (lrNPC). Methods Patients with lrNPC from two academic institutions (Sun Yat-Sen University Cancer Center [SYSUCC-A; n = 251 (training cohort)] and National Cancer Centre Singapore [NCCS; n = 114] and SYSUCC-B [n = 193 (validation cohorts)]) underwent salvage treatment with IMRT from 2001 to 2015. Primary and secondary clinical end points were overall survival (OS) and grade 5 toxicity-free rate (G5-TFR), respectively. Covariate inclusion to the PIs was qualified by a multivariable two-sided P < .05. Discrimination and calibration of the PIs were assessed. Results The primary PI comprised covariates that were adversely associated with OS in the training cohort (gross tumor volumerecurrence hazard ratio [HR], 1.01/mL increase [ P < .001], agerecurrence HR, 1.02/year increase [ P = .008]; repeat IMRT equivalent dose in 2-Gy fractions [EQD2] >= 68 Gy HR, 1.42 [ P = .03]; prior radiotherapy induced grade >= 3 toxicities HR, 1.90 [ P = .001]; recurrent tumor [rT]-category 3 to 4 HR, 1.96 [ P = .005]), in ascending order of weight. Discrimination of the PI for OS was comparable between training and both validation cohorts (Harrell's C = 0.71 [SYSUCC-A], 0.72 [NCCS], and 0.69 [SYSUCC-B]); discretization by using a fixed PI score cutoff of 252 determined from the training data set yielded low- and high-risk subgroups with disparate OS in the validation cohorts (NCCS HR, 3.09 [95% CI, 1.95 to 4.89]; SYSUCC-B HR, 3.80 [95% CI, 2.55 to 5.66]). Our five factor PI predicted OS and G5-TFR (predicted v observed 36-month OS and G5-TFR, 22% v 15% and 38% v 44% for high-risk NCCS and 26% v 31% and 45% v 46% for high risk SYSUCC-B). Conclusion We present a validated PI for robust clinical stratification of radioresistant NPC. Low-risk patients represent ideal candidates for curative repeat IMRT, whereas novel clinical trials are needed in the unfavorable high-risk subgroup. PMID- 29412782 TI - Reply to J.J. Boelens et al. PMID- 29412783 TI - Reply to J.J. Boelens et al. PMID- 29412784 TI - Phase II, Open-Label, Randomized, Multicenter Trial (HERBY) of Bevacizumab in Pediatric Patients With Newly Diagnosed High-Grade Glioma. AB - Purpose Bevacizumab (BEV) is approved in more than 60 countries for use in adults with recurrent glioblastoma. We evaluated the addition of BEV to radiotherapy plus temozolomide (RT+TMZ) in pediatric patients with newly diagnosed high-grade glioma (HGG). Methods The randomized, parallel group, multicenter, open-label HERBY trial ( ClinicalTrials.gov identifier: NCT01390948) enrolled patients age >= 3 years to <= 18 years with localized, centrally neuropathology-confirmed, nonbrainstem HGG. Eligible patients were randomly assigned to receive RT + TMZ (RT: 1.8 Gy, 5 days per week, and TMZ: 75 mg/m2 per day for 6 weeks; 4-week treatment break; then up to 12 * 28-day cycles of TMZ [cycle 1: 150 mg/m2 per day, days 1 to 5; cycles 2 to 12: 200 mg/m2 per day, days 1 to 5]) with or without BEV (10 mg/kg every 2 weeks). The primary end point was event-free survival (EFS) as assessed by a central radiology review committee that was blinded to treatment. We report findings of EFS at 12 months after the enrollment of the last patient. Results One hundred twenty-one patients were enrolled (RT+TMZ [n = 59]; BEV plus RT+TMZ [n = 62]). Central radiology review committee assessed median EFS did not differ significantly between treatment groups (RT+TMZ, 11.8 months; 95% CI, 7.9 to 16.4 months; BEV plus RT+TMZ, 8.2 months; 95% CI, 7.8 to 12.7 months; hazard ratio, 1.44; P = .13 [stratified log-rank test]). In the overall survival analysis, the addition of BEV did not reduce the risk of death (hazard ratio, 1.23; 95% CI, 0.72 to 2.09). More patients in the BEV plus RT+TMZ group versus the RT+TMZ group experienced one or more serious adverse events (n = 35 [58%] v n = 27 [48%]), and more patients who received BEV discontinued study treatment as a result of adverse events (n = 13 [22%] v n = 3 [5%]). Conclusion Adding BEV to RT+TMZ did not improve EFS in pediatric patients with newly diagnosed HGG. Our findings were not comparable to those of previous adult trials, which highlights the importance of performing pediatric-specific studies. PMID- 29412785 TI - Fine-Tuning Antithymocyte Globulin Dosing and Harmonizing Clinical Trial Design. PMID- 29412787 TI - Measurement of respiratory function decline in patients with Duchenne muscular dystrophy: a conjoint analysis. AB - AIM: In Duchenne muscular dystrophy (DMD), little attention has been paid to severity of respiratory function decline (RFD) based on disease progression. We performed a conjoint analysis among 123 Italian clinicians to generate a scale for RFD in DMD patients. METHODS: Before the interview, 11 attributes were selected by discussion among experts. 32 'patient profiles' were generated. Each physician assessed the severity of RFD for each profile. Each level/attribute was assigned an estimated usefulness to understand its impact on RFD. RESULTS: The identified attributes were forced vital capacity, forced vital capacity decline, dysphagia, type of ventilation and peak cough flow. These results allowed the development of a scale for RFD severity. CONCLUSION: This scale can stratify DMD patients according to the severity of their RFD. PMID- 29412786 TI - MeCP2 interacts with chromosomal microRNAs in brain. AB - Although methyl CpG binding domain protein-2 (MeCP2) is commonly understood to function as a silencing factor at methylated DNA sequences, recent studies also show that MeCP2 can bind unmethylated sequences and coordinate gene activation. MeCP2 displays broad binding patterns throughout the genome, with high expression levels similar to histone H1 in neurons. Despite its significant presence in the brain, only subtle gene expression changes occur in the absence of MeCP2. This may reflect a more complex regulatory mechanism of MeCP2 to complement chromatin binding. Using an RNA immunoprecipitation of native chromatin technique, we identify MeCP2 interacting microRNAs in mouse primary cortical neurons. In addition, comparison with mRNA sequencing data from Mecp2-null mice suggests that differentially expressed genes may indeed be targeted by MeCP2-interacting microRNAs. These findings highlight the MeCP2 interaction with microRNAs that may modulate its binding with chromatin and regulate gene expression. PMID- 29412788 TI - L-Carnitine supplementation increases expression of PPAR-gamma and glucose transporters in skeletal muscle of chronically and acutely exercised rats. AB - In this study, the effects of L-Carnitine supplementation on the lipid peroxidation and expression of PPAR-gamma and glucose transporters in the liver and muscles of chronically and acutely exercised rats were investigated. A total of 42 male Wistar Albino rats (8-week-old) were divided into six groups as follows: Control, L-Carnitine, Chronic Exercise (CE), Chronic Exercise + L Carnitine, Acute Exercise (AE) and L-Carnitine + Acute Exercise. Chronic exercise consists of 30 m/min, 30 min/day, and 5 days/week for 6 weeks. Rats in the acute exercise groups were run on the treadmill at 30 m/min until exhaustion. L Carnitine was given at the level of 300 mg per kilogram of diet for 6 weeks. There was no significant difference in the levels of serum ALT, AST, urea, creatinine and glucose levels between the exercise and L-Carnitine groups (P > 0.05). Cholesterol and triglyceride levels decreased by L- carnitine supplementation and chronic exercise in control groups but increased in the AE groups compared to the control group without reinforcement (P < 0.05). Serum, muscle, heart, and liver malondialdehyde (MDA) concentrations were lower in CE and higher in the AE groups (P < 0.001). However, L-Carnitine supplementation reduced MDA levels (P < 0.05). Liver and muscle PPAR-gamma, liver GLUT-2 and muscle GLUT-4 mRNA expressions were lower in AE group than in all other groups (P < 0.001). Both chronic exercise and supplemental L-Carnitine increased liver and muscle PPAR-gamma, GLUT-2 and GLUT-4 mRNA expression (P <0.05). As a result, although acute exercise increased oxidative stress, chronic exercise reduced oxidative stress by lowering lipid peroxidation level. L-Carnitine supplementation decreased oxidative stress and improved glucose and lipid metabolism by regulation of PPAR-gamma, GLUT-2 and GLUT-4 mRNA expression in rats. PMID- 29412789 TI - Long term treatment by mesenchymal stem cells conditioned medium modulates cellular, molecular and behavioral aspects of adjuvant-induced arthritis. AB - Neuroinflammation plays a crucial role in expression of symptoms of numerous autoimmune and neurodegenerative diseases such as pain during rheumatoid arthritis. Overproduction of pro-inflammatory cytokines and activation of intracellular signaling pathways have been strongly implicated in the generation of pathological pain states, particularly at central nervous system sites and induction of spinal neuroinflammatory symptoms. The wide ranges of research to define new therapeutic approaches, including neuroimmune-modulators like stem cells are in progress. Mesenchymal stem cells conditioned medium (MSC-CM) has anti-inflammatory factors which can regulate the immune responses. The aim of this study was to investigate the effect of administration of MSC-CM on behavioral, cellular and molecular aspects of adjuvant-induced arthritis in male Wistar rats. Complete Freund's adjuvant (CFA)-induced arthritis (AA) was caused by single subcutaneous injection of CFA into the rat's hind paw on day 0. MSC-CM was administered daily (i.p.) and during the 21 days of the study after injection. Hyperalgesia, Edema, Serum TNF-alpha levels and p38MAPK and NF-kappaB activities were assessed on days 0,7,14 and 21 of the study. The results of this study indicated the role of MSC-CM in reducing inflammatory symptoms, serum TNF alpha levels and activity of intracellular signaling pathway factors during different phases of inflammation caused by CFA. It seems that MSC-CM treatment due to its direct effects on inhibition of intracellular signaling pathways and pro-inflammatory cytokines can alleviate inflammatory symptoms and pain during CFA-induced arthritis. PMID- 29412790 TI - Knockdown of MPP8 suppresses cell proliferation via regulation of HOXA5 in non small cell lung cancer cells. AB - M-phase phosphoprotein 8 (MPP8) is reported to be closely implicated in cancer initiation and progression. In addition, the homeobox gene HOXA5 has been shown to play critical roles in hematopoiesis, embryogenesis, and tumorigenesis. Nevertheless, the functional relevance of MPP8 and it's relation with HOXA5 in non-small cell lung cancer (NSCLC) is unknown. Therefore, the present study aimed to detect the expression profile of MPP8 in NSCLC and further explore it's biological roles in lung cancer cells. Cell proliferation was measured by CCK-8 assay and EdU incorporation assay. Real-time PCR was applied to detect the mRNA expression of MPP8 and HOXA5. The protein levels of MPP8 and HOXA5 were evaluated by western blot. Our study found that the expression of MPP8 was significantly increased in the NSCLC tissue compared with the adjacent non-tumorous tissue. Compared with the human lung fibroblasts, the elevated gene expression of MPP8 was also detected in the human NSCLC cell lines including NCI-H23 and NCI-H1299. In addition, knockdown of MPP8 led to an obvious reduction in cell viability and DNA synthesis in NCI-H23 and NCI-H1299 cells. Furthermore, down-regulation of MPP8 resulted in elevated expression of HOXA5 in NSCLC cells both at the mRNA and protein levels. Moreover, depletion of HOXA5 abolished the anti-tumor function of MPP8 knockdown in NSCLC cells. The present study demonstrated that MPP8 was associated with NSCLC cell proliferation through regulation of HOXA5, suggesting that MPP8 may act as a novel therapeutic target for treatment of NSCLC. PMID- 29412791 TI - The relationship between the variations in Ggamma and Agamma promotors and the Hereditary Persistence of Fetal Hemoglobin (HPFH). AB - In the present study, sixty-two samples that have 1.5% and upper level of fetal hemoglobin (HbF), were examined to investigate the relationship between HbF level and non-deletional mutations in both Ggamma (G gamma) globin (HBG2) and Agamma (A gamma) globin (HBG1) genes. Four variations were observed in the promotor of Ggamma gene, which are -158C/T, -309A/G, -369C/G, and -567T/G. Also, four variations were observed in the 5'-UTR (untranslated regions) and promotor of Agamma gene, which are +25G/A, -369G/C, -499T/A, and -588G/A. One -222/-225 AGCA del homozygous and six variations as heterozygous in A gamma globin gene promotor region were also observed. The results of the current study suggested that there was a significant relationship between high HbF levels and two variations ( 309A/T and -369C/G) in Ggamma gene promotor. Additionally, a significant relationship between two variations (+25G/A and -499T/A) in Agamma gene promotor was also observed. Furthermore, the persons who carry these variations with high levels of HbF indicated that there might be a haplotype effect between these variations. PMID- 29412792 TI - The effects of caveolin1 on beta cell proliferation. AB - Our study aims to access the influence of caveolin1 (CAV1) on beta cell expression profiles. We knocked down the expression of CAV1 in both NIT-1 cells and islets isolated from C57BL/6J mice using an RNA interference technique, which was realized by the transfer of an shRNA vector targeting CAV1 mRNA into NIT-1 cells or islets through latent virus infection. First, we identified the change in gene expression profiles in islets, in which the CAV1 expression level was down-regulated, as ascertained by mouse gene expression microarray, and the results showed that pathways related to beta cell proliferation and pancreatic secretion functions were significantly influenced. The results of MTT demonstrated that the knockdown of CAV1 expression in NIT-1 cells promoted proliferation. The protein array results showed that pro-apoptotic cytokines were down-regulated in the NIT-1 cell line with CAV1 knockdown. These findings suggest that CAV1 might be involved in apoptosis and proliferation regulation in beta cells, and therefore could be a potential target for the development of novel therapies for diabetes mellitus. PMID- 29412793 TI - Effects of different levels of dietary Citrus Limon essential oil on some blood parameters and antioxidant status in Afshari Ewes. AB - Citrus Limon Oil (CLO) is known as antioxidant resource and contains limonoids, flavonoids and phenolic compounds. This study was conducted to investigate the effects of different levels of CLO on blood parameters and antioxidant status in Afshari ewes. Six adults Afshari ewes (3-4 years old and 51+/-5 kg) were randomly allocated to 3*3 Latin square design with three diets in 21 days period. Dietary treatments included:1) control diet, 2) control diet with 200 mg/day CLO, and 3) control diet with 400 mg/day CLO. To evaluate the antioxidant effect of the CLO, sustainable elimination of free radicals by DPPH and ABTS methods were used. The antioxidant activity of essential oils in DPPH method at doses of 32.5, 45, 130, 260 and 520 mg/ml were 9, 16, 31, 49 and 89%, respectively. Also, antioxidant activity of essential oils in ABTS method at doses of 32.5, 45, 130, 260 and 520 mg/ml were 49, 73, 81, 89 and 95%, respectively. CLO treatments did not affect glucose, blood urea nitrogen, albumin, total protein, low density lipoprotein, while improved the concentration of high-density lipoprotein (P>0.01). Results showed that supplementation with CLO significantly decreased (P<0.01) cholesterol, triglycerides and very low density lipoprotein concentrations compared with control. There was no significant difference in analyzed blood bio chemicals and serum enzymes level between different antioxidant activity methods and groups, suggesting general well-being of ewes. These results suggest that, CLO supplementation had a positive impact on blood traits and antioxidant status of the Afshari ewes. PMID- 29412794 TI - A comparative analysis of RAPD and ISSR markers for assessing genetic diversity in Iranian populations of Nigella sativa L. AB - : The genetic diversity of 18 Iranian populations of Nigella sativa L. was tested using RAPD (10 primers) and ISSR (12 primers) molecular markers. RAPD primers produced 103 acceptable bands and out of them, 42 bands were polymorphic and the total percentage of polymorphism was estimated 40.5%. Out of the 12 ISSR primers, only 5 of them produced acceptable bands. Five ISSR primers generated 39 amplified products and out of them, 19 bands were polymorphic and the total percentage of polymorphism was estimated 57.4%. As a result, the level of polymorphism obtained from the ISSR markers was higher than of the RAPD markers. Mean of marker index (MI) (0.822 for RAPD and 0.74 for ISSR) and Polymorphic information content (PIC) (0.402 for RAPD and 0.35 for ISSR) for each of the marker systems indicated that both markers were effective for evaluating genetic diversity. Cluster analysis classified the populations into 5 groups for both DNA markers. By integration and analyzing of the two marker systems, the populations were classified into 4 groups. The results of this research showed that RAPD and ISSR molecular markers can be useful for identifying and classifying the Iranian Nigella sativa L. POPULATIONS: PMID- 29412795 TI - A new target for the treatment of endometrium cancer by succinic acid. AB - Endometrium cancer is the most common invasive gynecologic malignancy in developed countries. Succinic acid (CO2HCH2-CH2CO2H) is a type of dibasic acid that has uncolored crystal. Succinic acid is used in bakery products and aromatized products. It is naturally found in some vegetables. Succinic acid has no adverse effects because it is metabolized by body cells and has a role in the tricarboxylic acid cycle (TCA) as a cycle media component. The TCA cycle and its enzyme components have some crucial roles for basal cell metabolism. Any mistakes, concentration differences in product, or enzyme deficiencies are important within the cell this cycle. In this proposal project, we aimed to investigate the effect of succinic acid at different doses and at different times in an endometrial cancer cell line. The study was performed using methods that determine for apoptosis (for cytotoxicity, WST-1, for caspase enzyme activity, Caspase 3/BCA; apoptotic determination using flow cytometry; Annexin V; to understand mitochondrial membrane potential; JC-1). The results showed that 5 and 10 uM concentration of succinic acid resulted in apoptosis in endometrium cancer; no such effect was seen in the control cell line, which comprised healthy lung cells. According to our results, it is thought that succinic acid would be effective for the treatment of endometrial cancer cell lines, thus providing new data for other areas of cancer research. PMID- 29412796 TI - Construction and recombinant expression of Pseudomonas aeruginosa truncated exotoxin A in Escherichia coli. AB - Pseudomonas aeruginosa exotoxin A (PE) is a bacterial toxin composed of three domains namely: cell binding, translocation and enzymatic domain. The cytotoxic activity of PE is attributed to the enzymatic domain, which inhibits protein synthesis through ADP-ribosylation of EF-2. PE can be genetically modified to fight cancer. In this regard, a truncated and modified form of PE was produced that could be used for more potent immunotoxins. This modified form termed PE38KDEL was completely devoid of cell binding domain and parts of translocation domain II and Ib which are reported to be inessential for cytotoxicity of the toxin. The resultant expressed protein consisted of the essential translocation domain II and catalytic subunit (domain Ib, III). The deletions in the exotoxin A gene for truncated protein production were made via overlapping PCR extension. The amplicon was cloned in pTZ57r-T vector for DNA works and sub cloned in pET22b expression vector. It is demonstrated here that PE38KDEL can be expressed in huge quantities in Escherichia coli by using the recombinant vector PE38KDEL/pET under control of T7 promoter and E. coli host strain BL21 (DE3) CodonPlus. The protein expression was optimized at 0.5 mM IPTG concentration for induction as soon as the OD600 nm reached 0.6 with 6 hours of post induction culturing at 37 degrees C. The recombinant protein was expressed both as soluble and inclusion body forms however the expression of the soluble form was more pronounced. PMID- 29412797 TI - Frequency Determination of Carbapenem-Resistant Klebsiella Pneumoniae (CRKP) Isolated from hospitals in Isfahan of Iran and Evaluation of Synergistic Effect of Colistin and Meropenem on them. AB - Overuse and misuse of Carbapenems among Klebsiella pneumoniae isolates have caused Carbapenem-Resistant Klebsiella Pneumonia (CRKP) during recent years. Colistin is one of the last available options, and there are increasing concerns about the dosage and resistance to this agent in long-term monotherapies. This study was designed to identification of carbapenemase producing isolates of K. pneumoniae via phenotypic and genotypic methods as well as evaluation of colistin meropenem combination therapy potential. This study was carried out in Isfahan, of Iran on 100 samples from Alzahra and Khorshid hospitals in 2017. The Modified Hodge Test (MHT) was used to investigate the carbapenemase presence. The minimum inhibitory concentration (MIC) and the Fractional Inhibitory Concentration (FIC) were determined using broth macrodilution and checkerboard assays (respectively) for both meropenem and colistin. The bla-KPC gene was studied by polymerase chain reaction (PCR).The highest and the lowest rate of resistance were observed for piperacillin (84%) and ertapenem (50%) respectively. 68 isolates by MHT were CRKP, but None of them were positive for bla-KPC gene. 21 isolates from CRKP cases were high resistant to used antimicrobial agents in the study that both MIC and FIC results showed significant synergy for this antibiotics in checkerboard test (p-value < 0.05). 21 resistant isolates from CRKP cases showed statistically significant synergy potential for meropenem and colistin. The meropenem-colistin combination therapy can be applied as a suitable antibiotic synergy but it requires further investigation in clinical assay. Regarding to our findings, Probably other mechanisms of resistance to Carbapenems ,except bla-kpc genes are involved. PMID- 29412798 TI - Identification of phenolic compounds, antioxidant activity and anti-cancer effects of the extract obtained from the shoots of Ornithogalum narbonense L. AB - This study aimed to examine the anti-cancer and antioxidant properties and identify the phenolic content of methanolic extract obtained from the shoots of the Ornithogalum narbonense L. (OR) species, which is used for folk-medicine and food in the Sanliurfa region of Turkey. The antioxidant activity of the extract was investigated using total phenolics, flavonoids, ABTS and CUPRAC methods. Phenolic component analysis of the plant extract was performed by LC-MS/MS. The anti-cancer property of OR extract was investigated on human colon (DLD-1), endometrium (ECC-1) cancer cells and embryonic kidney (HEK-293) cells. Cytotoxic effects were defined with MTT, apoptotic activity with DNA fragmentation ELISA and AO/EB fluorescent staining, the genotoxic effect with the comet assay and the intracellular oxidative status with TAS and TOS methods. As a result of the study, it was determined that OR extract showed an antioxidant effect, and as a result of the content analysis made with LC-MS/MS, phenolic components were determined, the most abundant being cosmosiin, followed by cinnamic acid, p coumaric acid and quinic acid. OR extract showed cytotoxic activity on DLD-1 and ECC-1 cancer cells, while the cytotoxic effect on HEK-293 cells was determined to be low. It was determined that through OR extract, by increasing the intracellular amount of free radicals on cancer cells, led to DNA damage, which consequently led to apoptosis of the cancer cells. PMID- 29412799 TI - Correlation between serum leptin and its gene expression to the anthropometric measures in overweight and obese children. AB - Obesity is a multifactor disorder with evidence supporting the role of the genetic factor in its etiology. The present study evaluates the relationship between leptin G2548A (rs7799039) and leptin receptors (Gln223Arg (rs1137101) genotyping and its leptin level and the risk of childhood obesity. This case control study was conducted on 168 overweight and obese Saudi children and 126 non obese one served as control. Fasting insulin, leptin, blood glucose, lipid profile levels were measured. HOMA- IR, and BMI were assessed. Genotyping of leptin and leptin receptor gene variants was done by SNP real-time PCR method. GG genotype and G allele of rs1137101 were significantly higher in overweight and obese children than controls. It showed significant association with risk of obesity OR 7.1 [ 95% CI: 3.4 - 14.8] and OR 2.8 [ 95% CI: 2.0 - 4.1] respectively. Leptin level was significantly greater in patients than controls (p<0.000*) with GG and AG genotypes having the highest level of leptin when compared with another genotype in the obese group. As regards, rs7799039 AA genotype showed significant higher leptin level than other genotypes in the same group with a non-significant difference in genotypes distribution between obese and controls. rs1137101 variant of leptin receptor and fasting leptin level are correlated with overweight and obesity in Saudi children. The GG genotype of leptin receptors rs1137101 and higher serum leptin levels can be used as risk factors for childhood obesity. PMID- 29412800 TI - Organ transplantation and donation from the point of view of medical students in Iran: Ethical aspects and knowledge. AB - Organ transplantation is an effective process that prolongs the lives of individuals suffering from incapacitating conditions. The aim of this study was to evaluate the view point of medical students in Iran regarding ethical aspects and knowledge on organ transplantation and donation. The participants included 165 medical students from different faculties of Shahid Beheshti University of Medical Sciences, Tehran, Iran. They were assessed using a reliable questionnaire that examined their ethical aspects and knowledge regarding organ transplantation and donation. All data analyses were performed using Chi-square and analysis of variance tests with SPSS software. Results showed that main sources of respondents' knowledge on organ transplantation and donation were TV, 51.52 % (n = 85) and Internet, 19.39 % (n = 32). 91.51% (n = 151) of the respondents understand and 8.48% (n =14) do not understand the concept of brain death. 49.69% (n = 82) of the respondents were willing to donate their organs. A brain death donor was selected by respondents as the best option for organs transplantation (72.12%; n = 119). The respondents selected young patients as the preferred recipients of an organ (69.69%; n = 115). There was no correlation between gender, age, educational level, marital status and attitude towards organ transplantation. From the results, there is need for an organized educational planning for medical students in ethical issue and knowledge on organ and tissue transplantation. PMID- 29412801 TI - Differentially expressed Secretoglobin 1C1 gene in nasal polyposis. AB - Nasal polyps (NP) are the most common pathological change that occurs in the nasal mucosa and is characterized by mucosal inflammation. Although its etiology and pathogenesis have not been clearly explained, its pathophysiology is arranged by the balance between pro-inflammatory and anti-inflammatory cytokines. The Secretoglobin 1C1 gene synthesizes odor molecule binding proteins (OBPs) in the nasal mucosa and regulates some cytokines. The Secretoglobin 1C1 gene expression could be disrupted by polymorphisms that may act as a possible cause of a disruption in the regulation of the promotor of the gene. Therefore, the main aim of this study was to determine the effects of Secretoglobin 1C1 gene promotor polymorphisms on the gene expression in NP. In this study, to determine the relationship between the Secretoglobin 1C1 gene promotor polymorphisms and the gene expression, the levels of 48 subjects were sequenced (24 patients with NP and 22 controls without sinonasal disease). The levels' expression of Secretoglobin 1C1 in the subjects' nasal mucosa was also detected using RT-PCR. In this study, the level of Secretoglobin 1C1's expression increased in NP (P= 0.003). Three polymorphisms were detected in the Secretoglobin 1C1 gene's promotor. The rs113795008 and rs2280540 variations were significantly high in NP (P= 0.005, P= 0.045). The the rs113795008 homozygous mutant type genotype (G/G) was associated with a high mRNA expression level of Secretoglobin 1C1 in NP (P= 0.009). A correlation was found between a high level of Secretoglobin 1C1 expression and its promotor polymorphism, which thus might increase and/or contribute to the susceptibility of developing NP in the Turkish population. These findings suggested that promotor variations in the function of the Secretoglobin 1C1 gene can alter the gene expression biology in NP. PMID- 29412802 TI - High-fat diet stimulates the gut pathogenic microbiota and maintains hepatic injury in antibiotic-treated rats. AB - The gut and the liver are closely linked to each other, as changes in the gut microbiota can play a significant role in the development of many liver diseases. Gut bacteria respond rapidly to changes in diet and thus can affect the liver through their metabolites. The impact of a high lipid diet on the liver in the presence of an altered gut flora modulated by ampicillin was investigated. The study was performed on 30 male Western albino rats randomly divided into 3 groups: control (phosphate buffered saline treated), group II (ampicillin 50 mg/kg for three weeks to induce microbiota alterations and fed on standard diet) and group III (same dose of ampicillin and fed on a lipid rich diet). Stool samples were collected for qualitative determination of bacteria. Serum hepato specific markers, in addition to Glutathione (GSH), Lipid peroxidase (MDA), Glutathione-S- transferase(GST), and vitamin C in liver tissues, were measured. Altered gut microbiota significantly increased the level of the hepato-specific marker MDA and reduced the GST, GSH and vitamin C levels. However, animals fed a lipid rich diet displayed a more significant shift in hepatic markers and antioxidants. Moreover, a new switch in composition of the gut bacteria was observed by feeding the lipid rich diet. Our study showed that bacterial overgrowth in the gut can be associated with liver dysfunction and that a high lipid diet can promote the overgrowth of some liver damaging microflora during antibiotic treatment. PMID- 29412803 TI - High temperature requirement factor A1 (HTRA1) regulates the activation of latent TGF-beta1 in keloid fibroblasts. AB - Scar treatments are considered a major issue in the plastic surgery field. Activation of the transforming growth factor-beta (TGF-beta)-mediated signaling pathway plays a key role in the scar pathogeneses, and high temperature requirement factor A1 (HTRA1) inhibits TGF-beta1 activation in tumor cells. Our study aims to investigate the role of HTRA1 in the pathogenesis of scars. The mRNA levels of HTRA1 was evaluated by real time PCR, HTRA1 protein expression was determined using western blot and immunohistochemistry, and a luciferase assay was applied to measure dynamic changes of TGF-beta1 activity. We found that the expression of HTRA1 was significantly elevated in keloid tissues, compared to normal skin, and TGF-beta1 mRNA levels slightly increase in the keloid tissue. Furthermore, active TGF-beta1 protein levels and Smad2 phosphorylation significantly increased in the keloid tissue. Treatment with the latent TGF-beta1 or recombinant human HTRA1 (rhHTRA1), alone or in combination, increased Smad2 phosphorylation levels in keloid fibroblasts and active TGF-beta1 contents of associated supernatants. Our results suggest that HTRA1 is involved in the pathogenesis of scars through regulating activation of latent TGF-beta1 in keloid fibroblasts, and our study reveals that HTRA1 is a novel target that regulates scar formation. PMID- 29412804 TI - Testosterone to estrogen conversion is not responsible for the vasodilating effects of testosterone ex vivo. AB - Men have a higher incidence of cardiovascular disease, but poorer vasodilatation than women. However, testosterone exerts vasodilating actions ex vivo. We aimed to determine if reactive oxygen species (ROS) produced in vivo could cause 'eNOS uncoupling' that accounts for the disparity between in vivo and ex vivo results. Ovariectomized SHR and WKY rats were divided into 3 groups: untreated, estradiol benzoate (EB) treated, and testosterone propionate (TP) treated. EB and TP rats were treated for 8 weeks, and blood pressure, serum estrogen, progesterone, and testosterone were measured. Rats were euthanized and aorta samples were taken for examination of nitric oxide, phosphorylated eNOS (p-eNOS), H2O2, gr91phos, and pAkt. Mesenteric arterial rings were used in myographic studies of endothelium dependent and independent vasorelaxation. The influence of testosterone added to the bathing solution of rings from testosterone-supplemented rats with/without an eNOS inhibitor, with/without blockade of androgen or estrogen receptors, and with/without an inhibitor of gp91phox was examined. Treatment with testosterone for 8 weeks did not change endothelium-dependent relaxation in response to acetylcholine in the presence or absence of the eNOS inhibitor L-NAME, or in the presence or absence of blockade of the androgen receptors, estrogen receptors, or gp91phox. No change in nitric oxide, p-eNOS, pAkt, or gp91phos of the aorta was noted. A significant increase in H2O2 was seen in testosterone-supplemented SHR rats, but this was not accompanied by eNOS uncoupling. These results suggest that conversion of testosterone to estrogen is not responsible for its vasodilating effects seen ex vivo. PMID- 29412805 TI - Molecular mechanisms underlying the participation of Ribonuclease T2 gene into self-incompatibility of Citrus grandis var. Shatianyu Hort. AB - The RIB (ribonuclease T2) of Citrus grandis var. Shatianyu Hort involved in self incompatibility (SI) mechanism was identified by prokaryotic expression. RT-qPCR results showed that the expression level of RIB in self pollinated stigma is significantly higher than that in cross pollinated stigma. A vector for prokaryotic expression of RIB was constructed after codon-optimization, and the recombinant protein was induced and purified. In vitro pollen germination test indicated that the RIB protein markedly inhibited pollen germination and pollen tube growth. The result is helpful for better understanding of the molecular mechanism underlying the SI in C. grandis. PMID- 29412806 TI - Ethanol promotes apoptosis in rat ovarian granulosa cells via the Bcl-2 family dependent intrinsic apoptotic pathway. AB - Excessive and indulgent alcohol consumption causes tremendous public health issues worldwide. Not only is ethanol associated with a broad spectrum of critical chronic diseases, ethanol is also demonstrated to exert striking reproductive toxicity for both males and females. Epidemiological investigations suggested that ethanol is closely related to fertility decrease in women. Animal studies showed that ethanol intake obstructed ovulation and reduced ovarian weight during gestation. However, cellular mechanism for this inhibitory effect of ethanol on female fertility is yet to be explored. This study recruited rat ovarian granulosa cells, the primary effector of ovary, to investigate the effects of ethanol on cell apoptosis and explore potential mechanism. Ovarian granulosa cells treated with ethanol for three hours manifested observable reduction in cell viability and apparent apoptosis. In the presence of 200 and 300 mmol/l of ethanol, the percentages of apoptotic cells increased to 33% and 36%, respectively. In addition, apoptosis related caspase-3 activity was elevated with increasing concentrations of ethanol, suggesting a dose dependent effect. Furthermore, high concentrations of ethanol significantly disturbed the transcriptional and translational regulation of anti-apoptotic Bcl-2 and pro apoptotic Bax, which are the two key members of Bcl-2 family tightly involved in intrinsic apoptotic pathway. These results indicated that ethanol promotes apoptosis in rat ovarian granulosa cells, possibly via the intrinsic apoptotic pathway. PMID- 29412807 TI - Association between Vitamin D level and/or deficiency, and systemic lupus erythematosus: a meta-analysis. AB - This study aimed to evaluate the relationship between the level of 25 hydroxyvitamin D [25(OH)D] and systemic lupus erythematosus (SLE). We searched the PUBMED, EMBASE, and Cochrane databases and performed a meta-analysis examining the vitamin D level and/or deficiency in patients with SLE, compared with that in healthy controls. In total, 18 studies consisting of 1,083 patients with SLE and 1,273 controls were included. Vitamin D level was significantly lower in the SLE group than in the control group (standardized mean difference [SMD] = -0.938, 95% CI = -1.352 to -0.524, p = 9.0 * 10-6). Stratification by ethnicity showed a significantly decreased vitamin D level in the SLE group in the European and Arab populations (SMD = -1.485, 95% CI = -2.427 to -0.543, p = 0.002; SMD = -1.067, 95% CI = -1.251 to -0.883, p < 1.0 * 10-8), and an association tendency between decreased vitamin D level and SLE in the Asian population (SMD = -0.874, 95% CI = -2.073 to -0.324, p = 0.153). Subgroup analysis by sample size showed a significantly lower vitamin D level in the SLE group in small- (n <= 100) and large-sample (n > 100) populations (SMD = -1.008, 95% CI = -1.672 to -0.344, p = 0.003; SMD = -0.863, 95% CI = -1.444 to -0.293, p = 0.003). Meta-analysis revealed a significant association between SLE and vitamin D deficiency (RR = 2.321, 95% CI = 1.361-3.960, p = 0.002). Stratification by ethnicity showed a significant association between SLE and vitamin D deficiency in European and Arab populations (RR = 2.182, 95% CI = 1.024 4.648, p = 0.043; RR = 4.550, 95% CI = 3.471-5.965, p < 1.0 * 10-8). Our meta analysis demonstrates that compared with controls, patients with SLE show significantly low serum levels of vitamin D, and that a deficiency of vitamin D is associated with SLE. PMID- 29412808 TI - Circulating prolactin levels and Behcet's disease: A meta-analysis. AB - This study aimed to summarize the current evidence on the relationship between circulating prolactin levels and Behcet's disease (BD). We performed a meta analysis comparing the serum/plasma prolactin levels in patients with BD with those of controls and performed a subgroup analysis based on ethnicity, disease activity, and sex. Ten articles with a total of 320 patients with BD and 259 controls were included. The prolactin levels were not significantly higher in the BD group than in the control group (SMD=0.208, 95% CI=-0.012-0.428, p=0.064). Stratification by ethnicity indicated no elevation in prolactin level in Turkish patients with BD (SMD=0.127, 95% CI=-0.111-0.366, p=0.295). Stratification by disease activity revealed no elevation in prolactin level in both the active and inactive BD groups compared with the control group (SMD=0.373, 95% CI=-0.095 0.841, p=0.119; SMD=0.055, 95% CI=-0.243-0.354, p=0.717). Stratification by sex revealed no elevation in prolactin level in both the female and male BD groups (SMD=0.031, 95% CI=-0.398-0.460, p=0.888; SMD=0.279, 95% CI=-1.411-1.969, p=0.746). The prolactin levels were not significantly elevated in patients with BD, regardless of the adjustments for age/sex, sample size, or data type evaluated. This meta-analysis of current evidence suggests that circulating prolactin levels may not be higher in patients with BD than in controls. PMID- 29412809 TI - Editorial: Newer peptide-based agents for treatment of patients with Type 2 diabetes. PMID- 29412810 TI - GLP-1 receptor agonists show neuroprotective effects in animal models of diabetes. AB - Enzyme-resistant receptor agonists of the incretin hormone glucagon-like peptide 1 (GLP-1) have shown positive therapeutic effects in people with type 2 diabetes mellitus (T2DM). T2DM has detrimental effects on brain function and impairment of cognition and memory formation has been described. One of the underlying mechanisms is most likely insulin de-sensitization in the brain, as insulin improves cognitive impairments and enhances learning. Treatment with GLP-1 receptor agonists improves memory formation and impairment of synaptic plasticity observed in animal models of diabetes-obesity. Furthermore, it has been shown that diabetes impairs growth factor signalling in the brain and reduces energy utilization in the cortex. Inflammation and apoptotic signalling was also increased. Treatment with GLP-1 receptor agonists improved neuronal growth and repair and reduced inflammation and apoptosis as well as oxidative stress. In comparison with the diabetes drug metformin, GLP-1 receptor agonists were able to improve glycemic control and reverse brain impairments, whereas metformin only normalized blood glucose levels. Clinical studies in non-diabetic patients with neurodegenerative disorders showed neuroprotective effects following administration with GLP-1 receptor agonists, demonstrating that neuroprotective effects are independent of blood glucose levels. PMID- 29412811 TI - Incretin-based therapy for the treatment of bone fragility in diabetes mellitus. AB - Bone fractures are common comorbidities of type 2 diabetes mellitus (T2DM). Bone fracture incidence seems to develop due to increased risk of falls, poor bone quality and/or anti-diabetic medications. Previously, a relation between gut hormones and bone has been suspected. Most recent evidences suggest indeed that two gut hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may control bone remodeling and quality. The GIP receptor is expressed in bone cells and knockout of either GIP or its receptor induces severe bone quality alterations. Similar alterations are also encountered in GLP-1 receptor knock-out animals associated with abnormal osteoclast resorption. Some GLP-1 receptor agonist (GLP-1RA) have been approved for the treatment of type 2 diabetes mellitus and although clinical trials may not have been designed to investigate bone fracture, first results suggest that GLP-1RA may not exacerbate abnormal bone quality observed in T2DM. The recent design of double and triple gut hormone agonists may also represent a suitable alternative for restoring compromised bone quality observed in T2DM. However, although most of these new molecules demonstrated weight loss action, little is known on their bone safety. The present review summarizes the most recent findings on peptide based incretin therapy and bone physiology. PMID- 29412812 TI - Intestinal peptide changes after bariatric and minimally invasive surgery: Relation to diabetes remission. AB - Bariatric surgery is very effective in achieving and maintaining weight loss but it is also associated with improvement of obesity metabolic complications, primarily type 2 diabetes (T2D). Remission of T2D or at least a net improvement of glycemic control persists for at least 5 years. The bypass of duodenum and of the first portion of the jejunum up to the Treitz ligament as in Roux-en-Y Gastric Bypass (RYGB), or the bypass of the duodenum, the entire jejunum and the first tract of the ileum, such as in Bilio-Pancreatic Diversion (BPD), achieve different results on insulin sensitivity. Insulin resistance is the major driver of T2D manifesting long before insulin secretion failure. In fact, T2D development can be prevented by treatment with insulin sensitizing agents. Interestingly, RYGB improves hepatic insulin sensitivity while BPD ameliorates whole-body insulin sensitivity. Two major theories have been advocated to explain the early remission of T2D following RYGB or BPD before a meaningful weight loss takes place, the foregut and the hindgut hypotheses. The former holds that the bypass of the proximal intestine, i.e. duodenum and jejunum, prevents the secretion of signals - including nervous transmitters and hormones - promoting insulin resistance, the latter instead states that the delivery of nutrients directly into the ileum stimulates the secretion of hormones improving glucose disposal. The most studied candidate is Glucagon Like Peptide 1 (GLP1). However, while there is unambiguous evidence that GLP-1 stimulates insulin secretion, its direct action in lowering insulin resistance, independently of the effect on weight loss secondary to its satiety action, is utterly controversial. In this review we examine the effects on T2D and gastrointestinal peptide secretion produced by different types of metabolic surgery and by minimally invasive endoscopic surgery, whose utilization for the treatment of obesity and T2D is gaining wider interest and acceptance. PMID- 29412813 TI - Insulin and IGF-1 receptor autocrine loops are not required for Exendin-4 induced changes to pancreatic beta-cell bioenergetic parameters and metabolism in BRIN BD11 cells. AB - Pharmacological long lasting Glucagon-like peptide-1 (GLP-1) analogues, such as Exendin-4, have become widely used diabetes therapies. Chronic GLP-1R stimulation has been linked to beta-cell protection and these pro-survival actions of GLP-1 are dependent on the activation of the mammalian target of rapamycin (mTOR) leading to accumulation of Hypoxia inducible factor 1 alpha (HIF-1alpha). Recent studies from our lab indicate that prolonged GLP-1R stimulation promotes metabolic reprograming of beta-cells towards a highly glycolytic phenotype and activation of the mTOR/HIF-1alpha pathway was required for this action. We hypothesised that GLP-1 induced metabolic changes depend on the activation of mTOR and HIF-1alpha, in a cascade that occurs after triggering of a potential Insulin-like growth factor 1 receptor (IGF-1R) or the Insulin receptor (IR) autocrine loops. Loss of function of these receptors, through the use of small interfering RNA, or neutralizing antibodies directed towards their products, was undertaken in conjunction with functional assays. Neither of these strategies mitigated the effect of GLP-1 on glucose uptake, protein expression or bioenergetic flux. Our data indicates that activation of IGF-1R and/or the IR autocrine loops resulting in beta-cell protection and function, involve mechanisms independent to the enhanced metabolic effects resulting from sustained GLP-1R activation. PMID- 29412814 TI - Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational drug design approach based on a thorough understanding of the endocrinology and degradation of glucagon-like peptide-1 (GLP-1). GLP-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2 diabetes as an example, this review summarises how knowledge of a peptide's biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any side effects are minor and largely predictable. Other peptides with metabolic effects which can also be degraded by DPP-4 will be reviewed, and their potential role as additional mediators of the effects of DPP-4 inhibitors will be assessed. PMID- 29412815 TI - Dipeptidyl peptidase inhibitor therapy in type 2 diabetes: Control of the incretin axis and regulation of postprandial glucose and lipid metabolism. AB - Dipeptidyl peptidase 4 (DPP4) is a widely expressed, serine protease which regulates the bioactivity of many peptides through cleavage and inactivation including the incretin hormones, glucagon like peptide -1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP). Inhibitors of DPP4 are used therapeutically to treat patients with Type 2 Diabetes Mellitus (T2DM) as they potentiate incretin action to regulate islet hormone secretion and improve glycemia and post-prandial lipid excursions. The widespread clinical use of DPP4 inhibitors has increased interest in the molecular mechanisms by which these drugs mediate their beneficial effects. Traditionally, focus has remained on inhibiting the catalytic activity of DPP4 within the plasma compartment, however evidence is emerging on the importance of inactivation of membrane-bound DPP4 in selective tissue beds to potentiate local hormone gradients. Here we review the recent advances in identifying the cellular sources of both circulating and membrane-bound DPP4 important for cleavage of the incretin hormones and regulation of glucose and lipoprotein metabolism. PMID- 29412816 TI - Tissue expression of DPP-IV in obesity-diabetes and modulatory effects on peptide regulation of insulin secretion. AB - Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent an important class of glucose-lowering drug for type 2 diabetes. DPP-4 enzyme activity has been observed to be significantly altered in type 2 diabetes. Here, the role of DPP-4 was examined in a high fat fed (HFF) mouse model of insulin resistance. HFF mice had an increased bodyweight (p < .01), were hyperglycaemic (p < .01) and hyperinsulinaemic (p < .05). Compared to normal diet, HFF mice exhibited increased plasma DPP-4 activity (p < .01). Tissue distribution patterns in lean and HFF mice demonstrated highest levels of DPP-4 activity in lung (20-26 MUmol/min/mg protein) and small intestine (13-14 MUmol/min/mg protein), and lowest activity in the spleen (3.8 MUmol/min/mg protein). Modulation of DPP-4 activity by high fat feeding was observed in several tissues with increases in the lung (p < .05), liver (p < .05), kidney (p < .05) and pancreas (p < .05). With a high fat diet, DPP-4 gene expression was upregulated in the liver (p < .001) and downregulated in the pancreas (p < 0.001) and small intestine (p < .001). Immunohistochemical analysis revealed increased DPP-4 immunostaining localised primarily in the pancreatic islets of HFF mice (p < .01) with no change in islet GLP-1 expression. Treatment of HFF mice with metformin for 21-days resulted in inhibition of circulating DPP-4 activity (p < .05), decreased blood glucose (p < .05) and increased GLP-1 gene expression (p < .001). These data indicate that DPP-4 is modulated in a tissue specific manner and is dependent on physiological conditions such as hyperglycaemia and insulin resistance, suggesting a significant role in disorders such as diabetes. PMID- 29412817 TI - Glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists as anti diabetic agents. AB - Glucose-dependent insulinotropic polypeptide (GIP) is an intestinal hormone with a broad range of physiological actions. In the postprandial state, the hormone stimulates insulin secretion and during eu- and hypoglycemia, it stimulates glucagon secretion. In addition, GIP increases triacylglycerol (TAG) uptake in adipose tissue and decreases bone resorption. However, the importance of these actions in humans are not clearly understood as a specific GIP receptor (GIPR) antagonist - an essential tool to study GIP physiology - has been missing. Several different GIPR antagonists have been identified comprising both peptides, vaccines against GIP, GIP antibodies or antibodies against the GIPR. However, most of these have only been tested in rodents. In vitro, N- and C-terminally truncated GIP variants are potent and efficacious GIPR antagonists. Recently, GIP(3-30)NH2, a naturally occurring peptide, was shown to block the GIPR in humans and decrease GIP-induced insulin secretion as well as adipose tissue blood flow and TAG uptake. So far, there are no studies with a GIPR antagonist in patients with type 2 diabetes (T2D), but because the elevations in fasting plasma glucagon and paradoxical postprandial glucagon excursions, seen in patients with T2D, are aggravated by GIP, a GIPR antagonist could partly alleviate this and possibly improve the fasting and postprandial glycemia. Since the majority of patients with T2D are overweight, inhibition of GIP-induced fat deposition may be beneficial as well. Here we summarize the studies of GIPR antagonists and discuss the therapeutic potential of the GIP system in humans. PMID- 29412818 TI - Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity. AB - In the treatment of insulin-dependent diabetes the risk of a fatal insulin overdose is a persistent fear to most patients. In order to potentially reduce the risk of overdose, we report the design, synthesis, and biochemical characterization of a set of insulin analogs designed to be fractionally reduced in maximal agonism at the insulin receptor isoforms. These analogs consist of native insulin that is site-specifically conjugated to a peptide-based insulin receptor antagonist. The structural refinement of the antagonist once conjugated to insulin provided a set of partial agonists exhibiting between 25 and 70% of the maximal agonism of native insulin at the two insulin receptor isoforms, with only slight differences in inherent potency. These rationally-designed partial agonists provide an approach to interrogate whether control of maximal activity can provide glycemic control with reduced hypoglycemic risk. PMID- 29412820 TI - A novel GLP-1/xenin hybrid peptide improves glucose homeostasis, circulating lipids and restores GIP sensitivity in high fat fed mice. AB - Combined modulation of peptide hormone receptors including, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and xenin, have established benefits for the treatment of diabetes. The present study has assessed the biological actions and therapeutic efficacy of a novel exendin 4/xenin-8-Gln hybrid peptide, both alone and in combination with the GIP receptor agonist (DAla2)GIP. Exendin-4/xenin-8-Gln was enzymatically stable and exhibited enhanced insulin secretory actions when compared to its parent peptides. Exendin 4/xenin-8-Gln also possessed ability to potentiate the in vitro actions of GIP. Acute administration of exendin-4/xenin-8-Gln in mice induced appetite suppressive effects, as well as significant and protracted glucose-lowering and insulin secretory actions. Twice daily administration of exendin-4/xenin-8-Gln, alone or in combination with (DAla2)GIP, for 21-days significantly reduced non fasting glucose and increased circulating insulin levels in high fat fed mice. In addition, all exendin-4/xenin-8-Gln treated mice displayed improved glucose tolerance, insulin sensitivity and metabolic responses to GIP. Combination therapy with (DAla2)GIP did not result in any obvious further benefits. Metabolic improvements in all treatment groups were accompanied by reduced pancreatic beta cell area and insulin content, suggesting reduced insulin demand. Interestingly, body weight, food intake, circulating glucagon, metabolic rate and amylase activity were unaltered by the treatment regimens. However, all treatment groups, barring (DAla2)GIP alone, exhibited marked reductions in total- and LDL cholesterol. Furthermore, exendin-4 therapy also reduced circulating triacylglycerol. This study highlights the positive antidiabetic effects of exendin-4/xenin-8-Gln, and suggests that combined modulation of GLP-1 and xenin related signalling pathways represents an exciting treatment option for type 2 diabetes. PMID- 29412821 TI - Role of islet peptides in beta cell regulation and type 2 diabetes therapy. AB - The endocrine pancreas is composed of islets of Langerhans, which secrete a variety of peptide hormones critical for the maintenance of glucose homeostasis. Insulin is the primary regulator of glucose and its secretion from beta-cells is tightly regulated in response to physiological demands. Direct cell-cell communication within islets is essential for glucose-induced insulin secretion. Emerging data suggest that islet connectivity is also important in the regulating the release of other islet hormones including glucagon and somatostatin. Autocrine and paracrine signals exerted by secreted peptides within the islet also play a key role. A great deal of attention has focused on classical islet peptides, namely insulin, glucagon and somatostatin. Recently, it has become clear that islets also synthesise and secrete a range of non-classical peptides, which regulate beta-cell function and insulin release. The current review summarises the roles of islet cell connectivity and islet peptide-driven autocrine and paracrine signalling in beta-cell function and survival. The potential to harness the paracrine effects of non-classical islet peptides for the treatment of type 2 diabetes is also briefly discussed. PMID- 29412822 TI - Apelin-13 analogues show potent in vitro and in vivo insulinotropic and glucose lowering actions. AB - Nine structurally modified apelin-13 analogues were assessed for their in vitro and acute in vivo antidiabetic potential. Stability was assessed in mouse plasma and insulinotropic efficacy tested in cultured pancreatic BRIN-BD11 cells and isolated mouse pancreatic islets. Intracellular Ca2+ and cAMP production in BRIN BD11 cells was determined, as was glucose uptake in 3T3-L1 adipocytes. Acute antihyperglycemic effects of apelin analogues were assessed following i.p. glucose tolerance tests (ipGGT, 18 mmol/kg) in normal and diet-induced-obese (DIO) mice and on food intake in normal mice. Apelin analogues all showed enhanced in vitro stability (up to 5.8-fold, t1/2 = 12.8 h) in mouse plasma compared to native apelin-13 (t1/2 = 2.1 h). Compared to glucose controls, stable analogues exhibited enhanced insulinotropic responses from BRIN-BD11 cells (up to 4.7-fold, p < 0.001) and isolated mouse islets (up to 5.3-fold) for 10-7 M apelin 13 amide (versus 7.6-fold for 10-7 M GLP-1). Activation of APJ receptors on BRIN BD11 cells increased intracellular Ca2+ (up to 3.0-fold, p < 0.001) and cAMP (up to 1.7-fold, p < 0.01). Acute ipGTT showed improved insulinotropic and glucose disposal responses in normal and DIO mice (p < 0.05 and p < 0.01, respectively). Apelin-13 amide and (pGlu)apelin-13 amide were the most effective analogues exhibiting acute, dose-dependent and persistent biological actions. Both analogues stimulated insulin-independent glucose uptake by differentiated adipocytes (2.9-3.3-fold, p < 0.05) and inhibited food intake (26-33%, p < 0.001), up to 180 min in mice, versus saline. In contrast, (Ala13)apelin-13 and (Val13)apelin-13 inhibited insulin secretion, suppressed beta-cell signal transduction and stimulated food intake in mice. Thus, stable analogues of apelin 13 have potential for diabetes/obesity therapy. PMID- 29412819 TI - Gut hormone polyagonists for the treatment of type 2 diabetes. AB - Chemical derivatives of the gut-derived peptide hormone glucagon-like peptide 1 (GLP-1) are among the best-in-class pharmacotherapies to treat obesity and type 2 diabetes. However, GLP-1 analogs have modest weight lowering capacity, in the range of 5-10%, and the therapeutic window is hampered by dose-dependent side effects. Over the last few years, a new concept has emerged: combining the beneficial effects of several key metabolic hormones into a single molecular entity. Several unimolecular GLP-1-based polyagonists have shown superior metabolic action compared to GLP-1 monotherapies. In this review article, we highlight the history of polyagonists targeting the receptors for GLP-1, GIP and glucagon, and discuss recent progress in expanding of this concept to now allow targeted delivery of nuclear hormones via GLP-1 and other gut hormones, as a novel approach towards more personalized pharmacotherapies. PMID- 29412823 TI - Cholecystokinin (CCK) and related adjunct peptide therapies for the treatment of obesity and type 2 diabetes. AB - Cholecystokinin (CCK) is a hormone secreted from I-cells of the gut, as well as neurons in the enteric and central nervous system, that binds and activates CCK-1 and CCK-2 receptors to mediate its biological actions. To date knowledge relating to the physiological significance of CCK has predominantly focused around induction of short-term satiety. However, CCK has also been highlighted to possess important actions in relation to the regulation of insulin secretion, as well as overall beta-cell function and survival. Consequently, this has led to the development of enzymatically stable, biologically active, CCK peptide analogues with proposed therapeutic promise for both obesity and type 2 diabetes. In addition, several studies have demonstrated metabolic, and therapeutically relevant, complementary biological actions of CCK with those of the incretin hormones GIP and GLP-1, as well as with amylin and leptin. Thus, stable CCK derivatives not only offer promise as potential independent weight-reducing and glucose-lowering drugs, but also as effective adjunctive therapies. This review focuses on the recent and ongoing developments of CCK in the context of new therapies for obesity and type 2 diabetes. PMID- 29412825 TI - Oral delivery of anti-diabetes therapeutics using cell penetrating and transcytosing peptide strategies. AB - Oral delivery of insulin and other anti-diabetic peptides is inhibited by low intestinal absorption caused by the poor permeability across cellular membranes and the susceptibility to enzymatic degradation in the gastrointestinal tract. Cell-penetrating peptides (CPPs) have been investigated for a number of years as oral absorption enhancers for hydrophilic macromolecules by electrostatic or covalent conjugation on in conjunction with nanotechnology. Endogenous cellular uptake mechanisms present in the intestine can be exploited by engineering peptide conjugates that transcytose; entering cells by endocytosis and leaving by exocytosis. Efficiently delivering hydrophilic and sensitive peptide drugs to safely transverse the digestive barrier with no effect on gut physiology using remains a key driver for formulation research. Here we review the use of CPP and transcytosis peptide approaches, their modification and use in delivering anti diabetic peptides (with the primary example of Insulin and engineered homologues) by direct oral administration to treat diabetes and associated metabolic disorders. PMID- 29412826 TI - Integrated insights into the role of alpha-melanocyte stimulatory hormone in the control of food intake and glycaemia. AB - Identifying peptide hormones with multipotent actions on both weight and glycaemia can have a significant impact on therapeutic options in the treatment of obesity and diabetes. This has been exemplified by recent advances involving pharmacological exploitation of glucagon-like peptide 1 biology. Herein, we summarise evidence supporting the potential candidacy in this light of alpha melanocyte stimulatory hormone, an endogenous peptide hormone and a breakdown product of the neuropeptide pro-opiomelanocortin. We reference its well described central actions in the control of food intake and moreover highlight new data pointing to an important role for this peptide hormone in the periphery, in relation to glycaemic control. PMID- 29412827 TI - Biochemical properties and biological actions of obestatin and its relevence in type 2 diabetes. AB - Obestatin was initially discovered in rat stomach extract, and although it is principally produced in the gastric mucosa, it can be found throughout the gastrointestinal tract. This 23-amino acid C-terminally amidated peptide is derived from preproghrelin and has been ascribed a wide range of metabolic effects relevant to type 2 diabetes. Obestatin reportedly inhibits gastrointestinal motility, reduces food intake and lowers body weight and improves lipid metabolism. Furthermore, it appears to exert actions on the pancreatic beta-cell, most notably increasing beta-cell mass and upregulating genes associated with insulin production and beta-cell regeneration, with relevance to type 2 diabetes. It is becoming evident that obestatin also exerts pleiotropic effects on the cardiovascular system, possibly modulating blood pressure, endothelial function and triggering cardioprotective mechanisms, which may be important in determining cardiovascular outcomes in type 2 diabetes. Furthermore, it seems that like other gut peptides obestatin has neuroprotective properties. This review examines the biochemical properties of the obestatin peptide (its structure, sequence, stability and distribution) and the candidate receptors through which it may act. It provides a balanced examination of the reported pancreatic and extrapancreatic actions of obestatin and evaluates its potential relevance with respect to diabetes therapy, together with discussion of direct evidence linking alterations in obestatin signalling with obesity/diabetes and other diseases. PMID- 29412824 TI - Ghrelin regulation of glucose metabolism. AB - The a 28-amino acid peptide ghrelin was discovered in 1999 as a growth hormone (GH) releasing peptide. Soon after its discovery, ghrelin was found to increase body weight and adiposity by acting on the hypothalamic melanocortinergic system. Subsequently, ghrelin was found to exert a series of metabolic effects, overall testifying ghrelin a pleiotropic nature of broad pharmacological interest. Ghrelin acts through the growth hormone secretagogue-receptor (GHS-R), a seven transmembrane G protein-coupled receptor with high expression in the anterior pituitary, pancreatic islets, thyroid gland, heart and various regions of the brain. Among ghrelins numerous metabolic effects are the most prominent the stimulation of appetite via activation of orexigenic hypothalamic neurocircuits and the food-intake independent stimulation of lipogenesis, which both together lead to an increase in body weight and adiposity. Ghrelin effects beyond the regulation of appetite and GH secretion include the regulation of gut motility, sleep-wake rhythm, taste sensation, reward seeking behaviour, and the regulation of glucose metabolism. The latter received recently increasing recognition because pharmacological inhibition of ghrelin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes. In this review we highlight the multifaceted nature of ghrelin and summarize its glucoregulatory action and discuss the pharmacological value of ghrelin pathway inhibition for the treatment of glucose intolerance and type 2 diabetes. PMID- 29412828 TI - Emerging therapeutic potential for peptide YY for obesity-diabetes. AB - The vast majority of research to date on the gut hormone Peptide YY (PYY) has focused on appetite suppression and body weight regulation effects. These biological actions are believed to occur through interaction of PYY with hypothalamic Y2 receptors. However, more recent studies have added additional knowledge to understanding of the physiological, and potential therapeutic, roles of PYY beyond obesity alone. Thus, PYY has now been shown to impart improvements in pancreatic beta-cell survival and function, with obvious benefits for diabetes. This effect has been linked mainly to binding and activation of Y1 receptors by PYY, but more evidence is still required in this regard. Given the potential therapeutic promise of PYY-derived compounds, and complexity of receptor interactions, it is important to fully understand the complete biological action profile of PYY. Therefore, the current review aims to compile, evaluate and summarise current knowledge on PYY, with particular emphasis on obesity and diabetes treatment, and the importance of specific Y receptor interactions for this. PMID- 29412830 TI - Glucagon receptor signaling in metabolic diseases. AB - Glucagon is a peptide hormone secreted from the pancreatic alpha cells in response to hypoglycemia but in some patients with type 2 diabetes a paradoxical hypersecretion results from the intake of glucose. In rodent, antagonizing the actions of glucagon have been shown to be effective for lowering blood glucose levels and this has recently have been solidified in patients with type 2 diabetes. Although the reported increases of liver enzymes, hyperglucagonemia, and alpha cell hyperplasia resulting from glucagon receptor antagonism may potentially limit the clinical applicability of glucagon receptor antagonists, they may serve as an instrumental toolbox for delineating the physiology of glucagon. Agonizing glucagon receptor signaling may be relevant, in particular when combined with glucagon-like peptide-1 receptor analogues in the perspective of body weight lowering therapy. Here, we will focus on new conceptual aspects of glucagon biology and how this may led to new diagnostics and treatment of metabolic diseases. PMID- 29412831 TI - Oxyntomodulin: Actions and role in diabetes. AB - Oxyntomodulin is a product of the glucagon precursor, proglucagon, produced and released from the endocrine L-cells of the gut after enzymatic processing by the precursor prohormone convertase 1/3. It corresponds to the proglucagon sequence 33-69 and thus contains the entire glucagon sequence plus a C-terminal octapeptide, comprising in total 37 amino acids. As might have been expected, it has glucagon-like bioactivity, but also and more surprisingly also activates the receptor for GLP-1. This has given the molecule an interesting status as a glucagon-GLP-1 co-agonist, which is currently attracting considerable interest for its potential in the treatment of diabetes and obesity. Here, we provide an update on oxyntomodulin with a focus on its potential role in metabolic diseases. PMID- 29412829 TI - Problem or solution: The strange story of glucagon. AB - Globally, 13% of the world's adult population is obese, and more than 400 million people suffer from diabetes. These conditions are both associated with significant morbidity, mortality and financial cost. Therefore, finding new pharmacological treatments is an imperative. Relative hyperglucagonaemia is seen in all types of diabetes, and has been implicated in its pathogenesis. Consequently, clinical trials are underway using drugs which block glucagon activity to treat type 2 diabetes. Conversely, exogenous glucagon can increase energy expenditure. Therefore, researchers are designing peptides that combine activation of the glucagon receptor with further incretin properties, which will treat obesity while mitigating the hyperglycaemic effects of glucagon. This review will discuss these conflicting physiological properties of glucagon, and the attempts to harness these effects pharmacologically. PMID- 29412832 TI - Alpha cell dysfunction in type 1 diabetes. AB - Type 1 diabetes is characterized by selective loss of beta cells and insulin secretion, which significantly impact glucose homeostasis. However, this progressive disease is also associated with dysfunction of the alpha cell component of the islet, which can exacerbate hyperglycemia due to paradoxical hyperglucagonemia or lead to severe hypoglycemia as a result of failed counterregulation. In this review, the physiology of alpha cell secretion and the potential mechanisms underlying alpha cell dysfunction in type 1 diabetes will be explored. Because type 1 diabetes is a progressive disease, a synthesized timeline of aberrant alpha cell function will be presented as an attempt to delineate the natural history of type 1 diabetes with respect to the alpha cell. PMID- 29412833 TI - Newer GLP-1 receptor agonists and obesity-diabetes. AB - Obesity is a major risk factor for type 2 diabetes and may complicate type 1 diabetes. In parallel with the global epidemic of obesity, the incidence of type 2 diabetes is increasing exponentially. To reverse these alarming trends, weight loss becomes a major therapeutic priority in prevention and treatment of type 2 diabetes. Given that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve glycaemic control and cause weight loss, they are receiving increasing attention for the treatment of diabetes-obesity. This review discusses current and emerging therapeutic options with GLP-1 RAs and considers the next generation of novel peptide co-agonists with the potential for improved therapeutic outcomes in obesity and type 2 diabetes. PMID- 29412835 TI - Control of insulin secretion by GLP-1. AB - Stimulation of insulin secretion by glucagon-like peptide-1 (GLP-1) and other gut derived peptides is central to the incretin response to ingesting nutriments. Analogues of GLP-1, and inhibitors of its breakdown, have found widespread clinical use for the treatment of type 2 diabetes (T2D) and obesity. The release of these peptides underlies the improvements in glycaemic control and disease remission after bariatric surgery. Given therapeutically, GLP-1 analogues can lead to side effects including nausea, which limit dosage. Greater understanding of the interactions between the GLP-1 receptor (GLP-1R) and both the endogenous and artificial ligands therefore holds promise to provide more efficacious compounds. Here, we discuss recent findings concerning the signalling and trafficking of the GLP-1R in pancreatic beta cells. Leveraging "bias" at the receptor towards cAMP generation versus the recruitment of beta-arrestins and extracellular signal-regulated kinases (ERK1/2) activation may allow the development of new analogues with significantly improved clinical efficacy. We describe how, unexpectedly, relatively low-affinity agonists, which prompt less receptor internalisation than the parent compound, provoke greater insulin secretion and consequent improvements in glycaemia. PMID- 29412836 TI - A role for Glucagon-Like Peptide-1 in the regulation of beta-cell autophagy. AB - Autophagy is a highly conserved intracellular recycling pathway that serves to recycle damaged organelles/proteins or superfluous nutrients during times of nutritional stress to provide energy to maintain intracellular homeostasis and sustain core metabolic functions. Under these conditions, autophagy functions as a cell survival mechanism but impairment of this pathway can lead to pro-death stimuli. Due to their role in synthesising and secreting insulin, pancreatic beta cells have a high requirement for robust degradation pathways. Recent research suggests that functional autophagy is required to maintain beta-cell survival and function in response to high fat diet suggesting a pro-survival role. However, a role for autophagy has also been implicated in the pathogenesis of type 2 diabetes. Thus, the pro-survival vs pro-death role of autophagy in regulating beta-cell mass requires discussion. Emerging evidence suggests that Glucagon-Like Peptide-1 (GLP-1) may exert beneficial effects on glucose homeostasis via autophagy-dependent pathways both in pancreatic beta-cells and in other cell types. The aim of the current review is to: i) summarise the literature surrounding beta-cell autophagy and its pro-death vs pro-survival role in regulating beta-cell mass; ii) review the literature describing the impact of GLP 1 on beta-cell autophagy and in other cell types; iii) discuss the potential underlying mechanisms. PMID- 29412834 TI - Targeted intestinal delivery of incretin secretagogues-towards new diabetes and obesity therapies. AB - A new strategy under development for the treatment of type 2 diabetes and obesity is to mimic some of the effects of bariatric surgery by delivering food-related stimuli to the distal gastrointestinal tract where they should enhance the release of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptideYY (PYY). Methods include inhibition of food digestion and absorption in the upper GI tract, or oral delivery of stimuli in capsules or pelleted form to protect them against gastric degradation. A variety of agents have been tested in humans using capsules, microcapsules or pellets, delivering nutrients, bile acids, fatty acids and bitter compounds. This review examines the outcomes of these different approaches and supporting evidence from intestinal perfusion studies. PMID- 29412837 TI - Glucose-lowering therapies in type 2 diabetes: Opportunities and challenges for peptides. AB - This overview considers the opportunities and challenges that face the use of gluco-regulatory peptides to treat type 2 diabetes. New insulin analogues and formulations are being developed with pharmacokinetic properties to speed-up or prolong transfer from a subcutaneous injection site to the target tissues, or to selectively favour effects on the liver. Alternative routes of insulin administration continue to attract attention, and advances in the integration of glucose monitoring with insulin pump devices are improving miniaturised 'closed loop' artificial pancreas systems. Proof of concept has been established for non cellular glucose-responsive insulin delivery ('smart insulins') to release insulin from implants or circulating depots in proportion to circulating glucose. The many peptides involved in blood glucose control offer diverse therapeutic opportunities. Exploitation of multiple selected receptor targets using constructs of hybrid and chimeric peptides, especially those based on glucagon and gastrointestinal hormones, has gained much credence from initial preclinical studies. Peptide templates identified from comparative endocrine studies have also provided valuable insights in this respect and indicated novel approaches to address associated conditions such as obesity and infections at the same time. Nevertheless, there are many challenges to the use of therapeutic peptides that impose on every step in the complex pathway from design and testing through to making a fully characterised therapeutic product, and optimising administration, tissue targeting and degradation. Stability of peptides and immunological uncertainties of novel structures require particular consideration as well as the need to avoid over-reduction of blood glucose into hypoglycaemia. PMID- 29412838 TI - Glucagon-like peptide-1 receptor mediated control of cardiac energy metabolism. AB - Glucagon-like peptide-1 receptor (GLP-1R) agonists are frequently used to improve glycemia in patients with type 2 diabetes (T2D). Recent data from cardiovascular outcomes trials for the GLP-1R agonists, liraglutide and semaglutide, have also demonstrated significant reductions in death rates from cardiovascular causes in patients with T2D. As cardiovascular death is the number one cause of death in patients with T2D, understanding the mechanisms by which GLP-1R agonists such as liraglutide and semaglutide improve cardiac function is essential. Yet despite strong evidence from preclinical and clinical studies supporting the cardioprotective actions of GLP-1R agonists, the precise mechanism(s) by which this drug-class for T2D may produce these beneficial actions remains enigmatic. Negligible GLP-1R expression in ventricular cardiac myocytes suggests that GLP-1R agonist-induced cardioprotection is likely partially attributed to indirect actions on peripheral tissues other than the heart. Because insulin increases glucose oxidation, whereas glucagon increases fatty acid oxidation in the heart, GLP-1R agonist-induced increases and decreases in insulin and glucagon secretion, respectively, may modify cardiac energy metabolism in T2D patients. This may represent a potential mechanism for GLP-1R agonist-induced cardioprotection in T2D, as increases in fatty acid oxidation and decreases in glucose oxidation are frequently observed in the hearts of animals and human subjects with T2D. PMID- 29412839 TI - Delirium in the Elderly. AB - Delirium is defined as an acute disturbance in attention and cognition, with significant associated morbidity and mortality. This article discusses the basic epidemiology of delirium and approaches to diagnosing, assessing, and working up patients for delirium. It delineates the pathophysiology and underlying predisposing and precipitating factors for delirium. It also discusses recent advances in prevention and treatment, particularly multicomponent, nonpharmacological interventions. PMID- 29412840 TI - Neurologic Changes and Depression. AB - This article covers current research on the relationship between depression and cognitive impairment in older adults. First, it approaches the clinical assessment of late-life depression and comorbid cognitive impairment. Cognitive risk factors for suicide are discussed. Research is then provided on neuropsychological changes associated with depression, discussing subjective cognitive impairment, mild cognitive impairment, and dementia profiles. Additionally, literature regarding neuroimaging and biomarker findings in depressed older adults is presented. Finally, therapeutic models for treatment of late-life depression are also discussed, including psychotherapy models, holistic treatments, pharmacologic approaches, and brain-stimulation therapies. PMID- 29412841 TI - Managing Behavioral and Psychological Symptoms of Dementia. AB - Behavioral and psychological symptoms of dementia (BPSD) are universally experienced by people with dementia throughout the course of the illness and cause a significant negative impact on quality of life for patients and caregivers. Nonpharmacologic treatments have been recommended as first-line treatment of BPSD by multiple professional organizations and should target patients with dementia factors, caregiver factors, and environmental factors. Psychotropic medications are often prescribed off-label without significant evidence to support their use. The Describe, Investigate, Create, Evaluate approach can provide a structured method to investigate and treat BPSD with flexibility to use in multiple treatment settings. PMID- 29412842 TI - Palliative Care for Dementia. AB - With the growing care needs for the older population at the end of their lives, there has been a substantial increase in attention to the management of the patient with dementia in hospice and palliative care services. This article reviews issues in access to care and the optimal management of the patient with dementia, particularly in the context of neuropsychiatric complexities. Special issues such as delirium, cachexia, behavioral symptoms, and pain management are addressed. Future challenges in research such as the development of better prognostic models are noted as well as the importance of attention to access to care. PMID- 29412843 TI - Integrated Care for Older Adults with Serious Mental Illness and Medical Comorbidity: Evidence-Based Models and Future Research Directions. AB - The excess risk of early mortality, medical comorbidity, early institutionalization, and high costs among older adults with serious mental illness necessitates development and dissemination of effective and sustainable integrated care models that simultaneously address mental and physical health needs. This overview highlights current, evidence-based integrated care models, which predominantly adopt the following approaches: (1) psychosocial skills training, (2) integrated illness self-management, and (3) collaborative care and behavioral health homes. Finally, innovative models that build on these approaches by incorporating novel uses of telehealth, mobile health technology and peer support, and strategies from developing economies are discussed. PMID- 29412844 TI - Posttraumatic Stress Disorder in the Elderly. AB - Posttraumatic stress disorder (PTSD) can occur at any point in the life span and can last for decades. Chronic PTSD can affect quality of life and have a negative impact on physical function and health in the elderly and may be associated with premature aging and dementia. It is critical that clinicians screen for trauma based symptoms and to treat as appropriate. PMID- 29412845 TI - Hearing Loss: The Silent Risk for Psychiatric Disorders in Late Life. AB - Hearing loss is among the most frequent problems experienced by older adults, yet psychiatrists and other clinicians often ignore the problem as an aggravation rather than recognizing that the problem might benefit from appropriate hearing health care. Many psychiatric disorders have been associated with hearing loss, including depression, schizophrenia and other psychoses, anxiety, and neurocognitive disorders. In this article, hearing loss among older adults is reviewed, with special attention directed toward the recognition and proper referral to a hearing health care provider. Finally, major advances in hearing health care are discussed. PMID- 29412846 TI - Depression and Cardiovascular Disorders in the Elderly. AB - The world's older population continues to grow at an unprecedented rate. This trend amplifies the necessity of improving the care of older patients with chronic health problems. Of those with chronic health problems, those with cardiovascular diseases and depression are particularly challenging due to the multifaceted nature of these conditions. This review discusses the significance of this aging trend and ways to better care for this particular population. PMID- 29412847 TI - Advances in the Conceptualization and Study of Schizophrenia in Later Life. AB - A crisis looms as research and clinical programs have not kept pace with dramatic increases in the number of older adults with schizophrenia. This article provides an overview of the advances in the conceptualization and study of schizophrenia in later life. Theoretic and clinical models in psychiatry and gerontology are integrated. Specifically, recovery is examined in the context of aging, how clinical dimensionality affects diagnoses in older adults, how various features of schizophrenia are implicated in models of accelerated and paradoxic aging, and how outcome in later life is a more dynamic and heterogeneous than assumed previously. PMID- 29412848 TI - Anxiety Disorders in Late Life. AB - Anxiety disorders in later life are some of the most significant mental health problems affecting older adults. Prevalence estimates of anxiety disorders in late life vary considerably based on multiple methodological issues. Current diagnostic criteria may not adequately capture the nature and experience of anxiety in older people, particularly those in ethnic and racial minority groups. This article reviews late-life anxiety disorders. Pharmacologic and psychotherapy approaches to treat late-life anxiety are reviewed, including a summary of current innovations in clinical care across settings, treatment models, and treatment delivery. PMID- 29412849 TI - Evaluating Cognitive Reserve Through the Prism of Preclinical Alzheimer Disease. AB - The concept of cognitive reserve (CR) was proposed to account for the discrepancy between levels of brain pathologic features or damage and clinical and cognitive function. This article provides a detailed review of prospective longitudinal studies that have investigated the interaction between CR and Alzheimer's disease (AD) biomarkers on clinical and cognitive outcomes among individuals with preclinical AD. Current evidence shows that higher levels of CR are associated with a delay in the onset of symptoms of mild cognitive impairment and that there may be multiple pathways by which CR exerts its protective effects. PMID- 29412850 TI - Electroconvulsive Therapy in Geriatric Psychiatry: A Selective Review. AB - Electroconvulsive therapy (ECT) remains an important treatment of geriatric patients. ECT treats severe depression, mania, psychosis, catatonia, and comorbid depression and agitation in dementia. ECT also serves a crucial role in treating urgent illness requiring expedient recovery, such as catatonia, or in patients with severe suicidal ideation or intent. ECT is even more effective in the elderly than in mixed-age adult populations. ECT is a safe treatment option with few medical contraindications. Cognitive effects are largely transient, even in patients with preexisting cognitive impairment. PMID- 29412851 TI - Older Age Bipolar Disorder. AB - Further understanding of older age bipolar disorder (OABD) may lead to more specific recommendations for treatment adjusted to the specific characteristics and needs caused by age-related somatic and cognitive changes. Late-onset mania has a broad differential diagnosis and requires full psychiatric and somatic work up, including brain imaging. Research on pharmacotherapy in OABD is limited. First-line treatment of OABD is similar to that for adult bipolar disorder (BD), with specific attention to vulnerability to side effects and somatic comorbidity. Because findings in younger adults with BD cannot be extrapolated to OABD, more research in OABD is warranted. PMID- 29412857 TI - Geriatric Psychiatry. PMID- 29412861 TI - Erratum. PMID- 29412864 TI - Flavonoid fraction of Cajanus cajan prohibited the mutagenic properties of cyclophosphamide in mice in vivo. AB - Cajanus cajan (L.) is a Pigeon pea cultivated in tropical and subtropical areas. It contains many bioactive components. The present study aimed to assess the antimutagenic efficacy of a flavonoid fraction of Cajanus cajan (FFCC) to reduce cytotoxicity and genotoxicity induced by cyclophosphamide (CP). We assessed genotoxic and cytotoxic effects using chromosome aberration, in mouse bone-marrow cells and spermatocytes, cell viability and DNA damage, in mouse bone-marrow cells. Animals received FFCC at concentrations 50,100 and 200 mg/kg b wt by oral gavage, and injected simultaneously with CP (20 mg/kg b wt) for 24 h. The results revealed that FFCC was safe and its effect was normal compared to control group. Moreover, we observed significant inhibition of CP-induced chromosome abnormalities in both, somatic and germ, cells (p ? 0.05) after concurrent administration of different concentrations of FFCC and CP. FFCC reduced chromosome aberrations by 14.29%, 25.21% and 28.57% in somatic cells, and 25.35%, 35.21% and 49.29% in germ cells after simultaneous treatment with CP respectively. Additionally, FFCC improved the cell viability of bone-marrow cells in a concentration-dependent manner when administered concurrently with CP. Similarly, FFCC diminished DNA damage (p ? 0.05) in CP-treated animals. The inhibitory index of tail DNA (%) reached 90.6% at the highest concentration of FFCC when administered simultaneously with CP. In conclusion, the flavonoid extract improved cell viability and protected animal cells from the cytotoxic and genotoxic effects exhibited by CP. Cajanus cajan flavonoids might contain the antioxidant bioactivity that effectively lessened chromosome aberrations and DNA damage induced by mutagenic agents. PMID- 29412865 TI - Interactive potential of genetic polymorphism in Xenobiotic metabolising and DNA repair genes for predicting lung cancer predisposition and overall survival in North Indians. AB - INTRODUCTION: Cancer, a multi-step, multifactorial and multi-gene disease, not only damages the genomic integrity of the cell but also hinders the DNA repair mechanisms of the body. Gene-gene and gene environment interactions amongst the genetic polymorphisms together modulate the susceptibility towards a cancer. We have studied the high order gene interactions between the genetic polymorphism of detoxifying genes (CYP1A1, Ahr, XRCC and GST1) that play a key role in the metabolism of the xenobiotics and have been proved to be prognostic markers for lung cancer METHODS: 237 cases and 250 controls have been genotyped using PCR RFLP technique. In order to find out the association, unconditional logistic regression approach was used and to analyse high order interactions MDR and CART was used. RESULTS: In the MDR analysis, the best model was one factor model which included GSTM1 (CVC 10/10, Prediction error = 0.43, p < .001). The best three factor model comprised of XRCC1 632, XRCC1 206, GSTM1 (CVC 10/10, Prediction error = 0.45, p < .0001). The CART analysis exhibited that Node 1 carrying mutant type of GSTM1 imposed the highest risk towards lung cancer (OR = 11.0, 95%C.I. = 6.05-20.03, p = .000001). Wild type of GSTM1 when combined with mutant type of CYP1A1 M2 and XRCC1 632, an 8 fold risk towards lung cancer was observed (95%C.I. = 4.07-16.29, p = .00001). The high order interactions were used to predict the prognosis of lung cancer patients. Of all the genetic variants, XRCC1 632, GSTM1 and AhR rs2066853 was the most important determinant of overall survival of lung cancer patients CONCLUSION: Through the study we introduced the concept of polygenic approach to get an insight about the various polymorphic variants in determining cancer susceptibility. Lesser number of subjects were found in the high risk subgroups. Further studies with larger sample size are required to warranty the above findings. PMID- 29412866 TI - Cypermethrin: Oxidative stress and genotoxicity in retinal cells of the adult zebrafish. AB - Cypermethrin (CM), widely used for control of indoor and field pests, is one of the most common contaminants in freshwater aquatic systems. We evaluated CM genotoxicity and the activities of superoxide dismutase (SOD) and catalase (CAT) in retinal cells of adult zebrafish. Histological and immunofluorescence techniques show the presence of apoptotic cells in the zebrafish retina after 9 d of treatment with 0.6 MUg/L CM. Histone gamma-H2AX, a marker of DNA damage, was detected in both outer and inner nuclear layers; caspase-3, an apoptotic marker, was detected in the outer nuclear layer. In the comet assay, the cells were sensitive to hydrogen peroxide-induced DNA damage, showing a dose-dependent response. We observed a positive comet assay response to CM that was dose- and time-dependent. Following exposure to CM, SOD and CAT enzyme activities, and sod and cat mRNA levels, increased. These results indicate that CM causes DNA damage and oxidative stress and can induce apoptosis in retinal cells. PMID- 29412867 TI - Urinary 1-hydroxypyrene and smoking are determinants of LINE-1 and AhRR promoter methylation in coke oven workers. AB - Coke oven emissions (COE) containing polycyclic aromatic hydrocarbons (PAHs) are predominant toxic constituents of particulate air pollution that have been linked to increased risk of lung cancer. Aberrant DNA methylation is one of the best known epigenetic changes in human cancers and healthy subjects exposed to carcinogens. The purpose of this study is to explore the factors influencing the methylation of long interspersed nuclear element-1 (LINE-1) and aryl-hydrocarbon receptor repressor (AhRR) in coke oven workers. The study population is composed by coke oven workers (348) and water treatment workers (131). And their urinary PAH metabolites were analyzed by high performance liquid chromatography; DNA methylation were measured by pyrosequencing. The urinary PAHs metabolites were significantly elevated in coke oven workers (P < 0.01). The results from multivariate logistic regression analysis showed that a high level of urinary 1 hydroxypyrene was associated with a significantly increased risk of hypomethylation of LINE-1 (OR: 1.80; 95% CI: 1.25, 2.60), and heavy smoking was associated with a significantly increased risk of hypomethylation of AhRR (OR: 1.44; 95% CI: 1.04, 2.00). Our findings demonstrate that urinary 1-hydroxypyrene may be a useful biomarker for evaluating the role of PAHs exposure on hypomethylation of LINE-1 among coke oven workers and that smoking may be an important factor affecting hypomethylation of AhRR. PMID- 29412868 TI - Aspirin and ibuprofen, in bulk and nanoforms: Effects on DNA damage in peripheral lymphocytes from breast cancer patients and healthy individuals. AB - Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) may be protective against tumours, including breast cancer. We have studied the effects of ibuprofen and aspirin on DNA damage in lymphocytes obtained from breast cancer patients and healthy female controls. Both nanoparticle (NPs) and bulk formulations were used in the comet and micronucleus (MN) assays. Non-toxic doses (250 ng/ml ibuprofen; 500 ng/ml aspirin) were tested. Aspirin, both bulk and nano formulations, significantly reduced DNA damage measured with the comet and micronucleus assays; the nano formulation was more effective. Ibuprofen was not effective in the comet assay but showed a significant reduction in MN frequency, with the nano formulation being more effective. NPs may have better penetration through the nuclear membrane relative to the bulk formulation. NSAIDs such as aspirin and ibuprofen may have a promising role in cancer prevention and treatment. PMID- 29412869 TI - Folate modulates guanine-quadruplex frequency and DNA damage in Werner syndrome. AB - Guanine-quadruplexes (G4) are stable tetra-stranded DNA structures that may cause DNA replication stress and inhibit gene expression. Defects in unwinding these structures by DNA helicases may result in telomere shortening and DNA damage. Furthermore, due to mutations in WRN helicase genes in Werner syndrome, G4 motifs are likely to be key elements in the expression of premature aging phenotypes. The methylation of DNA plays a significant role in the stability and occurrence of G4. Thus, G4 frequency and DNA methylation mechanisms may be affected by excesses or deficiencies in methyl donors such as folate. B-Lymphocytes from Werner patients (n = 5) and healthy individuals (n = 5) were cultured in RPMI medium under condition of folate deficiency (20 nM) or sufficiency (200 nM) for 14 days. Cells were fixed on microscope slides for immunofluorescent staining to measure G4 frequency and gammaH2AX (a marker of DNA strand breaks) intensity, using automated quantitative imaging fluorescent microscopy. There was a significant increase (p < 0.05) in G4 levels in Werner syndrome patients compared to healthy controls. Werner and control cells grown in 20 nM folate media also showed significant increases in G4 (p < 0.001) and gammaH2AX (p < 0.01) signals compared with the same cells grown in 200 nM folate. Control cells grown in 20 nM folate also showed a significant reduction in DNA methylation levels (P < 0.05). The results of this study suggest that the occurrence of DNA G4 structures can be modulated in vitro via nutrients with important roles in methylation. PMID- 29412870 TI - Assessing the impact of benzo[a]pyrene with the in vitro fish gut model: An integrated approach for eco-genotoxicological studies. AB - In vitro models are emerging tools for reducing reliance on traditional toxicity tests, especially in areas where information is sparse. For studies of fish, this is especially important for extrahepatic organs, such as the intestine, which, until recently, have been largely overlooked in favour of the liver or gill. Considering the importance of dietary uptake of contaminants, the rainbow trout (Oncorhynchus mykiss) intestine-derived cell line RTgutGC was cultured, to test its suitability as a high-throughput in vitro model. Benzo[a]pyrene (B[a]P) is an important contaminant and a model polycyclic aromatic hydrocarbon (PAH). Over 48 h exposure, a range of endpoints and xenobiotic metabolism rates were examined at three different pH levels indicative of the in vitro (pH 7.5) and in vivo mid-gut (pH 7.7) and hind-gut (pH 7.4) regions as a function of time. These endpoints included (i) cell viability: acid phosphatase (APH) and lactate dehydrogenase (LDH) assays; (ii) glucose uptake; (iii) cytochrome P450 enzyme activity: 7 ethoxyresoorufin-O-deethylase (EROD) assay; (iv) glutathione transferase (GST) activity; (v) genotoxic damage determined using the comet assay. Absence of cell viability loss, in parallel with decrease in the parent compound (B[a]P) in the medium and its subsequent increase in the cells suggested active sequestration, biotransformation, and removal of this representative PAH. With respect to genotoxic response, significant differences were observed at both the sampling times and the two highest concentrations of B[a]P. No significant differences were observed for the different pH conditions. Overall, this in vitro xenobiotic metabolism system appears to be a robust model, providing a basis for further development to evaluate metabolic and toxicological potential of contaminants without use of animals. PMID- 29412871 TI - In vivo antimutagenic and antiatherogenic effects of the (1 -> 3)(1 -> 6)-beta-d- glucan botryosphaeran. AB - The antimutagenic effect of botryosphaeran, an exocellular (1 -> 3)(1 -> 6)-beta d-glucan, from the ascomyceteous and plant-borne endophytic fungus, Botryosphaeria rhodina MAMB-05, was evaluated in young (6-8 weeks) and elderly (18 months) Swiss albino mice of both genders. The hypolipidemic, hypoglycemic and antiatherogenic potential was also evaluated in 18-month old male LDL receptor knockout (LDLr-/-) mice. Administration of botryosphaeran by gavage (doses: 7.5, 15, 30 mg/kg b.w./day) in a 30-day pretreatment protocol (young mice), or 15-day protocol (older mice), did not cause genotoxicity as assessed by the micronucleus test in peripheral blood (PB) and bone marrow cells (BMCs). Furthermore, there was no cytotoxic effect of this beta-d-glucan in the treatments. A lower frequency of micronuclei was observed in BMCs from young and old mice that received botryosphaeran, indicating its antimutagenic effect. Botryosphaeran (30 mg/kg b.w./day) promoted 102.22% (young) and 103.45% (elderly) reductions in cyclophosphamide-induced damage in male mice. Botryosphaeran also exerted chemoprotective effects in LDLr-/- and wild-type (C57BL/6) mice. Botryosphaeran treatment for 15 days at a dose of 30 mg/kg b.w./day improved the lipidic profile (reductions of 53.8-84.3%), and decreased aortic lipid deposition (32.8%) in the LDLr-/- atherosclerotic mice. The results indicate botryosphaeran has relevant biologic effects, making it a promising candidate for the development of new therapeutic agents. PMID- 29412872 TI - Editorial. PMID- 29412873 TI - Laboratories as the Core for Health Systems Building. AB - If it is accepted that health care access to diagnosis and treatment is a universal human right, the principal challenge is how to deliver that health care to all people. Health systems that function are the most effective way to deliver such care; these health systems should cover all of the diseases facing a population. The central role of laboratories in making medical decisions is crucial. If organizations engaged in health systems building tackle a disease category, such a cancer, multiple modalities within and outside of the laboratory have to be improved or installed to make an effective system. PMID- 29412874 TI - Building Laboratory Capacity to Strengthen Health Systems: The Partners In Health Experience. AB - The diagnostic laboratory is essential to patient care and to the achievement of health equity. Through the development of quality laboratories in settings burdened by poverty and weak health systems, Partners In Health has demonstrated the critical contributions of clinical laboratories to the care of patients with HIV, tuberculosis, and cancer, among other conditions. The lessons learned through the organization's experience include the importance of well-trained and well-supported staff; reliable access to supplies, reagents, and diagnostic equipment; adequate facilities to provide diagnostic services; the integration of laboratories into networks of care; and accompaniment of the public health sector. PMID- 29412875 TI - Voices from the Field: Interviews with Global Health Pathology Volunteers. AB - Volunteerism in pathology is an uncommon experience. This article attempts to shed light on this experience based on guided narrative interviews. The authors' interviews suggest that prototypical pathology volunteers participate in long term missions, tend to be later in their careers, are motivated by personal reasons, get involved in volunteering through nongovernmental organizations, focuses on capacity building, and at least partially self-funds their efforts. PMID- 29412876 TI - Building Cross-Country Networks for Laboratory Capacity and Improvement. AB - Laboratory networks are vital to well-functioning public health systems and disease control efforts. Cross-country laboratory networks play a critical role in supporting epidemiologic surveillance, accelerating disease outbreak response, and tracking drug resistance. The East Africa Public Health Laboratory Network was established to bolster diagnostic and disease surveillance capacity. The network supports the introduction of regional quality standards; facilitates the rollout and evaluation of new diagnostic tools; and serves as a platform for training, research, and knowledge sharing. Participating facilities benefitted from state-of-the art investments, capacity building, and mentorship; conducted multicountry research studies; and contributed to disease outbreak response. PMID- 29412877 TI - Strengthening Laboratory Management Toward Accreditation, A Model Program for Pathology Laboratory Improvement. AB - The Strengthening Laboratory Management Toward Accreditation (SLMTA) program and subsequent Stepwise Laboratory Quality Improvement Process Toward Accreditation (SLIPTA) checklist were a response to the need for high-quality laboratories to combat the human immunodeficiency virus (HIV) epidemic and provide patients with the highest-quality care. The two tools work together to create a culture of quality in laboratories and allow the identification of gaps. The ultimate goal for any laboratory is to achieve a standard benchmark for quality and these programs have been highly successful in initially affecting the HIV epidemic but continuously improving laboratory quality across all diseases. PMID- 29412878 TI - Practical Successes in Telepathology Experiences in Africa. AB - Across much of Africa, there is a critical shortage of pathology services necessary for clinical care. Even in settings where specialty-level clinical care, such as medical oncology, is available, access to anatomic pathology services has often lagged behind. Pathology laboratories in the region are challenging to establish and maintain. This article describes the successful implementation of telepathology services in Malawi and reviews other successful programs developed to support diagnostic pathology in resource-limited settings. PMID- 29412879 TI - World Health Organization List of Priority Medical Devices for Cancer Management to Promote Universal Coverage. AB - Universal coverage of basic laboratory services is fundamental to achieving sustainable development goals and attaining health for all. Yet, comprehensive laboratory services are unavailable to large percentages of the global population. To help policymakers identify a basic package of services for cancer, the World Health Organization (WHO) published Priority Medical Devices for Cancer Management. The package of services includes key interventions, associated devices and technologies, and the requirements for health workforce and infrastructure. These services must be linked to national strategic policies and plans and regulatory and quality assurance processes. PMID- 29412881 TI - Cytopathology in Low Medical Infrastructure Countries: Why and How to Integrate to Capacitate Health Care. AB - Fine-needle aspiration cytology is a rapid, accurate, minimally invasive, inexpensive biopsy technique requiring minimal laboratory infrastructure and proceduralist costs. It provides infectious and noncommunicable disease diagnoses and will play an essential role in the establishment of cancer services in low income and middle-income countries (LMICs). The use of molecular and other ancillary tests on cytology material is rapidly expanding in high-income countries and will spread to LMICs. Establishing cytology services requires increased training of cytopathologists and cytotechnologists, increased education of clinicians in the use of diagnostic cytopathology, and commitment and funding from governments and specialist training groups. PMID- 29412880 TI - Breast Cancer in Low- and Middle-Income Countries: Why We Need Pathology Capability to Solve This Challenge. AB - Breast cancer is the leading cause of cancer mortality among women in developing countries. Timely and accurate histopathological diagnosis of breast cancer is critical to delivering high-quality breast cancer care to patients in low- and middle-income countries (LMIC). The most important prognostic factors in breast cancer along with tumor size and nodal status are tumor grade, estrogen receptor status, as well as HER2 status in countries where specific targeted therapies are available. In addition, detailed and complete cancer registry data are needed to assess a country's disease burden and guide disease prioritization and allocation of resources for breast cancer treatment. Innovations in leapfrog technology and low-cost point-of-care tests for molecular evaluations are needed to provide accurate and timely pathology, with the ultimate goal of improving survival outcomes for patients with breast cancer in LMIC. PMID- 29412882 TI - Biospecimens and Biobanking in Global Health. AB - Biobanks provide a critical infrastructure to support research in human health. Biospecimens and their accompanying data are increasingly needed to support biomedical research and clinical care. The original text was initially published in the Handbook for Cancer Research in Africa. The value of this publication is great as it underlines the importance of biobanks in Africa as a key resource to increase quality scientific research and participate in global health research. Therefore, a revision to extend these principles to other low resource contexts, to include updated material and references and add the topic of biobank sustainability were relevant. PMID- 29412883 TI - Global Health Pathology Research: Purpose and Funding. AB - Like in all areas of science, it is important for funders and investigators of pathology to work together to develop a well-designed, well-executed clinical research agenda. In the first section of this article, the authors discuss how the National Institutes of Health (NIH) peer-review process applies to global health pathology research projects. Then, the authors present an illustrative sampling of NIH-funded projects with performance sites in low- and middle-income countries with 2 examples focused on cancer and anatomic pathology. Finally, the authors relate the research agenda to overarching strategic recommendations for enhancing global pathology. PMID- 29412884 TI - Training the Next Generation of African Pathologists. AB - Quality patient care requires correct and timely evidence-based diagnoses. Pathology and laboratory medicine training varies significantly across the continent, but is inadequate to serve the needs of the population. This article summarizes the current state of pathology workforce and training in sub-Saharan Africa; discusses challenges to recruitment and retention; and outlines the necessary elements for training and sustaining a robust workforce in pathology and laboratory medicine. The authors provide several case studies of institutions around the continent that include expansion of existing programs, a de novo program, South-South collaborations, and skill building for the existing workforce. PMID- 29412885 TI - From Access to Collaboration: Four African Pathologists Profile Their Use of the Internet and Social Media. AB - The shared practice of pathology via the Internet holds great potential for pathologists in sub-Saharan Africa (SSA) and their global partners. Application of the Internet is constrained by issues of bandwidth, cost, and power. The penetration of mobile telephony and the arrival of smartphones have changed the use of Internet and social media in Africa and therefore the work of the 4 African pathologists featured in this article. As pathology in SSA struggles for visibility and usefulness, the Internet and its electronic applications provide a critical infrastructure as well as a podium for pathologists across the continent. PMID- 29412888 TI - Global Health and Pathology. PMID- 29412893 TI - Pathology: Central and Essential. PMID- 29412886 TI - Pathology-Based Research in Africa. AB - The process of conducting pathology research in Africa can be challenging. But the rewards in terms of knowledge gained, quality of collaborations, and impact on communities affected by infectious disease and cancer are great. This report reviews 3 different research efforts: fatal malaria in Malawi, mucosal immunity to HIV in South Africa, and cancer research in Uganda. What unifies them is the use of pathology-based approaches to answer vital questions, such as physiology, pathogenesis, predictors of clinical course, and diagnostic testing schemes. PMID- 29412887 TI - Lymphoma and Pathology in Sub-Saharan Africa: Current Approaches and Future Directions. AB - The care of patients with lymphoma relies heavily on accurate tissue diagnosis and classification. In sub-Saharan Africa, where lymphoma burden is increasing because of population growth, aging, and continued epidemic levels of human immunodeficiency virus infection, diagnostic pathology services are limited. This article summarizes lymphoma epidemiology, current diagnostic capacity, and obstacles and opportunities for improving practice in the region. PMID- 29412894 TI - [In process]. PMID- 29412895 TI - Executive summary: Diagnosis and Treatment of Catheter-Related Bloodstream Infection: Clinical Guidelines of the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC) and the Spanish Society of Intensive Care Medicine and Coronary Units (SEMICYUC). AB - Catheter-related bloodstream infections (CRBSI) constitute an important cause of hospital-acquired infection associated with morbidity, mortality, and cost. The aim of these guidelines is to provide updated recommendations for the diagnosis and management of CRBSI in adults. Prevention of CRBSI is excluded. Experts in the field were designated by the two participating Societies (Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica and the Sociedad Espanola de Medicina Intensiva, Critica y Unidades Coronarias). Short-term peripheral venous catheters, non-tunneled and long-term central venous catheters, tunneled catheters and hemodialysis catheters are covered by these guidelines. The panel identified 39 key topics that were formulated in accordance with the PICO format. The strength of the recommendations and quality of the evidence were graded in accordance with ESCMID guidelines. Recommendations are made for the diagnosis of CRBSI with and without catheter removal and of tunnel infection. The document establishes the clinical situations in which a conservative diagnosis of CRBSI (diagnosis without catheter removal) is feasible. Recommendations are also made regarding empirical therapy, pathogen-specific treatment (coagulase-negative staphylococci, Sthaphylococcus aureus, Enterococcus spp, Gram-negative bacilli, and Candida spp), antibiotic lock therapy, diagnosis and management of suppurative thrombophlebitis and local complications. PMID- 29412896 TI - Preparing for the next Ebola epidemic. AB - Two years after an enormous international effort overcame the catastrophic Ebola virus epidemic in West Africa, research is now making the first steps towards better understanding, treatment and prevention of the disease. However, many scientific questions are still left to be answered and Ebola remains a threat. Michael Gross reports. PMID- 29412897 TI - Martin Raff. AB - Interview with Martin Raff, Emeritus Professor of Cell Biology and Affiliated Member of the MRC Laboratory for Molecular Cell Biology at University College London, by Jordan Raff, group leader at the Sir William Dunn School of Pathology, University of Oxford. PMID- 29412898 TI - Combination effects of NaOH and NaCl on the rheology and gel characteristics of hen egg white proteins. AB - The effects of NaOH and NaCl on the rheology and gel properties of hen egg white were investigated. As the concentration of NaOH increased, egg white gel exhibited lower opacity and particle turbidity with coincidental increase in zeta potential, while the addition of NaCl resulted in the formation of opaque egg white gel and increase of surface hydrophobicity, particle turbidity and zeta potential. Rheological tests showed that alkali treatment will affect the unfolding state of egg white proteins during the heat stage while NaCl addition can inhibit the unfolding of egg white proteins. The results of correlation analysis indicated that random coil and alpha-helix were in good correlation with gel textural properties. Therefore, the rheology and gel properties of alkali/salt-induced egg white dispersions were closely related to the changes in surface hydrophobicity, molecule surface charge, and protein secondary structure. PMID- 29412899 TI - Chromium speciation in foodstuffs: A review. AB - Numerous critical reviews have evaluated exposure to toxic and carcinogenic hexavalent chromium (Cr(VI)) from a number of pathways; including workplace air, cement and packaging materials. The contribution of foodstuffs to dietary Cr(VI) has been increasingly under investigation, however no summary of this work has been carried out. The objective of this article is to review the last twenty years of chromium speciation research in foodstuffs. Alkaline extraction, used for chromium speciation in other solids, is the most widely-reported procedure. Previous measurement of Cr(VI) in foodstuffs is questionable due to the reducing power of organic matter and antioxidants, leading to the development of speciated isotope dilution mass spectrometry (SIDMS) techniques to monitor interconversions. Evaluation of the genotoxicity of trivalent chromium (Cr(III)), which acts through a different pathway to that of Cr(VI), requires reconsideration towards measurement of Cr(III), which is present at higher concentrations in foodstuffs following reduction of the more-bioavailable Cr(VI). PMID- 29412900 TI - Extraction techniques and analysis of anthocyanins from food sources by mass spectrometry: An update. AB - This article reviews recent developments in methods of sample preparation and analytical methodologies for the quantification of anthocyanins and their extraction from food sources. Various methods for sample extraction and purification are highlighted and evaluated. The use of UV-diode array, along with improved liquid chromatography (LC) and mass spectrometry (MS) and/or the combination of both methods have facilitated the identification of analytes. The use of one-dimensional and two-dimensional HPLC has significantly improved resolution with a shorter amount of time. Other LC * LC combinations to improve orthogonality are also discussed. The most efficient anthocyanin extraction method from food sources is pressurized liquid extraction. Moreover, electrospray ionization (ESI) and MS2/time-of-flight are currently the most popular instruments used for identification of anthocyanins; being positive mode of ESI the most widely used procedure for anthocyanin identification. Several databases for mass spectrometry polyphenol identification have been described for reference. PMID- 29412901 TI - Determination of virginiamycin M1 residue in tissues of swine and chicken by ultra-performance liquid chromatography tandem mass spectrometry. AB - A reliable UPLC-MS/MS method with high sensitivity was developed and validated for the determination of virginiamycin M1 in muscle, fat, liver, and kidney samples of chicken and swine. Analytes were extracted using acetonitrile and extracts were defatted by N-hexane. Chromatographic separation was performed on a BEH C18 liquid chromatography column. The analytes were then detected using triplequadrupole mass spectrometry in positive electrospray ionization and multiple reaction monitoring mode. Calibration plots were constructed using standard working solutions and showed good linearity. Limits of quantification ranged from 2 to 60 ng mL-1. PMID- 29412902 TI - Development of direct competitive biomimetic immunosorbent assay based on quantum dot label for determination of trichlorfon residues in vegetables. AB - A direct competitive biomimetic immunosorbent assay method based on molecularly imprinted polymer was developed for the determination of trichlorfon. A CdSe/ZnS quantum dot label was used as the marker. The hydrophilic imprinted film was synthesized directly on the surface of a 96-well plate, and characterized by Fourier-transform infrared spectroscopy and thermo-gravimetric analyses. The method exhibited high stability, selectivity, and sensitivity. Under optimal conditions, the limits of detection and sensitivity of the biomimetic immunosorbent assay method were 9.0 MUg L-1 and 5.0 mg L-1 (0.1 mg kg-1 and 62.5 mg kg-1 for vegetable sample), respectively. Low cross-reactivity values of 19.2% and 15.6% were obtained for the structural analogues. Spinach and rape samples spiked with trichlorfon were extracted and determined by this method with recoveries ranging from 83.6% to 91.1%. The method was applied for the detection of trichlorfon residues in leek and cucumber samples, and results correlated well with those obtained using GC. PMID- 29412903 TI - Sucrose capped gold nanoparticles as a plasmonic chemical sensor based on non covalent interactions: Application for selective detection of vitamins B1 and B6 in brown and white rice food samples. AB - We report simple and selective method for detection of vitamins B1 and B6 in brown and white rice samples using localized surface plasmon resonance (LSPR) of sucrose capped gold nanoparticles (AuNPs) as a chemical sensor colorimetrically. Here, detection is based on the color change of AuNPs from pink to blue followed by a red shift of LSPR absorption band in UV-vis region with the addition of vitamins B1 and B6 into the NPs solution. A good linear range was observed in the range of 25-1000 ngmL-1 with detection limit of 8 ngmL-1 for B1 and 50-1000 ngmL 1 with detection limit of 15 ngmL-1 for vitamins B6. The employment of AuNPs for detection of B1 and B6 vitamins in rice food samples showed remarkable abilities in terms of the simplicity, low cost, stability, reproducibility and sensitivity. PMID- 29412904 TI - Pulse seed germination improves antioxidative activity of phenolic compounds in stripped soybean oil-in-water emulsions. AB - The purpose of this study was to investigate antioxidative activity of phenolic compounds extracted from germinated pulse seed including chickpeas, lentils and yellow peas. Phenolic compounds were extracted at different germination time and total phenolic content was examined by Folin Ciocalteu's reaction. Antioxidative activity of extracts was characterized by in vitro assay including 2, 2-diphenyl 1-picrylhydrazyl radical scavenging capacity (DPPH), oxygen radical absorbance capacity (ORAC), iron-binding assay, and in stripped soybean oil-in-water emulsions. The results suggested that germination time is critical for phenolic compounds production. The form variation of phenolic compounds influenced the antioxidative activity of phenolic compounds both in vitro assay and in emulsion systems. Soluble bound phenolic compounds showed higher antioxidative ability in emulsion system with the order of chickpea > yellow pea > lentil. On the basis of these results, soluble bound phenolic compounds may be considered as a promising natural antioxidant to prevent lipid oxidation in foods. PMID- 29412905 TI - Effect of lactobacillus strains on phenolic profile, color attributes and antioxidant activities of lactic-acid-fermented mulberry juice. AB - This study was conducted to investigate the effect of lactic acid bacteria (LAB) strains on color properties, phenolic profile and antioxidant activities of mulberry juice. Mulberry juice was separately fermented at 37 degrees C for 36 h using Lactobacillus plantarum, Lactobacillus acidophilus and Lactobacillus paracasei. The results showed that lactic acid fermentation impacted on the color of the juice. Moreover, the study demonstrated that LABs impacted on the phenolic profile of the juice. Syringic acid, cyanidin-3-O-rutinoside and quercetin were the predominant phenolic acid, anthocyanin and flavonol respectively in the lactic-acid-fermented mulberry juice. The degree of radical scavenging activity was species-specific with the L. plantarum fermented juice having the highest radical scavenging activities. The correlation analysis demonstrated that flavonols and anthocyanins were mostly responsible for the increased in 2,2' azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) scavenging activity while phenolic acids and flavonols were responsible for 2,2-diphenyl-1-picrylhydrazyl scavenging activity and reducing power capacity of the fermented juice. PMID- 29412906 TI - Determination of furan and furan derivatives in baby food. AB - A Headspace-Solid Phase Microextraction-Gas Chromatography-Mass Spectrometry (HS SPME-GC-MS) method was developed and validated for the simultaneous determination of furan, 2-methylfuran, 2-ethylfuran, 2-butylfuran, 2-pentylfuran, 2 acetylfuran, furfural and furfuryl alcohol in jarred baby food. The method was specific for the analytes. Good precision was obtained both in terms of intra-day repeatability (RSD <= 5.02) and inter-day precision (RSD <= 5.55%). The recovery values were between 98.42% and 99.8%. Linearity was established over two order of magnitude, and the achieved LODs and LOQs ranged between 0.018 and 0.035 ng/g and 0.060-0.117 ng/g, respectively, depending on the analyte. Finally, the method was successfully applied to investigate the content of furan and furan derivatives in several commercial baby food samples containing fruit or meat. The results showed that this simple, rapid and solvent free procedure could be used routinely for the analysis of baby food providing competent quantitative data functional to risk assessment. PMID- 29412907 TI - Investigation on antioxidant, angiotensin converting enzyme and dipeptidyl peptidase IV inhibitory activity of Bambara bean protein hydrolysates. AB - Protein isolate was hydrolysed by Alcalase, thermolysin and trypsin. BBPH produced by Alcalase showed highest angiotensin-converting enzyme (ACE) inhibitory properties (IC50: 52 ug/mL). Hydrolysates produced by Alcalase and thermolysin exhibited similar dipeptidyl peptidase-IV (DPP-IV) inhibitory activity (IC50: 1.73 mg/mL), while low inhibitory activity was observed for hydrolysate produced by trypsin. BBPH also showed protective effect against oxidative stress with significant 2,2-diphenyl-1-picrylhydrazyl radical scavenging and ferrous chelating activity. Bioactive peptides of BBPH produced by thermolysin showed better resistance to simulated gastrointestinal digestion (SGID), while the DPP-IV and ACE inhibitory properties were significantly reduced. Molecular weight distribution showed significant reduction in peptides of the molecular weight range 200-400 Da in BBPH produced by Alcalase, after SGID. LC-ESI-TOF-MS and in silico analysis showed the presence of potential peptides with both ACE and DPP-IV inhibitory properties in BBPH produced by thermolysin. PMID- 29412908 TI - Monoclonal antibody-based ELISA for the quantification of porcine hemoglobin in meat products. AB - Misusage of porcine blood proteins, such as misbranding and substitution, can cause religious objections, law violation, and food quality concerns. These issues highlight the need for detecting unlabeled or overuse of porcine blood in foods. Compared with acidic and neutral pHs, porcine hemoglobin (PHb) at alkaline pH retained the best solubility, molecular integrity, and immunoreactivity after heat treatment. PHb at acidic and alkaline pHs remained stable during storage at 4 degrees C for 29 days. A monoclonal antibody (mAb) specific to mammalian hemoglobin, 13F7, was developed. A mAb13F7-based indirect competitive ELISA (icELISA) was optimized for the quantification of PHb in meat products. This assay had a wide working range from 0.5 ppm to 1000 ppm. It was sensitive (limit of detection: 0.5 ppm), precise and reproducible with low inter- and intra coefficient of variances (<20%). This assay is suitable for government, food industry, and third-party authority to surveillance food quality. PMID- 29412909 TI - Peptidomic analysis of antioxidant and ACE-inhibitory peptides obtained from tomato waste proteins fermented using Bacillus subtilis. AB - In this study, tomato seeds were obtained as by-products and submitted to fermentation with the proteolytic strain Bacillus subtilis A14h. The resulting peptide mixture was fractionated and purified through different chromatographic steps. Fractions were assayed for antioxidant and angiotensin converting enzyme (ACE)-inhibitory activities and peptides were identified by using nano-liquid chromatography coupled to mass spectrometry in tandem (nLC-MS/MS). Most of the identified peptides were smaller than 1000 Da and had different aromatic and hydrophobic amino acid residues. Their sequences were novel but some of them showed active domains previously reported in other bioactive peptides. The hexapeptide DGVVYY showed an IC50 value of 2 uM in angiotensin-I converting enzyme (ACE-I) inhibitory activity, whereas the pentapeptide GQVPP displayed a 97% of DPPH activity at 0.4 mM. The results revealed that B. subtilis fermentation of tomato by-products could be a good strategy for obtaining added value peptides that might be used as an ingredient in functional foods and nutraceuticals. PMID- 29412910 TI - Mimicking new receptors based on molecular imprinting and their application to potentiometric assessment of 2,4-dichlorophenol as a food taint. AB - Innovative host-tailored polymers were prepared, characterized and used as recognition elements in potentiometric transducers for the selective quantification of 2,4-dichlorophenol (DCP).The polymer beads were synthesized using DCP as a template molecule, acrylamide (AM),methacrylic acid (MAA) and ethyl methacrylate (EMA) as functional monomers and divinylbenzene (DVB) and ethylene glycol dimethacrylate (EGDMA) as cross-linkers. The sensors were fabricated by the inclusion of MIPs in plasticized polyvinyl chloride (PVC) matrix. Response characteristics of the proposed sensors revealed anionic slopes of -59.2, -49.7 and -80.6 mV/decade with detection limits of 5.6 * 10-5,5.9 * 10 5 and 13.2 * 10-5 mol/L for MIP/AM/DVB, MIP/MAA/DVB and MIP/EMA/EGDMA membrane based sensors, respectively. Good selectivity was observed over common inorganic/organic anions. Validation of the assay method according to IUPAC recommendations was justified ensuring the synthesis of good reliable novel sensors for DCP determination. The method was successfully applied for routine analysis of food taint in fish and fish farms water samples. PMID- 29412911 TI - Analysis of the effects of biopolymer encapsulation and sodium replacement combination technology on the quality characteristics and inhibition of sodium absorption from sausage in mice. AB - The effects of biopolymer encapsulation and sodium replacement combination technology on quality characteristics (i.e., bitter taste) and inhibition of sodium absorption from pork sausage in mice were evaluated. The sausages were divided into three different sodium replacement groups (none, 40%, and 50%) and three different biopolymer encapsulation groups (none, cellulose, and chitosan) in combination. In groups with 50% sodium replacement by KCl and MgCl2, T8 (chitosan encapsulation) showed the highest inhibition of the sodium absorption rate. However, chitosan encapsulation groups (T2, T5, and T8) had higher bitterness and lower overall acceptability than other treatment groups. In contrast, in the group with 40% sodium replacement by KCl, T4 (cellulose encapsulation) exhibited the highest inhibition of sodium absorption without a bitter taste. This is the first report showing that 40-50% sodium replacement combined with 3% cellulose encapsulation reduced sodium absorption from sausage by 60% without causing a bitter taste. PMID- 29412912 TI - Methionine sulfone-containing orbitides, good indicators to evaluate oxidation process of flaxseed oil. AB - This study aimed to explore the possibility of using methionine sulfone (Msn) containing orbitides as indicators to evaluate the oxidation process of flaxseed oils. Results showed that after 4 days' heating, oxidation values slightly increased (p > .05) with significant decrease in methionine (Met)-containing peptides (p < .05) instead of gamma-tocopherol (p > .05). However, as oxidation time continues increasing, oxidation values significantly increased (p < .05) with significant reduction of gamma-tocopherol (p < .05). It demonstrated that Met-containing peptides were more readily oxidized compared with gamma-tocopherol and showed certain antioxidant activity. Besides, high logarithmic correlations were found between oxidation values and Msn-containing orbitides (0.94-1.00), such as between total carbonyl compounds and orbitide [1-8-NalphaC],[1-MetO2]-CLE (64.95 lnx - 52.14, R2 = 0.99, Dingya23 oil). Therefore, in comparison with common oxidation indices, Msn-containing orbitides may be better indicators for evaluating the oxidation process of flaxseed oil with superior separation efficiency, specific information and high stability. PMID- 29412913 TI - ROS-driven and preferential killing of HepG2 over L-02 cells by a short-term cooperation of Cu(II) and a catechol-type resveratrol analog. AB - This study was aimed at understanding why dietary polyphenols with a catechol skeleton tend to exhibit cancer chemopreventive activity by using a catechol-type stilbene (3,4-DHS) as a model molecule. Only a short-term cooperation of 3,4-DHS and exogenous Cu(II) exhibited a strong preferential ability to kill HepG2 cells over normal L02 cells. Mechanism studies reveal that this 3,4-DHS/Cu(II) system could produce extracellularly reactive oxygen species (ROS) and o-quinone through two sequential proton loss electron transfer followed by diffusion of ROS into cells, leading to higher intracellular accumulation of ROS, preferential disruption of redox homeostasis and more effective mitochondria-dependent apoptosis as well as necrosis of HepG2 cells than L-02 cells. This work provides further evidence that dietary catechol-type molecules show chemopreventive activity by virtue of their copper-dependent prooxidant action. PMID- 29412914 TI - Influence of two yeast strains in free, bioimmobilized or immobilized with alginate forms on the aromatic profile of long aged sparkling wines. AB - Production of sparkling wines involve a second alcoholic fermentation and contact with yeast less over an extended period of time, which influences the aroma composition and sensory quality of the resulting wines. Sparkling wines obtained with two yeast strains inoculated as free cells, immobilized in alginate bed and bioimmobilized as biocapsules, were aged during 32 months. Among the volatile compounds, high Odor Activity Values were obtained with isoamyl acetate, ethyl propanoate, ethyl butanoate, ethyl 3-methylbutanoate, ethyl hexanoate, ethyl octanoate, hexanol, 2-methoxy-4-vinylphenol, decanal, octanoic acid, decanoic acid and TDN. Taken together these contribute more than 70% of the overall aromatic series value. Although some results rely more on the yeast strain than the inoculation format, specific aroma compounds were associated with the immobilization format, allowing the classification of sparkling wines by PCA. As a result the aroma quality of sparkling wines could be improved using immobilized yeasts. PMID- 29412915 TI - Molecular interactions governing the incorporation of cholecalciferol and retinyl palmitate in mixed taurocholate-lipid micelles. AB - Cholecalciferol (D3) and retinyl palmitate (RP) are the two main fat-soluble vitamins found in foods from animal origin. It is assumed that they are solubilized in mixed micelles prior to their uptake by intestinal cells, but only scarce data are available on the relative efficiency of this process and the molecular interactions that govern it. The extent of solubilization of D3 and RP in micelles composed of lipids and sodium taurocholate (NaTC) was determined. Then, the molecular interactions between components were analyzed by surface tension and surface pressure measurements. The mixture of lipids and NaTC allowed formation of micelles with higher molecular order, and at lower concentrations than pure NaTC molecules. D3 solubilization in the aqueous phase rich in mixed micelles was several times higher than that of RP. This was explained by interactions between NaTC or lipids and D3 thermodynamically more favorable than with RP, and by D3 self-association. PMID- 29412916 TI - Storage stability of three organophosphorus pesticides on cucumber samples for analysis. AB - The residue sample storage stability of three organophosphorus pesticides, dichlorvos, diazinon, and malathion, under different conditions was investigated. The storage conditions studied included storage time, temperature, and sample form. The addition of extra enzyme to the samples was also studied to investigate its effect on stability. It was found that malathion was more unstable than dichlorvos and diazinon, there was an over 70% loss in 90 days even at -20 degrees C in coarsely chopped form. The pesticide residues were more stable when the cucumber was in homogenate form than coarsely chopped. Furthermore, the addition of catalase increased the degradation of malathion, where there was more decomposition with increasing levels of catalase. However, there was no obvious relationship between degradation of dichlorvos and diazinon and catalase concentration. Overall, this study revealed factors that can be optimized to increase the storage stability of organophosphorus pesticides, where enzyme was one of the main influencing factors. PMID- 29412917 TI - Comparative analysis of Hibiscus sabdariffa (roselle) hot and cold extracts in respect to their potential for alpha-glucosidase inhibition. AB - Roselle (Hibiscus sabdariffa) is a functional food with potential health benefits, consumed either as hot or cold beverage. To ensure quality control of its various products, accurate measurement of active metabolites is warranted. Herein, we propose a combination of ultra-high performance liquid chromatography mass spectrometry (UHPLC-MS) and nuclear magnetic resonance (NMR) analytical platforms for the untargeted characterization of metabolites in two roselle cultivars, Aswan and Sudan-1. The analyses revealed 33 metabolites, including sugars, flavonoids, anthocyanins, phenolic and aliphatic organic acids. Their relative contents in cultivars were assessed via principle component analysis (PCA) and orthogonal projection to latent structures analysis (OPLS). Impact of the different extraction methods (decoction, infusion and maceration) was compared by quantitative 1H NMR spectroscopy, revealing cold maceration to be optimal for preserving anthocyanins, whereas infusion was more suited for recovering organic acids. The metabolite pattern revealed by the different extraction methods was found in good correlation for their ability to inhibit alpha-glucosidase enzyme. PMID- 29412918 TI - Reverse phase protein arrays for the identification/validation of biomarkers of beef texture and their use for early classification of carcasses. AB - The validation of biomarkers and tools for the prediction of beef texture remains a challenging task. In this study, reverse phase protein arrays (RPPA) quantified 29 protein biomarkers in the m. Longissimus thoracis of Charolais cattle sampled early post-mortem. Myosin heavy chain 1 (MHC1, slow-oxidative fibers) and Retinal dehydrogenase 1 (ALDH1A1, oxidative enzyme) discriminated between tender and juicy vs. tough meat with residues classes and are validated as prime biomarkers of beef texture. Several proteins belonging to energy metabolism, heat shock and oxidative stress, cytoskeletal, cell signaling and apoptosis were related with tenderness. Among the unusual proteins, Four and a half LIM domains 1 (FHL1) and Tripartite motif protein 72 (TRIM72) correlated respectively negatively and positively with beef tenderness. Principal component regression was used for the first time to explain beef texture traits using biomarkers. The results are very promising as they revealed sophisticated mechanisms behind the tenderizing process. PMID- 29412919 TI - Effect of thermal treatment and light irradiation on the stability of lycopene with high Z-isomers content. AB - The stability of lycopene with high Z-isomers content during thermal treatment and light irradiation was investigated. Purified (all-E)-lycopene was thermally isomerized to the Z-isomers in dichloromethane (CH2Cl2) at 50 degrees C for 24 h. The total content of the Z-isomers of lycopene reached 56.1%. Then, the mixture of lycopene isomers was stored in the dark at 4, 25, and 40 degrees C for 30 days, and under light irradiation using a fluorescent light at 4 degrees C for 336 h. The degradation rate of lycopene during thermal treatment rose with increasing temperature and the activation energy for decomposition of the mixture of lycopene isomers was calculated to be 71.0 kJ mol-1. The degradation rate of lycopene isomers was almost the same under thermal treatment. On the other hand, during light irradiation, isomerization was promoted rather than decomposition, i.e. (9Z)- and (13Z)-lycopene converted to the (all-E)-isomer. PMID- 29412920 TI - Effects of UV-B radiation on the isoflavone accumulation and physiological biochemical changes of soybean during germination: Physiological-biochemical change of germinated soybean induced by UV-B. AB - In this study, the effects of UV-B radiation on the isoflavones accumulation, physiological and nutritional quality, water status, and characteristics of proteins in germinated soybeans were investigated. The results showed that isoflavones content in soybeans increased with appropriate intensity and time of UV-B radiation and decreased with excessive treatment. Fresh weight, length, free amino acids, reducing sugar contents and bulk water (T23) in germinated soybeans decreased with increasing radiation time, indicating that UV-B inhibited the growth and nutrients metabolism of soybean during germination. Cell damage was detected in germinated soybeans with excessive UV-B radiation, as shown by the black spots in cotyledons and the increased intercellular water determined by LF NMR. Germination resulted in an increase in random coil structures, while UV-B radiation induced no obvious changes in FT-IR spectrum and protein conformation of soybeans. Both UV-B radiation and germination caused the increase in soluble proteins, especially in 1.0-75.0 kDa fraction. PMID- 29412921 TI - Profiling wines in China for the biogenic amines: A nationwide survey and pharmacokinetic fate modelling. AB - Biogenic amines (BAs), a class of nitrogenous compounds that are frequently detected in wine, pose adverse effects to humans. However, with the largest red wine consumption in the world, little is known about national profiles correlating BAs in wines to toxicological/health risks in China. In this study, we conducted a nationwide survey of commercially available wines for the occurrence of BAs. Our sampling campaign covered >90% of wine brands (n = 456) in China in a three year span (2014-2016). The target BAs included tryptamine, phenylethylamine, putrescine, cadaverine, histamine, tyramine, spermidine and spermine. In order to quantitatively characterize the potential risk and/or support regulatory decision-making, chronic and acute BA exposure scenarios were developed and simulated with a physiologically based pharmacokinetic model. The model described the fate and transport of BAs within human body using physical descriptions of relevant processes. These results provided baseline data that are needed for the risk assessment of dietary uptake of BAs and evaluating winemaking processes by food safety authorities. PMID- 29412922 TI - Corrigendum to "Implications of hydration depletion in the in vitro starch digestibility of white bread crumb and crust" [Food Chem. 239 (2018) 295-303]. PMID- 29412923 TI - Corrigendum to "Synthesis of Fe3O4@SiO2@OSi(CH2)3NHRN(CH2PPh2)2PdCl2 type nanocomposite complexes: Highly efficient and magnetically-recoverable catalysts in vitamin K3 synthesis" [Food Chem. 213 (2016) 336-343]. PMID- 29412924 TI - Dissociation mechanisms-based UHPLC Q-Orbitrap strategy for screening of cephalosporins and metabolites in shrimp. AB - A screening method was explored for simultaneous analysis of 43 cephalosporins residues and their metabolites from four generations in shrimp utilizing a novel fully untargeted data acquisition method. Four generations of cephalosporins residues and their metabolites are extracted with online extraction simultaneously. Ultrahigh-performance liquid chromatography coupled to quadrupole orbitrap high resolution mass spectrometry was used for to determine cephalosporins and their metabolites in ten shrimp species. Precision in terms of relative standard deviation (RSD) was under 6.3% for all compounds, and the extraction recoveries ranged from 85% to 108%. The detection capabilities ranged from 0.011 to 0.223 mg kg-1. The fully untargeted vDIA acquisition way improves both selectivity and sensitivity for the compounds at trace levels, which is beneficial for screening performance. PMID- 29412925 TI - Generalized Likelihood Uncertainty Estimation (GLUE) methodology for optimization of extraction in natural products. AB - Optimization process is an important aspect in the natural product extractions. Herein, an alternative approach is proposed for the optimization in extraction, namely, the Generalized Likelihood Uncertainty Estimation (GLUE). The approach combines the Latin hypercube sampling, the feasible range of independent variables, the Monte Carlo simulation, and the threshold criteria of response variables. The GLUE method is tested in three different techniques including the ultrasound, the microwave, and the supercritical CO2 assisted extractions utilizing the data from previously published reports. The study found that this method can: provide more information on the combined effects of the independent variables on the response variables in the dotty plots; deal with unlimited number of independent and response variables; consider combined multiple threshold criteria, which is subjective depending on the target of the investigation for response variables; and provide a range of values with their distribution for the optimization. PMID- 29412926 TI - Controlled release of flavor oil nanoemulsions encapsulated in filled soluble hydrogels. AB - The goal of this project was to create hydrogels, a type of soluble biopolymer delivery system to encapsulate flavored nanoemulsions that are released under artificial saliva conditions. Low methoxyl (LM) pectin and whey protein isolate (WPI) at pH 4.0 were used to form the hydrogels at a ratio of 4:1 (w/w), respectively. Orange oil, medium-chain triglyceride (MCT) oil, and WPI were used to make stable nanoemulsions loaded with flavor oil. The nanoemulsions were encapsulated into hydrogels with a mean diameter of 768 +/- 36 nm. The ability of the hydrogels to encapsulate the orange oil and release the flavor in the presence of artificial saliva was determined using size distribution data, confocal microscopy, and the release of limonene as assessed by solid-phase microextraction using gas chromatography mass spectrometry. Results showed that the encapsulation of flavor nanoemulsions in filled hydrogels reduces the release of limonene. PMID- 29412927 TI - Phytochemical profile and antioxidant activity of caper berries (Capparis spinosa L.): Evaluation of the influence of the fermentation process. AB - In this work, we report the phytochemical profile and antioxidant activity of caper berries (Capparis spinosa L.) before and after a fermentation process. The phytochemical profiles were evaluated by high-performance liquid chromatography with UV and electrospray ionization mass spectrometry detection (HPLC-DAD-ESI MSn). Twenty-one compounds were characterized, and seven of them quantified. The main component of non-fermented berries was glucocapparin, which was degraded upon the fermentation process. Most of the compounds were quercetin and kaempferol glycosides, epicatechin, and proanthocyanidins. The main differences observed upon the fermentation process were a decrease in epicatechin concentration, the hydrolysis of quercetin glycosides, and the degradation of glucosinolates. Total phenolic and flavonoid contents, as well as the antioxidant activities by the in vitro antioxidant assays DPPH and ABTS+, were determined, observing that the values were slightly higher after the fermentation process. PMID- 29412928 TI - Synthesis and concentration of 2-monoacylglycerols rich in polyunsaturated fatty acids. AB - Polyunsaturated fatty acids (PUFA) in 2-monoacylglycerols form exhibit various biological activities and have potential applications in food and pharmaceuticals. Preparation of 2-monoacylglycerols was conducted by enzymatic enthanolysis. The effects of lipase type, substrate weight ratio, reaction time and lipase load on the 2-monoacylglycerols content in the crude product were investigated. Lipozyme 435 behaved as 1,3-specific and high-catalytic-activity lipase in this reaction. Under the optimal conditions (ethanol:oil = 3:1 (w/w), 8% Lipozyme 435, 3 h), 27% 2-monoacylglycerols were obtained. After solvent extraction of 2-monoacylglycerols, the abilities of low temperature crystallization and molecular distillation to concentrate 2-PUFA monoacylglycerols were compared. Low temperature crystallization concentrated 81.13% and 74.29% PUFA by acetonitrile and hexane, respectively, with over 90% in 2-monoacylglycerol forms. Conversely, molecular distillation yielded a PUFA concentration of 72% but decreased the 2-monoacylglycerols content to 69.81%. Thus, the method including enzymatic ethanolysis and low temperature crystallization is suitable for preparation of 2-monoacylglycerols rich in PUFA. PMID- 29412929 TI - Suitability of lemon balm (Melissa officinalis L.) extract rich in rosmarinic acid as a potential enhancer of functional properties in cupcakes. AB - Melissa officinalis (lemon balm) and its extracts have been frequently reported as possessing bioactive properties, offering the potential for use in development/enrichment of food products with additional functional capabilities, providing health benefits to consumers. The antioxidant, antibacterial and antifungal activity of lemon balm extract, as well as its potential hepatotoxicity were thoroughly evaluated. The extracts were then incorporated into cupcakes and their preserving effect, chemical composition, colour parameters and antioxidant activity were compared with those provided by potassium sorbate. In general, the variables with the largest differences among different storage times were energy level, sucrose, glucose, palmitic acid (C6:0) and oleic acid (C18:1n9). On the other hand, L* (top), a* (top), b* (top), pH, capric acid (C10:0) and lauric acid (C12:0) showed the greatest variation according to cupcake formulation. The results observed indicate that the lemon balm extract rich in rosmarinic acid can provide advantageous functional properties to bakery products. PMID- 29412930 TI - Sample preparation combined with electroanalysis to improve simultaneous determination of antibiotics in animal derived food samples. AB - A procedure based on liquid-liquid extraction (LLE) and phase separation using magnetically stirred salt-induced high-temperature liquid-liquid extraction (PS MSSI-HT-LLE) was developed to extract and pre-concentrate ciprofloxacin (CIPRO) and enrofloxacin (ENRO) from animal food samples before electroanalysis. Firstly, simple LLE was used to extract the fluoroquinolones (FQs) from animal food samples, in which dilution was performed to reduce interference effects to below a tolerable threshold. Then, adapted PS-MSSI-HT-LLE protocols allowed re extraction and further pre-concentration of target analytes in the diluted acid samples for simultaneous electrochemical quantification at low concentration levels. To improve the peak separation, in simultaneous detection, a baseline corrected second-order derivative approach was processed. These approaches allowed quantification of target FQs from animal food samples spiked at levels of 0.80 to 2.00 umol L-1 in chicken meat, with recovery values always higher than 80.5%, as well as in milk samples spiked at 4.00 umol L-1, with recovery values close to 70.0%. PMID- 29412931 TI - Impact of Prosopis alba exudate gum on sorption properties and physical stability of fish oil alginate beads prepared by ionic gelation. AB - This study was conducted to evaluate the effect of Prosopis alba exudate gum (G) as encapsulating matrix component on water-solid interactions, physical state, oxidative damage and appearance properties of alginate-chitosan encapsulates containing fish oil. With this purpose, water sorption isotherms were obtained at 25 degrees C. G increased the hygroscopicity of encapsulates, showing a higher monolayer water content (7.87 +/- 0.47% db.) than control (1.07 +/- 0.04% db.). G introduction reduced the plasticizing effect of water, increasing the aw range (aw < 0.45) at which samples were in amorphous state and providing the highest protection against lipid oxidation. Appearance properties (chromatic and optical) were affected by hydration and were better maintained in samples containing G at aw > 0.52. These results allow considering Prosopis alba exudate gum, as a novel excipient to protect fish oil encapsulated in low moisture polyelectrolyte systems, with the added benefits of employing an undervalued natural resource. PMID- 29412932 TI - Drying process of sodium alginate edible films forming solutions studied by LF NMR. AB - The dynamics of water in sodium alginate film-forming solutions during drying were investigated by low-field nuclear magnetic resonance. At the beginning of drying, three transverse relaxation times at around 1.74, 28.48 and 305.38 ms were assigned to the tightly bound, moderately bound, and free water, respectively. Moreover, the free water was evaporated, followed by the formation of water cluster in the entangled alginate chains network as the drying process continued (beyond 840 min of drying time). Towards the third stage of drying process, water clusters in alginate samples was disappeared, resulting that loosely bonded waters were constrained within the weak-gel network. The observed three relaxation times revealed the multi-exponential relaxation behavior of water in alginate, which indicated that this polymer exhibited spatial heterogeneity during drying. On the basis of diffusive exchange theory, the dimension range of alginate network decreased from 1.94-23.99 to 1.83-6.62 um as the alginate films solidified. PMID- 29412933 TI - Assessment of protected designation of origin for Colombian coffees based on HRMS based metabolomics. AB - An untargeted metabolomics approach based on HRMS has been applied to Colombian green coffee to develop a discrimination model to highlight the most differential compounds. For this purpose, 41 green coffee samples of different genotypes collected from 5 regions were analysed. Samples were extracted with aqueous and organic solvents to cover a wide range of compounds. Sample extracts were randomly injected and data were pre-processed with XCMS software. PCA was used to verify quality control samples behaviour, and PLS-DA and DD-SIMCA were employed to create models for discrimination using VIP variable selection method. Thirteen different compounds correctly separate green coffee samples according to their origin, several related to the quality and health benefits of coffee. Model validation was achieved using both cross-validation and an additional set with coffee samples from different harvest year. The results reveal that UHPLC-(Q)ToF MS-based metabolomics is a suitable tool to develop food origin discrimination strategies. PMID- 29412934 TI - Mitigation effects of proanthocyanidins with different structures on acrylamide formation in chemical and fried potato crisp models. AB - Proanthocyanidins with different structures were prepared from three condensed tannin-rich plant materials and then characterized using HPLC-ESI-MS coupled with thiolysis and MALDI-TOF MS. Their effects on acrylamide formation in asparagine glucose models and fried potato crisps were determined. Results showed that all proanthocyanidins significantly and dose dependently mitigated acrylamide formation at concentrations of 50, 100 and 200 ug/mL in chemical model system. Using the food model, acrylamide formation were inhibited when potato crisps were soaked in 0.01-1 mg/mL proanthocyanidin solutions for 15 min at room temperature before frying. Proanthocyanidins reduced up to 44.2% of the acrylamide level as concentration was increased to 0.1 mg/mL, whereas higher concentration resulted in a decrease of inhibition. B-type proanthocyanidins had stronger inhibitory activity than A-type. Unit composition and DP had nearly no effect on their inhibitory activity based on same mass. This study showed that proanthocyanidins with various structures were promising additives to mitigate harmful acrylamide. PMID- 29412935 TI - Chirality detection of amino acid enantiomers by organic electrochemical transistor. AB - Chiral recognition of alpha-amino acids is attracting increasing interest due to the importance of alpha-amino acids in protein metabolism as well as in food products and pharmaceuticals. Organic electrochemical transistors (OECTs) with gate electrodes modified with molecularly imprinted polymer (MIP) films were fabricated and successfully used as highly selective and sensitive chiral recognition biosensors for d/l-tryptophan (d/l-Trp) and d/l-tyrosine (d/l-Tyr). The MIP films, which can specifically recognize and has an electrocatalytic effect on the oxidation of Trp and Tyr, together with the amplification function of an OECT, provide a highly sensitive and selective OECT biosensor. The sensor showed a linear response range for l-Trp and L-Tyr from 300 nM to 10 MUM with a sensitivity of 3.19 and 3.64 MUA/MUM, respectivity. And the detection limit for L Trp and L-Tyr is of 2 nM and 30 nM (S/N > 3). The selectivity factors of L-Trp, D Trp, L-Tyr and D-Tyr to their enantiomers are 11.6, 3.5, 14.5 and 2.6, respectively. This method can pave the way for widespread applications of OECT based sensors in chiral material identification. PMID- 29412936 TI - Label-free electrochemical biosensors based on 3,3',5,5'-tetramethylbenzidine responsive isoporous silica-micelle membrane. AB - 3,3',5,5'-Tetramethylbenzidine (TMB) has been frequently used as an indicator in G-quadruplex/hemin DNAzyme (G4zyme)-based chemical and biochemical analysis, and its oxidation products are usually monitored by electrochemical or optical methods to quantify G4zyme formation-related analytes. Herein we report a simple electrochemical approach based on isoporous silica-micelle membrane (iSMM) to measure TMB, instead of its oxidation products, in G4zyme-based detection of specific analytes. The iSMM was grown on the indium tin oxide (ITO) electrode, which was composed of highly ordered, vertically oriented silica nanochannels and cylindrical micelles of cetyltrimethylammonium. The iSMM-ITO electrode was selectively responsive to neutral TMB but not its oxidation products, thanks to the sieving and pre-concentration capacity of micellar structures in terms of molecular charge and lipophilicity. In other words, only TMB could be extracted and enriched into micelles and subsequently oxidized at the underlying ITO electrode surface (namely the micelle/ITO interface), generating an amplified anodic current. Since the depletion of TMB was catalyzed by G4zymes formed in the presence of specific analyte, the decrease of this anodic current enabled the quantitative detection of this analyte. The current variation relative to its initial value ((j0-j)/j0), termed as the current attenuation ratio, showed the obvious dependence on the analyte concentration. As proof-of-concept experiments, four substances, i.e., potassium cation (K+), adenosine triphosphate, thrombin and nucleic acid, were detected in aqueous media and the analysis of K+ in pre treated human serum was also performed. PMID- 29412937 TI - A simple and non-amplification platform for femtomolar DNA and microRNA detection by combining automatic gold nanoparticle enumeration with target-induced strand displacement. AB - By combining the gold nanoparticle (AuNP) enumeration with target-induced strand displacement reaction, we have developed a non-amplification platform for DNA and miRNA detection based on a deliberately designed sandwich-structured nanocomplex probe (SNC Probe). The proposed strategy can realize the sensitive detection of nucleic acids within 40min with the detection limit of 6.6 fM for HBV DNA and 13.5 fM for miRNA-141, respectively. The method presents reasonable ability to discriminate miRNA-141 from all the other members of miRNA-200 family. And it can also be used for direct detection of miRNA-141 in samples of extracted total small RNA from different cell lines which are reported to have altered levels of miRNA-141. Furthermore, the spike recovery (n = 3) of miRNA-141 in total small RNA extracts of Hela cells is found to be 92.8% for 20 p.M. and 94.7% for 100 p.M. with the standard deviation of 9.2% and 6.8%, respectively. As the only reagent involved in the assay, the SNC Probe presents a very good stability with a relative standard deviation of 3.3% amongst eight tests in 30 days, which greatly simplifies the assay procedure and presents the suitability for routine analyses. On the basis of these findings, this simple non-amplification assay platform can be expected to find assorted applications that can make the best use of the simplicity and sensitivity. PMID- 29412938 TI - Molecularly imprinted electrochemical sensor, formed on Ag screen-printed electrodes, for the enantioselective recognition of d and l phenylalanine. AB - In this study, electrochemical sensors for the enantioselective recognition of d and l phenylalanine were prepared using a molecular imprinting technique in which the electro-polymerization of pyrrole was carried out by Chronopotentiometry(CP) with the target molecules being present on a Ag screen printed electrode's (SPE) surface. The sensing performance was evaluated by multi-potential steps at 0 and 2V(vs. Ag/AgCl) held for 1s and 2s, respectively, for 20 cycles (with the two enantiomers being present at the same concentration). The individual selectivity's for l and d- phenylalanine on their respective imprinted films were estimated to be L/D = 23.480 +/- 2.844/1 and D/L = 19.134 +/- 1.870/1 respectively, based on the current change between 0 and 2V (vs. Ag/AgCl) with the two enantiomers being present at the same concentration (10mM). Several parameters affecting recognition ability were investigated including: cross selectivity of d and l- phenylalanine imprinted film, phenylalanine concentration effects, interfering species, deactivation and the storage life of electrode. The phenylalanine imprinted films were also characterized by AC impedance, chronoamperometry, Fourier-transform infrared spectroscopy (FTIR), Scanning Electron Microscope(SEM), and Energy Dispersive X-Ray Spectroscopy (EDS). Finally, a recognition mechanism for the interaction of the polypyrrole film with its template under the influence of applied negative and positive potentials is proposed. PMID- 29412939 TI - Fast and sensitive near-infrared fluorescent probes for ALP detection and 3d printed calcium phosphate scaffold imaging in vivo. AB - Alkaline phosphatase (ALP) is a critical biological marker for osteoblast activity during early osteoblast differentiation, but few biologically compatible methods are available for its detection. Here, we describe the discovery of highly sensitive and rapidly responsive novel near-infrared (NIR) fluorescent probes (NIR-Phos-1, NIR-Phos-2) for the fluorescent detection of ALP. ALP cleaves the phosphate group from the NIR skeleton and substantially alters its photophysical properties, therefore generating a large "turn-on" fluorescent signal resulted from the catalytic hydrolysis on fluorogenic moiety. Our assay quantified ALP activity from 0 to 1.0UmL-1 with a 10-5-10-3UmL-1 limit of detection (LOD), showing a response rate completed within 1.5min. A potentially powerful approach to probe ALP activity in biological systems demonstrated real time monitoring using both concentration- and time-dependent variations of endogenous ALP in live cells and animals. Based on high binding affinity to bone tissue of phosphate moiety, bone-like scaffold-based ALP detection in vivo was accessed using NIR probe-labeled three-dimensional (3D) calcium deficient hydroxyapatite (CDHA) scaffolds. They were subcutaneously implanted into mice and monitored ALP signal changes using a confocal imaging system. Our results suggest the possibility of early-stage ALP detection during neo-bone formation inside a bone defect, by in vivo fluorescent evaluation using 3D CDHA scaffolds. PMID- 29412940 TI - Autonomous DNA nanomachine based on cascade amplification of strand displacement and DNA walker for detection of multiple DNAs. AB - DNA can be modified to function as a scaffold for the construction of a DNA nanomachine, which can then be used in analytical applications if the DNA nanomachine can be triggered by the presence of a diagnostic DNA or some other analyte. We herein propose a novel and powerful DNA nanomachine that can detect DNA via combining the tandem strand displacement reactions and a DNA walker. Three different DNA sensing platforms are described, where the whole DNA machine was constructed on a gold electrode (GE). This cascade multiple amplification strategy exhibited an excellent sensitivity. Under optimal conditions, the electrochemical sensor could achieve a detection limit of 36 fM with a linear range from 50 to 500 fM. In particular, the electrochemical sensor could easily distinguish the base mutations. More interestingly, the DNA nanomachine could be used to construct analog AND and OR logic gates. We demonstrate that electrochemical signals generated from the different input combinations can be used to distinguish multiple target DNAs. The practical applicability of the present biosensor is demonstrated by the detection of target DNA in human serum with satisfactory results, which holds great potential for a future application in clinical diagnosis. PMID- 29412941 TI - Furthering the state of knowledge on the electric properties of hemi-ellipsoidal single cells and cell patches on electrodes. AB - The impedance of electrodes with adherent biological cells correlates with cell viability and proliferation. To model this correlation, we exploited the idea that the introduction of a highly conductive layer into the equatorial equipotential slice of a system with an oriented, freely suspended, single ellipsoidal cell may split the system into mirror-symmetrical halves without changing the field distribution. Each half possesses half of the system's impedance and contains a hemiellipsoidal cell attached to the conductive layer, which can be considered a bottom electrode. For a hemiellipsoidal adherent cell model (ACM) with standard electrical properties for the external and cellular media, the assumption of a bottom membrane and a subcellular cleft in the 100 nm range, as found in adherent cells, changed the potential distribution over a one % range up to frequencies of 1 MHz. For simplicity, potential distributions for slices of spheroidal objects can be numerically calculated in 2D. The 2D distributions can be converted into three dimensions using simplified equations for the influential radii of spheroids. After the ACM approach was expanded to adherent cell patch models (APMs), the feasibility of our model modifications was tested using two criteria: the constancy of the equipotential plane touching the poles of ACMs or APMs and a comparison of the impedance, which could be numerically calculated from the overall current between the bottom electrode and a plane-parallel counter-electrode, with the impedance of the suspension obtained from Maxwell-Wagner's mixing equation applied to hemiellipsoidal cells. PMID- 29412942 TI - Fabrication of sensitive bioelectrode based on atomically thin CVD grown graphene for cancer biomarker detection. AB - Motivation behind the present work is to fabricate a cost effective and scalable biosensing platform for an easy and reliable detection of cancer biomarker Carcinoembryonic antigen (CEA). Here, we report the sensitive and selective detection of CEA using graphene based bio-sensing platform. Large sized (~ 2.5 * 1.0cm2), uniform, continuous, single and few layers graphene films have been grown on copper (Cu) substrate employing chemical vapor deposition (CVD) technique using hexane as a liquid precursor. Functional group has been created over Graphene/Cu substrate through pi-pi stacking of 1- pyrenebutanoic acid succinimidyl ester (PBSE). Further, to make the sensor specific to CEA, antibody of CEA (anti-CEA) has been covalently immobilized onto PBSE/Graphene/Cu electrode. Selective and sensitive detection of CEA is achieved by anti CEA/PBSE/Graphene/Cu electrode through electrochemical impedance spectroscopy (EIS) measurements. Under optimal condition, the fabricated sensor shows linear response in the physiological range 1.0-25.0ngmL-1 (normal value ~ 5.0ngmL-1), revealing sensitivity 563.4Omegang-1mLcm-2 with a correlation coefficient of 0.996 and limit of detection (LOD) 0.23ngmL-1. In this way, one step electrode fabrication with high specific surface area provides a light weight, low cost, reliable and scalable novel biosensing platform for sensitive and selective detection of CEA. We believe that this bioelectrode equipped with specific recognition elements could be utilized for detection of other biomolecules too. PMID- 29412943 TI - Homogeneous and label-free electrochemiluminescence aptasensor based on the difference of electrostatic interaction and exonuclease-assisted target recycling amplification. AB - The difference of electrostatic interaction between free Ru(phen)32+ and Ru(phen)32+ embedded in double strand DNA (dsDNA) to the negatively charged indium tin oxide (ITO) electrode has been applied to develop a homogeneous and label-free electrochemiluminescence (ECL) aptasensor for the first time. Ochratoxin A (OTA) has been chosen as the model target. The OTA aptamer is first hybridized with its complementary single strand DNA (ssDNA) to form dsDNA and then interacted with Ru(phen)32+ via the grooves binding mode to form dsDNA Ru(phen)32+ complex, which remains negatively charged feature as well as low diffusion capacity to the negatively charged ITO electrode surface owing to the electrostatic repulsion. Meanwhile, the intercalated Ru(phen)32+ in the grooves of dsDNA works as an ECL signal reporter instead of the labor-intensive labeling steps and can generate much more ECL signal than that from the labeling probe. In the presence of target, the aptamer prefers to form an aptamer-target complex in lieu of dsDNA, which induces the releasing of Ru(phen)32+ from the dsDNA Ru(phen)32+ complex into the solution. With the assistance of RecJf exonuclease (a ssDNA specific exonuclease), the released ssDNA and the aptamer in the target complex were digested into mononucleotides. In the meantime, the target can be also liberated from OTA-aptamer complex and induce target cycling and large amount of free Ru(phen)32+ present in the solution. Since Ru(phen)32+ contains positive charges, which can diffuses easily to the ITO electrode surface because of electrostatic attraction, causing an obviously enhanced ECL signal detected. Under the optimal conditions, the enhanced ECL of the system has a linear relationship with the OTA concentration in the range of 0.01-1.0 ng/mL with a detection limit of 2 pg/mL. This innovative system not only expands the immobilization-free sensors in the electrochemiluminescent fields, but also can be developed for the detection of different targets easily with the same strategy by changing the aptamer used. PMID- 29412944 TI - Advances in biosensors and optical assays for diagnosis and detection of malaria. AB - Vector-borne diseases are a major concern for human health globally, especially malaria in densely populated, less developed, tropical regions of the world. Malaria causes loss of human life and economic harm, and may spread through travelers to new regions. Though there are sufficient therapeutics available for the effective treatment and cure of malaria, it infects millions of people and claims several thousand lives every year. Early diagnosis of the infection can potentially prevent the spread of disease, save lives, and mitigate the financial impact. Conventional analytical techniques are being widely employed for malaria diagnosis, but with low sensitivity and selectivity. Due to the poor-resource settings where malaria outbreaks often occur, most conventional diagnostic methods are not affordable and hence not effective in detection and controlling the spread of the infection. However, biosensors have improved the scope for affordable malaria diagnosis. Advances in biotechnology and nanotechnology have provided novel recognition materials and transducer elements, discoveries which allow the fabrication of affordable biosensor platforms with improved attributes. The present work covers the advancement in biosensors with an introduction to malaria, followed by conventional methods of malaria diagnosis, malaria markers, novel recognition elements and the biosensor principle. Finally, a proactive role and a perspective on developed biosensor platforms are discussed with potential biomedical applications. PMID- 29412945 TI - Applying strand displacement amplification to quantum dots-based fluorescent lateral flow assay strips for HIV-DNA detection. AB - Up to now, the colloidal gold labeling immunochromatographic test strip is a mature and applicable technology. However, different from the conventional gold nanoparticle, quantum dot (QD) possesses larger specific surface area and better biocompatibility. So, as a novel nanomaterial, QD is capable of assembling more biomolecule which could enhance the sensitivity and accuracy of strips by rationality. Besides, strand displacement amplification was drawn into our test strips in this paper, this assumption made HIV-DNA recycling many times and converting it to plentiful QD-dsDNA (double-stranded deoxyribonucleic acid), where after these nano-structures would be captured by test zone. Meanwhile, the suggested scheme eliminated the hook effect owing to the target drop out of the incorporation on test zone, and any nucleotide sequence or substance which has aptamers can work as the target, such as carcinoembryonic antigen or mycotoxin. This assay realized the detection limit of as low as 0.76 pM (S/N = 3) and the detection range of 1 pM to 10 nM. In the end, we made use of this fluorescent lateral flow assay strips with great reproducibility for detecting HIV-DNA in human serum, that attested this method could be applied to practical application prospectively. PMID- 29412946 TI - Ultrasensitive microfluidic paper-based electrochemical/visual biosensor based on spherical-like cerium dioxide catalyst for miR-21 detection. AB - In this work, an electrochemical biosensor based on Au nanorods (NRs) modified microfluidic paper-based analytical devices (MUPADs) were constructed for sensitive detection of microRNA (miRNA) by using cerium dioxide - Au@glucose oxidase (CeO2-Au@GOx) as an electrochemical probe for signal amplification. Au NRs were synthesized by in-situ growth method in MUPADs surface to enhance the conductivity and modified hairpin probe through Au-S bonds. The construction of "the signal transducer layer" was carried out by GOx catalyzing glucose to produce H2O2, which was further electrocatalyzed by CeO2. After the biosensor was constructed, an obvious electrochemical signal was observed from the reduction of H2O2. In order to make the detection more convincing, the visual detection was performed based on the oxidation of 3,3',5,5'-tetramethylbenzidine by H2O2 with the help of Exonuclease I. The electrochemical biosensor provided a wide linear range of 1.0fM to 1000fM with a relatively low detection limit of 0.434fM by the electrochemical measurement. Linear range of 10fM to 1000fM with a relatively low detection limit of 7.382fM was obtained by visual detection. The results indicated the proposed platform has potential utility for detection of miRNA. PMID- 29412947 TI - Novel tungsten phosphide embedded nitrogen-doped carbon nanotubes: A portable and renewable monitoring platform for anticancer drug in whole blood. AB - Biosensors based on converting the concentration of analytes in complex samples into single electrochemical signals are attractive candidates as low cost, high throughput, portable and renewable sensor platforms. Here, we describe a simple but practical analytical device for sensing an anticancer drug in whole blood, using the detection of methotrexate (MTX) as a model system. In this biosensor, a novel carbon-based composite, tungsten phosphide embedded nitrogen-doped carbon nanotubes (WP/N-CNT), was fixed to the electrode surface that supported redox cycling. The electronic transmission channel in nitrogen doped carbon nanotubes (N-CNT) and the synergistic effect of uniform distribution tungsten phosphide (WP) ensured that the electrode materials have outstanding electrical conductivity and catalytic performance. Meanwhile, the surface electronic structure also endows its surprisingly reproducible performance. To demonstrate portable operation for MTX sensing, screen printing electrodes (SPE) was modified with WP/N-CNT. The sensor exhibited low detection limits (45 nM), wide detection range (0.01-540 MUM), good selectivity and long-term stability for the determination of MTX. In addition, the technique was successfully applied for the determination of MTX in whole blood. PMID- 29412948 TI - Simultaneous determination of ascorbic acid, dopamine and uric acid by a novel electrochemical sensor based on N2/Ar RF plasma assisted graphene nanosheets/graphene nanoribbons. AB - A novel nitrogen/argon (N2/Ar) radio frequency (RF) plasma functionalized graphene nanosheet/graphene nanoribbon (GS/GNR) hybrid material (N2/Ar/GS/GNR) was developed for simultaneous determination of ascorbic acid (AA), dopamine (DA) and uric acid (UA). Various nitrogen mites introduced into GS/GNR hybrid structure was evidenced by a detailed microscopic, spectroscopic and surface area analysis. Owing to the unique structure and properties originating from the enhanced surface area, nitrogen functional groups and defects introduced on both the basal and edges, N2/Ar/GS/GNR/GCE showed high electrocatalytic activity for the electrochemical oxidations of AA, DA, and UA with the respective lowest detection limits of 5.3, 2.5 and 5.7 nM and peak-to-peak separation potential (DeltaEP) (vs Ag/AgCl) in DPV of 220, 152 and 372 mV for AA/DA, DA/UA and AA/UA respectively. Moreover, the selectivity, stability, repeatability and excellent performance in real time application of the fabricated N2/Ar/GS/GNR/GCE electrode suggests that it can be considered as a potential electrode material for simultaneous detection of AA, DA, and UA. PMID- 29412949 TI - Caco-2 cell-based electrochemical biosensor for evaluating the antioxidant capacity of Asp-Leu-Glu-Glu isolated from dry-cured Xuanwei ham. AB - A cell-based electrochemical biosensor was developed to determine the antioxidant activity of Asp-Leu-Glu-Glu (DLEE) isolated from dry-cured Chinese Xuanwei ham. A platinized gold electrode (Pt NPs/GE) covered with silver nanowires (Ag NWs) was fabricated to detect H2O2 using redox signaling via cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS). Under optimal condition, the detection limit of the modified electrode was 0.12MUM with a linear relationship from 0.2 to 2MUM, which showed relatively outstanding catalytic effects towards the reduction of H2O2. Furthermore, the generation of reactive oxygen species (ROS) in the cell can be used to indirectly assess changes in intercellular oxidative stress by detecting variations in electrochemical signals. A 3D cell culture of alginate/graphene oxide (NaAlg/GO) was used to encapsulate and immobilize Caco-2 cells. Based on ROS generation and electrochemical results, we found that DLEE could effectively reduce oxidative stress level in Caco-2 cells under external stimulation. DLEE showed high antioxidant activity with a relative antioxidant capacity (RAC) rate of 88.17% at 1.5mg/mL. Finally, an efficient electrochemical biosensor was established using the active 3D Caco-2 cell platform. This system is sensitive and simple to operate with the property to evaluate the antioxidant activity of peptides by the detection of H2O2 in cell membrane. In summary, this work describes a new method for assessing antioxidant capacity of peptide DLEE using cell-based electrochemical signaling with a rapid screening pattern. PMID- 29412950 TI - Ultrasensitive sensor for detection of early stage chronic kidney disease in human. AB - A facile label free, ultrasensitive platform for a rapid detection of chronic kidney disease has been fabricated. Early intervention in patients with chronic kidney disease has the potential to delay, or even prevent, the development of end stage renal disease and complications, leading to a marked impact on life expectancy and quality of life. Thus, a potable electrochemical diagnostic biosensor has become an attractive option as electrochemical analysis is feasible to use for on-site detection of samples. In human, Cystatin C present in human body fluids is freely filtered by the glomerulus, but reabsorbed and catabolised by the renal tubules. Trace detectable amount is eliminated in urine, giving this molecular marker an edge over serum creatinine's disadvantages. A carboxyl functionalized multiwalled carbon nanotubes screen printed electrode was immobilized with papain (cysteine protease) where amino group of papain covalently bound carboxyl group on electrode surface by EDC (1-ethyl-3-(3 dimethylaminopropyl) carbodiimide) and NHS (N-hydroxysuccinimide) chemistry. The modifications on sensor surface were characterized by field emission scanning electron microscopy. Interaction between papain and chronic kidney disease specific biomarker, Cystatin C was detected by cyclic voltammetry and differential pulse voltammetry within 10min. The sensor is highly specific to Cystatin C and showed negligible response to non-specific macromolecules present in urine. The sensitivity of the sensor was 1583.49uAcm-2ug-1 and lower limit of detection of Cystatin C was found 0.58ngL-1 which presents as a promising platform for designing potable kidney disease detector. PMID- 29412951 TI - Chiral magnetic-nanobiofluids for rapid electrochemical screening of enantiomers at a magneto nanocomposite graphene-paste electrode. AB - The development of highly sensitive and selective enantiomeric platforms towards the rapid screening of active pharmaceutical ingredients (APIs) is nowadays a crucial challenge in several fields related to pharmacology, biomedicine, biotechnology and (bio)sensors. Herein, it is presented a novel, facile and generic methodology focused on exploiting the synergistically and electrocatalytic properties of chiral magnetic-nanobiofluids (mNBFs) with electrochemical enantiobiosensing at a magneto nanocomposite graphene paste electrode (mNC-GPE). The feasibility of this approach has been validated by chirally recognizing tryptophan (TRP) enantiomers as a proof-of-concept. For this aim, a specific chiral mNBF based on an aqueous dispersion of cobalt ferrite loaded with gold nanoparticles carrying a thiolated beta-cyclodextrin (beta-CD SH/Au/CoFe2O4-NPs) has been synthesized and used towards the supramolecular discrimination of TRP enantiomers at an advanced graphene-paste transducer via cyclic voltammetry. This strategy, which is the first demonstration of applicability of chiral mNBFs for electrochemical enantiorecognition, opens up new approaches into enantio(bio)sensing. PMID- 29412952 TI - The dengue vaccine dilemma. PMID- 29412953 TI - Are leprosy case numbers reliable? PMID- 29412955 TI - Reassessment of a meta-analysis of procalcitonin-guided antibiotic therapy for lower respiratory tract infections. PMID- 29412954 TI - A roadmap for zoonotic tuberculosis: a One Health approach to ending tuberculosis. PMID- 29412957 TI - Reassessment of a meta-analysis of procalcitonin-guided antibiotic therapy for lower respiratory tract infections - Authors' reply. PMID- 29412956 TI - Reassessment of a meta-analysis of procalcitonin-guided antibiotic therapy for lower respiratory tract infections. PMID- 29412958 TI - Campylobacter jejuni vertebral osteomyelitis or tuberculosis: persisting diagnostic ambiguity. PMID- 29412959 TI - Re-emergence of Aedes aegypti in Egypt. PMID- 29412960 TI - Campylobacter jejuni vertebral osteomyelitis or tuberculosis: persisting diagnostic ambiguity - Authors' reply. PMID- 29412961 TI - Expansion of the WHO public health approach to HIV. PMID- 29412962 TI - Isolation of viable Zika virus from spermatozoa. PMID- 29412963 TI - Incidence of active tuberculosis in rural China. PMID- 29412965 TI - WHO's who in tuberculosis. PMID- 29412966 TI - Ban on gain-of-function studies ends. PMID- 29412964 TI - Incidence of active tuberculosis in rural China - Authors' reply. PMID- 29412967 TI - Price hikes could affect treatment for NTDs in the USA. PMID- 29412970 TI - Twitter big data and infectious disease conferences. PMID- 29412971 TI - Upbeat nystagmus in an HIV-positive patient with a tuberculoma in the medulla. PMID- 29412972 TI - Vascular infection and vertebral destruction in a patient with Q fever. PMID- 29412973 TI - The role of waste-to-energy in the near future. PMID- 29412977 TI - Sleep and Nocturia in Older Adults. AB - Older adults frequently experience nocturia and sleep disturbance concurrently, and problems with sleep resulting from nocturia are a major factor accompanying the bother associated with nocturia. A multicomponent treatment strategy is usually warranted. Initial treatment includes lifestyle modification and behavioral treatment with consideration of pelvic floor muscle exercise-based therapy. Early evidence suggests that behavioral treatment results in similar nocturia reductions compared with the most frequently used drug therapies. Providers should consider formal sleep evaluation if initial treatment strategies for nocturia do not result in significant improvement, because specific sleep disorders may predispose to nocturia. PMID- 29412976 TI - Sleep in Normal Aging. AB - Sleep patterns change with aging, independent of other factors, and include advanced sleep timing, shortened nocturnal sleep duration, increased frequency of daytime naps, increased number of nocturnal awakenings and time spent awake during the night, and decreased slow wave sleep. Most of these changes seem to occur between young and middle adulthood; sleep parameters remain largely unchanged among healthy older adults. The circadian system and sleep homeostatic mechanisms become less robust with normal aging. The amount and pattern of sleep related hormone secretion change as well. The causes of sleep disturbances in older adults are multifactorial. PMID- 29412978 TI - Sleep and Long-Term Care. AB - Long-term care (LTC) involves a range of support and services for people with chronic illness and disabilities who can not perform activities of daily living independently. Poor sleep increases the risk of LTC placement, and sleep disturbance is extremely common among LTC residents. The identification and management of sleep disturbance in LTC residents is a vital, but perhaps underappreciated, aspect of offering high-quality care for this already compromised population. This review describes the nature and consequences of sleep disturbances in LTC, clinical assessment and management of sleep disturbances in LTC, and implications for future research and clinical practice. PMID- 29412979 TI - Sleep in Hospitalized Older Adults. AB - Hospitalization is a period of acute sleep deprivation for older adults owing to environmental, medical, and patient factors. Although hospitalized patients are in need of adequate rest and recovery during acute illness, older patients face unique risks owing to acute sleep loss during hospitalization. Sleep loss in the hospital is associated with worse health outcomes, including cardiometabolic derangements and an increased risk of delirium. Because older patients are at risk of polypharmacy and medication side effects, a variety of nonpharmacologic interventions are recommended first to improve sleep loss for hospitalized older adults. PMID- 29412980 TI - Insomnia in the Older Adult. AB - Although insomnia is not a normal part of the aging process, its prevalence increases with age. Factors such as medications and medical and psychiatric disorders can increase the risk for insomnia. To diagnose insomnia, it is important for older adults to complete comprehensive sleep and health histories. Cognitive-behavioral therapy for insomnia, which includes stimulus control, sleep restriction, sleep hygiene, and cognitive therapy, is the recommended first-line treatment of insomnia and is more effective than medications for the long-term management of insomnia. Medications, such as benzodiazepines and antidepressants, should be avoided for the treatment of insomnia in older adults. PMID- 29412981 TI - Apnea in Older Adults. AB - Sleep-disordered breathing (SDB) is a highly prevalent chronic disease in older adults. A growing body of evidence demonstrates that SDB in older adults is linked to many adverse cardiovascular, neurocognitive, and metabolic sequelae. However, several unanswered questions remain regarding the diagnosis, consequences, and treatment of SDB in older adults. This review presents the current evidence pertaining to the management of SDB in older adults and identifies crucial gaps in knowledge that need further investigation. PMID- 29412982 TI - Circadian Rhythm Sleep-Wake Disorders in Older Adults. AB - The timing, duration, and consolidation of sleep result from the interaction of the circadian timing system with a sleep-wake homeostatic process. When aligned and functioning optimally, this allows wakefulness throughout the day and a long consolidated sleep episode at night. Mismatch between the desired timing of sleep and the ability to fall and remain asleep is a hallmark of the circadian rhythm sleep-wake disorders. This article discusses changes in circadian regulation of sleep with aging; how age influences the prevalence, diagnosis, and treatment of circadian rhythm sleep-wake disorders; and how neurologic diseases in older patients affect circadian rhythms and sleep. PMID- 29412983 TI - Parasomnias and Sleep-Related Movement Disorders in Older Adults. AB - Parasomnias and sleep-related movement disorders are important problems in older adults. Sleep paralysis is rare, but may occur in families. In a minority of patients with disorders of arousal, the episodes persist until the age of 70. Zolpidem and other medications may induce sleepwalking and sleep-related eating. Most patients with idiopathic rapid eye movement (REM) sleep behavior disorder eventually develop Parkinson's disease or dementia with Lewy bodies. Anti-IgLON5 disease includes abnormal behaviors in NREM and REM sleep. Restless legs syndrome prevalence increases with age. A severe form of periodic limb movements in sleep may mimic REM sleep behavior disorder. PMID- 29412984 TI - Neurodegenerative Disorders and Sleep. AB - Sleep disorders are commonly found in cerebral degenerative disorders. The sleep disorders may be caused by the primary symptoms of the neurologic disease or may result from damage to sleep-controlling centers in the brain. Common sleep disorders found in this population include insomnia, hypersomnia, sleep apnea, restless legs syndrome, circadian rhythm disorders, and rapid eye movement sleep behavior disorder. The latter disorder can present years before other neurologic symptoms or signs are present, serving as a precursor of neurodegenerative conditions. There is growing evidence that poor sleep leads to acceleration in the progression of the neurodegenerative disorder and may play a role in pathogenesis. PMID- 29412985 TI - Chronic Medical Conditions and Sleep in the Older Adult. AB - Demographic changes in developed countries are leading to an aging population with a high prevalence of chronic medical conditions, disability, and sleep disorders. Evidence suggests that medical conditions and comorbid sleep disorders interact. This article aims to review frequently encountered medical conditions and examine their consequences on sleep in the older adult, and to review the possible impact of sleep disturbances on these common medical conditions. These medical conditions include pain, falls, cancer, and chronic heart failure. Strategies to improve sleep disturbances in older patients with comorbid medical conditions are provided according to available data and clinical experience. PMID- 29412986 TI - Psychiatric Illness and Sleep in Older Adults: Comorbidity and Opportunities for Intervention. AB - This article reviews the literature examining the association between sleep disorders and psychopathology among older adults. Similar to the younger adult literature, the authors found that sleep disorders are robustly associated with anxiety, depression, dementia, and suicidal behavior in late life. Clinical implications and opportunities for intervention are discussed. PMID- 29412993 TI - Sleep in Older Adults: Challenges and Opportunities. PMID- 29412994 TI - Analysis of Protein Interactions by Surface Plasmon Resonance. AB - Surface plasmon resonance is an optical technique that is utilized for detecting molecular interactions, such as interactions that occur between proteins or other classes of molecules. Binding of a mobile molecule (analyte) to a molecule immobilized on a thin metal film (ligand) changes the refractive index of the film. The angle of extinction of light that is completely reflected after polarized light impinges upon the film, is altered and monitored as a change in detector position for a dip in reflected intensity (the surface plasmon resonance phenomenon). Because the method strictly detects mass, there is no need to label the interacting components, thus eliminating possible changes of their molecular properties. In this chapter, we review essential SPR methodology and present applications to basic science and human disease. PMID- 29412987 TI - Sleep and Cognition in Older Adults. AB - Increased age is associated with normative declines in both sleep and cognitive functioning. Although there are some inconsistencies in the literature, negative sleep changes are associated with worse cognitive functioning. This negative relationship holds true across normal-sleeping older adults, older adults with insomnia, older adults with sleep disordered breathing, cognitively healthy older adults, and older adults with dementia. There are mixed results regarding potential benefits of sleep treatments on cognitive functions; however, this line of research deserves added attention because the potential mechanisms of action are likely distinct from other interventions to improve cognition. PMID- 29412995 TI - Targeting Protein-Protein Interactions in the Ubiquitin-Proteasome Pathway. AB - The ubiquitin-proteasome pathway (UPP) is a major venue for controlled intracellular protein degradation in Eukaryota. The machinery of several hundred proteins is involved in recognizing, tagging, transporting, and cleaving proteins, all in a highly regulated manner. Short-lived transcription factors, misfolded translation products, stress-damaged polypeptides, or worn-out long lived proteins, all can be found among the substrates of UPP. Carefully choreographed protein-protein interactions (PPI) are involved in each step of the pathway. For many of the steps small-molecule inhibitors have been identified and often they directly or indirectly target PPI. The inhibitors may destabilize intracellular proteostasis and trigger apoptosis. So far this is the most explored option used as an anticancer strategy. Alternatively, substrate-specific polyubiquitination may be regulated for a precise intervention aimed at a particular metabolic pathway. This very attractive opportunity is moving close to clinical application. The best known drug target in UPP is the proteasome: the end point of the journey of a protein destined for degradation. The proteasome alone is a perfect object to study the mechanisms and roles of PPI on many levels. This giant protease is built from multisubunit modules and additionally utilizes a service from transient protein ligands, for example, delivering substrates. An elaborate set of PPI within the highest-order proteasome assembly is involved in substrate recognition and processing. Below we will outline PPI involved in the UPP and discuss the growing prospects for their utilization in pharmacological interventions. PMID- 29412996 TI - Probing the Protein-Protein Interaction Network of Proteins Causing Maturity Onset Diabetes of the Young. AB - Protein-protein interactions (PPIs) play vital roles in various cellular pathways. Most of the proteins perform their responsibilities by interacting with an enormous number of proteins. Understanding these interactions of the proteins and their interacting partners has shed light toward the field of drug discovery. Also, PPIs enable us to understand the functions of a protein by understanding their interacting partners. Consequently, in the current study, PPI network of the proteins causing MODY (Maturity Onset Diabetes of the Young) was drawn, and their correlation in causing a disease condition was marked. MODY is a monogenic type of diabetes caused by autosomal dominant inheritance. Extensive research on transcription factor and their corresponding genetic pathways have been studied over the last three decades, yet, very little is understood about the molecular modalities of highly dynamic interactions between transcription factors, genomic DNA, and the protein partners. The current study also reveals the interacting patterns of the various transcription factors. Consequently, in the current work, we have devised a PPI analysis to understand the plausible pathway through which the protein leads to a deformity in glucose uptake. PMID- 29412997 TI - Structural Prediction of Protein-Protein Interactions by Docking: Application to Biomedical Problems. AB - A huge amount of genetic information is available thanks to the recent advances in sequencing technologies and the larger computational capabilities, but the interpretation of such genetic data at phenotypic level remains elusive. One of the reasons is that proteins are not acting alone, but are specifically interacting with other proteins and biomolecules, forming intricate interaction networks that are essential for the majority of cell processes and pathological conditions. Thus, characterizing such interaction networks is an important step in understanding how information flows from gene to phenotype. Indeed, structural characterization of protein-protein interactions at atomic resolution has many applications in biomedicine, from diagnosis and vaccine design, to drug discovery. However, despite the advances of experimental structural determination, the number of interactions for which there is available structural data is still very small. In this context, a complementary approach is computational modeling of protein interactions by docking, which is usually composed of two major phases: (i) sampling of the possible binding modes between the interacting molecules and (ii) scoring for the identification of the correct orientations. In addition, prediction of interface and hot-spot residues is very useful in order to guide and interpret mutagenesis experiments, as well as to understand functional and mechanistic aspects of the interaction. Computational docking is already being applied to specific biomedical problems within the context of personalized medicine, for instance, helping to interpret pathological mutations involved in protein-protein interactions, or providing modeled structural data for drug discovery targeting protein-protein interactions. PMID- 29412998 TI - Computational Resources for Predicting Protein-Protein Interactions. AB - Proteins are the essential building blocks and functional components of a cell. They account for the vital functions of an organism. Proteins interact with each other and form protein interaction networks. These protein interactions play a major role in all the biological processes and pathways. The previous methods of predicting protein interactions were experimental which focused on a small set of proteins or a particular protein. However, these experimental approaches are low throughput as they are time-consuming and require a significant amount of human effort. This led to the development of computational techniques that uses high throughput experimental data for analyzing protein-protein interactions. The main purpose of this review is to provide an overview on the computational advancements and tools for the prediction of protein interactions. The major databases for the deposition of these interactions are also described. The advantages, as well as the specific limitations of these tools, are highlighted which will shed light on the computational aspects that can help the biologist and researchers in their research. PMID- 29413000 TI - Protein-Protein Interaction Modulators for Epigenetic Therapies. AB - Targeting protein-protein interactions (PPIs) is becoming an attractive approach for drug discovery. This is particularly true for difficult or emerging targets, such as epitargets that may be elusive to drugs that fall into the traditional chemical space. The chemical nature of the PPIs makes attractive the use of peptides or peptidomimetics to selectively modulate such interactions. Despite the fact peptide-based drug discovery has been challenging, the use of peptides as leads compounds for drug discovery is still a valid strategy. This chapter discusses the current status of PPIs in epigenetic drug discovery. A special emphasis is made on peptides and peptide-like compounds as potential drug candidates. PMID- 29413001 TI - Intrinsic Disorder, Protein-Protein Interactions, and Disease. AB - It is recognized now that biologically active proteins without stable tertiary structure (known as intrinsically disordered proteins, IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are important players found in any given proteome. These IDPs/IDPRs possess functions that complement functional repertoire of their ordered counterparts, being commonly related to recognition, as well as control and regulation of various signaling pathways. They are interaction masters, being able to utilize a wide spectrum of interaction mechanisms, ranging from induced folding to formation of fuzzy complexes where significant levels of disorder are preserved, to polyvalent stochastic interactions playing crucial roles in the liquid-liquid phase transitions leading to the formation of proteinaceous membrane-less organelles. IDPs/IDPRs are tightly controlled themselves via various means, including alternative splicing, precisely controlled expression and degradation, binding to specific partners, and posttranslational modifications. Distortions in the regulation and control of IDPs/IDPRs, as well as their aberrant interactivity are commonly associated with various human diseases. This review presents some aspects of the intrinsic disorder-based functionality and dysfunctionality, paying special attention to the normal and pathological protein-protein interactions. PMID- 29412999 TI - Using TR-FRET to Investigate Protein-Protein Interactions: A Case Study of PXR Coregulator Interaction. AB - Time-resolved fluorescence resonance energy transfer (TR-FRET) protein-protein interaction assays, especially in the format of receptor coregulator (coactivator and corepressor) recruitment/repression assays, have been widely used in nuclear receptor research to characterize the modes of action, efficacies, and binding affinities of ligands (including their properties as agonists, antagonists, and inverse agonists). However, there has been only limited progress in using this assay format for pregnane X receptor (PXR). In this chapter, we discuss TR-FRET protein-protein interaction assays and focus on a novel PXR TR-FRET coactivator interaction assay that we have developed based on a PXR coactivator cocrystal study. This new PXR TR-FRET coactivator interaction assay can characterize the binding affinities of PXR ligands and also differentiate antagonists from agonists. This assay is very robust, with the signal remaining stable over a long incubation time (up to 300min has been tested). It can tolerate high concentrations of DMSO (up to 5%) and has a high signal-to-noise ratio (six under typical assay conditions). This newly developed PXR TR-FRET coactivator interaction assay has potential application in high-throughput screening to identify and characterize novel PXR agonists and antagonists. PMID- 29413002 TI - Preface. PMID- 29413003 TI - Effects of chitosan oligosaccharides on microbiota composition of silver carp (Hypophthalmichthys molitrix) determined by culture-dependent and independent methods during chilled storage. AB - This study evaluated the effects of chitosan oligosaccharides (COS) on the changes in quality and microbiota of silver carp fillets stored at 4 degrees C. During storage, 1% (w/v) COS treated samples maintained good quality, as evidenced by retarding sensory deterioration, inhibiting microbial growth, attenuating the production of total volatile basic nitrogen, putrescine, cadaverine and hypoxanthine, and delaying degradation of inosine monophosphate and hypoxanthine ribonucleotide. Meanwhile, variability in the predominant microbiota in different samples was investigated by culture-dependent and independent methods. Based on sensory analysis, shelf-life of silver carp fillets was 4 days for the control and 6 days for COS treated samples. Meanwhile, Pseudomonas, followed by Aeromonas, Acinetobacter, and Shewanella were dominated in the control samples at day 4 and contributed to fish spoilage at day 6. However, COS inhibited the growth of Pseudomonas, Aeromonas, and Shewanella significantly. Consequently, Acinetobacter followed by Pseudomonas became the predominant microbiota in COS treated samples at day 6. With the growth of Pseudomonas, COS treated samples were spoiled at day 8. Therefore, COS improved the quality of fillets and prolonged the shelf life of silver carp fillets by 2 days during chilled storage, which was mainly due to their modulating effects on microbiota. PMID- 29413004 TI - LC-MS/MS procedure for the simultaneous determination of N-acetyl-S-(1 naphthyl)cysteine and N-acetyl-S-(2-napthyl)cysteine in human urine. AB - A two-dimensional liquid chromatographic electrospray-ionization tandem mass spectrometric (LC/LC-ESI-MS/MS) procedure for the simultaneous determination of the expected mercapturic acids of naphthalene (1- and 2-naphthylmercapturic acids; 1- and 2-NpMA) and of the well-established parameter for benzene biomonitoring (S-phenylmercapturic acid; PhMA) in human urine was developed, validated and applied to human urine samples. Apart from sample acidification, the enrichment of analytes and sample clean-up as well as the separation of all analytes were completely automated using both a restricted access material column (RAM C18) and a core-shell biphenyl material. Sensitive, specific and reliable detection of all target substances, with limits of detection ranging from 0.03 to 0.04 MUg/L, was achieved using structurally well matching isotope-labelled internal standard substances for each analyte. Intraday and interday precision were determined, ranging from 2.2 to 4.3%, and mean accuracy from 98.4 to 100.8%. Due to the low limits of detection, the good precision and accuracy of the developed procedure, it is well suited for application in biomonitoring studies to evaluate the validity of mercapturic acids as biomarkers after naphthalene exposure. PMID- 29413005 TI - A note from the Editor's desk. PMID- 29413007 TI - Malnutrition in Gastrointestinal Disorders: Detection and Nutritional Assessment. AB - All patients with significant gastrointestinal disease should be clinically assessed for protein calorie malnutrition by using the Subjective Global Assessment. Blood tests for anemia, electrolytes, calcium, phosphorus, magnesium, ferritin, vitamin B12, and folate should be considered for assessment of major micronutrients. Where malabsorption or inflammatory bowel disease is diagnosed, bone mineral density using dual beam x-ray absorptiometry, 25-OH vitamin D levels, and measurement of other vitamins and trace elements should be considered. In addition, in at-risk patients, vitamin and trace element clinical deficiency syndromes should be considered during patient assessment. PMID- 29413008 TI - The Role of Diet in the Treatment of Irritable Bowel Syndrome: A Systematic Review. AB - Irritable bowel syndrome (IBS) is a multifaceted illness involving maladaptive shifts in the gut microbiota that affect the enteric nervous and immune systems, mucosal barrier function, the balance of neurotransmitters and hormones, and emotional well-being. There is abundant evidence indicating that certain foods elicit symptoms in IBS. Numerous elimination-type diets have been shown to alleviate symptoms. However, among these, the most controversial is a group of foods called fructo, oligo-, di-, and monosaccharides and polyols (FODMAPs). This paper reviews the role of diet and systematically analyze the literature for the role of FODMAPs in IBS. PMID- 29413009 TI - Nutritional Consideration in Celiac Disease and Nonceliac Gluten Sensitivity. AB - Celiac disease is an autoimmune disorder due to the inflammatory response to gluten in genetically predisposed individuals. It causes an enteropathy associated with several nutritional complications. Strict compliance to a gluten free diet (GFD) is the current primary therapy. Nonceliac gluten sensitivity (NCGS) is a condition in which gluten ingestion leads to systemic symptoms but is not associated with small bowel atrophy or abnormal celiac serologies. A GFD heals celiac disease enteropathy and improves symptoms in NCGS. However, a long term GFD can be associated with nutritional deficiencies and requires monitoring and guidance. PMID- 29413010 TI - Nutritional Interventions in the Patient with Inflammatory Bowel Disease. AB - Nutritional strategies have been explored as primary or adjunct therapies for inflammatory bowel disease (IBD). Exclusive enteral nutrition is effective for the induction of remission in Crohn disease and is recommended as a first-line therapy for children. Dietary strategies focus on adjusting the ratio of consumed nutrients that are proinflammatory or antiinflammatory. Treatments with dietary supplements focus on the antiinflammatory effects of the individual supplements (eg, curcumin, omega-3 fatty acids, vitamin D) or their positive effects on the intestinal microbiome (eg, prebiotics, probiotics). This article discusses the role of diets and dietary supplements in the treatment of IBD. PMID- 29413011 TI - The Role of Prebiotics and Probiotics in Gastrointestinal Disease. AB - With the advent of the scientific realization that the microbiota of the gastrointestinal tract was more than the cells that exist in the body, the full importance of prebiotics and probiotics has come forth. The importance has been stressed and is available in the new textbook entitled, "The Microbiota in Gastrointestinal Pathophysiology: Implication for Human Health, Prebiotics, Probiotics and Dysbiosis." There is enough evidence now published in the literature so that the scientific world now believes that prebiotics and probiotics are important in gastrointestinal disease. PMID- 29413012 TI - Small Intestinal Bacterial Overgrowth: Nutritional Implications, Diagnosis, and Management. AB - Small intestinal bacterial overgrowth (SIBO), characterized by the presence of excessive bacteria in the small intestine, is typically described as a malabsorptive syndrome occurring in the context of gut stasis syndromes. SIBO is now considered to be a disorder associated with diverse clinical conditions without classic risk factors for SIBO and a cause of several nonspecific gastrointestinal and nongastrointestinal symptoms. Because there is currently no gold standard for diagnosing SIBO, its prevalence and role in the pathogenesis of other diseases remain uncertain; as does optimal treatment of patients with relapsing symptoms. PMID- 29413013 TI - Nutritional Interventions in Chronic Intestinal Pseudoobstruction. AB - Although chronic intestinal pseudo-obstruction (CIPO) is a rare disorder, it presents a wide spectrum of severity that ranges from abdominal bloating to severe gastrointestinal dysfunction. In the worst cases, patients may become dependent upon artificial nutrition via parenteral nutrition or choose to have an intestinal transplant. However, whatever the severity, a patient's quality of life can be seriously compromised. This article defines the disorder and discusses the spectrum of disease and challenges to providing adequate nutrition to help improve a patient's quality of life. PMID- 29413014 TI - The Need to Reassess Dietary Fiber Requirements in Healthy and Critically Ill Patients. AB - This article provides evidence that current dietary fiber intake levels may be insufficient to maintain colonic mucosal health and defense, and reduce inflammation and cancer risk in otherwise healthy people. Current commercial tube feeds generally overlook the metabolic needs of the colon and may predispose patients to dysbiosis, bacterial overgrowth with pathogens such as Clostridium difficile, and acute colitis. These results raise concern about the wide-scale use of prophylactic antibiotics in the intensive care unit and the use of elemental, fiber-depleted tube feeds. Nutrition support is not complete without the addition of sufficient fiber to meet colonic nutritional needs. PMID- 29413015 TI - Enteral Access and Associated Complications. AB - Enteral access is the foundation for feeding in patients unable to meet their nutrition needs orally and have a functional gastrointestinal tract. Enteral feeding requires placement of a feeding tube. Tubes can be placed through an orifice or percutaneously into the stomach or proximal small intestine at the bedside or in specialized areas of the hospital. Bedside tubes can be placed by the nurse or the physician, such as in the intensive care unit. Percutaneous feeding tubes are placed by the gastroenterologist, surgeon, or radiologist. This article reviews the types of enteral access and the associated complications. PMID- 29413016 TI - Nutritional Therapy in Gastrointestinal Cancers. AB - Malnutrition is the most frequent nutritional disorder in patients with gastrointestinal cancer and is associated with cachexia syndrome, worsening of prognosis, and shortened survival rate. Early nutrition screening, assessment, and intervention are able to favorably modify the clinical evolution of affected patients. The adequate provision of nutritional requirements has been associated with improvement of immunologic status, and avoidance of further complications related to poor nutritional status, surgical treatment, and anticancer therapy. In malnourished patients, the supplementation of perioperative immunonutrition might contribute to fewer infectious and noninfectious complications, shorter length of hospitalization, and improved wound healing. PMID- 29413017 TI - Nutritional Considerations in Liver Disease. AB - Malnutrition occurs in most patients with advanced liver diseases and is associated with higher rates of morbidity and mortality. In this article, the authors discuss the pathophysiology of malnutrition and methods to optimize nutrition status in liver disease and include a brief section on perioperative and postoperative nutrition. PMID- 29413018 TI - Parenteral Nutrition: Indications, Access, and Complications. AB - Parenteral nutrition (PN) is a life-sustaining therapy in patients with intestinal failure who are unable to tolerate enteral feedings. Patient selection should be based on a thorough assessment to identify those at high nutrition risk based on both disease severity and nutritional status. This article reviews both the acute and chronic indications for PN as well as special formulation consideration in specific disease states, vascular access, and complications of both short-term and long-term PN. PMID- 29413019 TI - Nutritional Therapy in Adult Short Bowel Syndrome Patients with Chronic Intestinal Failure. AB - Intestinal failure (IF) is the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that parenteral support (PS) is required to maintain health and/or growth. This article critically revises the gaps in and evidence for providing general nutritional therapy recommendations in the Short Bowel Syndrome-IF population. It addresses the need for an individualized approach, aiming to reduce or even eliminate the need for PS, and emphasizes a need to focus on effects of dietary interventions on the quality of life of these patients. PMID- 29413020 TI - Nutritional Aspects of Acute Pancreatitis. AB - The goal of nutritional support in acute pancreatitis is to reduce inflammation, prevent nutritional depletion, correct a negative nitrogen balance, and improve outcomes. Enteral nutrition (EN) in severe acute pancreatitis (SAP) should be preferred to parenteral nutrition. It maintains the integrity of the gut barrier, decreases intestinal permeability, downregulates the systemic inflammatory response, maintains intestinal microbiota equilibrium, and reduces the complications of the early phase of SAP, improving morbidity and possibly improving mortality, and it is less expensive. Further studies to understand optimal timing of nutrition, route of delivery of EN, and the type of nutrition and nutrients are necessary. PMID- 29413021 TI - Nutritional Therapy in Chronic Pancreatitis. AB - Malnutrition is a frequent complication in patients with chronic pancreatitis. Maldigestion as a consequence of pancreatic exocrine insufficiency is the major cause of malnutrition in these patients. Together with that, toxic habits and alterations of the gastroduodenal transit may play a relevant role. Malnutrition in chronic pancreatitis is associated with osteoporosis, sarcopenia, poor quality of life, and increased mortality. An adequate nutritional evaluation including anthropometric, biochemical, and morphologic parameters is recommended in these patients. Nutritional advice and support together with an adequate pancreatic enzyme replacement therapy are indicated. PMID- 29413027 TI - Nutrition and Disease. PMID- 29413028 TI - Nutritional Management of Gastrointestinal Diseases. PMID- 29413029 TI - [In process]. PMID- 29413030 TI - The health of a president: an unnecessary distraction. PMID- 29413031 TI - Facial injuries. PMID- 29413032 TI - Institutional and coercive mental health treatment in Europe. PMID- 29413033 TI - Offline: Why we must learn to love economists. PMID- 29413034 TI - Mega-crisis in DR Congo. PMID- 29413035 TI - Senior WHO appointments are praised but raise questions. PMID- 29413036 TI - Taking control through drama. PMID- 29413037 TI - The updated Physician's Pledge and Chinese junior physicians. PMID- 29413038 TI - Atezolizumab and bladder cancer: facing a complex disease. PMID- 29413039 TI - Great expectations. PMID- 29413040 TI - Great expectations - Authors' reply. PMID- 29413041 TI - Underestimation of the global burden of schistosomiasis. PMID- 29413042 TI - Department of Error. PMID- 29413043 TI - Underestimation of the global burden of schistosomiasis - Authors' reply. PMID- 29413045 TI - PD-L1 expression according to the EGFR status in primary lung adenocarcinoma. AB - OBJECTIVES: It was reported that programmed cell death-ligand 1 (PD-L1) expression is associated with smoking and wild-type epidermal growth factor receptor (EGFR) in lung adenocarcinoma. However, the association between PD-L1 expression and EGFR mutation site in EGFR mutation-positive lung adenocarcinoma is unclear. MATERIALS AND METHODS: We retrospectively examined the relationship between PD-L1 expression and EGFR status in 441 surgically resected primary lung adenocarcinomas. Membrane PD-L1 expression on tumor cells was evaluated by immunohistochemical analysis using a PD-L1 antibody (clone SP142) and defined by tumor proportion scores (TPSs) of 0%, 1-4%, 5-49%, and >=50%, respectively. RESULTS: Two hundred and eighteen (49.4%) patients had wild-type EGFR, and 223 (50.6%) had mutant EGFR-98 (44.0%) with exon 19 deletion, 116 (52.0%) with exon 21 L858R point mutation, and nine (4.0%) with another EGFR mutation. Overall, Fisher's exact test showed that PD-L1 positivity was associated with wild-type EGFR, and there was only one case with PD-L1 TPS >=50% among the cases with mutant EGFR. The analysis of cases with mutant EGFR indicated no significant association between EGFR mutation site and PD-L1 expression. However, the prevalence of PD-L1 TPS 5-49% was higher among patients with EGFR exon 19 deletion than with EGFR exon 21 L858R point mutation. CONCLUSIONS: PD-L1 expression was significantly associated with wild-type EGFR, and PD-L1 TPS >=50% seldom overlaps with presence of driver oncogene EGFR. There was no significant difference in PD-L1 expression among the EGFR mutation sites. PMID- 29413046 TI - ALK fusion variants detection by targeted RNA-next generation sequencing and clinical responses to crizotinib in ALK-positive non-small cell lung cancer. AB - OBJECTIVES: The aim of the present study was firstly to assess in a clinical setting the yields of an amplicon-based parallel RNA sequencing (RNA-seq) assay for ALK fusion transcript variants detection in comparison with immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) in a selected population of ALK-positive and ALK-negative non-small cell lung cancer (NSCLC) cases, and secondly to evaluate the impact of the ALK variant on crizotinib efficacy. MATERIALS AND METHODS: The cohort used for the assessment of the RNA-seq assay comprised 53 samples initially diagnosed as being ALK-positive based on the results obtained by IHC and/or FISH, and 23 ALK-negative samples. A distinction was made between 'truly' IHC/FISH positive or 'truly' IHC/FISH negative samples, and those for which the IHC and/or FISH were equivocal (IHC) or borderline-positive (FISH). RESULTS: On the overall population, RNA-seq sensitivity (Se) and specificity (Spe) were of 80% and 100%, respectively when IHC and FISH were combined. For the 31 'truly positive' samples, Se and Spe of 100% were reached. An ALK status could be assigned by RNA-seq in 10/10 of the equivocal and/or borderline-positive IHC/FISH cases, 2/7 IHC/FISH discordant cases. When crizotinib efficacy was evaluated according to the type of ALK variant, better clinical outcomes were observed in crizotinib-treated patients with EML4-ALK v1/v2/others variants compared to v3a/b variants. CONCLUSION: RNA seq detects ALK rearrangements with a high sensitivity and specificity using only 10 ng of RNA. It appears to be a promising rescue technique for non-clear-cut IHC/FISH cases and also offers a unique opportunity to identify ALK fusion variants and evaluate their predictive value for ALK inhibitors efficacy. PMID- 29413047 TI - Utilization of genomic testing in advanced non-small cell lung cancer among oncologists in the Veterans Health Administration. AB - Current national guidelines recommend genomic testing on all stage 4 non-small cell lung cancers (NSCLC) of adenocarcinoma histology. Mutations are most often found among young, Asian, females without a history of smoking. As these characteristics are uncommon in the Veterans Health Administration (VHA) patient population, we sought to understand oncologists' decision-making processes regarding utilization of genomic testing in the VHA. We conducted in-depth qualitative interviews with 30 VHA-based medical oncologists. Interviews aimed to elicit oncologists' experiences and decision-making processes regarding genomic testing in patients with stage 4 non-small cell lung cancer with adenocarcinoma histology. Analysis was guided by principles of framework analysis. Sample size was determined by thematic saturation. We identified a wide variation in medical oncologists' genomic testing practices. Consistent with guidelines, advanced stage and adenocarcinoma histology most often influenced practice patterns among our participants. However, patient characteristics like gender, age, smoking status, and performance status were also taken in to account by some oncologists when making testing decisions. This does not reflect a widespread adoption of national guidelines for genomic testing in the VHA. Qualitative interviews with VHA-based oncologists demonstrated that genomic testing decisions are not always consistent with current national guidelines. Efforts should be made to address modifiable barriers to genomic testing in the VHA setting. PMID- 29413048 TI - Distinct clinicopathologic features, genomic characteristics and survival of central and peripheral pulmonary large cell neuroendocrine carcinoma: From different origin cells? AB - BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) represents a rare entity in lung cancer with dismal prognosis. In the present study, we investigated whether there are significant differences between central and peripheral tumors of LCNEC, in terms of clinicopathologic features, genomic profiles, and survival. METHODS AND MATERIALS: A total of 126 cases of LCNEC were included. The tumors with invasion of the segmental and/or lobar bronchus were classified as central LCNEC and those without as peripheral LCNEC. EGFR/BRAF/Kras mutations and ALK/ROS1 translocations were detected. Overall survival (OS) was evaluated by the Kaplan-Meier plots. RESULTS: The majority of LCNEC proved to be of the peripheral type (64.3%, 81/126). Central tumors were associated with smoking habit (p = 0.047), higher TNM-stage (p = 0.014) and larger tumor size (p < 0.001). Expression of neuroendocrine markers (CD56, CGA, and SYN) was not significantly different by tumor location but central tumors had higher serum levels of NSE (p = 0.004). Peripheral tumors had a higher incidence of EGFR mutations (18.8% vs. 0%, p = 0.023). ROS1 translocation was detected in 1 patient with peripheral LCNEC. RB1 protein was more frequently expressed in peripheral tumor than central tumor. The median OS was 3.71 years in the entire cohort. Peripheral tumors had better survival compared with central tumors (median OS: 4.04 vs. 1.51 years, p < 0.001). Multivariate analyses demonstrated tumor location (hazard ratio [HR], 6.07, 95% confidence interval [CI], 1.57-23.44, p = 0.009), resection status (HR, 6.58, 95% CI, 1.92-22.51, p = 0.003) and EGFR mutational status (HR, 0.18, 95% CI, 0.04-0.75, p = 0.018) were independent prognostic factors for OS. CONCLUSION: Primary tumor location of LCNEC, divided into central and peripheral type, has distinct clinicopathologic features, genomic characteristics and survival. These differences are likely due to differences in the origin cells and pathogenesis of these tumors. PMID- 29413049 TI - High cripto-1 and low miR-205 expression levels as prognostic markers in early stage non-small cell lung cancer. AB - OBJECTIVES: Cripto-1 (CR-1) plays a critical role in the activation of SMAD, SRC, and epithelial-to-mesenchymal transition (EMT) pathways and has been shown to be prognostic in several cancer types. In addition, we showed that CR-1 renders EGFR mutated NSCLC cells resistant to EGFR-TKI through the activation of SRC and EMT via miR-205 downregulation. This study aimed to investigate the correlation between expression of CR-1 and miR-205 and prognosis of NSCLC patients with or without EGFR mutations. MATERIALS AND METHODS: A total of 265 patients with stage I (AJCC 6th edition) radically resected NSCLC were tested for CR-1 expression and EGFR mutations by immunohistochemistry and miR-205 expression via qPCR assay. RESULTS: CR-1 expression was evaluated with immunohistochemistry using a tissue microarray on 265 T1-2N0 surgical NSCLC samples. Of the 265 tumors, 250 (94%) expressed various levels of CR-1. A significant inverse correlation was identified between expression of miR-205 and CR-1. NSCLC patients (T1N0, n = 106) with high CR-1 expression had worse prognosis (shorter recurrence-free survival, p = .045) than those with low CR-1 expression. A similar trend was observed in NSCLC patients with normal preoperative carcinoembryonic antigen (CEA) levels (serum CEA levels <5 ng/ml; n = 179; p = .085); however, no significant correlation was found between CR-1 expression and survival rate in the T2N0 or high CEA groups. In addition, NSCLC patients with low miR-205 expression (n = 126) had poorer prognosis in terms of recurrence than those with high miR-205 expression (n = 127; p = .001). CONCLUSION: High CR-1 expression is correlated with poor prognosis in NSCLC with low tumor burden and may be used to select high risk patients for adjuvant chemotherapy in early NSCLC. Moreover, low miR-205 expression likely related to high CR-1 expression could be a prognostic marker for patients with NSCLC. PMID- 29413050 TI - Exosomes as a liquid biopsy for lung cancer. AB - In lung cancer and other malignancies, the so-called "liquid biopsy" is quickly moving into clinical practice. Its full potential has not yet been fully identified, but the "liquid biopsy" is no longer a promise but has become a reality that allows for better treatment selection and monitoring of lung cancer. This emerging field has significant potential to make up for the limitations of the traditional tissue-derived biomaterials. Exosomes are spherical nano-sized vesicles with a diameter of 40-100 nm and a density of 1.13-1.19 g/ml. In both physiological and pathological conditions, exosomes can be released by different cell types, including immune cells, stem cells and tumor cells. These small molecules may serve as promising biomarkers in lung cancer "liquid biopsy" as they can be easily obtained from most body fluids. In addition, the lipid bilayer of exosomes allows for stable cargoes which are relatively hard to degrade. Furthermore, the composition of exosomes reflects that of their parental cells, suggesting that exosomes are potential surrogates of the original cells and, therefore, are useful for understanding cell biology. Previous studies have demonstrated that exosomes play important roles in cell-to-cell communication. Moreover, tumor-derived exosomes are evolved in tumor-specific biological process, including tumor proliferation and progression. Recently, a growing number of studies has focused on exosomal cargo and their use in lung cancer genesis and progression. In addition, their utility as lung cancer diagnostic, prognostic and predictive biomarkers have also been studied. The current review primarily summaries lung cancer-related exosomal biomarkers that have recently been identified and discusses their potential in clinical practice. PMID- 29413051 TI - Patterns of treatment and survival among older patients with stage III non-small cell lung cancer. AB - INTRODUCTION: Patterns of treatment and survival are largely unknown for older patients with stage III non-small cell lung cancer (NSCLC) in daily clinical practice. METHODS: All patients >=65 years with stage III NSCLC (2009-2013) were included from the population-based Netherlands Cancer Registry. Descriptive and multivariable treatment and survival analyses were stratified for patients aged 65-74 years and >=75 years. RESULTS: Compared to older patients (n = 3163), those aged 65-74 years (n = 3876) underwent more often surgery (21% vs 12% for stage IIIA), chemoradiotherapy (47% vs 22% for both stage IIIA and IIIB), and chemotherapy (23% vs 12% for stage IIIB), and received less radiotherapy (8% vs 22% for both stage IIIA and IIIB). One-year survival was significantly higher among patients aged 65-74 compared to those aged >=75 (61% vs 43%, for stage IIIA and 45% vs 30% for stage IIIB; P < .01). However, stratification of treatment showed similar survival rates between age groups. Among patients aged 65-74 years, the multivariably adjusted hazard ratio (HR) of death was twice as high for patients receiving radiotherapy (HR 1.9 (95%CI 1.6-2.2) for stage IIIA and HR 2.5 (95%CI 2.1-3.0) for stage IIIB) and chemotherapy (HR 2.2 (95%CI 1.9-2.5) and HR 2.2 (95%CI 1.8-2.7), respectively) compared to chemoradiotherapy, and were slightly lower for patients aged >=75 years receiving radiotherapy (HR 1.6 (95%CI 1.4-1.9) and HR 1.8 (95%CI 1.5-2.1), respectively) and chemotherapy (HR 2.2 (95%CI 1.8-2.7) and HR 1.8 (95%CI 1.5-2.2), respectively). Comorbidity was not significantly associated with poorer survival (p = .07). CONCLUSION: Chemoradiotherapy was more often applied among patients aged 65-74 years compared to those aged >=75. While survival was worse for patients aged >=75 years, differences between age groups largely disappeared after stratification for treatment. Future research should focus on predictive patient characteristics to distinguish patients within the heterogeneous older population who can benefit from curative-intent treatment. PMID- 29413052 TI - Intracerebral efficacy and tolerance of nivolumab in non-small-cell lung cancer patients with brain metastases. AB - OBJECTIVES: Although nivolumab has shown efficacy against non-small-cell lung cancers (NSCLCs), patients with active brain metastases (BMs) were excluded from pivotal clinical trials. Hence, data regarding nivolumab intracerebral activity and safety in NSCLC patients with BMs are scarce. MATERIALS AND METHODS: We conducted a retrospective multicenter study on NSCLC patients with BMs treated with nivolumab. The primary endpoint was intracerebral objective response rate (IORR), according to RECIST criteria. Secondary endpoints included intracerebral control rate, intracerebral and general progression-free survival (PFS), overall survival (OS) and tolerance. RESULTS AND CONCLUSION: Forty-three patients were included. BMs were locally pretreated in 34 (79%) patients and active in 16 (37%) patients. Median follow-up was 5.7 (95% CI: 2.7-8.4) months. IORR and extracerebral response rate were, respectively, 9% (95% CI: 3-23%) and 11% (95% CI: 4-26%). Intracerebral control rate was 51% (95% CI: 37-66%). Median intracerebral and general PFS lasted 3.9 (95% CI: 2.8-11.1) and 2.8 (95% CI: 1.8 4.6) months, respectively. Median OS was 7.5 (95% CI: 5.6-not reached) months. Five neurological adverse events occurred, including 1 grade-4 transient ischemic attack of uncertain imputability and 1 grade-3 neurological deficit; neither required nivolumab discontinuation. Nivolumab intracerebral activity was similar to its reported extracerebral efficacy, with an acceptable safety profile. Prospective and controlled data are needed to determine nivolumab's place in treatment of NSCLC patients with BMs. PMID- 29413053 TI - Primary pulmonary leiomyosarcoma: A population-based study. AB - OBJECTIVES: Primary pulmonary leiomyosarcoma (PPL) is a rare diagnosis with poorly understood clinicopathological characteristics and disease progression. What we know is derived from limited case reports, so identification of features associated with patient survival is warranted. MATERIALS AND METHODS: A population cohort study was conducted using prospectively extracted data from the Surveillance, Epidemiology and End Results (SEER) database for patients with histological diagnoses of PPL from 1973 to 2013 including demographic, treatment and outcome data. RESULTS: A total of 231 patients with PPL were included (mean 65.8 +/- 14.9 years-of-age). 43 were categorized with a regional stage, and 60 had localized stage, whereas 70 had distant stage. Most (60.4%) patients received cancer-directed surgery, and radiotherapy was performed for 14.1% of patients. Median overall survival (OS) was 14.0 months, and 1-, 3- and 5-year OS for PPL patients was 52.7%, 29.0% and 22.2%, respectively. Cancer-directed surgery significantly improved median OS for patients with PPL by almost 29.0 months (33.0 vs 4.0 months; p < .01). Multivariate Cox analysis showed that distant stage was independent prognostic factors for PPL (HR = 2.22, 95% CI 1.30-3.79). Conversely, cancer-directed surgery was an independent protective factor and this decreased risk of death by 57% (HR = 0.43, 95% CI 0.27-0.67) for patients with PPL. CONCLUSION: PPL is a rare pathological lung cancer, surgical resection and distant stage were associated with prognosis. In order to understand PPL more thoroughly, more cases with adequate information are required. PMID- 29413054 TI - A cross-sectional study examining the expression of splice variants K-RAS4A and K RAS4B in advanced non-small-cell lung cancer patients. AB - OBJECTIVES: Mammalian cells differently express 4 RAS isoforms: H-RAS, N-RAS, K RAS4A and K-RAS4B, which are important in promoting oncogenic processes when mutated. In lung cancer, the K-RAS isoform is the most frequently altered RAS protein, being also a difficult therapeutic target. Interestingly, there are two K-RAS splice variants (K-RAS4A and K-RAS4B) and little is known about the role of K-RAS4A. Most studies targeting K-RAS, or analysing it as a prognostic factor, have not taken into account the two isoforms. Consequently, the in-depth investigation of them is needed. METHODS: The present study analysed 98 specimens from advanced non-small cell lung cancer (NSCLC) adenocarcinoma patients originated from Brazil. The alterations present in K-RAS at the DNA level (Sanger sequencing) as well as the expression of the splicing isoforms at the RNA (qRT PCR) and protein levels (immunohistochemistry analysis), were evaluated. Possible associations between clinicopathological features and the molecular findings were also investigated. RESULTS: Our results showed that in the non-smoking population, the cancer incidence was higher among women. In contrast, in smokers and former smokers, the incidence was higher among men. Regarding sequencing results, 10.5% of valid samples presented mutations in exon 2, being all wild type for exon 3, and the most frequently occurring base change was the transversion G -> T. Our qRT-PCR and immunohistochemical analysis showed that both, K-RAS4A and K-RAS4B, were differently expressed in NSCLC tumour samples. For example, tumour specimens showed higher K-RAS4A mRNA expression in relation to commercial normal lung control than did K-RAS4B. In addition, K-RAS4B protein expression was frequently stronger than K-RAS4A in the patients analysed. CONCLUSION: Our results highlight the differential expression of K-RAS4A and K RAS4B in advanced adenocarcinoma NSCLC patients and underline the need to further clarify the enigma behind their biological significance in various cancer types, including NSCLC. PMID- 29413055 TI - Computed tomography in the evaluation of malignant pleural mesothelioma Association of tumor size to a sarcomatoid histology, a more advanced TNM stage and poor survival. AB - OBJECTIVES: Appropriate clinical staging of malignant pleural mesothelioma (MPM) is critical for correct treatment decisions. Newly revised TNM staging protocol has been released for MPM. We investigated baseline computed tomography (CT) characteristics of MPM patients, the new staging system and a simple tumor size (TS) assessment in terms of survival. MATERIALS AND METHODS: As part of our study that included all MPM patients diagnosed in Finland 2000-2012, we retrospectively reviewed 161 CT scans of MPM patients diagnosed between 2007 and 2012 in the Hospital District of Helsinki and Uusimaa. TS was estimated by using the maximal tumor thickness and grading tumor extension along the chest wall. Cox Regression models were used to identify relationships between survival, clinicopathological factors and CT-findings. RESULTS: The median length of follow-up was 9.7 months and the median survival 9.1 months. The right sided tumors tended to be more advanced at baseline and had worse prognosis in the univariate analyses. In the multivariate survival model, TS, pleural effusion along with non-epithelioid histology were predictors of poor survival. Tumor size correlated significantly with a sarcomatoid histopathological finding and several parameters linked to a more advanced TNM stage. Most patients were diagnosed with locally advanced stage, while 12 (7%) had no sign of the tumor in CT. CONCLUSION: In this study, we demonstrate a novel approach for MPM tumor size evaluation that has a strong relationship with mortality, sarcomatoid histology and TNM stage groups. TS could be used for prognostic purposes and it may be a useful method for assessing therapy responses. PMID- 29413056 TI - EGFR-mediated interleukin enhancer-binding factor 3 contributes to formation and survival of cancer stem-like tumorspheres as a therapeutic target against EGFR positive non-small cell lung cancer. AB - OBJECTIVES: YM155, an inhibitor of interleukin enhancer-binding factor 3 (ILF3), significantly suppresses cancer stemness property, implying that ILF3 contributes to cell survival of cancer stem cells. However, the molecular function of ILF3 inhibiting cancer stemness remains unclear. This study aimed to uncover the potential function of ILF3 involving in cell survival of epidermal growth factor receptor (EGFR)-positive lung stem-like cancer, and to investigate the potential role to improve the efficacy of anti-EGFR therapeutics. MATERIALS AND METHODS: The association of EGFR and ILF3 in expression and regulations was first investigated in this study. Lung cancer A549 cells with deprivation of ILF3 were created by the gene-knockdown method and then RNAseq was applied to identify the putative genes regulated by ILF3. Meanwhile, HCC827- and A549-derived cancer stem like cells were used to investigate the role of ILF3 in the formation of cancer stem-like tumorspheres. RESULTS: We found that EGFR induced ILF3 expression, and YM155 reduced EGFR expression. The knockdown of ILF3 reduced not only EGFR expression in mRNA and protein levels, but also cell proliferation in vitro and in vivo, demonstrating that ILF3 may play an important role in contributing to cancer cell survival. Moreover, the knockdown and inhibition of ILF3 by shRNA and YM155, respectively, reduced the formation and survival of HCC827- and A549 derived tumorspheres through inhibiting ErbB3 (HER3) expression, and synergized the therapeutic efficacy of afatinib, a tyrosine kinase inhibitor, against EGFR positive A549 lung cells. CONCLUSION: This study demonstrated that ILF3 plays an oncogenic like role in maintaining the EGFR-mediated cellular pathway, and can be a therapeutic target to improve the therapeutic efficacy of afatinib. Our results suggested that YM155, an ILF3 inhibitor, has the potential for utilization in cancer therapy against EGFR-positive lung cancers. PMID- 29413058 TI - EditorialJoyce J. Fitzpatrick Editor. PMID- 29413057 TI - Tumor biomarker testing in non-small-cell lung cancer: A decade of change. AB - INTRODUCTION: Although a growing list of essential genomic/immune-based biomarkers are linked to approved non-small-cell lung cancer (NSCLC) therapies worldwide, few reports have detailed the evolution of NSCLC predictive biomarker assessment in routine clinical practice. METHODS: We retrospectively reviewed the first one thousand plus NSCLC patient specimens from our institution analyzed for predictive biomarkers from 2004 to 2017 and evaluated patterns of testing as well as correlation with clinical-pathologic characteristics. RESULTS: The majority of 1009 NSCLC patients had advanced stages of adenocarcinoma with most tissues obtained from the lung, mediastinal/hilar nodes, or pleura. The majority of testing was performed on cytology or small biopsy specimens. All were tested for EGFR mutations, 895 for ALK rearrangement, 841 for KRAS mutation, 537 for ROS1 rearrangement, and 179 using comprehensive genomic profiling. Implementation of near-universal genomic biomarker testing at our institution for EGFR, ALK, ROS1 and PD-L1 all occurred within the first year following evidence of clinical activity or regulatory body approval of an associated inhibitor. The overall testing failure rate after use of the best specimen for the most common tests was <=5.5%. A quarter of tumors had a driver oncogene identified (EGFR/ALK/ROS1/BRAF V600E) with an approved oral targeted therapy, with the highest prevalence in those patients with no or light (<=15 pack-years) history of tobacco use. CONCLUSIONS: Tumor biomarker testing using clinical NSCLC specimens in routine oncologic care evolves rapidly following approval of targeted therapies linked to diagnostic assays. Our practice's decade plus experience highlights the rapid evolution of biomarker testing and confirms the therapeutic relevance of such testing in all patients-particularly those patients with light/no history of tobacco use. PMID- 29413059 TI - Factors Associated With Worsened or Improved Mental Health in the Great East Japan Earthquake Survivors. AB - OBJECTIVE: The aim of this study was to identify factors contributing to the worsening or improved mental health of long-term evacuees over three years following the Great East Japan Earthquake. METHOD: The Japanese version of the K6 questionnaire was used as a measure of mental health. The first- and third-year survey results were compared and differences in mental health status calculated. Respondents were then divided into two groups according to worsening or improved mental health status. Differences in stress factors, stress relief methods, and demographics were compared between the two groups. RESULTS: Factors associated with exacerbation of poor mental health were the stress factors "Uncertainty about future" (p=0.048) and "Loss of purpose in life" (p=0.023). Multivariable analysis identified two factors associated with improved mental health, the stress relief methods "Accepting myself" (odds ratio (OR): 2.15, 95% confidence interval (CI): 1.02-4.51) and "Interactions with others" (OR: 3.34, 95% CI: 1.43 7.79). CONCLUSION: While motivation and hope of livelihood reconstruction have gradually risen in the three years since the disaster, anxieties about an uncertain future, loss of purpose in life, and disruption of social networks continue adversely to affect the mental health of survivors. PMID- 29413060 TI - The Effect of a Brief Cognitive Behavioural Stress Management Programme on Mental Status, Coping with Stress Attitude and Caregiver Burden While Caring for Schizophrenic Patients. AB - This experimental study was carried out using a pre-test/post-test control group model to evaluate the effect of a "Brief Cognitive Behavioural Stress Management Programme" (BCBSMP) on mental status, coping with stress attitude, and caregiver burden while caring for patients with schizophrenia. A total of 61 caregivers who provided care for schizophrenia patients at a community mental health centre were included in the study. Caregivers were matched according to gender and scale scores and were assigned to either the study or the control group. Before and after the programme, caregivers in both groups were given the "Demografic Data Form", "Zarit Caregiver Burden Scale", "Coping Attitude Evaluation Scale", "Stress Indicators Scale", and the "General Health Survey-28". Caregivers in the study group were taken to a BCSMP one session per week (each session lasted 120min) for seven weeks. We determined that the stress indicators, the risk of developing a psychological disorder, and caregiver burden decreased and skills related to both the problem-oriented and emotion-oriented aspects of stress increased in the study group after the programme. PMID- 29413061 TI - Willingness to Interact After Therapeutic Recreation in a Patient With Schizophrenia. AB - The study aim was to describe how a patient with schizophrenia who had been in a psychiatric hospital for an extended period of time changed in his desire to interact with others after participating in the therapeutic recreation program, and to interpret his inner process based on symbolic interactionism theory. Data from a patient who showed marked changes in narratives of an interview held after the program and through observation during sessions were analyzed. The patient gained a sense of willingness, including the desire to interact with others and began to act accordingly. PMID- 29413062 TI - Factors Influencing on Mental Health Help-seeking Behavior Among Korean Women: A Path Analysis. AB - PURPOSE: The purpose of the study was to identify factors influencing mental health help-seeking behavior among women in the community. METHODS: A cross sectional design was used. Participants were 402 women in South Korea. Data were analyzed using descriptive statistics, Pearson's correlation coefficient, and a path analysis by IBM SPSS 21.0 and AMOS 21.0. RESULTS: There was a significant, but weak positive correlation between perceived need and help-seeking intentions for formal mental health help (r=0.09, p<0.05). In the path analysis, significant the factors influencing help-seeking intentions were perceived need, attitude, and belief toward mental illness, and the attitude of them had the greatest effect. These factors accounted for 12.2% of the total variance, and the model fit was acceptable. CONCLUSION: The findings of the study reveal that positive mental illness interpretation and consequence can predict mental health help seeking behavior of women as well as the perceived need for mental health help. PMID- 29413063 TI - What Works in a Nurse Led Self-Management Program for Patients with Serious Mental Illness (SMI) and Diabetes (DM). AB - OBJECTIVE: To develop a deeper understanding of "how" a nurse led self-management intervention in a successful randomized controlled trial (RCT) for individuals with both serious mental illness (SMI) and diabetes (DM) influenced health outcomes and the lives of the participants. METHODS: In depth interviews, were conducted with a sample of 10 participants who received the self-management intervention in the RCT. Interviews were audiotaped, transcribed verbatim, and analyzed using content analysis, with an emphasis on dominant themes. RESULTS: The mean age of the respondents was 53.9years (SD=5.6); 6 (60%) were women and the mean level of education was 12.4years (SD=2.4). Transcript based analysis generated 3 major mechanisms of action that led to improved self-management of their SMI and DM: (Colton & Manderscheid, 2006) positive group experience, (Osborn et al., 2008) increased health knowledge, and (Newcomer, 2005) increased self- confidence. CONCLUSIONS: Developing complex interventions for testing in RCTs of individuals with SMI and other comorbid conditions is of increasing importance in healthcare planning for this vulnerable population. Using qualitative methods to explore mechanisms of action underlying quantitative outcomes, can enrich our understanding of processes relevant for individuals with SMI and comorbid conditions. PMID- 29413064 TI - Nurses' perception of knowledge, attitudes and reported practice towards patients with eating disorders: A concurrent mixed-methods study. AB - Eating disorders are complex disorders requiring specialised care, thus knowledge and attitudes are crucial for management. This study aims to examine nurses' knowledge, attitudes, reported practice, and perceptions towards patients with eating disorders in Singapore. A concurrent mixed-methods study was carried out in Southeast Asia's only psychiatric unit with eating disorders programme. Twenty nurses were recruited using census sampling. Quantitative data were analysed with descriptive and inferential statistics, while qualitative data were analysed with content and thematic analysis. Certain personal factors were associated with nurses' levels of perceived knowledge. Different attitudes towards managing these patients were identified during interview sessions. PMID- 29413065 TI - Support Needs of Families of Adolescents With Mental Illness: A Systematic Mixed Studies Review. PMID- 29413066 TI - Resilience from the Perspectives of Caregivers of Persons with Dementia. PMID- 29413067 TI - Mental Health of Nurses Working at a Government-designated Hospital During a MERS CoV Outbreak: A Cross-sectional Study. AB - BACKGROUND: During an epidemic of a novel infectious disease, many healthcare workers suffer from mental health problems. OBJECTIVES: The aims of this study were to test the following hypotheses: stigma and hardiness exert both direct effects on mental health and also indirect (mediated) effects on mental health through stress in nurses working at a government-designated hospital during a Middle East Respiratory Syndrome coronavirus (MERS-CoV) epidemic. METHODS: A total of 187 participants were recruited using a convenience sampling method. The direct and indirect effects related to the study hypotheses were computed using a series of ordinary least-squares regressions and 95% bootstrap confidence intervals with 10,000 bootstrap resamples from the data. DISCUSSIONS: The influences of stigma and hardiness on mental health were partially mediated through stress in nurses working at a hospital during a MERS-CoV epidemic. Their mental health was influenced more by direct effects than by indirect effects. PMID- 29413068 TI - Health Care Professionals Attitudes Towards Mental Illness: Observational Study Performed at a Public Health Facility in Northern Italy. AB - The United Nations Convention on the Rights of Persons with Disabilities Defines stigma as the process of social oppression barring persons with mental illness from enjoying social interaction through discrimination, exclusion and denial of human and social rights. Modern stereotypes still portray the mentally ill as guilty, unpredictable and violent. Observational studies report how healthcare professionals, including nurses, are often part of the stigma. Such phenomenon belittles the needs of people seeking mental care. The aim of this study is to describe attitudes held by psychiatric nurses and mental care professionals from different care settings of an Italian Healthcare Facility, towards the mentally ill and to identify any associated factors. Mental health care professionals were recruited for this observational study from 10 Italian different psychiatric care units. The Italian version of the Community Attitudes Mentally Ill inventory (CAMI-I) was validated and used for this study. 120 completed questionnaires were deemed valid. Optimal internal consistency (alpha=0.856) was measured by calculating Cronbach's Alpha for the CAMI-I. Demographic variables were correlated to items grouped into three factors of the CAMI-I (authoritarian attitudes, benevolence, social restrictiveness). Parametric test (ANOVA) highlight significant differences between CAMI-I results for different demographic variables. Significant data were obtained by comparing responses for each factor of the CAMI-i per professional profile. All healthcare professionals studied show sensitivity and positive attitude towards mental illness. Positive approaches to mental illness contribute towards easing therapeutic care and recovery in patient-centred care. CAMI-I will be a useful tool to identifying discriminatory approaches and sensitize health professionals in Italy. PMID- 29413069 TI - Incidence, Type, Related Factors, and Effect of Workplace Violence on Mental Health Nurses: A Cross-sectional Survey. AB - OBJECTIVE: Workplace violence and its impact on mental health nurses have yet to be thoroughly explored in China. This study aims to investigate the incidence, type, related factors, and effects of workplace violence on mental health nurses as well as identifying coping strategies. METHODS: A researcher - designed workplace violence questionnaire and the Maslach Burnout Inventory-General Survey were distributed to nurses at a mental health hospital in Wuhan, China. RESULTS: Most nurses reported a high incidence of workplace violence (94.6%) in the past year ranging from verbal aggression, sexual harassment, to physical attack. The forms of violence significantly correlated with each other (r>0.5, p=0.000). Working on the psychiatric intensive care unit for adult males and being a male nurse placed nurses at significantly higher risk for workplace violence. Providing routine treatment, caring for male patients, and working the night shift increased the risk of sexual harassment. Nurses who believed that workplace violence was preventable experienced a significantly lower incidence of violence. Burnout levels of the mental health nurses were relatively mild, but increased with age, professional title, years of employment and frequency of workplace violence. CONCLUSION: The incidence of workplace violence among mental health nurses is common, and its frequency is correlated with nurses' level of burnout. Management and clinical nurses should work together on an organization-wide strategy targeting the major identified risk areas to reduce the incidence of workplace violence and minimize its impact on nurses. PMID- 29413070 TI - An Analysis of the Correlates of Aggression in a Social Learning Program for Severely and Persistently Mentally Ill Inpatients. AB - PURPOSE: This study aimed to examine the relationship between behavioral variables and aggression among severely and chronically mentally ill inpatients in a Social Learning Program (SLP) at a state psychiatric facility. METHODS: Using archival data over a 24-month period, a total of 23 severely and chronically mentally ill inpatients comprised the sample in this study. The predictor variables included length of current hospitalization; length of stay on SLP; basic activities of daily living (ADLs); instrumental ADLs; attendance in programming; participation in programming; and the number of minor, major, and intolerable infractions received. The criterion variable was number of aggressive episodes (e.g., hitting persons or objects). RESULTS: Results of a standard multiple regression analysis indicated an overall model of two predictors (intolerable infractions and instrumental ADLs) that significantly predicted number of aggressive episodes. Findings suggested that SLP patients who have a tendency to be aggressive are able to adequately and concurrently complete daily hygiene needs and participate in scheduled treatment groups and activities. DISCUSSION: Our findings provide valuable information regarding aggressive tendencies that can inform treatment planning. Specifically, our results suggested there are not necessarily obvious warning signs for aggression among severely and persistently mentally ill inpatients. Rather, other individualized patient factors may be at play in the expression of aggressive impulses, emphasizing the importance of adequate staff-to-patient ratios so that care planning and implementation can be appropriately individualized. PMID- 29413071 TI - The Magnitude and Determinants of Emotional-Behavioral Problems in Working Adolescents in Turkey. AB - OBJECTIVE: Working adolescents are at a greater risk of mental disorders than are non-working adolescents. The present study was aimed at determining the magnitude and determinants of emotional and behavioral problems in working adolescents. METHODS: This cross-sectional study was conducted with 343 adolescents attending two vocational training centers in the province of Balikesir between January 2016 and March 2016. The data were collected with the Personal Information Form, and the Strengths and Difficulties Questionnaire. In the analysis, descriptive statistics, the t-test, Mann Whitney U test and one way ANOVA were used. RESULTS: In the study of the adolescents, 16.9% were determined to have abnormal emotional and behavioral problems. Of the participating adolescents, girls, those with physical illnesses, living in fragmented families, perceiving their economic status as good, having fathers with primary school education and/or having mothers with high school or higher education had significantly higher emotional and behavioral problem scores (p<0.05). CONCLUSION: In this study, approximately one-fifth working Turkish adolescents had abnormal mental status. Based on the aforementioned results, it can be suggested to develop intervention programs for the prevention, early diagnosis and treatment of emotional and behavioral problems in working adolescents. PMID- 29413072 TI - Predictors of depressive symptoms in older adults living in care homes in Thailand. AB - BACKGROUND: Thai culture traditionally abhors elders living in care homes due to the belief that this represents a dereliction of filial piety by their children, thus care homes are stigmatized as the domain of poor older adults with no family. This may impact negatively on psychological wellbeing of residents, although little is known about the key factors influencing depressive symptoms. Therefore, this study explores factors associated with depressive symptoms, internalised stigma, self-esteem, social support and coping strategies among older adults residing in care homes in Thailand. METHOD/DESIGN: A cross-sectional questionnaire study was conducted with 128 older residents recruited from two care homes in Northeast Thailand. Data were collected using the 15-Item Thai Geriatric Depression Scale, Internalised Stigma of Living in a Care Home Scale, Thai Version of Rosenberg Self-Esteem Scale, Thai Version of Multidimensional Scale of Perceived Social Support and the Coping Strategies Inventory Short-Form. RESULTS: Depressive symptoms were significantly correlated with internalised stigma, self-esteem and social support (r=0.563, -0.574 and -0.333) (p<0.001), respectively. Perceived internalised stigma of living in a care home was the strongest predictor of care home residents reporting depressive symptoms (odds ratio=9.165). DISCUSSION: Older adults who perceived high internalised stigma of living in a care home were over nine times as likely to report experiencing depressive symptoms. Efforts to decrease or prevent perceived internalised stigma might help to reduce depressive symptoms. Interventions might include media collaboration, educational interventions in the care home setting and organising social activities for residents and their families. PMID- 29413073 TI - Validating the Psychometric Characteristics of the Perinatal Posttraumatic Stress Disorder Questionnaire (PPQ) in a Chinese Context. AB - BACKGROUND: Perinatal posttraumatic stress disorder (PPTSD) is a common stress induced mental disorder worldwide. The Perinatal Posttraumatic Stress Disorder Questionnaire (PPQ) is an excellent questionnaire that measures the symptoms of PPTSD, but has not been translated into Chinese yet. OBJECTIVES: The aims of this study were to develop a translated Chinese version of the (PPQ) and validate the psychometric characteristics of the PPQ in a Chinese context. METHODS: After translation, back-translation, and expert discussion, 280 mothers at 1 to 18months postpartum filled out the questionnaires through the Internet. Then the reliability and validity of the translated questionnaire were tested. RESULTS: The Chinese version of PPQ (PPQ-C) was composed of 14 items. Cronbach's alpha coefficient was 0.84, test-retest reliability was 0.88, and the content validity was 0.99. Exploratory factor analysis extracted three factors (representing "arousal", "avoidance" and "intrusion") accounted for 53.30% of the variance. The established 3 factors model was well fitted with the collected data (chi2=76.40, p<0.05). IMPLICATIONS FOR PRACTICE: The PPQ-C is a short, reliable, and valid instrument that measures the symptoms of PPTSD, and it is recommend for clinical screening. IMPLICATIONS FOR RESEARCH: Further research could involve diverse participants, as well as better adapt the PPQ-C to Chinese culture. PMID- 29413074 TI - An investigation of the relationship between schizophrenic patients' strength of religious faith and adherence to treatment. PMID- 29413075 TI - Anger and Tolerance Levels of the Inmates in Prison. PMID- 29413076 TI - Application of the SEIPS Model to Analyze Medication Safety in a Crisis Residential Center. AB - PURPOSE: Medication safety and error reduction has been studied in acute and long term care settings, but little research is found in the literature regarding mental health settings. Because mental health settings are complex, medication administration is vulnerable to a variety of errors from transcription to administration. The purpose of this study was to analyze critical factors related to a mental health work system structure and processes that threaten safe medication administration practices. BACKGROUND: The Systems Engineering Initiative for Patient Safety (SEIPS) model provides a framework to analyze factors affecting medication safety. The model approach analyzes the work system concepts of technology, tasks, persons, environment, and organization to guide the collection of data. METHODS: In the study, the Lean methodology tools were used to identify vulnerabilities in the system that could be targeted later for improvement activities. The project director completed face-to-face interviews, asked nurses to record disruptions in a log, and administered a questionnaire to nursing staff. The project director also conducted medication chart reviews and recorded medication errors using a standardized taxonomy for errors that allowed categorization of the prevalent types of medication errors. RESULTS: Results of the study revealed disruptions during the medication process, pharmacology training needs, and documentation processes as the primary opportunities for improvement. The project engaged nurses to identify sustainable quality improvement strategies to improve patient safety. CONCLUSION: The mental health setting carries challenges for safe medication administration practices. Through analysis of the structure, process, and outcomes of medication administration, opportunities for quality improvement and sustainable interventions were identified, including minimizing the number of distractions during medication administration, training nurses on psychotropic medications, and improving the documentation system. A task force was created to analyze the descriptive data and to establish objectives aimed at improving efficiency of the work system and care process involved in medication administration at the end of the project. PMID- 29413077 TI - Depression and Pharmacogenetics. AB - Depression is the most common and leading devastating psychiatric illness that affects a majority of the world population. The treatment of depression has been a challenge for a majority of patients and healthcare practitioners. The advent of pharmacogenomics (PGx) empowered the Food and Drug Administration to approve some antidepressant biomarkers for PGx model of treatment. The PGx testing identifies whether an individual is a poor metabolizer, ultra/rapid metabolizer, intermediate metabolizer, or essential metabolizer of an antidepressants before prescription. This is a cutting edge treatment that eliminates trial and error. PGx testing has shown to precisely identify the effective medication and dose for a patient. PMID- 29413078 TI - The Effects of Anger Management Education on Adolescents' Manner of Displaying Anger and Self-Esteem: A Randomized Controlled Trial. PMID- 29413079 TI - Yoga to Enhance Self Efficacy: An Intervention for At-risk Youth. AB - OBJECTIVE: Yoga has demonstrated effectiveness in improving self-management in a variety of disease states however little is known about the impact of yoga as a health promotion intervention for adolescent females in an urban school based environment. This pilot study was conducted to determine if yoga could improve the self-efficacy and body core tone in at-risk adolescent female participants. METHOD: A quasi-experimental design was employed, with data collection at baseline, end of program, and 1month post-program. Fifteen participants ages 11 14 were recruited. Yoga was practiced twice weekly for eight weeks. Self-efficacy was measured using a standardized tool, the Self-Efficacy Questionnaire for Children (SEQ-C). Improvements in flexibility and core body tone were also examined. The researchers collected data on adverse childhood events using the Adverse Childhood Event (ACEs) scale. RESULTS: Fifteen participants were successfully recruited and 14 (87%) were retained through the duration of the project. Based on the small sample size, non-parametric tests were used (Freidman's test). Although there were no significant improvements in total SEQ C, there were significant improvements in SEQ-C social subscale (p=0.028). Significant improvements were also identified in waist circumference (p=0.001) and in flexibility (p=0.034). CONCLUSIONS: Participant attendance/dose did not correlate to any of the outcomes, however with the physical and emotional improvements noted, it is assumed that any level of attendance was beneficial. Improvements in the social subscale of the SEQ-C could be the result of belonging to a group and strengthening healthy relationships. PMID- 29413080 TI - Rumination, Social Problem Solving and Suicide Intent Among Egyptians With a Recent Suicide Attempt. AB - The more complex influences of social problem-solving abilities and rumination specifically brooding and reflection-on suicide intent is not well understood. We hypothesized that social problem solving would moderate the association between reflection and suicide intent, and mediate the influence of brooding on suicide intent. A convenience sample (N=186) of individuals hospitalized for recent suicide attempt was interviewed, assessing suicide intent, social problem solving, brooding, reflection and depression. Brooding and reflection were positively associated with suicide intent. The mediating, but not the moderating, hypothesis was supported. Brooding was not significant (beta=0.15, t=1.92, p=0.06) with social problem solving controlled. Interventions to disengage rumination and improve social problem-solving skills are underscored. PMID- 29413081 TI - Lessons From the Light and Dark Sides of Psychiatric Clinical Experiences. PMID- 29413082 TI - The Relationship Between the Hope Levels of Patients With Schizophrenia and Functional Recovery. PMID- 29413084 TI - Idiopathic pulmonary fibrosis: idiopathic no more? PMID- 29413085 TI - Validation of multidisciplinary diagnosis in IPF. PMID- 29413086 TI - Tackling antimicrobial resistance in food-producing animals. PMID- 29413087 TI - A self-made coffin. PMID- 29413083 TI - Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic? AB - Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and typically fatal lung disease characterised by subpleural fibrosis, subepithelial fibroblast foci, and microscopic honeycombing. Although understanding of the pathogenic mechanisms continues to evolve, evidence indicates that distal airway and alveolar epithelial cells are central drivers of the disease. In this Viewpoint, we review the history of naming and classifications used to define the disease now referred to as IPF, in the context of understanding the clinical presentation, causes, and pathogenesis of the disease. We aim to generate discussion on whether, given the substantial progress made in understanding the clinical, genetic, cellular, and molecular mechanisms involved in the development of IPF, a change of name should be considered. To initiate this discussion, we offer new suggestions to update the name of this disease and new approaches to classify all forms of pulmonary fibrosis. PMID- 29413088 TI - Diagnostic criteria for idiopathic pulmonary fibrosis. PMID- 29413089 TI - Diagnostic criteria for idiopathic pulmonary fibrosis. PMID- 29413090 TI - Diagnostic criteria for idiopathic pulmonary fibrosis - Authors' reply. PMID- 29413092 TI - A single dose polyanhydride-based vaccine platform promotes and maintains anti GnRH antibody titers. AB - Traditionally, vaccination strategies require an initial priming vaccination followed by an antigen boost to generate adequate immunity. Here we describe vaccination against a self-peptide for reproductive sterilization utilizing a three-stage vaccine platform consisting of gonadotropin releasing hormone multiple antigenic peptide (GnRH-MAP) as a soluble injection coupled with subcutaneous administration of polyanhydride-immobilized GnRH-MAP and a cyto exclusive implant containing GnRH-MAP dendrimer-loaded polyanhydride. This strategy generated and maintained cell-mediated and humoral immunity for up to 41 weeks after a single vaccination in mice with enhanced antibody avidity over time. All intact implants had a grossly visible tissue interface with neovascularization and lymphocytic aggregates. Despite detectable immunity, sterility was not achieved and the immune response did not lead to azoospermia in male mice nor prevent estrus and ovulation in female mice. However, the vaccine delivery device is tunable and the immunogen, adjuvants and release rates can all be modified to enhance immunity. This technology has broad implications for the development of long-term vaccination schemes. PMID- 29413093 TI - A polyanhydride-based implantable single dose vaccine platform for long-term immunity. PMID- 29413094 TI - Vaccine-preventable, hospitalizations among American Indian/Alaska Native children using the 2012 Kid's Inpatient Database. AB - Our aim was to assess the odds of hospitalization for a vaccine-preventable, infectious disease (VP-ID) in American Indian/Alaska Native (AI/AN) children compared to other racial and ethnic groups using the 2012 Kid's Inpatient Database (KID) The KID is a nationally representative sample, which allows for evaluation of VP-ID in a non-federal, non-Indian Health Service setting. In a cross-sectional analysis, we evaluated the association of race/ethnicity and a composite outcome of hospitalization due to vaccine-preventable infection using multivariate logistic regression. AI/AN children were more likely (OR=1.81, 95% CI=1.34, 2.45) to be admitted to the hospital in 2012 for a VP-ID compared to Non Hispanic white children after adjusting for age, sex, chronic disease status, metropolitan location, and median household income. This disparity highlights the necessity for a more comprehensive understanding of immunization and infectious disease exposure among American Indian children, especially those not covered or evaluated by Indian Health Service. PMID- 29413095 TI - Editorial. PMID- 29413096 TI - Editor-in-Chief "Changing of the Guard" Editorial. PMID- 29413097 TI - A cross-sectional study of the relationship between infant Thimerosal-containing hepatitis B vaccine exposure and attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is characterized by a marked pattern of inattention and/or hyperactivity-impulsivity that is inconsistent with developmental level and interferes with normal functioning in at least two settings. This study evaluated the hypothesis that infant Thimerosal-containing hepatitis B vaccine (T-HepB) exposure would increase the risk of an ADHD diagnosis. This cross-sectional study examined 4393 persons between 13 and 19 years of age from the combined 1999-2004 National Health and Nutritional Examination Survey (NHANES) by analyzing demographic, immunization, socioeconomic, and health-related variables using the SAS system. Three doses of T-HepB exposure in comparison to no exposure significantly increased the risk of an ADHD diagnosis using logistic regression (adjusted odds ratio=1.980), linear regression (adjusted beta-coefficient=0.04747), Spearman's rank (Rho=0.04807), and 2*2 contingency table (rate ratio=1.8353) statistical modeling even when considering other covariates such as gender, race, and socioeconomic status. Current health status outcomes selected on an a priori basis to not be biologically plausibly linked to T-HepB exposure showed no relationship with T HepB. The observed study results are biologically plausible and supported by numerous previous epidemiological studies, but because the NHANES data is collected on a cross-sectional basis, it is not possible to ascribe a direct cause-effect relationship between exposure to T-HepB and an ADHD diagnosis. During the decade from 1991 to 2001 that infants were routinely exposed to T-HepB in the United States (US), an estimated 1.3-2.5 million children were diagnosed with ADHD with excess lifetime costs estimated at US $350-$660 billion as a consequence of T-HepB. Although Thimerosal use in the HepB in the US has been discontinued, Thimerosal remains in the HepB in developing countries. Routine vaccination is an important public health tool to prevent infectious diseases, but every effort should be made to eliminate Thimerosal exposure. PMID- 29413098 TI - Status and interrelationship of toenail elements in Pacific children. AB - OBJECTIVE: Elemental deficiencies or in excess effects growth and development. Pacific population are at a disadvantage due to food insecurity as compared to New Zealand European households. This study aims to evaluate the status and interrelationship of elements (essential, non-essential and toxic) in nine-year old Pacific children who were part of the Pacific Island Families Study living in New Zealand. MATERIALS AND METHODS: This observational study included 278 eligible nine-year-old children. Essential elements (including calcium, chromium, cobalt, copper, iodine, iron, magnesium, manganese, selenium, zinc, molybdenum), non-essential and toxic elements (arsenic, aluminum, antimony, boron, cadmium, lead, mercury, nickel,) were determined in toenails and after acid digestion, analysed using inductively coupled plasma mass spectrometry. Principal component analysis and multivariate analysis of covariance was used to identify differences in the groups of elements and the inter-correlations between elements. RESULTS: The mean calcium (868MUg/g Ca), selenium (0.35MUg/g Se) and zinc (129MUg/g Zn) concentrations were lower while the mean cadmium (0.21MUg/g Cd) lead (0.86MUg/g Pb) and mercury (0.72MUg/g Hg) concentrations were higher than the optimal health requirements. Ethnic differences in relation to toenail elemental concentrations were observed for aluminium and iron. Gender differences were observed for aluminium, antimony, arsenic and lead. Selenium and molybdenum were inversely associated with mercury. Manganese, zinc and calcium were positively associated. CONCLUSIONS: This research contributes to the understanding of the elemental concentrations for Pacific children by using tissue samples from toenails, which improves the completeness of sampling than other tissues and provides a longer exposure time frame. The study also reports several inter-correlations between essential, non-essential and toxic elements in Pacific Island population. PMID- 29413099 TI - Early pregnancy maternal trace mineral status and the association with adverse pregnancy outcome in a cohort of Australian women. AB - Maternal micronutrient deficiencies in pregnancy can have profound effects on fetal development and pregnancy outcome. Plasma trace minerals including copper, zinc, selenium and iron have been shown to be extremely important in supporting reproduction. We sought to determine whether there is an association between maternal trace mineral status in early pregnancy and pregnancy complications using a prospective cohort study of 1065 pregnant Australian women who were recruited as part of the Screening for Pregnancy Endpoints (SCOPE) study in Adelaide. Copper, zinc, selenium and iron present in the plasma were measured using mass spectrometry in samples collected at 15+/-1 weeks' gestation. After adjusting for covariates, women with lower plasma copper (<27.9MUmol/L and 27.9 32.5MUmol/L) had decreased risk for any pregnancy complication when compared with women with high plasma copper (>32.5MUmol/L) (aRR=0.87; 95% CI=0.76, 0.99 and aRR=0.88; 95% CI=0.78, 1.00, respectively). This was also observed when adjusting for plasma zinc and selenium status (<27.9MUmol/L: aRR=0.81; 95% CI=0.69, 0.96 and 27.9-32.5MUmol/L: aRR=0.84; 95% CI=0.72, 0.98). Combined low copper and zinc status was also associated with a reduced risk of any pregnancy complication as compared with high copper and zinc status (aRR=0.80; 95% CI=0.70, 0.93). These results provide justification for further work into elucidating the mechanistic role of trace elements in early pregnancy, as well as their interactions in supporting successful pregnancy outcomes. PMID- 29413100 TI - Interaction between iodine and glucosinolates in rutabaga sprouts and selected biomarkers of thyroid function in male rats. AB - Rutabaga sprouts belong to the Brassicaceae family and may exert a negative influence on thyroid function, because they are a rich in glucosinolates. These sprouts are also valuable source of iodine (6.5 +/- 0.6 MUg/100 g of fresh weight). Sprouts were tested in a long-term experiment with young male rats as an element of their diet, combined with two models of hypothyroidism, the first - deficit of iodine and the second - sulfadimethoxine ingestion as a pharmacological agent caused inhibition of thyroid peroxidase. Evaluations were performed for the serum TSH and thyroid hormones together with analyzes of thyroid histopathology, cytosolic glutathione peroxidase (GPX1), thioredoxin reductase in the thyroid, plasma GPX3 and CAT, erythrocyte GPX1. Rutabaga sprouts' intake by healthy rats did not cause any harmful effect on their health, including thyroid function. For animals with hypothyroidism, rutabaga sprouts enhanced the adverse effect of iodine deficiency or ingestion of sulfadimethoxine on the organism. According to the results obtained for young male rats thyroid function, the interpretation of data for human exposure to rutabaga sprouts has to be avoided. Furthermore, unless new scientific data confirms a lack of the negative effect of brassica sprouts on thyroid function in human, they should not be excluded from the group of goitrogenic products. PMID- 29413101 TI - The beneficial effects of Zn on Akt-mediated insulin and cell survival signaling pathways in diabetes. AB - Zinc is one of the essential trace elements and participates in numerous physiological processes. Abnormalities in zinc homeostasis often result in the pathogenesis of various chronic metabolic disorders, such as diabetes and its complications. Zinc has insulin-mimetic and anti-diabetic effects and deficiency has been shown to aggravate diabetes-induced oxidative stress and tissue injury in diabetic rodent models and human subjects with diabetes. Akt signaling pathway plays a central role in insulin-stimulated glucose metabolism and cell survival. Anti-diabetic effects of zinc are largely dependent on the activation of Akt signaling. Zn is also an inducer of metallothionein that plays important role in anti-oxidative stress and damage. However, the exact molecular mechanisms underlying zinc-induced activation of Akt signaling pathway remains to be elucidated. This review summarizes the recent advances in deciphering the possible mechanisms of zinc on Akt-mediated insulin and cell survival signaling pathways in diabetes conditions. Insights into the effects of zinc on epigenetic regulation and autophagy in diabetic nephropathy are also discussed in the latter part of this review. PMID- 29413103 TI - Iodine in Swiss milk depending on production (conventional versus organic) and on processing (raw versus UHT) and the contribution of milk to the human iodine supply. AB - The iodine content in milk depends on various factors, including the season, production system, and location of milk production. The aim of this study was 1) to obtain data on the iodine concentration of conventional and organically produced milk and according to seasons; 2) to compare these actual data with previous measurement data; 3) to study the influence of UHT treatment on the iodine content and 4) to estimate the contribution of organic and conventional milk to the consumer's iodine intake. A total of 110 samples of conventional and organic ultra-heat treated (UHT) whole milk were collected in the period between 1 May 2013 and 30 April 2014 from two large-scale companies, processing milk from two regions in Switzerland. The iodine concentration in organic milk (average 71 +/- 25 MUg/l) was significantly lower than in conventional milk (average 111 +/- 26 MUg/l) and varied between suppliers. Milk iodine concentration varied according to the month of collection in organic and conventionally produced milk, with lowest values between August and October (organic milk 42 MUg/l; conventional milk 75 MUg/l) and highest values in January (organic milk 99 MUg/l; conventional milk 145 MUg/l). Heat treatment did not influence iodine concentration. Since milk and dairy products are significant source of food related iodine intake in Switzerland, consumers who prefer organic milk and dairy products are likely to have an inferior iodine status. PMID- 29413102 TI - Synchrotron analysis of human organ tissue exposed to implant material. AB - BACKGROUND: Orthopaedic implants made of cobalt-chromium alloy undergo wear and corrosion that can lead to deposition of cobalt and chromium in vital organs. Elevated cardiac tissue cobalt levels are associated with myocardial injury while chromium is a well-established genotoxin. Though metal composition of tissues surrounding hip implants has been established, few investigators attempted to characterize the metal deposits in systemic tissues of total joint arthroplasty patients. METHODS: We report the first use of micro-X-ray fluorescence coupled with micro-X-ray absorption spectroscopy to probe distribution and chemical form of cobalt, chromium and titanium in postmortem samples of splenic, hepatic and cardiac tissue of patients with metal-on-polyethylene hip implants (n = 5). RESULTS: Majority of the cobalt was in the 2+ oxidation state, while titanium was present exclusively as titanium dioxide, in either rutile or anatase crystal structure. Chromium was found in a range of forms including a highly oxidised, carcinogenic species (CrV/VI), which has never been identified in human tissue before. CONCLUSIONS: Carcinogenic forms of chromium might arise in vital organs of total joint arthroplasty patients. Further studies are warranted with patients with metal-on-metal implants, which tend to have an increased release of cobalt and chromium compared to metal-on-polyethylene hips. PMID- 29413104 TI - Apoptosis in pancreatic beta-cells is induced by arsenic and atorvastatin in Wistar rats with diabetes mellitus type 2. AB - INTRODUCTION: Diabetes Mellitus type 2 (T2D) is a multifactorial disease. However, it is known that there is an important effect in pancreatic beta-cells caused by apoptosis of pro-apoptotic proteins, possibly related to arsenic exposure and atorvastatin treatment. OBJECTIVE: The goal of this study was to evaluate the effects of atorvastatin treatment on apoptosis of pancreatic beta cells in Wistar rats with induced diabetes type 2 exposed to arsenic. MATERIAL & METHODS: T2D in Wistar rats was induced by administration of Streptozotocin. The plasmatic glucose concentrations were measured using the glucose oxidase method, and the concentration of glycated hemoglobin (HbA1c) in whole blood was determined. Exposure to arsenic was measured from urine using atomic absorption with hydride generation, and pro-apoptotic proteins in pancreatic beta-cells were observed using the Western blotting technique. RESULTS: Caspase-3 was present in rats that were treated with 10 mg/kg of oral atorvastatin and exposed to 0.01 and 0.025 mg/L of arsenic, but no others proteins were present, such as pro Caspase 8, bcl-2, and Fas. The glycemic levels were 129.2 +/- 7.0 mg/dL in the control group and 161.8 +/- 14.6 mg/dL and 198.3 +/- 18.2 mg/dL (p < .05) in the study groups. HbA1c increased from 2.53% to 3.64% (p < .05) in the control and study groups. CONCLUSIONS: Atorvastatin treatment and arsenic exposure alone are capable of generating apoptosis in pancreatic beta-cells of Wistar rats with T2D. Together, all of these factors induce apoptosis in pancreatic cells. PMID- 29413105 TI - Diagnostic potential of major and trace elements in the serum of bladder cancer patients. AB - Major and trace elements may play a role in the diagnosis of diseases. In this study, we investigated the concentration of 26 major and trace elements in the serum by inductively coupled plasma (ICP) - optical emission spectrometry (OES) and ICP-sector field-mass spectrometry (sf-MS). We analyzed the serum from a discovery cohort of 6 bladder cancer (BCa) patients and 12 healthy controls as well as from a validation cohort of 21 BCa patients, 29 non-tumor bladder patients (with acute and chronic inflammation) and 18 healthy controls. Patients were recruited after written consent was obtained at one medical center. Serum was prepared from peripheral blood prior to surgical treatment. Differences in the levels of major and trace elements were determined by a nonparametric Mann Whitney test and Kruskal-Wallis statistics. In the discovery cohort, we measured significantly increased levels of calcium, mercury, potassium, lithium, nickel, phosphorus and strontium and a significantly decreased level of sodium in BCa patients compared with healthy controls. These findings were reassessed in our validation cohort. We measured significantly increased levels of boron, calcium, cadmium, copper, chromium, lead, lithium, potassium, magnesium, nickel, sulfur, strontium, titan, vanadium and zinc and significantly decreased levels of iron and molybdenum. When we studied the concordance for the discovery and validation cohorts, concentrations of five elements were detected as significantly increased in BCa patients compared with healthy controls: calcium, lithium, potassium, nickel, and strontium. Interestingly, the levels of three elements (calcium, potassium and strontium) were also significantly increased in non-tumor bladder patients compared with healthy controls. But no element was significantly altered between non-tumor bladder patients and BCa patients. In summary, we suggest that determination of the elements calcium, lithium, nickel and strontium in the serum could be a new and promising tool for the early diagnosis of BCa. PMID- 29413106 TI - Enhanced pharmacological actions of p,p'-methoxyl-diphenyl diselenide-loaded polymeric nanocapsules in a mouse model of neuropathic pain: Behavioral and molecular insights. AB - Neuropathic pain is a public health problem and its treatment is a global challenge. The organoselenium compound p,p'-methoxyl-diphenyl diselenide [(OMePhSe)2] has a potential antinociceptive action and its incorporation into nanocapsules improves this action. The current study evaluated if (OMePhSe)2 administration, free or incorporated into nanocapsules, reduces the chronic pain like behavior induced by the partial sciatic nerve ligation (PSNL) surgery, a neuropathic pain mouse model. It was also investigated the (OMePhSe)2 restorative effect against the increase in inflammatory and apoptotic protein contents at the central nervous system caused by PSNL to mice. Male Swiss mice were subjected to PSNL during 4 weeks and treated with (OMePhSe)2, free or incorporated into nanocapsules, in a single (25mg/kg, i.g.) or repeated administration schedule (25mg/kg, i.g., once a day for seven days). Both treatments reduced mechanical hypernociception induced by PSNL, but the nanoencapsulation increased the (OMePhSe)2 antinociceptive action two-fold in comparison to its free form. PSNL increased the inflammatory protein contents (iNOS, COX-2, NF-kappaB, IL-1beta and TNF-alpha) and those of bax and clivated PARP, and reduced bcl-2 content, apoptotic proteins, in the mouse cerebral contral lateral cortex. Furthermore, PSNL induced an activation of MAPK pathway (ERK1,2 and p38). The free or nanoencapsulated (OMePhSe)2 repeated administration restored the molecular changes in the protein contents. This study demonstrates the (OMePhSe)2 nanocapsule effectiveness in an animal model of chronic pain. PMID- 29413107 TI - Bioimpedance parameters in adolescent athletes in relation to bone maturity and biochemical zinc indices. AB - Phase angle (PA) is derived from resistance and reactance determined by bioimpedance analysis (BIA) and it appears to relate to cellular stability and integrity. Interpretation of PA values could be complemented by bioelectrical impedance vector analysis (BIVA), which relates to body hydration and structure. Body composition, age, sex, and nutrients are known to stabilize cell membranes, such as zinc, have been related to PA although information is scarce in adolescent athletes. The aim of the present study was to assess the association of body composition, skeletal maturity and zinc biochemical indices with phase angle and bioelectrical impedance parameters, in forty male adolescent soccer athletes (13.4+/-0.6years). BIA was performed with a single-frequency tetrapolar analyzer. PA and BIVA were determined using resistance and reactance BIA data. Plasma and erythrocyte zinc concentrations were measured using inductively coupled plasma-optical emission spectrometry. Body composition was determined by dual-energy X-ray absorptiometry, and bone age by hand X-ray measurements. PA was higher in adolescents classified by bone age as "Early" (6.8+/-0.9 degrees ) compared to "Late" (5.7+/-0.5 degrees ) (p<0.05). PA correlated with bone age (r=0.562), BMI (r=0.382), fat-free mass (r=0.468), and erythrocyte zinc (r=0.379) (p<0.05). BIVA confidence ellipses were sensitive to skeletal maturity status. Phase angle was higher in adolescents with erythrocyte zinc concentration above the median (>0.66MUmol.g hemoglobin-1) compared to those below the median. Multiple linear regression analysis showed that bone age (B=0.254, p=0.001) and erythrocyte zinc concentration (B=1.168, p=0.047) were significantly related to PA in this group, and accounted for 34% of its variability. Our results indicate that bone age and zinc erythrocyte contribute to PA values in the young male soccer athletes and that BIVA is influenced by skeletal maturity status in this group. PMID- 29413108 TI - Chronic exposure to low-level cadmium induced zinc-copper dysregulation. AB - BACKGROUND AND OBJECTIVES: Exposure to cadmium (Cd) has been associated with aberrant zinc and copper homeostasis. This study investigated if Cd exposure impairs renal reabsorption of metals. METHODS: Renal tubular reabsorption of metals were calculated from urine to serum metal ratios and analyzed for an independent association with Cd exposure levels, using data from 100 men and 100 women, aged 16-60 years. RESULTS: The smoking prevalence was 30% in men and 0% in women. The male and female means (SD) for urine Cd were 0.54 (0.43) and 0.62 (0.43) MUg/g creatinine. The mean (SD) for fractional zinc reabsorption was 77.2 (23) % in men and 87.7 (13.3) % in women, while the copper reabsorption was 100% in both men and women. Lower zinc reabsorption levels were associated with higher Cd exposure (P<0.001), higher serum copper to zinc ratios (P=0.007) and higher tubular impairment levels (P=0.024). Reduced zinc reabsorption was particularly severe in smokers as those with high Cd exposure had 44.9% and 37.2% (P<0.001) lower zinc reabsorption than those with low and moderate exposures. The mean zinc reabsorption in male non-smokers with high Cd exposure was 25.8% (P<0.001) and 18.2% (P=0.003) lower than those with low and moderate exposures, while the corresponding figure for female non-smokers was 17% (P<0.001), and 12.8% (P=0.013), respectively. CONCLUSIONS: This is the first report demonstrating Cd dose dependent reduction in renal zinc reabsorption and high serum copper to zinc ratios. PMID- 29413109 TI - Serum cobalt status during pregnancy and the risks of pregnancy-induced hypertension syndrome: A prospective birth cohort study. AB - Cobalt (Co) is an essential trace element and has been suggested to be involved in blood pressure regulation, but few studies have focused on serum Co status during pregnancy and the risks of pregnancy-induced hypertension syndrome (PIH). The aim of this study was to prospectively assess the association between serum Co levels during pregnancy and the risks of PIH, and to explore how the maternal Co status contributes to the incidence of PIH. 3260 non-hypertensive women before pregnancy with singleton births in Ma'anShan birth cohort study (MABC) were recruited with the assessment of maternal Co concentrations, additionally, the levels of 7 inflammatory factors and 3 stress factors in placentas were also determined. Relative risks (RRs) [95% confidence intervals (CIs)] for the risks of PIH were assessed and the relationships between 10 factors and maternal Co status during pregnancy were evaluated as well. A total of 194 (5.95%) women were diagnosed with PIH. The concentrations of Co varied from the first trimester to the second trimester, and maternal serum Co concentrations during pregnancy were negatively associated with the incidence of PIH in a linear fashion. There was a clear trend in RRs according to decreasing exposure to Co levels in the second trimester (RRa=1.80, 95% CI (1.26, 2.56); RRb=1.73, 95% CI (1.21, 2.46) and RRc=1.43, 95% CI (1.02, 2.04) when low Co levels comparing with high Co levels before and after adjustment for confounders; and RRa=1.29, 95% CI (0.88, 1.88); RRb=1.28, 95% CI (0.87, 1.87) and RRc=1.25, 95% CI (0.86, 1.82) when medium Co levels comparing with high Co levels before and after adjustment for confounders). In addition, the trend for the first trimester was nearly identifical to those for the second trimester (RRa=1.35, 95% CI (0.94, 1.93); RRb=1.33, 95% CI (0.93, 1.91); RRc=1.22, 95%CI (0.86, 1.73) when low Co levels comparing with high Co levels before and after adjustment for confounders; and RRa=1.10, 95% CI (0.76, 1.60); RRb=1.13, 95% CI (0.77, 1.64) and RRc=1.12, 95% CI (0.77, 1.63) before and after adjustment for confounders). Interestingly, Co concentrations in the second trimester were also inversely associated with the levels of some inflammatory factors and all three stress factors in placentas. This prospective study suggested that lower maternal serum Co concentration in the second trimester may associate with the incidence of PIH in Chinese population. Additionally, the maternal Co concentrations in the second trimester could reduce inflammatory and oxidative damage to the placenta. Further evidence is needed to support the findings and assess the mechanisms underlying the association. PMID- 29413110 TI - Usefulness of laser ablation ICP-MS for analysis of metallic particles released to oral mucosa after insertion of dental implants. AB - Despite the fact that titanium is considered highly biocompatible, its presence in the oral cavity (an environment of frequently changing pH and temperature) may result in the release of titanium from intraosseous implants into the oral mucosa, causing a range of reactions from the human body. Fragments of oral mucosa collected from patients after dental implant insertion were analyzed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The study revealed an elevated content of elements (Ti, Al, V) which are components of the metal implants and temporary cover screws. Dynamic ablation of the tissue surface was used in order to obtain maps of the content and distribution of analyzed elements. The material consisted of 30 oral mucosa tissue fragments collected 3-5 months after implantation and 10 samples collected before implantation (control group). The application of optical microscope allowed for indication and confirmation of the location of metal particles prior to LA-ICP-MS analysis. The so-obtained map permitted location of regions containing metal particles. LA-ICP-MS analysis revealed groups of samples with similar properties of metal particles, thus confirming that those metal particles were the main source of the elevated content of metals (Ti, Al, V) in the tissue after implantation. A calibration strategy based on matrix matched solid standards with powdered egg white proteins as matrix material was applied with 34S as an internal standard. The accuracy of the analytical method was verified by ablating pellets of certified reference material ERM-BB422 Fish muscle. PMID- 29413111 TI - Subclinical mastitis (SCM) and proinflammatory cytokines are associated with mineral and trace element concentrations in human breast milk. AB - The possibility that either subclinical mastitis (SCM), an inflammatory condition of the breast, or elevations in breast milk proinflammatory cytokines alter breast milk mineral and trace element composition in humans has not been investigated. In this cross-sectional study, breast milk samples (n=108) were collected from Guatemalan Mam-Mayan mothers at one of three stages of lactation (transitional, early and established), and categorized as SCM (Na:K >0.6) or non SCM (Na:K <=0.6). Milk concentrations of 12 minerals (calcium, copper, iron, magnesium, manganese, phosphorus, potassium, rubidium, selenium, sodium, strontium, and zinc) and 4 proinflammatory cytokines (IL-1beta, IL-6, IL-8, TNF alpha) were measured by inductively coupled plasma mass spectrometry (ICP-MS), Lachat analyzer or Luminex multiplex bead cytokine assay. SCM was more prevalent during transitional (30%) than early (15.6%) and established (8.9%) lactation. Analysis of variance revealed that breast milk minerals differed by stage of lactation and SCM status. Breast milk minerals with the exception of magnesium were lower in established lactation, whereas SCM was associated with higher selenium and lower phosphorus. Regression models that controlled for lactation stage also confirmed that SCM was associated with lower milk phosphorus and higher milk selenium concentrations. Furthermore, cytokine concentrations were independently associated with several mineral concentrations: IL-1beta with higher phosphorus and iron, IL-6 with higher calcium, magnesium, copper and manganese, IL-8 with higher calcium and zinc, and TNF-alpha with lower iron and manganese. We conclude that milk mineral and trace element concentrations are affected not only by the presence of SCM but also by proinflammatory cytokines in breast milk. PMID- 29413112 TI - Expression and immunolocalization of metallothioneins MT1, MT2 and MT3 in rat nephron. AB - Rodent kidneys exhibit three isoforms of metallothioneins (MTs), MT1, MT2 and MT3, with poorly characterized localization along the nephron. Here we studied in adult male Wistar rats the renal expression of MTs mRNA by end-point RT-PCR and MT proteins by immunochemical methods The expression pattern of MT1 mRNA was cortex (CO)>outer stripe (OS)=inner stripe (IS)=inner medulla (IM), of MT2 mRNA was IM>CO>IS=OS, and of MT3 mRNA was IM>CO=OS=IM. MT1/2-antibody stained with heterogeneous intensity the cell cytoplasm and nuclei in proximal tubule (PT) and thin ascending limb, whereas MT3-antibody stained weakly the cell cytoplasm in various cortical tubules and strongly the nuclei in all nephron segments. However, the isolated nuclei exhibited an absence of MT1/2 and presence of MT3 protein. In MT1/2-positive PT cells, the intracellular staining appeared diffuse or bipolar, but the isolated brush-border, basolateral and endosomal membranes were devoid of MT1/2 proteins. In the lumen of some PT profiles, the heterogeneously sized MT1/2-rich vesicles were observed, with the limiting membrane positive for NHE3, but negative for V-ATPase, CAIV, and megalin, whereas their interior was positive for CAII and negative for cytoskeleton. They seem to be pinched off from the luminal membrane of MT1/2-rich cells, as also indicated by transmission electron microscopy. We conclude that in male rats, MTs are heterogeneously abundant in the cell cytoplasm and/or nuclei along the nephron. The MT1/2-rich vesicles in the tubule lumen may represent a source of urine MT and membranous material, whereas MT3 in nuclei may handle zink and locally produced reactive oxygen species. PMID- 29413113 TI - Aluminium in brain tissue in autism. AB - Autism spectrum disorder is a neurodevelopmental disorder of unknown aetiology. It is suggested to involve both genetic susceptibility and environmental factors including in the latter environmental toxins. Human exposure to the environmental toxin aluminium has been linked, if tentatively, to autism spectrum disorder. Herein we have used transversely heated graphite furnace atomic absorption spectrometry to measure, for the first time, the aluminium content of brain tissue from donors with a diagnosis of autism. We have also used an aluminium selective fluor to identify aluminium in brain tissue using fluorescence microscopy. The aluminium content of brain tissue in autism was consistently high. The mean (standard deviation) aluminium content across all 5 individuals for each lobe were 3.82(5.42), 2.30(2.00), 2.79(4.05) and 3.82(5.17) MUg/g dry wt. for the occipital, frontal, temporal and parietal lobes respectively. These are some of the highest values for aluminium in human brain tissue yet recorded and one has to question why, for example, the aluminium content of the occipital lobe of a 15year old boy would be 8.74 (11.59) MUg/g dry wt.? Aluminium-selective fluorescence microscopy was used to identify aluminium in brain tissue in 10 donors. While aluminium was imaged associated with neurones it appeared to be present intracellularly in microglia-like cells and other inflammatory non neuronal cells in the meninges, vasculature, grey and white matter. The pre eminence of intracellular aluminium associated with non-neuronal cells was a standout observation in autism brain tissue and may offer clues as to both the origin of the brain aluminium as well as a putative role in autism spectrum disorder. PMID- 29413114 TI - Variations in serum concentrations of C-reactive protein, ceruloplasmin, lactoferrin and myeloperoxidase and their interactions during normal human pregnancy and postpartum period. AB - BACKGROUND: Serum proteins may provide information about homeostasis of redox status and inflammatory processes also during pregnancy. The aim of the study was to assess the dynamics of changes in serum concentrations of C-reactive protein (CRP), ceruloplasmin (CP), lactoferrin (LF) and myeloperoxidase (MPO) and their interactions during normal pregnancy and the postpartum period. METHODS: The concentrations of proteins were measured in serum (n=113) from pregnant in consecutive trimesters and in postpartum period (n=28) and in non-pregnant women (n=17), using immunoturbidimetric assays (CRP, CP) and ELISA Kits (LF, MPO). RESULTS: The concentrations [mg/dl] CP and CRP (mean+/-SD respectively): second trimester (43.1+/-6.2; 0.49+/-0.57), third trimester (44.5+/-5.8; 0.41+/-0.37), postpartum (42.39+/-6.4; 4.15+/-3.6) were higher than in the first trimester (33.0.5+/-8.7; 0.31+/-0.36) or non-pregnant women (24.12+/-7.4; 0.12+/-0.13). The increases in concentrations of CP and CRP between the first and the second trimesters were by approximately 35% and 50% respectively and the correlation coefficients in the first trimester and in non-pregnant women were twice higher than in the second trimester and the postpartum period. The concentrations [MUg/ml] LF and MPO were no significant differences (mean+/-SD respectively): first (6.19+/-4.54; 0.17+/-0.12), second (5.68+/-4.4; 0.14+/-0.08), third (6.34+/ 6.98; 0.17+/-0.14), the postpartum (4.86+/-3.64; 0.25+/-0.4), and non-pregnant (3.9+/-2.56; 3.2; 0.14+/-0.05). However, significant correlations were established (p<0.05) between MPO and LF in all groups and between the following ratios CRP/LF vs CP/MPO and CRP/MPO vs CP/LF. CONCLUSIONS: The concentrations of proteins synthesized by the liver (CP, CRP) dynamically increase during consecutive trimesters of pregnancy unlike neutrophil-derived proteins (LF, MPO). Statistically significant correlations between the proportions of the serum proteins may suggest their combined role for the maintenance of homeostasis during pregnancy. PMID- 29413115 TI - Mono and dihydroxy coumarin derivatives: Copper chelation and reduction ability. AB - : Due to the limited array of the currently available copper chelators, research of such compounds continues to be of clinical interest. Notably, o dihydroxycoumarins have been previously shown to be potent iron chelators under neutral conditions. Within this study, the interaction of a series of natural coumarins and their synthetic analogs with copper has been evaluated in order to obtain structure-activity relationships under different pathophysiological pH conditions. Both competitive and non-competitive methods have been employed. Analysis of cupric ion reduction has also been performed. Under mildly competitive conditions, cupric chelation was observed for o-dihydroxycoumarins, and partially for o-diacetoxycoumarin. Non-competitive studies showed that cuprous ions are not chelated at all and that the stoichiometries of the most active 6,7- and 7,8-dihydroxycoumarins to cupric ions ranged from 1:1 to 2:1 depending on pH and concentration. Interestingly, under highly competitive conditions, coumarins were not capable of chelating cupric ions, either. Reduction experiments have shown that 13 out of the 15 coumarins included in this study reduced cupric ions. However, significant differences depending on their structures were apparent in their potencies. O-dihydroxycoumarins were the most potent ones again. CONCLUSION: O-dihydroxycoumarins are moderately active cupric ion chelators with potent copper reducing properties. PMID- 29413116 TI - Effect of silicon-rich water intake on the systemic and peritoneal inflammation of rats with chronic low levels of aluminum ingestion. AB - BACKGROUND AND OBJECTIVES: Study evaluated effect of silicon-rich water intake on systemic inflammation and functional characteristics of peritoneal macrophages (PMs) of rats that were chronically exposed to dietary aluminum. METHODS: One month-old female Wistar Albino rats were administered aluminum chloride dissolved in distilled water (1.6mg/kg body weight in 0.5mL) by gavage for 90days. The rats were then given standard (6mg/L) or silicon-rich water (19mg/L silicon) (n=7/group). Control rats underwent sham gavage and received standard or silicon rich water (n=7/group). Blood was assessed for cytokine levels. Unstimulated and lipopolysaccharide (LPS)-stimulated PMs were assessed in terms of phagocytic activity and cytokine secretion in vitro. RESULTS: Chronic exposition to dietary aluminum and silicon-rich drinking water did not change serum TNF-alpha levels. Aluminum increased serum IL-2 and this was reversed by silicon-rich water. The aluminum-exposed rats had higher serum sICAM-1 than sham-gavaged, unrelated to type of water. LPS-stimulated PMs from aluminum-intoxicated animals exhibited low phagocytic activity and release of TNF-alpha, this was significantly improved by silicon-rich water intake. In the presence of silicon-rich water, LPS-stimulated and unstimulated PMs from aluminum-exposed rats produced significantly more IL 10. CONCLUSIONS: Chronic ingestion of aluminum, increases systemic and peritoneal inflammation and PM dysfunction. The presence of high levels of the natural aluminum antagonist silicon in the drinking water restored IL-10 and TNF-alpha PM secretion, preventing prolonged inflammation. Thus, silicon intake can decrease the immunotoxicity of aluminum. PMID- 29413117 TI - Emerging Technological Advances in Musculoskeletal Ultrasound. PMID- 29413118 TI - Re: Is the Routine Use of a Functional Electrical Stimulation Cycle for Lower Limb Movement Standard of Care for Acute Spinal Cord Injury Rehabilitation? PMID- 29413119 TI - Academy News - January PM&R. PMID- 29413120 TI - PM&R Manuscript Reviewers. PMID- 29413121 TI - Maintaining Opioid Prescription for Chronic Back Pain: Pro Versus Con. PMID- 29413123 TI - MCI in Parkinson's disease. PMID- 29413122 TI - The Family Caregiving Dilemma. PMID- 29413124 TI - Suicide and the criminal justice system: a more complete picture. PMID- 29413125 TI - Suicide and the criminal justice system: a more complete picture. PMID- 29413126 TI - Paternal and maternal depression and offspring risk: additive effects or worse? PMID- 29413127 TI - Suicide and the criminal justice system: a more complete picture - Authors' reply. PMID- 29413128 TI - Paternal and maternal depression and offspring risk: additive effects or worse? - Authors' reply. PMID- 29413129 TI - Mental Health Act reform must include carers. PMID- 29413130 TI - Human rights and sexuality: sexual fluidity. PMID- 29413131 TI - Brexit, the Leave campaign, and mental health of ethnic minority communities. PMID- 29413133 TI - Essi Viding: breaking down barriers. PMID- 29413134 TI - The politics of mental health. PMID- 29413135 TI - Just typical. PMID- 29413136 TI - Comic relief. PMID- 29413137 TI - Gaslight and gaslighting. PMID- 29413139 TI - Psychiatric classification: playing the game. PMID- 29413140 TI - Effective treatment of postnatal depression is associated with normal child development. PMID- 29413141 TI - Online interventions for the mental health needs of trans and gender diverse young people. PMID- 29413138 TI - Mitigating the effect of persistent postnatal depression on child outcomes through an intervention to treat depression and improve parenting: a randomised controlled trial. AB - BACKGROUND: Maternal postnatal depression occurs following 10-15% of births and is associated with a range of negative child outcomes. Risks to children are particularly increased when postnatal depression is persistent. We aimed to examine whether a parenting video-feedback therapy (VFT) intervention versus a control treatment of progressive muscle relaxation (PMR), both added to cognitive behavioural therapy (CBT) for persistent postnatal depression, would lead to improved child outcomes at age 2 years. METHODS: In this two-arm, parallel design, individually randomised controlled trial, we recruited a community sample of women aged 18 years or older living within 50 miles of Oxford, UK, between 4.5 and 9.0 months post partum. All participants met diagnostic criteria for current major depressive disorder that had persisted for at least 3 months and had infants at 35 or more weeks of gestation, with a birthweight of 2000 g or greater, and without serious neonatal complications. Through a centralised service, women were randomly assigned by use of a minimisation algorithm, to receive either VFT or PMR, balanced for child sex, temperament, age, socioeconomic status, and severity of depression. Both groups also received CBT for depression. Primary outcomes were child cognitive development, language development, behaviour problems, and attachment security at age 2 years. There were 11 home-based treatment sessions before child age 1 year, followed by two booster sessions in the second year. Assessors were masked to treatment group allocation. All analyses were done according to the intention-to-treat principle. This trial is registered with the ISRCTN registry, number ISRCTN07336477. FINDINGS: Between March 18, 2011, and Dec 9, 2013, we randomly assigned 144 women, 72 to each group. Primary outcome data were available for 62-64 (86-89%) VFT and 67-68 (93-94%) PMR participants. There were no group differences in child outcome (cognitive development, adjusted difference -1.01 [95% CI -5.11 to 3.09], p=0.63; language development, 1.33 [-4.16 to 6.82], p=0.63; behaviour problems, 1.77 [-4.39 to 0.85], p=0.19; attachment security, 0.02 [-0.06 to 0.10], p=0.58), with both groups achieving scores similar to non-clinical norms on all outcomes. There were six serious adverse events: five in the VFT group (in two participants) and one in the PMR group. None was treatment-related. INTERPRETATION: The effect of persistent postnatal depression on children is a major public health issue. For both treatment groups there was sustained remission from depression, and child development outcomes were in the normal range. The precise mechanisms accounting for the observed positive child outcomes cannot be ascertained from this study. FUNDING: Wellcome Trust. PMID- 29413142 TI - Biobehavioral Markers of Attention Bias Modification in Temperamental Risk for Anxiety: A Randomized Control Trial. AB - OBJECTIVE: Children with behavioral inhibition, a temperament characterized by biologically based hypervigilance to novelty and social withdrawal, are at high risk for developing anxiety. This study examined the effect of a novel attention training protocol, attention bias modification (ABM), on symptomatic, behavioral, and neural risk markers in children with behavioral inhibition. METHOD: Nine- to 12-year-old typically developing children identified as having behavioral inhibition (N = 84) were assigned to a 4-session active ABM training (n = 43) or placebo protocol (n = 41) using a double-blinded, randomized, controlled trial approach. Anxiety symptoms (Diagnostic Interview Schedule for Children-Fourth Edition), attention bias (AB; measured by a dot-probe task; AB = incongruent reaction time - congruent reaction time), and AB-related neural activation (measured by functional magnetic resonance imaging activation for the incongruent > congruent contrast in the dot-probe task) were assessed before and after the training sessions. RESULTS: Results showed that active ABM (n = 40) significantly alleviated participants' symptoms of separation anxiety, but not social anxiety, compared with the placebo task (n = 40); ABM did not modify behavioral AB scores in the dot-probe task; and at the neural level, active ABM (n = 15) significantly decreased amygdala and insula activation and increased activation in the ventrolateral prefrontal cortex compared with placebo (n = 19). CONCLUSION: These findings provide important evidence for ABM as a potentially effective protective tool for temperamentally at-risk children in a developmental window before the emergence of clinical disorder and open to prevention and intervention. Clinical trial registration information-Attention and Social Behavior in Children (BRAINS); http://clinicaltrials.gov/; NCT02401282. PMID- 29413143 TI - Longitudinal Diffusion Tensor Imaging Study of Adolescents and Young Adults With Bipolar Disorder. AB - OBJECTIVE: Longitudinal neuroimaging during adolescence/young adulthood, when bipolar disorder (BD) commonly emerges, can help elucidate the neurodevelopmental pathophysiology of BD. Adults with BD have shown reduced structural integrity in the uncinate fasciculus (UF), a white matter (WM) tract providing major connections between the amygdala and ventral prefrontal cortex (vPFC), important in emotion regulation. In this longitudinal diffusion tensor imaging (DTI) study of adolescents/young adults, we hypothesized differences in age- and time-related changes in UF integrity in BD compared to healthy controls (HC). METHOD: Two DTI scans were obtained in 27 adolescents/young adults with BD and 37 HC adolescents/young adults, on average approximately 2.5 years apart. Interactions between diagnosis with age and with time for UF fractional anisotropy (FA) were assessed. Exploratory analyses were performed including euthymic-only participants with BD, and for potential influences of demographic and clinical factors. Whole-brain analyses were performed to explore for interactions in other regions. RESULTS: There were significant interactions between diagnosis with age and with time for UF FA (p < .05). Healthy control adolescents/young adults showed significant UF FA increases with age and over time (p < .05), whereas no significant changes with age or over time were observed in the adolescents/young adults with BD. Significant interactions with age and time were also observed in analyses including euthymic-only participants with BD (p < .05). CONCLUSION: These findings provide neuroimaging evidence supporting differences in UF WM structural development during adolescence/young adulthood, suggesting that differences in the development of an amygdala-vPFC system subserving emotion regulation may be a trait feature of BD neurodevelopment. PMID- 29413144 TI - Sexual Risk Behavior Among Youth With Bipolar Disorder: Identifying Demographic and Clinical Risk Factors. AB - OBJECTIVE: This study aims to document rates of sexual activity among youth with bipolar spectrum disorder (BD) and to examine demographic and clinical factors associated with first sexual activity and sexual risk behavior during follow-up. METHOD: The sample was drawn from the Course and Outcome of Bipolar Youth (COBY) study of 413 youth 7 to 17 years at baseline who met criteria for bipolar spectrum disorder according to the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. Psychiatric symptoms during follow-up were assessed using the Adolescent Longitudinal Interview Follow-Up Evaluation (ALIFE). Sexual behavior and level of sexual risk (e.g., unprotected sex, multiple partners, and/or partners with known sexually transmitted infections) were assessed by trained evaluators using the ALIFE Psychosocial Functioning Scale. Analyses were conducted in relation to first sexual behavior during follow up and then to subsequent sexual behaviors (mean 9.7 years, standard deviation 3.2). RESULTS: Sexually active COBY youth (n = 292 of 413; 71%) were more likely females, using substances, and not living with both parents. Consistent with findings among healthy youth, earlier first sexual activity in the sample was significantly associated with low socioeconomic status, female sex, comorbid disruptive behavior disorder, and substance use. As with healthy youth, sexual risk behavior during follow-up was significantly associated with non-Caucasian race, low socioeconomic status, substance use, and history of sexual abuse. Of those COBY youth who were sexually active, 11% reported sexual assault or abuse, 36% reported becoming pregnant (or the significant other becoming pregnant), and 15% reported having at least 1 abortion (or the significant other having an abortion) during follow-up. Hypomanic symptoms during follow-up were temporally associated with the greatest risk for sexual risk behavior. CONCLUSION: Demographic and clinical factors could help identify youth with bipolar spectrum disorder at significantly greatest risk for sexual activity and sexual risk behavior. Attending to sexual risk behaviors in this population is warranted. PMID- 29413146 TI - Ode to the Brits. PMID- 29413145 TI - Effects of State Autism Mandate Age Caps on Health Service Use and Spending Among Adolescents. AB - OBJECTIVE: Many states with mandates requiring commercial insurers to cover autism spectrum disorder (ASD) health services specify upper age limits above which coverage is no longer mandated. It is unknown what effects these age caps have on health service use and spending among adolescents who have exceeded the age cap. METHOD: Using administrative claims data from 3 national commercial insurers, a difference-in-differences approach was used to estimate effects of age caps on health service use and spending among adolescents with ASD. Statistical models compared changes in use and spending between those above versus below the age cap among individuals eligible versus ineligible for mandated coverage. The analytic sample included data from 2008 through 2012 on 7,845 individuals (151,976 person-months) ages 10 to 21 years in 11 states imposing mandate age caps going into effect during adolescence. RESULTS: Age caps were associated with 4.2 percentage point (95% CI = -7.0, -1.5) lower probability of any ASD-specific service use in a month and $69 less (95% CI = -112, -$26) in average monthly spending on ASD-specific services than would have been expected given concomitant pre-post age cap differences among individuals in the same states who were never eligible for mandate-covered services. In addition, age caps were associated with $99 (95% CI = -$168, -$30) lower average monthly spending on all health care services. CONCLUSION: Insurance mandates that include age caps going into effect during adolescence reduce health service use and spending among individuals with ASD during a critical phase of the life course. PMID- 29413147 TI - Bias, the Scientific Method, and the Journal. PMID- 29413148 TI - Conflict of Interest and the Journal Revisited. PMID- 29413149 TI - Slowly Progressive Psychiatric Symptoms: Think Metachromatic Leukodystrophy. PMID- 29413150 TI - Two GWASs Are Better Than One: Enhancing Genetic Discovery for Developmental Phenotypes. PMID- 29413151 TI - Brain Games to Reduce Anxiety in High-Risk Children. PMID- 29413152 TI - Getting Off Tract: Developmental Disruptions of White Matter in Youth With Bipolar Disorder. PMID- 29413153 TI - New Evidence of Genetic Overlap Between Atypical Sensory Reactivity and Autistic Traits: Implications for Future Research. PMID- 29413154 TI - Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable psychiatric condition. By exploiting the reported relationship between ADHD and educational attainment (EA), we aimed to improve discovery of ADHD associated genetic variants and to investigate genetic overlap between these phenotypes. METHOD: A conditional/conjunctional false discovery rate (condFDR/conjFDR) method was applied to genome-wide association study (GWAS) data on ADHD (2,064 trios, 896 cases, and 2,455 controls) and EA (n=328,917) to identify ADHD-associated loci and loci overlapping between ADHD and EA. Identified single nucleotide polymorphisms (SNPs) were tested for association in an independent population-based study of ADHD symptoms (n=17,666). Genetic correlation between ADHD and EA was estimated using LD score regression and Pearson correlation. RESULTS: At levels of condFDR<0.01 and conjFDR<0.05, we identified 5 ADHD-associated loci, 3 of these being shared between ADHD and EA. None of these loci had been identified in the primary ADHD GWAS, demonstrating the increased power provided by the condFDR/conjFDR analysis. Leading SNPs for 4 of 5 identified regions are in introns of protein coding genes (KDM4A, MEF2C, PINK1, RUNX1T1), whereas the remaining one is an intergenic SNP on chromosome 2 at 2p24. Consistent direction of effects in the independent study of ADHD symptoms was shown for 4 of 5 identified loci. A polygenic overlap between ADHD and EA was supported by significant genetic correlation (rg=-0.403, p=7.90*10-8) and >10-fold mutual enrichment of SNPs associated with both traits. CONCLUSION: We identified 5 novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and EA. These findings could aid understanding of the genetic risk architecture of ADHD and its relation to EA. PMID- 29413155 TI - Examining the Association Between Autistic Traits and Atypical Sensory Reactivity: A Twin Study. AB - OBJECTIVE: Atypical responses to sensory stimuli are common features of autism spectrum disorders (ASD). Consequently, atypical sensory reactivity (SR) is now a diagnostic feature of ASD. Quantitative genetic research on ASD has overlooked these symptoms, however. We therefore investigated the association between autistic traits and SR using twin methods. METHOD: Autistic traits and SR were assessed by 2 separate scales in 12,419 Swedish twin pairs (n = 3,586 monozygotic [MZ], n = 8,833 dizygotic [DZ]) when the twins were 9 or 12 years of age. The classic twin design estimated the degree to which etiological factors associated with autistic traits were also associated with SR, and the degree to which such shared factors explained the covariance between these phenotypes. DeFries-Fulker analysis estimated the genetic correlation between screening diagnoses of ASD, defined broadly and strictly, and SR. RESULTS: Autistic traits and SR were both highly heritable (62%-75% and 66%-71%, respectively). There was a moderate phenotypic correlation between autistic traits and SR (r = 0.47). Genetic influences on these phenotypes correlated moderately (genetic correlation = 0.60). These overlapping genetic factors explained most of the correlation between autistic traits and SR. Genetic correlations with SR increased for broad ASD (genetic correlation = 0.72) and strict ASD (genetic correlation = 0.80). CONCLUSION: The genetic overlap observed between autistic traits and SR lends quantitative genetic support to the notion that ASD and SR are strongly linked. Such symptoms may thus comprise part of the ASD genotype, as well as phenotype. Associations persisted across all definitions of ASD, indicating a genetic link between the broader ASD phenotype and SR. PMID- 29413156 TI - Network, learn, and explore with thousands of your peers. PMID- 29413157 TI - Strategies to promote infection prevention and control in acute care hospitals with the help of infection control link nurses: A systematic literature review. AB - BACKGROUND: Infection control link nurses (ICLNs) are important backup personnel for the prevention and control of infections in hospitals. To identify facilitators and barriers for the implementation of and long-term collaboration with ICLNs. METHODS: We conducted a systematic literature review, following the preferred reporting items for systematic reviews and meta-analyses guidelines. Inclusion criteria were defined as description of de novo implementation of an ICLN system, strengthening of an existing ICLN system, or analysis of an ICLN system. RESULTS: In 10 publications, facilitators and barriers were identified for mode of selection of ICLN candidates, characteristics and responsibilities of ICLNs, composition of a training curriculum, educational strategies, and external influencing factors. Experienced nurses with an interest in infection control seemed appropriate candidates. The importance of psychological skills in addition to technical knowledge was emphasized. A clear definition of responsibilities was important. Viable tasks for ICLNs included surveillance and teaching activities and the implementation of prevention measures. Ongoing teaching was superior to a single course. Management support was pivotal for success. CONCLUSION: Research on ICLNs is scarce. The potential to decrease health care-associated infections with the help of ICLNs has been demonstrated. The training in psychological skills in addition to technical knowledge deserves more attention. PMID- 29413162 TI - Tackling childhood obesity: a step in the right direction. PMID- 29413163 TI - Technology and chronic disease management - Authors' reply. PMID- 29413164 TI - Technology and chronic disease management. PMID- 29413165 TI - Research digest: progress in microvascular complications. PMID- 29413166 TI - Jane Speight: tackling diabetes and its stigma Down Under. PMID- 29413168 TI - Patrick Groenestein (1959-2016): A Patient's Tribute to a Peoples' Cardiologist. PMID- 29413167 TI - Sympathetic Activation in Essential Hypertension: Understanding the Toxic Trifecta. PMID- 29413169 TI - In regard to: "Effect of Transradial Catheterisation on Patency Rates of Radial Arteries Used as a Conduit for Coronary Bypass". PMID- 29413170 TI - Elevated Troponin and Higher Mortality Risk After Stent Post-dilation. PMID- 29413171 TI - Transapical Transcatheter Mitral Valve-In-Valve Implantation Using an Edwards SAPIEN 3 Valve. PMID- 29413172 TI - Big Data Analytics, the Microbiome, Host-omic and Bug-omic Data and Risk for Cardiovascular Disease. PMID- 29413173 TI - The Presence of Prediabetes in Patients With Heart Failure-A New Venue for the Sodium-Glucose Co-Transporter 2 Inhibition? PMID- 29413174 TI - Chemical Probes in Sirtuin Research. AB - Sirtuins refer to a family of intracellular enzymes that are the yeast silent information regulator 2 (sir2) protein homologs found in organisms from all the three kingdoms of life. This family of enzymes primarily catalyze the protein NE acyl-lysine deacylation reaction despite the report for a type of bacterial/fungal sirtuins to robustly catalyze a protein mono-ADP-ribosylation reaction, however, these two group transfer reactions employ the redox coenzyme beta-nicotinamide adenine dinucleotide (beta-NAD+) as the obligatory cosubstrate. Since 2000, in addition to histone proteins, more and more nonhistone proteins have also been identified as native substrates for the sirtuin-catalyzed deacylation, consistent with the ever-increased demonstration that this enzymatic reaction plays an important regulatory role in a variety of cellular processes, such as gene transcription and metabolism. This latter role is also consistent with the absolute dependence on beta-NAD+ of the deacylation reaction catalyzed by sirtuin family members. The sirtuin-catalyzed deacylation has further been proposed as a contemporary therapeutic target for human diseases, such as cancer, neurodegenerative and metabolic diseases. In order to fully tap the therapeutic potential of the sirtuin-catalyzed deacylation, the past few years have witnessed a tremendous advancement in mechanistic elucidation, chemical modulator (inhibitor and activator) development, (chemical) biological and pharmacological exploration of the sirtuin-catalyzed deacylation reaction. During the journey of this knowledge advancement, the use of carefully designed chemical probes has played an elegant role. This chapter will delineate the development and application of these chemical probes in sirtuin research. PMID- 29413175 TI - Sirtuins as Modifiers of Huntington's Disease (HD) Pathology. AB - Sirtuins and their pharmacological activators/inhibitors have been associated with a range of neuroprotective effects or disease modifying influences in neurological disorders. Huntington's disease (HD) is an autosomal-dominant, progressive neurodegenerative disease characterized by movement disorder, psychiatric symptoms and cognitive decline. The monogenic mutation in HD encodes a variant of the protein Huntingtin (HTT). The disease is a consequence of a CAG repeat extension leading to an abnormally long polyglutamine (Q) stretch at HTT's N-terminus, which likely confers a toxic gain of function to the mutant polypeptide. HD has currently no effective disease-modifying therapy or preventive measures. In the past 2decades, a sizable body of work on Sirtuins' modification of HD pathology using HD cell and animal models has accumulated. In this chapter, evidence for Sirtuin activities as potential modifiers of HD pathology is reviewed. The conflicting findings of the impacts of mammalian Sirtuin paralogs on HD pathogenesis and disease progression are highlighted. The possible cellular and molecular mechanisms underlying Sirtuin activities in HD are discussed with reference to pathophysiological mechanisms of transcription perturbation, proteostasis, mitochondrial function, and microtubule dynamics. A brief therapeutic perspective on the use of Sirtuin activators and inhibitors is also presented. PMID- 29413176 TI - Mammalian Sirtuins SIRT4 and SIRT7. AB - Sirtuins are a family of intracellular enzymes whose enzymatic activities include catalyzing the beta-nicotinamide adenine dinucleotide (beta-NAD+)-dependent NE acyl-lysine deacylation and the beta-NAD+-dependent mono-ADP-ribosylation. Among the seven sirtuin family members (i.e., SIRT1-7) thus far identified in mammals including humans, we know SIRT1/2/3/5/6 better than SIRT4/7 as for their enzymatic activities and the cellular roles of the reactions they catalyze. This chapter will provide an updated account on the enzymology and biology of SIRT4 and SIRT7, the two less well-understood mammalian sirtuins. It is hoped that this article will also be able to set a stage for the medicinal chemistry work on SIRT4 and SIRT7, potentially developing novel therapeutic agents for human diseases. PMID- 29413177 TI - Targeting Sirtuins: Substrate Specificity and Inhibitor Design. AB - Lysine residues across the proteome are modified by posttranslational modifications (PTMs) that significantly enhance the structural and functional diversity of proteins. For lysine, the most abundant PTM is E-N-acetyllysine (Kac), which plays numerous roles in regulation of important cellular functions, such as gene expression (epigenetic effects) and metabolism. A family of enzymes, namely histone deacetylases (HDACs), removes these PTMs. A subset of these enzymes, the sirtuins (SIRTs), represent class III HDAC and, unlike the rest of the family, these hydrolases are NAD+-dependent. Although initially described as deacetylases, alternative deacylase functions for sirtuins have been reported, which expands the potential cellular roles of this class of enzymes. Currently, sirtuins are investigated as therapeutic targets for the treatment of diseases that span from cancers to neurodegenerative disorders. In the present book chapter, we review and discuss the current literature on novel E-N-acyllysine PTMs, targeted by sirtuins, as well as mechanism-based sirtuin inhibitors inspired by their substrates. PMID- 29413178 TI - Regulatory Effects of NAD+ Metabolic Pathways on Sirtuin Activity. AB - NAD+ acts as a crucial regulator of cell physiology and as an integral participant in cellular metabolism. By virtue of a variety of signaling activities this central metabolite can exert profound effects on organism health status. Thus, while it serves as a well-known metabolic cofactor functioning as a redox-active substrate, it can also function as a substrate for signaling enzymes, such as sirtuins, poly (ADP-ribosyl) polymerases, mono (ADP-ribosyl) transferases, and CD38. Sirtuins function as NAD+-dependent protein deacetylases (deacylases) and catalyze the reaction of NAD+ with acyllysine groups to remove the acyl modification from substrate proteins. This deacetylation provides a regulatory function and integrates cellular NAD+ metabolism into a large spectrum of cellular processes and outcomes, such as cell metabolism, cell survival, cell cycle, apoptosis, DNA repair, mitochondrial homeostasis and mitochondrial biogenesis, and even lifespan. Increased attention to how regulated and pharmacologic changes in NAD+ concentrations can impact sirtuin activities has motivated openings of new areas of research, including investigations of how NAD+ levels are regulated at the subcellular level, and searches for more potent NAD+ precursors typified by nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). This review describes current results and thinking of how NAD+ metabolic pathways regulate sirtuin activities and how regulated NAD+ levels can impact cell physiology. In addition, NAD+ precursors are discussed, with attention to how these might be harnessed to generate novel therapeutic options to treat the diseases of aging. PMID- 29413179 TI - Preface. PMID- 29413180 TI - Optimal cooling strategies in tennis. PMID- 29413181 TI - Renewed Interest in Regenerative Medicine. PMID- 29413182 TI - Expert Opinion Is Necessary: Delphi Panel Methodology Facilitates a Scientific Approach to Consensus. AB - Our current trend and focus on evidence-based medicine is biased in favor of randomized controlled trials, which are ranked highest in the hierarchy of evidence while devaluing expert opinion, which is ranked lowest in the hierarchy. However, randomized controlled trials have weaknesses as well as strengths, and no research method is flawless. Moreover, stringent application of scientific research techniques, such as the Delphi Panel methodology, allows survey of experts in a high quality and scientific manner. Level V evidence (expert opinion) remains a necessary component in the armamentarium used to determine the answer to a clinical question. PMID- 29413183 TI - Editorial Commentary: Is Arthroscopic Bone Grafting Nearly Equivalent to Open Bone Grafting for Glenoid Bone Defects in Recurrent Anterior Shoulder Instability? AB - Arthroscopic techniques are an emerging technology to deal with glenoid bone defects in patients with anterior shoulder instability, and improvements are being made to safely minimize the risk of injury to the anterior neurovascular structures including the axillary nerve. Arthroscopic glenoid reconstruction is a technically demanding procedure, but it does have promising short-term outcomes. I truly like the concept of anterior (and also posterior) bone grafting for defects of the glenoid, including the arthroscopic Latarjet. A free bone graft (iliac crest, distal tibia) is part of a logical surgical learning curve progression to treat bone defects from an arthroscopic standpoint. Before performing an arthroscopic Latarjet, I might suggest looking at performing free bone block fixation arthroscopically. But, for now, I still enjoy the success of an open bone grafting procedure and will continue to use open as my primary bone grafting (Latarjet, distal tibia, iliac crest), so as to optimize the position of the graft for successful long-term outcomes. We look forward to seeing more of the authors' work and a longer term follow-up of these patients to clearly delineate the development of osteoarthrosis, recurrent instability, and long-term stability of the bone graft and shoulder joint function. PMID- 29413184 TI - Editorial Commentary: Slow and Steady or Quick and Slick: What Really Wins the Race Between Operative Time and Shoulder Surgery Complications? AB - Studies have shown in many disciplines that longer operative times are correlated with increased complications. Recent research has shown that increased shoulder arthroscopy procedure time is associated with adverse short-term outcomes, especially infections and overnight hospital stay. This may be because longer operating time is a proxy for surgical difficulty or complexity, but it may be that operative time is itself a causative factor. Further study is warranted to see if reducing operative times may not only reduce costs but also improve quality, improving value in both the numerator and denominator. PMID- 29413185 TI - Editorial Commentary: Anchors Away! Reflections on Anchor Placement and Number in Rotator Cuff Repair. AB - The ideal construct for a rotator cuff repair continues to be a hot topic for debate and biomechanical investigation. A recent study shows that anchors could be placed as close as 1 mm apart without impact on pullout strength. However, further overlap (the buddy anchor construct) led to earlier failure. This conclusion differs from other studies that have recommended the "buddy anchor" construct as a bail-out option in osteoporotic bone. Biomechanical studies are an important source of information for surgical decision making, but often do not directly predict the in vivo environment. The final determination of anchor number and placement in a rotator cuff repair should be based on 4 factors: minimizing cost, avoiding complications, using appropriate technique, and proper restoration of anatomy. PMID- 29413186 TI - Editorial Commentary: Our Mentors Were Right, New Is Not Always Better: The Posterolateral Shoulder Trans-Rotator Cuff Portal Is Safe for SLAP Repairs. AB - Shoulder SLAP repair anchors have traditionally been placed through a posterolateral trans-rotator cuff "Port of Wilmington" portal. Alternative anterolateral portals have been proposed to place superior glenoid anchors that seemingly avoid traversing the rotator cuff via the rotator interval but put the suprascapular nerve at risk. A recent cadaveric study demonstrated that the traditional posterolateral portal safely traversed the infraspinatus muscle belly in all specimens, which was in contrast to the anterolateral portal that traversed the supraspinatus tendon in all specimens. In addition, 80% of anchors placed through the anterolateral portal perforated the posterior glenoid in proximity to the suprascapular nerve. As originally suggested nearly 20 years ago, the posterolateral Port of Wilmington trajectory is safe on both the rotator cuff and glenoid side for SLAP repairs. PMID- 29413187 TI - Editorial Commentary: The Effect of Scapula Tilt and Best-Fit Circle Placement When Measuring Glenoid Bone Loss in Shoulder Instability Patients-More Information Complicates an Already Difficult Problem. AB - Scapular tilt affects bone loss measurement used for glenohumeral instability. The larger question of how to manage bone loss in glenohumeral instability remains unanswered. PMID- 29413188 TI - Editorial Commentary: Are Shoulder Glenoid Labral Teardrop Lesions Reasons for Surgeons to Cry? AB - In the world of glenoid labral chondral injuries, perhaps the most recognizable by magnetic resonance imaging is the "teardrop" version, and the glenoid labral teardrop lesion is the glenoid chondral lesion most frequently associated with shoulder instability. PMID- 29413189 TI - Editorial Commentary: Wrist Ulnar Impaction Syndrome: When I Use the Wafer Procedure and When I Do Not. AB - Ulnar impaction syndrome is fundamentally a clinical diagnosis, which can be confirmed by magnetic resonance imaging. All palmer stages are amenable to surgical treatment with either arthroscopic wafer procedure (AWP) or ulnar shortening osteotomy, and neither the absence of a triangular fibrocartilage complex perforation nor neutral or negative variance contraindicate either. Because of its minimally invasive value proposition and likely success, there are few clinical scenarios for which I do not perform AWP preferentially. Furthermore, AWP is always preferable in smokers and in wrists in which a divergent orientation of the sigmoid notch and ulnar articular surfaces portend arthritic complication after ulnar shortening. PMID- 29413190 TI - Editorial Commentary: Wanted Dead or Alive: Primary Allograft Labral Reconstruction of the Hip Is As Successful, if Not More Successful, Than Primary Labral Repair. AB - Primary repair of acetabular labral tears has been the gold standard treatment with excellent short to mid-term results. Autograft and allograft labral reconstruction has been described mostly in the revision labral surgery setting with good short-term results. A recent study has compared primary labral reconstruction to labral repair head-to-head in the same patient. Primary labral reconstruction may be a suitable alternative to labral repair in patients with symptomatic labral pathology. Concerns remain, however, about sacrificing living labral tissue for dead allograft tissue for the long term. PMID- 29413191 TI - Editorial Commentary: Hip Arthroscopy in Hip Dysplasia: Just Because You Are Doing It, Should You? AB - As surgeons advance the field of hip arthroscopy and perform more hip arthroscopy in patients with hip dysplasia and associated femoroacetabular impingement, we need to publish more outcome studies to determine this procedure's success and safety in this specific group of patients. PMID- 29413192 TI - Editorial Commentary: Can We Achieve Personalized Risk Assessment in Hip Arthroscopy? AB - Gender, age, obesity, osteoarthritis, absence of labral repair, and index procedure performed by a lower volume surgeon were identified as risk factors for reoperation in a statewide study of hip arthroscopy. Although this analysis is helpful for benchmarking expectations for outcome in hip arthroscopy, unaccounted patient variables in the database could significantly complicate and confound the point of care application of the findings. PMID- 29413193 TI - Editorial Commentary: Buckle Up Surgeons: "Safety Belt" Reinforcement of Knee Anterior Cruciate Ligament Reconstruction Grafts. AB - Safety belt, or cerclage, reinforcement of anterior cruciate ligament (ACL) grafts may protect against various modes of failure including creep and irreversible stretch, traumatic tearing, and slippage of the tendon-bone interface. A time-zero, biomechanical study shows that suture reinforcement may protect small and vulnerable hamstring ACL reconstruction grafts from these various modes of failure. Thus, in vivo comparative outcome analysis is indicated to determine if the benefits of reinforcement translate from the benchtop to the operating room. PMID- 29413194 TI - Editorial Commentary: Medial Patellofemoral Ligament Reconstruction for Knee Patellar Instability: When Are Soft Tissue Procedures Not Enough? AB - Medial patellofemoral ligament reconstruction is commonly performed to treat patellofemoral instability by recreating the static soft tissue restraint to lateral patellar translation. Concurrent tibial tuberosity osteotomy can be indicated in the setting of bony malalignment, such as a lateralized tuberosity or patella alta; however, the exact indications for this have been difficult to define due to the multifactorial nature of this problem. Understanding the role of tuberosity lateralization and patella alta on the function of medial patellofemoral ligament grafts can help to identify the interplay of some factors that contribute to patellar stability and improve our understanding of when and how concurrent tibial tuberosity osteotomy may be indicated. PMID- 29413195 TI - Editorial Commentary: Knee Medial Meniscus Root Tears: "You May Not Have Seen It, But It's Seen You". AB - Medial meniscus root tears are becoming increasingly recognized in clinical practice as a source of profound pain and dysfunction in patients. There has been considerable debate about the cause of these distinct meniscus tears, and what the optimal treatment should be for an individual patient. Midterm medial meniscus root repair results suggest that in a well-aligned knee with minimal degenerative change, transtibial root repair is an effective technique for improving pain, function, and possibly preventing further cartilage degeneration. PMID- 29413196 TI - Editorial Commentary: A Revisit of an Old Clinical Dilemma-To Operate or Not to Operate on Acute Knee Anterior Cruciate Ligament Injuries. AB - There is a feeling among knee surgeons that operating on an acute anterior cruciate ligament injury will increase the incidence of arthrofibrosis. A recent systematic review and meta-analysis of 7 recent articles compared early versus delayed anterior cruciate ligament reconstruction. The conclusions were that the clinical and stability results were comparable in both groups. PMID- 29413198 TI - Erratum. PMID- 29413197 TI - Editorial Commentary: Knee Anterior Cruciate Ligament Hamstring Graft Fixation Wars Continue: Does Analysis of a Small Fraction of the Story Resolve the Dilemma? AB - After beginning with a search of more than 809 titles and ending up with 5 randomized controlled trials and 2 prospective comparative trials, the authors of a recent systematic review discovered that a statistically significant but nonclinical difference existed between anterior cruciate ligament reconstructions performed using a hamstring graft with either cross-pin or interference screw femoral fixation. PMID- 29413203 TI - Suggested Guidelines for the Practice of Arthroscopic Surgery. PMID- 29413204 TI - Gastrointestinal Manifestations of Autoimmune Diseases Requiring Critical Care. AB - Proper functioning within the gastrointestinal (GI) system is essential to immune integrity. Autoimmune diseases (ADs) can disrupt GI integrity and cause serious derangements of organ function. ADs exist on a continuum of mild to severe. Life threatening presentations of ADs can lead to rapid clinical demise. Additionally, the medications used to control ADs can precipitate gastric bleeding and predispose patients to sepsis in critical care. AD treatment focuses on diminishing symptoms through reducing autoantibody production that leads to cytokine release. This article details common and rare presentations of acute ADs associated with GI manifestations in critically ill patients. PMID- 29413205 TI - Common Gastrointestinal Complications Associated with Human Immunodeficiency Virus/AIDS: An Overview. AB - Highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus (HIV)/AIDS into a manageable chronic illness. People living with HIV/AIDS (PLWHA) can experience multiple physical symptoms or problems related to HIV infection and treatment. A common problem for PLWHA continues to be diarrhea and nausea and vomiting (NV). Diarrhea and NV can negatively impact the quality of life and adherence to medication therapy among PLWHA and are common reasons to change or discontinue HAART regimens. Because diarrhea and NV can have substantial negative health outcomes for PLWHA, it is important to understand the causes of these conditions. PMID- 29413206 TI - Gastrointestinal Motility Problems in Critically Ill Patients. AB - Gastrointestinal (GI) motility problems are common complications in critical care patients. GI problems contribute to an increased risk of morbidity and mortality. Toxic megacolon (TM) is a type of acquired megacolon categorized as a medical emergency and includes severe inflammation affecting all layers of the colon wall. The high incidence of GI complications in critically ill patients requires the critical care nurse to provide close monitoring of patients at risk and an acute awareness of the causation, signs and symptoms, and treatment of various GI motility disorders, including gastroparesis, ileus, and TM. PMID- 29413207 TI - Gastroesophageal Reflux in the Intensive Care Unit Patient. AB - The incidence of gastroesophageal reflux disease (GERD) in the critically ill patient in the intensive care unit is unknown. Interventions used in critically ill patients, such as sedation, tracheal tubes, mechanical ventilation, enteral feedings, positioning, and medications, along with specific patient characteristics and comorbid conditions contribute to an increased risk for gastroesophageal reflux (GER) in this population. Critical care nurses have an integral role in helping identify critically ill patients at risk for GER or with known GERD, in preventing complications associated with these conditions. PMID- 29413208 TI - Nutrition Options in Critical Care Unit Patients. AB - Critically ill patients have increased metabolic requirements and must rely on the administration of nutritional therapy to meet those demands. Yet, according to research almost half of all hospitalized patients are not fed, are underfed, or are malnourished while in the hospital. This article demonstrates the importance of early feedings in critical care unit, and the available options open to nurses supporting initiation and management of early feedings. Enteral nutrition has proven to be an important therapeutic strategy for improving the outcomes of critically ill patients and the critical care nurse plays an integral role in their success. PMID- 29413209 TI - Adults with Liver Failure in the Intensive Care Unit: A Transplant Primer for Nurses. AB - Liver transplant is the standard of care for treatment of many liver diseases. Patients with acute liver failure or end-stage liver disease may require intensive care management. Nurses play a vital role in the care of these patients before and immediately after transplant. Optimal patient outcomes depend on intensive care nurses being able to understand the process of liver failure and the necessary patient management during the pretransplant and early posttransplant periods. This article provides critical care nurses with an overview of liver disease and transplant for adult patients with a diagnosis of liver failure. PMID- 29413210 TI - Escherichia coli Complications in Pediatric Critical Care. AB - Escherichia coli is a bacterium that is an important part of the intestinal tract; however, it has the potential to become pathogenic. Shiga toxin-producing E coli (STEC) is a leading cause of E coli infections and has led to outbreaks in North America. Transmission is through ingestion of contaminated food sources, and via infected humans and animals. Young children infected with STEC are at high risk for developing hemolytic uremic syndrome (HUS). HUS is a clinical syndrome characterized by macroangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Early diagnosis and supportive treatment of HUS are essential to limit complications. PMID- 29413211 TI - Gastrointestinal Traumatic Injuries: Gastrointestinal Perforation. AB - The abdomen is a big place even in a small person. Gastrointestinal trauma can result in injury to the stomach, small bowel, colon, or rectum. Traumatic causes include blunt or penetrating trauma, such as gunshot wounds, stabbings, motor vehicle collisions, and crush injuries. Nontraumatic causes include appendicitis, Crohn disease, cancer, diverticulitis, ulcerative colitis, blockage of the bowel, and chemotherapy. The mechanism of injury will affect both the nature and severity of any resulting injuries. Treatment must address the critical and emergent nature of these injuries as well as issues that affect all trauma situations, which include management of hemodynamic instability. PMID- 29413212 TI - Gastroesophageal Reflux: Regurgitation in the Infant Population. AB - Gastroesophageal reflux (GER) is common in infancy and mainly treated through nonpharmacological interventions. Knowing the early warning signs of GER is important for nursing assessment. Untreated GER can become acute when an infant fails to gain weight and has recurrent, forceful vomiting. Further investigation of gastroesophageal reflux disease (GERD) is indicated when failure to gain weight, irritability, swallowing difficulties, regurgitation, and respiratory complications occur and should trigger referral to pediatric specialists. This article will share information about uncomplicated GER, GERD, and symptoms of these diagnoses, common screening tests, and treatment options. PMID- 29413214 TI - Clostridium difficile: More Challenging than Ever. AB - Clostridium difficile infection is not new, but it is posing more problems than ever before, described by the Centers for Disease Control and Prevention as an urgent threat. Its pathophysiology allows C difficile to be very difficult to manage, both within the hospital environment and in a patient's body. This article reviews clinical manifestations of the infection, outlines both medical and surgical treatment options, and discusses risk factors and predictors. Implications for nurses are thoroughly described. The epidemic proportion of C difficile infection gives cause for serious concern, especially for vulnerable populations, such as adults over age 65. PMID- 29413213 TI - Mesenteric Ischemia. AB - Mesenteric ischemia is an uncommon disease most often seen in the elderly. This disease results from blood flow in the mesenteric circulation that inadequately meets metabolic needs of the visceral organs and, if untreated, eventually leads to necrosis of the bowel wall. Mesenteric ischemia is divided into 2 types: acute mesenteric ischemia (AMI) and chronic mesenteric ischemia (CMI). Delayed diagnosis of CMI can lead to AMI. AMI is associated with extremely high mortalities. Early diagnosis via computed tomography angiography and prompt revascularization via endovascular therapy are recommended for symptomatic patients who have not developed bowel ischemia and necrosis. PMID- 29413215 TI - Management of Acute Gastrointestinal Bleed. AB - Acute gastrointestinal bleeding is a common problem found in critically ill patients that can range from self-limited bleeding to a hemorrhaging emergency. Patients can quickly develop shock and altered mental status when they develop hemodynamic instability. Therefore, it is essential that the frontline critical care nurse develop self-efficacy for management of these disorders. This article overviews standards of practice for the management of upper and lower acute gastrointestinal bleeding. Common bleeding disorders are reviewed with expanded focus on peptic ulcer, acute variceal hemorrhage, colonic diverticular bleeding, and angiodysplasias, which are commonly found in the critical care setting. PMID- 29413216 TI - Acute Diverticulitis Management. AB - Diverticular disease accounts for approximately 300,000 hospitalizations per year in the United States, resulting in 1.5 million days of inpatient care. Diverticulitis is defined as an inflammation of the diverticulum, which can be asymptomatic or symptomatic. This disease is the third most common gastrointestinal illness that requires hospitalization and the leading indication for elective colon resection. Abdominal pain is the most common complaint in patients with acute diverticulitis. The pain can be described as cramping, constant, and persistent for several days. Medical management is most often provided with antibiotics and clear liquid diet. PMID- 29413217 TI - Educating Nurses in the Intensive Care Unit About Gastrointestinal Complications: Using an Algorithm Embedded into Simulation. AB - It can be a challenge to prepare intensive care unit (ICU) nurses to recognize and care for the complex needs of deteriorating patients, especially in patients with gastrointestinal (GI) complications, who often present with vague but serious issues. Tools such as the sequential organ failure assessment tool and the GI failure tool have been used to assist nurses in decision making. This article discusses how to incorporate such tools into an algorithm for simulation training for ICU nurses that integrates a clinical judgment model to shape care for patients with GI complications. PMID- 29413219 TI - Gastrointestinal Issues and Complications. PMID- 29413218 TI - Evidence-Based Practice in the Treatment for Antibiotic-Associated Diarrhea in the Intensive Care Unit. AB - Unit nurses provide care to patients with serious health conditions. Often antibiotics are recommended to fight infections. Sometimes patients are on proton pump inhibitors (PPI). Antibiotics and PPIs may lead to diarrhea, causing the patient more discomfort, and possibly leading to a more serious infection. One serious infection is caused by Clostridium difficile, which causes death in some cases. About 75% of patients on antibiotics may not need antibiotics. Several studies showed less diarrhea in patients on probiotics. However, probiotics cause harm to some patients, which needs to be considered. Nurses need to ensure that antibiotic stewardship is followed. PMID- 29413224 TI - Gastrointestinal Issues and Complications. PMID- 29413225 TI - Microdissection testicular sperm extraction (micro-TESE): Predictive value of preoperative hormonal levels and pathology in non-obstructive azoospermia. AB - The aim of this study was to evaluate the predictive value of preoperative hormonal levels and pathology, as well as the outcome of microsurgical testicular sperm extraction in patients with non-obstructive azoospermia (NOA), presenting to our clinic for treatment of infertility. The records of 145 men with NOA who underwent microdissection testicular sperm extraction (micro-TESE) between March 2013 and November 2016 were studied. The patient's age, testicular volume, hormonal profile for follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (TT), and testicular pathology were recorded. The sperm retrieval, the clinical pregnancy and live birth delivery rates were noted. Our testicular sperm retrieval rate was 65.5%. There was no statistical difference in age, testicular volume, or hormonal levels in the TESE-positive and negative groups. Hypospermatogenesis was found in testicular histopathology in 57 of 117 patients (48.7%) who underwent testicular biopsy. Sertoli Cell-Only (SCO) syndrome was seen in 20.5%, Germ Cell Maturation Arrest (MA) in 16.3%, and Atrophy-hyalinization in 14.5%. Seven men had Klinefelter's syndrome (KS), four of whom were TESE-positive. There were no adverse effects of the procedure except for infection at the incision site in one patient. Single intracytoplasmic sperm injection (ICSI) cycles were performed in 92 couples leading to 41 clinical pregnancies and 26 live birth deliveries. Micro-TESE is a safe procedure in experienced hands and provides infertile men with NOA an opportunity to father children. However unselected candidates with NOA should be counselled at the outset that only 17.9% will eventually become biological fathers. PMID- 29413226 TI - An analysis of the risk factors of preeclampsia and prediction based on combined biochemical indexes. AB - This study aims to investigate the risk factors and the joint biochemical indicators predictive value for preeclampsia. Related factors and biochemical indicators were investigated in 558 patients with preeclampsia and 435 normal pregnant women. Multiplicity analysis was performed by logistic regression. The predictive value of the biochemical index and joint biochemical indicators for predicting the incidence of pregnant women preeclampsia were analyzed by ROC curve. A progestation BMI of >24 kg/m2 (OR = 5.412, 95% CI: 1.169-9.447), hypertension history (OR = 7.487, 95% CI: 2.541-11.247) and advanced age (>35 years old, OR = 6.321, 95% CI: 3.142-20.342) are risk factors for preeclampsia. Tumor necrosis factor-alpha and plasma protein-A are valuable for preeclampsia prediction. The predictive success of preeclampsia could be improved by clinical risk factors associated with biochemical indicators detection. PMID- 29413228 TI - A new technique for adult hypospadias repair: A combination of TIPU and Mathieu techniques. PMID- 29413227 TI - To use the brief psychiatric rating scale to detect disorganized speech in schizophrenia: Findings from the REAP-AP study. AB - Our study aimed to assess the psychometric validity of the conceptual disorganization item and other items of the Brief Psychiatric Rating Scale (BPRS) for detecting disorganized speech in patients with schizophrenia. We included 357 schizophrenia patients with disorganized speech and 1082 without disorganized speech from the survey centers in India, Indonesia, Japan, Malaysia, and Taiwan, using the data from the Research on Asian Psychotropic Patterns for Antipsychotics (REAP-AP) study. After adjusting the effects of confounding variables, a binary logistic regression model was fitted to identify BPRS items independently associated with disorganized speech. Receiver operating characteristic (ROC) curves were used to identify optimum cut-off scores and their sensitivities and specificities for detecting disorganized speech. After adjusting the effects of confounding variables, the fitted binary logistic regression model indicated that conceptual disorganization (P < 0.0001), uncooperativeness (P = 0.010) and excitement (P = 0.001) were independently associated with disorganized speech. The ROC curve revealed that the conceptual disorganization item could accurately detect disorganized speech in patients with schizophrenia both separately and in combination with uncooperativeness and excitement. The subscale for conceptual disorganization, uncooperativeness and excitement items in the BPRS is a promising psychometric tool for detecting disorganized speech. PMID- 29413229 TI - Unrelated umbilical cord stem cell transplantation in an eleven-month-old male infant with Wiskott-Aldrich syndrome. PMID- 29413230 TI - The diagnosis of microorganism involved in infective endocarditis (IE) by polymerase chain reaction (PCR) and real-time PCR: A systematic review. AB - Broad-range bacterial rDNA polymerase chain reaction (PCR) followed by sequencing may be identified as the etiology of infective endocarditis (IE) from surgically removed valve tissue; therefore, we reviewed the value of molecular testing in identifying organisms' DNA in the studies conducted until 2016. We searched Google Scholar, Scopus, ScienceDirect, Cochrane, PubMed, and Medline electronic databases without any time limitations up to December 2016 for English studies reporting microorganisms involved in infective endocarditis microbiology using PCR and real-time PCR. Most studies were prospective. Eleven out of 12 studies used valve tissue samples and blood cultures while only 1 study used whole blood. Also, 10 studies used the molecular method of PCR while 2 studies used real-time PCR. Most studies used 16S rDNA gene as the target gene. The bacteria were identified as the most common microorganisms involved in infective endocarditis. Streptococcus spp. and Staphylococcus spp. were, by far, the most predominant bacteria detected. In all studies, PCR and real-time PCR identified more pathogens than blood and tissue cultures; moreover, the sensitivity and specificity of PCR and real-time PCR were more than cultures in most of the studies. The highest sensitivity and specificity were 96% and 100%, respectively. The gram positive bacteria were the most frequent cause of infective endocarditis. The molecular methods enjoy a greater sensitivity compared to the conventional blood culture methods; yet, they are applicable only to the valve tissue of the patients undergoing cardiac valve surgery. PMID- 29413231 TI - Application of six multiplex PCR's among 200 clinical isolates of Pseudomonas aeruginosa for the detection of 20 drug resistance encoding genes. AB - Pseudomonas aeruginosa (P. aeruginosa) is a menacing opportunistic, nosocomial pathogen; become a growing concern as conventional antimicrobial therapy is now futile against it. Multi-drug resistant P. aeruginosa (MDRPA) has distinctive resistance mechanisms such as production of beta-lactamases, repression of porin genes and over-expression of efflux pumps. The focus of this study is to standardize and application of multiplex PCR (mPCR) to detect the presence of betalactamase genes encoding blaTem, blaOXA, blaCTX-M-15, blaVim, blaGes, blaVeb, blaDIM, AmpC and Efflux pump genes encoding Mex A,B-oprM, Mex C,D-oprJ, Mex X,Y oprN, oprD, nfxB, MexR. A total of 200 clinical isolates of P. aeruginosa were tested for the presence of the above mentioned genes genotypically through mPCR and characterized by phenotypic methods for ESBL and MBL production. Out of 200 isolates, 163 (81.5%) nfxB regulator gene, 102 (51%) MexA, 96 (48%) MexC, 93 (46.5%) MexB, 86 (43%) MexD, 81 (40.5%) OprM, 74 (37%) OprJ, 72 (36%) OprD and MexR, 53 (26.5%) Mex X and OprN, 49 (24.5%) MexY gene. Betalactamase genes 145 (72.5%) blaTem, 67 (33.5%) blaOXA, 35 (17.5%) blaVim, 25(12.50%), 23 (11.50%) blaVeb, 21 (11.5%) blaGes, 14 (7%) Ctx-m and 10 (5%) AmpC and 5 (2.5%) blaDim-1 gene were tested positive by mPCR. Phenotypically 38 (19%) and 29 (14.5%) out of 200 tested positive for ESBL and MBL production. Application of this mPCR on clinical specimens is fast, accurate, specific and low-cost reliable tool for the screening, where culture negative Eubacterial PCR positive cases for an early molecular detection of drug resistance mechanism assisting the clinician to treat the disease with appropriate antibiotic selection. PMID- 29413232 TI - PAH mutation spectrum and correlation with PKU manifestation in north Jiangsu province population. AB - Phenylketonuria (PKU) is a common autosomal recessive disorder of phenylalanine metabolism and mainly results a deficiency of phenylalanine hydroxylase gene (PAH). The incidence of various PAH mutations have race and ethnicity differences. We report a spectrum of PAH mutations complied from 35 PKU children who are all Chinese Han population from north Jiangsu in this study. All 13 exons and their flanking intron sequences of PAH were determined by Ion Torrent PGMTM sequencing. The relationship of genotype and phenotype was analyzed based on the sum of the arbitrary value (AV) values of the two alleles. We identified 61 mutations, with a frequency of 87.14%, among 70 alleles of 35 patients. The most prevalent mutations were R243Q (26.23%), R241C (9.84%) and V399V (8.20%). Furthermore, the consistency between prediction of the biochemical phenotype and the observed phenotype was 81.25%, with the highest consistency observed in classic PKU (87.50%). A significant correlation was found between pretreatment levels of phenylalanine and AV sum (r = -0.87, P < 0.05). Finally, our study constructs PAH mutation spectrum by next generation sequencing (NGS), and reveals that the PAH genotypes and biochemical phenotypes were significantly correlated. These offers facilitate the provision of appropriate genetic counseling for PKU patients. PMID- 29413234 TI - Fantastic species and where to find them. AB - Fantastic beasts are not only found in the imaginary worlds of authors like J.K. Rowling. The oceans are full of them. Michael Gross rounds up some unusual suspects. PMID- 29413233 TI - Adult-to-adult living donor liver transplantation preoperative survey using MDCT, a single medical center experience in Taiwan. AB - This study evaluated multi-detector computed tomography (MDCT) scans performed on potential living donors for adult-to-adult liver transplantation (LDLT), with the aim of identifying significant findings that could be used to exclude potential transplantation donors. We retrospectively reviewed the medical records of 151 consecutive potential adult donors for LDLT from May 2007 to January 2015. Liver parenchyma steatosis, focal hepatic mass or intraabdominal malignancy, vascular variations, and donor liver volume were evaluated via MDCT. Grounds for excluding potential donors were also recorded and analyzed. Of the 151 potential donors, nine (6.0%) had moderate to severe fatty liver, 37 (24.5%) had hepatic arterial variants, 22 (14.6%) had significant portal venous variants, and more than half were found to have right accessory inferior hepatic vein. No intraabdominal malignancies were found. Eighty-eight potential donors were rejected, with the most common cause being insufficient recipient volume or remnant donor volume (47.7%), moderate to severe parenchymal steatosis (10.2%), and recipient expiration prior to transplantation (8.0%). An additional 16 potential donors were excluded by the surgical team due to the complexity of their portal venous variations. The rate of exclusion by pre-transplant imaging evaluation with MDCT was 33.8%. MDCT can provide accurate quantification of donor liver volume and steatosis severity along with precise demonstration of vascular variants, which are crucial for the preoperative evaluation of LDLT. However, MDCT may be ineffective for evaluating the biliary system without hepatobiliary-excreted contrast agent and has the disadvantage of ionizing radiation. PMID- 29413235 TI - Patrick Keeling. AB - Patrick Keeling is a Canadian evolutionary microbiologist and Professor in Botany at the University of British Columbia. PMID- 29413237 TI - Antegrade Chronic Total Occlusion Crossing: CrossBoss First or Last? PMID- 29413236 TI - Randomized Comparison of a CrossBoss First Versus Standard Wire Escalation Strategy for Crossing Coronary Chronic Total Occlusions: The CrossBoss First Trial. AB - OBJECTIVES: The authors performed a multicenter, randomized-controlled, clinical trial comparing upfront use of the CrossBoss catheter versus antegrade wire escalation for antegrade crossing of coronary chronic total occlusions. BACKGROUND: There is equipoise about the optimal initial strategy for crossing coronary chronic total occlusions. METHODS: The primary endpoints were the time required to cross the chronic total occlusion or abort the procedure and the frequency of procedural major adverse cardiovascular events. The secondary endpoints were technical and procedural success, total procedure time, fluoroscopy time required to cross and total fluoroscopy time, total air kerma radiation dose, total contrast volume, and equipment use. RESULTS: Between 2015 and 2017, 246 patients were randomized to the CrossBoss catheter (n = 122) or wire escalation (n = 124) at 11 U.S. centers. The baseline clinical and angiographic characteristics of the study groups were similar. Technical and procedural success were 87.8% and 84.1%, respectively, and were similar in the 2 groups. Crossing time was similar: 56 min (interquartile range: 33 to 93 min) in the CrossBoss group and 66 min (interquartile range: 36 to 105 min) in the wire escalation group (p = 0.323), as was as the incidence of procedural major adverse cardiovascular events (3.28% vs. 4.03%; p = 1.000). There were no significant differences in the secondary study endpoints. CONCLUSIONS: As compared with wire escalation, upfront use of the CrossBoss catheter for antegrade crossing of coronary chronic total occlusions was associated with similar crossing time, similar success and complication rates, and similar equipment use and cost. PMID- 29413239 TI - The Heart or the Brain?: Which Takes Priority After Cardiac Arrest and Can We Identify Patients in Whom Aggressive Cardiac Care Is Futile? PMID- 29413241 TI - What Have We Learned From the ABSORB Trials? PMID- 29413238 TI - Should We Perform an Immediate Coronary Angiogram in All Patients After Cardiac Arrest?: Insights From a Large French Registry. AB - OBJECTIVES: This study sought to assess the relationship between an immediate invasive strategy and survival after an out-of-hospital cardiac arrest (OHCA) of presumed cardiac cause, according to prognosis evaluated on hospital arrival. BACKGROUND: An immediate coronary angiogram (CAG) may be associated with better outcome after OHCA in neurologically preserved patients but could be futile in other cases. METHODS: From May 2011 to May 2015, we collected data for all patients admitted in hospital after OHCA in Paris and its suburbs (France). Risk of in-hospital death was retrospectively calculated using the validated Cardiac Arrest Hospital Prognosis score, which includes age, setting, initial rhythm, durations from collapse to basic life support and from basic life support to return of spontaneous circulation, pH, and epinephrine dose. Independent predictors of survival at discharge (including immediate CAG) were assessed in multivariate logistic regression in each of the 3 pre-defined subgroups of Cardiac Arrest Hospital Prognosis score: low risk (<150 points), medium risk (150 to 200 points), and high risk (>200 points) for in-hospital death. RESULTS: A total of 1,410 patients were included and overall survival rate at hospital discharge was 32%. Distribution in the low-, medium-, and high-risk Cardiac Arrest Hospital Prognosis subgroups was 667 (47%), 469 (33%), and 274 patients (20%), respectively. The rate of early CAG was 86%, 66%, and 47% in the low-, medium-, and high-risk subgroups, respectively (p < 0.001). Early invasive strategy was independently associated with better survival in low-risk patients (odds ratio: 2.3; 95% confidence interval: 1.4 to 3.9; p = 0.001), but not in medium-risk (p = 0.55) and high-risk (p = 0.43) patients. Sensitivity analysis found consistent results. CONCLUSIONS: In cardiac arrest patients, our results suggest that investigations regarding early CAG after OHCA should focus on patients with preserved neurological status. PMID- 29413240 TI - A Randomized Trial Comparing the NeoVas Sirolimus-Eluting Bioresorbable Scaffold and Metallic Everolimus-Eluting Stents. AB - OBJECTIVES: The authors sought to evaluate the safety and effectiveness of the NeoVas bioresorbable scaffold (BRS) compared with metallic drug-eluting stents. BACKGROUND: BRS have the potential to improve very late outcomes compared with metallic drug-eluting stents, but some BRS have been associated with increased rates of device thrombosis before complete bioresorption. NeoVas is a new poly-l lactic acid BRS that elutes sirolimus from a poly-D, l-lactide coating. METHODS: Eligible patients with a single de novo native coronary artery lesion with a reference vessel diameter 2.5 to 3.75 mm and a lesion length <=20 mm were randomized 1:1 to NeoVas BRS versus cobalt-chromium everolimus-eluting stents (CoCr-EES). Angiographic follow-up was performed in all patients at 1 year. The primary endpoint was angiographic in-segment late loss (LL), and the major secondary endpoint was the rate of angina. Baseline and follow-up optical coherence tomography and fractional flow reserve were performed in a pre specified subgroup of patients. RESULTS: The authors randomized 560 patients at 32 centers to treatment with NeoVas (n = 278) versus CoCr-EES (n = 282). One-year in-segment LL with NeoVas and CoCr-EES were 0.14 +/- 0.36 mm versus 0.11 +/- 0.34 mm (difference 0.03 mm; upper 1-sided 97.5% confidence interval 0.09 mm; pnoninferiority < 0.0001; psuperiority = 0.36). Clinical outcomes at 1 year were similar in the 2 groups, as were the rates of recurrent angina (27.9% vs. 32.1%; p = 0.26). Optical coherence tomography at 1 year demonstrated a higher proportion of covered struts (98.7% vs. 96.2%; p < 0.001), less strut malapposition (0% vs. 0.6%; p <0.001), and a smaller minimal lumen area (4.71 +/- 1.64 vs. 6.00 +/- 2.15 mm2; p < 0.001) with NeoVas compared with CoCr-EES respectively, with nonsignificant differences in fractional flow reserve (0.89 +/ 0.08 vs. 0.91 +/- 0.06; p = 0.07). CONCLUSIONS: The NeoVas BRS was noninferior to CoCr-EES for the primary endpoint of 1-year angiographic in-segment LL, and resulted in comparable 1-year clinical outcomes, including recurrent angina. (NeoVas Bioresorbable Coronary Scaffold Randomized Controlled Trial; NCT02305485). PMID- 29413242 TI - A Randomized Comparison of Paclitaxel-Eluting Balloon Versus Everolimus-Eluting Stent for the Treatment of Any In-Stent Restenosis: The DARE Trial. AB - OBJECTIVES: The authors sought to evaluate the relative performance of a drug eluting balloon (DEB) and a drug-eluting stent (DES) in patients with any (bare metal or drug-eluting stent) in-stent restenosis (ISR). BACKGROUND: The treatment of ISR remains challenging in contemporary clinical practice. METHODS: In a multicenter randomized noninferiority trial, patients with any ISR were randomly allocated in a 1:1 fashion to treatment with a DEB (SeQuent Please paclitaxel eluting balloon, B. Braun Melsungen, Melsungen, Germany), or a DES (XIENCE everolimus-eluting stent, Abbott Vascular, Santa Clara, California). The primary endpoint was noninferiority in terms of in-segment minimal lumen diameter (MLD) at 6-month angiographic follow-up. Secondary endpoints included angiographic parameters at 6 months and clinical follow-up up to 12 months. RESULTS: A total of 278 patients, of whom 56% had DES-ISR, were randomized at 8 sites to treatment with DEB (n = 141) or DES (n = 137). As compared with DEB, DES was associated with larger MLD and lower % stenosis immediately post-procedure (1.84 +/- 0.46 vs. 1.72 +/- 0.35; p = 0.018; and 26 +/- 10% vs. 30 +/- 10%; p = 0.03). Angiographic follow up was completed at 196 +/- 53 days in 79% of patients. With respect to the primary endpoint of in-segment MLD at 6 months, DEB was noninferior to DES (DEB 1.71 +/- 0.51 mm vs. DES 1.74 +/- 0.61 mm; p for noninferiority <0.0001). Target vessel revascularization at 12-month follow-up was similar in both groups (DES 7.1% vs. DEB 8.8%; p = 0.65). CONCLUSIONS: In patients with ISR, treatment with DEB was noninferior compared with DES in terms of 6-month MLD. There were no differences in clinical endpoints, including target vessel revascularization up to 12 months. Therefore, use of a DEB is an attractive treatment option for in-stent restenosis, withholding the need for additional stent implantation. PMID- 29413243 TI - What Treatment Should We Dare in Patients With In-Stent Restenosis? PMID- 29413245 TI - Left Bundle Branch Block and New Permanent Pacemaker Implantation After Transcatheter Aortic Valve Replacement: Are They Benign? PMID- 29413244 TI - Long-Term Outcomes in Patients With New Permanent Pacemaker Implantation Following Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: This study sought to evaluate the long-term clinical impact of permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR). BACKGROUND: Conduction disturbances leading to PPI are common following TAVR. However, no data exist regarding the impact of PPI on long-term outcomes post-TAVR. METHODS: This was a multicenter study including a total of 1,629 patients without prior PPI undergoing TAVR (balloon- and self-expandable valves in 45% and 55% of patients, respectively). Follow-up clinical, echocardiographic, and pacing data were obtained at a median of 4 years (interquartile range: 3 to 5 years) post-TAVR. RESULTS: PPI was required in 322 (19.8%) patients within 30 days post-TAVR (26.9% and 10.9% in patients receiving self- and balloon-expandable CoreValve and Edwards systems, respectively). Up to 86% of patients with PPI exhibited pacing >1% of the time during follow-up (>40% pacing in 51% of patients). There were no differences between patients with and without PPI in total mortality (48.5% vs. 42.9%; adjusted hazard ratio [HR]: 1.15; 95% confidence interval [CI]: 0.95 to 1.39; p = 0.15) and cardiovascular mortality (14.9% vs. 15.5%, adjusted HR: 0.93; 95% CI: 0.66 to 1.30; p = 0.66) at follow-up. However, patients with PPI had higher rates of rehospitalization due to heart failure (22.4% vs. 16.1%; adjusted HR: 1.42; 95% CI: 1.06 to 1.89; p = 0.019), and the combined endpoint of mortality or heart failure rehospitalization (59.6% vs. 51.9%; adjusted HR: 1.25; 95% CI: 1.05 to 1.48; p = 0.011). PPI was associated with lesser improvement in LVEF over time (p = 0.051 for changes in LVEF between groups), particularly in patients with reduced LVEF before TAVR (p = 0.005 for changes in LVEF between groups). CONCLUSIONS: The need for PPI post TAVR was frequent and associated with an increased risk of heart failure rehospitalization and lack of LVEF improvement, but not mortality, after a median follow-up of 4 years. Most patients with new PPI post-TAVR exhibited some degree of pacing activity at follow-up. PMID- 29413246 TI - Double Trouble: Two Types of Stent Fracture in a Drug-Eluting Stent Secondary to Traction From a Saphenous Vein Graft. PMID- 29413247 TI - Chronic Kidney Disease and Antiplatelet Therapy: A Worrying Gap Between Evidence Based Medicine and Clinical Practice. PMID- 29413248 TI - Reply: Chronic Kidney Disease and Antiplatelet Therapy: A Worrying Gap Between Evidence Based Medicine and Clinical Practice. PMID- 29413249 TI - MitraClip in High- Versus Low-Volume Centers: An Analysis From the German TRAMI Registry. PMID- 29413250 TI - Combined MitraClip Edge-to-Edge Repair With Millipede IRIS Mitral Annuloplasty. PMID- 29413251 TI - The Top Papers of 2017: By Subsequent Citations and Online Views and Downloads. PMID- 29413253 TI - Reduction of Para-Ring Regurgitation After Transcatheter Mitral Valve Replacement Into a Failed Mitral Annuloplasty Ring. PMID- 29413254 TI - Mitral Bioprosthetic Valve Fracture: Bailout Procedure for Undersized Bioprosthesis During Mitral Valve-in-Valve Procedure With Paravalvular Leak Closure. PMID- 29413257 TI - News Beyond Our Pages. PMID- 29413255 TI - Vaccine-associated hypersensitivity. AB - Vaccine-associated hypersensitivity reactions are not infrequent; however, serious acute-onset, presumably IgE-mediated or IgG and complement-mediated anaphylactic or serious delayed-onset T cell-mediated systemic reactions are considered extremely rare. Hypersensitivity can occur because of either the active vaccine component (antigen) or one of the other components. Postvaccination acute-onset hypersensitivity reactions include self-limited localized adverse events and, rarely, systemic reactions ranging from urticaria/angioedema to full-blown anaphylaxis with multisystem involvement. Risk of anaphylaxis after all vaccines is estimated to be 1.31 (95% CI, 0.90-1.84) per million vaccine doses, respectively. Serious hypersensitivity reactions after influenza vaccines are particularly important because of the large number of persons vaccinated annually. Influenza vaccines are unique in requiring annual changes in the vaccines' antigenic composition to match the predicted circulating influenza strains. Recently, novel influenza vaccine types were introduced in the United States (recombinant vaccines, some with higher antigen content and a new adjuvanted vaccine). Providers should be aware of changing recommendations on the basis of recent published evidence for persons with a history of egg allergy to receive annual influenza vaccination. Further research is needed to elucidate the pathophysiology and risk factors for reported vaccine-associated adverse events. Further research is also needed to determine whether repeated annual inactivated influenza vaccination, the number of vaccine antigens administered at the same time, and the current timing of routine infant vaccinations are optimal for overall population well-being. PMID- 29413258 TI - Corrigendum. PMID- 29413259 TI - News & Notes. PMID- 29413261 TI - Switch to English: one year after. PMID- 29413262 TI - Stereotactic Radiosurgery for Resected Brain Metastases: New Evidence Supports a Practice Shift, but Questions Remain. PMID- 29413263 TI - Radiation Oncology in Egypt: A Model for Africa. PMID- 29413264 TI - Seymour H. Levitt, MD, 1928-2017. PMID- 29413265 TI - Coping With Knife: Postoperative Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma. PMID- 29413266 TI - Watch and Wait, Salvage Later. PMID- 29413267 TI - Involved-Site Radiation to Maximize Control. PMID- 29413268 TI - Observe, and Keep Chemotherapy Up the Sleeve. PMID- 29413269 TI - Development of a Radiation Oncology Resident Continuity Clinic to Improve Clinical Competency and Patient Compliance. PMID- 29413270 TI - Utilizing 10-Year Results From the American Board of Radiology Clinical Examination to Identify Areas for Programmatic Improvement. PMID- 29413271 TI - Value of Elective Radiation Oncology Rotations: How Many Is Too Many? PMID- 29413272 TI - Contact Radiation Therapy for Achieving Organ Preservation in Rectal Cancer After Standard Neoadjuvant Chemoradiation: Looking for a Place in the Sun. PMID- 29413273 TI - Safety and Efficacy of Accelerated Hypofractionation and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma Patients With Varying Degrees of Hepatic Impairment. AB - PURPOSE: To report the toxicities and outcomes for stereotactic body radiation therapy (SBRT) and accelerated hypofractionated radiation therapy (AHRT) in patients with Child-Pugh (CP) class A, B, or C and albumin-bilirubin (ALBI) score 1, 2, or 3 hepatocellular carcinoma. METHODS AND MATERIALS: We retrospectively reviewed the data from 146 patients with hepatocellular carcinoma who had undergone SBRT (50 Gy in 5 fractions) or AHRT (45 Gy in 18 fractions). The primary endpoint was liver toxicity, defined as an increase in the CP score of >=2 within 6 months of radiation therapy. The secondary endpoints of ALBI change, overall survival, and local control were also calculated. RESULTS: The median follow-up was 23 months (range 1-59). Most received SBRT (72%), and 28% received AHRT. Of all 146 patients, 45 (31%) had a CP score elevation of >=2 within 6 months of radiation therapy (RT) (27 patients [28%] with baseline CP-A/B7 and 18 [35%] with baseline CP-B8/B9/C cirrhosis; P = .45). On multivariate analysis, neither baseline CP nor ALBI score was predictive of toxicity. No patient with a decline in liver functionality of CP >=2 within 6 months of RT returned to baseline at later time points. Eleven grade 4 toxicities were observed. The mean change in the raw ALBI score at ~6 months was similar for all baseline ALBI groups. Twenty-two patients underwent orthotopic liver transplantation after RT, 13 of whom had baseline CP-B8/B9/C liver functionality. For all patients, the 1- and 2-year treated-lesion local control was greater for SBRT than for AHRT (2 year 94% vs 65%, P < .0001). CONCLUSIONS: The tolerability of SBRT or AHRT as measured by a CP score decline of >=2 within 6 months of RT was similar across baseline liver functionality groups. Compared with AHRT, SBRT was associated with superior local control. Because the true tolerability of limited-volume RT for patients with CP-B or CP-C cirrhosis is unknown, prospective trials validating its safety and efficacy are warranted. PMID- 29413274 TI - Volume, Dose, and Fractionation Considerations for IMRT-based Reirradiation in Head and Neck Cancer: A Multi-institution Analysis. AB - PURPOSE: Limited data exist to guide the treatment technique for reirradiation of recurrent or second primary squamous carcinoma of the head and neck. We performed a multi-institution retrospective cohort study to investigate the effect of the elective treatment volume, dose, and fractionation on outcomes and toxicity. METHODS AND MATERIALS: Patients with recurrent or second primary squamous carcinoma originating in a previously irradiated field (>=40 Gy) who had undergone reirradiation with intensity modulated radiation therapy (IMRT); (>=40 Gy re-IMRT) were included. The effect of elective nodal treatment, dose, and fractionation on overall survival (OS), locoregional control, and acute and late toxicity were assessed. The Kaplan-Meier and Gray's competing risks methods were used for actuarial endpoints. RESULTS: From 8 institutions, 505 patients were included in the present updated analysis. The elective neck was not treated in 56.4% of patients. The median dose of re-IMRT was 60 Gy (range 39.6-79.2). Hyperfractionation was used in 20.2%. Systemic therapy was integrated for 77.4% of patients. Elective nodal radiation therapy did not appear to decrease the risk of locoregional failure (LRF) or improve the OS rate. Doses of >=66 Gy were associated with improvements in both LRF and OS in the definitive re-IMRT setting. However, dose did not obviously affect LRF or OS in the postoperative re IMRT setting. Hyperfractionation was not associated with improved LRF or OS. The rate of acute grade >=3 toxicity was 22.1% overall. On multivariable logistic regression, elective neck irradiation was associated with increased acute toxicity in the postoperative setting. The rate of overall late grade >=3 toxicity was 16.7%, with patients treated postoperatively with hyperfractionation experiencing the highest rates. CONCLUSIONS: Doses of >=66 Gy might be associated with improved outcomes in high-performance patients undergoing definitive re IMRT. Postoperatively, doses of 50 to 66 Gy appear adequate after removal of gross disease. Hyperfractionation and elective neck irradiation were not associated with an obvious benefit and might increase toxicity. PMID- 29413275 TI - Reirradiation for Head and Neck Cancer: The Who and the How. PMID- 29413276 TI - Clinical Variables for Prediction of the Therapeutic Effects of Bevacizumab Monotherapy in Nasopharyngeal Carcinoma Patients With Radiation-Induced Brain Necrosis. AB - PURPOSE: To identify the predictive and prognostic factors for a decrease or recurrence of brain edema in patients who developed radiation-induced brain necrosis (RN) after radiation therapy for nasopharyngeal carcinoma (NPC) and who received bevacizumab monotherapy. METHODS AND MATERIALS: This was a retrospective study. The charts of 50 patients who were diagnosed with RN after radiation therapy for NPC, treated with bevacizumab, and followed up for 6 months were reviewed. Clinical data of these patients were collected, and their brain edema volume before bevacizumab administration, after bevacizumab administration, at 3 month follow-up, and at 6-month follow-up was evaluated on the basis of brain magnetic resonance imaging findings. The baseline serum vascular endothelial growth factor levels of 15 patients were measured by enzyme-linked immunosorbent assay. A random forests model was developed for statistical analysis. RESULTS: The median percentage of decrease in RN volume shown on T2-weighted fluid attenuated inversion recovery images at the end of bevacizumab therapy was 72.6% (interquartile range, 34.5% to 89.5%; P < .001). Twelve of these 50 patients (24.0%) did not have an effective response, and 38 patients (76.0%) showed an effective response after bevacizumab administration. Fifteen of the 38 patients showed RN recurrence. According to the random forests model the maximum radiation dose of the temporal lobe (Dmax of the temporal lobe) was a highly ranked predictor for the therapeutic effect of bevacizumab. The duration between radiation therapy and bevacizumab treatment and the duration between radiation therapy and RN diagnosis were highly ranked predictors for RN recurrence after bevacizumab treatment. CONCLUSIONS: Prediction models for the therapeutic effect of bevacizumab in RN patients were developed, using the random forests model. Bevacizumab might be more effective in patients with a lower maximum radiation dose to the temporal lobe. PMID- 29413277 TI - Prospective, Multicenter, Phase 2 Trial of Induction Chemotherapy Followed by Bio Chemoradiotherapy for Locally Advanced Recurrent Nasopharyngeal Carcinoma. AB - PURPOSE: To evaluate, in a phase 2 study, whether induction docetaxel, cisplatin, and fluorouracil (TPF) followed by weekly docetaxel and cetuximab in concurrence with intensity modulated radiation therapy can improve the treatment outcome for patients with advanced locally recurrent nasopharyngeal carcinoma (rNPC). METHODS AND MATERIALS: Thirty-three patients with rNPC (T3-T4, N0-N1, M0) were recruited. Of these, 19 patients (57.6%) had stage rT3 recurrence, and the rest had stage rT4. Eight patients also had rN1 at the time of relapse. Treatment outcomes and safety were evaluated. RESULTS: Among these 33 patients, 1 died after 1 cycle of TPF, 5 patients withdrew from the study during the induction period because of grade >=3 toxicities; 27 patients completed the whole course of treatment, but 1 died before any assessment could be made. The median follow-up period was 28.5 months. The progression-free survival and overall survival at 3 years for the whole group were 35.7% and 63.8%, respectively. Among the 26 patients who could be assessed after treatment, the complete response rate was 30.8%, and the locoregional control rate at 3 years was 49.2%. Temporal lobe necrosis (TLN) developed in 8 cases. The rates of grade >=3 hearing loss, soft tissue necrosis, dysphagia, and trismus were 30.8%, 15.4%, 11.5%, and 19.2%, respectively. Overall, 5 patients died owing to acute (1 after cycle 1 TPF and 1 after completion of bio-chemoradiotherapy) or late (2 epistaxis and 1 TLN) treatment related complications. CONCLUSIONS: The proposed salvage treatment regimen for advanced locally recurrent NPC could achieve a better treatment outcome than seen in previous studies. However, poor tolerability of induction TPF and the high rate of TLN limit its applicability outside clinical trials. PMID- 29413278 TI - Multicenter Study of Carbon-Ion Radiation Therapy for Adenoid Cystic Carcinoma of the Head and Neck: Subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN). AB - PURPOSE: To retrospectively analyze the treatment outcomes of carbon-ion radiation therapy for adenoid cystic carcinoma (ACC) of the head and neck at 4 active carbon-ion facilities in Japan. METHODS AND MATERIALS: A total of 289 patients who underwent carbon-ion radiation therapy for histology-proven ACC of the head and neck at 4 institutions in Japan between November 2003 and December 2014 were included in this study. RESULTS: Median patient age was 58 years (range, 12-83 years). Tumor sites included the nasal cavity and paranasal sinuses (42%), nasopharynx and oropharynx (19%), oral cavity (12%), major salivary glands (12%), and others (15%). Tumor classifications were T4 in 200 (69%) patients, T3 in 45 (16%), T2 in 22 (8%), T1 in 15 (5%), and unclassified in 7 (2%). The median total dose was 64 Gy (relative biological effectiveness [RBE]; range, 55.2-70.4 Gy [RBE]) in 16 fractions (range, 12-32 fractions). Median follow-up time was 30 months (range, 2-118 months). The 2-year overall survival, progression-free survival, and local control rates were 94%, 68%, and 88%, respectively. Estimated 5-year overall survival, progression-free survival, and local control rates were 74%, 44%, and 68%, respectively. In all, 43 patients (15%) experienced grade >=3 late toxicity, of which osteonecrosis of the jaw bone was the most common. Two patients treated for nasopharyngeal ACC died from a bleeding ulcer at the tumor site (grade 5 toxicity). CONCLUSIONS: Carbon-ion radiation therapy seems to be a promising treatment for ACC of the head and neck. PMID- 29413279 TI - Role of Radiation Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group. AB - Approximately 30% to 40% of patients with diffuse large B-cell lymphoma (DLBCL) will have either primary refractory disease or relapse after chemotherapy. In transplant-eligible patients, those with disease sensitive to salvage chemotherapy will significantly benefit from high-dose therapy with autologous stem cell transplantation. The rationale for considering radiation therapy (RT) for selected patients with relapsed/refractory DLBCL as a part of the salvage program is based on data regarding the patterns of relapse and retrospective series showing improved local control and clinical outcomes for patients who received peritransplant RT. In transplant-ineligible patients, RT can provide effective palliation and, in selected cases, be administered with curative intent if the relapsed/refractory disease is localized. We have reviewed the indications for RT in the setting of relapsed/refractory DLBCL and provided recommendations regarding the optimal timing of RT, dose fractionation scheme, and treatment volume in the context of specific case scenarios. PMID- 29413280 TI - Outcome After Radiation Therapy for Langerhans Cell Histiocytosis Is Dependent on Site of Involvement. AB - PURPOSE: To characterize the efficacy and safety of radiation therapy in a contemporary Langerhans cell histiocytosis (LCH) cohort and to explore whether there are sites at higher risk for local recurrence. PATIENTS AND METHODS: Between 1995 and 2015 we identified 39 consecutive LCH patients who were treated primarily with radiation therapy. Patients were staged by single/multisystem involvement and established risk organ criteria. In 46 irradiated lesions, clinical and radiologic responses were evaluated at multiple time points after radiation therapy. Patient demographics, treatment, and local failure were compared by site of lesion. RESULTS: Median age at radiation therapy was 35 years (range, 1.5-67 years). Twelve patients had multisystem involvement, and of those, 5 patients had disease in organs considered to be high risk. The following sites were irradiated: bone (31), brain (6), skin (3), lymph node (3), thyroid (2), and nasopharynx (1). Median dose was 11.4 Gy (range, 7.5-50.4 Gy). At a median follow up of 45 months (range, 6-199 months), local recurrence or progression was noted in 5 of 46 lesions (11%). There were no local failures of the 31 bone lesions evaluated, whereas the 3-year freedom from local failure in the 15 non-bone lesions was 63% (95% confidence interval 32-83%; P=.0008). Local failures occurred in 2 of 3 skin lesions, in 2 of 6 brain lesions, and 1 of 3 lymph node lesions. Deaths were recorded in 5 of 39 patients (13%), all of whom were adults with multisystem disease. CONCLUSION: Radiation therapy is a safe and effective measure for providing local control of LCH involving the bone. Whereas bone lesions are well controlled with low doses of radiation, disease in other tissues, such as the skin and brain, may require higher doses of radiation or additional treatment modalities. PMID- 29413281 TI - Secondary Acute Leukemia in Sarcoma Patients: A Population-Based Study. AB - PURPOSE: To compare rates of secondary acute leukemia between sarcoma patients and the general population, using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry, and to examine whether various patient, tumor, and treatment factors were associated with development of a secondary acute leukemia. METHODS AND MATERIALS: Patients with a primary diagnosis of connective tissue malignancy between 1973 and 2008 in the SEER database were included. Multivariable competing risk analysis was used to determine risk factors associated with subsequent development of acute leukemia. Using observed-to-expected ratios, we compared incidence rates of secondary acute leukemia between sarcoma patients and the general population. RESULTS: A total of 72,945 patients were identified, with median follow-up of 131 months. On multivariable competing risk analysis, factors associated with increased risk of secondary acute leukemia included receipt of radiation therapy (hazard ratio [HR] 1.67, P=.02), distant disease (HR 2.67, P=.004), male gender (HR 1.53, P=.03), year of diagnosis (HR 0.98, P=.049), and Ewing sarcoma histology (HR 9.95, P < .0001) and osteosarcoma histology (HR 5.06, P=.0001). The observed-to-expected ratio for development of a secondary acute leukemia was 3.67 (95% confidence interval [CI] 1.95-6.28), 3.41 (95% CI 2.73-4.20), and 1.6 (95% CI 1.38-8.19) for acute lymphocytic leukemia, acute myeloid leukemia, and acute monocytic leukemia, respectively. The 10-year cumulative incidence of secondary acute leukemia for patients who did and did receive radiation therapy was 0.3% versus 0.1% (P=.02). CONCLUSIONS: Patients treated for sarcoma, in particular those with Ewing sarcoma and osteosarcoma histology, seem to have a higher incidence of secondary acute leukemia as compared with the general population. Treatment factors including radiation therapy and chemotherapy seem to play a role in this increased risk, although the absolute incidence nevertheless remains very small. PMID- 29413282 TI - First Report of NRG Oncology/Radiation Therapy Oncology Group 0622: A Phase 2 Trial of Samarium-153 Followed by Salvage Prostatic Fossa Irradiation in High Risk Clinically Nonmetastatic Prostate Cancer After Radical Prostatectomy. AB - PURPOSE: To investigate the utility of 153Sm lexidronam (Quadramet) in the setting of men with prostate cancer status post radical prostatectomy who develop biochemical failure with no clinical evidence of osseous metastases. PATIENTS AND METHODS: Trial NRG Oncology RTOG 0622 is a single-arm phase 2 trial that enrolled men with pT2-T4, N0-1, M0 prostate cancer status post radical prostatectomy, who meet at least 1 of these biochemical failure criteria: (1) prostate-specific antigen (PSA) > 1.0 ng/mL; (2) PSA > 0.2 ng/mL if Gleason score 9 to 10; or (3) PSA > 0.2 ng/mL if N1. Patients received 153Sm (2.0 mCi/kg intravenously * 1) followed by salvage external beam radiation therapy (EBRT) to the prostatic fossa (64.8-70.2 Gy in 1.8-Gy daily fractions). No androgen deprivation therapy was allowed. The primary objective was PSA response within 12 weeks of receiving 153Sm. The secondary objectives were to: (1) assess the completion rate for the regimen of 153Sm and EBRT; (2) evaluate the hematologic toxicity and other adverse events (AEs) at 12 and 24 weeks; and (3) determine the freedom from progression rate at 2 years. RESULTS: A total of 60 enrolled eligible patients were included in this analysis. Median follow-up was 3.97 years. A PSA response was achieved in 7 of 52 evaluable patients (13.5%), compared with the 25% hypothesized. The 2-year freedom from progression rate was 25.5% (95% confidence interval 14.4%-36.7%), and the biochemical failure rate was 64.4% (95% CI 50.5% 75.2%). Samarium-153 was well tolerated, with 16 (of 60) grade 3 to 4 hematologic AEs and no grade 5 hematologic AEs. Radiation therapy was also well tolerated, with no grade 3 to 5 acute radiation therapy-related AEs and 1 grade 3 to 4 and no grade 5 late radiation therapy-related AEs. CONCLUSIONS: Trial NRG Oncology RTOG 0622 did not meet its primary endpoint of PSA response, although the regimen of 153Sm and salvage EBRT was well tolerated. Although the toxicity profile supports study of 153Sm in high-risk disease, it may not be beneficial in men receiving EBRT. PMID- 29413283 TI - Effects of Proton Center Closure on Pediatric Case Volume and Resident Education at an Academic Cancer Center. AB - PURPOSE: To analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education. METHODS AND MATERIALS: This was a review of 412 consecutive pediatric (age <=18 years) cases treated at a single institution from 2012 to 2016. Residents' Accreditation Council for Graduate Medical Education case logs for the same years were also analyzed. Characteristics of the patient population and resident case volumes before and after closure of the PTC are reported. RESULTS: Overall pediatric new starts declined by approximately 50%, from 35 to 70 per 6 months in 2012 to 2014 to 22 to 30 per 6 months in 2015 to 2016. Central nervous system (CNS) case volume declined sharply, from 121 patients treated in 2012 to 2015 to 18 patients in 2015 to 2016. In 2012 to 2014 our institution treated 36, 24, and 17 patients for medulloblastoma/intracranial primitive neuroectodermal tumor, ependymoma, and low-grade glioma, respectively, compared with 0, 1, and 1 patient(s) in 2015 to 2016. Forty-nine patients were treated with craniospinal radiation (CSI) from 2012 to 2014, whereas only 2 patients underwent CSI between 2015 and 2016. Hematologic malignancy patient volume and use of total body irradiation remained relatively stable. Patients treated when the PTC was open were significantly younger (9.1 vs 10.7 years, P=.010) and their radiation courses were longer (35.4 vs 20.9 days, P<.0001) than those treated after its closure. Resident case logs showed only a small decline in total pediatric cases, because the percentage of pediatric cases covered by residents increased after PTC closure; however, residents logged fewer CNS cases after PTC closure versus before. CONCLUSIONS: Overall pediatric case volume decreased after PTC closure, as did the number of patients treated for potentially curable CNS tumors. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become increasingly concentrated at specialized centers. PMID- 29413285 TI - Normal Tissue Complication Probability Modeling of Pulmonary Toxicity After Stereotactic and Hypofractionated Radiation Therapy for Central Lung Tumors. AB - PURPOSE: To evaluate clinical pulmonary and radiographic bronchial toxicity after stereotactic ablative radiation therapy and hypofractionated radiation therapy for central lung tumors, and perform normal tissue complication probability modeling and multivariable analyses to identify predictors for toxicity. METHODS AND MATERIALS: A pooled analysis was performed of patients with a central lung tumor treated using <=12 fractions at 2 centers between 2006 and 2015. Airways were manually contoured on planning computed tomography scans, and doses were recalculated to an equivalent dose of 2 Gy per fraction with an alpha/beta ratio of 3. Grade >=3 (>=G3) clinical pulmonary toxicity was evaluated by 2 or more physicians. Radiographic toxicity was defined as a stenosis or an occlusion with or without atelectasis using follow-up computed tomography scans. Logistic regression analyses were used for statistical analyses. RESULTS: A total of 585 bronchial structures were studied in 195 patients who were mainly treated using 5 or 8 fractions (60%). Median patient survival was 27.9 months (95% confidence interval 22.3-33.6 months). Clinical >=G3 toxicity was observed in 24 patients (12%) and radiographic bronchial toxicity in 55 patients (28%), both mainly manifesting <=12 months after treatment. All analyzed dosimetric parameters correlated with clinical and lobar bronchial radiographic toxicity, with V130Gy,EQD having the highest odds ratio. Normal tissue complication probability modeling showed a volume dependency for the development of both clinical and radiographic toxicity. On multivariate analyses, significant predictors for >=G3 toxicity were a planning target volume overlapping the trachea or main stem bronchus (P = .005), chronic obstructive pulmonary disease (P = .034), and the total V130Gy,EQD (P = .012). Radiographic bronchial toxicity did not significantly correlate with clinical toxicity (P = .663). CONCLUSIONS: We identified patient and dosimetric factors associated with clinical and radiographic toxicity after high-dose radiation therapy for central lung tumors. Additional data from prospective studies are needed to validate these findings. PMID- 29413284 TI - Brainstem Injury in Pediatric Patients With Posterior Fossa Tumors Treated With Proton Beam Therapy and Associated Dosimetric Factors. AB - PURPOSE: Proton radiation therapy is commonly used in young children with brain tumors for its potential to reduce late effects. However, some proton series report higher rates of brainstem injury (0%-16%) than most photon series (2.2% 8.6%). We report the incidence of brainstem injury and a risk factor analysis in pediatric patients with posterior fossa primary tumors treated with proton radiation therapy at our institution. METHODS AND MATERIALS: The study included 216 consecutive patients treated between 2000 and 2015. Dosimetry was available for all but 4 patients. Grade 2 to 5 late brainstem toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The histologies include medulloblastoma (n=154, 71.3%), ependymoma (n=56, 25.9%), and atypical teratoid rhabdoid tumor (n=6, 2.8%). The median age at irradiation was 6.6 years (range, 0.5-23.1 years); median dose, 54 gray relative biological effectiveness (Gy RBE) (range, 46.8-59.4 Gy RBE); and median follow-up period, 4.2 years (range, 0.1-15.3 years) among 198 survivors. Of the patients, 83.3% received chemotherapy; 70.4% achieved gross total resection. The crude rate of injury was 2.3% in all patients, 1.9% in those with medulloblastoma, 3.6% in those with ependymoma, and 0% in those with atypical teratoid rhabdoid tumor. The 5-year cumulative incidence of injury was 2.0% (95% confidence interval, 0.7%-4.8%). The median brainstem dose (minimum dose received by 50% of brainstem) in the whole cohort was 53.6 Gy RBE (range, 16.5-56.8 Gy RBE); maximum point dose within the brainstem (Dmax), 55.2 Gy RBE (range, 48.4 60.5 Gy RBE); and mean dose, 50.4 Gy RBE (range, 21.1-56.7 Gy RBE). In the 5 patients with injury, the median minimum dose received by 50% of the brainstem was 54.6 Gy RBE (range, 50.2-55.1 Gy RBE); Dmax, 56.2 Gy RBE (range, 55.0-57.1 Gy RBE); mean dose, 51.3 Gy RBE (range, 45.4-54.4 Gy RBE); and median volume of the brainstem receiving >=55 Gy RBE (V55), 27.4% (range, 0%-59.4%). Of the 5 patients with injury, 4 had a brainstem Dmax in the highest quartile (>=55.8 Gy RBE, P = .016) and a V55 in the highest tertile (>6.0%) of the cohort distribution (P = .047). Of the 5 patients with injury, 3 were aged >6 years (age range, 4.1-22.8 years), and 4 of 5 patients received chemotherapy and achieved gross total resection. CONCLUSIONS: The incidence of injury in pediatric patients with posterior fossa tumors is consistent with previous reports in the photon setting. Our data suggest that when Dmax and V55 are kept <55.8 Gy RBE and <=6.0%, respectively, the 5-year rate of radiation brainstem injury would be <2%. PMID- 29413286 TI - Radiation Dose to the Thoracic Vertebral Bodies Is Associated With Acute Hematologic Toxicities in Patients Receiving Concurrent Chemoradiation for Lung Cancer: Results of a Single-Center Retrospective Analysis. AB - PURPOSE: To test the hypothesis that increasing radiation therapy (RT) dose to the thoracic vertebral bodies (TVBs) contributes to the development of hematologic toxicities (HTs) in patients with lung cancer. METHODS AND MATERIALS: Cases of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) treated with definitive chemoradiation with concurrent platinum-based doublet chemotherapy at our institution from 2007 to 2016 were identified. Mean TVB dose and the volume of TVBs receiving at least 5 to 60 Gy (V5-V60) were retrospectively recorded. Logistic regression was used to test associations between grade >=3 HT (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability was evaluated using the Lyman-Kutcher-Burman (LKB) model for HT3+, and receiver operating characteristics analysis was used to determine dosimetric cut-points. RESULTS: We identified 201 patients, the majority having NSCLC (n=162, 81%) and stage III to IV disease (n=179, 89%). All patients received either cisplatin/etoposide (n=107, 53%) or carboplatin/paclitaxel (n=94, 47%). Median RT dose was 60 Gy (range, 60-70 Gy). The rate of HT3+ was 49% (n=99). Increasing mean TVB dose (per Gy) was associated with higher odds of developing HT3+ (odds ratio 1.041, 95% confidence interval 1.004-1.080, P=.032), as were increasing TVB V5 to V20. These dosimetric correlates to HT3+ persisted on multivariate analysis. Constrained optimization of the LKB model for HT3+ yielded the parameters: n=1, m=1.79, and TD50=21.4 Gy. Optimal cut-points identified were V5=65%, V10=60%, V20=50%, and mean dose=23.5 Gy. Patients with values above these cut-points had an approximately 2-fold increased risk of HT3+. CONCLUSIONS: We found that mean TVB dose and low-dose parameters (V5-V20) were associated with HT3+ in chemoradiation for lung cancer. Per the LKB model, bone marrow behaves like a parallel organ (n=1), implying that mean TVB dose is a useful predictor for toxicity. These data suggest that efforts to spare dose to the TVBs may reduce rates of severe HT. PMID- 29413287 TI - PARP Inhibition Combined With Thoracic Irradiation Exacerbates Esophageal and Skin Toxicity in C57BL6 Mice. AB - PURPOSE: Poly (ADP-ribose) polymerase (PARP) inhibitors have been shown to enhance the radiosensitivity of cancer cells in vitro in a replication-dependent manner. Their in vivo radiosensitizing effects have also been demonstrated in preclinical tumor models. However, whether PARP inhibition can enhance the response to radiation therapy in normal tissues has been largely neglected. We hypothesized that PARP inhibition might also potentiate the response of replicating normal tissues to radiation therapy. In this study, we examined the normal tissue response in mice treated with PARP inhibitors (BMN673 or AZD2281) in combination with thoracic irradiation. METHODS AND MATERIALS: The antitumor effects of fractionated irradiation (5 Gy * 4) in combination with BMN673 were evaluated in nude mice bearing established Calu-6 human lung cancer xenografts. The normal tissue response was evaluated in C57BL6 mice that were treated with BMN673 or AZD2281 combined with fractionated irradiation, 5 Gy * 4, delivered to the whole thorax. Body weight and histology of the esophagus and skin in the field of irradiation were examined. The DNA damage response in the esophagus and skin was assessed by gammaH2AX immunohistochemistry. RESULTS: While PARP inhibition enhanced irradiation-induced tumor growth inhibition in nude mice, it was also associated with significant body weight loss and increased damage to the esophagus and skin within the field of irradiation in C57BL6 mice. PARP inhibition compromised the repair of irradiation-induced DNA damage in the esophagus and skin. CONCLUSIONS: Although PARP inhibition enhanced the antitumor response to fractionated irradiation, it also enhanced the irradiation response in replicating normal tissues. Therefore, our study suggests that additional caution may be warranted in the clinical development of combination therapies using PARP inhibitors and radiation therapy, in particular where the field of irradiation includes the esophagus. PMID- 29413288 TI - Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response. AB - PURPOSE: To investigate the precise mechanism of recognition and processing of ionizing radiation (IR)-induced complex DNA damage (CDD), where two or more DNA lesions are in close proximity, in cellular DNA which is packaged with histones to form chromatin. METHODS AND MATERIALS: HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A and UMSCC6) cells were irradiated with high linear energy transfer (LET) alpha-particles or protons, versus low-LET protons and X rays. At various time points after irradiation, site-specific histone post-translational modifications were analyzed by quantitative Western blotting; DNA damage and repair were measured by different versions of the comet assay; and cell survival was determined using clonogenic assays. RESULTS: Site-specific histone post translational modifications after low- and high-LET radiation, particularly proton irradiation, were screened, aiming to identify those responsive to CDD. We demonstrate that histone H2B ubiquitylated on lysine 120 (H2Bub) is specifically induced several hours after irradiation in response to high-LET alpha-particles and protons but not by low-LET protons or X rays/gamma-radiation. This is associated with increased levels of CDD, which contributes to decreased cell survival. We further discovered that modulation of H2Bub is under the control of two E3 ubiquitin ligases, MSL2 and RNF20/RNF40 complex, whose depletion leads to defective processing and further persistence of CDD, and to additional decreased cell survival after irradiation. CONCLUSION: This study demonstrates that the signaling and repair of CDD, particularly induced by high-LET IR is co-ordinated through the specific induction of H2Bub catalyzed by MSL2 and RNF20/40, a mechanism that contributes significantly to cell survival after irradiation. PMID- 29413289 TI - Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy. AB - PURPOSE: This work investigates a new approach to enhance radiotherapy through a photo therapeutic agent activated by Cherenkov light produced from the megavoltage photon beam. The process is termed Radiotherapy Enhanced with Cherenkov photo-Activation (RECA). RECA is compatible with various photo therapeutics, but here we focus on use with psoralen, an ultraviolet activated therapeutic with extensive history of application in superficial and extracorporeal settings. RECA has potential to extend the scope of psoralen treatments beyond superficial to deep seated lesions. METHODS AND MATERIALS: In vitro studies in B16 melanoma and 4T1 murine breast cancer cells were performed to investigate the potential of RT plus RECA versus RT alone for increasing cytotoxicity (local control) and increasing surface expression of major histocompatibility complex I (MHC I). The latter represents potential for immune response amplification (increased antigen presentation), which has been observed in other psoralen therapies. Cytotoxicity assays included luminescence and clonogenics. The MHC I assays were performed using flow cytometry. In addition, Cherenkov light intensity measurements were performed to investigate the possibility of increasing the Cherenkov light intensity per unit dose from clinical megavoltage beams, to maximize psoralen activation. RESULTS: Luminescence assays showed that RECA treatment (2 Gy at 6 MV) increased cytotoxicity by up to 20% and 9.5% for 4T1 and B16 cells, respectively, compared with radiation and psoralen alone (ie, Cherenkov light was blocked). Similarly, flow cytometry revealed median MHC I expression was significantly higher in RECA treated cells, compared with those receiving radiation and psoralen alone (approximately 450% and 250% at 3 Gy and 6 Gy, respectively, P << .0001). Clonogenic assays of B16 cells at doses of 6 Gy and 12 Gy showed decreases in tumor cell viability of 7% (P = .017) and 36% (P = .006), respectively, when Cherenkov was present. CONCLUSION: This work demonstrates for the first time the potential for photo-activation of psoralen directly in situ, from Cherenkov light generated by a clinical megavoltage treatment beam. PMID- 29413290 TI - In Regard to Shah et al. PMID- 29413291 TI - In Reply to Leddy. PMID- 29413292 TI - In Regard to Sanford et al. PMID- 29413293 TI - In Regards to Stokes et al and Bledsoe et al. PMID- 29413294 TI - In Reply to McClelland et al. PMID- 29413295 TI - In Reply to Overgaard et al. PMID- 29413296 TI - In Regard to Bibault et al. PMID- 29413297 TI - In Reply to Daisne et al. PMID- 29413298 TI - Dedicating "Empowering Intensity Modulated Proton Therapy Through Physics and Technology: An Overview" to the Memory of Dr Michael Goitein. PMID- 29413299 TI - In Regard to Ramey et al. PMID- 29413302 TI - New year, new CRM, new editorial board, new look, and expanding opportunities. PMID- 29413303 TI - Safety and efficacy of drug-eluting stents combining biodegradable polymers with ultrathin stent platforms. PMID- 29413304 TI - Air pollution and brain health: an emerging issue. PMID- 29413305 TI - Long-term forgetting in preclinical Alzheimer's disease. PMID- 29413306 TI - The SeLECT score is inappropriate to predict post-stroke epilepsy. PMID- 29413308 TI - Evolving diagnostic criteria for multiple sclerosis. PMID- 29413307 TI - On progress in Africa, by African experts. PMID- 29413309 TI - Peter Turkeltaub. PMID- 29413310 TI - Facing up to brain injury. PMID- 29413311 TI - The fantastic legacy of Terry Pratchett. PMID- 29413312 TI - Journey in an unknown country. PMID- 29413313 TI - Prescribing sleep for better health. PMID- 29413314 TI - Accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer's disease: a cross-sectional study. AB - BACKGROUND: Tests sensitive to presymptomatic changes in Alzheimer's disease could be valuable for clinical trials. Accelerated long-term forgetting-during which memory impairment becomes apparent over longer periods than usually assessed, despite normal performance on standard cognitive testing-has been identified in other temporal lobe disorders. We assessed whether accelerated long term forgetting is a feature of presymptomatic autosomal dominant (familial) Alzheimer's disease, and whether there is an association between accelerated long term forgetting and early subjective memory changes. METHODS: This was a cross sectional study at the Dementia Research Centre, University College London (London, UK). Participants were recruited from a cohort of autosomal dominant Alzheimer's disease families already involved in research at University College London, and had to have a parent known to be affected by an autosomal dominant Alzheimer's disease mutation, and not report any current symptoms of cognitive decline. Accelerated long-term forgetting of three tasks (list, story, and figure recall) was assessed by comparing 7-day recall with initial learning and 30-min recall. 7-day recognition was also assessed. Subjective memory was assessed using the Everyday Memory Questionnaire. The primary outcome measure for each task was the proportion of material retained at 30 min that was recalled 7 days later (ie, 7-day recall divided by 30-min recall). We used linear regression to compare accelerated long-term forgetting scores between mutation carriers and non carriers (adjusting for age, IQ, and test set) and, for mutation carriers, to assess whether there was an association between accelerated long-term forgetting and estimated years to symptom onset (EYO). Spearman's correlation was used to examine the association between accelerated long-term forgetting and subjective memory scores. FINDINGS: Between Feb 17, 2015 and March 30, 2016, we recruited 35 people. 21 participants were mutation carriers (mean EYO 7.2 years, SD 4.5). Across the three tasks, we detected no differences between carriers and non carriers for initial learning or 30-min recall. The proportion of material recalled at 7 days was lower in carriers than non-carriers for list (estimated difference in mean for list recall -30.94 percentage points, 95% CI -45.16 to 16.73; p=0.0002), story (-20.10, -33.28 to -6.91; p=0.0048), and figure (-15.41, 26.88 to -3.93; p=0.012) recall. Accelerated long-term forgetting was greater in carriers nearer to their estimated age at onset (p<=0.01 for all three tests). Mutation carriers' 7-day recognition memory was also lower across all tasks (list [mean difference -5.80, 95% CI -9.96 to -2.47; p<0.01], story [-6.84, -10.94 to 3.37; p<0.01], and figure [-17.61, -27.68 to -7.72; p<0.01] recognition). Subjective memory scores were poorer in asymptomatic carriers compared with non carriers (adjusted difference in means 7.88, 95% CI 1.36 to 14.41; p=0.016), and we found a correlation between accelerated long-term forgetting and subjective memory in mutation carriers. INTERPRETATION: Accelerated long-term forgetting is an early presymptomatic feature of autosomal dominant Alzheimer's disease, which appears to pre-date other amnestic deficits and might underpin subjective memory complaints in Alzheimer's disease. Accelerated long-term forgetting testing might be useful in presymptomatic Alzheimer's disease trials. FUNDING: MRC, NIHR, Alzheimer's Research UK, Dementias Platform UK, Dunhill Medical Trust, ERUK, Great Western Research, Health Foundation, Patrick Berthoud Trust. PMID- 29413315 TI - Prediction of late seizures after ischaemic stroke with a novel prognostic model (the SeLECT score): a multivariable prediction model development and validation study. AB - BACKGROUND: Stroke is one of the leading causes of acquired epilepsy in adults. An instrument to predict whether people are at high risk of developing post stroke seizures is not available. We aimed to develop and validate a prognostic model of late (>7 days) seizures after ischaemic stroke. METHODS: In this multivariable prediction model development and validation study, we developed the SeLECT score based on five clinical predictors in 1200 participants who had an ischaemic stroke in Switzerland using backward elimination of a multivariable Cox proportional hazards model. We externally validated this score in 1169 participants from three independent international cohorts in Austria, Germany, and Italy, and assessed its performance with the concordance statistic and calibration plots. FINDINGS: Data were complete for 99.2% of the predictors (99.2% for Switzerland, 100% for Austria, 97% for Germany, and 99.7% for Italy) and 100% of the outcome parameters. Overall, the risk of late seizures was 4% (95% CI 4-5) 1 year after stroke and 8% (6-9) 5 years after stroke. The final model included five variables and was named SeLECT on the basis of the first letters of the included parameters (severity of stroke, large-artery atherosclerotic aetiology, early seizures, cortical involvement, and territory of middle cerebral artery involvement). The lowest SeLECT value (0 points) was associated with a 0.7% (95% CI 0.4-1.0) risk of late seizures within 1 year after stroke (1.3% [95% CI 0.7-1.8] within 5 years), whereas the highest value (9 points) predicted a 63% (42-77) risk of late seizures within 1 year (83% [62-93] within 5 years). The model had an overall concordance statistic of 0.77 (95% CI 0.71-0.82) in the validation cohorts. Calibration plots indicated high agreement of predicted and observed outcomes. INTERPRETATION: This easily applied instrument was shown to be a good predictor of the risk of late seizures after stroke in three external validation cohorts and is freely available as a smartphone app. The SeLECT score has the potential to identify individuals at high risk of seizures and is a step towards more personalised medicine. It can inform the selection of an enriched population for antiepileptogenic treatment trials and will guide the recruitment for biomarker studies of epileptogenesis. FUNDING: None. PMID- 29413316 TI - IgG4-related disease of the central and peripheral nervous systems. AB - IgG4-related disease can involve nearly any organ system, including the central and peripheral nervous systems. The pathology findings are consistent from organ to organ, but careful clinicopathological correlation is necessary to establish the diagnosis. Many non-neurological and neurological inflammatory conditions, previously regarded as idiopathic in nature, are now recognised to fall within the spectrum of IgG4-related disease. The condition is highly treatable, but probably remains substantially under-recognised. In this Review, we offer an important and timely update on the current and emerging aspects of this neurological disease. Following a short overview of IgG4-related disease, we describe the current understanding of neurological findings, pathophysiology, approaches to diagnosis, and treatment of IgG4-related disease affecting the central and peripheral nervous systems. PMID- 29413317 TI - Exploring Fertility Preservation Intentions Among Transgender Youth. PMID- 29413318 TI - Using School Disciplinary Context to Understand Adolescent Health Behaviors. PMID- 29413321 TI - GPCRs Moonlighting as Scramblases: Mechanism Revealed. AB - Phospholipids can undergo transverse diffusion, changing leaflets in the bilayer via translocase or scramblase activity. In this issue of Structure, Morra et al. (2018) provide insight into the mechanism used by one scramblase, opsin, based on large-scale ensemble atomistic molecular dynamics simulations. Results support a proposed "credit card reader" model. PMID- 29413320 TI - Approaching the Roundabout: cis and trans Robo1 Contacts Revealed. AB - In this issue of Structure,Aleksandrova et al. (2018) present low- and high resolution structures of Robo1, a key player in axonal guidance. The structures shed light on the arrangement of Robo1 at the plasma membrane and provide evidence for back-to-back trans Robo1 contacts. PMID- 29413322 TI - Human NUDT22 Is a UDP-Glucose/Galactose Hydrolase Exhibiting a Unique Structural Fold. AB - Human NUDT22 belongs to the diverse NUDIX family of proteins, but has, until now, remained uncharacterized. Here we show that human NUDT22 is a Mg2+-dependent UDP glucose and UDP-galactose hydrolase, producing UMP and glucose 1-phosphate or galactose 1-phosphate. We present the structure of human NUDT22 alone and in a complex with the substrate UDP-glucose. These structures reveal a partially conserved NUDIX fold domain preceded by a unique N-terminal domain responsible for UDP moiety binding and recognition. The NUDIX domain of NUDT22 contains a modified NUDIX box identified using structural analysis and confirmed through functional analysis of mutants. Human NUDT22's distinct structure and function as a UDP-carbohydrate hydrolase establish a unique NUDIX protein subfamily. PMID- 29413324 TI - The way forward in transfusion medicine, from a French perspective.... PMID- 29413323 TI - Saposin Lipid Nanoparticles: A Highly Versatile and Modular Tool for Membrane Protein Research. AB - Saposin-derived lipid nanoparticles (SapNPs) are a new alternative tool for membrane protein reconstitution. Here we demonstrate the potential and advantages of SapNPs. We show that SapA has the lowest lipid specificity for SapNP formation. These nanoparticles are modular and offer a tunable range of size and composition depending on the stoichiometric ratio of lipid and saposin components. They are stable and exhibit features typical of lipid-bilayer systems. Our data suggest that SapNPs are versatile and can adapt to membrane proteins of various sizes and architectures. Using SapA and various types of lipids we could reconstitute membrane proteins of different transmembrane cross sectional areas (from 14 to 56 transmembrane alpha helices). SapNP-reconstituted proteins bound their respective ligands and were more heat stable compared with the detergent-solubilized form. Moreover, SapNPs encircle membrane proteins in a compact way, allowing structural investigations of small membrane proteins in a detergent-free environment using small-angle X-ray scattering. PMID- 29413325 TI - Enhanced accuracy of the microwave field strength measurement in a CW-EPR by pulsed modulation technique. AB - The microwave magnetic field strength, B1, in the cavity of a conventional continuous wave electron paramagnetic resonance, CW-EPR, spectrometer was measured by employing modulation sidebands, MS, in the EPR spectrum. MS spectrum in CW-EPR is produced by applying the modulation frequency, omegarf, which exceeds the linewidth, deltaB, given in frequency units. An amplitude-modulated CW-EPR, AM-CW-EPR, was selected as detection method. Theoretical description of AM-CW-EPR spectrum was modified by adding Bloch-Siegert-like shift obtained by taking into account the cumulative effect of the non-resonant interactions between the driving fields and the spin system. This approach enables to enhance the precision of B1 measurement. In order to increase the sensitivity of the method when saturation effects, due to higher intensity of B1, decrease the resolution of AM-CW-EPR spectrum, detection at the second harmonic of CW-EPR has been employed. PMID- 29413326 TI - Storing quantum information in spins and high-sensitivity ESR. AB - Quantum information, encoded within the states of quantum systems, represents a novel and rich form of information which has inspired new types of computers and communications systems. Many diverse electron spin systems have been studied with a view to storing quantum information, including molecular radicals, point defects and impurities in inorganic systems, and quantum dots in semiconductor devices. In these systems, spin coherence times can exceed seconds, single spins can be addressed through electrical and optical methods, and new spin systems with advantageous properties continue to be identified. Spin ensembles strongly coupled to microwave resonators can, in principle, be used to store the coherent states of single microwave photons, enabling so-called microwave quantum memories. We discuss key requirements in realising such memories, including considerations for superconducting resonators whose frequency can be tuned onto resonance with the spins. Finally, progress towards microwave quantum memories and other developments in the field of superconducting quantum devices are being used to push the limits of sensitivity of inductively-detected electron spin resonance. The state-of-the-art currently stands at around 65 spins per Hz, with prospects to scale down to even fewer spins. PMID- 29413327 TI - 1H magic-angle spinning NMR evolves as a powerful new tool for membrane proteins. AB - Building on a decade of continuous advances of the community, the recent development of very fast (60 kHz and above) magic-angle spinning (MAS) probes has revolutionised the field of solid-state NMR. This new spinning regime reduces the 1H-1H dipolar couplings, so that direct detection of the larger magnetic moment available from 1H is now possible at high resolution, not only in deuterated molecules but also in fully-protonated substrates. Such capabilities allow rapid "fingerprinting" of samples with a ten-fold reduction of the required sample amounts with respect to conventional approaches, and permit extensive, robust and expeditious assignment of small-to-medium sized proteins (up to ca. 300 residues), and the determination of inter-nuclear proximities, relative orientations of secondary structural elements, protein-cofactor interactions, local and global dynamics. Fast MAS and 1H detection techniques have nowadays been shown to be applicable to membrane-bound systems. This paper reviews the strategies underlying this recent leap forward in sensitivity and resolution, describing its potential for the detailed characterization of membrane proteins. PMID- 29413328 TI - Editorial: The Sackler International Prize in Biophysical Sciences. PMID- 29413329 TI - Is the better part of valor truly discretion? PMID- 29413330 TI - Is eosinophilic esophagitis a member of the atopic march? PMID- 29413331 TI - Can the atopic march be predicted? PMID- 29413332 TI - The atopic march: Fact or folklore? PMID- 29413333 TI - Contribution of an impaired epithelial barrier to the atopic march. PMID- 29413334 TI - Thunderstorm asthma: An allergen-induced early asthmatic response. PMID- 29413335 TI - Recent advances in asthma. PMID- 29413337 TI - What can we learn about predictors of atopy from birth cohorts and cord blood biomarkers? PMID- 29413336 TI - The atopic march: Critical evidence and clinical relevance. PMID- 29413338 TI - The skin as a target for prevention of the atopic march. AB - OBJECTIVE: Allergic diseases have increased dramatically in the developed world during the past few decades, yet the understanding of risk factors and effective prevention approaches remain limited. In this review, we summarize the evidence supporting the hypothesis that skin-barrier impairment and early-life atopic dermatitis (AD) could play a causal role in the development of sensitization and subsequent food allergies and allergic airways disease (allergic asthma and rhinitis). We further discuss the potential to target the skin barrier as a means to lower the incidence of allergic disease. DATA SOURCES: Review of published literature. STUDY SELECTIONS: Narrative. RESULTS: There is a strong link between AD and sensitization, food allergy, asthma, and allergic rhinitis, particularly AD that is severe and commences in the first 6 months of life. There also is emerging evidence that regular use of prophylactic emollients can significantly decrease the expression of AD, at least while treatment continues. Studies are exploring whether decreased AD expression might modulate the allergic response at a more fundamental level and potentially alter the association between early-life AD and subsequent development of food allergy and allergic airways disease. CONCLUSION: Although at this point there is only indirect evidence that early life emollient use might prevent AD and food allergy, early studies are encouraging. The results of high-quality prevention trials that are in progress are eagerly anticipated. If found to be effective, then neonatal emollient use could be a simple public health measure to lower the incidence of AD, food allergies, and allergic airways disease in future generations. PMID- 29413339 TI - Current insights in allergen immunotherapy. AB - OBJECTIVE: Allergen-specific immunotherapy (AIT) in its subcutaneous and sublingual forms is currently a well-established and experimentally supported treatment for respiratory allergy and hymenoptera venom allergy. There have been advances in its use linked strictly to the advancement in the knowledge of the molecular mechanisms of allergy, the production of well-characterized extracts, and diagnostic techniques. The use of AIT in asthma and the application of new approaches are expanding. We briefly review the advances and concerns in the use of AIT. DATA SOURCES: PubMed and Scopus. STUDY SELECTIONS: The most recent and clinically relevant literature was selected and reviewed. RESULTS: The introduction of high-quality products supported by large dose-finding trials has yielded better defined indications, contraindications, and modalities of use. Some specific products in tablet form have recently been approved in the United States. Sublingual immunotherapy has been found to be effective in asthma, which until recently had been a matter of debate. Another promising therapy is oral and sublingual desensitization for food allergy, for which encouraging results have recently been reported. In the near future, other options will be available, including new routes of administration (intralymphatic and epicutaneous), allergoids, engineered allergens, and peptides. The use of component-resolved diagnosis techniques will further refine and target AIT prescriptions. CONCLUSION: This condensed and updated review shows that AIT remains a viable treatment option, especially after the introduction of standardized tablets for some allergens. Food allergy and new administration routes represent a promising expansion. PMID- 29413340 TI - Basophils from allergic rhinitis patients show allergen-specific upregulation of thymic stromal lymphopoietin receptor. AB - BACKGROUND: An allergic rhinitis (AR) diagnosis is based on typical nasal symptoms and allergen sensitization testing. However, it is sometimes difficult to distinguish AR from non-AR, and it is especially difficult to identify the causal allergen for immunotherapy of patients with AR. OBJECTIVE: To identify differences among patients with AR, subjects with asymptomatic sensitization (AS), and subjects without sensitization (NS) that could facilitate the diagnosis of AR. METHODS: We used RNA sequencing to examine differential gene expression in unstimulated and allergen-stimulated peripheral basophils from participants with NS, AS, and AR. We selected genes that were upregulated after allergen stimulation and showed differences in expression in patients with AR compared with subjects with AS and NS. Basophil surface expression of 1 gene product was examined by flow cytometry. The usefulness of gene expression in the diagnosis of AR was examined with receiver operating characteristic curves. RESULTS: Expression of cytokine receptor-like factor 2 and its product, thymic stromal lymphopoietin receptor (TSLPR), was significantly increased in basophils of patients with AR after allergen stimulation. A significantly larger percentage of TSLPR-positive cells was observed after allergen-specific stimulation of basophils from patients with AR compared with subjects with AS. Basophil TSLPR expression was as good as or better than CD203c expression in discriminating between patients with AR and subjects with AS, as judged by receiver operating characteristic curves. CONCLUSION: Our data suggest that TSLPR expression on basophils was specifically upregulated by allergen stimulation and might be useful for the identification of the causative allergen in patients with AR. PMID- 29413341 TI - Allergic asthma is associated with increased risk of infections requiring antibiotics. AB - BACKGROUND: Viral infection and allergy have been identified as major risk factors for exacerbation in asthma, especially in the presence of both. However, whether patients with allergic asthma are more susceptible to respiratory infections requiring antibiotics remains unknown. OBJECTIVE: To investigate allergy as a risk factor for respiratory infections requiring antibiotics based on register data from a nationwide population of patients with asthma. METHODS: A register-based prospective follow-up study was performed using the Danish prescription database. In the inclusion period from 2010 through 2011, we identified patients with allergic asthma 18 to 44 years old. Patients were investigated during the follow-up period from 2012 through 2013, depending on their prescription drug use of antiallergic medication and antibiotics. Odds ratios were adjusted for age, sex, asthma severity, education, and urban vs rural residence. RESULTS: In a nationwide population we identified 60,415 patients with asthma. Based on prescriptions fillings for antiallergic medication, patients were subdivided into (1) nonallergic asthma (n = 35,334, 51.5%) and (2) allergic asthma (n = 25,081, 48.5%). Allergic asthma was associated with an increased risk of filling at least 2 antibiotic prescriptions per year compared with nonallergic asthma (odds ratio 1.28, 95% confidence interval 1.24-1.33, P < .0001). Interestingly, a subgroup analysis showed a protective effect of immunotherapy against the risk of requiring antibiotics (odds ratio 0.76, 95% confidence interval 0.66-0.87, P = .0001). CONCLUSION: Patients with allergic asthma have an increased risk of being prescribed antibiotics for respiratory infections compared with those with nonallergic asthma. Treatment with allergen immunotherapy appears to have a protective effect against this risk. PMID- 29413342 TI - Component-resolved diagnosis in selecting patients for yellowjacket venom immunotherapy. AB - BACKGROUND: Venom immunotherapy is effective in preventing systemic allergic reactions (SARs), but the diagnosis of venom allergy is problematic. OBJECTIVE: To compare the performance of component-resolved diagnosis and conventional tests in patients referred for venom immunotherapy. METHODS: We measured serum-specific immunoglobulin E to yellowjacket and honeybee venoms (Ves v 1 and Ves v 5 and Api m 1), cross-reactive carbohydrate determinants, serum basal tryptase (ImmunoCAP, ThermoFisher Scientific, Uppsala, Sweden), and skin prick test reactions in 84 patients referred to receive venom immunotherapy. History of SAR and its severity were evaluated. RESULTS: Of the 78 patients with suspected yellowjacket venom (YJV) allergy, a history of SAR was confirmed in 47 (60%) and 31 (40%) had a non SAR reaction. The most accurate tests to confirm venom allergy after a SAR were serum-specific immunoglobulin E to yellowjacket whole-venom extract spiked with Ves v 5 (area under the curve 0.87, 95% confidence interval 0.77-0.97, P < .001) and Ves v 5 (area under the curve 0.86, 95% confidence interval 0.76-0.96, P < .001). Sensitization to Ves v 1 was infrequent and its area under the curve was low (0.62, 95% confidence interval 0.47-0.76, P = .106). Sensitivity of the YJV skin prick test was 86%, but its specificity was low at 54%. Double sensitization to yellowjacket and honeybee occurred frequently in skin prick tests. Of the patients without a SAR, 26% showed a positive reaction to YJV in any serum test and 46% showed a positive reaction in skin tests. CONCLUSION: Specific immunoglobulin E to the YJV spiked with Ves v 5 confirmed the allergy after a SAR. A history of SAR should be confirmed before testing, because venom sensitization is frequent in other types of reactions. PMID- 29413343 TI - Clinical and economic burden of hospitalizations with registration of penicillin allergy. AB - BACKGROUND: Penicillin allergy is commonly reported, but only a minority of claimants has a confirmed diagnosis. Nevertheless, patients labeled as having penicillin allergy are treated with second-line antibiotics, which are more expensive and less effective, possibly increasing the risk of drug-resistant infections. OBJECTIVE: To compare hospitalizations with and without registration of penicillin allergy concerning their morbidity and hospital resource use. METHODS: We analyzed a national administrative database containing a registration of all Portuguese hospitalizations from 2000 to 2014. All episodes occurring in adults with a penicillin allergy registration were compared with an equal number of hospitalizations without such registration and matched for inpatients' age, sex, and main diagnosis. We compared those episodes concerning their length of stay, hospital price charges, comorbidities, and frequency of drug-resistant infections. Differences between medical and surgical hospitalizations were explored. RESULTS: Hospitalizations with registration of penicillin allergy (n = 102,872) had a longer average length of stay than the remainder episodes (8 vs 7 days; P < .001) and higher hospital charges (3,809.0 vs 3,490.0 USD; P < .001). Inpatients with penicillin allergy registration also had a higher mean Charlson Comorbidity Index (0.91 vs 0.76; P < .001) and a significantly higher frequency of infections by several agents, including methicillin-resistant Staphylococcus aureus, Enterococcus species, and Escherichia coli. Among surgical episodes, septicemia was 1.2-fold more frequent among penicillin allergy cases. CONCLUSION: Hospitalizations with registration of penicillin allergy are associated with increased economic costs and frequency of infections by drug-resistant agents, reinforcing the need to establish a correct diagnosis of penicillin allergy. PMID- 29413344 TI - Home-based subcutaneous immunoglobulin therapy vs hospital-based intravenous immunoglobulin therapy: A prospective economic analysis. AB - BACKGROUND: Home-based subcutaneous immunoglobulin (SCIg) administration used for immunoglobulin replacement therapy for patients with primary immunodeficiency has been demonstrated to have benefits compared with hospital-based intravenous immunoglobulin (IVIg) therapy. OBJECTIVE: To estimate the cost savings associated with treating eligible patients with primary immunodeficiency with home-based SCIg compared with hospital-based IVIg in a prospective study. METHODS: This study was a 12-month prospective observational study that collected information from patient charts, directly from the nurse for time spent with patients and materials used, and directly from the physicians for billing. Data were collected on case report forms at each follow-up. Data were entered in a web-based REDCap database and statistical comparisons were performed. RESULTS: The average hospital (including hospital personnel such as nurses) and physician costs were significantly lower in the SCIg group ($1,836 and $84, respectively) than in the IVIg group ($4,187 and $744, respectively), which supported the findings in the number of hospital and physician visits in each group. The total cost was reported from the hospital's (only hospital-related costs) and the health system's (hospital- and physician-related costs) perspectives. For the 2 perspectives, the SCIg group reported significantly lower average total costs than the IVIg group. CONCLUSION: This is the first prospective analysis of the cost savings associated with home-based SCIG therapy compared with hospital-based IVIG therapy. These findings could help justify provision of home-based therapy training to suitable patients to lower health care costs or improve the capacity of care. PMID- 29413345 TI - Association between alpha1-antitrypsin and bronchiectasis in patients with humoral immunodeficiency receiving gammaglobulin infusions. AB - BACKGROUND: In patients with humoral immunodeficiency, the progression of bronchiectasis has been known to occur despite adequate gammaglobulin therapy and in the absence of recurrent infections. This observation suggests that factors other than gammaglobulin replacement might play a part in the prevention of lung damage in this population. alpha1-Antitrypsin deficiency can be associated with bronchiectasis, a chronic inflammatory lung disease. The protective levels of alpha1-antitrypsin and phenotype in preventing bronchiectasis have not been thoroughly studied in the immunodeficient population. We hypothesized that patients with humoral immunodeficiencies on gammaglobulin infusions and bronchiectasis have lower median levels, but not necessary "classically" deficient levels, of alpha1-antitrypsin compared with those without bronchiectasis. OBJECTIVE: To compare levels of alpha1-antitrypsin in subjects with immunodeficiency with and without bronchiectasis. METHODS: One hundred ninety-two subjects with humoral immunodeficiencies requiring gammaglobulin therapy had their alpha1-antitrypsin levels and phenotype screened. High resolution computed tomograms of the chest of participants were obtained and compared with alpha1-antitrypsin levels and phenotype. RESULTS: Participants without bronchiectasis were found to have higher median levels of alpha1 antitrypsin than those with bronchiectasis (P = .003). Furthermore, subjects with improving or resolved bronchiectasis since initiating gammaglobulin therapy had higher median levels of alpha1-antitrypsin than those with worsening bronchiectasis (P = .004). The prevalence of the alpha1-antitrypsin PiZZ mutation was higher than in the general public (P < .0001). CONCLUSION: Median alpha1 antitrypsin levels and phenotype in subjects were associated with humoral immunodeficiency and their bronchiectasis status. Prospective studies might be necessary to determine possible benefits of augmentation therapy. This study supports the idea that what is considered a "normal or protective" alpha1 antitrypsin range might need to be refined for patients with humoral immunodeficiency on gammaglobulin therapy. PMID- 29413346 TI - Penicillin skin testing without minor determinate mixture and amoxicillin challenge in the Appalachian region. PMID- 29413347 TI - Suspected asthma status and time spent in physical activity across multiple childhood age groups. PMID- 29413348 TI - Patterns of electronic cigarette use in youth with asthma: Results from a nationally representative sample. PMID- 29413349 TI - Authors' response. PMID- 29413350 TI - Allergic sensitization and sleep in children with asthma. PMID- 29413352 TI - Information for Readers. PMID- 29413354 TI - Fluorometric detection of nitroaromatics by fluorescent lead complexes: A spectroscopic assessment of detection mechanism. AB - Three Schiff base ligands such as 2-[(2-Hydroxy-3-methoxy-benzylidene)-amino]-2 hydroxymethyl-propane-1,3-diol (HL1), 2-[(2-Hydroxy-benzylidene)-amino]-2 hydroxymethyl-propane-1,3-diol (HL2), 2-[(3,5-Dichloro-2-hydroxy-benzylidene) amino]-2-hydroxymethyl-propane-1,3-diol (HL3) have been synthesized by condensation of aldehydes (such as 3,5-Dichloro-2-hydroxy benzaldehyde, 2-Hydroxy benzaldehyde, and 2-Hydroxy-3-methoxy-benzaldehyde) with Tris (hydroxymethyl)amino methane and characterized by IR, UV-vis and 1H NMR spectroscopy. Then all these three ligands have been used to prepare Pb(II) complexes by reaction with lead(II) acetate tri-hydrate in methanol. In view of analytical and spectral (IR, UV-vis and Mass) studies, it has been concluded that, except HL2, other two ligands form 1:1 metal complexes (1 and 3) with lead. Between two complexes, complex 3 is highly fluorescent and this property has been used to identify the pollutant nitroaromatics. Finally, the quenching mechanism has been established by means of spectroscopic investigation. PMID- 29413356 TI - Abnormal lipoprotein oxylipins in metabolic syndrome and partial correction by omega-3 fatty acids. AB - Metabolic syndrome (MetSyn) is characterized by chronic inflammation which mediates the associated high risk for cardiovascular and other diseases. Oxylipins are a superclass of lipid mediators with potent bioactivities in inflammation, vascular biology, and more. While their role as locally produced agents is appreciated, most oxylipins in plasma are found in lipoproteins suggesting defective regulation of inflammation could be mediated by the elevated VLDL and low HDL levels characteristic of MetSyn. Our objective was to compare the oxylipin composition of VLDL, LDL, and HDL in 14 optimally healthy individuals and 31 MetSyn patients, and then to determine the effects of treating MetSyn subjects with 4g/day of prescription omega-3 fatty acids (P-OM3) on lipoprotein oxylipin profiles. We compared oxylipin compositions of healthy (14) and MetSyn (31) subjects followed by randomization and assignment to 4g/d P-OM3 for 16 weeks using LC/MS/MS. Compared to healthy subjects, MetSyn is characterized by abnormalities of (1) pro-inflammatory, arachidonate-derived oxylipins from the lipoxygenase pathway in HDL; and (2) oxylipins mostly not derived from arachidonate in VLDL. P-OM3 treatment corrected many components of these abnormalities, reducing the burden of inflammatory mediators within peripherally circulating lipoproteins that could interfere with, or enhance, local effectors of inflammatory stress. We conclude that MetSyn is associated with a disruption of lipoprotein oxylipin patterns consistent with greater inflammatory stress, and the partial correction of these dysoxylipinemias by treatment with omega-3 fatty acids could explain some of their beneficial effects. PMID- 29413355 TI - Synthesis, characterization, vibrational spectroscopy, and factor group analysis of partially metal-doped phosphate materials. AB - A simple precipitating method was used to synthesize effectively a partially metal-doped phosphate hydrate (Mn0.9Mg0.1HPO4.3H2O), whereas the thermal decomposition process of the above hydrate precursor was used to obtain Mn1.8Mg0.2P2O7 and LiMn0.9Mg0.1PO4 compounds under different conditions. To separate the overlapping thermal decomposition peak, a deconvolution technique was used, and the separated peak was applied to calculate the water content. The factor group splitting analysis was used to exemplify their vibrational spectra obtained from normal vibrations of HPO42-, H2O, P2O74- and PO43- functional groups. Further, the deconvoluted bending mode of water was clearly observed. Mn0.9Mg0.1HPO4.3H2O was observed in the orthorhombic crystal system with the space group of Pbca (D2h15). The formula units per unit cell were found to be eight (Z = 8), and the site symmetric type of HPO42- was observed as Cs. For the HPO42- unit, the correlation filed splitting analysis of type C3v - Cs - D2h15 was calculated and had 96 internal modes, whereas H2O in the above hydrate was symbolized as C2v - Cs - D2h15 and had 24 modes. The symbol C2v - Cs - C2h3 was used for the correlation filed splitting analysis of P2O74- in Mn1.8Mg0.2P2O7 (monoclinic, C2/m (C2h3), Z = 2, and 42 modes). Finally, the symbol Td - Cs - D2h16 was used for the correlation filed splitting analysis of PO43- in LiMn0.9Mg0.1PO4 (orthorhombic, Pnma (D2h16), Z = 4, and 36 modes). PMID- 29413357 TI - Maternal dietary of n-3 polyunsaturated fatty acids affects the neurogenesis and neurochemical in female rat at weaning. AB - Long-chain polyunsaturated fatty acids (LC-PUFAs) are rapidly accumulated in brain during pre- and neonatal life, which is important for the development and function of central nervous system. Deficiency of biologically important n-3 PUFA docosahexaenoic acid (C22:6n-3, DHA) is associated with impaired visual, attention and cognition, and would precipitate psychiatric symptoms. However, clinical studies of the potential mechanism on the effect of dietary DHA deficiency on neural development remain unclear. In addition, the effects of n-6 PUFAs and n-3 PUFAs ingestion on the dynamic process of the cell proliferation in neurogenesis of offspring were investigated using immunefluorescence. And GC-MS was used to determine the fatty acid content in the liver of offspring. To further investigate the neurochemical influence on maternal PUFAs levels, we assessed the functioning of various neurotransmitter systems including glutamatergic, dopaminergic, norepinephrinergic and serotoninergic systems in the brain of female rats at weaning by HPLC-MS/MS. Lastly, we analyzed the turnover rates and between-metabolite ratios (the ratios between metabolites of monoamine neurotransmitters) to seek potential links between the neurotransmitters and dietary fatty acids compositions. There were significant differences between the deficiency group and the control or supplementary group in liver fatty acids compositions, showing that n-3 PUFAs were largely replaced by n-6 PUFAs. The generation of n-3 PUFAs deficiency rats exhibited abnormal neurogenesis and neurochemical. Altered dopamine or norepinephrine transmission and between metabolite ratios in brain areas may be a key neuronal mechanism that contributes to the potential detrimental effects of n-3 PUFAs deficiency for mental health. PMID- 29413358 TI - The role of fatty acid desaturase (FADS) genes in oleic acid metabolism: FADS1 Delta7 desaturates 11-20:1 to 7,11-20:2. AB - INTRODUCTION: In mammals, FADS2 catalyzes "front-end" Delta4-, Delta6-, and Delta8-desaturation of fatty acyl chains, whereas FADS1 has Delta5-desaturase activity. Eighteen and 20-carbon precursors to highly unsaturated n-3 and n-6 fatty acids are the usual substrates for FADS1 and FADS2. Our main objective was to characterize the metabolic fate of oleic acid (OA) due to action of FADS gene products. METHODS: MCF-7 cells were stably transformed with either FADS1 or FADS2 or empty vector. A series of dose-response experiments were conducted with albumin-bound fatty acid substrates (18:1n-9 and 20:1n-9) provided in concentrations up to 100uM. Cells were harvested after 24h, after which FAME were prepared and analyzed by GC-FID and covalent adduct chemical ionization tandem mass spectrometry (CACI-MS/MS). RESULTS: When stably transformed cells were incubated with 18:1n-9, FADS1 and control cells elongated 18:1n-9 -> 20:1n-9 (11 20:1), while FADS2 cells Delta6 desaturated, elongated, and then Delta5 desaturated via FADS1 coded activity leading to Mead acid, 9-18:1 -> 6,9-18:2 -> 8,11-20:2 (20:2n-9) -> 6,8,11-20:3 (20:3n-9). Surprisingly, FADS1 cells Delta7 desaturated 11-20:1 -> 7,11-20:2, the latter detected at low levels in control and FADS2 cells. Our results imply three pathways operate on 18:1n-9: 1) 18:1n-9 > 18:2n-9 -> 20:2n-9 -> 20:3n-9; 2) 18:1n-9 -> 20:1n-9 -> 20:2n-9 -> 20:3n-9 and 3) 18:1n-9 -> 20:1n-9 -> 7,11-20:2. CONCLUSION: Alternative pathways for oleic acid metabolism exist depending on FADS2 or FADS1 activities, we present the first evidence of Delta7 desaturation via the FADS1 gene product. PMID- 29413359 TI - DHA and ARA addition to infant formula: Current status and future research directions. AB - Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are present in breast milk and play important roles in early infant development. A supply of these fatty acids in infant formula (typically following breast milk as a model with ARA > DHA) is thought to be important since endogenous synthesis is insufficient to maintain tissue levels equivalent to breast-fed infants. Intervention studies assessing the impact of DHA- and ARA-supplemented formulas have resulted in numerous positive developmental outcomes (closer to breast-fed infants) including measures of specific cognition functions, visual acuity, and immune responses. A critical analysis of outcome assessment tools reveals the essentiality of selecting appropriate, focused techniques in order to provide accurate evaluation of DHA- and ARA-supplemented formulas. Future research directions should encompass in-depth assessment of specific cognitive outcomes, immune function, and disease incidence, as well as sources of experimental variability such as the status of fatty acid desaturase polymorphisms. PMID- 29413361 TI - Fish oil supplemental dose needed to reach 1g% DHA+EPA in mature milk. AB - INTRODUCTION: Erythrocyte (RBC) DHA+EPA is considered optimal at 8g%. Mothers with lifetime high fish intakes exhibiting this status produce milk with about 1g% DHA+EPA. We established DHA+EPA supplemental dosages needed to augment RBC DHA+EPA to 8g% and milk DHA+EPA to 1g%. MATERIALS AND METHODS: Pregnant women were randomly allocated to DHA+EPA dosages of: 225+90 (n=9), 450+180 (n=9), 675+270 (n=11) and 900+360 (n=7) mg/day. Samples were collected at 20 and 36 gestational weeks and 4 weeks postpartum. RESULTS: Linear regression revealed needed dosages rounded at 750mg/day to reach 8g% RBC DHA+EPA and 1000mg/day for 1g% milk DHA+EPA. RBC DHA+EPA increment depended on baseline values. There was no effect on milk AA, but milk EPA/AA ratio increased. CONCLUSION: Women with an RBC DHA+EPA status of 5.5g% need 750 and 1000mg DHA+EPA/day to reach 8g% RBC DHA+EPA at the pregnancy end and 1g% mature milk DHA+EPA, respectively. PMID- 29413360 TI - A sixteen-week three-armed, randomized, controlled trial investigating clinical and biochemical effects of targeted alterations in dietary linoleic acid and n-3 EPA+DHA in adults with episodic migraine: Study protocol. AB - : Migraine is a prevalent neurological disorder, affecting over 16% of adult women and 7% of adult men in the U.S., causing significant pain, disability, and medical expense, with incomplete benefits from conventional medical management. Migraine, as a chronic pain syndrome, provides a practical model for investigating the impact of dietary modifications in omega-3 (n-3) and omega-6 (n 6) fatty acids. This paper reports the protocol of a trial to assess whether targeted dietary modifications designed to increase n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with or without concurrent reduction in n-6 linoleic acid (LA), will alter nociceptive lipid mediators and mediate decreases in frequency and severity of migraine. This prospective, randomized, controlled trial in 153 male and female adult subjects, ages 18-99, with diagnosed and actively managed episodic migraine tests the efficacy, safety, and biochemical effects of targeted, controlled alterations in dietary omega-3 and omega-6 fatty acids. Participants are masked to diet hypotheses and all assessors are masked to treatment assignment. Following a four-week baseline period, participants with migraine headache frequency of 5-20 per month are randomized to one of three intensive dietary regimens for 16 additional weeks followed by a less intensive observation period. Dietary intervention arms include: 1) increased n-3 EPA+DHA with low n-6 linoleic acid (H3 L6); 2) increased n-3 EPA+DHA with usual US dietary intake of n-6 linoleic acid (H3 H6); and 3) usual US dietary content of n 3 and n-6 fatty acids (L3 H6). During the actual intervention, subjects receive content-specific study oils and foods sufficient for two meals and two snacks per day, as well as dietary counseling. Biochemical and clinical outcome measures are performed at intervals throughout this period. This randomized controlled trial is designed to determine whether targeted alterations in dietary n-3 and n-6 fatty acids can alter nociceptive lipid mediators in a manner that decreases headache pain and enhances quality of life and function in adults with frequent migraines. TRIAL REGISTRATION: NCT02012790. PMID- 29413362 TI - The type of dietary fat and dietary energy restriction affects the activity of the desaturases in the liver microsomes. AB - The aim of present study was to investigate the effect of different dietary oils and the dietary energy restriction on the activity of enzymes participating in the process of arachidonic acid synthesis and on fatty acid profile in serum. It was also evaluated how diet modification affects the weight of animals and weight of the specific organs: liver, kidney and spleen. Wistar male rats were divided into 6 groups according to the diet fed (control, sunflower oil, olive oil, rapeseed oil, fish oil and a group of dietary energy restriction - DER group). The enzyme activities were established indirectly in liver microsomes. To this aim the method of high performance liquid chromatography with UV/VIS detection was used. In addition, the indices of ?6-desaturase (D6D) and ?5-desaturase (D5D) were determined. Significant differences in the concentrations of fatty acids and enzyme activity were observed. The results concerning desaturases show the negative correlation between n-3 polyunsaturated fatty acids intake and enzymes activity. The highest D6D activity was observed in microsomes obtained from sunflower oil fed rats and the lowest D6D activity was in the DER group. D5D index did not differ much depending on the diet. Among groups supplemented with oils the higher mean values of the weight of liver were observed in the group supplemented with rapeseed oil. Consumption of diets supplemented with edible oils of different fatty acid profile influence both serum fatty acid composition and the activity of ?6- and Delta5-desaturase. PMID- 29413363 TI - Safflower (n-6) and flaxseed (n-3) high-fat diets differentially regulate hypothalamic fatty acid profiles, gene expression, and insulin signalling. AB - Polyunsaturated fatty acids (PUFA) have important signalling roles in the hypothalamus, a region of the brain that regulates whole-body energy homeostasis. While evidence suggests that high PUFA intake can impact hypothalamic activity, the underlying molecular mechanisms regulated by essential dietary n-6 and n-3 PUFA (i.e., linoleic acid and alpha-linolenic acid, respectively) remain poorly described in this brain region. To differentiate the roles of essential dietary PUFA on hypothalamic function, we fed male rats high-fat diets (35% kcal/d) containing either safflower (linoleic acid) or flaxseed (alpha-linolenic acid) oil for 2 months. Control rats were fed a low-fat (16% kcal/d) diet containing soybean oil. Hypothalamic fatty acids and gene expression were investigated by gas chromatography and microarray, respectively. Safflower-fed rats had higher total n-6 PUFA content due to increases in linoleic acid, arachidonic acid, and osbond acid compared to the other diet groups, while flaxseed-fed rats had higher total n-3 content due to increases in alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. Safflower-fed rats showed augmented expression of genes related to hypothalamic insulin signalling compared to controls. This was mirrored by significant increases in phosphorylated AKTthr308 and AKTser473 levels; indicative of increased PI(3)K/AKT pathway activity. These changes were not observed in the hypothalamus of flaxseed-fed rats. Our findings provide new molecular insights into how essential fatty acids influence the hypothalamus and, potentially, whole-body energy homeostasis. This work also provides new knowledge to better understand the impact of essential fatty acids on metabolic and behavioral phenotypes. PMID- 29413364 TI - Arachidonic acid supplementation modulates blood and skeletal muscle lipid profile with no effect on basal inflammation in resistance exercise trained men. AB - Arachidonic acid (ARA), an omega-6 polyunsaturated fatty acid (PUFA), is the metabolic precursor to the eicosanoid family of lipid mediators. Eicosanoids have potent pro-inflammatory actions, but also act as important autocrine/paracrine signaling molecules in skeletal muscle growth and development. Whether dietary ARA is incorporated into skeletal muscle phospholipids and the resulting impact on intramuscular inflammatory and adaptive processes in-vivo is not known. In the current study, resistance trained men (>=1 year) received dietary supplementation with 1.5g/day ARA (n=9, 24 +/- 1.5 years) or placebo (n=10, 26 +/- 1.3 years) for 4-weeks while continuing their normal training regimen. Plasma and vastus lateralis muscle biopsies were collected in an overnight fasted state at baseline and week 4. ARA supplementation increased plasma content of ARA and gamma linolenic acid, while decreasing relative abundance of linoleic acid, eicosapentaenoic acid, and dihomo-gamma-linolenic acid. In skeletal muscle, ARA and dihomo-gamma-linolenic acid content increased, whereas alpha-linolenic-acid was reduced. Compared to placebo, ARA supplementation reduced circulating platelet and monocyte number, and decreased the mRNA expression of the immune cell surface markers; neutrophil elastase/CD66b and interleukin 1-beta, in peripheral blood mononuclear cells. In muscle, ARA supplementation increased mRNA expression of the myogenic regulatory factors; MyoD and myogenin, but had no effect on a range of immune cell markers or inflammatory cytokines. These data show that dietary ARA supplementation can rapidly and safely modulate plasma and muscle fatty acid profile and promote myogenic gene expression in resistance trained men, without a risk of increasing basal systemic or intramuscular inflammation. PMID- 29413365 TI - Claudio Galli (1938-2017). PMID- 29413366 TI - Relative Impairments in Hemodynamic Exercise Reserve Parameters in Heart Failure With Preserved Ejection Fraction: A Study-Level Pooled Analysis. AB - OBJECTIVES: The aim of this study was to compare the relative impairment in different exercise hemodynamic reserve parameters in patients with heart failure with preserved ejection fraction (HFpEF) and control patients using a study-level meta-analysis. BACKGROUND: A cardinal manifestation of chronic HFpEF is severely decreased exercise capacity. Developing effective therapies for exercise intolerance in HFpEF requires optimal understanding of the factors underlying exercise intolerance. METHODS: Data were included from 17 unique cohorts that measured peak oxygen uptake and hemodynamic or echocardiographic parameters during exercise in patients with HFpEF and control subjects in this meta analysis. Standardized mean differences (SMDs) in the exercise reserve (exercise resting) measures of hemodynamic or echocardiographic parameters between the HFpEF and control groups were pooled in a random-effects meta-analysis. RESULTS: The pooled analysis included 910 patients with HFpEF and 476 control subjects. In pooled analysis, patients with HFpEF had significantly lower peak oxygen uptake (SMD: -2.13; 95% confidence interval [CI]: -2.68 to -1.57). Among hemodynamic exercise reserve parameters, the largest impairment was observed in chronotropic response reserve (change in heart rate from rest to peak exercise; SMD: -1.87; 95% CI: -2.44 to -1.29), followed by exaggerated increase in pulmonary capillary wedge pressure with exercise (SMD: 1.78; 95% CI: 1.46 to 2.09). Significant abnormalities were also observed in the arteriovenous oxygen difference reserve and stroke volume reserve between the HFpEF and control groups. CONCLUSIONS: The most consistent and severe hemodynamic reserve abnormalities observed in patients with HFpEF were impairment in chronotropic reserve and exaggerated increase in pulmonary capillary wedge pressure with exercise. These may be important targets for therapeutic strategies to improve exercise tolerance in patients with HFpEF. PMID- 29413367 TI - What Limits Functional Capacity in Heart Failure With Preserved Ejection Fraction?: Unravelling the Knots of an Enigma. PMID- 29413369 TI - Cardiac Rehabilitation After Ventricular Assist Device Implantation: A Worthwhile Exercise? PMID- 29413368 TI - Association of Cardiac Rehabilitation With Decreased Hospitalizations and Mortality After Ventricular Assist Device Implantation. AB - OBJECTIVES: This study characterized cardiac rehabilitation (CR) use in ventricular assist device (VAD) recipients in the United States and the association of CR with 1-year hospitalization and mortality by using the 2013 to 2015 Medicare files. BACKGROUND: Exercise-based CR is indicated in patients with heart failure with reduced ejection fraction, but no data exist regarding CR participation after VAD implantation. METHODS: The study included Medicare beneficiaries enrolled for disability or age >65 years. The investigators identified VAD recipients by diagnosis codes and cumulated CR sessions occurring within 1 year after VAD implantation. Multivariable-adjusted Andersen-Gill models were used to evaluate the association of CR with 1-year hospitalization risk, and Cox regression was used to evaluate the association of CR with 1-year mortality. RESULTS: There were 1,164 VADs implanted in Medicare beneficiaries in the United States in 2014. CR use was low, with 348 patients (30%) participating in CR programs. The Midwest had the highest proportion of VAD recipients who began CR (38%), whereas the Northeast had the lowest proportion of CR participants (25%). Each 5-year increase in age was associated with attending an additional 1.6 CR sessions (95% confidence interval [CI]: 0.7 to 2.5; p < 0.001). CR participation was associated with a 23% lower 1-year hospitalization risk (95% CI: 11% to 33%; p < 0.001) and a 47% lower 1-year mortality risk (95% CI: 18% to 66%; p < 0.01) after multivariable adjustment. CONCLUSIONS: Approximately one-third of VAD recipients attend CR. Although it is not possible to account fully for unmeasured confounding, VAD recipients who participate in CR appear to have lower risks for hospitalization and mortality. PMID- 29413370 TI - Addition of Supervised Exercise Training to a Post-Hospital Disease Management Program for Patients Recently Hospitalized With Acute Heart Failure: The EJECTION HF Randomized Phase 4 Trial. AB - OBJECTIVES: This study sought to measure the impact on all-cause death or readmission of adding center-based exercise training (ET) to disease management programs for patients with a recent acute heart failure (HF) hospitalization. BACKGROUND: ET is recommended for patients with HF, but evidence is based mainly on ET as a single intervention in stable outpatients. METHODS: A randomized, controlled trial with blinded outcome assessor, enrolling adult participants with HF discharged from 5 hospitals in Queensland, Australia. All participants received HF-disease management program plus supported home exercise program; intervention participants were offered 24 weeks of supervised center-based ET. Primary outcome was all-cause 12-month death or readmission. Pre-planned subgroups included age (<70 years vs. older), sex, left ventricular ejection fraction (<=40% vs. >40%), and exercise adherence. RESULTS: Between May 2008 and July 2013, 278 participants (140 intervention, 138 control) were enrolled: 98 (35.3%) age >=70 years, 71 (25.5%) females, and 62 (23.3%) with a left ventricular ejection fraction of >40%. There were no adverse events associated with ET. There was no difference in primary outcome between groups (84 of 140 [60.0%] intervention vs. 90 of 138 [65.2%] control; p = 0.37), but a trend toward greater benefit in participants age <70 years (OR: 0.56 [95% CI: 0.30 to 1.02] vs. OR: 1.56 [95% CI: 0.67 to 3.64]; p for interaction = 0.05). Participants who exercised to guidelines (72 of 101 control and 92 of 117 intervention at 3 months) had a significantly lower rate of death and readmission (91 of 164 [55.5%] vs. 41 of 54 [75.9%]; p = 0.008). CONCLUSIONS: Supervised center-based ET was a safe, feasible addition to disease management programs with supported home exercise in patients recently hospitalized with acute HF, but did not reduce combined end-point of death or readmission. (A supervised exercise programme following hospitalisation for heart failure: does it add to disease management?; ACTRN12608000263392). PMID- 29413371 TI - Preventing Readmission After Hospitalization for Acute Heart Failure: A Quest Incompletely Fulfilled. PMID- 29413372 TI - Low-Dose Aspirin in Heart Failure Not Complicated by Atrial Fibrillation: A Nationwide Propensity-Matched Study. AB - OBJECTIVES: This study sought to assess safety and effectiveness of low-dose aspirin in heart failure (HF) not complicated by atrial fibrillation. BACKGROUND: Despite lack of evidence, low-dose aspirin is widely used in patients with HF and sinus rhythm with and without prior ischemic heart disease. METHODS: The study included 12,277 patients with new-onset HF during 2007 to 2012 who had no history of atrial fibrillation. Of 5,450 patients using low-dose aspirin at baseline, 3,840 were propensity matched to non-aspirin users in a 1:1 ratio. Propensity matched Cox models were calculated with respect to the primary composite outcome of all-cause mortality, myocardial infarction, and stroke and the secondary outcomes of bleeding and HF readmission. RESULTS: The composite outcome occurred in 1,554 (40.5%) patients in the aspirin group and 1,604 (41.8%) patients in the non-aspirin group. Aspirin use was not associated with an altered risk of composite outcome (hazard ratio [HR]: 0.98; 95% confidence interval [CI]: 0.91 to 1.05), but it was associated with an increased risk of myocardial infarction (HR: 1.34; 95% CI: 1.08 to 1.67), whereas no differences were observed in all-cause mortality and stroke. An increased risk of HF readmission was observed in the aspirin group (HR: 1.25; 95% CI: 1.17 to 1.33). No difference in bleeding was observed. In subgroup analyses on the basis of a history of ischemic heart disease, the results were similar to the main result. CONCLUSIONS: No association was detected between low-dose aspirin use and the composite outcome of all-cause mortality, admission for myocardial infarction, and admission for stroke in patients with HF with no history of atrial fibrillation. Aspirin use was associated with an increased risk of readmission for HF. PMID- 29413373 TI - Physicians Addicted to Prescribing Aspirin-a Disorder Of Cardiologists (PAPA-DOC) Syndrome: The Headache of Nonevidence-Based Medicine for Ischemic Heart Disease? PMID- 29413374 TI - Human Touch. PMID- 29413375 TI - Smartphone, Mom, and HFpEF. PMID- 29413376 TI - Vildagliptin on Ventricular Function in Patients With Type 2 Diabetes Mellitus and Heart Failure: One Step Forward. PMID- 29413377 TI - Growth Differentiation Factor-15 in Chronic Heart Failure: The Role of miRNAs Regulation and of Wnt Signaling Modulation. PMID- 29413378 TI - Reply: Vildagliptin and Ventricular Function in Patients With Type 2 Diabetes Mellitus and Heart Failure: One Step Forward. PMID- 29413379 TI - Left Ventricular Dysfunction in Cancer Treatment: Is it Relevant? AB - Contemporary cancer therapies have dramatically improved cancer-free and overall survival but have been accompanied by increasing cancer treatment-related cardiovascular toxicity, including left ventricular (LV) systolic dysfunction. Previously, systemic chemotherapy with anthracyclines and radiation therapy were the only cancer treatments with significant cardiotoxicity. However, modern targeted cancer therapies, including HER2 inhibitors, tyrosine kinase inhibitors (TKIs), proteasome inhibitors, and immune checkpoint inhibitors, have all been associated with adverse cardiovascular events. As cancer treatment paradigms successfully move toward prolonged targeted therapy, cardiologists are increasingly needed to assess cardiotoxicity risk and manage asymptomatic and symptomatic LV systolic dysfunction. This state of the art review summarizes the present knowledge about the mechanisms and clinical practices of screening, diagnosis, and management of LV dysfunction associated with cancer therapeutic regimens. We utilize the framework of the ACCF/AHA stages of heart failure (HF) to summarize current evidence for risk stratification and modification (Stage A HF), asymptomatic structural heart disease detection and treatment (Stage B HF), and reduction of HF morbidity and mortality (Stages C and D HF) during cancer treatment and in survivorship. We also present new clinical practice challenges and opportunities for active engagement of cardiologists with multidisciplinary cancer treatment teams in order to ensure optimal patient outcomes. PMID- 29413380 TI - Realized niche analysis of phytoplankton communities involving HAB: Phaeocystis spp. as a case study. AB - The link between harmful algal blooms, phytoplankton community dynamics and global environmental change is not well understood. To tackle this challenging question, a new method was used to reveal how phytoplankton communities responded to environmental change with the occurrence of an harmful algae, using the coastal waters of the eastern English Channel as a case study. The great interannual variability in the magnitude and intensity of Phaeocystis spp. blooms, along with diatoms, compared to the ongoing gradual decrease in anthropogenic nutrient concentration and rebalancing of nutrient ratios; suggests that other factors, such as competition for resources, may also play an important role. A realized niche approach was used with the Outlying Mean Index analysis and the dynamics of the species' realized subniches were estimated using the Within Outlying Mean Indexes calculations under low (L) and high (H) contrasting Phaeocystis spp. abundance. The Within Outlying Mean Indexes allows the decomposition of the realized niche into realized subniches, found within the subset of habitat conditions and constrained by a subset of a biotic factor. The two contrasting scenarios were characterized by significantly different subsets of environmental conditions and diatom species (BV-step analysis), and different seasonality in salinity, turbidity, and nutrients. The subset L environmental conditions were potentially favorable for Phaeocystis spp. but it suffered from competitive exclusion by key diatom species such as Skeletonema spp., Thalassiosira gravida, Thalassionema nitzschioides and the Pseudo-nitzchia seriata complex. Accordingly, these diatoms species occupied 81% of Phaeocystis spp.'s existing fundamental subniche. In contrast, the greater number of diatoms, correlated with the community trend, within subset H exerted a weaker biological constraint and favored Phaeocystis spp. realized subniche expansion. In conclusion, the results strongly suggest that both abiotic and biotic interactions should be considered to understand Phaeocystis spp. blooms with greater consideration of the preceeding diatoms. HABs needs must therefore be studied as part of the total phytoplankton community. PMID- 29413381 TI - Colony formation in two Microcystis morphotypes: Effects of temperature and nutrient availability. AB - The ability of Microcystis to form large colonies is a key trait that contributes to competition ability over other phytoplankton and facilitates the formation of surface scums in many freshwater systems. The effect of temperature and nutrients on this trait, however, is far from clear and needs further investigation, especially under a warmer climate and nutrient overloading in aquatic systems globally. In this study, two colonial strains of Microcystis (M. wesenbergii and M. ichthyoblabe) originally isolated from Lake Taihu in China, were used to investigate cyanobacterial aggregation under a range of temperatures (15-30 degrees C), phosphorus availability (0.004-8 mg P L-1), and nitrogen availability (0.04-40 mg N L-1). The mechanism of colony formation in Microcystis was determined based on growth rates and extracellular polysaccharide (EPS) contents. The colony size of both strains increased significantly when the temperature rose from 15 to 25 degrees C. A further increase in temperature from 25 to 30 degrees C, however, reduced the colony size of M. ichthyoblabe significantly, and, in contrast, increased the colony size of M. wesenbergii. Higher phosphorus availability promoted the formation of larger colonies in both strains. In comparison, nitrogen had no significant effect on the colony size. Furthermore, although EPS was a significant contributor to the formation of large colonies in colonial Microcystis, growth rate was a dominant driving factor in this process. The findings of this study highlight that warmer temperatures and phosphorus enrichment might enhance surface Microcystis scums directly through increasing the colony size. This study also provides new insights into the mechanism of colony formation in Microcystis. PMID- 29413382 TI - Molecular detection of harmful cyanobacteria and expression of their toxin genes in Dutch lakes using multi-probe RNA chips. AB - Harmful cyanobacterial blooms are a major threat to water quality and human health. Adequate risk assessment is thus required, which relies strongly on comprehensive monitoring. Here, we tested novel multi-probe RNA chips developed in the European project, MUAqua, to determine the abundance of harmful cyanobacterial species and expression of selected toxin genes in six Dutch lakes. All of the targeted cyanobacterial genera, except for Planktothrix, were detected using the microarray, with predominance of Dolichospermum and Microcystis signals, of which the former was found across all sites and detected by the probes for Anabaena where it was formerly placed. These were confirmed by microscopic cell counts at three sites, whereas at the other sites, microscopic cell counts were lower. Probe signals of Microcystis showed larger variation across sites but also matched microscopic counts for three sites. At the other sites, microscopic counts were distinctly higher. We detected anatoxin-a in the water at all sites, but unfortunately no genes for this toxin were on this generation of the toxin array. For microcystins, we found none or low concentrations in the water, despite high population densities of putative microcystin producers (i.e. Microcystis, Dolichospermum). The described method requires further testing with a wider range of cyanobacterial communities and toxin concentrations before implementation into routine cyanobacterial risk assessment. Yet, our results demonstrate a great potential for applying multi probe RNA chips for species as well as toxins to eutrophic waters with high cyanobacterial densities as a routine monitoring tool and as a predictive tool for toxin potential. PMID- 29413383 TI - Effects of modified clay used for the control of harmful algal blooms on Alexandrium pacificum cysts. AB - Cyst formation plays an important role in the resistance of dinoflagellates to adverse environments, and cyst germination is considered one of the causes of harmful algal blooms (HABs). Among the methods for mitigating HABs, modified clay (MC) is considered a promising strategy because of its high efficiency and low environmental impacts. The typical HAB species Alexandrium pacificum was focused on in this study to clarify the effects of MC on cyst formation and germination. The results showed that more than 90% of the vegetative cells were removed under the 0.6 g/L MC treatment. The vegetative cell density was monitored over 90 d and increased slightly to the peak at 10 d after the cell removal experiment, but persistent growth was not observed. The amount of cysts was maximal at 20 d after removal, however, most of the cysts were temporary cysts that subsequently disappeared. After 80 d, all the remaining cysts were resting ones. The total density of resting cysts was higher under MC concentrations of 0.2 and 0.4 g/L and lower under concentrations of 0.6, 0.8 and 1.0 g/L compared with that in the control. The total formation rate of resting cysts was 29.6% in the control group, and the lowest formation rate in the experimental groups was 15.5% at 0.6 g/L MC. The total germination rate of resting cyst decreased as the MC concentration increased, and approximately 68.0% of the resting cysts in the control group germinated successfully, whereas the addition of MC reduced the germination rate to as low as 12.4%. Our results indicated that the application of appropriate MC concentrations may provide an effective mitigation strategy for A. pacificum blooms because it does not leave more residual cysts, which can act as "seeds" for the initiation of HABs. PMID- 29413384 TI - Advection of Karenia brevis blooms from the Florida Panhandle towards Mississippi coastal waters. AB - Harmful Algal Blooms (HABs) of Karenia brevis have been documented along coastal waters of every state bordering the Gulf of Mexico (GoM). Some Gulf Coast locations, such as Florida and Texas, suffer from recurrent intense and spatially large blooms, while others such as Mississippi seem to rarely observe them. The main objective of this work is to understand the dynamics that led to the K. brevis bloom in Mississippi coastal waters in fall 2015. Blooms of K. brevis from the Florida Panhandle region are often advected westward towards the Mississippi Alabama coast; however there is interannual variability in their presence and intensity in Mississippi coastal waters. The 2015 K. brevis bloom was compared to the 2007 Florida Panhandle K. brevis bloom, which showed a westward advection pattern, but did not intensify along the Mississippi coast. Cell counts and flow cytometry were obtained from the Mississippi Department of Marine Resources, Alabama Department of Public Health, Florida Fish and Wildlife Conservation Commission and The University of Southern Mississippi. Ocean color satellite imagery from the Moderate Resolution Imaging Spectroradiometer onboard the Aqua satellite was used to detect and delineate the blooms in 2007 and 2015. Two different regional applications of NCOM-Navy Coastal Ocean Model (1-km resolution NCOM-GoM/Gulf of Mexico and 6-km resolution NCOM-IASNFS/Intra Americas Sea Nowcast Forecast System) were used to understand the circulation and transport pathways. A Lagrangian particle tracking software was used to track the passive movement of particles released at different locations for both bloom events. Ancillary data (e.g., nutrients, wind, salinity, river discharge) from local buoys, monitoring stations and coincident oceanographic cruises were also included in the analysis. The blooms of K. brevis reached the Mississippi coast both years; however, the bloom in 2007 lasted only a few days and there is no evidence that it entered the Mississippi Sound. Two major differences were observed between both years. First, circulation patterns in 2015 resulting from an intense westward-northwestward that persisted until December allowed for continuous advection, whereas this pattern was not evident in 2007. Second, local river discharge was elevated throughout late fall 2015 while 2007 was below the average. Thus, elevated discharge may have provided sufficient nutrients for bloom intensification. These results illustrate the complex, but important interactions in coastal zones. Further, they emphasize the importance in establishing comprehensive HAB monitoring programs, which facilitate our understanding of nutrient and phytoplankton dynamics, and stress the importance for multi-agency cooperation across state boundaries. PMID- 29413385 TI - Niche separation of Baltic Sea cyanobacteria during bloom events by species interactions and autecological preferences. AB - Cyanobacterial blooms regularly occur in the Baltic Sea during the summer months, with filamentous, heterocystous Nodularia spumigena and Dolichospermum sp. and the coccoid picocyanobacterium Synechococcus spp. as important species. Under calm conditions, N. spumigena accumulate at the surface, whereas Dolichospermum sp. and Synechococcus sp. remain at the subsurface, in the upper water layer. This vertical separation allows co-occurring species to compete for the same resources. The factors that determine the vertical distribution within blooms, however, are mostly unknown. The present study examined the growth rates of these three cyanobacterial species in a two-factorial experiment, with temperature (16 and 24 degrees C) and radiation (38 and 150 MUmol photons m-2 s-1) conditions mimicking those at the water surface and directly below. To determine whether interactions between the three species influenced their growth rates (and therewith also their vertical distribution), paired and multi-species cultures were established. In the single-species cultures, the autecological preferences of the species matched the assumed natural occurrence in bloom events: N. spumigena grew best under high and Dolichospermum sp. and Synechococcus sp. under low light conditions (maximum growth rates at the preferred conditions: MU = 0.48 +/- 0.017, 0.88 +/- 0.092, and 0.67 +/- 0.012, respectively). High temperatures were tolerated by N. spumigena, but inhibited the growth of Dolichospermum sp. and Synechococcus sp. These results suggested that the factors resulting in the vertical separation of species within a bloom are species-specific: N. spumigena responded predominantly to irradiance and only slightly to temperature, Dolichospermum sp. was intensely affected by temperature and less by irradiance, and Synechococcus sp. responded more strongly to irradiance than to temperature. The interactions in paired and multi-species cultures revealed beneficial and detrimental effects, depending on species composition and abiotic conditions. Under the environmental conditions in which the three species occur, however, similar interactions resulted in no or only slight inhibition. Our observations demonstrate how autecological preferences together with the avoidance of negative interactions determine the vertical distribution of cyanobacteria during bloom events in the Baltic Sea. PMID- 29413386 TI - Akinete germination chamber: An experimental device for cyanobacterial akinete germination and plankton emergence. AB - Understanding how algal resting cells (e.g. akinetes) germinate and what factors influence their germination rate is crucial for elucidating the development of algal blooms and their succession. While laboratory studies have demonstrated algal germination rate and some key factors affecting the germination, the use of artificially induced akinetes and/or removal of the sediments are obviously limiting in simulating the natural environment when designing such controlled experiments. This study introduce a laboratory Akinete Germination Chamber (AGC) that facilitates research for cyanobacterial akinete germination and emergence in an environment similar to natural conditions while minimizing sediment disturbance. The fundamental difference between AGC method and the conventional microplate method is that AGC incorporates the substrate from the natural environment whereas the microplate method does not employ sediment. Therefore, authors of this study assume that the characteristics of akinete germination between the two methods differ because the sediment influences the germination environment. The present study developed the AGC method as an efficient tool to understand harmful cyanobacterial bloom formation. For validation of the AGC method, this study evaluated akinete germination of Dolichospermum circinale (Anabaena circinalis) with different temperature and nutrient condition and then compared the results with those generated by conventional methods The results showed a marked difference in the maximal germination rate between two methods (78% and 35% in the AGC and the microplate, respectively; p < 0.05) at optimum germination temperature (25 degrees C for both the AGC and the microplate). The nutrient effect also demonstrated clear difference (p < 0.01) in the germination rate between two methods; 88%, 68% and 78% in the AGC and 15%, 20% and 15% in the microplate with -N+P, +N-P, and +N+P condition of CB medium, respectively. Importantly, both DW and -N-P treatments in the AGC induced a little germination of akinete (4.2 +/- 1.4% and 5.0 +/- 7.1%, respectively), whereas no germination was occurred in the DW treatment in the microplate, suggesting a possible positive effect of sediment on akinete germination. With these results, this study suspects that these differences were largely attributable to natural sediment. Also sediment-accompanied properties, possibly such as nutrient availability, heat budget, micronutrients, and bacteria might have some potential effects on akinete germination. The AGC method can overcome the limitations of the conventional microplate method, and that it is applicable in studies on pelagic-benthic coupling. PMID- 29413387 TI - Problems in Meta-Analysis of Comparative Effectiveness of Conservative Interventions for Nonspecific Chronic Spinal Pain. PMID- 29413388 TI - Criticism for Following Recommended Practice. PMID- 29413391 TI - Mentoring the Next Generation: Irving Weissman. AB - Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Irving Weissman about his views. PMID- 29413392 TI - The Role of Physicians Practicing in Assisted Living: What Changes Do We Really Need? PMID- 29413393 TI - The Broken Lens of BPSD: Why We Need to Rethink the Way We Label the Behavior of People Who Live With Alzheimer Disease. AB - For the past 20 years, the behaviors of people who live with dementia (PLWD) that others find challenging or problematic have primarily been ascribed to Alzheimer disease and related dementias and have been assessed through the biomedical lens of Behavioral and Psychological Symptoms of Dementia (BPSD). This has led to the root causes of these behaviors being overlooked, which in turn leaves them unaddressed. Further, using the artificial construct of BPSD has led to many PLWD being inappropriately prescribed (off-label) medications that are largely ineffective in resolving the behaviors because they do nothing to remedy the underlying psychosocial and environmental causes. The fact that many of the behaviors we call BPSD are normal human responses to particular sets of circumstances can be relatively easily demonstrated by directly observing the individual behaviors of PWLD, and putting them in context, as well as by asking ourselves how we would respond under similar conditions. Re-evaluating the use of the construct of BPSD, and replacing it with a person-centered rather than disease-focused approach will result in better care as well as healthier and happier long-term care residents and staff. PMID- 29413394 TI - Polypharmacy, An Unfinished Term. PMID- 29413395 TI - Administrative Data for Research: An Increasingly Powerful Tool, but Still With Caveats. PMID- 29413396 TI - Biography, Guest Editor: Hidenori Matsuo. PMID- 29413399 TI - Roots of Mediterranean civilisations. AB - European culture traces its history back to the ancient Greek civilisations, while Christianity and Judaism have their roots in the populations on the eastern shore of the Mediterranean Sea. Genome studies of several Bronze Age individuals from each of these regions have now probed the genetic roots of early civilisations, revealing both migration and continuity in both cases. Michael Gross reports. PMID- 29413400 TI - Maya Schuldiner. AB - Interview with Maya Schuldiner, who studies the cell biology of organelles at the Weizmann Institute in Israel. PMID- 29413401 TI - Pawan Sinha. AB - An interview with Pawan Sinha, a computational neuroscientist interested in vision, particularly visual object discovery, something he has been investigating via 'Project Prakash' on children in rural India born with treatable blindness. PMID- 29413402 TI - Omission of radiotherapy in elderly women with early stage metaplastic breast cancer. AB - PURPOSE: Multiple studies have evaluated the omission of radiation therapy (RT) in elderly women with invasive carcinoma; no studies to date have assessed this question for metaplastic breast cancer (MBC). This study is the only known study describing national practice patterns and addressing the impact of RT versus observation on survival in elderly women with T1-2N0 MBC. METHODS: The National Cancer Data Base was queried (2004-2013) for women aged >=70 years with T1-T2N0 MBC that underwent lumpectomy. Multivariable logistic regression ascertained factors associated with RT administration. Kaplan-Meier analysis evaluated overall survival (OS) between patients treated with or without postoperative RT. Cox proportional hazards modeling determined variables associated with OS. Propensity matching was performed in order to address indication bias. RESULTS: Of 547 total patients, 176 (32%) underwent observation, and 371 (68%) received postoperative RT. Temporal trends revealed that withholding RT steadily declined over the studied time period. RT delivery was less likely in patients not undergoing hormonal therapy or those >=80 years old. In both the overall population and following propensity matching, delivery of RT was associated with higher OS (p < 0.001 for both). On Cox multivariate analysis, poorer OS was independently associated with advancing age, higher T stage, high-grade disease, and omitting postoperative RT (p < 0.05 for all). CONCLUSIONS: Although level I evidence exists to omit RT in select elderly women, this is the only study evaluating this notion for MBC. These results do not support the routine withholding of RT in T1-2N0 MBC owing to the independent association with worse survival. PMID- 29413403 TI - Oral etoposide in heavily pre-treated metastatic breast cancer: A retrospective series. AB - BACKGROUND: Patients with metastatic breast cancer (MBC) can derive clinical benefit from several subsequent lines of chemotherapy. However, in heavily pre treated patients, agents with clinical activity, a favourable side effects profile and a convenient administration modality are preferred. PATIENTS AND METHODS: We retrospectively analyzed 110 patients with previously treated MBC, who received oral etoposide at the dose of 50 mg/day for 20 days in 28 days cycles, between 2003 and 2017. Because this was not a prospectively planned study, to describe the clinical performance of oral etoposide we adopted the approach suggested by Dzimitrowicz and colleagues (J Clin Oncol. 2016; 34:3511 17); Tumour Response (TR) was defined as the proportion of physician-reported clinical or imaging response; Prolonged Duration on Therapy (PDT) as the proportion of non-progressing patients whose treatment lasted more than 6 months. Furthermore, we evaluated median duration on therapy (TD) and median Overall Survival (OS) by the Kaplan Meier method. RESULTS: The median number of previous chemotherapy lines was 5 (range 2-8). TR, PDT, median TD and median OS were 6.4%, 18.2% 4 (range 3.5-4.5) and 10.6 (range 8.4-12.8) months respectively. Interestingly, etoposide activity was unrelated to the number of previous lines and type of metastatic involvement. Oral etoposide was well tolerated with only two patients discontinuing therapy due to toxicity. CONCLUSIONS: In this large, single Institution, real practice analysis oral etoposide is a valuable and safe option for pre-treated metastatic breast cancer patients and might be considered in patients failing other approaches, but still suitable for chemotherapy. PMID- 29413404 TI - Comparison of failure patterns between tubular breast carcinoma and invasive ductal carcinoma (KROG 14-25). AB - PURPOSE: Information on tubular carcinoma (TC) of breast is limited due to its rarity. A multi-institutional study was performed to investigate the prognosis and failure patterns of TC compared to invasive ductal carcinoma (IDC). MATERIALS AND METHODS: We collected retrospective data on 205 patients with TC from eleven institutions. For each TC case, 3 cases with IDC were matched according to similar size, t-stage, and n-stage from the same institution. Patterns of failure, disease free survival (DFS) and overall survival (OS) were assessed and compared between the groups. RESULTS: DFS at 5 years was 98.8% and 97.3% and OS at 5 years was 99.5% and 99.6% in TC and IDC, respectively. Among the patients with TC, 5 patients (2.4%) developed contralateral breast cancer, while 3 patients (0.5%) presented with contralateral breast cancer in patients with IDC. CONCLUSIONS: The TC of breast presents an excellent prognosis, but the contralateral breast cancer tends to be more frequently observed compared to IDC in Korean women. PMID- 29413405 TI - A quantitative analysis of tumour characteristics in breast cancer patients with extranodal extension in non-sentinel nodes. AB - BACKGROUND: The presence of extranodal extension (ENE) is well documented as a predictor of non-sentinel lymph node (NSLN) metastasis. The ACOSOG Z0011 trial (2011) concluded that patients who satisfy criteria including the absence of sentinel lymph node (SLN) ENE can forgo axillary clearance (AC). Currently there are no studies analysing the rate of ENE in NSLN metastasis in which the sentinel node was positive but had no ENE. Determining this incidence will help determine if current paradigms are resulting in residual ENE in NSLN metastasis by forgoing AC based on the Z0011 trial.. METHODS: This study determined incidence of ENE at NSLN metastasis in patients with a positive SLN biopsy without ENE in 162 symptomatic breast cancer patients who underwent AC between 2009 and 2014 at Cork University Hospital Breast Cancer Service, a teaching hospital of University College Cork. RESULTS: Of 965 sentinel node biopsies performed 251 were identified as SLN positive, 162 (64.5%) underwent further AC. Of the 162 patients, 56.8% (92/162) were positive for ENE at SLN, of these 57.6% (53/92) had NSLN metastasis versus 17.1% (12/70) in the ENE-negative group (chi2 test; P < 0.001). On adjusted analysis, ENE at the SLN was a significant predictor of NSLN metastasis (odds ratio [OR] 8.63; 95% confidence interval [CI] 3.26-22.86; P < 0.001). The incidence of NSLN-ENE in patients without SLN-ENE was 1/70 (1.4%) compared with 33.7% (31/92) in patients who had ENE at the SLN (chi2 test; P < 0.001). CONCLUSION: ENE at the SLN is an independent predictor of NSLN involvement; its absence significantly reduces the likelihood of ENE in NSLN metastasis.. PMID- 29413406 TI - 2D strain mapping using scanning transmission electron microscopy Moire interferometry and geometrical phase analysis. AB - A strain characterization technique based on Moire interferometry in a scanning transmission electron microscope (STEM) and geometrical phase analysis (GPA) method is demonstrated. The deformation field is first captured in a single STEM Moire hologram composed of multiple sets of periodic fringes (Moire patterns) generated from the interference between the periodic scanning grating, fixing the positions of the electron probe on the sample, and the crystal structure. Applying basic principles from sampling theory, the Moire patterns arrangement is then simulated using a STEM electron micrograph reference to convert the experimental STEM Moire hologram into information related to the crystal lattice periodicities. The GPA method is finally applied to extract the 2D relative strain and rotation fields. The STEM Moire interferometry enables the local information to be de-magnified to a large length scale, comparable to what can be achieved in dark-field electron holography. The STEM Moire GPA method thus extends the conventional high-resolution STEM GPA capabilities by providing comparable quantitative 2D strain mapping with a larger field of view (up to a few microns). PMID- 29413407 TI - Monte Carlo simulation and theoretical calculation of SEM image intensity and its application in thickness measurement. AB - The intensity profiles of backscattered and secondary electrons from a pure Mg sample have shown a variation with sample thickness and acceleration voltage in the range of 5-30 kV, depending on the specimen holder used. The intensities of backscattered electron (BSE) and secondary electron (SE) signals increases with the sample thickness until saturation when using a scanning transmission electron microscopy (STEM) holder with a closed tube below the sample. However the SE signal increases to the maximum and then decreases with the sample thickness when using a transmission Kikuchi diffraction (TKD) holder with no shielding below the sample whereas the BSE signal again increases until saturation. The influence of the holder on the SE signals is caused by the fact that secondary electrons emitted from the bottom surface could be detected only when using the TKD holder but not the STEM holder. The experimental results obtained are consistent with the Monte Carlo simulation results. Application of the magnitude of the SE and BSE signals to measurement of sample thickness has been considered and the BSE image profile shows a reasonably good accuracy. PMID- 29413408 TI - Quantification of nanomechanical properties of surfaces by higher harmonic monitoring in amplitude modulated AFM imaging. AB - The determination of nanomechanical properties is an intensive topic of study in several fields of nanophysics, from surface and materials science to biology. At the same time, amplitude modulation force microscopy is one of the most established techniques for nanoscale characterization. In this work, we combine these two topics and propose a method able to extract quantitative nanomechanical information from higher harmonic amplitude imaging in atomic force microscopy. With this method it is possible to discriminate between different materials in the stiffness range of 1-3 GPa, in our case thin films of PS-PMMA based block copolymers. We were able to obtain a critical lateral resolution of less than 20 nm and discriminate between materials with less than a 1 GPa difference in modulus. We show that within this stiffness range, reliable values of the Young's moduli can be obtained under usual imaging conditions and with standard dynamic AFM probes. PMID- 29413409 TI - Ewald sphere correction using a single side-band image processing algorithm. AB - Curvature of the Ewald sphere limits the resolution at which Fourier components in an image can be approximated as corresponding to a projection of the object. Since the radius of the Ewald sphere is inversely proportional to the wavelength of the imaging electrons, this normally imposes a limit on the thickness of specimen for which images can be easily interpreted to a particular resolution. Here we present a computational method for precisely correcting for the curvature of the Ewald sphere using defocused images that delocalise the high-resolution Fourier components from the primary image. By correcting for each approximately Friedel-symmetry-related sideband separately using two distinct complex transforms that effectively move the displaced Fourier components back to where they belong in the structure, we can determine the amplitude and phase of each of the Fourier components separately. This precisely accounts for the effect of Ewald sphere curvature over a bandwidth defined by the defocus and the size of the particle being imaged. We demonstrate this processing algorithm using: 1. simulated images of a particle with only a single, high-resolution Fourier component, and 2. experimental images of gold nanoparticles embedded in ice. Processing micrographs with this algorithm will allow higher resolution imaging of thicker specimens at lower energies without any image degradation or blurring due to errors made by the assumption of a flat Ewald sphere. Although the procedure will work best on images recorded with higher defocus settings than used normally, it should still improve 3D single-particle structure determination using images recorded at any defocus and any electron energy. Finally, since the Ewald sphere curvature is in a known direction in the third dimension which is parallel to the direction of view, this algorithm automatically determines the absolute hand of the specimen without the need for pairs of images with a known tilt angle difference. PMID- 29413410 TI - Local low rank denoising for enhanced atomic resolution imaging. AB - Atomic resolution imaging and spectroscopy suffers from inherently low signal to noise ratios often prohibiting the interpretation of single pixels or spectra. We introduce local low rank (LLR) denoising as tool for efficient noise removal in scanning transmission electron microscopy (STEM) images and electron energy-loss (EEL) spectrum images. LLR denoising utilizes tensor decomposition techniques, in particular the multilinear singular value decomposition (MLSVD), to achieve a denoising in a general setting largely independent of the signal features and data dimension, by assuming that the signal of interest is of low rank in segments of appropriately chosen size. When applied to STEM images of graphene, LLR denoising suppresses statistical noise while retaining fine image features such as scan row-wise distortions, possibly related to rippling of the graphene sheet and consequent motion of atoms. When applied to EEL spectra, LLR denoising reveals fine structures distinguishing different lattice sites in the spinel system CoFe2O4. PMID- 29413411 TI - Charge accumulation in electron cryomicroscopy. AB - When irradiated in a transmission electron microscope, plunge-frozen, amorphous water ice specimens accumulate a pattern of static charge that changes dynamically as the specimen is irradiated, and which can deflect the transmitted electrons and blur the resultant micrographs. Here we provide a physical description of this charge accumulation and characterise its dynamic behaviour in the context of low-dose electron cryomicroscopy (cryoEM). We observe the accumulation of positive charge in the primary irradiation area as expected from earlier work. To our surprise, we also observed a build-up of negative charge in nearby unirradiated regions of the specimen. Using a standard carbon support foil containing a pure water ice specimen, we collect a portion of this negative charge in the micrometer sized specimen holes which act as electrostatic lenses. These unusual, diverging micro-lenses are extremely sensitive charge detectors that allow us to directly measure the magnitude and dynamics of charge accumulation and neutralisation that occur during cryoEM imaging. Using these measurements, we find that the build-up of charge on the specimen saturates to a dynamic equilibrium at an electron fluence which is orders of magnitude lower than required for a typical low-dose micrograph. The measurements here will guide the development of optimal imaging conditions for biological specimens and contribute to a complete theory of information loss in electron cryomicroscopy. PMID- 29413412 TI - "One-sample concept" micro-combinatory for high throughput TEM of binary films. AB - Phases of thin films may remarkably differ from that of bulk. Unlike to the comprehensive data files of Binary Phase Diagrams [1] available for bulk, complete phase maps for thin binary layers do not exist. This is due to both the diverse metastable, non-equilibrium or instable phases feasible in thin films and the required volume of characterization work with analytical techniques like TEM, SAED and EDS. The aim of the present work was to develop a method that remarkably facilitates the TEM study of the diverse binary phases of thin films, or the creation of phase maps. A micro-combinatorial method was worked out that enables both preparation and study of a gradient two-component film within a single TEM specimen. For a demonstration of the technique thin MnxAl1-x binary samples with evolving concentration from x = 0 to x = 1 have been prepared so that the transition from pure Mn to pure Al covers a 1.5 mm long track within the 3 mm diameter TEM grid. The proposed method enables the preparation and study of thin combinatorial samples including all feasible phases as a function of composition or other deposition parameters. Contrary to known "combinatorial chemistry", in which a series of different samples are deposited in one run, and investigated, one at a time, the present micro-combinatorial method produces a single specimen condensing a complete library of a binary system that can be studied, efficiently, within a single TEM session. That provides extremely high throughput for TEM characterization of composition-dependent phases, exploration of new materials, or the construction of phase diagrams of binary films. PMID- 29413413 TI - Microscopic charge fluctuations cause minimal contrast loss in cryoEM. AB - The fluctuating granularity or "bee swarm" effect seen in highly defocussed transmission electron micrographs is caused by microscopic charge fluctuations in the specimen created by the illuminating beam. In the field of high-resolution single particle electron cryomicroscopy (cryoEM), there has been a concern that this fluctuating charge might cause defocus-dependent Thon ring fading which would degrade the final image. In this paper, we have analysed the 2.35 A fringes from the (111) reflection in images of gold nanoparticles embedded in amorphous ice. We show that there is a small, yet detectable amount of defocus-dependent blurring of the lattice fringes when compared with those from a pure gold foil. The transverse electric field associated with the fluctuating charges on the insulating frozen water specimen deflects the electron beam locally and causes image blurring. The perturbation is small, decreasing the amplitude of the 2.35 A reflection at 10 um defocus by about 7% (intensity by 14%). For smaller defocus values in the range 2-4 um and for resolutions that are typical in cryoEM, the effects of source incoherence and the bee swarm effect are negligible for all reasonable cryoEM imaging conditions, assuming that a field emission gun (FEG) is used for illumination. This leaves physical movement of the specimen due to radiation damage as the outstanding problem and the major source of contrast loss in cryoEM micrographs. PMID- 29413414 TI - In situ electrochemical AFM monitoring of the potential-dependent deterioration of platinum catalyst during potentiodynamic cycling. AB - A platinum catalyst undergoes complex deterioration process during its operation as a cathode in a proton exchange membrane fuel cell. By using in situ electrochemical atomic force microscopy (EC-AFM) with super-sharp probes, we quantitatively describe the roughening of platinum thin films during electrochemical cycling to different upper potentials, which simulate critical operation regimes of the proton exchange membrane fuel cell. The comprehensive quantitative analysis of morphology changes obtained using common roughness descriptors such as the root mean square roughness, the correlation length and the roughness exponent is correlated with cyclic voltammetry performed simultaneously. PMID- 29413415 TI - Image feature delocalization in defocused probe electron ptychography. AB - Electron ptychography can in principle convert a conventional scanning electron microscope (SEM) into a good quality transmission electron microscope (TEM). An improvement in resolution of about a factor of 5 over the lens-defined resolution of an SEM was first demonstrated by Humphry et al. (2012). However, the results from that work showed some delocalization in the atomic fringes of the gold particles used as a test specimen for the technique. Here we explore factors that result in the delocalization effect when a defocused probe is used for the ptychographic data collection: source incoherence, the effects of detector faults, data truncation and a poorly calibrated illumination step size (or camera length). Various mitigation strategies are tested, including modal decomposition of the incoherence in the beam. We reprocess the data from the original SEM experiment to show that these refinements significantly improve the reconstruction. PMID- 29413416 TI - Thickness dependence of scattering cross-sections in quantitative scanning transmission electron microscopy. AB - In quantitative scanning transmission electron microscopy (STEM), scattering cross-sections have been shown to be very sensitive to the number of atoms in a column and its composition. They correspond to the integrated intensity over the atomic column and they outperform other measures. As compared to atomic column peak intensities, which saturate at a given thickness, scattering cross-sections increase monotonically. A study of the electron wave propagation is presented to explain the sensitivity of the scattering cross-sections. Based on the multislice algorithm, we analyse the wave propagation inside the crystal and its link to the scattered signal for the different probe positions contained in the scattering cross-section for detector collection in the low-, middle- and high-angle regimes. The influence to the signal from scattering of neighbouring columns is also discussed. PMID- 29413417 TI - Clinical Trials Transparency: Where Are We Today? AB - To prevent reporting bias, policies and regulations mandating trial prospective registration and disclosure of results have been implemented since 2005. To achieve full trial transparency, open access to participants' deidentified data policies have been issued. Funders and journals have made critical decisions on these requirements in 2017 that will impact the current scenario. PMID- 29413418 TI - DISE: A Seed-Dependent RNAi Off-Target Effect That Kills Cancer Cells. AB - Off-target effects (OTEs) represent a significant caveat for RNAi caused by substantial complementarity between siRNAs and unintended mRNAs. We now discuss the existence of three types of seed-dependent OTEs (sOTEs). Type I involves unintended targeting through the guide strand seed of an siRNA. Type II is caused by the activity of the seed on the designated siRNA passenger strand when loaded into the RNA-induced silencing complex (RISC). Both type I and II sOTEs will elicit unpredictable cellular responses. By contrast, in sOTE type III the guide strand seed preferentially targets essential survival genes resulting in death induced by survival gene elimination (DISE). In this Opinion article, we discuss DISE as a consequence of RNAi that may preferentially affect cancer cells. PMID- 29413419 TI - Dissemination from a Solid Tumor: Examining the Multiple Parallel Pathways. AB - Metastasis can be generalized as a linear sequence of events whereby halting one or more steps in the cascade may reduce tumor cell dissemination and ultimately improve patient outcomes. However, metastasis is a complex process with multiple parallel mechanisms of dissemination. Clinical strategies focus on removing the primary tumor and/or treating distant metastases through chemo- or immunotherapies. Successful strategies for blocking metastasis will need to address the parallel mechanisms of dissemination and identify common bottlenecks. Here, we review the current understanding of common dissemination pathways for tumors. Understanding the complexities of metastasis will guide the design of new therapies that halt dissemination. PMID- 29413420 TI - Transforming Biomarker Development with Exceptional Responders. AB - Curative therapy for cancer patients with advanced-stage disease remains elusive. While rare outlier responses to anticancer therapies exist, barriers limit our understanding of the molecular and genetic basis of such profound, life-altering responses. Here, we describe how phenotype-to-genotype studies are elucidating the molecular underpinnings of outlier responses and informing strategies to extend such unprecedented sensitivity to broader molecularly defined patient populations. PMID- 29413422 TI - PRC1: Linking Cytokinesis, Chromosomal Instability, and Cancer Evolution. AB - Cytokinesis is the final event of the cell cycle dividing one cell into two daughter cells. The protein regulator of cytokinesis (PRC)1 is essential for cytokinesis and normal cell cleavage. Deregulation of PRC1 causes cytokinesis defects that promote chromosomal instability (CIN) and thus tumor heterogeneity and cancer evolution. Consistently, abnormal PRC1 expression correlates with poor patient outcome in various malignancies, which may be caused by PRC1-mediated CIN and aneuploidy. Here, we review the physiological functions of PRC1 in cell cycle regulation and its contribution to tumorigenesis and intratumoral heterogeneity. We discuss targeting PRC1 within the complementary approaches of either normalizing CIN in aneuploid cancers or creating chromosomal chaos in genomically stable cancers to induce apoptosis. PMID- 29413423 TI - Genomic Landscape of Pheochromocytoma and Paraganglioma. AB - Recent comprehensive molecular analysis allowed the identification of unique molecular signatures in pheochromocytomas (PHEOs) and paragangliomas (PGLs). Here we summarize the main pathway clusters activated by PHEO- and PGL-susceptibility genes: pseudohypoxic, kinase, and Wnt signaling. Molecular characterization and clustering of PHEOs and PGLs may help in the application of principles of personalized medicine and in decision making for targeted therapy of these tumors. PMID- 29413424 TI - Gastrointestinal Stromal Tumors: The GIST of Precision Medicine. AB - The discovery of activated KIT mutations in gastrointestinal (GI) stromal tumors (GISTs) in 1998 triggered a sea change in our understanding of these tumors and has ushered in a new paradigm for the use of molecular genetic diagnostics to guide targeted therapies. KIT and PDGFRA mutations account for 85-90% of GISTs; subsequent genetic studies have led to the identification of mutation/epimutation of additional genes, including the succinate dehydrogenase (SDH) subunit A, B, C, and D genes. This review focuses on integrating findings from clinicopathologic, genetic, and epigenetic studies, which classify GISTs into two distinct clusters: an SDH-competent group and an SDH-deficient group. This development is important since it revolutionizes our current management of affected patients and their relatives, fundamentally, based on the GIST genotype. PMID- 29413421 TI - Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive 'Cold' Tumors 'Hot'. AB - We discuss how small-molecule inhibitors of the tryptophan (Trp) catabolic enzyme indoleamine 2,3-dioxygenase (IDO) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy, or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO inhibitors re-program inflammatory processes to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier. Recent work suggests that coordinate targeting of the Trp catabolic enzymes tryptophan 2,3 dioxygenase (TDO) and IDO2 may also safely broaden efficacy. Understanding IDO inhibitors as adjuvants to turn immunologically 'cold' tumors 'hot' can seed new concepts in how to improve the efficacy of cancer therapy while limiting collateral damage. PMID- 29413426 TI - Enhancing the comprehension of visual metaphors in individuals with intellectual disability with or without down syndrome. AB - This study is the first to investigate the effectiveness of deep and shallow intervention programs in the acquisition of visual metaphor comprehension in individuals with non-specific intellectual disability (NSID; aged 15-59, N = 53) or Down syndrome (DS; aged 15-52, N = 50). The deep intervention program was based on dynamic assessment model for enhancing analogical thinking. The shallow intervention program involves memorizing a metaphorical relationship between pairs of pictures. Visual metaphor comprehension was measured by the construction of a metaphorical connection between pairs of pictures. The results indicated that both etiology groups exhibited poor understanding of visual metaphors before the intervention. A significant improvement was observed in both interventions and both etiology groups, with greater improvement among individuals who underwent the deep processing. Moreover, the latter procedure led to greater generalization ability. The results also indicated that vocabulary contributed significantly to understanding unstudied metaphors and that participants with poorer linguistic abilities exhibited greater improvement in their metaphorical thinking. Thus, individuals with ID with or without DS are able to recruit the higher-order cognitive abilities required for visual metaphor comprehension. PMID- 29413425 TI - Attention deficit hyperactivity disorder and autism spectrum disorder symptoms in school-age children born very preterm. AB - BACKGROUND: Very preterm (VP) children face a broad range of neurodevelopmental sequelae, including behavioral problems. AIM: To investigate prevalence, pervasiveness and co-occurrence of symptoms of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in school-age children born very preterm. METHODS: Using questionnaire and diagnostic interview data, parent and teacher reported symptoms of ADHD and ASD of 57 VP-children (mean age = 9.2 years) were compared with 57 gender and age matched full-term children using t tests. Intra-class correlation coefficients quantified parent-teacher agreement. Correlation analysis investigated co-occurrence of ADHD/ASD symptoms. ADHD/ASD measures were aggregated using principal component analysis. Regression analyses investigated the contribution of perinatal risk factors, sex and SES to ADHD/ASD symptoms. RESULTS: VP-children showed higher levels of parent and teacher reported attention problems, social impairment and compromised communication skills. Fair to strong agreement was found between parent and teacher reported ADHD and ASD symptoms, indicating pervasiveness of observed difficulties. Co occurrence of ADHD and ASD symptoms in VP-children was found. Lower gestational age was associated with higher ADHD and ASD symptom levels, male sex with higher ADHD symptom levels and lower SES with higher ASD symptom levels. CONCLUSION: School-age VP-children show higher levels of ADHD and ASD symptoms, and attention, socialization and communication difficulties in particular. Routinely screening for these problems is recommended in follow-up care. PMID- 29413427 TI - Sexuality issues and the voices of adults with intellectual disabilities: A systematic review of the literature. AB - BACKGROUND: There is a growing and evolving research evidence base regarding sexuality issues and adults with intellectual disabilities. Individuals can face challenges, including the right to express their sexuality and to access necessary education and supports. AIMS: This systematic review explores sexuality experiences, the views and opinions of adults with intellectual disabilities and highlights areas for future practice developments. METHODS AND PROCEDURES: A comprehensive search of relevant databases from January 2006 to December 2016 was carried out. Included studies had to address specific criteria including: peer reviewed papers, the use of appropriate research methods, and focused exclusively on the individual views and opinions of people with an intellectual disability. The search of relevant databases yielded 230 hits. Following the application of explicit inclusion and exclusion criteria, 23 papers were deemed suitable for the review. OUTCOMES AND RESULTS: The data were analysed and key themes were identified that included: autonomy v's risk of harm, knowledge and sexuality, relationships and intimacy, self-determination and taking control, and encouragement and supports. CONCLUSIONS AND IMPLICATIONS: Adults with intellectual disabilities need education and support to express their sexuality and to meet individual needs. PMID- 29413428 TI - Quality of life and habitual physical activity in children with cerebral palsy aged 5 years: A cross-sectional study. AB - OBJECTIVE: To compare quality of life (QOL) according to ambulatory status and to investigate association with habitual physical activity (HPA) in children with cerebral palsy (CP) aged 5 years. METHODS: Fifty-eight participants were classified using Gross Motor Function Classification System (GMFCS) as level I = 33, II = 8, III = 6, IV = 3 and V = 8 and assessed for motor function using 66 item Gross Motor Function Measure (GMFM-66). Participants wore an ActiGraph(r) triaxial accelerometer for 3 days to measure HPA. Parents completed the parent proxy Cerebral Palsy Quality of Life questionnaire for Children (CP QOL-Child). Linear regression analyses were performed. RESULTS: Ambulant children with CP (GMFCS I-III) had better parent-reported QOL than non-ambulant children (GMFCS IV V) in domains of feelings about functioning (mean difference (MD) = 20.0; 95% confidence interval (CI) = 11.7, 28.2), participation and physical health (MD = 14.5; 95%CI = 4.7, 24.4), and emotional well-being and self-esteem (MD = 12.5; 95%CI = 4.8, 20.1). HPA was not associated with QOL domains after controlling for motor function. GMFM scores accounted for 39% of variation for feelings about functioning domain (MD = 0.4; 95%CI = 0.2, 0.6). CONCLUSIONS: In children with CP aged 5 years, HPA was not associated with parent-reported QOL. Gross motor function contributed to QOL domains of feelings about functioning. PMID- 29413429 TI - Auditory temporal perceptual learning and transfer in Chinese-speaking children with developmental dyslexia. AB - Perceptual learning refers to the improvement of perceptual performance as a function of training. Recent studies found that auditory perceptual learning may improve phonological skills in individuals with developmental dyslexia in alphabetic writing system. However, whether auditory perceptual learning could also benefit the reading skills of those learning the Chinese logographic writing system is, as yet, unknown. The current study aimed to investigate the remediation effect of auditory temporal perceptual learning on Mandarin-speaking school children with developmental dyslexia. Thirty children with dyslexia were screened from a large pool of students in 3th-5th grades. They completed a series of pretests and then were assigned to either a non-training control group or a training group. The training group worked on a pure tone duration discrimination task for 7 sessions over 2 weeks with thirty minutes per session. Post-tests immediately after training and a follow-up test 2 months later were conducted. Analyses revealed a significant training effect in the training group relative to non-training group, as well as near transfer to the temporal interval discrimination task and far transfer to phonological awareness, character recognition and reading fluency. Importantly, the training effect and all the transfer effects were stable at the 2-month follow-up session. Further analyses found that a significant correlation between character recognition performance and learning rate mainly existed in the slow learning phase, the consolidation stage of perceptual learning, and this effect was modulated by an individuals' executive function. These findings indicate that adaptive auditory temporal perceptual learning can lead to learning and transfer effects on reading performance, and shed further light on the potential role of basic perceptual learning in the remediation and prevention of developmental dyslexia. PMID- 29413430 TI - Social validity in single-case research: A systematic literature review of prevalence and application. AB - BACKGROUND: Single-case research (SCR) has been a valuable methodology in special education research. Montrose Wolf (1978), an early pioneer in single-case methodology, coined the term "social validity" to refer to the social importance of the goals selected, the acceptability of procedures employed, and the effectiveness of the outcomes produced in applied investigations. Since 1978, many contributors to SCR have included social validity as a feature of their articles and several authors have examined the prevalence and role of social validity in SCR. AIM AND METHODS: We systematically reviewed all SCR published in six highly-ranked special education journals from 2005 to 2016 to establish the prevalence of social validity assessments and to evaluate their scientific rigor. RESULTS: We found relatively low, but stable prevalence with only 28 publications addressing all three factors of the social validity construct (i.e., goals, procedures, outcomes). We conducted an in-depth analysis of the scientific rigor of these 28 publications. CONCLUSIONS: Social validity remains an understudied construct in SCR, and the scientific rigor of social validity assessments is often lacking. Implications and future directions are discussed. PMID- 29413431 TI - Evaluating the evidence for motor-based interventions in developmental coordination disorder: A systematic review and meta-analysis. AB - BACKGROUND: As part of the process of creating an update of the clinical practice guidelines for developmental coordination disorder (DCD) (Blank, Smits-Engelsman, Polatajko, & Wilson, 2012), a systematic review of intervention studies, published since the last guidelines statement was conducted. AIM: The aim of this study was to 1) systematically review the evidence published from January 2012 to February 2017 regarding the effectiveness of motor based interventions in individuals with DCD, 2) quantify treatment effects using a meta-analysis, 3) examine the available information on different aspects of delivery including use of group intervention, duration and frequency of therapy, and 4) identify gaps in the literature and make recommendations for future intervention research. METHOD: An electronic search of 5 databases (PubMed, Embase, Pedro, Scopus and Cochrane) was conducted for studies that evaluated motor-based interventions to improve performance for individuals with DCD. RESULTS: Thirty studies covering 25 datasets were included, 19 of which provided outcomes on standardized measures of motor performance. The overall effect size (Cohen's d) across intervention studies was large (1.06), but the range was wide: for 11 interventions, the observed effect was large (>0.80), in eight studies moderate (>0.50), and in five it was small or negligible (<0.50). Positive benefits were evident for activity oriented approaches, body function-oriented combined with activities, active video games, and small group programs. CONCLUSION: Results showed that activity oriented and body function oriented interventions can have a positive effect on motor function and skills. However, given the varied methodological quality and the large confidence intervals of some studies, the results should be interpreted with caution. PMID- 29413432 TI - Effects of nicotine-containing and "nicotine-free" e-cigarette refill liquids on intracranial self-stimulation in rats. AB - BACKGROUND: Animal models are needed to inform FDA regulation of electronic cigarettes (ECs) because they avoid limitations associated with human studies. We previously reported that an EC refill liquid produced less aversive/anhedonic effects at a high nicotine dose than nicotine alone as measured by elevations in intracranial self-stimulation (ICSS) thresholds, which may reflect the presence of behaviorally active non-nicotine constituents (e.g., propylene glycol) in the EC liquids. The primary objective of this study was to assess the generality of our prior ICSS findings to two additional EC liquids. We also compared effects of "nicotine-free" varieties of these EC liquids on ICSS, as well as binding affinity and/or functional activity of nicotine alone, nicotine-containing EC liquids, and "nicotine-free" EC liquids at nicotinic acetylcholine receptors (nAChRs). METHODS AND RESULTS: Nicotine alone and nicotine dose-equivalent concentrations of both nicotine-containing EC liquids produced similar lowering of ICSS thresholds at low to moderate nicotine doses, indicating similar reinforcement-enhancing effects. At high nicotine doses, nicotine alone elevated ICSS thresholds (a measure of anhedonia-like behavior) while the EC liquids did not. Nicotine-containing EC liquids did not differ from nicotine alone in terms of binding affinity or functional activity at nAChRs. "Nicotine-free" EC liquids did not affect ICSS, but bound with low affinity at some (e.g., alpha4beta2) nAChRs. CONCLUSIONS: These findings suggest that non-nicotine constituents in these EC liquids do not contribute to their reinforcement-enhancing effects. However, they may attenuate nicotine's acute aversive/anhedonic and/or toxic effects, which may moderate the abuse liability and/or toxicity of ECs. PMID- 29413433 TI - Factors associated with sedative use and misuse among heroin users. AB - BACKGROUND: Rates of both opioid and sedative use and misuse are rising. Comorbid opioid and sedative use is associated with especially severe consequences (e.g., overdose and poor health outcomes). Heroin users report multiple motivations for sedative use, including self-medication. We aimed to understand differences in lifetime substance use characteristics between heroin users with different sedative use histories. METHODS: Substance use data were collected from 385 non treatment seeking heroin users. Subjects were divided into four lifetime sedative use groups: no use, medical use only, non-medical use only, and mixed medical and non-medical use. We examined patterns of use of various substances of abuse (tobacco, alcohol, marijuana, cocaine, heroin, and sedatives) and individual characteristics associated with each. RESULTS: Non-medical sedative use (alone or in addition to medical use) was associated with more negative consequences from using all substances. Medical sedative use alone was not related to increased overdose or emergency room visits associated with heroin use. Non-medical sedative use was associated with increases in 15 of the 21 measured heroin consequences and only one of those - health problems - was also associated with medical sedative use. CONCLUSIONS: Concomitant non-medical sedative use and heroin use is associated with significantly greater negative outcomes than those experienced by heroin users who report use of sedatives only as prescribed. Understanding these differences offers insight into risks related to using both substances and may help treatment providers create targeted harm reduction interventions for this population. PMID- 29413434 TI - The effect of N-acetylcysteine on alcohol use during a cannabis cessation trial. AB - BACKGROUND: Individuals with alcohol use disorder (AUD) do not always respond to currently available treatments, and evaluation of new candidate pharmacotherapies is indicated. N-acetylcysteine (NAC), an over-the-counter supplement, has shown promise in treating a variety of substance use disorders, but little research has evaluated its merits as a treatment for AUD. This secondary analysis from the National Drug Abuse Treatment Clinical Trials Network examined the effects of NAC versus placebo on alcohol use among participants with cannabis use disorder (CUD) enrolled in a 12-week, multi-site cannabis cessation trial. METHODS: Participants (N = 302, ages 18-50) were randomized to double-blind NAC (1200 mg, twice daily) or placebo. Neither alcohol use nor desire for alcohol cessation were requirements for participation. Participants that returned for at least one treatment visit and had recorded alcohol use data (i.e., total drinks per week, drinking days per week, and binge drinking days per week) were included in the analysis (n = 277). RESULTS: Compared to the placebo group, participants in the NAC group had increased odds of between-visit alcohol abstinence [OR = 1.37; 95% CI = 1.06-1.78; p = 0.019], fewer drinks per week [RR = 0.67; 95% CI = 0.48-0.99; p = 0.045], and fewer drinking days per week [RR = 0.69; 95% CI = 0.51-0.92; p = 0.014]. Changes in concurrent cannabis use amounts were not correlated to any of the alcohol use variables. DISCUSSION: These findings indicate that NAC may be effective at reducing consumption of alcohol by ~30% among treatment-seeking adults with CUD, suggesting a need for further trials focused on the effects of NAC on alcohol consumption among individuals seeking treatment for AUD. PMID- 29413436 TI - E-cigarette use and quantity of cigarette smoking among adolescent cigarette smokers: A finite mixture model analysis. AB - BACKGROUND: E-cigarette use is popular among adolescents and youth, but its long term public health implications remain largely unknown. Much of the literature has focused on understanding the relationship between e-cigarette use and youth cigarette initiation. However, very little is known about e-cigarette use and cigarette quantity among those who continue to smoke cigarettes. The objective of the present study was to examine the association between current e-cigarette use and quantity of cigarette smoking. METHODS: Cross-sectional data on current smokers were drawn from the 2014-2015 Canadian Student Tobacco, Alcohol and Drugs Survey among high school students (n = 1411). A finite mixture model (FMM) was employed to account for unobserved heterogeneity due to clusters of finite sub populations. RESULTS: Current e-cigarette users reported smoking more conventional cigarettes in the past week compared to non-e-cigarette users (t [1409] = 4.7998; p < 0.001 in unadjusted analysis). Results from a finite mixture regression showed that current e-cigarette use was significantly associated with the number of cigarettes smoked in the past week, but only among light smokers (IRR = 1.40; CI = 1.05-1.85). However, additional analyses found that the association between e-cigarette use and quantity of cigarette smoked varied by individual smoking pattern. An FMM with a group or class modelling using individual smoking pattern showed a weaker association between e-cigarette use and quantity of cigarette smoking. CONCLUSION: Findings of this study suggest that the significant association between e-cigarette use and quantity of cigarette smoking may be driven by patterns of use among experimental or beginner smokers. PMID- 29413435 TI - Stress responding in cannabis smokers as a function of trauma exposure, sex, and relapse in the human laboratory. AB - BACKGROUND: Stress responding is linked to drug use, but little is known about stress responses in cannabis smokers. We investigated acute stress responding in cannabis smokers as a function of trauma exposure and sex, and relationships between stress responses and cannabis relapse. METHODS: 125 healthy, non treatment-seeking daily cannabis smokers (23F, 102 M) completed the Trier Social Stress Task (TSST), a standardized laboratory stressor; subsets also completed a trauma questionnaire (n = 106) and a laboratory cannabis relapse measure (n = 54). Stress responding was assessed with heart rate (HR), salivary cortisol (CORT), and self-rated mood. RESULTS: Cannabis smokers reporting at least one trauma exposure had higher CORT and anxiety overall compared to those reporting no trauma. Stress responding did not differ as a function of binary trauma exposure, although total number of exposures correlated positively with CORT and anxiety during stress. Females reported increased nervousness after stress relative to males matched to the females for cannabis and cigarette use. An interactive effect of sex and trauma on HR suggested that females with trauma exposure have increased cardiovascular stress responding relative to those without such exposure, with no differential effect in males. Stress responding did not predict laboratory cannabis relapse. CONCLUSION: We report differences in acute stress responding as a function of trauma, sex, and their interaction in a large sample of relatively homogenous cannabis smokers. Further investigation of how trauma impacts stress responding in male and female cannabis smokers, and how this relates to different aspects of cannabis use, is warranted. PMID- 29413438 TI - Early development of the enteric nervous system visualized by using a new transgenic zebrafish line harboring a regulatory region for choline acetyltransferase a (chata) gene. AB - The enteric nervous system (ENS) is the largest part of the peripheral nervous system in vertebrates. Toward the visualization of the development of the vertebrate ENS, we report our creation of a new transgenic line, Tg(chata:GGFF2) which has a 1.5-kb upstream region of the zebrafish choline acetyltransferase a (chata) gene followed by modified green fluorescent protein (gfp). During development, GFP + cells were detected in the gut by 60 h post-fertilization (hpf). In the gut of 6- and 12-days post-fertilization (dpf) larvae, an average of 92% of the GFP + cells were positive for the neuronal marker HuC/D, suggesting that GFP marks enteric neurons in this transgenic line. We also observed that 66% of the GFP + cells were choline acetyltransferase (ChAT)-immunopositive at 1.5 months. Thus, GFP is expressed at the larval stages at which ChAT protein expression is not yet detected by immunostaining. We studied the spatiotemporal pattern of neural differentiation in the ENS by live-imaging of this transgenic line. We observed that GFP + or gfp + cells initially formed a pair of bilateral rows at 60 hpf or 53 hpf, respectively, in the migrating enteric neural crest cells. Most of the GFP + cells did not migrate, and most of the new GFP + cells were added to fill the space among the previously formed GFP + cells. GFP expression reached the anus by 72 hpf. New GFP + cells then also appeared in the dorsal and ventral sides of the initial GFP + rows, resulting in their distribution on the entire gut by 4 dpf. A small number of new GFP + cells were found to move among older GFP + cells just before the cells stopped migration, suggesting that the moving GFP + cells may represent neural precursor cells searching for a place for the final differentiation. Our data suggest that the Tg(chata:GGFF2) line could serve as a useful tool for studies of enteric neural differentiation and cell behavior. PMID- 29413437 TI - Prenatal exposure to methadone or buprenorphine: Early childhood developmental outcomes. AB - BACKGROUND: Methadone and buprenorphine are recommended to treat opioid use disorders during pregnancy. However, the literature on the relationship between longer-term effects of prenatal exposure to these medications and childhood development is both spare and inconsistent. METHODS: Participants were 96 children and their mothers who participated in MOTHER, a randomized controlled trial of opioid-agonist pharmacotherapy during pregnancy. The present study examined child growth parameters, cognition, language abilities, sensory processing, and temperament from 0 to 36 months of the child's life. Maternal perceptions of parenting stress, home environment, and addiction severity were also examined. RESULTS: Tests of mean differences between children prenatally exposed to methadone vs. buprenorphine over the three-year period yielded 2/37 significant findings for children. Similarly, tests of mean differences between children treated for NAS relative to those not treated for NAS yielded 1/37 significant finding. Changes over time occurred for 27/37 child outcomes including expected child increases in weight, head and height, and overall gains in cognitive development, language abilities, sensory processing, and temperament. For mothers, significant changes over time in parenting stress (9/17 scales) suggested increasing difficulties with their children, notably seen in increasing parenting stress, but also an increasingly enriched home environment (4/7 scales) CONCLUSIONS: Findings strongly suggest no deleterious effects of buprenorphine relative to methadone or of treatment for NAS severity relative to not-treated for NAS on growth, cognitive development, language abilities, sensory processing, and temperament. Moreover, findings suggest that prenatal opioid agonist exposure is not deleterious to normal physical and mental development. PMID- 29413439 TI - Combined PET/DCE-MRI in a Rabbit Model of Atherosclerosis: Integrated Quantification of Plaque Inflammation, Permeability, and Burden During Treatment With a Leukotriene A4 Hydrolase Inhibitor. AB - OBJECTIVES: The authors sought to develop combined positron emission tomography (PET) dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to quantify plaque inflammation, permeability, and burden to evaluate the efficacy of a leukotriene A4 hydrolase (LTA4H) inhibitor in a rabbit model of atherosclerosis. BACKGROUND: Multimodality PET/MRI allows combining the quantification of atherosclerotic plaque inflammation, neovascularization, permeability, and burden by combined 18F-fluorodeoxyglucose (18F-FDG) PET, DCE MRI, and morphological MRI. The authors describe a novel, integrated PET-DCE/MRI protocol to noninvasively quantify these parameters in aortic plaques of a rabbit model of atherosclerosis. As proof-of-concept, the authors apply this protocol to assess the efficacy of the novel LTA4H inhibitor BI691751. METHODS: New Zealand White male rabbits (N = 49) were imaged with integrated PET-DCE/MRI after atherosclerosis induction and 1 and 3 months after randomization into 3 groups: 1) placebo; 2) high-dose BI691751; and 3) low-dose BI691751. All animals were euthanized at the end of the study. RESULTS: Among the several metrics that were quantified, only maximum standardized uptake value and target-to-background ratio by 18F-FDG PET showed a modest, but significant, reduction in plaque inflammation in rabbits treated with low-dose BI691751 (p = 0.03), whereas no difference was detected in the high-fat diet and in the high-dose BI691751 groups. No differences in vessel wall area by MRI and area under the curve by DCE-MRI were detected in any of the groups. No differences in neovessel and macrophage density were found at the end of study among groups. CONCLUSIONS: The authors present a comprehensive, integrated 18F-FDG PET and DCE-MRI imaging protocol to noninvasively quantify plaque inflammation, neovasculature, permeability, and burden in a rabbit model of atherosclerosis on a simultaneous PET/MRI scanner. A modest reduction was found in plaque inflammation by 18F-FDG PET in the group treated with a low dose of the LTA4H inhibitor BI691751. PMID- 29413440 TI - PET/MR Imaging of Atherosclerosis: Insights Into Atheroma Structure and Biology. PMID- 29413441 TI - Feasibility Evaluation of Myocardial Cannabinoid Type 1 Receptor Imaging in Obesity: A Translational Approach. AB - OBJECTIVES: The aim of this study was to evaluate the feasibility of targeted imaging of myocardial cannabinoid type 1 receptor (CB1-R) and its potential up regulation in obese mice with translation to humans using [11C]-OMAR and positron emission tomography (PET)/computed tomography (CT). BACKGROUND: Activation of myocardial CB1-R by endocannabinoids has been implicated in cardiac dysfunction in diabetic mice. Obesity may lead to an up-regulation of myocardial CB1-R, potentially providing a mechanistic link between obesity and the initiation and/or progression of cardiomyopathy. METHODS: Binding specificity of [11C]-OMAR to CB1-R was investigated by blocking studies with rimonabant in mice. The heart was harvested from each mouse, and its radioactivity was determined by gamma counter. Furthermore, [11C]-OMAR dynamic micro-PET/CT was carried out in obese and normal-weight mice. Ex vivo validation was performed by droplet digital polymerase chain reaction (absolute quantification) and RNAscope Technology (an in situ ribonucleic acid analysis platform). Subsequently, myocardial CB1-R expression was probed noninvasively with intravenous injection of CB1-R ligand [11C]-OMAR and PET/CT in humans with advanced obesity and normal-weight human control subjects, respectively. RESULTS: Rimonabant significantly blocked OMAR uptake in the heart muscle compared with vehicle, signifying specific binding of OMAR to the CB1-R in the myocardium. The myocardial OMAR retention quantified by micro-PET/CT in mice was significantly higher in obese compared with normal weight mice. Absolute quantification of CB1-R gene expression with droplet digital polymerase chain reaction and in situ hybridization confirmed CB1-R up regulation in all major myocardial cell types (e.g., cardiomyocytes, endothelium, vascular smooth muscle cells, and fibroblasts) of obese mice. Obese mice also had elevated myocardial levels of endocannabinoids anandamide and 2 arachidonoylglycerol compared with lean mice. Translation to humans revealed higher myocardial OMAR retention in advanced obesity compared with normal-weight subjects. CONCLUSIONS: Noninvasive imaging of cardiac CB1-R expression in obesity is feasible applying [11C]-OMAR and PET/CT. These results may provide a rationale for further clinical testing of CB1-R-targeted molecular imaging in cardiometabolic diseases. PMID- 29413442 TI - Myocardial Cannabinoid Receptor Imaging in Obesity. PMID- 29413443 TI - Cardiovascular Imaging With 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Patients With Fibroinflammatory Disorders. PMID- 29413446 TI - International Societies. PMID- 29413444 TI - Intravascular Optical Molecular Imaging of a Macrophage Subset Within Intraplaque Hemorrhages. PMID- 29413447 TI - TOC. PMID- 29413448 TI - Cover 1. PMID- 29413449 TI - Trunk movement compensations and corresponding core muscle demand during step ambulation in people with unilateral transtibial amputation. AB - The objective of this investigation was to identify demands from core muscles that corresponded with trunk movement compensations during bilateral step ambulation in people with unilateral transtibial amputation (TTA). Trunk rotational angular momentum (RAM) was measured using motion capture and bilateral surface EMG was measured from four bilateral core muscles during step ascent and descent tasks in people with TTA and healthy controls. During step ascent, the TTA group generated larger mediolateral (P = 0.01) and axial (P = 0.01) trunk RAM toward the leading limb when stepping onto the intact limb than the control group, which corresponded with high demand from the bilateral erector spinae and oblique muscles. During step descent, the TTA group generated larger trunk RAM in the sagittal (P < 0.01), frontal (P < 0.01), and transverse planes (P = 0.01) than the control group, which was an effect of falling onto the intact limb. To maintain balance and arrest trunk RAM, core muscle demand was larger throughout the loading period of step descent in the TTA group. However, asymmetric trunk movement compensations did not correspond to asymmetric core muscle demand during either task, indicating a difference in motor control compensations dependent on the leading limb. PMID- 29413450 TI - A strong linear relationship between Turns/Amplitude peak ratio and ratio at maximal effort. AB - In EMG interference pattern analysis, the peak value of turns to mean amplitude ratio [peak(T/A)] is an established clinically significant marker, but its calculation requires specific software available only in few EMG apparatuses. On the contrary, the turns to mean amplitude ratio obtained at maximal muscle contraction (T/Amax) is easily calculated but less well standardized. We aimed to quantitatively assess the association between T/Amax and peak(T/A). Data were derived from 642 muscle contractions (Nc) from 270 consecutive patients (Np) who underwent EMG at our laboratory (software Dantec Keypoint, QEMG) from May 2015 to September 2016 and had interference patterns obtained from at least one of the following muscles: triceps-lateral head, brachioradialis, extensor digitorum communis and biceps. Statistics were calculated separately for normal and neurogenic muscles. Peak(T/A) was calculated by the built-in "peak ratio" function. T/Amax was calculated by the built-in Interference Pattern analysis function. The ratio with the highest amplitude was selected as T/Amax. Linear regression models provided high Pearson correlation coeffficientscoefficients (R) between peak(T/A) and T/Amax for all 4 muscles, normal or neurogenic, except a subgroup of biceps in patients aged <40y. Specifically, R were: (A) triceps normal 0.79 (Nc = 99), neurogenic 0.83 (Nc = 50) (B) brachioradialis normal 0.81 (Nc = 84), neurogenic 0.78 (Nc = 66) (C) extensor digitorum communis normal 0.72 (Nc = 92), neurogenic 0.73 (Nc = 61) (D) biceps (age > 40y) normal 0.77 (Nc = 77), neurogenic 0.67 (Nc = 62). We conclude that T/Amax has a strong linear association with peak(T/A) and, therefore, the former may be further investigated as a potentially useful quantitative diagnostic marker, especially in cases where the latter is not available. PMID- 29413451 TI - Muscle activity and kinetics of lower limbs during walking in pronated feet individuals with and without low back pain. AB - : The objectives of this study were to investigate whether excessive feet pronation alters the joints' kinematics, kinetics and the activity of involved muscles during gait in low back pain patients. METHODS: The lower limb joints' motion, moment and power, as well as the activity of involved muscles during walking were measured in a control group, and two experimental groups including a group with excessive feet pronation only, and another group of low back pain patients with excessive feet pronation. RESULTS: In both experimental groups, ankle inversion, knee flexion and internal rotation, hip internal rotation, plantar flexors' moment, hip flexors' moment, and peak positive ankle power were lower than those in control group (p < .05). Besides, in patients, higher activity of gastrocnemius medialis, gluteus medius, erector spinae, and internal oblique muscles, and lower negative power at the ankle and peak positive power at the knee were observed (p < .05). In conclusion, pronated feet with low back pain was associated with less ankle inversion and knee flexion, higher knee and hip internal rotation, higher muscle activity, less energy absorption at the ankle, and reduced positive power at the knee. This study reveals that strengthening of the muscles especially knee extensors are of great importance in low back pain patients with feet pronation. PMID- 29413452 TI - The effects of short-term and long-term experiences on co-contraction of lower extremity postural control muscles during continuous, multi-directional support surface perturbations. AB - While reactive balance control in response to single perturbations in quiet standing is relatively well understood, some occupational environments (e.g. maritime environments) expose workers to continuous, multi-directional challenges to balance and postural control, which require workers to respond to the current perturbation, as well as anticipate coming perturbations. Investigation of muscle activation patterns during continuous, multi-directional perturbations, and the role of previous experience, is warranted to better understand postural control strategies in these types of environments. This study aimed to identify changes in co-contraction in the lower extremity postural control muscles during multi directional support-surface perturbations as a result of short-term and long-term experience. Twenty-five participants (12 with minimal experience (novice), 13 with >=6 months experience working in moving maritime environments (experienced)) were exposed to five 5-minute trials of continuous support-surface perturbations. Muscle activity was recorded from six muscles bilaterally. Co-contraction indices were calculated for selected muscle pairings and compared between groups and trials. Co-contraction decreased across trials, and was lower in the experienced group relative to the novice group. These findings provide insight into the influence of previous experience on muscle activation during reactive balance control, and suggest that increased co-contraction may be a potential mechanism of the increased risk of workplace fatigue, falls, and injury in novice maritime workers. The development and refinement of training programs targeting novice workers may be a potential avenue to reduce fall and injury risk in maritime environments. PMID- 29413453 TI - Reliability of ultrasound shear-wave elastography in assessing low back musculature elasticity in asymptomatic individuals. AB - Patients with low back pain commonly exhibit impaired morphology and function of spinal musculature that may be quantifiable using shear-wave elastography (SWE). The purpose of this study was to assess the intra-rater and test-retest reliability of SWE elasticity measures of the lumbar erector spinae and multifidus muscles during rest and differing levels of contraction in asymptomatic individuals. This single-group repeated-measures design involved a baseline measurement session and a follow-up session 3 days later. The lumbar multifidus was imaged at rest and during three levels of contraction (minimal, moderate, and maximum). The lumbar erector spinae (illiocostalis and longissimus muscles) were imaged at rest only. Overall reliability estimates were fair to excellent with ICCs ranging from 0.44 to 0.92. Reliability was higher in the lumbar multifidus muscles than the erector spinae muscles, slightly higher during contraction than during rest, and substantially improved by using the mean of 3 measurements. By reliably quantifying impaired spinal musculature, SWE may facilitate an improved understanding of the etiology and treatment of low back pain and other muscle pain-related conditions such as trigger points and fibromyalgia. PMID- 29413454 TI - Submaximal normalizing methods to evaluate load sharing changes in the shoulder during repetitive work. AB - The EMG-force relationship changes with muscle fatigue, making interpretation of load sharing between muscles challenging. The purpose of this investigation was to evaluate the efficacy of normalizing EMG to repeated, static, submaximal exertions to mitigate fatigue artifacts in EMG amplitude (increased amplitude without muscle force change). Participants completed repetitive work tasks, in 60 second cycles, until exhaustion. Surface EMG was recorded from 11 shoulder muscles (anterior, middle and posterior deltoids, infraspinatus, upper, middle and lower trapezius, latissimus dorsi, serratus anterior, sternal and clavicular heads of pectoralis major). Every 12 min, participants completed 4 submaximal reference exertions. Reference exertion EMG data were used in 6 normalizing methods including 1 standard (normalized to initial reference exertion) and 5 novel methods: (i) Fatigue Only, (ii) Linear, (iii) Cubic, (iv) Points Forward, and (v) Points Forward/Backward. Data normalized with each novel method were compared to the Standard Method using mixed effects modelling. Significant differences depended on the muscle and the number of time points included (p < .05). The cubic model correlated better to the actual data points than linear predicted values. The novel cubic normalizing method created muscle activity ratios that appear to mitigate the fatigue effects and better reflect muscular loads during fatiguing work. PMID- 29413455 TI - Characterization of cervical neuromuscular response to head-neck perturbation in active young adults. AB - BACKGROUND: The majority of studies examining the role of cervical muscles on head-neck kinematics focused on musculoskeletal attributes (e.g. strength). Cervical neuromuscular response to perturbation may represent a divergent construct that has not been examined under various perturbation conditions. This study examined the association between cervical musculoskeletal attributes and cervical neuromuscular response of the sternocleidomastoid (SCM) to perturbation. Furthermore, this study examined the effect of anticipation and preload on the SCM neuromuscular response. METHODS: Nineteen participants completed measurement of SCM muscle size, cervical flexion maximal voluntary isometric contraction, and the neuromuscular response of the SCM to cervical perturbation. Cervical perturbation was delivered by dropping a 1.59 kg mass from a loading apparatus. The impulsive load was delivered under four conditions: (1) Anticipated perturbation with no preload (A-NP), (2) Unanticipated perturbation with no preload (U-NP), (3) Anticipated perturbation with preload (A-P), and (4) Unanticipated perturbation with preload (U-P). RESULTS: None of the cervical musculoskeletal attributes were correlated with the SCM cervical neuromuscular response. This study demonstrated significant effect of preloading and anticipation on baseline EMG amplitude and EMG onset latency for the SCM. Furthermore, there was a significant effect of preloading on average EMG response amplitude for the SCM. DISCUSSION: The findings of this study indicate that cervical neuromuscular response of the SCM is different from musculoskeletal attributes and is influenced by perturbation conditions. These findings provide conceptual support to examine the neuromuscular response of the SCM in mitigating head-neck kinematics. PMID- 29413456 TI - Occurrence of bifid median nerve in healthy and carpal tunnel syndrome patients. AB - : We investigated the possible association between median nerve morphology and carpal tunnel size, hand side and nerve conduction measurements. The study included a patient group (n = 58; 44 women) with idiopathic carpal tunnel syndrome (CTS) in 100 hands and a control group of healthy volunteers (n = 56, 112 hands; 44 women). The following data were recorded: (1) median and ulnar motor and sensory nerve conduction parameters (2) ultrasonographic dimensions of the carpal tunnel inlet area (CTAin) and inlet area of the median nerve. The prevalence of bifid median nerve was 19% in the CTS hands and 13.3% in the control group. Bilateral bifid nerve was detected in 7 subjects and unilateral in 23, with no side or sex preponderance. The median nerve area was larger in the participants with single than those with bifid median nerve. No correlation was found between CTAin and median nerve area for single or bifid nerves in controls or patients. It was concluded that bifid median nerve was not a rare variation. We could not, however, support its etiological relation to CTS. Ultrasonographic examination of the carpal tunnel region supplementing neurophysiology provided a reliable means to detect median nerve size and morphology. CLINICAL TRIAL REGISTRATION NUMBER: 84; 5/3/15. PMID- 29413457 TI - [In process]. PMID- 29413458 TI - Long-term biodistribution study of HPMA-ran-LMA copolymers in vivo by means of 131I-labeling. AB - BACKGROUND: For the evaluation of macromolecular drug delivery systems suitable pre-clinical monitoring of potential nanocarrier systems is needed. In this regard, both short-term as well as long-term in vivo tracking is crucial to understand structure-property relationships of polymer carrier systems and their resulting pharmacokinetic profile. Based on former studies revealing favorable in vivo characteristics for 18F-labeled random (ran) copolymers consisting of N-(2 hydroxypropyl)methacrylamide (HPMA) and lauryl methacrylate (LMA) - including prolonged plasma half-life as well as enhanced tumor accumulation - the presented work focuses on their long-term investigation in the living organism. METHODS: In this respect, four different HPMA-based polymers (homopolymers as well as random copolymers with LMA as hydrophobic segment) were synthesized and subsequent radioactive labeling was accomplished via the longer-lived radioisotope 131I. In vivo results, concentrating on the pharmacokinetics of a high molecular weight HPMA-ran-LMA copolymer, were obtained by means of biodistribution and metabolism studies in the Walker 256 mammary carcinoma model over a time-span of up to three days. Besides, a direct comparison with the 18F-radiolabeled polymer was drawn. To consider physico-chemical differences between the differently labeled polymer (18F or 131I) on the critical micelle concentration (CMC) and the size of the polymeric micelles, those properties were determined using the 19F- or 127I functionalized polymer. Special emphasis was laid on the time-dependent correlation between blood circulation properties and corresponding tumor accumulation, particularly regarding the enhanced permeability and retention (EPR) effect. RESULTS: Studies revealed, at first, differences in the short time (2h) body distribution, despite the very similar properties (molecular structure, CMC and size of the micellar aggregates) of the non-radioactive 19F- and 127I functionalized polymers. Long-term investigations with the 131I-labeled polymer demonstrated that, despite a polymer clearance from the blood within 72h, there was still an increase in tumor uptake observed over time. Regarding the stability of the 131I-label, ex vivo biodistribution experiments, considering the uptake in the thyroid, indicated low metabolism rates. CONCLUSION: The observed in vivo characteristics strongly underline the EPR effect. The findings illustrate the need to combine information of different labeling approaches and in vivo evaluation techniques to generate an overall pharmacokinetic picture of potential nanocarriers in the pre-clinical setting. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENTS: The in vivo behavior of the investigated HPMA-ran-LMA copolymer demonstrates great potential in terms of an effective accumulation in the tumor. PMID- 29413460 TI - Generic drugs: are they the future for affordable medicine? PMID- 29413461 TI - In search of Mangomoments. PMID- 29413462 TI - Earliest evidence of malignant breast cancer in Renaissance paintings. PMID- 29413459 TI - 212Pb-labeled B7-H3-targeting antibody for pancreatic cancer therapy in mouse models. AB - INTRODUCTION: We recently validated monoclonal antibody (mAb) 376.96 as an effective carrier for targeted alpha-particle radioimmunotherapy (RIT) with 212Pb in ovarian cancer mouse models. In this study, we tested the binding of radiolabeled mAb 376.96 to human pancreatic ductal adenocarcinoma (PDAC) cells and localization in xenografts in immune-deficient mice and evaluated 212Pb labeled 376.96 (212Pb-376.96) for PDAC therapy. METHODS: In vitro Scatchard assays assessed the specific binding of 212Pb-376.96 to human PDAC3 adherent differentiated cells and non-adherent cancer initiating cells (CICs) dissociated from tumorspheres. In vitro clonogenic assays were used to measure the proliferation of adherent PDAC3 cells and CIC-enriched tumorspheres treated with 212Pb-376.96 or the irrelevant isotype-matched 212Pb-F3-C25. Mice bearing patient derived pancreatic cancer Panc039 xenografts were i.v. injected with 0.17-0.70 MBq 212Pb-376.96 or isotype control 212Pb-F3-C25, and used for biodistribution and tumor growth inhibition studies. Mice bearing orthotopic PDAC3 xenografts were i.v. co-injected with 99mTc-376.96 and 125I-F3-C25 and used for biodistribution studies. RESULTS: 212Pb-376.96 specifically bound to PDAC3 adherent and dissociated tumorsphere CICs; Kd values averaged 9.0 and 21.7 nM, respectively, with 104-105 binding sites/cell. 212Pb-376.96 inhibited the clonogenic survival of PDAC3 cells or CICs dissociated from tumorspheres 3-6 times more effectively than isotype-matched control 212Pb-F3-C25. Panc039 s.c. tumors showed significantly higher uptake of 212Pb-376.96 (14.0 +/- 2.1% ID/g) compared to 212Pb-F3-C25 (6.5 +/- 0.9% ID/g, p < .001) at 24 h after dosing. Orthotopic PDAC3 tumors showed significantly higher uptake of 99mTc-376.96 (6.4 +/- 1.8% ID/g) compared to 125I-F3-C25 (3.9 +/- 0.9% ID/g, p < .05) at 24 h after dosing. Panc039 tumor growth was significantly inhibited by 212Pb-376.96 compared to 212Pb-F3-C25 or non-treated control tumors (p < .05). CONCLUSION: Our results provide evidence for the efficacy of B7-H3 targeted RIT against preclinical models of pancreatic ductal adenocarcinoma (PDAC) and support future studies with 212Pb-376.96 in combination with chemotherapy to potentiate efficacy against PDAC. PMID- 29413463 TI - Demoralisation in palliative care. PMID- 29413464 TI - Harnessing genomics to improve outcomes for women with cancer in India: key priorities for research. AB - Cumulatively, breast, cervical, ovarian, and uterine cancer account for more than 70% of cancers in women in India. Distinct differences in the clinical presentation of women with cancer suggest underlying differences in cancer biology and genetics. The peak age of onset of breast and ovarian cancer appears to be a decade earlier in India (age 45-50 years) than in high-income countries (age >60 years). Understanding these differences through research to develop diagnosis, screening, prevention, and treatment frameworks that ar e specific to the Indian population are critical and essential to improving women's health in India. Since the sequencing of the human genome in 2001, applications of advanced technologies, such as massively parallel sequencing, have transformed the understanding of the genetic and environmental drivers of cancer. How can advanced technologies be harnessed to provide health-care solutions at a scale and to a budget suitable for a country of 1.2 billion people? What research programmes are necessary to answer questions specific to India, and to build capacity for innovative solutions using these technologies? In order to answer these questions, we convened a workshop with key stakeholders to address these issues. In this Series paper, we highlight challenges in tackling the growing cancer burden in India, discuss ongoing genomics research and developments in infrastructure, and suggest key priorities for future research in cancer in India. PMID- 29413466 TI - Autoimmune hypophysitis. PMID- 29413465 TI - Population-based cancer screening programmes in low-income and middle-income countries: regional consultation of the International Cancer Screening Network in India. AB - The reductions in cancer morbidity and mortality afforded by population-based cancer screening programmes have led many low-income and middle-income countries to consider the implementation of national screening programmes in the public sector. Screening at the population level, when planned and organised, can greatly benefit the population, whilst disorganised screening can increase costs and reduce benefits. The International Cancer Screening Network (ICSN) was created to share lessons, experience, and evidence regarding cancer screening in countries with organised screening programmes. Organised screening programmes provide screening to an identifiable target population and use multidisciplinary delivery teams, coordinated clinical oversight committees, and regular review by a multidisciplinary evaluation board to maximise benefit to the target population. In this Series paper, we report outcomes of the first regional consultation of the ICSN held in Agartala, India (Sept 5-7, 2016), which included discussions from cancer screening programmes from Denmark, the Netherlands, USA, and Bangladesh. We outline six essential elements of population-based cancer screening programmes, and share recommendations from the meeting that policy makers might want to consider before implementation. PMID- 29413467 TI - Adoption of robotic surgery: driven by market competition or a desire to improve patient care? PMID- 29413468 TI - Adoption of robotic surgery: driven by market competition or a desire to improve patient care? - Authors' reply. PMID- 29413469 TI - Negative phase 3 study of 90Y microspheres versus sorafenib in HCC. PMID- 29413470 TI - Negative phase 3 study of 90Y microspheres versus sorafenib in HCC. PMID- 29413471 TI - Negative phase 3 study of 90Y microspheres versus sorafenib in HCC. PMID- 29413472 TI - Negative phase 3 study of 90Y microspheres versus sorafenib in HCC - Authors' reply. PMID- 29413473 TI - Young adults: a unique group in cancer epidemiological research. PMID- 29413474 TI - Young adults: a unique group in cancer epidemiological research - Authors' reply. PMID- 29413476 TI - Use of olaparib in patients with advanced gastric cancer. PMID- 29413475 TI - Cancer in two Renaissance families. PMID- 29413477 TI - Use of olaparib in patients with advanced gastric cancer - Authors' reply. PMID- 29413479 TI - Correction to Lancet Oncol 2017; 18: 1089-103. PMID- 29413478 TI - The Study of Letrozole Extension (SOLE) revisited. PMID- 29413480 TI - Correction to Lancet Oncol 2017; 18: e713. PMID- 29413481 TI - Correction to Lancet Oncol 2016; 17: e149-62. PMID- 29413482 TI - Cervical cancer vaccine controversy in India. PMID- 29413483 TI - Cancer surveillance in northern Africa, and central and western Asia: challenges and strategies in support of developing cancer registries. AB - The Global Initiative for Cancer Registry Development partnership, led by the International Agency for Research on Cancer (IARC), was established in response to an overwhelming need for high-quality cancer incidence data from low-income and middle-income countries. The IARC Regional Hub for cancer registration in North Africa, Central and West Asia was founded in 2013 to support capacity building for cancer registration in each of the countries in this region. In this Series paper, we advocate the necessity for tailored approaches to cancer registration given the rapidly changing cancer landscape for this region, and the challenges faced at a national level in developing data systems to help support this process given present disparities in resources and health infrastructure. In addition, we provide an overview of the status of cancer surveillance and activities country-by-country, documenting tailored approaches that are informing local cancer-control policy, and potentially curbing the growing cancer burden across the region. PMID- 29413484 TI - Tackling cancer burden in low-income and middle-income countries: Morocco as an exemplar. AB - Examples of successful implementations of national cancer control plans in low income or middle-income countries remain rare. Morocco, a country where cancer is already the second leading cause of death after cardiovascular diseases, is one exception in this regard. Population ageing and lifestyle changes are the major drivers that are further increasing the cancer burden in the country. Facing this challenge, the Moroccan Ministry of Health has developed a we l planned and pragmatic National Plan for Cancer Prevention and Control (NPCPC) that, since 2010, has been implemented with government financial support to provide basic cancer care services across the entire range of cancer control. Several features of the development and implementation of the NPCPC and health-care financing in Morocco provide exemplars for other low-income and middle-income countries to follow. Additionally, from the first 5 years of NPCPC, several areas were shown to require further focus through implementation research, notably in strengthening cancer awareness, risk reduction, and the referral pathways for prevention, early detection, treatment, and follow-up care. Working together with a wide range of stakeholders, and engagement with stakeholders outside the health care system on a more holistic approach can provide further opportunities for the national authorities to build on their successes and realise the full potential of present and future cancer control efforts in Morocco. PMID- 29413485 TI - Perinatal supplementation of 4-phenylbutyrate and glutamine attenuates endoplasmic reticulum stress and improves colonic epithelial barrier function in rats born with intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) can affect the structure and function of the intestinal barrier and increase digestive disease risk in adulthood. Using the rat model of maternal dietary protein restriction (8% vs. 20%), we found that the colon of IUGR offspring displayed decreased mRNA expression of epithelial barrier proteins MUC2 and occludin during development. This was associated with increased mRNA expression of endoplasmic reticulum (ER) stress marker XBP1s and increased colonic permeability measured in Ussing chambers. We hypothesized that ER stress contributes to colonic barrier alterations and that perinatal supplementation of dams with ER stress modulators, phenylbutyrate and glutamine (PG) could prevent these defects in IUGR offspring. We first demonstrated that ER stress induction by tunicamycin or thapsigargin increased the permeability of rat colonic tissues mounted in Ussing chamber and that PG treatment prevented this effect. Therefore, we supplemented the diet of control and IUGR dams with PG during gestation and lactation. Real-time polymerase chain reaction and histological analysis of colons from 120-day-old offspring revealed that perinatal PG treatment partially prevented the increased expression of ER stress markers but reversed the reduction of crypt depth and goblet cell number in IUGR rats. In dextran sodium sulfate-induced injury and recovery experiments, the colon of IUGR rats without perinatal PG treatment showed higher XBP1s mRNA levels and histological scores of inflammation than IUGR rats with perinatal PG treatment. In conclusion, these data suggest that perinatal supplementation with PG could alleviate ER stress and prevent epithelial barrier dysfunction in IUGR offspring. PMID- 29413486 TI - Oleocanthal-rich extra-virgin olive oil enhances donepezil effect by reducing amyloid-beta load and related toxicity in a mouse model of Alzheimer's disease. AB - Previous evidence suggested that extra-virgin olive oil (EVOO) is linked to attenuating amyloid-beta (Abeta) pathology and improving cognitive function in Alzheimer's disease (AD) mouse models. In addition, we recently reported the beneficial effect of oleocanthal, a phenolic compound in EVOO, against AD pathology. Currently, medications available to target AD pathology are limited. Donepezil is an acetylcholine esterase inhibitor approved for use for all AD stages. Donepezil has been reported to have limited Abeta-targeting mechanisms beside its acetylcholine esterase inhibition. The aim of this study was to investigate the consumption of EVOO rich with oleocanthal (hereafter EVOO) as a medical food on enhancing the effect of donepezil on attenuating Abeta load and related toxicity in 5xFAD mouse model of AD. Our results showed that EVOO consumption in combination with donepezil significantly reduced Abeta load and related pathological changes. Reduced Abeta load could be explained, at least in part, by enhancing Abeta clearance pathways including blood-brain barrier (BBB) clearance and enzymatic degradation, and shifting amyloid precursor protein processing toward the nonamyloidogenic pathway. Furthermore, EVOO combination with donepezil up-regulated synaptic proteins, enhanced BBB tightness and reduced neuroinflammation associated with Abeta pathology. In conclusion, EVOO consumption as a medical food combined with donepezil offers an effective therapeutic approach by enhancing the noncholinergic mechanisms of donepezil and by providing additional mechanisms to attenuate Abeta-related pathology in AD patients. PMID- 29413487 TI - Maternal protein restriction during lactation induces early and lasting plasma metabolomic and hepatic lipidomic signatures of the offspring in a rodent programming model. AB - Perinatal undernutrition affects not only fetal and neonatal growth but also adult health outcome, as suggested by the metabolic imprinting concept. However, the exact mechanisms underlying offspring metabolic adaptations are not yet fully understood. Specifically, it remains unclear whether the gestation or the lactation is the more vulnerable period to modify offspring metabolic flexibility. We investigated in a rodent model of intrauterine growth restriction (IUGR) induced by maternal protein restriction (R) during gestation which time window of maternal undernutrition (gestation, lactation or gestation-lactation) has more impact on the male offspring metabolomics phenotype. Plasma metabolome and hepatic lipidome of offspring were characterized through suckling period and at adulthood using liquid chromatography-high-resolution mass spectrometry. Multivariate analysis of these fingerprints highlighted a persistent metabolomics signature in rats suckled by R dams, with a clear-cut discrimination from offspring fed by control (C) dams. Pups submitted to a nutritional switch at birth presented a metabolomics signature clearly distinct from that of pups nursed by dams maintained on a consistent perinatal diet. Control rats suckled by R dams presented transiently higher branched-chain amino acid (BCAA) oxidation during lactation besides increased fatty acid (FA) beta-oxidation, associated with preserved insulin sensitivity and lesser fat accretion that persisted throughout their life. In contrast, IUGR rats displayed permanently impaired beta oxidation, associated to increased glucose or BCAA oxidation at adulthood, depending on the fact that pups experienced slow postnatal or catch-up growth, as suckled by R or C dams, respectively. Taken together, these findings provide evidence for a significant contribution of the lactation period in metabolic programming. PMID- 29413488 TI - Marine fish oil is more potent than plant-based n-3 polyunsaturated fatty acids in the prevention of mammary tumors. AB - Marine-derived n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to inhibit mammary carcinogenesis. However, evidence regarding plant-based alpha-linolenic acid (ALA), the major n-3 PUFA in the Western diet, remains equivocal. The objective of this study was to examine the effect of lifelong exposure to plant- or marine derived n-3 PUFAs on pubertal mammary gland and tumor development in MMTV neu(ndl)-YD5 mice. It is hypothesized that lifelong exposure to n-3 PUFA reduces terminal end buds during puberty leading to delayed tumor onset, volume and multiplicity. It is further hypothesized that plant-derived n-3 PUFAs will exert dose-dependent effects. Harems of MMTV-FVB males were bred with wild-type females and fed either a (1) 10% safflower (10% SF, n-6 PUFA, control), (2) 10% flaxseed (10% FS), (3) 7% safflower plus 3% flaxseed (3% FS) or (4) 7% safflower plus 3% menhaden (3% FO) diet. Female offspring were maintained on parental diets. Compared to SF, 10% FS and 3% FO reduced (P<.05) terminal end buds at 6 weeks and tumor volume and multiplicity at 20 weeks. A dose-dependent reduction of tumor volume and multiplicity was observed in mice fed 3% and 10% FS. Antitumorigenic effects were associated with altered HER2, pHER-2, pAkt and Ki-67 protein expression. Compared to 10% SF, 3% FO significantly down-regulated expression of genes involved in eicosanoid synthesis and inflammation. From this, it can be estimated that ALA was 1/8 as potent as EPA+DHA. Thus, marine-derived n-3 PUFAs have greater potency versus plant-based n-3 PUFAs. PMID- 29413489 TI - Obesity-induced mouse benign prostatic hyperplasia (BPH) is improved by treatment with resveratrol: implication of oxidative stress, insulin sensitivity and neuronal growth factor. PMID- 29413490 TI - Select polyphenolic fractions from dried plum enhance osteoblast activity through BMP-2 signaling. AB - Dried plum supplementation has been shown to enhance bone formation while suppressing bone resorption. Evidence from previous studies has demonstrated that these responses can be attributed in part to the fruit's polyphenolic compounds. The purpose of this study was to identify the most bioactive polyphenolic fractions of dried plum with a focus on their osteogenic activity and to investigate their mechanisms of action under normal and inflammatory conditions. Utilizing chromatographic techniques, six fractions of polyphenolic compounds were prepared from a crude extract of dried plum. Initial screening assays revealed that two fractions (DP-FrA and DP-FrB) had the greatest osteogenic potential. Subsequent experiments using primary bone-marrow-derived osteoblast cultures demonstrated these two fractions enhanced extracellular alkaline phosphatase (ALP), an indicator of osteoblast activity, and mineralized nodule formation under normal conditions. Both fractions enhanced bone morphogenetic protein (BMP) signaling, as indicated by increased Bmp2 and Runx2 gene expression and protein levels of phosphorylated Smad1/5. DP-FrB was most effective at up regulating Tak1 and Smad1, as well as protein levels of phospho-p38. Under inflammatory conditions, TNF-alpha suppressed ALP and tended to decrease nodule formation (P=.0674). This response coincided with suppressed gene expression of Bmp2 and the up-regulation of Smad6, an inhibitor of BMP signaling. DP-FrA and DP FrB partially normalized these responses. Our results show that certain fractions of polyphenolic compounds in dried plum up-regulate osteoblast activity by enhancing BMP signaling, and when this pathway is inhibited by TNF-alpha, the osteogenic response is attenuated. PMID- 29413491 TI - Relative levels of dietary EPA and DHA impact gastric oxidation and essential fatty acid uptake. AB - Previous research showed that increasing the proportion of docosahexaenoic acid (DHA) in marine lipid supplements significantly reduces associated health benefits compared with balanced eicosapentaenoic acid (EPA):DHA supplementation Dasilva et al., 2015 [1]. It was therefore hypothesized that the EPA and DHA molecules might have differential resistance to oxidation during gastric digestion and that the oxidation level achieved could be inversely correlated with intestinal absorption and, hence, with the resultant health benefits. Accordingly, we tested this proposed mechanism of action by investigating the degree of oxidation in the stomach, and the levels of bioaccessible lipids, of varying molar proportions of DHA and EPA (2:1, 1:1 and 1:2) using the dynamic gastrointestinal tract model TIM-1. In addition, small intestine enterocyte absorption and metabolism were simulated by Caco-2 cell monolayers that were incubated with these same varying proportions of DHA and EPA, and comparing oxidized and nonoxidized polyunsaturated fatty acids (PUFAs). The results show an inverse correlation between lipid oxidation products in the stomach and the levels of bioaccessible lipids. The balanced 1:1 EPA:DHA diet resulted in lower oxidation of PUFAs during stomach digestion relative to the other ratios tested. Finally, cell-based studies showed significantly lower assimilation of oxidized EPA and DHA substrates compared to nonoxidized PUFAs, as well as significant differences between the net uptake of EPA and DHA. Overall, the present work suggests that the correct design of diets and/or supplements containing marine lipids can strongly influence the stability and bioaccessibility of PUFAs during gastrointestinal digestion and subsequent absorption. This could modulate their health benefits related with inflammation, oxidative stress and metabolic disorders. PMID- 29413492 TI - Attenuation of obesity and insulin resistance by fish oil supplementation is associated with improved skeletal muscle mitochondrial function in mice fed a high-fat diet. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to improve insulin sensitivity and glucose homeostasis in animal models of insulin resistance, but the involved mechanisms still remain unresolved. In this study, we evaluated the effects of fish oil (FO), a source of n-3 PUFAs, on obesity, insulin resistance and muscle mitochondrial function in mice fed a high-fat diet (HFD). C57Bl/6 male mice, 8 weeks old, were divided into four groups: control diet (C), high-fat diet (H), C+FO (CFO) and H+FO (HFO). FO was administered by oral gavage (2 g/kg b.w.), three times a week, starting 4 weeks before diet administration until the end of the experimental protocol. HFD-induced obesity and insulin resistance associated with impaired skeletal muscle mitochondrial function, as indicated by decreased oxygen consumption, tricarboxylic acid cycle intermediate (TCAi) contents (citrate, alpha-ketoglutarate, malate and oxaloacetate), oxidative phosphorylation protein content and mitochondrial biogenesis. These effects were associated with elevated reactive oxygen species production, decreased PGC1-a transcription and reduced Akt phosphorylation. The changes induced by the HFD were partially attenuated by FO, which decreased obesity and insulin resistance and increased mitochondrial function. In the H group, FO supplementation also improved oxygen consumption; increased TCAi content, and Akt and AMPK phosphorylation; and up-regulated mRNA expression of Gpat1, Pepck, catalase and mitochondrial proteins (Pgc1alpha, Pparalpha, Cpt1 and Ucp3). These results suggest that dietary FO attenuates the deleterious effects of the HFD (obesity and insulin resistance) by improving skeletal muscle mitochondrial function. PMID- 29413493 TI - Supplementation of suckling rats with cow's milk induces hyperphagia and higher visceral adiposity in females at adulthood, but not in males. AB - In humans, complementary feeding should be started after 6 months-old; the introduction of any food or water before this time is considered early weaning, which is associated with health problems in adulthood. Cow's milk is a common food introduced to children less than 6 months that has inadequate nutritional composition mainly due to a worse casein: whey protein ratio compared to human milk. We hypothesized that suckling rats fed with cow's milk, rich in bioactive peptides, develop further metabolic dysfunctions. From postnatal day (PN) 14 to 20, Wistar rat pups were divided into 3 groups: rat milk (RM) - pups received rat milk orally in a syringe; cow's milk (CM), pups received cow's milk; CM with high protein (CM-H), CM with twice protein amount of rat milk. Pups were killed on PN21 and PN180. At PN21, CM males had lower visceral fat mass compared with other groups. Serum corticosterone was higher in CM-H males, despite no change in glucocorticoid metabolism in liver and visceral fat. At PN180, CM and CM-H females had greater fat depots and hyperphagia, although no alteration in leptinemia and leptin signaling in hypothalamus. CM-H females had a trend of hypoinsulinemia and significant decrease in HOMA-beta, suggesting lower insulin secretion. Males from CM-H group had only lower total body protein mass. CM males had hypercorticosteronemia associated with lower expression of 11betaHDS1 in visceral fat. In conclusion, early introduction of cow's milk in neonate rats leads to gender-dependent differences in metabolic and endocrine parameters in the short- and long-term. PMID- 29413494 TI - Malnutrition and sarcopenia assessment in patients with chronic obstructive pulmonary disease according to international diagnostic criteria, and evaluation of raw BIA variables. AB - BACKGROUND: Various criteria have been used so far for the diagnosis of malnutrition or sarcopenia in patients suffering from chronic obstructive pulmonary disease (COPD). OBJECTIVE: To determine the prevalence of malnutrition and sarcopenia in COPD, as defined by international diagnostic criteria, and determine their relationships with raw BIA variables. METHODS: Two-hundred and sixty-three COPD patients (185 males and 78 females) underwent both clinical examination and respiratory, anthropometric, bioelectrical impedance analysis (BIA raw variables: phase angle and impedance ratio), handgrip strength (HGS), 4 m gait speed and biochemical measurements. Malnutrition and sarcopenia were diagnosed based on European Society for Clinical Nutrition and Metabolism (ESPEN) criteria and European Working Group on Sarcopenia in Older People (EWGSOP) criteria, respectively. RESULTS: The overall prevalence of malnutrition and sarcopenia was 19.8% and 24.0% respectively, increasing with disease severity. The prevalence of sarcopenia was significantly higher in patients with malnutrition (71.2% vs 12.3%; p < 0.001), especially in those with systemic inflammation (cachectic patients) (85.7% vs 61.3%; p < 0.001). Malnourished patients with sarcopenia had a significant reduction in BMI, fat-free mass and HGS compared to non-sarcopenic patients. Finally, impedance ratio significantly increased and phase angle decreased in patients with severe sarcopenia and in cachectic patients. CONCLUSION: A relatively high prevalence of malnutrition and sarcopenia was found in COPD patients applying international standard criteria, with some discrepancy between the two diagnoses. In addition, clear-cut changes in raw BIA variables were observed in malnourished patients with systemic inflammation and sarcopenic patients. PMID- 29413495 TI - Effects of respiratory muscle training on endothelium and oxidative stress biomarkers in hemodialysis patients: A randomized clinical trial. AB - INTRODUCTION: Hemodialysis (HD) patients have altered pulmonary function and this is associated with impaired endothelial function and cardiovascular events. Respiratory muscle training (RMT) has the potential to improve cardiovascular outcomes in patients undergoing maintenance HD. Here, we evaluated the effects of RMT on endothelium/glycocalyx, oxidative stress biomarkers and pulmonary function test in HD patients. METHODS: This is a randomized controlled clinical trial including 41 patients undergoing thrice-weekly maintenance HD. Patients were randomly assigned at a 2:1 ratio to receive or not RMT during HD sessions for 8 weeks. Main outcomes were changes in levels of the biomarkers related to endothelium activation (vascular cell adhesion molecule 1, VCAM-1, and intercellular adhesion molecule 1, ICAM-1), glycocalyx derangement (syndecan-1), aberrant angiogenesis (angiopoietin-2) and oxidative stress (malondialdehyde) compared to baseline. Also, maximal inspiratory/expiratory pressure (MIP, MEP), Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) were evaluated. Other outcomes included changes in functional capacity and pulmonary function test. We also performed a post-hoc analysis of plasma endothelin-1 levels. RESULTS: Of 56 randomly assigned patients, 41 were included in the primary final analyses. RMT increased all pulmonary function parameters evaluated and significantly reduced plasma syndecan-1 levels at 8 weeks compared to placebo (between-group difference: -84.5; 95% CI, -148.1 to -20.9). Also, there was a reduction in plasma levels of angiopoietin-2 (between-group difference: -0.48; 95% CI, -1.03 to -0.097). Moreover, there was a significant reduction in mean blood pressure at rest (between-group difference: -12.2; 95%CI, -17.8 to -6.6) associated with a reduction in endothelin-1 levels (between-group difference: -0.164; 95% CI, -0.293 to -0.034). There was no difference regarding biomarkers of endothelial activation or oxidative stress. CONCLUSION: A short term RMT program ameliorate FVC, FEV1 and reduces syndecan-1 and angiopoietin-2 biomarker levels. Finally, better blood pressure control was attained during training and it was associated with a reduction in endothelin-1 levels. PMID- 29413496 TI - Subclinical atherosclerosis in adults with steady-state bronchiectasis: A case control study. AB - BACKGROUND AND OBJECTIVE: Bronchiectasis has been associated with increased risks of cardiovascular disease, in which early-stage endothelial dysfunction might have played pivotal roles. We aimed to investigate endothelial function in bronchiectasis patients, by measuring flow-mediated dilatation (FMD) and carotid intima-media thickness (CIMT) as compared with control subjects, and to elucidate the impact of different risk factors on subclinical atherosclerosis. METHODS: The study included 80 bronchiectasis patients and 80 age- and sex-matched healthy subjects. Vascular endothelial function was evaluated with FMD in the brachial artery in response to reactive hyperemia, and CIMT was measured with high resolution ultrasonography. Disease severity was evaluated with Bronchiectasis Severity Index and FACED scores. Demographic, disease duration, radiology, spirometry, sputum bacteriology and systemic inflammatory indices were also assessed. RESULTS: FMD was significantly lower in bronchiectasis patients than in control subjects (8.92 +/- 2.70% vs. 11.17 +/- 3.44%, P < 0.001). FMD significantly correlated with Bronchiectasis Severity Index (rho = -0.60, P < 0.001) and FACED score (rho = -0.39, P < 0.001). In multivariate regression analysis, age, body-mass index, Pseudomonas aeruginosa colonization and high resolution computed tomography scores were independent factors influencing on the FMD in bronchiectasis patients, even after adjustment for other clinical variables. No significant difference in CIMT was detected between bronchiectasis patients and healthy subjects (P > 0.05). CONCLUSIONS: Compared with healthy subjects, bronchiectasis patients have greater risks of endothelial dysfunction which is independent of previously well-studied risk factors, calling for the vigilance to screen early for vascular changes to minimize the future risks of cardiovascular events. PMID- 29413497 TI - A retrospective cohort study in severe asthma describing commonly measured biomarkers: Eosinophil count and IgE levels. AB - BACKGROUND: Identifying asthma patients suitable for biologic therapy includes the assessment of blood biomarkers (IgE and eosinophils (EOS)). How they relate to each other is unclear. METHODS: This retrospective, database study used routinely collected clinical data to identify and evaluate an asthma cohort (classification code for asthma; >= 18 years; >=1 prescription for asthma; >=1 estimation of serum IgE, in 2 years prior to index date). Distribution into high and low IgE and EOS groups (IgE cut-point: > or <=75 kU/L; EOS cut point: >or <=400 MU/L), and characteristics by group are described. FINDINGS: In patients with severe asthma (British Thoracic Society Step (BTS) >=4; N = 884), using maximum recorded IgE/EOS, 33% had high IgE/high EOS, 28% low IgE/low EOS and approximately a fifth each had high IgE/low EOS or low IgE/high EOS. Proportions were similar when EOS values measured 2 or 4 weeks before an exacerbation were excluded. Using EOS/IgE 'same day' measurements (N = 578) only identified half of the high EOS group. Patients in high IgE groups were more likely to be younger males without comorbid COPD; those in high EOS groups were more likely to be on BTS treatment Step 5 vs 4. The low IgE/low EOS group had the lowest incidence of asthma-related hospital attendances, the highest incidence was observed in the high EOS groups. CONCLUSION: Maximum available EOS measurement irrespective of exacerbations may be relevant when considering therapy. These data showed low IgE/Low EOS to be more benign and high EOS groups at increased risk of frequent, severe exacerbations. PMID- 29413498 TI - Diagnostic performances of the Xpert MTB/RIF in Brazil. AB - BACKGROUND AND OBJECTIVES: As for all tests, the diagnostic performances of Xpert MTB/RIF might be different in settings with different tuberculosis prevalence. Aim of the study is to evaluate the performances of Xpert MTB/RIF to diagnose tuberculosis in Brazil, where 407 culture-confirmed tuberculosis patients were retrospectively enrolled in Rio Grande do Sul, between 2015 and 2016. METHODS: Sensitivity, specificity, positive and negative predictive values of the test were calculated and a logistic regression analysis was performed to assess the role played by explanatory variables in the occurrence of true positive and negative diagnostic results. RESULTS: Sensitivity of Xpert MTB/RIF was 100.0%, specificity 92.8%; positive and negative predictive values were 71.4% and 100.0%, respectively. In the HIV- infected sub-group specificity was 59.3%. In the multivariate logistic regression analysis, true positivity was associated with increasing age (1.0; p-value: 0.02) while true positivity and negativity were negatively associated with alcohol abuse. CONCLUSIONS: Xpert is sensitive and specific in the Brasilian settings. PMID- 29413499 TI - Pulmonary function predicts mortality and hospitalizations in outpatients with heart failure and preserved ejection fraction. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFPEF) is the most frequent form of heart failure in ambulatory patients with new-onset symptoms. We previously showed that lung function abnormalities are highly prevalent in HFPEF patients. In this observational, longitudinal study, we tested the hypothesis that the presence of airflow limitation and/or arterial hypoxemia predicts mortality and/or cardiovascular hospitalizations during follow-up in HFPEF outpatients. MATERIALS AND METHODS: HFPEF was diagnosed following the international recommendations. Forced spirometry and arterial blood gases were measured at recruitment according to international recommendations. The primary endpoint of the study was all-cause mortality and the secondary one was any cardiovascular hospitalization. RESULTS: We included in the analysis all consecutive outpatients newly diagnosed of HFPEF in our clinic between April 2009 and January 2013 (n = 71). Patients were prospectively followed up for a mean of 4 years (range 10 months to 5.8 years). All-cause mortality was 18.3%. It was higher in patients with airflow limitation (30%) than those with normal spirometry (10%) or other spirometric defects (19%) (p = 0.036). The presence of arterial hypoxemia did not predict mortality (p = 0.179) but was significantly related to cardiovascular hospitalizations during follow-up (p = 0.038). CONCLUSIONS: The presence of airflow limitation or arterial hypoxemia identify a group of patients with HFPEF at higher risk of death or cardiovascular hospitalizations, respectively. Given that both airflow limitation and arterial hypoxemia are treatable, we propose that lung function should be routinely evaluated in the outpatient management of HFPEF patients. PMID- 29413500 TI - Evaluation of a respiratory symptom diary for clinical studies of idiopathic pulmonary fibrosis. AB - BACKGROUND: There are no validated patient diaries for evaluating respiratory symptoms in idiopathic pulmonary fibrosis (IPF). PURPOSE: To evaluate the performance properties of the chronic obstructive pulmonary disease (COPD) Evaluating Respiratory SymptomsTM (E-RSTM: COPD) measure in patients with IPF. METHODS: Concept elicitation and cognitive interviews were conducted with IPF patients to evaluate content validity, including comprehensiveness, relevance, and interpretability of E-RSTM items in this patient population. Secondary analyses of IPF clinical study data were performed to evaluate the scoring structure of the tool. With modifications, reliability, validity, and responsiveness of the instrument (E-RSTM: IPF) were evaluated. RESULTS: Qualitative interviews (n = 30) were conducted. During the elicitation interviews (n = 20), concept saturation for IPF respiratory symptoms was achieved; all respiratory symptoms covered by the E-RSTM were endorsed by >= 30% of the sample. During cognitive interviews (n = 10), all participants found the items interpretable and relevant. Factor analyses conducted via secondary analysis of IPF clinical study data identified no total score and four symptom scales: Chest, Breathlessness, Cough, and Sputum. Reliability of each scale was high (internal consistency [alpha] >0.85); 2-day reproducibility (ICC >0.88). Validity was supported through significant (P < 0.0001) relationships with the St. George's Respiratory Questionnaire (SGRQ), the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ), and other variables. The scales were responsive to change when evaluated using SGRQ Symptoms, UCSD-SOBQ, and Patient Global Impression of Change as anchors (P < 0.01 to P < 0.0001). CONCLUSION: The E-RSTM: IPF is a valid, reliable, and responsive tool for evaluating respiratory symptoms in patients with IPF. PMID- 29413501 TI - Integration of 3D printing and additive manufacturing in the interventional pulmonologist's toolbox. AB - New 3D technologies are rapidly entering into the surgical landscape, including in interventional pulmonology. The transition of 2D restricted data into a physical model of pathological airways by three-dimensional printing (3DP) allows rapid prototyping and fabrication of complex and patient-specific shapes and can thus help the physician to plan and guide complex procedures. Furthermore, computer-assisted designed (CAD) patient-specific devices have already helped surgeons overcome several therapeutic impasses and are likely to rapidly cover a wider range of situations. We report herein with a special focus on our clinical experience: i) how additive manufacturing is progressively integrated into the management of complex central airways diseases; ii) the appealing future directions of these new technologies, including the potential of the emerging technique of bioprinting; iii) the main pitfalls that could delay its introduction into routine care. PMID- 29413502 TI - Efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma not receiving inhaled corticosteroids. AB - BACKGROUND: Asthma is a heterogeneous and complex disease in both its clinical course and response to treatment. IL-13 is central to Type 2 inflammation and contributes to many features of asthma. In a previous Phase 2 study, lebrikizumab, an anti-IL-13 monoclonal antibody, did not significantly improve FEV1 in mild-to-moderate asthma patients not receiving ICS therapy. This Phase 3 study was designed to further assess the efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma treated with daily short-acting beta2 agonist therapy alone. METHODS: Adult patients with mild-to-moderate asthma were randomised to receive lebrikizumab 125 mg subcutaneously (SC), placebo SC, or montelukast 10 mg orally for 12 weeks, with an 8-week follow-up period. The primary efficacy endpoint was absolute change in pre-bronchodilator FEV1 from baseline at Week 12. FINDINGS: A total of 310 patients were randomised and dosed in the study. The mean absolute change in FEV1 from baseline at Week 12 was higher in the lebrikizumab-treated arm compared with placebo (150 mL versus 67 mL); however, this improvement did not achieve statistical significance (overall adjusted difference of 83 mL [95% CI: -3, 170]; p = .06). Montelukast did not improve FEV1 as compared with placebo. Lebrikizumab was generally safe and well tolerated during the study. INTERPRETATION: Lebrikizumab did not significantly improve FEV1 in mild-to-moderate asthma patients at a dose expected to inhibit the IL-13 pathway. Inhibiting IL-13 in this patient population was not sufficient to improve lung function. These data support the findings of a previous trial of lebrikizumab in patients not receiving ICS. CLINICAL TRIALS REGISTRY NUMBER: This trial was registered under NCT02104674 at http://www.clinicaltrials.gov. PMID- 29413503 TI - Co-suspension delivery technology in pressurized metered-dose inhalers for multi drug dosing in the treatment of respiratory diseases. AB - Technologies for long-term delivery of aerosol medications in asthma and chronic obstructive pulmonary disease have improved over the past 2 decades with advancements in our understanding of the physical chemistry of aerosol formulations, device engineering, aerosol physics, and pulmonary biology. However, substantial challenges remain when a patient is required to use multiple inhaler types, multiple medications, and/or combinations of medications. Combining multiple drugs into a single inhaler while retaining appropriate dosing of the individual agents in the combination may enhance patient adherence to therapy and reduce device errors that occur when patients are using multiple inhalers. Pressurized metered-dose inhaler (pMDI) devices are widely used by patients for acute symptom relief as well as maintenance treatment, so the pMDI may be a suitable option with which to explore medication combinations. However, optimizing drug formulation remains a key challenge for pMDI delivery systems. This article introduces a new pMDI formulation approach: co-suspension delivery technology, which uses drug crystals with porous, low-density phospholipid particles engineered to deliver combinations of drugs to the airways with accurate and consistent dosing via pMDIs, independent of medication types and combinations. We describe the key characteristics of pMDIs, and discuss the rationale for the co-suspension delivery technology platform based on the limitations associated with traditional formulations. Finally, we discuss the clinical implications of co-suspension delivery technology for developing combination drug therapies administered by pMDIs. PMID- 29413504 TI - Several high-resolution computed tomography findings associate with survival and clinical features in rheumatoid arthritis-associated interstitial lung disease. AB - OBJECTIVE: To compare the presence and extent of several high-resolution computed tomography (HRCT) observations in different subtypes of rheumatoid arthritis related interstitial lung disease (RA-ILD) and to examine associations between radiological findings, hospitalization, age, RA duration, pulmonary function tests (PFT) and survival. MATERIALS AND METHODS: HRCTs from 60 RA-ILD patients were independently evaluated and re-categorized into usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and unclassified subtypes by two radiologists. The presence and extent, which was reported using a semi-quantitative scoring system, of e.g. reticulation, ground-glass opacity, honeycombing, emphysema, traction bronchiectasis and architectural distortion were further evaluated and compared between the subtypes. Associations between radiological findings and survival were identified with the Kaplan-Meier method and Cox's univariate model. The correlations between radiological findings, hospitalization, age, pack years, RA duration and PFT were calculated using Spearman's correlation coefficient. RESULTS: The extents of reticulation (HR 1.144, p = 0.041), traction bronchiectasis (HR 1.184, p = 0.030), architectural distortion (HR 1.094, p = 0.044) and the presence of pleural fluid (HR 14.969, p < 0.001) were associated with decreased survival. A negative correlation was observed between ground-glass opacity (GGO) and the duration of RA (r = -0.308, p = 0.023). The extents of honeycombing (r = 0.266, p = 0.046), traction bronchiectasis (r = 0.333, p = 0.012) and architectural distortion (r = 0.353, p = 0.007) correlated with hospitalizations due to respiratory reasons. CONCLUSIONS: Many radiological findings associate with the course of the disease of RA-ILD and could potentially be useful when planning the RA treatment or evaluating the risk of death in these patients. PMID- 29413505 TI - Progress and challenges in Mesothelioma: From bench to bedside. AB - Malignant Pleural Mesothelioma (MPM) is currently an incurable cancer with a typical survival of 1 year from the time of diagnosis. The recent genomic and transcriptomic characterization of MPM presents new opportunities and challenges for MPM researchers. Recent advances in clinical and laboratory diagnostics, and proposals for an updated, data-driven, staging system, also present new challenges for clinicians and hospital services involved in MPM care. The aim of this review is first to introduce the reader to the topic of MPM, a disease that is causally linked to prior, typically occupational, exposure to asbestos fibres. Secondly, we will discuss MPM from the clinical and laboratory perspectives, including reviews of current and evolving therapies and our present understanding of the molecular basis of the disease. Finally, we will attempt to identify critical knowledge gaps that currently prevent more effective treatment, including the challenges involved in early detection and chemoprophylaxis. PMID- 29413506 TI - Pulmonary arterial hypertension in the setting of scleroderma is different than in the setting of lupus: A review. AB - Pulmonary hypertension (PH) is a clinical syndrome that is subdivided into five groups per the World Health Organization (WHO) classification, based largely on hemodynamic and pathophysiologic criteria. WHO Group 1 PH, termed pulmonary arterial hypertension (PAH), is a clinically progressive disease that can eventually lead to right heart failure and death, and it is hemodynamically characterized by pre-capillary PH and increased pulmonary vascular resistance in the absence of elevated left ventricular filling pressures. PAH can be idiopathic, heritable, or associated with a variety of conditions. Connective tissue diseases make up the largest portion of these associated conditions, most commonly systemic sclerosis (SSc), followed by mixed connective tissue disease and systemic lupus erythematous. These etiologies (namely SSc and Lupus) have been grouped together as connective tissue disease-associated PAH, however emerging evidence suggests they differ in pathogenesis, clinical course, prognosis, and treatment response. This review highlights the differences between SSc-PAH and Lupus-PAH. After introducing the diagnosis, screening, and pathobiology of PAH, we discuss connective tissue disease-associated PAH as a group, and then explore SSc-PAH and SLE-PAH separately, comparing these 2 PAH etiologies. PMID- 29413507 TI - Respiratory effects of trichloroethylene. AB - Trichloroethylene (TCE) is a chlorinated solvent that has been used widely around the world in the twentieth century for metal degreasing and dry cleaning. Although TCE displays general toxicity and is classified as a human carcinogen, the association between TCE exposure and respiratory disorders are conflicting. In this review we aimed to systematically evaluate the current evidence for the respiratory effects of TCE exposure and the implications for the practicing clinician. There is limited evidence of an increased risk of lung cancer associated with TCE exposure based on animal and human data. However, the effect of other chlorinated solvents and mixed solvent exposure should be further investigated. Limited data are available to support an association between TCE exposure and respiratory tract disorders such as asthma, chronic bronchitis, or rhinitis. The most consistent data is the association of TCE with autoimmune and vascular diseases such as systemic sclerosis and pulmonary veno-occlusive disease. Although recent data are reassuring regarding the absence of an increased lung cancer risk with TCE exposure, clinicians should be aware of other potential respiratory effects of TCE. In particular, occupational exposure to TCE has been linked to less common conditions such as systemic sclerosis and pulmonary veno-occlusive disease. PMID- 29413508 TI - Weaning failure and respiratory muscle function: What has been done and what can be improved? AB - INTRODUCTION: Respiratory muscle dysfunction, being a common cause of weaning failure, is strongly associated with prolonged mechanical ventilation (MV) and prolonged stay in intensive care units. Inspiratory muscle training (IMT) has been described as an important contributor to the treatment of respiratory muscle dysfunction in critically ill patients. Its effectiveness is however yet controversial. OBJECTIVE: To discuss evidence for assessment of readiness and the effectiveness of interventions for liberation from MV, with special attention to the role of IMT. METHODS: PubMed, LILACS, PEDro and Web of Science were searched for papers of assessment and treatment of patients who failed liberation from MV after at least one attempt published in English or Portuguese until June 2016. RESULTS: Weaning predictors are related to weaning success (86%-100% for sensitivity and 7%-69% for specificity) and work of breathing (73%-100% for sensitivity and 56%-100% for specificity). Spontaneous breathing trials (SBT), noninvasive MV and early mobilization have been reported to improve weaning outcomes. Two modalities of IMT were identified in five selected studies: 1) adjustment of ventilator trigger sensitivity 2) inspiratory threshold loading. Both IMT training modalities promoted significant increases in respiratory muscle strength. IMT with threshold loading showed positive effect on endurance compared to control. CONCLUSION: Methods to indentify respiratory muscle weakness in critically ill patients are feasible and described as indexes that show good accuracy. Individualized and supervised rehabilitation programs including IMT, SBT, noninvasive MV and early mobilization should be encouraged in patients with inspiratory muscle weakness. PMID- 29413509 TI - Evaluation of the clinical characteristics of everolimus-induced lung injury and determination of associated risk factors. AB - BACKGROUND: Everolimus (ERL), a mammalian target of rapamycin (mTOR) inhibitor, has been used for the management of several advanced cancers. ERL frequently causes lung injury, although the clinical and radiographic features have not been clarified. The aim of this study was to assess the clinical features of ERL induced lung injury and determine the associated risk factors. METHODS: This single-center, retrospective study included 45 patients (29 men, 16 women; age, 12-78 years) who had received ERL at our hospital between August 2010 and March 2016. Drug-induced lung injury (DILI) was diagnosed using the Japanese Respiratory Society criteria. We obtained information regarding the clinical course, symptoms, clinical findings, blood test findings, and chest computed tomography findings from the patients' medical records. Risk factors for DILI onset were investigated using the Wilcoxon rank sum test. RESULTS: Fifteen patients (33%) were diagnosed with DILI. The median time from ERL administration to DILI onset was 64 days. High Serum Krebs von den Lungen-6 (KL-6) levels and a low estimated glomerular filtration rate (eGFR) before ERL administration were found to be significant risk factors for DILI. KL-6 and lactate dehydrogenase (LDH) were significantly elevated at the onset of DILI. All 15 patients recovered; 11 were without steroids. CONCLUSIONS: Our results suggest that patients with high KL-6 levels and a low eGFR at baseline are at increased risk of ERL-induced lung injury. In addition, KL-6 and LDH may be useful biomarkers of ERL-induced lung injury. PMID- 29413510 TI - Prevalence and impact of respiratory symptoms in a population of patients with COPD in Latin America: The LASSYC observational study. AB - BACKGROUND: To analyse the relationship between symptoms at different times during the 24-hour day and outcomes in COPD. METHODS: Observational cross sectional study in a patients from 7 Latin American countries. The frequency of symptoms in the morning, at night and during the day was explored by means of standardised and validated questionnaires, and the relationship between symptoms and exacerbations and quality of life were investigated. RESULTS: 734 patients (59.6% male, mean age 69.5 years, mean FEV1 50% predicted normal) were recruited. The most frequent symptoms during the day were dyspnea (75% of patients, of which 94% mild-moderate) and cough (72.2%, of which 93.4% mild-moderate). Highly symptomatic patients had a greater impairment in FEV1, more exacerbations and worse scores in COPD assessment test (CAT) and Body Mass Index, Obstruction, Dyspnoea and Exacerbations (BODEx) index (all p < 0.001). Morning symptoms were more frequent than night-time symptoms, particularly cough and dyspnoea (morning: 50.1% and 45.7%; night-time: 33.2% and 24.4%, respectively), and mostly rated as mild or moderate. Patients with morning or night-time symptoms presented with worse severity of daytime symptoms. There was a strong correlation between intensity of daytime with morning or night-time symptoms, as well as with CAT score (r = 0.715; p < 0.001), but a weak correlation with FEV1 (r = -0.205; p < 0.001). CONCLUSION: Morning symptoms were more frequent than night-time symptoms, and having either morning and/or night-time symptoms was associated with worse severity of daytime symptoms. Increased symptoms were strongly associated with worse quality of life and more frequent exacerbations, but weakly associated with airflow limitation. CLINICAL TRIAL REGISTRATION: NCT02789540. PMID- 29413511 TI - Mechanisms underlying the impact of exercise training in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a devastating disease characterized by progressive increases in pulmonary vascular resistance that can ultimately lead to right ventricle failure and death. Common symptoms include shortness of breath, fatigue, dizziness and chest pain, which negatively impact the functional capacity and quality of life. Despite the improvements in disease-targeted therapies, PAH remains incurable and with a high mortality rate, requiring effective therapeutic strategies. Exercise training is an important adjunct non pharmacological treatment for patients with left heart failure and chronic obstructive pulmonary disease. Although exercise training was discouraged in PAH because of safety concerns, recent studies support that supervised exercise training is safe and beneficial in patients with stable PAH. However, the molecular mechanisms underlying these improvements are still poorly understood. This review summarizes and integrates the emerging clinical and experimental studies describing the molecular alterations related with exercise training in PAH. PMID- 29413512 TI - The revised GOLD 2017 COPD categorization in relation to comorbidities. AB - INTRODUCTION: The COPD classification proposed by the Global Initiative for Obstructive Lung Disease was recently revised, and the A to D grouping is now based on symptoms and exacerbations only. Potential associations with comorbidities have not been assessed so far. Thus the aim of the present study was to determine the relationship between the revised (2017) GOLD groups A-D and major comorbidities. METHODS: We used baseline data from the COPD cohort COSYCONET. Comorbidities were identified from patient self-reports and disease specific medication: gastrointestinal disorders, asthma, sleep apnea, hyperuricemia, hyperlipidemia, diabetes, osteoporosis, mental disorders, heart failure, hypertension, coronary artery disease. The A-D groups were based on either the COPD Assessment Test or the modified Medical Research Council scale. Exacerbations were also categorized as per GOLD recommendations. RESULTS: Data from 2228 patients were analyzed. Using GOLD group A as a reference, group D was associated with nearly all comorbidities, followed by group B and C. When groups A-D were dichotomized as AC vs. BD (symptoms) and AB vs. CD (exacerbations), all comorbidities correlated with symptoms and/or exacerbations. This was true for both mMRC- and CAT-based categorizations. CONCLUSIONS: These findings suggest that the recently modified GOLD categorization is clinically relevant beyond being purely an assessment of symptoms and exacerbations. As the A-D groups correlated with the risk of important comorbidities, with some differences in terms of the correlation with symptoms and exacerbations, the findings underline the importance of identifying comorbidities in COPD, particularly in non responders to therapy who have high symptoms and/or exacerbation rates. PMID- 29413513 TI - Risk factors for nosocomial infection among hospitalised severe influenza A(H1N1)pdm09 patients. AB - BACKGROUND AND OBJECTIVE: Nosocomial infections following influenza are important causes of death, requiring early implementation of preventive measures, but predictors for nosocomial infection in the early stage remained undetermined. We aimed to determine risk factors that can help clinicians identify patients with high risk of nosocomial infection following influenza on admission. METHOD: Using a database prospectively collected through a Chinese national network for hospitalised severe influenza A(H1N1)pdm09 patients, we compared the characteristics on admission between patients with and without nosocomial infection. RESULT: A total of 2146 patients were enrolled in the final analysis with a median age of 36.0 years, male patients comprising 50.2% of the sample and 232 (10.8%) patients complicated with nosocomial infection. Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Staphylococcus aureus were the leading pathogens, and invasive fungal infection was found in 30 cases (12.9%). The in-hospital mortality was much higher in patients with nosocomial infection than those without (45.7% vs 11.8%, P < 0.001). Need for mechanical ventilation (OR: 3.336; 95% CI 2.362-4.712), sepsis (OR: 2.125; 95% CI 1.236-3.651), ICU admission on first day (OR: 2.074; 95% CI 1.425-3.019), lymphocytopenia (OR: 1.906; 95% CI 1.361-2.671), age > 65 years (OR: 1.83; 95% CI 1.04-3.21) and anaemia (OR: 1.39; 95% CI 1.39-2.79) were independently associated with nosocomial infection. CONCLUSION: Need for mechanical ventilation, sepsis, ICU admission on first day, lymphocytopenia, older age and anaemia were independent risk factors that can help clinicians identify severe influenza A(H1N1)pdm09 patients at high risk of nosocomial infection. PMID- 29413514 TI - Sputum plug selection under inverted microscopy improves microbial identification during exacerbations of airway diseases. AB - BACKGROUND: Salivary contamination decreases the yield of identifying potential airway bacterial and fungal pathogens in routine cultures of spontaneous or induced sputum during exacerbations of airway diseases. We investigated the utility of selecting out the squamous cells from sputum using inverted microscopy. METHODS: Sputum was obtained from fifty subjects, then divided to facilitate parallel processing of paired samples for gram-stain and semi quantitative cultures, and quantitative cytometry. RESULTS: Selective processing under inverted microscopy allowed for fewer sample rejections (2% vs. 24%) and greater culture positivity (58% vs. 24%) compared with routine practices, with significant yield of fungal organisms. While known pathogens were associated with intense sputum neutrophilia, organisms that were not routinely considered as airway pathogens were also associated with modest neutrophilia indicating that they are capable of inducing a clinically relevant cellular response. CONCLUSION: Sputum selection under inverted microscopy improves the detection of bacterial pathogens during infective exacerbations. The methods to assign pathogenicity to microbes in the airway needs to be re-visited by assessing the cellular responses that they evoke in the airways. PMID- 29413516 TI - Multiple Pathways Mediate MicroRNA Degradation: Focus on the Translin/Trax RNase Complex. AB - The discovery of the microRNA system has revolutionized our understanding of translational control. Furthermore, growing appreciation of the pivotal role that de novo translation plays in activity-dependent synaptic plasticity has fueled interest among neuroscientists in deciphering how the microRNA system impacts neuronal signaling and the pathophysiology of neuropsychiatric disorders. Although we have a general understanding of how the microRNA system operates, many key questions remain. In particular, the biosynthesis of microRNAs and their role in translational silencing are fairly well understood. However, much less is known about how microRNAs are degraded and silencing is reversed, crucial aspects of microRNA signaling. In contrast to microRNA synthesis which is mediated almost exclusively by a single pathway that culminates in Dicer, recent studies indicate that there are multiple pathways of microRNA degradation that target different subpopulations of microRNAs. While the Lin-28 pathway of microRNA degradation has been investigated extensively, the translin/trax RNase complex has emerged recently as another pathway mediating microRNA degradation. Accordingly, we summarize herein key features of the translin/trax RNase complex as well as important gaps in our understanding of its regulation and function that are the focus of ongoing studies. PMID- 29413515 TI - Baseline serum CXCL10 and IL-12 levels may predict severe asthmatics' responsiveness to omalizumab. AB - BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, is the first molecularly targeted drug for severe asthmatics. However, responses to omalizumab vary widely among patients. OBJECTIVES: This study aimed to assess the potential of baseline serum cytokine levels as predictors of responsiveness to omalizumab. METHODS: Thirty-one patients with severe, persistent asthma were enrolled in this study and administered omalizumab for at least 1 year. Response to omalizumab was assessed based on the physician's global evaluation of treatment effectiveness (GETE) at 48 weeks of treatment. Blood samples were collected at baseline and 16 and 32 weeks after starting omalizumab and measured for 30 cytokines by Luminex 200 and ELISA. Exhaled nitric oxide (FeNO) levels, peripheral blood eosinophil counts, pre-bronchodilator pulmonary functions and Asthma Quality of Life Questionnaire scores were determined at baseline and 16, 32 and 48 weeks after starting omalizumab. The numbers of clinically significant asthma exacerbations in the previous year and during 48 weeks of treatment with omalizumab were assessed. RESULTS: GETE assessment showed 19 responders (61.3%) and 12 non responders (38.7%). Responders showed significantly higher levels of CXCL10 and IL-12 at baseline compared to non-responders (CXCL10: responders, 1530.0 +/- 315.2 pg/ml vs. non-responders, 1066.0 +/- 396.8 pg/ml, P = 0.001; IL-12: responders, 60.2 +/- 39.2 pg/ml vs. non-responders, 32.2 +/- 26.3 pg/ml, P = 0.04). ROC curves to distinguish responders from non-responders using the baseline serum CXCL10 level showed a good AUC of 0.83. At 32 weeks of omalizumab therapy, serum CXCL10 tended to be increased (1350 +/- 412.3 pg/ml at baseline vs. 1529 +/- 637.6 pg/ml at 32 weeks, P = 0.16) and serum IL-12 tended to be decreased (49.4 +/- 37.0 pg/ml at baseline vs. 43.9 +/- 30.9 pg/ml at 32 weeks, P = 0.05). On the other hand, serum IL-5 and PDGF were significantly decreased (IL 5: 54.2 +/- 13.8 pg/ml at baseline vs. 49.1 +/- 12.5 pg/ml at 32 weeks, P = 0.008; PDGF: 4821 +/- 2458 pg/ml at baseline vs. 4219 +/- 1951 pg/ml at 32 weeks, P = 0.048). CONCLUSIONS: High baseline serum CXCL10 and IL-12 levels may be useful in predicting a good omalizumab response in severe asthmatics. PMID- 29413517 TI - Regulation of Mitochondrial, Cellular, and Organismal Functions by TSPO. AB - In 1999, the enigma of the 18kDa mitochondrial translocator protein (TSPO), also known as the peripheral-type benzodiazepine receptor, was the seeming disparity of the many functions attributed to TSPO, ranging from the potential of TSPO acting as a housekeeping gene at molecular biological levels to adaptations to stress, and even involvement in higher emotional and cognitive functioning, such as anxiety and depression. In the years since then, knowledge regarding the many functions modulated by TSPO has expanded, and understanding has deepened. In addition, new functions could be firmly associated with TSPO, such as regulation of programmed cell death and modulation of gene expression. Interestingly, control by the mitochondrial TSPO over both of these life and death functions appears to include Ca++ homeostasis, generation of reactive oxygen species (ROS), and ATP production. Other mitochondrial functions under TSPO control are considered to be steroidogenesis and tetrapyrrole metabolism. As TSPO effects on gene expression and on programmed cell death can be related to the wide range of functions that can be associated with TSPO, several of these five elements of Ca++, ROS, ATP, steroids, and tetrapyrroles may indeed form the basis of TSPO's capability to operate as a multifunctional housekeeping gene to maintain homeostasis of the cell and of the whole multicellular organism. PMID- 29413518 TI - Unique Effects of Clozapine: A Pharmacological Perspective. AB - Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine alpha-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance. PMID- 29413520 TI - RNA-Based Fluorescent Biosensors for Detecting Metabolites in vitro and in Living Cells. AB - Genetically encoded sensors are important tools for measuring metabolites and other small molecules in vitro and in live cells. Until recently, genetically encoded sensors exclusively comprised fluorescent proteins that undergo changes in Forster resonance energy transfer upon binding a target analyte. However, recently a new class of fluorescent sensor has been developed composed of RNA. These RNA-based sensors rely on Spinach and other RNA mimics of green fluorescent protein. In each case, the RNA-based sensors contain an analyte-binding aptamer domain which transduces binding of the analyte into a conformational change in Spinach. Two types of sensors have been developed: allosteric Spinach sensors and Spinach riboswitches. Allosteric Spinach sensors exhibit metabolite-induced folding and subsequent fluorescence. Spinach riboswitches are naturally occurring riboswitches that have been modified to contain the Spinach aptamer. The resulting RNA is a fluorogenic riboswitch, and produces fluorescence upon binding its cognate analyte. We describe the development of this new technology, its uses, and future directions to facilitate the use of this assay technology in mammalian cells and in high-throughput applications. PMID- 29413521 TI - Phosphorylation of the Amino Terminus of the Dopamine Transporter: Regulatory Mechanisms and Implications for Amphetamine Action. AB - Amphetamines (AMPHs) are potent psychostimulants that are widely used and abused, with profound medical and societal impact. Their actions at dopaminergic neurons are thought to mediate their therapeutic efficacy as well as their liability for abuse and dependence. AMPHs target the dopamine transporter (DAT), the plasmalemmal membrane protein that mediates the inactivation of released dopamine (DA) through its reuptake. AMPHs act as substrates for DAT and are known to cause mobilization of dopamine (DA) to the cell exterior via DAT-mediated reverse transport (efflux). It has become increasingly evident that the mechanisms that regulate AMPH-induced DA efflux are distinct from those that regulate DA uptake. Central to these mechanisms is the phosphorylation of the DAT amino (N)-terminus, which has been repeatedly demonstrated to facilitate DAT-mediated DA efflux, without impacting other aspects of DAT physiology. This review aims to summarize the current status of knowledge regarding DAT N-terminal phosphorylation and its regulation by protein modulators and the membrane microenvironment. A better understanding of these mechanisms may lead to the identification of novel therapeutic approaches that interfere selectively with the pharmacological effects of AMPHs without altering the physiological function of DAT. PMID- 29413519 TI - Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia. AB - Neuroinflammation has long been considered a potential contributor to neurodegenerative disorders that result in dementia. Accumulation of abnormal protein aggregates in Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies is associated with the activation of microglia and astrocytes into proinflammatory states, and chronic low-level activation of glial cells likely contributes to the pathological changes observed in these and other neurodegenerative diseases. The 18kDa translocator protein (TSPO) is a key biomarker for measuring inflammation in the brain via positron emission tomography (PET). Increased TSPO density has been observed in brain tissue from patients with neurodegenerative diseases and colocalizes to activated microglia and reactive astrocytes. Several radioligands have been developed to measure TSPO density in vivo with PET, and these have been used in clinical studies of different dementia syndromes. However, TSPO radioligands have limitations, including low specific-to-nonspecific signal and differential affinity to a polymorphism on the TSPO gene, which must be taken into consideration in designing and interpreting human PET studies. Nonetheless, most PET studies have shown that increased TSPO binding is associated with various dementias, suggesting that TSPO has potential as a biomarker to further explore the role of neuroinflammation in dementia pathogenesis and may prove useful in monitoring disease progression. PMID- 29413522 TI - Receptor Binding Assays and Drug Discovery. AB - Although Solomon Snyder authored hundreds of research reports and several books covering a broad range of topics in the neurosciences, he is best known by many as the person who developed neurotransmitter receptor radioligand binding assays. By demonstrating the utility of this approach for studying transmitter receptors in brain, Dr. Snyder provided the scientific community with a powerful new tool for identifying and characterizing these sites, for defining their relationship to neurological and psychiatric disorders, and their involvement in mediating the actions of psychotherapeutics. Although it was hoped the receptor binding technique could also be used as a primary screen to speed and simplify the identification of novel drug candidates, experience has taught that ligand binding is most useful for drug discovery when it is used in conjunction with functional, phenotypic assays. The incorporation of ligand binding assays into the drug discovery process played a significant role in altering the search for new therapeutics from solely an empirical undertaking to a mechanistic and hypothesis-driven enterprise. This illustrates the impact of Dr. Snyder's work, not only on neuroscience research but on the discovery, development, and characterization of drugs for treating a variety of medical conditions. PMID- 29413523 TI - Anti-NMDA Receptor Encephalitis: Clinical Features and Basic Mechanisms. AB - In slightly more than 10 years, anti-NMDA receptor (NMDAR) encephalitis has changed from a rare paraneoplastic syndrome to the most common cause of nonviral encephalitis. It presents fulminantly with progressive psychosis, seizures, and autonomic dysfunction, leading to death if untreated. However, rapid recognition and treatment can lead to survival and a return to baseline levels of functioning in many patients. While initially associated with ovarian teratomas, it is now associated with other tumors and can reflect a postviral event. The antibodies to the NMDAR made in this syndrome are pathogenic and are directed at the extracellular domain of the GluN1 subunit. Such antibodies lead to internalization of NMDARs in model systems, leading to a physiological state characterized by NMDAR hypofunction. Analogous disorders, characterized by antibodies to other synaptic receptors, present with neurological and psychiatric dysfunction and also appear to reflect antibody-induced internalization of receptors. However, this simple pathophysiology may be too simplistic to reflect the complexity of events in anti-NMDAR encephalitis. Future scientific investigations may allow a more complete understanding of this disorder and improve treatment of anti-NMDAR encephalitis. PMID- 29413524 TI - Mu Opioid Pharmacology: 40 Years to the Promised Land. AB - Opioids continue to play a major role in medicine, but not without problems. Side effects limit their utility medically, while the potential of addiction has had a major societal impact. Pharmacologists have been trying to develop opioids lacking side effects since the first derivative, heroin, was synthesized in the 1870s. The identification of opioid receptors about 40 years ago opened up new insights into our understanding of opioid action, fueled by the molecular biology revolution of the 1980s and 1990s. A major result of these studies was the discovery that the mu opioid receptor gene, Oprm1, undergoes extensive alternative splicing in mice, rats, and humans. This single gene generates three sets of proteins, each containing many variants. The object of this review is to describe these variants and how they can be targeted to generate safer, effective analgesic drugs. Mu opioid receptor multiplicity was first suggested over 35 years ago based upon a series of selective antagonists and detailed binding assays. The identification of the different classes of mu opioid receptor splice variants enabled us to target one of the classes of splice variants to obtain potent analgesics lacking respiratory depression, physical dependence, and reward behavior. They also displayed no cross tolerance to morphine analgesia and had diminished effects on gastrointestinal transit. Forty years after the identification of opioid-binding sites in brain the promised land of safer, nonaddictive analgesics is in sight. PMID- 29413526 TI - The Neurobiology of d-Serine Signaling. AB - d-Serine is a physiological coagonist of NMDA receptors involved in synaptic plasticity, neurodevelopment, and neurodegeneration. d-Serine is synthesized by the enzyme serine racemase, which converts l- to d-serine. Recent studies indicate that the supply of l-serine by astroglia fuels the neuronal synthesis of d-serine. This pathway, named the serine shuttle, highlights the importance of the glia-neuron metabolic crosstalk for regulating NMDA receptor activity. Dysfunction of different components of the serine shuttle pathway leads to neurodevelopmental defects, neurodegeneration, and may be involved in psychiatric diseases. Serine racemase and other components of the serine shuttle are therefore promising targets for neuroprotective drugs. Here we review several aspects of the neurobiology of d-serine focusing on mechanisms regulating d serine signaling in health and disease. PMID- 29413528 TI - Nitric Oxide Signaling in Neurodegeneration and Cell Death. AB - In this tribute to Solomon H. Snyder (Sol) we discuss the mechanisms by which nitric oxide (NO) kills neurons. We provide a historical perspective regarding the discovery that glutamate excitotoxicity is mediated by NO. It also contains a discussion of the discovery that neuronal nitric oxide synthase (nNOS) catalytic activity accounts for NADPH diaphorase activity and its localization in the central nervous system. NADPH diaphorase/nNOS neurons are unique in that they are resistant to toxic effects of excess glutamate and that they are resistant to neurodegeneration in a variety of neurodegenerative diseases. NADPH diaphorase/nNOS neurons are resistant to neurotoxicity and neurodegeneration through the overexpression of manganese superoxide dismutase. The review also delves into the mechanisms by which NO kills neurons including NO's activation of the glyceraldehyde-3-phosphate dehydrogenase-dependent cell pathway. In addition, there is a review of parthanatos in which NO combines with the superoxide anion ( [Formula: see text] ) to form peroxynitrite (ONOO-) that damages DNA and activates poly (ADP-ribose) (PAR) polymerase (PARP). This ultimately leads to activation of the PARP-dependent apoptosis-inducing factor-associated nuclease, the final executioner in NO-dependent cell death. Finally, there is a discussion of potential targets that are under development that target the mechanisms by which NO kills neurons. PMID- 29413525 TI - Synaptotoxic Signaling by Amyloid Beta Oligomers in Alzheimer's Disease Through Prion Protein and mGluR5. AB - Alzheimer's disease (AD) represents an impending global health crisis, yet the complexity of AD pathophysiology has so far precluded the development of any interventions to successfully slow or halt AD progression. It is clear that accumulation of Amyloid-beta (Abeta) peptide triggers progressive synapse loss to cause AD symptoms. Once initiated by Abeta, disease progression is complicated and accelerated by inflammation and by tau pathology. The recognition that Abeta peptide assumes multiple distinct states and that soluble oligomeric species (Abetao) are critical for synaptic damage is central to molecular understanding of AD. This knowledge has led to the identification of specific Abetao receptors, such as cellular prion protein (PrPC), mediating synaptic toxicity and neuronal dysfunction. The identification of PrPC as an Abetao receptor has illuminated an Abetao-induced signaling cascade involving mGluR5, Fyn, and Pyk2 that links Abeta and tau pathologies. This pathway provides novel potential therapeutic targets for disease-modifying AD therapy. Here, we discuss the methods by which several putative Abetao receptors were identified. We also offer an in-depth examination of the known molecular mechanisms believed to mediate Abetao-induced synaptic dysfunction, toxicity, and memory dysfunction. PMID- 29413529 TI - Carboxypeptidase E and the Identification of Novel Neuropeptides as Potential Therapeutic Targets. AB - Peptides and small molecules that bind to peptide receptors are important classes of drugs that are used for a wide variety of different applications. The search for novel neuropeptides traditionally involved a time-consuming approach to purify each peptide to homogeneity and determine its amino acid sequence. The discovery in the 1980s of enkephalin convertase/carboxypeptidase E (CPE), and the observation that this enzyme was involved in the production of nearly every known neuropeptide led to the idea for a one-step affinity purification of CPE substrates. This approach was successfully used to isolate hundreds of known neuropeptides in mouse brain, as well as over a dozen novel peptides. Some of the novel peptides found using this approach are among the most abundant peptides present in brain, but had not been previously identified by traditional approaches. Recently, receptors for two of the novel peptides have been identified, confirming their role as neuropeptides that function in cell-cell signaling. Small molecules that bind to one of these receptors have been developed and found to significantly reduce food intake and anxiety-like behavior in an animal model. This review describes the entire project, from discovery of CPE to the novel peptides and their receptors. PMID- 29413527 TI - The Role of Serine Racemase in the Pathophysiology of Brain Disorders. AB - The N-methyl-d-aspartate receptor (NMDAR) is unique in requiring two agonists to bind simultaneously to open its cation channel: the neurotransmitter, glutamate, and the coagonists, glycine, or d-serine. The Snyder laboratory was the first to clone serine racemase (SR), the enzyme that synthesizes d-serine, and to localize it immunocytochemically. Our laboratory has focused on the role of d-serine in brain disorders. Silencing the expression of SR, a risk gene for schizophrenia (SCZ), in mice (SR-/-), results in a phenotype that closely resembles SCZ including: cortical atrophy, reduced dendritic spine density and complexity, downregulation of parvalbumin-positive cortical GABAergic neurons, and cognitive impairments. This pathology can be reversed by treatment of SR-/- mice with d serine in adulthood. SR-/- mice also exhibit abnormal response toward abusable substances, such as stimulants. They show reduced behavioral sensitization to d amphetamine, but fail to extinguish it. Place preference to cocaine is altered, and the hedonic response to it is profoundly impaired as assessed by intracranial self-stimulation. d-cycloserine, a partial agonist at the NMDAR glycine modulatory site, shows therapeutic benefit for treating pathologic anxiety in combination with behavioral therapies. Studies in vitro with cortical culture and in vivo with middle cerebral artery occlusion show that silencing SR provides substantial protection against ischemic neuronal death. Finally, the switch of SR expression from neurons to reactive astrocytes after closed head trauma accounts for the reduced in vivo neuroplasticity, electroencephalogram abnormalities, and cognitive impairments. PMID- 29413530 TI - Preface. PMID- 29413531 TI - Foreword. PMID- 29413532 TI - Adolescent pruning and stabilization of dendritic spines on cortical layer 5 pyramidal neurons do not depend on gonadal hormones. AB - Pyramidal neurons in the neocortex receive a majority of their synapses on dendritic spines, whose growth, gain, and loss regulate the strength and identity of neural connections. Juvenile brains typically show higher spine density and turnover compared to adult brains, potentially enabling greater capacity for experience-dependent circuit 'rewiring'. Although spine pruning and stabilization in frontal cortex overlap with pubertal milestones, it is unclear if gonadal hormones drive these processes. To address this question, we used hormone manipulations and in vivo 2-photon microscopy to test for a causal relationship between pubertal hormones and spine pruning and stabilization in layer 5 neurons in the frontal cortex of female mice. We found that spine density, gains, and losses decreased from P27 to P60 and that these measures were not affected by pre pubertal hormone injections or ovariectomy. Further analyses of spine morphology after manipulation of gonadal hormones suggest that gonadal hormones may play a role in morphological maturation and dynamics. Our data help to segregate hormone sensitive and hormone-insensitive maturational processes that occur simultaneously in dorsomedial frontal cortex. These data provide more specific insight into adolescent development and may have implications for understanding the neurodevelopmental effects of changes in pubertal timing in humans. PMID- 29413533 TI - Anatomy of the dorsal default-mode network in conduct disorder: Association with callous-unemotional traits. AB - We recently reported that emotional detachment in adult psychopathy was associated with structural abnormalities in the dorsal 'default-mode' network (DMN). However, it is unclear whether these differences are present in young people at risk of psychopathy. The most widely recognised group at risk for psychopathy are children/adolescents with conduct disorder (CD) and callous unemotional (CU) traits. We therefore examined the microstructure of the dorsal DMN in 27 CD youths (14-with/13-without CU traits) compared to 16 typically developing controls using DTI tractography. Both CD groups had significantly (p < 0.025) reduced dorsal DMN radial diffusivity compared to controls. In those with diagnostically significant CU traits, exploratory analyses (uncorrected for multiple comparisons) suggested that radial diffusivity was negatively correlated with CU severity (Left: rho = -0.68, p = 0.015). These results suggest that CD youths have microstructural abnormalities in the same network as adults with psychopathy. Further, the association with childhood/adolescent measures of emotional detachment (CU traits) resembles the relationship between emotional detachment and network microstructure in adult psychopaths. However, these changes appear to occur in opposite directions - with increased myelination in adolescent CD but reduced integrity in adult psychopathy. Collectively, these findings suggest that developmental abnormalities in dorsal DMN may play a role in the emergence of psychopathy. PMID- 29413534 TI - Income change alters default mode network connectivity for adolescents in poverty. AB - Experiencing poverty during childhood and adolescence may affect brain function. However, income is dynamic, and studies have not addressed whether income change relates to brain function. In the present study, we investigated whether intrinsic functional connectivity of default mode network (DMN) regions was influenced by mean family income and family income change. Parents of 68 Mexican origin adolescents (35 females) reported family income annually when adolescents were 10-16 years old. Intercept and slope of income at each of these ages were calculated for each participant. At age 16 years, adolescents completed a resting state functional neuroimaging scan. Adolescents from high and low income families did not differ in their functional connectivity, but for adolescents in families with lower incomes, their connectivity patterns depended on their income slope. Low-income adolescents whose income increased demonstrated greater connectivity between the posterior cingulate cortex (PCC) and the medial prefrontal cortex (mPFC), both DMN regions, and between the PCC and the right inferior frontal gyrus. Increases in income were associated with greater connectivity of the mPFC with the right inferior frontal gyrus and the left superior parietal lobule regardless of mean income. Increases in income, especially among adolescents in poverty, may alleviate stressors, influencing the development of brain networks. PMID- 29413571 TI - Online extraction-high performance liquid chromatography-diode array detector quadrupole time-of-flight tandem mass spectrometry for rapid flavonoid profiling of Fructus aurantii immaturus. AB - Chemical profiling of natural products by high performance liquid chromatography (HPLC) was critical for understanding of their clinical bioactivities, and sample pretreatment steps have been considered as a bottleneck for analysis. Currently, concerted efforts have been made to develop sample pretreatment methods with high efficiency, low solvent and time consumptions. Here, a simple and efficient online extraction (OLE) strategy coupled with HPLC-diode array detector quadrupole time-of-flight tandem mass spectrometry (HPLC-DAD-QTOF-MS/MS) was developed for rapid chemical profiling. For OLE strategy, guard column inserted with ground sample (2 mg) instead of sample loop was connected with manual injection valve, in which components were directly extracted and transferred to HPLC-DAD-QTOF-MS/MS system only by mobile phase without any extra time, solvent, instrument and operation. By comparison with offline heat-reflux extraction for Fructus aurantii immaturus (Zhishi), OLE strategy presented higher extraction efficiency perhaps because of the high pressure and gradient elution mode. A total of eighteen flavonoids were detected according to their retention times, UV spectra, exact mass, and fragmentation ions in MS/MS spectra, and compound 9, natsudaidain-3-O-glucoside, was discovered in Zhishi for the first time. It is concluded that the developed OLE-HPLC-DAD-QTOF-MS/MS system offers new perspectives for rapid chemical profiling of natural products. PMID- 29413572 TI - Comparative pharmacokinetics of triterpenic acids in normal and immunosuppressed rats after oral administration of Jujubae Fructus extract by UPLC-MS/MS. AB - The fruit of Ziziphus jujuba (Jujubae Fructus) has been used as food and crude drug for thousands of years. Although several chemical and biological studies have revealed triterpenic acid as the main bioactive constituent of Jujubae Fructus responsible for immune-regulatory activity, only few pharmacokinetic studies have been conducted. To comprehend the kinetics of triterpenic acids and promote their curative application, a sensitive and efficient ultra-performance liquid chromatography coupled with mass spectrometry method (UPLC-MS/MS) was established. UPLC-MS/MS was applied for the simultaneous determination of ceanothic acid, epiceanothic acid, pomonic acid, alphitolic acid, maslinic acid, betulinic acid, and betulonic acid in normal and immunosuppressed rat plasma samples. After sample preparation, chromatographic separation was performed on an Acquity UPLC BEH C18 column (2.1 * 100 mm, 1.7 MUm) with acetonitrile: methanol (1:1, v/v) and 0.5% ammonium acetate in water as mobile phase. The established method was validated and found to be specific, accurate, and precise for the seven triterpenic acids, and was successfully applied for the pharmacokinetic study of rat plasma samples. The results showed that the pharmacokinetic parameters (Cmax, Tmax, AUC0-t, AUC0-infinity, and CLz/F) in the plasma samples of immunosuppressed rats were significantly different from those in normal rats, and might provide an insight for the clinical usage of triterpenic acids from Jujubae Fructus. PMID- 29413573 TI - Multiple fingerprinting analyses in quality control of Cassiae Semen polysaccharides. AB - Quality control issue overshadows potential health benefits of Cassiae Semen due to the analytic limitations. In this study, multiple-fingerprint analysis integrated with several chemometrics was performed to assess the polysaccharide quality of Cassiae Semen harvested from different locations. FT-IR, HPLC, and GC fingerprints of polysaccharide extracts from the authentic source were established as standard profiles, applying to assess the quality of foreign sources. Analyses of FT-IR fingerprints of polysaccharide extracts using either Pearson correlation analysis or principal component analysis (PCA), or HPLC fingerprints of partially hydrolyzed polysaccharides with PCA, distinguished the foreign sources from the authentic source. However, HPLC or GC fingerprints of completely hydrolyzed polysaccharides couldn't identify all foreign sources and the methodology using GC is quite limited in determining the monosaccharide composition. This indicates that FT-IR/HPLC fingerprints of non/partially hydrolyzed polysaccharides, respectively, accompanied by multiple chemometrics methods, might be potentially applied in detecting and differentiating sources of Cassiae Semen. PMID- 29413574 TI - Quantitative GC-MS assay of citric acid from humans and db/db mice blood serum to assist the diagnosis of diabetic nephropathy. AB - The early diagnosis of diabetic nephropathy (DN) is rather challenging. Our previous study suggested that citric acid is a potential marker for the early diagnosis of diabetic nephropathy in db/db mice. For the first time, in this study, a surrogate analyte of 13C6-citric acid was employed to generate calibration curves for the quantitative measurement of the endogenous citric acid in the sera of db/db mice and diabetic nephropathy patients by GC/MS after the analytes were extracted, methoximated and trimethylsilylated. The constant response factor of 13C6-citric acid versus citric acid over the linear range indicated the identical ionization efficiency of these two compounds. The full validation assessments suggested that the method is sensitive, specific, reliable, reproducible and has acceptable parameters. Statistical analysis revealed cut-off citric acid concentrations of 29.24 MUg/mL with a 95% confidence interval between 32.75 and 39.16 MUg/mL in the diabetic nephropathy patients and 16.74 and 22.57 MUg/mL in the normal controls. The areas under the receiver operating characteristic curves indicated accuracies of over 90% for the diagnoses of early diabetic nephropathy in both humans and db/db mice, which suggests that the serum citric acid level is potentially a biomarker that could assist in the diagnosis of diabetic nephropathy. PMID- 29413575 TI - Analysis of phosphatidylethanolamine, phosphatidylcholine, and plasmalogen molecular species in food lipids using an improved 2D high-performance liquid chromatography system. AB - Phospholipids are an important class of lipids in cell membranes and food. Several high-performance liquid chromatography (HPLC) methods have been developed to analyze phospholipids at the molecular species level. We developed a two dimensional HPLC system with a charged aerosol detector and mass spectrometry (MS) to analyze phosphatidylethanolamine (PE), phosphatidylcholine (PC), and their plasmalogens (pls) extracted from food materials. Accordingly, the phospholipid molecular species can be analyzed in a single step despite using smaller samples. We confirmed that chromatogram peaks from soybean lecithin are mostly baseline separated, assigned, and quantified (24 molecular species for PE and 27 for PC). In addition, it was confirmed that chromatograms of lipids extracted from chicken breast meat include plasmalogen peaks. The PE fraction in lipids extracted from chicken breast meat contained 17 types of ethanolamine plasmalogens, corresponding to approximately 57% of the total by weight. The PC fraction contained only four choline plasmalogens, corresponding to approximately 11% of the total weight. The composition of the pls-PC molecular species differed from that of pls-PEs. The polyunsaturated fatty acids connected at the sn-2 positions of the pls-PEs consisted of 20.5% 20:4 fatty acid and were independent of the carbon chain at the sn-1 position. However, the 18:1 fatty acid at the sn 2 position was dependent on the carbon chain at the sn-1 position. PMID- 29413576 TI - Determination of the low-abundant protein biomarker hCG from dried matrix spots using immunocapture and nano liquid chromatography mass spectrometry. AB - Using LC-MS/MS for determination of low-abundance protein biomarkers from dried blood spots is challenging due to the combination of low biomarker levels (low pM level) and small sample volumes (typically <50 MUL). In the present paper it is demonstrated that use of state-of-the-art nano liquid chromatography triple quadrupole mass spectrometry in combination with immunoaffinity sample clean-up enable determination of the low abundance biomarker human chorionic gonadotropin (hCG) from four different biological matrices (whole blood, serum, plasma and urine) at its upper reference level (low pM). Detection limits for hCG was determined for all matrices from both commercially available non-soluble DBS sampling material (DMPK-C) and the water-soluble material carboxymethyl cellulose (CMC). The detection limits (S/N = 3) were ranging from 5.0 IU/L (14.5 pM; whole blood) to 10.5 IU/L (30.5 pM; urine) for DMPK-C and from 2.1 IU/L (6.1 pM; urine) to 6.4 IU/L (18.6 pM; plasma) for CMC. A brief evaluation was performed for both sampling materials using serum as matrix resulting in sufficient linearity (r2 >= 0.93, range 20-1000 IU/mL (58-2900 pM) for DMPK-C and 10-1000 IU/mL (29-2900 pM) for CMC), repeatability (RSD% = 13-31%) and accuracy (95-106%). To demonstrate the applicability of the method to real samples, a serum sample from a patient previously diagnosed with cancer was also analyzed using both sampling materials. The concentration levels found using the two materials were similar (5280+/- 595 IU/L (15,312 +/- 1726 pM, n = 3) in the DMPK-C spot and 5060 +/- 430 IU/L (14,674 +/- 1247 pM, n = 3) in the CMC spot). All in all this demonstrated that the tools for determination of low abundance biomarkers at upper reference level from dried matrix spots now is available through a combination of immunoaffinity enrichment and state-of-the-art LC-MS/MS. PMID- 29413577 TI - Super paramagnetic core-shells anchored onto silica grafted with C8/NH2 nano particles for ultrasound-assisted magnetic solid phase extraction of imipramine and desipramine from plasma. AB - In current work the Fe3O4 magnetic nano-particles anchored to core-shells of SiO2 which grafted by C8/NH2 dual mixed groups, have been synthesized. The magnetic nano-particles were characterized by scanning electron microscopy, X-ray diffraction spectroscopy, and zeta-potential reader. The resulted nano-particles have spherical structure with diameters in the range of 105 to 110 nm. A magnetic solid phase extraction method was developed for extraction of imipramine and desipramine from human plasma samples under ultrasonic conditions by using of prepared NPs as sorbent. The MNPs were dispersion in plasma under sonicated conditions, accumulated by an external magnetic field and washed with Briton Robinson buffer-acetonitrile solution (0.05 mol l-1, pH = 5, 10%V/V). The drugs were removed by methanol and quantified by gas chromatography. The calibration curves (correlation coefficient > 0.99) for IMP and DES were linear in the concentration range of 0.005 to 5 and 0.01 to 4 MUg ml-1, respectively. The LOD, LOQ, intra and inter-day precision values were measured too. The proposed Fe3O4/SiO2/C8/NH2 MNPs could be applied for 3.0 times. PMID- 29413578 TI - Determination of pyrethrin and pyrethroid residues in animal fat using liquid chromatography coupled to tandem mass spectrometry. AB - A method was developed for the confirmatory and quantitative analysis of one pyrethrin and 18 pyrethroid residues in animal fat. Fat was extracted was collected from adipose tissue melted in an oven at 65 degrees C for 2 h. Fat samples (1 g) were dispersed with deactivated Florisil(r) sorbent and extracted with MeCN. Sample extracts were purified by cold temperature precipitation at -30 degrees C for 4 h and further purified using dispersive solid-phase extraction (d-SPE) clean-up in tubes containing 500 mg of Z-SEP+ and 125 mg of PSA bonded silica. Purified samples were analysed by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) detection. Chromatographic separation was carried out on a Acquity C8 BEH column, using a binary gradient separation comprising of mobile phase A, 5 mM ammonium formate in water:MeOH (80:20, v/v,) and mobile phase B, 5 mM ammonium formate in MeOH. The mass spectrometer was operated in the positive electrospray ionisation mode (ESI(+)). Validation was performed following the 2002/657/EC guidelines. Trueness ranged between 84% and 143% and precision ranged between 3.9% and 29%. The developed method is particularly advantageous because the sample preparation procedure does not require complex sample extraction equipment and uses less solvent compared to other sample preparation protocols. PMID- 29413579 TI - Enantiomeric separation and quantification of R/S-amphetamine in urine by ultra high performance supercritical fluid chromatography tandem mass spectrometry. AB - To distinguish between legal and illegal consumption of amphetamine reliable analytical methods for chiral separation of the R- and S-enantiomers of amphetamine in biological specimens are required. In this regard, supercritical fluid chromatography (SFC) has several potential advantages over liquid chromatography, including rapid separation of enantiomers due to low viscosity and high diffusivity of supercritical carbon dioxide, the main component in the SFC mobile phase. A method for enantiomeric separation and quantification of R- and S-amphetamine in urine was developed and validated using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC MS/MS). Sample preparation prior to UHPSFC-MS/MS analysis was a semi-automatic solid phase extraction method. The UHPSFC-MS/MS method used a Chiralpak AD-3 column with a mobile phase consisting of CO2 and 0.2% cyclohexylamine in 2 propanol. The injection volume was 2 MUL and run-time was 6 min. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions (m/z 136.1 > 119.0 and m/z 136.1 > 91.0). The calibration range was 50-10,000 ng/mL for each enantiomer. The between-assay relative standard deviations were in the range of 3.7-7.6%. Recovery was 92-93% and matrix effects ranged from 100 to 104% corrected with internal standard. After development and validation, the method has been successfully implemented in routine use at our laboratory for both separation and quantification of R/S amphetamine, and has proved to be a reliable and useful tool for distinguishing intake of R- and S-amphetamine in authentic patient samples. PMID- 29413580 TI - Serum metabolite profiling of cutaneous T-cell lymphoma based on a multiplatform approach. AB - Cutaneous T-cell lymphoma (CTCL) is a class of non-Hodgkin lymphoma with a difficult early diagnosis. The overall annual age-adjusted incidence of CTCL had consistently increased to around 10.2 cases per million persons. However, our knowledge regarding its mechanism of disease origin and progression remains unclear. In this study, serum samples from 31 CTCL patients and 31 matched healthy volunteers were analyzed in depth to screen metabolites capable of differentiating CTCL from controls. To obtain a higher coverage of metabolome with various hydrophilicity, a multiplatform approach with GC-MS and UHPLC-QTOF MS has been employed. Data were analyzed by multivariate statistical analysis and CTCL group was separated from control group successfully using supervised OPLS-DA model. A total of 51 CTCL-regulated metabolites were identified, among which 15 differential metabolites have an AUC > 0.9 in receiver operating characteristic (ROC) curve analysis. Glycerophospholipid metabolism, tryptophan metabolism and purine metabolism were highlighted as 3 major altered pathways in CTCL serum. These alterations revealed impacts to membrane stability and weakened immune as well as ATP depletion associated with CTCL. Overall, these results aid in improving understanding of the mechanism related to CTCL, and demonstrate this multiplatform approach is suitable for serum metabolomics researches. PMID- 29413581 TI - Analytical studies on the 2-naphthoyl substituted-1-n-pentylindoles: Regioisomeric synthetic cannabinoids. AB - The six 1-n-pentyl-2-, 3-, 4-, 5-, 6- and 7-(2-naphthoyl)-indoles each have the same substituents attached to the indole ring, identical elemental composition (C24H23NO) yielding identical nominal and accurate masses. The electron ionization mass spectra of the 2-naphthoyl substituted isomers share equivalent major fragment ions resulting from cleavage of the groups attached to the central indole nucleus with some differences in relative abundances. These six regioisomers were successfully resolved on an Rtx-5 and Rxi-17Sil MS stationary phases and the molecules having both substituent groups on the same side of the indole ring (1,2- and 1,7-substituents) show the least retention. The more linear molecules have higher relative retention properties. A comparison of the GC properties of the 1-naphthoyl- and 2-naphthoyl groups attached at identical positions of the indole ring showed higher GC retention for the 2-naphthoyl substituted isomer in all cases evaluated. The amide inverse isomers (1-naphthoyl 3-n-pentylindoles) were separated from the 1-n-pentyl-3-naphthoyl-indoles on an Rtx-200 stationary phase. The two inverse amide isomers having the 1- and 2 naphthoyl groups substituted at the 1-position of the indole ring elute before either of the N-alkyl-indole isomers having the 1- and 2-naphthoyl groups substituted at the 3-position of the indole ring. The amide inverse isomers yield EI mass spectra easily distinguishing these amides from the ketone isomers having the naphthoyl groups at the indole 3-position. PMID- 29413582 TI - Determination of human insulin in dog plasma by a selective liquid chromatography tandem mass spectrometry method: Application to a pharmacokinetic study. AB - A simple, sensitive and selective LC-MS/MS method for quantitative analysis of human insulin was developed and validated in dog plasma. Insulin glargine was used as the internal standard. After a simple step of solid-phase extraction, the chromatographic separation of human insulin was achieved by using InertSustain Bio C18 column with a mobile phase of acetonitrile containing 1% formic acid (A) water containing 1% formic acid (B). The detection was performed by positive ion electrospray ionization in multiple-reaction monitoring (MRM) mode. Good linearity was observed in the concentration range of 1-1000 MUIU/mL (r2 > 0.99), and the lower limit of quantification was 1 MUIU/mL (equal to 38.46 pg/mL). The intra- and inter-day precision (expressed as relative standard deviation, RSD) of human insulin were <=12.1% and <=13.0%, respectively, and the accuracy (expressed as relative error, RE) was in the range of -7.23-11.9%. The recovery and matrix effect were both within acceptable limits. This method was successfully applied for the pharmacokinetic study of human insulin in dogs after subcutaneous administration. PMID- 29413584 TI - Decision-making, financial risk aversion, and behavioral biases: The role of testosterone and stress. AB - We examine the relation between testosterone, cortisol, and financial decisions in a sample of naive investors. We find that testosterone level is positively related to excess risk-taking, whereas cortisol level is negatively related to excess risk-taking (correlation coefficient [r]: 0.75 and -0.21, respectively). Additionally, we find support for the dual-hormone hypothesis in a financial context. Specifically, the testosterone-to-cortisol ratio is significantly related to loss aversion. Individuals with a higher ratio are 3.4 times more likely to sell losing stocks (standard error [SE]: 1.63). Furthermore, we find a positive feedback loop between financial success, testosterone, and cortisol. Specifically, financial success is significantly related to higher post-trial testosterone and cortisol by a factor of 0.53 (SE: 0.14). Finally, we find that in a competitive environment, testosterone level increases significantly, leading to greater risk-taking than in noncompetitive environment. Overall, this study underscores the importance of the endocrine system on financial decision-making. The results of this study are relevant to a broad audience, including investors looking to optimize financial performance, industry human resources, market regulators, and researchers. PMID- 29413583 TI - Metal-organic framework UiO-66 for rapid dispersive solid phase extraction of neonicotinoid insecticides in water samples. AB - UIO-66 crystals were explored for the first time to adsorb neonicotinoid insecticides in environmental water samples. HPLC coupled with tandem MS was used for quantification and determination of neonicotinoid insecticides. UiO-66 crystals was successfully synthesized by a simple constant-temperature bath method. Synthesized UiO-66 was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetry and nitrogen adsorption porosimetry (NAP), which demonstrated a uniform particle size, a large Brunauer-Emmett-Teller (BET) surface area and high thermostability. The adsorbing results showed that UIO-66 crystals could be used as a promising adsorbents for rapid extraction of neonicotinoid insecticides and be reused at least 10 times. Under the optimized conditions, the limits of detection (LODs, S/N = 3) and limits of quantification (LOQs, S/N = 10) for the five insecticides were found to be 0.02-0.4 ng/mL and 0.05-1.0 ng/mL, respectively. This developed approach not only provided more simple and sensitive method, as well as possessing satisfactory recovery for neonicotinoid insecticides, but also for other traces in environmental samples. PMID- 29413585 TI - Health and health inequality during the great recession: Evidence from the PSID. AB - We estimate the impact of the Great Recession of 2007-2009 on health outcomes in the United States. We show that a one percentage point increase in the unemployment rate resulted in a 7.8-8.8% increase in reports of poor health. In addition, mental health was adversely impacted. These effects were concentrated among those with strong labor force attachments. Whites, the less educated, and women were the most impacted demographic groups. PMID- 29413586 TI - Smoking and early retirement due to chronic disability. AB - This paper considers the long-term effects of smoking on disability retirement in Sweden. Smoking is known to have damaging effects on health, but there is limited evidence on how the effects of smoking translate into worse labour market outcomes, such as the inability to work. In contrast to the few previous studies on smoking and disability retirement, we use a large population sample with registry information on smoking, which is recorded for all women who give birth in Sweden. Thanks to these comprehensive data, we are able to account for a much broader range of potential confounders. In particular, by the use of sibling and twin fixed effects, we account for unobserved heterogeneity in childhood environment and family characteristics. Given that smoking is often initiated in adolescence, one would suspect such factors to play important roles. Among individuals aged 50-64 in 2011, a simple model suggested smokers to have a 5 percentage point higher probability of receiving (full) disability pension, making them more than twice as likely as non-smokers to receive this. However, in a model with sibling fixed effects, the size of the effect was reduced by more than a third. The results point to the importance of confounders, such as childhood circumstances or behaviours, which were not accounted for by previous studies. We also consider effects on disability due to different health conditions. In relative terms, effects are the largest for circulatory conditions and tumours. Results are largely driven by health problems severe enough to merit hospitalization, and there is no evidence of a role played by financial incentives. PMID- 29413587 TI - Targeting the leptin receptor: To evaluate therapeutic efficacy and anti-tumor effects of Doxil, in vitro and in vivo in mice bearing C26 colon carcinoma tumor. AB - Leptin is an appetite regulatory hormone that is secreted into the blood circulation by the adipose tissue and it functions via its over expressed receptors (Ob-R) in a wide variety of cancers. In the present study, the function of a leptin-derived peptide (LP16, 91-110 of Leptin) was investigated as a targeting ligand to decorate PEGylated liposomal doxorubicin (PLD, Doxil(r)) surface and the anti-tumor activity and therapeutic efficacy of Doxil in C26 (Colon Carcinoma) tumor model were also evaluated. As a result of this, Doxil with different LP16 peptide density (25, 50, 100 and 200 peptide on the surface of each liposome) was successfully prepared and characterized. In vitro results showed significant enhanced cytotoxicity and cellular binding and uptake of LP16 targeted Doxil formulations (LP16-Doxil) in C26 cells as compared to Doxil. In BALB/c mice bearing C26 murine carcinoma, at a dose of 15 mg/kg, LP16-Doxil groups (100 ligand) significantly suppressed the growth of the tumor and showed higher inclination to tumor as compared to non-targeted Doxil. This study revealed that the potential of LP16 peptide targeting increased the therapeutic efficacy of Doxil and highlighted the importance of optimizing the ligand density to maximize the targeting ability of the nanocarriers and merits further investigations. PMID- 29413588 TI - Investigating the structural integrity of Bovine serum albumin in presence of newly synthesized metallosurfactants. AB - Bovine Serum Albumin is major transport protein and is often used as a drug carrier in body organs. Knowledge of its binding with metallosurfactant can significantly influence the biodistribution of metallodrugs. Current work demonstrated a facile method to prepare four different double chained metallosurfactants containing Fe, Co, Ni and Cu as part of their counter ion. The as-synthesized metallosurfactants were characterized using FTIR, AAS, TGA and XRD in solid form. The aggregation of these metallosurfactants in aqueous medium was investigated through conductivity, surface tension and SAXS. Further, we have investigated their binding with BSA through different analytical methods The effect of concentration of metallosurfactants on the primary and secondary structure of BSA was further examined by SDS-PAGE and Circular dichroism, respetively. It is found that at premicellar concentration, the primary structure of BSA was not affected but the secondary structure i.e. alpha-helical structure of BSA was altered as shown by circular dichroism. Interestingly, post micellar concentration of metallosurfactants shows the pronounced effect on the primary and secondary structure of BSA. SAXS study also supports the fact of unfolding of protein and its wrapping around the micelles. Zeta potential describes the electrical charge and stability of the protein in the presence of different concentration of metallosurfactant. Along with, it was found that presence of protein delays the aggregation behavior of metallosurfactant, as a sign of binding of BSA with metallosurfactant. PMID- 29413589 TI - Chitosan nanoencapsulation of flavonoids enhances their quorum sensing and biofilm formation inhibitory activities against an E.coli Top 10 biosensor. AB - Phytochemicals have been found to be promising alternatives to conventional antibiotic therapies for the control of bacterial infections, as they may entail less selective pressure and hence reduce the development of resistance. This study involved examining the inhibition of biofilm formation and of quorum sensing (QS), and the cytotoxicity on mammalian cells of two flavonoids, quercetin and baicalein, in free form and associated into chitosan-based nanocapsules. This was done by use of a transformed E. coli Top 10 biosensor strain, while the cytotoxicity was evaluated on MDCK-C7 cells. In free form, application both flavonoids exhibited slight inhibitory activity on the QS response and biofilm formation, a scenario that was improved positively upon encapsulation with chitosan (Mw ~115,000 g/mol and DA ~42%). The association efficiency of 99% (quercetin) and 87% (baicalein) was determined, and each formulation had an average diameter of 190 +/- 4 and 187 +/- 2 nm, and zeta (zeta) potential of +48.1 +/- 2.03 and +48.4 +/- 3.46 mV, respectively. Both types of systems were stable against aggregation in M9 and MEM media. The in vitro release kinetics data of both flavonoids seemed to be similar with only ~20% released over the first 5 h, or ~10% over the first 4 h, respectively, with subsequent sudden release increase up to ~40% in both cases. The free phytochemicals seemed to be cytotoxic to MDCK-C7 cells at higher doses, however, upon nanoencapsulation, a cytoprotective effect was evidenced. We have gained proof-of-principle of the advantages of encapsulation of two bioactive flavonoids. PMID- 29413590 TI - Does C60 fullerene act as a transporter of small aromatic molecules? AB - C60 fullerene is reported to directly interact with biomolecules, such as aromatic mutagens or anticancer drugs. Therefore, it is extensively studied for its potential application in the fields of drug delivery and chemoprevention. Understanding the nature of fullerene-drugs interactions might contribute to optimization and modification of the existing chemotherapy systems. Possible interactions between ICR-191, a model acridine mutagen, with well-established biophysical properties and mutagenic activity, and C60 fullerene aqueous solution were investigated by broad range of biophysical methods, such as Dynamic Light Scattering, Isothermal Titration Calorimetry, and Atomic Force Microscopy. Additionally, to determine biological activity of ICR-191-C60 fullerene mixtures, Ames mutagenicity test was employed. It was demonstrated that C60 fullerene interacts non-covalently with ICR-191 and has strong affinity to bacterial membranes. The obtained results provide practical insight into C60 fullerene interactions with aromatic compounds. PMID- 29413591 TI - Self-sterilizing ormosils surfaces based on photo-synzthesized silver nanoparticles. AB - Medical device-related infections represent a major healthcare complication, resulting in potential risks for the patient. Antimicrobial materials comprise an attractive strategy against bacterial colonization and biofilm proliferation. However, in most cases these materials are only bacteriostatic or bactericidal, and consequently they must be used in combination with other antimicrobials in order to reach the eradication condition (no viable microorganisms). In this study, a straightforward and robust antibacterial coating based on Phosphotungstate Ormosil doped with core-shell (SiO2@TiO2) was developed using sol-gel process, chemical tempering, and Ag nanoparticle photoassisted synthesis (POrs-CS-Ag). The coating was characterized by X-ray Fluorescence Spectroscopy (XRF), Field Emission Scanning Electron Microscopy (FE-SEM), Atomic Force Microscopy (AFM) and X-ray Photoelectron Microscopy (XPS). The silver free coating displays low antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa, in opposition to the silver loaded ones, which are able to completely eradicate these strains. Moreover, the antimicrobial activity of these substrates remains high until three reutilization cycles, which make them a promising strategy to develop self-sterilizing materials, such as POrs-CS-Ag impregnated fabric, POrs-CS-Ag coated indwelling metals and polymers, among other materials. PMID- 29413592 TI - Affinity induced immobilization of adenylate cyclase from the crude cell lysate for ATP conversion. AB - The development of an orientation immobilization technique via affinity between polyhistidine tags and metal ions aims at maintaining biocatalytic activity of the enzymes. In this work, to tackle the issue of the immobilization of adenylate cyclase (AC), a simple and effective approach of synthesizing iminodiacetic acid (IDA)-Ni2+ particles was applied for simultaneously purifying and immobilizing his-tagged AC. We chose agarose particles as carriers, and then decorated them with IDA, leading to the formation of a coordination combination of Ni2+. The porous carriers with a large pore size of 50 nm and a specific surface area of 45.8 m2/g exhibited favorable enzymatic activity and loading capacity. The optimal pH of the immobilized enzyme increased from 8.0 to 9.0 and the optimal temperature increased from 30 degrees C to 35 degrees C, compared to the free AC. Moreover, the immobilized AC retained a residual activity of approximately 80% after storing it at 25 degrees C for 48 h, whereas only 40% of the activity was left in the free AC at the same conditions. Maximum yield of cyclic adenosine 3', 5'- monophosphate (cAMP) reached up to the summit of the reaction. The immobilized AC by affinity adsorption will provide a promising route for the industrial production of cAMP. PMID- 29413594 TI - Innovative topical formulations from diclofenac sodium used as surfadrug: The birth of Diclosomes. AB - HYPOTHESIS: Due to the well-know surfactant-like properties of diclofenac sodium (DS), vesicular systems consisting exclusively of DS, named diclosomes, were designed with the aim to minimize or avoid the use of other excipients and to improve the formulation biocompatibility. EXPERIMENTS: Diclosomes were designed and characterized in terms of dimensions, polydispersity index, xi-potential, drug retained, stability as a function of storage time and ex-vivo percutaneous permeation profiles. Additionally, diclosomes were incorporated into gel dosage forms and their performance in terms of permeation enhancement were evaluated. FINDINGS: DS was found to form nanosized vesicular systems, both alone and in presence of cholesterol. Increasing hydrophobicity (due to the presence of cholesterol) resulted in smaller vesicles, always spherical and homogeneous in shape. Permeation of DS from free solution was found to be lower respect to ones obtained for all diclosomal formulations, allowing these aggregates to be considered as percutaneous permeation enhancers. DS permeated from diclosomal gels was higher than that obtained with traditional niosomal gel, DS plain gel and commercial specialty Voltaren Emulgel(r) 1%, while containing a considerably lower drug amount. PMID- 29413593 TI - Therapeutic strategies for flexor tendon healing by nanoparticle-mediated co delivery of bFGF and VEGFA genes. AB - Tendon injuries are a common injury of musculocutaneous system. Due to the lack of sufficient cellularity and low growth factor activity, healing of disrupted digital flexor tendon is troublesome and the process is lengthy and ineffective. bFGF and VEGFA gene were proved to be responsible and critical for promoting tendon healing. How to continuously enhance expression of these genes is a challenge. In this study, we developed a combination therapeutic approach that corrects the fundamental problem underlying intrasynovial tendon healing with introduction of growth factor genes via non-viral vector nanoparticle. PLGA nanoparticles as vehicle were used to delivery bFGF+VEGFA genes into injured tendon tissues. The expression of bFGF and VEGFA was upregulated in the tenocytes after transfection. We injected nanoparticle/bFGF+VEGFA gene complexes into injured tendons producing sufficient amounts of these factors required during early tendon healing period. After treatment, the ultimate strength of repaired tendons treated with nanoparticle/bFGF+VEGFA plasmid complexes was significantly increased, and combination therapy could also enhance flexor tendon gliding function. Therefore, combination gene therapy via nanoparticles may be an effective biological strategy for tendon repair. PMID- 29413595 TI - Linear self-assembly formation between gold nanoparticles and aminoglycoside antibiotics. AB - Ribostamycin is a broad-spectrum aminoglycoside antibiotic with a molecular weight of 454.5 g/mol. Under neutral pH conditions, ribostamycin is highly positive charged because it carries multiple amino groups in its structure. Negatively charged citrate ligand capped-gold nanoparticles (AuNPs) have been studied extensively for their interactions with a wide range of biomolecules including proteins, carbohydrates, and small drug compounds. These studies are aimed at developing new therapeutics and diagnostics by exploiting the unique properties of gold nanoparticles. Under this general aim, we studied the interaction between ribostamycin and AuNPs. Using a suite of analytical techniques including dynamic light scattering (DLS), UV-vis absorption spectroscopy, and dark field optical microscope imaging (DFM), we analyzed the mixture products of AuNPs with various sizes and ribostamycin under different concentrations. Our study revealed for the first time that ribostamycin has a tendency to self-assemble into linear oligomers at increased concentrations (above 250-500 MUM). Such self-assembled oligomers then interact with negatively charged AuNPs to produce rod-like AuNP assemblies. Similar findings were observed from another structurally related aminoglycoside antibiotic, amikacin. It is technically challenging to detect and characterize oligomer formation of small molecules. It is especially challenging when the interactions that are holding the oligomers are not very strong. Through their interaction with gold nanoparticles that have exceptionally strong light scattering properties, we were able to observe the self-assembling of ribostamycin and amikacin in solution using various spectroscopic and microscopic techniques. This concentration dependent self-assembling behavior of ribostamycin and amikacin may have direct relevance to the antibiotic effect of ribostamycin, amikacin and other structurally similar antibiotics. PMID- 29413596 TI - An aptamer-Fe3+ modified nanoparticle for lactate oxidation and tumor photodynamic therapy. AB - To develop a cancer targeting lactate attenuator in vivo for cancer phototherapy and inhibition of HIF-1, we report an aptamer modified photo-responsive nanoparticle (labeled as Mn-D@BPFe-A) for lactate oxidation and cancer phototherapy. Mn-D@BPFe-A was constructed by the assembly of functional complex with BSA, followed by surface metal coordination and the recognition of Fe3+ with GAG containing sequence. Upon irradiation, Mn-D@BPFe-A NPs can oxidize water with the generation of OH, which convert lactate into pyruvate both in vitro and in vivo. Obviously, the Mn-D@BPFe-A exhibits a significant tumor ablation owing to the light driven oxidation of lactic acid and dysfunction of mitochondria. Importantly, it can decrease both the level of lactate in cancer tissues and the expression of HIF-1alpha and Glut-1 in HepG-2 cells. These results demonstrated that oxidation of lactate with dysfunction of mitochondria by nucleic acid-Fe3+ modified nanoparticle is an effective strategy for the development of non-oxygen dependent photodynamic effect agents. PMID- 29413597 TI - Pickering emulsion stabilized by cashew gum- poly-l-lactide copolymer nanoparticles: Synthesis, characterization and amphotericin B encapsulation. AB - In this work, we provide proof-of-concept of formation, physical characteristics and potential use as a drug delivery formulation of Pickering emulsions (PE) obtained by a novel method that combines nanoprecipitation with subsequent spontaneous emulsification process. To this end, pre-formed ultra-small (d.~10 nm) nanoprecipitated nanoparticles of hydrophobic derivatives of cashew tree gum grafted with polylactide (CGPLAP), were conceived to stabilize Pickering emulsions obtained by spontaneous emulsification. These were also loaded with Amphotericin B (AmB), a drug of low oral bioavailability used in the therapy of neglected diseases such as leishmaniasis. The graft reaction was performed in two CG/PLA molar ratio conditions (1:1 and 1:10). Emulsions were prepared by adding the organic phase (Miglyol 812(r)) in the aqueous phase (nanoprecipitated CGPLAP), resulting the immediate emulsion formation. The isolation by centrifugation does not destabilize or separate the nanoparticles from oil droplets of the PE emulsion. Emulsions with CGPLAP 1:1 presented unimodal distributions at different CGPLA concentration, lower values in size and PDI and the best stability over time. The AmB was incorporated in the emulsions with a process efficiency of 21-47%, as determined by UV-vis. AmB in CGPLAP emulsions is in less aggregated state than observed in commercial AmB formulation. PMID- 29413598 TI - Garcinia indica mediated biogenic synthesis of silver nanoparticles with antibacterial and antioxidant activities. AB - This reports the optimization of various parameters for biogenic synthesis of Silver nanoparticles using fruit extract of Garcinia indica, popularly known as Kokum. For optimization, the effects of various parameters such as concentration of AgNO3, ratio of AgNO3 to extract, pH, incubation temperature and time were varied and studied for their effect on synthesis. 1.5 mM AgNO3, 1:1 ratio of AgNO3 to Kokum fruit extract, pH 10, incubation of reaction mixtures at 37 degrees C for 24 h were the optimum parameter for biogenic synthesis. The biogenic AgNPs were then characterized by UV-vis absorption spectroscopy, fourier transform infra-red (FT-IR) spectroscopy, field emission scanning electron microscope (FE-SEM) imaging, energy dispersive X-ray (EDS) spectrometer, X-ray powder diffractometer (XRD), transmission electron microscope (TEM) imaging and the selected area electron diffraction (SAED) pattern. The biogenic AgNPs alone and in combination with Tetracyclin showed antibacterial activity against the four of seven tested bacteria. In addition, biogenic AgNPs also demonstrated good antioxidant activities such as DPPH, hydrogen peroxide, nitric oxide (NO) radical scavenging and reducing power activities. This study demonstrates that Garcinia indica fruit extract can be used for biogenic production of AgNPs with potential antibacterial and antioxidant activities that can be exploited for commercial biomedical application. PMID- 29413599 TI - Hyaluronan based materials with catanionic sugar-derived surfactants as drug delivery systems. AB - In the present work novel drug delivery systems consisting in highly porous Hyaluronan foams for the administration of a non-steroidal anti-inflammatory drug (NSAID), ketoprofen, have been obtained. A sugar-derived surfactant associated with ketoprofen was prepared and incorporated into the porous hyaluronan materials. The association between a lactose derived surfactant, Lhyd12, and ketoprofen was obtained by acid-base reaction and its physicochemical properties were studied. Tensiometric and dynamic light scattering (DLS) determinations showed the formation of catanionic surfactant aggregates, Lhyd12/ketoprofen, in aqueous solution. Furthermore, the catanionic surfactants allowed greater solubilisation of ketoprofen. Hyaluronan porous materials were developed using butanediol diglycidyl ether as crosslinking agent. The profile release of Lhyd12/ketoprofen from hyaluronan based materials shows differences as a function of the aggregation state of catanionic surfactant. PMID- 29413600 TI - Yeast-assisted synthesis of polypyrrole: Quantification and influence on the mechanical properties of the cell wall. AB - In this study, the metabolism of yeast cells (Saccharomyces cerevisiae) was utilized for the synthesis of the conducting polymer - polypyrrole (Ppy).Yeast cells were modified in situ by synthesized Ppy. The Ppy was formed in the cell wall by redox-cycling of [Fe(CN)6]3-/4-, performed by the yeast cells. Fluorescence microscopy, enzymatic digestions, atomic force microscopy and isotope ratio mass spectroscopy were applied to determine both the polymerization reaction itself and the polymer location in yeast cells. Ppy formation resulted in enhanced resistance to lytic enzymes, significant increase of elasticity and alteration of other mechanical cell wall properties evaluated by atomic force microscopy (AFM). The suggested method of polymer synthesis allows the introduction of polypyrrole structures within the cell wall, which is build up from polymers consisting of carbohydrates. This cell wall modification strategy could increase the usefulness of yeast as an alternative energy source in biofuel cells, and in cell based biosensors. PMID- 29413601 TI - In vitro study of intestinal epithelial interaction with engineered oil in water nanoemulsions conveying curcumin. AB - The development of innovative nano-bio-encapsulation systems continues to be an area of intense activity as the demand of improved delivery systems is constantly increasing in several fields including nanomedicine. For this purpose, an important goal is carrying out appropriate engineering of the surface of these nanocarriers to satisfy the organ target features for an effective in situ release and elucidate the mechanism of action which most of the time is neglected. Here, an oil-in-water (O/W) nanoemulsion coated with a polysaccharide layer film - i.e. a glycol chitosan modified with a thiol moiety - was used as nanocarrier to convey a promising poorly water-soluble nature based drug, curcumin. The final nanocarrier was completely bio-compatible and bio-stable. We investigated the enhancement of the effect of curcumin loaded in our system across monolayers of intestinal epithelial cells CaCo-2 in Transwell culture. Such in vitro platform resulted suitable to evaluate the functionality of the proposed nanocarrier and its adhesion towards the mucosal epithelial layer and, as applicative example, to investigate the anti-inflammatory effects exerted by the encapsulation of curcumin. PMID- 29413602 TI - Molecular LEGO by domain-imprinting of cytochrome P450 BM3. AB - HYPOTHESIS: Electrosynthesis of the MIP nano-film after binding of the separated domains or holo-cytochrome BM3 via an engineered anchor should result in domain specific cavities in the polymer layer. EXPERIMENTS: Both the two domains and the holo P450 BM3 have been bound prior polymer deposition via a N-terminal engineered his6-anchor to the electrode surface. Each step of MIP preparation was characterized by cyclic voltammetry of the redox-marker ferricyanide. Rebinding after template removal was evaluated by quantifying the suppression of the diffusive permeability of the signal for ferricyanide and by the NADH-dependent reduction of cytochrome c by the reductase domain (BMR). FINDINGS: The working hypothesis is verified by the discrimination of the two domains by the respective MIPs: The holoenzyme P450 BM3 was ca. 5.5 times more effectively recognized by the film imprinted with the oxidase domain (BMO) as compared to the BMR-MIP or the non-imprinted polymer (NIP). Obviously, a cavity is formed during the imprinting process around the his6-tag-anchored BMR which cannot accommodate the broader BMO or the P450 BM3. The affinity of the MIP towards P450 BM3 is comparable with that to the monomer in solution. The his6-tagged P450 BM3 binds (30 percent) stronger which shows the additive effect of the interaction with the MIP and the binding to the electrode. PMID- 29413603 TI - The feasibility and application of PPy in cathodic polarization antifouling. AB - Cathodic polarization antifouling deserves attention because of its environmentally friendly nature and good sustainability. It has been proven that cathodic voltages applied on metal substrates exhibit outstanding antifouling effects. However, most metals immersed in marine environment are protected by insulated anticorrosive coatings, restricting the cathodic polarization applied on metals. This study developed a conducting polypyrrole (PPy)/acrylic resin coating (sigma = 0.18 Scm-1), which can be applied in cathodic polarization antifouling. The good stability and electro-activity of PPy in the negative polarity zone in alkalescent NaCl solution were verified by linear sweep voltammetry (LSV), chronoamperometry (CA), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), demonstrating the feasibility of PPy as cathodic polarization material. Furthermore, the antifouling effects of PPy/acrylicresin coating on 24-h old Escherichia coli bacteria (E. coli) which formed on PPy/acrylic resin-coated plastic plate were measured under different cathodic potentials and treatment time, characterized by fluorescent microscope. The results suggest that at cathodic potential around -0.5 V (vs. saturated calomel electrode (SCE)), there was little trace of attached bacteria on the substrate after 20 min of treatment. PPy/acrylicresin-coated substrates were also subjected to repeated cycles of biofilm formation and electrochemical removal, where high removal efficiencies were maintained throughout the total polarization process. Under these conditions, the generation of hydrogen peroxide is believed to be responsible for the antifouling effects because of causing oxidative damage to cells, suggesting the potential of the proposed technology for application on insulated surfaces in various industrial settings. PMID- 29413604 TI - Effect of electron beam irradiation on chemically synthesized nanoflake-like CdS electrodes for photoelectrochemical applications. AB - In this paper, we chemically synthesized interconnected nanoflake-like CdS thin films for photoelectrochemical solar cell applications and subsequently irradiated them with electron beam irradiation at various doses of irradiation. The as-synthesized and irradiated samples were characterized by means of X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), high resolution transmission electron microscopy (HR-TEM), and electrochemical measurements. XRD and XPS results confirmed the formation of CdS with a hexagonal crystal structure. FE-SEM and HR-TEM studies confirmed the photoelectrochemical performance, which was dependent on the surface morphology. The calculated values for efficiency demonstrated an outstanding photoelectrochemical performance with a fill factor of 0.38 and efficiency of 3.06% at 30 kGy. The high photoelectrochemical performance may be due to the interconnected nanoflake-like nanostructure and higher active surface area of the CdS samples. These results show that the electron beam irradiation is capable as an electrode for photoelectrochemical solar cells. PMID- 29413606 TI - Impact of oil type and WPI/Tween 80 ratio at the oil-water interface: Adsorption, interfacial rheology and emulsion features. AB - The relationship between the composition and structure of food emulsions was evaluated from the effect of a mixture of emulsifiers Whey protein (WPI) - Tween 80 (T80) and the oil phase features, such as chain length and unsaturation degree (sunflower oil, a long chain triacylglycerol - LCT or NEOBEE(r) 1053, a medium chain triacylglycerol - MCT). Emulsions with LCT showed higher droplet size than MCT as a consequence of its higher viscosity. All emulsions exhibited shear thinning behavior, but the viscosity was influenced by their interface composition. An occurrence of the destabilization mechanism by creaming was observed in turbidimetric measurements, but no visual phase separation could be observed, indicating a good kinetic stability after a 7-day storage. The initial interfacial tension of the water-LCT or water-MCT oil was about 25 mN/m, but the WPI addition (1% w/w) reduced the initial interfacial tension to approximately 20 mN/m. The increase of T80 concentration led to a decrease of the interfacial tension, reaching a value around 10 mN/m in systems with pure T80. The curves of interfacial tension of systems with LCT or MCT showed differences in the decay rate of tension over time. These differences were attributed to characteristics of the oil phase (hydrophobicity, unsaturation degree, presence of impurities) and the different proportions of each emulsifier within the mixture of emulsifiers. Finally, a higher viscoelastic interface was observed in LCT emulsions, which were mainly stabilized by WPI molecules. Such molecules presented a higher resistance to the displacement due to the competitive adsorption phenomenon, since the LCT is a more hydrophobic oil. On the other hand, the interface with MCT and a higher T80 concentration was less viscoelastic due to an easier displacement of WPI from the interface and the replacement by T80. The results indicate that T80 can be used in combination with WPI to produce emulsions with good stability and lower concentration of synthetic compounds. Lastly, the interfacial layer composition is not only dependent on the WPI-T80 ratio in the bulk phase, but also on the oily phase features. These results provide a potential strategy for designing emulsified foods based on the choice of ingredients and knowledge of the interaction between them. PMID- 29413605 TI - Two-step biocompatible surface functionalization for two-pathway antimicrobial action against Gram-positive bacteria. AB - The use of indwelling devices has emerged as a frequent and often life-saving medical procedure. However, infection in prosthetic surgery is one of the most important and devastating complications. Once the biofilm has been formed, its eradication is extremely difficult, due to an increased resistance to host defense and conventional antimicrobials. Thus, the design of novel strategies for inhibiting the bacterial adhesion on implantable devices is a key point for successful surgical procedures. In this work, the development of a simple two step protocol to prepare surfaces able to prevent the bacterial growth was successfully achieved. The surface-modification design includes a combined approach involving the multi-functionalization of Ti surfaces with silver nanoparticles (AgNPs) and/or ampicillin (AMP). The surface chemistry involved in AMP adsorption on titanium and silver surfaces was elucidated for the first time, thus establishing the basis for the further anchoring of other antibacterial compounds having similar functional groups. Our results show that the antibiotic binds to the titanium surface through covalent interactions between the COOH groups in AMP and the OH groups of the native TiO2 on the surface, although electrostatic interactions between protonated AMP and negatively charged TiO2 can also contribute to the antibiotic anchoring to the surface. The AMP immobilization on the AgNPs is carried out by thiolate-like bonds. The beta lactam ring functionality is preserved after the adsorption process, since the Ti AgNPs-AMP surface was able to decrease the bacterial viability in more than 80%. Moreover, the antimicrobial capacity is maintained over time due to a two-pathway antibacterial mechanism: death by contact (AMP) and death by release (AgNPs). The effect of AMP prevails on AgNPs at early stages of bacterial adhesion, while AgNPs are responsible for sustaining the relatively low but steady release of Ag(I), preserving the bacteriostatic activity of the surface over time. This effect would contribute to prevent infections due to sessile cells on indwelling devices, powering the action of the immune system and the conventional antibiotics usually dosed in implanted patients. PMID- 29413607 TI - Development of nanoparticles from natural lipids for topical delivery of thymol: Investigation of its anti-inflammatory properties. AB - Wound healing involves the integration of biological and molecular events and, in case of chronic wounds, the use of drugs can be associated to side effects. Therefore, there is a search for alternatives therapeutics that encompass minimal toxicity. The use of natural compounds is an attractive approach for treating inflammatory disorders, wounds and burns. In this context, thymol has antimicrobial, antioxidant and antiseptic properties and is a promising compound in wound healing and inflammation management. However, essential oils and their constituents such as thymol present high volatility and can also easily decompose, thereby the encapsulation of these compounds into nanoparticles may be an efficient approach to modulate the release of the active ingredient, to increase the physical stability and to eventually reduce the toxicity. The aims of this work were to encapsulate thymol in nanostructured lipid carriers (NLCs) composed of natural lipids and assess its in vivo anti-inflammatory and antipsoriatic activity. The carrier containing thymol was produced by sonication method and showed 107.7 (+/-3.8) nm of size, zeta potential of -11.6 (+/-2.9) mV and entrapment efficiency of 89.1 (+/-4.2)%. Thymol-NLCs were incorporated into a gel and the final formulation presented rheological characteristics and pH suitable for topic application. In addition, the gel containing thymol-NLCs was tested in vivo on two different mouse models of skin inflammation, showing anti inflammatory activity. Finally, this formulation was tested in an imiquimod induced psoriasis mouse model and showed improved healing, compared to negative control. Therefore, thymol-NLCs is an interesting formulation for future treatment of inflammatory skin diseases. PMID- 29413608 TI - Co-loading of photothermal agents and anticancer drugs into porous silicon nanoparticles with enhanced chemo-photothermal therapeutic efficacy to kill multidrug-resistant cancer cells. AB - The development of nanoparticles-based drug delivery systems with a high therapeutic efficacy is necessary to treat multidrug-resistant (MDR) cancer cells. Herein, photothermal agents (IR820 dyes) and anticacner drugs (doxorubicin, DOX) were successively incorporated into amino-terminated porous silicon nanoparticles (NH2-PSiNPs) via electrostatic attractions, to prepare DOX/IR820/NH2-PSiNPs nanocomposites with a high loading amount of DOX (13.3%, w/w) and IR820 (18.6%, w/w), respectively. Meanwhile, DOX molecules were also directly loaded into NH2-PSiNPs to form DOX/NH2-PSiNPs nanocomposites (DOX, 18.7%, w/w). Compared with low release percentage (20.3%) of DOX molecules from DOX/NH2-PSiNPs in acidic environments under NIR laser irradiation, DOX/IR820/NH2 PSiNPs had dual pH/NIR light-triggered release and their release percentage could reach 88.1% under the same conditions. Furthermore, cellular interactions tests demonstrated that DOX/IR820/NH2-PSiNPs could delivery more DOX molecules into the nuclei of MDR cancer cells, with efficient intracellular release triggered by NIR light, in contrast to DOX/NH2-PSiNPs. Finally, DOX/IR820/NH2-PSiNPs exhibited an enhanced chemo-photothermal therapeutic efficacy (cell viability, 38.4%) of killing MDR cancer cells in vitro, compared with 85.4% of free DOX and 75.9% of DOX/NH2-PSiNPs. Therefore, based on PSiNPs-based nanocarriers conjugated with photothermal agents and anticancer drugs, NIR light-triggered drug delivery system with higher efficacy of combined chemo-photothermal therapy would have important potential on MDR cancer treatments in future. PMID- 29413609 TI - Marrubiin-loaded solid lipid nanoparticles' impact on TNF-alpha treated umbilical vein endothelial cells: A study for cardioprotective effect. AB - Oxidative stress possesses a key role in the onset and development of cardiovascular diseases (CVDs), thus it can be an efficient target to tackle such ailment. Marrubiin, a bioactive diterpene, is a potent antioxidant against oxidative stress. Herein, we aimed to formulate marrubiin loaded solid lipid nanoparticles (SLNs) to improve its pharmacokinetics and bioavailability and also to investigate free drug and formulation's protective impact against intracellular reactive oxygen species (ROS) generation in HUVECs. Marrubiin-SLNs were formulated using hot homogenization/solidification method and then were subjected to physicochemical characterizations, i.e. size, zeta potential, morphology, polydispersity index (PDI), encapsulation efficiency (% EE), drug loading/content and physical stability assessments. MTT assay was performed to study the cytotoxicity of the intact and SLN incorporated marrubiin on HUVECs. Further, the antioxidant property of marrubiin and formulations was evaluated using DPPH radical scavenging assay and their protective effect against TNF-alpha induced oxidative stress was assessed by the means of intracellular ROS assessment, and also apoptosis/necrosis, cell cycle, and DNA fragmentation assays. Electron microscopy analysis showed spherical monodispersed SLNs with the size less than 100 nm, particle/zeta size analyses also approved the size of particles with a zeta potential of -1.28 +/- 0.17 mV. Results also showed high EE (98%), drug loading (31.74 mg/g) with 3.15% drug content. In vitro release studies revealed about 90% of marrubiin cumulative release during 24 h. The stability of marrubiin-SLNs in terms of size, zeta potential, polydispersity index, EE and drug leakage was approved. Marrubiin antioxidant stability after formulation was approved by DPPH analysis. MTT cell survival assay showed no significant cytotoxicity after 24 h and 48 h. Intracellular ROS detection assay revealed that marrubiin and marrubiin-SLNs, play protective effect against TNF alpha induced oxidative stress in HUVECs which was further approved by apoptosis assessment. Conclusively, based on our findings, marrubiin nanoparticles are proposed as a preventive/therapeutic remedy against disorders elicited by increased levels of intracellular ROS in CVDs. PMID- 29413610 TI - Genipin-stabilized caseinate-chitosan nanoparticles for enhanced stability and anti-cancer activity of curcumin. AB - Nanoparticles formed by the assembly of protein and polysaccharides are of great interest for the delivery of hydrophobic molecules. Herein, the formation of genipin-crosslinked nanoparticles from caseinate (CS) and chitosan (CH) is reported for the delivery of curcumin, a polyphenolic compound from turmeric, to cells. Genipin-crosslinked CS-CH nanoparticles (G-CCNPs) having a diameter of ~250 nm and a low polydispersity index showed excellent stability over a wide pH range, as indicated by dynamic light scattering and transmission electron microscopic measurements. Cellular uptake of curcumin loaded into G-CCNPs by HeLa cells was improved, as measured by confocal laser scanning microscopy (CLSM) and fluorescence-activated cell-sorting analysis. Cell proliferation assays indicated that G-CCNPs were nontoxic and that curcumin's anticancer activity in vitro was also improved by G-CCNPs. Stability of curcumin at neutral pH was enhanced by G CCNPs. CLSM study revealed that G-CCNPs were poorly internalized by HeLa cells, possibly because of strong cell membrane interactions and a negative zeta potential. Overall, our results suggested that the enhanced curcumin cytotoxicity might be associated with the enhanced stability of curcumin by G-CCNPs and free curcumin released from G-CCNPs into the cell. These biocompatible NPs might be suitable carriers for enhancing curcumin's therapeutic potential. PMID- 29413611 TI - Rationally designed magnetic nanoparticles as anticoagulants for blood purification. AB - Heparin-based anticoagulant drugs are widely used for the prevention of blood clotting during extracorporeal circuit (bloodlines or cassette system) and surgical procedures as well as for the treatment of thromboembolic events. However, these anticoagulants are associated with bleeding risks that demand continuous monitoring and neutralization with antidotes. We explore the possibility of utilizing anticoagulants for blood clotting prevention, then removing them before transfusing the blood back to body, thus avoid bleeding risks. Here, we report on the strength of a strategy to solve problems with bleeding risks by rationally designing and using superparamagnetic iron oxide nanoparticles (SPIONs) with layer-by-layer self-assembled heparin. The morphology of these SPIONs was investigated by using dynamic light scattering and transmission electron microscopy. In vitro assays demonstrated superior efficacy and safety profiles and significantly mitigated conventional heparin-induced bleeding risks. In addition, the in vivo assay in a model animal (dog) proved that it is possible to use magnetic anticoagulant (MAC) in blood purification. The new magnetic anticoagulant drugs may benefit patients undergoing high-risk surgical procedures and may overcome anticoagulant-related bleeding problems to a great extent. PMID- 29413612 TI - Biodegradable, pH-sensitive chitosan beads obtained under microwave radiation for advanced cell culture. AB - A new type of promising chitosan beads with advanced properties were obtained under microwave radiation according to Green Chemistry principles. Biomaterials were prepared using chitosan as raw material and glutamic acid/1,5-pentanodiol mixture as crosslinking agents. Additionally beads were modified with Tilia platyphyllos extract to enhance their antioxidant properties. Beads were investigated over their chemical structure by FT-IR analysis. Also their morphology has been investigated by SEM method. Additionally swelling capacity of the obtained hydrogels was determined. Lack of cytotoxicity has been confirmed by MTT assay. Proliferation studies were carried out on L929 mouse fibroblasts. Advanced properties of the obtained beads were investigated by studying pH sensitivity and antioxidant properties by DPPH method. Also susceptibility to degradation and biodegradation by Sturm Test method was evaluated. Results shows that proposed chitosan beads and their eco-friendly synthesis method can be applied in cell therapy and tissue engineering. PMID- 29413613 TI - Preparation, characterization, and optimization of auraptene-loaded solid lipid nanoparticles as a natural anti-inflammatory agent: In vivo and in vitro evaluations. AB - Auraptene (AUR) is a bioactive antioxidant coumarin with valuable pharmacological properties; however, poor water solubility is a substantial issue for the topical application of AUR. Therefore, we sought to prepare solid lipid nanoparticles (SLNs) containing AUR (AUR-SLNs) to enhance its anti-inflammatory effect. The prepared formulations were optimized by applying the response surface method. Furthermore, AUR-SLNs were compared to conventional cream containing AUR regarding both the permeation rate of the nanoparticles and the anti-inflammatory effect through both in vitro and in vivo studies. Particle size and entrapment efficiency of the optimized formulation were 140.9 +/- 3.55 nm and 84.11% +/- 3.30, respectively. Transmission electron microscopy revealed that the nanoparticles were spherical. Differential scanning calorimetry (DSC) analysis demonstrated no drug-lipid incompatibility in the formulation. Fourier transform infrared spectroscopy (FTIR) spectra revealed the amorphous state of AUR and the encapsulation of this agent in SLNs. The in vitro permeation studies exhibited that AUR-SLNs could significantly enhance cutaneous uptake of AUR and skin targeting. The anti-inflammatory and histopathological studies exhibited no significant differences between AUR-SLNs and indomethacin. AUR-SLNs did not induce skin sensitization in guinea pigs. The results suggest that SLNs could be appropriate carriers for the topical application of AUR as a natural anti inflammatory agent. PMID- 29413614 TI - Antifungal activity of newly synthesized chemodegradable dicephalic-type cationic surfactants. AB - The studies were aimed to contribute to the elucidation of the relationships between structure of the double-headed cationic surfactants - N,N-bis[3,3' (dimethylamine)propyl]alkylamide dihydrochlorides and N,N-bis[3,3' (trimethylammonio)propyl]alkylamide dibromides (alkyl: n-C9H19, n-C11H23, n C13H27, n-C15H31), which are of particular interest, as they contain a labile amide group in the molecule and their antifungal activity. Therefore, the minimal inhibitory and fungicidal concentrations (MIC and MFC) of dicephalic surfactants against various fungi were tested using standardized methods. Most of the tested fungi were resistant to the Cn(TAPABr)2 compounds. The strongest growth inhibition was caused by Cn(DAPACl)2 series, which MICs ranged from 6.5 to 16 MUM. The influence of dicephalic surfactants on Candida albicans biofilm and adhesion to the various surfaces was investigated with crystal violet staining or colony counting. The reduction of fungal adhesion was also observed, especially to the glass surface. One of the compounds (C14(DAPACl)2) caused DNA leakage from C. albicans cells. Further studies showed the impact of dicephalic surfactants on ROS production, accumulation of lipid droplets and filament formation. This study points to the possibility of application of dicephalic surfactants as the surface coating agents to prevent biofilm formation or as disinfectants. The results give an insight into the possible mechanism of action of newly synthesized dicephalic surfactants in yeast cells. PMID- 29413615 TI - Functionalized silk fibroin film scaffold using beta-Carotene for cornea endothelial cell regeneration. AB - Design of corneal endothelium substitute is important for replacement of cadaveric cornea tissue. Our previous study has shown the suitability of silk fibroin (SF) as a biomaterial for cornea scaffold. In this study, we used beta Carotene (beta-C) to enhance the regeneration of corneal endothelial cells (CEnCs) and maintain CEnC specific function. The fabricated film scaffolds showed desired transparency and hydrophilic properties which are crucial factors for vision recovery. The cell viability, phenotype and gene expression was examined using MTT assay, immunofluorescence and reverse transcription polymerase chain reactions. Compared with pristine SF scaffold, proper amount of beta-C incorporated with SF scaffolds showed higher initial cell attachment, cell viability and mRNA expression. The results indicate that the fabricated SF film scaffold incorporated with small amount of beta-C might be the suitable alternative corneal endothelium substitute for transplantation. PMID- 29413616 TI - Stimulation of cell responses and bone ingrowth into macro-microporous implants of nano-bioglass/polyetheretherketone composite and enhanced antibacterial activity by release of hinokitiol. AB - Poor osteogenesis and bacterial infection lead to the failure of implants, thus enhancements of osteogenic activity and antibacterial activity of the implants have significances in orthopedic applications. In this study, macro-microporous bone implants of nano-bioglass (nBG) and polyetheretherketone (PK) composite (mBPC) were fabricated. The results indicated that the mBPC with the porosity of around 70% exhibited interconnected macropores (sizes of about 400 MUm) and micropores (sizes of about 10 MUm). The apatite mineralization ability of mBPC in simulated body fluid (SBF) was significantly improved compared with macroporous nBG/PK composite (BPC) without micropores and macroporous PK (mPK). Drug of hinokitiol (HK) was loaded into mBPC (dmBPC), which displayed excellent in vitro antibacterial activity against Staphylococcus aureus. The MC3T3-E1 cells proliferation and ALP activity were significantly promoted by mBPC and dmBPC as compared with BPC and mPK. The micro-CT and histological evaluation showed that both mBPC and dmBPC containing nBG and micropores induced higher new bone formation into porous implants than mPK and BPC. The immunohistochemistry analysis indicated that the expression of BMP-2 in mBPC and dmBPC exhibited obviously higher level than mPK and BPC. The results suggested that the incorporation of nBG and micropores in mBPC obviously improved the osteogenic activity, and mBPC load with HK also promoted osteogenesis, indicating good biocompatibility. The dmBPC with HK significantly enhanced osteogenesis and antibacterial activity, which had great potential as bone implant for hard tissue repair. PMID- 29413617 TI - Functionally coated polyethersulfone hollow fiber membranes: A substrate for enhanced HepG2/C3A functions. AB - Hollow fiber membrane (HFM) based liver assist systems are a life-saving bridge for patients until a donor organ is available for transplantation or until liver regeneration. However, liver cell attachment and functional maintenance on HFM surface is a major challenge in bio-artificial liver (BAL) support systems. In the present study, novel glutaraldehyde (GTA)-crosslinked gelatin (gel)-coated polyethersulfone (X-gel-PT) HFMs were manufactured using triple orifice spinneret by the dry-wet spinning method. HFMs were characterized for morphology, outer surface roughness, hydrophilicity, tensile strength, thermal stability, BET surface area and pore volume measurements, permeability and rejection. Fourier transform infrared spectroscopy, and transmission electron microscopy confirmed the GTA-crosslinked gel-coating in the X-gel-PT HFMs, which provided the desirable extracellular matrix-like environment to the HepG2/C3A cells. The results of in-vitro hemocompatibility tests showed the better suitability of the developed HFMs for the blood-contact application. X-gel-PT HFMs showed significantly better cellular attachment and proliferation of HepG2/C3A cells on day 3 and 6, as shown by scanning electron and confocal microscopy. Significantly high urea synthesis and albumin secretion seen indicated the improved functional and metabolic activity of HepG2/C3A cells. Thus, the developed X-gel-PT HFMs is a suitable substrate for the hepatocyte culture, mass culture, and development of BAL support system. PMID- 29413618 TI - Electrostatic immobilization of antimicrobial peptides on polyethylenimine and their antibacterial effect against Staphylococcus epidermidis. AB - Staphylococcus epidermidis is a gram-positive bacterium, and one of the most prevalent causes of nosocomial infections due to its strong ability to form biofilms on catheters and surgical implants. Here we explore the antimicrobial properties of Tet-124 peptides, which are part of the innate defense against different multicellular organisms in nature. Two different Tet-124 peptides were immobilized on a polyethylenimine (PEI) film to determine their impact on the antimicrobial properties: KLWWMIRRW (Tet-124), which contains only natural amino acids, and KLWWMIRRWG-(F-Br)-G (F-Br = 4-Bromophenylalanine), a modified Tet-124 sequence with the addition of an unnatural amino acid. The immobilization was obtained as a result of the electrostatic interaction between PEI amino groups and the C-terminal carboxylic groups of tryptophan and glycine amino acids of Tet 124 and Tet-124-Br peptides, respectively. The process was monitored and studied by water contact angle, Atomic Force Microscopy (AFM), X-ray Photoelectron Spectroscopy (XPS) and Quartz Crystal Microbalance with Dissipation (QCM-D) measurements. The antibacterial effect of our samples against S. epidermis was evaluated by the spread plate counting method, and cytotoxicity was tested using fibroblast cultures. Our results indicate the feasibility to immobilize electrostatically both Tet-124 peptides for biomedical applications. PMID- 29413619 TI - Antibacterial cotton fabrics based on hydrophilic amino-containing scaffolds. AB - A hydrophilic amino compound, 4,7,10-trioxatridecane-1,13-diamine, has been utilized in several chemical and biochemical studies. Among previous applications is its use as a flexible and economical spacer molecule to increase the length between two moieties of interest, one of which may be a solid-phase interface. In this study, we immobilized this molecule on cotton fabrics and showed that this modified surface (DA) exhibited significant antibacterial activities in both Gram negative bacteria and a Gram-positive bacterium. Studies on the structure activity relationship revealed that additional chemical modifications on DA usually led to lowered antibacterial activities, emphasizing an importance of having free amino groups. Further investigation by fluorescence microscope indicated that this modified surface likely interfered with the membrane integrity of bacteria, leading to cell lysis. In addition, this scaffold was also tested for its biocompatibility with mouse fibroblast cells, and exerted no detrimental effect to the cell growth, highlighting its potential as a practical antibacterial surface modifier. PMID- 29413620 TI - Long term stability and interaction with epithelial cells of freeze-dried pH responsive liposomes functionalized with cholesterol-poly(acrylic acid). AB - Liposomes are exceptional carriers for therapeutic drug delivery. However, they generally suffer from poor cell penetration, low half-life in bloodstream and loss of functionality during storage. To overcome these problems some strategies can be applied, such as functionalization with polymers and the use of protective molecules during dehydration processes. This work reports a complete study about the stability, including freeze-drying in the presence of trehalose, storage and internalization into HEp-2 cells, of stable formulations of pH sensitive polymer liposome complexes (PLC) composed of soybean lecithin and crosslinked/non crosslinked poly(acrylic acid) with a cholesterol end-group (CHO-PAA). The results showed that the average hydrodynamic particle size of the complexes persisted unaffected for approximately 75 days after freeze-drying in the presence of 10% w/v trehalose. The efficiency of calcein encapsulation and release profiles in physiologic conditions exhibited no significant alterations when stored for 0 and 1 month, and for 2 and 3 months of storage the calcein release increased with time. The stored complexes were efficiently uptaken into HEp-2-cells, as determined by confocal microscopy. In all cases, the percentage of viable cells was above 90%, as determined by the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay, indicating no potential toxicity. Finally, transepithelial transport assays demonstrated that both fresh and 2 months-stored complexes could transport their calcein content through HEp-2 monolayers over time. PMID- 29413621 TI - Tuning surface properties of bone biomaterials to manipulate osteoblastic cell adhesion and the signaling pathways for the enhancement of early osseointegration. AB - Osteoblast cell adhesion is the initial step of early osseointegration responding to bone material implants. Enhancing the osteoblastic cell adhesion has become one of the prime aims when optimizing the surface properties of bone biomaterials. The traditional strategy focuses in improving the physical attachment of osteoblastic cells onto the surfaces of biomaterials. However, instead of a simple cell physical attachment, the osteoblastic cell adhesion has been revealed to be a sophisticated system. Despite the well-documented effect of bone biomaterial surface modifications on adhesion, few studies have focused on the underlying molecular mechanisms. Physicochemical signals from biomaterials can be transduced into intracellular signaling network and further initiate the early response cascade towards the implants, which includes cell survival, migration, proliferation, and differentiation. Adhesion is vital in determining the early osseointegration between host bone tissue and implanted bone biomaterials via regulating involving signaling pathways. Therefore, the modulation of early adhesion behavior should not simply target in physical attachment, but emphasize in the manipulation of downstream signaling pathways, to regulate early osseointegration. This review firstly summarized the basic biological principles of osteoblastic cell adhesion process and the activated downstream cell signaling pathways. The effects of different biomaterial physicochemical properties on osteoblastic cell adhesion were then reviewed. This review provided up-to-date research outcomes in the adhesion behavior of osteoblastic cells on bone biomaterials with different physicochemical properties. The strategy is optimised from traditionally focusing in physical cell adhesion to the proposed strategy that manipulating cell adhesion and the downstream signaling network for the enhancement of early osseointegration. PMID- 29413622 TI - Real-time investigation of interactions between nanoparticles and cell membrane model. AB - Understanding the internal cellular processes of micron/nanoparticles will be important for particles toxicity studies or drug-delivery systems designing. The details and mechanisms of the cellular up-take process of micron/nano particles can hardly be described in real-time. In this study, cellular internalization of micron/nanoparticles was investigated by fluorescence spectroscopy, flow cytometry and sum frequency generation vibrational spectroscopy (SFG). Model cell membranes such as substrate supported lipid bilayers and lipid vesicles were used in this research. Especially, SFG was used to examine the behavior of each leaflet of the lipid bilayer while interacting with micron/nanoparticles. Experiments of SFG show direct evidences that micron/nanoparticles attachment lead to the lipid orientation. Vesicle dye-leakage model were used to study long term interactions on model membrane. Results from this study provide in-depth insight into the molecular interactions between micron/nanoparticles and cell membranes, which will help to understand the particles toxicity and will be useful for the designing of micron/nanoparticles for applications. PMID- 29413623 TI - Self-assembled nanoformulation of methylprednisolone succinate with carboxylated block copolymer for local glucocorticoid therapy. AB - A new self-assembled formulation of methylprednisolone succinate (MPS) based on a carboxylated trifunctional block copolymer of ethylene oxide and propylene oxide (TBC-COOH) was developed. TBC-COOH and MPS associated spontaneously at increased concentrations in aqueous solutions to form almost monodisperse mixed micelles (TBC-COOH/MPS) with a hydrodynamic diameter of 19.6 nm, zeta potential of -27.8 mV and optimal weight ratio ~1:6.3. Conditions for the effective formation of TBC COOH/MPS were elucidated by comparing copolymers and glucocorticoids with different structure. The micellar structure of TBC-COOH/MPS persisted upon dilution, temperature fluctuations and interaction with blood serum components. TBC-COOH increased antiradical activity of MPS and promoted its intrinsic cytotoxicity in vitro attributed to enhanced cellular availability of the mixed micelles. Intracellular transportation and hydrolysis of MPS were analyzed using optimized liquid chromatography tandem mass spectrometry with multiple reaction monitoring which showed increased level of both MPS and methylprednisolone in neuronal cells treated with the formulated glucocorticoid. Our results identify TBC-COOH/MPS as an advanced in situ prepared nanoformulation and encourage its further investigation for a potential local glucocorticoid therapy. PMID- 29413624 TI - PEGylation of black kidney bean (Phaseolus vulgaris L.) protein isolate with potential functironal properties. AB - In this work, we investigated PEGylated black kidney bean protein isolates (BKBPI) by PEG succinimidyl carbonate (PEG-SC), PEG succinimidyl succinate (PEG SS) and PEG succinimidyl propionate (PEG-SPA) conjugation. The functional properties, thermodynamic stability, in vitro digestion stability, and hemagglutination activity of the modified products were evaluated. The degree of PEGylation was measured, and FTIR analysis revealed that protein-PEG conjugations were formed, and that no obvious changes in water- and fat-holding capacities were observed. The solubility, emulsifying property, and foaming property were all improved through the modification, while, higher thermodynamic stability was achieved with the increase in Td values and reduction of DeltaH. The PEGylated proteins were found to be more resistant to in vitro digestion, and the hemagglutination activity was significantly (P < 0.05) decreased, indicating the higher safety of the protein isolate. The results showed that the functional properties, thermodynamic stability, and biological safety of BKBPI were improved by PEGylation, which could serve to increase the applications for this protein. PMID- 29413625 TI - Formation and elasticity of membranes of the class II hydrophobin Cerato-ulmin at oil-water interfaces. AB - Protein surfactants show great potential to stabilize foams, bubbles, and emulsions. An important family of surface active proteins, the hydrophobins, is secreted by filamentous fungi. Two hydrophobin classes have been recognized, with Class II exhibiting slightly better solubility than Class I, although neither is very soluble in water. Hydrophobins are small proteins (8-14 kDa), but they are larger and more rigid than typical surfactants such as sodium dodecyl sulfate. This rigidity seems to be manifested in the strength of adsorbed hydrophobin layers on oil droplets or air bubbles. A particular Class II hydrophobin, Cerato ulmin, was characterized at the oil-water interface (the oil was squalane). The results are compared to measurements at the air-water interface, newly extended to lower Cerato-ulmin concentrations. For both oil-water and air-water interfaces, static and dynamic properties were measured during the evolution of the membrane structure. The static measurements reveal that dilute Cerato-ulmin solution efficiently decreases the interfacial tension, whether at oil-water or air-water interfaces. The reduction in surface tension requires several hours. Interfacial mechanics were characterized too, and the dilatational modulus was found to reach large values at both types of interfaces: 339 +/- 19 mN/m at the squalane-water interface and at least 764 +/- 45 mN/m at the air-water interface. Both values well exceed those typical of small-molecule surfactants, but come closer to those expected of particulate-loaded interfaces. Circular dichroism provides some insight to adsorption-induced molecular rearrangements, which seem to be more prevalent at the oil-water interface than at the air-water interface. PMID- 29413626 TI - De novo sequencing, assembly, and analysis of Iris lactea var. chinensis roots' transcriptome in response to salt stress. AB - As a halophyte, Iris lactea var. chinensis (I. lactea var. chinensis) is widely distributed and has good drought and heavy metal resistance. Moreover, it is an excellent ornamental plant. I. lactea var. chinensis has extensive application prospects owing to the global impacts of salinization. To better understand its molecular mechanism involved in salt resistance, the de novo sequencing, assembly, and analysis of I. lactea var. chinensis roots' transcriptome in response to salt-stress conditions was performed. On average, 74.17% of the clean reads were mapped to unigenes. A total of 121,093 unigenes were constructed and 56,398 (46.57%) were annotated. Among these, 13,522 differentially expressed genes (DEGs) were identified between salt-treated and control samples Compared to the transcriptional level of control, 7037 DEGs were up-regulated and 6539 down regulated. In addition, 129 up-regulated and 1609 down-regulated genes were simultaneously detected in all three pairwise comparisons between control and salt-stressed libraries. At least 247 and 250 DEGs encoding transcription factors and transporter proteins were identified. Meanwhile, 130 DEGs regarding reactive oxygen species (ROS) scavenging system were also summarized. Based on real-time quantitative RT-PCR, we verified the changes in the expression patterns of 10 unigenes. Our study identified potential salt-responsive candidate genes and increased the understanding of halophyte responses to salinity stress. PMID- 29413627 TI - An unusual strategy of stomatal control in the desert shrub Ammopiptanthus mongolicus. AB - Water deficit is one of the main environmental constraints that limit plant growth. Accordingly, plants evoke rather complex strategies to respond and/or acclimate to such frustrating circumstances. Due to insufficient understandings of acclimatory mechanisms of plants' tolerance to persistent water deficit, a desert shrub of an ancient origin, Ammopiptanthus mongolicus, has recently attracted growing attentions. Differed from Arabidopsis, the opening of stomata of A. mongolicus is constrained by low external K+ concentration of the guard cells. Although as a general consequence, a raised level of ABA is also induced in A. mongolicus following water deficit, this does not accordingly result in efficient stomatal closure. In consistent with this phenomenon, the expression of genes coding for the negative regulators of the ABA signaling cascade-the type 2C protein phosphatases (PP2Cs) are notably induced, whereas the transcription of the downstream SnRK2 protein kinase genes or the destination ion fluxing channel genes remain almost unaffected under water deficit treatments. Therefore, in term of stomatal control in response to water deficit, A. mongolicus seemingly employs an unusual strategy: a constrained stomatal opening controlled by extracellular K+ concentrations rather than a prompt stomatal closure triggered by ABA-induced signaling pathway. Additionally, an acute accumulation of proline is induced by water deficit which may partly compromise the activation of antioxidant enzymes in A. mongolicus. Such strategy of stomatal control found in A. mongolicus may in certain extents, reflect the acclimatory divergence for plants' coping with persistent stress of water deficit. PMID- 29413628 TI - Effect of soil salinity on fructan content and polymerization degree in the sprouting tubers of Jerusalem artichoke (Helianthus tuberosus L.). AB - In addition to their role as reserve carbohydrates, fructans have been recognized as compounds that are protective against adverse environments. The aim of this study was to identify changes in the content and the degree of polymerization (DP) of fructan in sprouting tubers of Jerusalem artichoke under salt stress. Fructan was extracted from tubers at 1, 3, 5, and 7 days after planting in sandy loam soil irrigated with NaCl solution. Fructan accumulation and polymerization and the expression of genes encoding enzymes for fructan synthesis and degradation were evaluated. No significant differences between the control and treatment groups were observed until 5 days after sowing. The highest level of salinity (250 mM) not only inhibited sprouting and root growth but also decreased the level of fructan in the tubers. The proportion of fructan at DP 2-5 rapidly increased one day after sowing and then decreased over time. Under various NaCl treatments, at 7 days after sowing, all fructans except fructan at DP 6-10 were present in proportions less than or equal to the control. The variation in the DP of fructan was related to the transcription level of fructan metabolism genes. Fructan may support sprouting or resistance to salt stress by changing the DP of fructan molecules through hydrolysis without changing the total amount of fructan. The low-molecular-weight oligosaccharides (DP < 5) may be the major carbohydrates that support tuber sprouting or that are involved in protection from salt stress. PMID- 29413629 TI - Transcriptome de novo assembly and analysis of differentially expressed genes related to cytoplasmic male sterility in onion. AB - Onion (Allium cepa L.) is one of the major vegetables in China and accounts for a large proportion of China's vegetable exports. Onion cytoplasmic male sterility, which is often used in onion breeding, is caused by the interaction between the nuclear genes and the cytoplasm. However, the underlying molecular mechanism of onion cytoplasmic male sterility remains unclear. In this study, we analysed the anther microstructure of the onion cytoplasmic male sterile line SA2 and the onion maintainer line SB2. We found that the pollen abortion in SA2 occurred at the tetrad stage during the microspore development, which was very different from that in SB2. We used the Illumina HiSeq platform to sequence RNA from anthers at the tetrad stage collected from the SA2 and SB2 lines. The RNA sequencing and transcriptome assembly produced 146,413 All-Unigenes. Based on an analysis of the differentially expressed genes, we identified two cytoplasmic control genes, atp9 and cox1, and three nuclear-related genes, SERK1, AG and AMS. These transcriptomic results were also verified by fluorescence quantitative PCR. Our study provides important information about genes related to onion cytoplasmic male sterility, and it will help improve the understanding of the molecular mechanism of onion cytoplasmic male sterility. PMID- 29413630 TI - Phosphorus and metal removal combined with lipid production by the green microalga Desmodesmus sp.: An integrated approach. AB - This work focused on the potential of Desmodesmus sp. to be employed for wastewater bioremediation and biodiesel production. The green microalga was grown in a culture medium with a phosphorus (P) content of 4.55 mg L-1 simulating an industrial effluent; it was also exposed to a bimetal solution of copper (Cu) and nickel (Ni) for 2 days. P removal was between 94 and 100%. After 2 days of exposure to metals, 94% of Cu and 85% of Ni were removed by Desmodesmus sp. Adsorption tests showed that the green microalga was able to remove up to 90% of Cu and 43% of Ni in less than 30 min. The presence of metals decreased the lipid yield, but biodiesel quality from the biomass obtained from metal exposed samples was higher than that grown without metals. This result revealed that this technology could offer a new alternative solution to environmental pollution and carbon-neutral fuel generation. PMID- 29413631 TI - Nitrogen metabolism correlates with the acclimation of photosynthesis to short term water stress in rice (Oryza sativa L.). AB - Nitrogen metabolism is as sensitive to water stress as photosynthesis, but its role in plant under soil drying is not well understood. We hypothesized that the alterations in N metabolism could be related to the acclimation of photosynthesis to water stress. The features of photosynthesis and N metabolism in a japonica rice 'Jiayou 5' and an indica rice 'Zhongzheyou 1' were investigated under mild and moderate soil drying with a pot experiment. Soil drying increased non photochemical quenching (NPQ) and reduced photon quantum efficiency of PSII and CO2 fixation in 'Zhongzheyou 1', whereas the effect was much slighter in 'Jiayou 5'. Nevertheless, the photosynthetic rate of the two cultivars showed no significant difference between control and water stress. Soil drying increased nitrate reducing in leaves of 'Zhongzheyou 1', characterized by enhanced nitrate reductase (NR) activity and lowered nitrate content; whereas glutamate dehydrogenase (GDH), glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) were relative slightly affected. 'Jiayou 5' plants increased the accumulation of nitrate under soil drying, although its NR activity was increased. In addition, the activities of GDH, GOT and GPT were typically increased under soil drying. Besides, amino acids and soluble sugar were significantly increased under mild and moderate soil drying, respectively. The accumulation of nitrate, amino acid and sugar could serve as osmotica in 'Jiayou 5'. The results reveal that N metabolism plays diverse roles in the photosynthetic acclimation of rice plants to soil drying. PMID- 29413632 TI - Test-retest reliability of ultrasound measures of intrinsic foot motor function. AB - OBJECTIVE: To establish test-retest reliability of Intrinsic Foot Muscle (IFM) motor function measured using ultrasound imaging (USI). SETTING: Laboratory. DESIGN: Reliability Study. PARTICIPANTS: 24 healthy young adults without history of ankle-foot injury. MAIN OUTCOME MEASURES: Ultrasound measures of Abductor hallucis (AbdH), flexor digitorum brevis (FDB), quadratus plantae (QP) and flexor hallucis brevis (FHB) cross-sectional area (CSA) and thickness were assessed on 2 occasions, 3-10 days apart. The IFM were measured at rest, during active and resisted contraction, and during IFM exercises using USI and reported as activation ratios. Reliability was assessed with intraclass correlation coefficients (ICC2,k) and interpreted as being excellent >0.75, 0.40-0.75 as fair to good, and <0.40 as poor. RESULTS: Reliability of AbdH, FDB, QP, and FHB CSA and thickness resting measures were excellent (0.76-0.98). Active and resisted measures and IFM exercises had good to excellent reliability (0.66-0.99). Standard error of measurement (SEM) of resting CSA thickness measures ranged from 0.09 to 0.14 cm2 and 0.05-0.09 cm. Minimal detectable change (MDC) for CSA resting measures ranged from 0.25 to 0.40 cm2 and 0.14-0.24 cm for thickness measures. IFM activation SEM during exercises ranged from 0.01 to 0.11, with MDCs ranging from 0.03 to 0.31. CONCLUSION: There is potential utility for USI assessment of IFM neuromotor function in research and clinical practice. PMID- 29413633 TI - Developmental validation of a Nextera XT mitogenome Illumina MiSeq sequencing method for high-quality samples. AB - Generating mitochondrial genome (mitogenome) data from reference samples in a rapid and efficient manner is critical to harnessing the greater power of discrimination of the entire mitochondrial DNA (mtDNA) marker. The method of long range target enrichment, Nextera XT library preparation, and Illumina sequencing on the MiSeq is a well-established technique for generating mitogenome data from high-quality samples. To this end, a validation was conducted for this mitogenome method processing up to 24 samples simultaneously along with analysis in the CLC Genomics Workbench and utilizing the AQME (AFDIL-QIAGEN mtDNA Expert) tool to generate forensic profiles. This validation followed the Federal Bureau of Investigation's Quality Assurance Standards (QAS) for forensic DNA testing laboratories and the Scientific Working Group on DNA Analysis Methods (SWGDAM) validation guidelines. The evaluation of control DNA, non-probative samples, blank controls, mixtures, and nonhuman samples demonstrated the validity of this method. Specifically, the sensitivity was established at >=25 pg of nuclear DNA input for accurate mitogenome profile generation. Unreproducible low-level variants were observed in samples with low amplicon yields. Further, variant quality was shown to be a useful metric for identifying sequencing error and crosstalk. Success of this method was demonstrated with a variety of reference sample substrates and extract types. These studies further demonstrate the advantages of using NGS techniques by highlighting the quantitative nature of heteroplasmy detection. The results presented herein from more than 175 samples processed in ten sequencing runs, show this mitogenome sequencing method and analysis strategy to be valid for the generation of reference data. PMID- 29413634 TI - Predicting the origin of stains from next generation sequencing mRNA data. AB - We used our previously published NGS mRNA approach for body fluid identification to analyse 183 body fluids/tissues, including mock casework samples. The resulting data set was used to build a probabilistic model that predicts the origin of a stain. Our approach uses partial least squares followed by linear discriminant analysis to classify samples into six commonly occurring forensic body fluids. The model differs from the ones previously suggested in that it incorporates quantitative information (NGS read counts) rather than just presence/absence of markers. The suggested approach also allows for visualisation of important markers and their correlation with the different body fluids. We compared our model to previously published methods to show that the inclusion of read count information improves the prediction. Finally, we applied the model to mixed body fluid samples to test its ability to identify the individual components in a mixture. PMID- 29413635 TI - Forensic genetic informativeness of an SNP panel consisting of 19 multi-allelic SNPs. AB - Current research focusing on forensic personal identification, phenotype inference and ancestry information on single-nucleotide polymorphisms (SNPs) has been widely reported. In the present study, we focused on tetra-allelic SNPs in the Chinese Han population. A total of 48 tetra-allelic SNPs were screened out from the Chinese Han population of the 1000 Genomes Database, including Chinese Han in Beijing (CHB) and Chinese Han South (CHS). Considering the forensic genetic requirement for the polymorphisms, only 11 tetra-allelic SNPs with a heterozygosity >0.06 were selected for further multiplex panel construction. In order to meet the demands of personal identification and parentage identification, an additional 8 tri-allelic SNPs were combined into the final multiplex panel. To ensure application in the degraded DNA analysis, all the PCR products were designed to be 87-188 bp. Employing multiple PCR reactions and SNaPshot minisequencing, 511 unrelated Chinese Han individuals from Sichuan were genotyped. The combined match probability (CMP), combined discrimination power (CDP), and cumulative probability of exclusion (CPE) of the panel were 6.07 * 10 11, 0.9999999999393 and 0.996764, respectively. Based on the population data retrieved from the 1000 Genomes Project, Fst values between Chinese Han in Sichuan (SCH) and all the populations included in the 1000 Genomes Project were calculated. The results indicated that two SNPs in this panel may contain ancestry information and may be used as markers of forensic biogeographical ancestry inference. PMID- 29413636 TI - Concordance of the ForenSeqTM system and characterisation of sequence-specific autosomal STR alleles across two major population groups. AB - By using sequencing technology to genotype loci of forensic interest it is possible to simultaneously target autosomal, X and Y STRs as well as identity, ancestry and phenotypic informative SNPs, resulting in a breadth of data obtained from a single run that is considerable when compared to that generated with standard technologies. It is important however that this information aligns with the genotype data currently obtained using commercially available kits for CE based investigations such that results are compatible with existing databases and hence can be of use to the forensic community. In this work, 400 samples were typed using commercially available STR kits and CE, as well as using the Ilumina ForenSeqTM DNA Signature Prep Kit and MiSeq(r) FGx to assess concordance of autosomal STRs and population variability. Results show a concordance rate between the two technologies exceeding 99.98% while numerous novel sequence based alleles are described. In order to make use of the sequence variation observed, sequence specific allele frequencies were generated for White British and British Chinese populations. PMID- 29413637 TI - Short Takes. PMID- 29413638 TI - Evidence of Diplopia in Children's Headache Drawings Helps to Differentiate Pseudotumor Cerebri From Migraine. AB - OBJECTIVE: This study aimed to determine whether children's headache drawings can distinguish between pseudotumor cerebri and migraine. BACKGROUND: Headache features associated with pseudotumor cerebri (pseudotumor; idiopathic intracranial hypertension) are nonspecific and are difficult to distinguish clinically from migraines. Children's headache drawings have a high predictive value for migraine versus nonmigraine headaches. We hypothesized that drawings could help to differentiate pediatric headaches due to pseudotumor cerebri from those associated with migraines. METHODS: Children aged six to 18 years old attending university hospital pediatric neurology clinics were asked to draw a picture of how their headache feels. From our database of children's headache drawings, pictures by children with clinically diagnosed pseudotumor were compared with migraine drawings. RESULTS: Headache drawings of 21 children (16 females) with pseudotumor were compared with those of 518 children with migraine. Pseudotumor drawings depicted a variety of symptoms including pounding pain (n = 11), pressure-like pain (n = 3), photophobia (3), dizziness (1), and recumbency (1). Severe pain indicators included hammers, bombs, anvil, and vise grip. Positive visual phenomena included scintillations, scotomata, or blurring (n = 8). Negative visual phenomena included field defects (n = 2). Pseudotumor drawings were similar to migraine drawings except that 6 of 21 pseudotumor drawings (28.6%) depicted diplopia (crossed eyes, double images), whereas only three of 518 migraine drawings (0.6%) depicted diplopia (P < 0.000001). CONCLUSIONS: Diplopia was depicted in a significantly higher percentage of pseudotumor drawings than migraine drawings. In all other respects, headache drawings by children with pseudotumor cerebri were similar to those drawn by children with migraine. PMID- 29413639 TI - Biotin and Acetazolamide for Treatment of an Unusual Child With Autism Plus Lack of Nail and Hair Growth. AB - BACKGROUND: Patients with autism spectrum disorder and developmental delay or encephalopathy rarely demonstrate no or negligible hair and nail growth, suggesting a biotin-responsive clinical disorder. METHODS: A ten-year-old girl presented with features of autism spectrum disorder, isolated headaches, and episodes of headaches and limb shaking. Her medical history revealed that her hair and nails did not grow. Administration of biotin restored her nail and hair growth and improved intellectual ability and school performance. Her episodes of headaches, single limb shaking, and loss of consciousness responded to administration of acetazolamide, and her school performance and social skills further improved. RESULTS: A de novo c.1091 C > T, p.T364M pathogenic variant was found in the ATP1A2 gene by whole-exome sequencing, but a genetic etiology in the biotin-responsive metabolic pathways was not identified. CONCLUSIONS: The combination of biotin and acetazolamide treatment was successful in restoring normal mental function and school performance. Poor or no clinical nail and hair growth in any child with a developmental delay-autism spectrum disorder presentation should be considered as evidence for a biotin-responsive genetic disorder even when exome testing is negative. PMID- 29413643 TI - National Institute on Aging - Alzheimer's Association Research Framework lays the groundwork for deeper understanding of Alzheimer's disease. PMID- 29413644 TI - App to model pandemic influenza. PMID- 29413645 TI - The Role of Cardiovascular Magnetic Resonance Imaging in the Assessment of Highly Trained Athletes. AB - Exercise-associated benefits on the cardiovascular systems are well established. Although exercise-associated sudden cardiac death is rare, most deaths in young athletes are due to hereditary or congenital cardiac diseases. Athletic adaptation itself is associated with several structural changes that overlap those observed in individuals with cardiomyopathies, often leading to dilemmas for the clinician regarding life-changing decisions including advice against competitive sports participation. Cardiac magnetic resonance plays an increasingly important role in helping to establish an accurate diagnosis in these individuals. This review highlights the role of cardiac magnetic resonance in differentiating physiological adaptation in athletes from pathology. PMID- 29413646 TI - Assessment of Left Ventricular Function by Echocardiography: The Case for Routinely Adding Global Longitudinal Strain to Ejection Fraction. AB - Left ventricular (LV) ejection fraction (LVEF) is a simple measure of global systolic function that pervades the risk evaluation and management of many cardiovascular diseases. However, this parameter is limited not only by technical challenges, but also by pathophysiological entities where the ratio of stroke volume to LV cavity size is preserved. The assessment of global longitudinal strain (GLS) from speckle-tracking analysis of 2-dimensional echocardiography has become a clinically feasible alternative to LVEF for the measurement of myocardial function. Evidence gathered over the last decade has shown GLS to be more sensitive to left ventricular dysfunction (LVD) than LVEF and to provide additional prognostic information. The technology is validated, reproducible within an acceptable range, and widely available. GLS has been proposed as the test of choice in guidelines for monitoring of asymptomatic cardiotoxicity related to chemotherapy. It also has the potential to improve risk stratification, redefine criteria for disease classification, and determine treatment in asymptomatic LVD resulting from a variety of etiologies. GLS provides utility across the spectrum of heart failure (and LVEF) as well as in the evaluation of valvular heart disease. There is a strong case for incorporation of GLS into clinical decision making. This review appraises the evidence addressing the utility of GLS as a complementary metric to LVEF for incorporation into mainstream clinical practice. PMID- 29413647 TI - The Location of Distal Coronary Artery Pressure Measurement Matters for Computed Tomography-Derived Fractional Flow Reserve. PMID- 29413648 TI - The Authors Reply. PMID- 29413649 TI - Predicting Cardiac Prognosis in Asymptomatic Chronic Kidney Disease Patients. PMID- 29413650 TI - The Authors Reply. PMID- 29413651 TI - A Strain by Any Other Tracking Would Perform as Sweet? PMID- 29413652 TI - Core Needle Biopsy of the Breast: An Evaluation of Contemporary Data. AB - Benign and atypical lesions associated with breast cancer risk are often encountered in core needle biopsies (CNBs) of the breast. For these lesions, the rate of "upgrade" to carcinoma in excision specimens varies widely in the literature. Many CNB studies are limited by a lack of radiological-pathological correlation, consistent criteria for excision, and clinical follow-up for patients who forego excision. This article highlights contemporary diagnostic criteria and outcome data that would support an evidence-based approach to the management of these nonmalignant lesions of the breast diagnosed on CNB. PMID- 29413654 TI - Ancillary Prognostic and Predictive Testing in Breast Cancer: Focus on Discordant, Unusual, and Borderline Results. AB - Ancillary testing in breast cancer has become standard of care to determine what therapies may be most effective for individual patients with breast cancer. Single-marker tests are required on all newly diagnosed and newly metastatic breast cancers. Markers of proliferation are also used, and include both single marker tests like Ki67 as well as panel-based gene expression tests, which have made more recent contributions to prognostic and predictive testing in breast cancers. This review focuses on pathologist interpretation of these ancillary test results, with a focus on expected versus unexpected results and troubleshooting borderline, unusual, or discordant results. PMID- 29413655 TI - A Diagnostic Approach to Fibroepithelial Breast Lesions. AB - Fibroepithelial breast lesions encompass a heterogeneous group of neoplasms that range from benign to malignant, each exhibiting differing degrees of stromal proliferation in relation to the epithelial compartment. Fibroadenomas are common benign neoplasms that may be treated conservatively. Phyllodes tumors are relatively rare lesions, and classified as benign, borderline, or malignant based on histologic evaluation of various parameters. The diagnostic interpretation of "gray-zone" fibroepithelial lesions often imposes formidable demands on a pathologist's skills. This article offers practical recommendations for the diagnostic workup of these lesions, including the appropriate utilization of ancillary investigations and the approach to core needle biopsies. PMID- 29413656 TI - Precursor Lesions of the Low-Grade Breast Neoplasia Pathway. AB - The nonobligate precursor lesions columnar cell change/hyperplasia and flat epithelial atypia, atypical ductal hyperplasia and atypical lobular hyperplasia, lobular carcinoma in situ, and low-grade ductal carcinoma in situ share morphologic, immunophenotypic, and molecular features supporting the existence of a low-grade breast neoplasia pathway. The practical implication for pathologists is that the identification of one of these lesions should prompt careful search for others. From a clinical management perspective, however, their designation as "precursor lesions" should not be overemphasized, as the risk of progression among the earliest lesions is exceedingly low. Factors determining which lesions will progress remain unknown. PMID- 29413653 TI - Lobular Carcinoma In Situ. AB - Lobular carcinoma in situ (LCIS) is a risk factor and a nonobligate precursor of breast carcinoma. The relative risk of invasive carcinoma after classic LCIS diagnosis is approximately 9 to 10 times that of the general population. Classic LCIS diagnosed on core biopsy with concordant imaging and pathologic findings does not mandate surgical excision, and margin status is not reported. The identification of variant LCIS in a needle core biopsy specimen mandates surgical excision, regardless of radiologic-pathologic concordance. The presence of variant LCIS close to the surgical margin of a resection specimen is reported, and reexcision should be considered. PMID- 29413657 TI - Genotype-Phenotype Correlations in Breast Cancer. AB - Only a few breast cancer histologic subtypes harbor distinct genetic alterations that are associated with a specific morphology (genotype-phenotype correlation). Secretory carcinomas and adenoid cystic carcinomas are each characterized by recurrent translocations, and invasive lobular carcinomas frequently have CDH1 mutations. Solid papillary carcinoma with reverse polarity is a rare breast cancer subtype with a distinctive morphology and recently identified IDH2 mutations. We review the clinical and pathologic features and underlying genetic alterations of those breast cancer subtypes with established genotype-phenotype correlations and discuss the phenotypes associated with germline mutations in genes associated with hereditary breast cancer. PMID- 29413658 TI - Processing and Reporting of Breast Specimens in the Neoadjuvant Setting. AB - Standardization of quantification of residual disease in the breast and lymph nodes with routine pathologic macroscopic and microscopic evaluation leads to accurate and reproducible measures of response to neoadjuvant treatment. Multidisciplinary collaboration and correlation of clinical, imaging, gross and microscopic findings is essential. The processing approach to post-neoadjuvant breast cancer surgical specimens and the elements needed in the pathology report are the same regardless of breast cancer subtype or type of neoadjuvant treatment. The residual cancer burden incorporates response in the breast and in the lymph nodes into a score that can be combined with other emerging prognostic factors. PMID- 29413659 TI - Axillary Lymph Node Inclusions. AB - Lymph node inclusions can occur in axillary lymph nodes, where they can mimic metastatic breast carcinoma. This article provides an overview of epithelial and nonepithelial lymph node inclusions, including mammary-type glandular inclusions, Mullerian-type glandular inclusions, squamous inclusions, mixed glandular squamous inclusions, and nodal nevi. The discussion emphasizes the histologic and immunophenotypic features and differential diagnoses of each entity. PMID- 29413660 TI - An Update of Mucinous Lesions of the Breast. AB - Mucinous lesions of the breast include a variety of benign and malignant epithelial processes that display intracytoplasmic or extracellular mucin, including mucocelelike lesions, mucinous carcinoma, solid papillary carcinoma, and other rare subtypes of mucin-producing carcinoma. The most important diagnostic challenge is the finding of free-floating or stromal mucin accumulations for which the significance depends on the clinical, radiologic, and pathologic context. This article emphasizes the differential diagnosis between mucocelelike lesions and mucinous carcinoma, with a brief consideration of potential mimics, such as biphasic and mesenchymal lesions with myxoid stroma ("stromal mucin") and foreign material. PMID- 29413661 TI - Differential Diagnosis of Benign Spindle Cell Lesions. AB - Spindle cell lesions of the breast cover a wide spectrum of diseases ranging from reactive tumor-like lesions to high-grade malignant tumors. The recognition of the benign spindle cell tumor-like lesions (nodular fasciitis; reactive spindle cell nodule after biopsy, inflammatory pseudotumor/inflammatory myofibroblastic tumor; fascicular variant of pseudoangiomatous stromal hyperplasia) and tumors (myofibroblastoma, benign fibroblastic spindle cell tumor, leiomyoma, schwannoma, spindle cell lipoma, solitary fibrous tumor, myxoma) is crucial to avoid confusion with morphologically similar but more aggressive bland-appearing spindle cell tumors, such as desmoid-type fibromatosis, low-grade (fibromatosis like) spindle cell carcinoma, low-grade fibrosarcoma/myofibroblastic sarcoma and dermatofibrosarcoma protuberans. PMID- 29413665 TI - Contemporary Topics in Breast Pathology. PMID- 29413668 TI - QTc prolongation, increased NT-proBNP and pre-clinical myocardial wall remodeling in excessive alcohol consumers: The SABPA study. AB - Alcohol contributes greatly to vascular and structural modifications. Due to differences in the metabolism and tolerance of alcohol between ethnic groups, the manner of these modifications may differ. We investigated the association between alcohol consumption - measured via ethnic-specific gamma glutamyl transferase (gamma-GT) cut-points - and markers of cardiac perfusion, electrical activity, and pre-clinical structural alterations. A South African target population study was performed in a bi-ethnic cohort (n = 405). Alcohol consumption was determined according to previously defined ethnic-specific gamma-GT cut-points, where gamma GT >= 19.5 U/L and gamma-GT >= 55 U/L indicated excessive alcohol consumption in Caucasians and Africans, respectively. Ambulatory 24-h blood pressure and electrocardiograms (ECG), 10-lead ECG left ventricular hypertrophy (LVH), ischemic events, N-terminal pro-brain natriuretic peptide (NT-proBNP), and QTc prolongation were assessed. Fasting blood samples were obtained. A poorer cardio metabolic profile and mean 24-h hypertensive and ECG-LVH values were evident in high gamma-GT groups of both ethnicities, when compared to their low counterparts. The African high gamma-GT group reported a higher intake of alcohol and presented significant increases in NT-proBNP (p < 0.001), QTc prolongation (p = 0.008), and ischemic events (p = 0.013). Regression analyses revealed associations between ECG-LVH and NT-proBNP, QTc prolongation, ischemic events, and SBP, in the African high gamma-GT group exclusively. High alcohol consumers presented delayed electrical conduction in the heart accompanied by ECG-LVH, ischemic events, and increased vaso-responsiveness, predominantly in Africans. Ultimately, increased left ventricular distension on a pre-clinical level may elevate the risk for future cardiovascular events in this population. PMID- 29413669 TI - Shelf life of meat from Boer-Saanen goats fed diets supplemented with vitamin E. AB - This work aims at evaluating shelf life of meat from Boer-Saanen cross goats fed on diets containing vitamin E. Thirty-five feedlot-fed goats with an initial body weight of 21.6+/-2.8kg were subjected to four treatments in a completely randomized design: a control treatment with vitamin E plus others containing 50, 150, and 450mg dl-alpha-tocopherol acetate/kg DM. Longissimus lumborum (LL) muscle samples were stored at temperatures between 4 and 6 degrees C during 15days, and evaluated for lipid peroxidation using the thiobarbituric acid reactive substances (TBARS) method and for visual acceptance by consumers by different survival analysis techniques. The addition, vitamin E in diets influenced shelf life of LL muscle, indicating longer meat preservation as the levels of the vitamin in diet increased, as the results obtained in chemical and subjective visual assessments showed. TBARS analysis showed to be more accurate in predicting shelf life of meat than subjective visual assessment by consumers, which reached a saturation threshold of 2mg malonaldehyde/kg of meat earlier at all tested levels of vitamin E inclusion. PMID- 29413670 TI - Modeling the effect of oregano essential oil on shelf-life extension of vacuum packed cooked sliced ham. AB - The present study modeled the effect of oregano essential oil, as an antimicrobial agent, on the shelf-life of vacuum-packed cooked sliced ham, based on the growth of lactic acid bacteria natural microbiota under isothermal conditions. The bacterial growth in ham without oregano essential oil (control) and with 0.4% oregano essential oil (v/w) was evaluated at five different temperatures (6, 12, 15, 20 and 25 degrees C). Baranyi and Roberts, and modified Gompertz primary models were fitted to microbial growth curves. Square Root and Exponential secondary models were fitted to MUmax parameter data. The addition of oregano essential oil increased lag phase, decreased growth rates and extended shelf-life of ham for all temperatures (at 6 degrees C extended for, at least, 30days when compared to control). Statistical indexes showed that Baranyi and Roberts, and Exponential were the primary and secondary models, respectively, that better fit to the data. Thus, oregano essential oil showed a good antimicrobial effect and extended the ham shelf-life. PMID- 29413671 TI - The prevalence of Clostridium difficile in cattle and sheep carcasses and the antibiotic susceptibility of isolates. AB - Clostridium difficile is an anaerobic, spore forming, rod shaped bacterium frequently isolated from butchery animals in recent years. The aim of this study is to evaluate the presence of C. difficile (especially ribotype 027 and 078) in cattle and sheep carcasses and to investigate the antibiotic susceptibility of isolates. The bacterium was isolated in 83 out of 247 (33.6%) cattle and 78 out of 308 (25.3%) sheep carcass samples. 15/83 (18.1%) cattle and 6/78 (7.7%) sheep isolates were identified as ribotype 027, whereas the other hypervirulent isolate ribotype 078 could not be detected among the analysed samples. Almost all isolates were susceptible to amoxicillin-clavulanic acid (98.8%), vancomycin (96.9%) and tetracycline (97.5%), whereas resistant to cefotaxim (97.5%) and imipenem (87.0%). In conclusion, the results demonstrate the presence of toxigenic C. difficile isolates in cattle and sheep carcasses on the slaughter line. As a result, the results of this study demonstrate the presence of toxigenic C. difficile isolates in cattle and sheep carcasses on the slaughter line. PMID- 29413672 TI - Impact of whey protein coating incorporated with Bifidobacterium and Lactobacillus on sliced ham properties. AB - Edible coatings/films with functional ingredients may be a solution to consumers' demands for high-quality food products and an extended shelf-life. The aim of this work was to evaluate the antimicrobial efficiency of edible coatings incorporated with probiotics on sliced ham preservation. Coatings was developed based on whey protein isolates with incorporation of Bifidobacterium animalis Bb 12(r) or Lactobacillus casei-01. The physicochemical analyses showed that coating decreased water and weight loss on the ham. Furthermore, color analysis showed that coated sliced ham, exhibited no color change, comparatively to uncoated slices. The edible coatings incorporating the probiotic strains inhibited detectable growth of Staphylococcus spp., Pseudomonas spp., Enterobacteriaceae and yeasts/molds, at least, for 45days of storage at 4 degrees C. The sensory evaluation demonstrated that there was a preference for the sliced coated ham. Probiotic bacteria viable cell numbers were maintained at ca. 108CFU/g throughout storage time, enabling the slice of ham to act as a suitable carrier for the beneficial bacteria. PMID- 29413674 TI - The effects of including corn silage, corn stalk silage, and corn grain in finishing ration of beef steers on meat quality and oxidative stability. AB - The effect of cattle feed on beef quality and oxidative stability was investigated. A corn silage (CS)-based finishing diet was compared with the diets based on corn stalk silage (SS) or corn stalk silage combined with its expected corn grain (SSC), containing a ratio of stalk to grain of corn plant of 1.5:1. Replacing CS with SS in the finishing diet had no effect on the proximate nutrients, cholesterol content, fatty acids profile, pH, color, water holding capacity, tenderness, texture profile, or oxidative stability of beef muscle. Compared to the CS diet and SS diet, cattle fed SSC diet showed an inferior antioxidant capacity, lower SOD and higher MDA concentrations in blood. SSC diet fed cattle also showed higher MDA and protein carbonyl concentrations in beef muscle indicating increased oxidation damage, and potentially resulting in a greater drip loss of the beef muscle. Corn silage can be replaced in the finishing feed of beef cattle with corn stalk silage without any negative effects on measures of beef quality. PMID- 29413673 TI - Supplementation of Nigella sativa seeds to Barbarine lambs raised on low- or high concentrate diets: Effects on meat fatty acid composition and oxidative stability. AB - Twenty-eight Barbarine male lambs were used to investigate the effect of dietary Nigella sativa seeds (NSS) on meat fatty acids and oxidative stability in two different feeding systems (high- or low-concentrate). Dietary treatments were planned to offer: 70% barley hay and 30% concentrate (LC); LC+12g/day of NSS (LCN); 30% barley hay and 70% concentrate (HC); HC+12g/day of NSS (HCN). NSS increased intramuscular fat only in the low-concentrate system (P=0.039); accordingly, the content of 14:0, c-9 14:1, t-9 18:1, t-11 18:1 and both individual and sum of odd and branched chain fatty acids were greater in LCN than LC meat. TBARS in raw meat increased from 0 to 3days of refrigerated storage regardless NSS supplementation. From 3 to 6days, TBARS further increased only in the meat from lambs not receiving NSS. At 6-days storage, TBARS were lower (P<0.05) in the meat of lambs receiving NSS compared to the meat of lambs not receiving NSS. PMID- 29413675 TI - Fatty acid composition of polar and neutral meat lipids of goats browsing in native pasture of Brazilian Semiarid. AB - Thirty six male goats grazing Caatinga native pasture were randomly assigned to 4 concentrate supplementation levels (0, 5, 10 and 15g/kg of body weight) and slaughtered after 120days. Longissimus muscle meat lipids were extracted and fractionated into neutral (NL) and polar (PL) lipids. Supplementation of grazing goats increased linearly (P<0.05) intramuscular fat (1 to 1.5% of meat) and NL (0.3 to 1% of meat) but decreased linearly (P=0.044) the PL (0.66 to 0.50% of meat). On NL, supplementation increased linearly (P=0.047) the proportion of c9 18:1 (31 to 40% of FA) with supplementation. On PL, supplementation reduced linearly (P<0.03) the dimethyl acetals, 18:3n-3 and most of long chain polyunsaturated FA (PUFA) proportions but increased linearly (P<0.001) the c9 18:1. Considering the total meat FA, supplementation led to an increase of the saturated and monounsaturated FA contents and a decrease of the long chain n-6 and n-3 PUFA contents. PMID- 29413676 TI - Effect of deboning time on the growth of Salmonella, E. coli, aerobic, and lactic acid bacteria during beef sausage processing and storage. AB - The objective of the current study was to determine the effects of deboning time, three steps of sausage processing (grinding, salting, and batter formulation), and storage time (of raw materials and cooked sausage) on the growth (log CFU/g) of aerobic bacteria, lactic acid bacteria, and inoculated Salmonella and E. coli. Beef deboning time did not influence bacterial counts (P>=0.138). However, salting of raw ground beef resulted in a 0.4-log reduction in both aerobic plate count (APC) and Salmonella (P<=0.001). Lactic acid bacteria were increased from non-detectable concentration (0.54 log) on d 0 to 3.8 log on d 120 of vacuum storage (P<=0.019). Salmonella counts were increased (P<0.001) over storage time (3.2 to 3.3 log CFU/g from d 0 to 10). Results indicated that salting and batter formulation had a greater impact on bacterial counts than rigor state of raw beef. PMID- 29413677 TI - Prolonging shelf life of lamb cutlets packed under high-oxygen modified atmosphere by spraying essential oils from North-African plants. AB - The aim of this study was to assess the effectiveness of sprayable essential oils for counteracting the pro-oxidant environment created during retail display of lamb cutlets packed under high-oxygen atmosphere. North-African essential oils from Pituranthos chloranthus (PC) and Teucrium ramosissimum (TR) were applied by spraying on the surface of whole-lamb cutlets. The bio-preservative treatment led to a significant increase of their shelf life in terms of protection against lipid and protein oxidative deterioration, discoloration of lean and bone and microbiological stability during 12days of chilled storage. Furthermore, the addition of TR and PC on the surface of lamb cutlets significantly improved their appearance, increasing hence the purchase intention and consumers' preferences towards treated retailed products. This study shows that the application of a high-oxygen active packaging in combination with natural sprayable extracts is a feasible and effective strategy for protecting whole-meat muscle foods against oxidation and microbial deterioration. PMID- 29413678 TI - A supply chain approach to improving the shelf life of lamb meat; vitamin E concentration, electrical stimulation, ageing period and packaging system. AB - This study investigated the effects of vitamin E, electrical stimulation, aging and packaging system on the colour stability of lamb meat. Eighty crossbred wether lambs, 6-8months old were fed on either vitamin E or control pelleted diet for 31days prior to slaughter. Half of the carcases from each group were electrically stimulated before being split longitudinally into 2. Each side was randomly allocated 1 of the 4 aging periods (5days fresh, 10, 20 and 30days CO2). Muscle samples were set for retail display, after the respective aging period, colour was measured over 96h. Supplementing vitamin E nutritionally is likely to lengthen the shelf life of lamb products aged longer than 10days. Muscle vitamin E concentrations >3.0mg/kg are required to increase the shelf life of lamb cuts aged for up to 30days to 60h. Medium voltage electrical stimulation did not have a detrimental effect on the display life of aged lamb meat. PMID- 29413679 TI - Assessment of the quality of refrigerated and frozen pork by multivariate exploratory techniques. AB - Pork loin and leg were evaluated 24h after slaughter and during refrigerated (5 degrees C) and frozen storage for microbial counts, pH, total volatile base nitrogen (TVB-N), thiobarbituric acid reactive substances (TBARS) and bioactive amines. Spermine was the prevalent amine in fresh pork loin and leg, followed by spermidine and agmatine. During refrigerated storage, pH, TVB-N, mesophilic and psychrotrophic counts increased and no changes (p<0.05) were observed on polyamines; however putrescine, cadaverine and histamine were produced and accumulated throughout storage. Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) for all parameters indicated a shelf life of 8days for both cuts, which was also coherent with safety regarding histamine levels. During frozen storage, there was no change on amines and pH, TVB-N decreased, and TBARS increased. None biogenic amine was produced. PCA and HCA were not able to classify frozen pork based on the analyzed parameters; however, a shelf life of 90days was suggested for the frozen cuts based on lipid oxidation. PMID- 29413680 TI - The effect of dietary energy content on quality characteristics of Boer goat meat. AB - The palatability and chemical composition of Longissimus lumborum muscles from 24 Boer goat castrates (eight goats per treatment), finished on diets varying in energy content (9.7, 10.2 and 10.6MJ ME/kg feed), were evaluated by a trained sensory panel on a line scale ranging from low to high intensity for aroma, flavour and texture attributes. Physical measurements as well as proximate analysis were performed for each sample. No differences (P>0.05) were found between the dietary treatments for any of the attributes analysed. Lamb flavour and aroma were the most prominent attributes, while only low levels of goat-like flavours were detected. Juiciness and tenderness had a strong correlation (r=0.864) and were rated to be moderate. The findings suggest that energy density of feedlot diets can be varied to still produce chevon with uniform meat quality characteristics. PMID- 29413681 TI - Tenderness classification of fresh broiler breast fillets using visible and near infrared hyperspectral imaging. AB - The aim of this study was to classify and visualize tenderness of intact fresh broiler breast fillets using hyperspectral imaging (HSI) technique. A total of 75 chicken fillets were scanned by HSI system of 400-1000nm in reflectance mode. Warner-Bratzler shear force (WBSF) value was used as reference tenderness indicator and fillets were grouped into least, moderately and very tender categories accordingly. To extract additional image textural features, principal component analysis (PCA) transform of images were conducted and gray level co occurrence matrix (GLCM) analysis was implemented in region of interests (ROIs) on first three PC score images. Partial least square discriminant analysis (PLS DA) or radial basis function-support vector machine (RBF-SVM) was developed for predicting tenderness based on full wavelengths (CCR=0.92), selected wavelengths (CCR=0.84), textural or combined data (CCR=0.88). Classification maps were created by pixels prediction in images and breast fillet tenderness was readily discernible. Overall, HSI technique is a promising methodology for predicting tenderness of intact fresh broiler breast meat. PMID- 29413682 TI - Rigor bonds cause reduced sarcomeric volume in skinned porcine skeletal muscle under PSE-like conditions. AB - Effects of rigor cross-bridge attachment on water holding in PSE-like conditions were investigated. A new model using permeabilised/skinned porcine longissimus thoracis et lumborum muscle fibres was established to study effects of varied pH, temperature and the presence of rigor bonds on the muscle fibre structure. Preparations were exposed during 30min to different temperatures (22 and 38 degrees C) and pH (7.0 and 5.5) in relaxed and rigor states, followed by evaluation of active force and filament lattice spacing (using small angle X-ray scattering) at standard pH (7.0) and temperature (22 degrees C) conditions. A significant reduction of active force and filament spacing was observed after treatment in rigor at denaturing (38 degrees C, pH5.5) conditions. The present study show that rigor bond attachment under denaturing conditions leads to a compressed interfilamental space, loss of sarcomeric water and affected contractile function. PMID- 29413683 TI - Presence of oxygen and mitochondria in skeletal muscle early postmortem. AB - Anaerobic glycolysis dominates energy metabolism postmortem. Even so, however, recent studies suggest mitochondria can modify postmortem energy metabolism and may contribute to pH decline, possibly affecting the transformation of muscle to meat and fresh meat quality development. Because oxygen is a necessary component of mitochondrial function, oxygenation of porcine and bovine longissimus thoracis et lumborum was determined postmortem using NIR spectroscopy. The ratio of oxy- to deoxymyoglobin decreased with time postmortem in both species. Metabolic analyses of muscle samples collected over the same timeframe also revealed fluctuations in TCA intermediates. Finally, mitochondria collected from muscle of electrically stimulated carcasses differed from those of non-stimulated muscle. Collectively, these data support the thesis that muscle mitochondria function early postmortem and may play a more active part in pH decline and possibly meat quality development. PMID- 29413684 TI - Human epidermal receptor family inhibitors in patients with ERBB3 mutated cancers: Entering the back door. AB - INTRODUCTION: Therapeutic inhibition of the human epidermal receptor 3 (ERBB3, HER3) has been challenged by the low frequency of ERBB3 somatic alterations across cancer types. We have evaluated the clinical utility to use available inhibitors of the HER family in the context of ERBB3 mutations. PATIENTS AND METHODS: In this study, we have selected patients with somatic ERBB3 alterations detected in their tumours from the molecular screening programs running at our institution. Techniques used for molecular screening were targeted next generation sequencing, comparative genomic hybridisation and/or whole exome sequencing on fresh frozen tumour biopsies. RESULTS: On the 844 patients with a molecular portrait of their tumours, 31 (3.7%) had a somatic mutation of ERBB3. Overall, 9 patients received available inhibitors of HER family, including trastuzumab and/or lapatinib or afatinib. Sixteen patients received other molecularly targeted agents, including the Mammalian Target Of Rapamycin (mTOR), the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K) or NOTCH inhibitors or chemotherapy, and 4 patients failed being treated. Thirteen different histological subtypes were affected by ERBB3 mutations; top ones were colorectal carcinomas (6 patients), non-small cell lung cancers (4 patients, including a squamous cell carcinoma), head and neck squamous cell carcinomas (3 patients) and breast carcinomas (3 patients). The presence of a mutation in the tyrosine kinase domain of the ERBB3/HER3 protein detected in four patients' tumours was significantly related to good progression-free survival (hazard ratio [HR] = 0.18, p value = 0.022) and overall survival (HR = 0.19, p value = 0.03) in univariate analysis. Treatment of these four patients included at least a tyrosine kinase inhibitor lapatinib or afatinib. CONCLUSION: Our exploratory analysis suggests that mutations in the tyrosine kinase domain of the HER3 protein are related to a favourable outcome under HER family inhibitors. PMID- 29413685 TI - PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer-a randomised biomarker-driven clinical phase II AIO study. AB - BACKGROUND: Combination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer. PATIENTS AND METHODS: Patients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.v q3w). The primary end point was the evaluation of progression-free survival (PFS) at 6 months. Secondary end-points included objective response rate (ORR), overall survival (OS), and toxicity. In addition, a post hoc assessment of genetic alterations was performed. Finally, we performed a meta-analysis of trials with chemotherapy with and without EGFR antibodies. RESULTS: Sixty-two patients were randomised in arm A and 28 patients in arm B. Patients received 7 treatment cycles in median (1-35) with a median treatment duration of 4.7 months (141 days, 8-765). PFS rate at 6 months was 54% in patients treated with cisplatin/gemcitabine and panitumumab but was 73% in patients treated with cisplatin/gemcitabine without antibody, respectively. Secondary end-points were an ORR of 45% in treatment arm A compared with 39% receiving treatment B and a median OS of 12.8 months (arm A) and of 20.1 months (arm B), respectively. In contrast to the p53-status, genetic alterations in IDH1/2 were linked to a high response after chemotherapy and prolonged survival. In accordance with our results, the meta-analysis of 12 trials did not reveal a survival advantage for patients treated with EGFR antibodies compared with chemotherapy alone. CONCLUSIONS: Panitumumab in combination with chemotherapy does not improve ORR, PFS and OS in patients with KRAS wild-type, advanced biliary cancer. Genetic profiling should be included in CCA trials to identify and validate predictive and prognostic biomarkers. CLINICAL TRIALS NUMBER: The trial was registered with NCT01320254. PMID- 29413686 TI - Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma. AB - BACKGROUND: Quality of life (QOL) is impaired in pancreatic cancer patients. Our aim was to investigate the determinants and prognostic value of QOL after diagnosis in a hospital-based cohort of racially/ethnically diverse patients with pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: QOL was prospectively assessed using the Short Form-12 in 2478 PDAC patients. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were categorised into tertiles based on their distribution. Ordered logistic regression was adopted to compare the risk of having lower PCS and MCS by patient sociodemographic and clinical characteristics. The association of PCS and MCS with mortality was assessed by Cox regression. RESULTS: Compared with non Hispanic whites, Hispanics were at significantly higher risk of having lower PCS (odds ratio [95% CI], 1.69 [1.26-2.26]; P < 0.001) and lower MCS (1.66 [1.24 2.23]; P < 0.001). Patients diagnosed with stage III (1.80 [1.10-2.94]; P = 0.02) and stage IV (2.32 [1.50-3.59]; P < 0.001) PDAC were more likely to have lower PCS than stage I patients. Other determinants of QOL included sex, age, drinking, smoking, education level, comorbidities and time since diagnosis. The low tertile of PCS (hazard ratio [95% CI], 1.94 [1.72-2.18]; P < 0.001) and MCS (1.42 [1.26 1.59]; P < 0.001) were each related to poor prognosis. Similar results were found for non-Hispanic whites as compared with African-Americans/Hispanics/others. CONCLUSION: QOL after diagnosis is a significant prognostic indicator for patients with PDAC. Multiple factors determine QOL, suggesting possible means of intervention to improve QOL and outcomes of PDAC patients. PMID- 29413687 TI - Olaratumab in soft tissue sarcoma - Current status and future perspectives. AB - Recent randomised phase II trial data have indicated that the addition of olaratumab, a novel monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFRalpha), to doxorubicin confers an unprecedented improvement in overall survival to patients with anthracycline-naive advanced soft tissue sarcoma. However, this result was disproportionate with progression-free survival and response rate, and consequently there are unanswered questions regarding the precise mechanism of action of olaratumab. While preclinical data show that olaratumab specifically inhibits PDGFRalpha-mediated oncogenic signalling with attendant anti-tumour effects, a lack of correlation between pharmacodynamics markers of PDGFRalpha inhibition and clinical benefit from olaratumab suggest other mechanisms beyond modulation of downstream PDGFRalpha molecular pathways. Proposed mechanisms of olaratumab activity include engagement of anti-tumour immune responses and alterations of the tumour stroma, but these require further evaluation. Meanwhile, the drug-specific contribution of cytotoxic agents to olaratumab-containing combinations has yet to be characterised. Ongoing and future preclinical and translational studies, coupled with the anticipated results of a phase III trial that has completed enrolment, should provide greater insight into the efficacy and mode of action of olaratumab in soft tissue sarcomas. PMID- 29413688 TI - Predictive factors of outcome in poorly differentiated thyroid carcinomas. AB - BACKGROUND: The prognosis of poorly differentiated thyroid carcinomas (PDTC) is heterogeneous though generally poor. The objectives of this study were to identify clinical and molecular factors of poor prognosis. METHODS: One hundred four consecutive patients treated for a PDTC between 01/01/2000 and 31/12/2010 were included in this study. A pathological review was done for all cases (blinded to clinical data and outcome). RESULTS: All patients underwent thyroidectomy. Adjuvant radioactive-iodine was administered in 95.2% of them. Tumours were pT3 or pT4 in 68.3% of cases and metastatic in 38.5% of patients. Extrathyroidal extension (ETE) was observed in 40% of patients. At the end of the initial treatment, only 37% of patients were considered in remission. Fifty-two patients (50%) became refractory to radioiodine during follow-up. The 5-year overall survival was 72.8% and the 5-year recurrence-free survival (RFS) was 45.3%. Remission after initial treatment was an independent factor of RFS (HR = 0.22; [0.10-0.49]). ETE was the only significant parameter influencing the overall survival in multivariate analysis. TERT promoter mutations at positions 124 (C228T) and -146 (C250T) were present in 38.1% of analysed patients and significantly associated with radioiodine resistance but not with overall survival. Half of TERT promoter mutant tumours harboured also RAS or BRAF mutations. CONCLUSION: PDTC form a heterogeneous group of patients with usual late-stage diagnosis, low radioactive iodine avidity and frequent metastatic spread. TERT promoter mutations could help to identify patients with high risk of radio-iodine refractoriness. PMID- 29413689 TI - Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy. AB - The germline BAP1 (BRCA1-associated protein-1) mutation and associated cancer pre disposition syndrome was first described in 2011. Since then, physicians have considered this diagnosis for patients with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions). However, a positive germline BAP1 mutation detection creates significant uncertainty in terms of appropriate cancer surveillance. A number of groups have proposed surveillance plans but important management dilemmas remain unresolved. The lifetime risk of developing cancer is not known and it is not clear if surveillance would lead to detecting cancer at an earlier stage or change survival outcomes. A consensus monitoring strategy was initially proposed at the Melanoma Institute Australia Melanoma Multidisciplinary Team meeting and later discussed with specialists in the field of cancer genetics, pathology, radiology, medical oncology, ophthalmology and dermatology. The objectives were to facilitate early diagnosis, incorporating where possible, clinically based and low/non-ionising radiation imaging modalities, applying the principles of a good screening test and a multidisciplinary focus. PMID- 29413690 TI - The future of blood-based biomarkers for the early detection of breast cancer. AB - Breast cancer (BC) is the most frequently diagnosed cancer and the most common cause of cancer-related mortality among women worldwide. Despite the extensive use of mammography as the gold standard for BC screening, the occurrences of false-positive and false-negative mammograms, as well as overdiagnosis, remain a concern in breast oncology. Thus, there is a need to identify reliable biomarkers from an easily accessible source that could generate cost-effective assays feasible for routine screening. Blood-based biomarkers may offer an alternative non-invasive strategy to improve cancer screening. Although none of the currently used blood-based biomarkers are sensitive enough for the early detection of BC, a plethora of significant findings pertaining to the development of screening tools using blood-based biomarkers have emerged in recent years. Promising candidate biomarkers such as proteins, autoantibodies, miRNAs, nucleic acid methylation, metabolites and lipids have shown great potential for detecting BC, including detection at the pre-invasive and early stages of the disease. Nevertheless, blood-based biomarkers for BC screening are still at the early phases of development, and various clinical and preclinical issues need to be addressed before these biomarkers can be used clinically. This review summarises the latest discoveries for harnessing blood-based biomarkers as novel BC screening tools, as well as discusses the limitations and challenges that need to be overcome before the translation of their use from the bench to the bedside. PMID- 29413691 TI - Susan Lee Lindquist (1949-2016). PMID- 29413692 TI - The molecular cues for the biological effects of ionizing radiation dose and post irradiation time on human breast cancer SKBR3 cell line: A Raman spectroscopy study. AB - Radiotherapy is one of the main modalities of cancer treatment. The utility of Raman spectroscopy (RS) for detecting the distinct radiobiological responses in human cancer cells is currently under investigation. RS holds great promises to provide good opportunities for personalizing radiotherapy treatments. Here, we report the effects of the radiation dose and post-irradiation time on the molecular changes in the human breast cancer SKBR3 cells, using RS. The SKBR3 cells were irradiated by gamma radiation with different doses of 0, 1, 2, 4, and 6 Gy. The Raman signals were acquired 24 and 48 h after the gamma radiation. The collected Raman spectra were analyzed by different statistical methods such as principal component analysis, linear discriminant analysis, and genetic algorithm. A thorough analysis of the obtained Raman signals revealed that 2 Gy of gamma radiation induces remarkable molecular and structural changes in the SKBR3 cells. We found that the wavenumbers in the range of 1000-1400 cm-1 in Raman spectra are selective for discriminating between the effects of the different doses of irradiation. The results also revealed that longer post irradiation time leads to the relaxation of the cells to their initial state. The molecular changes that occurred in the 2Gy samples were mostly reversible. On the other hand, the exposure to doses higher than 4Gy induced serious irreversible changes, mainly seen in 2700-2800 cm-1 in Raman spectra. The classification models developed in this study would help to predict the radiation-based molecular changes induced in the cancer cells by only using RS. Also, this designed framework may facilitate the process of biodosimetry. PMID- 29413693 TI - UV-B affects the immune system and promotes nuclear abnormalities in pigmented and non-pigmented bullfrog tadpoles. AB - Ultra-Violet (UV) radiation is a stressor of the immune system and causes DNA damage. Leukocytes can change in response to environmental changes in anurans, making them an important biomarker of stressful situations. The initial barrier against UV in ectothermic animals is melanin-containing cells in skin and in their internal organs. Here, we tested the effects of UV exposure on immune cells and DNA integrity in pigmented and non-pigmented tadpoles of Lithobates catesbeianus. We used an inflammation model with lipopolysaccharide (LPS) of Escherichia coli to test synergic effects of UV and LPS. We tested the following hypotheses: 1) DNA damage caused by UV will be more pronounced in non-pigmented than in pigmented animals; 2) LPS increases leukocytes in both pigmented and non pigmented animals by systemic inflammation; 3) The combined LPS and UV exposure will decrease the number of leukocytes. We found that the frequency of immune cells differed between pigmented and non-pigmented tadpoles. UV exposure increased mast cells and DNA damage in erythrocytes in both pigmented and non pigmented tadpoles, while leukocytes decreased after UV exposure. Non-pigmented tadpoles experienced DNA damage and a lower lymphocyte count earlier than pigmented tadpoles. UV altered immune cells likely as a consequence of local and systemic inflammation. These alterations were less severe in pigmented than in non-pigmented animals. UV and LPS increased internal melanin in pigmented tadpoles, which were correlated with DNA damage and leukocytes. Here, we described for the first time the effects of UV and LPS in immune cells of pigmented and non-pigmented tadpoles. In addition, we demonstrated that internal melanin in tadpoles help in these defenses, since leukocyte responses were faster in non-pigmented animals, supporting the hypothesis that melanin is involved in the initial innate immune response. PMID- 29413694 TI - Anticancer activity of crocin against cervical carcinoma (HeLa cells): Bioassessment and toxicity evaluation of crocin in male albino rats. AB - The present study was aimed to investigate anticancer activity of crocin against cervical carcinoma and bio-assessment and toxicological evaluation in male albino rats. Effect of crocin on cell viability (anticancer activity) was determined against cervical carcinoma cells. Chronic effect of crocin on body weight changes, serum enzymes, serum biochemical markers, lipid peroxidation, hematological markers and DNA damage in male albino rats were determined. Cell survival rate was reduced 98.4, 95.7, 87.2, 81.1 and 73.1% at 25, 50, 75, 100 and 125 mg/l of crocin respectively. Cell viability was reduced 97.1, 96.4, 85.5, 78.4 and 70.2% at 25, 50, 75, 100 and 125 mg/l of crocin respectively. Crocin reduced body weight significantly at 30 and 60th day. Alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), blood urea nitrogen (BUN), creatinine, bilirubin, albumin and total protein were decreased, while glucose, cholesterol, TG, and GSH were increased. Hemoglobin (Hb), white blood cells (WBC), lymphocytes, neutrophil and packed cell volume (PCV) were altered following crocin treatment. Necrosis, fibrosis, mononuclear infiltration, angiogenesis and DNA fragmentation were also noted. Taking all these data together, it is suggested that the crocin could be a potential antitumor agent against cervical carcinoma. However, the altered histological, biochemical and hematological markers may lead to an adverse effect on the cellular metabolism and physiological activity. PMID- 29413695 TI - Elucidation of intermolecular interaction of bovine serum albumin with Fenhexamid: A biophysical prospect. AB - Fenhexamid, as a hydroxyanilide, is widely applied to control Botrytis cinerea for protecting crops and fruits. But it could adversely affect human and animals health due to accumulation of residues in food production. Here, the affinity characteristics of fenhexamid on bovine serum albumin (BSA) was studied via a series of spectroscopic methods such as steady-state fluorescence spectroscopy, ultraviolet spectroscopy (UV), synchronous fluorescence spectroscopy (SFS), 3D fluorescence spectroscopy, and fourier transform infrared spectroscopy (FT-IR). The experimental results illustrated that the fluorescence quenching mechanism of BSA induced by fenhexamid was a static quenching. The binding constant (Kb) of fenhexamid with BSA was 2.399 * 104 M-1 at 298 K and the combination ratio was about 1:1. The competitive experiment demonstrated that fenhexamid was binding on the BSA at site II (subdomain IIIA), which was confirmed by the molecular docking studies. The negative values of thermodynamic parameter (DeltaH0, DeltaS0 and DeltaG0) revealed that the reaction of fenhexamid with BSA could proceed spontaneously, the van der Waals force and hydrogen bonding interaction conducted the main effect, and the binding process was enthalpy-driven. What's more, the 8 Anilino-1-naphthalenesulfonate (ANS) and sucrose binding studies were also performed and further verified the binding force between BSA and fenhexamid. PMID- 29413696 TI - PSII as an in vivo molecular catalyst for the production of energy rich hydroquinones - A new approach in renewable energy. AB - One of the pertinent issues in the field of energy science today is the quest for an abundant source of hydrogen or hydrogen equivalents. In this study, phenyl-p benzoquinone (pPBQ) has been used to generate a molecular store of hydrogen equivalents (phenyl-p-hydroquinone; pPBQH2) from thein vivo splitting of water by photosystem II of the marine cyanobacterium Synechococcus elongatus BDU 70542. Using this technique, 10.8 MUmol of pPBQH2 per mg chlorophyll a can be extracted per minute, an efficiency that is orders of magnitude higher when compared to the techniques present in the current literature. Moreover, the photo-reduction process was stable when tested over longer periods of time. Addition of phenyl-p benzoquinone on an intermittent basis resulted in the precipitation of phenyl-p hydroquinone, obviating the need for costly downstream processing units for product recovery. Phenyl-p-hydroquinone so obtained is a molecular store of free energy preserved through the light driven photolysis of water and can be used as a cheap and a renewable source of hydrogen equivalents by employing transition metal catalysts or fuel cells with the concomitant regeneration of phenyl-p benzoquinone. The cyclic nature of this technique makes it an ideal candidate to be utilized in mankind's transition from fossil fuels to solar fuels. PMID- 29413697 TI - The effect of light and temperature on the dynamic state of Rhodobacter sphaeroides reaction centers proteins determined from changes in tryptophan fluorescence lifetime and P+QA- recombination kinetics. AB - The temperature dependencies of the rate of dark recombination of separated charges between the photoactive bacteriochlorophyll and the primary quinone acceptor (QA) in photosynthetic reaction centers (RCs) of the purple bacteria Rhodobacter sphaeroides (Rb. sphaeroides) were investigated. Measurements were performed in water-glycerol and trehalose environments after freezing to -180 degrees C in the dark and under actinic light with subsequent heating. Simultaneously, the RC tryptophanyl fluorescence lifetime in the spectral range between 323 and 348 nm was measured under these conditions. A correlation was found between the temperature dependencies of the functional and dynamic parameters of RCs in different solvent mixtures. For the first time, differences in the average fluorescence lifetime of tryptophanyl residues were measured between RCs frozen in the dark and in the actinic light. The obtained results can be explained by the RC transitions between different conformational states and the dynamic processes in the structure of the hydrogen bonds of RCs. We assumed that RCs exist in two main microconformations - "fast" and "slow", which are characterized by different rates of P+ and QA- recombination reactions. The "fast" conformation is induced in frozen RCs in the dark, while the "slow" conformation of RC occurs when the RC preparation is frozen under actinic light. An explanation of the temperature dependencies of tryptophan fluorescence lifetimes in RC proteins was made under the assumption that temperature changes affect mainly the electron transfer from the indole ring of the tryptophan molecule to the nearest amide or carboxyl groups. PMID- 29413699 TI - Exploring the non-covalent binding behaviours of 7-hydroxyflavone and 3 hydroxyflavone with hen egg white lysozyme: Multi-spectroscopic and molecular docking perspectives. AB - The interactions of bio-active flavonoids, 7-hydroxyflavone (7HF) and 3 hydroxyflavone (3HF) with hen egg white lysozyme (HEWL) have been established using differential spectroscopic techniques along with the help of molecular docking method. The characteristic dual fluorescence of 3HF due to the excited intramolecular state proton transfer (ESIPT) process is altered markedly upon binding with HEWL. Both the flavonoids quenched the intrinsic fluorescence of HEWL through static quenching mechanism while the binding affinity of 7HF was found to be greater than 3HF under experimental conditions. The binding constant (Kb) values were estimated to be in the order of 104 M-1 and decreased with the rise in temperature. The contributions of the thermodynamic parameters (DeltaH degrees and DeltaS degrees ) revealed that hydrophobic forces along with hydrogen bonding played a crucial role in the interaction of HEWL with 7HF and 3HF respectively and this finding was aptly supported by the molecular docking studies. The donor (HEWL) to acceptors (7HF and 3HF) binding distances were calculated using the Foster's theory. The phenomena of blue shifting of the emission maxima of the residues indicated the increase in hydrophobicity around the Trp micro-environment upon addition of the flavonoids was observed from synchronous and 3D fluorescence measurements whereas REES study indicated the decrease in mobility of the Trp residues upon addition of the ligands. The CD, FTIR and thermal melting studies indicated the alteration in the structural stability of HEWL on ligand binding and it was found that the % alpha-helical content decreased on complexation with 7HF and 3HF respectively as compared to native state. The flavonoids were found to inhibit the enzymatic activity of HEWL. The molecular docking results and accessible surface area (ASA) calculations revealed that the flavonoids bind within the active site of HEWL. The negative DeltaG degrees values obtained from experimental and molecular docking studies indicate the spontaneity of the interaction processes. PMID- 29413698 TI - Platelet-rich plasma-induced feedback inhibition of activin A/follistatin signaling: A mechanism for tumor-low risk skin rejuvenation in irradiated rats. AB - BACKGROUND: Platelet-rich plasma (PRP) is a source of natural growth factors and is emerging as a treatment modality to mitigate radiotherapy- induced adverse effects. Activin A (ACTA) is a member of the transforming growth factor-beta (TGF beta) superfamily, which has been shown to modulate the inflammatory response and macrophages polarization between different phenotypes. The aim of this study is to determine the value of PRP in preventing radiation-induced malignancies in light of the cross-talk between PRP and activin A type II receptors (ActR IIA)/follistatin (FST) signaling pathways where the inflammatory responses at 2 different time points were evaluated. MATERIAL AND METHODS: Male albino rats were exposed to radiation and given PRP over the course of 6 days. Rats were sacrificed on day 7 or day 28 post radiation. RESULTS: Quantitative real-time reverse transcriptase polymerase chain reaction (QRT-PCR) and western-blot showed that after 7 days of administrating of PRP, ActR-IIA/FST signaling was markedly induced and was associated with the expressions of inflammatory, natural killer and M1 macrophages markers, TNF-alpha, IL-1beta, IFN-gamma and IL-12. By contrast, on day 28 of PRP administration, ActR-IIA/FST signaling and the expressions of proinflammatory cytokines were downregulated in parallel with inducing M2 macrophages phenotype as indicated by arginase-1, IL-10 and dectin-1. CONCLUSION: The suppression of inflammation and induction of M2 macrophages phenotype in response to PRP administration were found significantly linked to ActR-IIA/FST signaling downregulation. Furthermore, the specific M2 macrophage subtype was found to express dectin-1 receptors which have high affinity for tumor cells thereby is expected to reduce the potential for developing tumors after radiotherapy. PMID- 29413700 TI - Green synthesis of NiO nanoparticles using Aegle marmelos leaf extract for the evaluation of in-vitro cytotoxicity, antibacterial and photocatalytic properties. AB - In the present study, we report the green synthesis of NiO nanoparticles using Aegle marmelos as a fuel and this method is ecofriendly and cost effective. The plant Aegle marmelos is used in the field of pharmaceuticals to cure diseases like chronic diarrhea, peptic ulcers and dysentery in India for nearly 5 centuries. The as-prepared nanoparticles were confirmed as pure face centered cubic phase and single crystalline in nature by XRD. The formation of agglomerated spherical nanoparticles was shown by HR-SEM and HR-TEM images. The particle size calculated from HR-SEM was in the range 8-10 nm and it matches with the average crystallite size calculated from the XRD pattern. NiO shows intense emission peaks at 363 and 412 nm in its PL spectra. The band gap of 3.5 eV is observed from DRS studies and the formation of pure NiO is confirmed by FT-IR spectra. The as-prepared NiO nanoparticles show super paramagnetic behavior, when magnetization studies are carried out. It is then evaluated for cytotoxic activity towards A549 cell culture, antibacterial activity and photocatalytic degradation (PCD) of 4-chlorophenol (4-CP), which is known as the endocrine disrupting chemical (EDC). From the results, it is found that the cell viability of A549 cells was effectively reduced and it showed better antibacterial activity towards gram positive bacterial strains. It is also proved to be an efficient and stable photocatalyst towards the degradation of 4-CP. PMID- 29413701 TI - Calcium oxalate druses affect leaf optical properties in selenium-treated Fagopyrum tataricum. AB - Plants of the genus Fagopyrum contain high levels of crystalline calcium oxalate (CaOx) deposits, or druses, that can affect the leaf optical properties. As selenium has been shown to modify the uptake and accumulation of metabolically important elements such as calcium, we hypothesised that the numbers of druses can be altered by selenium treatment, and this would affect the leaf optical properties. Tartary buckwheat (Fagopyrum tataricum Gaertn.) was grown outdoors in an experimental field. At the beginning of flowering, plants were foliarly sprayed with sodium selenate solution at 10 mg selenium L-1 or only with water. Plant morphological, biochemical, physiological and optical properties were examined, along with leaf elemental composition and content. Se spraying did not affect leaf biochemical and functional properties. However, it increased leaf thickness and the contents of Se in the leaves, and decreased the density of calcium oxalate druses in the leaves. Except Se content, Se spraying did not affect contents of other elements in leaves, including total calcium per dry mass of leaf tissue. Redundancy analysis showed that of all parameters tested, only the calcium oxalate druses parameters were significant in explaining the variability of the leaf reflectance and transmittance spectra. The density of CaOx druses positively correlated with the reflectance in the blue, green, yellow and UV-B regions of the spectrum, while the area of CaOx druses per mm2 of leaf transection area positively correlated with the transmittance in the green and yellow regions of the spectrum. PMID- 29413702 TI - Waste chimney oil to nanolights: A low cost chemosensor for tracer metal detection in practical field and its polymer composite for multidimensional activity. AB - Proper waste disposal from household and restaurants is becoming an important and recurring waste-management concern. Herein, a method of upcycling of waste kitchen chimney oil has been adopted to prepare fluorescent multifunctional carbon quantum dots. These nanodots showed superior biocompatibility, excellent optical properties, water solubility and high yield. Preparation of C-dots from highly abundant carbon source of waste refusals is highly effective in commercial aspect as well as in reducing the immense environmental pollution. The C-dots showed quasi-spherical size obtained from high resolution transmission electron microscopy (HRTEM) having an abundance of 1-4 nm in size. The ease of water dispersibility of the nanodots is a mere reflection of their surface polarity which has been supported by Fourier transformed infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). In the field of practical acceptability, the C-dots have been experimented to sense Fe3+ ion in a wide range of concentration (1 nM to 600 MUM) with a detection limit of 0.18 nM which can be termed as 'tracer metal chemosensor'. Moreover, the prepared carbon dots were also tested against inter-cellular Fe3+ ion sensing probe. Lastly, we also fabricate the biopolymer-carbon dots composite for fluorescent marker ink and light emitting polymer film. PMID- 29413703 TI - Synthesis and characterization of Tamoxifen citrate modified reduced graphene oxide nano sheets for breast cancer therapy. AB - Theranostic agents are of immense consideration in the current generation nanomedicine. In this study, we have developed a facile approach for the fabrication of Tamoxifen citrate modified nanosized reduced graphene oxide (nano rGO) with more stability and low cytotoxicity. The prepared nano-rGO sheets were characterized using HR-TEM and AFM imaging techniques. Further, the cytotoxicity was assessed using MTT assay on female BALB/c nude mice MCF-7 cell lines. In addition, by means of continuous-wave near-infrared laser, cancer cells in vivo were significantly ablated because of the photothermal effect stimulated by tamoxifen modified nano-rGO. These results indicated that the prepared tamoxifen modified nano-rGO has the ability to apply in the photothermal therapy of breast cancers. Consequently, further exploration of photothermal therapeutics is desirable for the synthesis of novel nano materials with additional functionalities. PMID- 29413704 TI - Development of bupivacaine decorated reduced graphene oxide and its local anesthetic effect-In vivo study. AB - The present works aims to develop bupivacaine modified reduced graphene oxide (BPV/RGO), and comparative evaluation of their anesthetic effect with free bupivacaine (BPV). The prepared BPV/RGO was studied by using various spectroscopic and microscopic characterization studies. In vitro drug release from BPV/RGO was studied using HPLC analysis. The cytotoxicity of BPV/RGO was studied against fibroblast (3T3) cells. In vivo evaluation of anesthetic effects was performed on animal models. BPV/RGO showed a prolonged in vitro release and lower cytotoxicity when compared to free BPV. Also, BPV/RGO showed a significantly prolonged analgesic effect when compared to free BPV. Further, the prepared BPV/RGO drug delivery system demonstrated to function as gifted to overcome the drawbacks of free BPV and other available drug delivery systems by prolonging the anesthetic effect with poor cytotoxicity. PMID- 29413705 TI - New cationic and neutral copper(II) complexes containing 7-hydroxy-4-oxo-4[H] chromene derived ONO pincer ligands: Synthesis, characterization and in vitro biological evaluations. AB - New Schiff base ligands are prepared by the condensation of 7-hydroxy-3 formylchromone with semicarbazone and phenyl semicarbazone. The complexation of these ligands with Cu(II) ion is proposed in the light of spectral studies (IR, UV-Vis, 1H NMR, 13C NMR, Mass and ESR). In the complexes 1 and 2, the ligands coordinate to the Cu(II) ion in a neutral fashion via ONO donor atoms. The single crystal XRD studies reveal a slightly distorted square-pyramidal geometry for cationic complex (1) and an octahedral geometry for neutral complex (2). Preliminary biological studies such as DNA and Protein binding are carried out by using absorption and emission titration methods. Observation of intercalative mode of binding with Calf Thymus DNA (CT-DNA) is confirmed by means of viscosity measurements. The micro-environmental changes occurring in Bovine Serum Albumin (BSA) and Human Serum Albumin (HSA) are monitored via three dimensional (3D) fluorescence studies. The compounds ability in inhibiting microbial growth is tested against different pathogens. MCF-7 (human breast cancer) and A549 (human lung carcinoma) cell lines are utilized to check the anticancer potential of the synthesized compounds by using MTT, LDH and NO assays. The results show that complexes 1 and 2 exhibited potent cytotoxic activity over standard drug cisplatin. PMID- 29413706 TI - Photodynamic effect and mechanism study of selenium-enriched phycocyanin from Spirulina platensis against liver tumours. AB - Selenium-containing phycocyanin (Se-PC) has been proved to have many biological effects, including anti-inflammatory and antioxidant. In this study, we investigated the photodynamic therapy (PDT) effects of Se-PC against liver tumour in vitro and in vivo experiment. Our results demonstrated that the half lethal dose of Se-PC PDT on HepG2 cells was 100MUg/ml PC containing 20% selenium. Se-PC location migration from lysosomes to mitochondria was time dependent. In in vivo experiments, the tumour inhibition rate was 75.4% in the Se-PC PDT group, compared to 52.6% in PC PDT group. Histological observations revealed that the tumour cells outside the tissue showed cellular necrosis, and those inside the tissue exhibited apoptotic nuclei and digested vacuoles in the cytoplasm after Se PC PDT treatment. Antioxidant enzyme analysis indicated that GSH-Px activity was linked to the selenium content of Se-PC, and SOD activity was affected by PC PDT. Therefore, Se-PC PDT could induce cell death through free radical production of PDT in tumours and enhance the activity of antioxidant enzymes with selenium in vivo. The mechanism of Se-PC PDT against liver tumour involves hematocyte damage and mitochondria-mediated apoptosis accompanied with autophagy inhibition during early stage of tumour development, which displayed new prospect and offered relatively safe way for cancer therapy. PMID- 29413707 TI - Reduced graphene oxide coated Cu2-xSe nanoparticles for targeted chemo photothermal therapy. AB - Recently, copper chalcogenide semiconductors have been reported as new near infrared (NIR) photothermal agents. However, it is difficult to modify them with recognition molecules, and their photothermal conversion efficiencies are relatively low, making it difficult to achieve the targeted photothermal ablation of cancer cells with a high efficiency. In this study, reduced graphene oxide (rGO) was first coated on the surface of Cu2-xSe nanoparticles (NPs) to provide abundant functional groups for the next modification and to increase the photothermal conversion efficiency. Then, doxorubicin (DOX) was loaded and folic acid (FA) molecules were covalently linked onto the surface of Cu2-xSe/rGO nanocomposites. The formed DOX@Cu2-xSe@rGO-FA nanocomposites were successfully used as chemo-photothermal agents for the targeted killing of cancer cells by utilizing the recognition ability of FA, chemotherapy effect of DOX and photothermal effects of rGO and Cu2-xSe NPs. Under the 980-nm NIR laser irradiation, the nanocomposites showed significantly enhanced chemo-photothermal therapy effect, which can be potentially applied in the nanomedicine field. PMID- 29413708 TI - Regio- and stereoselective synthesis of new spirooxindoles via 1,3-dipolar cycloaddition reaction: Anticancer and molecular docking studies. AB - Owing to their structural novelty and inherent three-dimensionality, spiro scaffolds have been shown indisputable promise as chemopreventive agents. A new series of heterocycles containing spirooxindole and pyrrolidine rings were synthesized by the 1,3-dipolar cycloaddition of an azomethine ylide, which was generated in situ by the condensation of a secondary amino acid (l-proline) and dicarbonyl compounds (isatin), with dipolarophiles. This method is simple and provides diverse and biologically interesting products. The new series of compounds with a high degree of stereo- and regioselectivity were evaluated against breast cancer cell lines (MCF-7) and leukemia (K562). Among them, compound 4g was identified as the most potent with IC50 values of 15.49 +/- 0.04 MUM, against breast cancer cell lines (MCF-7) compared to standard drug 5-Fu (IC50 = 78.28 +/- 0.2 MUM) and compound 4i IC50 values of 13.38 +/- 0.14 MUM against leukemia (K562) compared to standard drug 5-fluorouracil (5-FU) (IC50 = 38.58 +/- 0.02). The selective apoptotic effects of 4g were investigated against MCF-12 normal mammary cell and the cytotoxicity of 4g was not associated with any induction of necrosis compared to untreated cells. Molecular docking studies were investigated. From the docking data, these compounds could be act as small molecules that inhibit the MDM2-p53 interaction. PMID- 29413709 TI - Spatial and population drivers of persistent cholera transmission in rural Bangladesh: Implications for vaccine and intervention targeting. AB - We identify high risk clusters and measure their persistence in time and analyze spatial and population drivers of small area incidence over time. The geographically linked population and cholera surveillance data in Matlab, Bangladesh for a 10-year period were used. Individual level data were aggregated by local 250 * 250 m communities. A retrospective space-time scan statistic was applied to detect high risk clusters. Generalized estimating equations were used to identify risk factors for cholera. We identified 10 high risk clusters, the largest of which was in the southern part of the study area where a smaller river flows into a large river. There is persistence of local spatial patterns of cholera and the patterns are related to both the population composition and ongoing spatial diffusion from nearby areas over time. This information suggests that targeting interventions to high risk areas would help eliminate locally persistent endemic areas. PMID- 29413710 TI - Comparing the geographic distribution and location characteristics of HIV seropositive and HIV-seronegative individuals with a diagnosis of cancer living in the southeast US. AB - As HIV-seropositive individuals live longer, they are more likely to acquire conditions seen in the general population. Excluding AIDS-defining malignancies, HIV-seropositive individuals are more likely to develop cancer than individuals in the general population. In order to better inform future screening and prevention efforts in this population, we compared the geographic distribution and location characteristics of HIV-seropositive and HIV-seronegative cancer cases in South Carolina (SC). To do this we obtained linked HIV and cancer data from the SC enhanced HIV/AIDS Reporting System and Central Cancer Registry. Location-related information on SC residents (e.g., employment status, income levels, race of householder, and educational attainment) was obtained from the 2000 US Census. Hotspot analyses were used to analyze the geographic distribution of HIV-seropositive and HIV-seronegative cancer cases using the Getis-Ord Gi* statistic. Poisson regression analyses assessed if county demographic and geographic characteristics were associated with HIV-positive cancer case rates. PMID- 29413711 TI - Bayesian hierarchical model of ceftriaxone resistance proportions among Salmonella serotype Heidelberg infections. AB - The National Antimicrobial Resistance Monitoring System (NARMS) at the Centers for Disease Control and Prevention tracks resistance among Salmonella infections. The annual number of Salmonella isolates of a particular serotype from states may be small, making direct estimation of resistance proportions unreliable. We developed a Bayesian hierarchical model to improve estimation by borrowing strength from relevant sampling units. We illustrate the models with different specifications of spatio-temporal interaction using 2004-2013 NARMS data for ceftriaxone-resistant Salmonella serotype Heidelberg. Our results show that Bayesian estimates of resistance proportions were smoother than observed values, and the difference between predicted and observed proportions was inversely related to the number of submitted isolates. The model with interaction allowed for tracking of annual changes in resistance proportions at the state level. We demonstrated that Bayesian hierarchical models provide a useful tool to examine spatio-temporal patterns of small sample size such as those found in NARMS. PMID- 29413713 TI - Diving into the consumer nutrition environment: A Bayesian spatial factor analysis of neighborhood restaurant environment. AB - Neighborhood restaurant environment (NRE) plays a vital role in shaping residents' eating behaviors. While NRE 'healthfulness' is a multi-facet concept, most studies evaluate it based only on restaurant type, thus largely ignoring variations of in-restaurant features. In the few studies that do account for such features, healthfulness scores are simply averaged over accessible restaurants, thereby concealing any uncertainty that attributed to neighborhoods' size or spatial correlation. To address these limitations, this paper presents a Bayesian Spatial Factor Analysis for assessing NRE healthfulness in the city of Kitchener, Canada. Several in-restaurant characteristics are included. By treating NRE healthfulness as a spatially correlated latent variable, the adopted modeling approach can: (i) identify specific indicators most relevant to NRE healthfulness, (ii) provide healthfulness estimates for neighborhoods without accessible restaurants, and (iii) readily quantify uncertainties in the healthfulness index. Implications of the analysis for intervention program development and community food planning are discussed. PMID- 29413712 TI - Approximate Bayesian computation for spatial SEIR(S) epidemic models. AB - Approximate Bayesia n Computation (ABC) provides an attractive approach to estimation in complex Bayesian inferential problems for which evaluation of the kernel of the posterior distribution is impossible or computationally expensive. These highly parallelizable techniques have been successfully applied to many fields, particularly in cases where more traditional approaches such as Markov chain Monte Carlo (MCMC) are impractical. In this work, we demonstrate the application of approximate Bayesian inference to spatially heterogeneous Susceptible-Exposed-Infectious-Removed (SEIR) stochastic epidemic models. These models have a tractable posterior distribution, however MCMC techniques nevertheless become computationally infeasible for moderately sized problems. We discuss the practical implementation of these techniques via the open source ABSEIR package for R. The performance of ABC relative to traditional MCMC methods in a small problem is explored under simulation, as well as in the spatially heterogeneous context of the 2014 epidemic of Chikungunya in the Americas. PMID- 29413714 TI - Assessing the association of diabetes self-management education centers with age adjusted diabetes rates across U.S.: Aspatial cluster analysis approach. AB - The purpose of this study is to identify regions with diabetes health-service shortage. American Diabetes Association (ADA)-accredited diabetes self-management education (DSME) is recommended for all those with diabetes. In this study, we focus on demographic patterns and geographic regionalization of the disease by including accessibility and availability of diabetes education resources as a critical component in understanding and confronting differences in diabetes prevalence, as well as addressing regional or sub-regional differences in awareness, treatment and control. We conducted an ecological county-level study utilizing publicly available secondary data on 3,109 counties in the continental U.S. We used a Bayesian spatial cluster model that enabled spatial heterogeneities across the continental U.S. to be addressed. We used the American Diabetes Association (ADA) website to identify 2012 DSME locations and national 2010 county-level diabetes rates estimated by the Centers for Disease Control and Prevention and identified regions with low DSME program availability relative to their diabetes rates and population density. Only 39.8% of the U.S. counties had at least one ADA-accredited DSME program location. Based on our 95% credible intervals, age-adjusted diabetes rates and DSME program locations were associated in only seven out of thirty five identified clusters. Out of these seven, only two clusters had a positive association. We identified clusters that were above the 75th percentile of average diabetes rates, but below the 25th percentile of average DSME location counts and found that these clusters were all located in the Southeast portion of the country. Overall, there was a lack of relationship between diabetes rates and DSME center locations in the U.S., suggesting resources could be more efficiently placed according to need. Clusters that were high in diabetes rates and low in DSME placements, all in the southeast, should particularly be considered for additional DSME programming. PMID- 29413715 TI - Evaluation of spatio-temporal Bayesian models for the spread of infectious diseases in oil palm. AB - In the field of epidemiology, studies are often focused on mapping diseases in relation to time and space. Hierarchical modeling is a common flexible and effective tool for modeling problems related to disease spread. In the context of oil palm plantations infected by the fungal pathogen Ganoderma boninense, we propose and compare two spatio-temporal hierarchical Bayesian models addressing the lack of information on propagation modes and transmission vectors. We investigate two alternative process models to study the unobserved mechanism driving the infection process. The models help gain insight into the spatio temporal dynamic of the infection by identifying a genetic component in the disease spread and by highlighting a spatial component acting at the end of the experiment. In this challenging context, we propose models that provide assumptions on the unobserved mechanism driving the infection process while making short-term predictions using ready-to-use software. PMID- 29413716 TI - Proteomic profiling of epileptogenesis in a rat model: Focus on cell stress, extracellular matrix and angiogenesis. AB - Information about epileptogenesis-associated changes in protein expression patterns is of particular interest for future selection of target and biomarker candidates. Bioinformatic analysis of proteomic data sets can increase our knowledge about molecular alterations characterizing the different phases of epilepsy development following an initial epileptogenic insult. Here, we report findings from a focused analysis of proteomic data obtained for the hippocampus and parahippocampal cortex samples collected during the early post-insult phase, latency phase, and chronic phase of a rat model of epileptogenesis. The study focused on proteins functionally associated with cell stress, cell death, extracellular matrix (ECM) remodeling, cell-ECM interaction, cell-cell interaction, angiogenesis, and blood-brain barrier function. The analysis revealed prominent pathway enrichment providing information about the complex expression alterations of the respective protein groups. In the hippocampus, the number of differentially expressed proteins declined over time during the course of epileptogenesis. In contrast, a peak in the regulation of proteins linked with cell stress and death as well as ECM and cell-cell interaction became evident at later phases during epileptogenesis in the parahippocampal cortex. The data sets provide valuable information about the time course of protein expression patterns during epileptogenesis for a series of proteins. Moreover, the findings provide comprehensive novel information about expression alterations of proteins that have not been discussed yet in the context of epileptogenesis. These for instance include different members of the lamin protein family as well as the fermitin family member 2 (FERMT2). Induction of FERMT2 and other selected proteins, CD18 (ITGB2), CD44 and Nucleolin were confirmed by immunohistochemistry. Taken together, focused bioinformatic analysis of the proteomic data sets completes our knowledge about molecular alterations linked with cell death and cellular plasticity during epileptogenesis. The analysis provided can guide future selection of target and biomarker candidates. PMID- 29413717 TI - Sustained increase in angiopoietin-2, heparin-binding protein, and procalcitonin is associated with severe sepsis. AB - PURPOSE: The identification of infection at its early stage in vulnerable patients is challenging. This study aimed to investigate potential biomarkers to distinguish patients progressing to severe sepsis from those with uncomplicated sepsis. MATERIALS AND METHODS: Serum samples were collected from sepsis patients admitted to the emergency department. The mRNA and protein levels of angiopoietin 2 (Ang-2), interleukin-10 (IL-10), heparin-binding protein (HBP), procalcitonin (PCT), adrenomedullin (ADM), and interleukin-6 (IL-6) were evaluated. RESULTS: Compared to those of healthy individuals (n = 47), mRNA levels of ANG2, IL10, HBP, PCT, and ADM were increased in patients who eventually developed sepsis. ANG2 was the only gene whose expression was significantly increased in patients developing severe sepsis than in those with uncomplicated sepsis. Serum levels of Ang-2, IL-10, HBP, PCT, and IL-6 were also increased in sepsis patients, but only Ang-2, HBP, and PCT were elevated in the serum of patients developing severe septic shock than in those with uncomplicated sepsis. Serum levels of Ang-2, HBP, and PCT were closely associated with the sequential organ failure assessment (SOFA) score of the patients. CONCLUSIONS: These findings indicated that sustained elevation of Ang-2, HBP, and PCT were associated with severe infection in critically ill patients. PMID- 29413718 TI - Postprandial hypotension in older survivors of critical illness. AB - PURPOSE: In older people postprandial hypotension occurs frequently; and is an independent risk factor for falls, cardiovascular events, stroke and death. The primary aim of this pilot study was to estimate the frequency of postprandial hypotension and evaluate the mechanisms underlying this condition in older survivors of an Intensive Care Unit (ICU). MATERIALS AND METHODS: Thirty-five older (>65 years) survivors were studied 3 months after discharge. After an overnight fast, participants consumed a 300 mL drink containing 75 g glucose, labelled with 20 MBq 99mTc-calcium phytate. Patients had concurrent measurements of blood pressure, heart rate, blood glucose and gastric emptying following drink ingestion. Proportion of participants is presented as percent (95% CI) and continuous variables as mean (SD). RESULTS: Postprandial hypotension was evident in 10 (29%; 95% CI 14-44), orthostatic hypotension in 2 (6%; 95% CI 0-13) and cardiovascular autonomic dysfunction in 2 (6%; 95% CI 0-13) participants. The maximal postprandial nadir for systolic blood pressure and diastolic blood pressures were -29 (14) mmHg and -18 (7) mmHg. CONCLUSIONS: In this cohort of older survivors of ICU postprandial hypotension occurred frequently . This suggests that postprandial hypotension is an unrecognised issue in older ICU survivors. PMID- 29413719 TI - Role of Ulinastatin, a trypsin inhibitor, in severe acute pancreatitis in critical care setting: A retrospective analysis. AB - PURPOSE: To evaluate the clinical utility of Ulinastatin, a multifunctional serine protease inhibitor, in the management of severe acute pancreatitis. MATERIALS AND METHODS: We conducted a retrospective analysis of the archived data of adult patients diagnosed with acute pancreatitis and admitted to surgical intensive care unit with one or more end organ dysfunction. The patients were divided into two groups depending on whether they did or did not receive ulinastatin. Outcome variables namely in-hospital mortality, development of new onset organ dysfunction, resolution of existing organ dysfunction by Day 5 and length of hospital stay were compared. RESULTS: Forty-eight patients, 25 who received Ulinastatin (Ulinastatin group) and 23 who did not (Control group) were analyzed. The in-hospital mortality was significantly lower in the Ulinastatin group (16% vs 69.6%; p = 0.0003). Significantly smaller proportion of patients (24% vs 73.9%; p = 0.0005) developed new-onset organ dysfunction in the ulinastatin group by day 5. Resolution of existing organ dysfunctions by day 5 was more frequent in the ulinastatin group. Duration of hospital stay was similar in the two groups. CONCLUSION: Ulinastatin treatment was associated with improved outcomes in patients with severe acute pancreatitis. PMID- 29413720 TI - Estimating attributable fraction of mortality from sepsis to inform clinical trials. AB - PURPOSE: Nearly all sepsis trials report no statistically significant difference in mortality. The attributable fraction of deaths due to sepsis (AFsepsis) may be an important, yet overlooked consideration. We derived AFsepsis and explored the effect of incorporating AFsepsis into sample size calculations. MATERIALS AND METHODS: We derived AFsepsis with a matched cohort study using consecutive admissions to adult general intensive care units (ICUs) in England (n = 614,509). Cases were ICU patients with sepsis and the two controls were ICU-non-sepsis controls, matched for propensity to have sepsis and age-sex-matched general population. The primary exposure was sepsis. The primary outcome was hospital mortality. We generated sample size graphs, by varying control group mortality (10%-60%), relative risk reduction (0-1), for 80% power and 5% alpha. We then compared AFsepsis derived sample sizes with sample size calculations from published sepsis trials. RESULTS: AFsepsis was 15% (95% CI: 14%-16%) compared with propensity matched ICU-non-sepsis controls and 93% (95% CI: 92%-93%) compared with age-sex-matched general population controls. When comparing AFsepsis derived sample sizes with sample size calculations from 18 trials meeting our selection criteria, these calculations assumed very high AFsepsis and/or very effective treatments. CONCLUSIONS: Estimating trial specific AFsepsis to inform sample size calculations could be an additional step in sepsis trial design. PMID- 29413721 TI - Isoflurane or propofol sedation in patients with targeted temperature management after cardiopulmonary resuscitation: A single center study. AB - PROPOSE: Targeted temperature management improves outcomes in comatose patients after cardiac arrest. Short lasting sedatives might enable rapid awakening after targeted temperature management and therefore early prognostication and extubation. Aim of the present study was to compare sedation with volatile isoflurane to intravenous propofol. MATERIALS AND METHODS: All patients after cardiopulmonary resuscitation undergoing targeted temperature management treated between 01/2014 and 02/2017 at a single tertiary referral hospital were screened. Exclusion criteria included extracorporeal support or a survival below 48 h. RESULTS: Data on 214 patients (median age 66.1 years, 62.6% shockable rhythm, survival 69.6%) are reported, 178 patients on propofol and sufentanil and 36 patients on isoflurane and sufentanil. Median time to first spontaneous breathing (9.3 h vs. 9.5 h, p = .373), median duration on mechanical ventilation in extubated patients (99.4 h vs. 105.7 h, p = .692) and median ICU stay (11.1d vs. 9.8d, p = .320) were similar in patients on propofol or isoflurane, respectively. Findings were confirmed by propensity score matching. Opioid dose was significantly lower in the isoflurane group (p < .001) while norepinephrine dose was significantly higher (p = .004). CONCLUSION: Isoflurane sedation is feasible on during targeted temperature management. Time to spontaneous breathing, mechanical ventilation duration or ICU stay was not reduced by isoflurane. PMID- 29413722 TI - Hyperchloraemia is associated with acute kidney injury and mortality in the critically ill: A retrospective observational study in a multidisciplinary intensive care unit. AB - PURPOSE: The aim of this study was to determine whether serum chloride and changes in serum chloride over time were associated with acute kidney injury (AKI) or intensive care unit (ICU) mortality in a heterogenous critically ill population. MATERIALS AND METHODS: The study was a retrospective observational study of 250 adult patients admitted to a multidisciplinary academic ICU. Serum chloride within 48 h of admission, changes in chloride, and other biochemical and clinical parameters were evaluated as predictors of AKI and mortality. RESULTS: Hyperchloraemia occurred in 143 (57.2%) patients within 48 h of ICU admission. Hyperchloraemia at 48 h was significantly associated with AKI, OR = 6.44 (95% CI 2.95-14.10) and mortality, OR = 2.46 (95% CI 1.22-4.94) on univariate analysis, with this association persisting on multivariable analysis. An increase in serum chloride was also associated with a significantly increased risk of AKI and mortality on univariate analysis. Hyperchloraemia on admission was, however, not associated with AKI or death. Of the 150 patients with AKI, 147 (98.0%) had developed AKI by 48 h. CONCLUSIONS: Hyperchloraemia and increasing serum chloride are associated with adverse outcomes in critically ill patients. There is equipoise as to whether this represents an association, an epiphenomenon or causation. PMID- 29413723 TI - Accuracy of SOFA, qSOFA, and SIRS scores for mortality in cancer patients admitted to an intensive care unit with suspected infection. AB - PURPOSE: To compare the prognostic accuracy of Sequential Organ Failure Assessment (SOFA) and quick SOFA (qSOFA) with systemic inflammatory response syndrome (SIRS) criteria in critically ill cancer patients with suspected infection. METHODS: Data for 450 cancer patients admitted to an intensive care unit (ICU) in 2014 with a suspected infection were retrospectively analyzed. Sensitivity, specificity, and area under the receiver operating curve (AUC) values for SOFA, qSOFA, and SIRS criteria for ICU and hospital mortalities were calculated. Mortalities according to Sepsis-2 stratification (e.g., sepsis, severe sepsis, and septic shock) and Sepsis-3 stratification (e.g., infection, sepsis, and septic shock) were also compared. RESULTS: SOFA outperformed SIRS in predicting mortalities for ICU [(AUC, 0.76; 95% confidence interval (CI) 95%, 0.71-0.81) vs. (AUC, 0.62; 95% CI, 0.56-0.67), p < .01] and hospital [(AUC, 0.69; 95% CI, 0.65-0.74) vs. (AUC, 0.58; 95% CI, 0.52-0.63), p < .01)] patients. Similarly, qSOFA outperformed SIRS for both settings [(AUC, 0.71; 95% CI, 0.65 0.76, p = .02) vs. (AUC, 0.69; 95% CI, 0.64-0.74; p < .01), respectively]. CONCLUSIONS: SOFA and qSOFA were more sensitive and accurate than SIRS in predicting ICU and hospital mortality for critically ill cancer patients with suspected infection. PMID- 29413724 TI - Characteristics, incidence and outcome of patients admitted to intensive care unit with Guillain-Barre syndrome in Australia and New Zealand. AB - PURPOSE: To describe characteristics, incidence and outcome of patients with Guillain-Barre syndrome (GBS) admitted to ICU. METHODS: We conducted a binational, retrospective, observational, epidemiological study. We compared the baseline characteristics, physiological conditions and outcomes for GBS patients with or without mechanical ventilation (MV) and of survivors and non-survivors. RESULTS: We studied 711 patients admitted to 173 ICUs between 2005 and 2015. We found an increasing proportion of GBS admissions per year (P < 0.03). 237 patients required MV. These patients had higher APACHE III scores (47 vs 31), worse PaO2/FiO2 ratio (P/F 258 v 341), a significantly longer ICU LOS (25 v 4 days) (P < 0.0001, all comparisons) and a greater incidence of pre-ICU cardio respiratory arrest (6.7% v 1.2%). Similarly, non-survivors were 5-times more likely to have experienced a pre-ICU cardio-respiratory arrest. Overall, ICU and hospital mortality were 3.9% and 6.9%, respectively and increased to 9.7% and 14.3% in the MV group. MV patients remained in hospital for almost 40 days. CONCLUSION: GBS represents a small but increasing proportion of ICU admissions with one-third of patients receiving MV. Overall in-hospital mortality is relatively low but doubles if MV is needed. These observations provide important prognostic information to clinicians involved in the care of these patients. PMID- 29413725 TI - Current practices and safety of medication use during rapid sequence intubation. AB - PURPOSE: Characterize medication practices during and immediately after rapid sequence intubation (RSI) by provider/location and evaluate adverse drug events. MATERIALS AND METHODS: This was a multicenter, observational, cross-sectional study of adult and pediatric intensive care unit and emergency department patients over a 24-h period surrounding first intubation. RESULTS: A total of 404 patients from 34 geographically diverse institutions were included (mean age 58 +/- 22 years, males 59%, pediatric 8%). During RSI, 21%, 87%, and 77% received pre-induction, induction, and paralysis, respectively. Significant differences in medication use by provider type were seen. Etomidate was administered to 58% with sepsis, but was not associated with adrenal insufficiency. Ketamine was associated with hypotension post-RSI [RR = 1.78 (1.36-2.35)] and use was low with traumatic brain injury/stroke (1.5%). Succinylcholine was given to 67% of patients with baseline bradycardia and was significantly associated with bradycardia post-RSI [RR = 1.81 (1.11-2.94)]. An additional 13% given succinylcholine had contraindications. Sedation practices post-RSI were not consistent with current practice guidelines and most receiving a non-depolarizing paralytic did not receive adequate sedation post-RSI. CONCLUSIONS: Medication practices during RSI vary amongst provider and medications are often used inappropriately. There is opportunity for optimization of medication use during RSI. PMID- 29413726 TI - Reduced circulating B cells and plasma IgM levels are associated with decreased survival in sepsis - A meta-analysis. AB - BACKGROUND: B cell function and antibody production are crucial factors in host protection during inflammation. We aimed to synthesize the available evidence on the association between the reduction of circulating B cells and plasma immunoglobulin (IgM) levels and decreased survival during sepsis. METHODS: We performed a systematic search in PubMed, Embase, ISI Web of Knowledge, Cochrane Central Register of Controlled Trials, BioMed Central, and Science Direct. We selected studies with data on circulating B cells and plasma IgM levels within the initial 24 h after sepsis onset. RESULTS: In total nine studies (n = 992 patients) were identified. Circulating B cells were reduced in septic patients as compared to non-septic patients (mean difference [MD] -88.2 cells/MUl; 95% confidence interval [CI] -148.6--27.9). Sepsis non-survivors showed a significant reduction of circulating B cells and IgM levels compared to sepsis survivors (MD 77.1 cells/MUl; 95% CI -111.4--42.7 and MD -20.9 mg/dl; 95% CI -33.8--8.0, respectively). CONCLUSIONS: Our results suggest that a reduction of circulating B cells and IgM levels at sepsis onset are associated with decreased sepsis survival. However, due to methodological limitations and the risk of bias, we need further prospective studies to confirm this association. REGISTRATION: The protocol was registered (PROSPERO 2016:CRD42016053184). PMID- 29413727 TI - Addressing spirituality during critical illness: A review of current literature. AB - OBJECTIVES: The purpose of this review is to provide an overview of research on spirituality and religiosity in the intensive care setting that has been published since the 2004-2005 American College of Critical Care Medicine (ACCM) Clinical Practice Guidelines for the Support of Family in the Patient-Centered Intensive Care Unit with an emphasis on its application beyond palliative and end of-life care. MATERIALS AND METHODS: ACCM 2004-2005 guidelines emphasized the importance of spiritual and religious support in the form of four specific recommendations: [1] assessment and incorporation of spiritual needs in ICU care plan; [2] spiritual care training for doctors and nurses; [3] physician review of interdisciplinary spiritual need assessments; and [4] honoring the requests of patients to pray with them. We reviewed 26 studies published from 2006 to 2016 and identified whether studies strengthened the grade of these recommendations. We further categorized findings of these studies to understand the roles of spirituality and religiosity in surrogate perceptions and decision-making and patient and family experience. CONCLUSIONS: Spiritual care has an essential role in the treatment of critically ill patients and families. Current literature offers few insights to support clinicians in navigating this often-challenging aspect of patient care and more research is needed. PMID- 29413728 TI - Bereaved donor families' experiences of organ and tissue donation, and perceived influences on their decision making. AB - PURPOSE: To elicit bereaved families' experiences of organ and tissue donation. A specific objective was to determine families' perceptions of how their experiences influenced donation decision-making. METHODS: Retrospective, qualitative interviews were undertaken with 43 participants of 31 donor families to generate rich, informative data. Participant recruitment was via 10 National Health Service Trusts, representative of five regional organ donation services in the UK. Twelve families agreed to DBD, 18 agreed to DCD, 1 unknown. Participants' responses were contextualised using a temporal framework of 'The Past', which represented families' prior knowledge, experience, attitudes, beliefs, and intentions toward organ donation; 'The Present', which incorporated the moment in time when families experienced the potential for donation; and 'The Future', which corresponded to expectations and outcomes arising from the donation decision. RESULTS: Temporally interwoven experiences appeared to influence families' decisions to donate the organs of their deceased relative for transplantation. CONCLUSIONS: The influence of temporality on donation-decision making is worthy of consideration in the planning of future education, policy, practice, and research for improved rates of family consent to donation. PMID- 29413729 TI - Characteristics, incidence, and outcome of patients admitted to the intensive care unit with myasthenia gravis. AB - BACKGROUND: There are limited data on the characteristics, incidence, and mortality of patients with myasthenia gravis (MG) admitted to the ICU. AIMS: To study the epidemiology, characteristics and outcome of patients with MG in Australian and New Zealand (ANZ) ICUs over a decade. METHODS: We performed a retrospective observational, cross sectional study of data from the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD). We collected data on all adult patients admitted with a primary diagnosis of MG to 159 Australian and 19 New Zealand ICUs between January 1, 2005 and December 31, 2015.We extracted detailed relevant data and performed statistical assessment. RESULTS: We identified 245 patients admitted to ICU with the primary diagnosis of MG, with an incidence increasing from 1 to 2.5 per thousand ICU admissions (P<0.0001) and from 1 to 2.2 per million people (P=0.02). Mean age was 60years with more patients being female (53.7% vs 47.3%) and 91 (37.1%) patients received mechanical ventilation. Hospital mortality occurred in 13 (5.3%) patients with a mortality rate lower than in other ICU patients. CONCLUSIONS: In ANZ, the ICU and population incidence of MG has increased over the last decade. However, its mortality rate was low. PMID- 29413730 TI - Healthcare-associated ventriculitis and meningitis in a neuro-ICU: Incidence and risk factors selected by machine learning approach. AB - PURPOSE: To define the incidence of healthcare-associated ventriculitis and meningitis (HAVM) in the neuro-ICU and to identify HAVM risk factors using tree based machine learning (ML) algorithms. METHODS: An observational cohort study was conducted in Russia from 2010 to 2017, and included high-risk neuro-ICU patients. We utilized relative risk analysis, regressions, and ML to identify factors associated with HAVM development. RESULTS: 2286 patients of all ages were included, 216 of them had HAVM. The cumulative incidence of HAVM was 9.45% [95% CI 8.25-10.65]. The incidence of EVD-associated HAVM was 17.2 per 1000 EVD-days or 4.3% [95% CI 3.47-5.13] per 100 patients. Combining all three methods, we selected four important factors contributing to HAVM development: EVD, craniotomy, superficial surgical site infections after neurosurgery, and CSF leakage. The ML models performed better than regressions. CONCLUSION: We first reported HAVM incidence in a neuro-ICU in Russia. We showed that tree-based ML is an effective approach to study risk factors because it enables the identification of nonlinear interaction across factors. We suggest that the number of found risk factors and the duration of their presence in patients should be reduced to prevent HAVM. PMID- 29413731 TI - The Berbeo-Sardi Angle (BSA): An Innovative Method to Effectively Estimate Pelvic Retroversion in Anteroposterior Radiographs-A Correlation With Traditional Parameters. AB - STUDY: Design: Diagnostic studies-concordance between diagnostic tests. OBJECTIVES: The purpose of this study was to develop a novel spinopelvic parameter (Berbeo-Sardi angle [BSA], the angle formed at the intersection of a line that connects the inferior margin of the sacroiliac joint to the midpoint of a horizontal line joining both femoral heads) measurable in anteroposterior radiographs that indirectly estimates pelvic retroversion and correlates with traditional measurements like pelvic tilt (PT). SUMMARY: Sagittal balance appraisal and surgical planning rely on the interpretation of spinopelvic parameters. An increased PT reflects pelvic retroversion as a compensatory mechanism to limit sagittal imbalance and correlates with increased pain and disability. However, poor imaging techniques and incorrect patient positioning frequently hamper landmark identification in lateral radiographs, and with no measurable angles in anteroposterior radiographs, it is often impossible to determine PT and pelvic retroversion. METHODS: Whole-spine radiographs from 105 consecutive patients were used to retrospectively measure conventional spinopelvic parameters and the BSA. Intraclass correlation coefficient was used to assess a quantitative correlation between the PT and BSA as indirect measures of pelvic retroversion. RESULTS: Average values for pelvic incidence, lumbar lordosis, sacral slope, PT, and BSA were 46.5 degrees (+/-10.23), 48.56 degrees (+/-12.30), 29.97 degrees (+/-9.77), 16.94 degrees (+/-8.03), and 54.47 degrees (+/-4.05), respectively. We encountered a moderately strong correlation (r = 0.66) between PT and BSA. Receiver operating characteristic plot analysis revealed that a BSA threshold of 46 degrees has a sensitivity of 90% to identify pathologic PT values (>20 degrees ), whereas a BSA >=60 degrees has a specificity of 90% to rule out pelvic retroversion using anteroposterior radiographs. CONCLUSIONS: There is a moderately strong correlation between the BSA, an innovative spinopelvic parameter measurable in anteroposterior radiographs, and PT. BSA seems to show great promise in simplifying spinopelvic appraisal by easily estimating pelvic retroversion associated with sagittal imbalance, while avoiding image-quality issues often encountered in lateral radiographs. LEVEL OF EVIDENCE: Level III. PMID- 29413732 TI - Vertebral Axial Asymmetry in Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: To investigate parameters of axial vertebral deformation in patients with scoliosis compared to a control group, and to determine whether these parameters correlated with the severity of spine curvature, measured as the Cobb angle. SUMMARY OF BACKGROUND DATA: Adolescent idiopathic scoliosis (AIS) is the most common type of spinal deformity. Many studies have investigated vertebral deformation, in terms of wedging and pedicle deformations, but few studies have investigated actual structural changes within vertebrae. METHODS: This study included 20 patients with AIS (Lenke 1-3, mean age: 15.6 years, range: 11-20). We compared preoperative low-dose computed tomography (CT) examinations of patients with AIS to those of a control group matched for age and sex. The control individuals had no spinal deformity, but they were admitted to the emergency department for trauma CTs. We measured the Cobb angles and the axial vertebral rotation (AVR), axial vertebral body asymmetry (AVBA), and frontal vertebral body rotation (FVBR) for the superior end, inferior end, and apical vertebrae, with in-house-developed software. Correlations between entities were investigated with the Pearson correlation test. RESULTS: The average Cobb angles were 49.3 degrees and 1.3 degrees for the scoliotic and control groups, respectively. The patient and control groups showed significant differences in the AVRs of all three vertebra levels (p < .01), the AVBAs of the superior end and apical vertebrae (p < .008), and the FVBR of the apical vertebra (p = .011). Correlations were only found between the AVBA and FVBR in the superior end vertebra (r = 0.728, p < .001) and in the apical vertebra (r = 0.713, p < .001). CONCLUSIONS: Compared with controls, patients with scoliosis showed clear morphologic differences in the midaxial plane vertebrae. Differences in AVR, AVBA, and FVBR were most pronounced at the apical vertebra. The FVBR provided valuable additional information about the internal rotation and deformation of vertebrae. LEVEL OF EVIDENCE: Level III. PMID- 29413733 TI - Building Consensus: Development of Best Practice Guidelines on Wrong Level Surgery in Spinal Deformity. AB - STUDY DESIGN: Consensus-building using the Delphi and nominal group technique. OBJECTIVE: To establish best practice guidelines using formal techniques of consensus building among a group of experienced spinal deformity surgeons to avert wrong-level spinal deformity surgery. SUMMARY OF BACKGROUND DATA: Numerous previous studies have demonstrated that wrong-level spinal deformity occurs at a substantial rate, with more than half of all spine surgeons reporting direct or indirect experience operating on the wrong levels. Nevertheless, currently, guidelines to avert wrong-level spinal deformity surgery have not been developed. METHODS: The Delphi process and nominal group technique were used to formally derive consensus among 16 fellowship-trained spine surgeons. Surgeons were surveyed for current practices, presented with the results of a systematic review, and asked to vote anonymously for or against item inclusion during three iterative rounds. Agreement of 80% or higher was considered consensus. Items near consensus (70% to 80% agreement) were probed in detail using the nominal group technique in a facilitated group meeting. RESULTS: Participants had a mean of 13.4 years of practice (range: 2-32 years) and 103.1 (range: 50-250) annual spinal deformity surgeries, with a combined total of 24,200 procedures. Consensus was reached for the creation of best practice guidelines (BPGs) consisting of 17 interventions to avert wrong-level surgery. A final checklist consisting of preoperative and intraoperative methods, including standardized vertebral-level counting and optimal imaging criteria, was supported by 100% of participants. CONCLUSION: We developed consensus-based best practice guidelines for the prevention of wrong-vertebral-level surgery. This can serve as a tool to reduce the variability in preoperative and intraoperative practices and guide research regarding the effectiveness of such interventions on the incidence of wrong-level surgery. LEVEL OF EVIDENCE: Level V. PMID- 29413734 TI - Accuracy of S2 Alar-Iliac Screw Placement Under Robotic Guidance. AB - STUDY DESIGN: Case series. OBJECTIVES: To determine the safety and feasibility of S2 alar-iliac (S2AI) screw placement under robotic guidance. SUMMARY OF BACKGROUND DATA: Similar to standard iliac fixation, S2AI screws aid in achieving fixation across the sacropelvic junction and decreasing S1 screw strain. Fortunately, the S2AI technique minimizes prominent instrumentation and the need for offset connectors to the fusion construct. Herein, we present an analysis of the largest series of robotic-guided S2AI screws in the literature without any significant author conflicts of interest with the robotics industry. METHODS: Twenty-three consecutive patients who underwent spinopelvic fixation with 46 S2AI screws under robotic guidance were analyzed from 2015 to 2016. Screws were placed by two senior spine surgeons, along with various fellow or resident surgical assistants, using a proprietary robotic guidance system (Renaissance; Mazor Robotics Ltd., Caesara, Israel). Screw position and accuracy was assessed on intraoperative CT O-arm scans and analyzed using three-dimensional interactive viewing and manipulation of the images. RESULTS: The average caudal angle in the sagittal plane was 31.0 degrees +/- 10.0 degrees . The average horizontal angle in the axial plane using the posterior superior iliac spine as a reference was 42.8 degrees +/- 6.6 degrees . The average S1 screw to S2AI screw angle was 11.3 degrees +/- 9.9 degrees . Two violations of the iliac cortex were noted, with an average breach distance of 7.9 +/- 4.8 mm. One breach was posterior (2.2%) and one was anterior (2.2%). The overall robotic S2AI screw accuracy rate was 95.7%. There were no intraoperative neurologic, vascular, or visceral complications related to the placement of the S2AI screws. CONCLUSIONS: Spinopelvic fixation achieved using a bone-mounted miniature robotic-guided S2AI screw insertion technique is safe and reliable. Despite two breaches, no complications related to the placement of the S2AI screws occurred in this series. LEVEL OF EVIDENCE: Level IV, therapeutic. PMID- 29413735 TI - Who Needs a Pediatric Intensive Care Unit After Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis? AB - BACKGROUND: Hypotensive events (HEs) following posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) can lead to delayed neurologic postoperative deficits (DNPD). This study aimed to determine the incidence of HEs (mean arterial pressure [MAP] <60 mmHg) after PSF for AIS and identify predictors for HEs. METHODS: Medical records of 99 consecutive patients who had PSF for AIS were retrospectively reviewed (2011-2013). Perioperative data were collected. Patients were divided into two groups based on MAP readings by an arterial line in the pediatric intensive care unit immediately postoperatively into postoperative day one: Group 1 (MAP >=60 mmHg) and Group 2 (multiple occurrences of MAPs <60 mmHg). Mean values were compared using the independent t test. Multiple logistic regression was used to estimate the association of preoperative and intraoperative parameters with multiple HEs. RESULTS: Group 1 had 68 patients (68.7%) and Group 2 had 31 patients (31.3%). None of the compared parameters were associated significantly with multiple HE. However, patients who did not exhibit HEs within the first four hours postoperatively remained stable throughout the rest of the postoperative period. Only those with HEs in the first four hours experienced subsequent HEs in the first 24 hours. There were no DNPD or other major complications. CONCLUSION: Results showed that the incidence of HEs after PSF in AIS can be as high as 31.3%. We did not find any significant risk factors. Although DNPD after PSF is a rare complication and we had none in this series, we suggest that these patients with multiple HEs may be at risk for DNPD as a result of hypotension and potential for cord ischemia. Therefore, all patients after PSF should be monitored in a pediatric intensive care unit-type environment or postanesthesia recovery room initially. If stable for, at least, the initial four hours, then patients should be good candidates for a less intensive environment. LEVEL OF EVIDENCE: Level 3. PMID- 29413736 TI - Deep Vein Thrombosis After Complex Posterior Spine Surgery: Does Staged Surgery Make a Difference? AB - STUDY DESIGN: Retrospective review of a prospectively collected database. OBJECTIVE: To assess the incidence of deep vein thrombosis (DVT) associated with single- versus multistage posterior-only complex spinal surgeries. SUMMARY OF BACKGROUND DATA: Dividing the physiologic burden of spinal deformity surgery into multiple stages has been suggested as a potential means of reducing perioperative complications. DVT is a worrisome complication owing to its potential to lead to pulmonary embolism. Whether or not staging affects DVT incidence in this population is unknown. METHODS: Consecutive patients undergoing either single- or multistage posterior complex spinal surgeries over a 12-year period at a single institution were eligible. All patients received lower extremity venous duplex ultrasonographic (US) examinations 2 to 4 days postoperatively in the single stage group and 2 to 4 days postoperatively after each stage in the multistage group. Multivariate logistic regression was used to assess the independent contribution of staging to developing a DVT. RESULTS: A total of 107 consecutive patients were enrolled-26 underwent multistage surgery and 81 underwent single stage surgery. The single-stage group was older (63 years vs. 45 years; p < .01) and had a higher Charlson comorbidity index (2.25 +/- 1.27 vs. 1.23 +/- 1.58; p < .01). More multistage patients had positive US tests than single-stage patients (5 of 26 vs. 6 of 81; 19% vs. 7%; p = .13). Adjusting for all the above-mentioned covariates, a multistage surgery was 8.17 (95% CI 0.35-250.6) times more likely to yield a DVT than a single-stage surgery. CONCLUSIONS: Patients who undergo multistage posterior complex spine surgery are at a high risk for developing a DVT compared to those who undergo single-stage procedures. The difference in DVT incidence may be understated as the multistage group had a lower pre- and intraoperative risk profile with a younger age, lower medical comorbidities, and less per-stage blood loss. PMID- 29413737 TI - Ethnic Variation in Satisfaction and Appearance Concerns in Adolescents With Idiopathic Scoliosis Undergoing Posterior Spinal Fusion With Instrumentation. AB - STUDY DESIGN: Cohort analysis. OBJECTIVE: Document satisfaction with management and appearance concerns in children of different ethnicity who underwent spinal fusion/instrumentation for adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Scoliosis Research Society Questionnaire (SRS-30) outcomes in AIS indicate a link between appearance and satisfaction as well as ethnic variation in appearance domain. Exploration of these findings in the Scoliosis Appearance Questionnaire (SAQ) will allow better understanding of ethnic variation in appearance concerns. METHODS: Children with AIS who underwent posterior-only operations and completed the SAQ's question 31 were identified. Univariate logistic regression of SAQ questions 12-30 was used to assess relationships with ethnicity. RESULTS: 1,977 children [boys: 281, girls: 1,290, unspecified: 406; average age 15.1 +/- 2.0 years preoperatively and 817 children (boys: 113, girls: 569, unspecified: 135; average age 15.1 +/- 2.0 years) at 2 years' follow-up met inclusion criteria. The majority were Caucasian (57.3%). Few were Hispanic (3.4%). Preoperatively, the largest percentage of patients in each ethnic group answered "very true" to "wanting to be more even." Preoperatively, Asians were least likely to be concerned about evenness of shoulders, hips, waist, ribs, and chest in back (p < .05); however, they expressed greatest concern about height (p < .05). African Americans and Hispanics were more likely to be concerned about breast evenness and anterior chest and looking better in clothes (p < .05). African Americans were most concerned about overall evenness and evenness of shoulders, hips, waist, ribs, posterior chest, leg length, and looking more attractive (p < .05). Surgical scar was most important postoperatively for all ethnicities. African Americans and Hispanics were more self-conscious about scar (p < .05). African Americans were most likely to want to be more even and have more even shoulders, hips, waist, leg lengths, ribs, breasts, and chest postoperatively. CONCLUSIONS: Ethnicity influenced appearance concerns in pre- and postoperative SAQ evaluation. Ethnic variation in appearance concerns should be taken into account and differentiated when counseling patients about AIS and surgical correction. LEVEL OF EVIDENCE: Level III. PMID- 29413738 TI - Evidence-Based Thresholds for the Volume-Value Relationship in Adolescent Idiopathic Scoliosis: Outcomes and Economies of Scale. AB - OBJECTIVES: Increased surgeon and hospital volume has been associated with improved patient outcomes and cost effectiveness for adolescent idiopathic scoliosis (AIS). However, no evidence-based thresholds that clarify the volume at which these strata occur exist. The objective of this study was to establish statistically meaningful thresholds that define high-volume surgeons and hospitals performing spinal fusion for AIS from those that are low volume with respect to length of stay (LOS) and cost. METHODS: Using 3,224 patients undergoing spinal fusion for AIS from an administrative database, we created and applied four models using stratum-specific likelihood ratio (SSLR) analysis of a receiver operating characteristic (ROC) curve. We generated four sets of thresholds predictive of adverse outcomes, namely, increased cost and LOS, for both surgeon and hospital volume. RESULTS: For both LOS and cost, surgeon volume produced the same strata with low volume identified as 0-5 annual surgeries and high as greater than 5. LOS and cost decreased significantly (p < .05) between volume strata. For hospital volume in terms of LOS, low volume was identified as 0-10 annual surgeries and high as greater than 10; in terms of cost, low volume was identified as 0-15 annual surgeries and high as greater than 15. LOS decreased significantly (p < .05) and cost was $1,500 less but not statistically significant between volume strata for hospital volume. CONCLUSIONS: Our study of risk-based volume stratification established a direct volume-value relationship for surgeons and hospitals performing fusion for AIS. A meaningful threshold for low- and high-volume surgeons was established at 5 annual surgeries, but no consensus or clinically meaningful conclusion was reached for hospitals, although the threshold approached 10-15 annual surgeries. This analysis should aid patients, surgeons, and administration reach value-based decisions in the optimal delivery of pediatric spinal fusion for AIS. PMID- 29413739 TI - Additional Risk Factors for Adding-On After Selective Thoracic Fusion in Adolescent Idiopathic Scoliosis: Implication of Lowest Instrumented Vertebra Angle and Lumbosacral Takeoff. AB - STUDY DESIGN: Retrospective chart and radiographic review. OBJECTIVE: The purpose of this study was to identify any additional risk factors adding-on after selective thoracic fusion in adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Previous studies have shown that the proper selection of lowest instrumented vertebra (LIV) is critical in preventing adding-on (AD) phenomenon after selective thoracic fusion (STF). However, even after selecting the correct LIV, AD can still occur. METHODS: This is a retrospective review of 380 consecutive AIS patients who underwent corrective surgery by a single surgeon. LIV was chosen as stable vertebra (SV) or SV-1 if intersected by the center sacral vertical line (CSVL). One hundred thirty-five patients were identified who had complete radiographic images stored in PACS. After Lenke 5, anterior or combined surgeries, TL fusion, and hybrid construct were excluded, two groups were identified out of 78 patients who received STF with all pedicle screw construct: Adding-on (AD) and Control. AD was defined as >5 degrees angle of the superior endplate of LIV-1 to the inferior endplate of LIV+1 between postoperation and the final follow-up. We analyzed the values for the AD group and compared them with those for the control group to identify risk factors not previously defined. RESULTS: Patients with other complication and follow-up less than 2 years were excluded, and there remained 11 patients in AD (14%), and 8 in the control group. There was no significant difference between the 2 groups in terms of demographic data, LIV selection, and curve types. In AD, there was significant curve progression within fused segments. Even though lumbosacral takeoff (LSTO) was not significantly different, (LIV-H)+LSTO and LIV-H (LIV horizontal) showed significant difference. CONCLUSION: After excluding the effect of known risk factors for AD, LIV-H angle, and LIV-H mismatch with LSTO were found to be the additional risk factors for AD. In addition to consideration of other risk factors such as LIV selection or Risser stage, these risk factors should be considered. PMID- 29413740 TI - Bone Mineral Density After Spinal Fusion Surgery for Adolescent Idiopathic Scoliosis at a Minimum 20-Year Follow-up. AB - STUDY DESIGN: A retrospective, long-term follow-up study. OBJECTIVE: We investigated the incidence and risk factors for osteopenia at a minimum of 20 years after spinal instrumented fusion for adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Surgically treated AIS patients may be likely to have osteopenia in adulthood because the association between AIS and osteopenia has been well documented. However, the long-term results of AIS surgery on BMD have not been evaluated. METHODS: Twenty-one (19 women; mean age, 45.3 years) of 45 consecutive patients with AIS who underwent spinal instrumented fusion surgery between 1973 and 1994 consented to inclusion in the current analysis. Based on their T scores for bone mineral density (BMD) of the left hip, participants were divided into an osteopenia/osteoporosis group (group P, T score < -1.0) and a normal group (group N, T score >= -1.0). Z scores of the left hip were used for analyses of the association between bone mineral status and individual factors. RESULTS: Eleven participants (52.4%) were categorized into group P. Mean body weight (kg) at survey (46.6 vs. 56.8) and mean body mass index (BMI) at both surgery (17.2 vs. 19.5) and survey (18.7 vs. 23.2) were significantly lower in group P than in group N (p < .05). Moreover, body weight at survey (Spearman rank correlation coefficient, rS = 0.49), as well as BMI at both surgery (rS = 0.67) and survey (rS = 0.61) demonstrated positive correlations with the Z-score (p < .05). CONCLUSION: More than half of the participants had osteopenia or osteoporosis, and both preoperative and postoperative low BMI were risk factors for osteopenia in adulthood. LEVEL OF EVIDENCE: Level IV. PMID- 29413741 TI - Reciprocal Changes in Sagittal Alignment With Operative Treatment of Adolescent Scheuermann Kyphosis-Prospective Evaluation of 96 Patients. AB - INTRODUCTION: Sagittal alignment abnormalities in Scheuermann kyphosis (SK) strongly correlate with quality of life measures. The changes in spinopelvic parameters after posterior spinal fusion have not been adequately studied. This study is to evaluate the reciprocal changes in spinopelvic parameters following surgical correction for SK. METHODS: Ninety-six operative SK patients (65% male; age 16 years) with minimum 2-year follow-up were identified in the prospective multicenter study. Changes in spinopelvic parameters and the incidence of proximal (PJK) and distal (DJK) junctional kyphosis were assessed as were changes in Scoliosis Research Society-22 (SRS-22) questionnaire scores. RESULTS: Maximum kyphosis improved from 74.4 degrees to 46.1 degrees (p < .0001), and lumbar lordosis was reduced by 10 degrees (-63.3 degrees to -53.3 degrees ; p < .0001) at 2-year postoperation. Pelvic tilt, sacral slope, and sagittal vertical axis remained unchanged. PJK and DJK incidence were 24.2% and 0%, respectively. In patients with PI <45 degrees , patients who developed PJK had greater postoperative T2-T12 (54.8 degrees vs. 44.2 degrees , p = .0019), and postoperative maximum kyphosis (56.4 degrees vs. 44.6 degrees , p = .0005) than those without PJK. In patients with PI >=45 degrees , patients with PJK had less postoperative T5-T12 than those without (23.6 degrees vs. 32.9 degrees , p = .019). Thoracic and lumbar apices migrated closer to the gravity line after surgery (-10.06 to -4.87 mm, p < .0001, and 2.28 to 2.10 mm, p = .001, respectively). Apex location was normalized to between T5-T8 in 68.5% of patients with a preoperative apex caudal to T8, whereas 90% of patients with a preoperative apex between T5 and T8 remained unchanged. Changes in thoracic apex location and lumbar apex translation were associated with improvements in the SRS function domain. CONCLUSION: PJK occurred in 1 in 4 patients, a lower incidence than previously reported perhaps because of improved techniques and planning. Both thoracic and lumbar apices migrated closer to the gravity line, and preoperative apices caudal to T8 normalized in more than two-thirds of patients, resulting in improved postoperative function. Individualizing kyphosis correction to prevent kyphosis and PI mismatch may be protective against PJK. PMID- 29413742 TI - Current Evidence Regarding the Diagnostic Methods for Pediatric Lumbar Spondylolisthesis: A Report From the Scoliosis Research Society Evidence Based Medicine Committee. AB - STUDY DESIGN: Structured literature review. OBJECTIVES: The Scoliosis Research Society (SRS) requested an assessment of the current state of peer-reviewed evidence regarding pediatric lumbar spondylolisthesis with the goal of identifying what is known and what gaps remain in further understanding the diagnostic methods for pediatric spondylolisthesis. SUMMARY OF BACKGROUND DATA: Spondylolisthesis in the lumbar spine is common among children and adolescents and no formal synthesis of the published literature regarding diagnostic methods has been previously performed. METHODS: A comprehensive literature search was performed. Abstracts were reviewed and data from included studies were analyzed by the committee. From 6600 initial citations with abstract, 663 articles underwent full-text review. The best available evidence for the clinical questions regarding diagnostic methods was provided by 26 included studies. Six of the studies were graded as Level III (retrospective comparative), and represent the current best available evidence whereas 20 of the studies were graded as Level IV (retrospective case series) evidence. No Level V (expert opinion) studies were included in the final list. None of the studies were graded as Level I or Level II. RESULTS: Plain radiography is the workhorse imaging modality for diagnosing spondylolisthesis. No association between radiologic grade of spondylolisthesis and clinical presentation were noted; however, grade III and IV slips more often required surgery, and increasing slip angles were associated with worse baseline outcome scores. There is Level III evidence that the Meyerding grade appears to be more accurate for measuring slip percentage whereas the Lonstein Slip angle and Dubousset Lumbosacral Kyphosis angles are the best for measuring lumbosacral kyphosis in spondylolisthesis. In addition, higher sacral table index, pelvic incidence, sacral slope, and lower sacral table angle were associated with spondylolisthesis. True incidence could not be determined by the current literature available. However, studies in adolescent athletes demonstrated an incidence of 6% to 7% across studies. CONCLUSIONS: The current "best available" evidence to guide the diagnosis and characterization of pediatric spondylolisthesis is presented. Future studies are needed to provide more high-quality evidence to answer these clinically relevant questions. LEVEL OF EVIDENCE: Level III, review of Level III studies. PMID- 29413743 TI - Safety of a High-Dose Tranexamic Acid Protocol in Complex Adult Spinal Deformity: Analysis of 100 Consecutive Cases. AB - STUDY DESIGN: Retrospective review of high-dose tranexamic acid (TXA) use in consecutive patients. OBJECTIVE: To determine the safety profile of a high-dose TXA protocol in complex adult spinal deformity patients. SUMMARY OF BACKGROUND DATA: Adult spinal deformity (ASD) surgery may involve significant amounts of blood loss, especially when various osteotomy techniques are used. Antifibrinolytic agents such as TXA have been used to reduce intraoperative blood loss. However, there is no universally accepted dosing protocol for its use during complex ASD surgery. METHODS: Consecutive patients undergoing spinal deformity correction over a 14-month period at a single institution were identified. Inclusion criteria were adults (age >=18 years) who underwent posterior spinal fusion of at least 5 levels and use of our standard TXA protocol of 50 mg/kg intravenous loading dose followed by a 5-mg/kg/h infusion until skin closure. Patient demographics, estimated blood loss (EBL), operative time, transfusion rates, complications, and other procedure-specific information were recorded. RESULTS: A total of 100 adult patients were included. All operative procedures were performed by the senior surgeon. The mean age was 47.3 years, and 71% of patients were female. Average body mass index was 24.9. The average fusion length was 14 levels; 33/100 patients had fusion constructs of 17 levels or more. Pedicle subtraction osteotomy was performed in 9 patients and vertebral column resections were performed in 14 patients. There were 45/100 patients who had a primary procedure, whereas the rest were revisions. Mean EBL was 1,336 mL (98 mL/level, 31% estimated blood volume). There were three thromboembolic complications, including one pulmonary embolism and two deep vein thromboses (DVTs), which were all treated successfully with anticoagulation. There were no cases of myocardial infarction, seizure, stroke, or acute renal failure. CONCLUSIONS: This is the first study to demonstrate the use of high-dose TXA in a complex ASD population. Larger prospective studies are needed to assess the efficacy and safety of high-dose TXA in ASD. LEVEL OF EVIDENCE: Level IV, therapeutic. PMID- 29413744 TI - An In Vitro Biomechanical Study on Ovine Rib Flexibility With Increasing Deconstruction-As an Alternative to Rib Resection for Costoplasty. AB - STUDY DESIGN: An in vitro biomechanical study into the effect of rib deconstruction on the flexibility in ovine ribs, using three-point bending. OBJECTIVE: To examine the feasibility and possible effectiveness of a more conservative costoplasty using an in vitro animal model. SUMMARY OF BACKGROUND DATA: Costoplasty remains useful in the treatment of adolescent idiopathic scoliosis, rib hump, and associated chest wall deformities. However, traditional costoplasty increases morbidity and blood loss. METHODS: Ribs 2-10 were dissected from four fresh half ovine rib cages. The ribs were randomly allocated to Groups 1 to 4. The ribs underwent deconstruction, 10 mm from the lateral tubercle and 30 mm long, according to their group: Group 1 = control; Group 2 = convex cortical bone removed; Group 3 = convex cortical and cancellous bone removed; Group 4 = all but the ventral cortex is removed. Flexibility was tested by loading the concave side of each rib while fixed at the rib head and equidistant from the center of the resected area. The ribs were deformed at 0.5 mm/s up to a maximum load of 9.99 kg or fracturing. Load was plotted against displacement to find the load/displacement coefficient for each group. Statistical analysis was by an analysis of variance with Tukey's honestly significant difference post hoc testing. RESULTS: The load/displacement coefficients were as follows: Group 1 = 131.93 (+/-27.52) N/mm, Group 2 = 93.36 (+/-40.71) N/mm, Group 3 = 88.66 (+/ 25.84) N/mm, and Group 4 = 29.69 (+/-29.11) N/mm. Group 4 was significantly less stiff than Groups 1, 2, and 3 (p < .01). No ribs in Groups 1, 2, and 4 fractured. Five of 8 ribs in Group 3 fractured during loading. CONCLUSIONS: Deconstructing the rib down to the concave side significantly increases the flexibility by approximately 4.5 times. Despite large removal of bone, it retains the ability to withstand 10 kg of load without fracture. PMID- 29413745 TI - Integrating bioinformatics approaches for a comprehensive interpretation of metabolomics datasets. AB - Access to high quality metabolomics data has become a routine component for biological studies. However, interpreting those datasets in biological contexts remains a challenge, especially because many identified metabolites are not found in biochemical pathway databases. Starting from statistical analyses, a range of new tools are available, including metabolite set enrichment analysis, pathway and network visualization, pathway prediction, biochemical databases and text mining. Integrating these approaches into comprehensive and unbiased interpretations must carefully consider both caveats of the metabolomics dataset itself as well as the structure and properties of the biological study design. Special considerations need to be taken when adopting approaches from genomics for use in metabolomics. R and Python programming language are enabling an easier exchange of diverse tools to deploy integrated workflows. This review summarizes the key ideas and latest developments in regards to these approaches. PMID- 29413746 TI - Advances in computational metabolomics and databases deepen the understanding of metabolisms. AB - Mass spectrometry (MS)-based metabolomics is the popular platform for metabolome analyses. Computational techniques for the processing of MS raw data, for example, feature detection, peak alignment, and the exclusion of false-positive peaks, have been established. The next stage of untargeted metabolomics would be to decipher the mass fragmentation of small molecules for the global identification of human-, animal-, plant-, and microbiota metabolomes, resulting in a deeper understanding of metabolisms. This review is an update on the latest computational metabolomics including known/expected structure databases, chemical ontology classifications, and mass spectrometry cheminformatics for the interpretation of mass fragmentations and for the elucidation of unknown metabolites. The importance of metabolome 'databases' and 'repositories' is also discussed because novel biological discoveries are often attributable to the accumulation of data, to relational databases, and to their statistics. Lastly, a practical guide for metabolite annotations is presented as the summary of this review. PMID- 29413747 TI - Design and optimization of genetically encoded biosensors for high-throughput screening of chemicals. AB - Evolutionary engineering of microbes for the production of metabolites requires efficient screening methods to test vast mutant libraries. Genetically encoded biosensors are regarded as promising screening devices owing to their wide range of detectable ligands and great applicability to high-throughput screening and selection. Here, we reviewed the current progress in design and optimization of biosensors for high-throughput screening of chemicals. First, we summarized genetic parts of biosensors and strategies for their discovery and development. Next, we explained the properties of biosensors that are relevant to high throughput screening. Finally, we described various methods for tuning biosensors to fulfill requirements of an efficient screening. PMID- 29413748 TI - Stretching, scrambling, piercing and entangling: Challenges for telomeres in mitotic and meiotic chromosome segregation. AB - The consequences of telomere loss or dysfunction become most prominent when cells enter the nuclear division stage of the cell cycle. At this climactic stage when chromosome segregation occurs, telomere fusions or entanglements can lead to chromosome breakage, wreaking havoc on genome stability. Here we review recent progress in understanding the mechanisms of detangling and breaking telomere associations at mitosis, as well as the unique ways in which telomeres are processed to allow regulated sister telomere separation. Moreover, we discuss unexpected roles for telomeres in orchestrating nuclear envelope breakdown and spindle formation, crucial processes for nuclear division. Finally, we discuss the discovery that telomeres create microdomains in the nucleus that are conducive to centromere assembly, cementing the unexpectedly influential role of telomeres in mitosis. PMID- 29413750 TI - Barhl1 is required for the differentiation of inner ear hair cell-like cells from mouse embryonic stem cells. AB - Inner ear hair cells are mechanoreceptors responsible for hearing. Pathogenic defects of hair cell-specific genes are one of the major causes of deafness. The BarH class homeobox gene Barhl1 is a deafness gene expressed in developing hair cells, yet the role of Barhl1 during hair cell development remains poorly understood. In the present study, we first established an in vitro differentiation system to efficiently obtain mouse embryonic stem cell (mESC) derived hair cell-like cells. Subsequently, a mESC line carrying a targeted disruption of Barhl1 was generated using CRISPR/Cas9 technology and subjected to the established in vitro hair cell differentiation protocol. Targeted disruption of Barhl1 does not affect the induction of mESCs toward early primitive ectoderm like (EPL) cells and otic progenitors but strongly inhibits the differentiation of hair cell-like cells. Using RNA-sequencing and bioinformatics, we further unravel the molecular mechanism underlying Barhl1-mediated hair cell development. Our data demonstrate the essential role of Barhl1 during hair cell development and provide a basis for the treatment of Barhl1 mutation-based deafness. PMID- 29413749 TI - How stem cells keep telomeres in check. AB - In multicellular organisms, regulation of telomere length in pluripotent stem cells is critical to ensure organism development and survival. Telomeres consist of repetitive DNA that are progressively lost with each cellular division. When telomeres become critically short, they activate a DNA damage response that results in cell cycle arrest. To counteract telomere attrition, pluripotent stem cells are equipped with telomere elongation mechanisms that ensure prolonged proliferation capacity and self-renewal capacity. Excessive telomere elongation can also be deleterious and is counteracted by a rapid telomere deletion mechanism termed telomere trimming. While the consequences of critically short telomeres are well established, we are only beginning to understand the mechanisms that counteract excessive telomere elongation. The balance between telomere elongation and shortening determine the telomere length set point in pluripotent stem cells and ensures sustained proliferative potential without causing chromosome instability. PMID- 29413751 TI - Evaluation of [18F]FNM biodistribution and dosimetry based on whole-body PET imaging of rats. AB - INTRODUCTION: The aim of this work was to study the biodistribution, metabolism and radiation dosimetry of rats injected with [18F]FNM using PET/CT images. This novel radiotracer targeting NMDA receptor has potential for investigation for neurological and psychiatric diseases. METHODS: Free fraction and stability in fresh human plasma were determined in vitro. PET/CT was performed on anesthetized rats. Organs were identified and 3D volumes of interest (VOIs) were manually drawn on the CT in the center of each organ. Time activity curves (TACs) were created with these VOIs, enabling the calculation of residence times. To confirm these values, ex vivo measurements of organs were performed. Plasma and urine were also collected to study in vivo metabolism. Data was extrapolated to humans, effective doses were estimated using ICRP-60 and ICRP-89 dosimetric models and absorbed doses were estimated using OLINDA/EXM V1.0 and OLINDA/EXM V2.0 (which use weighting factors from ICRP-103 to do the calculations). RESULTS: The [18F]FNM was stable in human plasma and the diffusible free fraction was 53%. As with memantine, this tracer is poorly metabolized in vivo. Ex vivo distributions validated PET/CT data as well as demonstrating a decrease of radiotracer uptake in the brain due to anesthesia. Total effective dose was around 6.11 MUSv/MBq and 4.65 MUSv/MBq for female and male human dosimetric models, respectively. CONCLUSIONS: This study shows that the presented compound exhibits stability in plasma and plasma protein binding very similar to memantine. Its dosimetry shows that it is suitable for use in humans due to a low total effective dose compared to other PET radiotracers. PMID- 29413752 TI - Development of radioiodine labeled acetaminophen for specific, high-contrast imaging of malignant melanoma. AB - INTRODUCTION: Due to its poor prognosis, specific imaging for early detection of malignant melanoma is strongly desired. Although radioiodine labeled 4 hydroxyphenylcysteamine, which we previously developed, has good affinity for tyrosinase, an enzyme in the melanin metabolic pathway, image contrast of the melanoma:organ ratios is not sufficiently high for detection of primary melanoma and metastases at early injection times. In this study, we developed radioiodine labeled acetaminophen (I-AP) for specific, high-contrast imaging of malignant melanoma. METHODS: Radioiodine-125-labeled AP (125I-AP) was prepared using the chloramine-T method under no carrier-added conditions. Accumulation of radioactivity and the mechanism were evaluated in vitro using B16 melanoma cells incubated with 125I-AP or 14C(U)-labeled AP (14C-AP) with and without l-tyrosine as a substrate of tyrosinase, phenylthiourea as an inhibitor of tyrosinase, and thymidine as an inhibitor of DNA polymerase. The biological distribution of radioactivity in B16 melanoma-bearing mice was evaluated to determine the accumulation of 125I-AP. The stability of 125I-AP over time was evaluated in mice. RESULTS: The labeling efficiency and radiochemical purity of 125I-AP were >80% and 95%, respectively. Accumulation of 125I-AP was higher than that of 14C AP at 60 min of incubation in vitro. The affinity of 14C-AP for tyrosinase and DNA polymerase was higher than that of 125I-AP, whereas the Vmax of 125I-AP was higher than that of 14C-AP. 125I-AP showed the highest accumulation in the gall bladder, and clearance from the blood and kidney was rapid. Melanoma:muscle and melanoma:normal skin ratios of 125I-AP for imaging contrast were the highest at 15 min after injection, whereas the melanoma:blood and melanoma:bone ratios gradually increased over time. 125I-AP remained stable for 60 min after injection in mice. CONCLUSIONS: 125I-AP has affinity for tyrosinase and high image contrast at early time points after injection. Therefore, 123I-AP imaging has great potential for specific, high-contrast detection of malignant melanoma. ADVANCES IN KNOWLEDGE: 123I-AP will provide specific, high-contrast imaging for malignant melanoma at early injection times. IMPLICATIONS FOR PATIENT CARE: 123I-AP has good potential for the diagnosis of malignant melanoma compared with 123I-labeled 4-hydroxyphenylcysteamine, which we previously developed. PMID- 29413753 TI - Imaging of isoproterenol-induced myocardial injury with 18F labeled fluoroglucaric acid in a rat model. AB - : Positron emission tomography (PET) of myocardial infarction (MI) by infarct avid imaging has the potential to reduce the time to diagnosis and improve diagnostic accuracy. The objective of this work was to synthesize 18F-labeled glucaric acid (FGA) for PET imaging of isoproterenol-induced cardiomyopathy in a rat model. METHODS: We synthesized 18F-FGA by controlled oxidation of 18F fluorodeoxy glucose (FDG), mediated by 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) in presence of NaBr and NaOCl in highly-buffered reaction conditions. After ascertaining preferential uptake of 18F-FGA in necrotic as compared to normal H9c2 myoblasts, the biodistribution and circulation kinetics of 18F-FGA was assessed in mice. Moreover, the potential of 18F-FGA to image myocardial damage was investigated in a rat model of isoproterenol-induced cardiomyopathy. Isoproterenol-induced myocardial injury was verified at necropsy by tissue staining and plasma cardiac troponin levels. RESULTS: Synthesis of radiochemically pure 18F-FGA was accomplished by a 5 min, one step oxidation of 18F-FDG. Reaction yield was quantitative and no side-products were detected. Biodistribution studies showed rapid elimination from the body (ke = 0.83 h-1); the major organ of 18F-FGA accumulation was kidney. In the rat model, isoproterenol-treatment resulted in significant increase in cardiac troponin. PET images showed that the hearts of isoproterenol-treated rats accumulated significant amounts of 18F-FGA, whereas healthy hearts showed negligible uptake of 18F-FGA. Target-to-nontarget contrast for 18F-FGA accumulation became significantly more pronounced in 4 h images as compared to images acquired 1 h post-injection. CONCLUSION: 18F-FGA can be easily and quantitatively synthesized from ubiquitously available 18F-FDG as a precursor. The resultant 18F-FGA has a potential to serve as an infarct-avid agent for PET imaging of MI. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: 18F-FGA/PET will complement existing perfusion imaging protocols in therapeutic decision making, determination of revascularization candidacy and success, differentiation of ischemia from necrosis in MI, discrimination of myocarditis from infarction, and surveillance of heart transplant rejection. PMID- 29413754 TI - Island. PMID- 29413755 TI - Association of AGTR1 (A1166C) and ACE (I/D) Polymorphisms with Breast Cancer Risk in North Indian Population. AB - Renin angiotensin system (RAS) comprising Angiotensin converting enzyme (ACE), Angiotensin II (Ang II) and its receptor Angiotensin II receptor type I (AGTR1), plays a critical role in several diseases including cancer. A single nucleotide polymorphism (SNP) A1166C located in 3' untranslated region (UTR) of AGTR1 and an insertion/deletion (I/D) polymorphism present in intron 16 of ACE gene have been associated with many diseases, but their association with Breast cancer (BCa) is still debatable. Here, we for the first time investigated the association of these polymorphisms in a North Indian BCa cohort including 161 patients and 152 healthy women. The polymorphisms were evaluated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) respectively. The association between these polymorphisms and BCa risk was estimated by calculating Odds Ratio (OR) and chi-square (chi2) test. The DD genotype/D allele of ACE (I/D) polymorphism and "AC and CC" genotype/C allele of AGTR1 (A1166C) polymorphism were associated with higher risk of BCa when evaluated independently. Furthermore, interaction analysis of "AC and CC" and DD genotype and combination of "C and D" alleles of both polymorphisms revealed significantly greater BCa risk than that observed independently. Conclusively, women harboring "AC or CC" genotype/C allele for AGTR1 (A1166C) polymorphism and DD genotype/D allele for ACE (I/D) polymorphisms have a predisposition to develop more aggressive disease with advanced staging and larger tumor size. Our study indicates importance of genetic screening based on these polymorphisms for women, who may have higher risk of BCa. PMID- 29413756 TI - The Assessment of Background Parenchymal Enhancement (BPE) in a High-Risk Population: What Causes BPE? AB - OBJECTIVE: To investigate promoting factors for background parenchymal enhancement (BPE) in MR mammography (MRM). METHODS: 146 patients were retrospectively evaluated, including 91 high-risk patients (50 BRCA patients, 41 patients with elevated lifetime risk). 56 screening patients were matched to the high-risk cases on the basis of age. The correlation of BPE with factors such as fibroglandular tissue (FGT), age, menopausal status, breast cancer, high-risk precondition as well as motion were investigated using linear regression. RESULTS: BPE positively correlated with FGT (P<.001) and negatively correlated with menopausal status (P<.001). Cancer did not show an effect on BPE (P>.05). A high-risk precondition showed a significant impact on the formation of BPE (P<.05). However, when corrected for motion, the correlation between BPE and a high-risk precondition became weak and insignificant, and a highly significant association between BPE and motion was revealed (P<.01). CONCLUSION: BPE positively correlated with FGT and negatively correlated with age. Cancer did not have an effect on BPE. A high-risk precondition appears to have a negative effect on BPE. However, when corrected for motion, high-risk preconditions became insignificant. Technical as well as physiological influences seem to play an important role in the formation of BPE. PMID- 29413757 TI - Dendritic Cells Pulsed with Exosomes in Combination with PD-1 Antibody Increase the Efficacy of Sorafenib in Hepatocellular Carcinoma Model. AB - Advanced hepatocellular carcinoma (HCC) has limited therapeutic options. Immunotherapy is a promising treatment, while sorafenib is a first-line drug based treatment for advanced HCC. However, the efficacy of sorafenib and immunotherapy in combination, have not been clearly evaluated. Sorafenib treatment has been shown to promote immunosuppression by increasing hypoxia in orthotopic HCC models. Here, we found that sorafenib treatment in mice with orthotopic HCC increased the expression of inhibitor programmed death-ligand 1 (PD-L1) and T-regulatory cells in tumor tissues. We pulsed dendritic cells with exosomes derived from tumor cells (DC-TEX) and found that the number of T regulatory cells decreased and the number of CD8+T cells increased. However, combining DC-TEX and sorafenib did not prolong survival in these mice. Moreover, we found that the number of PD-1+CD8+T cells significantly increased after DC-TEX treatment. Therefore, we next added PD-1 antibody (PD-1 Ab) to the treatment regimen to block the PD-1/PD-L1 pathway, and found that the exhausted CD8+T cells were restored, without affecting the number of T-regulatory cells. Thus, our data suggest that the combination of DC-TEX and PD-1 Ab enhanced the efficacy of sorafenib, but treatment with either DC-TEX or PD-1 Ab alone, did not. PMID- 29413758 TI - Therapeutic Effect of alpha-Emitting 224Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer. AB - BACKGROUND: Ovarian cancer patients with chemotherapy-resistant residual microscopic disease in the peritoneal cavity have a considerable need for new treatment options. Alpha-emitting radionuclides injected intraperitoneally may be an attractive therapeutic option in this situation as they are highly cytotoxic, while their short range in tissues can spare surrounding radiosensitive organs in the abdomen. Herein we evaluate the therapeutic efficacy of a novel alpha emitting compound specifically designed for intracavitary radiation therapy. METHODS: The alpha-emitter 224Ra was absorbed on calcium carbonate microparticles. Immunodeficient, athymic nude mice with human ovarian cancer cells growing intraperitoneally were treated with different activity levels of 224Ra-microparticles. Tumor growth, survival, and tolerance of the treatment were assessed. Two tumor models based on the cell lines, ES-2 and SKOV3-luc, with different growth patterns were studied. RESULTS: In both models, intraperitoneal treatment with 224Ra-microparticles gave significant antitumor effect with either considerably reduced tumor volume or a survival benefit. An advantageous discovery was that only a few kilobecquerels per mouse were needed to yield therapeutic effects. The treatment was well tolerated up to a dose of 1000 kBq/kg with no signs of acute or subacute toxicity observed. CONCLUSIONS: Intraperitoneal alpha-therapy with 224Ra-microparticles demonstrated a significant potential for treatment of peritoneal micrometastases in ovarian carcinoma. PMID- 29413759 TI - Mutational Profiling of Malignant Mesothelioma Revealed Potential Therapeutic Targets in EGFR and NRAS. AB - Pemetrexed and platinum (PP) combination chemotherapy is the current standard first-line therapy for treatment of malignant mesothelioma (MM). However, a useful predictive biomarker for PP therapy is yet to be found. Here, we performed targeted exome sequencing to profile somatic mutations and copy number variations in 12 MM patients treated with PP therapy. We identified 187 somatic mutations in 12 patients (65 synonymous, 102 missense, 2 nonsense, 5 splice site, and 13 small coding insertions/deletions). We identified somatic mutations in 23 genes including BAP1, TP53, NRAS, and EGFR. Interestingly, rare NRAS p.Q61K and EGFR exon 19 deletions were observed in 2 patients. We also found somatic chromosomal copy number deletions in CDKN2A and CDKN2B genes. Genetic alteration related to response after PP therapy was not found. Somatic mutation profiling in MM patients receiving PP therapy revealed genetic alterations in potential therapeutic targets such as NRAS and EGFR. No alterations in genes with potential predictive role for PP therapy were found. PMID- 29413761 TI - Endostar Combined with Gemcitabine and Cisplatin Chemotherapy for Patients with Metastatic Nasopharyngeal Carcinoma: an Update. AB - OBJECTIVE: A previous phase-2 trial to assess the addition of Endostar to gemcitabine and cisplatin (GC) chemotherapy showed that it improves prognosis in metastatic nasopharyngeal carcinoma (M-NPC) but the study cohort was small. We wished to update that phase-2 trial by enrolling an additional 44 patients and to assess the benefit of Endostar+GC chemotherapy. METHODS: An analysis of 72 M-NPC patients treated between July 2010 and November 2016 was done. The treatment regimen was a combination of gemcitabine (1,000 mg/m2) on days 1 and 8, cisplatin (80 mg/m2) on day 1, and Endostar (15 mg/day) from day 1 to day 14 of a 21-day cycle for >=2 cycles. The acute toxic effects and therapeutic efficacy were analyzed. RESULTS: The response rate was 77.8%. The median progression-free and overall survivals were 12 and 19.5 months, respectively. A total of 329 cycles of GC and 288 cycles of Endostar were delivered to 72 patients, with the median number of four (range, 2-10) cycles administered per patient. The main grade-3/4 hematologic toxicities were leukopenia (54.1%) and neutropenia (59.8%). The number of non-hematologic adverse events was minimal. The regimen was well tolerated. CONCLUSIONS: Endostar+GC chemotherapy is an effective, well-tolerated regimen for M-NPC. PMID- 29413760 TI - Multifaceted Roles of Interleukin-6 in Adipocyte-Breast Cancer Cell Interaction. AB - Breast cancer is the most common malignancy in women worldwide, with a developmental process spanning decades. The malignant cells recruit a variety of cells including fibroblasts, endothelial cells, immune cells, and adipocytes, creating the tumor microenvironment. The tumor microenvironment has emerged as active participants in breast cancer progression and response to treatment through autocrine and paracrine interaction with the malignant cells. Adipose tissue is abundant in the breast cancer microenvironment; interactions with cancer cells create cancer-associated adipocytes which produce a variety of adipokines that influence breast cancer initiation, metastasis, angiogenesis, and cachexia. Interleukin (IL)-6 has emerged as key compound significantly produced by breast cancer cells and adipocytes, with the potential of inducing proliferation, epithelial-mesenchymal phenotype, stem cell phenotype, angiogenesis, cachexia, and therapeutic resistance in breast cancer cells. Our aim is to present a brief knowledge of IL-6's role in breast cancer. This review summarizes our current understanding of the breast microenvironment, with emphasis on adipocytes as key players in breast cancer tumorigenesis. The effects of key adipocytes such as leptin, adipokines, TGF-b, and IL-6 are discussed. Finally, we discuss the role of IL-6 in various aspects of cancer progression. PMID- 29413762 TI - The Epithelial Sodium Channel (alphaENaC) Is a Downstream Therapeutic Target of ASCL1 in Pulmonary Neuroendocrine Tumors. AB - Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcitrant cancer by the National Cancer Institute, in urgent need of new rational therapeutic targets. Previous studies have determined that the basic helix-loop-helix transcription factor achaete-scute homolog 1 (ASCL1) is essential for the survival and progression of a fraction of pulmonary neuroendocrine cancer cells, which include both SCLC and a subset of non-SCLC. Previously, to understand how ASCL1 initiates tumorigenesis in pulmonary neuroendocrine cancer and identify the transcriptional targets of ASCL1, whole genome RNA-sequencing analysis combined with chromatin immunoprecipitation sequencing was performed with a series of lung cancer cell lines. From this analysis, we discovered that the gene SCNN1A, which encodes the alpha subunit of the epithelial sodium channel (alphaENaC), is highly correlated with ASCL1 expression in SCLC. The product of the SCNN1A gene ENaC can be pharmacologically inhibited with amiloride, a drug that has been used clinically for close to 50 years. Amiloride inhibited growth of ASCL1-dependent SCLC more strongly than ASCL1-independent SCLC in vitro and slowed growth of ASCL1-driven SCLC in xenografts. We conclude that SCNN1A/alphaENaC is a direct transcriptional target of the neuroendocrine lung cancer lineage oncogene ASCL1 that can be pharmacologically targeted with antitumor effects. PMID- 29413763 TI - CDC7-dependent transcriptional regulation of RAD54L is essential for tumorigenicity and radio-resistance of glioblastoma. AB - Accumulating evidence indicates that cell division cycle 7-related protein kinase(CDC7) plays an essential role in tumor cells and it could induces cell proliferation and could be related to prognosis in multiple types of cancer. However, the biological role and molecular mechanism of CDC7 in GBM still remains unclear. In this study, we identified that CDC7 expression was enriched in glioblastoma (GBM) tumors and was functionally required for tumor proliferation and its expression was associated to poor prognosis in GBM patients. Mechanically, CDC7 induced radio resistance in GBM cells and CDC7 knock down increased cell apoptosis when combined with radiotherapy. Moreover, CDC7 regulated The DNA repair/recombination protein 54L (RAD54L) expression via regulation of RAD54L promoter activity. Therapeutically, we found that CDC7 inhibitor attenuated tumor growth both in vitro and in vivo. Collectively, CDC7 promotes proliferation, induces radio resistance in GBM, and could become a potential therapeutic target for GBM. PMID- 29413764 TI - Comparison of Two Mathematical Models of Cellularity Calculation. AB - OBJECT: Nowadays, there is increasing evidence that functional magnetic resonance imaging (MRI) modalities, namely, diffusion-weighted imaging (DWI) and dynamic contrast enhanced MRI (DCE MRI), can characterize tumor architecture like cellularity and vascularity. Previously, two formulas based on a logistic tumor growth model were proposed to predict tumor cellularity with DWI and DCE. The purpose of this study was to proof these formulas. METHODS: 16 patients with head and neck squamous cell carcinomas were included into the study. There were 2 women and 14 men with a mean age of 57.0 +/- 7.5 years. In every case, tumor cellularity was calculated using the proposed formulas by Atuegwu et al. In every case, also tumor cell count was estimated on histopathological specimens as an average cell count per 2 to 5 high-power fields. RESULTS: There was no significant correlation between the calculated cellularity and histopathologically estimated cell count by using the formula based on apparent diffusion coefficient (ADC) values. A moderate positive correlation (r=0.515, P=.041) could be identified by using the formula including ADC and Ve values. CONCLUSIONS: The formula including ADC and Ve values is more sensitive to predict tumor cellularity than the formula including ADC values only. PMID- 29413765 TI - A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) is a high-risk malignancy due to its high capacity for invasion and lack of targeted therapy. Immunotherapy continues to demonstrate efficacy in a variety of cancers, and thus may be a promising strategy for TNBC given the limited therapeutic options currently available for TNBC. In this study, we performed an exhaustive analysis of immunogenic signatures in TNBC based on 2 large-scale breast cancer (BC) genomic data. We compared enrichment levels of 26 immune cell activities and pathways among TNBC, non-TNBC, and normal tissue, and within TNBCs of different genotypic or phenotypic features. We found that almost all analyzed immune activities and pathways had significantly higher enrichment levels in TNBC than non-TNBC. Elevated enrichment of these immune activities and pathways was likely to be associated with better survival prognosis in TNBC. This study demonstrated that TNBC likely exhibits the strongest immunogenicity among BC subtypes, and thus warrants the immunotherapeutic option for TNBC. PMID- 29413766 TI - Radiofrequency electromagnetic radiation exposure effects on amygdala morphology, place preference behavior and brain caspase-3 activity in rats. AB - The purpose of the study was to evaluate the changes in amygdala morphology and emotional behaviors, upon exposure to chronic RF-EMR in adolescent rats. Four weeks old male albino Wistar rats were exposed to 900 MHz (power density:146.60 MUW/cm2) from a mobile phone in silent-mode for 28 days. Amygdala morphology was studied using cresyl violet, TUNEL and Golgi-Cox staining. Place preference behavior was studied using light/dark chamber test and following this brain caspase-3 activity was determined. Number of healthy neurons was decreased in the basolateral amygdala and cortical amygdala but not in the central amygdala after RF-EMR exposure. It also induced apoptosis in the amygdala. RF-EMR exposure altered dendritic arborization pattern in basolateral amygdala but not in the central amygdala. Altered place preference and hyperactivity-like behavior was evident after RF-EMR exposure, but brain caspase-3 activity did not change. RF EMR exposure perturbed normal cellular architecture of amygdala and this was associated with altered place preference. PMID- 29413767 TI - The role of intramedullary fixation in ankle fractures - A systematic review. AB - BACKGROUND: Ankle fractures are one of the most commonly occurring fractures in the elderly population. The overall incidence has been reported to be up to 184 fractures per 100,000 persons per year, of which 20-30% occur in the elderly. Medical co-morbidities, osteoporosis, suboptimal skin quality and poor toleration of non-weight bearing status all contribute to difficulties in managing these injuries in this population. Intramedullary implants are advantageous as they utilise smaller incisions, minimise soft tissue disruption and may allow early weight bearing. This systematic review aims to analyse the use of both fibula nails and talo-tibial-calcaneal (TTC) implants in the management of fragility ankle fractures. METHODS: We conducted a systematic review of the literature using the online databases Medline and EMBASE on 26th December 2015. Only studies assessing ankle fractures that were treated with either an intramedullary fibula nail or TTC implant were included. Studies must have reported complications, patient mobility status or a functional outcome measure. Studies were excluded if the intramedullary device utilised was an adjunct to plate fixation or where a variety of surgical treatments were included in the study. The included studies were appraised with respect to a validated quality assessment scale. RESULTS: Our search strategy produced 350 studies although only 17 studies met inclusion criteria; ten assessed a fibula nail and seven assessed a standard hindfoot nail, a TTC implant. 15 studies were case series, the overall quality of the studies was low and only one randomised controlled trial was reviewed. The mean Olerud and Molander Ankle Score for fibula nail studies ranged from 58 to 97 and the complication rate from 0 to 22%. Two comparative studies reported a statistically significant increase in complication rate with plate fixation but similar functional outcomes. Studies assessing TTC implants reported a mean Olerud and Molander Ankle Score of 50-62 and complication rate from 18 to 22.6%. CONCLUSION: The studies reviewed suggest that fibula nails may be capable of producing similar functional outcomes with lower rates of complications to plate fixation. TTC implants produce lower functional outcomes but this may be acceptable in a subgroup of patients at high risk or with reduced pre-injury mobility. However, the low quality of evidence reviewed, the variation in patients included, implant used and outcome scores measured restricts the ability to draw definitive conclusions. Further comparative studies are required to explore the role of these implants further. PMID- 29413768 TI - Open and arthroscopic lateral ligament repair for treatment of chronic ankle instability: A systematic review. AB - BACKGROUND: Chronic ankle instability is defined by an instability lasting more than 6 months, in those cases where a comprehensive conservative treatment fails a surgical stabilization is required. Several surgical techniques have been proposed for the management of the chronic lateral instability of the ankle and even after 50 years, the Brostrom-Gould technique is still considered the gold standard for the treatment of this pathology. Recently, many authors have developed completely arthroscopic lateral ligament repair and the use of these procedures is rapidly increasing. The aim of this review is to provide an updated overview of open and new arthroscopic lateral ligament repair techniques in order to summarize and compare the effectiveness of these strategies. METHODS: A systematic literature review using PubMed/Medline databases was performed (July 1972-July 2015). Clinical results, satisfaction rate and complications of both patient populations were recorded and statistically analyzed. RESULTS: The total ankles treated with an open Brostrom ATFL repair in the 13 studies was 505 with a mean follow up of 73.4 months (range 9 months-27.9 years). Postoperative AOFAS score was reported in 11 studies, with a mean value of 90.1 (range, 60-100), patient's satisfaction rate was 91.7%. Surgery-related complications occurred in 40 (7.92%) out of 505 treated ankles. The total number of ankles treated within the 6 arthroscopic studies was 216 with a mean follow up of 37.2 months (range 6 months-14 years). Five studies reported a mean postoperative AOFAS score of 92.48 (range, 44-100) with a patient's satisfaction rate of 96.4%. Surgery-related complications were observed in 33 (15.27%) cases. CONCLUSIONS: The results of this review show the excellent efficacy of open and arthroscopic surgical procedures in the treatment of the chronic ankle instability. The higher complication rate of arthroscopic procedures respect to the open ones represents the major issue: however, this does not seem to affect the patient's satisfaction. Because of statistical heterogeneity observed no definitive conclusions can be statistically drawn. Finally, to definitively validate the effectiveness of arthroscopic procedures prospective and comparative studies are needed. PMID- 29413769 TI - Does thromboprophylaxis reduce symptomatic venous thromboembolism in patients with below knee cast treatment for foot and ankle trauma? A systematic review and meta-analysis. AB - BACKGROUND: Our aim was to determine the evidence for thromboprophylaxis for prevention of symptomatic venous thromboembolism (VTE) in adults with foot or ankle trauma treated with below knee cast or splint. Our secondary aim was to report major bleeding events. METHODS: MEDLINE and EMBASE databases were searched for randomized controlled trials from inception to 1st June 2015. RESULTS: Seven studies were included. All focused on low molecular weight heparin (LMWH). None found a statistically significant symptomatic DVT reduction individually. At meta analysis LMWH was protective against symptomatic DVT (OR 0.29, 95% CI 0.09-0.95). Symptomatic pulmonary embolism affected 3/692 (0.43%). None were fatal. 86 patients required LMWH thromboprophylaxis to prevent one symptomatic DVT event. The overall incidence of major bleeding was 1 in 886 (0.11%). CONCLUSIONS: Low molecular weight heparin reduces the incidence of symptomatic VTE in adult patients with foot or ankle trauma treated with below knee cast or splint. PMID- 29413770 TI - Results of subtalar arthroereisis for posterior tibial tendon dysfunction stage IIA1. Based on 35 patients. AB - BACKGROUND: The aim of the study was to evaluate the clinical and radiological results obtained in the treatment of adult flexible flatfoot secondary to posterior tibial dysfunction with subtalar arthroereisis using a Kalix (r) endorthesis. METHODS: 35 patients (37 feet) were studied, having been operated between January 2010 and January 2015 for reducible flatfoot secondary to posterior tibial tendon dysfunction stage IIA1 of Bluman. RESULTS: The average follow up was 47.52 months with a minimum of 14 months and a maximum of 75 months. The average age was 54.85, with an age range from 40 to 80 years old. In 74% of cases excellent or good results were obtained, according to our evaluation. The most common complication of this procedure was persistent pain in the sinus tarsi. 35% of cases in this group required implant removal for this reason. CONCLUSIONS: We believe that arthroereisis is valid for the treatment of flat foot secondary to posterior tibial tendon dysfunction at this stage, giving a high percentage of good and excellent results. PMID- 29413771 TI - Population-based epidemiology of 9767 ankle fractures. AB - BACKGROUND: The purpose was to provide up-to-date information concerning the incidence of ankle fractures in a large and complete population including all age groups, spanning a decade, and report the distribution of fractures, trauma mechanism and patient baseline demographics. METHODS: Population-based epidemiological study of all patients treated for an ankle fracture in a 10-year period from 2005 to 2014. RESULTS: A total of 9767 patients with ankle fractures were treated between 2005 and 2014. The mean age at time of fracture was 41.4 (24.3 SD) years. The mean incidence of ankle fractures between 2005 and 2014 was 168.7/100,000/year. Years with cold winters showed increased incidences compared with years with normal winters. For males, the incidence was 157.1/100,000/year, and for females, 179.5/100,000/year. The incidence shows a peak incidence among adolescents in both genders with a male predominance. After the age of 19 the male incidence declines with age, which is in contrast to females, who experience an increasing incidence. The most common fracture type in all age groups was a fracture of the lateral malleolus representing 55% of all fractures. The predominant mode of injury was falls (61%) followed by sports (22%). CONCLUSION: This study shows an incidence of 168.7/100,000/year spanning a decade. The most common fracture type in all age groups was a fracture of the lateral malleolus representing 55% of all fractures. The predominant mode of injury was falls (61%) followed by sports (22%). PMID- 29413772 TI - Increasing the safety of minimally invasive hallux surgery-An anatomical study introducing the clock method. AB - BACKGROUND: The purpose of this study is to describe a simple and reproducible method to localize the neurological structures at risk and to describe a safe zone for hallux minimally invasive surgery (MIS) procedures. METHODS: Ten fresh frozen cadaveric feet were dissected to identify the dorsomedial digital nerve (DMDN) and the dorsolateral digital nerve (DLDN) of the first toe. Axial sections were performed at the sites of metatarsal osteotomies. We documented the position of the nerves with respect to the extensor hallucis longus (EHL) tendon using a clock method superimposed on the axial section RESULTS: The DMDN was found at an average of 26.2 degrees medial to the medial border of the EHL tendon. (SD 11.26, range 14.5-45.5), whereas the average distance of the DLDN was 32.3 degrees lateral to the medial border of the EHL tendon. (SD 6.29, range 13.5 40). CONCLUSIONS: Using the clock method the DMDN and DLDN were found consistently between 10 o'clock and 2 o'clock in either right and left feet. The clock method may facilitate avoiding the area where these nerves are located serving as a valuable tool in minimally invasive foot surgery. PMID- 29413773 TI - Avulsion fracture of the posterosuperior tuberosity of the calcaneus managed with lag screw fixation. AB - BACKGROUND: To review the efficacy of lag screw fixation in management of avulsion fracture of the posterosuperior tuberosity of the calcaneus. METHODS: Since 2002, thirteen patients with displaced fracture of the posterior tuberosity of the calcaneus were treated with emergency reduction of the fracture and lag screw fixation. The medical records and radiographs of the patients were reviewed and the patients were assessed according to the Kerr calcaneal fracture scoring system during the latest follow up. RESULTS: There was no skin necrosis, but one wound dehisced in a patient with unstable diabetes and hypothyroidism. All fractures healed, but two had separation of the fracture fragments after the plaster was removed, both of them were elderly osteoporotic patients. The overall average calcaneal score was 93 (range, 77-100). The average calcaneal score of the patients with closed reduction was 91 (range, 77-100). The average calcaneal score of the patients with open reduction was 94 (range, 79-100). Complications occurred in seven patients (54%). CONCLUSIONS: Percutaneous or open reduction of the avulsion fracture of the posterosuperior tuberosity of the calcaneus together with lag screw fixation and equinus short leg cast immobilization can provide good results without skin necrosis. The surgeon should pay attention of the details of the operation and the rehabilitation program in order to minimize the complications. PMID- 29413774 TI - Effectiveness of the Cobb-Stainsby excision arthroplasty. AB - BACKGROUND: Dislocated metatarsophalangeal joints from clawed or hammer toes can be a disabling consequence of several conditions. The Cobb-Stainsby forefoot arthroplasty combines partial phalangectomy (Stainsby) with extensor tendon transfer to the metatarsal head (Cobb). We present a retrospective, three surgeon case series of 215 toes in 126 patients. METHODS: Early results and complications were gathered from the medical charts of 126 patients who met the inclusion criteria. Seventy-five patients were contactable by phone with a follow up range of 12-82 months (median follow up 45 months). Primary outcome measures were improvement of pain and function, reduction in plantar callosities and cosmetic improvement of the deformity. RESULTS: Pre-operatively all patients presented with pain and shoe wear problems. Post-operatively seventy-two patients (96%) were satisfied, 72 (96%) reported pain relief, 55 (73%) were happy with toe control, 61 (81%) were pleased with cosmesis and 56 (75%) reported unlimited daily activities. Superficial wound infections were observed in 13 of the 126 patients (10%) and two in 75 patients (2%) developed recurrent clawing. CONCLUSION: Our case series demonstrates improved outcomes over alternatives such as the Weil's osteotomy. PMID- 29413775 TI - A comparative prospective cohort health economic analysis comparing ankle fusion, isolated great toe fusion and hallux valgus surgery. AB - BACKGROUND: This study assessed the health economics and outcomes of three common foot and ankle operations. METHODS: Between July 2013 and October 2014 all patients undergoing ankle fusion (AF) for osteoarthritis, first metatarsophalangeal joint fusion for osteoarthritis (MF) or hallux valgus surgery (HV) were included. Patients having additional procedures were excluded. Patients completed the Manchester-Oxford Foot Questionnaire (MOX-FQ), the EuroQol EQ-5D-5L questionnaire and the EQ-VAS on presentation and at least 6 months post operatively. RESULTS: 63 patients undergoing AF (n=22), MF (n=22), or HV (n=32) completed preoperative and postoperative questionnaires. 76 completed preoperative questionnaires and 63 completed the follow up questionnaires. The follow up questionnaires were completed at a median of 12 months (range 6-24 months) following surgery. The mean age at surgery was 59 years (range 26-85 years). Pre-operative MOX-FQ and EQ-5D-5L scores differed significantly between the three groups with AF and MF patients reporting worse scores compared to HV patients. MOX-FQ and EQ-5D-5L significantly improved in all groups from pre operative levels. MOX-FQ: AF from 53.8 (CI 56.8-50.8) to 22.9 (CI 30.9-14.9), MF from 43.0 (CI 46.4-39.6) to 12.1 (CI 18.3-5.9), HV from 35.4 (CI 39.0-31.7) to 15.6 (CI 21.1-10.1). EQ-5D-5L: AF from 0.30 (CI 0.43-0.17) to 0.66 (CI 0.77 0.55), MF from 0.45(CI 0.52-0.38) to 0.83 (CI 0.90-0.76), HV from 0.71(CI 0.74 0.68) to 0.82 (CI 0.88-0.76). There was no significant difference in the EQ-VAS suggesting it may not be representative of foot and ankle health. Health economics analysis using the EQ-5D-5L data to estimate quality-adjusted life years (QALYs) suggested all three procedures were favourable compared to threshold levels of cost-effectiveness. There were differences in estimated costs between the three operations with AF at L2950 (threshold cost FHB > FHL > PER > FDB were all associated with FPI and able to explain 69% of the change in FPI scores. PF3 was the highest contributor explaining 52% of increases in FPI score. Decreased thickness was associated with increased FPI score. Smaller cross sectional area (CSA) in FHB and PER muscles explained 20% and 8% of increase in FPI score. Larger CSA of FDB and FHL muscles explained 4% and 14% increase in FPI score respectively. CONCLUSION: The medial plantar structures and the plantar fascia appear to be the major contributors to static foot posture. Elucidating the individual contribution of multiple muscles of the foot could provide insight about their role in the foot posture. PMID- 29413792 TI - Combined effects of knee brace, laterally wedged insoles and toe-in gait on knee adduction moment and balance in moderate medial knee osteoarthritis patients. AB - OBJECTIVE: To test the hypothesis that toe-in gait (TI) will further reduce first peak (Knee Adduction Moment) KAM and decrease balance when combined with a knee brace (KB) and laterally wedged insoles (LWI) in medial knee osteoarthritis (kOA) patients. PARTICIPANTS: Twenty patients with bilateral symptomatic medial kOA. INTERVENTIONS: 4-point leverage-based KB, full-length LWI with 5 degrees inclination and toe-in gait (TI). MAIN OUTCOME MEASURES: First and second peak knee adduction moment (fKAM and sKAM respectively), balance and pain. METHODS: The fKAM and sKAM were determined from 3-dimensional gait analysis with six randomized conditions: (1) N (without any intervention), (2) KB, (3) KB + TI, (4) LWI, (5) LWI + TI, (6) KB + LWI + TI. Balance was assessed by Biodex Balance System using three stability settings, (i) Static (ii) Moderate dynamic setting for fall risk (FR12) and (iii) High dynamic setting for fall risk (FR8). RESULTS: The reduction in fKAM and sKAM was greatest (19.75% and 12%) when TI was combined with KB and LWI respectively. No change in balance was observed when TI combined with KB, and LWI and when used concurrently with both the orthosis at static and FR12 conditions. Significant balance reduction was found at FR8 for KB + TI (22.22%), and KB + LWI + TI (35.71%). Pain increased significantly for KB (258%), KB + TI (305%), LWI + TI (210%) and KB + LWI + TI (316%). LWI showed no effect on pain. CONCLUSIONS: There is a synergistic effect of TI when combined with KB and LWI concurrently in sKAM reduction. However, the concurrent use of TI, KB and LWI decreases balance and pain as assessed on a highly dynamic platform. PMID- 29413793 TI - Chronic low back pain and back muscle activity during functional tasks. AB - There is evidence that patients with low back pain favor their trunk muscles when moving. However, it is unknown whether this maladaptive behavior is generalized across different functional tasks. This study analyzed the back muscle activity of patients with chronic low back pain compared to asymptomatic controls during five functional tasks. The secondary aim of this study was to test whether the electromyographic activity of patients' back muscles was correlated with either the TAMPA scale score or the Orebro Questionnaire. Forty patients with chronic, non-specific low back pain and 40 asymptomatic participants were assessed on the electromyographic activity of the lumbar longissimus, ilio-costal and multifidus while picking up and placing an object on the ground, sitting down and standing up, and climbing stairs. There was statistical evidence of two-way interactions involving group by task (F4,308 = 7.921, p < 0.001, eta2 = 0.049) and task by muscle (F18,1386 = 2.912, p < 0.001, eta2 = 0.004), but not group by muscle (F7,539 = 1.104, p = 0.359, eta2 = 0.004). Patients with chronic low back pain showed an increase in back muscle activity regardless of the type of functional task, except the left side of multifidus muscle during the picking up of a ball on the ground task. There was no correlation between the measure of kinesiophobia or the Orebro questionnaire score and the level of electromyographic activity. PMID- 29413794 TI - Gait adaptations of older adults on an uneven brick surface can be predicted by age-related physiological changes in strength. AB - BACKGROUND: Outdoor falls in community-dwelling older adults are often triggered by uneven pedestrian walkways. It remains unclear how older adults adapt to uneven surfaces typically encountered in the outdoor built-environment and whether these adaptations are associated to age-related physiological changes. RESEARCH QUESTION: The aims of this study were to (1) compare gait parameters over uneven and flat brick walkways, (2) evaluate the differences between older and young adults for these two surfaces, and (3) assess if physiological characteristics could predict adaptations in older adults. METHODS: Balance, strength, reaction-time, full-body marker positions, and acceleration signals from a trunk-mounted inertial measurement unit were collected in seventeen older (71.5 +/- 4.2 years) and eighteen young (27.0 +/- 4.7 years) healthy adults to compute lower-limb joint kinematics, spatio-temporal parameters, dynamic stability, and accelerometry-derived metrics (symmetry, consistency, and smoothness). RESULTS: Both groups increased hip flexion at foot-strike, while decreasing ankle dorsiflexion, margin of stability, symmetry, and consistency on the uneven, compared to flat, surface. Older, compared to young, adults showed a larger increase in knee flexion at foot-strike and a larger decrease in smoothness on the uneven surface. Only young adults decreased hip abduction on the uneven surface. Strength, not balance nor reaction-time, was the main predictor of hip abduction in older adults on both surfaces. SIGNIFICANCE: While older adults may be especially vulnerable, uneven surfaces negatively impact gait, irrespective of age, and could represent a risk to all pedestrians. PMID- 29413795 TI - Effects of sex and obesity on gait biomechanics before and six months after total knee arthroplasty: A longitudinal cohort study. AB - BACKGROUND: Gait biomechanics, sex, and obesity can contribute to suboptimal outcomes from primary total knee arthroplasty. The aims of this study were to i) determine if sex and/or obesity influence the amount of change in gait biomechanics from pre-surgery to six months post-surgery and; ii) assess if gait returns to normal in men and women. METHODS: Three-dimensional gait analysis was performed on 43 patients undergoing primary total knee arthroplasty for knee osteoarthritis (pre- and six months post-operative) and 40 asymptomatic controls. Mixed linear regression models were fit to assess which factors influenced change in gait biomechanics within the arthroplasty cohort, and interaction terms were included to assess if biomechanics returned to normal following surgery. FINDINGS: Male peak knee adduction moment (p < 0.001) and impulse (p < 0.001) decreased six months following arthroplasty, whilst gait in women remained unchanged after surgery. Obesity did not influence gait changes in men or women. Gait of female arthroplasty participants did not differ from female controls after surgery except for sagittal plane knee range of motion (p = 0.003), whilst men differed from controls for peak knee adduction moment (p = 0.011), knee range of motion (p < 0.001), and peak knee flexion moment (p < 0.001). INTERPRETATION: Sex, but not obesity, influenced changes in gait biomechanics after arthroplasty. Men retained abnormal gait patterns after surgery, whilst women did not. Further research should determine the long-term implications of gait abnormalities seen in men after arthroplasty. PMID- 29413796 TI - Varus thrust visualized during gait was associated with inverted foot in patients with knee osteoarthritis: An exploratory study. AB - The foot is speculated to play a role in knee joint kinematics. This exploratory cross-sectional study examined the association between static foot posture and the presence of varus thrust visualized during gait in patients with medial knee osteoarthritis (OA). Patients (n = 88 patients and 134 knees; age, 61-91 years; 68.2% female) with Kellgren/Lawrence (K/L) grade >=1 in the medial compartment were included in this study and underwent gait observation for varus thrust. These patients' three-dimensional static foot posture while standing was evaluated and their tibiofemoral joint K/L grades and anatomical axis angles were also assessed as covariates. Knees with varus thrust (22 knees, 16.4%) on average had a 4 degrees more inverted calcaneus relative to the floor than those without varus thrust (P < 0.001). A logistic regression analysis showed that an increased calcaneus inversion angle was significantly associated with higher odds of the presence of varus thrust with adjustments for age, sex, body mass index, K/L grade, and anatomical axis angle. The other predictors, such as navicular height, navicular height/foot length, and rearfoot angle relative to the lower leg, were not significantly associated with varus thrust. These results suggest that patients with varus thrust had a different static rearfoot posture as compared with those without varus thrust, a finding that may indicate an important role of static rearfoot posture in the pathogenesis of varus thrust. Furthermore, investigating the potential influence of foot posture on the efficacy of biomechanical interventions, such as lateral wedge insole use, on varus thrust would be of particular interest in the further studies. PMID- 29413797 TI - Hip rotation during standing and dynamic activities and the compensatory effect of femoral anteversion: An in-vivo analysis of asymptomatic young adults using three-dimensional computed tomography models and dual fluoroscopy. AB - BACKGROUND: Individuals are thought to compensate for femoral anteversion by altering hip rotation. However, the relationship between hip rotation in a neutral position (i.e. static rotation) and dynamic hip rotation is poorly understood, as is the relationship between anteversion and hip rotation. RESEARCH OBJECTIVE: Herein, anteversion and in-vivo hip rotation during standing, walking, and pivoting were measured in eleven asymptomatic, morphologically normal, young adults using three-dimensional computed tomography models and dual fluoroscopy. METHODS: Using correlation analyses, we: 1) determined the relationship between hip rotation in the static position to that measured during dynamic activities, and 2) evaluated the association between femoral anteversion and hip rotation during dynamic activities. Hip rotation was calculated while standing (static rotation), throughout gait, as a mean during gait (mean gait rotation), and as a mean (mid-pivot rotation), maximum (max-rotation) and minimum (min-rotation) during pivoting. RESULTS: Static-rotation (mean +/- standard deviation; 11.3 degrees +/- 7.3 degrees ) and mean gait rotation (7.8 degrees +/- 4.7 degrees ) were positively correlated (r = 0.679, p = 0.022). Likewise, static-rotation was strongly correlated with mid-pivot rotation (r = 0.837, p = 0.001), max-rotation (r = 0.754, p = 0.007), and min-rotation (r = 0.835, p = 0.001). Strong positive correlations were found between anteversion and hip internal rotation during all of the stance phase (0-60% gait) and during mid- and terminal-swing (86-100% gait) (all r > 0.607, p < 0.05). CONCLUSIONS: Our results suggest that the static position may be used cautiously to express the neutral rotational position of the femur for dynamic movements. Further, our results indicate that femoral anteversion is compensated for by altering hip rotation. As such, both anteversion and hip rotation may be important to consider when diagnosing hip pathology and planning for surgical procedures. PMID- 29413798 TI - Test-retest reliability of daily life gait speed as measured by smartphone global positioning system. AB - BACKGROUND: Gait speed is useful in predicting adverse health outcomes among older adults. In previous studies, gait speed has typically been measured when subjects walk in laboratory settings, where they are able to intentionally change their gait speed. Thus, it is unclear whether the gait speed captured in a laboratory setting is representative of the subjects' actual walking pace in daily life. RESEARCH QUESTION: This study proposes using the more accurate "daily life gait speed" (DGS), measured as the subject's average gait speed over a week long period using the global positioning system (GPS) in their smartphone. We examined the test-retest reliability of the DGS measure in the present study. METHODS: Three daily life gait parameters with 186 volunteers (57 men and 129 women), aged 19 to 84 years, were measured using a smartphone application: DGS, average of daily gait cycle during a week (DCY), and average of daily cadence during a week (DCA). Test-retest reliability of the daily gait parameters between test week (T1) and retest week (T2) was assessed with the intraclass correlation coefficient, ICC (2,1), and systematic biases were observed via Bland-Altman plots. RESULTS: The ICCs between the daily gait parameters at T1 and T2 were 0.902 for DGS, 0.916 for DCY, and 0.917 for DCA. The Bland-Altman plots showed no significant fixed or proportional bias between the measurements at T1 and T2. SIGNIFICANCE: These results verify that the test-retest reliability of the daily gait parameters in the present study was adequate. PMID- 29413799 TI - Criterion validity of the instrumented Timed Up and Go test: A partial least square regression study. AB - The Timed Up and Go (TUG) test is a common mobility measure in rehabilitation. With the instrumental TUG test (ITUG; i.e. the TUG measured by inertial measurement units, IMUs), several movement measures are newly available. However, the clinical meaning of these new measures is not totally clear. Aim of the current work is to evaluate the validity of different ITUG parameters as a measure of balance. Neurological patients (n = 122; 52 females; 89 older than 65 years) completed the TUG test with IMUs secured to their back. IMUs signals were used to split the TUG test in five phases (sit-to-stand, walk1, turn1, walk2 and turn-and-sit) and twelve movement parameters were obtained. Experienced clinicians administered the Mini-BESTest (MB) scale, a sound balance measure. The partial least square regression (PLSR) was used to explore the association between the ITUG variables and the MB measure. A PLSR model with twelve ITUG variables had satisfactory fit parameters (RMSEP: 11%; R2: 0.41, 95% CI: 0.28 0.54; regression line: 1, 95% CI: 0.78-1.22). Three ITUG variables (i.e. turn1 vertical angular velocity, turn1 duration and turn2 vertical angular velocity) were found to be the most important predictors of the MB measure. A PLSR model with the turning variables only had fit parameters comparable to that of the twelve variables model. Turning parameters from the TUG test are good predictors of the MB scale. The mean angular velocity during turning and the duration of the turning phase are thus proposed as a valid, ratio-level measures of balance in neurological patients. PMID- 29413800 TI - Healthy young adults implement distinctive avoidance strategies while walking and circumventing virtual human vs. non-human obstacles in a virtual environment. AB - This study examines how three types of obstacles (cylinder, virtual human and virtual human with footstep sounds) affect circumvention strategies of healthy young adults. Sixteen participants aged 25.2 +/- 2.5 years (mean +/- 1SD) were tested while walking overground and viewing a virtual room through a helmet mounted display. As participants walked towards a stationary target in the far space, they avoided an obstacle (cylinder or virtual human) approaching either from the right (+40 degrees ), left (-40 degrees ) or head-on (0 degrees ). Obstacle avoidance strategies were characterized using the position and orientation of the head. Repeated mixed model analysis showed smaller minimal distances (p = 0.007) while avoiding virtual humans as compared to cylinders. Footstep sounds added to virtual humans did not modify (p = 0.2) minimal distances compared to when no sound was provided. Onset times of avoidance strategies were similar across conditions (p = 0.06). Results indicate that the nature of the obstacle (human-like vs. non-human object) matters and can modify avoidance strategies. Smaller obstacle clearances in response to virtual humans may reflect the use of a less conservative avoidance strategy, due to a resemblance of obstacles to pedestrians and a recall of strategies used in daily locomotion. The lack of influence of footstep sounds supports the fact that obstacle avoidance primarily relies on visual cues and the principle of 'inverse effectiveness' whereby multisensory neurons' response to multimodal stimuli becomes weaker when the unimodal sensory stimulus (vision) is strong. Present findings should be taken into consideration to optimize the ecological validity of VR-based obstacle avoidance paradigms used in research and rehabilitation. PMID- 29413801 TI - Trunk rotation alters postural sway but not gait in female children and early adolescents: Results from a school-based screening for scoliosis. AB - OBJECTIVE: The purpose of this study was to assess the influence of trunk rotation (TR) on postural sway and spatial-temporal parameters of gait in children and early adolescents screened at school for the presence of scoliosis. METHODS: Two hundred and fifty-five individuals aged 9-14 (141 boys, 114 girls) underwent trunk rotation (TR) assessment by means of angle of trunk rotation (ATR) measurements performed with Bunnell's scoliometer. Participants with ATR >= 5 degrees formed the TR group whose data were compared with those of a control group (CON) composed of individuals with ATR < 5 degrees matched for age and anthropometric features. Postural sway was calculated on the basis of center of pressure (COP) time series acquired using a pressure plate. Spatial-temporal parameters of gait were derived from trunk accelerations collected by a single inertial sensor located in the low-back region. RESULTS: Sway area, sway path, COP velocities in medio-lateral (ML) and antero-posterior (AP) directions and COP displacements in ML direction were found significantly higher in girls with TR, while no differences between the TR and CON groups were detected in boys. Both boys and girls with TR exhibited gait patterns similar to those of their CON schoolmates. CONCLUSIONS: These findings suggest that even mild levels of TR may influence balance of female children and early adolescents screened for scoliosis, and thus early interventions including selective and task-oriented exercises appear advisable. In contrast, TR does not appear to influence gait, but further investigations are required to clarify whether different ATR cut-offs may reveal alterations of spatial-temporal parameters. PMID- 29413802 TI - Real-time visual biofeedback to improve therapy compliance after total hip arthroplasty: A pilot randomized controlled trial. AB - BACKGROUND: Previous studies have shown limited therapy compliance in weight bearing in patients following total hip arthroplasty. RESEARCH QUESTION: The purpose of this pilot RCT is to determine the immediate and late effect of real time, visual biofeedback on weight-bearing during rehabilitation after THA in elderly. METHODS: 24 participants who underwent THA were randomized to either the control or the intervention group. The intervention group received real-time, visual biofeedback on weight-bearing during training with the physical therapist during hospitalization and at twelve weeks follow up. RESULTS: Without biofeedback, therapy compliance was limited. Significant improvement in peak load was found in the intervention group in the early postoperative phase. In contrast to the control group, the peak load at twelve weeks was significantly higher in the intervention group compared to the pre-operative peak load, indicating a lasting effect of early biofeedback. Other gait parameters were not significantly different in the early postoperative phase. In the intervention group a longer walking distance was observed and the use of walking aids was reduced at twelve weeks. SIGNIFICANCE: Biofeedback systems could be promising to improve outcomes and reduce costs in future rehabilitation programs after THA. PMID- 29413803 TI - Motor learning in people with Parkinson's disease: Implications for fall prevention across the disease spectrum. AB - BACKGROUND: Falls are a significant burden for people with Parkinson's disease (PD), however, individuals across the spectrum of disease severity respond differently to fall prevention interventions. Despite the multifactorial causes of falls in people with PD, recent work has provided insight into interventions that hold promise for fall prevention. Further, studies have begun to identify patient characteristics that may predict responsiveness to such interventions. RESEARCH QUESTION: We discuss (i) the postural motor learning abilities of people with mild versus severe PD that could affect their ability to benefit from fall prevention interventions, (ii) how people with different severity of PD respond to such interventions, and (iii) the practical considerations of providing effective fall prevention interventions for people with PD across the spectrum of disease severity. METHODS: This narrative review consolidates recent work on postural motor learning and fall prevention rehabilitation involving exercise in people with PD. RESULTS: People with PD are able to improve postural motor control through practice, enabling them to benefit from exercise which challenges their gait and balance to reduce falling. Worsening of axial and cognitive symptoms may result in diminished learning, and those with more severe PD may require fully supervised, high intensity programs to reduce falls. SIGNIFICANCE: Understanding how people with PD across the spectrum of disease severity differ in their postural motor learning ability and response to different fall prevention interventions will enable researchers and clinicians to refine such interventions and their delivery to minimize falls and their negative sequelae in people with PD. PMID- 29413804 TI - Impacts of freezing of gait on forward and backward gait in Parkinson's disease. AB - Freezing of gait (FOG) is a major risk factor for falls and fall-related injuries in patients with Parkinson's disease (PD). The characteristics of gait in PD patients with FOG have been studied but remain controversial. To investigate gait characteristics of FOG in PD, this study analyzed the forward and backward walking of patients with PD. Twenty-six patients with PD were recruited [age: 71.0 +/- 6.2 years, Hoehn and Yahr stage: 2-3 (median 2.5)]. Based on responses to the New Freezing of Gait Questionnaire, we classified patients into either the "freezer" or "non-freezer" group. Spatiotemporal and kinematic analyses of forward and backward walking were completed using a three-dimensional motion analysis system over an 8 m walkway in the defined "off" state. There was no difference in demographic and clinical characteristics between the freezers (n = 10) and non-freezers (n = 16). Analysis of forward walking revealed no between group differences, except for faster walking speed among the non-freezers. During backward walking, the freezers exhibited slower walking speed, shorter stride length, and increased asymmetry of step length. Kinematic analysis of backward walking revealed smaller range of motion in hip and ankle joints and lower step height in freezers. Further investigations of backward walking might expand our understanding of the pathophysiology of FOG in patients with PD. PMID- 29413805 TI - Postural control deficit during sit-to-walk in patients with Parkinson's disease and freezing of gait. AB - INTRODUCTION: The intricate linkage between Freezing of Gait (FoG) and postural control in Parkinson's disease (PD) is unclear. We analyzed the impact of FoG on dynamic postural control. METHODS: 24 PD patients, 12 with (PD + FoG), 12 without FoG (PD-FoG), and 12 healthy controls, were assessed in ON state. Mobility and postural control were measured with clinical scales (UPDRS III, BBS, MPAS) and with kinematic and kinetic analysis during three tasks, characterized by levels of increasing difficulty to plan sequential movement of postural control: walk (W), gait initiation (GI) and sit-to-walk (STW). RESULTS: The groups were balanced by age, disease duration, disease severity, mobility and balance. During STW, the spatial distribution of COP trajectories in PD + FoG patients are spread over medial-lateral space more than in the PD-FoG (p < .001). Moreover, the distribution of COP positions. in the transition between sit-to-stand and gait initiation, is not properly shifted toward the leading leg, as in PD-FoG and healthy controls, but it is more centrally dispersed (p < .01) with a delayed weight forward progression (p < .05). In GI task and walk task, COM and COP differences are less evident and even absent between PD patients. CONCLUSION: PD + FoG show postural control differences in STW, compared with PD-FoG and healthy. Different spatial distribution of COP trajectories, between two PD groups are probably due to a deficit to plan postural control during a more demanding motor pattern, such as STW. PMID- 29413807 TI - Meta-analytical prognostic accuracy of the Comprehensive Assessment of at Risk Mental States (CAARMS): The need for refined prediction. AB - Primary indicated prevention is reliant on accurate tools to predict the onset of psychosis. The gold standard assessment for detecting individuals at clinical high risk (CHR-P) for psychosis in the UK and many other countries is the Comprehensive Assessment for At Risk Mental States (CAARMS). While the prognostic accuracy of CHR-P instruments has been assessed in general, this is the first study to specifically analyse that of the CAARMS. As such, the CAARMS was used as the index test, with the reference index being psychosis onset within 2 years. Six independent studies were analysed using MIDAS (STATA 14), with a total of 1876 help-seeking subjects referred to high risk services (CHR-P+: n=892; CHR-P-: n=984). Area under the curve (AUC), summary receiver operating characteristic curves (SROC), quality assessment, likelihood ratios, and probability modified plots were computed, along with sensitivity analyses and meta-regressions. The current meta-analysis confirmed that the 2-year prognostic accuracy of the CAARMS is only acceptable (AUC=0.79 95% CI: 0.75-0.83) and not outstanding as previously reported. In particular, specificity was poor. Sensitivity of the CAARMS is inferior compared to the SIPS, while specificity is comparably low. However, due to the difficulties in performing these types of studies, power in this meta analysis was low. These results indicate that refining and improving the prognostic accuracy of the CAARMS should be the mainstream area of research for the next era. Avenues of prediction improvement are critically discussed and presented to better benefit patients and improve outcomes of first episode psychosis. PMID- 29413806 TI - A quantitative PCR-based assay reveals that nucleotide excision repair plays a predominant role in the removal of DNA-protein crosslinks from plasmids transfected into mammalian cells. AB - DNA-protein crosslinks (DPCs) are complex DNA lesions that induce mutagenesis and cell death. DPCs are created by common antitumor drugs, reactive oxygen species, and endogenous aldehydes. Since these agents create other types of DNA damage in addition to DPCs, identification of the mechanisms of DPC repair is challenging. In this study, we created plasmid substrates containing site-specific DPC lesions, as well as plasmids harboring lesions that are selectively repaired by the base excision or nucleotide excision repair (NER) pathways. These substrates were transfected into mammalian cells and a quantitative real-time PCR assay employed to study their repair. This assay revealed that DPC lesions were rapidly repaired in wild-type human and Chinese hamster derived cells, as were plasmids harboring an oxoguanine residue (base excision repair substrate) or cholesterol lesion (NER substrate). Interestingly, the DPC substrate was repaired in human cells nearly three times as efficiently as in Chinese hamster cells (>75% vs ~25% repair at 8 h post-transfection), while there was no significant species-specific difference in the efficiency with which the cholesterol lesion was repaired (~60% repair). Experiments revealed that both human and hamster cells deficient in NER due to mutations in the xeroderma pigmentosum A or D genes were five to ten-fold less able to repair the cholesterol and DPC lesions than were wild-type control clones, and that both the global genome and transcription-coupled sub-pathways of NER were capable of repairing DPCs. In addition, analyses using this PCR-based assay revealed that a 4 kDa peptide DNA crosslink was repaired nearly twice as efficiently as was a ~38 kDa DPC, suggesting that proteolytic degradation of crosslinked proteins occurs during DPC repair. These results highlight the utility of this PCR-based assay to study DNA repair and indicate that the NER machinery rapidly and efficiently repairs plasmid DPC lesions in mammalian cells. PMID- 29413808 TI - Efficacy of non-invasive brain stimulation on the symptom dimensions of schizophrenia: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) have shown promise in the treatment of schizophrenia. OBJECTIVE: To quantify the efficacy of double-blind randomized controlled trials (RCT) of tDCS and rTMS for the positive and negative symptoms of schizophrenia and identify significant moderators relating to patient-related features and stimulation parameters. METHODS: Systemic review and meta-analyses of the relevant literature published until February 1st, 2017 to assess treatment efficacy and quantify the contribution of potential moderator variables. RESULTS: We identified 7 RCTs on tDCS (involving 105 participants) and 30 RCTs on rTMS (involving 768 participants). Compared to sham, tDCS improved all symptom dimensions but the effect reached significance for negative symptoms (Hedge's g = -0.63, p = 0.02). Efficacy for positive but not negative symptoms was linearly associated with cumulative tDCS stimulation. Compared to sham, rTMS improved hallucinations (Hedge's g = -0.51, p < 0.001) and negative symptoms (Hedge's g = 0.49, p = 0.01) but was associated with modest, non-significant worsening of positive symptoms (Hedge's g = 0.28, p = 0.13). Higher pulse frequency (>10 Hz), motor threshold intensity of 110%, left prefrontal cortical treatment site and trial duration over 3 weeks were associated with improvement in negative symptoms and worsening in positive symptoms (all p < 0.03). CONCLUSIONS: The symptom dimensions in schizophrenia may respond differently to brain stimulation interventions in a way that may reflect the interaction between disease- and treatment-related mechanisms. Our findings underscore the need for further research into patient selection prior to treatment assignment and greater refinement of stimulation protocols. PMID- 29413809 TI - Mass violence, radicalization and terrorism: A role for psychiatric profession? PMID- 29413810 TI - Transdiagnostic vs. disorder-focused perspective in children and adolescents with eating disorders: Findings from a large multisite exploratory study. AB - BACKGROUND: The transdiagnostic model of eating disorders (ED) proposes common cognitive mechanisms in patients with ED psychopathology. Little is known about their role in the maintenance of ED in children and adolescents. This study aimed to determine whether the relationships between key factors (low self-esteem, weight and shape control, clinical perfectionism, interpersonal problems, distress and mood instability) and core maintaining mechanisms (binge-eating and restraint) would support a transdiagnostic theory in young patients. METHODS: A total of 419 patients (mean age 14.7 +/- 2.14 years; age range: 7-18 years; males 13.8%) diagnosed with an ED were assessed in six Italian clinical centers in 2013. Multiple comparisons between ED diagnosis, correlation analysis and principal component analysis (PCA) were performed. RESULTS: Of the entire collective, 51.5% of patients were diagnosed with Anorexia Nervosa (AN), 12.3% were diagnosed with Bulimia Nervosa (BN) and 36.2% with Eating Disorder Not Otherwise Specified (EDNOS). In PCA, the core ED mechanisms, dietary restraint and binge eating, acted as poles of attraction of the other variables. The AN group was particularly linked to restraint and the BN group was particularly related to "Bulimia". Considering the diagnostic subtypes, there were no significant differences between the anorexic binge-purging group, bulimic purging group and bulimic non-purging group, which constituted a unique cluster related to affective, interpersonal problems and to perfectionism, indicating a very homogeneous subgroup. Restricting anorexic group (AN-R), related to shape concern and anxious-depressed mood, was not linked to the other subtypes. EDNOS appeared to be opposed to the AN-R group; the binge eating disorder group appeared to be independent from others. CONCLUSION: Our results suggest the presence of both specific and transdiagnostic mechanisms in ED subtypes, whose knowledge is of relevance for clinical practice. PMID- 29413811 TI - 3D QSAR Pharmacophore Based Virtual Screening for Identification of Potential Inhibitors for CDC25B. AB - Owing to its fundamental roles in cell cycle phases, the cell division cycle 25B (CDC25B) was broadly considered as potent clinical drug target for cancers. In this study, 3D QSAR pharmacophore models for CDC25B inhibitors were developed by the module of Hypogen. Three methods (cost analysis, test set prediction, and Fisher's test) were applied to validate that the models could be used to predict the biological activities of compounds. Subsequently, 26 compounds satisfied Lipinski's rule of five were obtained by the virtual screening of the Hypo-1 CDC25B against ZINC databases. It was then discovered that 9 identified molecules had better binding affinity than a known CDC25B inhibitors-compound 1 using docking studies. The molecular dynamics simulations showed that the compound had favorable conformations for binding to the CDC25B. Thus, our findings here would be helpful to discover potent lead compounds for the treatment of cancers. PMID- 29413812 TI - Molecular dynamics studies show solvation structure of type III antifreeze protein is disrupted at low pH. AB - Antifreeze proteins are a class of biological molecules of interest in many research and industrial applications due to their highly specialized function, but there is little information of their stability and properties under varied pH derived from computational studies. To gain novel insights in this area, we conducted molecular dynamics (MD) simulations with the antifreeze protein 1KDF at varied temperatures and pH. Water solvation and H-bond formation around specific residues - ASN14, THR18 and GLN44 - involved in its antifreeze activity were extensively studied. We found that at pH1 there was a disruption in water solvation around the basal and the ice binding surfaces of the molecule. This was induced by a small change in the secondary structure propensities of some titrable residues, particularly GLU35. This change explains the experimentally observed reduction in antifreeze activity previously reported for this protein at pH1. We also found that THR18 showed extremely low H-bond formation, and that the three antifreeze residues all had very low average H-bond lifetimes. Our results confirm long-standing assumptions that these small, compact molecules can maintain their antifreeze activity in a wide range of pH, while demonstrating the mechanism that may reduce antifreeze activity at low pH. This aspect is useful when considering industrial and commercial use of antifreeze proteins subject to extreme pH environments, in particular in food industrial applications. PMID- 29413813 TI - Identification of new antibacterial targets in RNA polymerase of Mycobacterium tuberculosis by detecting positive selection sites. AB - Bacterial RNA polymerase (RNAP) is an effective target for antibacterial treatment. In order to search new potential targets in RNAP of Mycobacterium, we detected adaptive selections of RNAP related genes in 13 strains of Mycobacterium by phylogenetic analysis. We first collected sequences of 17 genes including rpoA, rpoB, rpoC, rpoZ, and sigma factor A-M. Then maximum likelihood trees were constructed, followed by positive selection detection. We found that sigG shows positive selection along the clade (M. tuberculosis, M. bovis), suggesting its important evolutionary role and its potential to be a new antibacterial target. Moreover, the regions near 933Cys and 935His on the rpoB subunit of M. tuberculosis showed significant positive selection, which could also be a new attractive target for anti-tuberculosis drugs. PMID- 29413814 TI - Interferon induced Mx protein from Indian snow trout Schizothorax richardsonii (Gray) lacks critical functional features unlike its mammalian homologues. AB - Viral attack within host cells triggers the production of type I interferons and leads to the induction of interferon stimulated genes (ISGs). One of the ISG Mx, encodes type I interferon inducible GTPase that is responsible for the establishment of an anti-viral state within cells. Intriguingly, several isoforms of Mx have been reported in fish, but the structural analysis of fish Mx proteins remains unexplored. For the first time, we have identified and unraveled the molecular structure of Mx protein from Indian snow trout, Schizothorax richardsonii (Gray) a Coldwater fish that inhabits the water bodies in the sub Himalayan region. The snow trout Mx coding region consists of 2518 nucleotides with an open reading frame (ORF) of 1854 nucleotides. It codes for a polypeptide of 617 amino acids with a predicted molecular weight of 70 kDa. In silico analysis of snow trout Mx protein revealed signature of dynamin family (LPRGTGIVTR) along with a tripartite GTP-binding domain (GDQSSGKS, DLPG, and TKPD). Homology modelling established that the Mx protein is an elongated structure with a G domain, bundle signaling element (BSE) and a GTPase effector domain (GED). Moreover, the GED of Mx contains two highly conserved leucine zippers at the COOH-terminal of the protein suggesting its structural similarity with human homologues. However, snow trout Mx lacks the essential features of its mammalian homologues questioning its functional characteristics. Further, a ligand binding site in the said protein has also been predicted adjacent to the GTPase switch within the G domain. PMID- 29413816 TI - Complex non atypical hyperplasia and the subsequent risk of carcinoma, atypia and hysterectomy during the following 9-14 years. AB - INTRODUCTION: The aim of this study was to evaluate the long-term risk of developing atypical hyperplasia/endometrial cancer or having a hysterectomy after being diagnosed with complex non-atypical hyperplasia (CH). MATERIAL AND METHOD: A historic cohort study of 114 women diagnosed with CH between January 1st 2000 and December 31st 2005. All patient records and pathologic reports were reviewed with complete follow up on all patients in the national pathologic database until September 1st 2014. Kaplan-Meier analysis was used to determine (1) no hysterectomy and (2) no diagnosis of endometrial cancer or atypia after the CH diagnosis. RESULTS: 15% (n = 17) were diagnosed with endometrial cancer and 7% (n = 8) with atypia, most during the first year (10 cancer, 7 atypia). 9% (8/85) of the remaining women at risk developed cancer or atypia in the follow-up period after one year. By Kaplan-Meier the five-year risk for cancer or atypia was 20% (CI; 14-21). The risk of having undergone hysterectomy within five years was 30% (CI; 22-39). CONCLUSION: The long-term risk of being diagnosed with atypia or cancer after a CH diagnose is not insignificant, when disregarding patients having undergone hysterectomy. More than half the women with atypia or cancer are diagnosed or operated during the first year. This could indicate the presence of concomitant but unidentified cancer or atypia at the time of initial sampling. This study reinforces the importance of follow up or treatment of women with CH - especially, but not only during the first year. KEY MESSAGE: The risk of having a hysterectomy or diagnosed with atypical hyperplasia/cancer endometrie is high after a diagnosis of complex hyperplasia without atypia. PMID- 29413817 TI - [In process]. PMID- 29413815 TI - Natural killer cell education in human health and disease. AB - Natural killer (NK) cells maintain immune homeostasis by detecting and eliminating damaged cells. Simultaneous activating and inhibitory input are integrated by NK cells, with the net signal prompting cytotoxicity and cytokine production, or inhibition. Chief among the inhibitory ligands for NK cells are 'self' human leukocyte antigen (HLA) molecules, which are sensed by killer immunoglobulin-like receptors (KIR). Through a process called 'education', the functional capabilities of each NK cell are counterbalanced by their sensitivity for inhibition by co-inherited 'self' HLA. HLA and their ligands, the killer immunoglobulin-like receptors (KIR), are encoded by polymorphic, polygenic gene loci that segregate independently, therefore, NK education and function differ even between related individuals. In this review, we describe how variation in NK education, reactivity and sensitivity for inhibition impacts reproductive success, infection, cancer, inflammatory and autoimmune diseases. PMID- 29413818 TI - Drunkorexia among adolescents: The role of motivations and emotion regulation. AB - BACKGROUND: The co-occurrence of disordered eating and alcohol use and misuse has frequently been highlighted in literature. METHOD: The first aim of the present study was to examine the association of drunkorexia with various disordered eating behaviors and alcohol consumption in a sample of male and female adolescents. The second goal was to investigate the motivations underlying drunkorexia and the third goal was to examine the relationship between drunkorexia and different dimensions of emotion regulation. One thousand adolescents (608 females and 392 males; range 16-21) completed a survey of self report measures. RESULTS: Results from hierarchical multiple regression analyses revealed that fasting and engaging in binge drinking and getting drunk were significant predictors of drunkorexia in both males and females; furthermore, females were found to engage in drunkorexia mainly for enhancement motives. Conversely, drunkorexia in males was significantly predicted by difficulties regulating emotions. CONCLUSION: This research suggests that disordered eating and alcohol use similarly contribute to drunkorexia in male and female adolescents, even though highlights important gender differences. PMID- 29413819 TI - Caregiver burden and illness perceptions in caregivers of medically hospitalized youth with anorexia nervosa. AB - Caregiver burden is common in caregivers of youth with anorexia nervosa (AN) and could impede the successful implementation of family-based therapy (FBT). Thus, it is important to better understand mechanisms by which caregiver burden is developed and maintained. This study aimed to examine the relation between caregiver illness perceptions about AN, symptom severity indicators, and caregiver burden in a sample of medically hospitalized youth with AN. Fifty-one youth with AN (N = 34) or Atypical AN (AAN; N = 17; mean age = 14.85, SD = 1.41; 76% female) and their primary caregivers (N = 47 mothers and N = 4 fathers) completed self-report questionnaires at hospital admission. Collected data included caregiver and youth illness perceptions about AN, caregiver burden, and youth self-reports of psychological symptoms. Physiological data regarding symptom severity included admitting percent of expected body weight (%EBW) and minimum heart rate during admission. Findings indicated that caregiver beliefs about negative consequences of AN were associated with caregiver burden, independent of youth age, sex, illness duration, and diagnosis. Youth reports of symptom severity, %EBW, and low heart rate were not associated with increased caregiver burden. Findings suggest that the subjective experience of having a youth with AN are a greater determinant of caregiver burden than objective indicators of illness severity. Further, these findings provide support for the FBT clinician to strike a balance between providing information about the potential consequences of AN, while instilling hope for recovery and bolstering parent self-efficacy. PMID- 29413820 TI - The influence of non-clinical eating-related psychopathology on the recognition of emotion from static faces and realistic social interactions. AB - Emotion recognition deficits have consistently been reported in clinical and sub clinical disordered eating. However, most studies have used static faces, despite the dynamic nature of everyday social interactions. The current aims were to confirm previous findings of emotion recognition deficits in non-clinical disordered eating and to determine if these deficits would be more evident in response to static as compared to dynamic emotional stimuli. We also aimed to establish if these emotion recognition deficits could be explained by comorbid psychopathology (depression, anxiety or alexithymia). Eighty-nine females were assigned to groups based on scores on the Eating Disorders Inventory (EDI); high (n = 45) and low (n = 44). Participants were presented with emotional faces and video clips portraying fear, anger, disgust, sadness, happiness, surprise and neutral affect. As predicted, the high EDI group correctly recognised fewer emotional displays than did the low EDI group. However, this deficit was not more evident for negative as opposed to positive emotions. Furthermore, the deficit was not larger for static stimuli in comparison to dynamic. Overall emotion recognition accuracy was negatively associated with Drive for Thinness, but not Bulimia or Body Dissatisfaction. Importantly, the emotion recognition deficits observed in the high EDI group and that were associated with eating disorder symptoms were independent of depression, anxiety and alexithymia. Findings confirm that even minor elevations in disordered eating are associated with poorer emotion recognition. This is important, as problems in recognition of the emotional displays of others are thought to be a risk factor for clinical eating disorders. PMID- 29413822 TI - A study on the suitability of the PTW microDiamond detector for kilovoltage x-ray beam dosimetry. AB - Kilovoltage x-ray beams are widely used in treating skin cancers and in biological irradiators. In this work, we have evaluated four dosimeters (ionization chambers and solid state detectors) in their suitability for relative dosimetry of kilovoltage x-ray beams in the energy range of 50 - 280kVp. The solid state detectors, which have not been investigated with low energy x-rays, were the PTW 60019 microDiamond synthetic diamond detector and the PTW 60012 diode. The two ionization chambers used were the PTW Advanced Markus parallel plate chamber and the PTW PinPoint small volume chamber. For each of the dosimeters, percentage depth doses were measured in water over the full range of x-ray beams and for field sizes ranging from 2cm diameter to 12 * 12cm. In addition, depth doses were measured for a narrow aperture (7mm diameter) using the PTW microDiamond detector. For comparison, the measured data was compared with Monte Carlo calculated doses using the EGSnrc Monte Carlo package. The depth dose results indicate that the Advanced Markus parallel plate and PinPoint ionization chambers were suitable for depth dose measurements in the beam quality range with an uncertainty of less than 3%, including in the regions closer to the surface of the water as compared with Monte Carlo depth dose data for all six energy beams. The response of the PTW Diode E detector was accurate to within 4% for all field sizes in the energy range of 50-125kVp but showed larger variations for higher energies of up to 12% with the 12 * 12cm field size. In comparison, the microDiamond detector had good agreement over all energies for both smaller and larger field sizes generally within 1% as compared to the Advanced Markus chamber field and Monte Carlo calculations. The only exceptions were in measuring the dose at the surface of the water phantom where larger differences were found. For the 7mm diameter field, the agreement between the microDiamond detector and Monte Carlo calculations was good being better than 1% except at the surface. Based on these results, the PTW microDiamond detector has shown to be a suitable detector for relative dosimetry of low energy x-ray beams over a wide range of x ray beam energies. PMID- 29413821 TI - Posttraumatic stress disorder diagnosis and gender are associated with accelerated weight gain trajectories in veterans during the post-deployment period. AB - BACKGROUND: Veterans are disproportionately affected by overweight/obesity and growing evidence suggests that post-deployment is a critical period of accelerated weight gain. OBJECTIVE: We explored the relationship between posttraumatic stress disorder (PTSD) diagnosis, gender, and post-deployment weight trajectories among U.S. Operations Iraqi Freedom, Enduring Freedom, and New Dawn veterans. DESIGN: We used Veterans Affairs electronic health record data from 248,089 veterans (87% men) who, after their last deployment, had at least one medical visit between October 2001 and January 2009 and more than one BMI recorded through September 2010. We analyzed repeated BMI measurements using linear mixed models, with demographics, PTSD and other relevant psychiatric diagnoses as predictors. RESULTS: At the first recorded BMI, veterans' median age was 29, and 59% of women and 77% of men were overweight/obese. They had a median of 6 BMI measurements during a median follow-up of 2.4 years. Controlling for potential confounders, women with a PTSD diagnosis had a yearly BMI growth rate of 0.11 kg/m2 (95% CI 0.09 to 0.13, p < 0.001) higher than women without PTSD. For men, the corresponding PTSD effect was also significant, but slightly lower: 0.07 kg/m2 ((95% CI 0.05 to 0.09, p < 0.001); women-men difference: 0.03 (95% CI 0.01 to 0.06) kg/m2, p = 0.006). CONCLUSIONS: The post-deployment period is critical for weight gain, particularly for veterans diagnosed with PTSD and women veterans with PTSD. Efforts are needed to engage post-deployment veterans in weight management services, and to determine whether tailored recruitment/treatment interventions will reduce disparities for veterans with PTSD. PMID- 29413823 TI - Automated radiosynthesis and purification of [18F]flumazenil with solid phase extraction. AB - This paper describes the novel approach for preparation of [18F]flumazenil ([18F]FMZ), well known radioligand for assessment of GABAA receptors by PET. The optimized reaction conditions allowed us to implement commercially available SPE cartridges for [18F]FMZ purification avoiding HPLC. All procedures were performed with TRACERlab FX N Pro synthesizer in 53 min. Developed approach provided [18F]FMZ with high RCP (> 97%) and low level of chemical impurities (< 5 ug/mL). FMZ was routinely synthesized in 6.4 +/- 0.7% RCY at EOS (not decay corrected, n = 8) and the molar radioactivity was > 185 GBq/MUmol. PMID- 29413824 TI - Analysis of (n,p) cross sections near 14 MeV. AB - The present work aims to obtain new empirical formulae for calculating the cross sections of (n,p) reactions. The systematic behaviour of the (n,p) cross sections has been studied on 112 target nuclei with 4 <= Z <= 94 in energy range of 14-15 MeV. The new formulae compared with the literature data give a good fit in calculating the (n,p) reaction cross sections at neutron energies near 14 MeV. Thus, accurate predictions of unmeasured cross sections for the considered reaction channel can be provided with the present paper. PMID- 29413825 TI - Proposal of a neutron transmutation doping facility for n-type spherical silicon solar cell at high-temperature engineering test reactor. AB - The p-type spherical silicon solar cell is a candidate for future solar energy with low fabrication cost, however, its conversion efficiency is only about 10%. The conversion efficiency of a silicon solar cell can be increased by using n type silicon semiconductor as a substrate. This study proposed a new method of neutron transmutation doping silicon (NTD-Si) for producing the n-type spherical solar cell, in which the Si-particles are irradiated directly instead of the cylinder Si-ingot as in the conventional NTD-Si. By using a 'screw', an identical resistivity could be achieved for the Si-particles without a complicated procedure as in the NTD with Si-ingot. Also, the reactivity and neutron flux swing could be kept to a minimum because of the continuous irradiation of the Si particles. A high temperature engineering test reactor (HTTR), which is located in Japan, was used as a reference reactor in this study. Neutronic calculations showed that the HTTR has a capability to produce about 40t/EFPY of 10Omegacm resistivity Si-particles for fabrication of the n-type spherical solar cell. PMID- 29413826 TI - Fission products detection in irradiated TRIGA fuel by means of gamma spectroscopy and MCNP calculation. AB - Aim of this work was the detection of fission products activity distribution along the axial dimension of irradiated fuel elements (FEs) at the TRIGA Mark II research reactor of the Technische Universitat (TU) Wien. The activity distribution was measured by means of a customized fuel gamma scanning device, which includes a vertical lifting system to move the fuel rod along its vertical axis. For each investigated FE, a gamma spectrum measurement was performed along the vertical axis, with steps of 1 cm, in order to determine the axial distribution of the fission products. After the fuel elements underwent a relatively short cooling down period, different fission products were detected. The activity concentration was determined by calibrating the gamma detector with a standard calibration source of known activity and by MCNP6 simulations for the evaluation of self-absorption and geometric effects. Given the specific TRIGA fuel composition, a correction procedure is developed and used in this work for the measurement of the fission product Zr95. This measurement campaign is part of a more extended project aiming at the modelling of the TU Wien TRIGA reactor by means of different calculation codes (MCNP6, Serpent): the experimental results presented in this paper will be subsequently used for the benchmark of the models developed with the calculation codes. PMID- 29413827 TI - Correction of coincidence summing effects for add-back mode measurements with a 4pi clover detector using experimental total efficiency. AB - We demonstrated coincidence summing corrections for the measured spectra of multi gamma-ray emitters with the add-back mode of a 4pi clover detector with an almost 98% solid angle condition using a Monte Carlo calculation based on nuclear decay data. The total and peak efficiencies were determined by Monte Carlo simulation code GEANT4 so that the experimental efficiencies measured mono/quasi-mono energetic gamma-ray sources of 109Cd, 139Ce, 137Cs, 54Mn, 57, 60Co and 88Y may be reproduced well. Under a large solid angle condition, (i.e., a large coincidence summing condition), the corrected peak efficiencies, deduced from 134Cs and 152,154Eu measured, were in agreement within 5% with peak efficiencies in the absence of coincidence summing. The coincidence summing effects were corrected properly according to the decay scheme information, using experimental and simulated values of the total efficiency. We thus demonstrated the effectiveness of measurement with the add-back mode of the detector for gamma-ray spectroscopy. PMID- 29413828 TI - Multi-source irradiation facility with improved space configuration for neutron activation analysis: Design optimization. AB - A neutron irradiation facility consisting of six 241Am-Be neutron sources of 30 Ci total activity and 6.6 * 107 n/s total neutron yield is designed. The sources are embedded in a cubic paraffin wax, which plays a dual role as both moderator and reflector. The sample passage and irradiation channel are represented by a cylindrical path of 5 cm diameter passing through the facility core. The proposed design yields a high degree of space symmetry and thermal neutron homogeneity within 98% of flux distribution throughout the irradiated spherical sample of 5 cm diameter. The obtained thermal neutron flux is 8.0 * 104 n/cm2.s over the sample volume, with thermal-to-fast and thermal-to-epithermal ratios of 1.20 and 3.35, respectively. The design is optimized for maximizing the thermal neutron flux at sample position using the MCNP-5 code. The irradiation facility is supposed to be employed principally for neutron activation analysis. PMID- 29413829 TI - A study of electric field distribution in Benjamin type proportional counter using finite element method. AB - Tissue equivalent proportional counters (TEPCs) are commonly based on the Benjamin type of concept. Initially the electric field is optimized by pulse height measurement methods and only one optimum solution was established at that time. In this paper, the electric field distribution is analyzed and optimized using a three-dimensional finite element method. The calculations show that the characteristics of the radial electric field distribution of this type of counters can be equated to cylindrical counters using a pair of appropriate field shaping electrode. Furthermore, the paper analyzes the axial electric field distribution and the possibility of achieving a uniform electric field along its anode while reducing the size of Benjamin type proportional counter design down to 1/10 of currently feasible values with respect to the thinnest available anode wire diameters. PMID- 29413830 TI - Optimization of radiation shielding material aiming at compactness, lightweight, and low activation for a vehicle-mounted accelerator-driven D-T neutron source. AB - To minimize the size and weight of a vehicle-mounted accelerator-driven D-T neutron source and protect workers from unnecessary irradiation after the equipment shutdown, a method to optimize radiation shielding material aiming at compactness, lightweight, and low activation for the fast neutrons was developed. The method employed genetic algorithm, combining MCNP and ORIGEN codes. A series of composite shielding material samples were obtained by the method step by step. The volume and weight needed to build a shield (assumed as a coaxial tapered cylinder) were adopted to compare the performance of the materials visually and conveniently. The results showed that the optimized materials have excellent performance in comparison with the conventional materials. The "MCNP6-ACT" method and the "rigorous two steps" (R2S) method were used to verify the activation grade of the shield irradiated by D-T neutrons. The types of radionuclide, the energy spectrum of corresponding decay gamma source, and the variation in decay gamma dose rate were also computed. PMID- 29413831 TI - Measurement of thermal neutrons reflection coefficients for two-layer reflectors. AB - In this research, thermal neutrons albedo coefficients and relative number of excess counts have been measured experimentally for different thicknesses of two layer reflectors by using 241Am-Be neutron source (5.2Ci) and BF3 detector. Our used reflectors consist of two-layer which are combinations of water, graphite, polyethylene, and lead materials. Experimental results reveal that thermal neutron reflection coefficients slightly increased by addition of the second layer. The maximum value of growth for thermal neutrons albedo is obtained for lead-polyethylene compound (0.72 +/- 0.01). Also, there is suitable agreement between the experimental values and simulation results by using MCNPX code. PMID- 29413832 TI - Neutron tomography simulation by MAVRIC/Monaco code. AB - In this study, MAVRIC/Monaco module integrated with SCALE6.1 package is used to elucidate experimental neutron transmission for various neutron-absorbing materials. Neutron beam hardening and its effect on shielding calculation and tomographic image reconstruction accuracy are presented. The experimental data for studied materials are used for comparison purpose and to prove the capability of MAVRIC/Monaco code in neutron tomography simulation. The good agreement between experimental and calculated values confirms the capability of SCALE6.1 package in obtaining physical data exactly analogous to an experimental measurement. PMID- 29413833 TI - OSL dosimetric properties and efficiency of Brazilian natural calcium fluoride pellets. AB - Calcium fluoride (CaF2), in both natural and synthetic forms, has been exhaustively studied and explored as thermoluminescent (TL) detector. However its sensitivity to ambient light points to the applicability of CaF2 as OSL (Optically Stimulated Luminescence) detector, increasing the research about its luminescent properties. Although some properties to employ CaF2 detectors with OSL technique have been already demonstrated, there is a lack of some essential information as the OSL response to different types and energy of ionizing radiation. In order to extend the use of Brazilian natural CaF2 with OSL technique, we evaluated the efficiency and dosimetric properties of cold pressed CaF2:NaCl pellets. The CaF2 detectors presented good reproducibility and negligible fading of the signal over one month after irradiation. The dose response using OSL, TL and residual TL showed linear behavior for different radiation beams (protons, photons and alpha and beta particles), being equivalent to the results obtained with BeO and MTS (LiF) detectors through OSL and TL technique respectively. Moreover, differences were observed in OSL efficiency according the beam type and energy; CaF2 detectors presented a higher OSL and TL sensitivities to protons, photons and beta particles than to alpha particles. The energy response to photons obtained using OSL and residual TL intensities present an over response at lower photon energy similar to TL energy response. In addition, differences in the OSL curve shapes were observed according to radiation type and energy, pointing to the possibility of applying this material in mixed radiation fields and to estimate average LET (Linear Energy Transfer). PMID- 29413834 TI - A new method for removing false peaks to obtain a precise X-ray spectrum. AB - To get a precise X-ray energy spectrum from the latest high-performance silicon drift detector (fast SDD), a switch reset preamplifier circuit, which has a high signal to noise ratio and small ballistic loss, is used to amplify the weak signal transmitted by the detector. Aiming at the technical problem of fast SDD, which works at high-count rate conditions, we adopt a slow triangle shaping method and use switch reset type preamplifier, and a new method is put forward to remove the false peaks to obtain a precise X-ray spectrum, in essence, to eliminate the distorted pulses transmitted by the detector. 55Fe standard source and a certain kind of rock sample are regarded as measuring objects in the experiments. The spectral comparison figure, which contains the two measurement results of the pre and post elimination of the false peaks, respectively, shows that this method removes the false peaks located in the front of the full-energy peak in spectra and improves the peak-to-background ratio in a complex spectral analysis and the analytical precision of weak signals. PMID- 29413835 TI - Statistical assessment to magnetic susceptibility and heavy metal data for characterizing the coastal sediment of East coast of Tamilnadu, India. AB - A rapid urbanization and industrialization enhances the significant heavy metal pollution in the sediments of coastal area and introduced a serious threat to the human health. In the present study, concentration of heavy metals such as Al, Ti, Fe, V, Cr, Mn, Co, Zn, La, Pb, Mg, Ca, Ni, Cd and Ba are determined in sediments along Periyakalapet to Parangaipettai coastal area, Tamilnadu using energy dispersive X-ray fluorescence spectrometer (EDXRF).These metals have more affinity to establish metallic bond with ferrous material leading to enhancement of sediment magnetic susceptibility. Hence, a magnetic susceptibility (chiLF, chiHF, chiFD) measurement was carried for sediments by using MS2B dual frequency susceptibility meter. Multivariate statistical analysis (Pearson correlation, factor and cluster analysis) was carried out between heavy metals and magnetic susceptibility to assess the anthropogenic impact in the sediments. The study revealed that a magnetic susceptibility measurement is an inexpensive, fast, non destructive and suitable method to identify the heavy metal pollution sources. PMID- 29413836 TI - MCNP5 evaluation of photoneutron production from the Alexandria University 15 MV Elekta Precise medical LINAC. AB - Photoneutron production, and the dose equivalent, in the head assembly of the 15 MV Elekta Precise medical linac; operating in the faculty of Medicine at Alexandria University were estimated with the MCNP5 code. Photoneutron spectra were calculated in air and inside a water phantom to different depths as a function of the radiation field sizes. The maximum neutron fluence is 3.346*10-9 n/cm2-e for a 30*30 cm2 field size to 2-4 cm-depth in the phantom. The dose equivalent due to fast neutron increases as the field size increases, being a maximum of 0.912 +/- 0.05 mSv/Gy at depth between 2 and 4 cm in the water phantom for 40*40 cm2 field size. Photoneutron fluence and dose equivalent are larger to 100 cm from the isocenter than to 35 cm from the treatment room wall. PMID- 29413837 TI - Measurement of activity distribution in an Am-241 disc source using peeled-off Gafchromic EBT3 films. AB - Commercial alpha-emitting sources are fabricated mainly in a disc type. An alpha particle irradiator in Radiation Bioengineering Laboratory at Seoul National University was installed with an Am-241 disc source. Commercial Am-241 disc sources are fabricated by incorporating the radioactive element into a thin substrate layer. Those disc sources are utilized assuming that the radioactive element is uniformly distributed in the active layer of disc sources. In this study, we employed peeled-off Gafchromic EBT3 films to investigate the uniformity of areal radioactivity density over the disc source and to measure the effect of non-uniform activity distribution on dose distribution at the bottom of the cell culture dish positioned in a varying distance from the source. The measurements with the peeled-off EBT3 films informed that the areal activity density in the disc source differed by up to approximately 45% from the average. However, the inhomogeneous Am-241 distribution in a disc source did not affect the radial distribution of fluence rate at the inner bottom of cell dish when the dish is apart from the source sufficiently. The dose distribution measured with an EBT3 film nearly accorded with that obtained by Monte Carlo simulation assuming the uniform Am-241 activity distribution in the active layer of the disc source. Finally, the dose to a single-cell layer of 5 MUm in a nominal thickness was obtained by Monte Carlo simulation assuming a uniform Am-241 activity distribution in the disc source at distances of 20 and 30 mm from the source. The cellular dose estimates were higher than the film dose estimates at all radial distances. The cellular dose decreased with an increasing radial distance from the center to a smaller extent than the EBT3 film dose did. PMID- 29413838 TI - Application of thin layer activation technique for monitoring corrosion of carbon steel in hydrocarbon processing environment. AB - Acidic crude oil transportation and processing in petroleum refining and petrochemical operations cause corrosion in the pipelines and associated components. Corrosion monitoring is invariably required to test and prove operational reliability. Thin Layer Activation (TLA) technique is a nuclear technique used for measurement of corrosion and erosion of materials. The technique involves irradiation of material with high energy ion beam from an accelerator and measurement of loss of radioactivity after the material is subjected to corrosive environment. In the present study, TLA technique has been used to monitor corrosion of carbon steel (CS) in crude oil environment at high temperature. Different CS coupons were irradiated with a 13 MeV proton beam to produce Cobalt-56 radioisotope on the surface of the coupons. The corrosion studies were carried out by subjecting the irradiated coupons to a corrosive environment, i.e, uninhibited straight run gas oil (SRGO) containing known amount of naphthenic acid (NA) at high temperature. The effects of different parameters, such as, concentration of NA, temperature and fluid velocity (rpm) on corrosion behaviour of CS were studied. PMID- 29413839 TI - Monte Carlo dose distribution calculation at nuclear level for Auger-emitting radionuclide energies. AB - : The distribution of radiopharmaceuticals in tumor cells represents a fundamental aspect for a successful molecular targeted radiotherapy. It was largely demonstrated at microscopic level that only a fraction of cells in tumoral tissues incorporate the radiolabel. In addition, the distribution of the radionuclides at sub-cellular level, namely inside each nucleus, should also be investigated for accurate dosimetry estimation. The most used method to perform cellular dosimetry is the MIRD one, where S-values are able to estimate cellular absorbed doses for several electron energies, nucleus diameters, and considering homogeneous source distributions. However the radionuclide distribution inside nuclei can be also highly non-homogeneous. The aim of this study is to show in what extent a non-accurate cellular dosimetry could lead to misinterpretations of surviving cell fraction vs dose relationship; in this context, a dosimetric case study with 99mTc is also presented. METHODS: The state-of-art MCNP6 Monte Carlo simulation was used in order to model cell structures both in MIRD geometry (MG) and MIRD modified geometries (MMG), where also entire mitotic chromosome volumes were considered (each structure was modeled as liquid water material). In order to simulate a wide energy range of Auger emitting radionuclides, four mono energetic electron emissions were considered, namely 213eV, 6keV, 11keV and 20keV. A dosimetric calculation for 99mTc undergoing inhomogeneous nuclear internalization was also performed. RESULTS: After a successful validation step between MIRD and our computed S-values for three Auger-emitting radionuclides (99mTc, 125I and 64Cu), absorbed dose results showed that the standard MG could differ from the MMG from one to three orders of magnitude. These results were also confirmed by considering the 99mTc spectrum emission (Auger and internal conversion electrons). Moreover, considering an inhomogeneous radionuclide distribution, the average electron energy that maximizes the absorbed dose was found to be different for MG and MMG. CONCLUSIONS: The modeling of realistic radionuclide localization inside cells, including a inhomogeneous nuclear distribution, revealed that i) a strong bias in surviving cell fraction vs dose relationships (taking to different radiobiological models) can arise; ii) the alternative models might contribute to a more accurate prediction of the radiobiological effects inherent to more specific molecular targeted radiotherapy strategies. PMID- 29413840 TI - ALPHACAL: A new user-friendly tool for the calibration of alpha-particle sources. AB - In this work, we present and describe the program ALPHACAL, specifically developed for the calibration of alpha-particle sources. It is therefore more user-friendly and less time-consuming than multipurpose codes developed for a wide range of applications. The program is based on the recently developed code AlfaMC, which simulates specifically the transport of alpha particles. Both cylindrical and point sources mounted on the surface of polished backings can be simulated, as is the convention in experimental measurements of alpha-particle sources. In addition to the efficiency calculation and determination of the backscattering coefficient, some additional tools are available to the user, like the visualization of energy spectrum, use of energy cut-off or low-energy tail corrections. ALPHACAL has been implemented in C++ language using QT library, so it is available for Windows, MacOs and Linux platforms. It is free and can be provided under request to the authors. PMID- 29413842 TI - Simulation study on neutron multiplicity of plutonium based on liquid scintillation detector. AB - Fast neutron multiplicity counting (FNMC) is a new method of non-destructive analysis for nuclear materials. Using fast neutron detector array to detect the neutrons emitted from a sample, it obtains measurements according to the multiple counting method and analyzes the mass of plutonium in the sample. In this paper, A FNMC measuring device model has been constructed for simulation study in reference to the most advanced FNMC experimental device in the world. A series of typical plutonium sample models, including samples of plutonium metal and samples of plutonium oxide with different isotopic abundance and in different mass, have been designed. The correctness of the newly established fast neutron multiplicity measuring equation and the necessity of modifying the classical measuring equation have been verified by the computer simulated measurements. Compared with the calculation result from the equation developed in this paper and the calculation result from the classical NMC model, the simulated result shows that the new method is better than the classic method in result deviation. PMID- 29413841 TI - On similarity of various reactor spectra and 235U prompt fission neutron spectrum. AB - A well-defined neutron spectrum is an essential tool not only for calibration and testing of neutron detectors used in dosimetry and spectroscopy but also for validation and verification of evaluated cross sections. A new evaluation of thermal-neutron induced 235U PFNS was performed by the International Atomic Energy Agency (IAEA) in the CIELO (Collaborative International Evaluated Library Organisation Project) project; new measurements of Spectral Averaged Cross sections averaged in the evaluated spectrum are to be obtained. In general, a neutron spectrum in the core is not identical to the pure fission one because fission neutrons undergo many scattering reactions, but it can be shown that PFNS and reactor spectra become undistinguishable from a certain energy boundary. This limit is important for experiments, because when the studied reaction threshold is over this limit, the spectral averaged cross sections in PFNS can be derived from the measured reactions in the reactor core. The evaluation of the neutron spectrum measurements in three different thermal-reactor cores shows that this lower limit is around the energy of 5.5 - 6 MeV. Above this energy the reactor spectra becomes identical with the 235U PFNS. IAEA CIELO PFNS is within 5% of the measured PFNS from 10 to 14 MeV in a LR-0 reactor, while ENDF/B-VII evaluated PFNS underestimated measured neutron spectra. PMID- 29413843 TI - Beta Skin Dosimetry using Passivated Planar Silicon Detector. AB - Accurate measurement of beta skin dose remains a challenge. This dose is defined as the dose to the basil layer at 7 mg/cm2 (approximately 70 um) below the surface of the skin and averaged over an area of 1 cm2. This dose is dependent upon the energy of the beta contamination on the surface of the skin, the area of contamination and the attenuation of this radiation through the 7 mg/cm2 epidermal layer. Ideally, knowing the energy spectra of betas at this level below the surface of the skin would allow accurate prediction of dose. In this work, a Passivated Planar Silicon (PIPS) detector was tested by measuring beta spectra in a geometry simulating skin and, from that, estimating dose. Three calibrated beta sources were used, a low energy beta source, (147Pm), a medium energy source, (204Tl), and a high energy beta source, (90Sr/90Y) to cover the range of beta energies typically found in skin contamination events. Modelling utilized the MCNPX and VARSKIN 4.0 computer codes to calculate dose in skin and were found to be in good agreement with each other. Experimental measurements using a 300 um thick, 3 cm2 PIPS and the three sources identified above showed good agreement with MCNPX results (and thus, also with VARSKIN). Finally, MCNPX modelling compared the dose rates from a commercially available, 100 um thick, 1.5 cm2 PIPS detector and skin, and found that the beta dose could be accurately predicted within 17% over the range of beta energies tested. This result can be obtained with a single measurement and without the need for post data collection analysis. PMID- 29413844 TI - Ripk3 regulates cardiac microvascular reperfusion injury: The role of IP3R dependent calcium overload, XO-mediated oxidative stress and F-action/filopodia based cellular migration. AB - Ripk3-mediated cellular apoptosis is a major contributor to the pathogenesis of myocardial ischemia reperfusion (IR) injury. However, the mechanisms by which Ripk3 influences microvascular homeostasis and endothelial apoptosis are not completely understood. In this study, loss of Ripk3 inhibited endothelial apoptosis, alleviated luminal swelling, maintained microvasculature patency, reduced the expression of adhesion molecules and limited the myocardial inflammatory response. In vitro, Ripk3 deficiency protected endothelial cells from apoptosis and migratory arrest induced by HR injury. Mechanistically, Ripk3 had the ability to migrate onto the endoplasmic reticulum (ER), leading to ER damage, as evidenced by increased IP3R and XO expression. The higher IP3R content was associated with cellular calcium overload, and increased XO expression was involved in cellular oxidative injury. Furthermore, IP3R-mediated calcium overload and XO-dependent oxidative damage were able to initiate cellular apoptosis. More importantly, IP3R and XO also caused F-actin degradation into G actin via post-transcriptional modification of cofilin, impairing the formation of the filopodia and limiting the migratory response of endothelial cells. Altogether, our data confirmed that Ripk3 was involved in microvascular IR injury via regulation of IP3R-mediated calcium overload, XO-dependent oxidative damage and filopodia-related cellular migration, ultimately leading to endothelial apoptosis and migratory inhibition. These findings provide a potential target for treating cardiac microcirculatory IR injury. PMID- 29413845 TI - Cadherins in vascular smooth muscle cell (patho)biology: Quid nos scimus? AB - Vascular smooth muscle cells (SMCs) phenotypes span a reversible continuum from quiescent/contractile (differentiated) to proliferative/synthetic (dedifferentiated) enabling them to perform a diversity of functions that are context-dependent and important for vascular tone-diameter homeostasis, vasculogenesis, angiogenesis or vessel reparation after injury. Dysregulated phenotype modulation and failure to maintain/regain the mature differentiated and contractile phenotypic state is pivotal in the development of vascular diseases such as atherosclerosis and restenosis after angioplasty and coronary bypass grafting. Many functions of SMCs such as adhesion, migration, proliferation, contraction, differentiation and apoptosis are regulated by a broad spectrum of cell-cell and cell-matrix adhesion molecules. Cadherins represent a superfamily of cell surface homophilic adhesion molecules with fundamental roles in morphogenetic and differentiation processes during development and in the maintenance of tissue integrity and homeostasis in adults. The cadherins have major inputs on signalling pathways and cytoskeletal assemblies that participate in regulating processes such as cell polarity, migration, proliferation, survival, phenotype and differentiation. Abnormalities in these processes have long been recognized to underlie pathological SMC-driven reparation, but knowledge on the involvement of cadherins is remarkably limited. This article presents a comprehensive review of cadherin family members currently identified on vascular SMCs in relation to their functions, molecular mechanisms of action and relevance for vascular pathology. PMID- 29413846 TI - TNIP1 reduction sensitizes keratinocytes to post-receptor signalling following exposure to TLR agonists. AB - Cell level inflammatory signalling is a combination of initiation at cell membrane receptors and modulation by cytoplasmic regulatory proteins. For keratinocytes, the predominant cell type in the epidermis, this would include toll-like receptors (TLR) and cytoplasmic proteins that propagate or dampen post receptor signalling. We previously reported that increased levels of tumor necrosis factor alpha induced protein 3-interacting protein 1 (TNIP1) in HaCaT keratinocytes leads to decreased expression of stress response and inflammation associated genes. This finding suggested decreased TNIP1 levels, as seen in some cutaneous disease states, may produce the opposite effect, sensitizing cells to triggers of inflammatory signalling including those sensed by TLR. In this study of TNIP1-deficient HaCaT keratinocytes we examined intracellular signalling consequences especially those expected to produce gene expression changes downstream of TLR3 or TLR2/6 activation by Poly (I:C) or FSL-1, agonists modeling skin relevant pathogens. We found TNIP1-deficient keratinocytes are hyper sensitive to TLR activation compared to control cells with a normal complement of TNIP1 and receiving the same agonist stimulation. TNIP1-deficient keratinocytes have increased levels of activated (phosphorylated) cytoplasmic mediators such as JNK and p38 and greater nuclear translocation of NF-kappaB and phospho-p38 when exposed to TLR ligands. This is consistent with significantly increased expression of several inflammatory cytokines and chemokines, such as IL-6 and IL 8. These results describe how decreased TNIP1 levels promote a hyper-sensitive state in HaCaT keratinocytes evidenced by increased activation of signalling molecules downstream of TLR agonists and increased expression of pro-inflammatory mediators. TNIP1 keratinocyte deficiency as reported for some skin diseases may predispose these cells to excessive inflammatory signalling upon exposure to viral or bacterial ligands for TLR. PMID- 29413847 TI - Abstract ID: 103 GAMOS: Implementation of a graphical user interface for dosimetry calculation in radiotherapy. AB - There are several computer programs or combination of programs for radiation tracking and other information in tissues by using Monte Carlo simulation [1]. Among these are GEANT4 [2] programs provided as classes that can be incorporated in C++ codes to achieve different tasks in radiation interactions with matter. GEANT4 made the physics easier but requires often a long learning-curve that implies a good knowledge of C++ and the Geant4 architecture. GAMOS [3], the Geant4-based Architecture for Medicine-Oriented Simulations, facilitates the use of Geant4 by providing a script language that covers almost all the needs of a radiotherapy simulation but it is obviously out of reach of biological researchers. The aim of the present work was to report the design and development of a Graphical User Interface (GUI) for absorbed dose calculation and for particle tracking in humans, small animals and phantoms. The GUI is based on the open source GEANT4 for the physics of particle interactions, on the QT cross platform application for combining programming commands and for display. The calculation of the absorbed dose can be performed based on 3D CT images in DICOM format, from images of phantoms or from solid volumes that can be made from any pure or composite material to be specified by its molecular formulas. The GUI has several menus relative to the emitting source which can have different shapes, positions, energy as mono- or poly-energy such as X-ray spectra; the types of particles and particle interactions; energy deposition and absorbed dose; and the output results as histograms. In conclusion, the GUI we developed can be easily used by any researcher without the need to be familiar with computer programming, and it will be freely proposed as an open source. PMID- 29413848 TI - Abstract ID: 13 Monte Carlo simulations for the beam quality factors of a parallel-plate ion-chamber in the presence of magnetic field. AB - Magnetic resonance imaging-guided radiotherapy provides real-time imaging with a superior soft-tissue contrast without radiation exposure. Recently, several groups have been developing such a new technology. Strong magnetic fields can influence trajectories of the secondary electrons by the Lorentz force. The reference dosimetry using an ion-chamber in magnetic fields needs additional correction factors [1]. In this study, we calculated magnetic field correction factors by the Monte Carlo method for the reference dosimetry using a parallel plate ion-chamber. The EGSnrc user code, egs_chamber was used to simulate an ion chamber. The full head and spectral source models of Varian therapeutic linear accelerator of 6 MV, 10 MV, and 15 MV photon beam have been simulated by BEAMnrc and beamdp. A parallel-plate ion-chamber (NACP-02 model) was positioned in the water phantom (30 * 30 * 30 cm3) at a depth of 10 cm (5 cm for Co-60 beam). The beam quality factors (KQ) and magnetic field correction factors (KQ,B) were calculated. The absorbed dose of a parallel-plate ion-chamber was scored with and without a 1.5 T of magnetic field. The KQ of 6 MV, 10 MV, and 15 MV were 0.994, 0.980, and 0.976, respectively. These values were compatible to the previous published data (<0.3%) [2]. In a 1.5 T of magnetic field, the KQ,B of 6, 10, and 15 MV were 0.935, 0.985, and 0.994, respectively, compared to 0.975, 0.983, and 0.983 in a 0.35 T of magnetic field. All of simulation uncertainties were within 0.2%. When photon energy increases, KQ,B is also increased, but KQ,B in high strength of a magnetic field are not always smaller than those in low strength of a magnetic field. The magnetic field correction factors of a parallel-plate ion chamber were successfully calculated by the Monte Carlo method. The parallel plate ion-chambers need several percent of correction factors when measuring doses in the presence of a magnetic field. PMID- 29413849 TI - Abstract ID: 142 Monte Carlo modeling of Varian TrueBeam with Geant4-based VirtuaLinac and comparison to experiments. AB - Monte Carlo simulations can provide powerful insight into the physical phenomena and geometrical interactions of linear accelerator beams. This insight can be used to understand the phenomena that govern the beam characteristic and, for instance, to guide the development of treatment planning systems. In this study, we use the VirtuaLinac, a cloud-based application to model the treatment head of the Varian TrueBeam linear accelerator. VirtuaLinac implements the treatment head geometry into the Monte Carlo code Geant4, which is then utilized to provide the physics and numerical engine for the simulations. We consider both open fields and fields limited by multi-leaf collimators and compute the dose deposited in a water phantom. We then compare the simulation results with experimental measurements. The simulated data are also used to extract some of the characteristics of the multi-leaf collimators and to evaluate their impact on the beam properties and the dose distribution. PMID- 29413850 TI - Abstract ID: 171 A Monte Carlo study to reduce range uncertainty in proton beam therapy via prompt gamma-ray detection. AB - In proton beam therapy precise knowledge of the proton beam range is essential to guarantee the treatment's efficacy and to avoid unnecessary toxicities. Unlike photon beams, protons stop inside the patient's body, therefore a direct detection of the distal fall-off is impossible. One technique to determine the beam range is to detect the prompt gamma (PG) rays emitted from the nuclei de exciting following proton bombardment [1]. PG emission is almost instantaneous and has a high-production rate. The aim of this project is to develop a new method, based on an optimized PG detector system, which can achieve 3D range determination with an uncertainty of no more than 2 mm. The presented method is based on the detection of discrete gamma-rays. As a first step, the position reconstruction capability of the PG detector system was examined by means of Geant4 simulations. The prototype system is comprised of 12 LaBr3(Ce) detectors. The information recorded by each individual detector is fed into a reconstruction algorithm to determine the gamma-ray emission point in 3 dimensions. The development of the algorithm, proof-of-principle and simulation validation, have all been conducted using a sealed 60Co source. Our simulations demonstrate that an ideal detector system with the current reconstruction algorithm is capable of determining the source position with sub-millimetre accuracy. Having obtained proof-of-principle for the reconstruction algorithm the next stage is to investigate how implementing a realistic detector system affects the reconstruction performance. In addition, the ability of the detector system to discriminate between multiple sources in different positions is under evaluation. PMID- 29413851 TI - Abstract ID: 176 Geant4 implementation of inter-atomic interference effect in small-angle coherent X-ray scattering for materials of medical interest. AB - Advanced applications of digital mammography such as dual-energy and tomosynthesis require multiple exposures and thus deliver higher dose compared to standard mammograms. A straightforward manner to reduce patient dose without affecting image quality would be removal of the anti-scatter grid, provided that the involved reconstruction algorithms are able to take the scatter figure into account [1]. Monte Carlo simulations are very well suited for the calculation of X-ray scatter distribution and can be used to integrate such information within the reconstruction software. Geant4 is an open source C++ particle tracking code widely used in several physical fields, including medical physics [2,3]. However, the coherent scattering cross section used by the standard Geant4 code does not take into account the influence of molecular interference. According to the independent atomic scattering approximation (the so-called free-atom model), coherent radiation is indistinguishable from primary radiation because its angular distribution is peaked in the forward direction. Since interference effects occur between x-rays scattered by neighbouring atoms in matter, it was shown experimentally that the scatter distribution is affected by the molecular structure of the target, even in amorphous materials. The most important consequence is that the coherent scatter distribution is not peaked in the forward direction, and the position of the maximum is strongly material-dependent [4]. In this contribution, we present the implementation of a method to take into account inter-atomic interference in small-angle coherent scattering in Geant4, including a dedicated data set of suitable molecular form factor values for several materials of clinical interest. Furthermore, we present scatter images of simple geometric phantoms in which the Rayleigh contribution is rigorously evaluated. PMID- 29413852 TI - Abstract ID: 222 Clinical implementation of a Monte Carlo based QA platform for validation of Tomotherapy and Cyberknife treatment plans. AB - INTRODUCTION: This work describes the clinical implementation of a Monte Carlo based platform for treatment plan validation for Tomotherapy and Cyberknife, including a semi-automatic plan evaluation module based on dose constraints for organs-at-risk (OAR). METHODS: The Monte Carlo-based platform Moderato [1] is based on BEAMnrc/DOSXYZnrc and allows for automated re-calculation of doses planned with Tomotherapy and Cyberknife techniques. The Prescription/Validation module generates a set of dose constraints based on the anatomical region and fractionation scheme considered. Upon achievement of the planning, dose results are displayed with visual warnings in case of constraint violation. The system was tested on 83 patient cases in order to evaluate the influence of difference in calculation algorithms on OAR constraints. RESULTS: The first results with the Tomotherapy plans allowed for detecting and correcting a problem with the CT Hounsfield units when using a large reconstruction diameter (a CT artifact that lead to air voxels with an overestimated density). The Cyberknife results also showed some dose differences associated with different energy thresholds between Moderato and the Monte Carlo algorithm used in the Treatment Planning Station. Regarding OAR constraints, re-calculation generated few violations in thoracic, pelvic and abdominal cases. However, in spinal and head cases, significant differences can appear (-11% to +6%) on optic pathways and spinal cord, leading to doses above the limits. CONCLUSIONS: The Moderato platform constitutes a promising tool for the validation of plan quality, offering both dose re calculation and OAR constraints evaluation. First results show the importance of this verification for some specific regions. Further work is ongoing to optimize the quantity and relevance of the information displayed, before fully introducing the system in clinical routine. PMID- 29413853 TI - Abstract ID: 197 Monte Carlo simulations of X-ray grating interferometry based imaging systems. AB - Over the last couple of years the implementation of Monte Carlo (MC) methods of grating based imaging techniques is of increasing interest. Several different approaches were taken to include coherent effects into MC in order to simulate the radiation transport of the image forming procedure. These include full MC using FLUKA [1], which however are only considering monochromatic sources. Alternatively, ray-tracing based MC [2] allow fast simulations with the limitation to provide only qualitative results, i.e. this technique is not suitable for dose calculation in the imaged object. Finally, hybrid models [3] were used allowing quantitative results in reasonable computation time, however only two-dimensional implementations are available. Thus, this work aims to develop a full MC framework for X-ray grating interferometry imaging systems using polychromatic sources suitable for large-scale samples. For this purpose the EGSnrc C++ MC code system is extended to take Snell's law, the optical path length and Huygens principle into account. Thereby the EGSnrc library was modified, e.g. the complex index of refraction has to be assigned to each region depending on the material. The framework is setup to be user-friendly and robust with respect to future updates of the EGSnrc package. These implementations have to be tested using dedicated academic situations. Next steps include the validation by comparisons of measurements for different setups with the corresponding MC simulations. Furthermore, the newly developed implementation will be compared with other simulation approaches. This framework will then serve as bases for dose calculation on CT data and has further potential to investigate the image formation process in grating based imaging systems. PMID- 29413854 TI - Abstract ID: 240 A probabilistic-based nuclear reaction model for Monte Carlo ion transport in particle therapy. AB - In order to expand the Monte Carlo transport program AMOS to particle therapy applications, the ion module is being developed in the radiation physics group (ASP) at the TU Dresden. This module simulates the three main interactions of ions in matter for the therapy energy range: elastic scattering, inelastic collisions and nuclear reactions. The simulation of the elastic scattering is based on the Binary Collision Approximation and the inelastic collisions on the Bethe-Bloch theory. The nuclear reactions, which are the focus of the module, are implemented according to a probabilistic-based model developed in the group. The developed model uses probability density functions to sample the occurrence of a nuclear reaction given the initial energy of the projectile particle as well as the energy at which this reaction will take place. The particle is transported until the reaction energy is reached and then the nuclear reaction is simulated. This approach allows a fast evaluation of the nuclear reactions. The theory and application of the proposed model will be addressed in this presentation. The results of the simulation of a proton beam colliding with tissue will also be presented. PMID- 29413855 TI - Abstract ID: 241 Geant4 simulation studies of secondary particles emission in hadrontherapy treatments. AB - The aim of this work is the full simulation with Geant4 (vs. 10.0.p03) of secondary particles emitted during an hadrontherapy treatment with 12C. An accurate study of the ion beam fragmentation is important for both the evaluation of secondaries field inside and outside the target volume (i.e. for radioprotection and biological effects evaluation) and the prediction of nuclear particle interactions and their reaction products. In this study we investigate the depth energy deposition (Bragg curve) and the rate of secondary particles produced in the interaction between 12C and targets of different materials (water and Plexiglas). Simple irradiation setup was first implemented for a preliminary comparison of the Geant4 code with literature studies [1,2]. A good agreement (~0.04%) was found for the Bragg peak position and the peak-to-plateau ratio (~0.3%). The complete CNAO [3] (Centro Nazionale di Adroterapia Oncologica) extraction beamline with the target water phantom was then simulated for a characterization of secondary particles energy deposition along the beam axis, angular distributions for outgoing protons, neutrons, heavy secondary particles and prompt gammas. An agreement within 0.03% was found for the Bragg peak position with respect to CNAO data and Fluka simulation for 279.97 MeV/u 12C, highlighting the reliability of the Geant4 simulation. Preliminary results agree with literature studies but experimental data are needed to validate the code. Comparisons with additional simulation codes are foreseen. Geant4 simulations studies to predict the development of different physical processes as a function of the beam energy are also ongoing for both protons and carbon ions. PMID- 29413856 TI - Abstract ID: 230 Experimental and Monte Carlo investigation of the depth dependent fluence perturbation of parallel-plate chambers in clinical electron beams. AB - The electron fluence inside a parallel-plate ionization chamber positioned in a water phantom and exposed to a clinical electron beam deviates from the unperturbed fluence in water in absence of the chamber. One reason for the fluence perturbation is the "in-scattering effect" as described in ICRU 35. Aim of this work is a detailed experimental and with Monte Carlo simulations investigation of this effect. The experiments and Monte Carlo Simulations, with EGSnrc [1], were performed in a solid-water phantom (RW3) sized 30 * 30 * 30 cm3. One of the RW3 plates of height h = 0.5 cm had a hole with radius r = 1 cm which acts as the air cavity in the phantom. The phantom was placed below an electron applicator of field size 10 * 10 cm2 and irradiated with 6 MeV electrons from an Elekta Synergy accelerator. The air cavity was positioned at depths of 1.0, 1.5, 2.0 and 2.5 cm in the phantom. For the exerpiments the spatial resolved dose directly below the cavity was scored with GAFCHROMIC ETB3 films. The films were scanned with an Epson 10000xl-scanner (resolution 600 dpi, color depth 48 bit); a dose response calibration curve for the red channel was applied. At 1.0 cm depth the relative dose profile shows the well known dose increase at the air/RW3 boundary of about 4% relative to the dose at the center of the cavity and a de crease of about 8% outside the air cavity within the RW3-phantom. The amplitude of this "dose oscillation" decreases with increasing depth of the cavity within the phantom and disappears at about 2 cm, which is less than the half value thickness of the electron beam. The results are in agreement with already published Monte Carlo results [2]. The results are partly in contradiction to the ideas summarized in ICRU 35 but confirm recent Monte Carlo simulations from Zink et al. PMID- 29413857 TI - Abstract ID: 242 Simulation of a Fast Timing Micro-Pattern Gaseous Detector for TOF-PET. AB - Micro-Pattern Gas Detectors (MPGDs) are a new generation of gaseous detectors that have been developed thanks to advances in micro-structure technology. The main features of the MPGDs are: high rate capability (>50 MHz/cm2); excellent spatial resolution (down to 50 MUm); good time resolution (down to 3 ns); reduced radiation length, affordable costs, and possible flexible geometries. A new detector layout has been recently proposed that aims at combining both the high spatial resolution and high rate capability (100 MHz/cm2) of the current state-of the-art MPGDs with a high time resolution. This new type of MPGD is named the Fast Timing MPGD (FTM) detector [1,2]. The FTM developed for detecting charged particles can potentially reach sub-millimeter spatial resolution and 100 ps time resolution. This contribution introduces a Fast Timing MPGD technology optimized to detect photons, as an innovative PET imaging detector concept and emphases the importance of full detector simulation to guide the design of the detector geometry. The design and development of a new FTM, combining excellent time and spatial resolution, while exploiting the advantages of a reasonable energy resolution, will be a boost for the design of affordable TOF-PET scanner with improved image contrast. The use of such an affordable gas detector allows to instrument large areas in a cost-effective way, and to increase in image contrast for shorter scanning times (lowering the risk for the patient) and better diagnosis of the disease. In this report a dedicated simulation study is performed to optimize the detector design in the contest of the INFN project MPGD Fatima. Results are obtained with ANSYS, COMSOL, GARFIELD++ and GEANT4 simulation tools. The final detector layout will be trade-off between fast time and good energy resolution. PMID- 29413858 TI - Abstract ID: 247 Patient specific scatter reduction in SIRT gamma camera images. AB - INTRODUCTION: Clinical Bremsstrahlung imaging with gamma cameras or SPECT scanners, for example used in selective internal radiation therapy (SIRT) [1], suffers from low contrast due to a continuous spectrum and a high amount of scatter. Information about the scattering of the radionuclide within the patient's body can be obtained from Monte-Carlo simulations and subsequently being used to improve image quality. METHODS: An MAA-acquisition (CT+SPECT) of a HCC patient with a unifocal uptake in the right liver lobe is segmented (lesion) and loaded into the MC simulation framework GATE [2]. The voxelized lesion is used as Y90 source (1.5 GBq, 'fastY90' [3] is used yielding a speedup of 2.3*), the CT dataset is used for attenuation by converting HUs into corresponding materials. A mini gamma camera (Crystal Photonics, Germany) with a LEHR collimator and 4 * 4 cm2 detector size is positioned close to liver on the patient's skin, pointing towards the lesion. A simulation (60 s acquisition time) is performed on a cluster with 512 cores (2.2-2.5 Ghz each). The total number of counts, the energy spectrum and the order of scattered particles within each geometric volume are obtained from the ROOT output. Particles that have not scattered at all are defined as primary events. Scattering is only calculated within the phantom. RESULTS: The simulation took 172 min on the cluster with input data voxel size of 1 * 1 * 3.75 mm3. The number of emitted particles is 7.6 M with 600 k detected counts (~8% ratio). 13.3% of the detected particles are primary events. Additionally, scatter of multiple orders has been observed (41%, 24% and 13% and 8% for the first four orders). CONCLUSION: The energy-spectrum of the simulated 2D gamma camera image can be analyzed and used to correct the actual image acquired of that specific patient to achieve improved image quality and subsequently also dosimetry. PMID- 29413860 TI - Electrochemical corrosion, wear and cell behavior of ZrO2/TiO2 alloyed layer on Ti-6Al-4V. AB - Ti-6Al-4V (TC4) has received increasing attention as biomaterial but also raised concerns about the long-term safety of releasing of metal ions and poor wear resistance. In this work, an ZrO2/TiO2 alloyed layer was prepared on TC4 by plasma surface alloying with Zr and subsequently annealed in the air for improved corrosion and wear resistant. To assess the corrosion performance of the alloyed layer, the specimens were measured by open circuit potential, electrochemical impedance spectroscopy and potentiodynamic polarization in simulated body fluid solution. The result shows that the ZrO2/TiO2 alloyed layer exhibits strikingly high polarization resistance, wide passive region and very low current density, indicating the excellent corrosion resistance. The layer also displays significant improvement of wear resistance. Furthermore, the alloyed layer restricts cell adhesion and spreading. We infer that the ZrO2/TiO2 alloyed layer might be potentially useful implanted devices such as biosensors, bioelectronics or drug delivery devices. PMID- 29413859 TI - Brain damage and neurological symptoms induced by T-2 toxin in rat brain. AB - T-2 toxin, a trichothecene mycotoxin, is a common contaminant in food and animal feed, and is also present in processed cereal products. The most common route of T-2 toxin exposure in humans is through dietary ingestion. The cytotoxic effects of T-2 toxin include modifications to feeding behavior, nervous disorders, cardiovascular alterations, immunosuppression, and hemostatic derangements. However, to date, effects on the central nervous system (CNS) have rarely been reported. In the present study, female Wistar rat were given a single dose of T-2 toxin at 2 mg/kg b.w. and were sacrificed at one, three, and seven days post exposure. Histopathological analysis and transmission electron microscope (TEM) observations were used to investigate injury to the brain and pituitary gland. Damage to the brain and pituitary at the molecular level was detected by real time-polymerase chain reaction (RT-PCR), western blot, and immunohistochemical assays. Liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS) was used to investigate T-2 concentration in the brain. The results showed that pathological lesions were obvious in the brain at three days post-exposure; lesions in the pituitary were not observed until seven days post-exposure. Autophagy in the brain and apoptosis in the pituitary suggest that T-2 toxin may induce different acute reactions in different tissues. Importantly, low concentrations of T-2 toxin in the brain were observed in only one rat. Responsible for the above mentioned, we hypothesize that brain damage caused by this toxin may be due to the ability of the toxin to directly cross the blood brain barrier (BBB). Therefore, given its widespread pollution in food, we should pay more attention to the neurotoxic effects of the T-2 toxin, which may have widespread implications for human health. PMID- 29413861 TI - Preparation and application of a carbon paste electrode modified with multi walled carbon nanotubes and boron-embedded molecularly imprinted composite membranes. AB - An innovative electrochemical sensor was fabricated for the sensitive and selective determination of tinidazole (TNZ), based on a carbon paste electrode (CPE) modified with multi-walled carbon nanotubes (MWCNTs) and boron-embedded molecularly imprinted composite membranes (B-MICMs). Density functional theory (DFT) calculations were carried out to investigate the utility of template monomer interactions to screen appropriate monomers for the rational design of B MICMs. The distinct synergic effect of MWCNTs and B-MICMs was evidenced by the positive shift of the reduction peak potential of TNZ at B-MICMs/MWCNTs modified CPE (B-MICMs/MWCNTs/CPE) by about 200 mV, and the 12-fold amplification of the peak current, compared with a bare carbon paste electrode (CPE). Moreover, the coordinate interactions between trisubstituted boron atoms embedded in B-MICMs matrix and nitrogen atoms of TNZ endow the sensor with advanced affinity and specific directionality. Thereafter, a highly sensitive electrochemical analytical method for TNZ was established by different pulse voltammetry (DPV) at B-MICMs/MWCNTs/CPE with a lower detection limit (1.25 * 10-12 mol L-1) (S/N = 3). The practical application of the sensor was demonstrated by determining TNZ in pharmaceutical and biological samples with good precision (RSD 1.36% to 3.85%) and acceptable recoveries (82.40%-104.0%). PMID- 29413862 TI - In vitro antimicrobial effects and mechanisms of direct current air-liquid discharge plasma on planktonic Staphylococcus aureus and Escherichia coli in liquids. AB - The direct inactivation effects of an atmospheric pressure direct current (DC) air plasma against planktonic Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) in aqueous solution are investigated in vitro. Upon plasma treatment, extensively analyses on cell culturability, metabolic capacity, membrane integrity, surface morphology, cellular proteins, nucleic acids and intracellular reactive oxygen species (ROS) for both bacterial species were carried out and significant antimicrobial effects observed. Compared with the cellular culturability, a sub-lethal viable but non-culturable (VBNC) state was induced while more S. aureus entered this state than E. coli. Damaged bacterial outer structures were observed and the total concentrations of cellular protein and nucleic acid decreased for both bacteria after plasma treatment. The plasma induced aqueous reactive species (RS) and intracellular ROS might produce detrimental effects to the bacteria, while S. aureus was less susceptible to the discharge after a 20-min exposure compared to E. coli. PMID- 29413863 TI - Electropermeabilization of cells by closely spaced paired nanosecond-range pulses. AB - Decreasing the time gap between two identical electric pulses is expected to render bioeffects similar to those of a single pulse of equivalent total duration. In this study, we show that it is not necessarily true, and that the effects vary for different permeabilization markers. We exposed individual CHO or NG108 cells to one 300-ns pulse (3.7-11.6 kV/cm), or a pair of such pulses (0.4 1000 MUs interval), or to a single 600-ns pulse of the same amplitude. Electropermeabilization was evaluated (a) by the uptake of YO-PRO-1 (YP) dye; (b) by the amplitude of elicited Ca2+ transients, and (c) by the entry of Tl+ ions. For YP uptake, applying a 600-ns pulse or a pair of 300-ns pulses doubled the effect of a single 300-ns pulse; this additive effect did not depend on the time interval between pulses or the electric field, indicating that already permeabilized cells are as susceptible to electropermeabilization as naive cells. In contrast, Ca2+ transients and Tl+ uptake increased in a supra-additive fashion when two pulses were delivered instead of one. Paired pulses at 3.7 kV/cm with minimal separation (0.4 and 1 MUs) elicited 50-100% larger Ca2+ transients than either a single 600-ns pulse or paired pulses with longer separation (10-1000 MUs). This paradoxically high efficiency of the closest spaced pulses was emphasized when Ca2+ transients were elicited in a Ca2+-free solution (when the endoplasmic reticulum (ER) was the sole significant source of Ca2+), but was eliminated by Ca2+ depletion from the ER and was not observed for Tl+ entry through the electropermeabilized membrane. We conclude that closely spaced paired pulses specifically target ER, by either permeabilizing it to a greater extent than a single double-duration pulse thus causing more Ca2+ leak, or by amplifying Ca2+-induced Ca2+ release by an unknown mechanism. PMID- 29413864 TI - Simultaneous measurements of ascorbate and glutamate in vivo in the rat brain using carbon fiber nanocomposite sensors and microbiosensor arrays. AB - Nanocomposite sensors consisting of carbon fiber microelectrodes modified with Nafion(r) and carbon nanotubes, and ceramic-based microelectrode biosensor arrays were used to measure ascorbate and glutamate in the brain with high spatial, temporal and chemical resolution. Nanocomposite sensors displayed electrocatalytic properties towards ascorbate oxidation, translated into a negative shift from +0.20V to -0.05V vs. Ag/AgCl, as well as a significant increase (10-fold) of electroactive surface area. The estimated average basal concentration of ascorbate in vivo in the CA1, CA3 and dentate gyrus (DG) sub regions of the hippocampus were 276+/-60MUM (n=10), 183+/-30MUM (n=10) and 133+/ 42MUM (n=10), respectively. The glutamate microbiosensor arrays showed a high sensitivity of 5.3+/-0.8pAMUM-1 (n=18), and LOD of 204+/-32nM (n=10), and t50% response time of 0.9+/-0.02s (n=6) and high selectivity against major interferents. The simultaneous and real-time measurements of glutamate and ascorbate in the hippocampus of anesthetized rats following local stimulus with KCl or glutamate revealed a dynamic interaction between the two neurochemicals. PMID- 29413865 TI - Comparative performances of microbial capacitive deionization cell and microbial fuel cell fed with produced water from the Bakken shale. AB - This study evaluates and compares the performance of microbial fuel cells (MFCs) and microbial capacitive deionization cells (MCDCs) fed with wastewater produced from the Bakken shale. The produced water was characterized by high levels of dissolved solids and chemical oxygen demand (COD). Two-compartment MFCs and three compartment MCDCs were evaluated under batch-fed mode using mixed microbial consortia in the anode, ferricyanide in the cathode, and produced water as the electrolyte in the anode and capacitive deionization units. COD removal in the MFCs was 88%, while that in the MCDCs was limited to 76%. The lower performance of the MCDCs was due to the large impedance (6600 Omega cm2) compared with the MFCs (870 Omega cm2). However, the MCDCs achieved two-fold higher removal of dissolved solids. Both the MFCs and MCDCs suffered from a higher impedance induced by fouling in the latter stages of the operation. PMID- 29413867 TI - Electrochemical removal of biofilms from titanium dental implant surfaces. AB - The infection of dental implants may cause severe inflammation of tissue and even bone degradation if not treated. For titanium implants, a new, minimally invasive approach is the electrochemical removal of the biofilms including the disinfection of the metal surface. In this project, several parameters, such as electrode potentials and electrolyte compositions, were varied to understand the underlying mechanisms. Optimal electrolytes contained iodide as well as lactic acid. Electrochemical experiments, such as cyclic voltammetry or measurements of open circuit potentials, were performed in different cell set-ups to distinguish between different possible reactions. At the applied potentials of E < -1.4 V, the hydrogen evolution reaction dominated at the implant surface, effectively lifting off the bacterial films. In addition, several disinfecting species are formed at the anode, such as triiodide and hydrogen peroxide. Ex situ tests with model biofilms of E. coli clearly demonstrated the effectiveness of the respective anolytes in killing the bacteria, as determined by the LIVE/DEADTM assay. Using optimized electrolysis parameters of 30 s at 7.0 V and 300 mA, a 14 day old wildtype biofilm could be completely removed from dental implants in vitro. PMID- 29413866 TI - Denitrifying nirK-containing alphaproteobacteria exhibit different electrode driven nitrite reduction capacities. PMID- 29413868 TI - Adsorption effectiveness of beta-lactoglobulin onto gold surface determined by quartz crystal microbalance. AB - Bovine beta-lactoglobulin (LGB) is a transport protein that can bind to its structure hydrophobic bioactive molecules. Due to the lack of toxicity, high stability and pH-dependent molecular binding mechanism, lactoglobulin can be used as a carrier of sparingly soluble drugs. Dynamic light scattering has confirmed LGB's tendency to create oligomeric forms. The hydrodynamic diameter of LGB molecules varies from 4 nm to 6 nm in the pH range of 2-10 and ionic strength I = 0.001-0.15 M, which corresponds to the presence of mono or dimeric LGB forms. The LGB zeta potential varies from 26.5 mV to -33.3 mV for I = 0.01 M and from 13.3 mV to -16 mV for I = 0.15 M in the pH range of 2-10. The isoelectric point is at pH 4.8. As a result of strong surface charge compensation, the maximum effective ionization degree of the LGB molecule is 35% for ionic strength I = 0.01 M and 22% for I = 0.15 M. The effectiveness of adsorption is linked with the properties of the protein, as well as those of the adsorption surface. The functionalization of gold surfaces with beta-lactoglobulin (LGB) was studied using a quartz crystal microbalance with energy dissipation monitoring (QCM-D). The effectiveness of LGB adsorption correlates strongly with a charge of gold surface and the zeta potential of the molecule. The greatest value of the adsorbed mass was observed in the pH range in which LGB has a positive zeta potential values, below pH 4.8. This observation shows that electrostatic interactions play a dominant role in LGB adsorption on gold surfaces. Based on the adsorbed mass, protein orientation on gold surfaces was determined. The preferential side-on orientation of LGB molecules observed in the adsorption layer is consistent with the direction of the molecule dipole momentum determined by molecular dynamics simulations of the protein (MD). The use of the QCM-D method also allowed us to determine the effectiveness of adsorption of LGB on gold surface. Knowing the mechanism of LGB adsorption is significant importance for determining the optimum conditions for immobilizing this protein on solid surfaces. As beta-lactoglobulin is a protein that binds various ligands, the binding properties of immobilized beta lactoglobulin can be used to design controlled protein structures for biomedical applications. PMID- 29413870 TI - What's past is past: Neither perceptual preactivation nor prior motivational relevance decrease subsequent inattentional blindness. AB - Inattentional blindness-the phenomenon that clearly visible, yet currently unexpected objects go unnoticed when our attention is focused elsewhere-is an ecologically valid failure of awareness. It is currently subject to debate whether previous events and experiences determine whether or not inattentional blindness occurs. Using a simple two-phase paradigm in the present study, we found that the likelihood of missing an unexpected object due to inattention did not change when its defining characteristic (its color) was perceptually preactivated (Experiment 1; N = 188). Likewise, noticing rates were not significantly reduced if the object's color was previously motivationally relevant during an unrelated detection task (Experiment 2; N = 184). These results corroborate and extend recent findings questioning the influence of previous experience on subsequent inattentional blindness. This has implications for possible countermeasures intended to thwart the potentially harmful effects of inattention. PMID- 29413869 TI - Association between cognition and the retinal microvasculature in 11-year old children born preterm or at term. AB - BACKGROUND: Retinal microvessels can be visualized non-invasively and mirror the status of the cerebral microvasculature. AIMS: To investigate whether in young children born prematurely or at term cognitive performance is related to retinal microvascular traits. STUDY DESIGN, SUBJECTS: In 93 prematurely born infants (birth weight < 1000 g) and 87 controls born at term, we measured head circumference (HC) and determined intelligence quotient (IQ) by combining matrix reasoning and spatial span (Wechsler Non-Verbal test, Dutch version) and post processed retinal photographs using Singapore I Vessel Assessment software (version 3.6). OUTCOME MEASURES, RESULTS: Compared with controls, cases had smaller HC (51.7 vs 53.4 cm; p < 0.001), lower IQ (93.9 vs 109.2; p < 0.001), smaller retinal arteriolar (CRAE; 162.7 vs 174.0 MUm; p < 0.001) and venular (CRVE; 234.9 vs 242.8 MUm; p = 0.003) diameters and CRAE/CRVE ratio (0.69 vs 0.72; p = 0.001). A 1-SD decrease in CRAE was associated with smaller HC (-0.53 cm; p < 0.001) and lower total IQ (-3.74; p < 0.001), matrix reasoning (-1.77; p = 0.004) and spatial span (-2.03; p = 0.002). These associations persisted after adjustment for sex and age and risk factors for cognitive impairment, including blood pressure, body mass index and parental educational attainment. CONCLUSIONS: HC, total IQ, matrix reasoning and spatial span decrease with smaller retinal arteriolar diameter. Our findings suggest that maldevelopment of the cerebral microcirculation, as mirrored by the retinal microvasculature, has lasting effects on the growth of the brain and cognitive performance of prematurely born children. PMID- 29413871 TI - Time drawings: Spatial representation of temporal concepts. AB - Time representation is a fundamental property of human cognition. Ample evidence shows that time (and numbers) are represented in space. However, how the conceptual mapping varies across individuals, scales, and temporal structures remains largely unknown. To investigate this issue, we conducted a large online study consisting in five experiments that addressed different time scales and topology: Zones of time, Seasons, Days of the week, Parts of the day and Timeline. Participants were asked to map different kinds of time events to a location in space and to determine their size and color. Results showed that time is organized in space in a hierarchical progression: some features appear to be universal (i.e. selection order), others are shaped by how time is organized in distinct cultures (i.e. location order) and, finally, some aspects vary depending on individual features such as age, gender, and chronotype (i.e. size and color). PMID- 29413872 TI - Motivated forgetting reduces veridical memories but slightly increases false memories in both young and healthy older people. AB - The aim of the current study is to examine the effects of motivated forgetting and aging on true and false memory. Sixty young and 54 healthy older adults were instructed to study two lists of 18 words each. Each list was composed of three sets of six words associated with three non-presented critical words. After studying list 1, half of the participants received the instruction to forget List 1, whereas the other half received the instruction to remember List 1. Next, all the subjects studied list 2; finally, they were asked to remember the words studied in both lists. The results showed that when participants intended to forget the studied List 1, they were less likely to recall the studied words, but more likely to intrude the critical words. That is, we can intentionally forget something but this can also entail the intrusion of some related false memories. PMID- 29413873 TI - Spatial attention and the malleability of bodily self in the elderly. AB - A right-hemispheric specificity has been suggested both for spatial attention and for the feeling of body-ownership. Here, we assessed lateralization of spatial attention (Milner landmark task), rubber hand illusion (RHI), and their relationship in a group of 59 healthy elderly subjects. The occurrence of the RHI was assessed by objective (proprioceptive drift) and subjective (questionnaire) measures. Spatial attention was asymmetrical, with a slight, neglect-like overestimation of the right segment of mid-bisected lines. As to the RHI, the proprioceptive drift towards the plastic hand was significantly larger following synchronous compared to asynchronous stroking, but comparable between both sides. Subjective responses indicated an experience of the RHI during synchronous stimulation, without lateralization. On the left hand, however, the proprioceptive drift correlated significantly with the rightward bias of spatial attention. Thus, reduced attention towards sensory signals from one's own limb might facilitate the process of embodiment of an artificial hand into one's body representation. PMID- 29413874 TI - Primary and incisional ventral hernias are different in terms of patient characteristics and postoperative complications - A prospective cohort study of 4,565 patients. AB - BACKGROUND: Primary and incisional hernias are often pooled in publications studying hernia symptoms, treatment, or surgical outcomes. The question rises whether this is justified or if primary and incisional hernia should be considered as two separate entities. The aim of this prospective cohort study is to compare primary and incisional ventral hernias regarding patient characteristics, hernia characteristics, surgical characteristics, and postoperative complications. MATERIALS AND METHODS: A registry-based, prospective cohort study was performed. All patients undergoing primary or incisional hernia repair surgery between September 1st, 2011 and February 29th, 2016 were included. Patient baseline characteristics, hernia characteristics, surgical characteristics, and postoperative outcomes were collected and analyzed. RESULTS: A total of 4565 patients were included, of whom 2374 had a primary hernia and 2191 had an incisional hernia. All patient, hernia, and surgical characteristics were statistically significantly different between primary and incisional hernias except for corticosteroid use, history of inguinal hernia, incarceration, and emergency surgery. Overall complication rates (wound, surgical, and medical) were significantly different (105/2374 (4.4%) for primary hernia versus 323/2191 (15%) for incisional hernia, p < 0.001). CONCLUSION: Primary and incisional hernia are statistically significantly different for almost all patient, hernia, surgical, and postoperative characteristics analyzed. Given these differences, data on primary hernias and incisional hernias should not be pooled in studies reporting on hernia repair. PMID- 29413875 TI - Neoadjuvant chemotherapy in advanced gastric and esophago-gastric cancer. Meta analysis of randomized trials. AB - INTRODUCTION: Even in after curative surgery and adequate linfoadenectomy the survival of advanced gastric cancer (AGC) remains poor. At present some data have been published on the effects of NACT and perioperative chemotherapy on AGC and Esophago-gastric cancer (EGC) but not definitive ones. The present meta-analysis aims to evaluate the effects of neoadjuvant chemotherapy (NACT) on the AGC and EGC. MATERIAL AND METHODS: A systematic review with meta-analysis of randomized controlled trials (RCTs) of NACT + surgery vs. Surgery in patients with AGC and EGC was performed. RESULTS: 15 RCTs have been included (2001 patients: 977 into NACT + surgery arm and 1024 into control arm). NACT + Surgery reduces the overall mortality at 1, 3 and 5-year in cumulative analysis (RR = 0.78; 0.81; 0.88 respectively), at 1, 2, 3 and 5-years in EGC (RR = 0.79; 0.83; 0.84; 0.91 respectively) and at 3 and 5-years in AGC (RR = 0.74; 0.82 respectively). Morbidity and perioperative mortality rate are not influenced by NACT. Recurrence rate is reduced by NACT + surgery in EGC (RR = 0.80). CONCLUSIONS: NACT reduces the mortality in gastric and esophago-gastric cancer. Morbidity and perioperative mortality are not influenced by NACT. The overall recurrence rate is reduced by NACT in esophago-gastric cancer. PMID- 29413877 TI - Erratum to the article "Write your first article, but ..." Published in the issue (2017;134(6):371-72), in European Annals of Otorhinolaryngology, Head and Neck diseases. https://doi.org/10.1016/j.anorl.2017.09.002. PMID- 29413876 TI - Scoring system to guide decision making for the use of bilateral internal mammary arteries: The BIMA score. AB - OBJECTIVE: Currently, surgeons are unable to estimate whether the survival benefit from bilateral internal mammary artery (BIMA) grafting outweighs the increased deep sternal infection (DSWI) risk in the individual cases. As a consequence BIMA grafting is still largely underutilized. We aimed to develop and validate a scoring system to predict the individual risk for DSWI and 10 year survival probability to guide surgeons in decision making process for the use of BIMA over single internal mammary artery (SIMA). METHODS: Fast backward elimination on predictors was performed using Lawless and Singhal method. BIMA score was reported as a partial nomogram that can be used to manually obtain predicted individual risk of DSWI and 10 year survival probability from the regression models. Bootstrapping validation of the regression models was performed. RESULTS: The study population consisted of 5234 patients of which a total of 960 (18%) received BIMA and the remaining 4274 (82%) underwent conventional strategy using SIMA. A total of 119 patients experienced DSWI (2.3%). A total of 489 deaths were recorded after a median follow-up time of 5.68 years (interquartile range 2.7-8.8, range 0-12.1). BIMA grafting was found to have effect on both risk of DSWI and 10 year survival probability and was included into partial nomograms. Bootstrapping validation confirmed a good discriminative power of the models. CONCLUSION: The BIMA score provides an impartial assessment of the decision making process for clinicians to establish the optimum revascularization strategy for individual patients. PMID- 29413879 TI - Optimization of fMRI methods to determine laterality of cortical activation during ankle movements of children with unilateral cerebral palsy. AB - Measurement of laterality of motor cortical activations may provide valuable information about lower limb control in children with unilateral cerebral palsy (UCP). Evidence from upper limb research suggests that increased contralateral activity may accompany functional gains. However, lower limb areas of activation and associated changes have been underexplored due to challenges with imaging motor cortical leg representations. In this study, methods for a task-based functional magnetic resonance imaging (fMRI) ankle dorsiflexion paradigm were refined with three pilot groups of participants: (i) adults (n = 5); (ii) typically developing (TD) children (n = 5) and; (iii) children with UCP (n = 4). Parameters of experimental design, task resistance, reproducibility, and pre-scan procedures were tested/refined using a staged development approach with additions or changes introduced if image quality did not meet pre-defined standards. When image quality was acceptable for two consecutive participants, the next participant group was recruited to test/refine the next parameter. The final paradigm involved an event-related design of a single dorsiflexion movement against individualized resistance, with two runs per leg. It included a pre-scan session to increase child comfort and determine task resistance. This paradigm produced valid data for laterality index (LI) calculations to determine the ratio of activity in each hemisphere. Ventricle and lesion masks were used in non linear image registration, and individual thresholds were used for extent-based LI calculations. LI of dominant ankle movements were contralateral (LI >= +0.2) for TD children (mean LI = +0.89, std = 0.27) and children with UCP (mean LI = +0.86, std = 0.26). For the affected ankle of children with UCP, LI values indicated ipsilateral and/or contralateral activation (mean LI = +0.02, std = 0.71, range -0.92 to +1.00). This fMRI paradigm will support investigations of cortical activation and mechanisms of skill improvement following lower limb interventions. PMID- 29413878 TI - Neonatal systemic inflammation and the risk of low scores on measures of reading and mathematics achievement at age 10 years among children born extremely preterm. AB - BACKGROUND: Difficulties with reading and math occur more commonly among children born extremely preterm than among children born at term. Reasons for this are unclear. METHODS: We measured the concentrations of 27 inflammatory-related and neurotrophic/angiogenic proteins (angio-neurotrophic proteins) in multiple blood specimens collected a week apart during the first postnatal month from 660 children born before the 28th week of gestation who at age 10 years had an IQ >= 70 and a Wechsler Individual Achievement Test 3rd edition (WIAT-III) assessment. We identified four groups of children, those who had a Z-score <= -1 on the Word Reading assessment only, on the Numerical Operations assessment only, on both of these assessments, and on neither, which served as the referent group. We then modeled the risk of each learning limitation associated with a top quartile concentration of each protein, and with high and lower concentrations of multiple proteins. RESULTS: The protein profile of low reading scores was confined to the third and fourth postnatal weeks when increased risks were associated with high concentrations of IL-8 and ICAM-1 in the presence of low concentrations of angio neurotrophic proteins. The profile of low math scores was very similar, except it did not include ICAM-1. In contrast, the profile of low scores on both assessments was present in each of the first four postnatal weeks. The increased risks associated with high concentrations of TNF-alpha in the first two weeks and of IL-8 and ICAM-1 in the next two weeks were modulated down by high concentrations of angio-neurotrophic proteins. CONCLUSIONS: High concentrations of angio-neurotrophic proteins appear to reduce/moderate the risk of each learning limitation associated with systemic inflammation. The three categories of limitations have protein profiles with some similarities, and yet some differences, too. PMID- 29413880 TI - Do women with greater trait body dissatisfaction experience body dissatisfaction states differently? An experience sampling study. AB - The present study evaluated the relation of key features of state body dissatisfaction experiences - inertia, instability from moment-to-moment, and average level across time-points - to trait body dissatisfaction and/or eating disorder risk. Participants included 161 women who completed measures of trait body dissatisfaction and disordered eating pathology, and then completed reported state body dissatisfaction and contextual influences (binge eating, dietary restraint, exercise, and appearance comparison behaviors) 6 times daily for 7 days. Results indicated that individuals with elevated trait body dissatisfaction were reliably different from those with healthier body image in terms of average state body dissatisfaction ratings, but not for inertia or instability. State mean and trait body dissatisfaction uniquely predicted eating pathology, although their predictive accuracy for clinical caseness was comparable. Cost vs. benefit of using state body image data for understanding trait body image and eating pathology is discussed. PMID- 29413881 TI - Evolution of methicillin-resistant Staphylococcus aureus: Evidence of positive selection in a penicillin-binding protein (PBP) 2a coding gene mecA. AB - Methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) represents more and more S. aureus infections. MecA, the novel coding gene of penicillin-binding protein (PBP) 2a of MRSA, is the key resistance factor of beta-lactam, but little is known about the evolution of this gene. Given the crucial role of mecA in S. aureus physiology and beta-lactam resistance, the selective forces may contribute to adaptation of the bacteria to the special environments such as its host or antibiotics. To understand the evolution of this gene, we screened GenBank database and analyzed mecA of 249 S. aureus strains. Twenty-nine unique alleles with 26 unique amino acid sequences were identified. Phylogenetic analysis showed three main groups of mecA in the global S. aureus strains. Analysis of these alleles using codon-substitution models (M8, M3, and M2a) and likelihood ratio tests (LRTs) of the codeML package and a random-effects likelihood (REL) method of HyPhy package for the site-specific ratio of nonsynonymous to synonymous substitution rates suggested that fourteen sites in the allosteric domain of PBP2a have been subjected to strong positive selection pressure. Mutations of two positive selection sites (N146K and E239K) were reported to be essential for ceftaroline- or L-695, 256-resistant. Further study indicated that the positive selection pressure might be more likely related to the host's inflammatory or immune response during S. aureus infection. Our studies provide the first evidence of positive Darwinian selection in the mecA of S. aureus, contributing to a better understanding of the adaptive mechanism of this bacterium. PMID- 29413882 TI - Phylodynamics of Crimean Congo hemorrhagic fever virus in South Russia. AB - Phylodynamics of Crimean Congo Hemorrhagic fever virus (CCHFV) genotype V in South Russia was analyzed using 244 partial (452-571 nt) sequences in all three genomic segments and 38 complete genomic sequences. Despite increased number of sequences, the Russian lineage of the European genotype V (commonly termed GtVa) was distinct from GtV isolates from Turkey and the Balkan countries. No geographic pattern was observed in phylogenetic subgrouping of CCHFV within South Russia. Identical isolates could be found at distant locations spaced by hundreds of kilometers, while relatively divergent viruses circulated in the same region. Full genome analysis indicated that reassortment events within GtVa occurred every few decades (median half-life of a non-reassortant node 30-40 years) and involved M and S segments. Therefore, in South Russia CCHFV represents a highly dynamic population of frequently reassorting viruses. PMID- 29413883 TI - The role of regulatory T cells in immunopathogenesis and immunotherapy of viral infections. AB - Two hepatotropic viruses hepatitis C virus (HCV) and hepatitis B virus (HBV) have been considered as the main cause of chronic viral infections. In addition, human immunodeficiency virus (HIV) attacks the immune system by eradication of some white blood cell (T-helper cell). The role of Tregs in HCV, HBV and HIV infections ranges from suppressing antiviral T cell responses to protecting tissues as liver and immune cells from immune mediated injury. In this review, we discuss the influence of regulatory T cells in immunopathology of specific viral infections including HCV, HBV and HIV by focusing on targeting Tregs as novel approach in vaccinology against viral infections. PMID- 29413884 TI - Epidemiological investigation and analysis of the NS5B gene and protein variability of non-primate hepacivirus in several horse cohorts in Rio de Janeiro state, Brazil. AB - Among the hepacivirus species recently described, the non-primate hepacivirus/hepacivirus A found in horses and donkeys is closely related to the human hepatitis C virus (HCV). Therefore, the equine is an attractive surrogate large animal model for the study of HCV therapy, pathogenesis and prophylaxis. Despite global efforts, epidemiological and genetic studies have not elucidated the risk factors, virus distribution or genetic variability of the hepacivirus A, which are also important issues for the equine welfare. Little information about this background scenery is available in Brazil. The aims of this study were to investigate potential risk factors associated with hepacivirus A infection among different horse cohorts throughout the state of Rio de Janeiro and to evaluate the diversity of the viral NS5B gene and protein. Hepacivirus A RNA was detected in horse cohorts from all geographical mesoregions, independent of horse activity or breed investigated. Statewide prevalence ranged from 4.0% to 27.5%. Potential risk factors such as geographical location and age of female horses were significantly associated with the presence of virus RNA. Phylogenetic analysis revealed the circulation of subtype 2 in all mesoregions. NS5B gene sequences clustered according to geographical origin, while the NS5B fragments did not allow discriminant analysis. The predicted NS5B protein showed marked conservation, especially in the thumb domain. In conclusion, the higher frequency of hepacivirus A RNA detection in horses bred for reproduction purposes as well as in young females suggests a direct link between reproduction practices and the virus's spread. Additional studies are necessary to understand the distribution of this genetically conserved hepacivirus. PMID- 29413885 TI - Differences in rpoB, katG and inhA mutations between new and previously treated tuberculosis cases using the GenoType MTBDRplus assay. AB - Drug resistance in new cases reflects primary transmission of resistant strains, while drug resistance in previously treated patients is more likely to reflect acquired resistance during previous tuberculosis (TB) treatment. In this study from a rural hospital in South India, we compared molecular differences between new and previously treated TB patients who had isoniazid or rifampicin resistance conferring mutations using the GenoType MTBDRplus assay. Out of 2112 TB patients, 245 (11.6%) had rpoB mutations and 338 (16%) had isoniazid resistance-conferring mutations. Among patients with rpoB mutations, the proportion of new and previously treated cases with no isoniazid resistance-conferring mutations was 41.2% and 26% (P-value = 0.02; risk ratio [RR] 1.58, 95% confidence interval [CI] 1.09-2.31; risk difference [RD] 15.2%, 95% CI 18.2-28.6), respectively. Among patients with isoniazid resistance-conferring mutations, the proportion of new and previously treated cases with no rpoB mutations was 71.8% and 33.2% (P-value < 0.0001; RR 2.17, 95% CI 1.73-2.71; RD 38.7%, 95% CI 28.8-48.6), and the proportion with single inhA mutations (versus having katG mutations) was 33.1% and 20.9% (P-value = 0.012; RR 1.58, 95% CI 1.11-2.27; RD 12.2%, 95% CI 2.57 21.8), respectively. The most common resistance mutations were S531 L in the rpoB gene, S315T1 in the katG gene and C15T in the inhA gene, and there were no significant differences between new and previously treated patients. In conclusion, new TB cases were less likely to have combined isoniazid and rifampicin resistance-conferring mutations and, in cases with isoniazid resistance, they were more likely to have single inhA mutations than katG mutations. Taking into account that previous research has shown katG mutations precede mutations in the rpoB gene in most cases of rifampicin resistant TB, our results suggest a negative epistatic association between katG and rpoB mutations. PMID- 29413886 TI - First detection of Leishmania DNA in Psammomys obesus and Psammomys vexillaris: Their potential involvement in the epidemiology of leishmaniasis in Tunisia. AB - Leishmaniasis, a public health problem in Tunisia, are diseases caused by different Leishmania species. Cutaneous leishmaniasis is present from the North to the South under different forms, due to Leishmania (L.) major, L. infantum or L. tropica. Whereas, Psammomys (P.) obesus is the confirmed reservoir host of L. major, those of L. tropica and dermotropic L. infantum wait to be identified. Importantly, P. vexillaris species have been recently highlighted; however, no studies have been carried out to explore its potential role in leishmaniasis epidemiology. Seventy two rodents were collected from Central and South-West of Tunisia between 2007 and 2010. Using several methods, 43 animals were identified as P. obesus and 29 as P. vexillaris. Leishmania kinetoplast DNA was detected in liver samples by real-time PCR in 18 P. obesus and in 8 P. vexillaris. Then, the direct sequencing of the amplified internal transcribed spacer 1, allowed the identification of L. infantum DNA in five P. obesus and in three P. vexillaris, as well as L. tropica DNA in three other P. vexillaris. Whereas, PCR fluorescent fragment length analysis of the 7 spliced leaders, allowed identifying L. major among infected P. obesus and P. vexillaris, and interestingly co-infection (L. major/L. infantum) among two P. obesus. We report here for the first time, the infection of P. obesus, from Central Tunisia, by L. infantum. Suggesting that P. obesus the known reservoir host of L. major, may also serve as reservoir host for L. infantum and thus play a role in the spread of sporadic cutaneous or visceral leishmaniasis in this region. Of equal importance, this work establish for the first time, the natural infection of P. vexillaris by different Leishmania species, suggesting its potential epidemiological role as reservoir host. PMID- 29413887 TI - Parental alcohol consumption and adult children's educational attainment. AB - This study analyses whether an excessive parental alcohol consumption during childhood can affect long run children's educational attainments. Using 19 waves of the Russia Longitudinal Monitoring Survey (RLMS), where individuals and their families are followed from childhood to adulthood, this study analyses parental alcohol consumption during childhood (between 1994 and 2001) and its relation with children's educational attainment about twelve years later (from 2005 to 2014). Panel estimations show that mother's excessive alcohol consumption during childhood is consistently negatively associated with children educational outcomes, as years of education, the highest education grade achieved and the probability of having a tertiary education degree, a finding that is robust to possible endogeneity issues. In particular, while moderate drinking is not an issue, an additional standard glass of vodka (15.57 g of pure alcohol) consumed by the mother per day, reduces years of education by almost one year (0.88), and by 5.8 percentage points (or about 27%) the probability of having a university degree. The study also explores the transmission mechanisms suggested by the literature, identifying a significant role for prenatal exposure to alcohol and, to a lesser extent, for intergenerational transmission of drinking habits. PMID- 29413888 TI - Membrane Trafficking in Autophagy. AB - Macroautophagy is an intracellular pathway used for targeting of cellular components to the lysosome for their degradation and involves sequestration of cytoplasmic material into autophagosomes formed from a double membrane structure called the phagophore. The nucleation and elongation of the phagophore is tightly regulated by several autophagy-related (ATG) proteins, but also involves vesicular trafficking from different subcellular compartments to the forming autophagosome. Such trafficking must be tightly regulated by various intra- and extracellular signals to respond to different cellular stressors and metabolic states, as well as the nature of the cargo to become degraded. We are only starting to understand the interconnections between different membrane trafficking pathways and macroautophagy. This review will focus on the membrane trafficking machinery found to be involved in delivery of membrane, lipids, and proteins to the forming autophagosome and in the subsequent autophagosome fusion with endolysosomal membranes. The role of RAB proteins and their regulators, as well as coat proteins, vesicle tethers, and SNARE proteins in autophagosome biogenesis and maturation will be discussed. PMID- 29413889 TI - Profiling Celiac Disease-Related Transcriptional Changes. AB - Celiac disease (CD) is a chronic, autoimmune disease of the small intestine with a strong but complex genetic component. The disease is triggered by the consumption of dietary gluten through the presentation of immunogenic gliadin peptides to T helper lymphocytes by HLA-DQ2 and DQ8 heterodimers, which are the major contributors to the genetic risk. Recent large-scale genotyping efforts have identified a large number of additional association signals, but the functional role of the underlying genes in the pathogenesis of the disease is still unclear. In the last years, several whole transcriptome analyses have been performed in different tissues, including whole duodenal biopsies, isolated gut epithelial cells or peripheral blood from gluten-consuming CD patients at diagnosis, treated patients on gluten-free diet and nonceliac controls, sometimes after in vitro challenge with gluten-derived gliadin peptides. Although the results from the different experiments are difficult to reconcile, the main findings point to an exacerbation of the immune response, together with the dysregulation of signaling and cell cycle pathways. The effect of associated SNPs on the expression of candidate genes and the role of the noncoding genome are the new territories that the CD research community has only begun to explore. PMID- 29413891 TI - Loss of Nuclear Envelope Integrity in Aging and Disease. AB - The nuclear envelope (NE) serves as a central organizing unit for the eukaryotic cell. By virtue of its highly selective, semipermeable barrier function, the NE shields the enclosed genetic material, while at the same time ensuring its regulated transcription, replication, and repair. The NE has long been considered to only dismantle during mitosis. However, in recent years it has become clear that in a variety of pathologies, NE integrity becomes compromised during interphase as well. Loss of NE integrity, or briefly NE stress, is manifested in various ways, ranging from a gradual reduction in nucleocytoplasmic transport function, to selective loss and degradation of NE components, and finally to catastrophic rupture events that provoke abhorrent molecular fluxes between the nucleus and cytoplasm. Although cells manage to cope with such forms of NE stress, the different insults to nuclear compartmentalization alter gene regulation and jeopardize genome stability. Hence, loss of NE integrity is emerging as a broad-spectrum pathogenic mechanism. In this review, we discuss the relevance of nuclear compartmentalization and the loss thereof in aging and disease development. PMID- 29413890 TI - Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer. AB - The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers. IDO1 and TDO are upregulated widely in neoplastic cells but also variably in stromal, endothelial, and innate immune cells of the tumor microenviroment and in tumor-draining lymph nodes. Pharmacological and genetic proofs in preclinical models of cancer have validated IDO1 as a cancer therapeutic target. IDO1 inhibitors have limited activity on their own but greatly enhance "immunogenic" chemotherapy or immune checkpoint drugs. IDO/TDO function is rooted in inflammatory programming, thereby influencing tumor neovascularization, MDSC generation, and metastasis beyond effects on adaptive immune tolerance. Discovery and development of two small molecule enzyme inhibitors of IDO1 have advanced furthest to date in Phase II/III human trials (epacadostat and navoximod, respectively). Indoximod, a tryptophan mimetic compound with a different mechanism of action in the IDO pathway has also advanced in multiple Phase II trials. Second generation combined IDO/TDO inhibitors may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This review surveys knowledge about IDO1 function and how IDO1 inhibitors reprogram inflammation to heighten therapeutic responses in cancer. PMID- 29413892 TI - Mechanisms of Cortical Differentiation. AB - During fetal and postnatal development, the human brain generates 160 billion neuronal and glial cells, each with precise cellular phenotypes. To effectively manage such a complicated task, intrinsic (e.g., transcription factors) and extrinsic (environmental signals) cues cooperate to regulate the decision by neural progenitors to continue to proliferate or to differentiate. Loss- and gain of-function studies in the mouse brain have been instrumental in identifying these cues, leading to a fairly well-developed and well-integrated model of neocortical development. This research has revealed that the neurons, astrocytes, and oligodendrocytes that populate the mature neocortex are generated sequentially from neural progenitor pools in both the dorsal (pallial) and ventral (subpallial) telencephalon. Understanding how cellular diversity is established during neocortical development is critical, as appropriate numbers of inhibitory and excitatory neurons, oligodendrocytes, and astrocytes are required for normal neural function. Indeed, an imbalance in excitatory vs inhibitory neurotransmission or alterations in glial cell number are hallmark features of neuropsychological and intellectual disorders such as schizophrenia, bipolar disorder, and autism. Moreover, these fundamental studies are beginning to pave the way for the rational design of neural cell reprogramming strategies, which are of value for the assessment of disease etiology, and for the possible development of novel cell-based therapies. We review herein our current understanding of the intrinsic cues and environmental signals that govern cell fate specification and differentiation decisions during development of neuronal and glial lineages in the murine neocortex. PMID- 29413893 TI - New Insights Into Autophagy Dysfunction Related to Amyloid Beta Toxicity and Neuropathology in Alzheimer's Disease. AB - The fine control of neuronal proteostasis is an essential element that preserves cell viability. Advancing age is a major risk factor for Alzheimer's disease (AD), and autophagy is thought to dictate normal and pathological aging through intricate molecular machinery controlling protein aggregation. Although the role of autophagy dysfunction in AD is known, the dynamic changes during the progression of the disease remain unclear. Recent studies have provided new insight into the molecular mechanisms that link defective autophagy and cellular fate, underscoring the pathogenic events associated with AD. Here, we will focus on recent studies that underpin a distinct role for autophagy deficits and highly localized autophagic defects, impacting primarily the amyloidogenic pathway activity. By uniquely assessing the dynamic changes in key proteins during the disease progression in the context of the autophagy machinery function and amyloid beta toxicity, specifically, a connect between protein degradation failure and cell death susceptibility is revealed which may suggest new avenues for the development of better targeted therapeutic interventions. PMID- 29413894 TI - Altered Metabolism of Leukemic Cells: New Therapeutic Opportunity. AB - The cancer metabolic program alters bioenergetic processes to meet the higher demands of tumor cells for biomass production, nucleotide synthesis, and NADPH balancing redox homeostasis. It is widely accepted that cancer cells mostly utilize glycolysis, as opposed to normal cells, in which oxidative phosphorylation is the most employed bioenergetic process. Still, studies examining cancer metabolism had been overlooked for many decades, and it was only recently discovered that metabolic alterations affect both the oncogenic potential and therapeutic response. Since most of the published works concern solid tumors, in this comprehensive review, we aim to summarize knowledge about the metabolism of leukemia cells. Leukemia is a malignant disease that ranks first and fifth in cancer-related deaths in children and adults, respectively. Current treatment has reached its limits due to toxicity, and there has been a need for new therapeutic approaches. One of the possible scenarios is improved use of established drugs and another is to introduce new druggable targets. Herein, we aim to describe the complexity of leukemia metabolism and highlight cellular processes that could be targeted therapeutically and enhance the effectiveness of current treatments. PMID- 29413895 TI - Epigenetic alterations contribute to promoter activity of imprinting gene IGF2. AB - The expression of insulin-like growth factor 2 (IGF2), a classical imprinting gene, didn't completely correlate with its imprinting profiles in hepatocellular carcinoma (HCC). The mechanistic importance of promoter activity in regulation of IGF2 has not been fully clarified. Here we show that histone 3 lysine 4 trimethylation (H3K4me3) modified by menin-MLL complex of IGF2 promoter contributes to promoter activity of IGF2. The strong binding of menin and abundant H3K4me3 at the DNA demethylated P3/4 promoters were observed in Hep3B cells with the robust expression of IGF2. In IGF2-low-expressing HepG2 cells, menin didn't bind to DNA hypermethylated P3/4 regions; however, menin overexpression inhibited DNA methylation and promoted H3K4me3 at the P3/4 as well as IGF2 expression in HepG2. In addition, the H3K4me3 at P3/4 locus was activated in primary HCC specimens with high IGF2 expression. Furthermore, inhibition of the menin/MLL interaction via MI-2/3 reduced IGF2 expression, inhibited the IGF1R AKT pathway, and significantly repressed HCC with robust expression of IGF2. Taken together, we conclude that H3K4me3 of P3/4 locus mediated by the menin-MLL complex is a novel epigenetic mechanism for releasing IGF2. PMID- 29413896 TI - RETRACTED: WRKY71 and TGA1a physically interact and synergistically regulate the activity of a novel promoter isolated from Petunia vein-clearing virus. AB - Caulimoviral promoters have become excellent tools for efficient transgene expression in plants. However, the transcriptional framework controlling their systematic regulation is poorly understood. To understand this regulatory mechanism, we extensively studied a novel caulimoviral promoter, PV8 (-163 to +138, 301 bp), isolated from Petunia vein-clearing virus (PVCV). PVCV was found to be Salicylic acid (SA)-inducible and 2.5-3.0 times stronger than the widely used CaMV35S promoter. In silico analysis of the PV8 sequence revealed a unique clustering of two stress-responsive cis-elements, namely, as-11 and W-box1-2, located within a span of 31 bp (-74 to -47) that bound to the TGA1a and WRKY71 plant transcription factors (TFs), respectively. We found that as-1 (TTACG) and W box (TGAC) elements occupied both TGA1a and WRKY71 on the PV8 backbone. Mutational studies demonstrated that the combinatorial influence of as-1 (-57) and W-box1-2 (-74 and -47) on the PV8 promoter sequence largely modulated its activity. TGA1a and WRKY71 physically interacted and cooperatively enhanced the transcriptional activity of the PV8 promoter. Biotic stress stimuli induced PV8 promoter activity by ~1.5 times. We also established the possible pathogen elicitor function of AtWRKY71 and NtabWRKY71 TFs. Altogether, this study elucidates the interplay between TFs, biotic stress and caulimoviral promoter function. PMID- 29413897 TI - The AU-rich element landscape across human transcriptome reveals a large proportion in introns and regulation by ELAVL1/HuR. AB - Adenylate-uridylate (AU)-rich elements (AREs) are sequence instability elements that are known to be located in the 3' untranslated regions (UTR) in thousands of human transcripts. AREs regulate the expression of many genes at the post transcriptional level, and they are essential for many normal cellular functions. We conducted a transcriptome-wide screen for AREs and found that they are most abundant in introns, with up to 25% of introns containing AREs corresponding to 58% of human genes. Clustering studies of ARE size, complexity, and distribution revealed that, in introns, longer AREs with two or more overlapping repeats are more abundant than in the 3'UTR, and only introns can contain very long AREs with 6-14 overlapping AUUUA pentamers. We found that intronic sites of the ARE binding proteins HuR/ELAVL1, ZFP36/TTP, AUF1, and BRF1/ZFP36L1 overlap with the intronic AREs with HuR being most abundant. Accordingly, RNA-IP experiments demonstrated a specific association of HuR with reporter and endogenous pre-mRNAs that contain intronic AREs. Moreover, HuR knockdown led to a significant general reduction in the mRNA levels of genes that contain intronic AREs and to a specific reduction in the expression of ARE-intronic reporters. The data represent bioinformatics analysis for key RNA-binding proteins interactions with intronic AREs and provide experimental evidence for HuR binding to AREs. The widespread distribution of intronic AREs and their particular association with HuR and HuR binding sites indicates that more than half of human genes can be regulated post transcriptionally by AREs. PMID- 29413898 TI - Lrp6 is a target of the PTH-activated alphaNAC transcriptional coregulator. AB - In the nucleus of differentiated osteoblasts, the alpha chain of nascent polypeptide associated complex (alphaNAC) interacts with cJUN transcription factors to regulate the expression of target genes, including Osteocalcin (Bglap2). PTH induces the phosphorylation of alphaNAC on serine 99 through a Galphas-PKA dependent pathway. This leads to activation of alphaNAC and expression of Bglap2. To identify additional target genes regulated by PTH activated alphaNAC, we performed ChIP-Seq against alphaNAC in PTH-treated MC3T3 E1 cells. This identified Low density lipoprotein receptor-Related Protein 6 (Lrp6) as a potential alphaNAC target. LRP6 acts as a co-receptor for the PTH receptor to allow optimal activation of PTH signaling. PTH increased Lrp6 mRNA levels in primary osteoblasts. Conventional quantitative ChIP confirmed the ChIP Seq results. To assess whether alphaNAC plays a critical role in PTH-stimulated Lrp6 expression, we knocked-down Naca expression in MC3T3-E1 cells. Reduction of alphaNAC levels decreased basal expression of Lrp6 by 30% and blocked the stimulation of Lrp6 expression by PTH. We cloned the proximal mouse Lrp6 promoter (-2523/+120 bp) upstream of the luciferase reporter. Deletion and point mutations analysis in electrophoretic mobility shift assays and transient transfections identified a functional alphaNAC binding site centered around -343 bp. ChIP and ChIP-reChIP against JUND and alphaNAC showed that they cohabit on the proximal Lrp6 promoter. Luciferase assays confirmed that PTH-activated alphaNAC potentiated JUND-mediated Lrp6 transcription and Jund knockdown abolished this response. This study identified a novel alphaNAC target gene induced downstream of PTH signaling and represents the first characterization of the regulation of Lrp6 transcription in osteoblasts. PMID- 29413900 TI - Expression of the human TIMM23 and TIMM23B genes is regulated by the GABP transcription factor. AB - The TIM23 protein is a key component of the mitochondrial import machinery in yeast and mammals. TIM23 is the channel-forming subunit of the translocase of the inner mitochondrial membrane (TIM23) complex, which mediates preprotein translocation across the mitochondrial inner membrane. In this paper, we aimed to characterize the promoter region of the highly similar human TIM23 orthologs: TIMM23 and TIMM23B. Bioinformatic analysis revealed putative sites for the GA binding protein (GABP) and the recombination signal binding protein for immunoglobulin kappa J (RBPJ) transcription factors in both promoters. Luciferase reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation experiments showed three functional sites for GABP and one functional site for RBPJ in both promoters. Moreover, silencing of GABPA, the gene encoding the DNA-binding subunit of the GABP transcription factor, resulted in reduced expression of TIMM23 and TIMM23B. Our results show an essential role of GABP in activating TIMM23 expression. More broadly, they suggest that physiological signals involved in activating mitochondrial biogenesis and oxidative function also enhance the transcription but not the protein level of TIMM23, which is essential for maintaining mitochondrial function and homeostasis. PMID- 29413899 TI - Regulation of the ATF3 gene by a single promoter in response to amino acid availability and endoplasmic reticulum stress in human primary hepatocytes and hepatoma cells. AB - Activating transcription factor 3 (ATF3) is a highly regulated protein that is implicated in a wide range of pathological conditions including inflammation and transformation. Transcription from the ATF3 gene is induced by several stress induced signaling pathways, including amino acid limitation (amino acid response, AAR) and ER stress (unfolded protein response, UPR). Induction of ATF3 transcription by these pathways is mediated by ATF4 and cJUN recruitment to enhancer elements within the ATF3 gene. Although a canonical promoter (promoter A) has been studied by numerous laboratories, a second promoter activity (promoter A1), 43 kb upstream of the first, has been reported to respond to stress-induced signaling and to be critical for ATF3 expression in certain transformed cells. The results of the present study show that in normal human hepatocytes and HepG2 human hepatoma cells both basal as well as AAR- and UPR induced transcription occurs almost exclusively from promoter A. This selectivity between the two promoters correlated with increased binding of ATF4, recruitment of RNA polymerase II, and the expected histone modifications in the promoter A region of the gene. Time course studies of ATF3 transcription activity revealed that the temporal kinetics for ATF3 induction differ between the AAR and UPR, with the former being more transient than the latter. Collectively, the results document that ATF3 expression in normal and transformed human liver originates from the canonical promoter A that responds to multiple stress signals. PMID- 29413901 TI - MiR-137-3p rescue motoneuron death by targeting calpain-2. AB - Brachial plexus root avulsion (BPRA) is a type of injury that leads to motor function loss as a result of motoneurons (MNs) degeneration. Here we identified that the reduced expression of rat miR-137-3p in the ventral horn of spinal cord was associated with MNs death. However, the pathophysiological role of miR-137-3p in root avulsion remains poorly understood. We demonstrated that the calcium activated neutral protease-2 (calpain-2) was a direct target gene of miR-137-3p with miR-137-3p binding to the 3'-untranslated region of calpain-2. Silencing of calpain-2 suppressed the expression of neuronal nitric oxide synthase (nNOS), a primary source of nitric oxide (NO). After avulsion 2 weeks, up-regulation of miR 137-3p in the spinal cord reduced calpain-2 levels and nNOS expression inside spinal MNs, resulting in an amelioration of the MNs death. These events provide new insight into the mechanism by which upregulation of miR-137-3p can impair MN survival in the BPRA. PMID- 29413903 TI - Orexin A but not orexin B regulates lipid metabolism and leptin secretion in isolated porcine adipocytes. AB - It is well known that orexins are involved in the metabolism and endocrine function of rodent adipocytes, but there are no data on other animal species, including pigs. Therefore, in this study, we tested the hypothesis that orexin A (OxA) and orexin B (OxB) modulate the metabolism and endocrine functions of isolated porcine adipocytes and adipose tissue explants. Moreover, we characterized the possible mechanism of OxA action in porcine adipocytes. According to the results, both orexin receptor 1 and orexin receptor 2 were expressed in the porcine adipose tissue. We found that OxA suppressed the release of glycerol from porcine adipocytes both in the absence (basal lipolysis; P < 0.05) and in the presence (stimulated lipolysis; P < 0.05) of isoproterenol. Orexin A increased basal and insulin-stimulated glucose uptake (P < 0.05), as well as it enhanced the rate of glucose incorporation into lipids with insulin (stimulated lipogenesis; P < 0.01) or without insulin (basal; P < 0.05). We have also shown that OxA stimulated the mRNA expression of glucose transporter 4 (P < 0.05) and its translocation into the plasma membrane (P < 0.01). Moreover, OxA upregulated the mRNA expression of leptin in isolated porcine adipocytes (P < 0.05) and increased the secretion of leptin (P < 0.05). We have also demonstrated one of the possible mechanisms of OxA action in adipocytes. In the presence of extracellular-signal-regulated kinase 1 and 2 (ERK1/2) inhibitor, the effect of OxA was not detectable in porcine adipocytes, which indicates that this peptide increased cell viability via ERK1/2 pathway (P < 0.05). However, OxB did not show any effect on the metabolism and endocrine functions of porcine adipocytes. In summary, we have shown for the first time that OxA has a significant impact on the intensity of lipolysis, glucose uptake, lipogenesis, as well as on the expression and secretion of leptin. Therefore, we conclude that OxA but not OxB regulates lipid metabolism in porcine adipose tissue and that this regulation is partly mediated via ERK1/2 pathway. The action of orexins should be further explored to better understand their role in the regulation of adiposity in pigs. PMID- 29413902 TI - Transcriptome profiling of bovine ovarian theca cells treated with fibroblast growth factor 9. AB - We reported previously that fibroblast growth factor 9 (FGF9) acts as an antidifferentiation factor, stimulating proliferation of granulosa cells (GCs) and theca cells (TCs) while suppressing hormone-induced steroidogenesis of these cells. How FGF9 acts to simultaneously suppress steroidogenesis and stimulate proliferation remains to be fully elucidated. Thus, this study was undertaken to clarify the effects of FGF9 on the TC transcriptome. Ovaries were obtained from beef heifers at a local abattoir, TCs were isolated from large antral follicles, and cultured with or without 30 ng/mL of FGF9 for 24 h in the presence of LH and IGF-1. After treatment, total RNA was extracted from TC and processed for microarray using Affymetrix GeneChip Bovine Genome Arrays (n = 4/group). Transcriptome analysis comparing FGF9-treated TC with control TC using 1.3-fold cutoff, and a P < 0.05 significance level identified 355 differentially expressed transcripts, with 164 elements upregulated and 191 elements downregulated by FGF9. The ingenuity pathway analysis (IPA) was used to investigate how FGF9 treatment affects molecular pathways, biological functions, and the connection between molecules in bovine TC. The IPA software identified 346 pathways in response to FGF9 in TC involved in several biological functions and unveiled interesting relationships among genes related to cell proliferation (eg, CCND1, FZD5, and MYB), antioxidation/cytoprotection (eg, HMOX1 and NQO1), and steroidogenesis (eg, CYP11A1 and STAR). Overall, genes, pathways, and networks identified in this study painted a picture of how FGF9 may regulate folliculogenesis, providing novel candidate genes for further investigation of FGF9 functions in ovarian follicular development. PMID- 29413904 TI - Expression of membrane progestin receptors (mPRs) in the bovine corpus luteum during the estrous cycle and first trimester of pregnancy. AB - Progesterone (P4) affects luteal cell function through nuclear P4 receptors and via nongenomic mechanisms, presumably involving membrane P4 receptors. There are 2 types of these receptors: progesterone receptor membrane component (PGRMC) and membrane progestin receptor (mPR), including mPR alpha (mPRalpha), beta (mPRbeta), and gamma (mPRgamma), which belong to the progestin and adipoQ receptor family (PAQR 7, 8, and 5, respectively). The aim of this study was to evaluate mRNA expression, protein expression, and localization of mPRalpha, mPRbeta, and mPRgamma in the bovine corpus luteum (CL) on days 2-5, 6-10, 11-16, and 17-20 of the estrous cycle as well as on weeks 3-5, 6-8, and 9-12 of pregnancy (n = 5/each period). The highest mPRalpha mRNA expression was found on days 11-16 (P < 0.05) and 17-20 (P < 0.001) of the estrous cycle compared with other stages of the estrous cycle and pregnancy. The mPRbeta mRNA level was highest (P < 0.01) on days 11-20 of the estrous cycle and in all stages of pregnancy. mPRgamma mRNA expression was highest (P < 0.001) on days 17-20 of the estrous cycle and also during weeks 9-12 of pregnancy compared with the other stages of the estrous cycle and pregnancy. Only the mPRalpha protein was changed during the estrous cycle; there were no significant differences in protein expression of mPRbeta and mPRgamma during the estrous cycle and pregnancy. Immunostaining for the mPRalpha, mPRbeta, and mPRgamma proteins was detectable in the CL sections at all stages of the estrous cycle and pregnancy. Strong positive staining was observed in small luteal cells; this reaction was less evident in large luteal cells. All proteins were also localized in endothelial cells of blood vessels. The obtained data indicate variable expression of mPRalpha, mPRbeta, and mPRgamma in bovine CL during the estrous cycle and first trimester of pregnancy and suggest that P4 may be involved in the regulation of CL function via these membrane receptors during both the estrous cycle and pregnancy. PMID- 29413905 TI - The intrinsic flexibility of the aptamer targeting the ribosomal protein S8 is a key factor for the molecular recognition. AB - BACKGROUND: Aptamers are RNA/DNA biomolecules representing an emerging class of protein interactors and regulators. Despite the growing interest in these molecules, current understanding of chemical-physical basis of their target recognition is limited. Recently, the characterization of the aptamer targeting the protein-S8 has suggested that flexibility plays important functional roles. We investigated the structural versatility of the S8-aptamer by molecular dynamics simulations. METHODS: Five different simulations have been conducted by varying starting structures and temperatures. RESULTS: The simulation of S8 aptamer complex provides a dynamic view of the contacts occurring at the complex interface. The simulation of the aptamer in ligand-free state indicates that its central region is intrinsically endowed with a remarkable flexibility. Nevertheless, none of the trajectory structures adopts the structure observed in the S8-aptamer complex. The aptamer ligand-bound is very rigid in the simulation carried out at 300 K. A structural transition of this state, providing insights into the aptamer-protein recognition process, is observed in a simulation carried out at 400 K. These data indicate that a key event in the binding is linked to the widening of the central region of the aptamer. Particularly relevant is switch of the A26 base from its ligand-free state to a location that allows the G13-C28 base-pairing. CONCLUSIONS: Intrinsic flexibility of the aptamer is essential for partner recognition. Present data indicate that S8 recognizes the aptamer through an induced-fit rather than a population-shift mechanism. GENERAL SIGNIFICANCE: The present study provides deeper understanding of the structural basis of the structural versatility of aptamers. PMID- 29413906 TI - Dysfunction of pulmonary surfactant mediated by phospholipid oxidation is cholesterol-dependent. AB - Pulmonary surfactant forms a cohesive film at the alveolar air-lung interface, lowering surface tension, and thus reducing the work of breathing and preventing atelectasis. Surfactant function becomes impaired during inflammation due to degradation of the surfactant lipids and proteins by free radicals. In this study, we examine the role of reactive nitrogen (RNS) and oxygen (ROS) species on surfactant function with and without physiological cholesterol levels (5-10%). Surface activity was assessed in vitro in a captive bubble surfactometer (CBS). Surfactant chemistry, monolayer fluidity and thermodynamic behavior were also recorded before and after oxidation. We report that physiologic amounts of cholesterol combined with oxidation results in severe impairment of surfactant function. We also show that surfactant polyunsaturated phospholipids are the most susceptible to oxidative alteration. Membrane thermodynamic experiments showed significant surfactant film stiffening after free radical exposure in the presence of cholesterol. These results point to a previously unappreciated role for cholesterol in amplifying defects in surface activity caused by oxidation of pulmonary surfactant, a finding that may have implications for treating several lung diseases. PMID- 29413907 TI - Ophthalmic acid is a marker of oxidative stress in plants as in animals. AB - BACKGROUND: Ophthalmic acid (OPH), gamma-glutamyl-L-2-aminobutyryl-glycine, a tripeptide analogue of glutathione (GSH), has recently captured considerable attention as a biomarker of oxidative stress in animals. The OPH and GSH biosynthesis, as well as some biochemical behaviors, are very similar. Here, we sought to investigate the presence of OPH in plants and its possible relationship with GSH, known to possess multiple functions in the plant development, growth and response to environmental changes. METHODS: HPLC-ESI-MS/MS analysis was used to examine the occurrence of OPH in leaves from various plant species, and flours from several plant seeds. Different types of oxidative stress, i.e., water, dark, paraquat, and cadmium stress, were induced in rye, barley, oat, and winter wheat leaves to evaluate the effects on the levels of OPH and its metabolic precursors. RESULTS: OPH and its dipeptide precursor, gamma-glutamyl-2-aminobutyric acid, were found to occur in phylogenetically distant plants. Interestingly, the levels of OPH were tightly associated with the oxidative stress tested. Levels of OPH precursors, gamma-glutamyl-2-aminobutyric acid and 2-aminobutyric acid, the latter efficiently formed in plants via biosynthetic pathways absent in the animal kingdom, were also found to increase during oxidative stress. CONCLUSIONS: OPH occurs in plants and its levels are tightly associated with oxidative stress. GENERAL SIGNIFICANCE: OPH behaves as an oxidative stress marker and its biogenesis might occur through a biochemical pathway common to many living organisms. PMID- 29413908 TI - Melanoma metabolism contributes to the cellular responses to MAPK/ERK pathway inhibitors. AB - BACKGROUND: Besides its influence on survival, growth, proliferation, invasion and metastasis, cancer cell metabolism also greatly influences the cellular responses to molecular-targeted therapies. SCOPE OF THE REVIEW: To review the recent advances in elucidating the metabolic effects of BRAF and MEK inhibitors (clinical inhibitors of the MAPK/ERK pathway) in melanoma and discuss the underlying mechanisms involved in the way metabolism can influence melanoma cell death and resistance to BRAF and MEK inhibitors. We also underlined the therapeutic perspectives in terms of innovative drug combinations. MAJOR CONCLUSION: BRAF and MEK inhibitors inhibit aerobic glycolysis and induce high levels of metabolic stress leading to effective cell death by apoptosis in BRAF mutated cancer cells. An increase in mitochondrial metabolism is required to survive to MAPK/ERK pathway inhibitors and the sub-population of cells that survives to these inhibitors are characterized by mitochondrial OXPHOS phenotype. Consequently, mitochondrial inhibition could be combined with oncogenic "drivers" inhibitors of the MAPK/ERK pathway for improving the efficacy of molecular targeted therapy. GENERAL SIGNIFICANCE: Metabolism is a key component of the melanoma response to BRAF and/or MEK inhibitors. Mitochondrial targeting may offer novel therapeutic approaches to overwhelm the mitochondrial addiction that limits the efficacy of BRAF and/or MEK inhibitors. These therapeutic approaches might be quickly applicable to the clinical situation. PMID- 29413909 TI - Novel mesoporous MnCo2O4 nanorods as oxygen reduction catalyst at neutral pH in microbial fuel cells. AB - The aim of this work was to evaluate the comparative performance of hybrid metal oxide nanorods i.e. MnCo2O4 nanorods (MCON) and single metal oxide nanorods i.e. Co3O4 nanorods (CON) as oxygen reduction catalyst in microbial fuel cells (MFC). Compared to the single metal oxide, the hybrid MCON exhibited a higher BET surface area and provided additional positively charged ions, i.e., Co2+/Co3+ and Mn3+/Mn4+ on its surfaces, which increased the electro-conductivity of the cathode and improved the oxygen reduction kinetics significantly, achieved an io of 6.01 A/m2 that was 12.4% higher than CON. Moreover, the porous architecture of MCON facilitated the diffusion of electrolyte, reactants and electrons during the oxygen reduction, suggested by lower diffusion (Rd), activation (Ract) and ohmic resistance (Rohm) values. This enhanced oxygen reduction by MCON boosted the power generation in MFC, achieving a maximum power density of 587 mW/m2 that was ~29% higher than CON. PMID- 29413911 TI - Hyper-production of butyric acid from delignified rice straw by a novel consolidated bioprocess. AB - A novel consolidated bioprocess for hyper-production of butyric acid from delignified rice straw without exogenous enzymes involved was developed by co fermentation of Clostridium thermocellum ATCC 27405 and C. thermobutyricum ATCC 49875. Feasibility of the consolidated bioprocess was approved by batch fermentations, with the optimum pH of 6.5. Fed-batch fermentation with a constant pH of 6.5 at 55 degrees C could enhance the butyric acid yield to a remarkable 33.9 g/L with a selectivity as high as 78%. Metabolic analysis of the co-culture indicated that sugars liberated by C. thermocellum ATCC 27405 were effectively converted to butyric acid by C. thermobutyricum ATCC 49875. Secondary metabolism of C. thermobutyricum ATCC 49875 also contributed to the hyper-production of butyric acid, resulting in the re-assimilation of by-products such as acetic acid and ethanol. This work provides a more effective fermentation process for butyric acid production from lignocellulosic biomass for future applications. PMID- 29413910 TI - Extra metabolic burden by displaying over secreting: Growth, fermentation and enzymatic activity in cellobiose of recombinant yeast expressing beta glucosidase. AB - beta-Glucosidase was selected to be a reporter to study metabolic burden imposed by its expression in yeast. Cell growth, fermentation yield and enzymatic activity were used as indicators of the metabolic burden borne by 14 recombinant yeast strains. Various factors were found to affect metabolic burden, including BGLI gene source, gene dose, trafficking of the enzyme (either cell-surface display or secretion), and oxygen supply. While BGLI gene from Aspergillus aculeatus provided better performance for the host cells than that from Saccharomycopsis fibuligera, displaying beta-glucosidase on the cell surface generally led to lower MUm, total activity and ethanol titer, and longer lag period, lower (aerobic condition) or higher (anaerobic condition) biomass yield than that of secreting beta-glucosidase. The negative effect on growth increased with gene dose level until a final failure to grow. This growth difference implies that displaying beta-glucosidase on the cell surface imposes an extra metabolic burden. The molecular basis and mechanisms for this phenomenon need to further be investigated in order to develop better strategies for utilizing displayed and secreted enzymes in biotechnology and yeast breeding. PMID- 29413912 TI - Denitrification and desulphurization of industrial biowastes via hydrothermal modification. AB - In attempt to decrease NOX and SO2 emission from thermochemical utilization, three industrial biowastes (penicillin mycelia waste, sewage sludge and peat waste) contained high nitrogen (N) and sulfur (S) were chosen to investigate the denitrification and desulphurization of hydrothermal modification. The results demonstrated that hydrothermal modification destroyed the structure of N- and S containing components, thereby altering their existed conformations. Inorganic-N (N-IN) and most of amino-N/polyamide-N (N-A) were enriched by liquid phase in the forms of NH4+-N and soluble organic-N (Org-N), respectively; subsequently, Org-N could further decompose to NH4+-N at higher temperature. Residual N in hydrochars was converted from N-A to heterocyclic-N (pyrrolic-N, pyridinic-N and quaternary N) via hydrolysis and cyclization. Similarly, over 60% of S was remove form biowastes at 240 degrees C. In solid phase, part of organic-S was altered to thiophenes-S after modified, while the remainder was transformed to inorganic-S; but the variation of inorganic-S in hydrochars strongly affected by its specific species. PMID- 29413913 TI - Application of biomass pyrolytic polygeneration by a moving bed: Characteristics of products and energy efficiency analysis. AB - In order to overcome the shortcoming of batch production in the retort and improve the quality of three-state products, a moving bed as pyrolysis furnace and torrefaction pretreatment were both used in a demonstration of biomass pyrolytic polygeneration. The bench and demonstration scale experiments were both investigated in this work. The results show that when the pyrolysis temperature between 550 degrees C and 750 degrees C, it can not only maintain the relative stability of the tri-state products yield, but also guarantee the quality. When the demonstration ran at this temperature, it can continuously deal with biomass for about 7E+03 kg/h, and reach 5.42E+07 kg/yr, which can be converted into 1.12E+07 Nm3 of bio-gas, 3.78E+06 kg of tar, 7.63E+06 kg of vinegar and 1.14E+07 kg of biochar. The lower heating value of bio-gas and biochar were respectively 12.5 MJ/m3 and 30.5 MJ/kg, which showed the great potential as gas and solid fuel. PMID- 29413914 TI - Biomethanation potential for co-digestion of municipal solid waste and rice straw: A batch study. AB - Rice straw (RS) contains a high amount of lignocellulosic materials which are difficult to degrade without thermal pretreatment. In the present study, co digestion of municipal solid waste (MSW) and RS was carried out in three different ratios i.e., 1:1, 2:1, and 3:1 to get the maximum biomethanation potential and methane generation rate constant (k). The biogas and methane (CH4) potential increased by 60% and 57%, respectively for MSW and RS in the ratio 2:1 as compared to other combination. The values of k, biochemical methane potential (ub) and sludge activity were measured as 0.1 d-1, 0.99 CH4-COD/CODfed and 0.50 g CH4-COD/g VSS, respectively. The sludge activity was found to be 100% for 2:1 ratio. Co-digestion of RS with MSW can also optimize the C/N ratio which is an essential parameter in the anaerobic digestion process. PMID- 29413915 TI - Comparison of ultrasound-assisted ionic liquid and alkaline pretreatment of Eucalyptus for enhancing enzymatic saccharification. AB - Two ultrasound-assisted pretreatment technologies, ultrasound-assisted alkaline and ultrasound-assisted aqueous ionic liquid tetrabutylammonium hydroxide ([TBA][OH]), are compared systematically in regard to enzymatic saccharification. Pretreated Eucalyptus samples were characterized by powder X-ray diffraction, 13C cross polarization/magic-angle spinning solid state NMR spectroscopy, Fourier transform infrared spectroscopy, Scanning electron microscope (SEM) and chemistry composition analysis. These results not only explain the enzymatic saccharification difference between samples from the microstructure level, but also provide helpful information for relevant pretreatment research. Ultrasound assisted [TBA][OH] pretreatment acquired a significant enhancement in the initial enzymatic rate of cellulose (79.39 mg/g/h), and a reducing sugar yield of 426.6 mg/g at 48 h. The pretreatment combining inexpensive aqueous ionic liquid and ultrasound may provide a promising strategy in the field of bio-refinery because of its unique advantages. PMID- 29413916 TI - Expression of global regulator IrrE for improved succinate production under high salt stress by Escherichia coli. AB - Poor high salt stress resistance remained as a main hurdle limiting the efficient bio-based succinic acid production. In this study, the metabolically engineered E. coli not only showed improvement of high salt stress tolerance through expression of a global regulator IrrE, but also could use seawater for succinic acid fermentation. The recombinant strain showed an increased 1.20-fold of cell growth rate and 1.24-fold of succinic acid production. Expression levels of genes related glucose uptake and succinic acid synthesis were up-regulated, and more glycerol and trehalose were accumulated. Moreover, no significant differences were observed in cell growth even when tap water was replaced by 60% artificial seawater. In the fermentation using Yellow Sea seawater, 24.5 g/L succinic acid was achieved with a yield of 0.88 g/g. This strategy set up a platform for improving abiotic stress tolerances and provide a possible approach for fermentation processes with low cost. PMID- 29413917 TI - Fast start-up of the CANON process with a SABF and the effects of pH and temperature on nitrogen removal and microbial activity. AB - The long start-up time of the completely autotrophic nitrogen removal over nitrite (CANON) process is one of the main disadvantages of this system. In this paper, the CANON process with a submerged aerated biological filter (SABF) was rapidly started up within 26 days. It gave an average ammonium nitrogen removal rate (ANR) and a total nitrogen removal rate (TNR) of 94.2% and 81.3%, respectively. The phyla Proteobacteria and Planctomycetes were confirmed as the ammonia oxidizing bacteria (AOB) and anaerobic ammonium oxidation bacteria (AnAOB). The genus Candidatus Brocadia was the major contributor of nitrogen removal. pH and temperature affect the performance of the CANON process. This experimental results showed that the optimum pH and temperature were 8.0 and 30 degrees C, respectively, which gave the highest average ANR and TNR values of 94.6% and 85.1%, respectively. This research could promote the nitrogen removal ability of CANON process in the future. PMID- 29413918 TI - Electron transfer mechanism of biocathode in a bioelectrochemical system coupled with chemical absorption for NO removal. AB - A biocathode with the function of Fe(III)EDTA and Fe(II)EDTA-NO reduction was applied in a microbial electrolysis cell coupled with chemical absorption for NO removal from flue gas. As the mediated electron transfer was excluded by the same electrochemical characterizations of the biocathodes before and after a 48 h continuous operation, the profiles of reduction experiments indicated that direct electron transfer was the main mechanism of Fe(III)EDTA reduction, while Fe(III)EDTA-NO was mainly reduced via Fe(II)-assisted autotrophic denitrification. The microscopy of the biocathode confirmed the existence of pili, which was supposed to be bacterial nanowires for electron transfer. The analysis of microbial community revealed that iron-reducing bacteria, including Escherichia coli, had the possibility of electron uptake from electrode via physical contact. These results first time gave us in-depth understanding of the electron transfer in the multifunctional biocathode and mechanism for further enhancement of the bioreduction processes. PMID- 29413919 TI - Investigations in ultrasound-induced enhancement of astaxanthin production by wild strain Phaffia rhodozyma MTCC 7536. AB - This work reports ultrasound-induced enhancement of astaxanthin production in batch fermentation using wild strain of P. rhodozyma MTCC 7536. The methodology adopted in this study comprises of statistical optimization of the medium and fermentation parameters, followed by application of sonication at optimized conditions. P. rhodozyma fermentation at conditions of 20 g/L glucose, pH 4.4, temperature 21 degrees C, 4% v/v inoculum, shaking at 205 rpm with nitrogen sources of (NH4)2SO4 and yeast extract yielded 6.8 mg/L or 1360 MUg/g DCW astaxanthin in 84 h. Application of 33 kHz and 140 kPa sonication at 10% duty cycle in final 12 h of fermentation enhanced the astaxanthin yield to 8.6 mg/L or 1728 MUg/g DCW, which is higher than several mutant strains reported in literature. These results are essentially manifestations of intense microturbulence generated by sonication in fermentation mixture. PMID- 29413920 TI - Improved polycyclic aromatic hydrocarbon degradation in a crude oil by individual and a consortium of bacteria. AB - In this study, we report the ability of Stenotrophomonas maltophilia, Ochrobactrum anthropi, Pseudomonas mendocina, Microbacterium esteraromaticum and Pseudomonas aeruginosa to degrade multiple polycyclic aromatic hydrocarbons (PAHs) present in crude oil. The PAHs in the crude oil sample obtained from Digboi oil refinery, India were estimated to be naphthalene (10.0 mg L-1), fluorene (1.9 mg L-1), phenanthrene (3.5 mg L-1) and benzo(b)fluoranthene (6.5 mg L-1). Exposure of individual bacteria to crude oil showed high rate of biodegradation of specific PAHs by M. esteraromaticum, 81.4%-naphthalene; P. aeruginosa, 67.1%-phenanthrene and 61.0%-benzo(b)fluoranthene; S. maltophilia, 47.9%-fluorene in 45 days. However, consortium of these bacteria showed enhanced biodegradation of 89.1%-naphthalene, 63.8%-fluorene, 81% of phenanthrene and 72.8% benzo(b)fluoranthene in the crude oil. The degradation was further improved up to 10% by consortium on addition of 40 MUg mL-1 rhamnolipid JBR-425 biosurfactant. These results suggest that the developed bacterial consortium has significant potential in PAH remediation. PMID- 29413921 TI - Cathode potential regulation in a coupled bioelectrode-anaerobic sludge system for effective dechlorination of 2,4-dichloronitrobenzene. AB - For enhanced dechlorination of 2,4-dichloronitrobenzene (2,4-DClNB), a coupled microbial electrosynthesis-upflow anaerobic sludge reactor (MES-UASB) was established, and the effect of cathode potential on the performance of combined process was investigated in this study. Results showed that a higher dechlorination efficiency of 78.5 +/- 6.1% was achieved in the coupled MES-UASB at -660 mV, and the degradation rate of 4-chloroaniline (4-ClAn) reached 4.61 mg.L-1.d-1 within 120 h at -660 mV of cathode potential in batch experiments. The results of Illumina sequencing indicated that the biocathode operated at a lower potential favored the enrichment of dechlorination-related microbes such as Dehalobacter, Dehalococcoides and Anaeromyxobacter both in granular sludge and cathode biofilm. It could be speculated that a lower cathode potential is more feasible for the dechlorination of 2,4-DClNB due to the enrichment of dechlorination-related microbes as well as the production of electrons with higher energy for long-distance electron transfer (LDET). PMID- 29413922 TI - A process combining hydrothermal pretreatment, anaerobic digestion and pyrolysis for sewage sludge dewatering and co-production of biogas and biochar: Pilot-scale verification. AB - To fully dispose of/utilize sewage sludge, a process combing hydrothermal pretreatment (HTPT), anaerobic digestion (AD) and pyrolysis was developed and tested at the pilot scale. First, the improvement in sludge dewaterability by HTPT at 180 degrees C for 30 min was verified, and the water content decreased from 85 to 33 wt% after filter pressing. Then, the resulting filtrate underwent continuous mesophilic (37 +/- 2 degrees C) AD in an up-flow anaerobic sludge bed (UASB) reactor for producing biogas to compensate for the energy required for HTPT. Meanwhile, the filter cake was pyrolyzed in a rotary furnace (600 +/- 50 degrees C) to generate biochar, and heavy metals were well immobilized in the biochar. Finally, the material/energy balance made according to the pilot data showed that the proposed process was effective for full resource reuse of sewage sludge. PMID- 29413923 TI - Feasibility of enhancing short-chain fatty acids production from sludge anaerobic fermentation at free nitrous acid pretreatment: Role and significance of Tea saponin. AB - Short-chain fatty acids (SCFA), raw substrates for biodegradable plastic production and preferred carbon source for biological nutrients removal, can be produced from anaerobic fermentation of waste activated sludge (WAS). This paper reports a new, high-efficient and eco-friendly strategy, i.e., using free nitrous acid (FNA) pretreatment combined with Tea saponin (TS), to enhance SCFA production. Experimental results showed 0.90 mg/L FNA pretreatment and 0.05 g/g total suspended solids TS addition (FNA + TS) not only significantly increased SCFA production to 315.3 +/- 8.8 mg COD/g VSS (5.52, 1.76 and 1.93 times higher than that from blank, solo FNA and solo TS, respectively) but also shortened fermentation time to 4 days. Mechanism investigations revealed that FNA pretreatment combined with TS cause a positive synergetic effect on sludge solubilization, resulting in more release of organics. It was also found that the combination benefited hydrolysis and acidogenesis processes but inhibited the methanogenesis. PMID- 29413924 TI - Profitable ultrasonic assisted microwave disintegration of sludge biomass: Modelling of biomethanation and energy parameter analysis. AB - In this study, microwave irradiation has been employed to disintegrate the sludge biomass profitably by deagglomerating the sludge using a mechanical device, ultrasonicator. The outcomes of the study revealed that a specific energy input of 3.5 kJ/kg TS was found to be optimum for deagglomeration with limited cell lysis. A higher suspended solids (SS) reduction and biomass lysis efficiency of about 22.5% and 33.2% was achieved through ultrasonic assisted microwave disintegration (UMWD) when compared to microwave disintegration - MWD (15% and 20.9%). The results of biochemical methane potential (BMP) test were used to estimate biodegradability of samples. Among the samples subjected to BMP, UMWD showed better amenability towards anaerobic digestion with higher methane production potential of 0.3 L/g COD representing enhanced liquefaction potential of disaggregated sludge biomass. Economic analysis of the proposed method of sludge biomass pretreatment showed a net profit of 2.67 USD/Ton respectively. PMID- 29413925 TI - Simultaneous treatment and single cell protein production from agri-industrial wastewaters using purple phototrophic bacteria or microalgae - A comparison. AB - Resource recovery, preferably as high value products, is becoming an integral part of modern wastewater treatment, with conversion to heterotrophic or phototrophic/photosynthetic microbes a key option to minimise dissipation, and maximise recovery. This study compares the treatment capacities of purple phototrophic bacteria (PPB) and microalgae of five agri-industrial wastewaters (pork, poultry, red meat, dairy and sugar) to recover carbon, nitrogen, and phosphorous as a microbial product. The mediators have different advantages, with PPB offering moderate removals (up to 74% COD, 80% NH4-N, 55% PO4-P) but higher yields (>0.75 gCODremoved gCODadded-1) and a more consistent, PPB dominated (>50%) product, with a higher crude protein product (>0.6 gCP gVSS-1). The microalgae tests achieved a better removal outcome (up to 91%COD, 91% NH4-N, 73%PO4-P), but with poorer quality product, and <30% abundance as algae. PMID- 29413926 TI - Methane potential from municipal biowaste: Insights from six communities in Maharashtra, India. AB - Anaerobic digestion (AD) of biowaste can generate biogas with methane (CH4) as energy source and contribute to sustainable municipal solid waste management in India. Characteristic municipal biowastes sampled seasonally from household, fruit and vegetable market and agricultural waste collection points in villages, towns and cities in Maharashtra were analysed to assess the potential as substrate for AD. The mean biochemical methane potential (BMP, at 37 degrees C) across seasons and community sizes was between 200-260, 175-240 and 101-286 NLCH4 kgvs-1 for household, market and agricultural biowaste, respectively. CH4 yields were comparable in villages, towns and cities. Seasonal variations in CH4 yields were observed for market and agricultural biowaste with highest values during pre monsoon season. Results underpin that municipal biowaste is a suitable substrate for AD in India. However, low purity of available biowaste resulted in lower CH4 yields compared to recent studies using source-segregated biowaste. PMID- 29413927 TI - Temporal acclimation of Microchloropsis gaditana CCMP526 in response to hypersalinity. AB - Evaporation from culture ponds and raceways can subject algae to hypersalinity stress, and this is exacerbated by global warming. We investigated the effect of salinity on a marine microalga, Microchloropsis gaditana, which is of industrial significance because of its high lipid-accumulating capability. Both short-term (hours) and medium-term (days) effects of salinity were studied across various salinities (37.5, 55, 70 and 100 PSU). Salinity above 55 PSU suppressed cell growth and specific growth rate was significantly reduced at 100 PSU. Photosynthesis (Fv/Fm, rETRmax and Ik) was severely affected at high salinity conditions. Total carbohydrate per cell increased ~1.7-fold after 24 h, which is consistent with previous findings that salinity induces osmolyte production to counter osmotic shock. In addition, accumulation of lipid increased by ~4.6-fold in response to salinity. Our findings indicate a possible mechanism of acclimation to salinity, opening up new frontiers for osmolytes in pharmacological and cosmetics applications. PMID- 29413928 TI - Study on an alternative approach for the preparation of wood vinegar from the hydrothermolysis process of cotton stalk. AB - The yield and pH of the refined aqueous product (RAP) prepared by the hydrothermolysis of cotton stalk (CS) were investigated using response surface methodology with the variation of three parameters: CS/water ratio of 0.05 0.15w/w, temperature of 180-280 degrees C, and retention time of 0-30 min. At the best formulation (0.05w/w, 264.36 degrees C and 0 min), the yield and pH of RAP were 82.8% and 3.95, respectively. Additionally, the organic compounds contained in RAP prepared under the respective optimal formulation (pH: 0.05w/w, 251.43 degrees C and 0 min, yield: 0.05w/w, 280.00 degrees C and 0 min) were determined by gas chromatography and mass spectrometry. The results show that the kinds of compounds in RAP are identical or similar to those in the wood vinegar (WV), but their contents is slightly higher than that of the WV. In sum, it is feasible that RAP has the enormous potential to be utilized as WV probably because of its higher quality and value than WV. PMID- 29413929 TI - An efficient aqueous two phase systems using dual inorganic electrolytes to separate 1,3-propanediol from the fermented broth. AB - An aqueous two phase extraction using K2CO3:K2HPO4/Isoproponal was investigated for the recovery of 1,3-propanediol from the fermented broth. Initially, the concentration of K2CO3 on phase formation, the partition co-efficient and recovery of 1,3-PDO was evaluated with a optimum salt concentration of 60%. Later the partition co-efficient was improved using dual inorganic salts, K2CO3 and K2HPO4 with an optimum concentration of 45% and 15% respectively. Using Central Composite Design, pH and temperature on partition and recovery of 1,3-PDO was evaluated. With the optimized physical conditions and inorganic salts concentration, ATPS extraction was carried out in synthetic solution as well as fermented broth resulting in maximum 1,3-PDO partition co-efficient value of 42.46 and 56.93 and recovery yield of 97.69 and 98.27% respectively. A fair partition was observed with organic acids and 1,3-PDO, with removal of lactic acid and acetic acid up to 93.29 and 90.42% respectively. PMID- 29413930 TI - Screening of a microbial consortium for selective degradation of lignin from tree trimmings. AB - To acquire microbial consortia with effectively precedent degradation of lignin, samples obtained from rotten trunks, rotten stumps and soil near it were screened and isolated after generations of subculture. The dynamic change illustrated that their community structures were affected by pH and tended to be stable after 6 days' cultivation. The desired one, named DM-1, was gained through successive cultivation for over 5 generations, whose high selectivity in lignin degradation was observed within 16 days' cultivation (SV = 2.78). Meanwhile, a remarkable reduction in the fiber crystallinity of tree trimmings (10.35%) resulted from the bio-degradation of DM-1, displayed a greater exposure of cellulose by selective removal of lignin. The diversity analysis of DM-1 was investigated by PCR amplification and 16S rDNA sequencing, indicated that mesorhizobium, cellulosimicrobium, pandoraea, achromobacter and stenotrophomones were the predominant genera. Furthermore, fungi (3 strains), bacteria (4 strains) and actinomycetes (5 strains) constituted 12 strains in total were gained by plate isolation from DM-1. PMID- 29413931 TI - Effect of food to vegetable waste ratio on acidogenesis and methanogenesis during two-stage integration. AB - The mixing ratio of food waste (FW) to vegetable waste (VW) (2:3 FW:VW ~ 152.51 g VS and 2:1 FW:VW ~ 137.03 gVS) was optimized using two-stage (LBR-UASB) experimental process depending upon volatile solid (VS) load. The effect of FW to VW ratio was studied in Leach Bed Reactor (LBR) towards leachate production. Results revealed that hydrolysis rate (73.11%), sCOD (3294.3 g/KgVS) and tVFA (2664 g/KgVS) yield was higher in 2:1 FW:VW ratio. Acetate, propionate, lactate and methane yield for 2:3 FW:VW (420 g/KgVS, 87 g/KgVS, 180 g/KgVS and 226.86 ml/gVS respectively) was different from 2:1 FW:VW (340 g/KgVS, 247 g/KgVS, 340 g/KgVS and 218.54 ml/gVS respectively). 2:3 FW:VW ratio depicted higher VS (53.96%) and COD (54.1%) removal than 2:1 FW:VW ratio 46.34% and 41.8% respectively. VW addition regulated pH, restricted propionate and lactate production with enhanced methanogenesis by improving acetate production in two stage AD process which further boosted process stability and efficiency. PMID- 29413932 TI - Hypocholesterolemic and bioactive potential of exopolysaccharide from a probiotic Enterococcus faecium K1 isolated from kalarei. AB - Bioprospecting of novel probiotic strains especially from unexplored eco-niches has been a continuous practice. Enterococcus faecium K1, an isolate from indigenously fermented milk product kalarei possesses numerous desirable functional attributes. In current study, E. faecium K1 has been used for EPS production, and it yielded 355 +/- 0.019 mg/L EPS. EPS demonstrates remarkable hypocholesterolemic, antioxidant, antibiofilm, and emulsification characteristics. EPS is constituted of mannose, glucose and galactose. SEM analysis reveals flake like compact structure of EPS while TEM and X-ray diffractogram confirms the amorphous structure of EPS. FTIR substantiates the functional groups/bonds typical of polysaccharides. Thermal analysis indicates adequate stability of EPS at 237 degrees C with average weight loss of 22%. E. faecium K1 EPS possesses unique functional bioactivities and physicochemical characteristics, and may potentially be explored for applications in food/pharmaceutical industries. PMID- 29413933 TI - Responses of biofilm microorganisms from moving bed biofilm reactor to antibiotics exposure: Protective role of extracellular polymeric substances. AB - EPS can affect the migration of antibiotics in biofilm reactors, however the roles of biofilm EPS on the fate of antibiotics and the protective mechanisms to bacterial community remain unknown. We investigated the transport of three representative antibiotics in the biofilm suspension from a moving bed biofilm reactor. Spectral analysis suggested that proteins dominated the interactions between EPS and antibiotics. The adsorbed amounts of antibiotics onto EPS accounted for 14.5%, 88.2% and 13.1% of total concentration for sulfamethizole, tetracycline and norfloxacin, respectively at the biodegradation stage. The respiratory rates and representative enzymatic activities all experienced declines for biofilm without EPS in exposure to antibiotics. Gene sequencing results indicated that the bacterial community in biofilm without EPS was more vulnerable to antibiotics shocks. Our results demonstrated the protective roles of biofilm EPS in resisting antibiotics stresses, which provides important implications for understanding the bioremediation of antibiotics in biofilm systems. PMID- 29413934 TI - Mediator-free enzymatic electrosynthesis of formate by the Methanococcus maripaludis heterodisulfide reductase supercomplex. AB - Electrosynthesis of formate is a promising technology to convert CO2 and electricity from renewable sources into a biocompatible, soluble, non-flammable, and easily storable compound. In the model methanogen Methanococcus maripaludis, uptake of cathodic electrons was shown to proceed indirectly via formation of formate or H2 by undefined, cell-derived enzymes. Here, we identified that the multi-enzyme heterodisulfide reductase supercomplex (Hdr-SC) of M. maripaludis is capable of direct electron uptake and catalyzes rapid H2 and formate formation in electrochemical reactors (-800 mV vs Ag/AgCl) and in Fe(0) corrosion assays. In Fe(0) corrosion assays and electrochemical reactors, purified Hdr-SC primarily catalyzed CO2 reduction to formate with a coulombic efficiency of 90% in the electrochemical cells for 5 days. Thus, this report identified the first enzyme that stably catalyzes the mediator-free electrochemical reduction of CO2 to formate, which can serve as the basis of an enzyme electrode for sustained electrochemical production of formate. PMID- 29413935 TI - Microbial lipid production by Cryptococcus curvatus from vegetable waste hydrolysate. AB - This study primarily evaluated the effect of pre-treatment on release of reducing sugars (RS) from vegetable waste (VW). Different acids and alkalis viz., H2SO4, HCl, HNO3, H3PO4, NaOH and KOH were evaluated at varied concentration (0.5, 1.0, 1.5 and 2.0%) for pretreatment. The highest RS yield of 472.36 +/- 1.89 g/l and 439.13 +/- 1.04 g/l was obtained with 1.5% H2SO4 and 2% HCl respectively. Secondly, pre-treated vegetable waste hydrolysates (PT-VWH) were evaluated for yeast fermentation using Cryptococcus curvatus MTCC 2698 for lipid production. Maximum biomass (9.46 +/- 0.1 g/l and 8.12 +/- 0.1 g/l) and lipid (28.3 +/- 0.5% and 26 +/- 0.5%) was obtained with 1.5% H2SO4 PT-VWH and 2% HCl PT-VWH respectively. The FAME profiling revealed the predominance of palmitic, stearic, oleic and linoleic acid. The presence of these fatty acids in majority has beneficial effect on the biodiesel quality. PMID- 29413936 TI - Coproducts performances in biorefineries: Development of Claiming-based allocation models for environmental policy. AB - This study revisited the fundamentals of allocation to joint products and proposed new models for allocating common greenhouse gases emissions among coproducts of biorefineries. These emissions may account for more than 80% of the total emissions of greenhouse gases of the biorefineries. The proposed models optimize the reward of coproducts for their compliance to environmental requirements. They were illustrated by a case study of wheat straw biorefinery built on the literature. Several scenarios were considered with regard to the grain yield, field emissions of greenhouse gases, allocation between grain and straw and policy requirements. The results conform to the expectations and are sensitive to the policy targets and to the environmental performance of the counterpart system. Further research works are necessary to achieve a full application to complex processes. However, the proposed models are promising towards assessing the simultaneous compliance of coproducts of a biorefinery to environment policy requirements. PMID- 29413937 TI - Co-digestion of solid waste: Towards a simple model to predict methane production. AB - Modeling methane production is a key issue for solid waste co-digestion. Here, the effect of a step-wise increase in the organic loading rate (OLR) on reactor performance was investigated, and four new models were evaluated to predict methane yields using data acquired in batch mode. Four co-digestion experiments of mixtures of 2 solid substrates were conducted in semi-continuous mode. Experimental methane yields were always higher than the BMP values of mixtures calculated from the BMP of each substrate, highlighting the importance of endogenous production (methane produced from auto-degradation of microbial community and generated solids). The experimental methane productions under increasing OLRs corresponded well to the modeled data using the model with constant endogenous production and kinetics identified at 80% from total batch time. This model provides a simple and useful tool for technical design consultancies and plant operators to optimize the co-digestion and the choice of the OLRs. PMID- 29413938 TI - A novel single-stage process integrating simultaneous COD oxidation, partial nitritation-denitritation and anammox (SCONDA) for treating ammonia-rich organic wastewater. AB - In this study, simultaneous carbon oxidation, partial nitritation, denitritation and anammox (SCONDA) was successfully integrated into a one-stage sequencing biofilm batch reactor for treating ammonia-rich organic wastewater with carbon to nitrogen (C/N) ratio of 3. The results showed that 94.3% of COD removal together with 92.6% NH4+-N and 88% TN removal were achieved via SCONDA. High-throughout sequencing analysis further revealed that the microbial community developed in the proposed system was primarily dominated by heterotrophic bacteria (e.g. Thauera, Azovibrio, Ohtaekwangia, Azospira), autotrophic bacteria (e.g. Nitrosomona) and unclassified genus of anammox bacterium, which were all essential for COD and N removal via SCONDA. The observed spatial distributions of the functional species in stratified biofilms were found to be crucial for successful SCONDA at the low dissolved oxygen of 1.3 mg/L. The integrated SCONDA system is expected to offer a promising alternative for advanced nitrogen and organic removal from high-ammonia organic wastewater. PMID- 29413940 TI - Effect of dissolved oxygen on nitrogen removal and the microbial community of the completely autotrophic nitrogen removal over nitrite process in a submerged aerated biological filter. AB - Dissolved oxygen (DO) is a crucial parameter of the completely autotrophic nitrogen removal over nitrite (CANON) process. This study determined the nitrogen removal performance and microbial community of the CANON process in a laboratory scale submerged aerated biological filter (SABF) over a DO concentration range from 0 to 1.2 mg.L-1. The results showed that the optimum DO (0.2-0.3 mg.L-1) corresponded to an average ammonium nitrogen removal efficiency of 93.4% and a total nitrogen removal efficiency of 81.0%. A 16S rRNA gene high-throughput sequencing technology confirmed that the phyla Proteobacteria and Nitrospirae enriched, whereas the phylum Planctomycetes was inhibited with increasing DO concentration. At the genus level, the increase of DO concentration resulted in the enrichment of genera Dok59 and Nitrospira, but restrained the genus Candidatus Brocadia. This research can be used to improve the nitrogen removal ability of the CANON process in an SABF in the future. PMID- 29413939 TI - Energy and greenhouse gas life cycle assessment and cost analysis of aerobic and anaerobic membrane bioreactor systems: Influence of scale, population density, climate, and methane recovery. AB - This study calculated the energy and greenhouse gas life cycle and cost profiles of transitional aerobic membrane bioreactors (AeMBR) and anaerobic membrane bioreactors (AnMBR). Membrane bioreactors (MBR) represent a promising technology for decentralized wastewater treatment and can produce recycled water to displace potable water. Energy recovery is possible with methane generated from AnMBRs. Scenarios for these technologies were investigated for different scale systems serving various population densities under a number of climate conditions with multiple methane recovery options. When incorporating the displacement of drinking water, AeMBRs started to realize net energy benefits at the 1 million gallons per day (MGD) scale and mesophilic AnMBRs at the 5 MGD scale. For all scales, the psychrophilic AnMBR resulted in net energy benefits. This study provides insights into key performance characteristics needed before an informed decision can be made for a community to transition towards the adoption of MBR technologies. PMID- 29413941 TI - Effect of diclofenac on the production of volatile fatty acids from anaerobic fermentation of waste activated sludge. AB - In this study, the impact of diclofenac (DCF), an antiinflammatory drug being extensively used in human health care and veterinary treatment, on the production of volatile fatty acids (VFAs) from anaerobic fermentation of waste activated sludge (WAS) was investigated for the first time. Experimental results showed that when DCF concentration increased from 2.5 to 25 mg/kg total suspended solid (TSS), the maximum production of VFAs increased from 599 to 1113 mg COD/L, but further increase of DCF to 47.5 mg/kg TSS decreased VFAs yield to 896 mg COD/L. The mechanism investigation revealed that DCF had no effect on the hydrolysis process, promoted the process of acidogenesis, acetogenesis, and homoacetogenesis, but severely inhibited methanogenesis, leading to the accumulation of VFAs. Microbial community analysis showed that the addition of DCF could promote the relative abundance of VFAs (especially acetic acid) producers, which was well consistent with the results obtained above. PMID- 29413942 TI - Production, process optimization and molecular characterization of polyhydroxyalkanoate (PHA) by CO2 sequestering B. cereus SS105. AB - Carbon dioxide sequestering bacterial strains were previously isolated from free air CO2 enriched (FACE) soil. In the present study, these strains were screened for PHA accumulation and Bacillus cereus SS105 was found to be the most prominent PHA accumulating strain on sodium bicarbonate and molasses as carbon source. This strain was further characterized by Spectrofluorometric method and Confocal microscopy after staining with Nile red. PHA granules in inclusion bodies were visualized by Transmission Electron Microscopy. The PHA and its monomer composition were characterized by GC-MS followed by FTIR and NMR. The genetic basis of PHA production was confirmed by the amplification, cloning and analysis of PHA biosynthesis genes phaR, phaB and phaC from B. cereus with the degenerate primers. The PHA production was further optimized by Response Surface Methodology and the percent increase observed after optimization was 55.16% (w/v). PMID- 29413943 TI - Enhancing methane production from U. lactuca using combined anaerobically digested sludge (ADS) and rumen fluid pre-treatment and the effect on the solubilization of microbial community structures. AB - Methane production by the anaerobic digestion of seaweed is restricted by the slow degradation caused by the influence of the rigid algal cell wall. At the present time, there has been no study focusing on the anaerobic digestion of U. lactuca by co-fermentation and pre-treatment with rumen fluid. Rumen fluid can favor methane production from algal biomass by utilizing the diversity and quantity of bacterial and archaeal communities in the rumen fluid. This research presents a novel method based on combined ADS and rumen fluid pre-treatment to improve the production of methane from seaweed. Biochemical methane potential (BMP) tests were performed to investigate the biogas production using combined ADS and rumen fluid pre-treatment at varied inoculum ratios on the performance of methane production from U. lactuca biomass. Compared to the control (no rumen fluid pre-treatment), the highest BMP yields of U. lactuca increased from 3%, 27.5% and 39.5% to 31.1%, 73% and 85.6%, respectively, for three different types of treatment. Microbial community analysis revealed that the Methanobrevibacter species, known to accept electrons to form methane, were only detected when rumen fluid was added. Together with the significant increase in species of Methanoculleus, Methanospirillum and Methanosaeta, rumen fluid improved the fermentation and degradation of the microalgae biomass not only by pre-treatment to foster cell-wall degradation but also by relying on methane production within itself during anaerobic processes. Batch experiments further indicated that rumen fluid applied to the co-fermentation and pre-treatment could increase the economic value and hold promise for enhancing biogas production from different seaweed species. PMID- 29413944 TI - Cholesterol-oxidase-magnetic nanobioconjugates for the production of 4-cholesten 3-one and 4-cholesten-3, 7-dione. AB - Cholesterol oxidase(ChOx) enzyme isolated from Pseudomonas aeruginosa PseA(ChOxP) and Rhodococcus erythropolis MTCC 3951(ChOxR) strains as well as a commercial variant produced by Streptomyces sp.(ChOxS) were immobilized on silane modified iron(II, III)oxide magnetic nanoparticles(MNP) by covalent coupling methods. The nanobiocatalysts in case of ChOxP, ChOxR and ChOxS, retained 71, 91 and 86% of cholesterol oxidase activity respectively, as compared to their soluble counterparts. The catalytic efficiency of the immobilized enzymes on nanoparticles was more than 2.0 times higher than the free enzyme. They also showed enhanced pH and thermal stability. After 10 cycles of operation, the MNP bioconjugates retained 50, 52 and 51% of residual activity in case of ChOxP, ChOxR and ChOxS respectively. The presence of enzyme on nanoparticles was confirmed by FTIR, SEM and TEM. The nanobiocatalysts were used for the biotransformation of cholesterol and 7-ketocholesterol to 4-cholesten-3-one and 4 cholesten-3, 7-dione respectively, which are industrially and medically important steroid precursors. PMID- 29413946 TI - Trichomonas vaginalis cathepsin D-like aspartic proteinase (Tv-CatD) is positively regulated by glucose and degrades human hemoglobin. AB - Trichomonas vaginalis genome encodes ~440 proteases, six of which are aspartic proteases (APs). However, only one belongs to a clan AA (EC 3.4.23.5), family A1 (pepsin A), cathepsin D-like protease. This AP is encoded by an 1113-bp gene (tv catd), which translates into a 370-aa residues zymogen of 40.7-kDa and a theoretical pI of 4.6, generating a ~35 kDa active enzyme after maturation (Tv CatD). The goal of this study was to identify and analyze the effect of glucose on the expression of Tv-CatD at the transcript and protein levels, subcellular localization, and proteolytic activity. The qRT-PCR assays showed a ~2-fold increase in tv-catd mRNA under high-glucose (HG) conditions compared to glucose restriction (GR) conditions. We amplified, cloned, and expressed the tv-catd gene, and purified the recombinant precursor enzyme (Tv-CatDr) to generate a polyclonal antibody (anti-Tv-CatDr). Western blot (WB) and immunolocalization assays showed that glucose increases the amount of Tv-CatD in different subcellular localizations and in in vitro secretions. Additionally, Tv-CatD proteolytic activity was detected in protease-resistant extracts (PREs) using a synthetic fluorogenic peptide specific for cathepsin D/E APs at different pHs and in the presence of AP inhibitors. In a two-dimensional (2-DE) WB analysis of a PRE from parasites grown under GR and HG conditions, an anti-Tv-CatDr antibody detected a 35-kDa protein spot at pI 5.0 identified as the mature Tv-CatD form by mass spectrometry that showed proteolytic activity in 2-DE zymograms copolymerized with hemoglobin under both glucose conditions. Thus, Tv-CatD could be involved in trichomonal hemolysis. PMID- 29413945 TI - Characterization of a dual fluidized bed gasifier with blended biomass/coal as feedstock. AB - A one-dimensional model is built based on the commercial Aspen Plus software to kinetically simulate the biomass/coal co-gasification process in a dual fluidized bed gasifier. The synergistic effect on the co-gasification kinetics is allowed for, and is coupled with the gas-solid flow hydrodynamics. With the developed model, the effects of different key operating parameters including the biomass blending ratio (Rb), the initial bed temperature (Tg), the feedstock mass flow rate (Ffs), the bed material flux (Fbm) and the steam to carbon ratio (Rsc) on the resultant syngas composition and the supplemental fuel mass flow rate (Fsf) are investigated, and the operation parameters are optimized. It is found that increasing Rb and Tg can enhance the gasification, while increasing Ffs and Rsc restricts the gasification. Increasing Fbm has slight effect on the gasification results but can reduce Fsf. The cold gas efficiency is up to 78.9% under the proposed optimum condition. PMID- 29413947 TI - STYK1 promotes cancer cell proliferation and malignant transformation by activating PI3K-AKT pathway in gallbladder carcinoma. AB - Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract with extremely poor prognosis. The malignant transformation of GBC is associated with cell proliferation, invasion, and epithelial-mesenchymal transition (EMT). However, the molecular mechanisms underlying GBC progression are poorly understood. We found that serine threonine tyrosine kinase 1 (STYK1) was elevated in GBC and was negatively correlated with clinical outcomes and prognosis. Overexpression of STYK1 in GBC cell lines gave rise to increased cell proliferation, colony formation, migration and invasion, thus committing cells to undergoing EMT. In contrast, silence of STYK1 led to opposite effects on cell transformation. Consistent with STYK1 gene knockdown, AKT specific inhibitor MK2206 abrogated tumor promoting action induced by STYK1, suggesting that PI3K/AKT pathway is essential for the oncogenic role of STYK1 in GBC. STYK1 shRNA in GBC cells inhibited development of xenografted tumors compared with control cells. Collectively, our findings suggest that STYK1 is a critical regulator of tumor growth and metastasis, and may serve as a potential target for GBC therapy. PMID- 29413948 TI - Understanding physical activity promotion in physiotherapy practice: A qualitative study. AB - OBJECTIVE: Physical inactivity is a major public health issue and healthcare professionals are encouraged to promote physical activity during routine patient contacts in order to reduce non-communicable diseases and enhance individuals' quality of life. Little is known about physical activity promotion in physiotherapy practice in the UK. The aim of this study was to better understand physiotherapists' experience of physical activity promotion in clinical practice. DESIGN: A qualitative study was undertaken comprising 12 telephone interviews with participants using a quota sampling approach. The qualitative data was analysed using a thematic analysis approach and written up according to COREQ guidelines. FINDINGS: Four themes were identified (1) Current physiotherapy practice (2) Barriers to, and facilitators of physical activity promotion, (3) Exercise or physical activity? and (4) Functional restoration versus general wellbeing. CONCLUSIONS: Physiotherapists use routine clinical contacts to discuss physical activity. However, brief interventions are not consistently used and no common framework to guide physical activity promotion was identified. Approaches appear to be inconsistent and informal and focus largely on short-term restoration of function rather than health promotion. There is scope to improve practice in line with current guidance to maximise potential impact on inactivity. PMID- 29413949 TI - The clinical reasoning process in randomized clinical trials with patients with non-specific neck pain is incomplete: A systematic review. AB - OBJECTIVE: Primarily to evaluate the completeness of the description of the clinical reasoning process in RCTs with patients with non-specific neck pain with an argued or diagnosed cause i.e. an impairment or activity limitation. Secondly, to determine the association between the completeness of the clinical reasoning process and the degree of risk of bias. DATA SOURCES: Pubmed, Cinahl and PEDro were systematically searched from inception to July 2016. STUDY SELECTION: RCTs (n = 122) with patients with non-specific neck pain receiving physiotherapy treatment published in English were included. DATA EXTRACTION: Data extraction included study characteristics and important features of the clinical reasoning process based on the Hypothesis-Oriented Algorithm for Clinicians II (HOAC II)]. DATA SYNTHESIS: Thirty-seven studies (30%) had a complete clinical reasoning process of which 8 (6%) had a 'diagnosed cause' and 29 (24%) had an 'argued cause'. The Spearmans rho association between the extent of the clinical reasoning process and the risk of bias was -0.2. CONCLUSIONS: In the majority of studies (70%) the described clinical reasoning process was incomplete. A very small proportion (6%) had a 'diagnosed cause'. Therefore, a better methodological quality does not necessarily imply a better described clinical reasoning process. PMID- 29413950 TI - Detection of prostate specific antigen and semenogelin in specimens from female rape victims. AB - The presence of semen is generally accepted as evidence in sexual assault cases prosecution. Detection of sperm is confirmation of semen; however, sperm cannot always be detected. Prostate specific antigen (PSA) and semenogelin (Sg) are used as semen biomarkers. We compared the detection rate and persistence of sperm, PSA and Sg over a range of time intervals from the time of assault to specimen collection. The results show that sperm had the longest persistence and highest detection rate. The detection rate of the Sg test was significantly better than that of the PSA test overall, whether the sperm test was negative or positive. In conclusion, the detection of sperm should be the first test executed: if sperm is not detected, the Sg test is more suitable than the PSA test and could be used up to 72 h after assault. PMID- 29413951 TI - A comparison of malpractice lawsuits mediated and judged in court in China. AB - OBJECTIVE: An analysis of malpractice lawsuits judged in court compared with those mediated in court may help explain perceptions of malpractice risk. METHODS: We conducted a retrospective study of malpractice lawsuits mediated and judged in court using data from district courts in Beijing from 2010 through 2014. We evaluated the number of cases, the payment amount, and the time to resolution, by resolution type. Patient age, sex, the severity of injury, and adverse event type were measured. Subsequently, a binary logistic regression identified factors associated with patients' pursuit of judgment. RESULTS: Between 2010 and 2014, there were 1226 lawsuits (49.9%) mediated in court and 1259 (50.1%) judged in court. The proportion of the judged lawsuits varied significantly across the study period (p < 0.001). The mean payment amount and the time to resolution were significantly higher in judgment lawsuits (p < 0.001). The younger the patients, the greater the possibility of being judged in court (odds ratio [OR] = 0.831, p < 0.0001). Lawsuits where the adverse event type was treatment, obstetrics, or diagnostics were more likely to be judged than those where the adverse event type was surgical (OR = 2.311, p < 0.0001; OR = 2.311, p < 0.0001; OR = 3.302, p < 0.0001, respectively). When lawsuits were for a temporary injury, they were more likely to be judged in court than those for a permanent injury (OR = 0.723, p = 0.0139).results CONCLUSIONS: The patient physician relationship may in fact not be particularly close in our country. Lawsuits with certain characteristics tend to be judged in court. Understanding these characteristics may be useful for predicting the outcome of lawsuits against physicians. CONCLUSIONS: PMID- 29413952 TI - Optimising the measurement of bruises in children across conventional and cross polarized images using segmentation analysis techniques in Image J, Photoshop and circle diameter measurements. AB - BACKGROUND: Bruising is a common abusive injury in children, and it is standard practice to image and measure them, yet there is no current standard for measuring bruise size consistently. We aim to identify the optimal method of measuring photographic images of bruises, including computerised measurement techniques. METHODS: 24 children aged <11 years (mean age of 6.9, range 2.5-10 years) with a bruise were recruited from the community. Demographics and bruise details were recorded. Each bruise was measured in vivo using a paper measuring tape. Standardised conventional and cross polarized digital images were obtained. The diameter of bruise images were measured by three computer aided measurement techniques: Image J (segmentation with Simple Interactive Object Extraction (maximum Feret diameter), 'Circular Selection Tool' (Circle diameter), & the Photoshop 'ruler' software (Photoshop diameter)). Inter and intra-observer effects were determined by two individuals repeating 11 electronic measurements, and relevant Intraclass Correlation Coefficient's (ICC's) were used to establish reliability. Spearman's rank correlation was used to compare in vivo with computerised measurements; a comparison of measurement techniques across imaging modalities was conducted using Kolmogorov-Smirnov tests. Significance was set at p < 0.05 for all tests. RESULTS: Images were available for 38 bruises in vivo, with 48 bruises visible on cross polarized imaging and 46 on conventional imaging (some bruises interpreted as being single in vivo appeared to be multiple in digital images). Correlation coefficients were >0.5 for all techniques, with maximum Feret diameter and maximum Photoshop diameter on conventional images having the strongest correlation with in vivo measurements. There were significant differences between in vivo and computer-aided measurements, but none between different computer-aided measurement techniques. Overall, computer aided measurements appeared larger than in vivo. Inter- and intra-observer agreement was high for all maximum diameter measurements (ICC's > 0.7). CONCLUSIONS: Whilst there are minimal differences between measurements of images obtained, the most consistent results were obtained when conventional images, segmented by Image J Software, were measured with a Feret diameter. This is therefore proposed as a standard for future research, and forensic practice, with the proviso that all computer aided measurements appear larger than in vivo. PMID- 29413953 TI - Epidemiological aspects of child abuse and neglect in Sousse, Tunisia: A 10-year retrospective study. AB - The aim of our study was to examine epidemiological aspects of child abuse and neglect in Tunisia. We conducted a retrospective and descriptive study over a period of 10 years (January 2006-December 2015), based on the files handled by the Child Protective Services (CPS) agency in the city of Sousse, Tunisia. During the study period, 3736 referrals were received by the CPS agency of Sousse. Of the total, 2212 (59.2%) were screened in and investigated. Of the investigated cases, 317 (14,3%) were substantiated as abuse or neglect. The reports of maltreatment came mostly from parents (37.8%). Neglect was the major type of maltreatment (51.4%) and an association of 2 types of maltreatment was found in 76 cases (24%). Parents were the perpetrators in 221 cases (69.7%). The average age of the victims was 10 years and boys accounted for 56%. In the 257 cases where the marital status of the parents was noted in the files, the parents were divorced in 62 cases (24.1%) and the child lived with a single mother in 35 cases (13.6%). Alcohol addiction was found in 21 parents (6.6%) and one of the parents was incarcerated in 39 cases (12.3%). As for the socio-economic status, it was evaluated in 188 families and was low in 123 cases (65.4%). In the absence of studies related to this scourge in Tunisia, we hope to raise awareness of the abuse and alert those who come into contact with the child on the importance of detecting and reporting early maltreatment and thus to introduce more appropriate care. A comprehensive prevention strategy needs to be established by addressing risk factors, cultural norms conducive to abuse and unwanted pregnancies. PMID- 29413954 TI - Thoracic aortic dissection. Death may not always be due to rupture with haemorrhage. Unusual complications which can be missed at autopsy. AB - OBJECTIVES: Aortic dissection (AD) can be a challenging diagnosis. At autopsy, the aorta may not be dilated and intimal tears may be missed or found without obvious rupture or haemorrhage. We report our experience of AD at a tertiary referral centre with review of 32 cases and discuss 2 unusual complications. METHODS/RESULTS: 32 cases of which 12 females and 20 male and 18 out of 32 cases were aged below 40. All of the cases were examined macroscopically and microscopically. 30 out of 32 cases (93%) died due to rupture associated with the AD. Two unusual complications were proximal extension of AD into left coronary artery (CA) with intramural haematoma blocking the vessel and AD involving the ostium of the right CA resulting in avulsion of the right CA from the aorta. Mode of death in both these cases were myocardial ischemia. Sections of the aorta in all cases confirmed extensive cystic medial degeneration with disorganisation, fragmentation and disappearance of the elastin fibres with increased collagen and smooth muscle nuclear degeneration. CONCLUSION: Pathologists should be thorough when examining the aorta, the aortic valve and root in AD. When a rupture site cannot be found it is important to look for unusual complications involving the CAs. Histology plays an important role to corroborate the cause of death. PMID- 29413955 TI - Speeding up enzyme discovery and engineering with ultrahigh-throughput methods. AB - Exploring the sequence space of enzyme catalysts is ultimately a numbers game. Ultrahigh-throughput screening methods for rapid analysis of millions of variants are therefore increasingly important for investigating sequence-function relationships, searching large metagenomic libraries for interesting activities, and accelerating enzyme evolution in the laboratory. Recent applications of such technologies are reviewed here, with a particular focus on the practical benefits of droplet-based microfluidics for the directed evolution of natural and artificial enzymes. Broader implementation of such rapid, cost-effective screening technologies is likely to redefine the way enzymes are studied and engineered for academic and industrial purposes. PMID- 29413956 TI - Structural heterogeneity and dynamics in protein evolution and design. AB - Recent years have witnessed substantial progress in our ability to design proteins with specific structures and to introduce new functionalities into existing protein scaffolds. Such protein design efforts test our understanding of the biophysical and functional mechanisms of naturally evolved proteins. At the same time, we also know that proteins are dynamical entities, and that many proteins rely on detailed dynamical mechanisms for regulation and function. Thus, the success of design methods, especially in relation to functional proteins, might benefit from explicit considerations of conformational heterogeneity and dynamics. In this review, we compare results from the field of protein design with laboratory protein evolution with a focus on dynamics. Recent studies show that structural dynamics is altered during evolutionary trajectories, and that allosteric effects are pronounced. Interaction networks and the resulting coupling of structure and dynamics are suggested to facilitate these effects. PMID- 29413957 TI - 2-Chlorohexadecanoic acid induces ER stress and mitochondrial dysfunction in brain microvascular endothelial cells. AB - Peripheral leukocytes induce blood-brain barrier (BBB) dysfunction through the release of cytotoxic mediators. These include hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H2O2-chloride system of activated phagocytes. HOCl targets the endogenous pool of ether phospholipids (plasmalogens) generating chlorinated inflammatory mediators like e.g. 2-chlorohexadecanal and its conversion product 2-chlorohexadecanoic acid (2-ClHA). In the cerebrovasculature these compounds inflict damage to brain microvascular endothelial cells (BMVEC) that form the morphological basis of the BBB. To follow subcellular trafficking of 2-ClHA we synthesized a 'clickable' alkyne derivative (2-ClHyA) that phenocopied the biological activity of the parent compound. Confocal and superresolution structured illumination microscopy revealed accumulation of 2 ClHyA in the endoplasmic reticulum (ER) and mitochondria of human BMVEC (hCMEC/D3 cell line). 2-ClHA and its alkyne analogue interfered with protein palmitoylation, induced ER-stress markers, reduced the ER ATP content, and activated transcription and secretion of interleukin (IL)-6 as well as IL-8. 2 ClHA disrupted the mitochondrial membrane potential and induced procaspase-3 and PARP cleavage. The protein kinase R-like ER kinase (PERK) inhibitor GSK2606414 suppressed 2-ClHA-mediated activating transcription factor 4 synthesis and IL-6/8 secretion, but showed no effect on endothelial barrier dysfunction and cleavage of procaspase-3. Our data indicate that 2-ClHA induces potent lipotoxic responses in brain endothelial cells and could have implications in inflammation-induced BBB dysfunction. PMID- 29413958 TI - Multifaceted remodeling by vitamin C boosts sensitivity of Mycobacterium tuberculosis subpopulations to combination treatment by anti-tubercular drugs. AB - Bacterial dormancy is a major impediment to the eradication of tuberculosis (TB), because currently used drugs primarily target actively replicating bacteria. Therefore, decoding of the critical survival pathways in dormant tubercle bacilli is a research priority to formulate new approaches for killing these bacteria. Employing a network-based gene expression analysis approach, we demonstrate that redox active vitamin C (vit C) triggers a multifaceted and robust adaptation response in Mycobacterium tuberculosis (Mtb) involving ~ 67% of the genome. Vit C adapted bacteria display well-described features of dormancy, including growth stasis and progression to a viable but non-culturable (VBNC) state, loss of acid fastness and reduction in length, dissipation of reductive stress through triglyceride (TAG) accumulation, protective response to oxidative stress, and tolerance to first line TB drugs. VBNC bacteria are reactivatable upon removal of vit C and they recover drug susceptibility properties. Vit C synergizes with pyrazinamide, a unique TB drug with sterilizing activity, to kill dormant and replicating bacteria, negating any tolerance to rifampicin and isoniazid in combination treatment in both in-vitro and intracellular infection models. Finally, the vit C multi-stress redox models described here also offer a unique opportunity for concurrent screening of compounds/combinations active against heterogeneous subpopulations of Mtb. These findings suggest a novel strategy of vit C adjunctive therapy by modulating bacterial physiology for enhanced efficacy of combination chemotherapy with existing drugs, and also possible synergies to guide new therapeutic combinations towards accelerating TB treatment. PMID- 29413960 TI - Total sulfane sulfur bioavailability reflects ethnic and gender disparities in cardiovascular disease. AB - Hydrogen sulfide (H2S) has emerged as an important physiological and pathophysiological signaling molecule in the cardiovascular system influencing vascular tone, cytoprotective responses, redox reactions, vascular adaptation, and mitochondrial respiration. However, bioavailable levels of H2S in its various biochemical metabolite forms during clinical cardiovascular disease remain poorly understood. We performed a case-controlled study to quantify and compare the bioavailability of various biochemical forms of H2S in patients with and without cardiovascular disease (CVD). In our study, we used the reverse-phase high performance liquid chromatography monobromobimane assay to analytically measure bioavailable pools of H2S. Single nucleotide polymorphisms (SNPs) were also identified using DNA Pyrosequencing. We found that plasma acid labile sulfide levels were significantly reduced in Caucasian females with CVD compared with those without the disease. Conversely, plasma bound sulfane sulfur levels were significantly reduced in Caucasian males with CVD compared with those without the disease. Surprisingly, gender differences of H2S bioavailability were not observed in African Americans, although H2S bioavailability was significantly lower overall in this ethnic group compared to Caucasians. We also performed SNP analysis of H2S synthesizing enzymes and found a significant increase in cystathionine gamma-lyase (CTH) 1364 G-T allele frequency in patients with CVD compared to controls. Lastly, plasma H2S bioavailability was found to be predictive for cardiovascular disease in Caucasian subjects as determined by receiver operator characteristic analysis. These findings reveal that plasma H2S bioavailability could be considered a biomarker for CVD in an ethnic and gender manner. Cystathionine gamma-lyase 1346 G-T SNP might also contribute to the risk of cardiovascular disease development. PMID- 29413959 TI - Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches. AB - Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory". However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first "Achilles' heel" of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC. PMID- 29413962 TI - Homocysteine causes dysfunction of chondrocytes and oxidative stress through repression of SIRT1/AMPK pathway: A possible link between hyperhomocysteinemia and osteoarthritis. AB - Emerging evidence has indicated that the perturbed expression of homocysteine (Hcy) may induce mitochondrial dysfunction and disturb bone metabolism. Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) are two critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in osteoarthritis (OA). This study was designed to test whether Hcy caused pro osteoarthritic changes through modulation of SIRT1 and AMPK. Our results showed that administration of Hcy reduced the SIRT1/AMPK/PGC-1alpha signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress and apoptosis. Moreover, we demonstrated that the expression of NF-kappaB, COX-2, IL-8, and MMP-13 were elevated subsequent to inhibition of SIRT1/AMPK/PGC-1alpha/PPAR-gamma pathway by homocysteine, thereby causing detrimental effects on chondrocytes. In the animal model of diet-induced hyperhomocysteinemia (HHcy), we observed the similar findings that SIRT1/PGC 1alpha/PPAR-gamma cascades were downregulated with elevated MMP-13 and COX-2. Taken together, data from the current study revealed that the reduced SIRT1 by Hcy may contribute to degradative cartilage process, which provided insight into the etiology of OA. PMID- 29413963 TI - Renal protective effect of polysulfide in cisplatin-induced nephrotoxicity. AB - Cisplatin is a major chemotherapeutic drug for solid tumors whereas it may lead to severe nephrotoxicity. Despite decades of efforts, effective therapies remain largely lacking for this disease. In the current research, we investigated the therapeutic effect of hydrogen polysulfide, a novel hydrogen sulfide (H2S) derived signaling molecule, in cisplatin nephrotoxicity and the mechanisms involved. Our results showed that polysulfide donor Na2S4 ameliorated cisplatin caused renal toxicity in vitro and in vivo through suppressing intracellular reactive oxygen species (ROS) generation and downstream mitogen-activated protein kinases (MAPKs) activation. Additionally, polysulfide may inhibit ROS production by simultaneously lessening the activation of NADPH oxidase and inducing nucleus translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in RPT cells. Interestingly, polysulfide possesses anti-cancer activity and is able to add on more anti-cancer effect to cisplatin in non-small cell lung cancer (NSCLC) cell lines. Moreover, we observed that the number of sulfur atoms in polysulfide well reflected the efficacy of these molecules not only in cell protection but also cancer inhibition which may serve as a guide for further development of polysulfide donors for pharmaceutical usage. Taken together, our study suggests that polysulfide may be a novel and promising therapeutic agent to prevent cisplatin-induced nephrotoxicity. PMID- 29413961 TI - 13 reasons why the brain is susceptible to oxidative stress. AB - The human brain consumes 20% of the total basal oxygen (O2) budget to support ATP intensive neuronal activity. Without sufficient O2 to support ATP demands, neuronal activity fails, such that, even transient ischemia is neurodegenerative. While the essentiality of O2 to brain function is clear, how oxidative stress causes neurodegeneration is ambiguous. Ambiguity exists because many of the reasons why the brain is susceptible to oxidative stress remain obscure. Many are erroneously understood as the deleterious result of adventitious O2 derived free radical and non-radical species generation. To understand how many reasons underpin oxidative stress, one must first re-cast free radical and non-radical species in a positive light because their deliberate generation enables the brain to achieve critical functions (e.g. synaptic plasticity) through redox signalling (i.e. positive functionality). Using free radicals and non-radical derivatives to signal sensitises the brain to oxidative stress when redox signalling goes awry (i.e. negative functionality). To advance mechanistic understanding, we rationalise 13 reasons why the brain is susceptible to oxidative stress. Key reasons include inter alia unsaturated lipid enrichment, mitochondria, calcium, glutamate, modest antioxidant defence, redox active transition metals and neurotransmitter auto-oxidation. We review RNA oxidation as an underappreciated cause of oxidative stress. The complex interplay between each reason dictates neuronal susceptibility to oxidative stress in a dynamic context and neural identity dependent manner. Our discourse sets the stage for investigators to interrogate the biochemical basis of oxidative stress in the brain in health and disease. PMID- 29413964 TI - In situ generation, metabolism and immunomodulatory signaling actions of nitro conjugated linoleic acid in a murine model of inflammation. AB - Conjugated linoleic acid (CLA) is a prime substrate for intra-gastric nitration giving rise to the formation of nitro-conjugated linoleic acid (NO2-CLA). Herein, NO2-CLA generation is demonstrated within the context of acute inflammatory responses both in vitro and in vivo. Macrophage activation resulted in dose- and time-dependent CLA nitration and also in the production of secondary electrophilic and non-electrophilic derivatives. Both exogenous NO2-CLA as well as that generated in situ, attenuated NF-kappaB-dependent gene expression, decreased pro-inflammatory cytokine production and up-regulated Nrf2-regulated proteins. Importantly, both CLA nitration and the corresponding downstream anti inflammatory actions of NO2-CLA were recapitulated in a mouse peritonitis model where NO2-CLA administration decreased pro-inflammatory cytokines and inhibited leukocyte recruitment. Taken together, our results demonstrate that the formation of NO2-CLA has the potential to function as an adaptive response capable of not only modulating inflammation amplitude but also protecting neighboring tissues via the expression of Nrf2-dependent genes. PMID- 29413966 TI - Lipophilic ester and amide derivatives of rosmarinic acid protect cells against H2O2-induced DNA damage and apoptosis: The potential role of intracellular accumulation and labile iron chelation. AB - Phenolic acids represent abundant components contained in human diet. However, the negative charge in their carboxylic group limits their capacity to diffuse through biological membranes, thus hindering their access to cell interior. In order to promote the diffusion of rosmarinic acid through biological membranes, we synthesized several lipophilic ester- and amide-derivatives of this compound and evaluated their capacity to prevent H2O2-induced DNA damage and apoptosis in cultured human cells. Esterification of the carboxylic moiety with lipophilic groups strongly enhanced the capacity of rosmarinic acid to protect cells. On the other hand, the amide-derivatives were somewhat less effective but exerted less cytotoxicity at high concentrations. Cell uptake experiments, using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC MS/MS), illustrated different levels of intracellular accumulation among the ester- and amide-derivatives, with the first being more effectively accumulated, probably due to their extensive hydrolysis inside the cells. In conclusion, these results highlight the hitherto unrecognized fundamental importance of derivatization of diet-derived phenolic acids to unveil their biological potential. PMID- 29413965 TI - A glutaredoxin in the mitochondrial intermembrane space has stage-specific functions in the thermo-tolerance and proliferation of African trypanosomes. AB - Trypanosoma brucei glutaredoxin 2 (Grx2) is a dithiol glutaredoxin that is specifically located in the mitochondrial intermembrane space. Bloodstream form parasites lacking Grx2 or both, Grx2 and the cytosolic Grx1, are viable in vitro and infectious to mice suggesting that neither oxidoreductase is needed for survival or infectivity to mammals. A 37 degrees C to 39 degrees C shift changes the cellular redox milieu of bloodstream cells to more oxidizing conditions and induces a significantly stronger growth arrest in wildtype parasites compared to the mutant cells. Grx2-deficient cells ectopically expressing the wildtype form of Grx2 with its C31QFC34 active site, but not the C34S mutant, regain the sensitivity of the parental strain, indicating that the physiological role of Grx2 requires both active site cysteines. In the procyclic insect stage of the parasite, Grx2 is essential. Both alleles can be replaced if procyclic cells ectopically express authentic or C34S, but not C31S/C34S Grx2, pointing to a redox role that relies on a monothiol mechanism. RNA-interference against Grx2 causes a virtually irreversible proliferation defect. The cells adopt an elongated morphology but do not show any significant alteration in the cell cycle. The growth retardation is attenuated by high glucose concentrations. Under these conditions, procyclic cells obtain ATP by substrate level phosphorylation suggesting that Grx2 might regulate a respiratory chain component. PMID- 29413967 TI - Fatty acid profile in peri-prostatic adipose tissue and prostate cancer aggressiveness in African-Caribbean and Caucasian patients. AB - BACKGROUND: Genetic and nutritional factors have been linked to the risk of aggressive prostate cancer (PCa). The fatty acid (FA) composition of peri prostatic adipose tissue (PPAT), which reflects the past FA intake, is potentially involved in PCa progression. We analysed the FA composition of PPAT, in correlation with the ethno-geographical origin of the patients and markers of tumour aggressiveness. METHODS: From a cohort of 1000 men treated for PCa by radical prostatectomy, FA composition of PPAT was analysed in 156 patients (106 Caucasians and 50 African-Caribbeans), 78 with an indolent tumour (ISUP group 1 + pT2 + PSA <10 ng/mL) and 78 with an aggressive tumour (ISUP group 4-5 + pT3). The effect of FA extracted from PPAT on in-vitro migration of PCa cells DU145 was studied in 72 patients, 36 Caucasians, and 36 African-Caribbeans. RESULTS: FA composition differed according to the ethno-geographical origin. Linoleic acid, an essential n-6 FA, was 2-fold higher in African-Caribbeans compared with Caucasian patients, regardless of disease aggressiveness. In African-Caribbeans, the FA profile associated with PCa aggressiveness was characterised by low level of linoleic acid along with high levels of saturates. In Caucasians, a weak and negative association was observed between eicosapentaenoic acid level (an n-3 FA) and disease aggressiveness. In-vitro migration of PCa cells using PPAT from African-Caribbean patients was associated with lower content of linoleic acid. CONCLUSION: These results highlight an important ethno-geographical variation of PPAT, in both their FA content and association with tumour aggressiveness. PMID- 29413968 TI - Current perspective: Osimertinib-induced QT prolongation: new drugs with new side effects need careful patient monitoring. AB - An increasing number of tyrosine kinase inhibitors (TKIs) are available for the treatment of non-small cell lung cancer (NSCLC). QT prolongation is one of the known, but relatively rare, adverse events of several TKIs (e.g. osimertinib, crizotinib, ceritinib). Screening for QT prolongation in (high risk) patients is advised for these TKIs. When a QT prolongation develops, the physician is challenged with the question whether to (permanently) discontinue the TKI. In this perspective, we report on a patient who developed a grade III QT prolongation during osimertinib (a third-generation epidermal growth factor receptor [EGFR]-TKI) treatment. On discontinuation of osimertinib, she developed a symptomatic disease flare, not responding to subsequent systemic treatment. The main aim of this perspective is to describe the management of QT prolongation in stage IV EGFR driver mutation NSCLC patients. We also discuss the ethical question of how to weigh the risk of a disease flare due to therapy cessation against the risk of sudden cardiac death. A family history of sudden death and a prolonged QT interval might indicate a familiar long QT syndrome. We have summarised the current monitoring advice for TKIs used in the treatment of lung cancer and the most common drug-TKI interactions to consider and to optimise TKI treatment in lung cancer patients. PMID- 29413969 TI - Tracking the origin, development, and differentiation of hematopoietic stem cells. AB - PURPOSE OF REVIEW: The hierarchical nature of the hematopoietic system provides an ideal model system to illustrate the features of lineage tracing. We have outlined the utility of lineage tracing methods in establishing the origin and development of hematopoietic cells. RECENT FINDINGS: Methods such as CRISPR/Cas9, Polylox barcoding, and single-cell RNA-sequencing have improved our understanding of hematopoiesis. SUMMARY: This review chronicles the fate of the hematopoietic cells emerging from the mesoderm that subsequently develops into the adult blood lineages. Specifically, we explain classic techniques utilized in lineage tracing for the hematopoietic system, as well as novel state-of-the-art methods to elucidate clonal hematopoiesis and cell fate mapping at a single-cell level. PMID- 29413971 TI - "Gear mechanism" of bariatric interventions revealed by untargeted metabolomics. AB - Mechanisms responsible for metabolic gains after bariatric surgery are not entirely clear. The purpose of this study was evaluation of metabolic changes after laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy in semi-annual follow up. The study participants were selected from obese patients with T2DM who underwent one of the mentioned bariatric procedures. Serum metabolic fingerprinting by use of liquid and gas chromatography with mass spectrometry detection was performed on samples obtained from studied patients before, one, and six months post-surgery. Performed analyses resulted in 49 significant and identified metabolites. Comparison of the two described procedures has allowed to detect metabolites linked with numerous pathways, processes and diseases. Based on the metabolites detected and pathways affected, we propose a "gear mechanism" showing molecular changes evoked by both bariatric procedures. Critical evaluation of clinical data and obtained metabolomics results enables us to conclude that both procedures are very similar in terms of general clinical outcome, but they strongly differ from each other in molecular mechanisms leading to the final effect. For the first time general metabolic effect of bariatric procedures is described. New hypotheses concerning molecular mechanisms induced by bariatric surgeries and new gut microbiota modulations are presented. PMID- 29413970 TI - The epigenetic basis of cellular plasticity. AB - Cellular plasticity is now recognized as a fundamental feature of tissue biology. The steady-state differentiation of stem and progenitor cells into mature cells is, in itself, the index form of cellular plasticity in adult organisms. Following injury, when it is critical to quickly regenerate and restore tissue integrity and function, other types of cellular plasticity may be crucial for organismal survival. In these contexts, alterations in the epigenetic landscape of tissues are likely to occur in order to allow normally restricted cell fate transitions. Epigenetic mechanisms, particularly DNA methylation and histone modifications, have been shown to play an important role in regulating such plasticity. Relevant mechanisms have been well studied in the context of the direct reprograming of somatic cells into induced pluripotent stem cells. Indeed, epigenetic regulation of cell fate is part and parcel of normal embryonic development and is a central regulator of cellular diversity. This is normally thought to involve the establishment of divergent chromatin patterns that culminate in cells with distinct and what were previously thought to be irreversible fates. This brief review aims to put some of these new observations in the larger context of regeneration after injury. PMID- 29413973 TI - Novel bio analytical method development, validation and application for simultaneous determination of nebivolol and S-amlodipine in human plasma using ultra performance liquid chromatography-tandem mass spectrometry. AB - A sensitive and specific ultra-performance liquid chromatography tandem mass spectrometric (UPLC-MS/MS) method has been developed, validated and applied for the assay of Nebivolol and S-amlodipine in human plasma. Sample extraction was carried out through hybrid extraction method from 250 MUL of human plasma sample. Linearity of the method was (r >= 0.9996) was found to be dynamic for both the analytes over concentration range of 25.0-4000 pg/mL. Chromatographic separation was achieved on UPLC column {Waters Acquity UPLC BEH C18 (50 mm * 2.1 mm, 1.7 micrometer)} with the mobile phase composition of 0.1% (v/v) formic acid in 5 mM Ammonium formate in water-acetonitrile (20:80, %v/v). Analytes Stability was assured under different requisite conditions in human plasma, reconstitution solution and diluents. Inter and intra-day assay precision and relative error (accuracy) were within +/-5% for both analytes. The method was applied and reproduced to support a pharmacokinetic study of 5 mg Nebivolol (NEB) and 2.5 mg S-amlodipine (LAM) tablet on 9 healthy subjects. PMID- 29413972 TI - Anhydrates and hemihydrate of tasimelteon: Synthesis, structure, and pharmacokinetic study. AB - Two new crystal forms of tasimelteon TSM-I and TSM-II were reported here. Crystallization of crude in methanol or mixture solvent results in anhydrate crystal form (TSM-I) and hemihydrate crystal form (TSM-II) respectively. To the best of our knowledge, it is the first report about crystalline form of tasimelteon. The two crystal forms were exhaustively characterized by Scanning Electron Microscopy, Fourier Transform Infrared Spectroscopy, Raman Spectra, Differential Scanning Calorimetry, Thermogravimetric Analysis, Solid State NMR Spectroscopy and Powder X-ray diffraction and Single Crystal X-ray Diffraction. Furthermore, the pharmacokinetic behavior of TSM-I and TSM-II in rats were measured. We found that though TSM-II is considerably more soluble than TSM-I under water (pH = 7.0) and pH 1.2 buffer conditions, the bioavailability of TSM Ivia oral administration was better compared to that of TSM-II. PMID- 29413974 TI - Air assisted dispersive liquid-liquid microextraction with solidification of the floating organic droplets (AA-DLLME-SFO) and UHPLC-PDA method: Application to antibiotics analysis in human plasma of hospital acquired pneumonia patients. AB - An ultra high-performance liquid chromatographic (UHPLC) method with PDA detection was developed and validated for the simultaneous quantification of metronidazole, meropenem, ciprofloxacin, linezolid and piperacillin in human plasma and applied to patients suffering from hospital acquired pneumonia (HAP). The method uses an air assisted dispersive liquid-liquid microextraction for sample preparation. All parameters in the extraction step, including selection of extractant, amount of extractant, ionic strength, pH, and extraction cycles, were investigated and optimized. Chromatography was carried out using a Poroshell 120 SB C18 (50 * 2.1 mm I.D. 2.6 MUm particle size) column and a gradient mobile phase consisting of ammonium acetate buffer (10 mM, pH 4.0) (eluent A); and a mixture of acetonitrile-methanol in a ratio (80/20)(eluent B). Ulifloxacin was used as internal standard. The method demonstrated good linearity with correlation coefficients, r2 > 0.9995 for the drugs, as well as high precision (RSD% <= 9.87%), accuracy ranged from -8.14% to +8.98. The enrichment factor (EF) obtained ranged within 87 and 121. During the validation, the concentrations of the analytes were found to be stable after 3 freeze-thaw cycles and for at least 24 h after extraction. Subsequently, this method was used to quantify the drugs in patients with HAP in order to establish if the dosage regimen given was sufficient to eradicate the infection at the target site. PMID- 29413975 TI - Development and validation of an in-line NIR spectroscopic method for continuous blend potency determination in the feed frame of a tablet press. AB - A calibration model for in-line API quantification based on near infrared (NIR) spectra collection during tableting in the tablet press feed frame was developed and validated. First, the measurement set-up was optimised and the effect of filling degree of the feed frame on the NIR spectra was investigated. Secondly, a predictive API quantification model was developed and validated by calculating the accuracy profile based on the analysis results of validation experiments. Furthermore, based on the data of the accuracy profile, the measurement uncertainty was determined. Finally, the robustness of the API quantification model was evaluated. An NIR probe (SentroPAT FO) was implemented into the feed frame of a rotary tablet press (ModulTM P) to monitor physical mixtures of a model API (sodium saccharine) and excipients with two different API target concentrations: 5 and 20% (w/w). Cutting notches into the paddle wheel fingers did avoid disturbances of the NIR signal caused by the rotating paddle wheel fingers and hence allowed better and more complete feed frame monitoring. The effect of the design of the notched paddle wheel fingers was also investigated and elucidated that straight paddle wheel fingers did cause less variation in NIR signal compared to curved paddle wheel fingers. The filling degree of the feed frame was reflected in the raw NIR spectra. Several different calibration models for the prediction of the API content were developed, based on the use of single spectra or averaged spectra, and using partial least squares (PLS) regression or ratio models. These predictive models were then evaluated and validated by processing physical mixtures with different API concentrations not used in the calibration models (validation set). The beta-expectation tolerance intervals were calculated for each model and for each of the validated API concentration levels (beta was set at 95%). PLS models showed the best predictive performance. For each examined saccharine concentration range (i.e., between 4.5 and 6.5% and between 15 and 25%), at least 95% of future measurements will not deviate more than 15% from the true value. PMID- 29413976 TI - Development of a selective and sensitive LC-MS/MS method for the quantification of alpha-asarone in mouse plasma and its application to pharmacokinetic studies. AB - A simple, sensitive and selective liquid chromatography-tandem mass spectrometric method was developed and validated for the quantification of alpha-asarone in mouse plasma with its application to pharmacokinetic studies. An electrospray ionization (ESI) with multiple reaction monitoring (MRM) mode was used to monitor the precursor-product ion transitions of 209.1 > 193.9 m/z for alpha-asarone and 157.8 > 114.0 m/z for allantoin. Chromatographic separation was acquired on a Sepax BR-C18 (5 MUm, 120 A 1.0 * 100 mm) column with an isocratic mobile phase consisting of methanol and 0.1% formic acid (80:20, v/v). The developed bioanalytical method was successfully validated according to the United States Food and Drug Administration (US FDA) guidelines for linearity, selectivity, accuracy, precision, recovery, matrix effect, and stability. The validated method was successfully applied to a pharmacokinetics study of alpha-asarone along with a combination of pharmacokinetic techniques, including small-volume serial blood sampling in mice, reducing drug doses and the number of animals used, using a simple protein precipitation method and less solvent consumption will enable its use in further bioequivalence studies. PMID- 29413977 TI - A validated UHPLC method for the determination of caffeoylquinic and di caffeoylquinic acids in green coffee extracts using an RP-Amide fused-core column. AB - The presented work describes the development and validation of a rapid UHPLC-UV method using a fused core particle column with an RP-Amide stationary phase for the separation and quantitative analysis of caffeoylquinic and di-caffeoylquinic acids in green coffee extracts. Three caffeoylquinic acids (3-caffeoylquinic acid, 4-caffeoylquinic acid, and 5-caffeoylquinic acid) and two di-caffeoylquinic acids (1,3-di-caffeoylquinic acid, and 3,5-di-caffeoylquinic acid) were separated and analyzed in 8 min. That was possible due to the unique selectivity of the RP Amide stationary phase for the analyzed acids. The retention behavior of all analytes under different compositions of the mobile phase on different columns was evaluated in this study. The optimal chromatographic separation was performed using an Ascentis Express RP-Amide (100 * 2.1 mm) fused-core column with a particle size of 2.7 MUm at a temperature of 30 degrees C. For validation of the newly developed method, acetonitrile was used as mobile phase B and 5% formic acid, filtrated through a 0.22 MUm filter, was used as mobile phase A. They were delivered at a flow rate of 0.9 mL min-1 according to the elution gradient program. The detection wavelength was set at 325 nm. A solid-liquid extraction with a solution of methanol and a 5% water solution of formic acid (25 + 75 v/v) using an ultrasonic bath was chosen for the preparation of the available commercial samples of food supplements containing a green coffee extract. Recoveries for all analyzed acids were 98.2-101.0% and the relative standard deviation ranged from 0.3% to 1.4% for intra-day and from 0.3% to 3.0% for inter day repeatability. The limits of detection were in the range of 0.30-0.53 MUg mL 1. PMID- 29413978 TI - Metabolomics analysis of serum reveals the effect of Danggui Buxue Tang on fatigued mice induced by exhausting physical exercise. AB - Danggui Buxue Tang (DBT), believed to invigorate 'Qi' (vital energy) and nourish 'Blood' (body circulation), is a traditional Chinese medicine formula. In this study, a metabolomics approach with gas chromatography coupled to mass spectrometry combined with pattern recognition was adopted to investigate the underlying mechanism of the antifatigue effect of DBT on fatigue of mice induced by weight-loaded forced swimming. Fourteen endogenous metabolites, up-regulated or down-regulated, were identified in the model mice by analysis tools of partial least-squares discriminant analysis (PLS-DA) and XCMS online software. Furthermore, the metabolites were reversed by DBT treatment, offering evidence for the antifatigue effect. In addition, intervention of DBT changed the levels of biochemical parameters. DBT showed obvious efficacy on the fatigued mice possibly by regulating the pathways of phenylalanine, tyrosine and tryptophan metabolism, glycine, serine, and threonine metabolism, glyoxylate and dicarboxylate metabolism, pyruvate metabolism, and TCA cycle. This study demonstrated that DBT has a good antifatigue effect and that metabolomics is a powerful means to gain insights into the therapeutic effect of traditional Chinese medicine formulas. PMID- 29413979 TI - Effect of Tinospora cordifolia aqua-alcoholic extract on pharmacokinetic of Glibenclamide in rat: An herb-drug interaction study. AB - Tinospora cordifolia (TC) has been used as a complimentary/alternative medicine against diabetes. Considering its potential to modulate metabolic enzymes, Tinospora cordifolia extract (TCE) may influence the metabolism of the antidiabeic drug Glibenclamide following co-administration. Accordingly, this work was undertaken to evaluate impact of TCE on fate of Glibenclamide. Activity of clinically important Cytochrome P450 isoenzymes were inhibited in the order of CYP2C9 > CYP2D6 > CYP2C19 > CYP1A2 > CYP3A4. Formations of metabolites were inhibited with increasing concentration of TCE in both rat and human liver microsomes. TCE was co- administered in three different groups (0, 100 and 400 mg/kg) with Glibenclamide at 1 mg/kg dose to observe the alteration in pharmacokinetic parameters of Glibenclamide. The rats were pretreated with 0 (vehicle), 100 and 400 mg/kg dose of TCE b.i.d for 14 days and on the 14th day all three groups were administered with 1 mg/kg Glibenclamide. Pharmacokinetic parameters were analyzed based on plasma concentrations of Glibenclamide from all the groups by LC-HRMS methods using Glipizide as an internal standard. At 400 mg/kg dose, a marked increase in the bio availability of Glibenclamide was observed with a significant delay of Tmax and suppression of clearance. PMID- 29413980 TI - In vitro evaluation of the biological activities of IgG in seven Chinese intravenous immunoglobulin preparations. AB - The IgG activities of antigen recognition, Fc-mediated complement activation and cellular Fcgamma-receptors (FcgammaRs) binding are critical for intravenous immunoglobulin (IVIg) immunotherapy in a variety of immune deficiency diseases. Further, these activities could be influenced by different plasma sources and the IVIg manufacturing processes of different manufacturers. This study evaluated and compared the biological activities of IgG in 7 IVIg preparations produced by different Chinese manufacturers. By using ELISA and two-dimensional immunoblotting, the binding capacity and antibody repertoire of IVIg against typical pathogenic antigens were investigated. Further, Fc-mediated complement activation and receptor binding activities were measured by the haemolysis method and flow-cytometric assay respectively. The results showed that all of the preparations tested have a broad spectrum of antibodies against the E. coli O157:H7 proteome, and each IVIg has its own distinct antibody repertoire. Compared to the European Pharmacopoeia IgG standard, the mean indices of the pathogenic antigen binding capacity, complement activation activity and FcgammaRs binding activity in Chinese preparations were 152%, 143% and 87%. The biological activities varied widely among the 7 IVIg preparations, and no significant differences were observed between the different batches of most IVIgs from the same manufacturer. This study will contribute to the improvement of the IVIg product quality evaluation system and an increased understanding of the variety of IgG biological activities in Chinese IVIg preparations. PMID- 29413981 TI - Heparin molecularly imprinted polymer thin flm on gold electrode by plasma induced graft polymerization for label-free biosensor. AB - Heparin, a highly sulfated glycosaminoglycan, is an important biomaterial having biological and therapeutic functionalities such as anticoagulation, regeneration, and protein stabilization. This study addresses a label-free quartz crystal microbalance (QCM) biosensor for heparin detection based on a macromolecularly imprinted polymer (MIP) as an artificial recognition element. We demonstrate the novel strategy for MIP in the form of thin film on a gold (Au) electrode with the plasma-induced graft polymerization (PIP) technique. The procedure of PIP is as follows: (i) Hexamethyldisiloxane plasma-polymerized thin film (PPF) as a pre coating scaffold of active species for PIP (post-polymerization) is deposited on an Au electrode. (ii) The PPF/Au electrode is soaked in an water solution containing heparin (template), (2-(methacryloxy)-ethyl)trimethylammonium chloride acrylamide (functional monomer), acrylamide, and N,N-methylenebisacrylamide (crosslinker). Double bonds of monomer and crosslinker attacked by residually active species in pre-coating PPF cause radical chain reaction. Consequently, a growing polymer network of 20 nm thickness of PIP-MIP thin film is formed and grafted on the PPF/Au surface. (iii) The PIP-MIP/PPF/Au is washed by sodium chloride solution so as to remove the template. Non-imprinted polymer (NIP) is carried out like the same procedure without a template. The AFM, XPS, and QCM measurements show that the PIP process facilitates macromolecularly surface imprinting of template heparin where the template is easily removed and is rapidly rebound to PIP-MIP without a diffusional barrier. The heparin-PIP-MIP specifically binds to heparin compared with heparin analog chondroitin sulfate C (selective factor: 4.0) and a detectable range of heparin in the presence of CS (0.1 wt%) was 0.001-0.1 wt%. The PIP-NIP does not show selectivity between them. The evaluated binding kinetics are association (ka = 350 +/- 100 M-1 s-1), dissociation (kd = (5.0 +/- 2.0) * 10-4 s-1), and binding (KD = 1.3 +/- 0.6 MUM) constants, demonstrating that the PIP-MIP as a synthetic antibody can be applied to analytical chemistry. PMID- 29413982 TI - Rapid quantification of polysaccharide and the main onosaccharides in Dendrobium huoshanense by near-infrared attenuated total reflectance spectroscopy. AB - A rapid, green, low cost and nondestructive attenuated total reflection near infrared (ATR NIR) method was developed to quantify the total polysaccharide and the main monosaccharides mannose and glucose in Dendrobium huoshanense. Total 100 D. huoshanense samples from different places were analyzed using ATR NIR method. Potential outlying samples were initially removed from the collected NIR data using the PCA-Mahalanobis distance method. Spectral data preprocessing was studied in the construction of a partial least squares (PLS) model and six different signal pretreatment methods, including multiplicative scattering correction (MSC), standard normal transformation (SNV), first and second derivatives, the combination of MSC with the first derivative, and the combination of SNV with the first derivative, were compared. The results showed that the best signal pretreatment method was the spectral data pretreated by SNV combined with the first derivative due to it showed the lowest root-mean-square error of cross-validation (RMSECV), highest R2 for both the polysaccharide and its main monosaccharides. In order to improve the performance of the model, the pretreated full spectrum was calculated by different wavelength selection method. The results showed that the optional wavelength selection model was the one simultaneously selecting the NIR wavelength ranges 7500-5750 cm-1, 5250-4700 cm 1, 4450-4300 cm-1 and 4200-4100 cm-1 because of the lowest RMSECV and the highest R2 among the ten wavelength selection models. The external validation and the complete external validation confirmed the robustness and reliability of the developed NIR model. The contents of the total polysaccharide and the main monosaccharides are the essential quality assessment criterion for plant medicines while their traditional quantification methods involved sample destruction, tedious sample processing and non-environmentally friendly pretreatment, therefore, our study might provide an efficient technique tool for the rapid, green and nondestructive quantification of the total polysaccharide and the main monosaccharides for D. huoshanense and other rich-in-polysaccharide plant medicines. PMID- 29413983 TI - Evaluation of a novel micro-sampling device, MitraTM, in comparison to dried blood spots, for analysis of praziquantel in Schistosoma haematobium-infected children in rural Cote d'Ivoire. AB - Pharmacokinetic (PK) studies with paediatric populations are increasing in importance for drug development. However, conventional PK sampling methods are characterised by invasiveness and low patient adherence, unsuitable for use with sensitive population, such as children. MitraTM is a novel volumetric absorptive micro-sampling device, which offers an alternative to the dried blood spotting (DBS) technique, a current popular sampling technique within PK studies. We tested MitraTM for the first time in the framework of a randomised controlled trial in rural Cote d'Ivoire. Thirty-five school-aged children, infected with Schistosoma haematobium, were sampled with both DBS and MitraTM, at 10 time points after treatment with praziquantel (PZQ). An extraction method for PZQ from MitraTM was developed, optimised and validated. Analytes, namely R- and S praziquantel (R-/SPZQ) and the main human metabolite, R-trans-4-OH-praziquantel, were measured using liquid chromatography-tandem mass spectrometry and the results were compared with Bland-Altman analysis to determine agreement between matrices. PK parameters, such as maximal plasma concentration and area under the concentration-time curve, were estimated using non-compartmental analysis. While we observed strong positive correlation (R2 > 0.98) and agreement between both matrices within the calibration line and quality control samples, MitraTM revealed higher concentrations of all the analytes in the majority of patients' samples compared to DBS sampling, namely 63% samples for RPZQ, 49% for SPZQ and 78% for the metabolite were overestimated. While T1/2 and Tmax were in agreement between both matrices, area under the curve and maximal blood concentration were up to 2* higher for MitraTM samples, with P < 0.005 for all parameters except Cmax of SPZQ, which was not significantly different between the two matrices. The reasons for the higher PZQ concentrations, more pronounced in incurred MitraTM samples compared to spiked samples, are yet to be fully explored. MitraTM appears superior to DBS in terms of simplicity and practicality however labelling issues and the high price of MitraTM are difficult to overlook. PMID- 29413984 TI - Detection and quantification of phenethylamines in sports dietary supplements by NMR approach. AB - Phenethylamines (PEAs) are popular substances found in weight-loss and sports nutrition supplements. They are generally pharmacologically active and primarily affect the sympathetic nervous system. Many PEAs are synthetic chemicals and are on the prohibited list of the World Anti-Doping Agency. In this study, nuclear magnetic resonance (NMR) spectroscopy was applied to detect and identify the presence of PEAs in sports dietary supplements without the need for chromatographic separation or pre-knowledge on formulation. Eight PEAs, viz. phenethylamine, synephrine, oxilofrine, hordenine, beta-methylphenethylamine, N methyltyramine, octopamine and deterenol, were identified from 32 dietary supplements sold in the US market. Furthermore, a quantitative NMR method was developed and validated for simultaneous determination of the concentrations of the PEAs. The study demonstrated that NMR could be a potential tool to monitor and detect PEAs or other ingredients in dietary supplements. PMID- 29413985 TI - Beyond the limit of assignment of metabolites using minimal serum samples and 1H NMR spectroscopy with cross-validation by mass spectrometry. AB - Identification of NMR-based metabolic indexes is limited by the deleterious effects of copious proteins and lipoproteins in the serum that accentuate the need for advance and high-throughput method. We tried to explore the use of a novel filtration (2KDa molecular weight cut-off) approach to remove the proteins from serum following use of less sample volume (only 150 MUL of filtered serum), combining an array of 1D/2D NMR experiments (at 800 MHz spectrometer), spiking experiments with standard compounds, and validated by mass spectrometry. This novel method enabled the identification of a large number (n = 73) of metabolites and their percentage of abundance in the present study cohort. Mass spectrometry further validates and confirms the presence of all these 73 metabolites using same filtered serum. This study reveals seven new metabolites (citrulline, inosine, taurine, trimethyl amine, methylmalonate, uracil, methanol) in filtered serum using 1D/2D NMR spectroscopy that were not observed in earlier available literature using protein precipitation approach. This novel method delineates volatile metabolites, nitrogenous bases and nucleosides that may provide a milestone for the identification of inborn error of metabolism, pathogenicity at molecular level, disease identification and prognosis, and forensic studies using minimal volume of filtered serum samples and NMR spectroscopy. PMID- 29413986 TI - Eyes on our planet. AB - Combining several satellite-based tracking technologies with big data methods and machine learning, fisheries experts can now efficiently monitor the entirety of the oceans and ensure that legal limits and protected areas are respected. Observing our planet from space is also proving a fruitful approach in other areas of conservation, ecology and climate research. Michael Gross reports. PMID- 29413987 TI - Cathie Martin. AB - Interview with Cathie Martin, who studies plant science and nutritional enhancement of food at the John Innes Centre. PMID- 29413988 TI - LuAG:Pr3+-porphyrin based nanohybrid system for singlet oxygen production: Toward the next generation of PDTX drugs. AB - A highly prospective drug for the X-ray induced photodynamic therapy (PDTX), LuAG:Pr3+@SiO2-PpIX nanocomposite, was successfully prepared by a three step process: photo-induced precipitation of the Lu3Al5O12:Pr3+ (LuAG:Pr3+) core, sol gel technique for amorphous silica coating, and a biofunctionalization by attaching the protoporphyrin IX (PpIX) molecules. The synthesis procedure provides three-layer nanocomposite with uniform shells covering an intensely luminescent core. Room temperature radioluminescence (RT RL) spectra as well as photoluminescence (RT PL) steady-state and time resolved spectra of the material confirm the non-radiative energy transfer from the core Pr3+ ions to the PpIX outer layer. First, excitation of Pr3+ ions results in the red luminescence of PpIX. Second, the decay measurements exhibit clear evidence of mentioned non radiative energy transfer (ET). The singlet oxygen generation in the system was demonstrated by the 3'-(p-aminophenyl) fluorescein (APF) chemical probe sensitive to the singlet oxygen presence. The RT PL spectra of an X-ray irradiated material with the APF probe manifest the formation of singlet oxygen due to which enhanced luminescence around 530 nm is observed. Quenching studies, using NaN3 as an 1O2 inhibitor, also confirm the presence of 1O2 in the system and rule out the parasitic reaction with OH radicals. To summarize, presented features of LuAG:Pr3+@SiO2-PpIX nanocomposite indicate its considerable potential for PDTX application. PMID- 29413989 TI - Annonalide and derivatives: Semisynthesis, cytotoxic activities and studies on interaction of annonalide with DNA. AB - The cytotoxic activity of the pimarane diterpene annonalide (1) and nine of its semisynthetic derivatives (2-10) was investigated against the human tumor cell lines HL-60 (leukemia), PC-3 (prostate adenocarcinoma), HepG2 (hepatocellular carcinoma), SF-295 (glioblastoma) and HCT-116 (colon cancer), and normal mouse fibroblast (L929) cells. The preparation of 2-10 involved derivatization of the side chain of 1 at C-13. Except for 2, all derivatives are being reported for the first time. Most of the tested compounds presented IC50s below 4.0 MUM, being considered potential antitumor agents. The structures of all new compounds were elucidated by spectroscopic analyses including 2D NMR and HRMS. Additionally, the interaction of annonalide (1) with ctDNA was evaluated using spectroscopic techniques, and the formation of a supramolecular complex with the macromolecule was confirmed. Competition assays with fluorescent probes (Hoechst and ethidium bromide) and theoretical studies confirmed that 1 interacts preferentially via DNA intercalation with stoichiometric ratio of 1:1 (1:ctDNA). The DeltaG value was calculated as -28.24 kJ mol-1, and indicated that the interaction process occurs spontaneously. Docking studies revealed that van der Walls is the most important interaction in 1-DNA and EB-DNA complexes, and that both ligands (1 and EB) interact with the same DNA residues (DA6, DA17 and DT19). PMID- 29413990 TI - Mitochondrial gene expression changes in cultured human skin cells following simulated sunlight irradiation. AB - BACKGROUND: Exposure of skin to simulated sunlight irradiation (SSI) has being extensively researched and shown to be the main cause for changes in the skin including changes in cellular function and generation of reactive oxygen species (ROS). This oxidative stress can subsequently exert downstream effects and the subcellular compartments most affected by this oxidative stress are mitochondria. The importance of functional mitochondrial morphology is apparent as morphological defects are related to many human diseases including diabetes mellitus, liver disease, neurodegenerative diseases, aging and cancer. OBJECTIVE: The main objective of this study was to evaluate solar radiation-induced changes in mitochondrial gene expression in human skin cells using a Q-Sun solar simulator to deliver a close match to the intensity of summer sunlight. METHODS: Spontaneously immortalised human skin epidermal keratinocytes (HaCaT) and Human Dermal Fibroblasts (HDFn) were divided into two groups. Group A were irradiated once and Group B twice 7days apart; following irradiation, mitochondrial gene expression was evaluated 1, 4 and 7days post primary exposure for group A and 1, 4, 7 and 14days post-secondary exposure for group B. RESULTS: Both the epidermal and dermal cells displayed significant reduced expression of the genes analysed for mitochondrial morphology and function; however, epidermal cells displayed this reduction post SSI earlier then dermal cells at multiple time points. CONCLUSION: The data presented here reinforces the fact that epidermal cells, while displaying a heightened sensitivity to sunlight, are less prone to changes in gene expression, while dermal cells, which appear to be more resilient are possibly more prone to genomic instability and mitochondrial damage. PMID- 29413991 TI - Gas embolism as a potential cause of death by helium poisoning - Postmortem computed tomography changes in two cases of suicidal helium inhalation. AB - Evaluation of two suicidal helium inhalation cases is presented, comprising both conventional autopsy methods and postmortem computed tomography. Conventional postmortem examinations reveal no characteristic changes. Modern diagnostic techniques enabled to disclosethe presence of a very large amount of accumulated gas in all examined areas, including veins and arteries of the head, torso, lower extremities, heart chambers, and between muscle fibers in both cases. The changes due to possible putrefaction were taken into consideration - radiological alteration index was calculated. In forensic literature, the reported mechanism of death in helium poisoning is rapid asphyxiation due to oxygen deprivation. However, papers on clinical cases and animal studies with the use of helium report development of gas in body cavities and lethal gas embolism, comprehensible when we take into account the specific physical properties of helium: high permeability and very low solubility in blood. The results reported by the authors are consistent with massive gas embolism similar to changes presentedin cases of decompression illness. They suggest this as the cause of death in helium inhalation cases. Undoubtedly, this requiresconfirmation in further observations, taking into account differentiating diagnosis of air embolism versus oxygen deprivation. PMID- 29413992 TI - High-throughput determination of valproate in human samples by modified QuEChERS extraction and GC-MS/MS. AB - A new high-throughput method was developed for analysis of valproate in human plasma samples by QuEChERS extraction and gas chromatography-tandem mass spectrometry (GC-MS/MS). Plasma samples (0.2 ml) spiked with valproate and secobarbital-d5 (internal standard) were diluted with 1.3 ml of distilled water. Acetonitrile (1 ml) was added followed by 0.4 g MgSO4 and 0.1 g NaOAC. After a centrifugation step (2000 g for 10 min), 1 ml of the supernatant was transferred to a dispersive-solid phase extraction (dSPE) tube containing 150 mg MgSO4 and 50 mg C18. This mixture was vortexed and centrifuged at 3000 g for 5 min, and then the upper layer was evaporated to dryness under a stream of nitrogen. The residue was dissolved in 40 MUl ethyl acetate, and a 1-MUl aliquot was injected into the GC-MS/MS. The GC separation of the compounds was achieved on a fused-silica capillary column Rxi-5Sil MS (30 m * 0.25 mm i.d.; 0.25-um film thickness) and detected by MS/MS operating in electron ionization ion source mode. The regression equations showed excellent linearity (r > 0.9997) from 50 to 5000 ng/ml for plasma, with limit of detection of 10 ng/ml. The extraction efficiency of valproate for plasma ranged between 71.2%-103.5%. The coefficient of variation was <18.5%. The method was successfully applied to actual analyses of an autopsy case. This method can be useful for simple and reliable measurements of valproate in clinical and toxicological analyses; it can be integrated in screening and simultaneous determination methods for multiple drugs and poisons in the further studies. PMID- 29413993 TI - A validation study of DNA methylation-based age prediction using semen in forensic casework samples. AB - Previously, an age-predictive method based on DNA-methylation patterns in semen was developed, using three CpG sites (cg06304190 in the TTC7B gene, cg12837463, and cg06979108 in the NOX4 gene). Before considering the routine use of a new method in forensics, validation studies such as concordance and sensitivity tests are essential for obtaining expanded and more reliable forensic information. Here, we evaluated a previously described age-predictive method for semen for routine forensic use. Concordance testing showed a high correlation between the predicted and chronological age, with a mean absolute deviation from the chronological age of 4.8 years. Sensitivity testing suggested that age prediction with reliable accuracy and consistency was possible with >5 ng of bisulfite converted DNA. We also confirmed the applicability of the age-predictive method in forensic casework, using forensic samples. Thus, the proposed method could serve as a very valuable forensics tool for accurate age prediction with semen samples. PMID- 29413994 TI - Retained surgical sponge: Medicolegal aspects. AB - Retained surgical sponge events continue to occur despite the implementation of preventive surgical count policies, procedures, and adjunct technologies to manual counting. Such intraoperative mistakes can cause chronic nonspecific symptoms during the early postoperative period. When discovered years after surgery, they raise thorny medicolegal questions. We describe two cases from our practice that illustrate the need to identify the responsibility of the surgical team, as delineated in ministerial directives and the current legal framework, as well as the difficulty in evaluating clinical actions taken at different times and in different settings, with regard to the permanent health damage incurred by sponge retention. Finally, we discuss prevention actions operating room staff should take to reduce the risk of retained surgical sponges. PMID- 29413995 TI - Bioenergy potential of Wolffia arrhiza appraised through pyrolysis, kinetics, thermodynamics parameters and TG-FTIR-MS study of the evolved gases. AB - This study evaluated the bioenergy potential of Wolffia arrhiza via pyrolysis. The biomass was collected from the pond receiving city wastewater. Oven dried powdered biomass was exposed to thermal degradation at three heating rates (10, 30 and 50 degrees C min-1) using Thermogravimetry-Differential Scanning Calorimetry analyzer in an inert environment. Data obtained were subjected to the isoconversional models of Kissenger-Akahira-Sunose (KSA) and Flynn-Wall-Ozawa (FWO) to elucidate the reaction chemistry. Kinetic parameters including, Ea (136 172 kJmol-1) and Gibb's free energy (171 kJmol-1) showed the remarkable bioenergy potential of the biomass. The average enthalpies indicated that the product formation is favored during pyrolysis. Advanced coupled TG-FTIR-MS analyses showed the evolved gases to contain the compounds containing CO functional groups (aldehydes, ketones), aromatic and aliphatic hydrocarbons as major pyrolytic products. This low-cost abundant biomass may be used to produce energy and chemicals in a cost-efficient and environmentally friendly way. PMID- 29413996 TI - Pyrolysis and kinetic analyses of a perennial grass (Saccharum ravannae L.) from north-east India: Optimization through response surface methodology and product characterization. AB - The objective of the present investigation was to optimize the pyrolysis condition of an abundantly available and low cost perennial grass of north-east India Saccharum ravannae L. (S. ravannae) using response surface methodology based on central composite design. Kinetic study of the biomass was conducted at four different heating rates of 10, 20, 40 and 60 degrees C min-1 and results were interpreted by Friedman, Kissinger Akira Sunnose and Flynn-Wall-Ozawa methods. Average activation energy 151.45 kJ mol-1 was used for evaluation of reaction mechanism following Criado master plot. Maximum bio-oil yield of 38.1 wt% was obtained at pyrolysis temperature of 550 degrees C, heating rate of 20 degrees C min-1 and nitrogen flow rate of 226 mL min-1. Study on bio-oil quality revealed higher content of hydrocarbon, antioxidant property, total phenolic content and metal chelating capacity. These opened up probable applications of S. ravannae bio-oil in different fields including fuel, food industry and biomedical domain. PMID- 29413997 TI - Burkholderia sacchari DSM 17165: A source of compositionally-tunable block copolymeric short-chain poly(hydroxyalkanoates) from xylose and levulinic acid. AB - Burkholderia sacchari was used to produce poly-3-hydroxybutyrate-co-3 hydroxyvalerate block copolymers from xylose and levulinic acid. Levulinic acid was the preferred substrate resulting in 3-hydroxyvalerate (3HV) contents as high as 95 mol% at 24 h. The 3HB:3HV ratios were controlled by the initial levulinic acid media concentration and fermentation length. Higher levulinic acid concentrations and longer durations, resulted in polymers with two glass transition temperatures, each approximating those associated with poly-3HB and poly-3HV. 13C NMR confirmed the presence of high concentrations of 3HB-3HB and 3HV-3HV homopolymeric dyads, while mass spectrometry of the partial hydrolysis products did not conform to Bernoullian statistics for randomness, confirming block sequences. MS/MS analysis of specific oligomers showed the mass-loss of 86 amu (a 3HB unit) and 100 amu (a 3HV unit) attesting to some randomness within the polymers. This study verifies the potential for producing Poly-3HB-block-3HV copolymers from inexpensive biorenewable feedstocks without sequential addition of carbon sources. PMID- 29413998 TI - Lipid-lowering treatment in peripheral artery disease. AB - Peripheral artery disease (PAD) is characterized by increased cardiovascular (CV) risk, limb morbidity and all-cause mortality. According to the current guidelines (2016) of the American Heart Association/American College of Cardiology on the management of PAD patients, statin therapy is recommended for PAD patients in order to treat dyslipidemia and reduce CV risk. The present narrative review discusses the use of statins and other lipid-lowering drugs such as ezetimibe, fibrates, niacin, anacetrapib and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in PAD patients in terms of both CV and limb outcomes. The clinical implications of hypolipidemic drug therapy in special patient populations including those with metabolic syndrome, non-alcoholic fatty liver disease, chronic kidney disease and type 2 diabetes mellitus, which may frequently co-exist with PAD, are also considered. PMID- 29413999 TI - Flow velocity maps measured by nuclear magnetic resonance in medical intravenous catheter needleless connectors. AB - This work explains the motivation, advantages, and novel approach of using velocity magnetic resonance imaging (MRI) for studying the hydrodynamics in a complicated structural biomedical device such as an intravenous catheter needleless connector (NC). MRI was applied as a non-invasive and non-destructive technique to evaluate the fluid dynamics associated with various internal designs of the NC. Spatial velocity maps of fluid flow at specific locations within these medical devices were acquired. Dynamic MRI is demonstrated as an effective method to quantify flow patterns and fluid dynamic dependence on structural features of NCs. These spatial velocity maps could be used as a basis for groundtruthing computational fluid dynamics (CFD) methods that could impact the design of NCs. PMID- 29414000 TI - Simultaneous quantification of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid and piperacillin in human serum using an isotope-dilution HPLC-MS/MS method. AB - The aim of the current study was to develop and validate a robust multi-analyte high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for simultaneous quantification of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid and piperacillin, which are the most commonly used antibiotics in intensive care units. Sample clean-up included a protein precipitation protocol, followed by chromatographic separation on a C8 reverse phase HPLC column within 4 min, using a formic acid-ammonium formiate methanol step-elution gradient. All compounds were detected with electrospray ionization (ESI+) mass spectrometry in multiple reaction time monitoring. The method was validated according to the protocol from the European Medicines Agency and was thoroughly evaluated for interferences and quantification linearity. Linear relationships between peak area responses and drug concentrations were obtained in the range of 0.25-200 mg/l for cefepime, 0.25-120 mg/l for meropenem, 0.05-10 mg/l for ciprofloxacin, 0.125-10 mg/l for moxifloxacin, 0.125-50 mg/l for linezolid and 0.5-400 mg/l for piperacillin with an R2 > 0.997. Imprecision and inaccuracy values (both intra- and inter-assay) were <= 6.8% and <=10.9% for all analytes in quality control samples, respectively. The assay proved to be selective for the study antibiotics, and the internal standards consistently compensated for matrix effects. The described simple and reliable HPLC-MS/MS assay is a powerful tool for routine TDM of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid and piperacillin in human serum in clinical laboratories. With a total process time of approximately 30 min, it allows for accurate and selective quantification up to the expected pharmacokinetic peak concentrations. PMID- 29414001 TI - Detection and identification of multiple adulterants in plant food supplements using attenuated total reflectance-Infrared spectroscopy. AB - Due to the rising popularity of dietary supplements, especially plant food supplements, and alternative herbal medicines, a whole market developed and these products became freely available through internet. Though several searches revealed that at least a part of these products, especially the ones obtained from websites disclosing their physical identity, are aldulterated with pharmaceutical compounds. This causes a threat for public health, since these compounds are not declared and therefore adverse effects will not immediately be related to the product. The more the adulterants can interfere with other medicinal treatments. Since the present active pharmaceutical ingredients are not declared on the package and the products are sold as 100% natural or herbal in nature, it is very difficult for custom personnel to discriminate between products to be confiscated or not. Therefore easy to apply analytical approaches to discriminate between adulterated and non-adulterated products are necessary. This paper presents an approach based on infrared spectroscopy combined with attenuated total reflectance (ATR) and partial least squares- discriminant analysis (PLS-DA) to easily differentiate between adulterated and non- adulterated plant food supplements and to get a first idea of the nature of the adulterant present. The performance of PLS-DA models based on Mid-IR and NIR data were compared as well as models based on the combined data. Further three preprocessing strategies were compared. The best performance was obtained for a PLS-DA model using Mid-IR data with the second derivative as preprocessing method. This model showed a correct classification rate of 98.3% for an external test set. Also eight real samples were screened using the model and for seven of these samples a correct classification was obtained. Generally it could be concluded that the obtained model and the presented approach could be used at customs to discriminate between adulterated and non-adulterated herbal food supplements and even get a first idea of the nature of the adulterant present. The more the presented approach hardly needs sample preparation. PMID- 29414002 TI - Study of the use of axial viewed inductively coupled plasma atomic emission spectrometry with ultrasonic nebulization for the determination of select elemental impurities in oral drug products. AB - In efforts to control the potential presence of heavy metals in pharmaceuticals, the United States Pharmacopeia (USP) and International Conference on Harmonization (ICH) have put forth new requirements and guidelines for their control. The new requirements and guidelines establish specific daily exposures (PDE) for 24 heavy metals/elemental impurities (EI) based upon their toxicological properties. USP General Chapter <233> provides a general reference procedure for preparing pharmaceutical samples for analysis employing microwave assisted digestion (MWAD). It also provides two Compendial Procedures, Procedure 1 employing ICP-AES, and Procedure 2 employing ICP-MS. Given the extremely low detection limits afforded by ICP-MS, much work has been done in developing and evaluating analytical methods to support the analysis of elemental impurities in finished pharmaceutical products, active pharmaceutical ingredients, and excipients by this analytical technique. In this study, we have evaluated the use of axial ICP-AES. This employs ultrasonic nebulization (UN) for the determination of Class 1 and 2 EI, instead of traditional pneumatic nebulization. The study also employed closed vessel MWAD to prepare samples for analysis. Limits of quantitation were element specific and significantly lower than the PDEs for oral drugs. Spike recoveries for the elements studied ranged between 89.3% and 109.25%, except for Os, which was subject to OsO4 formation during MWAD. The use of axial ICP-AES UN provides an alternative to ICP-MS in the analysis of EI requiring low detection limits. PMID- 29414003 TI - Wavenumber selection method to determine the concentration of cocaine and adulterants in cocaine samples. AB - Street cocaine is typically altered with several compounds that increase its harmful health-related side effects, most notably depression, convulsions, and severe damages to the cardiovascular system, lungs, and brain. Thus, determining the concentration of cocaine and adulterants in seized drug samples is important from both health and forensic perspectives. Although FTIR has been widely used to identify the fingerprint and concentration of chemical compounds, spectroscopy datasets are usually comprised of thousands of highly correlated wavenumbers which, when used as predictors in regression models, tend to undermine the predictive performance of multivariate techniques. In this paper, we propose an FTIR wavenumber selection method aimed at identifying FTIR spectra intervals that best predict the concentration of cocaine and adulterants (e.g. caffeine, phenacetin, levamisole, and lidocaine) in cocaine samples. For that matter, the Mutual Information measure is integrated into a Quadratic Programming problem with the objective of minimizing the probability of retaining redundant wavenumbers, while maximizing the relationship between retained wavenumbers and compounds' concentrations. Optimization outputs guide the order of inclusion of wavenumbers in a predictive model, using a forward-based wavenumber selection method. After the inclusion of each wavenumber, parameters of three alternative regression models are estimated, and each model's prediction error is assessed through the Mean Average Error (MAE) measure; the recommended subset of retained wavenumbers is the one that minimizes the prediction error with maximum parsimony. Using our propositions in a dataset of 115 cocaine samples we obtained a best prediction model with average MAE of 0.0502 while retaining only 2.29% of the original wavenumbers, increasing the predictive precision by 0.0359 when compared to a model using the complete set of wavenumbers as predictors. PMID- 29414004 TI - Extraction of bioactive phenolics from black poplar (Populus nigra L.) buds by supercritical CO2 and its optimization by response surface methodology. AB - The scope of current study was to apply supercritical CO2 for extraction of black poplar buds (Populus nigra L.) and to optimize the extraction parameters (pressure and temperature) using response surface methodology aimed at maximum extraction yield, total phenolic content (TP), ferric reducing antioxidant power (FRAP) and individual amount of selected bioactive phenolics. The pressure and temperature influenced significantly the extract yield (0.38-10.28 g/100 g), TP content (21.62-31.09 MUg GAE/mg), FRAP capacity (0.30-0.48 MUmol Fe2+/mg), and the amounts of p-coumaric acid (0.33-1.52 MUg/mg), pinocembrin (20.99-47.24 MUg/mg) and galangin (4.04-10.25 MUg/mg). The extraction of pinostrobin (51.73 79.56 MUg/mg), pinobanksin (0.41-1.55 MUg/mg), and chrysin (0.97-2.03 MUg/mg) was significantly affected only by the operating pressure. Optimized extraction parameters (30 MPa and 60 degrees C) allow to obtain higher yield and extracts enriched with bioactive phenolics. PMID- 29414005 TI - Evaluation of benzodiazepines and zolpidem in nails and their stability after prolonged exposure to chlorinated water. AB - The study aims the development and validation of a LC-MS/MS method for the identification and quantification of benzodiazepines and zolpidem in nails as alternative keratinized matrix to hair in long-term monitoring of anxiolytic and hypnotic drugs. Both fingernail and toenail samples (1-2 mm) were collected by clipping the excess overhang of the nail from volunteers and from postmortem cases. They were washed twice with organic solvents, dried under nitrogen stream, pulverized, immersed in a methanol solution (internal standard: diazepam-D5) and sonicated up to two hours. The solution was then direct injected in the LC-MS/MS system. Mass spectrometry was set in MRM mode, selecting two transitions for each substance. 32 analytes among benzodiazepines, metabolites and hypnotics were included in the list. The method fulfilled the internationally required criteria for validation. Limits of detection ranged from 0.03 pg/mg (zolpidem) to 13.1 pg/mg (bromazepam). 9 subjects under therapy were positive at 7 different benzodiazepines and/or metabolites (lorazepam, desalkylflurazepam, bromazepam, diazepam, alprazolam, lormetazepam and prazepam), while 5 molecules were measured in 4 postmortem cases (diazepam, desmethyldiazepam, delorazepam, 7 aminoclonazepam and zolpidem). In vitro experiments on eight authentic samples suggested that benzodiazepines in nails are influenced by the prolonged exposure to chlorinated water. PMID- 29414006 TI - Profiling of dalcetrapib metabolites in human plasma by accelerator mass spectrometry and investigation of the free phenothiol by derivatisation with methylacrylate. AB - Dalcetrapib, a thioester prodrug, undergoes rapid and complete conversion in vivo to its phenothiol metabolite M1 which exerts the targeted pharmacological response in human. In clinical studies, M1 has been quantified together with its dimer and mixed disulfide species that represent the 'dalcetrapib active form' in plasma. In this article, we describe the determination of the free phenothiol M1 by derivatisation with methylacrylate as a percentage of 'dalcetrapib active form'. Pharmacokinetic profiles of M1 after oral administration of dalcetrapib to humans could be established, underscoring the validity to use a composite measure of 'dalcetrapib active form' as a surrogate marker for pharmacodynamic evaluations. 'Dalcetrapib active form' and M1 made up 8.9% and 3.6% of total drug related material, respectively. In addition, complete metabolite profiling of 14C labeled dalcetrapib was conducted after two-dimensional HPLC using fast fractionation into 384-well plates and ultrasensitive determination of the 14C content by accelerator mass spectrometry. M1 underwent further biotransformation to its S-methyl metabolite M3, which was further oxidized to its sulfoxide and sulfone. Another metabolic pathway was the formation of the S-glucuronide. All of these species underwent further oxidation in the ethylbutyl cyclohexyl moiety leading to a multitude of hydroxyl and keto metabolites undergoing further conjugation to O-glucuronides. More than 80 metabolites were identified, demonstrating extensive metabolism. However, it was unambiguously demonstrated that none of these metabolites were major according to the MIST guideline (exceeding 10% of drug related material in circulation). The combination of accelerator mass spectrometry with HPLC together with high resolution mass spectrometry allowed for structural characterization of the most relevant human metabolites. PMID- 29414007 TI - Ultrasensitive spectrofluorimetric method for rapid determination of daclatasvir and ledipasvir in human plasma and pharmaceutical formulations. AB - Direct-acting antivirals (DAAs) represent a revolution in the treatment of chronic hepatitis C which have emerged at an extremely rapid pace over the past few years. DAAs act directly on the hepatitis C virus at various points in the viral life cycle to inhibit viral production. Among these novel DAAs, are daclatasvir (DCS) and ledipasvir (LDS). Herein, a novel, fast, simple, ultrasensitive and cost-effective spectrofluorimetric method was designed for determination of DCS and LDS in miscellaneous matrices. The method is based on investigation of the native fluorescence of the cited drugs. The relative fluorescence intensity (RFI) was measured at lambdaex/lambdaem equal to 315/381 nm for DCS and 332/387 nm for LDS. Under the optimum conditions, the linear ranges of calibration curves were 0.2-30 and 6-120 ng mL-1 for DCS and LDS, respectively with correlation coefficients >=0.9998. The detection limits were 0.047 and 1.939 ng mL-1 for DCS and LDS, respectively indicating ultrasensitivity of the proposed method. Consequently, this permits in vitro and in vivo application of the proposed method in spiked and real human plasma with good percentage recovery (96.6-103.6%). The method was validated in compliance with ICH guidelines and US-FDA guidelines. Furthermore, the application was extended to analysis of DCS and LDS in its pharmaceutical formulations (either alone or in presence of other co-formulated drugs) and in synthetic mixture with sofosbuvir or ribavirin. PMID- 29414008 TI - Analysis by LC-MS/MS of endogenous steroids from human serum, plasma, endometrium and endometriotic tissue. AB - An LC-MS/MS method was developed and validated to analyze simultaneously estrogens (estradiol, E2; estrone, E1), androgens (testosterone, T; androstenedione, A4; dehydroepiandrosterone, DHEA), progestagens (17a hydroxypregnenolone, 17OHP5; 17a-hydroxyprogesterone, 17OHP4; progesterone, P4), glucocorticoids (cortisol, F; cortisone E; corticosterone, B; 11-deoxycortisol, S; 21-hydroxyprogesterone, 21OHP4), and mineralocorticoids (aldosterone, A) from 150 MUl of human serum, plasma, or endometrium and endometriotic tissue homogenates. Samples spiked with isotope-labeled steroids as internal standards were extracted with toluene prior to LC-MS/MS analysis. The chromatographic separation of underivatized steroids was achieved on a biphenyl column with 0.2 mM NH4F as the eluent additive and a water-methanol gradient to improve E2 and E1 ionization. Method validation was performed with human plasma samples, and analysis of certified E2, T, F, and P4 reference serums (BCR-576, ERM-DA346, ERM DA192, ERM-DA347), as well as homogenates of endometrium and endometriotic tissue. A total of 27 steroids were included in the method development to ensure the specificity of the method. After validation, the method was found suitable for quantitative analysis of 11 steroids: E2 (6.7 pM-13 nM), E1 (1.3 pM-6.6 nM), T (3.3 pM-13 nM), A4 (13 pM-33 nM), 17OHP5 (32 pM-65 nM), 17OHP4 (33 pM-13 nM), F (33 pM-133 nM), E (13 pM-130 nM), B (33 pM-134 nM), S (13 pM-129 nM), and A (32 pM-32 nM). In addition, DHEA (333 pM-32 nM), P4 (13 pM-13 nM) and 21OHP4 (13 pM 13 nM) can be analyzed semiquantitatively. PMID- 29414009 TI - A gold standard method for the evaluation of antibody-based materials functionality: Approach to forced degradation studies. AB - The scope of this paper is to present a gold standard method to evaluate functional activity of antibody (Ab)-based materials during the different phases of their development, after their exposure to forced degradations or even during routine quality control. Ab-based materials play a central role in the development of diagnostic devices, for example, for screening or therapeutic target characterization, in formulation development, and in novel micro(nano)technology approaches to develop immunosensors useful for the analysis of trace substances in pharmaceutical and food industries, clinical and environmental fields. A very important aspect in diagnostic device development is the construction of its biofunctional surfaces. These Ab surfaces require biocompatibility, homogeneity, stability, specificity and functionality. Thus, this work describes the validation and applications of a unique ligand binding assay to directly perform the quantitative measurement of functional Ab binding sites immobilized on the solid surfaces. The method called Antibody Anti HorseRadish Peroxidase (A2HRP) method, uses a covalently coated anti-HRP antibody (anti-HRP Ab) and does not need for a secondary Ab during the detection step. The A2HRP method was validated and gave reliable results over a wide range of absorbance values. Analyzed validation criteria were fulfilled as requested by the food and drug administration (FDA) and European Medicines Agency (EMA) guidance for the validation of bioanalytical methods with 1) an accuracy mean value within +15% of the nominal value; 2) the within-assay precision less than 7.1%, and 3) the inter-day variability under 12.1%. With the A2HRP method, it is then possible to quantify from 0.04 * 1012 to 2.98 * 1012 functional Ab binding sites immobilized on the solid surfaces. A2HRP method was validated according to FDA and EMA guidance, allowing the creation of a gold standard method to evaluate Ab surfaces for their resistance under laboratory constraints. Stability testing was described through forced degradation studies after exposure of Ab-surfaces to storage, pH and aqueous-organic solvent mixture stresses. PMID- 29414010 TI - 177Lu-labeled cyclic Asn-Gly-Arg peptide tagged carbon nanospheres as tumor targeting radio-nanoprobes. AB - This study explores the potential of 177Lu-labeled carbon nanospheres as radio nanoprobes for molecular imaging and therapy. The carboxyl functionalized surface of carbon nanospheres (CNS) was conjugated with [Gly-Gly-Gly-c(Asn-Gly-Arg)], G3 cNGR peptide through amide bond for targeting tumor vasculature and with [2-(4 Aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid], p-NH2-Bz-DOTA for chelation with 177Lu. The nanosphere-peptide conjugate, DOTA-CNS-cNGR, was characterized by dynamic light scattering and zeta potential measurements, IR and UV experiments and did not show any in vitro cytotoxicity. The pharmacokinetics and biodistribution of 177Lu-labeled nanosphere-peptide conjugate, 177Lu-DOTA-CNS cNGR was compared with 177Lu-DOTA-CNS (without the peptide) as well as with 177Lu DOTA-cNGR (without carbon nanospheres). The radiolabeled nanosphere-peptide conjugate exhibited higher tumor accumulation than nanosphere-free radiolabeled peptide. The accumulation of the two radiolabeled probes in the tumor reduced to half during blocking studies with unlabeled G3-cNGR peptide. 177Lu-DOTA-CNS exhibited higher tumor uptake than 177Lu-DOTA-CNS-cNGR but rapid clearance of the latter nanoprobe from non-target organs resulted in significantly higher (p < 0.05) tumor-to-blood and tumor-to-muscle ratios at 24 and 48 h p.i. It is evident from this study that carbon nanospheres conjugated to specific vectors shall form an important part of targeted radionanomedicine in future. PMID- 29414011 TI - Simultaneous determination of trimethylamine N-oxide, choline, betaine by UPLC MS/MS in human plasma: An application in acute stroke patients. AB - Trimethylamine-N-oxide (TMAO) is derived from the gut microbiome and tissues metabolism of dietary choline and betaine. These molecules are closely related to the development of cardiovascular and cerebrovascular diseases. A rapid, sensitive and accurate method has been developed and validated for the simultaneous determination of trimethylamine N-oxide (TMAO), choline and betaine in human plasma using d9-trimethylamine N-oxide (TMAO), d9-choline, d9-betaine as the internal standard (IS). After methanol precipitation with 10 MUL plasma samples, the analytes were extracted and then separated on Amide column (2.1 * 100 mm, 1.7 MUm, waters) with an isocratic elution program consisting of acetonitrile-water (containing 10 mM ammonium formate pH = 3.0) at a flow of 400 MUL/min. The detection was achieved under the selected reaction monitoring (SRM) scan using positive electrospray ionization (ESI+) in 3 min. The mass transitions monitored were as follows: m/z 76.3 -> 58.4 for TMAO, m/z 104.2 -> 60.3 for choline, m/z 118.1 -> 58.3 for betaine, m/z 85.1 -> 66.3 for d9-TMAO, m/z 113.2 > 69.3 for d9-choline, and m/z 127.1 -> 67.2 for d9-betaine, respectively. The method has been fully validated for specificity, lower limit of quantification, linearity, stability, intra- and inter-day accuracy and precision. This assay combines simple sample processing with a short run time and small plasma volumes, making it well suited for high-throughput routine clinical or research purposes. The newly developed method was successfully applied to the patients (n = 220) suffered from acute stroke, and the concentration of choline was firstly found to be closely related with the prognosis of these patients. PMID- 29414012 TI - Isolation, identification and characterization of two novel process-related impurities in olanzapine. AB - Olanzapine is a marketed antipsychotic agent for treatment of both positive and negative symptoms of schizophrenia. The chemical synthesis of olanzapine drug substance involved the reaction of thienobenzodiazepine hydrochloride with N methylpiperazine. During the manufacture of olanzapine, two unknown impurities were present in pilot batches in the range of 0.08-0.22% based upon HPLC analysis. These unknown impurities were enriched from the mother liquor of reaction by preparative HPLC, and characterized by UV, FT-IR, LC-MS/TOF, 1D-NMR (1H, 13C, DEPT), 2D-NMR (1H-1H COSY, HSQC, HMBC, ROESY) and single-crystal X-ray diffraction analysis. Based on the complete spectral analysis and knowledge of the synthetic route of olanzapine, these two new impurities were identified as 2 methyl-4-(4-methyl piperazin-1-yl)-10-((methylthio)methyl)-thieno[2,3-b][1,5] benzodiazepine (impurity-I) and 10-(3-(1H-benzo[d]imidazol-2-yl)-5-methylthiophen 2-yl)-2-methyl-4-(4-methyl piperazin-1-yl)-thieno[2,3-b][1,5]benzodiazepine (impurity-II). Finally, prospects to the formation and controlling of impurity-I and II were discussed in detail. PMID- 29414013 TI - Identification of leachable impurities in an ophthalmic drug product originating from a polymer additive Irganox 1010 using mass spectroscopy. AB - Pharmaceutical packaging employs a wide variety of polymers owing to their desirable features, but the compounds that could leach from the polymers into the drug products can pose serious health risks. Therefore, it is extremely important to identify such compounds so that they can be adequately quantified and evaluated for toxicological impact/safety assessments. Not only the polymer components and the additives should be considered as sources for leachable impurities, their reaction/degradation products should also be evaluated. Irganox 1010 is a common commercial antioxidant (polymer additive) used in the manufacturing of polyolefin materials for container closure systems. In our study, we identified two Irganox1010 related leachable impurities in an ophthalmic drug product using rapid and straightforward orthogonal mass spectroscopy (LC-MS and GC-MS) methods The identified impurities were 7,9-Di-tert butyl-1 oxaspiro[4.5]deca-6,9-diene-2,8-dione and 3-[3,5-bis(tert-butyl)-1 hydroxy-4-oxocyclohexa-2,5-dienyl]propanoic acid which leached into the ophthalmic drug solution during storage. The analytical methods employed could potentially be used to identify the similar class of compounds as is or in drug products. PMID- 29414014 TI - Determination of oxycodone and its major metabolites in haematic and urinary matrices: Comparison of traditional and miniaturised sampling approaches. AB - Oxycodone is a widely prescribed, full agonist opioid analgesic. As such, it is used clinically to treat different kinds of painful conditions, with a relatively high potential for doping practices in athletes. In this paper, different classic and innovative miniaturised matrices from blood and urine have been studied and compared, to evaluate their relative merits and drawbacks within therapeutic drug monitoring (TDM) and to implement new protocols for anti-doping analysis. Plasma, dried blood spots (DBS) and dried plasma spots (DPS) have been studied for TDM purposes, while urine, dried urine spots (DUS) and volumetric absorptive microsamples (VAMS) from urine for anti-doping. These sampling techniques were coupled to an original bioanalytical method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the evaluation and monitoring of the levels of oxycodone and its major metabolites (noroxycodone and oxymorphone) in patients under pain management and in athletes. The method was validated according to international guidelines, with good results in terms of precision, extraction yield and accuracy for all considered micromatrices. Thus, the proposed sampling, pre-treatment and analysis are attractive strategies for oxycodone determination in human blood and urine, with advanced options for application to derived micromatrices. Microsampling procedures have significant advantages over classic biological matrices like simplified sampling, storage and processing, but also in terms of precision (<9.0% for DBS, <7.7% for DPS, <7.1% for DUS, <5.3% for VAMS) and accuracy (>73% for DBS, >78% for DPS, >74% for DUS, >78% for VAMS). As regards extraction yield, traditional and miniaturised sampling approaches are comparable (>67% for DBS, >74% for DPS, >75% for DUS, >75% for VAMS). All dried matrices have very low volumes, leading to a significant advantage in terms of analysis feasibility. On the other hand, this also leads to a corresponding decrease in the overall sensitivity. PMID- 29414015 TI - Hydrazine determination in allopurinol using derivatization and SPE for sample preparation. AB - Hydrazine is a useful building block in the synthesis of organic pharmaceuticals but it is highly toxic so its determination at low ppm range is required. In this work, hydrazine was determined in allopurinol active pharmaceutical ingredient (API) sample at 2.5 ppm level by using derivatization and solid phase extraction (SPE) followed by reversed phase liquid chromatography (RPLC). Hydrazine does not contain chromophore part and is not retained in RPLC thus derivatization was necessary for its determination. Benzaldehyde was found to be the most appropriate derivatization reagent so the analyzed solute was benzaldehyde azine, which had adequate UV absorption and could be retained in RPLC. The derivatization reaction was performed in 0.2 M NaOH solution/MeOH = 50/50 (v/v) mixture, which is a proper solvent for allopurinol, too. Because of the low detection limit, 50 mg sample had to be dissolved in 5 mL solvent. This is a very concentrated solution therefore column overload is expected. Using a C18 SPE for sample preparation allowed to get rid of the huge amount of allopurinol. As allopurinol has a more polar character than benzaldehyde azine, it was easy to wash out from the SPE phase. The benzaldehyde azine can be eluted with a strong solvent and then the eluted sample can be analyzed by RPLC. Limit test validation of the liquid chromatographic method has been performed as well. This complex but not complicated analysis can be used for the accurate determination of hydrazine in allopurinol API. Furthermore it is applicable for other APIs which are more polar than benzaldehyde azine and soluble in high concentration in the aqueous solvent. PMID- 29414016 TI - Rapid analysis of glutamate, glutamine and GABA in mice frontal cortex microdialysis samples using HPLC coupled to electrospray tandem mass spectrometry. AB - In vivo measurement of multiple neurotransmitters is highly interesting but remains challenging in the field of neuroscience. GABA and l-glutamic acid are the major inhibitory and excitatory neurotransmitters, respectively, in the central nervous system, and their changes are related to a variety of diseases such as anxiety and major depressive disorder. This study described a simple method allowing the simultaneous LC-MS/MS quantification of l-glutamic acid, glutamine and GABA. Analytes were acquired from samples of the prefrontal cortex by microdialysis technique in freely moving mice. The chromatographic separation was performed by hydrophilic interaction liquid chromatography (HILIC) with a core-shell ammonium-sulfonic acid modified silica column using a gradient elution with mobile phases consisting of a 25 mM pH 3.5 ammonium formate buffer and acetonitrile. The detection of l-glutamic acid, glutamine and GABA, as well as the internal standards [d6]-GABA and [d5]-glutamate was performed on a triple quadrupole mass spectrometer in positive electrospray ionization and multiple reaction monitoring mode. The limit of quantification was 0.63 ng/ml for GABA, 1.25 ng/ml for l-glutamic acid and 3.15 ng/ml for glutamine, and the intra-day and inter-day accuracy and precision have been assessed for the three analytes. Therefore, the physiological relevance of the method was successfully applied for the determination of basal extracellular levels and potassium-evoked release of these neuroactive substances in the prefrontal cortex in adult awake C57BL/6 mice. PMID- 29414017 TI - A validated inductively coupled plasma mass spectrometry (ICP-MS) method for the quantification of total platinum content in plasma, plasma ultrafiltrate, urine and peritoneal fluid. AB - Oxaliplatin is a platinum (Pt)1 containing antineoplastic agent that is applied in current clinical practice for the treatment of colon and appendiceal neoplasms. A fully validated, highly sensitive, high throughput inductively coupled plasma mass spectrometry (ICP-MS) method is provided to quantify the total Pt content in plasma, plasma ultrafiltrate, urine and peritoneal fluid. In this ICP-MS approach, the only step of sample preparation is a 1000-fold dilution in 0.5% nitric acid, allowing the analysis of 17 samples per hour. Detection of Pt was achieved over a linear range of 0.01-100 ng/mL. The limit of quantification was 18.0 ng/mL Pt in plasma, 8.0 ng/mL in ultrafiltrate and 6.1 ng/mL in urine and peritoneal fluid. The ICP-MS method was further validated for inter-and intraday precision and accuracy (<=15%), recovery, robustness and stability. Short-term storage of the biofluids, for 14 days, can be performed at 4 degrees C, -24 degrees C and -80 degrees C. As to long-term stability, up to 5 months, storage at -80 degrees C is encouraged. Furthermore, a timeline assessing the total and unbound Pt fraction in plasma and ultrafiltrate over a period of 45 h is provided. Following an incubation period of 5 h at 37 degrees C, 19-21% of Pt was recovered in the ultrafiltrate, emphasizing the extensive and rapid binding of oxaliplatin-derived Pt to plasma proteins. The described method can easily be implemented in a routine setting for pharmacokinetic studies in patients treated with oxaliplatin-based hyperthermic intraperitoneal perioperative chemotherapy. PMID- 29414018 TI - Assessment of oral formulation-dependent characteristics of orodispersible tablets using texture profiles and multivariate data analysis. AB - Orodispersible tablets (ODTs) emerged as dosage forms recommended for special groups of patients like pediatrics or geriatrics, due to their multiple advantages. Among their critical quality attributes, palatability determines patient acceptance, with high impact on treatment efficacy. The aim of this study was to develop an instrumental method to assess in vivo disintegration time and palatability of ODTs. The formulation factors that can influence palatability were refined through an experimental design. The most important ones were taken forward and a calibration set was prepared for multivariate calibration model development. The ODTs were tested for their pharmaceutical properties, texture profile, followed by in vivo disintegration and palatability characteristics assessed by a panel of 16 healthy volunteers. Acceptability was correlated to high palatability scores, sweet taste and long disintegration time and negatively correlated to with the bitter taste and a voluminous residue. Results revealed the importance of choosing the right type of filler or filler ratio for the oral disintegration time and associated mouth feel. The calibration set included formulations with different ratios of mannitol and microcrystalline cellulose as fillers. Regression models were built by correlating the texture profiles to the in vivo evaluation parameters. The model performance was good on both external prediction set formulations and on marketed ODTs, with good predictive capacity (Q2 > 0.7) for most of the subjective ODTs characteristics: in vivo disintegration time, residual volume and palatability. PMID- 29414019 TI - Identification of metabolic pathway disturbances using multimodal metabolomics in autistic disorders in a Middle Eastern population. AB - We analyzed for the first time the metabolic profile of Lebanese children affected by autistic disorders to compare this profile to other metabolomics studies and to identify the associated metabolic disturbances. Urine samples of 40 patients with Autism spectrum disorder (ASD) and 40 healthy matched controls were analyzed using nuclear magnetic resonance (NMR) and liquid chromatography coupled to high-resolution mass spectrometry (LC-MS). Multivariate analysis on analytical data fusion was conducted on the training set of 50 urine samples, and then validated with a test set of 30 samples, this repeated 10 times. The model was also evaluated using a receiver operating characteristic curve showing a specificity and a sensitivity of 86% and 80%, respectively. Among the most significant metabolites that contributed to the discrimination between ASD and controls, we confirmed the perturbations of tyrosine, 2-hydroxybutyrate, creatine and glutamate. We found new metabolites such as trigonelline, cysteic acid and guanine. We found metabolic perturbations including amino acids, carbohydrates and oxidative stress pathways which added value for the contribution of known metabolic disturbances in ASD observed in populations of other ethnic and geographic origins. PMID- 29414020 TI - Evaluation of stir-bar sorptive extraction coupled with thermal desorption GC-MS for the detection of leachables from polymer single use systems to drugs. AB - Stir-bar Sorptive Extraction (SBSE) in combination with thermal desorption and gas chromatography-mass spectrometry (TD-GC-MS) is widely accepted as the gold standard analysis method for trace amounts of organic substances, including leachables in aqueous matrices. Meanwhile, as far as pharmaceutical quality control in protein-based parenteral drugs is concerned, the use of SBSE analysis remains unexplored. Previous studies reported a strong influence of the matrix on the method's recovery. The scope of the present work was to fill in the unexplored territory in a threefold manner 1) by quantifying the effects that various matrices commonly found in pharmaceutical processing have on the recovery, 2) by comparing between different coating materials for stir bar (namely between polydimethylsiloxane (PDMS) material and ethylene-glycol (EG) PDMS), and 3) by proposing a preparation step for stir-bar to mitigate inhibitory effects. The current study shows no inhibition of SBSE by protein matrices (p > 0.15). Further the influence of various drug matrices on the recovery of leachables with a log Ko/w >= 3.6 is negligible (-3.9 to 3.8%). In contrast, the inhibition effect caused by an alkaline media led to a recovery decrease of 42.9%. For leachables with a log Ko/w < 3.6, the relative recovery in the presence of various proteins ranged from -72.8% to 15.6%, depending on the excipients of the drug product and not on the protein itself. The highest loss in sensitivity was observed when the excipient benzyl alcohol was present in the drug. Nonetheless, the limit of detection for the tested leachables in the inhibitory matrices was still below 3 MUg/L (ppb). Additionally, SBSE was observed to be quantitatively reliable in all tested drug matrices for concentrations from 0.005 to 0.1 mg/mL (r2 > 0.992). On average, the conventional PDMS coating resulted in a 28-fold higher signal-to-noise ratio compared to EG PDMS. Furthermore, a broader range of leachables was detectable with the PDSM coating. Preceding stir-bar preparation consisting of a simple soaking step improved the enrichment by 14%, effectively lowering the limit of detection. PMID- 29414021 TI - Development and validation of a high-performance liquid chromatography method for the quantitation of intracellular PARP inhibitor Olaparib in cancer cells. AB - Olaparib is a potent PARP inhibitor in clinical use for cancer therapy. A bioanalytical assay was developed and validated for quantitation of intracellular level of olaparib in cells exposed to the drug. The assay involves an optimized and straightforward sample pretreatment with acetonitrile for olaparib solubilization, cell lysis and protein precipitation, and a high performance liquid chromatography (HPLC) method with ultraviolet detection. Several parameters in both the sample preparation and the detection steps were investigated. Optimal chromatographic conditions were achieved with a 5 MUL injection on a Nova-Pak(r) C18 column (150 * 3.9 mm, 4 MUm) using a mobile phase consisting of acetonitrile and ultra-pure water in gradient mode, at a constant 1.2 mL/min flow rate, at 35 degrees C. Detection was carried out at 254 nm and a diode array detector was used to insure purity of the olaparib peak. The method was validated according to Food and Drug Administration guidelines. Linearity, accuracy and precisions were satisfactory over the concentration range of 200 2000 ng/mL. Limits of detection and quantification for olaparib were 50 ng/mL and 200 ng/mL, respectively. Good stability was showed in three relevant analytical conditions. Finally, the validated analytical method was successfully used to estimate the intracellular level of olaparib in SUM1315 breast cancer cells. A significant difference was observed in intracellular drug level after 1 and 3 h incubations. This method permitting measurement of drug level in tumor cells would allow dosage optimization and improvement of treatment response predictions. PMID- 29414022 TI - A novel BRCA1 gene deletion detection in human breast carcinoma MCF-7 cells through FRET between quantum dots and silver nanoclusters. AB - BRCA1 (breast cancer 1) genomic deletions are the most important founder mutations in breast cancer patients and can be passed to you from your mother or father. Herein, we report a silver nanoclusters-based (AgNCs-based) fluorescence resonance energy transfer (FRET) method for detection of BRCA1 gene deletion. The method relies on the specific hybridization of DNA-AgNCs fluorescent probe to deleted genes and interaction between double stranded DNA-AgNCs and QD, and the signal amplification through energy transfer from fluorescent AgNCs to QDs during FRET. Such fabricated QDs/DNA-AgNCs interaction might be beneficial for the nanomaterials based biosensing methods Under best possible conditions a linear correlation was established between the fluorescence intensity and the concentration of deletion sequence in the range of 5.0 * 10-13-1.0 * 10-9 M with a detection limit of 1.2 * 10-13 M. Using this method, we could effectively determine gene deletions by using the nonamplified genomic DNAs that were extracted from the MCF-7 as a breast cancer cell line. PMID- 29414023 TI - A robust and easily reproducible protocol for the determination of size and size distribution of iron sucrose using dynamic light scattering. AB - Iron sucrose (IS), a nanocolloidal solution used in the treatment of iron deficiency anemia, is currently under investigation for the elucidation of its critical quality attributes. Assessment of IS's size and size distribution has been recently attempted using dynamic light scattering (DLS). However, due to heterogeneous interpretation of DLS data, variable results were retrieved. The aim of this work was to establish a simple and reproducible DLS protocol to unequivocally define the size and size distribution of IS by using size distribution approximation in Number. Underlining the limitations of the commonly used DLS approximations, we identified the drug as being composed of a population of monodisperse nanoparticles of about 7 nm in diameter. The method here described might therefore be useful for the evaluation of quality, safety and efficacy of IS and its follow-on versions. PMID- 29414024 TI - Metabolism of flavonolignans in human hepatocytes. AB - This study examined the in vitro biotransformation of eight structurally related flavonolignans, namely silybin, 2,3-dehydrosilybin, silychristin, 2,3 dehydrosilychristin, silydianin, 2,3-dehydrosilydianin, isosilybin A and isosilybin B. The metabolic transformations were performed using primary cultures of human hepatocytes and recombinant human cytochromes P450 (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). The metabolites produced were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry. We found that each of the tested compounds was metabolized in vitro by one or more CYP enzymes, which catalyzed O-demethylation, hydroxylation, hydrogenation and dehydrogenation reactions. In human hepatocytes, silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, and isosilybins A and B were directly conjugated by sulfation or glucuronidation. Moreover, isosilybin A was also converted to a methyl derivative, while isosilybin B was hydroxylated and methylated. Silydianin and 2,3-dehydrosilydianin were found to undergo hydrogenation and/or glucuronidation. In addition, 2,3-dehydrosilydianin was found to be metabolically the least stable flavonolignan in human hepatocytes, and its main metabolite was a cleavage product corresponding to a loss of CO. We conclude that the hepatic biotransformation of flavonolignans primarily involves the phase II conjugation reactions, however in some cases the phase I reactions may also occur. These results are highly relevant for research focused on flavonolignan metabolism and pharmacology. PMID- 29414026 TI - BDNF levels are associated with autistic traits in the general population. AB - Evidence supports the notion that autistic symptoms and behaviors should be regarded as dimensional traits. The present study aimed to investigate the role of vasopressin (AVP), brain-derived neurotrophic factor (BDNF) and oxytocin (OXT) as potential biochemical correlates of subclinical autistic traits in a cohort of healthy young adults. One hundred and fifty-three subjects (80 males, 73 females) were recruited. Participants completed the Autism Spectrum Quotient (AQ), a widely used measure for the identification of autistic traits in the general population. Additionally, blood samples were obtained from all participants at the same time of the day to control for circadian variation. We conducted a multiple regression analysis using the AQ score as the dependent variable and age, sex, AVP, BDNF and OXT levels as the independent variables. The model explained approximately the 22% of the variance of the AQ score. Among the parameters included in the analysis, only BDNF levels were independent predictors of AQ score. PMID- 29414025 TI - Effects of testosterone dose on spatial memory among castrated adult male rats. AB - Previous research on the activational effects of testosterone on spatial memory has produced mixed results, possibly because such effects are dose-dependent. We tested a wide range of testosterone doses using two spatial memory tasks: a working-reference memory version of the radial-arm maze (RAM) and an object location memory task (OLMT). Adult male Sprague-Dawley rats were castrated or sham-castrated and given daily injections of drug vehicle (Oil Sham and Oil GDX) or one of four doses of testosterone propionate (0.125, 0.250, 0.500, and 1.000 mg T) beginning seven days before the first day of behavioral tests and continuing throughout testing. For the RAM, four arms of the maze were consistently baited on each day of testing. Testosterone had a significant effect on working memory on the RAM, with the Oil Sham, 0.125 mg T, and 0.500 mg T groups performing better than the Oil GDX group. In contrast, there was no significant effect of testosterone on spatial reference memory on the RAM. For the OLMT, we tested long-term memory using a 2 h inter-trial interval between first exposure to two identical objects and re-exposure after one object had been moved. Only the 0.125 and 0.500 mg T groups showed a significant increase in exploration of the moved object during the testing trials, indicating better memory than all other groups. Testosterone replacement restored spatial memory among castrated male rats on both behavioral tasks, but there was a complex dose response relationship; therefore, the therapeutic value of testosterone is likely sensitive to dose. PMID- 29414027 TI - Associations of work stress with hair cortisol concentrations - initial findings from a prospective study. AB - There is ample evidence supporting the link between stress at the workplace and physical and mental health. One of the pathways potentially mediating those associations may involve the hypothalamic-pituitary-adrenal (HPA) axis, with cortisol as an end product. While theoretically plausible, findings on the association of self-reported work stress with hair cortisol concentrations (HCC) are inconclusive, being potentially biased by omitted pertinent factors. This issue can be addressed, among others, by eliminating time-invariant factors through consideration of variation within persons over time. To this end, the present study examined the association between variation in HCC and perceived work stress - as assessed by the Effort-Reward-Imbalance (ERI) model - between two points in time (t1 and t2) over one year in a sample of 40 male factory workers. Neither a cross-sectional association, nor a link between change in ERI and HCC levels at t2 was observed. There was however a robust association of the change in ERI with the change of HCC. This effect was independent of baseline HCC and other confounders (Beta = 0.414, S.E. = 0.155, p = 0.012). Accordingly, this is the first study revealing prospective evidence for the associations of work stress with HCC, while excluding potentially time-stable confounding factors, like genetic factors or phenotypic hair color. PMID- 29414029 TI - Control of cardiovascular responses to stress by CRF in the bed nucleus of stria terminalis is mediated by local NMDA/nNOS/sGC/PKG signaling. AB - The aims of the present study were to assess an interaction of corticotropin releasing factor (CRF) neurotransmission within the bed nucleus of the stria terminalis (BNST) with local nitrergic signaling, as well as to investigate an involvement of activation of local NMDA glutamate receptor and nitric oxide (NO) signaling in control of cardiovascular responses to acute restraint stress by BNST CRF neurotransmission in rats. We observed that CRF microinjection into the BNST increased local NO release during restraint stress. Furthermore, bilateral microinjection of CRF into the BNST enhanced both the arterial pressure and heart rate increases evoked by restraint stress, but without affecting the sympathetically-mediated cutaneous vasoconstriction. The facilitation of both pressor and tachycardiac responses to restraint stress evoked by BNST treatment with CRF were completely inhibited by local pretreatment with either the selective NMDA glutamate receptor antagonist LY235959, the selective neuronal nitric oxide synthase (nNOS) inhibitor Nomega-Propyl-l-arginine (NPLA), the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1 one (ODQ) or the protein kinase G (PKG) inhibitor KT5823. Taken together, these results provide evidence that BNST CRF neurotransmission facilitates local NMDA mediated glutamatergic neurotransmission and activates nitrergic signaling, and this pathway is involved in control of cardiovascular responses to stress. PMID- 29414030 TI - Effects of blood glucose on delay discounting, food intake and counterregulation in lean and obese men. AB - BACKGROUND: Delay discounting as a measure of impulsivity has been shown to be higher in obesity with an association of increased food intake. Moreover, obese humans showed a higher wanting for high-calorie food than lean men when blood glucose concentrations were low. First studies linking blood glucose levels to delay discounting yielded mixed results. We hypothesized that obese people - in comparison to lean men - have a relative lack of energy, especially when blood glucose levels are low, that results in higher levels of delay discounting, food intake and hormonal counterregulation. METHODS: We investigated 20 lean and 20 obese healthy young men in a single-blind balanced cross-over design. With a standardized glucose clamp technique, subjects underwent a hypoglycemic state in one condition and a euglycemic state in the control condition. Regularly, blood was sampled for assessment of hormonal status, and questionnaires were filled out to assess delay discounting and symptom awareness. After normalizing blood glucose concentrations, subjects were free to eat from a standardized test buffet, followed by a snack test. RESULTS: Delay discounting was higher in obese than in lean men throughout experiments (p < 0.03). However, we did not observe significant discounting differences between glucose conditions (p > 0.1). Furthermore, the discounting performance did not correlate with food intake from the test buffet or snack test (p > 0.3). As a response to hypoglycemia, hormonal counterregulation was pronounced in both weight groups (p < 0.03), but responses of ACTH, norepinephrine and glucagon were stronger in obese compared to lean men (p < 0.03). Also, intake from the high-calorie buffet after hypoglycemia compared to euglycemia was higher in obese subjects (p < 0.02) but comparable in lean men (p > 0.5). CONCLUSIONS: Our data suggest that augmented delay discounting is a robust feature in obesity that is not linked to glucose levels or actual food intake. With our systematically controlled approach, combining performance in delay discounting with regard to distinct blood glucose levels, different weight groups, counterregulatory behavior and food intake, our results imply that delay discounting is not susceptible to fluctuations of blood glucose and do not support the assumption that a low body's energy content leads to increased impulsivity. Further replications including women and larger sample sizes are needed to corroborate our data. PMID- 29414028 TI - Relation of long-term patterns in caregiving activity and depressive symptoms to telomere length in older women. AB - BACKGROUND: Research links psychological stress to accelerated cellular aging. Here we examined whether long-term patterns of depression and caregiving burden, forms of chronic psychological stress, were associated with shorter telomere length, a biomarker of cellular aging. METHODS: The study included 1250 healthy older women (mean: 68.0; range: 60-81 years) in the Nurses' Health Study. Long term patterns in depressive symptoms and caregiving activity (separated into care of children/grandchildren vs. ill or disabled family members/others) incorporated questionnaire data between 1992 and 2000; relative leukocyte telomere lengths (LTLs) were measured in 2000-2001. Least-squares means LTL z-scores were calculated across categories of depression patterns and caregiving intensity. RESULTS: Six empirically-derived latent classes of depressive symptom trajectories were identified: minimal-stable (63.7%), mild-worsening (3.9%), subthreshold-improving (22.8%), subthreshold-worsening (2.7%), clinical range depressive-improving (6.2%), and clinical range depressive-persistent (0.6%). After collapsing trajectory patterns into 4 groups (combining those with minimal and mild symptoms into one group and those with clinical range depressive symptoms into one group) due to very small sample sizes in some groups, we observed marginal associations (p = 0.07): e.g., the least-squares means LTL z scores were lowest (-0.08; 95% CI: -0.22 to 0.06) for the clinical range depressive symptoms group and highest (0.12; 0.04-0.20) for the subthreshold improving group (Tukey's post-hoc pairwise p = 0.07). With six depressive symptom trajectories, no significant associations were observed with regard to telomere lengths. There were no significant associations between caregiving intensity and LTLs. CONCLUSIONS: There were no associations between long-term patterns of caregiving burden and telomere lengths among older women. Possible differences in telomere lengths by types of long-term depressive symptom trajectories may warrant further investigation. PMID- 29414031 TI - Unfolded protein response and associated alterations in toll-like receptor expression and interaction in the hippocampus of restraint rats. AB - Recent evidence suggests that the cellular response to stress often elicits the unfolded protein response (UPR), which has an active role in major depression in emotionally relevant regions of the brain, such as the hippocampus. Much of the UPR activity has been found to be coalesced with the pro-inflammatory environment of the depressed brain. Specifically, downstream transcriptions of pro inflammatory cytokines and increased regulation of candidate inflammatory mediators, such as toll-like receptors (TLRs), are promoted by the UPR. The present study examined the hippocampus associated expression profile of Tlr genes and their interaction with the UPR chaperone GRP94 in stress-induced rodent model of depression (restraint stress model). Also, the expression status of UPR related genes was evaluated in hippocampus using the same model. mRNA and protein levels of Tlr and UPR associated genes were examined by qRT-PCR and Western blot, respectively. Co-immunoprecipitation (Co-IP) method was used to determine the direct interaction between TLRs with GRP94 in depressed rat brain. The results showed that both UPR (Xbp-1, its spliced variant sXbp-1, Atf-6, Chop, and Grp94) and Tlr (2, 3, 4, 7 and 9) genes were significantly upregulated in the hippocampi of rats who were exposed to restraint stress. Similar upregulation was observed in the protein levels of the above-mentioned TLRs and the UPR chaperone protein GRP94 as well as total and phosphorylated forms of sensor proteins IRE1alpha and PERK. Further, a significantly increased interaction was observed between GRP94 and the activated TLR proteins. Since, increased inflammatory activity in vulnerable areas like hippocampus is coherently associated with depressed brain; our present data suggest that the UPR may be an integral part of increased activity of inflammatory regulations in depression. PMID- 29414033 TI - Associations of inflammation with symptom burden in patients with acute myeloid leukemia. AB - The aim of the study was to assess the association inflammation with symptom burden in patients with acute myeloid leukemia (AML), assessed before and during remission induction chemotherapy (IC). Patients with AML (n = 95) were followed from baseline (before IC) to the third week of IC for severity of self-reported somatic symptoms (assessed with the MD Anderson Symptom Inventory) and plasma levels of 13 inflammation-related biomarkers (n = 64). A composite symptom burden severity score was computed as the average score of the six most severe somatic symptoms i.e., fatigue, disturbed sleep, drowsiness, dry mouth, lack of appetite, and pain. Results from cross-sectional analyses showed that inflammation was weakly associated with symptom burden before IC (multiple regression model, explained variance = 10%) but this association grew stronger during IC (week 3 explained variance = 35%). About half of the sample showed a change over time in symptom severity. These changes were not reflected in similar changes over time in inflammatory markers, suggesting that it is the absolute concentration of a given inflammatory marker at a given time point rather than its relative change over time that is of importance. In conclusion, inflammation was strongly associated with symptom burden only during IC, possibly because expression of cytokines only then becomes relevant for regulation of symptom burden. While the current study does not allow for determination of causality, the results suggest that AML patients might benefit from anti-inflammatory interventions during treatment to alleviate somatic symptom experience. PMID- 29414032 TI - Functional TSPO polymorphism predicts variance in the diurnal cortisol rhythm in bipolar disorder. AB - INTRODUCTION: Psychosocial stress contributes to onset/exacerbation of mood episodes and alcohol use, suggesting dysregulated diurnal cortisol rhythms underlie episodic exacerbations in Bipolar Disorder (BD). However, mechanisms underlying dysregulated HPA rhythms in BD and alcohol use disorders (AUD) are understudied. Knowledge of associated variance factors have great clinical translational potential by facilitating development of strategies to reduce stress-related relapse in BD and AUD. Evidence suggests structural changes to mitochondrial translocator protein (TSPO) (a regulator of steroid synthesis) due to the single nucleotide polymorphism rs6971, may explain much of this variance. However, whether rs6971 is associated with abnormal HPA rhythms and clinical exacerbation in humans is unknown. METHODS: To show this common TSPO polymorphism impacts HPA rhythms in BD, we tested whether rs6971 (dichotomized: presence/absence of polymorphism) predicted variance in diurnal cortisol rhythm (saliva: morning and evening for 3 days) in 107 BD (50 with and 57 without AUD) and 28 healthy volunteers of similar age and ethno-demographic distribution. RESULTS: Repeated measures ANOVA confirmed effects BD (F5,525 = 3.0, p = 0.010) and AUD (F5,525 = 2.9, p = 0.012), but not TSPO polymorphism (p > 0.05). Interactions were confirmed for TSPO * BD (F5,525 = 3.9, p = 0.002) and for TSPO * AUD (F5,525 = 2.8, p = 0.017). DISCUSSION: We identified differences in diurnal cortisol rhythm depending on presence/absence of common TSPO polymorphism in BD volunteers with or without AUD and healthy volunteers. These results have wide ranging implications but further validation is needed prior to optimal clinical translation. PMID- 29414034 TI - Stress induced cortisol release and schizotypy. AB - Cortisol is involved in preparing the body's response for stress. However, in those at risk for mental health problems, abnormal cortisol release following stress has been reported. In particular, we are yet to fully understand how stress leads to an exacerbation of symptoms and progression of risk in those who express psychosis proneness or schizotypy. Using the Trier Social Stress Test, we examined the effect of experimentally induced psychosocial stress on cortisol release in otherwise healthy individuals with schizotypal traits. This cross sectional study included 58 individuals (32.76% male, mean age 22.43). Schizotypy was assessed by total Schizotypal Personality Questionnaire score and we additionally captured ratings of subjective stress. Salivary cortisol was collected over six time points spread prior to and after stress induction and was available for analysis in 39 individuals (28.21% male, mean age 22.77). Those with high schizotypal traits exhibited higher baseline cortisol levels (5.18 nmoL vs 3.71 nmoL). However, those with high schizotypal traits also displayed reduced mean cortisol release (2.02 nmoL vs 5.11 nmoL) and had a delayed cortisol release peak following psychosocial stress. These results indicate those with high schizotypal traits do not display physiological readiness following psychosocial stressors, perhaps due to an already taxed stress system. PMID- 29414036 TI - Theoretical Insights into Imidazolidine Oxidation of Imidacloprid by Cytochrome P450 3A4. AB - The metabolic mechanisms for imidazolidine oxidation of imidacloprid (IMI) by cytochrome P450 3A4 (CYP3A4) have been investigated using quantum mechanical/molecular mechanical (QM/MM) calculations. The binding mode of CYP3A4 with IMI is examined by molecular docking in collaboration with molecular dynamics (MD) simulations. The results show that there are six amino acid residues, involving Arg192, Phe195, Ile349, Ala285, Phe284 and Phe88, closely distributed around the IMI. The binding free energy analysis exhibits that the CYP3A4-IMI binding structure is stabilized by electrostatic interaction and van der Waals interaction. Arg192 plays a major role in the binding of CYP3A4 with IMI based on its polarity and the hydrogen bond between the H atom in Arg192 side chain and the nitryl O atom of IMI. Two possible pathways, pathway 1 and pathway 2, are evaluated. Two spin states of the Fe (III) center, quartet and doublet, are considered. The free energy calculations are done using QM/MM steered molecular dynamics (SMD) simulation at the B3LYP/6-31 + G(d):ff14SB level for two pathways. The ONIOM QM/MM single-point calculations at the B3LYP/6-311 + G(2d,2p):ff99SB//B3LYP/6-31 + G(d): ff14SB and M06-2X/6-311 + G(2d,2p):ff99SB//B3LYP/6-31 + G(d):ff14SB levels are carried out to obtain more credible energy information. The results indicate that for both pathways, the free energy barriers on the low-spin doublet state are lower than those on the high-spin quartet state. Both pathways are the stepwise processes. Pathway 1 has higher possibility to occur with the free energy barriers being lower by 10-15 kcal.mol-1 compared with pathway 2, which gives rise to trans-5'-hydroxyl-IMI as the final product. The first proton-transfer is the rate-limiting step and the calculated activation free energy is consistent with the experimental conclusion. PMID- 29414035 TI - Hair cortisol and the relationship with chronic pain and quality of life in endometriosis patients. AB - Endometriosis is a chronic estrogen-dependent disease in which pelvic pain is the dominant symptom. The negative effects of endometriosis on the life of women with this disease can be a cause of stress. Stress levels can be measured in different ways, mostly reflecting acute stress responses. Hair cortisol measurements are a reflection of long-term systematic cortisol levels. In this study a first attempt is made to measure cortisol levels in hair of endometriosis patients in comparison with healthy controls. Moreover, it is explored whether chronic pain symptoms as well as different aspects of Health Related Quality of Life (HRQoL) are associated with hair cortisol levels in women with endometriosis. Results show that the mean hair cortisol level is significantly higher in women with endometriosis compared to healthy controls (p = 0.018). There is a positive correlation between hair cortisol level and HRQoL in patients but not in controls (Rho 0.426). The level of hair cortisol does not correlate with the reported pain intensity in patients (Rho -0.082). These results are indicative of an altered HPA-axis function in endometriosis patients, possibly caused by higher chronic stress level in these patients. Moreover, a potential explanation for the positive correlation of cortisol with the HRQoL in these patients is that patients with a high HRQoL have an adequate stress response by increasing their cortisol levels as a response to physical and emotional stress induced by the endometriosis. PMID- 29414037 TI - DFT investigation on the selective complexation of Fe3+ and Al3+ with hydroxypyridinones used for treatment of the aluminium and iron overload diseases. AB - The chelating agents for Al3+ and Fe3+ metal cations with therapeutic applications have been considered in the recent years. In designing of the hydroxypyridinones (HPOs) as the therapeutic chelating agents for iron and aluminium overload pathologies, quantum mechanical (QM) calculations are necessary for predicting the binding energies and thermodynamic parameters of the metal-HPO complexes. Three derivatives of the HPOs called 3-hydroxy-1,2 dimethylpyridin-4(1H)-one (DFP), 3-hydroxy-4(1H)-pyridinone (HOPO) and 5-hydroxy 2-(hydroxymethyl)pyridin-4(1H)-one (P1) were investigated for complexation with Fe3+ and Al3+ metal ions. Because of the maximum interaction between Fe3+ and HPOs, all HPOs form stable complexes with Fe3+ metal ion. Moreover, it was found that [Fe-P1]2+ is a more stable complex than [Fe-DFP]2+ and [Fe-3,4-HOPO]2+ in the gas phase and water, confirming that P1 is the strongest selective iron chelator. The more stability of [Fe-P1]2+ was attributed to an intramolecular hydrogen bond formation between the hydrogen atom of NH group and the oxygen atom of CH2OH chain. All complexes of the HPOs with Fe3+ and Al3+ were formed through the oxygen atoms of the CO and OH groups of the HPO. Natural bond orbital analysis showed that the interaction of the lone pair electrons of the oxygen atom of the chelator and antibonding orbitals of the Al3+ and Fe3+ are important in the complex formation. Topological parameters at the bond critical points confirmed the effective interaction between the Al3+ and Fe3+ metal ions and HPO as well as the nature of the metal-oxygen bonds. PMID- 29414038 TI - Investigation of 15-hydroxyprostaglandin dehydrogenase catalytic reaction mechanism by molecular dynamics simulations. AB - 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a prostaglandin metabolizing enzyme that oxidizes the hydroxyl group at carbon 15 (C15). The aim of the present work is to propose the main amino acids that catalyze the reaction through studying the intermolecular interaction between the ligand and the enzyme inside the active site using molecular dynamics simulation (MD). Therefore, MD simulations for two 15-PGDH systems bound with a substrate (PGE2) or an inhibitor (compound 4) were performed to investigate the importance of ligand interaction on the behavior of amino acids in the active site. Findings from this work proposed the amino acids: Tyr151, Gln148 & Asn95 to act as a catalytic triad for the reaction as hydrogen bond interactions, dihedral rotation analysis and MM GBSA free energy calculations revealed. PMID- 29414039 TI - Untying the knot of transcription factor druggability: Molecular modeling study of FOXM1 inhibitors. AB - The FOXM1 protein is a relevant transcription factor involved in cancer cell proliferation. The direct or indirect inhibition of this protein's transcriptional activity by small molecule drugs correlates well with a potentially significant anti-cancer profile, making this macro molecule a promising drug target. There are a few drug molecules reported to interact with (and inhibit) the FOXM1 DNA binding domain (FOXM1-BD), causing downregulation of protein expression and cancer cell proliferation inhibition. Among these drug molecules are the proteasome inhibitor thiostrepton, the former antidiabetic drug troglitazone, and the new FDI-6 molecule. Despite their structural differences, these drugs exert a similar inhibitory profile, and this observation prompted us to study a possible similar mechanism of action. Using a series of molecular dynamics simulations and docking protocols, we identified essential binding interactions exerted by all three classes of drugs, among which, a pi-sulfur interaction (between a His287 and a sulfur-containing heterocycle) was the most important. In this report, we describe the preliminary evidence suggesting the presence of a drug-binding pocket within FOXM1 DNA binding domain, in which inhibitors fit to dissociate the protein-DNA complex. This finding suggests a common mechanism of action and a basic framework to design new FOXM1 inhibitors. PMID- 29414040 TI - Identification and characterization of the druggable kinase targets of olmesartan and its analogues from a systematic kinase-chemical interaction profile in atherosclerosis. AB - Olmesartan (OL) is the pharmacologically active metabolite of Olmesartan medoxomil (OM), an FDA-approved angiotensin II receptor antagonist for administrating cardiovascular diseases. The drug has been found to have potential effects on diverse protein kinase signaling involved in the pathogenesis of atherosclerosis, either by directly inhibiting the hub kinases or by indirectly modulating marginal members in the signaling pathways. In the present study, we computationally model the kinase-chemical Interaction Profile between six OL related chemicals (i.e. OL, OM, Valsartan [VL], Losartan [LS], Candesartan [CD] and Telmisartan [TL]) and 23 human protein kinases in atherosclerosis. The profile is analyzed systematically at molecular level to identify unexpected kinase targets for OL. There is a good consistence between co-citation frequency and affinity scoring for the chemical association with kinase candidates; the OL and its analogs VL and LS exhibit a similar binding profile to the atherosclerosis kinase spectrum. It is suggested that the Ser/Thr-specific kinases PI3Kalpha and ROCK1 are potential druggable targets of OL for atherosclerosis therapy. As a paradigm, kinase assays reveal that the inhibitory potency of OL and Y-27632 (positive control) on ROCK1 is determined at micromolar level, while the OM (negative control) possesses no detectable activity for the kinase. PMID- 29414041 TI - Wisdom of crowds for synthetic accessibility evaluation. AB - Synthetic accessibility evaluation is a process to assess the ease of synthesis of compounds. A rapid method for the assessment of synthetic accessibility for a vast number of chemical compounds is expected to bring about a breakthrough in the drug discovery. Although several computational methods have been proposed, the compound evaluation has still been processed by medicinal chemists; however, the low throughput of the human evaluation due to the lack of chemists is a critical issue for handling a large number of compounds. We propose the use of crowdsourcing for addressing this problem, and we conducted experiments to investigate the feasibility of incorporating semi-experts and a statistical aggregation method into the synthetic accessibility evaluation. Our experimental results show that we can obtain accurate synthetic accessibility scores through the statistical aggregation of judgments from semi-experts. PMID- 29414042 TI - Conformational and NBO studies of serotonin as a radical scavenger. Changes induced by the OH group. AB - Serotonin (5-hydroxytryptamine, SER) is a neurotransmitter that affects many different processes within the human body. We studied the conformational space of SER, and explored in depth the significant stereoelectronic features for the structure stabilization and antioxidant activity. Forty-eight equilibrium structures were described at the B3LYP/6-311++G(d,p) level, characterizing four non-previously reported conformers. Electron distributions were analyzed by topological QTAIM (Quantum Theory of atoms in molecules) and natural bond orbital (NBO) studies. The study was supplemented by an exploration of molecular electrostatic potential (MEP). Intramolecular hydrogen interactions were also investigated; N10?HC4 or N10?HC2 hydrogen bondings were depicted in 5 conformers. The conformer stabilization and the corresponding energy arrangement were explained by hyperconjugation interactions obtained by NBO analysis. The present study is based on the effect of the 5-OH group on geometric and electronic behavior that we have previously reported on the similar structure tryptamine (TRA). Our interest also lies in SER's free radical scavenging capacity as a member of the indole family. The H-atom abstraction and single-electron transfer mechanisms were taken into account. Our results showed that donor-acceptor interactions play a major role in explaining the changes induced by the OH group, and free-radical scavenging capability of the indole compounds. PMID- 29414043 TI - Immuno-informatics driven proteome-wide investigation revealed novel peptide based vaccine targets against emerging multiple drug resistant Providencia stuartii. AB - The bacterium Providencia stuartii, is associated with urinary tract infections and is the most common cause of purple urine bag syndrome. The increasing multi drug resistance pattern shown by the pathogen and lack of licensed vaccines make treatment of infections caused by P. stuartii challenging. As vaccinology data against the pathogen is scarce, an in silico proteome based Reverse Vaccinology (RV) protocol, in combination with subtractive proteomics is introduced in this work to screen potential vaccine candidates against P. stuartii. The analysis identified three potential vaccine candidates for designing broad-spectrum and strain-specific peptide vaccines: FimD4, FimD6, and FimD8. These proteins are essential for pathogen survival, localized in the outer membrane, virulent, and antigenic in nature. Immunoproteomic tools mapped surface exposed and non allergenic 9mer B-cell derived T-cell antigenic epitopes for the proteins. The epitopes also show stable and rich interactions with the most predominant HLA allele (DRB1*0101) in the human population. Metabolic pathway annotation of the proteins indicated that fimbrial biogenesis outer membrane usher protein (FimD6) is the most suitable candidate for vaccine design, due to its involvement in several significant pathways. These pathways include: the bacterial secretion system, two-component system, beta-lactam resistance, and cationic antimicrobial peptide pathways. The predicted epitopes may provide a basis for designing a peptide-based vaccine against P. stuartii. PMID- 29414044 TI - Searching for potential mTOR inhibitors: Ligand-based drug design, docking and molecular dynamics studies of rapamycin binding site. AB - The PI3K/Akt/mTOR pathway is an important intracellular signaling pathway in cell cycle regulation and its dysregulation is associated with various types of diseases. mTOR (mechanistic or mammalian target of rapamycin) is the main enzyme that performs intermediate control of the signaling pathway through a phosphotransfer process. The classical inhibition of the mTOR pathway is effected by rapamycin and its analogous blocking allosterically the catalytic phosphorylation site, avoiding the deleterious side effects induced by ATP competitive inhibitors. We employed ligand-based drug design strategies such as pharmacophore searching and analysis, molecular docking, absorption, distribution, metabolism, excretion and toxicity (ADMETox) properties filtering, and molecular dynamics to select potential molecules to become non-ATP competitive inhibitors of the mTOR complex. According to our findings, we propose eight novel potential mTOR inhibitors with similar or better properties than the classic inhibitor complex, rapamycin. PMID- 29414045 TI - Molecular design of high performance zwitterionic liquids for enhanced heavy-oil recovery processes. AB - Branched gemini zwitterionic liquids, which contain two zwitterionic moieties of linked quaternary-ammonium and carboxylate groups, are proposed as chemicals to be applied in the Enhanced Oil Recovery (EOR) from fractured carbonate reservoirs. The zwitterionic moieties are bridged between them through an alkyl chain containing 12 ether groups, and each zwitterionic moiety has attached a long alkyl tail including a CC double bond. A theoretical molecular mechanism over which EOR could rest, consisting on both the disaggregation of heavy oil and the reservoir-rock wettability alteration, was suggested. Results show that chemicals can both reduce the viscosity and remove heavy-oil molecules from the rock surface. PMID- 29414046 TI - A detailed hydrogen bonding analysis on the compositions of H2SO4/HNO3/H2O ternary systems: A computational study. AB - Hydrogen bonding properties of H2SO4/HNO3/H2O ternary molecular clusters have been studied by means of structural, energetic, topological, and spectroscopic perspectives. The roles of the hydrogen bonds in the formation of these clusters are considered according to the molecule positions (proton donor or proton acceptor) in the clusters. 33 stable conformers were identified on the potential energy surface. The global minimum one was obtained when HNO3 donates a proton to H2SO4, however, the cooperativity effect contribution was found to be significant for the cluster where HNO3 acts as a proton donor to an H2O molecule. PMID- 29414047 TI - Computational assessment of thioether isosteres. AB - Replacement of the sulfur atom in biologically active diaryl and heteroaryl thioethers (Ar-S-Ar', HAr-S-Ar, and HAr-S-HAr') with any of several one-atom or two-atom linkers can be expected to reduce the susceptibility of the analogue to metabolic oxidation, a well-documented problem for thioethers intended for medicinal chemistry applications. Ab initio calculations indicate how well various proposed thioether isosteric groups, including some new and unusual ones, may perform structurally and electronically in replacing the bridging sulfur atom. Four of these are calculationally evaluated as proposed substructures in Axitinib analogues. The predicted binding behavior of the latter within two different previously crystallographically characterized protein-Axitinib binding sites (VEGFR2 kinase and ABL1 T315I gatekeeper mutant kinase), and an assessment of their suitability and anticipated shortcomings, are presented. PMID- 29414048 TI - The reaction pathways of the oxygen reduction reaction on IrN4 doped divacancy graphene: A theoretical study. AB - The transition metal and nitrogen co-doped graphene as efficient electrocatalysts of oxygen reduction reaction (ORR) is promising to achieve large-scale applications of the full cells. In this work, we investigated the active sites and ORR mechanism on IrN4 doped divacancy graphene (IrN4-Gra) by using the density functional method. The active sites are identified as the IrN4 moiety and its adjacent ten C atoms. ORR on IrN4-Gra is a four-electron process. OOH hydrogenated into OH + OH is the kinetically most favorable pathway. The rate determining step is OOH + H -> OH + OH with energy barrier 1.01 eV. The predicted working potential is 0.41 V. Hence, IrN4-Gra might be a promising ORR catalyst. PMID- 29414049 TI - Visualization of tandem repeat mutagenesis in Bacillus subtilis. AB - Mutations are crucial for the emergence and evolution of proteins with novel functions, and thus for the diversity of life. Tandem repeats (TRs) are mutational hot spots that are present in the genomes of all organisms. Understanding the molecular mechanism underlying TR mutagenesis at the level of single cells requires the development of mutation reporter systems. Here, we present a mutation reporter system that is suitable to visualize mutagenesis of TRs occurring in single cells of the Gram-positive model bacterium Bacillus subtilis using microfluidic single-cell cultivation. The system allows measuring the elimination of TR units due to growth rate recovery. The cultivation of bacteria carrying the mutation reporter system in microfluidic chambers allowed us for the first time to visualize the emergence of a specific mutation at the level of single cells. The application of the mutation reporter system in combination with microfluidics might be helpful to elucidate the molecular mechanism underlying TR (in)stability in bacteria. Moreover, the mutation reporter system might be useful to assess whether mutations occur in response to nutrient starvation. PMID- 29414050 TI - DNA damage in blood cells in relation to chemotherapy and nutritional status in colorectal cancer patients-A pilot study. AB - DNA damage can be considered as a biomarker for toxicity and response to chemotherapy. It is not known whether the chemotherapy-induced genotoxicity is associated with malnutrition. In this pilot study, we assess genotoxicity by means of DNA damage in patients with lymph-node positive colorectal cancer (CRC) and explore associations with chemotherapy treatment and nutritional status. DNA damage was compared between patients receiving chemotherapy (n = 24) and those not receiving chemotherapy (n = 20). DNA damage was measured in frozen whole blood by the comet assay. Associations between DNA damage and various indicators of malnutrition were also explored, including Patient-Generated Subjective Global Assessment (PG-SGA), bioelectrical impedance analysis (BIA) and anthropometric measurements, using multiple linear regression models. Patients on chemotherapy have higher levels of DNA damage in blood cells than patients not receiving chemotherapy (median of 16.9 and 7.9% tail DNA respectively, p = 0.001). The moderately malnourished patients (PG-SGA category B), representing 41% of the patients, have higher levels of cellular DNA damage than patients with good nutritional status (mean difference of 7.5% tail DNA, p = 0.033). In conclusion, adjuvant chemotherapy and malnutrition are both associated with increased levels of DNA damage in blood cells of CRC patients. Carefully controlled longitudinal studies or randomized controlled trials should be performed to determine whether good nutritional status may protect against chemotherapy-induced genotoxicity and enhance compliance to therapy in CRC patients. PMID- 29414051 TI - Repair of exogenous DNA double-strand breaks promotes chromosome synapsis in SPO11-mutant mouse meiocytes, and is altered in the absence of HORMAD1. AB - Repair of SPO11-dependent DNA double-strand breaks (DSBs) via homologous recombination (HR) is essential for stable homologous chromosome pairing and synapsis during meiotic prophase. Here, we induced radiation-induced DSBs to study meiotic recombination and homologous chromosome pairing in mouse meiocytes in the absence of SPO11 activity (Spo11YF/YF model), and in the absence of both SPO11 and HORMAD1 (Spo11/Hormad1 dko). Within 30 min after 5 Gy irradiation of Spo11YF/YF mice, 140-160 DSB repair foci were detected, which specifically localized to the synaptonemal complex axes. Repair of radiation-induced DSBs was incomplete in Spo11YF/YF compared to Spo11+/YF meiocytes. Still, repair of exogenous DSBs promoted partial recovery of chromosome pairing and synapsis in Spo11YF/YF meiocytes. This indicates that at least part of the exogenous DSBs can be processed in an interhomolog recombination repair pathway. Interestingly, in a seperate experiment, using 3 Gy of irradiation, we observed that Spo11/Hormad1 dko spermatocytes contained fewer remaining DSB repair foci at 48 h after irradiation compared to irradiated Spo11 knockout spermatocytes. Together, these results show that recruitment of exogenous DSBs to the synaptonemal complex, in conjunction with repair of exogenous DSBs via the homologous chromosome, contributes to homology recognition. In addition, the data suggest a role for HORMAD1 in DNA repair pathway choice in mouse meiocytes. PMID- 29414052 TI - Induction of reproductive cell death in Caenorhabditis elegans across entire linear-energy-transfer range of carbon-ion irradiation. AB - Heavy-ion radiation has attracted extensive attention as an effective cancer therapy because of the varying energy deposition along its track and its high cell-killing effect. Reproductive cell death (RCD), also known as clonogenic death, is an important mode of death of the cancer cells after radiotherapy. Although RCD induced by heavy-ion irradiation with various linear energy transfers has been demonstrated using clonogenic assay in vitro, little is known about the distribution of RCD across the range of heavy-ion irradiation at the level of whole organisms. In this study, a vulval tissue model of Caenorhabditis elegans was for the first time used to assess RCD in vivo induced by carbon-ion irradiation. A polymethyl methacrylate wedge was designed to provide a gradually varying thickness of shielding, so worms could be exposed to the entire range of carbon-ion irradiation. The carbon-ion irradiation led to a significant induction of RCD over the entire range in a dose-dependent manner. The biological peak did not correspond to the physical Bragg peak and moved forward, rather than spread forward, as radiation dose increased. The degree and shape of the range distribution of RCD were also affected by the developmental stages of the worms. The gene mutations in DNA-damage checkpoints did not affect the responses of mutant worms positioned in biological peaks, compared to wild-type worms, but decreased radio-sensitivity in the entrance region. An increased induction of RCD was observed in the worms impaired in homologous recombination (HR), but not in non-homologous end jointing pathway, suggesting a crucial role of HR repair in vulval cells of C. elegans in dealing with the carbon-ion-induced DNA damage. These unique manifestations of RCD in vivo in response to carbon-ion irradiation might provide new clues for further investigating the biological effects of heavy ion irradiation. PMID- 29414054 TI - Hijacking CRISPR-Cas for high-throughput bacterial metabolic engineering: advances and prospects. AB - High engineering efficiencies are required for industrial strain development. Due to its user-friendliness and its stringency, CRISPR-Cas-based technologies have strongly increased genome engineering efficiencies in bacteria. This has enabled more rapid metabolic engineering of both the model host Escherichia coli and non model organisms like Clostridia, Bacilli, Streptomycetes and cyanobacteria, opening new possibilities to use these organisms as improved cell factories. The discovery of novel Cas9-like systems from diverse microbial environments will extend the repertoire of applications and broaden the range of organisms in which it can be used to create novel production hosts. This review analyses the current status of prokaryotic metabolic engineering towards the production of biotechnologically relevant products, based on the exploitation of different CRISPR-related DNA/RNA endonuclease variants. PMID- 29414055 TI - Complete ammonia oxidation: an important control on nitrification in engineered ecosystems? AB - Nitrification has long been considered to be mediated by two distinct microbial guilds, the ammonia-oxidizing bacteria and archaea, and the nitrite-oxidizing bacteria. The process has been widely applied as an environmental biotechnology for ammonium removal during water and wastewater treatment. Recently, bacteria capable of complete nitrification of ammonia to nitrate (a process termed complete ammonia oxidation, or comammox) have been discovered. These novel nitrifiers have been identified in a range of engineered, natural freshwater and terrestrial ecosystems, challenging previously held knowledge on the key microorganisms and biochemical pathways controlling nitrification. This paper discusses the distribution of comammox bacteria with a focus on engineered ecosystems, as well as emerging insights from recent genomic and experimental studies on their ecophysiology. PMID- 29414056 TI - Nitrification in agricultural soils: impact, actors and mitigation. AB - Nitrogen is one of the most important nutrients for plant growth and hence heavily applied in agricultural systems via fertilization. Nitrification, that is, the conversion of ammonium via nitrite to nitrate by soil microorganisms, however, leads to nitrate leaching and gaseous nitrous oxide production and as such to an up to 50% loss of nitrogen availability for the plant. Nitrate leaching also results in eutrophication of groundwater, drinking water and recreational waters, toxic algal blooms and biodiversity loss, while nitrous oxide is a greenhouse gas with a global warming potential 300* greater than carbon dioxide. Logically, inhibition of nitrification is an important strategy used in agriculture to reduce nitrogen losses, and contributes to a more environmental-friendly practice. However, recently identified and crucial players in nitrification, that is, ammonia-oxidizing archaea and comammox bacteria, seem to be under-investigated in this respect. In this review, we give an update on the different pathways in ammonia oxidation, the relevance for agriculture and the interaction with nitrification inhibitors. As such, we hope to pinpoint possible strategies to optimize the efficiency of nitrification inhibition. PMID- 29414053 TI - Collaboration in the actions of Brh2 with resolving functions during DNA repair and replication stress in Ustilago maydis. AB - Cells maintain a small arsenal of resolving functions to process and eliminate complex DNA intermediates that result as a consequence of homologous recombination and distressed replication. Ordinarily the homologous recombination system serves as a high-fidelity mechanism to restore the integrity of a damaged genome, but in the absence of the appropriate resolving function it can turn DNA intermediates resulting from replication stress into pathological forms that are toxic to cells. Here we have investigated how the nucleases Mus81 and Gen1 and the helicase Blm contribute to survival after DNA damage or replication stress in Ustilago maydis cells with crippled yet homologous recombination-proficient forms of Brh2, the BRCA2 ortholog and primary Rad51 mediator. We found collaboration among the factors. Notable were three findings. First, the ability of Gen1 to rescue hydroxyurea sensitivity of dysfunctional Blm requires the absence of Mus81. Second, the response of mutants defective in Blm and Gen1 to hydroxyurea challenge is markedly similar suggesting cooperation of these factors in the same pathway. Third, the repair proficiency of Brh2 mutant variants deleted of its N terminal DNA binding region requires not only Rad52 but also Gen1 and Mus81. We suggest these factors comprise a subpathway for channeling repair when Brh2 is compromised in its interplay with DNA. PMID- 29414057 TI - Advances in metabolic engineering in the microbial production of fuels and chemicals from C1 gas. AB - The future sustainable production of chemicals and fuels from non-petrochemical sources, while at the same time reducing greenhouse gas (GHG) emissions, represent two of society's greatest challenges. Microbial chassis able to grow on waste carbon monoxide (CO) and carbon dioxide (CO2) can provide solutions to both. Ranging from the anaerobic acetogens, through the aerobic chemoautotrophs to the photoautotrophic cyanobacteria, they are able to convert C1 gases into a range of chemicals and fuels which may be enhanced and extended through appropriate metabolic engineering. The necessary improvements will be facilitated by the increasingly sophisticated gene tools that are beginning to emerge as part of the Synthetic Biology revolution. These tools, in combination with more accurate metabolic and genome scale models, will enable C1 chassis to deliver their full potential. PMID- 29414058 TI - Electrochemical biotechnologies minimizing the required electrode assemblies. AB - Microbial electrochemical systems (MESs) are expected to be put into practical use as an environmental technology that can support a future environmentally friendly society. However, conventional MESs present a challenge of inevitably increasing initial investment, mainly due to requirements for a large numbers of electrode assemblies. In this review, we introduce electrochemical biotechnologies that are under development and can minimize the required electrode assemblies. The novel biotechnologies, called electro-fermentation and indirect electro-stimulation, can drive specific microbial metabolism by electrochemically controlling intercellular and extracellular redox states, respectively. Other technologies, namely electric syntrophy and microbial photo electrosynthesis, obviate the need for electrode assemblies, instead stimulating targeted reactions by using conductive particles to create new metabolic electron flows. PMID- 29414059 TI - Applications of methylotrophs: can single carbon be harnessed for biotechnology? AB - This review summarizes developments in the field of applied research involving microbial conversion of single carbon compounds (methane, methanol, CO2). The potential of the microorganisms involved in biotechnological applications could be realized via engineering native C1 utilizers toward higher output of value added compounds, including biofuels, or via production of value chemicals as parts of novel, heterologously expressed biochemical pathways. Alternatively, C1 metabolism could be implemented in traditional industrial platforms (Escherichia coli, yeast), via introduction of specific metabolic modules. Most recent research spanning both approaches is covered. The potential of C1 utilizers in biomining of rare Earth elements, as well as the potential of C1 consuming microbial consortia in industrial applications are discussed. PMID- 29414060 TI - Adiabatic sweep pulses for earth's field NMR with a surface coil. AB - Adiabatic NMR sweep pulses are described for inversion and excitation in very low magnetic fields B0 and with broad distribution of excitation field amplitude B1. Two aspects distinguish the low field case: (1) when B1 is comparable to or greater than B0, the rotating field approximation fails and (2) inversion sweeps cannot extend to values well below the Larmor frequency because they would approach or pass through zero frequency. Three approaches to inversion are described. The first is a conventional tangent frequency sweep down to the Larmor frequency, a 180 degrees phase shift, and a sweep back up to the starting frequency. The other two are combined frequency and amplitude sweeps covering a narrower frequency range; one is a symmetric sweep from above to below the Larmor frequency and the other uses a smooth decrease of B1 immediately before and after the 180 degrees phase shift. These two AM/FM sweeps show excellent inversion efficiencies over a wide range of B1, a factor of 30 or more. We also demonstrate an excitation sweep that works well in the presence of the same wide range of B1. We show that the primary effect of the counter-rotating field (i.e., at low B0) is that the magnetization suffers large, periodic deviations from where it would be at large B0. Thus, successful sweep pulses must avoid any sharp features in the amplitude, phase, or frequency. PMID- 29414061 TI - Integration of a versatile bridge concept in a 34 GHz pulsed/CW EPR spectrometer. AB - We present a 34 GHz continuous wave (CW)/pulsed electron paramagnetic resonance (EPR) spectrometer capable of pulse-shaping that is based on a versatile microwave bridge design. The bridge radio frequency (RF)-in/RF-out design (500 MHz to 1 GHz input/output passband, 500 MHz instantaneous input/output bandwidth) creates a flexible platform with which to compare a variety of excitation and detection methods utilizing commercially available equipment external to the bridge. We use three sources of RF input to implement typical functions associated with CW and pulse EPR spectroscopic measurements. The bridge output is processed via high speed digitizer and an in-phase/quadrature (I/Q) demodulator for pulsed work or sent to a wideband, high dynamic range log detector for CW. Combining this bridge with additional commercial hardware and new acquisition and control electronics, we have designed and constructed an adaptable EPR spectrometer that builds upon previous work in the literature and is functionally comparable to other available systems. PMID- 29414062 TI - A novel analytical description of periodic volume coil geometries in MRI. AB - MRI volume coils can be represented by equivalent lumped element circuits and for a variety of these circuit configurations analytical design equations have been presented. The unification of several volume coil topologies results in a two dimensional gridded equivalent lumped element circuit which compromises the birdcage resonator, its multiple endring derivative but also novel structures like the capacitive coupled ring resonator. The theory section analyzes a general two-dimensional circuit by noting that its current distribution can be decomposed into a longitudinal and an azimuthal dependency. This can be exploited to compare the current distribution with a transfer function of filter circuits along one direction. The resonances of the transfer function coincide with the resonance of the volume resonator and the simple analytical solution can be used as a design equation. The proposed framework is verified experimentally against a novel capacitive coupled ring structure which was derived from the general circuit formulation and is proven to exhibit a dominant homogeneous mode. In conclusion, a unified analytical framework is presented that allows determining the resonance frequency of any volume resonator that can be represented by a two dimensional meshed equivalent circuit. PMID- 29414063 TI - Rotation relaxation splitting for optimizing parallel RF excitation pulses with T1- and T2-relaxations in MRI. AB - Exact solutions of the Bloch equations with T1- and T2-relaxation terms for piecewise constant magnetic fields are numerically challenging. We therefore investigate an approximation for the achieved magnetization in which rotations and relaxations are split into separate operations. We develop an estimate for its accuracy and explicit first and second order derivatives with respect to the complex excitation radio frequency voltages. In practice, the deviation between an exact solution of the Bloch equations and this rotation relaxation splitting approximation seems negligible. Its computation times are similar to exact solutions without relaxation terms. We apply the developed theory to numerically optimize radio frequency excitation waveforms with T1- and T2-relaxations in several examples. PMID- 29414064 TI - Optimal Tikhonov regularization for DEER spectroscopy. AB - Tikhonov regularization is the most commonly used method for extracting distance distributions from experimental double electron-electron resonance (DEER) spectroscopy data. This method requires the selection of a regularization parameter, alpha, and a regularization operator, L. We analyze the performance of a large set of alpha selection methods and several regularization operators, using a test set of over half a million synthetic noisy DEER traces. These are generated from distance distributions obtained from in silico double labeling of a protein crystal structure of T4 lysozyme with the spin label MTSSL. We compare the methods and operators based on their ability to recover the model distance distributions from the noisy time traces. The results indicate that several alpha selection methods perform quite well, among them the Akaike information criterion and the generalized cross validation method with either the first- or second derivative operator. They perform significantly better than currently utilized L curve methods. PMID- 29414065 TI - DNP enhanced NMR with flip-back recovery. AB - DNP methods can provide significant sensitivity enhancements in magic angle spinning solid-state NMR, but in systems with long polarization build up times long recycling periods are required to optimize sensitivity. We show how the sensitivity of such experiments can be improved by the classic flip-back method to recover bulk proton magnetization following continuous wave proton heteronuclear decoupling. Experiments were performed on formulations with characteristic build-up times spanning two orders of magnitude: a bulk BDPA radical doped o-terphenyl glass and microcrystalline samples of theophylline, l histidine monohydrochloride monohydrate, and salicylic acid impregnated by incipient wetness. For these systems, addition of flip-back is simple, improves the sensitivity beyond that provided by modern heteronuclear decoupling methods such as SPINAL-64, and provides optimal sensitivity at shorter recycle delays. We show how to acquire DNP enhanced 2D refocused CP-INADEQUATE spectra with flip back recovery, and demonstrate that the flip-back recovery method is particularly useful in rapid recycling regimes. We also report Overhauser effect DNP enhancements of over 70 at 592.6 GHz/900 MHz. PMID- 29414066 TI - Strategies to overcome HBV-specific T cell exhaustion: checkpoint inhibitors and metabolic re-programming. AB - HBV-specific T cells play a key role in antiviral protection and failure to control HBV is associated with severely dysfunctional T cell responses. Therefore, functional T cell reconstitution represents a potential way to treat chronically infected patients. The growing understanding of the dysregulated transcriptional/epigenetic and metabolic programs underlying T cell exhaustion allows to envisage functional T cell reconstitution strategies based on the combined/sequential use of compounds able to induce decline of antigen load, checkpoint modulation, metabolic and epigenetic reprogramming with possible boosting of functionally restored responses by specific vaccines. PMID- 29414067 TI - Enzymatic characterization of a NADH-dependent diaphorase from Lysinibacillus sp. strain PAD-91. AB - Diaphorases are flavin-containing enzymes with potential applications in biotransfomation reactions, biosensor design and in vitro diagnostic tests. In this paper, we present recombinant expression, characterization and medium optimization of a lipoamide dehydrogenase (DLD) with NADH-dependent diaphorase activity from a Lysinibacillus sp. strain. DLD encoding sequence showed an open reading frame of 1413-bp encoding a 470 amino acid chain. Lysinibacillus sp. DLD catalyzed the NADH-dependent reduction of electron acceptors and exhibited diaphorase activity. The molecular mass of the isolated enzyme was found to be about 50 kDa, and determined to be a monomeric protein. The optimum pH and temperature for the catalytic activity of the enzyme was about pH 7.5 and 30 degrees C. The Km and Vmax values were estimated to be 0.025 mM and 1.33 MUmol/min, respectively. Recombinant enzyme was optimally produced in fermentation medium containing 10 g/L sucrose, 25 g/L yeast extract, 5 g/L NaCl and 0.25 g/L MgSO4. By Scaling up fermentation from flask to bioreactor, enzyme activity was increased to 487.5 U/ml. This study provides data on the identification, characterization and medium optimization of a NADH-dependent diaphorase from a newly isolated Lysinibacillus sp. PAD-91. PMID- 29414068 TI - Rapid NMR-scale purification of 15N,13C isotope-labeled recombinant human STIM1 coiled coil fragments. AB - We report a new NMR-scale purification procedure for two recombinant wild type fragments of the stromal interaction molecule 1 (STIM1). This protein acts as a calcium sensor in the endoplasmic reticulum (ER) and extends into the cytosol accumulating at ER - plasma membrane (PM) junctions upon calcium store depletion ultimately leading to activation of the Orai/CRAC channel. The functionally relevant cytosolic part of STIM1 consists of three coiled coil domains, which are mainly involved in intra- and inter-molecular homomeric interactions as well as coupling to and gating of CRAC channels. The optimized one-step rapid purification procedure for two 15N,13C isotope-labeled cytosolic coiled coil fragments, which avoids the problems of previous approaches. The high yields of soluble well folded 15N,13C isotope-labeled cytosolic coiled coil fragments followed by detergent screening provide for initial NMR characterization of these domains. The longer 30.5 kDa fragment represents the largest STIM1 wild type fragment that has been recombinantly prepared and characterized in solution without need for mutation or refolding. PMID- 29414069 TI - A disinhibitory circuit motif and flexible information routing in the brain. AB - In the mammalian neocortex, an area typically receives inputs from, and projects to, dozens of other areas. Mechanisms are needed to flexibly route information to the right place at the right time, which we term 'pathway gating'. For instance, a region in your brain that receives signals from both visual and auditory pathways may want to 'gate in' the visual pathway while 'gating out' the auditory pathway when you try to read a book surrounded by people in a noisy cafe. In this review, we marshall experimental and computational evidence in support of a circuit mechanism for flexible pathway gating realized by a disinhibitory motif. Moreover, recent work shows an increasing preponderance of this disinhibitory motif from sensory areas to association areas of the mammalian cortex. Pathway input gating is briefly compared with alternative or complementary gating mechanisms. Predictions and open questions for future research on this puzzle about the complex brain system will be discussed. PMID- 29414071 TI - Sex differences in behavioral strategies: avoiding interpretational pitfalls. AB - Despite ample evidence for sex differences in brain structure and function, our understanding of the neurobiological basis of behavior comes almost exclusively from male animals. As neuroscientists move to comply with recent NIH mandates that biomedical researchers include both sexes in their studies, the ways we interpret outcomes in classic rodent behavioral models deserve closer scrutiny and more nuanced evaluation. In this mini-review, we highlight recent sex differences papers in learning, decision-making, and spatial navigation paradigms that underscore the distinctions between cognitive capabilities versus behavioral strategies that may confer unique benefits to males and females. PMID- 29414072 TI - Applications of proteomic methods for CHO host cell protein characterization in biopharmaceutical manufacturing. AB - Chinese hamster ovary (CHO) cells are the most prevalent host organism for production of recombinant therapeutic proteins, including monoclonal antibodies (mAbs). Regulatory guidance mandates control of the host cell protein (HCP) concentration in the production process, which remains a primary challenge. Although HCP concentrations are typically measured by ELISA, orthogonal proteomic methods are gaining popularity for identification and quantitation of individual HCP species. Recent applications of proteomic techniques to characterize extracellular CHO HCPs include those that have explored the effects of upstream factors (cell line, viability, process conditions), characterized specific HCPs likely to co-purify by mAb interactions, identified HCPs likely to impact drug product quality, and enabled strategies to limit HCP expression (media composition, temperature shift, genetic modification) and maximize clearance (polishing chromatography, wash additives). PMID- 29414070 TI - The promise and perils of causal circuit manipulations. AB - The development of increasingly sophisticated methods for recording and manipulating neural activity is revolutionizing neuroscience. By probing how activity patterns in different types of neurons and circuits contribute to behavior, these tools can help inform mechanistic models of brain function and explain the roles of distinct circuit elements. However, in systems where functions are distributed over large networks, interpreting causality experiments can be challenging. Here we review common assumptions underlying circuit manipulations in behaving animals and discuss the strengths and limitations of different approaches. PMID- 29414073 TI - Debottlenecking protein secretion and reducing protein aggregation in the cellular host. AB - Chinese hamster ovary (CHO) cells have been extensively used for industrial production of biotherapeutics. With advances in cell line development and process optimization, production levels of therapeutic proteins using the CHO expression system have increased to beyond 10g per liter scale. These high-titer processes could challenge the secretory capacity of CHO cells, which can result in degradation and aggregation of the protein of interest. This review discusses bottlenecks in the secretory pathway of CHO cells that lead to inefficient secretion and aggregation of proteins, and summarizes current strategies to tackle these bottlenecks. In addition, emerging technologies that facilitate better understanding of cellular mechanisms in protein production could provide new avenues to improve the secretion and quality of protein therapeutics. PMID- 29414074 TI - Selected landscape phage probe as selective recognition interface for sensitive total prostate-specific antigen immunosensor. AB - The level of total prostate-specific antigen (t-PSA) is generally known as the key index of prostate cancer. Here, phage probes against t-PSA were selected from f8/8 landscape phage library. After three rounds of biopanning, four t-PSA binding phage clones were isolated and identified by the DNA sequencing. Based on the phage capture assay, the phage clone displaying the fusion peptide ATRSANGM showed highest affinity and specificity against t-PSA. Subsequently, the t-PSA specific phage was used as t-PSA capture probe in a sandwich enzyme-linked immunosorbent assay (ELISA) and differential pulse voltammetry (DPV) assay systems. Both assay methods showed high specificity and acceptable reliability for real serum samples analysis. By comparison, DPV method showed wider linear range (0.01-100 ng mL-1) and lower limit of detection (3 pg mL-1) than those (3.3 330 ng mL-1 and 1.6 ng mL-1) of ELISA. Moreover, DPV system showed smaller distinction to the authoritative method in real samples assay. Excitingly, the phage probe based DPV immunosensor showed high sensitivity for the detection of t PSA and LOD achieved the pg mL-1 level, which was far lower than those values (usually above 0.1 ng mL-1) for reported immunosensors based on antibodies. Due to the biocompatibility, multivalency, stability, and high structural homogeneity, the t-PSA-specific landscape phage demonstrates as a novel specific interface in biosensors. PMID- 29414075 TI - Cost-effective flow-through nanohole array-based biosensing platform for the label-free detection of uropathogenic E. coli in real time. AB - Rapid, inexpensive and sensitive detection of uropathogenic Escherichia coli (UPEC), a common cause of ascending urinary tract infections (UTIs) including cystitis and pyelonephritis, is critical given the increasing number of cases and its recurrence worldwide. In this paper, we present a label-free nanoplasmonic sensing platform, built with off-the-shelf optical and electronic components, which can detect intact UPEC at concentrations lower than the physiological limit for UTI diagnosis, in real time. The sensing platform consists of a red LED light source, lens assembly, CMOS detector, Raspberry Pi interface in conjugation with a metallic flow-through nanohole array-based sensor. Detection is achieved exploiting nanoplasmonic phenomena from the nanohole arrays through surface plasmon resonance imaging (SPRi) technique. The platform has a bulk sensitivity of 212 pixel intensity unit (PIU)/refractive index unit (RIU), and a resolution in the order of 10-6 RIU. We demonstrate capture and detection of UPEC with a detection limit of ~100 CFU/ml - a concentration well below the threshold limit for UTI diagnosis in clinical samples. We also demonstrate detection of UPEC in spiked human urine samples for two different concentrations of bacteria. This work is particularly relevant for point-of-care applications, especially for regions around the world where accessibility to medical facilities is heavily dependent upon economy, and availability. PMID- 29414076 TI - Amplified QCM biosensor for type IV collagenase based on collagenase-cleavage of gold nanoparticles functionalized peptide. AB - The present study develops a rapid, simple and efficient method for the determination of type IV collagenase by using a specific peptide-modified quartz crystal microbalance (QCM). A small peptide (P1), contains a specific sequence (Pro-Gly) and a terminal cysteine, was synthetized and immobilized to the surface of QCM electrode via the reaction between Au and thiol of the cysteine. The peptide bond between proline and glycine can be specific hydrolyzed cleavage by type IV collagenase, which enabled the modified electrode with a high selectivity toward type IV collagenase. The cleaving process caused a frequency change of QCM to give a signal related to the concentration of type IV collagenase. The morphologies of the modified electrodes were characterized by scanning electron microscope (SEM) and the specific hydrolyzed cleavage process was monitored by QCM. When P1 was modified with gold nanoparticles (P1-Au NPs), the signal could be amplified to further enhance the sensitivity of the designed sensor due to the high-mass of the modified Au NPs. Compared the direct unamplified assay, the values obtained for the limit of detection for type IV collagenase was 0.96 ng mL 1, yielding about 6.5 times of magnitude improvement in sensitivity. This signal enhanced peptide based QCM biosensor for type IV collagenase also showed good selectivity and sensitivity in complex matrix. PMID- 29414077 TI - TriPleXTM waveguide-based fluorescence biosensor for multichannel environmental contaminants detection. AB - In order to realize the multi-analyte assays for environmental contaminants, an optical biosensor utilizing laser-induced fluorescence-based detection via the binding of biomolecules to the surface of an integrated TriPleXTM waveguide chip on a glass substrate (fused silica, FS) is described. As far as we know, this is the first demonstration of using the TriPleXTM technology to fabricate the waveguide chip on a FS substrate. The sensor consists of 32 individually addressable sensor patches, which were formed on the chip surface by exploiting 3 Y-junction splitters, creating four equal rows of eight evanescently excited windows in parallel. The basic low-loss SiO2/Si3N4 TriPleXTM waveguide configuration in combination with on-chip spotsize convertors allows for both high fiber-to-chip coupling efficiency and enables at the same time individually optimized high chip surface intensity and low patch-to-patch deviation. Moreover, the complementary metal-oxide-semiconductor compatible fabrication of waveguide chip allows for its mass production at low cost. By taking MC-LR, 2,4-D, atrazine and BPA as the model analytes, the as-proposed waveguide based biosensor was proven sensitive with the detection limits of 0.22 MUg/L for MC-LR, 1.18 MUg/L for 2, 4-D, 0.2 MUg/L for atrazine and 0.06 MUg/L for BPA. Recoveries of the biosensor towards simultaneous detection of MC-LR, 2, 4-D, atrazine and BPA in spiked real water samples varied from 84% to 120%, indicating the satisfactory accuracy of the established technology. PMID- 29414078 TI - Engineering nanomaterials-based biosensors for food safety detection. AB - Food safety always remains a grand global challenge to human health, especially in developing countries. To solve food safety pertained problems, numerous strategies have been developed to detect biological and chemical contaminants in food. Among these approaches, nanomaterials-based biosensors provide opportunity to realize rapid, sensitive, efficient and portable detection, overcoming the restrictions and limitations of traditional methods such as complicated sample pretreatment, long detection time, and relying on expensive instruments and well trained personnel. In this review article, we provide a cross-disciplinary perspective to review the progress of nanomaterials-based biosensors for the detection of food contaminants. The review article is organized by the category of food contaminants including pathogens/toxins, heavy metals, pesticides, veterinary drugs and illegal additives. In each category of food contaminant, the biosensing strategies are summarized including optical, colorimetric, fluorescent, electrochemical, and immune- biosensors; the relevant analytes, nanomaterials and biosensors are analyzed comprehensively. Future perspectives and challenges are also discussed briefly. We envision that our review could bridge the gap between the fields of food science and nanotechnology, providing implications for the scientists or engineers in both areas to collaborate and promote the development of nanomaterials-based biosensors for food safety detection. PMID- 29414079 TI - Label-free surface plasmon resonance biosensing with titanium nitride thin film. AB - In this report, titanium nitride thin film synthesized with reactive magneto sputtering technique is proposed as an alternative surface plasmon resonance sensing material. The physical and chemical natures were initially studied by atomic force microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. In virtue of white-light common-path sensing system, the wavelength modulated TiN films achieved tunable evanescent plasmonic field from 573 nm to 627 nm. The optimized TiN film with 29.8 nm thickness exhibited good differential phase sensitivity (i.e. 1.932 * 10-7 RIU) to refractive index alteration, which is comparable to the performance of gold film. We have also attained direct measurement of biotin adsorption on the TiN and monitored sub-sequential biotin streptavidin conjugation. It was found that TiN films have significantly higher binding affinity toward biotin than that of gold in experiments, so we are able to detect biotin directly to 0.22 ug/ml (0.90 uM) in label-free manner. The adsorption mechanism of biotin on TiN(200) are also explored with periodic density functional theory (DFT) via computer simulation and it was found that the exceptional biotin-TiN affinity may be due to the stacking formation of both N-Ti and O-Ti bonds. Also, the adsorption energy of biotin-TiN was found to be - 1.85 eV, which was two times higher than that of biotin-gold. Both experimental and computational results indicate, for the first time, that the TiN film can be directly functionalized with biotin molecules, thus it serves as an alternative plasmonic material to existing gold-based SPR biosensors. PMID- 29414080 TI - Electrochemical sensing of 4-nitrochlorobenzene based on carbon nanohorns/graphene oxide nanohybrids. AB - Owing to the harmful nature of 4-nitrochlorobenzene (4-NCB, one toxic organic pollutant) and the low cost, high sensitivity and ease of operation of electrochemical method, it is highly desirable to develop effect electrochemical sensor for the detection of 4-NCB. Herein, by partially unzipping carbon nanohorns (CNHs) via a simple wet-chemistry method, CNHs and graphene oxide (GO) (CNHs/GO) nanohybrids were produced for sensing 4-NCB with synergistic properties. While the retained CNHs offer a path for rapid electron transport, the GO sheets formed by partially unzipping CNHs provide abundant active sites, further increase in surface area as well as improved dispersibility of the CNHs/GO. Our results show that the CNHs/GO modified electrode has excellent sensitivity to 4-NCB with a wide linear response range and a detection limit as low as 10 nM. PMID- 29414081 TI - A novel label-free photoelectrochemical sensor based on N,S-GQDs and CdS co sensitized hierarchical Zn2SnO4 cube for detection of cardiac troponin I. AB - A novel label-free photoelectrochemical (PEC) sensor based on graphene quantum dots doped with nitrogen and sulfur (N,S-GQDs) and CdS co-sensitized hierarchical Zn2SnO4 cube was fabricated to detect cardiac troponin I (cTnI). The unique hierarchical Zn2SnO4 cube was synthesized successfully by the solvothermal method, which has a large specific surface to load functional materials. N,S-GQDs nanoparticles were assembled to the surface of cubic Zn2SnO4 coated ITO electrode, which efficiently accelerated the electronic transition and improved photo-to-current conversion efficiency. Then, CdS nanoparticles further were modified by in-situ growth method to form Zn2SnO4/N,S-GQDs/CdS composite with prominent photocurrent, which was 30 times that of the Zn2SnO4 cube alone. In this work, the specific immune recognition between cTnI antigens and cTnI antibodies (anti-cTnI) reduced the intensity of the photoelectric signal. And the intensity decreased linearly with the logarithm of cTnI concentration range from 0.001 ng/mL to 50 ng/mL with a detection limit of 0.3 pg/mL. With high sensitivity, excellent selectivity, good stability and reproducibility, the fabricated PEC sensor showed promising applications in the sensor, clinical diagnosis of myocardial infarction and PEC analysis. PMID- 29414082 TI - Sandwich-type electrochemical immunosensor based on Au@Ag supported on functionalized phenolic resin microporous carbon spheres for ultrasensitive analysis of alpha-fetoprotein. AB - Signal amplification is crucial for obtaining low detection limits in electrochemical immunosensor. In this work, we developed a novel signal amplification strategy using Au@Ag nanoparticles loaded by polydopamine functionalized phenolic resin microporous carbon spheres (Au@Ag/PDA-PR-MCS). Phenolic resin microporous carbon spheres (PR-MCS) possesses uniform size and a large surface area (1656.8 m2 g-1). Polydopamine (PDA) functionalized phenolic resin microporous carbon spheres (PDA-PR-MCS) retains the advantages of PR-MCS and possesses strong adsorption ability. With the unique structure of PDA-PR-MCS, it not only improves the loading capacity and dispersity of Au@Ag nanoparticles (Au@Ag NPs), but also enhances the stability for the combination of the Au@Ag NPs by chemical absorption between Au@Ag NPs and -NH2 of PDA. The Au@Ag/PDA-PR-MCS exhibits extraordinary electrocatalytic activity towards reduction of hydrogen peroxide (H2O2) to make the electrochemical response more sensitive. Furthermore, Au NPs with good biocompatibility and excellent conductivity were electrodeposited on the surface of electrode, which was used as a sensing platform to immobilize primary antibody (Ab1) and accelerate the electron transfer on the electrode interface. Herein, the designed immunosensor provided a broad linear range from 20 fg/mL to 100 ng/mL for alpha fetoprotein (AFP) detection and a low detection limit of 6.7 fg/mL (signal-to-noise ratio of 3) under optimal experimental conditions. Moreover, the excellent performance in detection of human serum samples indicated that the proposed immunosensor will provide promising applications in clinical monitoring of AFP. PMID- 29414083 TI - Progress in utilisation of graphene for electrochemical biosensors. AB - This review discusses recent graphene (GR) electrochemical biosensor for accurate detection of biomolecules, including glucose, hydrogen peroxide, dopamine, ascorbic acid, uric acid, nicotinamide adenine dinucleotide, DNA, metals and immunosensor through effective immobilization of enzymes, including glucose oxidase, horseradish peroxidase, and haemoglobin. GR-based biosensors exhibited remarkable performance with high sensitivities, wide linear detection ranges, low detection limits, and long-term stabilities. Future challenges for the field include miniaturising biosensors and simplifying mass production are discussed. PMID- 29414084 TI - Combined spectroelectrochemical and proteomic characterizations of bidirectional Alcaligenes faecalis-electrode electron transfer. AB - Bioelectrochemical systems use microbes as catalysts for current production or consumption. Up to now only a few microbes have been demonstrated to be capable of both outward and inward extracellular electron transfer (EET) (i.e. bidirectional electron transfer). However, the mechanisms of electron exchange between microbes and extracellular solids remain uncertain. Here, we showed that Alcaligenes faecalis catalyzed an outward EET and generated electricity at a poised potential of +0.3V vs. SHE, whereas it conducted an inward EET for autotrophic denitrification at -0.5V vs. SHE. Both cyclic voltammetry and in situ electrochemical FTIR spectroscopy revealed that different redox components were utilized during the outward and inward EET. Electron transport inhibitor experiments indicated for the first time that complex I, II, III, and the quinone pool on the plasma membrane were involved in the bidirectional EET. Comparative proteomics showed that the protein expression profile of outward-EET biofilms differed greatly from those of inward-EET biofilms, implying that the pili and outer membrane proteins might be responsible for the interfacial outward and inward EET, respectively. These results suggest different electron transport conduits of A. faecalis biofilms could be used for bidirectional EET. PMID- 29414085 TI - A sensitive electrochemical nonenzymatic biosensor for the detection of H2O2 released from living cells based on ultrathin concave Ag nanosheets. AB - Facile synthesis of ultrathin two-dimensional metallic nanosheets with special physical and chemical properties is still challenging. In this work, ultrathin silver nanosheets were synthesized through the galvanic replacement reaction between silver nitrate and Cu microcages without using any surfactant at room temperature. The as-prepared Ag nanosheets (NSs) were concave and had a thickness of sub-10 nm. And the nanosheets exhibited excellent H2O2 detection property with a high sensitivity of about 320.3 uA mM-1 cm-2 and a low detection limit of 0.17 uM in a wide linear range of 5-6000 MUM, and a fast response time (less than 2 s). Besides, the real-time detection of H2O2 induced from living HeLa and SH-SY5Y cells were also achieved, indicating the potential application of as-prepared Ag NSs in monitoring physiological and dynamic in-clinic pathological processes. PMID- 29414086 TI - Integration of reconfigurable potentiometric electrochemical sensors into a digital microfluidic platform. AB - This paper presents the demonstration of on-chip fabrication of a potassium selective sensor array enabled by electrowetting on dielectric digital microfluidics for the first time. This demonstration proves the concept that electrochemical sensors can be seamlessly integrated with sample preparation units in a digital microfluidic platform. More significantly, the successful on chip fabrication of a sensor array indicates that sensors become reconfigurable and have longer lifetime in a digital microfluidic platform. The on-chip fabrication of ion-selective electrodes includes electroplating Ag followed by forming AgCl layer by chemical oxidation and depositing a thin layer of desired polymer-based ion selective membrane on one of the sensor electrodes. In this study, potassium ionophores work as potassium ion channels and make the membrane selective to potassium ions. This selectiveness results in the voltage difference across the membrane layer, which is correlated with potassium ion concentration. The calibration curve of the fabricated potassium-selective electrode demonstrates the slope of 58 mV/dec for potassium concentration in KCl sample solutions and shows good agreement with the ideal Nernstian response. The proposed sensor platform is an outstanding candidate for a portable home-use for continuous monitoring of ions thanks to its advantages such as easy automation of sample preparation and detection processes, elongated sensor lifetime, minimal membrane and sample consumption, and user-definable/reconfigurable sensor array. PMID- 29414087 TI - Colorimetric and chemiluminescent dual-readout immunochromatographic assay for detection of pesticide residues utilizing g-C3N4/BiFeO3 nanocomposites. AB - Graphitic carbon nitride/bismuth ferrite nanocomposites (g-C3N4/BiFeO3 NCs) were synthesized by a facile one step sol-gel combustion method and employed as a peroxidase-like catalyst. Based on the catalytical activity on the luminol-H2O2 reaction, the nanocomposites were utilized as a colorimetric/chemiluminescent dual-readout immunochromatographic assay (ICA) for the multiplexed detection of pesticide residues by utilizing chlorpyrifos and carbaryl as the model analytes. In the proposed protocol, chlorpyrifos antibody and carbaryl antibody were tagged to g-C3N4/BiFeO3 NCs for developing the spatially-resolved multianalyte ICA. After two competitive immunoreactions completed on the ICA test strip, the tracer antibodies were captured by the immobilized antigens on two test lines. The accumulation of g-C3N4/BiFeO3 NCs led to the appearance of brown color, which were observed as a colorimetric and semi-quantitative signal. Furthermore, the g C3N4/BiFeO3 NCs-driven generation of CL signal was collected as a sensitively quantitative signal after initiating the luminol-H2O2 reaction on the test lines. Under the optimal conditions, the limits of detection of chlorpyrifos and carbaryl were both 0.033ng/mL. The dual-readout ICA was successfully used to detect chlorpyrifos and carbaryl spiked in environmental water and traditional Chinese medicine samples with acceptable recovery values of 80-119% and 90-118%. Due to many advantages including low cost, time efficiency, high sensitivity and good portability, the novel ICA showed great potential in many areas such as drug safety, environmental monitoring and clinical diagnosis. PMID- 29414088 TI - Ru(bpy)32+-Silica@Poly-L-lysine-Au as labels for electrochemiluminescence lysozyme aptasensor based on 3D graphene. AB - In this work, the feasibility of a novel sensitive electrochemiluminescence aptasensor for the detection of lysozyme using Ru(bpy)32+-Silica@Poly-L-lysine-Au (RuSiNPs@PLL-Au) nanocomposites labeling as an indicator was demonstrated. The substrate electrode of the aptasensor was prepared by depositing gold nanoparticles (AuNPs) on 3D graphene-modified electrode. The lysozyme binding aptamer (LBA) was attached to the 3D graphene/AuNPs electrode through gold-thiol affinity, hybridized with a complementary single-strand DNA (CDNA) of the lysozyme aptamer labeled by RuSiNPs@PLL-Au as an electrochemiluminescence intensity amplifier. Thanks to the synergistic amplification of the 3D graphene, the AuNPs and RuSiNPs@PLL-Au NPs linked to Ru(bpy)32+-ECL further enhanced the ECL intensity of the aptasensor. In presence of lysozyme, the CDNA segment of the self-assembled duplex was displaced by the lysozyme, resulting in decreased electrochemiluminescence signal. Under the optimized conditions, the decrease in electrochemiluminescence intensity varied proportionally with the logarithmic concentration of the lysozyme from 2.25 * 10-12 to 5.0 * 10-8 mol L-1, and the detection limit was estimated to 7.5 * 10-13 mol L-1. The aptasensor was further tested in real samples and found reliable for the detection of lysozyme, thus holding great potential application in food safety researches and bioassay analysis. PMID- 29414089 TI - A sensitive Potentiometric resolved ratiometric Photoelectrochemical aptasensor for Escherichia coli detection fabricated with non-metallic nanomaterials. AB - In this work, a sensitive potentiometric resolved ratiometric photoelectrochemical aptasensor for Escherichia coli (E. coli) detection was successfully fabricated with non-metallic nanomaterials. To avoid the use of precious metals or heavy metals, three-dimensional graphene hydrogel-loaded carbon quantum dots (C-dots/3DGH) and graphene-like carbon nitride (g-C3N4) with excellent PEC activity and matched potential were prepared. These two materials were modified onto two adjacent areas on the ITO electrode. By applying different bias voltage, the cathodic current generated by C-dots/3DGH and the anodic current generated by g-C3N4 can be clearly distinguished and would not interfere with one another. Then E. coli aptamer was modified onto the surface of C dots/3DGH. In the presence of targets, the binding of E. coli with aptamer lead to the steric hindrance greatly increased and the cathodic current decreased significantly. Meanwhile, the anodic current generated by g-C3N4 was not influenced and it can serve as a stable reference to evaluate the environmental factors. Therefore, the concentration of E. coli can be quantified by the ratio of cathodic current to anodic current, which can effectively eliminate these analyte-independent factors and provide a more precise analysis. In addition, this ratiometric PEC biosensor also showed a good sensitivity and a wide linear range (2.9 cfu/mL to 2.9 * 106 cfu/mL). PMID- 29414090 TI - A novel "dual-potential" ratiometric electrochemiluminescence DNA sensor based on enhancing and quenching effect by G-quadruplex / hemin and Au-Luminol bifunctional nanoparticles. AB - An ultrasensitive and stable "dual-potential" ratiometric electrochemiluminescence (ECL) sensor is reported for specific DNA, the femtomolar detection limit (0.12 fM, S/N = 3) and high selectivity insure its potential applications in cancer biomarkers searching or monitoring. The excellent performance of the sensor comes from simultaneously fabricated layer by layer structure "target DNA + Hemin / Au-Luminol NPs / DNA* / sl DNA / TGA / QDs / MWNTs / GCE" mode which was based on the enhancing effect of luminol by G quadruplex / hemin and Au nanoparticles and the quenching effect of CdSe/ZnS by G quadruplex / hemin. (i) DNA-SH could combine with Au-Luminol NPs via S-Au bond to solve the problem of poor solubility and weak ECL intensity of luminol in neutral medium. (ii) Target DNA and Hemin formed the G-quadruplex / hemin peroxidase mimicking DNAzyme could enhance the ECL of luminol and quench the ECL of CdSe/ZnS simultaneously. (iii) DNA* was employed to increase a certain distance between CdSe/ZnS and Au-Luminol for enhancing the CdSe/ZnS QDs initial ECL intensity. The dual-potential ratiometric mode lower the influence of background and side reaction of the ECL sensor which were the most important factors in trace sensing. PMID- 29414091 TI - Label-free photoelectrochemical aptasensor for tetracycline detection based on cerium doped CdS sensitized BiYWO6. AB - A novel photoelectrochemical (PEC) aptasensor based on cerium (Ce) doped CdS modified graphene (G)/BiYWO6 was designed, which exhibits enhanced PEC intensity compared with pure BiYWO6, G/BiYWO3 and BiYWO6/Ce:CdS. In this scenario, ascorbic acid (AA) was exploited as an efficient and non-poisonous electron donor for scavenging photogenerated holes. The doping of Ce in CdS promoted its visible light absorption range and facilitated the charge transfer rate as well as hindered the h+/e- recombination. Moreover, the combination of G further promoted the electron carrier separation and transfer process due to its excellent electron collection and shuttling characteristic. Thus, the G/BiYWO6/Ce:CdS heterostructure was successfully served as a matrix for the PEC detection of tetracycline (Tc) at 0 V (vs Hg/Hg2Cl2). Under optimal conditions, the PEC aptasensor could offer a sensitive and specific detection limit (3 S/N) of Tc down to 0.01 ng/mL, as well as acceptable reproducibility, selectivity and storage stability, which opened up a promising pathway for the development of PEC biosensors. PMID- 29414092 TI - A robust electrochemical sensing platform using carbon paste electrode modified with molecularly imprinted microsphere and its application on methyl parathion detection. AB - A highly sensitive electrochemical sensor using a carbon paste electrode (CPE) modified with surface molecularly imprinted polymeric microspheres (SMIPMs) was developed for methyl parathion (MP) detection. Molecular imprinting technique based on distillation precipitation polymerization was applied to prepare SMIPMs and non-surface imprinted microspheres (MIPMs). The polymer properties including morphology, size distribution, BET specific surface area and adsorption performance were investigated and compared carefully. Both MIPMs and SMIPMs were adopted to prepare CPE sensors and their electrochemical behaviors were characterized via cyclic voltammetry and electrochemical impedance spectroscopy. Compared with MIPMs packed sensor, SMIPMs/CPE exhibits a higher sensing response towards MP with linear detection range of 1 * 10-12-8 * 10-9 mol L-1 and detection limit of 3.4 * 10-13 mol L-1 (S/N = 3). Moreover, SMIPMs/CPE exhibits good selectivity and stability in multiple-cycle usage and after long-time storage. Finally, the developed sensor was used to determine MP in real samples including soil and vegetables and only simple pretreatment is needed. The detection results were consistent with those obtained from liquid chromatography. Collectively, this newly developed sensor system shows significant potential for use in a variety of fields like food safety, drug residue determination and environmental monitoring. PMID- 29414093 TI - Ultrasensitive direct impedimetric immunosensor for detection of serum HER2. AB - Assesment of human epidermal growth factor receptor 2 status is a key factor prompting definitive treatment decisions that help in reducing mortality rates associated with breast cancer. In this article, highly sensitive and low-cost impedimetric immunosensor using single-chain fragment variable antibody fragments was developed for quantitative detection of human epidermal growth factor receptor 2 from serum employing gold nanoparticle-modified disposable screen printed carbon electrodes. The gold nanoparticles facilitate fast electron transfer and offer a biocompatible surface for immobilization of small antibody fragments in an oriented manner, resulting in improved antigen binding efficiency. The single-chain fragment variable antibody fragment-modified screen printed immunosensor exhibits wide dynamic range of 0.01-100 ng mL-1 and detection limit of 0.01 ng mL-1. The advantages offered by this platform in terms of high sensitivity, broad dynamic range and low-cost demonstrates great potential for improved monitoring of human epidermal growth factor receptor 2 levels for the management of breast and other cancers. PMID- 29414094 TI - A silicon-based neural probe with densely-packed low-impedance titanium nitride microelectrodes for ultrahigh-resolution in vivo recordings. AB - In this study, we developed and validated a single-shank silicon-based neural probe with 128 closely-packed microelectrodes suitable for high-resolution extracellular recordings. The 8-mm-long, 100-um-wide and 50-um-thick implantable shank of the probe fabricated using a 0.13-um complementary metal-oxide semiconductor (CMOS) metallization technology contains square-shaped (20 * 20 um2), low-impedance (~ 50 kOmega at 1 kHz) recording sites made of rough and porous titanium nitride which are arranged in a 32 * 4 dense array with an inter electrode pitch of 22.5 um. The electrophysiological performance of the probe was tested in in vivo experiments by implanting it acutely into neocortical areas of anesthetized animals (rats, mice and cats). We recorded local field potentials, single- and multi-unit activity with superior quality from all layers of the neocortex of the three animal models, even after reusing the probe in multiple (> 10) experiments. The low-impedance electrodes monitored spiking activity with high signal-to-noise ratio; the peak-to-peak amplitude of extracellularly recorded action potentials of well-separable neurons ranged from 0.1 mV up to 1.1 mV. The high spatial sampling of neuronal activity made it possible to detect action potentials of the same neuron on multiple, adjacent recording sites, allowing a more reliable single unit isolation and the investigation of the spatiotemporal dynamics of extracellular action potential waveforms in greater detail. Moreover, the probe was developed with the specific goal to use it as a tool for the validation of electrophysiological data recorded with high-channel count, high-density neural probes comprising integrated CMOS circuitry. PMID- 29414095 TI - Cardiac Troponin T capture and detection in real-time via epitope-imprinted polymer and optical biosensing. AB - Millions of premature deaths per year from cardiovascular diseases represent a global threat urging governments to increase global initiatives, as advised by World Health Organization. In particular, together with prevention and management of risk factors, the development of portable platforms for early diagnosis of cardiovascular disorders appears a fundamental task to carry out. Contemporary assays demonstrated very good accuracy for diagnosis of acute myocardial infarction (AMI), but they are based on expensive and fragile capture antibodies. Accordingly, also considering the massive demand from developing countries, we have devoted our study to an affinity-based biosensor for detection of troponin T (TnT), a preferred biomarker of AMI. This combines a stable and inexpensive molecularly imprinted polymer (MIP) based on polydopamine (PDA) with surface plasmon resonance (SPR) transduction. Herein we report the fast and specific answer upon TnT binding onto an epitope-imprinted surface that strongly encourages the further development toward antibody-free point-of-care testing for cardiac injury. PMID- 29414096 TI - Ultrasensitive label-free optical microfiber coupler biosensor for detection of cardiac troponin I based on interference turning point effect. AB - Sensitive detection of cardiac biomarkers is critical for clinical diagnostics of myocardial infarction (MI) while such detection is quite challenging due to the ultra-low concentration of cardiac biomarkers. In this work, a label-free immunosensor based on optical microfiber coupler (OMC) has been developed for the ultrasensitive detection of cardiac troponin I (cTnI), a selective and highly sensitive biomarker of acute myocardial infarction (AMI). CTnI monoclonal antibodies were immobilized on the surface of the fiber through polyelectrolyte layer using layer-by-layer deposition technique. For refractive index sensing characterization, an ultra-high sensitivity of 91777.9 nm/RIU was achieved when the OMC works around the dispersion turning point, which is the highest experimental demonstration in the field of fiber-optic evanescent biosensors. For biosensing, the immunosensor with good specificity showed a linear wavelength shift in the range of 2-10 fg/mL and an ultra-low detection limit of 2 fg/mL. Such immunosensors have huge application potential for the detection of cardiac biomarkers of myocardial infarction due to simple detection scheme, quick response time, ease of handling and miniaturation. PMID- 29414097 TI - Normal mode analysis of Zika virus. AB - In recent years, Zika virus (ZIKV) caused a new pandemic due to its rapid spread and close relationship with microcephaly. As a result, ZIKV has become an obvious global health concern. Information about the fundamental viral features or the biological process of infection remains limited, despite considerable efforts. Meanwhile, the icosahedral shell structure of the mature ZIKV was recently revealed by cryo-electron microscopy. This structural information enabled us to simulate ZIKV. In this study, we analyzed the dynamic properties of ZIKV through simulation from the mechanical viewpoint. We performed normal mode analysis (NMA) for a dimeric structure of ZIKV consisting of the envelope proteins and the membrane proteins as a unit structure. By analyzing low-frequency normal modes, we captured intrinsic vibrational motions and defined basic vibrational properties of the unit structure. Moreover, we also simulated the entire shell structure of ZIKV at the reduced computational cost, similar to the case of the unit structure, by utilizing its icosahedral symmetry. From the NMA results, we can not only comprehend the putative dynamic fluctuations of ZIKV but also verify previous inference such that highly mobile glycosylation sites would play an important role in ZIKV. Consequently, this theoretical study is expected to give us an insight on the underlying biological functions and infection mechanism of ZIKV. PMID- 29414098 TI - NFkappaB pathway analysis: An approach to analyze gene co-expression networks employing feedback cycles. AB - The genes of the NFkappaB pathway are involved in the control of a plethora of biological processes ranking from inhibition of apoptosis to metastasis in cancer. It has been described that Gliobastoma multiforme (GBM) patients carry aberrant NFkappaB activation, but the molecular mechanisms are not completely understood. Here, we present a NFkappaB pathway analysis in tumor specimens of GBM compared to non-neoplasic brain tissues, based on the different kind of cycles found among genes of a gene co-expression network constructed using quantized data obtained from the microarrays. A cycle is a closed walk with all vertices distinct (except the first and last). Thanks to this way of finding relations among genes, a more robust interpretation of gene correlations is possible, because the cycles are associated with feedback mechanisms that are very common in biological networks. In GBM samples, we could conclude that the stoichiometric relationship between genes involved in NFkappaB pathway regulation is unbalanced. This can be measured and explained by the identification of a cycle. This conclusion helps to understand more about the biology of this type of tumor. PMID- 29414099 TI - An integrative in silico approach to the structure of Omp33-36 in Acinetobacter baumannii. AB - Omp33-36 in A. baumannii, a bacterium causing serious nosocomial infections, is a virulence factor associated with the pathogen metabolic fitness as well as its adherence and invasion to human epithelial cells. This protein is also involved in interaction of the bacteria with host cells by binding to fibronectin. Moreover, Omp33-36 renders cytotoxicity to A. baumannii in addition to inducing apoptosis and modulation of autophagy. In the present study, an integrated strategy is launched to pierce into the 3D structure of Omp33-36 protein. The signal peptide within the sequence was determined, then, topology as well as secondary and tertiary structures of the protein were predicted. The mature protein assigned as a 14-stranded barrel in which residues 1-19 is removed as signal peptide. The obtained 3D models were evaluated in terms of quality; and then, served as queries to find similar protein structures. The hits were analyzed regarding topology among which 14-stranded were considered. The most qualified model was refined and then its sequence aligned to its counterpart similar structure protein (CymA from Klebsiella oxytoca). The determined structure of Omp33-36 could justify its porin function and carbapenem-resistance associated with the loss of this protein. PMID- 29414100 TI - Physical quantity of residue electrostatic energy in flavin mononucleotide binding protein dimer. AB - The electrostatic (ES) energy of each residue was for the first time quantitatively evaluated in a flavin mononucleotide binding protein (FBP). A residue electrostatic energy (RES) was obtained as the sum of the ES energies between atoms in each residue and all other atoms in the FBP dimer using atomic coordinates obtained by a molecular dynamics (MD) simulation. ES is one of the most important energies among the interaction energies in a protein. It is determined from the RES, the residues which mainly contribute to stabilize the structure of each subunit, and the binding energy between two subunits can be estimated. The RES of all residues in subunit A (Sub A) and subunit B (Sub B) were attractive forces, even though the residues contain net negative or positive charges. This reveals that the ES energies of any of the residues can contribute to stabilize the protein structure. The total binding ES energy over all residues among the subunits was distributed between -0.2 to -1.2 eV (mean = -0.67 eV) from the MD simulation time. PMID- 29414101 TI - Pitfalls in MRI of rectal cancer: What radiologists need to know and avoid. AB - Preoperative staging of rectal cancer using magnetic resonance imaging (MRI) has become an important component of clinical management. Although MRI is the modality of choice for rectal cancer diagnosis and staging, there are certain inherent potential pitfalls that radiologists need to recognize in order to avoid imaging misinterpretation, including choice of MRI protocol; choice of MRI technique; potential mimickers of rectal cancer; mucinous rectal tumor; differentiation between extramural tumor invasion and desmoplastic reaction; differentiation between low rectal cancer and anal cancer; problems relating to nodal involvement, peritoneal reflection, and mesorectal fascia invasion; and, challenges associated with restaging, post-treatment changes, and complications. The aim of this article was to heighten radiologist awareness of these potential pitfalls in order to improve diagnosis, decision-making, and patient outcomes. PMID- 29414102 TI - Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein. AB - Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated alpha-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of alpha-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown. In the present work we investigated the effect of alpha-synuclein on mitochondrial dynamics and autophagy/mitophagy in SH-SY5Y cells, an in vitro model of Parkinson disease. We demonstrated that overexpression of wild type alpha-synuclein causes moderated toxicity, ROS generation and mitochondrial dysfunction. In addition, alpha synuclein induces the mitochondrial fragmentation on a Drp-1-dependent fashion. Overexpression of the fusion protein Opa-1 prevented both mitochondrial fragmentation and cytotoxicity. On the other hand, cells expressing alpha synuclein showed activated autophagy and particularly mitophagy. Employing a genetic strategy we demonstrated that autophagy is triggered in order to protect cells from alpha-synuclein-induced cell death. Our results clarify the role of Opa-1 and Drp-1 in mitochondrial dynamics and cell survival, a controversial alpha-synuclein research issue. The findings presented point to the relevance of mitochondrial homeostasis and autophagy in the pathogenesis of PD. Better understanding of the molecular interaction between these processes could give rise to novel therapeutic methods for PD prevention and amelioration. PMID- 29414103 TI - Reproductive role of miRNA in the hypothalamic-pituitary axis. AB - The hypothalamic-pituitary-gonadal (HPG) axis plays a critical role in regulating reproductive function. Gonadotropin-releasing hormone (GnRH), which is secreted by the hypothalamus, acts on pituitary gonadotrophs to stimulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and secretion, ultimately affecting the animal's fertility. MicroRNAs are small, non-coding RNAs that are widely expressed throughout the brain and can fine-tune gene expression post-transcriptionally. Recently, growing evidence has unveiled the central position of miRNAs within a key regulatory process involving GnRH secretion and subsequent activation in the pituitary. Although transcriptional regulation of reproduction has been well studied, the post-transcriptional processes are less well understood. In this review, we elaborate comprehensively on the critical role of miRNAs in the reproductive process, including both temporal and spatial aspects. A better understanding of how miRNAs impact the neuroendocrine system may improve our knowledge of reproduction and provide novel targets for therapeutic development. PMID- 29414104 TI - Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson's disease. AB - Growing evidence suggests that oxidative stress plays a critical role in neuronal destruction characteristic of Parkinson's disease (PD). However, the molecular mechanisms of oxidative stress-mediated dopaminergic cell death are far from clear. In the current investigation, we tested the hypothesis that acrolein, an oxidative stress and lipid peroxidation (LPO) product, is a key factor in the pathogenesis of PD. Using a combination of in vitro, in vivo, and cell free models, coupled with anatomical, functional, and behavioral examination, we found that acrolein was elevated in 6-OHDA-injected rats, and behavioral deficits associated with 6-OHDA could be mitigated by the application of the acrolein scavenger hydralazine, and mimicked by injection of acrolein in healthy rats. Furthermore, hydralazine alleviated neuronal cell death elicited by 6-OHDA and another PD-related toxin, rotenone, in vitro. We also show that acrolein can promote the aggregation of alpha-synuclein, suggesting that alpha-synuclein self assembly, a key pathological phenomenon in human PD, could play a role in neurotoxic effects of acrolein in PD models. These studies suggest that acrolein is involved in the pathogenesis of PD, and the administration of anti-acrolein scavengers such as hydralazine could represent a novel strategy to alleviate tissue damage and motor deficits associated with this disease. PMID- 29414105 TI - Discovery of ebselen as an inhibitor of Cryptosporidium parvum glucose-6 phosphate isomerase (CpGPI) by high-throughput screening of existing drugs. AB - Cryptosporidium parvum is a water-borne and food-borne apicomplexan pathogen. It is one of the top four diarrheal-causing pathogens in children under the age of five in developing countries, and an opportunistic pathogen in immunocompromised individuals. Unlike other apicomplexans, C. parvum lacks Kreb's cycle and cytochrome-based respiration, thus relying mainly on glycolysis to produce ATP. In this study, we characterized the primary biochemical features of the C. parvum glucose-6-phosphate isomerase (CpGPI) and determined its Michaelis constant towards fructose-6-phosphate (Km = 0.309 mM, Vmax = 31.72 nmol/MUg/min). We also discovered that ebselen, an organoselenium drug, was a selective inhibitor of CpGPI by high-throughput screening of 1200 known drugs. Ebselen acted on CpGPI as an allosteric noncompetitive inhibitor (IC50 = 8.33 MUM; Ki = 36.33 MUM), while complete inhibition of CpGPI activity was not achieved. Ebselen could also inhibit the growth of C. parvum in vitro (EC50 = 165 MUM) at concentrations nontoxic to host cells, albeit with a relatively small in vitro safety window of 4.2 (cytotoxicity TC50 on HCT-8 cells = 700 MUM). Additionally, ebselen might also target other enzymes in the parasite, leading to the parasite growth reduction. Therefore, although ebselen is useful in studying the inhibition of CpGPI enzyme activity, further proof is needed to chemically and/or genetically validate CpGPI as a drug target. PMID- 29414106 TI - Metabolism of albendazole, ricobendazole and flubendazole in Haemonchus contortus adults: Sex differences, resistance-related differences and the identification of new metabolites. AB - Haemonchus contortus (family Trichostrongylidae, Nematoda), a hematophagous gastrointestinal parasite found in small ruminants, has a great ability to develop resistance to anthelmintic drugs. We studied the biotransformation of the three benzimidazole anthelmintics: albendazole (ABZ), ricobendazole (albendazole S-oxide; RCB) and flubendazole (FLU) in females and males of H. contortus in both a susceptible ISE strain and resistant IRE strain. The ex vivo cultivation of living nematodes in culture medium with or without the anthelmintics was used. Ultrasensitive UHPLC/MS/MS analysis revealed 9, 7 and 12 metabolites of ABZ, RCB and FLU, respectively, with most of these metabolites now described in the present study for the first time in H. contortus. The structure of certain metabolites shows the presence of biotransformation reactions not previously reported in nematodes. There were significant qualitative and semi-quantitative differences in the metabolites formed by male and female worms. In most cases, females metabolized drugs more extensively than males. Adults of the IRE strain were able to form many more metabolites of all the drugs than adults of the ISE strain. Some metabolites were even found only in adults of the IRE strain. These findings suggest that increased drug metabolism may play a role in resistance to benzimidazole drugs in H. contortus. PMID- 29414108 TI - The optimal timing of post-treatment sampling for the assessment of anthelminthic drug efficacy against Ascaris infections in humans. AB - The egg reduction rate (ERR) is the current standard mean to assess the efficacy of drugs against human soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura and hookworm). Although the timing of post-treatment sampling is pivotal for a readily interpretation of drug efficacy, there is lack empirical data that allows recommending the optimal time point for a follow-up egg counting. In the present study, we re-analyzed both the kinetics of worm expulsion and egg output for Ascaris lumbricoides following a single oral dose of albendazole in a series of studies previously conducted in Kenyan communities. The results indicate that it takes up to 10 days post-treatment before the expulsion of both adult male and female Ascaris worms is completed, approximately 20% of the worms being expelled between day 7 and 10 post-treatment. The sequential analysis of the egg out put, indicated a poor ERR (89.4%) at day 7 post-treatment, but a 100% ERR at day 14 and 21 post-treatment. Based on our findings we recommend to wait at least 14 days after an albendazole treatment before conducting the follow-up egg count. Any sampling before this time point may result in biased ERR estimates, due the release of residual eggs from moribund or degenerating worms. PMID- 29414107 TI - Synthesis of aminophenylhydroxamate and aminobenzylhydroxamate derivatives and in vitro screening for antiparasitic and histone deacetylase inhibitory activity. AB - A series of aminophenylhydroxamates and aminobenzylhydroxamates were synthesized and screened for their antiparasitic activity against Leishmania, Trypanosoma, and Toxoplasma. Their anti-histone deacetylase (HDAC) potency was determined. Moderate to no antileishmanial or antitrypanosomal activity was found (IC50 > 10 MUM) that contrast with the highly efficient anti-Toxoplasma activity (IC50 < 1.0 MUM) of these compounds. The antiparasitic activity of the synthetized compounds correlates well with their HDAC inhibitory activity. The best-performing compound (named 363) express a high anti-HDAC6 inhibitory activity (IC50 of 0.045 +/- 0.015 MUM) a moderate cytotoxicity and a high anti-Toxoplasma activity in the range of known anti-Toxoplasma compounds (IC50 of 0.35-2.25 MUM). The calculated selectivity index (10-300 using different human cell lines) of the compound 363 makes it a lead compound for the future development of anti-Toxoplasma molecules. PMID- 29414109 TI - P-glycoprotein-9 and macrocyclic lactone resistance status in selected strains of the ovine gastrointestinal nematode, Teladorsagia circumcincta. AB - The Teladorsagia circumcincta P-glycoprotein-9 (Tci-pgp-9) gene has previously been implicated in multiple-anthelmintic resistance in this parasite. Here we further characterise genetic diversity in Tci-pgp-9 and its possible role in ivermectin (IVM) and multi-drug resistance using two UK field isolates of T. circumcincta, one susceptible to anthelmintics (MTci2) and the other resistant to most available anthelmintics including IVM (MTci5). A comparison of full-length Tci-pgp-9 cDNA transcripts from the MTci2 and MTci5 isolates (~3.8 kb in both cases) indicated that they shared 95.6% and 99.5% identity at the nucleotide and amino acid levels, respectively. Nine non-synonymous SNPs were found in the MTci5 sequences relative to their MTci2 counterparts. Twelve genomic sequence variants of the first internucleotide binding domain of Tci-pgp-9 were identified and up to 10 of these were present in some individual worms, strongly supporting previous evidence that amplification of this gene has occurred in T. circumcincta. On average, fewer distinct sequence variants of Tci-pgp-9 were present in individual worms of the MTci5 isolate than in those of the MTci2 isolate. A further reduction in the number of sequence variants was observed in individuals derived from an IVM-treated sub-population of MTci5. These findings suggest that Tci-pgp-9 was under purifying selection in the face of IVM treatment in T. circumcincta, with some sequence variants being selected against. PMID- 29414110 TI - The flip side of traditional nursing education: A literature review. AB - The flipped classroom (FC) andragogy purports an improvement of critical thinking and problem-solving skills in students. This literature review explores fourteen research studies and discusses outcome measures reported on the effectiveness of using this teaching modality. Students described the learning activities during the classroom meeting times as valuable and indicated the interaction and engagement were beneficial to their learning. Many students opined an increased comprehension of the subject matter. Overall, the FC required more work on the part of the students and the faculty, and the majority of students preferred the traditional classroom (TC) passive method of learning over the FC active learning andragogy as a result of the substantial time commitment required for preparation necessitated by the FC. Five of the fourteen studies evaluated student learning outcome measures; four studies showed an improvement in the FC environment compared to the TC and one reported the FC was at least as effective as the TC. Further studies with quantifiable outcome measures are required to determine the effectiveness of a FC on critical thinking and problem-solving skills of nursing students. PMID- 29414111 TI - Exploration of the perceived impact of carer involvement in mental health nurse education: Values, attitudes and making a difference. AB - Academic settings are seen to be an ideal, although potentially privileged, environments in which to demonstrate meaningful and authentic involvement. Despite the lack of evaluation and evidence relating to the impact of involvement being noted in the early 2000's, there continues to be a lack of evaluative research in this area (Happell et al., 2014) with the examination of the carers perspective being even more limited. This paper presents qualitative findings emerging from an Interpretive Phenomenological Analysis (IPA) carried out on transcripts from five individual semi-structured interviews with family carers who contribute to the Bachelor of Nursing (Mental Health) programme at Edinburgh Napier University. The study sets out to explore the perceptions family carers have relating to their involvement in nurse education. Findings are themed and offer insights into why family carers become involved in educating nurses, the impact they perceive this involvement has on students and themselves and the meaning they make of the feedback they receive. Drawing on these themes and narratives provides opportunities to understand the motivation and drive carers have to improve health and social care services for carers and for people who use services while offering knowledge about how carers perceive and evaluate the impact of their contributions. Conclusions made relate to the value of involvement and how connecting with students thought out their programme of study builds rapport and meaningful, authentic partnerships. However, the strategic planning and continued investment in co-production as well as a deeper understanding of the complex relationship students and carers have is needed. PMID- 29414112 TI - Attitudes of midwifery and nursing students in a Turkish university toward lesbians and gay men and opinions about healthcare approaches. AB - Lesbians and gay men are subjected to negative attitudes and poor quality health care by midwives in the process of having children and by nurses in the process of receiving general health care services. Our aim was to investigate midwifery and nursing students' attitudes towards lesbians and gay men and their opinions about health care approaches displayed towards them. The study was designed as a cross-sectional and descriptive one and conducted in one midwifery and two nursing schools in a city in Turkey and comprised 1321 students. To assess the participants' attitudes, the Attitudes toward Lesbians and Gays (ATLG) Scale was used. To assess opinions about health care approaches, the students were asked open-ended questions. All the participating students' attitude scores were below the average and they exhibited negative attitudes towards lesbians and gays. While very few of the participants had positive views about health care given to, most of them either had negative views or did not have any opinions. The midwifery students' attitudes were more positive than were those of the nursing students. Students' health care approaches towards lesbians and gay men were insufficient and negative. Educators need to develop training programs, which can help students gain cultural awareness of the health care needs of lesbians and gay men in different cultures before they graduate. PMID- 29414113 TI - Nursing students' alternative beliefs regarding care for patients suffering from depression. AB - Depression is an illness that constitutes a major challenge for Public Health worldwide. Therefore, there is a clear need to receive training to care for this type of patient. This study sets out to identify alternative non-scientific beliefs among nursing students regarding the topic of depression after studying the module of Psychopathology. This study enrolled 102 third year undergraduate nursing students. The students resolved a case on an individual basis in written form which was analysed qualitatively. In this study, we have found that, despite having undergone information-transfer educational training in relation to the physiopathology of depression, nursing students persist in holding unscientific beliefs about this condition. On the basis that the opinions of nurses about depression can influence the care of their future patients, it is important to consider these alternative beliefs as learning difficulties in order to design an effective teaching instruction. PMID- 29414114 TI - Factors related to nursing students' readiness to enter working life - A scoping literature review. AB - The aim of this scoping literature review was to identify the factors related to nursing students' readiness to enter working life. The literature search was carried out in autumn 2017 in PubMed and CINAHL databases. The studies selected for this review (n = 17) were analyzed thematically with inductive content analysis. Four subthemes that were combined into two main factors related to nursing students' readiness to enter working life were found. The main factors found were 1) educational factors and 2) personal factors. Educational factors consisted of professional competence and clinical practice, while personal factors consisted of nursing students' background and feelings. Some nursing students tend to feel insecure about entering working life as a newly graduated nurse. This literature review also supports the importance of clinical practice periods in nursing education and for readiness for working life. Nurse education needs to ensure clinical practice periods which support nursing students' professional growth. Further research is needed on how the factors related to nursing students' readiness to enter working life correlate with each other. Particularly, the association between competence, readiness and positive feelings towards graduation needs further investigation. PMID- 29414116 TI - Foot scan assessment of metatarsus adductus: A useful adjunct to Bleck's classification. AB - : To determine the severity of metatarsus adductus (MA) comparing with Bleck's classification as a commonly acceptable method for assessing MA, static foot scan has been used. In this cross-sectional descriptive research study, 100 subjects were equally divided into four groups according to Bleck's classification. The feet were scanned and MA severity (MAS) index was measured on the obtained foot scan images. The MAS index was the ratio of the transverse deviation of the forefoot from the lateral border heel line to the width of the ball of the foot. The mean of the MAS index in normal, mild, moderate, and severe MA was 0.02+/ 0.02, 0.1+/-0.01, 0.159+/-0.03, and 0.216+/-0.025, respectively. The difference of MAS index between each group was significant (p<0.001). The mean of MAS index in 4 groups was consistent with Bleck's classification, with a significant increase from normal to severe MA (p<0.05). Since the results of this method are consistent with Bleck's classification and this novel foot scan assessment appears to be more objective than Bleck's classification, the authors recommend this method to be used in examination of patients with MA. However, further studies should be conducted to define interobserver and intraobserver reliability. LEVEL OF EVIDENCE: III. PMID- 29414117 TI - Structural differences in the lower extremities in children aged 7-9 years, caused by playing football: A cross-sectional study. AB - BACKGROUND: Physical activity during childhood can be beneficial in the long term. However, this practice can influence the child's physiological development. The aim of this study was to determine whether the practice of soccer, in moderation, could be a risk factor for the inadequate development of the lower limb. METHODS: The study group was composed of 115 children, of whom 59 (mean age 8.03+/-0.89years) practised soccer 3 times a week and had a positive Physical Activity Questionnaire for Adolescents (PAQ-A) score, while a further 56 (mean age 7.96+/-0.87years) did not perform any additional physical activity and had a negative PAQ-A score. A foot posture analysis, based on the foot posture index (FPI), the valgus index, the orientation of the subtalar joint (STJ) and the Q angle of the knee, was carried out. RESULTS: For the group of soccer players, the following results were obtained: FPI 4.79+/-2.38 (R) and 3.95+/-2.31 (L); valgus index 13.56 degrees +/-1.66 degrees (R) and 13.42 degrees +/-1.48 degrees (L); STJ test 79% pronated; Q angle 13.13 degrees +/-2.06 degrees (R) and 13.18 degrees +/-1.93 degrees (L). For the non-players, the corresponding values were: FPI 3.62+/-2.82 (R) and 3.74+/-2.77 (L); valgus index 12.76 degrees +/-1.71 degrees (R) and 12.84 degrees +/-1.72 degrees (L); STJ test 50% pronated; Q angle 13.87 degrees +/-3.01 degrees (R) and 13.86 degrees +/-2.94 degrees (L). CONCLUSION: There is a degree of difference between the two groups, but the values do not vary greatly from those considered normal for this age group. Any alterations in this respect can be assumed to be caused at older ages than those analysed. PMID- 29414118 TI - The structured ambivalence of cannabis control in England & Wales. AB - The two reclassifications of cannabis in England & Wales in 2004 and 2009 have been subjected to a series of academic analyses which have largely been centred on either the relationship to evidence, or in terms of the implications and realities of policing and health under the changes. However, despite the wealth of attention on this area, there have been relatively few attempts to understand these policy movements through broader criminological theoretical frameworks. One recent exception is Shiner's (2015) utilisation of Garland's (2001) concept of 'structured ambivalence'. This paper seeks to test this application through drawing upon an alternative source of evidence, namely, a series of 'elite' qualitative interviews, and using Kingdon's (1995) Multiple Streams model to make sense of the policy processes. In doing so, it largely corroborates Shiner's conclusions whilst also further illuminating particular agentic aspects and their intertwining with other structural and cultural forces which led to the reclassifications. These findings demonstrate the value of triangulating evidential sources and advances knowledge about the role of individuals in pursuing policy agendas within a broader shifting political climate. This provides greater scope to further test and understand how structured ambivalence manifests itself in other cultural contexts and policy domains. PMID- 29414119 TI - Shikonin upregulates the expression of drug-metabolizing enzymes and drug transporters in primary rat hepatocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shikonin, a naphthoquinone pigment abundant in the root of the Chinese herb Lithospermum erythrorhizon, has been widely used to treat inflammatory diseases for thousands of years. Whether shikonin changes drug metabolism remains unclear. AIM OF THE STUDY: We investigated whether shikonin modulates the expression of hepatic drug-metabolizing enzymes and transporters as well as the possible mechanisms of this action. MATERIALS AND METHODS: Primary hepatocytes isolated from Sprague-Dawley rats were treated with 0-2 MUM shikonin and the protein and mRNA levels of drug-metabolizing enzymes and transporters as well as the activation of aryl hydrocarbon receptor (AhR) and NF-E2-related factor 2 (Nrf2) were determined. RESULTS: Shikonin dose-dependently increased the protein and RNA expression of phase I enzymes, i.e., cytochrome P450 (CYP) 1A1/2, CYP3A2, CYP2D1, and CYP2C6; phase II enzymes, i.e., glutathione S-transferase (GST), NADP(H) quinone oxidoreductase 1 (NQO1), and UDP glucuronosyltransferase 1A1; and phase III drug transporters, i.e., P-glycoprotein, multidrug resistance associated protein 2/3, organic anion transporting polypeptide (OATP) 1B1, and OATP2B1. Immunoblot analysis and EMSA revealed that shikonin increased AhR and Nrf2 nuclear contents and DNA binding activity. AhR and Nrf2 knockdown by siRNA attenuated the ability of shikonin to induce drug-metabolizing enzyme expression. In addition, shikonin increased p38, JNK, and ERK1/2 phosphorylation, and inhibitors of the respective kinases inhibited shikonin-induced Nrf2 nuclear translocation. CONCLUSIONS: Shikonin effectively upregulates the transcription of CYP isozymes, phase II detoxification enzymes, and phase III membrane transporters and this function is at least partially through activation of AhR and Nrf2. Moreover, Nrf2 activation is dependent on mitogen-activated protein kinases. PMID- 29414120 TI - Evaluation of the anthelminthic potential of Duranta erecta L. (Verbenaceae) fruits used in Nigerian ethnomedicine as a vermifuge. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Duranta erecta L. fruits have been reported to have in vitro anthelminthic properties. People living in the tropical South Eastern part of Nigeria use the plant in folk medicine for the treatment of malaria, abscesses and as a vermifuge. Although there are a few reports about its in vitro anthelminthic activity against different worm categories, scientific reports regarding its in vivo anthelminthic activity are limited. AIM OF THE STUDY: This study was designed with the aim of determining the potential of the plant as an anthelminthic and to verify the claims made by its local users. MATERIALS AND METHODS: Acute toxicity of the plant extract was determined using Lorke's method. Anthelminthic activity was investigated using adult male albino mice experimentally infected with Heligmosomoides bakeri infective L3. Graded ascending doses of the plant extract and Albendazole respectively were orally administered to the mice in the infected groups. Corprological and haematological parameters were recorded within the study period. Twenty-eight (28) days post infection, all infected mice were humanely sacrificed and the Post-Mortem Adult Worm Burden (WB) was estimated and recorded. RESULTS: The results showed that the extract had an LD50 greater than 5000 mg/kg BW and therefore was not acutely toxic for oral use. It also showed that the plant extract was unable to eliminate the faecal egg output or adult worms in the gastrointestinal tract of infected animals even at the high doses used in the study. This was in contrast to Albendazole which significantly (p < .05) reduced faecal egg counts and worm burdens by 71% and 92% respectively in treated mice. Following infection, there was anaemia in all infected groups seen from results of erythrocytic parameters. Treatment with the plant extract, regardless of the dose, was unable to effectively reverse the effect of parasite infection on erythrocytic parameters. However, treatment with Albendazole positively reversed the anaemia, restoring the mice to pre-infection values by the end of the experiment. The results showed significant (p < .05) increase in WBC counts across all groups following infection with the parasite. Treatment with the plant extract and Albendazole respectively, significantly (p < .05) reduced the WBC counts to near pre infection values in most treatment groups. CONCLUSION: As a result of the poor anthelminthic effects recorded in the study, it is therefore recommended that Duranta erecta L. fruits be explored for its other useful effects rather than as an anthelminthic. PMID- 29414122 TI - Examining mechanical properties of various pharmaceutical excipients with the gravitation-based high-velocity compaction analysis method. AB - The compression physics of powders must be considered when developing a suitable tablet formulation. In the present study, the gravitation-based high-velocity method was utilized to analyze mechanical properties of eight common pharmaceutical excipients: two grades of lactose, anhydrous glucose, anhydrous calcium hydrogen phosphate, three grades of microcrystalline cellulose and starch. Samples were compressed five times consecutively with varying pressure and speed so that Setup A produced higher pressure and longer contact time than Setup B. The important parameters obtained from samples were porosity profiles, compaction pressure, contact time, internal energy change and the amount of elastic recovery. All acquired data was only based on distance-time profile of the compression event. Lactose and glucose fragmented effectively while calcium hydrogen phosphate remained in rearrangement phase, due to its hardness and insufficient pressure applied. Microcrystalline cellulose samples showed plastic behaviour and starch was most elastic of all the samples. By utilizing the method, examined excipients could be categorized according to their compression behaviour in an accurate and cost-efficient manner. PMID- 29414121 TI - Sacred Maya incense, copal (Protium copal - Burseraceae), has antianxiety effects in animal models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Maya have traditionally used copal, Protium copal, as incense during ceremonies since pre-Columbian times. Anecdotally, copal (when burned as incense), is thought to elicit mentally uplifting and calming effects. The main objective of this study was to determine whether the incense elicits anxiolytic-like behavior in animal models using rats. A second objective was to characterize active constituents and discern potential mechanism(s) of action, specifically the involvement of the GABAergic and endocannabinoid (eCB) systems. Despite the extensive Central American use of this resin, there are currently no known scientific behavioral or pharmacological studies done with the incense. MATERIALS AND METHODS: Quantification of the triterpenes in the copal resin and cold trapped incense was achieved by HPLC MS. Behavioral effects in rats were assessed using the elevated plus maze (EPM), social interaction (SI) test, conditioned emotion response (CER) and Novel object recognition (NOR) paradigms. Rats were exposed to burning copal (200 mg) over 5 min in a smoking chamber apparatus and then immediately tested in each behavioral paradigm. Follow up SI tests were done using two antagonists flumazenil (1 mg/kg) and AM251 (1 mg/kg) administered systemically. Inhibition of MAGL (monoacylglycerol lipase) was measured by microplate assay with recombinant human enzyme and probe substrate. RESULTS: Phytochemical analysis revealed that copal resin and incense had high alpha- and beta-amyrins and low lupeol triterpene content. Exposure to Protium copal incense significantly reduced anxiety-like behavior in the SI and CER tests. In contrast, no anxiolytic effects were observed in the EPM. The CER effect was time dependent. Both flumazenil and AM251 blocked the anxiolytic activity of copal revealing the involvement of GABAergic and endocannabinoid systems. Copal, as well as the identified triterpenes, potently inhibited monoacylglycerol lipase (MAGL) activity in vitro (IC50 <= 811 ng/mL). CONCLUSIONS: This is the first study to show that copal incense from Protium copal elicits anxiolytic-like effects in fear and social interaction models as evidenced by a reduced learned fear behavior and an increase in active social interaction. It's high alpha and beta-amyrin content suggests behavioral effects may be mediated, in part, by the known action of these terpenes at the benzodiazepine receptor. Furthermore, P. copal's observed activity through the eCB system via MAGL offers a new potential mechanism underlying the anxiolytic activity. PMID- 29414123 TI - Development of a new class of sulforaphane-enabled self-emulsifying drug delivery systems (SFN-SEDDS) by high throughput screening: A case study with curcumin. AB - Self-emulsifying drug delivery systems (SEDDS) have been used as a formulation strategy to overcome the challenges in formulating poorly water soluble drugs. The objective of the present study was to report on the solubilizing capacity of sulforaphane (SFN) and its utilization to formulate SEDDS of poorly water soluble drugs. A set of 24 drugs was tested for their solubility in SFN of which Cyclosporine A, Celecoxib, Paclitaxel, Docetaxel, and Curcumin were selected for subsequent SEDDS formulation development utilizing SFN as common solubilizer. SFN SEDDS formulations were developed utilizing a step-wise screening method that enabled the selection of the most efficient surfactants and co-surfactants to yield transparent microemulsions by microscopic analysis and absorbance data. The optimized SEDDS formulation for curcumin was selected for further investigation by DSC and FTIR, and was subjected to a dissolution study where more than 95% of the drug was found to dissolve within 10 min in both simulated gastric and intestinal fluids. The physical stability of the SEDDS was also confirmed in both media when monitored at three different temperatures (4, 25 and 37 degrees C) up to 30 days. This study introduced a new approach to formulating SEDDS by utilizing the solubilizing capacity of SFN and introduced high throughput screening approach to formulation development and stability study. PMID- 29414124 TI - A novel unit-dose approach for the pharmaceutical compounding of an orodispersible film. AB - Orodispersible films (ODF) have clinical potential as extemporaneous pharmacy preparations for individualized pharmacotherapy. However, the conventional method of ODF preparation using a film applicator may limit its application, due to content uniformity challenges arising from viscosity changes of the casting solution and varied operator manipulation. This study proposes the unit-dose (UD) plate as an alternative to the film applicator for compounding individual ODFs. Using a design-of-experiments approach, we developed an extemporaneous ODF formulation for an antiemetic drug, ondansetron hydrochloride dihydrate (OND), at a clinically relevant dose. ODFs cast with the UD plate showed excellent content uniformity independent of the viscosity of the casting solution and drug concentration. Formulations were evaluated for performance with respect to patient acceptability and product quality. The effects of critical process parameters on critical quality attributes of the ODF were studied. HPMC concentration and volume of casting solution were the main factors affecting disintegration time and mechanical properties of the film, while drug concentration had no significant effect. However, further studies incorporating different drugs in larger concentration ranges are needed to investigate the impact of drug concentration and to establish a design space. Nevertheless, our results indicate the potential of using the UD plate to prepare ODFs with customized drug doses from a generic casting solution. Results from this study provide a framework for an extemporaneous ODF platform. PMID- 29414125 TI - A mesoporous silica based platform to enable tablet formulations of low dose drugs by direct compression. AB - Achieving adequate content uniformity (CU) is a significant challenge in the development and manufacturing of low dose oral tablets. Using four model active pharmaceutical ingredients (APIs), we show that loading APIs into a grade of mesoporous silica, Aeroperl(r), is effective for achieving excellent CU. All APIs in the Aeroperl(r) composites were amorphous. After six months under accelerated stability conditions, the drug-Aeoperl composites exhibited good physical stability for all four APIs. The performance of Aeroperl(r)-based formulations was robust since their good CU and manufacturability were insensitive to model APIs. In addition, the dissolution rate of composite-based formulations was higher than corresponding physical mixtures. Overall, the Aeroperl(r)-based platform formulation is a promising approach for successfully developing low dose oral tablet products. PMID- 29414126 TI - Proton magnetic resonance spectroscopy changes after lithium treatment. Systematic review. AB - 1H MRS is widely used in the research of mental disorders. It enables evaluation of concentration or ratios of several metabolites, which play important roles in brain metabolism: N-acetylaspartate (NAA), choline containing compounds, myo inositol and glutamate, glutamine and GABA (together as Glx complex or separately). Specifically in bipolar disorder brain metabolite abnormalities include mostly NAA reduces and Glx increases in different brain regions. Bipolar disorder is associated with impairment in neurotrophic and cellular plasticity, resilience pathways and in neuroprotective processes. Lithium, which is commonly used in BD treatment, modulates neurotransmitter release, reduces oxidative stress and apoptosis, induces angiogenesis, neurogenesis and neurotrophic response. Thus brain metabolite abnormalities may elucidate the mechanisms of this processes. In the present article we systematically reviewed 26 studies - the majority of them investigated bipolar disorder ( 7 follow-up and all 11 cross sectional studies). Moreover we dispute whether the influence of lithium on brain metabolites in bipolar disorder could explain the background of its potential neuroprotective action. The results of our literature review do not equivocally confirm Lithium's influence the metabolite changes in the brain. The majority of the follow-up studies do not support the initially assumed influence of Lithium on the increase of NAA level in various brain structures. The results of studies are inconclusive with regard to levels of Glx or Glu and Lithium intake, rather point a lack of relationship. The above results were reviewed according to the most recent theories in the field accounting for the impact of lithium (1)HMRS measures. PMID- 29414127 TI - Striatal neurometabolite levels in patients with schizophrenia undergoing long term antipsychotic treatment: A proton magnetic resonance spectroscopy and reliability study. AB - Previous proton magnetic resonance spectroscopy (1H-MRS) studies have reported disrupted levels of various neurometabolites in patients with schizophrenia. An area of particular interest within this patient population is the striatum, which is highly implicated in the pathophysiology of schizophrenia. The present study examined neurometabolite levels in the striatum of 12 patients with schizophrenia receiving antipsychotic treatment for at least 1 year and 11 healthy controls using 3-Tesla 1H-MRS (PRESS, TE = 35 ms). Glutamate, glutamate+glutamine (Glx), myo-inositol, choline, N-acetylaspartate, and creatine levels were estimated using LCModel, and corrected for fraction of cerebrospinal fluid in the 1H-MRS voxel. Striatal neurometabolite levels were compared between groups. Multiple study visits permitted a reliability assessment for neurometabolite levels (days between paired 1H-MRS acquisitions: average = 90.33; range = 7-306). Striatal neurometabolite levels did not differ between groups. Within the whole sample, intraclass correlation coefficients for glutamate, Glx, myo-inositol, choline, and N-acetylaspartate were fair to excellent (0.576-0.847). The similarity in striatal neurometabolite levels between groups implies a marked difference from the antipsychotic-naive first-episode state, especially in terms of glutamatergic neurometabolites, and might provide insight regarding illness progression and the influence of antipsychotic medication. PMID- 29414128 TI - The effects of 5-HTTLPR and BDNF Val66Met polymorphisms on neurostructural changes in major depressive disorder. AB - The serotonin-transporter-linked polymorphic region (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have been implicated in the pathophysiology of major depressive disorder (MDD). We aimed to investigate the effects of genetic variants of the 5-HTTLPR and BDNF Val66Met polymorphisms and their interactions with MDD on cortical volume and white matter integrity. Ninety five patients with MDD and 65 healthy participants aged 20-65 years were recruited. The subjects were genotyped for the 5-HTTLPR and BDNF Val66Met polymorphisms and scanned with T1-weighted and diffusion tensor imaging. The gray matter volumes of 24 gyri in the prefrontal and anterior cingulate cortices and the fractional anisotropy values of nine white matter tracts in both hemispheres were determined. In the pooled sample of subjects from both groups, 5-HTTLPR L allele carriers had significantly decreased cortical volume in the right anterior midcingulate gyrus compared to S-allele homozygotes. A significant effect of the interaction of the BDNF Val66Met polymorphism and MDD on the fractional anisotropy values of the right uncinate fasciculus was observed. Our results suggested that these genetic polymorphisms play important roles in the neurostructural changes of emotion-processing regions in subjects with MDD. PMID- 29414129 TI - Neural correlates of intimate picture stimuli in females. AB - Jacob et al. (2011) previously reported on intimate picture stimuli for emotion research in females in Psychiatry Research. Difficulties to engage in intimate relations constitute problems of many mental disorders, and intimacy must be differentiated from pure sex drive. Functional neuroimaging is an important tool to understand the pathophysiology of psychiatric disorders. We now studied cerebral activation in response to intimate stimuli in 35 healthy women. Comparison stimuli were taken from the International Affective Picture System. Neuroimaging revealed increased activation in bilateral occipitotemporal, parietal and anterior cingulate cortices extending to the orbitofrontal area. These data reflect cognitive, emotional and motivational compounds congruent with previous neuroimaging data of attachment and long term romantic relationships. Lateral prefrontal, posterior insular regions and the fusiform face area were more active during control images. Our data present a solid basis for use in psychiatric samples. PMID- 29414130 TI - Last call to save the rhinos. AB - The family Rhinocerotidae with many species spread around the world was a distinct feature of the global Pleistocene fauna, but most of these species are now extinct. Three of the five surviving species are critically endangered, due to habitat loss and a surge in criminal hunting for horns. To save these iconic species, conservation science will have to apply all methods at its disposal, from population management through to advanced genomics and forensics. Michael Gross reports. PMID- 29414131 TI - Steven E. Hyman. AB - Interview with Steven Hyman, Director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. PMID- 29414132 TI - A simulation of atomic force microscope microcantilever in the tapping mode utilizing couple stress theory. AB - The nonlinear vibration behavior of a Tapping mode atomic force microscopy (TM AFM) microcantilever under acoustic excitation force has been modeled and investigated. In dynamic AFM, the tip-surface interactions are strongly nonlinear, rapidly changing and hysteretic. First, the governing differential equation of motion and boundary conditions for dynamic analysis are obtained using the modified couple stress theory. Afterwards, closed-form expressions for nonlinear frequency and effective nonlinear damping ratio are derived utilizing perturbation method. The effect of tip connection position on the vibration behavior of the microcantilever are also analyzed. The results show that nonlinear frequency is size dependent. According to the results, an increase in the equilibrium separation between the tip and the sample surface reduces the overall effect of van der Waals forces on the nonlinear frequency, but its effect on the effective nonlinear damping ratio is negligible. The results also indicate that both the change in the distance between tip and cantilever free end and the reduction of tip radius have significant effects on the accuracy and sensitivity of the TM-AFM in the measurement of surface forces. The hysteretic behavior has been observed in the near resonance frequency response due to softening and hardening of the forced vibration response. PMID- 29414133 TI - Deconvoluting error in measurement of low angle misorientation distribution. AB - Misorientation angle distribution gives information about the type and fraction of grain boundaries present in a material. Since grain boundaries affect various mechanical and functional properties of the material, the distribution of grain boundary misorientation is important in order to evaluate these properties. This becomes particularly important when we want to study the microstructure in finer detail, such as understanding the average misorientation within a grain. One of the techniques increasingly used in past two decades for characterization of grain boundary misorientation is electron back scatter diffraction (EBSD). Reliable detection of very small misorientation angles using conventional EBSD system is quite challenging due to the presence of measurement error. This makes the comprehensive characterization of microstructures difficult and prone to error. In order to prevent such problems, it is important to understand the nature of measurement error and find ways to minimize it. The present work aims to elucidate the effect of measurement error on the observed misorientation angle and its statistical distribution in low misorientation angle regime. A true strain of 0.3 was imposed during cold-rolling of Cu-5%Zn alloy sample. The rolled sample was then subjected to in-situ heating from room temperature to 500 degrees C (~0.58 Tm). It was found that the overall measurement error in misorientation distribution consists of random error caused by limited angular precision and systematic error which manifests primarily in the statistical distribution of low angle misorientation. In this work, we show a way to deconvolute this overall error based on the measurement technique. We further show that this systematic error is not limited to any particular measurement technique, rather related to the presence of a lower bound in the measurement. PMID- 29414134 TI - Rapid and localized ion-beam etching of surfaces using initial notches. AB - Glancing-angle Ar+ broad ion beam erosion is widely used for the preparation of high-quality transmission electron microscopy (TEM) samples. However, low erosion rates and lack of site specificity are major drawbacks of the method. Being inexpensive and easy to use - in particular when compared to widely used focused ion beam preparation methods - overcoming these drawbacks would significantly improve many existing preparation workflows. We present a novel method for rapid and localized surface erosion which combines laser-machining preprocessing with broad ion beam etching. In this article, preliminary studies of the method on bulk samples are reported. Furthermore, an electron-transparent lamella has been prepared as proof of concept. Using an ultrashort-pulsed solid-state laser, notches were created on (100)-Si substrates. Due to the local change in surface inclination, preferential erosion took place behind the notches upon subsequent ion beam etching at glancing angles. As a consequence, a terrace structure possessing a well-defined jump in surface height was formed. The surface topography and its evolution dynamics were characterized and the findings compared to numerical simulations based on a deterministic, two-dimensional model. On this basis, a workflow utilizing these initial notches (iNotchesTM) for the preparation of an electron transparent lamella was realized and TEM micrographs of the prepared sample were taken. PMID- 29414135 TI - Specimen preparation for nano-scale investigation of cementitious repair material. AB - Cementitious Repair Materials (CRMs) in the construction industry have been used for many decades now and has become a very important part of activities in cement world. The performance of some of these CRMs when applied to retrofitting concrete structural elements is also well documented. However, the characterization of some of the CRMs at the micro- and nano level is not fully documented. The first step to studying materials at the microscopic level is to be able to fabricate proper specimens for microscopy. In this study, a special and newly developed class of CRM was selected and fabricated by Focused Ion Beam (FIB) using well-known "Lift-out" technique. The prepared specimen was later examined using various analytical techniques such as energy dispersive x-ray analysis using one of the highest and most stable Scanning Transmission Electron Holography Microscopy (STEHM) around the world. This process enabled understanding of the composition, morphology, and spatial distribution of various phases of the CRM. It was observed that the microstructure consisted of a very fine, compact, and homogenous amorphous structure. X-ray analysis indicated that there was considerable deviation between the Si/Ca ratios for the hydrated product. PMID- 29414136 TI - Optimising the use of EEG in non-epileptic attack disorder: Results of a UK national service evaluation. AB - PURPOSE: To produce an evidence base to formulate guidelines for optimal performance of EEG in patients referred with a possible diagnosis of non epileptic attack disorder (NEAD). METHODS: 51 UK EEG departments participated in the prospective study. A pro-forma was completed for all consecutive patients aged 5 years and over referred for EEG over a six month period. Information obtained included referral diagnosis, occurrence/type of attack during EEG, the use of suggestion, length of recording and who was present during the EEG. RESULTS: 11,298 patients were entered into the study. 376 psychogenic non epileptic seizures (PNES) occurred of which 337 were considered to be of the habitual type. In those patients suspected of having NEAD prior to referral, the use of verbal suggestion increased the yield of habitual attacks by a factor of three in both adults and children. Using suggestive techniques twice, improved the yield further. Non-habitual attacks occurred equally whether or not suggestion was used. At least 90% of habitual PNES occurred within the first 30 min of recording even in those patients having prolonged EEGs. In EEGs where additional professional personnel were present, PNES occurred more frequently. CONCLUSION: This large multicentre study provides evidence to inform recommendations for EEG to investigate NEAD. We recommend the use of verbal suggestion at least twice and where practical the presence of additional professional staff. A thirty minute recording is sufficient to record a habitual PNES in most instances. PMID- 29414137 TI - The effect of vagus nerve stimulator in controlling status epilepticus in children. AB - PURPOSE: This study explores the effect of Vagus Nerve Stimulator (VNS) on Status Epilepticus (SE) in children with medically intractable epilepsy. METHODS: Retrospective review was conducted in children with a history of at least two SE, who had VNS implantation and had at least one year follow up after the procedure. RESULTS: Sixteen patients met inclusion/exclusion criteria. The median age of seizure onset and surgery was 1.3 years and 9.0 years, respectively. Prior to VNS implantation, 81% (13/16) of patients had >=one seizure per month when all seizure types were combined. 75% (12/16) of patients experienced >=one generalized convulsive seizure per month. The median number of SE prior to VNS was three (2-9), and 63% (10/16) had at least one SE during a year prior to implantation. The proportion of patients who did not have any SE one year after VNS implantation increased compared to the year prior (75% vs. 37%, p = 0.07). The seizure frequency decreased in a minority of patients when all seizure types were combined (20% at one year, p = 1.00, 44% at the last follow up, p = 0.55), but generalized convulsive seizure decreased in 69% of patients at one year (p = 0.01) and 75% of patients at last follow up (p = 0.01). CONCLUSION: VNS appears to have favorable impact on SE and generalized convulsive seizures in children with medically intractable epilepsy. PMID- 29414138 TI - Comparative sensitivity of quantitative EEG (QEEG) spectrograms for detecting seizure subtypes. AB - PURPOSE: To assess the sensitivity of Persyst version 12 QEEG spectrograms to detect focal, focal with secondarily generalized, and generalized onset seizures. METHODS: A cohort of 562 seizures from 58 patients was analyzed. Successive recordings with 2 or more seizures during continuous EEG monitoring for clinical indications in the ICU or EMU between July 2016 and January 2017 were included. Patient ages ranged from 5 to 64 years (mean = 36 years). There were 125 focal seizures, 187 secondarily generalized and 250 generalized seizures from 58 patients analyzed. Seizures were identified and classified independently by two epileptologists. A correlate to the seizure pattern in the raw EEG was sought in the QEEG spectrograms in 4-6 h EEG epochs surrounding the identified seizures. A given spectrogram was interpreted as indicating a seizure, if at the time of a seizure it showed a visually significant departure from the pre-event baseline. Sensitivities for seizure detection using each spectrogram were determined for each seizure subtype. RESULTS: Overall sensitivities of the QEEG spectrograms for detecting seizures ranged from 43% to 72%, with highest sensitivity (402/562,72%) by the seizure detection trend. The asymmetry spectrogram had the highest sensitivity for detecting focal seizures (117/125,94%). The FFT spectrogram was most sensitive for detecting secondarily generalized seizures (158/187, 84%). The seizure detection trend was the most sensitive for generalized onset seizures (197/250,79%). CONCLUSIONS: Our study suggests that different seizure types have specific patterns in the Persyst QEEG spectrograms. Identifying these patterns in the EEG can significantly increase the sensitivity for seizure identification. PMID- 29414139 TI - IDH1 mutation is associated with a higher preoperative seizure incidence in low grade glioma: A systematic review and meta-analysis. AB - PURPOSE: Gliomas, particularly low-grade gliomas (LGGs), are highly epileptogenic. Seizure is the most common presenting sign of LGG patients and significantly decreases their quality of life. Accordingly, there is a need for a better understanding of the mechanisms and risk factors of glioma-related epilepsy. The current study aimed to perform a comprehensive meta-analysis to investigate the correlation of isocitrate-dehydrogenase 1 (IDH1), an important molecular biomarker for glioma classification and prognosis, to preoperative seizure incidence in LGG. METHODS: PUBMED, EMBASE, and Web of Science databases were searched for relevant studies. The odds ratio (OR) and corresponding 95% confidence interval (CI) were used as the primary measures to assess the correlation between IDH1 mutation and preoperative seizure incidence. RESULTS: A total of 722 LGG patients, including 555 patients with IDH1 mutation and 167 patients with wild-type IDH1 were enrolled in the current meta-analysis. The pooled OR was 2.47 (95% CI 1.70-3.57, Z = 4.78, p < 0.01). No significant heterogeneity was observed among all included studies and no publication bias was identified. CONCLUSION: The current meta-analysis identified that IDH1 mutation was correlated to a higher preoperative seizure incidence in LGG. This result would generate impetus for research on the mechanisms behind this correlation, and provide a new idea for the individualized treatment of glioma-related epilepsy. PMID- 29414140 TI - Evidence on the efficacy of primary radiosurgery or stereotactic radiotherapy for drug-resistant non-neoplastic focal epilepsy in adults: A systematic review. AB - PURPOSE: Although the majority of adult epilepsy patients respond well to the current antiepileptic drug treatment, 20-40% of them are drug-resistant. In these patients, resective epilepsy surgery is a curative treatment option, for which, however, only a limited number of patients is eligible. The purpose is to summarize the outcome of radiotherapy for drug-resistant non-neoplastic focal epilepsy and to elucidate its efficacy for seizure outcome and long-term toxicity in adults. METHOD: A systematic literature search was performed in Pubmed, Ovid Medline, Cochrane library, Embase and Web of Science. The methodological quality was evaluated using an adapted QUADAS checklist. RESULTS: Sixteen out of 170 initially identified studies were included in this systematic literature study (n = 170 patients). Twelve of the 16 studies described a positive effect of radiotherapy on seizure frequency reduction, with 98 of the patients (on average 58%, range 25%-95%) reporting no or rare seizures (defined as radiotherapy adapted Engel class [RAEC] I and II. In total, 20% (34 patients) of the patients needed subsequent surgery due to radionecrosis, cysts formation, edema, and intracranial hypertension or remaining seizures. A dose-effect model was fitted to the available response data in an attempt to derive a relationship between prescribed dose and RAEC frequency. CONCLUSIONS: Radiotherapy is a possible non invasive treatment option for patients with drug-resistant focal non-neoplastic epilepsy. This systematic review showed that there is only level 4 evidence of primary radiotherapy reducing seizure frequency in adult patients. Prospective randomized trials are needed to determine its exact value compared to other treatment approaches. PMID- 29414142 TI - Rationale and design of a pilot study examining Acceptance and Commitment Therapy for persistent pain in an integrated primary care clinic. AB - Most of the 100 million Americans with persistent pain are treated in primary care clinics, but evidence-based psychosocial approaches targeting pain-related disability are not usually provided in these settings. This manuscript describes the rationale and methods for a protocol to pilot test the feasibility and effectiveness of Acceptance and Commitment Therapy (ACT), an evidence-based psychological treatment for persistent pain, delivered by a Behavioral Health Consultant in primary care. Eligible patients are identified through electronic health record registries and invited to participate via secure messaging, letters and a follow-up phone call. Participants are also recruited with advertising and clinician referral. Patients agreeing to participate are consented and complete initial assessments, with a target of 60 participants. Randomization is stratified based on pain severity with participants assigned to either ACT or Enhanced Treatment as Usual (E-TAU). ACT participants receive one standardized Behavioral Health Consultation visit followed by three ACT-based group visits and one group booster visit. All patients attend six assessment visits, during which the E-TAU patients are provided with educational pain management handouts based on standard cognitive behavioral treatment of pain. The study aims to determine feasibility and effectiveness of brief ACT for persistent pain delivered by an integrated behavioral health clinician in primary care from pre- to post treatment, and to examine mechanisms of change in ACT participants. This study, in a "real-world" setting, will lay groundwork for a larger trial. If effective, it could improve treatment methods and quality of life for patients with persistent pain using a scalable approach. PMID- 29414141 TI - Health related quality of life of people with non-epileptic seizures: The role of socio-demographic characteristics and stigma. AB - PURPOSE: People with non-epileptic seizures (NES) consistently report poorer Health-Related Quality of Life (HRQoL) than people with epilepsy. Yet, unlike in epilepsy, knowledge of how social factors influence the HRQoL of adults with NES is limited. To add to the evidence base, this study explores the relationship between HRQoL and perceived stigma among adults with NES, and the role of socio demographic characteristics. METHODS: Data was gathered from a survey of 115 people living with the condition, recruited from online support groups. Participants provided socio-demographic and health-related data and completed a series of questions investigating their HRQoL (QOLIE-31) and stigma perceptions (10-item Epilepsy Stigma Scale). RESULTS: Participants were found to experience high levels of perceived stigma (median 5.2, mean 4.9). A significant and moderate inverse correlation was observed between HRQoL and stigma (rs - 0.474, p = < 0.001); suggesting higher perceptions of stigma contribute to poorer HRQoL among adults with NES. Stigma perceptions were found to be most strongly associated with the seizure worry (rs = - 0.479), emotional wellbeing (rs = - 0.421), and social functioning (rs = 0.407) HRQoL domains. Participants who reported being in employment or education were found to have significantly better HRQoL than those who were not (p = < 0.001). CONCLUSION: More (qualitative and quantitative) research is justified to understand how - and why - those with the condition experience stigmatisation, and the factors that impede and help facilitate the participation of people with NES in education and employment. PMID- 29414143 TI - Evaluation of the sST2-guided optimization of medical treatments of patients admitted for heart failure, to prevent readmission: Study protocol for a randomized controlled trial. PMID- 29414144 TI - View-dependent accuracy in body mass judgements of female bodies. AB - A fundamental issue in testing body image perception is how to present the test stimuli. Previous studies have almost exclusively used images of bodies viewed in front-view, but this potentially obscures key visual cues used to judge adiposity reducing the ability to make accurate judgements. A potential solution is to use a three-quarter view, which combines visual cues to body fat that can be observed in front and profile. To test this hypothesis, 20 female observers completed a 2 alternative forced choice paradigm to determine the smallest difference in body fat detectable in female bodies in front, three-quarter, and profile view. There was a significant advantage for three-quarter and profile relative to front-view. Discrimination accuracy is predicted by the saliency of stomach depth, suggesting that this is a key visual cue used to judge body mass. In future, bodies should ideally be presented in three-quarter to accurately assess body size discrimination. PMID- 29414145 TI - Factors affecting subjective appearance evaluations among patients with congenital craniofacial conditions: An application of Cash's cognitive behavioural model of body image development. AB - Satisfaction with appearance is of central importance for psychological well being and health. For individuals with an unusual appearance, such as congenital craniofacial anomalies (CFA), appearance evaluations could be especially important. However, few, if any papers have presented a comprehensive synthesis of the factors found to affect subjective satisfaction with appearance among children, adolescents, and adults born with a CFA. Further, only a handful of craniofacial studies have applied psychological theories or models to their findings, resulting in an overall lack of guidance for researchers in the field. This paper summarises the literature pertaining to satisfaction with appearance among those affected by CFAs, and examines the extent to which Cash's cognitive behavioural model of body image development (2012) fits with this literature. Given the overlap between factors of interest in the field of CFAs, and in the area of body image more broadly, a closer collaboration between the two research fields is suggested. PMID- 29414146 TI - A content analysis of an online pro-eating disorder community on Reddit. AB - Pro-eating disorder communities provide a refuge for individuals with eating disorders (EDs) who are ambivalent about seeking treatment. We investigated a pro ED community on Reddit, an anonymous social networking platform with topical forums, to identify expression of behaviors aligned with ED symptoms and support for these behaviors. A content analysis on four weeks of topic-specific discussion threads (N=125 comments, 115 replies to comments) was conducted to identify behaviors consistent with ED psychopathology and support for these behaviors (informational, tangible assistance, esteem/emotional support). Results indicated that the content aligned with expressions of clinically relevant ED psychopathology, with eating concerns (49/125) and shape concerns (47/125) being most prevalent. The majority (92/115) of replies provided esteem/emotional support to the comment author. Online interventions and/or recovery programs are needed to counteract reinforcing dialogue that occurs on social media sites, like Reddit, and promote ED recovery through supportive messages on these platforms. PMID- 29414147 TI - Clobenpropit, a histamine H3 receptor antagonist/inverse agonist, inhibits [3H] dopamine uptake by human neuroblastoma SH-SY5Y cells and rat brain synaptosomes. AB - BACKGROUND: Clobenpropit, a potent antagonist/inverse agonist at the histamine H3 receptor (H3R), reduced the cytotoxic action of 6-hydroxydopamine (6-OHDA) in neuroblastoma SH-SY5Y cells transfected with the human H3R. We therefore set out to study whether this effect involved a receptor-independent action on dopamine transport. METHODS: The uptake of [3H]-dopamine was assayed in SH-SY5Y cells and rat striatal or cerebro-cortical isolated nerve terminals (synaptosomes). Clobenpropit binding to the human norepinephrine (NET) and dopamine (DAT) transporters was analyzed by molecular modeling. RESULTS: In SH-SY5Y cells, [3H] dopamine uptake was inhibited by desipramine (selective NET inhibitor), GBR-12909 (selective DAT inhibitor), and fluoxetine (selective inhibitor of the serotonin transporter, SERT) with IC50 values 37, 537, and 2800nM, respectively. The potency rank order indicates that [3H]-dopamine uptake is primarily performed by NET. Clobenpropit inhibited [3H]-dopamine uptake (maximum inhibition 82.7+/-2.8%, IC50 490nM), and the effect was reproduced by the H3R antagonist/inverse agonist iodophenpropit, but not by the agonists R-alpha-methylhistamine and immepip or the antagonists/inverse agonists ciproxifan and A-331440. Clobenpropit also inhibited [3H]-dopamine uptake by rat striatal and cerebro-cortical synaptosomes (-54.6+/-11.3% and -46.3+/-9.6%, respectively, at 10MUM). Modeling of the human NET and DAT obtained by homology from the crystal of Drosophila melanogaster DAT showed that clobenpropit can bind to a site also recognized in both transporters by nisoxetine, a potent NET inhibitor. CONCLUSION: These data indicate a direct inhibitory effect of clobenpropit on catecholamine transport. PMID- 29414148 TI - Exenatide modulates metalloproteinase expression in human cardiac smooth muscle cells via the inhibition of Akt signaling pathway. AB - BACKGROUND: Incretin analogue drugs, a FDA-approved treatment in diabetes, has been tested for its therapeutic properties as modulators of atherosclerosis. We investigated the effects of incretin drugs on the modulation of gene expression and protein levels of matrix metalloproteinases (MMPs) as well as their inhibitors - tissue inhibitors of metalloproteinases (TIMPs) in coronary artery smooth muscle cells (hCASMC) in the context of atherosclerotic plaque formation and inflammation. METHODS: TNFalpha-stimulated hCASMC were treated with Glucagon like Peptide 1 (GLP-1) (10nM and 100nM) and Exendin-4 (1nM and 10nM). Messenger RNA (mRNA) levels and protein concentrations of MMP-1, MMP-2, MMP-9 and TIMP-1, TIMP-2 were measured and the effects on extracellular matrix turnover under TNFalpha-mediated microenvironment were evaluated. Intracellular signaling pathways were also examined. RESULTS: Our experiments reveal that GLP-1 receptor agonists downregulate the expression of MMP-1, MMP-2, MMP-9 in hCASMC under TNFalpha mediated inflammatory conditions. Signaling pathway analysis show that GLP-1 receptor agonists induced inhibition of AKT-Thr308 phosphorylation, PRAS40 and S6 proteins but not AKT-Ser473. CONCLUSIONS: These findings indicate that GLP 1 receptor agonists modulate the expression of MMPs through inhibition of AKT Thr308 phosphorylation in hCASMC. These results suggest a possible role of incretin analogue drugs in therapy of coronary atherosclerosis. PMID- 29414149 TI - Therapeutic drug monitoring of digoxin-20 years of experience. AB - BACKGROUND: Digoxin is the oldest drug used in the pharmacotherapy of heart failure (HF). However, digoxin remains an important therapeutic option for patients with persistent symptoms of HF occurring despite the implementation of standard pharmacotherapy. Digoxin concentration serum (SCD) should equal 1 2ng/ml. The aim of our study was to measure of SCD among the hospitalized patients as well as to determine the selected factors influencing the concentration of the digoxin in the blood. METHODS: The presented research was based on a retrospective analysis including 2149 patients treated with digoxin and hospitalized between 1980 and 2000. Was used for the determination of SCD automatic analyzer TDX ABBOTT GmbH - fluorescence polarization immunoassay (FPIA), with therapeutic range for digoxin of 0.8-2.0ng/ml. RESULTS: Average SCD result in the study population was located within the therapeutic range and amounted 1.06ng/ml (55.7% of patients). Statistically significant differences in digoxin level were observed depending on the way of medicine administration (p=0.000001) and the daily amount (p=0.001). Moreover, statistically significant differences in digoxin level were observed depending on sex (p=0.00002). CONCLUSIONS: An elevated level of digoxin was observed in the case of patients who received the medication both orally and intravenously, together with an increase in the daily amount of digoxin doses. It was confirmed that an elevated digoxin level occurs in the course of treatment in the case of women. PMID- 29414150 TI - Hypo-fractionated stereotactic radiotherapy of five fractions with linear accelerator for vestibular schwannomas: A systematic review and meta-analysis. AB - Vestibular schwannomas (VS) are benign tumors stemming from the eighth cranial nerve. Treatment options for VS include conservative management, microsurgery, stereotactic radiosurgery, and fractionated radiotherapy. Though microsurgery has been the standard of care for larger lesions, hypo-fractionated stereotactic radiotherapy (hypo-FSRT) is an emerging modality. However, its clinical efficacy and safety have yet to be established. We conducted a systematic review and meta analysis of manuscripts indexed in PubMed, Scopus, Web of Science, Embase, and Cochrane databases reporting outcomes of VS cases treated with hypo-FSRT. Five studies representing a total of 228 patients were identified. Across studies, the pooled rates of tumor control, hearing, facial nerve, and trigeminal nerve preservation were 95%, 37%, 97%, and 98%. No instances of malignant induction were observed at median follow-up of 34.8 months. Complications included trigeminal neuropathy (n = 3), maxillary paresthesia (n = 1), neuralgia (n = 1), vestibular dysfunction (n = 1), radionecrosis (n = 1), and hydrocephalus (n = 1). Hypo-FSRT may be another useful approach to manage VS, but studies with extended follow-up times are required to establish long-term safety. PMID- 29414151 TI - Migrainous aura as stroke-mimic: The role of perfusion-computed tomography. AB - OBJECTIVES: The acute-onset of migrainuos aura (MA) can be erroneously diagnosed in Emergency Department (ED) as acute stroke (AS) and it can be classified as "stroke mimic" (SM). Perfusion computer tomography (PCT) may be useful to improve detection of infarcts. The aim of the study was to investigate the role in ED of PCT in improving diagnosis of migrainous aura. Data were compared with the well defined perfusion patterns in patients with acute ischemic stroke. PATIENTS AND METHODS: A standardized Stroke Protocol was planned. The protocol consisted in centralizing in ED all the patients with acute-onset of neurological symptoms compatible with cerebrovascular disease and in performing a general and neurological examination, hematological tests, brain non-contrast computed tomography (NCCT), CT angiography (CTA) of the supra-aortic and intracranial arteries and cerebral PCT. Patients with diagnosis of definite or probable acute stroke were hospitalized in Stroke Unit (SU). A six-months retrospective analysis of all the patients included in the Stroke Protocol and discharged from ED or from SU with a diagnosis of migraine with aura was performed. RESULTS: 172 patients were included in the Stroke Protocol and 6 patients were enrolled. NCCT, CTA and PCT were performed after 60-90 min from symptoms onset and revealed normal perfusion. Intravenous thrombolysis was performed only in one patient. CONCLUSION: Patients with acute-onset of neurological symptoms, who have rapid progressive improvement of symptoms, normal neuroimaging, in particular PCT, and preceding episodes of migraine with aura, may be considered as suffering from MA. In these cases, even if thrombolysis is safe, clinicians may defer a prompt aggressive treatment. PMID- 29414152 TI - Inflammation role in sensory neuropathy in Chinese patients with diabetes/prediabetes. AB - OBJECTIVES: Prediabetes involves people with glucose-metabolism impairment, and is related to different diabetic complications, like peripheral neuropathy. We aimed to explore the relationship among inflammatory (tumor necrosis factor alpha [TNFalpha]) and antiinflammatory (interleukin 10 [IL10]) cytokines as well as neuropathy of very distal-sensory-nerves in Chinese patients with prediabetes/diabetes. PATIENTS AND METHODS: In the present study, 55 patients having prediabetes, 55 patients having type 2 diabetes mellitus (DM), and 48 controls were included. TNFalpha, HbA1c, and IL10 plasma levels were measured. Electrodiagnosis was conducted on dorsal-sural/medial-plantar sensory nerve, that is most distal feet sensory-nerves. RESULTS: Nerve conduction test (NCT) irregularities of dorsal-sural/medial-plantar sensory nerve were considerably greater in patients with prediabetes or diabetes. The means of TNFalpha levels demonstrated a significant increase in patients with diabetes when compared to prediabetes patients as well as controls showed a significant decrease in patients with prediabetes and diabetes contrasted with controls. No significant contrast with respect to serum biomarkers among patients having regular as well as irregular medial-plantar/dorsal-sural NCT was noted. Critical correlationship among TNFalpha as well as HbA1c with symptoms severity as well as disability while negative correlations of IL10 with neuropathy severity was noted. Biomarker levels of TNFalpha, IL10, and HbA1c were noted to differ significantly among patients without/with neuropathy. CONCLUSION: All in all, the proinflammatory phase appears to start from initial pre-clinical phases, sometime prior to advancement of diabetes. The higher neuropathy frequency in patients with prediabetes indicates conceivable causative impact; although, the prospective part of inflammation in pathogenetics of peripheral neuropathy requires more elucidation. PMID- 29414153 TI - Comparative study of hydrothermal pretreatment for rice straw and its corresponding mixture of cellulose, xylan, and lignin. AB - We herein investigated the effect of hemicellulose and lignin on the hydrothermal pretreatment of lignocellulosic biomass for glucose production from cellulose in terms of structural cross-linking between cellulose and the above components. A comparison was made between the hydrothermal pretreatment of biomass and a mixture containing the individual model compounds in the same composition ratio. Thus, rice straw biomass and the mixture containing cellulose, xylan, and lignin were treated in an autoclave reactor at temperatures between 150 and 250 degrees C for 30 min. The obtained products were then subjected to enzymatic hydrolysis. Interestingly, different results were obtained for the two samples, as the presence of cross-linking between cellulose and lignin in the original biomass sample affected the efficiency of hydrothermal pretreatment. A model was therefore proposed to account for the obtained result in accordance with previous knowledge regarding the behavior of these compounds under hydrothermal conditions. PMID- 29414154 TI - Investigation on the feasibility of Chlorella vulgaris cultivation in a mixture of pulp and aquaculture effluents: Treatment of wastewater and lipid extraction. AB - In this study, feasibility of Chlorella vulgaris cultivation in pulp wastewater (PWW) diluted with lake water (LW) and aquaculture wastewater (AWW) was investigated. The best ratios of PWW and AWW (PAWW) viz., 80% PWW:20% AWW and 60% PWW:40% AWW were selected as microalgal culture medium. Algal growth was investigated with and without addition of macro and micronutrients to the cultivation medium. The highest dry algal weight was observed as 1.31 g/L in 60% PWW:40% AWW without adding micronutrients. Nutrients and organic compounds removal efficiencies by microalga were studied in PAWW. Protein, carbohydrate and lipid percentage of harvested microalga from wastewater and Bold's Basal Medium (BBM) solution were analyzed. Fatty acids analysis revealed that C16 and C18 are the major fatty acids in C. vulgaris cultivated in BBM and PAWW. The results of this study revealed that C. vulgaris is a potential candidate for PAWW treatment and lipid and carbohydrate accumulation. PMID- 29414155 TI - Recovery of polyhydroxyalkanoates from municipal secondary wastewater sludge. AB - In the current study, the feasibility of utilizing municipal secondary wastewater sludge for Polyhydroxyalkanoate (PHA) extraction was improved by optimization of various parameters (temperature, duration and concentration of sludge solids). Optimized process parameters resulted in PHA recovery of 0.605 g, significantly higher than un-optimized conditions. The characterization of PHA was carried out by GC-MS, FT-IR and NMR (1H and 13C) spectroscopy. The PHA profile was found to be dominated by mcl PHA (58%) along with other diverse PHA. The results of the present study show rich diversity of PHA extracted from a raw material which is readily available at minimal cost. In conclusion, exploring the potential of wastes for production of bioplastics not only reduces the cost of bioplastic production, but also provides a sustainable means for waste management. PMID- 29414156 TI - Surfactant assisted disperser pretreatment on the liquefaction of Ulva reticulata and evaluation of biodegradability for energy efficient biofuel production through nonlinear regression modelling. AB - The present study aimed to increase the disintegration potential of marine macroalgae, (Ulva reticulata) through chemo mechanical pretreatment (CMP) in an energy efficient manner. By combining surfactant with disperser, the specific energy input was considerably reduced from 437.1 kJ/kg TS to 264.9 kJ/kg TS to achieve 10.7% liquefaction. A disperser rpm (10,000), pretreatment time (30 min) and tween 80 dosage (21.6 mg/L) were considered as an optimum for effective liquefaction of algal biomass. CMP was designated as an appropriate pretreatment resulting in a higher soluble organic release 1250 mg/L, respectively. Anaerobic fermentation results revealed that the volatile fatty acid (VFA) concentration was doubled (782 mg/L) in CMP when compared to mechanical pretreatment (MP) (345 mg/L). CMP pretreated algal biomass was considered as the suitable for biohydrogen production with highest H2 yield of about 63 mL H2/g COD than (MP) (45 mL H2/g COD) and control (10 mL H2/g COD). PMID- 29414157 TI - Changes in structure and function of fungal community in cow manure composting. AB - In this study, dynamic changes in fungal communities, trophic modes and effect factors in 60 days composting of cow manure were analyzed by using high throughput sequencing, FUNGuild and Biolog FF MicroPlate, respectively. Orpinomyces (relative abundance >10.85%) predominated in feedstock, and Mycothermus became the dominating genus (relative abundance >75%) during the active phase. Aerobic composting treatment had a significant effect on fungal trophic modes with pathogenic fungi fading away and wood saprotrophs increasing over composting time. Fungal communities had the higher carbon sources utilization capabilities at the thermophilic phase and mature phase than those in the other periods. Oxidation reduction potential (ORP) significantly increased from -180 to 180 mV during the treatment. Redundancy analysis showed that the succession of fungal community during composting had a significant association with ORP (p < .05). This indicated that aerobic composting treatment not only influenced fungal community structure, but also changed fungal trophic modes and metabolic characteristics. PMID- 29414158 TI - Deashing macroalgae biomass by pulsed electric field treatment. AB - Among all biomass constituents, the ashes are major hurdles for biomass processing. Ashes currently have low market value and can make a non-negligible fraction of the biomass dry weight significantly impacting its further processing by degrading equipment, lowering process yield, inhibiting reactions and decreasing products qualities. However, most of the current treatments for deashing biomass are of poor efficiency or industrial relevance. This work is the first report on the use of Pulsed Electric Field (PEF) to enhance deashing of biomass from a high ash content green marine macroalga, Ulva sp., using hydraulic pressing. By inducing cell permeabilization of the fresh biomass, PEF was able to enhance the ash extraction from 18.4% (non-treated control) to 37.4% of the total ash content in average, significantly enhancing the extraction of five of the major ash elements (K, Mg, Na, P and S) compared to pressing alone. PMID- 29414159 TI - Enhanced single cell oil production by mixed culture of Chlorella pyrenoidosa and Rhodotorula glutinis using cassava bagasse hydrolysate as carbon source. AB - The single cell oil (SCO) production by the mono and mixed culture of microalgae Chlorella pyrenoidosa and red yeast Rhodotorula glutinis was investigated using non-detoxified cassava bagasse hydrolysate (CBH) as carbon source. The results suggested that the two strains were able to tolerate and even degrade some byproducts presented in the CBH, and the mixed culture approach enhanced the degradation of certain byproducts. Biomass (20.37 +/- 0.38 g/L) and lipid yield (10.42 +/- 1.21 g/L) of the mixed culture achieved in the batch culture were significantly higher than that of the mono-cultures (p < 0.05). The fed-batch culture further raised the biomass and lipid yield to 31.45 +/- 4.93 g/L and 18.47 +/- 3.25 g/L, respectively. The lipids mainly composed of oleic acid and palmitic acid, suggesting the potential applications such as biofuel feedstock, cosmetics, food additives and lubricant. This study provided new insights for the integration of the economical SCO production with agro-industrial waste disposal. PMID- 29414160 TI - Continuous aryl alcohol oxidase production under growth-limited conditions using a trickle bed reactor. AB - An A. nidulans strain with a pyridoxine marker was used for continuous production of aryl alcohol oxidase (AAO) in a trickle bed reactor (TBR). Modified medium with reduced zinc, no copper, and 5 g/L ascorbic acid that reduced melanin production and increased AAO productivity under growth limited conditions was used. Two air flow rates, 0.11 L/min (0.1 vvm) and 1.1 L/min (1.0 vvm) were tested. More melanin formation and reduced protein productivity were observed with air flow rate of 1.1 L/min. Three random packings were used as support for the fungus inside the TBR column, two of which were hydrophobic and one which was hydrophilic, and three different dilution rates were tested. The use of GEA BCN 030 hydrophobic packing resulted in greater AAO yield and productivity than the other packings. Increasing dilution rates favored melanin formation and citric, lactic and succinic acid accumulation, which decreased AAO yield and productivity. PMID- 29414161 TI - Serial lantern-shaped draft tube enhanced flashing light effect for improving CO2 fixation with microalgae in a gas-lift circumflux column photobioreactor. AB - A novel serial lantern-shaped draft tube (LDT) that generates vortices is proposed to increase radial velocity between dark and light regions for improving CO2 fixation with microalgae in a gas-lift circumflux column (GCC) photobioreactor. Clockwise vortices are generated in the downflow outerloop of the GCC photobioreactor with LDT. Radial velocity was improved from 1.50 to 4.35 * 10-2 m/s, thereby decreased liquid cycle period between dark and light regions by 1.9 times. Mixing time decreased by 21%, and mass transfer coefficient increased by 26% with LDT. Liquid radial velocity in the downflow outerloop and mass transfer coefficient in the GCC photobioreactor both first increased and then decreased when single-lantern height was increased. Peak CO2 fixation rate increased from 0.62 to 0.87 g/L/d, microalgal biomass yield increased by 50%. Removal efficiencies of pollutants (chemical oxygen demand, ammonium, tilmicosin, and ethinylestradiol) in wastewater were 62-90% with microalgae growth in GCC photobioreactor with LDT. PMID- 29414162 TI - Degradation of organophosphate esters in sewage sludge: Effects of aerobic/anaerobic treatments and bacterial community compositions. AB - In this study, the degradation of organophosphate esters (OPEs) in sewage sludge with aerobic composting and anaerobic digestion was investigated. The total concentrations of six OPEs (SigmaOPEs) in the whole treatment process reduced in the order of anaerobic digestion combined with pig manure (T3) > aerobic composting combined with pig manure (T1) > aerobic composting (T2) > anaerobic digestion (T4). The addition of pig manure significantly enhanced the removal rate of OPEs in both aerobic and anaerobic treatments. The abundance and diversity of bacterial community reduced after the treatment process. Shannon index, principal component analysis, network analysis, and heat map further confirmed the variation of bacterial community compositions among different treatments. Five genera (i.e., Flavobacterium, Bacillus, Alcaligene, Pseudomonas, and Bacillus megaterium) might be responsible for the degradation of OPE compounds in sewage sludge. PMID- 29414163 TI - Two-stage processing of Miscanthus giganteus using anhydrous ammonia and hot water for effective xylan recovery and improved enzymatic saccharification. AB - A two-stage method using gaseous ammonia and hot water was proposed to recover xylan and lignin from Miscanthus. In this method, Miscanthus was treated with gaseous ammonia at elevated temperatures (60-150 degrees C) for various reaction times (1-48 h) in the first stage, termed as LMAA (low-moisture anhydrous ammonia) treatment. In the following stage, the LMAA-treated solid was subjected to hot-water treatment in a flow-through column reactor under various reaction conditions (170-220 degrees C, 30-90 min). After two-stage processing, the remaining solid contained mostly glucan (~80% cellulose), which became highly digestible by enzymes. The optimal treatment conditions for sugar recovery using two-stage process were 120 degrees C and 12 h for the 1st stage and 190 degrees C, 90 min, and 5 mL/min for the 2nd stage, which resulted in 84.2% xylan recovery in liquid phase and 95.3% glucan digestibility of the treated solid, using 15 FPU/g-glucan enzyme loading after the two-stage treatment. PMID- 29414164 TI - Bioflocculants' production from a cellulase-free xylanase-producing Pseudomonas boreopolis G22 by degrading biomass and its application in cost-effective harvest of microalgae. AB - The major problem for industrial application of bioflocculants is its high production cost. Here, a novel bacterium Pseudomonas boreopolis G22, which can secret a cellulase-free xylanase and simultaneously produce bioflocculants (MBF G22) through directly converting untreated biomass, was isolated. The bioflocculants' production of G22 was closely related to its xylanase activity, hydrolysis ability of biomass and the hemicellulose loss caused by G22. The optimal fermentation conditions with the highest bioflocculants' yield (3.75 mg g 1 dry biomass) were obtained at the fermentation time of 96 h, incubation temperature of 30 degrees C, inoculum concentration of 1.0% and biomass concentration of 1.0% in an initial pH value of 7.0. MBF-G22 mainly consisted of polysaccharides (63.3%) with a molecular weight of 3.982 * 106 Da and showed the highest flocculating efficiency of 97.1% at a dosage of 3.5 mg L-1. In addition, MBF-G22 showed high flocculating efficiency of microalgae (95.7%) at a dosage of 80 mg L-1. PMID- 29414165 TI - Enhancing nemadectin production by Streptomyces cyaneogriseus ssp. noncyanogenus through quantitative evaluation and optimization of dissolved oxygen and shear force. AB - In this study, effects of oxygen supply and shear stress on nemadectin production by Streptomyces cyaneogriseus ssp. noncyanogenus (S. cyaneogriseus) fermentation were investigated in shake flasks and 5-L bioreactors. Results showed sufficient dissolved oxygen level was essential for cells growth and nemadectin biosynthesis, while strong shear stress had negative impacts on both cell growth and nemadectin synthesis. Furthermore, when a combined paddle type was applied in culturing S. cyaneogriseus, the nemadectin production was increased by 23.6%. The influence of different agitation rates and paddle types on volumetric oxygen transfers coefficient (KLa) and shear stress were quantitatively studied through computational fluid dynamics simulation (CFD). The results of CFD revealed that high KLa as well as low shear stress co-existed under the combined impeller configuration at 650rpm. This study is expected to be helpful to the scale-up of nemadectin fermentation and other stress-sensitive but high-oxygen-consumption filamentous microorganism. PMID- 29414166 TI - Thermogravimetric analysis and kinetic modeling of low-transition-temperature mixtures pretreated oil palm empty fruit bunch for possible maximum yield of pyrolysis oil. AB - The impacts of low-transition-temperature mixtures (LTTMs) pretreatment on thermal decomposition and kinetics of empty fruit bunch (EFB) were investigated by thermogravimetric analysis. EFB was pretreated with the LTTMs under different duration of pretreatment which enabled various degrees of alteration to their structure. The TG-DTG curves showed that LTTMs pretreatment on EFB shifted the temperature and rate of decomposition to higher values. The EFB pretreated with sucrose and choline chloride-based LTTMs had attained the highest mass loss of volatile matter (78.69% and 75.71%) after 18 h of pretreatment. For monosodium glutamate-based LTTMs, the 24 h pretreated EFB had achieved the maximum mass loss (76.1%). Based on the Coats-Redfern integral method, the LTTMs pretreatment led to an increase in activation energy of the thermal decomposition of EFB from 80.00 to 82.82-94.80 kJ/mol. The activation energy was mainly affected by the demineralization and alteration in cellulose crystallinity after LTTMs pretreatment. PMID- 29414167 TI - Impact of dissolved oxygen on the microbial community structure of an intermittent biological aerated filter (IBAF) and the removal efficiency of gasification wastewater. AB - A novel IBAF system (altered conventional biological aerated filter (BAF) for intermittent aeration) was used to treat BDD anodes electrochemical oxidation gasification wastewater effluent, after which 454 pyrosequencing was applied to investigate the bacterial community of IBAF and demonstrate the relationship between dissolved oxygen (DO) and the bacterial community. The results showed that the concentration of COD, NH4+-N and NO3--N reached 55.08, 7.64 and 7.76 mg/L, respectively, in IBAF effluent because of changes in the DO concentration at 30 days after system start-up. The bacterial community results revealed that the 40 cm sample had the highest bacterial diversity. The bacterial species were approximate in total samples at phylum and family level, but the relative abundance was significantly different because of change in DO concentration. In addition, sample distance analysis indicated that the similarity of different samples was related to the DO concentration at different heights. PMID- 29414168 TI - Improving methane production from anaerobic digestion of Pennisetum Hybrid by alkaline pretreatment. AB - Alkaline pretreatment with NaOH was used to improve methane yield from Pennisetum Hybrid. The pretreatments were carried out with different NaOH solutions (2-8% w/w) at three temperatures (35, 55 and 121 degrees C) for different periods of time (24, 24 and 1 h). All treated and untreated Pennisetum Hybrid were digested under mesophilic conditions (37 degrees C) to biogas, significant effects of the pretreatments on the yield of methane were observed. Results showed the modified Gompertz equation was reliable (determination coefficients (R2) greater than 0.96) to describe the kinetic behavior of anaerobic digestion of Pennisetum Hybrid. The best result, obtained by the treatment at 35 degrees C 2% NaOH for 24 h, resulted in the methane yield of 301.7 mL/g VS, corresponding to 21.0% improvement in the methane yield. Compositional, SEM, XRD and FTIR analysis confirmed that lignin removal, structural modification and cellulose crystalline variation were responsible for the improvement. PMID- 29414169 TI - Effects of carbon sources on sludge performance and microbial community for 4 chlorophenol wastewater treatment in sequencing batch reactors. AB - Considering carbon sources are often supplied to satisfy the removal of high nitrogen and refractory pollutants in industrial wastewater, two sequencing batch reactors (SBRs) were used in this study to treat 1.5 +/- 0.5 mg/L 4-chlorophenol (4-CP) wastewater containing ammonium nitrogen and phosphate with different carbon sources. The favorable removal efficiencies of influent COD, NH4+-N, PO43- P, and 4-CP suggested that the both SBRs were not influenced by supplying dissolved starch and sodium acetate, respectively. The phyla Proteobacteria and Bacteroidetes were dominant in both SBRs, while the dominant phylum Candidatus Saccharibacteria was only existed in SBR with carbon source of dissolved starch. The relative abundance of bacterial communities had significant differences at class, family, and order level in both SBRs. And the mutually dominant genus in both SBRs was only Gemmobacter, which was first found in 4-CP wastewater treatment. The changed extracellular polymeric substances (EPS) were related with microbial communities. PMID- 29414170 TI - Changes in spectroscopic signatures in soluble microbial products of activated sludge under different osmotic stress conditions. AB - Spectroscopic techniques were used to examine the subtle changes in soluble microbial products (SMP) of batch activated sludge bioreactors working at different salinities (i.e., 0%, 1%, 3%, and 5% NaCl). The changes in different fluorescent constituent were tracked by excitation-emission matrix combined with parallel factor analysis (EEM-PARAFAC), and the sequential production was further identified by two-dimensional correlation spectroscopy (2D-COS). Greater enrichment of tryptophan-like component and large-sized biopolymer were found in SMP for higher saline bioreactors, suggesting the SMP sources from bound extracellular polymeric substances and excreted intercellular constituents. 2D COS revealed the opposite sequences of the fluorescence changes in SMP between the low and the high saline bioreactors, following the order of "tyrosine-like > tryptophan-like > humic-like fluorescence" for the latter. This study clarified the dominant mechanisms involved in SMP formation during elevating salinity, which were well supported by the changes in SMP spectroscopic features, microbial activity, and organic degradation rates. PMID- 29414171 TI - Life cycle, techno-economic and dynamic simulation assessment of bioelectrochemical systems: A case of formic acid synthesis. AB - A novel framework, integrating dynamic simulation (DS), life cycle assessment (LCA) and techno-economic assessment (TEA) of a bioelectrochemical system (BES), has been developed to study for the first time wastewater treatment by removal of chemical oxygen demand (COD) by oxidation in anode and thereby harvesting electron and proton for carbon dioxide reduction reaction or reuse to produce products in cathode. Increases in initial COD and applied potential increase COD removal and production (in this case formic acid) rates. DS correlations are used in LCA and TEA for holistic performance analyses. The cost of production of HCOOH is ?0.015-0.005 g-1 for its production rate of 0.094-0.26 kg yr-1 and a COD removal rate of 0.038-0.106 kg yr-1. The life cycle (LC) benefits by avoiding fossil-based formic acid production (93%) and electricity for wastewater treatment (12%) outweigh LC costs of operation and assemblage of BES (-5%), giving a net 61MJkg-1 HCOOH saving. PMID- 29414172 TI - Catalytic production of levulinic acid and ethyl levulinate from uniconazole induced duckweed (Lemna minor). AB - Duckweed (Lemna minor) with a high starch content of 50.4% was cultivated by uniconazole-induction method. The cultivated duckweed was used to produce value added chemicals such as glucose, levulinic acid and formic acid in diluted HCl aqueous solution. A high glucose yield of 93.4% (471 g/kg based on loading duckweed mass) could be achieved at 180 degrees C in short reaction time, and the generated glucose was converted into levulinic acid and formic acid with yields of 52.0% and 34.1%, respectively, for 150 min, corresponding to 262 g/kg levulinic acid yield and 171 g/kg formic acid yield based on the mass of loading duckweed, respectively. Moreover, the duckweed was efficiently converted to ethyl levulinate with 55.2% yield (400.6 g/kg) at 200 degrees C in ethanol. This work provides a promising strategy for the production of value-added chemicals from phytoplankton that is able to purify the wastewater containing high content of P and N. PMID- 29414173 TI - Nitrogen removal and intentional nitrous oxide production from reject water in a coupled nitritation/nitrous denitritation system under real feed-stream conditions. AB - A Coupled Aerobic-anoxic Nitrous Decomposition Operation (CANDO) was performed over five months to investigate the performance and dynamics of nitrogen elimination and nitrous oxide production from digester reject water under real feed-stream conditions. A 93% conversion of ammonium to nitrite could be maintained for adapted seed sludge in the first stage (nitritation). The second stage (nitrous denitritation), inoculated with conventional activated sludge, achieved a conversion of 70% of nitrite to nitrous oxide after only 12 cycles of operation. The development of an alternative feeding strategy and the addition of a coagulant (FeCl3) facilitated stable operation and process intensification. Under steady-state conditions, nitrite was reliably eliminated and different nitrous oxide harvesting strategies were assessed. Applying continuous removal increased N2O yields by 16% compared to the application of a dedicated stripping phase. These results demonstrate the feasible application of the CANDO process for nitrogen removal and energy recovery from ammonia rich wastewater. PMID- 29414175 TI - Pretreatment of grass waste using combined ionizing radiation-acid treatment for enhancing fermentative hydrogen production. AB - In this study, the combined ionizing radiation-acid pretreatment process was firstly applied to enhance hydrogen fermentation of grass waste. Results showed that the combined pretreatment synergistically enhanced hydrogen fermentation of grass waste. The SCOD and soluble polysaccharide contents of grass waste increased by 1.6 and 2.91 times after the combined pretreatment, respectively. SEM observation and crystallinity test showed the combined pretreatment effectively disrupted the grass structure. Owing to the more favorable substrate conditions, the hydrogen yield achieved 68 mL/g-dry grassadded after the combined pretreatment, which was 161.5%, 112.5% and 28.3% higher than those from raw, ionizing radiation pretreated and acid pretreated grass waste, respectively. The VS removal also increased from 13.9% to 25.6% by the combined pretreatment. Microbial community analysis showed that the abundance of dominant hydrogen producing genus Clostridium sensu stricto 1 increased from 37.9% to 69.4% after the combined pretreatment, which contributed to more efficient hydrogen fermentation. PMID- 29414174 TI - Valorisation of food and beverage waste via saccharification for sugars recovery. AB - Valorisation of mixed food and beverage (F&B) waste was studied for the recovery of sugars via saccharification. Glucoamylase and sucrase were employed to hydrolyse the starch and sucrose present in the mixed F&B waste because of the high cost-effectiveness for such recovery. The Michaelis-Menten kinetics model suggests that preservatives and additives in beverages did not inhibit glucoamylase and sucrase during saccharification. High levels of glucose (228.1 g L-1) and fructose (55.7 g L-1) were efficiently produced within 12 h at a solid to-liquid ratio of 37.5% (w/v) in 2.5 L bioreactors. An overall conversion yield of 0.17 g sugars per g of mixed F&B waste was obtained in mass balance analysis. Lastly, possible industrial applications of the sugar-rich hydrolysate and by products are discussed. This study is believed to cast insights into F&B waste recycling via biotechnology to produce high-value added products to promote the establishment of a circular bio-economy. PMID- 29414176 TI - Enhancing forward osmosis water recovery from landfill leachate by desalinating brine and recovering ammonia in a microbial desalination cell. AB - In this work, a microbial desalination cell (MDC) was employed to desalinate the FO treated leachate for reduction of both salinity and chemical oxygen demand (COD). The FO recovered 51.5% water from a raw leachate and the recovery increased to 83.5% from the concentrated leachate after desalination in the MDC fed with either acetate or another leachate as an electron source and at a different hydraulic retention time (HRT). Easily-degraded substrate like acetate and a long HRT resulted in a low conductivity desalinated effluent. Ammonia was also recovered in the MDC cathode with a recovery efficiency varying from 11 to 64%, affected by current generation and HRT. Significant COD reduction, as high as 65.4%, was observed in the desalination chamber and attributed to the decrease of both organic and inorganic compounds via diffusion and electricity-driven movement. PMID- 29414177 TI - Novel bufferless photosynthetic microbial fuel cell (PMFCs) for enhanced electrochemical performance. AB - Photosynthetic microbial fuel cells (PMFCs) are novel bioelectrochemical transducers that employ microalgae to generate oxygen, organic metabolites and electrons. Conventional PMFCs employ non-eco-friendly membranes, catalysts and phosphate buffer solution. Eliminating the membrane, buffer and catalyst can make the MFC a practical possibility. Therefore, single chambered (SPMFC) were constructed and operated at different recirculation flow rates (0, 40 and 240 ml/min) under bufferless conditions. Furthermore, maximum power density of 4.06 mW/m2, current density of 46.34 mA/m2 and open circuit potential of 0.43 V and low internal resistance of 611.8 Omega were obtained at 40 ml/min. Based on the results it was decided that SPMFC was better for operation at 40 ml/min. Therefore, these findings provided progressive insights for future pilot and industrial scale studies of PMFCs. PMID- 29414178 TI - Comparative thermogravimetric analyses of co-combustion of textile dyeing sludge and sugarcane bagasse in carbon dioxide/oxygen and nitrogen/oxygen atmospheres: Thermal conversion characteristics, kinetics, and thermodynamics. AB - Thermodynamic and kinetic parameters of co-combustion of textile dyeing sludge (TDS) and sugarcane bagasse (SB) were studied using thermogravimetric analysis in CO2/O2 and N2/O2 atmospheres. Our results showed that the comprehensive combustion characteristic index (CCI) of the blends was improved by 1.71-4.32 times. With the increased O2 concentration, co-combustion peak temperature decreased from 329.7 to 318.2 degrees C, with an increase in its maximum weight loss rate from 10.04 to 14.99%/min and its CCI by 1.31 times (beta = 20 degrees C.min-1). To evaluate the co-combustion characteristics, thermodynamic and kinetic parameters (entropy, Gibbs free energy and enthalpy changes, and apparent activation energy) were obtained in the five atmospheres. The lowest apparent activation energy of the TB64 blend was obtained in oxy-fuel atmosphere (CO2/O2 = 7/3). PMID- 29414179 TI - Long-term operation with an insight into a newly established green bio-sorption reactor: Can it achieve "1 + 1 > 2"? AB - An eco-friendly system of green bio-sorption reactor (GBR), constructed by embedding alum sludge-based constructed wetland (AlCW) into a conventional activated sludge process to achieve "1 + 1 > 2", was evaluated under a long-term operation basis. Insight into the pollutants removal, particularly the role of the AlCW in the GBR, was explored and discussed. The results showed that the GBR could achieve 90% and 95% removal for TN and TP (Stage 4), respectively, under the hydraulic and nitrogen loading rate of 2.07 m3/(m3.d) and 166.2 gN/(m3.d), respectively. Intriguingly, despite the P adsorption, the AlCW enlarged the size of the activated sludge flocs which benefited the simultaneous nitrification and denitrification. Subversively, the embedding AlCW brings about dual intensification in both capacity and efficiency. In addition, the GBR as an ecological engineering system can be employed closely to residential area in line with its green and pleasing appearance. PMID- 29414180 TI - Renal manifestations of dengue virus infections. AB - Dengue is a significant health problem in many countries. In recent years, complications involving specific organ systems have been increasingly observed and appear to have important effects on overall dengue related morbidity and mortality. Renal involvement in dengue could potentially cause increased mortality and long term effects. We review the different renal manifestations associated with dengue virus infections and explore their potential underlying pathophysiological mechanisms. The serum electrolyte and urinary abnormalities seen in dengue are discussed and Acute Kidney Injury (AKI) due to acute glomerulonephritis, rhabdomyolysis and haemolytic uraemic syndrome following dengue are explored. Renal manifestations of dengue in patients with chronic kidney disease or a transplanted kidney provides new insights into the pathophysiology of the disease. PMID- 29414182 TI - Laboratory findings in Zika infection: The experience of a reference centre in North-West Italy. AB - BACKGROUND: Zika virus (ZIKV) remains a public health concern due to its association with fetal malformation and neurologic disease. OBJECTIVE: To report a reference centre experience on ZIKA virus (ZIKV) infection in travelers from epidemic countries from January 1 to September, 30, 2016 in Italy North-West (a geographic area covering 4.424 million inhabitants, corresponding to almost 73% of Italy North-West area). STUDY DESIGN: One hundred and twelve febrile travelers were studied to rule out a tropical fever [e.g. malaria, dengue (DENV), chikungunya (CHIKV), West Nile (WNV) and ZIKV]. Molecular tests for detecting ZIKV RNA were applied on serum or urine as well as IgG and IgM specific serology. RESULTS: ZIKV was the most frequent "tropical infection (11.6%) with 12 infected travelers and one sexual partner of an infected traveler. At the time of the diagnosis, ZIKV RNA was detected in the blood from 9 patients (69%) within 7 days from symptom onset; afterwards, the virus was detected only in urine (5 patients) and ZIKV IgM was reactive in 9 patients (69%). Travelers with ZIKV infection tested negative for DENV, CHIKV, WNV and malaria and completely recovered. Other infections identified in travelers were DENV (5 patients, 4.5%), CHIKV (1, 0.9%), malaria (Plasmodium vivax, 1, 0.9%), measles (1, 0.9%) and tuberculosis (1, 0.9%). CONCLUSIONS: The etiologic diagnosis of a febrile illness in travelers where ZIKV is endemic is highly desirable as they are sentinel of a challenging epidemiology including the risk of autochthonous transmission in non endemic countries where the competent or carrier vector is present. PMID- 29414181 TI - Recommendations for enterovirus diagnostics and characterisation within and beyond Europe. AB - Enteroviruses (EV) can cause severe neurological and respiratory infections, and occasionally lead to devastating outbreaks as previously demonstrated with EV-A71 and EV-D68 in Europe. However, these infections are still often underdiagnosed and EV typing data is not currently collected at European level. In order to improve EV diagnostics, collate data on severe EV infections and monitor the circulation of EV types, we have established European non-polio enterovirus network (ENPEN). First task of this cross-border network has been to ensure prompt and adequate diagnosis of these infections in Europe, and hence we present recommendations for non-polio EV detection and typing based on the consensus view of this multidisciplinary team including experts from over 20 European countries. We recommend that respiratory and stool samples in addition to cerebrospinal fluid (CSF) and blood samples are submitted for EV testing from patients with suspected neurological infections. This is vital since viruses like EV-D68 are rarely detectable in CSF or stool samples. Furthermore, reverse transcriptase PCR (RT-PCR) targeting the 5'noncoding regions (5'NCR) should be used for diagnosis of EVs due to their sensitivity, specificity and short turnaround time. Sequencing of the VP1 capsid protein gene is recommended for EV typing; EV typing cannot be based on the 5'NCR sequences due to frequent recombination events and should not rely on virus isolation. Effective and standardized laboratory diagnostics and characterisation of circulating virus strains are the first step towards effective and continuous surveillance activities, which in turn will be used to provide better estimation on EV disease burden. PMID- 29414183 TI - Hepatitis E outbreak at a nursing home for aged people in Hokkaido, Japan, between February and March 2016. AB - BACKGROUND: Infection with hepatitis E virus (HEV) genotypes 3 and 4 are usually asymptomatic but can occasionally result in life-threatening acute hepatitis. To date, only sporadic cases together with a few outbreaks have been documented. Seroprevalence studies with assays for the detection of HEV IgG antibodies, suggest that HEV is more prevalent than previously thought, even in non-endemic regions. OBJECTIVES: The aim of this study was to characterize an outbreak of hepatitis E (HE) in a nursing home for aged people between February and March 2016. STUDY DESIGN: After the identification of two cases living in the same nursing home, the presence of antibodies against HEV and HEV RNA were examined in serum samples collected from the other residents and staff members to identify any additional cases. An epidemiological investigation was also carried out. RESULTS: Only 4 patients showed mild symptoms such as anorexia, abdominal pain and fatigue. Among the 125 persons tested, 28 residents and one dietitian were confirmed positive for anti-HEV IgA or IgM antibodies, and/or HEV RNA. Eight samples had only IgG antibodies. Finally, 22 cases were notified with HE on the basis of the presence of IgA antibodies. All HEV isolates obtained were 99.8-100% identical and belonged to genotype 3. CONCLUSION: HEV infections seem to be under reported or underestimated possibly due to cases being generally asymptomatic. Testing for the presence of both anti-HEV antibodies and HEV RNA would be beneficial for both the comprehensive diagnosis of HE infections and the prevention of further infections. PMID- 29414184 TI - Oligoadenylate synthetase 3 S381R gene polymorphism is associated with severity of EV71 infection in Chinese children. AB - BACKGROUND: Oligoadenylate synthetase 3 (OAS3) is interferon-induced antiviral enzyme, playing a significant role in the innate immune response. Genetic polymorphism in OAS3 gene has been reported to be a susceptibility factor in many infected diseases, but evidence of its effect on enterovirus 71 (EV71) infection is still lacking. OBJECTIVES: An attempt study was made to investigate whether genetic polymorphism of OAS3 S381R is associated with the severity of EV71 infection in Chinese children. STUDY DESIGN: Retrospectively sumed up the clinical onsets and experimental results for 249 cases with EV71 infection (including 151 mild cases and 98 severe cases) and 243 controls. An improved multiplex ligation detection reaction (iMLDR) technique was carried out to analyze polymorphism in OAS3 S381R G/C gene for genetic association analyses. The plasma levels of IFN-gamma were determined by enzyme-linked immunosorbent assays. RESULTS: The distribution of OAS3 S381R CC genotype (73.47%) and C allele (85.20%) in severe cases was markedly higher than in mild cases (45.70%, P < .01; 67.88%, P < .01). The blood IFN-gamma levels of severe cases were significantly lower in CC genotype (131.66 +/- 10.84 pg/mL) compared to GG (183.37 +/- 24.50 pg/mL, p < .01) and GC genotype (168.48 +/- 26.57 pg/mL, p < .01). CONCLUSIONS: Carrying the C allele of the OAS3 S381R gene could be a susceptibility factor in the development of severe EV71 infection in Chinese children. PMID- 29414185 TI - Prevalence and stability of antibodies to thirteen polyomaviruses and association with cutaneous squamous cell carcinoma: A population-based study. AB - BACKGROUND: Several new members of the human polyomavirus (HPyV) family that infect human skin and are potentially oncogenic have been identified in the last decade. OBJECTIVES: To investigate prospectively the seroprevalence and stability of 13 PyVs, and possible associations with different risk factors and cutaneous squamous cell carcinoma (cSCC). STUDY DESIGN: In this Australian population-based longitudinal study sera were collected at baseline in 1992 or during the next 4 years from 688 people. Of the 688, 226 developed a new cSCC between blood collection and the final follow up in 2003. The remaining 462 served as controls. Among the 462 controls, 161 had a second serum sample from 2003 analysed. Seroprevalence of 10 human PyVs (BKV, JCV, KIV, WUV, MCV, TSV, HPyV6, HPyV7, HPyV9 and HPyV10) and three non-human PyVs (SV40, LPV and ChPyV) was assessed using multiplex serology. RESULTS: There was no significant difference in PyV seroprevalence between people who developed cSCC during follow-up compared to those who did not. WUV and HPyV10 showed the highest serostability (93%) and JCV VP1 and SV40 VP1 the lowest (84%) over a 9-year time period (range 7-11 years). CONCLUSIONS: We found no evidence that HPyV seroprevalence is associated with subsequent development of cSCC and observed variable stability of antibodies to polyomaviruses. PMID- 29414186 TI - Substantial variation in the hepatitis B surface antigen (HBsAg) in hepatitis B virus (HBV)-positive patients from South Africa: Reliable detection of HBV by the Elecsys HBsAg II assay. AB - BACKGROUND: It is essential that hepatitis B surface antigen (HBsAg) diagnostic assays reliably detect genetic diversity in the major hydrophilic region (MHR) of HBsAg to avoid false-negative results. Mutations in this domain display marked ethno-geographic variation and may lead to failure to diagnose hepatitis B virus (HBV) infection. OBJECTIVES: Evaluate diagnostic performance of the Elecsys(r) HBsAg II Qualitative assay in a cohort of South African HBV-positive blood donors. STUDY DESIGN: A total of 179 South African HBsAg- and HBV DNA > 100 IU/mL positive blood donor samples were included. Samples were sequenced for genetic variation in HBsAg MHR using next-generation ultra-deep sequencing. HBsAg seropositivity was determined using the Roche Elecsys HBsAg II Qualitative assay. Mutation rates were compared between the first (amino acids 124-137) and second (amino acids 139-147) loops of the immunodominant MHR 'a' determinant region. Frequency of occult HBV infection-associated Y100C mutations was also determined. RESULTS: We observed a total of 279 MHR mutations (117 variants) in 102 (57%) samples, of which 91 were located in the 'a' determinant region. The major vaccine-induced escape mutation G145R was observed in two samples. All occult HBV infection-associated Y100C and common diagnostic and vaccine-escape-associated P120T, G145R, K122R, M133L, M133T, Q129H, G130N, and T126S mutations were reliably detected by the assay, which consistently detected the presence of HBsAg in all 179 samples including samples with 11 novel mutations. CONCLUSIONS: Despite substantial variation in HBsAg MHR, the Elecsys HBsAg II Qualitative assay robustly detects HBV infection in this South African cohort. PMID- 29414187 TI - Prevalence of pre-treatment hepatitis C virus NS5A resistance associated amino acid substitutions in genotype 1A infected patients in Scotland. AB - BACKGROUND: Hepatitis C (HCV) NS5A resistance associated amino-acid substitutions (RAS) can exist at baseline in treatment naive individuals and have been shown to be associated with lower rates of sustained virological response (SVR) for patients infected with HCV genotype 1A (G1A) following treatment with NS5A inhibitors. OBJECTIVES: The aim of this study was to measure the prevalence of baseline NS5A resistance in Scotland. STUDY DESIGN: The study population consisted of 531 treatment naive, G1A infected patients. The patient samples were collected between March and September 2017. The NS5A region was amplified and sequenced. RESULTS: Baseline NS5A resistance in Scotland is high (16.8%) and is comparable to rates reported by a number of previously published studies. The high rate of baseline RAS, together with the high cost of direct-acting antivirals (DAAs), supports resistance testing to guide current patient treatment. However, given the rate at which new DAAs are currently being licensed with ever broader genotype efficacy and higher SVR rates, baseline resistance testing may not be required in the near future. CONCLUSIONS: Baseline NS5A inhibitor resistance is high. The results of the present study support performing resistance testing at baseline for current regimens. PMID- 29414188 TI - Performance of the cobas Hepatitis B virus (HBV) test using the cobas 4800 system and comparison of HBV DNA quantification ability between the COBAS AmpliPrep/COBAS TaqMan HBV test version 2.0 and cobas HBV test. AB - BACKGROUND: Hepatitis B virus (HBV) DNA levels are used to predict the response to therapy, determine therapy initiation, monitor resistance to therapy, and establish treatment success. OBJECTIVE: To verify the performance of the cobas HBV test using the cobas 4800 system for HBV DNA quantification and to compare the HBV DNA quantification ability between the cobas HBV test and COBAS AmpliPrep/COBAS TaqMan HBV version 2.0 (CAP/CTM v2.0). STUDY DESIGN: The precision, linearity, and limit of detection of the cobas HBV test were evaluated using the 4th World Health Organization International Standard material and plasma samples. Clinical samples that yielded quantitative results using the CAP/CTM v2.0 and cobas HBV tests were subjected to correlational analysis. RESULTS: Three hundred forty-nine samples were subjected to correlational analysis, among which 114 samples showed results above the lower limit of quantification. Comparable results were obtained ([cobas HBV test] = 1.038 * [CAP/CTM v2.0]-0.173, r = 0.914) in 114 samples, which yielded values above the lower limit of quantification. The results for 86.8% of the samples obtained using the cobas HBV test were within 0.5 log10 IU/mL of the CAP/CTM v2.0 results. The total precision values against the low and high positive controls were 1.4% (mean level: 2.25 log10 IU/mL) and 3.2% (mean level: 6.23 log10 IU/mL), respectively. The cobas HBV test demonstrated linearity (1.15-6.75 log10 IU/mL, y = 0.95 * 6 + 0.17, r2 = 0.994). CONCLUSION: The cobas HBV test showed good correlation with CAP/CTM v2.0, and had good precision and an acceptable limit of detection. The cobas HBV test using the cobas 4800 is a reliable method for quantifying HBV DNA levels in the clinical setting. PMID- 29414189 TI - Diagnosis of HIV-1 infection: Performance of Xpert Qual and Geenius supplemental assays in fourth generation ELISA-reactive samples. AB - BACKGROUND: Architect (AR) and Vidas (VD) fourth generation HIV screening immunoassays, which identify early stages of HIV infections, could have false positive results especially at low signal/cutoff (S/C) AR values. Geenius HIV1/2 (GS) is a specific confirmation line immunoassay that is not highly sensitive to early HIV infections. An HIV-1 RNA assay may better detect such infections. OBJECTIVES: To evaluate all AR-VD reactive samples with GS results, and to assess Xpert Qual HIV-1 RNA assay (XQ) as an alternative to GS, in the first low S/C AR VD-reactive samples from a tested individual. STUDY DESIGN: First AR-VD-reactive GS-tested results from all individuals with resolved HIV status, collected between March 2015 and March 2017 (n = 749), were retrospectively assessed. Samples with AR-VD-reactive-GS-discordant results and those with low S/C AR-VD reactive results, were tested by XQ. Receiver operating characteristic (ROC) analysis of GS and XQ sensitivity/specificity was performed. RESULTS: Overall, 94.1% (705/749) of AR-VD-reactive results were true HIV-1 positive. All samples with <3 S/C AR values were false positive. XQ resolved all first samples with AR VD-reactive-GS-discordant results. The diagnostic accuracy of XQ in low (<=33 S/C) AR-VD-reactive samples was better than that of GS (97.6%, 81/83 versus 73.5%, 61/83, p < 0.01). ROC analysis for low S/C AR samples was optimal for pooled XQ and GS results. CONCLUSIONS: Incorporating XQ in the current screening algorithm for the first AR-VD-reactive-GS-discordant samples may significantly reduce overall turn-around time of HIV-1 diagnosis. PMID- 29414190 TI - Transcriptomic analysis of changes in gene expression of immune proteins of gill tissue in response to low environmental temperature in fathead minnows (Pimephales promelas). AB - In the face of ongoing climate change, it is imperative to understand better the effects of temperature on immune function in freshwater teleosts. It is unclear whether previously observed changes were caused by temperature per se. We studied changes in the gill transcriptome of fathead minnows (Pimephales promelas) at low temperature to understand better the effects of temperature on immune function. De novo assembly of the transcriptome using Trinity software resulted in 73,378 assembled contigs. Annotation using the Trinotate package yielded 58,952 Blastx hits (accessions). Expression of 194 unique mRNA transcripts changed in gill tissue of fathead minnows acclimatized to 5 degrees compared to controls at 22 degrees C. At 5 degrees C mRNAs coding for proteins involved in innate immune responses were up-regulated. Those included proteins that block early-stage viral replication and macrophage activation. Expression of mRNAs coding for pro inflammatory molecules and mucus secretion were also enhanced. Messenger RNAs coding for proteins associated with adaptive immune responses were down-regulated at 5 degrees C. Those included antigen-presenting proteins and proteins involved in immunoglobin production. Messenger RNAs coding for proteins that stimulate the cell cycle were also down-regulated at 5 degrees C. Histological comparison revealed that gills of cold acclimated fish had fewer mucus cells but cells contained larger mucus droplets. We conclude that decreased temperature modifies the immune systems of freshwater teleosts, leading to genome-wide upregulation of innate immunity and down regulation of adaptive immunity. Such acclimation likely evolved as an adaptive strategy against seasonal changes in infectious insults. PMID- 29414191 TI - A glance at the therapeutic potential of irisin against diseases involving inflammation, oxidative stress, and apoptosis: An introductory review. AB - Irisin is a hormone-like molecule mainly released by skeletal muscles in response to exercise. Irisin induces browning of the white adipose tissue and has been shown to regulate glucose and lipid homeostasis. Keeping its energy expenditure and metabolic properties in view, numerous studies have focused on its therapeutic potential for the treatment of metabolic disorders like obesity and type 2 diabetes. Recently, the anti-inflammatory, anti-apoptotic and anti oxidative properties of irisin have received a great deal of attention of the scientific society. These pathogenic processes are often associated with initiation, progression, and prognosis of numerous diseases like myocardial infarction, kidney diseases, cancer, lung injury, inflammatory bowel diseases, atherosclerosis, liver diseases, obesity and type 2 diabetes. In the current review, we present evidence regarding the anti-inflammatory, anti-apoptotic and anti-oxidative potential of irisin pertaining to various pathological conditions. Here, we explore multiple molecular pathways targeted by irisin therapy. Given the promising effects of irisin, many diseases with evident oxidative stress, inflammation and apoptosis can be targeted by irisin. PMID- 29414192 TI - Editor's Report: What's Now, What's New, and What's Coming. PMID- 29414193 TI - Cavoiliac Thrombectomy with Use of Snare Retrieval Technique. PMID- 29414194 TI - Embolization of a Mesenteric Arteriovenous Fistula. PMID- 29414195 TI - Comparative Analysis of Cone-Beam CT Angiogram and Conventional CT Angiogram for Prostatic Artery Identification Prior to Embolization. AB - Pre-prostatic artery embolization (PAE) cone-beam computed tomography (CT) angiograms (n = 31; mean age: 62.4 +/- 9.75 years) and conventional CT angiograms (n = 32; mean age: 62.5 +/- 7.2 years) were retrospectively compared. Mean signal to-noise ratio (SNR), contrast-to-noise ratio (CNR), radiation exposure, and prostatic artery (PA) identification scores (0-4) for cone-beam CT angiogram and conventional CT angiogram were 33.19 (+/- 14.31) and 18.13 (+/- 5.38) (P < .01); 27.42 (+/- 13.39) and 14.78 (+/- 4.92) (P < .01); 14.57 mSv (+/-2.5) and 19.25 mSv (+/-3.7) (P < .01); 3.36 (+/- 0.89) and 3.16 (+/- 0.95) (P = .08), respectively. Pre-PAE cone-beam CT angiogram allows for PA identification with improved SNR and CNR and less radiation dose compared to conventional CT angiogram. PMID- 29414196 TI - Percutaneous Sclerotherapy for Giant Symptomatic Liver Hemangiomas: A Pilot Study. AB - This single-center prospective trial evaluated the safety and efficacy of percutaneous sclerotherapy for liver hemangiomas in 5 patients (1 man, 4 women; mean age 41.2 y) between 2016 and 2017. All patients were symptomatic (4 abdominal pain; 1 early satiety) and refused surgery. A single session of sclerotherapy with 20 cc mixture of 45 IU. Bleomycin in 10 cc distilled water and 10 cc Lipiodol (Ultra Fluide, Guerbet, France) was performed in all patients, achieving a 45.6%-71.1% lesion volume reduction and a 12.9%-41% reduction in the largest diameter of the lesion. Symptoms subsided in all patients during the 5 month follow-up period. Adverse events included a self-limited intraperitoneal hemorrhage in 1 patient. PMID- 29414197 TI - Adrenal Biopsy under Wide-Bore MR Imaging Guidance. AB - Twenty-four magnetic resonance (MR) imaging-guided percutaneous adrenal biopsies performed between April 2009 and October 2016 were reviewed retrospectively. Epidemiologic, procedural, and histopathologic data were retrospectively collected. Mean size of tumors was 4.3 cm (range, 1.5-16.0 cm). Mean procedure time was 49 min (range, 24-95 min). Mean needle angulation was 27.7 degrees (range, 0 degrees -60 degrees ). Mean depth was 9.6 cm (range, 5.8-13.7 cm). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MR imaging-guided biopsy were 95.5%, 100%, 100%, 66.7%, and 95.8%, respectively. There were no immediate or delayed complications. MR imaging guidance seems safe and accurate to target adrenal-gland masses. PMID- 29414198 TI - Re: Percutaneous Suprapubic Cystolitholapaxy in Adult Patients with Previous Mitrofanoff Repair: Considerations for the Interventional Radiologist. PMID- 29414199 TI - Reply to: "Re: Percutaneous Suprapubic Cystolitholapaxy in Adult Patients with Previous Mitrofanoff Repair: Considerations for the Interventional Radiologist". PMID- 29414200 TI - [In process]. PMID- 29414201 TI - [In process]. PMID- 29414202 TI - [In process]. PMID- 29414203 TI - [In process]. PMID- 29414204 TI - [In process]. PMID- 29414205 TI - [In process]. PMID- 29414206 TI - [In process]. PMID- 29414207 TI - [In process]. PMID- 29414208 TI - [In process]. PMID- 29414209 TI - [In process]. PMID- 29414210 TI - [In process]. PMID- 29414211 TI - [In process]. PMID- 29414212 TI - [In process]. PMID- 29414213 TI - [In process]. PMID- 29414214 TI - [In process]. PMID- 29414215 TI - [In process]. PMID- 29414216 TI - [In process]. PMID- 29414217 TI - [In process], PMID- 29414218 TI - [In process]. PMID- 29414219 TI - [In process]. PMID- 29414220 TI - [In process]. PMID- 29414221 TI - [In process]. PMID- 29414222 TI - [In process]. PMID- 29414223 TI - [In process]. PMID- 29414224 TI - [In process]. PMID- 29414225 TI - [In process]. PMID- 29414226 TI - [In process]. PMID- 29414227 TI - [In process]. PMID- 29414228 TI - [In process]. PMID- 29414230 TI - [In process]. PMID- 29414229 TI - [In process]. PMID- 29414231 TI - [In process]. PMID- 29414232 TI - [In process]. PMID- 29414233 TI - [In process]. PMID- 29414234 TI - [In process]. PMID- 29414235 TI - [In process]. PMID- 29414236 TI - [In process]. PMID- 29414237 TI - Infrared Spectroscopy of Matrix-Isolated Neutral and Ionized Anthracoronene in Argon. AB - The matrix-isolated mid-IR (MIR) spectrum of neutral and ionized anthracoronene (C36H18, AnthCor) in argon has been measured experimentally, compared to the spectrum of its parent molecules, coronene and anthracene, and analyzed by comparison to a theoretical spectrum computed using density functional theory (DFT). The experimental and theoretical band positions generally agree within 0 10 cm-1. Anthracoronene exhibits extremely intense cation and anion bands around 1330 and 1318 cm-1. The intensity of these two bands approaches what is traditionally observed over the entire 1000-1600 cm-1 range for a typical PAH cation or anion. The matrix-isolated near-IR (NIR) through overlap region (OVR) spectrum of ionized AnthCor in argon has been reported for the first time and compared to the spectrum of its parent molecules, coronene and anthracene. The spectrum of AnthCor contains a very strong electronic transition around 6175 cm 1, placing it outside the range of the electronic transitions typically observed for PAHs. Anthracoronene is one of the few PAHs studied to date which has exhibited the formation of anions upon UV photolysis. PMID- 29414239 TI - Effects of Highland Barley Bran Extract Rich in Phenolic Acids on the Formation of Nepsilon-Carboxymethyllysine in a Biscuit Model. AB - Highland barley, a staple food in northwest China, is a well-known source of bioactive phytochemicals, including phenolic compounds. This study evaluated the inhibitory effects of highland barley bran extract (HBBE) on the advanced glycation end product (AGE) levels in a biscuit model, as measured by Nepsilon carboxymethyllysine (CML) content. CML was detected in all inhibition models using HBBE extracted with different solvents. Under optimal conditions, CML formation in the heated model system composed of glucose/lysine/linoleic acid was effectively inhibited by HBBE. This inhibition effect using extracts from 60% acetone solution was 45.58%. Five major phenolic acids from HBBE (ferulic, syringic, sinapic, p-coumaric, and caffeic acids) were further tested for their trapping and scavenging abilities of glyoxal, a reactive carbonyl species and a key intermediate compound for forming CML. This study has demonstrated that HBBE can potentially control CML formation during food processing, therefore effectively reducing glycation in foods and benefiting those with chronic diseases. PMID- 29414238 TI - Selective [1,4]-Hydrovinylation of 1,3-Dienes with Unactivated Olefins Enabled by Iron Diimine Catalysts. AB - The selective, intermolecular [1,4]-hydrovinylation of conjugated dienes with unactivated alpha-olefins catalyzed by alpha-diimine iron complexes is described. Value-added "skipped" diene products were obtained with exclusive [1,4] selectivity, and the formation of branched, ( Z)-olefin products was observed with no evidence for alkene isomerization. Mechanistic studies conducted with the well-defined, single-component iron precatalyst (MesDI)Fe(COD) (MesDI = [2,4,6 Me3-C6H2-N?CMe]2); COD = 1,5-cyclooctadiene) provided insights into the origin of the high selectivity. An iron diene complex was identified as the catalyst resting state, and one such isoprene complex, (iPrDI)Fe(eta4-C5H8), was isolated and characterized. A combination of single crystal X-ray diffraction, Mobetabauer spectroscopy, magnetic measurements, and DFT calculations established that the complex is best described as a high-spin Fe(I) center ( SFe = 3/2) engaged in antiferromagnetic coupling to an alpha-diimine radical anion ( SDI = -1/2), giving rise to the observed S = 1 ground state. Deuterium-labeling experiments and kinetic analyses of the catalytic reaction provided support for a pathway involving oxidative cyclization of an alkene with the diene complex to generate an iron metallacycle. The observed selectivity can be understood in terms of competing steric interactions in the transition states for oxidative cyclization and subsequent beta-hydrogen elimination. PMID- 29414240 TI - Self-Standing Nanocellulose Janus-Type Films with Aldehyde and Carboxyl Functionalities. AB - Nanocellulose-based self-standing films are becoming a substrate for flexible electronics, diagnostics, and sensors. Strength and surface chemistry are vital variables for these film-based endeavors, the former is one of the assets of nanocellulose. To contribute to the latter, nanocellulose films are tuned with a side-specific functionalization, having an aldehyde and a carboxyl side. The functionalities were obtained combining premodification of the film components by periodate oxidation with ozone post-treatment. Periodate oxidation of cellulose nanocrystals results in film components that interact through intra- and intermolecular hemiacetals and lead to films with an elastic modulus of 11 GPa. The ozone treatment of one film side induces conversion of the aldehyde into carboxyl functionalities. The ozone treatment on individual crystals was largely destructive. Remarkably, such degradation is not observed for the self-standing film, and the film strength at break is preserved. Preserving a physically intact film despite ozone treatment is a credit to using the dry film structure held together by interparticle covalent linkages. Additionally, gas-phase post treatment avoids disintegration that could result from immersion into solvents. The crystalline cellulose "Janus" film is suggested as an interfacial component in biomaterial engineering, separation technology, or in layered composite materials for tunable affinity between the layers. PMID- 29414241 TI - Effect of Abscission Zone Formation on Orange ( Citrus sinensis) Fruit/Juice Quality for Trees Affected by Huanglongbing (HLB). AB - Orange trees affected by huanglongbing (HLB) exhibit excessive fruit drop, and fruit loosely attached to the tree may have inferior flavor. Fruit were collected from healthy and HLB-infected ( Candidatus liberibacter asiaticus) 'Hamlin' and 'Valencia' trees. Prior to harvest, the trees were shaken, fruit that dropped collected, tree-retained fruit harvested, and all fruit juiced. For chemical analyses, sugars and acids were generally lowest in HLB dropped (HLB-D) fruit juice compared to nonshaken healthy (H), healthy retained (H-R), and healthy dropped fruit (H-D) in early season (December) but not for the late season (January) 'Hamlin' or 'Valencia' except for sugar/acid ratio. The bitter limonoids, many flavonoids, and terpenoid volatiles were generally higher in HLB juice, especially HLB-D juice, compared to the other samples. The lower sugars, higher bitter limonoids, flavonoids, and terpenoid volatiles in HLB-D fruit, loosely attached to the tree, contributed to off-flavor, as was confirmed by sensory analyses. PMID- 29414242 TI - Hepatoprotective influence of quercetin and ellagic acid on thioacetamide-induced hepatotoxicity in rats. AB - Despite all the studies performed to date, therapy choices for liver injuries are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries remains a challenge. Quercetin (QR) and ellagic acid (EA) had potent antioxidant and anti-inflammatory activities. The current study aimed at evaluating the potential hepatoprotective influence of QR and EA against thioacetamide (TAA)-induced liver toxicity in rats and the underlying mechanism using silymarin as a reference drug. Fifty mature male rats were orally treated daily with EA and QR in separate groups for 45 consecutive days, and then were injected with TAA twice with 24 h intervals in the last 2 days of the experiment. Administration of TAA resulted in marked elevation of liver indices, alteration in oxidative stress parameters, and significant elevation in expression level of fibrosis-related genes (MMP9 and MMP2). Administration of QR and EA significantly attenuated the hepatic toxicity through reduction of liver biomarkers, improving the redox status of the tissue, as well as hampering the expression level of fibrosis-related genes. In this study, QR and EA were proved to attenuate the hepatotoxicity through their antioxidant, metal-chelating capacity, and anti-inflammatory effects. PMID- 29414243 TI - The underlying physiological mechanisms whereby anticholinergics alleviate asthma. AB - The mechanisms whereby anticholinergics improve asthma outcomes, such as lung function, symptoms, and rate of exacerbation, can be numerous. The most obvious is by affecting the contraction of airway smooth muscle (ASM). The acetylcholine released from the cholinergic nerves is the most important bronchoconstrictor that sets the baseline degree of contractile activation of ASM in healthy individuals. Although the degree of ASM's contractile activation can also be fine tuned by a plethora of other bronchoconstrictors and bronchodilators in asthma, blocking the ceaseless effect of acetylcholine on ASM by anticholinergics reduces, at any given moment, the overall degree of contractile activation. Because the relationships that exist between the degree of contractile activation, ASM force, ASM shortening, airway narrowing, airflow resistance, and respiratory resistance are not linear, small decreases in the contractile activation of ASM can be greatly amplified and thus translate into important benefits to a patient's well-being. Plus, many inflammatory and remodeling features that are often found in asthmatic lungs synergize with the contractile activation of ASM to increase respiratory resistance. This review recalls that the proven effectiveness of anticholinergics in the treatment of asthma could be merely attributed to a small reduction in the contractile activation of ASM. PMID- 29414244 TI - The influence of high-intensity interval training and moderate-intensity continuous training on sedentary time in overweight and obese adults. AB - High-intensity interval training (HIIT) elicits health benefits but it is unclear how HIIT impacts sedentary behaviour. In this preliminary study, we compared the effects of supervised HIIT or moderate-intensity continuous training (MICT) on sedentary time in overweight/obese adults. In both groups, percentage of time spent in sedentary activities was significantly reduced during the supervised exercise intervention (time main effect, P = 0.03), suggesting that both HIIT and MICT replaced time spent previously being sedentary. PMID- 29414245 TI - Bifunctional fusion proteins containing the sequence of the bradykinin homologue maximakinin: activities at the rat bradykinin B2 receptor. AB - To support bradykinin (BK) B2 receptor (B2R) detection and therapeutic stimulation, we developed and characterized fusion proteins consisting of the BK homolog maximakinin (MK), or variants, positioned at the C-terminus of functional proteins (enhanced green fluorescent protein (EGFP), the peroxidase APEX2, or human serum albumin (HSA)). EGFP-MK loses its reactivity with anti-BK antibodies and molecular mass as it progresses in the endosomal tract of cells expressing rat B2Rs (immunoblots, epifluorescence microscopy). APEX2-(NG)15-MK is a bona fide agonist of the rat, but not of the human B2R (calcium and c-Fos signaling) and is compatible with the cytochemistry reagent TrueBlue (microscopy), a luminol based reagent, or 3,3',5,5'-tetramethylbenzidine (luminescence or colourimetric B2R detection, cell well plate format). APEX2-(NG)15-MK is a non-isotopic ligand suitable for drug discovery via binding competition. Affinity-purified secreted forms of HSA fused with peptides possessing the C-terminal MK or BK sequence failed to stimulate the rat B2R in the concentration range of 50-600 nmol/L. However, the non-secreted construction myc-HSA-MK is a B2R agonist, indicating that protein denaturation made the C-terminal sequence available for receptor binding. Fusion protein ligands of the B2R are stable but subjected to slow intracellular inactivation, strong species specificity, and possible steric hindrance between the receptor and large proteins. PMID- 29414246 TI - Perspectives from a Pathologist: My Journey on the Path to Women's Health Research, Sex and Gender Policy, and Practice Implications. AB - These words reflect my recollections of major transition points in my life and career: as I first became dedicated to becoming a physician, being introduced to the field of pathology and research, and then transitioning to a somewhat different career focus by becoming the first director of the National Institutes of Health Office of Research on Women's Health. Many of the experiences that I gained during my years in pathology served me well as I made efforts to establish women's health research and sex and gender based studies as scientific endeavors. Participating in research and teaching as an academic pathologist, setting funding priorities, and supporting and encouraging research careers through governmental office programs have been the essence of my more than 50 years as a pathologist and physician. PMID- 29414247 TI - Intrinsic Neuronal Stress Response Pathways in Injury and Disease. AB - From injury to disease to aging, neurons, like all cells, may face various insults that can impact their function and survival. Although the consequences are substantially dictated by the type, context, and severity of insult, distressed neurons are far from passive. Activation of cellular stress responses aids in the preservation or restoration of nervous system function. However, stress responses themselves can further advance neuropathology and contribute significantly to neuronal dysfunction and neurodegeneration. Here we explore the recent advances in defining the cellular stress responses within neurodegenerative diseases and neuronal injury, and we emphasize axonal injury as a well-characterized model of neuronal insult. We highlight key findings and unanswered questions about neuronal stress response pathways, from the initial detection of cellular insults through the underlying mechanisms of the responses to their ultimate impact on the fates of distressed neurons. PMID- 29414248 TI - Epithelial Mesenchymal Transition in Tumor Metastasis. AB - Metastasis is the major cause of cancer-related deaths; therefore, the prevention and treatment of metastasis are fundamental to improving clinical outcomes. Epithelial mesenchymal transition (EMT), an evolutionarily conserved developmental program, has been implicated in carcinogenesis and confers metastatic properties upon cancer cells by enhancing mobility, invasion, and resistance to apoptotic stimuli. Furthermore, EMT-derived tumor cells acquire stem cell properties and exhibit marked therapeutic resistance. Given these attributes, the complex biological process of EMT has been heralded as a key hallmark of carcinogenesis, and targeting EMT pathways constitutes an attractive strategy for cancer treatment. However, demonstrating the necessity of EMT for metastasis in vivo has been technically challenging, and recent efforts to demonstrate a functional contribution of EMT to metastasis have yielded unexpected results. Therefore, determining the functional role of EMT in metastasis remains an area of active investigation. Studies using improved lineage tracing systems, dynamic in vivo imaging, and clinically relevant in vivo models have the potential to uncover the direct link between EMT and metastasis. This review focuses primarily on recent advances in and emerging concepts of the biology of EMT in metastasis in vivo and discusses future directions in the context of novel diagnostic and therapeutic opportunities. PMID- 29414249 TI - Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches based on a profound understanding of its pathogenesis to halt disease progression to advanced fibrosis or cirrhosis and cancer. The pathogenesis of NAFLD involves a complex interaction among environmental factors (i.e., Western diet), obesity, changes in microbiota, and predisposing genetic variants resulting in a disturbed lipid homeostasis and an excessive accumulation of triglycerides and other lipid species in hepatocytes. Insulin resistance is a central mechanism that leads to lipotoxicity, endoplasmic reticulum stress, disturbed autophagy, and, ultimately, hepatocyte injury and death that triggers hepatic inflammation, hepatic stellate cell activation, and progressive fibrogenesis, thus driving disease progression. In the present review, we summarize the currently available data on the pathogenesis of NAFLD, emphasizing the most recent advances. A better understanding of NAFLD/NASH pathogenesis is crucial for the design of new and efficient therapeutic interventions. PMID- 29414250 TI - Desmosomes in Human Disease. AB - Tissue integrity is crucial for maintaining the homeostasis of living organisms. Abnormalities that affect sites of cell-cell contact can cause a variety of debilitating disorders. The desmosome is an essential cell-cell junctional protein complex in tissues that undergo stress, and it orchestrates intracellular signal transduction. Desmosome assembly and junctional integrity are required to maintain the overall homeostasis of a tissue, organ, and organism. This review discusses the desmosome and the human diseases associated with its disruption. PMID- 29414251 TI - Pathogenesis of Peripheral T Cell Lymphoma. AB - Peripheral T cell lymphomas (PTCLs) are highly heterogeneous tumors, displaying distinct clinical and biological features. The pathogenesis and normal counterpart of such entities have been elusive for decades. Recent studies have, however, disclosed key mechanisms of peripheral T cell transformation, including (a) the deregulation of signaling pathways controlling T cell development, differentiation, and maturation; (b) the remodeling of the peritumor microenvironment; and (c) the virus-mediated rewiring of T cell biology. Uncovering the molecular mechanisms of T cell transformation will help elucidate the peculiar clinical and pathological features of each PTCL entity and will lead to the characterization of novel antitumor therapies. These therapies will combine conventional and new-generation compounds with immune-modulating agents to ablate both the neoplastic cells and the tumor-supporting microenvironment. This review addresses the pathogenic mechanisms of PTCLs, with special attention paid to novel therapeutic strategies for the clinical management of such aggressive tumors. PMID- 29414252 TI - Heart Failure with Preserved Ejection Fraction. AB - Heart failure (HF) is a clinical syndrome of diverse etiologies and can be associated with preserved, reduced, or mid-range ejection fraction (EF). In the community, heart failure with preserved ejection fraction (HFpEF) is emerging as the most common form of HF. There remains considerable uncertainty regarding its pathogenesis, diagnosis, and optimal therapeutic approach. Hypotheses have been advanced to explain the underlying pathophysiology responsible for HFpEF, but to date, no specific therapy based on these hypotheses has been proven to improve outcomes in HFpEF. We provide a clinically focused review of the epidemiology, clinical presentation, diagnostic approach, pathophysiology, and treatment of HFpEF. PMID- 29414254 TI - What Metrics Accurately Reflect Surgical Quality? AB - Surgeons are increasingly under pressure to measure and improve their quality. While there is broad consensus that we ought to track surgical quality, there is far less agreement about which metrics matter most. This article reviews the important statistical concepts of case mix and chance as they apply to understanding the observed wide variation in surgical quality. We then discuss the benefits and drawbacks of current measurement strategies through the framework of structure, process, and outcomes approaches. Finally, we describe emerging new metrics, such as video evaluation and network optimization, that are likely to take on an increasingly important role in the future of measuring surgical quality. PMID- 29414253 TI - Recombinant Poliovirus for Cancer Immunotherapy. AB - Mechanisms to elicit antiviral immunity, a natural host response to viral pathogen challenge, are of eminent relevance to cancer immunotherapy. "Oncolytic" viruses, naturally existing or genetically engineered viral agents with cell type specific propagation in malignant cells, were ostensibly conceived for their tumor cytotoxic properties. Yet, their true therapeutic value may rest in their ability to provoke antiviral signals that engage antitumor immune responses within the immunosuppressive tumor microenvironment. Coopting oncolytic viral agents to instigate antitumor immunity is not an easy feat. In the course of coevolution with their hosts, viruses have acquired sophisticated strategies to block inflammatory signals, intercept innate antiviral interferon responses, and prevent antiviral effector responses, e.g., by interfering with antigen presentation and T cell costimulation. The resulting struggle of host innate inflammatory and antiviral responses versus viral immune evasion and suppression determines the potential for antitumor immunity to occur. Moreover, paradigms of early host:virus interaction established in normal immunocompetent organisms may not hold in the profoundly immunosuppressive tumor microenvironment. In this review, we explain the mechanisms of recombinant nonpathogenic poliovirus, PVSRIPO, which is currently in phase I clinical trials against recurrent glioblastoma. We focus on an unusual host:virus relationship defined by the simple and cytotoxic replication strategy of poliovirus, which generates inflammatory perturbations conducive to tumor antigen-specific immune priming. PMID- 29414255 TI - Impact of the SPRINT Trial on Hypertension Management. AB - The Systolic Blood Pressure Intervention Trial is the first large prospective randomized controlled trial to demonstrate the benefit of an intensive systolic blood pressure (SBP) treatment target (<120 mm Hg) compared to a standard target (<140 mm Hg) in reducing cardiovascular morbidity and mortality and all-cause mortality in high-risk hypertensive patients. The impact of SPRINT on hypertension treatment has been large, but major questions remain about the feasibility of achieving the SPRINT intensive SBP target in routine practice, the generalizability of the SPRINT findings to hypertensive populations that were excluded from the trial, and the cost effectiveness of adopting the SPRINT intensive treatment goal. In this review, we discuss the generalizability of SPRINT data to the general population of adults with hypertension and with various comorbidities, the cost effectiveness of intensive SBP-lowering therapy, and the implications of SPRINT for future hypertension guideline development and clinical practice. PMID- 29414256 TI - Updated Recommendations for Athletes with Heart Disease. AB - Professional society recommendations to decrease sudden cardiac death in athletes, including eligibility requirements with disqualification for athletes with diagnosed disease as well as preparticipation screening and emergency preparedness, were updated in 2015. The update includes new sections on aortic disease, channelopathies, and sickle cell trait, as well as a change in format from the previous binary yes/no format to the more nuanced and contemporary "class and level of evidence" format. Eighty-four of the 246 recommendations now carry Class II designation-"reasonable," or "may be considered." New language in the document emphasizes counseling as part of the decision process. New data on athletes with implantable cardioverter-defibrillators, and on those with long QT syndrome, have led to a change from blanket restriction of competitive sports participation to a Class IIB "may be considered" recommendation. PMID- 29414257 TI - New Therapeutic Approaches for Familial Hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is a common genetic condition characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), premature atherosclerotic cardiovascular disease, and considerable unmet medical need with conventional LDL-C-lowering therapies. Between 2012 and 2015, the US Food and Drug Administration approved four novel LDL-C-lowering agents for use in patients with FH based on the pronounced LDL-C-lowering efficacy of these medicines. We review the four novel approved agents, as well as promising LDL-C-lowering agents in clinical development, with a focus on their mechanism of action, efficacy in FH cohorts, and safety. PMID- 29414258 TI - Common Cardiovascular Complications of Cancer Therapy: Epidemiology, Risk Prediction, and Prevention. AB - There is growing awareness of the overlap between oncologic and cardiovascular (CV) diseases, including a wide range of CV effects of anticancer therapies. As novel anticancer therapeutics become available and cancer survival outcomes improve, the CV implications of cancer therapy become increasingly important. In addition to outlining the CV effects of commonly used cancer therapies and their consequences for long-term survivorship, this review highlights the recent efforts to improve the risk prediction and prevention of CV toxicity through the evaluation of sensitive measures for early toxicity detection and the implementation of cardioprotective strategies. PMID- 29414259 TI - CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions. AB - Antigen-specific CD8 T cells are central to the control of chronic infections and cancer, but persistent antigen stimulation results in T cell exhaustion. Exhausted CD8 T cells have decreased effector function and proliferative capacity, partly caused by overexpression of inhibitory receptors such as programmed cell death (PD)-1. Blockade of the PD-1 pathway has opened a new therapeutic avenue for reinvigorating T cell responses, with positive outcomes especially for patients with cancer. Other strategies to restore function in exhausted CD8 T cells are currently under evaluation-many in combination with PD 1-targeted therapy. Exhausted CD8 T cells comprise heterogeneous cell populations with unique differentiation and functional states. A subset of stem cell-like PD 1+ CD8 T cells responsible for the proliferative burst after PD-1 therapy has been recently described. A greater understanding of T cell exhaustion is imperative to establish rational immunotherapeutic interventions. PMID- 29414260 TI - Computed Tomography Scanning for Early Detection of Lung Cancer. AB - Parallel and often unrelated developments in health care and technology have all been necessary to bring about early detection of lung cancer and the opportunity to decrease mortality from lung cancer through early detection of the disease by computed tomography. Lung cancer screening programs provide education for patients and clinicians, support smoking cessation as primary prevention for lung cancer, and facilitate health care for tobacco-associated diseases, including cardiovascular and chronic lung diseases. Guidelines for lung cancer screening will need to continue to evolve as additional risk factors and screening tests are developed. Data collection from lung cancer screening programs is vital to the further development of fiscally responsible guidelines to increase detection of lung cancer, which may include small groups with elevated risk for reasons other than tobacco exposure. PMID- 29414261 TI - The Affordable Care Act: What's Next? AB - The postelection efforts to repeal, replace, or modify the Affordable Care Act (ACA) suggest that the debate over healthcare coverage will remain contentious, particularly because of the high and rising cost of health care. Feasible, potentially bipartisan approaches to improving access to coverage should emphasize reforming health care to achieve higher quality at a lower cost. In the individual market, where many enrollees face limited options and rising premiums, a combination of high-risk pools, reinsurance, and risk adjustment could improve coverage options while encouraging innovations in care for the highest-risk patients. State Medicaid programs, which are increasingly important sources of coverage but are crowding out other important budget priorities that affect population health, could achieve better results through federal reforms that provide more flexibility for states alongside greater emphasis on achieving better outcomes. Accelerating payment reforms and other policy changes to encourage more innovative and efficient care delivery models, along with developing better evidence on successful models, can also improve the prospects for coverage reform. PMID- 29414262 TI - Antibody-Drug Conjugates for Cancer Treatment. AB - The concept of exploiting the specific binding properties of monoclonal antibodies as a mechanism for selective delivery of cytotoxic agents to tumor cells is an attractive solution to the challenge of increasing the therapeutic index of cell-killing agents for treating cancer. All three parts of an antibody drug conjugate (ADC)-the antibody, the cytotoxic payload, and the linker chemistry that joins them together-as well as the biologic properties of the cell surface target antigen are important in designing an effective anticancer agent. The approval of brentuximab vedotin in 2011 for treating relapsed Hodgkin's lymphoma and systemic anaplastic large cell lymphoma, and the approval of ado trastuzumab emtansine in 2013 for treating HER2-positive metastatic breast cancer, have sparked vigorous research in the field, with >65 ADCs currently in clinical evaluation. This review highlights the ADCs that are approved for marketing, in pivotal clinical trials, or in at least phase II clinical development for treating both hematologic malignancies and solid tumors. PMID- 29414263 TI - Measuring Patient-Reported Outcomes: Key Metrics in Reconstructive Surgery. AB - Satisfaction and improved quality of life are among the most important outcomes for patients undergoing plastic and reconstructive surgery for a variety of diseases and conditions. Patient-reported outcome measures (PROMs) are essential tools for evaluating the benefits of newly developed surgical techniques. Modern PROMs are being developed with new psychometric approaches, such as Rasch Measurement Theory, and their measurement properties (validity, reliability, responsiveness) are rigorously tested. These advances have resulted in the availability of PROMs that provide clinically meaningful data and effectively measure functional as well as psychosocial outcomes. This article guides the reader through the steps of creating a PROM and highlights the potential research and clinical uses of such instruments. Limitations of PROMs and anticipated future directions in this field are discussed. PMID- 29414264 TI - Risk Stratification for Sudden Cardiac Death After Myocardial Infarction. AB - Sudden cardiac death (SCD) accounts for ~50% of mortality after myocardial infarction (MI). Most SCDs result from ventricular tachyarrhythmias, and the tachycardias that precipitate cardiac arrest result from multiple mechanisms. As a result, it is highly unlikely that any single test will identify all patients at risk for SCD. Current guidelines for use of implantable cardioverter defibrillators (ICDs) to prevent SCD are based primarily on measurement of left ventricular ejection fraction (LVEF). Although reduced LVEF is associated with increased total cardiac mortality after MI, the focus of current guidelines on LVEF omits ~50% of patients who die suddenly. In addition, there is no evidence of a mechanistic link between reduced LVEF and arrhythmias. Thus, LVEF is neither sensitive nor specific as a tool for post-MI risk stratification. Newer tests to screen for predisposition to ventricular arrhythmias and SCD examine abnormalities of ventricular repolarization, autonomic nervous system function, and electrical heterogeneity. These tests, as well as older methods such as programmed stimulation, the signal-averaged electrocardiogram, and spontaneous ventricular ectopy, do not perform well in patients with LVEF <=30%. Recent observational studies suggest, however, that these tests may have greater utility in patients with LVEF >30%. Because SCD results from multiple mechanisms, it is likely that combinations of risk factors will prove more precise for risk stratification. Prospective trials that evaluate the performance of risk stratification schema to determine ICD use are necessary for cost-effective reduction of the incidence of SCD after MI. PMID- 29414266 TI - Branchial-Cleft Sinus Manifesting as Recurrent Neck Abscess. PMID- 29414265 TI - New Molecular Diagnostic Approaches to Bacterial Infections and Antibacterial Resistance. AB - Recent advances in the field of infectious disease diagnostics have given rise to a number of host- and pathogen-centered diagnostic approaches. Most diagnostic approaches in contemporary infectious disease focus on pathogen detection and characterization. Host-focused diagnostics have recently emerged and are based on detecting the activation of biological pathways that are highly specific to the type of infecting pathogen (e.g., viral, bacterial, protozoan, fungal). Although this progress is encouraging, it is unlikely that any single diagnostic platform will fully address the clinician's need for actionable data with short turnaround times in all settings. PMID- 29414267 TI - Single-Dose Cholera Vaccine in Response to an Outbreak in Zambia. PMID- 29414268 TI - Alpha-Adrenergic Receptors in PTSD - Failure or Time for Precision Medicine? PMID- 29414269 TI - ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes. PMID- 29414270 TI - Nutritional Management of Chronic Kidney Disease. PMID- 29414271 TI - Herpetic Whitlow. PMID- 29414273 TI - Acute Graft-versus-Host Disease. PMID- 29414274 TI - Maternal Health in the United States. PMID- 29414272 TI - Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans. AB - BACKGROUND: In randomized trials, prazosin, an alpha1-adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans. METHODS: We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 ("recurrent distressing dreams"; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change). RESULTS: A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between-group difference, 0.2; 95% confidence interval [CI], 0.3 to 0.8; P=0.38), in the mean change in PSQI score (between-group difference, 0.1; 95% CI, -0.9 to 1.1; P=0.80), or in the CGIC score (between-group difference, 0; 95% CI, -0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo. CONCLUSIONS: In this trial involving military veterans who had chronic PTSD, prazosin did not alleviate distressing dreams or improve sleep quality. (Funded by the Department of Veterans Affairs Cooperative Studies Program; PACT ClinicalTrials.gov number, NCT00532493 .). PMID- 29414275 TI - The Judicial Threat to Public Health Innovation - The Sword of Boreali. PMID- 29414276 TI - Case 4-2018: A Newborn with Thrombocytopenia, Cataracts, and Hepatosplenomegaly. PMID- 29414277 TI - Post-Transplantation Lymphoproliferative Disorders in Adults. PMID- 29414278 TI - Effects of Spaceflight on Astronaut Brain Structure. PMID- 29414279 TI - Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy. AB - BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) causes the debilitating neuroinflammatory disease HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP) as well as adult T-cell leukemia-lymphoma (ATLL). In patients with HAM-TSP, HTLV-1 infects mainly CCR4+ T cells and induces functional changes, ultimately causing chronic spinal cord inflammation. We evaluated mogamulizumab, a humanized anti-CCR4 monoclonal antibody that targets infected cells, in patients with HAM-TSP. METHODS: In this uncontrolled, phase 1-2a study, we assessed the safety, pharmacokinetics, and efficacy of mogamulizumab in patients with glucocorticoid-refractory HAM-TSP. In the phase 1 dose-escalation study, 21 patients received a single infusion of mogamulizumab (at doses of 0.003 mg per kilogram of body weight, 0.01 mg per kilogram, 0.03 mg per kilogram, 0.1 mg per kilogram, or 0.3 mg per kilogram) and were observed for 85 days. Of those patients, 19 continued on to the phase 2a study and received infusions, over a period of 24 weeks, of 0.003 mg per kilogram, 0.01 mg per kilogram, or 0.03 mg per kilogram at 8-week intervals or infusions of 0.1 mg per kilogram or 0.3 mg per kilogram at 12-week intervals. RESULTS: The side effects of mogamulizumab did not limit administration up to the maximum dose (0.3 mg per kilogram). The most frequent side effects were grade 1 or 2 rash (in 48% of the patients) and lymphopenia and leukopenia (each in 33%). The dose-dependent reduction in the proviral load in peripheral-blood mononuclear cells (decrease by day 15 of 64.9%; 95% confidence interval [CI], 51.7 to 78.1) and inflammatory markers in cerebrospinal fluid (decrease by day 29 of 37.3% [95% CI, 24.8 to 49.8] in the CXCL10 level and of 21.0% [95% CI, 10.7 to 31.4] in the neopterin level) was maintained with additional infusions throughout the phase 2a study. A reduction in spasticity was noted in 79% of the patients and a decrease in motor disability in 32%. CONCLUSIONS: Mogamulizumab decreased the number of HTLV-1-infected cells and the levels of inflammatory markers. Rash was the chief side effect. The effect of mogamulizumab on clinical HAM-TSP needs to be clarified in future studies. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare; UMIN trial number, UMIN000012655 .). PMID- 29414281 TI - Errata. PMID- 29414280 TI - Errata. PMID- 29414282 TI - Errata. PMID- 29414283 TI - Beneficial effect of plasma exchange in acute attack of neuromyelitis optica spectrum disorders. AB - BACKGROUND: Plasma exchange (PLEX) is routinely performed in neuromyelitis optica spectrum disorders (NMOSD) patients with an acute attack who do not respond to corticosteroids treatment. OBJECTIVE: To compare treatment outcomes in NMOSD patients with an acute attack between the two groups. METHODS: We retrospectively studied 67 attacks from 52 NMOSD patients. Outcome measurements using Expanded Disability Status Scale (EDSS), modified Rankin Scale (mRS) were compared. RESULTS: There were 23 IVMP responders, 16 IVMP non-responders refusing PLEX, 12 IVMP non-responders/PLEX responders, and 16 IVMP/PLEX non-responders. The IVMP responders showed faster improvement since the time of discharge but seemed to have less treatment benefit over time. However, IVMP non-responders/PLEX responders showed continuous and maximum improvement at 6 months (DeltaEDSS from nadir: 1 for IVMP-responders vs 0.5 for IVMP non-responders without PLEX vs 2.75 IVMP non-responders/PLEX-responders vs 0.5 IVMP/PLEX non-responders; p = 0.49) and had comparable outcomes to the IVMP-responders (nadir EDSS 8.0 to 5.25 [DeltaEDSS = 2.75] vs nadir EDSS 6.5 to 5.0; [DeltaEDSS = 1.5], respectively). CONCLUSION: Add - on PLEX treatment in NMOSD patients with an acute attack should be considered in those not responding to IVMP alone. PMID- 29414284 TI - Relationship between Social Cognition and traditional cognitive impairment in Progressive Multiple Sclerosis and possible implicated neuroanatomical regions. AB - BACKGROUND: Cognitive impairment is a relevant contributor of the medical and social burden in Progressive MS. Social Cognition, the neurocognitive processes underlying social interaction, has been explored mainly in European and North American cohorts, influencing social aspects of quality of life (QOL) of early MS patients and families. Few studies have studied Social Cognition in Progressive MS and the literature on its neuroanatomical bases or brain atrophy measurements is still scarce. OBJECTIVES: To explore the relationship between Social Cognition performance and its correlations with traditional cognitive domains, brain atrophy and QOL in primary and secondary Progressive MS patients. METHODS: Cross sectional analysis including: mini-Social-Cognition-and-Emotional-Assessment (mini-SEA), neuropsychological battery, disability, depression, fatigue, QOL, and brain volume. RESULTS: Forty-three MS patients, 23 primary and 20 secondary Progressive, 65% women, mean age and disease duration of 57.2 and 15.7 years, respectively, with high levels of disability (median EDSS 6.0) and a widespread impairment in traditional domains (mostly episodic verbal/visual and working memories) were assessed. The Mini-SEA score was correlated with executive functions (cognitive shifts Rho:0.55; p = 0.001) analyzing the whole group, and with visual episodic memory (Rho:0.58, p = 0.009) in the primary Progressive MS group. Mini-SEA score was also correlated with total normalized grey matter volume (Rho:0.48; p = 0.004). Particularly, atrophy within bilateral cortical regions of orbitofrontal, insula and cerebellum, and right regions of fusiform gyrus and precuneus were significantly associated with higher Social Cognition impairment. In this cohort, QOL was not correlated with Social Cognition, but with EDSS, fatigue and depression. CONCLUSIONS: In Progressive MS, Social Cognition is directly correlated with traditional cognitive domains such as executive function and episodic memory. It is also associated with global grey matter atrophy and regional atrophy within associative visual and executive cortical areas, but no correlations with QOL were found in this cohort. These findings may contribute to the understanding of the pathological bases behind Social Cognition in Progressive MS. PMID- 29414285 TI - Digital epidemiology confirms a latitude gradient of MS in France. AB - BACKGROUND: A gradient of prevalence of MS has been previously reported, and this may be due to different environmental and genetic features of the different populations, but also to methodological issues. In France, for example, three studies analysed the presence of such a gradient with conflicting results. The aim of this study was to assess whether digital epidemiology could confirm the presence of such a gradient. METHODS: through Google Trends, we analysed the relative search volume (RSV) for 'multiple sclerosis' in France, from 2004 to 2017, and assessed if an association with the decimal degree of latitude existed. RESULTS: Latitude was correlated with crude RSV (r2 0.39, p 0.04) in the 21 regions considered, with a southwest/northeast gradient. A multiple linear regression model adjusted for sex and age confirmed the existence of such a latitudinal effect, with an increase of 2.43 RSV units for each unit increase in latitude (95% CIs 0.62-4.24, p < 0.01, adjusted r2 0.61). CONCLUSIONS: our study provides additional evidence for the existence of a latitude gradient in MS, and the value of Internet-acquired data as real-time surveillance tools and alerts for healthcare systems. PMID- 29414286 TI - A longitudinal study of JC virus serostatus stability among multiple sclerosis patients. AB - BACKGROUND: Anti-JC virus (JCV) antibody testing has been used increasingly to stratify multiple sclerosis (MS) patients into different disease modifying therapies. OBJECTIVES: We assessed JCV serostatus stability longitudinally in MS patients who were regularly tested for anti-JCV antibody and examined the demographic and clinical factors associated with JCV serostatus. METHODS: The data of MS patients who were screened for anti-JCV antibody using the two-step second-generation ELISA were collected between 1st October 2014 and 31st October 2015 at the MS clinic, Kuwait. Demographics, disease characteristics and JCV serostatus, including antibody index (AI), were obtained for patients with at least 12-months of follow-up results. Stable JCV serostatus was defined as anti JCV antibody status that remained consistently negative or positive throughout the observation period. A change in serostatus was confirmed by a follow-up test at 6 months. Patients were labeled as JCV seroconverters (negative to positive), JCV seroreverters (positive to negative) or intermittently seropositive. RESULTS: This study included 168 MS patients with anti-JCV antibody results for at least 1 year. Mean age and mean disease duration were 33.4 +/- 9.8 and 8.1 +/- 5.6 years respectively. In this cohort, 94% (n = 158) patients received natalizumab treatment with a mean of 27.2 +/- 13.8 infusions. JCV stable serostatus (positive or negative) was observed in 84.5% (n = 142) with a mean follow-up duration of 23.8 +/- 7.0 months. In this longitudinal study, relatively high frequencies of seroconverters (11.5%), intermittently seropositive (9.7%) and seroreverters (3.6%) were recorded. Age, gender, disease duration and number of natalizumab infusions did not influence JCV serostatus stability. JCV seroconversion risk was low with persistent AI < 0.9 beyond 18 months of initial testing. CONCLUSION: Anti-JCV antibody index at baseline predicted stable negative as well as stable positive JCV serostatus over the observational period. The AI < 0.9 appeared to have a significant implication in the longitudinal stability of JCV AI in patients who were intermittently seropositive. PMID- 29414287 TI - Symbol Digit Modalities Test adaptation for Magnetic Resonance Imaging environment: A systematic review and meta-analysis. AB - BACKGROUND: The Symbol Digit Modalities Test (SDMT) is widely used for cognitive evaluation of information processing speed (IPS), required in many cognitive operations. Despite being unspecific for different neurological disorders, it is sensitive to assess impaired performance related to stroke, Parkinson's disease, traumatic brain injury, and multiple sclerosis. However, in addition to evaluate the presence and severity of IPS impairment, it is of interest to determine the localization and integration of brain regions responsible for the functions assessed by the SDMT. OBJECTIVE: To review the studies that adapted the SDMT to the magnetic resonance environment and obtain the brain areas associated with the performance of the task in healthy subjects with a meta-analysis. METHODOLOGY: A systematic review was performed using ten studies published between 1990 and 2017, and selected from four databases. All studies included participants of both genders and age between 18 and 50 years, used Functional Magnetic Resonance Imaging (fMRI) and SDMT adaptation and reported brain regions associated with the task. Six of them also reported the region coordinates in a standard space, so they were included in a meta-analysis. Activation Likelihood Estimation algorithm, with significance for p < 0.05 corrected for multiple comparisons, was used to identify areas that are robustly related to the performance of the SDMT. RESULTS: The areas predominantly reported in the studies of our meta-analysis were regions of the frontoparietal attentional network and occipital cortex, as well as cuneus, precuneus, and cerebellum. Individually all regions that survived the statistical threshold are consistent with what is expected after reviewing prospective studies. CONCLUSIONS: The present study allowed the identification of brain areas activated during the performance of the SDMT in healthy subjects, and therefore it will help understanding the differences in brain activation by this task in clinical populations. Moreover, it may guide future studies of therapeutic strategies and interventions in those populations. PMID- 29414289 TI - Neuromyelitis optica and neuromyelitis optica like spectrum disorders: Is it not the time to change the criteria? PMID- 29414288 TI - Comparison of myelin oligodendrocyte glycoprotein (MOG)-antibody disease and AQP4 IgG-positive neuromyelitis optica spectrum disorder (NMOSD) when they co-exist with anti-NMDA (N-methyl-D-aspartate) receptor encephalitis. AB - BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG)-antibody (ab) disease and AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) can co-exist with anti-NMDA (N-methyl-D-aspartate) receptor encephalitis (NMDARe). OBJECTIVES: To characterize MOG-ab disease and AQP4-IgG-positive NMOSD during NMDARe. METHODS: We analyzed all the patients with overlapping MOG-ab disease and NMDARe (MNOS) and patients with AQP4-IgG-positive NMOSD and NMDARe (ANOS) in our hospital and compared those data with data from systematically review of previously published reports. RESULTS: In our cohorts, 11.9% patients with MOG-ab disease and 0.6% patients with NMOSD had overlapping NMDARe (P < 0.01). After treatment with steroids and/or intravenous immunoglobulin (IVIg), the median modified Rankin Scale (mRS) of the MNOS group decreased significantly during attacks associated with or without NMDARe (P < 0.01 for both), while that of the ANOS group did not (attack: P < 0.05; attack associated with NMDARe: P > 0.05). Analyzed together with previously reported cases, 6% patients with MNOS and 40% patients with ANOS also used rituximab or cyclophosphamide after steroids and/or IVIg (P < 0.05) during attacks associated with NMDARe. CONCLUSION: Compared with NMOSD, MOG-ab disease may more commonly co-exist with NMDARe. MNOS patients respond better to steroids and IVIg than do ANOS patients during attacks associated with NMDARe. PMID- 29414290 TI - Correlation between the corpus callosum index and brain atrophy, lesion load, and cognitive dysfunction in multiple sclerosis. AB - BACKGROUND: The corpus callosum index (CCI) can be easily and reliably obtained from conventional magnetic resonance imaging (MRI) and has been proposed as a possible marker of brain atrophy in MS. However, further validation of its correlation with volumetric measurements is still warranted. OBJECTIVE: To assess the correlation of the CCI with the corpus callosum volume (CCV), brain and lesion volumes, and level of disability in MS. METHODS: Cross-sectional, exploratory study including patients with relapsing-remitting MS. Clinical assessment comprised of physical and cognitive disability scales. MRI parameters included conventional volumetric measurements, the CCI (manual), and the CCV (automated). RESULTS: Twenty-four patients were included. There was a strong correlation between the CCI and CCV. The CCI correlated strongly with the white matter and lesion volumes, and moderately with the whole brain volume and scores on the Paced Auditory Serial Addition Test and MS Functional Composite. There were no correlations between the CCI and either gray matter volume or scores on the Expanded Disability Status Scale, the 9-Hole Peg Test, or the Timed 25-Foot Walk test. CONCLUSION: The findings support the validity of the CCI as an easy-to obtain marker of brain atrophy, lesion load, and cognitive dysfunction in patients with MS. PMID- 29414291 TI - A cerebral phenotype of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids: A case report and review of the literature. AB - CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is an inflammatory central nervous system disorder that gives rise to brainstem symptoms such as diplopia and articulatory disorders. It shows characteristic "salt-and-pepper" enhancing brainstem lesions on magnetic resonance imaging (MRI) scans. We present an unusual case of CLIPPERS, in which a 29-year-old man initially presented with a seizure. Brain MRI revealed faint open ring enhancements in the right frontal lobe, and a brain biopsy was performed to make a definitive diagnosis. Immunohistological tests showed perivascular infiltration by primarily CD3- and CD20-positive cells, albeit including a few CD68-positive cells, which confirmed a diagnosis of CLIPPERS. Both the symptoms and the MRI findings were markedly improved by 3 courses of steroid (methylprednisolone) pulse therapy, followed by oral steroid (prednisolone) administration. This case shows that CLIPPERS can present as a phenotype of cortical lesions and seizures as the first signs. A brain biopsy should therefore be actively carried out for differential diagnosis, especially when other, cortically based inflammatory disorders are suspected. PMID- 29414292 TI - Uncovering the link between reproductive factors and multiple sclerosis: A case control study on Iranian females. AB - BACKGROUND: Increase of MS prevalence in females compared to males, especially in reproductive age, highlights the important role of reproductive factors in MS pathology. OBJECTIVES: We examined the association between females' reproductive age-related factors and MS risk. METHODS: A case-control study including 399 cases and 541 controls was carried out. The adjusted associations between MS risk and reproductive variables including age at menarche, oral contraceptive pills (OCPs) use history, OCP usage duration and age at first use, history of assisted reproductive technologies (ARTs) use, parity history, age at first childbirth and the number of parities, abortion and exclusive breast feeding > 2 months were assessed. RESULTS: We found protective relationships between MS and older age at menarche (OR = 0.90 {95% CI = 0.82-0.98}), ART use history (OR = 0.45 {95% CI = 0.21-0.99}), older maternal age at first childbirth (OR = 0.94{95% CI = 0.89 - 0.99}) and higher number of parities(OR = 0.61 {95% CI = 0.49 - 0.75), whereas using OCPs was associated with higher risk of developing MS (OR = 1.80 {95% CI = 1.35-2.41}). CONCLUSIONS: Links were noted between a number of reproductive factors and risk of MS. PMID- 29414293 TI - Physical activity and disability outcomes in multiple sclerosis: A systematic review (2011-2016). AB - BACKGROUND: Physical activity may be neuroprotective in multiple sclerosis (MS). One review (2011) of exercise and MS disability was inconclusive, but highlighted the need for more studies. OBJECTIVE: To perform an updated systematic literature review examining the relationship between physical activity and physical ability outcomes in persons with MS. METHODS: EMBASE and MEDLINE were searched for original interventional studies (2011-2016) evaluating exercise on quantitative outcomes of physical disability in MS. We also assessed any reported adverse outcomes. RESULTS: Of the 153 articles identified, 12 were included; 3 examined endurance training; 6 resistance training; and 3 explored less conventional exercises, specifically, tai chi, kickboxing, and vestibular rehabilitation, each lasting 5-24 weeks. In total, 568 unique individuals were included, and >10 different scales used to assess outcomes. Endurance training provided benefits in walking ability, while mindfulness exercises (tai chi and vestibular rehabilitation), and dynamic workouts (kickboxing) led to improvements in balance and coordination. Resistance training alone did not improve walking ability, but improved lower limb muscular strength and endurance. When resistance and endurance training were combined, improvements were seen in mobility, balance and coordination. Four studies assessed discontinuation; most reported a return to pre-intervention function. Adverse outcomes were reported in 6 studies, and appeared generally mild, ranging from mild muscle soreness to exacerbation of MS symptoms. CONCLUSIONS: Physical activity was associated with measurable benefits on ability outcomes, but continuation is likely required to maintain benefits. While adverse events were generally mild, approximately half of studies actually reported safety outcomes. PMID- 29414294 TI - Multiple sclerosis onset after granulocyte macrophage colony-stimulating factor withdrawal. AB - A 51-year old woman with stage III melanoma participated in a phase II clinical trial in which she received subcutaneous rhGM-CSF injections for 3 years. She was in remission by the end of the trial. Seven months after discontinuing GM-CSF she had her first MS event. The unique timeline of rh-GM-CSF injections in a melanoma trial, during which yearly MRI scans showed subtle stable demyelination followed by RRMS onset shortly after discontinuation of treatment, may provide some insight on the role of GM-CSF in MS. PMID- 29414295 TI - Knee flexor strength and balance control impairment may explain declines during prolonged walking in women with mild multiple sclerosis. AB - BACKGROUND: Physiological factors such as muscle weakness and balance could explain declines in walking distance by multiple sclerosis (MS) patients. The purpose of this study was to characterize levels and examine associations among decline in walking distance, balance and muscular strength in women with mild MS. METHODS: Participants included 28 women with mild relapsing-remitting MS and 21 women without MS. We executed the 6-min walk test (6MWT) to verify declines in walking distance. Isokinetic knee flexion (KF) and extension (KE) muscle strength was measured using a dynamometer. Balance was quantified using a force platform, with eyes open and closed, on a rigid and foam surface. RESULTS: The MS patients presented declines in walking, lower KF muscle strength, and worse balance than controls. KF strength and balance correlated with walking in the MS group. The KF strength explained differences between groups in walking. The KF strength and balance presented as predictors of walking slowing down in the 6MWT, in mild MS. CONCLUSION: Women with mild MS have strength impairment of knee flexor muscles and balance control impairment that may explain walking related motor fatigability during prolonged walking. PMID- 29414296 TI - Investigating the dynamic plantar pressure distribution and loading pattern in subjects with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a complex disorder affecting subjects by multiple system impairments. Gait problems are common in subjects with MS and various factors such as; ataxia, hypertonic muscles or/and seconder musculoskeletal system deformities affect the normal plantigrade contact by disturbing accommodation of foot to the ground while walking. The aim of this study was investigating the dynamic plantar pressure distribution and time of maximum pressure in subjects with MS and determining the differences from healthy subjects (HS). METHODS: Fifty-five subjects with MS (110 foot) and 20 HS (40 foot) were the participants of the study. The dynamic pedobarograph was utilized for evaluation of dynamic loading parameters; maximum pressure (N/cm2) and time of maximum pressure (ms) collected from heel medial, heel lateral, midfoot, heads of first, second, third, fourth and fifth metatarsal bones. RESULTS: There were differences between the groups in maximum pressure of heel medial (p < .001) and heel lateral (p < .001) was higher in HS. Also, there were differences between the groups the time of maximum pressure of all metatarsal head areas, midfoot, heel medial and heel lateral (p < .001). Subjects with MS spent lesser time to reach maximum pressure for forefoot loading and longer time for hindfoot loading. CONCLUSION: The study provided basic data about foot pressure distribution and time of maximum pressure in subjects with MS. Results of the study showed that the hindfoot loading was disrupted and inappropriate timing during load transfer from hindfoot to forefoot is exist in subjects with MS. PMID- 29414297 TI - Rituximab-induced interstitial lung disease in a patient with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder. AB - Aquaporin-4 immunoglobulin G -positive neuromyelitis optica spectrum disorder (NMOSD-AQP4) is an inflammatory disease of the central nervous system that predominantly affects the optic nerves and spinal cord. Rituximab (RTX)-a monoclonal antibody to CD20 in B cells-is effective in the treatment of NMOSD. However, interstitial lung disease (ILD) is a very rare yet potentially fatal complication of RTX treatment. Here, we detail the first reported case of RTX induced ILD in a patient with NMOSD-AQP4. ILD should be suspected in patients with NMOSD undergoing RTX treatment who present with dyspnea and/or cough without any signs or symptoms of infection. PMID- 29414298 TI - Multiple sclerosis in pediatric patients in Slovenia. AB - AIM: The purpose of this study is to review the Slovenian experience with the diagnostics, treatment and outcome in pediatric multiple sclerosis (MS) patients. METHODS: Children and adolescent diagnosed with MS and followed by Department of Child, Adolescent and Developmental Neurology, University Childrens' Hospital Ljubljana, between 1 January 2000 and 31 December 2012 were included. Data from patients' documentation were analyzed retrospectively to record demographic data, clinical presentation, paraclinical findings, disability progression, relapse rate and treatment strategies. RESULTS: The study includes 38 patients up to 18 years with MS diagnosis, with female: male ratio 2.8:1 and the incidence of 0.81 per 100.000 children of 0-18 years. The mean age at the time of diagnosis was 15 years 4 months. Most frequent presenting symptoms were sensory, motor, brain stem, visual and ataxia and 65% of patients had a relapse in the first year. The value of paraclinical findings was asessed. 74% of patients with definite MS and 36% of those with clinically isolated syndrome received disease modifyng therapy and 68% of them was not affected at the follow-up. INTERPRETATION: The characteristics of pediatric MS patients in Slovenia disclose higher annual relapse rates than in adults but also favorable impact of disease modifying treatment on a clinical course. Our data suggest a good treatment tolerance but also the influence of the formulation on a decision to start or switch the treatment. PMID- 29414299 TI - Predicting falls in multiple sclerosis: Do electrophysiological measures have a better predictive accuracy compared to clinical measures? AB - BACKGROUND: The risk of falls in people with Multiple Sclerosis (MS) is much greater than that of the general population due to impaired coordination, gait, sensation, muscle tone, strength, and cognition. These MS related falls hamper the day to day living of these individuals and are one of the prime factors aggravating the disease related morbidity. The fear of falling itself may make these individuals more dependent and hinder their professional and leisurely activities. Hence, the significance of identifying individuals who are at risk of falling and instituting preventive counter-measures cannot be overemphasized. Various simple clinical tests and questionnaires have been recommended for this purpose, but are far from ideal. OBJECTIVE: The objective was to find accurate measures to predict a future fall in MS patients. We also aimed to enquire about the prevalence of falls in MS population and its clinical profile which included detailed history about the past falls, Expanded disability status scale (EDSS) scores, Timed 25 foot walk (T25FW) scores, Activities specific balance confidence (ABC) scores, Falls efficacy scale international (FESI) scores, Multiple Sclerosis Walking Scale 12 (MSWS12) questionnaire. DESIGN/METHODS: This was a prospective cohort study conducted at the Institute of Neurology, Chennai from January 2015 to August 2017. MS patients of any subtype attending Neurology OPD satisfying revised 2010 McDonald criteria were recruited. 134 subjects with MS consented to participate in this study and 113 of them who met the criteria were included. Baseline history was obtained about the number of falls in the previous year. EDSS, T25FW, ABC, FESI, and MSWS12 scores were obtained at the baseline. VEMP and SEP tests were done and the baseline P13/N23 cVEMP latencies, N10 oVEMP latency, and P37 lower limb SEP latency were obtained. These subjects were followed up for one year and were enquired if they had fallen during that period and the number of falls was recorded. Logistic regression models were used to compute the area under receiver operating characteristic curve (AUC) for each variable tested. Pearson correlation coefficients were calculated for each variable with the number of future falls. RESULTS: Among the 113 patients, 72% (n = 81) had one or more falls during follow-up. Among all variables tested P13 cervical VEMP latency had the highest predictive accuracy (AUC = 0.820) followed by N10 ocular VEMP latency (AUC = 0.794) and P37 SEP latency (AUC = 0.732). P13 latency also had the highest correlation coefficient (R = 0.689, R2 = 0.475) with the number of future falls. CONCLUSION: P13, N10 and P37 latencies were the most accurate in predicting a future fall when compared to clinical measures. PMID- 29414300 TI - Letter to the Editors - Multiple sclerosis and related disorders - Birnbaum et al., 2017. PMID- 29414302 TI - Imaging of human epidermal growth factor receptors for patient selection and response monitoring - From PET imaging and beyond. AB - The Human Epidermal Growth Factor Receptor (ErbB/HER) family - EGFR/HER1, ErbB 2/HER2, ErbB-3/HER3, and ErbB-4/HER4 - play a key role in tumor development. Moreover, positive status of HER2 and specific mutations of EGFR are necessary to initiate HER2 directed and EGFR mutation directed therapies. The status of these receptors is usually determined by assaying biopsy specimens of tumor tissues; however, tissue samples are insufficient to account for the complex dynamics and heterogeneity involved in HER status. Molecular imaging of receptors of the HER family have undergone much development, and some show promise for facilitating patient selection for HER therapy and monitoring of treatment response. This review provides a general overview of HER family expression and signaling in tumor tissue and more importantly discusses the available EGFR, HER2 and HER3 molecular imaging modalities, highlighting their use not only for selecting patients for receptor-targeted therapy, but also for monitoring therapeutic response. Additionally, the design and the biological evaluation of HER-specific imaging probes using different cancer models and clinical data are discussed. PMID- 29414301 TI - Palmatine suppresses glutamine-mediated interaction between pancreatic cancer and stellate cells through simultaneous inhibition of survivin and COL1A1. AB - Reciprocal interaction between pancreatic stellate cells (PSCs) and cancer cells (PCCs) in the tumor microenvironment (TME) promotes tumor cell survival and progression to lethal, therapeutically resistant pancreatic cancer. The goal of this study was to test the ability of Palmatine (PMT) to disrupt this reciprocal interaction in vitro and examine the underlying mechanism of interaction. We show that PSCs secrete glutamine into the extracellular environment under nutrient deprivation. PMT suppresses glutamine-mediated changes in GLI signaling in PCCs resulting in the inhibition of growth and migration while inducing apoptosis by inhibition of survivin. PMT-mediated inhibition of (glioma-associated oncogene 1) GLI activity in stellate cells leads to suppression (collagen type 1 alpha 1) COL1A1 activation. Remarkably, PMT potentiated gemcitabine's growth inhibitory activity in PSCs, PCCs and inherently gemcitabine-resistant pancreatic cancer cells. This is the first study that shows the ability of PMT to inhibit growth of PSCs and PCCs either alone or in combination with gemcitabine. These studies warrant additional investigations using preclinical models to develop PMT as an agent for clinical management of pancreatic cancer. PMID- 29414303 TI - Long noncoding RNAs in cancer cells. AB - Long noncoding RNA (lncRNA) has recently been investigated as key modulators that regulate many biological processes in human cancers via diverse mechanisms. LncRNAs can interact with macromolecules such as DNA, RNA, or protein to exert cellular effects and to act as either tumor promoters or tumor suppressors in various malignancies. Moreover, the aberrant expression of lncRNAs may be detected in multiple cancer phenotypes by employing the rapidly developing modern gene chip technology and bioinformatics analysis. Herein, we highlight the mechanisms of action of lncRNAs, their functional cellular roles and their involvement in cancer progression. Finally, we provide an overview of recent progress in the lncRNA field and future potential for lncRNAs as cancer diagnostic markers and therapeutics. PMID- 29414304 TI - Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment. AB - Hepatocellular carcinoma (HCC) commonly arises from a liver damaged by extensive inflammation and fibrosis. Various factors including cytokines, morphogens, and growth factors are involved in the crosstalk between HCC cells and the stromal microenvironment. Increasing our understanding of how stromal components interact with HCC and the signaling pathways involved could help identify new therapeutic and/or chemopreventive targets. It has become increasingly clear that the cross talk between tumor cells and host stroma plays a key role in modulating tumor growth. Emerging reports suggest a relationship between HCC and thyroid hormone signaling (dysfunction), raising the possibility that perturbed thyroid hormone (TH) regulation influences the cancer microenvironment and cancer phenotype. This review provides an overview of the role of thyroid hormone and its related pathways in HCC and, specifically, its role in regulating the tumor microenvironment. PMID- 29414306 TI - Repurposing psychiatric drugs as anti-cancer agents. AB - Cancer is a major public health problem and one of the leading contributors to the global disease burden. The high cost of development of new drugs and the increasingly severe burden of cancer globally have led to increased interest in the search and development of novel, affordable anti-neoplastic medications. Antipsychotic drugs have a long history of clinical use and tolerable safety; they have been used as good targets for drug repurposing. Being used for various psychiatric diseases for decades, antipsychotic drugs are now reported to have potent anti-cancer properties against a wide variety of malignancies in addition to their antipsychotic effects. In this review, an overview of repurposing various psychiatric drugs for cancer treatment is presented, and the putative mechanisms for the anti-neoplastic actions of these antipsychotic drugs are reviewed. PMID- 29414307 TI - Microemulsion containing triamcinolone acetonide for buccal administration. AB - The aim of the present work was to investigate the potential of microemulsions for the buccal administration of triamcinolone acetonide. Microemulsions were developed by the construction of pseudoternary phase diagrams, using the aqueous titration method. Among all microemulsions prepared and tested for stability, three were selected and submitted to characterization and in vitro permeation/retention experiments, using pig esophageal epithelium, an accepted model of the buccal mucosa. Furthermore, one microemulsion was added of excipients (stearylamine, CTAB and chitosan) able to alter the charge of droplets. The results obtained show that the permeation of triamcinolone acetonide across pig esophageal epithelium was not influenced by the droplet size nor by the composition, but only by the presence of chitosan, polysaccharide able to increase the transport across mono and stratified epithelia. The determination of the permeation parameters allowed us to show that chitosan acts on the diffusion parameter across the tissue and not on the partitioning parameter; for the same reason the tissue retention of triamcinolone acetonide was not modified. Triamcinolone flux (2.6 MUg cm-2 h-1) was too low to make systemic administration feasible (dose required 2.5 to 60 mg/day). The amount of triamcinolone acetonide recovered in the mucosa after only 10 min. of microemulsion application was much higher than after overnight application of the commercial paste Omicilon(r) A. This suggests that triamcinolone acetonide microemulsions can be an interesting alternative to the commercial formulation to treat diseases of the buccal mucosa. Owing to the fast uptake by the tissue, the formulation can be used as a mouthwash. PMID- 29414305 TI - Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy. AB - Conventional cytotoxic cancer chemotherapy is often immunosuppressive and associated with drug resistance and tumor regrowth after a short period of tumor shrinkage or growth stasis. However, certain cytotoxic cancer chemotherapeutic drugs, including doxorubicin, mitoxantrone, and cyclophosphamide, can kill tumor cells by an immunogenic cell death pathway, which activates robust innate and adaptive anti-tumor immune responses and has the potential to greatly increase the efficacy of chemotherapy. Here, we review studies on chemotherapeutic drug induced immunogenic cell death, focusing on how the choice of a conventional cytotoxic agent and its dose and schedule impact anti-tumor immune responses. We propose a strategy for effective immunogenic chemotherapy that employs a modified metronomic schedule for drug delivery, which we term medium-dose intermittent chemotherapy (MEDIC). Striking responses have been seen in preclinical cancer models using MEDIC, where an immunogenic cancer chemotherapeutic agent is administered intermittently and at an intermediate dose, designed to impart strong and repeated cytotoxic damage to tumors, and on a schedule compatible with activation of a sustained anti-tumor immune response, thereby maximizing anti cancer activity. We also discuss strategies for combination chemo-immunotherapy, and we outline approaches to identify new immunogenic chemotherapeutic agents for drug development. PMID- 29414308 TI - Cosmetic and pharmaceutical qualifications of Egyptian bentonite and its suitability as drug carrier for Praziquantel drug. AB - The aim of this paper is to characterize and evaluate newly discovered bentonite deposits in Egypt for pharmaceutical and cosmetic applications as well as its suitability as carrier for Praziquantel drug. The study was performed for the raw bentonite sample, purified bentonite sample and alkali activated purified bentonite sample. The raw bentonite sample composed mainly of montmorillonite contaminated by little amounts of quartz and calcite, while the purified sample composed of montmorillonite without detected mineral impurities and matches the mineralogical properties of Wyoming bentonite as an international standard. Geochemically, the studied raw and purified samples appear to high purity with a chemical composition close to those of Wyoming bentonite and match the pharmacopeia specifications. The chemical properties in addition to the textural properties of the surface area, porosity, particle size distribution qualify the bentonite products to use as a function in powder, emulsion and creams. Investigation of pharmacopeia properties of pH, sedimentation volume and swelling capacity revealed the suitability of the raw and purified samples for pharmaceutical and cosmetic applications. Moreover, the microbiological tests indicated that the samples free from harmful microbial pathogens. At the optimum conditions of time (240 min), bentonite dose (250 mg) and reaction temperature (60 degrees C), the obtained encapsulation percentages of Praziquantel drug are 62%, 78.4% and 93.2% for raw bentonite, purified and alkali activated bentonite, respectively. The releasing percentage of the drug using an intestinal buffer at pH 7.4 is more efficient and the maximum obtained values were obtained after 420 min. The obtained releasing values are 71%, 79.2% and 87.4% for raw bentonite, purified bentonite and alkali activated bentonite, respectively. PMID- 29414309 TI - The role of carboxyl group of pressure sensitive adhesive in controlled release of propranolol in transdermal patch: Quantitative determination of ionic interaction and molecular mechanism characterization. AB - Acrylic pressure sensitive adhesives (PSAs) are widely used in transdermal drug delivery system (TDDS). However, there was little research about the quantitative relationship between drug release and drug-PSAs interaction. In this study, five acrylic PSAs with different molar fraction of carboxyl group were designed and synthesized. Propranolol (PRO) was used as model drug to evaluate release profiles in the PSAs in vitro and in vivo. The drug release percent in the PSAs were 81.66, 78.22, 51.66, 21.81 and 11.73%, and their release behaviors were decreased with carboxyl group content of PSAs. Furthermore, it was found that quantity of carboxyl group of PSAs was equal to residual drug by the quantitative determination. In addition, the ionic interaction between PRO and PSAs was confirmed by FT-IR and MDSC results qualitatively. Using the FT-IR, MDSC, Flory Huggins interaction parameters and molecular dynamic simulation, interaction strength between drug and PSAs was determined quantitatively, which demonstrated that the drug release amount decreased linearly with interaction strength. Based on above results, we proposed that the PRO was possibly binding to the carboxyl group of PSAs one-by-one, which provided references for the accurate design of TDDS. PMID- 29414310 TI - Pressure-volume (P-V) curves in Atriplex nummularia Lindl. for evaluation of osmotic adjustment and water status under saline conditions. AB - The survival of Atriplex nummularia plants in saline environments is possible mainly due to the presence of salt-accumulating epidermal vesicles. Commonly, destructive methods, such as plant material maceration and subsequent reading in osmometers, are employed in studies on water relations and osmotic adjustment and are inconvenient due to their underestimation of the total water potential inside the cells, which can cause overestimation of an osmotic adjustment that is not present. As a result, methods that preserve leaf structure, such as pressure volume (P-V) curves, which take into consideration only the salts that compose the symplastic solution, are more adequate. Thus, the main objectives of this study were to evaluate the effect of determination methods of osmotic potential (Psio) in Atriplex nummularia through destructive and leaf structure-preserving techniques and to determine the water relations of the species under increasing NaCl concentrations. Plants were subjected to daily irrigations, maintaining soil moisture at 80% of field capacity, with solutions of increasing NaCl concentration (0, 0.05, 0.1, 0.2, 0.25 and 0.3 M) for 84 days. Water potential, osmotic potential and osmotic adjustment were determined. In addition, P-V curves were constructed using pressure chambers. Water and osmotic potentials decreased linearly with increasing NaCl concentration in the irrigation solution. The main discrepancies observed were related to the osmotic adjustments determined through maceration and P-V curves. Based on the present research, it was possible to conclude that in studies with species that have salt-accumulating vesicles in the epidermis, such as the plants in the genus Atriplex, constructing P-V curves is more adequate than destructive methods. PMID- 29414311 TI - Gene expression analysis, subcellular localization, and in planta antimicrobial activity of rice (Oryza sativa L.) defensin 7 and 8. AB - Defensins are a group of plant antimicrobial peptides. In a previous study, it was reported that two recombinant rice (Oryza sativa L.) defensin (OsDEF) genes (OsDEF7 and OsDEF8) produced heterologously by bacteria inhibited the growth of several phytopathogen. Here, we analyzed gene expression patterns in Thai jasmine rice (O. sativa L. ssp. indica 'KDML 105') using quantitative reverse transcription-polymerase chain reaction and compared them with those in Japanese rice (O. sativa L. ssp. japonica 'Nipponbare'). Although the cultivars exhibited similar gene expression patterns at the developmental stages examined, the expression levels differed between organs. Upon Xanthomonas oryzae pv. oryzae infection in the leaves, both OsDEFs were highly upregulated at 8 days post infection, suggesting that they play a role in pathogen defense. Moreover, in silico analyses revealed that OsDEF expression levels were affected by drought, cold, imbibition, anoxia, and dehydration stress. Using green fluorescent protein (GFP) fusions, we found that both OsDEFs were in the extracellular compartment, confirming their functions against pathogen infection. However, when recombinant OsDEFs (without GFP) were produced in tobacco BY-2 cells or Nicotiana benthamiana leaves, they could not be detected in either the culture medium or the cells. Yet, N. benthamiana leaves infiltrated with OsDEF7 or OsDEF8 constructs exhibited in planta inhibitory activity against the phytopathogen Xanthomonas campestris pv. glycines, suggesting that recombinant OsDEFs were present. Additionally, when targeting them to the ER compartment, recombinant OsDEFs could be detected. Lower inhibitory activity was observed when recombinant OsDEFs were targeted to the ER. These results suggest that OsDEFs play a role in controlling plant diseases. PMID- 29414312 TI - SIP1, a novel SOS2 interaction protein, is involved in salt-stress tolerance in Arabidopsis. AB - A novel salt overly-sensitive 2 (SOS2) interaction protein was identified by yeast two hybrid (Y2H) library and was referred to as SOS2 interaction protein 1 (SIP1). SIP1 belongs to a plant-specific protein family, which contains a conserved domain that corresponds to a putative N-acetyltransferase. The members of this family are tolerant to heavy metals and oxidative stress. Here, SIP1 was identified as a salt-responsive gene. The sos2*sip1-1 double mutant was more sensitive than the sos2 single mutant upon salt stress, whereas the overexpression of SIP1 gene enhanced the plant salt tolerance, suggesting that SIP1 was involved in plant salt tolerance. We also found that SIP1 increasingly accumulated in response to salt stress, and this accumulation was inhibited in the sos2 mutant background. This finding suggests that the function of SIP1 upon salt stress was dependent on SOS2 protein. Further investigation suggested that SIP1 improved Arabidopsis tolerance to salt stress by reducing the ROS accumulation. Taken together, these findings reveal a novel function of SIP1 in adjusting Arabidopsis adaptation to salt stress. PMID- 29414313 TI - The effect of 24-epibrassinolide on the green alga Acutodesmus obliquus (Chlorophyceae). AB - Brassinosteroids play an important role in the plant growth and development as well as in the adaptation of plants to environmental stresses. Studies have shown the effect of 24-epibrassinolide (EBL) in the range of concentrations 0.0001-10 MUM on the green unicellular alga Acutodesmus obliquus (Chlorophyceae) during 7 days of cultivation. EBL is an effective stimulator of algal growth as it causes an increase in the number of cells and the contents of selected metabolites such as proteins, monosaccharides, and photosynthetic pigments (chlorophylls, carotenes, and xanthophylls). Furthermore, EBL inhibits the formation of reactive oxygen species such as hydrogen peroxide and oxidative damage as evidenced by a decrease of the lipid peroxidation. The positive effect of EBL resulting from the cellular oxidative state can be alleviated by antioxidants such as ascorbate peroxidase, catalase, superoxide dismutase, and ascorbate. PMID- 29414314 TI - Profiling of proteasome activity in Alyssum species on serpentine soils in Turkey reveals possible insight into nickel tolerance and accumulation. AB - In crops and most plants, nickel induces oxidative stress resulting in oxidized and misfolded proteins. Proteasomes maintain cellular homeostasis during stress by removing these damaged proteins. Although mild stress tolerance is mediated by proteasomal proteolysis of misfolded and oxidized proteins, previous studies have observed that severe nickel stress decreases proteasome activity in nickel sensitive plants. Whether or not proteasome function is impaired in nickel tolerant plants is not know. Therefore, we tested the hypothesis that proteasome activity is elevated in nickel-tolerant Alyssum species capable of accumulating nickel to unusually high levels. Our field studies examined Alyssum sibiricum and Alyssum caricum, a moderate nickel accumulator and hyper-accumulator respectively, growing on their native serpentine soil in Turkey. A. sibiricum had higher proteasome activity on serpentine soil compared to non-serpentine soil; these plants also had elevated levels of nickel accumulation and higher proteasome activity compared to other low accumulating plants in the genus Festuca or Astragalus. In A. caricum, proteasome activity was very weakly correlated with nickel soil bioavailability or accumulation in leaf tissue, suggesting that proteasome function was not impaired in plants that accumulated the highest concentration of nickel. We discuss if maintained proteasome activity might underpin nickel tolerance and the unique ecophysiology of nickel hyper accumulation in plants. PMID- 29414315 TI - Overexpression of the wheat expansin gene TaEXPA2 improves oxidative stress tolerance in transgenic Arabidopsis plants. AB - Expansins play an important role in plant stress tolerance. In a previous study, we cloned the wheat expansin gene TaEXPA2. Here, we analyze its involvement in oxidative stress tolerance. First, we observed that the expression of TaEXPA2 in wheat seedlings was upregulated during H2O2 stress. Then, we assembled a TaEXPA2 gene expression vector, transformed it to Arabidopsis, and obtained transgenic plants overexpressing TaEXPA2 (labeled OE). When exposed to H2O2, both OE and wild-type (Col) plants were damaged by oxidative stress, as indicated by decolored leaves and increased malondialdehyde (MDA) content. Damage in OE plants was less severe than in Col plants (WT), and this was accompanied by higher activity of cell wall peroxidase (POD) enzymes, including soluble POD, ionically bound POD, and covalently bound POD. The expansin activities of the OE plants were also higher than WT under oxidative stress. We further obtained the Arabidopsis mutant atexpa2 (AtEXPA2 is homologous to TaEXPA2), and found that the antioxidant ability of atexpa2 was lower than that in Col plants, accompanied by depressed activity of POD enzymes and expansins in cell walls. We transformed wheat TaEXPA2 to atexpa2 and obtained plants (labeled Rs) capable of recovering the antioxidant capacity. Oxidative stress tolerance in Rs plants was higher than that of Col plants, and the Rs plants also had higher levels of cell wall POD enzyme and expansin activity. Finally, we identified 13 POD genes in Arabidopsis thaliana and analyzed their expression patterns using quantitative real-time PCR. The expression of 4 of these genes (AtPOD31, AtPOD33, AtPOD34 and AtPOD71) was significantly upregulated during exposure to H2O2. We speculate that the 4 genes upregulated by H2O2 treatment are involved in the increased activity of POD in the cell wall. We suggest that TaEXPA2 may regulate antioxidant capacity in plants by regulating the activity of cell wall peroxidase. PMID- 29414316 TI - PPARgamma agonist rosiglitazone switches fuel preference to lipids in promoting thermogenesis under cold exposure in C57BL/6 mice. AB - : Brown and beige adipose tissues play key roles in adaptive thermogenesis, which is essential for homoiotherms to maintain core temperature under cold exposure. PPARgamma is a transcriptional regulator critical for brown adipose tissue (BAT) recruitment and white adipose tissue (WAT) browning. Here we evaluated the impact of PPARgamma activation on thermogenic activity in C57BL/6 mice under thermo neutral and 4 degrees C cold environment, and revealed the regulating mechanism and metabolic basis. Rosiglitazone slowed body temperature loss in cold environment in C57BL/6 mice, suppressed cold-induced decreases in blood glucose, reversed cold-promoted 18F-FDG uptake, and increased lipid consumption in BAT. Serum/adipose tissue metabolomic and transcriptomic analyses revealed that cold exposure and rosiglitazone affect metabolism in different way, especially in terms of free fatty acid/lipid metabolism. While all tested treatments stimulated stored-substance mobilization in epididymal WAT, in heat-generating adipose tissues (BAT and subcutaneous WAT), rosiglitazone-only treatment promoted the storage of substances such as lipids for subsequent thermogenic activation; conversely, cold exposure favoured glucose consumption and mobilization/transport of extracellular lipids. When combined with cold exposure, rosiglitazone treatment preferentially triggered BAT lipid consumption, mobilized and transported lipids from epididymal to subcutaneous WAT, and reduced glucose usage. Thus, rosiglitazone might promote thermogenesis under cold exposure by switching fuel preference. SIGNIFICANCE: In current study, for the first time, PPARgamma agonism by rosiglitazone was proved to promote thermogenesis under near freezing conditions and enhance the heat generating response against cold-induced hypothermia in mice by switching the fuel preference from carbohydrates to lipids. The lipid substrates stored in BAT in response to PPARgamma activation are spared for eventual thermogenic activation. These findings thus underline the remarkable actions of PPARgamma in the control of energy metabolism in adipose tissues, especially the BAT. PMID- 29414317 TI - Genomic resequencing combined with quantitative proteomic analyses elucidate the survival mechanisms of Lactobacillus plantarum P-8 in a long-term glucose-limited experiment. AB - : Lactobacillus plantarum, commonly isolated from plant material, is widely used to produce various types of fermented foods. However, nutrient-limiting conditions are often encountered during industrial applications. The present study aimed to investigate the response of L. plantarum P-8 to glucose-limited conditions in a long-term experiment. Genotypic and proteomic changes in L. plantarum P-8 were monitored over 3 years in glucose-limited and glucose-normal media using whole-genome resequencing and tandem mass tag-based quantitative proteomic analysis. Results showed that L. plantarum employed numerous survival mechanisms, including alteration of the cell envelope, activation of the PTS system, accumulation and consumption of amino acids, increase in the metabolism of carbohydrates (via glycolysis, citric acid cycle, and pyruvate metabolism), and increase in the production of ATP in response to glucose starvation. This study demonstrates the feasibility of experimental evolution of L. plantarum P-8, while whole-genome resequencing of adapted isolates provided clues toward bacterial functions involved and a deeper mechanistic understanding of the adaptive response of L. plantarum to glucose-limited conditions. SIGNIFICANCE: We have conducted a 3-year experiment monitoring genotypic and proteomic changes in Lactobacillus plantarum P-8 in glucose-limited and glucose-normal media. Whole genome resequencing and tandem mass tag-based quantitative proteomics were performed for analyzing genomic evolution of L. plantarum P-8 in glucose-limited and glucose-normal conditions. In addition, differential expressed proteins in all generations between these two conditions were identified and functions of these proteins specific to L group were predicted. L. plantarum employed numerous survival mechanisms, including alteration of the cell envelope, activation of the PTS system, accumulation and consumption of amino acids, increase in the metabolism of carbohydrates (glycolysis, citric acid cycle, and pyruvate metabolism), and increase in the production of ATP in response to glucose starvation. PMID- 29414318 TI - Genes related to cell-mediated cytotoxicity and interferon response are induced in the retina of European sea bass upon intravitreal infection with nodavirus. AB - Viral diseases are responsible for high rates of mortality and subsequent economic losses in modern aquaculture. The nervous necrosis virus (NNV) produces viral encephalopathy and retinopathy (VER), which affects the central nervous system, is considered one of the most serious viral diseases in marine aquaculture. Although some studies have localized NNV in the retina cells, none has dealt with immunity in the retina. Thus, for the first time, we intravitreally infected healthy specimens of European sea bass (Dicentrarchus labrax) with NNV with the aim of characterizing the immune response in the retina. Ultrastructural analysis detected important retinal injuries and structure degradation, including pycnosis, hydropic degeneration and vacuolization in some cell layers as well as myelin sheaths in the optic nerve fibres. Immunohistochemistry demonstrated that NNV replicated in the eyes. Regarding retinal immunity, NNV infection elicited the transcription of genes encoding proteins involved in the interferon (IFN) and cell-mediated cytotoxicity (CMC) responses as well as B and T cell markers, demonstrating that viral replication influences innate and adaptive responses. Further studies are needed to understand the retina immunity and whether the main retinal function, vision, is affected by nodavirus. PMID- 29414319 TI - Symbiont replacement between bacteria of different classes reveals additional layers of complexity in the evolution of symbiosis in the ciliate Euplotes. AB - Symbiosis is a diverse and complex phenomenon requiring diverse model systems. The obligate relationship between a monophyletic group of Euplotes species ("clade B") and the betaproteobacteria Polynucleobacter and "Candidatus Protistobacter" is among the best-studied in ciliates, and provides a framework to investigate symbiont replacements. Several other Euplotes-bacteria relationships exist but are less understood, such as the co-dependent symbiosis between Euplotes magnicirratus (which belongs to "clade A") and the alphaproteobacterium "Candidatus Devosia euplotis". Here we describe a new Devosia inhabiting the cytoplasm of a strain of Euplotes harpa, a clade B species that usually depends on Polynucleobacter for survival. The novel bacterial species, "Candidatus Devosia symbiotica", is closely related to the symbiont of E. magnicirratus, casting a different light on the history of bacteria colonizing ciliates of this genus. The two Devosia species may have become symbionts independently or as the result of a symbiont exchange between hosts, in either case replacing a previous essential bacterium in E. harpa. Alternatively, both may be remnants of an ancient symbiotic relationship between Euplotes and Devosia, in which case Polynucleobacter and "Ca. Protistobacter" are recent invaders. Either way, symbiont replacement between bacteria belonging to different classes must be evoked to explain this fascinating system. PMID- 29414320 TI - Urine epidermal growth factor, monocyte chemoattractant protein-1 or their ratio as predictors of complete remission in primary glomerulonephritis. AB - BACKGROUND: The balance of several cytokines likely influences the resolution of glomerulonephritis. Monocyte chemoattractant protein-1(MCP-1) is a chemokine that promotes renal inflammation whereas epidermal growth factor (EGF) stimulates protective responses. Previously, high urine MCP-1(MCP-1) and low urine EGF (EGF) levels were found to be associated with tubulointerstitial fibrosis, but there is limited information on the value of these mediators as predictors of therapeutic responses or long term outcome in primary glomerulonephritis. OBJECTIVES: To determine the performance of urine EGF, MCP-1 or their ratio at baseline as biomarkers to predict complete remission, and the relationship of these mediators with subsequent renal function 24 months later in primary glomerulonephritis. METHODS: This is a prospective study of patients with biopsy-proven primary glomerulonephritis. Baseline urine samples were collected at biopsy before therapy. MCP-1 and EGF were analyzed by enzyme-linked immunosorbent assays and expressed as a ratio to urine creatinine (ng/mgCr) or as EGF/MCP-1 ratio (ng/ng). Proteinuria and estimated glomerular filtration rate (eGRF) were monitored after therapy. Complete remission (CR) was defined as proteinuria <= 0.3 g/gCr. RESULTS: Median follow-up was 20 months. Of all patients (n = 74), 38 patients (51.4%) subsequently achieved CR. Baseline urine EGF and EGF/MCP-1 levels were significantly higher in CR compared to Not CR. By contrast, MCP-1 was not different. High EGF (EGF > 75 ng/mgCr) was a significant predictor (OR 2.28) for CR by multivariate analysis after adjusting for proteinuria, blood pressure, baseline eGFR. In patients who completed 24 months follow-up (n = 43), baseline EGF correlated inversely with proteinuria and positively with eGFR at 24 months. CONCLUSION: High urine EGF level is a promising biomarker of CR. Baseline EGF levels correlated with kidney function at 2 years. EGF/MCP-1 was not superior to EGF alone. Further studies are necessary to determine the role of urine EGF as a guide to therapy in primary GN. PMID- 29414321 TI - A novel Th1-type T-cell immunity-biasing effect of malate dehydrogenase derived from Mycobacterium avium subspecies paratuberculosis via the activation of dendritic cells. AB - Mycobacterium avium subspecies paratuberculosis (MAP) is the causative pathogen of Johne's disease in ruminants, characterized by chronic granulomatous enteritis; it also has zoonotic potential and is associated with Crohn's disease in humans. A better understanding of the mycobacterial antigens and their roles in the host immune response may facilitate the rational design of control strategies, including the development of effective vaccines and diagnostic tools. However, the functional roles of a large proportion of MAP antigens involved in modulating the host immune response remain unknown. In this study, an immunological role of MAP malate dehydrogenase (MDH, MAP2541c), an antigen that is upregulated in stress culture conditions, such as nutrient starvation and hypoxia, in polarizing naive CD4+/CD8+ T cells toward Th1-biased T-cell immunity via the activation of dendritic cells (DCs) was identified. DCs treated with MAP MDH displayed characteristics of the activated and mature immune status, with augmented expression of cell surface molecules and pro-inflammatory cytokines, including TNF-alpha, IL-1beta, IL-6, and IL-12p70, but not IL-10, along with a dose-dependent decrease in the antigen uptake capacity. A mechanistic investigation revealed that the observed DC maturation is mediated by the activation of JNK, ERK, and p38 MAP kinases, and the NF-kappaB signaling pathway. Notably, DCs activated by MAP MDH treatment promoted naive CD4+/CD8+ T cell proliferation; in particular, they effectively polarized naive CD4+ T cells to secrete IFN-gamma and IL-2 and activate T-bet, but, unlike the LPS control, did not influence IL-5 and GATA-3. These results indicated that MAP MDH has the potential to induce the Th1 cell response via DC activation. Collectively, our data demonstrated that MAP MDH is a novel immunostimulatory antigen that drives Th1-biased T cell polarization via interactions with DCs, suggesting that MDP MDH has the potential to be an effective MAP vaccine antigen target and diagnostic marker. PMID- 29414322 TI - Upregulated fractalkine levels in Chinese patients with lupus nephritis. AB - OBJECTIVE: To investigate the expression levels of fractalkine (FKN) mRNA in peripheral blood mononuclear cells (PBMCs) and FKN protein in serum of patients with lupus nephritis (LN) from China, and to evaluate the associations between the expression of FKN and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2 K), anti-double-stranded DNA and complement proteins in LN patients. METHODS: Real-time quantitative polymerase chain reaction and enzyme linked immunosorbent assay were used to detect the expression levels of FKN mRNA in PBMCs and FKN protein in serum separately from 105 patients with LN and 52 healthy controls. RESULTS: Serum level and mRNA level of FKN were significantly increased in LN patients when compared to controls (P < 0.001). Higher FKN levels were found in active LN patients and LN patients with renal damage when compared with inactive LN patients and LN patients without renal damage (P < 0.001). Higher serum FKN levels were detected in inactive LN patients in comparison with healthy controls (Z = -7.165, P < 0.001). The FKN expression levels were positively correlated with SLEDAI-2 K, and was associated with the presence of autoantibodies and negatively correlated with complement proteins C3 and C4 in LN patients. CONCLUSIONS: The results suggest that upregulation of FKN is associated with the pathogenesis and activity of LN in Chinese patients. PMID- 29414323 TI - Letter to Yokoyama et al. (Yokoyama Y. Cytokine. 2017 Dec 29; 103: 25-28). PMID- 29414324 TI - ADAR1 prevents small intestinal injury from inflammation in a murine model of sepsis. AB - Adenosine deaminase acting on RNA 1 (ADAR1), a double-stranded RNA-editing enzyme that converts adenosine (A) to inosine (I), has been identified as a modulator of immune responses. However, the role of ADAR1 in small intestinal homeostasis during sepsis remains unclear. In this study, we examined the role of ADAR1 on intestinal inflammation in a murine model of sepsis. We found that ADAR1 was highly expressed in "septic" macrophages and small intestinal tissue of septic mice. Deletion of ADAR1 in "septic" macrophages led to rapid apoptosis. In addition, suppression of ADAR1 in "septic" macrophages significantly enhanced inflammation, while over-expression of ADAR1 significantly suppressed the level of inflammatory cytokines. Furthermore, suppression of ADAR1 in septic mice significantly enhanced inflammation and intestinal damage, while enhanced ADAR1 expression resulted in reduced damage and inflammation. Finally, over-expression of ADAR1 improved survival of septic mice. In conclusion, we have identified a novel ADAR1 protective effect for maintaining intestinal homeostasis. Our findings may provide a new targeted therapy for sepsis treatment. PMID- 29414325 TI - A deamidated interferon-beta variant binds to integrin alphavbeta3. AB - Human type I interferons are a family of pleiotropic cytokines with antiviral, anti-proliferative and immunomodulatory activities. They signal through the same cell surface receptors IFNAR1 and IFNAR2 yet evoking markedly different physiological effects. One differentiating factor of interferon-beta (IFN-beta) from other type I interferons is the presence of theAsn-Gly-Arg (NGR) sequence motif, which, upon deamidation, converts to Asp-Gly-Arg (DGR) and iso-Asp-Gly-Arg (iso-DGR) motifs. In other proteins, the NGR and iso-DGR motifs are reported as CD13- and alphavbeta3, alphavbeta5, alphavbeta6, alphavbeta8 and alpha5beta1 integrin-binding motifs, respectively. The scope of this study was to perform exploratory surface plasmon resonance (SPR) experiments to assess the binding properties of a deamidated IFN-beta variant to integrins. For this purpose, integrin alphavbeta3 was selected as a reference model within the iso-DGR- integrin binding members. The obtained results show that deamidated IFN-beta binds integrin alphavbeta3 with nanomolar affinity and that the response was dependent on the deamidation extent. Based on these results, it can be expected that deamidated IFN-beta also binds to other integrin family members that are able to bind to the iso-DGR binding motif. The novel binding properties could help elucidate specific IFN-beta attributes that under physiological conditions may be modulated by the deamidation. PMID- 29414326 TI - Ex vivo analysis of serum chemerin activity in murine models of obesity. AB - OBJECTIVES: Chemerin is an adipokine with established roles in inflammation, adipogenesis and the regulation of glucose and lipid homeostasis. Extracellular proteolytic processing of chemerin generates a spectrum of isoforms that differ significantly with respect to the ability to activate the cognate receptors chemokine-like receptor 1 (CMKLR1) and G-protein-coupled receptor 1 (GPR1). Increased total serum chemerin has been widely reported in obese humans as well as in preclinical rodent models of adiposity. However, very little information is available regarding the correspondence, if any, of changes in total serum chemerin protein with chemerin bioactivity. METHODS: Total serum chemerin and ex vivo CMKLR1 and GPR1 activation was compared using two widely used murine obesity models: high fat diet feeding (HFD) and leptin deficiency (ob/ob). RESULTS: Total serum chemerin levels and ex vivo CMKLR1 and GPR1 activation were significantly induced in HFD. The bioactivity ratio (bioactive chemerin/total chemerin) was also increased when measured with CMKLR1, but not GPR1. In contrast, while ob/ob mice exhibited increased total serum chemerin protein, ex vivo receptor activation was observed with GPR1, but not CMKLR1. There was no change in bioactivity ratio for either receptor. Of note, GPR1 but not CMKLR1 bioactivity positively correlated with adipose tissue inflammation. CONCLUSIONS: While increased total serum chemerin is a consistent finding among rodent obesity models, this may not accurately reflect changes in chemerin bioactivity which is the major determinant of biological effects. PMID- 29414327 TI - MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) has been recognized as a highly pathogenic virus to humans that infects the respiratory tract and is associated with high morbidity and mortality. Studies in animal models suggest that MERS-CoV infection induces a strong inflammatory response, which may be related to the severity of disease. Data showing the cytokine profiles in humans during the acute phase of MERS-CoV infection are limited. In this study, we have analyzed the profile of cytokine responses in plasma samples from patients with confirmed MERS-CoV infections (n = 7) compared to healthy controls (n = 13). The cytokine profiles, including T helper (Th) 1, Th2 and Th17 responses, were analyzed using cytometric bead array (CBA). A prominent pro-inflammatory Th1 and Th17 response was clearly seen in patients with MERS-CoV infection, with markedly increased concentrations of IFN-gamma, TNF-alpha, IL-15 and IL-17 compared to controls. IL-12 expression levels showed no difference between patients with MERS CoV infection and the healthy controls despite the significantly increased levels of IFN-alpha2 and IFN-gamma (P < .01). No changes were observed in the levels of IL-2, IL-4, IL-5, IL-13, and TGF-alpha (P > .05). Our results demonstrate a marked pro-inflammatory cytokine response during the acute phase of MERS-CoV infection in humans. PMID- 29414328 TI - Concentration of uranium in the soils of the west of Spain. AB - While determining the uranium concentration in the rock (background level) and soils on the Iberian Massif of western Spain, several geochemical anomalies were observed. The uranium concentration was much higher than the geochemical levels at these locations, and several uranium minerals were detected. The proposed uranium background levels for natural soils in the west of Salamanca Province (Spain) are 29.8 mg kg-1 in granitic rock and 71.2 mg kg-1 in slate. However, the soil near the tailings of abandoned mines exhibited much higher concentrations, between 207.2 and 542.4 mg kg-1. The calculation of different pollution indexes (Pollution Factor and Geo-accumulation Index), which reveal the conditions in the superficial horizons of the natural soils, indicated that a good percentage of the studied samples (16.7-56.5%) are moderately contaminated. The spatial distribution of the uranium content in natural soils was analysed by applying the inverse distance weighted method. The distribution of uranium through the horizons of the soils shows a tendency to accumulate in the horizons with the highest clay content. The leaching of uranium from the upper horizons and accumulation in the lower horizons of the soil could be considered a process for natural attenuation of the surface impacts of this radiogenic element in the environment. Environmental restoration is proposed in the areas close to the abandoned mining facilities of this region, given the high concentration of uranium. First, all the tailings and other mining waste would be covered with a layer of impermeable material to prevent leaching by runoff. Then, a layer of topsoil with organic amendments would be added, followed by revegetation with herbaceous plants to prevent surface erosion. PMID- 29414329 TI - Performance evaluation of Bacteroidales genetic markers for human and animal microbial source tracking in tropical agricultural watersheds. AB - Microbial source tracking (MST) DNA-based assays have been used to successfully solve fecal pollution problems in many countries, particularly in developed nations. However, their application in developing countries has been limited but continues to increase. In this study, sixteen endpoint and quantitative PCR (qPCR) assays targeting universal and human-, swine-, and cattle-specific Bacteroidales gene markers were modified for endpoint PCR, evaluated for their performance with sewage and fecal samples from the Tha Chin watershed and subsequently validated with samples from the Chao Phraya watershed, Thailand. Sample sizes of 81 composite samples (from over 1620 individual samples) of farm animals of each type as well as 19 human sewage samples from the Tha Chin watershed were calculated using a stratified random sampling design to achieve a 90% confidence interval and an expected prevalence (i.e., desired assay's sensitivity) of 0.80. The best universal and human-, swine-, and cattle-specific fecal markers were BacUni EP, HF183/BFDrev EP, Pig-2-Bac EP, and Bac3 assays, respectively. The detection limits for these assays ranged from 30 to 3000 plasmid copies per PCR. The positive predictive values were high in universal and swine- and cattle-specific markers (85-100%), while the positive predictive value of the human-specific assay was 52.2%. The negative predictive values in all assays were relatively high (90.8-100%). A suite of PCR assays in Thailand was established for potential MST use in environmental waters, which supports the worldwide applicability of Bacteroidales gene markers. This study also emphasizes the importance of using a proper sample size in assessing the performance of MST markers in a new geographic region. PMID- 29414330 TI - An optimized method for the analysis of cyclic and linear siloxanes and their distribution in surface and core sediments from industrialized bays in Korea. AB - Environmental contamination by siloxanes is a matter of concern due to their widespread consumption in personal care as well as industrial products and potential toxicity. Nevertheless, methods for simultaneous determination of cyclic and linear siloxanes in sediment are lacking. In this study, we developed an optimized analytical method to determine cyclic and linear siloxanes based on gas chromatography coupled to tandem mass spectrometry (GC-MS/MS). This method was applied to determine concentrations of 19 siloxane compounds in surface and core sediments from industrialized bays in Korea to assess contamination status, spatial distribution, and historical trends. Total concentrations of siloxanes ranged from 15.0 to 11730 (mean: 712) ng/g dry weight, which were similar to or higher than those reported in other countries. The highest concentrations of siloxanes were found in rivers/streams that discharge into coastal waters and bays close to industrial complexes, indicating that industrial activities are major sources of siloxane contamination. Cyclic siloxanes such as D5 and D6 were predominant in surface and core sediments. A significant correlation existed between the concentrations of cyclic and linear siloxanes, suggesting similar sources in the marine coastal environment. The historical record of cyclic siloxanes in core sediments revealed a clear increasing trend since the 1970s. This finding is consistent with the history of local industrialization and global production of siloxanes. This is the first study of historical trends in siloxanes in the coastal environment. PMID- 29414331 TI - UV-irradiation and leaching in water reduce the toxicity of imidacloprid contaminated leaves to the aquatic leaf-shredding amphipod Gammarus fossarum. AB - Systemic neonicotinoid insecticides such as imidacloprid are increasingly applied against insect pest infestations on forest trees. However, leaves falling from treated trees may reach nearby surface waters and potentially represent a neonicotinoid exposure source for aquatic invertebrates. Given imidacloprid's susceptibility towards photolysis and high water solubility, it was hypothesized that the leaves' toxicity might be modulated by UV-irradiation during decay on the forest floor, or by leaching and re-mobilization of the insecticide from leaves within the aquatic ecosystem. To test these hypotheses, the amphipod shredder Gammarus fossarum was fed (over 7 d; n = 30) with imidacloprid contaminated black alder (Alnus glutinosa) leaves that had either been pre treated (i.e., leached) in water for up to 7 d or UV-irradiated for 1 d (at intensities relevant during autumn in Central Europe) followed by a leaching duration of 1 d. Gammarids' feeding rate, serving as sublethal response variable, was reduced by up to 80% when consuming non-pretreated imidacloprid-contaminated leaves compared to imidacloprid-free leaves. Moreover, both leaching of imidacloprid from leaves (for 7 d) as well as UV-irradiation reduced the leaves' imidacloprid load (by 46 and 90%) thereby mitigating the effects on gammarids' feeding rate to levels comparable to the respective imidacloprid-free controls. Therefore, natural processes, such as UV-irradiation and re-mobilization of foliar insecticide residues in water, might be considered when evaluating the risks systemic insecticide applications in forests might pose for aquatic organisms in nearby streams. PMID- 29414332 TI - Effects of MCLR exposure on sex hormone synthesis and reproduction-related genes expression of testis in male Rana nigromaculata. AB - Microcystin-leucine-arginine (MCLR) is the most popular and toxic variant among microcystins, which can cause severe reproductive toxicity to animals. However, the mechanisms of reproductive toxicity induced by MCLR in amphibians are still not entirely clear. In the current study, toxicity mechanisms of MCLR on the reproductive system of male Rana nigromaculata followed by low concentration (0, 0.1, 1, and 10 MUg/L) and short-term (0, 7, and 14 days) MCLR exposure were shown. It was observed that MCLR could be bioaccumulated in the testes of male frogs, and the theoretical bioaccumulation factor values were 0.24 and 0.19 exposed to 1 MUg/L and 10 MUg/L MCLR for 14 days, respectively. MCLR exposure significantly decreased testosterone (T) concentrations and increased estradiol (E2) concentrations exposed to 1 and 10 MUg/L MCLR for 14 days. The mRNA levels of HSD17B3 were downregulated, and HSD17B1 and CYP19A1 mRNA expression levels were upregulated, respectively. Only 10 MUg/L MCLR group showed significant induction of follicle-stimulating hormone (FSH) levels and cyclic adenosine monophosphate (cAMP) content. Moreover, AR and ESR1 mRNA expression levels were significantly upregulated exposed to 1 and 10 MUg/L MCLR for 14 days, respectively. Our results suggested that low-concentration MCLR induced transcription changes of CYP19A1, HSD17B3, and HSD17B1 led to endocrine disorders, and caused interference of spermatogenesis by the decrease of T and abnormal gene expressions of AR and ESR1 in the testes of R. nigromaculata. PMID- 29414333 TI - Occurrence of intracellular and extracellular antibiotic resistance genes in coastal areas of Bohai Bay (China) and the factors affecting them. AB - Coastal areas are the transition zones between ocean and land where intracellular antibiotic resistance genes (iARGs) and extracellular antibiotic resistance genes (eARGs) could spread among marine organisms, and between humans and marine organisms. However, little attention has been paid to the combined research on iARGs and eARGs in marine environment. In this context, we collected water and sediment samples from the coastal areas of the Bohai Bay in China and performed molecular and chemical analyses. The results of quantitative real-time PCR (qPCR) showed that the relative abundance of eARGs was up to 4.3 +/- 1.3 * 10-1 gene copies/16S rRNA copies in the water samples and 2.6 +/- 0.3 * 10-3 gene copies/16S rRNA copies in the sediment samples. Also, the abundance of eARGs was significantly higher than that of iARGs. Furthermore, the average abundances of antibiotic resistance genes (ARGs, include iARGs and eARGs) were the highest in both the water and sediment samples from the estuaries. The results of liquid chromatography-mass spectrometry showed that the concentrations of antibiotics in estuaries and areas near the mariculture site were higher than that in the other sites. The class 1 integron gene (int1) and sul1 in the intracellular DNA were significantly correlated in the water samples. Moreover, significant correlation between int1 and sul2 in the extracellular DNA was also found in the sediment samples. The combination of sulfamerazine and tetracycline as well as the combination of sulfamethazine and dissolved oxygen can both explain the abundance of ARGs, implying the combined effects of multiple stresses on ARGs. PMID- 29414334 TI - Organophosphorus flame retardants and heavy metals in municipal landfill leachate treatment system in Guangzhou, China. AB - The occurrence, distribution and removal efficiencies of organophosphorus flame retardants (OPFRs) and metals were examined in a municipal landfill leachate treatment system in Guangzhou, China. Five OPFRs and thirty-five metals were detected in wastewater samples collected at different treatment stages. ?OPFRs was reduced from 4807.02 ng L-1 to 103.91 ng L-1 through the treatment system, with close to 98% removed from the dissolved phase. Tris(clorisopropyl) phosphates (TCPPs) dominated through the treatment process and accounted for over 80% and 50% of ?OPFRs at the influent and the effluent, respectively. TCPPs were most efficiently removed (98.6%) followed by tris(2-chloroethyl) phosphate (TCEP) (96.6%) and triphenyl phosphate (TPP) (88.5%). For metals, Fe, Cr, and Rb were dominant in the raw leachate, detected at 7.55, 2.82, and 4.50 mg L-1, respectively. Thirteen regulated heavy metals - including eight major pollutants (i.e., As. Cd, Cr, Cu, Hg, Ni, Pb, and Zn) - have been detected in all wastewater samples at sub-mg L-1 levels. Over 99.5% removal was achieved for Cr, Ni, and Fe, and close to 95% removal efficiency was observed for Rb. For the eight major heavy metals, over 99% removal was observed; the only exception was Cu, which was removed at 89%. It was found that microfiltration/reverse osmosis was critical for the removal of OPFRs and heavy metals while the core biological treatment played a minor role towards their removal. Remobilization of Co, Cu, Fe, Hg, Mn, Ni, Sb, and Sr from the returned sludge occurred during the second denitrification, indicating the need for additional post-biological process for effective removal of both contaminants. This study highlights the critical need to develop cheap, effective treatment technologies for contaminants-laden leachate generated from open dumps and under-designed landfills. PMID- 29414335 TI - The gains in life expectancy by ambient PM2.5 pollution reductions in localities in Nigeria. AB - Global burden of disease estimates reveal that people in Nigeria are living shorter lifespan than the regional or global average life expectancy. Ambient air pollution is a top risk factor responsible for the reduced longevity. But, the magnitude of the loss or the gains in longevity accruing from the pollution reductions, which are capable of driving mitigation interventions in Nigeria, remain unknown. Thus, we estimate the loss, and the gains in longevity resulting from ambient PM2.5 pollution reductions at the local sub-national level using life table approach. Surface average PM2.5 concentration datasets covering Nigeria with spatial resolution of ~1 km were obtained from the global gridded concentration fields, and combined with ~1 km gridded population of the world (GPWv4), and global administrative unit layers (GAUL) for territorial boundaries classification. We estimate the loss or gains in longevity using population weighted average pollution level and baseline mortality data for cardiopulmonary disease and lung cancer in adults >=25 years and for respiratory infection in children under 5. As at 2015, there are six "highly polluted", thirty "polluted" and one "moderately polluted" States in Nigeria. People residing in these States lose ~3.8-4.0, 3.0-3.6 and 2.7 years of life expectancy, respectively, due to the pollution exposure. But, assuming interventions achieve global air quality guideline of 10 MUg/m3, longevity would increase by 2.6-2.9, 1.9-2.5 and 1.6 years for people in the State-categories, respectively. The longevity gains are indeed high, but to achieve them, mitigation interventions should target emission sources having the highest population exposures. PMID- 29414336 TI - Biochars change the sorption and degradation of thiacloprid in soil: Insights into chemical and biological mechanisms. AB - One interest of using biochar as soil amendment is to reduce pesticide adverse effects. In this paper, the sorption and degradation of thiacloprid (THI) in a black soil amended by various biochars were systematically investigated, and the mechanisms therein were explored by analyzing the changes in soil physicochemical properties, degrading enzymes and genes and microorganism community. Biochar amendment increased THI sorption in soil, which was associated with an increase in organic carbon and surface area and a decrease in H/C. Amendments of 300-PT (pyrolyzing temperature) biochar promoted the biodegradation of THI by increasing the microbe abundance and improving nitrile hydratase (NHase) activity. In contrast, 500- and 700-PT biochar amendments inhibited biodegradation by reducing THI availability and changing NHase activity and THI-degradative nth gene abundance, and instead promoted chemical degradation mainly through elevated pH, active groups on mineral surface and generation of *OH and other free radicals. Furthermore, THI shifted the soil microbial community, stimulated the NHase activity and elevated nth gene abundance. Biochar amendments also changed soil bacterial community by modulating soil pH, dissolved organic matter and nitrogen and phosphorus levels, which further influenced THI biodegradation. Therefore, the impact of biochars on the fate of a pesticide in soil depends greatly on their type and properties, which should be comprehensively examined when applying biochar to soil. PMID- 29414337 TI - Effect of physicochemical factors on transport and retention of graphene oxide in saturated media. AB - Fate and transport of graphene oxide (GO) have received much attention recently with the increase of GO applications. This study investigated the effect of salt concentration on the transport and retention behavior of GO particles in heterogeneous saturated porous media. Transport experiments were conducted in NaCl solutions with three concentrations (1, 20, and 50 mM) using six structurally packed columns (two homogeneous and four heterogeneous) which were made of fine and coarse grains. The results showed that GO particles had high mobility in all the homogeneous and heterogeneous columns when solution ionic strength (IS) was low. When IS was high, GO particles showed distinct transport ability in six structurally heterogeneous porous media. In homogeneous columns, decreasing ionic strength and increasing grain size increased the mobility of GO. For the column containing coarse-grained channel, the preferential flow path resulted in an early breakthrough of GO, and further larger contact area between coarse and fine grains caused a lower breakthrough peak and a stronger tailing at different IS. In the layered column, there was significant GO retention at coarse fine grain interface where water flowed from coarse grain to fine grain. Our results indicated that the fate and transport of GO particles in the natural heterogeneous porous media was highly related to the coupled effect of medium structure and salt solution concentration. PMID- 29414338 TI - Nitrogen source track and associated isotopic dynamic characteristic in a complex ecosystem: A case study of a subtropical watershed, China. AB - By identifying the main sources of nitrate (NO3-) can obtain useful information to support the management of NO3- pollution, particularly in subtropical catchments with shallow drinking water wells. This study used water chemistry and dual stable isotopes delta15N and delta18O methods to assess seasonal and spatial variations of NO3- in precipitation, surface water, and groundwater in an agricultural and forest subtropical catchment in Jiangxi Province, China. The maximum concentrations of nitrate-nitrogen (NO3--N) and ammonium-nitrogen (NH4+ N) were 10.4 and 10.8 mg L-1in samples collected from 221 rainfall events from 2011 to 2013. About 4.4% and 12.3% NH4+-N concentrations of surface water and groundwater exceeded the thresholds of 1.0 and 0.2 mg L-1. The NO3--N concentrations in surface water were closely correlated with NH4+-N concentrations in surface water and groundwater (r = -0.71 and r = -0.71, P < 0.05). The concentrations of NH4+-N and NO3--N were significantly higher in a fishery pond and nearby drinking wells than in other monitoring points. Annual exports of NO3--N and NH4+-N were 4.06 * 104 and 8.14 * 103 kg yr-1, respectively and NO3--N is the main form of N loss. The delta15N values ranged from 00/00 to 200/00 in surface water and groundwater, and the delta18O values ranged from 00/00 to 150/00 and 10/00-130/00, respectively. Dual stable isotope natural abundance distribution and water chemistry [NO3-]/[Cl-] molar ratio information suggested that manure and sewage and soil N were the main sources of NO3- in surface water and manure and sewage in groundwater in summer and winter. In spring, water occurred denitrification and ammonium fertilizer, manure and sewage were the main sources of NO3- in surface water and groundwater which sampling points were closer residential area and fish ponds than paddy field and local farmers used more Manure. Manure applications should be reasonable around drinking water wells to protect the drinking water quality. PMID- 29414339 TI - The influence of exposure and physiology on microplastic ingestion by the freshwater fish Rutilus rutilus (roach) in the River Thames, UK. AB - Microplastics are widespread throughout aquatic environments. However, there is currently insufficient understanding of the factors influencing ingestion of microplastics by organisms, especially higher predators such as fish. In this study we link ingestion of microplastics by the roach Rutilus rutilus, within the non-tidal part of the River Thames, to exposure and physiological factors. Microplastics were found within the gut contents of roach from six out of seven sampling sites. Of sampled fish, 33% contained at least one microplastic particle. The majority of particles were fibres (75%), with fragments and films also seen (22.7% and 2.3% respectively). Polymers identified were polyethylene, polypropylene and polyester, in addition to a synthetic dye. The maximum number of ingested microplastic particles for individual fish was strongly correlated to exposure (based on distance from the source of the river). Additionally, at a given exposure, the size of fish correlated with the actual quantity of microplastics in the gut. Larger (mainly female) fish were more likely to ingest the maximum possible number of particles than smaller (mainly male) fish. This study is the first to show microplastic ingestion within freshwater fish in the UK and provides valuable new evidence of the factors influencing ingestion that can be used to inform future studies on exposure and hazard of microplastics to fish. PMID- 29414340 TI - Transport and retention of surfactant- and polymer-stabilized engineered silver nanoparticles in silicate-dominated aquifer material. AB - Packed column experiments were conducted to investigate the transport and blocking behavior of surfactant- and polymer-stabilized engineered silver nanoparticles (Ag-ENPs) in saturated natural aquifer media with varying content of material < 0.063 mm in diameter (silt and clay fraction), background solution chemistry, and flow velocity. Breakthrough curves for Ag-ENPs exhibited blocking behavior that frequently produced a delay in arrival time in comparison to a conservative tracer that was dependent on the physicochemical conditions, and then a rapid increase in the effluent concentration of Ag-ENPs. This breakthrough behavior was accurately described using one or two irreversible retention sites that accounted for Langmuirian blocking on one site. Simulated values for the total retention rate coefficient and the maximum solid phase concentration of Ag ENPs increased with increasing solution ionic strength, cation valence, clay and silt content, decreasing flow velocity, and for polymer-instead of surfactant stabilized Ag-ENPs. Increased Ag-ENP retention with ionic strength occurred because of compression of the double layer and lower magnitudes in the zeta potential, whereas lower velocities increased the residence time and decreased the hydrodynamics forces. Enhanced Ag-ENP interactions with cation valence and clay were attributed to the creation of cation bridging in the presence of Ca2+. The delay in breakthrough was always more pronounced for polymer-than surfactant stabilized Ag-ENPs, because of differences in the properties of the stabilizing agents and the magnitude of their zeta-potential was lower. Our results clearly indicate that the long-term transport behavior of Ag-ENPs in natural, silicate dominated aquifer material will be strongly dependent on blocking behavior that changes with the physicochemical conditions and enhanced Ag-ENP transport may occur when retention sites are filled. PMID- 29414341 TI - Comparisons of microplastic pollution between mudflats and sandy beaches in Hong Kong. AB - Most of the previous studies of microplastic pollution on coastal habitats focused on high energy beaches although low energy areas such as mudflats are supposed to retain more microplastics, not to mention that mudflats are biologically more diverse. We quantified and characterized microplastics from 10 mudflats and 10 sandy beaches in Hong Kong spanning from the eastern to western waters. Sediment samples were collected at 1.0 m and 1.5 m above chart datum (CD) and at the strandline. Abundance of microplastics ranged between 0.58 and 2116 items kg-1 sediment with that on mudflats being ten times more than on beaches. Polyethylene (46.9%) was the most abundant and followed by polypropylene (13.8%) and polyethylene terephthalate (13.5%). Expanded polystyrene was the most abundant in the strandline samples but not at 1.0 m and 1.5 m above CD. Although previous studies have concluded that the input from Pearl River is a major source of microplastics on Hong Kong shores, this study has demonstrated that the contribution of local pollution sources such as discharge from sewage treatment plants to microplastic pollution should not be neglected. PMID- 29414342 TI - DEP and DBP induce cytotoxicity in mouse embryonic stem cells and abnormally enhance neural ectoderm development. AB - Diethyl phthalate (DEP) and dibutyl phthalate (DBP) are two typical small phthalate esters, extensively used in personal care and consumer products. Although previous studies have linked phthalate esters to several health issues, it is still unclear whether they can affects the early stages of embryonic development. In this study, we evaluated the early developmental neurotoxicity as well as the cytotoxicity of DEP and DBP, using mouse embryonic stem cells (mESCs). Our results showed that both DEP and DBP could decrease mESC viability in a dose-dependent manner. Moreover, while DBP could activate the caspase-3/7 enzymes and cause cell membrane damage as well as intracellular ROS accumulation, interestingly DEP treatment only showed stimulation of ROS production. In addition, DEP and DBP treatment at non-cytotoxic concentrations, abnormally altered the expression levels of several vitally important regulators of embryo development. For instance, neural ectoderm markers, such as Pax6, Nestin, Sox1 and Sox3, were significantly up-regulated upon DEP and DBP exposure. In conclusion, our work suggests a potential developmental toxicity of DEP and DBP on mammals, especially for neural ectoderm specification. Our findings help better understand the association between health problems and DEP/DBP exposure and most significantly remind us of the importance of additional health risk tests for these two largely used chemicals. PMID- 29414343 TI - Sorption of organic compounds by aged polystyrene microplastic particles. AB - Microplastics that are released into the environment undergo aging and interact with other substances such as organic contaminants. Understanding the sorption interactions between aged microplastics and organic contaminants is therefore essential for evaluating the impact of microplastics on the environment. There is little information available on how the aging of microplastics affects their sorption behavior and other properties. We have therefore investigated the effects of an accelerated UV-aging procedure on polystyrene microplastics, which are used in products such as skin cleaners and foams. Physical and chemical particle characterizations showed that aging led to significant surface oxidation and minor localized microcrack formation. Sorption coefficients of organic compounds by polystyrene microplastics following aging were up to one order of magnitude lower than for pristine particles. Sorption isotherms were experimentally determined using a diverse set of probe sorbates covering a variety of substance classes allowing an in-depth evaluation of the poly parameter linear free-energy relationship (ppLFER) modelling used to investigate the contribution of individual molecular interactions to overall sorption. The ppLFER modelling was validated using internal cross-validation, which confirmed its robustness. This approach therefore yields improved estimates of the interactions between aged polystyrene microplastics and organic contaminants. PMID- 29414344 TI - Empirical analysis of the effect of descent flight path angle on primary gaseous emissions of commercial aircraft. AB - In this study, the effects of descent flight path angle (between 1.25 degrees and 4.25 degrees ) on aircraft gaseous emissions (carbon monoxide, total hydrocarbons and nitrogen oxides) are explored using actual flight data from aircraft flight data recording system and emissions indices from the International Civil Aviation Organization. All emissions parameters are corrected to flight conditions using Boeing Fuel Flow Method2, where the ambient air pressure, temperature and humidity data are obtained from long-term radiosonde data measured close to the arrival airport. The main findings highlight that the higher the flight path angle, the higher the emission indices of CO and HC, whereas the lower the emissions index of NOx and fuel consumption. Furthermore, during a descent, a heavier aircraft tends to emit less CO and HC, and more NOx. For a five-tonne aircraft mass increase, the average change in emissions indices are found to be -4.1% and -5.7% (CO), -5.4% and -8.2% (HC), and +1.1% and +1.6% (NOx) for high and low flight path angle groups, respectively. The average emissions indices for CO, HC and NOx during descent are calculated to be 24.5, 1.7 and 5.6 g/kg of fuel, whereas the average emissions for descending from 32,000 ft (9.7 km) and 24,000 ft (7.3 km) are calculated to be 7-8 kg (CO), ~0.5 kg (HC) and ~3 kg (NOx). PMID- 29414345 TI - Dried blood spots for estimating mercury exposure in birds. AB - Mercury (Hg) is a pervasive environmental contaminant that can impair avian health, consequently there is a need to gauge exposures. Bird blood provides a measure of recent dietary exposure to Hg, but blood collection and storage can be complex and costly. Dried blood spots (DBS) may help overcome challenges of whole blood analyses, therefore, this study aimed to develop and validate a novel method to assess Hg exposure in birds using DBS. First, accuracy and precision of blood Hg concentrations for entire DBS and DBS punches were determined for white leghorn chicken (Gallus gallus domesticus) dosed with methylmercury (MeHg) via egg injection. Next, we investigated Hg stability in chicken DBS subjected to time, temperature, and humidity treatments. Lastly, we applied the method to DBS created using standard field methods from zebra finch (Taeniopygia guttatato) in the laboratory and American golden-plover (Pluvalis dominica) sampled in the field. All samples were analyzed for total Hg (THg) using direct Hg analysis. Accuracy was determined by comparing DBS concentrations with those of corresponding whole blood and reported as percent recovery. Accuracy for entire chicken DBS was 101.8 +/- 5.4%, while DBS punches revealed lower recovery (87.7 +/- 4.0 to 92.4 +/- 4.1%). There was little effect of time, temperature, and humidity storage treatments on Hg concentrations of DBS, with mean DBS THg concentrations within +/-8% of whole blood (n = 10 treatments). For zebra finch, DBS punches were more accurate (93.7 +/- 9.7%) compared to entire DBS (126.8 +/- 19.4%). While for American golden-plover, entire DBS resulted in the most accurate THg concentrations (111.5 +/- 7.6%) compared to DBS punches (edge: 115.4 +/- 18.9%, interior: 131.4 +/- 16.1%). Overall, results indicate that DBS analysis using direct Hg analysis can accurately evaluate Hg exposure in birds. PMID- 29414346 TI - Street-level emissions of methane and nitrous oxide from the wastewater collection system in Cincinnati, Ohio. AB - Recent studies have indicated that urban streets can be hotspots for emissions of methane (CH4) from leaky natural gas lines, particularly in cities with older natural gas distribution systems. The objective of the current study was to determine whether leaking sewer pipes could also be a source of street-level CH4 as well as nitrous oxide (N2O) in Cincinnati, Ohio, a city with a relatively new gas pipeline network. To do this, we measured the carbon (delta13C) and hydrogen (delta2H) stable isotopic composition of CH4 to distinguish between biogenic CH4 from sewer gas and thermogenic CH4 from leaking natural gas pipelines and measured CH4 and N2O flux rates and concentrations at sites from a previous study of street-level CH4 enhancements (77 out of 104 sites) as well as additional sites found through surveying sewer grates and utility manholes (27 out of 104 sites). The average isotopic signatures for delta13C-CH4 and delta2H-CH4 were 48.50/00 +/- 6.00/00 and -3020/00 +/- 1420/00. The measured flux rates ranged from 0.0 to 282.5 mg CH4 day-1 and 0.0-14.1 mg N2O day-1 (n = 43). The average CH4 and N2O concentrations measured in our study were 4.0 +/- 7.6 ppm and 392 +/- 158 ppb, respectively (n = 104). 72% of sites where fluxes were measured were a source of biogenic CH4. Overall, 47% of the sampled sites had biogenic CH4, while only 13% of our sites had solely thermogenic CH4. The other sites were either a source of both biogenic and thermogenic CH4 (13%), and a relatively large portion of sites had an unresolved source (29%). Overall, this survey of emissions across a large urban area indicates that production and emission of biogenic CH4 and N2O is considerable, although CH4 fluxes are lower than those reported for cities with leaky natural gas distribution systems. PMID- 29414347 TI - Uptake kinetics of pesticides chlorpyrifos and tebuconazole in the earthworm Eisenia andrei in two different soils. AB - Agriculture is today indispensably connected with enormous use of pesticides. Despite tough regulation, their entrance into soil cannot be excluded and they might enter soil organisms and plants and continue further to terrestrial food chains. This study was conducted to investigate the bioaccumulation of two pesticides currently used in large amounts, the insecticide chlorpyrifos (CLP) and the fungicide tebuconazole (TBZ). Their detailed uptake kinetics in the model earthworm species Eisenia andrei were measured in two arable soils differing in organic carbon content (1.02 and 1.93% respectively). According to our results, a steady state was reached after 3-5 days for both pesticides and soils. The values of bioaccumulation factors calculated at the steady state ranged from 4.5 to 6.3 for CLP and 2.2-13.1 for TBZ. Bioaccumulation factors were also calculated as the ratio of uptake and elimination rate constants with results comparable with steady-state bioaccumulation factors. The results suggested that the degradation and bioaccumulation of tested compounds might be influenced by other factors than only total organic carbon (e.g. clay content). The lower Koc and hydrophobicity of TBZ relative to CLP probably led to higher availability of TBZ through pore water exposure. On the other hand, CLP's higher hydrophobicity probably caused an increase in availability by its additional uptake via ingestion. To enable a proper ecological risk assessment of current pesticides in soils, it is necessary to accurately determine their bioaccumulation in soil invertebrates. We believe that our study not only brings such information for two specific pesticides but also addresses key methodological issues in this area. PMID- 29414348 TI - Evaluation of total phenol pollution in water of San Martin Canal from Santiago del Estero, Argentina. AB - Santiago del Estero is a province located in northwestern Argentina. The Dulce River is used for irrigation through a vast network of channels and ditches, including the San Martin Canal (SMC), which crosses the capital city of Santiago del Estero. This canal's water is used for drinking, as well as recreational use for the general population. However, this river has been seriously polluted for several decades. The present study focuses on the identification and the quantification of the water pollution levels of total phenols in the SMC according to the seasonal periods. Water samples from various areas of the canal in different months of the year, extending from December to September, were collected for analysis. Additionally, the concentration of total dissolved solids (TDS), chlorides, sulphates, nitrites and organic matter, as well as water hardness and alkalinity, were analysed in order to conduct a more complete study of the contamination of this area. The results showed a worrying total phenol concentration that exceeded the limit set by Argentine legislation for drinking water, as well as water for recreational use (5 MUg/L). The total phenol (TP) concentration was directly determined by a molecular absorption spectroscopy method based on a new flow injection analysis system (FIA). Under the selected experimental conditions, the detection and quantification limits were 0.0490 and 0.1633 MUg/mL, respectively. The developed method provides a number of improvements related to the speed of analysis, the restricted consumption of the reagents and sample volumes and the unnecessary sample treatment that contribute to environmentally friendly analytical chemistry. The results showed that TP make a significant contribution in the SMC pollution, especially during the months of April (400 +/- 110 MUg/L) and September (240 +/- 20 MUg/L). A high sulphate concentration that was higher than the limit allowed by the legislation was also found. PMID- 29414349 TI - The intensified constructed wetlands are promising for treatment of ammonia stripped effluent: Nitrogen transformations and removal pathways. AB - This study investigated the treatment performance and nitrogen removal mechanism of highly alkaline ammonia-stripped digestate effluent in horizontal subsurface flow constructed wetlands (CWs). A promising nitrogen removal performance (up to 91%) was observed in CWs coupled with intensified configurations, i.e., aeration and effluent recirculation. The results clearly supported that the higher aeration ratio and presence of effluent recirculation are important to improve the alkalinity and pollutant removal in CWs. The influent pH (>10) was significantly decreased to 8.2-8.8 under the volumetric hydraulic loading rates of 0.105 and 0.21 d-1 in the CWs. Simultaneously, up to 91% of NH4+-N removal was achieved under the operation of a higher aeration ratio and effluent recirculation. Biological nitrogen transformations accounted for 94% of the consumption of alkalinity in the CWs. The significant enrichment of delta15N-NH4+ in the effluent (47-580/00) strongly supports the occurrence of microbial transformations for NH4+-N removal. However, relatively lower enrichment factors of delta15N-NH4+ (-1.80/00 to -11.60/00) compared to the values reported in previous studies reflected the inhibition effect of the high pH alkaline environment on nitrifiers in these CWs. PMID- 29414350 TI - An overview of hexabromocyclododecane (HBCDs) in environmental media with focus on their potential risk and management in China. AB - Hexabromocyclododecanes (HBCDs) are the subject of recent interest and potential risk assessment particularly in China due to its ubiquitous existence in a variety of environmental media. This paper reviews the recent studies conducted on HBCDs in different environmental media (air, soil, water, river sediment, sewage sludge, biota and daily food) in China. At the same time, human health risks via food and occupational exposure of HBCDs in production plants, expanded polystyrene (EPS) and extruded polystyrene (XPS) plants were assessed. The review reveals that HBCDs levels of air, soil, sediment, sewage sludge, biota and food presented a geographical variation in the eastern coastal regions of China. There were many factors resulting in the variation, such as sampling sites, climate and analytical method. In terms of diastereoisomer, alpha-HBCD and gamma-HBCD were the predominant diastereoisomers in air, soil, sediment, and sewage sludge. In the water, alpha-HBCD and gamma-HBCD shared the major proportion to the total HBCDs. However, only alpha-HBCD was the predominant diastereoisomer in biota. With regard to human exposure pathway to HBCDs, food was the major route for human exposure to HBCDs, especially meat. In addition, soil and road dust were also important exposure pathways. Furthermore, workers and residents, especially infants in and around waste dumping sites and industrial areas are exposed to the highest HBCDs levels among all the populations studied thus far. HBCDs posed a potential threat to the environment and human health. Therefore, risk assessment and management have an important role to play in preventing and mitigating HBCDs risks. PMID- 29414351 TI - Nitric oxide alleviates wheat yield reduction by protecting photosynthetic system from oxidation of ozone pollution. AB - Accelerated industrialization has been increasing releases of chemical precursors of ozone. Ozone concentration has risen nowadays, and it's predicted that this trend will continue in the next few decades. The yield of many ozone-sensitive crops suffers seriously from ozone pollution, and there are abundant reports exploring the damage mechanisms of ozone to these crops, such as winter wheat. However, little is known on how to alleviate these negative impacts to increase grain production under elevated ozone. Nitric oxide, as a bioactive gaseous, mediates a variety of physiological processes and plays a central role in response to biotic and abiotic stresses. In the present study, the accumulation of endogenous nitric oxide in wheat leaves was found to increase in response to ozone. To study the functions of nitric oxide, its precursor sodium nitroprusside was spayed to wheat leaves under ozone pollution. Wheat leaves spayed with sodium nitroprusside accumulated less hydrogen peroxide, malondialdehyde and electrolyte leakage under ozone pollution, which can be accounted for by the higher activities of superoxide dismutase and peroxidase than in leaves treated without sodium nitroprusside. Consequently, net photosynthetic rate of wheat treated using sodium nitroprusside was much higher, and yield reduction was alleviated under ozone fumigation. These findings are important for our understanding of the potential roles of nitric oxide in responses of crops in general and wheat in particular to ozone pollution, and provide a viable method to mitigate the detrimental effects on crop production induced by ozone pollution, which is valuable for keeping food security worldwide. PMID- 29414352 TI - Triclosan affects axon formation in the neural development stages of zebrafish embryos (Danio rerio). AB - Triclosan (TCS) is an organic compound with a wide range of antibiotic activity and has been widely used in items ranging from hygiene products to cosmetics; however, recent studies suggest that it has several adverse effects. In particular, TCS can be passed to both fetus and infants, and while some evidence suggests in vitro neurotoxicity, there are currently few studies concerning the mechanisms of TCS-induced developmental neurotoxicity. Therefore, this study aimed to clarify the effect of TCS on neural development using zebrafish models, by analyzing the morphological changes, the alterations observed in fluorescence using HuC-GFP and Olig2-dsRED transgenic zebrafish models, and neurodevelopmental gene expression. TCS exposure decreased the body length, head size, and eye size in a concentration-dependent manner in zebrafish embryos. It increased apoptosis in the central nervous system (CNS) and particularly affected the structure of the CNS, resulting in decreased synaptic density and shortened axon length. In addition, it significantly up-regulated the expression of genes related to axon extension and synapse formation such as alpha1-Tubulin and Gap43, while decreasing Gfap and Mbp related to axon guidance, myelination and maintenance. Collectively, these changes indicate that exposure to TCS during neurodevelopment, especially during axonogenesis, is toxic. This is the first study to demonstrate the toxicity of TCS during neurogenesis, and suggests a possible mechanism underlying the neurotoxic effects of TCS in developing vertebrates. PMID- 29414353 TI - The toxic effect of sodium fluoride on Spodoptera frugiperda 9 cells and differential protein analysis following NaF treatment of cells. AB - Accumulation of excess fluoride has a destructive effect on the environment, endangering human health, affecting organism growth and development, and leading to damage to the biological chain, thereby affecting ecological environment balance. In recent years, numerous studies focused on the molecular mechanisms associated with fluoride toxicity; however, fluoride-toxicity mechanisms in insect cells remain unclear. This study explored the toxic impact of sodium fluoride (NaF) on Spodoptera frugiperda 9 (Sf9) insect cells. High concentrations of NaF (10-4 M, 10-3 M and 10-2 M) resulted in cell enlargement, cell membrane blurring and breakage, and release of cellular contents. Dose-response curves indicated that NaF-specific inhibition rates on Sf9-cell activity increased along with increases in NaF concentration, with a half-inhibitory concentration (IC50) for NaF of 5.919 * 10-3 M at 72 h. Compared with controls, the percentages of early and late apoptotic and necrotic cells clearly increased based on observed increases in NaF concentrations. Two-dimensional gel electrophoresis combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to detect differentially expressed proteins in Sf9 cells treated with IC50 NaF, identifying 17 proteins, seven of which were upregulated and 10 downregulated. These results demonstrated that Sf9 cells showed signs of NaF mediated toxicity through alterations in cell morphology, apoptosis rates, and protein expression. PMID- 29414354 TI - A high temporal-spatial vehicle emission inventory based on detailed hourly traffic data in a medium-sized city of China. AB - To improve the accuracy and temporal-spatial resolution for a vehicle emission inventory in a medium-sized city with a strip road network, this study was conducted based on detailed hourly traffic-flow data for each day of 2014, and covered all road types and regions in the city of Foshan. Detailed hourly emission characteristics and sources in five regions were analysed. The results showed that the total vehicle emissions of CO, NOX, VOCs, and PM2.5 were 13.10 * 104, 0.23 * 104, 4.46 * 104, and 0.18 * 104 tons, respectively. Motorcycles (MCs) and light passenger cars (LPCs) were the dominant contributors of CO emissions, while buses and heavy passenger cars (HPCs) were the dominant contributors for NOX. As a whole, the daytime contributions to total emissions were close to 80%, and emissions during the peak periods accounted for almost 40%. Specifically, the hourly emissions of each pollutant on workdays were higher than on non-workdays (maximum up to 64.2%), and for some roads the early peak periods changed significantly from workdays to non-workdays. At expressways, artery roads, and local roads, the daily emission intensities of CO, NOx, and PM2.5 in Foshan were close to or even higher than that of Beijing. On a regional scale, the temporal variation of vehicle emissions on workdays at artery roads of different regions were similar. In addition, the higher emission intensities of CO and VOCs were identified in DaLiang-RongGui (DLRG) and that of NOX and PM2.5 were in Central Region (CR). These results are meaningful for decision-makers to help provide more detailed vehicle pollution control measures in Foshan with a strip road network and only one ring road. PMID- 29414355 TI - Synergism of mixtures of dicamba and 2,4-dichlorophenoxyacetic acid herbicide formulations on the neotropical fish Cnesterodon decemmaculatus (Pisces, Poeciliidae). AB - Dicamba (DIC) and 2,4-dichlorophenoxyacetic acid (2,4-D) are two of the most applied auxinic herbicides worldwide, both individually and as part of a mixture. However, the toxicity and interactions achieved when applied as a mixture have not yet been characterised. The equitoxic and non-equitoxic acute toxicity exerted by binary mixtures of Banvel(r) (57.71% DIC) and DMA(r) (58.4% 2,4-D) on the Neotropical fish Cnesterodon decemmaculatus were evaluated. Results revealed mean values of 1.02 (range, 0.96-1.08) for the toxic unit (TU) that induced 50% mortality (TU50 96 h) to the fish exposed to binary equitoxic mixtures of the commercial formulations Banvel(r)-DMA(r). These results suggest that the mixture is nearly concentration additive. Furthermore, results demonstrated the occurrence of synergistic interaction when non-equitoxic combinations of Banvel(r)-or DMA(r)-formulated herbicides were assayed. In this context and regardless of their concentrations, either Banvel(r)- or DMA(r)-induced toxicity were synergised by the presence of the counterpart within mixtures. The present study represents the first evidence of the lethality exerted by mixtures of two auxinic herbicides-namely, DIC and 2,4-D-reported to date for fish and other biotic matrices. When C. decemmaculatus is used as the target organism, a synergistic pattern is observed following exposure to a mixture of both herbicides. PMID- 29414356 TI - Effects of exposure to polychlorinated biphenyls during different periods of development on ethanol consumption by male and female rats. AB - In two experiments, male and female Sprague-Dawley rats were exposed to Polychlorinated Biphenyls (PCBs) to assess the effect PCBs, an estrogenic endocrine disrupting chemical (EEDC), would have on the voluntary consumption of alcohol. There are several EEDCs in our food that are known to increase estrogen in adolescent females. Our objective was to assess the effect that increasing estrogen, by adding the EEDC PCBs would have on volitional intake of alcohol. In Experiment 1, pregnant dams were exposed from gestational days 5-19 to a 1:1 mixture of Aroclor 1254/1260. In Experiment 2, lactating females were exposed to the same dose of 1254:1260 from postnatal days 1-21. In both experiments, a fade in procedure was used to gradually introduce the rats to the taste of alcohol. At the end of the fade-in series all animals were given limited access (1 h/day) to a water/alcohol solution. We found that females exposed to PCBs, at two developmental periods, consumed significantly more alcohol than unexposed females and exposed and unexposed males. Results of the experiments are discussed in terms of how PCB exposure can disrupt endocrine processes (e.g., estrogenic endocrine disrupting chemicals, EEDC) that increase estrogen in females, thereby leading to increased alcohol consumption. Thus, the present findings suggest that EEDCs, such as PCBs, could contribute to the increase abuse of alcohol in adolescent females. PMID- 29414357 TI - Time-dependent bacterial community and electrochemical characterizations of cathodic biofilms in the surfactant-amended sediment-based bioelectrochemical reactor with enhanced 2,3,4,5-tetrachlorobiphenyl dechlorination. AB - Applying an electric field to stimulate the microbial reductive dechlorination of polychlorinated biphenyls (PCBs) represents a promising approach for bioremediation of PCB-contaminated sites. This study aimed to demonstrate the biocathodic film-facilitated reduction of PCB 61 in a sediment-based bioelectrochemical reactor (BER) and, more importantly, the characterizations of electrode-microbe interaction from microbial and electrochemical perspectives particularly in a time-dependent manner. The application of a cathodic potential (-0.45 V vs. SHE) significantly improved the rate and extent of PCB 61 dechlorination compared to the open-circuit scenario (without electrical stimulation), and the addition of an external surfactant further increased the dechlorination, with Tween 80 exerting more pronounced effects than rhamnolipid. The bacterial composition of the biofilms and the bioelectrochemical kinetics of the BERs were found to be time-dependent and to vary considerably with the incubation time and slightly with the coexistence of an external surfactant. Excellent correlations were observed between the dechlorination rate and the relative abundance of Dehalogenimonas, Dechloromonas, and Geobacter, the dechlorination rate and the cathodic current density recorded from the chronoamperometry tests, and the dechlorination rate and the charge transfer resistance derived from the electrochemical impedance tests, with respect to the 120 day-operation. After day 120, PCB 61 was resistant to further appreciable reduction, but substantial hydrogen production was detected, and the bacterial community and electrochemical parameters observed on day 180 were not distinctly different from those on day 120. PMID- 29414358 TI - Benzyldimethyldodecyl ammonium chloride shifts the proliferation of functional genes and microbial community in natural water from eutrophic lake. AB - Benzylalkyldimethylethyl ammonium compounds are pervasive in natural environments and toxic at high concentrations. The changes in functional genes and microbial diversity in eutrophic lake samples exposed to benzyldimethyldodecyl ammonium chloride (BAC) were assessed. BAC exerted negative effects on bacteria abundance, particularly at concentrations of 100 MUg L-1 and higher. A significant increase in the number of the quaternary ammonium compound-resistant gene qacA/B was recorded within the 10 MUg L-1 treatment after the first day of exposure. Not all antibiotic resistance genes increased in abundance as the concentrations of BAC increased; rather, gene abundances were dependent on the gene type, concentrations of BAC, and contact time. The nitrogen fixation-related gene nifH and ammonia monooxygenase gene amoA were inhibited by high concentrations of BAC after the first day, whereas an increase of the nitrite reductase gene nirK was stimulated by exposure. Microbial communities within higher treatment levels (1000 and 10 000 MUg L-1) exhibited significantly different community composition compared to other treatment levels and the control. Selective enrichment of Rheinheimera, Pseudomonas, and Vogesella were found in the higher treatment levels, suggesting that these bacteria have some resistance or degradation capacity to BAC. Genes related with RNA processing and modification, transcription, lipid transport and metabolism, amino acid transport and metabolism, and cell motility of microbial community function were involved in the process exposed to the BAC stress. PMID- 29414359 TI - Quadratic discriminant analysis model for assessing the risk of cadmium pollution for paddy fields in a county in China. AB - In China, the cadmium (Cd) levels in paddy fields have increased, which has led to the excessive uptake of Cd into rice grains. In this study, we determined the physicochemical properties of soil samples, including the pH, soil organic matter (SOM) content, cation exchange capacity (CEC), and total Cd content (Cdsoil) in order to establish a quadratic discriminant analysis (QDA) model for assessing the risk of Cd in rice and to calculate its prior probability. Decision tree and logistic regression models were also established for comparison. The results showed that the accuracy rate was 74% with QDA, which was significantly higher than that obtained using the decision tree (67%) and logistic regression (68%) models. The correlation coefficients between the soil pH and the other three factors (CEC, SOM, and Cdsoil) were higher in the inaccurate set than the accurate set, whereas the correlation coefficients were smaller in the inaccurate set than the accurate set. PMID- 29414360 TI - Current and historical concentrations of poly and perfluorinated compounds in sediments of the northern Great Lakes - Superior, Huron, and Michigan. AB - Current and historical concentrations of 22 poly- and perfluorinated compounds (PFASs) in sediment collected from Lake Superior and northern Lake Michigan in 2011 and Lake Huron in 2012 are reported. The sampling was performed in two ways, Ponar grabs of surface sediments for current spatial distribution across the lake and dated cores for multi-decadal temporal trends. Mean concentrations of the sum of PFASs (?PFASs) were 1.5, 4.6 and 3.1 ng g-1 dry mas (dm) in surface sediments for Lakes Superior, Michigan and Huron, respectively. Of the five Laurentian Lakes, the watersheds of Superior and Huron are the less densely populated by humans, and concentrations observed were typically less and from more diffuse sources, due to lesser urbanization and industrialization. However, some regions of greater concentrations were observed and might indicate more local, point sources. In core samples concentrations ranged from 7 that include perfluoro-n octane sulfonate (PFOS) bind more strongly to sediment, which resulted in more accurate analyses of temporal trends. Shorter-chain PFASs, such as perfluoro-n butanoic acid which is the primary replacement for C8 PFASs that have been phased out, are more soluble and were identified in some core layers at depths corresponding to pre-production periods. Thus, analyses of temporal trends of these more soluble compounds in cores of sediments were less accurate. Total elemental fluorine (TF) and extractable organic fluorine (EOF) indicated that identified PFASs were not a significant fraction of fluorine containing compounds in sediment (<0.01% in EOF). PMID- 29414361 TI - Effects of ambient air pollution from municipal solid waste landfill on children's non-specific immunity and respiratory health. AB - This cross-sectional study investigated the association between air pollutant (AP) and respiratory health of 951 children residing near a municipal solid waste (MSW) landfill in Northern China. Results showed that students in non-exposure areas had significantly higher levels of lysozyme, secretory immunoglobulin A (SIgA), and better lung capacity than students in exposure areas (p < .05). Multiple regression model analysis indicated that lysozyme levels exhibited a consistent negative association with methane (CH4: beta = -76.3, 95% CI -105 to 47.7) and sulfuretted hydrogen (H2S: beta = -11.7, 95% CI -20.2 to -3.19). In addition, SIgA levels were negatively associated with H2S (beta = -68.9, 95% CI 97.9 to -39.9) and ammonia (NH3: beta = -30.3, 95% CI -51.7 to -8.96). Among all AP, H2S and sulfur dioxide (SO2) were the most robustly related with reduced lung function. H2S exposure was negatively associated with six lung function indices, 1-s forced expiratory volume (FEV1%), mean forced expiratory flow between 25% and 75% (MMF), maximum voluntary ventilation (MVV), and forced expiratory flow at 25%, 50%, and 75% of the pulmonary volume (FEF25, FEF50, FEF75); and SO2 was negatively associated with FEV1%, MVV, FEF25, FEF50 and FEF75. Our results suggested that AP exposure was negatively associated with more lung function parameters in boys than in girls. In conclusion, our findings suggested that children living adjacent to landfill sites were more likely to have deficient non specific immunity and impaired lung function. PMID- 29414362 TI - Regional variations of organophosphorus flame retardants - Fingerprint of large river basin estuaries/deltas in Europe compared with China. AB - This study reports the occurrence and distribution of organophosphorus flame retardants and plasticizer (OPEs) in sediments of eight large river basin estuaries and deltas across Europe. A robust and sensitive OPE analysis method was developed through the application of an in-cell clean-up in an accelerated solvent extraction and the use of an GC-MSMS System for instrumental analyses. OPEs were detected in all sediment samples with sum concentrations of up to 181 ng g-1 dw. A fingerprinting method was used to identify river specific pattern to compare river systems. The estuaries and deltas were chosen to have a conglomerate print of the whole river. The results are showing very similar OPE patterns across Europe with minor differences driven by local industrial input. The European estuary concentrations and patterns were compared with OPEs detected in the Xiaoquing River in China, as an example for a region with other production, usage and legislative regulations. The Chinese fingerprint differed significant from the overall European pattern. PMID- 29414363 TI - Hourly disaggregation of industrial CO2 emissions from Shenzhen, China. AB - Shenzhen's total industrial CO2 emission was calculated using the IPCC recommended bottom-up approach and data obtained from the China High Resolution Emission Gridded Data (CHRED). Monthly product yield was then used as the proxy to disaggregate a facility's total emission into monthly emissions. Since a thermal power unit's emission changes with daily and hourly power loads, typical power load curves were used as the proxy to disaggregate the monthly emissions on a daily and hourly basis. The daily and hourly emissions of other facilities were calculated according to two specially designed models: the "weekdays + Spring Festival holidays" model for February and the "weekdays + weekends" model for non February months. The uncertainty ranges associated with the process of the total amount calculation, monthly disaggregation, daily disaggregation and hourly disaggregation were quantitatively estimated. The total combined uncertainty of the hourly disaggregation of "weekdays + weekends" mode was +/-26.19%, and that of the "weekdays + Spring Festival holidays" mode was +/-33.06%. These temporal disaggregation methods and uncertainty estimate approaches could also be used for the industrial air pollutant emission inventory and easily reproduced in the whole country. PMID- 29414364 TI - Association patterns for size-fractioned indoor particulate matter and black carbon and autonomic function differ between patients with chronic obstructive pulmonary disease and their healthy spouses. AB - BACKGROUND: The effect of health status on the relationship between particulate matter (PM) and black carbon (BC) and cardiac autonomic function has not been examined sufficiently directly comparing patients with healthy participants. OBJECTIVES: To evaluate the association patterns between size-fractioned indoor PM and BC and cardiac autonomic function in chronic obstructive pulmonary disease (COPD) patients and their healthy spouses. METHODS: Twenty-four-hour heart rate variability (HRV) and heart rate (HR) was measured in eight pairs of stable COPD patients and their healthy spouses. Real-time size-fractioned indoor PM and BC levels were monitored on the same, and preceding, days. Mixed-effects models were used to estimate the changes in health indices and pollutants after controlling for potential confounding variables. RESULTS: Increases in size-fractioned PM and BC were associated with alterations in cardiac autonomic function in both COPD patients and their healthy spouses. However, the association patterns differed between the two groups. In COPD group, an IQR (13.65 MUg/m3) increase in PM0.5 at 12-h moving average was associated with reductions of 14.62% (95% CI: -21.74%, 6.86%) in total power (TP) and 10.14% (95% CI: -16.11%, -3.76%) in high frequency (HF) power. In healthy volunteers, however, TP and HF declined immediately upon exposure to PM and then returned to normal levels gradually. In this group, an IQR increase in PM0.5 at 5 min moving average was associated a 20.30% (95% CI: 25.49%, -14.73%) reduction in TP and a 31.79% (95% CI: -36.48%, -26.72%) reduction in HF. CONCLUSIONS: Exposure to indoor PM and BC was associated with cardiac autonomic dysfunction in COPD patients and their healthy spouses. Exposure had a greater lagged effect on HRV in COPD patients than in healthy participants. These findings will aid the formulation of targeted measures to prevent the adverse effects of indoor air pollution for individuals with different health statuses. PMID- 29414365 TI - Marine litter in an EBSA (Ecologically or Biologically Significant Area) of the central Mediterranean Sea: Abundance, composition, impact on benthic species and basis for monitoring entanglement. AB - Marine litter is commonly observed everywhere in the ocean. In this study, we analyzed 17 km of video footage, collected by a Remotely Operated Vehicle (ROV) at depths ranging between 20 and 220 m, during 19 transects performed on the rocky banks of the Straits of Sicily. Recently, the Contracting Parties of the Convention on Biological Diversity (CBD) recognized this site as an Ecologically or Biologically Significant Area (EBSA). The research aim was to quantify the abundance of marine litter and its impact on benthic fauna. Litter density ranged from 0 items/100 m2 to 14.02 items/100 m2 with a mean (+/-standard error) of 2.13 (+/-0.84) items/100 m2. The observed average density was higher (5.2 items/100 m2) at depths >100 m than at shallower depths (<100 m, 0.71 items/100 m2). Lost or abandoned fishing lines contributed to 98.07% of the overall litter density, then representing the dominant source of marine debris. Litter interactions with fauna were frequently observed, with 30% of litter causing "entanglement/coverage" and 15% causing damage to sessile fauna. A total of 16 species showed interaction (entanglement/coverage or damage) with litter items and 12 of these are species of conservation concern according to international directives and agreements (CITES, Berne Convention, Habitat Directive, SPA/BD Protocol, IUCN Red List); we also observed 7 priority habitats of the SPA/BD Protocol. This research will support the implementation of monitoring "Harm" as recommended by the UN Environment/MAP Regional Plan on Marine Litter Management in the Mediterranean, and the Marine Strategy Framework Directive (MSFD). The institution of a SPAMI in the investigated area could represent a good management action for the protection of this hotspot of biodiversity and to achieve a Good Environmental Status (GES) for the marine environment by 2020, under the MSFD. PMID- 29414366 TI - What is the aquatic toxicity of saponin-rich plant extracts used as biopesticides? AB - Saponin-rich extracts from Quillaja saponaria and Chenopodium quinoa have been registered by US EPA as active ingredients in biopesticides, and extract from tea seed powder, Camellia oleifera has been proposed for biocidal use. If saponin rich biopesticides are efficient against pests, they are most likely also bioactive in the aquatic environment against non-target organisms. The aim of this study was to conduct an effect assessment of saponin-rich plant extracts by using species sensitivity distributions based on acute toxicity tests. The maximal concentrations protecting 95% of the aquatic species (HC5) of saponins extracted from quillaja bark, tea seed coat and quinoa seed coat were 2.91 +/- 1.00, 0.22 +/- 0.11 and 22.9 +/- 5.84 mg/L, respectively. The 100-fold difference in toxicity between the saponin-rich extracts from different plant species, indicate that saponin toxicity depends on the species it origins from, making "read-across" between saponins a dubious exercise. In addition, the predicted environmental concentrations of different saponins are close to or higher than their water quality standard, which means that the extracts might pose a risk to the aquatic environment if not used cautiously. PMID- 29414367 TI - Environmentally relevant concentrations of polyethylene microplastics negatively impact the survival, growth and emergence of sediment-dwelling invertebrates. AB - Microplastics are a widespread environmental pollutant in aquatic ecosystems and have the potential to eventually sink to the sediment, where they may pose a risk to sediment-dwelling organisms. While the impacts of exposure to microplastics have been widely reported for marine biota, the effects of microplastics on freshwater organisms at environmentally realistic concentrations are largely unknown, especially for benthic organisms. Here we examined the effects of a realistic concentration of polyethylene microplastics in sediment on the growth and emergence of a freshwater organism Chironomus tepperi. We also assessed the influence of microplastic size by exposing C. tepperi larvae to four different size ranges of polyethylene microplastics (1-4, 10-27, 43-54 and 100-126 MUm). Exposure to an environmentally relevant concentration of microplastics, 500 particles/kgsediment, negatively affected the survival, growth (i.e. body length and head capsule) and emergence of C. tepperi. The observed effects were strongly dependent on microplastic size with exposure to particles in the size range of 10 27 MUm inducing more pronounced effects. While growth and survival of C. tepperi were not affected by the larger microplastics (100-126 MUm), a significant reduction in the number of emerged adults was observed after exposure to the largest microplastics, with the delayed emergence attributed to exposure to a stressor. While scanning electron microscopy showed a significant reduction in the size of the head capsule and antenna of C. tepperi exposed to microplastics in the 10-27 MUm size range, no deformities to the external structure of the antenna and mouth parts in organisms exposed to the same size range of microplastics were observed. These results indicate that environmentally relevant concentrations of microplastics in sediment induce harmful effects on the development and emergence of C. tepperi, with effects greatly dependent on particle size. PMID- 29414368 TI - Effects of imidacloprid on the ecology of sub-tropical freshwater microcosms. AB - The neonicotinoid insecticide imidacloprid is used in Bangladesh for a variety of crop protection purposes. Imidacloprid may contaminate aquatic ecosystems via spray drift, surface runoff and ground water leaching. The present study aimed at assessing the fate and effects of imidacloprid on structural (phytoplankton, zooplankton, macroinvertebrates and periphyton) and functional (organic matter decomposition) endpoints of freshwater, sub-tropical ecosystems in Bangladesh. Imidacloprid was applied weekly to 16 freshwater microcosms (PVC tanks containing 400 L de-chlorinated tap water) at nominal concentrations of 0, 30, 300, 3000 ng/L over a period of 4 weeks. Results indicated that imidacloprid concentrations from the microcosm water column declined rapidly. Univariate and multivariate analysis showed significant effects of imidacloprid on the zooplankton and macroinvertebrate community, some individual phytoplankton taxa, and water quality variables (i.e. DO, alkalinity, ammonia and nitrate), with Cloeon sp., Diaptomus sp. and Keratella sp. being the most affected species, i.e. showing lower abundance values in all treatments compared to the control. The observed high sensitivity of Cloeon sp. and Diaptomus sp. was confirmed by the results of single species tests. No significant effects were observed on the species composition of the phytoplankton, periphyton biomass and organic matter decomposition for any of the sampling days. Our study indicates that (sub )tropical aquatic ecosystems can be much more sensitive to imidacloprid compared to temperate ones. PMID- 29414369 TI - Potential transfer of organic pollutants from littoral plastics debris to the marine environment. AB - Plastic polymers act as passive samplers in air system and concentrate hydrophobic organic contaminants by sorption or specific interactions, which can be transported to other systems such as the marine environment. In this study plastic debris was sampled in the surrounding area of a Mediterranean lagoon in order to determine the concentration of persistent and emerging organic contaminants. More specifically, desorption of 91 regulated and emerging organic contaminants (polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorinated pesticides, current-use pesticides, personal care products, other pesticides and plastic additives) was characterized for the first 24 h from different polymers to seawater and the remaining content of these contaminants was also extracted by ultrasonic extraction with methanol. All samples were analyzed by Stir Bar Sorptive Extraction coupled to GC/MS. A significant fraction of sorbed contaminants in polymers was desorbed in the first 24 h, particularly for triazines and organophosphorus pesticides due to their lower hydrophobicity than other considered analytes. The remaining contaminants contained in plastics can be also transferred to seawater, sediments or biota. Considering 24 h desorbed fraction plus the remaining methanol extracted fraction, the highest transfer levels corresponded to personal care products, plastic additives, current-use pesticides and PAHs. This is the first study to show the relevance of the transport of organic contaminants on plastic debris from littoral areas to the marine environment. PMID- 29414370 TI - Toxicity of Co nanoparticles on three species of marine microalgae. AB - Cobalt nanoparticles (CoNPs) are being used in wide range of applications and may enter aquatic environments where they pose a potential threat to aquatic organisms. Algal growth inhibition tests were conducted to explore the potential toxicity of CoNPs on marine microalgae, Platymonas subcordiforus, Chaetoceros curvisetus and Skeletonema costatum. This is one of the first time to explore toxicity of CoNPs on marine algae systematically. The results showed that CoNPs induced toxicity on the three algae. The CoNP toxicity on three species microalgae was partly attributed to the Co2+ released by CoNPs in the f/2 seawater medium. The particle size distribution of CoNPs in seawater revealed that CoNPs were agglomerated in the seawater. The shading effect of CoNPs and scanning electron microscope (SEM) images also showed the aggregating of CoNPs and microalgae, which influenced the photosynthetic utilization and inhibited the growth of the three algae. The order of toxic sensitivity of CoNPs on the three algae was as follows: Platymonas subcordiforus < Chaetoceros curvisetus < Skeletonema costatum. PMID- 29414371 TI - Significance of metallothioneins in differential cadmium accumulation kinetics between two marine fish species. AB - Impacted marine environments lead to metal accumulation in edible marine fish, ultimately impairing human health. Nevertheless, metal accumulation is highly variable among marine fish species. In addition to ecological features, differences in bioaccumulation can be attributed to species-related physiological processes, which were investigated in two marine fish present in the Canary Current Large Marine Ecosystem (CCLME), where natural and anthropogenic metal exposure occurs. The European sea bass Dicentrarchus labrax and Senegalese sole Solea senegalensis were exposed for two months to two environmentally realistic dietary cadmium (Cd) doses before a depuration period. Organotropism (i.e., Cd repartition between organs) was studied in two storage compartments (the liver and muscle) and in an excretion vector (bile). To better understand the importance of physiological factors, the significance of hepatic metallothionein (MT) concentrations in accumulation and elimination kinetics in the two species was explored. Accumulation was faster in the sea bass muscle and liver, as inferred by earlier Cd increase and a higher accumulation rate. The elimination efficiency was also higher in the sea bass liver compared to sole, as highlighted by greater biliary excretion. In the liver, no induction of MT synthesis was attributed to metal exposure, challenging the relevance of using MT concentration as a biomarker of metal contamination. However, the basal MT pools were always greater in the liver of sea bass than in sole. This species-specific characteristic might have enhanced Cd biliary elimination and relocation to other organs such as muscle through the formation of more Cd/MT complexes. Thus, MT basal concentrations seem to play a key role in the variability observed in terms of metal concentrations in marine fish species. PMID- 29414372 TI - Indoor PM2.5 in an urban zone with heavy wood smoke pollution: The case of Temuco, Chile. AB - Temuco is a mid-size city representative of severe wood smoke pollution in southern Chile; however, little is known about the indoor air quality in this region. A field measurement campaign at 63 households in the Temuco urban area was conducted in winter 2014 and is reported here. In this study, indoor and outdoor (24-hr) PM2.5 and its elemental composition were measured and compared. Infiltration parameters and outdoor/indoor contributions to indoor PM2.5 were also determined. A statistical evaluation of how various air quality interventions and household features influence indoor PM2.5 was also performed. This study determined median indoor and outdoor PM2.5 concentrations of 44.4 and 41.8 MUg/m3, respectively. An average infiltration factor (0.62 +/- 0.06) was estimated using sulfur as a tracer species. Using a simple mass balance approach, median indoor and outdoor contributions to indoor PM2.5 concentrations were then estimated as 12.5 and 26.5 MUg/m3, respectively; therefore, 68% of indoor PM2.5 comes from outdoor infiltration. This high percentage is due to high outdoor pollution and relatively high household air exchange rates (median: 1.06 h-1). This study found that S, Br and Rb were dominated by outdoor contributions, while Si, Ca, Ti, Fe and As originated from indoor sources. Using continuous indoor and outdoor PM2.5 measurements, a median indoor source strength of 75 MUg PM2.5/min was estimated for the diurnal period, similar to literature results. For the evening period, the median estimate rose to 135 MUg PM2.5/min, reflecting a more intense wood burning associated to cooking and space heating at night. Statistical test results (at the 90% confidence level) support the ongoing woodstove replacement program (reducing emissions) and household weatherization subsidies (reducing heating demand) for improving indoor air quality in southern Chile, and suggest that a cookstove improvement program might be helpful as well. PMID- 29414373 TI - On the risks from sediment and overlying water by replenishing urban landscape ponds with reclaimed wastewater. AB - The extensive use of reclaimed wastewater (RW) as a source of urban landscape pond replenishment, stimulated by the lack of surface water (SW) resources, has raised public concern. Greater attention should be paid to pond sediments, which act as 'sinks' and 'sources' of contaminants to the overlying pond water. Three ponds replenished with RW (RW ponds) in three Chinese cities were chosen to investigate 22 indices of sediment quality in four categories: eutrophication, heavy metal, ecotoxicity and pathogens risk. RW ponds were compared with other ponds of similar characteristics in the same cities that were replenished with SW (SW ponds). Our results show a strong impact of RW to the eutrophication and pathogenic risks, which are represented by organic matter, water content, total nitrogen, total phosphorus and phosphorus fractions, and pathogens. In particular, total phosphorus concentrations in the RW pond sediments were, on average, 50% higher than those of SW ponds. Moreover, the content of phosphorus, extracted by bicarbonate/dithionite (normally represented by BD-P) and NaOH (NaOH P), were 2.0- and 2.83-times higher in RW ponds, respectively. For pathogens, the concentrations of norovirus and rotavirus in RW pond sediments were, on average, 0.52 and 0.30- log times those of SW ponds. The duration of RW replenishment was proved to have a marked impact on the eutrophication and pathogens risks from sediments. The continued use of RW for replenishment increases the eutrophication risk, and the pathogens risk, especially by viral pathogens, becomes greater. PMID- 29414374 TI - Shipping emission forecasts and cost-benefit analysis of China ports and key regions' control. AB - China established Domestic Emission Control Area (DECA) for sulphur since 2015 to constrain the increasing shipping emissions. However, future DECA policy-makings are not supported due to a lack of quantitive evaluations. To investigate the effects of current and possible Chinese DECAs policies, a model is presented for the forecast of shipping emissions and evaluation of potential costs and benefits of an DECA policy package set in 2020. It includes a port-level and regional level projection accounting for shipping trade volume growth, share of ship types, and fuel consumption. The results show that without control measures, both SO2 and particulate matter (PM) emissions are expected to increase by 15.3-61.2% in Jing-Jin-Ji, the Yangtze River Delta, and the Pearl River Delta from 2013 to 2020. However, most emissions can be reduced annually by the establishment of a DECA that depends on the size of the control area and the fuel sulphur content limit. Costs range from 0.667 to 1.561 billion dollars (control regional shipping emissions) based on current fuel price. A social cost method shows the regional control scenarios benefit-cost ratios vary from 4.3 to 5.1 with large uncertainty. Chemical transportation model combined with health model method is used to get the monetary health benefits and then compared with the results from social cost method. This study suggests that Chinese DECAs will reduce the projected emissions at a favorable benefit-cost ratio, and furthermore proposes policy combinations that provide high cost-effective benefits as a reference for future policy-making. PMID- 29414375 TI - Biological responses of two marine organisms of ecological relevance to on-going ocean acidification and global warming. AB - Recently, there has been a growing concern that climate change may rapidly and extensively alter global ecosystems with unknown consequences for terrestrial and aquatic life. While considerable emphasis has been placed on terrestrial ecology consequences, aquatic environments have received relatively little attention. Limited knowledge is available on the biological effects of increments of seawater temperature and pH decrements on key ecological species, i.e., primary producers and/or organisms representative of the basis of the trophic web. In the present study, we addressed the biological effects of global warming and ocean acidification on two model organisms, the microbenthic marine ciliate Euplotes crassus and the green alga Dunaliella tertiocleta using a suite of high level ecological endpoint tests and sub-lethal stress measures. Organisms were exposed to combinations of pH and temperature (TR1: 7.9[pH], 25.5 degrees C and TR2: 7.8[pH], 27,0 degrees C) simulating two possible environmental scenarios predicted to occur in the habitats of the selected species before the end of this century. The outcomes of the present study showed that the tested scenarios did not induce a significant increment of mortality on protozoa. Under the most severe exposure conditions, sub-lethal stress indices show that pH homeostatic mechanisms have energetic costs that divert energy from essential cellular processes and functions. The marine protozoan exhibited significant impairment of the lysosomal compartment and early signs of oxidative stress under these conditions. Similarly, significant impairment of photosynthetic efficiency and an increment in lipid peroxidation were observed in the autotroph model organism held under the most extreme exposure condition tested. PMID- 29414376 TI - Potential human exposures to neonicotinoid insecticides: A review. AB - Due to their systemic character and high efficacy to insect controls, neonicotinoid insecticides (neonics) have been widely used in global agriculture since its introduction in early 1990. Recent studies have indicated that neonics may be ubiquitous, have longer biological half-lives in the environment once applied, and therefore implicitly suggested the increasing probability for human exposure to neonics. Despite of neonics' persistent characters and widespread uses, scientific literature in regard of pathways in which human exposure could occur is relatively meager. In this review, we summarized results from peer reviewed articles published prior to 2017 that address potential human exposures through ingestion and inhalation, as well as results from human biomonitoring studies. In addition, we proposed the use of relative potency factor approach in order to facilitate the assessment of concurrent exposure to a mixture of neonics with similar chemical structures and toxicological endpoints. We believe that the scientific information that we presented in this review will aid to future assessment of total neonic exposure and subsequently human health risk characterization. PMID- 29414377 TI - Photons and foraging: Artificial light at night generates avoidance behaviour in male, but not female, New Zealand weta. AB - Avoiding foraging under increased predation risk is a common anti-predator behaviour. Using artificial light to amplify predation risk at ecologically valuable sites has been proposed to deter introduced mice (Mus musculus) and ship rats (Rattus rattus) from degrading biodiversity in island ecosystems. However, light may adversely affect native species; in particular, little is known about invertebrate responses to altered lighting regimes. We investigated how endemic orthopterans responded to artificial light at Maungatautari Ecological Island (Waikato, New Zealand). We predicted that based on their nocturnal behaviour, ecology and evolutionary history, tree weta (Hemideina thoracica) and cave weta (Rhaphidophoridae) would reduce their activity under illumination. Experimental stations (n = 15) experienced three evenings under each treatment (order randomised): (a) light (illuminated LED fixture), (b) dark (unilluminated LED fixture) and (c) baseline (no lighting fixture). Weta visitation rates were analysed from images captured on infra-red trail cameras set up at each station. Light significantly reduced the number of observations of cave (71.7% reduction) and tree weta (87.5% reduction). In observations where sex was distinguishable (53% of all visits), male tree weta were observed significantly more often (85% of visits) than females (15% of visits) and while males avoided illuminated sites, no detectable difference was observed across treatments for females. Sex could not be distinguished for cave weta. Our findings have implications for the use of light as a novel pest management strategy, and for the conservation of invertebrate diversity and abundance within natural and urban ecosystems worldwide that may be affected by light pollution. PMID- 29414378 TI - Development of a nematode offspring counting assay for rapid and simple soil toxicity assessment. AB - Since the introduction of standardized nematode toxicity assays by the American Society for Testing and Materials (ASTM) and International Organization for Standardization (ISO), many studies have reported their use. Given that the currently used standardized nematode toxicity assays have certain limitations, in this study, we examined the use of a novel nematode offspring counting assay for evaluating soil ecotoxicity based on a previous soil-agar isolation method used to recover live adult nematodes. In this new assay, adult Caenorhabditis elegans were exposed to soil using a standardized toxicity assay procedure, and the resulting offspring in test soils attracted by a microbial food source in agar plates were counted. This method differs from previously used assays in terms of its endpoint, namely, the number of nematode offspring. The applicability of the bioassay was demonstrated using metal-spiked soils, which revealed metal concentration-dependent responses, and with 36 field soil samples characterized by different physicochemical properties and containing various metals. Principal component analysis revealed that texture fraction (clay, sand, and silt) and electrical conductivity values were the main factors influencing the nematode offspring counting assay, and these findings warrant further investigation. The nematode offspring counting assay is a rapid and simple process that can provide multi-directional toxicity assessment when used in conjunction with other standard methods. PMID- 29414379 TI - Prion-like seeding and nucleation of intracellular amyloid-beta. AB - Alzheimer's disease (AD) brain tissue can act as a seed to accelerate aggregation of amyloid-beta (Abeta) into plaques in AD transgenic mice. Abeta seeds have been hypothesized to accelerate plaque formation in a prion-like manner of templated seeding and intercellular propagation. However, the structure(s) and location(s) of the Abeta seeds remain unknown. Moreover, in contrast to tau and alpha synuclein, an in vitro system with prion-like Abeta has not been reported. Here we treat human APP expressing N2a cells with AD transgenic mouse brain extracts to induce inclusions of Abeta in a subset of cells. We isolate cells with induced Abeta inclusions and using immunocytochemistry, western blot and infrared spectroscopy show that these cells produce oligomeric Abeta over multiple replicative generations. Further, we demonstrate that cell lysates of clones with induced oligomeric Abeta can induce aggregation in previously untreated N2a APP cells. These data strengthen the case that Abeta acts as a prion-like protein, demonstrate that Abeta seeds can be intracellular oligomers and for the first time provide a cellular model of nucleated seeding of Abeta. PMID- 29414380 TI - Gene therapy mediated seizure suppression in Genetic Generalised Epilepsy: Neuropeptide Y overexpression in a rat model. AB - Neuropeptide Y (NPY) is an important 36 amino acid peptide that is abundantly expressed in the mammalian CNS and is known to be an endogenous modulator of seizure activity, including in rat models of Genetic Generalised Epilepsy (GGE) with absence seizures. Studies have shown that viral-mediated "gene therapy" with overexpression of NPY in the hippocampus can suppress seizures in acquired epilepsy animal models. This study investigated whether NPY gene delivery to the thalamus or somatosensory cortex, using recombinant adeno-associated viral vector (rAAV), could produce sustained seizure suppression in the GAERS model of GGE with absence seizures. Three cohorts of GAERS were injected bilaterally into the thalamus (short term n = 14 and long term n = 8) or the somatosensory cortex (n = 26) with rAAV-NPY or rAAV-empty. EEG recordings were acquired weekly post treatment and seizure expression was quantified. Anxiety levels were tested using elevated plus maze and open field test. NPY and NPY receptor mRNA and protein expression were evaluated using quantitative PCR, immunohistochemistry and immunofluorescence. Viral overexpression of human NPY in the thalamus and somatosensory cortex in GAERS significantly reduced the time spent in seizure activity and number of seizures, whereas seizure duration was only reduced after thalamic NPY overexpression. Human and rat NPY and rat Y2 receptor mRNA expression was significantly increased in the somatosensory cortex. NPY overexpression in the thalamus was observed in rAAV-NPY treated rats compared to controls in the long term cohort. No effect was observed on anxiety behaviour. We conclude that virally-mediated human NPY overexpression in the thalamus or somatosensory cortex produces sustained anti-epileptic effects in GAERS. NPY gene therapy may represent a novel approach for the treatment of patients with genetic generalised epilepsies. PMID- 29414382 TI - Interictal dysphoric disorder: Further doubts about its epilepsy-specificity and its independency from common psychiatric disorders. AB - PURPOSE: The interictal dysphoric disorder (IDD) is a proposed epilepsy-specific psychiatric condition characterized by a conglomerate of symptoms such as depression, irritability, euphoria, and anxiety. However, there are doubts about IDD as an independent entity and about its presumed epilepsy-specific nature. METHODS: Here, we investigated the association between psychiatric disorders and IDD in 120 patients with epilepsy, also analyzing potential associations between IDD symptoms and epilepsy-related variables. To test the epilepsy-specificity of IDD, we also studied IDD rates in 28 patients with pure psychogenic non-epileptic seizures. For the assessment of psychopathology, we used a structured clinical interview to determine the presence and nature of Axis I disorders and clinical questionnaires to assess psychopathological symptoms (anxiety, depression and severity of global distress). In accordance with most previous studies, we used the Interictal Dysphoric Disorder Inventory to assess IDD symptoms. RESULTS: In our epilepsy group, we observed an IDD in 33% (42 of 120) of the patients. We diagnosed IDD in 39% (11 of 28) of the patients with psychogenic non-epileptic seizures without epilepsy. The majority of the patients with epilepsy with IDD have or had a psychiatric disorder (33 with a current, 6 with a past Axis I diagnosis). Patients with epilepsy with IDD had higher scores on all psychopathology questionnaires compared to the epilepsy patients without IDD. CONCLUSION: Our findings suggest that IDD is not epilepsy-specific in nature, but occurs with the same frequency and the same pattern of symptoms in a purely psychiatric sample. We found a large overlap of IDD and common psychiatric comorbidities, mainly depression and anxiety disorders. This result calls the presumed nosological independency of IDD into question. PMID- 29414383 TI - Mammillary body changes and seizure outcome after laser interstitial thermal therapy of the mesial temporal lobe. AB - OBJECTIVE: The mammillary bodies have long been known as the primary relay center for the hippocampus. The fornix is the primary efferent pathway of the hippocampus, with its postcommissural fibers terminating in the mammillary bodies. In this study, we describe change in mammillary body volume after laser interstitial thermal therapy (LiTT) for mesial temporal lobe epilepsy and correlate it with seizure outcome. METHODS: Pre- and post-LiTT ablation magnetic resonance imaging was reviewed in axial and coronal planes to determine mammillary body volume as calculated by the ellipsoid method. Patient demographics, clinical semiology, and seizure localization were analyzed. The primary end-point was seizure freedom at 1 year after LiTT. The change in the size of the mammillary body were correlated with the postoperative seizure freedom at 1 year using the Wilcoxon/Kruskal-Wallis test for statistical significance. RESULTS: Between December 1, 2012 and June 1, 2015, 22 patients underwent LiTT for mesial temporal lobe epilepsy. Two patients were excluded due to lack of follow-up. Of the remaining 20 patients, 13 were seizure free at 1 year. In the seizure free group, there was an average 34.6% (+/- 13%) decline in ipsilateral mammillary body volume, as opposed to an average decline of 8.4% (+/- 10.9%) in patients with continued seizures (P = 0.0026). CONCLUSIONS: Our findings show a statistically significant correlation between postoperative volume reduction in ipsilateral mammillary body and seizure outcomes after LiTT. With further validation, this finding could be a useful marker of adequacy of ablation independent of ablation volumes and determinant of potential benefit of additional surgical intervention in patients with poor outcomes after LiTT. PMID- 29414381 TI - Dexmedetomidine stops benzodiazepine-refractory nerve agent-induced status epilepticus. AB - Nerve agents are highly toxic chemicals that pose an imminent threat to soldiers and civilians alike. Nerve agent exposure leads to an increase in acetylcholine within the central nervous system, resulting in development of protracted seizures known as status epilepticus (SE). Currently, benzodiazepines are the standard of care for nerve agent-induced SE, but their efficacy quickly wanes as the time to treatment increases. Here, we examine the role of the alpha2 adrenoceptor in termination of nerve agent-induced SE using the highly specific agonist dexmedetomidine (DEX). Adult male rats were exposed to soman and entered SE as confirmed by electroencephalograph (EEG). We observed that administration of DEX in combination with the benzodiazepine midazolam (MDZ) 20 or 40 min after the onset of SE stopped seizures and returned processed EEG measurements to baseline levels. The protective effect of DEX was blocked by the alpha2 adrenoceptor antagonist atipamezole (ATI), but ATI failed to restore seizure activity after it was already halted by DEX in most cases, suggesting that alpha2 adrenoceptors may be involved in initiating SE cessation rather than merely suppressing seizure activity. Histologically, treatment with DEX + MDZ significantly reduced the number of dying neurons as measured by FluoroJade B in the amygdala, thalamus, and piriform cortex, but did not protect the hippocampus or parietal cortex even when SE was successfully halted. We conclude that DEX serves not just as a valuable potential addition to the anticonvulsant regimen for nerve agent exposure, but also as a tool for dissecting the neural circuitry that drives SE. PMID- 29414384 TI - A classification system for verifying the long-term efficacy of resective surgery for drug-resistant seizures. AB - OBJECTIVE: To verify the long-term efficacy of resective surgery, we created a classification system in which strictly defined patterns of postoperative seizure emergence are incorporated as basic components and the seizure states throughout the entire follow-up period are assessed comprehensively. METHODS: In our system, Class I has three subclasses (A-C); subclasses A and B are identical to Engel I-A and I-B, respectively. Subclass C comprises patients whose disabling seizures remit within the first 2 years postoperatively. Patients in Class II have only 1 3 days with disabling seizures throughout follow-up after the first 2 years. Patients in Class III have a maximum of 3 seizure days annually, and those in Class IV have >=4 seizure days annually after the first 2 years. Classes II-IV each have 2 subclasses (A and B): subclass A, late recurrence (i.e., the first seizure occurs after 2 years postoperatively); and subclass B, early recurrence (i.e., first seizure within 2 years). In 646 patients who underwent resective surgery (temporal lobe resection, 74.6%) and were followed for at least 8 years (mean, 14.6 years), we analyzed three patterns of postoperative seizures: early remission, late recurrence, and occasional seizures. In addition, we investigated the differences between the long-term seizure outcomes of the cohort as determined according to our system and the Engel scale. RESULTS: Overall, 52.9% of the cohort experienced at least one disabling seizure postoperatively throughout the follow-up period; in 1/3 of these patients, the first seizure occurred after 2 years. In 73.8% of the 80 patients who manifested the running down phenomenon, seizure remission occurred within the first 2 years. In addition, 36.7% of the 283 patients who had disabling seizures after 2 years experienced only 1-3 seizure days. Engel Class I-C included about 30% of the patients who had >=4 seizure days after 2 years. The long-term seizure outcomes, determined according to our system, were: Class I, 56.2% (C, 9.1%) of the overall cohort; Class II, 16.1% (A, 11.0%); and Class III/IV, 27.7% (A, 6.6%). CONCLUSION: Our system clarifies the actual effect of resective surgery more precisely than the Engel scale and thus may be useful for comparing outcomes between different surgical procedures or for identifying potential risk factors predicting unfavorable outcome. PMID- 29414385 TI - Penile self-amputation for suicidal attempt in an elderly depressed case. PMID- 29414386 TI - Electroconvulsive Therapy among Elderly patients: A study from Tertiary care centre in north India. AB - OBJECTIVE: This retrospective study aimed to evaluate the effectiveness and safety of ECT among elderly patients receiving electroconvulsive therapy (ECT). METHODS: During the study period of January 2008 to May 2017, 151 patients aged >=60 years received ECT and they formed the study sample. Data on patients aged 19 to 59 years for the period of 3 years (2014-2016) was also extracted for comparison purposes. RESULTS: The mean age of the elderly subjects was 65.8 years. In contrast to the young patients, elderly patients who received ECT more often had diagnosis of affective disorder, especially unipolar depression. Compared to young patients, elderly patients had higher prevalence of physical comorbidity with one third having more than one physical illness. The most common reason for use of ECT among elderly was poor response to medications (62.3%), followed by requirement of early response (49.6%). Four-fifth (80.8%) of the elderly patients showed >=50% reduction in the symptoms with ECT. In terms of side effects, acute blood pressure changes were seen in 40.3% of patients during the ECT procedure and about half of the patients reported cognitive disturbances. CONCLUSION: Present study suggests that ECT can be safely used among elderly patients, especially those with depressive disorders, not responding to medications. PMID- 29414387 TI - Methamphetamine dependence in methadone treatment services in Iran: the first literature review of a new health concern. AB - BACKGROUND: Methamphetamine dependence is a serious health problem among Iranian methadone patients. AIM: The current study is the first research that reviewed the prevalence of methamphetamine dependence and the associated harms among Iranian methadone patients. The other aims were to review the history of receiving methamphetamine treatment among methadone patients and the evaluated psychosocial treatments for methamphetamine dependence and/or associated harms. METHODS: Searching included both peer-reviewed literature and grey literature in English and Persian. Reference lists of the relevant papers and reports were searched manually for more information. The time period between 1 January 2005 and 28 October 2017 was set for searching. FINDINGS: Available evidence indicated that methamphetamine dependence increased from 3.9% among the two genders in 2007 to 60.3% among men in 2014 and 89.5% among women in 2015-2016. The prevalence of methamphetamine dependence was higher among female methadone patients than their male counterparts. Methamphetamine dependence was associated with multiple health problems in the social and health contexts of the two genders especially women. However, receiving methamphetamine treatment was negligible. The review indicated that cognitive-behavioural therapy improved psychological well-being. The Matrix Model led to abstinence from methamphetamine and improved psychological well being. Motivational interviewing increased attendance in treatment. Family therapy improved the quality of life and social support. However, more similar studies were needed. CONCLUSION: Despite a serious increase in methamphetamine dependence, there were a few evaluated psychosocial treatments. There is an immediate need to evaluate efficacious psychosocial treatments especially for women. Methamphetamine treatment should be provided in methadone treatment services. PMID- 29414389 TI - Mental health literacy in family caregivers: A comparative analysis. AB - The present study was undertaken to examine the current level of mental health literacy in family caregivers and to compare the changes over a 23-year period between 1993 and 2016. The current sample consisted of 60 family caregivers of patients with major mental illness from the in-patient and out-patient departments of NIMHANS, assessed on the Orientation towards Mental Illness Scale (OMI). This was compared with data of 80 family caregivers from previous study done in 1993. Family caregivers in the current study showed a significant positive trend on comparison with the previous study. However, area of abnormal behaviour shows a worsening of negative attitudes. Hopelessness and hypo functioning, relating to the factor of after-effects of mental illness show no significant difference. While knowledge about mental illnesses can be improved by providing information, this does not automatically translate to integration of the mentally ill in society. Current initiatives need to be matched with specific and sustained efforts to reduce stigma associated with mental illness which have persisted unchanged. PMID- 29414388 TI - A whale of a challenge for Pakistan and the World. PMID- 29414390 TI - Primary jejunal interdigitating dendritic cell sarcoma. PMID- 29414391 TI - Increased expression of importin-beta, exportin-5 and nuclear transportable proteins in Alzheimer's disease aids anatomic pathologists in its diagnosis. AB - Understanding the metabolic profile of neurons with the hyperphosphorylated tau protein characteristic of Alzheimer's disease is essential to unraveling new potential therapies and diagnostics for the surgical pathologist. We stratified 75 brain tissues from Alzheimer's disease into hyperphosphorylated tau positive or negative and did co-expression analyses and qRTPCR for importin-beta and exportin-5 plus several bcl2 family members and compared the data to controls, Down's dementia and Parkinson's disease. There was a significant increase in the expression of importin-beta and exportin-5 in Alzheimer's disease relative to the three other categories (each p value<0.0001) where each protein co-localized with hyperphosphorylated tau. Both apoptotic and anti-apoptotic proteins were each significantly increased in Alzheimer's disease relative to the three other groups. Neurons with hyperphosphorylated tau in Alzheimer's disease have the profile of metabolically active cells including increased exportin-5 and importin beta mRNA and proteins which indicates that immunohistochemistry testing of these proteins may aid the surgical pathologist in making a definitive diagnosis. PMID- 29414392 TI - Spatial distribution of osteopontin, CD44v6 and podoplanin in the lining epithelium of odontogenic keratocyst, and their biological relevance. AB - BACKGROUND AND AIMS: The odontogenic keratocyst (OKC) remains the most challenging jaw cyst to treat because of its locally-aggressive behaviour and high recurrence potential. Emerging evidence suggests that osteopontin, its receptors CD44v6 and integrin alphav, and podoplanin, have a role in the local invasiveness of this cyst. However the spatial distribution characteristics of these pro-invasive markers in the lining epithelium of OKC, and their association with the clinicopathologic parameters of OKC are largely unexplored. This study sought to address these issues in comparison with dentigerous cysts (DCs) and radicular cysts (RCs) and to evaluate their biological relevance. METHODS: A sample consisting of 20 OKC cases, 10 DCs and 10 RCs was subjected to immunohistochemical staining for osteopontin, CD44v6 and integrin alphav, and podoplanin, and semiquantitative analysis was performed. RESULTS: All factors (except integrin alphav) were detected heterogeneously in the constitutive layers of the lining epithelium in all three cyst types. Key observations were significant upregulation of CD44v6 and podoplanin in OKC compared to DCs and RCs, suggesting that these protein molecules may play crucial roles in promoting local invasiveness in OKC (P<0.05). Osteopontin underexpression and distribution patterns were indistinctive among all three cysts indicating its limited role as pro-invasive factor. Clinical parameters showed no significant correlations with all protein factors investigated. CONCLUSIONS: Present findings suggest that an osteopontinlow CD44v6high and podoplaninhigh immunoprofile most probably represent epithelial signatures of OKC and are markers of local invasiveness in this cyst. PMID- 29414393 TI - Complete sequence of the ATP6 and ND3 mitochondrial genes in breast cancer tissue of postmenopausal women with different body mass indexes. AB - Due to the fact that mitochondrial defects and oxidative stress have been related with obesity and breast cancer is more aggressive in women with obesity, we investigated if postmenopausal Mexican-Mestizo women with breast cancer presented somatic mutations in the sequence of the ATP6 and/or ND3 genes. Twenty one postmenopausal Mexican-Mestizo women with breast cancer who underwent mastectomy or breast conserving surgery were studied. Height and weight were used to calculate body mass index. DNA from tumor tissue samples and blood leukocytes was amplified by polymerase chain reaction and sequenced the ATP6 and ND3 mitochondrial genes. Ages ranged from 46 to 82. According to World Health Organization criteria among the 21 women, 7 had a normal BMI, 7 were overweight and 7 had obesity. In regard to the molecular study, after sequencing the coding region of ATP6 and ND3 genes of the DNA obtained from both leukocytes and tumor tissue, we did not find somatic mutations. All of the changes that we found in both genes were polymorphisms: in ATP6, we identified in ten patients 3 non synonymous nucleotide changes and in ND3 we observed that six patients presented polymorphisms, three of them were synonymous and two non-synonymous. To our knowledge, this constitutes the first report where the complete sequence of the ATP6 and ND3 genes has been analyzed in postmenopausal Mexican-Mestizo women with breast cancer and diverse BMI. Our results differ with those reported in Caucasian and Asian populations, possibly due to ethnic differences. PMID- 29414395 TI - Nuclear features of papillary thyroid carcinoma: Comparison of Core needle biopsy and thyroidectomy specimens. AB - BACKGROUND: Core needle biopsy (CNB) has been used as an alternative or a complementary method for diagnosis of thyroid nodules. However, morphological analysis of the nuclear features of papillary thyroid carcinoma (PTC) cells obtained via CNB remains unclear. Hence, we examined the differences between the PTC nuclear features in CNB and thyroidectomy specimens. METHODS: Ten PTC patients, who underwent both CNB and thyroidectomy, were selected. Microscopic photographs of three representative areas of the PTC and adjacent parenchyma were taken. Ten cells per photograph were chosen, and 1200 cells were evaluated (300 PTC and 300 follicular cells in the CNB and thyroidectomy specimens, respectively). The area, circumference, major axis, and minor axis were measured using an image analyzer. Detailed nuclear features (size and shape, membrane irregularity, chromatin characteristics) were scored using a 3-point scale. RESULTS: The mean nuclear area, circumference, major axis, and minor axis of PTC cells in the CNB specimen were 1.76, 1.34, 1.34, and 1.29 times larger than those of the follicular cells (p<0.001); similar results were seen in the thyroidectomy specimens (2.04, 1.41, 1.37, and 1.37: p<0.001). Comparative analysis revealed that these parameters were significantly smaller in the CNB specimens than those in the thyroidectomy specimens (p<0.001). Nuclear grades were also lower in the former owing to poor chromatin characteristics (clearing and margination) (p<0.01). CONCLUSION: Considering that the PTC nuclei in CNB specimens are smaller with fewer irregularities and less clear than those in thyroidectomy specimens, we need to emphasize caution when using CNB specimens for diagnosis. PMID- 29414394 TI - Importin-beta and exportin-5 are strong biomarkers of productive reoviral infection of cancer cells. AB - Acute reoviral infection has been extensively studied given the virus's propensity to target malignant cells and activate caspase-3 mediated apoptosis. Reovirus infection of malignant N1E-115 mouse neuroblastoma cells led to significant increased expression of importin-beta and exportin-5 mRNAs (qRTPCR) and proteins (immunohistochemistry) which was partially blocked by small interfering LNA oligomers directed against the reoviral genome. Co-expression analysis showed that the N1E-115 cells that contained reoviral capsid protein had accumulated importin-beta and exportin-5, as well as activated caspase 3. Reoviral oncolysis using a syngeneic mouse model of multiple myeloma similarly induced a significant increase in importin-beta and exportin-5 proteins that were co-expressed with reoviral capsid protein and caspase-3. Apoptotic proteins (BAD, BIM, PUMA, NOXA, BAK, BAX) were increased with infection and co-localized with reoviral capsid protein. Surprisingly the anti-apoptotic MCL1 and bcl2 were also increased and co-localized with the capsid protein suggesting that it was the balance of pro-apoptotic molecules that correlated with activation of caspase-3. In summary, productive reoviral infection is strongly correlated with elevated importin-beta and exportin-5 levels which may serve as biomarkers of the disease in clinical specimens. PMID- 29414396 TI - Increased CD105 expression is associated with disease progression in phyllodes tumors - A report of a borderline phyllodes tumor with lung metastases and a study of 54 phyllodes tumors. PMID- 29414397 TI - Colorectal signet ring cell carcinoma: Influence of EGFR, E-cadherin and MMP-13 expression on clinicopathological features and prognosis. AB - Signet ring cell carcinoma (SRCC) is unique rare subtype of mucin-producing colorectal adenocarcinoma characterized by presence of signet ring cells, in >50% of the tumor tissue. This study aims to investigate expression of EGFR, E cadherin and MMP-13 expression on clinicopathological features of signet ring cell type and its prognostic effect using manual tissue microarray technique. In this work, we studied tumor tissue specimens from 150 patients with colorectal cancer cases among which 19 cases of SRCC. High density manual tissue microarrays were constructed using modified mechanical pencil tips technique and immunohistochemistry for EGFR, E-cadherin and MMP-13 expression was done. We found that SRCC was significantly associated with younger age and more frequency of LN metastasis than all other groups. SRCC was also significantly associated with annular gross picture, more depth of invasion, advanced stage, more lymphovascular emboli, more perineural invasion and less arousal from an overlying adenoma. In conclusion, colorectal SRCC has distinctive clinicopathological and histological features with different unique mechanisms of carcinogenesis and more aggressive biologic behavior than other colorectal carcinoma subtypes. Negative/low expressions of EGFR and E-cadherin and MMP-13 were found in SRCC with no effect on the prognosis. PMID- 29414399 TI - Goblet cell carcinoid of the appendix - An interobserver variability study using two proposed classification systems. AB - Goblet cell carcinoid (GCC) is an uncommon tumor of the vermiform appendix. Due to a broad spectrum of morphological differentiation, subclassification and grading of GCCs remains an area of controversy. Two separate systems have proposed classifying GCC tumors into three (classical GCC; adenocarcinoma ex-GCC, signet ring cell type; adenocarcinoma ex-GCC, poorly differentiated carcinoma type) OR two subgroups (low and high grade GCC) based on morphological criteria. We independently compared the inter-observer variability associated with each classification system. Overall, both systems had moderate interobserver agreement, with the two-tiered system (kappa=0.54) performing slightly better than the three-tiered system (kappa=0.42). GI-specialist pathologists had substantial agreement for both two and three-tiered systems (kappa=0.65 vs. 0.65). Non-GI trained pathologists had lower overall agreement than GI trained pathologists, but their agreement was better using the two-tiered system (kappa=0.44) than the three-tiered system (kappa=0.22). A sub-analysis of 6 cases with a high rate of discordant classification revealed several challenges that exist in applying current criteria, including differentiating "goblet" vs. "signet ring" cell morphology, applying a 1 mm2 criteria to multifocal non contiguous glandular and single infiltrating cell architecture, differentiating fibro-inflammatory stroma from desmoplastic stroma, and solid architecture in cases with abundant extracellular mucin, and distinguishing "reactive" nuclear atypia from true "cytologic atypia". Despite these challenges, the study identified better agreement among GI pathologists than non-GI trained pathologists. While GI pathologist review may be helpful, further research on objective classification criteria remains an area of interest. PMID- 29414398 TI - Use of CD42b immunohistochemical stain for the detection of Histoplasma. AB - In pathologic specimen, Histoplasma capsulatum can frequently be identified by morphology and special stains such as GMS and PAS. Incidentally, we noted unusual staining of the platelet associated marker CD42b/GP1b expressed on the surface of fungal organisms. Evaluation of additional cases demonstrated that a majority of histoplasmosis cases (15/18 cases; 83%) showed positive staining with CD42b/GP1b, comparable to GMS stain results. Other platelet associated markers such as Factor VIII and CD61 showed no or rare expression (1/18 cases with Factor VIII). Studies have shown that 14-3-3 proteins bind directly to cytoplasmic domain of CD42b/GP1b. Significant homology is seen between fungal and human 14-3-3 proteins which may represent a molecular basis for our observation. Our study demonstrated that CD42b/GP1b staining by immunohistochemistry can aid in detection of Histoplasma organisms. Further studies with organisms with similar morphologic features such as Blastomyces and Leishmania may demonstrate a diagnostic utility in speciating organisms. PMID- 29414400 TI - Primary cutaneous histiocytic sarcoma: A report of five cases with primary cutaneous involvement and review of the literature. AB - INTRODUCTION: Histiocytic sarcoma is an extremely rare hematologic malignancy of histiocytic origin. Five cases of primary cutaneous histiocytic sarcoma are presented. MATERIALS AND METHODS: Cases of primary cutaneous histiocytic sarcoma were identified using a natural language search from the dermatopathology data base of Cornell University. RESULTS: There was a male predominance (4 males and 1 female) ranging in age from 33years to 92years (mean age of 73years); all presented with a solitary nodule which involved the head and neck area in four and thigh in one. The 73-year-old male had chronic myeloproliferative disorder. Biopsies showed a nonepitheliotropic dermal-based atypical large cell histiocytoid appearing infiltrate dermis showing positivity for common leukocyte antigen, CD4, CD14, CD68, CD163, CD2, CD11c, and lysozyme. Markers of terminal histiocytic differentiation such as S100, langerin, MXA, and CD83 were not seen. In two of the cases there was evidence of extracutaneous dissemination. The treatment in three of the cases was wide excision; there was no evidence of recurrent or metastatic disease. One case was given palliative radiation; the patient died. The other patient with underlying myelodysplastic syndrome died within a few weeks of initial cutaneous presentation. CONCLUSION: HS must be differentiated from other malignant histiocytoid lesions. Staining for common leukocyte antigen and CD163 are the most reliable markers allowing this distinction. Patients who present with primary involvement of the skin may have a favorable outcome but only if treated relatively early in the course of the disease with complete excision. PMID- 29414401 TI - Predicting postoperative language outcome using presurgical fMRI, MEG, TMS, and high gamma ECoG. AB - OBJECTIVE: To predict the postoperative language outcome using the support vector regression (SVR) and results of multimodal presurgical language mapping. METHODS: Eleven patients with epilepsy received presurgical language mapping using functional MRI (fMRI), magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), and high-gamma electrocorticography (hgECoG), as well as pre- and postoperative neuropsychological evaluation of language. We constructed 15 (24-1) SVR models by considering the extent of resected language areas identified by all subsets of four modalities as input feature vector and the postoperative language outcome as output. We trained and cross-validated SVR models, and compared the cross-validation (CV) errors of all models for prediction of language outcome. RESULTS: Seven patients had some level of postoperative language decline and two of them had significant postoperative decline in naming. Some parts of language areas identified by four modalities were resected in these patients. We found that an SVR model consisting of fMRI, MEG, and hgECoG provided minimum CV error, although an SVR model consisting of fMRI and MEG was the optimal model that facilitated the best trade-off between model complexity and prediction accuracy. CONCLUSIONS: A multimodal SVR can be used to predict the language outcome. SIGNIFICANCE: The developed multimodal SVR models in this study can be utilized to calculate the language outcomes of different resection plans prior to surgery and select the optimal surgical plan. PMID- 29414402 TI - Contact heat evoked potentials: Reliable acquisition from lower extremities. AB - OBJECTIVE: To investigate test-retest reliability of contact heat evoked potentials (CHEPs) from lower extremities using two different stimulation protocols, i.e., normal and increased baseline temperature. METHODS: A total of 32 able-bodied subjects were included and a subset (N = 22) was retested. CHEPs were recorded from three different dermatomes of the lower extremity (i.e., L2, L5, and S2). Test-retest reliability of CHEPs acquisition after simulation in various lower limb dermatomes using different stimulation protocols was analyzed. RESULTS: The study revealed an improved acquisition of CHEPS employing the increased baseline protocol, particularly when stimulating more distal sites, i.e., dermatome L5 and S2. Based on repeatability coefficients, CHEP latency (N2 potential) emerged as the most robust CHEP parameter. Although CHEP amplitudes (N2P2 complex) and pain ratings were decreased in the retest, amplitudes still showed fair to excellent intraclass correlation coefficients using normal baseline or increased baseline temperature, respectively. CONCLUSIONS: This is the first study to demonstrate that CHEPs acquisition from the lower extremities is improved by increasing the baseline temperature of the thermode. SIGNIFICANCE: This study highlights the usability of CHEPs as a viable diagnostic method to study small fiber integrity. PMID- 29414403 TI - Postoperative rehabilitation after deep brain stimulation surgery for movement disorders. AB - Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy for a set of neurological and psychiatric conditions and especially movement disorders such as Parkinson's disease, essential tremor and dystonia. Recent developments have improved the DBS technology. However, no unequivocal algorithms for an optimized postoperative care exist so far. The aim of this review is to provide a synopsis of the current clinical practice and to propose guidelines for postoperative and rehabilitative care of patients who undergo DBS. A standardized work-up in the DBS centers adapted to each patient's clinical state and needs is important, including a meticulous evaluation of clinical improvement and residual symptoms with a definition of goals for neurorehabilitation. Efficient and complete information transfer to subsequent caregivers is essential. A coordinated therapy within a multidisciplinary team (trained in movement disorders and DBS) is needed to achieve the long-range maximal efficiency. An optimized postoperative framework might ultimately lead to more effective results of DBS. PMID- 29414404 TI - The cortical focus in childhood absence epilepsy; evidence from nonlinear analysis of scalp EEG recordings. AB - OBJECTIVE: To determine the origin and dynamic characteristics of the generalised hyper-synchronous spike and wave (SW) discharges in childhood absence epilepsy (CAE). METHODS: We applied nonlinear methods, the error reduction ratio (ERR) causality test and cross-frequency analysis, with a nonlinear autoregressive exogenous (NARX) model, to electroencephalograms (EEGs) from CAE, selected with stringent electro-clinical criteria (17 cases, 42 absences). We analysed the pre ictal and ictal strength of association between homologous and heterologous EEG derivations and estimated the direction of synchronisation and corresponding time lags. RESULTS: A frontal/fronto-central onset of the absences is detected in 13 of the 17 cases with the highest ictal strength of association between homologous frontal followed by centro-temporal and fronto-central areas. Delays consistently in excess of 4 ms occur at the very onset between these regions, swiftly followed by the emergence of "isochronous" (0-2 ms) synchronisation but dynamic time lag changes occur during SW discharges. CONCLUSIONS: In absences an initial cortico cortical spread leads to dynamic lag changes to include periods of isochronous interhemispheric synchronisation, which we hypothesize is mediated by the thalamus. SIGNIFICANCE: Absences from CAE show ictal epileptic network dynamics remarkably similar to those observed in WAG/Rij rats which guided the formulation of the cortical focus theory. PMID- 29414405 TI - EEG synchronization measures predict epilepsy-related BOLD-fMRI fluctuations better than commonly used univariate metrics. AB - OBJECTIVE: We hypothesize that the hypersynchronization associated with epileptic activity is best described by EEG synchronization measures, and propose to use these as predictors of epilepsy-related BOLD fluctuations. METHODS: We computed the phase synchronization index (PSI) and global field synchronization (GFS), within two frequency bands, a broadband (1-45 Hz) and a narrower band focused on the presence of epileptic activity (3-10 Hz). The associated epileptic networks were compared with those obtained using conventional unitary regressors and two power-weighted metrics (total power and root mean square frequency), on nine simultaneous EEG-fMRI datasets from four epilepsy patients, exhibiting inter ictal epileptiform discharges (IEDs). RESULTS: The average PSI within 3-10 Hz achieved the best performance across several measures reflecting reliability in all datasets. The results were cross-validated through electrical source imaging of the IEDs. The applicability of PSI when no IEDs are recorded on the EEG was evaluated on three additional patients, yielding partially plausible networks in all cases. CONCLUSIONS: Epileptic networks can be mapped based on the EEG PSI metric within an IED-specific frequency band, performing better than commonly used EEG metrics. SIGNIFICANCE: This is the first study to investigate EEG synchronization measures as potential predictors of epilepsy-related BOLD fluctuations. PMID- 29414406 TI - Epidural motor cortex stimulation for intractable leg pain. PMID- 29414407 TI - Epileptiform and periodic EEG activities induced by rapid sevoflurane anaesthesia induction. AB - OBJECTIVES: The aim of the study was to compare the EEG findings and haemodynamic parameters of adult male patients while undergoing mask induction with sevoflurane anaesthesia with either controlled hyperventilation (CH) or spontaneous breathing (SB). METHODS: Twenty male patients, aged 23-52 (mean 42) years were anaesthetized randomly with either spontaneous breathing or mild controlled hyperventilation via mask. EEG was recorded using a full 10-20 electrode set. RESULTS: Anaesthesia induction with high inhaled concentrations of sevoflurane produced several epileptiform and periodic EEG patterns. CH doubled the amount of these EEG patterns compared to SB. Higher heart rate was recorded in the CH group. CONCLUSIONS: We describe a high incidence of paroxysmal EEG activity: epileptiform and generalized periodic discharges (GPDs) during rapid sevoflurane in nitrous oxide-oxygen mask induction in hyperventilated male patients. However these activities have no effect to the heart rate or the mean arterial pressure. SIGNIFICANCE: The monitoring of GPDs and burst suppression patterns during rapid anaesthesia induction with sevoflurane provides possibility to study the effects of volatile anaesthetics in the healthy brain. In order to analyse the different sources of EEG patterns a wide-band multichannel EEG recording is necessary. PMID- 29414408 TI - The utility of motor unit number estimation methods versus quantitative motor unit potential analysis in diagnosis of ALS. AB - OBJECTIVE: To compare the diagnostic utility of motor unit number estimation (MUNE) methods to motor unit potential (MUP) analysis in amyotrophic lateral sclerosis (ALS). METHODS: Twenty-five patients (1 definite, 11 probable, 9 possible ALS and 4 progressive muscular atrophy) and 22 healthy controls were prospectively included. Quantitative MUP analysis and three MUNE methods; Multiple Point Stimulation MUNE (MPS), Motor Unit Number Index (MUNIX) and MScanFit MUNE (MScan) were done in abductor pollicis brevis muscle. The sensitivities were compared by McNemar chi-square test. MUNE, MUP and revised ALS Functional Rating Scale (ALSFRS-R) parameters were correlated by regression analysis. RESULTS: The sensitivities of MPS (76%) and MScan (68%) were higher than MUP duration (36%) and amplitude (40%) in detecting motor unit loss (p < 0.05). MUNE methods increased the categorical probability from possible to probable ALS in 4 patients (16%). There was only significant correlation between ALSFRS-R and MScan (r = 0.443, p = 0.027) among the electrophysiological tests. MUNE methods did not correlate to MUP parameters. CONCLUSIONS: MUNE methods are more sensitive in showing abnormality than MUP analysis. SIGNIFICANCE: MUNE methods, in particular MScan, may have the potential to be implemented in the clinical practice for diagnosis and follow-up of neuromuscular disorders particularly ALS. PMID- 29414410 TI - Generation of 2 induced pluripotent stem cell lines derived from patients with Parkinson's disease carrying LRRK2 G2385R variant. AB - Leucine rich repeat kinase (LRRK2) is the most prevalent genetic cause for Parkinson's disease. LRRK2 p.G2385R is an Asian specific genetic risk factor for sporadic Parkinson's disease. We generated two induced pluripotent stem cells (iPSCs), IBMS-iPSC-018-09 and IBMS-iPSC-020-01, from the peripheral blood mononuclear cells of two patients carrying LRRK2 p.G2385R variant by using the Sendai-virus delivery system. These iPSCs had a normal karyotype and exhibited pluripotency, such as an embryonic stem cell-like morphology, expression of pluripotent markers, and capacity to differentiate into three germ layers. This cellular model will provide a platform for pathophysiological studies of neurodegeneration in Parkinson's disease. PMID- 29414409 TI - Better diagnostic accuracy of neuropathy in obesity: A new challenge for neurologists. AB - OBJECTIVE: To determine the comparative diagnostic characteristics of neuropathy measures in an obese population. METHODS: We recruited obese participants from the University of Michigan's Weight Management Program. Receiver operative characteristic analysis determined the area under the curve (AUC) of neuropathy measures for distal symmetric polyneuropathy (DSP), small fiber neuropathy (SFN), and cardiovascular autonomic neuropathy (CAN). The best test combinations were determined using stepwise and Score subset selection models. RESULTS: We enrolled 120 obese participants. For DSP, seven of 42 neuropathy measures (Utah Early Neuropathy Score (UENS, N = 62), Michigan Neuropathy Screening Instrument (MNSI) reduced combined index, MNSI examination, nerve fiber density (NFD) leg, tibial F response, MNSI questionnaire, peroneal distal motor latency) had AUCs >= 0.75. Three of 19 small fiber nerve measures for SFN (UENS, NFD leg, Sudoscan feet (N = 70)) and zero of 16 CAN measures had AUCs >= 0.75. Combinations of tests performed better than individual tests with AUCs of 0.82 for DSP (two parameters) and 0.84 for SFN (three parameters). CONCLUSIONS: Many neuropathy measures demonstrate good test performance for DSP in obese participants. Select few small fiber nerve measures performed well for SFN, and none for CAN. SIGNIFICANCE: Specific combinations of tests should be used for research studies to maximize diagnostic performance in obese cohorts. PMID- 29414411 TI - Establishment and characterization of a human embryonic stem cell line, NERCe002 A-3, with inducible 14-3-3zeta overexpression. AB - NERCe002-A-3 cells were generated from the normal human embryonic stem cell line NERCe002-A. NERCe002-A-3 cells overexpressed 14-3-3zeta after exposure to doxycycline. 14-3-3zeta protein have the ability to bind a multitude of functionally diverse signalling proteins. The NERCe002-A-3 cell line is considered a model for functional studies of the 14-3-3zeta protein in hESC self renewal and cell differentiation. Doxycycline-treated NERCe002-A-3 cells showed a>27-fold increase in relative expression of 14-3-3zeta as compared with un induced cells. Characterization assays proved that NERCe002-A-3 cells express typical markers of pluripotency and have the ability to form the three germ layers in vivo. PMID- 29414412 TI - Generation and characterization of the human iPSC line IDISi001-A isolated from blood cells of a CADASIL patient carrying a NOTCH3 mutation. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary stroke disorder. It is caused by mutations in NOTCH3 that lead to progressive degeneration of the smooth muscle cells in blood vessels. There is currently no treatment for this disorder. We reprogrammed to pluripotency blood mononuclear cells isolated from a patient carrying a NOTCH3 mutation by using a commercially available non-integrating system. The success in the generation of this iPSC line (IDISi001-A) suggests that the NOTCH3 mutation did not limit cell reprogramming and offers an unprecedented opportunity for studying and modeling CADASIL pathology. PMID- 29414413 TI - Generation of induced pluripotent stem cells from a Becker muscular dystrophy patient carrying a deletion of exons 45-55 of the dystrophin gene (CCMi002BMD-A-9 ?45-55). AB - Becker muscular dystrophy (BMD) is a dystrophinopathy caused by mutations in the dystrophin gene on chromosome Xp21. BMD mutations result in truncated semi functional dystrophin isoforms. Consequently, less severe clinical symptoms become apparent later in life compared to Duchenne muscular dystrophy. Dermal fibroblasts from a BMD patient were electroporated with episomal plasmids containing reprogramming factors to create the induced pluripotent stem cell line: CCMi002BMD-A-9 that showed pluripotent markers, were karyotypically normal and capable of trilineage differentiation. MLPA analyses performed on DNA extracted from CCMi002BMD-A-9 showed an in-frame deletion of exons 45 to 55 (CCMi002BMD-A-9 Delta45-55). PMID- 29414414 TI - Generation of GZKHQi001-A and GZWWTi001-A, two induced pluripotent stem cell lines derived from peripheral blood mononuclear cells of Duchenne muscular dystrophy patients. AB - Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene, which spans ~2.4Mb of genomic sequence at locus Xp21. This mutation results in the loss of the protein dystrophin. DMD patients die in their second or third decade due to either respiratory failure or cardiomyopathy, as the absence of dystrophin leads to myofiber membrane fragility and necrosis, eventually resulting in muscle atrophy and contractures. Currently, there is no effective treatment for DMD, therefore induced pluripotent stem cells from DMD patients would be a powerful tool for studying disease mechanisms. PMID- 29414416 TI - Imatinib-mesylate enhances the maintenance of chronic myeloid leukemia stem cell potential in the absence of glucose. AB - The introduction of BCR/Abl tyrosine kinase inhibitors (TKI), such as imatinib mesylate (IM), has revolutioned the treatment of chronic myeloid leukemia (CML). However, although extremely effective in inducing CML remission, IM is unable to eliminate leukemia stem cells (LSC). This is largely due to the suppression of BCR/Abl protein, driven by the reduction of energy supply due to oxygen or glucose shortage, in stem cell niches of bone marrow. Here, we investigated whether, in K562 and KCL22 CML cell cultures, glucose shortage induces refractoriness of stem cell potential to IM. In the absence of glucose, IM, while maintaining its detrimental effect on CML cell bulk, actually enhanced colony formation ability and stem cell potential. This was paralleled by an increased expression of the Nanog and Sox-2 stem cell markers. These evidences stress further the importance of developing strategies alternative to TKI capable to target LSC of CML. PMID- 29414415 TI - Generation of human embryonic stem cell line with heterozygous RB1 deletion by CRIPSR/Cas9 nickase. AB - The Retinoblastoma 1 (RB1) tumor suppressor, a member of the Retinoblastoma gene family, functions as a pocket protein for the functional binding of E2F transcription factors. About 1/3 of retinoblastoma patients harbor a germline RB1 mutation or deletion, leading to the development of retinoblastoma. Here, we demonstrate generation of a heterozygous deletion of the RB1 gene in the H1 human embryonic stem cell line using CRISPR/Cas9 nickase genome editing. The RB1 heterozygous knockout H1 cell line shows a normal karyotype, maintains a pluripotent state, and is capable of differentiation to the three germline layers. PMID- 29414417 TI - Generation of novel induced pluripotent stem cell (iPSC) line from a 16-year-old sialidosis patient with NEU-1 gene mutation. AB - Sialidosis is a rare autosomal recessive disorder that affects the intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in NEU1, which encodes the sialidase enzyme, result in sialidosis. Sialidosis is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. In this study, we used Sendai virus reprogramming to generate an induced pluripotent stem cell (iPSC) line carrying the A544G mutation combined with the 667-679 deletion of the NEU1 gene from a sialidosis patient. The patient-specific iPSCs expressed pluripotent markers, possessed a normal karyotype, and displayed the capability to differentiate into three germ layers. PMID- 29414418 TI - Generation of an induced pluripotent stem cell line (CSC-41) from a Parkinson's disease patient carrying a p.G2019S mutation in the LRRK2 gene. AB - The leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation is the most common genetic cause of Parkinson's disease (PD). An induced pluripotent stem cell (iPSC) line CSC-41 was generated from a 75-year old patient diagnosed with PD caused by a p.G2019S mutation in LRRK2. Skin fibroblasts were reprogrammed using a non-integrating Sendai virus-based technology to deliver OCT3/4, SOX2, c-MYC and KLF4 transcription factors. The generated iPSC line exhibits expression of common pluripotency markers, differentiates into the three germ layers and has a normal karyotype. The iPSC line can be used to explore the association between LRRK2 mutation and PD. PMID- 29414419 TI - Generation of a human embryonic stem cell line expressing tetrameric Zoanthus sp. green fluorescent protein: NERCe002-A-1. AB - The human embryonic stem cell (hESC) line NERCe002-A-1 was generated through lentiviral transduction of the original NERCe002-A-1 hESC line with Zoanthus sp. green fluorescent protein (ZsGreen). Cells that expressed ZsGreen showed a >8.6 fold increase in fluorescence intensity compared with that of cells that expressed enhanced green fluorescent protein. The fluorescent hESC line can aid in identification of biological characteristics in vitro and in vivo by tracking cell growth, migration, and differentiation. Characteristic tests confirmed that the NERCe002-A-1 cell line expressed typical markers of pluripotency and had the capability to form the three germ layers in vivo. PMID- 29414420 TI - Expression of the transcription factor FOXP2 in brainstem respiratory circuits of adult rat is restricted to upper-airway pre-motor areas. AB - Expression of the transcription factor FOXP2 is linked to brain circuits that control motor function and speech. Investigation of FOXP2 protein expression in respiratory areas of the ponto-medullary brainstem of adult rat revealed distinct rostro-caudal expression gradients. A high density of FOXP2 immunoreactive nuclei was observed within the rostral pontine Kolliker-Fuse nucleus, compared to low densities in caudal pontine and rostral medullary respiratory nuclei, including the: (i) noradrenergic A5 and parafacial respiratory groups; (ii) Botzinger and pre-Botzinger complex and; (iii) rostral ventral respiratory group. Moderate densities of FOXP2 immunoreactive nuclei were observed in the caudal ventral respiratory group and the nucleus retroambiguus, with significant density levels found in the caudal half of the dorsal respiratory group and the hypoglossal pre motor area lateral around calamus scriptorius. FOXP2 immunoreactivity was absent in all cranial nerve motor nuclei. We conclude that FOXP2 expression in respiratory brainstem areas selectively delineates laryngeal and hypoglossal pre motor neuron populations essential for the generation of sound and voice. PMID- 29414421 TI - Negotiating home base: Narratives of psychological well-being among female military members. AB - The current study aimed to understand how active duty service women with low levels of current psychological distress make sense of their military experiences in ways that might contribute to psychological well-being. Semi-structured interviews were conducted with active duty female members in the Canadian Forces and transcripts were analyzed using narrative analysis. A sense of belonging was found to be of utmost salience to the women, with several participants negotiating and constructing places that felt like home to them, and with different degrees of attachment to the military versus civilian world. The findings of this work are discussed within the context of focusing prevention and intervention efforts on increasing belongingness and a sense of home for female service members. PMID- 29414422 TI - Psychosocial wellbeing and place characteristics in Mexico. AB - This paper investigates the relationship between individual psychosocial wellbeing and place characteristics in Mexico, using multi-level models and nationally representative survey data. We explore psychosocial wellbeing in terms of self-reported depression symptoms, feelings of sadness and experience of stress; analyse place characteristics at the level of municipality and at the level of locality; and investigate individual-level heterogeneities in the relationship by gender, age, wealth and employment status. Our results suggest the existence of a significant relationship between individual psychosocial wellbeing and place characteristics, and provide evidence of heterogeneity in how place characteristics affect the psychosocial wellbeing of different groups. PMID- 29414423 TI - Sociodemographic disparities in e-cigarette retail environment: Vape stores and census tract characteristics in Orange County, CA. AB - Research shows disproportionate availability of tobacco retailers in disadvantaged neighborhoods, but little is known about the neighborhood correlates of e-cigarette specialty retailers (i.e., "vape stores"). We compiled addresses for all vape stores in Orange County (OC) (n = 174), CA, using a systematic internet search. Using American Community Survey data, we investigated the spatial structure and census tract correlates of vape store count. 23.4% of census tracts had at least one vape store, and those areas had higher percentage Hispanic population. Multivariate zero-inflated Poisson regressions revealed a higher incidence rate of vape stores in tracts with larger proportions of Hispanics, lower population density, and greater tobacco retailer density, net of other sociodemographic factors and zoning. These results suggest nicotine control initiatives in the age of e-cigarettes must consider the locational strategies of e-cigarette retailers, which are more common in Hispanic communities and areas already marked by tobacco retail activity. PMID- 29414424 TI - International Voluntary Health Networks (IVHNs). A social-geographical framework. AB - Trans-national medicine, historically associated with colonial politics, is now central to discourses of global health and development, thrust into mainstream media by catastrophic events (earthquakes, disease epidemics), and enshrined in the 2015 Sustainable Development Goals. Volunteer human-resource is an important contributor to international health-development work. International Voluntary Health Networks (IVHNs, that connect richer and poorer countries through healthcare) are situated at a meeting-point between geographies and sociologies of health. More fully developed social-geographic understandings will illuminate this area, currently dominated by instrumental health-professional perspectives. The challenge we address is to produce a geographically and sociologically-robust conceptual framework that appropriately recognises IVHNs' potentials for valuable impacts, while also unlocking spaces of constructive critique. We examine the importance of the social in health geography, and geographical potentials in health sociology (focusing on professional knowledge construction, inequality and capital, and power), to highlight the mutual interests of these two fields in relation to IVHNs. We propose some socio-geographical theories of IVHNs that do not naturalise inequality, that understand health as a form of capital, prioritise explorations of power and ethical practice, and acknowledge the more than-human properties of place. This sets an agenda for theoretically-supported empirical work on IVHNs. PMID- 29414425 TI - Neighborhood characteristics, food deserts, rurality, and type 2 diabetes in youth: Findings from a case-control study. AB - Little is known about the influence of neighborhood characteristics on risk of type 2 diabetes (T2D) among youth. We used data from the SEARCH for Diabetes in Youth Case-Control Study to evaluate the association of neighborhood characteristics, including food desert status of the census tract, with T2D in youth. We found a larger proportion of T2D cases in tracts with lower population density, larger minority population, and lower levels of education, household income, housing value, and proportion of the population in a managerial position. However, most associations of T2D with neighborhood socioeconomic characteristics were attributable to differences in individual characteristics. Notably, in multivariate logistic regression models, T2D was associated with living in the least densely populated study areas, and this finding requires further exploration. PMID- 29414426 TI - Investigating connectivity in the urban food landscapes of migrant women facing food insecurity in Washington, DC. AB - The survival strategies of migrant women living in urban poverty are embedded in urban food landscapes ('foodscapes') characterized by dynamic social relationships and mobility. Relying on interviews with 31 migrant women in Washington, DC, this paper traces the socio-spatial conditions of their urban foodscapes to show that urban environments inhabited by low-income migrants are dynamic, stretching across multiple neighborhoods as they move throughout the city with social networks to obtain affordable, quality, and culturally appropriate food. Investigating these foodscapes demonstrates the relational nature of food provisioning strategies thus providing a critique of simplistic explanations of hunger that treat food insecure residents as static, ignorant, and individual economic actors. These explanations risk producing equally simplistic and inefficient approaches to addressing food insecurity such as increasing mainstream consumption opportunities in so-called food deserts or focusing on nutrition education and individual choice without considering residents' dynamic urban experiences. As a result, this paper argues that programmatic responses to insecure urban foodscapes should be developed that foster social and physical connectivity while better addressing structural causes of hunger. PMID- 29414427 TI - Context matters: Community social cohesion and health behaviors in two South African areas. AB - BACKGROUND: Understanding how social contexts shape HIV risk will facilitate development of effective prevention responses. Social cohesion, the trust and connectedness experienced in communities, has been associated with improved sexual health and HIV-related outcomes, but little research has been conducted in high prevalence settings. METHODS: We conducted population-based surveys with adults 18-49 in high HIV prevalence districts in Mpumalanga (n = 2057) and North West Province (n = 1044), South Africa. Community social cohesion scores were calculated among the 70 clusters. We used multilevel logistic regression stratified by gender to assess individual- and group-level associations between social cohesion and HIV-related behaviors: recent HIV testing, heavy alcohol use, and concurrent sexual partnerships. RESULTS: Group-level cohesion was protective in Mpumalanga, where perceived social cohesion was higher. For each unit increase in group cohesion, the odds of heavy drinking among men were reduced by 40% (95%CI 0.25, 0.65); the odds of women reporting concurrent sexual partnerships were reduced by 45% (95%CI 0.19, 1.04; p = 0.06); and the odds of reporting recent HIV testing were 1.6 and 1.9 times higher in men and women, respectively. CONCLUSIONS: We identified potential health benefits of cohesion across three HIV related health behaviors in one region with higher overall evidence of group cohesion. There may be a minimum level of cohesion required to yield positive health effects. PMID- 29414428 TI - Survival kinase-dependent pathways contribute to gender difference in the response to myocardial ischemia-reperfusion and ischemic post-conditioning. AB - The response to ischemia/reperfusion and the effects of ischemic post conditioning (IPC) are sex-dependent, but the mechanisms have not been clarified. Male (M) and female (F) rat hearts isolated and perfused using the Langendorff technique were subject to 30 min of global ischemia (GI) and 60 min reperfusion (R). In IPC hearts, three cycles of 30-sec GI/30-sec R were applied at the beginning of R. Infarct size and myocardial function were assessed. Superoxide production, antioxidant systems, and expressions of phosphorylated forms of serine/threonine kinase (Akt), glycogen synthase kinase 3beta (GSK-3beta), protein kinase C epsilon (PKCepsilon), endothelial nitric oxide synthase (eNOS), and apoptosis were measured. In the basal state, superoxide production and apoptosis were lower, and antioxidant systems and phospho-kinase expressions were higher in F rather than in M hearts. After ischemia-reperfusion, infarct size was less in F hearts, and post-ischemic recovery of myocardial function was higher in F rather than in M hearts. Superoxide production, phospho-kinase activity, phospho-eNOS, and apoptosis increased in both sexes while antioxidants decreased in both sexes. After IPC, infarct size, superoxide production, and apoptosis decreased and phospho-eNOS increased in F and M hearts but phospho-kinase expressions and post-ischemic recovery of myocardial function improved only in M hearts. These results show that Akt/GSK-3beta/PKCepsilon/eNOS-dependent pathways mediated superoxide production and apoptosis appear as important factors involved in the observed gender differences. PMID- 29414429 TI - Characteristics, survival and incidence rates and trends of primary cardiac malignancies in the United States. AB - BACKGROUND: The available literature on the incidence, management and prognosis of primary malignant cardiac tumors [PMCTs] is limited to single-center studies, prone to small sample size and referral bias. We used data from the Surveillance, Epidemiology, and End Results [SEER]-18 registry (between 2000 and 2014) to investigate the distribution, incidence trends and the survival rates of PMCTs. METHODS: We used SEER*Stat (version 8.3.4) and the National Cancer Institute's Joinpoint Regression software (version 4.5.0.1) to calculate the incidence rates and annual percentage changes [APC] of PMCTs, respectively. We later used SPSS software (version 23) to perform Kaplan-Meier survival tests and covariate adjusted Cox models. RESULTS: We identified 497 patients with PMCTs, including angiosarcomas (27.3%) and Non-Hodgkin's lymphomas [NHL] (26.9%). Unlike the incidence rate of NHL (0.108 per 106 person-years) that increased significantly (APC=3.56%, 95% CI, [1.445 to 5.725], P=.003) over the study period, we detected no significant change (APC=1.73%, 95% CI [-3.354 to 7.081], P=.483) in the incidence of cardiac angiosarcomas (0.107 per 106 person-years). Moreover, our analysis showed that the overall survival of NHL is significantly better than angiosarcomas (P<.001). In addition, surgical treatment was associated with a significant improvement (P=.027) in the overall survival of PMCTs. CONCLUSION: Our analysis showed a significant increase in the incidence of cardiac-NHL over the past 14 years with a significantly better survival than angiosarcomas. To further characterize these rare tumors, future studies should report data on the medical history and diagnostic and treatment modalities in these patients. PMID- 29414430 TI - Surgical pathology of subaortic septal myectomy: histology skips over clinical diagnosis. AB - BACKGROUND: Subaortic septal myectomy is usually performed to mitigate obstruction in patients with the obstructive form of hypertrophic cardiomyopathy (HCM) or in those with congenital subaortic stenosis. Moreover, it is combined with aortic valve replacement in patients with severe aortic valve stenosis (SAS) and asymmetrical septal hypertrophy causing concomitant left ventricular outflow tract obstruction. When both conditions coexist, it is conceptually difficult to identify a cardiomyopathy beyond an adaptive myocardial hypertrophy, strictly related to pressure overload. Myectomy histopathology might be useful to enlighten the cause of the obstruction and establish the diagnosis. AIM: The aim was to describe the pathological findings of surgical septal myectomy specimens obtained from a group of patients with diverse clinical diagnosis, including HCM, severe aortic stenosis, and asymmetrical septal hypertrophy. METHODS: This was a retrospective study of 56 patients undergoing septal myectomy along a 10-year period at a tertiary cardiac surgical center. Clinical, interventional, and anatomopathological findings between patients with and without a preoperative diagnosis of HCM were analyzed and compared. RESULTS: Mean age at intervention was 67.5+/-20.5 years; 37 (66.1%) were female Preoperative diagnosis of sarcomeric obstructive HCM was assumed in 23 (41.1%) patients. All the other patients (58.9%) were referred for surgery with preoperative diagnosis of asymmetric septal hypertrophy, mainly in the context of severe aortic stenosis (24 patients). Twenty-seven (48.2%) patients had a greater than 30 mmHg intraventricular gradient at rest. Patients with presumed HCM were significantly younger (56.5+/-15.8 vs. 70.2+/-13.3 years, P<.001), had higher prevalence of significant intraventricular obstruction at rest [20 (87.0%) vs. 8 (34.8%), P<.001], and more frequently had moderate or severe mitral regurgitation [9 (39.1%) vs. 5(15.1%), P=.043]. All patients with aortic valve stenosis underwent both aortic valve replacement and septal myectomy. Twelve (52.1%) of the patients with obstructive HCM had isolated septal myectomy, while in the remaining 11, the procedure was combined with intervention on the mitral valve. Histopathological final diagnosis was of nonspecific reactive myocardial hypertrophy in all but 4 (92.2%) patients. In those, 2 (3.6%) had the final diagnosis of HCM and 2 (3.6%) the diagnosis of congenital subaortic membranous stenosis with reactive myocardial hypertrophy. Different grades of subendocardial fibroelastosis and myocardial fibrosis, mainly interstitial, were present [27 (48.2%) and 18 (32%) patients, respectively]. When microscopic data were compared between patients with or without a preoperative clinical diagnosis of HCM, no significant differences were found. CONCLUSION: In patients submitted to surgical septal myectomy, histology was mostly indistinctive among different clinical entities. Since different myocardial hypertrophy etiologies may share similar pathological expression, there is a need for detailed clinical assessment when trying to define the best strategy for clinical management. PMID- 29414431 TI - A case of vasculopathy of unknown etiology associated with fatal hydrops fetalis and review of the literature on intimomedial mucoid degeneration. AB - Non-immune hydrops fetalis (NIHF) has a high mortality rate [1]. Many etiologies of NIHF have been identified, including cardiovascular abnormalities, severe anemia, and genetic defects. In patients with cardiovascular etiology, structural malformations lead to fluid accumulation resulting in increased intravascular hydrostatic pressure. We report a fatal case of NIHF in a 31 week gestational age, Caucasian neonate with heart remodeling associated with a stenotic vasculopathy of the right pulmonary artery. The artery revealed partial occlusion with vascular wall abnormalities, including disarrayed smooth muscle fibers, hyperplasia within the tunica media, and myxoid change within the media and intima. Identical vasculopathy was also identified within a mesenteric artery, and this contributed to hemorrhage and early ischemic necrosis of the small intestine, discovered on postmortem examination. PMID- 29414432 TI - Clinicopathologic features and outcomes of primary cardiac tumors: a 16-year experience with 212 patients at a Chinese medical center. AB - Primary cardiac tumors are uncommon, and the majority of them are benign which are curable but can cause significant morbidity if not diagnosed and treated in a timely fashion. The objective of this study was to review the clinicopathologic features and surgical outcomes of patients with primary cardiac tumors in a single medical center in China. We have retrospectively reviewed 212 consecutive adult patients who underwent surgical resection of primary cardiac tumors at our center from January of 2001 to June of 2017. All available clinicopathological features, imaging characteristics, and disease outcomes were summarized and presented. The present series enrolled 180 cardiac myxomas (84.9%) and 32 non myxoma cases that included hemangioma, lipoma, papillary fibroelastoma, schwannoma, pericardial cyst, teratoma, paraganglioma, lymphoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, angiosarcoma, and liposarcoma. All patients were diagnosed ante-mortem. The most frequent complaint was dyspnea. Benign tumors accounted for 93.9% of cases (199/212) and malignant tumors accounted for 5.7% (12/212), and the remaining one case was intermediate (paraganglioma). The outcome of benign tumors was favorable and only three recurrent cases were documented (1.5%) after surgical resection. All the seven patients with primary cardiac sarcomas (undifferentiated pleomorphic sarcoma, myxofibrosarcoma, angiosarcoma, and liposarcoma) suffered postoperative recurrence or disease related death. Cardiac myxoma represents the most frequent primary cardiac tumors. The clinical presentations, treatment strategies and outcomes of the primary cardiac tumors depend on the tumor location and histopathological type. PMID- 29414434 TI - Fast elastic registration of soft tissues under large deformations. AB - A fast and accurate fusion of intra-operative images with a pre-operative data is a key component of computer-aided interventions which aim at improving the outcomes of the intervention while reducing the patient's discomfort. In this paper, we focus on the problematic of the intra-operative navigation during abdominal surgery, which requires an accurate registration of tissues undergoing large deformations. Such a scenario occurs in the case of partial hepatectomy: to facilitate the access to the pathology, e.g. a tumor located in the posterior part of the right lobe, the surgery is performed on a patient in lateral position. Due to the change in patient's position, the resection plan based on the pre-operative CT scan acquired in the supine position must be updated to account for the deformations. We suppose that an imaging modality, such as the cone-beam CT, provides the information about the intra-operative shape of an organ, however, due to the reduced radiation dose and contrast, the actual locations of the internal structures necessary to update the planning are not available. To this end, we propose a method allowing for fast registration of the pre-operative data represented by a detailed 3D model of the liver and its internal structure and the actual configuration given by the organ surface extracted from the intra-operative image. The algorithm behind the method combines the iterative closest point technique with a biomechanical model based on a co-rotational formulation of linear elasticity which accounts for large deformations of the tissue. The performance, robustness and accuracy of the method is quantitatively assessed on a control semi-synthetic dataset with known ground truth and a real dataset composed of nine pairs of abdominal CT scans acquired in supine and flank positions. It is shown that the proposed surface matching method is capable of reducing the target registration error evaluated of the internal structures of the organ from more than 40 mm to less then 10 mm. Moreover, the control data is used to demonstrate the compatibility of the method with intra-operative clinical scenario, while the real datasets are utilized to study the impact of parametrization on the accuracy of the method. The method is also compared to a state-of-the art intensity-based registration technique in terms of accuracy and performance. PMID- 29414433 TI - IL-6 expression is correlated with increased T-cell proliferation and survival in the arterial wall in giant cell arteritis. AB - Giant cell arteritis (GCA) is the most common vasculitis in adults affecting large and medium-sized arteries. IL-6 and T cell accumulation within the arterial wall contribute to the pathogenesis of GCA, and blockade of IL-6 activity is efficacious in its treatment. We examined the relationship between levels of IL-6 expression and immunological processes that control the expansion of T cells in GCA-positive temporal artery biopsies. CD4 T cells accumulated in clusters within the media and deep intima of all GCA lesions. There was a significant positive correlation between the expression of IL-6 mRNA and increased frequency of proliferating CD4 T cells. The expansion of T cells can be inhibited by T regs but IL-6 expression was not correlated with differences in T reg accumulation. Increased IL-6 levels were also significantly correlated with lower frequencies of CD4 T cells undergoing apoptotic cell death. In conclusion, IL-6 may contribute to the accumulation of CD4 T cells in GCA by supporting their proliferation and survival within the arterial wall through mechanisms that are independent of effects on local T reg expansion. PMID- 29414435 TI - 3D multi-scale FCN with random modality voxel dropout learning for Intervertebral Disc Localization and Segmentation from Multi-modality MR Images. AB - Intervertebral discs (IVDs) are small joints that lie between adjacent vertebrae. The localization and segmentation of IVDs are important for spine disease diagnosis and measurement quantification. However, manual annotation is time consuming and error-prone with limited reproducibility, particularly for volumetric data. In this work, our goal is to develop an automatic and accurate method based on fully convolutional networks (FCN) for the localization and segmentation of IVDs from multi-modality 3D MR data. Compared with single modality data, multi-modality MR images provide complementary contextual information, which contributes to better recognition performance. However, how to effectively integrate such multi-modality information to generate accurate segmentation results remains to be further explored. In this paper, we present a novel multi-scale and modality dropout learning framework to locate and segment IVDs from four-modality MR images. First, we design a 3D multi-scale context fully convolutional network, which processes the input data in multiple scales of context and then merges the high-level features to enhance the representation capability of the network for handling the scale variation of anatomical structures. Second, to harness the complementary information from different modalities, we present a random modality voxel dropout strategy which alleviates the co-adaption issue and increases the discriminative capability of the network. Our method achieved the 1st place in the MICCAI challenge on automatic localization and segmentation of IVDs from multi-modality MR images, with a mean segmentation Dice coefficient of 91.2% and a mean localization error of 0.62 mm. We further conduct extensive experiments on the extended dataset to validate our method. We demonstrate that the proposed modality dropout strategy with multi modality images as contextual information improved the segmentation accuracy significantly. Furthermore, experiments conducted on extended data collected from two different time points demonstrate the efficacy of our method on tracking the morphological changes in a longitudinal study. PMID- 29414437 TI - Conversion and time-to-conversion predictions of mild cognitive impairment using low-rank affinity pursuit denoising and matrix completion. AB - In this paper, we aim to predict conversion and time-to-conversion of mild cognitive impairment (MCI) patients using multi-modal neuroimaging data and clinical data, via cross-sectional and longitudinal studies. However, such data are often heterogeneous, high-dimensional, noisy, and incomplete. We thus propose a framework that includes sparse feature selection, low-rank affinity pursuit denoising (LRAD), and low-rank matrix completion (LRMC) in this study. Specifically, we first use sparse linear regressions to remove unrelated features. Then, considering the heterogeneity of the MCI data, which can be assumed as a union of multiple subspaces, we propose to use a low rank subspace method (i.e., LRAD) to denoise the data. Finally, we employ LRMC algorithm with three data fitting terms and one inequality constraint for joint conversion and time-to-conversion predictions. Our framework aims to answer a very important but yet rarely explored question in AD study, i.e., when will the MCI convert to AD? This is different from survival analysis, which provides the probabilities of conversion at different time points that are mainly used for global analysis, while our time-to-conversion prediction is for each individual subject. Evaluations using the ADNI dataset indicate that our method outperforms conventional LRMC and other state-of-the-art methods. Our method achieves a maximal pMCI classification accuracy of 84% and time prediction correlation of 0.665. PMID- 29414436 TI - How does the femoral cortex depend on bone shape? A methodology for the joint analysis of surface texture and shape. AB - In humans, there is clear evidence of an association between hip fracture risk and femoral neck bone mineral density, and some evidence of an association between fracture risk and the shape of the proximal femur. Here, we investigate whether the femoral cortex plays a role in these associations: do particular morphologies predispose to weaker cortices? To answer this question, we used cortical bone mapping to measure the distribution of cortical mass surface density (CMSD, mg/cm2) in a cohort of 125 females. Principal component analysis of the femoral surfaces identified three modes of shape variation accounting for 65% of the population variance. We then used statistical parametric mapping (SPM) to locate regions of the cortex where CMSD depends on shape, allowing for age. Our principal findings were increased CMSD with increased gracility over much of the proximal femur; and decreased CMSD at the superior femoral neck, coupled with increased CMSD at the calcar femorale, with increasing neck-shaft angle. In obtaining these results, we studied the role of spatial normalization in SPM, identifying systematic misregistration as a major impediment to the joint analysis of CMSD and shape. Through a series of experiments on synthetic data, we evaluated a number of registration methods for spatial normalization, concluding that only those predicated on an explicit set of homologous landmarks are suitable for this kind of analysis. The emergent methodology amounts to an extension of Geometric Morphometric Image Analysis to the domain of textured surfaces, alongside a protocol for labelling homologous landmarks in clinical CT scans of the human proximal femur. PMID- 29414439 TI - Quantitative -omic data empowers bottom-up systems biology. AB - The large-scale generation of '-omic' data holds the potential to increase and deepen our understanding of biological phenomena, but the ability to synthesize information and extract knowledge from these data sets still represents a significant challenge. Bottom-up systems biology overcomes this hurdle through the integration of disparate -omic data types, and absolutely quantified experimental measurements allow for direct integration into quantitative, mechanistic models. The human red blood cell has served as a starting point for the application of systems biology approaches and has been the focus of a recent burst of generated quantitative metabolomics and proteomics data. Thus, the red blood cell represents the perfect case study through which to examine our ability to glean knowledge from the integration of multiple disparate data types. PMID- 29414438 TI - Universal ventricular coordinates: A generic framework for describing position within the heart and transferring data. AB - Being able to map a particular set of cardiac ventricles to a generic topologically equivalent representation has many applications, including facilitating comparison of different hearts, as well as mapping quantities and structures of interest between them. In this paper we describe Universal Ventricular Coordinates (UVC), which can be used to describe position within any biventricular heart. UVC comprise four unique coordinates that we have chosen to be intuitive, well defined, and relevant for physiological descriptions. We describe how to determine these coordinates for any volumetric mesh by illustrating how to properly assign boundary conditions and utilize solutions to Laplace's equation. Using UVC, we transferred scalar, vector, and tensor data between four unstructured ventricular meshes from three different species. Performing the mappings was very fast, on the order of a few minutes, since mesh nodes were searched in a KD tree. Distance errors in mapping mesh nodes back and forth between meshes were less than the size of an element. Analytically derived fiber directions were also mapped across meshes and compared, showing < 5 degrees difference over most of the ventricles. The ability to transfer gradients was also demonstrated. Topologically variable structures, like papillary muscles, required further definition outside of the UVC framework. In conclusion, UVC can aid in transferring many types of data between different biventricular geometries. PMID- 29414440 TI - Induction of broadly neutralizing antibodies in Germinal Centre simulations. AB - Vaccines against mutating pathogens such as influenza, HIV, or plasmodium are poorly protective towards new evolving strains. Rare individuals naturally mount broadly neutralizing antibodies covering most strains, but the requirements for their induction are unknown. The antibody response to vaccination has been recapitulated by in silico models that proposed two opposite schemes: A theory of 'frustration' where one epitope at a time leads to optimal antibody breadth through sequential immunizations, that was proven successful for HIV vaccination in primates. Another theory supports vaccination with cocktails of multiple representative epitopes in a unique prime and boost, which succeeded for influenza in mice. We discuss how in silico models differ in their assumptions, with particular focus on protein affinity representation. PMID- 29414441 TI - Intracellular zinc increase affects phosphorylation state and subcellular localization of protein kinase C delta (delta). AB - Protein kinase C delta (PKCdelta) is a Ser/Thr-specific kinase involved in many fundamental cellular processes including growth, differentiation and apoptosis. PKCdelta is expressed ubiquitously in all known cell types, and can be activated by diacylglycerol, phorbol esters and other kinases. Multiple lines of evidence have indicated that the mode of activation greatly influences the role PKCdelta plays in cellular function. Divalent metal ions, such as zinc are released as a response to cellular stress and injury, often resulting in oxidative damage and cell death. In this study, we evaluate the effect increased concentrations of intracellular zinc has on the phosphorylation state and subcellular localization of PKCdelta. More specifically, we demonstrate that intracellular zinc inhibits the phosphorylation of PKCdelta at Thr505 in a concentration-dependent manner and facilitates the translocation of PKCdelta from the cytosol to the Golgi complex. Analysis of a PKCdelta structural model revealed a potential His-Cys3 zinc binding domain adjacent to residue Thr505 and suggests that interaction with a Zn2+ ion may preclude phosphorylation at this site. This study establishes zinc as a potent modulator of PKCdelta function and suggests a novel mechanism by which PKCdelta is able to "sense" changes in the concentration of intracellular zinc. These findings illuminate a new paradigm of metal ion-protein interaction that may have significant implications on a broad spectrum of cellular processes. PMID- 29414442 TI - Microscopy of fungal biofilms. AB - Fungal biofilms are heterogeneous, surface-associated colonies comprised of filamentous hyphae (chains of elongated cells), pseudohyphal cells, yeast-form cells, and various forms of extracellular matrix. When grown on a substratum under liquid culture medium, the microbial fungus Candida albicans forms dense biofilms that range in thickness from 100 to 600MUm. Apical hyphae in the medium and invasive hyphae in the substratum may add greatly to the thickness and complexity of the biofilm. Because of the heterogeneity of the structure, and the large refractive index differences between cell walls, cytoplasm, and medium, fungal biofilms appear optically opaque. For fixed specimens that can be transferred out of an aqueous medium, refractive index matching methods provide a high degree of clarification. Confocal scanning, 2-photon scanning, or selective plane illumination microscopy then can be used to obtain high-quality image data spanning the full thickness of the biofilm. Using refractive index matching and confocal microscopy, we have imaged many interesting features within wild-type, mutant, and engineered biofilms, including cellular phenotypes that vary with position, the effect of growth conditions, and gene expression through reporter constructs. This approach greatly expands the range of microscopical studies, allowing researchers to observe and quantify specific phenomena within medically or industrially relevant forms of microbial growth. PMID- 29414443 TI - Endolithic microbial habitats as refuges for life in polyextreme environment of the Atacama Desert. AB - The extremely harsh conditions of hyperarid deserts are a true challenge for microbial life. Microorganisms thriving in such polyextreme environments are fascinating as they can tell us more about life, its strategies and its boundaries than other groups of organisms. The Atacama Desert (North Chile) holds two world records of extreme environmental characteristics: the lowest rainfall and greatest surface ultraviolet radiation and total solar irradiance ever measured on Earth. Despite these limiting conditions for life, we recently identified several remarkable examples of endolithic habitats colonized by phototrophic and heterotrophic microorganisms in the hyperarid core of the Atacama Desert. PMID- 29414444 TI - Correlative microscopy for structural microbiology. AB - Understanding how microbes utilize their environment is aided by visualizing them in their natural context at high resolution. Correlative imaging enables efficient targeting and identification of labelled viral and bacterial components by light microscopy combined with high resolution imaging by electron microscopy. Advances in genetic and bioorthogonal labelling, improved workflows for targeting and image correlation, and large-scale data collection are increasing the applicability of correlative imaging methods. Furthermore, developments in mass spectroscopy and soft X-ray imaging are expanding the correlative imaging modalities available. Investigating the structure and organization of microbes within their host by combined imaging methods provides important insights into mechanisms of infection and disease which cannot be obtained by other techniques. PMID- 29414445 TI - Microbiomes in extremely acidic environments: functionalities and interactions that allow survival and growth of prokaryotes at low pH. AB - Extremely acidic environments have global distribution and can have natural or, increasingly, anthropogenic origins. Extreme acidophiles grow optimally at pH 3 or less, have multiple strategies for tolerating stresses that accompany high levels of acidity and are scattered in all three domains of the tree of life. Metagenomic studies have expanded knowledge of the diversity of extreme acidophile communities, their ecological networks and their metabolic potentials, both confirmed and inferred. High resolution compositional and functional profiling of these microbiomes have begun to reveal spatial diversity patterns at global, regional, local, zonal and micro-scales. Future integration of genomic and other meta-omic data will offer new opportunities to utilize acidic microbiomes and to engineer beneficial interactions within them in biotechnologies. PMID- 29414446 TI - Altitude above 1500 m is a major determinant of asthma incidence. An ecological study. AB - BACKGROUND: Previous studies suggest an inverse correlation between asthma and altitude. In the present work, we performed an in-depth analysis of asthma incidence in the 758 Mexican counties covered by the largest medical institution in the country (~37.5 million insured subjects), and evaluated its relationships with altitude and other factors. METHODS: Asthma incidence in each county was calculated from new cases diagnosed by family physicians. Other variables in the same counties, including selected diseases, geographical variables, and socioeconomic factors, were also obtained and their association with asthma was evaluated through bivariate and multivariate analyses. RESULTS: Median asthma incidence was 296.2 * 100,000 insured subjects, but tended to be higher in those counties located on or near the coast. When asthma incidence was plotted against altitude, a two-stage pattern was evident: asthma rates were relatively stable in counties located below an altitude of ~1500 m, while these rates progressively decreased as altitude increased beyond this level (rS = -0.51, p < .001). Multivariate analysis showed that, once each variable was adjusted by the potential influence of the others, asthma incidence was inversely correlated with altitude (standardized beta coefficient, -0.577), helminthiasis (-0.173), pulmonary tuberculosis (-0.130), and latitude (-0.126), and was positively correlated with acute respiratory tract infection (0.382), pneumonia (0.289), type 2 diabetes (0.138), population (0.108), and pharyngotonsillitis (0.088), all with a p <= .001. CONCLUSION: Our study showed that altitude higher than ~1500 m comprises a major factor in determining asthma incidence, with the risk of new onset asthma decreasing as altitude increases. Other less influential conditions were also identified. PMID- 29414447 TI - Physical ability of people with rheumatoid arthritis and age-sex matched controls to use four commonly prescribed inhaler devices. AB - BACKGROUND: Respiratory disease is a common co-morbidity with rheumatoid arthritis (RA). RA commonly affects the hands, but there is little research investigating whether these patients are physically able to operate inhalers. AIM: To compare the physical ability of people with and without RA to use four commonly prescribed inhaler devices (pressurised metered dose inhaler (pMDI), Easi-Breathe(r), HandiHaler(r) and Turbohaler(r)). METHODS: Adults with RA and an equal number of age-sex matched controls were observed using placebo inhaler devices. Maximum inhalation flow rate was measured with an In-Check Dial device. Dichotomous data were compared (RA versus control) using Fisher's exact test. RESULTS: Thirty four participants were recruited for each group. For all inhalers, fewer participants with RA were able to complete all the steps necessary to operate the device: pMDI (50% vs. 91%), Easi-Breathe(r) (77% vs. 97%), HandiHaler(r) (15% vs. 94%) and Turbohaler(r) (85% vs. 100%). This difference was significant (p < .05) for the pMDI, Easi-Breathe(r) and HandiHaler(r). Significantly fewer people (p < .05) with RA were able to depress the pMDI canister, or to complete three steps in the operation of the Handihaler(r) (open the dust cap, remove the capsule from its blister, pierce the capsule). Only one participant (RA group) was unable to achieve the minimum flow rates required to operate the Turbohaler(r) and HandiHaler(r) (p = 1.000). CONCLUSIONS: People with RA have varying physical abilities to use inhalers effectively. A person-centred approach is required to assess which inhaler device is appropriate for each individual patient. PMID- 29414448 TI - Anti-parietal cell autoimmunity is associated with an accelerated decline of lung function in IPF patients. AB - BACKGROUND: Autoantibodies against lung epithelial antigens are often detected in patients with Idiopathic Pulmonary Fibrosis (IPF). Anti-Parietal Cell Antibodies (APCA) target the H+/K+ATPase (proton pump). APCA prevalence and lung H+/K+ATPase expression was never studied in IPF patients. METHODS: We retrospectively collected clinical, lung function and imaging data from APCA positive patients (APCA+IPF) and compared them with APCA negative IPF patients matched on the date of diagnostic assessment. H+/K+ATPase expression was assessed with immunohistochemistry and PCR. RESULTS: Among 138 IPF patients diagnosed between 2007 and 2014 and tested for APCA, 19 (13.7%) APCA+ patients were identified. APCA+IPF patients were 16 men and 3 women, mean age 71 years. The median titer of APCA was 1:160. A pernicious anemia was present in 5 patients and preceded the fibrosis in 3 cases. With a mean follow up of 31 months, 2 patients had an exacerbation and 7 patients died. As compared with 19 APCA- IPF patients, APCA+IPF patients had a less severe disease with better DLCO (57% vs 43% predicted), preserved PaO2 (85 +/- 8 mmHg vs 74 +/- 11 mmHg), a lower rate of honeycombing on HRCT (58% vs 89%), but they experienced an accelerated decline of FVC (difference 61.4 ml/year; p = .0002). The H+/K+ATPase was strongly expressed by hyperplastic alveolar epithelial cells in the fibrotic lung. CONCLUSION: Anti parietal cell autoimmunity is detected in some IPF patients and is associated with an accelerated decline of lung function. Anti-parietal cell autoimmunity may promote lung fibrosis progression. PMID- 29414449 TI - Mucus hypersecretion in asthma is associated with rhinosinusitis, polyps and exacerbations. AB - BACKGROUND: Bronchial hypersecretion is a poorly studied symptom in asthma. The aim of the study was to determine the specific characteristics of asthmatics with bronchial hypersecretion. METHODS: A total of 142 asthmatics (21.8% men; mean age 49.8 years) were prospectively followed for one year. Mucus hypersecretion was clinically classified into two severity categories: daily sputum production and frequent expectoration but not every day. Clinical and pulmonary function variables associated with mucus hypersecretion were assessed by multiple logistic regression analysis. RESULTS: Daily cough was recorded in 28.9% of patients and sputum production daily or most of the days in 52.1%. Patients with mucus hypersecretion had more dyspnoea, poorer asthma control and quality of life, had suffered from more exacerbations and showed anosmia associated with chronic rhinosinusitis and nasal polyposis more frequently. Factors associated to mucus hypersecretion were anosmia, one exacerbation or more in the previous year and FEV1/FVC <70% (AUC 0.75, 95% CI 0.66-0.85) for the first definition of hypersecretion, and anosmia, poor asthma control and age (AUC 0.75, 95% CI 0.67 0.83) for the second definition. CONCLUSIONS: Mucus hypersecretion is frequent in patients with asthma, and is associated with chronic upper airways disease, airway obstruction, poor asthma control and more exacerbations. PMID- 29414450 TI - Peak circulatory power is a strong prognostic factor in patients with idiopathic pulmonary arterial hypertension. AB - BACKGROUND: Studies have shown that peak circulatory power (peak CircP; peak oxygen uptake * peak systolic blood pressure) is a variable predictor of prognosis in patients with left heart failure. It remains unknown whether peak CircP also predicts outcome in patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS: Patients with newly diagnosed IPAH who underwent symptom-limited cardiopulmonary exercise testing (CPET) from 1 January 2011 to 1 January 2014 in Fuwai Hospital were prospectively enrolled and followed for up to 66 months for cardiac events (mortality and lung transplantation). RESULTS: One hundred forty patients with IPAH (104 female, mean age: 33 +/- 11 years) were studied. During follow-up (mean: 42 +/- 14 months), 24 patients died and 1 patient underwent lung transplantation. In the univariate analysis, peak oxygen uptake(VO2), oxygen uptake at anaerobic threshold, ventilation (VE)/carbon dioxide output (VCO2) slope, end-tidal partial pressure of carbon dioxide at anaerobic threshold, peak systolic blood pressure (SBP), the change of SBP, the change of heart rate, peak work rate, peak CircP, pulmonary vascular resistance, cardiac index and World Health Organization functional class were predictive of cardiac events (all P < .05).In the multivariate analysis, Peak CircP in the fourth model had the highest significance compared with peak VO2 and VE/VCO2 slope in the second and third model (chi-square = 5.26, P < .02, HR: 0.99, 95% CI: 0.99 to 1.00). CONCLUSIONS: Peak CircP, better than peak VO2 and VE/VCO2slope, was a strong predictor of cardiac events among exercise parameters in patients with IPAH. PMID- 29414451 TI - The influence of psychiatric disorders on the course of lung cancer, chronic obstructive pulmonary disease and tuberculosis. AB - BACKGROUND: This Danish study evaluated the association between psychiatric comorbidity and the course of chronic obstructive pulmonary disease (COPD), lung cancer and tuberculosis (TB) of an entire nation. METHODS: Data from the Danish National Patient Registry (1998-2009), material status, gender, educational level, comorbidities, age at diagnosis and death, medication, and causes of death were extracted from national databases. We identified 71,874 patients with COPD and found 32,282 with a pre-index psychiatric comorbidity, 20,787 patients with lung cancer and found 8406 with a pre-index psychiatric comorbidity, and 3495 patients with TB and found 797 with a pre-index psychiatric morbidity. Within the three groups we compared the patients with/without a pre-index psychiatric comorbidity. RESULTS: We found a reduced survival in patients with COPD or TB and a pre-existing psychiatric comorbidity. For all three pulmonary diseases, we found significantly higher age (p < .001) at time of diagnosis, higher Deyo Charlson Comorbidity Index (p < .001), and an overrepresentation of singles (p < .001) in patients with a psychiatric comorbidity. COPD and lung cancer patients with a psychiatric comorbidity were significantly overrepresented by women (p < .001). Patients with COPD and a psychiatric comorbidity died most frequently of lung cancer (24%). Advancing age and Deyo-Charlson index were associated with a higher mortality rate whereas being a woman and married/co-habiting yielded a lower mortality rate for patients with a psychiatric comorbidity. CONCLUSION: To our knowledge, this is the first epidemiological study investigating the influence of a psychiatric comorbidity on the course of COPD, lung cancer and TB at a national level. Our results emphasize the importance of detecting these major respiratory diseases in patients with psychiatric comorbidities and intensifying the treatment and follow up of these patients. PMID- 29414452 TI - Association of exercise-induced wheeze and other asthma symptoms with emergency department visits and hospitalizations in a large cohort of urban adolescents. AB - OBJECTIVE: Exercise-induced wheeze (EIW) has been found to be associated with asthma-related urgent care in school-aged children. Despite asthma's high prevalence and morbidity among adolescents, this association has not been examined in adolescents. We tested the association of EIW and other asthma symptoms to asthma-related ED visits and hospitalizations in urban adolescents with probable asthma. We hypothesized that EIW would be associated with urgent care. METHODS: In this cross-sectional study 30,467 high school students (mean age = 16.0) from 49 NYC schools completed two brief validated measures, one assessing probable asthma and the other the frequency of six asthma symptoms over the past year. Adolescents also reported if in the past year they had an asthma related ED visit or hospitalization. Analyses presented here included students with probable asthma (n = 9149). Using logistic regression, we modeled each asthma symptom as a function of ED visits and hospitalizations adjusting for sex, age, race/ethnicity and asthma severity. Multivariable models included all symptoms to account for the potential interaction between symptoms. RESULTS: Among adolescents with probable asthma, EIW was associated with ED visits and hospitalizations. In multivariable models wheeze without a cold, chest tightness, night wakening, but not EIW, were significantly associated with both ED visits and hospitalizations. CONCLUSIONS: Unlike findings with younger children, EIW does not appear to be associated with ED visits and hospitalizations among urban adolescents with probable asthma. Instead, symptoms, such as chest tightness and night wakening, appear to be important at identifying adolescents at risk for asthma-related urgent care. PMID- 29414453 TI - Physiological predictors of Hypoxic Challenge Testing (HCT) outcomes in Interstitial Lung Disease (ILD). AB - BACKGROUND: Pre-flight risk assessments are currently recommended for all Interstitial Lung Disease (ILD) patients. Hypoxic challenge testing (HCT) can inform regarding the need for supplemental in-flight oxygen but variables which might predict the outcome of HCT and thus guide referral for assessment, are unknown. METHODS: A retrospective analysis of ILD patients attending for HCT at three tertiary care ILD referral centres was undertaken to investigate the concordance between HCT and existing predictive equations for prediction of in flight hypoxia. Physiological variables that might predict a hypoxaemic response to HCT were also explored with the aim of developing a practical pre-flight assessment algorithm for ILD patients. RESULTS: A total of 106 ILD patients (69 of whom (65%) had Idiopathic Pulmonary Fibrosis (IPF)) underwent HCT. Of these, 54 (51%) patients (of whom 37 (69%) had IPF) failed HCT and were recommended supplemental in-flight oxygen. Existing predictive equations were unable to accurately predict the outcome of HCT. ILD patients who failed HCT had significantly lower resting SpO2, baseline PaO2, reduced walking distance, FEV1, FVC and TLCO, but higher GAP index than those who passed HCT. CONCLUSIONS: TLCO >50% predicted and PaO2 >9.42 kPa were independent predictors for passing HCT. Using these discriminators, a novel, practical pre-flight algorithm for evaluation of ILD patients is proposed. PMID- 29414454 TI - Recognition of unprovoked (idiopathic) pulmonary embolism-Prospective observational study. AB - BACKGROUND: The assessment of the clinical symptoms is the weakest link of the pulmonary embolism (PE) diagnostic algorithm. Despite the presence of highly sensitive and specific imaging methods, verifying PE remains difficult due to nonspecific clinical symptoms and frequently its subclinical course. OBJECTIVE: The aim of this study is to improve the recognition of PE by investigating the clinical presentation and short-term prognosis of unprovoked PE in comparison to provoked PE. The study was directed to patients who suffer from PE as a primary disease. METHODS: This prospective observational study included 331 patients with PE, approved by computer tomographic pulmoangiography. They were categorized as having unprovoked or provoked PE, according to their epidemiological data. The clinical characteristics and one-month mortality rate were compared between both groups. RESULTS: About 67% of the patients had provoking factors and ~33% had unprovoked PE. The patients in the unprovoked PE-group were younger compared to provoked PE-group (56.67 +/- 17.95 vs 63.76 +/- 14.58, p < .0001) and the males predominated vs females (62.04% vs 37.96%, p = .012). The patients with unprovoked PE had more previous thromboembolic events compared to provoked PE group (30.56% vs 19.45%, p = .022) and a larger thrombotic burden (p = .001). Dyspnea (85.18% vs 85.13%), chest pain (47.22% vs 46.85%), cough (43.92% vs 45.94%), hemoptysis (16.67% vs 14.41%), hemodynamic instability (9.26% vs 8.56%), deep venous thrombosis (49.51% vs 44.5%) had similar frequencies in both groups. No significant differences in the means of systolic pressure of arteria pulmonalis, D-dimer, arterial blood gases, Revised Geneva probability score were found. One-month mortality was lower in unprovoked PE-group than in provoked (1.85% vs 8.52%, p = .042). CONCLUSIONS: Unprovoked PE occurs at a younger age, more frequently in males. It is characterized by the following significant variables: higher Wells score, lower PESI score, lower CRP, higher thrombotic burden and lower one-month mortality rate, compared to provoked PE. PMID- 29414455 TI - Aspirin exacerbated respiratory disease: Current topics and trends. AB - Aspirin-exacerbated respiratory disease is a chronic and treatment-resistant disease, characterized by the presence of eosinophilic rhinosinusitis, nasal polyposis, bronchial asthma, and nonsteroidal anti-inflammatory drugs hypersensitivity. Alterations in arachidonic acid metabolism may induce an imbalance between pro-inflammatory and anti-inflammatory substances, expressed as an overproduction of cysteinyl leukotrienes and an underproduction of prostaglandin E2. Although eosinophils play a key role, recent studies have shown the importance of other cells and molecules in the development of the disease like mast cells, basophils, lymphocytes, platelets, neutrophils, macrophages, epithelial respiratory cells, IL-33 and thymic stromal lymphopoietin, making each of them promissory diagnostic and treatment targets. In this review, we summarize the most important clinical aspects of the disease, including the current topics about diagnosis and treatment, like provocation challenges and aspirin desensitization. We also discuss recent findings in the pathogenesis of the disease, as well as future trends in diagnosis and treatment, including monoclonal antibodies and a low salicylate diet as a treatment option. PMID- 29414457 TI - Visualising numerals: An ERPs study with the attentional SNARC task. AB - Inspecting or transforming the position of Arabic numbers in mental space helps everyday mathematical calculations. Nonetheless the neural and functional bases of this ability are poorly understood. Here we show that imagining the position of Arabic numbers on a horizontal mental number line speeds up the detection of targets appearing at corresponding positions in visual space. No similar advantage is found when numbers are merely perceived or classified according to their magnitude. Imagery enhanced electrophysiological activity in the extrastriate cortex contralateral to the imagined number position. Speeded detection of targets that were spatially congruent with the imagined number position was matched with enhanced C1 responses in primary visual cortex. In contrast, imagery had no effect on later target-related responses that are usually modulated by spatial attention. These results shed new light on the mechanisms that evoke sensory-like spatial representations of Arabic numbers in everyday mental computations. PMID- 29414456 TI - Smoking status and cognitive performance among vocational school students in Beijing, China. AB - INTRODUCTION: In countries where smoking is associated with lower socioeconomic status, smokers tend to perform worse on cognitive tasks than non-smokers. China is now undergoing a similar process with a recent study showing that there is a reduced cognitive performance in middle aged but not in elderly smokers. We examined the links between smoking status and cognitive functioning among vocational school students in Beijing, China. METHODS: A total of 213 students aged 16-20 (98 smokers and 115 non-smokers) were recruited from three vocational schools in Beijing. Participants completed three subtests of Wechsler Adult Intelligence Scale (WAIS) (information, arithmetic, digit span) and Dysexecutive Questionnaire (DEX). Smokers also completed a cigarette smoking questionnaire and Fagerstrom Test of Nicotine Dependence (FTND). RESULTS: Smokers performed worse than non-smokers in tests of arithmetic and digit span forward (t = 4.25, 2.05, both P < .05). Scores on digit span backward did not differentiate smokers and non-smokers, but among smokers, the performance on this subtest was related to the age of starting smoking (r = 0.26, p < .001). Cognitive performance in smokers was not related to tobacco dependence or intensity of smoking. Compared to non-smokers, smokers had a higher total DEX score and higher scores on three of its five subscales (Inhibition, Knowing-doing dissociation and Social regulation, all p < .05). Another subscale, In-resistance, did not differentiate smokers and non-smokers, but differentiated smokers with lower and higher levels of nicotine dependence (t = -2.12, p < .05). CONCLUSION: Smokers performed worse on some cognitive tasks than non-smokers and scored higher on a questionnaire assessing executive dysfunction. PMID- 29414459 TI - Spatially generalizable representations of facial expressions: Decoding across partial face samples. AB - A network of cortical and sub-cortical regions is known to be important in the processing of facial expression. However, to date no study has investigated whether representations of facial expressions present in this network permit generalization across independent samples of face information (e.g., eye region vs mouth region). We presented participants with partial face samples of five expression categories in a rapid event-related fMRI experiment. We reveal a network of face-sensitive regions that contain information about facial expression categories regardless of which part of the face is presented. We further reveal that the neural information present in a subset of these regions: dorsal prefrontal cortex (dPFC), superior temporal sulcus (STS), lateral occipital and ventral temporal cortex, and even early visual cortex, enables reliable generalization across independent visual inputs (faces depicting the 'eyes only' vs 'eyes removed'). Furthermore, classification performance was correlated to behavioral performance in STS and dPFC. Our results demonstrate that both higher (e.g., STS, dPFC) and lower level cortical regions contain information useful for facial expression decoding that go beyond the visual information presented, and implicate a key role for contextual mechanisms such as cortical feedback in facial expression perception under challenging conditions of visual occlusion. PMID- 29414458 TI - Predictability's aftermath: Downstream consequences of word predictability as revealed by repetition effects. AB - Stimulus processing in language and beyond is shaped by context, with predictability having a particularly well-attested influence on the rapid processes that unfold during the presentation of a word. But does predictability also have downstream consequences for the quality of the constructed representations? On the one hand, the ease of processing predictable words might free up time or cognitive resources, allowing for relatively thorough processing of the input. On the other hand, predictability might allow the system to run in a top-down "verification mode", at the expense of thorough stimulus processing. This electroencephalogram (EEG) study manipulated word predictability, which reduced N400 amplitude and inter-trial phase clustering (ITPC), and then probed the fate of the (un)predictable words in memory by presenting them again. More thorough processing of predictable words should increase repetition effects, whereas less thorough processing should decrease them. Repetition was reflected in N400 decreases, late positive complex (LPC) enhancements, and late alpha/beta band power decreases. Critically, prior predictability tended to reduce the repetition effect on the N400, suggesting less priming, and eliminated the repetition effect on the LPC, suggesting a lack of episodic recollection. These findings converge on a top-down verification account, on which the brain processes more predictable input less thoroughly. More generally, the results demonstrate that predictability has multifaceted downstream consequences beyond processing in the moment. PMID- 29414460 TI - Re-emergence of modular brain networks in stroke recovery. AB - Studies of stroke have identified local reorganization in perilesional tissue. However, because the brain is highly networked, strokes also broadly alter the brain's global network organization. Here, we assess brain network structure longitudinally in adult stroke patients using resting state fMRI. The topology and boundaries of cortical regions remain grossly unchanged across recovery. In contrast, the modularity of brain systems i.e. the degree of integration within and segregation between networks, was significantly reduced sub-acutely (n = 107), but partially recovered by 3 months (n = 85), and 1 year (n = 67). Importantly, network recovery correlated with recovery from language, spatial memory, and attention deficits, but not motor or visual deficits. Finally, in depth single subject analyses were conducted using tools for visualization of changes in brain networks over time. This exploration indicated that changes in modularity during successful recovery reflect specific alterations in the relationships between different networks. For example, in a patient with left temporo-parietal stroke and severe aphasia, sub-acute loss of modularity reflected loss of association between frontal and temporo-parietal regions bi hemispherically across multiple modules. These long-distance connections then returned over time, paralleling aphasia recovery. This work establishes the potential importance of normalization of large-scale modular brain systems in stroke recovery. PMID- 29414461 TI - Interpreting the Czech drug decriminalization: The glass is half full - Response to Cerveny, J., Chomynova, P., Mravcik, V., & van Ours, J.C. (2017). Cannabis decriminalization and the age of onset of cannabis use. PMID- 29414462 TI - Determinants of hepatitis C antiviral effectiveness awareness among people who inject drugs in the direct-acting antiviral era. AB - BACKGROUND & AIMS: Although people who inject drugs (PWID) are at greatest risk of hepatitis C (HCV), treatment uptake in this population has historically been low. Highly effective direct acting antiviral (DAA) treatments for HCV have recently become available. Our aim was to assess the awareness among PWID of these new therapies and their effectiveness. METHODS: A national survey of PWID attending injecting equipment provision sites in Scotland during 2015-2016 included questions to gauge the awareness in this population of antiviral treatment and the high cure rates associated with new therapies (defined here as >80%). RESULTS: Among 2623 PWID, 92% had ever been tested for HCV. After excluding those ever treated for HCV (n = 226), 79% were aware of HCV treatment. Awareness was more likely among those who had ever been tested and self-reported either a positive (adjusted odds ratio: 16.04, 95%CI 10.57-24.33) or negative (3.11, 2.30-4.22) test result, compared to those who were never tested. The minority of all respondents (17%) were aware of high cure rates. This awareness was more likely among those who had ever been in HCV specialist care (9.76, 5.13 18.60) and those who had not been in specialist care but had been tested and self reported either a positive (3.91, 2.20-7.53) or negative (2.55, 1.35-4.81) test result, compared to those who had never been tested. CONCLUSION: We found poor awareness of the high cure rates associated with DAAs among PWID in Scotland, despite relatively high rates of HCV testing in this population. Increased effort is needed to ensure population groups with high risk of HCV infection are fully informed of the highly effective antiviral medications now available to treat this chronic disease. PMID- 29414463 TI - A novel approach to determine primary stability of acetabular press-fit cups. AB - Today hip cups are used in a large variety of design variants and in increasing numbers of units. Their development is steadily progressing. In addition to conventional manufacturing methods for hip cups, additive methods, in particular, play an increasingly important role as development progresses. The present paper describes a modified cup model developed based on a commercially available press fit cup (Allofit 54/JJ). The press-fit cup was designed in two variants and manufactured using selective laser melting (SLM). Variant 1 (Ti) was modeled on the Allofit cup using an adapted process technology. Variant 2 (Ti-S) was provided with a porous load bearing structure on its surface. In addition to the typical (complete) geometry, both variants were also manufactured and tested in a reduced shape where only the press-fit area was formed. To assess the primary stability of the press-fit cups in the artificial bone cavity, pull-out and lever out tests were carried out. Exact fit conditions and two-millimeter press-fit were investigated. The closed-cell PU foam used as an artificial bone cavity was mechanically characterized to exclude any influence on the results of the investigation. The pull-out forces of the Ti-variant (complete-526 N, reduced-468 N) and the Ti-S variant (complete-548 N, reduced-526 N) as well as the lever-out moments of the Ti-variant (complete-10 Nm, reduced-9.8 Nm) and the Ti-S variant (complete-9 Nm, reduced-7.9 N) show no significant differences in the results between complete and reduced cups. The results show that the use of reduced cups in a press-fit design is possible within the scope of development work. PMID- 29414464 TI - Larger vertebral endplate concavities cause higher failure load and work at failure under high-rate impact loading of rabbit spinal explants. AB - Vertebral fractures are among the most common of all osteoporosis related fracture types and its risk assessment is largely based on bone quality measures. Morphometric parameters are not yet considered, although endplate thickness and concavity shape were found to be important in fracture prediction in low-rate tests. We hypothesized that, under high-rate impact loading, the shape and size of the central endplate concavity are of key importance for fracture prediction. Therefore, we tested rabbit spinal segment explants in vitro under high-rate impact loading. With a combination of microCT to describe endplate morphometry, high-speed video imaging, and impact force measurement, endplate morphometry was correlated to the mechanical response. We found that endplate concavity shape and volume were important in describing the mechanical response: larger concavities caused higher failure load. We suggest a model for the fracture mechanism under high-rate impact loading, considering the morphometry of the endplates: wider and more voluminous concavities are protective whereas steeper slopes of the concavity edges and increasing bone volume fraction of the central endplate moiety are disadvantageous. Therefore, the shape and size of endplate morphometry are important in vertebral fracture prediction and should be considered included in vertebral fracture risk assessment. PMID- 29414465 TI - Preparation and characterization of silane-modified SiO2 particles reinforced resin composites with fluorinated acrylate polymer. AB - A series of fluorinated dental resin composites were prepared with two kinds of SiO2 particles. Bis-GMA (bisphenol A-glycerolate dimethacrylate)/4-TF-PQEA (fluorinated acrylate monomer)/TEGDMA (triethylene glycol dimethacrylate) (40/30/30, wt/wt/wt) was introduced as resin matrix. SiO2 nanopartices (30nm) and SiO2 microparticles (0.3um) were silanized with 3-methacryloxypropyl trimethoxysilane (gamma-MPS) and used as fillers. After mixing the resin matrix with 0%, 10%, 20%, 30% SiO2 nanopartices and 0%, 10%, 20%, 30%, 40%, 50% SiO2 microparticles, respectively, the fluorinated resin composites were obtained. Properties including double bond conversion (DC), polymerization shrinkage (PS), water sorption (Wp), water solubility (Wy), mechanical properties and cytotoxicity were investigated in comparison with those of neat resin system. The results showed that, filler particles could improve the overall performance of resin composites, particularly in improving mechanical properties and reducing PS of composites along with the addition of filler loading. Compared to resin composites containing SiO2 microparticles, SiO2 nanoparticles resin composites had higher DC, higher mechanical properties, lower PS and lower Wp under the same filler content. Especially, 50% SiO2 microparticles reinforced resins exhibited the best flexural strength (104.04 +/- 7.40MPa), flexural modulus (5.62 +/- 0.16GPa), vickers microhardness (37.34 +/- 1.13 HV), compressive strength (301.54 +/- 5.66MPa) and the lowest polymerization (3.42 +/- 0.22%). PMID- 29414466 TI - Influence of crosslinking on the mechanical behavior of 3D printed alginate scaffolds: Experimental and numerical approaches. AB - Tissue scaffolds fabricated by three-dimensional (3D) bioprinting are attracting considerable attention for tissue engineering applications. Because the mechanical properties of hydrogel scaffolds should match the damaged tissue, changing various parameters during 3D bioprinting has been studied to manipulate the mechanical behavior of the resulting scaffolds. Crosslinking scaffolds using a cation solution (such as CaCl2) is also important for regulating the mechanical properties, but has not been well documented in the literature. Here, the effect of varied crosslinking agent volume and crosslinking time on the mechanical behavior of 3D bioplotted alginate scaffolds was evaluated using both experimental and numerical methods. Compression tests were used to measure the elastic modulus of each scaffold, then a finite element model was developed and a power model used to predict scaffold mechanical behavior. Results showed that crosslinking time and volume of crosslinker both play a decisive role in modulating the mechanical properties of 3D bioplotted scaffolds. Because mechanical properties of scaffolds can affect cell response, the findings of this study can be implemented to modulate the elastic modulus of scaffolds according to the intended application. PMID- 29414467 TI - Continuous functionally graded porous titanium scaffolds manufactured by selective laser melting for bone implants. AB - A significant requirement for a bone implant is to replicate the functional gradient across the bone to mimic the localization change in stiffness. In this work, continuous functionally graded porous scaffolds (FGPSs) based on the Schwartz diamond unit cell with a wide range of graded volume fraction were manufactured by selective laser melting (SLM). The micro-topology, strut dimension characterization and effect of graded volume fraction on the mechanical properties of SLM-processed FGPSs were systematically investigated. The micro topology observations indicate that diamond FGPSs with a wide range of graded volume fraction from 7.97% to 19.99% were fabricated without any defects, showing a good geometric reproduction of the original designs. The dimensional characterization demonstrates the capability of SLM in manufacturing titanium diamond FGPSs with the strut size of 483-905um. The elastic modulus and yield strength of the titanium diamond FGPSs can be tailored in the range of 0.28 0.59GPa and 3.79-17.75MPa respectively by adjusting the graded volume fraction, which are comparable to those of the cancellous bone. The mathematical relationship between the graded porosity and compression properties of a FGPS was revealed. Furthermore, two equations based on the Gibson and Ashby model have been established to predict the modulus and yield strength of SLM-processed diamond FGPSs. Compared to homogeneous diamond porous scaffolds, FGPSs provide a wide range of mutative pore size and porosity, which are potential to be tailored to optimize the pore space for bone tissue growth. The findings provide a basis of new methodologies to design and manufacture superior graded scaffolds for bone implant applications. PMID- 29414468 TI - A novel fracture mechanics model explaining the axial penetration of bone-like porous, compressible solids by various orthopaedic implant tips. AB - Many features of orthopaedic implants have been previously examined regarding their influence on migration in trabecular bone under axial loading, with screw thread design being one of the most prominent examples. There has been comparatively little investigation, however, of the influence that implant tip design has on migration under axial loads. We present a novel fracture mechanics model that explains how differences in tip design affect the force required for axial penetration of porous, compressible solids similar to trabecular bone. Three tip designs were considered based on typical 5 mm diameter orthopaedic locking screws: flat and conical tip designs, as well as a novel elastomeric tip. Ten axial penetration trials were conducted for each tip design. In order to isolate the effect of tip design on axial migration from that of the threads, smooth steel rods were used. Tip designs were inserted into polyurethane foam commonly used to represent osteoporotic trabecular bone tissue (ASTM Type 10, 0.16 g/cc) to a depth of 10 mm at a rate of 2 mm/min, while force and position were recorded. At maximum depth, elastomeric tips were found to require the greatest force for axial migration (mean of 248.24 N, 95% Confidence Interval [CI]: 238.1-258.4 N), followed by conical tips (mean of 143.46 N, 95% CI: 142.1 144.9 N), and flat tips (mean of 113.88 N, 95% CI: 112.2-115.5 N). This experiment was repeated in cross-section while recording video of material compaction through a transparent window. Strain fields for each tip design were then generated from these videos using digital image correlation (DIC) software. A novel fracture mechanics model, combining the Griffith with porous material compaction, was developed to explain the performance differences observed between the three tip designs. This model predicted that steady-state stress would be roughly the same (~ 4 MPa) across all designs, a finding consistent with the experimental results. The model also suggested that crack formation and friction are negligible mechanisms of energy absorption during axial penetration of porous compressible solids similar to trabecular bone. Material compaction appears to be the dominant mechanism of energy absorption, regardless of tip design. The cross sectional area of the compacted material formed during migration of the implant tip during axial penetration was shown to be a strong determinant of the force required for migration to occur (Pearson Coefficient = 0.902, p < .001). As such, implant tips designed to maximize the cross-sectional area of compacted material such as the elastomeric and conical tips in the present study - may be useful in reducing excessive implant migration under axial loads in trabecular bone. PMID- 29414469 TI - Physico-chemical characterization and biocompatibility of hydroxyapatite derived from fish waste. AB - The aim of this study was to synthesize hydroxyapatite (HAP) powder from fish waste. The powder was characterized through X-ray diffraction, Fourier transform infrared spectroscopy, ion exchange chromatography, scanning electron microscopy and plasma emission spectrometry. The cyto- and genotoxicity was carried out to demonstrate biocompatibility in vivo by means of rat subcutaneous tissue test. The results showed that the visible crystalline nature of typical apatite crystal structure when they were calcined at 800 degrees C. Infrared spectroscopy analysis showed similar composition to HAP standard with the presence of carbonate ion demonstrated by wave number values of 871 cm-1 and 1420 cm-1 for calcinations at 800 degrees C. The scanning electronmicrographies depicted the crystal morphology and porous nature with average pore size of ~10 um. Plasma emission spectrometry and ion exchange chromatography confirmed the presence of Ca and P in the samples. The mean of calcium content was 36.8; Mg was 0.8, Na was 0.7 and K was 0.5. Rat subcutaneous tissue test revealed that HAP presented biocompatibility. Furthermore, the lack of cyto- and genotoxicity in blood, liver, kidney and lung were noticed after 30 days of HAP implantation. Taken together, our results demonstrated that HAP from fish waste exhibits a great potential for using as biomaterial since is represents a simple, effective, low cost process and satisfactory degree of biocompatibility. PMID- 29414470 TI - Improved tribocorrosion performance of bio-functionalized TiO2 nanotubes under two-cycle sliding actions in artificial saliva. AB - After insertion into bone, dental implants may be subjected to tribocorrosive conditions resulting in the release of metallic ions and solid wear debris, which can induce to peri-implant inflammatory reactions accompanied by bone loss, and ultimately implant loosening. Despite the promising ability of TiO2 nanotubes (NTs) to improve osseointegration and avoid infection-related failures, the understanding of their degradation under the simultaneous action of wear and corrosion (tribocorrosion) is still very limited. This study aims, for the first time, to study the tribocorrosion behavior of bio-functionalized TiO2 NTs submitted to two-cycle sliding actions, and compare it with conventional TiO2 NTs. TiO2 NTs grown by anodization were doped with bioactive elements, namely calcium (Ca), phosphorous (P), and zinc (Zn), through reverse polarization anodization treatments. Characterization techniques such as scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and scanning transmission electron microscopy (STEM), were used to characterize the films. Tribocorrosion tests were carried out in artificial saliva (AS) by applying two cycles of reciprocating sliding actions. The open circuit potential (OCP) was monitored before, during, and after both cycles of sliding, during which the coefficient of friction (COF) was calculated. The resulting wear scars were analyzed by SEM and EDS, and wear volume measurements were performed by 2D profilometry. Finally, the mechanical features of TiO2 NTs were accessed by nanoindentation. The results show that bio-functionalized TiO2 NTs display an enhanced tribocorrosion performance, ascribed to the growth of a nano-thick oxide film at Ti/TiO2 NTs interface, which significantly increased their adhesion strength to the substrate and consequently their hardness. Furthermore, it was discovered that during tribo-electrochemical solicitations, the formation of a P rich tribofilm takes place, which grants both electrochemical protection and resistance to mechanical wear. This study provides fundamental and new insights for the development of multifunctional TiO2 NTs with long-term biomechanical stability and improved clinical outcomes. PMID- 29414471 TI - Assessing women's lacrosse head impacts using finite element modelling. AB - Recently studies have assessed the ability of helmets to reduce peak linear and rotational acceleration for women's lacrosse head impacts. However, such measures have had low correlation with injury. Maximum principal strain interprets loading curves which provide better injury prediction than peak linear and rotational acceleration, especially in compliant situations which create low magnitude accelerations but long impact durations. The purpose of this study was to assess head and helmet impacts in women's lacrosse using finite element modelling. Linear and rotational acceleration loading curves from women's lacrosse impacts to a helmeted and an unhelmeted Hybrid III headform were input into the University College Dublin Brain Trauma Model. The finite element model was used to calculate maximum principal strain in the cerebrum. The results demonstrated for unhelmeted impacts, falls and ball impacts produce higher maximum principal strain values than stick and shoulder collisions. The strain values for falls and ball impacts were found to be within the range of concussion and traumatic brain injury. The results also showed that men's lacrosse helmets reduced maximum principal strain for follow-through slashing, falls and ball impacts. These findings are novel and demonstrate that for high risk events, maximum principal strain can be reduced by implementing the use of helmets if the rules of the sport do not effectively manage such situations. PMID- 29414472 TI - Positioning of the cross-stitch on the modified Kessler core tendon suture. AB - Cryopreserved human tendons were sutured with different variations of a modified Kessler-type grasping suture in a series of different designs in order to assess the influence of the distance between the cross-stitch on the core suture (5 and 10 mm from the cut tendon edge) on the peripheral suture. An original mathematical model was employed to explain the mechanical behavior (strength, deformation, and distribution of load) of the different suture designs. The effect of the peripheral epitendinous suture, combined with the distance of the core suture, was evaluated. The variation of core suture distance had no relevant consequences on the overall resilience of the design. However, increasing the distance between the cross-stitches of the core suture reduces the deformation that is absorbed not only by the core suture itself but also by the peripheral suture. Adding a peripheral epitendinous suture to a 10-mm design almost doubles the breaking load in absolute values. The mathematical model predicts that the peripheral suture will support a greater load when the distance of the core suture cross-stitches is increased. The evidence level is II. PMID- 29414473 TI - Formulation and viscoelasticity of mineralised hydrogels for use in bone cartilage interfacial reconstruction. AB - Articular cartilage is a viscoelastic tissue whose structural integrity is important in maintaining joint health. To restore the functionality of osteoarthritic joints it is vital that regenerative strategies mimic the dynamic loading response of cartilage and bone. Here, a rotating simplex model was employed to optimise the composition of agarose and gellan hydrogel constructs structured with hydroxyapatite (HA) with the aim of obtaining composites mechanically comparable to human cartilage in terms of their ability to dissipate energy. Addition of ceramic particles was found to reinforce both matrices up to a critical concentration (< 3w/v%). Beyond this, larger agglomerates were formed, as evidenced by micro computed tomography data, which acted as stress risers and reduced the ability of composites to dissipate energy demonstrated by a reduction in tan delta values. A maximum compressive modulus of 450.7+/-24.9 kPa was achieved with a composition of 5.8w/v% agarose and 0.5w/v% HA. Interestingly, when loaded dynamically (1-20Hz) this optimised formulation did not exhibit the highest complex modulus instead a sample with a higher concentration of mineral was identified (5.8w/v% agarose and 25w/v% HA). Thus, demonstrating the importance of examining the mechanical behaviour of biomaterials under conditions representative of physiological environments. While the complex moduli of the optimised gellan (1.0 +/- 0.2MPa at 1Hz) and agarose (1.7 +/- 0.2MPa at 1Hz) constructs did not match the complex moduli of healthy human cartilage samples (26.3 +/- 6.5MPa at 1Hz), similar tan delta values were observed between 1 and 5Hz. This is promising since these frequencies represent the typical heel strike time of the general population. In summary, this study demonstrates the importance of considering more than just the strength of biomaterials since tissues like cartilage play a more complex role. PMID- 29414474 TI - Effects of water and microbial-based aging on the performance of three dental restorative materials. AB - The objective of this study was to evaluate the performance changes of three restorative materials before and after three different aging treatments: storage in distilled water, Streptococcus mutans (S. mutans) and oral salivary microbes suspensions for one month. Resin composite (RC), giomer and glass ionomer cement (GIC) were chosen for aging procedures. Surface morphology, roughness average (Ra), color changes and mechanical properties were all determined before and after aging respectively. Biomass and metabolism difference of early attached biofilm on the material surface were tested through 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and lactic acid measurement. The results showed that after S. mutans or salivary microbes aging treatments, GIC group displayed significant morphology changes, with Ra value significantly higher than that before aging (p < .001). Color changes of giomer and GIC group after S. mutans aging were not clinically acceptable. All materials after two microbial-based aging treatments had higher flexural strength than that before aging (p < .05). Giomer after salivary microbes aging had higher elastic modulus than the initial values (p < .05). Additionally, early attached biofilm biomass and lactic acid production in GIC group after S. mutans or salivary microbes aging were higher than that before aging (p < .05). While one-month water aging showed less influences on material performance to some extent. In conclusion, to better simulate the harsh oral environment, in vitro microbial-based aging models showed more advantages in evaluating dental restorative materials' degradation over time. PMID- 29414475 TI - Effects of cross-linking on mechanical, biological properties and biodegradation behavior of Nile tilapia skin collagen sponge as a biomedical material. AB - The objective of this study was to explore the effects of dehydrothermal treatment (DHT) and glutaraldehyde (GTA) cross-linking on mechanical, biological properties and biodegradation behavior of Nile tilapia skin collagen sponge fabricated by freeze-drying technology. It was found that the GTA cross-linked collagen sponge exhibited a higher degree of cross-linking in comparison with DHT. The extent of increased tensile strength as well as hygroscopicity indicated that GTA cross-linking was superior to DHT in mechanical properties and liquid absorption, which was attributed to different cross-linking mechanisms. Hygroscopicity assay indicated that cross-linking could improve stability of collagen in solutions. No obvious changes in porosity and blood coagulation time were observed whether cross-linking or not. Results from collagenase biodegradation assay in vitro illustrated that GTA-treated collagen sponge was more resistant to collagenase biodegradation, while DHT exhibited negligible resistance. In addition, photochemical stability of collagen sponge was studied by Fourier transforms infrared spectroscopy (FTIR), which indicated that both cross-linking treatments could not change the backbone structure of collagen. Furthermore, the microstructure of collagen sponge was stable after cross linking. The highly porous and interconnected structure of collagen sponge was helpful to the absorption of wound exudates, supplement of oxygen and cell proliferation, accompanied with good blood compatibility, which indicated that our fabricated collagen sponge could be applied in biomedical materials field as wound dressings. PMID- 29414476 TI - Fracture-free surfaces of CAD/CAM lithium metasilicate glass-ceramic using micro slurry jet erosion. AB - This paper reports the use of micro-slurry jet erosion (MSJE) on CAD/CAM lithium mesilicate glass ceramic (LMGC) that is capable of achieving the fracture-free surface quality. A computer-controlled MSJE process using a low-pressure and low concentration alumina slurry was applied to diamond-ground LMGC surfaces with surface and subsurface damage. The MSJE processed and diamond-ground LMGC surfaces were examined using scanning electron microscopy (SEM) to examine surface morphology, fractures, and residual defects. 3D confocal laser microscopy (CLM) was used to quantitatively characterize all machined surface textures as a function of processing conditions. Our results show that surface and subsurface damage induced in diamond-ground surfaces were significantly diminished after 50 cycle MSJE processing. Fracture-free surfaces were obtained after 100 MSJE cycles. Our measured parameters of the 3D surface topography included the average surface roughness, maximum peak-valley height, highest peak height, lowest valley height, and kurtosis and absolute skewness of height distributions. All these parameters were significantly reduced with the increase of MSJE cycles. This work implies that MSJE promises to be an effective manufacturing technique for the generation of fracture-free LMGC surfaces which are crucial for high-quality monolithic restorations made from the material. PMID- 29414477 TI - Effect of porous orthopaedic implant material and structure on load sharing with simulated bone ingrowth: A finite element analysis comparing titanium and PEEK. AB - Osseointegration of load-bearing orthopaedic implants, including interbody fusion devices, is critical to long-term biomechanical functionality. Mechanical loads are a key regulator of bone tissue remodeling and maintenance, and stress shielding due to metal orthopaedic implants being much stiffer than bone has been implicated in clinical observations of long-term bone loss in tissue adjacent to implants. Porous features that accommodate bone ingrowth have improved implant fixation in the short term, but long-term retrieval studies have sometimes demonstrated limited, superficial ingrowth into the pore layer of metal implants and aseptic loosening remains a problem for a subset of patients. Polyether-ether ketone (PEEK) is a widely used orthopaedic material with an elastic modulus more similar to bone than metals, and a manufacturing process to form porous PEEK was recently developed to allow bone ingrowth while preserving strength for load bearing applications. To investigate the biomechanical implications of porous PEEK compared to porous metals, we analyzed finite element (FE) models of the pore structure-bone interface using two clinically available implants with high (> 60%) porosity, one being constructed from PEEK and the other from electron beam 3D-printed titanium (Ti). The objective of this study was to investigate how porous PEEK and porous Ti mechanical properties affect load sharing with bone within the porous architectures over time. Porous PEEK substantially increased the load share transferred to ingrown bone compared to porous Ti under compression (i.e. at 4 weeks: PEEK = 66%; Ti = 13%), tension (PEEK = 71%; Ti = 12%), and shear (PEEK = 68%; Ti = 9%) at all time points of simulated bone ingrowth. Applying PEEK mechanical properties to the Ti implant geometry and vice versa demonstrated that the observed increases in load sharing with PEEK were primarily due to differences in intrinsic elastic modulus and not pore architecture (i.e. 4 weeks, compression: PEEK material/Ti geometry = 53%; Ti material/PEEK geometry = 12%). Additionally, local tissue energy effective strains on bone tissue adjacent to the implant under spinal load magnitudes were over two-fold higher with porous PEEK than porous Ti (i.e. 4 weeks, compression: PEEK = 784 +/- 351 microstrain; Ti = 180 +/- 300 microstrain; and 12 weeks, compression: PEEK = 298 +/- 88 microstrain; Ti = 121 +/- 49 microstrain). The higher local strains on bone tissue in the PEEK pore structure were below previously established thresholds for bone damage but in the range necessary for physiological bone maintenance and adaptation. Placing these strain magnitudes in the context of literature on bone adaptation to mechanical loads, this study suggests that porous PEEK structures may provide a more favorable mechanical environment for bone formation and maintenance under spinal load magnitudes than currently available porous 3D-printed Ti, regardless of the level of bone ingrowth. PMID- 29414478 TI - Role of particulate concentration in tooth wear. AB - Results are presented for wear tests on human molar enamel in silica particle mediums. Data for different particle concentrations show severe wear indicative of material removal by plasticity-induced microcrack formation, in accordance with earlier studies. The wear rates are independent of low vol% particles, consistent with theoretical models in which occlusal loads are distributed evenly over all interfacial microcontacts. However, perhaps counter-intuitively, the wear rate diminishes substantially at higher vol%. This is attributed to a greater proportion of lower-load microcontacts transitioning into a region of mild wear, where microcracking is suppressed. Implications of these results in relation to evolutionary biology and dentistry are explored. PMID- 29414479 TI - Modelling a soft composite accumulator for human mobility assist devices. AB - Research in the field of human mobility assist devices, aiming to reduce the metabolic cost of daily activities, is seeing the benefits of the exclusive use of accumulators to store and release energy during the gait cycle. The Pneumatic Artificial Muscle, used in a passive state, has proven to be a superior choice for these devices when compared to its alternatives, however, challenges regarding muscle pressure dissipation and a limited elongation potential have been identified. A recently developed, novel Soft Composite material has been shown to experimentally replicate the distinctive mechanical behaviour of the Pneumatic Artificial Muscle, without the need for internal pressurization. This paper presents two separate constitutive models to provide a closer insight into the behaviour of these Soft Composite accumulators. Both models were derived from methods involving finite elasticity theory and employed either a structural strain energy function of Holzapfel, Gasser, and Ogden's type or a phenomenological strain energy function of Fung's type. Both models were in good agreement with the experimental data that were collected through a modified extension-inflation test and, therefore, provide a basis for further examination as a Soft Composite design model. PMID- 29414480 TI - Different models for simulation of mechanical behaviour of porous materials. AB - Commercially pure Titanium (cpTi) and its alloys are the most successful metallic biomaterials for bone replacement, due to its excellent biomechanical and biofunctional balance. However, these materials have higher elastic modulus when compared with bone, leading to the stress-shielding phenomenon and promoting bone resorption. Development of porous implants with low elastic modulus, providing a good mechanical and functional balance (suitable mechanical strength and optimum osseointegration), is the focus of emergent research in advanced Ti-based alloy biomaterials. With the aim of understanding the mechanical behaviour of porous materials with relation to the porosity level and the porous morphology, a new improved model with three different versions have been developed in this work. The proposed FE model combines the simplicity of a 2D periodic geometry with the complex information of the pore morphology extracted from experimentation. The methodology to generate the 2D simulated microstructure is based on a series of nxn pores distributed in a square matrix. The different versions of the model differ in the way of building the porous geometry. In the first version of the model ("Basic-Pattern Model"), the pores are supposed to be circular and periodically distributed in the matrix, following a perfect pattern. The second version of the model ("Pattern Model") is similar to the previous one, but with elliptic pores with a morphology randomly generated, following statistical information from experiments. In the third version ("Semi-random Model"), a controlled random distribution of the pores is obtained by including a randomness factors in both directions. By making use of the proposed FE model with its different versions, five different porous titanium obtained by the space-holders technique (with porosities theta = 28%, 37%, 47%, 57% and 66%) have been modeled based on experimental information of the pore morphology, and its macroscopic mechanical behaviour has been simulated, showing relatively good agreement with experimental results. PMID- 29414481 TI - Modeling the effects of lipid contamination in poly(styrene-isobutylene-styrene) (SIBS). AB - Lipid uptake and subsequent degradation was characterized as a function of molecular weight and styrene content in four different formulations of poly(styrene-block-Isobutylene-block-styrene) (SIBS). Mechanical testing in uniaxial tension at varying lipid concentrations showed a consistent decrease in tensile strength for all specimens due to lipid contamination. Higher styrene content was associated with an improved resistance to lipid intrusion. A decrease in elongation at break was observed for low molecular weight formulations only; an expected result of the stiffer network and local chain motion restriction due to increased entanglements in high molecular weight SIBS. A new, coupled diffusion/finite element method was used to recover the swelling coefficient of the four different SIBS formulations. The Ogden strain-density energy function recovered from unidirectional tensile testing and diffusion properties from gravimetric analysis were used to construct the finite element model. The predicted swelling behavior matched experimental data and the swelling coefficients were recovered for all formulations tested. Results indicate that the higher lipid affinity of the isobutylene phase contributed to increased swelling, as expected. This novel method to calculate swelling coefficient effectively circumvents the inability of commonly-used thermal deswelling methods to characterize lipid and oil-induced swelling behavior; enabling better prediction of long-term in vivo performance of polymer-based biomedical devices and more accurate evaluation of lipid-induced degradation and swelling. PMID- 29414482 TI - Reducing opioid overdose in Kazakhstan: A randomized controlled trial of a couple based integrated HIV/HCV and overdose prevention intervention "Renaissance". AB - OBJECTIVES: To evaluate the efficacy of a couple-based integrated HIV/HCV and overdose prevention intervention on non-fatal and fatal overdose and overdose prevention behaviors among people who use heroin or other opioids in Almaty, Kazakhstan. METHODS: We selected 479 participants who reported lifetime heroin or opioid use from a sample of 600 participants (300 couples) enrolled in a randomized controlled trial (RCT) conducted between May 2009 and February 2013. Participants were randomized to either (1) a 5-session couple-based HIV/HCV and overdose prevention intervention condition or (2) a 5-session Wellness Promotion and overdose prevention comparison condition. We used multilevel mixed-effects model with modified Poisson regression to estimate effects of the intervention as risk ratios (RR) and the corresponding 95% CIs. RESULTS: About one-fifth (21.9%) of the sample reported that they had experienced an opioid overdose in the past 6 months at baseline. At the 12-month follow-up, both the intervention and comparison conditions reported significant reductions in non-fatal overdose and injection heroin/opioid use and significant increases in drug treatment attendance and naloxone use to prevent death from overdose. However, we found no differences between the study arms on any of these outcomes. There were three intervention condition participants (1.3%), compared to seven comparison condition participants (2.9%) who died from opioid overdose during the 12-month follow up period although this difference was not significant. DISCUSSION: There were no significant conditions on any outcomes: both conditions showed promising effects of reducing non-fatal overdose and overdose risks. Integrating overdose prevention into a couple-based HIV/HCV intervention may be an efficient strategy to target the syndemic of opioid overdose, HIV and HCV in Kazakhstan. PMID- 29414483 TI - Police crackdowns, structural violence and impact on the well-being of street cannabis users in a Nigerian city. AB - BACKGROUND: There is abundant literature on the impact of law enforcement on cannabis markets, but scant literature on the effects of law enforcement on cannabis users. This study undertook a qualitative exploration of police crackdowns as a form of structural violence and examined their impact on the well being of street cannabis users in a Nigerian city. METHODS: The study was qualitative and descriptive. It was carried out in Uyo, southern Nigeria. Ninety seven (97) frequent cannabis users (78 males and 19 females) took part. They were aged between 21 and 34 years and recruited from 11 cannabis hot-points in the city. Data were collected through in-depth, individual interviews, conducted over six-months. Data analysis was thematic and data-driven, involving identifying themes, assigning codes, revising codes and verification by independent qualitative methodology experts. RESULTS: Police crackdowns are commonly experienced by street cannabis users. These do not reduce cannabis use, but displace cannabis markets. Crackdowns are associated with police brutality, confiscation of funds, drugs and belongings, stigma and discrimination, arrest and incarceration, which impacts negatively on the health, livelihoods and well being of cannabis users. Cannabis users try to escape arrest by running from police, disposing of cannabis, disguising themselves and, when caught, bribing officers to secure release. CONCLUSION: Crackdowns constitute a form of structural violence in the everyday life of cannabis users, and have negative effects on their health and social and economic well-being. Cannabis use should be decriminalized de facto and arrested users directed to treatment and skills training programmes. Treatment and social services for users should be expanded and legal aid interventions should be mounted to support users in addressing discriminatory practices and human rights violations. PMID- 29414484 TI - Post opioid overdose outreach by public health and public safety agencies: Exploration of emerging programs in Massachusetts. AB - BACKGROUND: Opioid overdose is a significant public health problem. Collaborative programs between local public health and public safety agencies have emerged to connect overdose survivors and their personal networks with harm reduction and addiction treatment services following a non-fatal overdose event. This study explored the prevalence of these programs in Massachusetts and the different ways they have been structured and function. METHODS: We sent an online screening questionnaire to police and fire departments in all 351 communities in Massachusetts to find instances in which they collaborated with a community-based public health agency to implement a post-overdose outreach and support program. We conducted telephone interviews with communities that implemented this type of program and categorized programs based on their structure, outreach approach, and other key characteristics. RESULTS: Police and fire personnel from 110 of the 351 communities in Massachusetts (31% response rate) completed the screening survey. Among respondents, 21% (23/110) had implemented a collaborative, community-based, post-overdose program with a well-defined process to connect overdose survivors and their personal networks with support services or addiction treatment services. Using data from the interviews, we identified four types of programs: (1) Multi-Disciplinary Team Visit, (2) Police Visit with Referrals, (3) Clinician Outreach, and (4) Location-Based Outreach. CONCLUSIONS: This study represents the first attempt to systematically document an emerging approach intended to connect opioid overdose survivors and their personal networks with harm reduction and addiction treatment services soon after a non-fatal overdose event. These programs have the potential to increase engagement with the social service and addiction treatment systems by those who are at elevated risk for experiencing a fatal opioid overdose. PMID- 29414485 TI - Assessing the effect of public health information by incentivised risk estimation: An example on Swedish snus. AB - BACKGROUND: The provision of accurate information on health damaging behaviours and products is a widely accepted and widespread governmental task. It is easily mismanaged. This study demonstrates a simple method which can help to evaluate whether such information corrects recipient risk beliefs. METHODS: Participants assess risks numerically, before and after being exposed to a relevant risk communication. Accuracy is incentivised by awarding financial prizes to answers closest to a pursued risk belief. To illustrate this method, 228 students from the University of Oslo, Norway, were asked to estimate the mortality risk of Swedish snus and cigarettes twice, before and after being exposed to one of three risk communications with information on the health dangers of snus. RESULTS: The data allow us to measure how participants updated their risk beliefs after being exposed to different risk communications. Risk information from the government strongly distorted risk perceptions for snus. A newspaper article discussing the relative risks of cigarettes and snus reduced belief errors regarding snus risks, but increased belief errors regarding smoking. The perceived quality of the risk communication was not associated with decreased belief errors. CONCLUSION: Public health information can potentially make the public less informed on risks about harmful products or behaviours. This risk can be reduced by targeting identified, measurable belief errors and empirically assessing how alternative communications affect these. The proposed method of incentivised risk estimation might be helpful in future assessments of risk communications. PMID- 29414486 TI - Newest policy developments regarding surrogate alcohol consumption in Russia. PMID- 29414487 TI - Following the moving and changing attachments and assemblages of 'addiction': Applying the actor network approach to autobiographies. AB - The article applies actor network theory (ANT) to autobiographical data on alcohol dependence to explore what ANT can offer to the analysis of 'addiction stories'. By defining 'addiction' as a relational achievement, as the effect of elements acting together as a configuration of human and non-human actors, the article demonstrates how the moving and changing attachments of addiction can be dynamically analyzed with concepts of 'assemblage', 'mediator', 'tendency', 'translation', 'trajectory', 'immutable mobile', 'fluid' and 'bush fire'. The article shows how the reduction of alcohol dependence simply to genetic factors, neurobiological causes, personality disorders and self-medication constitutes an inadequate explanation. As 'meta theories', they illuminate addiction one sidedly. Instead, as ANT pays attention to multiple heterogeneous mediators, it specifies in what way the causes identified in 'meta theories' may together with other actors participate in addiction assemblages. When following the development of addiction assemblages, we focus on situational sequences of action, in which human and non-human elements are linked to each other, and we trace how the relational shape of addiction changes from one sequence to another as a transforming assemblage of heterogeneous attachments that either maintain healthy subjectivities or destabilize them. The more attachments assemblages of addiction are able to make that are flexible and durable from one event to another, the stronger also the addiction-based subjectivities. Similarly, the fewer attachments that assemblages of addiction are able to keep in their various translations, the weaker the addiction-based subjectivities also become. An ANT inspired analysis has a number of implications for the prevention and treatment of addiction: it suggests that in the prevention and treatment of addiction, the aim should hardly be to get rid of dependencies. Rather, the ambition should be the identification of attachments and relations that enable unhealthy practices and the development of harm as part of specific actor networks. PMID- 29414488 TI - Examining social supply among nonmedical prescription stimulant users in the San Francisco Bay Area. AB - In the US, prescription stimulants are prescribed for a variety of conditions including attention deficit hyperactivity disorder (ADHD) and narcolepsy. Over the last two decades, dramatic increases in stimulant prescriptions have led to greater availability and increased risk for diversion and nonmedical use. Our own and other investigators' findings indicate that many drug "suppliers" do not fit into the traditional image of drug "dealers." These suppliers typically do not identify themselves as "dealers," but instead understand their drug distribution as sharing with people they know. Coomber and colleagues' (2007; 2013) concept of "social supply" raises the question: When friends supply or facilitate supply of drugs to friends, is this really dealing? Further, if dealing and supplying are distinct kinds of social transactions, should different types of criminal justice approaches be applied? Social supply extends our understanding of drug dealing as a complex social activity. In this article, we examine the issue of social supply among nonmedical users of prescription stimulants. We conducted a 36-month National Institute on Drug Abuse-funded project to conduct a qualitative, mixed methods study of 150 adult nonmedical prescription stimulant users in the San Francisco Bay Area. We explore intersecting factors, including life stage and social location, that contribute to decisions to use prescription stimulants nonmedically, motivations to use, knowledge about risks and benefits of prescription stimulant use, any adverse health or social consequences experienced, availability, acquisition and diversion of prescription stimulants, and differences in attitudes and behaviours. For this analysis, we rely on participants' narratives concerning prescription stimulant acquisition practices and how they understood these interactions, purchases, and exchanges with the suppliers of prescription stimulants in their social networks. The authors argue that acknowledging the distinction between social supply and "proper" drug dealing would redress the disparity between drug sharing and profiteering particularly regarding criminal sentencing. PMID- 29414489 TI - Impacts of alcohol availability on Tribal lands where alcohol is prohibited: A community-partnered qualitative investigation. AB - On a Northern Plains reservation where alcohol was prohibited, we investigated community members' views on the impacts of alcohol availability. Our methods combined elements of Tribal community participatory research with qualitative inquiry to elicit these perspectives. We used rapid appraisal techniques to conduct confidential interviews with 31 key leaders representing 7 relevant major community systems, and representing a variety of perspectives. Topics included respondents' understandings of the current systems of alcohol availability and use on the reservation, the impacts of these systems on reservation residents, and possible ways to measure these impacts. Respondents reported impacts on individuals, families, and the tribe overall. Alcohol-related problems shaped and were shaped by a constellation of social-ecological conditions: kinship, housing, employment, public/social service capacity, and the supply of alcohol in nearby off-reservation areas, as well as inter-governmental relationships and the spiritual life of reservation residents. A variety of social-structural determinants magnified alcohol impacts, so that the problem drinking of a small number of individuals could have broad effects on their families and the entire community. Our participatory qualitative methods enabled us to directly include the voices as well as the personal experiences and expertise of community members in this presentation. These methods may be broadly applied within policy analysis to identify ways to reduce harms related to alcohol and other drugs for Indigenous communities. PMID- 29414490 TI - Assessing market competition and vendors' size and scope on AlphaBay. AB - BACKGROUND: Since 2011, drug market participants have traded illegal drugs through cryptomarkets, a user-friendly infrastructure in which drug market participants can conduct business transactions. This study assesses market competition and the size and scope of drug vendors' activities on one of the largest cryptomarkets, AlphaBay, in order to better understand the challenges that drug vendors face when selling on this venue. METHODS: Relying on data collected from AlphaBay, we calculate the degree of competition within the drug market using the Herfindhal-Hirshmann Index (HHI). We then follow a micro analytical approach and assess the size and scope of vendors' accounts. This is done by evaluating each vendor's market share over time using a group-based trajectory model (GBTM). Results from the GBTM are then used to assess vendors' exposure, diversity and experience based on their selling position in the market. RESULTS: The HHI scores demonstrate that cryptomarkets offer a highly competitive environment that fits in a top-heavy market structure. However, the distribution of vendors' market share trajectories shows that only a small portion of vendors (referred to as high-level vendors) succeed in generating regular sales, whereas the majority of vendors are relegated to being mere market spectators with almost zero sales. This inequality is exacerbated by the aggressive advertising of high level vendors who post many listings. Overall, product diversity and experience is limited for all market participants regardless of their level of success. We interpret these results through Reuter's work on traditional illegal markets, e commerce studies and the growing field of cryptomarket research. CONCLUSION: We conclude that, while offering a new venue for illegal drug transactions, in many ways, the economics of cryptomarkets for drug dealing are consistent with Reuter's classic assessment of illegal markets and the consequences of product illegality that underlie it. Cryptomarkets conflicting features, a relatively open setting with relatively high barriers to entry and sales, shape the competitive, yet top-heavy market that emerges from our analysis. This creates a challenging environment for cryptomarket drug dealers. PMID- 29414491 TI - How will e-cigarettes affect health inequalities? Applying Bourdieu to smoking and cessation. AB - This paper uses the work of Bourdieu to theorise smoking and cessation through a class lens, showing that the struggle for distinction created the social gradient in smoking, with smoking stigma operating as a proxy for class stigma. This led to increased policy focus on the health of bystanders and children and later also to concerns about electronic cigarettes. Bourdieu's concept of habitus is deployed to argue that the e-cigarette helps middle-class smokers resolve smoking as a symptom of cleft habitus associated with social mobility or particular subcultures. E-cigarette use is also compatible with family responsibility and sociable hedonism; aspects of working-class habitus which map to the 'practical family quitter' and the 'recreational user' respectively. The effectiveness of class stigma in changing health behaviours is contested, as is the usefulness of youth as a category of analysis and hence the relevance of concerns about young people's e-cigarette use outside a class framework of smoking and cessation. With regard to health inequalities, whilst middle-class smokers have in class disgust a stronger incentive to quit than working-class smokers, there is potential for tobacco control to tap into a working-class ethos of family care and responsibility. PMID- 29414492 TI - Age-related differences in BOLD modulation to cognitive control costs in a multitasking paradigm: Global switch, local switch, and compatibility-switch costs. AB - It is well documented that older adults recruit additional brain regions compared to those recruited by younger adults while performing a wide variety of cognitive tasks. However, it is unclear how such age-related over-recruitment interacts with different types of cognitive control, and whether this over-recruitment is compensatory. To test this, we used a multitasking paradigm, which allowed us to examine age-related over-activation associated with three types of cognitive costs (i.e., global switch, local switch, compatibility-switch costs). We found age-related impairments in global switch cost (GSC), evidenced by slower response times for maintaining and coordinating two tasks vs. performing only one task. However, no age-related declines were observed in either local switch cost (LSC), a cognitive cost associated with switching between the two tasks while maintaining two task loads, or compatibility-switch cost (CSC), a cognitive cost associated with incompatible vs. compatible stimulus-response mappings across the two tasks. The fMRI analyses allowed for identification of distinct cognitive cost-sensitive brain regions associated with GSC and LSC. In fronto-parietal GSC and LSC regions, older adults' increased activations were associated with poorer performance (greater costs), whereas a reverse relationship was observed in younger adults. Older adults also recruited additional fronto-parietal brain regions outside the cognitive cost-sensitive areas, which was associated with poorer performance or no behavioral benefits. Our results suggest that older adults exhibit a combination of inefficient activation within cognitive cost sensitive regions, specifically the GSC and LSC regions, and non-compensatory over-recruitment in age-sensitive regions. Age-related declines in global switching, compared to local switching, was observed earlier in old age at both neural and behavioral levels. PMID- 29414493 TI - Simultaneous estimation of population receptive field and hemodynamic parameters from single point BOLD responses using Metropolis-Hastings sampling. AB - We introduce a new approach to Bayesian pRF model estimation using Markov Chain Monte Carlo (MCMC) sampling for simultaneous estimation of pRF and hemodynamic parameters. To obtain high performance on commonly accessible hardware we present a novel heuristic consisting of interpolation between precomputed responses for predetermined stimuli and a large cross-section of receptive field parameters. We investigate the validity of the proposed approach with respect to MCMC convergence, tuning and biases. We compare different combinations of pRF - Compressive Spatial Summation (CSS), Dumoulin-Wandell (DW) and hemodynamic (5 parameter and 3-parameter Balloon-Windkessel) models within our framework with and without the usage of the new heuristic. We evaluate estimation consistency and log probability across models. We perform as well a comparison of one model with and without lookup table within the RStan framework using its No-U-Turn Sampler. We present accelerated computation of whole-ROI parameters for one subject. Finally, we discuss risks and limitations associated with the usage of the new heuristic as well as the means of resolving them. We found that the new algorithm is a valid sampling approach to joint pRF/hemodynamic parameter estimation and that it exhibits very high performance. PMID- 29414494 TI - Neuroanatomical morphometric characterization of sex differences in youth using statistical learning. AB - Exploring neuroanatomical sex differences using a multivariate statistical learning approach can yield insights that cannot be derived with univariate analysis. While gross differences in total brain volume are well-established, uncovering the more subtle, regional sex-related differences in neuroanatomy requires a multivariate approach that can accurately model spatial complexity as well as the interactions between neuroanatomical features. Here, we developed a multivariate statistical learning model using a support vector machine (SVM) classifier to predict sex from MRI-derived regional neuroanatomical features from a single-site study of 967 healthy youth from the Philadelphia Neurodevelopmental Cohort (PNC). Then, we validated the multivariate model on an independent dataset of 682 healthy youth from the multi-site Pediatric Imaging, Neurocognition and Genetics (PING) cohort study. The trained model exhibited an 83% cross-validated prediction accuracy, and correctly predicted the sex of 77% of the subjects from the independent multi-site dataset. Results showed that cortical thickness of the middle occipital lobes and the angular gyri are major predictors of sex. Results also demonstrated the inferential benefits of going beyond classical regression approaches to capture the interactions among brain features in order to better characterize sex differences in male and female youths. We also identified specific cortical morphological measures and parcellation techniques, such as cortical thickness as derived from the Destrieux atlas, that are better able to discriminate between males and females in comparison to other brain atlases (Desikan-Killiany, Brodmann and subcortical atlases). PMID- 29414495 TI - Direct electrophysiological evidence for the maintenance of retrieval orientations and the role of cognitive control. AB - Retrieval orientations are memory states that bias retrieval towards specific memory contents. Many neuroimaging studies have examined the influence of retrieval orientations on stimulus processing, but very little direct evidence exists regarding the ongoing maintenance of orientations themselves. Participants completed two memory tasks with different retrieval goals. ERPs were time-locked to a pre-stimulus fixation asterisk and contrasted according to retrieval goals. Pre-stimulus ERPs elicited during the two retrieval tasks diverged at frontal electrode sites. These differences onset early and were sustained throughout the fixation-stimulus interval. The functional and spatiotemporal characteristics of this ERP effect comprise the first direct electrophysiological evidence of the ongoing maintenance of retrieval orientations throughout a task. Moreover, this effect was eliminated in participants who performed a stroop task prior to the memory tests, indicating that reserves of cognitive control play an important role in the maintenance of retrieval orientations throughout memory tasks. PMID- 29414496 TI - Changes in dynamic functional connections with aging. AB - Despite numerous studies on age-related changes in static functional connections (FCs), the available literature on the changes in dynamic FCs with aging is lacking. This study investigated the changes in dynamic FCs with aging based on resting state fMRI data of 61 healthy adults aged 30-85 years. The time-resolved FCs among 160 pre-defined regions of interest (ROIs) were first estimated using sliding-window correlation. Based on the dynamic FC matrices, we then analyzed the dynamic switches between different FC states using k-means clustering, and correlated age with the dwell time of each FC state across subjects. The elderly were observed to spend more time in an FC state characterized by weak interactions throughout the brain and less time in an FC state characterized by strong interactions within the sensory-motor network and the cognitive control network. These results may reflect an overall weakening of connections in the elderly, which support less efficient information transfer in them. Based on the dynamic FC matrices, we also evaluated the variability and amplitude of FC time series, which measure the relative (to mean) and absolute strength of FC fluctuations, respectively, and correlated age with the two measures across subjects. Relatively weak age-vs-variability correlations were observed, but we did observe significant negative age-vs-amplitude correlations at both the global and regional level. These results indicate that amplitude may be another effective metric for assessing FC fluctuations, in addition to the widely-used variability metric. Moreover, the observed declines in the amplitude of FC fluctuations in the elderly may support the assumption that it should be the weakening of absolute interactions between brain regions, rather than toggling between positive and negative correlations, that causes the repeatedly reported widespread (static) FC decreases with aging. Overall, the present results not only reflect an overall weakening of connections in the elderly, but indicate the potential of dynamic FC analyses in studies of age-related psychiatric and neurological disorders. PMID- 29414497 TI - Evaluation of standardized and study-specific diffusion tensor imaging templates of the adult human brain: Template characteristics, spatial normalization accuracy, and detection of small inter-group FA differences. AB - Digital diffusion tensor imaging (DTI) templates of the adult human brain are commonly used in neuroimaging research, and their characteristics influence the accuracy of the application. However, a systematic evaluation of the characteristics and performance of standardized and study-specific DTI templates has not been conducted. The purpose of this work was to compare eight available standardized DTI templates to each other (ICBM81, ENIGMA, FMRIB58, SRI24, IIT2, NTU-DSI-122-DTI, IIT v.3.0, Eve), as well as to study-specific templates, in terms of template characteristics (image sharpness, ability to identify small brain structures, artifacts, mean values, noise properties) and performance in spatial normalization and detection of small inter-group FA differences. The IIT v.3.0 template was shown to combine a number of desirable characteristics: includes full-tensor information, is population-based, has high image sharpness, shows no visible artifacts, has low noise levels, has diffusion tensor properties and spatial features representative of data from the average individual adult brain. Furthermore, the IIT v.3.0 template was shown to allow higher inter subject DTI spatial normalization accuracy, and detection of smaller inter-group FA differences, compared to all other templates, including study-specific templates. These findings were consistent when evaluating the templates in younger as well as older adult cohorts. PMID- 29414498 TI - Functional connectivity under six anesthesia protocols and the awake condition in rat brain. AB - Resting-state functional magnetic resonance imaging (rsfMRI) is a translational imaging method with great potential in several neurobiologic applications. Most preclinical rsfMRI studies are performed in anesthetized animals, but the confounding effects of anesthesia on the measured functional connectivity (FC) are poorly understood. Therefore, we measured FC under six commonly used anesthesia protocols and compared the findings with data obtained from awake rats. The results demonstrated that each anesthesia protocol uniquely modulated FC. Connectivity patterns obtained under propofol and urethane anesthesia were most similar to that observed in awake rats. FC patterns in the alpha-chloralose and isoflurane-medetomidine combination groups had moderate to good correspondence with that in the awake group. The FC patterns in the isoflurane and medetomidine groups differed most from that in the awake rats. These results can be directly exploited in rsfMRI study designs to improve the data quality, comparability, and interpretation. PMID- 29414499 TI - Antrochoanal polyp concomitant with turbinoethmoidal osteoma: A case report. AB - INTRODUCTION: Antrochoanal polyps (ACPs) have several unique features that distinguish them from other nasal polyps. Despite many investigations, the pathogenesis of ACP has not yet been elucidated. Sinonasal osteoma is the most common type of tumor of the sinonasal tract and can be caused by trauma, infection and developmental anomaly. PRESENTATION OF CASE: We report the case of a 35-year-old man with left nasal obstruction for more than 20 years. Examination revealed ACP concomitant with an osteoma that arose from the middle turbinate and ethmoid sinus. The osteoma had an air cell in its anterosuperior area and was in a position of being pulled downward. The intranasal part of the ACP covered the posterior area of the osteoma. DISCUSSION: Considering the radiological and surgical findings, the intranasal part of the ACP seems to have affected the turbinoethmoidal osteoma during its growth. CONCLUSION: The authors describe a very rare condition in which an ACP was connected with a turbinoethmoidal osteoma. PMID- 29414500 TI - Priapism as the initial sign in hematologic disease: Case report and literature review. AB - INTRODUCTION: Priapism is an uncommon sign and sometimes considered a diagnosis challenge into systemic disease; this is defined as >=4 h continuous penile erection, without sexual stimulation. We state that this work has been reported in line with the SCARE criteria PRESENTATION OF CASE: A Mexican 52-year-old man was brought to the emergency room with priapism of six days of evolution. His medical history reported fatigue and waxy pallor had begun a month ago, the rest of interrogation was unremarked. Hyperleukocitosis (>250,000 cells/ml) was documented on his preoperative evaluation, the initial step was hematology consultation due to malignance suspicion, followed by corpora cavernosa drainage irrigation and surgery penis shunts. After of procedure, we realized bone marrow aspiration, kariotype and cytogenetic analysis, histopathological and moleculars assay reported myeloid hyperplasia compatible with acute phase CML and Philadelphia translocation t(9:22) (q34;q11.2) with P210 BCR-ABL1 fusion transcriber, patient was discharged with dasatinib for maintenance phase. Actually, he has a satisfactory evolution without relapses. DISCUSSION: The majority of reported cases shows the individual importance of hematological diseases in priapism as it is shown in the analysis of the literature of 10 years (2006-2016) that we made. It is imperative to consider the type of priapism, and the genetic and demographic patient aspects due to the early and correct approach improves the short and long term outcome of the hematological patients. CONCLUSION: Priapism is an uncommon sign of systemic disease. In the presence of warning signs, malignancy should be considered until proven otherwise. PMID- 29414501 TI - Gallstone ileus: A possible cause of bowel obstruction in the elderly population. AB - INTRODUCTION: Gallstone ileus (GI) is characterized by a mechanical occlusion of the ileal lumen as a result of migration of one or more gallstones in the intestinal tract. Less than 1-4% of all cases of intestinal obstruction are derived from this etiology (1,2,3). CASE REPORT: We present a case of small intestinal obstruction owing to a large gallstone in lower ileum in a 66 years old woman. The diagnosis was made by computed tomography, and treated successfully with an enterotomy, with a removal of a 5 cm gallstone, carried out through a longitudinal incision on the antimesenteric border. Post-operative course presented no adverse effects. CONCLUSION: Gallstone ileus should be considered in case of bowel obstruction in the elderly population. Abdominal CT scan is the preferred investigation for a timely diagnosis. PMID- 29414502 TI - Intraorbital hemorrhage following a secondary intervention at integrated zygomatic implants: A case report. AB - INTRODUCTION: Zygomatic implant placement can be the best option for restoring masticatory function of an extremely atrophic upper jaw, but the procedure is more invasive than conventional implant placement and can be associated with complications. PRESENTATION OF CASE: We report a complication that occurred during a secondary corrective surgical procedure four years after zygomatic implant placement. The patient was a 54-year-old female who had been edentulous for 25 years. Four zygomatic implants were placed. Subsequent prosthetic rehabilitation was successful. Four years later, the patient complained of discomfort. It was found that the tips of the implants on the right side were subcutaneously palpable and surrounded by granulomatous tissue. Intraoral surgery was performed to remove the protruding tips of the two implants. Post operatively, the patient developed severe orbital pain on the right side with proptosis and diffuse swelling of the eyelids. Emergency surgery was performed to drain the intraorbital hemorrhage. The patient healed uneventfully without loss of visual acuity. DISCUSSION: Scarce prior reports describe trauma to the orbit during zygomatic implant surgery, mostly involving orbital penetration during zygoma implant placement. To our knowledge, the present case report is the first to describe an intraorbital hemorrhage that led to an orbital compression syndrome necessitating emergency surgery. CONCLUSION: In our case, corrective surgery in a patient with zygomatic implants resulted in an intraorbital hemorrhage, followed by an orbital compression syndrome. Emergency surgery was immediately performed, allowing hematoma drainage and eliminating compression of the intraorbital content. Symptoms quickly resolved and eyesight was not compromised. PMID- 29414503 TI - Ileo-ileal fistula with severe malnutrition caused by strangulated ileus surgery while preserving ischemic ileum: A case report. AB - INTRODUCTION: Entero-enteric fistulas are rare complications that occur in patients with inflammatory bowel disease and other intestinal diseases. In this report, we present an ileo-ileal fistula accompanied by severe malnutrition caused by strangulated ileus surgery while preserving the ischemic ileum in a very elderly patient. CASE PRESENTATION: A 90-year-old woman underwent emergency surgery without bowel resection for strangulated ileus in another hospital. Minor abdominal pain and slight fever persisted after surgery. She lost weight, losing approximately 10 kg within half a year. She gradually became difficult to move due to dyspnea upon exertion and generalized edema and visited at our hospital. Pleural effusions, ascites and severe malnutrition were observed. An elastic hard mass with mild tenderness was palpated in her abdomen. Computed tomography showed a loop-like ileum and ileo-ileal fistula with adjacent fat stranding. We performed a partial small bowel resection. The resected specimen demonstrated an ileo-ileal fistula and circumferential ulceration in the loop-like adhesion. After the operation, the nutrition status was resolved immediately without any medications. DISCUSSION: In cases of strangulated ileus, there are no deterministic criteria for evaluating intestinal blood flow. This is the first report of ileo-ileal fistula onset after surgery for strangulated ileus without intestinal resection. Furthermore, this fistula caused severe malnutrition duo to chronic inflammation, ulcer formation, and the blind-loop syndrome. CONCLUSIONS: When preserving the intestinal tract in the operation of strangulated ileus, the occurrence of entero-enteric fistulas should be considered. Since malnutrition in the elderly is a serious problem, it should be treated promptly. PMID- 29414504 TI - Novel use of a balloon dilatation catheter to enable mechanical lithotripsy of difficult common bile duct stones after initial failed attempt: A case report. AB - INTRODUCTION: Difficult and large common bile duct stones can be crushed and removed using a mechanical lithotripter. Very often the lack of working space within the common bile duct causing the failure of mechanical lithotripsy would inevitably mean repeat or further invasive procedures. PRESENTATION OF CASE: A patient with large and multiple common bile duct stones underwent ERCP, and initial deployment of a mechanical lithotripter failed due to the lack of working space within the common bile duct. A through-the-scope (TTS) dilator was utilized to increase the working space before successful deployment of the mechanical lithotripter, and subsequent clearance of all stones within the same setting. DISCUSSION: We herein describe a novel and ingenious technique of utilizing a through-the-scope (TTS) dilator in helping to expand the space within the common bile duct to allow for full deployment of a mechanical lithotripter and successful clearance of common bile duct stones. This method can be easily applied by advanced endoscopists and is expected to lead to increased success rates of difficult common bile duct stones clearance in a single setting. CONCLUSION: Use of TTS dilators to increase working space within the common bile duct can be useful in increasing the success rates of mechanical lithotripsy in the setting of large and multiple common bile duct stones. PMID- 29414505 TI - Inter-operator variability in compartmental kinetic analysis of 18F fluoromisonidazole dynamic PET. AB - PURPOSE: To assess the inter-operator variability in compartment analysis (CA) of dynamic-FMISO (dyn-FMISO) PET. METHODS: Study-I: Five investigators conducted CA for 23 NSCLC dyn-FMISO tumor time-activity-curves. Study-II: Four operators performed CA for four NSCLC dyn-FMISO datasets. Repeatability of Kinetic-Rate Constants (KRCs) was assessed. RESULTS: Study-I: Strong correlation (ICC > 0.9) and interchangeable results among operators existed for all KRCs. Study-II: Up to 103% variability in tumor segmentation, and weaker ICC in KRCs (ICC-VB = 0.53; ICC-K1 = 0.91; ICC-K1/k2 = 0.25; ICC-k3 = 0.32; ICC-Ki = 0.54) existed. All KRCs were repeatable among the different operators. CONCLUSIONS: Inter-operator variability in CA of dyn-FMISO was shown to be within statistical errors. PMID- 29414506 TI - Scimitar-like ossification of patellae led to diagnosis of Zellweger syndrome in newborn: a case report. AB - Zellweger syndrome is the most severe form of a group of autosomal recessive disorders with defective peroxisomes. We report a case of Zellweger syndrome in a newborn baby, which was first suspected by the presence of scimitar-like patella seen on skeletal survey. The subsequent brain MRI showed germinolytic cysts and polymicrogyria, which furthered the suspicion. Laboratory and genetic results confirmed the diagnosis. To date, there are a limited number of case reports of this rare disease. We emphasize skeletal findings that can lead to targeted genetic and laboratory testing and hence earlier diagnosis. PMID- 29414507 TI - A comparison of contrast-free MRA at 3.0T in cases of intracranial aneurysms with or without subarachnoid hemorrhage. AB - PURPOSE: To determine the diagnostic accuracy of contrast-free MRA at 3.0T for detection of intracranial aneurysms in patients with subarachnoid hemorrhage. METHODS: 411 patients (183 with SAH and 228 with non-SAH) underwent MRA. Accuracy, sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) were measured and compared with DSA. RESULTS: Except for a slight difference in sensitivity in patient-based and aneurysm-based evaluations (P=0.037), there were no other significant differences in accuracy, specificity, PPV, and NPV. CONCLUSION: VR 3D-TOF-MRA is a non-invasive approach with high accuracy in the diagnosis of intracranial aneurysms. PMID- 29414508 TI - Atypical 18F-FDG PET-CT uptake in the head and neck; a case-based pictorial review. AB - Positron emission tomography - computed tomography (PET-CT) with fluorine-18 fluorodeoxy-d-glucose (18F-FDG) has an increasing role in head and neck imaging. Interpretation of 18F-FDG-tracer uptake in the head and neck requires an understanding of normal physiological patterns of tracer uptake, as well as knowledge of potential pitfalls and atypical patterns. This article presents a select series of unusual patterns of 18F-FDG uptake on PET-CT imaging of the head and neck. PMID- 29414509 TI - Ultrasonic histogram assessment of early response to concurrent chemo radiotherapy in patients with locally advanced cervical cancer: a feasibility study. AB - PURPOSE: To monitor early response for locally advanced cervical cancers undergoing concurrent chemo-radiotherapy (CCRT) by ultrasonic histogram. METHODS: B-mode ultrasound examinations were performed at 4 time points in thirty-four patients during CCRT. Six ultrasonic histogram parameters were used to assess the echogenicity, homogeneity and heterogeneity of tumors. RESULTS: Ipeak increased rapidly since the first week after therapy initiation, whereas Wlow, Whigh and Ahigh changed significantly at the second week. The average ultrasonic histogram progressively moved toward the right and converted into more symmetrical shape. CONCLUSION: Ultrasonic histogram could be served as a potential marker to monitor early response during CCRT. PMID- 29414510 TI - Adiponectin AS lncRNA inhibits adipogenesis by transferring from nucleus to cytoplasm and attenuating Adiponectin mRNA translation. AB - Adiponectin (AdipoQ) is an adipocyte-derived hormone with positive function on systemic glucose and lipid metabolism. Long noncoding RNA (lncRNA) is emerging as a vital regulator of adipogenesis. However, AdipoQ-related lncRNAs in lipid metabolism have not been explored. Here, AdipoQ antisense (AS) lncRNA was first identified, and we further found that it inhibited adipogenesis. The half-life of AdipoQ AS lncRNA was 10 h, whereas that of AdipoQ mRNA was 4 h. During adipogenic differentiation, AdipoQ AS lncRNA translocated from nucleus to cytoplasm. AdipoQ AS lncRNA and AdipoQ mRNA formed an RNA duplex. Moreover, AdipoQ AS lncRNA delivered via injection of adenovirus expressing AdipoQ AS lncRNA decreases white adipose tissue (WAT), brown adipose tissue (BAT) and liver triglycerides (TG) in mice consuming a high fat diet (HFD). Interestingly, the non-overlapping region of AdipoQ AS lncRNA improved serum glucose tolerance and insulin sensitivity in HFD mice, but not AdipoQ AS lncRNA. In conclusion, AdipoQ AS lncRNA transfer from nucleus to cytoplasm inhibits adipogenesis through formation of an AdipoQ AS lncRNA/AdipoQ mRNA duplex to suppress the translation of AdipoQ mRNA. Taken together, we suggest that AdipoQ AS lncRNA is a novel therapeutic target for obesity-related metabolic diseases. PMID- 29414511 TI - Human plasma retinol-binding protein (RBP4) is also a fatty acid-binding protein. AB - RBP4 (plasma retinol-binding protein) is the 21 kDa transporter of all-trans retinol that circulates in plasma as a moderately tight 1:1 molar complex of the vitamin with the protein. RBP4 is primarily synthesized in the liver but is also produced by adipose tissue and circulates bound to a larger protein, transthyretin, TTR, that serves to increase its molecular mass and thus avoid its elimination by glomerular filtration. This paper reports the high resolution three-dimensional structures of human RBP4 naturally lacking bound retinol purified from plasma, urine and amniotic fluid. In all these crystals we found a fatty acid molecule bound in the hydrophobic ligand-binding site, a result confirmed by mass spectrometry measurements. In addition we also report the 1.5 A resolution structures of human holo-RBP4 and of the protein saturated with palmitic and lauric acid and discuss the interaction of the fatty acids and retinol with the protein. PMID- 29414512 TI - Molecular mechanisms of RNA polymerase II transcription elongation elucidated by kinetic network models. AB - Transcription elongation cycle (TEC) of RNA polymerase II (Pol II) is a process of adding a nucleoside triphosphate to the growing messenger RNA chain. Due to the long timescale events in Pol II TEC, an advanced computational technique, such as Markov State Model (MSM), is needed to provide atomistic mechanism and reaction rates. The combination of MSM and experimental results can be used to build a kinetic network model (KNM) of the whole TEC. This review provides a brief protocol to build MSM and KNM of the whole TEC, along with the latest findings of MSM and other computational studies of Pol II TEC. Lastly, we offer a perspective on potentially using a sequence dependent KNM to predict genome-wide transcription error. PMID- 29414513 TI - Exploring RNA structure and dynamics through enhanced sampling simulations. AB - RNA function is intimately related to its structural dynamics. Molecular dynamics simulations are useful for exploring biomolecular flexibility but are severely limited by the accessible timescale. Enhanced sampling methods allow this timescale to be effectively extended in order to probe biologically relevant conformational changes and chemical reactions. Here, we review the role of enhanced sampling techniques in the study of RNA systems. We discuss the challenges and promises associated with the application of these methods to force field validation, exploration of conformational landscapes and ion/ligand-RNA interactions, as well as catalytic pathways. Important technical aspects of these methods, such as the choice of the biased collective variables and the analysis of multi-replica simulations, are examined in detail. Finally, a perspective on the role of these methods in the characterization of RNA dynamics is provided. PMID- 29414514 TI - QM/MM methods for free energies and photochemistry. AB - Hybrid computational methods describing a small region of a biomolecular system with quantum mechanics and the bulk with molecular mechanics, referred to as QM/MM methods, are now a central part of computational biochemistry. This review considers developments in the QM/MM approach that make it easier to calculate free energies using accurate QM-based potential energy expressions. We also describe techniques to treat electronic coupling between the core region and the MM environment. Polarizability of the protein matrix is important but so is electronic coupling. Applications of these new methods, especially to photochemistry, are discussed. PMID- 29414515 TI - Towards a complete structural deciphering of Type VI secretion system. AB - The Type VI secretion system (T6SS) is a dynamic nanomachine present in many Gram negative bacteria. Using a contraction mechanism similar to that of myophages, bacteriocins or anti-feeding prophages, it injects toxic effectors into both eukaryotic and prokaryotic cells. T6SS assembles three large ensembles: the trans membrane complex (TMC), the baseplate and the tail. Recently, the tail structure has been elucidated by cryo electron microscopy (cryoEM) in extended and contracted forms. The structure of the trans-membrane complex has been deciphered using a combination of X-ray crystallography and EM. However, the structural characterisation of the baseplate lags behind and should be the target of future studies. Finally, cryo-tomography should provide low/medium resolution maps allowing to assemble the different parts ultimately leading to a complete structural description of T6SS. PMID- 29414517 TI - Non-equilibrium coupling of protein structure and function to translation elongation kinetics. AB - Protein folding research has been dominated by the assumption that thermodynamics determines protein structure and function. And that when the folding process is compromised in vivo the proteostasis machinery-chaperones, deaggregases, the proteasome-work to restore proteins to their soluble, functional form or degrade them to maintain the cellular pool of proteins in a quasi-equilibrium state. During the past decade, however, more and more proteins have been identified for which altering only their speed of synthesis alters their structure and function, the efficiency of the down-stream processes they take part in, and cellular phenotype. Indeed, evidence has emerged that evolutionary selection pressures have encoded translation-rate information into mRNA molecules to coordinate diverse co-translational processes. Thus, non-equilibrium physics can play a fundamental role in influencing nascent protein behavior, mRNA sequence evolution, and disease. Here, we discuss how our understanding of this phenomenon is being advanced by the application of theoretical tools from the physical sciences. PMID- 29414516 TI - Assembly and structure of the SSU processome-a nucleolar precursor of the small ribosomal subunit. AB - The small subunit processome is the first precursor of the small eukaryotic ribosomal subunit. During its assembly in the nucleolus, many ribosome biogenesis factors, an RNA chaperone, and ribosomal proteins associate with the nascent pre rRNA. Biochemical studies have elucidated the rRNA-subdomain dependent recruitment of these factors during SSU processome assembly and have been complemented by structural studies of the assembled particle. Ribosome biogenesis factors encapsulate and guide subdomains of pre-ribosomal RNA in distinct compartments. This prevents uncoordinated maturation and enables processing of regions not accessible in the mature subunit. By sequentially reducing conformational freedom, flexible proteins facilitate the incorporation of dynamic subcomplexes into a globular particle. Large rearrangements within the SSU processome are required for compaction into the mature small ribosomal subunit. PMID- 29414518 TI - Peering beneath the surface: Juxtacortical tumors of bone (part I). AB - Juxtacortical or surface tumors of bone are neoplasms arising from or just outside the cortex, and are composed of different histologic types. Although the imaging appearances of these lesions have similarities to their intramedullary counterparts, their location alters their radiographic and MR characteristics, creating difficulties in diagnosis. Meanwhile, several non-neoplastic lesions, such as stress reaction/stress fracture and indolent infectious processes, compound the differential diagnosis. Neoplastic juxtacortical lesions of bone have been classified into five categories: cartilaginous, fibrous, lipomatous, osseous, and metastatic tumors. Our goal in part one of this review is to illustrate the characteristic radiographic, CT and MR imaging features of various juxtacortical neoplasms, including pathognomonic imaging findings that can aid in diagnosis, and to develop an appropriate differential diagnosis for surface lesions based on imaging characteristics, lesion location and patient age. PMID- 29414519 TI - Fat status detection and histotypes differentiation in solid renal masses using Dixon technique. AB - PURPOSE: To detect fat status and differentiate histotypes of renal masses by using Dixon technique. MATERIALS AND METHODS: This study included 134 solid renal masses. Signal intensity index (SII) and fat fraction (FF) in different histotypes were compared. RESULTS: Only angiomyolipoma (AML), clear cell renal cell carcinoma (RCC), and papillary RCC were confirmed to contain fat. The FF of 16.8% can effectively differentiate AML from clear cell RCC, so did the SII of 9.2% can differentiate clear cell RCC from non-clear cell RCC and rare benign histotypes. CONCLUSION: Dixon technique successfully evaluated the fat status and histotypes of renal masses. PMID- 29414520 TI - Diagnosing conduit leak after esophagectomy for esophageal cancer by computed tomography leak protocol and standard esophagram: Is old school still the best? AB - The imaging modalities available to evaluate anastomotic leak complicating esophagectomy include CT-Esophageal Protocol (CTEP) and esophagram. The purpose of this study was to compare the performance of these two modalities, alone or in combination, with the final diagnosis of leak established by endoscopy, surgery and/or the clinical course and evaluate management implications. PMID- 29414521 TI - Association between epicardial fat volume and fractional flow reserve: An analysis of the determination of fractional flow reserve (DeFACTO) study. AB - BACKGROUND: This study examines the relationship between epicardial fat volume (EFV) and lesion-specific ischemia by fractional flow reserve (FFR). METHODS: In a study of 173 patients (63.0 +/- 8.3 years) undergoing FFR, EFV was determined using cardiac computed tomography. Relationships between EFV and FFR were assessed using multivariable linear and logistic regression. RESULTS: Using multivariable linear and logistic regression, no association between EFV and FFR was observed (beta [SE] = -0.001 [0.003], P = 0.6, OR [95% CI]: 1.02 [0.94-1.11], P = 0.64, respectively). CONCLUSION: In patients with suspected or known coronary artery disease undergoing invasive angiography, EFV was not associated with FFR. PMID- 29414522 TI - Don't be short-sighted: cervical incompetence in a pregnant patient with acute appendicitis. AB - Delay in diagnosis of cervical incompetence can be detrimental to the fetus. Up to 20-25% of miscarriages in the second trimester can be attributed to the incompetent cervix. Given the profound impact of cervical incompetence on obstetric outcomes, careful attention should be given to evaluation of the cervix on MRI studies in pregnant patients. We present a case of incompetent cervix diagnosed incidentally at the time of MRI performed to evaluate for acute appendicitis. PMID- 29414523 TI - As Clear as Mud. PMID- 29414524 TI - PKC/CREB pathway mediates the expressions of GABAA receptor subunits in cultured hippocampal neurons after low-Mg2+ solution treatment. AB - OBJECTIVE: To investigate the potential effects of the PKC/CREB pathway on the expressions of GABAA receptor subunits alpha1, gamma2, and delta in cultured hippocampal neurons using a model of epilepsy that employed conditions of low magnesium (Mg2+). METHODS: A total of 108 embryonic rats at the age of 18 embryonic days (E18)prepared from adult female SD rats were used as experimental subjects. Primary rat hippocampal cultures were prepared from the embryonic 18 days rats. The cultured hippocampal neurons were then treated with artificial cerebrospinal fluid containing low Mg2+ solutions to generate a low Mg2+ model of epilepsy. The low Mg2+ stimulation lasted for 3 h and then returned to in maintenance medium for 20 h. The changes of the GABAA receptor subunit alpha1, gamma2, delta were observed by blocking or activating the function of the CREB. The quantification of the GABAA receptor subunit alpha1, gamma2, delta and the CREB were determined by a qRT-PCR and a Western blot method. RESULTS: After the neurons were exposed to a low-Mg2+ solution for 3 h, GABAA receptor mRNA expression markedly increased compared to the control, and then gradually decreased. In contrast, CREB mRNA levels exhibited a dramatic down-regulation 3 h after terminating low-Mg2+ treatment, and then peaked at 9 h. Western blot analyses verified that staurosporine suppressed CREB phosphorylation (p-CREB). The mRNA expression of GABAA receptor subunit alpha1 increased only in the presence of staurosporine, whereas the expressions of subunits gamma2 and delta significantly increased in the presence of either KG-501 or staurosporine. Furthermore, phorbol 12-myristate 13-acetate (PMA) decreased the expressions of GABAA subunits alpha1, gamma2, and delta when administered alone. However, the administration of either KG-501 or staurosporine reversed the inhibitory effects of PMA. CONCLUSIONS: The PKC/CREB pathway may negatively regulate the expressions of GABAA receptor subunits alpha1, gamma2, and delta in cultured hippocampal neurons in low Mg2+ model of epilepsy. PMID- 29414525 TI - Electrographic and pharmacological characterization of a progressive epilepsy phenotype in female MeCP2-deficient mice. AB - Rett Syndrome is a neurodevelopmental disorder caused primarily by mutations in the gene encoding Methyl-CpG-binding protein 2 (MECP2). Spontaneous epileptiform activity is a common co-morbidity present in Rett syndrome, and hyper-excitable neural networks are present in MeCP2-deficient mouse models of Rett syndrome. In this study we conducted a longitudinal assessment of spontaneous cortical electrographic discharges in female MeCP2-deficient mice and defined the pharmacological responsiveness of these discharges to anti-convulsant drugs. Our data show that cortical discharge activity in female MeCP2-deficient mice progressively increases in severity as the mice age, with discharges being more frequent and of longer durations at 19-24 months of age compared to 3 months of age. Semiologically and pharmacologically, this basal discharge activity in female MeCP2-deficient mice displayed electroclinical properties consistent with absence epilepsy. Only rarely were convulsive seizures observed in these mice at any age. Since absence epilepsy is infrequently observed in Rett syndrome patients, these results indicate that the predominant spontaneous electroclinical phenotype of MeCP2-deficient mice we examined does not faithfully recapitulate the most prevalent seizure types observed in affected patients. PMID- 29414526 TI - Morphometric analysis on T1-weighted MRI complements visual MRI review in focal cortical dysplasia. AB - OBJECTIVE: Focal cortical dysplasia (FCD) is a common pathology in focal drug resistant epilepsy (DRE). Voxel based morphometric MRI analysis has been proposed as an adjunct to visual detection of FCD, which remains challenging given the subtle radiographic appearance of FCD. This study evaluates the diagnostic value of morphometric analysis program (MAP) in focal DRE with pathology-confirmed FCD. METHODS: Automated morphometric analysis program analysis generated z-score maps derived from T1 images, referenced to healthy adult or pediatric controls for each of 39 cases with pathology-confirmed FCD. MAP identified abnormal extension of gray matter into white matter (MAP-E) and blurring of the gray-white matter junction (MAP-J), independently of clinical data and other imaging modalities. MRI was visually reviewed by neuroradiologists as part of usual clinical care, and independently re-reviewed retrospectively by a neuroradiologist with >10 years' experience in epilepsy MRI. Sensitivity and specificity were calculated for MRI, MAP, scalp-EEG, PET and SISCOM compared to resection area (RA). RESULTS: In this cohort of 39 histologically proven FCD cases, the sensitivity and specificity of MAP-J [64% (95% CI 48%-77%) and 96% (95% CI 93%-0.98%)] and MAP-E [74% (95% CI 59%-86%) and 94% (95% CI 91%-97%)] were higher than qualitative MRI review, SISCOM, and FDG-PET. Initial MRI review detected FCD in 17, expert review identified 26. Among cases not detected by initial MRI review, MAP-J correctly identified FCD in 12 additional cases and MAP-E in 13 cases. Among cases not detected by expert MRI review, MAP-J correctly identified 6 and MAP-E 8 cases. Excellent surgical outcome was achieved in 76% of patients. SIGNIFICANCE: MAP showed favorable sensitivity compared to visual inspection and other non-invasive imaging modalities. MAP complements non-invasive imaging evaluation for detection of FCD in focal DRE patients. PMID- 29414527 TI - Echocardiographic risk markers of sudden death in patients with temporal lobe epilepsy. AB - Patients with epilepsy (PWE) have an increased risk for sudden unexpected death compared to the general population. Echocardiography can analyze structural and functional heart changes that have impact on outcomes, including sudden cardiac and all-cause death. Our hypothesis is that subtle heart abnormalities occur in PWE. Thirty patients with temporal lobe epilepsy without any known cardiovascular disease, followed for at least 1 year, were enrolled between July 2015 and July 2016 and submitted to a 12-lead electrocardiogram, treadmill test and transthoracic echocardiogram. PWE were matched with individuals without epilepsy by sex, age and body mass index. A literature review of studies comparing echocardiographic findings in PWE and individuals without epilepsy was performed. PWE had a higher left ventricle stiffness (beta= 5.97 +/- 0.05 * 5.94 +/- 0.03; p = 0.02), left ventricle filling pressures (9.7 +/- 1.3 mmHg * 9 +/- 0.8; p = 0.02) and a greater left atrial volume (44.7 +/- 13.6 ml * 34.1 +/- 9.6 ml; p = 0.003). Seventeen (56.6%) PWE had a total of 22 of six known echocardiographic markers related to increased risk for sudden death in the general population, versus 11 (36.7%) controls with 12 markers (p = 0.07). Stiffness is related to fibrosis through extracellular matrix deposition, which promotes systolic and diastolic dysfunction and arrhythmogenesis. Subtle echocardiographic findings in PWE could help to explain why this population has an increased risk to die suddenly. PMID- 29414529 TI - The regulation of lymphocyte activation and proliferation. AB - Activation induced proliferation and clonal expansion of antigen specific lymphocytes is a hallmark of the adaptive immune response to pathogens. Recent studies identify two distinct control phases. In the first T and B lymphocytes integrate antigen and additional costimuli to motivate a programmed proliferative burst that ceases with a return to cell quiescence and eventual death. This proliferative burst is autonomously timed, ensuring an appropriate response magnitude whilst preventing uncontrolled expansion. This initial response is subject to further modification and extension by a range of signals that modify, expand and direct the emergence of a rich array of new cell types. Thus, both robust clonal expansion of a small number of antigen specific T cells, and the concurrent emergence of extensive cellular diversity, confers immunity to a vast array of different pathogens. The in vivo response to a given pathogen is made up by the sum of all responding clones and is reproducible and pathogen specific. Thus, a precise description of the regulatory principles governing lymphocyte proliferation, differentiation and survival is essential to a unified understanding of the immune system. PMID- 29414528 TI - Control of B-1a cell development by instructive BCR signaling. AB - B-1a cells remain one of the most enigmatic lymphocyte subsets. In this review, we discuss recent advances in our understanding of the development of these cells and their regulation by the transcription factors Bhlhe41 and Arid3a as well as by the RNA-binding protein Lin28b. A large body of literature supports an instructive role of BCR signaling in B-1a cell development and lineage commitment, which is initiated only after signaling from an autoreactive BCR. While both fetal and adult hematopoiesis can generate B-1a cells, the contribution of adult hematopoiesis to the B-1a cell compartment is low under physiological conditions. We discuss several models that can reconcile the instructive role of BCR signaling with this fetal bias in B-1a cell development. PMID- 29414530 TI - Halogenases: powerful tools for biocatalysis (mechanisms applications and scope). PMID- 29414531 TI - Enzymatic amidation for industrial applications. AB - Nature has developed a robust toolbox for the formation of amide bonds, enabling a variety of disconnections applicable to small molecule synthesis. In spite of this, the exploitation of biocatalytic techniques for industrial synthesis remains limited to a few very important cases. This review discusses previously demonstrated techniques for the biocatalytic synthesis of amide bonds, reviews examples of industrial scale-up of these techniques, and identifies a number of limitations to the scalability within the current state of the art. PMID- 29414532 TI - Multiple types of synchronization analysis for discontinuous Cohen-Grossberg neural networks with time-varying delays. AB - This paper is devoted to the exponential synchronization, finite time synchronization, and fixed-time synchronization of Cohen-Grossberg neural networks (CGNNs) with discontinuous activations and time-varying delays. Discontinuous feedback controller and Novel adaptive feedback controller are designed to realize global exponential synchronization, finite time synchronization and fixed-time synchronization by adjusting the values of the parameters omega in the controller. Furthermore, the settling time of the fixed time synchronization derived in this paper is less conservative and more accurate. Finally, some numerical examples are provided to show the effectiveness and flexibility of the results derived in this paper. PMID- 29414533 TI - A border-ownership model based on computational electromagnetism. AB - The mathematical relation between a vector electric field and its corresponding scalar potential field is useful to formulate computational problems of lower/middle-order visual processing, specifically related to the assignment of borders to the side of the object: so-called border ownership (BO). BO coding is a key process for extracting the objects from the background, allowing one to organize a cluttered scene. We propose that the problem is solvable simultaneously by application of a theorem of electromagnetism, i.e., "conservative vector fields have zero rotation, or "curl." We hypothesize that (i) the BO signal is definable as a vector electric field with arrowheads pointing to the inner side of perceived objects, and (ii) its corresponding scalar field carries information related to perceived order in depth of occluding/occluded objects. A simple model was developed based on this computational theory. Model results qualitatively agree with object-side selectivity of BO-coding neurons, and with perceptions of object order. The model update rule can be reproduced as a plausible neural network that presents new interpretations of existing physiological results. Results of this study also suggest that T-junction detectors are unnecessary to calculate depth order. PMID- 29414534 TI - Decentralized adaptive neural control for high-order interconnected stochastic nonlinear time-delay systems with unknown system dynamics. AB - This paper is concerned with the problem of decentralized adaptive backstepping state-feedback control for uncertain high-order large-scale stochastic nonlinear time-delay systems. For the control design of high-order large-scale nonlinear systems, only one adaptive parameter is constructed to overcome the over parameterization, and neural networks are employed to cope with the difficulties raised by completely unknown system dynamics and stochastic disturbances. And then, the appropriate Lyapunov-Krasovskii functional and the property of hyperbolic tangent functions are used to deal with the unknown unmatched time delay interactions of high-order large-scale systems for the first time. At last, on the basis of Lyapunov stability theory, the decentralized adaptive neural controller was developed, and it decreases the number of learning parameters. The actual controller can be designed so as to ensure that all the signals in the closed-loop system are semi-globally uniformly ultimately bounded (SGUUB) and the tracking error converges in the small neighborhood of zero. The simulation example is used to further show the validity of the design method. PMID- 29414535 TI - Unsupervised heart-rate estimation in wearables with Liquid states and a probabilistic readout. AB - Heart-rate estimation is a fundamental feature of modern wearable devices. In this paper we propose a machine learning technique to estimate heart-rate from electrocardiogram (ECG) data collected using wearable devices. The novelty of our approach lies in (1) encoding spatio-temporal properties of ECG signals directly into spike train and using this to excite recurrently connected spiking neurons in a Liquid State Machine computation model; (2) a novel learning algorithm; and (3) an intelligently designed unsupervised readout based on Fuzzy c-Means clustering of spike responses from a subset of neurons (Liquid states), selected using particle swarm optimization. Our approach differs from existing works by learning directly from ECG signals (allowing personalization), without requiring costly data annotations. Additionally, our approach can be easily implemented on state-of-the-art spiking-based neuromorphic systems, offering high accuracy, yet significantly low energy footprint, leading to an extended battery-life of wearable devices. We validated our approach with CARLsim, a GPU accelerated spiking neural network simulator modeling Izhikevich spiking neurons with Spike Timing Dependent Plasticity (STDP) and homeostatic scaling. A range of subjects is considered from in-house clinical trials and public ECG databases. Results show high accuracy and low energy footprint in heart-rate estimation across subjects with and without cardiac irregularities, signifying the strong potential of this approach to be integrated in future wearable devices. PMID- 29414536 TI - Hinfinity state estimation of stochastic memristor-based neural networks with time-varying delays. AB - This paper addresses the problem of Hinfinity state estimation for a class of stochastic memristor-based neural networks with time-varying delays. Under the framework of Filippov solution, the stochastic memristor-based neural networks are transformed into systems with interval parameters. The present paper is the first to investigate the Hinfinity state estimation problem for continuous-time Ito-type stochastic memristor-based neural networks. By means of Lyapunov functionals and some stochastic technique, sufficient conditions are derived to ensure that the estimation error system is asymptotically stable in the mean square with a prescribed Hinfinity performance. An explicit expression of the state estimator gain is given in terms of linear matrix inequalities (LMIs). Compared with other results, our results reduce control gain and control cost effectively. Finally, numerical simulations are provided to demonstrate the efficiency of the theoretical results. PMID- 29414537 TI - An optimal control strategy for hybrid actuator systems: Application to an artificial muscle with electric motor assist. AB - Humans use multiple muscles to generate such joint movements as an elbow motion. With multiple lightweight and compliant actuators, joint movements can also be efficiently generated. Similarly, robots can use multiple actuators to efficiently generate a one degree of freedom movement. For this movement, the desired joint torque must be properly distributed to each actuator. One approach to cope with this torque distribution problem is an optimal control method. However, solving the optimal control problem at each control time step has not been deemed a practical approach due to its large computational burden. In this paper, we propose a computationally efficient method to derive an optimal control strategy for a hybrid actuation system composed of multiple actuators, where each actuator has different dynamical properties. We investigated a singularly perturbed system of the hybrid actuator model that subdivided the original large scale control problem into smaller subproblems so that the optimal control outputs for each actuator can be derived at each control time step and applied our proposed method to our pneumatic-electric hybrid actuator system. Our method derived a torque distribution strategy for the hybrid actuator by dealing with the difficulty of solving real-time optimal control problems. PMID- 29414538 TI - Antiepileptic drug reduction and increased risk of stimulation-evoked focal to bilateral tonic-clonic seizure during cortical stimulation in patients with focal epilepsy. AB - INTRODUCTION: Stimulation-evoked focal to bilateral tonic-clonic seizure (FBTCS) can be a stressful and possibly harmful adverse event for patients during cortical stimulation (CS). We evaluated if drug load reduction of antiepileptic drugs (AEDs) during CS increases the risk of stimulation-evoked FBTCS. MATERIAL AND METHODS: In this retrospective cohort study, we searched our local database for patients with drug-resistant epilepsy who underwent invasive video-EEG monitoring and CS in the University Hospital la Fe Valencia from January 2006 to November 2016. The AED drug load was calculated with the defined daily dose. We applied a uni- and multivariate logistic regression model to estimate the risk of stimulation-evoked FBTCS and evaluate possible influencing factors. Furthermore, we compared patients whose AEDs were completely withdrawn with those whose AEDs were not. RESULTS: Fifty-eight patients met the inclusion criteria and were included in the analysis. Stimulating 3806 electrode contact pairs, 152 seizures were evoked in 28 patients (48.3%). Ten seizures (6.6%) in seven patients (12.1%) evolved to FBTCS. In the univariate and multivariate analysis, a 10% reduction in drug load was associated with an increase of the odds ratio (OR) of stimulation evoked FBTCS by 1.9 (95%-CI 1.2, 4.0, p-value=0.04) and 1.9 (95%-CI 1.2, 4.6, p value=0.04), respectively. In patients, whose AEDs were completely withdrawn the OR of FBTCS increased by 9.1 (95%CI 1.7, 69.9, p-value=0.01) compared with patients whose AEDs were not completely withdrawn. No other factor (implantation type, maximum stimulus intensity, number of stimulated contacts, history of FBTCS, age, gender, or epilepsy type) appears to have a significant effect on the risk of stimulation-evoked FBTCS. CONCLUSIONS: The overall risk of stimulation evoked FBTCS during CS is relatively low. However, a stronger reduction and, especially, a complete withdrawal of AEDs are associated with an increased risk of stimulation-evoked FBTCS. PMID- 29414539 TI - The direct and indirect costs of Dravet Syndrome. AB - OBJECTIVE: The objective of this study was to estimate the annual direct and indirect costs associated with Dravet Syndrome (DS). METHODS: A survey was electronically administered to the caregivers of patients with DS treated at Children's Hospital Colorado. Survey domains included healthcare utilization of the patient with DS and DS caregiver work productivity and activity impairment. Patient healthcare utilization was measured using modified questions from the National Health Interview Survey; caregiver work productivity and activity impairment were measured using modified questions from the Work Productivity and Activity Impairment questionnaire. Direct costs were calculated by multiplying the caregiver-reported healthcare utilization rates by the mean unit cost for each healthcare utilization category. Indirect costs included lost productivity, income loss, and lost leisure time. The indirect costs were a function of caregiver-reported hours spent caregiving and an hourly unit cost. RESULTS: The survey was emailed to 60 DS caregivers, of which 34 (57% response rate) responded. Direct costs on average were $27,276 (95% interval: $15,757, $41,904) per patient with DS. Hospitalizations ($11,565 a year) and in-home medical care visits ($9894 a year) were substantial cost drivers. Additionally, caregivers reported extensive time spent providing care to an individual with DS. This caregiver time resulted in average annual indirect costs of $81,582 (95% interval: $57,253, $110,151), resulting in an average total annual financial burden of $106,378 (95% interval: $78,894, $137,906). CONCLUSION: Dravet Syndrome results in substantial healthcare utilization, financial burden, and time commitment. Establishing evidence on the financial burden of DS is essential to understanding the overall impact of DS, identifying potential areas for support needs, and assessing the impact of novel treatments as they become available. Based on the study findings, in-home visits, hospitalizations, and lost productivity and leisure time of caregivers are key domains for DS economic evaluations. Future research should extend these estimates to include the potential additional healthcare utilization of the DS caregiver. PMID- 29414540 TI - Psychiatric symptoms and health-related quality of life in children with epilepsy and their mothers. AB - PURPOSE: This study evaluated the psychiatric symptoms and health-related quality of life (HRQL) of children with epilepsy and psychiatric symptoms of their mothers, and compared them to those of healthy children and their mothers. This study also explored the influence of the child-related and maternal psychiatric variables and seizure-specific factors on the HRQLs of children with epilepsy according to both the children's and parents' perspectives. METHOD: Ninety-nine children with epilepsy (8 to 17years old), their mothers, and a control group (n=51) participated in this study. The depression and anxiety symptoms of the children were assessed using the Child Depression Inventory (CDI) and the Screen for Child Anxiety-Related Emotional Disorders (SCARED), respectively. The severities of the attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) symptoms were assessed via the mother-rated Turgay DSM-IV-Based Child and Adolescent Behavioral Disorders Screening and Rating Scale (T-DSM-IV-S). In addition, the mothers completed the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) to assess their depression and anxiety symptoms, respectively. Child-reported and parent-reported Pediatric Quality of Life Inventories were used to evaluate the HRQLs of the children. RESULTS: The patients exhibited higher inattention and ODD scores than the controls did. With the exception of the child-reported physical health scores, all of the child- and parent-reported HRQL scores were significantly lower in the patient group. According to the regression analysis, the child related psychiatric and seizure-specific factors, but not the maternal psychiatric factors, were associated with the child's HRQL. The explained variances for the overall HRQL and HRQL subscales were similar between the child reported (0.373 to 0.654) and parent-reported (0.499 to 0.682) questionnaires. The largest contributors to the total variance were the child-related psychiatric factors for both the child-reported and parent-reported HRQLs by far. CONCLUSION: Epilepsy is associated with a poor psychiatric status and HRQL in childhood. The impact of epilepsy on the HRQL occurs mainly through child-related psychiatric factors. Both the child-reported and parent-reported questionnaires seem to be useful for the evaluation of the HRQL in pediatric epilepsy cases. PMID- 29414541 TI - Women with epilepsy in childbearing age: Pregnancy-related knowledge, information sources, and antiepileptic drugs. AB - Pregnancy-related issues in epilepsy (PRIE) are essential for management of epilepsy in women. We conducted a study among women with epilepsy (WWE) aged 15 45years about their knowledge, sources, and needs for information regarding PRIE, which included their current antiepileptic drugs (AEDs) usage. Women with epilepsy, visitors of Croatian Association for Epilepsy webpage, were offered an online questionnaire, and 200 responses were analyzed. The mean number of correct answers about PRIE was 3.5 out of 5. Main predictors of knowledge on PRIE were a prior consultation with a neurologist and higher usage of books/brochures. A prior neurologist consultation on PRIE was stated by 45% of subjects. As the preferred future mode of being informed on PRIE, majority of women (61%) chooses their neurologist, 22% written materials distributed by a neurologist, and only 13% Internet. Levetiracetam was the most commonly used AED (34.5%). Valproate was used by 26%, and of those 59% stated no previous consultation on PRIE with their neurologist. In summary, we believe our study shows that knowledge of PRIE among WWE in their childbearing age is unsatisfactory, as are the neurologist consultation rates about PRIE. Our results demonstrate that, despite modern technologies, educational activities should be based on neurologist consultations and providing the patients with appropriate written materials. This is especially true for the relatively large proportion of women still taking valproate. PMID- 29414542 TI - Efficacy, safety, and tolerability of brivaracetam with concomitant lamotrigine or concomitant topiramate in pooled Phase III randomized, double-blind trials: A post-hoc analysis. AB - OBJECTIVE: The objective was to assess the efficacy and safety of adjunctive brivaracetam (BRV) with concomitant use of lamotrigine (LTG) or topiramate (TPM) in patients with uncontrolled focal seizures. METHODS: Data were pooled from three randomized, placebo-controlled Phase III studies (NCT00490035/N01252, NCT00464269/N01253, NCT01261325/N01358) of adults with focal (partial-onset) seizures. Patients taking concomitant levetiracetam were excluded from the efficacy populations, but included in the safety populations. This post-hoc analysis reports data from patients taking BRV in the approved therapeutic range (50-200mg/day) concomitantly with LTG or TPM. RESULTS: The number of patients in each of the three BRV dosage groups was small, particularly for the TPM subgroup. Mean percent reduction over placebo in baseline-adjusted focal seizure frequency/28days for BRV 50, 100, and 200mg/day was 8.7, 5.3, and 8.9 in the LTG subgroup (n=220), and 8.4, 21.3, and -4.2 in the TPM subgroup (n=122). The >=50% responder rate with concomitant LTG or TPM with BRV 50, 100, and 200mg/day or placebo was LTG: 28.1%, 36.1%, 34.1%, and 29.1%; and TPM: 14.3%, 44.4%, 25.0%, and 17.5%. There were numerically >=50%, >=75%, >=90%, and 100% responder rates for patients taking BRV >=50mg/day compared with placebo in both subgroups. In the LTG and TPM safety populations (n=245 versus n=125), treatment-emergent adverse events (TEAEs) were reported with LTG 68.7% versus 68.4%, and TPM 65.6% versus 57.8% (BRV >=50mg/day versus placebo). Discontinuations due to TEAEs versus placebo were LTG 7.3% versus 6.3% and TPM 8.2% versus 4.7%. The three most frequently reported TEAEs for both subgroups were somnolence, dizziness, and fatigue. Of these, the incidence of fatigue in the LTG population appeared to increase with dose. SIGNIFICANCE: In this post-hoc pooled analysis, BRV administered with concomitant LTG or TPM reduced seizure frequency and was generally well tolerated for BRV doses of 50-200mg/day. PMID- 29414543 TI - Epilepsy in Hildegard of Bingen's writings: A comprehensive overview. AB - Hildegard of Bingen (1098-1179AD) is one of the most relevant figures of the Middle Ages. She wrote two medical books, Physica (Natural history) and Causae et curae (Causes and remedies). Our aim was to provide a comprehensive account of Hildegard of Bingen's conception of epilepsy, of the remedies proposed to treat it, and of the medical and physiological theories behind their use. We searched Hildegard of Bingen's entire body of writings to identify any possible reference to epilepsy or epileptic seizures. We reported the identified passages referring to epilepsy and discussed their content in light of medieval medical and physiological theories. Most references to epilepsy were found in Physica and Causae et curae. The suggested remedies against epilepsy range from herbal preparations to animal remedies and jewel therapy. Hildegard's conception of epilepsy gives the impression of an original revisitation of the traditional theory of humors, and carries strong moral connotations. Hildegard of Bingen's conception of epilepsy appears strongly rooted in medieval thinking and less in physiological theories. However, it differs in many respects to the traditional medieval beliefs and is a further proof of her unique personality. As living testimony of the past, Hildegard's writings enable us to shed a fascinating light on the beliefs concerning epilepsy in the middle ages. PMID- 29414544 TI - Effect of traditional medicine brahmi vati and bacoside A-rich fraction of Bacopa monnieri on acute pentylenetetrzole-induced seizures, amphetamine-induced model of schizophrenia, and scopolamine-induced memory loss in laboratory animals. AB - OBJECTIVE: Brahmi vati (BV) is an Ayurvedic polyherbal formulation used since ancient times and has been prescribed in seizures associated with schizophrenia and related memory loss by Ayurvedic practitioners in India. The aim of the study was to investigate these claims by evaluation of anticonvulsant, antischizophreniac, and memory-enhancing activities. Antioxidant condition of brain was determined by malondialdehyde (MDA) and reduced glutathione (GSH) levels estimations. Acetylcholinesterase (AChE) was quantitatively estimated in the brain tissue. METHODS: Brahmi vati was prepared in-house by strictly following the traditional Ayurvedic formula. Bacoside A rich fraction (BA) of Bacopa monnieri was prepared by extraction and fractionation. It was than standardized by High Performance Liquid Chromatography (HPLC) and given in the dose of 32.5mg/kg body weight to the different groups of animals for 7days. On the seventh day, activities were performed adopting standard procedures. KEY FINDINGS: Brahmi vati showed significant anticonvulsant, memory-enhancing and antischizophrenia activities, when compared with the control groups and BA. It cause significantly higher brain glutathione levels. Acetylcholinesterase activity was found to be significantly low in BV-treated group. CONCLUSION: The finding of the present study suggests that BV may be used to treat seizures associated with schizophrenia and related memory loss. PMID- 29414545 TI - Assessing the impact of caring for a child with Dravet syndrome: Results of a caregiver survey. AB - OBJECTIVE: The objective of this study was to describe and quantify the impact of caring for a child with Dravet syndrome (DS) on caregivers. METHODS: We surveyed DS caregivers at a single institution with a large population of patient with DS. Survey domains included time spent/difficulty performing caregiving tasks (Oberst Caregiving Burden Scale, OCBS); caregiver health-related quality of life (EuroQoL 5D-5L, EQ-5D); and work/activity impairment (Work Productivity and Activity Impairment questionnaire, WPAI). Modified National Health Interview Survey (NHIS) questions were included to assess logistical challenges associated with coordinating medical care. RESULTS: Thirty-four primary caregivers responded, and 30/34 respondents completed the survey. From OCBS, providing transportation, personal care, and additional household tasks required the greatest caregiver time commitment; arranging for child care, communication, and managing behavioral problems presented the greatest difficulty. EuroQoL 5D-5L domains with the greatest impact on caregivers (0=none, 5=unable/extreme) were anxiety/depression (70% of respondents>=slight problems, 34%>=moderate) and discomfort/pain (57% of respondents>=slight problems, 23%>=moderate). The mean EQ-5D general health visual analogue scale (VAS) score (0=death; 100=perfect health) was 67 (range, 11 94). Respondents who scored <65 were two- to fourfold more likely to report >=moderate time spent and difficulty managing child behavior problems and assisting with walking, suggesting that children with DS with high degrees of motor or neurodevelopmental problems have an especially high impact on caregiver health. On the WPAI, 26% of caregivers missed >1day of work in the previous week, with 43% reporting substantial impact (>=6, scale=1-10) on work productivity; 65% reported switching jobs, quitting jobs, or losing a job due to caregiving responsibilities. National Health Interview Survey responses indicated logistical burdens beyond the home; 50% of caregivers made >=10 outpatient visits in the past year with their child with DS. CONCLUSIONS: Caring for patients with DS exerts physical, emotional, and time burdens on caregivers. Supportive services for DS families are identified to highlight an unmet need for DS treatments. PMID- 29414546 TI - Unique and shared areas of cognitive function in children with intractable frontal or temporal lobe epilepsy. AB - OBJECTIVE: Previous findings have been mixed in terms of identifying a distinct pattern of neuropsychological deficits in children with frontal lobe epilepsy (FLE) and in those with temporal lobe epilepsy (TLE). The current study investigated the neuropsychological similarities and differences across these two pediatric medically intractable localization-related epilepsies. METHOD: Thirty eight children with FLE, 20 children with TLE, and 40 healthy children (HC) participated in this study. A comprehensive battery of standardized tests assessed five neuropsychological domains including intelligence, language, memory, executive function, and motor function. A principal component analysis (PCA) was used to distill our neuropsychological measures into latent components to compare between groups. RESULTS: Principal component analysis extracted 5 latent components: executive function (F1), verbal semantics (F2), motor (F3), nonverbal cognition/impulsivity (F4), and verbal cognition/attention (F5). The group with FLE differed from the HC group on F1, F2, F4, and F5, and had worse performance than the group with TLE on F1; the group with TLE had lower performance relative to the HC group on F2. CONCLUSION: Our findings suggest that, in comparison with neurotypically developing children, children with medically intractable FLE have more widespread neuropsychological impairments than do children with TLE. The differences between the two patient groups were greatest for the factor score most clearly related to executive function. The results provide mixed support for the concept of specificity in neuropsychological dysfunction among different subtypes of localization-related medically intractable childhood epilepsies. PMID- 29414547 TI - Stress, seizures, and epilepsy: Patient narratives. AB - In epilepsy, individual seizures can be triggered by a variety of external and internal stimuli. One of the most common trigger factors reported by patients is stress. However prevalent, stress-related triggering of episodes seems underappreciated in epilepsy for various reasons, and its misinterpretation often leads to other diagnoses, e.g., psychogenic nonepileptic seizures (PNES) or normal reactions. This article illustrates the significant role of stress as a seizure-provoking factor by referring to nine patient narratives. From this perspective, it appears that there are characteristic patterns of stress triggering, e.g., stress-induced sleep disruption, forms of acute stress, or relaxation after stress. Sometimes seizures are mistaken as symptoms of stress. Patient narratives contain interesting clues relating reports about stress and seizure histories to different epilepsy syndromes as well as nonepileptic episodes in a way that can strongly support the diagnostic process. A narrative approach is particularly valuable in this context. Therefore, accounts of stress triggering in seizures and other episodes should not be neglected, but rather taken seriously, sought and actively explored as a crucial element when taking clinical histories in patients with episodic attacks. PMID- 29414548 TI - Efficacy and tolerability of perampanel and levetiracetam as first add-on therapy in patients with epilepsy: A retrospective single center study. AB - Perampanel (PER) is a third generation antiepileptic drug (AED), recently approved as add-on therapy in both focal and generalized seizures. Levetiracetam (LEV) is a second generation AED, widely used in patients with epilepsy because of its favorable safety and efficacy profiles. Perampanel and LEV treatments have been associated with the occurrence of similar adverse events (AEs) (sleepiness, irritability, depression, anxiety, aggressiveness). The aim of the present retrospective single center study was to verify the efficacy and tolerability of PER and LEV used as first add-on therapy in patients with epilepsy affected by secondarily generalized seizures. We collected data from 15 patients treated with PER and 26 patients treated with LEV and followed at our site with follow-up visits at 3, 6, and 12months. This retrospective study documented the comparable efficacy of PER and LEV as first add-on treatments in patients affected by uncontrolled secondarily generalized seizures. However, more patients withdrawn LEV because of AEs compared with PER at the 3- and 12-month follow-up visits. The better tolerability of PER observed in this study could be related to the low therapeutic dose of PER prescribed when it is used as first adjunctive treatment for better controlling secondarily generalized seizures. PMID- 29414549 TI - Symptoms of depression, anxiety, and stress in parents of young children with epilepsy: A case controlled population-based study. AB - The objective was to provide population-based data on depression, anxiety, and stress in parents of young children with epilepsy and to compare findings with those of parents of developmental-, age-, and gender-matched children with nonepilepsy-related neurodisability (neurological and/or neurodevelopmental concerns). The parents (mothers and fathers) of 47 (89% ascertainment) young children (1-7years) with epilepsy in a defined geographical area of the UK completed the Depression Anxiety Stress Scales - Short Form (DASS-21), a screening measure for depression, anxiety, and stress. The responses of parents of children with epilepsy were compared with parents of developmental-, age-, and gender-matched children with nonepilepsy-related neurodisability (n=48). Factors associated with parental symptoms were analyzed using regression. In the group with epilepsy, 47 mothers and 39 fathers completed the DASS-21. Seventy-two percent of mothers scored in the at-risk range on at least one DASS-21 subscale (Fathers 49%). Mothers of children with epilepsy were significantly more likely to score in the at risk range than fathers on depression (55% vs. 33%), anxiety (47% vs. 26%), and stress (55% vs. 31%) subscales (all p<0.05). Mothers of children with epilepsy were also significantly more likely to score in the at risk range than mothers of children with neurodisability on measures of depression (p=0.005) and stress (p=0.03). There was not a significant difference between fathers in both groups on any measures. In the group with epilepsy, increased child emotional-behavioral difficulties were associated with increased DASS-21 scores on multivariable analysis (p=0.04). Mothers of young children with epilepsy are at high risk for mental health difficulties, and all should be screened for such difficulties. There is a need to explore what parent and/or child focused interventions might be useful to reduce the mental health difficulties reported by mothers of young children with epilepsy. PMID- 29414550 TI - Clinical aspects, neuroimaging, and electroencephalography of 35 cases of hemiconvulsion-hemiplegia syndrome. AB - INTRODUCTION: The hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a rare consequence of febrile seizures during childhood. It is characterized by the presence of prolonged unilateral clonic seizures occurring during febrile illness in a child less than 4years of age. Then, a flaccid unilateral hemiplegia with variable duration occurs. OBJECTIVES: The objective of the study was to describe the clinical, electroencephalogram (EEG), and neuroimaging treatment and outcome of series of cases of HHE syndrome followed for 10years in our clinical neurophysiology department of the specialty hospital of Rabat. PATIENTS AND METHODS: We report a retrospective study of 35 patients followed up for HHE syndrome from January 2005 to December 2015. All patients included in the study met the definition criteria for HHE syndrome. RESULTS: The age of onset ranged from 1 to 10years. Hemiplegia or spastic hemiparesis of the ipsilateral side to the convulsion was present in all patients. Abnormal brain magnetic resonance imaging (MRI) was found in all patients. All patients developed drug-resistant focal epilepsy during the course of the disease. CONCLUSIONS: The management of HHE syndrome constitutes a real public health problem in developing countries like Morocco. The neurological morbidity and the severe sequels are of high impact in these young kids. On the one hand, authors highlight the need for improving emergency care of status epilepticus. On the other hand, in our context, the prophylaxis of febrile seizures seems to be the corner stone of the prevention of HHE Syndrome. PMID- 29414551 TI - Oxidative stress in patients with refractory temporal lobe epilepsy and mesial temporal sclerosis: Possible association with major depressive disorder? AB - OBJECTIVE: The objective was to evaluate the genetic and biochemical profiles associated with oxidative stress (OS) in patients with temporal lobe epilepsy with mesial temporal sclerosis (TLE-MTS) and a healthy control group, and also to verify the possible existence of association between OS markers and psychiatric disorders (PD) in group with TLE-MTS. METHODS: Forty-six patients with refractory TLE-MTS and 112 healthy controls were included. Psychiatric evaluation occurred through Diagnostical and Statistical Manual of Mental Disorders (DSM-5) criteria. A peripheral blood sample was collected for analysis of glutathione S-transferase (GST) T1/M1 polymorphisms and serum levels of malondialdehyde (MDA) and antioxidant capacity equivalent to the trolox (TEAC), serum markers of OS. Student's t-test, Fisher's exact test, Chi-square test, and Analysis of Variance (ANOVA) were used, with a significance level of P<0.05. RESULTS: The PD were observed in 27 patients of the group with TLE-MTS (58.6%); major depressive disorder (MDD) was the most frequent. Serum levels of MDA (P<0.0001) and TEAC (P<0.0001) were higher in group with TLE-MTS. When patients with MDD were compared with patients without PD, significant differences were observed between MDA (P=0.002) and TEAC (P=0.003) serum levels. Patients with TLE-MTS and MDD presented higher levels when compared with patients with TLE-MTS without PD and with another PD except MDD. CONCLUSIONS: The present study observed significantly higher serum levels of MDA and of TEAC in patients with refractory TLE-MTS in comparison with the control group. The MDD was observed as an important issue associated with higher OS levels in refractory TLE-MTS. Further studies are needed to investigate the association of OS, TLE-MTS, and PD. PMID- 29414552 TI - Does surgery help in reducing stigma associated with drug refractory epilepsy in children? AB - INTRODUCTION: Epilepsy has several comorbidities and associated stigma. Stigma associated with epilepsy is well known and prevalent worldwide. Surgical treatment is an established treatment for drug refractory epilepsy. Following surgery in children, it is possible that the stigma may reduce, but such an effect has not been studied earlier. MATERIALS AND METHODS: Analysis of prospectively collected data was performed for pediatric patients at a single tertiary center for treating epilepsy. Child stigma scale, as described by Austin et al., was used to evaluate stigma both pre- and postoperatively. Analysis was done using Paired t test. RESULTS: In this study, following surgery, there was significant reduction of stigma (P<0.001). This was proportional to the reduction in seizures, though there were 9 (30%) patients, who due to persistent neurodisability did not have any reduction of stigma despite having good seizure outcome. CONCLUSION: Surgery in drug-resistant epilepsy helps in reducing stigma. Seizure reduction is probably not the only factor responsible for a change in stigma outcome. PMID- 29414553 TI - Cognitive and motor outcomes in children with unilateral Sturge-Weber syndrome: Effect of age at seizure onset and side of brain involvement. AB - PURPOSE: Most children with Sturge-Weber syndrome (SWS) develop seizures that may contribute to neurocognitive status. In this study, we tested the hypothesis that very early seizure onset has a particularly detrimental effect on the cognitive and/or motor outcomes of children with unilateral SWS. We also tested whether side of SWS brain involvement modulates the effect of seizure variables on the pattern of cognitive abnormalities. METHODS: Thirty-four children (22 girls; mean age 6.1years) with unilateral SWS and history of epilepsy in a longitudinal cohort underwent neurological and cognitive evaluations. Global intelligent quotient (GIQ), verbal intelligent quotient (VIQ), nonverbal intelligent quotient (IQ), and motor function were correlated with epilepsy variables, side and extent of brain involvement on magnetic resonance imaging (MRI). RESULTS: Mean age at seizure onset was 1.3years (0.1-6years) and mean IQ at follow-up was 86 (45-118). Age at seizure onset showed a logarithmic association with IQ, with maximum impact of seizures starting before age 1year, both in uni- and multivariate regression analyses. In the left SWS group (N=20), age at seizure onset was a strong predictor of nonverbal IQ (p=0.001); while early seizure onset in the right-hemispheric group had a more global effect on cognitive functions (p=0.02). High seizure frequency and long epilepsy duration also contributed to poor outcome IQ independently in multivariate correlations. Children with motor involvement started to have seizures at/before 7months of age, while frontal lobe involvement was the strongest predictor of motor deficit in a multivariate analysis (p=0.017). CONCLUSION: These findings suggest that seizure onset prior to age 1year has a profound effect on severity of cognitive and motor dysfunction in children with SWS; however, the effect of seizures on the type of cognitive deficit is influenced by laterality of brain involvement. PMID- 29414554 TI - Economic impact of epilepsy and the cost of nonadherence to antiepileptic drugs in older Medicare beneficiaries. AB - Epilepsy is most prevalent among older individuals, and its economic impact is substantial. The development of economic burden estimates that account for known confounders, and using percent incremental costs may provide meaningful comparison across time and different health systems. The first objective of the current study was to estimate the percent incremental healthcare costs and the odds ratio (OR) for inpatient utilization for older Medicare beneficiaries with epilepsy and without epilepsy. The second objective was to estimate the percent incremental healthcare costs and the OR for inpatient utilization associated with antiepileptic drug (AED) nonadherence among Medicare beneficiaries with epilepsy. The OR of inpatient utilization for cases compared with controls (i.e., non cases) were 2.4 (95% CI 2.3 to 2.6, p-value<0.0001) for prevalent epilepsy and 3.6 (95% CI 3.2 to 4.0, p-value<0.0001) for incident epilepsy. With respect to total health care costs, prevalent cases incurred 61.8% (95% CI 56.6 to 67.1%, p value<0.0001) higher costs than controls while incident cases incurred 71.2% (95% CI 63.2 to 79.5%, p-value <0.0001) higher costs than controls. The nonadherence rates were 33.6 and 32.9% for prevalent and incident cases, respectively. Compared to nonadherent cases, the OR of inpatient utilization for adherent prevalent cases was 0.66 (95% CI 0.55 to 0.81, p-value <0.0001). The cost saving for a prevalent case adherent to AEDs was 13.2% (95% CI 6.6 to 19.4%, p value=0.0001) compared to a nonadherent case. An incident case adherent to AEDs spent 16.4% (95% CI 6.5 to 25.2%, p-value=0.002) less than a nonadherent incident case on health care. Epilepsy is associated with higher health care costs and utilization. Older Medicare beneficiaries with epilepsy incur higher total health care spending and have higher inpatient utilization than those without epilepsy. Total health care spending is less for older Medicare beneficiaries who have prevalent or incident epilepsy if they are adherent to AEDs. PMID- 29414555 TI - Specificity of electroclinical features in the diagnosis of ring chromosome 20. AB - BACKGROUND: Ring chromosome 20 (R20) syndrome is a chromosomal disorder characterized mainly by drug-resistant frontal lobe seizures, recurrent nonconvulsive status epilepticus (NCSE), and typical EEG features. The aim of this study was to investigate if this triad is common and specific to all patients with R20. METHODS: In this cross-sectional study (from 2000 to 2011), we selected patients who fulfilled at least two out of three criteria: drug resistant frontal lobe seizures, recurrent NCSE, and characteristic electroencephalography (EEG) features. In all patients, diagnosis was based on karyotype analysis of at least 100 metaphases. RESULTS: We identified 36 patients who met at least two of the selected criteria: six patients (16.7%) with R20 and 30 (83.3%) without R20 (non-R20). All patients with R20 met all three criteria. Eleven (36.7%) patients without R20, however, also displayed the full triad. In 19 patients without R20 (63.3%), one of the three clinical features was missing: frontal lobe seizures were not resistant to antiepileptic drugs (AED) in four (13.3%), recurrent NCSE was missing in six (20%), and nine (30%) patients did not have typical EEG features. Based on this data, specificity was 63.3%, positive predictive value was 35.3%, and sensitivity and negative predictive values were 100%. Additionally, a review of all publications describing the R20 phenotype revealed that 81.98% of patients with R20 display the full electroclinical triad. CONCLUSIONS: In our study, all patients with R20 displayed the three electroclinical characteristics. This is in line with previous reports (presenting high sensitivity and negative predictive value). However, these features can also be observed in other epilepsies and are not specific to R20. Our findings suggest that in the presence of the full triad of symptoms, karyotype analysis focused on chromosome 20 should be conducted. PMID- 29414556 TI - Memory complaints in epilepsy: An examination of the role of mood and illness perceptions. AB - : The study examined the role of mood and illness perceptions in explaining the variance in the memory complaints of patients with epilepsy. METHOD: Forty-four patients from an outpatient tertiary care center and 43 volunteer controls completed a formal assessment of memory and a verbal fluency test, as well as validated self-report questionnaires on memory complaints, mood, and illness perceptions. RESULTS: In hierarchical multiple regression analyses, objective memory test performance and verbal fluency did not contribute significantly to the variance in memory complaints for either patients or controls. In patients, illness perceptions and mood were highly correlated. Illness perceptions correlated more highly with memory complaints than mood and were therefore added to the multiple regression analysis. This accounted for an additional 25% of the variance, after controlling for objective memory test performance and verbal fluency, and the model was significant (model B). In order to compare with other studies, mood was added to a second model, instead of illness perceptions. This accounted for an additional 24% of the variance, which was again significant (model C). In controls, low mood accounted for 11% of the variance in memory complaints (model C2). SUMMARY: A measure of illness perceptions was more highly correlated with the memory complaints of patients with epilepsy than with a measure of mood. In a hierarchical multiple regression model, illness perceptions accounted for 25% of the variance in memory complaints. Illness perceptions could provide useful information in a clinical investigation into the self-reported memory complaints of patients with epilepsy, alongside the assessment of mood and formal memory testing. PMID- 29414557 TI - Caffeine and seizures: A systematic review and quantitative analysis. AB - PURPOSE: Caffeine is the most commonly used central nervous system (CNS) stimulant. The relationship between caffeine, seizures, epilepsy, and antiepileptic drugs (AEDs) is complex and not fully understood. Case reports suggest that caffeine triggers seizures in susceptible people. Our systematic review reports on the relationship between caffeine, seizures, and drugs in animal and human studies. Quantitative analyses were also done on animal studies regarding the effects of caffeine on AEDs. METHODS: PubMed was searched for studies assessing the effects of caffeine on seizure susceptibility, epilepsy, and drug interactions in people and in animal models. To quantify the interaction between AEDs and caffeine, the data of six animal studies were pooled and analyzed using a general linear model univariate analysis or One-way Analysis of Variance (ANOVA). RESULTS: In total, 442 items were identified from which we included 105 studies. Caffeine can increase seizure susceptibility and protect from seizures, depending on the dose, administration type (chronic or acute), and the developmental stage at which caffeine exposure started. In animal studies, caffeine decreased the antiepileptic potency of some drugs; this effect was strongest in topiramate. CONCLUSION: Preclinical studies suggest that caffeine increases seizure susceptibility. In some cases, chronic use of caffeine may protect against seizures. Caffeine lowers the efficacy of several drugs, especially topiramate. It is unclear how these findings in models can be translated to the clinical condition. Until clinical studies suggest otherwise, caffeine intake should be considered as a factor in achieving and maintaining seizure control in epilepsy. PMID- 29414558 TI - Illness identity in young adults with refractory epilepsy. AB - INTRODUCTION: Refractory epilepsy is an intrusive condition with important implications for daily functioning in emerging and young adulthood. The present study examined the degree to which refractory epilepsy is integrated in one's identity, and examined how such a sense of illness identity was related to health related quality of life (HRQOL). METHODS: A total of 121 18- to 40-year-old patients with refractory epilepsy (56.2% women) completed self-report questionnaires assessing the four illness identity states of acceptance, enrichment, engulfment, and rejection (Illness Identity Questionnaire (IIQ)); HRQOL (Quality of Life in Epilepsy Inventory - 31); and seizure frequency and severity (Liverpool Seizure Severity Scale (LSSS)). Illness identity scores were compared with a sample of 191 patients with a nonneurological chronic disease (congenital heart disease). Hierarchical regression analyses were conducted to assess the predictive value of illness identity for HRQOL when simultaneously controlling for demographic and clinical features. RESULTS: Patients with refractory epilepsy scored higher on rejection and engulfment and lower on acceptance when compared with patients with congenital heart disease. Further, seizure severity and number of medication side-effects were positively related to engulfment and negatively to acceptance. Finally, when simultaneously controlling for various demographic and clinical variables, illness identity significantly predicted HRQOL (with engulfment being the strongest and most consistent predictor). CONCLUSION: The extent to which patients with refractory epilepsy succeed in integrating their illness into their identity may have important implications for HRQOL. Clinicians should be especially attentive for signs that patients feel engulfed by their epilepsy. PMID- 29414559 TI - Development of outcome criteria to measure effectiveness of antiepileptic therapy in children. AB - PURPOSE: Clinical trials of antiepileptic drugs frequently measure outcomes of seizure control, which demonstrate efficacy. Yet, functional status, quality of life, and long-term treatment effects reflecting effectiveness are scarcely assessed. We sought to use a consensus method to help identify which outcome criteria key stakeholders consider should be used to measure effectiveness in trials of antiepileptic treatments for children. METHOD: A two-round Delphi survey was used; parents of children with epilepsy and local, international experts comprising academics and clinicians participated in the survey. In the first round, 32 experts, 50 parents, and 15 children with epilepsy aged >13years suggested outcomes that they considered important in determining effectiveness of antiepileptic therapy in children, separately for preschool and school age. In the second round, 29 experts and 42 parents scored the importance of outcomes from the list suggested by at least 10% of round 1 respondents and also proposed five most important outcomes. RESULTS: Complete seizure freedom (67%), seizure frequency (48%), ability to perform normal day-to-day activities (45%), and quality of life (40%) were identified as the most important outcomes of antiepileptic therapy in children of both age groups. Additionally, effect on developmental milestones (47%) and child's compliance to treatment regimen (39%) were identified as most important in preschool age group and school performance (49%); adverse effects (39%) were identified as most important in school age group. CONCLUSION: For the first time, this study has identified outcome priorities regarding antiepileptic treatment in children based on the key stakeholders' perspectives. It could be used as a provisional list of outcomes for inclusion in a core outcome set for children with epilepsy. PMID- 29414560 TI - The relationship between structural MRI, FDG-PET, and memory in temporal lobe epilepsy: Preliminary results. AB - Structural and metabolic abnormalities of the temporal lobe are frequently found in temporal lobe epilepsy (TLE). In the present retrospective study, we investigated whether structural abnormalities evident in magnetic resonance imaging (MRI) and hypometabolism evident in [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) independently influence verbal and nonverbal learning and delayed memory in patients with TLE. Sixty-eight patients with refractory unilateral TLE (35 left TLE, 33 right TLE) were divided into three groups: (1) no evidence of pathology in either MRI or FDG-PET studies (MRI-/PET-, n=15), (2) temporal FDG-PET determined hypometabolism with normal MRI findings (MRI-/PET+, n=21), and (3) evidence of temporal abnormalities in both MRI and FDG PET studies (MRI+/PET+, n=32). A fourth group (MRI+/PET-, n=4) was too small for further statistical analysis and could not be included. Patients with MRI+/PET+ showed worse verbal memory than patients with MRI-/PET- (p<0.01), regardless of side of seizure focus. Verbal memory performance of patients with MRI-/PET+ was located between patients with MRI+/PET+ and MRI-/PET-, although group differences did not achieve statistical significance (ps>0.1). No group differences were found for nonverbal memory (p=0.27). Our results may suggest an interactive negative effect of metabolic and structural temporal lobe abnormalities on verbal memory. Still, our results are preliminary and need further validation by studies involving larger patient groups and up-to date quantitative imaging analysis methods. PMID- 29414561 TI - A modern epilepsy surgery treatment algorithm: Incorporating traditional and emerging technologies. AB - Epilepsy surgery has seen numerous technological advances in both diagnostic and therapeutic procedures in recent years. This has increased the number of patients who may be candidates for intervention and potential improvement in quality of life. However, the expansion of the field also necessitates a broader understanding of how to incorporate both traditional and emerging technologies into the care provided at comprehensive epilepsy centers. This review summarizes both old and new surgical procedures in epilepsy using an example algorithm. While treatment algorithms are inherently oversimplified, incomplete, and reflect personal bias, they provide a general framework that can be customized to each center and each patient, incorporating differences in provider opinion, patient preference, and the institutional availability of technologies. For instance, the use of minimally invasive stereotactic electroencephalography (SEEG) has increased dramatically over the past decade, but many cases still benefit from invasive recordings using subdural grids. Furthermore, although surgical resection remains the gold-standard treatment for focal mesial temporal or neocortical epilepsy, ablative procedures such as laser interstitial thermal therapy (LITT) or stereotactic radiosurgery (SRS) may be appropriate and avoid craniotomy in many cases. Furthermore, while palliative surgical procedures were once limited to disconnection surgeries, several neurostimulation treatments are now available to treat eloquent cortical, bitemporal, and even multifocal or generalized epilepsy syndromes. An updated perspective in epilepsy surgery will help guide surgical decision making and lay the groundwork for data collection needed in future studies and trials. PMID- 29414563 TI - Genital automatisms: Reappraisal of a remarkable but ignored symptom of focal seizures. AB - OBJECTIVES: Genital automatisms (GAs) are uncommon clinical phenomena of focal seizures. They are defined as repeated fondling, grabbing, or scratching of the genitals. The aim of this study was to determine the lateralizing and localizing value and associated clinical characteristics of GAs. METHODS: Three hundred thirteen consecutive patients with drug-resistant seizures who were referred to our tertiary center for presurgical evaluation between 2009 and 2016 were investigated. The incidence of specific kinds of behavior, clinical semiology, associated symptoms/signs with corresponding ictal electroencephalography (EEG) findings, and their potential role in seizure localization and lateralization were evaluated. RESULTS: Fifteen (4.8%) of 313 patients had GAs. Genital automatisms were identified in 19 (16.4%) of a total 116 seizures. Genital automatisms were observed to occur more often in men than in women (M/F: 10/5). Nine of fifteen patients (60%) had temporal lobe epilepsy (right/left: 4/5) and three (20%) had frontal lobe epilepsy (right/left: 1/2), whereas the remaining two patients could not be classified. One patient was diagnosed as having Rasmussen encephalitis. Genital automatisms were ipsilateral to epileptic focus in 12 patients and contralateral in only one patient according to ictal interictal EEG and neuroimaging findings. Epileptic focus could not be lateralized in the last 2 patients. Genital automatisms were associated with unilateral hand automatisms such as postictal nose wiping or manual automatisms in 13 (86.7%) of 15 and contralateral dystonia was seen in 6 patients. All patients had amnesia of the performance of GAs. CONCLUSION: Genital automatisms are more frequent in seizures originating from the temporal lobe, and they can also be seen in frontal lobe seizures. Genital automatisms seem to have a high lateralizing value to the ipsilateral hemisphere and are mostly concordant with other unilateral hand automatisms. Men exhibit GAs more often than women. PMID- 29414562 TI - An objective score to identify psychogenic seizures based on age of onset and history. AB - OBJECTIVE: Psychogenic nonepileptic seizure (PNES) is a common diagnosis after evaluation of medication resistant or atypical seizures with video electroencephalographic monitoring (VEM), but usually follows a long delay after the development of seizures, during which patients are treated for epilepsy. Therefore, more readily available diagnostic tools are needed for earlier identification of patients at risk for PNES. A tool based on patient-reported psychosocial history would be especially beneficial because it could be implemented in the outpatient clinic. METHODS: Based on the data from 1375 patients with VEM-confirmed diagnoses, we used logistic regression to compare the frequency of specific patient-reported historical events, demographic information, age of onset, and delay from first seizure until VEM in five mutually exclusive groups of patients: epileptic seizures (ES), PNES, physiologic nonepileptic seizure-like events (PSLE), mixed PNES plus ES, and inconclusive monitoring. To determine the diagnostic utility of this information to differentiate PNES only from ES only, we used multivariate piecewise-linear logistic regression trained using retrospective data from chart review and validated based on data from 246 prospective standardized interviews. RESULTS: The prospective area under the curve of our weighted multivariate piecewise linear by-sex score was 73%, with the threshold that maximized overall retrospective accuracy resulting in a prospective sensitivity of 74% (95% CI: 70 79%) and prospective specificity of 71% (95% CI: 64-82%). The linear model and piecewise linear without an interaction term for sex had very similar performance statistics. In the multivariate piecewise-linear sex-split predictive model, the significant factors positively associated with ES were history of febrile seizures, current employment or active student status, history of traumatic brain injury (TBI), and longer delay from first seizure until VEM. The significant factors associated with PNES were female sex, older age of onset, mild TBI, and significant stressful events with sexual abuse, in particular, increasing the likelihood of PNES. Delays longer than 20years, age of onset after 31years for men, and age of onset after 40years for women had no additional effect on the likelihood of PNES. DISCUSSION: Our promising results suggest that an objective score has the potential to serve as an early outpatient screening tool to identify patients with greater likelihood of PNES when considered in combination with other factors. In addition, our analysis suggests that sexual abuse, more than other psychological stressors including physical abuse, is more associated with PNES. There was a trend of increasing frequency of PNES for women during childbearing years and plateauing outside those years that was not observed in men. PMID- 29414564 TI - Positive psychological interventions for people with epilepsy: An assessment on factors related to intervention participation. AB - BACKGROUND: Positive psychological interventions (PPI) are increasingly employed as a coping strategy with physical and mental conditions, including neurological diseases. Its effectiveness on improving wellbeing in people with epilepsy (PWE) has been shown in a few studies. This study aimed to explore factors related to participants' willingness to engage in psychological interventions from the perspective of patients with epilepsy. METHODS: Participants answered a needs assessment questionnaire eliciting information about their illness perception (Brief Illness Perception Questionnaire (Brief-IPQ)), emotions (Hospital Anxiety and Depression Scale (HADS)), willingness to participate in psychological interventions, preferences in types of PPI and intervention designs, as well as barriers in seeking mental health services. RESULTS: A total of 154 patients with epilepsy participated, with a mean age of 37.3years (range 16-86years). Most patients had focal epilepsy (68.2%), and drug-resistant (59.1%). Majority (71.4%) of them indicated a strong willingness to participate in PPI. Out of nine types of PPI, character strengths, mindfulness-based and expressive-based interventions were highly preferred. Those with negative illness perception (p=0.001), anxiety (p=0.004), and being unemployed (p=0.048) were more willing to participate in PPI. Most participants preferred group rather than individual session, and a shorter duration (30min) was favored by most. CONCLUSION: This study captured the self-report willingness to participate in psychological interventions. Findings suggested that psychological interventions delivered in short-group session were highly preferred. Future study is required to determine the feasibility of such design for patients with epilepsy. PMID- 29414565 TI - Current state of the union of epilepsy care in the United States: Antiepileptic drugs - An introduction to the Connectors Project. AB - PURPOSE: How antiepileptic drugs (AEDs) are used in the United States (US) is one proxy public health indicator for the current state of epilepsy management. The use of phenytoin, other older AEDs, and newer AEDs may act as an indicator for the quality of epilepsy practice in addition to the current American Academy of Neurology quality measures. Data on AED used by states and populations can help identify which public health interventions are necessary to improve the status of epilepsy care. The Connectors Project, a collaboration between the Epilepsy Foundation and UCB Pharma, is a multiyear project designed to improve epilepsy awareness and management in underserved communities. The objective of the first phase of the Connectors Project was to assess geographic variation in epilepsy care and identify locations in need of improved epilepsy care by initially evaluating AED use in the US. METHODS: A retrospective cross-sectional administrative claim analysis was conducted using the QuintilesIMSTM database which included US longitudinal retail prescription and office medical claims data. Patients with a confirmed epilepsy diagnosis who were prescribed AEDs were identified. Patients with an AED prescription over a 3-year period from January 2013 to December 2015 were included if they had an epilepsy diagnosis in the 2 year period before their first AED prescription in the reporting period. The percentages of patients initially prescribed phenytoin, other older AEDs (carbamazepine and valproate), and newer AEDs (eslicarbazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, topiramate) were calculated and stratified by US state and Washington, DC. Patients were considered newly treated if they had an epilepsy diagnosis code and had not received an epilepsy drug in the 1-year period preceding the first AED prescription in the reporting period. Data are reported using the moving annual total ending December 2015. RESULTS: Approximately 2.5 million US patients with epilepsy and their AED prescriptions were identified from 2013 to 2015. Predictably, states with the largest population had the highest number of patients with epilepsy who were prescribed an AED, including California, Texas, Florida, and New York. Regions with the highest total proportion of phenytoin use with a low proportion of newer AED use were Mississippi (24.4% and 53.1%, respectively) and Washington, DC (24.7% and 58.1%). Montana had the lowest proportion of phenytoin use with the highest proportion of newer AED use (7.9% and 70.4%). Among newly treated patients (N=237,347), Hawaii (39.1%) and Alaska (38.8%) had the highest percentage of phenytoin use compared with all other states. Idaho (86.1%) and Montana (84.4%) had the highest proportion of newer AED use. Washington, DC (50.9%) and Hawaii (60.9%) had the lowest proportion of patients treated with newer AEDs. North Dakota (29.6%) and Washington, DC (27.9%) had the highest rates of other older AEDs use. CONCLUSIONS: A substantial proportion of newly treated US patients with epilepsy are underserved regarding newer AED use with Mississippi and Washington, DC having the highest proportion of phenytoin use relative to newer AED use. Understanding the socioeconomic and demographic barriers for these observations is essential in planning interventions to improve the quality of life and care for patients with epilepsy, including newly treated patients. These data provide a baseline to target educational and clinical interventions for improving the quality of US epilepsy care. PMID- 29414566 TI - Capabilities and limitations of handheld Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS) for the analysis of colourants and binders in 20th-century reverse paintings on glass. AB - A non-invasive method has been carried out to show the capabilities and limitations of Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS) for identifying of colourants and binders in modern reverse glass paintings. For this purpose, the reverse glass paintings "Zwei Frauen am Tisch" (1920-22), "Baume" (1946) (both by Heinrich Campendonk), "Lofoten" (1933) (Edith Campendonk-van Leckwyck) and "Ohne Titel" (1954) (Marianne Uhlenhuth), were measured. In contrast to other techniques (e.g. panel and mural painting), the paint layers are applied in reverse succession. In multi-layered paint systems, the front paint layer may no longer be accessible. The work points out the different spectral appearance of a given substance (gypsum, basic lead white) in reverse glass paintings. However, inverted bands, band overlapping and derivative shaped spectral features can be interpreted by comparing the spectra from the paintings with spectra from pure powders and pigment/linseed oil mock-ups. Moreover, the work focuses on this method's capabilities in identifying synthetic organic pigments (SOP). Reference spectra of three common SOP (PG7, PY1, PR83) were obtained from powders and historical colour charts. We identified PR83 and PY1 in two reverse glass paintings, using the measured reference spectra. The recorded DRIFTS spectra of pure linseed oil, gum Arabic, mastic, polyvinyl acetate resin and bees wax can be used to classify the binding media of the measured paintings. PMID- 29414567 TI - Solid state speciation of uranium and its local structure in Sr2CeO4 using photoluminescence spectroscopy. AB - An effort was taken to carry our speciation study of uranium ion in technologically important cerate host Sr2CeO4 using time resolved photoluminescence spectroscopy. Such studies are not relevant only to nuclear industry but can give rich insight into fundamentals of 5f electron chemistry in solid state systems. In this work both undoped and varied amount of uranium doped Sr2CeO4 compound is synthesized using complex polymerization method and is characterized systematically using X-ray diffraction (XRD), Raman spectroscopy, impedance spectroscopy and scanning electron microscopy (SEM). Both XRD and Raman spectroscopy confirmed the formation of pure Sr2CeO4 which has tendency to decompose peritectically to SrCeO3 and SrO at higher temperature. Uranium doping is confirmed by XRD. Uranium exhibits a rich chemistry owing to its variable oxidation state from +3 to +6. Each of them exhibits distinct luminescence properties either due to f-f transitions or ligand to metal charge transfer (LMCT). We have taken Sr2CeO4 as a model host lattice to understand the photophysical characteristics of uranium ion in it. Emission spectroscopy revealed the stabilization of uranium as U (VI) in the form of UO66- (octahedral uranate) in Sr2CeO4. Emission kinetics study reflects that uranate ions are not homogeneously distributed in Sr2CeO4 and it has two different environments due to its stabilization at both Sr2+ as well as Ce4+ site. The lifetime population analysis interestingly pinpointed that majority of uranate ion resided at Ce4+ site. The critical energy-transfer distance between the uranate ion was determined based on which the concentration quenching mechanism was attributed to electric multipolar interaction. These studies are very important in designing Sr2CeO4 based optoelectronic material as well exploring it for actinides studies. PMID- 29414568 TI - Influence of ligand chemistry on silver nanoparticles for colorimetric detection of Cr3+ and Hg2+ ions. AB - In this work, we describe the role of ligand chemistry on the surfaces of silver nanoparticles (Ag NPs) for tuning their analytical applications. The citrate and melamine (MA) molecules were used as ligands for the surface modification of Ag NPs. The addition of Cr3+ ion in citrate-Ag NPs (Cit-Ag NPs) and of Hg2+ ion in melamine-Ag NPs (MA-Ag NPs) cause Ag NPs aggregation, and are accompanied by a color change and a red-shift. The resulting distinctly visual readouts are favorable for colorimetric detection of Cr3+ and Hg2+ ions. Under optimal conditions, the linear ranges are observed in the concentration ranges of 1.0 50.0 and of 10.0-100.0 MUM, and with detection limit of 0.52 and 1.80 MUM for Cr3+ and Hg2+ ions. The simultaneous detection of Cr3+ and Hg2+ ion is driven by the changing the ligand chemistry on the surfaces of Ag NPs that allows to tune their specific interactions with target analytes. Finally, the functionalized Ag NPs were successfully applied to detect Cr3+ and Hg2+ ions in water samples with satisfactory recoveries. PMID- 29414569 TI - Experimental and theoretical approach on the optical properties of zinc borotellurite glass doped with dysprosium oxide. AB - A series of glass samples with chemical formula {[(TeO2)0.7(B2O3)0.3]0.7(ZnO)0.3}1-x(Dy2O3)x where x=0.01, 0.02, 0.03, 0.04 and 0.05M fraction were synthesized through conventional melt-quenching method. The most common way to fabricate a glass material is by fusion of two or more component oxides followed by their quenching. This technique is known as melt quenching technique. Kaur et al. (2016) [1] highlighted that the melt-quenching method able to enhance the mechanical properties like hardness and flexural strength of the material. The nature of the glass systems is proven to be amorphous based on the XRD pattern. The FTIR spectra of the glass systems confirm the existence of five bands which are assigned for the BO4, BO3, TeO4 and TeO3 vibrational groups. The density of the glass systems is increased with the addition of Dy2O3 while the molar volume is found to be inversely proportional to the density of the proposed glass. The optical properties of the glasses are determined through the absorption spectra obtained from the UV-VIS spectrophotometer. From the absorption spectra, the indirect and direct optical band gaps and the Urbach energy are found to be inversely proportional to each other. As the molar fraction of the Dy2O3 increased, the optical band gaps are observed to increase as opposed to the Urbach energy. For this glass system, the values of refractive index, electronic polarizability, oxide ion polarizability and the optical basicity are found to decrease as the addition of the dysprosium oxide is increased. From the emission spectra, two intense blue and yellow emission bands are observed, which correspond to the 4F9/2->6H15/2 and 4F9/2 >6H13/2 transitions of Dy3+ ions respectively. The CIE chromaticity coordinates of the zinc borotellurite glass systems are found to be located in the white light region. PMID- 29414570 TI - A chromogenic and fluorogenic rhodol-based chemosensor for hydrazine detection and its application in live cell bioimaging. AB - A rhodol-based fluorescent probe has been developed as a selective hydrazine chemosensor using levulinate as a recognition site. The rhodol levulinate probe (RL) demonstrated high selectivity and sensitivity toward hydrazine among other molecules. The chromogenic response of RL solution to hydrazine from colorless to pink could be readily observed by the naked eye, while strong fluorescence emission could be monitored upon excitation at 525 nm. The detection process occurred via a ring-opening process of the spirolactone initiated by hydrazinolysis, triggering the fluorescence emission with a 53-fold enhancement. The probe rapidly reacted with hydrazine in aqueous medium with the detection limit of 26 nM (0.83 ppb), lower than the threshold limit value (TLV) of 10 ppb suggested by the U.S. Environmental Protection Agency. Furthermore, RL impregnated paper strips could detect hydrazine vapor. For biological applicability of RL, its membrane-permeable property led to bioimaging of hydrazine in live HepG2 cells by confocal fluorescence microscopy. PMID- 29414571 TI - Highly selective and sensitive determination of Cu2+ in drink and water samples based on a 1,8-diaminonaphthalene derived fluorescent sensor. AB - A new simple and efficient fluorescent sensor L based on 1,8-diaminonaphthalene Schiff-base for highly sensitive and selective determination of Cu2+ in drink and water has been developed. This Cu2+-selective detection over other tested metal ions displayed an obvious color change from blue to colorless easily detected by naked eye. The detection limit is determined to be as low as 13.2 nM and the response time is very fast within 30 s. The 1:1 binding mechanism was well confirmed by fluorescence measurements, IR analysis and DFT calculations. Importantly, this sensor L was employed for quick detection of Cu2+ in drink and environmental water samples with satisfactory results, providing a simple, rapid, reliable and feasible Cu2+-sensing method. PMID- 29414572 TI - Magnetic polymer microcapsules loaded with Nile Red fluorescent dye. AB - Fabrication of multifunctional smart vehicles for drug delivery is a fascinating challenge of multidisciplinary research at the crossroads of materials science, physics and biology. We demonstrate a prototypical microcapsule system that is capable of encapsulating hydrophobic molecules and at the same time reveals magnetic properties. The microcapsules are prepared using a templated synthesis approach where the molecules to be encapsulated (Nile Red) are present in the organic droplets that are suspended in the polymerization solution which also contains magnetic nanoparticles. The polymer (polypyrrole) grows on the surface of organic droplets encapsulating the fluorescent dye in the core of the formed microcapsule which incorporates the nanoparticles into its wall. For characterization of the resulting structures a range of complementary physicochemical methodology is used including optical and electron microscopy, magnetometry, 1H NMR and spectroscopy in the visible and X-ray spectral ranges. Moreover, the microcapsules have been examined in biological environment in in vitro and in vivo studies. PMID- 29414573 TI - Highly selective and sensitive turn-on fluorescent sensor for detection of Al3+ based on quinoline-base Schiff base. AB - A new aluminum ion fluorescent probe (4-(diethylamino)-2 hydroxybenzylidene)isoquinoline-1-carbohydrazide (HL1) has been conveniently synthesized and characterized. HL1 exhibited a highly selective and pronounced enhancement for Al3+ in the fluorescence emission over other common cations by forming a 2:1 complex, with a recognition mechanism based on excited-state intramolecular proton transfer (ESIPT) and intramolecular charge transfer (ICT). The strong fluorescent emission can be observed even at ppm level concentration of the probe in the presence of Al3+ with 41 fold intensity enhancement at 545 nm. HL1 displays good linear relationship with Al3+ in the low concentration and the limit of detection is 8.08 * 10-8 mol/L. Similar molecules with different substituents on salicylaldehyde phenyl ring were synthesized for studying the structure-activity relationship. Density-functional theory (DFT) calculations are in agreement with the proposed mechanism. It is confirmed that HL1 could be used to detect Al3+ ions in real sample by fluorescence spectrometry and Al3+ ions in cells by bioimaging. PMID- 29414574 TI - Highly reproducible and sensitive silver nanorod array for the rapid detection of Allura Red in candy. AB - Allura Red (AR) is a highly stable synthetic red azo dye, which is widely used in the food industry to dye food and increase its attraction to consumers. However, the excessive consumption of AR can result in adverse health effects to humans. Therefore, a highly reproducible silver nanorod (AgNR) array was developed for surface enhanced Raman scattering (SERS) detection of AR in candy. The relative standard deviation (RSD) of AgNR substrate obtained from the same batch and different batches were 5.7% and 11.0%, respectively, demonstrating the high reproducibility. Using these highly reproducible AgNR arrays as the SERS substrates, AR was detected successfully, and its characteristic peaks were assigned by the density function theory (DFT) calculation. The limit of detection (LOD) of AR was determined to be 0.05 mg/L with a wide linear range of 0.8-100 mg/L. Furthermore, the AgNR SERS arrays can detect AR directly in different candy samples within 3 min without any complicated pretreatment. These results suggest the AgNR array can be used for rapid and qualitative SERS detection of AR, holding a great promise for expanding SERS application in food safety control field. PMID- 29414575 TI - A reagent-assisted method in SERS detection of methyl salicylate. AB - With the explosive application of methyl salicylate (MS) molecules in food and cosmetics, the further detection of MS molecules becomes particularly important. Here we investigated the detection of MS molecules based on surface-enhanced Raman scattering (SERS) in a novel molecule/assistant/metal system constructed with MS, 4,4'-(hexafluoroisopropylidene) bis (benzoic acid) and Ag nanoparticles (AgNPs). The minimum detection concentration is 10-4 M. To explore the function of assisted reagent, we also referred another system without assistant molecules. The result demonstrates that SERS signals were not acquired, which proves that the assistant molecules are critical for the capture of MS molecules. Two possible mechanisms of MS/assistant/AgNPs system were speculated through two patterns of hydrogen bonds. The linker molecules acted as the role of the bridge between metallic substrates and target molecules through the molecular recognition. This strategy is very beneficial to the expanding of MS detection techniques and other hydrogen bond based coupling detections with SERS. PMID- 29414576 TI - Theoretical studies on the possible sensitizers of DSSC: Nanocomposites of graphene quantum dot hybrid phthalocyanine/tetrabenzoporphyrin/tetrabenzotriazaporphyrins/cis tetrabenzodiazaporphyrins/tetrabenzomonoazaporphyrins and their Cu-metallated macrocycles. AB - The feasibility of nanocomposites of cir-coronene graphene quantum dot (GQD) with phthalocyanine, tetrabenzoporphyrin, tetrabenzotriazaporphyrins, cis tetrabenzodiazaporphyrins, tetrabenzomonoazaporphyrins and their Cu-metallated macrocycles as a sensitizer of dye-sensitized solar cells (DSSC) are investigated. Based on the first principles density functional theory (DFT), the geometrical structures of the separate GQD and 10 macrocycles, and their hybridized nanocomposites are fully optimized. The energy stabilities of the obtained structures are confirmed by harmonic frequency analysis. The optical absorptions of the optimized structures are calculated with time-dependent DFT. The feasibility of the nanocomposites as the sensitizer of DSSC is examined by the charge spatial separation, the electron transfer, the molecular orbital energy levels of the nanocomposites and the electrolyte, and the conduction band minimum of TiO2 electrode. The results demonstrate that all the nanocomposites have enhanced absorptions in the visible light range, and their molecular orbital energies satisfy the requirement of sensitizers. However, only two of the ten considered nanocomposites demonstrate significantly charge spatial separation. The GQD-Cu-TBP is identified as the most favorable candidate sensitizer of DSSC by the most enhanced in optical absorption, obvious charge spatial separation, suitable LUMO energy levels and driving force for electron transfer, and low recombination rate of electron and hole. PMID- 29414577 TI - Influence of Ar-ion implantation on the structural and mechanical properties of zirconia as studied by Raman spectroscopy and nanoindentation techniques. AB - In this study, structural and nanomechanical properties of zirconia polymorphs induced by ion irradiation were investigated by means of Raman spectroscopy and nanoindentation techniques. The zirconia layer have been produced by high temperature oxidation of pure zirconium at 600 degrees C for 5 h at normal atmospheric pressure. In order to distinguish between the internal and external parts of zirconia, the spherical metallographic sections have been prepared. The samples were irradiated at room temperature with 150 keV Ar+ ions at fluences ranging from 1 * 1015 to 1 * 1017 ions/cm2. The main objective of this study was to distinguish and confirm different structural and mechanical properties between the interface layer and fully developed scale in the internal/external part of the oxide. Conducted studies suggest that increasing ion fluence impacts Raman bands positions (especially characteristic for tetragonal phase) and increases the nanohardness and Young's modulus of individual phases. This phenomenon has been examined from the point of view of stress-induced hardening effect and classical monoclinic -> tetragonal (m -> t) martensitic phase transformation. PMID- 29414578 TI - Quantitative measurement of carbon isotopic composition in CO2 gas reservoir by Micro-Laser Raman spectroscopy. AB - The use of Micro-Laser Raman spectroscopy technology for quantitatively determining gas carbon isotope composition is presented. In this study, 12CO2 and 13CO2 were mixed with N2 at various molar fraction ratios to obtain Raman quantification factors (F12CO2 and F13CO2), which provide a theoretical basis for calculating the delta13C value. And the corresponding values were 0.523 (07 American Society of Anesthesiologists base units; and c) performed during a hospitalization with a Diagnosis Related Group with a mean length of stay >=4.0days. The number of procedures of each type of PCMTP commonly performed at each hospital was calculated by taking 1/Herfindahl index (i.e., sum of the squares of the proportions of all procedures of each type of PCMTP). MAIN RESULTS: Over the 8 successive years studied, there was no change in the number of PCMTP being performed (Kendall's taub=-0.014+/-0.017 [standard error], P=0.44; N=1479 hospital*years). Busier and larger hospitals commonly performed more types of PCMTP, respectively categorized based on performed PCMTP (tau=0.606+/-0.017, P<0.0001) or hospital beds (tau=0.524+/-0.017, P<0.0001). There was no association between greater diversity of types of PCMTP commonly performed and greater annual growth in numbers of PCMTP (tau=0.002+/-0.019, P=0.91; N=1295 hospital*years). Conclusions were the same with multiple sensitivity analyses. Post hoc, it was recognized that hospitals performing a greater diversity of PCMTP were more similar to the aggregate of other hospitals within the same health district (tau=0.550+/-0.017, P<0.0001). CONCLUSIONS: During a period with no overall growth in PCMTP, hospitals with greater diversities of types of PCMTP had growth that was, at most, minimally larger than that of the smaller hospitals, and vice-versa. Diversity is important operationally. From the perspective of delivering surgical care within a market, the unique contributions of each large teaching hospital performing many different types of PCMTP needs to be considered relative to the combined capabilities of other hospitals in its region. PMID- 29414624 TI - Differences in the incidence and timing of reintubation in the postanesthesia care unit among large teaching hospitals. PMID- 29414625 TI - Combination of video and manikin hybrid simulation for rapid response emergency airway management training in medical students. PMID- 29414626 TI - Ultrasound guided quadratus lumborum block for postoperative analgesia in pediatric ambulatory inguinal hernia repair. PMID- 29414627 TI - Infraclavicular versus axillary nerve catheters: A retrospective comparison of early catheter failure rate. AB - STUDY OBJECTIVES: Continuous brachial plexus catheters are often used to decrease pain following elbow surgery. This investigation aimed to assess the rate of early failure of infraclavicular (IC) and axillary (AX) nerve catheters following elbow surgery. DESIGN: Retrospective study. SETTING: Postoperative recovery unit and inpatient hospital floor. PATIENTS: 328 patients who received IC or AX nerve catheters and underwent elbow surgery were identified by retrospective query of our institution's database. MEASUREMENTS: Data collected included unplanned catheter dislodgement, catheter replacement rate, postoperative pain scores, and opioid administration on postoperative day 1. Catheter failure was defined as unplanned dislodging within 24 h of placement or requirement for catheter replacement and evaluated using a covariate adjusted model. MAIN RESULTS: 119 IC catheters and 209 AX catheters were evaluated. There were 8 (6.7%) failed IC catheters versus 13 (6.2%) failed AX catheters. After adjusting for age, BMI, and gender there was no difference in catheter failure rate between IC and AX nerve catheters (p = 0.449). CONCLUSIONS: These results suggest that IC and AX nerve catheters do not differ in the rate of early catheter failure, despite differences in anatomic location and catheter placement techniques. Both techniques provided effective postoperative analgesia with median pain scores < 3/10 for patients following elbow surgery. Reasons other than rate of early catheter failure should dictate which approach is performed. PMID- 29414628 TI - Transapical transcatheter aortic valve implantation performed with an erector spinae plane block. PMID- 29414629 TI - Trends of incidence, mortality, and survival of multiple myeloma in Switzerland between 1994 and 2013. AB - BACKGROUND: Treatment of multiple myeloma has changed considerably over the last two decades with remarkable reduction in mortality rates in clinical trials and in population-based studies. Since health care systems and patient management differ between countries, population-based data from cancer registries with high coverage may provide further insight into real-life achievements and unmet needs. We report on the first population-based nation-wide study of incidence, mortality and survival of multiple myeloma in Switzerland covering the era of autologous stem cell transplantation and the first proteasome inhibitors and immunomodulatory drugs. METHODS: We performed a retrospective registry study with data from the National Institute for Cancer Epidemiology and Registration (NICER) database in Switzerland from 1994 to 2013. RESULTS: We identified 5770 patients with multiple myeloma. Incidence has increased from 419 new cases per year in 1994-1998 to 557 new cases per year in 2009-2013 while the age-adjusted incidence rate remained stable at 4.7-5.0 per 100'000 person-years. Five- and 10-year relative survival increased from 32.6% (95%CI 29.3-36.0) and 17.8% (95%CI 14.9 21.0) in 1994-1998 to 46.4% (95%CI 43.3-49.3) and 25.0% (95%CI 21.9-28.3) in 2009 2013. CONCLUSION: The increase in incidence can be attributed to demographic changes. There is a trend to longer relative survival in all age groups with substantial increase in myeloma patients aged less than 75 years and only minimal changes in older persons. PMID- 29414630 TI - Development and validation of a prognostic index for survival in non-small cell lung cancer: Results from a Tunisian cohort study. AB - INTRODUCTION: Despite the continuous efforts made with the TNM system, the issue of heterogeneity of prognosis within the stages of non-small cell lung cancer (NSCLC) could not be resolved. Our aim was to identify prognostic factors and develop an index to predict NSCLC survival with greater accuracy. METHODS: We conducted a survival study over 5 years on patients with NSCLC. Kaplan-Meier analysis followed by Cox regression modelling were used. Prognostic indices were derived, using either an additive or a multiplicative pattern, and were compared by their receiver operating characteristics (ROC) curves. We then proceeded to a risk stratification and validation of the index on the derivation cohort. RESULTS: Two hundred and sixty-two NSCLC patients were included. Two models were constructed, using the following nine variables as prognostic factors: age, performance status, haemoglobin level, leucocyte count, calcium, lactate dehydrogenase, alkaline phosphatase levels, histological type and TNM stage. Four prognostic indices were derived, and the best one was picked and validated on a population of five risk groups. The higher the risk group, the shorter the survival. CONCLUSIONS: This novel and simple prognostic tool could predict survival more accurately in patients with NSCLC. PMID- 29414632 TI - Socio-economic patterning in early mortality of patients aged 0-49 years diagnosed with primary bone cancer in Great Britain, 1985-2008. AB - BACKGROUND: Studies have shown marked improvements in survival between 1981 and 2000 for Ewing sarcoma patients but not for osteosarcoma. This study aimed to explore socio-economic patterning in early mortality rates for both tumours. PROCEDURE: The study analysed all 2432 osteosarcoma and 1619 Ewing sarcoma cases, aged 0-49 years, diagnosed in Great Britain 1985-2008 and followed to 31/12/2009. Logistic regression models were used to calculate risk of dying within three months, six months, one year, three years and five years after diagnosis. Associations with Townsend deprivation score and its components were examined at small-area level. Urban/rural status was studied at larger regional level. RESULTS: For osteosarcoma, after age adjustment, mortality at three months, six months and one year was associated with higher area unemployment, OR = 1.05 (95% CI 1.00, 1.10), OR = 1.04 (95% CI 1.01, 1.08) and OR = 1.04 (95% CI 1.02, 1.06) respectively per 1% increase in unemployment. Mortality at six months was associated with greater household non-car ownership, OR = 1.02 (95% CI 1.00, 1.03). For Ewing sarcoma, there were no significant associations between mortality and overall Townsend score, nor its components for any time period. For both tumours increasing mortality was associated with less urban and more remote rural areas. CONCLUSIONS: This study found that for osteosarcoma, early mortality was associated with residence at diagnosis in areas of higher unemployment, suggesting risk of early death may be socio-economically determined. For both tumours, distance from urban centres may lead to greater risk of early death. PMID- 29414631 TI - Esophageal cancer male to female incidence ratios in Africa: A systematic review and meta-analysis of geographic, time and age trends. AB - Esophageal squamous cell carcinoma (ESCC) remains the predominant histological subtype of esophageal cancer (EC) in many transitioning countries, with an enigmatic and geographically distinct etiology, and consistently elevated incidence rates in many Eastern and Southern African countries. To gain epidemiological insights into ESCC patterns across the continent, we conducted a systematic review and meta-analysis of male-to-female (M:F) sex ratios of EC age standardised (world) incidence rates in Africa according to geography, time and age at diagnosis. Data from 197 populations in 36 countries were included in the analysis, based on data from cancer registries included in IARC's Cancer Incidence in Five Continents, Cancer in Africa and Cancer in Sub-Saharan Africa reports, alongside a systematic search of peer-reviewed literature. A consistent male excess in incidence rates overall (1.7; 95% CI: 1.4, 2.0), and in the high risk Eastern (1.6; 95% CI: 1.4, 1.8) and Southern (1.8; 95% CI: 1.5, 2.0) African regions was observed. Within the latter two regions, there was a male excess evident in 30-39 year olds that was not observed in low-risk regions. Despite possible referral biases affecting the interpretability of the M:F ratios in place and time, the high degree of heterogeneity in ESCC incidence implies a large fraction of the disease is preventable, and directs research enquiries to elucidate early-age exposures among young men in Africa. PMID- 29414633 TI - The impact of rectal cancer tumor height on recurrence rates and metastatic location: A competing risk analysis of a national database. AB - BACKGROUND: The impact of rectal cancer tumor height on local recurrence and metastatic spread is unknown. The objective was to evaluate the impact of rectal cancer tumor height from the anal verge on metastatic spread and local recurrence patterns. METHODS: The Norwegian nationwide surgical quality registry was reviewed for curative rectal cancer resections from 1/1/1996-12/15/2006. Cancers were stratified into five height groups: 0-3 cm, >3-5 cm, >5-9 cm, >9-12 cm, 12 cm-HI. Competing risk and proportional hazards models assessed the relationship between tumor height and patterns of metastasis and survival. RESULTS: 6859 patients were analyzed. After median follow-up of 52 months (IQR 20-96), 26.7% (n = 1835) experienced recurrence. With tumors >12 cm, the risk of liver metastases increased (crude HR 1.49, p = 0.03), while lung metastases decreased (crude HR 0.66, p = 0.03), and risk of death decreased (crude HR 0.81, p = 0.001) The cumulative incidence of pelvic recurrence were highest for the low tumors (p = 0.01). Median time to liver metastases was 14months (IQR 7-24), lung metastases 25months (IQR 13-39), pelvic recurrence 19months (IQR10-32), (p < 0.0001). Time to metastases in liver and lungs were significantly associated with tumor height (p < 0.001) CONCLUSION: There are distinct differences in metastatic recurrence patterns and time to recurrence from different anatomic areas of the rectum. In crude analyses, tumor height impacted metastatic spread to the liver and lungs. However, when adjusting for treatment variables, the hazard of metastatic spread to the liver and lungs are limited. Nevertheless, time to metastases in liver and lungs is significantly impacted by tumor height. Venous drainage of the rectal cancer may be a significant contributor of rectal cancer metastatic spread, but further research is warranted. PMID- 29414634 TI - Anaplastic thyroid carcinoma in Denmark 1996-2012: A national prospective study of 219 patients. AB - BACKGROUND: Anaplastic thyroid carcinoma (ATC) is the least common but most malignant thyroid cancer. We aimed to examine the characteristics as well as evaluate the incidence, prognostic factors, and if introduction of a fast track cancer program might influence survival in a cohort of ATC patients. METHODS: A cohort study based on prospective data from the national Danish thyroid cancer database DATHYRCA and the national Danish Pathology Register including 219 patients diagnosed from 1996 to 2012, whom were followed until death or through September 2014. RESULTS: We found the median age in the 7th decade, the majority of patients being women presenting with a growing mass at the neck, diagnosed with stage T4b disease. At diagnosis, 56% of the patients had lymph node metastasis and 38% distant metastasis. We observed one- and five-year survival of 20.7% and 11.0%, respectively. Both univariate and multivariate analyses showed age (above 73.6 years), respiratory impairment, T4b stage, and distant metastasis at diagnosis to be significant prognostic factors. Further, introduction of a national fast track cancer program increased survival nearly two-fold. CONCLUSION: As new information, our study adds "respiratory impairment at diagnosis" and "introduction of a national fast track cancer program" to the list of already established prognostic indicators for ATC. PMID- 29414635 TI - A new approach to estimate time-to-cure from cancer registries data. AB - BACKGROUND: Cure models have been adapted to net survival context to provide important indicators from population-based cancer data, such as the cure fraction and the time-to-cure. However existing methods for computing time-to-cure suffer from some limitations. METHODS: Cure models in net survival framework were briefly overviewed and a new definition of time-to-cure was introduced as the time TTC at which P(t), the estimated covariate-specific probability of being cured at a given time t after diagnosis, reaches 0.95. We applied flexible parametric cure models to data of four cancer sites provided by the French network of cancer registries (FRANCIM). Then estimates of the time-to-cure by TTC and by two existing methods were derived and compared. Cure fractions and probabilities P(t) were also computed. RESULTS: Depending on the age group, TTC ranged from to 8 to 10 years for colorectal and pancreatic cancer and was nearly 12 years for breast cancer. In thyroid cancer patients under 55 years at diagnosis, TTC was strikingly 0: the probability of being cured was >0.95 just after diagnosis. This is an interesting result regarding the health insurance premiums of these patients. The estimated values of time-to-cure from the three approaches were close for colorectal cancer only. CONCLUSIONS: We propose a new approach, based on estimated covariate-specific probability of being cured, to estimate time-to-cure. Compared to two existing methods, the new approach seems to be more intuitive and natural and less sensitive to the survival time distribution. PMID- 29414636 TI - Population risk factors for late-stage presentation of cervical cancer in sub Saharan Africa. AB - BACKGROUND: Cervical cancer is the most prevalent malignancy in sub-Saharan Africa (SSA) with many women only seeking professional help when they are experiencing symptoms, implying late-stage malignancy and higher mortality rates. This ecological study assesses population-level exposures of SSA women to the numerous risk factors for HPV infection and cervical cancer, against late-stage presentation of cervical cancer. MATERIALS AND METHOD: A literature review revealed the relevant risk factors in SSA. Open-access databases were mined for variables closely representing each risk factor. A proxy for late-stage presentation was used (ratio of incidence-to-mortality, IMR), and gathered from IARC's GLOBOCAN 2012 database. Variables showing significant correlation to the IMR were used in stepwise multiple regression to quantify their effect on the IMR. RESULTS: Countries with high cervical cancer mortality rates relative to their incidence have an IMR nearer one, suggesting a larger proportion of late stage presentation. Western Africa had the lowest median IMR (1.463), followed by Eastern Africa (IMR = 1.595) and Central Africa (IMR = 1.675), whereas Southern Africa had the highest median IMR (1.761). Variables selected for the final model explain 65.2% of changes seen in the IMR. Significant predictors of IMR were GDP (coefficient = 2.189 * 10-6, p = 0.064), HIV infection (-1.936 * 10-3, p = 0.095), not using a condom (-1.347 * 10-3, p = 0.013), high parity (-1.744 * 10 2, p = 0.008), and no formal education (-1.311 * 10-3, p < 0.001). CONCLUSION: Using an IMR enables identification of factors predicting late-stage cervical cancer in SSA including: GDP, HIV infection, not using a condom, high parity and no formal education. PMID- 29414637 TI - First data from a population based cancer registry in Ethiopia. AB - BACKGROUND: The Addis Ababa City Cancer Registry, established in September 2011, is the only population-based cancer registry in Ethiopia, covering a catchment population of just over three million habitants. Herein, we report incidence data based on the first two years of registration, 2012-2013. METHODS: Newly-diagnosed cancer cases in the capital city were actively collected from 22 hospitals, clinics, and diagnostic facilities. RESULTS: During 2012-2013, a total of 4139 newly diagnosed cases were recorded, with the majority (67%) occurring in females. Cancers of the breast (31.5%) and cervix (14.1%) were the two most common cancers among females, while colorectal cancers (10.6%) and non-Hodgkin lymphomas (10.2%) were the most common cancers among males. The average annual age-standardized rate for all sites 2012-13 were 136.2 (per 100,000) and 70.7 in females and males, respectively. Female age-standardized rates were 40.6 for breast cancer and 21.5 for cervix, while equivalent rates in males were 7.6 per 100,000 for colorectal cancer and 6.8 per 100,000 for non-Hodgkin lymphoma. CONCLUSION: In general, these incidence patterns were similar to those reported in neighboring countries, which suggests that the majority of cancer cases occurring in Addis Ababa are captured within this starting phase of the registry. However, our finding of colorectal cancer as the most commonly-diagnosed cancer in males is novel and requires further investigation. PMID- 29414638 TI - Obesity surgery and risk of colorectal and other obesity-related cancers: An English population-based cohort study. AB - BACKGROUND: The association between obesity surgery (OS) and cancer risk remains unclear. We investigated this association across the English National Health Service. A population-based Swedish study has previously suggested that OS may increase the risk of developing colorectal cancer (CRC). METHODS: A retrospective observational study of individuals who underwent OS (surgery cohort) or diagnosed with obesity, but had no OS (no-surgery cohort) (1997-2013) were identified using Hospital Episode Statistics. Subsequent diagnosis of CRC, breast, endometrial, kidney and lung cancer, as well as time 'at risk', were determined by linkage to National Cancer Registration & Analysis Service and Office of National Statistics data, respectively. Standardised incidence ratios (SIR) in relation to OS were calculated. RESULTS: 1 002 607 obese patients were identified, of whom 3.9% (n = 39 747) underwent OS. In the no-surgery obese population, 3 237 developed CRC (SIR 1.12 [95% CI 1.08-1.16]). In those who underwent OS, 43 developed CRC (SIR 1.26 [95% CI 0.92-1.71]). The OS cohort demonstrated decreased breast cancer risk (SIR 0.76 [95% CI 0.62-0.92]), unlike the no surgery cohort (SIR 1.08 [95% CI 1.04-1.11]). Increased risk of endometrial and kidney cancer was observed in surgery and no-surgery cohorts. CONCLUSIONS: CRC risk is increased in individuals diagnosed as obese. Prior obesity surgery was not associated with an increased CRC risk. However, the OS population was small, with limited follow-up. Risk of breast cancer after OS is reduced compared with the obese no-surgery population, while the risk of endometrial and kidney cancers remained elevated after OS. PMID- 29414639 TI - Oxyresveratrol prevents lipopolysaccharide/d-galactosamine-induced acute liver injury in mice. AB - Oxyresveratrol (Oxy) is a natural polyhydroxystilbene abundant in mulberry that has anti-inflammation and anti-oxidant activities. We evaluated the protective effect of Oxy in the context of the lipopolysaccharide and d-galactosamine (LPS/d GalN) induced acute liver injury. Oxy restricted the development of histopathological changes, markedly reduced the activity of alanine transaminase (ALT) and aspartate transaminase (AST), which are indicators of impaired liver function. Oxy significantly regulated the contents of oxidative stress related enzymes and products, and inhibited expressions of inflammatory mediators and cytokines. Oxy treatment diminished the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-kappaB) signaling pathway in liver, activated the Kelch-like ECH associated protein 1(Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, and increased expressions of heme oxygenase 1 (HO-1) and quinine oxidoreductase 1(NQO1). Pretreatment with Oxy decreased LPS/d-GalN stimulated hepatocyte apoptosis by efficaciously raising the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X (Bax) ratio, inhibiting the expression and activation of caspases, and activating the phosphoinoside-3-kinase (PI3K)-Akt pathway. Our results demonstrate the hepatoprotective efficacy of Oxy. The protection is mainly due to the prevention of TLR4/NF-kappaB pathway activation, induced activation of Keap1 Nrf2 signaling pathway, and decreased hepatocyte apoptosis. Oxy warrants further study as a potential therapeutic agent candidate for the management of acute liver injury. PMID- 29414640 TI - Malondialdehyde-acetaldehyde antibody concentrations in rheumatoid arthritis and other rheumatic conditions. AB - OBJECTIVE: To compare anti-malondialdehyde-acetaldehyde (MAA) antibody concentrations between rheumatoid arthritis (RA) patients and healthy and rheumatic disease controls. METHODS: Anti-MAA antibody (IgA, IgM, IgG) was measured using ELISA and banked serum from patients with RA (n = 284), osteoarthritis (OA, n = 330), spondyloarthropathy (SpA, n = 50), and systemic lupus erythematosus (SLE, n = 88) as well as healthy controls (n = 82). Anti-MAA antibody concentrations and the frequency of positivity were compared across groups. Multivariable linear regression analysis limited to RA and OA patients (due to sample size and data availability) was used to identify factors associated with anti-MAA antibody concentrations. RESULTS: Although RA patients demonstrated among the highest circulating concentrations across isotypes, only IgA anti-MAA antibody was significantly higher than all other groups (p <= 0.02). Proportions (7% to 74%) of OA and SLE (less so for SpA) samples were positive for anti-MAA antibody, limiting the discriminatory capacity of anti-MAA antibody in RA (positive in 18% to 80%). In analyses limited to those with RA or OA, factors associated with higher anti-MAA antibody concentrations included RA case status, younger age (IgM), male sex (IgG), African American race (IgA, IgG) and current smoking (IgA). C-reactive protein levels and comorbidities were not associated with anti-MAA antibody concentrations. CONCLUSION: With the possible exception of the IgA isotype, serum anti-MAA antibodies measured with currently available assays do not appear to adequately discriminate RA from other rheumatic conditions. With the identification of specific proteins that are MAA-modified in diseased tissues and requisite assay refinement, anti-MAA antibody holds potential promise as a biomarker in RA. PMID- 29414641 TI - Lactobacillus plantarum AN1 cells increase caecal L. reuteri in an ICR mouse model of dextran sodium sulphate-induced inflammatory bowel disease. AB - To clarify the different effects of live and heat-killed probiotics on inflammatory bowel disease (IBD), the anti-inflammatory and protective effects of Lactobacillus plantarum AN1 cells isolated from the fermented fish aji-narezushi on murine macrophage RAW264.7 cells and in ICR mice with dextran sodium sulphate (DSS)-induced IBD were determined. L. plantarum AN1 cells showed anti inflammatory activities in vitro, indicated by secretion of nitric oxide (NO) from RAW264.7 cells in the presence and absence of Escherichia coli 0111 lipopolysaccharide (LPS). L. plantarum AN1 cells also protected RAW264.7 cells against hydrogen peroxide toxicity. There was no difference between these effects in heat-killed and ultraviolet irradiation-killed cells. In the murine IBD model, both live and heat-killed L. plantarum AN1 cells via drinking water tended to ameliorate atrophy of colon length, mucosal tissue damage, and spleen enlargement. Amplicon sequencing of 16S rDNA (V4) revealed that both live and heat-killed AN1 cells increased abundance of indigenous lactic acid bacteria, particularly Lactobacillus reuteri. The results suggest that increased indigenous lactic acid bacterial abundance and feeding with L. plantarum AN1 cells synergistically improve effects against IBD. PMID- 29414642 TI - Expression of B7-H2 on CD8+ T cells in colorectal cancer microenvironment and its clinical significance. AB - The knowledge about B7-H2 expression in tumor is growing, but many questions remain unresolved. Especially in human tumor microenvironment, little studies were done. To explore the expression and clinical significance of B7-H2 on T cells in colorectal cancer microenvironment, fresh tumor tissues and paired non tumor tissues collected from 25 patients with colorectal cancer were made to research B7-H2 expression on the infiltrating T cells including CD8+ T cells and CD4+ T cells. Also, tumor bearing mice were sacrificed on day 5, day 10, day 15, day 20, day 25 and flow cytometry was used to analyze B7-H2 expression on CD8+ T cells and CD4+ T cells in mouse tumors and spleens. Then, it was found that B7-H2 expression on CD8+ T cells in patients' tumor tissues was significantly higher than in non-tumor tissues. The expression of B7-H2 on CD8+ T cells in tumor microenvironment was significantly higher in patients with age <=60 years old and the stage I-II. The expression level of B7-H2 on CD8+ T cells in mouse tumors and spleens both reached the highest level at the early stage of inoculation (on day 5), decreased to the lowest level on day 10 and day 15 separately, and then gradually increased. In mouse spleens, B7-H2 expression on CD8+ T cells was all significantly higher than on CD4+ T cells in five time periods. So, in this study, it was found that B7-H2 expression on CD8+ T cells in tumor microenvironment was closely related to the progression of colorectal cancer. PMID- 29414643 TI - Effect of peiminine on DNCB-induced atopic dermatitis by inhibiting inflammatory cytokine expression in vivo and in vitro. AB - Peiminine (PMN) is the main component derived from Fritillaria ussuriensis and is used in traditional medicine in East Asia. The aim of this study was to evaluate the effects of PMN on atopic dermatitis (AD) induced by a dinitrochlorobenzene (DNCB) in Balb/c mice. Inflammatory cytokine expression of PMN was investigated in vitro. Eosinophil infiltration and the thickness of DNCB-induced AD mouse skin were measured. The levels of IgE, IL-4, IL-6, IL-13, and TNF-alpha in the serum were measured by ELISA. The effects of PMN on the transcription level of MAPK and nuclear factor (NF)-kappaB were evaluated in mouse skin. In addition, the inhibitory effect of TNF-alpha, IL-1beta, COX-2 and PGE2 were measured in RAW264.7 cells; TARC was investigated in HaCaT cells; and beta-hexosaminidase was examined in RBL-2H3 cells. PMN decreased the number of eosinophils in the dermis as well as mast cells and decreased the thickness of the epidermis and dermis. The PMN High group had a significantly reduced serum level of IgE, IL-4, IL-13 and TNF-alpha. Moreover, P-ERK and P-P38 were inhibited in the PMN High group compared with the DNCB-treated group. PMN additionally attenuated the expression of inflammatory cytokines in cells, including RAW264.7, HaCaT and RBL-2H3 cells. Our results suggest that PMN could be a potential therapeutic candidate for the treatment of AD. PMID- 29414644 TI - Platelet-to-lymphocyte ratio in peripheral blood: A novel independent prognostic factor in patients with melanoma. AB - OBJECTIVES: This retrospective study aimed to investigate the prognostic value of pre-treatment platelet-to-lymphocyte ratio (PLR), which is an inflammatory indicator, in patients with melanoma. METHODS: Patients in this retrospective analysis were admitted between January 1, 2010 and December 31, 2015 in Henan Cancer Hospital. Receiver operating characteristic (ROC) curve was performed the optimal cut-off value for PLR. The 140 patients were divided into two groups: high PLR group and low PLR group. The relationship between PLR and overall survival (OS) was analyzed. The Kaplan-Meier and Log rank tests were used for univariate survival analysis and Cox proportional hazards regression model for multivariate analysis. RESULTS: The optimal cut-off value of PLR determined by ROC curve was 120.15. Univariate and Cox multivariate survival analysis all showed that PLR and clinical stage were factors affecting OS in melanoma patients (P < 0.05). The overall median OS was 21.0 months (95% confidence interval (CI): 18.1-23.9), for 17.0 months in the high PLR group, and 34.0 months in the low PLR group (hazard ratio: 0.436, 95% CI: 0.291-0.652, P < 0.001), respectively. Clinical subgroup analysis showed that PLR was a risk factor in patients with stage II, III, and IV disease (P < 0.05). CONCLUSION: The elevated PLR was an independent prognostic predictor for OS in patients with melanoma. PMID- 29414645 TI - Activation of autophagy is required for Oroxylin A to alleviate carbon tetrachloride-induced liver fibrosis and hepatic stellate cell activation. AB - Liver fibrosis is a reversible pathophysiological process correlated with intense repair and cicatrization mechanisms, and its end-stage cirrhosis is responsible for high morbidity and mortality worldwide. Interestingly, the use of natural products as a realistic option for the treatment of liver fibrosis has broadly been accepted. Oroxylin A, a safe and natural product, shows a wide range of pharmacological activities such as anti-inflammatory, anti-oxidant, and anti tumor properties. However, the effects of Oroxylin A on liver fibrosis remain poorly understood. In the present study, we sought to determine the effect of Oroxylin A on carbon tetrachloride (CCl4)-induced liver fibrosis, and to further examine the molecular mechanisms. We found that treatment with Oroxylin A markedly decreased the level of liver injury markers, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), in a dose dependent manner. Moreover, Oroxylin A treatment remarkably inhibited extracellular matrix (ECM) deposition, and significantly down-regulated the mRNA and protein expression of liver fibrosis markers including alpha1(I)collagen, fibronectin, alpha-smooth muscle actin (alpha-SMA), PDGF-betaR, and TGF-betaR1 in CCl4-induced murine model of liver fibrosis. Furthermore, experimental results in vitro showed that Oroxylin A treatment reduced the mRNA and protein expression of HSC activation markers, alpha-SMA, desmin, alpha1 (I) collagen, fibronectin, TGF beta, and TNF-alpha, in a dose dependent manner. Attractively, Oroxylin A treatment also markedly up-regulated the expression of autophagy makers, LC3-B, Atg3, Atg4, Atg5, Beclin1/Atg6, Atg7, Atg9, ATG12, and Atg14, and apparently reduced the expression of autophagy substrate p62 in both CCl4-induced murine model of liver fibrosis and PDGF-BB-treated HSCs. Importantly, inhibition of autophagy by specific inhibitor 3-methyladenine (3-MA) completely abolished Oroxylin A-induced anti-fibrosis effect, indicating that activation of autophagy was required for Oroxylin A to alleviate liver fibrosis. Overall, these results provide novel implications to reveal the molecular mechanism of Oroxylin A induced anti-fibrosis properties, by which points to the possibility of using Oroxylin A for the treatment of liver fibrosis. PMID- 29414646 TI - Morin hydrate ameliorates cisplatin-induced ER stress, inflammation and autophagy in HEK-293 cells and mice kidney via PARP-1 regulation. AB - The present study assessed the possible therapeutic potential of a natural flavonoid morin hydrate (MH), against cisplatin (CP) induced toxicity in HEK-293 cells and mice kidney. Herein, we observed that exposure of HEK-293 cells to CP (20 MUM, 24 h) reduced the cell viability, and increased the intracellular ROS generation, nuclear DNA damage, Ca++ release, and accumulation of acidic vacuoles. Concomitantly, acute exposure of CP (30 mg/kg, 72 h) to male ICR mice induced histopathological changes in kidney tissue, and alterations in serum creatinine and blood urea nitrogen (BUN) levels. Oxidative stress mediated ER stress was evidenced by the reduced expression of antioxidant enzymes such as SOD 1, SOD-2, GR, and Trx, and increased expression levels of CytP450, IRE1-alpha, PERK, and CHOP. The expression levels of major inflammatory response markers such as NF-kappaB, TNF-alpha, IL-1beta, COX-2 and iNOS were significantly increased in the HEK-293 cells and mice kidney. Temporal up-regulation of p-AMPK and LC3I/II, and down regulation of mTOR was also noticed after CP treatment. CP-induced DNA damage led to activation of PARP-1, which plays a crucial role in inflammation, apoptosis and autophagy activation. Concurrently, co-treatment of CP-MH and CP ANI (PARP-1 inhibitor) significantly attenuated the expression level of PARP-1, reduced cellular death, alleviated inflammatory responses, and inhibited autophagy stimulation in HEK-293 cells and mice kidney. On the basis of above findings, we suggest MH as a potential therapeutic agent against CP-induced nephrotoxicity. PMID- 29414647 TI - Methamphetamine modulates the production of interleukin-6 and tumor necrosis factor-alpha via the cAMP/PKA/CREB signaling pathway in lipopolysaccharide activated microglia. AB - Methamphetamine (METH) elicits neuroinflammatory effects that may implicate its regulatory role on the microglial immune response. However, the mechanism underlying this remains unclear. In the present study, the effects of METH on lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) productions were tested in BV-2 cells and primary microglial cells. Additionally, western blot analysis was used to examine the phosphorylation of mitogenactivated protein kinases (MAPKs). Next, we detected the alterations in cAMP content and the phosphorylation levels of CREB in microglial cells to determine the involvement of the cAMP/CREB signaling pathway. We also used an adenylyl cyclase (AC) agonist (forskolin) and antagonist (MDL 12330A) and a PKA antagonist (H89) to confirm their participation. We observed that METH alone did not affect the production of IL-6 or TNF-alpha. In contrast, METH augmented the IL-6 production and inhibited the TNF-alpha production induced by LPS. A similar effect of forskolin was also observed in BV-2 cells. While MAPK activation was not influenced by METH alone, the LPS-induced phosphorylation of p38, JNK and ERK1/2 were all reduced by METH. Both the concentration of cAMP and the phosphorylation of CREB were increased by METH in LPS-activated microglial cells. The effects of METH were altered by MDL-12330A and H89. Moreover, the inhibition of the phosphorylation of ERK1/2 by METH was also reversed. These results suggest that the differential regulation of IL-6 and TNF-alpha by METH in LPS-activated microglial cells may be attributable to the cAMP/PKA/CREB signaling pathway. PMID- 29414648 TI - Oleamide suppresses inflammatory responses in LPS-induced RAW264.7 murine macrophages and alleviates paw edema in a carrageenan-induced inflammatory rat model. AB - Oleamide compounds purified from green algae have been used for the prevention and treatment of atherosclerosis, thrombosis, arthritis, and cancer. They function through their metabolic conversion into prostaglandins, thromboxanes, and leukotrienes. However, the actual mechanism of action has not been well characterized. To investigate the underlying anti-inflammatory activity and associated mechanisms, oleamide purified from Codium fragile was studied using RAW264.7 murine macrophages and a carrageenan-induced inflammatory rat model. Our results indicate that pre-treatment of RAW264.7 cells with oleamide significantly suppressed LPS-induced nitrite production and PGE2 secretion. Oleamide inhibited LPS-induced iNOS and COX-2 mRNA and protein expression. It also inhibited the LPS induced production of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6. In addition, oleamide prevented the nuclear translocation of NF-kappaB by suppressing the phosphorylation of the inhibitor of kappa B (IkappaB)-alpha. Oleamide also suppressed the phosphorylation of mitogen-activated protein kinases such as ERK1/2 and JNK. Furthermore, inhibition of paw swelling (%) was suppressed 2 h after the intraperitoneal injection of oleamide (20 mg/kg, body weight) in a carrageen induced rat model. Therefore, our results suggest that oleamide can be used as a single ingredient treatment for inflammatory diseases. PMID- 29414649 TI - Passive immunization against methicillin resistant Staphylococcus aureus recombinant PBP2a in sepsis model of mice: Comparable results with antibiotic therapy. AB - Methicillin resistant Staphylococcus aureus (MRSA) is a representative pathogen that is responsible for a nosocomial infection and considerable yearly mortality rate. Antibiotic resistance provides a great reason for immunotherapy as an alternative strategy to prevent and/or treat the infection. Herein, following the preparation of recombinant penicillin binding protein 2a (r-PBP2a), rabbit polyclonal IgG was purified. Specificity of IgG to r-PBP2a was evaluated by ELISA and western blotting. IgG fraction was prepared by sulfate ammonium precipitation. In addition opsonophagocytosis assay confirmed bioactivity of purified IgG. Experimental mice were challenged with lethal dose of MRSA (5 * 108) and mortality rate was recorded in the mice treated with IgG fraction for anti-rPBP2a, normal rabbit IgG, vancomycin therapy, and PBS control group. Bacterial quantity was evaluated by culture of liver, kidney and spleen homogenates. Results showed that passive immunization with anti r-PBP2a resulting in a significant improvement in survival rate as well as vancomycin treatment compared with control groups. Furthermore, anti r-PBP2a IgG enhanced considerably the phagocytosis of the S. aureus COL strain, reduced bacterial load, and inhibited the systemic spread of COL strain to the internal organs. These results confirmed that passive immunization by anti-r-PBP2a plays a considerable role in the control of infections caused by S. aureus similar to that of antibiotic therapy. PMID- 29414650 TI - Role of Malt1 protease activity in pathogenesis of inflammatory disorders mediated by FcgammaR signaling. AB - MALT lymphoma-translocation protein 1 (Malt1) protease activity is triggered by stimulation of various immune receptors. Activation of Malt1 protease induces cleavage of negative regulators for immune responses, resulting in lymphocytes activation. Although Malt1 protease mediates the signaling process downstream of the T cell, B cell, and dectin receptors, its contribution in Fcgamma receptor (FcgammaR) signaling has not been elucidated. In this study, we investigated the role of Malt1 protease activity in FcgammaR signaling using Malt1 protease deficient (PD) mouse. In addition, role of Malt1 protease for the development of FcgammaR-mediated autoimmune disease was also investigated in vivo. Malt1 protease cleaves their substrates, such as RelB and cylindromatosis (CYLD). However, the Malt1 proteolytic activity was silenced in the Malt1 PD mice. Production of inflammatory cytokines via FcgammaR stimulation was decreased on dendritic cells prepared from Malt1 PD mice. In FcgammaR-dependent murine immune thrombocytopenia (ITP) model, gene expressions of the inflammatory cytokines in the spleen of Malt1 PD mice were lower than those of WT mice. Then, Malt1 PD mice protected the development of thrombocytopenia. These results clearly figured out that Malt1 protease activity plays an important role in the activation of innate immune cells via FcgammaR, and the development of FcgammaR-mediated autoimmune diseases. Therefore, Malt1 is an attractive target for the treatment of inflammatory diseases mediated by FcgammaR. PMID- 29414651 TI - High-fat-diet induces airway hyperresponsiveness partly through activating CD38 signaling pathway. AB - CD38 is a plasma membrane bound multifunctional enzyme. It can be activated by inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-13, inducing calcium responses to agonist in airway smooth muscle cells (ASMC). Previous studies have found that high-fat-diet (HFD) induced obesity exhibited innate airway hyperresponsiveness (AHR). This study aimed to detect the effect of CD38 signaling pathway on the AHR of overweight/obese mice. The HFD-fed mice exhibited a significantly higher baseline airway resistance (Rn), and the increasing rates of Rn responded to increasing doses of methacholine compared with the LFD-fed mice. High-fat-diet increased CD38 expressions both in lung tissues and primary cultured ASMCs. Besides, preincubation with TNF-alpha led to a higher expression of CD38 protein and increased intracellular calcium in ASMC of the HFD-fed mice. Furthermore, CD38 gene knockdown through transfection of CD38 siRNA decreased the concentration of intracellular calcium. Additionally, the upregulations of CD38 protein and CD38 mRNA were also found in the lung tissues of HFD-fed mice challenged by ovalbumin (OVA). Collectively, our findings demonstrated a role of CD38 signaling pathway on the AHR of obesity and might be a potential therapeutic target for treating difficult-to-control obese asthma phenotype. PMID- 29414652 TI - Administration of Lactococcus lactis strain Plasma induces maturation of plasmacytoid dendritic cells and protection from rotavirus infection in suckling mice. AB - Lactococcus lactis subsp. lactis JCM 5805 (LC-Plasma) is a strain of lactic acid bacteria (LAB) that activates murine and human plasmacytoid dendritic cells (pDCs) to express interferons (IFNs). Oral administration of LC-Plasma drastically decreased fatality levels caused by parainfluenza virus infection in a murine model. In this study, we investigated the anti-viral effects of oral administration of LC-Plasma using a suckling mouse model of rhesus rotavirus (RV) infection. LC-Plasma-fed mice showed improvement in retardation of body weight gain, fecal scores, and a reduction in RV titer in the feces when compared to control mice. The mechanism of anti-viral effects elicited by LC-Plasma administration was investigated using naive mice: in the LC-Plasma -fed mice, lamina propria (LP) pDCs resident in the small intestine were significantly matured and the proportion of pDCs was increased. The expression levels of anti viral factors induced by IFNs, such as Isg15, Mx1, Oasl2 and Viperin, and an anti bacterial factor Reg3gamma, were up-regulated in the small intestinal epithelial cells (IECs) of LC-Plasma-fed mice. The specific LAB strain may affect the anti viral immunological profile of IECs via maturation of LP pDCs, leading to protection from RV virus infection in vivo. PMID- 29414653 TI - mRNA chip-based analysis on transcription factor regulatory network central nodes of protection targets of Deproteinized Extract of Calf Blood on acute liver injury in mice. AB - Our previous study found that Deproteinized Extract of Calf Blood (DECB) could protect the acute liver injury induced by carbon tetrachloride in mice, but the target-related transcription factors and their regulatory networks were not comprehensively studied. Based on the mRNA expression microarray data obtained in the previous study, the mRNA transcription factor regulatory networks were constructed by screening the transcription factors of differentially expressed genes and their corresponding target proteins, and the analysis on the functions and pathways of the regulatory network central nodes was performed. Eight genes Ltf, Tnf, Il6, Jun, Il12b, Stat3, Rel and Crem could regulate the inflammatory factors, and TNF signaling pathway and Jak-STAT signaling pathway might play an important role in the mechanism through which DECB protected the liver of mice. DECB can not only inhibit the apoptosis of hepatocytes, but also inhibit the inflammatory cytokines. PMID- 29414654 TI - Interleukin-8 favors pro-inflammatory activity of human monocytes/macrophages. AB - Interleukin-8 (IL-8, CXCL8) belongs to major chemokines to stimulate migration of neutrophils and monocytes/macrophages (Mc/Mphs) into the inflammation sites. We studied the direct effects of IL-8 on the functionality of human Mc/Mphs in vitro. CD14-positive cells were isolated from human peripheral blood mononuclear cells (PBMCs) by positive magnetic separation and were further cultured with or without lipopolysaccharide (LPS, 1.0 MUg/ml) for 24 h. We showed that upon LPS activation of Mc/Mphs, IL-8 reduced markedly both the percentages and median fluorescence intensity (MFI) of CD16 (FcgammaRIII)-positive cells among CD14high cells, as well as in cells that reduced the expression of SD14 during their culturing. IL-8 was also found to be capable of reducing the expression of SD124 (IL-4 receptor subunit alpha, IL-4RA), with concomitant enhancement of the expression of both CD119 (interferon-gamma receptor 1) and CD197 (CCR7) in Mph cells. In addition, IL-8 up-regulated production of IL-6 and IL-1beta [but not tumor necrosis factor-alpha (TNF-alpha) and IL-10] by activated Mc/Mphs. Our results suggest the ability for IL-8 to directly favor pro-inflammatory M1-type Mph activity. PMID- 29414655 TI - Cholinergic regulation of proliferation of the urothelium in response to E. coli lipopolysaccharide exposition. AB - How the proliferation of the urothelium is regulated is known to a little degree. E. coli lipopolysaccharide (LPS) activates the innate immune response of the urinary bladder via the Toll-like receptor 4 (TLR4) on the urothelium but induces also urothelial proliferation. We wanted to assess whether muscarinic receptors are involved in the regulation of urothelial proliferation triggered by LPS stimulation. Female Fischer 344 rats were instilled with LPS or saline (control) in the urinary bladder in the absence or presence of muscarinic receptor blockade with atropine and regeneration of the urothelium was assessed 4h and 24h later. In the Fischer 344 bladder, urothelial thinning and urothelial caspase 3 up regulation occurred at 4h after LPS urinary bladder instillation, which were totally blocked in rats pre-treated with atropine. TLR4 was only expressed in blood vessels in the Fischer 344 bladder, while it was also expressed in umbrella cells in the Sprague-Dawley bladder. Proliferation (Ki67 incorporation) of the human urothelial cell line UROtsa was reduced in the presence of the muscarinic receptor antagonists methoctramine (M2/M4-selective) and pirenzepine (M1/M4 selective), while proliferation instead was enhanced in the presence of atropine. In UROtsa cells exposed to LPS for 24h, 4-DAMP (M3/M1/M5-selective) inhibited instead proliferation. In conclusion, muscarinic receptors regulate urothelial proliferation and LPS may induce urothelial apoptosis via muscarinic receptor dependent pathways. Our findings also suggest that species differences exist in the expressional pattern of TLR4 in the urothelium. PMID- 29414656 TI - Inhibition of histone deacetylase reduces lipopolysaccharide-induced-inflammation in primary mammary epithelial cells by regulating ROS-NF-kB signaling pathways. AB - Histone deacetylase 6 (HDAC6) is the sole member of the HDAC family, that is predominantly located in the cytoplasm and has substrate specificity for nonhistone proteins, such as alpha-Tubulin. Although an increasing number of studies have shown that HDAC6 is involved in inflammatory diseases, but little is known about the participation of HDAC6 in the transcriptional regulation of inflammatory cytokines. Here, we examined the effects of Tubastatin (Tub), a highly selective HDAC6 inhibitor, on lipopolysaccharide (LPS)-stimulated primary bovine mammary epithelial cells (bMECs). The specific inhibition of HDAC6 using Tub significantly decreased the release of pro-inflammatory cytokines, such as TNF-alpha and IL-1beta, which was associated with increased alpha-Tubulin acetylation. HDAC6 overexpression significantly induced reactive oxygen species (ROS) generation via upregulation of NADPH oxidase activity. Administration of Tub dose-dependently inhibited ROS production and NADPH oxidase activity. In addition, inhibition of HDAC6 led to suppression of the NF-kappaB signaling pathway. Thus, we report herein that HDAC6 is involved in ROS-NF-kappaB signaling pathway related to pro-inflammatory cytokine expression and that selective HDAC6 inhibition by Tub is a potent approach for preventing LPS-mediated inflammation. PMID- 29414657 TI - Mechanisms of action involved in ozone-therapy in skin diseases. AB - Ozone-therapy initially applied in medicine by an empirical approach, has now reached a new stage where most of the biological mechanisms of ozone action have been clarified, that refers to antimicrobial effects, immunoregulation, antioxidant defenses and epigenetic modification. Current ozone medical preparation in dermatology mainly classified as ozone hydrotherapy, ozonated oil externally used and ozone autohemotherapy (OAHT). Admittedly, ozone is widely used in various fields against gram-negative and gram-positive bacteria, viruses, and fungi. More recently, great progress has been obtained in wound healing which is a multiphase process that consists of three overlapping but distinct stages: inflammation, tissue proliferation and remodeling. While the exact mechanisms of ozone-therapy still remain unclear. Therefore, more evidence is required before ozone can be presented as a promising method for the management and prevention of various skin diseases. In this review, we review the application status of ozone in dermatology and summarize possible mechanisms of ozone-therapy on skin diseases, aims to shed a light on providing a series of theoretical basis for its applications. PMID- 29414658 TI - Sodium butyrate alleviates LPS-induced acute lung injury in mice via inhibiting HMGB1 release. AB - Sodium butyrate (SB) is a short chain 4-carbon fatty acid salt naturally exists in animal fats. Previous studies have proven that sodium butyrate has many beneficial functions such as anti-tumor and anti-inflammatory actions. In the current study we investigated the effect and possible mechanism of sodium butyrate in LPS-induced acute lung injury (ALI). ALI was induced by intratracheal administration of LPS (10 mg/kg) in male BALB/c mice. Sodium butyrate (500 mg/kg) was administered intraperitoneally 30 min prior to LPS exposure. We found that sodium butyrate significantly protected animals from LPS-induced ALI as evidenced by decreased the lung wet to dry weight ratio, total cells, neutrophils, macrophages, myeloperoxidase (MPO) activity, and lung histological damage compared to vehicle control. Sodium butyrate pretreatment markedly inhibited the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Furthermore, sodium butyrate pretreatment dramatically suppressed HMGB1 release and NF-kappa B activation. Together, these results suggest that sodium butyrate pretreatment protects mice from LPS-induced acute lung injury, possibly through the modulation of HMGB1 and inflammatory responses. PMID- 29414659 TI - Evaluation of immune responses induced by a novel human papillomavirus type 16 E7 peptide-based vaccine with Candida skin test reagent as an adjuvant in C57BL/6 mice. AB - Cell mediated immune (CMI) responses are crucial for the clearance of human papillomavirus (HPV) infection and HPV-associated lesions. Activated CD8 T cells are critical effector cells in recognizing and killing HPV-infected or HPV transformed cells. CD4 T cells provide help for priming the generation and maintenance of CD8 T cells as well as for tumors immunity. An ideal therapeutic HPV peptide-based vaccine should induce both a robust CD8 T-cell response as well as a CD4 T-cell response for ensuring their efficiency. Candida skin test reagent was demonstrated to be able to induce the secretion of IL-12 by Langerhans cells and T-cell proliferation in vitro by our group, which indicated the potential of Candida to enhance CMI response. In this current study, we designed a novel HPV peptide-based vaccine which includes HPV16 E7 peptides and Candida as an adjuvant. The immune responses induced by the vaccine were comprehensively evaluated. The results showed that the vaccine induced significant HPV-specific CD8 T-cell and Th1 CD4 T-cell responses as well as humoral immune response. It is interesting that Candida alone induced a significant polarization of Th1 response an production of IFN-gamma, which indicated Candida alone may be used as a potential immunotherapeutic reagent not only for HPV-associated lesions but also for other viral infection or even cancers. PMID- 29414660 TI - Increased circulating CD4+CXCR5+FoxP3+ follicular regulatory T cells correlated with severity of systemic lupus erythematosus patients. AB - As one specialized subset of regulatory T cells (Tregs), follicular regulatory T cells (TFR) could suppress follicular helper T cells (TFH) and B cells in germinal centers to maintain immune homeostasis. The unbalance of TFR and TFH cells could result in abnormal germinal center responses and contribute to pathogenesis of autoimmune diseases. However, the role of TFR cells in systemic lupus erythematosus (SLE) remains unclear. This study revealed a significant increase of CD4+CXCR5+FOXP3+ TFR cells in peripheral blood of SLE patients compared with healthy controls. Meanwhile, the suppression ability of circulating TFR cells was not altered. The ratios of TFR/TFH were increased in SLE patients and the frequency of TFR was positively correlated with auto-antibodies and SLEDAI scores of SLE patients. Our results demonstrated that circulating TFR cells were increased during SLE, which suggested that elevated TFR might be a response to the pathogenesis of SLE to suppress TFH function and may provide novel insight for the pathogenesis of SLE. PMID- 29414661 TI - Fine tuning subsets of CD4+ T cells by low-dosage of IL-2 and a new therapeutic strategy for autoimmune diseases. AB - Although Interleukin-2 (IL-2) was identified almost 40 years ago, only recently low dosage IL-2 therapy is proved to be an effective approach to treat autoimmune diseases. The underlining mechanism is that IL-2 can fine-tune subsets of CD4+ T cells by promoting the development and maintenance of regulatory T cells (Treg) at low-dosage (ld) and enhance the functions of effector T cells (Teff) at high dosage (hd). Since the successful clinical trials of IL-2 to treat patients with autoimmune diseases and inflammatory conditions, including Systemic lupus erythematosus (SLE) and Type 1 Diabetes (T1D), ld IL-2 therapy is a promising strategy to treat autoimmune diseases. PMID- 29414663 TI - Implication of increased serum stromal cell-derived factor-1 for primary biliary cholangitis. AB - BACKGROUND: Stromal cell-derived factor-1 (SDF-1), also called chemokine (C-X-C motif) ligand 12 (CXCL12), as a chemokine for premature B cells, T cells and monocytes, is detected in liver, pancreas, spleen and heart. However, its diagnostic value for primary biliary cholangitis (PBC) as well as the association of SDF-1 with inflammatory and fibrotic progression is unclear. The aim of this study was to determine serum stromal cell-derived factor-1 (SDF-1) level and to explore its diagnostic value for primary biliary cholangitis (PBC) as well as the association of SDF-1 with inflammatory and fibrotic progression of PBC. METHODS: A total of 60 PBC patients who received liver biopsy, 32 age- and sex-matched patients with chronic hepatitis B (CHB) and 30 age- and sex-matched healthy controls (HC) were recruited. The sera were measured for SDF-1, interleukin-4 (IL 4), interferon gamma (IFN-gamma) and IL-17 using multiplex immunoassay. PBC was divided into four histologic stages according to Scheuer's classification. RESULTS: The results showed significantly higher median level of serum SDF-1 (median, interquartile (IQR), 1186.96, 1002.05-1471.33 pg/mL) in PBC patients than those with CHB (median, IQR, 740.69,600.30-1239.27 pg/mL) and HC (median, IQR, 738.44, 687.65-879.33 pg/mL) (P < 0.001). There was no significant difference between CHB patients and HC (P = 0.526). The receiver operating characteristic curves (ROC) showed good diagnostic performance of serum SDF-1 for PBC, AMA-positive and -negative PBC. In particular for AMA-negative PBC, the area under ROC was 0.817, with optimal cutoff value of 802.64 pg/mL and the sensitivity of 100%. Serum SDF-1 level was not associated with other immune, inflammatory and fibrotic indicators, including AMA, ANA, anti-gp210, sp100 and centromere antibodies, bilirubin, ALT, AST, ALP, GGT, WBC, neutrophil, lymphocyte, platelet, Neutrophil- (NLR) and platelet-lymphocyte (PLR), AST to ALT ratio, AST to platelet ratio index (APRI) and FIB-4 index (P > 0.05). Also, there was no significant difference for serum SDF-1 among histological stages (P = 0.091). However, Serum SDF-1 level was significantly correlated with serum IL-17 (r = 0.373, P = 0.004), but not with IL-4 (r = 0.110, P = 0.407) and IFN-gamma (r = 0.215, P = 0.098) in those with PBC. CONCLUSION: Serum SDF-1 is increased in and may be a potential useful marker for PBC. Moreover, it may be associated with Th17 recruitment and differentiation in PBC. However, serum SDF-1 may not be associated with the progression of PBC. PMID- 29414662 TI - HMGB1 silencing in macrophages prevented their functional skewing and ameliorated EAM development: Nuclear HMGB1 may be a checkpoint molecule of macrophage reprogramming. AB - High-mobility group box 1 (HMGB1), an important inflammatory factor, plays significant roles in CD4+T cell differentiation, cancer and autoimmune disease development. Our previous data have demonstrated that HMGB1 contributes to macrophage reprogramming and is involved in experimental autoimmune myocarditis (EAM) development. In contrast to the well-explored function of HMGB1, little is known about the nuclear function. Whether HMGB1 can serve as an architectural factor and control functional skewing of macrophages remains unclear. Therefore, the present work was performed to address the above speculation. The adenovirus mediated shRNA (Ad-shRNA) was employed to knock down HMGB1 in RAW264.7 and monocytes/macrophages of EAM mice. Our data showed that in vitro HMGB1 silencing limited functional skewing of macrophages and down-regulated inflammatory factors secretion, which can't be reversed by the exogenous HMGB1. In M1 polarization system, the phosphorylations of NF-kappaB, p38 and Erk1/2 were inhibited following HMGB1 silencing. In vivo, HMGB1 silencing could effectively ameliorate EAM development. Our data suggest that HMGB1 may be a checkpoint nuclear factor of macrophage reprogramming. Our findings also provide an exciting therapeutic method for inflammatory disorders. PMID- 29414664 TI - GLMEEMSAL epitope common in different isoforms of hMena elicits in vitro activation of cytotoxic T cells and stimulates specific antitumor immunity in BALB/c mice. AB - BACKGROUND: Alternative expression of human ortholog of murine Mena (hMena) hMena/hMena11a and hMena/hMenaDeltav6 isoforms regulate the invasiveness and metastatic potential of tumor cells. It is then important to identify epitopes of these proteins that can elicit antitumor immune response to contribute to the elimination of cells with metastatic potential. METHODS: We assayed the capacity of the peptide GLMEEMSAL, common in hMena/hMena11a and hMena/hMenaDeltav6 isoforms, to generate an antitumor immune response through an in vitro vaccination system with mature dendritic cells (MDC) loaded with this peptide and in vivo immunization using a tumor model with the mammary adenocarcinoma JC cell line to induce tumors in BALBc mice. RESULTS: MDC loaded with the peptide GLMEEMSAL elicited strong proliferation and activation of CD8+ T lymphocytes. The CTLs generated with this system were capable to lyse specifically BrCa and CeCa cell lines expressing either hMena/hMena11a or hMena/hMenaDeltav6. Immunization with GLMEEMSAL provided protective and therapeutic antitumor activity as well as increased survival in BALB/c mice. CONCLUSION: These results are highly relevant for the use of common peptides among the different isoforms of hMena to develop immunotherapy protocols to counteract the growth and metastatic potential of tumors with over-expression of hMena. PMID- 29414665 TI - Improving hyperglycemic effect of FGF-21 is associated with alleviating inflammatory state in diabetes. AB - Type 2 diabetes mellitus (T2DM) is accompanied by abnormal glucose metabolism and low-grade chronic inflammation. Fibroblast growth factor 21 (FGF-21) is a novel metabolic regulator and can function as an endocrine hormone to regulate glucose and lipid metabolism. Recently, FGF-21 was found to have anti-inflammatory effect, to our knowledge, the effect of FGF-21 on inflammatory state in diabetes has not been elucidated. Here, we use db/db mice as a Type 2 diabetes model to determine whether FGF-21 alleviates inflammatory state while improves hyperglycemia. Our results demonstrated that FGF-21 not only showed potent long lasting hypoglycemic effect, but also demonstrated strong anti-inflammatory effect in the serum and white adipose tissue. Besides, in vitro experiments, insulin resistance (IR) was induced in 3T3-L1 adipocytes by treating with TNF alpha. Our results showed that TNF-alpha impaired glucose metabolism of 3T3-L1 adipocytes but FGF-21 repressed gene expression of inflammatory factors caused by IR and consequently improved the glucose metabolism in 3T3-L1 adipocytes. Furthermore, FGF-21 ameliorated glucose uptake of TNF-alpha-induced IR in 3T3-L1 adipocytes by inhibiting NF-kappaB signaling pathway. PMID- 29414666 TI - Dexamethasone restores transforming growth factor-beta activated kinase 1 expression and phagocytosis activity of Kupffer cells in cholestatic liver injury. AB - The role of transforming growth factor-beta activated kinase 1 (TAK1) in modulating the function of Kupffer cells (KCs) within cholestatic livers remains unclear. This study examined the immunopharmacological action of dexamethasone (DEX) in modulating hepatic TAK1 expression and related signaling activity in a rat model of bile duct ligation-mimicked obstructive jaundice. The in vitro effects of DEX on porcine biliary extract (PBE)-modulated gene expression and phagocytosis of KCs were examined using a rat alveolar macrophage cell line (NR8383 cells). Although DEX therapy did not restore the downregulated TAK1 expression and phosphorylation, it significantly attenuated the upregulation of high-mobility group box 1 expression and caspase-3 activation in whole liver extracts of cholestatic rats, possibly via enhancing extracellular signal regulated kinase-mediated signaling. Dual immunofluorescence staining of cholestatic livers and western detection on primary KCs isolated from cholestatic livers identified that DEX treatment indeed increased both the expression and phosphorylation levels of TAK1 in the KCs of cholestatic livers. In vitro studies using alveolar NR8383 macrophages with KC-characteristic gene expression further demonstrated that DEX not only repressed the pro-inflammatory cytokine production including with respect to interleukin (IL)-1beta and IL-6, but also enhanced gene expression of TAK1 and a phagocytic marker, natural-resistance-associated macrophage protein 1, under PBE-mimicked cholestatic conditions. However, WST-1 assay showed that DEX did not protect NR8383 macrophages against the PBE-induced cytotoxicity. Immunofluorescence visualization of cellular F-actin by phalloidin suggested that DEX sustained the PBE-induced phagocytosis morphology of NR8383 macrophages. In conclusion, DEX treatment may pharmacologically restore the expression and activity of TAK1 in KCs, and sustain the phagocytic phenotype of KCs in cholestatic livers. PMID- 29414667 TI - The therapeutic effect of fraxetin on ethanol-induced hepatic fibrosis by enhancing ethanol metabolism, inhibiting oxidative stress and modulating inflammatory mediators in rats. AB - The present study was designed to investigate the possible protective effects of fraxetin against ethanol induced liver fibrosis in rats. Rats were underwent intragastric administration of ethanol (5.0-9.5 g/kg) once a day for 24 weeks. Effect of fraxetin against ethanol induced liver fibrosis was investigated by giving 20 or 50 mg/kg fraxetin. At the end of experiment, the livers were collected for histopathological analyses, protein extraction, and enzymatic activities. Our results indicated that fraxetin significantly corrected ethanol induced hepatic fibrosis, as evidenced by the decrease in serum ALT and AST, the attenuation of histopathological changes. Fraxetin also expedited ethanol metabolism by enhancing the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities. Besides, fraxetin alleviated lipid peroxidation, enhanced hepatic antioxidant capabilities, inhibited CYP2E1 activity, and reduced the inflammatory mediators, including TNF-alpha and IL-1beta via up-regulation of hemeoxygenase-1 (HO-1) protein. In summary, the hepatoprotection of fraxetin is mostly attributed to its antioxidant capability, alcohol metabolism, and anti inflammation effect. PMID- 29414668 TI - Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/beta catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas. AB - Innate or acquired drug resistance and consequent tumor relapse in lung cancer patients have been linked to activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that garcinol, a polyisoprenylated benzophenone isolated from fruiting bodies of Garcinia indica, and possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory, and anticancer activities, modulates activities of lung CSCs (LCSCs) and their associated aggressiveness. Herein, we demonstrated the inhibitory effect of garcinol on the LCSC phenotype of human NSCLC cells using analytical drug cytotoxicity or cell viability, flow cytometric, and functional assay approaches. Garcinol significantly diminished the ability of the H441 and A549 NSCLC cell lines to form spheres. In parallel assays, garcinol inhibited differentiated lung cancer cell and LCSC viability in dose-dependent manners. Consistent with these observations, flow cytometric data showed that garcinol reduced the putative LCSC pool, evidenced by the dose-dependent decreasing proportion of side-population (SP) cells and associated ALDH activity in garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In the same assay, garcinol down-regulated beta-catenin, Dvl2, Axin2, and cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/beta-catenin signaling pathway. The results were further verified in vivo using H441 LCSC mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Taken together, we demonstrated herein that garcinol modulates the LCSC phenotype via regulation of Wnt/beta catenin signaling and inactivation of STAT3, thus showing that garcinol may be a putative novel anti-LCSC therapeutic agent. PMID- 29414669 TI - COX-2 activity and expression pattern during regenerative wound healing of tail in lizard Hemidactylus flaviviridis. AB - Cyclooxygenase-2 (COX-2) is an important mediator of the immune response. It is found upregulated after pathogen invasion or tissue injury and also in many cancers. Of the lesser known functions of this enzyme is its role in effecting epimorphic regeneration. We have previously shown that COX-2 activity is essential for proper regeneration of tail in lizard Hemidactylus flaviviridis; however, the pattern of its activity and expression during the early stages of regeneration was unknown. The present work provides the first report of the trend in COX-2 activity and expression during the wound healing in epimorphic regeneration. It was found in H. flaviviridis that COX-2 gene was induced on the first day after amputation of the tail and expression and activity remained high through the course of wound healing. Further it was revealed that the COX-2 signal was mediated through the PKA/cAMP pathway via binding with the prostaglandin E2 receptor 2 (EP2). In order to delineate the mechanism of epimorphic regeneration, we must understand the regulation of the major regulatory molecules therein. Therefore, the current study on the role of COX-2 during the regenerative wound healing is of paramount significance. Optimistically, such a mechanistic insight will help us achieve large scale tissue regeneration in humans in the future. PMID- 29414670 TI - Novel relocation methods for automatic external defibrillator improve out-of hospital cardiac arrest coverage under limited resources. AB - BACKGROUND: Mathematical optimisation models have recently been applied to identify ideal Automatic External Defibrillator (AED) locations that maximise coverage of Out of Hospital Cardiac Arrest (OHCA). However, these fixed location models cannot relocate existing AEDs in a flexible way, and have nearly exclusively been applied to urban regions. We developed a flexible location model for AEDs, compared its performance to existing fixed location and population models, and explored how these perform across urban and rural regions. METHODS: Optimisation techniques were applied to AED deployment and OHCA coverage was assessed. A total of 2802 geolocated OHCAs occurred in Canton Ticino, Switzerland, from January 1st 2005 to December 31st 2015. RESULTS: There were 719 AEDs in Canton Ticino. 635 (23%) OHCA events occurred within 100 m of an AED, with 306 (31%) in urban, and 329 (18%) in rural areas. Median distance from OHCA events to the nearest AED was 224 m (168 m urban vs. 269 m rural). Flexible location models performed better than fixed location and population models, with the cost to deploy 20 new AEDs instead relocating 171 existing AEDs to new locations, improving OHCA coverage to 38%, compared to 26% using fixed models, and 24% with the population based model. CONCLUSIONS: Optimisation models for AEDs placement are superior to population models and should be strongly considered by communities when selecting areas for AED deployment. Compared to other models, flexible location models increase overall OHCA coverage, and decreases the distance to nearby AEDs, even in rural areas, while saving significant financial resources. PMID- 29414671 TI - Fibrinogen and fibrin are novel substrates for Fasciola hepatica cathepsin L peptidases. AB - Cathepsin peptidases form a major component of the secreted proteins of the blood feeding trematodes Fasciola hepatica and Schistosoma mansoni. These peptidases fulfill many functions, from facilitating infection to feeding and immune evasion. In this study, we examined the Fasciola cathepsin L peptidases FhCL1, FhCL2, and FhCL3 and the schistosomal cathepsin peptidases SmCB1 and SmCL3 for their anticoagulant properties. Although no direct anticoagulant effect of these peptidases was observed, we discovered that cathepsin peptidases from Fasciola, but not from Schistosoma, were able to degrade purified fibrinogen, with FhCL1 having the highest fibrinogenolytic activity. Additionally, FhCL1 and FhCL2 both efficiently degraded fibrin. The lack of a direct anticoagulant or fibrinolytic effect of these peptidases is explained by their inhibition by plasma components. However, within the parasite gut, high concentrations of these peptidases could induce an anticoagulant environment, facilitating blood-feeding for extended periods. PMID- 29414672 TI - Recombinant buckwheat glutaredoxin intake increases lifespan and stress resistance via hsf-1 upregulation in Caenorhabditis elegans. AB - Glutaredoxin (Grx) is a polypeptide with low molecular weight, which has been extracted from buckwheat and has been suggested to have multiple functions revolving around oxidative stress responses and cell signaling. Here, we report the antioxidant activity of recombinant buckwheat Grx (rbGrx) to reduce aging effects in Caenorhabditis elegans (C. elegans) as well as the mechanism involved. Our results showed that rbGrx beneficially affected the health span of C. elegans, including pharyngeal-pumping rate, locomotion, and lipofuscin accumulation. Furthermore, stress assay showed that rbGrx could extend the lifespan under both oxidative and heat stress. Further studies indicated that the longevity-extending effects of rbGrx could be attributed to its in vitro and in vivo antioxidant activities. After treatment with rbGrx, SOD activity, CAT activity, GSH content, and GSH/GSSG ratio were increased, while MDA content was decreased, which led to low intracellular levels of reactive oxygen species in C. elegans. Moreover, rbGrx up-regulated hsf-1 mRNA level and could not expand the lifespan of the hsf-1 mutant C. elegans (sy441); however, this had no effect on the transcription of daf-16 and skn-1 and could expand the lifespan of both daf 16 and skn-1 mutants. These results suggested dependency of the rbGrx effect on the heat shock transcription factor (HSF-1) and independency on both DAF-16 and SKN-1. In summary, our results demonstrated the anti-aging activity of rbGrx, which increased resistance to cellular stress and improved the health span of C. elegans. These results are very important for the use of rbGrx in anti-aging research. PMID- 29414673 TI - Evolving targets for the treatment of atherosclerosis. AB - Atherosclerosis is a progressive disease of large arteries and a leading cause of cardiovascular diseases and stroke. Chronic inflammation, aberrant immune response, and disturbances to key enzymes involved with lipid metabolism are characteristic features of atherosclerosis. Apart from targeting the derangements in lipid metabolism, therapeutic modulation to regulate chronic inflammation and the immune system response may prove to be very promising strategies in the management of atherosclerosis. In recent years, various targets have been studied for the treatment of atherosclerosis. PCSK9, a serine protease, actively targets the LDL-R and causes lysosomal degradation, which leads to excessive accumulation of LDL-C. Regulatory T cells (Tregs) and Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) affects the adaptive and innate immune response, respectively, and thus, therapeutic intervention of either of these targets would directly modulate disease progression. Advanced atherosclerotic lesions are characterized by an accumulation of apoptotic cells. Cluster of differentiation-47 (CD47), an anti-phagocytic known as the "don't eat me" signaling molecule, inhibits efferocytosis, which causes accumulation of cell debris in plaque. ADAMTS and Notch signaling potentially affect the formation of neointima by modulation of extracellular matrix components such as macrophages and vascular smooth muscle cells. This review provides insights on the molecular targets for therapeutic intervention of atherosclerosis, their effect at various stages of atherosclerosis development, and the therapies that have been designed and currently being evaluated in clinical trials. PMID- 29414674 TI - Integrins in wound healing, fibrosis and tumor stroma: High potential targets for therapeutics and drug delivery. AB - Wound healing is a complex process, which ultimately leads to fibrosis if not repaired well. Pathologically very similar to fibrosis is the tumor stroma, found in several solid tumors which are regarded as wounds that do not heal. Integrins are heterodimeric surface receptors which control various physiological cellular functions. Additionally, integrins also sense ECM-induced extracellular changes during pathological events, leading to cellular responses, which influence ECM remodeling. The purpose and scope of this review is to introduce integrins as key targets for therapeutics and drug delivery within the scope of wound healing, fibrosis and the tumor stroma. This review provides a general introduction to the biology of integrins including their types, ligands, means of signaling and interaction with growth factor receptors. Furthermore, we highlight integrins as key targets for therapeutics and drug delivery, based on their biological role, expression pattern within human tissues and at cellular level. Next, therapeutic approaches targeting integrins, with a focus on clinical studies, and targeted drug delivery strategies based on ligands are described. PMID- 29414675 TI - Cooperative RNA Recognition by a Viral Transcription Antiterminator. AB - RNA transcription of mononegavirales decreases gradually from the 3' leader promoter toward the 5' end of the genome, due to a decay in polymerase processivity. In the respiratory syncytial virus and metapneumovirus, the M2-1 protein ensures transcription anti-termination. Despite being a homotetramer, respiratory syncytial virus M2-1 binds two molecules of RNA of 13mer or longer per tetramer, and temperature-sensitive secondary structure in the RNA ligand is unfolded by stoichiometric interaction with M2-1. Fine quantitative analysis shows positive cooperativity, indicative of conformational asymmetry in the tetramer. RNA binds to M2-1 through a fast bimolecular association followed by slow rearrangements corresponding to an induced-fit mechanism, providing a sequential description of the time events of cooperativity. The first binding event of half of the RNA molecule to one of the sites increases the affinity of the second binding event on the adjacent contacting protomer by 15-fold, product of increased effective concentration caused by the entropic link. This mechanism allows for high-affinity binding with an otherwise relaxed sequence specificity, and instead suggests a yet undefined structural recognition signature in the RNA for modulating gene transcription. This work provides a basis for an essential event for understanding transcription antitermination in pneumoviruses and its counterpart Ebola virus VP30. PMID- 29414676 TI - Personalisation of warfarin therapy using thermal ink-jet printing. AB - Warfarin is a widely used anticoagulant that is critical in reducing patient morbidity and mortality associated with thromboembolic disorders. However, its narrow therapeutic index and large inter-individual variability can lead to complex dosage regimes. Formulating warfarin as an orodispersible film (ODF) using thermal ink-jet (TIJ) printing could enable personalisation of therapy to simplify administration. Commercial TIJ printers are currently unsuitable for printing the milligram dosages, typically required for warfarin therapy. As such, this study aimed to modify a commercial TIJ printing system to formulate personalised warfarin ODFs containing therapeutic dosages. A TIJ printer was modified successfully with the printer functionality intact; the substrate (paper) rolling mechanism of the printer was replaced by printing onto a stationary stage. Free film substrates were composed of hydroxypropyl methylcellulose (20%w/w) and glycerol (3%w/w). The resulting ODFs were characterised for morphology, disintegration, solid-state properties and drug content. Printed film stability was assessed at 40 degrees C/75% relative humidity for 30 days. Therapeutic warfarin doses (1.25 and 2.5 mg) were successfully printed onto the film substrates. Excellent linearity was observed between the theoretical and measured dose by changing the warfarin feed concentration (R2 = 0.9999) and length of the print objective, i.e. the Y-value, (R2 = 0.9998). Rapid disintegration of the ODFs was achieved. As such, this study successfully formulated personalised warfarin ODFs using a modified TIJ printer, widening the range of applications for TIJ printing to formulate narrow therapeutic index drugs. PMID- 29414677 TI - Whole genome typing of the recently emerged Canadian serogroup W Neisseria meningitidis sequence type 11 clonal complex isolates associated with invasive meningococcal disease. AB - OBJECTIVES: This study was performed to analyze the Canadian invasive serogroup W Neisseria meningitidis (MenW) sequence type 11 (ST-11) clonal complex (CC) isolates by whole genome typing and to compare Canadian isolates with similar isolates from elsewhere. METHODS: Whole genome typing of 30 MenW ST-11 CC, 20 meningococcal group C (MenC) ST-11 CC, and 31 MenW ST-22 CC isolates was performed on the Bacterial Isolate Genome Sequence database platform. Canadian MenW ST-11 CC isolates were compared with the 2000 MenW Hajj outbreak strain, as well as with MenW ST-11 CC from other countries. RESULTS: Whole genome typing showed that the Canadian MenW ST-11 CC isolates were distinct from the traditional MenW ST-22 CC; they were not capsule-switched contemporary MenC strains that incorporated MenW capsules. While some recent MenW disease cases in Canada were caused by MenW ST-11 CC isolates showing relatedness to the 2000 MenW Hajj strain, many were non-Hajj isolates similar to current MenW ST-11 isolates found globally. Geographical and temporal variations in genotypes and surface protein antigen genes were found among the MenW ST-11 CC isolates. CONCLUSIONS: The current MenW ST-11 isolates did not arise by capsule switching from contemporary MenC ST-11 isolates. Both the Hajj-related and non-Hajj MenW ST-11 CC strains were associated with invasive meningococcal disease in Canada. PMID- 29414678 TI - Structure and function of wild-type and subunit-depleted photosystem I in Synechocystis. AB - The ability of photosynthetic organisms to use the sun's light as a sole source of energy sustains life on our planet. Photosystems I (PSI) and II (PSII) are large, multi-subunit, pigment-protein complexes that enable photosynthesis, but this intriguing process remains to be explained fully. Currently, crystal structures of these complexes are available for thermophilic prokaryotic cyanobacteria. The mega-Dalton trimeric PSI complex from thermophilic cyanobacterium, Thermosynechococcus elongatus, was solved at 2.5 A resolution with X-ray crystallography. That structure revealed the positions of 12 protein subunits (PsaA-F, PsaI-M, and PsaX) and 127 cofactors. Although mesophilic organisms perform most of the world's photosynthesis, no well-resolved trimeric structure of a mesophilic organism exists. Our research model for a mesophilic cyanobacterium was Synechocystis sp. PCC6803. This study aimed to obtain well resolved crystal structures of [1] a monomeric PSI with all subunits, [2] a trimeric PSI with a reduced number of subunits, and [3] the full, trimeric wild type PSI complex. We only partially succeeded with the first two structures, but we successfully produced the trimeric PSI structure at 2.5 A resolution. This structure was comparable to that of the thermophilic species, but we provided more detail. The PSI trimeric supercomplex consisted of 33 protein subunits, 72 carotenoids, 285 chlorophyll a molecules, 51 lipids, 9 iron-sulfur clusters, 6 plastoquinones, 6 putative calcium ions, and over 870 water molecules. This study showed that the structure of the PSI in Synechocystis sp. PCC6803 differed from previously described PSI structures. These findings have broadened our understanding of PSI structure. PMID- 29414679 TI - Cultivating a Relationship with Gut Bacteria. AB - While the gut microbiome largely benefits host physiology, the impact of symbiosis on bacterial fitness has not been rigorously investigated. In this issue, Storelli et al. (2018) provide evidence that Drosophila actively cultivate a relationship with the growth-promoting bacterium Lactobacillus plantarum, delivering mutual benefits under nutrient-poor conditions. PMID- 29414680 TI - Mealtime Is NONO Speckled: Timing Hepatic Adaptation to Food. AB - You are what you eat; but when you eat also seems to be important for a healthy metabolism. In this issue of Cell Metabolism, Benegiamo et al. (2018) uncover a mechanism by which the RNA-binding protein NONO promotes the time-of-day dependent expression of key metabolic genes at a post-transcriptional level in response to nutrition. PMID- 29414681 TI - Metabolite-Induced Protein Expression Guided by Metabolomics and Systems Biology. AB - Metabolomics combined with systems biology can be used to identify endogenous metabolites that modulate protein expression. Recent examples include the 2-fold enhancements of pertussis toxin protein in vaccine production and myelin basic protein expression in oligodendrocyte maturation; both applied a metabolomics systems strategy to identify active metabolites. PMID- 29414682 TI - The HETE Is on FFAR1 and Pancreatic Islet Cells. AB - It is known but generally unappreciated that the fatty acid receptor FFAR1 (GPR40) is responsible for a major part of glucose-induced insulin secretion. This puzzling fact is now explained by Tunaru et al. (2018), who demonstrate that glucose-induced 20-hydroxyeicosatetraenoic acid (20-HETE) amplifies insulin secretion through autocrine activation of FFAR1. PMID- 29414683 TI - Metabolism in Pluripotent Stem Cells and Early Mammalian Development. AB - Emerging and seminal studies have shown that cell metabolism influences gene expression by modifying the epigenome, which can regulate stem cell pluripotency, differentiation, and somatic cell reprogramming. Core pluripotency factors and developmental regulators reciprocally control the expression of key metabolism genes and their encoded pathways. Recent technological advances enabling sensitive detection methods during early mammalian development revealed the state specific and context-dependent coordination of signal transduction, histone modifications, and gene expression in developing, resting, and malnourished embryos. Here, we discuss metabolism as a potential driver of earliest cell fate through its influence on the epigenome and gene expression in embryos and their in vitro surrogate pluripotent stem cells. PMID- 29414684 TI - Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1alpha Transactivation in Steatohepatitis. AB - Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1alpha signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis and suppressing HIF-1alpha pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independently of PKM2 kinase activity results in chromatin remodeling and downregulation of HIF-1alpha transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin that can effectively protect the liver from ASH and NASH. PMID- 29414685 TI - The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids. AB - Excessive consumption of sweets is a risk factor for metabolic syndrome. A major chemical feature of sweets is fructose. Despite strong ties between fructose and disease, the metabolic fate of fructose in mammals remains incompletely understood. Here we use isotope tracing and mass spectrometry to track the fate of glucose and fructose carbons in vivo, finding that dietary fructose is cleared by the small intestine. Clearance requires the fructose-phosphorylating enzyme ketohexokinase. Low doses of fructose are ~90% cleared by the intestine, with only trace fructose but extensive fructose-derived glucose, lactate, and glycerate found in the portal blood. High doses of fructose (>=1 g/kg) overwhelm intestinal fructose absorption and clearance, resulting in fructose reaching both the liver and colonic microbiota. Intestinal fructose clearance is augmented both by prior exposure to fructose and by feeding. We propose that the small intestine shields the liver from otherwise toxic fructose exposure. PMID- 29414686 TI - Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation. AB - The role of tryptophan-kynurenine metabolism in psychiatric disease is well established, but remains less explored in peripheral tissues. Exercise training activates kynurenine biotransformation in skeletal muscle, which protects from neuroinflammation and leads to peripheral kynurenic acid accumulation. Here we show that kynurenic acid increases energy utilization by activating G protein coupled receptor Gpr35, which stimulates lipid metabolism, thermogenic, and anti inflammatory gene expression in adipose tissue. This suppresses weight gain in animals fed a high-fat diet and improves glucose tolerance. Kynurenic acid and Gpr35 enhance Pgc-1alpha1 expression and cellular respiration, and increase the levels of Rgs14 in adipocytes, which leads to enhanced beta-adrenergic receptor signaling. Conversely, genetic deletion of Gpr35 causes progressive weight gain and glucose intolerance, and sensitizes to the effects of high-fat diets. Finally, exercise-induced adipose tissue browning is compromised in Gpr35 knockout animals. This work uncovers kynurenine metabolism as a pathway with therapeutic potential to control energy homeostasis. PMID- 29414687 TI - Palmitic Acid Hydroxystearic Acids Activate GPR40, Which Is Involved in Their Beneficial Effects on Glucose Homeostasis. AB - Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti diabetic and anti-inflammatory effects. PAHSA levels are reduced in serum and adipose tissue of insulin-resistant people and high-fat diet (HFD)-fed mice. Here, we investigated whether chronic PAHSA treatment enhances insulin sensitivity and which receptors mediate PAHSA effects. Chronic PAHSA administration in chow- and HFD-fed mice raises serum and tissue PAHSA levels ~1.4- to 3-fold. This improves insulin sensitivity and glucose tolerance without altering body weight. PAHSA administration in chow-fed, but not HFD-fed, mice augments insulin and glucagon-like peptide (GLP-1) secretion. PAHSAs are selective agonists for GPR40, increasing Ca+2 flux, but not intracellular cyclic AMP. Blocking GPR40 reverses improvements in glucose tolerance and insulin sensitivity in PAHSA-treated chow- and HFD-fed mice and directly inhibits PAHSA augmentation of glucose-stimulated insulin secretion in human islets. In contrast, GLP-1 receptor blockade in PAHSA-treated chow-fed mice reduces PAHSA effects on glucose tolerance, but not on insulin sensitivity. Thus, PAHSAs activate GPR40, which is involved in their beneficial metabolic effects. PMID- 29414688 TI - Glucose-Dependent Granule Docking Limits Insulin Secretion and Is Decreased in Human Type 2 Diabetes. AB - Glucose-stimulated insulin secretion is biphasic, with a rapid first phase and a slowly developing sustained second phase; both are disturbed in type 2 diabetes (T2D). Biphasic secretion results from vastly different release probabilities of individual insulin granules, but the morphological and molecular basis for this is unclear. Here, we show that human insulin secretion and exocytosis critically depend on the availability of membrane-docked granules and that T2D is associated with a strong reduction in granule docking. Glucose accelerated granule docking, and this effect was absent in T2D. Newly docked granules only slowly acquired release competence; this was regulated by major signaling pathways, but not glucose. Gene expression analysis indicated that key proteins involved in granule docking are downregulated in T2D, and overexpression of these proteins increased granule docking. The findings establish granule docking as an important glucose dependent step in human insulin secretion that is dysregulated in T2D. PMID- 29414689 TI - Suppression of Insulin Production and Secretion by a Decretin Hormone. PMID- 29414690 TI - RNA-seq analysis of the transcriptome of the liver of cynomolgus monkeys with type 2 diabetes. AB - Genetic and environmental factors such as high-fat diet are involved in the development of type 2 diabetes mellitus (T2DM). Cynomolgus monkey shares similar genetic makeup, tissue structures, physiology and metabolic function to human. This study aimed to establish T2DM model in cynomolgus monkey and compare expression profiles of hepatic genes and their associated pathways in normal cynomolgus monkeys and those with T2DM. We employed RNA-seq technique and identified 1451 differentially expressed genes (DEGs) with a false discovery rate (FDR) of 0.1% between normal and T2DM animals. KEGG pathway analysis revealed that DEGs were associated with 12 KEGG pathways (P < 0.05). Two of these pathways were associated with metabolism and five were related to immunity. Unexpected, we found ECM-receptor interaction pathway. In conclusion, our data suggest that three major pathways may be implicated in the development of T2DM, including steroid biosynthesis, immune response and ECM. Further characterization of these pathways may provide new targets for the prevention and therapy of T2DM. PMID- 29414691 TI - Differential association of ESR1 and ESR2 gene variants with the risk of breast cancer and associated features: A case-control study. AB - BACKGROUND: Estrogen is key to breast cancer pathogenesis, and acts by binding its receptor (ER), which exists as ERalpha and ERbeta, encoded by ESR1 and ESR2 genes, respectively. Studies that investigated the association of ESR1 and ESR2 variants with breast cancer yielded mixed outcome, and ethnic contribution was proposed. We evaluated the association between ESR1 and ESR2 variants and breast cancer and associated features in Tunisian women. METHODS: Retrospective case control study involving 207 female breast cancer patients, and 284 control women. Genotyping was done by real-time PCR. RESULTS: Minor allele frequencies (MAF) of tagging SNPs rs2234693 and rs3798577 (ESR1) were significantly higher, while MAF of rs1256049 (ESR2) was significantly lower in breast cancer patients vs. CONTROLS: Patients carrying rs3798577 genotypes had higher risk, while rs1256049 genotype carriers had reduced risk of breast cancer. The association of ESR1 and ESR2 gene variants with breast cancer depended on ER and Her-2 status. ESR1 rs3798577 and ESR2 rs1256049 were associated with breast cancer in ER-positive cases, and ESR1 rs2234693, and rs3798577 were associated with breast cancer in Her-2-negative cases, while the association of ESR2 rs1256049 with breast cancer was seen in Her-2 positive cases. Haploview analysis identified 4-locus ESR1 haplotypes that were positively (CGTT, TACC, and TACT), and negatively (CGTC) associated with breast cancer. No ESR2 haplotypes associated with breast cancer were identified. CONCLUSION: ESR1 alleles and genotypes, and specific 3-locus ESR1 haplotypes are related with increased breast cancer susceptibility in Tunisian women. However, ESR2 variant and specific 1-locus ESR1 haplotype have a protective effect. PMID- 29414692 TI - Legumain suppresses OxLDL-induced macrophage apoptosis through enhancement of the autophagy pathway. AB - OBJECTIVE: Autophagy plays a prominent role in the pathogenesis of plaques formation and progression of atherosclerosis (AS). The cysteine protease legumain is known to participate in atherogenesis, but its function and underlying mechanism in AS macrophages remain unclear. METHODS: The expressions of legumain in plaques isolated from AS patients and in macrophages stimulated with oxLDL were examined. Moreover, we effectively altered legumain expression in macrophages to characterize the effect of legumain on oxLDL-induced macrophage apoptosis. The expression of apoptotic and autophagic factors was analysed. RESULTS: Legumain was present in plaques, and its expression was upregulated in macrophages treated with oxLDL. Suppressing legumain significantly increased oxLDL-induced macrophage apoptosis and the expression of caspase 3, caspase 9 and Bax. However, legumain overexpression decreased macrophage apoptosis upon oxLDL exposure and the levels of caspase 3, caspase 9 and Bax. In addition, recombinant legumain protein suppressed macrophage apoptosis. Biochemical experiments revealed that legumain deficiency decreased the levels of Beclin1 and LC3, whereas increased legumain expression increased the levels of Beclin1 and LC3 significantly. CONCLUSION: Legumain regulates oxLDL-induced macrophage apoptosis by enhancing the autophagy pathway, which may also influence the vulnerability of atherosclerotic plaques. PMID- 29414693 TI - Translation control of mRNAs encoding mammalian translation initiation factors. AB - Eukaryotic cells evolved highly complex and accurate protein synthesis machinery that is finely tuned by various signaling pathways. Dysregulation of translation is a hallmark of many diseases, including cancer, and thus pharmacological approaches to modulate translation become very promising. While there has been much progress in our understanding of mammalian mRNA-specific translation control, surprisingly, relatively little is known about whether and how the protein components of the translation machinery shape translation of their own mRNAs. Here we analyze mammalian mRNAs encoding components of the translation initiation machinery for potential regulatory features such as 5'TOP motifs, TISU motifs, poor start codon nucleotide context and upstream open reading frames. PMID- 29414694 TI - Unlocking Collagen Proteolysis with a Gentle Pull. PMID- 29414695 TI - The Bacterial Flagellar Motor Continues to Amaze. PMID- 29414696 TI - Dynamics of Posttranslational Modification Systems: Recent Progress and Future Directions. AB - Posttranslational modification of proteins is important for signal transduction, and hence significant effort has gone toward understanding how posttranslational modification networks process information. This involves, on the theory side, analyzing the dynamical systems arising from such networks. Which networks are, for instance, bistable? Which networks admit sustained oscillations? Which parameter values enable such behaviors? In this Biophysical Perspective, we highlight recent progress in this area and point out some important future directions. Along the way, we summarize several techniques for analyzing general networks, such as eliminating variables to obtain steady-state parameterizations, and harnessing results on how incorporating intermediates affects dynamics. PMID- 29414697 TI - PyFolding: Open-Source Graphing, Simulation, and Analysis of the Biophysical Properties of Proteins. AB - For many years, curve-fitting software has been heavily utilized to fit simple models to various types of biophysical data. Although such software packages are easy to use for simple functions, they are often expensive and present substantial impediments to applying more complex models or for the analysis of large data sets. One field that is reliant on such data analysis is the thermodynamics and kinetics of protein folding. Over the past decade, increasingly sophisticated analytical models have been generated, but without simple tools to enable routine analysis. Consequently, users have needed to generate their own tools or otherwise find willing collaborators. Here we present PyFolding, a free, open-source, and extensible Python framework for graphing, analysis, and simulation of the biophysical properties of proteins. To demonstrate the utility of PyFolding, we have used it to analyze and model experimental protein folding and thermodynamic data. Examples include: 1) multiphase kinetic folding fitted to linked equations, 2) global fitting of multiple data sets, and 3) analysis of repeat protein thermodynamics with Ising model variants. Moreover, we demonstrate how PyFolding is easily extensible to novel functionality beyond applications in protein folding via the addition of new models. Example scripts to perform these and other operations are supplied with the software, and we encourage users to contribute notebooks and models to create a community resource. Finally, we show that PyFolding can be used in conjunction with Jupyter notebooks as an easy way to share methods and analysis for publication and among research teams. PMID- 29414698 TI - FRET Image Correlation Spectroscopy Reveals RNAPII-Independent P-TEFb Recruitment on Chromatin. AB - Biochemical studies have revealed that the RNA Polymerase II (RNAPII) pause release is triggered by phosphorylation of the transcription machinery by the positive transcription elongation factor b (P-TEFb). However, there are no direct report that P-TEFb and RNA polymerase II interact in single living cells and the biophysical mechanisms mediating this association are still unclear. Forster resonance energy transfer (FRET) detects molecular interactions at the subcellular level. Time domain fluorescence lifetime imaging provides an accurate quantification of FRET efficiency, EFRET, because it is fluorochrome concentration-independent and insensitive to fluorescence bleed-through. However, the way FRET signal is usually analyzed does not provide information about the areas where protein-protein interactions take place. In this work, we developed a method, dubbed FRET image correlation spectroscopy (FICS), which relied on FRET fluorescence lifetime imaging image acquisition and image correlation spectroscopy of EFRET clusters to quantify the spatial distribution of interaction clusters in the nucleus. The combination of high content FRET microscopy with batch image analysis allowed a robust statistical analysis. By applying FICS, we characterized the area and density of interaction clusters between P-TEFb and RNAPII or histone H2A in single living cells. The FICS method applied to cells expressing genetically engineered mutated proteins confirmed that the histidine-rich domain of P-TEFb is required for its interaction with RNAPII. Furthermore, it demonstrated that P-TEFb was also located in close vicinity to histone H2A, independently of its interactions with RNAPII. These results support the hypothesis that P-TEFb dynamics on chromatin regulate its recruitment on RNAPII. PMID- 29414699 TI - Propagation of an Abeta Dodecamer Strain Involves a Three-Step Mechanism and a Key Intermediate. AB - Proteinaceous deposits composed of fibrillar amyloid-beta (Abeta) are the primary neuropathological hallmarks in Alzheimer disease (AD) brains. The nucleation dependent aggregation of Abeta is a stochastic process with frequently observed heterogeneity in aggregate size, structure, and conformation that manifests in fibril polymorphism. Emerging evidence indicates that polymorphic variations in Abeta fibrils contribute to phenotypic diversity and the rate of disease progression in AD. We recently demonstrated that a dodecamer strain derived from synthetic Abeta42 propagates to morphologically distinct fibrils and selectively induces cerebral amyloid angiopathy phenotype in transgenic mice. This report supports the growing contention that stable oligomer strains can influence phenotypic outcomes by faithful propagation of their structures. Although we determined the mechanism of dodecamer propagation on a mesoscopic scale, the molecular details of the microscopic reactions remained unknown. Here, we have dissected and evaluated individually the kinetics of macroscopic phases in aggregation to gain insight into the process of strain propagation. The bulk rates determined experimentally in each phase were used to build an ensemble kinetic simulation model, which confirmed our observation that dodecamer seeds initially grow by monomer addition toward the formation of a key intermediate. This is followed by conversion of the intermediate to fibrils by oligomer elongation and association mechanisms. Overall, this report reveals important insights into the molecular details of oligomer strain propagation involved in AD pathology. PMID- 29414700 TI - Structural Impact of Phosphorylation and Dielectric Constant Variation on Synaptotagmin's IDR. AB - We used time-resolved Forster resonance energy transfer, circular dichroism, and molecular dynamics simulation to investigate the structural dependence of synaptotagmin 1's intrinsically disordered region (IDR) on phosphorylation and dielectric constant. We found that a peptide corresponding to the full-length IDR sequence, a ~60-residue strong polyampholyte, can sample structurally collapsed states in aqueous solution, consistent with its kappa-predicted behavior, where kappa is a sequence-dependent parameter that is used to predict IDR compaction. In implicit solvent simulations of this same sequence, lowering the dielectric constant to more closely mimic the environment near a lipid bilayer surface promoted further sampling of collapsed structures. We then examined the structural tendencies of central region residues of the IDR in isolation. We found that the exocytosis-modulating phosphorylation of Thr112 disrupts a local disorder-to-order transition induced by trifluoroethanol/water mixtures that decrease the solution dielectric constant and stabilize helical structure. Implicit solvent simulations on these same central region residues testing the impact of dielectric constant alone converge on a similar result, showing that helical structure is formed with higher probability at a reduced dielectric. In these helical conformers, lysine-aspartic acid salt bridges contribute to stabilization of transient secondary structure. In contrast, phosphorylation results in formation of salt bridges unsuitable for helix formation. Collectively, these results suggest a model in which phosphorylation and compaction of the IDR sequence regulate structural transitions that in turn modulate neuronal exocytosis. PMID- 29414701 TI - Soft Vibrational Modes Predict Breaking Events during Force-Induced Protein Unfolding. AB - We investigate the correlation between soft vibrational modes and unfolding events in simulated force spectroscopy of proteins. Unfolding trajectories are obtained from molecular dynamics simulations of a Go model of a monomer of a mutant of superoxide dismutase 1 protein containing all heavy atoms in the protein, and a normal mode analysis is performed based on the anisotropic network model. We show that a softness map constructed from the superposition of the amplitudes of localized soft modes correlates with unfolding events at different stages of the unfolding process. Soft residues are up to eight times more likely to undergo disruption of native structure than the average amino acid. The memory of the softness map is retained for extensions of up to several nanometers, but decorrelates more rapidly during force drops. PMID- 29414702 TI - Single-Molecule Assay for Proteolytic Susceptibility: Force-Induced Collagen Destabilization. AB - Force plays a key role in regulating dynamics of biomolecular structure and interactions, yet techniques are lacking to manipulate and continuously read out this response with high throughput. We present an enzymatic assay for force dependent accessibility of structure that makes use of a wireless mini-radio centrifuge force microscope to provide a real-time readout of kinetics. The microscope is designed for ease of use, fits in a standard centrifuge bucket, and offers high-throughput, video-rate readout of individual proteolytic cleavage events. Proteolysis measurements on thousands of tethered collagen molecules show a load-enhanced trypsin sensitivity, indicating destabilization of the triple helix. PMID- 29414703 TI - PyContact: Rapid, Customizable, and Visual Analysis of Noncovalent Interactions in MD Simulations. AB - Molecular dynamics (MD) simulations have become ubiquitous in all areas of life sciences. The size and model complexity of MD simulations are rapidly growing along with increasing computing power and improved algorithms. This growth has led to the production of a large amount of simulation data that need to be filtered for relevant information to address specific biomedical and biochemical questions. One of the most relevant molecular properties that can be investigated by all-atom MD simulations is the time-dependent evolution of the complex noncovalent interaction networks governing such fundamental aspects as molecular recognition, binding strength, and mechanical and structural stability. Extracting, evaluating, and visualizing noncovalent interactions is a key task in the daily work of structural biologists. We have developed PyContact, an easy-to use, highly flexible, and intuitive graphical user interface-based application, designed to provide a toolkit to investigate biomolecular interactions in MD trajectories. PyContact is designed to facilitate this task by enabling identification of relevant noncovalent interactions in a comprehensible manner. The implementation of PyContact as a standalone application enables rapid analysis and data visualization without any additional programming requirements, and also preserves full in-program customization and extension capabilities for advanced users. The statistical analysis representation is interactively combined with full mapping of the results on the molecular system through the synergistic connection between PyContact and VMD. We showcase the capabilities and scientific significance of PyContact by analyzing and visualizing in great detail the noncovalent interactions underlying the ion permeation pathway of the human P2X3 receptor. As a second application, we examine the protein-protein interaction network of the mechanically ultrastable cohesin-dockering complex. PMID- 29414704 TI - Protein Dynamics of the Sensor Protein HemAT as Probed by Time-Resolved Step-Scan FTIR Spectroscopy. AB - The heme-based aerotactic transducer (HemAT) is an oxygen-sensor protein consisting of a sensor and a signaling domain in the N- and C-terminal regions, respectively. Time-resolved step-scan FTIR spectroscopy was employed to characterize protein intermediate states obtained by photolysis of the carbon monoxide complexes of sensor-domain, full-length HemAT, and the Y70F (B-helix), L92A (E-helix), T95A (E-helix), and Y133F (G-helix) HemAT mutants. We assign the spectral components to discrete substructures, which originate from a helical structure that is solvated (1638 cm-1) and a native helix that is protected from solvation by interhelix tertiary interactions (1654 cm-1). The full-length protein is characterized by an additional amide I absorbance at 1661 cm-1, which is attributed to disordered structure suggesting that further protein conformational changes occur in the presence of the signaling domain in the full length protein. The kinetics monitored within the amide I absorbance of the polypeptide backbone in the sensor domain exhibit two distinct relaxation phases (t1 = 24 and t2 = 694 MUs), whereas that of the full-length protein exhibits monophasic behavior for all substructures in a time range of t = 1253-2090 MUs. These observations can be instrumental in monitoring helix motion and the role of specific mutants in controlling the dynamics in the communication pathway from the sensor to the signaling domain. The kinetics observed for the amide I relaxation for the full-length protein indicate that the discrete substructures within full-length HemAT, unlike those of the sensor domain, relax independently. PMID- 29414705 TI - ESR Resolves the C Terminus Structure of the Ligand-free Human Glutathione S Transferase A1-1. AB - Nitroxide- and Cu2+-based electron spin resonance (ESR) are combined to provide insight into the conformational states of the functionally important alpha-helix of the human glutathione S-transferase A1. Distance measurements on various spin labeled dimeric human glutathione S-transferase A1-1 all result in bimodal distance distributions, indicating that the C-terminus exists in two distinct conformations in solution, one of which closely matches that found in the crystal structure of the ligand-bound enzyme. These measurements permit the generation of a model of the unliganded conformation. Room temperature ESR indicates that the second conformation has high mobility, potentially enabling the enzyme's high degree of substrate promiscuity. This model is then validated using computational modeling and further Cu2+-based ESR distance measurements. Cu2+-based ESR also provides evidence that the secondary structure of the second conformation is of helical nature. Addition of S-hexyl glutathione results in a shift in relative populations, favoring the state that is similar to the previously known structure of the ligand-bound enzyme. PMID- 29414706 TI - Solution Structure of an Intramembrane Aspartyl Protease via Small Angle Neutron Scattering. AB - Intramembrane aspartyl proteases (IAPs) comprise one of four families of integral membrane proteases that hydrolyze substrates within the hydrophobic lipid bilayer. IAPs include signal peptide peptidase, which processes remnant signal peptides from nascent polypeptides in the endoplasmic reticulum, and presenilin, the catalytic component of the gamma-secretase complex that processes Notch and amyloid precursor protein. Despite their broad biomedical reach, basic structure function relationships of IAPs remain active areas of research. Characterization of membrane-bound proteins is notoriously challenging due to their inherently hydrophobic character. For IAPs, oligomerization state in solution is one outstanding question, with previous proposals for monomer, dimer, tetramer, and octamer. Here we used small angle neutron scattering (SANS) to characterize n dodecyl-beta-D-maltopyranoside (DDM) detergent solutions containing and absent a microbial IAP ortholog. A unique feature of SANS is the ability to modulate the solvent composition to mask all but the enzyme of interest. The signal from the IAP was enhanced by deuteration and, uniquely, scattering from DDM and buffers were matched by the use of both tail-deuterated DDM and D2O. The radius of gyration calculated for IAP and the corresponding ab initio consensus model are consistent with a monomer. The model is slightly smaller than the crystallographic IAP monomer, suggesting a more compact protein in solution compared with the crystal lattice. Our study provides direct insight into the oligomeric state of purified IAP in surfactant solution, and demonstrates the utility of fully contrast-matching the detergent in SANS to characterize other intramembrane proteases and their membrane-bound substrates. PMID- 29414707 TI - Analyzing Thermal Stability of Cell Membrane of Salmonella Using Time-Multiplexed Impedance Sensing. AB - Heat treatment is one of the most widely used methods for inactivation of bacteria in food products. Heat-induced loss of bacterial viability has been variously attributed to protein denaturation, oxidative stress, or membrane leakage; indeed, it is likely to involve a combination of these processes. We examine the effect of mild heat stress (50-55 degrees C for <=12 min) on cell permeability by directly measuring the electrical conductance of samples of Salmonella enterica serovar Typhimurium to answer a fundamental biophysical question, namely, how bacteria die under mild heat stress. Our results show that when exposed to heat shock, the cell membrane is damaged and cells die mainly due to the leakage of small cytoplasmic species to the surrounding media without lysis (confirmed by fluorescent imaging). We measured the conductance change, DeltaY, of wild-type versus genetically modified heat-resistant (HR) cells in response to pulse and ramp heating profiles with different thermal time constants. In addition, we developed a phenomenological model to correlate the membrane damage, cytoplasmic leakage, and cell viability. This model traces the differential viability and DeltaY of wild-type and HR cells to the difference in the effective activation energies needed to permeabilize the cells, implying that HR cells are characterized by stronger lateral interactions between molecules, such as lipids, in their cell envelope. PMID- 29414709 TI - An Asymmetry in Monolayer Tension Regulates Lipid Droplet Budding Direction. AB - Cells store excess energy in the form of neutral lipids that are synthesized and encapsulated within the endoplasmic reticulum intermonolayer space. The lipids next demix to form lipid droplets (LDs), which, surprisingly, bud off mostly toward the cytosol. This directional LD formation is critical to energy metabolism, but its mechanism remains poorly understood. Here, we reconstituted the LD formation topology by embedding artificial LDs into the intermonolayer space of bilayer vesicles. We provide experimental evidence that the droplet behavior in the membrane is recapitulated by the physics of three-phase wetting systems, dictated by the equilibrium of surface tensions. We thereupon determined that slight tension asymmetries between the membrane monolayers regulate the droplet budding side. A differential regulation of lipid or protein composition around a forming LD can generate a monolayer tension asymmetry that will determine the LD budding side. Our results offer, to our knowledge, new insights on how the proteins might regulate LD formation side by generating a monolayer tension asymmetry. PMID- 29414710 TI - CW and CCW Conformations of the E. coli Flagellar Motor C-Ring Evaluated by Fluorescence Anisotropy. AB - The molecular cascade that controls switching of the direction of rotation of Escherichia coli flagellar motors is well known, but the conformational changes that allow the rotor to switch are still unclear. The signaling molecule CheY, when phosphorylated, binds to the C-ring at the base of the rotor, raising the probability that the motor spins clockwise. When the concentration of CheY-P is so low that the motor rotates exclusively counterclockwise (CCW), the C-ring recruits more monomers of FliM and tetramers of FliN, the proteins to which CheY P binds, thus increasing the motor's sensitivity to CheY-P and allowing it to switch once again. Motors that rotate exclusively CCW have more FliM and FliN subunits in their C-rings than motors that rotate exclusively clockwise. How are the new subunits accommodated? Does the diameter of the C-ring increase, or do FliM and FliN get packed in a different pattern, keeping the overall diameter of the C-ring constant? Here, by measuring fluorescence anisotropy of yellow fluorescent protein-labeled motors, we show that the CCW C-rings accommodate more FliM monomers without changing the spacing between them, and more FliN monomers at the same time as increasing their effective spacing and/or changing their orientation within the tetrameric structure. PMID- 29414708 TI - Why Enveloped Viruses Need Cores-The Contribution of a Nucleocapsid Core to Viral Budding. AB - During the lifecycle of many enveloped viruses, a nucleocapsid core buds through the cell membrane to acquire an outer envelope of lipid membrane and viral glycoproteins. However, the presence of a nucleocapsid core is not required for assembly of infectious particles. To determine the role of the nucleocapsid core, we develop a coarse-grained computational model with which we investigate budding dynamics as a function of glycoprotein and nucleocapsid interactions, as well as budding in the absence of a nucleocapsid. We find that there is a transition between glycoprotein-directed budding and nucleocapsid-directed budding that occurs above a threshold strength of nucleocapsid interactions. The simulations predict that glycoprotein-directed budding leads to significantly increased size polydispersity and particle polymorphism. This polydispersity can be explained by a theoretical model accounting for the competition between bending energy of the membrane and the glycoprotein shell. The simulations also show that the geometry of a budding particle leads to a barrier to subunit diffusion, which can result in a stalled, partially budded state. We present a phase diagram for this and other morphologies of budded particles. Comparison of these structures against experiments could establish bounds on whether budding is directed by glycoprotein or nucleocapsid interactions. Although our model is motivated by alphaviruses, we discuss implications of our results for other enveloped viruses. PMID- 29414711 TI - MMP Secretion Rate and Inter-invadopodia Spacing Collectively Govern Cancer Invasiveness. AB - Invadopodia are micron-sized invasive structures that mediate extracellular matrix (ECM) degradation through a combination of membrane-bound and soluble matrix metalloproteinases (MMPs). However, how such localized degradation is converted into pores big enough for cancer cells to invade, and the relative contributions of membrane-bound versus soluble MMPs to this process remain unclear. In this article, we address these questions by combining experiments and simulations. We show that in MDA-MB-231 cells, an increase in ECM density enhances invadopodia-mediated ECM degradation and decreases inter-invadopodia spacing. ECM degradation is mostly mediated by soluble MMPs, which are activated by membrane-bound MT1-MMP. We present a computational model of invadopodia mediated ECM degradation, which recapitulates the above observations and identifies MMP secretion rate as an important regulator of invadopodia stability. Simulations with multiple invadopodia suggest that inter-invadopodia spacing and MMP secretion rate collectively dictate the size of the degraded zones. Taken together, our results suggest that for creating pores conducive for cancer invasion, cells must tune inter-invadopodia spacing and MMP secretion rate in an ECM density-dependent manner, thereby striking a balance between invadopodia penetration and ECM degradation. PMID- 29414712 TI - Diffusion as a Ruler: Modeling Kinesin Diffusion as a Length Sensor for Intraflagellar Transport. AB - An important question in cell biology is whether cells are able to measure size, either whole cell size or organelle size. Perhaps cells have an internal chemical representation of size that can be used to precisely regulate growth, or perhaps size is just an accident that emerges due to constraint of nutrients. The eukaryotic flagellum is an ideal model for studying size sensing and control because its linear geometry makes it essentially one-dimensional, greatly simplifying mathematical modeling. The assembly of flagella is regulated by intraflagellar transport (IFT), in which kinesin motors carry cargo adaptors for flagellar proteins along the flagellum and then deposit them at the tip, lengthening the flagellum. The rate at which IFT motors are recruited to begin transport into the flagellum is anticorrelated with the flagellar length, implying some kind of communication between the base and the tip and possibly indicating that cells contain some mechanism for measuring flagellar length. Although it is possible to imagine many complex scenarios in which additional signaling molecules sense length and carry feedback signals to the cell body to control IFT, might the already-known components of the IFT system be sufficient to allow length dependence of IFT? Here we investigate a model in which the anterograde kinesin motors unbind after cargo delivery, diffuse back to the base, and are subsequently reused to power entry of new IFT trains into the flagellum. By mathematically modeling and simulating such a system, we are able to show that the diffusion time of the motors can in principle be sufficient to serve as a proxy for length measurement. We found that the diffusion model can not only achieve a stable steady-state length without the addition of any other signaling molecules or pathways, but also is able to produce the anticorrelation between length and IFT recruitment rate that has been observed in quantitative imaging studies. PMID- 29414713 TI - Controlling Cellular Volume via Mechanical and Physical Properties of Substrate. AB - The mechanical and physical properties of substrate play a crucial role in regulating many cell functions and behaviors. However, how these properties affect cell volume is still unclear. Here, we show that an increase in substrate stiffness, available spread area, or effective adhesion energy density results in a remarkable cell volume decrease (up to 50%), and the dynamic cell spreading process is also accompanied by dramatic cell volume decrease. Further, studies of ion channel inhibition and osmotic shock suggest that these volume decreases are due to the efflux of water and ions. We also show that disrupting cortex contractility leads to bigger cell volume. Collectively, these results reveal the "mechanism of adhesion-induced compression of cells," i.e., stronger interaction between cell and substrate leads to higher actomyosin contractility, expels water and ions, and thus decreases cell volume. PMID- 29414714 TI - The Effect of Fluorophore Conjugation on Antibody Affinity and the Photophysical Properties of Dyes. AB - Because the degree of labeling (DOL) of cell-bound antibodies, often required in quantitative fluorescence measurements, is largely unknown, we investigated the effect of labeling with two different fluorophores (AlexaFluor546, AlexaFluor647) in a systematic way using antibody stock solutions with different DOLs. Here, we show that the mean DOL of the cell-bound antibody fraction is lower than that of the stock using single molecule fluorescence measurements. The effect is so pronounced that the mean DOL levels off at approximately two fluorophores/IgG for some antibodies. We developed a method for comparing the average DOL of antibody stocks to that of the isolated, cell-bound fraction based on fluorescence anisotropy measurements confirming the aforementioned conclusions. We created a model in which individual antibody species with different DOLs, present in an antibody stock solution, were assumed to have distinct affinities and quantum yields. The model calculations confirmed that a calibration curve constructed from the anisotropy of antibody stocks can be used for determining the DOL of the bound fraction. The fluorescence intensity of the cell-bound antibody fractions and of the antibody stocks exhibited distinctly different dependence on the DOL. The behavior of the two dyes was systematically different in this respect. Fitting of the model to these data revealed that labeling with each dye affects quantum yield and antibody affinity differentially. These measurements also implied that fluorophores in multiply labeled antibodies exhibit self-quenching and lead to decreased antibody affinity, conclusions directly confirmed by steady state intensity measurements and competitive binding assays. Although the fluorescence lifetime of antibodies labeled with multiple fluorophores decreased, the magnitude of this change was not sufficient to account for self-quenching indicating that both dynamic and static quenching processes occur involving H aggregate formation. Our results reveal multiple effects of fluorophore conjugation, which must not be overlooked in quantitative cell biological measurements. PMID- 29414715 TI - Orientations of Cells on Compliant Substrates under Biaxial Stretches: A Theoretical Study. AB - Mechanical cues from the microenvironments play a regulating role in many physiological and pathological processes, such as stem cell differentiation and cancer cell metastasis. Experiments showed that cells adhered on a compliant substrate may change orientation with an externally applied strain in the substrate. By accounting for actin polymerization, actin retrograde flow, and integrin binding dynamics, here we develop a mechanism-based tensegrity model to study the orientations of polarized cells on a compliant substrate under biaxial stretches. We show that the cell can actively regulate its mechanical state by generating different traction force levels along its polarized direction. Under static or ultralow-frequency cyclic stretches, stretching a softer substrate leads to a higher increase in the traction force and induces a narrower distribution of cell alignment. Compared to static loadings, high-frequency cyclic loadings have a more significant influence on cell reorientation on a stiff substrate. In addition, the width of the cellular angular distribution scales inversely with the stretch amplitude under both static and cyclic stretches. Our results are in agreement with a wide range of experimental observations, and provide fundamental insights into the functioning of cellular mechanosensing systems. PMID- 29414716 TI - Modeling the Dynamics of Cdc42 Oscillation in Fission Yeast. AB - Regulation of polarized cell growth is essential for many cellular processes, including spatial coordination of cell morphology changes during growth and division. We present a mathematical model of the core mechanism responsible for the regulation of polarized growth dynamics by the small GTPase Cdc42. The model is based on the competition of growth zones of Cdc42 localized at the cell tips for a common substrate (inactive Cdc42) that diffuses in the cytosol. We consider several potential ways of implementing negative feedback between Cd42 and its GEF in this model that would be consistent with the observed oscillations of Cdc42 in fission yeast. We analyze the bifurcations in this model as the cell length increases, and total amount of Cdc42 and GEF increase. Symmetric antiphase oscillations at two tips emerge via saddle-homoclinic bifurcations or Hopf bifurcations. We find that a stable oscillation and a stable steady state can coexist, which is consistent with the experimental finding that only 50% of bipolar cells oscillate. The mean amplitude and period can be tuned by parameters involved in the negative feedback. We link modifications in the parameters of the model to observed mutant phenotypes. Our model suggests that negative feedback is more likely to be acting through inhibition of GEF association rather than upregulation of GEF dissociation. PMID- 29414717 TI - Steady-State Differential Dose Response in Biological Systems. AB - In pharmacology and systems biology, it is a fundamental problem to determine how biological systems change their dose-response behavior upon perturbations. In particular, it is unclear how topologies, reactions, and parameters (differentially) affect the dose response. Because parameters are often unknown, systematic approaches should directly relate network structure and function. Here, we outline a procedure to compare general non-monotone dose-response curves and subsequently develop a comprehensive theory for differential dose responses of biochemical networks captured by non-equilibrium steady-state linear framework models. Although these models are amenable to analytical derivations of non equilibrium steady states in principle, their size frequently increases (super) exponentially with model size. We extract general principles of differential responses based on a model's graph structure and thereby alleviate the combinatorial explosion. This allows us, for example, to determine reactions that affect differential responses, to identify classes of networks with equivalent differential, and to reject hypothetical models reliably without needing to know parameter values. We exemplify such applications for models of insulin signaling. PMID- 29414720 TI - Comparison of techniques for visualisation of the airway anatomy for ultrasound assisted intubation: A prospective study of emergency department patients. AB - PURPOSE: Ultrasound has been shown to be a highly accurate adjunct for confirming endotracheal tube (ETT) placement, however there is no universally accepted scanning technique. The objective of this study was to determine which ultrasound technique provides the highest rate of adequate airway visualisation in a sample of stable emergency department (ED) patients. METHODS: We conducted a prospective observational study using a convenience sample of ED patients. Airway imaging was performed using the following five techniques: 1) transcricothryoid membrane (TCM), 2) suprasternal notch (SSN) without transducer pressure, 3) SSN with pressure, 4) SSN with pressure to the left of the trachea and 5) SSN with pressure to the right of the trachea. A blinded reviewer scored the adequacy of airway visualisation for each technique. RESULTS: A total of 100 patients were enrolled in the study. SSN to the left of the trachea with pressure had the highest rate of adequate airway visualisation (93.0%, 95% CI 86.1-97.1%), followed by 82.0% (95% CI 73.1-89.0%) for SSN with pressure, 74.0% (95% CI 64.3 82.3%) for TCM, 44.0% (95% CI 34.1-54.3%) for SSN without pressure, and 1.0% (95% CI 0.0-5.4%) for SSN to the right of the trachea. In 76.0% (95% CI 66.4-84.0%) of patients, the SSN view was improved by moving the probe off the midline towards the patient's left. CONCLUSIONS: In a sample of ED patients, the airway anatomy relevant for use in endotracheal intubation is best visualised at the SSN to the left of the trachea with transducer pressure applied. PMID- 29414718 TI - Circuit-Host Coupling Induces Multifaceted Behavioral Modulations of a Gene Switch. AB - Quantitative modeling of gene circuits is fundamentally important to synthetic biology, as it offers the potential to transform circuit engineering from trial and-error construction to rational design and, hence, facilitates the advance of the field. Currently, typical models regard gene circuits as isolated entities and focus only on the biochemical processes within the circuits. However, such a standard paradigm is getting challenged by increasing experimental evidence suggesting that circuits and their host are intimately connected, and their interactions can potentially impact circuit behaviors. Here we systematically examined the roles of circuit-host coupling in shaping circuit dynamics by using a self-activating gene switch as a model circuit. Through a combination of deterministic modeling, stochastic simulation, and Fokker-Planck equation formalism, we found that circuit-host coupling alters switch behaviors across multiple scales. At the single-cell level, it slows the switch dynamics in the high protein production regime and enlarges the difference between stable steady state values. At the population level, it favors cells with low protein production through differential growth amplification. Together, the two-level coupling effects induce both quantitative and qualitative modulations of the switch, with the primary component of the effects determined by the circuit's architectural parameters. This study illustrates the complexity and importance of circuit-host coupling in modulating circuit behaviors, demonstrating the need for a new paradigm-integrated modeling of the circuit-host system-for quantitative understanding of engineered gene networks. PMID- 29414719 TI - Forward and Reverse Waves: Modeling Distortion Products in the Intracochlear Fluid Pressure. AB - Distortion product otoacoustic emissions are sounds that are emitted by the cochlea due to the nonlinearity of the outer hair cells. These emissions play an important role both in clinical settings and research laboratories. However, how distortion products propagate from their generation location to the middle ear remains unclear; whether distortion products propagate as a slow reverse traveling wave, or as a fast compression wave, through the cochlear fluid has been debated. In this article, we evaluate the contributions of the slow reverse wave and fast compression wave to the propagation of intracochlear distortion products using a physiologically based nonlinear model of the gerbil cochlea. This model includes a 3D two-duct model of the intracochlear fluid and a realistic model of outer hair cell biophysics. Simulations of the distortion products in the cochlear fluid pressure in response to a two-tone stimulus are compared with published in vivo experimental results. Whereas experiments have characterized distortion products at a limited number of locations, this model provides a complete description of the fluid pressure at all locations in the cochlear ducts. As in experiments, the spatial variations of the distortion products in the fluid pressure have some similarities with what is observed in response to a pure tone. Analysis of the fluid pressure demonstrates that although a fast wave component is generated, the slow wave component dominates the response. Decomposition of the model simulations into forward and reverse wave components shows that a slow forward propagating wave is generated due to the reflection of the slow reverse wave at the stapes. Wave interference between the reverse and forward components sometimes complicates the analysis of distortion products propagation using measurements at a few locations. PMID- 29414721 TI - Vascular complication after percutaneous femoral cerclage wire. AB - Cerclage wire is an effective fracture fixation method. However, its mechanical benefits are countered by local ischemia. Its efficacy for treating femoral periprosthetic fractures has been demonstrated since femoral fixation is possible even there is a stem in the diaphysis. It securely holds the proximal femur typically with an additional plate. The development of minimally-invasive surgery with plate fixation has led to the cerclage wire being inserted percutaneously. Here, we report on a case of secondary femoral ischemia following percutaneous cerclage wire of a periprosthetic femoral fracture. This was a Vancouver type B1 fracture. On the 3rd day after admission, minimally-invasive fixation with a femoral locking plate was performed with five cerclage wires added percutaneously. During the immediate postoperative course, the patient developed ischemia of the operated leg that required vascular surgery after confirmation by CT angiography. An arterial stop was visible with deviation of the superior femoral artery, which was not properly surrounded by the cerclage wire. The latter pulled perivascular tissues towards the femur. When combined with reduced arterial elasticity due to severe atherosclerosis, it resulted in arterial plication. The postoperative course was marked by multiple organ failure and death of the patient. Percutaneous surgery is an attractive option but has risks. The presence of severe atherosclerosis is a warning sign for loss of tissue elasticity. This complication can be prevented by preparing the bone surfaces and carefully positioning the patient on the traction table to avoid forced adduction. The surgeon must also be familiar with alternative techniques to cerclage wire such as polyaxial screws and additional plates. PMID- 29414722 TI - Crystal-induced oligoarthritis triggered by pembrolizumab, an immune checkpoint inhibitor. PMID- 29414723 TI - Are pharmacists' good knowledge and awareness on antibiotics taken for granted? The situation in Albania and future implications across countries. AB - OBJECTIVES: Irrational use of antibiotics is a major driver of antimicrobial resistance (AMR), exacerbated by dispensing of antibiotics without a prescription especially for typically viral infections. Such dispensing is common despite legislation. Pharmacists play a key role in advising on medicines, especially in countries where most patients seek pharmacist help as they cannot afford both physician fees and medicines. Consequently, our objective was to ascertain pharmacists' skills and knowledge regarding antibiotics when patients present to them with typically viral infections. METHODS: This was a qualitative cross sectional survey among 370 community pharmacists in Albania, with carefully selected and validated topics. The main outcome measure was knowledge of antibiotics and current legislation. RESULTS: Variable knowledge regarding antibiotics among community pharmacists. 55% knew colds are caused by viruses and 93% that antibiotics are ineffective against influenza. However, 18% believed if colds last >4 days an antibiotic can bring a patient back to work, and only 13% stated antibiotics are ineffective against viruses. Encouragingly, 93% knew penicillins can cause anaphylactic shock, 74% that antibiotics kill bacteria causing infections, and only 7% that antibiotic misuse cannot cause AMR. However, 13% stated the main disadvantage of antibiotics is that they are ineffective against viruses and 93% admitted they had no treatment protocols to consult in their daily work to direct patient care. CONCLUSION: Encouraging signs regarding pharmacists' knowledge of antibiotics in Albania; however, concerns. Instigating educational programmes among patients and pharmacists and greater enforcement of legislation should reduce AMR rates in Albania and across countries. PMID- 29414724 TI - First report of colistin resistance in OXA-181 carbapenemase-producing Klebsiella pneumoniae ST3130 in Japan. PMID- 29414725 TI - Metallo-beta-lactamase- and serine carbapenemase-producing Klebsiella spp.: a global challenge. PMID- 29414726 TI - Enzymatic degradation of poly-[(R)-3-hydroxybutyrate]: Mechanism, kinetics, consequences. AB - Poly-[(R)-3-hydroxybutyrate] (PHB) films prepared by compression molding and solvent casting, respectively, were degraded with the intracellular depolymerase enzyme natively synthetized by the strain Bacillus megaterium. Quantitative analysis proved that practically only (R)-3-hydroxybutyric acid (3-HBA) forms in the enzyme catalyzed reaction, the amount of other metabolites or side products is negligible. The purity of the product was verified by several methods (UV-VIS spectroscopy, liquid chromatography, mass spectroscopy). Degradation was followed as a function of time to determine the rate of enzymatic degradation. Based on the Michaelis-Menten equation a completely new kinetic model has been derived which takes into consideration the heterogeneous nature of the enzymatic reaction. Degradation proceeds in two steps, the adsorption of the enzyme onto the surface of the PHB film and the subsequent degradation reaction. The rate of both steps depend on the preparation method of the samples, degradation proceed almost twice as fast in compression molded films than in solvent cast samples. The model can describe and predict the formation of the reaction product as a function of time. The approach can be used even for the commercial production of 3-HBA, the chemical synthesis of which is complicated and expensive. PMID- 29414727 TI - Protective potential of thymoquinone against peroxynitrite induced modifications in histone H2A: In vitro studies. AB - Peroxynitrite (ONOO-) is a reactive oxidant involved in numerous pathological conditions. Thymoquinone (TQ) is an active constituent of Nigella sativa and is reported to have anti-disease activities, but its role on ONOO- has never been investigated. This study was undertaken to investigate the role of TQ on ONOO- induced damage of histone-H2A. Our novel data showed TQ significantly inhibited ONOO--induced oxidative damage in histone-H2A. ONOO- induces UV-hypochromicity of histone-H2A, whereas TQ reversed this effect to hyperchromicity. Tyrosine fluorescence was significantly reduced by ONOO- and was significantly increased upon TQ treatment. TQ reduces ONOO--induced hydrophobicity in histone-H2A and also reduces thermal stability of ONOO--histone H2A complex. SDS-PAGE of native histone-H2A showed a single band, which disappeared when treated with ONOO- alone. This changed was retained when protein samples were treated with TQ. Similar protective effects of TQ were found when protein carbonyl contents were estimated. In conclusion, this is the first study that shows the potential of TQ against ONOO--induced damaged of histone-H2A. TQ inhibits oxidative modification of tyrosine, lysine, arginine, proline and threonine in histone-H2A. These results have importance for the development of novel therapeutic strategies for the treatment of disorders, where ONOO- plays a role. PMID- 29414728 TI - Biophysical characterization of the DNA interaction with the biogenic polyamine putrescine: A single molecule study. AB - We have performed a biophysical characterization, at single molecule level, of the interaction between the DNA molecule and the biogenic polyamine putrescine. By using force spectroscopy, we were able to monitor the complexes formation as putrescine is added to the sample, determining the mechanical properties of such complexes and the physicochemical (binding) parameters of the interaction for three different ionic strengths. In particular, it was shown that the behavior of the equilibrium binding constant as a function of the counterion concentration deviates from the prediction of the Record-Lohman model. The measured constants were (1.3 +/- 0.2) * 105 M- 1 for [Na] = 150 mM, (2.1 +/- 0.2) * 105 M- 1 for [Na] = 10 mM, and (2.2 +/- 0.3) * 105 M- 1 for [Na] = 1 mM. The cooperativity degree of the binding reaction, on the other hand, increases with the ionic strength. From these analysis, the DNA-putrescine binding mechanisms are inferred, and a comparison with results reported for ordinary bivalent ions like magnesium is performed. Such study provides new insights on the general behavior of the DNA interactions with biogenic polyamines. PMID- 29414729 TI - Improvement of catalytic, thermodynamics and antifungal activity of constitutive Trichoderma longibrachiatum KT693225 exochitinase by covalent coupling to oxidized polysaccharides. AB - Our study full filled in two main goals preparation of constitutive exochitinase with low cost, utilizing non-chitin containing agricultural wastes, and improving the thermodynamics of purified Trichoderma longibrachiatum KT693225 exochitinase by covalent coupling to sodium periodate activated agar. Central composite design (CCD) was used to improve the chemical modification of Trichoderma longibrachiatum KT693225 exochitinase. Optimum temperature for conjugated exochitinase 60 degrees C was higher than native form 40 degrees C. Covalent coupling to oxidized agar caused 4.32, 2.75 and 2.44-fold increase in half-life values at 50, 55 and 60 degrees C, respectively. Also, conjugated exochitinase showed higher D-values (decimal reduction time) 1790.49 compared to 733.08 min for native form at 60 degrees C. Moreover, conjugated form had lower deactivation constant rate (kd) 0.39 * 10-3 min-1at 60 degrees C than native form 1.7 * 10-3 min-1. Native exochitinase exhibited higher activation energy (Ea) 3.39 Kcal.mol-1 and lower energy for denaturation (Ed) 6.88 Kcal.mol-1 compared to 3.21 and 13.05 Kcal.mol-1, respectively for conjugated form. The values of thermodynamic parameters for inactivation of native and conjugated exochitinase indicated that conjugation significantly decreased entropy (DeltaS degrees ) and increased enthalpy (DeltaH degrees ) and free energy (DeltaG degrees ) of deactivation. Conjugated exochitinase exhibited higher antifungal effect against Alternaria alternata, Fusarium oxysporium and Aspergillus niger than native form. PMID- 29414730 TI - The preparation, characterization and in vitro application evaluation of soluble soybean polysaccharide films incorporated with cinnamon essential oil nanoemulsions. AB - In this study, we developed the new bioactive film from soluble soybean polysaccharide (SSPS) incorporated with different concentrations of cinnamon essential oil nanoemulsions (CNO) and the functional properties of them were evaluated. Then CNO-SSPS film was applied on the meat during refrigerate for 8 days. The use of CNO in film production has reduced thickness, water vapor permeability, water solubility, lightness (L*), redness (a*) and whiteness (WI) and increased antioxidant activity of SSPS-films. Also, the SSPS- film containing 0.6% CNO activity only on gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes) and SSPS- film containing 0.8% CNO had antimicrobial activity on gram-positive and gram-negative bacteria. In vitro application, the pH of the meat treated with CON remained in the natural pH of meat during storage (8 days). Based on the results, the highest and lowest hardness values were for the samples of CNO- 0.8 and control, respectively. Incorporating CON at 0.6 and 0.8% concentration of cinnamon reduced 4.14 and 5.71 log cycle in the total aerobic viable count compared to uncoated and decreased of yeast and molds on 8th day by 1 log cycle compared uncoated. These resulted showed CNO-SSPS film can be used as a good preservative in meat products. PMID- 29414731 TI - Partially hydrolyzed guar gum as a potential prebiotic source. AB - Guar galactomannan was enzymatically hydrolyzed to obtain partially hydrolyzed guar gum which can be utilized as prebiotic source. In present study, growth of probiotics (Lactic Acid Bacteria strains) were studied with glucose, partially hydrolyzed guar gum and native guar gum. All the six strains were galactose &/or mannose positive using the API CHl 50 test. Almost all these strains showed an ability to assimilate partially hydrolyzed guar gum with respect to increase in optical density and viable cell count with concomitant decrease in the pH of the growth medium. Streptococcus thermophilus MD2 exhibited higher growth (7.78 log cfu/ml) while P. parvulus AI1 showed comparatively less growth (7.24 log cfu/ml) as compared to used lactobacillus and Weissella strains. Outcomes of the current study suggest that partially hydrolyzed guar can be considered as potential prebiotic compound that may further stimulate the growth of potentially probiotic bacteria or native gut microflora. PMID- 29414732 TI - Host-bacteria interaction and adhesin study for development of therapeutics. AB - Host-pathogen interaction is one of the most important areas of study to understand the adhesion of the pathogen to the host organisms. To adhere on the host cell surface, bacteria assemble the diverse adhesive structures on its surface, which play a foremost role in targeting to the host cell. We have highlighted different bacterial adhesins which are either protein mediated or glycan mediated. The present article listed examples of different bacterial adhesin proteins involved in the interactions with their host, types and subtypes of the fimbriae and non-fimbriae bacterial adhesins. Different bacterial surface adhesin subunits interact with host via different host surface biomolecules. We have also discussed the interactome of some of the pathogens with their host. Therefore, the present study will help researchers to have a detailed understanding of different interacting bacterial adhesins and henceforth, develop new therapies, adhesin specific antibodies and vaccines, which can effectively control pathogenicity of the pathogens. PMID- 29414733 TI - Preparation and antimicrobial activity of oregano essential oil Pickering emulsion stabilized by cellulose nanocrystals. AB - An effective antimicrobial system was developed by using oregano essential oil (OEO) Pickering emulsion. The Pickering emulsion was stabilized by cellulose nanocrystals (CNCs), which were from microcrystalline cellulose (MCC) by selective oxidization ammonium persulfate. Factors affecting the stability of OEO Pickering emulsions, such as oil/water ratio, CNCs concentration, ionic concentration and pH, were studied and analysed by the measurement of the droplet sizes and Zeta potential. The results showed that the emulsions had good stability at higher CNCs concentration and pH values, or at lower oil/water ratio and salt concentration. In addition, the antimicrobial efficacy of OEO Pickering emulsions against four food-related microorganisms was evaluated by determining the minimal inhibitory concentration (MIC). The results showed that prepared OEO Pickering emulsions could efficiently inhibit the growth of four tested microorganisms by destroying the integrity of the cells' membrane. The research would have a certain leading meaning on the design and use of OEO Pickering emulsions stabilized by CNCs for the delivery of antimicrobial essential oils in the food and other industries. PMID- 29414734 TI - Fabrication of whey proteins aggregates by controlled heat treatment and pH: Factors affecting aggregate size. AB - Protein aggregates can be formed by heating globular proteins above the thermal denaturation of the proteins. These aggregates can be used as delivery systems or to modulate the physicochemical and sensory properties of food products. In this study, the effects of heat treatment (15 min at 80 degrees C), pH adjustment (between 4 and 9), aging at different temperatures (between 10 and 60 degrees C) and the rate of acidification (pH decreased from 6.25 to 4 at 5 different rates) on whey proteins aggregates were studied. The results indicated that these treatments led to creation of aggregates with different sizes (0.72-5.1 MUm). Heat treatment and reducing the pH down to nearly 4 led to an increase in the size of aggregates. At pH < 7, by increasing the aging temperature, the size of aggregates increased (without heat treatment). In the heat treated samples with pH < 9, increasing the aging temperature led to an increase in the size of aggregates. Also larger aggregates were formed by increasing acidification rate. The amount of insoluble whey proteins aggregates increased as a result of applying heat treatment, decreasing pH and increasing aging temperature. The results of this study can be used for fabrication of whey proteins aggregates with specific size and functionality. PMID- 29414735 TI - Efficacy of photodynamic therapy or low level laser therapy against steroid therapy in the treatment of erosive-atrophic oral lichen planus. AB - BACKGROUND: The efficacy of photodynamic therapy (PDT) or low level laser therapy (LLLT) in the treatment of oral lichen planus (OLP) is debatable. The aim of this study was to compare the effects of PDT, LLLT or topical corticosteroid application in the treatment of erosive-atrophic OLP. MATERIALS AND METHODS: Forty-five adult patients with erosive-atrophic biopsy-proven OLP on the tongue or buccal mucosa (size <=3 cm) were randomly divided into three groups. Group-1: patients receiving PDT topical application of 50 MUl toluidine blue (1 mg/ml) with micropipette and after 10 min treated by laser irradiation using GaAlAs laser (630 nm, 10 mW/cm2, continuous wave, spot size: 1 cm2); Group-2: patients receiving LLLT using diode laser (630 nm, 10 mW, continuous wave, spot size: 1 cm2); and Group-3: patients receiving topical corticosteroid applications consisting of dexamethasone (0.5 mg in 5 ml water) mouthwash for 5 min. Demographic data, type, and severity of the lesions and pain were recorded before and after treatment and then at the 1 year follow-up. RESULTS: There was a significant difference in sign score changes before and after the treatment in the PDT group (p = 0.03), LLLT group (p = 0.04) and in the control group (p = 0.02). There was a statistically significant difference between group-1 (p = 0.001) and group-2 (p = 0.001) against group-3 before and after treatment. Mean amount of improvement in pain was significantly greater in the control group in comparison with the PDT and LLLT groups (p < 0.001). The efficacy index of the PDT group improved significantly more than the LLLT (p = 0.001) and corticosteroid groups (p = 0.001). CONCLUSION: Within the limits of the present RCT, it is indicated that PDT and LLLT are effective in the treatment of erosive atrophic forms of OLP in adult patients. However, further comparative clinical trials are needed to obtain strong conclusions in this regard. PMID- 29414736 TI - A novel cosmetic and clinically practicable laser immunotherapy for facial verruca plana: Intense pulsed light combined with BCG-PSN. AB - BACKGROUND: There is no standard method to remove facial verruca plana and achieve better cosmetic effects. The present study is the first study to use intense pulsed light (IPL) as photothermal therapy (PTT) combined with intra gluteal injection of bacillus calmette-guerin polysaccharide nucleic acid (BCG PSN), which function as immunotherapy, contracting a new type of clinically available laser immunotherapy (LIT) for the treatment of facial verruca plana. The aim of this study was to evaluate the efficacy, cosmetic outcome, and adverse reactions of IPL combined with BCG-PSN for facial verruca plana. METHODS: Twenty three patients with facial verruca plana were treated with IPL (560-nm filter, 15 17 J/cm2) and all patients were given intra-gluteal injections of BCG-PSN twice a week for 8 weeks combined with IPL once a month in two times. The clinical responses, recurrences, adverse reactions, and rejuvenation outcomes were evaluated. RESULTS: A complete and excellent response was noted in 17 patients (74%). Of the 676 treated warts, 548 were eradicated and the overall clearance rate was 81%. No patient relapsed during the 20-week follow-up. No obvious adverse reactions was observed. Almost all patients showed an improvement in skin texture after IPL treatment CONCLUSION: We conclude that a novel LIT based on BCG PSN and IPL for the treatment of facial verruca plana proved to be a well tolerated and effective treatment modality. This novel LIT can clear skin lesions and achieve a very good cosmetic effect. PMID- 29414737 TI - Assessment of safety of 5-aminolevulinic acid-mediated photodynamic therapy in rat brain. AB - BACKGROUND: Oral 5-aminolevulinic acid (ALA) induces biosynthesis/accumulation of the natural photo-sensitizer protoporphyrin IX (PpIX) in cancer cells. ALA is used widely in photodynamic diagnosis (PDD) and therapy (PDT) during malignant glioma surgery, but few studies have examined the effects of photodynamics plus ALA on normal brain tissue in vivo. We investigated the effects of ALA-mediated PDD and PDT on normal brain tissue. METHODS: We established a rat model in which the brain surface was irradiated through the skull by light-emitting diode (635 nm) after ALA administration. Using this model, we investigated the effects of various amounts of light irradiation with various ALA doses on brain tissue. RESULTS: Neurological symptoms developed with administration of ALA at 240 or 120 mg/kg accompanied by irradiation at 100 or 400 J/cm2, respectively. Dye leakage occurred due to disruption of the blood-brain barrier (BBB) at 90 mg/kg and 100 J/cm2, respectively. Thickness of the cortex increased significantly at 240 mg/kg and 400 J/cm2, respectively. The number of neurons appeared to decrease at 200 mg/kg plus 400 J/cm2, respectively, and there was an increase in the number of cells that were positive for terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) staining. CONCLUSIONS: ALA-mediated PDT is safe at doses of 90 mg/kg or less followed by light irradiation of 100 J/cm2 in rat brains. At doses above this threshold, ALA-PDT led to irreversible BBB and brain damage in rats. PMID- 29414738 TI - Integrated optoelectronic microprobes. AB - Optogenetics opened not only new exciting opportunities to interrogate the nervous system but also requires adequate probes to facilitate these wishes. Therefore, a multidisciplinary effort is essential to match these technical opportunities with biological needs in order to establish a stable and functional material-tissue interface. This in turn can address an optical intervention of the genetically modified, light sensitive cells in the nervous system and recording of electrical signals from single cells and neuronal networks that result in behavioral changes. In this review, we present the state of the art of optoelectronic probes and assess advantages and challenges of the different design approaches. At first, we discuss mechanisms and processes at the material tissue interface that influence the performance of optoelectronic probes in acute and chronic implantations. We classify optoelectronic probes by their property of delivering light to the tissue: by waveguides or by integrated light sources at the sites of intervention. Both approaches are discussed with respect to size, spatial resolution, opportunity to integrate electrodes for electrical recording and potential interactions with the target tissue. At last, we assess translational aspects of the state of the art. Long-term stability of probes and the opportunity to integrate them into fully implantable, wireless systems are a prerequisite for chronic applications and a transfer from fundamental neuroscientific studies into treatment options for diseases and clinical trials. PMID- 29414739 TI - A new approach to estimate bioavailability of pyrethroids in soil by compound specific stable isotope analysis. AB - In this study, the microbial degradation of six pyrethroids (bifenthrin, fenpropathrin, permethrin, alpha-cypermethrin, fenvalerate and deltamethrin) was investigated in soil to develop a new approach to estimate bioavailability of pyrethoids by compound-specific stable isotope analysis (CSIA). After 56-day incubation, the residual concentrations of pyrethroids in unsterilized soil were much lower than those in sterilized soil, indicating that microbial degradation was dominant for the elimination of pyrethroids. Meanwhile, the stable carbon isotope ratios of the six pyrethroids were determined during the degradation. Significant stable carbon isotope fractionation was observed during the microbial degradation of fenpropathrin, alpha-cypermethrin and deltamethrinhe. The enrichment factor epsilon was determined as -1.880/00, -1.820/00 and -2.000/00, respectively. A new approach was then developed to estimate the bioavailability of the three pyrethroids by determining stable carbon isotope ratios. The approach established in the study provides an alternative method to dynamically and quantitatively estimate bioavailability of compounds in soil based on CSIA. PMID- 29414740 TI - Airborne microbial communities in the atmospheric environment of urban hospitals in China. AB - Clinically relevant antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in bioaerosols have become a greater threat to public health. However, few reports have shown that ARB and ARGs were found in the atmosphere. High-throughput sequencing applied to environmental sciences has enhanced the exploration of microbial populations in atmospheric samples. Thus, five nosocomial bioaerosols were collected, and the dominant microbial and pathogenic microorganisms were identified by high-throughput sequencing in this study. The results suggested that the dominant microorganisms at the genus level were Massilia, Sphingomonas, Methylobacterium, Methylophilus, Micrococcineae, and Corynebacterineae. The most abundant pathogenic microorganisms were Staphylococcus saprophyticus, Corynebacterium minutissimum, Streptococcus pneumoniae, Escherichia coli, Arcobacter butzleri, Aeromonas veronii, Pseudomonas aeruginosa, and Bacillus cereus. The relationship between microbial communities and environmental factors was evaluated with canonical correspondence analysis (CCA). Meanwhile, differences in the pathogenic bacteria between bioaerosols and dust in a typical hospital was investigated. Furthermore, cultivable Staphylococcus isolates with multi-drug resistance phenotype (>3 antibiotics) in the inpatient departments were much higher than those in the transfusion area and out-patient departments, possibly attributed to the dense usage of antibiotics in inpatient departments. The results of this study might be helpful for scientifically air quality control in hospitals. PMID- 29414741 TI - Zinc, zinc nanoparticles and plants. AB - Zinc belongs to the mineral elements, the so-called micronutrients, which are essential for all types of plants. Embedding itself into the enzymes associated with proteosynthesis and energy processes, zinc is necessary for maintaining the integrity of biomembranes and also plays an important role in the development of seeds and generative organs. This review focuses on summarising the findings on the interaction of zinc and plants and translates into the knowledge of the effect of zinc nanoparticles on plants. The findings include an overview of both positive and negative effects on plants. In conclusion there is a great interest in nano-zinc as improving the knowledge about individual forms of zinc and their uptake and assimilation within higher plants may be the first step towards a wider involvement of zinc nanoparticles into agriculture. PMID- 29414742 TI - Study on highly enhanced photocatalytic tetracycline degradation of type II AgI/CuBi2O4 and Z-scheme AgBr/CuBi2O4 heterojunction photocatalysts. AB - Removal of antibiotics from aqueous solutions by photocatalysis is an advanced technology for environmental remediation. Herein, we have fabricated a series of AgX (X = I, Br)/CuBi2O4 composites through an in-situ precipitation method. The photocatalytic activity of the obtained photocatalysts was measured by the degradation of tetracycline (TC) under visible light irradiation (lambda > 420 nm). All the AgX (X = I, Br)/CuBi2O4 composites exhibit much higher photocatalytic activity than that of pure CuBi2O4. The enhanced photocatalytic activity is mainly attributed to the efficient interfacial charge separation and migration in the AgX (X = I, Br)/CuBi2O4 heterojunctions. Meanwhile, AgX (X = I, Br)/CuBi2O4 heterojunctions display excellent photocatalytic stability, and the photocatalytic degradation rates were not obvious decreased even after five successive cycles. Based on the energy band structure, the radicals trapping and electronic spin resonance (ESR) experiments, the Z-scheme mechanism of AgBr/CuBi2O4 and type II mechanism of AgI/CuBi2O4 heterojunction photocatalysts were tentatively discussed, respectively. PMID- 29414743 TI - Insights into the high performance of Mn-Co oxides derived from metal-organic frameworks for total toluene oxidation. AB - Mn-Co mixed metal oxide is considered as efficient catalyst for the total oxidation of volatile organic compounds. In this study, nanocube-like metal organic frameworks (Mn3[Co(CN)6]2.nH2O) are adopted as the precursor to generate Mn-Co oxides with different Mn/Co molar ratios, which affect little on phase structure and textural properties. The obtained MOF-Mn1Co1 with uniform metal dispersion is rich in high valence of surface Mn4+ and Co3+ species, leading to high low-temperature catalytic activity of total toluene oxidation. The results of toluene-TPD followed by TPO and toluene-TPSR match well with the catalytic performances of MOF-Mn1Co1, MOF-Mn1Co2, and MOF-Mn2Co1, and in situ FITR proves that the benzoate route exists over MOF-Mn1Co1. It is found that a moderate ratio of Mn/Co (1:1) favors good low-temperature reducibility and high Oads/Olatt, resulting in superior oxidation performance. However, the stability in the existence of water for MOF-Mn1Co1 is not satisfied, which should be overcome in the future. PMID- 29414744 TI - Does leaching of naturally occurring radionuclides from roadway pavements stabilised with coal fly ash have negative impacts on groundwater quality and human health? AB - We assessed the potential impact of using coal fly ash to stabilise roadway pavements on groundwater quality and human health. The leaching potential of naturally occurring radionuclides (NORs) typically present in the fly ash was assessed with the HYDRUS-1D code and data representative of a segment of the Wisconsin State Trunk Highway 60 as a case study. Our assessment suggests that the impact would be mainly from the chemical toxicity of uranium (U). In our particular case study, U concentration in the leachate exceeded the maximum contaminant level for this element (MCL = 30 MUg L-1) in almost all the scenarios. In the groundwater, the MCL was only exceeded under conditions of high leaching and low dilution in the aquifer. The radiological toxicity from the consumption of the contaminated groundwater by a hypothetical adult, however, was at maximum 43% of the individual dose criterion (IDC = 0.1 mSv y-1). The results also highlight the need to consider site-specific conditions such as climate and hydrogeology when assessing the environmental impacts of utilising fly ash in roadway construction applications since they could have profound effects on the assessment findings. There is also a pressing need for reliable and representative data to support realistic assessments. PMID- 29414745 TI - Characteristics and performance of aerobic algae-bacteria granular consortia in a photo-sequencing batch reactor. AB - The characteristics and performance of algae-bacteria granular consortia which cultivated with aerobic granules and targeted algae (Chlorella and Scenedesmus), and the essential difference between granular consortia and aerobic granules were investigated in this experiment. The result indicated that algae-bacteria granular consortia could be successfully developed, and the algae present in the granular consortia were mainly Chlorella and Scenedesmus. Although the change of chlorophyll composition revealed the occurrence of light limitation for algal growth, the granular consortia could maintain stable granular structure, and even showed better settling property than aerobic granules. Total nitrogen and phosphate in the algal-bacterial granular system showed better removal efficiencies (50.2% and 35.7%) than those in the aerobic granular system (32.8% and 25.6%) within one cycle (6 h). The biodiesel yield of aerobic granules could be significantly improved by algal coupled process, yet methyl linolenate and methyl palmitoleate were the dominant composition of biodiesel obtained from granular consortia and aerobic granules, respectively. Meanwhile, the difference of dominant bacterial communities in the both granules was found at the order level and family level, and alpha diversity indexes revealed the granular consortia had a higher microbial diversity. PMID- 29414746 TI - Biotransformation of macrolide antibiotics using enriched activated sludge culture: Kinetics, transformation routes and ecotoxicological evaluation. AB - The biotransformation of three prominent macrolide antibiotics (azithromycin, clarithromycin and erythromycin) by an activated sludge culture, which was adapted to high concentrations of azithromycin (10 mg/L) was investigated. The study included determination of removal kinetics of the parent compounds, identification of their major biotransformation products (TPs) and assessment of ecotoxicological effects of biotransformation. The chemical analyses were performed by ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry, which enabled a tentative identification of TPs formed during the experiments. The ecotoxicological evaluation included two end-points, residual antibiotic activity and toxicity to freshwater algae. The enriched activated sludge culture was capable of degrading all studied macrolide compounds with high removal efficiencies (>99%) of the parent compounds at elevated concentrations (10 mg/L). The elimination of all three macrolide antibiotics was associated with the formation of different TPs, including several novel compounds previously unreported in the literature. Some of the TPs were rather abundant and contributed significantly to the overall mass balance at the end of the biodegradation experiments. Biodegradation of all investigated macrolides was associated with a pronounced reduction of the residual antibiotic activity and algal toxicity, indicating a rather positive ecotoxicological outcome of the biotransformation processes achieved by the enriched sludge culture. PMID- 29414747 TI - Remediation of heavy hydrocarbon impacted soil using biopolymer and polystyrene foam beads. AB - A green chemistry solution is presented for the remediation of heavy hydrocarbon impacted soils. The two-phase recovery system relies on a plant-based biopolymer, which releases hydrocarbons from soil, and polystyrene foam beads, which recover them from solids and water. The efficiency of the process was demonstrated by comparisons with control experiments, where water, biopolymer, or beads alone yielded total petroleum hydrocarbon (TPH) reductions of 25%, 52%, and 58%, respectively, compared to 94% when 1.25 mL of 1% biopolymer and 15 mg beads per gram of soil were agitated for 30 min. Reductions in TPH content were substantial regardless of soil fraction, with removals of 97%, 91%, and 75% from sand, silt, and clay size fractions, respectively. Additionally, treatment efficiency was independent of carbon number, C13 to C43, as demonstrated by reductions in both diesel fuel (C13-C28) and residual-range organics (C25-C43) of ~90%. Compared to other published polymer- and surfactant-based treatment methods, this system requires less mobilizing agent, sorbent, and mixing time. The remediation process is both efficient and sustainable because the biopolymer is re-useable and sourced from renewable crops and polystyrene beads are obtained from recycled materials. PMID- 29414748 TI - Optimization of crystal growth of sub-micron ZSM-5 zeolite prepared by using Al(OH)3 extracted from fly ash as an aluminum source. AB - A novel approach was proposed to prepare ZSM-5 zeolite via hydrothermal synthesis by using Al(OH)3, which was extracted from fly ash by a staged treatment, as an aluminum source. The synthesis parameters and crystal growth of ZSM-5 were optimized. The optimization of crystal growth for ZSM-5 was investigated under the effect of organic steric-hindrance agents. The crystal phase and morphology of the ZSM-5 were characterized by X-ray diffractometry and scanning electron microscopy, and the particle size distribution was measured by laser particle size analyzer. The crystal growth of ZSM-5 under different hydrothermal conditions obeyed the "S" regulation. According to the analysis, the formation of ZSM-5 crystal occurred via four steps: (1) the formation of amorphous aluminosilicate by the condensation of silicate ions and aluminate ions; (2) the particle growth and aggregation of the amorphous aluminosilicate; (3) crystallization and crystal growth of ZSM-5; (4) Gentle growth after the zeolite crystal reaches a certain size. The addition of organic steric hindrance agents resulted in a decrease in grain size and crystal-particle formation with a narrow size distribution. Single-grain dispersion resulted and the micropore volume, mesopore volume, and specific surface areas were improved by the presence of organic steric agents. PMID- 29414749 TI - A field study of bioavailable polycyclic aromatic hydrocarbons (PAHs) in sewage sludge and biochar amended soils. AB - The bioavailable PAHs (freely dissolved concentration, Cfree) were determined in sewage sludge (SL) or sewage sludge and biochar (BC) amended soil. SL or SL with a 2.5, 5 or 10% of BC was applied to the soil. The study was conducted as a long term field experiment. Addition of BC to SL at a dose of 2.5 and 5% did not affect the content of Cfree PAHs in soils. However a significant difference (by 13%) in Cfree PAHs content was noted in experiment with 10% addition of BC. During the experiment, the concentration of Cfree PAHs in SL- and SL/BC-amended soil decreased. In particular sampling terms the content of Cfree PAHs in SL/BC amended soil was significantly lower comparing to the Cfree PAHs content in SL amended soil. After 18 months, Cfree PAH content was significantly lower in SL/BC amended soil than in the experiment with SL alone, and did not differ significantly from the Sigma16 Cfree content in the control soil. The largest decrease relative to the soil with sewage sludge alone was observed for 3-, 5- and 6-ring PAHs. This is the first field-based evidence that biochar soil amendment was effective to reduce of the Cfree of PAHs in sewage sludge-amended soils. PMID- 29414750 TI - Degradation of trichloroethylene in aqueous solution by rGO supported nZVI catalyst under several oxic environments. AB - The reduced graphene oxide (rGO) supported nano zero-valent iron (nZVI) (nZVI rGO) was synthesized successfully and applied in the several oxic environments to remove trichloroethylene (TCE). The nZVI-rGO had a better catalytic performance than bare nZVI for the TCE removal. Both aggregation of nZVI and agglomeration of rGO were in part prevented by loading the nZVI nanoparticles on the rGO sheet. Among all the oxic environments, the better removal of TCE was followed as the order of PMS > SPS > H2O2. Chemical scavenger tests were carried out to identify the reactive oxygen species (ROSs) generated in the removal of TCE, showing that in PMS and SPS systems, SO4- and HO were main radicals responsible for TCE removal, while HO and O2- were main radicals in H2O2 system. The possible mechanisms were proposed with nZVI-rGO under several oxic environments. The recyclability of nZVI-rGO, dechlorination and mineralization of TCE were investigated. These fundamental data confirmed the effectiveness of nZVI-rGO to remove TCE and could help selecting the suitable oxidants to use with nZVI-rGO in the actual field groundwater remediation. PMID- 29414751 TI - Dark fermentation process as pretreatment for a sustainable denaturation of asbestos containing wastes. AB - A cement asbestos compound (CAC) sample was detoxified by a treatment train based on a dark fermentation (DF) process followed by a hydrothermal phase, which led to the complete degradation of the chrysotile fibers. During the biological pretreatment, the glucose was converted in biogas rich in H2 and volatile fatty acids (VFA). The latter caused the dissolution of all the Ca-based compounds and the solubilisation of 50% brucite-like layers of chrysotile fibers contained in the CAC suspended in the bioreactor (5 g/L). XRD analysis of the solids contained in the effluents of the DF process highlighted the disappearance of the chrysotile fiber peaks. However, a complete destruction of all the asbestos fibers is hard to prove and a hydrothermal treatment was carried out to dissolve the "brucite" layers still present in solution. Due to the presence of the VFA produced during the DF, a complete destruction of chrysotile fibers was achieved by a 24 h hydrothermal process performed with a [H2SO4]/[CAC] ratio 50% lower than that adopted in a previous finding. Consequently, the DF pre-treatment can contribute to lower the H2SO4 and the energy consumption of a CAC hydrothermal treatment, due to the production of VFA and H2. PMID- 29414752 TI - Differential regulation of phenanthrene biodegradation process by kaolinite and quartz and the underlying mechanism. AB - Natural and cost-effective materials such as minerals can serve as supportive matrices to enhance biodegradation of polycyclic aromatic hydrocarbons (PAHs). In this study we evaluated and compared the regulatory role of two common soil minerals, i.e. kaolinite and quartz in phenanthrene (a model PAH) degradation by a PAH degrader Sphingomonas sp. GY2B and investigated the underlying mechanism. Overall kaolinite was more effective than quartz in promoting phenanthrene degradation and bacterial growth. And it was revealed that a more intimate association was established between GY2B and kaolinite. Si and O atoms on mineral surface were demonstrated to be involved in GY2B-mineral interaction. There was an higher polysaccharide/lipid content in the EPS (extracellular polymeric substances) secreted by GY2B on kaolinite than on quartz. Altogether, these results showed that differential bacterial growth, enzymatic activity, EPS composition as well as the interface interaction may explain the effects minerals have on PAH biodegradation. It was implicated that different interface interaction between different minerals and bacteria can affect microbial behavior, which ultimately results in different biodegradation efficiency. PMID- 29414753 TI - Modeling photodegradation kinetics of organic micropollutants in water bodies: A case of the Yellow River estuary. AB - Predicting photodegradation rate constants (k) of pollutants in water bodies is important for assessing their persistence and fate. This prediction used to be based on the k values determined under laboratory conditions that seldom consider underwater downward sunlight attenuation in the field. We studied a procedure to predict k taking the Yellow River estuary and two model chemicals (sulfamethoxazole and acyclovir) as a case. Models were developed for predicting underwater sunlight intensities from optically-active substances. Based on the predicted underwater sunlight intensities, hourly variation of k for the model compounds was predicted as a function of water depth, for a fresh water, an estuarine water and a seawater body in the estuary. Results show that photodegradation half-lives (t1/2) of the two compounds will be underestimated by dozens of times if underwater downward sunlight attenuation and intensity variation are not considered. Outdoor validation experiments show the maximum deviation between the predicted and measured k values is a factor of 2. The developed models can be employed to predict k of environmental chemicals in coastal water bodies once they are locally calibrated. PMID- 29414754 TI - Bayesian source term estimation of atmospheric releases in urban areas using LES approach. AB - The estimation of source information from limited measurements of a sensor network is a challenging inverse problem, which can be viewed as an assimilation process of the observed concentration data and the predicted concentration data. When dealing with releases in built-up areas, the predicted data are generally obtained by the Reynolds-averaged Navier-Stokes (RANS) equations, which yields building-resolving results; however, RANS-based models are outperformed by large eddy simulation (LES) in the predictions of both airflow and dispersion. Therefore, it is important to explore the possibility of improving the estimation of the source parameters by using the LES approach. In this paper, a novel source term estimation method is proposed based on LES approach using Bayesian inference. The source-receptor relationship is obtained by solving the adjoint equations constructed using the time-averaged flow field simulated by the LES approach based on the gradient diffusion hypothesis. A wind tunnel experiment with a constant point source downwind of a single building model is used to evaluate the performance of the proposed method, which is compared with that of the existing method using a RANS model. The results show that the proposed method reduces the errors of source location and releasing strength by 77% and 28%, respectively. PMID- 29414755 TI - The integrated analysis of transcriptome and proteome for exploring the biodegradation mechanism of 2, 4, 6-trinitrotoluene by Citrobacter sp. AB - Citrobacter sp. has been shown to degrade 2,4,6-trinitrotoluene (TNT). However, the mechanism of its TNT biodegradation is poorly understood. An integrated proteome and transcriptome analysis was performed for investigating the differential genes and differential proteins in bacterial growth at the onset of experiments and after 12 h treatment with TNT. With the RNA sequencing, we found a total of 3792 transcripts and 569 differentially expressed genes (>=2 fold, P < 0.05) by. Genes for amino acid transport, cellular metabolism and stress-shock proteins were up-regulated, while carbohydrate transport and metabolism were down regulated. A total of 42 protein spots (>=1.5 fold, P < 0.05) showed differential expression on two-dimensional gel electrophoresis and these proteins were identified by mass spectrometry. The most prominent proteins up-regulated were involved in energy production and conversion, amino acid transport and metabolism, posttranslational modification, protein turnover and chaperones. Proteins involved in carbohydrate transport and metabolism were down-regulated. Most notably, we observed that nemA encoding N-ethylmaleimide reductase was the most up-regulated gene involved in TNT degradation, and further proved that it can transform TNT to 4-amino-2,6-dinitrotoluene (4-ADNT) and 2-amino-4,6 dinitrotoluene (2-ADNT). This study highlights the molecular mechanisms of Citrobacter sp. for TNT removal. PMID- 29414756 TI - Synergistically catalytic oxidation of toluene over Mn modified g-C3N4/ZSM-4 under vacuum UV irradiation. AB - The process of vacuum ultraviolet (VUV)-assisted photocatalytic oxidation (PCO) has attracted great interest for volatile organic compounds (VOCs) degradation owing to its strong oxidation capability. However, the O3 by-product from VUV irradiation causes secondary pollution and needs to be overcome. In this study, a multi-functional photocatalyst of Mn/g-C3N4/ZSM-4 was thus developed by a one-pot hydrothermal method, and then combined with VUV irradiation to eliminate O3 byproduct as well as enhance toluene degradation via ozone-assisted catalytic oxidation (OZCO). Under VUV irradiation alone, 64% of toluene degradation was occurred but 51 ppm of O3 was residual. In contrast, toluene degradation was enhanced to 96% over the Mn/g-C3N4/ZSM-4 while residual O3 was decreased to 4 ppm. The enhanced performance was attributed to the synergistic PCO and OZCO, as the Mn modification can efficiently enhance the photocatalytic activity of g-C3N4 and trigger the catalytic ozonation simultaneously. The results of electron spin resonance (ESR) confirmed the generation of reactive species such as OH and O2- by VUV irradiation and then greatly enhanced after Mn/g-C3N4/ZSM-4 was added. Moreover, the possible mechanism of toluene degradation was also revealed through monitoring of reaction intermediate. Obviously, the process of Mn/g-C3N4/ZSM-4 cooperated well with VUV is promising for VOCs degradation. PMID- 29414757 TI - Effect of physical exercise on musculoskeletal pain in multiple body regions among healthcare workers: Secondary analysis of a cluster randomized controlled trial. AB - BACKGROUND: While physical exercise is beneficial for back and neck-shoulder pain, only few intervention studies have evaluated effects on pain in multiple body regions. Furthermore, direct measurement of pain threshold can provide additional information to self-reported pain intensity. OBJECTIVES: To evaluate the effect of workplace versus home-based physical exercise on pressure pain threshold (PPT) and musculoskeletal pain intensity in multiple body regions. STUDY DESIGN: Secondary analysis of an examiner-blinded, cluster randomized controlled trial with allocation concealment. METHOD: Two-hundred female healthcare workers from 18 departments at three hospitals were cluster-randomized to 10 weeks of: 1) home-based physical exercise (HOME) performed alone during leisure time for 5 * 10 min per week or 2) workplace physical exercise (WORK) performed in groups during working hours for 5 * 10 min per week and up to 5 motivational coaching sessions. PPT (neck, lower back, lower leg) and perceived pain intensity in multiple body regions (feet, knee, hips, lower and upper back, elbow, hand, shoulder, neck, and head) were measured at baseline and 10-week follow-up. RESULTS: In some of the body regions, PPT and pain intensity improved more following WORK than HOME. Between-group differences at follow-up (WORK vs. HOME) were 41 kPA [95% CI 13-70, effect size (ES): 0.22] for PPT in the lower back, and -0.7 [95% CI -1.0-0.3, ES: 0.26] and -0.6 points [95% CI -0.9--0.2, ES: 0.23] for pain intensity in the lower back and feet, respectively. HOME did not improve more than WORK for any of the measurements. CONCLUSION: Physical exercise recommendations for healthcare workers should consider the setting, i.e. performing supervised group-based exercise at work and motivational coaching sessions is more effective than exercising alone at home. PMID- 29414758 TI - Morphometric changes of the cervical intervertebral foramen: A comparative analysis of pre-manipulative positioning and physiological axial rotation. AB - BACKGROUND: Cervical foraminal impingement has been described as a source of radicular pain. Clinical tests and head motions have been reported for affecting the intervertebral foramen (IVF) dimensions. Although manual approaches are proposed in the management of cervical radiculopathy, their influence on the foraminal dimensions remains unclear. OBJECTIVES: To investigate the influence of pre-manipulative positioning versus cervical axial rotation on the foraminal dimensions of the lower cervical spine. METHODS: Thirty asymptomatic volunteers underwent CT scan imaging in neutral position and axial rotation or pre manipulative positioning. The manipulation task was performed at C4-C5 following a multiple components procedure. 3D kinematics and IVF (height, width and area) were computed for each cervical segment. RESULTS: The results showed that foraminal changes are dependent on motion types and cervical levels. With reference to head rotation, IVF opening occurred on the ipsilateral side during pre-manipulative positioning while axial rotation involved the contralateral side. Regardless of the side considered, magnitudes of opening were similar between both attitudes while narrowing was lower at the target and adjacent levels during the pre-manipulative positioning. Some associations between segmental motion and IVF changes were observed for the target level and the overlying level. CONCLUSIONS: The present study demonstrated that pre manipulative positioning targeting C4-C5 modified IVF dimensions differently than the passive axial rotation. The findings suggest that techniques which incorporate combined movement positioning influence segmental motion and IVF dimensions differently at the target segment, compared to unconstrained rotation. Further investigations are needed to determine the clinical outcomes of such an approach. PMID- 29414759 TI - Proteomic Analysis of Urothelium of Rats with Detrusor Overactivity Induced by Bladder Outlet Obstruction. AB - Overactive bladder (OAB) syndrome is a condition that has four symptoms: urgency, urinary frequency, nocturia, and urge incontinence and negatively affects a patient's life. Recently, it is considered that the urinary bladder urothelium is closely linked to pathogenesis of OAB. However, the mechanisms of pathogenesis of OAB at the molecular level remain poorly understood, mainly because of lack of modern molecular analysis. The goal of this study is to identify a potential target protein that could act as a predictive factor for effective diagnosis and aid in the development of therapeutic strategies for the treatment of OAB syndrome. We produced OAB in a rat model and performed the first proteomic analysis on the mucosal layer (urothelium) of the bladders of sham control and OAB rats. The resulting data revealed the differential expression of 355 proteins in the bladder urothelium of OAB rats compared with sham subjects. Signaling pathway analysis revealed that the differentially expressed proteins were mainly involved in the inflammatory response and apoptosis. Our findings suggest a new target for accurate diagnosis of OAB that can provide essential information for the development of drug treatment strategies as well as establish criteria for screening patients in the clinical environment. PMID- 29414760 TI - Proteome Data Improves Protein Function Prediction in the Interactome of Helicobacter pylori. AB - Helicobacter pylori is a common pathogen that is estimated to infect half of the human population, causing several diseases such as duodenal ulcer. Despite one of the first pathogens to be sequenced, its proteome remains poorly characterized as about one-third of its proteins have no functional annotation. Here, we integrate and analyze known protein interactions with proteomic and genomic data from different sources. We find that proteins with similar abundances tend to interact. Such an observation is accompanied by a trend of interactions to appear between proteins of similar functions, although some show marked cross-talk to others. Protein function prediction with protein interactions is significantly improved when interactions from other bacteria are included in our network, allowing us to obtain putative functions of more than 300 poorly or previously uncharacterized proteins. Proteins that are critical for the topological controllability of the underlying network are significantly enriched with genes that are up-regulated in the spiral compared with the coccoid form of H. pylori Determining their evolutionary conservation, we present evidence that 80 protein complexes are identical in composition with their counterparts in Escherichia coli, while 85 are partially conserved and 120 complexes are completely absent. Furthermore, we determine network clusters that coincide with related functions, gene essentiality, genetic context, cellular localization, and gene expression in different cellular states. PMID- 29414761 TI - Global Analyses of Selective Insulin Resistance in Hepatocytes Caused by Palmitate Lipotoxicity. AB - Obesity is tightly linked to hepatic steatosis and insulin resistance. One feature of this association is the paradox of selective insulin resistance: insulin fails to suppress hepatic gluconeogenesis but activates lipid synthesis in the liver. How lipid accumulation interferes selectively with some branches of hepatic insulin signaling is not well understood. Here we provide a resource, based on unbiased approaches and established in a simple cell culture system, to enable investigations of the phenomenon of selective insulin resistance. We analyzed the phosphoproteome of insulin-treated human hepatoma cells and identified sites in which palmitate selectively impairs insulin signaling. As an example, we show that palmitate interferes with insulin signaling to FoxO1, a key transcription factor regulating gluconeogenesis, and identify altered FoxO1 cellular compartmentalization as a contributing mechanism for selective insulin resistance. This model system, together with our comprehensive characterization of the proteome, phosphoproteome, and lipidome changes in response to palmitate treatment, provides a novel and useful resource for unraveling the mechanisms underlying selective insulin resistance. PMID- 29414762 TI - Peptide Level Turnover Measurements Enable the Study of Proteoform Dynamics. AB - The coordination of protein synthesis and degradation regulating protein abundance is a fundamental process in cellular homeostasis. Today, mass spectrometry-based technologies allow determination of endogenous protein turnover on a proteome-wide scale. However, standard dynamic SILAC (Stable Isotope Labeling in Cell Culture) approaches can suffer from missing data across pulse time-points limiting the accuracy of such analysis. This issue is of particular relevance when studying protein stability at the level of proteoforms because often only single peptides distinguish between different protein products of the same gene. To address this shortcoming, we evaluated the merits of combining dynamic SILAC and tandem mass tag (TMT)-labeling of ten pulse time points in a single experiment. Although the comparison to the standard dynamic SILAC method showed a high concordance of protein turnover rates, the pulsed SILAC-TMT approach yielded more comprehensive data (6000 proteins on average) without missing values. Replicate analysis further established that the same reproducibility of turnover rate determination can be obtained for peptides and proteins facilitating proteoform resolved investigation of protein stability. We provide several examples of differentially turned over splice variants and show that post-translational modifications can affect cellular protein half-lives. For example, N-terminally processed peptides exhibited both faster and slower turnover behavior compared with other peptides of the same protein. In addition, the suspected proteolytic processing of the fusion protein FAU was substantiated by measuring vastly different stabilities of the cleavage products. Furthermore, differential peptide turnover suggested a previously unknown mechanism of activity regulation by post-translational destabilization of cathepsin D as well as the DNA helicase BLM. Finally, our comprehensive data set facilitated a detailed evaluation of the impact of protein properties and functions on protein stability in steady-state cells and uncovered that the high turnover of respiratory chain complex I proteins might be explained by oxidative stress. PMID- 29414763 TI - Production of lipid mediators across different disease stages of dextran sodium sulfate-induced colitis in mice. AB - Although several studies have revealed the role of different lipid mediators in colitis, the comprehensive analysis of their production across different phases of colitis remained unclear. Here, we performed the following analysis in the dextran sodium sulfate (DSS)-induced colitis model using LC-MS/MS. Oral administration of 2% DSS in mice for 4 days resulted in severe intestinal inflammation by day 7, which gradually subsided by day 18. Based on the disease scoring index (assigned on the basis of fecal condition and weight loss), we defined the phases of colitis as induction (days 0-4), acute inflammation (days 4 7), recovery (days 7-9), and late recovery (days 9-18). Across all phases, 58 lipid mediators were detected in the inflamed colon tissue. In the induction phase, the production of n-6 fatty acid-derived prostaglandin E2 and thromboxane B2 increased by ~2-fold. In the acute inflammation phase, the production of n-6 fatty acid-derived leukotrienes increased by >10-fold, while that of n-3 fatty acid-derived hydroxyeicosapentaenoic acids and dihydroxyeicosatetraenoic acids decreased. In the recovery phase, a precursor of protectin D1 (17 hydroxydocosahexaenoic acid) increased over 3-fold. These observations suggested dynamic changes in the production of lipid mediators across different phases of the disease and their potential regulation in healing colitis. PMID- 29414764 TI - Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo. AB - The ketogenic diet (KD) is a high-fat, very-low-carbohydrate diet that triggers a fasting state by decreasing glucose and increasing ketone bodies, such as beta hydroxybutyrate (betaHB). In experimental models and clinical trials, the KD has shown anti-tumor effects, possibly by reducing energy supplies to cells, which damage the tumor microenvironment and inhibit tumor growth. Here, we determined expression levels of genes encoding the ketolytic enzymes 3-hydroxybutyrate dehydrogenase 1 (BDH1) and succinyl-CoA: 3-oxoacid CoA transferase 1 (OXCT1) in 33 human cancer cell lines. We then selected two representative lines, HeLa and PANC-1, for in vivo examination of KD sensitivity in tumors with high or low expression, respectively, of these two enzymes. In mice with HeLa xenografts, the KD increased tumor growth and mouse survival decreased, possibly because these tumors actively consumed ketone bodies as an energy source. Conversely, the KD significantly inhibited growth of PANC-1 xenograft tumors. betaHB added to each cell culture significantly increased proliferation of HeLa cells, but not PANCI-1 cells. Downregulation of both BDH1 and OXCT1 rendered HeLa cells sensitive to the KD in vitro and in vivo. Tumors with low ketolytic enzyme expression may be unable to metabolize ketone bodies, thus predicting a better response to KD therapy. PMID- 29414766 TI - Expanding the molecular weaponry of bacterial species. AB - The type VI secretion system (T6SS) delivers toxic effectors between Gram negative bacteria. Most antibacterial T6SS effectors are peptidoglycanases, nucleases, or lipases. In the current work, Tang et al. structurally and functionally characterize a novel family of NAD(P)+-hydrolyzing effectors (NADases), thus expanding the documented types of T6SS substrates. Bioinformatic identification of NADase family members putatively secreted by the bacteriolytic type VII secretion system (T7SS) of Gram-positive bacteria further points to NADases as a diverse and important class of effectors. PMID- 29414765 TI - Delta9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation. AB - Phytocannabinoids, such as Delta9-tetrahydrocannabinol (THC), bind and activate cannabinoid (CB) receptors, thereby "piggy-backing" on the same pathway's endogenous endocannabinoids (ECs). The recent discovery that liver fatty acid binding protein-1 (FABP1) is the major cytosolic "chaperone" protein with high affinity for both Delta9-THC and ECs suggests that Delta9-THC may alter hepatic EC levels. Therefore, the impact of Delta9-THC or EC treatment on the levels of endogenous ECs, such as N-arachidonoylethanolamide (AEA) and 2 arachidonoylglycerol (2-AG), was examined in cultured primary mouse hepatocytes from WT and Fabp1 gene-ablated (LKO) mice. Delta9-THC alone or 2-AG alone significantly increased AEA and especially 2-AG levels in WT hepatocytes. LKO alone markedly increased AEA and 2-AG levels. However, LKO blocked/diminished the ability of Delta9-THC to further increase both AEA and 2-AG. In contrast, LKO potentiated the ability of exogenous 2-AG to increase the hepatocyte level of AEA and 2-AG. These and other data suggest that Delta9-THC increases hepatocyte EC levels, at least in part, by upregulating endogenous AEA and 2-AG levels. This may arise from Delta9-THC competing with AEA and 2-AG binding to FABP1, thereby decreasing targeting of bound AEA and 2-AG to the degradative enzymes, fatty acid amide hydrolase and monoacylglyceride lipase, to decrease hydrolysis within hepatocytes. PMID- 29414767 TI - Fic-mediated deAMPylation is not dependent on homodimerization and rescues toxic AMPylation in flies. PMID- 29414768 TI - Lipids and phosphates at odds in synaptic depression. AB - Long-term depression (LTD) is a reduction in the efficacy of neuronal synapses, but the molecular basis of LTD signaling and how these signals lead to phenotypic outcomes, such as the shrinkage of synaptic regions, is not clear. In a new report, Woolfrey et al use chemically-induced LTD and a multitude of in vitro biochemical assays to provide evidence that synaptic removal of the scaffolding protein AKAP79/150 promotes LTD-induced spine shrinkage. The further identification of CaMKII, a kinase primarily associated with long-term potentiation (LTP), as a requirement for AKAP79/150 removal, uncovers unexpected interplay between different post-translational modifications and points to a new model of LTD. PMID- 29414769 TI - High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in Caenorhabditis elegans. AB - The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine de novo synthesis. It metabolizes 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which is an AMP analogue, leading to activation of AMP activated kinase (AMPK). We investigated whether the AICAR-ATIC pathway plays a role in the high glucose (HG)-mediated DNA damage response and AICAR-mediated AMPK activation, explaining the detrimental effects of glucose on neuronal damage and shortening of the lifespan. HG up-regulated the expression and activity of the Caenorhabditis elegans homologue of ATIC, C55F2.1 (atic-1), and increased the levels of reactive oxygen species and methylglyoxal-derived advanced glycation end products. Overexpression of atic-1 decreased the lifespan and head motility and increased neuronal damage under both standard and HG conditions. Inhibition of atic-1 expression, by RNAi, under HG was associated with increased lifespan and head motility and reduced neuronal damage, reactive oxygen species, and methylglyoxal-derived advanced glycation end product accumulation. This effect was independent of an effect on DNA damage or antioxidant defense pathways, such as superoxide dismutase (sod-3) or glyoxalase-1 (glod-4), but was dependent on AMPK and accumulation of AICAR. Through AMPK, AICAR treatment also reduced the negative effects of HG. The mitochondrial inhibitor rotenone abolished the AICAR/AMPK-induced amelioration of HG effects, pointing to mitochondria as a prime target of the glucotoxic effects in C. elegans We conclude that atic-1 is involved in glucotoxic effects under HG conditions, either by blocked atic-1 expression or via AICAR and AMPK induction. PMID- 29414770 TI - Homocysteine regulates fatty acid and lipid metabolism in yeast. AB - S-Adenosyl-l-homocysteine hydrolase (AdoHcy hydrolase; Sah1 in yeast/AHCY in mammals) degrades AdoHcy, a by-product and strong product inhibitor of S-adenosyl l-methionine (AdoMet)-dependent methylation reactions, to adenosine and homocysteine (Hcy). This reaction is reversible, so any elevation of Hcy levels, such as in hyperhomocysteinemia (HHcy), drives the formation of AdoHcy, with detrimental consequences for cellular methylation reactions. HHcy, a pathological condition linked to cardiovascular and neurological disorders, as well as fatty liver among others, is associated with a deregulation of lipid metabolism. Here, we developed a yeast model of HHcy to identify mechanisms that dysregulate lipid metabolism. Hcy supplementation to wildtype cells up-regulated cellular fatty acid and triacylglycerol content and induced a shift in fatty acid composition, similar to changes observed in mutants lacking Sah1. Expression of the irreversible bacterial pathway for AdoHcy degradation in yeast allowed us to dissect the impact of AdoHcy accumulation on lipid metabolism from the impact of elevated Hcy. Expression of this pathway fully suppressed the growth deficit of sah1 mutants as well as the deregulation of lipid metabolism in both the sah1 mutant and Hcy-exposed wildtype, showing that AdoHcy accumulation mediates the deregulation of lipid metabolism in response to elevated Hcy in yeast. Furthermore, Hcy supplementation in yeast led to increased resistance to cerulenin, an inhibitor of fatty acid synthase, as well as to a concomitant decline of condensing enzymes involved in very long-chain fatty acid synthesis, in line with the observed shift in fatty acid content and composition. PMID- 29414771 TI - Glycation of human serum albumin impairs binding to the glucagon-like peptide-1 analogue liraglutide. AB - The long-acting glucagon-like peptide-1 analogue liraglutide has proven efficiency in the management of type 2 diabetes and also has beneficial effects on cardiovascular diseases. Liraglutide's protracted action highly depends on its capacity to bind to albumin via its palmitic acid part. However, in diabetes, albumin can undergo glycation, resulting in impaired drug binding. Our objective in this study was to assess the impact of human serum albumin (HSA) glycation on liraglutide affinity. Using fluorine labeling of the drug and 19F NMR, we determined HSA affinity for liraglutide in two glycated albumin models. We either glycated HSA in vitro by incubation with glucose (G25- or G100-HSA) or methylglyoxal (MGO-HSA) or purified in vivo glycated HSA from the plasma of diabetic patients with poor glycemic control. Nonglycated commercial HSA (G0-HSA) and HSA purified from plasma of healthy individuals served as controls. We found that glycation decreases affinity for liraglutide by 7-fold for G100-HSA and by 5 fold for MGO-HSA compared with G0-HSA. A similarly reduced affinity was observed for HSA purified from diabetic individuals compared with HSA from healthy individuals. Our results reveal that glycation significantly impairs HSA affinity to liraglutide and confirm that glycation contributes to liraglutide's variable therapeutic efficiency, depending on diabetes stage. Because diabetes is a progressive disease, the effect of glycated albumin on liraglutide affinity found here is important to consider when diabetes is managed with this drug. PMID- 29414772 TI - Fungal melanin stimulates surfactant protein D-mediated opsonization of and host immune response to Aspergillus fumigatus spores. AB - Surfactant protein D (SP-D), a C-type lectin and pattern-recognition soluble factor, plays an important role in immune surveillance to detect and eliminate human pulmonary pathogens. SP-D has been shown to protect against infections with the most ubiquitous airborne fungal pathogen, Aspergillus fumigatus, but the fungal surface component(s) interacting with SP-D is unknown. Here, we show that SP-D binds to melanin pigment on the surface of A. fumigatus dormant spores (conidia). SP-D also exhibited an affinity to two cell-wall polysaccharides of A. fumigatus, galactomannan (GM) and galactosaminogalactan (GAG). The immunolabeling pattern of SP-D was punctate on the conidial surface and was uniform on germinating conidia, in accordance with the localization of melanin, GM, and GAG. We also found that the collagen-like domain of SP-D is involved in its interaction with melanin, whereas its carbohydrate-recognition domain recognized GM and GAG. Unlike un-opsonized conidia, SP-D-opsonized conidia were phagocytosed more efficiently and stimulated the secretion of proinflammatory cytokines by human monocyte-derived macrophages. Furthermore, SP-D-/- mice challenged intranasally with wildtype conidia or melanin ghosts (i.e. hollow melanin spheres) displayed significantly reduced proinflammatory cytokines in the lung compared with wildtype mice. In summary, SP-D binds to melanin present on the dormant A. fumigatus conidial surface, facilitates conidial phagocytosis, and stimulates the host immune response. PMID- 29414773 TI - MinC and FtsZ mutant analysis provides insight into MinC/MinD-mediated Z ring disassembly. AB - The Min system negatively regulates the position of the Z ring, which serves as a scaffold for the divisome that mediates bacterial cytokinesis. In Escherichia coli, this system consists of MinC, which antagonizes assembly of the tubulin homologue FtsZ. MinC is recruited to the membrane by MinD and induced by MinE to oscillate between the cell poles. MinC is a dimer with each monomer consisting of functionally distinct MinCN and MinCC domains, both of which contact FtsZ. According to one model, MinCC/MinD binding to the FtsZ tail positions MinCN at the junction of two GDP-containing subunits in the filament, leading to filament breakage. Others posit that MinC sequesters FtsZ-GDP monomers or that MinCN caps the minus end of FtsZ polymers and that MinCC interferes with lateral interactions between FtsZ filaments. Here, we isolated minC mutations that impair MinCN function and analyzed FtsZ mutants resistant to MinC/MinD. Surprisingly, we found mutations in both minC and ftsZ that differentiate inhibition by MinC from inhibition by MinC/MinD. Analysis of these mutations suggests that inhibition of the Z ring by MinC alone is due to sequestration, whereas inhibition by MinC/MinD is not. In conclusion, our genetic and biochemical data support the model that MinC/MinD fragments FtsZ filaments. PMID- 29414774 TI - Hexokinase 2 and nuclear factor erythroid 2-related factor 2 transcriptionally coactivate xanthine oxidoreductase expression in stressed glioma cells. AB - A dynamic network of metabolic adaptations, inflammatory responses, and redox homeostasis is known to drive tumor progression. A considerable overlap among these processes exists, but several of their key regulators remain unknown. To this end, here we investigated the role of the proinflammatory cytokine IL-1beta in connecting these processes in glioma cells. We found that glucose starvation sensitizes glioma cells to IL-1beta-induced apoptosis in a manner that depended on reactive oxygen species (ROS). Although IL-1beta-induced JNK had no effect on cell viability under glucose deprivation, it mediated nuclear translocation of hexokinase 2 (HK2). This event was accompanied by increases in the levels of sirtuin 6 (SIRT6), nuclear factor erythroid 2-related factor 2 (Nrf2), and xanthine oxidoreductase (XOR). SIRT6 not only induced ROS-mediated cell death but also facilitated nuclear Nrf2-HK2 interaction. Recruitment of the Nrf2-HK2 complex to the ARE site on XOR promoter regulated its expression. Importantly, HK2 served as transcriptional coactivator of Nrf2 to regulate XOR expression, indicated by decreased XOR levels in siRNA-mediated Nrf2 and HK2 knockdown experiments. Our results highlight a non-metabolic role of HK2 as transcriptional coactivator of Nrf2 to regulate XOR expression under conditions of proinflammatory and metabolic stresses. Our insights also underscore the importance of nuclear activities of HK2 in the regulation of genes involved in redox homeostasis. PMID- 29414775 TI - The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF-ERK signaling. AB - Myc-associated zinc-finger protein (MAZ) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression is associated with the progression of pancreatic ductal adenocarcinoma (PDAC). However, the mechanism of action of MAZ in PDAC progression is largely unknown. Here, we present evidence that MAZ mRNA expression and protein levels are increased in human PDAC cell lines, tissue samples, a subcutaneous tumor xenograft in a nude mouse model, and spontaneous cancer in the genetically engineered PDAC mouse model. We also found that MAZ is predominantly expressed in pancreatic cancer stem cells. Functional analysis indicated that MAZ depletion in PDAC cells inhibits invasive phenotypes such as the epithelial-to-mesenchymal transition, migration, invasion, and the sphere-forming ability of PDAC cells. Mechanistically, we detected no direct effects of MAZ on the expression of K-Ras mutants, but MAZ increased the activity of CRAF-ERK signaling, a downstream signaling target of K-Ras. The MAZ-induced activation of CRAF-ERK signaling was mediated via p21-activated protein kinase (PAK) and protein kinase B (AKT/PKB) signaling cascades and promoted PDAC cell invasiveness. Moreover, we found that the matricellular oncoprotein cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) regulates MAZ expression via Notch-1-sonic hedgehog signaling in PDAC cells. We propose that Cyr61/CCN1-induced expression of MAZ promotes invasive phenotypes of PDAC cells not through direct K-Ras activation but instead through the activation of CRAF-ERK signaling. Collectively, these results highlight key molecular players in PDAC invasiveness and may help inform therapeutic strategies to improve clinical management and outcomes of PDAC. PMID- 29414776 TI - Identification of a staphylococcal complement inhibitor with broad host specificity in equid Staphylococcus aureus strains. AB - Staphylococcus aureus is a versatile pathogen capable of causing a broad range of diseases in many different hosts. S. aureus can adapt to its host through modification of its genome (e.g. by acquisition and exchange of mobile genetic elements that encode host-specific virulence factors). Recently, the prophage phiSaeq1 was discovered in S. aureus strains from six different clonal lineages almost exclusively isolated from equids. Within this phage, we discovered a novel variant of staphylococcal complement inhibitor (SCIN), a secreted protein that interferes with activation of the human complement system, an important line of host defense. We here show that this equine variant of SCIN, eqSCIN, is a potent blocker of equine complement system activation and subsequent phagocytosis of bacteria by phagocytes. Mechanistic studies indicate that eqSCIN blocks equine complement activation by specific inhibition of the C3 convertase enzyme (C3bBb). Whereas SCIN-A from human S. aureus isolates exclusively inhibits human complement, eqSCIN represents the first animal-adapted SCIN variant that functions in a broader range of hosts (horses, humans, and pigs). Binding analyses suggest that the human-specific activity of SCIN-A is related to amino acid differences on both sides of the SCIN-C3b interface. These data suggest that modification of this phage-encoded complement inhibitor plays a role in the host adaptation of S. aureus and are important to understand how this pathogen transfers between different hosts. PMID- 29414777 TI - A cross-domain charge interaction governs the activity of NO synthase. AB - NO synthase (NOS) enzymes perform interdomain electron transfer reactions during catalysis that may rely on complementary charge interactions at domain-domain interfaces. Guided by our previous results and a computer-generated domain docking model, we assessed the importance of cross-domain charge interactions in the FMN-to-heme electron transfer in neuronal NOS (nNOS). We reversed the charge of three residues (Glu-762, Glu-816, and Glu-819) that form an electronegative triad on the FMN domain and then individually reversed the charges of three electropositive residues (Lys-423, Lys-620, and Lys-660) on the oxygenase domain (NOSoxy), to potentially restore a cross-domain charge interaction with the triad, but in reversed polarity. Charge reversal of the triad completely eliminated heme reduction and NO synthesis in nNOS. These functions were partly restored by the charge reversal at oxygenase residue Lys-423, but not at Lys-620 or Lys-660. Full recovery of heme reduction was probably muted by an accompanying change in FMN midpoint potential that made electron transfer to the heme thermodynamically unfavorable. Our results provide direct evidence that cross domain charge pairing is required for the FMN-to-heme electron transfer in nNOS. The unique ability of charge reversal at position 423 to rescue function indicates that it participates in an essential cross-domain charge interaction with the FMN domain triad. This supports our domain-docking model and suggests that it may depict a productive electron transfer complex formed during nNOS catalysis. PMID- 29414778 TI - Modifications to a common phosphorylation network provide individualized control in caspases. AB - Caspase-3 activation and function have been well-defined during programmed cell death, but caspase activity, at low levels, is also required for developmental processes such as lymphoid proliferation and erythroid differentiation. Post translational modification of caspase-3 is one method used by cells to fine-tune activity below the threshold required for apoptosis, but the allosteric mechanism that reduces activity is unknown. Phosphorylation of caspase-3 at a conserved allosteric site by p38-MAPK (mitogen-activated protein kinase) promotes survival in human neutrophils, and the modification of the loop is thought to be a key regulator in many developmental processes. We utilized phylogenetic, structural, and biophysical studies to define the interaction networks that facilitate the allosteric mechanism in caspase-3. We show that, within the modified loop, Ser150 evolved with the apoptotic caspases, whereas Thr152 is a more recent evolutionary event in mammalian caspase-3. Substitutions at Ser150 result in a pH-dependent decrease in dimer stability, and localized changes in the modified loop propagate to the active site of the same protomer through a connecting surface helix. Likewise, a cluster of hydrophobic amino acids connects the conserved loop to the active site of the second protomer. The presence of Thr152 in the conserved loop introduces a "kill switch" in mammalian caspase-3, whereas the more ancient Ser150 reduces without abolishing enzyme activity. These data reveal how evolutionary changes in a conserved allosteric site result in a common pathway for lowering activity during development or a more recent cluster-specific switch to abolish activity. PMID- 29414780 TI - Decarboxylation involving a ferryl, propionate, and a tyrosyl group in a radical relay yields heme b. AB - The H2O2-dependent oxidative decarboxylation of coproheme III is the final step in the biosynthesis of heme b in many microbes. However, the coproheme decarboxylase reaction mechanism is unclear. The structure of the decarboxylase in complex with coproheme III suggested that the substrate iron, reactive propionates, and an active-site tyrosine convey a net 2e-/2H+ from each propionate to an activated form of H2O2 Time-resolved EPR spectroscopy revealed that Tyr-145 formed a radical species within 30 s of the reaction of the enzyme coproheme complex with H2O2 This radical disappeared over the next 270 s, consistent with a catalytic intermediate. Use of the harderoheme III intermediate as substrate or substitutions of redox-active side chains (W198F, W157F, or Y113S) did not strongly affect the appearance or intensity of the radical spectrum measured 30 s after initiating the reaction with H2O2, nor did it change the ~270 s required for the radical signal to recede to <=10% of its initial intensity. These results suggested Tyr-145 as the site of a catalytic radical involved in decarboxylating both propionates. Tyr-145* was accompanied by partial loss of the initially present Fe(III) EPR signal intensity, consistent with the possible formation of Fe(IV)=O. Site-specifically deuterated coproheme gave rise to a kinetic isotope effect of ~2 on the decarboxylation rate constant, indicating that cleavage of the propionate Cbeta-H bond was partly rate-limiting. The inferred mechanism requires two consecutive hydrogen atom transfers, first from Tyr-145 to the substrate Fe/H2O2 intermediate and then from the propionate Cbeta-H to Tyr-145*. PMID- 29414779 TI - Structure and biophysical characterization of the human full-length neurturin GFRa2 complex: A role for heparan sulfate in signaling. AB - Neurturin (NRTN) provides trophic support to neurons and is considered a therapeutic agent for neurodegenerative diseases, such as Parkinson's disease. It binds to its co-receptor GFRa2, and the resulting NRTN-GFRa2 complex activates the transmembrane receptors rearranged during transfection (RET) or the neural cell adhesion molecule (NCAM). We report the crystal structure of NRTN, alone and in complex with GFRa2. This is the first crystal structure of a GFRa with all three domains and shows that domain 1 does not interact directly with NRTN, but it may support an interaction with RET and/or NCAM, via a highly conserved surface. In addition, biophysical results show that the relative concentration of GFRa2 on cell surfaces can affect the functional affinity of NRTN through avidity effects. We have identified a heparan sulfate-binding site on NRTN and a putative binding site in GFRa2, suggesting that heparan sulfate has a role in the assembly of the signaling complex. We further show that mutant NRTN with reduced affinity for heparan sulfate may provide a route forward for delivery of NRTN with increased exposure in preclinical in vivo models and ultimately to Parkinson's patients. PMID- 29414781 TI - Maresin 1 attenuates NAFLD by suppression of endoplasmic reticulum stress via AMPK-SERCA2b pathway. AB - Maresin 1 (MAR1), which is derived from docosahexaenoic acid biosynthesized by macrophages, has been reported to improve insulin resistance. Recently, it has been documented that MAR1 could ameliorate inflammation and insulin resistance in obese mice. These findings led us to investigate the effects of MAR1 on hepatic lipid metabolism. We found that MAR1 could stimulate AMP-activated protein kinase (AMPK), thereby augmenting sarcoendoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) expression. This stimulation suppressed lipid accumulation by attenuating the endoplasmic reticulum (ER) stress in hepatocytes under hyperlipidemic conditions. Attenuation was mitigated by knockdown of AMPK or thapsigargin, a SERCA2b inhibitor. We also demonstrated that MAR1 administration resulted in increased hepatic AMPK phosphorylation and Serca2b mRNA expression, whereas hepatic ER stress was reduced in high-fat diet (HFD)-fed mice. Moreover, MAR1 treatment suppressed hepatic lipid synthesis, thereby attenuating hepatic steatosis in HFD fed mice. In conclusion, our results suggest that MAR1 ameliorates hepatic steatosis via AMPK/SERCA2b-mediated suppression of ER stress. Therefore, MAR1 may be an effective therapeutic strategy for treating non-alcoholic fatty liver disease (NAFLD) via regulation of ER stress-induced hepatic lipogenesis. PMID- 29414782 TI - B cell lymphoma 2 (Bcl-2) residues essential for Bcl-2's apoptosis-inducing interaction with Nur77/Nor-1 orphan steroid receptors. AB - Apoptosis is mediated through the extrinsic or intrinsic pathway. Key regulators of the intrinsic apoptotic pathway are the family of B cell lymphoma 2 (Bcl-2) proteins. The activity of the prototypical Bcl-2 protein is usually considered antiapoptotic. However, under some conditions, Bcl-2 associates with the orphan nuclear hormone receptors Nur77 and Nor-1, converting Bcl-2 into a proapoptotic molecule. Expression of Nur77 and Nor-1 is induced by a variety of signals, including those leading to apoptosis. Translocation of Nur77/Nor-1 to mitochondria results in their association with Bcl-2, exposing the Bcl-2 homology (BH) 3 domain and causing apoptosis. However, the molecular details of this interaction are incompletely understood. Here, through extensive Bcl-2 mutagenesis and functional assays, we identified residues within Bcl-2 that are essential for its interaction with Nur77/Nor-1. Although an initial report has suggested that an unstructured loop region between the Bcl-2 BH4 and BH3 domains is required for Bcl-2's interaction with Nur77/Nor-1, we found that it is dispensable for this interaction. Instead, we found important interacting residues at the BH4 domain and crucial interacting residues between the BH1 and BH2 domains. Bcl-2 alanine mutants at this region could no longer interact with Nur77/Nor-1 and could not initiate Nur77/Bcl-2-mediated cell death. However, they still retained their anti-apoptotic capability in two different death assays. These results establish crucial residues in Bcl-2 required for Nur77/Nor-1 mediated apoptosis and point to potential new strategies for manipulating Bcl-2 function. PMID- 29414783 TI - The bacterial pigment pyocyanin inhibits the NLRP3 inflammasome through intracellular reactive oxygen and nitrogen species. AB - Inflammasomes are cytosolic complexes that mature and secrete the inflammatory cytokines interleukin 1beta (IL-1beta) and IL-18 and induce pyroptosis. The NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome detects many pathogen- and danger-associated molecular patterns, and reactive oxygen species (ROS)/reactive nitrogen species (RNS) have been implicated in its activation. The phenazine pyocyanin (PCN) is a virulence factor of Pseudomonas aeruginosa and generates superoxide in cells. Here we report that PCN inhibits IL-1beta and IL 18 release and pyroptosis upon NLRP3 inflammasome activation in macrophages by preventing speck formation and Caspase-1 maturation. Of note, PCN did not regulate the AIM2 (absent in melanoma 2) or NLRC4 inflammasomes or tumor necrosis factor (TNF) secretion. Imaging of the fluorescent glutathione redox potential sensor Grx1-roGFP2 indicated that PCN provokes cytosolic and nuclear but not mitochondrial redox changes. PCN-induced intracellular ROS/RNS inhibited the NLRP3 inflammasome posttranslationally, and hydrogen peroxide or peroxynitrite alone were sufficient to block its activation. We propose that cytosolic ROS/RNS inhibit the NLRP3 inflammasome and that PCN's anti-inflammatory activity may help P. aeruginosa evade immune recognition. PMID- 29414784 TI - Coenzyme M biosynthesis in bacteria involves phosphate elimination by a functionally distinct member of the aspartase/fumarase superfamily. AB - For nearly 30 years, coenzyme M (CoM) was assumed to be present solely in methanogenic archaea. In the late 1990s, CoM was reported to play a role in bacterial propene metabolism, but no biosynthetic pathway for CoM has yet been identified in bacteria. Here, using bioinformatics and proteomic approaches in the metabolically versatile bacterium Xanthobacter autotrophicus Py2, we identified four putative CoM biosynthetic enzymes encoded by the xcbB1, C1, D1, and E1 genes. Only XcbB1 was homologous to a known CoM biosynthetic enzyme (ComA), indicating that CoM biosynthesis in bacteria involves enzymes different from those in archaea. We verified that the ComA homolog produces phosphosulfolactate from phosphoenolpyruvate (PEP), demonstrating that bacterial CoM biosynthesis is initiated similarly as the phosphoenolpyruvate-dependent methanogenic archaeal pathway. The bioinformatics analysis revealed that XcbC1 and D1 are members of the aspartase/fumarase superfamily (AFS) and that XcbE1 is a pyridoxal 5'-phosphate-containing enzyme with homology to d-cysteine desulfhydrases. Known AFS members catalyze beta-elimination reactions of succinyl containing substrates, yielding fumarate as the common unsaturated elimination product. Unexpectedly, we found that XcbC1 catalyzes beta-elimination on phosphosulfolactate, yielding inorganic phosphate and a novel metabolite, sulfoacrylic acid. Phosphate-releasing beta-elimination reactions are unprecedented among the AFS, indicating that XcbC1 is an unusual phosphatase. Direct demonstration of phosphosulfolactate synthase activity for XcbB1 and phosphate beta-elimination activity for XcbC1 strengthened their hypothetical assignment to a CoM biosynthetic pathway and suggested functions also for XcbD1 and E1. Our results represent a critical first step toward elucidating the CoM pathway in bacteria. PMID- 29414785 TI - A chondroitin sulfate and hyaluronic acid lyase with poor activity to glucuronyl 4,6-O-disulfated N-acetylgalactosamine (E-type)-containing structures. AB - GlcUAbeta1-3GalNAc(4S,6S) (E unit)-rich domains have been shown to play key roles in various biological functions of chondroitin sulfate (CS). However, an enzyme that can specifically isolate such domains through the selective digestion of other domains in polysaccharides has not yet been reported. Here, we identified a glycosaminoglycan lyase from a marine bacterium Vibrio sp. FC509. This enzyme efficiently degraded hyaluronic acid (HA) and CS variants, but not E unit-rich CS E, into unsaturated disaccharides; therefore, we designated this enzyme a CS-E resisted HA/CS lyase (HCLase Er). We isolated a series of resistant oligosaccharides from the final product of a low-sulfated CS-E exhaustively digested by HCLase Er and found that the E units were dramatically accumulate in these resistant oligosaccharides. By determining the structures of several resistant tetrasaccharides, we observed that all of them possessed a Delta4,5HexUAalpha1-3GalNAc(4S,6S) at their non-reducing ends, indicating that the disulfation of GalNAc abrogates HCLase Er activity on the beta1-4 linkage between the E unit and the following disaccharide. Delta4,5HexUAalpha1 3GalNAc(4S,6S)beta1-4GlcUAbeta1-3GalNAc(4S,6S) was most strongly resistant to HCLase Er. To our knowledge, this study is the first reporting a glycosaminoglycan lyase specifically inhibited by both 4-O- and 6-O-sulfation of GalNAc. Site-directed and truncation mutagenesis experiments indicated that HCLase Er may use a general acid-base catalysis mechanism and that an extra domain (Gly739-Gln796) is critical for its activity. This enzyme will be a useful tool for structural analyses and for preparing bioactive oligosaccharides of HA and CS variants, particularly from E unit-rich CS chains. PMID- 29414787 TI - Ubiquitin-conjugating enzyme E2 D1 (Ube2D1) mediates lysine-independent ubiquitination of the E3 ubiquitin ligase March-I. AB - March-I is a membrane-bound E3 ubiquitin ligase belonging to the membrane associated RING-CH (March) family. March-I ubiquitinates and down-regulates the expression of major histocompatibility complex (MHC) class II and cluster of differentiation 86 (CD86) in antigen-presenting cells. March-I expression is regulated both transcriptionally and posttranslationally, and it has been reported that March-I is ubiquitinated and that this ubiquitination contributes to March-I turnover. However, the molecular mechanism regulating March-I ubiquitination and the importance of March-I's E3 ligase activity for March-I ubiquitination are not fully understood. Here we confirmed that, although March-I is ubiquitinated, it is not ubiquitinated on a lysine residue, as a lysine-less March-I variant was ubiquitinated similarly as wildtype March-I. We found that March-I E3 ligase activity is not required for its ubiquitination and does not regulate March-I protein expression, suggesting that March-I does not undergo autoubiquitination. Knocking down ubiquitin-conjugating enzyme E2 D1 (Ube2D1) impaired March-I ubiquitination, increased March-I expression, and enhanced March I-dependent down-regulation of MHC-II proteins. Taken together, our results suggest that March-I undergoes lysine-independent ubiquitination by an as yet unidentified E3 ubiquitin ligase that, together with Ube2D1, regulates March-I expression. PMID- 29414786 TI - The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis. AB - Apolipoprotein-E (apoE) is a glycoprotein highly expressed in the brain, where it appears to play a role in lipid transport, beta-amyloid clearance, and neuronal signaling. ApoE proteolytic fragments are also present in the brain, but the enzymes responsible for apoE fragmentation are unknown, and the biological activity of specific apoE fragments remains to be determined. Here we utilized SK N-SH neuroblastoma cells differentiated into neurons with all-trans-retinoic acid (ATRA) to study extracellular apoE proteolysis. ApoE fragments were detectable in culture supernatants after 3 days, and their levels were increased for up to 9 days in the presence of ATRA. The concentration of apoE fragments was positively correlated with levels of the neuronal maturation markers (PSD95 and SMI32). The most abundant apoE fragments were 25- and 28-kDa N-terminal fragments that both contained sialylated glycosylation and bound to heparin. We detected apoE fragments only in the extracellular milieu and not in cell lysates, suggesting that an extracellular protease contributes to apoE fragmentation. Of note, siRNA mediated knockdown of high-temperature requirement serine peptidase A1 (HtrA1) and a specific HtrA1 inhibitor reduced apoE 25-kDa fragment formation by 41 and 86%, respectively. Recombinant 25-kDa fragment apoE and full-length apoE both stimulated neuritogenesis in vitro, increasing neuroblastoma neurite growth by more than 2-fold over a 6-day period. This study provides a cellular model for assessing apoE proteolysis, indicates that HtrA1 regulates apoE 25-kDa fragment formation under physiological conditions, and reveals a new neurotrophic function for the apoE 25-kDa fragment. PMID- 29414788 TI - Extensive peptide and natural protein substrate screens reveal that mouse caspase 11 has much narrower substrate specificity than caspase-1. AB - Inflammatory cell death, or pyroptosis, is triggered by pathogenic infections or events. It is executed by caspase-1 (in the canonical pyroptosis pathway) or caspase-11 (noncanonical pathway), each via production of a cell-lytic domain from the pyroptosis effector protein gasdermin D through specific and limited proteolysis. Pyroptosis is accompanied by the release of inflammatory mediators, including the proteolytically processed forms of interleukin-1beta (IL-1beta) and IL-18. Given the similar inflammatory outcomes of the canonical and noncanonical pyroptosis pathways, we hypothesized that caspase-1 and -11 should have very similar activities and substrate specificities. To test this hypothesis, we purified recombinant murine caspases and analyzed their primary specificities by massive hybrid combinatorial substrate library (HyCoSuL) screens. We correlated the substrate preferences of each caspase with their activities on the recombinant natural substrates IL-1beta, IL-18, and gasdermin D. Although we identified highly selective and robust peptidyl substrates for caspase-1, we were unable to do so for caspase-11, because caspase-1 cleaved even the best caspase 11 substrates equally well. Caspase-1 rapidly processed pro-IL-1beta and -18, but caspase-11 processed these two pro-ILs extremely poorly. However, both caspase-1 and -11 efficiently produced the cell-lytic domain from the gasdermin D precursor. We hypothesize that caspase-11 may have evolved a specific exosite to selectively engage pyroptosis without directly activating pro-IL-1beta or -18. In summary, comparing the activities of caspase-1 and -11 in HyCoSuL screens and with three endogenous protein substrates, we conclude that caspase-11 has highly restricted substrate specificity, preferring gasdermin D over all other substrates examined. PMID- 29414789 TI - A long noncoding (lnc)RNA governs expression of the phosphate transporter Pho84 in fission yeast and has cascading effects on the flanking prt lncRNA and pho1 genes. AB - The expression of the phosphate transporter Pho84 in fission yeast Schizosaccharomyces pombe is repressed in phosphate-rich medium and induced during phosphate starvation. Two other phosphate-responsive genes in S. pombe (pho1 and tgp1) had been shown to be repressed in cis by transcription of a long noncoding (lnc) RNA from the upstream flanking gene, but whether pho84 expression is regulated in this manner is unclear. Here, we show that repression of pho84 is enforced by transcription of the SPBC8E4.02c locus upstream of pho84 to produce a lncRNA that we name prt2 ( pho-repressive transcript 2). We identify two essential elements of the prt2 promoter, a HomolD box and a TATA box, mutations of which inactivate the prt2 promoter and de-repress the downstream pho84 promoter under phosphate-replete conditions. We find that prt2 promoter inactivation also elicits a cascade effect on the adjacent downstream prt (lncRNA) and pho1 (acid phosphatase) genes, whereby increased pho84 transcription down-regulates prt lncRNA transcription and thereby de-represses pho1 Our results establish a unified model for the repressive arm of fission yeast phosphate homeostasis, in which transcription of prt2, prt, and nc-tgp1 lncRNAs interferes with the promoters of the flanking pho84, pho1, and tgp1 genes, respectively. PMID- 29414790 TI - Histone acetyltransferase 7 (KAT7)-dependent intragenic histone acetylation regulates endothelial cell gene regulation. AB - Although the functional role of chromatin marks at promoters in mediating cell restricted gene expression has been well characterized, the role of intragenic chromatin marks is not well understood, especially in endothelial cell (EC) gene expression. Here, we characterized the histone H3 and H4 acetylation profiles of 19 genes with EC-enriched expression via locus-wide chromatin immunoprecipitation followed by ultra-high-resolution (5 bp) tiling array analysis in ECs versus non ECs throughout their genomic loci. Importantly, these genes exhibit differential EC enrichment of H3 and H4 acetylation in their promoter in ECs versus non-ECs. Interestingly, VEGFR-2 and VEGFR-1 show EC-enriched acetylation across broad intragenic regions and are up-regulated in non-ECs by histone deacetylase inhibition. It is unclear which histone acetyltransferases (KATs) are key to EC physiology. Depletion of KAT7 reduced VEGFR-2 expression and disrupted angiogenic potential. Microarray analysis of KAT7-depleted ECs identified 263 differentially regulated genes, many of which are key for growth and angiogenic potential. KAT7 inhibition in zebrafish embryos disrupted vessel formation and caused loss of circulatory integrity, especially hemorrhage, all of which were rescued with human KAT7. Notably, perturbed EC-enriched gene expression, especially the VEGFR 2 homologs, contributed to these vascular defects. Mechanistically, KAT7 participates in VEGFR-2 transcription by mediating RNA polymerase II binding, H3 lysine 14, and H4 acetylation in its intragenic region. Collectively, our findings support the importance of differential histone acetylation at both promoter and intragenic regions of EC genes and reveal a previously underappreciated role of KAT7 and intragenic histone acetylation in regulating VEGFR-2 and endothelial function. PMID- 29414791 TI - Proteasome substrate capture and gate opening by the accessory factor PafE from Mycobacterium tuberculosis. AB - In all domains of life, proteasomes are gated, chambered proteases that require opening by activators to facilitate protein degradation. Twelve proteasome accessory factor E (PafE) monomers assemble into a single dodecameric ring that promotes proteolysis required for the full virulence of the human bacterial pathogen Mycobacterium tuberculosis Whereas the best characterized proteasome activators use ATP to deliver proteins into a proteasome, PafE does not require ATP. Here, to unravel the mechanism of PafE-mediated protein targeting and proteasome activation, we studied the interactions of PafE with native substrates, including a newly identified proteasome substrate, the ParA-like protein, Rv3213c, and with proteasome core particles. We characterized the function of a highly conserved feature in bacterial proteasome activator proteins: a glycine-glutamine-tyrosine-leucine (GQYL) motif at their C termini that is essential for stimulating proteolysis. Using cryo-electron microscopy (cryo-EM), we found that the GQYL motif of PafE interacts with specific residues in the alpha subunits of the proteasome core particle to trigger gate opening and degradation. Finally, we also found that PafE rings have 40-A openings lined with hydrophobic residues that form a chamber for capturing substrates before they are degraded, suggesting PafE has a previously unrecognized chaperone activity. In summary, we have identified the interactions between PafE and the proteasome core particle that cause conformational changes leading to the opening of the proteasome gate and have uncovered a mechanism of PafE-mediated substrate degradation. Collectively, our results provide detailed insights into the mechanism of ATP-independent proteasome degradation in bacteria. PMID- 29414792 TI - The complex genetics of human insulin-like growth factor 2 are not reflected in public databases. AB - Recent advances in genetics present unique opportunities for enhancing knowledge about human physiology and disease susceptibility. Understanding this information at the individual gene level is challenging and requires extracting, collating, and interpreting data from a variety of public gene repositories. Here, I illustrate this challenge by analyzing the gene for human insulin-like growth factor 2 (IGF2) through the lens of several databases. IGF2, a 67-amino acid secreted peptide, is essential for normal prenatal growth and is involved in other physiological and pathophysiological processes in humans. Surprisingly, none of the genetic databases accurately described or completely delineated human IGF2 gene structure or transcript expression, even though all relevant information could be found in the published literature. Although IGF2 shares multiple features with the mouse Igf2 gene, it has several unique properties, including transcription from five promoters. Both genes undergo parental imprinting, with IGF2/Igf2 being expressed primarily from the paternal chromosome and the adjacent H19 gene from the maternal chromosome. Unlike mouse Igf2, whose expression declines after birth, human IGF2 remains active throughout life. This characteristic has been attributed to a unique human gene promoter that escapes imprinting, but as shown here, it involves several different promoters with distinct tissue-specific expression patterns. Because new testable hypotheses could lead to critical insights into IGF2 actions in human physiology and disease, it is incumbent that our fundamental understanding is accurate. Similar challenges affecting knowledge of other human genes should promote attempts to critically evaluate, interpret, and correct human genetic data in publicly available databases. PMID- 29414793 TI - High-throughput screen for inhibitors of protein-protein interactions in a reconstituted heat shock protein 70 (Hsp70) complex. AB - Protein-protein interactions (PPIs) are an important category of putative drug targets. Improvements in high-throughput screening (HTS) have significantly accelerated the discovery of inhibitors for some categories of PPIs. However, methods suitable for screening multiprotein complexes (e.g. those composed of three or more different components) have been slower to emerge. Here, we explored an approach that uses reconstituted multiprotein complexes (RMPCs). As a model system, we chose heat shock protein 70 (Hsp70), which is an ATP-dependent molecular chaperone that interacts with co-chaperones, including DnaJA2 and BAG2. The PPIs between Hsp70 and its co-chaperones stimulate nucleotide cycling. Thus, to re-create this ternary protein system, we combined purified human Hsp70 with DnaJA2 and BAG2 and then screened 100,000 diverse compounds for those that inhibited co-chaperone-stimulated ATPase activity. This HTS campaign yielded two compounds with promising inhibitory activity. Interestingly, one inhibited the PPI between Hsp70 and DnaJA2, whereas the other seemed to inhibit the Hsp70-BAG2 complex. Using secondary assays, we found that both compounds inhibited the PPIs through binding to allosteric sites on Hsp70, but neither affected Hsp70's intrinsic ATPase activity. Our RMPC approach expands the toolbox of biochemical HTS methods available for studying difficult-to-target PPIs in multiprotein complexes. The results may also provide a starting point for new chemical probes of the Hsp70 system. PMID- 29414794 TI - Bacterial copper storage proteins. AB - Copper is essential for most organisms as a cofactor for key enzymes involved in fundamental processes such as respiration and photosynthesis. However, copper also has toxic effects in cells, which is why eukaryotes and prokaryotes have evolved mechanisms for safe copper handling. A new family of bacterial proteins uses a Cys-rich four-helix bundle to safely store large quantities of Cu(I). The work leading to the discovery of these proteins, their properties and physiological functions, and how their presence potentially impacts the current views of bacterial copper handling and use are discussed in this review. PMID- 29414797 TI - Plasma Cell Disorders and Dialysis-Dependent Renal Failure: Safety and Efficacy of Autologous Stem Cell Transplantation. PMID- 29414796 TI - The teaching and learning of health advocacy in an Australian medical school. AB - Objectives: To determine if medical graduates from an Australian university are educated and skilled in health advocacy for their future practice with patients and the wider community. Methods: The authors used an exploratory mixed methodology starting with curriculum mapping of the medical curriculum, followed by key informant interviews with the University of Notre Dame, School of Medicine academics (n = 6) and alumni (n = 5) on teaching/learning and practice of health advocacy. The final stage consisted of a cross-sectional survey on teaching/learning health advocacy among third and fourth (final) year medical students (N = 195). Results: The medical curriculum contained no explicit learning objectives on health advocacy. Key informant interviews demonstrated an appreciation of health advocacy and its importance in the medical curriculum but a deficit in explicit and practical 'hands-on' teaching. Survey response rate was 47% (n = 92). A majority of students (76%, n = 70) had heard of health advocacy, with this being more likely among third (92%, n = 33) compared with fourth-year students (67%, n = 37) (Fisher's Exact Test chi2 (2, N = 91) = 7.311, p = 0.02). Students reported having opportunities to observe (76%, n = 70) and practise health advocacy (50%, n = 46) in the curriculum. Conclusions: Students and medical graduates demonstrated sound recognition of the term health advocacy. Deficits identified in the curriculum include lack of explicit learning objectives and "hands-on" learning opportunities in health advocacy. PMID- 29414795 TI - How cells ensure correct repair of DNA double-strand breaks. AB - DNA double-strand breaks (DSBs) arise regularly in cells and when left unrepaired cause senescence or cell death. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are the two major DNA-repair pathways. Whereas HR allows faithful DSB repair and healthy cell growth, NHEJ has higher potential to contribute to mutations and malignancy. Many regulatory mechanisms influence which of these two pathways is used in DSB repair. These mechanisms depend on the cell cycle, post-translational modifications, and chromatin effects. Here, we summarize current research into these mechanisms, with a focus on mammalian cells, and also discuss repair by "alternative end-joining" and single-strand annealing. PMID- 29414798 TI - Fusion to Human Serum Albumin Extends the Circulatory Half-Life and Duration of Antithrombotic Action of the Kunitz Protease Inhibitor Domain of Protease Nexin 2. AB - BACKGROUND/AIMS: The Kunitz Protease Inhibitor (KPI) domain of protease nexin 2 (PN2) potently inhibits coagulation factor XIa. Recombinant KPI has been shown to inhibit thrombosis in mouse models, but its clearance from the murine circulation remains uncharacterized. The present study explored the pharmacokinetic and pharmacodynamic effects of fusing KPI to human serum albumin (HSA) in fusion protein KPIHSA. METHODS: Hexahistidine-tagged KPI (63 amino acids) and KPIHSA (656 amino acids) were expressed in Pichia pastoris yeast and purified by nickel chelate chromatography. Clearance profiles in mice were determined, as well as the effects of KPI or KPIHSA administration on FeCl3-induced vena cava thrombus size or carotid artery time to occlusion, respectively. RESULTS: Fusion to HSA increased the mean terminal half-life of KPI by 8-fold and eliminated its interaction with the low density lipoprotein receptor-related protein. KPI and KPIHSA similarly reduced thrombus size and occlusion in both venous and arterial thrombosis models when administered at the time of injury, but only KPI was effective when administered one hour before injury. CONCLUSIONS: Albumin fusion deflects KPI from rapid in vivo clearance without impairing its antithrombotic properties and widens its potential therapeutic window. PMID- 29414800 TI - Autologous Hematopoietic Cell Transplantation for Dialysis-Dependent Myeloma: More Efficient, Less Toxic. PMID- 29414799 TI - Berberine Suppresses Cell Motility Through Downregulation of TGF-beta1 in Triple Negative Breast Cancer Cells. AB - BACKGROUND/AIMS: Transforming growth factor-beta proteins (TGF-betas) are multifunctional growth factors and powerful modulators of the epithelial mesenchymal transition (EMT) in a variety of cancer types including breast and lung cancer cells. Here, we demonstrated the inhibitory effect of berberine (BBR) on tumor growth and metastasis of triple negative breast cancer (TNBC) cells via suppression of TGF-beta1 expression. METHODS: The levels of mRNA expression were analyzed by real-time PCR. The levels of MMP-2, MMP-9 and TGF-beta1 protein expression were analyzed by zymography and confocal microscopy, respectively. Cell migration was analyzed by wound healing assay. Tumorigenicity of TNBC cells such as tumor growth and metastasis was analyzed using xenograft models. RESULTS: In a clinical data set, aberrant TGF-beta1 expression was associated with poor prognosis of breast cancer patients. Our in vitro results using TNBC cells showed that the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 and the capacity for cell migration were increased by TGF-beta1 treatment. In contrast, basal levels of MMP-2 and MMP-9 were suppressed by a specific TGF-beta receptor I inhibitor, SB431542. In addition, TGF-beta1-induced MMP-2 and MMP-9 expression and cell migration were decreased by SB431542. Interestingly, we showed for the first time that BBR decreased the level of TGF-beta1, but not TGF-beta2, in TNBC cells. Furthermore, BBR significantly decreased the level of MMP-2 expression as well as the capacity for cell migration in TNBC cells. Finally, we examined the effect of BBR on in vivo tumor growth and lung metastasis in MDA-MB231 and 4T1 breast cancer xenograft models and showed that both were significantly decreased following BBR treatment. CONCLUSION: BBR suppresses tumorigenicity of TNBC cells through inhibition of TGF-beta1 expression. Therefore, we demonstrate that BBR could be a promising drug for treatment of TNBC. PMID- 29414801 TI - Ultramorphological Characteristics of Podocyte Development in the Human Fetal Metanephros. AB - The aim of this study was to determine the developmental characteristics of podocytes in the human fetal metanephros using scanning electron microscopy, light microscopy, and transmission electron microscopy. Kidney samples of 15 human fetuses of both sexes (gestational age 10-22 weeks) were analyzed. At the S shaped body stage, primitive podocytes were arranged in a layer of cuboidal cells beneath the vascular cleft. When observed from Bowman's space, the demarcation between adjacent podocytes was not clear, but mild depressions indicated cell boundaries. At the more advanced S-shaped body stage, podocytes were polygonal, with a flat apical surface. They were in close contact, but boundaries between adjacent cells were distinct. After initial separation of their apical parts, podocytes continued to separate from each other along their lateral sides. Their shape changed from polygonal to spherical, resembling clusters of grapes. Cytoplasmic buds could be seen at the base of some podocytes initially, when all podocytes were spherical. Parallel with the development of the first capillary loops, wider intercellular spaces were noted between elliptical-shaped podocytes. Podocytes then developed cytoplasmic processes and became flattened and star shaped. Their cell bodies separated from the glomerular basement membrane through the insertion of thick processes under the cell body. Thick primary processes ramified to form the foot processes, which interdigitated on the surface of capillary loops. During the capillary loop stage, the degree of differentiation of the podocytes varied among various glomerular regions, as well as within the same capillary loop. PMID- 29414802 TI - Proteomics Based Identification of Autotaxin As An Anti-Hepatitis B Virus Factor and a Promoter of Hepatoma Cell Invasion and Migration. AB - BACKGROUND/AIMS: Hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma. Therefore, we aimed to obtain further information on HBV pathogenesis, and to search for novel putative molecules for anti-HBV therapy. METHODS: We utilized Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) to identify the secretory proteins that are differentially expressed in the HBV DNA-transfected HepG2.2.15 cell line and its parental HepG2 cell line. Immunohistochemistry (IHC) was employed to assess the clinical relevance of the observations. Small interfering (si)RNA-based silencing transfection methods were carried out to study the function of ENPP2. RESULTS: Totally, 133 unique proteins were identified as differentially expressed in HepG2.2.15 cell line compared with HepG2 cell line. Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 precursor (ENPP2) is one of the most significantly up-regulated secretory proteins associated with HBV replication. This differential expression of ENPP2 was further validated by real time quantitative RT-PCR, Western Blot and immunohistochemical analysis. To study the function of ENPP2, we knockdown ENPP2 expression in HepG2.2.15 cell line by RNA interference. ENPP2 silencing increased HBV replication approximately 2.3 fold by enhancing, via the type I IFN signaling pathway, HBV cccDNA (covalently closed circular DNA) translation into viral RNA. Moreover, attenuation of ENPP2 expression inhibited both the invasion and migration ability of hepatoma cells in vitro via interacting with the molecules in the tumor microenvironment. CONCLUSION: Our study demonstrates that ENPP2 may be a novel anti-HBV target and indicate that suppression of its expression may inhibit the invasion and migration ability of hepatoma cells. PMID- 29414803 TI - Knockdown MiR-302b Alleviates LPS-Induced Injury by Targeting Smad3 in C28/I2 Chondrocytic Cells. AB - BACKGROUND/AIMS: Osteoarthritis (OA) is one of the most common chronic degenerative diseases. Many studies have demonstrated the role of microRNAs (miRNAs) in OA; however, the role of miR-302b in OA remains elusive. The aim of this study was to identify the role of miR-302b in LPS-induced injury in chondrocytes. METHODS: Human OA chondrocytes (C28/12 cell line) were transfected with miR-302b inhibitor and miR-302b mimic to investigate the effects of miR-302b expression on chondrocyte apoptosis and inflammation, and to identify the miR 302b target proteins. RESULTS: LPS treatment of chondrocytes significantly reduced cell viability and increased apoptotic rate. LPS treatment also increased the expression of inflammatory cytokines compared to control. miR-302b was up regulated in LPS-induced chondrocytes. miR-302b was either suppressed or overexpressed in LPS-induced chondrocytes by transient transfection. miR-302b mimic transfection accelerated the effects of LPS on cell viability, apoptosis and inflammation. Of contrast, miR-302b inhibition represented a reverse effect. Dual luciferase activity demonstrated that Smad3 is a direct target for miR-302b and its expression was negatively regulated by miR-302b. In addition, miR-302b inhibition suppressed inflammation in LPS treated chondrocytes by up-regulating Smad3 expression. Moreover, LPS induced down-regulation of Notch and mTOR signaling pathway-related protein expressions, and miR-302b inhibition increased the expressions of Notch and mTOR signaling pathway-related proteins. We further found that miR-302b negatively regulated Notch2 levels through direct targeting its 3'UTR. CONCLUSIONS: These results suggest that miR-302b suppression may function as a protector in suppressing the inflammation during the development and progression of OA by up-regulating the target Smad3 expression. PMID- 29414804 TI - MicroRNA-223 Targeting STIM1 Inhibits the Biological Behavior of Breast Cancer. AB - BACKGROUND/AIMS: To investigate the cellular effects and clinical significance of microRNA-223 (miR-223) in breast cancer by targeting stromal interaction molecule1 (STIM1). METHODS: Breast cancer cell lines (T47D, MCF-7, SKB-R3, MDA-MB 231 and MDA-MB-435) and a normal breast epithelial cell line (MCF-10A) were prepared for this study. MiR-223 mimics, anti-miR-223 and pcDNA 3.1-STIM1 were transiently transfected into cancer cells independently or together, and then RT qPCR was performed to detect the expressions of miR-223 and STIM1 mRNA, dual luciferase reporter assay was conducted to examine the effects of miR-223 on STIM1, Western blotting was used to measure the expressions of the STIM1 proteins, MTT and Trans-well assays were performed to detect cell proliferation and invasion. Finally, the correlation of miR-223 and STIM1 was investigated by detecting with ISH and IHC in breast cancer specimens or the corresponding adjacent normal tissues. RESULTS: Compared with normal cells and tissues, breast cancer tissues and cells exhibited significantly lower expression of miR-223, but higher expression of STIM1. MiR-223 could inhibit the proliferation and invasiveness of breast cancer cells by negatively regulating the expressions of STIM1. Reimplantation with STIM1 partially rescued the miRNA-223-induced inhibition of breast cancer cells. Clinical data revealed that high expression of STIM1 and miR-223 was respectively detrimental and beneficial factor impacting patient's disease-free survival (DFS) rather than overall survival (OS). Moreover, Pearson correlation analysis also confirmed that STIM1 was inversely correlated with miR-223. CONCLUSION: MiR-223 inhibits the proliferation and invasion of breast cancer by targeting STIM1. The miR-223/STIM1 axis could possibly be a potential therapeutic target for treating breast cancer patients. PMID- 29414805 TI - A Novel Approach for Hepatic Arterial Reconstruction after Total Pancreatectomy with Common Hepatic Artery Resection Using Inferior Phrenic Artery. AB - BACKGROUND/AIMS: Because of the anatomical characteristics, pancreatic cancers (PC) can easily invade to visceral vessels such as celiac artery, superior mesenteric artery, common hepatic artery (CHA) and portal vein, which makes curative resection difficult. In this study, we report an R0 resection for locally advanced PC by total pancreatectomy, combined resection of CHA, and reconstruction of hepatic artery using autologous left inferior phrenic artery (IPA). METHODS: A 47-year-old woman with complaints of low back pain was referred to our department. Contrast-enhanced computed tomography revealed a hypo attenuation tumor of the pancreatic body measuring 70 mm, which completely encased the CHA. When unresectable locally advanced PC was diagnosed, systematic chemotherapy was administrated. After downstaging, she underwent surgery with curative intent. The tumor completely infiltrated the peripheral part of the CHA and gastroduodenal artery. As the tumor also extended to the head of the pancreas, total pancreatectomy and combined resection of CHA were performed. Then the exposed left IPA and proper hepatic artery were anastomosed with a microvascular technique. RESULTS: R0 resection was performed for restoring hepatic arterial flow and the postoperative course was uneventful without any postoperative morbidity. CONCLUSION: Hepatic artery reconstruction using IPA is a simple and safe procedure in selected patients. PMID- 29414806 TI - Prognostic Significance of Pre- and Postoperative Lymphocyte Counts in Patients with Gastric Cancer. AB - BACKGROUND: Although preoperative lymphopenia is reportedly a prognostic factor in cancer patients, the association between postoperative lymphopenia and patient prognosis has not been widely studied. METHODS: We enrolled 352 patients who underwent surgery for gastric cancer (GC) between January 2005 and April 2013 to analyze correlations among pre- and postoperative lymphocyte counts (LCs) and prognosis in GC patients. RESULTS: Pre- and postoperative (obtained 1 day after surgery) LCs were significantly correlated (r = 0.496, p < 0.0001). Pre- and postoperative LCs of elderly patients were significantly lower than those of non elderly patients. Postoperative lymphocyte count was significantly lower in patients with a differentiated tumor than in those with an undifferentiated tumor. Based on the results of receiver operating characteristic analysis, patients were classified into subgroups as: preoperative LC >=1,676 (pre-LCHigh), preoperative LC <1,676 (pre-LCLow); and as postoperative LC >=855 (post-LCHigh), and postoperative LC <855 (post-LCLow). Five-year overall survival rates significantly differed between pre-LCHigh (82.5%) and pre-LCLow (71.6%) groups (p = 0.023); and also between the post-LCHigh (81.5%) and post-LCLow (69.5%) groups (p = 0.0072). The 5-year disease specific survival rates were 91.3 and 82.4% in patients with post-LCHigh and those with post-LCLow, respectively, and differences were statistically significant (p = 0.015). Multivariate analysis indicated that postoperative lymphocyte count was an independent prognostic indicator, along with age, gender, tumor size, lymph node metastasis, and venous invasion. CONCLUSIONS: Postoperative lymphocyte count is a useful predictive factor for prognosis in GC patients. PMID- 29414807 TI - Hypoxia-Induced TPM2 Methylation is Associated with Chemoresistance and Poor Prognosis in Breast Cancer. AB - BACKGROUND/AIMS: Tropomyosin-2 (TPM2) plays important roles in functions of the cytoskeleton, such as cytokinesis, vesicle transport, cell proliferation, migration and apoptosis,and these functions imply that TPM2 also plays a role in cancer development. Indeed, it has been shown that TPM2 plays a critical role in some cancers. However, the role of TPM2 in breast cancer is still poorly characterized. Thus, we explored the role of TPM2 in breast cancer. METHODS: We analysed TPM2 expression and its correlation with the clinicopathological features in breast cancer. Then, we examined the influence of hypoxia on TPM2 expression and methylation status using bisulfite sequencing PCR. Furthermore, we performed TPM2-mediated migration and invasion assays in the context of hypoxia and examined changes in matrix metalloproteinase-2 (MMP2) expression. Finally, we detected the influence of TPM2 on survival and chemotherapy drug sensitivity. RESULTS: We found that TPM2 expression is down-regulated in breast cancer cells compared to that in normal breast cells. The data from TCGA supported these results. Promoter methylation of TPM2, which could be induced by hypoxia, was responsible for its low expression. Hypoxia might regulate cell invasiveness partly by TPM2 down-regulation-mediated changes of MMP2 expression. Importantly, low TPM2 expression was correlated with lymph node metastasis (P=0.031), tumour node metastasis stage (P=0.01), histological grade (P=0.037), and shorter overall survival (P=0.028). Univariate and multivariate analyses indicated that TPM2 was an independent predictor in breast cancer patients. Paclitaxel chemotherapy did not benefit patients with low TPM2 expression (P<0.0001). TPM2 knockdown significantly reduced cell sensitivity to paclitaxel. CONCLUSION: TPM2 is a potential novel tumour suppressor gene in breast cancer. TPM2 is associated with poor survival and chemoresistance to paclitaxel in breast cancer, and TPM2 may represent a promising therapeutic gene target for breast cancer patients with chemoresistance. PMID- 29414808 TI - Remineralization Potential of Mints Containing Bioactive Agents in Artificially Induced Root Caries. AB - This study investigated the remineralization effect of experimental mint formulations containing bioactive agents (xylitol; green tea extract, GT; and amorphous calcium phosphate, ACP) in the progression of artificially induced root caries. Root caries lesions were induced by demineralization solution (pH 4.6; 96 h; 37 degrees C). The lesions were treated with mint A, mint B, mint C, xylitol, GT, ACP, or remineralization solution (RS; negative control). Specimens were pH cycled through treatments (5*/day; 3 min) and 6 cycles of acidic (pH 5.0; 30 min) and neutral (pH 7.0; 10 min) buffers for 8 days. Bacterial collagenase (Clostridium histolyticum) was used overnight to simulate proteolytic challenge. Caries depth and porosity as well as mineral density were estimated using fluorescence microscopy (n = 15) and microcomputed tomography (n = 6). Analysis of variance (ANOVA, alpha = 0.05) showed no statistically significant difference in caries depth among all groups (p = 0.172). The highest fluorescence intensity decrease was observed for GT followed by mint C, with no significant difference between them (p = 0.868). There were significant differences among GT and mints A, B, and C when compared to RS (p < 0.001). No statistically significant differences in fluorescence intensity were observed among ACP, xylitol, and RS (p > 0.05). The mineral density of the lesions in GT, mints A, B, and C, and ACP was statistically similar (p > 0.05) and significantly higher than that in RS (p < 0.05). No significant difference was observed between xylitol and RS (p = 0.728). The experimental mints showed remineralization action on artificial root caries, and GT was found to be the main active ingredient in the investigated formulations. PMID- 29414809 TI - Interference with PSMB4 Expression Exerts an Anti-Tumor Effect by Decreasing the Invasion and Proliferation of Human Glioblastoma Cells. AB - BACKGROUND/AIMS: Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis. Proteasome subunit beta type-4 (PSMB4) is an essential subunit that contributes to the assembly of the 20S proteasome complex. However, the role of PSMB4 in glioblastomas remains to be clarified. The aim of this study was to investigate the role of PSMB4 in GBM tumor progression. METHODS: We first analyzed the PSMB4 protein and mRNA expression in 80 clinical brain specimens and 77 datasets from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Next, we inhibited the PSMB4 expression by siRNA in cellular and animal models to explore PSMB4's underlying mechanisms. The cell survival after siPSMB4 transfection was assayed by MTT assay. Annexin V and propidium iodide staining was used to monitor the apoptosis by flow cytometric analysis. Moreover, the migration and invasion were evaluated by wound healing and Transwell assays. The expression of migration-related and invasion-related proteins after PSMB4 inhibition was detected by Western blotting. In addition, an orthotropic xenograft mouse model was used to assay the effect of PSMB4 knockdown in the in vivo study. RESULTS: Basis on the results of bioinformatics study, glioma patients with higher PSMB4 expression had a shorter survival time than those with lower PSMB4 expression. The staining of clinical brain tissues showed elevated PSMB4 expression in GBM tissues compared with normal brain tissues. The PSMB4 inhibition decreased proliferation, migration and invasion abilities in human GBM cells. Downregulated PSMB4 resulted in cell cycle arrest and apoptosis in vitro. In an orthotropic xenograft mouse model, the glioma tumors progression was reduced when PSMB4 was down-regulated. The decreased PSMB4 enhanced the anti tumor effect of temozolomide (TMZ) on tumor growth. In addition, the absence of PSMB4 decreased the expression of phosphorylated focal adhesion kinase and matrix metallopeptidase 9 in vivo. CONCLUSION: PSMB4 inhibition in combination with TMZ may exert an anti-tumor effect by decreasing cell proliferation and invasion as well as by promoting apoptosis in human glioblastoma cells. This research may improve the therapeutic efficacy of glioblastoma treatment. PMID- 29414810 TI - Knockdown of Long Non-Coding RNA RP11-445H22.4 Alleviates LPS-Induced Injuries by Regulation of MiR-301a in Osteoarthritis. AB - BACKGROUND/AIMS: Several long non-coding RNAs (lncRNAs) play vital roles in osteoarthritis (OA), whereas the role of lncRNA RP11-445H22.4 in OA remains unclear. The study aimed to investigate the effect of lncRNA RP11-445H22.4 on lipopolysaccharide (LPS)-induced cell viability, apoptosis and inflammatory injury of OA. METHODS: The expression of RP11-445H22.4, miR-301a and CXCR4 in human cartilage ATDC5 cells were altered by transfection, and then cells were exposed to 5 ug/ml LPS for 12 h. Then cell viability, apoptosis, apoptosis related factors and inflammatory cytokines were analyzed by CCK-8, flow cytometry, western blot, RT-qPCR and ELISA, respectively. Dual-luciferase reporter assay was performed to assess the binging sites of RP11-445H22.4 and miR 301a. The signal pathways of NF-kappaB and MAPK/ ERK were determined by western blot. RESULTS: LPS reduced cell viability, increased apoptosis and stimulated release of IL-1beta, IL-6, IL-8 and TNF-alpha. However, RP11-445H22.4 inhibition significantly rescued LPS-induced injuries by promoting cell viability, suppressing apoptosis and inflammatory cytokines secretions in ATDC5 cells. In addition, miR-301a directly bound to RP11-445H22.4, and suppression of miR-301a inversed the effects of RP11-445H22.4 inhibition. Furthermore, CXCR4 was a direct target of miR-301a, and CXCR4 silencing increased cell viability, decreased apoptosis and inflammatory cytokines secretions in LPS-treated ATDC5 cells. Besides, we found that CXCR4 silencing blocked LPS-activated NF-kappaB and MAPK/ERK pathways. CONCLUSIONS: The study indicated that lncRNA RP11-445H22.4-miR 301a-CXCR4 axis played an important role in cartilage ATDC5 cells and provided a theoretical basis of lncRNA RP11-445H22.4 in OA. PMID- 29414811 TI - Functional Implications of Cross-Linked Actin Networks in Trabecular Meshwork Cells. AB - BACKGROUND/AIMS: The Trabecular meshwork (TM) is the tissue responsible for outflow resistance and therefore intraocular pressure. TM cells contain a contractile apparatus that is composed of actin stress fibres which run parallel to the axis of the cell and are responsible for facilitating contraction. Cross Linked Actin Networks (CLANs) are polygonal arrangements of actin that form a geodesic network found predominantly in TM cells both in situ and in vitro. The aim of this work is to determine the functional significance of CLANs in TM cells and to assess the effect of mechanical stretch stimulation on the induction (or not) of CLANs. METHODS: We used collagen gel contraction models to demonstrate functional impairment of cells when induced to express CLANs in situ. Cyclic mechanical stretch was used to stimulate cells and measure CLANs Results: CLANs inhibited contraction and cyclic mechanical stretch induced CLANs. Furthermore, we also demonstrated that using shape alone we could predict the appearance of CLANs using a simple light microscopy technique. CONCLUSION: Taken together we have now shown, for the first time, a functional deficit In TM cells with CLANs Furthermore that shape alone can predict the appearance of CLAN containing cells. CLANs can now be linked to a functional effect and may underlie the appearance of CLANs with the pathology of primary open angle glaucoma (POAG). PMID- 29414813 TI - Minimally Invasive versus Open Approach for Right-Sided Colectomy: A Study in 12,006 Patients from the Dutch Surgical Colorectal Audit. AB - BACKGROUND: There is ongoing debate whether laparoscopic right colectomy is superior to open surgery. The purpose of this study was to address this issue and arrive at a consensus using data from a national database. METHODS: Patients who underwent elective open or laparoscopic right colectomy for colorectal cancer during the period 2009-2013 were identified from the Dutch Surgical Colorectal Audit. Complications that occurred within 30 days after surgery and 30-day mortality rates were calculated and compared between open and laparoscopic resection. RESULTS: In total, 12,006 patients underwent elective open or laparoscopic surgery for right-sided colorectal cancer. Of these, 6,683 (55.7%) underwent open resection and 5,323 (44.3%) underwent laparoscopic resection. Complications occurred within 30 days after surgery in the laparoscopic group in 26.1% of patients and in 32.1% of patients in the open group (p < 0.001). Thirty day mortality was also significantly lower in the laparoscopic group (2.2 vs. 3.6% p < 0.001). CONCLUSION: In this non-randomized, descriptive study conducted in the Netherlands, open right colectomy seems to have a higher risk for complications and mortality as compared to laparoscopic right colectomy, even after correction for confounding factors. PMID- 29414812 TI - Prognostic Role of Tumor-Infiltrating Lymphocytes in Esophagus Cancer: a Meta Analysis. AB - BACKGROUND/AIMS: Several studies have verified the correlation between tumor infiltrating lymphocytes (TILs) and survival of patients with esophagus cancer (EC). However, the prognostic role of TILs is still controversial. Therefore, we performed this meta-analysis. METHODS: We searched PubMed, Embase and the Cochrane Library (last update by August 30, 2017) to identify studies assessing the effect of TILs on survival of patients with EC. Pooled hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS) and cancer specific survival (CSS) were estimated using fixed-effects models or random-effects models, which depends on the heterogeneity. RESULTS: Data from 22 observational studies including 2909 patients were summarized. Pooled analysis indicated that generalized TILs were favorable prognostic markers for OS in patients with EC (pooled HR = 0.48; 95% CI = 0.38-0.61; P < 0.001). For TIL subsets, CD8+ TILs were associated with improved OS (pooled HR = 0.68; 95% CI = 0.58-0.84; P < 0.001) and DFS (pooled HR = 0.90; 95% CI = 0.85-0.95; P < 0.001); FoxP3+ TILs were associated with patients' DFS (pooled HR = 0.88; 95% CI = 0.81-0.96; P = 0.003). High CD57+ TILs indicated a better OS in patients with EC (pooled HR = 0.50; 95% CI = 0.35-0.72; P < 0.001). In addition, the pooled results showed that other TIL subsets including CD3+, CD4+ and CD45RO+ TILs were not associated with patients' survival (P > 0.05). CONCLUSIONS: For patients with EC, some TIL subsets could serve as prognostic biomarkers. The application of TILs in the immunotherapy of EC needs to be verified through a large amount of clinical research. PMID- 29414814 TI - APOE epsilon4 Genotype and Cognitive Reserve Effects on the Cognitive Functioning of Healthy Elders. AB - AIM: To test the association between cognitive performance and APOE genotype, and to assess potential modifications of this association by sociodemographic and neuroanatomical factors in a sample of 74 healthy elders. METHODS: Firstly, we explored the isolated role of the APOE E4 genotype (i.e., APOE4) in different neuropsychological tests, and then the effects of its interaction with sociodemographic (i.e., age, gender, and educational level) and neuroanatomical (i.e., hippocampal volumes) variables. Subsequently, we performed the same analyses after dividing the sample into two subgroups according to their Mini Mental State Examination scores (control-high group >=29 and control-low group < 29). RESULTS: In the whole group, APOE4 carriers exhibited a significantly poorer execution in several cognitive domains including global cognitive functioning, episodic memory, verbal fluency, and naming. This effect was more noticeable in older and less educated subjects. The separated analyses revealed that APOE4 carriers in the control-low group exhibited lower scores in global cognitive functioning and episodic memory, while no effects were observed in the control high group. Neither gender nor hippocampal volumes showed a significant interaction effect with APOE genotype. CONCLUSIONS: Current results point out that APOE4 genotype influences healthy aged cognition, although factors such age or educational attainment seem to modulate its effects. PMID- 29414815 TI - LncRNA GAS5 Represses Osteosarcoma Cells Growth and Metastasis via Sponging MiR 203a. AB - BACKGROUND/AIMS: LncRNA GAS5, a growth suppressor, has been reported to exert anti-tumor actions in various cancers, whereas the exact mechanism underling the anti-tumor action is still unclear. This study was aimed to investigate the effect of lncRNA GAS5 on osteosarcoma and tried to decode the underling mechanisms. METHODS: Expressions of lncRNA GAS5 in MG-63 cells were silenced by shRNA transfection, while were overexpressed by vector transfection. Cell viability, migration, invasion and apoptosis were respectively assessed by MTT, Transwell assay and flow cytometry. Regulations between lncRNA GAS5 and miR-203a, as well as between miR-203a and TIMP2 were detected by qPCR, western blot and dual luciferase activity assay. RESULTS: LncRNA GAS5 was down-regulated in MG-63 and OS-732 cells compared to hFOB1.19 cells. Silence of lncRNA GAS5 significantly promoted MG-63 cells viability, migration and invasion, and up-regulated Cyclin D1, Cyclin B1, CDK1 and CDK4 expressions. miR-203a was negatively regulated by lncRNA GAS5. The promoting activities of lncRNA GAS5 silence on MG-63 cells growth and metastasis were reversed by miR-203a suppression. TIMP2 was a target of miR-203a and the anti-growth and anti-metastasis actions of miR-203a suppression were reversed by TIMP2 silence. Further, lncRNA GAS5 silence, miR 203a overexpression, and TIMP2 silence could activate PI3K/AKT/GSK3beta signaling while block NF-kappaB signaling. CONCLUSION: LncRNA GAS5 might be a tumor suppressor in osteosarcoma via sponging miR-203a, sequestering miR-203a away from TIMP2. PMID- 29414816 TI - Battery Life Matters in Deep Brain Stimulation. PMID- 29414817 TI - Attitudes towards Personal Genomics and Sharing of Genetic Data among Older Swiss Adults: A Qualitative Study. AB - OBJECTIVE: To assess the willingness of older Swiss adults to share genetic data for research purposes and to investigate factors that might impact their willingness to share data. METHODS: Semi-structured interviews were conducted among 40 participants (19 male and 21 female) aged between 67 and 92 years, between December 2013 and April 2014 attending the Seniorenuniversitat Zurich, Switzerland. All interviews were audio-recorded, transcribed verbatim, and anonymized. For the analysis of the interviews, an initial coding scheme was developed, refined over time, and applied afterwards to all interviews. RESULTS: The majority of participants were in favor of placing genetic data to research's disposal. Participant's motivations to share data were mainly driven by altruistic reasons and by contributing to the greater good. Furthermore, several factors which might impact the willingness to share data such as sharing data with private companies, generational differences, differences between sharing genetic data or health data, and sharing due to financial incentives were highlighted. Last, some participants indicated concerns regarding data sharing such as misuse of data, the fear of becoming a transparent citizen, and data safety. However, 20% of the participants express confidence in data protection. Even participants who were skeptical in the beginning of the interviews admitted the benefits of data sharing. DISCUSSION: Overall, this study suggests older citizens are willing to share their data for research purposes. However, most of them will only contribute if their data is appropriately protected and if they trust the research institution to use the shared data responsibly. More transparency and detailed information regarding the data usage are urgently needed. There is a great need to increase the engagement of older adults in research since they present a large segment of our society - one which is often underexamined in research. CONCLUSION: Increased focus on general public engagement, especially of older adults, in scientific research activities known as "citizen science" is needed to further strengthen the uptake of personalized medicine. PMID- 29414818 TI - Tumor Heterogeneity in Colorectal Cancer: What Do We Know So Far? AB - Colorectal cancer is not one disease but rather a collection of neoplastic diseases. Due to heterogeneity in the disease biology, therapy response, and prognosis, extensive disease stratification is required. Therefore, TNM stage, microsatellite status, tumor grade, lymphovascular invasion, and other parameters are assessed in the pathology report to indicate the extent and prognosis of the disease. The mutation status of KRAS, BRAF, and NRAS is also investigated in a metastatic context to predict the response to anti-EGFR therapy. Recently, 4 distinct molecular subtypes of colorectal cancer have been described that have both prognostic and therapeutic relevance. In addition, characterization of the inflammatory infiltrate revealed major differences in the amount and location of inflammatory cells in distinct colorectal tumor types. Together, all of these parameters help to stratify patients into different therapeutic and prognostic subgroups. However, this stratification is not unambiguous since tumors often display intratumoral heterogeneity, whereby several subpopulations within one tumor show differences in morphology, inflammatory infiltrate, mutational status, or gene expression profile. This article gives an overview of all of the current known data with regard to tumor heterogeneity at both inter- and intratumoral levels. PMID- 29414820 TI - Osteoconduction of Unrestricted Somatic Stem Cells on an Electrospun Polylactic Co-Glycolic Acid Scaffold Coated with Nanohydroxyapatite. AB - The limitation of traditional bone grafts could be overcome by applying engineered bone constructs, which are mainly produced by seeding suitable stem cells on appropriate scaffolds. So far, bone marrow-derived stromal cells have been the most applied cells in bone tissue engineering, but current data show that unrestricted somatic stem cells (USSCs) from human cord blood might actually be a better stem cell source due to the accessibility and noninvasive procedure of collection. In this study, we cultured USSCs on a plasma-treated electrospun polylactic-co-glycolic acid (PLGA) scaffold coated with nanohydroxyapatite (nHA). Adhesion and proliferation of USSCs on PLGA/nHA were assessed by scanning electron microscopy and MTT assay. Osteogenic differentiation of USSCs into osteoblast lineage cells was evaluated via alkaline phosphatase (ALP) activity and real-time polymerase chain reaction. Our observation showed that USSCs attached and proliferated on PLGA/nHA. Osteogenic differentiation was confirmed by increased ALP activity and OSTEONECTIN expression in USSCs on PLGA/nHA after the 1st week of the osteogenic period. Therefore, using USSCs on electrospun PLGA/nHA is a promising approach in bone tissue engineering. PMID- 29414819 TI - DBStar: An Open-Source Tool Kit for Imaging Analysis with Patient-Customized Deep Brain Stimulation Platforms. AB - BACKGROUND/OBJECTIVES: To create an open-source method for reconstructing microelectrode recording (MER) and deep brain stimulation (DBS) electrode coordinates along multiple parallel trajectories with patient-specific DBS implantation platforms to facilitate DBS research. METHODS: We combined the surgical geometry (extracted from WayPoint Planner), pre-/intra-/postoperative computed tomography (CT) and/or magnetic resonance (MR) images, and integrated them into the Analysis of Functional NeuroImages (AFNI) neuroimaging analysis environment using functions written in Python. Electrode coordinates were calculated from image-based electrode surfaces and recording trajectory depth values. Coordinates were translated into appropriate trajectories, and were tested for proximity to patient-specific or atlas-based anatomical structures. Final DBS electrode coordinates for 3 patient populations (ventral intermediate nucleus [VIM], subthalamic nucleus [STN], and globus pallidus pars interna [GPi]) were calculated. For STN cases, MER site coordinates were then analyzed to see whether they were inside or outside the STN. RESULTS: Final DBS electrode coordinates were described for VIM, STN, and GPi patient populations. 115/169 (68%) STN MER sites were within 1 mm of the STN in AFNI's Talairach and Tournoux (TT) atlas. CONCLUSIONS: DBStar is a robust tool kit for understanding the anatomical location and context of electrode locations, and can easily be used for imaging, behavioral, or electrophysiological analyses. PMID- 29414821 TI - Procedures Performed during Hospitalizations for Malignant Pleural Effusions: Data from the 2012 National Inpatient Sample. AB - BACKGROUND: Malignant pleural effusions (MPE) are a common clinical problem. Little is known about the burden of MPE and of the treatments used to alleviate its symptoms on the United States Health Care System. OBJECTIVES: We aimed to obtain a better portrait of inpatient pleural procedures performed in the United States. METHODS: We conducted a retrospective analysis of MPE-associated hospitalizations using the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample, Agency for Healthcare Research and Quality (HCUP-NIS 2012). Descriptive statistics were used to analyze procedures performed and their complications. Univariate and multivariate logistic regression models were used to explore the relationship between procedures performed and inpatient mortality and length of stay. RESULTS: Among the 126,825 hospital admissions with a diagnosis of MPE, 72,240 included one or more pleural procedures. Thoracentesis (54,070) was the most frequently performed procedure followed by chest tube placement (23,035), chemical pleurodesis (10,240), and thoracoscopy (6,615). Hospitalization for lung and breast cancer was more likely to include pleural procedures compared to hospitalization for other types of cancer (59.2 and 65.6%, respectively, p < 0.0001). Chemical pleurodesis through a chest tube compared to thoracoscopic chemical pleurodesis was performed more frequently (57 vs. 43%, p < 0.001) and associated with a longer hospital stay (4.9 vs. 5.9 days, p < 0.001). CONCLUSIONS: Hospital admissions for MPE represent a large burden on the US Health Care System. Many hospitalizations are associated with procedures not expected to reduce the recurrence rate of this condition. PMID- 29414822 TI - Expression Profiling Identifies Circular RNA Signature in Hepatoblastoma. AB - BACKGROUND/AIMS: Hepatoblastoma is the most common malignant pediatric liver cancer. circular RNAs (circRNAs) play important roles in fine-tuning gene expression and are often deregulated in cancers. However, the expression profile and clinical significance of circRNAs in hepatoblastoma is still unknown. METHODS: Circular RNA microarray was conducted to identify hepatoblastoma-related circRNAs. GO analysis, pathway analysis, and miRNA response elements analysis was conducted to predict the potential roles of differentially expressed circRNAs in hepatoblastoma. MTT assays, Ki67 staining, and Transwell assays were conducted to clarify the role of circRNA in hepatoblastoma in vitro. Bioinformatics analysis and in vitro experiments were conducted to clarify the mechanism of circRNA mediated gene regulation in hepatoblastoma cell. RESULTS: 869 differentially expressed circRNAs were identified between hepatoblastoma and adjacent normal liver samples, including 421 up-regulated circRNAs and 448 down-regulated circRNAs. The significant enriched GO term of hepatoblastoma-related circRNAs in biological process, cellular component, and molecular function were "chromosome organization", "cytoplasm", and "organic cyclic compound binding". Tight junction signaling pathway was ranked the Top 1 potentially affected by circRNA-mediated regulatory network. circ_0015756 was significantly up-regulated in human hepatoblastoma specimens and metastatic hepatoblastoma cell lines. circ_0015756 silencing decreased hepatoblastoma cell viability, proliferation, and invasion in vitro. circ_0015756 acted as miR-1250-3p sponge to regulate hepatoblastoma cell function. CONCLUSIONS: circRNAs are involved in the pathogenesis of hepatoblastoma. circ_0015756 is a promising target for the prognosis, diagnosis, and treatment of hepatoblastoma. PMID- 29414823 TI - Serine/Threonine Kinase 35, a Target Gene of STAT3, Regulates the Proliferation and Apoptosis of Osteosarcoma Cells. AB - BACKGROUND/AIMS: Serine/threonine kinase 35 (STK35) may be associated with Parkinson disease and human colorectal cancer, but there have been no reports on the expression levels or roles of STK35 in osteosarcoma. METHODS: STK35 mRNA expression was determined in osteosarcoma and bone cyst tissues by real-time PCR. Cell proliferation and apoptosis were assessed by Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis, respectively. RESULTS: STK35 was up-regulated in osteosarcoma tissues as indicated by analyzing publicly available expression data (GEO dataset E-MEXP-3628) and real-time PCR analysis on our own cohort. We subsequently investigated the effects of STK35 knockdown on two osteosarcoma cell lines, MG63 and U2OS. STK35 knockdown inhibited the growth of osteosarcoma cells in vitro and in xenograft tumors. Meanwhile, STK35 knockdown enhanced apoptosis. Expression of the active forms and the activity of two major executioner caspases, caspase 3 and caspase 7, were also increased in osteosarcoma cells with STK35 silenced. Additionally, Gene Set Enrichment Analysis (GSEA) identified that the JAK/STAT signaling pathway was positively correlated with STK35 expression. The mRNA expression of STK35 was repressed by STAT3 small interfering RNA (siRNA), but not by siRNA of STAT4, STAT5A or STAT6. A luciferase reporter assay further demonstrated that STAT3 transcriptionally regulated STK35 expression. A chromatin immunoprecipitation (ChIP) assay confirmed the direct recruitment of STAT3 to the STK35 promoter. The promotion effects of STAT3 knockdown on cell apoptosis were partially abolished by STK35 overexpression. Furthermore, STK35 mRNA expression was positively correlated with STAT3 mRNA expression in osteosarcoma tissues by Pearson correlation analysis. CONCLUSIONS: These results collectively reveal that STAT3 regulates the transcription of STK35 in osteosarcoma. STK35 may exert an oncogenic role in osteosarcoma. PMID- 29414825 TI - Wilms' Tumor 1 Overexpression in Granulosa Cells Is Associated with Polycystic Ovaries in Polycystic Ovary Syndrome Patients. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic ovulatory dysfunction, hyperandrogenism, and polycystic ovaries. Wilms' tumor 1 (WT1) encoding a transcription factor involved in the differentiation of granulosa cells (GCs) regulates androgen receptor in the development of male genitalia. However, the expression pattern and possible role of WT1 in ovaries of PCOS patients are still unknown. METHODS: GCs from 95 PCOS patients (PCOS group) and 62 healthy controls (control group) were isolated. The expression of WT1 in GCs was quantified using the reverse transcription polymerase chain reaction. The correlation between WT1 expression and clinical characteristics was evaluated in PCOS patients. RESULTS: WT1 expression was increased in PCOS patients compared with the normal controls. The expression of WT1 was moderately correlated with testosterone (r = 0.334, p = 0.001) and luteinizing hormone (r = 0.357, p = 0.001) levels and the antral follicle counts (r = 0.337, p = 0.001). CONCLUSIONS: Our study provided novel insights into the relationship between hyperandrogenism and polycystic ovaries of PCOS and WT1. PMID- 29414826 TI - The Bioavailability of Allergens in Allergy Tablets Depends on Several Factors. PMID- 29414824 TI - Overexpression of LncRNA AC067945.2 Down-Regulates Collagen Expression in Skin Fibroblasts and Possibly Correlates with the VEGF and Wnt Signalling Pathways. AB - BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) are thought to play crucial roles in human diseases. However, the function of lncRNAs in hypertrophic scar formation remains poorly understood. METHODS: Utilizing qRT-PCR, we explored the expression changes of AC067945.2. Overexpression of AC067945.2 in normal skin fibroblasts was performed by transient plasmid transfection. Western blot was used to check the proteins' expression changes. Cell Counting Kit-8 (CCK-8) assay and Annexin V/7-AAD staining were used to examine cell proliferation and apoptosis, respectively. mRNA-seq was applied to dissect the differentially expressed mRNAs in AC067945.2 overexpressed cells. We also performed ELISA to detect the VEGF secretion. RESULTS: AC067945.2 was down-regulated in hypertrophic scar tissues. Overexpression of AC067945.2 did not affect cell proliferation, but it mildly promoted early apoptosis in normal skin fibroblasts. Furthermore, AC067945.2 overexpression inhibited the expression of COL1A1, COL1A2, COL3A1 and alpha-SMA proteins. Transforming growth factor-beta1 (TGF-beta1) could inhibit the expression of AC067945.2. Based on mRNA-seq data, compared with mRNAs in the control group, 138 mRNAs were differentially expressed, including 14 up-regulated and 124 down-regulated transcripts, in the AC067945.2 overexpression group. Gene ontology and pathway analyses revealed that AC067945.2 overexpression was correlated with developmental processes, binding, extracellular region, and the vascular endothelial cell growth factor (VEGF) and Wnt signalling pathways. ELISA confirmed that AC067945.2 overexpression could repress VEGF secretion. CONCLUSION: Taken together, our data uncovered the functions of a novel lncRNA AC067945.2, which might help us understand the mechanisms regulated by AC067945.2 in the pathogenesis of hypertrophic scar formation. PMID- 29414827 TI - Statin Therapy and Outcomes in Trials of Nintedanib in Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Cardiovascular comorbidities are frequent in patients with idiopathic pulmonary fibrosis (IPF), and many patients with IPF receive treatment with statins to reduce cardiovascular risk. OBJECTIVES: We investigated whether statin use at baseline was associated with differences in disease progression in placebo treated patients or influenced the treatment effect of nintedanib in the INPULSIS(r) trials. METHODS: Post-hoc subgroup analyses of patients receiving versus not receiving statins at baseline using pooled data from the INPULSIS(r) trials. RESULTS: At baseline, 312 patients received statins and 749 did not. The annual rates of decline in forced vital capacity (FVC) in patients treated with nintedanib and placebo, respectively, were -78.9 and -187.6 mL/year in patients who received statins at baseline, and -127.9 and -237.9 mL/year in patients who did not. The effect of nintedanib was consistent across subgroups (p = 0.9590). CONCLUSIONS: In the INPULSIS(r) trials, there was a numerically lower FVC decline in placebo-treated patients with IPF who received statins at baseline versus those who did not. Use of statins at baseline did not influence the treatment effect of nintedanib. Prospective data are needed to assess the impact of statins on the course of IPF. PMID- 29414828 TI - Endoscopy and Laparoscopy in Disorders of Sex Development. AB - Endoscopy and laparoscopy are used for the assessment of disorders of sex development (DSD) and therapeutic interventions. Endoscopy (urethra-cystoscopy, vaginoscopy) is especially useful when vaginal or urethral surgery is planned. It is also valuable for the assessment of complications. Laparoscopy is used to identify sex ducts and gonads and to perform minimally invasive abdominal and pelvic surgery. This article reviews clinical indications, limitations, findings, and their reporting. It further discusses the impact of these findings on care in typical clinical situations. PMID- 29414829 TI - The Association of Weekly pre-Hemodialysis Systolic Blood Pressure and Following Week Mortality. AB - BACKGROUND/AIMS: Few studies examine the impact of systolic blood pressure (SBP) on mortality in the incident hemodialysis (HD) period, and throughout the first HD year. This large retrospective observational study analyzes the impact of "current" and cumulative low preSBP <110 mmHg (L), and variations in preSBP on short-term (1 week) mortality over the first HD year. METHODS: Weekly mean preSBP for HD weeks 1 to 51 was categorized into L or high preSBP>=110 mmHg (H) for each patient. A generalized linear model (GLM) was used to compute the probability of death in the following week. The model includes age, gender, race and three preSBP-related parameters: (a) percent of prior weeks with L preSBP; (b) percent of prior weeks with switching between L to H; (c) "current" week's preSBP as a binary variable. Separate models were constructed that include demographics and BP-related parameters (a), (b), and (c) separately. RESULTS: In a model combining (a), (b), and (c) above, "current" week L preSBP is associated with increased odds ratio for following week mortality throughout the first HD year. The percent of prior week's L and more switching between L and H are less significantly associated with short-term mortality. In models including (a), (b), and (c) separately, "current" L preSBP is associated with higher mortality. CONCLUSION: This study confirms an association of L preSBP with increased short-term mortality which is maintained over the first HD year. Percent of L preSBP in prior weeks, switching between L and H, and "current" week L are all associated with short-term mortality risk, but "current" week L preSBP is most significant. PMID- 29414830 TI - Pulmonary Diseases in Refugees and Migrants in Europe. AB - More than 2 million people fleeing conflict, persecution, and poverty applied for asylum between 2015 and 2016 in the European Union. Due to this, medical practitioners in recipient countries may be facing a broader spectrum of conditions and unusual presentations not previously encountered, including a wide range of infections with pulmonary involvement. Tuberculosis is known to be more common in migrants and has been covered broadly in other publications. The scope of this review was to provide an overview of exotic infections with pulmonary involvement that could be encountered in refugees and migrants and to briefly describe their epidemiology, diagnosis, and management. As refugees and migrants travel from numerous countries and continents, it is important to be aware of the various organisms that might cause disease according to the country of origin. Some of these diseases are very rare and geographically restricted to certain regions, while others have a more cosmopolitan distribution. Also, the spectrum of severity of these infections can vary from very benign to severe and even life threatening. We will also describe infectious and noninfectious complications that can be associated with HIV infection as some migrants might originate from high HIV prevalence countries in sub-Saharan Africa. As the diagnosis and treatment of these diseases can be challenging in certain situations, patients with suspected infection might require referral to specialized centers with experience in their management. Additionally, a brief description of noncommunicable pulmonary diseases will be provided. PMID- 29414831 TI - "Real-life" Efficacy and Safety Aspects of 4-Year Omalizumab Treatment for Asthma. AB - OBJECTIVE: To evaluate the long-term efficacy and safety of omalizumab in asthma in a real-life setting. SUBJECTS AND METHODS: This 4-year observational study included 65 patients treated with omalizumab during clinic visits; treatment response was rated as excellent, good, and partial based on a modified physician's Global Evaluation of Treatment Effectiveness (mGETE) scale of emergency room visits (ERV), hospitalization, use of oral corticosteroids, inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) dose, and short acting beta-agonist rescue. The following tests were done: forced expiratory volume in 1 s (FEV1) and the asthma control test (ACT). Measurements were performed 1 month before therapy and at 16 weeks, 1 year, and 4 years of treatment. Statistical analyses were done using the Wilcoxon signed-rank test, Spearman rank correlation, and McNemar chi2 test. RESULTS: The dropout rate was 15 (18.5%): 8 nonresponders (10.0%); 2 patients died (2.5%), and 5 were lost to follow-up (6.25%). Treatment response was excellent in 35 (53.8%); good in 23 (35.4%), and partial in 7 patients (10.8%). The number of excellent responders increased from 35 (53.8%) at 16 weeks to 48 (73.8%) at the 4-year follow-up. The number of patients who did not require ERV improved from 0 to 59 (90.8%), and the lowest rate of hospitalization was 1 in year 4 (p < 0.001); patients who did not require courses of oral corticosteroids improved from 0 to 54 (83%). ICS/LABA dose significantly reduced from 65 (100%) to 25 (38.5%) after 4 years of treatment (p < 0.001); ACT scores significantly increased from 15 +/- 3 at baseline to 23 +/- 3 (p < 0.001) and FEV1 level from 55.6 +/- 10.6 to 76.63 +/- 10.34 at year 4. CONCLUSION: In this study, omalizumab therapy resulted in better asthma control, and was effective and well tolerated as an add-on therapy for patients with moderate-to-severe asthma. PMID- 29414832 TI - Overexpression of SNX3 Decreases Amyloid-beta Peptide Production by Reducing Internalization of Amyloid Precursor Protein. AB - BACKGROUND: Sorting nexins (SNXs) have diverse functions in protein sorting and membrane trafficking. Recently, single-nucleotide polymorphisms in SNX3 were found to be associated with Alzheimer disease. However, it remains unknown whether SNX3 participates in amyloid (A)beta peptide production. OBJECTIVE: To examine the role of SNX3 in Abeta production and APP processing. METHODS: The effect of increased expression of SNX3 was studied in HEK293T cells. Abeta peptides were measured by immunoassay. Protein-protein association was analyzed by a bimolecular fluorescence complementation (BiFC) assay. APP uptake was measured with an alpha-bungarotoxin-binding assay, and flow cytometry was used to measure cell surface APP levels. RESULTS: We found that overexpression of SNX3 in HEK293T cells decreases the levels of secreted Abeta and soluble N-terminal APP fragments (sAPPbeta). The reduction correlated with a decreased association of APP with BACE1, as revealed by BiFC. This effect may, in part, be explained by a reduced internalization of APP; SNX3 overexpression reduced APP internalization as determined by an alpha-bungarotoxin-binding assay, and caused increased APP levels on the cell surface, as shown by flow cytometry. In addition, SNX3 overexpression increased the cellular levels of full-length APP. CONCLUSION: These results provide evidence that SNX3 regulates Abeta production by influencing the internalization of APP. PMID- 29414833 TI - Increased Proportion of Tc17 and Th17 Cells and Their Significant Reduction after Thymectomy May Be Related to Disease Progression in Myasthenia Gravis. AB - OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies against the neuromuscular junction. The thymus has an important role in the pathogenesis of MG because most patients have thymic pathology, and thymectomy (TE) can reduce the severity of the disease. METHODS: In this study, the frequency of Th17 and Tc17 cells was studied in 12 MG patients (pre-TE and 6 months post-TE) and in 12 healthy controls (HC). RESULTS: The frequency of Tc17 cells in the pre-TE patients was significantly higher than in the HC (p < 0.05), and after TE, these cells had significantly decreased compared to before TE (p < 0.05). The frequency of Th17 cells in pre-TE patients was significantly higher than in the HC (p < 0.05), and after TE, these cells had significantly decreased compared to before TE (p < 0.05). CONCLUSION: Our findings indicated a possible role of Tc17 and Th17 in MG pathogenesis. PMID- 29414834 TI - Phosphate Removal During Conventional Hemodialysis: a Decades-Old Misconception. AB - BACKGROUND/AIMS: Hyperphosphatemia is associated with high mortality rate in patients on dialysis. Conventional hemodialysis (HD) is a limit technique in removing phosphate (P). There is a widespread belief that P is removed mainly in the first hour of HD. The aim of this study was to certify the percentage of 1 hour removal of P as compared to the entire procedure. METHODS: data from the first dialysis of the week of 21 patients (13 men, age 44+/-15 years), for 3 consecutive dialysis sessions were evaluated. Fresh dialysate samples were collected at 1 hour and at the end of the session from a partial spent dialysate collection method. RESULTS: Pre dialysis serum P was 4.7+/-1.7 mg/dl. Reduction rate of serum P was 47.4 +/- 14.3 and 45.1 +/- 10.8% in 1- and 4-hour of HD, respectively (p=0.322). P removal was 194 (145, 242) mg in 1-hour (p<0.0001), which represents 25.0 +/- 0.2% of the total removed during the entire HD. Patients with pre dialysis P >= 5.5mg/dl had higher P removal during HD than those with P < 5.5mg/dl [975 (587, 1354) vs. 776 (580, 784) mg, p=0.025], although the percentage of removal in 1 hour was not different from those with P < 5.5mg/d (24.9 +/- 0.3 vs. 25.0 +/- 0.1%, p=0.918). P removal during dialysis correlated with pre dialysis serum P (r=0.455, p=0.001), parathormone (r=0.264, p=0.037) and ultrafiltration volume (r=0.343, p=0.019). CONCLUSION: despite the P serum concentration normalizing in the first hour of hemodialysis, the removal in the same period reaches only 25% of the entire session. PMID- 29414835 TI - Choroidal Thickness with Swept-Source Optical Coherence Tomography versus Foveal Morphology in Young Children with a History of Prematurity. AB - AIM: Comparison of choroidal thickness (CT) and foveal morphology as seen with swept-source optical coherence tomography (SS-OCT) in children with a history of treated or spontaneously regressed retinopathy of prematurity (tROP or srROP) to assess the impact on best-corrected visual acuity (BCVA). METHODS: CT was measured by SS-OCT (DRI-OCT Triton; Topcon, USA) single scans of a 6-mm diameter around the fovea in 17 children with tROP or srROP (4-7 years of age) and compared to 25 controls (age-matched children and adults). The disproportion of the outer nuclear layer and inner retinal layers at the fovea (i.e., the ONL+/IRL ratio) as a measure of macular developmental arrest (MDA) was manually analyzed. BCVA was tested with ETDRS letter charts and correlated with the morphology. RESULTS: CT was significantly thinner in children with tROP and srROP compared to term-born healthy children (nKids) at all measurement marks (p < 0.001), and mostly affected in the subfoveal area. tROP showed the lowest CT. CT allowed no direct conclusion about ONL+/IRL, but correlated positively with BCVA. CONCLUSIONS: Reduced CT in children with a history of ROP is linked to ROP severity. These findings overlap with the degree of MDA. CT appears to be involved in ROP, but MDA showed a higher impact on the BCVA of the examined cohort. PMID- 29414836 TI - Estimating of Residual Kidney Function by Multi-Frequency Bioelectrical Impedance Analysis in Hemodialysis Patients Without Urine Collection. AB - BACKGROUND/AIMS: Residual kidney function (RKF) is a pivotal predictor of better clinical outcomes in maintenance hemodialysis (MHD) patients. So far there has been no attempt to use bioimpedance analysis (BIA) measurements to calculate residual glomerular filtration rate (GFR) in dialysis population. We hypothesized that performing of multi-frequency BIA at the beginning and end of hemodialysis session can enable us to predict the measured residual GFR in MHD patients. Thus our aim was to develop and validate a new RKF prediction equation using multi frequency BIA in MHD patients. METHODS: It was diagnostic test evaluation study in a prospective cohort. Participants (n=88; mean age, 66.3+/-13.2 years, 59.1% males) were recruited from a single hemodialysis center. A new equation (eGFRBIA) to predict RKF, utilizing BIA measurements performed pre- and post-dialysis, was generated and cross-validated by the leave-one-out procedure. GFR estimated as the mean of urea and creatinine clearance (mGFR) using urine collections during entire interdialytic period. RESULTS: A prediction equation for mGFR that includes both pre- and post-dialysis BIA measurements provided a better estimate than either pre- or post-dialysis measurements alone. Mean bias between predicted and measured GFR was -0.12 ml/min. Passing and Bablok regression showed no bias and no significant deviation in linearity. Concordance correlation coefficient indicated good agreement between the eGFRBIA and mGFR (0.75, P<0.001). Using cut off predicted mGFR levels >2 ml/min/1.73 m2 yielded an area under curve of 0.96, sensitivity 85%, and specificity 89% in predicting mGFR. The kappa scores for intraobserver reproducibility were consistent with substantial agreement between first and second estimation of RKF according to eGFRBIA (weighted kappa was 0.60 [0.37-0.83]). CONCLUSION: We present a valid and clinically obtainable method to predict RKF in MHD patients. This method, which uses BIA, may prove as accurate, convenient and easily reproducible while it is operator independent. PMID- 29414838 TI - MOF-Derived Ultrathin Cobalt Phosphide Nanosheets as Efficient Bifunctional Hydrogen Evolution Reaction and Oxygen Evolution Reaction Electrocatalysts. AB - The development of a highly efficient and stable bifunctional electrocatalyst for water splitting is still a challenging issue in obtaining clean and sustainable chemical fuels. Herein, a novel bifunctional catalyst consisting of 2D transition metal phosphide nanosheets with abundant reactive sites templated by Co-centered metal-organic framework nanosheets, denoted as CoP-NS/C, has been developed through a facile one-step low-temperature phosphidation process. The as-prepared CoP-NS/C has large specific surface area and ultrathin nanosheets morphology providing rich catalytic active sites. It shows excellent electrocatalytic performances for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in acidic and alkaline media, with the Tafel slopes of 59 and 64 mV/dec and a current density of 10 mA/cm2 at the overpotentials of 140 and 292 mV, respectively, which are remarkably superior to those of CoP/C, CoP particles, and comparable to those of commercial noble-metal catalysts. In addition, the CoP NS/C also shows good durability after a long-term test. PMID- 29414837 TI - Purification and Characterization of a Biofilm-Degradable Dextranase from a Marine Bacterium. AB - This study evaluated the ability of a dextranase from a marine bacterium Catenovulum sp. (Cadex) to impede formation of Streptococcus mutans biofilms, a primary pathogen of dental caries, one of the most common human infectious diseases. Cadex was purified 29.6-fold and had a specific activity of 2309 U/mg protein and molecular weight of 75 kDa. Cadex showed maximum activity at pH 8.0 and 40 degrees C and was stable at temperatures under 30 degrees C and at pH ranging from 5.0 to 11.0. A metal ion and chemical dependency study showed that Mn2+ and Sr2+ exerted positive effects on Cadex, whereas Cu2+, Fe3+, Zn2+, Cd2+, Ni2+, and Co2+ functioned as inhibitors. Several teeth rinsing product reagents, including carboxybenzene, ethanol, sodium fluoride, and xylitol were found to have no effects on Cadex activity. A substrate specificity study showed that Cadex specifically cleaved the alpha-1,6 glycosidic bond. Thin layer chromatogram and high-performance liquid chromatography indicated that the main hydrolysis products were isomaltoogligosaccharides. Crystal violet staining and scanning electron microscopy showed that Cadex impeded the formation of S. mutans biofilm to some extent. In conclusion, Cadex from a marine bacterium was shown to be an alkaline and cold-adapted endo-type dextranase suitable for development of a novel marine agent for the treatment of dental caries. PMID- 29414839 TI - Mechanism-Based FE Simulation of Tool Wear in Diamond Drilling of SiCp/Al Composites. AB - The aim of this work is to analyze the micro mechanisms underlying the wear of macroscale tools during diamond machining of SiCp/Al6063 composites and to develop the mechanism-based diamond wear model in relation to the dominant wear behaviors. During drilling, high volume fraction SiCp/Al6063 composites containing Cu, the dominant wear mechanisms of diamond tool involve thermodynamically activated physicochemical wear due to diamond-graphite transformation catalyzed by Cu in air atmosphere and mechanically driven abrasive wear due to high-frequency scrape of hard SiC reinforcement on tool surface. An analytical diamond wear model, coupling Usui abrasive wear model and Arrhenius extended graphitization wear model was proposed and implemented through a user defined subroutine for tool wear estimates. Tool wear estimate in diamond drilling of SiCp/Al6063 composites was achieved by incorporating the combined abrasive-chemical tool wear subroutine into the coupled thermomechanical FE model of 3D drilling. The developed drilling FE model for reproducing diamond tool wear was validated for feasibility and reliability by comparing numerically simulated tool wear morphology and experimentally observed results after drilling a hole using brazed polycrystalline diamond (PCD) and chemical vapor deposition (CVD) diamond coated tools. A fairly good agreement of experimental and simulated results in cutting forces, chip and tool wear morphologies demonstrates that the developed 3D drilling FE model, combined with a subroutine for diamond tool wear estimate can provide a more accurate analysis not only in cutting forces and chip shape but also in tool wear behavior during drilling SiCp/Al6063 composites. Once validated and calibrated, the developed diamond tool wear model in conjunction with other machining FE models can be easily extended to the investigation of tool wear evolution with various diamond tool geometries and other machining processes in cutting different workpiece materials. PMID- 29414840 TI - A Fine Grain, High Mn Steel with Excellent Cryogenic Temperature Properties and Corresponding Constitutive Behaviour. AB - A Fe-34.5 wt % Mn-0.04 wt % C ultra-high Mn steel with a fully recrystallised fine-grained structure was produced by cold rolling and subsequent annealing. The steel exhibited excellent cryogenic temperature properties with enhanced work hardening rate, high tensile strength, and high uniform elongation. In order to capture the unique mechanical behaviour, a constitutive model within finite strain plasticity framework based on Hill-type yield function was established with standard Armstrong-Frederick type isotropic hardening. In particular, the evolution of isotropic hardening was determined by the content of martensite; thus, a relationship between model parameters and martensite content is built explicitly. PMID- 29414841 TI - Structure and Infrared Emissivity Properties of the MAO Coatings Formed on TC4 Alloys in K2ZrF6-Based Solution. AB - Micro-arc oxidation (MAO) ceramic coatings were formed on TC4 alloy surface in silicate and metaphosphate electrolytes based with K2ZrF6 for various concentrations. X-ray diffraction (XRD), Scanning electron microscopy (SEM), X ray photoelectron spectroscopy (XPS) were used to characterize the phase composition, microstructure and chemical compositions of the coatings. The infrared emissivity of the coatings was measured at 50 degrees C in a wavelength range of 8-20 um. The microstructural observations all revealed the typical porousstructures. Moreover, adecline in roughness and thickness of the prepared coatings can be observed when the concentration of K2ZrF6 increases. Combined with the results of XRD and XPS, it was found that all the oxides existed as the amorphous form in the coatings except the TiO2 phase. The coatings exhibited the highest infrared emissivity value (about 0.89) when the concentration of K2ZrF6 was 6 g/L, which was possibly attributed to the defect microstructure and the optimal role of ZrO2. PMID- 29414843 TI - The Moss Physcomitrella patens Is Hyperresistant to DNA Double-Strand Breaks Induced by gamma-Irradiation. AB - The purpose of this study was to investigate whether the moss Physcomitrella patens cells are more resistant to ionizing radiation than animal cells. Protoplasts derived from P. patens protonemata were irradiated with gamma-rays of 50-1000 gray (Gy). Clonogenicity of the protoplasts decreased in a gamma-ray dose dependent manner. The dose that decreased clonogenicity by half (LD50) was 277 Gy, which indicated that the moss protoplasts were 200-times more radioresistant than human cells. To investigate the mechanism of radioresistance in P. patens, we irradiated protoplasts on ice and initial double-strand break (DSB) yields were measured using the pulsed-field gel electrophoresis assay. Induced DSBs linearly increased dependent on the gamma-ray dose and the DSB yield per Gb DNA per Gy was 2.2. The DSB yield in P. patens was half to one-third of those reported in mammals and yeasts, indicating that DSBs are difficult to induce in P. patens. The DSB yield per cell per LD50 dose in P. patens was 311, which is three- to six-times higher than those in mammals and yeasts, implying that P. patens is hyperresistant to DSBs. Physcomitrella patens is indicated to possess unique mechanisms to inhibit DSB induction and provide resistance to high numbers of DSBs. PMID- 29414842 TI - Chemical Constituents and Pharmacological Activity of Agarwood and Aquilaria Plants. AB - Agarwood, a highly precious non-timber fragrant wood of Aquilaria spp. (Thymelaeaceae), has been widely used in traditional medicine, religious rites, and cultural activities. Due to the inflated demanding and depleted natural resources, the yields of agarwood collected from the wild are shrinking, and the price is constantly rising, which restricts agarwood scientific research and wide application. With the sustainable planting and management of agarwood applied, and especially the artificial-inducing methods being used in China and Southeast Asian countries, agarwood yields are increasing, and the price is becoming more reasonable. Under this condition, illuminating the scientific nature of traditional agarwood application and developing new products and drugs from agarwood have become vitally important. Recently, the phytochemical investigations have achieved fruitful results, and more than 300 compounds have been isolated, including numerous new compounds that might be the characteristic constituents with physiological action. However, no one has focused on the new compounds and presented a summary until now. Alongside phytochemical advances, bioactivity screening and pharmacological investigation have also made a certain progress. Therefore, this review discussed the new compounds isolated after 2010, and summarized the pharmacological progress on agarwood and Aquilaria plants. PMID- 29414844 TI - Efficacy of Compounds Isolated from the Essential Oil of Artemisia lavandulaefolia in Control of the Cigarette Beetle, Lasioderma serricorne. AB - To develop natural product resources to control cigarette beetles (Lasioderma serricorne), the essential oil from Artemisia lavandulaefolia (Compositae) was investigated. Oil was extracted by hydrodistillation of the above-ground portion of A. lavandulaefolia and analyzed using gas chromatography-mass spectrometer (GC MS). Extracted essential oil and three compounds isolated from the oil were then evaluated in laboratory assays to determine the fumigant, contact, and repellent efficacy against the stored-products' pest, L. serricorne. The bioactive constituents from the oil extracts were identified as chamazulene (40.4%), 1,8 cineole (16.0%), and beta-caryophyllene (11.5%). In the insecticidal activity assay, the adults of L. serricorne were susceptible to fumigant action of the essential oil and 1,8-cineole, with LC50 values of 31.81 and 5.18 mg/L air. The essential oil, 1,8-cineole, chamazulene, and beta-caryophyllene exhibited contact toxicity with LD50 values of 13.51, 15.58, 15.18 and 35.52 MUg/adult, respectively. During the repellency test, the essential oil and chamazulene had repellency approximating the positive control. The results indicated that chamazulene was abundant in A. lavandulaefolia essential oil and was toxic to cigarette beetles. PMID- 29414846 TI - Pediatric Palliative Care in Infants and Neonates. AB - The application of palliative and hospice care to newborns in the neonatal intensive care unit (NICU) has been evident for over 30 years. This article addresses the history, current considerations, and anticipated future needs for palliative and hospice care in the NICU, and is based on recent literature review. Neonatologists have long managed the entirety of many newborns' short lives, given the relatively high mortality rates associated with prematurity and birth defects, but their ability or willingness to comprehensively address of the continuum of interdisciplinary palliative, end of life, and bereavement care has varied widely. While neonatology service capacity has grown worldwide during this time, so has attention to pediatric palliative care generally, and neonatal perinatal palliative care specifically. Improvements have occurred in family centered care, communication, pain assessment and management, and bereavement. There remains a need to integrate palliative care with intensive care rather than await its application solely at the terminal phase of a young infant's life-when s/he is imminently dying. Future considerations for applying neonatal palliative care include its integration into fetal diagnostic management, the developing era of genomic medicine, and expanding research into palliative care models and practices in the NICU. PMID- 29414847 TI - On the Stability of c-BN-Reinforcing Particles in Ceramic Matrix Materials. AB - Cubic boron nitride (c-BN) composites produced at high pressures and temperatures are widely used as cutting tool materials. The advent of new, effective pressure assisted densification methods, such as spark plasma sintering (SPS), has stimulated attempts to produce these composites at low pressures. Under low pressure conditions, however, transformation of c-BN to the soft hexagonal BN (h BN) phase can occur, with a strong deterioration in hardness and wear. In the present work, the influence of secondary phases (B2O3, Si3N4, and oxide glasses) on the transformation of c-BN was studied in the temperature range between 1100 degrees C and 1575 degrees C. The different heat treated c-BN particles and c-BN composites were analyzed by SEM, X-ray diffraction, and Raman spectroscopy. The transformation mechanism was found to be kinetically controlled solution diffusion-precipitation. Given a sufficiently low liquid phase viscosity, the transformation could be observed at temperatures as low as 1200 degrees C for the c-BN-glass composites. In contrast, no transformation was found at temperatures up to 1575 degrees C when no liquid oxide phase is present in the composite. The results were compared with previous studies concerning the c-BN stability and the c-BN phase diagram. PMID- 29414845 TI - Protective Effects of Olive Leaf Extract on Acrolein-Exacerbated Myocardial Infarction via an Endoplasmic Reticulum Stress Pathway. AB - Many studies reported that air pollution particulate matter (PM) exposure was associated with myocardial infarction (MI). Acrolein representing the unsaturated aldehydes, the main component of PM, derives from the incomplete combustion of wood, plastic, fossil fuels and the main constitute of cigarette smoking. However, the effect of acrolein on MI remains not that clear. In the current study, the effect of acrolein-exacerbated MI was investigated. In vivo, male Sprague-Dawley rats received olive leaf extract (OLE) followed by acrolein, then isoprenaline (ISO) was received by subcutaneous injection to induce MI. Results showed that the expression levels of GRP78 and CHOP, two major components of endoplasmic reticulum (ER) stress were higher in the combination of acrolein and ISO than those in ISO treatment. The apoptosis marker, Bax, was also higher while the anti-apoptosis indicator, Bcl2 expression was lower both at protein and mRNA levels in the combination group. Also, the acrolein-protein adducts and myocardial pathological damage increased in the combination of acrolein and ISO relative to the ISO treatment. Besides, cardiac parameters, ejection fraction (EF) and fractional shortening (FS) were reduced more significantly when acrolein was added than in ISO treatment. Interestingly, all the changes were able to be ameliorated by OLE. Since hydroxytyrosol (HT) and oleuropein (OP) were the main components in OLE, we next investigated the effect of HT and OP on cardiomyocyte H9c2 cell apoptosis induced by acrolein through ER stress and Bax pathway. Results showed that GRP78, CHOP and Bax expression were upregulated, while Bcl2 expression was downregulated both at the protein and mRNA levels, when the H9c2 cells were treated with acrolein. In addition, pretreatment with HT can reverse the expression of GRP78, CHOP, Bax and Bcl2 on the protein and mRNA levels, while there was no effect of OP on the expression of GRP78 and CHOP on the mRNA levels. Overall, all these results demonstrated that OLE and the main components (HT and OP) could prevent the negative effects of acrolein on myocardium and cardiomyocytes. PMID- 29414848 TI - NADA Protocol for Behavioral Health. Putting Tools in the Hands of Behavioral Health Providers: The Case for Auricular Detoxification Specialists. AB - Background: The National Acupuncture Detoxification Association (NADA) protocol, a simple standardized auricular treatment has the potential to provide vast public health relief on issues currently challenging our world. This includes but is not limited to addiction, such as the opioid epidemic, but also encompasses mental health, trauma, PTSD, chronic stress, and the symptoms associated with these conditions. Simple accessible tools that improve outcomes can make profound differences. We assert that the NADA protocol can have greatest impact when broadly applied by behavioral health professionals, Auricular Detoxification Specialists (ADSes). Methods: The concept of ADS is described and how current laws vary from state to state. Using available national data, a survey of practitioners in three selected states with vastly different laws regarding ADSes, and interviews of publicly funded programs which are successfully incorporating the NADA protocol, we consider possible effects of ADS-friendly conditions. Results: Data presented supports the idea that conditions conducive to ADS practice lead to greater implementation. Program interviews reflect settings in which adding ADSes can in turn lead to improved outcomes. Discussion: The primary purpose of non-acupuncturist ADSes is to expand the access of this simple but effective treatment to all who are suffering from addictions, stress, or trauma and to allow programs to incorporate acupuncture in the form of the NADA protocol at minimal cost, when and where it is needed. States that have changed laws to allow ADS practice for this standardized ear acupuncture protocol have seen increased access to this treatment, benefiting both patients and the programs. PMID- 29414849 TI - Washable and Reliable Textile Electrodes Embedded into Underwear Fabric for Electrocardiography (ECG) Monitoring. AB - A medical quality electrocardiogram (ECG) signal is necessary for permanent monitoring, and an accurate heart examination can be obtained from instrumented underwear only if it is equipped with high-quality, flexible, textile-based electrodes guaranteeing low contact resistance with the skin. The main objective of this article is to develop reliable and washable ECG monitoring underwear able to record and wirelessly send an ECG signal in real time to a smart phone and further to a cloud. The article focuses on textile electrode design and production guaranteeing optimal contact impedance. Therefore, different types of textile fabrics were coated with modified poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) in order to develop and manufacture reliable and washable textile electrodes assembled to female underwear (bras), by sewing using commercially available conductive yarns. Washability tests of connected underwear containing textile electrodes and conductive threads were carried out up to 50 washing cycles. The influence of standardized washing cycles on the quality of ECG signals and the electrical properties of the textile electrodes were investigated and characterized. PMID- 29414850 TI - Statistical Analysis of Stress Signals from Bridge Monitoring by FBG System. AB - In this paper, a fiber Bragg grating (FBG)-based stress monitoring system instrumented on an orthotropic steel deck arch bridge is demonstrated. The FBG sensors are installed at two types of critical fatigue-prone welded joints to measure the strain and temperature signals. A total of 64 FBG sensors are deployed around the rib-to-deck and rib-to-diagram areas at the mid-span and quarter-span of the investigated orthotropic steel bridge. The local stress behaviors caused by the highway loading and temperature effect during the construction and operation periods are presented with the aid of a wavelet multi resolution analysis approach. In addition, the multi-modal characteristic of the rainflow counted stress spectrum is modeled by the method of finite mixture distribution together with a genetic algorithm (GA)-based parameter estimation approach. The optimal probability distribution of the stress spectrum is determined by use of Bayesian information criterion (BIC). Furthermore, the hot spot stress of the welded joint is calculated by an extrapolation method recommended in the specification of International Institute of Welding (IIW). The stochastic characteristic of stress concentration factor (SCF) of the concerned welded joint is addressed. The proposed FBG-based stress monitoring system and probabilistic stress evaluation methods can provide an effective tool for structural monitoring and condition assessment of orthotropic steel bridges. PMID- 29414851 TI - Breaking Symmetry in Viral Icosahedral Capsids as Seen through the Lenses of X ray Crystallography and Cryo-Electron Microscopy. AB - The majority of viruses on Earth form capsids built by multiple copies of one or more types of a coat protein arranged with 532 symmetry, generating an icosahedral shell. This highly repetitive structure is ideal to closely pack identical protein subunits and to enclose the nucleic acid genomes. However, the icosahedral capsid is not merely a passive cage but undergoes dynamic events to promote packaging, maturation and the transfer of the viral genome into the host. These essential processes are often mediated by proteinaceous complexes that interrupt the shell's icosahedral symmetry, providing a gateway through the capsid. In this review, we take an inventory of molecular structures observed either internally, or at the 5-fold vertices of icosahedral DNA viruses that infect bacteria, archea and eukaryotes. Taking advantage of the recent revolution in cryo-electron microscopy (cryo-EM) and building upon a wealth of crystallographic structures of individual components, we review the design principles of non-icosahedral structural components that interrupt icosahedral symmetry and discuss how these macromolecules play vital roles in genome packaging, ejection and host receptor-binding. PMID- 29414853 TI - The Structure of PrPSc Prions. AB - PrPSc (scrapie isoform of the prion protein) prions are the infectious agent behind diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids (deer, elk, moose, and reindeer), as well as goat and sheep scrapie. PrPSc is an alternatively folded variant of the cellular prion protein, PrPC, which is a regular, GPI anchored protein that is present on the cell surface of neurons and other cell types. While the structure of PrPC is well studied, the structure of PrPSc resisted high-resolution determination due to its general insolubility and propensity to aggregate. Cryo-electron microscopy, X-ray fiber diffraction, and a variety of other approaches defined the structure of PrPSc as a four-rung beta solenoid. A high-resolution structure of PrPSc still remains to be solved, but the four-rung beta-solenoid architecture provides a molecular framework for the autocatalytic propagation mechanism that gives rise to the alternative conformation of PrPSc. Here, we summarize the current knowledge regarding the structure of PrPSc and speculate about the molecular conversion mechanisms that leads from PrPC to PrPSc. PMID- 29414852 TI - Interactions Between Epilepsy and Plasticity. AB - Undoubtedly, one of the most interesting topics in the field of neuroscience is the ability of the central nervous system to respond to different stimuli (normal or pathological) by modifying its structure and function, either transiently or permanently, by generating neural cells and new connections in a process known as neuroplasticity. According to the large amount of evidence reported in the literature, many stimuli, such as environmental pressures, changes in the internal dynamic steady state of the organism and even injuries or illnesses (e.g., epilepsy) may induce neuroplasticity. Epilepsy and neuroplasticity seem to be closely related, as the two processes could positively affect one another. Thus, in this review, we analysed some neuroplastic changes triggered in the hippocampus in response to seizure-induced neuronal damage and how these changes could lead to the establishment of temporal lobe epilepsy, the most common type of focal human epilepsy. PMID- 29414855 TI - Recent Perspectives Regarding the Role of Dietary Protein for the Promotion of Muscle Hypertrophy with Resistance Exercise Training. AB - Skeletal muscle supports locomotion and serves as the largest site of postprandial glucose disposal; thus it is a critical organ for physical and metabolic health. Skeletal muscle mass is regulated by the processes of muscle protein synthesis (MPS) and muscle protein breakdown (MPB), both of which are sensitive to external loading and aminoacidemia. Hyperaminoacidemia results in a robust but transient increase in rates of MPS and a mild suppression of MPB. Resistance exercise potentiates the aminoacidemia-induced rise in MPS that, when repeated over time, results in gradual radial growth of skeletal muscle (i.e., hypertrophy). Factors that affect MPS include both quantity and composition of the amino acid source. Specifically, MPS is stimulated in a dose-responsive manner and the primary amino acid agonist of this process is leucine. MPB also appears to be regulated in part by protein intake, which can exert a suppressive effect on MPB. At high protein doses the suppression of MPB may interfere with skeletal muscle adaptation following resistance exercise. In this review, we examine recent advancements in our understanding of how protein ingestion impacts skeletal muscle growth following resistance exercise in young adults during energy balance and energy restriction. We also provide practical recommendations for exercisers who wish to maximize the hypertrophic response of skeletal muscle during resistance exercise training. PMID- 29414857 TI - Vitamin B12 Status of Various Ethnic Groups Living in New Zealand: An Analysis of the Adult Nutrition Survey 2008/2009. AB - Vitamin B12 deficiency leads to serious health problems, whilst sub-optimal status is associated with raised biochemical markers of disease risk. Identifying at-risk groups could benefit both individuals and public health. Dietary data were sourced from the New Zealand Adult Nutrition Survey 2008/2009, involving a nationally representative sample of 4721 participants. Ethnic groupings were by regional origin: Maori and Pacific Islands, New Zealand European, East and South East Asian, and South Asian. Diets were assessed using 24-h recalls and from responses to a questionnaire. Blood samples were obtained from a subset (n = 3348). The mean (95% CI) vitamin B12 intake of the Maori and Pacific Islands group was 5.1 (4.7, 5.5) ug/day, New Zealand Europeans 4.1 (3.8, 4.3) ug/day, East and South-East Asians 4.5 (3.7, 5.3) ug/day, and South Asians 3.0 (2.5, 3.6) ug/day. Overall, 20.1% of the sample had vitamin B12 inadequacy (<221 pmol/L). South Asians had the lowest vitamin B12 concentration at 282 (251, 312) pmol/L, whilst Maori/Pacific and East/South-East Asians had the highest, at 426 (386, 466) and 425 (412, 437) pmol/L, respectively. The main dietary determinant of serum vitamin B12 concentration was whether or not people ate red meat, with a regression coefficient of 27.0 (95% CI: 6.6, 47.5). It would be helpful for health agencies to be aware of the potential for compromised vitamin B12 status in South Asian communities. PMID- 29414854 TI - Practical Application of Aptamer-Based Biosensors in Detection of Low Molecular Weight Pollutants in Water Sources. AB - Water pollution has become one of the leading causes of human health problems. Low molecular weight pollutants, even at trace concentrations in water sources, have aroused global attention due to their toxicity after long-time exposure. There is an increased demand for appropriate methods to detect these pollutants in aquatic systems. Aptamers, single-stranded DNA or RNA, have high affinity and specificity to each of their target molecule, similar to antigen-antibody interaction. Aptamers can be selected using a method called Systematic Evolution of Ligands by EXponential enrichment (SELEX). Recent years we have witnessed great progress in developing aptamer selection and aptamer-based sensors for low molecular weight pollutants in water sources, such as tap water, seawater, lake water, river water, as well as wastewater and its effluents. This review provides an overview of aptamer-based methods as a novel approach for detecting low molecular weight pollutants in water sources. PMID- 29414856 TI - Identification, Characteristics and Mechanism of 1-Deoxy-N-acetylglucosamine from Deep-Sea Virgibacillus dokdonensis MCCC 1A00493. AB - Xanthomonas oryzae pv. oryzae, which causes rice bacterial blight, is one of the most destructive pathogenic bacteria. Biological control against plant pathogens has recently received increasing interest. 1-Deoxy-N-acetylglucosamine (1 DGlcNAc) was extracted from the supernatant of Virgibacillus dokdonensis MCCC 1A00493 fermentation through antibacterial bioassay-guided isolation. Its structure was elucidated by LC/MS, NMR, chemical synthesis and time-dependent density functional theory (TD-DFT) calculations. 1-DGlcNAc specifically suppressed X. oryzae pv. oryzae PXO99A (MIC was 23.90 MUg/mL), but not other common pathogens including Xanthomonas campestris pv. campestris str.8004 and Xanthomonas oryzae pv. oryzicola RS105. However, its diastereomer (2-acetamido 1,5-anhydro-2-deoxy-d-mannitol) also has no activity to X. oryzae pv. oryzae. This result suggested that activity of 1-DGlcNAc was related to the difference in the spatial conformation of the 2-acetamido moiety, which might be attributed to their different interactions with a receptor. Eighty-four unique proteins were found in X. oryzae pv. oryzae PXO99A compared with the genome of strains8004 and RS105 by blastp. There may be unique interactions between 1-DGlcNAc and one or more of these unique proteins in X. oryzae pv. oryzae. Quantitative real-time PCR and the pharmMapper server indicated that proteins involved in cell division could be the targets in PXO99A. This research suggested that specificity of active substance was based on the active group and spatial conformation selection, and these unique proteins could help to reveal the specific mechanism of action of 1-DGlcNAc against PXO99A. PMID- 29414858 TI - Lower Dietary Inflammatory Index Scores Are Associated with Lower Glycemic Index Scores among College Students. AB - The association between the Dietary Inflammatory Index (DII(r)), the glycemic index (GI), and the glycemic load (GL) is not known, although it is known that carbohydrates are pro-inflammatory. We aimed to measure the association between the DII and both GI and GL among college students. In this cross-sectional study, 110 college students completed a 3-day food diary, which was used to calculate the DII, the GI, the GL, and the healthy eating index (HEI)-2010. Least square means and 95% confidence intervals of the GI, the GL, and the HEI-2010 were presented per DII tertile using generalized linear mixed models. Participants in tertile 1 of DII scores had lower GI and GL scores, but higher HEI-2010 scores than those in tertile 3. Pearson correlations showed that DII score was positively correlated with the GI score (r = 0.30, p < 0.01), but negatively correlated with the HEI-2010 (r = -0.56, p < 0.001). DII score was not correlated with GL score. Results from this study suggest that increased inflammatory potential of diet, as represented by higher DII scores, was associated with increased GI scores and lower quality of diet on the HEI-2010. Use of the DII suggests new directions for dietary approaches for preventing chronic diseases that moves beyond convention by decreasing systemic inflammation. PMID- 29414859 TI - The Assessment of Bone Regulatory Pathways, Bone Turnover, and Bone Mineral Density in Vegetarian and Omnivorous Children. AB - Vegetarian diets contain many beneficial properties as well as carry a risk of inadequate intakes of several nutrients important to bone health. The aim of the study was to evaluate serum levels of bone metabolism markers and to analyze the relationships between biochemical bone markers and anthropometric parameters in children on vegetarian and omnivorous diets. The study included 70 prepubertal children on a lacto-ovo-vegetarian diet and 60 omnivorous children. Body composition, bone mineral content (BMC), and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry. Biochemical markers-bone alkaline phosphatase (BALP), C-terminal telopeptide of type I collagen (CTX-I), osteoprotegerin (OPG), nuclear factor kappaB ligand (RANKL), sclerostin, and Dickkopf-related protein 1 (Dkk-1)-were measured using immunoenzymatic assays. In vegetarians, we observed a significantly higher level of BALP (p = 0.002) and CTX I (p = 0.027), and slightly lower spine BMC (p = 0.067) and BMD (p = 0.060) than in omnivores. Concentrations of OPG, RANKL, sclerostin, and Dkk-1 were comparable in both groups of children. We found that CTX-I was positively correlated with BMC, total BMD, and lumbar spine BMD in vegetarians, but not in omnivores. A well planned vegetarian diet with proper dairy and egg intake does not lead to significantly lower bone mass; however, children following a lacto-ovo-vegetarian diet had a higher rate of bone turnover and subtle changes in bone regulatory markers. CTX-I might be an important marker for the protection of vegetarians from bone abnormalities. PMID- 29414861 TI - Customizable Optical Force Sensor for Fast Prototyping and Cost-Effective Applications. AB - This paper presents the development of an optical force sensor architecture directed to prototyping and cost-effective applications, where the actual force requirements are still not well defined or the most suitable commercial technologies would highly increase the cost of the device. The working principle of this sensor consists of determining the displacement of a lens by measuring the distortion of a refracted light beam. This lens is attached to an elastic interface whose elastic constant is known, allowing the estimation of the force that disturbs the optical system. In order to satisfy the requirements of the design process in an inexpensive way, this sensor can be built by fast prototyping technologies and using non-optical grade elements. To deal with the imperfections of this kind of manufacturing procedures and materials, four fitting models are proposed to calibrate the implemented sensor. In order to validate the system, two different sensor implementations with measurement ranges of +/-45 N and +/-10 N are tested with the proposed models, comparing the resulting force estimation with respect to an industrial-grade load cell. Results show that all models can estimate the loads with an error of about 6% of the measurement range. PMID- 29414862 TI - High Temperature Growth of Graphene from Cobalt Volume: Effect on Structural Properties. AB - Several transition metals other than the largely used Cu and Ni can be, in principle, employed to catalyze carbon precursors for the chemical vapor deposition of graphene, because the thermodynamics of their alloying with carbon is well known. For example, the wealth of information in the Co-C phase diagram can be used to predict the properties of graphene grown in this way. It is, in fact, expected that growth occurs at a temperature higher than in Ni, with beneficial consequences to the mechanical and electronic properties of the final product. In this work, the growth of graphene onto Co film is presented together with an extensive Raman characterization of the structural properties of the material so far obtained. Previous results reporting the full coverage with negligible defective areas, in spite of discontinuities in the underlying metal, are confirmed, together with the occurrence of strain in the graphene sheet. Strain is deeply investigated in this work, in view of possible employment in engineering the material properties. The observed strain is ascribed to the high thermal mismatch with the substrate, even if an effect of the crystallographic transition of Co cannot be excluded. PMID- 29414860 TI - Consecutive Isoproterenol and Adenosine Treatment Confers Marked Protection against Reperfusion Injury in Adult but Not in Immature Heart: A Role for Glycogen. AB - Consecutive treatment of adult rat heart with isoproterenol and adenosine (Iso/Aden), known to consecutively activate PKA/PKC signaling, is cardioprotective against ischemia and reperfusion (I/R). Whether this is cardioprotective in an immature heart is unknown. Langendorff-perfused hearts from adult and immature (60 and 14 days old) male Wistar rats were exposed to 30 min ischemia and 120 min reperfusion, with or without prior perfusion with 5 nM Iso for 3 min followed by 30 MUM Aden for 5 min. Changes in hemodynamics (developed pressure and coronary flow) and cardiac injury (Lactate Dehydrogenase (LDH) release and infarct size) were measured. Additional hearts were used to measure glycogen content. Iso induced a similar inotropic response in both age groups. Treatment with Iso/Aden resulted in a significant reduction in time to the onset of ischemic contracture in both age groups whilst time to peak contracture was significantly shorter only in immature hearts. Upon reperfusion, the intervention reduced cardiac injury and functional impairment in adults with no protection of immature heart. Immature hearts have significantly less glycogen content compared to adult. This work shows that Iso/Aden perfusion confers protection in an adult heart but not in an immature heart. It is likely that metabolic differences including glycogen content contribute to this difference. PMID- 29414863 TI - A Polysulfide-Infiltrated Carbon Cloth Cathode for High-Performance Flexible Lithium-Sulfur Batteries. AB - For practical application of lithium-sulfur batteries (LSBs), it is crucial to develop sulfur cathodes with high areal capacity and cycle stability in a simple and inexpensive manner. In this study, a carbon cloth infiltrated with a sulfur containing electrolyte solution (CC-S) was utilized as an additive-free, flexible, high-sulfur-loading cathode. A freestanding carbon cloth performed double duty as a current collector and a sulfur-supporting/trapping material. The active material in the form of Li2S6 dissolved in a 1 M LiTFSI-DOL/DME solution was simply infiltrated into the carbon cloth (CC) during cell fabrication, and its optimal loading amount was found to be in a range between 2 and 10 mg/cm2 via electrochemical characterization. It was found that the interwoven carbon microfibers retained structural integrity against volume expansion/contraction and that the embedded uniform micropores enabled a high loading and an efficient trapping of sulfur species during cycling. The LSB coin cell employing the CC-S electrode with an areal sulfur loading of 6 mg/cm2 exhibited a high areal capacity of 4.3 and 3.2 mAh/cm2 at C/10 for 145 cycles and C/3 for 200 cycles, respectively, with minor capacity loss (<0.03%/cycle). More importantly, such high performance could also be realized in flexible pouch cells with dimensions of 2 cm * 6 cm before and after 300 bending cycles. Simple and inexpensive preparation of sulfur cathodes using CC-S electrodes, therefore, has great potential for the manufacture of high-performance flexible LSBs. PMID- 29414864 TI - IoT-Forensics Meets Privacy: Towards Cooperative Digital Investigations. AB - IoT-Forensics is a novel paradigm for the acquisition of electronic evidence whose operation is conditioned by the peculiarities of the Internet of Things (IoT) context. As a branch of computer forensics, this discipline respects the most basic forensic principles of preservation, traceability, documentation, and authorization. The digital witness approach also promotes such principles in the context of the IoT while allowing personal devices to cooperate in digital investigations by voluntarily providing electronic evidence to the authorities. However, this solution is highly dependent on the willingness of citizens to collaborate and they may be reluctant to do so if the sensitive information within their personal devices is not sufficiently protected when shared with the investigators. In this paper, we provide the digital witness approach with a methodology that enables citizens to share their data with some privacy guarantees. We apply the PRoFIT methodology, originally defined for IoT-Forensics environments, to the digital witness approach in order to unleash its full potential. Finally, we show the feasibility of a PRoFIT-compliant digital witness with two use cases. PMID- 29414865 TI - Development of an Effective 6-Methylpurine Counterselection Marker for Genetic Manipulation in Thermococcus barophilus. AB - A gene disruption system for Thermococcus barophilus was developed using simvastatin (HMG-CoA reductase encoding gene) for positive selection and 5 Fluoroorotic acid (5-FOA), a pyrF gene for negative selection. Multiple gene mutants were constructed with this system, which offers the possibility of complementation in trans, but produces many false positives (<80%). To significantly reduce the rate of false positives, we used another counterselective marker, 6-methylpurine (6-MP), a toxic analog of adenine developed in Thermococcus kodakarensis, consistently correlated with the TK0664 gene (encoding a hypoxanthine-guanine phosphoribosyl-transferase). We thus replaced pyrF by TK0664 on our suicide vector and tested T. barophilus strain sensitivity to 6-MP before and after transformation. Wild-Type (WT) T. barophilus is less sensitive to 6-MP than WT T. kodakarensis, and an increase of cell resistance was achieved after deletion of the T. barophilusTERMP_00517 gene homologous to T. kodakarensisTK0664. Results confirmed the natural resistance of T. barophilus to 6-MP and show that TK0664 can confer sensitivity. This new counterselection system vastly improves genetic manipulations in T. barophilus MP, with a strong decrease in false positives to <15%. Using this genetic tool, we have started to investigate the functions of several genes involved in genomic maintenance (e.g., polB and rnhB). PMID- 29414867 TI - Surrenderers' Relationships with Cats Admitted to four Australian Animal Shelters. AB - The surrender of cats to animal shelters results in financial, social and moral burdens for the community. Correlations of caretaking and interactions with surrendered cats were calculated, to understand more about humans' relationships with surrendered cats and the contribution of semi-owned cats to shelter intakes. A questionnaire was used to collect detailed information about 100 surrenderers' relationships with cats they surrendered to four animal shelters in Australia, with each surrenderer classifying themselves as being either the owner or a non owner of the surrendered cat (ownership perception). Method of acquisition of the cat, association time, closeness of the relationship with the cat and degree of responsibility for the cat's care were all associated with ownership perception. Many non-owners (59%) fed and interacted with the cat they surrendered but rarely displayed other caretaking behaviours. However, most surrenderers of owned and unowned cats were attached to and felt responsible for the cat. Based on these results and other evidence, a causal model of ownership perception was proposed to provide a better understanding of factors influencing ownership perception. This model consisted of a set of variables proposed as directly or indirectly influencing ownership perception, with connecting arrows to indicate proposed causal relationships. Understanding ownership perception and the contribution of semi-owned cats to shelter intake is important as these can inform the development of more targeted and effective intervention strategies to reduce numbers of unwanted cats. PMID- 29414866 TI - Weed Suppressing Potential and Isolation of Potent Plant Growth Inhibitors from Castanea crenata Sieb. et Zucc. AB - This study isolated, determined, and quantified plant growth inhibitors in Japanese chestnut (Castanea crenata Sieb. et Zucc), a deciduous species native to Japan and Korea. In laboratory assays, C. crenata leaves showed strong inhibition on germination and seedling growth of Echinochloa crus-galli (barnyardgrass), Lactuca sativa (lettuce), and Raphanus sativus (radish). Laboratory and greenhouse trials showed that leaves of C. crenata appeared as a promising material to manage weeds, especially the dicot weeds. By GC-MS and HPLC analyses, gallic, protocatechuic, p-hydroxybenzoic, caffeic, ferulic, ellagic, and cinnamic acids were identified and quantified, of which ellagic acid was present in the highest quantity (2.36 mg/g dried leaves). By column chromatography and spectral data (1H- and 13C-NMR, IR, and LC-MS) analysis, a compound identified as 2alpha,3beta,7beta,23-tetrahydroxyurs-12-ene-28-oic acid (1) was purified from the methanolic leaf extract of C. crenata (0.93 mg/g dried leaves). This constituent showed potent inhibition on growth of E. crus-galli, a problematic weed in agricultural practice. The inhibition of the compound 1 (IC50 = 2.62 and 0.41 mM) was >5 fold greater than that of p-hydroxybenzoic acid (IC50 = 15.33 and 2.11 mM) on shoot and root growth of E. crus-galli, respectively. Results suggest that the isolated the compound 1 has potential to develop natural herbicides to manage E. crus-galli. This study is the first to isolate and identify 2alpha,3beta,7beta,23-tetrahydroxyurs-12-ene-28-oic acid in a plant and report its plant growth inhibitory potential. PMID- 29414868 TI - Frequency Response of Graphene Electrolyte-Gated Field-Effect Transistors. AB - This work develops the first frequency-dependent small-signal model for graphene electrolyte-gated field-effect transistors (EGFETs). Graphene EGFETs are microfabricated to measure intrinsic voltage gain, frequency response, and to develop a frequency-dependent small-signal model. The transfer function of the graphene EGFET small-signal model is found to contain a unique pole due to a resistive element, which stems from electrolyte gating. Intrinsic voltage gain, cutoff frequency, and transition frequency for the microfabricated graphene EGFETs are approximately 3.1 V/V, 1.9 kHz, and 6.9 kHz, respectively. This work marks a critical step in the development of high-speed chemical and biological sensors using graphene EGFETs. PMID- 29414869 TI - Hydroxyapatite Microspheres as an Additive to Enhance Radiopacity, Biocompatibility, and Osteoconductivity of Poly(methyl methacrylate) Bone Cement. AB - This study demonstrates the utility of hydroxyapatite (HA) microspheres as an additive to enhance the radiopaque properties, biocompatibility, and osteoconductivity of poly(methyl methacrylate) (PMMA)-based bone cements. HA microspheres were synthesized using spray drying. They had well-defined spherical shapes, thus allowing for the production of PMMA/HA composites with a very high HA content (20 vol % and 40 vol %). The uniform distribution of these HA microspheres in the PMMA matrix resulted in a remarkable increase in compressive modulus (p < 0.05), while preserving a reasonably high compressive strength. The PMMA/HA bone cements showed much higher radiopacity than PMMA containing BaSO4 as the additive. This was attributed to the high HA content up to 40 vol %. In addition, the biocompatibility and osteoconductivity of PMMA/HA bone cements were significantly enhanced compared to those of PMMA bone cements containing BaSO4, which were assessed using in vitro tests and in vivo animal experiments. PMID- 29414870 TI - Delivery of Mesenchymal Stem Cells from Gelatin-Alginate Hydrogels to Stomach Lumen for Treatment of Gastroparesis. AB - Gastroparesis (GP) is associated with depletion of interstitial cells of Cajal (ICCs) and enteric neurons, which leads to pyloric dysfunction followed by severe nausea, vomiting and delayed gastric emptying. Regenerating these fundamental structures with mesenchymal stem cell (MSC) therapy would be helpful to restore gastric function in GP. MSCs have been successfully used in animal models of other gastrointestinal (GI) diseases, including colitis. However, no study has been performed with these cells on GP animals. In this study, we explored whether mouse MSCs can be delivered from a hydrogel scaffold to the luminal surfaces of mice stomach explants. Mouse MSCs were seeded atop alginate-gelatin, coated with poly-l-lysine. These cell-gel constructs were placed atop stomach explants facing the luminal side. MSCs grew uniformly all across the gel surface within 48 h. When placed atop the lumen of the stomach, MSCs migrated from the gels to the tissues, as confirmed by positive staining with vimentin and N-cadherin. Thus, the feasibility of transplanting a cell-gel construct to deliver stem cells in the stomach wall was successfully shown in a mice stomach explant model, thereby making a significant advance towards envisioning the transplantation of an entire tissue-engineered 'gastric patch' or 'microgels' with cells and growth factors. PMID- 29414871 TI - Mudskippers and Their Genetic Adaptations to an Amphibious Lifestyle. AB - Mudskippers are the largest group of amphibious teleost fish that are uniquely adapted to live on mudflats. During their successful transition from aqueous life to terrestrial living, these fish have evolved morphological and physiological modifications of aerial vision and olfaction, higher ammonia tolerance, aerial respiration, improved immunological defense against terrestrial pathogens, and terrestrial locomotion using protruded pectoral fins. Comparative genomic and transcriptomic data have been accumulated and analyzed for understanding molecular mechanisms of the terrestrial adaptations. Our current review provides a general introduction to mudskippers and recent research advances of their genetic adaptations to the amphibious lifestyle, which will be helpful for understanding the evolutionary transition of vertebrates from water to land. Our insights into the genomes and transcriptomes will also support molecular breeding, functional identification, and natural compound screening. PMID- 29414872 TI - Suramin-Induced Neurotoxicity: Preclinical Models and Neuroprotective Strategies. AB - Suramin is a trypan blue analogon originally developed to treat protozoan infections, which was found to have diverse antitumor effects. One of the most severe side effects in clinical trials was the development of a peripheral sensory-motor polyneuropathy. In this study, we aimed to investigate suramin induced neuropathy with a focus on calcium (Ca2+) homeostasis as a potential pathomechanism. Adult C57Bl/6 mice treated with a single injection of 250 mg/kg bodyweight suramin developed locomotor and sensory deficits, which were confirmed by electrophysiological measurements showing a predominantly sensory axonal demyelinating polyneuropathy. In a next step, we used cultured dorsal root ganglia neurons (DRGN) as an in vitro cell model to further investigate underlying pathomechanisms. Cell viability of DRGN was significantly decreased after 24-hour suramin treatment with a calculated IC50 of 283 uM. We detected a suramin-induced Ca2+ influx into DRGN from the extracellular space, which could be reduced with the voltage-gated calcium channel (VGCC) inhibitor nimodipine. Co incubation of suramin and nimodipine partially improved cell viability of DRGN after suramin exposure. In summary, we describe suramin-induced neurotoxic effects on DRGN as well as potentially neuroprotective agents targeting intracellular Ca2+ dyshomeostasis. PMID- 29414873 TI - Hexosomes with Undecylenic Acid Efficient against Candida albicans. AB - Due to the growing issues with fungal infections, especially with Candida, there is still a need to develop novel anti-Candida materials. One of the known antifungal agents is undecylenic acid (UA), which still cannot be efficiently used due to its oily nature, and thus limited solubility. By taking advantage of the properties of UA, we developed an emulsion with hexagonal phase, i.e., hexosomes, whose structure and morphology was studied by small-angle X-ray scattering and cryo-electron microscopy, respectively. The presence of UA in the hexosome was confirmed by spectroscopy. Moreover, we studied the anti-Candida effect of hexosomes and their cytotoxicity toward human cells. The minimal inhibitory concentration for the 50% and 90% Candida-growth reduction was found at 0.01 and 0.16 wt % hexosomes, respectively (i.e., 2 and 32 pghex/C.a.cell, respectively). The percentage of metabolically active Candida was reduced by 72 96% at hexosome concentrations of 1.0-8.2 pghex/C.a.cell as compared to untreated Candida. Furthermore, at the same concentration range the embedded filamentation test after 24 and 48 h showed the inhibition of both the filamentation and growth of Candida, while the preliminary toxicity test showed that hexosomes were nontoxic for human cells. All these render the here-developed hexosomes with UA efficient and promising anti-Candida agents. PMID- 29414874 TI - Acute Confusional Migraine: Distinct Clinical Entity or Spectrum of Migraine Biology? AB - The goal of this review is to explore the literature reports of acute confusional migraine (ACM) including patient characteristics, migraine symptomatology, and proposed diagnostic criteria. A literature review was conducted using PubMed, Scopus and Web of Science using the terms "confusional migraine" and "confusional state in migraine". All the relevant articles from 1970 to 2016 were included. A total of 120 patients were found in the literature. Most of the cases were seen in the pediatric population with a slight male predominance. Personal or family history of migraine was common. Most patients had a headache prior to the confusional state. In addition to confusion and agitation, some developed visual (32.5%) and/or sensory symptoms (19%) and/or speech problems (39%) either prior to or during the confusional state. Data on treatment outcomes is lacking. Patients with most common forms of migraine report attention and cognitive disturbances but awareness remains intact as opposed to patients with ACM. ACM is a distinct entity and should be included as part of the appendix of International Classification of Headache Disoders-3 beta version (ICHD-3beta) criteria. Prospective studies are needed to further study this disorder and its association with other migraine forms. PMID- 29414876 TI - Measurement of Axial Rigidity and Postural Instability Using Wearable Sensors. AB - Axial Bradykinesia is an important feature of advanced Parkinson's disease (PD). The purpose of this study is to quantify axial bradykinesia using wearable sensors with the long-term aim of quantifying these movements, while the subject performs routine domestic activities. We measured back movements during common daily activities such as pouring, pointing, walking straight and walking around a chair with a test system engaging a minimal number of Inertial Measurement (IM) based wearable sensors. Participants included controls and PD patients whose rotation and flexion of the back was captured by the time delay between motion signals from sensors attached to the upper and lower back. PD subjects could be distinguished from controls using only two sensors. These findings suggest that a small number of sensors and similar analyses could distinguish between variations in bradykinesia in subjects with measurements performed outside of the laboratory. The subjects could engage in routine activities leading to progressive assessments of therapeutic outcomes. PMID- 29414875 TI - 3D Biomimetic Magnetic Structures for Static Magnetic Field Stimulation of Osteogenesis. AB - We designed, fabricated and optimized 3D biomimetic magnetic structures that stimulate the osteogenesis in static magnetic fields. The structures were fabricated by direct laser writing via two-photon polymerization of IP-L780 photopolymer and were based on ellipsoidal, hexagonal units organized in a multilayered architecture. The magnetic activity of the structures was assured by coating with a thin layer of collagen-chitosan-hydroxyapatite-magnetic nanoparticles composite. In vitro experiments using MG-63 osteoblast-like cells for 3D structures with gradients of pore size helped us to find an optimum pore size between 20-40 um. Starting from optimized 3D structures, we evaluated both qualitatively and quantitatively the effects of static magnetic fields of up to 250 mT on cell proliferation and differentiation, by ALP (alkaline phosphatase) production, Alizarin Red and osteocalcin secretion measurements. We demonstrated that the synergic effect of 3D structure optimization and static magnetic stimulation enhances the bone regeneration by a factor greater than 2 as compared with the same structure in the absence of a magnetic field. PMID- 29414877 TI - Photodynamic Therapy in Ocular Oncology. AB - Although introduced for the treatment of maculopathies, photodynamic therapy (PDT) is now largely used in some eye cancers treatment. The selective tissue damage with PDT is achieved by sequestration of the photosensitizer in the target tissue and focal activation of the photosensitizer by low energy directed light. In this way, it is possible to achieve the destruction of the tumor tissue by safeguarding the surrounding healthy structures. Our study describes the clinical uses and efficacy of photodynamic therapy in ocular oncology. PMID- 29414879 TI - Determining Biogenic Content of Biogas by Measuring Stable Isotopologues 12CH4, 13CH4, and CH3D with a Mid-Infrared Direct Absorption Laser Spectrometer. AB - A tunable laser absorption spectrometer (TLAS) was developed for the simultaneous measurement of delta13C and deltaD values of methane (CH4). A mid-infrared interband cascade laser (ICL) emitting around 3.27 um was used to measure the absorption of the three most abundant isotopologues in CH4 with a single, mode hop free current sweep. The instrument was validated against methane samples of fossil and biogenic origin with known isotopic composition. Three blended mixtures with varied biogenic content were prepared volumetrically, and their delta13C and deltaD values were determined. Analysis demonstrated that, provided the isotopic composition of the source materials was known, the delta13C and deltaD values alone were sufficient to determine the biogenic content of the blended samples to within 1.5%. PMID- 29414878 TI - Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure. AB - Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of gamma-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 MUM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 MUM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 MUM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of gamma-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells. PMID- 29414880 TI - Hematological Abnormality, Oxidative Stress, and Genotoxicity Induction in the Greenhouse Pesticide Sprayers; Investigating the Role of NQO1 Gene Polymorphism. AB - The widespread use of pesticides in agriculture represents a threat to the human populations exposed to them. In this cross-sectional study, the hematological and biochemical parameters, plasma cholinesterase (PChE) activity, oxidative stress, genotoxicity, and NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism were measured in 100 greenhouse workers occupationally exposed to pesticide mixture and 104 normal healthy controls. There was a decrease in erythrocytes (5.45%, p = 0.026) and hemoglobin (3.26%, p = 0.025), and an increase in mean corpuscular hemoglobin (3.54%, p = 0.013) in the exposed workers. Sprayers showed a reduction in PChE (23%) and GSH (50%) levels, and an increase in lipid peroxidation (LPO) (55%), protein carbonyl (145%), Superoxide dismutase activity (61%), and total antioxidant capacity (35%) (p < 0.001 for all parameters but LPO: p = 0.009). Genotoxicity parameters were significantly high in the exposed cases (for all parameters: p < 0.001 but tail length: p = 0.002). There was a significant correlation between oxidative stress and genotoxicity parameters, and also between these biomarkers and PChE activity. The NQO1 C609T polymorphism was not significantly associated with studied biomarkers. The findings indicate that occupational exposure to a mixture of pesticides can induce hematotoxicity, oxidative stress, and genotoxicity in greenhouse workers. PMID- 29414881 TI - Depressive Symptoms of Chinese Children: Prevalence and Correlated Factors among Subgroups. AB - Economic growth and socioeconomic changes have transformed nearly every aspect of childhood in China, and many are worried by the increasing prevalence of mental health issues among children, particularly depression. To provide insight into the distribution of depressive symptoms among children in China and identify vulnerable groups, we use data from the 2012 China Family Panel Survey (CFPS), a survey that collected data from a large, nationally representative sample of the Chinese population. Using the CFPS data, we construct a sample of 2679 children aged 10-15 years old from 25 provinces in China. According to our results, the incidence of depression varies by geographic area. Specifically, we find that rates of depressive symptoms are significantly lower in urban areas (14% of sample children) than in rural areas (23% of sample children). Our results also show that children from ethnic minorities, from poorer families, and whose parents are depressed are more likely to be depressed than other children. In contrast, we find that depressive symptoms do not vary by gender. PMID- 29414882 TI - PhcrTx2, a New Crab-Paralyzing Peptide Toxin from the Sea Anemone Phymanthus crucifer. AB - Sea anemones produce proteinaceous toxins for predation and defense, including peptide toxins that act on a large variety of ion channels of pharmacological and biomedical interest. Phymanthus crucifer is commonly found in the Caribbean Sea; however, the chemical structure and biological activity of its toxins remain unknown, with the exception of PhcrTx1, an acid-sensing ion channel (ASIC) inhibitor. Therefore, in the present work, we focused on the isolation and characterization of new P. crucifer toxins by chromatographic fractionation, followed by a toxicity screening on crabs, an evaluation of ion channels, and sequence analysis. Five groups of toxic chromatographic fractions were found, and a new paralyzing toxin was purified and named PhcrTx2. The toxin inhibited glutamate-gated currents in snail neurons (maximum inhibition of 35%, IC50 4.7 uM), and displayed little or no influence on voltage-sensitive sodium/potassium channels in snail and rat dorsal root ganglion (DRG) neurons, nor on a variety of cloned voltage-gated ion channels. The toxin sequence was fully elucidated by Edman degradation. PhcrTx2 is a new beta-defensin-fold peptide that shares a sequence similarity to type 3 potassium channels toxins. However, its low activity on the evaluated ion channels suggests that its molecular target remains unknown. PhcrTx2 is the first known paralyzing toxin in the family Phymanthidae. PMID- 29414883 TI - Possible Role of Inflammation and Galectin-3 in Brain Injury after Subarachnoid Hemorrhage. AB - Aneurysmal subarachnoid hemorrhage (SAH) is known as one of the most devastating diseases in the central nervous system. In the past few decades, research on SAH has focused on cerebral vasospasm to prevent post-SAH delayed cerebral ischemia (DCI) and to improve outcomes. However, increasing evidence has suggested that early brain injury (EBI) is an important mechanism contributing to DCI, cerebral vasospasm as well as poor outcomes. Though the mechanism of EBI is very complex, inflammation is thought to play a pivotal role in EBI. Galectin-3 is a unique chimera type in the galectin family characterized by its beta-galactoside-binding lectin, which mediates various pathologies, such as fibrosis, cell adhesion, and inflammation. Recently, two clinical studies revealed galectin-3 to be a possible prognostic biomarker in SAH patients. In addition, our recent report suggested that higher acute-stage plasma galectin-3 levels correlated with subsequent development of delayed cerebral infarction that was not associated with vasospasm in SAH patients. We review the possible role and molecular mechanisms of inflammation as well as galectin-3 in brain injuries, especially focusing on EBI after SAH, and discuss galectin-3 as a potential new therapeutic or research target in post-SAH brain injuries. PMID- 29414884 TI - Degradation Investigation of Selected Taste and Odor Compounds by a UV/Chlorine Advanced Oxidation Process. AB - Taste- and odor-causing (T&O) compounds are a major concern in drinking water treatment plants due to their negative impacts on the safety and palatability of water supply. This study explored the degradation kinetics and radical chemistry of four often-detected T&O compounds, geosmin (GSM), 2-methylisoborneol (MIB), benzothiazole (BT), and 2-isobutyl-3-methoxypyrazine (IBMP), in the ultraviolet/chlorine (UV/chlorine) advanced oxidation process. All experiments were carried out in a 700 mL photoreactor and the process effectively degraded the investigated T&O compounds in a slightly acidic environment. The degradation of T&O decreased with increasing pH but slightly with decreasing chlorine dosage. When the pH increased from 6 to 8, the pseudo-first-order rate constants of GSM, MIB, BT, and IBMP dropped from 2.84 * 10-3, 2.29 * 10-3, 3.64 * 10-3, and 2.76 * 10-3 s-1 to 3.77 * 10-4, 2.64 * 10-4, 6.48 * 10-4, and 6.40 * 10-4 s-1, respectively. Increasing the chlorine dosage slightly accelerated the degradation of the investigated T&O compounds, but excessive hypochlorous acid and hypochlorite scavenged the HO* radicals and reactive chlorine species (RCS). Generally, HO* primarily contributed to the degradation of all of the investigated T&O compounds as compared to RCS. The degradation by RCS was found to be structurally selective. RCS could not degrade GSM, but contributed to the degradation of MIB, BT, and IBMP. The results confirmed that the proposed oxidation process effectively degraded typical T&O compounds in aqueous phase. PMID- 29414885 TI - An Improved Calibration Method for a Rotating 2D LIDAR System. AB - This paper presents an improved calibration method of a rotating two-dimensional light detection and ranging (R2D-LIDAR) system, which can obtain the 3D scanning map of the surroundings. The proposed R2D-LIDAR system, composed of a 2D LIDAR and a rotating unit, is pervasively used in the field of robotics owing to its low cost and dense scanning data. Nevertheless, the R2D-LIDAR system must be calibrated before building the geometric model because there are assembled deviation and abrasion between the 2D LIDAR and the rotating unit. Hence, the calibration procedures should contain both the adjustment between the two devices and the bias of 2D LIDAR itself. The main purpose of this work is to resolve the 2D LIDAR bias issue with a flat plane based on the Levenberg-Marquardt (LM) algorithm. Experimental results for the calibration of the R2D-LIDAR system prove the reliability of this strategy to accurately estimate sensor offsets with the error range from -15 mm to 15 mm for the performance of capturing scans. PMID- 29414886 TI - A Novel Sugar Transporter from Dianthus spiculifolius, DsSWEET12, Affects Sugar Metabolism and Confers Osmotic and Oxidative Stress Tolerance in Arabidopsis. AB - Plant SWEETs (sugars will eventually be exported transporters) play a role in plant growth and plant response to biotic and abiotic stresses. In the present study, DsSWEET12 from Dianthus spiculifolius was identified and characterized. Real-time quantitative PCR analysis revealed that DsSWEET12 expression was induced by sucrose starvation, mannitol, and hydrogen peroxide. Colocalization experiment showed that the DsSWEET12-GFP fusion protein was localized to the plasma membrane, which was labeled with FM4-64 dye, in Arabidopsis and suspension cells of D. spiculifolius. Compared to wild type plants, transgenic Arabidopsis seedlings overexpressing DsSWEET12 have longer roots and have a greater fresh weight, which depends on sucrose content. Furthermore, a relative root length analysis showed that transgenic Arabidopsis showed higher tolerance to osmotic and oxidative stresses. Finally, a sugar content analysis showed that the sucrose content in transgenic Arabidopsis was less than that in the wild type, while fructose and glucose contents were higher than those in the wild type. Taken together, our results suggest that DsSWEET12 plays an important role in seedling growth and plant response to osmotic and oxidative stress in Arabidopsis by influencing sugar metabolism. PMID- 29414887 TI - Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2 Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents. AB - : The complex nature of Alzheimer's disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2 (benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward beta-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human beta-secretase (hBACE-1), and beta-amyloid (Abeta-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC50 = 3.33 MUM), hBACE-1 (43.7% at 50 MUM), and Abeta aggregation (24.9% at 10 MUM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes acetylcholinesterase and beta-secretase. IN CONCLUSION: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti Alzheimer's agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: beta secretase and Abeta-aggregation. PMID- 29414888 TI - Mass Spectrometry-Based Proteomic Profiling of Thrombotic Material Obtained by Endovascular Thrombectomy in Patients with Ischemic Stroke. AB - Thrombotic material retrieved from acute ischemic stroke (AIS) patients represents a valuable source of biological information. In this study, we have developed a clinical proteomics workflow to characterize the protein cargo of thrombi derived from AIS patients. To analyze the thrombus proteome in a large scale format, we developed a workflow that combines the isolation of thrombus by endovascular thrombectomy and peptide chromatographic fractionation coupled to mass-spectrometry. Using this workflow, we have characterized a specific proteomic expression profile derived from four AIS patients included in this study. Around 1600 protein species were unambiguously identified in the analyzed material. Functional bioinformatics analyses were performed, emphasizing a clustering of proteins with immunological functions as well as cardiopathy related proteins with blood-cell dependent functions and peripheral vascular processes. In addition, we established a reference proteomic fingerprint of 341 proteins commonly detected in all patients. Protein interactome network of this subproteome revealed protein clusters involved in the interaction of fibronectin with 14-3-3 proteins, TGFbeta signaling, and TCP complex network. Taken together, our data contributes to the repertoire of the human thrombus proteome, serving as a reference library to increase our knowledge about the molecular basis of thrombus derived from AIS patients, paving the way toward the establishment of a quantitative approach necessary to detect and characterize potential novel biomarkers in the stroke field. PMID- 29414890 TI - WHO Environmental Noise Guidelines for the European Region: A Systematic Review on Environmental Noise and Cognition. AB - This systematic review assesses the quality of the evidence across individual studies on the effect of environmental noise (road traffic, aircraft, and train and railway noise) on cognition. Quantitative non-experimental studies of the association between environmental noise exposure on child and adult cognitive performance published up to June 2015 were reviewed: no limit was placed on the start date for the search. A total of 34 papers were identified, all of which were of child populations. 82% of the papers were of cross-sectional design, with fewer studies of longitudinal or intervention design. A range of cognitive outcomes were examined. The quality of the evidence across the studies for each individual noise source and cognitive outcome was assessed using an adaptation of GRADE methodology. This review found, given the predominance of cross-sectional studies, that the quality of the evidence across studies ranged from being of moderate quality for an effect for some outcomes, e.g., aircraft noise effects on reading comprehension and on long-term memory, to no effect for other outcomes such as attention and executive function and for some noise sources such as road traffic noise and railway noise. The GRADE evaluation of low quality evidence across studies for some cognitive domains and for some noise sources does not necessarily mean that there are no effects: rather, that more robust and a greater number of studies are required. PMID- 29414889 TI - Pharmacokinetics of Snake Venom. AB - Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974-present) and Medline (1946 present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 +/- 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans. PMID- 29414891 TI - Norisoprenoids from the Brown Alga Sargassum naozhouense Tseng et Lu. AB - A new C11-norisoprenoid derivative, sargassumone (1), has been isolated from Sargassum naozhouense together with six known norisoprenoids and a highly oxygenated cyclopentene: (2R,6S,8S,9S)-hexahydro-2,9-dihydroxy-4,4,8-trimethyl-6 acetyloxy-3(2H)-benzofuranone (2), (6S,8S,9R)-hexahydro-6,9-dihydroxy-4,4,8 trimethyl-2(2H)-benzofuranone (3), (6S,8S,9R)-hexahydro-6,9-dihydroxy-4,4,8 trimethyl-2(2H)-benzofuranone (4), loliolide (5), (+)-epiloliolide (6), spheciospongones A (7), and (+)-kjellmanianone (8). Compound 1 was identified on the basis of nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis, and the absolute stereochemistry was defined by NOESY spectroscopy, minimizing energy calculation, and circular dichroism (CD) spectra. The known compounds 2-8, isolated from S. naozhouense for the first time, were identified by comparison of their physical and spectroscopic data with those reported in the literature. Compound 6 was tested for its inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), antioxidant activity with 1,1-diphyl-2 picrylhydrazyl (DPPH) free radicals, and antimicrobial activity against resistant clinical isolates of Candida albicans, methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia coli. PMID- 29414893 TI - Spatio-Temporal Super-Resolution Reconstruction of Remote-Sensing Images Based on Adaptive Multi-Scale Detail Enhancement. AB - There are many problems in existing reconstruction-based super-resolution algorithms, such as the lack of texture-feature representation and of high frequency details. Multi-scale detail enhancement can produce more texture information and high-frequency information. Therefore, super-resolution reconstruction of remote-sensing images based on adaptive multi-scale detail enhancement (AMDE-SR) is proposed in this paper. First, the information entropy of each remote-sensing image is calculated, and the image with the maximum entropy value is regarded as the reference image. Subsequently, spatio-temporal remote-sensing images are processed using phase normalization, which is to reduce the time phase difference of image data and enhance the complementarity of information. The multi-scale image information is then decomposed using the L0 gradient minimization model, and the non-redundant information is processed by difference calculation and expanding non-redundant layers and the redundant layer by the iterative back-projection (IBP) technique. The different-scale non redundant information is adaptive-weighted and fused using cross-entropy. Finally, a nonlinear texture-detail-enhancement function is built to improve the scope of small details, and the peak signal-to-noise ratio (PSNR) is used as an iterative constraint. Ultimately, high-resolution remote-sensing images with abundant texture information are obtained by iterative optimization. Real results show an average gain in entropy of up to 0.42 dB for an up-scaling of 2 and a significant promotion gain in enhancement measure evaluation for an up-scaling of 2. The experimental results show that the performance of the AMED-SR method is better than existing super-resolution reconstruction methods in terms of visual and accuracy improvements. PMID- 29414892 TI - Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice. AB - Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, Kp, for the liver and kidney were higher in the piperine-pretreated group, while the Kp for kidney, brain and liver were higher in the capsaicin-pretreated group. [6]-Gingerol did not affect doxorubicin tissue distribution. The data demonstrated that the phytochemicals modulated doxorubicin tissue distribution, which suggested their potential to induce food-drug interactions and act as a strategy for the delivery of P-gp substrate drugs to target tissues and tumors. PMID- 29414894 TI - Acoustic Sensors for Air and Surface Navigation Applications. AB - This paper presents the state-of-the-art and reviews the state-of-research of acoustic sensors used for a variety of navigation and guidance applications on air and surface vehicles. In particular, this paper focuses on echolocation, which is widely utilized in nature by certain mammals (e.g., cetaceans and bats). Although acoustic sensors have been extensively adopted in various engineering applications, their use in navigation and guidance systems is yet to be fully exploited. This technology has clear potential for applications in air and surface navigation/guidance for Intelligent Transport Systems (ITS), especially considering air and surface operations indoors and in other environments where satellite positioning is not available. Propagation of sound in the atmosphere is discussed in detail, with all potential attenuation sources taken into account. The errors introduced in echolocation measurements due to Doppler, multipath and atmospheric effects are discussed, and an uncertainty analysis method is presented for ranging error budget prediction in acoustic navigation applications. Considering the design challenges associated with monostatic and multi-static sensor implementations and looking at the performance predictions for different possible configurations, acoustic sensors show clear promises in navigation, proximity sensing, as well as obstacle detection and tracking. The integration of acoustic sensors in multi-sensor navigation systems is also considered towards the end of the paper and a low Size, Weight and Power, and Cost (SWaP-C) sensor integration architecture is presented for possible introduction in air and surface navigation systems. PMID- 29414895 TI - A Case of Spontaneous Pneumomediastinum with Subcutaneous Emphysema in Children. AB - Spontaneous pneumomediastinum is defined as free air or gas contained within the mediastinum, which almost invariably originates from the alveolar space or the conducting airways. It is rare in pediatric patients; however, occasional cases are reported to result from forced Valsalva's maneuver due to cough, emesis, a first attack of wheeze, or asthma exacerbations. We report the case of a 7-year old previously healthy girl, with a history of persistent dry cough one day before, who was brought to our unit with face, neck and chest swelling. The chest X-ray and computed tomography (CT) scan showed subcutaneous emphysema with pneumomediastinum and pneumopericardium without evidence of the origin of this air leak. Laboratory tests and the bronchoscopy were normal. The patient was admitted in the pediatric critical care and received noninvasive monitoring, analgesia, oxygen, and omeprazole as a prophylaxis for a gastric ulcer. The patient improved, subcutaneous emphysema resolved, and she was discharged on the third day. PMID- 29414896 TI - Anaerobic Degradation of Bicyclic Monoterpenes in Castellaniella defragrans. AB - The microbial degradation pathways of bicyclic monoterpenes contain unknown enzymes for carbon-carbon cleavages. Such enzymes may also be present in the betaproteobacterium Castellaniella defragrans, a model organism to study the anaerobic monoterpene degradation. In this study, a deletion mutant strain missing the first enzyme of the monocyclic monoterpene pathway transformed cometabolically the bicyclics sabinene, 3-carene and alpha-pinene into several monocyclic monoterpenes and traces of cyclic monoterpene alcohols. Proteomes of cells grown on bicyclic monoterpenes resembled the proteomes of cells grown on monocyclic monoterpenes. Many transposon mutants unable to grow on bicyclic monoterpenes contained inactivated genes of the monocyclic monoterpene pathway. These observations suggest that the monocyclic degradation pathway is used to metabolize bicyclic monoterpenes. The initial step in the degradation is a decyclization (ring-opening) reaction yielding monocyclic monoterpenes, which can be considered as a reverse reaction of the olefin cyclization of polyenes. PMID- 29414897 TI - Real-Time and Meter-Scale Absolute Distance Measurement by Frequency-Comb Referenced Multi-Wavelength Interferometry. AB - We report on a frequency-comb-referenced absolute interferometer which instantly measures long distance by integrating multi-wavelength interferometry with direct synthetic wavelength interferometry. The reported interferometer utilizes four different wavelengths, simultaneously calibrated to the frequency comb of a femtosecond laser, to implement subwavelength distance measurement, while direct synthetic wavelength interferometry is elaborately introduced by launching a fifth wavelength to extend a non-ambiguous range for meter-scale measurement. A linearity test performed comparatively with a He-Ne laser interferometer shows a residual error of less than 70.8 nm in peak-to-valley over a 3 m distance, and a 10 h distance comparison is demonstrated to gain fractional deviations of ~3 * 10 8 versus 3 m distance. Test results reveal that the presented absolute interferometer enables precise, stable, and long-term distance measurements and facilitates absolute positioning applications such as large-scale manufacturing and space missions. PMID- 29414898 TI - A Glider-Assisted Link Disruption Restoration Mechanism in Underwater Acoustic Sensor Networks. AB - Underwater acoustic sensor networks (UASNs) have become a hot research topic. In UASNs, nodes can be affected by ocean currents and external forces, which could result in sudden link disruption. Therefore, designing a flexible and efficient link disruption restoration mechanism to ensure the network connectivity is a challenge. In the paper, we propose a glider-assisted restoration mechanism which includes link disruption recognition and related link restoring mechanism. In the link disruption recognition mechanism, the cluster heads collect the link disruption information and then schedule gliders acting as relay nodes to restore the disrupted link. Considering the glider's sawtooth motion, we design a relay location optimization algorithm with a consideration of both the glider's trajectory and acoustic channel attenuation model. The utility function is established by minimizing the channel attenuation and the optimal location of glider is solved by a multiplier method. The glider-assisted restoration mechanism can greatly improve the packet delivery rate and reduce the communication energy consumption and it is more general for the restoration of different link disruption scenarios. The simulation results show that glider assisted restoration mechanism can improve the delivery rate of data packets by 15-33% compared with cooperative opportunistic routing (OVAR), the hop-by-hop vector-based forwarding (HH-VBF) and the vector based forward (VBF) methods, and reduce communication energy consumption by 20-58% for a typical network's setting. PMID- 29414900 TI - Predicting Long-Term Stability of Precise Oscillators under Influence of Frequency Drift. AB - High-performance oscillators, atomic clocks for instance, are important in modern industries, finance and scientific research. In this paper, the authors study the estimation and prediction of long-term stability based on convex optimization techniques and compressive sensing. To take frequency drift into account, its influence on Allan and modified Allan variances is formulated. Meanwhile, expressions for the expectation and variance of discrete-time Hadamard variance are derived. Methods that reduce the computational complexity of these expressions are also introduced. Tests against GPS precise clock data show that the method can correctly predict one-week frequency stability from 14-day measured data. PMID- 29414901 TI - The Band-Gap Modulation of Graphyne Nanoribbons by Edge Quantum Entrapment. AB - Using ab initio calculation coupled with the bond-order-length-strength (BOLS) approximation, we investigate the configurations and electronic properties of (alpha, beta)-graphyne nanoribbons (GYNRs) with armchair (AGYNRs) and zigzag (ZGYNRs) edges. Our investigation shows that the armchair-edged beta-GYNRs and all alpha-GYNRs are semiconductors with suitable band-gaps, and that their band gaps increase as the widths of nanoribbons decrease; on the other hand, zigzag edged beta-GYNRs appear to be zero-band-gap materials. Observation results suggest that (i) atomic undercoordination shortens and stiffens the C-C bond, which contributes to the Hamiltonian and hence widens the band-gap intrinsically; (ii) zigzag-edged beta-GYNRs lack a band-gap due to the edge-undercoordinated atoms lacking the energy to open the beta-graphyne gap; and (iii) the edge undercoordination of atoms occurs during charge entrapment. PMID- 29414899 TI - Complex Epigenetic Regulation of Chemotherapy Resistance and Biohlogy in Esophageal Squamous Cell Carcinoma via MicroRNAs. AB - BACKGROUND: Resistance towards chemotherapy is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). We investigated the role of specific microRNAs in chemotherapy resistance and tumor biology. METHODS: We selected three microRNAs from characteristic microRNA signatures of resistant ESCC (hsa-miR-125a-5p, hsa-miR-130a-3p, hsa-miR-1226-3p), and hsa-miR-148a-3p. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed in six ESCC cell lines. Target analyses were performed using Western blotting and luciferase techniques. RESULTS: MiR-130a-3p sensitized cells towards cisplatin in 100% of cell lines, miR-148a-3p in 83%, miR-125a-5p in 67%, miR-1226 3p in 50% (p <= 0.04). MiR-130a-3p sensitized 83% of cell lines towards 5-FU, miR 148a-3p/miR-125a-5p/miR-1226-3p only 33% (p <= 0.015). Several resistance relevant pathways seem to be targeted on various levels. Bcl-2 was confirmed as a direct target of miR-130a-3p and miR-148a-3p, and p53 as a target of miR-125a-5p. All microRNAs decreased migration and adhesion, except miR-130a-3p, and increased apoptosis. Simultaneous manipulation of two microRNAs exhibited additive sensitizing effects towards cisplatin in 50% (miR-125a-5p/miR-148a-3p), and 75% (miR-148a-3p/miR-130a-3p) of cell lines (p <= 0.006). CONCLUSION: Our data present strong evidence that specific microRNA signatures are responsible for drug resistance and aggressiveness of ESCC. Final functional readout of these complex processes appears to be more important than single microRNA-target interactions. PMID- 29414902 TI - Wearable Driver Distraction Identification On-The-Road via Continuous Decomposition of Galvanic Skin Responses. AB - One of the main reasons for fatal accidents on the road is distracted driving. The continuous attention of an individual driver is a necessity for the task of driving. While driving, certain levels of distraction can cause drivers to lose their attention, which might lead to an accident. Thus, the number of accidents can be reduced by early detection of distraction. Many studies have been conducted to automatically detect driver distraction. Although camera-based techniques have been successfully employed to characterize driver distraction, the risk of privacy violation is high. On the other hand, physiological signals have shown to be a privacy preserving and reliable indicator of driver state, while the acquisition technology might be intrusive to drivers in practical implementation. In this study, we investigate a continuous measure of phasic Galvanic Skin Responses (GSR) using a wristband wearable to identify distraction of drivers during a driving experiment on-the-road. We first decompose the raw GSR signal into its phasic and tonic components using Continuous Decomposition Analysis (CDA), and then the continuous phasic component containing relevant characteristics of the skin conductance signals is investigated for further analysis. We generated a high resolution spectro-temporal transformation of the GSR signals for non-distracted and distracted (calling and texting) scenarios to visualize the associated behavior of the decomposed phasic GSR signal in correlation with distracted scenarios. According to the spectrogram observations, we extract relevant spectral and temporal features to capture the patterns associated with the distracted scenarios at the physiological level. We then performed feature selection using support vector machine recursive feature elimination (SVM-RFE) in order to: (1) generate a rank of the distinguishing features among the subject population, and (2) create a reduced feature subset toward more efficient distraction identification on the edge at the generalization phase. We employed support vector machine (SVM) to generate the 10 fold cross validation (10-CV) identification performance measures. Our experimental results demonstrated cross-validation accuracy of 94.81% using all the features and the accuracy of 93.01% using reduced feature space. The SVM-RFE selected set of features generated a marginal decrease in accuracy while reducing the redundancy in the input feature space toward shorter response time necessary for early notification of distracted state of the driver. PMID- 29414903 TI - Bacillus subtilis Type I antitoxin SR6 Promotes Degradation of Toxin yonT mRNA and Is Required to Prevent Toxic yoyJ Overexpression. AB - yonT/SR6 is the second type I toxin-antitoxin (TA) system encoded on prophage SPbeta in the B. subtilis chromosome. The yonT ORF specifying a 58 aa toxin is transcribed on a polycistronic mRNA under control of the yonT promoter. The antitoxin SR6 is a 100 nt antisense RNA that overlaps yonT at its 3' end and the downstream gene yoyJ encoding a second, much weaker, toxin at its 5' end. SR6 displays a half-life of >60 min, whereas yonT mRNA is less stable with a half life of ~8 min. SR6 is in significant excess over yonT mRNA except in minimal medium with glucose. It interacts with the 3' UTR of yonT mRNA, thereby promoting its degradation by RNase III. By contrast, SR6 does not affect the amount or half life of yoyJ mRNA. However, in its absence, a yoyJ overexpression plasmid could not be established in Bacillus subtilis suggesting that SR6 inhibits yoyJ translation by directly binding to its ribosome-binding site. While the amounts of both yonT RNA and SR6 were affected by vancomycin, manganese, heat-shock and ethanol stress as well as iron limitation, oxygen stress decreased only the amount of SR6. PMID- 29414904 TI - Photodynamic Therapy Activated by Intense Pulsed Light in the Treatment of Nonmelanoma Skin Cancer. AB - Photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) has proven to be a highly effective conservative method for the treatment of actinic keratosis (AK), Bowen's disease (BD), and superficial basal cell carcinoma (sBCC). PDT is traditionally performed in association with broad-spectrum continuous-wave light sources, such as red or blue light. Recently, intense pulsed light (IPL) devices have been investigated as an alternative light source for PDT in the treatment of nonmelanoma skin cancers (NMSC). We herein report our observational findings in a cohort of patients with a diagnosis of AK, sBCC, and BD that is treated with MAL-PDT using IPL, as well as we review published data on the use of IPL-PDT in NMSC. PMID- 29414905 TI - Clinical Aspects of Foot Health in Individuals with Alzheimer's Disease. AB - Alzheimer's disease (AD) shows a marked presence of physiologic changes and the start or aggravation of underlying diseases such as physical frailty in diverse anatomical regions. It is believed to have a particularly harmful effect on the health of the foot. We examined the foot health status in older persons with AD, with a specific focus on the extent to which people with AD may be using inadequate footwear in old age. Seventy-three community-dwelling people with probable, mild to moderate AD aged 65-95 years were recruited from a center of excellence for AD. A single trained physician evaluated health status and foot conditions. Current shoe and foot length and width measurements were taken using a calibrated Brannock device. The results indicate that sixty-five participants (89.04%) suffered from feet problems. Also, only twenty-two subjects (30.14%) used the correct shoes in width and size related with the morphology of their feet. Fifty-one participants (69.86%) were using incorrect shoes in length or width. The present study revealed that peoples with AD had a high presence of foot health problems. Also, the use of inappropriate shoes revealed measurable differences of association between shoe size and the morphology of the foot. PMID- 29414906 TI - Microplastics Reduce Short-Term Effects of Environmental Contaminants. Part II: Polyethylene Particles Decrease the Effect of Polycyclic Aromatic Hydrocarbons on Microorganisms. AB - Microplastic particles in terrestrial and aquatic ecosystems are currently discussed as an emerging persistent organic pollutant and as acting as a vector for hydrophobic chemicals. Microplastic particles may ultimately deposit and accumulate in soil as well as marine and freshwater sediments where they can be harmful to organisms. In this study, we tested the sensitivity of natural freshwater sediment bacterial communities (by genetic fingerprint) to exposure to microplastics (polyethylene, 2 and 20 mg/g sediment) and microplastics loaded with polycyclic aromatic hydrocarbons (PAHs, phenanthrene and anthracene), using a laboratory-based approach. After two weeks of incubation, the bacterial community composition from an unpolluted river section was altered by high concentrations of microplastics, whereas the community downstream of a wastewater treatment plant remained unchanged. Low microplastic concentrations loaded with phenanthrene or anthracene induced a less pronounced response in the sediment communities compared to the same total amount of phenanthrene or anthracene alone. In addition, biodegradation of the PAHs was reduced. This study shows, that microplastic can affect bacterial community composition in unpolluted freshwater sediments. Moreover, the results indicate that microplastics can serve as a vehicle for hydrophobic pollutants but bioavailability of the latter is reduced by the sorption to microplastics. PMID- 29414907 TI - Smokers' Views on Personal Carbon Monoxide Monitors, Associated Apps, and Their Use: An Interview and Think-Aloud Study. AB - Smartphone-based personal carbon monoxide (CO) monitors and associated apps, or "CO Smartphone Systems" (CSSs) for short, could enable smokers to independently monitor their smoking and quitting. This study explored views and preferences regarding CSSs and their use among 16 adult, UK-based smokers. First, semi structured interviews explored participants' expectations of CSSs. Secondly, a think-aloud study identified participants' reactions to a personal CO monitor and to existing or prototype apps. Framework Analysis identified five themes: (1) General views, needs, and motivation to use CSSs; (2) Views on the personal CO monitor; (3) Practicalities of CSS use; (4) Desired features in associated apps; and (5) Factors affecting preferences for CSSs and their use. Participants had high expectations of CSSs and their potential to increase motivation. Priority app features included: easy CO testing journeys, relevant and motivating feedback, and recording of contextual data. Appearance and usability of the personal CO monitor, and accuracy and relevance of CO testing were considered important for engagement. Participants differed in their motivation to use and preferences for CSSs features and use, which might have non-trivial impact on evaluation efforts. Personal CO monitors and associated apps may be attractive tools for smokers, but making CSSs easy to use and evaluating these among different groups of smokers may be challenging. PMID- 29414908 TI - The Reaction of Oxy Hemoglobin with Nitrite: Mechanism, Antioxidant-Modulated Effect, and Implications for Blood Substitute Evaluation. AB - The autocatalytic reaction between nitrite and the oxy form of globins involves free radicals. For myoglobin (Mb), an initial binding of nitrite to the iron coordinated oxygen molecule was proposed; the resulting ferrous-peroxynitrate species was not detected, but its decay product, the high-valent ferryl form, was demonstrated in stopped-flow experiments. Reported here are the stopped flow spectra recorded upon mixing oxy Hb (native, as well as chemically-derivatized in the form of several candidates of blood substitutes) with a supraphysiological concentration of nitrite. The data may be fitted to a simple kinetic model involving a transient met-aqua form, in contrast to the ferryl detected in the case of Mb in a similar reaction sequence. These data are in line with a previous observation of a transient accumulation of ferryl Hb under auto-catalytic conditions at much lower concentrations of nitrite (Grubina, R. et al. J. Biol. Chem. 2007, 282, 12916). The simple model for fitting the stopped-flow data leaves a small part of the absorbance changes unaccounted for, unless a fourth species is invoked displaying features similar to the oxy and tentatively assigned as ferrous-peroxynitrate. Density functional theory (DFT) calculations support this latter assignment. The reaction allows for differentiating between the reactivities of various chemically modified hemoglobins, including candidates for blood substitutes. Polymerization of hemoglobin slows the nitrite-induced oxidation, in sharp contrast to oxidative-stress type reactions which are generally accelerated, not inhibited. Sheep hemoglobin is found to be distinctly more resistant to reaction with nitrite compared to bovine Hb, at large nitrite concentrations (stopped-flow experiments directly observing the oxy + nitrite reaction) as well as under auto-catalytic conditions. Copolymerization of Hb with bovine serum albumin (BSA) using glutaraldehyde leads to a distinct increase of the lag time compared to native Hb as well as to any other form of derivatization examined in the present study. The Hb-BSA copolymer also displays a slower initial reaction with nitrite under stopped-flow conditions, compared to native Hb. PMID- 29414909 TI - Exploring Protein Cavities through Rigidity Analysis. AB - The geometry of cavities in the surfaces of proteins facilitates a variety of biochemical functions. To better understand the biochemical nature of protein cavities, the shape, size, chemical properties, and evolutionary nature of functional and nonfunctional surface cavities have been exhaustively surveyed in protein structures. The rigidity of surface cavities, however, is not immediately available as a characteristic of structure data, and is thus more difficult to examine. Using rigidity analysis for assessing and analyzing molecular rigidity, this paper performs the first survey of the relationships between cavity properties, such as size and residue content, and how they correspond to cavity rigidity. Our survey measured a variety of rigidity metrics on 120,323 cavities from 12,785 sequentially non-redundant protein chains. We used VASP-E, a volume based algorithm for analyzing cavity geometry. Our results suggest that rigidity properties of protein cavities are dependent on cavity surface area. PMID- 29414910 TI - Hepatoprotective Effects of a Functional Formula of Three Chinese Medicinal Herbs: Experimental Evidence and Network Pharmacology-Based Identification of Mechanism of Action and Potential Bioactive Components. AB - Various Chinese herbal medicines (CHMs) have shown beneficial liver protection effects. Jian-Gan-Bao (JGB), a functional herbal formula, consists of three famous CHMs, including Coriolus versicolor, Salvia miltiorrhiza and Schisandra chinensis, which has been used as a folk medicine for several chronic liver diseases. In the present study, we aim systemically to evaluate the effects of JGB on acute and chronic alcoholic liver diseases (ALD) as well as non-alcoholic fatty liver disease (NAFLD) in mouse models, and identify its potential bioactive components and mechanism of action. JGB showed preventive effects for acute and chronic ALD as well as NAFLD, while post-treatment of JGB showed no significant effect, suggesting the nature of JGB as a health supplement rather than a drug. Furthermore, a compound-target network was constructed to identify the potential bioactive compounds and pathways that regulate its hepatoprotective effects. There are 40 bioactive compounds and 15 related targets that have been identified via this network pharmacology study. Among them are miltirone, neocryptotanshinone II and deoxyshikonin, with desirable pharmaceutical properties. Pathways relating to inflammation, fatty acid oxidation, tumor necrosis factor (TNF) production and cell proliferation were predicted as bioactive compounds and potential underlying mechanisms, which should be the focus of study in this field in the future. PMID- 29414912 TI - A Study on the Rheological and Mechanical Properties of Photo-Curable Ceramic/Polymer Composites with Different Silane Coupling Agents for SLA 3D Printing Technology. AB - Silane coupling agents (SCAs) with different organofunctional groups were coated on the surfaces of Al2O3 ceramic particles through hydrolysis and condensation reactions, and the SCA-coated Al2O3 ceramic particles were dispersed in a commercial photopolymer based on interpenetrating networks (IPNs). The organofunctional groups that have high radical reactivity and are more effective in UV curing systems are usually functional groups based on acryl, such as acryloxy groups, methacrloxy groups, and acrylamide groups, and these silane coupling agents seem to improve interfacial adhesion and dispersion stability. The coating morphology and the coating thickness distribution of SCA-coated Al2O3 ceramic particles according to the different organofunctional groups were observed by FE-TEM. The initial dispersibility and dispersion stability of the SCA-coated Al2O3/High-temp composite solutions were investigated by relaxation NMR and Turbiscan. The rheological properties of the composite solutions were investigated by viscoelastic analysis and the mechanical properties of 3D-printed objects were observed with a nanoindenter. PMID- 29414911 TI - With a Little Help from My Friends: The Role of Intraoperative Fluorescent Dyes in the Surgical Management of High-Grade Gliomas. AB - High-grade gliomas (HGGs) are the most frequent primary malignant brain tumors in adults, which lead to death within two years of diagnosis. Maximal safe resection of malignant gliomas as the first step of multimodal therapy is an accepted goal in malignant glioma surgery. Gross total resection has an important role in improving overall survival (OS) and progression-free survival (PFS), but identification of tumor borders is particularly difficult in HGGS. For this reason, imaging adjuncts, such as 5-aminolevulinic acid (5-ALA) or fluorescein sodium (FS) have been proposed as superior strategies for better defining the limits of surgical resection for HGG. 5-aminolevulinic acid (5-ALA) is implicated as precursor in the synthetic pathway of heme group. Protoporphyrin IX (PpIX) is an intermediate compound of heme metabolism, which produces fluorescence when excited by appropriate light wavelength. Malignant glioma cells have the capacity to selectively synthesize or accumulate 5-ALA-derived porphyrins after exogenous administration of 5-ALA. Fluorescein sodium (FS), on the other hand, is a fluorescent substance that is not specific to tumor cells but actually it is a marker for compromised blood-brain barrier (BBB) areas. Its effectiveness is confirmed by multicenter phase-II trial (FLUOGLIO) but lack of randomized phase III trial data. We conducted an analytic review of the literature with the objective of identifying the usefulness of 5-ALA and FS in HGG surgery in adult patients. PMID- 29414913 TI - Novel Biomaterials Used in Medical 3D Printing Techniques. AB - The success of an implant depends on the type of biomaterial used for its fabrication. An ideal implant material should be biocompatible, inert, mechanically durable, and easily moldable. The ability to build patient specific implants incorporated with bioactive drugs, cells, and proteins has made 3D printing technology revolutionary in medical and pharmaceutical fields. A vast variety of biomaterials are currently being used in medical 3D printing, including metals, ceramics, polymers, and composites. With continuous research and progress in biomaterials used in 3D printing, there has been a rapid growth in applications of 3D printing in manufacturing customized implants, prostheses, drug delivery devices, and 3D scaffolds for tissue engineering and regenerative medicine. The current review focuses on the novel biomaterials used in variety of 3D printing technologies for clinical applications. Most common types of medical 3D printing technologies, including fused deposition modeling, extrusion based bioprinting, inkjet, and polyjet printing techniques, their clinical applications, different types of biomaterials currently used by researchers, and key limitations are discussed in detail. PMID- 29414914 TI - Incidence Rates of and Mortality after Hip Fracture among German Nursing Home Residents. AB - Little is known about hip fracture rates and post-fracture mortality among nursing home residents. This retrospective cohort study examined incidence rates (IR) of and mortality after hip fracture in this population focusing on sex differences. A cohort of >127,000 residents >=65 years, newly admitted to German nursing homes between 2010 and 2014 were used to calculate age-, sex-, care-need- and time after admission-specific IR. To determine mortality, the Kaplan-Meier method was applied. Using Cox regression, we studied mortality and estimated time dependent hazard ratios (HRs). For this purpose, to each person with a hip fracture, one resident without a hip fracture was matched by sex, age and care need using risk-set sampling. 75% were women (mean age: 84.0 years). During 168,588 person-years (PY), 8537 residents with at least one hip fracture were observed. The IR for women and men were 52.9 and 42.5/1000 PY. For both sexes, IR increased with rising age and decreased with increasing care-level. IR were highest in the first months after admission and subsequently declined afterwards. The impact of hip fractures on mortality was time-dependent. Mortality of residents with hip fracture was highest in the first two months after fracture compared to those without (HR): 2.82; 95% CI 2.57-3.11) and after six months, no differences were found (HR: 1.10; 95% CI 0.98-1.22) Further research should always include analyses stratified by sex, age and time period after admission. PMID- 29414915 TI - Characteristics of Stress and Suicidal Ideation in the Disclosure of Sexual Orientation among Young French LGB Adults. AB - BACKGROUND: Lesbians, gays, and bisexual people (LGB) present high levels of suicidal ideation. The disclosure of sexual orientation is a stressful experience which presents a high suicide risk. Research has not paid sufficient attention to stress during this disclosure in order to understand suicide among LGB people. The aims of this study were to investigate: (1) the characteristics of stress during this revelation, more precisely cognitive appraisal, emotions, and coping; and (2) associations between these characteristics and suicidal ideation. METHOD: A total of 200 LGB young adults answered the "Stressful situation assessment questionnaire", focusing on the most stressful disclosure of sexual orientation they have ever experienced. RESULTS: Avoidance coping is a good predictor of suicidal ideation, and mediates the association between primary appraisal (risk "Harm myself and others") and suicidal ideation. CONCLUSIONS: Our study illustrates the need to better understand stress during the disclosure of sexual orientation to prevent and care for suicide risk among LGB young adults. PMID- 29414917 TI - A Scheme for Enhancing Precision in 3-Dimensional Positioning for Non-Contact Measurement Systems Based on Laser Triangulation. AB - Laser triangulation allows non-contact measurement in the third dimension. Due to the nonlinearities presented in camera and laser sensor, large range distances are quite difficult to measure with high precision. In order to enhance the precision and accuracy of large range measurement based on laser triangulation, we propose a novel scheme composed of four laser emitters, curve fitting subpixel location algorithm for laser center detection, and the linear regression approach based on the Gaussian model for calibration. When an object performs a 100 mm displacement from a closer to a farther point, our system achieved a repeatability up to +/-7 um, an estimated standard deviation of fitting error within 0.0027 mm, an expanded uncertainty of repeatability within 0.13 mm, an average error variation of rotational plane within 0.15 degree and a nonlinearity error within +/-0.04% in full scale. Compared to published results, our proposed method shows an enhancement in accuracy. The error is significantly reduced and maintains at the low level for large ranges, which makes this system applicable and suitable for industrial and indoor applications. PMID- 29414916 TI - Daily Patterns of Preschoolers' Objectively Measured Step Counts in Six European Countries: Cross-Sectional Results from the ToyBox-Study. AB - This study is part of the ToyBox-study, which is conducted in six European countries (Belgium, Bulgaria, Germany, Greece, Poland and Spain), aiming to develop a cost-effective kindergarten-based, family-involved intervention to prevent overweight and obesity in four- to six-year-old preschool children. In the current study, we aimed to examine and compare preschoolers' step count patterns, across the six European countries. A sample of 3578 preschoolers (mean age: 4.8 +/- 0.4) was included. Multilevel analyses were performed to take clustering of measurements into account. Based on the average hourly steps, step count patterns for the six European countries were created for weekdays and weekend days. The step count patterns during weekdays were related to the daily kindergarten schedules. Step count patterns during weekdays showed several significant peaks and troughs (p < 0.01) and clearly reflected the kindergartens' daily schedules, except for Germany. For example, low numbers of steps were observed during afternoon naptimes and high numbers of steps during recess. In Germany, step count patterns did not show clear peaks and troughs, which can be explained by a less structured kindergarten schedule. On weekend days, differences in step count patterns were observed in the absolute number of steps in the afternoon trough and the period in which the evening peak occurred. Differences in step count patterns across the countries can be explained by differences in (school) policy, lifestyle habits, and culture. Therefore, it might be important to respond to these step count patterns and more specifically to tackle the inactive periods during interventions to promote physical activity in preschoolers. PMID- 29414918 TI - High Whole-Genome Sequence Diversity of Human Papillomavirus Type 18 Isolates. AB - BACKGROUND: The most commonly found human papillomavirus (HPV) types in cervical cancer are HPV16 and HPV18. Genome variants of these types have been associated with differential carcinogenic potential. To date, only a handful of studies have described HPV18 whole genome sequencing results. Here we describe HPV18 variant diversity and conservation of persistent infections in a longitudinal retrospective cohort study. METHODS: Cervical self-samples were obtained annually over four years and genotyped on the SPF10-DEIA-LiPA25 platform. Clearing and persistent HPV18 positive infections were selected, amplified in two overlapping fragments, and sequenced using 32 sequence primers. RESULTS: Complete viral genomes were obtained from 25 participants with persistent and 26 participants with clearing HPV18 infections, resulting in 52 unique HPV18 genomes. Sublineage A3 was predominant in this population. The consensus viral genome was completely conserved over time in persistent infections, with one exception, where different HPV18 variants were identified in follow-up samples. CONCLUSIONS: This study identified a diverse set of HPV18 variants. In persistent infections, the consensus viral genome is conserved. The identification of only one HPV18 infection with different major variants in follow-up implies that this is a potentially rare event. This dataset adds 52 HPV18 genome variants to Genbank, more than doubling the currently available HPV18 information resource, and all but one variant are unique additions. PMID- 29414919 TI - Online Relinquishments of Dogs and Cats in Australia. AB - While traditionally people relinquish their pets to an animal shelter or pound, the internet provides a newer method to re-home. We analyzed advertisements (ads) on the largest website in Australia for trading dogs and cats: Gumtree. Data was collected in 2016. Dogs were sampled on 7, 16 and 24 February 2016 and cats on 9, 19 and 26 February 2016, with 2640 ads for relinquished dogs, and 2093 ads for relinquished cats. It was estimated >31,000 puppies/dogs and >24,000 kittens/cats are relinquished on Gumtree per year. The median age of dogs was 1.42 and cats 0.9 years of age. There were 23% of dog ads and 62% of cat ads for free animals. Compared to the human population, there were proportionately more ads in Queensland and fewer ads in Victoria. A total of 15 people were surveyed who had relinquished a dog or cat using Gumtree. The dog owners used Gumtree for two reasons: because they believed the shelters were full (n = 4); and they wanted to see/interview the new owner (n = 2). For cat owners: they had originally got the cat on Gumtree (n = 2); they use Gumtree for other things, and it works (n = 2), and; they wanted to see/interview the new owner (n = 2). The data collected will be valuable for implementation of policy and interventions to protect the welfare of unwanted dogs and cats. PMID- 29414920 TI - Interventional Left Atrial Appendage Closure Affects the Metabolism of Acylcarnitines. AB - BACKGROUND: Left atrial appendage closure (LAAC) represents the interventional alternative to oral anticoagulation for stroke prevention in atrial fibrillation (AF). The metabolism of acylcarnitines was shown to affect cardiovascular diseases. This study evaluates the influence of successful LAAC on the metabolism of acylcarnitines. METHODS: Patients undergoing successful LAAC were enrolled prospectively. Peripheral blood samples for metabolomics measurements were collected immediately before (i.e., index) and six months after LAAC (i.e., mid term). A targeted metabolomics analysis based on electrospray ionization-liquid chromatography-mass spectrometry (ESI-LC-MS/MS) and MS/MS measurements was performed. RESULTS: 44 patients with non-valvular AF (median CHA2DS2-VASc score 4, median HAS-BLED score 4) and successful LAAC were included. Significant changes in acylcarnitine levels were found in the total cohort, which were mainly attributed to patients with impaired left ventricular and renal function, elevated amino-terminal pro-brain natriuretic peptide (NT-proBNP) and diabetes mellitus. Adjusted multivariable regression models revealed significant changes of five metabolites over mid-term follow-up: C2, C14:1, C16, and C18:1 decreased significantly (each p < 0.05); short-chain C5 acylcarnitine plasma levels increased significantly (p < 0.05). CONCLUSION: This study demonstrates that successful LAAC affects the metabolism of acylcarnitines at mid-term follow-up. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02985463. PMID- 29414922 TI - Perspective Insight into Future Potential Fusion Gene Transcript Biomarker Candidates in Breast Cancer. AB - Next generation sequencing has accelerated the discovery of a variety of new fusion gene types in clinical breast cancer samples by analyzing cancer genomes and transcriptomes. Although previous studies have focused on a few clinically validated oncogenic fusion genes as diagnostic and therapeutic targets in breast cancer, a perspective consideration has not been given thus far for a plethora of breast cancer fusion genes, which are being newly identified at an overwhelmingly increasing pace. In this perspective review, we discuss diverse fusion gene types recently identified in a variety of breast cancer subtypes, including breast clinical cancer samples in TCGA (The Cancer Genome Atlas) database. This perspective review will confer fresh and promising guidance onto breast cancer surgeons, clinical oncologists, and tumor biologists in determining research directions for seeking and developing novel fusion gene biomarkers for breast cancer diagnostics and therapeutic treatment in upcoming years. PMID- 29414921 TI - MicroRNA-125a-5p Affects Adipocytes Proliferation, Differentiation and Fatty Acid Composition of Porcine Intramuscular Fat. AB - Intramuscular fat (IMF) content and composition are considered crucial indicators of porcine meat quality. However, the molecular mechanism of porcine IMF development is still mostly unclear. Recently, new evidence suggested that microRNA (miRNAs) play important roles in porcine intramuscular adipogenesis. Previously, microRNA-125a-5p (miR-125a-5p) was identified as an important regulator of adipogenesis. In the present study, we found that the expression of miR-125a-5p is dynamically regulated during porcine intramuscular preadipocytes differentiation and that its expression levels in different porcine muscle tissues were negatively involved with IMF content. To investigate the potential function role of miR-125a-5p in IMF development, porcine intramuscular preadipocytes were collected and transfected with miR-125a-5p mimics, inhibitors, or a negative control (NC), respectively. The results showed that overexpression of miR-125a-5p promoted proliferation and inhibited differentiation of porcine intramuscular preadipocytes while inhibition of miR-125a-5p had the opposite effects. Furthermore, a luciferase reporter assay demonstrated that porcine kruppel like factor 3 (KLF13) is a target gene of miR-125a-5p during porcine intramuscular preadipocytes differentiation. Interestingly, porcine ELOVL fatty acid elongase 6 (ELOVL6), a regulator of fatty acid composition, was also identified as a target gene of miR-125a-5p during porcine intramuscular adipogenesis. Further studies show that miR-125a-5p overexpression reduced total saturated fatty acids (SFA) content and monounsaturated fatty acids (MUFA)/SFA ratios while having no significant impact on polyunsaturated fatty acids (PUFA)/SFA and n-6/n-3 ratios. Taken together, our results identified that miR 125a-5p may be a novel regulator of porcine intramuscular adipogenesis and the fatty acid composition of porcine IMF. PMID- 29414923 TI - Palladium Nanoparticles: Toxicological Effects and Potential Implications for Occupational Risk Assessment. AB - The increasing technological applications of palladium nanoparticles (Pd-NPs) and their consequent enhancing release into the community and occupational environments, have raised public health concerns regarding possible adverse effects for exposed subjects, and particularly for workers chronically and highly exposed to these materials, whose toxico-kinetic and dynamic behavior remains to be fully understood. Therefore, this review aimed to critically analyze literature data to achieve a more comprehensive knowledge on the toxicological profile of Pd-NPs. Results from available studies demonstrated the potential for these chemicals to affect the ecosystem function, to exert cytotoxic and pro inflammatory effects in vitro as well as to induce early alterations in different target organs in in vivo models. However, our revision pointed out the need for future studies aimed to clarify the role of the NP physico-chemical properties in determining their toxicological behavior, as well as the importance to carry out investigations focused on environmental and biological monitoring to verify and validate experimental biomarkers of exposure and early effect in real exposure contexts. Overall, this may be helpful to support the definition of suitable strategies for the assessment, communication and management of Pd-NP occupational risks to protect the health and safety of workers. PMID- 29414924 TI - VSpipe, an Integrated Resource for Virtual Screening and Hit Selection: Applications to Protein Tyrosine Phospahatase Inhibition. AB - The use of computational tools for virtual screening provides a cost-efficient approach to select starting points for drug development. We have developed VSpipe, a user-friendly semi-automated pipeline for structure-based virtual screening. VSpipe uses the existing tools AutoDock and OpenBabel together with software developed in-house, to create an end-to-end virtual screening workflow ranging from the preparation of receptor and ligands to the visualisation of results. VSpipe is efficient and flexible, allowing the users to make choices at different steps, and it is amenable to use in both local and cluster mode. We have validated VSpipe using the human protein tyrosine phosphatase PTP1B as a case study. Using a combination of blind and targeted docking VSpipe identified both new and known functional ligand binding sites. Assessment of different binding clusters using the ligand efficiency plots created by VSpipe, defined a drug-like chemical space for development of PTP1B inhibitors with potential applications to other PTPs. In this study, we show that VSpipe can be deployed to identify and compare different modes of inhibition thus guiding the selection of initial hits for drug discovery. PMID- 29414925 TI - Vitamin D-Binding Protein Polymorphisms, 25-Hydroxyvitamin D, Sunshine and Multiple Sclerosis. AB - Blacks have different dominant polymorphisms in the vitamin D-binding protein (DBP) gene that result in higher bioavailable vitamin D than whites. This study tested whether the lack of association between 25-hydroxyvitamin D (25OHD) and multiple sclerosis (MS) risk in blacks and Hispanics is due to differences in these common polymorphisms (rs7041, rs4588). We recruited incident MS cases and controls (blacks 116 cases/131 controls; Hispanics 183/197; whites 247/267) from Kaiser Permanente Southern California. AA is the dominant rs7041 genotype in blacks (70.0%) whereas C is the dominant allele in whites (79.0% AC/CC) and Hispanics (77.1%). Higher 25OHD levels were associated with a lower risk of MS in whites who carried at least one copy of the C allele but not AA carriers. No association was found in Hispanics or blacks regardless of genotype. Higher ultraviolet radiation exposure was associated with a lower risk of MS in blacks (OR = 0.06), Hispanics and whites who carried at least one copy of the C allele but not in others. Racial/ethnic variations in bioavailable vitamin D do not explain the lack of association between 25OHD and MS in blacks and Hispanics. These findings further challenge the biological plausibility of vitamin D deficiency as causal for MS. PMID- 29414928 TI - Taking personalized medicine to heart. PMID- 29414926 TI - Stability of Anthocyanins and Their Degradation Products from Cabernet Sauvignon Red Wine under Gastrointestinal pH and Temperature Conditions. AB - This study investigated the stability of wine anthocyanins under simulated gastrointestinal pH and temperature conditions, and further studied the evolution of anthocyanin degradation products through simulated digestive conditions. The aim of this study was to investigate the relation between anthocyanins' structure and their digestive stability. Results showed that a total of 22 anthocyanins were identified in wine and most of these anthocyanins remained stable under simulated gastric digestion process. However, a dramatic concentration decrease happened to these anthocyanins during simulated intestinal digestion. The stability of anthocyanins in digestive process appeared to be related to their structure. The methoxy group in the B-ring enhanced the stability of anthocyanins, whereas hydroxyl group resulted in a reduction of their stability. Acylation decreased the stability of malvidin 3-O-glucoside. Pyruvic acid conjugation enhanced the structural stability of pyranoanthocyanins, whereas acetaldehyde attachment weakened their stability. A commercial malvidin 3-O glucoside standard was used to investigate anthocyanin degradation products under simulated digestion process, and syringic acid, protocatechuic acid and vanillic acid were confirmed to be the degradation products via anthocyanin chalcone conversion path. Gallic acid, protocatechuic acid, vanillic acid, syringic acid, and p-coumaric acid in wine experienced a significant concentration decrease during digestion process. However, wine model solution revealed that phenolic acids remained stable under gastrointestinal conditions, except gallic acid. PMID- 29414927 TI - Diagnostic Value of T1 Slope in Degenerative Cervical Spondylotic Myelopathy. AB - BACKGROUND To explore the diagnostic value of sagittal measurement of thoracic inlet parameters for degenerative cervical spondylotic myelopathy (DCSM). MATERIAL AND METHODS Sixty patients with DCSM (study group) and the same number of normal subjects (control group) were initially enrolled in the study. All data from X-ray in the standing position and computed tomography (CT) in the supine position were collected and carefully analyzed. Cervical sagittal parameters, including C2-C7 angle, C2-C7 sagittal vertical axis (C2-C7 SVA), T1 slope, thoracic inlet angle (TIA), and neck tilt (NT), were measured at the lateral radiographs by using standard X-rays and CT. Univariate analysis and multivariate logistic regression analysis were carried out to explore the diagnostic value of cervical sagittal parameters for the DCSM. RESULTS All the enrolled patients in the study and control groups completed the follow-up, and the mean follow-up periods were 35.8 months in the study group and 36.3 months in the control group. The DCSM group had smaller T1 slope and TIA when compared with that of the control group (18.14+/-2.67 degrees vs. 24.16+/-3.7 degrees , p=0.00; 66.42+/ 12.36 degrees vs. 70.42+/-10.21 degrees , p=0.01). Logistic regression analysis and receiver operating characteristic (ROC) curve revealed that preoperative T1 slope of less than 18.5 degrees had significant diagnostic value for the incidence of DCSM (p<0.05). CONCLUSIONS Patients with sagittal imbalance of thoracic inlet parameters have higher risk of DCSM, while T1 slope of less than 18.5 degrees showed significant diagnostic value for the incidence of DCSM. PMID- 29414929 TI - Animals on the verge: What different species can teach us about human puberty. PMID- 29414931 TI - Correction. AB - This corrects the article DOI: 10.1038/nm0118-2. PMID- 29414930 TI - Gene therapies for hemophilia hit the mark in clinical trials. PMID- 29414932 TI - A new vaccine for tuberculosis in rhesus macaques. PMID- 29414933 TI - Macrophages and platelets join forces to release kidney-damaging DNA traps. PMID- 29414934 TI - A shot at contraception: In India, a nonagenarian renews testing of a birth control vaccine. PMID- 29414935 TI - Selective enhancer changes in osteosarcoma lung metastasis. PMID- 29414936 TI - A potential biomarker for anti-PD-1 immunotherapy. PMID- 29414939 TI - A clumpy and anisotropic galaxy halo at redshift 1 from gravitational-arc tomography. AB - Every star-forming galaxy has a halo of metal-enriched gas that extends out to at least 100 kiloparsecs, as revealed by the absorption lines that this gas imprints on the spectra of background quasars. However, quasars are sparse and typically probe only one narrow beam of emission through the intervening galaxy. Close quasar pairs and gravitationally lensed quasars have been used to circumvent this inherently one-dimensional technique, but these objects are rare and the structure of the circumgalactic medium remains poorly constrained. As a result, our understanding of the physical processes that drive the recycling of baryons across the lifetime of a galaxy is limited. Here we report integral-field (tomographic) spectroscopy of an extended background source-a bright, giant gravitational arc. We can thus coherently map the spatial and kinematic distribution of Mg ii absorption-a standard tracer of enriched gas-in an intervening galaxy system at redshift 0.98 (around 8 billion years ago). Our gravitational-arc tomography unveils a clumpy medium in which the absorption strength decreases with increasing distance from the galaxy system, in good agreement with results for quasars. Furthermore, we find strong evidence that the gas is not distributed isotropically. Interestingly, we detect little kinematic variation over a projected area of approximately 600 square kiloparsecs, with all line-of-sight velocities confined to within a few tens of kilometres per second of each other. These results suggest that the detected absorption originates from entrained recycled material, rather than in a galactic outflow. PMID- 29414937 TI - c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. AB - Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases. There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts. However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus, is mediated by the induction of RORgammat+FOXP3+ regulatory T (iTreg) cells that selectively restrain pro inflammatory T helper 17 (TH17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORgammat-expressing microorganism-specific iTreg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic TH17 cells. Inactivation of c-MAF in the Treg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg cells, and resulted in the accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. By contrast, RORgammat inactivation in Treg cells had only a minor effect on the bacteria-specific Treg and TH17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iTreg-TH17 homeostasis. PMID- 29414938 TI - Teneurin-3 controls topographic circuit assembly in the hippocampus. AB - Brain functions rely on specific patterns of connectivity. Teneurins are evolutionarily conserved transmembrane proteins that instruct synaptic partner matching in Drosophila and are required for vertebrate visual system development. The roles of vertebrate teneurins in connectivity beyond the visual system remain largely unknown and their mechanisms of action have not been demonstrated. Here we show that mouse teneurin-3 is expressed in multiple topographically interconnected areas of the hippocampal region, including proximal CA1, distal subiculum, and medial entorhinal cortex. Viral-genetic analyses reveal that teneurin-3 is required in both CA1 and subicular neurons for the precise targeting of proximal CA1 axons to distal subiculum. Furthermore, teneurin-3 promotes homophilic adhesion in vitro in a splicing isoform-dependent manner. These findings demonstrate striking genetic heterogeneity across multiple hippocampal areas and suggest that teneurin-3 may orchestrate the assembly of a complex distributed circuit in the mammalian brain via matching expression and homophilic attraction. PMID- 29414940 TI - Fluctuating interaction network and time-varying stability of a natural fish community. AB - Ecological theory suggests that large-scale patterns such as community stability can be influenced by changes in interspecific interactions that arise from the behavioural and/or physiological responses of individual species varying over time. Although this theory has experimental support, evidence from natural ecosystems is lacking owing to the challenges of tracking rapid changes in interspecific interactions (known to occur on timescales much shorter than a generation time) and then identifying the effect of such changes on large-scale community dynamics. Here, using tools for analysing nonlinear time series and a 12-year-long dataset of fortnightly collected observations on a natural marine fish community in Maizuru Bay, Japan, we show that short-term changes in interaction networks influence overall community dynamics. Among the 15 dominant species, we identify 14 interspecific interactions to construct a dynamic interaction network. We show that the strengths, and even types, of interactions change with time; we also develop a time-varying stability measure based on local Lyapunov stability for attractor dynamics in non-equilibrium nonlinear systems. We use this dynamic stability measure to examine the link between the time varying interaction network and community stability. We find seasonal patterns in dynamic stability for this fish community that broadly support expectations of current ecological theory. Specifically, the dominance of weak interactions and higher species diversity during summer months are associated with higher dynamic stability and smaller population fluctuations. We suggest that interspecific interactions, community network structure and community stability are dynamic properties, and that linking fluctuating interaction networks to community-level dynamic properties is key to understanding the maintenance of ecological communities in nature. PMID- 29414941 TI - Structural basis for DNMT3A-mediated de novo DNA methylation. AB - DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-angstrom crystal structure of the DNMT3A DNMT3L-DNA complex in which two DNMT3A monomers simultaneously attack two cytosine-phosphate-guanine (CpG) dinucleotides, with the target sites separated by 14 base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain, a catalytic loop, and DNMT3A homodimeric interface. Arg836 of the target recognition domain makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Haematological cancer associated somatic mutations of the substrate-binding residues decrease DNMT3A activity, induce CpG hypomethylation, and promote transformation of haematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease. PMID- 29414942 TI - Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel. AB - Somatic stem cells constantly adjust their self-renewal and lineage commitment by integrating various environmental cues to maintain tissue homeostasis. Although numerous chemical and biological signals have been identified that regulate stem cell behaviour, whether stem cells can directly sense mechanical signals in vivo remains unclear. Here we show that mechanical stress regulates stem-cell differentiation in the adult Drosophila midgut through the stretch-activated ion channel Piezo. We find that Piezo is specifically expressed in previously unidentified enteroendocrine precursor cells, which have reduced proliferation ability and are destined to become enteroendocrine cells. Loss of Piezo activity reduces the generation of enteroendocrine cells in the adult midgut. In addition, ectopic expression of Piezo in all stem cells triggers both cell proliferation and enteroendocrine cell differentiation. Both the Piezo mutant and overexpression phenotypes can be rescued by manipulation of cytosolic Ca2+ levels, and increases in cytosolic Ca2+ resemble the Piezo overexpression phenotype, suggesting that Piezo functions through Ca2+ signalling. Further studies suggest that Ca2+ signalling promotes stem-cell proliferation and differentiation through separate pathways. Finally, Piezo is required for both mechanical activation of stem cells in a gut expansion assay and the increase of cytosolic Ca2+ in response to direct mechanical stimulus in a gut compression assay. Thus, our study demonstrates the existence of a specific group of stem cells in the fly midgut that can directly sense mechanical signals through Piezo. PMID- 29414943 TI - Genomics of the origin and evolution of Citrus. AB - The genus Citrus, comprising some of the most widely cultivated fruit crops worldwide, includes an uncertain number of species. Here we describe ten natural citrus species, using genomic, phylogenetic and biogeographic analyses of 60 accessions representing diverse citrus germ plasms, and propose that citrus diversified during the late Miocene epoch through a rapid southeast Asian radiation that correlates with a marked weakening of the monsoons. A second radiation enabled by migration across the Wallace line gave rise to the Australian limes in the early Pliocene epoch. Further identification and analyses of hybrids and admixed genomes provides insights into the genealogy of major commercial cultivars of citrus. Among mandarins and sweet orange, we find an extensive network of relatedness that illuminates the domestication of these groups. Widespread pummelo admixture among these mandarins and its correlation with fruit size and acidity suggests a plausible role of pummelo introgression in the selection of palatable mandarins. This work provides a new evolutionary framework for the genus Citrus. PMID- 29414944 TI - Posterior parietal cortex represents sensory history and mediates its effects on behaviour. AB - Many models of cognition and of neural computations posit the use and estimation of prior stimulus statistics: it has long been known that working memory and perception are strongly impacted by previous sensory experience, even when that sensory history is not relevant to the current task at hand. Nevertheless, the neural mechanisms and regions of the brain that are necessary for computing and using such prior experience are unknown. Here we report that the posterior parietal cortex (PPC) is a critical locus for the representation and use of prior stimulus information. We trained rats in an auditory parametric working memory task, and found that they displayed substantial and readily quantifiable behavioural effects of sensory-stimulus history, similar to those observed in humans and monkeys. Earlier proposals that the PPC supports working memory predict that optogenetic silencing of this region would impair behaviour in our working memory task. Contrary to this prediction, we found that silencing the PPC significantly improved performance. Quantitative analyses of behaviour revealed that this improvement was due to the selective reduction of the effects of prior sensory stimuli. Electrophysiological recordings showed that PPC neurons carried far more information about the sensory stimuli of previous trials than about the stimuli of the current trial. Furthermore, for a given rat, the more information about previous trial sensory history in the neural firing rates of the PPC, the greater the behavioural effect of sensory history, suggesting a tight link between behaviour and PPC representations of stimulus history. Our results indicate that the PPC is a central component in the processing of sensory stimulus history, and could enable further neurobiological investigation of long standing questions regarding how perception and working memory are affected by prior sensory information. PMID- 29414945 TI - Cognitive performance is linked to group size and affects fitness in Australian magpies. AB - The social intelligence hypothesis states that the demands of social life drive cognitive evolution. This idea receives support from comparative studies that link variation in group size or mating systems with cognitive and neuroanatomical differences across species, but findings are contradictory and contentious. To understand the cognitive consequences of sociality, it is also important to investigate social variation within species. Here we show that in wild, cooperatively breeding Australian magpies, individuals that live in large groups show increased cognitive performance, which is linked to increased reproductive success. Individual performance was highly correlated across four cognitive tasks, indicating a 'general intelligence factor' that underlies cognitive performance. Repeated cognitive testing of juveniles at different ages showed that the correlation between group size and cognition emerged in early life, suggesting that living in larger groups promotes cognitive development. Furthermore, we found a positive association between the task performance of females and three indicators of reproductive success, thus identifying a selective benefit of greater cognitive performance. Together, these results provide intraspecific evidence that sociality can shape cognitive development and evolution. PMID- 29414947 TI - ?Es tiempo de exigir publicidad basada en la evidencia? AB - Claims made in current advertising for medical products is not necessarily scientifically proven, yet at the same time clinicians are required to adopt evidence-based practices and undergo periodic certifications. This is a clear contradiction. It is crucial to begin to reflect on the need to regulate information presented in the media and to place greater emphasis on patient well being and safety instead of on third-party interests. The medical community must demand stricter regulations and evidence-based advertising policies. PMID- 29414948 TI - Eumicetoma: actualidades y perspectivas. AB - The eumycetoma is a severely debilitating chronic progressive fungal cutaneous infection. Classic clinical triad is characterized by painless subcutaneous mass, sinus tracts formation and sero-purulent discharge that contain aggregates of fungal hyphae called grains. Any part of the body can have affected, with extension to muscular or bone, even visceral compromised. The eumycetoma is observed in tropical and subtropical countries; In Latin-America, is reported with less frequency. In endemic areas, antibody presence again etiological agents were higher compared with number of people affected, thus it is supposed that individual genetic susceptibility most by exist. Recently, it was reported specific polymorphism in genes CR1, IL-8, NOS2 and chitriosidase, which were associated with development of eumycetoma. The diagnosis is suggested by clinical presentation; the histopathology and microbiology studies, plus radiologic valuation confirmed diagnosis. Madurella mycetomatis is the most informed etiological agent. Using phylogenetic tools new species in genus Madurella were reported; moreover, Trematosphaeria grisea and Pseudallescheria boydii were reclassified. Etiological agent Identification is important, because differences in antifungal susceptibility exist. Eumycetoma treatment includes surgery plus antifungal drugs. Identification of etiological agents is primordial, because antifungal resistance could exist. To development new pharmacological strategies, comprehension of grain formation physiology and drugs effects are necessary. PMID- 29414949 TI - Paracetamol (acetaminofeno) intravenoso para cierre de conducto arterioso permeable en prematuros <= 32 semanas de gestacion. AB - Objective: To identify the effectiveness of intravenous paracetamol for closure of patent ductus arteriosus in preterm <=32 weeks gestation. Method: This was a series of cases, a therapeutic intervention to closure was applied for ductus arteriosus >2 mm, identified by echocardiogram after 3 days of life, intravenous paracetamol was used, for a time range from 3 up to 6 days. Results: The prevalence of patent ductus arteriosus in <=32 weeks gestation, was 40%. 21 patients were included, there was a predominance of female. Average age at diagnosis was 29 weeks gestation. The minimum weight 750 g, maximum 1350 g. Echocardiogram corroborated closure in 76%, intravenous paracetamol was more successful with 6 days treatment. Conclusions: The prevalence of patent ductus arteriosus is directly proportional to the gestational age, being more common in women. Successful closure was 76%, this drug shows to be as effective as the first-choice drug, and a good alternative for intravenous therapy. PMID- 29414946 TI - Asparagine bioavailability governs metastasis in a model of breast cancer. AB - Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient's primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with l asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression. PMID- 29414950 TI - Visualizando el desarrollo de la nanomedicina en Mexico. AB - Objective: In this article we present a set of different visualizations of Mexico's nanomedicine scientific production data. Method: Visualizations were developed using different methodologies for data analysis and visualization such as social network analysis, geography of science maps, and complex network communities analysis. Results: Results are a multi-dimensional overview of the evolution of nanomedicine in Mexico. Moreover, visualizations allowed to identify trends and patterns of collaboration at the national and international level. Trends are also found in the knowledge structure of themes and disciplines. Finally, we identified the scientific communities in Mexico that are responsible for the new knowledge production in this emergent field of science. PMID- 29414951 TI - Amaurosis congenita de Leber RPE-65, seguimiento a 7 anos. AB - Leber congenital amaurosis is a retinal dystrophy with several forms of presentation due to its genetic variability. Case of a female girl followed up from 4 to 11 years old is presented, with positive clinical data of nyctalopia, myopia and choroid ocular fundus. Electroretinogram was not measurable in all phases but diagnostic was confirmed by RPE65 mutation genetic study. RPE65 Leber congenital amaurosis is particularly important as it has been researched for a gene therapy treatment with good functional outcomes up to now, awaiting to offer hope and a better quality of life to people with this disease. PMID- 29414952 TI - Alteraciones puberales en adolescentes con leucemia en fase de vigilancia. AB - Objective: To evaluate which factors are associated with alterations in pubertal development in pediatric patients with leukemia in the surveillance phase. Method: A case-control study was carried out, including patients aged 8-14 years with diagnosis of acute lymphoblastic leukemia under surveillance. Demographic data were collected, age at diagnosis, type of leukemia, risk of leukemia, duration and type of treatment received, time of surveillance phase; and pubertal development was assessed by Tanner stage, bone age, pelvic ultrasound for women, and LH levels. Fisher's exact test and Mann-Whitney U-test were used. Results: Twenty-five pediatric patients with a diagnosis of acute lymphoblastic leukemia between 8 and 14 years of age with a median of 8 were included, only 4 (16%) presented pubertal alterations, 1 had pubertal delay and 3 advanced puberty. The history of radiotherapy was related to pubertal alterations (p = 0.03). Conclusions: The antecedent of having received radiotherapy as part of the treatment in patients with acute lymphoblastic leukemia is a risk factor for developing pubertal abnormalities. PMID- 29414953 TI - Paciente inmunocompetente con criptococosis cerebral: reporte de un caso. AB - A 14-year-old female, presenting sudden and progressive holocraneal headache along with incoercible vomiting arrived to emergency room. Acute confusional state and meningoencephalitis syndrome where identified. Brain computed tomography-scan with normal results was performed. Lumbar puncture with crystal clear cerebrospinal fluid was obtained: low glucose, elevated proteins and cell count of 15/mm. China-Ink and Criptococcus neoformans culture both positive. Viral, lupus-anticoagulant, and HIV tests negative. Fluconazole 200 mg/kg/day, amphotericin-B 0.7 mg/kg/day, dexamethasone 1 mg/kg/day were prescribed. 48-h later evolved to cerebral edema, multiple-organ-failure and death. Hereby we present a Cryptococcus spp. infection case report, addressing the public health challenge and vulnerability of immunocompromised patients in Mexico. PMID- 29414954 TI - Comision Nacional de Arbitraje Medico: a dos decadas de su formacion. PMID- 29414955 TI - ? AB - Objective: To establish the frequency and results in patients carriers with multiple aneurysms (MA) treated by microsurgery and/or neurological endovascular therapy (NET) in the Hospital of Specialties on The National Medical Center La Raza. Method: It is an ambispective, descriptive and longitudinal study that includes patients carriers of MA treated in the National Medical Center La Raza from March the 1st of 2009 to April the 30th of 2014. Results: 62 patients carriers of 151 aneurysms were treated. According to the type of treatment, 30 patients (49%) were included in the surgical group (GQ), 25 (40%) in the endovascular group (GE) and 7 (11%) in the combinated group (GC). The number of aneurysms was distributed this way: 69 (46%) in the GQ, 61 (40%) in the GE and 21 (14%) in the GC. At GQ, it was not possible to exclude all their aneurysms on 21% of the patients, while it was feasible in only 27%. In all GE patients (40%) the exclusion of all aneurysms was achieved. The GC, meaning surgical cases that were not completed by NET, formed 11% of the cases. At GQ there was a rate of 6% of complications, meanwhile at GE it was 0.5%. PMID- 29414956 TI - Auditoria transfusional en un Hospital de Alta Especialidad. Analisis retrospectivo de 12 meses. AB - Objective: Human blood is the only source of red blood cells, platelets and plasma, and includes the clotting factors. Transfusion of concentrated erythrocyte and blood products is a simple form of organ transplant, the benefits of blood transfusion are real, and the life of the patients depends on how is used. to know the transfusion adherence to the recommendations in the Hospital of High Specialty of Veracruz. Method: For a period of 12 months an audit took place in the Transfusion Service of the Hospital of High Specialty of Veracruz, Mexico, on a basis of 3 168 requests for transfusion from which 2314 corresponded to erythrocyte concentrate, 220 to platelet concentrate, 493 to fresh frozen plasma and 41 to cryoprecipitate. Results and conclusions: An analysis of concordance was made with the different established regulations for a right indication and the results showed that 2171 (67.26%) were appropriate and 1037 were inadequate, which means that the lack of academic training in medicine transfusional affects the risk for patients and cost for Health Institutions. PMID- 29414958 TI - Sindrome de Susac en un paciente con colitis ulcerosa. AB - The Susac's syndrome is a rare disorder that was first described in 1979 and is characterized by a classic triad consisting in encephalopathy, visual impairment and sensorineural hearing loss. However, the etiology of the disease is still unclear. We report the case of a 29-year-old with ulcerative colitis treated with mercaptopurine, six months before to her admission started with personality changes attributed to symptoms of depression who subsequently present neurological symptoms characteristic of Susac's Syndrome. In the literature there is no clear association between inflammatory bowel disease and Susac's -syndrome, but this case is presented in order to emphasize the simultaneous presentation of these two diseases with a tendency to vasospasm and an autoimmune pathogenesis. PMID- 29414957 TI - Lipomatosis encefalocraneocutanea: reporte de caso. AB - The encephalocraniocutaneous lipomatosis (ECCL), also known as Fishman or Haberland syndrome, is a rare neurocutaneous syndrome of unknown etiology. Clinically characterized by skin, eye and central nervous system lesions. We present the case of a 7-year-old female who presents to the outpatient clinic of Pediatric Neurology because of the presence of seizures detecting clinical and neuroimaging manifestations compatible with ECCL. The objective of this article is to present the case because of its rare presentation and the variety of alterations found in the tomography. PMID- 29414959 TI - Adaptaciones al ejercicio fisico en el perfil lipidico y la salud cardiovascular de obesos morbidos. AB - Objective: To assess the effects of a physical exercise program on the lipid profile, weight status and the cardiovascular health of obese candidates for bariatric surgery. Method: 22 morbidly obese patients participated in a 6-month physical exercise program. 16 formed the adherent group (attendance >= 80%; age: 37.81 +/- 11.90 years) and six the non-adherent group (attendance < 80%; age: 45.83 +/- 14.23 years). Before and 72 h after the last session were evaluated: weight, body mass index (BMI), contour waist, blood pressure, fasting, cardio respiratory fitness, cholesterol and triglycerides. Results: Weight, BMI and WC showed significant changes (p < 0.05) in both groups, with the results of the adherent group being better. In the adherent group, cardiorespiratory capacity (p = 0.001) was also increased, while diastolic pressure (p = 0.011), basal glycemia (p = 0.021) and triglycerides decreased significantly (p < 0.001). The non adherent group did not present significant changes in these variables (p >= 0.05). Conclusions: The intervention was feasible to perform without negative effects for the participants, and it is possible to recommend improving the cardiovascular health of these of patients. PMID- 29414960 TI - Los receptores epidermicos humanos en el cancer gastrico: alteraciones moleculares y su papel como diana terapeutica. AB - Gastric cancer (GC) is the third leading cause of cancer death worldwide; both environmental and genetic factors are involved in the etiology of this neoplasia. The human epidermal receptor (HER) pathway is essential for proliferation and differentiation of normal cells; but it is also implicated in the growth of cancer cells. In this work we investigate the molecular alterations in genes that encodes for HER receptors reported in GC, as well the role as therapeutic targets. We reviewed the literature reported to date regarding overexpression of HER-receptors, amplification and somatic mutations in ERBB genes occurred in gastric tumors, as well as the anti-HER therapies tested for treatment of GC. In GC, the overexpression of HER family is reported in a range of 12-87% of cases; up to 67% of cases with amplification, and 90 somatic mutations in ERBB genes. The only drug anti-HER approved for using combined with chemotherapy, in treatment of patients with advanced GC is trastuzumab; however, other targeted therapies are being investigated. The role of the HER family as a therapeutic target has not shown significant improvements in recent years; hence, further studies are required to find better options for treatment of GC. PMID- 29414961 TI - Sindrome metabolico y otros factores asociados a gonartrosis. AB - Objective: To evaluate whether an association exists between gonarthrosis and metabolic syndrome X (MS) as well as other potential risk factors. Method: Comparative cross-sectional study of 310 patients evaluated by pathology of knee grouped in patients with gonarthrosis and without it. Sociodemographic, anthropometric and laboratory data was obtained. Gonarthrosis was defined as a >= 2 score in Kellgren-Lawrence radiological scale, and MS was assessed using the International Diabetes Federation criteria. Odds ratio and logistic regression were used for bivariate and multivariate analysis respectively. Results: The prevalence of MS in patients who had gonarthrosis was 79.9%, statistically higher than in patients without gonarthrosis (p = 0.001). Other factors that had a statistically higher frequency in this group included diabetes mellitus (p = 0.02) and hypertension (p = 0.02). Multivariate analysis revealed MS had an association with a higher prevalence of gonarthrosis (p = 0.003), while high density lipoproteins (p = 0.02) was associated with a lower prevalence. Conclusions: MS and its related alterations are associated to gonarthrosis; their adequate control could prevent patients from developing the disease. PMID- 29414962 TI - El Dr. Manuel Justo Dominguez Quintanar, fundador de la puericultura racional y la pediatria tecnica en Mexico. AB - This paper presents some biographical notes, both personal and professional, for Dr. Manuel Justo Dominguez Quintanar; a native of Queretaro, who over 80 years lived firsthand the historical stages in which Mexico turned into an independent country: from the First Federal Republic to the Porfiriato. He had an active participation in them all; either as a doctor, a teacher, administrator or politician. He was renowned for his charity work, especially in the Foundling House (The Cradle), which made him years later, to be considered as the founder of rational childcare and the creator of technical pediatrics in Mexico. PMID- 29414963 TI - El papel de los acidos grasos libres en la resistencia a la insulina. AB - Free fatty acids are essential nutritional components and recent studies identified them as signaling molecules in various physiological processes. It has now been shown that high levels of free fatty acids, particularly saturated fatty acids, may be associated with insulin resistance in obese patients with type 2 diabetes mellitus. Insulin resistance is important in clinical since it is related to various diseases including type 2 diabetes mellitus, dyslipidemia, and abnormalities at cardiovascular level. Recent studies have proposed different molecular mechanisms by which these lipids may alter the signaling pathway of insulin. The purpose of this review is to highlight recent advances in the study of the effect of free fatty acids as modulators of insulin response. PMID- 29414964 TI - Proyeccion de medicos especialistas para el Sector Salud de Mexico a 2030. Un metodo para estimar requerimientos y planificar su formacion. AB - Objective: Carry out the projection of medical specialists in the Health Sector Mexico by 2030. Method: A predictive approach was developed to project the number of medical specialists by 2030, according to a trend, a desired goal and two conventional scenarios of increased demand for health services. The methodology was developed based on the General Framework to Assess the Future Supply and Demand of Health Personnel, published in 2013 by the Organization for Economic Co operation and Development (OECD), and a mathematical model and a software were designed to make projections about the number of specialists. Results: According to the trend, between 2013 and 2030, the number of specialists will be increased by 90,554 to 124,558 and the rate will be change of 77/100.000 population to 91/100,000 population. If is necessary to achieve a goal of 120/100,000, will be necessary to train 40,420 additional specialists to the trend number and if the demand for services increases 15% or 30%, will require further training specialists 65,166 and 89,913, respectively. Conclusions: Even with the trend increase, in the 2030 Mexico will not achieve the desired goal of 126/100,000 population, that the OECD countries had in 2011. The results of the projections made, can help to planning the training of specialists in the medium term. PMID- 29414965 TI - Genes relacionados con microftalmia y anoftalmia hereditarias. AB - Congenital eye malformations are the second most common cause of childhood blindness and are originated by disruption of the normal process of eye development during embryonic stage. Their etiology is variable, although monogenic causes are of great importance as they have a high risk of familial recurrence. Included among the most severe congenital eye abnormalities are microphthalmia, defined by an abnormally small eye, and anophthalmia, characterized by congenital absence of ocular structures. The currrent knowledge of the genes involved in human microphthalmia and anophthalmia in humans is revised in this work. PMID- 29414967 TI - Metaevidencia: ?que evidencia hay sobre los resultados de la aplicacion de la evidencia? AB - The evidence-based medicine has enjoyed wide acceptance in the last two decades as the necessary tool for the adequate management of information, but it is necessary to reflect that exists after making an analysis of the written and possible implementation to the patient. PMID- 29414966 TI - Epidemiologia genetica sobre las teorias causales y la patogenesis de la diabetes mellitus tipo 2. AB - Diabetes mellitus type 2 (DM2) is a worldwide public health problem. The etiology of the disease is multifactorial and is characterized by great heterogeneity of metabolic disorders. The most common are the insufficient production of insulin, insulin resistance and impaired incretin system. The specialist must understand the multi-causal nature of DM2 in the post-genomic era. This nature is determined by the additive effect of genes and environment, so there is no simple genetic epidemiological model to explain the inheritance pattern. Hence the need to establish the proportion of disease that is determined by genes and the contribution of environmental factors, the combination of which regulates the threshold or tolerance level for diabetes development. Given this complexity in DM2 in this work are discussed the various existing theories of causality of this disease, which will permit us to understand the interaction between the environment and the human genome, and also to know how risk factors or predisposition to this disease influence, laying the grounds that delimit environment interaction with the genome. PMID- 29414968 TI - Glomerulopati del trasplante. Resultados clinicos y seguimiento de casos. AB - Objective: We describe the evolution of graft function in patients with transplant glomerulopathy measure by levels of serum creatinine, proteinuria and estimated glomerular filtration rate. Method: Cross-sectional study conducted in the Regional General Hospital No. 46 IMSS. Included patients with kidney allograft and diagnosis of renal biopsy of transplant glomerulopathy grafting between January 1, 2006 to April 31, 2013 serum creatinine, proteinuria and estimated glomerular filtration rate at diagnosis, 6, 12 and 24 was recorded months. The results are shown with numbers, percentages and standard deviations. Results: 42 patients were included. At 6 months of diagnosis, 14% decline in graft function and 7.1% graft loss. At 12 months, 17.9% graft loss, and at 24 months 36.3% had chronic graft dysfunction and graft loss as return to dialysis. Conclusions: Evolution in our patients seems to be better to other series of cases reported in the literature. PMID- 29414969 TI - Gasto catastrofico en salud en Mexico y sus factores determinantes, 2002-2014. AB - Objective: To assess the financial protection of public health insurance by analyzing the percentage of households with catastrophic health expenditure (HCHE) in Mexico and its relationship with poverty status, size of locality, federal entity, insurance status and items of health spending. Method: Mexican National Survey of Income and Expenditures 2002-2014 was used to estimate the percentage of HCHE. Through a probit model, factors associated with the occurrence of catastrophic spending are identified. Analysis was performed using Stata-SE 12. Results: In 2014 there were 2.08% of HCHE (1.82-2.34%; N = 657,474). The estimated probit model correctly classified 98.2% of HCHE (Pr (D) >= 0.5). Factors affecting the catastrophic expenditures were affiliation, presence of chronic disease, hospitalization expenditure, rural condition and that the household is below the food poverty line. Conclusions: The percentage of HCHE decreased in recent years, improving financial protection in health. This decline seems to have stalled, keeping inequities in access to health services, especially in rural population without affiliation to any health institution, below the food poverty line and suffering from chronic diseases. PMID- 29414970 TI - Condiciones biopsicosociales de adultos mayores mexicanos con diabetes mellitus. AB - Objective and methods: Diabetes mellitus (DM) is a global health problem, which significantly affects older adults. . The prevalence and biopsychosocial conditions of DM in older adults in the State of Hidalgo, Mexico, are analyzed using the Health and Aging Survey 2014 (SABE-Hidalgo, Mexico). Results: DM in older adults presents a prevalence of 28.22% in the State, predominating in women and becoming more common with increasing age. The highest frequency occurs in residents of urban areas (57.2%), those with less schooling (79.6%), and those who live with relatives (77%). In addition, 54.7% of older adults with DM had cognitive impairment, 67.9% had arterial hypertension and 45.28% presented joint disease. 41.2% suffered falls, 68.52% visual problems and 87.3% tooth loss. Finally, 85.8% receive care but only 29.2% perceive improvement in their health. Conclusions: It is fundamental to develop integral programs and policies to care for older adults with DM. PMID- 29414971 TI - 350 anos de la medicina hiperbarica: aspectos historicos, fisiopatogenicos y terapeuticos. AB - The early use of hyperbaric therapy started with the quest to relieve respiratory problems among inhabitants of large cities during the industrial revolution, and from this, we have explored the benefits of treatment with hyperbaric oxygen in different areas of medicine. With the advances of the medical sciences, our knowledge concerning the therapies with hyperbaric oxygenation certainly has broadened and hyperbaric medicine still intrigues the contemporary medical researchers that are in seek of improve the quality of life of their patients. PMID- 29414972 TI - Prevalencia de sintomas de enfermedad de la superficie ocular en pacientes que acuden a consulta oftalmologica. AB - Objective: To determine the prevalence of symptoms of ocular surface disease (OSDI) surface disease and its relationship with associated risk factors in patients of ophthalmic practices using OSDI questionnaire. Method: A cross sectional survey was conducted Between September and December 2014 to assess the prevalence and risk factors for OSDI. Results: The OSDI average value was 40.46 +/- 23.62 points, with 86.4% of patients (1967) having a OSDI score higher than 12 points. Women had OSDI symptoms more frequently than men (odds ratio: 1.17; 95% confidence interval: 1.08-1.28) and higher OSDI score (42.12 +/- 24.03 vs. 38.01 +/- 22.81 points). Patients without disease were younger than the patients with severe disease (45.30 +/- 18.32 vs. 50.62 +/- 18.86). Conclusions: Ophthalmological patients have a prevalence of 80.4% of OSDI. Female and older age was associated with ocular surface disease. PMID- 29414973 TI - Asociacion de la hemorragia prerretiniana con la presencia y la gravedad de la retinopatia del prematuro en pacientes de alto riesgo. AB - Objective: To assess whether preretinal hemorrhage (PRH) is associated with the presence and severity of retinopathy of prematurity (ROP) in high-risk patients. Method: Prospective cohort study, patients referred to the Department of Ophthalmology for ROP screening during October-November 2016 were evaluated weekly on 4 occasions to assess the relationship with PRH and the development of ROP as well as degree of severity associated. We used absolute, median frequencies with minimum and maximum values, chi2 test and Mann-Whitney U-test, as well as relative risk with 95% confidence interval. Results: A total of 30 patients, in the first week 11 females (36%) and 4 males (13%) had PRH; in the 2nd week 13 patients (43%) presented PRH and 14 (46%) developed ROP; on the 3rd week there were no changes; in the last week 8 presented HPR (26%) and 11 patients (36%) with ROP. Stage I severity occurred more frequently. Statistical significance (p = 0.040) was found in the presence of PRH and the development of ROP in the first week with. Conclusions: HPR is a risk factor for the development of ROP during the first weeks of life and is associated with stages of mild severity. PMID- 29414974 TI - Desigualdad social y tendencias de mortalidad por diabetes. AB - Objective: To identify the trend of national diabetes mortality by level of marginality at the state and municipal levels. Method: A descriptive study was conducted with records of deaths from diabetes in over 20 years from 1990 to 2013. The national mortality rate was calculated standardized by age according to the 2000 world population and the state level 2013 saw the projected naational population by join point analysis for trend analysis was performed. Results: For the general population, the annual percentage change between 1990 and 1996 was 2.2, from 1996 to 2005 was 4.3, and from 2005 to 2013 was 0.1. The largest increase among women occurred between 1998 and 2005 while among men occurred between 1995 and 2006. At the state level was found higher annual percentage change between the towns with the highest degree of marginalization. Conclusions: The mortality of diabetes in women shows a significant decrease since 2004, among men, the mortality with a continuous upward trend, consistent with the trend that the disease has had in recent years. PMID- 29414975 TI - Factores relacionados con la eleccion de una especialidad en medicos residentes mexicanos. AB - Objective: This study explored choice factors in four specialties in Mexico. Method: Mixed methods design. Qualitative phase: four focus groups with first year residents, to obtain information of how specialty choice was done. With this information a web-based cross-sectional questionnaire was applied to residents registered in the 1st year of Postgraduate Studies Division, UNAM. Results: 32 residents participated in qualitative phase and for the quantitative phase, the survey was answered by 35 surgical, 28 gynecology, 61 internal medicine and 62 pediatric residents. The specialty choice decision was done during the last years of the medical career. The majority of the resident choice was a subspecialty after the general residency. The type of patient was more crucial to choose pediatrics while a good academic program was for internal medicine. Negative models and bullying were decisive to rule out surgery as well as a not well-known hospital was to rule out pediatrics. Conclusion: The specialty choice is done during undergraduate training, with the intention of doing a subspecialty. Demographic and personality traits were identified. PMID- 29414976 TI - Profesor Dr. Marshall Raymond Urist (1914-2001): descubridor de la formacion osea por induccion. AB - Marshall R. Urist was an American orthopedic surgeon who worked in University of California at Los Angeles. His scientific work about bone formation brought to medical science the discovery of a bone growth inductor substance known as bone morphogenetic protein in 1965. The protein today is a recombinant genetically produced substance which helps to regenerate connective tissues and stimulates non specialized cells to transform in to osteoblastic cell lineage. This biographical document about Urist reviews his life, career, classic scientific papers and those landmark contributions to medical science. PMID- 29414977 TI - Habitos podologicos en personas con alteraciones ungueales. AB - Objective: To determine the prevalence of onychocryptosis and onychomycosis confirmed by culture in subjects attending a Podiatric University Hospital and to describe their podiatric habits. Method: Cross-sectional study of prevalence. The study was carried out at the Clinic University of Podology of A Coruna University (Ferrol, Spain). Review of 1082 clinical histories, of which 170 were selected, persons who had onychocryptosis diagnosed clinically. The presence of onychomycosis confirmed by cultivation, presence of onychocryptosis through clinical diagnosis and a questionnaire was handed out of podologic habits. Results: Mean age of the total sample (n = 1082) was 47.9 +/- 22.1 years. Prevalence of onychocryptosis was 15.7% (n = 170) with a mean age of 54.1 +/- 20.1 years and with a significantly higher affectation in women and people under 65. Prevalence of onychomycosis was 17.6% (n = 30), mean age 59.5 +/- 20.5 years with greater involvement in women and people over 65 years. With regard to the questionnaire of habits, the footwear more employee was the closed, cordoned off and heel flat. The majority of the subject came to a podiatrist for the first time; walked approximately 1 hour and their daily activity made of foot with short displacements. Conclusions: A high prevalence of onychocryptosis and onychomycosis in people attending Podiatric services has been found. For its part using a type of flat or low heel and who does the care of toenails are shown as predictive variables of onychomycosis. PMID- 29414978 TI - Characterizing uncertain sea-level rise projections to support investment decisions. AB - Many institutions worldwide are considering how to include uncertainty about future changes in sea-levels and storm surges into their investment decisions regarding large capital infrastructures. Here we examine how to characterize deeply uncertain climate change projections to support such decisions using Robust Decision Making analysis. We address questions regarding how to confront the potential for future changes in low probability but large impact flooding events due to changes in sea-levels and storm surges. Such extreme events can affect investments in infrastructure but have proved difficult to consider in such decisions because of the deep uncertainty surrounding them. This study utilizes Robust Decision Making methods to address two questions applied to investment decisions at the Port of Los Angeles: (1) Under what future conditions would a Port of Los Angeles decision to harden its facilities against extreme flood scenarios at the next upgrade pass a cost-benefit test, and (2) Do sea level rise projections and other information suggest such conditions are sufficiently likely to justify such an investment? We also compare and contrast the Robust Decision Making methods with a full probabilistic analysis. These two analysis frameworks result in similar investment recommendations for different idealized future sea-level projections, but provide different information to decision makers and envision different types of engagement with stakeholders. In particular, the full probabilistic analysis begins by aggregating the best scientific information into a single set of joint probability distributions, while the Robust Decision Making analysis identifies scenarios where a decision to invest in near-term response to extreme sea-level rise passes a cost-benefit test, and then assembles scientific information of differing levels of confidence to help decision makers judge whether or not these scenarios are sufficiently likely to justify making such investments. Results highlight the highly-localized and context dependent nature of applying Robust Decision Making methods to inform investment decisions. PMID- 29414979 TI - Identification of functional features of synthetic SINEUPs, antisense lncRNAs that specifically enhance protein translation. AB - SINEUPs are antisense long noncoding RNAs, in which an embedded SINE B2 element UP-regulates translation of partially overlapping target sense mRNAs. SINEUPs contain two functional domains. First, the binding domain (BD) is located in the region antisense to the target, providing specific targeting to the overlapping mRNA. Second, the inverted SINE B2 represents the effector domain (ED) and enhances translation. To adapt SINEUP technology to a broader number of targets, we took advantage of a high-throughput, semi-automated imaging system to optimize synthetic SINEUP BD and ED design in HEK293T cell lines. Using SINEUP-GFP as a model SINEUP, we extensively screened variants of the BD to map features needed for optimal design. We found that most active SINEUPs overlap an AUG-Kozak sequence. Moreover, we report our screening of the inverted SINE B2 sequence to identify active sub-domains and map the length of the minimal active ED. Our synthetic SINEUP-GFP screening of both BDs and EDs constitutes a broad test with flexible applications to any target gene of interest. PMID- 29414981 TI - Brownian orientational lath model (BOLD): A computational model relating the self assembly in a fluid of lath like particles with its rheology and gelation. AB - By means of a computational model, we study the relation between two complementary views of gelation, rheological tests against the characterization of a network of consecutive particles. The model we propose consists of slender, plane, colloidal sized particles, which we name laths, which self-assemble into long ordered aggregates of several particles; called whiskers in the literature. Within a whisker, the interaction potential is a minimum when: the planes of two consecutive laths are aligned, thus favoring their alignment; when the center of three consecutive laths lie in a straight line, thus favoring stacking; and when the center of two consecutive laths are located at a certain distance, which mimics excluded volume. A threshold value of the potential gives a condition for sticking free laths into whiskers, and for the breaking of whiskers. The simplicity of the model allows the simulation to reach large enough times, of the order of minutes, needed to simulate numerical rheology tests. We are able to characterize the whisker formation, as well as to simulate the gel transition, by means of an oscillatory shear numerical experiment. We conclude that according to the usual rheological definition a gel transition occurs at about 250K, even though there is no branching and less than 10% of whiskers are long enough as to percolate the system. PMID- 29414980 TI - Diagnostic pathways and direct medical costs incurred by new adult pulmonary tuberculosis patients prior to anti-tuberculosis treatment - Tamil Nadu, India. AB - BACKGROUND: Tuberculosis (TB) patients face substantial delays prior to treatment initiation, and out of pocket (OOP) expenditures often surpass the economic productivity of the household. We evaluated the pre-diagnostic cost and health seeking behaviour of new adult pulmonary TB patients registered at Primary Health Centres (PHCs) in Vellore district, Tamil Nadu, India. METHODS: This descriptive study, part of a randomised controlled trial conducted in three rural Tuberculosis Units from Dec 2012 to Dec 2015, collected data on number of health facilities, dates of visits prior to the initiation of anti-tuberculosis treatment, and direct OOP medical costs associated with TB diagnosis. Logistic regression analysis examined the factors associated with delays in treatment initiation and OOP expenditures. RESULTS: Of 880 TB patients interviewed, 34.7% presented to public health facilities and 65% patients sought private health facilities as their first point of care. The average monthly individual income was $77.79 (SD 57.14). About 69% incurred some pre-treatment costs at an average of $39.74. Overall, patients experienced a median of 6 days (3-11 IQR) of time to treatment initiation and 21 days (10-30 IQR) of health systems delay. Age <= 40 years (aOR: 1.73; CI: 1.22-2.44), diabetes (aOR: 1.63; CI: 1.08-2.44) and first visit to a private health facility (aOR: 17.2; CI: 11.1-26.4) were associated with higher direct OOP medical costs, while age <= 40 years (aOR: 0.64; CI: 0.48 0.85) and first visit to private health facility (aOR: 1.79, CI: 1.34-2.39) were associated with health systems delay. CONCLUSION: The majority of rural TB patients registering at PHCs visited private health facilities first and incurred substantial direct OOP medical costs and delays prior to diagnosis and anti tuberculosis treatment initiation. This study highlights the need for PHCs to be made as the preferred choice for first point of contact, to combat TB more efficiently. PMID- 29414982 TI - Laser additive manufacturing of 3D meshes for optical applications. AB - Selective laser melting (SLM) is a widely used additive manufacturing process that can be used for printing of intricate three dimensional (3D) metallic structures. Here we demonstrate the fabrication of titanium alloy Ti-6Al-4V alloy based 3D meshes with nodally-connected diamond like unit cells, with lattice spacing varying from 400 to 1000 microns. A Concept Laser M2 system equipped with laser that has a wavelength of 1075 nm, a constant beam spot size of 50MUm and maximum power of 400W was used to manufacture the 3D meshes. These meshes act as optical shutters / directional transmitters and display interesting optical properties. A detailed optical characterisation was carried out and it was found that these structures can be optimised to act as scalable rotational shutters with high efficiencies and as angle selective transmission screens for protection against unwanted and dangerous radiations. The efficiency of fabricated lattice structures can be increased by enlarging the meshing size. PMID- 29414983 TI - Architecture of Paradiplozoon homoion: A diplozoid monogenean exhibiting highly developed equipment for ectoparasitism. AB - Diplozoidae (Monogenea) are blood-feeding freshwater fish gill ectoparasites with extraordinary body architecture and a unique sexual behaviour in which two larval worms fuse and transform into one functioning individual. In this study, we describe the body organisation of Paradiplozoon homoion adult stage using a combined approach of confocal laser scanning and electron microscopy, with emphasis on the forebody and hindbody. Special attention is given to structures involved in functional adaptation to ectoparasitism, i.e. host searching, attachment and feeding/metabolism. Our observations indicate clear adaptations for blood sucking, with a well-innervated mouth opening surrounded by sensory structures, prominent muscular buccal suckers and a pharynx. The buccal cavity surface is covered with numerous tegumentary digitations that increase the area in contact with host tissue and, subsequently, with its blood. The buccal suckers and the well-innervated haptor (with sclerotised clamps controlled by noticeable musculature) cooperate in attaching to and moving over the host. Putative gland cells accumulate in the region of apical circular structures, pharynx area and in the haptor middle region. Paired club-shaped sacs lying laterally to the pharynx might serve as secretory reservoirs. Furthermore, we were able to visualise the body wall musculature, including peripheral innervation, the distribution of uniciliated sensory structures essential for reception of external environmental information, and flame cells involved in excretion. Our results confirm in detail that P. homoion displays a range of sophisticated adaptations to an ectoparasitic life style, characteristic for diplozoid monogeneans. PMID- 29414984 TI - Correction: Continental synchronicity of human influenza virus epidemics despite climactic variation. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006780.]. PMID- 29414985 TI - The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: A theoretical and experimental study. AB - A major constraint in the treatment of cancer is inadequate oxygenation of the tumor mass, which can reduce chemotherapeutic efficacy. We hypothesize that polymerized human hemoglobin (PolyhHb) can be transfused into the systemic circulation to increase solid tumor oxygenation, and improve chemotherapeutic outcomes. By locking PolyhHb in the relaxed (R) quaternary state, oxygen (O2) offloading at low O2 tensions (<20 mm Hg) may be increased, while O2 offloading at high O2 tensions (>20 mm Hg) is facilitated with tense (T) state PolyhHb. Therefore, R-state PolyhHb may deliver significantly more O2 to hypoxic tissues. Biophysical parameters of T and R-state PolyhHb were used to populate a modified Krogh tissue cylinder model to assess O2 transport in a tumor. In general, we found that increasing the volume of transfused PolyhHb decreased the apparent viscosity of blood in the arteriole. In addition, we found that PolyhHb transfusion decreased the wall shear stress at large arteriole diameters (>20 MUm), but increased wall shear stress for small arteriole diameters (<10 MUm). Therefore, transfusion of PolyhHb may lead to elevated O2 delivery at low pO2. In addition, transfusion of R-state PolyhHb may be more effective than T-state PolyhHb for O2 delivery at similar transfusion volumes. Reduction in the apparent viscosity resulting from PolyhHb transfusion may result in significant changes in flow distributions throughout the tumor microcirculatory network. The difference in wall shear stress implies that PolyhHb may have a more significant effect in capillary beds through mechano-transduction. Periodic top-load transfusions of PolyhHb into mice bearing breast tumors confirmed the oxygenation potential of both PolyhHbs via reduced hypoxic volume, vascular density, tumor growth, and increased expression of hypoxia inducible genes. Tissue section analysis demonstrated primary PolyhHb clearance occurred in the liver and spleen indicating a minimal risk for renal damage. PMID- 29414986 TI - The prevalence of Escherichia coli O157:H7 fecal shedding in feedlot pens is affected by the water-to-cattle ratio: A randomized controlled trial. AB - Escherichia coli O157:H7 fecal shedding in feedlot cattle is common and is a public health concern due to the risk of foodborne transmission that can result in severe, or even fatal, disease in people. Despite a large body of research, few practical and cost-effective farm-level interventions have been identified. In this study, a randomized controlled trial was conducted to assess the effect of reducing the level of water in automatically refilling water-troughs on fecal shedding of E. coli O157:H7 in feedlot cattle. Pens in a feedlot in the Texas Panhandle were randomly allocated as control (total number: 17) or intervention (total number: 18) pens. Fecal samples (2,759 in total) were collected both at baseline and three weeks after the intervention, and tested for the presence of E. coli O157:H7 using immunomagnetic bead separation and selective culture. There was a strong statistical association between sampling date and the likelihood of a fecal sample testing positive for E. coli O157:H7. Pen was also a strong predictor of fecal prevalence. Despite accounting for this high level of clustering, a statistically significant association between reduced water levels in the trough and increased prevalence of E. coli O157:H7 in the feces was observed (Odds Ratio = 1.6; 95% Confidence Interval: 1.2-2.0; Likelihood Ratio Test: p = 0.02). This is the first time that such an association has been reported, and suggests that increasing water-trough levels may be effective in reducing shedding of E. coli O157:H7 in cattle feces, although further work would be needed to test this hypothesis. Controlling E. coli O157:H7 fecal shedding at the pre-harvest level may lead to a reduced burden of human foodborne illness attributed to this pathogen in beef. PMID- 29414987 TI - Who presents past the gestational age limit for first trimester abortion in the public sector in Mexico City? AB - OBJECTIVE: To identify socio-demographic factors associated with presenting for abortion services past the gestational age (GA) limit (12 weeks), and thus not receiving services, in Mexico City's public sector first trimester abortion program. METHODS: We used clinical data from four high volume sites in the Interrupcion Legal de Embarazo (ILE) program, 2007-2015. We used descriptive statistics to quantify the proportion of women who did not receive an abortion due to presenting past the gestational age limit. We used multivariable logistic regression to identify associations between women's characteristics and presenting past the GA limit and calculated predicted probabilities of late presentation for key characteristics. RESULTS: Our sample included 52,391 women, 8.10% (n = 4,246) of whom did not receive abortion services due to presenting past the GA limit. Adolescents (12-17) made up 8.69% of the total sample and 13.40% of those presenting past the GA limit (p< 0.05). In multivariable analyses, all age groups of adult women had significantly lower odds than adolescents of presenting past the limit (aOR = 0.77, aOR = 0.63, aOR = 0.58 and aOR = 0.37 for 19-24, 25-29, 30-39, and > = 40 years' old respectively). Women living in Mexico City and with higher levels of education had lower odds of presenting past the GA limit, and there was an educational gradient across all age groups. In the multivariable predicted probability models, adolescents at every level of education have significantly higher probabilities of not receiving an abortion due to presenting past the gestational age limit compared with adults (among women with a primary education: 11.75% adolescents vs. 9.02-4.26% across adult age groups). CONCLUSIONS: Our results suggest that continued efforts are needed to educate women, especially younger and less educated women, about early pregnancy recognition. In addition, all women need information about the availability of first trimester legal abortion to ensure timely access to abortion services. PMID- 29414988 TI - Laboratory- and community-based health outcomes in people with transtibial amputation using crossover and energy-storing prosthetic feet: A randomized crossover trial. AB - : Contemporary prosthetic feet are generally optimized for either daily or high level activities. Prosthesis users, therefore, often require multiple prostheses to participate in activities that span a range of mobility. Crossover feet (XF) are designed to increase the range of activities that can be performed with a single prosthesis. However, little evidence exists to guide clinical prescription of XF relative to traditional energy storing feet (ESF). The objective of this study was to assess the effects of XF and ESF on health outcomes in people with transtibial amputation. A randomized crossover study was conducted to assess changes in laboratory-based (endurance, perceived exertion, walking performance) and community-based (step activity and self-reported mobility, fatigue, balance confidence, activity restrictions, and satisfaction) outcomes. Twenty-seven participants were fit with XF and ESF prostheses with standardized sockets, interfaces, and suspensions. Participants were not blinded to the intervention, and wore each prosthesis for one month while their steps were counted with an activity monitor. After each accommodation period, participants returned for data collection. Endurance and perceived exertion were measured with the Six-Minute Walk Test and Borg-CR100, respectively. Walking performance was measured using an electronic walkway. Self-reported mobility, fatigue, balance confidence, activity restrictions, and satisfaction were measured with survey instruments. Participants also reported foot preferences upon conclusion of the study. Differences between feet were assessed with a crossover analysis. While using XF, users experienced improvements in most community-based outcomes, including mobility (p = .001), fatigue (p = .001), balance confidence (p = .005), activity restrictions (p = .002), and functional satisfaction (p < .001). Participants also exhibited longer sound side steps in XF compared to ESF (p < .001). Most participants (89%) reported an overall preference for XF; others (11%) reported no preference. Results indicate that XF may be a promising alternative to ESF for people with transtibial amputation who engage in a range of mobility activities. TRIAL REGISTRATION: ClinicalTrials.gov NCT02440711. PMID- 29414989 TI - Harvesting interacts with climate change to affect future habitat quality of a focal species in eastern Canada's boreal forest. AB - Many studies project future bird ranges by relying on correlative species distribution models. Such models do not usually represent important processes explicitly related to climate change and harvesting, which limits their potential for predicting and understanding the future of boreal bird assemblages at the landscape scale. In this study, we attempted to assess the cumulative and specific impacts of both harvesting and climate-induced changes on wildfires and stand-level processes (e.g., reproduction, growth) in the boreal forest of eastern Canada. The projected changes in these landscape- and stand-scale processes (referred to as "drivers of change") were then assessed for their impacts on future habitats and potential productivity of black-backed woodpecker (BBWO; Picoides arcticus), a focal species representative of deadwood and old growth biodiversity in eastern Canada. Forest attributes were simulated using a forest landscape model, LANDIS-II, and were used to infer future landscape suitability to BBWO under three anthropogenic climate forcing scenarios (RCP 2.6, RCP 4.5 and RCP 8.5), compared to the historical baseline. We found climate change is likely to be detrimental for BBWO, with up to 92% decline in potential productivity under the worst-case climate forcing scenario (RCP 8.5). However, large declines were also projected under baseline climate, underlining the importance of harvest in determining future BBWO productivity. Present-day harvesting practices were the single most important cause of declining areas of old-growth coniferous forest, and hence appeared as the single most important driver of future BBWO productivity, regardless of the climate scenario. Climate induced increases in fire activity would further promote young, deciduous stands at the expense of old-growth coniferous stands. This suggests that the biodiversity associated with deadwood and old-growth boreal forests may be greatly altered by the cumulative impacts of natural and anthropogenic disturbances under a changing climate. Management adaptations, including reduced harvesting levels and strategies to promote coniferous species content, may help mitigate these cumulative impacts. PMID- 29414990 TI - Equid herpesvirus 8: Complete genome sequence and association with abortion in mares. AB - Equid herpesvirus 8 (EHV-8), formerly known as asinine herpesvirus 3, is an alphaherpesvirus that is closely related to equid herpesviruses 1 and 9 (EHV-1 and EHV-9). The pathogenesis of EHV-8 is relatively little studied and to date has only been associated with respiratory disease in donkeys in Australia and horses in China. A single EHV-8 genome sequence has been generated for strain Wh in China, but is apparently incomplete and contains frameshifts in two genes. In this study, the complete genome sequences of four EHV-8 strains isolated in Ireland between 2003 and 2015 were determined by Illumina sequencing. Two of these strains were isolated from cases of abortion in horses, and were misdiagnosed initially as EHV-1, and two were isolated from donkeys, one with neurological disease. The four genome sequences are very similar to each other, exhibiting greater than 98.4% nucleotide identity, and their phylogenetic clustering together demonstrated that genomic diversity is not dependent on the host. Comparative genomic analysis revealed 24 of the 76 predicted protein sequences are completely conserved among the Irish EHV-8 strains. Evolutionary comparisons indicate that EHV-8 is phylogenetically closer to EHV-9 than it is to EHV-1. In summary, the first complete genome sequences of EHV-8 isolates from two host species over a twelve year period are reported. The current study suggests that EHV-8 can cause abortion in horses. The potential threat of EHV-8 to the horse industry and the possibility that donkeys may act as reservoirs of infection warrant further investigation. PMID- 29414991 TI - Positive age beliefs protect against dementia even among elders with high-risk gene. AB - One of the strongest risk factors for dementia is the epsilon4 variant of the APOE gene. Yet, many who carry it never develop dementia. The current study examined for the first time whether positive age beliefs that are acquired from the culture may reduce the risk of developing dementia among older individuals, including those who are APOE epsilon4 carriers. The cohort consisted of 4,765 Health and Retirement Study participants who were aged 60 or older and dementia free at baseline. As predicted, in the total sample those with positive age beliefs at baseline were significantly less likely to develop dementia, after adjusting for relevant covariates. Among those with APOE epsilon4, those with positive age beliefs were 49.8% less likely to develop dementia than those with negative age beliefs. The results of this study suggest that positive age beliefs, which are modifiable and have been found to reduce stress, can act as a protective factor, even for older individuals at high risk of dementia. PMID- 29414992 TI - Can we induce spermatogenesis in the domestic cat using an in vitro tissue culture approach? AB - The reduced number of animals in most wild felid populations implies a loss of genetic diversity. The death of juveniles, prior to the production of mature sperm, represents a loss of potential genetic contribution to future populations. Since 2011 mouse testicular organ culture has introduced an alternative mechanism to produce sperm in vitro from immature tissue. However, extension of this technology to other species has remained limited. We have used the domestic cat (Felis catus) as a model for wild felids to investigate spermatogenesis initiation and regulation, with the mouse serving as a control species. Testicular tissue fragments were cultured in control medium or medium supplemented with knockout serum replacement (KSR), AlbuMax, beta-estradiol or AlbuMax plus beta-estradiol. Contrary to expectations, and unlike results obtained in mouse controls, no germ cell differentiation could be detected. The only germ cells observed after six weeks of culture were spermatogonia regardless of the initial stage of tubule development in the donor tissue. Moreover, the number of spermatogonia decreased with time in culture in all media tested, especially in the medium supplemented with KSR, while AlbuMax had a slight protective effect. The combination of AlbuMax and beta-estradiol led to an increase in the area occupied by seminiferous tubules, and thus to an increase in total number of spermatogonial cells. Considering all the media combinations tested the stimulus for felid germ cell differentiation in this type of system seems to be different from the mouse. Studies using other triggers of differentiation and tissue survival factors should be performed to pursue this technology for the genetic diversity preservation in wild felids. PMID- 29414993 TI - Accurately tracking single-cell movement trajectories in microfluidic cell sorting devices. AB - Microfluidics are routinely used to study cellular properties, including the efficient quantification of single-cell biomechanics and label-free cell sorting based on the biomechanical properties, such as elasticity, viscosity, stiffness, and adhesion. Both quantification and sorting applications require optimal design of the microfluidic devices and mathematical modeling of the interactions between cells, fluid, and the channel of the device. As a first step toward building such a mathematical model, we collected video recordings of cells moving through a ridged microfluidic channel designed to compress and redirect cells according to cell biomechanics. We developed an efficient algorithm that automatically and accurately tracked the cell trajectories in the recordings. We tested the algorithm on recordings of cells with different stiffness, and showed the correlation between cell stiffness and the tracked trajectories. Moreover, the tracking algorithm successfully picked up subtle differences of cell motion when passing through consecutive ridges. The algorithm for accurately tracking cell trajectories paves the way for future efforts of modeling the flow, forces, and dynamics of cell properties in microfluidics applications. PMID- 29414994 TI - Insectivorous birds eavesdrop on the pheromones of their prey. AB - Chemical cues play a fundamental role in mate attraction and mate choice. Lepidopteran females, such as the winter moth (Operophtera brumata), emit pheromones to attract males in the reproductive period. However, these chemical cues could also be eavesdropped by predators. To our knowledge, no studies have examined whether birds can detect pheromones of their prey. O. brumata adults are part of the winter diet of some insectivorous tit species, such as the great tit (Parus major) and blue tit (Cyanistes caeruleus). We performed a field experiment aimed to disentangle whether insectivorous birds can exploit the pheromones emitted by their prey for prey location. We placed artificial larvae and a dispenser on branches of Pyrenean oak trees (Quercus pyrenaica). In half of the trees we placed an O. brumata pheromone dispenser and in the other half we placed a control dispenser. We measured the predation rate of birds on artificial larvae. Our results show that more trees had larvae with signs of avian predation when they contained an O. brumata pheromone than when they contained a control dispenser. Furthermore, the proportion of artificial larvae with signs of avian predation was greater in trees that contained the pheromone than in control trees. Our results indicate that insectivorous birds can exploit the pheromones emitted by moth females to attract males, as a method of prey detection. These results highlight the potential use of insectivorous birds in the biological control of insect pests. PMID- 29414995 TI - The peroxisome proliferator-activated receptor agonist pioglitazone and 5 lipoxygenase inhibitor zileuton have no effect on lung inflammation in healthy volunteers by positron emission tomography in a single-blind placebo-controlled cohort study. AB - BACKGROUND: Anti-inflammatory drug development efforts for lung disease have been hampered in part by the lack of noninvasive inflammation biomarkers and the limited ability of animal models to predict efficacy in humans. We used 18F fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a human model of lung inflammation to assess whether pioglitazone, a peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonist, and zileuton, a 5-lipoxygenase inhibitor, reduce lung inflammation. METHODS: For this single center, single blind, placebo-controlled cohort study, we enrolled healthy volunteers sequentially into the following treatment cohorts (N = 6 per cohort): pioglitazone plus placebo, zileuton plus placebo, or dual placebo prior to bronchoscopic endotoxin instillation. 18F-FDG uptake pre- and post-endotoxin was quantified as the Patlak graphical analysis-determined Ki (primary outcome measure). Secondary outcome measures included the mean standard uptake value (SUVmean), post-endotoxin bronchoalveolar lavage (BAL) cell counts and differentials and blood adiponectin and urinary leukotriene E4 (LTE4) levels, determined by enzyme-linked immunosorbent assay, to verify treatment compliance. One- or two-way analysis of variance assessed for differences among cohorts in the outcome measures (expressed as mean +/- standard deviation). RESULTS: Ten females and eight males (29+/-6 years of age) completed all study procedures except for one volunteer who did not complete the post-endotoxin BAL. Ki and SUVmean increased in all cohorts after endotoxin instillation (Ki increased by 0.0021+/-0.0019, 0.0023+/-0.0017, and 0.0024+/-0.0020 and SUVmean by 0.47+/-0.14, 0.55+/-0.15, and 0.54+/-0.38 in placebo, pioglitazone, and zileuton cohorts, respectively, p<0.001) with no differences among treatment cohorts (p = 0.933). Adiponectin levels increased as expected with pioglitazone treatment but not urinary LTE4 levels as expected with zileuton treatment. BAL cell counts (p = 0.442) and neutrophil percentage (p = 0.773) were similar among the treatment cohorts. CONCLUSIONS: Endotoxin-induced lung inflammation in humans is not responsive to pioglitazone or zileuton, highlighting the challenge in translating anti-inflammatory drug efficacy results from murine models to humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT01174056. PMID- 29414996 TI - Chronic morphine exposure potentiates p-glycoprotein trafficking from nuclear reservoirs in cortical rat brain microvessels. AB - The rates of opioid prescription and use have continued to increase over the last few decades resulting in a greater number of opioid tolerant patients. Treatment of acute pain from surgery and injury is a clinical challenge for these patients. Several pain management strategies including prescribing increased opioids are used clinically with limited success; all currently available strategies have significant limitations. Many opioids are a substrate for p-glycoprotein (p-gp), an efflux transporter at the blood-brain barrier (BBB). Increased p-gp is associated with a decreased central nervous system uptake and analgesic efficacy of morphine. Our laboratory previously found that acute peripheral inflammatory pain (PIP) induces p-gp trafficking from the nucleus to the luminal surface of endothelial cells making up the BBB concomitant with increased p-gp activity and decreased morphine analgesic efficacy. In the current study, we tested whether PIP-induced p-gp trafficking could contribute to decreased opioid efficacy in morphine tolerant rats. A 6-day continuous dosing of morphine from osmotic minipumps was used to establish morphine tolerance in female rats. PIP induced p gp trafficking away from nuclear stores showed a 2-fold increase in morphine tolerant rats. This observation suggests that p-gp trafficking contributes to the decreased morphine analgesic effects in morphine tolerant rats experiencing an acute pain stimulus. Attenuating p-gp trafficking during an acute pain stimulus could improve pain management by increasing the amount of opioid that could reach CNS analgesic targets and decrease the need for the dose escalation that is a serious challenge in pain management. PMID- 29414997 TI - Who is where at risk for Chronic Obstructive Pulmonary Disease? A spatial epidemiological analysis of health insurance claims for COPD in Northeastern Germany. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) has a high prevalence rate in Germany and a further increase is expected within the next years. Although risk factors on an individual level are widely understood, only little is known about the spatial heterogeneity and population-based risk factors of COPD. Background knowledge about broader, population-based processes could help to plan the future provision of healthcare and prevention strategies more aligned to the expected demand. The aim of this study is to analyze how the prevalence of COPD varies across northeastern Germany on the smallest spatial-scale possible and to identify the location-specific population-based risk factors using health insurance claims of the AOK Nordost. METHODS: To visualize the spatial distribution of COPD prevalence at the level of municipalities and urban districts, we used the conditional autoregressive Besag-York-Mollie (BYM) model. Geographically weighted regression modelling (GWR) was applied to analyze the location-specific ecological risk factors for COPD. RESULTS: The sex- and age adjusted prevalence of COPD was 6.5% in 2012 and varied widely across northeastern Germany. Population-based risk factors consist of the proportions of insurants aged 65 and older, insurants with migration background, household size and area deprivation. The results of the GWR model revealed that the population at risk for COPD varies considerably across northeastern Germany. CONCLUSION: Area deprivation has a direct and an indirect influence on the prevalence of COPD. Persons ageing in socially disadvantaged areas have a higher chance of developing COPD, even when they are not necessarily directly affected by deprivation on an individual level. This underlines the importance of considering the impact of area deprivation on health for planning of healthcare. Additionally, our results reveal that in some parts of the study area, insurants with migration background and persons living in multi-persons households are at elevated risk of COPD. PMID- 29414998 TI - Pharmaceutical companies and healthcare providers: Going beyond the gift - An explorative review. AB - INTRODUCTION: Interactions between pharmaceutical companies and healthcare providers are increasingly scrutinized by academics, professionals, media, and politicians. Most empirical studies and professional guidelines focus on unilateral donor-recipient types of interaction and overlook, or fail to distinguish between, more reciprocal types of interaction. However, the degree of goal alignment and potential for value creation differs in these two types of interactions. Failing to differentiate between these two forms of interaction between pharmaceutical companies and healthcare providers could thus lead to biased conclusions regarding their desirability. This study reviews the empirical literature regarding the effects of bilateral forms of interactions between pharmaceutical companies and healthcare providers in order to explore their effects. MATERIAL AND METHODS: We searched two medical databases (i.e. PubMed and Cochrane Library) and one business database (i.e. EBSCO) for empirical, peer reviewed articles concerning any type of bilateral interaction between pharmaceutical companies and healthcare providers. We included quantitative articles which were written in English and published between January 1st, 2000 and October 31st, 2016, and where the title or abstract included a combination of synonyms of the following keywords: pharmaceutical companies, healthcare providers, interaction, and effects. RESULTS: Our search results yielded 10 studies which were included in our analysis. These studies focused on either research-oriented interaction or on education-oriented interaction. The included studies reported various outcomes of interaction such as prescribing behavior, ethical dilemmas, and research output. Regardless of the type of interaction, the studies either reported no significant effects or ambivalent outcomes such as affected clinical practice or ethical issues. DISCUSSION AND CONCLUSION: The effects of bilateral interactions reported in the literature are similar to those reported in studies concerning unilateral interactions. The theoretical notion that bilateral interactions between pharmaceutical companies and healthcare providers have different effects given their increased level of goal alignment thus does not seem to hold. However, most of the empirical studies focus on intermediary, provider-level, outcomes such as altered prescribing behavior. Outcomes at the health system level such as overall costs and quality of care are overlooked. Further research is necessary in order to disentangle various forms of value created by different types of interactions between pharmaceutical companies and healthcare providers. PMID- 29415000 TI - A case for conserving common species. PMID- 29415001 TI - First report of Meloidogyne graminis on golf courses turfgrass in Brazil. AB - Plant-parasitic nematodes of the genus Meloidogyne, known as root-knot nematodes (RKN), have an important economic impact on golf course turfgrasses. The most prevalent RKN species associated with grasses are M. chitwoodi, M. graminicola, M. graminis, M. incognita, M. marylandi, M. microtyla, M. minor, M. naasi and M. sasseri. In 2010, slight thickening of the roots and RKN females with unusual features were observed in turfgrass roots on golf courses in Araras, Sao Paulo state, Brazil. This population (MgARA) was maintained in the lab and studied including morphological, morphometrical, biochemical and molecular markers. Morphology and morphometry were variable and not useful for identification, although perineal pattern morphology showed highly similarity with M. graminis description. Concerning to biochemical characterisation, the esterase phenotype Mg1, characterised by a very slow and fainter band, was detected in some protein homogenates. Regarding to molecular analysis, D2-D3 region of 28S rDNA gene and cytochrome oxidase subunit II region from mitochondrial DNA were amplified by PCR and sequenced. Phylogenetic analysis revealed that the Brazilian isolate, found associated with turfgrass, grouped with M. graminis isolates (98-99% bootstrap; variation of 8-11 and 0-24 bp, respectively), close to M. marylandi, supporting its identification as M. graminis. This is the first report of M. graminis on golf courses in Brazil. PMID- 29414999 TI - Diversity, distribution and conservation of the terrestrial reptiles of Oman (Sauropsida, Squamata). AB - In the present work, we use an exceptional database including 5,359 records of 101 species of Oman's terrestrial reptiles together with spatial tools to infer the spatial patterns of species richness and endemicity, to infer the habitat preference of each species and to better define conservation priorities, with especial focus on the effectiveness of the protected areas in preserving this unique arid fauna. Our results indicate that the sampling effort is not only remarkable from a taxonomic point of view, with multiple observations for most species, but also for the spatial coverage achieved. The observations are distributed almost continuously across the two-dimensional climatic space of Oman defined by the mean annual temperature and the total annual precipitation and across the Principal Component Analysis (PCA) of the multivariate climatic space and are well represented within 17 out of the 20 climatic clusters grouping 10% of the explained climatic variance defined by PC1 and PC2. Species richness is highest in the Hajar and Dhofar Mountains, two of the most biodiverse areas of the Arabian Peninsula, and endemic species richness is greatest in the Jebel Akhdar, the highest part of the Hajar Mountains. Oman's 22 protected areas cover only 3.91% of the country, including within their limits 63.37% of terrestrial reptiles and 50% of all endemics. Our analyses show that large areas of the climatic space of Oman lie outside protected areas and that seven of the 20 climatic clusters are not protected at all. The results of the gap analysis indicate that most of the species are below the conservation target of 17% or even the less restrictive 12% of their total area within a protected area in order to be considered adequately protected. Therefore, an evaluation of the coverage of the current network of protected areas and the identification of priority protected areas for reptiles using reserve design algorithms are urgently needed. Our study also shows that more than half of the species are still pending of a definitive evaluation by the International Union for Conservation of Nature (IUCN). PMID- 29415002 TI - Vocal individuality in drumming in great spotted woodpecker-A biological perspective and implications for conservation. AB - Animals-including conservation biologists-use acoustic signals to recognise and track individuals. The majority of research on this phenomenon has focused on sounds generated by vocal organs (e.g., larynx or syrinx). However, animals also produce sounds using other parts of the body, such as the wings, tail, legs, or bill. In this study we focused on non-syrinx vocalisation of the great spotted woodpecker, called drumming. Drumming consists of strokes of a bill on a tree in short, repeated series, and is performed by both males and females to attract mates and deter rivals. Here, we considered whether the great spotted woodpecker's drumming patterns are sex-specific and whether they enable individual identification. We recorded drumming of 41 great spotted woodpeckers (26 males, 9 females, 6 unsexed). An automatic method was used to measure the intervals between succeeding strokes and to count strokes within a drumming roll. The temporal parameters of drumming that were analysed here had lower within- than between-individual coefficients of variation. Discriminant function analyses correctly assigned 70-88% of rolls to the originating individual, but this depended on whether all individuals were analysed together or split into males and females. We found slight, but significant, differences between males and females in the length of intervals between strokes-males drummed faster than females-but no difference in the number of strokes within a roll. Our study revealed that temporal patterns of drumming in the great spotted woodpecker cannot be used for unambiguous sex determination. Instead, discrimination among individuals may be possible based on the intervals between strokes and the number of strokes within a roll. Therefore, it is possible that differences in the temporal parameters of drumming may be used by birds to identify each other, as well as by researchers to aid in census and monitoring tasks. PMID- 29415003 TI - The rise of health biotechnology research in Latin America: A scientometric analysis of health biotechnology production and impact in Argentina, Brazil, Chile, Colombia, Cuba and Mexico. AB - This paper analyzes the patterns of health biotechnology publications in six Latin American countries from 2001 to 2015. The countries studied were Argentina, Brazil, Chile, Colombia, Cuba and Mexico. Before our study, there were no data available on HBT development in half of the Latin-American countries we studied, i.e., Argentina, Colombia and Chile. To include these countries in a scientometric analysis of HBT provides fuller coverage of HBT development in Latin America. The scientometric study used the Web of Science database to identify health biotechnology publications. The total amount of health biotechnology production in the world during the period studied was about 400,000 papers. A total of 1.2% of these papers, were authored by the six Latin American countries in this study. The results show a significant growth in health biotechnology publications in Latin America despite some of the countries having social and political instability, fluctuations in their gross domestic expenditure in research and development or a trade embargo that limits opportunities for scientific development. The growth in the field of some of the Latin American countries studied was larger than the growth of most industrialized nations. Still, the visibility of the Latin American research (measured in the number of citations) did not reach the world average, with the exception of Colombia. The main producers of health biotechnology papers in Latin America were universities, except in Cuba were governmental institutions were the most frequent producers. The countries studied were active in international research collaboration with Colombia being the most active (64% of papers co authored internationally), whereas Brazil was the least active (35% of papers). Still, the domestic collaboration was even more prevalent, with Chile being the most active in such collaboration (85% of papers co-authored domestically) and Argentina the least active (49% of papers). We conclude that the Latin American countries studied are increasing their health biotechnology publishing. This strategy could contribute to the development of innovations that may solve local health problems in the region. PMID- 29415004 TI - Facilitators and barriers for HIV-testing in Zambia: A systematic review of multi level factors. AB - It was estimated that 1.2 million people live with HIV/AIDS in Zambia by 2015. Zambia has developed and implemented diverse programs to reduce the prevalence in the country. HIV-testing is a critical step in HIV treatment and prevention, especially among all the key populations. However, there is no systematic review so far to demonstrate the trend of HIV-testing studies in Zambia since 1990s or synthesis the key factors that associated with HIV-testing practices in the country. Therefore, this study conducted a systematic review to search all English literature published prior to November 2016 in six electronic databases and retrieved 32 articles that meet our inclusion criteria. The results indicated that higher education was a common facilitator of HIV testing, while misconception of HIV testing and the fear of negative consequences were the major barriers for using the testing services. Other factors, such as demographic characteristics, marital dynamics, partner relationship, and relationship with the health care services, also greatly affects the participants' decision making. The findings indicated that 1) individualized strategies and comprehensive services are needed for diverse key population; 2) capacity building for healthcare providers is critical for effectively implementing the task-shifting strategy; 3) HIV testing services need to adapt to the social context of Zambia where HIV-related stigma and discrimination is still persistent and overwhelming; and 4) family-based education and intervention should involving improving gender equity. PMID- 29415005 TI - Influence of tissue conductivity on foetal exposure to extremely low frequency magnetic fields at 50 Hz using stochastic dosimetry. AB - Human exposure to extremely low frequency magnetic fields (ELF-MF) at 50 Hz is still a topic of great interest due to the possible correlation with childhood leukaemia. The estimation of induced electric fields in human tissues exposed to electromagnetic fields (EMFs) strictly depends on several variables which include the dielectric properties of the tissues. In this paper, the influence of the conductivity assignment to foetal tissues at different gestational ages on the estimation of the induced electric field due to ELF-MF exposure at 50 Hz has been quantified by means of a stochastic approach using polynomial chaos theory. The range of variation in conductivity values for each foetal tissue at each stage of pregnancy have been defined through three empirical approaches and the induced electric field in each tissue has been modelled through stochastic dosimetry. The main results suggest that both the peak and median induced electric fields in foetal fat vary by more than 8% at all gestational ages. On the contrary, the electric field induced in foetal brain does not seem to be significantly affected by conductivity data changes. The maximum exposure levels, in terms of the induced electric field found in each specific tissue, were found to be significantly below the basic restrictions indicated in the ICNIRP Guidelines, 2010. PMID- 29415006 TI - A single beta-octyl glucoside molecule induces HIV-1 Nef dimer formation in the absence of partner protein binding. AB - The HIV-1 Nef accessory protein is essential for viral pathogenicity and AIDS progression. Nef forms complexes with multiple host cell factors to facilitate viral replication and promote immune escape of HIV-infected cells. Previous X-ray crystal structures demonstrate that Nef forms homodimers, the orientation of which are influenced by host cell binding partners. In cell-based fluorescence complementation assays, Nef forms homodimers at the plasma membrane. However, recombinant Nef proteins often exist as monomers in solution, suggesting that membrane interaction may also trigger monomer to dimer transitions. In this study, we show that monomeric Nef core proteins can be induced to form dimers in the presence of low concentrations of the non-ionic surfactant, beta-octyl glucoside (betaOG). X-ray crystallography revealed that a single betaOG molecule is present in the Nef dimer, with the 8-carbon acyl chain of the ligand binding to a hydrophobic pocket formed by the dimer interface. This Nef-betaOG dimer interface involves helix alphaB, as observed in previous dimer structures, as well as a helix formed by N-terminal residues 54-66. Nef dimer formation is stabilized in solution by the addition of betaOG, providing biochemical validation for the crystal structure. These observations together suggest that the interaction with host cell lipid mediators or other hydrophobic ligands may play a role in Nef dimerization, which has been previously linked to multiple Nef functions including host cell protein kinase activation, CD4 downregulation, and enhancement of HIV-1 replication. PMID- 29415007 TI - Gli3 is a negative regulator of Tas1r3-expressing taste cells. AB - Mouse taste receptor cells survive from 3-24 days, necessitating their regeneration throughout adulthood. In anterior tongue, sonic hedgehog (SHH), released by a subpopulation of basal taste cells, regulates transcription factors Gli2 and Gli3 in stem cells to control taste cell regeneration. Using single-cell RNA-Seq we found that Gli3 is highly expressed in Tas1r3-expressing taste receptor cells and Lgr5+ taste stem cells in posterior tongue. By PCR and immunohistochemistry we found that Gli3 was expressed in taste buds in all taste fields. Conditional knockout mice lacking Gli3 in the posterior tongue (Gli3CKO) had larger taste buds containing more taste cells than did control wild-type (Gli3WT) mice. In comparison to wild-type mice, Gli3CKO mice had more Lgr5+ and Tas1r3+ cells, but fewer type III cells. Similar changes were observed ex vivo in Gli3CKO taste organoids cultured from Lgr5+ taste stem cells. Further, the expression of several taste marker and Gli3 target genes was altered in Gli3CKO mice and/or organoids. Mirroring these changes, Gli3CKO mice had increased lick responses to sweet and umami stimuli, decreased lick responses to bitter and sour taste stimuli, and increased glossopharyngeal taste nerve responses to sweet and bitter compounds. Our results indicate that Gli3 is a suppressor of stem cell proliferation that affects the number and function of mature taste cells, especially Tas1r3+ cells, in adult posterior tongue. Our findings shed light on the role of the Shh pathway in adult taste cell regeneration and may help devise strategies for treating taste distortions from chemotherapy and aging. PMID- 29415008 TI - Genome-wide associations for multiple pest resistances in a Northwestern United States elite spring wheat panel. AB - Northern areas of the western United States are one of the most productive wheat growing regions in the United States. Increasing productivity through breeding is hindered by several biotic stresses which slow and constrain targeted yield improvement. In order to understand genetic variation for stripe rust (Puccinia striiformis f. sp. tritici), Septoria tritici blotch (Mycosphaerella graminicola), and Hessian fly (Mayetiola destructor) in regional germplasm, a panel of 408 elite spring wheat lines was characterized and genotyped with an Illumina 9K wheat single nucleotide polymorphism (SNP) chip to enable genome-wide association study (GWAS) analyses. Significant marker-trait associations were identified for stripe rust (38 loci), Septoria tritici blotch (8) and Hessian fly (9) resistance. Many of the QTL corresponded with previously reported gene locations or QTL, but we also discovered new resistance loci for each trait. We validated one of the stripe rust resistance loci detected by GWAS in a bi parental mapping population, which confirmed the detection of Yr15 in the panel. This study elucidated well-defined chromosome regions for multiple pest resistances in elite Northwest germplasm. Newly identified resistance loci, along with SNPs more tightly linked to previously reported genes or QTL will help future breeding and marker assisted selection efforts. PMID- 29415010 TI - shinyGISPA: A web application for characterizing phenotype by gene sets using multiple omics data combinations. AB - While many methods exist for integrating multi-omics data or defining gene sets, there is no one single tool that defines gene sets based on merging of multiple omics data sets. We present shinyGISPA, an open-source application with a user friendly web-based interface to define genes according to their similarity in several molecular changes that are driving a disease phenotype. This tool was developed to help facilitate the usability of a previously published method, Gene Integrated Set Profile Analysis (GISPA), among researchers with limited computer programming skills. The GISPA method allows the identification of multiple gene sets that may play a role in the characterization, clinical application, or functional relevance of a disease phenotype. The tool provides an automated workflow that is highly scalable and adaptable to applications that go beyond genomic data merging analysis. It is available at http://shinygispa.winship.emory.edu/shinyGISPA/. PMID- 29415009 TI - Synthesis of magnolol and honokiol derivatives and their effect against hepatocarcinoma cells. AB - The hepatocellular carcinoma is one of the most common malignant tumour with high level of mortality rate due to its rapid progression and high resistance to conventional chemotherapies. Thus, the search for novel therapeutic leads is of global interest. Herein, a small set of derivatives of magnolol 1 and honokiol 2, the main components of Magnolia grandiflora and Magnolia obovata, were evaluated in in vitro assay using tumoral hepatocytes. The pro-drug approach was applied as versatile strategy to the improve bioactivity of the compounds by careful transformation of the hydroxyl groups of magnolol 1 and honokiol 2 in suitable ester derivatives. Compounds 10 and 11 resulted to be more potent than the parental honokiol 2 at concentration down to 1 MUM with complete viability of treated fibroblast cells up to concentrations of 80 MUM. The combination of a butyrate ester and a bare phenol-OH group in the honokiol structure seemed to play a significant role in the antiproliferative activity identifying an interesting pharmacological clue against hepatocellular carcinoma. PMID- 29415011 TI - Piloting very early infant diagnosis of HIV in Lesotho: Acceptability and feasibility among mothers, health workers and laboratory personnel. AB - INTRODUCTION: Mortality associated with in-utero HIV infection rises rapidly within weeks after birth. Very early infant diagnosis of HIV (VEID)-testing within 2 weeks of birth-followed by immediate initiation of antiretroviral therapy has potential to avert mortality associated with in-utero transmission. However, our understanding of acceptability and feasibility of VEID is limited. METHODS: VEID was piloted in an observational prospective cohort of HIV-positive pregnant women and their infants in 13 Lesotho health facilities. Between March July 2016, semi-structured interviews were conducted with HIV-positive women attending 6-week or 14-week postnatal visits and health workers (HWs) in 8 study facilities in 3 districts as well as with district and central laboratory staff. Interview themes included acceptability of birth and subsequent HIV testing and early treatment, perceived VEID challenges, and HIV birth testing procedures and how well they were performed. RESULTS: Interviews were conducted with 20 women, 18 HWs and 9 district/central laboratory staff. Nearly all mothers perceived knowing their child's HIV status at birth positively. Mothers and HWs did not indicate that birth testing affected subsequent acceptance of infant HIV testing or clinic attendance. HWs and laboratory staff reported weak follow-up systems for mothers with home deliveries, and concern regarding the increased workload associated with additional testing requirements. All groups reported turnaround time delays for EID, and that sometimes results were never received. CONCLUSIONS: Women, HWs, and laboratory staff found VEID acceptable and were supportive of national implementation of birth testing. However, they identified challenges within the EID system that could be exacerbated by adding a test to the diagnostic algorithm, such as delays in receiving test results, suggesting VEID may not be feasible in certain settings. Policymakers will need to consider whether adding birth testing or strengthening the current clinic and laboratory system is the most appropriate course of action. PMID- 29415013 TI - Population impact of lung cancer screening in the United States: Projections from a microsimulation model. AB - BACKGROUND: Previous simulation studies estimating the impacts of lung cancer screening have ignored the changes in smoking prevalence over time in the United States. Our primary rationale was to perform, to our knowledge, the first simulation study that estimates the health outcomes of lung cancer screening with explicit modeling of smoking trends for the whole US population. METHODS/FINDINGS: Utilizing a well-validated microsimulation model, we estimated the benefits and harms of an annual low-dose computed tomography screening scenario with a realistic screening adherence rate versus a no-screening scenario for the US population from 2016-2030. The Centers for Medicare and Medicaid Services (CMS) eligibility criteria were applied: age 55-77 years at time of screening, history of at least 30 pack-years of smoking, and current smoker or former smoker with fewer than 15 years since quitting. In the screened population, cumulative mortality reduction was projected to reach 16.98% (95% CI 16.90%-17.07%). Cumulative mortality reduction was estimated to be 3.52% (95% CI 3.50%-3.53%) for the overall study population, with annual mortality reduction peaking at 4.38% (95% CI 4.36%-4.41%) in 2021 and falling to 3.53% (95% CI 3.50% 3.56%) by 2030. Lung cancer screening would save a projected 148,484 life-years (95% CI 147,429-149,540) across the total population through 2030. There were estimated to be 9,054 (95% CI 9,011-9,098) overdiagnosed cases among the 252,429 (95% CI 251,208-253,649) screen-detected lung cancer diagnoses, yielding an overdiagnosis rate of 3.59%. The limitations of our study are that we do not explicitly model race or socioeconomic status and our model was calibrated to data from studies performed in academic centers, both of which may impact the generalizability of our results. We also exclusively model the effects of the CMS guidelines for lung cancer screening and not any other screening strategies. CONCLUSIONS: The mortality reduction and life-years gained estimated by this study are lower than those of single birth cohort studies. Single cohort studies neglect the changing dynamics of smoking behavior across generations, whereas this study reflects the trend of decreasing smoking prevalence since the 1960s. Maximum benefit could be derived from lung cancer screening through 2021; in later years, mortality reduction due to screening will decline. If a comprehensive screening program is not implemented in the near future, the opportunity to achieve these benefits will have passed. PMID- 29415012 TI - Environmental epidemiology of Kawasaki disease: Linking disease etiology, pathogenesis and global distribution. AB - BACKGROUND: The pathogenesis of Kawasaki disease (KD) is commonly ascribed to an exaggerated immunologic response to an unidentified environmental or infectious trigger in susceptible children. A comprehensive framework linking epidemiological data and global distribution of KD has not yet been proposed. METHODS AND FINDINGS: Patients with KD (n = 81) were enrolled within 6 weeks of diagnosis along with control subjects (n = 87). All completed an extensive epidemiological questionnaire. Geographic localization software characterized the subjects' neighborhood. KD incidence was compared to atmospheric biological particles counts and winds patterns. These data were used to create a comprehensive risk framework for KD, which we tested against published data on the global distribution. Compared to controls, patients with KD were more likely to be of Asian ancestry and were more likely to live in an environment with low exposure to environmental allergens. Higher atmospheric counts of biological particles other than fungus/spores were associated with a temporal reduction in incidence of KD. Finally, westerly winds were associated with increased fungal particles in the atmosphere and increased incidence of KD over the Greater Toronto Area. Our proposed framework was able to explain approximately 80% of the variation in the global distribution of KD. The main limitations of the study are that the majority of data used in this study are limited to the Canadian context and our proposed disease framework is theoretical and circumstantial rather than the result of a single simulation. CONCLUSIONS: Our proposed etiologic framework incorporates the 1) proportion of population that are genetically susceptible; 2) modulation of risk, determined by habitual exposure to environmental allergens, seasonal variations of atmospheric biological particles and contact with infectious diseases; and 3) exposure to the putative trigger. Future modelling of individual risk and global distribution will be strengthened by taking into consideration all of these non-traditional elements. PMID- 29415014 TI - Buttock tissue response to loading in men with spinal cord injury. AB - OBJECTIVE/BACKGROUND: Despite the fact that most people with a spinal cord injury who use a wheelchair for mobility are considered at-risk for pressure ulcer (PrU) development, there still exists a spectrum of risk amongst this group. Efforts to differentiate risk level would benefit from clinical tools that can measure or predict the buttocks response to loading. Therefore, the goal of this study was to identify how tissue compliance and blood flow were impacted by clinically measurable risk factors in young men with SCI. METHODS: Blood flow at the ischial tuberosity was measured using laser Doppler flowmetry while the seated buttock was unloaded, and loaded at lower (40-60 mmHg) and high (>200 mmHg) loads. Tissue compliance of the buttock was measured using the Myotonometer while subject were lifted in a Guldmann Net. RESULTS: Across 28 participants, blood flow was significantly reduced at high loads, while no consistent, significant changes were found at lower loads. At 40-60 mmHg, blood flow decreased in participants with a pressure ulcer history and lower BMI, but stayed the same or increased in most other participants. The buttock displaced an average of 9.3 mm (2.7 mm) at 4.2 N, which represented 82% (7%) of maximum displacement. BMI was related to the amount of buttock tissue displacement while smoking status explained some of the variation in the percent of max displacement. CONCLUSION: Wide variability in tissue compliance and blood flow responses across a relatively homogeneous population indicate that differences in biomechanical risk may provide an explanation for the spectrum of PrU risk among persons with SCI. PMID- 29415015 TI - Inpatient mortality rates during an era of increased access to HIV testing and ART: A prospective observational study in Lilongwe, Malawi. AB - BACKGROUND: In the era of increased access to HIV testing and antiretroviral treatment (ART), the impact of HIV and ART status on inpatient mortality in Malawi is unknown. METHODS: We prospectively followed adult inpatients at Kamuzu Central Hospital medical wards in Lilongwe, Malawi, between 2011 and 2012, to evaluate causes of mortality, and the impact of HIV and ART status on mortality. We divided the study population into five categories: HIV-negative, new HIV positive, ART-naive patients, new ART-initiators, and ART-experienced. We used multivariate binomial regression models to compare risk of death between categories. RESULTS: Among 2911 admitted patients the mean age was 38.5 years, and 50% were women. Eighty-one percent (81%) of patients had a known HIV status at the time of discharge or death. Mortality was 19.4% and varied between 13.9% (HIV-negative patients) and 32.9% (HIV-positive patients on ART <=1 year). In multivariable analyses adjusted for age, sex and leading causes of mortality, being new HIV-positive (RR = 1.64 95% CI: 1.16-2.32), ART-naive (RR = 2.28 95% CI: 1.66-2.32) or being a new ART-initiator (RR = 2.41 95% CI: 1.85-3.14) were associated with elevated risk of mortality compared to HIV-negative patients. ART experienced patients had comparable mortality (RR = 1.33 95% CI: 0.94-1.88) to HIV-negative patients. CONCLUSION: HIV related mortality remains high among medical inpatients, especially among HIV-positive patients who recently initiated ART or have not started ART yet. PMID- 29415016 TI - Increase in suicides the months after the death of Robin Williams in the US. AB - Investigating suicides following the death of Robin Williams, a beloved actor and comedian, on August 11th, 2014, we used time-series analysis to estimate the expected number of suicides during the months following Williams' death. Monthly suicide count data in the US (1999-2015) were from the Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research (CDC WONDER). Expected suicides were calculated using a seasonal autoregressive integrated moving averages model to account for both the seasonal patterns and autoregression. Time-series models indicated that we would expect 16,849 suicides from August to December 2014; however, we observed 18,690 suicides in that period, suggesting an excess of 1,841 cases (9.85% increase). Although excess suicides were observed across gender and age groups, males and persons aged 30-44 had the greatest increase in excess suicide events. This study documents associations between Robin Williams' death and suicide deaths in the population thereafter. PMID- 29415017 TI - gDNA extraction yield and methylation status of blood samples are affected by long-term storage conditions. AB - Epigenetics is believed to provide great chances for a better understanding of the development and treatment of many diseases where the analysis of genomic DNA has so far failed to provide conclusive answers. Methylcytosine is a frequently used quantitative marker of epigenetic studies. Since immediate analysis of sampled material is in most cases not possible, storage time and conditions are critical aspects regarding the quality of genomic DNA and reliability of analysis. Blood is frequently used for such analyses. We, therefore, collected blood samples of ten volunteers and stored them under various conditions for ten months: -70 degrees C, -20 degrees C, 2-8 degrees C and room temperature. An additional aliquot was frozen at -70 degrees C and thawed once a week at room temperature. We then compared the DNA extraction yields and methylation status in relation to storage time and conditions. We found significantly lower DNA extraction yields (up to -97.45%; p <= 0.001) as well as significantly higher methylation levels after ten months of storage (up to +42.0%; p <= 0.001). These results suggest that storage time has an important influence on DNA analyses of blood samples for all storage conditions. This might be due to differences in stability of methylated and non-methylated DNA. Our study indicates that storage conditions and time may be a critical factor for epigenetic methylation studies and require rigorous validation. For reliable analyses we, therefore, recommend to perform epigenetic analysis directly after sample collection. PMID- 29415018 TI - Relationships between carbon fluxes and environmental factors in a drip irrigated, film-mulched cotton field in arid region. AB - Environmental factors and human activities play important roles in carbon fixation and emissions generated from croplands. Eddy covariance measurements in a drip-irrigated, film-mulched cotton field were used to analyze the relationships between carbon fluxes and environmental factors in Wulanwusu, northern Xinjiang, an arid region of Northwest China. Our results showed that the cumulative net carbon flux (NEE) was -304.8 g C m-2 (a strong sink) over the whole cotton growing season in 2012, which was more than that in cotton cropland without plastic film mulching and drip-irrigation. Moreover, when time is scaled up from a half-hour to a month, the correlations of gross primary production (GPP) to air temperature (Tair), net solar radiation (Rn) and soil water content (SWC) gradually become stronger due to ecosystem resistance and resilience as well as the protection of plastic film mulching. The GPP is more strongly correlated with Rn than Tair at time scales from minutes to days, while it reverses at time scales from days to weeks. This outcome is largely determined by the biochemical characteristics of photosynthesis. SWC and vapor pressure deficit (VPD) at all time scales are weakly correlated with GPP because plastic film mulching and regularly drip-irrigation allow soil to maintain sufficient water. PMID- 29415019 TI - Modeling convection-diffusion-reaction systems for microfluidic molecular communications with surface-based receivers in Internet of Bio-Nano Things. AB - We consider a microfluidic molecular communication (MC) system, where the concentration-encoded molecular messages are transported via fluid flow-induced convection and diffusion, and detected by a surface-based MC receiver with ligand receptors placed at the bottom of the microfluidic channel. The overall system is a convection-diffusion-reaction system that can only be solved by numerical methods, e.g., finite element analysis (FEA). However, analytical models are key for the information and communication technology (ICT), as they enable an optimisation framework to develop advanced communication techniques, such as optimum detection methods and reliable transmission schemes. In this direction, we develop an analytical model to approximate the expected time course of bound receptor concentration, i.e., the received signal used to decode the transmitted messages. The model obviates the need for computationally expensive numerical methods by capturing the nonlinearities caused by laminar flow resulting in parabolic velocity profile, and finite number of ligand receptors leading to receiver saturation. The model also captures the effects of reactive surface depletion layer resulting from the mass transport limitations and moving reaction boundary originated from the passage of finite-duration molecular concentration pulse over the receiver surface. Based on the proposed model, we derive closed form analytical expressions that approximate the received pulse width, pulse delay and pulse amplitude, which can be used to optimize the system from an ICT perspective. We evaluate the accuracy of the proposed model by comparing model based analytical results to the numerical results obtained by solving the exact system model with COMSOL Multiphysics. PMID- 29415021 TI - Exploratory palynological studies at the Tell el-Daba'a-Avaris archaeological site. AB - A palynological study of samples collected from the Tell el-Daba'a (Avaris) archaeological site, the capital of the Hyksos located in the Northeastern Nile Delta, Egypt, was conducted. A range of samples were analyzed for pollen content: mudbricks from tomb walls dating from the Middle (cal. 2124-1778 BC) and New Kingdom ages (cal. 1550-1750 BC), kitchen remains dating from the Middle Kingdom, kitchen middens from the 19th Dynasty (cal. 1750-1058 BC), and tomb offering jars from the Late Period (cal.1000-600 BC). Floristic composition of modern vegetation analysis at different habitats revealed four community types and nine associated types, providing an indicator of high soil salinity and moisture content. Cereal and Achillea-type pollen were common in the mudbrick samples, indicating the probable use of these plants as temper during mudbrick manufacturing in the Middle and New Kingdoms. The kitchen samples were dominated by cereals, broad bean, celery, and other weed pollen types, indicating the importance of cereals, legumes, and celery as strategic crops for food or medicines during the Middle Kingdom period. Weed pollen types were probably associated with crops, with "Cheno-am" pollen type recorded at highest abundance in the tomb filling jar, which may indicate the use of these aromatic herbs to repel insects and animals from tombs. PMID- 29415020 TI - The evolution of the epidemiological landscape of head and neck cancer in Italy: Is there evidence for an increase in the incidence of potentially HPV-related carcinomas? AB - The current study aimed to investigate the incidence and survival patterns of HNSCCs arising from different anatomic sites, potentially related (the oropharynx) or unrelated (the oral cavity, the larynx/hypopharynx) to HPV, to provide clues on possible growing impact of HPV in the epidemiology of HNSCC in Italy. Epidemiological data were retrieved from ten long-term Cancer Registries covering a population of 7.8 million inhabitants. Trends were described by means of the estimated annual percent change (APC) stratified by age and gender, and compared between HPV-related and HPV-unrelated anatomical sites. The data regarding 28,295 HNSCCs diagnosed in Italy between 1988 and 2012 were analyzed. In males, the incidence rate (IR) of cancers arising from sites unrelated to HPV infection significantly decreased in all age groups (APC:-3.31 for larynx/hypopharynx; APC:-1.77 for oral cavity), whereas stable IR were observed for cancers arising from sites related to HPV infection. In females, IR for cancers from HPV-related sites increased significantly over the observed period; the largest increment was noted in those over 60 (APC:2.92%) who also showed a significantly lower number of HNSCCs from the larynx/hypopharynx (APC:- 0.84) and a significantly higher number of oral cavity tumors (APC = 2.15). The five-year relative survival remained largely unchanged in the patients with laryngeal/hypopharyngeal SCC and, conversely, significantly improved in the patients with SCC at HPV-related sites. The trends observed suggest a potential increasing impact of HPV infection on the epidemiology of HNSCC in Italy, but to a lesser extent and with a different pattern from that observed in other Western countries. PMID- 29415023 TI - Short- and mid-wavelength artificial light influences the flash signals of Aquatica ficta fireflies (Coleoptera: Lampyridae). AB - Urbanization can radically disrupt natural ecosystems through alteration of the sensory environment. Habitat disturbances are predicted to favor behaviorally flexible species capable of adapting to altered environments. When artificial light at night (ALAN) is introduced into urban areas, it has the potential to impede reproduction of local firefly populations by obscuring their bioluminescent courtship signals. Whether individual fireflies can brighten their signals to maintain visibility against an illuminated background remains unknown. In this study, we exposed male Aquatica ficta fireflies to diffused light of varying wavelength and intensity, and recorded their alarm flash signals. When exposed to wavelengths at or below 533 nm, males emitted brighter signals with decreased frequency. This is the first evidence of individual-level light signal plasticity in fireflies. In contrast, long wavelength ambient light (>= 597 nm) did not affect signal morphology, likely because A. ficta cannot perceive these wavelengths. These results suggest long wavelength lighting is less likely to impact firefly courtship, and its use in place of broad spectrum white lighting could augment firefly conservation efforts. More generally, this study demonstrates benefits of bioluminescent signal plasticity in a "noisy" signaling environment, and sheds light on an important yet understudied consequence of urbanization. PMID- 29415022 TI - Rictor/TORC2 mediates gut-to-brain signaling in the regulation of phenotypic plasticity in C. elegans. AB - Animals integrate external cues with information about internal conditions such as metabolic state to execute the appropriate behavioral and developmental decisions. Information about food quality and quantity is assessed by the intestine and transmitted to modulate neuronal functions via mechanisms that are not fully understood. The conserved Target of Rapamycin complex 2 (TORC2) controls multiple processes in response to cellular stressors and growth factors. Here we show that TORC2 coordinates larval development and adult behaviors in response to environmental cues and feeding state in the bacterivorous nematode C. elegans. During development, pheromone, bacterial food, and temperature regulate expression of the daf-7 TGF-beta and daf-28 insulin-like peptide in sensory neurons to promote a binary decision between reproductive growth and entry into the alternate dauer larval stage. We find that TORC2 acts in the intestine to regulate neuronal expression of both daf-7 and daf-28, which together reflect bacterial-diet dependent feeding status, thus providing a mechanism for integration of food signals with external cues in the regulation of neuroendocrine gene expression. In the adult, TORC2 similarly acts in the intestine to modulate food-regulated foraging behaviors via a PDF-2/PDFR-1 neuropeptide signaling-dependent pathway. We also demonstrate that genetic variation affects food-dependent larval and adult phenotypes, and identify quantitative trait loci (QTL) associated with these traits. Together, these results suggest that TORC2 acts as a hub for communication of feeding state information from the gut to the brain, thereby contributing to modulation of neuronal function by internal state. PMID- 29415024 TI - Identifying evidence-practice gaps and strategies for improvement in Aboriginal and Torres Strait Islander maternal health care. AB - INTRODUCTION: Adverse pregnancy outcomes are more common among Aboriginal and Torres Strait Islander populations than non-Indigenous populations in Australia. Later in life, most of the difference in life expectancy between Aboriginal and Torres Strait Islander women and non-Indigenous women is due to non-communicable diseases (NCDs). Most Aboriginal and Torres Strait Islander women attend health services regularly during pregnancy. Providing high-quality care within these appointments has an important role to play in improving the current and future health of women and babies. AIM: This study engaged stakeholders in a theory informed process to use aggregated continuous quality improvement (CQI) data to identify 1) priority evidence-practice gaps in Aboriginal and Torres Strait Islander maternal health care, 2) barriers and enablers to high-quality care, and 3) strategies to address identified priorities. METHODS: Three phases of reporting and feedback were implemented using de-identified CQI data from 91 health services between 2007 and 2014 (4,402 client records). Stakeholders (n = 172) from a range of professions and organisations participated. RESULTS: Stakeholders identified four priority areas relating to NCDs: smoking, alcohol, psychosocial wellbeing and nutrition. Barriers or enablers to high-quality care included workforce support, professional development, teamwork, woman-centred care, decision support, equipment and community engagement. Strategies to address the priorities included upskilling staff to provide best practice care in priority areas, advocating for availability of healthy food, housing and local referral options, partnering with communities on health promotion projects, systems to facilitate continuity of care and clear referral pathways. CONCLUSIONS: This novel use of large-scale aggregate CQI data facilitated stakeholder input on priority evidence-practice gaps in maternal health care in Australia. Evidence-practice gaps relating to NCD risk factors and social determinants of health were prioritised, and stakeholders suggested both healthcare-focussed initiatives and approaches involving the community and the wider health sector. The findings can inform health service planning, advocacy, inter-agency strategies, and future research. PMID- 29415025 TI - Collecting standardised oral health data via mobile application: A proof of concept study in the Netherlands. AB - FDI World Dental Federation, founded as Federation Dentaire Internationale, has taken the initiative to develop the Oral Health Observatory, a mobile application to conduct oral health surveys worldwide. The aim is to collect reliable standardized international data on oral health and oral health care via a network of dentists. A proof of concept study project was set up in the Netherlands to test the methodology and to validate the approach. Data about caries, gingivitis, oral self-care and oral health related quality of life were analysed and compared to datasets validated in other studies. The Android app embeds three questionnaires addressing oral health history, status and patient behaviour. One questionnaire was completed by the patient and two by the dentist. The proof of concept study involved two phases: in the first phase, five dentists, regular participants in KNMT-surveys, evaluated the usability of the app; after the first phase, the app was adjusted for a second phase. For this phase an extra 15 dentists were recruited from a group of 20 other dentists: five of them declined to participate. Attention was paid to ensuring there was a proportional representation of gender, age and region. In the second phase the five first and 15 new participants collected data on up to a maximum of 38 patients. Data from this 653 patients correspond with results from previously published surveys on the prevalence of caries and gingivitis in the Netherlands. Hence demonstrating an association between caries and gingivitis with oral self-care, problems eating and experiencing oral pain. This proof of concept study shows that the app makes it possible to collect reliable information on oral health in a short period of time. Both dentists and patients evaluated the methodology as user-friendly. Altogether, the results of this proof of concept study are promising. PMID- 29415027 TI - Picornavirus 2A protease regulates stress granule formation to facilitate viral translation. AB - Stress granules (SGs) contain stalled messenger ribonucleoprotein complexes and are related to the regulation of mRNA translation. Picornavirus infection can interfere with the formation of SGs. However, the detailed molecular mechanisms and functions of picornavirus-mediated regulation of SG formation are not clear. Here, we found that the 2A protease of a picornavirus, EV71, induced atypical stress granule (aSG), but not typical stress granule (tSG), formation via cleavage of eIF4GI. Furthermore, 2A was required and sufficient to inhibit tSGs induced by EV71 infection, sodium arsenite, or heat shock. Infection of 2A protease activity-inactivated recombinant EV71 (EV71-2AC110S) failed to induce aSG formation and only induced tSG formation, which is PKR and eIF2alpha phosphorylation-dependent. By using a Renilla luciferase mRNA reporter system and RNA fluorescence in situ hybridization assay, we found that EV71-induced aSGs were beneficial to viral translation through sequestering only cellular mRNAs, but not viral mRNAs. In addition, we found that the 2A protease of other picornaviruses such as poliovirus and coxsackievirus also induced aSG formation and blocked tSG formation. Taken together, our results demonstrate that, on one hand, EV71 infection induces tSG formation via the PKR-eIF2alpha pathway, and on the other hand, 2A, but not 3C, blocks tSG formation. Instead, 2A induces aSG formation by cleaving eIF4GI to sequester cellular mRNA but release viral mRNA, thereby facilitating viral translation. PMID- 29415026 TI - Organoids with cancer stem cell-like properties secrete exosomes and HSP90 in a 3D nanoenvironment. AB - Ability to form cellular aggregations such as tumorspheres and spheroids have been used as a morphological marker of malignant cancer cells and in particular cancer stem cells (CSC). However, the common definition of the types of cellular aggregation formed by cancer cells has not been available. We examined morphologies of 67 cell lines cultured on three dimensional morphology enhancing NanoCulture Plates (NCP) and classified the types of cellular aggregates that form. Among the 67 cell lines, 49 cell lines formed spheres or spheroids, 8 cell lines formed grape-like aggregation (GLA), 8 cell lines formed other types of aggregation, and 3 cell lines formed monolayer sheets. Seven GLA-forming cell lines were derived from adenocarcinoma among the 8 lines. A neuroendocrine adenocarcinoma cell line PC-3 formed asymmetric GLA with ductal structures on the NCPs and rapidly growing asymmetric tumors that metastasized to lymph nodes in immunocompromised mice. In contrast, another adenocarcinoma cell line DU-145 formed spheroids in vitro and spheroid-like tumors in vivo that did not metastasize to lymph nodes until day 50 after transplantation. Culture in the 3D nanoenvironment and in a defined stem cell medium enabled the neuroendocrine adenocarcinoma cells to form slowly growing large organoids that expressed multiple stem cell markers, neuroendocrine markers, intercellular adhesion molecules, and oncogenes in vitro. In contrast, the more commonly used 2D serum contained environment reduced intercellular adhesion and induced mesenchymal transition and promoted rapid growth of the cells. In addition, the 3D stemness nanoenvironment promoted secretion of HSP90 and EpCAM-exosomes, a marker of CSC phenotype, from the neuroendocrine organoids. These findings indicate that the NCP-based 3D environment enables cells to form stem cell tumoroids with multipotency and model more accurately the in vivo tumor status at the levels of morphology and gene expression. PMID- 29415029 TI - Rates and risk factors for human cutaneous anthrax in the country of Georgia: National surveillance data, 2008-2015. AB - INTRODUCTION: Anthrax is endemic in the country of Georgia. The most common cutaneous anthrax form accounts for 95% of anthrax cases and often is self resolving. Humans are infected from processing contaminated animal products, contacting sick animals, or by insect bites. OBJECTIVE: We aimed to describe the burden of human cutaneous anthrax and associated risk factors using the national surveillance data. METHODS: We extracted all human cutaneous anthrax cases from Electronic Integrated Disease Surveillance System (EIDSS) from 1 January 2008 to 31 December 2015. We conducted descriptive analyses to characterize the number of confirmed, probable and suspected cases by age groups, gender, ethnicity, year and geographic area. RESULTS: Out of 911 reported cutaneous anthrax cases, 299 (33%) were rejected. Out of remaining 612 cases, 437 (71%), 172 (28%), and 3 (<0.004%) were classified as confirmed, probable and suspected cases of cutaneous Anthrax, respectively; 467 (76.3%) were male. Georgians accounted for 56% (343/612) of cutaneous anthrax cases. Handling animal products (aOR 4.36, 95% CI 2.61-7.26) and living near pastoralist routes (aOR 2.74, 95%CI 1.57-4.76) were associated with cutaneous anthrax. CONCLUSIONS: This study provides eight-year trends for cutaneous anthrax in humans in the country of Georgia. A comprehensive explanation for the observed rise and fall of the incidence rates of human cutaneous anthrax in 2008-2015 remains to be clarified but is likely associated with discontinuation of mandatory national livestock vaccination in 2008 coupled with weakened human and animal national health systems which were disrupted after the Soviet Union collapsed. Our analysis identifies living near pastoralist routes, handling animal products and travel to endemic areas within two weeks before the disease onset as risk factors for cutaneous anthrax. The evidence underscores the importance of One Health recommendations to activate anthrax awareness campaigns, supervise the destruction of known anthrax carcasses, record global position system coordinates of sites and disinfect infected soils and introduce a participatory health education tool on anthrax. PMID- 29415028 TI - Polymicrobial sepsis and non-specific immunization induce adaptive immunosuppression to a similar degree. AB - Sepsis is frequently complicated by a state of profound immunosuppression, in its extreme form known as immunoparalysis. We have studied the role of the adaptive immune system in the murine acute peritonitis model. To read out adaptive immunosuppression, we primed post-septic and control animals by immunization with the model antigen TNP-ovalbumin in alum, and measured the specific antibody responses via ELISA and ELISpot assay as well as T-cell responses in a proliferation assay after restimulation. Specific antibody titers, antibody affinity and plasma cell counts in the bone marrow were reduced in post-septic animals. The antigen-induced splenic proliferation was also impaired. The adaptive immunosuppression was positively correlated with an overwhelming general antibody response to the septic insult. Remarkably, antigen "overload" by non specific immunization induced a similar degree of adaptive immunosuppression in the absence of sepsis. In both settings, depletion of regulatory T cells before priming reversed some parameters of the immunosuppression. In conclusion, our data show that adaptive immunosuppression occurs independent of profound systemic inflammation and life-threatening illness. PMID- 29415030 TI - Religiosity prevalence and its association with depression and anxiety symptoms among Hispanic/Latino adults. AB - OBJECTIVES: Religion plays an important role in the lives of people in the United States. We examined the prevalence of religiosity among Hispanic/Latinos in four regions of the United States and looked at its correlation to depression and anxiety symptoms. DESIGN: The population-based Hispanic Community Health Study/ Study of Latinos enrolled a cohort of Hispanic/Latino adults (N = 16,415) ages 18 74 in four US cities from June 2008 to June 2011. Participants with complete data on religiosity (i.e., religious affiliation, frequency of attending religious activities and importance of religion), depression (assessed with the CESD-10), and trait anxiety (assessed with the STAI-10) were included in the present study. Distribution of religiosity is described by sociodemographic characteristics. Associations between religiosity with depression and anxiety were examined with logistic regression models controlling for sex, age group, education, Hispanic/Latino background, clinical center, and nativity. RESULTS: The majority of the population (89.5%) reported having a religious affiliation. Weekly attendance at religious activities was reported by 41.6% of participants, while 20.6% did not attend any religious activities. Religion was very important to 63.9% and not at all important to 6.7% of the population. The CES-D scores and trait anxiety scores were not significantly related in the overall group to frequency of attending religious activity or perceived importance of religion. However, in age-stratified analyses, among older individuals (65+ years old) reporting "never" participating in religious activities compared to more than once per week was associated with an 80% higher likelihood of having high depressive symptomatology. Similarly, in the older age group, no religious affiliation or reporting that religion is "not at all important" was associated with greater anxiety symptomatology. CONCLUSION: Religiosity varied by Hispanic/Latino background. Lack of religiosity was associated with elevated depressive or anxiety symptomology in older adults but not in young or middle aged adults. PMID- 29415031 TI - The genetic tale of a recovering lion population (Panthera leo) in the Save Valley region (Zimbabwe): A better understanding of the history and managing the future. AB - The rapid decline of the African lion (Panthera leo) has raised conservation concerns. In the Save Valley Conservancy (SVC), in the Lowveld of Zimbabwe, lions were presumably reduced to approximately 5 to 10 individuals. After ten lions were reintroduced in 2005, the population has recovered to over 200 lions in 2016. Although the increase of lions in the SVC seems promising, a question remains whether the population is genetically viable, considering their small founding population. In this study, we document the genetic diversity in the SVC lion population using both mitochondrial and nuclear genetic markers, and compare our results to literature from other lion populations across Africa. We also tested whether genetic diversity is spatially structured between lion populations residing on several reserves in the Lowveld of Zimbabwe. A total of 42 lions were genotyped successfully for 11 microsatellite loci. We confirmed that the loss of allelic richness (probably resulting from genetic drift and small number of founders) has resulted in low genetic diversity and inbreeding. The SVC lion population was also found to be genetically differentiated from surrounding population, as a result of genetic drift and restricted natural dispersal due to anthropogenic barriers. From a conservation perspective, it is important to avoid further loss of genetic variability in the SVC lion population and maintain evolutionary potential required for future survival. Genetic restoration through the introduction of unrelated individuals is recommended, as this will increase genetic heterozygosity and improve survival and reproductive fitness in populations. PMID- 29415032 TI - Mechanical and phytochemical protection mechanisms of Calligonum comosum in arid deserts. AB - Unlike animals, plants are sessile organisms, lacking circulating antibodies and specialized immune cells and are exposed to various harsh environmental conditions that make them at risk of being attacked by different pathogens and herbivores. Plants produce chemo-signals to respond to the surroundings and be able to distinguish between harmless and harmful signals. In this study, the production of phytochemicals as plant signaling mechanisms and their defensive roles in disease resistance and repelling herbivores are examined in Calligonum comosum. C. comosum is a leafless standalone perennial shrub widespread in sand dunes. The plant has the ability to survive the drastic environmental conditions of the arid/ hyperarid deserts of the Arabia. Structural anatomy and phytochemicals analyses were used to identify both mechanical and chemical defensive mechanisms in C. comosum. Microscopy-based investigations indicated that stems of this species developed hard structures in its outer layers including sclerenchyma and cluster crystals of calcium oxalate (CaOx). Sclerenchyma and CaOx are difficult to be eaten by herbivores and insects and can harm their mouthparts. On the other hand, the plant developed both short-distance (local) and long-distance (systematic over limited sphere) phytochemicals producing cells located at its outer regions that is surrounding the inner nutrient-rich vascular system (VS). Local chemical was represented by phenolic idioblasts that were released in response to plant cutting. Systematic chemical was represented by toxic volatile oil containing ~50% benzaldehyde derivative (cuminaldehyde). The oil caused strong killing effect on both mammalian cells and microbial pathogens via either direct addition or indirect exposure to its vapor. The plants lost the oil content and allowed fungal growth once cut and dried. The localization of both defensive mechanisms to the outer region of the plant seemed to protect the inner nutrient-rich VS and hence maintained the plant survival. Surprisingly, in relation to traditional folklore use as medicine, local people use only green parts of the plant and only during the winter, where the plant found devoid of volatile oil and phenolic idioblasts. Moreover, it turns into recommendations for local people to avoid any health problems caused by the plant supply. PMID- 29415034 TI - Molecular characterization of the recombinant protein RmLTI-BmCG-LTB: Protective immunity against Rhipicephalus (Boophilus) microplus. AB - The bovine tick Rhipicephalus (Boophilus) microplus is found in several tropical and subtropical regions of the world. This parasite transmits pathogens that cause disease, such as babesiosis (Babesia bovis and B. bigemina) and anaplasmosis (Anaplasma marginale). Tick infestations cause enormous livestock losses, and controlling tick infestations and the transmission of tick-borne diseases remains a challenge for the livestock industry. Because the currently available commercial vaccines offer only partial protection against R. (B.) microplus, there is a need for more efficient vaccines. Several recombinant antigens have been evaluated using different immunization strategies, and they show great promise. This work describes the construction and immunological characterization of a multi-antigen chimera composed of two R. (B.) microplus antigens (RmLTI and BmCG) and one Escherichia coli antigen (B subunit, LTB). The immunogenic regions of each antigen were selected and combined to encode a single polypeptide. The gene was cloned and expressed in E. coli. For all of the experiments, two groups (treated and control) of four Angus heifers (3-6 months old) were used. The inoculation was performed via intramuscular injection with 200 MUg of purified recombinant chimeric protein and adjuvated. The chimeric protein was recognized by specific antibodies against each subunit and by sera from cattle inoculated with the chimera. Immunization of RmLTI-BmCG-LTB cattle reduced the number of adult female ticks by 6.29% and vaccination of cattle with the chimeric antigen provided 55.6% efficacy against R. (B.) microplus infestation. The results of this study indicate that the novel chimeric protein is a potential candidate for the future development of a more effective vaccine against R. (B.) microplus. PMID- 29415033 TI - Theta rhythm-like bidirectional cycling dynamics of living neuronal networks in vitro. AB - The phenomena of synchronization, rhythmogenesis and coherence observed in brain networks are believed to be a dynamic substrate for cognitive functions such as learning and memory. However, researchers are still debating whether the rhythmic activity emerges from the network morphology that developed during neurogenesis or as a result of neuronal dynamics achieved under certain conditions. In the present study, we observed self-organized spiking activity that converged to long, complex and rhythmically repeated superbursts in neural networks formed by mature hippocampal cultures with a high cellular density. The superburst lasted for tens of seconds and consisted of hundreds of short (50-100 ms) small bursts with a high spiking rate of 139.0 +/- 78.6 Hz that is associated with high frequency oscillations in the hippocampus. In turn, the bursting frequency represents a theta rhythm (11.2 +/- 1.5 Hz). The distribution of spikes within the bursts was non-random, representing a set of well-defined spatio-temporal base patterns or motifs. The long superburst was classified into two types. Each type was associated with a unique direction of spike propagation and, hence, was encoded by a binary sequence with random switching between the two "functional" states. The precisely structured bidirectional rhythmic activity that developed in self-organizing cultured networks was quite similar to the activity observed in the in vivo experiments. PMID- 29415035 TI - Predicting outcome of Morris water maze test in vascular dementia mouse model with deep learning. AB - The Morris water maze test (MWM) is one of the most popular and established behavioral tests to evaluate rodents' spatial learning ability. The conventional training period is around 5 days, but there is no clear evidence or guidelines about the appropriate duration. In many cases, the final outcome of the MWM seems predicable from previous data and their trend. So, we assumed that if we can predict the final result with high accuracy, the experimental period could be shortened and the burden on testers reduced. An artificial neural network (ANN) is a useful modeling method for datasets that enables us to obtain an accurate mathematical model. Therefore, we constructed an ANN system to estimate the final outcome in MWM from the previously obtained 4 days of data in both normal mice and vascular dementia model mice. Ten-week-old male C57B1/6 mice (wild type, WT) were subjected to bilateral common carotid artery stenosis (WT-BCAS) or sham operation (WT-sham). At 6 weeks after surgery, we evaluated their cognitive function with MWM. Mean escape latency was significantly longer in WT-BCAS than in WT-sham. All data were collected and used as training data and test data for the ANN system. We defined a multiple layer perceptron (MLP) as a prediction model using an open source framework for deep learning, Chainer. After a certain number of updates, we compared the predicted values and actual measured values with test data. A significant correlation coefficient was derived form the updated ANN model in both WT-sham and WT-BCAS. Next, we analyzed the predictive capability of human testers with the same datasets. There was no significant difference in the prediction accuracy between human testers and ANN models in both WT-sham and WT-BCAS. In conclusion, deep learning method with ANN could predict the final outcome in MWM from 4 days of data with high predictive accuracy in a vascular dementia model. PMID- 29415036 TI - The association between obesity and dengue severity among pediatric patients: A systematic review and meta-analysis. AB - BACKGROUND: Severe dengue infection often has unpredictable clinical progressions and outcomes. Obesity may play a role in the deterioration of dengue infection due to stronger body immune responses. Several studies found that obese dengue patients have a more severe presentation with a poorer prognosis. However, the association was inconclusive due to the variation in the results of earlier studies. Therefore, we conducted a systematic review and meta-analysis to explore the relationship between obesity and dengue severity. METHODS: We performed a systematic search of relevant studies on Ovid (MEDLINE), EMBASE, the Cochrane Library, Web of Science, Scopus and grey literature databases. At least two authors independently conducted the literature search, selecting eligible studies, and extracting data. Meta-analysis using random-effects model was conducted to compute the pooled odds ratio with 95% confidence intervals (CI). FINDINGS: We obtained a total of 13,333 articles from the searches. For the final analysis, we included a total of fifteen studies among pediatric patients. Three cohort studies, two case-control studies, and one cross-sectional study found an association between obesity and dengue severity. In contrast, six cohort studies and three case-control studies found no significant relationship between obesity and dengue severity. Our meta-analysis revealed that there was 38 percent higher odds (Odds Ratio = 1.38; 95% CI:1.10, 1.73) of developing severe dengue infection among obese children compared to non-obese children. We found no heterogeneity found between studies. The differences in obesity classification, study quality, and study design do not modify the association between obesity and dengue severity. CONCLUSION: This review found that obesity is a risk factor for dengue severity among children. The result highlights and improves our understanding that obesity might influence the severity of dengue infection. PMID- 29415037 TI - Exploring chronic disease in Bolivia: A cross-sectional study in La Paz. AB - PURPOSE: This study seeks to develop an understanding that can guide development of programs to improve health and care for individuals with Non-Communicable Diseases (NCDs) in La Paz, Bolivia, where NCDs are prevalent and primary care systems are weak. This exploratory investigation examines the characteristics of chronic disease patients in the region, key health related behaviors, and their perceptions of the care that they receive. The longer-term goal is to lay groundwork for interventional studies based on the principles of the Chronic Care Model (CCM). SUBJECTS AND METHODS: The study is based on two surveys of adults (> 18 years old) administered in 2014 in La Paz, Bolivia. A total of 1165 adult patients participated in the first screening survey. A post-screening second survey, administered only on those who qualified based on Survey 1, collected more detailed information about the subjects' general health and health related personal circumstances, several health behaviors, health literacy, and their perceptions of care received. A final data set of 651 merged records were used for analysis. RESULTS: Characteristic of a low-income country, the majority of participants had low levels of education, income, health literacy and high rates of under/unemployment. Nearly 50% of participants reported 2 or more NCDs. Seventy-four percent (74%) of respondents reported low levels of medication adherence and 26% of the population was found to have an undiagnosed depressive disorder. Overall, the perception of care quality was low (60%), particularly in those under the age of 45. Significant relationships emerged between several sociodemographic characteristics, health behaviors, and perceptions that have major implications for improving NCD care in this population. CONCLUSIONS: These findings illustrate some of the challenges facing low-income countries where reversing the tide of NCDs is of great importance. The prevalence of NCDs coupled with challenging social determinants of health, poor medication adherence, low health literacy, and perceptions of low quality of healthcare highlight several areas of opportunity for intervention. PMID- 29415038 TI - BACHD rats expressing full-length mutant huntingtin exhibit differences in social behavior compared to wild-type littermates. AB - BACKGROUND: Huntington disease (HD) is a devastating inherited neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms without any cure to slow down or stop the progress of the disease. The BACHD rat model for HD carrying the human full-length mutant huntingtin protein (mHTT) with 97 polyQ repeats has been recently established as a promising model which reproduces several HD-like features. While motor and cognitive functions have been characterized in BACHD rats, little is known about their social phenotype. OBJECTIVE: This study focuses especially on social behavior since evidence for social disturbances exists in human patients. Our objective was to compare social behavior in BACHD and wild-type (WT) rats at different ages, using two different measures of sociability. METHODS: Animals were tested longitudinally at the age of 2, 4 and 8 months in the social interaction test to examine different parameters of sociability. A separate cohort of 7 month old rats was tested in the three chamber social test to measure both sociability and social novelty. Gene expression analyses in 8 months old animals were performed by real time qRT PCR to evaluate a potential involvement of D1 and D2 dopaminergic receptors and the contribution of Brain-derived neurotrophic factor (BDNF) to the observed behavioral alterations. RESULTS: In the social interaction test, BACHD rats showed age-dependent changes in behaviour when they were-re introduced to their cagemate after a 24 hours-period of individual housing. The time spent on nape attacks increased with aging. Furthermore, a significant higher level of pinning at 2 months of age was shown in the BACHD rats compared to wild-types, followed by a reduction at 4 and 8 months. On the other hand, BACHD rats exhibited a decreased active social behaviour compared to wild-types, reflected by genotype effects on approaching, following and social nose contact. In the three chamber social test, BACHD rats seemed to show a mild deficit in preference for social novelty, but no changes in social interest. Molecular analyses revealed that BACHD animals exposed to the social interaction test displayed decreased mRNA levels of the total form of BDNF in ventral striatum and unaltered striatal expression of D1 and D2 dopamine receptors. CONCLUSIONS: Taken together, these results indicate deficits in several parameters representative of sociability. Altered BDNF expression in the ventral striatum may contribute to the deficits in sociability in 8 months old BACHD rats. These data support the validity of the BACHD rat model in mimicking features of certain social deficits that could be relevant to symptoms in patients. PMID- 29415039 TI - Discovery of a diverse cave flora in China. AB - Few studies document plants in caves. Our field observations of a widespread and seemingly angiosperm-rich cave flora in SW China lead us to test the following hypotheses, 1) SW China caves contain a diverse vascular plant flora, 2) that this is a relic of a largely absent forest type lacking endemic species, and 3) that the light environment plants occupy in caves is not distinct from non-cave habitats. To do so we surveyed 61 caves and used species accumulation curves (SAC) to estimate the total diversity of this flora and used a subsample of 14 caves to characterise the light environment. We used regional floras and existing conservation assessments to evaluate the conservation value of this flora. We used observations on human disturbance within caves to evaluate anthropogenic activities. Four-hundred-and-eighteen vascular plant species were documented with SACs predicting a total diversity of 529-846. Ninety-three percent of the species documented are known karst forest species, 7% are endemic to caves and 81% of the species are angiosperms. We demonstrate that the light environment in caves is distinct to that of terrestrial habitats and that a subset of the flora likely grow in the lowest light levels documented for vascularised plants. Our results suggest that the proportion of species threatened with extinction is like that for the terrestrial habitat and that almost half of the entrance caverns sampled showed signs of human disturbance. We believe that this is the first time that such an extensive sample of cave flora has been undertaken and that such a diverse vascular plant flora has been observed in caves which we predict occurs elsewhere in SE Asia. We argue that the cave flora is an extension of the karst forest understory present prior to catastrophic deforestation in the 20thC. We suggest that within SW China caves serve as both refuges and a valuable source of germplasm for the restoration of karst forest. We also propose that caves represent a distinct habitat for plants that is most similar to that of the forest understory, but distinct with respect to the absence of trees, leaf litter, root mats, higher levels of atmospheric CO2, and lower diurnal and annual variation in temperature and humidity. We highlight tourism, agriculture and the absence of legislated protection of caves as the main current threats to this flora. PMID- 29415040 TI - The role of family size, employment and education of parents in the prevalence of intestinal parasitic infections in school children in Accra. AB - INTRODUCTION: Intestinal parasitic infections (IPIs) in school children are a public health problem in most developing countries. METHODS AND PRINCIPAL FINDINGS: A cross sectional survey was conducted from May to July 2016 with school children living in overcrowded urban slums in Accra, Ghana. A simple random sample of 300 children aged 2-9 years was collected. The study used structured pre-tested questionnaire and stool tests to obtain information on epidemiological, sanitation habits, employment and education status of parents and children. Data were analysed using appropriate descriptive, univariate and multivariable logistic tools of analyses. The mean age of participants was 6.9 years and 49% were males and 51.3% were females. Giardia lamblia was found in males (10.95%) and females (7.79%). Very low prevalences for Schistosoma mansoni, Ascaris lumbricoides, Taenia species, and Entamoeba coli were detected. Whilst children from mothers (62.2%) and fathers (55.6%) with no education were often infected, a few children from fathers (22.2%) and mothers (6.7%) with no jobs were infected. Most of the infected children's (93.7%) parents did not have any knowledge of IPIs. The educational and employment status of the mothers [p = 1.0 and p = 0.422] was not significant, however, the family size was a predisposing factor (p = 0.031) for parasitic infections. CONCLUSIONS: Intestinal parasites were prevalent in children from overcrowded families and with no knowledge of IPIs. Educative programmes on IPIs, improving hygiene, and application of supportive programmes to elevate socioeconomic conditions may help reduce the burden of intestinal parasite carriage in children. PMID- 29415041 TI - full-FORCE: A target-based method for training recurrent networks. AB - Trained recurrent networks are powerful tools for modeling dynamic neural computations. We present a target-based method for modifying the full connectivity matrix of a recurrent network to train it to perform tasks involving temporally complex input/output transformations. The method introduces a second network during training to provide suitable "target" dynamics useful for performing the task. Because it exploits the full recurrent connectivity, the method produces networks that perform tasks with fewer neurons and greater noise robustness than traditional least-squares (FORCE) approaches. In addition, we show how introducing additional input signals into the target-generating network, which act as task hints, greatly extends the range of tasks that can be learned and provides control over the complexity and nature of the dynamics of the trained, task-performing network. PMID- 29415043 TI - Empirical evidence that metabolic theory describes the temperature dependency of within-host parasite dynamics. AB - The complexity of host-parasite interactions makes it difficult to predict how host-parasite systems will respond to climate change. In particular, host and parasite traits such as survival and virulence may have distinct temperature dependencies that must be integrated into models of disease dynamics. Using experimental data from Daphnia magna and a microsporidian parasite, we fitted a mechanistic model of the within-host parasite population dynamics. Model parameters comprising host aging and mortality, as well as parasite growth, virulence, and equilibrium abundance, were specified by relationships arising from the metabolic theory of ecology. The model effectively predicts host survival, parasite growth, and the cost of infection across temperature while using less than half the parameters compared to modeling temperatures discretely. Our results serve as a proof of concept that linking simple metabolic models with a mechanistic host-parasite framework can be used to predict temperature responses of parasite population dynamics at the within-host level. PMID- 29415042 TI - Comparing autotransporter beta-domain configurations for their capacity to secrete heterologous proteins to the cell surface. AB - Monomeric autotransporters have been extensively used for export of recombinant proteins to the cell surface of Gram-negative bacteria. A bottleneck in the biosynthesis of such constructs is the passage of the outer membrane, which is facilitated by the beta-domain at the C terminus of an autotransporter in conjunction with the Bam complex in the outer membrane. We have evaluated eight beta-domain constructs for their capacity to secrete fused proteins to the cell surface. These constructs derive from the monomeric autotransporters Hbp, IgA protease, Ag43 and EstA and the trimeric autotransporter Hia, which all were selected because they have been previously used for secretion of recombinant proteins. We fused three different protein domains to the eight beta-domain constructs, being a Myc-tag, the Hbp passenger and a nanobody or VHH domain, and assessed expression, membrane insertion and surface exposure. Our results show that expression levels differed considerably between the constructs tested. The constructs that included the beta-domains of Hbp and IgA protease appeared the most efficient and resulted in expression levels that were detectable on Coomassie-stained SDS-PAGE gels. The VHH domain appeared the most difficult fusion partner to export, probably due to its complex immunoglobulin-like structure with a tertiary structure stabilized by an intramolecular disulfide bond. Overall, the Hbp beta-domain compared favorably in exporting the fused recombinant proteins, because it showed in every instance tested a good level of expression, stable membrane insertion and clear surface exposure. PMID- 29415044 TI - A computational approach to distinguish somatic vs. germline origin of genomic alterations from deep sequencing of cancer specimens without a matched normal. AB - A key constraint in genomic testing in oncology is that matched normal specimens are not commonly obtained in clinical practice. Thus, while well-characterized genomic alterations do not require normal tissue for interpretation, a significant number of alterations will be unknown in whether they are germline or somatic, in the absence of a matched normal control. We introduce SGZ (somatic germline-zygosity), a computational method for predicting somatic vs. germline origin and homozygous vs. heterozygous or sub-clonal state of variants identified from deep massively parallel sequencing (MPS) of cancer specimens. The method does not require a patient matched normal control, enabling broad application in clinical research. SGZ predicts the somatic vs. germline status of each alteration identified by modeling the alteration's allele frequency (AF), taking into account the tumor content, tumor ploidy, and the local copy number. Accuracy of the prediction depends on the depth of sequencing and copy number model fit, which are achieved in our clinical assay by sequencing to high depth (>500x) using MPS, covering 394 cancer-related genes and over 3,500 genome-wide single nucleotide polymorphisms (SNPs). Calls are made using a statistic based on read depth and local variability of SNP AF. To validate the method, we first evaluated performance on samples from 30 lung and colon cancer patients, where we sequenced tumors and matched normal tissue. We examined predictions for 17 somatic hotspot mutations and 20 common germline SNPs in 20,182 clinical cancer specimens. To assess the impact of stromal admixture, we examined three cell lines, which were titrated with their matched normal to six levels (10-75%). Overall, predictions were made in 85% of cases, with 95-99% of variants predicted correctly, a significantly superior performance compared to a basic approach based on AF alone. We then applied the SGZ method to the COSMIC database of known somatic variants in cancer and found >50 that are in fact more likely to be germline. PMID- 29415045 TI - Linear programming model can explain respiration of fermentation products. AB - Many differentiated cells rely primarily on mitochondrial oxidative phosphorylation for generating energy in the form of ATP needed for cellular metabolism. In contrast most tumor cells instead rely on aerobic glycolysis leading to lactate to about the same extent as on respiration. Warburg found that cancer cells to support oxidative phosphorylation, tend to ferment glucose or other energy source into lactate even in the presence of sufficient oxygen, which is an inefficient way to generate ATP. This effect also occurs in striated muscle cells, activated lymphocytes and microglia, endothelial cells and several mammalian cell types, a phenomenon termed the "Warburg effect". The effect is paradoxical at first glance because the ATP production rate of aerobic glycolysis is much slower than that of respiration and the energy demands are better to be met by pure oxidative phosphorylation. We tackle this question by building a minimal model including three combined reactions. The new aspect in extension to earlier models is that we take into account the possible uptake and oxidation of the fermentation products. We examine the case where the cell can allocate protein on several enzymes in a varying distribution and model this by a linear programming problem in which the objective is to maximize the ATP production rate under different combinations of constraints on enzymes. Depending on the cost of reactions and limitation of the substrates, this leads to pure respiration, pure fermentation, and a mixture of respiration and fermentation. The model predicts that fermentation products are only oxidized when glucose is scarce or its uptake is severely limited. PMID- 29415046 TI - The application of rumen simulation technique (RUSITEC) for studying dynamics of the bacterial community and metabolome in rumen fluid and the effects of a challenge with Clostridium perfringens. AB - The rumen simulation technique (RUSITEC) is a well-established semicontinuous in vitro model for investigating ruminal fermentation; however, information on the stability of the ruminal bacterial microbiota and metabolome in the RUSITEC system is rarely available. The availability of high resolution methods, such as high-throughput sequencing and metabolomics improve our knowledge about the rumen microbial ecosystem and its fermentation processes. Thus, we used Illumina MiSeq 16S rRNA amplicon sequencing and a combination of direct injection mass spectrometry with a reverse-phase LC-MS/MS to evaluate the dynamics of the bacterial community and the concentration of several metabolites in a RUSITEC experiment as a function of time and in response to a challenge with a pathogenic Clostridium perfringens (C. perfringens) strain. After four days of equilibration, samples were collected on days 5, 6, 7, 10, 12 and 15 of the steady-state and experimental period. From a total of six fermenters, three non infected fermenters were used for investigating time-dependent alterations; three fermenters were incubated with C. perfringens and compared with the non-infected vessels at days 10, 12 and 15. Along the time-line, there was no statistically significant change of the overall bacterial community, however, some phylotypes were enriched at certain time points. A decrease in Fibrobacter and Elusimicrobia over time was followed by an increase in Firmicutes and Actinobacteria. In contrast, classical fermentation measurements such as pH, redox potential, NH3-N, short chain fatty acids and the concentrations of metabolites determined by metabolomics (biogenic amines, hexoses and amino acids) remained stable throughout the experiment. In response to C. perfringens addition the concentrations of several amino acids increased. Although the overall bacterial community was not altered here either, some minor changes such as an enrichment of Synergistetes and Bacteroidetes were detectable over time. In conclusion, both, the bacterial community composition and the metabolome in the RUSITEC system were relatively stable during the experiment. PMID- 29415047 TI - Does engagement predict research use? An analysis of The Conversation Annual Survey 2016. AB - The impact of research on the world beyond academia has increasingly become an area of focus in research performance assessments internationally. Impact assessment is expected to incentivise researchers to increase engagement with industry, government and the public more broadly. Increased engagement is in turn expected to increase translation of research so decision-makers can use research to inform development of policies, programs, practices, processes, products, and other mechanisms, through which impact can be realised. However, research has shown that various factors affect research use, and evidence on 'what works' to increase decision-makers' use of research is limited. The Conversation is an open access research communication platform, published under Creative Commons licence, which translates research into news articles to engage a general audience, aiming to improve understanding of current issues and complex social problems. To identify factors that predict use of academic research and expertise reported in The Conversation, regression analyses were performed using The Conversation Australia 2016 Annual Survey data. A broad range of factors predicted use, with engagement actions being the most common. Interestingly, different types of engagement actions predicted different types of use. This suggests that to achieve impact through increased engagement, a deeper understanding of how and why different engagement actions elicit different types of use is needed. Findings also indicate The Conversation is overcoming some of the most commonly identified barriers to the use of research: access, relevance, actionable outcomes, and timeliness. As such, The Conversation offers an effective model for providing access to and communicating research in a way that enables use, a necessary precursor to achieving research impact. PMID- 29415048 TI - Phosphate is a potential biomarker of disease severity and predicts adverse outcomes in acute kidney injury patients undergoing continuous renal replacement therapy. AB - Hyperphosphatemia is associated with mortality in patients with chronic kidney disease, and is common in critically ill patients with acute kidney injury (AKI); however, its clinical implication in these patients is unknown. We conducted an observational study in 1144 patients (mean age, 63.2 years; male, 705 [61.6%]) with AKI who received continuous renal replacement therapy (CRRT) between January 2009 and September 2016. Phosphate levels were measured before (0 h) and 24 h after CRRT initiation. We assessed disease severity using various clinical parameters. Phosphate at 0 h positively correlated with the Acute Physiology and Chronic Health Evaluation II (APACHE II; P < 0.001) and Sequential Organ Failure Assessment (SOFA; P < 0.001) scores, and inversely with mean arterial pressure (MAP; P = 0.02) and urine output (UO; P = 0.01). In a fully adjusted linear regression analysis for age, sex, Charlson comorbidity index (CCI), MAP, and estimated glomerular filtration rate (eGFR), higher 0 h phosphate level was significantly associated with high APACHE II (P < 0.001) and SOFA (P = 0.04) scores, suggesting that phosphate represents disease severity. A multivariable Cox model also showed that hyperphosphatemia was significantly associated with increased 28-day (HR 1.05, 95% CI 1.02-1.08, P = 0.001) and 90-day (HR 1.05, 95% CI 1.02-1.08, P = 0.001) mortality. Furthermore, patients with increased phosphate level during 24 h were at higher risk of death than those with stable or decreased phosphate levels. Finally, c-statistics significantly increased when phosphate was added to a model that included age, sex, CCI, body mass index, eGFR, MAP, hemoglobin, serum albumin, C-reactive protein, and APACHE II score. This study shows that phosphate is a potential biomarker that can reflect disease severity and predict mortality in critically ill patients receiving CRRT. PMID- 29415049 TI - Characterization of inorganic phosphate transport in the triple-negative breast cancer cell line, MDA-MB-231. AB - BACKGROUND: Recent studies demonstrate that interstitial inorganic phosphate is significantly elevated in the breast cancer microenvironment as compared to normal tissue. In addition it has been shown that breast cancer cells express high levels of the NaPi-IIb carrier (SLC34A2), suggesting that this carrier may play a role in breast cancer progression. However, the biochemical behavior of inorganic phosphate (Pi) transporter in this cancer type remains elusive. METHODS: In this work, we characterize the kinetic parameters of Pi transport in the aggressive human breast cancer cell line, MDA-MB-231, and correlated Pi transport with cell migration and adhesion. RESULTS: We determined the influence of sodium concentration, pH, metabolic inhibitors, as well as the affinity for inorganic phosphate in Pi transport. We observed that the inorganic phosphate is dependent on sodium transport (K0,5 value = 21.98 mM for NaCl). Furthermore, the transport is modulated by different pH values and increasing concentrations of Pi, following the Michaelis-Menten kinetics (K0,5 = 0.08 mM Pi). PFA, monensin, furosemide and ouabain inhibited Pi transport, cell migration and adhesion. CONCLUSIONS: Taken together, these results showed that the uptake of Pi in MDA-MB 231 cells is modulated by sodium and by regulatory mechanisms of intracellular sodium gradient. General Significance: Pi transport might be regarded as a potential target for therapy against tumor progression. PMID- 29415050 TI - Associations of hyperuricemia and obesity with remission of nonalcoholic fatty liver disease among Chinese men: A retrospective cohort study. AB - Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease that is associated with high serum uric acid (SUA) levels, although the effects of high SUA levels on NAFLD remission remain unclear. In addition, it is unclear whether obesity and high SUA levels have a combined effect on NAFLD remission. This retrospective cohort study evaluated male employees of seven Chinese companies and investigated the association between high SUA levels and NAFLD remission, as well as the potential combined effect of high SUA levels and obesity on NAFLD remission. The study followed 826 men with NAFLD for 4 years, and the NAFLD remission rate was 23.2% (192/826). Comparing to obese and non-obese individuals with normouricemia, individuals with hyperuricemia had significant higher values for total cholesterol, triglycerides, creatinine, and aspartate transaminase (all P < 0.05). Among non-obese individuals, hyperuricemia was associated with a lower NAFLD remission rate, compared to normouricemia (P < 0.001). However, no significant difference was observed between hyperuricemia and normouricemia among obese subjects (P > 0.05). Similar results were observed in the multivariate cox proportional hazard regression analyses. Compared to the normouricemia subjects, individuals with hyperuricemia had a significant lower likelihood of NAFLD remission (RR = 0.535, 95% CI: 0.312-0.916); and obese subjects had a significant lower likelihood of NAFLD remission than the non-obese individuals (RR = 0.635, 95% CI: 0.439-0.918). In addition, the interaction between hyperuricemia and obesity had a statistically significant effect on NAFLD remission (P = 0.048). In conclusion, hyperuricemia and obesity may be involved in NAFLD development and remission, with similar pathogenic mechanisms. Further studies are needed to confirm our findings and determine how to improve these individuals' conditions. PMID- 29415051 TI - RavN is a member of a previously unrecognized group of Legionella pneumophila E3 ubiquitin ligases. AB - The eukaryotic ubiquitylation machinery catalyzes the covalent attachment of the small protein modifier ubiquitin to cellular target proteins in order to alter their fate. Microbial pathogens exploit this post-translational modification process by encoding molecular mimics of E3 ubiquitin ligases, eukaryotic enzymes that catalyze the final step in the ubiquitylation cascade. Here, we show that the Legionella pneumophila effector protein RavN belongs to a growing class of bacterial proteins that mimic host cell E3 ligases to exploit the ubiquitylation pathway. The E3 ligase activity of RavN was located within its N-terminal region and was dependent upon interaction with a defined subset of E2 ubiquitin conjugating enzymes. The crystal structure of the N-terminal region of RavN revealed a U-box-like motif that was only remotely similar to other U-box domains, indicating that RavN is an E3 ligase relic that has undergone significant evolutionary alteration. Substitution of residues within the predicted E2 binding interface rendered RavN inactive, indicating that, despite significant structural changes, the mode of E2 recognition has remained conserved. Using hidden Markov model-based secondary structure analyses, we identified and experimentally validated four additional L. pneumophila effectors that were not previously recognized to possess E3 ligase activity, including Lpg2452/SdcB, a new paralog of SidC. Our study provides strong evidence that L. pneumophila is dedicating a considerable fraction of its effector arsenal to the manipulation of the host ubiquitylation pathway. PMID- 29415052 TI - Progressive derivation of serially homologous neuroblast lineages in the gnathal CNS of Drosophila. AB - Along the anterior-posterior axis the central nervous system is subdivided into segmental units (neuromeres) the composition of which is adapted to their region specific functional requirements. In Drosophila melanogaster each neuromere is formed by a specific set of identified neural stem cells (neuroblasts, NBs). In the thoracic and anterior abdominal region of the embryonic ventral nerve cord segmental sets of NBs resemble the ground state (2nd thoracic segment, which does not require input of homeotic genes), and serial (segmental) homologs generate similar types of lineages. The three gnathal head segments form a transitional zone between the brain and the ventral nerve cord. It has been shown recently that although all NBs of this zone are serial homologs of NBs in more posterior segments, they progressively differ from the ground state in anterior direction (labial > maxillary > mandibular segment) with regard to numbers and expression profiles. To study the consequences of their derived characters we traced the embryonic lineages of gnathal NBs using the Flybow and DiI-labelling techniques. For a number of clonal types serial homology is rather clearly reflected by their morphology (location and projection patterns) and cell specific markers, despite of reproducible segment-specific differences. However, many lineages, particularly in the mandibular segment, show a degree of derivation that impedes their assignment to ground state serial homologs. These findings demonstrate that differences in gene expression profiles of gnathal NBs go along with anteriorly directed progressive derivation in the composition of their lineages. Furthermore, lineage sizes decrease from labial to mandibular segments, which in concert with decreasing NB-numbers lead to reduced volumes of gnathal neuromeres, most significantly in the mandibular segment. PMID- 29415053 TI - The association between glutamine repeats in the androgen receptor gene and personality traits in dromedary camel (Camelus dromedarius). AB - Temperament traits such as fearfulness are important as they define an animal's responses to its environment and handling. The increasing automation of daily tasks and growing population limits contact between camels and humans. Such limitations contribute to fear of humans and changes in physical environment. Monoamine oxidase A (MAOA) and androgen receptor (AR) genes are important candidates associated with mammal personality. In our analysis, MAOA exon 15 showed no polymorphism but a novel polymorphism was seen in the camel AR exon 1; 16, 17, 18, and 19 glutamine repeats were detected. We genotyped 138 camels belonging to four Egyptian breeds: Maghrabi (n = 90), Sudani (n = 15), Somali (n = 23), and Baladi (n = 10) for AR. Out of the 90 genotyped Maghrabi camels, we evaluated responses of 33 and 32 mature females to a novel object and exposure to an unfamiliar person, respectively. AR gene showed a significant association based on the principal component (PC) score, which indicated the fear of human touch, and the PC score indicates fear during interaction with novel objects. Individuals carrying a shorter genotype in homozygote (S/S) were found to be more fearful. Furthermore, we found that Sudani and Somali breeds had a higher frequency of shorter genotype (S/S), which was associated with increased fearfulness. These findings reflect the behavioral tendency and consequently, affect the use of this breed. This is the first report showing the role of AR glutamine repeats influencing a behavioral trait in dromedary camels and leading to inter-breed differences. Fear-related traits reported here are important because camels cope with various types of stresses and fear, resulting from the demands of intensive production systems and racing events. However, further studies, employing functional genomics and linkage analysis are necessary for confirming the relationship between fearfulness and genetic variation. PMID- 29415054 TI - Chitosan oligosaccharide ameliorates acute lung injury induced by blast injury through the DDAH1/ADMA pathway. AB - OBJECTIVE: To investigate the protective effect of chitosan oligosaccharide (COS) on acute lung injury (ALI) caused by blast injury, and explore possible molecular mechanisms. METHODS: A mouse model of blast injury-induced ALI was established using a self-made explosive device. Thirty mice were randomly assigned to control, ALI and ALI + COS groups. An eight-channel physiological monitor was used to determine the mouse physiological index. Enzyme linked immunosorbent assay was used to measure serum inflammatory factors. Hematoxylin-eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, immunofluorescence staining, real time-polymerase chain reaction and western blot assay were used to detect inflammatory reactions, oxidative stress and apoptosis. RESULTS: Mice were sacrificed 24 hours after successful model induction. Compared with the ALI group, the heart rate, respiration and PCO2 were significantly lower, but the PO2, TCO2 and HCO3- were significantly higher in the ALI + COS group. Compared to ALI alone, COS treatment of ALI caused a significant decrease in the wet/dry lung weight ratio, indicating a reduction in lung edema, inflammatory cell infiltration, levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-4, IL-6 and nuclear factor kappa B mRNA and protein expression were reduced and IL-10 mRNA and protein expression was increased (P < 0.05). COS significantly inhibited reactive oxygen species, MDA5 and IREalpha mRNA and protein expressions, cell apoptosis and Bax and Caspase-3 mRNA and protein expressions, and significantly increased superoxide dismutase-1 mRNA expression, and Bcl-2 and Caspase-8 mRNA and protein expression (all P<0.05). COS significantly increased dimethylarginine dimethylaminohydrolase 1 (DDAH1) protein expression, and reduced ADMA and p38 protein expression (P< 0.05). CONCLUSION: Blast injury causes inflammation, oxidative stress and apoptosis in the lung tissues of mice. COS has protective effects on blast injury-induced ALI, possibly by promoting DDAH1 expression and inhibiting ADMA and mitogen-activated protein kinase pathways. PMID- 29415055 TI - Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer. AB - OBJECTIVES: Selective targeting of cancer-associated fibroblasts (CAFs) has been proposed to synergize with immune-checkpoint inhibitors. While the roles of CAFs in cancer development are well described, their immune-regulatory properties remain incompletely understood. This study investigates correlations between CAF and immune-markers in tumor stroma from non-small cell lung cancer (NSCLC) patients, and examines whether a combination of CAF and immune cell scores impact patient prognosis. METHODS: Tumor specimens from 536 primary operable stage I-III NSCLC patients were organized in tissue microarrays. Expression of protein markers was evaluated by immunohistochemistry. RESULTS: Fibroblast and stromal markers PDGFRalpha, PDGFRbeta, FAP-1 and vimentin showed weak correlations while alphaSMA, and Masson's trichrome did not correlate with any of the investigated markers. Hierarchical clustering indicated the existence of different CAF subsets. No relevant correlations were found between any CAF-marker and the immune-markers CD3, CD4, CD8, CD20, CD68, CD1a, CD56, FoxP3 and CD45RO. High density of fibroblast-activation protein positive mesenchymal cells (CAFFAP) was associated with better prognosis in tumors with high infiltration of CD8 and CD3 T-lymphocytes. CONCLUSIONS: The presented data suggest that CAFs, irrespective of identity, have low influence on the degree of tumor infiltration by inflammatory- and/or immune-cells. However, CAFFAP may exert immuno-adjuvant roles in NSCLC, and targeting CAFs should be cautiously considered. PMID- 29415056 TI - Novel role of the LPS core glycosyltransferase WapH for cold adaptation in the Antarctic bacterium Pseudomonas extremaustralis. AB - Psychrotroph microorganisms have developed cellular mechanisms to cope with cold stress. Cell envelopes are key components for bacterial survival. Outer membrane is a constituent of Gram negative bacterial envelopes, consisting of several components, such as lipopolysaccharides (LPS). In this work we investigated the relevance of envelope characteristics for cold adaptation in the Antarctic bacterium Pseudomonas extremaustralis by analyzing a mini Tn5 wapH mutant strain, encoding a core LPS glycosyltransferase. Our results showed that wapH strain is impaired to grow under low temperature but not for cold survival. The mutation in wapH, provoked a strong aggregative phenotype and modifications of envelope nanomechanical properties such as lower flexibility and higher turgor pressure, cell permeability and surface area to volume ratio (S/V). Changes in these characteristics were also observed in the wild type strain grown at different temperatures, showing higher cell flexibility but lower turgor pressure under cold conditions. Cold shock experiments indicated that an acclimation period in the wild type is necessary for cell flexibility and S/V ratio adjustments. Alteration in cell-cell interaction capabilities was observed in wapH strain. Mixed cells of wild type and wapH strains, as well as those of the wild type strain grown at different temperatures, showed a mosaic pattern of aggregation. These results indicate that wapH mutation provoked marked envelope alterations showing that LPS core conservation appears as a novel essential feature for active growth under cold conditions. PMID- 29415057 TI - A novel approach to adenine-induced chronic kidney disease associated anemia in rodents. AB - To date, good experimental animal models of renal anemia are not available. Therefore, the purpose of this study was to establish a novel approach to induce chronic kidney disease (CKD) with severe anemia by oral administration of adenine in rodents. Adenine was administered to 6-week-old male C57BL/6 mice (25 and 50 mg/kg body weight) by oral gavage daily for 28 days. Serum creatinine and BUN as well as hematocrit, hemoglobin (Hb) and plasma erythropoietin (EPO) levels were monitored to assess renal function and anemia, respectively. Adenine at 25 mg/kg for 28 days slightly increased plasma creatinine levels, but did not induce anemia. In contrast, 50 mg/kg of adenine daily for 28 days showed severe renal dysfunction (plasma creatinine 1.9 +/- 0.10 mg/dL) and anemia (hematocrit 36.5 +/ 1.0% and EPO 28 +/- 2.4 pg/mL) as compared with vehicle-treated mice (0.4 +/- 0.02 mg/dL, 49.6 +/- 1.6% and 61 +/- 4.0 pg/mL, respectively). At the end of experiment, level of Hb also significantly reduced in 50 mg/kg adenine administration group. Remarkable histological changes of kidney tissues characterized by interstitial fibrosis and cystic appearance in tubules were observed in 50 mg/kg of adenine treatment group. These results have demonstrated that oral dosing with adenine at 50 mg/kg for 28 days is suitable to induce a stable anemia associated with CKD in mice. PMID- 29415059 TI - The use of geographic information system and 1860s cadastral data to model agricultural suitability before heavy mechanization. A case study from Malta. AB - The present study seeks to understand the determinants of land agricultural suitability in Malta before heavy mechanization. A GIS-based Logistic Regression model is built on the basis of the data from mid-1800s cadastral maps (cabreo). This is the first time that such data are being used for the purpose of building a predictive model. The maps record the agricultural quality of parcels (ranging from good to lowest), which is represented by different colours. The study treats the agricultural quality as a depended variable with two levels: optimal (corresponding to the good class) vs. non-optimal quality (mediocre, bad, low, and lowest classes). Seventeen predictors are isolated on the basis of literature review and data availability. Logistic Regression is used to isolate the predictors that can be considered determinants of the agricultural quality. Our model has an optimal discriminatory power (AUC: 0.92). The positive effect on land agricultural quality of the following predictors is considered and discussed: sine of the aspect (odds ratio 1.42), coast distance (2.46), Brown Rendzinas (2.31), Carbonate Raw (2.62) and Xerorendzinas (9.23) soils, distance to minor roads (4.88). Predictors resulting having a negative effect are: terrain elevation (0.96), slope (0.97), distance to the nearest geological fault lines (0.09), Terra Rossa soil (0.46), distance to secondary roads (0.19) and footpaths (0.41). The model isolates a host of topographic and cultural variables, the latter related to human mobility and landscape accessibility, which differentially contributed to the agricultural suitability, providing the bases for the creation of the fragmented and extremely variegated agricultural landscape that is the hallmark of the Maltese Islands. Our findings are also useful to suggest new questions that may be posed to the more meagre evidence from earlier periods. PMID- 29415058 TI - Integration of neural and epigenetic contributions to posttraumatic stress symptoms: The role of hippocampal volume and glucocorticoid receptor gene methylation. AB - Many Veterans exposed to physical and psychological trauma experience symptoms of posttraumatic stress disorder (PTSD). As the etiology of PTSD symptoms is complex, a better understanding of the underlying biological mechanisms may improve preventative care and treatment for PTSD. Recent findings from the fields of neuroimaging and epigenetics offer important insights into the potential brain structures and biochemical pathways of modified gene expression associated with PTSD. We combined neuroimaging and epigenetic measures to assess current PTSD symptoms by measuring overall hippocampal volume and methylation of the glucocorticoid receptor (GR) gene (promoter region). Multiple regression analyses indicated that the hippocampal volume/GR methylation interaction was a predictor of PTSD symptoms. Our findings suggest that neuroimaging and epigenetic measures contribute interactively to PTSD symptoms. Incorporation of these metrics may aid in the identification and treatment of PTSD patients. PMID- 29415060 TI - Precision of MRI-based body composition measurements of postmenopausal women. AB - OBJECTIVES: To determine precision of magnetic resonance imaging (MRI) based fat and muscle quantification in a group of postmenopausal women. Furthermore, to extend the method to individual muscles relevant to upper-body exercise. MATERIALS AND METHODS: This was a sub-study to a randomized control trial investigating effects of resistance training to decrease hot flushes in postmenopausal women. Thirty-six women were included, mean age 56 +/- 6 years. Each subject was scanned twice with a 3.0T MR-scanner using a whole-body Dixon protocol. Water and fat images were calculated using a 6-peak lipid model including R2*-correction. Body composition analyses were performed to measure visceral and subcutaneous fat volumes, lean volumes and muscle fat infiltration (MFI) of the muscle groups' thigh muscles, lower leg muscles, and abdominal muscles, as well as the three individual muscles pectoralis, latissimus, and rhomboideus. Analysis was performed using a multi-atlas, calibrated water-fat separated quantification method. Liver-fat was measured as average proton density fat-fraction (PDFF) of three regions-of-interest. Precision was determined with Bland-Altman analysis, repeatability, and coefficient of variation. RESULTS: All of the 36 included women were successfully scanned and analysed. The coefficient of variation was 1.1% to 1.5% for abdominal fat compartments (visceral and subcutaneous), 0.8% to 1.9% for volumes of muscle groups (thigh, lower leg, and abdomen), and 2.3% to 7.0% for individual muscle volumes (pectoralis, latissimus, and rhomboideus). Limits of agreement for MFI was within +/- 2.06% for muscle groups and within +/- 5.13% for individual muscles. The limits of agreement for liver PDFF was within +/- 1.9%. CONCLUSION: Whole-body Dixon MRI could characterize a range of different fat and muscle compartments with high precision, including individual muscles, in the study-group of postmenopausal women. The inclusion of individual muscles, calculated from the same scan, enables analysis for specific intervention programs and studies. PMID- 29415061 TI - A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy. AB - The Double homeobox 4 (DUX4) gene is an important regulator of early human development and its aberrant expression is causal for facioscapulohumeral muscular dystrophy (FSHD). The DUX4-full length (DUX4-fl) mRNA splice isoform encodes a transcriptional activator; however, DUX4 and its unique DNA binding preferences are specific to old-world primates. Regardless, the somatic cytotoxicity caused by DUX4 expression is conserved when expressed in cells and animals ranging from fly to mouse. Thus, viable animal models based on DUX4-fl expression have been difficult to generate due in large part to overt developmental toxicity of low DUX4-fl expression from leaky transgenes. We have overcome this obstacle and here we report the generation and initial characterization of a line of conditional floxed DUX4-fl transgenic mice, FLExDUX4, that is viable and fertile. In the absence of cre, these mice express a very low level of DUX4-fl mRNA from the transgene, resulting in mild phenotypes. However, when crossed with appropriate cre-driver lines of mice, the double transgenic offspring readily express DUX4-fl mRNA, protein, and target genes with the spatiotemporal pattern of nuclear cre expression dictated by the chosen system. When cre is expressed from the ACTA1 skeletal muscle-specific promoter, the double transgenic animals exhibit a developmental myopathy. When crossed with tamoxifen-inducible cre lines, DUX4-mediated pathology can be induced in adult animals. Thus, the appearance and progression of pathology can be controlled to provide readily screenable phenotypes useful for assessing therapeutic approaches targeting DUX4-fl mRNA and protein. Overall, the FLExDUX4 line of mice is quite versatile and will allow new investigations into mechanisms of DUX4-mediated pathophysiology as well as much-needed pre-clinical testing of DUX4-targeted FSHD interventions in vivo. PMID- 29415063 TI - Dengue virus infection among long-term travelers from the Netherlands: A prospective study, 2008-2011. AB - BACKGROUND: Dengue is increasing rapidly in endemic regions. Data on incidence among travelers to these areas are limited. Five prospective studies have been performed thus far, mainly among short-term travelers. OBJECTIVE: To obtain the attack and incidence rate (AR, IR) of dengue virus (DENV) infection among long term travelers and identify associated risk factors. METHODS: A prospective study was performed among long-term travelers (12-52 weeks) attending the Public Health Service in Amsterdam. Clients planning to travel to (sub)tropical countries were invited to participate. Participants kept a travel diary, recording itinerary, symptoms, and physician visits. Pre- and post-travel blood samples were serologically tested for the presence of Anti-DENV IgG antibodies. Seroconversion was considered suggestive of a primary DENV infection. Anti-DENV IgG present in both corresponding samples in combination with a post-/pre-travel ratio of >=4:1 was suggestive of a secondary infection. Risk factors for a DENV infection were studied using poisson regression. RESULTS: In total, 600 participants were included; median age was 25 years (IQR: 23-29), 35.5% were male, and median travel duration was 20 weeks (IQR: 15-25). In 39 of 600 participants (AR: 6.5%; 95% CI 4.5-8.5%) anti-DENV IgG test results were suggestive of a recent infection, yielding an IR of 13.9 per 1,000 person-months traveling (95%CI: 9.9 19.1). No secondary infections were found. IR for Asia, Africa, and America were comparable and 13.5, 15.8, and 13.6 per 1,000 person-months respectively. Of participants with a recent DENV infection, 51% did not report dengue-like illness (DLI) or fever, but 10% were hospitalized. In multivariable analysis, travelers who seroconverted were significantly more likely to be vaccinated with >=2 flavivirus vaccines for the current trip or to have reported DLI in >1 consecutive weeks. CONCLUSIONS: Long-term travelers are at substantial risk of DENV infection. Half of those with a DENV infection reported no symptoms, but 10% were hospitalized, demonstrating the importance of advising anti-mosquito measures during travel. PMID- 29415064 TI - The jaguar and the PhD. PMID- 29415062 TI - Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans. AB - Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intra-islet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxide-induced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D. PMID- 29415066 TI - Integrating landscape system and meta-ecosystem frameworks to advance the understanding of ecosystem function in heterogeneous landscapes: An analysis on the carbon fluxes in the Northern Highlands Lake District (NHLD) of Wisconsin and Michigan. AB - The successful integration of ecosystem ecology with landscape ecology would be conducive to understanding how landscapes function. There have been several attempts at this, with two main approaches: (1) an ecosystem-based approach, such as the meta-ecosystem framework and (2) a landscape-based approach, such as the landscape system framework. These two frameworks are currently disconnected. To integrate these two frameworks, we introduce a protocol, and then demonstrate application of the protocol using a case study. The protocol includes four steps: 1) delineating landscape systems; 2) classifying landscape systems; 3) adjusting landscape systems to meta-ecosystems and 4) integrating landscape system and meta ecosystem frameworks through meta-ecosystems. The case study is the analyzing of the carbon fluxes in the Northern Highlands Lake District (NHLD) of Wisconsin and Michigan using this protocol. The application of this protocol revealed that one could follow this protocol to construct a meta-ecosystem and analyze it using the integrative framework of landscape system and meta-ecosystem frameworks. That is, one could (1) appropriately describe and analyze the spatial heterogeneity of the meta-ecosystem; (2) understand the emergent properties arising from spatial coupling of local ecosystems in the meta-ecosystem. In conclusion, this protocol is a useful approach for integrating the meta-ecosystem framework and the landscape system framework, which advances the describing and analyzing of the spatial heterogeneity and ecosystem function of interconnected ecosystems. PMID- 29415065 TI - High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children. AB - Enteropathies such as Crohn's disease are associated with enteric inflammation characterized by impaired TGF-beta signaling, decreased expression of phosphorylated (p)-SMAD2,3 and increased expression of SMAD7 (an inhibitor of SMAD3 phosphorylation). Environmental enteropathy (EE) is an acquired inflammatory disease of the small intestine (SI), which is associated with linear growth disruption, cognitive deficits, and reduced oral vaccine responsiveness in children <5 y in resource-poor countries. We aimed to characterize EE inflammatory pathways by determining SMAD7 and p-SMAD2,3 levels (using Western blotting) in EE duodenal biopsies (N = 19 children, 7 from Pakistan, 12 from Zambia) and comparing these with healthy controls (Ctl) and celiac disease (CD) patients from Italy. Densitometric analysis of immunoblots showed that EE SI biopsies expressed higher levels of both SMAD7 (mean+/-SD in arbitrary units [a.u.], Ctl = 0.47+/-0.20 a.u., EE = 1.13+/-0.25 a.u., p-value = 0.03) and p SMAD2,3 (mean+/-SD, Ctl = 0.38+/-0.14 a.u., EE = 0.60+/-0.10 a.u., p-value = 0.03). Immunohistochemistry showed that, in EE, SMAD7 is expressed in both the epithelium and in mononuclear cells of the lamina propria (LP). In contrast, p SMAD3 in EE is expressed much more prominently in epithelial cells than in the LP. The high SMAD7 immunoreactivity and lack of p-SMAD3 expression in the LP suggests defective TGF-beta signaling in the LP in EE similar to a previously reported SMAD7-mediated inflammatory pathway in refractory CD and Crohn's disease. However, Western blot densitometry showed elevated p-SMAD2,3 levels in EE, possibly suggesting a different inflammatory pathway than Crohn's disease but more likely reflecting cumulative protein expression from across all compartments of the mucosa as opposed to the LP alone. Further studies are needed to substantiate these preliminary results and to illustrate the relationship between SMAD proteins, TGF-beta signaling, and inflammatory cytokine production, all of which may be potential therapeutic targets. PMID- 29415067 TI - Transcriptomic analysis reveals the roles of gibberellin-regulated genes and transcription factors in regulating bolting in lettuce (Lactuca sativa L.). AB - A cool temperature is preferred for lettuce cultivation, as high temperatures cause premature bolting. Accordingly, exploring the mechanism of bolting and preventing premature bolting is important for agriculture. To explore this relationship in depth, morphological, physiological, and transcriptomic analyses of the bolting-sensitive line S39 at the five-leaf stage grown at 37 degrees C were performed in the present study. Based on paraffin section results, we observed that S39 began bolting on the seventh day at 37 degrees C. During bolting in the heat-treated plants, GA3 and GA4 levels in leaves and the indoleacetic acid (IAA) level in the stem reached a maximum on the sixth day, and these high contents were maintained. Additionally, bolting begins in the fifth day after GA3 treatment in S39 plants, GA3 and GA4 increased and then decreased, reaching a maximum on the fourth day in leaves. Similarly, IAA contents reached a maximum in the stem on the fifth day. No bolting was observed in the control group grown at 25 degrees C, and significant changes were not observed in GA3 and GA4 levels in the controls during the observation period. RNA-sequencing data implicated transcription factors (TFs) in regulating bolting in lettuce, suggesting that the high GA contents in the leaves and IAA in the stem promote bolting. TFs possibly modulate the expression of related genes, such as those encoding hormones, potentially regulating bolting in lettuce. Compared to the control group, 258 TFs were identified in the stem of the treatment group, among which 98 and 156 were differentially up- and down-regulated, respectively; in leaves, 202 and 115 TFs were differentially up- and down-regulated, respectively. Significant changes in the treated group were observed for C2H2 zinc finger, AP2 EREBP, and WRKY families, indicating that these TFs may play important roles in regulating bolting. PMID- 29415069 TI - Administration of L-arginine plus L-citrulline or L-citrulline alone successfully retarded endothelial senescence. AB - L-citrulline and L-arginine supplementation has been shown to have several beneficial effects on the cardiovascular system. Nitric oxide (NO) protects against the progression of atherosclerosis and is synthesized by nitric oxide synthase (NOS), which converts L-arginine (L-Arg) into L-citrulline (L-Cit). Our previous study revealed that chronic administration of a combination of L-Cit and L- Arg has a better therapeutic effect on high cholesterol-induced atherosclerosis in rabbits. We investigated how L-Arg and L-Cit affect endothelial function, aging and atherosclerosis. Following a 3-day stimulation of human umbilical venous endothelial cells (HUVECs) with high glucose (HG: 22 mM) and L-Arg (300 MUM), L-Cit (300 MUM) or L-Arg plus L-Cit (LALC: each 150 MUM) supplementation, endothelial senescence and function were evaluated. These amino acids were also administered to dyslipidemic type 2 diabetic (ZDFM) rats fed a high cholesterol diet. They were fed L-Arg or L-Cit or LALC for four weeks. Aortic senescence was investigated by measuring senescence-associated beta galactosidase (SA-beta-gal), telomerase activity, DNA damage and p16INK4a protein expression. Only L-Cit and LALC supplementation retarded the HG-induced endothelial senescence, as evaluated by SA-beta-gal activity, a widely used marker of cellular senescence, p16INK4a expression, a senescence-related protein, and DNA damage. Under HG conditions, L-Cit and LCLA restored telomerase activity to levels observed under normal glucose (NG) conditions. Under HG conditions, L Cit decreased ROS production, as measured by CM-H2DCFDA and the expression of p67phox, a major component of NADPH oxidase. Under HG conditions, L-Cit and LALC increased NO production, as measured by DAF-2AM. Endothelial NO synthase (eNOS) and phosphorylated eNOS were decreased under HG conditions and L-Cit and LALC significantly increased these levels. Arginase 2 protein expression increased under the HG conditions, and L-Cit and LALC significantly attenuated this effect. In ZDFM rats, SA-beta-gal activity was detected on the aortic endothelial surface; however, L-Cit and LALC reduced these levels. L-Cit and LALC both decreased the proportion of senescent cells. Furthermore, treatment with LALC for 4 weeks increased plasma NO production. Therefore conclusively, L-citrulline supplementation rescued NO levels better than L-arginine supplementation by inhibiting ROS production and arginase 2 protein expression. Consequently, L-Cit and LCLA supplementation retaeded HG-induced endothelial senescence. PMID- 29415068 TI - The nonlinear relationship between cerebrospinal fluid Abeta42 and tau in preclinical Alzheimer's disease. AB - Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid beta 1-42 (Abeta42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer's disease (AD). However, the preclinical prediction accuracy for low CSF Abeta42 levels, a surrogate for brain Abeta42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Abeta initiated cascade. CSF Abeta42 and tau data from 3 normal aging cohorts (45-90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Abeta42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Abeta2) best describes the relationship for CSF Abeta42 with CSF tau levels. Furthermore we found that the relationship between Abeta42 and tau changes with age-between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Abeta42 and tau. The quadratic effect appears to be unique to Abeta42, as Abeta38 and Abeta40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Abeta42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Abeta42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Abetaxx analyte levels prior to Abeta42 deposition in brain. PMID- 29415070 TI - Evidence for chikungunya and dengue transmission in Quelimane, Mozambique: Results from an investigation of a potential outbreak of chikungunya virus. AB - BACKGROUND: In January 2016, health authorities from Zambezia province, Mozambique reported the detection of some patients presenting with fever, arthralgia, and a positive result for chikungunya in an IgM-based Rapid Diagnostic Test (RDT). We initiated a study to investigate a potential chikungunya outbreak in the city of Quelimane. METHODS/PRINCIPAL FINDINGS: From February to June 2016, we conducted a cross-sectional study enrolling febrile patients attending five outpatient health units in Quelimane. Serum from each patient was tested for CHIKV and DENV, using IgM and IgG ELISA and qRT-PCR. Patients were also tested for malaria by RDT. Entomological surveys were performed around patients' households, and we calculated the proportion of positive ovitraps and the egg density per trap. A total of 163 patients were recruited, of which 99 (60.7%) were female. The median age was 28 years. IgM and IgG anti-CHIKV antibodies were identified in 17 (10.4%) and 103 (63.2%) patients, respectively. Plaque reduction neutralization assay confirmed the presence of anti-CHIKV antibodies in a subset of 11 tested patients with positive IgG results. IgM anti-DENV antibodies were found in 1 (0.9%) of 104 tested patients. Malaria was diagnosed in 35 (21.5%) patients, 2 of whom were also IgM-positive for CHIKV. Older age and lower education level were independently associated with the prevalence of IgG anti-CHIKV antibodies. Immature forms of Aedes aegypti were collected in 16 (20.3%) of 79 surveyed households. We also found that 25.0% (16/64) of the traps were positive, with an average of 90.8 eggs per pallet. CONCLUSIONS: Our investigation demonstrated that no CHIKV outbreak was ongoing in Quelimane; rather, endemic transmission of the virus has been ongoing. Aedes aegypti mosquitoes are abundant, but dengue cases occurred only sporadically. Further population-based cohort studies are needed to improve our understanding of aspects related to the dynamics of arboviral transmission in Mozambique, as well as in other parts of Sub-Saharan Africa. PMID- 29415071 TI - Stability of lutein encapsulated whey protein nano-emulsion during storage. AB - Lutein is a hydrophobic carotenoid that has multiple health functions. However, the application of lutein is limited due to its poor solubility in water and instability under certain conditions during storage. Hereby we generated lutein loaded nano-emulsions using whey protein isolate (WPI) or polymerized whey protein isolate (PWP) with assistance of high intensity ultrasound and evaluate their stability during storage at different conditions. We measured the particle size, zeta-potential, physical stability and lutein content change. Results showed that the PWP based nano-emulsion system was not stable in the tested Oil/Water/Ethanol system indicated by the appearance of stratification within only one week. The WPI based nano-emulsion system showed stable physiochemical stability during the storage at 4 degrees C. The lutein content of the system was reduced by only 4% after four weeks storage at 4 degrees C. In conclusion, our whey protein based nano-emulsion system provides a promising strategy for encapsulation of lutein or other hydrophobic bioactive molecules to expand their applications. PMID- 29415073 TI - Urbanization may reduce the risk of frost damage to spring flowers: A case study of two shrub species in South Korea. AB - Regional warming, owing to urbanization, leads to earlier spring phenological events and may expose plants to hard freeze damage. This study examined the influence of urbanization on the risk of frost damage to spring flowers in South Korea from 1973 to 2015. For the analysis period, we categorized 25 cities into two groups: those showing rapid population growth (rPG) >= 200,000, including 13 cities, and those showing no or decreased population growth (nPG), including 12 cities. We then investigated the time from the last frost dates (LFDs) in spring to the first flowering dates (FFDs) for each group. The rPG group experienced significant spring warming of 0.47 degrees C per decade, resulting in earlier LFDs and FFDs. For this group, the advancement of LFD was more rapid than that of FFD, and the days between these two dates increased from 0.42 to 0.47 days per decade, implying a reduced risk of frost damage. Spring warming and the advancement of FFDs and LFDs were relatively small for the nPG group, and the LFDs were rather delayed. Consequently, the days between LFDs and FFDs were reduced from -1.05 to -1.67 days per decade, indicating an increased risk of frost damage. The contrasting changes in the frost-damage risk between the two city groups can be attributed to distinct urban warming at night, which makes the LFDs substantially earlier in the rPG group. Therefore, this study suggests that the warming associated with urbanization may lessen the risk of spring frost damage to plants in rapidly growing urban areas. PMID- 29415072 TI - NS2 proteases from hepatitis C virus and related hepaciviruses share composite active sites and previously unrecognized intrinsic proteolytic activities. AB - Over the recent years, several homologues with varying degrees of genetic relatedness to hepatitis C virus (HCV) have been identified in a wide range of mammalian species. HCV infectious life cycle relies on a first critical proteolytic event of its single polyprotein, which is carried out by nonstructural protein 2 (NS2) and allows replicase assembly and genome replication. In this study, we characterized and evaluated the conservation of the proteolytic mode of action and regulatory mechanisms of NS2 across HCV and animal hepaciviruses. We first demonstrated that NS2 from equine, bat, rodent, New and Old World primate hepaciviruses also are cysteine proteases. Using tagged viral protein precursors and catalytic triad mutants, NS2 of equine NPHV and simian GBV-B, which are the most closely and distantly related viruses to HCV, respectively, were shown to function, like HCV NS2 as dimeric proteases with two composite active sites. Consistent with the reported essential role for NS3 N terminal domain (NS3N) as HCV NS2 protease cofactor via NS3N key hydrophobic surface patch, we showed by gain/loss of function mutagenesis studies that some heterologous hepacivirus NS3N may act as cofactors for HCV NS2 provided that HCV like hydrophobic residues are conserved. Unprecedently, however, we also observed efficient intrinsic proteolytic activity of NS2 protease in the absence of NS3 moiety in the context of C-terminal tag fusions via flexible linkers both in transiently transfected cells for all hepaciviruses studied and in the context of HCV dicistronic full-length genomes. These findings suggest that NS3N acts as a regulatory rather than essential cofactor for hepacivirus NS2 protease. Overall, unique features of NS2 including enzymatic function as dimers with two composite active sites and additional NS3-independent proteolytic activity are conserved across hepaciviruses regardless of their genetic distances, highlighting their functional significance in hepacivirus life cycle. PMID- 29415074 TI - Extraocular muscle regeneration in zebrafish requires late signals from Insulin like growth factors. AB - Insulin-like growth factors (Igfs) are key regulators of key biological processes such as embryonic development, growth, and tissue repair and regeneration. The role of Igf in myogenesis is well documented and, in zebrafish, promotes fin and heart regeneration. However, the mechanism of action of Igf in muscle repair and regeneration is not well understood. Using adult zebrafish extraocular muscle (EOM) regeneration as an experimental model, we show that Igf1 receptor blockage using either chemical inhibitors (BMS754807 and NVP-AEW541) or translation blocking morpholino oligonucleotides (MOs) reduced EOM regeneration. Zebrafish EOMs regeneration depends on myocyte dedifferentiation, which is driven by early epigenetic reprogramming and requires autophagy activation and cell cycle reentry. Inhibition of Igf signaling had no effect on either autophagy activation or cell proliferation, indicating that Igf signaling was not involved in the early reprogramming steps of regeneration. Instead, blocking Igf signaling produced hypercellularity of regenerating EOMs and diminished myosin expression, resulting in lack of mature differentiated muscle fibers even many days after injury, indicating that Igf was involved in late re-differentiation steps. Although it is considered the main mediator of myogenic Igf actions, Akt activation decreased in regenerating EOMs, suggesting that alternative signaling pathways mediate Igf activity in muscle regeneration. In conclusion, Igf signaling is critical for re-differentiation of reprogrammed myoblasts during late steps of zebrafish EOM regeneration, suggesting a regulatory mechanism for determining regenerated muscle size and timing of differentiation, and a potential target for regenerative therapy. PMID- 29415076 TI - Development of septic polysynovitis and uveitis in foals experimentally infected with Rhodococcus equi. AB - Rhodococcus equi is one of the most important causes of disease in foals. Infection is typically characterized by pyogranulomatous pneumonia although extrapulmonary infections occur occasionally. Uveitis and polysynovitis have been reported in foals naturally infected with R. equi and are thought to be the result of an immune-mediated process. However, the pathogenesis of these conditions is poorly understood. The objectives of this study were to document the occurrence of uveitis and polysynovitis after experimental infection with R. equi and to determine if these disorders are the direct result of infection at these sites. Foals between 3 and 4 weeks of age were infected intratracheally with virulent R. equi using inocula of 1*108 CFU (high inoculum; n = 16) or 1*107 CFU (low inoculum; n = 12). Foals were monitored twice daily and necropsy was performed 14 days post-infection. Aqueous humor and synovial fluid were collected aseptically and the percentage of affected lung was calculated. The mean (+/- SD) percentage of affected lung was significantly higher with the high inoculum (31.8 +/- 14.6%) than with the low inoculum (14.4 +/- 11.4%). Fourteen of 25 foals developed uveitis and 20 of 28 foals developed polysynovitis. R. equi was cultured from the aqueous humor of 11 foals and from the synovial fluid of 14 foals. The risk of development of polysynovitis and protein concentration in the aqueous humor were significantly higher in foals that received the high inoculum. These results indicate that polysynovitis and uveitis are septic complications associated with the severity of lung disease. PMID- 29415075 TI - The other Campylobacters: Not innocent bystanders in endemic diarrhea and dysentery in children in low-income settings. AB - BACKGROUND: Campylobacter is one of the main causes of gastroenteritis worldwide. Most of the current knowledge about the epidemiology of this food-borne infection concerns two species, C. coli and C. jejuni. Recent studies conducted in developing countries and using novel diagnostic techniques have generated evidence of the increasing burden and importance of other Campylobacter species, i.e. non-C. coli/jejuni. We performed a nested case-control study to compare the prevalence of C. coli/jejuni and other Campylobacter in children with clinical dysentery and severe diarrhea as well as without diarrhea to better understand the clinical importance of infections with Campylobacter species other than C. coli/jejuni. METHODOLOGY/PRINCIPAL FINDINGS: Our nested case-control study of 439 stool samples included dysenteric stools, stools collected during severe diarrhea episodes, and asymptomatic stools which were systematically selected to be representative of clinical phenotypes from 9,160 stools collected during a birth cohort study of 201 children followed until two years of age. Other Campylobacter accounted for 76.4% of the 216 Campylobacter detections by qPCR and were more prevalent than C. coli/jejuni across all clinical groups. Other Campylobacter were also more prevalent than C. coli/jejuni across all age groups, with older children bearing a higher burden of other Campylobacter. Biomarkers of intestinal inflammation and injury (methylene blue, fecal occult test, myeloperoxidase or MPO) showed a strong association with dysentery, but mixed results with infection. MPO levels were generally higher among children infected with C. coli/jejuni, but Shigella-infected children suffering from dysentery recorded the highest levels (26,224 ng/mL); the lowest levels (10,625 ng/mL) were among asymptomatic children infected with other Campylobacter. Adjusting for age, sex, and Shigella infection, dysentery was significantly associated with C. coli/jejuni but not with other Campylobacter, whereas severe diarrhea was significantly associated with both C. coli/jejuni and other Campylobacter. Compared to asymptomatic children, children suffering from dysentery had a 14.6 odds of C. coli/jejuni infection (p-value < 0.001, 95% CI 5.5-38.7) but were equally likely to have other Campylobacter infections-odds ratio of 1.3 (0.434, 0.7-2.4). Children suffering from severe diarrhea were more likely than asymptomatic children to test positive for both C. coli/jejuni and other Campylobacter-OR of 2.8 (0.034, 1.1-7.1) and 1.9 (0.018, 1.1-3.1), respectively. Compared to the Campylobacter-free group, the odds of all diarrhea given C. coli/jejuni infection and other Campylobacter infection were 8.8 (<0.001, 3.0 25.7) and 2.4 (0.002, 1.4-4.2), respectively. Eliminating other Campylobacter in this population would eliminate 24.9% of the diarrhea cases, which is almost twice the population attributable fraction of 15.1% due to C. coli/jejuni. CONCLUSIONS/SIGNIFICANCE: Eighty-seven percent of the dysentery and 59.5% of the severe diarrhea samples were positive for Campylobacter, Shigella, or both, emphasizing the importance of targeting these pathogens to limit the impact of dysentery and severe diarrhea in children. Notably, the higher prevalence of other Campylobacter compared to C. coli/jejuni, their increasing burden during early childhood, and their association with severe diarrhea highlight the importance of these non-C. coli/jejuni Campylobacter species and suggest a need to clarify their importance in the etiology of clinical disease across different epidemiological contexts. PMID- 29415077 TI - Genetic responsiveness of African buffalo to environmental stressors: A role for epigenetics in balancing autosomal and sex chromosome interactions? AB - In the African buffalo (Syncerus caffer) population of the Kruger National Park (South Africa) a primary sex-ratio distorter and a primary sex-ratio suppressor have been shown to occur on the Y chromosome. A subsequent autosomal microsatellite study indicated that two types of deleterious alleles with a negative effect on male body condition, but a positive effect on relative fitness when averaged across sexes and generations, occur genome-wide and at high frequencies in the same population. One type negatively affects body condition of both sexes, while the other acts antagonistically: it negatively affects male but positively affects female body condition. Here we show that high frequencies of male-deleterious alleles are attributable to Y-chromosomal distorter-suppressor pair activity and that these alleles are suppressed in individuals born after three dry pre-birth years, likely through epigenetic modification. Epigenetic suppression was indicated by statistical interactions between pre-birth rainfall, a proxy for parental body condition, and the phenotypic effect of homozygosity/heterozygosity status of microsatellites linked to male-deleterious alleles, while a role for the Y-chromosomal distorter-suppressor pair was indicated by between-sex genetic differences among pre-dispersal calves. We argue that suppression of male-deleterious alleles results in negative frequency dependent selection of the Y distorter and suppressor; a prerequisite for a stable polymorphism of the Y distorter-suppressor pair. The Y distorter seems to be responsible for positive selection of male-deleterious alleles during resource rich periods and the Y suppressor for positive selection of these alleles during resource-poor periods. Male-deleterious alleles were also associated with susceptibility to bovine tuberculosis, indicating that Kruger buffalo are sensitive to stressors such as diseases and droughts. We anticipate that future genetic studies on African buffalo will provide important new insights into gene fitness and epigenetic modification in the context of sex-ratio distortion and infectious disease dynamics. PMID- 29415079 TI - Correction: Effect of early dietary energy restriction and phosphorus level on subsequent growth performance, intestinal phosphate transport, and AMPK activity in young broilers. AB - [This corrects the article DOI: 10.1371/journal.pone.0186828.]. PMID- 29415078 TI - Risk factors for anthroponotic cutaneous leishmaniasis in unresponsive and responsive patients in a major focus, southeast of Iran. AB - Cutaneous leishmaniasis (CL) is a serious health challenge at the global level due to Leishmania tropica. This study was conducted to evaluate the risk factors associated with anthroponotic CL (ACL) in unresponsive (patient who does not heal and remains with an active lesion, despite receiving two courses of intra lesional Glucantime along with cryotherapy and one cycle of systemic Glucantime) and responsive patients in a major focus in southeastern Iran. A case-control study was conducted from April 2015 to October 2016 in the southeast of Iran. Patients were recruited in a major ACL focus from unresponsive and responsive cases. These patients were compared for environmental, clinical, and demographic characteristic factors. Twenty-five risk related factors were analyzed using multivariate logistic regression and backward elimination stepwise models. P<0.05 was defined to be statistically significant. In general, 340 patients with ACL comprising 72 (21.2%) unresponsive cases and 268 (78.8%) responsive cases with active lesions or scars were analyzed by estimating odds ratio (OR). All isolates from 15 responsive and 15 unresponsive patients were characterized as Leishmania tropica based on the BLAST and phylogenic analyses by PCR sequences of the Hsp70 and ITS1 loci. Among the 25 variables, 4 major risk factors including poor interior housing conditions (OR = 1.99, confidence interval (CI) = 1-3.93, P<0.04), history of chronic diseases (OR = 6.22, CI = 2.51-15.44, P<=0.001), duration of lesion in the patients referred >=13 months (OR = 74.99, CI = 17.24 326.17, P<=0.001), and 5-12 months (OR = 7.42, CI = 3.07-17.92, P<=0.001) than lesions with <=4 months of age and age groups >=51 years (OR = 3.85, CI = 1.04 14.22, P<0.04) than those <=7 years, were significantly associated with unresponsive forms. Improving interior house construction protecting high risk individuals and those with debilitating diseases from being bitten by sand flies, together with the early detection and effective treatment of older age groups with history of chronic diseases are highly important measures for preventing unresponsive forms in patients with ACL in southeastern Iran. PMID- 29415080 TI - Present and future thermal environments available to Sharp-tailed Grouse in an intact grassland. AB - Better understanding animal ecology in terms of thermal habitat use has become a focus of ecological studies, in large part due to the predicted temperature increases associated with global climate change. To further our knowledge on how ground-nesting endotherms respond to thermal landscapes, we examined the thermal ecology of Sharp-tailed Grouse (Tympanuchus phasianellus) during the nesting period. We measured site-specific iButton temperatures (TiB) and vegetation characteristics at nest sites, nearby random sites, and landscape sites to assess thermal patterns at scales relevant to nesting birds. We asked if microhabitat vegetation characteristics at nest sites matched the characteristics that directed macrohabitat nest-site selection. Grouse selected sites sheltered by dense vegetation for nesting that moderated TiB on average up to 2.7 degrees C more than available landscape sites. Successful nests were positioned in a way that reduced exposure to thermal extremes by as much as 4 degrees C relative to failed nests with an overall mean daytime difference (+/-SE) of 0.4 +/-0.03 degrees C. We found that macrohabitat nest-site selection was guided by dense vegetation cover and minimal bare ground as also seen at the microhabitat scale. Global climate projections for 2080 suggest that TiB at nest sites may approach temperatures currently avoided on the landscape, emphasizing a need for future conservation plans that acknowledge fine-scale thermal space in climate change scenarios. These data show that features of grassland landscapes can buffer organisms from unfavorable microclimatic conditions and highlight how thermal heterogeneity at the individual-level can drive decisions guiding nest site selection. PMID- 29415081 TI - Auditory steady-state responses in primary and non-primary regions of the auditory cortex in neonatal ventral hippocampal lesion rats. AB - Auditory steady-state responses (ASSRs) represent the electrophysiological activity of the auditory nervous system in response to a periodic acoustic stimulus. Spectrogram analysis can reveal the frequency and phase information entrained in ASSRs. Clinically, the ASSR is used to detect abnormalities in electroencephalographs obtained from schizophrenia patients, who show reduced power and phase locking of ASSRs. The neonatal ventral hippocampal lesion (NVHL) rat is a widely used model to investigate the neurodevelopmental mechanisms of schizophrenia. It has been established that NVHL rats exhibit several schizophrenia-like behavioral and molecular abnormalities. However, no clear abnormalities in ASSRs have been reported to date. The present study compared ASSRs of adult NVHL and sham-operated rats. We inserted microelectrodes into the primary auditory cortex (A1) or posterior auditory field (PAF) and recorded the local field potential (LFP) in response to 40- and 80-Hz click train stimuli. Spectrogram analysis was performed to obtain the mean trial power (MTP) and phase locking factor (PLF) of the click train-evoked LFPs. We found that in the control animals, A1 showed a stronger MTP and PLF of ASSR than PAF, and NVHL operation mainly impaired the ASSR in PAF. Analysis of spike activity also indicated that NVHL operation extended the duration of tone-evoked responses in PAF neurons. Our results reveal, for the first time, that NVHL may distinctly influence the neural activities of primary and non-primary fields of the auditory cortex. PMID- 29415082 TI - SubID, a non-median dichotomization tool for heterogeneous populations, reveals the pan-cancer significance of INPP4B and its regulation by EVI1 in AML. AB - Our previous studies demonstrated that INPP4B, a member of the PI3K/Akt signaling pathway, is overexpressed in a subset of AML patients and is associated with lower response to chemotherapy and shorter survival. INPP4B expression analysis in AML revealed a right skewed frequency distribution with 25% of patients expressing significantly higher levels than the majority. The 75% low/25% high cut-off revealed the prognostic power of INPP4B expression status in AML, which would not have been apparent with a standard median cut-off approach. Our identification of a clinically relevant non-median cut-off for INPP4B indicated a need for a generalizable non-median dichotomization approach to optimally study clinically relevant genes. To address this need, we developed Subgroup Identifier (SubID), a tool which examines the relationship between a continuous variable (e.g. gene expression), and a test parameter (e.g. CoxPH or Fisher's exact P values). In our study, Fisher's exact SubID was used to reveal EVI1 as a transcriptional regulator of INPP4B in AML; a finding which was validated in vitro. Next, we used CoxPH SubID to conduct a pan-cancer analysis of INPP4B's prognostic significance. Our analysis revealed that INPP4Blow is associated with shorter survival in kidney clear cell, liver hepatocellular, and bladder urothelial carcinomas. Conversely, INPP4Blow was shown to be associated with increased survival in pancreatic adenocarcinoma in three independent datasets. Overall, our study describes the development and application of a novel subgroup identification tool used to identify prognostically significant rare subgroups based upon gene expression, and for investigating the association between a gene with skewed frequency distribution and potentially important upstream and downstream genes that relate to the index gene. PMID- 29415083 TI - No maternal or direct effects of ocean acidification on egg hatching in the Arctic copepod Calanus glacialis. AB - Widespread ocean acidification (OA) is transforming the chemistry of the global ocean and the Arctic is recognised as the region where this transformation will occur at the fastest rate. Moreover, many Arctic species are considered less capable of tolerating OA due to their lower capacity for acid-base regulation. This inability may put severe restraints on many fundamental functions, such as growth and reproductive investments, which ultimately may result in reduced fitness. However, maternal effects may alleviate severe effects on the offspring rendering them more tolerant to OA. In a highly replicated experiment we studied maternal and direct effects of OA predicted for the Arctic shelf seas on egg hatching time and success in the keystone copepod species Calanus glacialis. We incubated females at present day conditions (pHT 8.0) and year 2100 extreme conditions (pHT 7.5) during oogenesis and subsequently reciprocally transplanted laid eggs between these two conditions. Statistical tests showed no effects of maternal or direct exposure to OA at this level. We hypothesise that C. glacialis may be physiologically adapted to egg production at low pH since oogenesis can also take place at conditions of potentially low haemolymph pH of the mother during hibernation in the deep. PMID- 29415085 TI - Correction: Design and fabrication of a realistic anthropomorphic heterogeneous head phantom for MR purposes. AB - [This corrects the article DOI: 10.1371/journal.pone.0183168.]. PMID- 29415084 TI - MR-guided transcranial focused ultrasound safely enhances interstitial dispersion of large polymeric nanoparticles in the living brain. AB - Generating spatially controlled, non-destructive changes in the interstitial spaces of the brain has a host of potential clinical applications, including enhancing the delivery of therapeutics, modulating biological features within the tissue microenvironment, altering fluid and pressure dynamics, and increasing the clearance of toxins, such as plaques found in Alzheimer's disease. Recently we demonstrated that ultrasound can non-destructively enlarge the interstitial spaces of the brain ex vivo. The goal of the current study was to determine whether these effects could be reproduced in the living brain using non-invasive, transcranial MRI-guided focused ultrasound (MRgFUS). The left striatum of healthy rats was treated using MRgFUS. Computer simulations facilitated treatment planning, and targeting was validated using MRI acoustic radiation force impulse imaging. Following MRgFUS treatments, Evans blue dye or nanoparticle probes were infused to assess changes in the interstitial space. In MRgFUS-treated animals, enhanced dispersion was observed compared to controls for 70 nm (12.8 +/- 0.9 mm3 vs. 10.6 +/- 1.0 mm3, p = 0.01), 200 nm (10.9 +/- 1.4 mm3 vs. 7.4 +/- 0.7 mm3, p = 0.01) and 700 nm (7.5 +/- 0.4 mm3 vs. 5.4 +/- 1.2 mm3, p = 0.02) nanoparticles, indicating enlargement of the interstitial spaces. No evidence of significant histological or electrophysiological injury was identified. These findings suggest that transcranial ultrasound can safely and effectively modulate the brain interstitium and increase the dispersion of large therapeutic entities such as particulate drug carriers or modified viruses. This has the potential to expand the therapeutic uses of MRgFUS. PMID- 29415086 TI - Impact of primary influenza infection on the immune response to secondary bacterial infection in aged mice. AB - Background: Increased susceptibility of older populations to secondary bacterial pneumonia-like infections following influenza infection has been well documented.1 Recent evidence in mouse models suggests that this increased risk from secondary bacterial infection occurs through a desensitization of the innate immune response.2 This recent finding, however, does not account for potential differences in immune responsiveness due to age. Materials and methods: To address this parameter, we used three age groups (aged, adult, and young mice) to evaluate the role of age in influenza-mediated vulnerability to secondary bacterial challenge with Pseudomonas aeruginosa. All mice were evaluated for multiple parameters including: (i) survival; (ii) lung bacterial load; (iii) total lung protein content; (iv) immune cell infiltration; (v) cytokine/chemokine expression; and (vi) toll-like receptor (TLR) RNA expression profiles. Results: Prior challenge with influenza contributed to aberrant cytokine/chemokine profiles and increased lung cellular infiltrate in response to secondary bacterial infection across all age groups, supporting a critical role for influenza infection in the alteration of immune responses to other pathogens. Also similar to human influenza, these changes were exacerbated by age in mice as demonstrated by increased bacterial load, mortality, and total lung protein content (an indicator of lung damage) after P. aeruginosa challenge. Conclusions: These data support a potential role for virus-mediated and age-mediated alteration of innate immune effectors in the pathogenesis of influenza and the increased susceptibility of influenza virus infected mice to secondary bacterial infection. The understanding of the complex interaction of host and pathogen - and the role of age - in human influenza is critical in the development of novel therapeutics and improved vaccine approaches for influenza. Our results support further examination of influenza-mediated alterations in innate immune responses in aged and non-aged animals to allow elucidation of the molecular mechanisms of influenza pathogenesis in humans. PMID- 29415087 TI - Convective evaporation of vertical films. AB - Motivated by the evaporation of soap films, which has a significant effect on their lifetime, we performed an experimental study on the evaporation of vertical surfaces with model systems based on hydrogels. From the analogy between heat and mass transfer, we adopt a model describing the natural convection in the gas phase due to a density contrast between dry and saturated air. Our measurements show a good agreement with this model, both in terms of scaling law with the Grashof number and in terms of order of magnitude. We discuss the corrections to take into account, notably the contribution of edge effects, which have a small but visible contribution when lateral and bottom surface areas are not negligible compared to the main evaporating surface area. PMID- 29415088 TI - Solvent triggered irreversible shape morphism of biopolymer films. AB - We report the controlled reversible and irreversible folding behavior of a biopolymer film simply by tuning the solvent characteristics. Generally, solvent triggered folding of soft membranes or film is achieved by unfolding. Here, we show that this unfolding behavior can be suppressed/delayed or even completely eliminated by altering the intrinsic nature of the solvent. A reversible folding of biopolymer film is observed in response to water, whereas, an irreversible folding is observed in the presence of an aromatic alcohol (AA) solution of different molar concentrations. The folding and unfolding behavior originates from the coupled deformation-diffusion phenomena. Our study indicates that the presence of an AA influences the relaxation behavior of polymer chains, which in turn affects the release of stored strain energy during folding. Controlling the reversibility as well as the actuation time of the biopolymer film by tuning the solvent is explained in detail at the bulk scale by applying appropriate experimental techniques. The underlying mechanism for the observed phenomena is complemented by performing a simulation study for a single polymer chain at the molecular length scale. Due to the solvent-triggered hygromorphic response, biopolymer films exhibit huge potential as sensors, soft robots, drug delivery agents, morphing medical devices and in biomedical applications. We provide experimental evidence for the weight lifting capacity of permanently folded membranes, amounting to ~200 times their own weight. PMID- 29415094 TI - Directed self-assembly of dual metal ions with ligands: towards the synthesis of noble metal/metal oxide composites with controlled facets. AB - The large-scale synthesis of noble metal/metal oxide spheres with controlled facets was for the first time enabled by making use of a bottom-up self-assembly strategy. PMID- 29415095 TI - Effect of Dairy Manure Storage Conditions on the Survival of E. coli O157:H7 and Listeria. AB - Dairy manure is regularly applied to crop fields as a solid or liquid to improve the soil nutrient status. However, pathogens may survive during manure storage and enter the environment during application. In this study, three storage practices were evaluated to understand the survival patterns of O157:H7 and spp. in dairy manure using a culture-based approach. To replicate common farm manure storage techniques, solid manure was stacked as piles with periodic turning or as static piles without turning, whereas liquid manure (feces, urine, and water) was stored as a slurry in small tanks to simulate lagoon conditions. The and levels in the manure samples were determined for 29 wk. Results showed that there was an initial reduction in bacteria levels in the first month; however, both and managed to survive in the solid manure piles for the full study period. In slurry samples, was not detected after 14 wk, but survived until the end of the experiment at relatively lower levels than in the solid manure piles. Ambient weather and pile size were identified as the main reasons for bacteria survival during the course of the experiment. The outcome of this study is important in terms of understanding pathogen survival in manure piles and slurries prior to their application to crop fields. PMID- 29415096 TI - Changes in Water Quality of Grand Lake St. Marys Watershed Following Implementation of a Distressed Watershed Rules Package. AB - Grand Lake St. Marys watershed has drawn attention over the past decade as water quality issues resulting from nutrient loading have come to the forefront of public opinion, political concern, and scientific study. The objective of this study was to assess long-term changes in water quality (nutrient and sediment concentrations) following the distressed watershed rules package instituted in 2011. Since that time, a variety of rules (e.g., winter manure ban) and best management practices (cover crops, manure storage or transfers, buffers, etc.) have been implemented. We used a general linear model to assess variation in total suspended solids, particulate phosphorus, soluble reactive phosphorus (SRP), nitrate N, and total Kjeldahl nitrogen concentrations from daily Chickasaw Creek (drains ~25% of watershed) samples spanning 2008 to 2016. Parameters were related to flow (higher values during high flows), timing (lower values during winter months), and the implementation of the distressed watershed rules package (lower values following implementation). Overall, reductions following the distressed designation for all parameters ranged from 5 to 35% during medium and high flow periods (with exception of SRP). Reductions were even more pronounced during winter months covered by the manure ban, where all parameters (including SRP) exhibited decreases at medium and high flows between 20 and 60%. While the reductions seen in this study are significant, concentrations are still highly elevated and continue to be a problem. We are optimistic that this study will serve to inform future management in the region and elsewhere. PMID- 29415097 TI - Beyond the Edge: Linking Agricultural Landscapes, Stream Networks, and Best Management Practices. AB - Despite much research and investment into understanding and managing nutrients across agricultural landscapes, nutrient runoff to freshwater ecosystems is still a major concern. We argue there is currently a disconnect between the management of watershed surfaces (agricultural landscape) and river networks (riverine landscape). These landscapes are commonly managed separately, but there is limited cohesiveness between agricultural landscape-focused research and river science, despite similar end goals. Interdisciplinary research into stream networks that drain agricultural landscapes is expanding but is fraught with problems. Conceptual frameworks are useful tools to order phenomena, reveal patterns and processes, and in interdisciplinary river science, enable the joining of multiple areas of understanding into a single conceptual-empirical structure. We present a framework for the interdisciplinary study and management of agricultural and riverine landscapes. The framework includes components of an ecosystems approach to the study of catchment-stream networks, resilience thinking, and strategic adaptive management. Application of the framework is illustrated through a study of the Fox Basin in Wisconsin, USA. To fully realize the goal of nutrient reduction in the basin, we suggest that greater emphasis is needed on where best management practices (BMPs) are used within the spatial context of the combined watershed-stream network system, including BMPs within the river channel. Targeted placement of BMPs throughout the riverine landscape would increase the overall buffering capacity of the system to nutrient runoff and thus its resilience to current and future disturbances. PMID- 29415098 TI - Arsenic Speciation and Availability in Orchard Soils Historically Contaminated with Lead Arsenate. AB - Lead arsenate is an environmentally hazardous contaminant that was applied as a pesticide in orchards during the early 1900s. Elevated arsenic (As) concentrations persist in soils where lead arsenate was applied. To assess the risk associated with historic lead arsenate contamination, the retention, bioavailability, and speciation of soil As were evaluated in three historically contaminated orchard soils. Stirred-flow desorption studies and in vitro physiologically based extractions were used to assess the mobility and relative bioavailability of soil As, respectively. Synchrotron-based X-ray absorption spectroscopy was used to determine soil As speciation. Arsenic concentrations in former orchard soils ranged from 11.8 to 59.0 mg kg. Less than 22% of total As was considered bioavailable according to in vitro extractions. Up to 15% of soil As was desorbed in 10 mM KCl, but desorption with phosphate solutions resulted in release of up to 70% of total As dependent on soil type. Desorption data suggest that arsenate is primarily sorbed via inner-sphere complexation, and elevated concentrations of competing ions in soil solution may increase mobility of soil As. Arsenic was primarily present in the As(V) oxidation state, the less mobile form of As. Combined results from X-ray absorption spectroscopy and desorption studies indicate that As primarily exists as sorbed species, likely to ubiquitously present Fe- and Al-oxides in soils. Results demonstrate that soil As from these historically contaminated orchards is mostly in stable, nonhazardous forms, but factors such as Fe- and Al-oxide content and land management practices have a significant effect on As transport and bioavailability. PMID- 29415099 TI - Evaluation of Watershed-Scale Simulations of In-Stream Pesticide Concentrations from Off-Target Spray Drift. AB - The estimation of pesticide concentrations in surface water bodies is a critical component of the environmental risk assessment process required by regulatory agencies in North America, the European Union, and elsewhere. Pesticide transport to surface waters via deposition from off-field spray drift can be an important route of potential contamination. The spatial orientation of treated fields relative to receiving water bodies make prediction of off-target pesticide spray drift deposition and resulting aquatic estimated environmental concentrations (EECs) challenging at the watershed scale. The variability in wind conditions further complicates the simulation of the environmental processes leading to pesticide spray drift contributions to surface water. This study investigates the use of the Soil Water Assessment Tool (SWAT) for predicting concentrations of malathion (O,O-deimethyl thiophosphate of diethyl mercaptosuccinate) in a flowing water body when exposure is a result of off-target spray drift, and assesses the model's performance using a parameterization typical of a screening-level regulatory assessment. Six SWAT parameterizations, each including incrementally more site-specific data, are then evaluated to quantify changes in model performance. Results indicate that the SWAT model is an appropriate tool for simulating watershed scale concentrations of pesticides resulting from off-target spray drift deposition. The model predictions are significantly more accurate when the inputs and assumptions accurately reflect application practices and environmental conditions. Inclusion of detailed wind data had the most significant impact on improving model-predicted EECs in comparison to observed concentrations. PMID- 29415100 TI - Litter Type and Number of Flocks Affect Sex Hormones in Broiler Litter. AB - Broiler litter contains 17beta-estradiol, estrone, and testosterone, which can contaminate surface waters when surface applied to grasslands and no-till fields. The objective of this study was to evaluate the effects of litter type (full or cake cleanout), litter treatment (none or sodium bisulfate), and number of flocks raised on the litter (1-5) on sex hormone concentrations. Our results showed that in untreated broiler litter, cake cleanout had greater concentrations of 17beta estradiol, estrone, and testosterone than full cleanout, whereas in litter treated with sodium bisulfate, only the concentration of 17beta-estradiol was greater in cake than in full cleanout. The concentrations of 17beta-estradiol and estrone in untreated broiler litter increased as the number of flocks increased from one to three, with the largest increase observed for estrone in cake cleanout. We also sampled three broiler houses in brooding and nonbrooding sections during the growout period. We found no differences in hormone concentrations between sections of each house, but changes in hormone concentrations during growout varied depending on broiler litter water content. Water contents corresponding to ~60% water-filled porosity favored a decrease in hormone concentrations with time, whereas a water-filled porosity of 44% was associated with increases in hormone concentration, probably due to slow decomposition rates. Our results suggest that cake cleanout of untreated litter, as well as all cleanouts from houses that have raised several flocks on the same bedding, may be good targets for treatments that can reduce hormone concentrations before the litter is surface applied to fields. PMID- 29415101 TI - Urea Hydrolysis and Calcium Carbonate Precipitation in Gypsum-Amended Broiler Litter. AB - Broiler () litter is subject to ammonia (NH) volatilization losses. Previous work has shown that the addition of gypsum to broiler litter can increase nitrogen mineralization and decrease NH losses due to a decrease in pH, but the mechanisms responsible for these effects are not well understood. Therefore, three laboratory studies were conducted to evaluate the effect of gypsum addition to broiler litter on (i) urease activity at three water contents, (ii) calcium carbonate precipitation, and (iii) pH. The addition of gypsum to broiler litter increased ammonium concentrations ( < 0.0033) and decreased litter pH by 0.43 to 0.49 pH units after 5 d ( < 0.0001); however, the rate of urea hydrolysis in treated litter only increased on Day 0 for broiler litter with low (0.29 g HO g) and high (0.69 g HO g) water contents, and on Day 3 for litter with medium (0.40 g HO g) water content ( < 0.05). Amending broiler litter with gypsum also caused an immediate decrease in litter pH (0.22 pH units) due to the precipitation of calcium carbonate (CaCO) from gypsum-derived calcium and litter bicarbonate. Furthermore, as urea was hydrolyzed, more urea-derived carbon precipitated as CaCO in gypsum-treated litter than in untreated litter ( < 0.001). These results indicate that amending broiler litter with gypsum favors the precipitation of CaCO, which buffers against increases in litter pH that are known to facilitate NH volatilization. PMID- 29415102 TI - Applicability of Eddy Covariance to Estimate Methane Emissions from Grazing Cattle. AB - Grazing systems represent a significant source of enteric methane (CH), but available techniques for quantifying herd scale emissions are limited. This study explores the capability of an eddy covariance (EC) measurement system for long term monitoring of CH emissions from grazing cattle. Measurements were made in two pasture settings: in the center of a large grazing paddock, and near a watering point where animals congregated during the day. Cattle positions were monitored through time-lapse images, and this information was used with a Lagrangian stochastic dispersion model to interpret EC fluxes and derive per animal CH emission rates. Initial grazing paddock measurements were challenged by the rapid movement of cattle across the measurement footprint, but a feed supplement placed upwind of the measurements helped retain animals within the footprint, allowing emission estimates for 20% of the recorded daytime fluxes. At the water point, >50% of the flux measurement periods included cattle emissions. Overall, cattle emissions for the paddock site were higher (253 g CH m adult equivalent [AE] d, SD = 75) and more variable than emissions at the water point (158 g CH AE d, SD = 34). Combining results from both sites gave a CH production of 0.43 g kg body weight, which is in range of other reported emissions from grazing animals. With an understanding of animal behavior to allow the most effective use of tower placement, the combination of an EC measurement platform and a Lagrangian stochastic model could have practical applications for long-term monitoring of fluxes in grazing environments. PMID- 29415103 TI - Thermocouple Probe Orientation Affects Prescribed Fire Behavior Estimation. AB - Understanding the relationship between fire intensity and fuel mass is essential information for scientists and forest managers seeking to manage forests using prescribed fires. Peak burning temperature, duration of heating, and area under the temperature profile are fire behavior metrics obtained from thermocouple datalogger assemblies used to characterize prescribed burns. Despite their recurrent usage in prescribed burn studies, there is no simple protocol established to guide the orientation of thermocouple installation. Our results from dormant and growing season burns in coastal longleaf pine ( Mill.) forests in South Carolina suggest that thermocouples located horizontally at the litter soil interface record significantly higher estimates of peak burning temperature, duration of heating, and area under the temperature profile than thermocouples extending 28 cm vertically above the litter-soil interface ( < 0.01). Surprisingly, vertical and horizontal estimates of these measures did not show strong correlation with one another ( <= 0.14). The horizontal duration of heating values were greater in growing season burns than in dormant season burns ( < 0.01), but the vertical values did not indicate this difference ( = 0.52). Field measures of fuel mass and depth before and after fire showed promise as significant predictive variables ( <= 0.05) for the fire behavior metrics. However, all correlation coefficients were less than or equal to = 0.41. Given these findings, we encourage scientists, researchers, and managers to carefully consider thermocouple orientation when investigating fire behavior metrics, as orientation may affect estimates of fire intensity and the distinction of fire treatment effects, particularly in forests with litter-dominated surface fuels. PMID- 29415104 TI - Impact of Nanoparticle Surface Properties on the Attachment of Cerium Oxide Nanoparticles to Sand and Kaolin. AB - Soil texture has been found to be a critical factor in regulating the fate and transport of cerium oxide nanoparticles (CeONPs) in the terrestrial environment. However, the underlying mechanisms for the interactions between CeONPs and different components of soil are still poorly understood. The attachment of CeONPs onto two typical components of soil (sand and kaolin) in batch experiments were investigated to provide insights into the retention and bioavailability of CeONPs in soil. Surface properties of CeONPs, including surface charge and surface coating condition, had strong impacts on the interactions between CeONPs and soil particles. Positively charged CeONPs [CeONPs(+)] displayed the greatest attachment onto kaolin, whereas the negatively charged CeONPs [CeONPs(-)] showed poorest attachment onto sand. The attachment of CeONPs onto kaolin was significantly greater than onto sand, irrespective of surface charge. Homoaggregation of CeONPs increased the size of CeONPs on the surface of sand and kaolin. Extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) calculations agreed with the experimental observations that surface charge and coating condition of CeONPs played a vital role in the homoaggregation and adsorption of CeONPs. For CeONPs(-) coated with polyvinylpyrrolidone (PVP), the steric repulsion between soil particles and CeONPs increases rapidly with the increase of maximum surface concentration of PVP. Adsorption isothermal fittings indicated that the adsorption of CeONPs onto sand and kaolin can be properly described by the Dubinin-Radushkevich isotherm. The results obtained in this study are crucial for the understanding of the fate and transport of engineered nanomaterials in the environment. PMID- 29415105 TI - Potential Nitrogen Losses in Relation to Spatially Distinct Soil Management History and Biochar Addition. AB - Soil functional zone management strategies including ridge tillage have been shown to increase in-row (IR) compared with between-row (BR) soil nitrogen (N) availability due to the development of contrasting soil properties and carbon (C) and N cycling processes. However, potential N losses may also increase for IR positions, representing an environmental tradeoff. Although biochar has putative contributions to tightening N cycles, its effect within spatially distinct management zones has not been quantified. This study evaluated the potential for biochar to reduce soil nitrous oxide (NO) emissions and leachate nitrate (NO) concentrations as influenced by changes in soil properties after 5 yr of ridge tillage in a silty clay loam soil. Soil columns for IR and BR positions were treated with and without biochar at 10 Mg ha in a 100-d laboratory incubation ( = 4 replications). Results indicate that biochar increased average daily NO emissions in IR by 30% but decreased them by 39% in BR. In both positions, biochar decreased NO concentrations in soil solution and leachate by 11 to 20% and 10 to 15%, respectively. Our findings suggest that long-term changes in soil C and N cycling processes may increase the potential for NO emissions in IR compared with BR positions. Although most biochar studies have not accounted for within-field soil variability, our results indicate that biochar may differentially affect soil NO emissions depending on spatially distinct soil management history. Findings from this laboratory study stress the need for field research evaluating spatial differences in biochar NO mitigation potential. PMID- 29415106 TI - Decreased Electron Transfer between Cr(VI) and AH2DS in the Presence of Goethite. AB - 9,10-Anthraquinone-2,6-disulfonic acid (AQDS) is commonly used as a model species to examine the influence of quinones on different biogeochemical cycles. The reduced form of this quinone, AHDS, can donate electrons to the toxic metal species Cr(VI), leading to the precipitation of less soluble Cr(III) phases. Due to the environmental abundance of Fe(III) (oxyhydr)oxides, such as goethite (alpha-FeOOH), it is important to study the role of these mineral phases on the electron transfer reaction between AHDS and Cr(VI). In this study, this electron transfer reaction is examined in the presence and absence of goethite at three different ratios of AHDS/Cr(VI). Ultraviolet-visible spectroscopy is used to qualitatively assess the oxidation state of AQDS during reactions with goethite. Iron K-edge and Cr K-edge X-ray absorption spectroscopy are used to examine the role of goethite in electron transfer and identify Cr(III) phases that form. Goethite inhibits the extent of Cr(VI) reduction to Cr(III), most notably at the highest ratio of AHDS/Cr(VI) investigated. Production of semiquinone radical species may limit electron transfer and decrease the yields of Fe(II) and Cr(III), both in the presence and absence of goethite. Understanding abiotic electron transfer reactions that occur in systems with multiple redox active species is important to determine the contribution of abiotic redox reactions to Fe biogeochemical cycling in natural soils. PMID- 29415107 TI - Nitrogen Management Affects Nitrous Oxide Emissions under Varying Cotton Irrigation Systems in the Desert Southwest, USA. AB - Irrigation of food and fiber crops worldwide continues to increase. Nitrogen (N) from fertilizers is a major source of the potent greenhouse gas nitrous oxide (NO) in irrigated cropping systems. Nitrous oxide emissions data are scarce for crops in the arid western United States. The objective of these studies was to assess the effect of N fertilizer management on NO emissions from furrow irrigated, overhead sprinkler-irrigated, and subsurface drip-irrigated cotton ( L.) in Maricopa, AZ, on Trix and Casa Grande sandy clay loam soils. Soil test- and canopy-reflectance-based N fertilizer management were compared. In the furrow and overhead sprinkler-irrigated fields, we also tested the enhanced efficiency N fertilizer additive Agrotain Plus as a NO mitigation tool. Nitrogen fertilizer rates as liquid urea ammonium nitrate ranged from 0 to 233 kg N ha. Two applications of N fertilizer were made with furrow irrigation, three applications under overhead sprinkler irrigation, and 24 fertigations with subsurface drip irrigation. Emissions were measured weekly from May through August with 1-L vented chambers. NO emissions were not agronomically significant, but increased as much as 16-fold following N fertilizer addition compared to zero-N controls. Emission factors ranged from 0.10 to 0.54% of added N fertilizer emitted as NO-N with furrow irrigation, 0.15 to 1.1% with overhead sprinkler irrigation, and <0.1% with subsurface drip irrigation. The reduction of NO emissions due to addition of Agrotain Plus to urea ammonium nitrate was inconsistent. This study provides unique data on NO emissions in arid-land irrigated cotton and illustrates the advantage of subsurface drip irrigation as a low NO source system. PMID- 29415108 TI - Export of Total, Particulate, and Apatite Phosphorus from Forested and Agricultural Watersheds. AB - Concentrations of apatite phosphorus (P) have been shown to be greater in the soils of agricultural and disturbed watersheds than in soils of forested watersheds. This observation suggests that changes in the relative concentration of apatite P in the sedimentary record of lakes might be a useful marker for land use changes in the watershed where sediments are dominated by allochthonous loading. To determine if P export in streams is indicative of soil P in the watershed, we measured the export of total, particulate, and apatite P in first order streams draining four forested and four agricultural watersheds in western Pennsylvania. Streams draining agricultural watersheds exported significantly more total suspended solids (TSS) and more total, particulate, soluble, and apatite P, particularly during periods of high discharge, than did streams draining forested watersheds. Total suspended solids exported from forested watersheds contained similar amounts of apatite P (MUg apatite P g TSS), as did agricultural watersheds in spite of lower soil concentrations. However, since agricultural watershed exported almost four times the mass of TSS, the net export of apatite P was greater than from forested streams. These results confirm the increased apatite P export from agricultural watersheds and suggest that inferences drawn from the profiles of apatite P in the sedimentary record of lakes may reliably indicate historical disturbances in watersheds caused by agriculture or other erosional events. PMID- 29415109 TI - Adsorption of Selenite and Selenate on Ferrihydrite in the Presence and Absence of Dissolved Organic Carbon. AB - This study examines selenite [Se(IV)] and selenate [Se(VI)] adsorption on two line ferrihydrite in the presence and absence of two low-molecular-weight dissolved organic carbon (DOC) species, citric and salicylic acid. Ferrihydrite surface potential measurements were also examined to identify shifts in isoelectric points, which suggest possible adsorption mechanisms. Sorption was completed in batch reactor systems at environmentally relevant pH. Our results indicate citric acid suppressed both Se(IV) and Se(VI) sorption on ferrihydrite, which may be caused by competition. This was especially evident at pH 5 to 7 for Se(IV) and pH 5 to 6 for Se(VI). Little sorption suppression was observed for both Se species in the presence of salicylic acid. In the presence of Se(IV) and Se(VI), citric acid adsorption was reduced (pH 5-8). Salicylic acid sorption was almost completely suppressed in the presence of Se(IV) throughout the entire pH range examined, with minimal sorption occurring at pH 5. In the presence of Se(VI), the largest reduction in salicylic acid sorption occurred at pH 5 to 6. Small shifts in the surface potential of ferrihydrite at higher pH suggest that Se(VI) and salicylic acid form weak, outer-sphere complexes. However, at pH 5 and 6, there is a shift in the surface potential measurements to more negative values, indicating possible formation of stronger, inner-sphere complexes. Larger surface potential shifts for Se(IV) and citric acid suggest the formation of strong, inner-sphere complexes. This work demonstrates the ability of low molecular-weight DOC species (particularly for citric acid) to increase Se(IV) and Se(VI) solubility through sorption suppression. PMID- 29415110 TI - Use of Molecular Markers to Compare Escherichia coli Transport with Traditional Groundwater Tracers in Epikarst. AB - Bacterial contamination of karst aquifers is a global concern as water quality deteriorates in the face of decreasing water security. Traditional abiotic groundwater tracers, which do not exhibit surface properties similar to bacteria, may not be good proxies for risk assessment of bacterial transport in karst environments. This study examined the transport and attenuation of two isolates of in relation to traditional groundwater tracers (rhodamine WT dye and 1-MUm diam. latex microspheres) through ~30 m of epikarst in western Kentucky. Differential movement of the four tracers was observed, with tracer behavior dependent on flow conditions. Dye arrived at the sampling site prior to particulates. Molecular biology techniques successfully detected bacteria in the cave and showed attenuation was greater for a bacterial isolate with high attachment efficiency compared with an isolate known to have low attachment efficiency. Microspheres were first detected simultaneously with the low attachment isolate but attained maximum concentrations during increases in discharge >11 d post-injection. Bacteria were remobilized by storm events >60 d after injection, illustrating the storage capacity of epikarst with regard to potential contaminants. The two bacterial strains were not transported at the same rate within the epikarst, showing breakthroughs during differing storm events and illustrating the importance of cell surface chemistry in the prediction of microorganism movement. Moreover, this study has shown that molecular analysis can be successfully used to target, quantify, and track introduced microbial tracers in karst terrains. PMID- 29415111 TI - A Comprehensive Review of the Fate of Pathogens during Vermicomposting of Organic Wastes. AB - Management of both municipal and industrial organic wastes remains a major threat to biota and the environment due to the presence of pathogens in abundance. Vermicomposting employing earthworms is increasingly gaining attention as a sustainable and ecofriendly technique to transform and sanitize a variety of organic wastes into nutrient-rich biofertilizer. Although considerable research has been undertaken to show that vermicomposting can significantly reduce pathogenic contents, there is little effort to summarize the various mechanisms responsible for it. With the aim to assess the fate of pathogens during vermicomposting of various organic wastes, this article provides a comprehensive summary on the occurrence of pathogens in a variety of wastes vis-a-vis pathogens standards, the efficacy of the process for pathogen reduction, and current knowledge of the plausible mechanisms involved. It is evident from the present study that earthworms and endosymbiotic microbes during vermicomposting tend to eliminate pathogens by enhancing enzymatic activities in both gut- and cast associated processes. Pathogen reduction during vermicomposting can be plausibly attributed to direct actions like microbial inhibition due to intestinal enzymatic action, and secretion of coelomic fluids with antibacterial properties, as well as indirect actions like stimulation of endemic microbes leading to competition and antagonism, and aeration by burrowing activity. Further, the pathogen reduction during vermicomposting is largely selective, and earthworms exert a differential effect according to the earthworm species and whether the pathogen considered is Gram-positive or -negative, owing to its cell wall composition. However, further research is necessary to understand the exact mechanisms involved for pathogen reduction during vermistabilization of municipal and industrial organic wastes. PMID- 29415112 TI - Integrated Crop-Livestock Systems and Water Quality in the Northern Great Plains: Review of Current Practices and Future Research Needs. AB - Integrated crop-livestock systems hold potential to achieve environmentally sustainable production of crop and livestock products. Although previous studies suggest that integrated crop-livestock systems improve soil health, impacts of integrated crop-livestock systems on water quality and aquatic ecosystems are largely unknown. This review (i) summarizes studies examining surface water quality and soil leachate for management practices commonly used in integrated crop-livestock systems (e.g., no-till, cover crops, livestock grazing) with emphasis on the Northern Great Plains ecoregion of North America, (ii) quantifies management system effects on nutrient and total suspended solids concentrations and loads, and (iii) identifies information gaps regarding water quality associated with integrated crop-livestock systems and research needs in this area. In general, management practices used in integrated crop-livestock systems reduced losses of total suspended solids, nitrogen (N), and phosphorus (P) in surface runoff and soil leachate. However, certain management practices (e.g., no till or reduced tillage) reduced losses of total N (relative median change = 65%), whereas soluble P losses in runoff increased (57%). Conversely, practices such as grazing increased median total suspended solids (22%), nitrate (45%), total N (85%), and total P (25%) concentrations and loads in surface runoff and aquatic ecosystems. An improved understanding of the interactive effects of integrated crop-livestock management practices on surface water quality and soil leachate under current and future climate scenarios is urgently needed. To close this knowledge gap, future studies should focus on determining concentrations and loads of total suspended solids, N, P, and organic carbon in runoff and soil leachate from integrated crop-livestock systems. PMID- 29415113 TI - Supply and Transport Limitations on Phosphorus Losses from Agricultural Fields in the Lower Great Lakes Region, Canada. AB - Phosphorus (P) mobilization in agricultural landscapes is regulated by both hydrologic (transport) and biogeochemical (supply) processes interacting within soils; however, the dominance of these controls can vary spatially and temporally. In this study, we analyzed a 5-yr dataset of stormflow events across nine agricultural fields in the lower Great Lakes region of Ontario, Canada, to determine if edge-of-field surface runoff and tile drainage losses (total and dissolved reactive P) were limited by transport mechanisms or P supply. Field sites ranged from clay loam, silt loam, to sandy loam textures. Findings indicate that biogeochemical processes (P supply) were more important for tile drain P loading patterns (i.e., variable flow-weighted mean concentrations ([]) across a range of flow regimes) relative to surface runoff, which trended toward a more chemostatic or transport-limited response. At two sites with the same soil texture, higher tile [] and greater transport limitations were apparent at the site with higher soil available P (STP); however, STP did not significantly correlate with tile [] or P loading patterns across the nine sites. This may reflect that the fields were all within a narrow STP range and were not elevated in STP concentrations (Olsen-P, <=25 mg kg). For the study sites where STP was maintained at reasonable concentrations, hydrology was less of a driving factor for tile P loadings, and thus management strategies that limit P supply may be an effective way to reduce P losses from fields (e.g., timing of fertilizer application). PMID- 29415114 TI - Greenhouse Gas and Ammonia Emissions from Different Stages of Liquid Manure Management Chains: Abatement Options and Emission Interactions. AB - Farm livestock manure is an important source of ammonia and greenhouse gases. Concerns over the environmental impact of emissions from manure management have resulted in research efforts focusing on emission abatement. However, questions regarding the successful abatement of manure-related emissions remain. This study uses a meta-analytical approach comprising 89 peer-reviewed studies to quantify emission reduction potentials of abatement options for liquid manure management chains from cattle and pigs. Analyses of emission reductions highlight the importance of accounting for interactions between emissions. Only three out of the eight abatement options considered (frequent removal of manure, anaerobic digesters, and manure acidification) reduced ammonia (3-60%), nitrous oxide (21 55%), and methane (29-74%) emissions simultaneously, whereas in all other cases, tradeoffs were identified. The results demonstrate that a shift from single-stage emission abatement options towards a whole-chain perspective is vital in reducing overall emissions along the manure management chain. The study also identifies some key elements like proper clustering, reporting of influencing factors, and explicitly describing assumptions associated with abatement options that can reduce variability in emission reduction estimates. Prioritization of abatement options according to their functioning can help to determine low-risk emission reduction options, specifically options that alter manure characteristics (e.g., reduced protein diets, anaerobic digestion, or slurry acidification). These insights supported by comprehensive emission measurement studies can help improve the effectiveness of emission abatement and harmonize strategies aimed at reducing air pollution and climate change simultaneously. PMID- 29415115 TI - Cultural Eutrophication Is Reflected in the Stable Isotopic Composition of the Eastern Mudsnail, Nassarius obsoletus. AB - In aquatic ecosystems, biological indicators are used in concert with nutrient concentration data to identify habitat impairments related to cultural eutrophication. This approach has been less commonly implemented in coastal areas due to the dominance of physical conditions in structuring biological assemblage data. Here, we describe the use of the stable isotopic composition of (Say), the eastern mudsnail, as an indicator of cultural eutrophication for 40 locations in coastal estuaries in New York. We found N enrichment in mudsnail tissue where watersheds had high population densities, land use patterns were more urbanized, and when sampling sites were adjacent to wastewater treatment plant discharges. Stable carbon isotopes were responsive to salinity and watershed forest cover, with more saline sites reflecting a predominantly C or algal carbon isotopic signature and more forested sites a lighter isotopic signature reflecting greater inputs of C terrestrial detrital carbon. Mudsnail nitrogen isotopic composition had a high level of separation between more affected and pristine watersheds (from 6.6 to 14.10/00), highlighting its utility as an indicator. We thus propose that stable isotope values of estuarine biota, such as the eastern mudsnail, can be used in concert with water quality data to identify areas where improvements in water quality are needed and can also be used to identify sources of detrital carbon to estuarine environments. PMID- 29415116 TI - Effectiveness of probiotics on the occurrence of infections in older people: systematic review and meta-analysis. AB - Background: infectious diseases in older people are associated with higher mortality rates and probiotics have been hypothesised to reduce the occurrence of infection. Objectives: to assess the effectiveness and safety of probiotics in the occurrence of infections in older adults in comparison to placebo. Methods: a systematic review and meta-analysis of randomised placebo-controlled trials were conducted on 30 December 2016 using Medline, Embase, CENTRAL, Web of Science and LILACS databases. Efficacy outcomes were: occurrence of infection, quality of life, mortality and mean duration of infection per episode. Safety outcomes were adverse events. Data were analysed using relative risk ratios with 95% confidence intervals. Relative risk ratios were pooled where more than three estimates were available. Results: fifteen articles were included, with a total of 5,916 participants with a mean age of 75.21 years. The effect of probiotics was not significantly different from that reported for placebo on the occurrence of infection, adverse events, mortality or mean duration of infection episodes (relative risk (RR) 0.90, 95% confidence interval (CI) 0.76 to 1.08; RR 1.01, 95% CI 0.91 to 1.12; RR 1.09, 95% CI 0.70 to 1.72; MD -0.35, 95% CI -1.57 to 0.87, respectively). Conclusion: the current low-quality evidence does not support the use of probiotics for the reduction in the occurrence of infection in older adults, however, the safety outcomes were similar between probiotics and placebo. Further research is required to confirm these findings. PROSPERO: CRD42014013707. PMID- 29415117 TI - Attenuated Macrophage Infiltration in Glomeruli of Aged Mice Resulting in Ameliorated Kidney Injury in Nephrotoxic Serum Nephritis. AB - Senescent cells have deleterious effects on the tissue microenvironment through proinflammatory senescence-associated secretory phenotypes; meanwhile, the onset of glomerulonephritis is predominant in younger adults. To clarify the influence of aging on the onset and development of glomerulonephritis, we used a murine model of antibody-mediated nephritis. Sheep nephrotoxic serum was administered in C57BL/6J mice at 12 weeks (adult) or 18 months old (aged) after pre-immunization with sheep IgG. Depositions of sheep IgG and autologous mouse IgG along the glomerular basement membrane and the serum titer of anti-sheep IgG-specific mouse IgG were similar between adult and aged mice. However, kidney injury was depressed in aged mice, accompanied by reduced macrophage infiltration in the glomeruli. The mRNA expression of most chemokines involved in monocyte/macrophage chemotaxis was not different between adult and aged mice, but the cell surface expression of C-C chemokine receptor (CCR) 1 and CCR2 was down-regulated in the monocyte/macrophage lineage cells infiltrating the kidneys of aged nephritic mice. Furthermore, expression of all four isotypes of the Fcgamma receptor (FcgammaR) was reduced in these cells. Both CCR and FcgammaR expression were down regulated in monocyte/macrophage lineage cells, resulting in attenuated glomerular infiltration of these cells and impaired glomerular injury in aged mice. PMID- 29415118 TI - Corrigendum to: "Phenology of the Potato Psyllid, Bactericera cockerelli (Hemiptera: Triozidae), and "Candidatus Liberibacter solanacearum" in Commercial Potato Fields in Idaho". PMID- 29415119 TI - Schizophrenia polygenic risk score predicts mnemonic hippocampal activity. AB - The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001. PMID- 29415120 TI - Impact of the ST101 clone on fatality among patients with colistin-resistant Klebsiella pneumoniae infection. AB - Objectives: We describe the molecular characteristics of colistin resistance and its impact on patient mortality. Methods: A prospective cohort study was performed in seven different Turkish hospitals. The genotype of each isolate was determined by MLST and repetitive extragenic palindromic PCR (rep-PCR). Alterations in mgrB were detected by sequencing. Upregulation of pmrCAB, phoQ and pmrK was quantified by RT-PCR. mcr-1 and the genes encoding OXA-48, NDM-1 and KPC were amplified by PCR. Results: A total of 115 patients diagnosed with colistin resistant K. pneumoniae (ColR-Kp) infection were included. Patients were predominantly males (55%) with a median age of 63 (IQR 46-74) and the 30 day mortality rate was 61%. ST101 was the most common ST and accounted for 68 (59%) of the ColR-Kp. The 30 day mortality rate in patients with these isolates was 72%. In ST101, 94% (64/68) of the isolates had an altered mgrB gene, whereas the alteration occurred in 40% (19/47) of non-ST101 isolates. The OXA-48 and NDM-1 carbapenemases were found in 93 (81%) and 22 (19%) of the total 115 isolates, respectively. In multivariate analysis for the prediction of 30 day mortality, ST101 (OR 3.4, CI 1.46-8.15, P = 0.005) and ICU stay (OR 7.4, CI 2.23-29.61, P = 0.002) were found to be significantly associated covariates. Conclusions: Besides ICU stay, ST101 was found to be a significant independent predictor of patient mortality among those infected with ColR-Kp. A significant association was detected between ST101 and OXA-48. ST101 may become a global threat in the dissemination of colistin resistance and the increased morbidity and mortality of K. pneumoniae infection. PMID- 29415121 TI - Mayer-Rokitansky-Kuster-Hauser Syndrome: A Unique Case Presentation. AB - Background: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a congenital condition characterized by aplasia of the vagina with or without concurrent uterine and/or cervical aplasia. Type II (MURCS) is a rare form involving MUllerian agenesis, Renal agenesis, and Cervicothoracic Somite anomalies. Case: A 17-yr-old virginal female presented for evaluation of primary amenorrhea and pelvic pain. Her medical history was significant for a bicuspid aortic valve and right radial dysplasia. She demonstrated normal secondary sexual development and a normal karyotype. Pelvic magnetic resonance imaging revealed an aplastic vaginal, no identifiable cervix or uterus, and normal ovaries. A laparoscopy was performed for the evaluation of pain and findings were significant for bilateral uterine horn and fallopian tube remnants noted along the pelvic sidewalls. This patient evaluation suggests a unique presentation of MURCS association. Conclusion: To our knowledge, this is the first case of MRKH presenting with a bicuspid aortic valve and radial dysplasia. A review of the literature reveals no other cases of MRKH with these unique anomalies. PMID- 29415122 TI - How to swim with sharks: a perspective on Voltaire Cousteau's primer. PMID- 29415123 TI - Mechanistic modelling of coupled phloem/xylem transport for L-systems: combining analytical and computational methods. AB - Background and Aims: Transport of carbohydrates and water are essential aspects of plant function. The aim of this study was to develop and test the methods for mechanistic modelling of quasi-stationary coupled phloem/xylem transport in the context of functional-structural plant modelling. Methods: The novelty of this approach is in combining analytical and computational methods. The plant structure is modelled at a metamer level with the internodes represented by conduit elements and the lateral organs represented by sources and sinks. Transport equations are solved analytically for each internode and then the solutions are adjusted and 'sewn' together using an iterative computational procedure taking into account concentration-dependent sinks and sources. The model is implemented in L-studio and uses the aspect-oriented modelling approach for phloem/xylem coupling. Key Results: To our knowledge, this is the first transport model that provides continuous distributions of the system variables in a complex developing structure. The model takes into account non-linear dependence of phloem resistance and osmotic potential on the local carbohydrate concentration. The model solutions show excellent agreement with the existing results of other analytical and numerical models. These comparisons confirm the validity of the approximations made in the model. Combining analytical and computational methods made it possible to take into account continuous sink/source distribution within internodes without much increase in the complexity of the computational procedure, because the necessary changes in the model were mostly in the analytical part. The results emphasize sensitivity of phloem flux and lateral xylem flux to the presence of distributed sinks and sources along the transport system. Conclusions: The presented approach provides a new insight into mechanistic modelling of phloem/xylem transport in growing plants. It will be useful for both fine-scale modelling of carbohydrate dynamics and for creating simpler models at a growth unit level. PMID- 29415124 TI - Distinct Beta-band Oscillatory Circuits Underlie Corticospinal Gain Modulation. AB - Rhythmic synchronization of neurons is known to affect neuronal interactions. In the motor system, oscillatory power fluctuations modulate corticospinal excitability. However, previous research addressing phase-specific gain modulation in the motor system has resulted in contradictory findings. It remains unclear how many time windows of increased responsiveness each oscillatory cycle provides. Moreover, we still lack conclusive evidence as to whether the motor cortex entails an intrinsic response modulation along the rhythm cycle, as shown for spinal neurons. We investigated this question with single-pulse transcranial magnetic stimulation over the primary motor cortex at rest. Application of near motor threshold stimuli revealed a frequency- and phase-specific gain modulation at both cortical and spinal level, independent of the spontaneous oscillatory power fluctuations at each level. We detected bilateral sensorimotor circuits in the lower beta-band (14-17 Hz) and unilateral corticospinal circuits in the upper beta-band (20-24 Hz). These findings provide novel evidence that intrinsic activity in the human motor cortex modulates input gain along the beta oscillatory cycle within distinct circuits. In accordance with periodic alternations of synchronous hyper- and depolarization, increased neuronal responsiveness occurred once per oscillatory beta cycle. This information may lead to new brain state-dependent and circuit-specific interventions for targeted neuromodulation. PMID- 29415126 TI - Central Nervous System Germinomas Express Programmed Death Ligand 1. AB - Immunomodulation and tumor-induced tolerance is one of the central mechanisms in the oncogenesis of malignant and benign neoplasms. While numerous pathways have been described, signaling through the programmed death receptor 1 (PD-1) on T lymphocytes, via activation through its ligand, programmed death ligand 1 (PD-L1) expressed on tumor cells is one of the central pathways involved in tumor-induced tolerance. While the neoplastic component of germinomas of the CNS is the germ cell, these tumors also exhibit an abundance of quiescent tumor-infiltrating lymphocytes. We therefore investigated whether PD-L1 expression may be responsible for germinoma-induced T cell anergy, and if these tumors may be susceptible to immunotherapy. Pathologic specimens obtained from 21 cases of CNS germinomas between 2000 and 2016 were analyzed for the presence of PD-L1 and PD-1 expression by immunohistochemistry. Nineteen of 21 germinomas (90%) harbored germ cell components that stained positively for PD-L1. Positive lymphocyte staining for PD-L1 was evident in 16 cases. PD-1 expression was largely confined to lymphocytes; PD-L1 therefore may contribute to lymphocyte quiescence observed in these tumors. These results raise the possibility that immune checkpoint inhibitors such as nivolumab may have a therapeutic role in future treatment of germinomas. PMID- 29415127 TI - Response to Weisman et al. PMID- 29415125 TI - Elongator subunit 3 (ELP3) modifies ALS through tRNA modification. AB - Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder of which the progression is influenced by several disease-modifying factors. Here, we investigated ELP3, a subunit of the elongator complex that modifies tRNA wobble uridines, as one of such ALS disease modifiers. ELP3 attenuated the axonopathy of a mutant SOD1, as well as of a mutant C9orf72 ALS zebrafish model. Furthermore, the expression of ELP3 in the SOD1G93A mouse extended the survival and attenuated the denervation in this model. Depletion of ELP3 in vitro reduced the modified tRNA wobble uridine mcm5s2U and increased abundance of insoluble mutant SOD1, which was reverted by exogenous ELP3 expression. Interestingly, the expression of ELP3 in the motor cortex of ALS patients was reduced and correlated with mcm5s2U levels. Our results demonstrate that ELP3 is a modifier of ALS and suggest a link between tRNA modification and neurodegeneration. PMID- 29415128 TI - Expression III: patients' expectations and preferences regarding physician patient relationship and clinical management-results of the international NOGGO/ENGOT-ov4-GCIG study in 1830 ovarian cancer patients from European countries. AB - Backround: The primary aim of this study was to investigate information needs and treatment preferences of patients with ovarian cancer, focusing especially on physician-patient relationship and treatment. Patients and methods: A questionnaire was developed based on the experiences of the national German survey 'Expression II', and was provided to patients with ovarian cancer either at initial diagnosis or with recurrent disease via Internet (online-version) or as print-out-version. Results: From December 2009 to October 2012, a total of 1830 patients with ovarian cancer from eight European countries (Austria, Belgium, France, Germany, Italy, Poland, Romania, Spain) participated, 902 (49.3%) after initial diagnosis and 731 (39.9%) with recurrent ovarian cancer. The median age was 58 years (range 17-89). Nearly all patients (96.2%) had experienced upfront surgery followed by first-line chemotherapy (91.8%). The majority of patients were satisfied with the completeness and comprehensibility of the explanation about the diagnosis and treatment options. The three most important aspects, identified by patients to improve the treatment for ovarian cancer included: 'the therapy should not induce alopecia' (42%), 'there must be more done to counter fatigue' (34.5%) and 'the therapy should be more effective' (29.7%). Out of 659 (36%) patients, who were offered participation in a clinical trial, 476 (26%) were included. Conclusion: This study underlines the high need of patients with ovarian cancer for all details concerning treatment options irrespective of their cultural background, the stage of disease and the patient's age. Increased information requirements regarding potential side effects and treatment alternatives were recorded. Besides the need for more effective therapy, alopecia and fatigue are the most important side effects of concern to patients. PMID- 29415130 TI - Editorial: EP Europace - Present and Future. PMID- 29415131 TI - Bark Colonization of Kiln-Dried Wood by the Walnut Twig Beetle: Effect of Wood Location and Pheromone Presence. AB - The walnut twig beetle (Pityophthorus juglandis Blackman) (Coleoptera: Curculionidae) is a regulated pest in the United States due to its causal role in thousand cankers disease of walnut trees, including the commercially valuable eastern black walnut (Juglans nigra L.). Several state quarantines designed to limit spread of P. juglandis regulate movement of kiln-dried walnut lumber that contains bark. Previous research demonstrated that P. juglandis will enter and re emerge from bark of kiln-dried, J. nigra slabs subjected to extreme beetle pressure (baited with a pheromone lure and hung in infested J. nigra trees). This study evaluated P. juglandis bark colonization of both kiln-dried and fresh J. nigra slabs, varying the presence of aggregation pheromone and relative proximity to a beetle source. Wood treatment, slab location, and pheromone presence all significantly affected P. juglandis colonization, as assessed by subsequent beetle emergence. When placed on the ground directly beneath infested trees, kiln dried slabs were not colonized, and fresh slabs were colonized only when baited with the pheromone lure (6/14 replicates). When placed in crowns of infested trees, kiln-dried slabs were colonized only when baited with pheromone (3/14 replicates), whereas fresh slabs were colonized with and without pheromone (14/14 and 1/13 replicates, respectively). Timing of emergence indicated that beetles did not reproduce in kiln-dried bark. Results suggest that the risk of kiln-dried walnut bark becoming colonized by the P. juglandis during movement of commercial wood products is very low. This information may be useful to government agencies that administer quarantines regulating the transport of walnut lumber. PMID- 29415132 TI - Effects of Irradiation Dose on Sterility Induction and Quality Parameters of Drosophila suzukii (Diptera: Drosophilidae). AB - Drosophila suzukii (Matsumura, 1931) (Diptera: Drosophilidae) is a widely distributed pest of soft-skinned and stone fruits that is controlled mainly with pesticides. An alternative to the chemical control is the sterile insect technique (SIT), an ecologically friendly method of pest management that could be used against D. suzukii. The objective of the present study was to evaluate the effects of gamma radiation on reproductive sterility, ovarian morphometry, and quality parameters of D. suzukii. Full female sterility was achieved at 75 Gy, while an adequate level of male sterility (99.67%) was obtained at 200 Gy. The ovarian size showed an exponential decay in function of irradiation dose increase. There was no significant influence of irradiation dose on the quality parameters evaluated. Our data suggest that gamma radiation can be recommended to be used in an SIT program for D. suzukii. PMID- 29415135 TI - A Case of Delayed Traumatic Vertebral Artery Dissection. AB - Vertebral artery dissection is of special clinical importance because of its often-delayed presentation and the risk of potentially permanent neurological deficit, or even death, as a result of injury. Once a rarely discovered injury, the better availability and use of computed tomography and magnetic resonance imaging have contributed to an increased incidence. Early diagnosis and treatment can almost eliminate the threat of acute cerebral vascular injury and save lives. In this report, we review a case of delayed traumatic vertebral artery dissection and discuss the key clinical findings and management strategies. PMID- 29415133 TI - Translation initiation of alphavirus mRNA reveals new insights into the topology of the 48S initiation complex. AB - The topology and dynamics of the scanning ribosomal 43S pre-initiation complex (PIC) bound to mRNA and initiation factors (eIFs) are probably the least understood aspects of translation initiation in eukaryotes. Recently, we described a trapping mechanism in alphavirus that stalls the PIC during scanning of viral mRNA. Using this model, we were able to snapshot for the first time the eIF4A helicase bound to mRNA in a 48S initiation complex assembled in vitro. This interaction was only detected in the presence of the natural stem loop structure (DLP) located downstream from the AUG in viral mRNA that promoted stalling of the PIC, suggesting that DLP stability was enough to jam the helicase activity of eIF4A in a fraction of assembled 48S complexes. However, a substantial proportion of DLP mRNA molecules were effectively unwound by eIF4A in vitro, an activity that alphaviruses counteract in infected cells by excluding eIF4A from viral factories. Our data indicated that eIF4A-mRNA contact occurred in (or near) the ES6S region of the 40S subunit, suggesting that incoming mRNA sequences penetrate through the ES6S region during the scanning process. We propose a topological model of the scanning PIC and how some viruses have exploited this topology to translate their mRNAs with fewer eIF requirements. PMID- 29415134 TI - Induction of a Senescence-Like Phenotype in Cultured Human Fetal Microglia During HIV-1 Infection. AB - HIV-1 causes premature aging in chronically infected patients. Despite effective anti-retroviral therapy, around 50% of patients suffer HIV-associated neurocognitive disorders (HAND), which likely potentiate aging-associated neurocognitive decline. Microglia support productive HIV-1 infection in the brain. Elevated markers of cellular senescence, including p53 and p21, have been detected in brain tissues from patients with HAND, but the potential for microglia senescence during HIV-1 infection has not been investigated. We hypothesized that HIV-1 can induce senescence in microglia. Primary human fetal microglia were exposed to single-round infectious HIV-1 pseudotypes or controls, and examined for markers of senescence. Post-infection, microglia had significantly elevated: senescence-associated beta-galactosidase activity, p21 levels, and production of cytokines such as IL-6 and IL-8, potentially indicative of a senescence-associated secretory phenotype. We also found increased detection of p53-binding protein foci in microglia nuclei post-infection. Additionally, we examined mitochondrial reactive oxygen species (ROS) and respiration, and found significantly increased mitochondrial ROS levels and decreased ATP-linked respiration during HIV-1 infection. Supernatant transfer from infected cultures to naive microglia resulted in elevated p21 and caveolin-1 levels, and IL-8 production. Finally, nucleoside treatment reduced senescence markers induction in microglia. Overall, HIV-1 induces a senescence-like phenotype in human microglia, which could play a role in HAND. PMID- 29415129 TI - Ramifications of secreted mucin MUC5AC in malignant journey: a holistic view. AB - Heavily glycosylated secreted mucin MUC5AC, by the virtue of its cysteine-rich repeats, can form inter- and intramolecular disulfide linkages resulting in complex polymers, which in turn craft the framework of the polymeric mucus gel on epithelial cell surfaces. MUC5AC is a molecule with versatile functional implications including barrier functions to epithelial cells, host-pathogen interaction, immune cell attraction to sites of premalignant or malignant lesions and tumor progression in a context-dependent manner. Differential expression, glycosylation and localization of MUC5AC have been associated with a plethora of benign and malignant pathologies. In this era of robust technologies, overexpression strategies and genetically engineered mouse models, MUC5AC is emerging as a potential diagnostic, prognostic and therapeutic target for various malignancies. Considering the clinical relevance of MUC5AC, this review holistically encompasses its genomic organization, domain structure, glycosylation patterns, regulation, functional and molecular connotation from benign to malignant pathologies. Furthermore, we have here explored the incipient and significant experimental tools that are being developed to study this structurally complex and evolutionary conserved gel-forming mucin. PMID- 29415136 TI - ASSESSMENT OF THE NATURAL RADIOACTIVITY AND RADIOLOGICAL HAZARDS IN LAO CEMENT SAMPLES. AB - The radioactivity concentrations of 226Ra, 232Th and 40K natural radionuclides in Lao Portland cement samples were measured using a gamma-spectrometry with a HPGe detector. The activity concentrations were found to vary from 28.32 +/- 2.23 to 65.50 +/- 2.83 Bq kg-1 with a mean value of 41.12 +/- 2.44 Bq kg-1 for 226Ra; from 7.25 +/- 2.00 to 44.01 +/- 2.45 Bq kg-1 with a mean of 16.60 +/- 2.37 Bq kg 1 for 232Th and from 49.19 +/- 4.27 to 196.74 +/- 4.75 Bq kg-1 with a mean of 141.48 +/- 4.50 Bq kg-1 for 40K, respectively. The radiological parameters were estimated to assess the potential radiological hazard including radium equivalent activity, total external absorbed dose rate in outdoor air at 1 m above the earth's surface, the annual effective dose, the gamma and alpha-indices were calculated using the activity concentrations of 226Ra, 232Th and 40K. The results obtained in this study show no significant radiological hazards arising from using Lao Portland cement for building construction. PMID- 29415137 TI - NEUTRON FIELD CHARACTERISTICS AT RADIATION METROLOGY LABORATORY OF STUK. AB - Radiation metrology laboratory at Radiation and Nuclear Safety Authority (STUK) is Finnish national laboratory for ionizing radiation. In order to establish personal dose equivalent available for neutron calibration service, a project was started to evaluate the neutron reference fields in the present facility. The irradiation room conditions were characterized in order to establish reference conditions for personal dose equivalent. To verify the validity of the calculations, ambient dose equivalent rates and room return were measured and calculated for 241AmBe and 252Cf sources. First results of Monte Carlo calculations and measurements are presented in this article. PMID- 29415138 TI - Validation of 2-year 123I-meta-iodobenzylguanidine-based cardiac mortality risk model in chronic heart failure. AB - Aims: The aim of this study was to validate a four-parameter risk model including 123I-meta-iodobenzylguanidine (MIBG) imaging, which was previously developed for predicting cardiac mortality, in a new cohort of patients with chronic heart failure (CHF). Methods and results: Clinical and outcome data were retrospectively obtained from 546 patients (age 66 +/- 14 years) who had undergone 123I-MIBG imaging with a heart-to-mediastinum ratio (HMR). The mean follow-up time was 30 +/- 20 months, and the endpoint was cardiac death. The mortality outcome predicted by the model was compared with actual 2-year event rates in pre-specified risk categories of three or four risk groups using Kaplan Meier survival analysis for cardiac death and receiver-operating characteristic (ROC) analysis. Cardiac death occurred in 137 patients, including 105 (68%) patients due to heart-failure death. With a 2-year mortality risk from the model divided into three categories of low- (<4%), intermediate- (4-12%), and high-risk (>12%), 2-year cardiac mortality was 1.1%, 7.9%, and 54.7%, respectively in the validation population (P < 0.0001). In a quartile analysis, although the predicted numbers of cardiac death was comparable with actual number of cardiac death for low- to intermediate-risk groups with a mortality risk <13.8%, it was underestimated in the high-risk group with a mortality risk >=13.8%. The ROC analysis showed that the 2-year risk model had better (P < 0.0001) diagnostic ability for predicting heart failure death than left ventricular ejection fraction, natriuretic peptides or HMR alone. Conclusion: The 2-year risk model was successfully validated particularly in CHF patients at a low to intermediate cardiac mortality risk. PMID- 29415139 TI - Improved hearing in Swedish 70-year olds-a cohort comparison over more than four decades (1971-2014). AB - Objective: the world population is ageing rapidly. In light of these demographic changes, it is of interest to generate current data regarding the prevalence and characteristics of age-related hearing loss. The purpose of this study was to investigate hearing acuity and the prevalence of hearing loss in a contemporary age-homogenous cohort of old adults, and to assess secular trends in hearing function during the last half-century (1971-2014). Methods: we performed a prospective population-based cohort comparison study of unscreened populations. As part of a geriatric population-based study (H70), a new cohort of 70-year olds (n = 1,135) born in 1944 was tested with computerised automated pure-tone audiometry. The hearing thresholds were compared to three earlier born cohorts of 70-year olds, born in 1901-02 (n = 376), 1906-07 (n = 297) and 1922 (n = 226), respectively. Results: significant improvements in median pure-tone thresholds were seen at several frequencies in both men (range: 5-20 dB, P < 0.01) and women (range: 5-10 dB, P < 0.01). When investigating the effect of birth cohort on hearing in a linear regression, significant trends were found. Men's hearing improved more than women's. The prevalence of hearing loss declined in the study period (1971-2014) from 53 to 28% for men and 37 to 23% for women (P < 0.01). Conclusions: these results indicate that the hearing acuity in Swedish 70-year olds has improved significantly over more than four decades. The largest improvements were seen at 4-6 kHz in men, possibly reflecting a decrease in occupational noise exposure. Further studies are required to pinpoint the reasons for improved hearing-health among older people. PMID- 29415140 TI - Analysis of the presence of erroneous Qnr sequences in GenBank. AB - Background: Twenty years ago the first transferable mechanism of quinolone resistance (TMQR), QnrA, was described. Thereafter, innumerable TMQRs, either Qnr related or not, were described. Ten years ago the exponential description of Qnr genes/alleles led to the proposal of a common nomenclature. Objectives: This analysis aims to determine the degree of correctness of the Qnr sequences currently present in GenBank. Methods: The Qnr amino acid type sequence of the first allele (e.g. QnrA1) of each Qnr family present in http://www.lahey.org/qnrStudies/ was compared with what is present in GenBank. Only the first 30 obtained annealings or those with a >90% identity were considered. No synthetic or chromosomal sequences (other than those included in http://www.lahey.org/qnrStudies/) were included in the analyses. Results: Overall, 1657 amino acid sequences were analysed: 224 QnrA, 499 QnrB, 1 QnrC, 102 QnrD, 13 QnrE, 758 QnrS and 60 QnrVC. Of these, 340 (20.5%) sequences presented a major error, including erroneous gene name, erroneous Qnr family attribution, erroneous allele identification, presence of partial sequences with allele assignation and/or erroneous initial codon. In addition, 449 (27.1%) Qnr sequences were present in GenBank with a partial identification or not identified as Qnr. Finally, nine new transferable Qnr alleles were detected. Conclusions: These data highlight the frequent presence of erroneously identified qnr genes in GenBank and the need to be fully adherent to current nomenclature rules. PMID- 29415141 TI - Reply: High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. PMID- 29415142 TI - A Hidden Culprit Illuminated with Advanced Cardiac Imaging. AB - This case demonstrates the complementary benefit of utilizing multimodality cardiac imaging in the assessment of myocardial infarction with nonobstructive coronary artery disease especially when a culprit lesion is not discovered upon initial coronary catheterization. Use of cardiac magnetic resonance imaging, optical coherence tomography, and invasive coronary angiography together solidified the diagnosis of unstable, complex coronary artery disease in this case. PMID- 29415143 TI - Safety and durability of the biodegradable felt in aortic surgery: a propensity score-matched study. AB - OBJECTIVES: Suture line disruption is a serious complication after aortic surgery. We previously reported in a canine model that basic fibroblast growth factor-incorporated biodegradable polyglycolic acid (PGA) felt prevented tissue derangement at the anastomotic site. This study sought to evaluate the safety and durability of this biodegradable felt. METHODS: Between January 2007 and December 2011, 67 patients who consented to undergo aortic surgery with the basic fibroblast growth factor-incorporated PGA felt were enrolled (Group P). As a control, we retrospectively reviewed the charts of 129 patients who underwent aortic surgery using a polytetrafluoroethylene felt during the same registration period (Group N). On the basis of 18 preoperative covariates, 60 well-matched patient pairs were identified using propensity matching, and their clinical indices were compared. RESULTS: Among the matched pairs, in-hospital mortality and postoperative complication rates did not statistically differ between the groups. During a median follow-up of 4.8 years, the rate of anastomotic aneurysm was 1.7% (1 patient) in both groups. The rates of overall survival and freedom from aortic events did not differ between the groups. In total, 65 anastomoses in Group P and 54 anastomoses in Group N were monitored via computed tomography, and the diameters of the juxta-anastomotic sites in Group N were more likely to be increased than those in Group P {dilatation ratio [(post-discharge diameter - predischarge diameter)/predischarge diameter * 100 (%)]: 4.3% +/- 0.6% vs 2.5% +/ 0.5%, P = 0.01}. CONCLUSIONS: The basic fibroblast growth factor-incorporated PGA felt was as safe and durable as conventional felt for reinforcement in aortic surgery. The attenuation of juxta-anastomotic aortic dilatation by PGA felt reinforcement may provide more beneficial effects on long-term outcomes. PMID- 29415144 TI - Purification and characterization of 1-acyl-sn-glycerol-3-phosphate acyltransferase with a substrate preference for polyunsaturated fatty acyl donors from the eicosapentaenoic acid-producing bacterium Shewanella livingstonensis Ac10. AB - 1-Acyl-sn-glycerol-3-phosphate acyltransferase (designated as PlsC in bacteria) catalyzes the acylation of lysophosphatidic acid and is responsible for the de novo production of phosphatidic acid, a precursor for the synthesis of various membrane glycerophospholipids. Because PlsC is an integral membrane protein, it is generally difficult to solubilize it without causing its inactivation, which has been hampering its biochemical characterization despite its ubiquitous presence and physiological importance. Most biochemical studies of PlsC have been carried out using crude membrane preparations or intact cells. In this study, we succeeded in solubilization and purification of a recombinant PlsC in its active form from the eicosapentaenoic acid-producing bacterium Shewanella livingstonensis Ac10 using 6-cyclohexyl-1-hexyl-beta-d-maltoside as the detergent. We characterized the purified enzyme and found that it has a substrate preference for the acyl donors with a polyunsaturated fatty acyl group, such as eicosapentaenoyl group. These results provide a new method for purification of the PlsC family enzyme and demonstrate the occurrence of a new PlsC with unique substrate specificity. PMID- 29415145 TI - Response to baricitinib based on prior biologic use in patients with refractory rheumatoid arthritis. AB - Objective: RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on baricitinib efficacy and safety. Methods: RA BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ?10. An interaction P-value ?0.10 was considered significant, with significance at both weeks 12 and 24 given more weight. Results: The odds ratios predominantly favored baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ?10 by disease duration (larger effect ?10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use. Conclusion: Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use. Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044. PMID- 29415146 TI - Mental Health Across the Reproductive Cycle in Women Veterans. AB - Introduction: Premenstrual, perinatal, and/or perimenopausal psychiatric problems require specific screening, assessment, and treatment strategies. The scope of these reproductive-linked psychiatric symptoms among women veterans is unknown. Due to high rates of sexual trauma among women veterans, it is also important to ascertain relationships between sexual trauma experiences and reproductive cycle mood problems. This pilot study investigates the prevalence of self-reported premenstrual, perinatal, and perimenopausal emotional problems and whether these correlate with pre-military sexual abuse, military sexual harassment, and/or military sexual assault, among veterans receiving psychiatric evaluations within a Veterans Administration Women's Health Clinic. Materials and Methods: Participants included all women veterans (N = 186) who received psychiatric evaluations within a Veterans Administration Women's Health Clinic over a 13-mo period. Evaluations included a clinical questionnaire, a psychiatric interview, and medical record review. De-identified data were extracted from a clinical data repository for this descriptive study. Results: High proportions of study participants reported emotional problems premenstrually (43.3%), during pregnancy (35.1%), postpartum (30.4%), or during perimenopause (31.2%). Unintended pregnancy (73.3% of pregnancies) and pregnancy loss (56.6% of women who had been pregnant) were prominent perinatal stressors. Military sexual harassment was significantly associated with emotional problems during pregnancy and postpartum. Conclusion: These pilot data suggest the need for further study of the reproductive mental health needs of women veterans and their relationship with sexual trauma. The findings underscore the need for Veterans Administration facilities and other providers of veterans' health care to be prepared to detect, diagnose, and treat premenstrual, perinatal, and perimenopausal mental health problems. PMID- 29415147 TI - Association Analysis Between Genetic Variation in GATA Binding Protein 4 (GATA4) and Alcohol Use Disorder. AB - Aims: Previous genetic association studies have shown that variation in the GATA4 gene encoding the GATA binding protein 4, a binding protein that binds to the ANA sequence GATA, increase susceptibility for alcohol use disorder (AUD). In this study, we aimed to replicate those findings in an independent sample and analyze their association with anxiety. Methods: Overall, 1044 individuals with AUD [534 European American (EA), 510 African Americans (AA)] and 645 controls [413 EA, 232 AA] were genotyped using 34 markers. Genotype and allele frequencies were compared between cases and controls using chi-square analysis. Other phenotype data were analyzed for possible associations with GATA4 single-nucleotide polymorphisms (SNPs) in individuals with AUD. Results: Rs6601604 was nominally significantly associated with AUD in EA, and 3 SNPs (rs6990313, rs11250159 and rs17153694) showed trend-level significance (P < 0.10) in AA. However, none of the SNPs were significant after correcting for multiple testing. Haplotype analysis of the 34 SNPs did not find a significant association between haplotype blocks and AUD diagnosis after correcting for multiple testing. From the phenotype analysis, anxiety was associated with GATA4 SNP rs10112596 among the AA group with AUD after a correction for multiple testing. Conclusions: Although previous studies have shown a relationship between variants of the GATA4 gene and a diagnosis of AUD, we did not replicate these findings in our sample. Additional studies of variation in this gene are needed to elucidate whether polymorphisms of the GATA4 gene are associated with AUD and other alcohol-related phenotypes. Short Summary: GATA4 variants were not associated with AUD in either the European ancestry or African ancestry groups after correcting for multiple comparisons. Rs10112596 demonstrated a significant relationship with an anxiety measure among the African ancestry group with AUD. PMID- 29415149 TI - Response to 'Minimally conscious state or cortically mediated state?' PMID- 29415148 TI - EXPERIMENTAL EVALUATION OF DOSIMETRIC CHARACTERIZATION OF GAFCHROMIC EBT3 AND EBT XD FILMS FOR CLINICAL CARBON ION BEAMS. AB - Radiochromic film is a very useful tool for 2D dosimetric measurements in radiotherapy because it is self-developing and has very high-spatial resolution. However, considerable care has to be taken in ion beam radiotherapy owing to the quenching effect of high-linear energy transfer (LET) radiation. In this study, the dose responses of GAFchromic EBT3 and EBT-XD films were experimentally investigated using the clinical carbon ion beam at the Heavy Ion Medical Accelerator in Chiba. Results showed that the relations between absorbed dose and net optical density could be expressed well using an equation proposed by Reinhardt (2015). The quenching effect was evaluated by determining their relative efficiencies for photon irradiation as a function of LET. A correction equation derived in this study allowed the absorbed dose to be determined in the small irradiation field used for carbon ion radiotherapy eye treatments. This study contributes to establishing an absolute dosimetry procedure for heavy ion beams using radiochromic film. PMID- 29415150 TI - Kaempferol protects ethanol-induced gastric ulcers in mice via pro-inflammatory cytokines and NO. AB - Gastric ulcers (GUs) are common pathologies that affect many people around the world. Excessive alcohol consumption is one of the main causes of GUs; however, there are still lack of effective drugs for the prevention or therapy of GUs. In this study, we evaluated the protective effects and possible mechanisms of kaempferol (KAE) against acute ethanol-induced lesions to the gastric mucosa in mice. Fasted mice were orally given vehicle (0.9% saline), omeprazole (20 mg/kg), or KAE (40, 80, or 160 mg/kg) for 1 h in different experimental sets prior to the establishment of the GU model by challenge with absolute ethanol (10 ml/kg). Animals were euthanized 1 h after ethanol intake, and their plasma and stomach tissues were subject to further examination. Macroscopic and microscopic lesions, and immunological and biochemical parameters were observed. The effects of inflammation were investigated using the following indicators: tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, myeloperoxidase (MPO), and nitric oxide (NO). Results showed that KAE significantly decreased the ulcer index, increased the preventive index, completely protected the mucosa from lesions, and preserved gastric mucosal glycoprotein. KAE decreased MPO activity and pro-inflammatory cytokine (TNF-alpha, and IL-1beta) levels, and improved NO levels. The gastroprotective activity of KAE might be attributed to the preservation of gastric mucous glycoproteins levels, thus by inhibiting neutrophil accumulation and MPO activity, adjusting the levels of pro inflammatory cytokines, and improving NO production. PMID- 29415151 TI - Occupancy strongly influences faecal microbial composition of wild lemurs. AB - The microbiota of the mammalian gut is a complex ecosystem, the composition of which is greatly influenced by host genetics and environmental factors. In this study, we aim to investigate the influence of occupancy (a geographical area of habitation), species, age and sex on intestinal microbiota composition of the three lemur species: Eulemur fulvus, E. rubriventer and E. rufifrons. Faecal samples were collected from a total of 138 wild lemurs across Madagascar, and microbial composition was determined using next-generation sequencing of PCR amplified 16S rRNA gene fragments. Consistent with reports from other primate species, the predominant phyla were Firmicutes (43 +/- 6.4% [s.d.]) and Bacteroidetes (30.3 +/- 5.3%). The microbial composition was strongly associated with occupancy in the E. fulvus population, with up to 19.9% of the total variation in microbial composition being explained by this factor. In turn, geographical differences observed in faecal microbiota of sympatric lemur species were less pronounced, as was the impact of the factors sex and age. Our findings showed that among the studied factors occupancy had the strongest influence on intestinal microbiota of congeneric lemur species. This suggests adaptation of microbiota to differences in forest composition, climate variations and correspondingly available diet in different geographical locations of Madagascar. PMID- 29415152 TI - High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. PMID- 29415153 TI - Intraspecific ecological niche divergence and reproductive shifts foster cytotype displacement and provide ecological opportunity to polyploids. AB - Background and Aims: Niche divergence between polyploids and their lower ploidy progenitors is one of the primary mechanisms fostering polyploid establishment and adaptive divergence. However, within-species chromosomal and reproductive variability have usually been neglected in community ecology and biodiversity analyses even though they have been recognized to play a role in the adaptive diversification of lineages. Methods: We used Paspalum intermedium, a grass species with diverging genetic systems (diploidy vs. autopolyploidy, allogamy vs. autogamy and sexuality vs. apomixis), to recognize the causality of biogeographic patterns, adaptation and ecological flexibility of cytotypes. Chromosome counts and flow cytometry were used to characterize within-species genetic systems diversity. Environmental niche modelling was used to evaluate intraspecific ecological attributes associated with environmental and climatic factors and to assess correlations among ploidy, reproductive modes and ecological conditions ruling species' population dynamics, range expansion, adaptation and evolutionary history. Key Results: Two dominant cytotypes non-randomly distributed along local and regional geographical scales displayed niche differentiation, a directional shift in niche optima and signs of disruptive selection on ploidy-related ecological aptitudes for the exploitation of environmental resources. Ecologically specialized allogamous sexual diploids were found in northern areas associated with higher temperature, humidity and productivity, while generalist autogamous apomictic tetraploids occurred in southern areas, occupying colder and less productive environments. Four localities with a documented shift in ploidy and four mixed populations in a zone of ecological transition revealed an uneven replacement between cytotypes. Conclusions: Polyploidy and contrasting reproductive traits between cytotypes have promoted shifts in niche optima, and increased ecological tolerance and niche divergence. Ecologically specialized diploids maintain cytotype stability in core areas by displacing tetraploids, while broader ecological preferences and a shift from sexuality to apomixis favoured polyploid colonization in peripheral areas where diploids are displaced, and fostered the ecological opportunity for autotetraploids supporting range expansion to open southern habitats. PMID- 29415154 TI - Temperature and Exposure Time in Cold Storage Reshape Parasitic Performance of Habrobracon hebetor (Hymenoptera: Braconidae). AB - Cold storage can extend shelf life of parasitoids for use in biocontrol. However, cold storage may have negative impacts on life history traits of the parasitoids and, therefore, on their performance as biocontrol agents. Here, we examine the effect of cold storage on life history traits of Habrobracon hebetor (Say) (Hymenoptera: Braconidae), a parasitoid of several economic lepidopteran pests. Newly emerged wasps were stored at three constant temperatures (3 degrees C, 5 degrees C, 7 degrees C) for up to 4 wk. Both temperature and exposure time significantly affected longevity, parasitism, fecundity, and sex ratio. Significant reduction in longevity was observed at 3 degrees C and 7 degrees C, whereas longevity of wasps stored at 5 degrees C remained stable up to the second week and then gradually decreased in Weeks 3 and 4. Parasitism rate also significantly decreased after cold storage at 3 degrees C, 5 degrees C, and 7 degrees C (ranked from high to low). Fecundity decreased at T 3 degrees C and T 5 degrees C but this trait was not affected by storage at T 7 degrees C. A significant shift in male production was observed at T 5 degrees C in Week 3, but in Week 4, the only treatment with male biased reproduction was T 3 degrees C. These results show that the effect of temperature and exposure time in cold storage is trait dependent. Overall, storage at 5 degrees C for a period of 3 wk least impacted most life-history traits of H. hebetor wasps. PMID- 29415155 TI - Prognostic value of Twist, Snail and E-cadherin expression in pathological N0 non small-cell lung cancer: a retrospective cohort study. AB - OBJECTIVES: Lung cancer is the leading cause of cancer-related death worldwide. The 5-year survival rate for patients after curative surgery with pathological N0 non-small-cell lung cancer (NSCLC) is as low as 56%, which is due to recurrence and metastasis. Emerging evidence suggests that epithelial-mesenchymal transition is important for cancer metastasis. Twist and Snail are epithelial-mesenchymal transition regulators that induce metastasis by down-regulating E-cadherin. The aim of this study was to evaluate the prognostic value of Twist, Snail and E cadherin expression in patients with resectable pathological N0 NSCLC. METHODS: The expression levels of Twist, Snail and E-cadherin in 78 patients with resected pathological N0 NSCLC were assessed using immunohistochemistry. The association between the expression of Twist/Snail/E-cadherin and overall survival (OS) and recurrence-free survival (RFS) was investigated. RESULTS: High expression of Twist, Snail and E-cadherin was detected in 18%, 21% and 53% of NSCLC samples, respectively. High expression of Twist and Snail and low expression of E-cadherin were associated with worse RFS [hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.07-4.87, P = 0.026; HR 2.54, 95% CI 1.24-5.20, P = 0.008 and HR 2.41, 95% CI 1.23-4.73, P = 0.007, respectively] and worse OS (HR 2.26, 95% CI 1.01-5.04, P = 0.040; HR 2.56, 95% CI 1.20-5.43, P = 0.011 and HR 2.42, 95% CI 1.18-4.95, P = 0.012, respectively). Co-expression of at least 2 markers from the combination of high Twist/high Snail/low E-cadherin expression predicted poor RFS and OS (HR 4.12, 95% CI 2.08-8.16, P < 0.001 and HR 4.28, 95% CI 2.08-8.77, P < 0.001, respectively), and it was an independent predictor of RFS and OS (HR 3.99, 95% CI 1.89-8.44, P < 0.001 and HR 4.16, 95% CI 1.88-9.18, P < 0.001, respectively). CONCLUSIONS: Co-expression of at least 2 markers from the combination of high Twist/high Snail/low E-cadherin expression was a significant prognostic predictor in patients with pathological N0 NSCLC. PMID- 29415156 TI - Frontoparietal Activity Interacts With Task-Evoked Changes in Functional Connectivity. AB - Flexible interactions between brain regions enable neural systems to adaptively transfer and process information. However, the neural substrates that regulate adaptive communications between brain regions are understudied. In this human fMRI study, we investigated this issue by tracking time-varying, task-evoked changes in functional connectivity between localized occipitotemporal regions while participants performed different tasks on the same visually presented stimuli. We found that functional connectivity between ventral temporal and the primary visual regions selectively increased during the processing of task relevant information. Further, additional task demands selectively strengthen these targeted connectivity patterns. To identify candidate regions that contribute to this increase in inter-regional coupling, we regressed the task specific time-varying connectivity strength between primary visual and occipitotemporal regions against voxel-wise activity patterns elsewhere in the brain. This allowed us to identify a set of frontal and parietal regions whose activity increased as a function of task-evoked functional connectivity. These results suggest that frontoparietal regions may provide top-down biasing signals to influence task-specific interactions between brain regions. PMID- 29415158 TI - Postsynaptic density proteins and their involvement in neurodevelopmental disorders. AB - Synaptic connections are essential for neural circuits in order to convey brain functions. The postsynaptic density (PSD) is a huge protein complex associated with postsynaptic membranes of excitatory synapses. In mammals, the PSD is composed of more than 1,000 proteins including receptors, scaffold proteins, signalling enzymes and cytoskeletal proteins. PSD proteins are crucial for synaptic transmission and plasticity. Proteomic studies have revealed the composition of PSD proteins in various species, brain regions and specific physiological conditions. Abnormalities with PSD proteins are linked to various neuropsychiatric diseases including neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Here, we review different kinds of proteomic studies of the PSD and the involvement of PSD proteins in physiological and pathological conditions. PMID- 29415157 TI - Antibiotic resistance ABCF proteins reset the peptidyl transferase centre of the ribosome to counter translational arrest. AB - Several ATPases in the ATP-binding cassette F (ABCF) family confer resistance to macrolides, lincosamides and streptogramins (MLS) antibiotics. MLS are structurally distinct classes, but inhibit a common target: the peptidyl transferase (PTC) active site of the ribosome. Antibiotic resistance (ARE) ABCFs have recently been shown to operate through direct ribosomal protection, but the mechanistic details of this resistance mechanism are lacking. Using a reconstituted translational system, we dissect the molecular mechanism of Staphylococcus haemolyticus VgaALC and Enterococcus faecalis LsaA on the ribosome. We demonstrate that VgaALC is an NTPase that operates as a molecular machine strictly requiring NTP hydrolysis (not just NTP binding) for antibiotic protection. Moreover, when bound to the ribosome in the NTP-bound form, hydrolytically inactive EQ2 ABCF ARE mutants inhibit peptidyl transferase activity, suggesting a direct interaction between the ABCF ARE and the PTC. The likely structural candidate responsible for antibiotic displacement by wild type ABCF AREs, and PTC inhibition by the EQ2 mutant, is the extended inter-ABC domain linker region. Deletion of the linker region renders wild type VgaALC inactive in antibiotic protection and the EQ2 mutant inactive in PTC inhibition. PMID- 29415159 TI - NATURAL RADIOACTIVITY STUDIES OF PHOSPHATE FERTILIZERS APPLIED ON GREEK FARM SOILS USED FOR WHEAT CULTIVATION. AB - Naturally Occurring Radionuclide Materials (NORM) such as fertilizers, agricultural soils fertilized and wheat grain cultivated at those soils were studied regarding the radiation hazard to the public and workers. Activity of 238U, 226Ra, 232Th and 40K was measured hermitical sealing the marinelli beaker using the Stopaq FN 2100L material that prevent 222Rn escape from the baker. The phosphate fertilization of soil did not affect natural radioactivity in comparison with non-fertilized soils and also did not affect natural radioactivity of wheat grain cultivated since only 40K was measured. The high mean value of Dair 211 nGy h-1 for fertilizers compared to soils fertilized 53 nGy h-1 highlights the raising concern about radioprotection of workers occupied with tasks involving fertilizers. The maximum external dose rate 1.15 mSv y-1 calculated for truck drivers involved to transportation section is similar to annual external effective dose limit 1 mSv. Real concerns rise for workers in the fertilizers storage and supply department since the maximum dose rate estimated is 1.98 mSv y-1, while the mean value is 0.89 mSv y-1. PMID- 29415160 TI - Genital Autoinoculation with Vaccinia: A Look at Two Cases. AB - Introduction: Smallpox, or vaccinia, has been eradicated worldwide as a disease; however, it may be weaponized and is thus a required immunization when military members deploy to certain parts of the world. Materials and Methods: We report two unusual cases of genital autoinoculation following smallpox vaccination. Results: Both patients' lesions resolved without sequelae within 20 d. Conclusions: We advocate for thorough education on this potential vaccination adverse event. These cases highlight the importance of a broad differential diagnosis when dealing with vulvar lesions, particularly in our military population. PMID- 29415161 TI - ENVIRONMENTAL IONIZING RADIATION DOSE OUTDOOR IN AN INHABITED AREA WITH A HIGH CONCENTRATION OF URANO-PHOSPHATE IN NORTHEAST OF BRAZIL. AB - A marine phosphorus region with high concentrations of phosphate, coastwise of Pernambuco, Northeast of Brazil, is densely inhabited. Rock phosphate deposits naturally contain uranium ore that produces ionizing radiation from it and its natural descendants, furthermore, its thorium and potassium concentrations are comparable to those usually found in soils. Radiological monitoring of this environment is important to verify the occurrence of harmful effective doses for the adjacent population. This study aimed at the in situ radiometric monitoring in four cities of the north of the Metropolitan Region of Recife-Pernambuco, estimating the effective environmental dose to which the local population is subject. In total, 91 points were monitored with a discriminator-type detector. The outdoor environmental effective dose rates ranged from 1.99 +/- 0.09 to 7.59 +/- 0.36 mSv y-1, with an average of 2.60 +/- 0.69 mSv y-1. PMID- 29415162 TI - Anatomy and ultrastructure of embryonic leaves of the C4 species Setaria viridis. AB - Background and Aims: Setaria viridis is being promoted as a model C4 photosynthetic plant because it has a small genome (~515 Mb), a short life cycle (~60 d) and it can be transformed. Unlike other C4 grasses such as maize, however, there is very little information about how C4 leaf anatomy (Kranz anatomy) develops in S. viridis. As a foundation for future developmental genetic studies, we provide an anatomical and ultrastructural framework of early shoot development in S. viridis, focusing on the initiation of Kranz anatomy in seed leaves. Methods: Setaria viridis seeds were germinated and divided into five stages covering development from the dry seed (stage S0) to 36 h after germination (stage S4). Material at each of these stages was examined using conventional light, scanning and transmission electron microscopy. Key Results: Dry seeds contained three embryonic leaf primordia at different developmental stages (plastochron 1-3 primordia). The oldest (P3) leaf primordium possessed several procambial centres whereas P2 displayed only ground meristem. At the tip of P3 primordia at stage S4, C4 leaf anatomy typical of the malate dehydrogenase dependent nicotinamide dinucleotide phosphate (NADP-ME) subtype was evident in that vascular bundles lacked a mestome layer and were surrounded by a single layer of bundle sheath cells that contained large, centrifugally located chloroplasts. Two to three mesophyll cells separated adjacent vascular bundles and one mesophyll cell layer on each of the abaxial and adaxial sides delimited vascular bundles from the epidermis. Conclusions: The morphological trajectory reported here provides a foundation for studies of gene regulation during early leaf development in S. viridis and a framework for comparative analyses with other C4 grasses. PMID- 29415163 TI - Genetic Variation of a DRD2 Co-expression Network is Associated with Changes in Prefrontal Function After D2 Receptors Stimulation. AB - Dopamine D2 receptors (D2Rs) contribute to the inverted U-shaped relationship between dopamine signaling and prefrontal function. Genetic networks from post mortem human brain revealed 84 partner genes co-expressed with DRD2. Moreover, eight functional single nucleotide polymorphisms combined into a polygenic co expression index (PCI) predicted co-expression of this DRD2 network and were associated with prefrontal function in humans. Here, we investigated the non linear association of the PCI with behavioral and Working Memory (WM) related brain response to pharmacological D2Rs stimulation. Fifty healthy volunteers took part in a double-blind, placebo-controlled, functional MRI (fMRI) study with bromocriptine and performed the N-Back task. The PCI by drug interaction was significant on both WM behavioral scores (P = 0.046) and related prefrontal activity (all corrected P < 0.05) using a polynomial PCI model. Non-linear responses under placebo were reversed by bromocriptine administration. fMRI results on placebo were replicated in an independent sample of 50 participants who did not receive drug administration (P = 0.034). These results match earlier evidence in non-human primates and confirm the physiological relevance of this DRD2 co-expression network. Results show that in healthy subjects, different alleles evaluated as an ensemble are associated with non-linear prefrontal responses. Therefore, brain response to a dopaminergic drug may depend on a complex system of allelic patterns associated with DRD2 co-expression. PMID- 29415164 TI - Suitability of the porcine aortic model for transcatheter aortic root repair. AB - OBJECTIVES: To treat aortic valve disease and concomitant root disease with transcatheter techniques, 'composite graft' implants are required. Our goal was to assess the suitability of the porcine aortic root for transcatheter root repair tests. METHODS: Eight pig hearts explanted from domestic pigs used in experimental surgery were compared to data from the literature on human hearts. The measured diameters included those of the annulus, sinuses of Valsalva, coronary ostia, sinotubular junction, ascending aorta, innominate artery and aortic arch. The measured distances were from the coronary ostia to the nadir of the corresponding annulus; from the innominate artery to the nadir of the corresponding annulus; from the small curvature of the arch to the nadir of the corresponding annulus. RESULTS: The mean weight of the pigs was 89 +/- 5.4 kg. The mean aortic annulus diameter was 20 +/- 1.2 mm (human: 23.0 +/- 2.5 mm), the sinus of Valsalva diameter was 20.5 +/- 0.5 mm (human: 31.4 +/- 3.4 mm) and the sinotubular junction diameter was 20 +/- 0.9 mm (human: 27.2 +/- 3.0 mm). The diameter of the mean ascending aorta was 19 +/- 0.7 mm (human: 29.3 +/- 4 mm); the diameter of the innominate artery was 8.5 +/- 0.7 mm, that of the aortic arch was 15 +/- 0.7 mm and that of the coronary ostia was 5 +/- 0.5 mm (left) and 4.7 +/- 0.5 mm (right) (human: 4.8 +/- 0.5 mm and 3.7 +/- 0.9 mm). The distances from the left and right coronary orifices to the corresponding annuli were 8 +/- 1.5 mm and 14 +/- 2.4 mm, respectively (human: 14.7 +/- 1.3 mm; 15.4 +/- 1.7 mm). The distances from the innominate artery to the nadirs of the left and right coronary annuli were 44 +/- 4.3 mm and 41 +/- 4 mm (human: 80 +/- 17 mm). The distance from the curvature of the small arch to the annulus was 35 +/- 4.9 mm. CONCLUSIONS: The porcine heart can be used as an experimental model to design and test new devices for catheter-based composite repair of the aortic root. Nevertheless, caution is required in using devices with tailored dimensions that must be adapted to the smaller pig's root. PMID- 29415165 TI - Neonatal Cytomegalovirus Palatal Ulceration and Bocavirus Pneumonitis Associated With a Defect of Lymphocyte Cytotoxicity Caused by Mutations in UNC13D. AB - Single gene defects that impair lymphocyte cytotoxicity can predispose to severe viral infection that normally remains subclinical. The classic severe presentation is hemophagocytic lymphohistiocytosis. Here, we report the case of a neonate who presented with cytomegalovirus palatal ulceration and bocavirus pneumonitis secondary to impaired cytotoxicity caused by biallelic mutations in the UNC13D gene. PMID- 29415166 TI - Membrane Lipid Oscillation: An Emerging System of Molecular Dynamics in the Plant Membrane. AB - Biological rhythm represents a major biological process of living organisms. However, rhythmic oscillation of membrane lipid content is poorly described in plants. The development of lipidomic technology has led to the illustration of precise molecular profiles of membrane lipids under various growth conditions. Compared with conventional lipid signaling, which produces unpredictable lipid changes in response to ever-changing environmental conditions, lipid oscillation generates a fairly predictable lipid profile, adding a new layer of biological function to the membrane system and possible cross-talk with the other chronobiological processes. This mini review covers recent studies elucidating membrane lipid oscillation in plants. PMID- 29415168 TI - Loss of Trust and Empathy Ends an Era of Opioid Self-Assessment. PMID- 29415167 TI - Repellency of Naturally Occurring or Related Compounds, DEET, and Para-Menthane 3,8-Diol to Bed Bugs (Hemiptera: Cimicidae). AB - Bed bugs, Cimex lectularius L. (Hemiptera: Cimicidae), have become a major health nuisance in the past 20 ysin cities and elsewhere throughout many areas of the world. Few studies have reported on repellent compounds that could reduce their transport in luggage. We evaluated the repellency of six naturally occurring or related compounds used in flavor/fragrance applications or structurally related compounds, para-menthane-3,8-diol, and N,N-diethyl-meta-toluamide (DEET) to bed bugs in a 183 * 183-cm arena . Repellency was assessed using soft-sided polyester lunch bags serving as surrogates of luggage and barrier cloth towels upon which rested untreated lunch bags. We report for the first time repellency of delta dodecalactone, 2-(3, 7-dimethyl-2, 6-nonadien-1-yl)-cyclopentanone (a.k.a. 'methyl apritone'), gamma dodecalactone, and para-menthane-3,8-diol to bed bugs. Propyl dihydrojasmonate, 3-methyl-5-hexyl-2-cyclohexenone, gamma methyl tridecalactone, and DEET are also documented to be repellent to bed bugs. These compounds provided relatively long-term protection. Propyl dihydrojasmonate prevented bed bugs from seeking refuge in treated lunch bags 27 d after treatment, and when applied to cloth towels repelled harborage-seeking bed bugs for 146 d. Methyl apritone blended with 3-methyl-5-hexyl-2-cyclohexenone and delta dodecalactone as an individual compound applied to cloth towels repelled bed bugs for 190 and 276 d, respectively. The above-mentioned compounds, either individually or as blends, may reduce risk of bed bugs seeking harborage in treated suitcases or towels upon which untreated luggage is placed. PMID- 29415169 TI - Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events-a meta-analysis. AB - Background: Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. Materials and methods: We searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials. Results: The literature-based meta-analysis included 166 trials (72 024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12-2.73; P < 0.001], but this risk was overestimated by 1.68 (95% CI 1.33-2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04-1.35; P = 0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83-1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19-1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30-1.94; P < 0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13-2.43) in open-label trials. Conclusions: Open-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta analyses assessing adverse drug events should therefore be restricted to DB randomized trials. PMID- 29415170 TI - Developing androgen receptor targeting for salivary gland cancers. PMID- 29415171 TI - Osteoglycin attenuates cardiac fibrosis by suppressing cardiac myofibroblast proliferation and migration through antagonizing lysophosphatidic acid 3/matrix metalloproteinase 2/epidermal growth factor receptor signalling. AB - Aims: Cardiac myofibroblasts (CMFs) play a crucial role in the progression of pathological fibrotic cardiac remodelling. The expression of osteoglycin (OGN) is increased in diseased hearts; however, the role of OGN in pathological cardiac remodelling is not understood. Here, we sought to determine the effect of OGN on cardiac interstitial fibrosis and investigate the molecular mechanisms of OGN in CMF activation and matrix production. Methods and results: We found that OGN expression was significantly upregulated in mouse hearts in response to chronic 14-day angiotensin II (Ang II) infusion. Mice lacking OGN (OGN-/-) exhibited enhanced cardiac interstitial fibrosis and significantly more severe cardiac dysfunction following Ang II infusion compared to wild-type mice. OGN deficiency did not alter blood pressure, nor had effect on transforming growth factor-beta signalling activation, but presented with increased proliferative activity in hearts. In vitro studies with isolated CMFs revealed that OGN deficiency significantly increased proliferation and migration and enhanced the transactivation of epidermal growth factor receptor (EGFR) signalling by Ang II. On the other hand, OGN overexpression in CMFs decreased their proliferation and migration via reducing EGFR activation. Overexpression of OGN also suppressed the shedding of membrane anchored EGFR ligand. Moreover, OGN was found to interact with a lysophosphatidic acid (LPA) receptor isoform 3 and thus to attenuate EGFR transactivation through blocking cell surface translocation of membrane type 1 matrix metalloproteinase (MT1-MMP) and subsequent pro-MMP-2 activation in a Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil containing protein kinase (ROCK)-dependent manner. Conclusion: These findings suggest that OGN negatively regulates cardiac fibrotic remodelling by attenuating CMF proliferation and migration through LPA3-mediated and Rho/ROCK-dependent inhibition of MT1-MMP translocation, MMP2 activation and EGFR transactivation. PMID- 29415172 TI - Reply: Response to 'Minimally conscious state or cortically mediated state?' PMID- 29415173 TI - Integrative pipeline for profiling DNA copy number and inferring tumor phylogeny. AB - Summary: Copy number variation is an important and abundant source of variation in the human genome, which has been associated with a number of diseases, especially cancer. Massively parallel next-generation sequencing allows copy number profiling with fine resolution. Such efforts, however, have met with mixed successes, with setbacks arising partly from the lack of reliable analytical methods to meet the diverse and unique challenges arising from the myriad experimental designs and study goals in genetic studies. In cancer genomics, detection of somatic copy number changes and profiling of allele-specific copy number (ASCN) are complicated by experimental biases and artifacts as well as normal cell contamination and cancer subclone admixture. Furthermore, careful statistical modeling is warranted to reconstruct tumor phylogeny by both somatic ASCN changes and single nucleotide variants. Here we describe a flexible computational pipeline, MARATHON, which integrates multiple related statistical software for copy number profiling and downstream analyses in disease genetic studies. Availability and implementation: MARATHON is publicly available at https://github.com/yuchaojiang/MARATHON. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29415174 TI - The influence of cattle grazing on methane fluxes and engaged microbial communities in alpine forest soils. AB - Recent dynamics and uncertainties in global methane budgets necessitate a dissemination of current knowledge on the controls of sources and sinks of atmospheric methane. Forest soils are considered to be efficient methane sinks; however, as they are microbially mediated they are sensitive to anthropogenic influences and tend to switch from being sinks to being methane sources. With regard to global changes in land use, the present study aimed at (i) investigating the influence of grazing on flux rates of methane in forest soils, (ii) deducing possible (a)biotic factors regulating these fluxes, and (iii) gaining an insight into the complex interactions between methane-cycling microorganisms and ecosystem functioning. Here we show that extensive grazing significantly mitigated the soil's sink strength for atmospheric methane through alterations of both microbial activity and community composition. In situ flux measurements revealed that all native, non-grazed areas were net methane consumers, while the adjacent, grazed areas were net methane producers. Whereas neither parent material nor soil properties including moisture and organic matter showed any correlation to the ascertained fluxes, significantly higher archaeal abundances at the grazed study sites indicated that small inputs of methanogens associated with cattle grazing may be sufficient to sustainably increase methane emissions. PMID- 29415176 TI - Deltamethrin-resistant German Cockroaches Are Less Sensitive to the Insect Repellents DEET and IR3535 than Non-resistant Individuals. AB - The German cockroach, Blattella germanica (L.) (Blattodea: Blattellidae), is a serious worldwide pest with a considerable economical and sanitary impact. It is mainly controlled by the application of synthetic insecticides, but repeated use of these substances has promoted the appearance of resistance in cockroach populations throughout the world. The aim of this study was to compare the behavior of deltamethrin-susceptible (CIPEIN colony) and deltamethrin-resistant (JUBA and VGBA colonies) first instar nymphs exposed to the repellents N,N diethyl-3-methylbenzamide (DEET) and ethyl 3-[acetyl(butyl)amino]propanoate (IR3535). Firstly, the behavior of the nymphs was assessed in an experimental arena in the absence of repellents. The parameters Distance Traveled, Velocity, Mobility Time, and Time Spent (in each half of the arena) were quantified using an image analyser, and showed that the behavior elicited by the three colonies was similar. After this, the behavior of the nymphs was quantified in an arena, half of which had been treated with repellent. The repellency of DEET increased as a linear function of log concentration for the three colonies. DEET elicited repellency as from a concentration of 97.49 ug/cm2 for the CIPEIN and JUBA colonies and 194.98 ug/cm2 for the VGBA colony. The repellency of IR3535 was weaker and started at a concentration of 389.96 ug/cm2 for the CIPEIN colony, 779.92 MUg/cm2 for JUBA, and 1559.84 MUg/cm2 for VGBA . Finally, nymphs were exposed to 3:1, 1:1, and 1:3 DEET:IR3535 mixtures, and a synergistic effect was observed only in the CIPEIN colony. PMID- 29415175 TI - Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir Disoproxil Fumarate and Emtricitabine. AB - Background: Antiretroviral drugs have been associated with changes in lipids, fat mass and dat distribution. Tenofovir disoproxil fumarate (TDF) has been shown to have a more favorable metabolic profile than other drugs in its class. However, the metabolic effects of TDF in preexposure prophylaxis (PrEP) are unknown. Methods: We evaluated the effects of TDF/emtricitabine (FTC) on lipids and body composition in a blinded, placebo-controlled PrEP trial. Participants enrolled in a metabolic subcohort (N = 251, TDF/FTC; N = 247, placebo) consented to fasting lipid panels, dual-energy X-ray absorptiometry scans for body composition, and pharmacologic testing of drug metabolites at baseline and every 24 weeks thereafter. Results: Lean body mass was stable and unaffected by TDF/FTC. Body weight increased in both groups but was lower on TDF/FTC through week 72. This difference was explained by lower fat accumulation on TDF/FTC. The net median percent difference (standard error, P value) for TDF/FTC vs placebo at week 24 was -0.8% (0.4%, P = .02), +0.3% (0.4%, P = .46), and -3.8% (1.4%, P = .009) for total, lean, and fat mass, respectively. There was no apparent differential regional fat accumulation on TDF/FTC. Decreases in cholesterol, but not triglycerides, were seen in TDF/FTC participants, with detectable drug levels compared to placebo. Conclusions: TDF/FTC for PrEP showed cholesterol reductions and appeared to transiently suppress the accumulation of weight and body fat compared to placebo. There was no evidence of altered fat distribution or lipodystrophy during daily oral TDF/FTC PrEP. Clinical Trials Registration: NCT00458393. PMID- 29415177 TI - Effect of levosimendan on clinical outcomes in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. AB - It is currently unknown whether levosimendan can improve clinical outcomes in patients undergoing cardiac surgery. This meta-analysis aimed to assess the effect of levosimendan on mortality and the duration of intensive care unit (ICU) and hospital stay in adult patients undergoing cardiac surgery. A comprehensive search for eligible articles was conducted in PubMed, OVID and Cochrane databases of clinical trials and the Web of Science from database inception to August 2017. Stata/SE 11.0 was used to calculate the pooled odds ratio for postoperative mortality and the pooled standardized mean difference (SMD) for the duration of ICU stay and hospital stay. A total of 30 randomized controlled trials were included in the final analysis; the pooled results indicated that perioperative administration of levosimendan was associated with a reduction in postoperative mortality [5.8% vs 8.5%; odds ratio 0.66, 95% confidence interval 0.50-0.86, P = 0.002; I2 = 17.1%; 25 trials; 3239 patients] and length of ICU stay (SMD -0.32, 95% CI -0.58 to 0.06, P = 0.017; I2 = 88.0%; 23 trials; 2536 patients) compared with the control group but not in length of hospital stay (SMD -0.41, 95% CI 0.89 to 0.07, P = 0.094; I2 = 95.9%; 18 trials; 2047 patients). A subanalysis was conducted for trials published after 2015, and it suggested that levosimendan could not reduce the postoperative mortality (odds ratio = 0.91, 95% CI 0.63 1.31, P = 0.626; I2 = 0.9%), length of ICU stay (SMD -0.03, 95% CI -0.32 to 0.27, P = 0.850; I2 = 81.2%) or length of hospital stay (SMD 0.06, 95%CI -0.43 to 0.54, P = 0.821; I2 = 91.3%). To summarize, the evidence from studies published in the last 3 years indicated that perioperative administration of levosimendan was not associated with better clinical outcomes in adult patients undergoing cardiac surgery. PMID- 29415179 TI - Incidence of organizing pneumonia after whole-breast radiotherapy for breast cancer, and risk factor analysis. AB - Radiation-induced organizing pneumonia (OP) reportedly occurs in ~2% of patients who receive whole-breast radiotherapy (WBRT). Though there are several reported risk factors, they remain unclear and controversial. We analyzed the incidence of and risk factors for OP after WBRT at our institution. We analyzed 665 breast cancer patients (with WBRT of 679 breasts) who underwent WBRT from October 2007 to September 2012 at our institution and were followed up for more than 1 year after completion of WBRT. Factors included in the analysis were age, the side affected, central lung distance (CLD), radiation dose, concurrent endocrine therapy, and chemotherapy. The median age was 56 years (range, 23-89 years). The sides affected were left, right and bilateral in 342, 309 and 14 patients, respectively. The median CLD was 1.1 cm (range, 0-3.0 cm). Concurrent endocrine therapy was performed in 236 patients, and chemotherapy was given in 215 patients; of these, 4 received concurrent chemotherapy. OP developed in nine patients (1.4%). The median time taken to develop OP after the completion of WBRT was 4 months (range, 2-12 months). All nine patients were treated with steroids, and symptoms promptly improved, except in two patients who relapsed. Statistical analysis revealed that only CLD (>=1.5 cm) was significantly associated with the development of OP (P = 0.004). In conclusion, the incidence of OP after WBRT was 1.4%, and CLD was a significant risk factor. In these patients, OP was controlled with steroid administration. PMID- 29415178 TI - The Sm-core mediates the retention of partially-assembled spliceosomal snRNPs in Cajal bodies until their full maturation. AB - Cajal bodies (CBs) are nuclear non-membrane bound organelles where small nuclear ribonucleoprotein particles (snRNPs) undergo their final maturation and quality control before they are released to the nucleoplasm. However, the molecular mechanism how immature snRNPs are targeted and retained in CBs has yet to be described. Here, we microinjected and expressed various snRNA deletion mutants as well as chimeric 7SK, Alu or bacterial SRP non-coding RNAs and provide evidence that Sm and SMN binding sites are necessary and sufficient for CB localization of snRNAs. We further show that Sm proteins, and specifically their GR-rich domains, are important for accumulating snRNPs in CBs. Accordingly, core snRNPs containing the Sm proteins, but not naked snRNAs, restore the formation of CBs after their depletion. Finally, we show that immature but not fully assembled snRNPs are able to induce CB formation and that microinjection of an excess of U2 snRNP-specific proteins, which promotes U2 snRNP maturation, chases U2 snRNA from CBs. We propose that the accessibility of the Sm ring represents the molecular basis for the quality control of the final maturation of snRNPs and the sequestration of immature particles in CBs. PMID- 29415180 TI - Neonatal BCG Vaccination Influences Cytokine Responses to Toll-like Receptor Ligands and Heterologous Antigens. AB - Background: BCG vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The underlying mechanisms remain uncertain, but long-term modulation of the innate immune response (trained immunity) may be involved. Methods: Whole-blood specimens, collected 7 days after randomization from 212 neonates enrolled in a randomized trial of neonatal BCG vaccination, were stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses. Results: BCG-vaccinated infants had increased production of interleukin 6 (IL-6) in unstimulated samples and decreased production of interleukin 1 receptor antagonist, IL-6, and IL-10 and the chemokines macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and monocyte chemoattractant protein 1 (MCP-1) following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination. Conclusions: Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterized by decreased antiinflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is warranted to determine whether there is an association between these findings and the beneficial nonspecific (heterologous) effects of BCG vaccine on all-cause mortality. PMID- 29415181 TI - RADIONUCLIDE AND MAJOR ELEMENT ANALYSIS OF THERMAL AND MINERAL WATERS IN CROATIA WITH A RELATED DOSE ASSESSMENT. AB - Major elements concentrations (Na, K, Ca, Mg) and the activity concentrations of 226,228Ra, 234,238U, 210Po, 210Pb, 40K and 137Cs in northern and eastern Croatian thermal and mineral waters, collected directly from springs (or wells), are presented herein with total effective doses assessed for those waters that are considered as drinking 'cures' and are available for consumption. The methods used for radionuclide determination included alpha-particle spectrometry, gas proportional counting and gamma-ray spectrometry, while the major element composition was determined by ICP-MS. The activity concentrations of all of the radionuclides were found to be below the guidance levels set by the WHO and EC Directive, with the exception of one water sample that measured 0.26 Bq L-1 of 228Ra. The effective ingestion dose assessment for the consumption of the so called water 'cures' during 1, 2 or 4 weeks' time period throughout 1 year was well below the recommended 0.1 mSv for drinking water. PMID- 29415182 TI - Arabidopsis Zinc-Finger-Like Protein ASYMMETRIC LEAVES2 (AS2) and Two Nucleolar Proteins Maintain Gene Body DNA Methylation in the Leaf Polarity Gene ETTIN (ARF3). AB - Arabidopsis ASYMMETRIC LEAVES2 (AS2) plays a critical role in leaf adaxial abaxial partitioning by repressing expression of the abaxial-determining gene ETTIN/AUXIN RESPONSE FACTOR3 (ETT/ARF3). We previously reported that six CpG dinucleotides in its exon 6 are thoroughly methylated by METHYLTRASFERASE1, that CpG methylation levels are inversely correlated with ETT/ARF3 transcript levels and that methylation levels at three out of the six CpG dinucleotides are decreased in as2-1. All these imply that AS2 is involved in epigenetic repression of ETT/ARF3 by gene body DNA methylation. The mechanism of the epigenetic repression by AS2, however, is unknown. Here, we tested mutations of NUCLEOLIN1 (NUC1) and RNA HELICASE10 (RH10) encoding nucleolus-localized proteins for the methylation in exon 6 as these mutations enhance the level of ETT/ARF3 transcripts in as2-1. Methylation levels at three specific CpGs were decreased in rh10-1, and two of those three overlapped with those in as2-1. Methylation levels at two specific CpGs were decreased in nuc1-1, and one of those three overlapped with that in as2-1. No site was affected by both rh10-1 and nuc1-1. One specific CpG was unaffected by these mutations. These results imply that the way in which RH10, NUC1 and AS2 are involved in maintaining methylation at five CpGs in exon 6 might be through at least several independent pathways, which might interact with each other. Furthermore, we found that AS2 binds specifically the sequence containing CpGs in exon 1 of ETT/ARF3, and that the binding requires the zinc finger-like motif in AS2 that is structurally similar to the zinc finger-CxxC domain in vertebrate DNA methyltransferase1. PMID- 29415183 TI - The unique epigenetic features of Pack-MULEs and their impact on chromosomal base composition and expression spectrum. PMID- 29415184 TI - Nlrp3 Gene Expression in Circulating Leukocytes Declines During Healthy Aging. AB - Aging is often associated with elevated levels of low grade inflammation supposed to drive age-associated diseases. Here, we conducted a cross-sectional study on 58 healthy volunteers, aged from 19 to 81, to investigate the relationship between age and the expression of three inflammasome component genes (Nlrp3, Asc, Casp1), the up-stream transcription factor NFkB, and the pro-inflammatory cytokine Il-1beta in leukocytes. We also assessed C-reactive protein (CRP) and IL 1beta in plasma, as additional inflammatory markers. We did not find any support to the hypothesis that inflammasone activation increases with age. Expression of Asc, Casp1, NFkB, and Il-1beta did not vary with age, body mass index (BMI), and CRP levels. In addition, expression did not differ between males and females or between smokers and non-smokers. A notable exception was the expression of Nlrp3 which varied non-linearly with age. Specifically, Nlrp3 expression strongly declined during aging, in subjects who were between 50 and 81 years old. CRP was higher in women and increased as a function of age-corrected BMI, while only four subjects showed detectable amount of IL-1beta in plasma. Further work on larger cohorts with a longitudinal monitoring should be conducted to corroborate the finding that healthy aging is associated with a decrease in inflammasome activation. PMID- 29415185 TI - Induced Sputum as a Diagnostic Tool in Pneumonia in Under Five Children-A Hospital-based Study. AB - Objective: The objective of this articlewas to study the success, tolerability of sputum induction and the bacterial isolates of induced sputum in children aged <5 years. Methods: The cross-sectional study included 120 hospitalized children aged 1-59 months meeting WHO criteria for pneumonia. Sputum induction was performed using hypertonic (3%) saline. Results: Mean age of the subjects was 19.5 months (2-59 months). Overall success of sputum induction was 53.3% and highest (64.28%) in 37-59 months age group. Adverse events such as tachypnea, hypoxemia (SpO2 <90) and vomiting were observed in 41.6, 17.5 and 15.8%, respectively. A potential pathogen was isolated in 45 (70.3%) of 64 cases with good quality sputum. Klebsiella pneumoniae was the commonest (38.2%) followed by Streptococcus pneumoniae (14.8%) and others. Conclusion: Sputum induction in young children is safe and feasible in Indian settings. While the success was limited, bacterial yield was high. PMID- 29415187 TI - Microarray is an efficient tool for circRNA profiling. AB - Circular RNAs (circRNAs) are emerging as a new class of endogenous and regulatory noncoding RNAs in latest years. With the widespread application of RNA sequencing (RNA-seq) technology and bioinformatics prediction, large numbers of circRNAs have been identified. However, at present, we lack a comprehensive characterization of all these circRNAs in interested samples. In this study, we integrated 87 935 circRNAs sequences that cover most of circRNAs identified till now represented in circBase to design microarray probes targeting back-splice site of each circRNA to profile expression of those circRNAs. By comparing the circRNA detection efficiency of RNA-seq with this circRNA microarray, we revealed that microarray is more efficient than RNA-seq for circRNA profiling. Then, we found ~80 000 circRNAs were expressed in cervical tumors and matched normal tissues, and ~25 000 of them were differently expressed. Notably, many of these circRNAs detected by this microarray can be validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR) or RNA-seq. Strikingly, as many as ~18 000 circRNAs could be robustly detected in cell-free plasma samples, and the expression of ~2700 of them differed after surgery for tumor removal. Our findings provided a comprehensive and genome-wide characterization of circRNAs in paired normal tissues and tumors and plasma samples from multiple individuals. In addition, we also provide a rich resource with 41 microarray data sets and 10 RNA seq data sets and strong evidences for circRNA expression in cervical cancer. In conclusion, circRNAs could be efficiently profiled by circRNA microarray to target their reported back-splice sites in interested samples. PMID- 29415186 TI - Microbial Spectrum of Intra-Abdominal Abscesses in Perforating Crohn's Disease: Results from a Prospective German Registry. AB - Background: Intra-abdominal abscesses [IAAs] are common life-threatening complications in patients with Crohn's disease [CD]. In addition to interventional drainage and surgical therapy, empirical antibiotic therapy represents a cornerstone of treatment, but contemporary data on microbial spectra and antimicrobial resistance are scarce. Methods: We recruited 105 patients with CD and IAAs from nine German centres for a prospective registry in order to characterize the microbiological spectrum, resistance profiles, antibiotic therapy and outcome. Results: In 92 of 105 patients, microbial investigations of abscess material revealed pathogenic microorganisms. A total of 174 pathogens were isolated, with a median of 2 pathogens per culture [range: 1-6]. Most frequently isolated pathogens were E. coli [45 patients], Streptococcus spp. [28 patients], Enterococci [27 patients], Candida [13 patients] and anaerobes [12 patients]. Resistance to third-generation cephalosporins, penicillins with beta lactamase inhibitors and quinolones were observed in 51, 36 and 35 patients, respectively. Seven patients had multiple-drug-resistant bacteria. Thirty patients received inadequate empirical treatment, and this was more frequent in patients receiving steroids or immunosuppression [37%] than in patients without immunosuppression [10%: p = 0.001] and was associated with a longer hospital stay [21 days vs 13 days, p = 0.003]. Conclusion: Based on antimicrobial resistance profiles, we herein report a high rate of inadequate empirical first-line therapy for IAAs in CD, especially in patients receiving immunosuppression, and this is associated with prolonged hospitalization. PMID- 29415188 TI - Phase I-II trial designs: how early should efficacy guide the dose recommendation process? PMID- 29415189 TI - Minority resistant variants are also present in HIV-2-infected antiretroviral naive patients. AB - Objectives: To assess the prevalence of minority resistant variants (MRV) and X4 tropic minority variants in ART-naive HIV-2-infected patients. Patients and methods: ART-naive HIV-2-infected patients with detectable plasma viral load (>100 copies/mL) included in the ANRS HIV-2 CO5 Cohort were assessed. We performed ultra-deep sequencing (UDS) of protease, RT, integrase and gp105 regions. Only mutations in the HIV-2 ANRS list >1% were considered. HIV-2 tropism was assessed by V3 loop region UDS, and each read was interpreted with determinants of CXCR4-coreceptor use. Results: Among the 47 patients assessed, three displayed plasma viruses with a resistance-associated mutation (RAM) above the 20% detection threshold, all in RT, resulting in a prevalence of transmitted drug resistance for NRTI of 7.9% (95% CI 0.0%-16.5%). No RAM above the 20% detection threshold was found in protease or integrase. At the 1% detection threshold the transmitted drug resistance prevalence was 9.8% (95% CI 0.6% 19.0%), 13.2% (95% CI 3.5%-22.9%) and 4.5% (95% CI 0%-17.5%) for PI, NRTI and integrase inhibitors. The most prevalent MRV was the PI RAM I50V detected in three samples. Tropism analysis showed that 21% of patients (4 of 19) exhibited X4-tropic viruses: two in majority proportion and two in minority proportions (1.5% and 1.9%). Conclusions: In this first study assessing the prevalence of MRV in HIV-2 infection among ART-naive patients, we observed a 2-3-fold higher prevalence of RAM when a 1% detection threshold of mutations was used compared with a 20% threshold. Similarly, the proportion of patients with X4-tropic viruses was twice as high when UDS was used. PMID- 29415191 TI - Training and Spontaneous Reinforcement of Neuronal Assemblies by Spike Timing Plasticity. AB - The synaptic connectivity of cortex is plastic, with experience shaping the ongoing interactions between neurons. Theoretical studies of spike timing dependent plasticity (STDP) have focused on either just pairs of neurons or large scale simulations. A simple analytic account for how fast spike time correlations affect both microscopic and macroscopic network structure is lacking. We develop a low-dimensional mean field theory for STDP in recurrent networks and show the emergence of assemblies of strongly coupled neurons with shared stimulus preferences. After training, this connectivity is actively reinforced by spike train correlations during the spontaneous dynamics. Furthermore, the stimulus coding by cell assemblies is actively maintained by these internally generated spiking correlations, suggesting a new role for noise correlations in neural coding. Assembly formation has often been associated with firing rate-based plasticity schemes; our theory provides an alternative and complementary framework, where fine temporal correlations and STDP form and actively maintain learned structure in cortical networks. PMID- 29415192 TI - Chilaiditi's Syndrome Causing High-Grade Small-Bowel Obstruction Requiring Exploratory Laparotomy. AB - Chilaiditi's sign is a radiological finding that occurs when the small or large intestine is positioned superior to the liver in the sub-diaphragmatic space. This is typically an asymptomatic radiological sign, but when symptoms occur, e.g., abdominal pain, nausea, emesis, it is termed Chilaiditi's syndrome. Currently, majority of the cases of Chilaiditi's syndrome, described in the literature, requiring operative intervention are due to large bowel obstruction or colonic volvulus. The following is a single case report of a patient presenting to Keesler Medical Center in Biloxi, Mississippi. This report details a 57-yr-old female who has found to have Chilaiditi's syndrome causing a high grade small-bowel obstruction. She failed non-operative intervention and required exploratory laparotomy, lysis of adhesions, and manual reduction of small bowel from the sub-diaphragmatic space. The rate of failure of non-operative management of Chilaiditi's syndrome has not been established. Our patient had a surgical history of laparotomy and was found to have adhesions superior to her liver. Patients with prior abdominal surgery may require a lower threshold for operative management for Chilaiditi's syndrome due to the possibility of concomitant adhesive disease particularly if the prior procedure involved the upper abdomen. PMID- 29415190 TI - Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine. AB - Background: Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication. Methods: This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points. Results: The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-gamma, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities. Conclusions: The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications. Clinical Trials Registration: NCT02771249. PMID- 29415193 TI - Ten-year experience of the thoraco-abdominal aortic aneurysm treatment using a hybrid thoracic endovascular aortic repair. AB - OBJECTIVES: The treatment of thoraco-abdominal aortic aneurysm continues to have a high mortality and paraplegia rate. In superaging societies, the methods of performing less invasive operations remain a major issue. We reviewed our 10-year experience in the treatment of thoraco-abdominal aortic aneurysm using a hybrid procedure of combined visceral reconstruction and thoracic endovascular aortic repair. METHODS: Sixty patients underwent a hybrid repair for the treatment of the thoraco-abdominal aortic aneurysm between 2007 and 2016. The mean age was 72.7 years. A true aneurysm was found in 43 (72%) patients and a chronic dissection in 17 (28%) patients. The standard operative procedure involved replacing the abdominal aorta with an artificial graft, and the visceral arteries were reconstructed using a quadrifurcated graft. Renovisceral debranching and stent grafting were performed as a 2-stage procedure. RESULTS: The hospital mortality rate was 5%. Two (3%) patients died due to an aneurysmal rupture in the hospital just after renovisceral debranching. The other 2 patients died due to an aneurysmal rupture in the long-term period after preventive renovisceral debranching. Two (3%) patients experienced spinal cord ischaemia after the stenting procedure. Four (7%) patients required additional treatment during the follow-up period. The overall survival was 75.9% at 2 years, 65.2% at 5 years and 43.5% at 8 years. The rates of freedom from aorta-related events were 92.9% at 2 years, 80.5% at 5 years and 72.5% at 8 years. CONCLUSIONS: The hybrid repair is considered to be a good option for elderly and high-risk patients. Further long term follow-up is necessary to extend the indication in younger patients. PMID- 29415194 TI - A semiparametric model for wearable sensor-based physical activity monitoring data with informative device wear. AB - Wearable sensors provide an exceptional opportunity in collecting real-time behavioral data in free living conditions. However, wearable sensor data from observational studies often suffer from information bias, since participants' willingness to wear the monitoring devices may be associated with the underlying behavior of interest. The aim of this study was to introduce a semiparametric statistical approach for modeling wearable sensor-based physical activity monitoring data with informative device wear. Our simulation study indicated that estimates from the generalized estimating equations showed ignorable bias when device wear patterns were independent of the participants physical activity process, but incrementally more biased when the patterns of device non-wear times were increasingly associated with the physical activity process. The estimates from the proposed semiparametric modeling approach were unbiased both when the device wear patterns were (i) independent or (ii) dependent to the underlying physical activity process. We demonstrate an application of this method using data from the 2003-2004 National Health and Nutrition Examination Survey ($N=4518$), to examine gender differences in physical activity measured using accelerometers. The semiparametric model can be implemented using our R package acc, free software developed for reading, processing, simulating, visualizing, and analyzing accelerometer data, publicly available at the Comprehensive R Archive Network. PMID- 29415195 TI - Disease and survival on the Thai-Burma railway: lessons for modern tropical medicine? AB - During the 2nd World War, large numbers of allied military personnel in south east Asia became prisoners-of-war (POWs) of the Japanese. During their internment of three and a half years, they suffered undernutrition, exposure to tropical diseases and frequently overwork. Perhaps the harshest POW experience was the construction of the railway between Thailand and Burma. This paper explores the medical conditions during Far East imprisonment, and in particular on the Thai Burma Railway, as well as the long-term health effects in post-war decades. PMID- 29415197 TI - lncRNA ENSMUST00000134285 Increases MAPK11 Activity, Regulating Aging-Related Myocardial Apoptosis. AB - Previous studies have demonstrated that aging promotes myocardial apoptosis after ischemia/reperfusion, via unknown specific mechanisms. The present study investigates the potential relationship between lncRNAs and aging-related apoptosis by lncRNA/mRNA microarray technology. The results indicate aging increased myocardial lncRNA ENSMUST00000134285 and mMAPK11, confirmed by both bioinformatics analysis and polymerase chain reaction (PCR). Mouse cardiomyocytes were subjected to gene manipulation (ENSMUST00000134285 knockdown and overexpression). Knockdown of ENSMUST00000134285 inhibited MAPK11 activity and increased the myocardial apoptotic ratio (determined by TUNEL staining and caspase activity assays) after hypoxia/reoxygenation. Conversely, overexpression of ENSMUST00000134285 increased MAPK11 activity and decreased the myocardial apoptotic ratio. Furthermore, luciferase reporter assay revealed that miR760 may be a mediator between ENSMUST00000134285 and mMAPK11. We have provided evidence that lncRNAs are the important regulatory molecules in aging-mediated effects upon apoptosis. The apoptosis regulatory effects of aging are complex. Except apoptosis-promoting effects, aging could also inhibit myocardial apoptosis after hypoxia or ischemia. Further studies investigating the mechanisms that aging inhibit myocardial apoptosis after hypoxia/ischemia. PMID- 29415196 TI - Multidimensional correlation among plan complexity, quality and deliverability parameters for volumetric-modulated arc therapy using canonical correlation analysis. AB - A multidimensional exploratory statistical method, canonical correlation analysis (CCA), was applied to evaluate the impact of complexity parameters on the plan quality and deliverability of volumetric-modulated arc therapy (VMAT) and to determine parameters in the generation of an ideal VMAT plan. Canonical correlations among complexity, quality and deliverability parameters of VMAT, as well as the contribution weights of different parameters were investigated with 71 two-arc VMAT nasopharyngeal cancer (NPC) patients, and further verified with 28 one-arc VMAT prostate cancer patients. The average MU and MU per control point (MU/CP) for two-arc VMAT plans were 702.6 +/- 55.7 and 3.9 +/- 0.3 versus 504.6 +/- 99.2 and 5.6 +/- 1.1 for one-arc VMAT plans, respectively. The individual volume-based 3D gamma passing rates of clinical target volume (gammaCTV) and planning target volume (gammaPTV) for NPC and prostate cancer patients were 85.7% +/- 9.0% vs 92.6% +/- 7.8%, and 88.0% +/- 7.6% vs 91.2% +/- 7.7%, respectively. Plan complexity parameters of NPC patients were correlated with plan quality (P = 0.047) and individual volume-based 3D gamma indices gamma(IV) (P = 0.01), in which, MU/CP and segment area (SA) per control point (SA/CP) were weighted highly in correlation with gamma(IV) , and SA/CP, percentage of CPs with SA < 5 * 5 cm2 (%SA < 5 * 5 cm2) and PTV volume were weighted highly in correlation with plan quality with coefficients of 0.98, 0.68 and -0.99, respectively. Further verification with one-arc VMAT plans demonstrated similar results. In conclusion, MU, SA-related parameters and PTV volume were found to have strong effects on the plan quality and deliverability. PMID- 29415198 TI - Extended surgery using anterior mediastinal tracheostomy for recurrent mediastinal liposarcoma. AB - Mediastinal liposarcoma is an extremely rare malignancy with a poor prognosis. We report the case of a 73-year-old man who presented with severe respiratory distress. He had previously been diagnosed with mediastinal liposarcoma, which had been treated with extirpation 6 years ago. The histological type was a well differentiated liposarcoma. Three years ago, he experienced respiratory distress due to postoperative recurrence of mediastinal liposarcoma. To establish an airway, tracheotomy was urgently performed. Tracheal stenosis also developed because the sarcoma progressed to the trachea after tracheostomy. We performed radical resection of the recurrent mediastinal liposarcoma combined with the resection of the laryngopharynx and cervical oesophagus and reconstruction using a free jejunal graft. We then performed anterior mediastinal tracheostomy with a pedicled omental flap. There has been no recurrence in the 3 years since the last operation. PMID- 29415199 TI - Cerebral Osmolytes and Plasma Osmolality in Pregnancy and Preeclampsia: A Proton Magnetic Resonance Spectroscopy Study. AB - BACKGROUND: Cerebral complications contribute substantially to mortality in preeclampsia. Pregnancy calls for extensive maternal adaptations, some associated with increased propensity for seizures, but the pathophysiology behind the eclamptic seizures is not fully understood. Plasma osmolality and sodium levels are lowered in pregnancy. This could result in extrusion of cerebral organic osmolytes, including the excitatory neurotransmitter glutamate, but this remains to be determined. The hypothesis of this study was that cerebral levels of organic osmolytes are decreased during pregnancy, and that this decrease is even more pronounced in women with preeclampsia. METHODS: We used proton magnetic resonance spectroscopy to compare levels of cerebral organic osmolytes, in women with preeclampsia (n = 30), normal pregnancy (n = 32), and nonpregnant controls (n = 16). Cerebral levels of organic osmolytes were further correlated to plasma osmolality and plasma levels of glutamate and sodium. RESULTS: Compared to nonpregnant women, women with normal pregnancy and preeclampsia had lower levels of the cerebral osmolytes, myo-inositol, choline and creatine (P = 0.001 or less), and all these metabolites correlated with each other (P < 0.05). Women with normal pregnancies and preeclampsia had similar levels of osmolytes, except for glutamate, which was significantly lower in preeclampsia. Cerebral and plasma glutamate levels were negatively correlated with each other (P < 0.008), and myo inositol, choline and creatine levels were all positively correlated with both plasma osmolality and sodium levels (P < 0.05). CONCLUSIONS: Our results indicate that pregnancy is associated with extrusion of cerebral organic osmolytes. This includes the excitatory neurotransmitter glutamate, which may be involved in the pathophysiology of seizures in preeclampsia. PMID- 29415200 TI - Sleep Duration and Sleep Disturbances as Predictors of Healthy and Chronic Disease-Free Life Expectancy between Ages 50 and 75: A Pooled Analysis of Three Cohorts. AB - Background: The aim of this study was to examine the associations of sleep duration and sleep disturbances with healthy and chronic disease-free life expectancy (LE) between ages 50 and 75. Methods: Data were drawn from repeated waves of three occupational cohort studies in England, Finland and Sweden (n=55,494) and the follow-up ranged from 6 to 18 years. Self-reported sleep duration was categorized into <7h, 7-8.5h and >=9h and sleep disturbances into no, moderate, and severe. Health expectancy was estimated with two health indicators: healthy LE based on years in good self-rated health and chronic disease-free LE based on years without chronic diseases. Multistate life table models were used to estimate healthy and chronic disease-free LE from age 50 to 75 years for each category of sleep measures in each cohort. Fixed-effects meta analysis was used to pool the cohort-specific results into summary estimates. Results: Persons who slept 7-8.5 hours could expect to live 19.1 (95% CI 19.0 19.3) years in good health and 13.5 (95% CI 13.2-13.7) years without chronic diseases between ages 50 and 75. Healthy and disease-free years were 1-3 years shorter for those who slept less than 7 hours or slept 9 hours or more. Persons who did not have sleep disturbances could expect to live 20.4 (95% CI 20.3-20.6) years in good health and 14.3 (95% CI 14.1-14.5) years without chronic diseases between ages 50 and 75. Healthy and disease-free years were 6-3 years shorter for those who reported severe sleep disturbances. Conclusions: Sleeping 7-8.5 hours and having no sleep disturbances between ages 50 to 75 are associated with longer healthy and chronic disease-free LE. PMID- 29415201 TI - Genetic Variation in FOXO3 is Associated with Self-Rated Health in a Population Based Sample of Older Individuals. AB - Self-rated health (SRH) strongly predicts mortality. Twin studies estimate that genetic factors account for a substantial part of the variability in SRH. Variations in the gene FOXO3 (forkhead box O3), and in genes located at the APOE (apoplipoprotein E) locus, are associated with longevity. This study explores the relationship between SRH and genetic variation related to longevity, in a population-based cohort of older individuals. SRH was assessed among 1,520 individuals aged 75-87, and five single nucleotide polymorphisms (SNPs), in APOE, TOMM40 (translocase of outer mitochondrial membrane 40 homolog), and FOXO3 were genotyped. Two SNPs (rs10457180 and rs2802292) in FOXO3 were associated with SRH (OR = 2.18 [CI: 1.27-3.76], p = .005 and OR = 1.63 [CI: 1.11-2.40], p = .013), while no associations were found with SNPs in APOE and TOMM40. Several factors, such as depression, cardiovascular disease (CVD), and diabetes, were related to SRH, but the only factor that had any influence on the association with FOXO3 was CVD. Still, after including CVD as a covariate, the associations between FOXO3 SNPs and SRH remained significant. Our results suggest that FOXO3 is related to SRH in older individuals. This relationship seems to be influenced by CVD, but not by mental and cognitive status. PMID- 29415203 TI - Left atrial appendage patency and device-related thrombus after percutaneous left atrial appendage occlusion: a computed tomography study. AB - Aims: Transoesophageal echocardiography studies have reported frequent peri device leaks and device-related thrombi (DRT) after percutaneous left atrial appendage (LAA) occlusion. We assessed the prevalence, characteristics and correlates of leaks and DRT on cardiac computed tomography (CT) after LAA occlusion. Methods and results: Consecutive patients underwent cardiac CT before LAA occlusion to assess left atrial (LA) volume, LAA shape, and landing zone diameter. Follow-up CT was performed after >3 months to assess device implantation criteria, device leaks and DRT. CT findings were related to patient and device characteristics, as well as to outcome during follow-up. One-hundred and seventeen patients (age 74 +/- 9, 37% women, CHA2DS2VASc 4.4 +/- 1.3, and HASBLED 3.5 +/- 1.0) were implanted with Amplatzer cardiac plug (ACP)/Amulet (71%) or Watchman (29%). LAA patency was detected in 44% on arterial phase CT images and 69% on venous phase images. The most common leak location was postero inferior. LAA patency related to LA dilatation, left ventricular ejection fraction impairment, non-chicken wing LAA shape, large landing zone diameter, incomplete device lobe thrombosis, and disc/lobe misalignment in patients with ACP/Amulet. DRT were detected in 19 (16%), most being laminated and of antero superior location. DRT did not relate to clinical or imaging characteristics nor to implantation criteria, but to total thrombosis of device lobe. Over a mean 13 months follow-up, stroke/transient ischaemic attack occurred in eight patients, unrelated to DRT or LAA patency. Conclusion: LAA patency on CT is common after LAA occlusion, particularly on venous phase images. Leaks relate to LA/LAA size at baseline, and device malposition and incomplete thrombosis at follow-up. DRT is also quite common but poorly predicted by patient and device-related factors. PMID- 29415202 TI - CsATAF1 Positively Regulates Drought Stress Tolerance by an ABA-Dependent Pathway and by Promoting ROS Scavenging in Cucumber. AB - The NAC transcription factors play vital roles in responding to drought stress in plants; however, the molecular mechanisms remain largely unknown in cucumber. Suppression of CsATAF1 via RNA interference (RNAi) weakened drought stress tolerance in cucumber due to a higher water loss rate in leaves, a higher level of hydrogen peroxide (H2O2) and superoxide radicals (O2.-), increased malondialdehyde (MDA) content, lower Fv/Fm ratios and lower antioxidant enzyme activity. The analysis of root length and stomatal apertures showed that CsATAF1 RNAi cucumber plants were less responsive to ABA. In contrast, CsATAF1 overexpression (OE) plants showed increased drought stress tolerance and sensitivity to ABA. Quantitative PCR (qPCR) analysis showed that expression of several stress-responsive genes was significantly up-regulated in CsATAF1-OE transformants and down-regulated in CsATAF1-RNAi transformants. CsABI5, CsCu ZnSOD and CsDREB2C were verified as direct target genes of CsATAF1. Yeast one hybrid analysis and electrophoretic mobility shift assay (EMSA) further substantiated that CsATAF1 bound to the promoters of CsABI5, CsCu-ZnSOD and CsDREB2C. Transient expression in tobacco leaves and cucumber protoplasts showed that CsATAF1 directly up-regulated the expression of CsABI5, CsCu-ZnSOD and CsDREB2C. Our results demonstrated that CsATAF1 functioned as a positive regulator in response to drought stress by an ABA-dependent pathway and decreasing reactive oxygen species (ROS) accumulation in cucumber. PMID- 29415204 TI - Characterization of glycoengineered anti-HER2 monoclonal antibodies produced by using a silkworm-baculovirus expression system. AB - Silkworm-baculovirus expression systems are efficient means for the production of recombinant proteins that provide high expression levels and post-translational modifications. Here, we characterized the stability, glycosylation pattern and antibody-dependent cell-mediated cytotoxicity activity of anti-HER2 monoclonal antibodies containing native or glycoengineered mammalian-like N-glycans that were produced by using a silkworm-baculovirus expression system. Compared with a monoclonal antibody produced by using a Chinese hamster ovary cell expression system, the glycoengineered monoclonal antibody had comparable thermal stability and a higher antibody-dependent cell-mediated cytotoxicity activity. These results suggest that silkworm-baculovirus expression systems are next-generation expression systems potentially useful for the cost-effective production of therapeutic antibodies. PMID- 29415206 TI - Does Familial IBD Have its Own Signature? PMID- 29415205 TI - HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease. AB - Peripheral nerve axons require a well-organized axonal microtubule network for efficient transport to ensure the constant crosstalk between soma and synapse. Mutations in more than 80 different genes cause Charcot-Marie-Tooth disease, which is the most common inherited disorder affecting peripheral nerves. This genetic heterogeneity has hampered the development of therapeutics for Charcot Marie-Tooth disease. The aim of this study was to explore whether histone deacetylase 6 (HDAC6) can serve as a therapeutic target focusing on the mutant glycyl-tRNA synthetase (GlyRS/GARS)-induced peripheral neuropathy. Peripheral nerves and dorsal root ganglia from the C201R mutant Gars mouse model showed reduced acetylated alpha-tubulin levels. In primary dorsal root ganglion neurons, mutant GlyRS affected neurite length and disrupted normal mitochondrial transport. We demonstrated that GlyRS co-immunoprecipitated with HDAC6 and that this interaction was blocked by tubastatin A, a selective inhibitor of the deacetylating function of HDAC6. Moreover, HDAC6 inhibition restored mitochondrial axonal transport in mutant GlyRS-expressing neurons. Systemic delivery of a specific HDAC6 inhibitor increased alpha-tubulin acetylation in peripheral nerves and partially restored nerve conduction and motor behaviour in mutant Gars mice. Our study demonstrates that alpha-tubulin deacetylation and disrupted axonal transport may represent a common pathogenic mechanism underlying Charcot-Marie-Tooth disease and it broadens the therapeutic potential of selective HDAC6 inhibition to other genetic forms of axonal Charcot-Marie-Tooth disease. PMID- 29415207 TI - Progression of calcium density in the ascending thoracic aorta is inversely associated with incident cardiovascular disease events. AB - Aims: Little is known regarding the risk of atherosclerotic cardiovascular disease (ASCVD) conferred by changes in the volume and density of ascending thoracic aorta calcium (ATAC) over time. We evaluated changes in ATAC volume and density scores and incident ASCVD events. Methods and results: The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of individuals without baseline clinical ASCVD. Ascending thoracic aorta calcium was measured from baseline and follow-up (mean interval 2.4 years) cardiac computed tomography (CT). Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) per standard deviation for events after the follow-up exam adjusted for ASCVD risk factors, baseline ATAC and coronary artery calcium (CAC) volume and density, and changes in CAC volume and density. Among 5887 participants, 296 (5.0%) had detectable ATAC at baseline, follow-up, or both exams. A total of 403 events occurred over 9.5 years. An increase in ATAC volume was associated with coronary heart disease (CHD) (HR 1.90, 95% CI 1.14-3.16), ASCVD (HR 1.93, 95% CI 1.26-2.94), and ischaemic stroke (HR 2.14, CI 1.21-3.78). An increase in ATAC density was inversely associated with CHD (HR 0.29, 95% CI 0.14-0.60) and ASCVD (HR 0.42, 95% CI 0.23-0.76), but not stroke (HR 0.61, CI 0.23-1.61). Conclusion: Ascending thoracic aorta calcium is uncommon on serial cardiac CT. However, changes in ATAC volume and density are both associated with incident ASCVD events, but in opposite directions. Serial assessments in those with baseline ATAC may provide insight into an individual's trajectory of ASCVD risk. PMID- 29415208 TI - Breathprinting Reveals Malaria-Associated Biomarkers and Mosquito Attractants. AB - Current evidence suggests that malarial infection could alter metabolites in the breath of patients, a phenomenon that could be exploited to create a breath-based diagnostic test. However, no study has explored this in a clinical setting. To investigate whether natural human malarial infection leads to a characteristic breath profile, we performed a field study in Malawi. Breath volatiles from children with and those without uncomplicated falciparum malaria were analyzed by thermal desorption-gas chromatography/mass spectrometry. Using an unbiased, correlation-based analysis, we found that children with malaria have a distinct shift in overall breath composition. Highly accurate classification of infection status was achieved with a suite of 6 compounds. In addition, we found that infection correlates with significantly higher breath levels of 2 mosquito attractant terpenes, alpha-pinene and 3-carene. These findings attest to the viability of breath analysis for malaria diagnosis, identify candidate biomarkers, and identify plausible chemical mediators for increased mosquito attraction to patients infected with malaria parasites. PMID- 29415209 TI - Xylogenesis reveals the genesis and ecological signal of IADFs in Pinus pinea L. and Arbutus unedo L. AB - Background and Aims: Mediterranean trees have patterns of cambial activity with one or more pauses per year, leading to intra-annual density fluctuations (IADFs) in tree rings. We analysed xylogenesis (January 2015-January 2016) in Pinus pinea L. and Arbutus unedo L., co-occurring at a site on Mt. Vesuvius (southern Italy), to identify the cambial productivity and timing of IADF formation. Methods: Dendrochronological methods and quantitative wood anatomy were applied and enabled IADF identification and classification. Key Results: We showed that cambium in P. pinea was productive throughout the calendar year. From January to March 2015, post-cambial (enlarging) earlywood-like tracheids were observed, which were similar to transition tracheids. The beginning of the tree ring was therefore not marked by a sharp boundary between latewood of the previous year and the new xylem produced. True earlywood tracheids were formed in April. L IADFs were formed in autumn, with earlywood-like cells in latewood. In A. unedo, a double pause in cell production was observed, in summer and winter, leading to L-IADFs in autumn as well. Moreover, the formation of more than one IADF was observed in A. unedo. Conclusions: Despite having completely different wood formation models and different life strategies, the production of earlywood, latewood and IADF cells was strongly controlled by climatic factors in the two species. Such cambial production patterns need to be taken into account in dendroecological studies to interpret climatic signals in wood from Mediterranean trees. PMID- 29415211 TI - Unnatural death: a major but largely preventable cause-of-death among homeless people? AB - Background: We aimed to assess the contribution of specific causes-of-death to excess mortality of homeless persons and to identify differences in cause specific mortality rates after vs. before implementing social policy measures. Methods: We conducted a register based 10-year follow-up study of homeless adults in Rotterdam and calculated the proportion of deaths by cause-of-death in this cohort in the period 2001-2010. We estimated cause-specific mortality among the homeless compared to the general population with Standardized Mortality Ratios. We calculated Hazard Ratios adjusted for age and sex to compare mortality rates by cause-of-death among the homeless in the period after (2006-2010) vs. before (2001-2005) implementing social policy measures. Results: Our cohort consisted of 2130 homeless persons with a mean age of 40, 3 years. Unnatural death, cardiovascular disease and cancer were the main causes of death. Compared to the general population of Rotterdam, the homeless had an excess risk of death for all causes. The largest mortality differences with Rotterdam citizens were observed for unnatural death (SMR 14.8, CI 11.5-18.7), infectious diseases (SMR 10.0, CI 5.2-17.5) and psychiatric disorders (SMR 7.7, CI 4.0-13.5). Mortality due to intentional injuries (suicide and homicide) differed significantly between the two study periods (HR 0.45, CI 0.20-0.97). Conclusions: Reducing unnatural death should be a target in social policies aimed at improving the health of the homeless. We generated the hypothesis that social policies aimed at housing, work and improved contact with health care could be accompanied by less suicides and homicides within this vulnerable group. PMID- 29415212 TI - A mathematical model-based analysis of the time-kill kinetics of ceftazidime/avibactam against Pseudomonas aeruginosa. AB - Objectives: To characterize quantitatively the effect of avibactam in potentiating ceftazidime against MDR Pseudomonas aeruginosa by developing a mathematical model to describe the bacterial response to constant concentration time-kill information and validating it using both constant and time-varying concentration-effect data from in vitro and in vivo infection systems. Methods: The time course of the bacterial population dynamics in the presence of static concentrations of ceftazidime and avibactam was modelled using a two-state pharmacokinetic/pharmacodynamic (PK/PD) model, consisting of active and resting states, to account for bactericidal activities, bacteria-mediated ceftazidime degradation and inhibition of degradation by avibactam. Ceftazidime's effect on the bacterial population was described as an enhancement of the death rate of the active population, with the effect of avibactam being to increase ceftazidime potency. Model validation was performed by comparing simulated time courses of bacterial responses with those from in vitro and in vivo experimental exposures of ceftazidime and avibactam that represented those predicted in an average patient dosed with 2 g/0.5 g ceftazidime/avibactam administered every 8 h as 2 h infusions. Results: The two-state model successfully described the bacterial population dynamics, ceftazidime degradation and its inhibition by avibactam. For external validation, the model correctly predicted the bacterial response of P. aeruginosa isolates evaluated in in vitro hollow-fibre and in vivo neutropenic mouse thigh and lung infection models. Conclusions: The PK/PD model and modelled strains successfully replicated the spread in activity when compared with a large selection of P. aeruginosa strains reported in the literature. PMID- 29415213 TI - Risk of Exertional Heat Illnesses Associated with Sickle Cell Trait in U.S. Military. AB - Introduction: A number of studies have found an association between sickle cell trait (SCT) and exertional heat illnesses (EHIs) including heat stroke, a potentially fatal condition. The strength of this association varied across studies, limiting the ability to quantify potential benefits of SCT-screening policies for competitive athletics and military service members. We determined the relative rate and attributable risk of developing EHI associated with being SCT positive and the EHI health care utilization. Methods: We conducted a retrospective cohort study among U.S. enlisted, active duty service members during 1992-2012 from the Department of Defense Military Healthcare System databases. All 15,081 SCT-positive individuals and a sample of 60,320 from those considered SCT negative were followed through 2013 for EHI outcomes ranging from mild heat illness to heat stroke. Results: The adjusted hazard ratio for EHI in SCT-positive compared with SCT-negative individuals was 1.24 (95% confidence interval 1.06, 1.45). Risk factors for EHI included age over 30 yr at enlistment, female gender, Marine Corps, combat occupations, and enlistment between April and June. An estimated 216 Department of Defense enlistees (95% confidence interval: 147, 370) would need to be screened to identify and potentially prevent one case of EHI. The attributable risk of EHI due to SCT was 33% (95% confidence interval 19, 45%). Conclusion: Our findings suggest that SCT screening will identify approximately a third of SCT individuals at risk for EHI, but does not provide definitive evidence for universal compared with selective (e.g., occupational based) in military enlistees. A cost-effectiveness analysis is needed for policy makers to assess the overall value of universal SCT screening to prevent morbidity and mortality in both the military and the collegiate athletic populations. PMID- 29415214 TI - Performance evaluation of the QMAC-dRAST for staphylococci and enterococci isolated from blood culture: a comparative study of performance with the VITEK-2 system. AB - Objectives: To evaluate the performance of a rapid antimicrobial susceptibility testing (AST) platform based on microfluidic chip technology, the QMAC-dRAST, which enables AST from colony isolates or positive blood culture broth (PBCB), and to compare the performance of the QMAC-dRAST for staphylococci and enterococci with that of the VITEK-2 system based on reference broth microdilution (BMD). Methods: A total of 110 staphylococcal and enterococcal isolates from blood cultures were included. AST was performed directly using the QMAC-dRAST with PBCB. Thereafter, colony isolates derived from subculture of PBCB were used for the QMAC-dRAST, the VITEK-2 system and BMD. Results: The overall agreement between the QMAC-dRAST with PBCB and BMD was 91.5%. There were 1.2% very major errors (VMEs), 4.3% major errors (MEs) and 5.4% minor errors (mEs). The QMAC-dRAST with colony isolates yielded 94.6% agreement and error rates of 1.0% VMEs, 1.8% MEs and 4.0% mEs. The VITEK-2 system showed 96.2% agreement and error rates of 2.3% VMEs, 0.5% MEs and 2.6% mEs. The incubation time in the QMAC dRAST was significantly shorter than in the VITEK-2 system (median of 6 versus 10 h; P < 0.0001). Conclusions: The QMAC-dRAST system provided rapid results and represents an alternative to conventional AST methods. The QMAC-dRAST with colony isolates produced more reliable results for staphylococci and enterococci than the QMAC-dRAST with PBCB. The QMAC-dRAST system also performed comparably to BMD and the VITEK-2 system. PMID- 29415210 TI - The cell biology of secondary cell wall biosynthesis. AB - Background: Secondary cell walls (SCWs) form the architecture of terrestrial plant biomass. They reinforce tracheary elements and strengthen fibres to permit upright growth and the formation of forest canopies. The cells that synthesize a strong, thick SCW around their protoplast must undergo a dramatic commitment to cellulose, hemicellulose and lignin production. Scope: This review puts SCW biosynthesis in a cellular context, with the aim of integrating molecular biology and biochemistry with plant cell biology. While SCWs are deposited in diverse tissue and cellular contexts including in sclerenchyma (fibres and sclereids), phloem (fibres) and xylem (tracheids, fibres and vessels), the focus of this review reflects the fact that protoxylem tracheary elements have proven to be the most amenable experimental system in which to study the cell biology of SCWs. Conclusions: SCW biosynthesis requires the co-ordination of plasma membrane cellulose synthases, hemicellulose production in the Golgi and lignin polymer deposition in the apoplast. At the plasma membrane where the SCW is deposited under the guidance of cortical microtubules, there is a high density of SCW cellulose synthase complexes producing cellulose microfibrils consisting of 18-24 glucan chains. These microfibrils are extruded into a cell wall matrix rich in SCW-specific hemicelluloses, typically xylan and mannan. The biosynthesis of eudicot SCW glucuronoxylan is taken as an example to illustrate the emerging importance of protein-protein complexes in the Golgi. From the trans-Golgi, trafficking of vesicles carrying hemicelluloses, cellulose synthases and oxidative enzymes is crucial for exocytosis of SCW components at the microtubule rich cell membrane domains, producing characteristic SCW patterns. The final step of SCW biosynthesis is lignification, with monolignols secreted by the lignifying cell and, in some cases, by neighbouring cells as well. Oxidative enzymes such as laccases and peroxidases, embedded in the polysaccharide cell wall matrix, determine where lignin is deposited. PMID- 29415216 TI - Distinct Neocortical Progenitor Lineages Fine-tune Neuronal Diversity in a Layer specific Manner. AB - How the variety of neurons that organize into neocortical layers and functional areas arises is a central question in the study of cortical development. While both intrinsic and extrinsic cues are known to influence this process, whether distinct neuronal progenitor groups contribute to neuron diversity and allocation is poorly understood. Using in vivo genetic fate-mapping combined with whole-cell patch clamp recording, we show that the firing pattern and apical dendritic morphology of excitatory neurons in layer 4 of the barrel cortex are specified in part by their neural precursor lineage. Further, we show that separate precursors contribute to unique features of barrel cortex topography including the intralaminar position and thalamic innervation of the neurons they generate. Importantly, many of these lineage-specified characteristics are different from those previously measured for pyramidal neurons in layers 2-3 of the frontal cortex. Collectively, our data elucidate a dynamic temporal program in neuronal precursors that fine-tunes the properties of their progeny according to the lamina of destination. PMID- 29415215 TI - Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study. AB - Background: Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev refractory GBM. Methods: Twenty-eight patients with Bev-refractory GBM were enrolled in a dose escalation study receiving from 240 mg/m2 (cohort 1) to 670 mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev. Patients deemed surgical candidates underwent a single dose of Evo or placebo with pimonidazole immediately prior to surgery for biomarker evaluation, followed by dose escalation upon recovery. Assessments included adverse events, response, and survival. Results: Evo plus Bev was well tolerated up to and including the maximum dose of 670 mg/m2, which was determined to be the recommended phase II dose. Overall response rate was 17.4%, with disease control (complete response, partial response, and stable disease) observed in 14 (60.9%) of the 23 patients. The ratio of enhancement to non-enhancement was significant on log-rank analysis with time to progression (P = 0.023), with patients having a ratio of less than 0.37 showing a median progression-free survival of 98 days versus 56 days for those with more enhancement. Conclusions: Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation. PMID- 29415217 TI - Evaluating the Risk of Noise-Induced Hearing Loss Using Different Noise Measurement Criteria. AB - Objectives: This article examines whether the Occupational Safety and Health Administration's (OSHA) average noise level (LAVG) or the National Institute of Occupational Safety and Health's (NIOSH) equivalent continuous average (LEQ) noise measurement criteria better predict hearing loss. Methods: A cohort of construction workers was followed for 10 years (2000-2010), during which time their noise exposures and hearing threshold levels (HTLs) were repeatedly assessed. Linear mixed models were constructed with HTLs as the outcome, either the OSHA (LAVG) or NIOSH (LEQ) measurement criteria as the measure of exposure, and controlling for age, gender, duration of participation, and baseline HTLs (as both a covariate or an additional repeated measure). Model fit was compared between models for HTLs at 0.5, 1, 2, 3, 4, 6, and 8 kHz using the Akaike information criterion (AIC). The 10th, 50th, and 90th percentiles of hearing outcomes predicted by these models were then compared with the hearing outcomes predicted using the ISO 1999:2013 model. Results: The mixed models using the LEQ were found to have smaller AIC values than the corresponding LAVG models. However, only the 0.5, 3, and 4 kHz models were found to have an AIC difference greater than 2. When comparing the distribution of predicted hearing outcomes between the mixed models and their corresponding ISO outcomes, it was found that LEQ generally produced the smallest difference in predicted hearing outcomes. Conclusions: Despite the small difference and high correlation between the LEQ and LAVG, the LEQ was consistently found to better predict hearing levels in this cohort and, based on this finding, is recommended for the assessment of noise exposure in populations with similar exposure characteristics. PMID- 29415218 TI - Packing and Postirradiation Handling of the Anastrepha ludens (Diptera: Tephritidae) Tapachula-7 Genetic Sexing Strain: Combined Effects of Hypoxia, Pupal Size, and Temperature on Adult Quality. AB - The production of genetic sexing strains (GSS) of tephritid flies for sterile insect technique (SIT) programs convey the need to determine new conditions for packing and shipment since these flies are more susceptible to stressors than standard bisexual strains. We studied the effect of hypoxia, pupae size, and temperature on the new GSS Tapachula-7 of Anastrepha ludens flies (Diptera: Tephritidae). In one experiment, we tested the interaction size hypoxia using three pupae sizes, 6 (11.6 +/- 1.1 mg), 7 (15.3 +/- 1.5 mg), and 8 (17.9 +/- 1.3 mg) (95% of produced pupae exhibit these categories of size), and four hypoxia periods, 12, 24, 36, 48 h and a control. In a second experiment, we tested two periods of hypoxia (24 and 48 h) and four temperatures: 15, 20, 25, and 30 degrees C and a control (without hypoxia at laboratory temperature). Our results showed that the emergence and percent of fliers from the pupae exposed to hypoxia were adversely affected; however, emergence was higher in pupae of size 7. Treatment for 12 and 24 h hypoxia led to a higher number of fliers. In the case of the interaction of hypoxia and temperature, it was observed that those flies that emerged from the pupae exposed to hypoxia at 15 and 20 degrees C exhibited quality control parameters similar to those that were not exposed to hypoxia. We discuss our results on the basis of the metabolic response to these factors and its application in the SIT programs. PMID- 29415219 TI - Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography. PMID- 29415220 TI - Eye Movement Reinstatement and Neural Reactivation During Mental Imagery. AB - Half a century ago, Donald Hebb posited that mental imagery is a constructive process that emulates perception. Specifically, Hebb claimed that visual imagery results from the reactivation of neural activity associated with viewing images. He also argued that neural reactivation and imagery benefit from the re-enactment of eye movement patterns that first occurred at viewing (fixation reinstatement). To investigate these claims, we applied multivariate pattern analyses to functional MRI (fMRI) and eye tracking data collected while healthy human participants repeatedly viewed and visualized complex images. We observed that the specificity of neural reactivation correlated positively with vivid imagery and with memory for stimulus image details. Moreover, neural reactivation correlated positively with fixation reinstatement, meaning that image-specific eye movements accompanied image-specific patterns of brain activity during visualization. These findings support the conception of mental imagery as a simulation of perception, and provide evidence consistent with the supportive role of eye movement in neural reactivation. PMID- 29415221 TI - Binder of Sperm Proteins 1 and 5 have contrasting effects on the capacitation of ram spermatozoa. AB - Binder of Sperm Proteins (BSPs) are the most abundant seminal plasma protein family in the ram and bull. They have been extensively studied in the bull but less is known about their function in ovine seminal plasma and current knowledge suggests that BSPs may have different effects in these two species. In the bull, they facilitate capacitation and destabilize the sperm membrane during in vitro handling, whereas in the ram, they appear to stabilize the sperm membrane and prevent cryopreservation-induced capacitation-like changes. Further investigation into the effects of BSPs on ram spermatozoa under capacitating conditions is required to further clarify their physiological roles in the ram. We investigated the effects of Binder of Sperm Proteins 1 and 5 on epididymal ram spermatozoa in conditions of low, moderate, and high cAMP. BSPs had minimal effects on sperm function in low-cAMP conditions, but caused significant changes under cAMP upregulation. BSP1 stabilized the membrane and qualitatively reduced protein tyrosine phosphorylation, but significantly increased cholesterol efflux and induced spontaneous acrosome reactions. BSP5 slightly increased spontaneous acrosome reactions and caused sperm necrosis. However, BSP5 had minimal effects on membrane lipid order and cholesterol efflux and did not inhibit protein tyrosine phosphorylation. These findings demonstrate that under maximal cAMP upregulation, BSP1 affected ram spermatozoa in a manner comparable to bull spermatozoa, while BSP5 did not. PMID- 29415222 TI - Military-Tailored Yoga for Veterans with Post-traumatic Stress Disorder. AB - Introduction: Among veterans of post-9/11 conflicts, estimates of post-traumatic stress disorder (PTSD) range from 9% shortly after returning from deployment to 31% a year after deployment. Clinical and pharmaceutically based treatments are underutilized. This could be due to concerns related to lost duty days, as well as PTSD patients' fears of stigma of having a mental health condition. Yoga has been shown to reduce PTSD symptoms in the civilian population, but few studies have tested the impact of yoga on veterans of post-9/11 conflicts. The purpose of this study is to test the impact of yoga on post-9/11 veterans diagnosed with PTSD. Materials and Methods: Participants were 18 yr of age or older and veterans of post-9/11 conflicts. They had subthreshold or diagnostic-level PTSD related to their combat military service, as determined by a score of 30 or higher on the PTSD Checklist-Military version (PCL-M). Veterans participated in 60-min weekly yoga sessions for 6 wk taught by a Warriors at Ease-trained yoga instructor who is a, post-9/11 veteran. The yoga sessions incorporated Vinyasa-style yoga and a trauma-sensitive, military-culture informed approach advocated by two separate organizations: Warriors at Ease and Meghan's Foundation. Data were collected at baseline and again after 7 wk. The primary outcome was PCL-M score. Participants also completed the Patient Health Questionnaire, the Beck Anxiety Inventory, the Pittsburgh Sleep Quality Index, and the Mindful Attention Awareness Scale at both time points. Results: Eighteen Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans completed the pre- and post-intervention self-report questionnaires. Age ranged from 26 to 62 yr (median = 43 yr), length of service ranged from 2 to 34 yr (median = 18.8 yr), and 13 (72.2%) had completed college. Decreased PTSD symptomatology was demonstrated in the three symptom clusters represented in the PCL-M (i.e., hyperarousal, re-experiencing, and avoidance). In addition, the total score on the PCL-M decreased significantly, by both statistical and clinical measures. The participants also demonstrated improved mindfulness scores and reported decreased insomnia, depression, and anxiety symptoms. Conclusion: This study demonstrates that a trauma-sensitive yoga intervention may be effective for veterans with PTSD symptoms, whether as stand-alone or adjunctive therapy. The impressive decrease in PTSD symptomatology may be due to the tailored military-specific nature of this intervention and the fact that it was led by a veteran of post-9/11 conflicts. More research is needed with a larger sample and a more diverse veteran population. PMID- 29415223 TI - A Maisonneuve Fracture in an Active Duty Sailor: A Case Report. AB - Maisonneuve fractures are relatively well known in the sports medicine, and orthopedic communities, however, can be commonly missed among primary care providers. The following case outlines an active duty 35-yr-old female patient who presented with acute pain on the left ankle and lower leg after she misjudged a step. The injury is a combination of high fibular and medial malleolar fractures with a disruption of the tibiofibular syndesmosis ligaments. This is a result of extreme external rotation and pronation of a fixed foot. The proper diagnosis is reliant on ankle and tibiofibular films, to include orthogonal views. This case serves as a reminder to always examine joints above and below the injury site, obtain orthogonal views of a fracture, as well as the unstable nature of syndesmosis injuries. This fracture is commonly a sports-related injury; thus, it is particularly important for military providers to be aware of Maisonneuve fractures and the common pitfalls in diagnosis and treatment. PMID- 29415224 TI - Factors Associated with Severe Dehydrating Diarrhoea in the Rural Western Cape, South Africa. AB - Background: Acute diarrhoea (AD) remains a leading cause of childhood death. We evaluated whether delayed healthcare seeking was associated with severe dehydration in rural South Africa. Methods: In a prospective cohort study of children with AD admitted to a secondary-level hospital, data were collected through structured caregiver interviews and hospital record review. The primary outcome was severe dehydration/death, and the primary determinant was delay >12 h between AD symptom onset and healthcare facility presentation. Results: Total 68% (71 of 104) of children experienced a delay, and 51% (54 of 104) had severe dehydration with no in-hospital deaths. There was no difference in children with (35 of 71) or without (19 of 33) delay for severe dehydration. Mothers of children with severe dehydration tended to be younger [median (interquartile range) 24 (21-28) vs. 27 (23-30) years, p = 0.07] and used less oral rehydration solution (63 vs. 80%, p = 0.08). Conclusion: Delay of >12 h in seeking healthcare for AD was not associated with severe dehydration. PMID- 29415225 TI - Reply: Is single ovary a detrimental factor for live-birth rate in IVF? Understanding the real clinical effect of unilateral oophorectomy. PMID- 29415226 TI - Temporal Regulation of Dendritic Spines Through NrCAM-Semaphorin3F Receptor Signaling in Developing Cortical Pyramidal Neurons. AB - Neuron-glial related cell adhesion molecule NrCAM is a newly identified negative regulator of spine density that genetically interacts with Semaphorin3F (Sema3F), and is implicated in autism spectrum disorders (ASD). To investigate a role for NrCAM in spine pruning during the critical adolescent period when networks are established, we generated novel conditional, inducible NrCAM mutant mice (Nex1Cre ERT2: NrCAMflox/flox). We demonstrate that NrCAM functions cell autonomously during adolescence in pyramidal neurons to restrict spine density in the visual (V1) and medial frontal cortex (MFC). Guided by molecular modeling, we found that NrCAM promoted clustering of the Sema3F holoreceptor complex by interfacing with Neuropilin-2 (Npn2) and PDZ scaffold protein SAP102. NrCAM-induced receptor clustering stimulated the Rap-GAP activity of PlexinA3 (PlexA3) within the holoreceptor complex, which in turn, inhibited Rap1-GTPase and inactivated adhesive beta1 integrins, essential for Sema3F-induced spine pruning. These results define a developmental function for NrCAM in Sema3F receptor signaling that limits dendritic spine density on cortical pyramidal neurons during adolescence. PMID- 29415227 TI - Successful use of secukinumab in a 4-year-old patient with deficiency of interleukin-36 antagonist. PMID- 29415228 TI - Plasma Tryptophan-Kynurenine Metabolites Are Altered in Human Immunodeficiency Virus Infection and Associated With Progression of Carotid Artery Atherosclerosis. AB - Background: It is unknown whether disrupted tryptophan catabolism is associated with cardiovascular disease (CVD) in human immunodeficiency virus (HIV)-infected individuals. Methods: Plasma tryptophan and kynurenic acid were measured in 737 women and men (520 HIV+, 217 HIV-) from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. Repeated B-mode carotid artery ultrasound imaging was obtained from 2004 through 2013. We examined associations of baseline tryptophan, kynurenic acid, and kynurenic acid-to-tryptophan (KYNA/TRP) ratio, with risk of carotid plaque. Results: After a 7-year follow-up, 112 participants developed carotid plaque. Compared to those without HIV infection, HIV-infected participants had lower tryptophan (P < .001), higher KYNA/TRP (P = .01), and similar kynurenic acid levels (P = .51). Tryptophan, kynurenic acid, and KYNA/TRP were correlated with T-cell activation (CD38+HLA-DR+) and immune activation markers (serum sCD14, galectin-3) but had few correlations with interleukin-6, C reactive protein, or CVD risk factors (blood pressure, lipids). Adjusted for demographic and behavioral factors, each standard deviation (SD) increment in tryptophan was associated with a 29% (95% confidence interval [CI], 17%-38%) decreased risk of carotid plaque (P < .001), while each SD increment in kynurenic acid (P = .02) and KYNA/TRP (P < .001) was associated with a 34% (6%-69%) and a 47% (26%-73%) increased risk of carotid plaque, respectively. After further adjustment for CVD risk factors and immune activation markers, these associations were attenuated but remained significant. Conclusions: Plasma tryptophan kynurenine metabolites are altered in HIV infection and associated with progression of carotid artery atherosclerosis. PMID- 29415229 TI - Military Personnel Who Seek Health and Mental Health Services Outside the Military. AB - Background: Although research conducted within the military has assessed the health and mental health problems of military personnel, little information exists about personnel who seek care outside the military. The purpose of this study is to clarify the personal characteristics, mental health diagnoses, and experiences of active duty U.S. military personnel who sought civilian sector services due to unmet needs for care. Materials and Methods: This prospective, multi-method study included 233 clients, based in the United States, Afghanistan, South Korea, and Germany, who obtained care between 2013 and 2016 from a nationwide network of volunteer civilian practitioners. A hotline organized by faith-based and peace organizations received calls from clients and referred them to the network when the clients described unmet needs for physical or mental health services. Intake and follow-up interviews at 2 wk and 2 mo after intake captured demographic characteristics, mental health diagnoses, and reasons for seeking civilian rather than military care. Non-parametric bootstrap regression analyses identified predictors of psychiatric disorders, suicidality, and absence without leave (AWOL). Qualitative analyses of clients' narratives clarified their experiences and reasons for seeking care. The research protocol has been reviewed and approved annually by the Institutional Review Board at the University of New Mexico. Results: Depression (72%), post-traumatic stress disorder (62%), alcohol use disorder (27%), and panic disorder (25%) were the most common diagnoses. Forty-eight percent of clients reported suicidal ideation. Twenty percent were absence without leave. Combat trauma predicted post-traumatic stress disorder (odds ratio [OR] = 8.84, 95% confidence interval [CI] 1.66, 47.12, p = 0.01) and absence without leave (OR = x3.85, 95% CI 1.14, 12.94, p = 0.03). Non-combat trauma predicted panic disorder (OR = 3.64, 95% CI 1.29, 10.23, p = 0.01). Geographical region was associated with generalized anxiety disorder (OR 0.70, 95% CI 0.49, 0.99, p = 0.05). Significant predictors were not found for major depression, alcohol use disorder, or suicidal ideation. Clients' narrative themes included fear of reprisal for seeking services, mistrust of command, insufficient and unresponsive services, cost as a barrier to care, deception in recruitment, voluntary enlistment remorse, guilt about actual or potential killing of combatants or non-combatant civilians, preexisting mental health disorders, family and household challenges that contributed to distress, and military sexual trauma. Conclusions: Our work clarified substantial unmet needs for services among active duty military personnel, the limitations of programs based in the military sector, and the potential value of civilian sector services that are not linked to military goals. We and our institutional review board opted against using a control group that would create ethical problems stemming from the denial of needed services. For future research, an evaluative strategy that can assess the impact of civilian services and that reconciles ethical concerns with study design remains a challenge. Due to inherent contradictions in the roles of military professionals, especially the double agency that makes professionals responsible to both clients and the military command, the policy alternative of providing services for military personnel in the civilian sector warrants serious consideration, as do preventive strategies such as non-military alternatives to conflict resolution. PMID- 29415230 TI - Factors influencing early referral, early diagnosis and management in patients with diffuse cutaneous systemic sclerosis. AB - Objective: To gain insight into clinical practice regarding referral, early diagnosis and other aspects of the management of patients with dcSSc in Europe and the USA. Methods: Semi-structured interviews were conducted with 84 rheumatologists (or internal medicine physicians) and 40 dermatologists in different countries (the UK, France, Germany, Italy, Spain and the USA). Physicians were asked to identify key steps in the patient pathway relating to patient presentation, diagnosis and referral, in addition to other treatment and follow-up processes. Results: The interviewed physicians reported that late presentation with dcSSc was common, with some patients presenting to primary care physicians after symptoms had persisted for up to 1 year. Awareness of dcSSc is reported to vary widely among primary care physicians. Final diagnosis, generally following guideline-based recommendations, was by rheumatologists in most cases (or internal medicine physicians in France) and they remained responsible for global patient management, with lesser involvement in diagnosis and management by dermatologists. Specialist centres were not well defined and did not exist in all countries. Conclusion: Patients and primary healthcare providers can be unaware of the symptoms of dcSSc, therefore presentation and referral to specialist care are often late. Thus, improved awareness among patients and primary care physicians is necessary to facilitate earlier referral and diagnosis. Once referred, more consistent use of the modified Rodnan skin score at diagnosis and follow-up may help to monitor disease progression. Furthermore, establishing specialist centres may help to promote such changes and improve patient care. PMID- 29415232 TI - Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: a population-based cohort study. AB - Background: The early life microbiome contributes to immune development. Antibiotics during pregnancy alter the microbiome and may influence disease risks in the offspring. We investigated the relationship between maternal antibiotic exposure before and during pregnancy, and risk of childhood hospitalization with infection. Methods: We used population-based Danish national databases for pregnancies between 1995 and 2009. Infants were followed from birth until their first infection-related hospitalization, death, 14th birthday, emigration or end 2009. Exposure was maternal antibiotics prescribed before and during pregnancy. Outcome was infection-related hospitalization. Results: 141 359 (18%) mothers had at least one antibiotic prescription during pregnancy, 230 886 (29.4% of those with complete data) in the 18 months before pregnancy. Of 776 657 live-born singletons, 443 546 infection-related hospitalizations occurred in 222 524 (28.6%) children. Pregnancy antibiotic exposure was associated with increased risk of childhood infection-related hospitalization [hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.17-1.19]. In mothers prescribed antibiotics only during pregnancy whose child did not receive pre-hospitalization antibiotics, this association was present only in those born vaginally. Higher risks of infection-related hospitalization occurred when pregnancy antibiotic prescriptions were closer to birth and in mothers receiving more pregnancy antibiotics. Children born to mothers exposed to antibiotics before (but not during) pregnancy also had increased risk of infection-related hospitalization (HR 1.10, 95% CI 1.07-1.12). Conclusions: Antibiotic exposure before or during pregnancy was associated with increased risk of childhood hospitalized infections. Alteration of the maternally derived microbiome and shared heritable and environmental determinants are possible contributory mechanisms. PMID- 29415231 TI - Detection of Alzheimer Disease (AD)-Specific Tau Pathology in AD and NonAD Tauopathies by Immunohistochemistry With Novel Conformation-Selective Tau Antibodies. AB - Aggregation of tau into fibrillar structures within the CNS is a pathological hallmark of a clinically heterogeneous set of neurodegenerative diseases termed tauopathies. Unique misfolded conformations of tau, referred to as strains, are hypothesized to underlie the distinct neuroanatomical and cellular distribution of pathological tau aggregates. Here, we report the identification of novel tau monoclonal antibodies (mAbs) that selectively bind to an Alzheimer disease (AD) specific conformation of pathological tau. Immunohistochemical analysis of tissue from various AD and nonAD tauopathies demonstrate selective binding of mAbs GT-7 and GT-38 to AD tau pathologies and absence of immunoreactivity for tau aggregates that are diagnostic of corticobasal degenerations (CBD), progressive supranuclear palsy (PSP), and Pick's disease (PiD). In cases with co-occurring AD tauopathy, GT-7 and GT-38 distinguish comorbid AD tau from pathological tau in frontotemporal lobar degeneration characterized by tau inclusions (FTLD-Tau), as confirmed by the presence of both 3 versus 4 microtubule-binding repeat isoforms (3R and 4R tau isoforms, respectively), in AD neurofibrillary tangles but not in the tau aggregates of CBD, PSP, or PiD. These findings support the concept of an AD-specific tau strain. The mAbs described here enable the selective detection of AD tau pathology in nonAD tauopathies. PMID- 29415233 TI - Osteitis fibrosa cystica. PMID- 29415234 TI - Masks, Gowns, and Caps for Interventional Spine Pain Procedures. PMID- 29415235 TI - Hypoxia in grape berries: the role of seed respiration and lenticels on the berry pedicel and the possible link to cell death. AB - Mesocarp cell death (CD) during ripening is common in berries of seeded Vitis vinifera L. wine cultivars. We examined if hypoxia within berries is linked to CD. The internal oxygen concentration ([O2]) across the mesocarp was measured in berries from Chardonnay and Shiraz, both seeded, and Ruby Seedless, using an oxygen micro-sensor. Steep [O2] gradients were observed across the skin and [O2] decreased toward the middle of the mesocarp. As ripening progressed, the minimum [O2] approached zero in the seeded cultivars and correlated to the profile of CD across the mesocarp. Seed respiration declined during ripening, from a large proportion of total berry respiration early to negligible at later stages. [O2] increased towards the central axis corresponding to the presence of air spaces visualized using X-ray micro-computed tomography (CT). These air spaces connect to the pedicel where lenticels are located that are critical for berry O2 uptake as a function of temperature, and when blocked caused hypoxia in Chardonnay berries, ethanol accumulation, and CD. The implications of hypoxia in grape berries are discussed in terms of its role in CD, ripening, and berry water relations. PMID- 29415236 TI - Allocation of development assistance for health: is the predominance of national income justified? AB - Gross national income (GNI) per capita is widely regarded as a key determinant of health outcomes. Major donors heavily rely on GNI per capita to allocate development assistance for health (DAH). This article questions this paradigm by analysing the determinants of health outcomes using cross-sectional data from 99 countries in 2012. We use disability-adjusted life years (Group I) per capita as our main indicator for health outcomes. We consider four primary variables: GNI per capita, institutional capacity, individual poverty and the epidemiological surroundings. Our empirical strategy has two innovations. First, we construct a health poverty line of 10.89 international-$ per day, which measures the minimum level of income an individual needs to have access to basic healthcare. Second, we take the contagious nature of communicable diseases into account, by estimating the extent to which the population health in neighbouring countries (the epidemiological surroundings) affects health outcomes. We apply a spatial two-stage least-squares model to mitigate the risks of reverse causality. Our model captures 92% of the variation in health outcomes. We emphasize four findings. First, GNI per capita is not a significant predictor of health outcomes once other factors are controlled for. Second, the poverty gap below the 10.89 health poverty line is a good measure of universal access to healthcare, as it explains 19% of deviation in health outcomes. Third, the epidemiological surroundings in which countries are embedded capture as much as 47% of deviation in health outcomes. Finally, institutional capacity explains 10% of deviation in health outcomes. Our empirical findings suggest that allocation frameworks for DAH should not only take into account national income, which remains an important indicator of countries' financial capacity, but also individual poverty, governance and epidemiological surroundings to increase impact on health outcomes. PMID- 29415237 TI - Allocating external financing for health: a discrete choice experiment of stakeholder preferences. AB - Most donors of external financing for health use allocation policies to determine which countries are eligible to receive financial support and how much support each should receive. Currently, most of these policies place a great deal of weight on income per capita as a determinant of aid allocation but there is increasing interest in putting more weight on other country characteristics in the design of such policies. It is unclear, however, how much weight should be placed on other country characteristics. Using an online discrete choice experiment designed to elicit preferences over country characteristics to guide decisions about the allocation of external financing for health, we find that stakeholders assign a great deal of importance to health inequalities and the burden of disease but put very little weight on income per capita. We also find considerable variation in preferences across stakeholders, with people from low- and middle-income countries putting more weight on the burden of disease and people from high-income countries putting more weight on health inequalities. These findings suggest that stakeholders put more weight on burden of disease and health inequalities than on income per capita in evaluating which countries should received external financing for health and that that people living in aid recipient may have different preferences than people living in donor countries. Donors may wish to take these differences in preferences in mind if they are reconsidering their aid allocation policies. PMID- 29415238 TI - New approaches to ranking countries for the allocation of development assistance for health: choices, indicators and implications. AB - The distributions of income and health within and across countries are changing. This challenges the way donors allocate development assistance for health (DAH) and particularly the role of gross national income per capita (GNIpc) in classifying countries to determine whether countries are eligible to receive assistance and how much they receive. Informed by a literature review and stakeholder consultations and interviews, we developed a stepwise approach to the design and assessment of country classification frameworks for the allocation of DAH, with emphasis on critical value choices. We devised 25 frameworks, all which combined GNIpc and at least one other indicator into an index. Indicators were selected and assessed based on relevance, salience, validity, consistency, and availability and timeliness, where relevance concerned the extent to which the indicator represented country's health needs, domestic capacity, the expected impact of DAH, or equity. We assessed how the use of the different frameworks changed the rankings of low- and middle-income countries relative to a country's ranking based on GNIpc alone. We found that stakeholders generally considered needs to be the most important concern to be captured by classification frameworks, followed by inequality, expected impact and domestic capacity. We further found that integrating a health-needs indicator with GNIpc makes a significant difference for many countries and country categories-and especially middle-income countries with high burden of unmet health needs-while the choice of specific indicator makes less difference. This together with assessments of relevance, salience, validity, consistency, and availability and timeliness suggest that donors have reasons to include a health-needs indicator in the initial classification of countries. It specifically suggests that life expectancy and disability-adjusted life year rate are indicators worth considering. Indicators related to other concerns may be mainly relevant at different stages of the decision-making process, require better data, or both. PMID- 29415239 TI - Resource allocation processes at multilateral organizations working in global health. AB - International institutions provide well over US$10 billion in development assistance for health (DAH) annually and between 1990 and 2014, DAH disbursements totaled $458 billion but how do they decide who gets what, and for what purpose? In this article, we explore how allocation decisions were made by the nine convening agencies of the Equitable Access Initiative. We provide clear, plain language descriptions of the complete process from resource mobilization to allocation for the nine multilateral agencies with prominent agendas in global health. Then, through a comparative analysis we illuminate the choices and strategies employed in the nine international institutions. We find that resource allocation in all reviewed institutions follow a similar pattern, which we categorized in a framework of five steps: strategy definition, resource mobilization, eligibility of countries, support type and funds allocation. All the reviewed institutions generate resource allocation decisions through well structured and fairly complex processes. Variations in those processes seem to reflect differences in institutional principles and goals. However, these processes have serious shortcomings. Technical problems include inadequate flexibility to account for or meet country needs. Although aid effectiveness and value for money are commonly referenced, we find that neither performance nor impact is a major criterion for allocating resources. We found very little formal consideration of the incentives generated by allocation choices. Political issues include non-transparent influence on allocation processes by donors and bureaucrats, and the common practice of earmarking funds to bypass the normal allocation process entirely. Ethical deficiencies include low accountability and transparency at international institutions, and limited participation by affected citizens or their representatives. We find that recipient countries have low influence on allocation processes themselves, although within these processes they have some influence in relatively narrow areas. PMID- 29415240 TI - The financing gaps framework: using need, potential spending and expected spending to allocate development assistance for health. AB - As growth in development assistance for health levels off, development assistance partners must make allocation decisions within tighter budget constraints. Furthermore, with the advent of comprehensive and comparable burden of disease and health financing estimates, empirical evidence can increasingly be used to direct funding to those most in need. In our 'financing gaps framework', we propose a new approach for harnessing information to make decisions about health aid. The framework was designed to be forward-looking, goal-oriented, versatile and customizable to a range of organizational contexts and health aims. Our framework brings together expected health spending, potential health spending and spending need, to orient financing decisions around international health targets. As an example of how the framework could be applied, we develop a case study, focused on global goals for child health. The case study harnesses data from the Global Burden of Disease 2013 Study, Financing Global Health 2015, the WHO Global Health Observatory and National Health Accounts. Funding flows are tied to progress toward the Sustainable Development Goal's target for reductions in under five mortality. The flexibility and comprehensiveness of our framework makes it adaptable for use by a diverse set of governments, donors, policymakers and other stakeholders. The framework can be adapted to short- or long-run time frames, cross-country or subnational scales, and to a number of specific health focus areas. Depending on donor preferences, the framework can be deployed to incentivize local investments in health, ensuring the long-term sustainability of health systems in low- and middle-income countries, while also furnishing international support for progress toward global health goals. PMID- 29415241 TI - Global health aid allocation in the 21st century. PMID- 29415242 TI - A Single-Blind Study Evaluating the Efficacy of Gold Nanoparticle Photothermal Assisted Liposuction in an Ex Vivo Human Tissue Model. AB - Background: Liposuction is one of the most performed cosmetic surgery procedures. In a previously reported study, gold-nanoparticle (GNP) laser-assisted liposuction (NanoLipo) was shown to improve procedure parameters and outcomes in a porcine model. Objectives: An ex vivo human liposuction model was developed to assess the ease, efficacy, and outcomes of NanoLipo, and to further explore its mechanism of action in facilitating liposuction. Methods: NanoLipo was compared to a control without GNPs in sets of fresh, nonperfused, anatomically symmetric, matched tissue specimens from 12 patients. A subset of three experiments was performed under single-blinded conditions. Intraoperative assessments included lipoaspirate volume, percentage of free oil, ease of removal, and temperature rise. Specimens were palpated, visualized for evenness, and graded with and without skin. Postoperative assessment included viability staining of the lipoaspirate and remaining tissues. Microcomputed tomography was used to assess the distribution of infused GNPs within the tissues. Results: NanoLipo consistently removed more adipose tissue with more liberated triglycerides compared to control. NanoLipo specimens were smoother, thinner, and had fewer and smaller irregularities. Infused solutions preferentially distributed between fibrous membranes and fat pearls. After NanoLipo, selective structural-tissue disruptions, indicated by loss of metabolic activity, were observed. Thus, NanoLipo likely creates a bimodal mechanism of action whereby fat lobules are dislodged from surrounding fibro-connective tissue, while lipolysis is simultaneously induced. Conclusions: NanoLipo showed many advantages compared to control under blinded and nonblinded conditions. This technology may be promising in facilitating fat removal. Level of Evidence 5: PMID- 29415243 TI - AN ONLINE, RADIATION HARD PROTON ENERGY-RESOLVING SCINTILLATOR STACK FOR LASER DRIVEN PROTON BUNCHES. AB - We report on a scintillator-based online detection system for the spectral characterization of polychromatic proton bunches. Using up to nine stacked layers of radiation hard polysiloxane scintillators, coupled to and readout edge-on by a large area pixelated CMOS detector, impinging polychromatic proton bunches were characterized. The energy spectra were reconstructed using calibration data and simulated using Monte-Carlo simulations. Despite the scintillator stack showed some problems like thickness inhomogeneities and unequal layer coupling, the prototype allows to obtain a first estimate of the energy spectrum of proton beams. PMID- 29415244 TI - The more we are in control, the merrier? Partner Perceived Control and Negative Affect in the Daily Lives of Older Couples. AB - Objectives: It is well established that daily perceived control is closely associated with lower negative affect among older adults. However, it is an open question whether control perceptions of one's partner are also uniquely associated with one's own negative affect. Method: To examine such associations in dyads of older long-term partners, we make use of data obtained six times a day over seven consecutive days as participants went about their everyday lives (N = 87 couples; mean age = 75 years; mean relationship length = 46 years). Our multilevel actor-partner models for dyadic data analyses covary for relevant individual and couple differences in socio-demographic characteristics, self reported physical health, and cognitive functioning. Results: Corroborating and extending earlier reports, results reveal that higher momentary perceived control was associated with lower negative affect. Most importantly, we found that higher momentary perceived control of the partner is additionally and uniquely associated with lower negative affect of the actor. Discussion: We discuss possible mechanisms and underlying pathways of how perceived control may help both partners down-regulate their negative emotions in daily life. We close by considering conceptual and practical implications. PMID- 29415245 TI - A Breathprint for Malaria: New Opportunities for Noninterventional Diagnostics and Mosquito Traps? PMID- 29415246 TI - Cutaneous Leishmaniasis in the Metropolitan City of Multan, Pakistan, a Neglected Tropical Disease. AB - Cutaneous leishmaniasis is a vector-borne infection caused by flagellated parasitic protozoans in the genus Leishmania. Promastigotes are the infective stage, which are transmitted by the bite of female sand flies of the genera Phlebotomus or Lutzomyia. Three clinical forms of Leishmania infection are recognized in humans, and they are caused by different Leishmania species. They are cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (ML), and visceral leishmaniasis (VL). Up to 2 million cases of leishmaniasis are reported annually worldwide. In Pakistan, CL is widely distributed in endemic areas. In the current study, a survey was conducted to investigate the occurrence of CL in an endemic area of the metropolitan city of Multan, Pakistan. The material for diagnosis of CL was obtained from 461 patients from 239 clinical laboratories and health care centers in Multan. Of these patients, 42.9% (198 of 461) having positive findings of amastigotes in Giemsa stained tissue impression smears. The distribution of CL skin lesions was highly variable. Most patients (76.2%) had a single lesion. Most CL lesions were found on a single hand (23.7%). The prevalence of two CL lesions per patient was 21.7%, while three or more positive CL lesions were observed in 2.0% of patients. The 198 CL-positive patients ranged in age 10-40 yr old, 101 were males, and 97 were females. Logistic regression analysis of leishmaniasis versus age and gender showed that both the age and gender had a significant (P < 0.05) effect on the occurrence of infection. Outbreaks of CL were reported in 14 of the 68 Union Councils of Multan. PMID- 29415247 TI - Polycomb Protein Eed is Required for Neurogenesis and Cortical Injury Activation in the Subventricular Zone. AB - The postnatal subventricular zone (SVZ) harbors neural stem cells (NSCs) that exhibit robust neurogenesis. However, the epigenetic mechanisms that maintain NSCs and regulate neurogenesis remain unclear. We report that label-retaining SVZ NSCs express Eed, the core component of Polycomb repressive complex 2. In vivo and in vitro conditional knockout and knockdown show Eed is necessary for maintaining NSC proliferation, neurogenesis and neurosphere formation. We discovered that Eed functions to maintain p21 protein levels in NSCs by repressing Gata6 transcription. Both Gata6 overexpression and p21 knockdown reduced neurogenesis, while Gata6 knockdown or p21 overexpression partially rescued neurogenesis after Eed loss. Furthermore, genetic deletion of Eed impaired injury induced SVZ proliferation and emigration. These data reveal a novel epigenetic regulated pathway and suggest an essential role for Eed in SVZ homeostasis and injury. PMID- 29415248 TI - Alcohol use among Norwegian workers: associations with health and well-being. AB - Background: There is a lack of published data on the association between alcohol consumption and health and well-being in working populations. Aims: To determine how levels of alcohol consumption are associated with psychological distress, somatic complaints, sleep and job satisfaction in the Norwegian workforce. Methods: Survey questionnaire data from a probability sample comprising Norwegian employees. The association between alcohol consumption and health and well-being was assessed using analysis of covariance. Results: There were 1608 respondents (response rate 32%); 20% of the sample were abstainers, 72% were low- to moderate alcohol users, 6% were moderate to high users and 2% were risky users. Adjusting for age, gender and tobacco use, employees with risky alcohol use reported significantly higher levels of psychological distress and lower job satisfaction when compared to employees who drank less. There were no differences between risky users and other employees with regard to sleep problems and somatic complaints, nor were there any gender differences. Conclusions: Our findings indicate that risky alcohol use in the Norwegian workforce is associated with impaired health and well-being, with no evidence of a gender differential. The findings support the thresholds for risky alcohol use as proposed by internationally recognized guidelines for alcohol consumption. PMID- 29415249 TI - On the Difficulties of Studying Pain Management in Individuals with Developmental Delay. PMID- 29415250 TI - Intra- and interspecific trait variations reveal functional relationships between specific leaf area and soil niche within a subtropical forest. AB - Background and Aims: How functional traits vary with environmental conditions is of fundamental importance in trait-based community ecology. However, how intraspecific variability in functional traits is connected to species distribution is not well understood. This study investigated inter- and intraspecific variation of a key functional trait, i.e. specific leaf area (leaf area per unit dry mass; SLA), in relation to soil factors and tested if trait variation is more closely associated with specific environmental regimes for low variability species than for high-variability species. Methods: In a subtropical evergreen forest plot (50 ha, southern China), 106 700 leaves from 5335 individuals of 207 woody species were intensively collected, with 30 individuals sampled for most species to ensure a sufficient sample size representative of intraspecific variability. Soil conditions for each plant were estimated by kriging from more than 1700 observational soil locations across the plot. Intra- and interspecific variation in SLA were separately related to environmental factors. Based on the species-specific variation of SLA, species were categorized into three groups: low-, intermediate- and high-intraspecific variability. Intraspecific habitat ranges and the strength of SLA-habitat relationships were compared among these three groups. Key Results: Interspecific variation in SLA overrides the intraspecific variation (77 % vs. 8 %). Total soil nitrogen (TN, positively) and total organic carbon (TOC, negatively) are the most important explanatory factors for SLA variation at both intra- and interspecific levels. SLA, both within and between species, decreases with decreasing soil nitrogen availability. As predicted, species with low intraspecific variability in SLA have narrower habitat ranges with respect to soil TOC and TN and show a stronger SLA-habitat association than high-variability species. Conclusions: For woody plants low SLA is a phenotypic and probably adaptive response to nitrogen stress, which drives the predominance of species with ever-decreasing SLA towards less fertile habitats. Intraspecific variability in SLA is positively connected to species' niche breadth, suggesting that low-variability species may play a more deterministic role in structuring plant assemblages than high-variability species. This study highlights the importance of quantifying intraspecific trait variation to improve our understanding of species distributions across a vegetated landscape. PMID- 29415251 TI - Supercharged free omental flap plombage for empyema in a patient with an artificial pericardium. AB - Cavernostomy and fenestration were performed in a patient who developed a lung abscess and empyema in the left lung, which was damaged after multimodality therapy for advanced thymoma. The hospitalized patient suddenly experienced cardiopulmonary arrest due to major bleeding from the left main pulmonary artery. We immediately performed the main pulmonary arterial embolization, and the patient was resuscitated. Subsequently, the patient underwent supercharged free omental flap plombage performed in the following manner: first, laparoscopic harvesting of the omentum was performed in the supine position. Then, the right gastroepiploic artery and vein were anastomosed with the left axillary artery and vein, respectively. The lung cavity, bleeding point of the pulmonary artery and the surface of the artificial pericardium were filled and covered by the supercharged omentum, and the skin was closed. The postoperative course was uneventful. The patient has had no bleeding, recurrence of empyema and thymoma or skin abnormalities at 36 months postoperatively. Supercharged free omental flap plombage was a useful option for treatment of an intractable chest infection involving an artificial pericardium. PMID- 29415252 TI - Effects of Different Dietary Protocols on General Activity and Frailty of Male Wistar Rats During Aging. AB - Dietary restriction (DR) is an important experimental paradigm for lifespan and healthspan extension, but its specific contribution regarding the type, onset, and duration are still debatable. This study was designed to examine the impact of different dietary protocols by assessing the behavioral changes during aging. We exposed male Wistar rats of various age to ad libitum (AL) or DR (60 per cent of AL daily intake) feeding regimens with different onsets. The impact of DR on locomotor activity, memory, and learning was examined in 12-, 18-, and 24-month old treated animals and controls using open field and Y-maze tests. We have also evaluated the effects of different DR's through the quantification of animal frailty, using behavioral data to create the frailty score. Our results indicated that DR improves general animal activity and spatial memory and decreases frailty with the effect being highly dependent on DR duration and onset. Notably, life long restriction started at young age had the most profound effect. In contrast, shorter duration and later onset of restricted diet had significantly lower or no impact on animal's behavior and frailty. This study signifies the importance of DR starting point and duration as critical determinants of DR effects on healthspan. PMID- 29415253 TI - Verbal Creativity Correlates with the Temporal Variability of Brain Networks During the Resting State. AB - Creativity is the ability to see the world in new ways. Creative individuals exhibit the ability to switch between different modes of thinking and shift their mental focus. This suggests a connection between creativity and dynamic interactions of brain networks. We report here the first investigation into the relationship between the reconfiguration of dynamic brain networks during the resting state and verbal creativity using two fMRI datasets involving 574 subjects. We find that verbal creativity correlates with temporal variability of the functional-connectivity (FC) patterns of the lateral prefrontal cortex, the precuneus, and the parahippocampal gyrus. High variability of these regions indicates flexible connectivity patterns which may facilitate executive functions. Furthermore, verbal creativity correlates with the temporal variability of FC patterns within the default mode network (DMN), between the DMN and attention/sensorimotor network, and between control and sensory networks. High variability of FCs between the DMN and attention networks characterizes frequent adjustments of attention. Finally, dynamic interaction between the cerebellum and task control network also contributes to verbal creativity, suggesting a relationship between the cerebellum and creativity. This study reveals a close relationship between verbal creativity and high variability of cortical networks involved in spontaneous thought, attention and cognitive control. PMID- 29415254 TI - Potential relationship between the biological effects of low-dose irradiation and mitochondrial ROS production. AB - Exposure to ionizing radiation (IR) induces various types of DNA damage, of which DNA double-strand breaks are the most severe, leading to genomic instability, tumorigenesis, and cell death. Hence, cells have developed DNA damage responses and repair mechanisms. IR also causes the accumulation of endogenous reactive oxidative species (ROS) in the irradiated cells. Upon exposure to low-dose irradiation, the IR-induced biological effects mediated by ROS were relatively more significant than those mediated by DNA damage. Accumulating evidence suggests that such increase in endogenous ROS is related with mitochondria change in irradiated cells. Thus, in this review we focused on the mechanism of mitochondrial ROS production and its relationship to the biological effects of IR. Exposure of mammalian cells to IR stimulates an increase in the production of endogenous ROS by mitochondria, which potentially leads to mitochondrial dysfunction. Since the remains of damaged mitochondria could generate or leak more ROS inside the cell, the damaged mitochondria are removed by mitophagy. The disruption of this pathway, involved in maintaining mitochondrial integrity, could lead to several disorders (such as neurodegeneration) and aging. Thus, further investigation needs to be performed in order to understand the relationship between the biological effects of low-dose IR and mitochondrial integrity. PMID- 29415255 TI - Validation of the 'United Registries for Clinical Assessment and Research' [UR CARE], a European Online Registry for Clinical Care and Research in Inflammatory Bowel Disease. AB - Background: The 'United Registries for Clinical Assessment and Research' [UR CARE] database is an initiative of the European Crohn's and Colitis Organisation [ECCO] to facilitate daily patient care and research studies in inflammatory bowel disease [IBD]. Herein, we sought to validate the database by using fictional case histories of patients with IBD that were to be entered by observers of varying experience in IBD. Methods: Nineteen observers entered five patient case histories into the database. After 6 weeks, all observers entered the same case histories again. For each case history, 20 key variables were selected to calculate the accuracy for each observer. We assumed that the database was such that >= 90% of the entered data would be correct. The overall proportion of correctly entered data was calculated using a beta-binomial regression model to account for inter-observer variation and compared to the expected level of validity. Re-test reliability was assessed using McNemar's test. Results: For all case histories, the overall proportion of correctly entered items and their confidence intervals included the target of 90% (Case 1: 92% [88-94%]; Case 2: 87% [83-91%]; Case 3: 93% [90-95%]; Case 4: 97% [94-99%]; Case 5: 91% [87-93%]). These numbers did not differ significantly from those found 6 weeks later [NcNemar's test p > 0.05]. Conclusion: The UR-CARE database appears to be feasible, valid and reliable as a tool and easy to use regardless of prior user experience and level of clinical IBD experience. UR-CARE has the potential to enhance future European collaborations regarding clinical research in IBD. PMID- 29415256 TI - An Unbiased Genome-Wide View of the Mutation Rate and Spectrum of the Endosymbiotic Bacterium Teredinibacter turnerae. AB - Mutations contribute to genetic variation in all living systems. Thus, precise estimates of mutation rates and spectra across a diversity of organisms are required for a full comprehension of evolution. Here, a mutation-accumulation (MA) assay was carried out on the endosymbiotic bacterium Teredinibacter turnerae. After ~3,025 generations, base-pair substitutions (BPSs) and insertion deletion (indel) events were characterized by whole-genome sequencing analysis of 47 independent MA lines, yielding a BPS rate of 1.14 * 10-9 per site per generation and indel rate of 1.55 * 10-10 events per site per generation, which are among the highest within free-living and facultative intracellular bacteria. As in other endosymbionts, a significant bias of BPSs toward A/T and an excess of deletion mutations over insertion mutations are observed for these MA lines. However, even with a deletion bias, the genome remains relatively large (~5.2 Mb) for an endosymbiotic bacterium. The estimate of the effective population size (Ne) in T. turnerae is quite high and comparable to free-living bacteria (~4.5 * 107), suggesting that the heavy bottlenecking associated with many endosymbiotic relationships is not prevalent during the life of this endosymbiont. The efficiency of selection scales with increasing Ne and such strong selection may have been operating against the deletion bias, preventing genome erosion. The observed mutation rate in this endosymbiont is of the same order of magnitude of those with similar Ne, consistent with the idea that population size is a primary determinant of mutation-rate evolution within endosymbionts, and that not all endosymbionts have low Ne. PMID- 29415257 TI - Boron Toxicity Reduces Water Transport from Root to Shoot in Arabidopsis Plants. Evidence for a Reduced Transpiration Rate and Expression of Major PIP Aquaporin Genes. AB - Toxic boron (B) concentrations cause impairments in several plant metabolic and physiological processes. Recently we reported that B toxicity led to a decrease in the transpiration rate of Arabidopsis plants in an ABA-dependent process within 24 h, which could indicate the occurrence of an adjustment of whole-plant water relations in response to this stress. Since plasma membrane intrinsic protein (PIP) aquaporins are key components influencing the water balance of plants because of their involvement in root water uptake and tissue hydraulic conductance, the aim of the present work was to study the effects of B toxicity on these important parameters affecting plant water status over a longer period of time. For this purpose, transpiration rate, water transport to the shoot and transcript levels of genes encoding four major PIP aquaporins were measured in Arabidopsis plants treated or not with a toxic B concentration. Our results indicate that, during the first 24 h of B toxicity, increased shoot ABA content would play a key role in reducing stomatal conductance, transpiration rate and, consequently, the water transport to the shoot. These physiological responses to B toxicity were maintained for up to 48 h of B toxicity despite shoot ABA content returning to control levels. In addition, B toxicity also caused the down regulation of several genes encoding root and shoot aquaporins, which could reduce the cell to cell movement of water in plant tissues and, consequently, the water flux to shoot. All these changes in the water balance of plants under B toxicity could be a mechanism to prevent excess B accumulation in plant tissues. PMID- 29415258 TI - A Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Maintenance Treatment in Adults with Schizophrenia. AB - Background: Brexpiprazole is a serotonin-dopamine activity modulator with efficacy in acute schizophrenia and relapse prevention. The aim of this Phase 3, multicenter study was to assess the long-term safety, tolerability, and efficacy of treatment with brexpiprazole flexible-dose 1-4 mg/d. Methods: Patients rolled over into this 52-week open-label study (amended to 26 weeks towards the end) from 3 randomized, double-blind, placebo-controlled Phase 3 studies. De novo patients, not part of the previous studies, were also enrolled. The primary outcome variable was the frequency and severity of treatment-emergent adverse events. Efficacy was assessed as a secondary objective using the Positive and Negative Syndrome Scale and the Personal and Social Performance scale. Results: A total of 1072 patients was enrolled (952 for 52 weeks and 120 for 26 weeks), 47.4% of whom completed the study. Among patients who took at least one dose of brexpiprazole, 14.6% discontinued due to treatment-emergent adverse events, most commonly schizophrenia (8.8%) and psychotic disorder (1.5%). Treatment-emergent adverse events with an incidence of >=5% were schizophrenia (11.6%), insomnia (8.6%), weight increased (7.8%), headache (6.4%), and agitation (5.4%). Most treatment-emergent adverse events were mild or moderate in severity. The mean increase in body weight from baseline to week 26 was 1.3 kg and to week 52 was 2.1 kg. There were no clinically relevant findings related to prolactin, lipids, and glucose, or QT prolongation. On average, patients' symptoms and functioning showed continual improvement. Conclusions: Treatment with brexpiprazole 1-4 mg/d was generally well tolerated for up to 52 weeks in patients with schizophrenia. ClinicalTrials.gov identifier: NCT01397786 (https://clinicaltrials.gov/show/NCT01397786). PMID- 29415259 TI - Analysis of Homologs of Cry-toxin Receptor-Related Proteins in the Midgut of a Non-Bt Target, Nilaparvata lugens (Stal) (Hemiptera: Delphacidae). AB - The brown planthopper (BPH) Nilaparvata lugens is one of the most destructive insect pests in the rice fields of Asia. Like other hemipteran insects, BPH is not susceptible to Cry toxins of Bacillus thuringiensis (Bt) or transgenic rice carrying Bt cry genes. Lack of Cry receptors in the midgut is one of the main reasons that BPH is not susceptible to the Cry toxins. The main Cry-binding proteins (CBPs) of the susceptible insects are cadherin, aminopeptidase N (APN), and alkaline phosphatase (ALP). In this study, we analyzed and validated de novo assembled transcripts from transcriptome sequencing data of BPH to identify and characterize homologs of cadherin, APN, and ALP. We then compared the cadherin-, APN-, and ALP-like proteins of BPH to previously reported CBPs to identify their homologs in BPH. The sequence analysis revealed that at least one cadherin, one APN, and two ALPs of BPH contained homologous functional domains identified from the Cry-binding cadherin, APN, and ALP, respectively. Quantitative real-time polymerase chain reaction used to verify the expression level of each putative Cry receptor homolog in the BPH midgut indicated that the CBPs homologous APN and ALP were expressed at high or medium-high levels while the cadherin was expressed at a low level. These results suggest that homologs of CBPs exist in the midgut of BPH. However, differences in key motifs of CBPs, which are functional in interacting with Cry toxins, may be responsible for insusceptibility of BPH to Cry toxins. PMID- 29415260 TI - Identity Rights and Sensitive Ethical Questions: The European Convention on Human Rights and the Regulation of Surrogacy Arrangements. AB - Attitudes to surrogacy vary widely across Europe, leading to great variation in the domestic legal regimes of the Member States of the Council of Europe. Confronted with such diverse approaches, the European Court of Human Rights (ECtHR) faces a difficult task in seeking to apply Convention rights in the surrogacy context, which it has tackled in the recent cases of Mennesson v France and Paradiso and Campanelli v Italy. The primary purpose of this article is to propose an argument as to what the Convention requires of the Member States in the field of surrogacy. It is argued that while tensions exist between the leading cases, they may be reconciled by appreciating the importance of the right to identity, a facet of the right to respect for private life. Properly understood, the case law imposes obligations on the Member States as regards the legal status of surrogate-born children in both cross-border and domestic surrogacy. The secondary purpose of this article is to argue that, in the surrogacy context, the concept of identity should be given a richer interpretation which encompasses the child's relationship with genetic, gestational, and intended parents, and therefore that a narrow margin of appreciation must apply to all State interventions concerning the legal status of surrogate-born children. PMID- 29415261 TI - Re: Sagy I, Zeldetz V, Halerin D, Abu Tailakh M, Novack V. The effect of Ramadan fast on the incidence of renal colic emergency department visits. PMID- 29415262 TI - Anatomical Comparison of Radiofrequency Ablation Techniques for Sacroiliac Joint Pain. AB - Objective: To compare the percentage of sacral lateral branches (LBs) that would be captured if lesions were created by seven current sacroiliac joint (SIJ) radiofrequency ablation (RFA) techniques: three monopolar and four bipolar. Design: Cadaveric fluoroscopy study. Setting: Anatomy and surgical skills laboratories. Subjects: Forty cadaveric SIJs. Methods: LBs were exposed, radiopaque wires were sutured to LBs, and anterior-posterior fluoroscopic images through the S1 superior endplate were obtained. Lesions that would be created by 17 versions of seven current SIJ RFA techniques were mapped on the fluoroscopic images. These 17 versions were compared: 1) percentage of LBs that would be captured; 2) percentage of SIJ specimens in which 100% of LBs would be captured; and 3) percentage of LBs that would not be captured at each level (S1-S4). Results: Both the mean LB and 100% capture rates were greater for the bipolar techniques (93.4-99.7% and 62.5-97.5%, respectively) than for the monopolar techniques (49.6-99.1% and 2.5-92.5%, respectively) evaluated. For the bipolar techniques, 1.5-29.2% of LBs would not be captured at S1 and 0% at S2-S4 vs 0 29.2% at S1-S4 for the cooled monopolar techniques vs 36.9-100% at S1-S4 for the conventional monopolar technique. Conclusions: The findings suggest that, if lesions were created, the RFA needle placement locations of the bipolar techniques evaluated may be capable of capturing all LBs, but those of the current monopolar techniques evaluated may not. Future in vivo imaging studies are required to compare the lesion morphology generated by different SIJ RFA techniques and correlate the findings with clinical outcomes. PMID- 29415263 TI - scEpath: energy landscape-based inference of transition probabilities and cellular trajectories from single-cell transcriptomic data. AB - Motivation: Single-cell RNA-sequencing (scRNA-seq) offers unprecedented resolution for studying cellular decision-making processes. Robust inference of cell state transition paths and probabilities is an important yet challenging step in the analysis of these data. Results: Here we present scEpath, an algorithm that calculates energy landscapes and probabilistic directed graphs in order to reconstruct developmental trajectories. We quantify the energy landscape using 'single-cell energy' and distance-based measures, and find that the combination of these enables robust inference of the transition probabilities and lineage relationships between cell states. We also identify marker genes and gene expression patterns associated with cell state transitions. Our approach produces pseudotemporal orderings that are-in combination-more robust and accurate than current methods, and offers higher resolution dynamics of the cell state transitions, leading to new insight into key transition events during differentiation and development. Moreover, scEpath is robust to variation in the size of the input gene set, and is broadly unsupervised, requiring few parameters to be set by the user. Applications of scEpath led to the identification of a cell-cell communication network implicated in early human embryo development, and novel transcription factors important for myoblast differentiation. scEpath allows us to identify common and specific temporal dynamics and transcriptional factor programs along branched lineages, as well as the transition probabilities that control cell fates. Availability and implementation: A MATLAB package of scEpath is available at https://github.com/sqjin/scEpath. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29415264 TI - Regional Spread of an Outbreak of Carbapenem-Resistant Enterobacteriaceae Through an Ego Network of Healthcare Facilities. AB - Background: In 2013, New Delhi metallo-beta-lactamase (NDM)-producing Escherichia coli, a type of carbapenem-resistant Enterobacteriaceae uncommon in the United States, was identified in a tertiary care hospital (hospital A) in northeastern Illinois. The outbreak was traced to a contaminated duodenoscope. Patient-sharing patterns can be described through social network analysis and ego networks, which could be used to identify hospitals most likely to accept patients from a hospital with an outbreak. Methods: Using Illinois' hospital discharge data and the Illinois extensively drug-resistant organism (XDRO) registry, we constructed an ego network around hospital A. We identified which facilities NDM outbreak patients subsequently visited and whether the facilities reported NDM cases. Results: Of the 31 outbreak cases entered into the XDRO registry who visited hospital A, 19 (61%) were subsequently admitted to 13 other hospitals during the following 12 months. Of the 13 hospitals, the majority (n = 9; 69%) were in our defined ego network, and 5 of those 9 hospitals consequently reported at least 1 additional NDM case. Ego network facilities were more likely to identify cases compared to a geographically defined group of facilities (9/22 vs 10/66; P = .01); only 1 reported case fell outside of the ego network. Conclusions: The outbreak hospital's ego network accurately predicted which hospitals the outbreak patients would visit. Many of these hospitals reported additional NDM cases. Prior knowledge of this ego network could have efficiently focused public health resources on these high-risk facilities. PMID- 29415265 TI - Oxidation Products of 5-Methylcytosine are Decreased in Senescent Cells and Tissues of Progeroid Mice. AB - 5-Hydroxymethylcytosine and 5-formylcytosine are stable DNA base modifications generated from 5-methylcytosine by the ten-eleven translocation protein family that function as epigenetic markers. 5-Hydroxymethyluracil may also be generated from thymine by ten-eleven translocation enzymes. Here, we asked if these epigenetic changes accumulate in senescent cells, since they are thought to be inversely correlated with proliferation. Testing this in ERCC1-XPF-deficient cells and mice also enabled discovery if these DNA base changes are repaired by nucleotide excision repair. Epigenetic marks were measured in proliferating, quiescent and senescent wild-type (WT) and Ercc1-/- primary mouse embryonic fibroblasts. The pattern of epigenetic marks depended more on the proliferation status of the cells than their DNA repair capacity. The cytosine modifications were all decreased in senescent cells compared to quiescent or proliferating cells, whereas 5-(hydroxymethyl)-2'-deoxyuridine was increased. In vivo, both 5 (hydroxymethyl)-2'-deoxyuridine and 5-(hydroxymethyl)-2'-deoxycytidine were significantly increased in liver tissues of aged WT mice compared to young adult WT mice. Livers of Ercc1-deficient mice with premature senescence and aging had reduced level of 5-(hydroxymethyl)-2'-deoxycytidine and 5-formyl-2'-deoxycytidine compared to aged-matched WT controls. Taken together, we demonstrate for the first time, that 5-(hydroxymethyl)-2'-deoxycytidine is significantly reduced in senescent cells and tissue, potentially yielding a novel marker of senescence. PMID- 29415266 TI - Combined minimally invasive repair of the adult form of the scimitar syndrome and organic mitral regurgitation. AB - Scimitar syndrome is a rare congenital cardiac malformation defined as an anomalous pulmonary venous return from the right lung to the inferior vena cava. In adult patients, the surgical strategy chosen is very important because of concomitant diseases and conditions. Herein, we present a case in which a minimally invasive approach was successful for treating a combination of the adult form of the scimitar syndrome and severe degenerative mitral regurgitation. PMID- 29415268 TI - Comparative analysis of the countermeasures taken to mitigate exposure of the public to radioiodine following the Chernobyl and Fukushima accidents: lessons from both accidents. AB - In the case of a severe radiation accident at a nuclear power station, the most important radiation hazard for the public is internal exposure of the thyroid to radioiodine. The purposes of this paper were (i) to compare countermeasures conducted (following the Chernobyl and Fukushima accidents) aimed at mitigation of exposure to the thyroid for the public, (ii) to present comparative estimates of doses to the thyroid and (iii) to derive lessons from the two accidents. The scale and time of countermeasures applied in the early phase of the accidents (sheltering, evacuation, and intake of stable iodine to block the thyroid) and at a later time (control of 131I concentration in foodstuffs) have been described. After the Chernobyl accident, the estimation of the thyroid doses for the public was mainly based on direct thyroid measurements of ~400 000 residents carried out within the first 2 months. The highest estimates of thyroid doses to children reached 50 Gy. After the Fukushima accident, the estimation of thyroid doses was based on radioecological models due to a lack of direct thyroid measurements (only slightly more than 1000 residents were measured). The highest estimates of thyroid doses to children were a few hundred mGy. Following the Chernobyl accident, ingestion of 131I through cows' milk was the dominant pathway. Following the Fukushima accident, it appears that inhalation of contaminated air was the dominant pathway. Some lessons learned following the Chernobyl and Fukushima accidents have been presented in this paper. PMID- 29415269 TI - Cohort Profile: The Integrated Women's Health Programme (IWHP): a study of key health issues of midlife Singaporean women. PMID- 29415270 TI - Telomere Length and Depression among Ex-Prisoners of War: The Role of Subjective Age. AB - Objectives: Exposure to captivity increases the risk for multiple disturbances that may intensify during old age. In later phases of life, former-prisoners-of war (ex-POWs) may suffer from depression as well as from accelerated aging, manifested in older subjective age and leukocyte telomere shortening. The current study assesses the link between these varied facets of increased vulnerability during old age and explores (a) the associations between subjective age and telomere length; (b) the mediating role of changes in subjective age over time within the associations between depression and telomere length. Methods: Eighty eight ex-POWs were assessed prospectively 30 (T1), 35 (T2) and 45 (T3) years after the 1973 Israeli Yom-Kippur War. Depression was assessed at T1; subjective age was assessed at T2 and T3; and telomere length and control variables were assessed at T3. Results: Older subjective age at T3 was associated with concurrent shorter telomeres, beyond the effect of chronological age. Change in subjective age between T2 and T3 mediated the relations between depression at T1 and shorter telomeres at T3 beyond the effects of control variables. Discussion: Findings suggest that the detrimental ramifications of accelerated subjective age involve premature cellular senesces, and may explain the relation between depression and accelerated aging processes among trauma victims. Hence, clinical interventions may seek to address accelerated subjective age among trauma survivors who suffer from depression. PMID- 29415271 TI - Interplay between the unfolded protein response and reactive oxygen species: a dynamic duo. AB - Secretory proteins undergo modifications such as glycosylation and disulphide bond formation before proper folding, and move to their final destination via the endomembrane system. Accumulation of unfolded proteins in the endoplasmic reticulum (ER) due to suboptimal environmental conditions triggers a response called the unfolded protein response (UPR), which induces a set of genes that elevate protein folding capacity in the ER. This review aims to establish a connection among ER stress, UPR, and reactive oxygen species (ROS), which remains an unexplored topic in plants. For this, we focused on mechanisms of ROS production originating from ER stress, the interaction between ER stress and overall ROS signalling process in the cell, and the interaction of ER stress with other organellar ROS signalling pathways such as of the mitochondria and chloroplasts. The roles of the UPR during plant hormone signalling and abiotic and biotic stress responses are also discussed in connection with redox and ROS signalling. PMID- 29415272 TI - Can't read my broker face: Learning about trustworthiness with age. AB - Objectives: We assessed how age impacted learning who to trust, and the extent to which this type of learning relied on explicit memory. In contrast to prior studies, target faces were neutral without prior reputational information. Method: Younger and older adults made investment decisions for 36 brokers, who yielded a good, neutral, or bad outcome. Brokers were encountered three times to measure adaptive learning. After the investment task, participants completed a surprise explicit source memory test for brokers. Results: Although younger and older adults learned to distinguish good and bad brokers from neutral ones, older adults did not learn the brokers' behavior as well as younger adults. In addition, explicit source memory was highly correlated with investment decisions, although less so for good brokers for older than younger adults. Discussion: Findings extend prior work by establishing that older adults' impairments in learning who to trust extend to neutral faces, and highlighting the role of explicit memory in investment performance. Future work should vary the task demands to explore the contribution of explicit and implicit processes. PMID- 29415273 TI - Characterization of the Selective Recording of Workplace Exposure Measurements into OSHA's IMIS Databank. AB - Objectives: The Integrated Management Information System (IMIS) is the largest multi-industry source of exposure results available in North America. In 2010, the Occupational Safety and Health Administration (OSHA) released the Chemical Exposure Health Data (CEHD) that contains analytical results of samples collected by OSHA inspectors. However, the two databanks only partially overlap, raising suspicion of bias in IMIS data. We investigated the factors associated with selective recording of CEHD results into the IMIS databank. Methods: This analysis was based on personal exposure measurements of 24 agents from 1984 to 2009. The association between nine variables (level of exposure coded as detected versus non-detected (ND), whether a sampling result was part of a panel of chemicals, duration of sampling, issuance of a citation, presence of other detected levels during the same inspection, year, OSHA region, amount of penalty, and establishment size) and a CEHD sampling result being reported in IMIS was analyzed using modified Poisson regression. Results: A total of 461900 CEHD sampling results were examined. The proportion of CEHD sampling results recorded into IMIS was 38% (51% for detected and 28% for ND measurements). In the models, the detected sampling results were associated with a higher probability of recording into IMIS than ND sampling results, and this difference was similar for panel versus non-panel samples. Probability of recording remained constant from 1984 to 2009 for sampling results measured on panels but increased for sampling results of single determinations of an agent. Some OSHA regions had probability of recording two times higher than others. No other variables that we examined were associated with a CEHD sampling result being reported in IMIS. Conclusions: Our results indicate that the under-reporting of sampling results in IMIS is differential: ND results (especially those determined from the panels) seem less likely to be recorded in IMIS than other results. It is important to consider both IMIS and CEHD data in order to reduce bias in evaluation of exposures in workplaces inspected by OSHA. PMID- 29415274 TI - Single Neurons in Anterior Cingulate Cortex Signal the Need to Change Action During Performance of a Stop-change Task that Induces Response Competition. AB - Several human imaging studies have suggested that anterior cingulate cortex (ACC) is highly active when participants receive competing inputs, and that these signals may be important for influencing the downstream planning of actions. Despite increasing evidence from several neuroimaging studies, no study has examined ACC activity at the level of the single neuron in rodents performing similar tasks. To fill this gap, we recorded from single neurons in ACC while rats performed a stop-change task. We found higher firing on trials with competing inputs (STOP trials), and that firing rates were positively correlated with accuracy and movement speed, suggesting that when ACC was engaged, rats tended to slow down and perform better. Finally, firing was the strongest when STOP trials were preceded by GO trials and was reduced when rats adapted their behavior on trials subsequent to a STOP trial. These data provide the first evidence that activity of single neurons in ACC is elevated when 2 responses are in competition with each other when there is a need to change the course of action to obtain reward. PMID- 29415275 TI - Between science and industry-applied yeast research. AB - I was fortunate to enter yeast research at the Alko Research Laboratories with a strong tradition in yeast biochemistry and physiology studies. At the same time in the 1980s there was a fundamental or paradigm change in molecular biology research with discoveries in DNA sequencing and other analytical and physical techniques for studying macromolecules and cells. Since that time biotechnological research has expanded the traditional fermentation industries to efficient production of industrial and other enzymes and specialty chemicals. Our efforts were directed towards improving the industrial production organisms: minerals enriched yeasts (Se, Cr, Zn) and high glutathione content yeast, baker's, distiller's, sour dough and wine yeasts, and the fungal Trichoderma reesei platform for enzyme production. I am grateful for the trust of my colleagues in several leadership positions at the Alko Research Laboratories, Yeast Industry Platform and at the international yeast community. PMID- 29415276 TI - Apathy is Associated with Greater Decline in Subjective, but Not in Objective Measures of Physical Functioning in Older People without Dementia. AB - Background: In older people, both apathy and depression (which frequently co occurs with apathy) have been associated with poor physical functioning, a major health concern. We investigated the association between apathy and physical functioning in older people without dementia and whether this association is modified by depression. Methods: We used the data from 380 older participants (with and without depression) taking part in the Netherlands Study of Depression in Older Persons, with baseline scores on the Apathy Scale and baseline and 2 year follow-up scores on at least one measure of physical functioning. These included the International Physical Activities Questionnaire (IPAQ, self reported), WHO Disability Assessment Schedule (WHO-DASII mobility subset, self reported), walking speed or handgrip strength. Multivariable linear regression analyses were performed to examine the association between apathy at baseline and physical functioning at 2 year follow-up. We also investigated effect modification by sex, age, and depression. Results: Cross-sectionally, participants with higher baseline Apathy Scale scores performed significantly worse on all measures of physical functioning. Longitudinally, higher baseline Apathy Scale scores were associated with higher delta scores on the IPAQ (B= 59.81) in the basic model, and higher delta scores on the WHO-DASII (B= .09) in all models. Apathy was not associated with higher delta scores for walking speed or handgrip strength. Furthermore, sex, age, and depression did not modify any association. Conclusion: In a Dutch cohort of older people without dementia, apathy was associated with more decline in self-reported, but not in objective physical functioning. Sex, age, and depression did not modify these associations. In older people with apathy, subjective decline may precede decline in physical performance tests. PMID- 29415277 TI - Complete genome sequence and analysis of the industrial Saccharomyces cerevisiae strain N85 used in Chinese rice wine production. AB - Chinese rice wine is a popular traditional alcoholic beverage in China, while its brewing processes have rarely been explored. We herein report the first gapless, near-finished genome sequence of the yeast strain Saccharomyces cerevisiae N85 for Chinese rice wine production. Several assembly methods were used to integrate Pacific Bioscience (PacBio) and Illumina sequencing data to achieve high-quality genome sequencing of the strain. The genome encodes more than 6,000 predicted proteins, and 238 long non-coding RNAs, which are validated by RNA-sequencing data. Moreover, our annotation predicts 171 novel genes that are not present in the reference S288c genome. We also identified 65,902 single nucleotide polymorphisms and small indels, many of which are located within genic regions. Dozens of larger copy-number variations and translocations were detected, mainly enriched in the subtelomeres, suggesting these regions may be related to genomic evolution. This study will serve as a milestone in studying of Chinese rice wine and related beverages in China and in other countries. It will help to develop more scientific and modern fermentation processes of Chinese rice wine, and explore metabolism pathways of desired and harmful components in Chinese rice wine to improve its taste and nutritional value. PMID- 29415278 TI - Protease-Activated Receptor 2 Facilitates Bacterial Dissemination in Pneumococcal Pneumonia. AB - Streptococcus pneumoniae is the most common causative pathogen in community acquired pneumonia. Protease-activated receptor 2 (PAR2) is expressed by different cell types in the lungs and can mediate inflammatory responses. We sought to determine the role of PAR2 during pneumococcal pneumonia. Pneumococcal pneumonia or sepsis was induced in wild-type and PAR2 knock-out (Par2-/-) mice by infection with viable S. pneumoniae. Par2-/- mice demonstrated improved host defense, a largely preserved lung barrier integrity, and reduced mortality during pneumococcal pneumonia. PAR2 deficiency did not influence bacterial growth after intravenous infection. Inhibition of the endogenous PAR2 activating proteases tissue factor/factor VIIa or tryptase did not impact on bacterial burdens during pneumonia. In a PAR2 reporter cell line it was demonstrated that S. pneumoniae derived proteases are able to cleave PAR2. These results show that S. pneumoniae is able to cleave and exploit PAR2 to disseminate systemically from the airways. PMID- 29415280 TI - Youth labour force absence and chronic health conditions in Australia. AB - Background: Among older workers, chronic disease is known to be a key reason for early retirement. Aims: To determine whether chronic health conditions act as a barrier to young Australians (aged 15-29) participating in the labour force. Methods: Multiple logistic regression analysis to assess the adjusted odds ratio of people with different chronic health conditions being out of the labour force compared to those with no chronic conditions. Negative binomial regression models to predict the number of years people with different chronic health conditions would remain out of the labour force for. Results: Of the 550000 people aged 15 29 who were not in the labour force, 20% cited ill-health as the reason, reducing Australia's gross domestic product by around $3.7 billion per annum. When adjusted for age and education attainment, males with mental and behavioural disorders had 5.95 times the odds (95% confidence interval [CI] 3.90-9.08) of being out of the labour force, and females with development/intellectual disorders had 2.90 times the odds (95% CI 1.47-2.51), compared to those with no chronic health conditions. Males and females with development/intellectual disorders who were out of the labour force were estimated to spend an additional 2.7 and 3.5 years out of the labour force over the next 5 years. Conclusions: Prevention of chronic health conditions may help more younger Australians participate in the labour force, reducing the known long-term health and social problems associated with labour force absence. PMID- 29415281 TI - Genetic variation in Sorghum bicolor strigolactones and their role in resistance against Striga hermonthica. AB - Sorghum is an important food, feed, and industrial crop worldwide. Parasitic weeds of the genus Striga constitute a major constraint to sorghum production, particularly in the drier parts of the world. In this study we analysed the Striga germination stimulants, strigolactones, in the root exudates of 36 sorghum genotypes and assessed Striga germination and infection. Low germination stimulating activity and low Striga infection correlated with the exudation of low amounts of 5-deoxystrigol and high amounts of orobanchol, whereas susceptibility to Striga and high germination-stimulating activity correlated with high concentrations of 5-deoxystrigol and low concentrations of orobanchol. Marker analysis suggested that similar genetics to those previously described for the resistant sorghum variety SRN39 and the susceptible variety Shanqui Red underlie these differences. This study shows that the strigolactone profile in the root exudate of sorghum has a large impact on the level of Striga infection. High concentrations of 5-deoxystrigol result in high infection, while high concentrations of orobanchol result in low infection. This knowledge should help to optimize the use of low germination stimulant-based resistance to Striga by the selection of sorghum genotypes with strigolactone profiles that favour normal growth and development, but reduce the risk of Striga infection. PMID- 29415282 TI - Delivering Intensive Rehabilitation in Stroke: Factors Influencing Implementation. AB - Background: The evidence base for stroke rehabilitation recommends intensive and repetitive task-specific practice, as well as aerobic exercise. However, translating these -evidence-based interventions from research into clinical practice remains a major -challenge. Objective: The objective of this study was to investigate factors influencing implementation of higher-intensity activity in stroke rehabilitation settings. Design: This qualitative study used a cross sectional design. Methods: Semi-structured interviews were conducted with rehabilitation therapists from 4 sites across 2 Canadian provinces who had experience in delivering a higher-intensity intervention as part of a clinical trial (Determining Optimal post-Stroke Exercise [DOSE]). An interview guide was developed, and data were analyzed using implementation frameworks. Results: Fifteen therapists were interviewed before data saturation was reached. Therapists and patients generally had positive experiences regarding high intensity interventions. However, therapists felt they would adapt the protocol to accommodate their beliefs about ensuring movement quality. The requirement for all patients to have a graded exercise test and the use of sensors (eg, heart rate monitors) gave therapists confidence to push patients harder than they normally would. Paradoxically, a system that enables routine graded exercise testing and the availability of staff and equipment contribute challenges for implementation in everyday practice. Conclusions: Even therapists involved in delivering a high-intensity intervention as part of a trial wanted to adapt it for clinical practice; therefore, it is imperative that researchers are explicit regarding key intervention components and what can be adapted to help ensure implementation fidelity. Changes in therapists' beliefs and system-level changes (staffing and resources) are likely necessary to facilitate higher-intensity rehabilitation in practice. PMID- 29415279 TI - Paternal and maternal obesity but not gestational weight gain is associated with type 1 diabetes. AB - Background: Our objective was to examine the associations of parental body mass index (BMI) and maternal gestational weight gain with childhood-onset type 1 diabetes. Comparing the associations of maternal and paternal BMI with type 1 diabetes in the offspring will provide further insight into the role of unmeasured confounding by characteristics linked to BMI in both parents. Methods: We studied 132 331 children participating in the Norwegian Mother and Child Cohort Study (MoBa) and the Danish National Birth Cohort (DNBC) who were born between February 1998 and July 2009. Exposures of interest included parental BMI and maternal gestational weight gain obtained by maternal report. We used Cox proportional hazards regression to examine the risk of type 1 diabetes (n=499 cases), which was ascertained by national childhood diabetes registers. Results: The incidence of type 1 diabetes was 32.7 per 100 000 person-years in MoBa and 28.5 per 100 000 person-years in DNBC. Both maternal pre-pregnancy obesity, adjusted hazard ratio (HR) 1.41 [95% confidence interval (CI): 1.06, 1.89] and paternal obesity, adjusted HR 1.51 (95% CI: 1.11, 2.04), were associated with childhood-onset type 1 diabetes. The associations were similar after mutual adjustment. In contrast, maternal total gestational weight gain was not associated with childhood-onset type 1 diabetes, adjusted HR 1.00 (95% CI: 0.99, 1.02) per kilogram increase. Conclusions: Our study suggests that the association between maternal obesity and childhood-onset type 1 diabetes is not likely explained by intrauterine mechanisms, but possibly rather by unknown environmental factors influencing BMI in the family. PMID- 29415283 TI - A Rare Case of Postoperative Iris Pigment Epithelium Detachment. PMID- 29415284 TI - Endothelial Cell-Specific Overexpression of Del-1 Drives Expansion of Haematopoietic Progenitor Cells in the Bone Marrow. PMID- 29415285 TI - Correction: Covered vs. uncovered self-expandable metal stents for malignant distal biliary strictures: a systematic review and meta-analysis. PMID- 29415286 TI - Gaze patterns hold key to unlocking successful search strategies and increasing polyp detection rate in colonoscopy. AB - BACKGROUND: The adenoma detection rate (ADR) is an important quality indicator in colonoscopy. The aim of this study was to evaluate the changes in visual gaze patterns (VGPs) with increasing polyp detection rate (PDR), a surrogate marker of ADR. METHODS: 18 endoscopists participated in the study. VGPs were measured using eye-tracking technology during the withdrawal phase of colonoscopy. VGPs were characterized using two analyses - screen and anatomy. Eye-tracking parameters were used to characterize performance, which was further substantiated using hidden Markov model (HMM) analysis. RESULTS: Subjects with higher PDRs spent more time viewing the outer ring of the 3 * 3 grid for both analyses (screen-based: r = 0.56, P = 0.02; anatomy: r = 0.62, P < 0.01). Fixation distribution to the "bottom U" of the screen in screen-based analysis was positively correlated with PDR (r = 0.62, P = 0.01). HMM demarcated the VGPs into three PDR groups. CONCLUSION: This study defined distinct VGPs that are associated with expert behavior. These data may allow introduction of visual gaze training within structured training programs, and have implications for adoption in higher-level assessment. PMID- 29415287 TI - Residual adenoma after cold snare polypectomy for small colorectal adenomas: a prospective clinical study. AB - BACKGROUND: Endoscopic resection of all colonic adenomas prevents the occurrence of colon cancer and death. The European Society of Gastrointestinal Endoscopy Clinical Guideline recommends resection of all polyps predicted to be adenomas and cold snare polypectomy (CSP) for removal of adenomas <= 9 mm on the basis of safety; however, it also states that this recommendation lacks adequate evidence of efficacy. The residual adenoma rate after resection is an important indicator of efficacy, but there have been no reports showing this prospectively. Therefore, we aimed to investigate the residual adenoma rate after CSP of small colonic polyps. METHODS: Between March 2015 and April 2017, patients who were endoscopically diagnosed with colorectal adenomas < 9 mm underwent CSP, the site being marked with endoscopic clips. Patients with pathologically confirmed adenomas underwent follow-up colonoscopy 3 weeks after CSP and any post-CSP scars were biopsied. The primary endpoint was the presence of pathological residual adenoma 3 weeks after CSP. RESULTS: Overall, 126 lesions in 39 patients were removed and 125 (99.2 %) were resected en bloc using CSP. Pathologically, 111 lesions (88.1 %) were confirmed as adenomas (4.2 +/- 1.5 mm), with 36 of these (32.4 %) determined to be R0 resections. No complications were observed. All 37 patients with pathologically confirmed adenomas underwent follow-up colonoscopy, and 102 of 111 scars were detected in 33 patients. One pathological residual adenoma (0.98 %, 95 % confidence interval 0.02 % - 5.3 %) was identified. CONCLUSIONS: CSP appears to be an effective treatment for diminutive and small colorectal adenomas, with a low residual adenoma rate. PMID- 29415288 TI - Video Comment on Tomoya Sako et al. PMID- 29415289 TI - [Sudden hearing loss, vertigo and Tinnitus - a patient's 12-year odyssey]. PMID- 29415290 TI - [Necrotising cervical lymphadenitis with unclear skin lesions]. PMID- 29415292 TI - Vertical Impulse as a Determinant of Combination of Step Length and Frequency During Sprinting. AB - This study aimed to clarify the influence of vertical impulse on the magnitude of step length (SL) and frequency (SF) and their ratio during the entire acceleration phase of maximal sprinting. Thirty-nine male soccer players performed 60-m sprints, during which step-to-step ground reaction forces were recorded over a 50-m distance. The mean values of spatiotemporal variables and vertical and anteroposterior impulses for each set of four steps during the acceleration phase until the 28th step were computed to examine relationships among variables in seven sections. When controlling for the influence of running speed, stature and corresponding duration of braking or propulsion, vertical impulses during the propulsive phase at the 1st-4th step section and those during the braking phases in the sections from the 5th-8th to the 25th-28th step were positively correlated with SL and SL/SF ratio and negatively correlated with SF, whereas the anteroposterior impulses were not correlated with SL or SF. In conclusion, the current results demonstrate that vertical impulse during the propulsive phase in the initial acceleration stage and that during the braking phase in the middle and later acceleration stages are the most likely determinants of the combination of SL and SF during sprinting. PMID- 29415293 TI - Velocity-Dependent Changes in Electrical Efficiency of the Leg Extensors during Eccentric Isokinetic Muscle Actions. AB - The mechanisms underlying velocity-specific decreases in torque production during eccentric muscle actions remain unclear. Therefore, the purpose of the present study was to examine electrical efficiency at 60 and 180 degrees .s -1 during fatiguing, maximal eccentric isokinetic muscle actions of the leg extensors. Thirteen men visited the lab on two occasions and randomly performed 30 repeated maximal eccentric isokinetic muscle actions of the leg extensors at 60 and 180 degrees .s - 1 through a 90 degrees range of motion. Polynomial regression analyses and separate repeated measures ANOVAs were used to examine the composite patterns of responses for electromyographic amplitude, eccentric torque, and electrical efficiency across the 60 and 180 degrees .s - 1 protocols. Eccentric torque remained unchanged across the 30 maximal eccentric muscle actions performed at 60 and 180 degrees .s -1. Electromyographic amplitude and electrical efficiency, however, increased linearly across the 180 degrees .s -1 protocol, but there were no changes for either electromyographic amplitude or electrical efficiency during the 60 degrees .s -1 fatiguing protocol. These findings indicated that performing eccentric muscle actions at a fast velocity (i. e., 180 degrees .s -1) was characterized by greater efficiency (i. e., decreased electrical efficiency) compared to eccentric muscle actions performed at a slow velocity (i. e., 60 degrees .s -1). Thus, it is possible that eccentric muscle actions performed at fast velocities are more robust to fatigue due, in part, to greater efficiency compared to slow-velocity eccentric muscle actions. PMID- 29415294 TI - The Impact of Mild Heat Stress During Prolonged Running On Gastrointestinal Integrity, Gastrointestinal Symptoms, Systemic Endotoxin and Cytokine Profiles. AB - The study aimed to determine the effects of mild exertional heat stress on intestinal injury, permeability, gastrointestinal symptoms, and systemic endotoxin and cytokine responses. Ten endurance runners completed 2 h of running at 60% VO2max in warm (WARM: 30 degrees C) and temperate (TEMP: 22 degrees C) ambient conditions. Rectal temperature (Tre) and gastrointestinal symptoms were recorded every 10 min during exercise. Blood samples were collected pre- and post exercise, and during recovery to determine plasma intestinal fatty acid-binding protein (I-FABP) and cortisol concentrations, and systemic endotoxin and inflammatory cytokine profiles. Urinary lactulose:L-rhamnose ratio (L/R) was used to measure small intestine permeability. Compared with TEMP, WARM significantly increased Tre from 50 min onwards (38.1+/-0.3 degrees C vs. 38.4+/-0.5 degrees C, respectively; p<0.01), gastrointestinal symptoms (p=0.017), post-exercise plasma cortisol (26% vs. 59%, respectively; p<0.001) and I-FABP (127% vs. 184%, respectively; p<0.001) concentrations. Circulatory anti-endotoxin antibodies increased post-exercise (p<0.001) on WARM (20%) and TEMP (28%). No differences were observed for plasma endotoxin concentration (6% vs. 5% increase, respectively) or small intestine permeability (L/R 0.026+/-0.010 and 0.025+/ 0.015, respectively). Both pro- and anti-inflammatory cytokines increased post exercise, with inflammatory response cytokines TNF-alpha (p=0.015) and IL-8 (p=0.044), and compensatory anti-inflammatory cytokines IL-10 (p=0.065), and IL 1ra higher on WARM than TEMP. Findings suggest that exposure to warm ambient conditions during prolonged submaximal running induces transient intestinal epithelial injury, increases gastrointestinal symptoms, and promotes greater perturbations to the systemic cytokine profile compared to running in temperate conditions. PMID- 29415295 TI - Externally Acquired Radiological Data for the Clinical Routine - A Review of the Reimbursement Situation in Germany. AB - BACKGROUND: Interdisciplinary radiological conferences and boards can improve therapeutic pathways. Because of the reinterpretation and presentation of external image data, which already was read, an additional workload is created which is currently not considered by health care providers. In this review we discuss the ongoing basics and possibilities in health economy for a radiological second opinion for the outpatient and inpatient sector in Germany. METHOD: Based on up-to-date literature and jurisdiction, we discuss the most important questions for the reimbursement for second opinions and conference presentations of external image data in an FAQ format. Additionally, we focus on the recently introduced E-Health law accordingly. RESULTS: Radiological services considering second opinion or board presentation of externally acquired image data are currently not adequately covered by health care providers. In particular, there is no reimbursement possibility for the inpatient sector. Only patients with private insurance or privately paid second opinions can be charged when these patients visit the radiologist directly. CONCLUSION: Currently there is no adequate reimbursement possibility for a radiological second opinion or image demonstrations in clinical conferences. It will be essential to integrate adequate reimbursement by health care providers in the near future because of the importance of radiology as an essential diagnostic and therapeutic medical partner. KEY POINTS: . Currently there is no reimbursement for image interpretation and presentation in boards.. . Second opinions can only be reimbursed for patients with private insurance or privately recompensed.. . The E Health law allows reimbursement for tele-counsel in very complex situations.. . It will be crucial to integrate radiological second opinion in future reimbursement policies by health care providers.. CITATION FORMAT: . Schreyer AG, Steinhauser RT, Rosenberg B. Externally Acquired Radiological Data for the Clinical Routine - A Review of the Reimbursement Situation in Germany. Fortschr Rontgenstr 2018; DOI: 10.1055/s-0044-101552. PMID- 29415297 TI - [Hepatic epithelioid hemangioendothelioma: Characteristic signs in MRI]. PMID- 29415296 TI - Vascular Anomalies (Part II): Interventional Therapy of Peripheral Vascular Malformations. AB - BACKGROUND: The International Society for the Study of Vascular Anomalies (ISSVA) categorizes vascular anomalies into vascular tumors and vascular malformations. Vascular malformations are further divided into slow-flow (venous, lymphatic, and capillary malformation) and fast-flow malformations (arteriovenous malformation and arteriovenous fistula). This interdisciplinary classification has therapeutic implications. METHODS: The objective of this article is to provide concise information about the current terminology and treatment strategies of peripheral vascular malformations, based on the currently available literature, with a focus on interventional therapy of venous malformations (VM), lymphatic malformations (LM), arteriovenous malformations (AVM) and arteriovenous fistulae (AVF). RESULTS AND CONCLUSION: Accurate classification is crucial for appropriate therapy of peripheral vascular malformations. Modern imaging technologies and refined interventional treatment strategies are now central parts in the multidisciplinary management of these patients. Slow-flow and fast flow vascular malformations can be treated successfully by percutaneous sclerotherapy and endovascular embolotherapy as first-line interventions. KEY POINTS: . The ISSVA classification is essential for the correct diagnosis of vascular malformations. . The Schobinger classification as well as the Cho classification should be used for description of arteriovenous malformations (AVM). . Sclerotherapy and embolotherapy are the primary treatments of choice for vascular malformations. CITATION FORMAT: . Muller-Wille R, Wildgruber M, Sadick M et al. Vascular Anomalies (Part II): Interventional Therapy of Peripheral Vascular Malformations. Fortschr Rontgenstr 2018; DOI: 10.1055/s-0044-101266. PMID- 29415298 TI - ? PMID- 29415300 TI - Statement from the DEGUM board regarding the editorial entitled "Who's Doing Your Scan? A European Perspective on Ultrasound Services." PMID- 29415299 TI - What Future for Ultrasound in Medicine? PMID- 29415301 TI - Endobronchial Ultrasound (EBUS) - Update 2017. AB - Endobronchial ultrasound (EBUS) has revolutionized the diagnosis of lung cancer over the last decade. This minimally invasive diagnostic method has also become increasingly important in the case of other diseases such as sarcoidosis, thereby helping to avoid unnecessary diagnostic interventions. This review article provides an update regarding EBUS and discusses current and future developments of this method. PMID- 29415303 TI - Letter to the editor: Who's doing your scan? A European perspective on ultrasound services by Edwards and Sidhu. PMID- 29415304 TI - Reply to Dr Seitz. PMID- 29415305 TI - High quality vascular ultrasound by non-physicians is established and effective: the UK perspective. PMID- 29415309 TI - [The Economic Challenge of Centralised Treatment of Patients with Periprosthetic Infections]. AB - INTRODUCTION: Periprosthetic infection (PJI) is one of the most severe complications in joint arthroplasty. Correct diagnosis and adequate therapy represent an enormous interdisciplinary challenge. The necessary interdisciplinarity and complexity of treatment require therapy in centres. However, the high costs have not yet been analysed or discussed and are problematic. The aim of this work is therefore to compare the costs within a year of treatment in a department specialised in the treatment of periprosthetic infections. METHOD: A retrospective evaluation of the patients who were hospitalised in our Centre for Septic Surgery in 2015 was carried out using data from the hospital information system and medical controlling. Demographic data, diagnoses, the length of hospital stay, the number of surgical interventions and the pathogen spectrum were recorded and the costs of treatment were determined. These were compared to the DRG revenues. RESULTS: A total of 281 patients were treated in 2015 due to an infection of the musculoskeletal system, 144 of these with a periprosthetic infection of the knee or hip joint (ratio 1.5 : 1). The mean duration of treatment was 16 days; the mean treatment costs per day and patient were approximately 820 ?. The total cost of the 281 treatments was 3.3 million ?, of which only 2.7 million were covered by DRG revenues (underfill of approx. - 20%). This corresponded to a deficit of 633,000 ?, with a mean deficit per treatment case of 2300 ?. The deficit for infected THA was 8585 ? on average and was five times greater than for infected TKA - with 1638 ?. The main reasons for the high treatment costs were the length of hospital stay, multiple surgical interventions and the isolation treatment. CONCLUSION: The increasing number of PJI requires interdisciplinary treatment in centres. However, the costs not covered by the DRG system prevent such highly specialised treatment in centres, implying a loss of quality in treatment. There is an urgent need for social discussion and resolution. PMID- 29415308 TI - Clinical Information Systems Integration in New York City's First Mobile Stroke Unit. AB - BACKGROUND: Mobile stroke units (MSUs) reduce time to thrombolytic therapy in acute ischemic stroke. These units are widely used, but the clinical information systems underlying MSU operations are understudied. OBJECTIVE: The first MSU on the East Coast of the United States was established at New York Presbyterian Hospital (NYP) in October 2016. We describe our program's 7-month pilot, focusing on the integration of our hospital's clinical information systems into our MSU to support patient care and research efforts. METHODS: NYP's MSU was staffed by two paramedics, one radiology technologist, and a vascular neurologist. The unit was equipped with four laptop computers and networking infrastructure enabling all staff to access the hospital intranet and clinical applications during operating hours. A telephone-based registration procedure registered patients from the field into our admit/discharge/transfer system, which interfaced with the institutional electronic health record (EHR). We developed and implemented a computerized physician order entry set in our EHR with prefilled values to permit quick ordering of medications, imaging, and laboratory testing. We also developed and implemented a structured clinician note to facilitate care documentation and clinical data extraction. RESULTS: Our MSU began operating on October 3, 2016. As of April 27, 2017, the MSU transported 49 patients, of whom 16 received tissue plasminogen activator (t-PA). Zero technical problems impacting patient care were reported around registration, order entry, or intranet access. Two onboard network failures occurred, resulting in computed tomography scanner malfunctions, although no patients became ineligible for time-sensitive treatment as a result. Thirteen (26.5%) clinical notes contained at least one incomplete time field. CONCLUSION: The main technical challenges encountered during the integration of our hospital's clinical information systems into our MSU were onboard network failures and incomplete clinical documentation. Future studies are necessary to determine whether such integrative efforts improve MSU care quality, and which enhancements to information systems will optimize clinical care and research efforts. PMID- 29415310 TI - [10-year development of spine surgery in Germany - An analysis of health insurance funds data from 2005 to 2014]. AB - BACKGROUND: Analysis of the regional development of spine surgery in Germany between 2005 and 2014. MATERIAL AND METHODS: A secondary data analysis of inpatient data from the Scientific Institute of the AOK (WIdO) was carried out for the period 2005 to 2014. The number of spinal procedures was determined on the basis of 14 defined intervention groups (procedures according to OPS codes). The regional numbers of spine surgery procedures in the 402 districts in Germany and the regional age- and gender-standardised distribution are displayed as healthcare utilisation charts. RESULTS: 796,870 AOK-insured individuals received inpatient spinal surgery during the observation period. The relative increase in the 10-year period was 82%, with 51,053 interventions in 2005 and 91,971 interventions in 2014. The increase in spine surgery cases occurred mainly between 2005 and 2011. An increase in the number of operations was observed in all intervention groups except "excision of intervertebral discs and bones". It was different in different spinal procedures, with the greatest increases in "bone decompression" (280% increase). Regional differences were found in all intervention groups. In 2014, the number of interventions varied between 109 and 729 interventions per 100,000 AOK-insured individuals in the districts. CONCLUSION: The significant increases of more than 80% in 10 years cannot be explained solely by sociodemographic changes. The pronounced regional differences alone do not allow firm conclusions on the existence of regional underuse, overuse or misuse. The results, however, emphasise the need for further health services research on the quality of the medical indication and the determinants of regional variation. PMID- 29415311 TI - [Disease-specific Knowledge in Conservative Treatment of Adolescent Idiopathic Scoliosis]. AB - BACKGROUND: The typical onset of adolescent idiopathic scoliosis falls in a sensitive stage of life. Nevertheless, conservative brace treatment requires a high degree of compliance. Disease-specific knowledge influences therapy outcome in many diseases and potentially improves patient compliance and quality of life. We analysed disease-specific knowledge and quality of life of patients with adolescent idiopathic scoliosis. METHODS: Scoliosis patients (n = 67) undergoing conservative brace treatment were asked to answer a questionnaire with items about scoliosis-specific knowledge. This was anonymous and prior to regular interviews and examinations. The scoliosis-research-society-22 r score was determined in order to assess quality of life. RESULTS: The major sources of information for the patients were the attending physicians and the world wide web. The majority stated that they understood the nature of scoliosis, although their answers to more detailed questions revealed a major lack of knowledge. A significant gap in provision of information was found, especially in the field of therapy regimen and treatment goals. The expected duration of the therapy was unclear to most patients. Nevertheless, higher quality of life correlated with high compliance and patients who regarded alleviation of the disturbing appearance of their trunk as a main treatment aim also experienced a lower quality of life in the section of self image. CONCLUSIONS: Our study revealed a significant lack of disease-specific knowledge in patients with idiopathic scoliosis. Facilitation of knowledge might improve quality of life and therapy outcome in the future. As the attending physicians are the main source of information, it is up to us to improve this situation. PMID- 29415312 TI - Novel Demonstration of the Anterior Femoral Cutaneous Nerves using Ultrasound. AB - PURPOSE: Neuropathy of the intermediate (IFCN) and medial femoral cutaneous nerve (MFCN) is a potential iatrogenic complication of thigh surgery and its diagnosis is limited. This study aimed to evaluate the possibility of the visualization and diagnostic assessment of the IFCN and MFCN with high-resolution ultrasound (HRUS). MATERIALS AND METHODS: In this study, HRUS with high frequency probes (15 - 22MHz) was used to locate the IFCN and the MFCN in 16 fresh cadaveric lower limbs. The correct identification of the nerves was verified by ink-marking and consecutive dissections at sites correlating to nerve positions (R1 - 3), namely, the origin, the mid portion, and the distal portion, respectively. 12 cases with suspected IFCN and MFCN lesions referred to our clinic for HRUS examinations were also assessed. RESULTS: Anatomical dissection confirmed the correct identification of the IFCN in 16/16 branches at all of the different locations (100 %). MFCN was correctly identified at R1 + 3, in all cases (16/16; 100 %), and in 14/16 cases (88 %) at (R2). 12 cases of patients with IFCN and MFCN pathologies (all of iatrogenic origin) were identified. 9 instances of structural damage were visible on HRUS, and all pathologies were confirmed by almost complete resolution of symptoms after selective HRUS-guided blocks with 0.5 - 1 ml lidocaine 2 %. CONCLUSION: This study confirms that the IFCN and the MFCN can be reliably visualized with HRUS throughout the course of these nerves, both in anatomical specimens and in patients. PMID- 29415313 TI - Fetal Cardiac Remodeling in Response to Anemia: Using Hemoglobin Bart's Disease as a Study Model. AB - OBJECTIVE: To assess fetal cardiac remodeling in response to anemia, by comparing the fetal cardiac dimensions and global sphericity index (GSI) of normal fetuses and fetuses with anemia using fetal Hb Bart's disease as a study model. METHODS: Fetuses at risk for Hb Bart's disease undergoing cordocentesis at 18 to 22 weeks of gestation were recruited. Fetal cardiac dimensions including GSI (cardiac length to cardiac width ratio), interventricular septum thickness (IVST), left ventricular wall thickness (LVWT) and right ventricular wall thickness (RVWT) were measured. RESULTS: 215 pregnancies at risk met the inclusion criteria, including 54 affected fetuses and 161 normal fetuses. The mean GSI was significantly lower in the affected group (1.11 +/- 0.06 vs. 1.26 +/ 0.09, p-value 0.017). The GSI of the normal group was relatively constant regardless of gestational age. The IVST and LVWT tended to increase, but not significantly, in the affected group, whereas the RVWT was minimally but significantly increased. The ROC curve for GSI had an area under curve of 0.844. The best cut-off of GSI was 1.17, giving a sensitivity of 74.1 % and a specificity of 88.2 %. CONCLUSION: Fetal cardiac remodeling in response to anemia causes a marked decrease in global GSI with minimal hypertrophy as an adaption to volume overload. Importantly, GSI is a new maker for anemia and may play a role in clinical application for early detection of fetal anemia, possibly due to any cause. Additionally, GSI measurement is simple and gestational age independent. PMID- 29415314 TI - A patient with lower gastrointestinal bleeding: common history, very uncommon cause, minimally invasive treatment. AB - An 81-year-old patient with significant cardiac comorbidities, a history of sigmoid resection 6 years ago, and iliac bypass surgery 19 years ago presented with mild hematochezia for the previous 3 days. While hemodynamically stable at first, he developed massive bleeding during preparation for colonoscopy and underwent a short course of cardiopulmonary resuscitation. Colonoscopy revealed no active bleeding but a protuberance of the colonic wall and a coagulation clot. In ultrasonography immediately after endoscopy, a large aneurysm was diagnosed and diagnosis of an iliaco-colonic fistula was assumed. CT scan demonstrated a large pseudoaneurysm of the distal anastomosis after iliaco-iliac bypass. With endovascular treatment, the original lumen of the iliac artery could be recanalized, and 2 covered stents were placed to cover both anastomosis of the prosthetic bypass leading to a complete shutdown of bypass perfusion. A double barreled transversostoma was established to minimize contamination of the aneurysmal sac. Seven months after these procedures, the patient is well and free of infection.Though aorto- or iliaco-colonic fistula after aortic or iliac surgery are very rare, endoscopists should be aware of their possibility. A high index of clinical suspicion in patients with prior abdominal vascular bypass surgery should prompt rapid imaging studies, possibly before endoscopy. In critically ill patients, endovascular treatment may be a suitable alternative and result in a favorable outcome. PMID- 29415315 TI - [When to operate Crohn's disease patients with ileocaecal manifestation ?] PMID- 29415316 TI - [Animal Naming Test - Animals as diagnostic solution?] PMID- 29415317 TI - ? PMID- 29415318 TI - Association of AlkB homolog 3 expression with tumor recurrence and unfavorable prognosis in hepatocellular carcinoma. AB - BACKGROUND AND AIM: The mammalian AlkB homolog protein family has been reported to promote tumor cell invasion and metastasis of human cancer. However, the expression status and clinical significance of AlkB homolog 3 (ALKBH3) in hepatocellular carcinoma (HCC) have not been reported yet. METHODS: In the present study, we investigated the protein expression of ALKBH3 by immunohistochemistry assay and evaluated its association with tumor progression, recurrence, and prognosis in 272 patients with HCC. In addition, we explored ALKBH3 function via gene overexpression and knockdown of ALKBH3. RESULTS: AlkB homolog 3 was overexpressed in HCC compared with adjacent non-tumorous specimens. Moreover, ALKBH3 expression was closely related to tumor differentiation and tumor-node-metastasis stage. Interestingly, the ALKBH3 high expression in tumor tissues of HCC patients had more poor disease-free survival and overall survival than low-expression patients. Consistently, we found that knockdown of ALKBH3 inhibits HCC cell proliferation in vitro and xenograft tumor formation in vivo and overexpressing ALKBH3 showed the opposite results. ALKBH3 knockdown may inhibit cell proliferation, presumably through p21/p27-mediated cell-cycle arrest at G1 phase in human HCC. ALKBH3 may also play some role on chemosensitivity to certain genotoxic reagents, such as cisplatin (CDDP) and epirubicin. CONCLUSIONS: These findings reveal an important role of ALKBH3 in HCC, indicating that ALKBH3 could be used as a new therapeutic target in future. PMID- 29415319 TI - Local-Curvature-Controlled Non-Epitaxial Growth of Hierarchical Nanostructures. AB - Site-selective growth on non-spherical seeds provides an indispensable route to hierarchical complex nanostructures that are interesting for diverse applications. However, this has only been achieved through epitaxial growth, which is restricted to crystalline materials with similar crystal structures and physicochemical properties. A non-epitaxial growth strategy is reported for hierarchical nanostructures, where site-selective growth is controlled by the curvature of non-spherical seeds. This strategy is effective for site-selective growth of silica nanorods from non-spherical seeds of different shapes and materials, such as alpha-Fe2 O3 , NaYF4 , and ZnO. This growth strategy is not limited by the stringent requirements of epitaxy and is thus a versatile general method suitable for the preparation of hierarchical nanostructures with controlled morphologies and compositions to open up a verity of applications in self-assembly, nanorobotics, catalysis, electronics, and biotechnology. PMID- 29415320 TI - Three-Coordinate Boron(III) and Diboron(II) Dications. AB - The enhanced electron-donor properties of the bulky bisimino ligand 1,2-(LMes N)2 -C2 H4 (1; LMes =1,3-bis(mesityl)-imidazolin-2-ylidene), mesityl=2,4,6 trimethylphenyl) were exploited for the stabilization of elusive electron deficient and low-coordinate boron dication species. The reaction of 1 with PhBBr2 or (B(Cl)NMe2 )2 afforded a dicationic mononuclear boron(III) complex or a dicationic dinuclear boron(II) complex, respectively (42+ , 62+ ). The bonding situations of 42+ and 62+ were examined by means of single crystal X-ray diffraction analysis, as well as theoretical methods. Significant allocation of positive charge density into the ligand system was diagnosed for both dications. However, the metalloid-centered Lewis acidity of the dications was confirmed via hydride transfer reactions. PMID- 29415321 TI - Reply to Matsubara et al. PMID- 29415322 TI - A Total Synthesis of Salinosporamide A. AB - Salinosporamide A is a beta-lactone proteasome inhibitor currently in clinical trials for the treatment of multiple-myeloma. Herein we report a short synthesis of this small, highly functionalized, biologically important natural product that uses an oxidative radical cyclization as a key step and allows for the preparation of gram quantities of advanced synthetic intermediates. PMID- 29415323 TI - Rapidly developing multimorbidity and disability in older adults: does social background matter? AB - BACKGROUND: Multimorbidity is among the most disabling geriatric conditions. In this study, we explored whether a rapid development of multimorbidity potentiates its impact on the functional independence of older adults, and whether different sociodemographic factors play a role beyond the rate of chronic disease accumulation. METHODS: A random sample of persons aged >=60 years (n = 2387) from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K) was followed over 6 years. The speed of multimorbidity development was estimated as the rate of chronic disease accumulation (linear mixed models) and further dichotomized into the upper versus the three lower rate quartiles. Binomial negative mixed models were used to analyse the association between speed of multimorbidity development and disability (impaired basic and instrumental activities of daily living), expressed as the incidence rate ratio (IRR). The effect of sociodemographic factors, including sex, education, occupation and social network, was investigated. RESULTS: The risk of new activity impairment was higher among participants who developed multimorbidity faster (IRR 2.4, 95% CI 1.9-3.1) compared with those who accumulated diseases more slowly overtime, even after considering the baseline number of chronic conditions. Only female sex (IRR for women vs. men 1.6, 95% CI 1.2-2.0) and social network (IRR for poor vs. rich social network 1.7, 95% CI 1.3-2.2) showed an effect on disability beyond the rate of chronic disease accumulation. CONCLUSIONS: Rapidly developing multimorbidity is a negative prognostic factor for disability. However, sociodemographic factors such as sex and social network may determine older adults' reserves of functional ability, helping them to live independently despite the rapid accumulation of chronic conditions. PMID- 29415324 TI - Illegal bowling actions contribute to performance in cricket finger-spin bowlers. AB - With advances in technology, scientists are now able to more accurately measure elbow displacement changes during the cricket bowling action. This has led to the realization that the majority of bowlers undergo some degree of elbow extension during the forward swing phase of bowling. Consequently, the International Cricket Council were obliged to revise the once zero tolerance for elbow extension threshold to a 15 degrees range. However, it is still not understood if bowling with >15 degrees of elbow extension aids performance or alters other kinematic movements. The purpose of this study was to compare performance and technique measures between legal and illegal finger-spin bowlers. Data were collected from 48 pathway and elite bowlers using a 22-camera motion analysis system. Results indicated that the ball velocity and revolutions at ball release of pathway bowlers with illegal actions showed no significant difference and were similar to elite legal bowlers. Technique differences were also identified, with illegal bowlers being more front-on, forcing a reliance on increased elbow flexion and supination to impart effective ball kinematics at ball release. The performance benefit of greater ball velocity and revolutions is obtained when finger-spin bowlers deliver the ball with more than the allowable 15 degrees of elbow extension, thus reinforcing the validity of the current bowling laws. To counteract bowling with an illegal action, it is recommended that a more side-on technique at back foot impact and rotating the trunk through to the point of ball release will assist bowlers in reducing undesirable elbow extension levels. PMID- 29415325 TI - New thiophene-acridine compounds: Synthesis, antileishmanial activity, DNA binding, chemometric, and molecular docking studies. AB - In this study, we synthesized eight new compounds containing the 2-amino cycloalkyl[b]thiophene and acridine moieties (ACT01 and ACS01 -ACS07 ). None tested compounds presented human erythrocyte cytotoxicity. The new compounds presented antipromastigote activity, where ACS01 and ACS02 derivatives presented significant antileishmanial activity, with better performance than the reference drugs (tri and pentavalent antimonials), with respective IC50 values of 9.60 +/- 3.19 and 10.95 +/- 3.96 MUm. Additionally, these two derivatives were effective against antimony-resistant Leishmania (Leishmania) amazonensis strains. In addition, binding and fragmentation DNA assays were performed. It was observed that the antileishmanial activity of ACS01 is not associated with DNA fragmentation of the promastigote forms. However, it interacted with DNA with a binding constant of 104 m-1 . In partial least-squares studies, it was observed that the most active compounds (ACS01 and ACS02 ) showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. Furthermore, the docking molecular studies showed interactions between thiophene-acridine derivatives and the active site of pyruvate kinase enzyme with the major contribution of asparagine 152 residue for the interaction with thiophene moiety. Thus, the results suggested that the new thiophene-acridine derivatives are promising molecules as potential drug candidates. PMID- 29415326 TI - Pediatric acute lymphoblastic leukemia: Proportion of patients who continue hospital visits. AB - BACKGROUND: Long-term follow up in adulthood after childhood cancer therapy is particularly important because of the risk of late effects, and information on the rate of continuing hospital visits by childhood cancer survivors (CCS) is also important for the planning of studies on the risk of late effects. METHODS: The rate of continuing hospital visits ("long-term follow up") in 1,252 cases registered in the multicenter Japan Association of Childhood Leukemia Study on Acute Lymphoblastic Leukemia (JACLS ALL-02) was investigated using data from its electronic data capture (EDC) system, including case number, date of diagnosis, date of therapy completion, date of birth, sex, survival or death, date of death, date of last outcome confirmation, and facility code. EDC entries of confirmed survival or death during the 2 years preceding the data lock represented continuing visitors, and the number of those cases, divided by the total number of cases (excluding cases of confirmation of death prior to those 2 years), was calculated as the proportion of continuing visitors (PCV). RESULTS: The PCV for survivors of childhood acute lymphoblastic leukemia was found to decline over time from diagnosis. For subjects aged 21-29 years who were >=9 years from diagnosis, PCV was approximately 30% overall, representing 23.5% for men and 41.8% for women, thus indicating a gender difference. CONCLUSIONS: Further studies may be necessary to assess whether CCS who stopped visiting childhood cancer treatment facilities, actually received therapeutic intervention or appropriate screening for late effects as adults. PMID- 29415327 TI - Associations between parity and maternal BMI in a population-based cohort study. AB - INTRODUCTION: We aimed to investigate the change in prevalence of overweight and obesity in pregnant Danish women from 2004 to 2012, and investigate whether increasing parity was associated with a change in body mass index (BMI) prevalence. MATERIAL AND METHODS: We obtained a population-based cohort from the Danish Medical Birth Registry consisting of all Danish women giving birth in 2004 2012 (n = 572 321). This registry contains information on 99.8% of all births in Denmark. We calculated the overall change in prepregnancy BMI status among pregnant women in Denmark, and a multiple linear regression model with adjustment for several potential confounders was used to examine the change in prepregnancy BMI with increasing parity. RESULTS: In 2004, the prevalence of prepregnancy overweight and obesity (BMI >= 25) and obesity alone (BMI >= 30) was 31.9 and 11%, respectively. In 2012, the prevalence had reached 34.2 and 12.8%. The mean BMI increased for every additional parity from 23.80 (95% CI 23.77-23.82) in parity group 1 to 26.70 (26.52-26.90) in parity group 5+. A multiple linear regression adjusted for potential confounders showed that women on average gained 0.62 (0.58-0.65) BMI units after every additional birth. CONCLUSIONS: This study showed a 7.2% increase in overweight and obesity (BMI >= 25) and a 16.4% increase in obesity alone (BMI >= 30) for pregnant women in Denmark from 2004 to 2012. In addition, an increase in interpregnancy BMI was seen at every additional delivery, suggesting that obesity is an increasing challenge in obstetrics. PMID- 29415328 TI - Reflections on traumatic brain injury research in 2018. PMID- 29415329 TI - How to investigate and adjust for selection bias in cohort studies. AB - Longitudinal cohort studies can provide important evidence about preventable causes of disease, but the success relies heavily on the commitment of their participants, both at recruitment and during follow up. Initial participation rates have decreased in recent decades as have willingness to participate in subsequent follow ups. It is important to examine how such selection affects the validity of the results. In this article, we describe the conceptual framework for selection bias due to nonparticipation and loss to follow up in cohort studies, using both a traditional epidemiological approach and directed acyclic graphs. Methods to quantify selection bias are introduced together with analytical strategies to adjust for the bias including controlling for covariates associated with selection, inverse probability weighting and bias analysis. We use several studies conducted in the Danish National Birth Cohort as examples of how to quantify selection bias and also understand the underlying selection mechanisms. Although women who chose to participate in this cohort were typically of higher social status, healthier and with less disease than all those eligible for study, differential selection was modest and the influence of selection bias on several selected exposure-outcome associations was limited. These findings are reassuring and support enrolling a subset of motivated participants who would engage in long-term follow up rather than prioritize representativeness. Some of the presented methods are applicable even with limited data on nonparticipants and those lost to follow up, and can also be applied to other study designs such as case-control studies and surveys. PMID- 29415331 TI - Immunoglobulin G4-related sclerosing oesophagitis in a 9-year-old girl. PMID- 29415330 TI - Maternal supplementation alone with Lactobacillus rhamnosus HN001 during pregnancy and breastfeeding does not reduce infant eczema. AB - BACKGROUND: In a randomized placebo-controlled trial, we previously found that the probiotic Lactobacillus rhamnosus HN001 (HN001) taken by mothers from 35 weeks of gestation until 6 months post-partum if breastfeeding and their child from birth to age 2 years halved the risk of eczema during the first 2 years of life. We aimed to test whether maternal supplementation alone is sufficient to reduce eczema and compare this to our previous study when both the mother and their child were supplemented. METHODS: In this 2-centre, parallel double-blind, randomized placebo-controlled trial, the same probiotic as in our previous study (HN001, 6 * 109 colony-forming units) was taken daily by mothers from 14-16 weeks of gestation till 6 months post-partum if breastfeeding, but was not given directly to the child. Women were recruited from the same study population as the first study, where they or their partner had a history of treated asthma, eczema or hay fever. RESULTS: Women were randomized to HN001 (N = 212) or placebo (N = 211). Maternal-only HN001 supplementation did not significantly reduce the prevalence of eczema, SCORAD >= 10, wheeze or atopic sensitization in the infant by 12 months. This contrasts with the mother and child intervention study, where HN001 was associated with reductions in eczema (hazard ratio (HR): 0.39, 95% CI 0.19-0.79, P = .009) and SCORAD (HR = 0.61, 95% 0.37-1.02). However, differences in the HN001 effect between studies were not significant. HN001 could not be detected in breastmilk from supplemented mothers, and breastmilk TGF-beta/IgA profiles were unchanged. CONCLUSION: Maternal probiotic supplementation without infant supplementation may not be effective for preventing infant eczema. PMID- 29415332 TI - CCL23: a new CC chemokine involved in human brain damage. AB - BACKGROUND: CCL23 role in the inflammatory response after acute brain injuries remains elusive. Here, we evaluated whether CCL23 blood levels associate with acquired cerebral lesions and determined CCL23 predictive capacity for assessing stroke prognosis. We used preclinical models to study the CCL23 homologous chemokines in rodents, CCL9 and CCL6. METHODS: Baseline CCL23 blood levels were determined on 245 individuals, including ischaemic strokes (IS), stroke mimics and controls. Temporal profile of circulating CCL23 was explored from baseline to 24 h in 20 of the IS. In an independent cohort of 120 IS with a 3-month follow up, CCL23 blood levels were included in logistic regression models to predict IS outcome. CCL9/CCL6 cerebral expression was evaluated in rodent models of brain damage. Both chemokines were also profiled in circulation and histologically located on brain following ischaemia. RESULTS: Baseline CCL23 blood levels did not discriminate IS, but permitted an accurate discrimination of patients presenting acute brain lesions (P = 0.003). IS exhibited a continuous increase from baseline to 24 h in circulating CCL23 (P < 0.001). Baseline CCL23 blood levels resulted an independent predictor of IS outcome at hospital discharge (ORadj : 19.702 [1.815-213.918], P = 0.014) and mortality after 3 months (ORadj : 21.47 [3.434-134.221], P = 0.001). In preclinics, expression of rodent chemokines in neurons following cerebral lesions was elevated. CCL9 circulating levels decreased early after ischaemia (P < 0.001), whereas CCL6 did not alter within the first 24 h after ischaemia. CONCLUSIONS: Although preclinical models do not seem suitable to characterize CCL23, it might be a novel promising biomarker for the early diagnosis of cerebral lesions and might facilitate the prediction of stroke patient outcome. PMID- 29415333 TI - CRISPR/Cas9: A tool for immunological research. AB - The CRISPR/Cas9-system was originally identified as part of the adaptive immune system in bacteria and has since been adapted for the genetic manipulation of eukaryotic cells. The technique is of particular value for biomedical sciences, as it enables the genetic manipulation of cell lines and primary cells as well as whole organisms with unprecedented ease and efficiency. Furthermore, the CRISPR/Cas9-technology has the potential for future therapeutic applications in the clinic. Here, we discuss the use of CRISPR/Cas9 for the genetic modification of haematopoietic cells and the generation of mouse models for immunological research. Additionally, we explain how the technique can be applied as a screening-tool to identify genes involved in different immunological processes. Moreover, we will talk about recent extensions of using the CRISPR/Cas9 technology, such as a transcriptional activator or repressor. Finally, we discuss the first clinical trials that use CRISPR/Cas9 and discuss potential future applications. PMID- 29415334 TI - High-throughput, non-invasive prenatal testing for fetal Rhesus D genotype to guide antenatal prophylaxis with anti-D immunoglobulin: a cost-effectiveness analysis. AB - OBJECTIVE: To evaluate the cost-effectiveness of high-throughput, non-invasive prenatal testing (HT-NIPT) for fetal Rhesus D (RhD) genotype to guide antenatal prophylaxis with anti-D immunoglobulin compared with routine antenatal anti-D immunoglobulin prophylaxis (RAADP). DESIGN: Cost-effectiveness decision-analytic modelling. SETTING: Primary care. PARTICIPANTS: A simulated population of 100 000 RhD-negative women not known to be sensitised to the RhD antigen. METHODS: A decision tree model was used to characterise the antenatal care pathway in England and the long-term consequences of sensitisation events. The diagnostic accuracy of HT-NIPT was derived from a systematic review and bivariate meta analysis; estimates of other inputs were derived from relevant literature sources and databases. Women in whom the HT-NIPT was positive or inconclusive continued to receive RAADP, whereas women with a negative result received none. Five alternative strategies in which the use of HT-NIPT may affect the existing postpartum care pathway were considered. MAIN OUTCOME MEASURES: Costs expressed in 2015GBP and impact on health outcomes expressed in terms of quality-adjusted life-years over a lifetime. RESULTS: The results suggested that HT-NIPT appears cost saving but also less effective than current practice, irrespective of the postpartum strategy evaluated. A postpartum strategy in which inconclusive test results are distinguished from positive results performed best. HT-NIPT is only cost-effective when the overall test cost is L26.60 or less. CONCLUSIONS: HT-NIPT would reduce unnecessary treatment with routine anti-D immunoglobulin and is cost saving when compared with current practice. The extent of any savings and cost effectiveness is sensitive to the overall test cost. TWEETABLE ABSTRACT: HT-NIPT is cost saving compared with providing anti-D to all RhD-negative pregnant women. PMID- 29415335 TI - High density of M2-macrophages in acral lentiginous melanoma compared to superficial spreading melanoma. AB - AIMS: Acral lentiginous melanoma (ALM) is the most common type of melanoma in people with darker skin phototypes. There is some evidence that the aetiology, pathogenesis, risk factors and natural history of ALM differ from those of superficial spreading melanoma (SSM). ALM behaves more aggressively than SSM, but the biological explanation for these differences remains unknown. The presence of one subtype of macrophages, termed M2-macrophage (M2-M), has been found to be related to local progression, metastasis and poor prognosis in several neoplasms. The aim of this study was to compare the density of M2-Ms in ALMs versus SSMs, and to examine whether or not the density of M2-Ms is associated with histopathological features predictive of adverse prognosis in cutaneous melanoma (CM), as well as development of metastasis. METHODS AND RESULTS: Sixty-seven ALMs and 67 SSMs cases were analysed. The tumours were classified according to thickness, ulceration, mitosis and metastasis. M2-M quantity was evaluated using immunohistochemistry with anti-CD163 and anti-CD206 antibodies. M2-Ms were increased in ALM compared with SSM, and were related to the histopathological features predictive of adverse prognosis in CM, such as thickness > 1.0 mm, ulceration and mitotic activity, and the development of metastasis. CONCLUSIONS: Our study is the first, to our knowledge, to demonstrate the increased presence of M2-Ms in ALM compared with SSM. Our findings suggest that the increased M2-Ms in ALM are associated with the main histopathological features predictive of adverse prognosis in CM, as well as the presence of metastasis, and that these cells can be related to the aggressive behaviour seen in ALMs. PMID- 29415336 TI - Synthesis and evaluation of pyridinium-hydrazone derivatives as potential antitumoral agents. AB - The hydrazones of 4-hydrazinylpyridinium bearing alkylphenyl groups on pyridinium nitrogen were synthesized and evaluated for their cytotoxic activity against MCF 7, PC3, U2OS, and HEK293 cell lines by Wst1 cell proliferation assay. Cytotoxic activity results indicated that d derivatives having butylene chain; 4 and 5 series having naphthalene and anthracene ring systems showed high cytotoxic activity (IC50 = 3.27-8.54 MUm) on cancer cells. 3d (4-(2-(4 hydroxybenzylidene)hydrazinyl)-1-(4-phenylbutyl)pyridinium bromide) was the most cytotoxic compound with IC50 value of 3.27 MUm against MCF-7. The most active derivatives (1d, 2d, 3d, 4, and 5 series) were selected to investigate for the effects on autophagy by analyzing the expression of autophagy marker proteins. The conversion of LC3-I to its lipidated form LC3-II is essential for autophagy and related to autophagosomes. According to our results, all tested compounds except for 3d induced lipidated form LC3-II accumulation. Then, the effects of the compounds on p62 protein level were also analyzed by the immunoblotting as the autophagy inhibition results in accumulation of p62. Further molecular mechanistic studies including morphological analysis and live-death assays indicated that all tested compounds (1d, 2d, 3d, 4, and 5 series) are potent antitumoral molecules and all except for 3d have potential to inhibit autophagic flux. PMID- 29415337 TI - Host response genes associated with nodular gastritis in Helicobacter pylori infection. AB - BACKGROUND: Chronic Helicobacter pylori infection in children induces lymphoid hyperplasia called nodular gastritis (NG) at the antral gastric mucosa. The aim of this study was to evaluate genes in gastric biopsy on microarray analysis, to identify molecules associated with NG on comparison with NG-negative pediatric corpus tissue and with H. pylori-infected adult tissue with atrophic gastritis (AG). METHODS: Eight pediatric and six adult H. pylori-infected patients, as well as six pediatric and six adult uninfected patients were evaluated. All infected adults had AG. NG was observed in the antrum of all eight pediatric patients and in the corpus of three patients. Adult and uninfected patients were free of NG; that is, only pediatric H. pylori-infected patients had NG. Total RNA was purified from gastric biopsy, and microarray analysis was performed to compare gene expression between groups. The three infected children with NG in both the antrum and corpus were excluded from analysis of corpus samples. RESULTS: The number of genes significantly up- or downregulated (fold change >3, P < 0.01) compared with uninfected controls varied widely: 72 in pediatric antrum, 45 in pediatric corpus, 103 in adult antrum and 71 in adult corpus. Nineteen genes had significantly altered expression in the antrum of NG tissue compared with NG negative pediatric corpus tissue and adult AG tissue. The CD20 B-cell specific differentiation antigen had the most pronounced increase. Previously described regulators of NG development were not predominantly upregulated in the NG mucosa. CONCLUSIONS: CD20 overexpression may play an important role in lymphoid follicle enlargement and NG. PMID- 29415339 TI - Silver-109-based laser desorption/ionization mass spectrometry method for detection and quantification of amino acids. AB - A new methodology applicable for both high-resolution laser desorption/ionization mass spectrometry and mass spectrometry imaging of amino acids is presented. The matrix-assisted laser desorption ionization-type target containing monoisotopic cationic 109 Ag nanoparticles (109 AgNPs) was used for rapid mass spectrometry measurements of 11 amino acids of different chemical properties. Amino acids were directly tested in 100,000-fold concentration change conditions ranging from 100 MUg/mL to 1 ng/mL which equates to 50 ng to 500 fg of amino acid per measurement spot. Limit of detection values obtained suggest that presented method/target system is among the fastest and most sensitive ones in laser mass spectrometry. Mass spectrometry imaging of spots of human blood plasma spiked with amino acids showed their surface distribution allowing optimization of quantitative measurements. PMID- 29415338 TI - A statewide program providing colorectal cancer screening to the uninsured of South Carolina. AB - BACKGROUND: Cancer screening rates are lowest in those without insurance or a regular provider. Since 2008, the Colorectal Cancer Prevention Network (CCPN) has provided open access colonoscopy to uninsured residents of South Carolina through established, statewide partnerships and patient navigation. Herein, we describe the structure, implementation, and clinical outcomes of this program. METHODS: The CCPN provides access to colonoscopy screening at no cost to uninsured, asymptomatic patients aged 50-64 years (African Americans age 45-64 years are eligible) who live at or below 150% of the poverty line and seek medical care in free medical clinics, federally qualified health centers, or hospital-based indigent practices in South Carolina. Screening is performed by board-certified gastroenterologists. Descriptive statistics and regression analysis are used to describe the population screened, and to assess compliance rates and colonoscopy quality metrics. RESULTS: Out of >4000 patients referred to the program, 1854 were deemed eligible, 1144 attended an in-person navigation visit, and 1030 completed a colonoscopy; 909 were included in the final sample. Nearly 90% of participants exhibited good-to-excellent bowel preparation. An overall cecal intubation rate of 99% was measured. The polyp detection rate and adenoma detection rate were 63% and 36%, respectively, with male sex and urban residence positively associated with adenoma detection. Over 13% of participants had an advanced polyp, and 1% had a cancer diagnosis or surgical intervention. CONCLUSION: The CCPN program is characterized by strong collaboration with clinicians statewide, low no-show rates, and high colonoscopy quality. Future work will assess the effectiveness of the navigation approach and will explore the mechanisms driving higher adenoma detection in urban participants. Cancer 2018;124:1912-20. (c) 2018 American Cancer Society. PMID- 29415340 TI - Comparing anadromous brown trout Salmo trutta in small, neighbouring catchments across contrasting landscapes: What is the role of environment in determining life-history characteristics? AB - Study of anadromous brown trout Salmo trutta in Orkney, U.K., burns (small streams) with a common-garden sea in Scapa Flow supports the key role of nutrient availability in fresh water, independent of day length, as a determinant of smolt age, with a systematic increase in mean smolt age from 1 to 3 years related inversely to productivity. Whole catchment (8 km2 ) population budgets indicated annual smolt production of around 650 individuals from approximately 100 spawners. Egg-to-smolt survival was 0.65%, while marine survival was estimated from mark-recapture to be between 3.5 and 10%. The question of B-type growth (accelerated growth immediately prior to or during smolt migration) was also addressed, with a strong negative correlation between B-type growth and size at end of winter suggesting that this represents a freshwater compensatory growth response. The data obtained indicate the potential importance of small catchments for supporting anadromous Salmo trutta populations and suggest that small runs of spawners (<100 individuals) are adequate to maintain stocks in such situations. Furthermore, they support the key role of freshwater productivity in determining life-history characteristics over small spatial scales, with Orkney providing a useful natural laboratory for future research into metapopulation genetic structuring and environmental factors at a tractable scale. PMID- 29415341 TI - Clinical characteristics affecting length of stay in patients with cellulitis. AB - BACKGROUND: This study aimed to profile the clinical characteristics of patients presenting to Middlemore Hospital with cellulitis in order to identify factors that are associated with an increased length of stay (LOS). METHODS: Retrospective clinical data were collected for all patients aged 18 and above who were admitted with cellulitis to Middlemore Hospital General Surgical Department between 1 January and 31 March 2014. Comorbidities, laboratory results and medical conditions were included in the investigation. RESULTS: The study included 201 patients. Significant factors associated with increased LOS include type 2 diabetes mellitus (P < 0.012), obesity (P < 0.001), raised C-reactive protein (P < 0.0001), raised white cell count (P < 0.0001), raised temperature (P < 0.0001), septic shock (P < 0.003), multiorgan failure (P < 0.01), extended spectrum beta-lactamases or methicillin-resistant Staphylococcus aureus colonization (P < 0.04) and intensive care unit admission (P < 0.0004). CONCLUSION: This single-centre, retrospective clinical study has identified several factors that are significantly associated with an increased LOS. These factors provide a basis for future studies that may facilitate identification and timely medical optimization of high-risk patients. PMID- 29415342 TI - The clock-drawing test: normative data in adult and elderly Israeli Arabs. AB - AIM: Despite the widespread use of the clock-drawing test (CDT), normative data and information regarding the influence of sociodemographic factors on test performance by adult and elderly Israeli Arabs are lacking. The current study aimed to establish normative data for this population group by exploring the impact of sociodemographic factors such as age, education, and gender on CDT performance. In addition, this study examined the association between CDT performance and Mini-Mental State Examination (MMSE) scores. METHODS: The sample consisted of 295 community-dwelling healthy adult and elderly Israeli Arabs, aged 20-86 years, with a MMSE score >=24. The MMSE and the CDT were administered to participants. RESULTS: Statistical analyses revealed that age had a negative effect on CDT performance, which was most pronounced in the 60-86 age group, but education and occupation (academic vs non-academic) had a positive effect. Gender and place of residence (urban vs rural) had no effect. CDT performance predicted the MMSE score. CONCLUSIONS: The present study provides preliminary normative data on adult and elderly Israeli Arabs. The CDT appears to be applicable to Israeli Arabs, while the normative data might help interpret cognitive function results in this population. PMID- 29415343 TI - Picking the winners: Outcome prediction in pleural disease. PMID- 29415344 TI - Texture analysis of T1-w and T2-w MR images allows a quantitative evaluation of radiation-induced changes of internal obturator muscles after radiotherapy for prostate cancer. AB - PURPOSE: To investigate the potential of texture analysis applied on T2-w and postcontrast T1-w images acquired before radiotherapy for prostate cancer (PCa) and 12 months after its completion in quantitatively characterizing local radiation effect on the muscular component of internal obturators, as organs potentially involved in urinary toxicity. METHODS: T2-w and postcontrast T1-w MR images were acquired at 1.5 T before treatment (MRI1) and at 12 months of follow up (MRI2) in 13 patients treated with radiotherapy for PCa. Right and left internal obturator muscle contours were manually delineated upon MRI1 and then automatically propagated on MRI2 by an elastic registration method. Planning CT images were coregistered to both MRIs and dose maps were deformed accordingly. A high-dose region receiving >55 Gy and a low-dose region receiving <55 Gy were identified in each muscle volume. Eighteen textural features were extracted from each region of interest and differences between MRI1 and MRI2 were evaluated. RESULTS: A signal increase was highlighted in both T2-w and T1-w images in the portion of the obturators near the prostate, i.e., in the region receiving medium high doses. A change in the spatial organization was identified, as an increase in homogeneity and a decrease in contrast and complexity, compatible with an inflammatory status. In particular, the region receiving medium-high doses presented more significant or, at least, stronger differences. CONCLUSIONS: Texture analysis applied on T1-w and T2-w MR images has demonstrated its ability in quantitative evaluating radiation-induced changes in obturator muscles after PCa radiotherapy. PMID- 29415345 TI - James Augustus McCloskey (1936-2017). PMID- 29415346 TI - Audit of 117 otoplasties for prominent ear by one surgeon using a cartilage cutting procedure. AB - BACKGROUND: The plethora of surgical procedures for prominent ear correction reflects lack of satisfaction with outcomes achieved. This paper describes a cartilage-cutting otoplasty procedure and reports an audit of its outcomes. METHODS: Discharge coding was used to retrospectively identify patients who had undergone the otoplasty of interest at Middlemore Hospital, Auckland, during the 5 years from March 2010 to the end of February 2015. Hospital records were accessed. Demographic, procedure and patient satisfaction data were recorded and analysed (PASW/SPSS Statistics 18.0). Chi-square test and t-test were used to assess associations, with significance accepted at two-sided P < 0.05. RESULTS: Sixty-four patients underwent the specified otoplasty (54.7% females: mean age 9.5 years (standard deviation, SD: 4.2; range: 4-20)), of whom 93.8% had bilateral procedures with mean surgical time of 61 min (SD: 14; range: 34-94). This was significantly shorter (P < 0.001) than for bilateral surgeries by all other techniques and surgeons in the review period. None of the 117 procedures of interest subsequently had suture extrusion or revision surgery. Mean time from surgery to satisfaction determination was 993 days (SD: 521; range: 111-1850) for 43 (67.2%) patients. 23.3% believed that there had been aesthetically insignificant partial recurrence of prominence, typically of one ear only. This was insufficient for all but one patient to consider repeat otoplasty. Surgery outcome was rated 'very satisfactory' and 'satisfactory' by 90.7% and 9.3% of patients/parents, respectively. All would recommend the surgery to others. CONCLUSION: With infrequent complications and recurrence requiring revision, and without long-term reliance on sutures, the otoplasty reported is time-efficient, safe and generates high patient satisfaction. PMID- 29415348 TI - Corrigendum. PMID- 29415347 TI - Lipid metabolism and functional assessment of discarded human livers with steatosis undergoing 24 hours of normothermic machine perfusion. PMID- 29415349 TI - Management of neurosyphilis: time for a new approach? AB - Given the long term sequelae of untreated neurosyphilis and insensitive tests to detect treponemes in the cerebrospinal fluid, questions regarding the utility of a lumbar puncture and cerebrospinal fluid analysis either to confirm or exclude neurosyphilis are raised. PMID- 29415350 TI - Lipid-lowering therapy use and achievement of cholesterol targets in an Australian diabetes clinic. AB - We documented temporal changes in the use of lipid-lowering medications and achievement of cholesterol targets in an Australian diabetes clinic. The number of patients using lipid-lowering therapy for primary or secondary cardiovascular prevention increased from 6 to 69% between 1993-1995 and 2014-2016, which corresponded to a decrease in low-density lipoprotein cholesterol levels from 3.7 to 2.4 mmol/L (P < 0.01). PMID- 29415351 TI - Considerations for pre-transfusion immunohaematology testing in patients receiving the anti-CD38 monoclonal antibody daratumumab for the treatment of multiple myeloma. AB - In recent years, the anti-CD38 monoclonal antibody daratumumab (Darzalex; Janssen Cilag Pty Ltd) has been shown to be highly efficacious in relapsed and refractory multiple myeloma, with the final results of treatment in newly diagnosed patients awaited. Despite awareness of the potential interference of daratumumab in pre transfusion immunohaematology testing during phase I and II clinical studies, there was a degree of unpreparedness in the community upon the introduction of this drug into the clinics, particularly the impact that it has on the operational processes in hospital transfusion laboratories and timely issue of red blood cells (RBCs). Anti-CD38 interference in pre-transfusion immunohaematology tests is a particular problem in patients being treated with daratumumab for multiple myeloma as many will require RBC transfusions during their disease treatment. Panagglutination caused by anti-CD38 monoclonal antibody during the indirect antiglobulin test may mask the presence of a clinically significant RBC alloantibody in the patient's plasma during the antibody screen and identification process, which may be overlooked, particularly in urgent situations, subsequently resulting in a delayed or acute haemolytic transfusion reaction. Here, we summarise daratumumab's effects on pre-transfusion immunohaematology testing and its impact on clinical practice and make practical recommendations based on a consensus from medical and scientific transfusion experts and myeloma specialists on behalf of the Australian and New Zealand Society of Blood Transfusion and Myeloma Scientific Advisory Group to Myeloma Australia, respectively. PMID- 29415352 TI - Starting beta-blockers during exacerbations of chronic obstructive pulmonary disease. PMID- 29415353 TI - Clinical need for standardised multidisciplinary meeting assessment processes. PMID- 29415354 TI - Climate change: allergens and allergic diseases. AB - Climate change has been described as the biggest global health threat of the 21st century. The atmospheric concentrations of greenhouse gases, such as carbon dioxide, methane and nitrous oxide, have increased significantly since the start of the Industrial Era around 1750, with much of this increase occurring over just the last 50 years or so. This is resulting in warming of the climate system as well as changes in precipitation and weather and climate extremes. These changes in climate are having wide-ranging impacts on the Earth's physical, biological and human systems, including human health. It is these impacts of climate change on human health that are the focus of this paper, particularly the impacts on allergens and allergic diseases. Such impacts are particularly significant in many countries where the prevalence of such diseases is high and/or increasing. There is now compelling evidence that rising air temperatures and carbon dioxide concentrations are, in some plant species, resulting in increased pollen production and allergenicity and advancement and lengthening of the pollen season. Changes in extreme events, such as thunderstorms and tropical cyclones, will also have impacts on allergic diseases, with, for example, the flooding associated with tropical cyclones leading to proliferation of mould growth in damp homes. The article also considers a range of responses to these health threats, including greenhouse gas mitigation, and adaptation strategies, such as enhanced environmental monitoring and health surveillance and adequate planning for the future medical workforce. PMID- 29415355 TI - Iron polymaltose infusion therapy during pregnancy. PMID- 29415356 TI - What we know and do not know about women and kidney diseases: questions unanswered and answers unquestioned: reflection on World Kidney Day and International Women's Day. PMID- 29415357 TI - High urinary interleukin-8 levels is associated with poor prognosis in idiopathic membranous nephropathy. AB - Biomarkers required to assess accurately the prognosis of idiopathic membranous nephropathy (IMN) are still unavailable. A retrospective study on 156 IMN patients showed only urinary IL-8 was associated with the achievement of initial complete remission (CR) in IMN patients. A urinary IL-8 level of less than 61.25 pg/mL was more sensitive for prediction of CR in IMN patients. Therefore, urinary IL-8 may be a potential biomarker for evaluating short-term prognosis of IMN patients. PMID- 29415358 TI - Role of radiotherapy in management of gingival infiltration of chronic myelomonocytic leukaemia. PMID- 29415359 TI - Author reply. PMID- 29415360 TI - Metformin-induced encephalopathy: the role of thiamine. AB - A case of metformin encephalopathy is presented in a patient on haemodialysis for end-stage diabetic renal failure. The patient presented with frequent falls and clinical signs of Parkinsonism, on a background of recent anorexia and significant weight loss. Magnetic resonance imaging showed bilateral, symmetrical abnormalities centred on the lentiform nuclei. Metformin was withheld and signs and symptoms quickly resolved. We hypothesise that metformin may cause thiamine deficiency in patients with end-stage renal failure resulting in a specific metabolic encephalopathy. PMID- 29415361 TI - Boerhaave syndrome: a common manifestation of a rare disease. PMID- 29415362 TI - Author reply. PMID- 29415363 TI - Encephaloclastic cyst: a rare complication of a malfunctioning methotrexate Ommaya reservoir. PMID- 29415364 TI - Assessment of potential opioid toxicity and response to naloxone by rapid response teams at an urban Melbourne hospital. AB - Opioid prescriptions have significantly increased in recent years and are used for a wide variety of indications. Electronic medical records of 45 patients who received naloxone by a rapid response team over an 18-month period were retrospectively reviewed. This study found inconsistencies in the management of possible opioid toxicity with variation in the total naloxone dose and number of doses administered. This highlights the importance of a standardised protocol for recognition and management of opioid overdose. PMID- 29415365 TI - Benefit of routine testicular examination: hypogonadism in a person with 47XYY. PMID- 29415366 TI - Time of administration of treatment for hypertension in renal patients. PMID- 29415367 TI - Uterine colorectal metastatic disease: a rare occurrence. PMID- 29415368 TI - A control for the day-to-day normalization of the flow cytometry gamma-H2AX assay for clinical routine. AB - BACKGROUND: The phosphorylation of histone H2AX (gamma-H2AX) at the DNA double strand break (DSB) site is frequently used for quantifying DSBs and may be useful as a biomarker for clinical applications. We have previously reported a flow cytometry-based quantification of gamma-H2AX for clinical routine. One major challenge, however, is the lack of a control sample for normalization of the day to-day variation of the flow cytometry gamma-H2AX assay. METHODS: Here, we report development of a mix-control sample containing peripheral blood mononuclear cells (PBMC) from 10 control individuals, for normalization of day-to-day variation of the flow cytometry-gamma-H2AX assay. RESULTS: We showed that control individuals sampled on different days show an average day-to-day variation (CV) of 34%, which was reduced to 12% after normalization to the control sample. The normalization allowed detection of radiosensitivity of lymphoblastoid cell lines from ataxia telangiectasia patients, sampled over three days. CONCLUSION: The mix-control sample, consisting of 10 control individuals' PBMC, can be used as a control sample to normalize for day-to-day variation of the gamma-H2AX assay. The use of this sample will facilitate integration of the gamma-H2AX assay into clinical routine. (c) 2018 International Clinical Cytometry Society. PMID- 29415369 TI - Surgery of giant right coronary artery aneurysm complicated with coronary artery fistula to left ventricle. PMID- 29415370 TI - Screening for pulmonary hypertension in interstitial lung disease: Many reasons to ECHO! PMID- 29415371 TI - Effectiveness of the polysaccharide hemostatic powder in non-variceal upper gastrointestinal bleeding: Using propensity score matching. AB - BACKGROUND AND AIM: Recently, the application of hemostatic powder to the bleeding site has been used to treat active upper gastrointestinal bleeding (UGIB). We aimed to assess the effectiveness of the polysaccharide hemostatic powder (PHP) in patients with non-variceal UGIB. METHODS: We reviewed prospectively collected 40 patients with UGIB treated with PHP therapy between April 2016 and January 2017 (PHP group) and 303 patients with UGIB treated with conventional therapy between April 2012 and October 2014 (conventional therapy group). We compared the rate of successful hemostasis and the rebleeding between the two groups after as well as before propensity score matching using the Glasgow-Blatchford score and Forrest classification. RESULTS: Thirty patients treated with the PHP and 60 patients treated with conventional therapy were included in the matched groups. Baseline patient characteristics including comorbidities, vital signs, and bleeding scores were similar in the matched groups. The rate of immediate hemostasis and 7-day and 30-day rebleeding were also similar in the two groups before and after matching. In the subgroup analysis, no significant differences in immediate hemostasis or rebleeding rate were noted between PHP in monotherapy and PHP combined with a conventional hemostatic method. At 30 days after the therapy, there were no significant PHP related complications or mortality. CONCLUSIONS: Given its safety, the PHP proved feasible for endoscopic treatment of UGIB, having similar effectiveness as that of conventional therapy. The PHP may become a promising hemostatic method for non variceal UGIB. PMID- 29415372 TI - One-stage replacement of the aorta from arch to thoracoabdominal region. AB - OBJECTIVES: We present our experience with one-stage replacement of thoracic aneurysm from the ascending aorta to the thoracoabdominal aorta. PATIENTS AND METHODS: Fourteen patients (10 male and 4 female; mean age 53.6 +/- 12.4 years) with extended thoracic aortic aneurysms underwent graft replacement. The pathology of the diseased aorta was chronic aortic dissection in 13 patients and intraoperative retrograde aortic dissection in 1 patient. Five patients had Marfan syndrome. In a previous operation, 1 patient had undergone the Bentall procedure, 4 had hemiarch replacement for acute type A dissection, and 1 had a Y graft for abdominal aortic aneurysm. The approach to the aneurysm was posterolateral thoracotomy with rib-cross incision extended to the retroperitoneal abdominal aorta. Arterial inflow for cardiopulmonary bypass consisted of the femoral artery in 13 patients and abdominal aortic aneurysm graft in 2. Venous drainage site was the femoral vein in 7, femoral vein and pulmonary artery in 3, and pulmonary artery in 1. All patients had antegrade cerebral perfusion and visceral perfusion. RESULTS: Hospital mortality occurred in 1 patient due to acute myocardial infarction. Actuarial survival at 5 years after the operations was 96.5 +/- 9.8%. Freedom from the subsequent aortic events was 91.0 +/- 2.9% at 5 years. CONCLUSIONS: Our treatment method for extensive thoracic aneurysm, from the ascending aorta to the thoracoabdominal aorta, achieved satisfactory results via the use of specific strategies and appropriate organ protection according to the aneurysm extension in the selected patients. PMID- 29415373 TI - Beware, cardiovascular surgeons! Dangerous plaque has been sighted in your operative field. PMID- 29415374 TI - Noncoronary sinus replacement in bicuspid valve: The other fate? PMID- 29415375 TI - Management of the moderately dilated sinus of Valsalva: To cut or not to cut? PMID- 29415376 TI - Partial root repair: Paths to a middle ground. PMID- 29415377 TI - Understanding why are we doing what we are doing. PMID- 29415378 TI - Total arch replacement for repair of porcelain aorta. PMID- 29415379 TI - Response to: Total arch replacement for repair of porcelain aorta. PMID- 29415380 TI - Cardiac surgery in patients with a porcelain aorta. PMID- 29415381 TI - Early and mid-term results of autograft rescue by Ross reversal: A one-valve disease need not become a two-valve disease. AB - OBJECTIVES: Risk of reoperation and loss of a second native valve are major drawbacks of the Ross operation. Rather than discarding the failed autograft, it can be placed back into the native pulmonary position by "Ross reversal." We review our early and mid-term results with this operation. METHODS: From 2006 to 2017, 39 patients underwent reoperation for autograft dysfunction. The autograft was successfully rescued in 35 patients: by Ross reversal in 30, David procedure in 4, and autograft repair in 1. Medical records were reviewed for patient characteristics (mean age was 46 +/- 13 years, range 18-67 years, and 23 were male), previous operations, indications for reoperation, hospital outcomes, and echocardiographic findings for the 30 patients undergoing successful Ross reversal. Follow-up was 4.1 +/- 3.5 years (range 7 months-11 years). RESULTS: Median interval between the original Ross procedure and Ross reversal was 12 years (range 5-19 years). Eight patients also had absolute indications for replacement of the pulmonary allograft. There was no operative mortality. One patient required reoperation for bleeding. Another had an abdominal aorta injury from use of an endoballoon clamp. There was no other major postoperative morbidity, and median postoperative hospital stay was 7.2 days (range 4-41 days). No patient required reoperation during follow-up. Twenty-four patients had acceptable pulmonary valve function, and 6 had clinically well-tolerated moderate or severe pulmonary regurgitation. CONCLUSIONS: Ross reversal can be performed with low morbidity and acceptable pulmonary valve function, reducing patient risk of losing 2 native valves when the autograft fails in the aortic position. PMID- 29415383 TI - Respect versus resect: Two different repair techniques or two different tools in the toolbox? PMID- 29415384 TI - Mitral valve repair with resection versus neochordae: A call for high-quality evidence. PMID- 29415382 TI - One-year outcomes after rapid-deployment aortic valve replacement. AB - OBJECTIVE: The goals of rapid-deployment aortic valve replacement include facilitation of minimally invasive surgery and reduced aortic crossclamp time. We report the short-term outcomes of a series of 493 patients undergoing rapid deployment aortic valve replacement with the EDWARDS INTUITY valve system (Edwards Lifesciences, LLC, Irvine, Calif). METHODS: Assessing Standard oF Care and Clinical Outcomes UsiNg the EDWARDS INTUITY VAlve SysTem in a European multI center, Active, pOst-market surveillaNce Study was a prospective, multicenter (n = 26) European registry designed to evaluate the safety and performance of the valve system. During rapid-deployment aortic valve replacement, device technical success and crossclamp time were assessed. Procedural outcomes, hemodynamic performance, and various adverse events and clinical outcomes were evaluated up to 2 years. RESULTS: Between 2012 and 2014, 493 of 517 enrolled patients successfully received implants with the study valve (95.4% technical success). Mean crossclamp times for 163 full sternotomies, 128 mini-upper sternotomies, and 36 right anterior thoracotomies isolated aortic valve replacements were 47.3, 52.0, and 73.3 minutes, respectively. Mean follow-up was 1.8 years, with 870 total patient-years of follow-up. Mean effective orifice area increased from 0.72 (baseline) to 1.88 cm2, and mean pressure gradient decreased from 47.6 to 9.6 mm Hg (1 year). Mean effective orifice area index increased (0.39-1.01 cm2/m2), and 28 of 287 patients (9.8%) exhibited severe prosthesis-patient mismatch at 1 year. After 1 year, 68.1% and 21.7% of patients were in New York Heart Association class I and II, respectively. Freedom from death, major bleeding, major perivalvular leak, reoperation, and device explant at 1 year were 0.935, 0.939, 0.976, 0.975, and 0.983, respectively. CONCLUSIONS: These results demonstrate commendable safety and performance of the test valve system over the short term in a broad European setting. PMID- 29415385 TI - Revisiting posterior mitral leaflet prolapse: Resect, respect, or resect with respect? PMID- 29415386 TI - Euler's elastica-based biomechanical assessment for neochordal insertion in the treatment of degenerative mitral valve repair. PMID- 29415387 TI - Is individualized mitral valve repair in the future? PMID- 29415388 TI - Patient-specific computational biomechanical modeling to guide mitral valve repair strategy: Practicality and value? PMID- 29415389 TI - Deactivation without explantation of a durable left ventricular assist device: A durable solution? PMID- 29415390 TI - Chasing the 6-sigma: Drawing lessons from the cockpit culture. PMID- 29415391 TI - Cockpit culture: Avoiding the crash and burn. PMID- 29415392 TI - A mind is like a parachute. PMID- 29415393 TI - Medical operability and inoperability drive survival in retrospective analyses comparing surgery and SBRT for early-stage lung cancer. PMID- 29415395 TI - AATS Aortic Symposium 2018. PMID- 29415394 TI - When in doubt, abstain. PMID- 29415396 TI - AATS Mechanical Circulatory Support Symposium: 21st Century State-of-the-Art Treatment of Advanced Heart and Lung Failure. PMID- 29415397 TI - AATS 98th Annual Meeting. PMID- 29415398 TI - AATS Clinical Trials Methods Course. PMID- 29415399 TI - AATS Surgical Patient Safety Course 2018. PMID- 29415400 TI - 2018 Donald B. Doty Education Award. PMID- 29415401 TI - WTSA 44th Annual Meeting Call for Abstracts. PMID- 29415402 TI - AATS Foundation. PMID- 29415403 TI - Applications for Membership. PMID- 29415405 TI - ABTS Requirements for the 10-Year Milestone for Maintenance of Certification. PMID- 29415404 TI - ABTS Announcement. PMID- 29415406 TI - Editors. PMID- 29415407 TI - Recent Papers in the Seminars and Op Techs. PMID- 29415408 TI - Angelica sinensis polysaccharide protects against acetaminophen-induced acute liver injury and cell death by suppressing oxidative stress and hepatic apoptosis in vivo and in vitro. AB - Acetaminophen (APAP)-induced hepatic damage is prevalent in western countries. The present study aimed to investigate the hepatoprotective effects of Angelica sinensis polysaccharide (ASP), an active constituent derived from a water extract of Angelica sinensis, in rats exposed to an APAP overdose. The mechanisms underlying the activity of this compound were also considered. Specifically, serum and hepatic biochemical parameters including alanine aminotransferase (ALT), aspartate transaminase (AST), glutathione (GSH), malondialdehyde (MDA) and superoxide dismutase (SOD) were evaluated, and key proteins involved in hepatic apoptosis, including cleaved caspase-3, Bax and Bcl-2 were quantified. In vivo, H&E staining reveals that ASP reduces the degeneration of hepatocytes and the amount of cytoplasmic vacuolation in rats exposed to an overdose of APAP. ASP markedly alleviated liver injury via an increase in GSH levels and the inhibition of hepatic apoptosis. In vitro, ASP significantly elevated the survival rate of rat primary hepatocytes exposed to an overdose of APAP. The beneficial effect might be, at least in part, due to the amelioration of lipid peroxidation and oxidative stress, along with the inhibition of apoptosis. Taken together, our findings reveal that ASP has potential to be used as a hepatoprotective agent for the management of APAP-induced liver injury. PMID- 29415409 TI - Antibacterial and lead ions adsorption characteristics of chitosan-manganese dioxide bionanocomposite. AB - In the current study, a facile and an eco-friendly manganese oxide nanoparticles dispersed in chitosan (CS-MnO2) nanocomposite was synthesized. A chemical precipitation method was used for the product synthesis. The product characterization was performed using various spectroscopic techniques such as X ray scattering, scanning electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis and zeta potential which confirmed its successful formation. The CS-MnO2 nanocomposite was evaluated in the Pb2+ ions adsorption from it aqueous solution. The CS-MnO2 showed an approvable accomplishment for the removal of Pb2+ ions and evidence was provided from the adsorption experiments. The efficiency of adsorbent did not change much even after 5 cycles of reuse. Therefore, CS-MnO2 would serve as promising adsorbent. Additionally, the CS-MnO2 nanocomposite showed low to moderate antibacterial efficacy against Escherichia coli and Staphylococcus aureus by inhibiting nearly 50% of the bacterial growth. Colony forming units method was used in the antibacterial studies which showed that the bio-nanocomposite had moderate antibacterial activity against the stated strains of bacteria. PMID- 29415410 TI - Functional role of Kv1.1 and Kv1.3 channels in the neoplastic progression steps of three cancer cell lines, elucidated by scorpion peptides. AB - Voltage-gated potassium (Kv) channels are known to play a pivotal role in the progression of various cancer types and considered as new targets for designing anti-cancer therapy. However, the fact that many Kv channels are expressed in different cell lines makes it difficult to ascribe a functional role for a given Kv channel on a specific aspect of the tumorogenesis. In this work, we showed that although both Kv1.1 and Kv1.3 channels are expressed in U87 (glioblastoma), MDA-MB-231 (breast cancer) and LS174 (colon adenocarcinoma) cells, these respond differently to KAaH1 or KAaH2, two homologous Kv1 blockers from scorpion venom. KAaH1 is active on Kv1.1 and Kv1.3 and was found to inhibit migration and adhesion of U87 cells whereas KAaH2 which is slightly active only on Kv1.1 channel, inhibits their proliferation via the EGFR signaling pathway. The correlation between the electro-physiological activity of the scorpion peptides and their anti-migratory effects suggests the involvement of the Kv1.1 and Kv1.3 channels in the mobility of the three cancer cell lines. Our results showed that besides they can elucidate the implication of Kv1.1 and Kv1.3 channels in molecular mechanisms of neoplastic progression, KAaH1 and KAaH2 may be used as therapeutic tools against glioblastoma. PMID- 29415411 TI - A new cold-adapted, alkali-stable and highly salt-tolerant esterase from Bacillus licheniformis. AB - Bacterial esterases and lipases, especially extremozymes attract increasing attention due to various advantages both in good properties and wide applications. In the present study, a cold-adapted, alkali-stable and highly salt tolerant esterase (Est700) was cloned from Bacillus licheniformis, expressed and purified with a molecular mass of 25 kDa. The optimal temperature of Est700 was 30 degrees C, with 35% maximal activity retaining at 0 degrees C. Its optimal pH was 8.0 and showed high stability at pH 5.0-11.0. Noticeably, Est700 was highly activated by 3.5 M NaCl and the extent of this activation is much stronger than that of currently reported halophilic ones. It was also stable in 5 M NaCl with no activity loss. High salt concentrations changed the secondary structure and folding properties of Est700 with formation of more alpha-helix and less beta sheet domains. With salt incubation, its melting temperature was estimated to be 57.2 degrees C, which is 12.8 degrees C higher than that of native one. Interestingly, Est700 lacks the acidic surface that is considered essential for enzyme stability at high salinity. However, it has a mainly positive surface electrostatic potential, which is probably different from most reported halotolerant esterases. These multiple properties make Est700 a valuable candidate in both basic research and industrial applications. PMID- 29415412 TI - Immobilization of Aspergillus awamori beta-glucosidase on commercial gelatin: An inexpensive and efficient process. AB - In this work, a beta-glucosidase of Aspergillus awamori with a molecular weight of 180 kDa was produced in solid-state cultures using a mixture of pineapple crown leaves and wheat bran. Maximum production of the enzyme (820 +/- 30 U/g substrate) was obtained after 8 days of culture at 28 degrees C and initial moisture of 80%. The crude enzyme was efficiently immobilized on glutaraldehyde cross-linked commercial gelatin. Immobilization changed the kinetics of the enzyme, whose behavior could no longer be described by a saturation function of the Michaelis-Menten type. Comparative evaluation of the free and immobilized enzyme showed that the immobilized enzyme was more thermostable and less inhibited by glucose than the free form. In consequence of these properties, the immobilized enzyme was able to hydrolyze cellobiose more extensively. In association with Trichoderma reesei cellulase, the free and immobilized beta glucosidase increased the liberation of glucose from cellulose 3- and 5-fold, respectively. Immobilization of the A. awamori beta-glucosidase on glutaraldehyde cross-linked commercial gelatin is an efficient and cheap method allowing the reuse of the enzyme by at least 10 times. PMID- 29415413 TI - Structural characterization and anticancer activity (MCF7 and MDA-MB-231) of polysaccharides fractionated from brown seaweed Sargassum wightii. AB - The purpose of this study was to investigate the anticancer activity of polysaccharides from brown seaweed Sargassum wightii (SWP) on human breast cancer cells. Initially, two polysaccharide fractions (SWP1 and SWP2) were isolated and purified from the crude polysaccharides using DEAE-52 cellulose and Sephadex G 100 column chromatography. As a result, SWP1 was obtained with the yield of 21.48% was characterized using chemical analysis, GC-MS, 1H NMR and 13C NMR. The chemical composition of the extracted polysaccharide contains a neutral polysaccharide with a high total sugar content and low protein, phenol and flavonoid content. GC-MS analysis revealed the presence of galactofuranose and arabinose and NMR spectra shows the presence of beta-galactose signals. Anticancer activity shows that the polysaccharides significantly reduce the proliferation of breast cancer cells (MCF7 and MDA-MB-231) in a dose-dependent manner. Further, polysaccharides induced the apoptosis in the breast cancer cells by increasing ROS generation, cleaving mitochondrial membrane and nuclei damage. Finally, polysaccharides increased the activity of caspase 3/9, thus leads to apoptosis of breast cancer. Together, polysaccharides from S. wightii could be a new source of natural anticancer agent against breast cancer with potential value in the manufacturing supplements and drugs. PMID- 29415414 TI - Antibacterial activities of R-(+)-Limonene emulsion stabilized by Ulva fasciata polysaccharide for fruit preservation. AB - It was previously found that R-(+)-Limonene emulsion could be stabilized by Ulva fasciata polysaccharide. In the present study, emulsions of R-(+)-Limonene were developed for coating of strawberries to improve the shelf life and microbiological safety. Edible coatings with at least 0.15% w/w of R-(+)-Limonene improved the microbial stability of the strawberries, resulted effective in the decontamination of external pathogens such as Escherichia coli, Bacillus subtilis and Staphylococcus aureus. Changes in weight loss, total soluble solid (TSS), pH, total phenolic, ascorbic acid, textural properties and surface color of strawberries during storage were evaluated. R-(+)-Limonene emulsions were effective for decreasing water loss of all the fruit samples tested. The decrease in TSS values was higher in the control strawberries. Initial decreases followed by increases of pH during storage of strawberries. The amount of total phenols detected in control fruit sharply increased during the first 6 days then remained steady, whereas the total soluble phenols content of treated strawberries gradually increased during storage. Strawberries coated with emulsion had higher L* and a* values as compared to control fruits. The R-(+)-Limonene coatings have demonstrated the potential to inhibit foodborne pathogen contamination of strawberries, and prolong their shelf life. PMID- 29415415 TI - Agar-agar immobilization: An alternative approach for the entrapment of protease to improve the catalytic efficiency, thermal stability and recycling efficiency. AB - The catalytic performance of an immobilized enzyme could be enhanced by using entrapment technique. In this contemporary study agar-agar, a natural polysaccharide, is subjected to entrap serine-protease produced by Aspergillus niger KIBGE-IB36. The results revealed that maximum enzymatic activity was attained when 3.0% agar-agar was used. It was observed that in case of both free and entrapped forms the enzyme was stable at pH-5.0. While, an increment in reaction temperature and time was noticed from 50 to 55 degrees C and 15.0 to 20.0 min, respectively. Km value increased from 1.883 mM to 2.399 mM and Vmax value decreased from 1753 U mg-1 to 1372 U mg-1 after agar-agar entrapment of protease as compared to soluble enzyme. Additionally, entrapped protease within the polymer exhibited significant increase in the thermal stability at various temperatures and retained approximately 68.0% of its residual activity at 60 degrees C. However, at this extreme temperature the soluble protease lost its catalytic performance. Storage stability considerably improved as entrapped protease revealed enzymatic activity up to 30 days as compared to soluble enzyme. Recycling efficiency was calculated up to eight cycles which is an exceptional characteristic for economic feasibility and continuous reusability of protease. PMID- 29415416 TI - Nano-biocomposite scaffolds of chitosan, carboxymethyl cellulose and silver nanoparticle modified cellulose nanowhiskers for bone tissue engineering applications. AB - In the present work, we aimed to synthesize highly efficient nano-composite polymeric scaffolds with controllable pore size and mechanical strength. We prepared nanocomposite (CCNWs-AgNPs) of silver nanoparticles (AgNPs) decorated on carboxylated CNWs (CCNWs) which serves dual functions of providing mechanical strength and antimicrobial activity. Scaffolds containing chitosan (CS) and carboxymethyl cellulose (CMC) with varying percent of nanocomposite were fabricated using freeze drying method. XRD and FESEM analysis of nanocomposite revealed highly crystalline structure with AgNPs (5.2 nm dia) decorated on ~200 nm long CCNWs surface. FTIR analysis confirmed the interaction between CCNWs and AgNPs. Incorporation of nanocomposite during scaffolds preparation helped in achieving the desirable 80-90% porosity with pore diameter ranging between 150 and 500 MUm and mechanical strength was also significantly improved matching with the mechanical strength of cancellous bone. The swelling capacity of scaffolds decreased after the incorporation of nanocomposite. In turn, scaffold degradation rate was tuned to support angiogenesis and vascularization. Scaffolds apart from exhibiting excellent antimicrobial activity, also supported MG63 cells adhesion and proliferation. Incorporation of CCNWs also resulted in improved biomineralization for bone growth. Overall, these studies confirmed excellent properties of fabricated scaffolds, making them self-sustained and potential antimicrobial scaffolds (without any loaded drug) to overcome bone related infections like osteomyelitis. PMID- 29415417 TI - Chitosan/nano-hydroxyapatite/nano-zirconium dioxide scaffolds with miR-590-5p for bone regeneration. AB - Bone tissue engineering (BTE) relies on biocomposite scaffolds and bioactive molecules for bone regeneration. The present study was aimed to synthesize and characterize biocomposite scaffolds containing chitosan (CS), nano-hydroxyapatite (nHAp) and nano-zirconium dioxide (nZrO2) along with microRNA (miRNA) for BTE applications. miRNAs act as post-transcriptional regulator of gene expression. The fabricated biocomposite scaffolds were characterized using SEM, FT-IR and XRD analyses. The effect of a bioactive molecule (miR-590-5p) with scaffolds was tested for osteoblast differentiation at the cellular and molecular levels using mouse mesenchymal stem cells (C3H10T1/2). The results showed that CS/nHAp/nZrO2 scaffolds promoted osteoblast differentiation, and this effect was further increased in the presence of miR-590-5p in C3H10T1/2 cells. Thus, we suggested that CS/nHAp/nZrO2 scaffolds with miR-590-5p would have potential towards the treatment of bone defects. PMID- 29415418 TI - Integrin Inhibitors in Prostate Cancer. AB - Prostate cancer (PCa) is the most frequently diagnosed cancer and the third highest cause of cancer-related deaths in men in the U.S. The development of chemotherapeutic agents that can bind PCa tumor cells with high specificity is critical in order to increase treatment effectiveness. Integrin receptors and their corresponding ligands have different expression patterns in PCa cells. They have been identified as promising targets to inhibit pathways involved in PCa progression. Currently, several compounds have proven to target specific integrins and their subunits in PCa cells. In this article, we review the role of integrins inhibitors in PCa and their potential as therapeutic targets for PCa treatments. We have discussed the following: natural compounds, monoclonal antibodies, statins, campothecins analog, aptamers, d-aminoacid, and snake venom. Recent studies have shown that their mechanisms of action result in decrease cell migration, cell invasion, cell proliferation, and metastasis of PCa cells. PMID- 29415419 TI - Polyacetylene: Myth and Reality. AB - Polyacetylene, the simplest and oldest of potentially conducting polymers, has never been made in a form that permits rigorous determination of its structure. Trans polyacetylene in its fully extended form will have a potential energy surface with two equivalent minima. It has been assumed that this results in bond length alternation. It is, rather, very likely that the zero-point energy is above the Peierls barrier. The experimental studies that purport to show bond alternation are reviewed and shown to be compromised by serious experimental inconsistencies or by the presence, for which there is considerable evidence, of finite chain polyenes. In this view, addition of dopants results in conductivity by facilitation of charge transport between finite polyenes. The double minimum potential that necessarily occurs for polyacetylene, if viewed as the result of elongation of finite chains, originates from admixture of the 11Ag ground electronic state with the 21Ag excited electronic singlet state. This excitation is diradical (two electron) in character. The polyacetylene limit is an equal admixture of these two 1Ag states making theory intractable for long chains. A method is outlined for preparation of high molecular weight polyacetylene with fully extended chains that are prevented from reacting with neighboring chains. PMID- 29415420 TI - Hyperspectral-Enhanced Dark Field Microscopy for Single and Collective Nanoparticle Characterization in Biological Environments. AB - We review how the hyperspectral dark field analysis gives us quantitative insights into the manner that different nanoscale materials interact with their environment and how this relationship is directly expressed in an optical readout. We engage classification tools to identify dominant spectral signatures within a scene or to qualitatively characterize nanoparticles individually or in populations based on their composition and morphology. Moreover, we follow up the morphological evolution of nanoparticles over time and in different biological environments to better understand and establish a link between the observed nanoparticles' changes and cellular behaviors. PMID- 29415421 TI - Effect of Co-Production of Renewable Biomaterials on the Performance of Asphalt Binder in Macro and Micro Perspectives. AB - Conventional asphalt binder derived from the petroleum refining process is widely used in pavement engineering. However, asphalt binder is a non-renewable material. Therefore, the use of a co-production of renewable bio-oil as a modifier for petroleum asphalt has recently been getting more attention in the pavement field due to its renewability and its optimization for conventional petroleum-based asphalt binder. Significant research efforts have been done that mainly focus on the mechanical properties of bio-asphalt binder. However, there is still a lack of studies describing the effects of the co-production on performance of asphalt binders from a micro-scale perspective to better understand the fundamental modification mechanism. In this study, a reasonable molecular structure for the co-production of renewable bio-oils is created based on previous research findings and the observed functional groups from Fourier transform infrared spectroscopy tests, which are fundamental and critical for establishing the molecular model of bio-asphalt binder with various biomaterials contents. Molecular simulation shows that the increase of biomaterial content causes the decrease of cohesion energy density, which can be related to the observed decrease of dynamic modulus. Additionally, a parameter of Flexibility Index is employed to characterize the ability of asphalt binder to resist deformation under oscillatory loading accurately. PMID- 29415422 TI - Importance of a Laccase Gene (Lcc1) in the Development of Ganoderma tsugae. AB - In this study, a novel laccase gene (Lcc1) from Ganoderma tsugae was isolated and its functions were characterized in detail. The results showed that Lcc1 has the highest expression activity during mycelium development and fruit body maturation based on the analysis of Lcc1 RNA transcripts at different developmental stages of G. tsugae. To investigate the exact contribution of Lcc1 to mycelium and fruit body development in G. tsugae, Lcc1 transgenic strains were constructed by targeted gene replacement and over-expression approaches. The results showed that the lignin degradation rate in Lcc1 deletion mutant was much lower than the degradation efficiency of the wild-type (WT), over-expression and rescue strains. The lignin degradation activity of G. tsugae is dependent on Lcc1 and the deletion of Lcc1 exerted detrimental influences on the development of mycelium branch. Furthermore, the study uncovered that Lcc1 deletion mutants generated much shorter pale grey fruit bodies, suggesting that Lcc1 contributes directly to pigmentation and stipe elongation during fruit body development in G. tsugae. The information obtained in this study provides a novel and mechanistic insight into the specific role of Lcc1 during growth and development of G. tsugae. PMID- 29415423 TI - Vitamin E Phosphate Nucleoside Prodrugs: A Platform for Intracellular Delivery of Monophosphorylated Nucleosides. AB - Vitamin E phosphate (VEP) nucleoside prodrugs are designed to bypass two mechanisms of tumor resistance to therapeutic nucleosides: nucleoside transport and kinase downregulation. Certain isoforms of vitamin E (VE) have shown activity against solid and hematologic tumors and result in chemosensitization. Because gemcitabine is one of the most common chemotherapeutics for the treatment of cancer, it was used to demonstrate the constructs utility. Four different VE isoforms were conjugated with gemcitabine at the 5' position. Two of these were delta-tocopherol-monophosphate (MP) gemcitabine (NUC050) and delta-tocotrienol-MP gemcitabine (NUC052). NUC050 was shown to be able to deliver gemcitabine-MP intracellularly by a nucleoside transport independent mechanism. Its half-life administered IV in mice was 3.9 h. In a mouse xenograft model of non-small cell lung cancer (NSCLC) NCI-H460, NUC050 at a dose of 40 mg/kg IV qwk * 4 resulted in significant inhibition to tumor growth on days 11-31 (p < 0.05) compared to saline control (SC). Median survival was 33 days (NUC050) vs. 25.5 days (SC) ((hazard ratio) HR = 0.24, p = 0.017). Further, NUC050 significantly inhibited tumor growth compared to historic data with gemcitabine at 135 mg/kg IV q5d * 3 on days 14-41 (p < 0.05). NUC052 was administered at a dose of 40 mg/kg IV qwk * 2 followed by 50 mg/kg qwk * 2. NUC052 resulted in inhibition to tumor growth on days 14-27 (p < 0.05) and median survival was 34 days (HR = 0.27, p = 0.033). NUC050 and NUC052 have been shown to be safe and effective in a mouse xenograft of NSCLC. PMID- 29415425 TI - Knowledge, Awareness and Practices Regarding Cystic Echinococcosis among Livestock Farmers in Basrah Province, Iraq. AB - Cystic echinococcosis (CE) is an endemic neglected parasitic zoonosis in many of the countries of the Middle East. The disease poses a remarkable economic burden for both animals and humans. In this study, we conducted a questionnaire survey among livestock farmers in Basrah province, southern Iraq, in order to evaluate their knowledge and awareness about CE, and to understand some of the risky practices that could contribute to spread and persistence of such disease. Of the interviewed participants (N = 314), 27.4% owned dogs on their farms. Among farmers owning dogs, 76.7% (66/86) never tied up their dogs, and 43% (37/86) indicated feeding uncooked animal viscera to their dogs. The majority (96.5%) of the farmers indicated that they did not de-worm their dogs at all. Only 9.8% (31/314) of the respondents indicated eating raw leafy vegetables without washing. Added to that, 32% of the interviewees indicated that they source water for domestic use from a river; meanwhile 94.3% (296/314) of them do not boil water before using it for domestic purposes. Half of the interviewed livestock farmers in Basrah were not aware about how humans get infected with CE disease, and 41.4% (130/314) did not even realize that CE is a dangerous disease to human health. Almost one in three of the respondents who owned dogs on their farms viewed de-worming of their dogs as a low priority practice. This study highlights the gap in knowledge and awareness about CE among the study population. Risky practices associated with dog keeping management and food and water handling practices were identified. The insight from this research could be used to improve the delivery of a health education message relevant to cystic echinococcosis control at the human-animal interface in Iraq. PMID- 29415426 TI - Prevalence and Correlates of Cyberbullying Perpetration. Findings from a German Representative Student Survey. AB - Based on a survey of 9512 ninth-grade students conducted in Lower Saxony in 2013, this paper examines the prevalence of cyberbullying perpetration and the correlates of this behavior. Binary logistic multilevel regression was used in order to analyze correlates of sexual and psychological cyberbully perpetration. In the preceding semester, 2.4% of the adolescents were perpetrators of psychological cyberbullying and 0.4% bullied someone online sexually. Low levels of empathy, frequent consumption of violent media, and being victims of aggressive online behaviors are correlated with the risk that a child will become a bully. Female adolescents are less likely than boys to engage in sexual cyberbullying perpetration, but they are more likely to engage in psychological cyberbullying perpetration. Only a small share of adolescents engage in sexual and psychological cyberbullying perpetration. Both behaviors differ in their correlates, however being a victim of aggressive online behaviors increase the risk for perpetration of both behaviors, respectively. PMID- 29415424 TI - A Role for Exercise in Attenuating Unhealthy Food Consumption in Response to Stress. AB - It is well established that both acute and chronic stress can be detrimental to health and wellbeing by directly increasing the risk of several chronic diseases and related health problems. In addition, stress may contribute to ill-health indirectly via its downstream effects on individuals' health-related behaviour, such as promoting the intake of unhealthy palatable foods high in fat and sugar content. This paper reviews (a) the research literature on stress-models; (b) recent research investigating stress-induced eating and (c) the potential physiological and psychological pathways contributing to stress-induced eating. Particular attention is given to (d) the role of physical exercise in attenuating acute stress, with exploration of potential mechanisms through which exercise may reduce unhealthy food and drink consumption subsequent to stressor exposure. Finally, exercise motivation is discussed as an important psychological influence over the capacity for physical exercise to attenuate unhealthy food and drink consumption after exposure to stressors. This paper aims to provide a better understanding of how physical exercise might alleviate stress-induced unhealthy food choices. PMID- 29415427 TI - Qualitative Evaluation of the Five-Year 'Red Collar' Campaign to End Inhumane Culling of Dogs as a Method of Rabies Control. AB - Dog-mediated human rabies can be eliminated through mass dog vaccination. Despite leading authorities in human and animal health uniting to advance effective and humane rabies control, some governments resort to lethal methods, which are unethical, often inhumane and ineffective. To end the inhumane culling of dogs in response to rabies, World Animal Protection launched 'Red Collar'; a five-year campaign (2011-2016) that worked with governments to promote the implementation of mass dog vaccination for rabies control. We present the findings from a qualitative evaluation of 'Red Collar', conducted both regionally and with national focus on Bangladesh, China, Indonesia, the Philippines and Zanzibar, Tanzania. Through semi-structured interviews and written contributions from stakeholders (n = 54), we compared perceptions of changes with stated campaign goals to capture recommendations for future work. The campaign successfully generated momentum for implementation of mass dog vaccination by targeted governments. Lessons learned were established: Value of a consistent animal welfare 'voice'; the need to explore the motivations behind culling; the need to capacity build; time required for the 'ripple effect' to inspire humane control in other countries; importance of monitoring and evaluation of indicators; time and effort required for exit strategies and prior preparation for a robust response to culling. PMID- 29415428 TI - Functions of PDE3 Isoforms in Cardiac Muscle. AB - Isoforms in the PDE3 family of cyclic nucleotide phosphodiesterases have important roles in cyclic nucleotide-mediated signalling in cardiac myocytes. These enzymes are targeted by inhibitors used to increase contractility in patients with heart failure, with a combination of beneficial and adverse effects on clinical outcomes. This review covers relevant aspects of the molecular biology of the isoforms that have been identified in cardiac myocytes; the roles of these enzymes in modulating cAMP-mediated signalling and the processes mediated thereby; and the potential for targeting these enzymes to improve the profile of clinical responses. PMID- 29415429 TI - LncRNA HOTTIP-Mediated HOXA11 Expression Promotes Cell Growth, Migration and Inhibits Cell Apoptosis in Breast Cancer. AB - As the most common cause of cancer death in women, the pathogenesis of breast cancer still remains unclear. Here, we reported a long non-coding RNA (lncRNA), HOTTIP (HOXA transcript at the distal tip), that may play an important role in the pathogenesis of breast cancer. Using gain-and-loss-of experiments in vitro and in vivo, we observed the marked upregulation of HOTTIP/HOXA11 in the breast cancer cell line, MCF-7, and the downregulation of HOTTIP or HOXA11, which might inhibit cell proliferation and migration but promote cell apoptosis in breast cancer MCF-7 cells. In addition, by further rescue experiments with HOXA11 overexpression, we uncovered a novel potential regulatory mechanism between HOTTIP and one of its physical HOXA clusters, HOXA11. Hence, HOTTIP may mediate, at least partly, HOXA11 expression involved in cell growth, migration, and apoptosis of breast cancer MCF-7 cells. PMID- 29415430 TI - Mexican Propolis: A Source of Antioxidants and Anti-Inflammatory Compounds, and Isolation of a Novel Chalcone and epsilon-Caprolactone Derivative. AB - The propolis produced by bees are used in alternative medicine for treating inflammation, and infections, presumably due to its antioxidant properties. In this context, five propolis from Mexico were investigated to determine their inhibitory lipid peroxidation properties. The ethyl acetate extract from a red propolis from Chiapas State (4-EAEP) was the most potent (IC50 = 1.42 +/- 0.07 MUg/mL) in the TBARS assay, and selected for further studies. This extract afforded two new compounds, epoxypinocembrin chalcone (6), and an epsilon caprolactone derivative (10), as well as pinostrobin (1), izalpinin (2), cinnamic acid (3), pinocembrin (4), kaempherol (5), 3,3-dimethylallyl caffeate in mixture with isopent-3-enyl caffeate (7a + 7b), 3,4-dimethoxycinnamic acid (8), rhamnetin (9) and caffeic acid (11). The HPLC profile, anti-mycobacterial, and antioxidant properties of this extract was also determined. Most of the isolated compounds were also tested by inhibition of reactive oxygen species (ROS) in challenged mouse bone marrow-derived mast cells (BMMCs), and DPPH. Their anti-inflammatory activity was evaluated by TPA, and MPO (myeloperoxidase) activity by ear edema test in mice. The most potent compounds were 7a + 7b in the TBARS assay (IC50 = 0.49 +/- 0.06 MUM), and 2 which restored the ROS baseline (3.5 MUM). Our results indicate that 4-EAEP has anti-oxidant, and anti-inflammatory properties due to its active compounds, suggesting it has anti-allergy and anti-asthma potential. PMID- 29415431 TI - The Magistral Phage. AB - Since time immemorial, phages-the viral parasites of bacteria-have been protecting Earth's biosphere against bacterial overgrowth. Today, phages could help address the antibiotic resistance crisis that affects all of society. The greatest hurdle to the introduction of phage therapy in Western medicine is the lack of an appropriate legal and regulatory framework. Belgium is now implementing a pragmatic phage therapy framework that centers on the magistral preparation (compounding pharmacy in the US) of tailor-made phage medicines. PMID- 29415432 TI - Impact of RNA Degradation on Viral Diagnosis: An Understated but Essential Step for the Successful Establishment of a Diagnosis Network. AB - The current global conditions, which include intensive globalization, climate changes, and viral evolution among other factors, have led to an increased emergence of viruses and new viral diseases; RNA viruses are key drivers of this evolution. Laboratory networks that are linked to central reference laboratories are required to conduct both active and passive environmental surveillance of this complicated global viral environment. These tasks require a continuous exchange of strains or field samples between different diagnostic laboratories. The shipment of these samples on dry ice represents both a biological hazard and a general health risk. Moreover, the requirement to ship on dry ice could be hampered by high costs, particularly in underdeveloped countries or regions located far from each other. To solve these issues, the shipment of RNA isolated from viral suspensions or directly from field samples could be a useful way to share viral genetic material. However, extracted RNA stored in aqueous solutions, even at -70 degrees C, is highly prone to degradation. The current study evaluated different RNA storage conditions for safety and feasibility for future use in molecular diagnostics. The in vitro RNA-transcripts obtained from an inactivated highly pathogenic avian influenza (HPAI) H5N1 virus was used as a model. The role of secondary structures in the protection of the RNA was also explored. Of the conditions evaluated, the dry pellet matrix was best able to protect viral RNA under extreme storage conditions. This method is safe, cost effective and assures the integrity of RNA samples for reliable molecular diagnosis. This study aligns with the globally significant "Global One Health" paradigm, especially with respect to the diagnosis of emerging diseases that require confirmation by reference laboratories. PMID- 29415433 TI - miRNA as a New Regulatory Mechanism of Estrogen Vascular Action. AB - The beneficial effects of estrogen on the cardiovascular system have been reported extensively. In fact, the incidence of cardiovascular diseases in women is lower than in age-matched men during their fertile stage of life, a benefit that disappears after menopause. These sex-related differences point to sexual hormones, mainly estrogen, as possible cardiovascular protective factors. The regulation of vascular function by estrogen is mainly related to the maintenance of normal endothelial function and is mediated by both direct and indirect gene transcription through the activity of specific estrogen receptors. Some of these mechanisms are known, but many remain to be elucidated. In recent years, microRNAs have been established as non-coding RNAs that regulate the expression of a high percentage of protein-coding genes in mammals and are related to the correct function of human physiology. Moreover, within the cardiovascular system, miRNAs have been related to physiological and pathological conditions. In this review, we address what is known about the role of estrogen-regulated miRNAs and their emerging involvement in vascular biology. PMID- 29415434 TI - Pathogenesis and Animal Models of Post-Primary (Bronchogenic) Tuberculosis, A Review. AB - Primary and post-primary tuberculosis (TB) are different diseases caused by the same organism. Primary TB produces systemic immunity. Post-primary TB produces cavities to support massive proliferation of organisms for transmission of infection to new hosts from a person with sufficient immunity to prevent systemic infection. Post-primary, also known as bronchogenic, TB begins in humans as asymptomatic bronchial spread of obstructive lobular pneumonia, not as expanding granulomas. Most lesions regress spontaneously. However, some undergo caseation necrosis that is coughed out through the necrotic bronchi to form cavities. Caseous pneumonia that is not expelled through the bronchi is retained to become the focus of fibrocaseous disease. No animal reproduces this entire process. However, it appears that many mammals utilize similar mechanisms, but fail to coordinate them as do humans. Understanding this makes it possible to use human tuberculous lung sections to guide manipulation of animals to produce models of particular human lesions. For example, slowly progressive and reactivation TB in mice resemble developing human bronchogenic TB. Similarly, bronchogenic TB and cavities resembling those in humans can be induced by bronchial infection of sensitized rabbits. Granulomas in guinea pigs have characteristics of both primary and post primary TB. Mice can be induced to produce a spectrum of human like caseating granulomas. There is evidence that primates can develop bronchogenic TB. We are optimistic that such models developed by coordinated study of human and animal tissues can be used with modern technologies to finally address long-standing questions about host/parasite relationships in TB, and support development of targeted therapeutics and vaccines. PMID- 29415436 TI - Fabrication and Optimization of Bilayered Nanoporous Anodic Alumina Structures as Multi-Point Interferometric Sensing Platform. AB - Herein, we present an innovative strategy for optimizing hierarchical structures of nanoporous anodic alumina (NAA) to advance their optical sensing performance toward multi-analyte biosensing. This approach is based on the fabrication of multilayered NAA and the formation of differential effective medium of their structure by controlling three fabrication parameters (i.e., anodization steps, anodization time, and pore widening time). The rationale of the proposed concept is that interferometric bilayered NAA (BL-NAA), which features two layers of different pore diameters, can provide distinct reflectometric interference spectroscopy (RIfS) signatures for each layer within the NAA structure and can therefore potentially be used for multi-point biosensing. This paper presents the structural fabrication of layered NAA structures, and the optimization and evaluation of their RIfS optical sensing performance through changes in the effective optical thickness (EOT) using quercetin as a model molecule. The bilayered or funnel-like NAA structures were designed with the aim of characterizing the sensitivity of both layers of quercetin molecules using RIfS and exploring the potential of these photonic structures, featuring different pore diameters, for simultaneous size-exclusion and multi-analyte optical biosensing. The sensing performance of the prepared NAA platforms was examined by real-time screening of binding reactions between human serum albumin (HSA) modified NAA (i.e., sensing element) and quercetin (i.e., analyte). BL-NAAs display a complex optical interference spectrum, which can be resolved by fast Fourier transform (FFT) to monitor the EOT changes, where three distinctive peaks were revealed corresponding to the top, bottom, and total layer within the BL-NAA structures. The spectral shifts of these three characteristic peaks were used as sensing signals to monitor the binding events in each NAA pore in real-time upon exposure to different concentrations of quercetin. The multi-point sensing performance of BL-NAAs was determined for each pore layer, with an average sensitivity and low limit of detection of 600 nm (mg mL-1)-1 and 0.14 mg mL-1, respectively. BL-NAAs photonic structures have the capability to be used as platforms for multi-point RIfS sensing of biomolecules that can be further extended for simultaneous size-exclusion separation and multi-analyte sensing using these bilayered nanostructures. PMID- 29415437 TI - Conventional Chromosome Analysis of Fetuses with Central Nervous System Anomalies and Associated Anomalies: Is Anything Changed? AB - Central nervous system (CNS) abnormalities are often isolated but can accompany various genetic syndromes. In this study, we evaluated conventional karyotype results and associated findings of fetuses that were diagnosed with CNS abnormalities. Cases included in the study were diagnosed with fetal CNS anomalies and underwent conventional karyotyping. Conventional karyotype results of subjects were compared with karyotype results of fetal karyotyped patients as a result of maternal anxiety in a two-year period. In this period, 69 patients were diagnosed with fetal CNS anomalies and 64 of them underwent invasive fetal karyotyping. Of these, 32 patients had isolated CNS anomalies, while 32 were associated with other anomalies. There was no significant difference between karyotype results when compared with the control group (p = 0.76). Apart from some specific anomalies, the aneuploidy rate does not significantly differ between fetuses with CNS anomalies and the control group. Advanced genetic evaluation may provide additional diagnostic benefits, especially for this group. PMID- 29415435 TI - Review of Current Cell-Penetrating Antibody Developments for HIV-1 Therapy. AB - The discovery of highly active antiretroviral therapy (HAART) in 1996 has significantly reduced the global mortality and morbidity caused by the acquired immunodeficiency syndrome (AIDS). However, the therapeutic strategy of HAART that targets multiple viral proteins may render off-target toxicity and more importantly results in drug-resistant escape mutants. These have been the main challenges for HAART and refinement of this therapeutic strategy is urgently needed. Antibody-mediated treatments are emerging therapeutic modalities for various diseases. Most therapeutic antibodies have been approved by Food and Drug Administration (FDA) mainly for targeting cancers. Previous studies have also demonstrated the promising effect of therapeutic antibodies against HIV-1, but there are several limitations in this therapy, particularly when the viral targets are intracellular proteins. The conventional antibodies do not cross the cell membrane, hence, the pathogenic intracellular proteins cannot be targeted with this classical therapeutic approach. Over the years, the advancement of antibody engineering has permitted the therapeutic antibodies to comprehensively target both extra- and intra-cellular proteins in various infections and diseases. This review aims to update on the current progress in the development of antibody-based treatment against intracellular targets in HIV-1 infection. We also attempt to highlight the challenges and limitations in the development of antibody-based therapeutic modalities against HIV-1. PMID- 29415438 TI - Carbon Nano-Allotrope/Magnetic Nanoparticle Hybrid Nanomaterials as T2 Contrast Agents for Magnetic Resonance Imaging Applications. AB - Magnetic resonance imaging (MRI) is the most powerful tool for deep penetration and high-quality 3D imaging of tissues with anatomical details. However, the sensitivity of the MRI technique is not as good as that of the radioactive or optical imaging methods. Carbon-based nanomaterials have attracted significant attention in biomaterial research in recent decades due to their unique physical properties, versatile functionalization chemistry, as well as excellent biological compatibility. Researchers have employed various carbon nano allotropes to develop hybrid MRI contrast agents for improved sensitivity. This review summarizes the new research progresses in carbon-based hybrid MRI contrast agents, especially those reported in the past five years. The review will only focus on T2-weighted MRI agents and will be categorized by the different carbon allotrope types and magnetic components. Considering the strong trend in recent bio-nanotechnology research towards multifunctional diagnosis and therapy, carbon based MRI contrast agents integrated with other imaging modalities or therapeutic functions are also covered. PMID- 29415439 TI - Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is a promising therapeutic target for IPF. We examined whether disrupting Skp2 suppressed pulmonary fibrosis in a bleomycin (BLM)-induced mouse model and found that pulmonary fibrosis was significantly suppressed in Skp2 deficient mice compared with controls. The pulmonary accumulation of fibrotic markers such as collagen type 1 and fibronectin in BLM-infused mice was decreased in Skp2-deficient mice. Moreover, the number of bronchoalveolar lavage fluid cells accompanied with pulmonary fibrosis was significantly diminished. Levels of the Skp2 target p27 were significantly decreased by BLM-administration in wild type mice, but recovered in Skp2-/- mice. In vimentin-positive mesenchymal fibroblasts, the decrease of p27-positive cells and increase of Ki67-positive cells by BLM-administration was suppressed by Skp2-deficency. As these results suggested that inhibiting Skp2 might be effective for BLM-induced pulmonary fibrosis, we next performed a treatment experiment using the Skp2 inhibitor SZL P1-41. As expected, BLM-induced pulmonary fibrosis was significantly inhibited by SZL-P1-41. Moreover, p27 levels were increased by the SZL-P1-41 treatment, suggesting p27 may be an important Skp2 target for BLM-induced pulmonary fibrosis. Our study suggests that Skp2 is a potential molecular target for human pulmonary fibrosis including IPF. PMID- 29415441 TI - In Vitro Study of the Cytotoxic, Cytostatic, and Antigenotoxic Profile of Hemidesmus indicus (L.) R.Br. (Apocynaceae) Crude Drug Extract on T Lymphoblastic Cells. AB - In traditional Indian medicine, the crude drug Hemidesmus indicus root-commonly known as Indian sarsaparilla-is used alone or in poly-herbal preparations for the treatment of a wide range of diseases. The present study focuses on the cancer chemopreventive and therapeutic potential of H. indicus extracts on an acute lymphoblastic leukemia cell line (CCRF-CEM). With this aim in mind, we subjected H. indicus roots to two subsequent extractions (hydro-alcoholic extraction and soxhlet extraction). As DNA damage is an important prerequisite for the induction of mutations/cancer by genotoxic carcinogens, cancer chemoprevention may be achieved by preventing genotoxicity. Through an integrated experimental approach, we explored the genoprotective potential of the soxhlet H. indicus extract against different mutagenic compounds and its cytotoxic, proapoptotic, and cytostatic properties. In our experimental conditions, H. indicus induced a cytotoxic effect involving the activation of both intrinsic and extrinsic apoptotic pathways and blocked the cell cycle in the S phase. Moreover, the antigenotoxicity results showed that the extract was able to mitigate DNA damage, an essential mechanism for its applicability as a chemopreventive agent, via either the modulation of extracellular and intracellular events involved in DNA damage. These data add to the growing body of evidence that H. indicus can represent a noteworthy strategy to target early and late stages of cancer. PMID- 29415442 TI - Electric Field Comparison between Microelectrode Recording and Deep Brain Stimulation Systems-A Simulation Study. AB - The success of deep brain stimulation (DBS) relies primarily on the localization of the implanted electrode. Its final position can be chosen based on the results of intraoperative microelectrode recording (MER) and stimulation tests. The optimal position often differs from the final one selected for chronic stimulation with the DBS electrode. The aim of the study was to investigate, using finite element method (FEM) modeling and simulations, whether lead design, electrical setup, and operating modes induce differences in electric field (EF) distribution and in consequence, the clinical outcome. Finite element models of a MER system and a chronic DBS lead were developed. Simulations of the EF were performed for homogenous and patient-specific brain models to evaluate the influence of grounding (guide tube vs. stimulator case), parallel MER leads, and non-active DBS contacts. Results showed that the EF is deformed depending on the distance between the guide tube and stimulating contact. Several parallel MER leads and the presence of the non-active DBS contacts influence the EF distribution. The DBS EF volume can cover the intraoperatively produced EF, but can also extend to other anatomical areas. In conclusion, EF deformations between stimulation tests and DBS should be taken into consideration as they can alter the clinical outcome. PMID- 29415440 TI - Revisiting the Therapeutic Potential of Bothrops jararaca Venom: Screening for Novel Activities Using Connectivity Mapping. AB - Snake venoms are sources of molecules with proven and potential therapeutic applications. However, most activities assayed in venoms (or their components) are of hemorrhagic, hypotensive, edematogenic, neurotoxic or myotoxic natures. Thus, other relevant activities might remain unknown. Using functional genomics coupled to the connectivity map (C-map) approach, we undertook a wide range indirect search for biological activities within the venom of the South American pit viper Bothrops jararaca. For that effect, venom was incubated with human breast adenocarcinoma cell line (MCF7) followed by RNA extraction and gene expression analysis. A list of 90 differentially expressed genes was submitted to biosimilar drug discovery based on pattern recognition. Among the 100 highest ranked positively correlated drugs, only the antihypertensive, antimicrobial (both antibiotic and antiparasitic), and antitumor classes had been previously reported for B. jararaca venom. The majority of drug classes identified were related to (1) antimicrobial activity; (2) treatment of neuropsychiatric illnesses (Parkinson's disease, schizophrenia, depression, and epilepsy); (3) treatment of cardiovascular diseases, and (4) anti-inflammatory action. The C-map results also indicated that B. jararaca venom may have components that target G protein-coupled receptors (muscarinic, serotonergic, histaminergic, dopaminergic, GABA, and adrenergic) and ion channels. Although validation experiments are still necessary, the C-map correlation to drugs with activities previously linked to snake venoms supports the efficacy of this strategy as a broad-spectrum approach for biological activity screening, and rekindles the snake venom-based search for new therapeutic agents. PMID- 29415443 TI - Mental Health Effects of Stress over the Life Span of Refugees. AB - Information about the relative impact of stressful events across the lifespan on the mental health of refugees is needed. Cross-sectional data from a community sample of 135 Kurdish and 117 Vietnamese refugees were fit to a path model about the effects of non-war stress, war-related stress, and post-migration stress on mental health. Kurdish and Vietnamese data were generally consistent with the model. However, war-related stress produced no direct but a large indirect effect through post-migration stress on mental health in Kurds. Vietnamese data indicated a modest direct war-related stress effect but no indirect influence through post-migration stress. Different types of stressful events lead to adverse mental health of displaced refugees in a somewhat group-dependent manner. Implications for prevention and treatment are discussed. PMID- 29415444 TI - Knowledge Reasoning with Semantic Data for Real-Time Data Processing in Smart Factory. AB - The application of high-bandwidth networks and cloud computing in manufacturing systems will be followed by mass data. Industrial data analysis plays important roles in condition monitoring, performance optimization, flexibility, and transparency of the manufacturing system. However, the currently existing architectures are mainly for offline data analysis, not suitable for real-time data processing. In this paper, we first define the smart factory as a cloud assisted and self-organized manufacturing system in which physical entities such as machines, conveyors, and products organize production through intelligent negotiation and the cloud supervises this self-organized process for fault detection and troubleshooting based on data analysis. Then, we propose a scheme to integrate knowledge reasoning and semantic data where the reasoning engine processes the ontology model with real time semantic data coming from the production process. Based on these ideas, we build a benchmarking system for smart candy packing application that supports direct consumer customization and flexible hybrid production, and the data are collected and processed in real time for fault diagnosis and statistical analysis. PMID- 29415445 TI - Microbial Degradation of Amino Acid-Containing Compounds Using the Microcystin Degrading Bacterial Strain B-9. AB - Strain B-9, which has a 99% similarity to Sphingosinicella microcystinivorans strain Y2, is a Gram-negative bacterium with potential for use in the degradation of microcystin-related compounds and nodularin. We attempted to extend the application area of strain B-9 and applied it to mycotoxins produced by fungi. Among the tested mycotoxins, only ochratoxin A was completely hydrolyzed to provide the constituents ochratoxin alpha and l-phenylalanine, and levels of fumonisin B1 gradually decreased after 96 h. However, although drugs including antibiotics released into the aquatic environment were applied for microbial degradation using strain B-9, no degradation occurred. These results suggest that strain B-9 can only degrade amino acid-containing compounds. As expected, the tested compounds with amide and ester bonds, such as 3,4-dimethyl hippuric acid and 4-benzyl aspartate, were readily hydrolyzed by strain B-9, although the sulfonamides remained unchanged. The ester compounds were characteristically and rapidly hydrolyzed as soon as they came into contact with strain B-9. Furthermore, the degradation of amide and ester compounds with amino acids was not inhibited by the addition of ethylenediaminetetraacetic acid (EDTA), indicating that the responsible enzyme was not MlrC. These results suggest that strain B-9 possesses an additional hydrolytic enzyme that should be designated as MlrE, as well as an esterase. PMID- 29415447 TI - Deep Learning-Based Banknote Fitness Classification Using the Reflection Images by a Visible-Light One-Dimensional Line Image Sensor. AB - In automatic paper currency sorting, fitness classification is a technique that assesses the quality of banknotes to determine whether a banknote is suitable for recirculation or should be replaced. Studies on using visible-light reflection images of banknotes for evaluating their usability have been reported. However, most of them were conducted under the assumption that the denomination and input direction of the banknote are predetermined. In other words, a pre-classification of the type of input banknote is required. To address this problem, we proposed a deep learning-based fitness-classification method that recognizes the fitness level of a banknote regardless of the denomination and input direction of the banknote to the system, using the reflection images of banknotes by visible-light one-dimensional line image sensor and a convolutional neural network (CNN). Experimental results on the banknote image databases of the Korean won (KRW) and the Indian rupee (INR) with three fitness levels, and the Unites States dollar (USD) with two fitness levels, showed that our method gives better classification accuracy than other methods. PMID- 29415448 TI - A Quantization-Based Multibit Data Fusion Scheme for Cooperative Spectrum Sensing in Cognitive Radio Networks. AB - Spectrum sensing remains a challenge in the context of cognitive radio networks (CRNs). Compared with traditional single-user sensing, cooperative spectrum sensing (CSS) exploits multiuser diversity to overcome channel fading, shadowing, and hidden terminal problems, which can effectively enhance the sensing performance and protect licensed users from harmful interference. However, for a large number of sensing nodes that need high bandwidth of the control channel for data transmitting, CSS increases cooperative overhead. To address this problem, we investigated the soft decision fusion strategy under a limited bandwidth of the control channel and proposed a simple quantization-based multibit data soft fusion rule for CSS for its simple structure and easily implementation. Under the quantization-based sensing strategy, each cooperative secondary user (SU) adopts an energy detector for local spectrum sensing. Each SU transmits quantized multibit data that sends local sensing information, instead of forwarding local one-bit hard decision results or original observation statistics, to the fusion center (FC). Furthermore, the closed-form expressions of the quantization levels and the quantization thresholds are analytically derived. Simulation results indicate that the detection performance of the proposed method approaches that of the conventional soft fusion rule with less cooperative overhead and outperforms the hard decision rules. Extensive simulations also show that multibit quantization fusion achieves a desirable tradeoff between the sensing performance and the control channel overhead for CSS. PMID- 29415449 TI - A Self-Switchable Polymer Reactor for Controlled Catalytic Chemistry Processes with a Hyperbranched Structure. AB - A self-switchable polymer reactor with a hyperbranched structure for controlled catalytic chemistry processes is reported. This polymer reactor was made of silver nanoparticles and a polymer carrier consisting of hyperbranched polyethylenimine and hydroxyethyl acrylate that behaved as thermally switchable domains. Below the transfer temperature, relatively strong catalytic reactivity was demonstrated due to the leading role of hydrophilic groups in the switchable domains, which opened access to the substrate for the packaged silver nanoparticles. In contrast, it showed weak catalysis at relatively high temperatures, reducing from the significantly increased hydrophobicity in the switchable domains. In this way, the polymer reactor displays controllable, tunable, catalytic activity based on this approach. This novel design opens up the opportunity to develop intelligent polymer reactors for controlled catalytic processes. PMID- 29415446 TI - Melatonin: A Molecule for Reducing Breast Cancer Risk. AB - The objective of this article is to review the basis supporting the usefulness of melatonin as an adjuvant therapy for breast cancer (BC) prevention in several groups of individuals at high risk for this disease. Melatonin, as a result of its antiestrogenic and antioxidant properties, as well as its ability to improve the efficacy and reduce the side effects of conventional antiestrogens, could safely be associated with the antiestrogenic drugs presently in use. In individuals at risk of BC due to night shift work, the light-induced inhibition of melatonin secretion, with the consequent loss of its antiestrogenic effects, would be countered by administering this neurohormone. BC risk from exposure to metalloestrogens, such as cadmium, could be treated with melatonin supplements to individuals at risk of BC due to exposure to this xenoestrogen. The BC risk related to obesity may be reduced by melatonin which decrease body fat mass, inhibits the enhanced aromatase expression in obese women, increases adiponectin secretion, counteracts the oncogenic effects of elevated concentrations of leptin; and decreases blood glucose levels and insulin resistance. Despite compelling experimental evidence of melatonin's oncostatic actions being susceptible to lowering BC risk, there is still a paucity of clinical trials focused on this subject. PMID- 29415450 TI - Design and Implementation of Cloud-Centric Configuration Repository for DIY IoT Applications. AB - The Do-It-Yourself (DIY) vision for the design of a smart and customizable IoT application demands the involvement of the general public in its development process. The general public lacks the technical knowledge for programming state of-the-art prototyping and development kits. The latest IoT kits, for example, Raspberry Pi, are revolutionizing the DIY paradigm for IoT, and more than ever, a DIY intuitive programming interface is required to enable the masses to interact with and customize the behavior of remote IoT devices on the Internet. However, in most cases, these DIY toolkits store the resultant configuration data in local storage and, thus, cannot be accessed remotely. This paper presents the novel implementation of such a system, which not only enables the general public to customize the behavior of remote IoT devices through a visual interface, but also makes the configuration available everywhere and anytime by leveraging the power of cloud-based platforms. The interface enables the visualization of the resources exposed by remote embedded resources in the form of graphical virtual objects (VOs). These VOs are used to create the service design through simple operations like drag-and-drop and the setting of properties. The configuration created as a result is maintained as an XML document, which is ingested by the cloud platform, thus making it available to be used anywhere. We use the HTTP approach for the communication between the cloud and IoT toolbox and the cloud and real devices, but for communication between the toolbox and actual resources, CoAP is used. Finally, a smart home case study has been implemented and presented in order to assess the effectiveness of the proposed work. PMID- 29415451 TI - Investigation on the Mechanical Properties of SMA/GF/Epoxy Hybrid Composite Laminates: Flexural, Impact, and Interfacial Shear Performance. AB - In this article, hybrid composite laminates with shape memory alloy (SMA) and glass fiber (GF) as the reinforced phase, and epoxy resin as the host material, were manufactured by vacuum-assisted resin injection (VARI) processing. The SMA wires were embedded into the GF/epoxy composites with three kinds of modes. The effect of SMA content and the position on the flexural, low-velocity impact performance of the hybrid composite laminates was investigated. It was found that the bonding performance between the SMA wire and the host material is the key factor that determined the final overall performance of the hybrid composite laminates in both the static and dynamics tests. Based on these experimental phenomenon, we further carried out the fiber pull-out experiment to improve the interfacial shear strength between the SMA and epoxy resin. It was found that the interfacial performance could be enhanced significantly by adding nanoparticles in the interface phase. PMID- 29415452 TI - Hard Fusion Based Spectrum Sensing over Mobile Fading Channels in Cognitive Vehicular Networks. AB - An explosive growth in vehicular wireless applications gives rise to spectrum resource starvation. Cognitive radio has been used in vehicular networks to mitigate the impending spectrum starvation problem by allowing vehicles to fully exploit spectrum opportunities unoccupied by licensed users. Efficient and effective detection of licensed user is a critical issue to realize cognitive radio applications. However, spectrum sensing in vehicular environments is a very challenging task due to vehicle mobility. For instance, vehicle mobility has a large effect on the wireless channel, thereby impacting the detection performance of spectrum sensing. Thus, gargantuan efforts have been made in order to analyze the fading properties of mobile radio channel in vehicular environments. Indeed, numerous studies have demonstrated that the wireless channel in vehicular environments can be characterized by a temporally correlated Rayleigh fading. In this paper, we focus on energy detection for spectrum sensing and a counting rule for cooperative sensing based on Neyman-Pearson criteria. Further, we go into the effect of the sensing and reporting channel conditions on the sensing performance under the temporally correlated Rayleigh channel. For local and cooperative sensing, we derive some alternative expressions for the average probability of misdetection. The pertinent numerical and simulating results are provided to further validate our theoretical analyses under a variety of scenarios. PMID- 29415453 TI - Chemically Surface Tunable Solubility Parameter for Controllable Drug Delivery-An Example and Perspective from Hollow PAA-Coated Magnetite Nanoparticles with R6G Model Drug. AB - Solubility parameter-dependent drug releasing property is essential in practical drug delivery systems (DDS), and how to combine magnetic nanoparticles(NPs) and suitable polymer coating towards DDS is always a crucial and valuable challenge in biomedical application. Herein, a controllable drug delivery model with a surface having a chemically tunable solubility parameter is presented using hollow magnetite/polyacrylic acid (Fe3O4/PAA) nanocomposites as nanocarrier towards DDS. This composite is prepared by simply coating the modified hollow Fe3O4 with PAA. The coating amount of PAA onto the surface of Fe3O4 (measured by TGA) is about 40% (w/w). Then, Rhodamine 6G (R6G) is selected as model drug in drug delivery experiment. The efficiency of drug loading and drug release of these Fe3O4/PAA nanocarriers are evaluated under various temperature, solvent and pH values. As a result, the best drug releasing rate was achieved as 93.0% in pH = 7.4 PBS solution after 14 h. The releasing efficiency is 86.5% in acidic condition, while a lower releasing rate (30.0%) is obtained in aqueous solution, as different forms (polyacrylic acid and polyacrylate) of PAA present different solubility parameters, causing different salt and acid effects in various solvents, swelling property of PAA, and binding force between PAA and R6G. Therefore, by changing the solubility parameter of coating polymers, the drug delivery properties could be effectively tuned. These findings prove that the DDS based on magnetic particle cores and polymer encapsulation could efficiently regulate the drug delivery properties by tuning surface solubility parameter in potential cancer targeting and therapy. PMID- 29415454 TI - Chromosome Evolution in Marsupials. AB - Marsupials typically possess very large, distinctive chromosomes that make them excellent subjects for cytogenetic analysis, and the high level of conservation makes it relatively easy to track chromosome evolution. There are two speciose marsupial families with contrasting rates of karyotypic evolution that could provide insight into the mechanisms driving genome reshuffling and speciation. The family Dasyuridae displays exceptional karyotype conservation with all karyotyped species possessing a 2n = 14 karyotype similar to that predicted for the ancestral marsupial. In contrast, the family Macropodidae has experienced a higher rate of genomic rearrangement and one genus of macropods, the rock wallabies (Petrogale), has experienced extensive reshuffling. For at least some recently diverged Petrogale species, there is still gene flow despite hybrid fertility issues, making this species group an exceptional model for studying speciation. This review highlights the unique chromosome features of marsupial chromosomes, particularly for these two contrasting families, and the value that a combined cytogenetics, genomics, and epigenomics approach will have for testing models of genome evolution and speciation. PMID- 29415455 TI - Proteome Profiling of Diabetic Mellitus Patient Urine for Discovery of Biomarkers by Comprehensive MS-Based Proteomics. AB - Diabetic mellitus (DM) is a disease that affects glucose homeostasis and causes complications, such as diabetic nephropathy (DN). For early diagnosis of DN, microalbuminuria is currently one of the most frequently used biomarkers. However, more early diagnostic biomarkers are desired in addition to microalbuminuria. In this study, we performed comprehensive proteomics analysis of urine proteomes of diabetic mellitus patients without microalbuminuria and healthy volunteers to compare the protein profiles by mass spectrometry. With high confidence criteria, 942 proteins in healthy volunteer urine and 645 proteins in the DM patient urine were identified with label-free semi quantitation, respectively. Gene ontology and pathway analysis were performed with the proteins, which were up- or down-regulated in the DM patient urine to elucidate significant changes in pathways. The discovery of a useful biomarker for early DN discovery is expected. PMID- 29415456 TI - BET Family Protein BRD4: An Emerging Actor in NFkappaB Signaling in Inflammation and Cancer. AB - NFkappaB (Nuclear Factor-kappa-light-chain-enhancer of activated B cells) signaling elicits global transcriptional changes by activating cognate promoters and through genome-wide remodeling of cognate regulatory elements called "super enhancers". BET (Bromodomain and Extra-Terminal domain) protein family inhibitor studies have implicated BET protein member BRD4 and possibly other BET proteins in NFkappaB-dependent promoter and super-enhancer modulation. Members of the BET protein family are known to bind acetylated chromatin to facilitate access by transcriptional regulators to chromatin, as well as to assist the activity of transcription elongation complexes via CDK9/pTEFb. BET family member BRD4 has been shown to bind non-histone proteins and modulate their activity. One such protein is RELA, the NFkappaB co-activator. Specifically, BRD4 binds acetylated RELA, which increases its transcriptional transactivation activity and stability in the nucleus. In aggregate, this establishes an intimate link between NFkappaB and BET signaling, at least via BRD4. The present review provides a brief overview of the structure and function of BET family proteins and then examines the connections between NFkappaB and BRD4 signaling, using the inflammatory response and cancer cell signaling as study models. We also discuss the potential of BET inhibitors for relief of aberrant NFkappaB signaling in cancer, focusing on non-histone, acetyl-lysine binding functions. PMID- 29415458 TI - Alterations of Subchondral Bone Progenitor Cells in Human Knee and Hip Osteoarthritis Lead to a Bone Sclerosis Phenotype. AB - Subchondral bone tissue plays a key role in the initiation and progression of human and experimental osteoarthritis and has received considerable interest as a treatment target. Elevated bone turnover and remodeling leads to subchondral bone sclerosis that is characterized by an increase in bone material that is less mineralized. The aim of this study was to investigate whether perturbations in subchondral bone-resident progenitor cells might play a role in aberrant bone formation in osteoarthritis. Colony formation assays indicated similar clonogenicity of progenitor cells from non-sclerotic and sclerotic subchondral trabecular bone tissues of osteoarthritic knee and hip joints compared with controls from iliac crest bone. However, the osteogenic potential at the clonal level was approximately two-fold higher in osteoarthritis than controls. An osteogenic differentiation assay indicated an efficient induction of alkaline phosphatase activity but blunted in vitro matrix mineralization irrespective of the presence of sclerosis. Micro-computed tomography and histology demonstrated the formation of de novo calcified tissues by osteoblast-like cells in an ectopic implantation model. The expression of bone sialoprotein, a marker for osteoblast maturation and mineralization, was significantly less in sclerotic progenitor cells. Perturbation of resident progenitor cell function is associated with subchondral bone sclerosis and may be a treatment target for osteoarthritis. PMID- 29415457 TI - Role of Zinc Homeostasis in the Pathogenesis of Diabetes and Obesity. AB - Zinc deficiency is a risk factor for obesity and diabetes. However, until recently, the underlying molecular mechanisms remained unclear. The breakthrough discovery that the common polymorphism in zinc transporter SLC30A8/ZnT8 may increase susceptibility to type 2 diabetes provided novel insights into the role of zinc in diabetes. Our group and others showed that altered ZnT8 function may be involved in the pathogenesis of type 2 diabetes, indicating that the precise control of zinc homeostasis is crucial for maintaining health and preventing various diseases, including lifestyle-associated diseases. Recently, the role of the zinc transporter ZIP13 in the regulation of beige adipocyte biogenesis was clarified, which indicated zinc homeostasis regulation as a possible therapeutic target for obesity and metabolic syndrome. Here we review advances in the role of zinc homeostasis in the pathophysiology of diabetes, and propose that inadequate zinc distribution may affect the onset of diabetes and metabolic diseases by regulating various critical biological events. PMID- 29415459 TI - Chemometric Analysis of the Volatile Compounds Generated by Aspergillus carbonarius Strains Isolated from Grapes and Dried Vine Fruits. AB - Ochratoxin A (OTA) contamination in grape production is an important problem worldwide. Microbial volatile organic compounds (MVOCs) have been demonstrated as useful tools to identify different toxigenic strains. In this study, Aspergillus carbonarius strains were classified into two groups, moderate toxigenic strains (MT) and high toxigenic strains (HT), according to OTA-forming ability. The MVOCs were analyzed by GC-MS and the data processing was based on untargeted profiling using XCMS Online software. Orthogonal projection to latent structures discriminant analysis (OPLS-DA) was performed using extract ion chromatogram GC MS datasets. For contrast, quantitative analysis was also performed. Results demonstrated that the performance of the OPLS-DA model of untargeted profiling was better than the quantitative method. Potential markers were successfully discovered by variable importance on projection (VIP) and t-test. (E)-2-octen-1 ol, octanal, 1-octen-3-one, styrene, limonene, methyl-2-phenylacetate and 3 unknown compounds were selected as potential markers for the MT group. Cuparene, (Z)-thujopsene, methyl octanoate and 1 unknown compound were identified as potential markers for the HT groups. Finally, the selected markers were used to construct a supported vector machine classification (SVM-C) model to check classification ability. The models showed good performance with the accuracy of cross-validation and test prediction of 87.93% and 92.00%, respectively. PMID- 29415460 TI - The Plant Defensin NaD1 Enters the Cytoplasm of Candida Albicans via Endocytosis. AB - Antimicrobial peptides are widespread in nature and are produced by many organisms as a first line of defence against pathogens. These peptides have a broad range of biological activities, such as antibacterial or antifungal activities and act with varied mechanisms of action. A large number of the peptides are amphipathic alpha-helices which act by disrupting plasma membranes and allowing leakage of intracellular contents. However, some peptides have more complex mechanisms of action that require internalisation into the target organisms' cytoplasm. The method by which these peptides enter the cytoplasm varies, with some requiring the energy dependent processes of endocytosis or polyamine transport and others entering via passive transport. Here we describe the mechanism that the antimicrobial peptide, the plant defensin NaD1, uses to transverse the fungal membrane and gain access to the fungal cytoplasm. By inhibiting ATP synthesis and using an inhibitor of actin polymerisation, we show that NaD1 is internalised into C. albicans yeast cells by the energy-dependent process of endocytosis. PMID- 29415462 TI - The Use of Tactile Sensors and PIV Analysis for Understanding the Bearing Mechanism of Pile Groups. AB - Model tests were carried out in dry silica sand under pile loading and visualizing observation to investigate the behavior of a pile group. The pile group consisted of nine cylindrical model piles of 40 mm in diameter in most tests or three rectangular parallelepiped model piles in the visualizing observation. Pile spacings of 200 mm and 100 mm between pile centers were used in the models. Tactile sensors were installed to measure the pressure distribution in the ground and colored sand layer with particle image velocimetry (PIV) analysis to reveal the ground deformation in addition to strain gauges inside the model piles to investigate the interaction among group piles. The tests results showed that a narrower spacing between piles resulted in a wider affected area of the ground and the interaction was more significant below the tips. PMID- 29415461 TI - Does Walkability Contribute to Geographic Variation in Psychosocial Distress? A Spatial Analysis of 91,142 Members of the 45 and Up Study in Sydney, Australia. AB - Walkability describes the capacity of the built environment to promote walking, and has been proposed as a potential focus for community-level mental health planning. We evaluated this possibility by examining the contribution of area level walkability to variation in psychosocial distress in a population cohort at spatial scales comparable to those used for regional planning in Sydney, Australia. Data on psychosocial distress were analysed for 91,142 respondents to the 45 and Up Study baseline survey between January 2006 and April 2009. We fit conditional auto regression models at the postal area level to obtain smoothed "disease maps" for psychosocial distress, and assess its association with area level walkability after adjusting for individual- and area-level factors. Prevalence of psychosocial distress was 7.8%; similar for low (7.9%), low-medium (7.9%), medium-high (8.0%), and high (7.4%) walkability areas; and decreased with reducing postal area socioeconomic disadvantage: 12.2% (most), 9.3%, 7.5%, 5.9%, and 4.7% (least). Unadjusted disease maps indicated strong geographic clustering of psychosocial distress with 99.0% of excess prevalence due to unobserved and spatially structured factors, which was reduced to 55.3% in fully adjusted maps. Spatial and unstructured variance decreased by 97.3% and 39.8% after adjusting for individual-level factors, and another 2.3% and 4.2% with the inclusions of area-level factors. Excess prevalence of psychosocial distress in postal areas was attenuated in adjusted models but remained spatially structured. Postal area prevalence of high psychosocial distress is geographically clustered in Sydney, but is unrelated to postal area walkability. Area-level socioeconomic disadvantage makes a small contribution to this spatial structure; however, community-level mental health planning will likely deliver greatest benefits by focusing on individual-level contributors to disease burden and inequality associated with psychosocial distress. PMID- 29415463 TI - Changes in DNA Methylation from Age 18 to Pregnancy in Type 1, 2, and 17 T Helper and Regulatory T-Cells Pathway Genes. AB - To succeed, pregnancies need to initiate immune biases towards T helper 2 (Th2) responses, yet little is known about what establishes this bias. Using the Illumina 450 K platform, we explored changes in DNA methylation (DNAm) of Th1, Th2, Th17, and regulatory T cell pathway genes before and during pregnancy. Female participants were recruited at birth (1989), and followed through age 18 years and their pregnancy (2011-2015). Peripheral blood DNAm was measured in 245 girls at 18 years; from among these girls, the DNAm of 54 women was repeatedly measured in the first (weeks 8-21, n = 39) and second (weeks 22-38, n = 35) halves of pregnancy, respectively. M-values (logit-transformed beta-values of DNAm) were analyzed: First, with repeated measurement models, cytosine-phosphate guanine sites (CpGs) of pathway genes in pregnancy and at age 18 (nonpregnant) were compared for changes (p <= 0.05). Second, we tested how many of the 348 pathway-related CpGs changed compared to 10 randomly selected subsets of all other CpGs and compared to 10 randomly selected subsets of other CD4+-related CpGs (348 in each subset). Contrasted to the nonpregnant state, 27.7% of Th1 related CpGs changed in the first and 36.1% in the second half of pregnancy. Among the Th2 pathway CpGs, proportions of changes were 35.1% (first) and 33.8% (second half). The methylation changes suggest involvement of both Th1 and Th2 pathway CpGs in the immune bias during pregnancy. Changes in regulatory T cell and Th17 pathways need further exploration. PMID- 29415464 TI - Comment on Tomaskova et al. Mortality in Miners with Coal-Workers' Pneumoconiosis in the Czech Republic in the Period 1992-2013. Int. J. Environ. Res. Public Health, 2017, 14, 269. AB - With interest, I read the recent analysis by Tomaskova and co-workers (2017) about mortality from coal workers' pneumoconiosis (CWP). The research question remains unclear whether coal workers' pneumoconiosis (CWP) resulting from exposure to respirable coal dust containing crystalline silica accelerates the development of lung cancer or whether it is an intermediate stage in the pathway. I made several points of considerations with respect to (1) qualified data; (2) alternate measures for excessive risks; and (3) methodological flaws that should be avoided. PMID- 29415467 TI - Comparison of Ultra-Rapid Orbit Prediction Strategies for GPS, GLONASS, Galileo and BeiDou. AB - Currently, ultra-rapid orbits play an important role in the high-speed development of global navigation satellite system (GNSS) real-time applications. This contribution focuses on the impact of the fitting arc length of observed orbits and solar radiation pressure (SRP) on the orbit prediction performance for GPS, GLONASS, Galileo and BeiDou. One full year's precise ephemerides during 2015 were used as fitted observed orbits and then as references to be compared with predicted orbits, together with known earth rotation parameters. The full nine parameter Empirical Center for Orbit Determination in Europe (CODE) Orbit Model (ECOM) and its reduced version were chosen in our study. The arc lengths of observed fitted orbits that showed the smallest weighted root mean squares (WRMSs) and medians of the orbit differences after a Helmert transformation fell between 40 and 45 h for GPS and GLONASS and between 42 and 48 h for Galileo, while the WRMS values and medians become flat after a 42 h arc length for BeiDou. The stability of the Helmert transformation and SRP parameters also confirmed the similar optimal arc lengths. The range around 42-45 h is suggested to be the optimal arc length interval of the fitted observed orbits for the multi-GNSS joint solution of ultra-rapid orbits. PMID- 29415465 TI - Modulation of Telomerase Activity in Cancer Cells by Dietary Compounds: A Review. AB - Telomerase is expressed in ~90% of human cancer cell lines and tumor specimens, whereas its enzymatic activity is not detectable in most human somatic cells, suggesting that telomerase represents a highly attractive target for selective cancer treatment. Accordingly, various classes of telomerase inhibitors have been screened and developed in recent years. We and other researchers have successfully found that some dietary compounds can modulate telomerase activity in cancer cells. Telomerase inhibitors derived from food are subdivided into two groups: one group directly blocks the enzymatic activity of telomerase (e.g., catechin and sulfoquinovosyldiacylglycerol), and the other downregulates the expression of human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, via signal transduction pathways (e.g., retinoic acid and tocotrienol). In contrast, a few dietary components, including genistein and glycated lipid, induce cellular telomerase activity in several types of cancer cells, suggesting that they may be involved in tumor progression. This review summarizes the current knowledge about the effects of dietary factors on telomerase regulation in cancer cells and discusses their molecular mechanisms of action. PMID- 29415466 TI - The Role of Trio, a Rho Guanine Nucleotide Exchange Factor, in Glomerular Podocytes. AB - Nephrotic syndrome is a kidney disease featured by heavy proteinuria. It is caused by injury to the specialized epithelial cells called "podocytes" within the filtration unit of the kidney, glomerulus. Previous studies showed that hyperactivation of the RhoGTPase, Rac1, in podocytes causes podocyte injury and glomerulosclerosis (accumulation of extracellular matrix in the glomerulus). However, the mechanism by which Rac1 is activated during podocyte injury is unknown. Trio is a guanine nucleotide exchange factor (GEF) known to activate Rac1. By RNA-sequencing, we found that Trio mRNA is abundantly expressed in cultured human podocytes. Trio mRNA was also significantly upregulated in humans with minimal change disease and focal segmental glomerulosclerosis, two representative causes of nephrotic syndrome. Reduced expression of Trio in cultured human podocytes decreased basal Rac1 activity, cell size, attachment to laminin, and motility. Furthermore, while the pro-fibrotic cytokine, transforming growth factor beta1 increased Rac1 activity in control cells, it decreases Rac1 activity in cells with reduced Trio expression. This was likely due to simultaneous activation of the Rac1-GTPase activation protein, CdGAP. Thus, Trio is important in the basal functions of podocytes and may also contribute to glomerular pathology, such as sclerosis, via Rac1 activation. PMID- 29415468 TI - UV Absorption Spectroscopy in Water-Filled Antiresonant Hollow Core Fibers for Pharmaceutical Detection. AB - Due to a worldwide increased use of pharmaceuticals and, in particular, antibiotics, a growing number of these substance residues now contaminate natural water resources and drinking supplies. This triggers a considerable demand for low-cost, high-sensitivity methods for monitoring water quality. Since many biological substances exhibit strong and characteristic absorption features at wavelengths shorter than 300 nm, UV spectroscopy presents a suitable approach for the quantitative identification of such water-contaminating species. However, current UV spectroscopic devices often show limited light-matter interaction lengths, demand sophisticated and bulky experimental infrastructure which is not compatible with microfluidics, and leave large fractions of the sample analyte unused. Here, we introduce the concept of UV spectroscopy in liquid-filled anti resonant hollow core fibers, with large core diameters and lengths of approximately 1 m, as a means to overcome such limitations. This extended light matter interaction length principally improves the concentration detection limit by two orders of magnitude while using almost the entire sample volume-that is three orders of magnitude smaller compared to cuvette based approaches. By integrating the fibers into an optofluidic chip environment and operating within the lowest experimentally feasible transmission band, concentrations of the application-relevant pharmaceutical substances, sulfamethoxazole (SMX) and sodium salicylate (SS), were detectable down to 0.1 uM (26 ppb) and 0.4 uM (64 ppb), respectively, with the potential to reach significantly lower detection limits for further device integration. PMID- 29415471 TI - Analysis of Dark Current in BRITE Nanostellite CCD Sensors. AB - The BRightest Target Explorer (BRITE) is the pioneering nanosatellite mission dedicated for photometric observations of the brightest stars in the sky. The BRITE charge coupled device (CCD) sensors are poorly shielded against extensive flux of energetic particles which constantly induce defects in the silicon lattice. In this paper we investigate the temporal evolution of the generation of the dark current in the BRITE CCDs over almost four years after launch. Utilizing several steps of image processing and employing normalization of the results, it was possible to obtain useful information about the progress of thermal activity in the sensors. The outcomes show a clear and consistent linear increase of induced damage despite the fact that only about 0.14% of CCD pixels were probed. By performing the analysis of temperature dependencies of the dark current, we identified the observed defects as phosphorus-vacancy (PV) pairs, which are common in proton irradiated CCD matrices. Moreover, the Meyer-Neldel empirical rule was confirmed in our dark current data, yielding E M N = 24.8 meV for proton induced PV defects. PMID- 29415469 TI - CircSMARCA5 Inhibits Migration of Glioblastoma Multiforme Cells by Regulating a Molecular Axis Involving Splicing Factors SRSF1/SRSF3/PTB. AB - Circular RNAs (circRNAs) have recently emerged as a new class of RNAs, highly enriched in the brain and very stable within cells, exosomes and body fluids. To analyze their involvement in glioblastoma multiforme (GBM) pathogenesis, we assayed the expression of twelve circRNAs, physiologically enriched in several regions of the brain, through real-time PCR in a cohort of fifty-six GBM patient biopsies and seven normal brain parenchymas. We focused on hsa_circ_0001445 (circSMARCA5): it was significantly downregulated in GBM biopsies as compared to normal brain tissues (p-value < 0.00001, student's t-test), contrary to its linear isoform counterpart that did not show any differential expression (p-value = 0.694, student's t-test). Analysis of a public dataset revealed a negative correlation between the expression of circSMARCA5 and glioma's histological grade, suggesting its potential negative role in the progression to malignancy. Overexpressing circSMARCA5 in U87MG cells significantly decreased their migration, but not their proliferation rate. In silico scanning of circSMARCA5 sequence revealed an enrichment in binding motifs for several RNA binding proteins (RBPs), specifically involved in splicing. Among them, serine and arginine rich splicing factor 1 (SRSF1), a splicing factor known to be a positive controller of cell migration and known to be overexpressed in GBM, was predicted to bind circSMARCA5 by three different prediction tools. Direct interaction between circSMARCA5 and SRSF1 is supported by enhanced UV crosslinking and immunoprecipitation (eCLIP) data for SRSF1 in K562 cells from Encyclopedia of DNA Elements (ENCODE). Consistently, U87MG overexpressing circSMARCA5 showed an increased expression of serine and arginine rich splicing factor 3 (SRSF3) RNA isoform containing exon 4, normally skipped in a SRSF1-dependent manner, resulting in a non-productive non-sense mediated decay (NMD) substrate. Interestingly, SRSF3 is known to interplay with two other splicing factors, polypyrimidine tract binding protein 1 (PTBP1) and polypyrimidine tract binding protein 2 (PTBP2), that positively regulate glioma cells migration. Collectively, our data show circSMARCA5 as a promising druggable tumor suppressor in GBM and suggest that it may exert its function by tethering the RBP SRSF1. PMID- 29415472 TI - Dynamic Vertical Mapping with Crowdsourced Smartphone Sensor Data. AB - In this paper, we present our novel approach for the crowdsourced dynamic vertical mapping of buildings. For achieving this, we use the barometric sensor of smartphones to estimate altitude differences and the moment of the outdoor to indoor transition to extract reference pressure. We have identified the outdoor indoor transition (OITransition) via the fusion of four different sensors. Our approach has been evaluated extensively over a period of 6 months in different humidity, temperature, and cloud-coverage situations, as well as over different hours of the day, and it is found that it can always predict the correct number of floors, while it can approximate the altitude with an average error of 0.5 m. PMID- 29415470 TI - Multimodal Discrimination between Normal Aging, Mild Cognitive Impairment and Alzheimer's Disease and Prediction of Cognitive Decline. AB - Alzheimer's Disease (AD) and mild cognitive impairment (MCI) are associated with widespread changes in brain structure and function, as indicated by magnetic resonance imaging (MRI) morphometry and 18-fluorodeoxyglucose position emission tomography (FDG PET) metabolism. Nevertheless, the ability to differentiate between AD, MCI and normal aging groups can be difficult. Thus, the goal of this study was to identify the combination of cerebrospinal fluid (CSF) biomarkers, MRI morphometry, FDG PET metabolism and neuropsychological test scores to that best differentiate between a sample of normal aging subjects and those with MCI and AD from the Alzheimer's Disease Neuroimaging Initiative. The secondary goal was to determine the neuroimaging variables from MRI, FDG PET and CSF biomarkers that can predict future cognitive decline within each group. To achieve these aims, a series of multivariate stepwise logistic and linear regression models were generated. Combining all neuroimaging modalities and cognitive test scores significantly improved the index of discrimination, especially at the earliest stages of the disease, whereas MRI gray matter morphometry variables best predicted future cognitive decline compared to other neuroimaging variables. Overall these findings demonstrate that a multimodal approach using MRI morphometry, FDG PET metabolism, neuropsychological test scores and CSF biomarkers may provide significantly better discrimination than any modality alone. PMID- 29415473 TI - Optimized Calibration Procedure of the Damage Parameters of AA6082-T6 Sheets. AB - The constitutive equation of AA6082-T6 sheets is investigated by an extended Rousselier damage model. Previous research is mainly comprised of single-pull test specimens, notched tensile specimens, tensile specimens with a hole, and shear specimens. To decrease the natural material errors, a new specimen is used. In this paper, a clinched joint is regarded as a specimen to calibrate the initial void volume fraction k omega and the shear damage parameter f 0 by using the orthogonal analysis method, which can reduce the simulation times and accuracy. It also reveals that the initial void volume fraction f 0 affects the void volume fraction in the neck and the groove of the clinched joint, and the shear damage parameter k omega affects just the void volume fraction f in the neck of the clinched joint. It checks the force-displacement curve, shape of the clinched joint, and the fracture location, and approves that these damage parameters can describe the deformation process, fracture location, and shape of the clinched joint. PMID- 29415474 TI - Self-Tuning Threshold Method for Real-Time Gait Phase Detection Based on Ground Contact Forces Using FSRs. AB - This paper presents a novel methodology for detecting the gait phase of human walking on level ground. The previous threshold method (TM) sets a threshold to divide the ground contact forces (GCFs) into on-ground and off-ground states. However, the previous methods for gait phase detection demonstrate no adaptability to different people and different walking speeds. Therefore, this paper presents a self-tuning triple threshold algorithm (STTTA) that calculates adjustable thresholds to adapt to human walking. Two force sensitive resistors (FSRs) were placed on the ball and heel to measure GCFs. Three thresholds (i.e., high-threshold, middle-threshold andlow-threshold) were used to search out the maximum and minimum GCFs for the self-adjustments of thresholds. The high threshold was the main threshold used to divide the GCFs into on-ground and off ground statuses. Then, the gait phases were obtained through the gait phase detection algorithm (GPDA), which provides the rules that determine calculations for STTTA. Finally, the STTTA reliability is determined by comparing the results between STTTA and Mariani method referenced as the timing analysis module (TAM) and Lopez-Meyer methods. Experimental results show that the proposed method can be used to detect gait phases in real time and obtain high reliability when compared with the previous methods in the literature. In addition, the proposed method exhibits strong adaptability to different wearers walking at different walking speeds. PMID- 29415475 TI - Low-Pass Filter for HV Partial Discharge Testing. AB - The most common cause of high voltage electric machine malfunction is an electrical failure of the insulation system due to extreme partial discharges activity. The paper discusses the methodology for the construction of a low-pass high voltage filter for partial discharge measurement. It focuses mainly on the shape optimization, using an analytical approach with subsequent verification using the finite element method. The experimental verification is given together with important conclusions. PMID- 29415477 TI - Fiber-Optic Pyrometer with Optically Powered Switch for Temperature Measurements. AB - We report the experimental results on a new infrared fiber-optic pyrometer for very localized and high-speed temperature measurements ranging from 170 to 530 degrees C using low-noise photodetectors and high-gain transimpedance amplifiers with a single gain mode in the whole temperature range. We also report a shutter based on an optical fiber switch which is optically powered to provide a reference signal in an optical fiber pyrometer measuring from 200 to 550 degrees C. The tests show the potential of remotely powering via optical means a 300 mW power-hungry optical switch at a distance of 100 m, avoiding any electromagnetic interference close to the measuring point. PMID- 29415478 TI - Empirically Derived Dietary Patterns in UK Adults Are Associated with Sociodemographic Characteristics, Lifestyle, and Diet Quality. AB - The aim of this study was to examine empirical dietary patterns in UK adults and their association with sociodemographic characteristics, lifestyle factors, self reported nutrient intake, nutrient biomarkers, and the Nutrient-based Diet Quality Score (NDQS) using National Diet and Nutrition Survey data 2008-2012 (n = 2083; mean age 49 years; 43.3% male). Four patterns explained 13.6% of the total variance: 'Snacks, fast food, fizzy drinks' (SFFFD), 'Fruit, vegetables, oily fish' (FVOF), 'Meat, potatoes, beer' (MPB), and 'Sugary foods, dairy' (SFD). 'SFFFD' was associated positively with: being male; smoking; body mass index (BMI); urinary sodium; intake of non-milk extrinsic sugars (NMES), fat and starch; and negatively with: age; plasma carotenoids; and NDQS. 'FVOF' was associated positively with: being non-white; age; income; socioeconomic classification (National Statistics Socio-economic Classifications; NSSEC); plasma carotenoids; intake of non-starch polysaccharides and polyunsaturated fatty acids. It was negatively associated with: being male, smoking, BMI, urinary sodium, intake of saturated fat; and NMES and NDQS. Whilst the patterns explained only 13.6% of the total variance, they were associated with self-reported nutrient intake, biomarkers of nutrient intake, sociodemographic and lifestyle variables, and the NDQS. These findings provide support for dietary patterns analyses as a means of exploring dietary intake in the UK population to inform public health nutrition policy and guidance. PMID- 29415476 TI - The Impact of Aging on Cardio and Cerebrovascular Diseases. AB - A growing number of evidences report that aging represents the major risk factor for the development of cardio and cerebrovascular diseases. Understanding Aging from a genetic, biochemical and physiological point of view could be helpful to design a better medical approach and to elaborate the best therapeutic strategy to adopt, without neglecting all the risk factors associated with advanced age. Of course, the better way should always be understanding risk-to-benefit ratio, maintenance of independence and reduction of symptoms. Although improvements in treatment of cardiovascular diseases in the elderly population have increased the survival rate, several studies are needed to understand the best management option to improve therapeutic outcomes. The aim of this review is to give a 360 degrees panorama on what goes on in the fragile ecosystem of elderly, why it happens and what we can do, right now, with the tools at our disposal to slow down aging, until new discoveries on aging, cardio and cerebrovascular diseases are at hand. PMID- 29415480 TI - Predictors of Dietary Energy Density among Preschool Aged Children. AB - Childhood obesity is a global problem with many contributing factors including dietary energy density (DED). This paper aims to investigate potential predictors of DED among preschool aged children in Victoria, Australia. Secondary analysis of longitudinal data for 209 mother-child pairs from the Melbourne Infant Feeding, Activity and Nutrition Trial was conducted. Data for predictors (maternal child feeding and nutrition knowledge, maternal dietary intake, home food availability, socioeconomic status) were obtained through questionnaires completed by first-time mothers when children were aged 4 or 18 months. Three 24 h dietary recalls were completed when children were aged ~3.5 years. DED was calculated utilizing three methods: "food only", "food and dairy beverages", and "food and all beverages". Linear regression analyses were conducted to identify associations between predictors and these three measures of children's DED. Home availability of fruits (beta: -0.82; 95% CI: -1.35, -0.29, p = 0.002 for DEDfood; beta: -0.42; 95% CI: -0.82, -0.02, p = 0.041 for DEDfood+dairy beverages) and non core snacks (beta: 0.11; 95% CI: 0.02, 0.20, p = 0.016 for DEDfood; beta: 0.09; 95% CI: 0.02, 0.15, p = 0.010 for DEDfood+dairy beverages) were significantly associated with two of the three DED measures. Providing fruit at home early in a child's life may encourage the establishment of healthful eating behaviors that could promote a diet that is lower in energy density later in life. Home availability of non-core snacks is likely to increase the energy density of preschool children's diets, supporting the proposition that non-core snack availability at home should be limited. PMID- 29415479 TI - Telomere Length Dynamics and the Evolution of Cancer Genome Architecture. AB - Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB) repair machinery, leading to telomere fusion with both telomeric and non telomeric loci. The consequences of telomere fusions in promoting genome instability have long been appreciated through the breakage-fusion-bridge (BFB) cycle mechanism, although recent studies using high-throughput sequencing technologies have uncovered evidence of involvement in a wider spectrum of genomic rearrangements including chromothripsis. A critical step in cancer progression is the transition of a clone to immortality, through the stabilisation of the telomere repeat array. This can be achieved via the reactivation of telomerase, or the induction of the alternative lengthening of telomeres (ALT) pathway. Whilst telomere dysfunction may promote genome instability and tumour progression, by limiting the replicative potential of a cell and enforcing senescence, telomere shortening can act as a tumour suppressor mechanism. However, the burden of senescent cells has also been implicated as a driver of ageing and age-related pathology, and in the promotion of cancer through inflammatory signalling. Considering the critical role of telomere length in governing cancer biology, we review questions related to the prognostic value of studying the dynamics of telomere shortening and fusion, and discuss mechanisms and consequences of telomere-induced genome rearrangements. PMID- 29415481 TI - Genome-Wide Analysis of the NF-YB Gene Family in Gossypium hirsutum L. and Characterization of the Role of GhDNF-YB22 in Embryogenesis. AB - Members of the NF-YB transcription factor gene family play important roles in diverse processes related to plant growth and development, such as seed development, drought tolerance, and flowering time. However, the function of NF YB genes in cotton remains unclear. A total of 23, 24, and 50 NF-YB genes were identified in Gossypium arboreum (G. arboreum), Gossypium raimondii (G. raimondii), and G. hirsutum, respectively. A systematic phylogenetic analysis was carried out in G. arboretum, G. raimondii, G. hirsutum, Arabidopsis thaliana, cacao, rice and, sorghum, where the 150 NF-YB genes were divided into five groups (alpha-epsilon). Of these groups, alpha is the largest clade, and gamma contains the LEC1 type NF-YB proteins. Syntenic analyses revealed that paralogues of NF-YB genes in G. hirsutum exhibited good collinearity. Owing to segmental duplication within the A sub-genome (At) and D sub-genome (Dt), there was an expanded set of NF-YB genes in G. hirsutum. Furthermore, we investigated the structures of exons, introns, and conserved motifs of NF-YB genes in upland cotton. Most of the NF-YB genes had only one exon, and the genes from the same clade exhibited a similar motif pattern. Expression data show that most NF-YB genes were expressed ubiquitously, and only a few genes were highly expressed in specific tissues, as confirmed by quantitative real-time PCR (qRT-PCR) analysis. The overexpression of GhDNF-YB22 gene, predominantly expressed in embryonic tissues, indicates that GhDNF-YB22 may affect embryogenesis in cotton. This study is the first comprehensive characterization of the GhNF-YB gene family in cotton, and showed that NF-YB genes could be divided into five clades. The duplication events that occurred over the course of evolution were the major impetus for NF-YB gene expansion in upland cotton. Collectively, this work provides insight into the evolution of NF-YB in cotton and further our knowledge of this commercially important species. PMID- 29415482 TI - Long Chain Omega-3 Polyunsaturated Fatty Acid Supplementation Protects Against Adriamycin and Cyclophosphamide Chemotherapy-Induced Bone Marrow Damage in Female Rats. AB - Although bone marrow and bone toxicities have been reported in breast cancer survivors, preventative strategies are yet to be developed. Clinical studies suggest consumption of long chain omega-3 polyunsaturated fatty acids (LCn3PUFA) can attenuate age-related bone loss, and recent animal studies also revealed benefits of LCn3PUFA in alleviating bone marrow and bone toxicities associated with methotrexate chemotherapy. Using a female rat model for one of the most commonly used anthracycline-containing breast cancer chemotherapy regimens (adriamycin + cyclophosphamide) (AC) chemotherapy, this study investigated potential effects of daily LCn3PUFA consumption in preserving bone marrow and bone microenvironment during chemotherapy. AC treatment for four cycles significantly reduced bone marrow cellularity and increased marrow adipocyte contents. It increased trabecular bone separation but no obvious changes in bone volume or bone cell densities. LCn3PUFA supplementation (375 mg/100 g/day) attenuated AC-induced bone marrow cell depletion and marrow adiposity. It also partially attenuated AC-induced increases in trabecular bone separation and the cell sizes and nuclear numbers of osteoclasts formed ex vivo from bone marrow cells isolated from AC-treated rats. This study suggests that LCn3PUFA supplementation may have beneficial effects in preventing bone marrow damage and partially protecting the bone during AC cancer chemotherapy. PMID- 29415484 TI - Effects of Interactions between ZnO Nanoparticles and Saccharides on Biological Responses. AB - Zinc oxide (ZnO) nanoparticles (NPs) are widely used as a Zn supplement, because Zn plays a role in many cellular and immune functions but public concern about their potentially undesirable effects on the human body is growing. When NPs are added in food matrices, interactions between NPs and food components occur, which can affect biological systems. In this study, interactions between ZnO NPs and saccharides were investigated by measuring changes in hydrodynamic radius, zeta potential and solubility and by quantifying amounts of adsorbed saccharides on NPs; acacia honey, sugar mixtures (containing equivalent amounts of fructose, glucose, sucrose and maltose) and monosaccharide solutions were used as model compounds. Biological responses of NPs dispersed in different saccharides were also evaluated in human intestinal cells and rats in terms of cytotoxicity, cellular uptake, intestinal transport and oral absorption. The results demonstrate that the hydrodynamic radii and zeta potentials of NPs were highly affected by saccharides. In addition, trace nutrients influenced NP/saccharide interactions and interactive effects between saccharides on the interactions were found. NPs in all saccharides increased inhibition of cell proliferation and enhanced cellular uptake. Oral absorption of NPs was highly enhanced by 5% glucose, which is in-line with intestinal transport result. These findings show that ZnO NPs interact with saccharides and these interactions affects biological responses. PMID- 29415485 TI - Experimental in Vivo Models of Candidiasis. AB - Candidiasis is a multifaceted fungal disease including mucosal-cutaneous, visceral, and disseminated infections caused by yeast species of the genus Candida. Candida infections are among the most common human mycoses. Candida species are the third to fourth most common isolates from bloodstream infections in neutropenic or immunocompromised hospitalized patients. The mucosal-cutaneous forms-particularly vaginal infections-have a high prevalence. Vaginitis caused by Candida species is the second most common vaginal infection. Hence, candidiasis is a major subject for research, including experimental in vivo models to study pathogenesis, prevention, or therapy of the disease. The following review article will focus on various experimental in vivo models in different laboratory animals, such as mammals (mice, rats, rabbits), the fruit fly-Drosophila melanogaster, the larvae of the moth Galleria mellonella, or the free-living nematode Caenorhabditis elegans. The review will describe the induction of the different clinical forms of candidiasis in the various models and the validity of such models in mimicking the human clinical situations. The use of such models for the assessment of antifungal drugs, evaluation of potential vaccines to protect before candidiasis, exploration of Candida virulence factors, and comparison of pathogenicity of different Candida species will be included in the review. All of the above will be reported as based on published studies of numerous investigators as well as on the research of the author and his group. PMID- 29415483 TI - Integrins in T Cell Physiology. AB - From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing cytoskeletal remodeling and modulating receptor signaling. LFA-1 (alphaLbeta2 integrin) and VLA-4 (alpha4beta1 integrin) play a key role throughout the T cell lifecycle from thymocyte differentiation to lymphocyte extravasation and finally play a fundamental role in organizing immune synapse, providing an essential costimulatory signal for the T cell receptor. Apart from tuning T cell signaling, integrins also contribute to homing to specific target organs as exemplified by the importance of alpha4beta7 in maintaining the gut immune system. However, apart from those well-characterized examples, the physiological significance of the other integrin dimers expressed by T cells is far less understood. Thus, integrin-mediated cell-to-cell and cell-to-matrix interactions during the T cell lifespan still represent an open field of research. PMID- 29415486 TI - Impact of PSP Technique on Clinical Outcomes Following Bioresorbable Scaffolds Implantation. AB - Bioresorbable scaffolds (BRS) were introduced in clinical practice to overcome the long-term limitations of newer-generation drug-eluting stents. Despite some initial promising results of the Absorb BRS, safety concerns have led to the discontinuation of the commercialization of this device. Several retrospective studies have assessed the impact of the so-called Pre-dilation, Sizing and Post dilation (PSP) technique concluding that an optimal PSP technique can improve clinical outcomes following BRS implantation. In this article, the definition of the PSP technique, and the current evidence of its impact on clinical outcomes are put in perspective. Additionality, the relationship between the PSP technique and the dual-antiplatelet therapy to prevent scaffold thrombosis is addressed. Finally, the future perspectives of BRS technology in clinical practice are commented. PMID- 29415487 TI - Effect of MUC8 on Airway Inflammation: A Friend or a Foe? AB - In this review, we compile identifying molecular mechanisms of MUC8 gene expression and studies characterizing the physiological functions of MUC8 in the airway and analyzing how altered MUC8 gene expression in the lung is affected by negative regulators. PMID- 29415488 TI - Analytic and Unambiguous Phase-Based Algorithm for 3-D Localization of a Single Source with Uniform Circular Array. AB - This paper presents an analytic algorithm for estimating three-dimensional (3-D) localization of a single source with uniform circular array (UCA) interferometers. Fourier transforms are exploited to expand the phase distribution of a single source and the localization problem is reformulated as an equivalent spectrum manipulation problem. The 3-D parameters are decoupled to different spectrums in the Fourier domain. Algebraic relations are established between the 3-D localization parameters and the Fourier spectrums. Fourier sampling theorem ensures that the minimum element number for 3-D localization of a single source with a UCA is five. Accuracy analysis provides mathematical insights into the 3-D localization algorithm that larger number of elements gives higher estimation accuracy. In addition, the phase-based high-order difference invariance (HODI) property of a UCA is found and exploited to realize phase range compression. Following phase range compression, ambiguity resolution is addressed by the HODI of a UCA. A major advantage of the algorithm is that the ambiguity resolution and 3-D localization estimation are both analytic and are processed simultaneously, hence computationally efficient. Numerical simulations and experimental results are provided to verify the effectiveness of the proposed 3-D localization algorithm. PMID- 29415489 TI - Identification of Pancreatic Injury in Patients with Elevated Amylase or Lipase Level Using a Decision Tree Classifier: A Cross-Sectional Retrospective Analysis in a Level I Trauma Center. AB - BACKGROUND: In trauma patients, pancreatic injury is rare; however, if undiagnosed, it is associated with high morbidity and mortality rates. Few predictive models are available for the identification of pancreatic injury in trauma patients with elevated serum pancreatic enzymes. In this study, we aimed to construct a model for predicting pancreatic injury using a decision tree (DT) algorithm, along with data obtained from a population-based trauma registry in a Level I trauma center. METHODS: A total of 991 patients with elevated serum levels of amylase (>137 U/L) or lipase (>51 U/L), including 46 patients with pancreatic injury and 865 without pancreatic injury between January 2009 and December 2016, were allocated in a ratio of 7:3 to training (n = 642) or test (n = 269) sets. Using the data on patient and injury characteristics as well as laboratory data, the DT algorithm with Classification and Regression Tree (CART) analysis was performed based on the Gini impurity index, using the rpart function in the rpart package in R. RESULTS: Among the trauma patients with elevated amylase or lipase levels, three groups of patients were identified as having a high risk of pancreatic injury, using the DT model. These included (1) 69% of the patients with lipase level >=306 U/L; (2) 79% of the patients with lipase level between 154 U/L and 305 U/L and shock index (SI) >= 0.72; and (3) 80% of the patients with lipase level <154 U/L with abdomen injury, glucose level <158 mg/dL, amylase level <90 U/L, and neutrophil percentage >=76%; they had all sustained pancreatic injury. With all variables in the model, the DT achieved an accuracy of 97.9% (sensitivity of 91.4% and specificity of 98.3%) for the training set. In the test set, the DT achieved an accuracy of 93.3%, sensitivity of 72.7%, and specificity of 94.2%. CONCLUSIONS: We established a DT model using lipase, SI, and additional conditions (injury to the abdomen, glucose level <158 mg/dL, amylase level <90 U/L, and neutrophils >=76%) as important nodes to predict three groups of patients with a high risk of pancreatic injury. The proposed decision-making algorithm may help in identifying pancreatic injury among trauma patients with elevated serum amylase or lipase levels. PMID- 29415490 TI - On the Potential of Bulk Metallic Glasses for Dental Implantology: Case Study on Ti40Zr10Cu36Pd14. AB - Ti40Zr10Cu36Pd14 Bulk Metallic Glass (BMG) appears very attractive for future biomedical applications thanks to its high glass forming ability, the absence of toxic elements such as Ni, Al or Be and its good mechanical properties. For the first time, a complete and exhaustive characterization of a unique batch of this glassy alloy was performed, together with ISO standard mechanical tests on machined implant-abutment assemblies. The results were compared to the benchmark Ti-6Al-4V ELI (Extra-Low-Interstitial) to assess its potential in dental implantology. The thermal stability, corrosion and sterilization resistance, cytocompatibility and mechanical properties were measured on samples with a simple geometry, but also on implant-abutment assemblies' prototypes. Results show that the glassy alloy exhibits a quite high thermal stability, with a temperature range of 38 degrees C between the glass transition and crystallization, a compressive strength of 2 GPa, a certain plastic deformation (0.7%), a hardness of 5.5 GPa and a toughness of 56 MPa.?m. Moreover, the alloy shows a relatively lower Young's modulus (96 GPa) than the Ti-6Al-4V alloy (110 115 GPa), which is beneficial to limit bone stress shielding. The BMG shows a satisfactory cytocompatibility, a high resistance to sterilization and a good corrosion resistance (corrosion potential of -0.07 V/SCE and corrosion current density of 6.0 nA/cm2), which may ensure its use as a biomaterial. Tests on dental implants reveal a load to failure 1.5-times higher than that of Ti-6Al-4V and a comparable fatigue limit. Moreover, implants could be machined and sandblasted by methods usually conducted for titanium implants, without significant degradation of their amorphous nature. All these properties place this metallic glass among a promising class of materials for mechanically challenging applications such as dental implants. PMID- 29415491 TI - Is an Appreciation of Isomerism the Key to Unlocking the Mysteries of the Cardiac Findings in Heterotaxy? AB - Pediatric cardiologists treating patients with severe congenital cardiac defects define "visceral heterotaxy" on the basis of isomerism of the atrial appendages. The isomeric features represent an obvious manifestation of disruption of left right asymmetry during embryonic development. Thus, there are two subsets of individuals within the overall syndrome, with features of either right or left isomerism. Within the heart, it is only the atrial appendages that are truly isomeric. The remainder of the cardiac components shows variable morphology, as does the arrangement of the remaining body organs. Order is provided in this potentially chaotic arrangement simply by describing the specific features of each of the systems. These features as defined by clinicians, however, seem less well recognized by those investigating the developmental origins of the disruption of symmetry. Developmental biologists place much greater emphasis on ventricular looping. Although the direction of the loop can certainly be interpreted as representing an example of asymmetry, it is not comparable to the isomeric features that underscore the clinical syndromes. This is because, thus far, there is no evidence of ventricular isomerism, with the ventricles distinguished one from the other on the basis of their disparate anatomical features. In similar fashion, some consider transposition to represent abnormal lateralization, but again, clinical diagnosis depends on recognition of the lateralized features. In this review, therefore, we discuss the key questions that currently underscore the mismatch in the approaches to "lateralization" as taken by clinicians and developmental biologists. PMID- 29415492 TI - Cerium Addition Improved the Dry Sliding Wear Resistance of Surface Welding AZ91 Alloy. AB - In this study, the effects of cerium (Ce) addition on the friction and wear properties of surface welding AZ91 magnesium alloys were evaluated by pin-on-disk dry sliding friction and wear tests at normal temperature. The results show that both the friction coefficient and wear rate of surfacing magnesium alloys decreased with the decrease in load and increase in sliding speed. The surfacing AZ91 alloy with 1.5% Ce had the lowest friction coefficient and wear rate. The alloy without Ce had the worst wear resistance, mainly because it contained a lot of irregularly shaped and coarse beta-Mg17Al12 phases. During friction, the beta phase readily caused stress concentration and thus formed cracks at the interface between beta phase and alpha-Mg matrix. The addition of Ce reduced the size and amount of Mg17Al12, while generating Al4Ce phase with a higher thermal stability. The Al-Ce phase could hinder the grain-boundary sliding and migration and reduced the degree of plastic deformation of subsurface metal. Scanning electron microscopy observation showed that the surfacing AZ91 alloy with 1.5% Ce had a total of four types of wear mechanism: abrasion, oxidation, and severe plastic deformation were the primary mechanisms; delamination was the secondary mechanism. PMID- 29415494 TI - A Highly Sensitive Immunochromatographic Strip Test for Rapid and Quantitative Detection of Saikosaponin d. AB - A quantitative lateral-flow immunoassay using gold nanoparticles (AuNPs) conjugated with a monoclonal antibody (MAb) against saikosaponin d (SSd) was developed for the analysis of SSd. The AuNPs were prepared in our laboratory. The AuNPs were polyhedral, with an average diameter of approximately 18 nm. We used the conjugation between AuNPs and MAbs against SSd to prepare immunochromatographic strips (ICSs). For the quantitative experiment, the strips with the test results were scanned using a membrane strip reader, and a detection curve (regression equation, y = -0.113ln(x) + 1.5451, R2 = 0.983), representing the averages of the scanned data, was obtained. This curve was linear from 96 ng/mL to 150 MUg/mL, and the IC50 value was 10.39 MUg/mL. In this study, we bring the concept ofPOCT (point-of-care testing) to the measurement of TCM compounds, and this is the first report of quantitative detection of SSd by an ICS. PMID- 29415495 TI - Chromatographic and Spectroscopic Identification and Recognition of Natural Dyes, Uncommon Dyestuff Components, and Mordants: Case Study of a 16th Century Carpet with Chintamani Motifs. AB - A multi-tool analytical practice was used for the characterisation of a 16th century carpet manufactured in Cairo. A mild extraction method with hydrofluoric acid has been evaluated in order to isolate intact flavonoids and their glycosides, anthraquinones, tannins, and indigoids from fibre samples. High performance liquid chromatography coupled to spectroscopic and mass spectrometric detectors was used for the identification of possible marker compounds with special attention paid to natural dyes present in the historical samples. Weld, young fustic, and soluble redwood dye were identified as the dye sources in yellow thread samples. Based on the developed method, it was possible to establish that red fibres were coloured with lac dye, whereas green fibre shades were obtained with indigo and weld. Tannin-containing plant material in combination with indigo and weld were used to obtain the brown hue of the thread. Hyphenation of high-performance liquid chromatography (HPLC) with quadrupole time of-flight mass spectrometry (QTOF MS) and triple-quadrupole mass spectrometry (QqQ MS) enabled us to recognise four uncommon and thus-far unknown dye components that were also found in the historical samples. These compounds probably represent a unique fingerprint of dyed threads manufactured in a Turkish workshop. Scanning electron microscopy with energy-dispersive X-ray detector (SEM EDS) and Fourier transform infrared spectroscopy (FT-IR) were used for the identification and characterisation of substrates and mordants present in the historical carpet. Carbon and oxygen were detected in large quantities as a part of the wool protein. The presence of aluminium, iron, and calcium indicated their usage as mordants. Trace amounts of copper, silica, and magnesium might originate from the contaminants. FT-IR analysis showed bands characteristic for woollen fibres and SEM micrographs defined the structure of the wool. PMID- 29415497 TI - Modification and Assembly of a Versatile Lactonase for Bacterial Quorum Quenching. AB - This work sets out to provide a self-assembled biopolymer capsule activated with a multi-functional enzyme for localized delivery. This enzyme, SsoPox, which is a lactonase and phosphotriesterase, provides a means of interrupting bacterial communication pathways that have been shown to mediate pathogenicity. Here we demonstrate the capability to express, purify and attach SsoPox to the natural biopolymer chitosan, preserving its activity to "neutralize" long-chain autoinducer-1 (AI-1) communication molecules. Attachment is shown via non specific binding and by engineering tyrosine and glutamine affinity 'tags' at the C-terminus for covalent linkage. Subsequent degradation of AI-1, in this case N (3-oxododecanoyl)-l-homoserine lactone (OdDHL), serves to "quench" bacterial quorum sensing (QS), silencing intraspecies communication. By attaching enzymes to pH-responsive chitosan that, in turn, can be assembled into various forms, we demonstrate device-based flexibility for enzyme delivery. Specifically, we have assembled quorum-quenching capsules consisting of an alginate inner core and an enzyme "decorated" chitosan shell that are shown to preclude bacterial QS crosstalk, minimizing QS mediated behaviors. PMID- 29415493 TI - Interplay between P-Glycoprotein Expression and Resistance to Endoplasmic Reticulum Stressors. AB - Multidrug resistance (MDR) is a phenotype of cancer cells with reduced sensitivity to a wide range of unrelated drugs. P-glycoprotein (P-gp)-a drug efflux pump (ABCB1 member of the ABC transporter gene family)-is frequently observed to be a molecular cause of MDR. The drug-efflux activity of P-gp is considered as the underlying mechanism of drug resistance against P-gp substrates and results in failure of cancer chemotherapy. Several pathological impulses such as shortages of oxygen and glucose supply, alterations of calcium storage mechanisms and/or processes of protein N-glycosylation in the endoplasmic reticulum (ER) leads to ER stress (ERS), characterized by elevation of unfolded protein cell content and activation of the unfolded protein response (UPR). UPR is responsible for modification of protein folding pathways, removal of misfolded proteins by ER associated protein degradation (ERAD) and inhibition of proteosynthesis. However, sustained ERS may result in UPR-mediated cell death. Neoplastic cells could escape from the death pathway induced by ERS by switching UPR into pro survival mechanisms instead of apoptosis. Here, we aimed to present state of the art information about consequences of P-gp expression on mechanisms associated with ERS development and regulation of the ERAD system, particularly focused on advances in ERS-associated therapy of drug resistant malignancies. PMID- 29415498 TI - Fluorescent Nano-Probes to Image Plant Cell Walls by Super-Resolution STED Microscopy. AB - Lignocellulosic biomass is a complex network of polymers making up the cell walls of plants. It represents a feedstock of sustainable resources to be converted into fuels, chemicals, and materials. Because of its complex architecture, lignocellulose is a recalcitrant material that requires some pretreatments and several types of catalysts to be transformed efficiently. Gaining more knowledge in the architecture of plant cell walls is therefore important to understand and optimize transformation processes. For the first time, super-resolution imaging of poplar wood samples has been performed using the Stimulated Emission Depletion (STED) technique. In comparison to standard confocal images, STED reveals new details in cell wall structure, allowing the identification of secondary walls and middle lamella with fine details, while keeping open the possibility to perform topochemistry by the use of relevant fluorescent nano-probes. In particular, the deconvolution of STED images increases the signal-to-noise ratio so that images become very well defined. The obtained results show that the STED super-resolution technique can be easily implemented by using cheap commercial fluorescent rhodamine-PEG nano-probes which outline the architecture of plant cell walls due to their interaction with lignin. Moreover, the sample preparation only requires easily-prepared plant sections of a few tens of micrometers, in addition to an easily-implemented post-treatment of images. Overall, the STED super-resolution technique in combination with a variety of nano-probes can provide a new vision of plant cell wall imaging by filling in the gap between classical photon microscopy and electron microscopy. PMID- 29415496 TI - Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids. AB - We have synthesized a small series of five 3-[4-arylmethoxy)phenyl]propanoic acids employing an easy and short synthetic pathway. The compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: G protein-coupled receptor 40 (GPR40), aldose reductase (AKR1B1), peroxisome proliferator-activated receptor gama (PPARgamma) and solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT-4). Compound 1 displayed an EC50 value of 0.075 MUM against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7.4 MUM. Compounds 2 and 3 act as slightly AKR1B1 inhibitors, potent GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPARgamma, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active molecules on these targets, showing several coincidences with co-crystal ligands. Compounds 1-3 were tested in vivo at an explorative 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non-insulin-dependent diabetes mice model. Compounds 2 and 3 displayed robust in vitro potency and in vivo efficacy, and could be considered as promising multitarget antidiabetic candidates. This is the first report of a single molecule with these four polypharmacological target action. PMID- 29415499 TI - In Vivo Assessment of Resistant Starch Degradation by the Caecal Microbiota of Mice Using RNA-Based Stable Isotope Probing-A Proof-of-Principle Study. AB - Resistant starch (RS) is the digestion resistant fraction of complex polysaccharide starch. By reaching the large bowel, RS can function as a prebiotic carbohydrate, i.e., it can shape the structure and activity of bowel bacterial communities towards a profile that confers health benefits. However, knowledge about the fate of RS in complex intestinal communities and the microbial members involved in its degradation is limited. In this study, 16S ribosomal RNA (rRNA)-based stable isotope probing (RNA-SIP) was used to identify mouse bowel bacteria involved in the assimilation of RS or its derivatives directly in their natural gut habitat. Stable-isotope [U13C]-labeled native potato starch was administrated to mice, and caecal contents were collected before 0 h and 2 h and 4 h after administration. 'Heavy', isotope-labeled [13C]RNA species, presumably derived from bacteria that have metabolized the labeled starch, were separated from 'light', unlabeled [12C]RNA species by fractionation of isolated total RNA in isopycnic-density gradients. Inspection of different density gradients showed a continuous increase in 'heavy' 16S rRNA in caecal samples over the course of the experiment. Sequencing analyses of unlabeled and labeled 16S amplicons particularly suggested a group of unclassified Clostridiales, Dorea, and a few other taxa (Bacteroides, Turicibacter) to be most actively involved in starch assimilation in vivo. In addition, metabolic product analyses revealed that the predominant 13C-labeled short chain fatty acid (SCFA) in caecal contents produced from the [U13C] starch was butyrate. For the first time, this study provides insights into the metabolic transformation of RS by intestinal bacterial communities directly within a gut ecosystem, which will finally help to better understand its prebiotic potential and possible applications in human health. PMID- 29415500 TI - Impact, Characterization, and Rescue of Pre-mRNA Splicing Mutations in Lysosomal Storage Disorders. AB - Lysosomal storage disorders (LSDs) represent a group of more than 50 severe metabolic diseases caused by the deficiency of specific lysosomal hydrolases, activators, carriers, or lysosomal integral membrane proteins, leading to the abnormal accumulation of substrates within the lysosomes. Numerous mutations have been described in each disease-causing gene; among them, about 5-19% affect the pre-mRNA splicing process. In the last decade, several strategies to rescue/increase normal splicing of mutated transcripts have been developed and LSDs represent excellent candidates for this type of approach: (i) most of them are inherited in an autosomic recessive manner and patients affected by late onset (LO) phenotypes often retain a fair amount of residual enzymatic activity; thus, even a small recovery of normal splicing may be beneficial in clinical settings; (ii) most LSDs still lack effective treatments or are currently treated with extremely expensive approaches; (iii) in few LSDs, a single splicing mutation accounts for up to 40-70% of pathogenic alleles. At present, numerous preclinical studies support the feasibility of reverting the pathological phenotype by partially rescuing splicing defects in LSDs. This review provides an overview of the impact of splicing mutations in LSDs and the related therapeutic approaches currently under investigation in these disorders. PMID- 29415502 TI - Transcriptomics Sequencing Provides Insights into Understanding the Mechanism of Grass Carp Reovirus Infection. AB - Grass carp is an important aquaculture fish species in China that is affected by severe diseases, especially haemorrhagic disease caused by grass carp reovirus (GCRV). However, the mechanisms of GCRV invasion and infection remain to be elucidated. In the present study, Ctenopharyngodon idellus kidney (CIK) cells were infected with GCRV, harvested at 0, 8, 24, and 72 h post infection, respectively, and then subjected to transcriptomics sequencing. Each sample yielded more than 6 Gb of clean data and 40 million clean reads. To better understand GCRV infection, the process was divided into three phases: the early (0-8 h post infection), middle (8-24 h post infection), and late (24-72 h) stages of infection. A total of 76 (35 up-regulated, 41 down-regulated), 553 (463 up regulated, 90 down-regulated), and 284 (150 up-regulated, 134 down-regulated) differently expressed genes (DEGs) were identified during the early, middle, and late stages of infection, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that DEGs were mainly involved in carbohydrate biosynthesis, transport, and endocytosis in the early stage, phagocytosis and lysosome pathways were mainly enriched in the middle stage, and programmed cell death, apoptosis, and inflammation were largely associated with the late stage. These results suggest GCRV infection is a gradual process involving adsorption on the cell surface, followed by endocytosis into cells, transport by lysosomes, and eventually resulted in cell necrosis and/or apoptosis. Our findings provide insight into the mechanisms of grass carp reovirus infection. PMID- 29415501 TI - Peptide-Based Membrane Fusion Inhibitors Targeting HCoV-229E Spike Protein HR1 and HR2 Domains. AB - Human coronavirus 229E (HCoV-229E) infection in infants, elderly people, and immunocompromised patients can cause severe disease, thus calling for the development of effective and safe therapeutics to treat it. Here we reported the design, synthesis and characterization of two peptide-based membrane fusion inhibitors targeting HCoV-229E spike protein heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains, 229E-HR1P and 229E-HR2P, respectively. We found that 229E HR1P and 229E-HR2P could interact to form a stable six-helix bundle and inhibit HCoV-229E spike protein-mediated cell-cell fusion with IC50 of 5.7 and 0.3 uM, respectively. 229E-HR2P effectively inhibited pseudotyped and live HCoV-229E infection with IC50 of 0.5 and 1.7 uM, respectively. In a mouse model, 229E-HR2P administered intranasally could widely distribute in the upper and lower respiratory tracts and maintain its fusion-inhibitory activity. Therefore, 229E HR2P is a promising candidate for further development as an antiviral agent for the treatment and prevention of HCoV-229E infection. PMID- 29415503 TI - Physicochemical Properties of the Mammalian Molecular Chaperone HSP60. AB - The E. coli GroEL/GroES chaperonin complex acts as a folding cage by producing a bullet-like asymmetric complex, and GroEL exists as double rings regardless of the presence of adenosine triphosphate (ATP). Its mammalian chaperonin homolog, heat shock protein, HSP60, and co-chaperonin, HSP10, play an essential role in protein folding by capturing unfolded proteins in the HSP60/HSP10 complex. However, the structural transition in ATPase-dependent reaction cycle has remained unclear. We found nucleotide-dependent association and dissociation of the HSP60/HSP10 complex using various analytical techniques under near physiological conditions. Our results showed that HSP60 exist as a significant number of double-ring complexes (football- and bullet-type complexes) and a small number of single-ring complexes in the presence of ATP and HSP10. HSP10 binds to HSP60 in the presence of ATP, which increased the HSP60 double-ring formation. After ATP is hydrolyzed to Adenosine diphosphate (ADP), HSP60 released the HSP10 and the dissociation of the double-ring to single-rings occurred. These results indicated that HSP60/HSP10 undergoes an ATP-dependent transition between the single- and double-rings in their system that is highly distinctive from the GroEL/GroES system particularly in the manner of complex formation and the roles of ATP binding and hydrolysis in the reaction cycle. PMID- 29415505 TI - In Vivo Evaluation of Cerebral Hemodynamics and Tissue Morphology in Rats during Changing Fraction of Inspired Oxygen Based on Spectrocolorimetric Imaging Technique. AB - During surgical treatment for cerebrovascular diseases, cortical hemodynamics are often controlled by bypass graft surgery, temporary occlusion of arteries, and surgical removal of veins. Since the brain is vulnerable to hypoxemia and ischemia, interruption of cerebral blood flow reduces the oxygen supply to tissues and induces irreversible damage to cells and tissues. Monitoring of cerebral hemodynamics and alteration of cellular structure during neurosurgery is thus crucial. Sequential recordings of red-green-blue (RGB) images of in vivo exposed rat brains were made during hyperoxia, normoxia, hypoxia, and anoxia. Monte Carlo simulation of light transport in brain tissue was used to specify relationships among RGB-values and oxygenated hemoglobin concentration (CHbO), deoxygenated hemoglobin concentration (CHbR), total hemoglobin concentration (CHbT), hemoglobin oxygen saturation (StO2), and scattering power b. Temporal courses of CHbO, CHbR, CHbT, and StO2 indicated physiological responses to reduced oxygen delivery to cerebral tissue. A rapid decrease in light scattering power b was observed after respiratory arrest, similar to the negative deflection of the extracellular direct current (DC) potential in so-called anoxic depolarization. These results suggest the potential of this method for evaluating pathophysiological conditions and loss of tissue viability. PMID- 29415504 TI - Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses. AB - The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse. During the past two-dozen years, the critical molecular players, responsible for assembling the specialized postsynaptic membrane and regulating nerve terminal differentiation, have begun to be identified and their mechanism of action better understood. Here, we describe and discuss five of these key molecular players, paying heed to their discovery as well as describing their currently understood mechanisms of action. In addition, we discuss the important gaps that remain to better understand how these proteins act to control synaptic differentiation and maintenance. PMID- 29415507 TI - VEHIOT: Design and Evaluation of an IoT Architecture Based on Low-Cost Devices to Be Embedded in Production Vehicles. AB - Nowadays, the current vehicles are incorporating control systems in order to improve their stability and handling. These control systems need to know the vehicle dynamics through the variables (lateral acceleration, roll rate, roll angle, sideslip angle, etc.) that are obtained or estimated from sensors. For this goal, it is necessary to mount on vehicles not only low-cost sensors, but also low-cost embedded systems, which allow acquiring data from sensors and executing the developed algorithms to estimate and to control with novel higher speed computing. All these devices have to be integrated in an adequate architecture with enough performance in terms of accuracy, reliability and processing time. In this article, an architecture to carry out the estimation and control of vehicle dynamics has been developed. This architecture was designed considering the basic principles of IoT and integrates low-cost sensors and embedded hardware for orchestrating the experiments. A comparison of two different low-cost systems in terms of accuracy, acquisition time and reliability has been done. Both devices have been compared with the VBOX device from Racelogic, which has been used as the ground truth. The comparison has been made from tests carried out in a real vehicle. The lateral acceleration and roll rate have been analyzed in order to quantify the error of these devices. PMID- 29415506 TI - VHH Antibodies: Reagents for Mycotoxin Detection in Food Products. AB - Mycotoxins are the toxic secondary metabolites produced by fungi and they are a worldwide public health concern. A VHH antibody (or nanobody) is the smallest antigen binding entity and is produced by heavy chain only antibodies. Compared with conventional antibodies, VHH antibodies overcome many pitfalls typically encountered in clinical therapeutics and immunodiagnostics. Likewise, VHH antibodies are particularly useful for monitoring mycotoxins in food and feedstuffs, as they are easily genetic engineered and have superior stability. In this review, we summarize the efforts to produce anti-mycotoxins VHH antibodies and associated assays, presenting VHH as a potential tool in mycotoxin analysis. PMID- 29415508 TI - Off-Line Evaluation of Mobile-Centric Indoor Positioning Systems: The Experiences from the 2017 IPIN Competition. AB - The development of indoor positioning solutions using smartphones is a growing activity with an enormous potential for everyday life and professional applications. The research activities on this topic concentrate on the development of new positioning solutions that are tested in specific environments under their own evaluation metrics. To explore the real positioning quality of smartphone-based solutions and their capabilities for seamlessly adapting to different scenarios, it is needed to find fair evaluation frameworks. The design of competitions using extensive pre-recorded datasets is a valid way to generate open data for comparing the different solutions created by research teams. In this paper, we discuss the details of the 2017 IPIN indoor localization competition, the different datasets created, the teams participating in the event, and the results they obtained. We compare these results with other competition-based approaches (Microsoft and Perf-loc) and on-line evaluation web sites. The lessons learned by organising these competitions and the benefits for the community are addressed along the paper. Our analysis paves the way for future developments on the standardization of evaluations and for creating a widely-adopted benchmark strategy for researchers and companies in the field. PMID- 29415509 TI - Multi-Sensor Optimal Data Fusion Based on the Adaptive Fading Unscented Kalman Filter. AB - This paper presents a new optimal data fusion methodology based on the adaptive fading unscented Kalman filter for multi-sensor nonlinear stochastic systems. This methodology has a two-level fusion structure: at the bottom level, an adaptive fading unscented Kalman filter based on the Mahalanobis distance is developed and serves as local filters to improve the adaptability and robustness of local state estimations against process-modeling error; at the top level, an unscented transformation-based multi-sensor optimal data fusion for the case of N local filters is established according to the principle of linear minimum variance to calculate globally optimal state estimation by fusion of local estimations. The proposed methodology effectively refrains from the influence of process-modeling error on the fusion solution, leading to improved adaptability and robustness of data fusion for multi-sensor nonlinear stochastic systems. It also achieves globally optimal fusion results based on the principle of linear minimum variance. Simulation and experimental results demonstrate the efficacy of the proposed methodology for INS/GNSS/CNS (inertial navigation system/global navigation satellite system/celestial navigation system) integrated navigation. PMID- 29415510 TI - A Mobility Management Using Follow-Me Cloud-Cloudlet in Fog-Computing-Based RANs for Smart Cities. AB - Mobility management for supporting the location tracking and location-based service (LBS) is an important issue of smart city by providing the means for the smooth transportation of people and goods. The mobility is useful to contribute the innovation in both public and private transportation infrastructures for smart cities. With the assistance of edge/fog computing, this paper presents a fully new mobility management using the proposed follow-me cloud-cloudlet (FMCL) approach in fog-computing-based radio access networks (Fog-RANs) for smart cities. The proposed follow-me cloud-cloudlet approach is an integration strategy of follow-me cloud (FMC) and follow-me edge (FME) (or called cloudlet). A user equipment (UE) receives the data, transmitted from original cloud, into the original edge cloud before the handover operation. After the handover operation, an UE searches for a new cloud, called as a migrated cloud, and a new edge cloud, called as a migrated edge cloud near to UE, where the remaining data is migrated from the original cloud to the migrated cloud and all the remaining data are received in the new edge cloud. Existing FMC results do not have the property of the VM migration between cloudlets for the purpose of reducing the transmission latency, and existing FME results do not keep the property of the service migration between data centers for reducing the transmission latency. Our proposed FMCL approach can simultaneously keep the VM migration between cloudlets and service migration between data centers to significantly reduce the transmission latency. The new proposed mobility management using FMCL approach aims to reduce the total transmission time if some data packets are pre-scheduled and pre-stored into the cache of cloudlet if UE is switching from the previous Fog-RAN to the serving Fog-RAN. To illustrate the performance achievement, the mathematical analysis and simulation results are examined in terms of the total transmission time, the throughput, the probability of packet loss, and the number of control messages. PMID- 29415511 TI - Plant Cation-Chloride Cotransporters (CCC): Evolutionary Origins and Functional Insights. AB - Genomes of unicellular and multicellular green algae, mosses, grasses and dicots harbor genes encoding cation-chloride cotransporters (CCC). CCC proteins from the plant kingdom have been comparatively less well investigated than their animal counterparts, but proteins from both plants and animals have been shown to mediate ion fluxes, and are involved in regulation of osmotic processes. In this review, we show that CCC proteins from plants form two distinct phylogenetic clades (CCC1 and CCC2). Some lycophytes and bryophytes possess members from each clade, most land plants only have members of the CCC1 clade, and green algae possess only the CCC2 clade. It is currently unknown whether CCC1 and CCC2 proteins have similar or distinct functions, however they are both more closely related to animal KCC proteins compared to NKCCs. Existing heterologous expression systems that have been used to functionally characterize plant CCC proteins, namely yeast and Xenopus laevis oocytes, have limitations that are discussed. Studies from plants exposed to chemical inhibitors of animal CCC protein function are reviewed for their potential to discern CCC function in planta. Thus far, mutations in plant CCC genes have been evaluated only in two species of angiosperms, and such mutations cause a diverse array of phenotypes seemingly more than could simply be explained by localized disruption of ion transport alone. We evaluate the putative roles of plant CCC proteins and suggest areas for future investigation. PMID- 29415513 TI - A Strain-Based Method to Detect Tires' Loss of Grip and Estimate Lateral Friction Coefficient from Experimental Data by Fuzzy Logic for Intelligent Tire Development. AB - Tires are a key sub-system of vehicles that have a big responsibility for comfort, fuel consumption and traffic safety. However, current tires are just passive rubber elements which do not contribute actively to improve the driving experience or vehicle safety. The lack of information from the tire during driving gives cause for developing an intelligent tire. Therefore, the aim of the intelligent tire is to monitor tire working conditions in real-time, providing useful information to other systems and becoming an active system. In this paper, tire tread deformation is measured to provide a strong experimental base with different experiments and test results by means of a tire fitted with sensors. Tests under different working conditions such as vertical load or slip angle have been carried out with an indoor tire test rig. The experimental data analysis shows the strong relation that exists between lateral force and the maximum tensile and compressive strain peaks when the tire is not working at the limit of grip. In the last section, an estimation system from experimental data has been developed and implemented in Simulink to show the potential of strain sensors for developing intelligent tire systems, obtaining as major results a signal to detect tire's loss of grip and estimations of the lateral friction coefficient. PMID- 29415512 TI - Linking Extracellular Matrix Agrin to the Hippo Pathway in Liver Cancer and Beyond. AB - In addition to the structural and scaffolding role, the extracellular matrix (ECM) is emerging as a hub for biomechanical signal transduction that is frequently relayed to intracellular sensors to regulate diverse cellular processes. At a macroscopic scale, matrix rigidity confers long-ranging effects contributing towards tissue fibrosis and cancer. The transcriptional co activators YAP/TAZ, better known as the converging effectors of the Hippo pathway, are widely recognized for their new role as nuclear mechanosensors during organ homeostasis and cancer. Still, how YAP/TAZ senses these "stiffness cues" from the ECM remains enigmatic. Here, we highlight the recent perspectives on the role of agrin in mechanosignaling from the ECM via antagonizing the Hippo pathway to activate YAP/TAZ in the contexts of cancer, neuromuscular junctions, and cardiac regeneration. PMID- 29415515 TI - Prevention of Common Mental Disorders in Employees. Perspectives on Collaboration from Three Health Care Professions. AB - Collaboration among occupational health physicians, primary care physicians and psychotherapists in the prevention and treatment of common mental disorders in employees has been scarcely researched. To identify potential for improvement, these professions were surveyed in Baden-Wurttemberg (Germany). Four hundred and fifty occupational health physicians, 1000 primary care physicians and 700 resident medical and psychological psychotherapists received a standardized questionnaire about their experiences, attitudes and wishes regarding activities for primary, secondary and tertiary prevention of common mental disorders in employees. The response rate of the questionnaire was 30% (n = 133) among occupational health physicians, 14% (n = 136) among primary care physicians and 27% (n = 186) among psychotherapists. Forty percent of primary care physicians and 33% of psychotherapists had never had contact with an occupational health physician. Psychotherapists indicated more frequent contact with primary care physicians than vice versa (73% and 49%, respectively). Better cooperation and profession-specific training on mental disorders and better knowledge about work related stress were endorsed. For potentially involved stakeholders, the importance of interdisciplinary collaboration for better prevention and care of employees with common mental disorders is very high. Nevertheless, there is only little collaboration in practice. To establish quality-assured cooperation structures in practice, participants need applicable frameworks on an organizational and legal level. PMID- 29415516 TI - Seasonal and Spatial Variability of Anthropogenic and Natural Factors Influencing Groundwater Quality Based on Source Apportionment. AB - Globally, groundwater resources are being deteriorated by rapid social development. Thus, there is an urgent need to assess the combined impacts of natural and enhanced anthropogenic sources on groundwater chemistry. The aim of this study was to identify seasonal characteristics and spatial variations in anthropogenic and natural effects, to improve the understanding of major hydrogeochemical processes based on source apportionment. 34 groundwater points located in a riverside groundwater resource area in northeast China were sampled during the wet and dry seasons in 2015. Using principal component analysis and factor analysis, 4 principal components (PCs) were extracted from 16 groundwater parameters. Three of the PCs were water-rock interaction (PC1), geogenic Fe and Mn (PC2), and agricultural pollution (PC3). A remarkable difference (PC4) was organic pollution originating from negative anthropogenic effects during the wet season, and geogenic F enrichment during the dry season. Groundwater exploitation resulted in dramatic depression cone with higher hydraulic gradient around the water source area. It not only intensified dissolution of calcite, dolomite, gypsum, Fe, Mn and fluorine minerals, but also induced more surface water recharge for the water source area. The spatial distribution of the PCs also suggested the center of the study area was extremely vulnerable to contamination by Fe, Mn, COD, and F-. PMID- 29415514 TI - Covalent Strategies for Targeting Messenger and Non-Coding RNAs: An Updated Review on siRNA, miRNA and antimiR Conjugates. AB - Oligonucleotide-based therapy has become an alternative to classical approaches in the search of novel therapeutics involving gene-related diseases. Several mechanisms have been described in which demonstrate the pivotal role of oligonucleotide for modulating gene expression. Antisense oligonucleotides (ASOs) and more recently siRNAs and miRNAs have made important contributions either in reducing aberrant protein levels by sequence-specific targeting messenger RNAs (mRNAs) or restoring the anomalous levels of non-coding RNAs (ncRNAs) that are involved in a good number of diseases including cancer. In addition to formulation approaches which have contributed to accelerate the presence of ASOs, siRNAs and miRNAs in clinical trials; the covalent linkage between non-viral vectors and nucleic acids has also added value and opened new perspectives to the development of promising nucleic acid-based therapeutics. This review article is mainly focused on the strategies carried out for covalently modifying siRNA and miRNA molecules. Examples involving cell-penetrating peptides (CPPs), carbohydrates, polymers, lipids and aptamers are discussed for the synthesis of siRNA conjugates whereas in the case of miRNA-based drugs, this review article makes special emphasis in using antagomiRs, locked nucleic acids (LNAs), peptide nucleic acids (PNAs) as well as nanoparticles. The biomedical applications of siRNA and miRNA conjugates are also discussed. PMID- 29415517 TI - Distribution of Porcine Cytomegalovirus in Infected Donor Pigs and in Baboon Recipients of Pig Heart Transplantation. AB - The porcine cytomegalovirus (PCMV) is a herpesvirus that may pose a risk for xenotransplantation using pig cells, tissues, or organs. Here, three orthotopic pig heart transplantations into baboons were studied. To detect PCMV, a real-time PCR and a Western blot assay based on four PCMV protein sequences, including two tegument proteins, were used. The transmission of PCMV from the donor pig to the recipient baboon was found in two cases, despite PCMV not being detected in the blood of the donor pigs by real-time PCR. Although it was not in the blood, PCMV was detected in different organs of the donor pigs, and in sibling animals. Immunohistochemistry using an antiserum that is specific for PCMV detected virus protein-expressing cells in all of the organs of the recipient baboon, most likely representing disseminated pig cells. Therefore, for the first time, the distribution of PCMV in organs of the donor pigs and the recipient baboons was described. In addition, baboon cytomegalovirus (BaCMV) was found activated in the recipient, and a screening for hepatitis E virus (HEV) and porcine lymphotropic herpesviruses (PLHV) was performed. For the first time, a cross-reactivity between antibodies directed against PCMV and BaCMV was found. PMID- 29415519 TI - Microplastics Reduce Short-Term Effects of Environmental Contaminants. Part I: Effects of Bisphenol A on Freshwater Zooplankton Are Lower in Presence of Polyamide Particles. AB - Abstract: Microplastics can have direct physical effects on organisms in freshwater systems, and are considered as vectors for absorbed environmental pollutants. It is still under discussion if microplastics are relevant pollutant vectors for uptake into aquatic organisms in comparison to further uptake pathways, e.g., via water or sediment particles. We analyzed how the presence of microplastics (polyamide particles, PA) modifies acute effects of the environmental pollutant bisphenol A (BPA) on freshwater zooplankton (Daphnia magna). Daphnids were exposed to PA particles and BPA alone, before combining them in the next step with one concentration of PA and varying concentrations of BPA. The PA particles themselves did not induce negative effects, while the effects of BPA alone followed a typical dose-dependent manner. Sorption of BPA to PA particles prior to exposure led to a reduction of BPA in the aqueous phase. The combination of BPA and PA led to decreased immobilization, although PA particles loaded with BPA were ingested by the daphnids. Calculations based on physiochemistry and equilibrium assumptions indicated lower BPA body burden of daphnids in the presence of PA particles. These results confirm model-based studies, and show that investigated microplastic concentrations are negligible for the overall pollutant uptake of daphnids with water as additional uptake pathway. PMID- 29415520 TI - Consequences of Lamin B1 and Lamin B Receptor Downregulation in Senescence. AB - Anchoring of heterochromatin to the nuclear envelope appears to be an important process ensuring the spatial organization of the chromatin structure and genome function in eukaryotic nuclei. Proteins of the inner nuclear membrane (INM) mediating these interactions are able to recognize lamina-associated heterochromatin domains (termed LAD) and simultaneously bind either lamin A/C or lamin B1. One of these proteins is the lamin B receptor (LBR) that binds lamin B1 and tethers heterochromatin to the INM in embryonic and undifferentiated cells. It is replaced by lamin A/C with specific lamin A/C binding proteins at the beginning of cell differentiation and in differentiated cells. Our functional experiments in cancer cell lines show that heterochromatin in cancer cells is tethered to the INM by LBR, which is downregulated together with lamin B1 at the onset of cell transition to senescence. The downregulation of these proteins in senescent cells leads to the detachment of centromeric repetitive sequences from INM, their relocation to the nucleoplasm, and distension. In cells, the expression of LBR and LB1 is highly coordinated as evidenced by the reduction of both proteins in LBR shRNA lines. The loss of the constitutive heterochromatin structure containing LADs results in changes in chromatin architecture and genome function and can be the reason for the permanent loss of cell proliferation in senescence. PMID- 29415521 TI - Stakeholders Opinions on Multi-Use Deep Water Offshore Platform in Hsiao-Liu Chiu, Taiwan. AB - This paper describes a group model building activity designed to elicit the potential effects a projected multi-use deep water offshore platform may have on its local environment, including ecological and socio-economic issues. As such a platform is proposed for construction around the island of Hsiao-Liu-Chiu, Taiwan, we organized several meetings with the local stakeholders and structured the debates using group modeling methods to promote consensus. During the process, the participants iteratively built and revised a causal-loop diagram that summarizes their opinions. Overall, local stakeholders concluded that a multi-use deep water offshore marine platform might have beneficial effects for Hsiao-Liu-Chiu because more tourists and fish could be attracted by the structure, but they also raised some potential problems regarding the law in Taiwan and the design of the offshore platform, especially its resistance to extreme weather. We report the method used and the main results and insights gained during the process. PMID- 29415522 TI - In Their Own Words: The Significance of Participant Perceptions in Assessing Entomology Citizen Science Learning Outcomes Using a Mixed Methods Approach. AB - A mixed methods study was used to transcend the traditional pre-, post-test approach of citizen science evaluative research by integrating adults' test scores with their perceptions. We assessed how contributory entomology citizen science affects participants' science self-efficacy, self-efficacy for environmental action, nature relatedness and attitude towards insects. Pre- and post-test score analyses from citizen scientists (n = 28) and a control group (n = 72) were coupled with interviews (n = 11) about science experiences and entomological interactions during participation. Considering quantitative data alone, no statistically significant changes were evident in adults following participation in citizen science when compared to the control group. Citizen scientists' pre-test scores were significantly higher than the control group for self-efficacy for environmental action, nature relatedness and attitude towards insects. Interview data reveal a notable discrepancy between measured and perceived changes. In general, citizen scientists had an existing, long-term affinity for the natural world and perceived increases in their science self efficacy, self-efficacy for environmental action, nature relatedness and attitude towards insects. Perceived influences may act independently of test scores. Scale instruments may not show impacts with variances in individual's prior knowledge and experiences. The value of mixed methods on citizen science program evaluation is discussed. PMID- 29415518 TI - The Biology of Monocytes and Dendritic Cells: Contribution to HIV Pathogenesis. AB - Myeloid cells such as monocytes, dendritic cells (DC) and macrophages (MPhi) are key components of the innate immune system contributing to the maintenance of tissue homeostasis and the development/resolution of immune responses to pathogens. Monocytes and DC, circulating in the blood or infiltrating various lymphoid and non-lymphoid tissues, are derived from distinct bone marrow precursors and are typically short lived. Conversely, recent studies revealed that subsets of tissue resident MPhi are long-lived as they originate from embryonic/fetal precursors that have the ability to self-renew during the life of an individual. Pathogens such as the human immunodeficiency virus type 1 (HIV-1) highjack the functions of myeloid cells for viral replication (e.g., MPhi) or distal dissemination and cell-to-cell transmission (e.g., DC). Although the long term persistence of HIV reservoirs in CD4+ T-cells during viral suppressive antiretroviral therapy (ART) is well documented, the ability of myeloid cells to harbor replication competent viral reservoirs is still a matter of debate. This review summarizes the current knowledge on the biology of monocytes and DC during homeostasis and in the context of HIV-1 infection and highlights the importance of future studies on long-lived resident MPhi to HIV persistence in ART-treated patients. PMID- 29415525 TI - Pertussis in Poland in 2015 AB - INTRODUCTION: In Poland, the high incidence of pertussis has been maintained for many years - the fiveyear median for 2005-2009 and 2010-2014 were 5.2 and 5.5 per 100,000 population. In 2015 there was another dynamic increase (by 136%) of incidence to 12.86 per 100 000 population. While the tendency of high incidence of pertussis in the years 2009-2011 (the results of the National Epidemiologic Research of Pertussis), in the subsequent years, ie 2012-2014, was halted, in 2015 there was an increase in morbidity with significantly increased dynamics and different age groups. Still, the most effective prevention strategy is vaccination according to the current calendar and expert recommendations (1) THE AIM OF THE STUDY: The aim of the study is to assess the epidemiological situation of pertussis in Poland in 2015 in comparison with previous years, including vaccine coverage of children MATERIALS AND METHODS: Assessment of the epidemiology of pertussis in Poland was based on analysis of individual reports of suspected cases of pertussis sent to the NIPH-NIH by the regional sanitaryepidemiological stations, data from the bulletin "Infectious diseases and poisonings in Poland in 2015" (2) and bulletin "Immunizations in Poland in 2015 " (3). SUMMARY AND CONCLUSIONS: The significant increase in pertussis disease observed in 2015 indicates the persistent circulation of bacteria in the environment and the continuing susceptibility of the population to infection. Still, the only effective strategy for reducing the incidence of disease remains the use of vaccines according to the current calendar and recommendations of experts PMID- 29415524 TI - Modulation of Magnetic Properties at the Nanometer Scale in Continuously Graded Ferromagnets. AB - Abstract: Ferromagnetic alloy materials with designed composition depth profiles provide an efficient route for the control of magnetism at the nanometer length scale. In this regard, cobalt-chromium and cobalt-ruthenium alloys constitute powerful model systems. They exhibit easy-to-tune magnetic properties such as saturation magnetization MS and Curie temperature TC while preserving their crystalline structure over a wide composition range. In order to demonstrate this materials design potential, we have grown a series of graded Co1-xCrx and Co1 wRuw (1010) epitaxial thin films, with x and w following predefined concentration profiles. Structural analysis measurements verify the epitaxial nature and crystallographic quality of our entire sample sets, which were designed to exhibit in-plane c-axis orientation and thus a magnetic in-plane easy axis to achieve suppression of magnetostatic domain generation. Temperature and field dependent magnetic depth profiles have been measured by means of polarized neutron reflectometry. In both investigated structures, TC and MS are found to vary as a function of depth in accordance with the predefined compositional depth profiles. Our Co1-wRuw sample structures, which exhibit very steep material gradients, allow us to determine the localization limit for compositionally graded materials, which we find to be of the order of 1 nm. The Co1-xCrx systems show the expected U-shaped TC and MS depth profiles, for which these specific samples were designed. The corresponding temperature dependent magnetization profile is then utilized to control the coupling along the film depth, which even allows for a sharp onset of decoupling of top and bottom sample parts at elevated temperatures. PMID- 29415523 TI - Testing Cessation Messages for Cigarette Package Inserts: Findings from a Best/Worst Discrete Choice Experiment. AB - This study assessed smokers' responses to different smoking cessation topics and imagery for cigarette package inserts. Adult smokers from Canada (n = 1000) participated in three discrete choice experiments (DCEs): DCE 1 assessed five cessation benefit topics and five imagery types; DCE 2 assessed five messages with tips to improve cessation success and five imagery types; DCE 3 assessed four reproductive health benefits of cessation topics and four imagery types. In each DCE, participants evaluated four or five sets of four inserts, selecting the most and least motivating (DCEs 1 & 3) or helpful (DCE 2) for quitting. Linear mixed models regressed choices on insert and smoker characteristics. For DCE 1, the most motivating messages involved novel disease topics and imagery of younger women. For DCE 2, topics of social support, stress reduction and nicotine replacement therapy were selected as most helpful, with no differences by imagery type. For DCE 3, imagery influenced choices more than topic, with imagery of a family or a mom and baby selected as most motivating. Statistically significant interactions for all three experiments indicated that the influence of imagery type on choices depended on the message topic. Messages to promote smoking cessation through cigarette pack inserts should consider specific combinations of message topic and imagery. PMID- 29415526 TI - Chickenpox in Poland in 2015 AB - BACKGROUND: A large number of chickenpox cases, indicates the rationale for the use of chickenpox vaccinations. In Poland since 2002, chickenpox vaccination is included in the National Immunisation Programme as recommended.(1) AIM: To assess epidemiological situation of chickenpox in Poland in 2015 in comparison to previous years METHODS: The descriptive analysis was based on based on the results of the analysis of aggregate data published in the annual bulletins "Infectious diseases and poisonings in Poland in 2015" and "Vaccinations in Poland in 2015" (2,3). National Immunisation Programme for year 2015 was also used (4) RESULTS: In 2015, 187 624 cases of chickenpox were registered in Poland, the highest number of cases in Mazowieckie voivodeship and the lowest in Opolskie voivodeship. The incidence was 487.9 and was lower than in 2014 (575.9). The highest incidence 4532.5 was recorded in children in 0-4 age group. The chickenpox incidence among men (515.5) was higher comparing to women (462.1), and among rural residents (508.0) was higher by 9.8 % than among urban residents (474.7). Number of cases hospitalized due to chickenpox was 1 340. Number of people vaccinated against chickenpox was 63 138 SUMMARY: In 2015, there was decrease in number of chickenpox in Poland, which can be related to the periodicity of the increase in morbidity, the use of vaccination against chickenpox, prophylactic vaccination activities and the benefits of vaccination, as well as the increase of knowledge of the general public on the ability to prevent infectious diseases that can be prevented by vaccination PMID- 29415527 TI - Meningitis and encephalitis in Poland in 2015 AB - AIM OF THE STUDY: The aim of this study was to assess the epidemiology of meningitis and/or encephalitis in Poland in 2015 INTRODUCTION: In the last four years in Poland, about 3 000 cases of meningitis and/or encephalitis of viral or bacterial etiology were recorded annually MATERIALS AND METHODS: Assessment of the epidemiological situation of meningitis and/or encephalitis in Poland in 2015, was based on the results of the analysis of epidemiological reports sent to the NIZP-PZH by the Regional Sanitary-Epidemiological Stations published in the annual bulletin "Infectious diseases and poisonings in Poland in 2015" and "Vaccination in Poland in 2015" RESULTS: In 2015 in Poland 2 428 cases of bacterial meningitis and/or encephalitis were recorded. 43.1% of these were viral infections SUMMARY AND CONCLUSIONS: In 2015, in comparison to 2014, a 21.8% decrease in the number of cases of meningitis and/or encephalitis was observed PMID- 29415528 TI - Foodborne infections and intoxications in Poland in 2015 AB - AIM: The purpose of the study is to assess the epidemiological situation of food poisonings and infections in Poland in 2015 MATERIALS AND METHODS: The evaluation was based on the analysis of information sent to Department of Epidemiology NIPH NIH through ROE (Pol. Rejestr Ognisk Epidemicznych)- (an electronic system created for uploading, transfer and analysis of data acquired during the outbreak investigations). Additional sources for the analysis were NIZP-PZH annual bulletins (Czarkowski MP et al. "Infectious diseases and poisonings in Poland", 2007-2015. Warsaw, NIPH-NIH and GIS) RESULTS: In 2015 a total number of 560 foodborne infections and intoxications outbreaks were reported in which 21 962 persons were exposed and 7 037 (including 1 896 children up to 14 years of age) got sick. Hospitalization was required for 1 905 of patients. The most frequent etiological agent was Salmonella sp. - 34.3%, and 21.4 % of cases). Viruses were responsible for 23.9% of outbreaks and 29.7 % of cases (And among them rotaviruses- 13% of outbreaks and 7.1% of cases and noroviruses- 10.5% of outbreaks and 26.9% of cases). In 25.2% of outbreaks no etiological agent was found. Just as in 2014 private household was the most frequent place of an outbreak (235 outbreaks), and after that- hospital (148 outbreaks). In 2014 the most frequent vehicle were cakes and desserts (25.6% of all outbreaks with known etiological agent). In 2015 the most frequent vehicle of infection were eggs and egg products) (19% of outbreaks of known vehicle). In 57.3% of outbreaks no vehicle was found or proved. Moreover in 2015 a total number of 4 outbreaks in which more than 100 cases were reported CONCLUSIONS: The increase in the number of foodborne outbreaks of Salmonella Enteritidis etiology along with the fact of eggs and egg products being the most frequent vehicle indicates an alarming situation and the necessity of microbiological surveillance enchantment in relation to those products PMID- 29415529 TI - Lyme disease in Poland in 2015 AB - INTRODUCTION: Lyme disease is the most common tick-borne disease in Poland. Borrelia burgdorferi spirochete can occur in the whole country, which, according to ECDC, should be considered as an endemic area. Borrelia strains are transmitted to humans and certain other animals by Ixodes (1). Human infection is caused by saliva or tick vomit. Reservoir spirochete are numerous species of animals, mainly rodents. Lyme disease, due to its multifocal character, rich symptomatology and diagnostic problems, is a serious challenge for clinicians and epidemiologists OBJECTIVES: The aim of this study was to assess the epidemiological situation of Lyme disease in Poland in 2015 in comparison to the previous years MATERIALS AND METHODS: The descriptive analysis was based on data retrieved from routine mandatory surveillance system and published in the annual bulletin "Infectious diseases and poisonings in Poland in 2015" (2) RESULTS: Despite observed in recent years the tendency to growth of number of cases, in 2015 was marked by growth inhibition incidence of Lyme disease.In 2015, 13 625 cases were registered in Poland, ie by 0.7% less than in the previous year. The overall incidence in the country was 35.4 per 100 000 population - the highest was recorded in the Podlaskie voivodeship - 96.3 per 100 000 inhabitants. In 2015, 1905 (14%) people were hospitalized due to Lyme disease SUMMARY AND CONCLUSIONS: In 2015, for the first time in a few years, the growth rate of Lyme disease has been stopped. Registered 0.7% less cases than in the previous year. There is still a need for bringing awareness of the need for diagnostic laboratory testing according to recommendations, which will improve the accuracy of the diagnosis PMID- 29415530 TI - Assessment of the occurrence of nosocomial infections in the Intensive Care Unit in the St. Lukas District Hospital in Tarnow in 2012-2016 AB - INTRODUCTION: Healthcare-Associated Infections (HAI) are the cause of complications in the treatment process. The possibility of infecting a sick person in the Intensive Care Unit (ICU) is many times greater than in other hospital departments OBJECTIVES: The objective of the study was to investigate the epidemiological indicators and to determine the clinical types of HAI that are present in the ICU during the 5-year period in the St. Lukas District Hospital in Tarnow MATERIALS AND METHODS: HAI has been detected and documented in patients in ICU in the years 2012-2016 by the use of the active monitoring method. We studied patients who spent over 2 days in ICU with a general profile. These studies were conducted in accordance with the methodology recommended by Healthcare-Associated Infections Surveillance Network (HAI-Net) European Center for Disease Prevention and Control (ECDC) RESULTS: Among 886 patients who were hospitalized for a total of 6711 days, HAI was diagnosed in 195 patients (22.0% incidence rate), the incidence density rate was 29.1 per 1000 person-days of hospitalization. The rate for Ventilator-Associated Pneumonia (VAP) was 12.5 per 1000 ventilator days, for Central Line Associated Bloodstream Infection (CA-BSI) the rate was 8.2 per 1000 central line days, for Catheter-Associated Urinary Tract Infection (CA-UTI) the rate was 3.3 per 1000 urinary catheter days. The average duration of a patient stay in ICU was 24 days (19 days for patients without HAI and 43 days for patients with HAI). The following microorganisms isolated from HAI were prevailing: Acinetobacter baumannii 46 (27%), Staphylococcus aureus 12 (21%), Enterococcus faecalis 17 (10%) CONCLUSIONS: A five-year HAI study in ICU showed that the most common types of infections were bloodstream infections and pneumonia. The incidence rate of VAP remained at similar levels in subsequent years. The CA-BSI rates were reduced over the next three years of the study, but their rise in the last year can prove the lack of stability of the preventive actions. CA-UTI was detected twice less frequently, which can suggest poor detection of this type of infection PMID- 29415531 TI - Borrelia miyamotoi - new etiologic agent of neuroborreliosis? AB - Borrelia miyamotoi spirochetes discovered in Ixodes persulcatus ticks in Japan, in 1994 and documented in ticks and rodents in moderate climate zone of northern hemisphere. They belong to tick-borne relapsing fever group spirochetes.Borrelia miyamotoi is an etiologic agent of B.miyamotoi disease with acute febrile illness, including fever, headache, dizziness, fatigue, chills, and muscle and joint pain. Recurrence of fever has been observer in more than 10% patients. In some patients meningoencephalitis, encephalitis and cranial neuritis were observed.Laboratory recognition is based mainly upon PCR testing. Serological testing is limited due to inaccessibility of tests. PMID- 29415532 TI - Genetic diversity of Blastocystis hominis sensu lato isolated from humans in Poland AB - INTRODUCTION AND OBJECTIVES: Blastocystis hominis s. l. is one of the most commonly detected protozoa in the human large intestine. The aim of the study was to determine the genetic subtypes of Blastocystis hominis s. l. occurring in humans in Poland. MATERIALS AND METHODS: Stool samples from patients diagnosed in the Laboratory of the Department of Parasitology, National Institute of Public Health - National Institute of Hygiene (NIZP-PZH) and in the Parasitology Laboratory of the Hospital for Infectious Diseases in Warsaw were examined. Blastocystis subtypes were assayed based on the fragment of small-subunit ribosomal RNA gene sequences (SSU rDNA). RESULTS: The examined isolates were classified into five Blastocystis subtypes (STs), fifteen of which belonged to ST3, three to ST1, two to ST2, two to ST6, and one isolate belonged to ST7. In three cases the subtype of isolate was not identified. DISCUSSION AND CONCLUSIONS: In Poland, the subtypes ST1, ST2, ST3, ST4, ST6 and ST7 have been reported in humans so far. The ST6 and ST7 subtypes are rarely detected in humans in Europe. In Poland, the ST6 subtype was previously described in chickens. On the basis of the studies, it was found that Blastocystis isolated from humans in Warsaw show high genetic diversity. In order to determine the possible pathogenic potential of individual Blastocystis subtypes, special epidemiological studies are required. PMID- 29415533 TI - The prevalence of Trichomonas vaginalis infections in the population of Warminsko Mazurskie voivodeship (North-Eastern Poland) AB - INTRODUCTION: Trichomonas vaginalis is considered to be the most common non-viral sexually transmitted infection. Trichomoniasis is not a reportable disease and due to this fact only estimates can be made about its incidence AIM OF THE STUDY: The aim of the study was to determine the prevalence of T. vaginalis in the female population of north-eastern Poland as well as to conduct an epidemiological analysis on the basis of the data from the years of 2009 - 2015 derived from the registers of the National Health Fund MATERIALS AND METHODS: In this study 300 women aged 19 - 50 were examined. Two vaginal swabs were taken from each patient. The first swab was used to prepare microscope slides, and stained with Giemsa stain. The second swab was used for a diagnostic immunochromatographic rapid test (OSOM Trichomonasis test). Each woman was also asked to complete a questionnaire. Additionally, on the basis of the data from the National Health Fund, epidemiological analysis was conducted. Statistical analysis was performed with SPSS Statistics ver. 24 using Fisher test RESULTS: T. vaginalis infection was confirmed in two women. The diagnosis of trichomoniasis was confirmed as a result of T.vaginalis antigen detection with the use of immunochromatographic diagnostic test (OSOM Trichomonas test). The data from the National Health Fund show that 160 cases of trichomoniasis were reported, of which women accounted for 135 (84%), and men for 25 (16%). The highest infection rate was found in women aged 50 - 59 and those over 60 years old CONCLUSIONS: Our results show that the prevalence of T. vaginalis infection remains low, the infection occurs mainly in elderly women. However, one should pay attention to the differences in the detection of T. vaginalis connected with a particular method used. Conducting screen tests on a larger scale using more advanced tests would allow a more accurate assessment of the scale of the problem in our country PMID- 29415534 TI - Long-term outcomes of thyroid dysfunction in patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin AB - INTRODUCTION: Thyroid dysfunctions (TDs) are associated with pegylated interferon and ribavirin (PegIFN-alpha/RBV) therapy in patients with chronic hepatitis C (CHC) and are considered as possible extrahepatic manifestation of HCV infection OBJECTIVES: This study aimed to assess the long-term outcomes of TDs in patients with CHC treated with PegIFN-alpha/RBV METHODS: A total of 1,047 treatment-naive patients with CHC were treated with PegIFN-alpha/RBV. TSH and FT4 were assessed at baseline, every 3 months during therapy and 6, 12 and 24 months after the end of therapy. Analysis was performed for two groups of patients depending on the absence (group A, n=77) or presence (group B, n=39) of TDs at baseline RESULTS: At baseline, TDs' prevalence was 3.7%; 53.8% hypothyroidism, 38.5% goiters, and 7.7% hyperthyroidism. 77 (7.4%) out of 1,008 euthyroid patients developed TDs; 45.5% hypothyroidism, 33.8% hyperthyroidism, 19.5% destructive thyroiditis, and 1.3% goiters. TDs' remission (TDR) was achieved in 59/116 (50.9%) of treated patients; 64.9% in group A and 23.1% in group B (p<0.001). Hyperthyroidism as compared to hypothyroidism increases the odds of TDR (OR=4.87 (1.65-14.35), p=0.004), whereas preexisting TDs and higher baseline viral load tend to decrease the probability of TDR (OR=0.21 (0.07-0.58), p=0.003 and OR=0.4 (0.22-0.73), p=0.003, respectively) CONCLUSIONS: The prevalence of TDs was low but over one third of patients in whom TDs developed under PegIFN-alpha/RBV therapy did not recover. In one-fourth of patients with preexisting TDs remissions were observed. Treatment with PegIFN-alpha in the past must be taken into account as a potential cause of TDs PMID- 29415535 TI - DNA Facilitates the Sorption of Polycyclic Aromatic Hydrocarbons on Montmorillonites. AB - The sorption of polycyclic aromatic hydrocarbons (PAHs) to montmorillonites is largely influenced by their interactions with dissolved organic matter (DOM). However, the role of DOM rather than humic and fulvic acids (e.g., extracellular DNA) in the PAH sorption to soil clays is little known. Here, we demonstrate that extracellular double-stranded salmon testes DNA substantially increased the sorption of phenanthrene and pyrene to Na-, Ca-, and Fe-modified montmorillonites. All PAH sorption isotherms fitted the linear and Freundlich models reasonably well ( R2 = 0.918-0.999). Distribution coefficients were increased from 0.0458-0.103 and 0.0493-0.141 L/g at 0 mg/L DNA to 0.413-0.589 and 0.385-0.560 L/g at 10 mg/L DNA for phenanthrene and pyrene, respectively. Spectroscopic and computational chemistry analyses confirmed that PAHs were first inserted into DNA by binding with the nucleobases via van der Waals and pi-pi electron donor-acceptor interactions. Compared to PAHs, the DNA-PAH complex can be more easily sorbed to cation-modified montmorillonites by complexation between DNA phosphate and exchangeable cations in addition to intercalation into clay interlayers. This work highlights the importance of understanding the control on contaminant sorption by many organic compounds that are ubiquitous in soils but not represented by humic and fulvic acids. PMID- 29415536 TI - Quantum-Confined Electronic States Arising from the Moire Pattern of MoS2-WSe2 Heterobilayers. AB - A two-dimensional (2D) heterobilayer system consisting of MoS2 on WSe2, deposited on epitaxial graphene, is studied by scanning tunneling microscopy and spectroscopy at temperatures of 5 and 80 K. A moire pattern is observed, arising from lattice mismatch of 3.7% between the MoS2 and WSe2. Significant energy shifts are observed in tunneling spectra observed at the maxima of the moire corrugation, as compared with spectra obtained at corrugation minima, consistent with prior work. Furthermore, at the minima of the moire corrugation, sharp peaks in the spectra at energies near the band edges are observed for spectra acquired at 5 K. The peaks correspond to discrete states that are confined within the moire unit cells. Conductance mapping is employed to reveal the detailed structure of the wave functions of the states. For measurements at 80 K, the sharp peaks in the spectra are absent, and conductance maps of the band edges reveal little structure. PMID- 29415537 TI - A Microfluidic Chip Integrated with Hyaluronic Acid-Functionalized Electrospun Chitosan Nanofibers for Specific Capture and Nondestructive Release of CD44 Overexpressing Circulating Tumor Cells. AB - Detection of circulating tumor cells (CTCs) in peripheral blood is of paramount significance for early-stage cancer diagnosis, estimation of cancer development, and individualized cancer therapy. Herein, we report the development of hyaluronic acid (HA)-functionalized electrospun chitosan nanofiber (CNF) integrated microfludic platform for highly specific capture and nondestructive release of CTCs. First, electrospun CNFs were formed and modified with zwitterion of carboxyl betaine acrylamide (CBAA) via Michael addition reaction and then targeting ligand HA through a disulfide bond. We show that the formed nanofibers still maintain the smooth fibrous morphology after sequential surface modifications, have a good hemocompatibility, and exhibit an excellent antifouling property due to the CBAA modification. After being embedded within a microfluidic chip, the fibrous mat can capture cancer cells (A549, a human lung cancer cell line) with an efficiency of 91% at a flow rate of 1.0 mL/h. Additionally, intact release of cancer cells is able to be achieved after treatment with glutathione for 40 min to have a release efficiency of 90%. Clinical applications show that 9 of 10 nonsmall-cell lung cancer patients and 5 of 5 breast cancer patients are diagnosed to have CTCs (1 to 18 CTCs per mL of blood). Our results suggest that the developed microfluidic system integrated with functionalized CNF mats may be employed for effective CTCs capture for clinical diagnosis of cancer. PMID- 29415538 TI - Laminaria japonica Polysaccharide Inhibits Vascular Calcification via Preventing Osteoblastic Differentiation of Vascular Smooth Muscle Cells. AB - This study aimed to investigate the effect and underlying mechanism of a purified Laminaria japonica polysaccharide (LJP61A) on preventing vascular calcification (VC). In the adenine-induced chronic renal failure (CRF) mice VC model and the beta-glycerophosphate (beta-GP)-induced vascular smooth muscle cells (VSMC) calcification model, LJP61A was found to significantly inhibit VC phenotypes as determined by biochemical analysis and von Kossa, alizarin red, and immunohistochemical staining. Meanwhile, LJP61A remarkably up-regulated the mRNA levels of VSMC related markers and down-regulated the mRNA levels of sodium dependent phosphate cotransporter Pit-1. In addition, LJP61A could significantly decrease the protein levels of core-binding factor-1, osteocalcin, bone morphogenetic protein 2, and receptor activator for nuclear factor-kappaB ligand, and it can increase the protein levels of osteoprotegerin and matrix gla protein. These results indicated that LJP61A ameliorated VC both in vivo and in vitro via preventing osteoblastic differentiation of VSMC, suggesting LJP61A might be a potential therapeutic agent for VC in CRF patients. PMID- 29415539 TI - Comparison of Elemental Mercury Oxidation Across Vanadium and Cerium Based Catalysts in Coal Combustion Flue Gas: Catalytic Performances and Particulate Matter Effects. AB - This paper discussed the field test results of mercury oxidation activities over vanadium and cerium based catalysts in both coal-fired circulating fluidized bed boiler (CFBB) and chain grate boiler (CGB) flue gases. The characterizations of the catalysts and effects of flue gas components, specifically the particulate matter (PM) species, were also discussed. The catalytic performance results indicated that both catalysts exhibited mercury oxidation preference in CGB flue gas rather than in CFBB flue gas. Flue gas component studies before and after dust removal equipment implied that the mercury oxidation was well related to PM, together with gaseous components such as NO, SO2, and NH3. Further investigations demonstrated a negative PM concentration-induced effect on the mercury oxidation activity in the flue gases before the dust removal, which was attributed to the surface coverage by the large amount of PM. In addition, the PM concentrations in the flue gases after the dust removal failed in determining the mercury oxidation efficiency, wherein the presence of different chemical species in PM, such as elemental carbon (EC), organic carbon (OC) and alkali (earth) metals (Na, Mg, K, and Ca) in the flue gases dominated the catalytic oxidation of mercury. PMID- 29415540 TI - Per- and Polyfluoroalkyl Substances (PFASs) in Indoor Air and Dust from Homes and Various Microenvironments in China: Implications for Human Exposure. AB - A newly developed solid-phase extraction cartridge composed of mixed sorbents was optimized for collection of both neutral and ionizable per- and polyfluoroalkyl substances (PFASs) in indoor air. Eighty-one indoor air samples and 29 indoor dust samples were collected from rooms of homes and hotels, textile shops, and cinemas in Tianjin, China. Fluorotelomer alcohols (FTOHs) were the predominant PFASs found in air (250-82 300 pg/m3) and hotel dust (24.8-678 ng/g). Polyfluoroalkyl phosphoric acid diesters were found at lower levels of nd-125 pg/m3 in air and 0.32-183 ng/g in dust. Perfluoroalkyl carboxylic acids (PFCAs) were dominant ionizable PFASs in air samples (121-20 600 pg/m3) with C4-C7 PFCAs contributing to 54% +/- 17% of the profiles, suggesting an ongoing shift to short chain PFASs. Long-chain PFCAs (C > 7) were strongly correlated and the intermediate metabolite of FTOHs, fluorotelomer unsaturated carboxylic acids, occurred in all the air samples at concentrations up to 413 pg/m3, suggesting the transformation of precursors such as FTOHs in indoor environment. Daily intake of ?PFASs via air inhalation and dust ingestion was estimated at 1.04-14.1 ng/kg bw/d and 0.10-8.17 ng/kg bw/d, respectively, demonstrating that inhalation of air with fine suspended particles was a more important direct exposure pathway than dust ingestion for PFASs to adults. PMID- 29415541 TI - Ru Modulation Effects in the Synthesis of Unique Rod-like Ni@Ni2P-Ru Heterostructures and Their Remarkable Electrocatalytic Hydrogen Evolution Performance. AB - The construction of highly efficient and stable Pt-free catalysts for electrochemical hydrogen generation is highly desirable. Herein, we demonstrate the first metal-phosphides-metal system consisting of Ru, Ni2P, and Ni, which forms unique multiheterogeneous Ni@Ni2P-Ru nanorods. Interestingly, a Ru modulation effects that promotes the desorption of H2 to achieve a moderate hydrogen adsorption energy (DeltaGH), and enables the formation of Ni@Ni2P nanorods via Ru-Ni coordination to enhance the conductivity was discovered. Due to its optimal DeltaGH, improved conductivity and rod-like morphology, this catalyst shows superior electrocatalytic HER performances in both acidic and alkaline conditions, which are superior to those of some recently reported phosphides and close to that of commercial 20% Pt/C. Such a design strategy is not limited to Ni2P and Ru but also may be extended to other similar phosphides and noble metals, providing a new promising approach and an alternative to Pt catalysts for electrocatalytic applications. PMID- 29415542 TI - DNA Origami Inside-Out Viruses. AB - A synthetic topology for everted viruses is reported. The topology is a single stranded virion DNA assembled into a hollow cube with exterior decorated with HIV Tat transduction domains. The cube incorporates a pH-responsive lid allowing for the controlled encapsulation of functional proteins and their transfer and release into live cells. Unlike viruses, which are protein shells with a [3,5] fold rotational symmetry that encase nucleic acids, these cubes are [3, 4]-fold DNA boxes encapsulating proteins. Like viruses, such everted DNA-built viruses are monodisperse nanoscale assemblies that infect human cells with a specialist cargo. The design offers a bespoke bottom-up platform for engineering nonpolyhedral, nonprotein synthetic viruses. PMID- 29415543 TI - Unsaturated Drift Velocity of Monolayer Graphene. AB - We observe that carriers in graphene can be accelerated to the Fermi velocity without heating the lattice. At large Fermi energy | EF| > 110 meV, electrons excited by a high-power terahertz pulse ETHz relax by emitting optical phonons, resulting in heating of the graphene lattice and optical-phonon generation. This is owing to enhanced electron-phonon scattering at large Fermi energy, at which the large phase space is available for hot electrons. The emitted optical phonons cause carrier scattering, reducing the drift velocity or carrier mobility. However, for | EF| <= 110 meV, electron-phonon scattering rate is suppressed owing to the diminishing density of states near the Dirac point. Therefore, ETHz continues to accelerate carriers without them losing energy to optical phonons, allowing the carriers to travel at the Fermi velocity. The exotic carrier dynamics does not result from the massless nature, but the electron-optical phonon scattering rate depends on Fermi level in the graphene. Our observations provide insight into the application of graphene for high-speed electronics without degrading carrier mobility. PMID- 29415544 TI - Biodegradation and Uptake of the Pesticide Sulfluramid in a Soil-Carrot Mesocosm. AB - N-ethyl perfluorooctane sulfonamide (EtFOSA) is the active ingredient of Sulfluramid, a pesticide which is used extensively in South America for control of leaf-cutting ants. Despite being a known precursor to perfluorooctanesulfonate (PFOS), the importance of EtFOSA as a source of environmental PFOS remains unclear. In the present work, uptake, leaching, and biodegradation of EtFOSA and its transformation products were assessed over 81 days in soil-carrot ( Daucus carota ssp sativus) mesocosms for the first time. Experiments performed in the presence of carrot produced PFOS yields of up to 34% using a technical EtFOSA standard and up to 277% using Grao Forte, a commercial Sulfluramid bait formulation containing 0.0024% EtFOSA. Perfluorooctane sulfonamido acetate (FOSAA), perfluorooctane sulfonamide (FOSA), and perfluorooctanoic acid (PFOA) also formed over the course of the experiments, with the latter substance attributed to the presence of perfluorooctanamide impurities. The leachate contained low levels of transformation products and a high FOSA:PFOS ratio, consistent with recent observations in Brazilian surface water. In carrots, the more hydrophilic transformation products (e.g., PFOS) occurred primarily in the leaves, while the more hydrophobic products (e.g., FOSA, FOSAA, and EtFOSA) occurred in the peel and core. Remarkably, isomer-specific analysis revealed that the linear EtFOSA isomer biodegraded significantly faster than branched isomers. These data collectively show that the application of Sulfluramid baits can lead to the occurrence of PFOS in crops and in the surrounding environment, in considerably higher yields than previously thought. PMID- 29415545 TI - Veronica Vaida: Autobiographical Notes. PMID- 29415546 TI - Curriculum Vita of Veronica Vaida. PMID- 29415547 TI - Publications of Veronica Vaida. PMID- 29415548 TI - Tribute to Veronica Vaida. PMID- 29415549 TI - Concerns related to CCR5 gene delta 32 mutation role in hepatitis B virus infection AB - STUDY OBJECTIVE: A literature review to analyze potential evidence regarding the influence of Delta32 CCR5 gene mutation on resistance to/clinical recovery from HBV infection METHODS: Literature search, covering the period 1996-2017, was performed using Medline. Comparativebetween-studies analysis was conducted with regard to reliability as well as statistical and clinical significanceof results RESULTS: Data on the influence of Delta32 CCR5 mutation on the course of HBV infection are sparse and results obtained in various scientific studies are not consistent. As the example, heterozygosity for CCR5/CCR5Delta32 in healthy Iranian blood donors was greater than in cases with chronic HBV infection; in the American study on Caucasian subjects who had been infected with HBV CCR5 Delta32 reduced the risk of developing a persistent HBV infection by nearly half. Conversely, the Indian study revealed that heterozygosity for CCR5/CCR5Delta32 was more often present in patients with chronic hepatitis B than in healthy controls. However, there were some methodological errors found in previously published studies such as limited sample size and/or incorrect selection of controls; this could influence the fact that results were not heterogeneous CONCLUSIONS: The evidence for potential association of CCR5 gene Delta32 mutation on HBV infection in regard to the resistance to HBV infection or recovery from an HBV infection are insufficient. Previously conducted studies presented the lack of results' consistency, possibly due to between-population differences in the context of genetic determinants, ethnic and geographical origin, as well as methodological errors. There is an urgent need to conduct further, methodologically correct studies on larger populations from different regions, including Polish subjects PMID- 29415550 TI - Management of severe acute malnutrition in children under 5 years through the lens of health care workers in two rural South African hospitals. AB - BACKGROUND: Despite the widespread implementation of the World Health Organization (WHO) guidelines for the management of severe malnutrition in South Africa, poor treatment outcomes for children under 5 years are still observed in some hospitals, particularly in rural areas. OBJECTIVE: To explore health care workers' perceptions about upstream and proximal factors contributing to poor treatment outcomes for severe acute malnutrition in two district hospitals in South Africa. METHODS: An explorative descriptive qualitative study was conducted. Four focus group discussions were held with 33 hospital staff (senior clinical and management staff, and junior clinical staff) using interview guide questions developed based on the findings from an epidemiological study that was conducted in the same hospitals. Qualitative data were analysed using the framework analysis. FINDINGS: Most respondents believed that critical illness, which was related to early and high case fatality rates on admission, was linked to a web of factors including preference for traditional medicine over conventional care, gross negligence of the child at household level, misdiagnosis of severe malnutrition at the first point of care, lack of specialised skills to deal with complex presentations, shortage of patient beds in the hospital and policies to discharge patients before optimal recovery. The majority believed that the WHO guidelines were effective and relatively simple to implement, but that they do not make much difference among severe acute malnutrition cases that are admitted in a critical condition. Poor management of cases was linked to the lack of continuity in training of rotating clinicians, sporadic shortages of therapeutic resources, inadequate staffing levels after normal working hours and some organisational and system-wide challenges beyond the immediate control of clinicians. CONCLUSION: Findings from this study suggest that effective management of paediatric severe acute malnutrition in the study setting is affected by a multiplicity of factors that manifest at different levels of the health system and the community. A verificatory study is encouraged to collaborate these findings. PMID- 29415551 TI - Caesarean section deliveries: Experiences of mothers of midwifery care at a public hospital in Nelson Mandela Bay. AB - BACKGROUND: The rate of caesarean section deliveries has increased globally and mothers are faced with challenges of postoperative recovery and caring thereof. Midwives have a duty to assist these mothers to self-care. OBJECTIVE: The objective was to explore and describe experiences of post-caesarean section delivered mothers of midwifery care at a public hospital in Nelson Mandela Bay. METHODS: A qualitative, descriptive and explorative research design was used in the study. Data were collected from 11 purposively criterion-selected mothers who had a caesarean section delivery. One-on-one semi-structured interviews were conducted in the post-natal wards. Research ethics, namely autonomy, beneficence, justice and informed consent, were adopted in the study. All participants were informed of their right to withdraw from the study at any stage without penalties. Interviews were analysed using Tesch's method of data analysis. RESULTS: Three main themes were identified as experiences of: diverse pain, physical limitation and frustration and health care services as different. CONCLUSION: Experiences of mothers following a caesarean section delivery with midwifery services at a public hospital in Nelson Mandela Bay were explored and described as diverse. A need for adequate pain management as well as assistance and breastfeeding support to mothers following caesarean delivery was identified as crucial to promote a good mother-to-child relationship. PMID- 29415552 TI - Eveningness is associated with poor sleep quality and negative affect in obsessive-compulsive disorder. AB - Background Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive behaviors that severely encumber daily functioning. OCD patients seem to exhibit sleep disturbances, especially delayed bedtimes that reflect disrupted circadian rhythmicity. Morningness-eveningness is a fundamental factor reflecting individual variations in diurnal preferences related to sleep and waking activities. Eveningness reflecting a delayed sleep-wake timing has repeatedly been associated with sleep problems and negative affect (NA). Therefore, the aim of this study was to examine the associations between morningness-eveningness, sleep complaints, and symptom severity in OCD patients and compared with a mixed psychiatric control group. Materials and methods The data of 49 OCD and 49 mixed psychiatric inpatients (with unipolar depression and anxiety disorders) were analyzed. Patients completed questionnaires regarding morningness-eveningness, sleep quality, nightmare frequency, depression, anxiety, and affective states. Obsessive and compulsive symptom severity was also assessed within the OCD group by clinician-rated scales. Results Eveningness preference was associated with impaired sleep quality and higher NA in OCD patients. In addition, impaired sleep quality showed a moderate correlation with anxiety and strong correlations with depressive symptoms and NA. Interestingly, in the mixed psychiatric group, eveningness was not linked to NA, and sleep quality also showed weaker associations with depressive symptoms and NA. Within the OCD group, eveningness preference was predictive of poorer sleep quality regardless the influence of depressive symptoms. Conclusion Our findings suggest that eveningness and sleep complaints are predictive of affective dysfunctions, and should be carefully considered in the evaluation and treatment of OCD patients. PMID- 29415553 TI - Problematic smartphone use, nature connectedness, and anxiety. AB - Background Smartphone use has increased greatly at a time when concerns about society's disconnection from nature have also markedly increased. Recent research has also indicated that smartphone use can be problematic for a small minority of individuals. Methods In this study, associations between problematic smartphone use (PSU), nature connectedness, and anxiety were investigated using a cross sectional design (n = 244). Results Associations between PSU and both nature connectedness and anxiety were confirmed. Receiver operating characteristic (ROC) curves were used to identify threshold values on the Problematic Smartphone Use Scale (PSUS) at which strong associations with anxiety and nature connectedness occur. The area under the curve was calculated and positive likelihood ratios used as a diagnostic parameter to identify optimal cut-off for PSU. These provided good diagnostic ability for nature connectedness, but poor and non significant results for anxiety. ROC analysis showed the optimal PSUS threshold for high nature connectedness to be 15.5 (sensitivity: 58.3%; specificity: 78.6%) in response to an LR+ of 2.88. Conclusions The results demonstrate the potential utility for the PSUS as a diagnostic tool, with a level of smartphone use that users may perceive as non-problematic being a significant cut-off in terms of achieving beneficial levels of nature connectedness. Implications of these findings are discussed. PMID- 29415554 TI - The relationship between gastrointestinal symptom attribution, bothersomeness, and antiretroviral adherence among adults with HIV. AB - Patients who attribute their symptoms to HIV medications, rather than disease, may be prone to switching antiretrovirals (ARVs) and experience poor retention/adherence to care. Gastrointestinal (GI) symptoms (e.g., nausea/vomiting) are often experienced as a side effect of ARVs, but little is known about the relationship of symptom attribution and bothersomeness to adherence. We hypothesized that attribution of a GI symptom to ARVs is associated with a reduction in adherence, and that this relationship is moderated by the bothersomeness of the symptom. Data for our analysis come from the pre randomization enrollment period of a larger study testing an adherence improvement intervention. Analyses revealed that patients with diarrhea who attributed the symptom to ARVs (compared to those who did not) had significantly worse adherence. We did not find a significant moderating effect of bothersomeness on this relationship. Incorporating patient beliefs about causes of symptoms into clinical care may contribute to improved symptom and medication management, and better adherence. PMID- 29415555 TI - Stable Liquid Glucagon: Beyond Emergency Hypoglycemia Rescue. AB - Glycemic control is the mainstay of preventing diabetes complications at the expense of increased risk of hypoglycemia. Severe hypoglycemia negatively impacts the quality of life of patients with type 1 diabetes and can lead to morbidity and mortality. Currently available glucagon emergency kits are effective at treating hypoglycemia when correctly used, however use is complicated especially by untrained persons. Better formulations and devices for glucagon treatment of hypoglycemia are needed, specifically stable liquid glucagon. Out of the scope of this review, other potential uses of stable liquid glucagon include congenital hyperinsulinism, post-bariatric surgery hypoglycemia, and insulinoma induced hypoglycemia. In the 35 years since Food and Drug Administration (FDA) approval of the first liquid stable human recombinant insulin, we continue to wait for the glucagon counterpart. For mild hypoglycemia, a commercially available liquid stable glucagon would enable more widespread implementation of mini-dose glucagon use as well as glucagon in dual hormone closed-loop systems. This review focuses on the current and upcoming pharmaceutical uses of glucagon in the treatment of type 1 diabetes with an outlook on stable liquid glucagon preparations that will hopefully be available for use in patients in the near future. PMID- 29415556 TI - Patterns of use, survival and prognostic factors in patients receiving home mechanical ventilation in Western Australia: A single centre historical cohort study. AB - Home mechanical ventilation (HMV) is used in a wide range of disorders associated with chronic hypoventilation. We describe the patterns of use, survival and predictors of death in Western Australia. We identified 240 consecutive patients (60% male; mean age 58 years and body mass index 31 kg m-2) referred for HMV between 2005 and 2010. The patients were grouped into four categories: motor neurone disorders (MND; 39%), pulmonary disease (PULM; 25%, mainly chronic obstructive pulmonary disease), non-MND neuromuscular and chest wall disorders (NMCW; 21%) and the obesity hypoventilation syndrome (OHS; 15%). On average, the patients had moderate ventilatory impairment (forced vital capacity: 51%predicted), sleep apnoea (apnoea-hypopnea index: 25 events h-1), sleep-related hypoventilation (transcutaneous carbon dioxide rise of 20 mmHg) and daytime hypercarbia (PCO2: 54 mmHg). Median durations of survival from HMV initiation were 1.0, 4.2, 9.9 and >11.5 years for MND, PULM, NMCW and OHS, respectively. Independent predictors of death varied between primary indications for HMV; the predictors included (a) age in all groups except for MND (hazard ratios (HRs) 1.03-1.10); (b) cardiovascular disease (HR: 2.35, 95% confidence interval (CI): 1.08-5.10) in MND; (c) obesity (HR: 0.28, 95% CI: 0.13-0.62) and oxygen therapy (HR: 0.33, 95% CI: 0.14-0.79) in PULM; and (d) forced expiratory volume in 1 s (%predicted; HR: 0.93, 95% CI: 0.88-1.00) in OHS. PMID- 29415557 TI - Outcomes of Resection and Joint-Preserving Arthroplasty for Forefoot Deformities for Rheumatoid Arthritis. AB - BACKGROUND: We investigated the clinical outcomes of resection and joint preserving arthroplasty for forefoot deformities in patients with rheumatoid arthritis. METHODS: Sixteen feet of 14 women (average age, 67.1 years; range, 53 82) underwent resection arthroplasty of the metatarsal head (resection group), and 18 feet of 15 women (average age, 61.3 years; range, 40-73) underwent a metatarsophalangeal joint-preserving procedure with shortening oblique metatarsal osteotomies of the lesser toes (joint preservation group). The mean disease duration in the resection and joint preservation groups was 23.6 and 19.1 years, and the average follow-up period was 37.3 and 33.5 months, respectively. The classification of Larsen was used to assess the severity of destruction of the metatarsophalangeal (MTP) joint. Preoperative and postoperative clinical evaluation included Japanese Society for Surgery of the Foot (JSSF) score and postoperative complications. RESULTS: The number of preoperative radiographic destruction of the MTP joints (Larsen grade II, III, IV, and V) was 0, 29, 39, and 12 joints in the resection group and 13, 67, 9, and 1 joints in the joint preservation group. The mean JSSF score improved significantly from 61.3 to 83.9 points in the resection group ( P < .001) and from 62.2 to 90.8 points in the joint preservation group ( P < .001). In the resection group, recurrence of callosities and claw toe deformity was observed in 6 and 3 feet, respectively. In the joint-preserving group, recurrence of callosities and hammer toe deformity was observed in 1 foot each. CONCLUSION: The resection arthroplasty and joint preserving procedure showed satisfactory clinical outcomes. However, whether both procedures can maintain the good clinical results without the recurrence of forefoot deformity will require longer follow-up. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 29415558 TI - 'Something needs to change': Mental health experiences of young autistic adults in England. AB - There is a high incidence and prevalence of mental health problems among young people, with several barriers to help-seeking noted in this group. High rates of mental health problems have also been reported in children and adults on the autism spectrum. Taken together, young autistic people may be a particularly vulnerable group when it comes to mental health. Yet, there has been remarkably little work on the mental health needs and experiences of young autistic adults (16-25 years). Adopting a community-based participatory research (CBPR) approach in which academic researchers and young autistic adults collaborated in an equitable research partnership - we explored young autistic people's experiences of mental health problems and their perspectives on the support they sought, if any, for these problems. A total of 130 young autistic adults took part in the research: 109 completed an online survey and 21 took part in detailed interviews. The results highlight how young autistic people find it difficult to evaluate their mental health, experience high levels of stigma and often face severe obstacles when trying to access mental health support. The findings also demonstrate how listening to - and learning from - young autistic people is crucial in ensuring that their mental health needs are met. PMID- 29415559 TI - Development of a brief version of the Autism Detection in Early Childhood. AB - While autism spectrum disorder screening tools provide a useful resource for practitioners, the reality is they are underused. The justifications often provided include the time required for administration and the training involved. A brief tool with good psychometric properties that require minimal training is required. This study examined the development and the psychometric properties of a brief version of the Autism Detection in Early Childhood. The data showed the potential of the brief version of Autism Detection in Early Childhood for screening children age 12-36 months. Our dataset comprised 106 Diagnostic and Statistical Manual of Mental Disorders, 5th edition autism spectrum disorder, 86 non-typical development and 78 typical development participants age 12-36 months. Analyses comparing autism spectrum disorder and non-typical development groups supported the use of five critical items (i.e. response to name, social smiling, gaze switch, response to verbal command and use of gestures) to form the brief version Autism Detection in Early Childhood. The brief version of Autism Detection in Early Childhood's optimal cutoff score of 4 had sensitivity of 0.81, specificity of 0.78, positive predictive value of 0.81 and negative predictive value of 0.78. However, the results would need to be viewed as preliminary given the nature of the study sample and the findings might not be generalisable to samples with higher levels of cognitive functioning. PMID- 29415561 TI - Psychological and physical violence towards children with disabilities in Finland and Sweden. AB - This article describes psychological aggression and physical violence by Swedish and Finnish mothers ( N = 3420) towards their 0- to 12-year-old children with disabilities ( N = 286) by comparing such behaviour with the mothers of children without disabilities ( N = 3134). The survey data are based on representative samples from Finland and Sweden of mothers' reports of their behaviour towards their child in conflict situations. Mothers of children with disabilities reported more psychological aggression towards their child than did mothers of children without disabilities. Mothers used psychological aggression, especially towards children with neurological/psychological disabilities. However, the only significant difference regarding physical violence was repetitive use of mild physical violence. Overall, the analysis suggests that children with neurological/psychological disabilities are more exposed to both psychological and physical violence than children without disabilities or children with somatic/developmental disabilities. PMID- 29415560 TI - Current model systems for the study of preeclampsia. AB - Preeclampsia (PE) is a pregnancy complex disease, distinguished by high blood pressure and proteinuria, diagnosed after the 20th gestation week. Depending on the values of blood pressure, urine protein concentrations, symptomatology, and onset of disease there is a wide range of phenotypes, from mild forms developing predominantly at the end of pregnancy to severe forms developing in the early stage of pregnancy. In the worst cases severe forms of PE could lead to systemic endothelial dysfunction, eclampsia, and maternal and/or fetal death. Worldwide the fetal morbidity and mortality related to PE is calculated to be around 8% of the total pregnancies. PE still being an enigma regarding its etiology and pathophysiology, in general a deficient trophoblast invasion during placentation at first stage of pregnancy, in combination with maternal conditions are accepted as a cause of endothelial dysfunction, inflammatory alterations and appearance of symptoms. Depending on the PE multifactorial origin, several in vitro, in vivo, and in silico models have been used to evaluate the PE pathophysiology as well as to identify or test biomarkers predicting, diagnosing or prognosing the syndrome. This review focuses on the most common models used for the study of PE, including those related to placental development, abnormal trophoblast invasion, uteroplacental ischemia, angiogenesis, oxygen deregulation, and immune response to maternal-fetal interactions. The advances in mathematical and computational modeling of metabolic network behavior, gene prioritization, the protein-protein interaction network, the genetics of PE, and the PE prediction/classification are discussed. Finally, the potential of these models to enable understanding of PE pathogenesis and to evaluate new preventative and therapeutic approaches in the management of PE are also highlighted. Impact statement This review is important to the field of preeclampsia (PE), because it provides a description of the principal in vitro, in vivo, and in silico models developed for the study of its principal aspects, and to test emerging therapies or biomarkers predicting the syndrome before their evaluation in clinical trials. Despite the current advance, the field still lacking of new methods and original modeling approaches that leads to new knowledge about pathophysiology. The part of in silico models described in this review has not been considered in the previous reports. PMID- 29415562 TI - Retrospective Review of a Prothrombin Complex Concentrate (Beriplex P/N) for the Management of Perioperative Bleeding Unrelated to Oral Anticoagulation. AB - A multicenter, retrospective, observational study of 4-factor prothrombin complex concentrate (PCC) and/or fresh frozen plasma (FFP) use within routine clinical care unrelated to vitamin K antagonists was conducted. The PCC was administered preprocedure for correction of coagulopathy (prophylactic cohort) and treatment of bleeding postsurgery (treatment cohort). Of the 445 patients included, 40 were in the prophylactic cohort (PCC alone [n = 16], PCC and FFP [n = 5], FFP alone [n = 19]) and 405 were in the treatment cohort (PCC alone [n = 228], PCC and FFP [n = 123], FFP alone [n = 54]). Cardiovascular surgery was the most common setting. PCC doses ranged between 500 and 5000 IU. Effectiveness (assessed retrospectively) was reported as effective in 93.0% in the PCC-only group (95% confidence interval, 89.1% to 95.9%), 78.9% (70.8% to 85.6%) with PCC and FFP, and 86.3% (76.2% to 93.2%) with FFP alone. In the treatment cohort, international normalized ratio was significantly reduced in all 3 groups. In patients who received PCC, the rate of thromboembolic events (1.9%) was below rates in the literature for similar procedures. PCCs offer a potential alternative to FFP in the management of perioperative bleeding unrelated to oral anticoagulant therapy. PMID- 29415564 TI - Plate Alone Versus Plate and Lag Screw for Lapidus Arthrodesis: A Biomechanical Comparison of Compression. AB - BACKGROUND: Arthrodesis of the first tarsal metatarsal joint can be accomplished in many ways. The compressive force attained between various constructs remains unclear. This study compares compression achieved through a locking/compression Lapidus plate both with and without the addition of a lag screw. METHODS: A dorsal medial Lapidus/locking compression plate (Total Compression Plate System, OrthoPro, Salt Lake City, UT, now Wright Medical) was applied to one cadaveric limb, while the same plate with the addition of a 4.0-mm cannulated lag screw was applied to the contralateral limb for a total of 5 matched pairs of cadaveric specimens. Compressive force was recorded over time and compared between the constructs using a compression sensor (8" FlexiForce Resistive Force Sensor, Phidgets Inc, Calgary, Alberta, Canada). RESULTS: Compression was maintained for 45.4 minutes in the plate only construct, and 317 minutes with the addition of the lag screw ( P = .010). The mean time to 50% peak compression for the plate only construct was 4.90 minutes compared with 15.11 minutes for plate with lag screw construct (P = .012). CONCLUSION: The addition of a lag screw is recommended for extending the length of compression and possibly reducing nonweightbearing time and the risk of nonunion. LEVELS OF EVIDENCE: Level V. PMID- 29415563 TI - Body Mass Index Effect on Differing Responses to Psychological Stress in Blood Glucose Dynamics in Patients With Type 1 Diabetes. AB - OBJECTIVE: The objective was to investigate the relationship of body mass index (BMI) to differing glycemic responses to psychological stress in patients with type 1 diabetes. METHODS: Continuous blood glucose monitor (CGM) data were collected for 1 week from a total of 37 patients with BMI ranging from 21.5-39.4 kg/m2 (mean = 28.2 +/- 4.9). Patients reported daily stress levels (5-point Likert-type scale, 0 = none, 4 = extreme), physical activity, carbohydrate intake, insulin boluses and basal rates. Daily reported carbohydrates, total insulin bolus, and average blood glucose (BG from CGM) were compared among patients based on their BMI levels on days with different stress levels. In addition, daily averages of a model-based "effectiveness index" (quantifying the combined impact of insulin and carbohydrate on glucose levels) were defined and compared across stress levels to capture meal and insulin independent glycemic changes. RESULTS: Analyses showed that patient BMI likely moderated stress related glycemic changes. Linear mixed effect model results were significant for the stress-BMI interaction on both behavioral and behavior-independent glycemic changes. Across participants, under stress, an increase was observed in daily carbohydrate intake and effectiveness index at higher BMI. There was no significant interactive effect on daily insulin or average BG. CONCLUSION: Findings suggest that (1) stress has both behavioral and nonbehavioral glycemic effects on T1D patients and (2) the direction and magnitude of these effects are potentially influenced by level of stress and patient BMI. Possibly responsible for these observed effects are T1D/BMI related alterations in endocrine response. PMID- 29415565 TI - Effect of Mannitol on Ultrasonographically Measured Optic Nerve Sheath Diameter as a Surrogate for Intracranial Pressure During Robot-Assisted Laparoscopic Prostatectomy with Pneumoperitoneum and the Trendelenburg Position. AB - INTRODUCTION: CO2 pneumoperitoneum and the steep Trendelenburg position during robot-assisted laparoscopic prostatectomy (RALP) can increase intracranial pressure (ICP). Mannitol is widely used to treat increased ICP. However, no studies to date have specifically evaluated the effect of mannitol on ICP in patients undergoing RALP. Ultrasonographic measurement of the optic nerve sheath diameter (ONSD) is considered a reliable technique to noninvasively evaluate the ICP. Therefore, this study compared ONSDs as a surrogate for ICP before and after mannitol administration in prostate cancer patients undergoing RALP. METHODS: Mannitol (0.5 g/kg) was administered after pneumoperitoneum establishment and shifting to the Trendelenburg position. ONSDs were measured at six predetermined time points: 10 minutes after anesthesia induction (T0); 5 minutes after pneumoperitoneum and the Trendelenburg position before mannitol administration (T1); 30 minutes (T2), 60 minutes (T3), and 90 minutes (T4) after completion of mannitol administration during pneumoperitoneum and the Trendelenburg position; and at skin closure in the supine position (T5). Moreover, intraoperative hemodynamic and respiratory variables were evaluated simultaneously. RESULTS: Thirty-six patients were analyzed. ONSDs were significantly lower at T2, T3, and T4 than at T1 (all p < 0.001), with the greatest decrease observed at T4 compared with T1 (4.46 +/- 0.2 mm vs 4.81 +/- 0.3 mm, p < 0.001). Regional cerebral oxygen saturation, cardiac output, corrected flow time, peak velocity, body temperature, arterial CO2 partial pressure, peak airway pressure, plateau airway pressure, dynamic compliance, and static compliance were not significantly different during pneumoperitoneum and the Trendelenburg position; however, mean arterial blood pressure and heart rate were significantly different. CONCLUSIONS: Mannitol decreases the ONSD in patients undergoing RALP with CO2 pneumoperitoneum and the steep Trendelenburg position. This result provides useful information on the beneficial effects of mannitol administration on prostate cancer patients who may develop increased ICP during RALP. PMID- 29415567 TI - The Clinimetric Properties of Instruments Measuring Home Hazards for Older People at Risk of Falling: A Systematic Review. AB - Home hazards are associated with falls among older people living in the community. However, evaluating home hazards is a complex process as environmental factors vary according to geography, culture, and architectural design. As a result, many health practitioners commonly use nonstandardized assessment methods that may lead to inaccurate findings. Thus, the aim of this systematic review was to identify standardized instruments for evaluating home hazards related to falls and evaluate the clinimetric properties of these instruments for use by health practitioners. A systematic search was conducted in the Medline, CINAHL, AgeLine, Web of Science databases, and the University of Sydney Library CrossSearch Engine. Study screening, assessment, and quality ratings were conducted independently. Thirty-six studies were identified describing 19 instruments and three assessment techniques. The clinimetric properties varied between instruments. The Home Falls and Accidents Screening Tool, Home Safety Self Assessment Tool, In-Home Occupational Performance Evaluation, and Westmead Home Safety Assessment were the instruments with high potential for evaluating home hazards associated with falls. Health practitioners can choose the most appropriate instruments for their practice, as a range of standardized instruments with established clinimetric properties are available. PMID- 29415566 TI - Tracing changes in the diet and habitat use of black-tailed godwits in Western France, using a stable isotope approach. AB - Western France is at the crossroads of the migratory routes of two subspecies of black-tailed godwit, Limosa limosa. After leaving Iceland, the godwit L.l. islandica Icelandic black-tailed godwit (IBTG) winters on the coast of western Europe, while the continental black-tailed godwit (CBTG) L.l. limosa can stop in France when migrating between Iberia or Africa and their main breeding grounds in the Netherlands. In this study, we analysed delta15N and delta13C from flight feathers and whole blood throughout the non-breeding period to trace variations in habitat use for both subspecies on the western French coast. Adults and juveniles of IBTG adopt the same feeding habitats as soon as they arrive in the study area, progressively losing the Icelandic freshwater habitat signal, and becoming clearly restricted to marine habitats in winter. Some individuals begin to move locally to freshwater habitats, joining CBTG in a stopover at the end of the wintering period in preparation for northward migration. PMID- 29415569 TI - The adhesins of non-typeable Haemophilus influenzae. AB - INTRODUCTION: Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen of the respiratory tract and the greatest contributor to invasive Haemophilus disease. Additionally, in children, NTHi is responsible for the majority of otitis media (OM) which can lead to chronic infection and hearing loss. In adults, NTHi infection in the lungs is responsible for the onset of acute exacerbations in chronic obstructive pulmonary disease (COPD). Unfortunately, there is currently no vaccine available to protect against NTHi infections. Areas covered: NTHi uses an arsenal of adhesins to colonise the respiratory epithelium. The adhesins also have secondary roles that aid in the virulence of NTHi, including mechanisms that avoid immune clearance, adjust pore size to avoid antimicrobial destruction, form micro-colonies and invoke phase variation for protein mediation. Bacterial adhesins can also be ideal antigens for subunit vaccine design due to surface exposure and immunogenic capabilities. Expert commentary: The host-pathogen interactions of the NTHi adhesins are not fully investigated. The relationship between adhesins and the extracellular matrix (ECM) play a part in the success of NTHi colonisation and virulence by immune evasion, migration and biofilm development. Further research into these immunogenic proteins would further our understanding and enable a basis for better combatting NTHi disease. PMID- 29415570 TI - The multiple myeloma treatment landscape: international guideline recommendations and clinical practice in Europe. AB - INTRODUCTION: Guidelines provide recommendations on the management of multiple myeloma (MM), but there are no standard algorithms for the choice and sequencing of treatments. As a result, there is widespread variation in the interpretation and implementation of these guidelines. Areas covered: This review will cover: the real-world data on MM treatment patterns; the approved agents available for the treatment of MM; a comparative summary of the national and international clinical guidelines; a discussion on the impact reimbursement decisions have on treatment availability. Expert commentary: In the future, treatment choices may become even more complex as clonal heterogeneity is better understood in the context of response to treatment, and next-generation agents become available. Although information on real-world practice patterns can provide further guidance, to date, few studies have generated data on patients treated with the newer agents in real-world settings. Furthermore, the translation of guideline recommendations into clinical practice across Europe is inconsistent. Additional real-world data are therefore vital to understanding current clinical practice patterns, so that new agents can be effectively incorporated into existing treatment strategies. Such information may aid the development of better guidance, which will ultimately help to ensure that patients receive the best possible care. PMID- 29415571 TI - High beat-to-beat blood pressure variability in atrial fibrillation compared to sinus rhythm. AB - PURPOSE: Atrial fibrillation (AF) is associated with an increased risk for cardiovascular morbidity and mortality, not entirely explained by thromboembolism. The underlying mechanisms for this association are largely unknown. Similarly, high blood pressure (BP) increases the risk for cardiovascular events. Despite this the interplay between AF and BP is insufficiently studied. The purpose of this study was to examine and quantify the beat-to-beat blood pressure variability in patients with AF in comparison to a control group of patients with sinus rhythm. MATERIALS AND METHODS: We studied 33 patients - 21 in atrial fibrillation and 12 in sinus rhythm - undergoing routine coronary angiography. Invasive blood pressure was recorded at three locations: radial artery, brachial artery and ascending aorta. Blood pressure variability, defined as average beat-to-beat blood pressure difference, was calculated for systolic and diastolic blood pressure at each site. RESULTS: We observed a significant difference (p < .001) in systolic and diastolic blood pressure variability between the atrial fibrillation and sinus rhythm groups at all locations. Systolic blood pressure variability roughly doubled in the atrial fibrillation group compared to the sinus rhythm group (4.9 and 2.4 mmHg respectively). Diastolic beat-to-beat blood pressure variability was approximately 6 times as high in the atrial fibrillation group compared to the sinus rhythm group (7.5 and 1.2 mmHg respectively). No significant difference in blood pressure variability was seen between measurement locations. CONCLUSIONS: Beat-to-beat blood pressure variability in patients with atrial fibrillation was substantially higher than in patients with sinus rhythm. Hemodynamic effects of this beat-to-beat variation in blood pressure may negatively affect vascular structure and function, which may contribute to the increased cardiovascular morbidity and mortality seen in patients with atrial fibrillation. PMID- 29415572 TI - Three dimensional typological studies using scanning electron microscopy for characterization of Termitomyces pellets obtained from submerged growth conditions. AB - There are gaps in existing understanding of fungal pellet growth dynamics. We used scanning electron microscopy (SEM) for morphological characterization of the biomass organization of Termitomyces pellets for seven species: T. microcarpus (TMI1), T. albuminosus (TAL1, TAL2), T. striatus (TSTR), T. aurantiacus (TAUR), T. heimii (THE1, THE2), T. globulus (TGLO) and T. clypeatus (TCL1, TCL2, TCL3, TCL4, TCL5). We assessed the utility of SEM for morphological and structural characterization of Termitomyces spp. in three dimensional (3D) pellet form to identify ideal pellet morphology for industrial use. Typological classification of Termitomyces species was based on furrows, isotropy, total motifs and fractal dimensions. The pellets formed were entangled and exhibited highly compacted mycelial mass with microheterogeneity and microporosity. The mean density of furrows of Termitomyces species was between 10,000 and 11,300 cm/cm2, percentage isotropy was 30-80 and total motifs varied from 300 to 2500. TGLO exhibited the highest furrow mean density, 11243 cm/cm2, which indicated a compact, cerebroid structure with complex ridges and furrows, whereas TAL2 exhibited the lowest furrow density. TMI1a exhibited a high percentage isotropic value, 74.6, TSTR exhibited the lowest, 30.9. Total motif number also was used as a typological classification parameter. Fractal values were 2.64-2.78 for various submerged conditions of Termitomyces species. TAL1 exhibited the highest fractal dimension and TAL2 the lowest, which indicates the complexity of branching patterns. Three dimensional SEM image analysis can provide insight into pellet micromorphology and is a powerful tool for exploring topographical details of pellets. PMID- 29415573 TI - All cases of pediatric methotrexate ingestion should be referred to hospital for assessment until more robust evidence suggests the contrary. PMID- 29415574 TI - Quirks of dye nomenclature. 10. Eosin Y and its close relatives. AB - The long history of eosin Y, eosin B and the methyl and ethyl eosins is recounted as well as their synthesis, the variety of their molecular species and some of the myriad applications of these dyes. Chromatographic techniques are described that reveal the purity or lack of it in commercial samples. Toxicological studies are discussed that suggest that the eosins are virtually non toxic, but efforts to remove them from the environment imply that there may be some risk. PMID- 29415575 TI - Drug delivery across length scales. AB - Over the last century, there has been a dramatic change in the nature of therapeutic, biologically active molecules available to treat disease. Therapies have evolved from extracted natural products towards rationally designed biomolecules, including small molecules, engineered proteins and nucleic acids. The use of potent drugs which target specific organs, cells or biochemical pathways, necessitates new tools which can enable controlled delivery and dosing of these therapeutics to their biological targets. Here, we review the miniaturisation of drug delivery systems from the macro to nano-scale, focussing on controlled dosing and controlled targeting as two key parameters in drug delivery device design. We describe how the miniaturisation of these devices enables the move from repeated, systemic dosing, to on-demand, targeted delivery of therapeutic drugs and highlight areas of focus for the future. PMID- 29415576 TI - Predictors and psychological pathways for binge drinking among South African men. AB - OBJECTIVE: To develop targeted interventions for high-risk drinkers among South African men, we assessed whether sociodemographic factors and history of childhood sexual abuse predicted binge drinking at six-month follow-up assessment and their psychological pathways according to the extended Theory of Reasoned Action (TRA). DESIGN: Survey responses with a sample of 1181 South African men from randomly selected neighbourhoods in Eastern Cape Province were collected at baseline and six-month follow-up. Multiple logistic regression analysis examined the baseline predictors of binge drinking. Serial multiple mediation analysis examined the psychological pathways. MAIN OUTCOME MEASUREMENTS: Binge drinking at six-month follow-up. RESULTS: Age (OR = 1.03, 95% CI: 1.01, 1.05), religious participation (OR = .73, CI: .65, .82) and history of childhood sexual abuse (OR = 1.82, CI: 1.32, 2.51) were significant predictors of binge drinking. Predictions of religious participation and history of childhood sexual abuse were partially mediated through attitude, subjective norm, descriptive norm and intention to binge drinking. CONCLUSION: South African men with childhood sexual abuse experience and low religious participation were at higher risk for binge drinking. The extended TRA model explains the associations of these factors to binge drinking and can contribute to the design and evaluation of interventions. PMID- 29415577 TI - Janus kinase inhibition and symptom control in myeloproliferative neoplasms. PMID- 29415578 TI - Exogenous luteinizing hormone supplementation in controlled ovarian stimulation: why, when and to whom? PMID- 29415579 TI - Use of spacers for patients treated with pressurized metered dose inhalers: focus on the VENTOLINTM Mini Spacer. AB - INTRODUCTION: Spacers offer a multitude of benefits by reducing the requirement to coordinate inhalation with actuation and improving inhaler technique in patients using a pressurized metered dose inhaler (pMDI). Spacers improve drug targeting by retaining within the spacer large particles normally deposited in the oropharynx, and by creating a prolonged aerosol cloud of fine particles to give the user increased time to inhale after actuation. This is particularly important in young children and the elderly to effectively deliver medication to the airways. Areas covered: By investigating the history and features of spacers, we demonstrate that the advantages of using spacers far outweigh their limitations. We also discuss the optimal characteristics of spacers in terms of shape, volume, presence of valve and static charge, and present a detailed discussion of the VENTOLINTM Mini Spacer. Expert opinion: Generally, the shape and size of spacers makes them inherently inconvenient. Consideration of human factors and modern design may make them more attractive to patients. However, the incentive to use spacers should be their ability to help patients correctly use inhaled medications delivered by pMDIs. Understanding of these principles through education is key to their acceptance by patients. PMID- 29415580 TI - A non-interventional comparative study of the 20:1 combination of cafedrine/theodrenaline versus ephedrine for the treatment of intra-operative arterial hypotension: the 'HYPOTENS' study design and rationale. AB - OBJECTIVE: To compare the effectiveness of 20:1 cafedrine/theodrenaline approved for use in Germany to ephedrine in the restoration of arterial blood pressure and on post-operative outcomes in patients with intra-operative arterial hypotension of any origin under standard clinical practice conditions. METHODS AND RESULTS: 'HYPOTENS' is a national, multi-center, prospective, open-label, two-armed, non interventional study. Effectiveness and post-operative outcome following cafedrine/theodrenaline or ephedrine therapy will be evaluated in two cohorts of hypotensive patients. Cohort A includes patients aged >=50 years with ASA classification 2-4 undergoing non-emergency surgical procedures under general anesthesia. Cohort B comprises patients undergoing Cesarean section under spinal anesthesia. Participating surgical departments will be assigned to a treatment arm by routinely used anti-hypotensive agent. To minimize bias, matched department pairs will be compared in a stratified selection process. The composite primary end-point is the lower absolute deviation from individually determined target blood pressure (IDTBP) and the incidence of heart rate >=100 beats/min in the first 15 min. Secondary end-points include incidence and degree of early post-operative delirium (cohort A), severity of fetal acidosis in the newborn (cohort B), upper absolute deviation from IDTBP, percentage increase in systolic blood pressure, and time to IDTBP. CONCLUSION: This open-label, non interventional study design mirrors daily practice in the treatment of patients with intra-operative hypotension and ensures full treatment decision autonomy with respect to each patient's individual condition. Selection of participating sites by a randomization process addresses bias without interfering with the non interventional nature of the study. First results are expected in 2018. ClinicalTrials.gov identifier: NCT02893241; DRKS identifier: DRKS00010740. PMID- 29415581 TI - A new approach to assess drug sensitivity in cells for novel drug discovery. AB - INTRODUCTION: There is a pressing need to improve strategies to select candidate drugs early on in the drug development pipeline, especially in oncology, as the efficiency of new drug approval has steadily declined these past years. Traditional methods of drug screening have relied on low-cost assays on cancer cell lines growing on plastic dishes. Recent massive-scale screens have generated big data amenable for sophisticated computational modeling and integration with clinical data. However, 2D culturing has several intrinsic limitations and novel methodologies have been devised for culturing in three dimensions, to include cells from the tumor immune microenvironment. These major improvements are bringing in vitro systems even closer to a physiological, more clinically relevant state. Areas covered: In this article, the authors review the literature on methodologies for early-phase drug screening, focusing on in vitro systems and analyzing both novel experimental and statistical approaches. The article does not cover the expanding literature on in vivo systems. Expert opinion: The popularity of three-dimensional systems is exploding, driven by the development of 'organoid' derivation technology in 2009. These assays are growing in sophistication to accommodate the increasing need by modern oncology to develop drugs that target the microenvironment. PMID- 29415582 TI - Date seed oil loaded niosomes: development, optimization and anti-inflammatory effect evaluation on rats. AB - OBJECTIVE: An optimized date seed oil (DSO) loaded niosomes was formulated. SIGNIFICANCE: Maximize the extract anti-inflammatory efficacy and govern its release characteristics from nanoparticles for osteoarthritis prevention and treatment purposes. METHODS: By using Box-Behnken Design, the effect of three formulation factors on the entrapment efficiency percentage (Y1), initial DSO release percentage after 2 h (Y2), and cumulative DSO release percentage of DSO after 12 h (Y3), were optimized and studied. The optimized DSO formulation was specified, elaborated, particle size and zeta potential assessed, examined morphologically under electron and light microscope, and in vivo evaluated via carrageenan-induced rat paw edema study. RESULTS: 65.89%, 18.39%, and 58.27% were the measured responses of the optimized niosomes for Y1, Y2, and Y3, respectively. The vesicular structure of the optimized DSO loaded nano-vesicles with nano-size range and good stability features were confirmed. Furthermore, a distinguished anti-inflammatory activity in both prompt and sustained effectiveness were exhibited via the optimized DSO niosomes. Interestingly, the delayed efficacy outcomes of the extract loaded nanoparticles showed a similarity profile as well as the negative control group outcomes. CONCLUSIONS: To emphasize, DSO loading in niosomes revealed a significant enhancement toward inflammation alleviation, which offers a promising implement in osteoarthritis remediation and prohibition. PMID- 29415583 TI - Correction to: Sekhon et al., Review of the mechanism of action of coal tar in psoriasis. PMID- 29415584 TI - Management of chronic viral hepatitis in the hematological patient. AB - INTRODUCTION: Infection with HBV and HCV represents a growing challenge in the management of patients with hematological malignancies. Recently, hepatitis E (HEV) was recognized as an endemic infection in developed countries and as an emerging health problem in immunocompromised patients. Areas covered: We reviewed the current knowledge on the impact of chronic viral hepatitis in the hematological setting. Epidemiological features, screening strategies and indications for treatment and monitoring have been explored and commented. Expert commentary: Knowing patient's complete HBV serostatus is mandatory in order to choose between treatment, prophylaxis or a pre-emptive approach. Recent guidelines favor treatment with high barrier molecules in all patients with chronic HBV infection and long lasting prophylaxis with those with inactive or resolved one. With regard to HCV, the new direct-acting antiviral agents have been safely administered in the hematological setting. Their use as first-line single treatment in indolent lymphomas, and combined with chemotherapy in aggressive ones, should be considered. Due to the existing risk of chronic HEV infection in the immunocompromised, screening with serum HEV-RNA should be performed in case of signs and symptoms indicative of hepatitis. In the event of HEV infection, reduction of immunosuppression and, if not feasible or unsuccessful, ribavirin treatment should be prescribed. PMID- 29415585 TI - Semantic context improves speech intelligibility and reduces listening effort for listeners with hearing impairment. AB - OBJECTIVE: We investigated whether speech intelligibility and listening effort for hearing-aid users is affected by semantic context and hearing-aid setting. DESIGN: Participants heard target sentences spoken in a reverberant background of cafeteria noise and competing speech. Participants reported each sentence verbally. Eight participants also rated listening effort after each sentence. Sentence topic was either the same as, or different from, the previous target sentence. STUDY SAMPLE: Twenty participants with sensorineural hearing loss were fit binaurally with Signia receiver-in-the-canal hearing aids. Participants performed the task twice: once using the hearing aid's omnidirectional setting and once using the "Reverberant Room" setting, designed to aid listening in reverberant environments. RESULTS: Participants achieved better speech intelligibility for same-topic than different-topic sentences, and when they used the "Reverberant Room" than the omnidirectional hearing-aid setting. Participants who rated effort showed a reliable reduction in listening effort for same-topic sentences and for the "Reverberant Room" hearing-aid setting. The improvement in speech intelligibility from semantic context (i.e. same-topic compared to different-topic sentences) was greater than the improvement gained from changing hearing-aid setting. CONCLUSIONS: These findings highlight the enormous potential of cognitive (specifically, semantic) factors for improving speech intelligibility and reducing perceived listening effort in noise for hearing-aid users. PMID- 29415587 TI - An evaluation of nutritional and vasoactive stimulants as risk factors for gastroschisis: a pilot study. AB - OBJECTIVE: The objective of this study is to evaluate poor maternal nutrition, environmental exposures and vasoactive stimulants as potential risk factors for gastroschisis. METHODS: A case-control study was conducted among singleton pregnancies diagnosed in a tertiary teaching hospital in a 22-month period. Cases of gastroschisis were matched to controls at the time of diagnosis by race and maternal age. Demographics, periconceptual exposures, nutritional biomarkers, and illicit drug hair analysis were evaluated. Analyses were performed using conditional logistic regression. RESULTS: Thirty gastroschisis cases and 76 controls were studied with no associations observed for illicit drug use or serum levels of ferritin, iron, B6, B12, folate, or zinc. Neither prescription medication nor over the counter mediation use differed between cases and controls. Following adjustment for insurance, education, low BMI, and nulliparity, mothers of gastroschisis cases had an increased odds of alcohol use 1 month prior and/or during early pregnancy compared with controls, with adjusted odds ratio (OR) 3.19 (95% CI 1.01-11.61). CONCLUSIONS: Our findings suggest that further investigation of vasoactive stimulants such as alcohol is warranted in the search to identify risk factors for gastroschisis. PMID- 29415586 TI - What we know and what we don't know about perinatal Zika virus infection: a systematic review. AB - INTRODUCTION: Zika virus (ZIKV) infection has caused the most challenging worldwide infectious epidemic outbreak in recent months. ZIKV causes microcephaly and other congenital malformations. There is a need to perform updated systematic reviews on ZIKV infection periodically because this epidemic is bringing up new evidence with extraordinary speed. Areas covered: Evidence related to ZIKV infection in the gestational, perinatal, and early infant periods covering epidemiology, virology, pathogenesis, risk factors, time of infection during pregnancy, newborn symptoms, treatment, and vaccines. To this end, a search was performed using terms ['Zika'] AND ['Perinatal Infection'] OR ['Congenital Infection'] in the PubMed(r) international electronic database. Out of a total of 1,538 articles published until 30 November 2017, we finally assessed 106 articles articles that were relevant to the research areas included in this study. Expert commentary: ZIKV is a new teratogenic/neurotropic virus affecting fetuses. Many challenges are still far from being solved regarding the epidemiology, case definition, clinical and laboratory diagnosis, and preventive measures. An approach using 'omics' and new biomarkers for diagnosis, and a ZIKV-vaccine for treatment, might finally give us the tools to solve these challenges. PMID- 29415588 TI - Proportion and characteristics of patients who were offered, enrolled in and completed audiologist-delivered cognitive behavioural therapy for tinnitus and hyperacusis rehabilitation in a specialist UK clinic. AB - OBJECTIVE: The aim was to determine the proportion and characteristics of patients who were offered, enrolled in and completed an audiologist-delivered cognitive behavioural therapy (CBT) programme for tinnitus and/or hyperacusis in a specialist Audiology Department in the National Health Service, UK. DESIGN: This was a retrospective study. STUDY SAMPLE: Data were gathered for 266 consecutive patients with an average age of 56 y (standard deviation =15 y). RESULTS: Following an initial assessment session, 68% of patients were judged to have problems sufficient for them to be offered audiologist-delivered CBT. The remaining 32% were discharged. Of those enrolled for CBT, 31% were discharged after the first CBT session, because they were judged to have insufficient tinnitus and/or hyperacusis distress. Of those offered continuing CBT, 45% declined to continue. Patients who continued were younger, had worse insomnia and had better hearing in their better ear than patients who declined. Of those who continued, 68% completed the six sessions of CBT. CONCLUSION: Although CBT is resource intensive, only 17% of the total patient sample received the full course of six sessions of CBT. Patients who accepted continuing CBT were younger, had worse insomnia and had better hearing than those who declined. PMID- 29415589 TI - Late preterm birth and previous cesarean section: a population-based cohort study. AB - BACKGROUND: Late preterm birth (LPB) is increasingly common and associated with higher morbidity and mortality than term birth. Yet, little is known about the influence of previous cesarean section (PCS) and the occurrence of LPB in subsequent pregnancies. We aim to evaluate this association along with the potential mediation by cesarean sections in the current pregnancy. METHODS: We use population-based birth registry data (2005-2012) to establish a cohort of live born singleton infants born between 34 and 41 gestational weeks to multiparous mothers. PCS was the primary exposure, LPB (34-36 weeks) was the primary outcome, and an unplanned or emergency cesarean section in the current pregnancy was the potential mediator. Associations were quantified using propensity weighted multivariable Poisson regression, and mediating associations were explored using the Baron-Kenny approach. RESULTS: The cohort included 481,531 births, 21,893 (4.5%) were LPB, and 119,983 (24.9%) were predated by at least one PCS. Among mothers with at least one PCS, 6307 (5.26%) were LPB. There was increased risk of LPB among women with at least one PCS (adjusted Relative Risk (aRR): 1.20 (95%CI [1.16, 1.23]). Unplanned or emergency cesarean section in the current pregnancy was identified as a strong mediator to this relationship (mediation ratio = 97%). CONCLUSIONS: PCS was associated with higher risk of LPB in subsequent pregnancies. This may be due to an increased risk of subsequent unplanned or emergency preterm cesarean sections. Efforts to minimize index cesarean sections may reduce the risk of LPB in subsequent pregnancies. PMID- 29415590 TI - The mortality of very low birth weight infants: the benefit and relative impact of changes in population and therapeutic variables. AB - OBJECTIVE: Very low birth weight (VLBW, <=1500 g) infants' mortality rates have decreased markedly. We aimed to quantify the relative contribution of changes in the distribution of population characteristics and changes in specific mortality rates on the decline in mortality rates of VLBW infants. STUDY DESIGN: A population-based observational study of the Israel national VLBW infant database. The study population comprised singleton VLBW infants of 24-32 weeks' gestation born during the epochs 1995-2000 (n = 3728) and 2006-2010 (n = 3246). The Kitagawa methodology was applied to determine the contribution of changes in demographic and perinatal characteristics and changes in specific mortality rates on the decline in mortality between the periods. RESULTS: During the study epochs, VLBW infant mortality rates decreased from 19.7 to 13.8%. Of the 5.9% decrease in mortality, 60.6% was attributed to the decrease in specific mortality rates and 39.4% to changes in the proportions of population characteristics and therapies, predominantly early initiation of prenatal care (8.1%), antenatal steroids (25.1%), and cesarean delivery (8.1%). For most of the demographic and perinatal categories considered the relative contribution of changes in their proportions was <3%, whereas >97% could be attributed to changes in the specific mortality rates for these characteristics. CONCLUSIONS: The decrease in preterm VLBW infant mortality was attributable predominantly to changes in variable specific mortality rates whereas changes in the proportions of demographic, perinatal risk factors, and therapies had a limited impact on VLBW infant mortality. Future assessment of determinants of VLBW infant mortality data should be dissected by discriminatory models. PMID- 29415591 TI - Cardiac function and tadalafil used for treating fetal growth restriction in pregnant women without cardiovascular disease. AB - BACKGROUND: The aim of the present study was to evaluate tadalafil for the treatment of fetal growth restriction (FGR) and the cardiac function in pregnant women without cardiovascular disease who used tadalafil for this reason. MATERIALS AND METHODS: We examined nine pregnant women without cardiovascular disease who were using tadalafil to treat FGR. Maternal heart rate, systolic blood pressure (BP), and echocardiographic findings were assessed before and after tadalafil use. RESULTS: Diastolic BP was lower after compared to that before using tadalafil, but the difference was not significant. Echocardiographic findings were not significantly different before and after tadalafil use. CONCLUSIONS: Tadalafil did not adversely affect pregnant women without cardiovascular disease and was considered acceptable for use since it did not affect the mother's cardiac function. PMID- 29415592 TI - Effect of subcutaneous tissue closure technique in cesarean section on postoperative wound complications in obese Egyptian women. AB - : Subcutaneous tissue closure technique is a wide area of interest for obstetricians who perform cesarean section especially on obese women while many observers studied in an extensive manner postoperative pain and wound cosmetic results. AIM OF THE WORK: The main goal of our work was to display the differences in wound outcome results as regard postoperative wound complications comparing the two widely implemented techniques in subcutaneous tissue closure (interrupted versus continuous methods). RESULTS: A comparative analysis between continuous and interrupted techniques regarding wound complications (gapping, seroma, erythema, and infection) showing statistical significant differences in all four wound complications presented with p values = .019, .011, .015, and .001, in consecutive order with odds ratio in wound gapping = 5.239, wound seroma OR = 9.429, wound erythema OR = 3.709, and wound infection OR = 6.136. CONCLUSIONS: Subcutaneous wound closure using interrupted technique of suturing in obese patients is superior to continuous technique as regard wound complications. Clinical trials.gov ID Identifier (NCT 03354078). PMID- 29415593 TI - Maternal obesity, fish intake, and recurrent spontaneous preterm birth. AB - OBJECTIVE: Moderate fish intake in early pregnancy is associated with decreased risk of preterm birth (PTB). Obesity during pregnancy is characterized by inflammation and insufficiency of essential fatty acids. The objective of this study was to measure the association between fish intake during pregnancy and risk of recurrent spontaneous (s) PTB among lean, overweight, and obese women. DESIGN: This is secondary analysis of a randomized controlled trial of omega-3 fatty acid supplementation for recurrent PTB prevention, 2005-2006. The primary exposure was fish intake at time of enrollment (16-22.9-week gestation). The primary outcomes were sPTB <37 weeks and sPTB <35 weeks. Maternal prepregnancy body mass index was treated as an effect modifier. SUBJECTS: Eight hundred and fifty-two women were included, 47% were lean, 25% overweight, and 28% obese. RESULTS: In this cohort, among lean, but not overweight or obese women, >=1 serving of fish per week was associated with decreased frequency of sPTB <37 weeks compared with <1 serving of fish per week (45.1% versus 27.5%, p = .001) and spontaneous PTB <35 (21.4% versus 11.6%, p = .01). In adjusted models, as fish intake increased, the predicted probability of sPTB decreased in lean women but increased in overweight and obese women (p for interaction < .10). CONCLUSION: Fish intake was associated with lower probability of sPTB in lean women and higher probability in obese women. These findings warrant further investigation to understand the dietary or metabolic factors associated with obesity that may modulate benefit of fish intake during pregnancy. PMID- 29415594 TI - Maternal obesity is not associated with increased crown-rump length in first trimester ultrasounds of singleton gestations. AB - OBJECTIVE: To evaluate whether or not obesity affects fetal growth in the first trimester of pregnancy. STUDY DESIGN: A retrospective cohort study of obese versus non-obese women in our ultrasound database was performed to compare crown rump length (CRL), a surrogate of fetal growth, at the first-trimester genetic screening. RESULTS: A total of 50 obese and 50 non-obese women were included. CRL for both groups was performed at an average of 12wk5d +/- 3 d. A linear regression analysis demonstrated that there was no difference between the cohorts in respect to CRL in the first trimester (p = .482). However, the estimated fetal weight at second-trimester anatomy ultrasound and the neonatal birth weight were increased in obese women (p < .001 for both analyses). CONCLUSION: Maternal obesity does not significantly alter the fetal CRL. However, maternal obesity appears to be associated with increased fetal growth as early as the second trimester. PMID- 29415595 TI - Reasons for initiation of treatment and predictors of response for patients with Rai stage 0/1 chronic lymphocytic leukemia (CLL) receiving first-line therapy: an analysis of the Connect(r) CLL cohort study. AB - A 'watch-and-wait' strategy is recommended for most patients with early-stage chronic lymphocytic leukemia (CLL) prior to treatment initiation. In the Connect(r) CLL registry, a prospective observational cohort study of 1494 patients treated in 199 US centers, median time to first-line treatment initiation was 3.8, 1.5, and 0.6 years for patients with Rai stage 0, 1, and >=2, respectively. Only 60% of patients with Rai stage 0/1 underwent FISH/cytogenetic testing prior to initiation of a new line of therapy. Lymphocytosis and lymphadenopathy were the most common reasons for treatment initiation. Lymphocytosis as a reason for treatment initiation was associated with inferior event-free survival at Rai stage 0/1. Short treatment duration was associated with inferior overall survival regardless of Rai stage; sensitivity analyses confirmed the association. The Connect CLL registry provides valuable information on a real-world population of patients with CLL, clarifying both the timing and rationale for initiating therapy. PMID- 29415596 TI - The launch of opicapone for Parkinson's disease: negatives versus positives. AB - INTRODUCTION: Opicapone is a novel, third generation COMT inhibitor approved for the treatment of Parkinson's disease. Safety and tolerability data is critical to determine the benefit-harm balance and anticipate therapeutic adherence. Areas covered: This review evaluates the tolerability and safety profile of opicapone. These data were extracted from all published clinical trials, including preclinical, phase I, phase II and phase III studies as well as postmarketing data. Opicapone was safe and well tolerated, with frequencies of treatment emergent adverse events similar to placebo. Expert opinion: Opicapone have shown a good safety and tolerability profile. This adds to its proven efficacy and convenient once-daily administration, supporting a role of opicapone as a first line therapy for motor complications in Parkinson's disease patients. PMID- 29415597 TI - Prediction of postnatal arrhythmia in fetuses with cardiac rhabdomyoma. AB - OBJECTIVES: Fetal cardiac rhabdomyomas are rare but well-known to be associated with arrhythmia or conduction abnormalities. However, since in utero electrophysiological information is quite limited, it remains unclear which type of rhabdomyoma will develop arrhythmia after birth. The aim of this study is to identify factors that predict postnatal arrhythmia requiring therapy in fetuses with cardiac rhabdomyoma. STUDY DESIGN: A retrospective review of infants prenatally diagnosed with cardiac rhabdomyoma was performed at our tertiary pediatric cardiac center between 1990 and 2016. Fetal arrhythmia was diagnosed using fetal echocardiography and magnetocardiography. We compared the characteristics of cases with and without antiarrhythmic therapy after birth. Cases without antiarrhythmic therapy after birth consisted of those who had postnatal arrhythmia but did not require antiarrhythmic therapy and those who had no postnatal arrhythmia. RESULTS: A total of 20 fetuses with cardiac rhabdomyoma were included in this study. Ten cases (50%) were confirmed as having tuberous sclerosis after birth. The mean gestational week at diagnosis and delivery were 32.1 +/- 2.7 and 37.6 +/- 2.8 weeks, respectively. Mean cardiac tumor size in utero was 21 +/- 11 mm (range, 7-54 mm) in diameter. Fetal arrhythmia was found in six cases; three resolved in utero with transplacental antiarrhythmic therapy. Postnatal arrhythmia or conduction abnormalities were found in 12 cases; 7 required antiarrhythmic therapy. Cases with antiarrhythmic therapy after birth had larger cardiac tumor in utero than those without therapy (29.6 +/- 12.8 mm versus 16.3 +/- 5.8 mm, p < .01). Cardiac tumor size >30 mm in diameter predicted postnatal arrhythmia requiring therapy with sensitivity of 57.1% and specificity of 100%. Location and number of cardiac tumor and presence of arrhythmia or conduction abnormalities in utero were similar between the two groups. CONCLUSIONS: Cardiac rhabdomyomas >30 mm in diameter are associated with postnatal arrhythmia requiring therapy regardless of number and location. PMID- 29415598 TI - Mantle Cell Lymphoma with t(11;22) (q13;q11.2) an indolent clinical variant? PMID- 29415599 TI - Connected, attracted, and concerned: A Q study on medical crossborder curriculum partnerships. AB - INTRODUCTION: A new form of internationalization has been trending upward in the medical education realm: crossborder medical curriculum partnerships established to deliver the same, or adapted, curriculum to groups of geographically separated students. This study aims to investigate crossborder medical curriculum partnerships by exploring the experiences of teachers at the recipient institution who have a key role in delivering the program. METHODS: From four pioneering recipient medical schools, 24 teachers participated in a Q-sort study. Each participant rank-ordered 42 statements about teaching in a crossborder medical curriculum on a scale from -5 (indicating strong disagreement) to +5 (indicating strong agreement). The authors conducted a "by-person" factor analysis to uncover distinct patterns in the ranking of statements, using the statistical results and participants' comments about their Q sorts to interpret these patterns and translate them into distinct viewpoints. RESULTS: Three viewpoints emerged, reflecting: (1) a feeling of connectedness with the partner institution, trust in the quality of the curriculum, and appreciation of interinstitutional relationships; (2) the partnership's attractiveness because of the career opportunities it offers; and (3) concerns over the quality of graduates because of doubts about the appropriateness of the didactic model and insufficient attention to local healthcare needs, and over the practical feasibility of such partnerships. CONCLUSIONS: The three viewpoints identified revealed a pallet of views on how host teachers might experience their work. It shows the heterogeneous features of this group and seems to counterbalance reports that they are feeling "deprived" from their role as teacher. Two viewpoints featured an appreciation of interinstitutional relationships and of the partnership, especially when perceiving a degree of autonomy. Partners can capitalize on all different viewpoints by deploying procedure and policies to raise the quality of education delivery. PMID- 29415600 TI - Quantifying the effects of postcesarean adhesions on incision to delivery time. AB - OBJECTIVE: To quantify the effects of postcesarean section adhesions severity on the incision to delivery time. METHODS: Secondary analysis of data of a prospective randomized controlled trial of women undergoing first repeat cesarean section. The presence and severity of adhesions were reported by surgeons postoperatively and accrued into an adhesion severity score. The primary outcome measure was the correlation between adhesion severity score and incision to delivery time. RESULTS: Of the 97 women analyzed, 47 (48.5%) had an urgent cesarean delivery. Forty-four patients (45.4%) had adhesions. Adhesion score correlated with incision to delivery time (R = .38, p < .01). Patients with adhesions had a significantly longer incision to delivery time (10.3 + 5.9 versus 8.2 = 3.7 minutes, respectively; p = .04). In the Kaplan-Meier analysis, more patients with adhesions remained undelivered at any time point after incision (p = .036). The mean delivery time of patients with adhesion score three was significantly longer in comparison with women with no adhesions (13.0 versus 8.2 minutes, respectively; p = .002). CONCLUSIONS: Post cesarean adhesions delay delivery of the newborn. There is a linear correlation between adhesion severity and the incision to delivery interval. PMID- 29415601 TI - Sleep, Internalizing Problems, and Social Withdrawal: Unique Associations in Clinic-Referred Youth With Elevated Sluggish Cognitive Tempo Symptoms. AB - OBJECTIVE: We compared clinic-referred youth with ADHD + sluggish cognitive tempo (SCT; n = 34), ADHD Only ( n = 108), and SCT Only ( n = 22) on demographics, co occurring symptomatology, comorbid diagnoses, and social functioning. METHOD: In total, 164 youth (age = 6-17 years, M = 9.97) and their parent(s) presented to an outpatient clinic for a psychoeducational assessment. Between-group analyses and regressions were used to examine study variables. RESULTS: SCT groups were older and exhibited more parent-reported internalizing problems, externalizing problems, sleep problems, and social withdrawal on the Child Behavior Checklist. No significant differences emerged between groups on the Teacher Report Form. Regression analyses involving multiple covariates revealed that SCT symptoms were uniquely related to social withdrawal but not general social problems. CONCLUSION: Based on parent report, SCT symptoms have a unique relationship with internalizing problems, sleep problems, and social withdrawal. Future research should explore correlates of SCT in youth using multiple informants. PMID- 29415602 TI - Common Items on a Bucket List. AB - BACKGROUND: To provide preference-sensitive care, we propose that clinicians might routinely inquire about their patients' bucket-lists and discuss the impact (if any) of their medical treatments on their life goals. METHODS: This cross sectional, mixed methods online study explores the concept of the bucket list and seeks to identify common bucket list themes. Data were collected in 2015-2016 through an online survey, which was completed by a total of 3056 participants across the United States. Forty participants who had a bucket list were identified randomly and used as the development cohort: their responses were analyzed qualitatively using grounded theory methods to identify the six key bucket list themes. The responses of the remaining 3016 participants were used for the validation study. The codes identified from the development cohort were validated by analyses of responses from 50 randomly drawn subjects from the validation cohort. All the 3016 validation cohort transcripts were coded for presence or absence of each of the six bucket list themes. RESULTS: Around 91.2% participants had a bucket list. Age and spirituality influence the patient's bucket-list. Participants who reported that faith/religion/spirituality was important to them were most likely (95%) to have a bucket list compared with those who reported it to be unimportant (68.2%), chi2 = 37.67. Six primary themes identified were the desire to travel (78.5%), desire to accomplish a personal goal (78.3%), desire to achieve specific life milestones (51%), desire to spend quality time with friends and family (16.7%), desire to achieve financial stability (24.3%), and desire to do a daring activity (15%). CONCLUSIONS: The bucket list is a simple framework that can be used to engage patients about their healthcare decision making. Knowing a patient's bucket list can aid clinicians in relating each treatment option to its potential impact (if any) on the patient's life and life goals to promote informed decision making. PMID- 29415603 TI - A real-world study of clofarabine and cytarabine combination therapy for patients with acute myeloid leukemia. AB - Clofarabine and cytarabine (Clo + Ara-C) combinations have efficacy in treatment of acute myeloid leukemia (AML). We retrospectively analyzed clinical outcomes of 71 AML patients receiving Clo + Ara-C regimens at the University of Minnesota from 2011 to 2016: 44 patients (62%) had newly diagnosed AML and 27 patients (38%) had relapsed/refractory AML. The median age of patients was 69 years (interquartile range [IQR], 63-75 years). Nearly 60% of the patients had secondary AML, and about half of patients had adverse risk cytogenetics. Objective response rate (ORR) was 42% in all patients with complete remission (CR) rate of 20%. Progression-free survival (PFS) at 2 years was 16% (95% CI 8 27%) and overall survival (OS) at 2 years was 21% (95% CI 11-33%) for all patients. The 30-day mortality rate was 18%. Clo + Ara-C- containing regimens are an acceptable upfront therapy option for patients who are not candidates for "7 + 3" induction, but do not induce durable remissions. PMID- 29415604 TI - Long-term programing of psychopathology-like behaviors in male rats by peripubertal stress depends on individual's glucocorticoid responsiveness to stress. AB - Experience of adversity early in life and dysregulation of hypothalamus-pituitary adrenocortical (HPA) axis activity are risk factors often independently associated with the development of psychopathological disorders, including depression, PTSD and pathological aggression. Additional evidence suggests that in combination these factors may interact to shape the development and expression of psychopathology differentially, though little is known about underlying mechanisms. Here, we studied the long-term consequences of early life stress exposure on individuals with differential constitutive glucocorticoid responsiveness to repeated stressor exposure, assessing both socio-affective behaviors and brain activity in regions sensitive to pathological alterations following stress. Two rat lines, genetically selected for either low or high glucocorticoid responsiveness to repeated stress were exposed to a series of unpredictable, fear-inducing stressors on intermittent days during the peripuberty period. Results obtained at adulthood indicated that having high glucocorticoid responses to repeated stress and having experience of peripuberty stress independently enhanced levels of psychopathology-like behaviors, as well as increasing basal activity in several prefrontal and limbic brain regions in a manner associated with enhanced behavioral inhibition. Interestingly, peripuberty stress had a differential impact on aggression in the two rat lines, enhancing aggression in the low-responsive line but not in the already high-aggressive, high-responsive rats. Taken together, these findings indicate that aberrant HPA axis activity around puberty, a key period in the development of social repertoire in both rats and humans, may alter behavior such that it becomes anti social in nature. PMID- 29415605 TI - A Semi-natural Approach for Studying Seasonal Diapause in Drosophila melanogaster Reveals Robust Photoperiodicity. AB - The fruit fly Drosophila melanogaster survives thermally stressful conditions in a state of reproductive dormancy (diapause), manifested by reduced metabolic activity and arrested ovarian development in females. Unlike insects that rely primarily on photoperiodic stimuli to initiate the diapause program, in this species dormancy is regulated by low temperature and enhanced by shorter photoperiods. Overwintering phenotypes are usually studied under simple laboratory conditions, where animals are exposed to rectangular light-dark (LD) cycles at a constant temperature. We sought to adopt more realistic diapause protocols by generating LD profiles that better mimic outdoor conditions. Experimental flies were subjected to semi-natural late autumn and summer days, while control females received the same amounts of light but in rectangular LD cycles (LD 8:16 and LD 15:9, respectively). We observed that semi-natural autumnal days induced a higher proportion of females to enter dormancy, while females in semi-natural summer days showed reduced diapause compared with their corresponding rectangular controls, generating an impressive photoperiodic response. In contrast, under rectangular light regimes, the diapause of Drosophila field lines exhibited minimal photoperiodicity. Our semi-natural method reveals that D. melanogaster diapause is considerably more photoperiodic than previously believed and suggests that this seasonal response is best studied under simulated natural lighting conditions. PMID- 29415606 TI - Cutaneous irritancy of an ibuprofen medicated plaster in healthy volunteers. AB - OBJECTIVES: To assess the irritation and contact sensitization potential of a 200 mg ibuprofen medicated plaster. METHODS: This double-blind, phase-1 placebo controlled study had two phases; the induction phase to evaluate the irritant potential of continuous application of the plaster, and the challenge phase to assess contact sensitivity (allergy). The cumulative irritancy potential was evaluated using an adaptation of the Shelanski method. Healthy adults (>=18 years of age) (N = 210) were treated simultaneously with one ibuprofen medicated and one placebo plaster applied in a randomized fashion to either the left or right side of the lower back. During the induction phase, plasters were applied on Days 1, 3, 5, 8, 10, 12, 15, 17, and 19 and the final plaster removed on Day 22. At each scheduled visit plasters and applications sites were assessed for degree of adhesion and skin irritation (score of 1 = no irritation to 7 = strong reaction spreading beyond test sites), respectively. The challenge phase followed a two week washout period. A plaster was applied on Day 36 for 48 h and assessment occurred on Days 38, 39, and 40. RESULTS: The mean cumulative irritation score during the induction phase was lower for the ibuprofen medicated plaster than the placebo plaster (0.32 vs. 1.23, respectively). Three (1.4%) subjects experience a dermal reaction of grade >=3 for the ibuprofen medicated plaster compared with 27 (12.7%) for the placebo plaster. Following challenge with ibuprofen or placebo plasters, 12 subjects (6.2%) with the ibuprofen medicated plaster and four (2.2%) with the placebo plaster had skin reaction of assessment grade higher than the induction phase. One subject for the ibuprofen and two for the placebo plaster had reactions with grade >2. No subjects showed an increase in sensitization on Day 39 or 40 compared with Day 38. CONCLUSIONS: The findings indicate that the both the irritancy and contact sensitization of the ibuprofen medicated plaster is acceptable. PMID- 29415607 TI - Approximal sealings on lesions in neighbouring teeth requiring operative treatment: an in vitro study. AB - OBJECTIVES: With this in vitro study we aimed to assess the possibility of precise application of sealant on accessible artificial white spot lesions (WSL) on approximal surfaces next to a tooth surface under operative treatment. A secondary aim was to evaluate whether the use of magnifying glasses improved the application precision. MATERIAL AND METHODS: Fifty-six extracted premolars were selected, approximal WSL lesions were created with 15% HCl gel and standardized photographs were taken. The premolars were mounted in plaster-models in contact with a neighbouring molar with Class II/I-II restoration (Sample 1) or approximal, cavitated dentin lesion (Sample 2). The restorations or the lesion were removed, and Clinpro Sealant was placed over the WSL. Magnifying glasses were used when sealing half the study material. The sealed premolar was removed from the plaster-model and photographed. Adobe Photoshop was used to measure the size of WSL and sealed area. The degree of match between the areas was determined in Photoshop. RESULTS: Interclass agreement for WSL, sealed, and matched areas were found as excellent (kappa = 0.98-0.99). The sealant covered 48-100% of the WSL-area (median = 93%) in Sample 1 and 68-100% of the WSL-area (median = 95%) in Sample 2. No statistical differences were observed concerning uncovered proportions of the WSL-area between groups with and without using magnifying glasses (p values >= .19). However, overextended sealed areas were more pronounced when magnification was used (p = .01). The precision did not differ between the samples (p = .31). CONCLUSIONS: It was possible to seal accessible approximal lesions with high precision. Use of magnifying glasses did not improve the precision. PMID- 29415608 TI - Functional Status Examination in Patients with Moderate-to-Severe Traumatic Brain Injuries. AB - The assessment of functional status after traumatic brain injury (TBI) is important. The Glasgow Outcome Scale (GOS) and its revised version, the Glasgow Outcome Scale Extended (GOSE), have been used most frequently in TBI research, but there are concerns about the sensitivity of these measures. The current study evaluated the psychometric properties of the Functional Status Examination (FSE) using a sample of 448 moderately to severely injured subjects with TBI. It was shown that the FSE is significantly related to other measures of functional status including the GOSE, Short Form Health Survey, and European Quality of Life Checklist (p < 0.001), is sensitive to TBI severity (p < 0.001), and is responsive to recovery from 3 to 6 months post-injury (p < 0.001). In addition, there was a significant agreement (r = 0.817, p < 0.001) between the patient and significant other's assessment of functional status on the FSE at 6 months post injury. The FSE may be a valuable measure of functional status after TBI given its strong psychometric properties, including validity, sensitivity to brain injury severity, and recovery over time. PMID- 29415609 TI - Built environment analysis for road traffic hotspot locations in Moshi, Tanzania. AB - Road traffic injuries (RTIs) cause significant morbidity and mortality in low- and middle-income countries. Investigation of high risk areas for RTIs is needed to guide improvements. This study provides built environmental analysis of road traffic crash hotspots within Moshi, Tanzania. Spatial analysis of police data identified 36 hotspots. Qualitative comparative analysis revealed 40% of crash sites were on local roads without night lighting and increased motorcycle density. Paved narrow roads represented 26% of hotspots and 13% were unpaved roads with uneven roadsides. Roadside unevenness was more predominate in low risk [n = 19, (90.5%)] than high risk sites [n = 7 (46.7%)]. Both low [n = 6 (28.6%)] and high risk [n = 1 (6.7%)] sites had minimal signage. All sites had informal pedestrian pathways. Little variability between risk sites suggests hazardous conditions are widespread. Findings suggest improvement in municipal infrastructure, signage and enforcement is needed to reduce RTI burden. PMID- 29415611 TI - Safety features of freeway weaving segments with a buffer-separated high occupancy-vehicle (HOV) lane. AB - This paper investigates the crash-rate distribution of the freeway weaving segments with a buffer-separated high-occupancy-vehicle lane. For this purpose, crash, traffic and geometry data were extracted from various sources. These extracted data were either spatially or spatiotemporally matched with one another, and used for both descriptive and model-based analyses. The descriptive analysis revealed that crash-rate distributions of the weaving segments depend not only on the class of the subject highway but also on the presence of an access point. This finding was statistically confirmed by crash frequency models. Notably, both descriptive and model-based analyses showed that weaving segments with an access point tend to show lower crash-rates than the counterparts without one. One might attribute this counterintuitive phenomenon to a certain underlying tendency by which traffic engineers or planners generally follow in selecting locations of an access point along the freeway. Further research is required to resolve such a conjecture. PMID- 29415610 TI - Orbital apex disorders: Imaging findings and management. AB - Orbital apex disorders include orbital apex syndrome, superior orbital fissure syndrome and cavernous sinus syndrome. These disorders result from various etiologies, including trauma, neoplastic, developmental, infectious, inflammatory as well as vascular causes. In the past, these have been described separately based on anatomical locations of disease process; however, these three disorders share similar causes, diagnostic evaluation and management strategies. The etiology is diverse and management is directed to the causative process. This imaging review summarizes the pertinent anatomy of the orbital apex and illustrates representative pathological processes that may affect this region. The purpose of this review is to provide an update on the current status of diagnostic imaging and management of patients with orbital apex disorders. PMID- 29415612 TI - Valproic Acid Treatment Decreases Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels in Swine Subjected to Traumatic Brain Injury. AB - The primary aim of this study was to examine the effects of valproic acid (VPA) treatment on serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NF-L) levels. To achieve this aim, we obtained serum samples from: 1) 10 Yorkshire swine subjected to controlled cortical impact traumatic brain injury (CCI TBI) + polytrauma and randomized to receive either normal saline (NS) + VPA (n = 5) or NS alone (n = 5) and 2) five additional swine subjected to CCI TBI without polytrauma and treated with VPA. GFAP and NF-L levels were measured in samples obtained from baseline until 10 days post-injury using a digital immunoassay from Quanterix Corporation. We found that elevated GFAP and NF-L levels were first detected at 2 h post-injury; and peaked at 24 h and 72 h respectively. GFAP levels returned to baseline levels by Day 10, while NF-L remained elevated at Day 10. In TBI + polytrauma swine, the magnitude and duration of biomarker elevation, quantified by the area under the biomarker concentration-versus-time curve during the first 10 days (AUC0-10days), was higher in the NS group, compared with the VPA group. For GFAP, the AUC0-10days was 45,535 (IQR: 35,741-105,711) and 22,837 (IQR: 8,082-46,627) for the NS and NS+VPA groups, respectively. For NF-L, the AUC0-10days was 43,073 (IQR: 18,739 120,794) and 4,475 (2,868-11,157) for the NS and NS+VPA groups, respectively. Twenty-four hour GFAP and NF-L levels had the strongest correlation with lesion size and time to normalization of behavior. Accordingly, we conclude that treatment with VPA results in significantly lower serum GFAP and NF-L levels. The time-point at which GFAP and NF-L levels have the strongest correlation with outcome is 24 h post-injury. PMID- 29415613 TI - Individual differences in episodic memory abilities predict successful prospective memory output monitoring. AB - Output monitoring refers to memory for one's previously completed actions. In the context of prospective memory (PM) (e.g., remembering to take medication), failures of output monitoring can result in repetitions and omissions of planned actions (e.g., over- or under-medication). To be successful in output monitoring paradigms, participants must flexibly control attention to detect PM cues as well as engage controlled retrieval of previous actions whenever a particular cue is encountered. The current study examined individual differences in output monitoring abilities in a group of younger adults differing in attention control (AC) and episodic memory (EM) abilities. The results showed that AC ability uniquely predicted successful cue detection on the first presentation, whereas EM ability uniquely predicted successful output monitoring on the second presentation. The current study highlights the importance of examining external correlates of PM abilities and contributes to the growing body of research on individual differences in PM. PMID- 29415614 TI - Prevalence and attitude of university students towards mobile phone use while driving in Jeddah, Saudi Arabia. AB - This study aimed to investigate the prevalence and attitude of university students towards mobile phone use while driving. The present study was conducted at King Abdulaziz University, Jeddah, Saudi Arabia. Five hundred and ninety-three participants were recruited for this study. Attitude, consequences and their involvement in various reckless behaviours pertaining to the use of mobile phone while driving were checked by a questionnaire. Overall, the majority of the respondents (90%) use a mobile phone while driving. About half of the participants had experienced consequences regarding texting while driving and had engaged in reckless behaviour. The majority of the students of Faculty of Medicine, Engineering Sciences, Earth Sciences, Administration and Economics and Orientation Classes were more frequently texting while driving (p < .001). The unmarried students were more often texting while driving as compared to married (p < .001). Overall, the majority of the respondents use the mobile phone while driving. PMID- 29415615 TI - Perceptions of the risk of drowning at surf beaches among New Zealand youth. AB - In many countries, beaches are a high-risk location for drowning. In New Zealand, youth and young adults are particularly at risk of drowning at beaches, accounting for 17.4% of drowning deaths and 18.4% of rescues at surf beaches between 2008 and 2013, over 90% of fatalities were male. This study explored New Zealand youth risk perceptions of drowning and their coping appraisal processes at a surf beach. A cross-sectional survey of high school students (n = 599) was conducted between February and April 2014. Females and non-New Zealand European students reported higher levels of perceived vulnerability and severity of drowning risk, and New Zealand European students reported higher levels of self efficacy of preventive actions. By addressing the underlying causes of underestimation of risk and overestimation of ability, these findings can be utilized to increase awareness and to enhance water safety risk strategies for youth, especially males, in the surf beach setting. PMID- 29415616 TI - Platelet-rich plasma for the spinal fusion. AB - There has been a wide interest in using platelet-rich plasma (PRP) as a therapeutic agent to enhance spinal fusion. There are two review articles based only on clinical studies regarding the effect of PRP on spinal fusion. However, with regard to both animal model studies and clinical studies, there is no review studies regarding its effect on spinal fusion and no review studies focusing on the platelet count and the concentration of the growth factor in the PRP. The purpose is to review the literatures about the effect of PRP on spinal fusion according to the animal model studies and clinical studies, focusing on the effect of the platelet count and the concentration of the growth factor in the PRP. A PubMed search was performed for English-language articles. We identified 20 articles regarding the effect of PRP on fusion in animal model studies and clinical studies, of which 16 articles met the study criteria of case-control studies or prospective randomized studies for the spinal fusion. The articles were categorized into small-sized animal model, middle-sized animal model, and clinical studies. Studies have shown both beneficial and inhibitory effects. The conclusion that PRP has the stimulating effect on spinal fusion was not reached. However, PRP might promote the human spinal fusion if the platelet count or the concentration of growth factors in the PRP increases. PMID- 29415618 TI - Corrigendum. PMID- 29415617 TI - Sagittal band reconstruction in the index finger using a modified Elson technique. AB - PURPOSE: The Elson technique is a rigid reconstruction method for a hypoplastic or absent sagittal band in the treatment of chronic extensor digitorum communis (EDC) tendon dislocation. We performed a modified procedure based on the Elson technique for reconstruction of the radial sagittal band in case involving the index finger. We investigated the postoperative outcomes of chronic EDC dislocation after treatment with the original and modified Elson technique. METHODS: We examined five fingers of five patients (2 males and 3 females) with a mean age of 41 years. The chronic EDC tendon dislocation was due to an old trauma, or a spontaneous or congenital condition involving the index in two, middle in two, and ring finger in one patient. Sagittal band reconstruction was performed using the modified Elson technique for the index finger and the original technique for the other fingers. The mean duration of postoperative follow-up was 58 months. Clinical findings such as pain and discomfort at metacarpophalangeal flexion associated with the tendon dislocation, range of motion (ROM), and disabilities of the arm, shoulder and hand were evaluated. We also examined postoperative recurrence and subjective patient evaluation. RESULTS: All cases achieved pain-free stability of the EDC tendon with no recurrence, and full ROM was maintained at the latest examination after surgery. The postoperative subjective evaluation by the patients was "very satisfied" in four fingers and "neutral" in one finger. CONCLUSION: We demonstrated our modified Elson technique for the treatment of chronic extensor tendon dislocation of the index finger. PMID- 29415619 TI - Is Parkinson's Disease a Neurodevelopmental Disorder and Will Brain Organoids Help Us to Understand It? AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. The incidence of PD cases increases with age, accordingly classically PD is considered to be an age-associated neurodegenerative disease. In this review, the hypothesis that PD is actually a neurodevelopmental disorder that is compensated for a long time will be discussed. However, patients who suffer from PD typically do not show symptoms early in their lives. This implies that, if the hypothesis that PD has a significant neurodevelopmental component is correct, the developmental defects are compensated for a long time. Furthermore, these developmental defects might not causally lead to the disease but increase the susceptibility for disease onset after a "second hit." In this logic, deregulated developmental processes might represent the "first hit." Even a minor developmental defect could lead to a reduced compensatory capacity or reduced fault tolerance of the entire system. In such a case of an already imbalanced system one or more additional hits could perturb the entire system sufficiently to bring it out of balance and lead to the pathology and symptoms which we classify as PD. However, if the developmental hypothesis and the "multiple hit" hypothesis are correct, an early diagnosis of these developmental defects might allow the start of a therapy for at-risk individuals before disease pathology becomes severe and before symptoms occur. Modern stem cell technologies, including the generation of personalized brain organoids, might play an important role in these strategies. PMID- 29415623 TI - Gun violence: Care ethicists making the invisible visible. PMID- 29415620 TI - Neuropilin-1 Mediated Arterial Differentiation of Murine Pluripotent Stem Cells. AB - Pluripotent stem cell-derived endothelial cells (ECs) have great potential to be used in vascular therapy or tissue engineering. It is also much desired to obtain arterial or venous ECs for specific applications. Factors that are critical for the proper arterial or venous differentiation from pluripotent stem cells still need to be understood. Here, we aim at investigating this problem deeper by examining neuropilin-1 (Nrp1), an early arterial marker that may be critical for arterial cell fate commitment. Using murine embryonic stem cells as the model system, this study investigates the neuropilin-1 (Nrp1) expression during the differentiation of pluripotent stem cells toward a vascular progenitor population. We hypothesize that Nrp1, an early arterial marker present in a developing embryo, may be more responsive when further induced in vitro toward an arterial fate. We developed a two-step differentiation approach that yielded a large percentage of Nrp1+ vascular progenitor cells (VPCs) and investigated their potential to become arterial ECs. We have defined the culture parameters that contribute greatly to the emergence of Nrp1+ VPCs: certain soluble factors, especially Wnt and BMP4, early cell-cell contact, and hypoxia. Subsequent isolation of this population demonstrated a highly proliferative and network forming behavior. The Nrp1+ VPCs exhibited increased gene expression of several Notch pathway-related arterial markers compared with Nrp1- VPCs. Most importantly, Nrp1+ VPCs demonstrated a dramatically greater response to hemodynamic stimuli by upregulating many arterial markers whereas Nrp1- VPCs have very little response. Surprisingly, these differences between Nrp1+ and Nrp1- VPCs are not evident with vascular endothelial growth factor (VEGF) treatment. Our data suggest that Nrp1+ VPCs may serve as the arterial progenitor by enhanced response to hemodynamic flow but not to VEGF, whereas Nrp1- VPCs lack the plasticity to become arterial ECs. The findings of this research indicate that Nrp1+ VPCs in the murine model act as an important step in the arterial differentiation process. PMID- 29415624 TI - Assessing covariate balance when using the generalized propensity score with quantitative or continuous exposures. AB - Propensity score methods are increasingly being used to estimate the effects of treatments and exposures when using observational data. The propensity score was initially developed for use with binary exposures (e.g., active treatment vs. control). The generalized propensity score is an extension of the propensity score for use with quantitative exposures (e.g., dose or quantity of medication, income, years of education). A crucial component of any propensity score analysis is that of balance assessment. This entails assessing the degree to which conditioning on the propensity score (via matching, weighting, or stratification) has balanced measured baseline covariates between exposure groups. Methods for balance assessment have been well described and are frequently implemented when using the propensity score with binary exposures. However, there is a paucity of information on how to assess baseline covariate balance when using the generalized propensity score. We describe how methods based on the standardized difference can be adapted for use with quantitative exposures when using the generalized propensity score. We also describe a method based on assessing the correlation between the quantitative exposure and each covariate in the sample when weighted using generalized propensity score -based weights. We conducted a series of Monte Carlo simulations to evaluate the performance of these methods. We also compared two different methods of estimating the generalized propensity score: ordinary least squared regression and the covariate balancing propensity score method. We illustrate the application of these methods using data on patients hospitalized with a heart attack with the quantitative exposure being creatinine level. PMID- 29415625 TI - A predominant cardiac phenotype of Anderson-Fabry disease in presence of a MYBPC3 gene mutation and a LAMA4 gene mutation. PMID- 29415626 TI - Exosomes Derived from Hypoxia-Treated Human Adipose Mesenchymal Stem Cells Enhance Angiogenesis Through the PKA Signaling Pathway. AB - Angiogenesis is a complicated and sequential process that plays an important role in different physiological processes. Mesenchymal stem cells (MSCs), which are pluripotent stem cells, are widely used for the treatment of ischemic and traumatic diseases, and exosomes derived from these cells can also promote angiogenesis. Therefore, we aimed to uncover mechanisms to improve MSC exosome mediated angiogenesis. For this study, we isolated human adipose-derived MSCs (hAD-MSCs) and assessed differentiation ability and markers. Cells were divided into hypoxia-treated MSCs (H-MSCs) and normoxia-treated MSCs (N-MSC), and exosomes were extracted by ultrafiltration. Exosomes (100 MUg/mL) from H-MSCs and N-MSCs were added to human umbilical vein endothelial cells (HUVECs). Exosome uptake and the ability of endothelial cells to form tubes were detected in real time. Protein samples were collected at different time points to detect the expression of inhibitors (Vash1) and enhancers (Angpt1 and Flk1) of angiogenesis; we also assessed their related signaling pathways. We found that exosomes from the hypoxia group were more easily taken up by HUVECs; furthermore, their angiogenesis stimulatory activity was also significantly enhanced compared to that with exosomes from the normoxia group. HUVECs exposed to exosomes from H MSCs significantly upregulated angiogenesis-stimulating genes and deregulated angiogenesis-inhibitory genes. The expression of vascular endothelial growth factor (VEGF) and activation of the protein kinase A (PKA) signaling pathway in HUVECs were significantly increased by hypoxia-exposed exosomes. Moreover, a PKA inhibitor was shown to significantly suppress angiogenesis. Finally, we concluded that hypoxia-exposed exosomes derived from hAD-MSCs can improve angiogenesis by activating the PKA signaling pathway and promoting the expression of VEGF. These results could be used to uncover safe and effective treatments for traumatic diseases. PMID- 29415627 TI - In-silico screening and validation of high-affinity tetra-peptide inhibitor of Leishmania donovani O-acetyl serine sulfhydrylase (OASS). AB - OASS is a specific enzyme that helps Leishmania parasite to survive the oxidative stress condition in human macrophages. SAT C-terminal peptides in several organisms, including Leishmania, were reported to inhibit or reduce the activity of OASS. Small peptide and small molecules mimicking the SAT C-terminal residues are designed and tested for the inhibition of OASS in different organisms. Hence, in this study, all the possible tetra-peptide combinations were designed and screened based on the docking ability with Leishmania donovani OASS (Ld-OASS). The top ranked peptides were further validated for the stability using 50 ns molecular dynamic simulation. In order to identify the better binding capability of the peptides, the top peptides complexed with Ld-OASS were also subjected to molecular dynamic simulation. The docking and simulation results favored the peptide EWSI to possess greater advantage than previously reported peptide (DWSI) in binding with Ld-OASS active site. Also, screening of non-peptide inhibitor of Asinex Biodesign library based on the shape similarity of EWSI and DWSI was performed. The top similar molecules of each peptides were docked on to Ld-OASS active site and subsequently simulated for 20 ns. The results suggested that the ligand that shares high shape similarity with EWSI possess better binding capability than the ligand that shares high shape similarity with DWSI. This study revealed that the tetra-peptide EWSI had marginal advantage over DWSI in binding with Ld-OASS, thereby providing basis for defining a pharmacophoric scaffold for the design of peptidomimetic inhibitors as well as non-peptide inhibitors of Ld-OASS. PMID- 29415628 TI - Methods for determining the methane generation potential and methane generation rate constant for the FOD model: a review. AB - In the first order decay (FOD) model of landfill methane generation, the methane generation potential ( L0) and methane generation rate constant ( k) for both bulk municipal solid waste (MSW) and individual waste components have been determined by a variety of approaches throughout various literature. Differences in the determination methods for L0 and k are related to differences in our understanding of the waste decomposition dynamics. A thorough understanding of the various available methods for determining L0 and k values is critical for comparative study and the drawing of valid conclusions. The aim of this paper is to review the literature on the available determining methods and the ranges for L0 and k values of both bulk MSW and individual waste components, while focusing on understanding the decomposition of waste, including the role of lignin. L0 estimates in the literature are highly variable and have been derived from theoretical stoichiometric calculations, laboratory experiments, or actual field measurements. The lignin concentration in waste is correlated with the fraction of total degradable organic carbon (DOCf) that will actually anaerobically degrade in the landfill. The k value has been determined by precipitation rates, laboratory simulations, aged-defined waste sample, and model fitting or regression analysis using actual gas data. However, the lignin concentration does not correlate well with the k value, presumably due to the impact of lignin arrangement and structure on cellulose bioavailability and degradation rate. In sum, this review summarizes the literature on the measurement of L0 and k values, including the dynamics and decomposition of bulk MSW and individual waste components within landfills. PMID- 29415629 TI - Mild Maternal Hypothyroxinemia During Pregnancy Induces Persistent DNA Hypermethylation in the Hippocampal Brain-Derived Neurotrophic Factor Gene in Mouse Offspring. AB - BACKGROUND: Thyroid hormones are essential for normal development of the central nervous system (CNS). Experimental rodents have shown that even a subtle thyroid hormone insufficiency in circulating maternal thyroid hormones during pregnancy may adversely affect neurodevelopment in offspring, resulting in irreversible cognitive deficits. This may be due to the persistent reduced expression of the hippocampal brain-derived neurotrophic factor gene Bdnf, which plays a crucial role in CNS development. However, the underlying molecular mechanisms remain unclear. METHODS: Thiamazole (MMI; 0.025% [w/v]) was administered to dams from two weeks prior to conception until delivery, which succeeded in inducing mild maternal hypothyroxinemia during pregnancy. Serum thyroid hormone and thyrotropin levels of the offspring derived from dams with mild maternal hypothyroxinemia (M offspring) and the control offspring (C offspring) were measured. At 70 days after birth, several behavior tests were performed on the offspring. Gene expression and DNA methylation status were also evaluated in the promoter region of Bdnf exon IV, which is largely responsible for neural activity-dependent Bdnf gene expression, in the hippocampus of the offspring at day 28 and day 70. RESULTS: No significant differences in serum thyroid hormone or thyrotropin levels were found between M and C offspring at day 28 and day 70. M offspring showed an impaired learning capacity in the behavior tests. Hippocampal steady state Bdnf exon IV expression was significantly weaker in M offspring than it was in C offspring at day 28. At day 70, hippocampal Bdnf exon IV expression at the basal level was comparable between M and C offspring. However, it was significantly weaker in M offspring than in C offspring after the behavior tests. Persistent DNA hypermethylation was also found in the promoter region of Bdnf exon IV in the hippocampus of M offspring compared to that of C offspring, which may cause the attenuation of Bdnf exon IV expression in M offspring. CONCLUSIONS: Mild maternal hypothyroxinemia induces persistent DNA hypermethylation in Bdnf exon IV in offspring as epigenetic memory, which may result in long-term cognitive disorders. PMID- 29415630 TI - Impact on Therapists Working With Sex Offenders: A Systematic Review of Gender Findings. AB - Although there is a great deal of literature about the distress of therapists who work with sex offenders, little is known about possible gender differences in their distress. The article presents a systematic review and small-scale meta analysis that address two questions: whether one gender is more susceptible than the other to the adverse effects of treating sex offenders and whether their distress is manifested similarly or differently. Findings of 36 measures of association reported in 10 eligible studies with a total of 1,754 sex offender therapists (785 males) indicate that males are somewhat more vulnerable to the adverse effects of treating sex offenders ( d = .204, p = .002). Moderator analysis indicates that male therapists show similar levels of burnout and disruption of sexual life as their female counterparts, but a significantly higher level of vicarious traumatization ( d = .365, p < .001). These findings challenge Farrenkopf's well-known claim that female therapists who work with sex offenders are more prone to experiencing adverse emotional reactions than their male counterparts. PMID- 29415631 TI - Silk Biomaterials-Mediated miRNA Functionalized Orthopedic Devices. AB - Silk-based bioresorbable medical devices, such as screws, plates, and rods, have been under investigation due to their promising properties for orthopedic repairs. Options to functionalize these new devices for enhanced control of bone regeneration would also exploit the compatible processing methods used to generate the devices. MicroRNAs are important regulators of bone maintenance and formation, and miRNA-based therapeutics have the potential to aid bone repair, utilizing a transient therapeutic approach with local bioactivity. We hypothesized that silk-based orthopedic devices could be used for the local delivery of miRNAs, using anti-sense miR-214 (AS-miR-214), to inhibit endogenous expression of osteoinductive antagonist and thereby supporting the upregulation of osteoinductive target molecules activating transcription factor 4 (ATF4) and Osterix (Osx). AS-miR-214 silk devices, prepared using surface coating, demonstrated continuous release of miRNA inhibitors up to 7 days in vitro. Additionally, human mesenchymal stem cells seeded on AS-miR-214 silk films expressed higher levels of osteogenic genes ATF4, Osx, Runx2, and Osteocalcin. Interestingly, these cells exhibited lower cell viability and DNA content over 21 days. Conversely, the cells demonstrated significantly higher levels of alkaline phosphatase expression and calcium deposition compared with cells seeded on silk films with nontargeting miRNA controls. The study demonstrated that the silk based orthopedic devices, in conjunction with bioactive miRNA-based therapeutics, may serve as a novel system for localized bone tissue engineering, enhancing osteogenesis at the implant interface while avoiding detrimental systematic side effects. PMID- 29415632 TI - The demographic impact and development benefits of meeting demand for family planning with modern contraceptive methods. AB - BACKGROUND: Meeting demand for family planning can facilitate progress towards all major themes of the United Nations Sustainable Development Goals (SDGs): people, planet, prosperity, peace, and partnership. Many policymakers have embraced a benchmark goal that at least 75% of the demand for family planning in all countries be satisfied with modern contraceptive methods by the year 2030. OBJECTIVE: This study examines the demographic impact (and development implications) of achieving the 75% benchmark in 13 developing countries that are expected to be the furthest from achieving that benchmark. METHODS: Estimation of the demographic impact of achieving the 75% benchmark requires three steps in each country: 1) translate contraceptive prevalence assumptions (with and without intervention) into future fertility levels based on biometric models, 2) incorporate each pair of fertility assumptions into separate population projections, and 3) compare the demographic differences between the two population projections. Data are drawn from the United Nations, the US Census Bureau, and Demographic and Health Surveys. RESULTS: The demographic impact of meeting the 75% benchmark is examined via projected differences in fertility rates (average expected births per woman's reproductive lifetime), total population, growth rates, age structure, and youth dependency. On average, meeting the benchmark would imply a 16 percentage point increase in modern contraceptive prevalence by 2030 and a 20% decline in youth dependency, which portends a potential demographic dividend to spur economic growth. CONCLUSIONS: Improvements in meeting the demand for family planning with modern contraceptive methods can bring substantial benefits to developing countries. To our knowledge, this is the first study to show formally how such improvements can alter population size and age structure. Declines in youth dependency portend a demographic dividend, an added bonus to the already well-known benefits of meeting existing demands for family planning. PMID- 29415633 TI - Danazol increases T regulatory cells in patients with aplastic anemia. AB - OBJECTIVES: Danazol is an attenuated androgen and is used in the treatment of aplastic anemia (AA) in resource constraint settings. We chose to study the role of CD4+ CD25high CD127low FoxP3+ T regulatory cells (T-regs) in the pathophysiology of AA and their response to treatment with Danazol alone or in combination with immunosuppressive treatment (IST). METHODS: T-regs' percentages of 25 acquired idiopathic AA patients and 25 healthy controls who completed study protocol were analyzed by performing multicolor flowcytometry on peripheral blood samples. RESULTS: More than one-third (36%) of AA patients in our study received Danazol as monotherapy, whereas less than a third (32%) each received standard doses of IST with equine Anti Thymocyte Globulin (ATG) and Cyclosporine combination, or Cyclosporine and Danazol combination, respectively. Results showed that all AA patients had a significantly lower percentage of T-regs at the time of diagnosis when compared to healthy controls (p < 0.0001), implicating their role in the pathophysiology. On treatment, all 25 patients showed a significant rise in the percentage of T-regs when compared to baseline (p < 0.0001). DISCUSSION: The rise in T-regs' percentage was higher in patients treated with Danazol alone when compared to standard IST (ATG with Cyclosporine), or Cyclosporine with Danazol combinations (p = 0.585). CONCLUSION: We conclude that Danazol also leads to increase in T-regs in acquired idiopathic AA. PMID- 29415634 TI - Too Long to Wait: Obstetric Fistula and the Sociopolitical Dynamics of the Fourth Delay in Soroti, Uganda. AB - Uganda has one of the highest obstetric fistula rates in the world with approximately 200,000 women currently suffering. Surgical closure successfully treats fistula in the majority of cases, yet there is a severe shortage of facilities and trained surgeons in low-resource countries. The purpose of this study was to examine Ugandan women's experiences of obstetric fistula with the aim of adding narrative depth to the clinical literature on this devastating birth injury. Data were collected through semistructured interviews, focus groups, and participant observation. Resulting narratives were consensus coded, and key themes were member-checked using reciprocal ethnography. Women who suffered from fistula described barriers in accessing essential obstetric care during labor-barriers that are consistent with the three delays framework developed by Thaddeus and Maine. In this article, we extend this scholarship to discuss a fourth, critical delay experienced by fistula survivors-the delay in the diagnosis and treatment of their birth injury. PMID- 29415635 TI - "Why Come for Treatment?" Clients' and Therapists' Accounts of the Presenting Problems When Seeking Mental Health Care. AB - Although identification of main problems is the foundation for treatment planning, limited research has examined reasons for seeking mental health care. We identified reasons for seeking mental health care as reported by clients and therapists upon initial contact with mental health services. We conducted in depth interviews with clients and their therapists immediately following the intake. We analyzed 117 therapist and 112 client interviews using thematic analysis. Overall interrater reliability among three raters who coded the interviews was high (kappa = 0.72). Our findings suggest that, overall, clients and therapists report similar main area problems that bring clients to care. Emotional distress and other psychiatric symptoms as well as interpersonal problems were most prevalent. Therapists tended to ignore some problem areas that clients highlighted, including physical problems and socioeconomic strains. Raising awareness to potential gaps in perception of main problems that bring clients to care will promote a shared understanding and improve quality of care. PMID- 29415636 TI - Health Care Experiences of Korean Women Divers (Jeju Haenyeos). AB - Jeju haenyeos who enter the sea without equipment to collect seafood while holding their breath have a unique culture; however, studies of their health are limited. This study, using an ethnographic approach, explores how Jeju haenyeos have managed and maintained their health. Snowball sampling yielded 15 participants between July and October 2016. We collected data through participant observation and in-depth interviews and conducted Spradley's research sequence. The main theme of the health-management approach of these women was "a life of listening to the body and mind, controlling greed, and adjusting work for safe diving." However, Jeju haenyeos used preventive drugs and excessive doses of other drugs and lacked an understanding of the ways diverse drugs potentially interact. These findings suggest that community nurses should be cautious and should attempt to educate these patients. PMID- 29415637 TI - An Alternative View of Self-Discharge Against Medical Advice: An Opportunity to Demonstrate Empathy, Empowerment, and Care. AB - In this article, we present the experiences of discharging against medical advice from the perspectives of 17 hospital and community-based health care practitioners, and 16 patients, and relatives from a range of medical and surgical wards. Semistructured, in-depth interviews were conducted and thematically analyzed. We identified that practitioners, patients, and relatives frequently expressed empathy for each other during the interviews, and discharge against medical advice was presented as a way for patients to have control over their health. Contrary to predominantly negative framings that highlight increased mortality and morbidity, and portray people who discharge against medical advice as poor decision makers, we conclude discharge against medical advice can be framed positively. It can be an opportunity to empathize, empower, and care. We recommend that the vocabulary used in hospital discharge against medical advice policies and documents should be updated to reflect a culture of medicine that values patient autonomy, patient centeredness, and shared decision making. PMID- 29415638 TI - Prior exposure to nutritive and artificial sweeteners differentially alters the magnitude and persistence of sucrose-conditioned flavor preferences in BALB/c and C57BL/6 inbred mouse strains. AB - Murine genetic variance affects sucrose's ability to condition flavor preferences (CFP) relative to saccharin. Whereas BALB/c mice display robust sucrose- and fructose-CFP, C57BL/6 mice only display sucrose-CFP. Prior exposure to sucrose or saccharin solutions alters subsequent food choice responsiveness. The present study examined whether pre-exposure for one month to 10% sucrose or 0.2% saccharin altered subsequent sucrose-CFP in male and female BALB/c and C57BL/6 mice. Two weeks later, food-restricted mice were exposed to 10 CFP training trials with uniquely flavored 16% sucrose and 0.2% saccharin solutions. Two bottle choice tests of the flavors mixed in saccharin followed for 4 weeks. Male mice weighed more than females across all conditions, and male BALB/c, but not C57BL mice consumed more 85 sucrose than females. No other notable sex differences were observed. BALB/c mice consumed more sucrose during pre-exposure and one-bottle training than C57BL/6 mice. Although the magnitudes of sucrose-CFP were comparable in two-bottle choice tests in water-exposed BALB/c and C57BL/6 mice, sucrose- and saccharin-exposed BALB/c mice displayed significantly greater sucrose-CFP preferences relative to C57BL/6 counterparts. These data indicate murine genetic variance in the effects of prior exposure to nutritive or non nutritive sweeteners upon the magnitude of adult sugar-CFP. PMID- 29415639 TI - Low expression of Mda-7/IL-24 and high expression of C-myb in tumour tissues are predictors of poor prognosis for Burkitt lymphoma patients. AB - : Objectives Burkitt lymphoma is one of the most common types of haematopoietic malignancy in children and adolescents. Mda-7/IL-24 had been identified as a differentiation inducer of Burkitt lymphoma cells. Previous studies have revealed that knockdown of C-myb can also lead to the terminal differentiation of Burkitt lymphoma cells. The aim of the present study was to investigate the correlation between the expression of Mda-7/IL-24 and C-myb, as well as their prognostic significance, for Burkitt lymphoma patients. Methods The tumour tissues were collected from 59 cases of Burkitt lymphoma patients and detected with Western blotting and immunohistochemistry. Results The results showed that the expression of Mda-7/IL-24 was lower, whereas the expression of C-myb was higher in Burkitt lymphoma tissues compared to specimens of normal lymph node tissues. Furthermore, C-myb expression was negatively correlated with Mda-7/IL-24 expression at the protein level in Burkitt lymphoma tissues and cell lines. Both the expression of Mda-7/IL-24 and C-myb in Burkitt lymphoma tissues was associated with some clinicopathological parameters, such as clinical stage, infiltration in the bone marrow, Ki67 and overall survival rates. Conclusion These results indicated that low expression of Mda-7/IL-24 along with high expression of C-myb are predictors for poor prognosis of Burkitt lymphoma patients; this outcome suggests that Mda 7/IL-24 and C-myb might be potential targets for clinical treatment of Burkitt lymphoma. ABBREVIATIONS: Mda-7/IL-24: melanoma differentiation associated gene7/interleukin 24; FCM: flow cytometry; Ecog: Eastern Cooperative Oncology Group; IPI: International lymphoma prognosis index. PMID- 29415640 TI - In vivo effects of intravenous lipid emulsion on lung tissue in an experimental model of acute malathion intoxication. AB - Malathion can be ingested, inhaled, or absorbed through the skin, but acute toxicity is maximized when administered orally. Intravenous lipid emulsion (ILE) treatment is used as a new therapeutic method in cases of systemic toxicity caused by some lipid soluble agents. This study aimed to examine the potential treatment effect of ILE on rat lung tissue in a toxicokinetic model of malathion exposure. Twenty-one adult Wistar albino rats were randomly divided into three equal groups. The groups were organized as group I (control), group II (malathion), and group III (malathion + ILE treatment). Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were evaluated in lung tissues. Immunohistochemical and Western blot analyses were performed to determine the bax, bcl-2, and caspase-3 expression levels. Tissue GSH-Px and SOD activities were decreased and MDA levels were increased in the malathion group. ILE administration increased GSH-Px and SOD activity and decreased MDA levels compared to the malathion group. Furthermore, expression of bax, bcl-2, and caspase-3 significantly increased in the malathion group, and ILE infusion reduced these expression levels. The present study revealed that acute oral malathion administration increased oxidative stress and apoptosis in the lung tissue of rats. ILE infusion prevented oxidative stress and decreased the deleterious effects of malathion. Taken together, the findings of our study suggest that lipid emulsion infusion has treatment efficacy on malathion-induced lung toxicity. PMID- 29415641 TI - Comparison of the in vitro toxicological activity of various particulate matter. AB - Ultrafine particles (UFPs, < 2.5 um) in air pollutants have been identified as a major cause of respiratory diseases, since they can affect the lung alveoli through the bronchus. In particular, if toxicants such as heavy metals and polycyclic aromatic hydrocarbons (PAHs) are present in UFPs, they can cause diseases such as asthma, chronic obstructive pulmonary disease, and lung cancer. This study compared in vitro toxicity of various particulate matter including UFPs from combustion particles of diesel (diesel exhaust particles (DEP)), rice straw (RS), pine stem (PS) and coal (CC), and road dust particles from tunnel (TD) and roadside (RD). UFPs from combustion particles and road dust were collected with a glass fiber filter using burning systems and a solid aerosol generator. Cell viability was determined by neutral red uptake assay using Chinese hamster ovary strain K1 cells. Redox cycling activity and intracellular reactive oxygen species were measured using 1,4-dithiothreitol (DTT) and 2',7' dichlorofluorescin diacetate (DCF-DA) assay, respectively. Our in vitro studies validated that combustion particles had high toxicological activity. PS demonstrated the highest activity in cytotoxicity but DEP had the highest activity in the DTT and DCF-DA assays. Overall, since the toxicological activity of particles generated by various means was different, risk assessment should be conducted through various toxicity evaluations rather than one toxicity evaluation. PMID- 29415642 TI - Short-term induction of vitellogenesis in the immature male yellowfin seabream ( Acanthopagrus latus) exposed to bisphenol A and 17 beta-estradiol. AB - Bisphenol A (BPA) is a known environmental endocrine-disrupting chemical that is widely used in plastics manufacturing. BPA enters in the aquatic environment mainly through urban and industrial sewage effluents, thereby posing a potential threat to organisms living in these ecosystems. This study was conducted to investigate the effect of BPA on VTG production with direct (sodium dodecyl sulfate-polyarylamide gel electrophoresis) and indirect (alkali-labile phosphate (ALP), total plasma calcium and protein) methods in immature male yellowfin seabream ( Acanthopagrus latus) as a marine fish model. Fish were randomly distributed into seven groups that were administered 1, 10, 50, and 100 ug g-1 week-1 of BPA and 2 ug g-1week-1 of 17beta-estradiol (E2) over a period of 2 weeks. Solvent controls received olive oil, whereas controls were not injected. The fish were sampled on days 0, 7, and 14, and their blood plasma and liver were obtained. The results showed that the hepatosomatic index of all treated fish was elevated in comparison with controls. Direct and indirect indicators showed that fish VTG protein was induced by BPA and E2 exposure. The protein was found to have two bands with molecular weights around 210 and 190 KDa. ALP, total plasma calcium and protein levels were increased in dose- and time-dependent manners. The results of this study demonstrated that short-term exposure of yellowfin seabream to BPA induced adverse effects in the reproductive system of hermaphrodite fish. PMID- 29415643 TI - Integrating Orthographic Information Across Time and Space. AB - Research has suggested that the word recognition process is influenced by the integration of orthographic information across words. The precise nature of this integration process may vary, however, depending on whether words are in temporal or spatial proximity. Here we present a lexical decision experiment, designed to compare temporal and spatial integration processes more directly. Masked priming was used to reveal effects of temporal integration, while the flanker paradigm was used to reveal effects of spatial integration. Primes/flankers were high frequency orthographic neighbors of the target (blue-blur) or unrelated control words (head-blur). We replicated prior observations of inhibition in trials where the neighbor was used as a masked prime, while facilitation was observed in trials where the neighbor was presented as flanker. We conclude that sub-lexical orthographic information is integrated both temporally and spatially, but that spatial information is used to segregate lexical representations activated by spatially distinct sources. PMID- 29415644 TI - A Bird in the Hand Isn't Good for Long. AB - Folk wisdom tells us that additional time to make a decision helps us to refrain from the first impulse to take the bird in the hand. However, the question why the time to decide plays an important role is still unanswered. Here we distinguish two explanations, one based on a bias in value accumulation that has to be overcome with time, the other based on cognitive control processes that need time to set in. In an intertemporal decision task, we use mouse tracking to study participants' responses to options' values and delays which were presented sequentially. We find that the information about options' delays does indeed lead to an immediate bias that is controlled afterwards, matching the prediction of control processes needed to counter initial impulses. Hence, by using a dynamic measure, we provide insight into the processes underlying short-term oriented choices in intertemporal decision making. PMID- 29415646 TI - Adults' and Children's Understanding of How Expertise Influences Learning. AB - Adults and children use information about expertise to infer what a person is likely to know, but it is unclear whether they realize that expertise also has implications for learning. We explore adults' and children's understanding that expertise in a particular category supports learning about a closely related category. In four experiments, 5-year-olds and adults (n = 160) judged which of two people would be better at learning about a new category. When faced with an expert and a nonexpert, adults consistently indicated that expertise supports learning in a closely related category; however, children's judgments were inconsistent and were strongly influenced by the description of the nonexpert. The results suggest that although children understand what it means to be an expert, they may judge an individual's learning capacity based on different considerations than adults. PMID- 29415645 TI - Shared Processing of Language and Music. AB - The present study sought to explore whether musical information is processed by the phonological loop component of the working memory model of immediate memory. Original instantiations of this model primarily focused on the processing of linguistic information. However, the model was less clear about how acoustic information lacking phonological qualities is actively processed. Although previous research has generally supported shared processing of phonological and musical information, these studies were limited as a result of a number of methodological concerns (e.g., the use of simple tones as musical stimuli). In order to further investigate this issue, an auditory interference task was employed. Specifically, participants heard an initial stimulus (musical or linguistic) followed by an intervening stimulus (musical, linguistic, or silence) and were then asked to indicate whether a final test stimulus was the same as or different from the initial stimulus. Results indicated that mismatched interference conditions (i.e., musical - linguistic; linguistic - musical) resulted in greater interference than silence conditions, with matched interference conditions producing the greatest interference. Overall, these results suggest that processing of linguistic and musical information draws on at least some of the same cognitive resources. PMID- 29415647 TI - Contagion via Magical Thinking and via Mere Proximity. AB - People show an irrational dislike for objects that were once contaminated or had come into contact with an undesirable person, even if they are currently indistinguishable from other similar objects. To date, such negative contagion within the magical thinking literature has been shown only with inanimate objects. We addressed a boundary condition to see if it also extended to animate targets (dogs and children) while teasing out mere-proximity effects that would predict a similar contagion in the case of children. We used two different types of contagion, one based on proximity and one based on self-information. We found that magical thinking did extend to dogs but not to children when not confounded by mere-proximity effects. Also, contagion was less strong in the case of animate targets, but pity was not related to either this reduction or to the disappearance of the effect with children. PMID- 29415648 TI - Interference in Dutch-French Bilinguals. AB - In the present manuscript, we investigate the source of congruency effects in a group of Dutch-French bilinguals. In particular, participants performed a color identification Stroop task, in which both (first language) Dutch and (second language) French distracting color words were presented in colors. The typical finding is impaired responding when the word and color are incongruent (e.g., "red" in blue) relative to congruent (e.g., "red" in red). This congruency effect is observed for both first and second language distracting color words. The current experiment used a 2-to-1 keypress mapping manipulation, which allows one to separate stimulus conflict (i.e., conflict between word and color meanings) and response conflict (i.e., conflict between potential responses). For both the first and second language, both stimulus and response conflict were observed. These results suggest that second language words influence semantic and response processing similarly to first language words, rather than having diminished semantic and/or response influences. PMID- 29415649 TI - Gender differences in the prevalence and impact factors of hysterical tendencies in adolescents from three eastern Chinese provinces. AB - BACKGROUND: Few studies have attempted to compare the differences in the prevalence and impact factors of hysterical tendencies (HTs) in adolescents. Thus, the aim of this study was to examine gender differences in the prevalence and impact factors of adolescents' HTs across three eastern Chinese provinces (Anhui, Jiangsu, and Zhejiang). METHODS: A multicenter, school-based, cross sectional study was conducted in three provinces (Anhui, Jiangsu, and Zhejiang) in China in 2014. The sample included 10,131 middle-school students aged 13-18 years who were randomly selected using a multiphase, stratified, cluster sampling technique. A two-stage appraisal procedure was used to determine the adolescents' HTs. We also designed a multicenter, school-based, case control (1329 cases with 2661 control individuals) study to collect data on the common factors affecting this population using a common protocol and questionnaire. RESULTS: An overall positive rate of HTs among adolescents across the three eastern Chinese provinces studied was found at 13.1% (95% confidence interval (CI) 12.5-13.8%), at 14.5% (95% CI 13.3-15.7%) for females, and at 12.2% (95% CI 11.1-13.4%) for males. Gender-stratified, multiple conditional regression analyses revealed that superstitious beliefs pertaining to life, somatotype, teacher-student satisfaction, and family achievement orientation were significantly linked to HTs only in males, while left-behind adolescents, emotional and social adaptation, teacher-student support, family cohesion, and the Hospital Anxiety and Depression Scale - depression scores were significantly associated with female HTs only. The models indicated that of all the independent variables studied, family medical history was the strongest impact factor for both male HTs (adjusted matched odds ratio (amOR) = 2.92, 95% CI = 1.84-4.86) and female HTs (amOR = 2.74, 95% CI = 1.59-4.98). CONCLUSIONS: HTs are prevalent among adolescents in the three eastern Chinese provinces studied. Gender differences in the prevalence and impact factors of HTs are significant in adolescents, and HTs seem to affect more females than males. Therefore, sex-specific intervention programs against HTs in adolescents should be considered to reduce HT prevalence in adolescents by modifying influential social, school, and family factors. PMID- 29415650 TI - Conservation of polypyrimidine tract binding proteins and their putative target RNAs in several storage root crops. AB - BACKGROUND: Polypyrimidine-tract binding proteins (PTBs) are ubiquitous RNA binding proteins in plants and animals that play diverse role in RNA metabolic processes. PTB proteins bind to target RNAs through motifs rich in cytosine/uracil residues to fine-tune transcript metabolism. Among tuber and root crops, potato has been widely studied to understand the mobile signals that activate tuber development. Potato PTBs, designated as StPTB1 and StPTB6, function in a long-distance transport system by binding to specific mRNAs (StBEL5 and POTH1) to stabilize them and facilitate their movement from leaf to stolon, the site of tuber induction, where they activate tuber and root growth. Storage tubers and root crops are important sustenance food crops grown throughout the world. Despite the availability of genome sequence for sweet potato, cassava, carrot and sugar beet, the molecular mechanism of root-derived storage organ development remains completely unexplored. Considering the pivotal role of PTBs and their target RNAs in potato storage organ development, we propose that a similar mechanism may be prevalent in storage root crops as well. RESULTS: Through a bioinformatics survey utilizing available genome databases, we identify the orthologues of potato PTB proteins and two phloem-mobile RNAs, StBEL5 and POTH1, in five storage root crops - sweet potato, cassava, carrot, radish and sugar beet. Like potato, PTB1/6 type proteins from these storage root crops contain four conserved RNA Recognition Motifs (characteristic of RNA-binding PTBs) in their protein sequences. Further, 3' UTR (untranslated region) analysis of BEL5 and POTH1 orthologues revealed the presence of several cytosine/uracil motifs, similar to those present in potato StBEL5 and POTH1 RNAs. Using RT-qPCR assays, we verified the presence of these related transcripts in leaf and root tissues of these five storage root crops. Similar to potato, BEL5-, PTB1/6- and POTH1-like orthologue RNAs from the aforementioned storage root crops exhibited differential accumulation patterns in leaf and storage root tissues. CONCLUSIONS: Our results suggest that the PTB1/6-like orthologues and their putative targets, BEL5- and POTH1-like mRNAs, from storage root crops could interact physically, similar to that in potato, and potentially, could function as key molecular signals controlling storage organ development in root crops. PMID- 29415651 TI - Integrative analysis of microRNAs and mRNAs revealed regulation of composition and metabolism in Nelore cattle. AB - BACKGROUND: The amount of intramuscular fat can influence the sensory characteristics and nutritional value of beef, thus the selection of animals with adequate fat deposition is important to the consumer. There is growing knowledge about the genes and pathways that control the biological processes involved in fat deposition in muscle. MicroRNAs (miRNAs) belong to a well-conserved class of non-coding small RNAs that modulate gene expression across a range of biological functions in animal development and physiology. The aim of this study was to identify differentially expressed (DE) miRNAs, regulatory candidate genes and co expression networks related to intramuscular fat (IMF) deposition. To achieve this, we used mRNA and miRNA expression data from the Longissimus dorsi muscle of 30 Nelore steers with high (H) and low (L) genomic estimated breeding values (GEBV) for IMF deposition. RESULTS: Differential miRNA expression analysis between animals with extreme GEBV values for IMF identified six DE miRNAs (FDR 10%). Functional annotation of the target genes for these microRNAs indicated that the PPARs signaling pathway is involved with IMF deposition. Candidate regulatory genes such as SDHAF4, FBXO17, ALDOA and PKM were identified by partial correlation with information theory (PCIT), phenotypic impact factor (PIF) and regulatory impact factor (RIF) co-expression approaches from integrated miRNA mRNA expression data. Two DE miRNAs (FDR 10%), bta-miR-143 and bta-miR-146b, which were upregulated in the Low IMF group, were correlated with regulatory candidate genes, which were functionally enriched for fatty acid oxidation GO terms. Co-expression patterns obtained by weighted correlation network analysis (WGCNA), which showed possible interaction and regulation between mRNAs and miRNAs, identified several modules related to immune system function, protein metabolism, energy metabolism and glucose catabolism according to in silico analysis performed herein. CONCLUSION: In this study, several genes and miRNAs were identified as candidate regulators of IMF by analyzing DE miRNAs using two different miRNA-mRNA co-expression network methods. This study contributes to the understanding of potential regulatory mechanisms of gene signaling networks involved in fat deposition processes measured in muscle. Glucose metabolism and inflammation processes were the main pathways found in silico to influence intramuscular fat deposition in beef cattle in the integrative mRNA-miRNA co expression analysis. PMID- 29415652 TI - Transcriptomic changes in Cucurbita pepo fruit after cold storage: differential response between two cultivars contrasting in chilling sensitivity. AB - BACKGROUND: Zucchini fruit is susceptible to chilling injury (CI), but the response to low storage temperature is cultivar dependent. Previous reports about the response of zucchini fruit to chilling storage have been focused on the physiology and biochemistry of this process, with little information about the molecular mechanisms underlying it. In this work, we present a comprehensive analysis of transcriptomic changes that take place after cold storage in zucchini fruit of two commercial cultivars with contrasting response to chilling stress. RESULTS: RNA-Seq analysis was conducted in exocarp of fruit at harvest and after 14 days of storage at 4 and 20 degrees C. Differential expressed genes (DEGs) were obtained comparing fruit stored at 4 degrees C with their control at 20 degrees C, and then specific and common up and down-regulated DEGs of each cultivar were identified. Functional analysis of these DEGs identified similarities between the response of zucchini fruit to low temperature and other stresses, with an important number of GO terms related to biotic and abiotic stresses overrepresented in both cultivars. This study also revealed several molecular mechanisms that could be related to chilling tolerance, since they were up-regulated in cv. Natura (CI tolerant) or down-regulated in cv. Sinatra (CI sensitive). These mechanisms were mainly those related to carbohydrate and energy metabolism, transcription, signal transduction, and protein transport and degradation. Among DEGs belonging to these pathways, we selected candidate genes that could regulate or promote chilling tolerance in zucchini fruit including the transcription factors MYB76-like, ZAT10-like, DELLA protein GAIP, and AP2/ERF domain-containing protein. CONCLUSIONS: This study provides a broader understanding of the important mechanisms and processes related to coping with low temperature stress in zucchini fruit and allowed the identification of some candidate genes that may be involved in the acquisition of chilling tolerance in this crop. These genes will be the basis of future studies aimed to identify markers involved in cold tolerance and aid in zucchini breeding programs. PMID- 29415653 TI - Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Xanthine oxidase inhibitors (XOI), classified as purine-like (allopurinol and oxypurinol) and non-purine (febuxostat and topiroxostat) XOI, present antioxidant properties by reducing the production of reactive oxygen species derived from purine metabolism. Oxidative stress is an important factor related to endothelial dysfunction and ischemia-reperfusion injury, and may be implicated in the pathogenesis of heart failure, hypertension, and ischemic heart disease. However, there is contradictory evidence regarding the possible cardiovascular (CV) protective effect exerted by XOI. Our objective is to compare the incidence of major adverse cardiovascular events (MACE), mortality, total (TCE) and specific CV events in randomized controlled trials (RCTs) testing XOI against placebo or no treatment. METHODS: PubMed, EMBASE, Web of Science, Cochrane Central, Lilacs databases were searched from inception to Dec 30 2016, along with hand searching. RCTs including exclusively adult individuals, lasting >= 4 weeks, with no language restriction, were eligible. Independent paired researchers selected studies and extracted data. Considering the expected rarity of events, Peto and DerSimonian/Laird odds ratios (OR), the latter in case of heterogeneity, were used for analysis. Random-effects meta-regression was used to explore heterogeneity. RESULTS: The analysis of MACE included 81 articles (10,684 patients, 6434 patient-years). XOI did not significantly reduce risk of MACE (ORP = 0.71, 95% CI 0.46-1.09) and death (0.89, 0.59-1.33), but reduced risk of TCE (0.60, 0.44-0.82; serious TCE: 0.64, 0.46 to 0.89), and hypertension (0.54, 0.37 to 0.80). There was protection for MACE in patients with previous ischemic events (0.42, 0.23-0.76). Allopurinol protected for myocardial infarction (0.38, 0.17 0.83), hypertension (0.32, 0.18-0.58), TCE (0.48, 0.31 to 0.75, I2 = 55%) and serious TCE (0.56, 0.36 to 0.86, I2 = 44%). Meta-regression associated increasing dose of allopurinol with higher risk of TCE and serious TCE (P < 0.05). Accordingly, lower doses (<= 300 mg/day) of allopurinol reduced the risk of TCE, unlike higher doses. Non-purine-like XOI did not significantly reduce or increase the risk of adverse CV events, but confidence intervals were wide. Quality of evidence was generally low to moderate. CONCLUSIONS: Purine-like XOI may reduce the incidence of adverse CV outcomes. However, higher doses of allopurinol (> 300 mg/day) may be associated with loss of CV protection. PMID- 29415654 TI - The research on gene-disease association based on text-mining of PubMed. AB - BACKGROUND: The associations between genes and diseases are of critical significance in aspects of prevention, diagnosis and treatment. Although gene disease relationships have been investigated extensively, much of the underpinnings of these associations are yet to be elucidated. METHODS: A novel method integrates MeSH database, term weight (TW), and co-occurrence methods to predict gene-disease associations based on the cosine similarity between gene vectors and disease vectors. Vectors are transformed from the texts of documents in the PubMed database according to the appearance and location of the gene or disease terms. The disease related text data has been optimized during the process of constructing vectors. RESULTS: The overall distribution of cosine similarity value was investigated. By using the gene-disease association data in OMIM database as golden standard, the performance of cosine similarity in predicting gene-disease linkage was evaluated. The effects of applying weight matrix, penalty weights for keywords (PWK), and normalization were also investigated. Finally, we demonstrated that our method outperforms heterogeneous network edge prediction (HNEP) in aspects of precision rate and recall rate. CONCLUSIONS: Our method proposed in this paper is easy to be conducted and the results can be integrated with other models to improve the overall performance of gene-disease association predictions. PMID- 29415655 TI - Coping better with health problems after a visit to the family physician: associations with patients and physicians characteristics. AB - BACKGROUND: Good patient experience is recognized as an important component of a strong primary care system. Among the dimensions related to experience in family medicine, the ability to cope better with health problems is considered to be a measure of the quality of a consultation with a family physician (FP). The objective is to identify factors related to patients, physicians and practice, associated with patients' ability to cope better with their health problems after a family medicine consultation. METHODS: The data stemmed from the Swiss part of the Quality and Costs of Primary Care (QUALICOPC) study, an international cross sectional survey aiming to compare quality, cost and equity in primary care. In Switzerland, a random sample of 199 FPs and 1791 patients participated. The negative answer to the question: "After this visit, I feel I can cope better with my health problems" was modeled using multilevel logistic regressions. RESULTS: Difficulty to cope better with health problems was positively associated with the following: younger age (OR: 1.58, 95% CI [1.03-2.41]), cultural aspects related to the Swiss area of language (French speaking people declared higher inability than German and Italian ones), presence of chronic disease (OR: 1.54 95% CI [1.00 2.39]). Conversely an intermediate number (1-4) of visits during the last 6 months (OR: 0.37 95% CI [0.23-0.62]) and the satisfaction with the physician (OR: 0.18 95% CI [0.08-0.44]) are negative predictors of the patient inability to cope better with his health problems. A self-reported effort-reward imbalance at work (OR: 0.64 95% CI [0.41-1.00]) was the only predictive FP characteristic (negatively associated). CONCLUSIONS: Although the design of the study does not allow causal inference, this study showed that the predictors of patient difficulties to cope better with health problem are mainly centered on the patients' characteristics. The patient-physician relationship both in terms of quality and frequency of visits is probably also important. Organizational practice characteristics do not seem to play a major role but stress at work among physicians should be further investigated. PMID- 29415656 TI - Comparison of lumbar plexus block using the short axis in-plane method at the plane of the transverse process and at the articular process: a randomized controlled trial. AB - BACKGROUND: Although the safety and effectiveness of the short-axis in-plane method has been confirmed for lumbar plexus block, the operation is difficult and has a high rate of epidural spread at the plane of the articular process. Therefore, we developed a new in-plane technique, called the beach chair method, which displays images from the transverse process. We compared the operative difficulty and incidence of epidural spread of the beach chair method with those of the control method (at the plane of the articular process) in this randomized controlled clinical trial. METHODS: Sixty patients, aged 18 to 75 years, scheduled for unilateral arthroscopic knee surgery were randomized to receive double-guided lumbar plexus block by the beach chair method (n = 30) or the control method (n = 30) with 30 ml 0.5% ropivacaine hydrochloride; all patients received a sciatic nerve block with 10 ml 1% lidocaine hydrochloride and 10 ml 0.5% ropivacaine hydrochloride. RESULTS: The incidence of epidural spread after lumbar plexus block was significantly lower in the beach chair group than that in the control group [1 case (3.3%) vs. 9 (30.0%), P = 0.006]. Moreover, the imaging time (34.2 +/- 16.7 s vs. 48.9 +/- 16.8 s, P = 0.001), needling time (85.0 +/- 45.3 s vs. 131.4 +/- 88.2 s, P = 0.013) and number of needle punctures (2.7 +/- 1.3 vs. 4.5 +/- 2.1, P = 0.000) were significantly lower in the beach chair group than those in the control group; the ultrasound visibility score of the beach chair group was better than that of the control group. There were no significant differences in the remaining indicators. CONCLUSIONS: The beach chair method was easier and was associated with a lower incidence of epidural spread than the control method. Therefore, the beach chair method (at the plane of the transverse process) provides another promising option for lumbar plexus block for the non obese population. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR), Registration number:ChiCTR-INR-15007505, registered on November 06, 2015. PMID- 29415657 TI - Assessment of blood pressure control in adult hypertensive patients in eastern Sudan. AB - BACKGROUND: The rate of blood pressure (BP) control in adult hypertensive patients is poor and the reasons for poor control of BP pressure are not fully understood globally. This study aimed to assess the rate and factors associated with BP control in adult hypertensive patients in Sudan. METHODS: A hospital based cross-sectional study was conducted in adult hypertensive Sudanese patients at Gadarif Hospital in eastern Sudan from November 2016 to March 2017. Information on sociodemographic characteristics of the participants, comorbidities, antihypertensive medication, and adherence to antihypertensive medication was gathered from patients using a questionnaire. Fasting cholesterol and triglyceride levels were measured. RESULTS: A total of 380 patients were enrolled. Of them, 234 (61.6%) were women. The mean (SD) age of the participants was 57.8 (11.1) years (range: 25-93 years). Over one-third (n = 147, 38.7%) of the participants were taking more than one antihypertensive medication. Approximately one-third (29.5%) of the participants were non-adherent to medication. The rate of BP control was 45.3%. In binary logistic regression analyses, age, sex, physical inactivity, adding salt to food, drinking coffee, body mass index, and the lipid profile were not associated with uncontrolled BP. However, non-adherence to medication was the main factor associated with uncontrolled BP (odds ratio = 5.29, 95% confidence interval = 3.16-8.83, P < 0.001). CONCLUSIONS: Almost half of hypertensive patients in follow-up have uncontrolled BP, mainly due to non-adherence to medicine. We recommend further research on drug adherence to improve the rate of BP control in this setting (Gadarif) of the Sudan. PMID- 29415658 TI - Late-onset postoperative Mycobacterium haemophilum endophthalmitis masquerading as inflammatory uveitis: a case report. AB - BACKGROUND: Although atypical mycobacteria had been increasingly found in various ocular infections in the past decades, a slow-growing Mycobacterium haemophilum (M. haemophilum) was scarcely reported. Similar to tuberculous infection, the presentation can masquerade as low-grade granulomatous intraocular inflammation with partial response to corticosteroids. Besides, the special requirements for culture make this pathogen difficult to diagnose. The study aims to report the clinical presentation and notify the awareness of NTM endophthalmitis among clinicians. This is the first case report of late-onset, postoperative M. haemophilum endophthalmitis in the literature. CASE PRESENTATION: A 66-year-old man with non-insulin-dependent diabetes mellitus (NIDDM) manifested chronic granulomatous inflammation in the left eye after multiple glaucoma surgeries. With a diagnosis of noninfectious panuveitis, he was treated with systemic corticosteroids. The inflammation initially responded to therapy although it subsequently worsened and became purulent endophthalmitis. The vitreous cultures grew M. haemophilum. Intraocular and systemic antimicrobial treatments were administered early, but the patient eventually turned blind. CONCLUSIONS: M. haemophilum endophthalmitis is a rare but serious intraocular complication leading to loss of vision or eyeball. Awareness of atypical mycobacterial infections is necessary especially in patients with impaired immune function, previous intraocular surgery, and corticosteroid resistance. Proper laboratory investigations and treatments should be performed. However, due to the rarity of the disease, the development of guidelines for its investigation and therapy is still challenging. PMID- 29415659 TI - Increasing prevalence of familial recurrence of multiple sclerosis in Iran: a population based study of Tehran registry 1999-2015. AB - BACKGROUND: Tehran is the capital of Iran with an increasing multiple sclerosis (MS) prevalence. A retrospective population-based study was conducted to evaluate the trends of MS prevalence in Tehran. METHODS: A population-based survey was conducted for the period 1999 to 2015, based on Iranian MS Society (IMSS) registry system of Tehran, the capital city of Iran. Point regression analysis was applied on MS trend data to find annual percent change (APC). The logistic regression analysis was used to estimate the odds ratio (OR) for individual variables in order to assess factors associating with familial recurrence of MS. P values < 0.05 were considered significant. RESULTS: MS prevalence has significantly increased during the study period from 1999 to 2015 (56.22 per 100,000). Total point prevalence of MS was 115.94 per 100,000 persons in 2015 compared to general population. Positive family history of MS was observed among 12.4% of patients. The strongest association amongst first-degree relatives was found in siblings, p value <= 0.001. CONCLUSION: MS prevalence is rising in Tehran and this city is one of the regions with highest MS prevalence in Asia. In this sample, the largest proportion of relatives with MS were found among first degree relatives, particularly siblings. Familial recurrence correlated with relative type. PMID- 29415660 TI - Transmission dynamics for Methicilin-resistant Staphalococous areus with injection drug user. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterial pathogen resistance to antibiotics including methicillin. The resistance first emerged in 1960 in a healthcare setting only after two years of using methicillin as a viable treatment for methicillin-susceptible Staphylococcus aureus. MRSA leads to infections in different parts of the body including the skin, bloodstream, lungs, or the urinary tract. METHODS: A deterministic model for methicillin-resistant Staphylococcus aureus (MRSA) with injection drug users is designed. The model incorporates transmission of MRSA among non-injection drug users and injection drug users (IDUs) who are both low-and high-risk users. A reduced MRSA transmission model with only non-IDUs is fitted to a 2008-2013 MRSA data from the Agency for Healthcare and Research and Quality (AHRQ). The parameter estimates obtained are projected onto the parameters for the low-and high-risk IDUs subgroups using risk factors obtained by constructing a risk assessment ethogram. Sensitivity analysis is carried out to determine parameters with the greatest impact on the reproduction number using the reduced non-IDUs model. Change in risk associated behaviors was studied using the full MRSA transmission model via the increase in risky behaviors and enrollment into rehabilitation programs or clean needle exchange programs. Three control effectiveness levels determined from the sensitivity analysis were used to study control of disease translation within the subgroups. RESULTS: The sensitivity analysis indicates that the transmission probability and recovery rates within the subgroup have the highest impact on the reproduction number of the reduced non-IDU model. Change in risk associated behaviors from non-IDUs to low-and high risk IDUs lead to more MRSA cases among the subgroups. However, when more IDUs enroll into rehabilitation programs or clean needle exchange programs, there was a reduction in the number of MRSA cases in the community. Furthermore, MRSA burden within the subgroups can effectively be curtailed in the community by implementing moderate- and high-effectiveness control strategies. CONCLUSIONS: MRSA burden can be curtailed among and within non-injection drug users and both low-and high-risk injection drug users by encouraging positive change in behaviors and by moderate- and high-effectiveness control strategies that effectively targets the transmission probability and recovery rates within the subgroups in the community. PMID- 29415661 TI - Diethylnitrosamine induces lung adenocarcinoma in FVB/N mouse. AB - BACKGROUND: Diethylnitrosamine is a well known carcinogen that induces cancers of various organs in mice and rats. Using FVB/N mouse strain, here we show that diethylnitrosamine induces primarily lung adenocarcinomas with modest tumor development in the liver, offering a new model to study chemical carcinogenesis in the lung. METHODS: Animals were exposed to a single high dose of diethylnitrosamine, and more than 70% of the mice developed lung cancer. To obtain a new transplantable tumor line, pieces of primary tumors were inoculated and maintained subcutaneously in the same mouse strain. We used immunohistochemistry to characterize the tumor for main lung adenocarcinoma markers. We searched for mutations in KRAS exon 2 and EGFR exon 19, 21 with Sanger sequencing. We also compared the normal lung tissue with the diethylnitrosamine induced primary adenocarcinoma, and with the subcutaneously maintained adenocarcinoma using Western blot technique for main cell cycle markers and to identify the main pathways. RESULTS: Primary and subcutaneous tumors express cytokeratin-7 and thyroid transcription factor-1, markers characteristic to lung adenocarcinoma. In addition, no mutations were found in the hot spot regions of KRAS and EGFR genes. We found high mTOR activation, but the level of p-Akt Ser473 and p-Akt Thr308 decreased in the tumorous samples. CONCLUSIONS: We established a new lung adenocarcinoma model using FVB/N mouse strain and diethylnitrosamine. We believe that this new model system would be highly useful in lung cancer research. PMID- 29415662 TI - Smoking and prostate cancer: a life course analysis. AB - BACKGROUND: Inconsistent associations between smoking status and prostate cancer (PC) could be due to exposure assessment error. Reconstructing smoking behaviors over the life course could reduce exposure assessment error. METHODS: As part of a case-control study, we identified 402 incident and histologically confirmed PC cases that were matched by age (+/-5 years) to 805 population controls. Through direct interview, we obtained information about: age at smoking onset, intensity and frequency of cigarette smoking at different life stages, and smoking cessation age. Smoking status at interview and average smoking index over the lifetime (packs/year) were estimated. Life course smoking patterns were obtained applying the k-means+ method for longitudinal data to the smoking index (pack/year) for each life stage. RESULTS: Two life-course smoking patterns were identified among ever smokers: "pattern A" characterized by males who reported low and constant smoking intensity (87.8%), and "pattern B" (12.2%) males with an initial period of low intensity, followed by an increase during the second period. Compared to never smokers, pattern B was associated with higher poorly differentiated PC, (OR 2.30; 95% CI 1.21-4.38). No association was observed with average smoking index. CONCLUSION: Life course smoking patterns seem to capture the smoking variability during life course and reduce the likelihood of reverse causation. Using this assessment strategy our findings support the potential role of tobacco smoking in PC, particularly poorly differentiated PC. Prospective studies with comprehensive smoking history during the lifetime are needed to confirm these findings. PMID- 29415664 TI - Gender-related differences in clinicopathological characteristics and renal outcomes of Chinese patients with IgA nephropathy. AB - BACKGROUND: The prognostic effect of gender on immunoglobulin A nephropathy (IgAN) is not clear. We explored gender-related differences in clinicopathological features and renal outcomes in IgAN. METHODS: This was a single-centre retrospective study. Patients were divided into two groups according to gender. The clinicopathological features at biopsy and renal outcomes during the follow-up were collected and analysed. Renal outcomes were defined as the doubling of baseline serum creatinine and end-stage renal disease (ESRD) (estimated glomerular filtration rate < 15 mL/min/1.73 m2, dialysis, or renal transplantation). The prognostic effects of gender were evaluated by Cox regression models. RESULTS: A total of 988 eligible IgAN patients were enrolled, and the ratio of males to females was 1:1.4. Compared with female patients, male patients had worse renal function, greater proteinuria, a higher prevalence of hypertension, hypertriglyceridaemia and hyperuricaemia, and more severe segmental sclerosis and tubular atrophy/interstitial fibrosis. However, haematuria occurred more frequently in female patients. During a median follow-up time of 48.6 (34.7, 62.7) months, no differences in renal survival rates were noted between the male and female groups. Multivariable Cox regression analyses revealed that gender was not a significant risk factor for renal outcomes after frequency matching of baseline eGFR and serum uric acid (SUA) levels. In addition, male and female patients shared similar risk factors, including a low eGFR and increased proteinuria and segmental sclerosis. In males, however, an elevated proportion of global glomerulosclerosis was also a poor prognostic factor for renal survival. CONCLUSIONS: Male IgAN patients presented with worse clinicopathologic features than female patients, but no significant differences were observed in long-term renal survival between male and female patients by eGFR- and SUA level-matching. PMID- 29415663 TI - The impact of disease severity on paradoxical association between body mass index and mortality in patients with acute kidney injury undergoing continuous renal replacement therapy. AB - BACKGROUND: Association between high body mass index (BMI) and survival benefit is confounded by comorbid conditions such as nutritional status and inflammation. Patients with acute kidney injury (AKI), particularly those receiving continuous renal replacement therapy (CRRT), are highly catabolic and more susceptible to loss of energy. Herein, we evaluated whether disease severity can modify the relationship between BMI and mortality. METHODS: We conducted an observational study in 1144 patients who had undergone CRRT owing to various causes of AKI between 2010 and 2014. Patients were categorized into four groups; underweight (< 18.5 kg/m2), normal (18.5-22.99 kg/m2), overweight (23.0-24.99 kg/m2), and obesity (>=25 kg/m2) according to BMI classification by the Committee of Clinical Practice Guidelines and Korean Society for the Study of Obesity. More severe disease was defined as sepsis-related organ failure assessment (SOFA) score of >= a median value of 12. The study endpoint was death that occurred within 30 days after the initiation of CRRT. RESULTS: The mean age was 63.2 years and 439 (38.4%) were females. The median BMI was 23.6 (20.9-26.2) kg/m2. The obese group were younger and higher SOFA score than normal BMI group. In a multivariable Cox regression analysis, we found a significant interaction between BMI and SOFA score (P < 0.001). Furthermore, obese patients were significantly associated with a lower risk of death as compared to normal BMI group after adjusting confounding factors [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.68 0.97; P = 0.03]. This association was only evident among patients with high severity (HR, 0.61; 95% CI, 0.48-0.76, P < 0.001). In contrast, in those with low severity, survival benefit of high BMI was lost, whereas underweight was associated with an increased risk of death (HR, 1.74; 95% CI, 1.16-2.60; P = 0.007). CONCLUSION: In this study, we found a survival benefit of high BMI in AKI patients undergoing CRRT, particularly in those with more disease severity; the effect was not observed in those with less disease severity. PMID- 29415665 TI - Prognostic implications of polycomb proteins ezh2, suz12, and eed1 and histone modification by H3K27me3 in sarcoma. AB - BACKGROUND: Polycomb repressive complex 2 (PRC2; formed by EZH2, SUZ12, and EED protein subunits) and PRC1 (BMI1 protein) induce gene silencing through histone modification by H3K27me3. In the present study, we characterized the PRC expression pattern and its clinical implication in sarcoma. METHODS: Using immunohistochemistry, we analyzed PRC expression in 105 sarcoma patients with 5 subtypes: synovial sarcoma (n = 18), rhabdomyosarcoma (n = 28), Ewing sarcoma (n = 15), osteosarcoma (n = 30), and others (n = 14). RESULTS: The median age at diagnosis in the patient cohort was 26.8 years (range: 1-78 years) and the male to-female ratio was 1:4. Initial disease presentation was locoregional disease in 83% of patients and initial metastatic disease in the remaining 17%. PRC expression was not significantly different according to histologic subtype (P = 0.400). Overall survival (OS) was significantly poor for SUZ12 high (P = 0.001), EED1 high (P = 0.279), and H3K27me3 high (P = 0.009). Ultimately, patients with PRC2high had significantly inferior OS than the no expression group (P = 0.009). In the Cox proportional hazard model adjusted for stage, histologic grade, surgery, margin and initial metastasis, SUZ12 expression (P = 0.020, HR 29.069, 95% CI 1.690-500.007), H3K27me3 (P = 0.010, HR 3.743, 95% CI 1.370-10.228) expression was significantly associated with shorter OS. CONCLUSION: We detected PRC expression in various sarcomas and demonstrated its independent negative prognostic role, suggesting the PRC axis as promising therapeutic target for treating sarcoma. PMID- 29415666 TI - Influence of vitamin D receptor polymorphisms on biochemical markers of mineral bone disorders in South African patients with chronic kidney disease. AB - BACKGROUND: It remains unclear whether genetic factors may explain the reported variation in the levels of biochemical markers of chronic kidney disease mineral and bone disorders (CKD- MBD) across ethnic groups. Therefore, the aim of this study was to examine the influence of vitamin D receptor (VDR) polymorphisms on secondary hyperparathyroidism and its association with vitamin D levels in black and white South African study participants. METHODS: This was a cross sectional study involving 272 CKD stage 3- 5D patients and 90 healthy controls. The four major VDR polymorphisms (Bsm 1, Fok 1, Taq 1, and Apa1) were genotyped using the polymerase chain reaction- restriction fragment length polymorphism (PCR -RFLP) method. In addition, biochemical markers of CKD-MBD were measured to determine their associations with the four VDR polymorphisms. RESULTS: With the exception of Taq I polymorphism, the distribution of the VDR polymorphisms differed significantly between blacks and whites. In hemodialysis patients, the Bb genotype was significantly associated with moderate secondary hyperparathyroidism (OR, 3.88; 95 CI 1.13-13.25, p = 0.03) and severe hyperparathyroidism (OR, 2.54; 95 CI 1.08-5.96, p = 0.03). This was consistent with the observed higher levels of median parathyroid hormone, fibroblast growth factor 23 and mean phosphate in patients with Bb genotype. This candidate risk genotype (Bb) was over represented in blacks compared to whites (71.0% versus 55.6%, p < 0.0001). In an unadjusted regression model, FokFf genotype was found to be significantly associated with the risk of developing severe vitamin D deficiency < 15 ng/ml (OR, 1.89; 95 CI 1.17-3.07, p = 0.01). CONCLUSION: The VDR Bb genotype is an independent predictor of developing secondary hyperparathyroidism in patients with end stage kidney disease. In addition, study participants with FokFf genotype are at increased of developing severe 25 -hydroxyvitamin D [25(OH)D] deficiency. PMID- 29415667 TI - Short-term effect of a developed warming moist chamber goggle for video display terminal-associated dry eye. AB - BACKGROUND: Video display terminal (VDT)-associated dry eye (DE) patients are the rising group worldwide, and moisture goggles are the preferable treatment since they are capable of improving tear film stability and DE discomfort. The current study aims to evaluate the short-term efficacy and safety of the developed warming moist chamber goggles (WMCGs) for VDT-associated DE patients. METHODS: In this prospective self-control study, 22 DE patients (22 eyes) working with VDTs over 4 h daily were enrolled and instructed to wear WMCGs for 15 min. Sodium hyaluronate (SH, 0.1%) eyedrops were applied as a control on another day on these same patients, however 4 subjects denied the eyedrop application. The symptomatology visual analog scale (VAS) score, tear meniscus height (TMH), noninvasive tear film break-up time (NI-BUT), tear film lipid layer thickness (LLT), and bulbar conjunctival redness were assessed with Keratograph 5 M at baseline, 5, 30 and 60 min after treatment. The WMCGs wearing comfort was also evaluated. RESULTS: The ocular discomfort evaluated by VAS decreased in the WMCGs group throughout 60 min (P<0.001), better than the control group levels (P <= 0.015). TMH, NI-BUT (including the first BUT and average BUT) increased than baseline level accross 60 min in the WMCG group (P <= 0.012), while those in the control group only showed temporary improvements in 5 min. LLT also increased obviously after WMCGs wear, while the change in the control group was nearly innoticeable. No adverse responses were detected. CONCLUSIONS: Temporary use of the WMCGs is able to relieve ocular discomfort, and improves tear film stability in DE patients for at least 1 h, making it a promising alternative to other treatments. PMID- 29415668 TI - The effect of propofol and sevoflurane on cancer cell, natural killer cell, and cytotoxic T lymphocyte function in patients undergoing breast cancer surgery: an in vitro analysis. AB - BACKGROUND: To clarify the effect of anaesthetic agents on cancer immunity, we evaluated the effects of propofol and sevoflurane on natural killer (NK) cell, cytotoxic T lymphocyte (CTL) counts and apoptosis rate in breast cancer and immune cells co-cultures from patients who underwent breast cancer surgery. METHODS: Venous blood samples were collected after inducing anaesthesia and at 1 and 24 h postoperatively in patients who had undergone breast cancer surgery. The patients were allocated randomly to the propofol- or sevoflurane-based anaesthesia groups. We counted and detected apoptosis in cancer cell, NK cell and CTL of patients with breast cancer by co-culture with a breast cancer cell line in both groups. We also evaluated changes in the cytokines tumour necrosis factor alpha, interleukin (IL)-6 and IL-10 during the perioperative period. RESULTS: Forty-four patients were included in the final analysis. No difference in NK cell count, CTL count or apoptosis rate was detected between the groups. Furthermore, the number of breast cancer cells undergoing apoptosis in the breast cancer cell co-cultures was not different between the groups. No changes in cytokines were detected between the groups. CONCLUSION: Although basic science studies have suggested the potential benefits of propofol over a volatile agent during cancer surgery, propofol was not superior to sevoflurane, on the aspects of NK and CTL cells counts with apoptosis rate including breast cancer cell, during anaesthesia for breast cancer surgery in a clinical environment. TRIAL REGISTRATION: NCT02758249 on February 26, 2016. PMID- 29415669 TI - Factors predicting patient satisfaction in women with advanced breast cancer: a prospective study. AB - BACKGROUND: The present study (1) examined patient satisfaction with care over the first year following the diagnosis of advanced breast cancer and (2) tested if unmet health system and information needs, physical symptom distress, and psychological distress predicted patient satisfaction. METHODS: Prospective study of 213 Chinese women with advanced breast cancer assessed while awaiting or receiving initial chemotherapy (baseline), then again at 1.5-, 3-, 6-, and 12 months post-baseline. Health system and information unmet (HSI) needs, psychological distress, physical symptom distress, and patient satisfaction were assessed at baseline; patient satisfaction was reassessed at each follow-up assessment. Latent growth curve analysis assessed changes in patient satisfaction over the 12 months follow-up; hierarchical multiple regression analysis tested if baseline health system information needs, physical symptom distress, anxiety and depression predicted patient satisfaction at one-year post-baseline. RESULTS: The level of patient satisfaction was high and did not change significantly over time. Only HSI needs (beta = - 0.27, p < 0.005) significantly associated with baseline patient satisfaction. Patient satisfaction at one-year post-baseline was predicted by HSI needs (beta = - 0.26, p < 0.005), Anxiety (beta = 0.23, p < 0.05) and Depression (beta = - 0.28, p < 0.005), adjusting for the effect of baseline patient satisfaction (beta = 0.22, p < 0.005). CONCLUSIONS: Unmet health information needs and greater depressive symptoms at initial treatment phased predicted subsequent poorer patient satisfaction. This highlights a need to reinforce the importance of patient-centered care model in managing advanced breast cancer. PMID- 29415670 TI - The Alabama VIP older driver study rationale and design: examining the relationship between vision impairment and driving using naturalistic driving techniques. AB - BACKGROUND: Older drivers aged >=70 years old have among the highest rates of motor vehicle collisions (MVC) compared to other age groups. Driving is a highly visual task, and older adults have a high prevalence of vision impairment compared to other ages. Most studies addressing visual risk factors for MVCs by older drivers utilize vehicle accident reports as the primary outcome, an approach with several methodological limitations. Naturalistic driving research methods overcome these challenges and involve installing a high-tech, unobtrusive data acquisition system (DAS) in an older driver's own vehicle. The DAS continuously records multi-channel video of driver and roadway, sensor-based kinematics, GPS location, and presence of nearby objects in front of the vehicle, providing an objective measure of driving exposure. In this naturalistic driving study, the purpose is to examine the relationship between vision and crashes and near-crashes, lane-keeping, turning at intersections, driving performance during secondary tasks demands, and the role of front-seat passengers. An additional aim is to compare results of the on-road driving evaluation by a certified driving rehabilitation specialist to objective indicators of driving performance derived from the naturalistic data. METHODS: Drivers >=70 years old are recruited from ophthalmology clinics and a previous population-based study of older drivers, with the goal of recruiting persons with wide ranging visual function. Target samples size is 195 drivers. At a baseline visit, the DAS is installed in the participant's vehicle and a battery of health and functional assessments are administered to the driver including visual-sensory and visual-cognitive tests. The DAS remains installed in the vehicle for six months while the participant goes about his/her normal driving with no imposed study restrictions. After six months, the driver returns for DAS de-installation, repeat vision testing, and an on-road driving evaluation by a certified driving rehabilitation specialist (CDRS). The data streams recorded by the DAS are uploaded to the data coordinating center for analysis. DISCUSSION: The Alabama VIP Older Driver Study is the first naturalistic older driver study specifically focused on the enrollment of drivers with vision impairment in order to study the relationship between visual dysfunction and driver safety and performance. PMID- 29415671 TI - Trends in molecular subtypes of breast cancer: description of incidence rates between 2007 and 2012 from three French registries. AB - BACKGROUND: The incidence and incidence trends of breast cancer according to molecular subtype are unknown at a population level in France. The registry data enables this study and may give this information, that is crucial to describe and understand breast cancer epidemiology. METHODS: We estimated the incidence rates of breast cancer for each molecular subtype using data from three cancer registries in France for the period from 2007 to 2012. Molecular subtypes were defined with immunohistochemical data. Poisson models were estimated to modelize the course of breast cancer incidence and to test the trends. RESULTS: The study included 12,040 patients diagnosed between 2007 and 2012 in the three administrative areas covered by the registries. There was no significant trends in the proportion of each molecular subtype year by year. The age distribution of incident cases was different depending on the molecular subtypes (p < 0.001). The course of incidence between 2007 and 2012 was also different depending on molecular subtype according to the multivariate Poisson model (p < 0.001). CONCLUSION: The description of incident cases of breast cancer according to molecular subtype at a population level showed differences in trends. The trends in incidence differed according to molecular subtype, and this should improve our understanding of overall changes in incidence. This analysis is important to plan screening and treatment resources at a population level. PMID- 29415672 TI - Incidence and histological patterns of thyroid cancer in Sri Lanka 2001-2010: an analysis of national cancer registry data. AB - BACKGROUND: An increasing incidence of thyroid cancer is observed in many developed countries. Increasing incidence may also reflect better reporting or increased diagnostic scrutiny. We conducted this study to examine trends in thyroid cancer incidence and histological patterns in Sri Lanka. METHODS: A retrospective cohort evaluation of patients with thyroid cancer during 2001-2010 was performed using population based data published from the Sri Lanka National Cancer Registry. Trends in incidence and histological patterns were analysed by age and gender. RESULTS: The age-standardized incidence of thyroid cancer increased from 2.44 per 100,000 in 2001 (95% confidence interval [95% CI]: 2.21 2.67) to 5.16 per 100,000 in 2010 (95% CI: 4.85-5.47); a 2.1-fold increase (p < 0.05 for trend). A greater part of this increase is attributable to increase in incidence of papillary thyroid cancer, which increased from 1.64 to 3.61 per 100,000; a 2.2-fold increase (p < 0.05 for trend). Follicular cancer showed lesser, yet a significant increase from 0.56 to 0.95 per 100,000 (p < 0.05). Other varieties of thyroid cancer showed no significant increases in incidence. Trends in the increases in incidence of papillary cancer in females showed a much greater increase compared with males (from 2.45 to 5.60 per 100,000, a 2.28-fold increase in females compared with from 0.82 to 1.55; a 1.89-fold increase in males, p < 0.001). Highest incidence of papillary cancer was observed in 30-39 year age group, which has increased from 5.56 to 12.9 per 100,000; a 2.32-fold increase (p < 0.001). CONCLUSIONS: The increasing incidence of thyroid cancer in Sri Lanka is predominantly due to the increasing incidence of papillary cancers. These trends may reflect increased detection and better reporting, although an inherent increase in the incidence is the likely main contributor. Further studies including tumour stage and mortality may help answer these questions. PMID- 29415673 TI - Performance of anthropometric indicators as predictors of metabolic syndrome in Brazilian adolescents. AB - BACKGROUND: It is not clear which is the best anthropometric indicator to predict metabolic syndrome (MetS) in adolescents. Our objective was to identify the predictive power, with respective cut-off points, of anthropometric indicators associated with the quantity and distribution of body fat for the presence of MetS and to determine the strength of the association between the proposed cut off points and MetS in adolescents. METHODS: The sample consisted of 1035 adolescents (565 girls and 470 boys) aged between 12 and 20 years. Four anthropometric indicators were considered: waist circumference (WC), body mass index (BMI), waist-height ratio (WHtR), and conicity index (C-Index). MetS was defined according to the criteria of the International Diabetes Federation. Predictive performance was described through analysis of Receiver Operating Characteristic (ROC) curves with a 95% confidence interval. The most accurate cut off points were identified through sensitivity, specificity and Area Under the Curve (AUC) values. RESULTS: The four anthropometric indicators presented significant AUCs close to 0.70. At younger ages (12-15 years) the girls presented a statistically greater capacity to discriminate MetS; however, at more advanced ages (16-20 years) both sexes presented similar AUCs. Among the anthropometric indicators investigated, regardless of sex and age, the WHtR showed the highest discriminant value for MetS, while the C-Index demonstrated a significantly lower capacity to predict MetS. The AUCs equivalent to WC and BMI did not differ statistically. The proposed cut-off points for WHtR (12-15 years = 0.46, 16-20 years = 0.48) presented the highest values of sensitivity and specificity, between 60% and 70%, respectively. CONCLUSION: Considering that the best AUC was found for WHtR, we suggest the use of this anthropometric indicator, with the cut off points presented herein, for the prediction of MetS in adolescents with characteristics similar to the study sample. PMID- 29415674 TI - Observations on the health of infants at a time of rapid societal change: a longitudinal study from birth to fifteen months in Abu Dhabi. AB - BACKGROUND: Rapid economic and cultural transition in the United Arab Emirates has been accompanied by a rise in chronic disease. Early childhood is known to affect health outcomes in adulthood. This prospective longitudinal study examined the general health of Emirati infants born in a government maternity hospital in the Emirate of Abu Dhabi in October 2002. METHODS: One hundred twenty-five women, who had recently given birth, were interviewed as part of a larger study encompassing a wide range of cultural, social, and behavioural aspects of health. They were then re-interviewed at three (n = 94), six (n = 59) and 15 months postpartum (n = 52). Data are presented using univariate statistics. RESULTS: In this study seven infants (6%) were born prematurely and four infants (3%) were classified as small for gestational age, while 11 (9%) of the infants weighed less than 2500 g. Low birth weight infants (LBW) were significantly more likely to require treatment in the neonatal intensive care unit (OR = 30.83, p = 0.00). Iron supplementation during pregnancy was associated with fewer underweight infants (OR = 3.92, p = 0.042). No associations were found between infant birth weight and maternal age, age at marriage, consanguinity, education level, current maternal employment, parity, pre-existing anaemia or anaemia in pregnancy, diabetes, folic acid intake, multivitamin intake or infant gender. Maternally reported infant health issues, vaccination, medication, breast-feeding and infant nutrition, and use of secure car seats are also reported. CONCLUSIONS: The health of infants at birth in this UAE sample showed improvements compared to previous studies. The proportion of LBW infants is decreasing and continuing improvements in health care in the UAE are having a positive impact on infant health. PMID- 29415675 TI - Teaching children road safety through storybooks: an approach to child health literacy in Pakistan. AB - BACKGROUND: Road traffic injuries (RTIs) commonly affect the younger population in low- and-middle-income countries. School children may be educated about road safety using storybooks with colorful pictures, which tends to increase the child's interest in the text. Therefore, this study assessed the use of bilingual pictorial storybooks to improve RTI prevention knowledge among school children. METHODS: This pretest-posttest study was conducted in eight public and nine private schools of Karachi, Pakistan, between February to May 2015. Children in grades four and five were enrolled at baseline (n = 410). The intervention was an interactive discussion about RTI prevention using a bilingual (Urdu and English) pictorial storybook. A baseline test was conducted to assess children's pre existing knowledge about RTI prevention followed by administration of the intervention. Two posttests were conducted: first immediately after the intervention, and second after 2 months. Test scores were analyzed using McNemar test and paired sample t-test. RESULTS: There were 57% girls and 55% public school students; age range 8-16 years. Compared to the overall baseline score (5.1 +/- 1.4), the number of correct answers increased in both subsequent tests (5.9 +/- 1.2 and 6.1 +/- 1.1 respectively, p-value < 0.001). Statistically significant improvement in mean scores was observed based on gender, grades and school type over time (p-value < 0.001). CONCLUSION: Discussions using bilingual pictorial storybooks helped primary school children in Pakistan grasp knowledge of RTI prevention. RTI education sessions may be incorporated into school curricula using storybooks as teaching tools. Potential exists to create similar models for other developing countries by translating the storybooks into local languages. PMID- 29415676 TI - Chiari malformation type 1 presenting as unilateral progressive foot drop: a case report and review of literature. AB - BACKGROUND: Foot drop is a disabling clinical condition with multiplicity of causes, which requires detailed evaluation to identify the exact aetiology. Here, we report an extremely rare cause of foot drop in a child, which if not recognized early, could lead to multiple complications. CASE PRESENTATION: A 6 year-old girl presented with difficulty in walking and left sided foot droop for1 month duration. On examination she had reduced muscle power in dorsiflexors and plantar flexors and diminished knee and absent ankle jerk in the left side. Sensory loss was noted in L4 and L5 dermatomes on the left side. Superficial abdominal reflex was absent on the left side while preserved in the right. Nerve conduction and electromyography revealed nerve root or spinal cord cause for the foot drop. These results prompted ordering MRI spine and brain which revealed Chiari malformation type-1 with holocord syrinx extending from the cervicomedullary junction to conus medullaris. CONCLUSIONS: This case highlights the importance of considering broad differential diagnosis for foot drop and value of the complete neurological examination including superficial reflexes in arriving at a diagnosis. Prompt diagnosis helped to early neurosurgical referral and intervention which is an important prognostic factor. PMID- 29415677 TI - Expression profiling and intracellular localization studies of the novel Proline , Histidine-, and Glycine-rich protein 1 suggest an essential role in gastro intestinal epithelium and a potential clinical application in colorectal cancer diagnostics. AB - BACKGROUND: The primary function of the intestines is the absorption of water and nutrients. Although our knowledge about these processes on the cellular level is extensive, a number of important intracellular elements remain unknown. Here, we characterize the novel proline-, histidine-, glycine-rich 1 (PHGR1) mRNA and protein on the molecular level and propose a functional role of the PHGR1 protein in the intestinal and gastric epithelium. METHODS: PHGR1 mRNA and protein expression in human tissues and cell lines were characterized by quantitative RT PCR, in situ hybridization, Northern blotting, Western blotting, and immunohistochemistry. Glycosylation was assessed by a chemical deglycosylation assay, whereas intracellular localization was studied by immunofluorescent staining of cell line cells. PHGR1 mRNA levels in HT29 cells was reduced by RNA interference and the resulting global changes in gene expression assessed by microarray hybridization. RESULTS: PHGR1 mRNA and protein were found to be expressed specifically in epithelial cells of intestinal mucosa, with the highest expression in the most mature and differentiated cells. PHGR1 protein was found to be glycosylated and to localize to both the cytoplasm and nucleus. Transcript profiling and gene ontology analysis of HT29 cells subjected to PHGR1 knockdown suggested a functional relationship with transport and metabolic processes. Examination of PHGR1 mRNA and protein levels in lymph nodes with known colorectal cancer metastases indicated that they may serve as biomarkers for detection of such metastases. CONCLUSIONS: Functional analyses of the novel PHGR1 mRNA and protein suggest an essential role in gastrointestinal epithelium and a clinical application in detection of colorectal cancer lymph node metastases. PMID- 29415679 TI - Downstream consequences of diagnostic error in pediatric anaphylaxis. AB - BACKGROUND: Pediatric anaphylaxis is commonly misdiagnosed in the Emergency Department (ED). We aimed to determine the impact of inaccurate diagnosis on the management and follow-up of pediatric anaphylaxis presenting to the ED. METHODS: Retrospective chart review of ED management of children aged 0-18 years with allergic presentations to three EDs in Melbourne, Australia in 2014. Cases were included if an ED diagnosis of anaphylaxis was recorded, or the presentation met international consensus criteria for anaphylaxis. RESULTS: Of the 60,143 pediatric ED presentations during the study period, 1551 allergy-related presentations were identified and reviewed. 187 met consensus criteria for anaphylaxis, and another 24 were diagnosed with anaphylaxis without meeting criteria. Of the 211 presentations, 105 cases were given an ED diagnosis of anaphylaxis and 106 cases were given an alternative diagnosis in ED. Those diagnosed with anaphylaxis were more likely to receive epinephrine [85.7% vs 31.1% (OR = 13.27, 95% CI: 6.09-26.3)], to be observed for the recommended four hours [56.2% vs 29.2% (OR = 3.10, 95% CI 1.76-5.48, p < 0.001)], to have an epinephrine autoinjector available on discharge [81.9% vs 35.8% (OR = 4.12, 95% CI 2.07-8.22, p < 0.001)] and to be referred to an allergist [35.2% vs 16.0% (OR = 2.85, 95% CI 1.48-5.49, p < 0.01)]. Provision of anaphylaxis action plans and allergen avoidance advice was poorly documented for all patients. CONCLUSION: Accurate diagnosis of anaphylaxis in ED has a significant impact on observation times, prescription of epinephrine autoinjectors and referral to an allergist. These factors are key to reducing mortality and the significant morbidity that results from childhood anaphylaxis. PMID- 29415678 TI - Plocabulin, a novel tubulin-binding agent, inhibits angiogenesis by modulation of microtubule dynamics in endothelial cells. AB - BACKGROUND: Vascular supply of tumors is one of the main targets for cancer therapy. Here, we investigated if plocabulin (PM060184), a novel marine-derived microtubule-binding agent, presents antiangiogenic and vascular-disrupting activities. METHODS: The effects of plocabulin on microtubule network and dynamics were studied on HUVEC endothelial cells. We have also studied its effects on capillary tube structures formation or destabilization in three dimensional collagen matrices. In vivo experiments were performed on different tumor cell lines. RESULTS: In vitro studies show that, at picomolar concentrations, plocabulin inhibits microtubule dynamics in endothelial cells. This subsequently disturbs the microtubule network inducing changes in endothelial cell morphology and causing the collapse of angiogenic vessels, or the suppression of the angiogenic process by inhibiting the migration and invasion abilities of endothelial cells. This rapid collapse of the endothelial tubular network in vitro occurs in a concentration-dependent manner and is observed at concentrations lower than that affecting cell survival. The in vitro findings were confirmed in tumor xenografts where plocabulin treatment induced a large reduction in vascular volume and induction of extensive necrosis in tumors, consistent with antivascular effects. CONCLUSIONS: Altogether, these data suggest that an antivascular mechanism is contributing to the antitumor activities of plocabulin. PMID- 29415680 TI - Smartphones in the secondary prevention of cardiovascular disease: a systematic review. AB - BACKGROUND: Cardiac Rehabilitation (CR) and secondary prevention are effective components of evidence-based management for cardiac patients, resulting in improved clinical and behavioural outcomes. Mobile health (mHealth) is a rapidly growing health delivery method that has the potential to enhance CR and heart failure management. We undertook a systematic review to assess the evidence around mHealth interventions for CR and heart failure management for service and patient outcomes, cost effectiveness with a view to how mHealth could be utilized for rural, remote and Indigenous cardiac patients. METHODS: A comprehensive search of databases using key terms was conducted for the years 2000 to August 2016 to identify randomised and non-randomised trials utilizing smartphone functionality and a model of care that included CR and heart failure management. Included studies were assessed for quality and risk of bias and data extraction was undertaken by two independent reviewers. RESULTS: Nine studies described a mix of mHealth interventions for CR (5 studies) and heart failure (4 studies) in the following categories: feasibility, utility and uptake studies; and randomised controlled trials. Studies showed that mHealth delivery for CR and heart failure management is feasible with high rates of participant engagement, acceptance, usage, and adherence. Moreover, mHealth delivery of CR was as effective as traditional centre-based CR (TCR) with significant improvement in quality of life. Hospital utilization for heart failure patients showed inconsistent reductions. There was limited inclusion of rural participants. CONCLUSION: Mobile health delivery has the potential to improve access to CR and heart failure management for patients unable to attend TCR programs. Feasibility testing of culturally appropriate mHealth delivery for CR and heart failure management is required in rural and remote settings with subsequent implementation and evaluation into local health care services. PMID- 29415681 TI - Prenatal and perinatal risks for late language emergence in a population-level sample of twins at age 2. AB - BACKGROUND: Late Language Emergence (LLE) in the first two years of life is one of the most common parental concerns about child development and reasons for seeking advice from health professionals. LLE is much more prevalent in twins (38%) than singletons (20%). In studies of language development in twins without overt disability, adverse prenatal and perinatal environments have been reported to play a lesser role in the etiology of LLE than adverse postnatal environments. However, there is a lack of population-level evidence about prenatal and perinatal risk factors for LLE in twins. This study investigated the extent to which prenatal and perinatal risk factors were associated with LLE in a population-level sample of twins at age 2 without overt disability. METHODS: The sample comprised 473 twin pairs drawn from a population sample frame comprising statutory notifications of all births in Western Australia (WA), 2000-2003. Twin pairs in which either twin had a known developmental disorder or exposure to language(s) other than English were excluded. Of the 946 twins, 47.9% were male. There were 313 dizygotic and 160 monozygotic twin pairs. LLE was defined as a score at or below the gender-specific 10th percentile on the MacArthur Communicative Development Inventories: Words and Sentences (CDI-WS) (Words Produced). Bivariate and multivariable logistic regression was used to investigate risk factors associated with LLE. RESULTS: In the multivariable model, risk factors for LLE in order of decreasing magnitude were: Gestational diabetes had an adjusted odds ratio (aOR) of 19.5 (95% confidence interval (CI) 1.2, 313.1); prolonged TSR (aOR: 13.6 [2.0, 91.1]); multiparity (aOR: 7.6 [1.6, 37.5]), monozygosity (aOR: 6.9 [1.7, 27.9]) and fetal growth restriction (aOR: 4.6 [1.7, 12.7]). Sociodemographic risk factors (e.g., low maternal education, socioeconomic area disadvantage) were not associated with increased odds of LLE. CONCLUSIONS: The results suggest that adverse prenatal and perinatal environments are important in the etiology of LLE in twins at age 2. It is important that health professionals discuss twin pregnancy and birth risks for delayed speech and language milestones with parents and provide ongoing developmental monitoring for all twins, not just twins with overt disability. PMID- 29415682 TI - Effects of eating dinner alone on overweight in Japanese adolescents: a cross sectional survey. AB - BACKGROUND: The decrease in the frequency of family meals among Asian youth is often lamented. In Japan, adolescents who eat breakfast alone might have an unhealthy diet, which increases the risk of overweight or obese. However, there are few studies on the relationship between eating dinner alone and overweight in Japanese adolescents. Here, we investigated if eating dinner alone is associated with being overweight in Japanese adolescents of each sex. METHODS: The participants consisted of 890 seventh graders (12-13 years of age) from the junior high schools of Ina, Japan who were recruited from 2011 to 2012. Information about eating dinner alone was obtained using a self-reported questionnaire, which was given to each participant. The participants were classified into the following three groups: does not eat alone, eats alone 1-2 times/week, or eats alone >=3 times/week. A logistic regression model was used to examine the relationship between eating dinner alone and being overweight. The height and weight of each participant were measured. Childhood overweight status was defined using the body mass index cutoff points proposed by the International Obesity Task Force. RESULTS: When compared with girls who did not eat dinner alone, a significantly increased odds ratio (OR) was observed among girls who ate dinner alone >=1 time/week (adjusted OR = 2.78; 95% confidence interval = 1.21 6.38). In contrast, there was no statistically significant difference between eating dinner alone and being overweight among boys. CONCLUSION: The present study found that eating dinner alone is associated with being overweight among adolescent girls in this community in Japan. Therefore, reducing the frequency of eating dinner alone might contribute to decreasing the risk for becoming overweight or obese among adolescent girls. PMID- 29415683 TI - The risks, needs and stages of recovery of a complete forensic patient cohort in an Australian state. AB - BACKGROUND: Routine outcome measures are increasingly being mandated across mental health services in Australia and overseas. This requirement includes forensic mental health services, but their utility in such specialist services and the inter-relationships between the measures remain unclear. This study sought to characterise the risks, needs and stages of recovery of an entire cohort of forensic patients in one jurisdiction in Australia. METHODS: Local expert groups, comprising of members of the forensic patient treating teams, were formed to gather information about the status and needs of all forensic patients in the State of New South Wales, Australia. The expert groups provided demographic information and completed three assessment tools concerning the risks, needs and stages of recovery of each forensic patient. RESULTS: The cohort of 327 forensic patients in NSW appears to be typical of forensic mental health service populations internationally when considering factors such as gender, diagnosis, and index offence. A number of important differences across the three structured tools for forensic patients in different levels of secure service provision are presented. The DUNDRUM Quartet demonstrated interesting findings, particularly in terms of the therapeutic security needs, the treatment completion, and the stages of recovery for the forensic patients in the community. The CANFOR highlighted the level of needs across the forensic patient population, whilst the HCR-20 data showed there was no significant difference in the mean clinical and risk management scores between male forensic patients across levels of security. CONCLUSIONS: To the authors' knowledge this is the first study of its kind in New South Wales, Australia. We have demonstrated the utility of using a suite of measures to evaluate the risks, needs, and stages of recovery for an entire cohort of forensic patients. The data set helps inform service planning and development, together with providing various avenues for future research. PMID- 29415684 TI - Effects of combat training on visuomotor performance in children aged 9 to 12 years - an eye-tracking study. AB - BACKGROUND: Data on visuomotor performance in combat training and the effects of combat training on visuomotor performance are limited. This study aimed to investigate the effects of a specially designed combat sports (CS) training program on the visuomotor performance levels of children. METHODS: A pre-post comparative design was implemented. A total of 26 students aged 9-12 years underwent 40-min CS training sessions twice a week for 8 weeks during their physical education classes. The CS training program was designed by a karate coach and a motor control specialist. The other 30 students continued their regular activities and were considered as a control group. Each student's eye movement was monitored using an eye tracker, whereas the motor performance was measured using a target hitting system with a program-controlled microprocessor. The measurements were taken 8 weeks before (baseline), 1 day before (pretest), and 1 week after (posttest) the designated training program. The task used for evaluating these students was hitting or tracking random illuminated targets as rapidly as possible. A two-way analysis of variance [group(2) * time(3)] with repeated measures of time was performed for statistical analysis. RESULTS: For the children who received combat training, although the eye response improvement was not significant, both the primary and secondary saccade onset latencies were significantly earlier compared to the children without combat training. Both groups of students exhibited improvement in their hit response times during the target hitting tasks. CONCLUSION: The current finding supported the notion that sports training efforts essentially enhance visuomotor function in children aged 9-12 years, and combat training facilitates an earlier secondary saccade onset. PMID- 29415685 TI - Gluten-free diet may improve obstructive sleep apnea-related symptoms in children with celiac disease. AB - BACKGROUND: Enlarged tonsils and adenoids are the major etiology of obstructive sleep apnea (OSA) in children. Lymphatic hyperplasia is common to both OSA and celiac disease. We aimed to investigate the effect of a gluten-free diet on OSA symptoms in children with celiac disease. METHODS: Children with celiac disease aged 2-18 years were prospectively recruited before the initiation of a gluten free diet. Children with negative celiac serology who underwent gastrointestinal endoscopies for other indications served as controls. All participants completed a validated OSA-related symptoms questionnaire and the pediatric sleep questionnaire (PSQ) at baseline and 6 months later. RESULTS: Thirty-four children with celiac disease (mean age 6.6 +/- 3.5 years) and 24 controls (mean age 7.3 +/ 4.6 years, P = 0.5) were recruited. There were no significant differences in gender, body mass index or season at recruitment between the two groups. The rate of positive PSQ scores was higher (more OSA-related symptoms) in the control group compared to the celiac group, both at recruitment and at the 6-month follow up (33.3% vs. 11.8%, P = 0.046, and 16.7% vs. 0, P = 0.014, respectively). PSQ scores improved significantly in both groups at the 6-month follow-up (P < 0.001 for both). Improvement was significantly higher in the celiac group compared to controls (0.1 +/- 0.09 vs.0.06 +/- 0.06, respectively, P = 0.04). CONCLUSIONS: Children with celiac disease had fewer OSA-related symptoms than controls, but the degree of improvement following the initiation of a gluten-free diet was significantly higher. These findings suggest that a gluten-free diet may improve OSA-related symptoms in children with celiac disease. PMID- 29415686 TI - Prenatal and accurate perinatal diagnosis of type 2 H or ductular duplicate gallbladder. AB - BACKGROUND: Double gallbladder is a rare biliary anomaly. Perinatal diagnosis of the disorder has been reported in only 6 cases, and in 5 of them the diagnosis was based on ultrasound imaging only. However, the ultrasound technique alone does not provide a sufficiently precise description of cystic ducts and biliary anatomy, an information that is crucial for a correct classification and for a possible future surgery. CASE PRESENTATION: At 21 weeks of gestational age of an uneventful pregnancy in a 38 year old primipara mother, a routine ultrasound screening detected a biliary anomaly in the fetus suggestive of a double gallbladder. A neonatal abdominal ultrasonography performed on postnatal day 2 confirmed the diagnosis. On day 12 the newborn underwent a Magnetic Resonance Cholangiopancreatography (MRCP) that clearly characterized the anatomy of the anomaly: both gallbladders had their own cystic duct and both had a separate insertion in the main biliary duct. CONCLUSIONS: We report a case of early prenatal suspected duplicate gallbladder that was confirmed by a neonatal precise diagnosis of a Type 2, H or ductular duplicate gallbladder, using for the first time 3D images of Magnetic resonance cholangiopancreatography in a newborn. An accurate anatomical diagnosis is mandatory in patients undergoing a possible future cholecystectomy, to avoid surgical complications or reoperations. Therefore, in case of a perinatal suspicion of a double gallbladder, neonates should undergo a Magnetic resonance cholangiopancreatography. A review of the Literature about this variant is included. PMID- 29415687 TI - A physical activity intervention for children with type 1 diabetes- steps to active kids with diabetes (STAK-D): a feasibility study. AB - BACKGROUND: This study describes the development and feasibility evaluation of a physical activity intervention for children with type 1 diabetes called 'Steps to Active Kids with Diabetes' (STAK-D). It aims to explore the feasibility and acceptability of the intervention and study design. METHODS: Thirteen children aged 9-11 years and their parents were recruited from one paediatric diabetes clinic. A process evaluation was conducted alongside a two-arm randomised feasibility trial, including assessment of rate of recruitment, adherence, retention, data completion and burden, implementation fidelity and adverse events. Qualitative interviews with children (n = 9), parents (n = 8), healthcare professionals (n = 3) and STAK-D volunteers (n = 8) explored intervention acceptability. Interviews were analysed thematically. RESULTS: Rate of recruitment was 25%, with 77% retention at 3-month follow-up. Study burden was low, data completion was high and the intervention was delivered as per protocol. No serious adverse event was reported. Engagement with intervention materials was generally good, but attendance at group activity sessions was low due to logistical barriers. Interview analysis identified preferred methods of recruitment, motivations for recruitment, barriers and facilitators to adherence, the experience of data collection, experience of the STAK-D programme and its perceived benefits. CONCLUSIONS: STAK-D was feasible and acceptable to children, their parents and healthcare professionals, but group sessions may present logistical issues. Recruitment and retention may be improved with a clinic-wide approach to recruitment. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT02144337 (16/01/2014). PMID- 29415688 TI - Risk of dementia in patients with primary insomnia: a nationwide population-based case-control study. AB - BACKGROUND: To investigate the association between primary insomnia and dementia using a Taiwanese population-based database. METHODS: This case-control study involved a subset of Taiwan's National Health Insurance Research Database of reimbursement claims. We included 51,734 patients who were diagnosed with primary insomnia from 2002 to 2004 as the test group and 258,715 nonprimary insomnia participants aged 20 years or older as the reference group. We excluded patients under 20 and those with depression, post-traumatic stress disorder, and/or sleep disorders caused by organic lesion(s), drugs, or alcohol. We used a Cox proportional hazards model to assess the primary insomnia on the risk of developing dementia after adjusting for sociodemographic characteristics and comorbidities. RESULTS: The primary insomnia cohort had a higher prevalence of diabetes, dyslipidemia, hypertension, coronary heart disease, chronic liver disease, and chronic kidney disease at baseline. After adjusting for select comorbidities, primary insomnia remained a significant predisposing factor for developing dementia, and was associated with a 2.14-fold (95% confidence interval, 2.01-2.29) increase in dementia risk. We also found a higher risk of dementia in younger patients. CONCLUSIONS: Taiwanese patients with primary insomnia, especially those under 40, had a higher risk of developing dementia than those without primary insomnia. PMID- 29415689 TI - Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study. AB - BACKGROUND: Lithium remains first choice as maintenance treatment for bipolar affective disorder. Yet, about half of all individuals may stop their treatment at some point, despite lithium's proven benefits concerning the prevention of severe affective episodes and suicide. METHODS: Retrospective cohort study in the Swedish region of Norrbotten into the causes of lithium discontinuation. The study was set up to (1) test whether patients with bipolar affective disorder or schizoaffective disorder, treated with lithium maintenance therapy, were more likely to discontinue lithium because of adverse effects than lack of therapeutic effectiveness, (2) explore gender differences, (3) understand the role of diagnosis and (4) identify who, patient or doctor, took the initiative to stop lithium. Review of medical records for all episodes of lithium discontinuation that had occurred between 1997 and 2013 with the intent to stop lithium for good. RESULTS: Of 873 patients treated with lithium, 54% discontinued lithium, corresponding to 561 episodes of lithium discontinuation. In 62% of episodes, lithium was discontinued due to adverse effects, in 44% due to psychiatric reasons, and in 12% due to physical reasons interfering with lithium treatment. The five single most common adverse effects leading to lithium discontinuation were diarrhoea (13%), tremor (11%), polyuria/polydipsia/diabetes insipidus (9%), creatinine increase (9%) and weight gain (7%). Women were as likely as men to take the initiative to stop lithium, but twice as likely to consult a doctor before taking action (p < 0.01). Patients with type 1 BPAD or SZD were more likely to discontinue lithium than patients with type 2 or unspecified BPAD (p < 0.01). Patients with type 1 BPAD or SZD were more likely to refuse medication (p < 0.01). Conversely, patients with type 2 or unspecified BPAD were three times as likely to discontinue lithium for lack or perceived lack of effectiveness (p < 0.001). CONCLUSIONS: Stopping lithium treatment is common and occurs mostly due to adverse effects. It is important to discuss potential adverse effects with patients before initiation and continuously during lithium treatment, to reduce the frequency of potentially unnecessary discontinuations. PMID- 29415690 TI - The role of venues in structuring HIV, sexually transmitted infections, and risk networks among men who have sex with men. AB - BACKGROUND: Venues form part of the sampling frame for time-location sampling, an approach often used for HIV surveillance. While sampling location is often regarded as a nuisance factor, venues may play a central role in structuring risk networks. We investigated individual reports of risk behaviors and infections among men who have sex with men (MSM) attending different venues to examine structuring of HIV risk behaviors. However, teasing apart 'risky people' from 'risky places' is difficult, as individuals cannot be randomized to attend different venues. However, we can emulate this statistically using marginal structural models, which inversely weight individuals according to their estimated probability of attending the venue. METHODS: We conducted a cross sectional survey of 609 MSM patrons of 14 bars in San Diego, California, recruited using the Priorities for Local AIDS Control Efforts (PLACE) methodology, which consists of a multi-level identification and assessment of venues for HIV risk through population surveys. RESULTS AND DISCUSSION: Venues differed by many factors, including participants' reported age, ethnicity, number of lifetime male partners, past sexually transmitted infection (STI), and HIV status. In multivariable marginal structural models, venues demonstrated structuring of HIV+ status, past STI, and methamphetamine use, independently of individual-level characteristics. CONCLUSIONS: Studies using time-location sampling should consider venue as an important covariate, and the use of marginal structural models may help to identify risky venues. This may assist in widespread, economically feasible and sustainable targeted surveillance and prevention. A more mechanistic understanding of how 'risky venues' emerge and structure risk is needed. PMID- 29415691 TI - Disparities in severe shigellosis among adults - Foodborne diseases active surveillance network, 2002-2014. AB - BACKGROUND: Shigella causes approximately 500,000 illnesses, 6000 hospitalizations, and 40 deaths in the United States annually, but incidence and populations at risk for severe shigellosis among adults are unclear. This study describes severe shigellosis among US adults. METHODS: We analyzed Foodborne Diseases Active Surveillance Network data for infections caused by Shigella among adults >=18 years old during 2002-2014. Criteria to define severe shigellosis included hospitalization, bacteremia, or death. We estimated annual incidence of shigellosis per 100,000 among adult populations, and conducted multivariable mixed-effects logistic regression to assess associations between severe shigellosis, demographic factors and Shigella species among adults with shigellosis. RESULTS: Among 9968 shigellosis cases, 2764 (28%) were severe. Restricting to cases due to S. sonnei and S. flexneri, median annual incidence of severe shigellosis among adults was 0.56 and highest overall incidence was among black males 18-49 years old (1.58). Among adults with shigellosis, odds of severe disease were higher among males than females aged 18-49 years old (OR [95% CI] = 1.32 [1.15-1.52], p < 0.001) and among males than females with S. flexneri infections (OR [95% CI] =1.39 [1.10-1.75], p = 0.005). The odds of severe shigellosis were higher among blacks than whites (OR [95% CI] = 1.36 [1.22-1.52], p < 0.001). CONCLUSIONS: Among adults, men 18-49 years old, particularly blacks, have the highest incidence of severe shigellosis. Among adults with shigellosis, severe shigellosis was associated with being male in age group 18-49 years, with infections caused by S. flexneri, and with black race. Future research should assess associations between severe shigellosis and sexual practices, antimicrobial resistance, comorbidities, and access to care. PMID- 29415692 TI - Marketing messages accompanying online selling of low/er and regular strength wine and beer products in the UK: a content analysis. AB - BACKGROUND: Increased availability of low/er strength alcohol products has the potential to reduce alcohol consumption if they are marketed as substitutes for higher strength products rather than as additional products. The current study compares the main marketing messages conveyed by retailers and producers for low/er and regular strength wine and beer products. METHODS: A content analysis of the marketing messages stated (in text) or depicted (in image) for low/er and regular strength wines and beers sold online on the websites of the four main UK retailers (Tesco, ASDA, Sainsbury's, and Morrisons), and the producers of these products between February-March 2016. RESULTS: Four themes were identified: (a) suggested occasions for consumption, (b) health-related associations, (c) alcohol content, and (d) taste. Compared with regular strength products, low/er strength equivalents were more often marketed in association with occasions deemed to be suitable for their consumption including lunchtimes [wine: X 2 (1, n = 172) = 11.75, p = .001], outdoor events/barbeques [beer: X 2 (1, n = 96) = 11.16, p = .001] and on sport/fitness occasions [beer: X 2 (1, n = 96) = 7.55, p = .006]. Compared with regular strength wines and beers, low/er strength equivalents were more frequently marketed with images or text associated with health. These included images of fruit [wine: X 2 (1, n = 172) = 7.78, p = .005; beer: X 2 (1, n = 96) = 22.00, p < .001] and the provision of their energy (calorie) content [wine: X 2 (1, n = 172) = 47.97, p < .001; beer: X 2 (1, n = 96) = 15.10, p < .001]. Low/er strength products were also more often marketed with information about their alcohol content. There were few differences in the marketing messages regarding taste. CONCLUSIONS: Low/er strength wines and beers appear to be marketed not as substitutes for higher strength products but as ones that can be consumed on additional occasions with an added implication of healthiness. PMID- 29415693 TI - Elucidating mechanistic insights into drug action for atopic dermatitis: a systems biology approach. AB - BACKGROUND: Topical Betamethasone (BM) and Pimecrolimus (PC) are widely used drugs in the treatment of atopic dermatitis (AD). Though the biomolecules and biological pathways affected by the drugs are known, the causal inter relationships among these pathways in the context of skin is not available. We aim to derive this insight by using transcriptomic data of AD skin samples treated with BM and PC using systems biology approach. METHODS: Transcriptomic datasets of 10 AD patients treated with Betamethasone and Pimecrolimus were obtained from GEO datasets. We used a novel computational platform, eSkIN ( www.persistent.com/eskin ), to perform pathway enrichment analysis for the given datasets. eSkIN consists of 35 skin specific pathways, thus allowing skin-centric analysis of transcriptomic data. Fisher's exact test was used to compute the significance of the pathway enrichment. The enriched pathways were further analyzed to gain mechanistic insights into the action of these drugs. RESULTS: Our analysis highlighted the molecular details of the mechanism of action of the drugs and corroborated the known facts about these drugs i.e. BM is more effective in triggering anti-inflammatory response but also causes more adverse effect on skin barrier than PC. In particular, eSkIN helped enunciate the biological pathways activated by these drugs to trigger anti-inflammatory response and its effect on skin barrier. BM suppresses pathways like TNF and TLRs, thus inhibiting NF-kappaB while PC targets inflammatory genes like IL13 and IL6 via known calcineurin-NFAT pathway. Furthermore, we show that the reduced skin barrier function by BM is due to the suppression of activators like AP1 transcription factors, CEBPs. CONCLUSION: We thus demonstrate the detailed mechanistic insight into drug action of AD using a novel computational approach. PMID- 29415694 TI - In-vivo study of osseointegration in Prestige LP cervical disc prosthesis. AB - BACKGROUND: A study was designed to quantify the extent of porous osseointegration at the prosthesis-bone interface in the Prestige LP prosthesis containing a plasma-sprayed titanium coating. METHODS: Using an anterior surgical approach, cervical disc arthroplasty was performed in 8 mature male goats at the C3-C4 segment, followed by implantation of the Prestige LP prosthesis. The vertebral specimens were examined using microcomputed tomograph for histomorphometric quantification, and proceeded by routine paraffin processing for histological observation. Hence, the porous osseointegration at the prosthesis-bone interface was evaluated based on histologic and histomorphometric analyses. RESULTS: At 6 months after surgery, there was no evidence of prosthesis migration, loosening, subsidence, or neurologic or vascular complications. Based on gross histologic analysis, there was excellent porous ingrowth at the prosthesis-bone interface, without significant histopathologic changes. Histomorphometric analysis at the prosthesis-bone interface indicated the mean porous ingrowth of 48.5% +/- 10.4% and the total ingrowth range of 36.6 to 59.8%. CONCLUSIONS: As the first comprehensive in vivo investigation into the Prestige LP prosthesis, this project established a successful animal model in the evaluation of cervical disc arthroplasty. Moreover, histomorphometric analysis of porous ingrowth at the prosthesis-bone interface was more favorable for cervical disc arthroplasty with the Prestige LP prosthesis compared to historical reports of appendicular total joint arthroplasty. PMID- 29415695 TI - Bi-directional association between sleep and outdoor active play among 10-13 year olds. AB - BACKGROUND: The purpose of this study was to investigate whether there is a bi directional relationship between sleep characteristics (time in bed, sleep duration, sleep chronology, and sleep efficiency) and time spent participating in outdoor active play among children. METHODS: Participants consisted of 433 children aged 10-13 years from Kingston, ON, Canada. Time in bed, sleep duration, sleep chronology, and sleep efficiency were measured for 8 consecutive nights using data from a sleep log and Actical accelerometer. Outdoor active play was measured for the 7 days that fell in between these 8 nights using a combination of data from accelerometers, global positioning system loggers, and geographic information systems. Generalized estimating equation models were used to assess the relationships between sleep characteristics and outdoor active play. These models accounted for the repeated measures nested within participants and adjusted for several confounders (e.g., age, sex, family income, neighborhood traffic and green space). RESULTS: Time in bed, sleep duration, sleep chronology, and sleep efficiency were not significantly associated with the following day's outdoor active play. There was a significant (p = 0.017) association between outdoor active play and the following night's time in bed, which suggested that each hour increase in outdoor active play was associated with a 4.0 min increase in time in bed. Outdoor active play was not significantly associated with sleep duration, sleep chronology, or sleep efficiency. CONCLUSIONS: None of the sleep characteristics predicted the following day's outdoor active play. Increase time spent in outdoor active play predicted a longer time in bed, but not sleep duration, sleep chronology, or sleep efficiency. PMID- 29415696 TI - Osteoporosis knowledge and beliefs in diabetic patients: a cross sectional study from Palestine. AB - BACKGROUND: Osteoporosis is a potential metabolic complication of diabetes mellitus (DM). Therefore, patients with DM should have adequate osteoporosis knowledge and beliefs in order to get engaged in osteoporosis preventive behaviors. The objective of this study was to assess osteoporosis knowledge and beliefs among diabetic patients. METHODS: This was a cross sectional study carried out at Al-Makhfiah governmental primary healthcare unit in Nablus, Palestine from September 2016 to December 2016. The tools used to assess knowledge and beliefs were Osteoporosis Health Belief Scale (OHBS) and the Osteoporosis Knowledge Test (OKT) respectively. RESULTS: Three hundred diabetic patients were interviewed regarding their knowledge and belief about osteoporosis. The study sample included 192 (64.0%) females. Mean +/- standard deviation (SD) of the participants was 58.5 +/- 9.3 years. Regarding co morbidities, 229 (76.3%) had at least one co-morbidity other than DM. The majority of participants incorrectly answered 19 out of 32 questions of OKT scale. The mean OKT score was 13.5 +/- 4.2 indicating poor osteoporosis - related knowledge. Females had significantly higher nutrition (p = 0.037), exercise (p = 0.043), and OKT score (p = 0.021) than males. Regarding OHBS, female participants had significantly higher belief score of susceptibility (p < 0.01) and seriousness (p < 0.01) of osteoporosis compared to males. CONCLUSIONS: Diabetic patients had poor osteoporosis knowledge and moderate perception of susceptibility and seriousness of osteoporosis. These results require implementation of awareness programs among DM patients to increase their practices regarding preventive measures of osteoporosis such as calcium intake and exercise. PMID- 29415697 TI - Study protocol of a randomized controlled trial to test the effect of a smartphone application on oral-health behavior and oral hygiene in adolescents with fixed orthodontic appliances. AB - BACKGROUND: Adolescents with fixed orthodontic appliances are at high risk of developing dental caries. To date, new smartphone technologies have seldom been used to support them in the preventive behavior that can help prevent dental caries. After an intervention-mapping process, we developed a smartphone application (the WhiteTeeth app) for preventing dental caries through improved oral-health behavior and oral hygiene. The app, which is intended to be used at home, will help adolescents with fixed orthodontic appliances perform their oral self-care behavior. The app is based on the Health Action Process Approach (HAPA) theory, and incorporates several behavior-change techniques that target the psychosocial factors of oral-health behavior. This article describes the protocol of a randomized controlled trial (RCT) to evaluate the effects of the WhiteTeeth app on oral-health behavior and oral-hygiene outcomes (presence of dental plaque and gingival bleeding) compared with those of care as usual, in patients aged 12 16 with fixed orthodontic appliances. METHODS/DESIGN: The RCT has two conditions: an experimental group that will receive the WhiteTeeth app in addition to care as usual, and a control group that will only receive care as usual. Care as usual will include routine oral-health education and instruction at orthodontic check ups. In the western part of the Netherlands 146 participants will be recruited from four orthodontic clinics. Data will be collected during three orthodontic check-ups: baseline (T0), 6 weeks of follow-up (T1) and 12 weeks of follow-up (T2). The primary study outcomes are the presence of dental plaque (measured with a modified Silness and Loe Plaque Index); and gingival bleeding (measured with the Bleeding on Marginal Probing Index). Secondary outcomes include changes in self-reported oral-health behaviors and its psychosocial factors identified by the HAPA theory, such as outcome expectancies, intention, action self-efficacy, coping planning and action control. DISCUSSION: Since the intervention was designed to target psychosocial factors in the motivational and volitional components of the behavior-change process, we hypothesize that the app will cause greater improvements in oral-health behavior and oral hygiene more than traditional oral-health-promotion programs (i.e., care as usual). TRIAL REGISTRATION: The trial has been registered with the Dutch Trial Register ( NTR6206 : 20 February 2017). PMID- 29415698 TI - Nutritional quality of new food products released into the Australian retail food market in 2015 - is the food industry part of the solution? AB - BACKGROUND: Food manufacturers have made public statements and voluntary commitments, such as the Healthier Australia Commitment (HAC), to improve the nutritional quality of foods. However, limited information about the nutritional quality or healthfulness of new products makes it difficult to determine if manufacturers are doing this. The purpose of this study was to assess the healthfulness of new food products released into the Australian retail market in 2015, and whether those companies who were HAC members released healthier food options compared to non-HAC members. METHODS: This cross-sectional study assessed the healthfulness of all new retail food products launched in Australia in 2015 as indexed in Mintel's Global New Products Database. Healthfulness was assessed using three classification schemes: Healthy Choices Framework Victoria, Australian Dietary Guidelines and NOVA Food Classification System. Descriptive statistics and chi-squared tests described and compared the number and proportions of new foods falling within each of the food classification schemes' categories for companies that were and were not HAC members. RESULTS: In 2015, 4143 new food products were launched into the Australian market. The majority of new products were classified in each schemes' least healthy category (i.e. red, discretionary and ultra-processed). Fruits and vegetables represented just 3% of new products. HAC members launched a significantly greater proportion of foods classified as red (59% vs 51% for members and non-members, respectively) discretionary (79% vs 61%), and ultra-processed (94% vs 81%), and significantly fewer were classified as green (8% vs 15%), core foods (18% vs 36%) and minimally processed (0% vs 6%) (all p < 0.001). CONCLUSIONS: This study found that the majority of new products released into the Australian retail food market in 2015 were classified in each of three schemes' least healthy categories. A greater proportion of new products launched by companies that publicly committed to improve the nutritional quality of their products were unhealthy, and a lower proportion were healthy, compared with new products launched by companies that did not so commit. Greater monitoring of industry progress in improving the healthfulness of the food supply may be warranted, with public accountability if the necessary changes are not seen. PMID- 29415699 TI - Can an app supporting psoriasis patients improve adherence to topical treatment? A single-blind randomized controlled trial. AB - BACKGROUND: Topical corticosteroid or corticosteroid/calcipotriol preparations are recommended first-line topical treatments of psoriasis, but a main cause for the lack of efficacy of topical treatments is considered low rates of adherence to topical drugs. Patient support by the use of applications (apps) for smartphones is suggested to improve medical adherence. METHODS/DESIGN: Design: An investigator-initiated, single-center, single-blind, parallel-group, phase-4 clinical superiority randomized controlled trial (RCT). PARTICIPANTS: 134 patients 18 to 75 years of age with mild-to-moderate psoriasis, who are capable of reading English language, own a smartphone, and are candidates for the study drug calcipotriol and betamethasone dipropionate (Cal/BD) cutaneous foam once daily prn (pro re nata). INTERVENTION: A 28-day adherence-supporting app providing compulsory daily treatment reminders that pop-up on the smartphone screen with a short alert sound. The app synchronizes through Bluetooth(r) to an electronic monitor (EM) attached to the medication canister. The EM contains a chip registering the amount of foam, day and time the patient use the foam dispenser. The information is displayed in a diary that shows the amount of Cal/BD cutaneous foam used and the number of applied treatment sessions. The app has an optional diary with the patient's rating of symptoms. Non-intervention: Use of Cal/BD cutaneous foam and EM without the app. All participants are prescribed Cal/BD cutaneous foam prn for the entire study period. Primary outcome obtained in week 4: rates of adherence measured by patient report, weight of medication canisters, and number of treatment sessions measured by the EM. Secondary outcomes obtained at baseline, weeks 4, 8, and 26: Lattice System Physician's Global Assessment (LS-PGA) and Dermatology Quality of Life Index (DLQI). DISCUSSION: This trial tests of whether an app can improve rates of adherence to a topical antipsoriatic drug. If the app improves rates of adherence and reduces the burden of psoriasis in a clinically significant way, the app could easily be implemented as a standard routine of care in the clinic. TRIAL REGISTRATION: NCT02858713 , registered on August 3, 2016. EudraCT number 2016 002143-42. PMID- 29415700 TI - Health promotion initiatives at school related to overweight, insulin resistance, hypertension and dyslipidemia in adolescents: a cross-sectional study in Recife, Brazil. AB - BACKGROUND: The emergence of diseases such as dyslipidemia, systemic arterial hypertension, insulin resistance and metabolic syndrome in children and adolescents has brought about a change in the epidemiologic profile of the pediatric population. As action to promote health in the school environment is a useful tool for changing the pattern of health/disease in the young population, the present study aimed to identify schools that promote healthy eating and physical activity and to study the relationship between these practices and the prevalence of overweight, hypertension, insulin resistance and hypercholesterolemia in adolescents. METHODS: A cross-sectional population-based study was conducted with 2400 adolescents aged from 12 to 17 years old and participating in the "Study of Cardiovascular Risk in Adolescents" (ERICA - Estudo de Riscos Cardiovasculares em Adolescente). The association between dependent (overweight, insulin resistance, hypertension and dyslipidemia) and independent variables (implementation of health promoting initiative in schools) was investigated using the chi-square test and prevalence ratio (PR) with a confidence index (CI) of 95%. RESULTS: The unsatisfactory implementation of a "health promoting environment" (PR = 1.02; CI 95%: 1.0; 1.04) and "partnerships with the health sector" (PR = 1.03; CI 95%: 1.01; 1.05) were linked to a high prevalence of overweight in adolescents. Hypercholesterolemia was found to be higher in the schools with unsatisfactory implementation of "healthy eating and health on the scholar curriculum" (PR = 1.71; CI 95%: 1.22; 2.44) and those lacking a "healthy-eating promoting environment" (PR = 1.29; CI 95%: 1.10; 1.54). Schools with unsatisfactory implementation of a "health-eating promoting environment" (PR = 1.36; CI 95%: 1.04; 1.79) and those lacking "partnership with the health sector" (PR = 2.12; CI 95%: 1.38; 3.24) had more adolescents with insulin resistance. There was no association between hypertension and any other component studied. CONCLUSION: Schools which have implemented adequate health promotion in their curriculums showed a lower prevalence of overweight, insulin resistance and hypercholesterolemia in adolescents. PMID- 29415701 TI - The relationship between high-dose corticosteroid treatment and mortality in acute respiratory distress syndrome: a retrospective and observational study using a nationwide administrative database in Japan. AB - BACKGROUND: In the 1980s, randomized-controlled trials showed that high-dose corticosteroid treatment did not improve the mortality of acute respiratory distress syndrome (ARDS). However, while the diagnostic criteria for ARDS have since changed, and supportive therapies have been improved, no randomized controlled trials have revisited this issue since 1987; thus, the effect of high dose corticosteroid treatment may be different in this era. We evaluated the effect of high-dose corticosteroid treatment in patients with ARDS using a nationwide administrative database in Japan in a retrospective and observational study. METHODS: This study was performed with a large population using the 2012 Japanese nationwide administrative database (diagnostic procedure combination). We evaluated the mortality of ARDS patients receiving or not receiving high-dose corticosteroid treatment within 7 days of hospital admission. We employed propensity score weighting with a Cox proportional hazards model in order to minimize the bias associated with the retrospective collection of data on baseline characteristics and compared the mortality between the high-dose and non high-dose corticosteroid groups. RESULTS: Data from 2707 patients were used; 927 patients were treated with high-dose corticosteroid and 1780 patients were treated without high-dose corticosteroid, within 7 days of admission. After adjusting for confounds, mortality rates within 3 months were significantly higher in the high-dose corticosteroid group compared to the non-high-dose corticosteroid group (weighted hazard ratio: 1.59; 95% CI: 1.37-1.84; P < 0.001). CONCLUSIONS: Our results suggest that high-dose corticosteroid treatment does not improve the prognosis of patients with ARDS, even in this era. However, this study has limitations owing to its retrospective and observational design. PMID- 29415702 TI - Eco-physiological basis of shade adaptation of Camellia nitidissima, a rare and endangered forest understory plant of Southeast Asia. AB - BACKGROUND: Camellia nitidissima, a rare and endangered shrub is narrowly distributed in South China and North Vietnam occurring in forest understory. Their light tolerance mechanism is unclear. We measured photosynthesis and related parameters on 2-years-old cuttings growing at 10, 30, 50 and 100% sunlight. Our research question was: At what light level are C. nitidissima cuttings responding most favorably, and what is the eco-physiological basis for their response to light? We hypothesized that as a forest understory growth of C. nitidissima would respond most favorably at low to intermediate light by optimizing photosynthetic activity, and high light will affect photosynthetic functions due to photoinhibition, damage of photosynthetic apparatus and concomitant enzyme activity. RESULTS: With increasing light, the maximum net photosynthetic rate (PNmax) and apparent quantum yield (AQY) decreased, while the light compensation point increased, and light saturation point first increased followed by a decrease. The PNmax and AQY under 50 and 100% sunlight were significantly lower than that under 10 and 30% sunlight. The chlorophyll fluorescence parameters Fm, Fv, Fv/Fm all decreased under high light (> 50%). The contents of chlorophyll a (Chla), chlorophyll b (Chlb), and carotenoid (Car) decreased with increasing light. Relative conductivity, malondialdehyde (MDA) and proline contents in leaves were significantly increased in high light but we found no significant difference in these indices at 10 and 30% sunlight. CONCLUSIONS: We conclude that C. nitidissima is a shade adapted plant with poor adaptability to high light (> 50%). The novelty of this research is the demonstration of the eco-physiological basis of its light tolerance (conversely, shade adaptation) mechanisms indicated by decreased photosynthetic activity, chlorophyll fluorescence, Chla, Chlb and Car contents and concomitant increase in relative conductivity, MDA and proline contents at high light causing photoinhibition. For artificial propagation of C. nitidissima we recommend growing cuttings below 30% sunlight. For in situ conservation of this valuable, rare and endangered shrub it is necessary to protect its natural habitats. PMID- 29415703 TI - FSH may be a useful tool to allow early diagnosis of Turner syndrome. AB - BACKGROUND: Ultrasensitive assays to measure pre-pubertal gonadotropins levels could help identify patients with Turner syndrome (TS) in mid-childhood, but studies in this field are scarce. The aim of this study was to analyze gonadotropins levels in girls with TS throughout childhood. METHODS: Retrospective longitudinal study conducted with 15 girls with TS diagnosed with < 5 years whose FSH and LH measures were available since then. Hormones were evaluated in newborn/mini-puberty (< 0.5 years), early childhood (0.5-5 years), mid-childhood (5-10 years) and late childhood/adolescence (> 10 years). In newborn/mini-puberty and late childhood/adolescence pre-pubertal or pubertal gonadotropins were considered normal; in early childhood and mid-childhood concentrations above the pre-pubertal range were considered abnormal. RESULTS: Abnormally high FSH alone was found in four of five patients in newborn/mini puberty, 13 of 15 during early childhood and nine of 15 during mid-childhood. In the group of 12 patients in late childhood/adolescence, the three girls with spontaneous puberty had only normal levels; the remaining showed only post menopausal concentrations. In mid-childhood one patient exhibited only pre pubertal FSH. Conversely, most LH measurements in early and mid-childhood were normal. CONCLUSION: Karyotyping of girls with short stature and high FSH levels would allow early diagnosis of Turner syndrome in a significant number of patients, particularly when resources for chromosome study of all girls with growth deficiency are limited. PMID- 29415704 TI - A new approach for detecting adventitious viruses shows Sf-rhabdovirus-negative Sf-RVN cells are suitable for safe biologicals production. AB - BACKGROUND: Adventitious viral contamination in cell substrates used for biologicals production is a major safety concern. A powerful new approach that can be used to identify adventitious viruses is a combination of bioinformatics tools with massively parallel sequencing technology. Typically, this involves mapping or BLASTN searching individual reads against viral nucleotide databases. Although extremely sensitive for known viruses, this approach can easily miss viruses that are too dissimilar to viruses in the database. Moreover, it is computationally intensive and requires reference cell genome databases. To avoid these drawbacks, we set out to develop an alternative approach. We reasoned that searching genome and transcriptome assemblies for adventitious viral contaminants using TBLASTN with a compact viral protein database covering extant viral diversity as the query could be fast and sensitive without a requirement for high performance computing hardware. RESULTS: We tested our approach on Spodoptera frugiperda Sf-RVN, a recently isolated insect cell line, to determine if it was contaminated with one or more adventitious viruses. We used Illumina reads to assemble the Sf-RVN genome and transcriptome and searched them for adventitious viral contaminants using TBLASTN with our viral protein database. We found no evidence of viral contamination, which was substantiated by the fact that our searches otherwise identified diverse sequences encoding virus-like proteins. These sequences included Maverick, R1 LINE, and errantivirus transposons, all of which are common in insect genomes. We also identified previously described as well as novel endogenous viral elements similar to ORFs encoded by diverse insect viruses. CONCLUSIONS: Our results demonstrate TBLASTN searching massively parallel sequencing (MPS) assemblies with a compact, manually curated viral protein database is more sensitive for adventitious virus detection than BLASTN, as we identified various sequences that encoded virus-like proteins, but had no similarity to viral sequences at the nucleotide level. Moreover, searches were fast without requiring high performance computing hardware. Our study also documents the enhanced biosafety profile of Sf-RVN as compared to other Sf cell lines, and supports the notion that Sf-RVN is highly suitable for the production of safe biologicals. PMID- 29415705 TI - Resource allocations and disparities in the Brazilian health care system: insights from organ transplantation services. AB - BACKGROUND: To date, few studies have assessed how Brazil's universal healthcare system's (SUS, Sistema Unico de Saude) systemic, infrastructural, and geographical challenges affect individuals' abilities to access organ transplantation services and receive quality treatment. DISCUSSION: In this article we evaluated the existing literature to examine the impact that SUS has had on an increasingly important healthcare sector: organ transplantation services. We assess how equity challenges within the transplantation system can be explained by wider problems within SUS. Findings suggest stark disparities in access to transplantation services both within and across Brazil's regions. We found that these regional differences are partially due to logistical challenges, especially in loosely populated areas but are also a consequence of disparities in resource allocations within SUS and under-capacitated health care facilities affecting transplantation services. We suggest that Brazil needs to improve its health outcome measurement system for organ transplantations and epidemiological surveillance, to gain more comprehensive and comparable data. Finally, we recommend policy strategies to reduce barriers to access to transplantation services by increasing transplantation service coverage in some areas and investing in emerging technologies. PMID- 29415706 TI - Dental caries prevention strategies among children and adolescents with immigrant - or low socioeconomic backgrounds- do they work? A systematic review. AB - BACKGROUND: This systematic review was designed to uncover the most reliable evidence about the effects of caries preventive strategies in children and adolescents of immigrant or low socioeconomic backgrounds. METHODS: According to pre-determined inclusion and exclusion criteria, relevant articles focusing on underprivileged groups were electronically selected between January1995 and October 2015. The literature search was conducted in five databases; PubMed, Embase, CINAHL, SweMed+ and Cochrane Library. Accepted languages for included articles were English, German and Scandinavian languages. Abstracts and selected articles in full text were read and assessed independently by two review authors. Systematic reviews and meta-analyses were not included. Also articles with topics of water fluoridation and fluoride toothpaste were excluded, this due to all existing evidence of anti-caries effect for disadvantaged groups. The key data about the main characteristics of the study were compiled in tables and a quality grading was performed. RESULTS: Thirty-seven articles were selected for further evaluation. Supervised toothbrushing for 5-year-old school children was found to be an effective prevention technique for use in underprivileged groups. Also a child/mother approach, targeting nutrition and broad oral health education of mothers showed effectiveness. For older children, a slow-release fluoride device and application of acidulated phosphate fluoride (APF) gel showed to be effective. CONCLUSION: On the basis of this review, we maintain that in addition to studies of water fluoridation and fluoride toothpaste, there are other preventive intervention studies providing scientific evidence for caries reduction among children and adolescents with immigrant or low socioeconomic backgrounds. PMID- 29415707 TI - Threatened species richness along a Himalayan elevational gradient: quantifying the influences of human population density, range size, and geometric constraints. AB - BACKGROUND: A crucial step in conserving biodiversity is to identify the distributions of threatened species and the factors associated with species threat status. In the biodiversity hotspot of the Himalaya, very little is known about which locations harbour the highest diversity of threatened species and whether diversity of such species is related to area, mid-domain effects (MDE), range size, or human density. In this study, we assessed the drivers of variation in richness of threatened birds, mammals, reptiles, actinopterygii, and amphibians along an elevational gradient in Nepal Himalaya. RESULTS: Although geometric constraints (MDE), species range size, and human population density were significantly related to threatened species richness, the interaction between range size and human population density was of greater importance. Threatened species richness was positively associated with human population density and negatively associated with range size. CONCLUSIONS: In areas with high richness of threatened species, species ranges tend to be small. The preponderance of species at risk of extinction at low elevations in the subtropical biodiversity hotspot could be due to the double impact of smaller range sizes and higher human density. PMID- 29415708 TI - IL-13 -1112 polymorphism and periodontitis susceptibility: a meta-analysis. AB - BACKGROUND: Several studies have examined the association between the IL-13 1112C/T polymorphism and the risk of periodontitis. However, these studies have reached different conclusions. The aim of the current study was to investigate the link between this IL-13 -1112 polymorphism and susceptibility to periodontitis. METHODS: We utilized electronic databases, including the CNKI (China National Knowledge Infrastructure), Wanfang, PubMed, Embase, and Cochrane Library databases, to manually search for relevant research published through November 30, 2016. The Chinese and English terms used to search the literature included "periodontitis", "periodontal disease", "IL 13", "IL-13", and "interleukin-13". In accordance with our inclusion criteria, we selected studies that involved case-control trials. All of these case-control trials described their objectives, design and specific statistical methods. For all included studies, odds ratios (ORs) and 95% confidence intervals (95% CIs) were provided or could be calculated from the study data. The quality of the included literature was evaluated using the Newcastle-Ottawa scale (NOS). STATA 12.0 was used to calculate the sizes of the combined effects and conduct a sensitivity analysis of the results. RESULTS: Our meta-analysis included 4 articles representing 5 case-control studies with a total of 710 cases and 671 control subjects. The meta-analysis results indicated that the CC vs TT model, CT vs TT model and TT vs CT + CC model (CC VS TT: OR = 0.615, 95% CI = 0.395-0.957; CT vs TT: OR = 0.518, 95% CI = 0.323-0.830; and TT vs CT + CC: OR = 1.739, 95% CI = 1.130-2.676) were significant in five IL-13 -1112 gene polymorphism and periodontitis susceptibility models. Subgroup analysis indicated that the CC vs TT, CT vs TT and TT vs CT + CC models were significant in the chronic periodontitis (CP) group, whereas no significant differences were found in the five aggressive periodontitis (AgP) group models. The sensitivity analysis showed that dropping any single study did not affect the pooled analysis results. CONCLUSION: The IL-13 -1112 polymorphism may be associated with susceptibility to periodontitis. The IL-13 -1112 gene polymorphism may be associated with susceptibility to CP but not to AgP. Thus, large-scale, multi-ethnic case-control trials are still warranted. PMID- 29415709 TI - An update on the "empirical turn" in bioethics: analysis of empirical research in nine bioethics journals. AB - BACKGROUND: A review of literature published a decade ago noted a significant increase in empirical papers across nine bioethics journals. This study provides an update on the presence of empirical papers in the same nine journals. It first evaluates whether the empirical trend is continuing as noted in the previous study, and second, how it is changing, that is, what are the characteristics of the empirical works published in these nine bioethics journals. METHOD: A review of the same nine journals (Bioethics; Journal of Medical Ethics; Journal of Clinical Ethics; Nursing Ethics; Cambridge Quarterly of Healthcare Ethics; Hastings Center Report; Theoretical Medicine and Bioethics; Christian Bioethics; and Kennedy Institute of Ethics Journal) was conducted for a 12-year period from 2004 to 2015. Data obtained was analysed descriptively and using a non-parametric Chi-square test. RESULTS: Of the total number of original papers (N = 5567) published in the nine bioethics journals, 18.1% (n = 1007) collected and analysed empirical data. Journal of Medical Ethics and Nursing Ethics led the empirical publications, accounting for 89.4% of all empirical papers. The former published significantly more quantitative papers than qualitative, whereas the latter published more qualitative papers. Our analysis reveals no significant difference (chi2 = 2.857; p = 0.091) between the proportion of empirical papers published in 2004-2009 and 2010-2015. However, the increasing empirical trend has continued in these journals with the proportion of empirical papers increasing from 14.9% in 2004 to 17.8% in 2015. CONCLUSIONS: This study presents the current state of affairs regarding empirical research published nine bioethics journals. In the quarter century of data that is available about the nine bioethics journals studied in two reviews, the proportion of empirical publications continues to increase, signifying a trend towards empirical research in bioethics. The growing volume is mainly attributable to two journals: Journal of Medical Ethics and Nursing Ethics. This descriptive study further maps the still developing field of empirical research in bioethics. Additional studies are needed to completely map the nature and extent of empirical research in bioethics to inform the ongoing debate about the value of empirical research for bioethics. PMID- 29415710 TI - Maternal mental health priorities, help-seeking behaviors, and resources in post conflict settings: a qualitative study in eastern Uganda. AB - BACKGROUND: Limited knowledge exists to inform the selection and introduction of locally relevant, feasible, and effective mental health interventions in diverse socio-cultural contexts and health systems. We examined stakeholders' perspectives on mental health-related priorities, help-seeking behaviors, and existing resources to guide the development of a maternal mental health component for integration into non-specialized care in Soroti, eastern Uganda. METHODS: We employed rapid ethnographic methods (free listing and ranking; semi-structured interviews; key informant interviews and pile sorting) with community health workers (n = 24), primary health workers (n = 26), perinatal women (n = 24), traditional and religious healers (n = 10), and mental health specialists (n = 9). Interviews were conducted by trained Ateso-speaking interviewers. Two independent teams conducted analyses of interview transcripts following an inductive and thematic approach. Smith's Salience Index was used for analysis of free listing data. RESULTS: When asked about common reasons for visiting health clinics, the most salient responses were malaria, general postnatal care, and husbands being absent. Amongst the free listed items that were identified as mental health problems, the three highest ranked concerns were adeka na aomisio (sickness of thoughts); ipum (epilepsy), and emalaria (malaria). The terms epilepsy and malaria were used in ways that reflected both biomedical and cultural concepts of distress. Sickness of thoughts appeared to overlap substantially with major depression as described in international classification, and was perceived to be caused by unsupportive husbands, intimate partner violence, chronic poverty, and physical illnesses. Reported help-seeking for sickness of thoughts included turning to family and community members for support and consultation, followed by traditional or religious healers and health centers if the problem persisted. CONCLUSION: Our findings add to existing literature that describes 'thinking too much' idioms as cultural concepts of distress with roots in social adversity. In addition to making feasible and effective treatment available, our findings indicate the importance of prevention strategies that address the social determinants of psychological distress for perinatal women in post-conflict low-resource contexts. PMID- 29415711 TI - Cross-sectional relationship of perceived familial protective factors with depressive symptoms in vulnerable youth. AB - BACKGROUND: There are multiple negative consequences associated with heavy episodic drinking and close associations between substance abuse and depression, alcohol-intoxicated adolescents (AIA) represent a vulnerable group. We aim to add to the current literature by investigating the cross-sectional relationship of perceived familial protective factors with depressive symptoms in AIA in hospitals, with respect to sex. Depression is among the 10 leading causes of disabilities during childhood and adolescence, with girls being more vulnerable than boys. Considerable evidence reveals a strong association between depression and alcohol abuse. The family provides the possibility to positively influence depressive symptoms. METHODS: We present cross-sectional data of a German multisite, epidemiological cohort study on AIA. By using youth's self-reports, we assessed sociodemographic data, as well as data on perceived familial protective factors and depressive symptoms using items of the Communities that Care Youth Survey instrument. We performed descriptive and multigroup analyses to evaluate the measurement invariance of the used instruments. Moreover, to investigate the relationships between the constructs, we used structural equation modelling. RESULTS: The study sample comprised 342 AIA, with a mean age of 15.5 years (SD = 1.2; 48.1% girls). The final structural equation model achieved an acceptable model fit of chi2 (69, 342) = 110.056; p = .001; TLI = 0.97; CFI = 0.98; RMSEA = 0.046; SRMR = 0.042, and the rewards for prosocial involvement in the family context correlated significantly negatively with present depressive symptoms, (beta = - 0.540, p < 0.001). The effects were stronger in boys (beta = - 0.576, p < 0.001) than in girls (beta = - 0.519, p < 0.001). CONCLUSION: In vulnerable youth in Germany, depressive symptoms are correlated to good experiences within the family. Future research should assess whether interventions that enhance parental support reduce the risk of depressive symptoms in AIA. Our findings highlight the need for family-based prevention programmes, particularly for AIA with an increased risk of depression. PMID- 29415712 TI - Anti-aging potential of extracts from Sclerocarya birrea (A. Rich.) Hochst and its chemical profiling by UPLC-Q-TOF-MS. AB - BACKGROUND: Degradation of components of the extracellular matrix such as elastin and collagen by elastase and collagenase accelerates skin aging. Phytochemicals that inhibit the activity of these enzymes can be developed as anti-aging ingredients. In this study, an investigation of the anti-aging properties of Sclerocarya birrea (A. Rich.) Hochst (Marula) extracts was conducted in vitro with the aim of developing chemically characterized anti-aging ingredients. METHODS: Marula stems, leaves and fruits were extracted using methanol:dichloromethane (DCM) (1:1). The stems were later extracted using acetone, ethanol, methanol:DCM (1:1) and sequentially using hexane, DCM, ethyl acetate and methanol. The stem ethanol extract was defatted and concentrated. Elastase and collagenase inhibition activities of these extracts and Marula oil were determined using spectrophotometric methods. The chemical profile of the ethanolic stem extract was developed using Ultra-performance-liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) with MassLynx software. Pure standards were used to confirm the identity of major compounds and were screened for anti-elastase and anti-collagenase activity. RESULTS: Marula stems extracts were the most active as they exhibited anti elastase activity comparable to that of elafin (> 88%) and anti-collagenase activity as potent as EDTA (> 76%). The leaf extract had moderate anti-elastase activity (54%) but was inactive agains collagenase. Marula fruits and oil exhibited limited activity in both assays. The ethanolic extract of Marula stems was the most suitable based on its acceptability to the cosmetic industry and its anti-collagenase activity (99%). Defatting and concentration improved its antiaging activity and lowered the colour intensity. Six compounds have been tentatively identified in the chemical profile of the ethanolic extract of Marula stems of which four; quinic acid, catechin, epigallocatechin gallate and epicatechin gallate have been confirmed using pure standards. Epigallocatechin gallate and epicatechin gallate were as potent (p < 0.05) as EDTA at 5 MUg/ml in the anti-collagenase assay. CONCLUSIONS: The ethanolic extract of Marula stems can be developed into an anti-aging ingredient as it exhibited very good in vitro anti-aging activity and its chemical profile has been developed. Epicatechin gallate and epigallocatechin gallate contribute to the anti-aging activity of Marula stem ethanol extract. PMID- 29415713 TI - A phosphoinositide map at the shoot apical meristem in Arabidopsis thaliana. AB - BACKGROUND: In plants, the shoot apical meristem (SAM) has two main functions, involving the production of all aerial organs on the one hand and self maintenance on the other, allowing the production of organs during the entire post-embryonic life of the plant. Transcription factors, microRNA, hormones, peptides and forces have been involved in meristem function. Whereas phosphatidylinositol phosphates (PIPs) have been involved in almost all biological functions, including stem cell maintenance and organogenesis in animals, the processes in meristem biology to which PIPs contribute still need to be delineated. RESULTS: Using biosensors for PI4P and PI(4,5)P2, the two most abundant PIPs at the plasma membrane, we reveal that meristem functions are associated with a stereotypical PIP tissue-scale pattern, with PI(4,5)P2 always displaying a more clear-cut pattern than PI4P. Using clavata3 and pin-formed1 mutants, we show that stem cell maintenance is associated with reduced levels of PIPs. In contrast, high PIP levels are signatures for organ-meristem boundaries. Interestingly, this pattern echoes that of cortical microtubules and stress anisotropy at the meristem. Using ablations and pharmacological approaches, we further show that PIP levels can be increased when the tensile stress pattern is altered. Conversely, we find that katanin mutant meristems, with increased isotropy of microtubule arrays and slower response to mechanical perturbations, exhibit reduced PIP gradients within the SAM. Comparable PIP pattern defects were observed in phospholipase A3beta overexpressor lines, which largely phenocopy katanin mutants at the whole plant level. CONCLUSIONS: Using phospholipid biosensors, we identified a stereotypical PIP accumulation pattern in the SAM that negatively correlates with stem cell maintenance and positively correlates with organ-boundary establishment. While other cues are very likely to contribute to the final PIP pattern, we provide evidence that the patterns of PIP, cortical microtubules and mechanical stress are positively correlated, suggesting that the PIP pattern, and its reproducibility, relies at least in part on the mechanical status of the SAM. PMID- 29415714 TI - Improving quality of care through patient-reported outcome measures (PROMs): expert interviews using the NHS PROMs Programme and the Swedish quality registers for knee and hip arthroplasty as examples. AB - BACKGROUND: Patient reported outcome measures (PROMs) have been integrated in national quality registries or specific national monitoring initiatives to inform the improvement of quality of care on a national scale. However there are many unanswered questions, such as: how these systems are set up, whether they lead to improved quality of care, which stakeholders use the information once it is available. The aim of this study was to examine supporting and hindering factors relevant to integrating patient-reported outcome measures (PROMs) in selected health information systems (HIS) tailored toward improving quality of care across the entire health system. METHODS: First, a systematic search and review was conducted to outline previously identified factors relevant to the integration of PROMs in the selected HIS. A social network analysis was performed to identify networks of experts in these systems. Second, expert interviews were conducted to discuss and elaborate on the identified factors. Directive content analysis was applied using a HIS Evaluation Framework as the frame of reference. This framework is structured into four components: Organization, Human, Technology, and Net benefits. RESULTS: The literature review revealed 37 papers for the NHS PROMs Programme and 26 papers for the SHPR and SKAR: Five networks of researchers were identified for the NHS PROMs Programme and 1 for the SHPR and SKAR. Seven experts related to the NHS PROMs Programme and 3 experts related to the SKAR and SHPR participated in the study. The main themes which revealed in relation to Organization were Governance and Capacity building; to Human: Reporting and Stakeholder Engagement; to Technology: the Selection and Collection of PROMs and Data linkage. In relation to Net benefits, system-specific considerations are presented. CONCLUSION: Both examples succeeded in integrating PROMs into HIS on a national scale. The lack of an established standard on what change PROMs should be achieved by an intervention limits their usefulness for monitoring quality of care. Whether the PROMs data collected within these systems can be used in routine clinical practice is considered a challenge in both countries. PMID- 29415715 TI - Hospital-acquired fever in oriental medical hospitals. AB - BACKGROUND: Traditional Oriental medicine is used in many Asian countries and involves herbal medicines, acupuncture, moxibustion, and cupping. We investigated the incidence and causes of hospital-acquired fever (HAF) and the characteristics of febrile inpatients in Oriental medical hospitals (OMHs). METHODS: Patients hospitalized in two OMHs of a university medical institute in Seoul, Korea, were retrospectively reviewed from 2006 to 2013. Adult patients with HAF were enrolled. RESULTS: There were 560 cases of HAF (5.0%). Infection, non-infection, and unknown cause were noted in 331 cases (59.1%), 109 cases (19.5%), and 120 cases (21.4%) of HAF, respectively. Respiratory tract infection was the most common cause (51.2%) of infectious fever, followed by urinary tract infection. Drug fever due to herbal medicine was the most common cause of non-infectious fever (53.1%), followed by procedure-related fever caused by oriental medical procedures. The infection group had higher white blood cell count (WBC) (10,400/mm3 vs. 7000/mm3, p < 0.001) and more frequent history of antibiotic therapy (29.6% vs. 15.1%, p < 0.001). Multivariate analysis showed that older age (odds ratio (OR) 1.67, 95% confidence interval (C.I.) 1.08-2.56, p = 0.020), history of antibiotic therapy (OR 3.17, C.I. 1.85-5.41, p < 0.001), and WBC > 10,000/mm3 (OR 2.22, C.I. 1.85-3.32, p < 0.001) were associated with infection. CONCLUSIONS: Compared to previous studies on HAF in Western medicine, the incidence of HAF in OMHs was not high. However, Oriental medical treatment does play some role in HAF. Fever in patients with history of antibiotic therapy, or high WBC was more likely of infectious origin. PMID- 29415716 TI - Disaster impacts on cost and utilization of Medicare. AB - BACKGROUND: To estimate changes in the cost and utilization of Medicare among beneficiaries over age 65 who have been impacted by a natural disaster, we merged publically available county-level Medicare claims for the years 2008-2012 with Federal Emergency Management Agency (FEMA) data related to disasters in each U.S. County from 2007 to 2012. METHODS: Fixed-effects generalized linear models were used to calculate change in per capita costs standardized by region and utilization per 1000 beneficiaries at the county level. Aggregate county demographic characteristics of Medicare participants were included as predictors of change in county-level utilization and cost. FEMA data was used to determine counties that experienced no, some, high, and extreme hazard exposure. FEMA data was merged with claims data to create a balanced panel dataset from 2008 to 2012. RESULTS: In general, both cost and utilization of Medicare services were higher in counties with more hazard exposure. However, utilization of home health services was lower in counties with more hazard exposure. CONCLUSIONS: Additional research using individual-level data is needed to address limitations and determine the impacts of the substitution of services (e.g., inpatient rehabilitation for home health) that may be occurring in disaster affected areas during the post-disaster period. PMID- 29415717 TI - Implementing large scale fast track diagnostics in a comprehensive cancer center, pre- and post-measurement data. AB - BACKGROUND: In general, patients with a cancer suspicion visit the hospital multiple times before diagnosis is completed. Using various "operations management" techniques a few fast track diagnostic services were implemented in the Netherlands Cancer Institute (NKI) in 2006. Growing patient numbers and increasing process complexity, led to diminished service levels. To decrease the amount of patient visits and to extend these services beyond the (obvious) breast cancer services, fast track diagnostics is now implemented for all 18 cancer types that present with a frequency of minimally one per week. METHODS: The throughput time (first visit to diagnosis conversation) was measured before, and after implementation of fast track diagnostics. The process was redesigned closely involving the multidisciplinary teams. In an eclectic approach elements from lean management, theory of constraints and mathematical analysis were used to organize slots per tumor type for MRI, CT, PET and echography. A post measurement was performed after 3 and 6 months. RESULTS: In pre measurement access time was calculated to be 10 to 15 workdays, mean throughput time was 6.0 workdays. It proved possible to design the process of 18 tumors as a fast track, of which 7 as "one stop shop" (diagnosis completed in one visit). Involvement of clinical- and board leadership, massive communication efforts and commitment of physicians to reschedule their work proved decisive. After 3 and 6 months of implementation, the mean access time was 8.2 and 8.7 workdays respectively and mean throughput time was 3.4 and 3.3 workdays respectively. CONCLUSIONS: Throughput- and access time were considerably shortened after implementation of fast track diagnostics for 18 cancer types. The involvement of physicians in reorganizing their work and rapid responding to their needs during the implementation phase were a crucial success factor. PMID- 29415718 TI - Moving anticoagulation initiation and monitoring services into the community: evaluation of the Brighton and hove community pharmacy service. AB - BACKGROUND: As part of the NHS desire to move services closer to where people live, and provide greater accessibility and convenience to patients, Brighton and Hove Clinical Commissioning Group (CCG) underwent a review of their anticoagulation services during 2008. The outcome was to shift the initiation and monitoring service in secondary care for non-complex patients, including domiciliary patients, into the community. This was achieved via a procurement process in 2008 resulting in the Community Pharmacy Anticoagulation Management Service (CPAMs) managed by Boots UK (a large chain of community pharmacies across the United Kingdom). METHODS: This evaluation aims to review the outcomes (International Normalised Ratio [INR] readings) and experiences of those patients attending the anticoagulation monitoring service provided by community pharmacists in Brighton and Hove. All patients on warfarin are given a target INR range they need to achieve; dosing of and frequency of appointment are dependent on the INR result. Outcome measures for patients on the CPAM service included percentage INR readings that were within target range and the percentage time the patient was within therapeutic range. Data collected from 2009 to 2016 were analysed and results compared to the service targets. Patient experience of the service was evaluated via a locally developed questionnaire that was issued to patients annually in the pharmacy. RESULTS: The evaluation shows that community pharmacy managed anticoagulation services can achieve outcomes at a level consistently exceeding national and local targets for both percentage INR readings in therapeutic target range (65.4%) compared to the recommended minimum therapeutic target range of 60.0% and percentage time in therapeutic range (72.5%, CI 71.9-73.1%) compared to the national target of 70.0%. Patients also indicated they were satisfied with the service, with over 98.6% patients rating the service as good, very good or excellent. CONCLUSION: The Brighton and Hove CPAM service achieved above average national target management of INR and positive patient feedback, demonstrating that community pharmacy is ideally placed to provide this service safely and deliver enhanced clinical outcomes and positive patient experience. PMID- 29415719 TI - MicroRNA-365 alleviates morphine analgesic tolerance via the inactivation of the ERK/CREB signaling pathway by negatively targeting beta-arrestin2. AB - BACKGROUND: Morphine is widely used in clinical practice for a class of analgesic drugs, long-term use of morphine will cause the action of tolerance. MicroRNAs have been reported to be involved in morphine analgesic tolerance.. METHODS: Forty male SD rats were selected and randomly divided into 5 groups: the control group, morphine tolerance group, miR-365 mimic + morphine (miR-365 mimic) group, miR-365 inhibitor + morphine (miR-365 inhibitor) group and miR-365 negative control (NC) + morphine (miR-365 NC) group. After the administration of morphine at 0 d, 1 d, 3 d, 5 d and 7 d, behavioral testing was performed. A dual luciferase reporter gene assay was performed to confirm the relationship between miR-365 and beta-arrestin2, RT-qPCR was used to detect miR-365, beta-arrestin2, ERK and CREB mRNA expressions, western blotting was used to evaluate the protein expressions of beta-arrestin2, ERK, p-ERK, CREB and p-CREB, ELISA was used to detect the contents of IL-1beta, TNF-alpha and IL-18, while immunofluorescence staining was used to measure the GFAP expression. Intrathecal injection of mir365 significantly increased the maximal possible analgesic effect (%MPE) in morphine tolerant rats. beta-arrestin2 was the target gene of miR-365. RESULTS: The results obtained showed that when compared with the morphine tolerance group, there was an increase in miR-365 expression and a decrease in the beta-arrestin2, ERK, CREB protein expressions, contents of IL-1beta, TNF-alpha, IL-18 and GFAP expression in the miR-365 mimic group, while the miR-365 inhibitor group displayed an opposite trend. CONCLUSIONS: The results of this experiment suggest that by targeting beta-arrestin2 to reduce the contents of IL-1beta, TNF-alpha and IL-18 and by inhibiting the activation of ERK/CREB signaling pathway, miR-365 could lower morphine analgesic tolerance. PMID- 29415720 TI - Facilitators and barriers of implementing and delivering social prescribing services: a systematic review. AB - BACKGROUND: Social Prescribing is a service in primary care that involves the referral of patients with non-clinical needs to local services and activities provided by the third sector (community, voluntary, and social enterprise sector). Social Prescribing aims to promote partnership working between the health and the social sector to address the wider determinants of health. To date, there is a weak evidence base for Social Prescribing services. The objective of the review was to identify factors that facilitate and hinder the implementation and delivery of SP services based in general practice involving a navigator. METHODS: We searched eleven databases, the grey literature, and the reference lists of relevant studies to identify the barriers and facilitators to the implementation and delivery of Social Prescribing services in June and July 2016. Searches were limited to literature written in English. No date restrictions were applied. Findings were synthesised narratively, employing thematic analysis. The Mixed Methods Appraisal Tool Version 2011 was used to evaluate the methodological quality of included studies. RESULTS: Eight studies were included in the review. The synthesis identified a range of factors that facilitate and hinder the implementation and delivery of SP services. Facilitators and barriers were related to: the implementation approach, legal agreements, leadership, management and organisation, staff turnover, staff engagement, relationships and communication between partners and stakeholders, characteristics of general practices, and the local infrastructure. The quality of most included studies was poor and the review identified a lack of published literature on factors that facilitate and hinder the implementation and delivery of Social Prescribing services. CONCLUSION: The review identified a range of factors that facilitate and hinder the implementation and delivery of Social Prescribing services. Findings of this review provide an insight for commissioners, managers, and providers to guide the implementation and delivery of future Social Prescribing services. More high quality research and transparent reporting of findings is needed in this field. PMID- 29415721 TI - The associations between malaria, interventions, and the environment: a systematic review and meta-analysis. AB - BACKGROUND: Malaria transmission is driven by multiple factors, including complex and multifaceted connections between malaria transmission, socioeconomic conditions, climate and interventions. Forecasting models should account for all significant drivers of malaria incidence although it is first necessary to understand the relationship between malaria burden and the various determinants of risk to inform the development of forecasting models. In this study, the associations between malaria risk, environmental factors, and interventions were evaluated through a systematic review. METHODS: Five electronic databases (CAB Abstracts, EMBASE, Global Health, MEDLINE and ProQuest Dissertations & Theses) were searched for studies that included both the effects of the environment and interventions on malaria within the same statistical model. Studies were restricted to quantitative analyses and health outcomes of malaria mortality or morbidity, outbreaks, or transmission suitability. Meta-analyses were conducted on a subset of results using random-effects models. RESULTS: Eleven studies of 2248 potentially relevant articles that met inclusion criteria were identified for the systematic review and two meta-analyses based upon five results each were performed. Normalized Difference Vegetation Index was not found to be statistically significant associated with malaria with a pooled OR of 1.10 (95% CI 0.07, 1.71). Bed net ownership was statistically associated with decreasing risk of malaria, when controlling for the effects of environment with a pooled OR of 0.75 (95% CI 0.60, 0.95). In general, environmental effects on malaria, while controlling for the effect of interventions, were variable and showed no particular pattern. Bed nets ownership, use and distribution, have a significant protective effect while controlling for environmental variables. CONCLUSIONS: There are a limited number of studies which have simultaneously evaluated both environmental and interventional effects on malaria risk. Poor statistical reporting and a lack of common metrics were important challenges for this review, which must be addressed to ensure reproducibility and quality research. A comprehensive or inclusive approach to identifying malaria determinants using standardized indicators would allow for a better understanding of its epidemiology, which is crucial to improve future malaria risk estimations. PMID- 29415722 TI - Clinical relevance of oncologic prognostic factors in the decision-making of pre hepatectomy chemotherapy for colorectal cancer hepatic metastasis: the priority of hepatectomy. AB - BACKGROUND: Although liver resection (LR) provides the best chance of long-term survival for patients with colorectal cancer (CRC) hepatic metastasis, concerns regarding chemotherapy before liver resection remain unresolved. METHODS: A retrospective review of patients who underwent curative LR for CRC hepatic metastasis between January 2008 and February 2016 was performed. Outcome relevance based on oncologic prognostic factors and chemotherapy prior to liver resection was assessed. RESULTS: Patients who had received pre-hepatectomy chemotherapy for CRC hepatic metastasis and delayed liver resection had a worse outcome in terms of CRC recurrence following liver resection. The hazard ratio (HR) of pre-hepatectomy chemotherapy in patients with minor oncologic prognostic factors was 1.55 (confidence interval, CI = 1.07-2.26, p = 0.021) for CRC recurrence after liver resection for hepatic metastasis, whereas the HR of pre hepatectomy chemotherapy was 1.34 (CI = 0.99-1.81, p = 0.062) for CRC recurrence in patients with multiple oncologic prognostic factors. CONCLUSION: The administration of pre-hepatectomy chemotherapy and delaying liver resection seems not to be an optimal strategy to provide a clinical benefit for patients with CRC hepatic metastasis. Hence, liver resection should be attempted without delay at the initial detection of CRC hepatic metastasis whenever possible. PMID- 29415723 TI - Characterizing undiagnosed chronic obstructive pulmonary disease: a systematic review and meta-analysis. AB - BACKGROUND: A significant proportion of patients with chronic obstructive pulmonary disease (COPD) remain undiagnosed. Characterizing these patients can increase our understanding of the 'hidden' burden of COPD and the effectiveness of case detection interventions. METHODS: We conducted a systematic review and meta-analysis to compare patient and disease factors between patients with undiagnosed persistent airflow limitation and those with diagnosed COPD. We searched MEDLINE and EMBASE for observational studies of adult patients meeting accepted spirometric definitions of COPD. We extracted and pooled summary data on the proportion or mean of each risk factor among diagnosed and undiagnosed patients (unadjusted analysis), and coefficients for the adjusted association between risk factors and diagnosis status (adjusted analysis). RESULTS: Two thousand eighty-three records were identified through database searching and 16 articles were used in the meta-analyses. Diagnosed patients were less likely to have mild (v. moderate to very severe) COPD (odds ratio [OR] 0.30, 95%CI 0.24 0.37, 6 studies) in unadjusted analysis. This association remained significant but its strength was attenuated in the adjusted analysis (OR 0.72, 95%CI 0.58 0.89, 2 studies). Diagnosed patients were more likely to report respiratory symptoms such as wheezing (OR 3.51, 95%CI 2.19-5.63, 3 studies) and phlegm (OR 2.16, 95% CI 1.38-3.38, 3 studies), had more severe dyspnea (mean difference in modified Medical Research Council scale 0.52, 95%CI 0.40-0.64, 3 studies), and slightly greater smoking history than undiagnosed patients. Patient age, sex, current smoking status, and the presence of coughing were not associated with a previous diagnosis. CONCLUSIONS: Undiagnosed patients had less severe airflow obstruction and fewer respiratory symptoms than diagnosed patients. The lower disease burden in undiagnosed patients may significantly delay the diagnosis of COPD. PMID- 29415724 TI - Improvement of malaria diagnostic system based on acridine orange staining. AB - BACKGROUND: Rapid diagnosis of malaria using acridine orange (AO) staining and a light microscope with a halogen lamp and interference filter was deployed in some malaria-endemic countries. However, it has not been widely adopted because: (1) the lamp was weak as an excitation light and the set-up did not work well under unstable power supply; and, (2) the staining of samples was frequently inconsistent. METHODS: The halogen lamp was replaced by a low-cost, blue light emitting diode (LED) lamp. Using a reformulated AO solution, the staining protocol was revised to make use of a concentration gradient instead of uniform staining. To evaluate this new AO diagnostic system, a pilot field study was conducted in the Lake Victoria basin in Kenya. RESULTS: Without staining failure, malaria infection status of about 100 samples was determined on-site per one microscopist per day, using the improved AO diagnostic system. The improved AO diagnosis had both higher overall sensitivity (46.1 vs 38.9%: p = 0.08) and specificity (99.0 vs 96.3%) than the Giemsa method (N = 1018), using PCR diagnosis as the standard. CONCLUSIONS: Consistent AO staining of thin blood films and rapid evaluation of malaria parasitaemia with the revised protocol produced superior results relative to the Giemsa method. This AO diagnostic system can be set up easily at low cost using an ordinary light microscope. It may supplement rapid diagnostic tests currently used in clinical settings in malaria-endemic countries, and may be considered as an inexpensive tool for case surveillance in malaria-eliminating countries. PMID- 29415725 TI - Nischarin regulates focal adhesion and Invadopodia formation in breast cancer cells. AB - BACKGROUND: During metastasis, tumor cells move through the tracks of extracellular matrix (ECM). Focal adhesions (FAs) are the protein complexes that link the cell cytoskeleton to the ECM and their presence is necessary for cell attachment. The tumor suppressor Nischarin interacts with a number of signaling proteins such as Integrin alpha5, PAK1, LIMK1, LKB1, and Rac1 to prevent cancer cell migration. Although previous findings have shown that Nischarin exerts this migratory inhibition by interacting with other proteins, the effects of these interactions on the entire FA machinery are unknown. METHODS: RT-PCR, Western Blotting, invadopodia assays, and immunofluorescence were used to examine FA gene expression and determine whether Nischarin affects cell attachment, as well as the proteins that regulate it. RESULTS: Our data show that Nischarin prevents cell migration and invasion by altering the expression of key focal adhesion proteins. Furthermore, we have found that Nischarin-expressing cells have reduced ability to attach the ECM, which in turn leads to a decrease in invadopodia mediated matrix degradation. CONCLUSIONS: These experiments demonstrate an important role of Nischarin in regulating cell attachment, which adds to our understanding of the early events of the metastatic process in breast cancer. PMID- 29415726 TI - Advances in intelligent diagnosis methods for pulmonary ground-glass opacity nodules. AB - Pulmonary nodule is one of the important lesions of lung cancer, mainly divided into two categories of solid nodules and ground glass nodules. The improvement of diagnosis of lung cancer has significant clinical significance, which could be realized by machine learning techniques. At present, there have been a lot of researches focusing on solid nodules. But the research on ground glass nodules started late, and lacked research results. This paper summarizes the research progress of the method of intelligent diagnosis for pulmonary nodules since 2014. It is described in details from four aspects: nodular signs, data analysis methods, prediction models and system evaluation. This paper aims to provide the research material for researchers of the clinical diagnosis and intelligent analysis of lung cancer, and further improve the precision of pulmonary ground glass nodule diagnosis. PMID- 29415727 TI - New insights into the regulatory role of microRNA in tumor angiogenesis and clinical implications. AB - Angiogenesis is essential for tumor growth and metastasis. Understanding the regulation of tumor angiogenesis has become increasingly important. MicroRNAs (miRNAs) are small noncoding RNAs that function in diverse biological processes via post-transcriptional regulation. Extensive studies have revealed two important regulatory roles of miRNAs in tumor angiogenesis: miRNAs in tumor cells affect the activity of endothelial cells via non-cell-autonomous mechanisms, and miRNAs in endothelial cells regulate the cell-autonomous behavior. Recent advances have further highlighted the role of tumor-derived extracellular vesicles in the regulation of tumor angiogenesis via transferring miRNAs to endothelial cells. In this review, we summarize the regulatory role of miRNA in tumor angiogenesis, with a highlight on clinical implications of miRNAs as biomarkers for anti-angiogenic therapy response, and as therapeutic interventions against tumor angiogenesis in vivo. PMID- 29415728 TI - Genetic variation analysis of PCV1 strains isolated from Guangxi Province of China in 2015. AB - BACKGROUND: Porcine circovirus type 1 (PCV1) was discovered in 1974 as a contaminant of a porcine kidney (PK-15) cell line and was generally accepted to be nonpathogenic. But recently it was shown to cause lesions in experimentally infected pig fetuses. Serological evidence and genetic studies suggested that PCV1 was widespread in domestic pigs. Thus, the molecular epidemiology and genetic variation of PCV1 are still necessary to understand. RESULTS: Here 247 tissue samples were collected from piglets in Guangxi Province, China and performed whole-genome sequencing of the PCV1 genome. Thirteen PCV1 strains were sequenced from the samples. Similarity analysis showed that there were 97.8% to 99.6% nucleotide similarity to each other and 97.1% to 99.8% nucleotide similarity to the 40 reference strains. Besides, based on sequence analysis, we found one putative recombinant virus named GXdx84 strain contained the open reading frame 1 (ORF1) of PCV1 and the ORF2 of PCV2d-2, which was consistent with the results of phylogenetic analysis that compared PCV1 and PCV2 strains. Variation analysis of the amino acids of the capsid protein revealed that the GXyl224 strain, which encoded 235 amino acids, had two amino acids more than other strains. This is the first study to report that a cap gene mutation resulted in lengthening of in the gene sequence. CONCLUSIONS: These data contribute to the understanding of PCV1 evolution and molecular epidemiology that will facilitate programs for its control and prevention. PMID- 29415729 TI - Trajectories of self-reported physical activity and predictors during the transition to old age: a 20-year cohort study of British men. AB - BACKGROUND: Maintenance of physical activity (PA) during later life is associated with optimal health; however, the long-term trajectories of PA into old age and their predictors have not been extensively researched using latent class methods. This study aimed to identify trajectories of self-reported PA and their predictors in men transitioning from midlife to old age. METHODS: 7735 men (aged 40-59 years) recruited in 1978-80 were followed up after 12, 16 and 20 years, reporting PA, health status, lifestyle behaviours and socio-demographic characteristics. Group-based trajectory modelling identified the trajectories of PA and associations with time-stable and time-varying covariates. We considered a range of sociodemographic and health and lifestyle factors as potential covariates. RESULTS: 4952 men (mean baseline age 49.1 +/- 5.6 years) providing PA data at >=3 time points were included in analyses. Three distinct 20-year trajectories were identified: low decreasing (24.6%, n = 1218), light stable (51.1%, n = 2530) and moderate increasing (24.3%, n = 1204). Being older, having a manual occupation, having never married or had children, residing in the midlands or North of England, suffering from a range of health conditions, being a smoker/ex-smoker and never consuming breakfast cereal or alcohol were independently associated with reduced odds of belonging to the moderate increasing trajectory group compared to the low decreasing group. Of the time varying covariates considered, leaving employment was associated with a decrease in PA in the low decreasing group (beta -0.306, p < 0.001) but an increase in the light stable (beta 0.324, p < 0.001) and moderate increasing groups (beta 0.847, p < 0.001). Developing cardiovascular-related conditions was associated with a decrease in PA in the low decreasing (beta -0.408, p < 0.001) and light stable groups (beta -0.118, p < 0.001) but no association was observed in the moderate increasing group (beta -0.060, p = 0.313). CONCLUSIONS: Three distinct trajectories of PA were identified in men transitioning from midlife to old age, of which nearly a quarter had persistently low levels of PA. Promotion efforts may need to focus attention prior to middle age and consider a number of sociodemographic, health and lifestyle factors to sustain PA into old age. The effects of retirement and development of cardiovascular disease may vary according to PA trajectories. PMID- 29415730 TI - Effect of nutrient supplementation on the acquisition of humoral immunity to Plasmodium falciparum in young Malawian children. AB - BACKGROUND: There is evidence that suggests that undernutrition has a detrimental effect on malarial immunity in children. The aim of the study was to discover whether nutrient supplementation improved development of malarial antibody immunity in children up to 18 months of age. METHODS: The study was conducted with a subset of 432 Malawian children from a randomized controlled trial of nutritional supplements. The arms included pre- and postnatal small-quantity lipid-based nutrient supplements for both mother and child; prenatal supplementation with iron and folic acid; and pre- and postnatal supplementation with multiple micronutrients. Paired plasma samples were collected at 6 and 18 months of age. The levels of antibodies against merozoite surface protein 1 (MSP1 19kD) and MSP2, erythrocyte binding antigen 175 (EBA175), reticulocyte binding protein homologue 2A (Rh2A9), schizont extract and variant antigens expressed on the surface of infected erythrocytes were measured. RESULTS: At 18 months of age, 5.4% of children were parasitaemic by microscopy and 49.1% were anaemic. Antibodies to the tested merozoite antigens and schizont extract increased between 6 and 18 months and this increase was statistically significant for MSP1, MSP2 and EBA175 (p < 0.0001) whereas IgG to variant surface antigens decreased with increasing age (p < 0.0001). However, the supplementation type did not have any impact on the prevalence or levels of antibodies at either 6 or 18 months of age to any of the tested malaria antigens in either univariate analysis or multivariate analysis after adjusting for covariates. CONCLUSIONS: Pre- and postnatal lipid-based nutrient supplementation did not alter malaria antibody acquisition during infancy, compared to prenatal supplementation with iron and folic acid or pre- and postnatal supplementation with multiple micronutrients. Trail registeration Clinicaltrials.gov registration number NCT01239693. PMID- 29415731 TI - Population genetic structure and natural selection of Plasmodium falciparum apical membrane antigen-1 in Myanmar isolates. AB - BACKGROUND: Plasmodium falciparum apical membrane antigen-1 (PfAMA-1) is one of leading blood stage malaria vaccine candidates. However, genetic variation and antigenic diversity identified in global PfAMA-1 are major hurdles in the development of an effective vaccine based on this antigen. In this study, genetic structure and the effect of natural selection of PfAMA-1 among Myanmar P. falciparum isolates were analysed. METHODS: Blood samples were collected from 58 Myanmar patients with falciparum malaria. Full-length PfAMA-1 gene was amplified by polymerase chain reaction and cloned into a TA cloning vector. PfAMA-1 sequence of each isolate was sequenced. Polymorphic characteristics and effect of natural selection were analysed with using DNASTAR, MEGA4, and DnaSP programs. Polymorphic nature and natural selection in 459 global PfAMA-1 were also analysed. RESULTS: Thirty-seven different haplotypes of PfAMA-1 were identified in 58 Myanmar P. falciparum isolates. Most amino acid changes identified in Myanmar PfAMA-1 were found in domains I and III. Overall patterns of amino acid changes in Myanmar PfAMA-1 were similar to those in global PfAMA-1. However, frequencies of amino acid changes differed by country. Novel amino acid changes in Myanmar PfAMA-1 were also identified. Evidences for natural selection and recombination event were observed in global PfAMA-1. Among 51 commonly identified amino acid changes in global PfAMA-1 sequences, 43 were found in predicted RBC binding sites, B-cell epitopes, or IUR regions. CONCLUSIONS: Myanmar PfAMA-1 showed similar patterns of nucleotide diversity and amino acid polymorphisms compared to those of global PfAMA-1. Balancing natural selection and intragenic recombination across PfAMA-1 are likely to play major roles in generating genetic diversity in global PfAMA-1. Most common amino acid changes in global PfAMA-1 were located in predicted B-cell epitopes where high levels of nucleotide diversity and balancing natural selection were found. These results highlight the strong selective pressure of host immunity on the PfAMA-1 gene. These results have significant implications in understanding the nature of Myanmar PfAMA-1 along with global PfAMA-1. They also provide useful information for the development of effective malaria vaccine based on this antigen. PMID- 29415732 TI - Maternal physical activity before IVF/ICSI cycles improves clinical pregnancy rate and live birth rate: a systematic review and meta-analysis. AB - OBJECTIVE: This meta-analysis was aimed to evaluate the association between maternal physical activity before IVF/ICSI cycles and reproductive outcomes. METHODS: We searched databases of PubMed, EMBASE and Web of Science electronic databases, and ongoing trials up to November 2017 to identify studies that focused on the relationship between maternal physical activity before IVF/ICSI cycles and reproductive outcomes, including implantation rate, clinical pregnancy rate, miscarriage rate and live birth rate. Odds ratio (OR) with 95% confidence intervals, were calculated to assess the results of each outcome. RESULTS: Eight published studies encompassing 3683 infertile couples undergoing IVF/ICSI treatment were included into the analysis. There was an increasing, but not statistically significant, trend in implantation rate for physically active women when compared with physically inactive women (OR = 1.95, 95% CI 0.99-3.83, I2 = 77%). No significant difference was found in miscarriage rate between physically active women and physically inactive women (OR = 0.76, 95% CI 0.41-1.44, I2 = 49%). However, rates of clinical pregnancy and live births in physically active women were significantly higher than those in physically inactive women (OR = 1.96, 95% CI 1.40, 2.73, I2 = 42% and OR = 1.95, 95% CI 1.06-3.59, I2 = 82%, respectively). Subgroup analysis helped to confirm these results. CONCLUSIONS: Female physical activity before IVF/ICSI cycles was associated with increased rates of clinical pregnancy and live births, whereas only a small but not statistically significant increase was found in implantation rate, and no effect was shown on miscarriage rate. PMID- 29415733 TI - Semi-automated ultrasound guidance applied to nasogastrojejunal tube replacement for enteral nutrition in critically ill adults. AB - BACKGROUND AND OBJECTIVE: At present, the enteral nutrition approaches via nose and duodenum (or nose and jejunum) are the preferred method of nutritional support in the medical engineering field, given the superiority of in line with physiological processes and no serious complication. In this study, the authors adopted saline as the acoustic window, and gave enteral nutrition support to critically ill patients, via the nasogastrojejunal approach guided by semi automated ultrasound. These above patients benefited a lot from this kind of nutrition support treatment, and we aimed to report the detailed information. METHODS: Critically ill patients (n = 41) who had been treated with hospitalized intestine nutrition were identified. The Apogee 1200 ultrasonic diagnostic apparatus, and nasogastrojejunal tubes were adopted to carry out intestine nutrition treatment guided by semi-automated ultrasound. In order to confirm the specific positions of cardia, gastric body, antrum of stomach, and pylorus, the semi-automated ultrasound was utilized to probe the stomach cavity. And then, the ultrasonic probe was placed in the cardia location, and the nasogastrojejunal tube was slowly inserted through the metal thread. After operation, the nursing service satisfaction of patients and mean operation time were calculated, respectively. RESULTS: All the patients were treated with enteral nutrition via nasogastrojejunal tube, and the whole procedure was under the guidance of semi automated ultrasonography. The end of the feeding tube is attached to the surface of the stomach with a greater curvature, which can be bent on account of a no gastric peristalsis squeeze function, and thereby were prevented from entering into the antrum and pylorus locations. After this procedure, the mental thread was taken out, and the tube was pushed forward by a "drift" approach in order to allow it to enter into the intestine. The total nursing service satisfaction of patients was 90.24%, and the total incidence of adverse reactions was 17.07%. CONCLUSIONS: In summary, the application of saline can be taken as sound window, and the metal wire as the tracking target, the bedside nasogastrojejunal tube guided by semi-automated ultrasound is an effective feeding tube placement method, with relatively good clinical application value in medical engineering. PMID- 29415734 TI - Patient engagement in Canada: a scoping review of the 'how' and 'what' of patient engagement in health research. AB - BACKGROUND: Over the last 10 years, patient engagement in health research has emerged as the next evolution in healthcare research. However, limited evidence about the clear role and scope of patient engagement in health research and a lack of evidence about its impact have influenced the uptake, implementation and ongoing evolution of patient engagement. The present study aims to conduct a scoping review to identify methods for and outcomes of patient engagement in health research. METHODS: An adaptation of the scoping review methodology originally described by Arksey and O'Malley and updated by Levac, Colquhoun and O'Brien was applied. Sources from a formal database search and relevant documents from a grey literature search were compiled into data extraction tables. Articles were synthesised into key themes according to the (1) methods and (2) outcomes of patient engagement in health research. RESULTS: The total yield for the scoping review was 55 records from across Canada, the United Kingdom and the United States. While evidence about the methods used to engage patients in health research is increasing, stronger evidence of specific patient and healthcare system outcomes is required. This necessitates further mobilisation of research that explores outcomes and that validates specific tools to evaluate engagement. Additionally, theoretical frameworks that can better inform and sustain patient engagement across the lifecycle of health research are lacking. CONCLUSION: Further increasing the volume and reach of evidence about patient engagement in health research will support the paradigmatic shift needed to normalise the patient's role in research beyond 'subject' or 'participant', so as to ultimately improve patient health outcomes and better address healthcare reform in Canada. PMID- 29415735 TI - Common issues raised during the quality assurance process of WHO guidelines: a cross-sectional study. AB - BACKGROUND: In 2007, WHO established the Guidelines Review Committee (GRC) to ensure that WHO guidelines adhere to the highest international standards. The GRC reviews guideline proposals and final guidelines. The objectives of this study were to examine the rates of and reasons for conditional approval and non approval of documents submitted for the first time to the GRC, and calculate the time intervals and numbers of submissions to achieve approval for documents conditionally approved or not approved at first submission. METHODS: All initial submissions to the GRC between 2014 and 2017 were examined. Data were extracted from the GRC's records of written comments and discussions. RESULTS: Of a total of 85 proposals and 88 final guidelines, 32 (37.6%) proposals and 37 (42.0%) final guidelines were conditionally approved, and 15 (17.6%) proposals and 28 (31.8%) final guidelines were not. For both conditionally approved and not approved proposals, the most frequent reasons were suboptimal composition or inadequate description of the guideline contributor groups (in all proposals), followed by inadequate formulation of key questions (in 90.6% of conditionally approved proposals and all not approved proposals). For both conditionally approved and not approved final guidelines, the most frequent reasons were problems with recommendations (in all final guidelines), followed by inappropriate methods for evidence retrieval or an inadequate description thereof (in all conditionally approved final guidelines and 75.0% of not approved final guidelines). The median time to achieve approval was 2 months for proposals and 1 2 months for final guidelines. The median number of submissions was 2 for proposals and 2-2.5 for final guidelines. CONCLUSION: The GRC implements a rigorous quality assurance process and identifies problems with a significant percentage of initial submissions. WHO needs to continuously evaluate its guideline development processes to inform effective quality improvement measures and optimise the quality of its guidelines. PMID- 29415736 TI - Uterine Foxl2 regulates the adherence of the Trophectoderm cells to the endometrial epithelium. AB - BACKGROUND: Forkhead Transcription Factor L2 (FOXL2) is a member of the forkhead family with important roles in reproduction. Recent studies showed that FOXL2 is expressed in human and bovine endometrium and that its levels fluctuate during pregnancy. In this study, we aimed at evaluating the expression and function of FOXL2 in embryo implantation. METHODS: Mouse uteri at different days of pregnancy were isolated and analyzed for the expression and localization of FOXL2. A lentiviral strategy was further employed to either knockdown or overexpress FOXL2 in non-receptive human endometrial AN3-CA cells and in receptive Ishikawa cells, respectively. These genetically modified cells were compared to cells infected with a control lentivirus to determine the function of FOXL2 in trophectoderm cells adherence to Endometrial Epithelium was associated with the expression of genes known to be involved in acquisition of uterine receptivity. RESULTS: We report that FOXL2 is expressed in both, the luminal epithelium and the myometrium of the mouse uterus and that its expression declines prior to implantation. We found that endometrial cells expressing low FOXL2 levels, either endogenous or genetically manipulated, were associated with a higher attachment rate of mouse blastocysts or human Jeg3 spheroids and mouse blastocysts. In accordance, low FOXL2 levels were associated with changes in the expression level of components of the Wnt/Fzd and apoptotic pathways, both of which are involved in uterine receptivity. Furthermore, FOXL2 expression was inversely correlated with G protein signaling protein 2 (Rgs2) and cytokine expression. CONCLUSIONS: These results suggest that FOXL2 interferes with embryo attachment. Better understanding of the function of FOXL2 in the uterus would possibly suggest novel strategies for treatment of infertility attributed to repeated implantation failure. PMID- 29415737 TI - Correction to: Mercury exposure, nutritional deficiencies and metabolic disruptions may affect learning in children. AB - The original version of this article [1] unfortunately contained an error which has since been acknowledged in this Correction article. The URL link in the Reference 19 was broken and it needs to be replaced with the active link given below. PMID- 29415738 TI - What adaptation to research is needed following crises: a comparative, qualitative study of the health workforce in Sierra Leone and Nepal. AB - BACKGROUND: Health workers are critical to the performance of health systems; yet, evidence about their coping strategies and support needs during and post crisis is lacking. There is very limited discussion about how research teams should respond when unexpected crises occur during on-going research. This paper critically presents the approaches and findings of two health systems research projects that explored and evaluated health worker performance and were adapted during crises, and provides lessons learnt on re-orientating research when the unexpected occurs. METHODS: Health systems research was adapted post crisis to assess health workers' experiences and coping strategies. Qualitative in-depth interviews were conducted with 14 health workers in a heavily affected earthquake district in Nepal and 25 frontline health workers in four districts in Ebola affected Sierra Leone. All data were transcribed and analysed using the framework approach, which included developing coding frameworks for each study, applying the frameworks, developing charts and describing the themes. A second layer of analysis included analysis across the two contexts, whereas a third layer involved the research teams reflecting on the approaches used to adapt the research during these crises and what was learned as individuals and research teams. RESULTS: In Sierra Leone, health workers were heavily stigmatised by the epidemic, leading to a breakdown of trust. Coping strategies included finding renewed purpose in continuing to serve their community, peer and family support (in some cases), and religion. In Nepal, individual determination, a sense of responsibility to the community and professional duty compelled staff to stay or return to their workplace. The research teams had trusting relationships with policy-makers and practitioners, which brought credibility and legitimacy to the change of research direction as well as the relationships to maximise the opportunity for findings to inform practice. CONCLUSIONS: In both contexts, health workers demonstrated considerable resilience in continuing to provide services despite limited support. Embedded researchers and institutions are arguably best placed to navigate emerging ethical and social justice challenges and are strategically positioned to support the co-production of knowledge and ensure research findings have impact. PMID- 29415740 TI - Guidelines for responsible short-term global health activities: developing common principles. AB - BACKGROUND: Growing concerns about the value and effectiveness of short-term volunteer trips intending to improve health in underserved Global South communities has driven the development of guidelines by multiple organizations and individuals. These are intended to mitigate potential harms and maximize benefits associated with such efforts. METHOD: This paper analyzes 27 guidelines derived from a scoping review of the literature available in early 2017, describing their authorship, intended audiences, the aspects of short term medical missions (STMMs) they address, and their attention to guideline implementation. It further considers how these guidelines relate to the desires of host communities, as seen in studies of host country staff who work with volunteers. RESULTS: Existing guidelines are almost entirely written by and addressed to educators and practitioners in the Global North. There is broad consensus on key principles for responsible, effective, and ethical programs- need for host partners, proper preparation and supervision of visitors, needs assessment and evaluation, sustainability, and adherence to pertinent legal and ethical standards. Host country staff studies suggest agreement with the main elements of this guideline consensus, but they add the importance of mutual learning and respect for hosts. CONCLUSIONS: Guidelines must be informed by research and policy directives from host countries that is now mostly absent. Also, a comprehensive strategy to support adherence to best practice guidelines is needed, given limited regulation and enforcement capacity in host country contexts and strong incentives for involved stakeholders to undertake or host STMMs that do not respect key principles. PMID- 29415739 TI - Hepcidin, an emerging and important player in brain iron homeostasis. AB - Hepcidin is emerging as a new important factor in brain iron homeostasis. Studies suggest that there are two sources of hepcidin in the brain; one is local and the other comes from the circulation. Little is known about the molecular mediators of local hepcidin expression, but inflammation and iron-load have been shown to induce hepcidin expression in the brain. The most important source of hepcidin in the brain are glial cells. Role of hepcidin in brain functions has been observed during neuronal iron-load and brain hemorrhage, where secretion of abundant hepcidin is related with the severity of brain damage. This damage can be reversed by blocking systemic and local hepcidin secretion. Studies have yet to unveil its role in other brain conditions, but the rationale exists, since these conditions are characterized by overexpression of the factors that stimulate brain hepcidin expression, such as inflammation, hypoxia and iron-overload. PMID- 29415741 TI - Elucidating the impact of the pneumococcal conjugate vaccine programme on pneumonia, sepsis and otitis media hospital admissions in England using a composite control. AB - BACKGROUND: The seven-valent pneumococcal conjugate vaccine (PCV) was introduced in England in September 2006, changing to the 13-valent vaccine in April 2010. PCV impact on invasive pneumococcal disease (IPD) has been extensively reported, but less described is its impact on the burden of pneumonia, sepsis and otitis media in the hospital. METHODS: Using details on all admissions to hospitals in England, we compared the incidence of pneumococcal-specific and syndromic disease endpoints in a 24-month pre-PCV period beginning April 2004 to the 24-month period ending March 2015 to derive incidence rate ratios (IRRs). To adjust for possible secular trends in admission practice, IRRs were compared to the IRRs for five control conditions over the same period and the relative change assessed using the geometric mean of the five control IRRs as a composite, and individually for each control condition to give the min-max range. Relative changes were also compared with IRRs for IPD from the national laboratory database. The effect of stratifying cases into those with and without clinical risk factors for pneumococcal infection was explored. RESULTS: Relative reductions in pneumococcal pneumonia were seen in all age groups and in those with and without risk factors; in children under 15 years old reductions were similar in magnitude to reductions in IPD. For pneumonia of unspecified cause, relative reductions were seen in those under 15 years old (maximum reduction in children under 2 years of 34%, min-max: 11-49%) with a relative increase in 65+ year olds most marked in those with underlying risk conditions (41%, min-max: 0 82%). Reductions in pneumococcal sepsis were seen in all age groups, with the largest reduction in children younger than 2 years (67%, min-max 56-75%). Reductions in empyema and lung abscess were also seen in under 15 year olds. Results for other disease endpoints were varied. For disease endpoints showing an increase in raw IRR, the increase was generally reduced when expressed as a relative change. CONCLUSIONS: Use of a composite control and stratification by risk group status can help elucidate the impact of PCV on non-IPD disease endpoints and in vulnerable population groups. We estimate a substantial reduction in the hospitalised burden of pneumococcal pneumonia in all age groups and pneumonia of unspecified cause, empyema and lung abscess in children under 15 years of age since PCV introduction. The increase in unspecified pneumonia in high-risk 65+ year olds may in part reflect their greater susceptibility to develop pneumonia from less pathogenic serotypes that are replacing vaccine types in the nasopharynx. PMID- 29415742 TI - H19 knockdown suppresses proliferation and induces apoptosis by regulating miR 148b/WNT/beta-catenin in ox-LDL -stimulated vascular smooth muscle cells. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have been identified as critical regulators in the development of atherosclerosis (AS). Here, we focused on discussing roles and molecular mechanisms of lncRNA H19 in vascular smooth muscle cells (VSMCs) progression. METHODS: RT-qPCR assay was used to detect the expression patterns of H19 and miR-148b in clinical samples and cells. Cell proliferative ability was evaluated by CCK-8 and colony formation assays. Cell apoptotic capacity was assessed by apoptotic cell percentage and the caspase-3 activity. Bioinformatics analysis, luciferase and RNA immunoprecipitation (RIP) assays were employed to demonstrate cell percentage and the relationship among H19, miR-148b and wnt family member 1 (WNT1). Western blot assay was performed to determine expressions of proliferating cell nuclear antigen (PCNA), ki-67, Bax, Bcl-2, WNT1, beta-catenin, C-myc and E-cadherin. RESULTS: The level of H19 was increased and miR-148b expression was decreased in human AS patient serums and oxidized low-density lipoprotein (ox-LDL)-stimulated human aorta vascular smooth muscle cells (HA-VSMCs). H19 knockdown suppressed proliferation and promoted apoptosis in HA-VSMCs following the treatment of ox-LDL. H19 inhibited miR-148b expression by direct interaction. Moreover, miR-148b inhibitor could reverse the effects of H19 depletion on proliferation and apoptosis in ox-LDL-stimulated HA VSMCs. Further mechanical explorations showed that WNT1 was a target of miR-148b and H19 acted as a competing endogenous RNA (ceRNA) of miR-148b to enhance WNT1 expression. Furthermore, miR-148 inhibitor exerted its pro-proliferation and anti apoptosis effects through activating WNT/beta-catenin signaling in ox-LDL stimulated HA-VSMCs. CONCLUSION: H19 facilitated proliferation and inhibited apoptosis through modulating WNT/beta-catenin signaling pathway via miR-148b in ox-LDL-stimulated HA-VSMCs, implicating the potential values of H19 in AS therapy. PMID- 29415743 TI - Thyroid function test evolution in children with Hashimoto's thyroiditis is closely conditioned by the biochemical picture at diagnosis. AB - : ?: Aim of this commentary is to summarize the salient literature views on the relationships between presentation and evolution patterns of thyroid function in children with Hashimoto's thyroiditis (HT). According to the most recent reports, children with HT and subclinical hypothyroidism (SH) are more prone to the risk of developing severe thyroid dysfunctions over time, if compared to those presenting with euthyroidism. In contrast, children presenting with HT and either overt or subclinical hyperthyroidism are incline to exhibit a definitive resolution of the hyperthyroid phase within some months, although there is a wide variability between the different individuals. The natural history of frank hypothyroidism in the children with HT has never been investigated so far, since in these cases an immediate onset of replacement treatment is mandatory. CONCLUSIONS: 1) a deterioration of thyroid status over time may be observed especially in the children presenting with SH, but also in those presenting with euthyroidism; 2) a definitive resolution of the hyperthyroid phase is generally observed in those presenting with either overt or subclinical hyperthyroidism. PMID- 29415744 TI - Correction to: Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: A consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI). AB - CORRECTION TO: J CARDIOVASC MAGN RESON (2017) 19: 75. DOI: 10.1186/S12968-017 0389-8: In the original publication of this article [1] the "Competing interests" section was incorrect. The original publication stated the following competing interests. PMID- 29415745 TI - Cutaneous neurofibromas in Neurofibromatosis type I: a quantitative natural history study. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by a predisposition to develop multiple benign tumors. A major feature of NF1 is the development of localized cutaneous neurofibromas. Cutaneous neurofibromas manifest in > 99% of adults with NF1 and are responsible for major negative effects on quality of life. Previous reports have correlated increased burden of cutaneous neurofibromas with age and pregnancy, but longitudinal data are not available to establish a quantitative natural history of these lesions. The purpose of this study is to conduct a prospective natural history study of 22 adults with NF1 over an 8-year period to quantify cutaneous neurofibroma number and size. RESULTS: The average monthly increase in volume for cutaneous neurofibromas was 0.37 mm3 in the back region (95% CI (0.23, 0.51), p < 0.0001), 0.28 mm3 in the abdominal region (95% CI (0.16, 0.41), p < 0.0001), and 0.21 mm3 in the arm/leg region (95% CI (0.08, 0.34), p = 0.0022). The number of cutaneous neurofibromas significantly increased in the back (slope = 0.032, p = 0.011) and abdominal (slope = 0.018, p = 0.026) regions, while the leg/arm regions retained a positive trend (slope = 0.004, p = 0.055). CONCLUSIONS: The number and volume of cutaneous neurofibromas significantly increased over an 8-year timespan; however, the rate of increase is variable by individual and body region. These findings may provide insight into cutaneous neurofibroma development and benefit researchers considering clinical trials targeting cutaneous neurofibromas. PMID- 29415746 TI - Ground-glass opacity heralding invasive lung adenocarcinoma with prodromal dermatomyositis: a case report. AB - BACKGROUND: Dermatomyositis, an inflammatory myopathy with cutaneous involvement, is associated with malignancy and often manifests paraneoplastically. While co occurrence with small cell carcinoma is well attested, primary lung adenocarcinoma, which may present as focal ground-glass opacification on computed tomography of the thorax, is less frequently coincident. CASE PRESENTATION: We report the case of a 72-year-old female patient with dermatomyositis - treated with a combination of prednisone, methotrexate, and intravenous immunoglobulin - and an indolent, subsolid, non-hypermetabolic pulmonary lesion, which was determined to be invasive primary lung adenocarcinoma. Supporting a paraneoplastic basis, immunosuppressive therapy was discontinued following tumor excision without relapse of signs or symptoms of dermatomyositis. CONCLUSIONS: While dermatomyositis prodromal to lung adenocarcinoma is not without precedent, association with an indolent, subsolid lesion has, to the best of our knowledge, not been reported. The case described herein illustrates the importance of maintaining a high index of suspicion for malignancy in the setting of dermatomyositis. PMID- 29415747 TI - Flavagline analog FL3 induces cell cycle arrest in urothelial carcinoma cell of the bladder by inhibiting the Akt/PHB interaction to activate the GADD45alpha pathway. AB - BACKGROUND: Prohibitin 1 (PHB) is a potential target for the treatment of urothelial carcinoma of the bladder (UCB). FL3 is a newly synthesized agent that inhibits cancer cell proliferation by targeting the PHB protein; however, the effect of FL3 in UCB cells remains unexplored. METHODS: FL3 was identified to be a potent inhibitor of UCB cell viability using CCK-8 (cell counting kit-8) assay. Then a series of in vitro and in vivo experiments were conducted to further demonstrate the inhibitory effect of FL3 on UCB cell proliferation and to determine the underlying mechanisms. RESULTS: FL3 inhibited UCB cell proliferation and growth both in vitro and in vivo. By targeting the PHB protein, FL3 inhibited the interaction of Akt and PHB as well as Akt-mediated PHB phosphorylation, which consequently decreases the localization of PHB in the mitochondria. In addition, FL3 treatment resulted in cell cycle arrest in the G2/M phase, and this inhibitory effect of FL3 could be mimicked by knockdown of PHB. Through the microarray analysis of mRNA expression after FL3 treatment and knockdown of PHB, we found that the mRNA expression of the growth arrest and DNA damage-inducible alpha (GADD45alpha) gene were significantly upregulated. When knocked down the expression of GADD45alpha, the inhibitory effect of FL3 on cell cycle was rescued, suggesting that FL3-induced cell cycle inhibition is GADD45alpha dependent. CONCLUSION: Our data provide that FL3 inhibits the interaction of Akt and PHB, which in turn activates the GADD45alpha-dependent cell cycle inhibition in the G2/M phase. PMID- 29415748 TI - An ethnobotanical study in Midyat (Turkey), a city on the silk road where cultures meet. AB - BACKGROUND: Studies of ethnobotanical usages in south-eastern Turkey are rare. To widen this field of knowledge, we conducted an ethnobotanical study in Midyat (Mardin Province), Turkey. METHODS: The field study was completed during three years (2007-2010). Our aim was to document the ethnobotanical uses of local plants and to make an ethnobotanical inventory of uncommon plants using qualitative interviews. RESULTS: During field studies, 368 voucher specimens were collected in the investigated area. Ninety-two traditionally used plant species were reported from Midyat and surrounding vicinities in Turkey. Among the 92 taxa (129 usages), 35% were used for medical purposes, 22% for food, 13% for animal fodder, 7% as ornamental plants and dyes, 6% as brooms, 4% for latex and as fragrance, 4% for herbal tea, molasses and wine preparation, 3% for agricultural purposes, and 6% for other purposes. Comparative assessment showed that Teucrium polium (0.51), Matricaria aurea (0.26), Alcea setosa (0.21), and Malva neglecta (0.21) have the highest recorded UVs, and the following taxa had UVs between 0.10 0.20: Anthemis cotula (0.12), Allium cepa (0.13), Alcea striata subsp. striata (0.14), Crupina crupinastrum (0.12), Papaver rhoeas (0.13), Salvia multicaulis (0.14), Thymbra spicata (0.11), and Vicia pannonica subsp. striata (0.15). We reported the ethnobotanical usages of 21 taxa for the first time, in addition to indicating usages previously recorded in the literature. We also recorded four endemic plant usages in the area: Alkanna trichophila var. mardinensis, Centaurea kurdica, Centaurea stapfiana, and Sideritis libanotica subsp. linearis. They have variable leaf and flower morphology that are used traditionally. They are present as well-developed populations and thus their conservation status is not compromised. Additionally, Thymbra sintenisii is a recorded species that is classified as a rare and extensively used species in the region. CONCLUSIONS: These results contribute to the fundamental knowledge of ethnobotanical usages in Midyat. To date, ethnobotanical studies have not been carried out in this region. This investigation uncovered usages of endemic medicinal plant species and traditional knowledge of Midyat communities living in a mixed culture. The people of Midyat, Batman, and Sirnak are Turkish citizens from various ethnic backgrounds, such as Kurdish, Arabic, and Syriac. We compared our data with results from other studies conducted in Turkey, particularly in south-eastern and eastern regions, as well as with studies from bordering countries, Iraq, Jordan, Syria, and Iran. Nonetheless, more work needs to be conducted to extend the present knowledge for locals to contribute to and evaluate economic potential in the region. PMID- 29415750 TI - Acute malnutrition among children aged 6-59 months of the nomadic population in Hadaleala district, Afar region, northeast Ethiopia. AB - BACKGROUND: Acute malnutrition to be a major health burden in the world, particularly in the developing world. Acute malnutrition is associated with more than one third of the global disease burden for children. Malnourished children are physically, emotionally and intellectually less productive and suffer more from chronic illnesses and disabilities. The nature, magnitude and determinants of acute malnutrition are determined among the general populations; however, there is a lack of evidence in the nomadic communities. METHODS: A cross sectional study was conducted to assess the magnitude and factors associated with acute malnutrition among children aged 6-59 months in Hadaleala district, Afar Region. A total of 591 under-five children were included in this study, and subjects were recruited by the multistage cluster sampling technique. Data were collected by a pre-tested questionnaire and a simple anthropometric index so called mid-upper arm circumference (MUAC). The multivariable binary logistic regression analysis was used to identify factors associated with acute malnutrition on the basis of adjusted odds ratio (AOR) with 95% confidence interval (CI) and p < 0.05. RESULTS: The prevalence of acute malnutrition was 11.8% (95% CI = 9.3, 14.8%). The highest prevalence (50%) of acute malnutrition occurred among children aged between 12.0-23.0 months. Childhood acute malnutrition was associated with the presence of two (AOR = 2.49, p < 0.05) and three (AOR = 12.87, p < 0.001) children in each household, unprotected drinking water sources (AOR = 3.78, p < 0.05), absence of the latrine (AOR = 5.24, p < 0.05), hand washing with soap (AOR = 0.21, p < 0.05), childhood diarrheal disease (AOR = 2.72, p < 0.05), and child vaccination (AOR = 0.15, p < 0.001). CONCLUSION: The prevalence of acute malnutrition among children aged 6-59 months was was higher than the national prevalence. The number of children in each household, drinking water sources, latrine availability, hand washing practice before food preparation and child feeding, childhood diarrheal disease, and child vaccination were identified as factors affecting the childhood acute malnutrition in the nomadic community. Protecting drinking water sources from possible contaminants, improving hand washing practices, utilization of latrine, preventing diarrheal diseases and vaccinating children integrated with the access of nutrition education is important to improve nutrition of children of the nomadic people. PMID- 29415749 TI - The impact of inter-organizational alignment (IOA) on implementation outcomes: evaluating unique and shared organizational influences in education sector mental health. AB - BACKGROUND: Integrated healthcare delivered by work groups in nontraditional service settings is increasingly common, yet contemporary implementation frameworks typically assume a single organization-or organizational unit-within which system-level processes influence service quality and implementation success. Recent implementation frameworks predict that inter-organizational alignment (i.e., similarity in values, characteristics, activities related to implementation across organizations) may facilitate the implementation of evidence-based practices (EBP), but few studies have evaluated this premise. This study's aims examine the impact of overlapping organizational contexts by evaluating the implementation contexts of externally employed mental health clinicians working in schools-the most common integrated service delivery setting for children and adolescents. Aim 1 is to estimate the effects of unique intra organizational implementation contexts and combined inter-organizational alignment on implementation outcomes. Aim 2 is to examine the underlying mechanisms through which inter-organizational alignment facilitates or hinders EBP implementation. METHODS/DESIGN: This study will conduct sequential, exploratory mixed-methods research to evaluate the intra- and inter organizational implementation contexts of schools and the external community based organizations that most often employ school-based mental health clinicians, as they relate to mental health EBP implementation. Aim 1 will involve quantitative surveys with school-based, externally-employed mental health clinicians, their supervisors, and proximal school-employed staff (total n = 120 participants) to estimate the effects of each organization's general and implementation-specific organizational factors (e.g., climate, leadership) on implementation outcomes (fidelity, acceptability, appropriateness) and assess the moderating role of the degree of clinician embeddedness in the school setting. Aim 2 will explore the mechanisms through which inter-organizational alignment influences implementation outcomes by presenting the results of Aim 1 surveys to school-based clinicians (n = 30) and conducting semi-structured qualitative interviews. Qualitative data will be evaluated using an integrative inductive and deductive approach. DISCUSSION: The study aims are expected to identify intra- and inter-organizational constructs that are most instrumental to EBP implementation success in school-based integrated care settings and illuminate mechanisms that may account for the influence of inter-organizational alignment. In addition to improving school-based mental health, these findings will spur future implementation science that considers the relationships across organizations and optimize the capacity of implementation science to guide practice in increasingly complex systems of care. PMID- 29415751 TI - When participants get involved: reconsidering patient and public involvement in clinical trials at the MRC Clinical Trials Unit at UCL. AB - BACKGROUND: Patient and public involvement (PPI) in clinical trials aims to ensure that research is carried out collaboratively with patients and/or members of the public. However, current guidance on involving clinical trial participants in PPI activities is not consistent. METHODS: We reviewed the concept of participant involvement, based on our experience. Two workshops were held at the MRCCTU at UCL with the aim of defining participant involvement, considering its rationale; benefits and challenges; and identifying appropriate models for participant involvement in clinical trials. We considered how participant involvement might complement the involvement of other public contributors. Both workshops were attended by two patient representatives and seven staff members with experience of PPI in trials. Two of the staff members had also been involved in studies that had actively involved participants. They shared details of that work to inform discussions. RESULTS: We defined trial participants as individuals taking part in the study in question, including those who had already completed their trial treatment and/or follow-up. Because of their direct experience, involving participants may offer advantages over other public contributors; for example, in studies of new interventions or procedures, and where it is hard to identify or reach patient or community groups that include or speak for the study population. Participant involvement is possible at all stages of a trial; however, because there are no participants to involve during the design stage of a trial, prior to enrolment, participant involvement should complement and not replace involvement of PPI stakeholders. A range of models, including those with managerial, oversight or responsive roles are appropriate for involving participants; however, involvement in data safety and monitoring committees may not be appropriate where there is a potential risk of unblinding. Involvement of participants can improve the trial experience for other participants; optimising study procedures, improving communications; however, there are some specific, notably, managing participant confidentiality and practicalities relating to payments. CONCLUSIONS: Participant involvement in clinical trials is feasible and complements other forms of PPI in clinical trials. Involving active participants offers significant advantages, particularly in circumstances where trials are assessing new, or otherwise unavailable, therapies or processes. We recommend that current guidance on PPI should be updated to routinely consider including participants as valid stakeholders in PPI and potentially useful approach to PPI. PMID- 29415752 TI - Correction to: A statistical framework for analyzing deep mutational scanning data. AB - CORRECTION: After publication of our article [1] it was brought to our attention that a line of code was missing from our program to combine the within-replicate variance and between-replicate variance. This led to an overestimation of the standard errors calculated using the Enrich2 random-effects model. PMID- 29415753 TI - Recurrent anterior uveitis and subsequent incidence of ankylosing spondylitis: a nationwide cohort study from 2002 to 2013. AB - BACKGROUND: Anterior uveitis is the most common extra-articular manifestation of ankylosing spondylitis (AS). AS-related anterior uveitis frequently presents as acute, recurrent iridocyclitis; therefore, AS is often initially suspected by an ophthalmologist, not by a rheumatologist. In this study, we aimed to investigate the relationship between the recurrence of anterior uveitis and the subsequent incidence of AS. METHODS: From a national sample cohort, 10,483 patients with new onset uveitis between 2004 and 2013 and 52415 matched control subjects who had never experienced uveitis were selected. Among the patients with new-onset uveitis, a subpopulation of patients with recurrent uveitis, defined as a minimum 120-day reported interval between consecutive claims of uveitis (based on diagnostic codes) treated with local or systemic steroids or immune-modulating drugs, was identified. The incidence rates of AS were calculated according to the number of episodes of uveitis, and the incidence rate ratios (IRRs) were derived on the basis of the incidence rate in the control group. RESULTS: The incidence rate per 100,000 person-years of AS after the first uveitis episode was 121.5, whereas the incidence in the control group was 16.9 (IRR, 7.40; 95% CI, 4.99 10.98); after the second uveitis episode, the IRR increased to 17.71 (95% CI, 10.44-30.06). In male and female patients with recurrent uveitis, the incidence rates of AS were 284.1 and 268.7 per 100,000 person-years, respectively. In patients aged under 40 years, the IRR of the recurrent uveitis group was 46.78 (95% CI, 19.61-111.61). In patients aged over 59 years, AS incidence in the recurrent uveitis group did not differ from that in the control group. CONCLUSIONS: The risk of subsequent AS increased with the number of episodes of anterior uveitis. This quantitative evidence could contribute to the establishment of a rationale for ancillary workup for possible systemic associations in patients with recurrent uveitis. PMID- 29415754 TI - Guanxinning tablet for patients who switch from dual antiplatelet therapy to aspirin alone after percutaneous coronary intervention: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: One-year dual antiplatelet therapy (DAPT), generally aspirin in combination with a P2Y12 receptor inhibitor, has been a standard treatment for patients undergoing percutaneous coronary intervention (PCI). Prolonged DAPT has proven itself effective in further reducing cardiovascular events, yet with increased risk of bleeding. Thus, it is of great necessity to find an alternative drug that is as effective but safer and more economic than the P2Y12 inhibitors after termination of one-year DAPT. METHODS: We will conduct a cluster randomized controlled trial in 3600 eligible post-PCI patients from 36 tertiary hospitals (100 patients per hospital) across mainland China. The hospitals served as clusters are randomized in a 2:1 ratio to Guanxinning tablet (GXNT) plus aspirin or aspirin alone for 12 months, with other conventional treatment applied in both groups. After the treatment period, all patients will be followed up for another 12 months. The primary outcome measure is composite cardiovascular events including cardiovascular death, non-fatal myocardial infarction, stent thrombosis, revascularization, ischemic stroke, and re-admission due to unstable angina. Secondary outcome measures are all-cause mortality, each individual component of the primary outcome measure, and stopping or reducing the rate of nitroglycerin administration. Adverse events, including bleeding, will be closely monitored during the whole trial period. In addition, a cost-effectiveness study of GXNT for the study population will be conducted along with this trial. DISCUSSION: This trial aims to determine whether the addition of GXNT will further improve prognosis without increasing bleeding risk for patients with coronary artery disease who have switched from DAPT to aspirin alone after PCI. Completion of this clinical trial might provide a novel, promising, and safer alternative to P2Y12 inhibitors for prolonged antiplatelet therapy in post-PCI patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IIR 17010688 . Registered on 20 February 2017. PMID- 29415755 TI - The new aims and scope of Arthritis Research & Therapy. PMID- 29415756 TI - Fli1-haploinsufficient dermal fibroblasts promote skin-localized transdifferentiation of Th2-like regulatory T cells. AB - BACKGROUND: Friend leukemia virus integration 1 (Fli1) deficiency, a predisposing factor of systemic sclerosis (SSc), induces SSc-like phenotypes in various cell types. A recent study demonstrated the transdifferentiation of T helper type 2 cell (Th2)-like regulatory T cells (Tregs) in SSc lesional skin through interleukin (IL)-33 produced by fibroblasts. Therefore, we investigated the role of Fli1 deficiency in dermal fibroblast-mediated transdifferentiation of Tregs. METHODS: Cytokine expression was assessed in Tregs by flow cytometry and in skin samples and cultivated cells by immunostaining, immunoblotting, and/or qRT-PCR. Fli1 binding to the target gene promoters was examined by chromatin immunoprecipitation. Murine dermal fibroblasts and Tregs were cocultured with or without blocking antibodies against target cytokines. RESULTS: Th2- and Th17-like cell proportions in skin-homing Tregs were increased in bleomycin-treated Fli1 +/ mice compared with bleomycin-treated wild-type mice, whereas Th1-, Th2-, and Th17-like cell proportions in splenic Tregs were comparable. Fli1+/- fibroblasts overproduced IL-33 and IL-6, in particular IL-33, and Fli1 occupied the IL33 and IL6 promoters in dermal fibroblasts. Importantly, the IL-4-producing cell proportion was significantly higher in wild-type Tregs cocultured with Fli1+/- fibroblasts than in those cocultured with wild-type fibroblasts, which were canceled by neutralizing anti-IL-33 antibody. Under the same coculture condition, an increased tendency of IL-17A-producing cell proportion, which was possibly mediated by IL-6, was evident. CONCLUSIONS: Fli1 haploinsufficiency increases the proportions of Th2- and Th17-like Tregs in bleomycin-induced profibrotic skin conditions, in which IL-33-producing dermal fibroblasts contribute to Th2-like Treg transdifferentiation, suggesting a critical role of Fli1 deficiency in the interaction of dermal fibroblasts with immune cells in pathological skin fibrosis. PMID- 29415757 TI - Soluble uric acid increases PDZK1 and ABCG2 expression in human intestinal cell lines via the TLR4-NLRP3 inflammasome and PI3K/Akt signaling pathway. AB - BACKGROUND: In addition to the kidney, the intestine is one of the most important organs involved in uric acid excretion. However, the mechanism of urate excretion in the intestine remains unclear. Therefore, the relationship between soluble uric acid and the gut excretion in human intestinal cells was explored. The relevant signaling molecules were then also examined. METHODS: HT-29 and Caco-2 cell lines were stimulated with soluble uric acid. Western blotting and qRT-PCR were used to measure protein and mRNA levels. Subcellular fractionation methods and immunofluorescence were used to quantify the proteins in different subcellular compartments. Flow cytometry experiments examined the function of ATP binding cassette transporter, subfamily G, member 2 (ABCG2). Small interfering RNA transfection was used to assess the interaction between ABCG2 and PDZ domain containing 1 (PDZK1). RESULTS: Soluble uric acid increased the expression of PDZK1 and ABCG2. The stimulation of soluble uric acid also facilitated the translocation of ABCG2 from the intracellular compartment to the plasma membrane and increased its transport activity. Moreover, the upregulation of PDZK1 and ABCG2 by soluble uric acid was partially decreased by either TLR4-NLRP3 inflammasome inhibitors or PI3K/Akt signaling inhibitors. Furthermore, PDZK1 knockdown significantly inhibited the expression and transport activity of ABCG2 regardless of the activation by soluble uric acid, demonstrating a pivotal role for PDZK1 in the regulation of ABCG2. CONCLUSIONS: These findings suggest that urate upregulates the expression of PDZK1 and ABCG2 for excretion in intestinal cells via activating the TLR4-NLRP3 inflammasome and PI3K/Akt signaling pathway. PMID- 29415758 TI - Trustworthy or flawed clinical prediction rule? PMID- 29415759 TI - Occurrence of Giardia duodenalis assemblages in farmed long-tailed chinchillas Chinchilla lanigera (Rodentia) from Romania. AB - BACKGROUND: Giardia duodenalis is a parasitic protist that infects a large number of species, being localized in the small intestine. Two of the eight recognized assemblages have zoonotic potential, but studies regarding their distribution in less important pet or farm species are scarce. Of these species, the long-tailed chinchilla is a host for Giardia spp., although data on the spread of infection and assemblages involved are confined. The present work aimed to determine the prevalence of Giardia infection and assemblage identification in farmed chinchillas in Romania. A total of 341 fecal samples were collected from 5 farms and microscopically examined using flotation test based on saturated sodium chloride solution. DNA from all positive samples was extracted and identified by PCR targeting the gdh gene. RESULTS: The overall prevalence of Giardia infection was 55.7% (190/341); there was no statistically significant difference (P = 0.25) in prevalence between young animals (58.8%) and adults (52.6%). Assemblages B (151/190), D (33/190) and E (6/190) were identified. Among assemblage B, sub assemblages BIII (6/151) and BIV (145/151) were determined. CONCLUSIONS: This study demonstrates that Giardia spp. infection is highly prevalent in farmed chinchillas from Romania, and the sub-assemblages identified are potentially zoonotic. PMID- 29415761 TI - Direct serogrouping of Dichelobacter nodosus from Victorian farms using conventional multiplex polymerase chain reaction. AB - OBJECTIVE: Dichelobacter nodosus is the causative agent of footrot in sheep. Ovine footrot is a major problem in Australia that results in large economic losses and a represents a very significant animal welfare issue. D. nodosus is divided into 10 serogroups (A-I, M), based on sequence variation in the type IV fimbriae gene, fimA. Control of the bacteria is possible through use of serogroup specific vaccination, however traditional identification of the serogroups of D. nodosus on infected sheep is time-consuming and costly. With the aim of reducing time and cost, a PCR assay was used to identify serogroups of D. nodosus directly from foot swabs of infected sheep in Victoria. RESULTS: It was shown that serogroup B was most common (10 locations), followed by A, G and H (4 locations), I and C (2 locations), D, E and F (1 location). Infections with multiple serotypes were observed in 50% of farms, with the remaining 50% having only a single serogroup detected. The ability to identify serogroups quickly and cheaply direct from foot swabs will aid the understanding of the epidemiology of D. nodosus and support control programs. PMID- 29415760 TI - Mobile critical care recovery program (m-CCRP) for acute respiratory failure survivors: study protocol for a randomized controlled trial. AB - BACKGROUND: Patients admitted to intensive care units (ICU) with acute respiratory failure (ARF) face chronic complications that can impede return to normal daily function. A mobile, collaborative critical care model may enhance the recovery of ARF survivors. METHODS: The Mobile Critical Care Recovery Program (m-CCRP) study is a two arm, randomized clinical trial. We will randomize 620 patients admitted to the ICU with acute respiratory failure requiring mechanical ventilation in a 1:1 ratio to one of two arms (310 patients per arm) - m-CCRP intervention versus attention control. Those in the intervention group will meet with a care coordinator after hospital discharge in predetermined intervals to aid in the recovery process. Baseline assessments and personalized goal setting will be used to develop an individualized care plan for each patient after discussion with an interdisciplinary team. The attention control arm will receive printed material and telephone reminders emphasizing mobility and management of chronic conditions. Duration of the intervention and follow-up is 12 months post randomization. Our primary aim is to assess the efficacy of m-CCRP in improving the quality of life of ARF survivors at 12 months. Secondary aims of the study are to evaluate the efficacy of m-CCRP in improving function (cognitive, physical, and psychological) of ARF survivors and to determine the efficacy of m CCRP in reducing acute healthcare utilization. DISCUSSION: The proposed randomized controlled trial will evaluate the efficacy of a collaborative critical care recovery program in accomplishing the Institute of Healthcare Improvement's triple aims of better health, better care, at lower cost. We have developed a collaborative critical care model to promote ARF survivors' recovery from the physical, psychological, and cognitive impacts of critical illness. In contrast to a single disease focus and clinic-based access, m-CCRP represents a comprehensive, accessible, mobile, ahead of the curve intervention, focused on the multiple aspects of the unique recovery needs of ARF survivors. TRIAL REGISTRATION: NCT03053245 , clinicaltrials.gov, registered February 1, 2017. PMID- 29415762 TI - Altered white matter microstructure in lupus patients: a diffusion tensor imaging study. AB - BACKGROUND: The purpose of this study was to investigate whether white matter microstructure is altered in patients suffering from systemic lupus erythematosus (SLE), and if so, whether such alterations differed between patients with and without neuropsychiatric symptoms. METHODS: Structural MRI and diffusion tensor imaging (DTI) were performed in 64 female SLE patients (mean age 36.9 years, range 18.2-52.2 years) and 21 healthy controls (mean age 36.7 years, range 23.3 51.2 years) in conjunction with clinical examination, laboratory tests, cognitive evaluation, and self-assessment questionnaires. The patients were subgrouped according to the American College of Rheumatology Neuropsychiatric Systemic Lupus Erythematosus case definitions into non-neuropsychiatric SLE (nonNPSLE) and neuropsychiatric SLE (NPSLE). RESULTS: Comparisons between the SLE group and healthy controls showed that the mean fractional anisotropy (FA) was significantly reduced in the right rostral cingulum (p = 0.038), the mid-sagittal corpus callosum (CC) (p = 0.050), and the forceps minor of the CC (p = 0.015). The mean diffusivity (MD) was significantly increased in the left hippocampal cingulum (p = 0.017). No significant differences in MD or FA values were identified between NPSLE and nonNPSLE patients. Disease duration among all SLE patients correlated significantly with reduced FA in the CC (p < 0.05). No correlations were found between DTI parameters and white matter hyperintensities, SLE Disease Activity Index-2000, Systemic Lupus International Collaborating Clinical/ACR Organ Damage Index, or Montgomery Asberg Depression Rate Score Self report. CONCLUSIONS: We found alterations of white matter microstructure in SLE patients that were related to disease duration and fatigue. Our results indicate that cerebral involvement in SLE is not isolated to the NPSLE subgroup. PMID- 29415763 TI - Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor mediated cytokine production in human macrophages in IDO-dependent manner. AB - BACKGROUND: The anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and rheumatoid factor [RF]). Considering that autoantibodies trigger inflammatory cytokine production by monocytes and that abatacept binds to monocytes, influencing their functional state, we hypothesized that abatacept may effectively inhibit the production of several different cytokines by ACPA- or RF challenged monocytes. METHODS: Peripheral blood CD68+ monocytes stimulated with macrophage colony-stimulating factor for 24 h were exposed to random immunoglobulin G alone (negative control), purified ACPA, purified RF, or lipopolysaccharide (positive control) in cell culture plates coated with citrullinated vimentin (to allow ACPA immune complex formation). Stimulations were done in the presence or absence of abatacept or tumor necrosis factor (TNF) antibody (adalimumab) with or without indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan. Supernatants were analyzed for key proinflammatory cytokines TNF-alpha, interleukin (IL)-1beta, IL-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) after 24 h. RESULTS: Exposure to ACPA or RF significantly induced the production of TNF-alpha (20-fold and 27-fold, respectively), IL-1beta (each 4-fold), IL-6 (12-fold and 11-fold, respectively), IL-8 (43-fold and 30 fold, respectively), and CCL2 (each 4-fold) in human monocytes. Abatacept inhibited this autoantibody-mediated upregulation of cytokines, reducing TNF alpha by > 75%, IL-1beta by > 65%, IL-6 and IL-8 by > 80%, and CCL2 by > 60%. In contrast, a TNF inhibitor did not influence autoantibody-induced proinflammatory cytokine production. IDO inhibition reversed the effect of abatacept and again permitted the induction of cytokine production by ACPA and RF. CONCLUSIONS: These data show that abatacept interferes with autoantibody-mediated cytokine production by monocytes through induction of IDO. This inhibitory effect on the production of several effector cytokines in RA may explain the fast anti inflammatory effect of abatacept as well as its preferential efficacy in patients with high-titer ACPA and RF. PMID- 29415764 TI - Discrimination between some Mycoplasma spp. and Acholeplasma laidlawii in bovine milk using high resolution melting curve analysis. AB - OBJECTIVES: This study aimed to provide a rapid, accurate and cost-effective diagnostic real time polymerase chain reaction-high resolution melting curve assay (PCR-HRM) to identify and distinguish between four different mycoplasmas and Acholeplasma laidlawii isolated at cow-level from a single commercial dairy farm in South Australia. One set of genus-level universal primers was designed targeting the 16S ribosomal RNA gene. RESULTS: Real time PCR-HRM analysis was able to identify and distinguish between five different mollicutes, namely A. laidlawii, M. arginini, M. bovirhinis, M. bovis and uncultured Mycoplasma. Results were confirmed through sequencing. Our developed assay provides rapid and accurate screening for Mycoplasma mastitis detection. PMID- 29415765 TI - Double non-contiguous fractures in a patient with spondylo-epiphyseal dysplasia with spinal ankylosis treated with open and percutaneous spinal fixation technique: a case report. AB - BACKGROUND: Patients with ankylosing spines are susceptible to developing spinal fractures even with minor trauma and can develop early or late neurological injuries. These fractures require early and aggressive surgical management to enable spinal stability and/or neural decompression. Being highly unstable by nature, they require relatively long segment instrumentation and fusion, which can increase paravertebral soft tissue damage and perioperative bleeding. The purpose of this report is to describe a rare case of traumatic double fractures at the cervico-thoracic and thoraco-lumbar transition zones in ankylosing spine with spondylo-epiphyseal dysplasia (SED) of unknown cause, which were successfully treated with a combined open and percutaneous spinal fusion procedure. CASE PRESENTATION: A 46-year-old woman who was diagnosed with non contiguous fractures in cervico-thoracic and thoraco-lumbar junction zones among multiple injuries sustained in a traffic accident was treated with hybrid techniques for posterior instrumentation with an open approach using a computed tomography (CT)-based navigation system and percutaneous pedicle-screwing method. She regained mobility to pre-admission levels and started walking on crutches 3 months postoperatively. Genetic testing for the cause of SED revealed no mutation in the COL2A1 or TRPVR4 genes. The union of fractured spine was confirmed on CT scan 1 year postoperatively. CONCLUSION: This is the first report of double spinal fractures in an ankylosing spine with genetically undetermined spondyloepiphyseal dysplasia. A long-segment posterior instrumentation procedure incorporating the invasive treatment of spinal fractures in ankylosing spondylitis or diffuse idiopathic hyperostosis was effective. PMID- 29415766 TI - Cryptosporidium infection in bovine calves: prevalence and potential risk factors in northwest Ethiopia. AB - OBJECTIVE: Cryptosporidium is an enteric protozoan organism that causes gastrointestinal disorders in different animals, mainly in calves. The parasite has also a zoonotic importance of children and immunocompromised patients. However, data are limited to northwest Ethiopia. Therefore, we conducted a cross sectional survey from October 2014 to April 2015 to estimate the prevalence of Cryptosporidium infection and to identify potential risk factors in bovine calves in northwest Ethiopia. RESULTS: Out of the 360 examined calves, Cryptosporidium oocysts were recorded in 67 (18.6%) calves. Risk factors such as age, hygiene, faecal consistency, feed source, water source and contact with other domestic animals were significantly (P < 0.05) affected the occurrence of Cryptosporidium infection. However, significant variations (P > 0.05) were not recorded between Cryptosporidium infection and gender, body condition score, breed and study sites. Using multivariable analysis, age, feed source, water source, hygiene and close contact with other domestic animals were recognized as potential risk factors for the occurrence of Cryptosporidium infection. This study clearly figures out that Cryptosporidium infection is prevalent in the study area. Therefore, further studies, extension services and community education are recommended to adopt an integrated control approaches. PMID- 29415767 TI - Swinepox virus vector-based vaccines: attenuation and biosafety assessments following subcutaneous prick inoculation. AB - Swinepox virus (SPV) has several advantages as a potential clinical vector for a live vector vaccine. In this study, to obtain a safer and more efficient SPV vector, three SPV mutants, Delta003, Delta010, and DeltaTK were successfully constructed. A virus replication experiment showed that these SPV mutants had lower replication abilities compared to wtSPV in 10 different host-derived cell lines. Animal experiments with mouse and rabbit models demonstrate that these three mutants and wtSPV did not cause any clinical signs of dermatitis. No fatalities were observed during a peritoneal challenge assay with these mutants and wtSPV in a mouse model. Additionally, the three mutants and wtSPV were not infectious at 60 h after vaccination in rabbit models. Furthermore, we evaluated biosafety, immunogenicity and effectiveness of the three mutants in 65 1-month old piglets. The results show that there were no clinical signs of dermatitis in the Delta003 and DeltaTK vaccination groups. However, mild signs were observed in the Delta010 vaccination groups when virus titres were high, and apparent clinical signs were observed at the sites of inoculation. Samples from all experimental pig groups were assessed by qPCR, and no SPV genomic DNA was found in five organs, faeces or blood. This suggests that the infectious abilities of wtSPV and the SPV mutants were poor and limited. In summary, this study indicates that two mutants of SPV, Delta003 and DeltaTK, may be promising candidates for an attenuated viral vector in veterinary medicine. PMID- 29415768 TI - Design and first baseline data of the DZNE multicenter observational study on predementia Alzheimer's disease (DELCODE). AB - BACKGROUND: Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer's disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention. METHODS: The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics. In addition, individuals with amnestic MCI, mild Alzheimer's dementia patients, first-degree relatives of patients with Alzheimer's dementia, and cognitively unimpaired control subjects are studied. The total number of subjects to be enrolled is 1000. Participants receive extensive clinical and neuropsychological assessments, magnetic resonance imaging, positron emission tomography, and biomaterial collection is perfomed. In this publication, we report cognitive and clinical data as well as apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) biomarker results of the first 394 baseline data sets. RESULTS: In comparison with the control group, patients with SCD showed slightly poorer performance on cognitive and functional measures (Alzheimer's Disease Assessment Scale-cognitive part, Clinical Dementia Rating, Functional Activities Questionnaire), with all mean scores in a range which would be considered unimpaired. APOE4 genotype was enriched in the SCD group in comparison to what would be expected in the population and the frequency was significantly higher in comparison to the control group. CSF Abeta42 was lower in the SCD group in comparison to the control group at a statistical trend with age as a covariate. There were no group differences in Tau or pTau concentrations between the SCD and the control groups. The differences in all measures between the MCI group and the AD group were as expected. CONCLUSIONS: The initial baseline data for DELCODE support the approach of using SCD in patients recruited through memory clinics as an enrichment strategy for late-stage preclinical AD. This is indicated by slightly lower performance in a range of measures in SCD in comparison to the control subjects as well as by enriched APOE4 frequency and lower CSF Abeta42 concentration. TRIAL REGISTRATION: German Clinical Trials Register DRKS00007966 . Registered 4 May 2015. PMID- 29415769 TI - Incidence of acute lymphocytic leukemia in Calgary, Alberta, Canada: a retrospective cohort study. AB - OBJECTIVE: Acute lymphocytic leukemia (ALL) is a rare malignant neoplasm that develops from abnormal lymphoid stem cells. ALL incidence is highest among children and declines towards adolescence. There is limited data on the epidemiology of ALL, especially in Canada. This retrospective cohort study used patient data from the Calgary Laboratory Services Cancer Cytogenetics Laboratory to report the incidence rate of ALL in Calgary, Alberta, Canada. New cases of ALL were identified for the 5-year period of January 1, 2011 until December 31, 2015. Reported incidence rates were categorized by sex and age groups, and age standardized to the Canadian population. RESULTS: There were an average of 11.4 new cases of ALL diagnosed per year between 2011 and 2015. The total incidence rate per 100,000 person-years was 0.84. Incidence rates peaked in children aged 0 4 with 7.55 and 3.32 cases per 100,000 person-years for males and females, respectively. The median age of diagnosis was 8 years. Incidence rates were generally lowest for adults aged 20 and over. The ratio of males to females diagnosed with ALL was 1.59. Overall, the recent incidence of ALL in Calgary is comparatively low with a preference for males and children below 5 years of age. PMID- 29415770 TI - Early brain connectivity alterations and cognitive impairment in a rat model of Alzheimer's disease. AB - BACKGROUND: Animal models of Alzheimer's disease (AD) are essential to understanding the disease progression and to development of early biomarkers. Because AD has been described as a disconnection syndrome, magnetic resonance imaging (MRI)-based connectomics provides a highly translational approach to characterizing the disruption in connectivity associated with the disease. In this study, a transgenic rat model of AD (TgF344-AD) was analyzed to describe both cognitive performance and brain connectivity at an early stage (5 months of age) before a significant concentration of beta-amyloid plaques is present. METHODS: Cognitive abilities were assessed by a delayed nonmatch-to-sample (DNMS) task preceded by a training phase where the animals learned the task. The number of training sessions required to achieve a learning criterion was recorded and evaluated. After DNMS, MRI acquisition was performed, including diffusion weighted MRI and resting-state functional MRI, which were processed to obtain the structural and functional connectomes, respectively. Global and regional graph metrics were computed to evaluate network organization in both transgenic and control rats. RESULTS: The results pointed to a delay in learning the working memory-related task in the AD rats, which also completed a lower number of trials in the DNMS task. Regarding connectivity properties, less efficient organization of the structural brain networks of the transgenic rats with respect to controls was observed. Specific regional differences in connectivity were identified in both structural and functional networks. In addition, a strong correlation was observed between cognitive performance and brain networks, including whole-brain structural connectivity as well as functional and structural network metrics of regions related to memory and reward processes. CONCLUSIONS: In this study, connectivity and neurocognitive impairments were identified in TgF344-AD rats at a very early stage of the disease when most of the pathological hallmarks have not yet been detected. Structural and functional network metrics of regions related to reward, memory, and sensory performance were strongly correlated with the cognitive outcome. The use of animal models is essential for the early identification of these alterations and can contribute to the development of early biomarkers of the disease based on MRI connectomics. PMID- 29415771 TI - Bibliometric analysis of global scientific activity on umbilical cord mesenchymal stem cells: a swiftly expanding and shifting focus. AB - Several studies have focused on umbilical cord-derived mesenchymal stem cells (UC MSCs) due to their potential therapeutic effects in a cluster of diseases. However, there has been no bibliometric analysis evaluating the evolution in UC MSC research. Therefore, this study aimed to assess scientific activity regarding UC-MSC research. Publications on UC-MSCs were retrieved from the Science Citation Index-Expanded (SCI-E) of the Web of Science (WoS) from 1975 to 2017. Statistical analyses were performed using Excel, GraphPad Prism 5, and VOSviewer software. Comparative analyses were employed to assess contributions between different countries, institutes, and researchers. With 21.26 citations per paper, 1206 papers cited 25,517 times were included. Mainland China contributed the most with 558 papers, with the most citations (6858 times) and the highest H-index (43). South Korea ranked first for number of papers per million people and per trillion gross domestic product (GDP). Keywords were stratified into two clusters by VOSviewer software: cluster 1, "treatments and effects"; and cluster 2, "characteristics". The average appearing years (AAY) of keywords in cluster 1 was more recent than that in cluster 2. For promising hotspots, "TNF-alpha" showed the latest AAY at 2014.09, followed by "migration", "angiogenesis", and "apoptosis". We conclude that the number of publications has been continuously growing dramatically since 2002 and that mainland China and South Korea are the most productive regions. The focus gradually shifts from "characteristics" to "treatments and effects". Attention should be drawn to the latest hotspots, such as "TNF-alpha", "migration", "angiogenesis", and "apoptosis". Furthermore, funding agencies might increase investments in exploring the therapeutic potential of UC-MSCs. PMID- 29415772 TI - Kourami: graph-guided assembly for novel human leukocyte antigen allele discovery. AB - Accurate typing of human leukocyte antigen (HLA) is important because HLA genes play important roles in immune responses and disease genesis. Previously available computational methods are database-matching approaches and their outputs are inherently limited by the completeness of already known types, making them unsuitable for discovery of novel alleles. We have developed a graph-guided assembly technique for classical HLA genes, which can construct allele sequences given high-coverage whole-genome sequencing data. Our method delivers highly accurate HLA typing, comparable to the current state-of-the-art methods. Using various data, we also demonstrate that our method can type novel alleles. PMID- 29415773 TI - End-expiratory occlusion maneuver to predict fluid responsiveness in the intensive care unit: an echocardiographic study. AB - BACKGROUND: In mechanically ventilated patients, an increase in cardiac index during an end-expiratory-occlusion test predicts fluid responsiveness. To identify this rapid increase in cardiac index, continuous and instantaneous cardiac index monitoring is necessary, decreasing its feasibility at the bedside. Our study was designed to investigate whether changes in velocity time integral and in peak velocity obtained using transthoracic echocardiography during an end expiratory-occlusion maneuver could predict fluid responsiveness. METHODS: This single-center, prospective study included 50 mechanically ventilated critically ill patients. Velocity time integral and peak velocity were assessed using transthoracic echocardiography before and at the end of a 12-sec end-expiratory occlusion maneuver. A third set of measurements was performed after volume expansion (500 mL of saline 0.9% given over 15 minutes). Patients were considered as responders if cardiac output increased by 15% or more after volume expansion. RESULTS: Twenty-eight patients were responders. At baseline, heart rate, mean arterial pressure, cardiac output, velocity time integral and peak velocity were similar between responders and non-responders. End-expiratory-occlusion maneuver induced a significant increase in velocity time integral both in responders and non-responders, and a significant increase in peak velocity only in responders. A 9% increase in velocity time integral induced by the end-expiratory-occlusion maneuver predicted fluid responsiveness with sensitivity of 89% (95% CI 72% to 98%) and specificity of 95% (95% CI 77% to 100%). An 8.5% increase in peak velocity induced by the end-expiratory-occlusion maneuver predicted fluid responsiveness with sensitivity of 64% (95% CI 44% to 81%) and specificity of 77% (95% CI 55% to 92%). The area under the receiver operating curve generated for changes in velocity time integral was significantly higher than the one generated for changes in peak velocity (0.96 +/- 0.03 versus 0.70 +/- 0.07, respectively, P = 0.0004 for both). The gray zone ranged between 6 and 10% (20% of the patients) for changes in velocity time integral and between 1 and 13% (62% of the patients) for changes in peak velocity. CONCLUSIONS: In mechanically ventilated and sedated patients in the neuro Intensive Care Unit, changes in velocity time integral during a 12-sec end-expiratory-occlusion maneuver were able to predict fluid responsiveness and perform better than changes in peak velocity. PMID- 29415774 TI - Burkitt's lymphoma with placental invasion diagnosed at cesarean delivery: a case report. AB - BACKGROUND: Burkitt's lymphoma is a highly aggressive B cell non-Hodgkin lymphoma subtype. Its occurrence in pregnancy is rare and often results in a delayed diagnosis. The treatment plan and prognosis depend on a number of variables including the stage at diagnosis. CASE PRESENTATION: A 32 weeks pregnant, 34-year old white woman presented with weeks of complaints that were similar to typical pregnancy symptoms. Laboratory and ultrasound findings suggested a pathologic process and during the workup non-reassuring fetal surveillance resulted in an emergency cesarean delivery. Biopsies were obtained that confirmed Burkitt's lymphoma. Placental histology revealed microscopic involvement. CONCLUSIONS: The placenta should be inspected for microscopic disease if Burkitt's lymphoma is suspected, even if a vaginal delivery occurs and the placenta is ordinarily discarded. Repetitive somatic complaints during pregnancy should not be assumed to be secondary to the normal symptoms of pregnancy. PMID- 29415776 TI - Nutritional interventions among old people receiving support at home. AB - With the focus of care shifting from the hospital to the community, supportive nutritional care to old people is to become an important issue to address in the community, since undernutrition has serious consequences, both for the quality of life and for the health care costs. Several modifiable nutritional risk factors relate to undernutrition. Unfortunately, the problem with (risk of) undernutrition is aggravated due to a lack of alertness among e.g. health care staff, leading to insufficient attention for systemic screening and nutritional care. Only a few of the existing screening tools have been validated among old people receiving support at home. Few studies have assessed the beneficial effect of nutritional support among old people in their own home, and recently, it was concluded that such have shown limited effects. One reason may be that the nutritional interventions performed have not taken the multiple nutritional risk factors afore-mentioned into consideration when formulating the action/treatment plan and hence not used a multidisciplinary approach. Another reason may be that the intervention studies have not used validated screening tools to identify those old people most likely to benefit from the nutritional support. However, three recent studies have used a multidisciplinary approach and two have proven a beneficial effect on the quality of life of the old people and the health care costs. These findings suggest that when planning nutritional intervention studies for old people receiving support at home, modifiable nutritional risk factors should be taken into consideration, and a multidisciplinary approach considered. PMID- 29415775 TI - Effects of cumulative illness severity on hippocampal gray matter volume in major depression: a voxel-based morphometry study. AB - BACKGROUND: Patients with major depression show reduced hippocampal volume compared to healthy controls. However, the contribution of patients' cumulative illness severity to hippocampal volume has rarely been investigated. It was the aim of our study to find a composite score of cumulative illness severity that is associated with hippocampal volume in depression. METHODS: We estimated hippocampal gray matter volume using 3-tesla brain magnetic resonance imaging in 213 inpatients with acute major depression according to DSM-IV criteria (employing the SCID interview) and 213 healthy controls. Patients' cumulative illness severity was ascertained by six clinical variables via structured clinical interviews. A principal component analysis was conducted to identify components reflecting cumulative illness severity. Regression analyses and a voxel-based morphometry approach were used to investigate the influence of patients' individual component scores on hippocampal volume. RESULTS: Principal component analysis yielded two main components of cumulative illness severity: Hospitalization and Duration of Illness. While the component Hospitalization incorporated information from the intensity of inpatient treatment, the component Duration of Illness was based on the duration and frequency of illness episodes. We could demonstrate a significant inverse association of patients' Hospitalization component scores with bilateral hippocampal gray matter volume. This relationship was not found for Duration of Illness component scores. CONCLUSIONS: Variables associated with patients' history of psychiatric hospitalization seem to be accurate predictors of hippocampal volume in major depression and reliable estimators of patients' cumulative illness severity. Future studies should pay attention to these measures when investigating hippocampal volume changes in major depression. PMID- 29415777 TI - Influence of food availability on mate-guarding behaviour of ladybirds. AB - A recent study on ladybird, Menochilus sexmaculatus (Fabricius) demonstrates that males perform post-copulatory mate guarding in the form of prolonged mating durations. We investigated whether food resource fluctuation affects pre- and post-copulatory behaviour of M. sexmaculatus. It has not been studied before in ladybirds. For this, adults were subjected to prey resource fluctuations sequentially at three levels: post-emergence (Poe; 10 days), pre-mating (Prm; 24 h) and post-mating (Pom; 5 days; only female). The food resource conditions at each level could be any one of scarce, optimal or abundant. Pre-copulatory and post-copulatory behaviour, and reproductive output were assessed. Post-emergence and pre-mating nutrient conditions significantly influenced the pre-copulatory behaviour. Males reared on scarce post-emergence conditions were found to require significantly higher number of mating attempts to establish mating unlike males in the other two food conditions. Under scarce post-emergence and pre-mating conditions, time to commencement of mating and latent period were high but opposite result was obtained for mate-guarding duration. Fecundity and per cent egg viability were more influenced by post-mating conditions, with scarce conditions stopping oviposition regardless of pre-mating and post-emergence conditions. Present results indicate that pre- and post-copulatory behaviour of ladybird is plastic in nature in response to food resource fluctuations. PMID- 29415778 TI - The history of transdisciplinary race classification: methods, politics and institutions, 1840s-1940s. AB - A recently blossoming historiographical literature recognizes that physical anthropologists allied with scholars of diverse aspects of society and history to racially classify European peoples over a period of about a hundred years. They created three successive race classification coalitions - ethnology, from around 1840; anthropology, from the 1850s; and interwar raciology - each of which successively disintegrated. The present genealogical study argues that representing these coalitions as 'transdisciplinary' can enrich our understanding of challenges to disciplinary specialization. This is especially the case for the less well-studied nineteenth century, when disciplines and challenges to disciplinary specialization were both gradually emerging. Like Marxism or structuralism, race classification was a holistic interpretive framework, which, at its most ambitious, aimed to structure the human sciences as a whole. It resisted the organization of academia and knowledge into disciplines with separate organizational institutions and research practices. However, the 'transdisciplinarity' of this nationalistic project also bridged emerging borderlines between science and politics. I ascribe race classification's simultaneous longevity and instability to its complex and intricately entwined processes of political and interdisciplinary coalition building. Race classification's politically useful conclusions helped secure public support for institutionalizing the coalition's component disciplines. Institutionalization in turn stimulated disciplines to professionalize. They emphasized disciplinary boundaries and insisted on apolitical science, thus ultimately undermining the 'transdisciplinary' project. PMID- 29415779 TI - Severe bicuspid aortic stenosis in pregnancy: balancing the risk of prematurity and maternal mortality. AB - We report a case of combined severe aortic stenosis and regurgitation in a pregnant patient with a history of congenital bicuspid aortic valve. The patient presented at 22 weeks of gestation with angina and pre-syncopal symptoms. During her admission, she experienced intermittent episodes of non-sustained ventricular tachycardia and hypotension. A multi-disciplinary healthcare team was assembled to decide on the appropriate medical and surgical treatment options. At 28 weeks of gestation, the patient underwent a caesarean delivery immediately followed by a mechanical aortic valve replacement. PMID- 29415780 TI - Rearing conditions and life history influence the progress of gametogenesis and reproduction performances in pikeperch males and females. AB - Pikeperch (Sander lucioperca) is a highly valuable fish in Europe. However, development of aquaculture of pikeperch is highly limited due to seasonality of production. This can be overcome by the controlled reproduction of domesticated fish. The first steps of domestication process may induce changes at anatomical, physiological and molecular levels, thereby affecting a variety of biological functions. While there is abundant literature on their effects on stress and growth for example, these effects on reproduction received limited attention notably in pikeperch, a promising candidate for the development of aquaculture. To answer the question of this life-history effect on pikeperch's reproduction, we compared two groups (weight: 1 kg) originated from Czech Republic and with the same domestication level (F0). The first group was a recirculating aquatic system cultured one (2 years, previously fed with artificial diet, never exposed to natural changes in temperature/photoperiod conditions) and the second one was a pond cultured group (3 to 4 years, bred under natural feeding and temperature/photoperiod). The wild group successfully spawned, while the farmed one did not spawn at all. During the program, gonadosomatic indexes of both males and females were significantly higher for the wild fish, as well as the sexual steroids. Gene expression analysis revealed significantly lower LH transcript levels at the pituitary level for the farmed females and lower FSH transcript levels at the pituitary level for the males. In conclusion this study showed that the previous rearing conditions (e.g. culture system, age, diet, etc.) alter the further progress of gametogenesis and the reproductive performances in response to controlled photothermal program for both sexes in pikeperch. PMID- 29415781 TI - Control of helminth ruminant infections by 2030. AB - Helminth infections have large negative impacts on production efficiency in ruminant farming systems worldwide, and their effective management is essential if livestock production is to increase to meet future human needs for dietary protein. The control of helminths relies heavily on routine use of chemotherapeutics, but this approach is unsustainable as resistance to anthelmintic drugs is widespread and increasing. At the same time, infection patterns are being altered by changes in climate, land-use and farming practices. Future farms will need to adopt more efficient, robust and sustainable control methods, integrating ongoing scientific advances. Here, we present a vision of helminth control in farmed ruminants by 2030, bringing to bear progress in: (1) diagnostic tools, (2) innovative control approaches based on vaccines and selective breeding, (3) anthelmintics, by sustainable use of existing products and potentially new compounds, and (4) rational integration of future control practices. In this review, we identify the technical advances that we believe will place new tools in the hands of animal health decision makers in 2030, to enhance their options for control and allow them to achieve a more integrated and sustainable approach to helminth control in support of animal welfare and production. PMID- 29415782 TI - The potential of Dicyphus hesperus as a biological control agent of potato psyllid and sweetpotato whitefly in tomato. AB - The potential of the mirid predator Dicyphus hesperus Knight (Heteroptera: Miridae) as a biological control agent of the sweetpotato whitefly, Bemisia tabaci Gennadius (Hemiptera: Aleyrodidae) and the potato psyllid, Bactericera cockerelli Sulcer (Hemiptera: Psyllidae) in tomato was investigated in two experiments. The first experiment focused on the study of the life history traits of D. hesperus when fed on nymphs of the potato psyllid compared with the factitious prey Ephestia kuehniella Zeller (Lepidoptera: Pyrallidae) eggs. Although reproductive and development rates were higher on E. kuehniella eggs, the predator exhibited a good intrinsic rate of natural increase (rm) when feeding on B. cockerelli nymphs (rm: B. cockerelli 0.069 +/- 0.0001; E. kuehniella 0.078 +/- 0.0001), thus reflecting good potential as a biocontrol agent of this pest. The second experiment focused on the efficacy of D. hesperus as a biocontrol agent of the potato psyllid and the sweetpotato whitefly in a tomato greenhouse. Prey species were offered individually or together in a series of five treatments in greenhouse cages. Results showed that the predator was able to establish and suppress populations of both pests inhabiting tomato plants when pests occurred alone or together. Thus, D. hesperus was demonstrated to be a suitable biocontrol agent of these two important pests that could be used in tomato greenhouses. PMID- 29415783 TI - The relationship between cognitive impairment in schizophrenia and metabolic syndrome: a systematic review and meta-analysis - CORRIGENDUM. PMID- 29415784 TI - PEER-REVIEWED JOURNAL EDITORS' VIEWS ON REAL-WORLD EVIDENCE. AB - OBJECTIVES: Peer-review publication is a critical step to the translation and dissemination of research results into clinical practice guidelines, health technology assessment (HTA) and payment policies, and clinical care. The objective of this study was to examine current views of journal editors regarding: (i) The value of real-world evidence (RWE) and how it compares with other types of studies; (ii) Education and/or resources journal editors provide to their peer reviewers or perceive as needed for authors, reviewers, and editors related to RWE. METHODS: Journal editors' views on the value of RWE and editorial procedures for RWE manuscripts were obtained through telephone interviews, a survey, and in-person, roundtable discussion. RESULTS: In total, seventy-nine journals were approached, resulting in fifteen telephone interviews, seventeen survey responses and eight roundtable participants. RWE was considered valuable by all interviewed editors (n = 15). Characteristics of high-quality RWE manuscripts included: novelty/relevance, rigorous methodology, and alignment of data to research question. Editors experience challenges finding peer reviewers; however, these challenges persist across all study designs. Journals generally do not provide guidance, assistance, or training for reviewers, including for RWE studies. Health policy/health services research (HSR) editors were more likely than specialty or general medicine editors to participate in this study, potentially indicating that HSR researchers are more comfortable/interested in RWE. CONCLUSIONS: Editors report favorable views of RWE studies provided studies examine important questions and are methodologically rigorous. Improving peer review processes across all study designs, has the potential to improve the evidence base for decision making, including HTA. PMID- 29415785 TI - A risk-based intervention approach to eliminate diabetes health disparities. AB - Type 2 diabetes plays a major role in racial/ethnic health disparities. We conducted the first study to examine whether multifaceted interventions targeting patients with poorly controlled diabetes (HgbA1c >9%) can reduce racial/ethnic disparities in diabetes control. Among 4595 patients with diabetes at a Federally Qualified Health Center in New York, a higher percentage of blacks (32%) and Hispanics/Latinos (32%) had poorly controlled diabetes than whites (25%) at baseline (prevalence ratio, 1.28; 95% CI, 1.14-1.43; P<0.001). After four years, this percentage was reduced in all groups (blacks, 21%; Hispanics/Latinos, 20%; whites, 20%; P<0.001 for each relative to baseline). Disparities in diabetes control also were significantly reduced (change in disparity relative to whites: blacks, P=0.03; Hispanics/Latinos, P=0.008). In this diverse population, interventions targeting patients with poorly controlled diabetes not only improved diabetes control in all racial/ethnic groups, but significantly reduced disparities. This approach warrants further testing and may help reduce disparities in other populations. PMID- 29415786 TI - Effects of self-reported hearing or vision impairment on depressive symptoms: a population-based longitudinal study. AB - AIMS: The aims of this study were to investigate the effects of either hearing, vision or dual sensory impairment on depressive symptoms and to identify subgroups that are vulnerable and significantly affected. METHODS: Data from the 2006-2014 Korean Longitudinal Study of Aging (KLoSA) were used and a total of 5832 individuals were included in this study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D10) scale. Sensory impairment was assessed according to the levels of self-reported hearing or vision, which were categorised as either good (excellent, very good or good) or poor (fair or poor). The changes in hearing or vision from records of previous survey were investigated. Changes from good to poor, which indicates new onset, were defined as hearing impairment or vision impairment. Interactions of changes in hearing and vision were considered in the analysis. Dual sensory impairment was indicated when hearing impairment and vision impairment both developed at the same time. Demographic, socioeconomic and health-related factors were considered as potential confounders and were adjusted for in the generalised estimating equation model. RESULTS: Individuals with hearing impairment demonstrated significantly more severe depressive symptoms [beta = 0.434, standard errors (s.e.) = 0.097, p < 0.001] than those who had good hearing. Those with vision impairment also showed significantly elevated depressive symptoms (beta = 0.253, s.e. = 0.058, p < 0.001) than those with good vision. When the interactions between hearing and vision were considered, participants with dual sensory impairment showed significantly more severe depressive symptoms (beta = 0.768, s.e. = 0.197, p < 0.001) than those with good hearing and vision. The effect of a single and dual sensory impairment on depressive symptoms was significant in both sexes and across age groups, except for vision impairment in male participants. CONCLUSIONS: Hearing, vision and dual sensory impairment are significantly associated with depressive symptoms. Our results suggest that treatment or rehabilitation of either hearing or vision impairment would help prevent depression. PMID- 29415787 TI - Comparison of ketorolac dosing in an emergency department setting. AB - Clinical questionDoes the analgesic effect of intravenous ketorolac differ if given in doses of 10, 15, or 30 mg to patients presenting to the emergency department with acute pain?Article chosenMotov S, Yasavolian M, Likourezos A, et al. Comparison of intravenous ketorolac at three single-dose regimens for treating acute pain in the emergency department: a randomized controlled trial. Ann Emerg Med 2017;70(2):177-84. PMID- 29415788 TI - Children with ADHD symptoms show deficits in reactive but not proactive inhibition, irrespective of their formal diagnosis. AB - BACKGROUND: Attenuated inhibitory control is one of the most robust findings in the neuropsychology of attention-deficit/hyperactivity disorder (ADHD). However, it is unclear whether this represents a deficit in outright stopping (reactive inhibition), whether it relates to a deficit in anticipatory response slowing (proactive inhibition), or both. In addition, children with other development disorders, such as autism spectrum disorder (ASD), often have symptoms of inattention, impulsivity, and hyperactivity similar to children with ADHD. These may relate to similar underlying changes in inhibitory processing. METHODS: In this study, we used a modified stop-signal task to dissociate reactive and proactive inhibition. We included not only children with ADHD, but also children primarily diagnosed with an ASD and high parent-rated levels of ADHD symptoms. RESULTS: We replicated the well-documented finding of attenuated reactive inhibition in children with ADHD. In addition, we found a similar deficit in children with ASD and a similar level of ADHD symptoms. In contrast, we found no evidence for deficits in proactive inhibition in either clinical group. CONCLUSIONS: These findings re-emphasize the role of reactive inhibition in children with ADHD and ADHD symptoms. Moreover, our findings stress the importance of a trans-diagnostic approach to the relationship between behavior and neuropsychology. PMID- 29415789 TI - Neurodevelopmental Outcomes of Twins Compared With Singleton Children: A Systematic Review. AB - More than 200 million children aged <5 years fail to reach their full cognitive potential, and children born as twins are particularly at risk. In this article, we review studies that examined differences in the neurodevelopmental outcomes of twins compared to singletons. We searched the Medline database for articles on twins, singletons, neuro, and cognitive development. We also inspected bibliographies of relevant publications to identify related articles from 2011 to 2017. Our search criteria yielded 162 studies, 8 of which met the inclusion criteria. Of the eight studies examined, four were prospective follow-up studies, three were cross-sectional studies, and one was a randomized controlled trial. Five of these studies were carried out in developed countries, and they found no statistically significant difference in neurodevelopmental outcomes among twins and singletons. However, two of the three studies carried out in developing countries found a difference with singletons having significantly higher academic ratings than twins. Studies in which neurodevelopmental outcomes were measured early in life (1-5 years) showed no significant twin-singleton differences, while those in which it was measured later in life showed mixed twin-singleton differences. Overall, these studies may have been underpowered and may not have been optimally designed and implemented. There is need for studies with adequate sample sizes, good design, and optimal measurement of all relevant covariates in order to resolve the conflicting reports in the literature. PMID- 29415790 TI - Salmonella Typhimurium in livestock in Great Britain - trends observed over a 32 year period. AB - In this retrospective study, we describe and analyse Salmonella data from four livestock species in Great Britain between 1983 and 2014, focusing on Salmonella Typhimurium. A total of 96 044 Salmonella isolates were obtained during the study period. S. Typhimurium was the predominant serovar isolated from cattle and pigs and represented 40.7% (18 455/45 336) and 58.3% (4495/7709) of isolates from these species respectively, while it only accounted for 6.7% (2114/31 492) of chicken isolates and 8.1% (926/11 507) of turkey isolates. Over the study period, DT104 was the most common phage type in all four species; however, DT104 peaked in occurrence between 1995 and 1999, but is currently rare. Monophasic strains of S. Typhimurium represented less than 3% of all Salmonella isolates in cattle and chickens in 2014, but accounted for 10.4% of all turkey isolates and 39.0% of all pig isolates in the same year. Salmonella isolates were tested for their in vitro susceptibility to 16 antimicrobials. Antimicrobial resistance of S. Typhimurium isolates is largely influenced by the dominance of specific phage types at a certain time, which are commonly associated with particular resistance patterns. Changes in resistance patterns over time were analysed and compared between species. PMID- 29415791 TI - Association between increased serum interleukin-6 levels and sustained attention deficits in patients with major depressive disorder. AB - BACKGROUND: The pathophysiology of cognitive impairment in patients with the major depressive disorder (MDD) may involve neuroinflammation mediated by cytokines. OBJECTIVE: The aim of this study was to examine the serum interleukin 6 (IL-6) levels, sustained attention, and their association in patients with MDD. METHODS: Thirty patients with MDD and 30 healthy controls were enrolled in this case-control study. Sustained attention was measured using the Rapid Visual Information Processing (RVP) task in the Cambridge Neuropsychological Tests Automated Battery. The serum IL-6 levels of all subjects were assessed by sandwich enzyme-linked immunosorbent assays. RESULTS: There were significant differences in the log10RVP total hits, log10RVP total misses, and log10RVP mean latency between patients with MDD and healthy controls (F = 6.04, p = 0.017; F = 19.77, p < 0.0001; F = 14.42, p < 0.0001, respectively). The serum levels of Log10IL-6 were significantly higher in patients with MDD than in healthy controls (F = 192.27, p < 0.0001). The log10IL-6 levels were also positively correlated with the log10RVP mean latency in patients with MDD (r = 0.45, p = 0.013). A further stepwise multivariate regression analysis indicated that the log10IL-6 levels were significantly associated with the log10RVP mean latency in patients with MDD (beta = 0.31, t = 2.41, p = 0.025). CONCLUSIONS: Our data suggested that increased IL-6 levels were associated with the psychopathology of MDD, and that abnormal IL-6 levels were implicated in the impairment of sustained attention in patients with MDD. PMID- 29415792 TI - RE: Intestinal Parasitic Infections in Human Immunodeficiency Virus-Infected and Noninfected Persons in a High Human Immunodeficiency Virus Prevalence Region of Cameroon. PMID- 29415793 TI - Erratum. PMID- 29415796 TI - Erratum. PMID- 29415794 TI - Metronidazole-Associated Encephalopathy. PMID- 29415797 TI - Erratum. PMID- 29415798 TI - Towards a strategy for clinical quality registries in Australia. AB - The healthcare value of Australian clinical quality registries (CQRs) has recently been highlighted by the Australian Commission of Safety and Quality in Health Care (ACSQHC) as being similar to the benefits of CQRs reported internationally. However, the development of CQRs in Australia is currently limited by a lack of coordination and strategic planning, leading to governance and funding processes that are varied and non-sustainable. Despite this, Australia has achieved recognised success with exemplar clinical registries where funding has been sustained at least partly by public funds. To this end, Australia can learn from international CQR governance and funding models to support CQR sustainability, most notably those from European and Scandinavian countries. Further, following the release of the ACSQHC's prioritised domains for CQRs and anticipated funding from the Medical Research Future Fund, the ACSQHC is well positioned to lead a national strategic approach for clinical registries. Together with medical leadership and engagement, operational and data management support from the jurisdictions and financial support from both the public and private sectors, a prioritised and coordinated approach may soon become a reality. PMID- 29415799 TI - HealthPathways improving access to care. AB - Objective HealthPathways (HPW) is an international web-based information portal that provides health practitioners with guidelines and referral pathways to specialists and services. The present study explored usage of HPW by general practitioners (GPs) in the Barwon region, south-west Victoria, and any benefits and barriers to its use.Methods Approximately 421 GPs provide services in 86 clinics across the Barwon region, south-west Victoria and Barwon Health is the public health service providing acute, subacute, residential aged care and community health services to approximately 350000 people. The present study was a mixed-methods analysis of all GPs in the region, who were invited to complete a survey in two waves (2014 and 2016) and participate in focus groups. Data were survey/questionnaire (fixed response and free text options, analysed with descriptive statistics and content analysis), and focus groups (interview and facilitated group discussion, analysed using the principles of thematic analysis).Results Most GPs surveyed used HPW and usage increased over time from 2014 to 2016 (67% vs 77% respectively). Junior GPs used HPW more often than the more experienced practitioners. GPs reported that HPW was easy to access and navigate, improved their knowledge of local services, improved their confidence, changed their clinical management and saved them time. Main barriers to use of HPW were: GPs did not think to look at HPW, or simply did not know about it.Conclusions HPW has the potential to improve patient management and health outcomes, and use of HPW is increasing over time.What is known about the topic? Initiatives such as HPW are viewed positively by clinicians and have the potential to address challenges at the primary-secondary care interface, specifically, referral to secondary specialists.What does this paper add? Proof of concept that the ongoing availability of localised HPW for common clinical conditions improves GP usage of HPW and has increased access to HPW as the first source of clinical information. Benefits and barriers to use have been identified.What are the implications for practitioners? HPW improves knowledge of local services and provides GPs with easy access to referral pathways. PMID- 29415800 TI - Short Sleep Duration Is Weakly Associated with Carotid Intima-Media Thickness in Adolescents. AB - OBJECTIVE: To investigate the relationship between sleep duration and carotid intima-media thickness (CIMT) in adolescents. We hypothesized that short sleep duration was associated with an increased CIMT. STUDY DESIGN: This was a cross sectional study. Healthy participants aged 10-18 years were recruited from a school-based cohort established to examine the prevalence of obstructive sleep apnea in Hong Kong. All participants completed a prospective 7-day sleep diary, underwent anthropometric measurements, overnight polysomnography, and CIMT assessment. Overweight participants or those with an obstructive apnea hypopnea index of >=5 were excluded from analysis. Regression analysis was used to assess the association between CIMT and sleep duration and other possible correlates. RESULTS: One hundred forty-two participants completed the assessments. Male participants tended to have shorter sleep duration than females (P = .012). There were no differences in age, body mass index, Tanner developmental stage, or parental history of hypertension between groups of different sleep durations. There was a weak but significant association between short sleep duration and CIMT (r = -0.273; P < .001). CONCLUSION: Sleep duration was found to have a weakly negative association with CIMT. Further research is needed to determine whether adult adverse cardiovascular events may originate in childhood owing to short sleep duration. PMID- 29415801 TI - Bio-profiling and bio-prognostication of chronic heart failure with mid-range ejection fraction. AB - BACKGROUND: Recent ESC guidelines on heart failure (HF) have introduced a new phenotype based on left ventricular ejection fraction (LVEF), called the mid range (HFmrEF). This phenotype falls between the classical reduced (HFrEF) and preserved (HFpEF) HF phenotypes. We aimed to characterize the HFmrEF biomarker profile and outcomes. METHODS: 1069 consecutive ambulatory patients were included in the study (age 66.2 +/- 12.8 years); 800 with HFrEF (74.8%), 134 with HFmrEF (12.5%), and 135 with HFpEF (12.5%). We measured serum concentrations of N terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenicity (ST2), galectin-3, high sensitivity C-reactive protein, cystatin-C, neprilysin, and soluble transferrin receptor, during 4.9 +/- 2.8 years of follow-up. The primary end-point was the composite: cardiovascular death or HF-related hospitalization. We also examined all-cause, cardiovascular death, and the composite: all-cause death or HF-related hospitalization. RESULTS: NTproBNP levels in HFmrEF were similar to levels in HFpEF, but significantly lower than levels in HFrEF. No other studied biomarkers were different between HFmrEF and HFrEF. All biomarkers, except neprilysin, showed higher risk prediction capabilities in HFmrEF than in HFrEF or HFpEF. The largest difference between HFrEF and HFmrEF was the hs-TnT level (hazard ratio [HR]: 4.72, 95% CI: 2.81-7.94 vs. HR: 1.67, 95%CI: 1.74-1.89; all p < 0.001). CONCLUSIONS: Although HFmrEF is acknowledged as an intermediate phenotype between HFrEF and HFpEF, from a multi-biomarker point of view, HFmrEF was similar to HFrEF, except that NTproBNP levels were lower. Biomarkers commonly used for HFrEF risk prediction are more valuable for HFmrEF risk stratification. PMID- 29415802 TI - ? PMID- 29415803 TI - Ethical considerations in bipolar disorders. AB - The implications of biomedical ethics principles extend to both medical care and biomedical research. They are particularly relevant for psychiatry in which pathologies are often chronic and disabling. Bipolar disorders impact the ability to make judgements and to take decisions during mood episodes and remain a stigmatised condition. Early interventions, even those in the prodromal phase, pose ethical questions for both clinicians and researchers. The degree of patients' autonomy in their clinical care must also now be considered from a biomedical ethics perspective. PMID- 29415804 TI - Answer to letter to the editor concerning "Beware of an allergic reaction in stented patients". PMID- 29415805 TI - Continuous assessment of volunteers' satisfaction in clinical research through simplified questionnaires. AB - OBJECTIVES: In our clinical research center, a 27 multiple-choice and 3 verbatim questions satisfaction questionnaire has been used since 2008 in order to assess the satisfaction of the volunteers participating in our studies. In this work, we aimed at reducing the number of questions of this cumbersome questionnaire while exploring the same dimensions. MATERIALS AND METHODS: We used k-mean and hierarchical clustering to determine which questions provided the same information or, on the contrary, which questions were able to discriminate a satisfied volunteer from an unsatisfied volunteer. RESULTS: We were able to reduce our satisfaction questionnaire from 30 questions to 6 closed-ended and 2 open-ended questions, which will allow to save volunteers time while increasing their participation rate. CONCLUSION: This questionnaire could be used in other structures practicing clinical research, as part of their quality process. PMID- 29415806 TI - Role of tomosynthesis in breast imaging going forward. AB - Digital breast tomosynthesis (DBT) is a modified mammographic technique that overcomes some of the limitations of full-field digital mammography (2DDM) by eliminating the effect of overlapping breast tissue. In the UK, DBT is utilised in both the symptomatic setting and in breast screening assessment clinics. A literature search was conducted from 2010-2017 to ensure that the most recent developments in DBT technology, clinical applications, and assessment of its usefulness in breast screening were reviewed. Technological advances in DBT include the addition of synthetic 2D mammograms, which are generated from the DBT data set, and the use of DBT to guide vacuum-assisted biopsy and excisions. The units from each vendor vary in several aspects, which are detailed in this article. DBT improves diagnostic accuracy and reader confidence when identifying benign and malignant lesions. It has also been shown to be more accurate than 2DDM in assessing tumour size and in the assessment of multifocal tumours. In the screening setting, retrospective reader studies have shown that the addition of DBT to 2DDM showed equivalent or an improvement in sensitivity and specificity when compared to 2DDM alone. Many of these trials showed an increase in invasive cancer detection and a reduction in recall rates. Large prospective randomised controlled trials conducted in Europe and North America will evaluate effectiveness, practicalities, and cost implications of utilising DBT in routine breast screening practice. PMID- 29415807 TI - Improvement of Door-to-Electrocardiogram Time Using the First-Nurse Role in the ED Setting. AB - INTRODUCTION: This quality improvement project compared door-to-electrocardiogram (ECG) times for patients presenting with symptoms suggestive of acute coronary syndrome within a community hospital emergency department before and after first nurse (emergency nurse stationed in the ED waiting room) training. METHOD: Door to-ECG time was compared before and after the educational intervention using Acute Coronary Treatment and Intervention Outcomes Network (ACTION) registry data reported by the facility. RESULTS: Statistical significance was not achieved using a 2-group t-test. However, when comparing monthly means, data trend lines showed favorable improvement for door-to-ECG time after the intervention. DISCUSSION: Limitations included using only those patients in the ACTION registry and not accounting for RN turnover with first-nurse education. Future studies should focus on all patients presenting with symptoms of acute coronary syndrome as well as other patients presenting with time-sensitive needs to determine the efficacy of the first-nurse role. PMID- 29415808 TI - Procedural Outcome and Midterm Survival of Lower Risk Transfemoral Transcatheter Aortic Valve Implantation Patients Treated With the SAPIEN XT or SAPIEN 3 Device. AB - Over the years increasing experience and technical device improvements in transcatheter aortic valve implantation (TAVI) have led to treatment of patients with lower surgical risks. Specifically for this population, device performance and longer term outcome are of great importance. In this single center, we performed a retrospective analysis of 515 consecutive patients with low- to intermediate surgical risk (STS-PROM <=8), who underwent transfemoral TAVI between January 2009 and February 2017 with the SXT and ES3 prostheses, and we assessed procedural outcome and procedural and 3-year survival. Mean age (82 years in both groups, p = 0.344) and STS-PROM risk score (3.862 vs 3.992, p = 0.154) did not differ between the ES3 and SXT group. ES3-treated patients showed favorable procedural outcomes, with significantly higher device success (90% vs 73%, p <0.0001) and less paravalvular leakage (7% vs 13%, p <0.0001). Procedural mortality (0.87% vs 1.45%, p = 0.245) and the very low rate of permanent pacemaker implantations (7.4% vs 6.1%, p = 0.234) did not differ significantly. Three-year survival was 87% in the ES3 vs 80% in the SXT group (log-rank p = 0.385). In conclusion, we showed excellent survival and procedural outcomes in patients receiving a transfemoral TAVI with either the SAPIEN 3 or the SAPIEN XT device. The newer SAPIEN 3 even outperforms the SAPIEN XT in terms of less major bleeding complications, substantially higher device success rates, and less paravalvular leakage, with the permanent pacemaker implantation rate being very low in both groups. Survival curves show a nonsignificant trend toward better midterm survival in the ES3 group. PMID- 29415809 TI - Expression profile of polycomb group proteins in odontogenic keratocyst and ameloblastoma. AB - Polycomb group (PcG) proteins are repressive chromatin modifiers required for proliferation and development. PcG proteins form two large repressive complexes, namely, Polycomb Repressive Complex 1 and 2. These proteins have been shown to drive tumorigenesis by repressing cell-type specific sets of target genes. Using immunohistochemistry, we investigated the expression patterns of five human PcG proteins, including Bmi-1, Ring1b, Mel-18, Ezh2, and Suz12, in various cellular components of odontogenic keratocysts (OKCs), ameloblastomas and, pericoronal follicles (PFs). In OKCs, expression of PcG proteins were found in the majority of cases while the expression pattern was relatively different for each PcG proteins. All PcG proteins were strongly expressed in the basal cells while some proteins showed variable expression in the parabasal and luminal cell layer of OKCs. In ameloblastomas, almost all PcG proteins showed a similar expression pattern of moderate to strong staining in the peripheral ameloblast-like cells and metaplastic squamous cells. Some of the central stellate reticulum-like cells also showed positive reaction to most PcG proteins. In PFs, most PcG proteins were intensely expressed in odontogenic epithelium lining the follicles, except Mel-18 and Suz12. The present study provides the initial evidence regarding epigenetic involvement by PcG proteins in these odontogenic lesions. Although these proteins are known to be in the same repressive group proteins, differential expression patterns of these proteins in OKCs and ameloblastomas indicates that these proteins may play different roles in pathogenesis of these odontogenic lesions. PMID- 29415810 TI - Patient-reported reasons for seeking emergency care at a freestanding emergency department compared to a hospital-based ED. PMID- 29415811 TI - [Simple mucinous cyst of the pancreas: Case-report and literature review]. AB - Simple mucinous cyst of the pancreas is an unusual pancreatic cyst, first described by Kosmahl et al. in 2002 with 5 cases. We describe a case of simple mucinous cyst of the pancreas, followed by a literature review. The physiopathology of this cyst is still unclear. It is an epithelial cyst, presenting as unilocular cystic lesion of the pancreatic body or tail, with a clear content, and no communication with the pancreatic duct. Microscopically, the cyst is lined by mucin-producing cells with mild atypia, and contains a fibrous wall without ovarian-like stroma. The prognosis is excellent, as no recurrent disease and progression to malignancy have been described. The non neoplastic origin of this lesion is debated, as cases with KRAS mutation and intra-epithelial neoplastic lesions have been recently reported. It is important to distinguish this lesion from macrocystic serous cystadenoma, mucinous cystic neoplasms and intraductal papillary mucinous neoplasms, by clinical, radiological and pathological features, as the treatment varies from simple surveillance to surgical resection. PMID- 29415812 TI - Prediction of massive bleeding in a prehospital setting: validation of six scoring systems. AB - OBJECTIVE: To validate the diagnostic ability of six different scores to predict massive bleeding in a prehospital setting. DESIGN: Retrospective cohort. SETTING: Prehospital attention of patients with severe trauma. SUBJECTS: Subjects with more than 15 years, a history of severe trauma (defined by code 15 criteria), that were initially assisted in a prehospital setting by the emergency services between January 2010 and December 2015 and were then transferred to a level one trauma center in Madrid. VARIABLES: To validate: 1. Trauma Associated Severe Haemorrhage Score. 2. Assessment of Blood Consumption Score. 3. Emergency Transfusion Score. 4. Indice de Shock. 5. Prince of Wales Hospital/Rainer Score. 6. Larson Score. RESULTS: 548 subjects were studied, 76,8% (420) were male, median age was 38 (interquartile range [IQR]: 27-50). Injury Severity Score was 18 (IQR: 9-29). Blunt trauma represented 82,5% (452) of the cases. Overall, frequency of MB was 9,2% (48), median intensive care unit admission days was 2,1 (IQR: 0,8 - 6,2) and hospital mortality rate was 11,2% (59). Emergency Transfusion Score had the highest precisions (AUC 0,85), followed by Trauma Associated Severe Haemorrhage score and Prince of Wales Hospital/Rainer Score (AUC 0,82); Assessment of Blood Consumption Score was the less precise (AUC 0,68). CONCLUSION: In the prehospital setting the application of any the six scoring systems predicts the presence of massive hemorrhage and allows the activation of massive transfusion protocols while the patient is transferred to a hospital. PMID- 29415813 TI - Advances in Behavioral Psychopharmacology. AB - Recent studies have led to some groundbreaking findings regarding the use of medications for the support of behavioral health in dogs and cats. Despite tantalizing results, these studies should be viewed in light of their limitations. Consequently, the results of these studies should be applied in the clinical setting with caution and with a full understanding of the potential pros and cons of using these medications. A review of the research available on trazodone, clonidine, detomidine, dexmedetomidine, propranolol, pindolol, maropitant, memantine, venlafaxine, and gabapentin discusses these pros and cons and highlights key points regarding their clinical use and application. PMID- 29415814 TI - Application of the FOUR Score in Intracerebral Hemorrhage Risk Analysis. AB - BACKGROUND: The Full Outline of Unresponsiveness (FOUR) Score is a validated scale describing the essentials of a coma examination, including motor response, eye opening and eye movements, brainstem reflexes, and respiratory pattern. We incorporated the FOUR Score into the existing ICH Score and evaluated its accuracy of risk assessment in spontaneous intracerebral hemorrhage (ICH). MATERIALS AND METHODS: Consecutive patients admitted to our institution from 2009 to 2012 with spontaneous ICH were reviewed. The ICH Score was calculated using patient age, hemorrhage location, hemorrhage volume, evidence of intraventricular extension, and Glasgow Coma Scale (GCS). The FOUR Score was then incorporated into the ICH Score as a substitute for the GCS (ICH ScoreFS). The ability of the 2 scores to predict mortality at 1 month was then compared. RESULTS: In total, 274 patients met the inclusion criteria. The median age was 73 years (interquartile range 60-82) and 138 (50.4%) were male. Overall mortality at 1 month was 28.8% (n = 79). The area under the receiver operating characteristic curve was .91 for the ICH Score and .89 for the ICH ScoreFS. For ICH Scores of 1, 2, 3, 4, and 5, 1-month mortality was 4.2%, 29.9%, 62.5%, 95.0%, and 100%. In the ICH ScoreFS model, mortality was 10.7%, 26.5%, 64.5%, 88.9%, and 100% for scores of 1, 2, 3, 4, and 5, respectively. CONCLUSIONS: The ICH Score and the ICH ScoreFS predict 1-month mortality with comparable accuracy. As the FOUR Score provides additional clinical information regarding patient status, it may be a reasonable substitute for the GCS into the ICH Score. PMID- 29415815 TI - [Systemic sclerosis: Efficacy of intravenous immunoglobulins in severe cardiac involvement?] AB - BACKGROUND: The heart involvement in systemic sclerosis is frequent and can touch various sites. The prognosis in the presence of heart disease is poor, but few data are available about its management. CASE: We report the case of 48 years old woman with systemic sclerosis which presented severe heart involvement. She has severe heart failure, supraventricular arrhythmias and symptomatic pericarditis, which required surgical intervention and immunosuppressive drugs (steroids with rituximab). Despite this treatment, she has persistent severe heart impaired function and intravenous immunoglobulins have been initiated. She experienced progressively the improvement of dyspnea, of heart systolic ejection fraction and decrease of Rodnan scale. CONCLUSION: Our case illustrates a severe heart involvement in systemic sclerosis which have been improved by intravenous immunoglobulins. PMID- 29415816 TI - [Impact of the 2009 Afssaps guidelines on the management of venous thromboembolic disease in emergency department: Before/after study]. AB - INTRODUCTION: The French Agency for Health Safety of Products published recommendations of good practices (RGP) for the treatment of venous thromboembolic disease in 2009. Four of these recommendations apply to the initial management of the disease, with the objective of this study is to determine whether the development and diffusion of the four RGP has had an impact on the practice. METHODS: A retrospective before/after study comparing 132 patients treated in emergency department of the Civil Hospices of Lyon for pulmonary embolism (PE) and/or deep venous thrombosis (DVT) in 2008-2009 ("before") and 153 patients in 2010-2011 ("after"). RESULTS: In the "before" period, 70 patients were treated for DVT and 62 patients for PE. In the "after" period, 50 patients were treated for DVT and 103 patients for PE. The compliance rate was not significantly different for the two periods for each RGP except for the indication of low molecular weight Heparin (LMWH) or fondaparinux in the absence of severe renal failure (21% "before" vs. 45% "after"; P=0.02) for patients with PE. Management for the four recommendations was conform for 5.6% of eligible patients in the "before" period and for 3.7% for the "after" period. CONCLUSION: Our study shows that globally there is no impact of RGP. The reasons appear multiple with first, the mere dissemination and the absence of implementation of these guidelines. PMID- 29415817 TI - Heterologous human/rat HER2-specific exosome-targeted T cell vaccine stimulates potent humoral and CTL responses leading to enhanced circumvention of HER2 tolerance in double transgenic HLA-A2/HER2 mice. AB - DNA vaccines composed of heterologous human HER2 and rat neu sequences induce stronger antibody response and protective antitumor immunity than either HER2 or neu DNA vaccines in transgenic mice. We previously developed HER2-specific exosome-targeted T-cell vaccine HER2-TEXO capable of stimulating HER2-specific CD8+ T-cell responses, but only leading to partial protective immunity in double transgenic HLA-A2/HER2 mice with self-immune tolerance to HER2. Here, we constructed an adenoviral vector AdVHuRt expressing HuRt fusion protein composed of NH2-HER21-407 (Hu) and COOH-neu408-690 (Rt) fragments, and developed a heterologous human/rat HER2-specific exosome-targeted T-cell vaccine HuRt-TEXO using polyclonal CD4+ T-cells uptaking exosomes released by AdVHuRt-transfected dendritic cells. We found that the HuRt-TEXO vaccine stimulates enhanced CD4+ T cell responses leading to increased induction of HER2-specific antibody (~70 ug/ml) compared to that (~40 ug/ml) triggered by the homologous HER2-TEXO vaccine. By using PE-H-2Kd/HER223-71 tetramer, we determined that HuRt-TEXO stimulates stronger HER2-specific CD8+ T-cell responses eradicating 90% of HER2 specific target cells, while HER2-TEXO-induced CD8+ T-cell responses only eliminating 53% targets. Furthermore, HuRt-TEXO, but not HER2-TEXO vaccination, is capable of suppressing early stage-established HER2-expressing 4T1HER2 breast cancer in its lung metastasis or subcutaneous form in BALB/c mice, and of completely protecting transgenic HLA-A2/HER2 mice from growth of HLA-A2/HER2 expressing BL6-10A2/HER2 melanoma. HuRt-TEXO-stimulated HER2-specific CD8+ T cells not only are cytolytic to trastuzumab-resistant HLA-A2/HER2-expressing BT474/A2 breast tumor cells in vitro but also eradicates pre-established BT474/A2 tumors in athymic nude mice. Therefore, our novel heterologous human/rat HER2 specific T-cell vaccine HuRt-TEXO, circumventing HER2 tolerance, may provide a new therapeutic alternative for patients with trastuzumab-resistant HER2+ breast tumor. PMID- 29415818 TI - Percutaneous treatment of tricuspid regurgitation: A new therapeutic horizon. AB - Functional tricuspid regurgitation is a prevalent disease, especially among patients with other valve disorders, and is associated with significant morbidity and mortality. Its management is challenging, and many patients deemed at high surgical risk are managed conservatively. Despite optimization of pharmacological treatment, many patients continue to be symptomatic, thus leading to interest in percutaneous interventional techniques. The Mitralign system has recently been used for the treatment of functional tricuspid regurgitation, with favorable clinical and imaging results. We report the first case in Portugal to our knowledge of percutaneous tricuspid regurgitation treatment with the Mitralign system. PMID- 29415819 TI - A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. AB - Even in the presence of excess glucose, the proximal renal tubules continue to resorb more glucose. Sodium glucose cotransporter 2 (SGLT2) inhibitors are drugs that control this "greed" (H. Ito, Keio University, Japan). Negative feedback mechanisms maintain homeostasis for various physiological functions. However, there is no negative feedback mechanism for resorption of glucose by the proximal renal tubules. When food was scarce during human evolution, not limiting nutrient reabsorption was advantageous for survival, but the opposite is true in the era of satiation. SGLT2 inhibitors were designed to apply the brakes to uncontrolled glucose resorption by the kidneys in patients with diabetes. It has become clear that SGLT2 inhibitors not only improve the blood glucose level, but also show cardiovascular and renal protective effects irrespective of the reduction of blood glucose in patients with type 2 diabetes mellitus (T2DM). The mechanisms underlying cardiovascular and renal protection by SGLT2 inhibitors in T2DM are complex, multifactorial, and not completely understood. A common, and perhaps underappreciated, feature of T2DM is chronic activation of the sympathetic nervous system. This elevation of sympathetic activity contributes to the development of hypertension. It is also associated with a poor prognosis and with increased cardiovascular and renal morbidity/mortality independently of the effect on blood pressure. This review discusses novel insights into cardiovascular protection by SGLT2 inhibitors, focusing on the interaction between SGLT2 and the sympathetic nervous system. PMID- 29415820 TI - Differentially methylated circulating DNA: A novel biomarker to monitor beta cell death. AB - Diabetes mellitus (DM) is a metabolic disorder of glucose homeostasis caused by insufficient secretion or inadequate action of insulin. Nowadays, the increased morbidity of DM is a worldwide issue. Pancreatic beta cell death plays a key role in the progress of DM, especially Type 1 diabetes (T1D). Traditional biomarkers, such as C-peptide and islet autoimmune antibodies are limited to reflect beta cell death and to identify high risk patients in the clinical practice. Recently, a novel biomarker, differentially methylated circulating DNA, has become a research hotspot. It has better sensitivity and specificity in the detection of beta cell death. Assays of beta cell-derived differentially methylated insulin DNA in serum are helpful to predict the possibility to develop T1D in the high risk population. They have also been applied to evaluate beta cell death in Type 2 diabetes (T2D), gestational diabetes mellitus (GDM), islet transplantation and islet specific immune therapy. Although more studies are needed to identify the best methylation target sites in the INS gene, differentially methylated circulating DNA may be a good method to evaluate the progression and prognosis of islet related diseases in the future. PMID- 29415821 TI - Reproductive Health-Care Utilization of Young Adults Insured as Dependents. AB - PURPOSE: The common practice of sending an explanation of benefits to policyholders may inadvertently disclose sensitive services to the parents of dependents, making confidentiality a potential barrier to reproductive health care. This study compares the reproductive health-care utilization of young adult dependents and young adult policyholders using nationally representative data collected after full implementation of the Affordable Care Act. METHODS: Data from 2,108 young adults aged 18-25 years in the 2015 National Health Interview Survey were analyzed. Logistic regressions predicted utilization of two preventive services (general doctor visit and flu vaccination) and four reproductive health services (HIV testing, obstetrician/gynecologist visit, hormonal contraceptive use, and Pap testing) from the insurance type of the young adult (dependent, privately insured policyholder, or Medicaid). RESULTS: In unadjusted analyses, young adult dependents had lower utilization of HIV tests than their peers who were privately insured or Medicaid policyholders. Young women dependents had lower utilization of Pap tests than young women on Medicaid. Once controls were included, young adult dependents did not have significantly lower odds of obtaining reproductive health care than privately insured policyholders. Dependent young men still had marginally lower odds of ever having an HIV test (adjusted odds ratio = .65, p = .08) and dependent young women still had marginally lower odds of ever having a Pap test (adjusted odds ratio = .58, p = .06) than comparable Medicaid policyholders. CONCLUSIONS: Despite confidentiality concerns, young adults insured as dependents have utilization of several reproductive health services similar to that of comparable young adult policyholders. PMID- 29415822 TI - [Anti-tumor immunotherapy in malignant pleural mesothelioma]. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is a quite rare cancer, but with increasing incidence, that is usually induced by previous asbestos exposure. Its prognosis is poor and there is no validated curative therapy to date. Surgery of MPM, done only by few expert teams within a multimodal treatment is of limited and still disputed value. The standard treatment of MPM, relying on first-line chemotherapy by combined cisplatin-pemetrexed is often poorly effective, even if combination with bevacizumab anti-VEGF antibodies has slightly improved the results. Moreover, no second line treatment is recommended in case of failure of this chemotherapy. Therefore, the search of new therapies or strategies is crucial and the recruitment of patients in clinical trials is highly encouraged. BACKGROUND: Among the treatments under investigation, various anti-tumour immunotherapies, in particular immune checkpoints inhibitors (ICI), currently exhibit the most promising preliminary results. First data from the phase II, randomized "IFCT MAPS-2", recently presented during the 2017 ASCO meeting, confirmed the value of ICI in MPM patients in cases of chemotherapy failure. OUTLOOK AND CONCLUSIONS: However, several exciting immunotherapies other than ICI are presently being evaluated in MPM and are reported in this article. Moreover, many questions still need to be answered about immunotherapy: what is its potential value as first line treatment? How to target the best candidates for these treatments? Which combinations between immunotherapy and standard chemotherapy, targeted therapies, surgery or radiotherapy? Finally, it is now essential that every clinician has sufficient knowledge about the possible toxicities of immunotherapy. PMID- 29415823 TI - Contribution of ultrasonography to the evaluation of peripheral nerve disorders. AB - OBJECTIVE: Although ultrasonographic (US) visualization of peripheral nerves is becoming more and more frequently used, there are few studies on its actual contribution to the diagnosis and management of patients with peripheral nerve disorders. METHODS: The electronic records of consecutive patients referred to our US laboratory over an eight-month period were retrospectively analyzed. The contribution of US examination to patient management was evaluated. RESULTS: Two hundred and thirty one consecutive patients (43% men) were analyzed. The US result was pathologic in 71% of patients. US provided a new diagnosis in 3% of patients (including 4 with tumors), contributed other additional information in 60%, and only confirmed the referral diagnosis in 11%. In 26% of patients, US was neither confirmatory nor contributive, nor did it provide a new diagnosis. US sensitivity in electrodiagnostically (EDx) confirmed ulnar neuropathy at the elbow (UNE) was 77% and median neuropathy at the wrist 84%. In EDx negative patients, US sensitivities were 47% and 40%, respectively. DISCUSSION: The study demonstrated the ability of peripheral nerve US to provide useful diagnostic information in the majority of adequately referred patients. PMID- 29415824 TI - A morphovolumetric study of head malposition in proximal humeral fractures based on 3-dimensional computed tomography scans: the control volume theory. AB - BACKGROUND: This study regards a volumetric analysis of proximal humeral fractures. The main purpose was to investigate the head displacement in relation to the shaft and its link to volume reductions ("bone loss") of the anatomic segments interposed between the head and the shaft: the tuberosities and the calcar. We call this area "control volume." METHODS: In 20 fractures, we used 3 dimensional virtual reconstruction to create a reference system that divides geometrically the control volume and allows the evaluation of displacement angles of the humeral head. We calculated the volumetric reduction of control volume segments for each fracture through a specific mathematical protocol. RESULTS: The measurement of the head displacement angles in 20 fractures led to following results: in the coronal plane, 10 varus, 6 valgus, 4 neutral; in the sagittal plane, 6 anterior tilt, 9 posterior tilt, 5 neutral position. There was a reduction of control volume in 19 of 20 fractures. Only in 1 fracture was the control volume intact and the fracture was nonimpacted. In 19 impacted fractures, the volume reduction was variable (4% minimum loss, 98% maximum loss). In head varus position, loss was greater in the medial area than in the lateral area. There was generally a clear correspondence between the positions assumed by the head and the volumetric losses of the respective control volume segments. CONCLUSIONS: The control volume is an important anatomic and functional area of the proximal humerus. A morphovolumetric 3-dimensional approach improves knowledge about pathomorphology of proximal humeral fractures. PMID- 29415825 TI - Green tea extract outperforms metformin in lipid profile and glycaemic control in overweight women: A double-blind, placebo-controlled, randomized trial. AB - BACKGROUND & AIMS: Both green tea and metformin are used as adjuvants to treat and prevent complications associated with obesity; however, studies comparing their action and interaction in non-diabetic overweight women have not been reported. Thus, the current study evaluated the effects of green tea extract and metformin, both individually and in combination, on type 2 diabetes risk factors in non-diabetic overweight women. METHODS: A total of 120 overweight women were randomly assigned in a double-blind manner to 1 of 4 groups, as follows: control (n = 29; 1 g of cellulose), green tea (n = 32; 1 g of dry green tea extract), metformin (n = 28; 1 g of metformin), and green tea + metformin (n = 31; 1 g of dry green tea extract + 1 g of metformin). Each group took the indicated capsules daily for 12 weeks. Anthropometric measurements, body composition, and fasting blood samples were evaluated. RESULTS: Although no significant interactions were observed in glycaemic control (p = 0.07), green tea in the absence of metformin reduced fasting glucose (-4.428 +/- 2.00; p = 0.031), but when combined the lowering effect was nullified. In contrast, metformin increased HbA1c concentration (0.048 +/- 0.189%; p = 0.017) and also reduced body weight (-1.318 +/- 0.366 kg; p = 0.034) and LM (lean mass) (-1.249 +/- 0.310; p = 0.009). Regarding lipid parameters, green tea significantly reduced total cholesterol and LDL-c. CONCLUSIONS: Green tea was superior to metformin in improving glycaemic control and lipid profile in non-diabetic overweight women and, therefore, green tea extract is a promising alternative for reducing type 2 diabetes risk in overweight women. PMID- 29415826 TI - Difficulties in thickened water ingestion in healthy subjects. AB - BACKGROUND: For some patients with dysphagia who have airway aspiration, it is not possible to drink water as a thin liquid, as they need their water to be thickened. OBJECTIVE: To evaluate in healthy volunteers the difficulties and dynamics of ingestion of thickened water. METHOD: In 94 healthy volunteers aged 18-67 years, the ingestion of 100 mL of water with consistencies of thin liquid and thickened with 1.2 g (nectar-thick), 2.4 g (honey-thick) and 3.6 g (pudding thick) of a commercial thickener with maltodextrin, xanthan gum and potassium chloride was evaluated. The volunteers drank in a random sequence 100 mL of each consistency. The duration and the number of swallows to drink the volume were measured. The interval between swallows, the flux of ingestion and the volume of each swallow were calculated. After each test, the individual was asked about the sensation during drinking, with ten as the best sensation and zero as the worst sensation, and about the difficulty to swallow each consistency. STATISTICAL ANALYSIS: The analysis was done using a linear model with mixed effects. RESULTS: The time to ingest the volume increased (liquid: 5.8 s; nectar: 7.9 s; honey: 9.5 s; pudding: 12.7 s; p < 0.01), the flux of ingestion decreased (liquid: 20.3 mL/s; nectar: 15.6 mL/s; honey: 13.4 mL/s; pudding: 10.6 mL/s; p < 0.01), the sensation worsened (liquid: 9.7; nectar: 5.7; honey: 4.3; pudding: 2.8), and the difficult of ingestion increase with the increase of the water consistency. Individuals with dental prosthesis (n = 11) had a decrease in the flux of ingestion with 3.6 g of thickener (prosthesis: 11.1 mL/s, no prosthesis: 6.8 mL/s, p = 0.05) and a decrease in the volume in each swallow (prosthesis: 17.6 mL, no prosthesis: 10.5 mL). CONCLUSIONS: There is some difficulty to drink thickened water. The use of dental prosthesis cause further difficulties. PMID- 29415827 TI - BMI calculation in older people: The effect of using direct and surrogate measures of height in a community-based setting. AB - BACKGROUND & AIMS: There is currently no consensus on which measure of height should be used in older people's body mass index (BMI) calculation. Most estimates of nutritional status include a measurement of body weight and height which should be reliable and accurate, however at present several different methods are used interchangeably. BMI, a key marker in malnutrition assessment, does not reflect age-related changes in height or changes in body composition such as loss of muscle mass or presence of oedema. The aim of this pilot study was to assess how the use of direct and surrogate measures of height impacts on BMI calculation in people aged >=75 years. METHODS: A cross-sectional study of 64 free-living older people (75-96 yrs) quantified height by two direct measurements, current height (HC), and self-report (HR) and surrogate equations using knee height (HK) and ulna length (HU). BMI calculated from current height measurement (BMIC) was compared with BMI calculated using self-reported height (BMIR) and height estimated from surrogate equations for knee height (BMIK) and ulna length (BMIU). RESULTS: Median difference of BMIC-BMIR was 2.31 kg/m2. BMIK gave the closest correlation to BMIC. The percentage of study participants identified at increased risk of under-nutrition (BMI < 20 kg/m2) varied depending on which measure of height was used to calculate BMI; from 5% (BMIC), 7.8% (BMIK), 12.5% (BMIU), to 14% (BMIR) respectively. CONCLUSIONS: The results of this pilot study in a relatively healthy sample of older people suggest that interchangeable use of current and reported height in people >=75 years can introduce substantial significant systematic error. This discrepancy could impact nutritional assessment of older people in poor health and lead to misclassification during nutritional screening if other visual and clinical clues are not taken into account. This could result in long-term clinical and cost implications if individuals who need nutrition support are not correctly identified. A consensus is required on which method should be used to quantify height in older people to improve accuracy of nutritional assessment and clinical care. PMID- 29415828 TI - Sporulated Bacillus as alternative treatment for diarrhea of hospitalized adult patients under enteral nutrition: A pilot randomized controlled study. AB - BACKGROUND & AIMS: Among hospitalized patients receiving enteral nutrition (EN), malnutrition and antibiotic use are some of the most common causes of diarrhea. Prebiotics and probiotics agents have been used for treatment of diarrhea in such patients. The aim of this study was to assess the efficacy of a sporulated Bacillus strain (Bacillus cereus A 05), compared to a control group using a prebiotic (soluble fiber), in reducing diarrhea in patients receiving EN and antibiotic therapy. METHODS: Patients with diarrhea receiving EN were randomized to receive either B. cereus (study group) or soluble fiber (control group) for five days. The group treated with B. cereus received 4 vials with 5 mL * 106 every 6 h. The control group treated with fiber received 10 g of soluble fiber every 8 h. Data assessed were serum albumin, nutrition status through Subjective Global Assessment (SGA), antibiotic use and osmolality (normal or hyperosmolar) of the tube feeding diets. RESULTS: Twenty-nine patients were treated in each group. There was no significant difference between the groups regarding age, serum albumin, SGA score, dietary osmolality and antibiotic use. There was no significant difference between groups in ceasing diarrhea. However, the group treated with B. cereus took fewer days to cease diarrhea (2.5 +/- 1.3 versus 3.7 +/- 1.1 days, p = 0.011). Specifically, in the group treated with B. cereus A 05, malnourished patients did better than non-malnourished patients regarding diarrhea cessation (100% versus 25%, p < 0.001). CONCLUSIONS: B. cereus A 05 was more effective than fiber in reducing diarrhea among patients under EN and antibiotic therapy and was more effective among malnourished patients. PMID- 29415829 TI - Evaluation of Curcumin's effect on inflammation in hemodialysis patients. AB - OBJECTIVE: Despite advances in prevention of inflammatory milieu with different anti-inflammatory modalities in hemodialysis patients the rate of inflammatory markers in this population are still high. Inflammation is considered as a major player in uremia associated with morbidity and mortality in hemodialysis patients. The aim of this study was to evaluate the turmeric s effects on reduction of inflammatory markers in hemodialysis patients. METHODS: Hemodialysis patients over 18 years were recruited after fulfilling the inclusion criteria. Seventy-one hemodialysis patients were randomized into two groups: the trial group (n = 35) and the controls (n = 36); a randomization numeric table was used for allocation sequence. Trial group received turmeric and control group received placebo for 12 weeks. Biochemical determinations included levels of serum albumin (Alb), potassium (K), blood urea nitrogen (BUN), serum creatinine (Cr), IL-6 level, TNF-alpha, and liver function tests and hs-CRP at the start and end of the study were measured. RESULTS: Although there was a significant reduction in hs CRP level, IL-6 level and TNF-alpha level in turmeric group (p = 0.002, p = 0.001, p = 0.001), there was no statistical difference between intervention and control groups. Albumin level was significantly increased in turmeric group (p = 0.001) and no meaningful changes were seen in potassium or liver function tests neither within nor between groups. CONCLUSION: Programmed ingestion of turmeric has no adverse effects and reduces plasma level of hs-CRP, IL-6 and TNF-alpha accompanying with increases albumin levels in hemodialysis patients. Turmeric can be considered as an effective anti-inflammatory supplement in hemodialysis patients. PMID- 29415830 TI - The new body mass index formula; not validated as a predictor of outcome in a large cohort study of patients undergoing general surgery. AB - BACKGROUND AND AIMS: A new and interesting body mass index (BMI) formula has been proposed. This formula was designed to provide a more accurate estimation of weight categories, not limited in a two-dimensional manner. The objective of this study was to evaluate the predictive value of the new BMI formula on postoperative complications and long-term survival in a large cohort of patients undergoing general surgery. METHODS: 4293 consecutive patients undergoing general surgery in a general teaching hospital were included. Data on comorbidity and demographics were gathered prior to surgery. We also collected data on surgery related characteristics. BMI was calculated using the conventional as well as the new BMI formula. Patients were then divided into four weight categories (BMI < 18.5, 18.5-25, 25-30 and >30 kg/m2) as recommended by the World Health Organization. RESULTS: The study population consisted of 4293 patients. Multivariate regression analyses and the area under the ROC-curve (0.531 +/- 0.011 and 0.539 +/- 0.011) showed comparable results in predicting outcome between the two formulas. A demographic shift was noticed after complementing the new BMI formula. Male patients were the subjects of this shift, usually towards a lower BMI. According to the conventional BMI formula, 58% of men were overweight BMI > 25 kg/m2, compared to 51.4% according to the new formula. CONCLUSIONS: This study showed no difference in prediction of outcome after general surgery when comparing the current BMI formula to the new BMI formula. Thus, despite the fact that the new mathematical proposition seemed more logical and interesting, both calculations can be used in clinical practice. Moreover, our results do not support a change from the conventional BMI formula, currently used and accepted worldwide. PMID- 29415831 TI - Evaluation of a short protocol for indirect calorimetry in females with eating disorders and healthy controls. AB - BACKGROUND AND AIMS: To enable clinicians to identify the clinical picture and treatment progress and to adjust eating plans according to personal energy needs, it is important to know the patient's correct resting metabolic rate (RMR). Indirect calorimetry (IC) is the preferred method for assessment of RMR, but long duration of measurement increases the load on the patients, and reduces the effectiveness in clinical and scientific settings. Further; not all patients reach a valid RMR according to the suggested best practice protocol, with 5 min of steady state (SS) where respiratory gas volume exchange varies less than 10%. The aim of this study was to evaluate the possibility for an abbreviated RMR protocol and SS criterion. METHODS: Forty two women diagnosed with bulimia nervosa or binge eating disorder (eating disorder group, ED), originally recruited for an outpatient treatment study, and 26 age and gender matched healthy controls (HC) were studied during a single, prolonged IC measurement. Participants rested for 10 min in supine position wearing a two-way breathing facemask, before a continuous measurement period of 20 min. Results from a standard 5 min SS criterion was compared to an abbreviated 3 min SS criterion. Both SS-criteria were evaluated through three different SS protocols (<10% variation in respiratory gas exchange), being: 1) measurement during the first 3 or 5 min, 2) measurement after discarding the first 5 min, and 3) the lowest identified RMR during the 20 min of measurement. RESULTS: About 50% of the participants reached an early SS in both the defined SS minute criteria. Participants reaching a valid SS throughout the 20 min of measurement increased from ~90% to 100% with an abbreviated 3 min SS. With a 5 min SS criterion, the median (range) RMR for the 3 protocols were 1639.9 (1239.2), 1508.8 (1457.6) and 1500.6 (1328.8) respectively for the ED group, and 1702.2 (1239.4), 1608.4 (1076.4) and 1594.8 (1029.2) respectively for the HC group, (p > 0.05 for all between-group analysis). With a 3 min SS criterion, the median (range) RMR were 1533.6 (1298.2), 1461.2 (1406.1), and 1395.8 (1447.3) respectively for the ED group and 1681.7 (1332.4), 1613.7 (1266.0) and 1523.1 (1050.3), respectively for the HC group, (p > 0.05 for all between-group analysis). Lowest measured RMR was different compared to the other two SS protocols in both the ED- and the HC group, and for both the 5 min- and the 3 min SS criteria, respectively (p < 0.04). Furthermore, a SS of 3 min resulted in lower RMR compared to 5 min SS (p < 0.00) and an increased number of participants classified as hypo-metabolic (RMRmeasured/RMRcalculated < 0.9). CONCLUSIONS: An abbreviated measurement protocol to identify the lowest RMR using IC was not successful. Abbreviating the SS criteria from 5 to 3 min, resulted in a lower RMR, hence encouraging further examination of the validity of shorter SS criterion than practiced today. Registered in Clinical Trials by id-number NCT02079935, and approved by the Norwegian Regional Committee for Medical and Health Research Ethics with id number 2013/1871. The trial in which control persons were recruited, is approved by the Norwegian Regional Committees for Medical and Health Research Ethics with the id-number 2016/1718, and prospectively registered in Clinical Trials with the id-number NCT03007459. PMID- 29415832 TI - Metabolic characteristics of Appalachian children. AB - PURPOSE: The purpose of this investigation is to assess the physiological characteristics and the resting metabolic rates of a representative population of children in Buchanan County in order to identify those factors that may be contributing to the predisposition for being overweight or obese and provide nutritional and physical activity guidance for prevention. METHODS: Twenty-three volunteers from grades 5, 6 and 7 from Buchannan County, VA underwent parametric and metabolic testing over three consecutive years in order to determine their height, weight, BMI, percent body fat, resting oxygen consumption (VO2), resting energy expenditure (REE), respiratory exchange ratio (RER) and daily energy expenditure (DEE) and consumption. RESULTS: Over the 3 year study period, subjects' BMI increased significantly over time (p = 0.001) while there were no changes in their, REE, RER, VO2, percent fat and DEE. However, there was a moderate negative correlation between VO2 and BMI in grade 5 (r = -0.578, p = 0.002), grade 6 (r = -0.477, p = 0.015) and grade 7 (r = -0.438, p = 0.023). Gender specific differences in percent body fat were evident among subjects during the last two measurement cycles and were strongly correlated with BMI (r = 0.907, r = 0.959, p = 0.000). CONCLUSIONS: The use of resting VO2, REE, and RER values as a screening tool for identifying those children or adolescents at risk for becoming overweight or obese is most likely cost and time prohibitive due to the need for several repeated measures to ensure accurate results. However increased VO2 is correlated with decreased BMI. PMID- 29415833 TI - Short-term l-arginine supplementation attenuates elevation of interleukin 6 level after resistance exercise in overweight men. AB - BACKGROUND AND AIM: l-Arginine (l-arg) supplementation and resistance exercise can induce changes in inflammatory and anti-inflammatory cytokines; however, it has not been investigated in obese hypertensive men. This study examines the effects of short-term l-arg supplementation and acute resistance exercise (AREX) on cytokine levels in obese hypertensive men. METHODS: Eight obese hypertensive men aged 46 +/- 6 yrs. with an average body weight of 92.56 +/- 9.9 kg and a BMI of 31.68 +/- 2.18 kg/m2 participated in a randomized, double-blinded, crossover study. The patients were distributed into exercise groups based on the type of supplementation (6 g/day of placebo or l-arg for 7 days). Supplementation periods were separated by a seven-day washout period. The AREX regimen consisted of eight exercises with an exercise intensity of 60% of 1 repetition maximum. The interleukins IL-1ra, IL-6, and IL-10 and the IL-6/IL10 ratio were determined at rest, immediately after exercise and 1 h after exercise sessions. RESULTS: IL-1ra levels exhibited a significant difference both immediately and 1 h after exercise when the l-arg and placebo groups were compared (P < 0.05). IL-6 levels increased significantly after exercise in the placebo group compared with the l-arg group (P < 0.05). The placebo group showed a decrease in the IL-10 levels 1 h after exercise compared with resting levels (P < 0.05). The IL-6/IL-10 ratio showed a statistically significant increase in the placebo group after exercise compared to the l-arg group (P < 0.05). CONCLUSIONS: LARG supplementation attenuates the cytokine increase after AREX, in particular peak IL-6 levels decrease and exercise induced decreases in IL-10 levels are attenuated. PMID- 29415834 TI - Greater early and mid-pregnancy gestational weight gain are associated with increased risk of gestational diabetes mellitus: A prospective cohort study. AB - BACKGROUND & AIMS: Gestational diabetes mellitus is associated with adverse short and long-term consequences for both the mother and the offspring. To examine the relationship between the rates of gestational weight gain (RGWG) during early and mid-pregnancy and the risk of gestational diabetes mellitus (GDM). METHODS: 2090 singleton pregnant women from the Tongji Maternal and Child Health Cohort (TMCHC) without overt diabetes before pregnancy were analyzed in our study. Gestational weight were measured regularly in every antenatal visit. Gestational diabetes mellitus was assessed with the 75-g, 2-h oral glucose tolerance test at 24-28 weeks of gestation. Multivariable logistic regression was performed to estimate effect of RGWG on GDM. RESULTS: A total of 8.3% (n = 173) of pregnant women were diagnosed with GDM. Women with elevated rate of gestational weight gain prior to glucose screening test (RGWG-PG) increased the risk of GDM (adjusted p-trend = 0.004; odds ratios (OR) 1.64, 95% confidence intervals (CI) 1.01-2.68 and OR 2.30,95% CI 1.44-3.66 for 0.297-0.384 kg/wk and 0.385 kg/wk or more vs. 0.213 kg/wk or less, respectively). Women with greater rate of gestational weight gain in the first trimester (RGWG-F) increased the risk of GDM (adjusted p-trend = 0.048; OR 1.83, 95% CI 1.14-2.94 and OR 1.76, 95% CI 1.10-2.83 for 0.086-0.200 kg/wk and 0.201 kg/wk or more vs. -0.025 kg/wk or less, respectively). The rate of gestational weight gain in the second trimester (RGWG-S) was significantly associated with GDM only among women with RGWG-F more than 0.086 kg/wk (adjusted p-trend = 0.035; OR 2.04, 95% CI 1.16-3.59 for 0.658 kg/wk or more vs. 0.418 kg/wk or less). CONCLUSIONS: Greater early pregnancy weight gain are associated with increased risk of GDM. Elevated weight gain in mid-pregnancy increased the risk of GDM only among pregnant women with greater weight gain in the first trimester. PMID- 29415835 TI - Elderly Nutritional Indicators for Geriatric Malnutrition Assessment (ENIGMA): Development and validation of a nutritional prognostic index. AB - BACKGROUND: Few nutritional measurement tools have been validated that predict long-term mortality risks in community-living older persons. OBJECTIVE: To develop and validate a new nutritional prognostic index (ENIGMA) for use in geriatric outpatient or primary care. DESIGN: We developed the ENIGMA (four questions: unable to shop, cook or feed one's self, difficulty eating due to oral problem, eat few fruits or vegetables, 3 or more drugs a day, and four blood indicators: low albumin, hemoglobin, total cholesterol and lymphocyte count), and evaluated its predictive validity for 10 years mortality outcome in a development cohort (N = 1550) of community-living older persons, in comparison with the Geriatric Nutritional Risk Index (GNRI), Mini Nutritional Assessment (MNA) and ESPEN Malnutrition (ESPEN-M), and calibrated it externally in a validation cohort (N = 924). RESULTS: In the development cohort, ENIGMA component indicators and summary risk score (0-10) were independently associated with significantly increased mortality hazard ratio (HR), adjusted for age, sex, chronic diseases, comorbidity and inflammatory status. Increasing risk categories predicted increasing adjusted HRs (95% CI); low (0-1): reference, moderate (2-3): 1.48 (1.10-2.00), high (4-5): 2.32 (1.52-3.55), very high (6+): 4.97 (2.52-9.77). ENIGMA showed better discriminatory accuracy (C = 0.67, 95% CI = 0.63-0.71) than MNA (C = 0.59, 95% CI = 0.55-0.63), GNRI (C = 0.57, 95% CI = 0.52-0.61), and ESPEN-M (C = 0.52, 95% CI = 0.48-0.56). The predictive accuracy and utility of ENIGMA was supported in the validation cohort (C = 0.68, 95% CI = 0.62-0.74); calibration-at-large, a = 0.00007, p = 0.187; calibration slope = 0.997, 95% CI, 0.997-0.998). CONCLUSION: The ENIGMA is a validated nutritional prognostic tool that strongly predicts long-term mortality risks and is recommended for use in geriatric outpatient and primary care settings. PMID- 29415836 TI - Validity of predictive equations for resting metabolic rate in healthy older adults. AB - BACKGROUND & AIMS: Accurate estimation of energy expenditure in older people is important for nutritional support. The current literature contains controversial or inconsistent data regarding the resting metabolic rate (RMR, or basal metabolic rate) in older adults, including the relationship between the RMR and ethnicity. Little information about the RMR in healthy Asian older adults is available. This study was performed to examine the RMR in healthy Japanese older adults and compare it with previously established 16 equations. METHODS: Thirty two community-dwelling, healthy, and active elderly Japanese adults were enrolled (age, 64-87 years; 14 men, 18 women; mean height, 154.9 +/- 8.9 cm; mean weight, 53.5 +/- 9.1 kg; mean body mass index, 22.2 +/- 2.5 kg/m2). The RMR was measured by indirect calorimetry. The measured RMR was compared among 16 equations. Correlation analysis, a paired t test, and a Bland-Altman plot were used to assess the agreement among the equations. RESULTS: The average RMR was 1132 +/- 178 kcal/day with 2233 +/- 437 kcal/day average total energy expenditure (TEE) measured by doubly labeled water (DLW). The smallest bias was established by De Lorenzo et al.'s equation as bias +/-1.96SD = 4 +/- 121 kcal/day. De Lorenzo et al. and Ikeda et al.'s equations had no significant average bias both in men and women (P > 0.05). The 1.96SD of bias in six equations was within 160 kcal/day. In contrast, residuals between the measured and predicted RMR were largely correlated with the RMR in four equations. A sex-related difference in the mean bias was observed in many equations. CONCLUSION: Although the average Japanese healthy older adult has a shorter stature and lower weight than older adults in the Western population, the current data suggest that a similar predictive equation for the RMR can be applied to both Japanese and Western older adults. This study demonstrate that the De Lorenzo et al.'s or Ikeda's equation may be useful for estimating RMR in the community-dwelling, healthy, and active elderly Japanese adults without any systematic bias. PMID- 29415837 TI - Parenteral nutrition-associated cholestasis and triglyceridemia in surgical term and near-term neonates: A pilot randomized controlled trial of two mixed intravenous lipid emulsions. AB - BACKGROUND: Cholestasis is a common complication in infants receiving prolonged parenteral nutrition (PN). We studied the effects of two intravenous lipid emulsions composed with either 30% soybean oil, 30% medium-chain triglycerides (MCT), 25% olive oil, and 15% fish oil (SMOF) or with 50% MCT and 50% soybean oil n-6 (MCT/SOY) on the incidence of cholestasis in surgical term and near-term neonates. METHODS: A single-center, double-blinded, randomized controlled trial compared the incidence of cholestasis using either SMOF or MCT/SOY in neonates born at gestational age >=34 weeks undergoing major surgery. The primary outcome was the incidence of conjugated serum bilirubin >1 mg/dL. Other liver enzymes were assessed as secondary outcomes. A post-hoc analysis assessed serum triglycerides levels. Odds ratios were estimated by mixed-effects regression models. RESULTS: Enrollment was prematurely interrupted because the MCT/SOY became unavailable, thus 49 infants (SMOF 22, MCT/SOY 27) completed the study. The exposure (time on PN, cumulative dose of lipids) was similar in both groups. Similar cumulative incidence rates were found for elevated conjugated bilirubinemia and other liver enzymes. Hypertriglyceridemia >250 mg/dL (12/49) was more frequent in MCT/SOY (37.0%, 95% CI 21.53-55.77) than in SMOF (9.1%, 95% CI 2.53-27.81, p = 0.024). Triglyceridemia at the first assessment (median 8 postnatal days) was significantly higher with MCT/SOY than with SMOF (181 vs. 134 mg/dL, p = 0.006). Over the whole study period, mean triglyceride concentration was 36.5 mg/dL higher with MCT/SOY compared with SMOF (p = 0.013). CONCLUSION: Both emulsions had similar effects on the incidence of cholestasis and markers of liver integrity, but MCT/SOY induced higher serum triglyceride concentrations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02633384. PMID- 29415838 TI - Methods to validate the accuracy of an indirect calorimeter in the in-vitro setting. AB - INTRODUCTION: The international ICALIC initiative aims at developing a new indirect calorimeter according to the needs of the clinicians and researchers in the field of clinical nutrition and metabolism. The project initially focuses on validating the calorimeter for use in mechanically ventilated acutely ill adult patient. However, standard methods to validate the accuracy of calorimeters have not yet been established. This paper describes the procedures for the in-vitro tests to validate the accuracy of the new indirect calorimeter, and defines the ranges for the parameters to be evaluated in each test to optimize the validation for clinical and research calorimetry measurements. METHODS: Two in-vitro tests have been defined to validate the accuracy of the gas analyzers and the overall function of the new calorimeter. 1) Gas composition analysis allows validating the accuracy of O2 and CO2 analyzers. Reference gas of known O2 (or CO2) concentration is diluted by pure nitrogen gas to achieve predefined O2 (or CO2) concentration, to be measured by the indirect calorimeter. O2 and CO2 concentrations to be tested were determined according to their expected ranges of concentrations during calorimetry measurements. 2) Gas exchange simulator analysis validates O2 consumption (VO2) and CO2 production (VCO2) measurements. CO2 gas injection into artificial breath gas provided by the mechanical ventilator simulates VCO2. Resulting dilution of O2 concentration in the expiratory air is analyzed by the calorimeter as VO2. CO2 gas of identical concentration to the fraction of inspired O2 (FiO2) is used to simulate identical VO2 and VCO2. Indirect calorimetry results from publications were analyzed to determine the VO2 and VCO2 values to be tested for the validation. RESULTS: O2 concentration in respiratory air is highest at inspiration, and can decrease to 15% during expiration. CO2 concentration can be as high as 5% in expired air. To validate analyzers for measurements of FiO2 up to 70%, ranges of O2 and CO2 concentrations to be tested were defined as 15-70% and 0.5-5.0%, respectively. The mean VO2 in 426 adult mechanically ventilated patients was 270 ml/min, with 2 standard deviation (SD) ranges of 150-391 ml/min. Thus, VO2 and VCO2 to be simulated for the validation were defined as 150, 250, and 400 ml/min. CONCLUSION: The procedures for the in-vitro tests of the new indirect calorimeter and the ranges for the parameters to be evaluated in each test have been defined to optimize the validation of accuracy for clinical and research indirect calorimetry measurements. The combined methods will be used to validate the accuracy of the new indirect calorimeter developed by the ICALIC initiative, and should become the standard method to validate the accuracy of any future indirect calorimeters. PMID- 29415839 TI - Sarcopenia in liver transplantation: A review. AB - BACKGROUND & AIMS: The most recent definition of sarcopenia includes the presence of both low skeletal muscle mass and low skeletal muscle function. As sarcopenia has been associated with numerous poor outcomes in the general surgical population, investigation into its presence in the liver transplantation population is warranted. This review aims to synthesize the available data regarding sarcopenia and liver transplantation. METHODS: Data sourcing was completed by searching the following databases: PubMed, Google Scholar and Cochrane. RESULTS: Perioperative sarcopenia has been associated with poorer survival, increased wait list mortality and increased length of stay. Although the Model for End-Stage Liver Disease score is routinely used to predict post liver transplantation mortality and morbidity, literature suggests it does not reflect sarcopenic status. DISCUSSION: Sarcopenia is associated with poor liver transplantation outcomes. Future research should consider utilizing the recent working definition of sarcopenia and generating diagnostic reference values. PMID- 29415840 TI - Palliative home parenteral nutrition: Clinical service evaluation and identifying potential prognostic factors to assist with patient selection. AB - BACKGROUND AND AIMS: Home parenteral nutrition (HPN) for palliation has little evidence supporting existing guidance. Patient selection remains challenging. We aimed to evaluate use of palliative HPN in our service against ESPEN guidance, and to identify potential prognostic indicators. METHODS: Palliative care patients commenced on HPN were identified. Medical notes, computer records and HPN database were accessed to identify patient demographics, primary diagnosis and aetiology of intestinal failure, blood test results potentially associated with prognosis (eGFR, albumin, CRP, Hb), presence of ascites, and PN duration. By dichotomising blood results Kaplan-Meier survival plots were derived to identify potential associations with survival. RESULTS: From the HPN database of 111 patients, 20 (18%) were identified as palliative. Six were male (30%), median age (interquartile range (IQR)) 56.4 (51.5-66.8) years. Four patients commenced palliative HPN between 2000 and 2006, while 2007-2013 there were 16. The median number (IQR) of nights on HPN was 85 (19-352). The most common indication was gastro-intestinal obstruction (n = 13, 65%) and short bowel syndrome following palliative surgical resection (n = 4, 20%). Kaplan-Meier survival plots identified worse prognosis on HPN if the presenting albumin was <=30 g/L p = 0.016. CONCLUSION: The use of HPN in palliative care is increasing. Current patient selection meets with ESPEN guidance with respect to aetiology of intestinal failure and length of survival on PN. We suggest that a low albumin (not a marker of malnutrition) may help to predict those who are likely to survive less long on palliative HPN. A multi-centre prospective study, also examining quality of life would help define improved guidance. PMID- 29415841 TI - Interrater reliability of the Volume-Viscosity Swallow Test; screening for dysphagia among hospitalized elderly medical patients. AB - BACKGROUND: Oropharyngeal dysphagia (OD) is prevalent among medical and geriatric patients admitted due to acute illness and it is associated with malnutrition, increased length of stay and increased mortality. A valid and reliable bedside screening test for patients at risk of OD is essential in order to detect patients in need of further assessment. The Volume-Viscosity Swallow Test (V-VST) has been shown to be a valid screening test for OD in mixed outpatient populations. However, as reliability of the test has yet to be investigated in a population of medical and geriatric patients admitted due to acute illness, we aimed to determine the interrater reliability of the V-VST in this clinical setting. Reporting in this study is in accordance with proposed guidelines for the reporting of reliability and agreement studies (GRRAS). METHODS: In three Danish hospitals (CRD-BFH, CRD-GH, NDR-H) 11 skilled occupational therapists examined an unselected group of 110 patients admitted to geriatric or medical wards. In an overall agreement phase raters reached >=80% agreement before data collection phase was commenced. The V-VST was applied to patients twice within maximum one hour by raters who administrated the test in an order based on randomization, blinded to each other's results. Agreement, Kappa values, weighed Kappa values and Kappa adjusted for bias and prevalence are reported. RESULTS: The interrater reliability of V-VST as screening test for OD in patients admitted to geriatric or medical wards was substantial with an overall Kappa value of 0.77 (95% CI 0.65-0.89) however interrater reliability varied among hospitals ranging from 0.37 (95% CI -0.01 to 0.41) to 0.85 (95% CI 0.75-1.00). Interrater reliability of the accompanying recommendations of volume and viscosity was moderate with a weighted kappa value of 0.55 (95% CI 0.37-0.73) for viscosity and 0.53 (95% CI 0.36-0.7) for volume. The overall prevalence of OD was 34.5%, ranging from 8% to 53.6% across hospitals. The prevalence and bias adjusted Kappa value (PABAK) was 0.76 (range 0.6-0.85). Mean time to perform the test was 13.1 min (SD 6.924). CONCLUSIONS: The V-VST seems to be a moderately reliable screening tool for detecting OD among medical and geriatric patients. However, the recommendations of volume and viscosity add limited clinical value to the test. PMID- 29415842 TI - Nurse's perceptions of barriers to optimal nutritional therapy for hospitalized patients. AB - BACKGROUND & AIMS: Nurses have crucial roles in optimizing nutritional therapy for patients. The aim of this study was to explore nurses' perceptions regarding barriers to effective nutritional therapy. METHODS: Hospital-based nurses completed a questionnaire regarding various aspects of malnutrition/risk identification and barriers to effective nutritional treatment. The study was conducted at Rambam Health Care Campus with 100 nurses completing the questionnaire. RESULTS: Eighty-eight percent of those surveyed perceived identification of patients at risk for malnutrition as the nurse's responsibility. Significant differences were found when comparing head vs. bedside nurses regarding recognition of barriers to optimal nutritional therapy. More than 40% of the nurses found that the following issues were significant barriers to optimal patient treatment: the time it takes to prescribe nutritional therapy, lack of protocols, and awareness of the staff of the nutritional therapy. Overall bedside nurses found significantly more barriers preventing optimal nutritional therapy than did head nurses. CONCLUSIONS: Barriers to optimal nutrition are often remediable. Head nurses set ward policies but had a significantly different perception of barriers to nutritional care than bedside nurses. Collaboration is imperative for all sectors and authorities involved in patient care, including bedside nurses, to ensure that workable policies are implemented for the patients' benefit. PMID- 29415843 TI - Association between nutrient patterns and bone mineral density among ageing adults. AB - BACKGROUND AND AIM: There is limited evidence on the link between the overall nutrients intake from diet and bone mineral density (BMD). We assessed the association between nutrient patterns and BMD among an ageing Australian population. METHODS: Participants (n = 1135; males, 45.8%; median age, 62.0 years) with dietary and BMD data in the North West Adelaide Health Study (NWAHS) were included. Dietary intake was assessed using a food frequency questionnaire. BMD was measured using dual-energy X-ray absorptiometry. Nutrient patterns were identified by factor analysis. Linear regression analyses were conducted to assess the association between nutrient patterns and BMD (mg/cm2). Multiple imputation and sensitivity analyses were conducted to investigate the effect of missing data on the estimates. RESULTS: Three nutrient patterns (mixed-source [potassium, calcium, fibre, retinol and Vitamin B12], animal-sourced [cholesterol, protein, Vitamin B12 and fat] and plant-sourced [fibre, carotene, vitamin C and Lutein]) were identified. After adjusting for socio-demographic, lifestyle and behavioural characteristics, chronic conditions and energy intake, animal (beta = -4.07; 95% confidence interval (CI): -11.89, 3.76) and plant sourced (beta = -0.99; 95% CI: -7.43, 5.45) patterns were not associated with BMD. However, we found that the mixed-source pattern was positively associated with BMD (beta = 10.86; 95% CI: 1.91, 19.80). We did not find interactions between the pattern, other covariates and BMD. The multiple imputation and sensitivity analyses including missing data identified similar patterns of association between nutrient patterns and BMD. CONCLUSIONS: Whereas animal- and plant-sourced nutrient patterns are not associated with BMD, mixed-source pattern may have benefit in prevention of reduced BMD. PMID- 29415844 TI - A potential drug interaction between phenobarbital and dolutegravir: A case report. AB - In this report, we describe a human immunodeficiency virus (HIV)-infected patient in whom changes in phenobarbital (PB) dosage resulted in associated changes in plasma concentrations of dolutegravir (DTG). His plasma concentrations of DTG were 0.934, 0.584, 1.003 and 3.25 MUg/mL, respectively, with concomitant daily PB doses of 40, 70, 30 and 0 mg, respectively. This case suggests that PB can lead to a remarkable reduction in the plasma concentration of DTG in a dose-dependent manner. PMID- 29415845 TI - Understanding the role of emotion-oriented coping in women's motivation for change. AB - This study tested a sequential mediation model that emotion-oriented coping and motivation for change mediate the relations between anxiety and depressive symptoms and the change in substance use. Data included 183 substance using women, randomly assigned to family therapy (N=123) or individual therapy (N=60). They reported their baseline anxiety and depressive symptoms, emotion-oriented coping, as well as motivation for change throughout treatment, and substance use over a time period of 1.5years. Latent growth curve modeling showed that increased baseline motivation was associated with a faster decline in alcohol and drug use. Moreover, higher baseline anxiety and depressive symptoms were associated with a faster decrease in drug use through higher emotion-oriented coping and higher baseline motivation. This study underscores the importance of emotion-oriented coping in increasing clients' motivation and reducing their drug use. PMID- 29415846 TI - Associations between pharmacotherapy for opioid dependence and clinical and criminal justice outcomes among adults with co-occurring serious mental illness. AB - Adults suffering from a serious mental illness (SMI) and a substance use disorder are at especially high risk for poor clinical outcomes and also arrest and incarceration. Pharmacotherapies for treating opioid dependence could be a particularly important mode of treatment for opioid-dependent adults with SMI to lower their risk for overdose, high-cost hospitalizations, repeated emergency department visits, and incarceration, given relapse rates are very high following detoxification in the absence of one of the three FDA-approved pharmacotherapies. This study estimates the effects of methadone, buprenorphine, and oral naltrexone on clinical and justice-related outcomes in a sample of justice-involved adults with SMI, opioid dependence, and criminal justice involvement. Administrative data were merged from several public agencies in Connecticut for 8736 adults 18years of age or older with schizophrenia spectrum disorder, bipolar disorder, or major depression; co-occurring moderate to severe opioid dependence; and who also had at least one night in jail during 2002-2009. Longitudinal multivariable regression models estimated the effect of opioid-dependence pharmacotherapy as compared to outpatient substance abuse treatment without opioid-dependence pharmacotherapy on inpatient substance abuse or mental health treatment, emergency department visits, criminal convictions, and incarcerations, analyzing instances of each outcome 12months before and after an index treatment episode. Several baseline differences between the study groups (opioid-dependence pharmacotherapy group versus outpatient treatment without opioid-dependence pharmacotherapy) were adjusted for in the regression models. All three opioid dependence pharmacotherapies were associated with reductions in inpatient substance abuse treatment, and among the oral naltrexone subgroup, also reductions in inpatient mental health treatment, as well as improved adherence to SMI medications. Overall, the opioid-dependence pharmacotherapy group had higher rates of arrest and incarceration in the follow-up period than the comparison group; but those using oral naltrexone had lower rates of arrest (including felonies). The analysis of observational administrative data provides useful population-level estimates but also has important limitations that preclude conclusive causal inferences. Large reductions in crisis-driven service utilization associated with opioid-dependence pharmacotherapy in this study suggest that evidence-based medications for treating opioid dependence can be used successfully in adults with SMI and should be considered more systematically during assessments of treatment needs for this population. PMID- 29415847 TI - Predictors of treatment retention in postpartum women prescribed buprenorphine during pregnancy. AB - AIM: To determine variables related to treatment retention in women six and twelve months postpartum that were in medication treatment using buprenorphine during pregnancy. METHODS: This retrospective cohort study of 190 maternal-infant dyads exposed to buprenorphine during pregnancy examines rates of treatment retention at six and twelve months postpartum and also analyzes a variety of potential predictors of treatment retention including illicit drug use in the third trimester, delayed entry into medication treatment and co-occurring mental health diagnoses requiring prescription medication. RESULTS: At 12months postpartum, women appeared more likely to remain in medication treatment if they entered treatment early in pregnancy (defined as either being in treatment at the time of conception, p=0.001, or entering medication treatment prior to 13weeks gestation, p=0.037). Being prescribed an antidepressant medication during the third trimester was also associated with enhanced treatment retention at six months postpartum (p=0.005). At both six and twelve months postpartum, the use of illicit drugs (including opioids, cocaine and benzodiazepines) during the third trimester was negatively correlated with treatment retention (p=0.012 and p<0.001, respectively). CONCLUSIONS: Early access to medication treatment is associated with treatment retention in women prescribed buprenorphine during pregnancy. This has important public health implications as access to treatment is limited in many parts of the country and many women are only able to obtain treatment after becoming pregnant. Being prescribed an antidepressant medication during pregnancy may enhance treatment retention, supporting the work of previous authors. PMID- 29415848 TI - Opioid recovery initiation: Pilot test of a peer outreach and modified Recovery Management Checkup intervention for out-of-treatment opioid users. AB - The recent surge in opioid-related overdoses and related fatalities underscores the need for assertive mechanisms for linking individuals with opioid use disorders (OUD) to medication-assisted treatment (MAT). This pilot study investigated the feasibility of an intervention that used peer outreach workers to identify out-of-treatment individuals with OUD combined with a modified version of the Recovery Management Checkup to link individuals to methadone treatment. The study was conducted in high-risk communities in Chicago over 8weeks; peer outreach workers identified 88 active opioid/heroin users; 72 were screened as eligible, and 70 showed to the study intake/initial linkage meeting. Most participants were male (73%) and African American (94%), with an average age of 52.0 (sd=7.6). Nearly all (67/70, 96%) were admitted to methadone treatment; median time from initial linkage meeting to treatment admission was 2.6days. Most were still in treatment at 30 and 60days post-intake (69% and 70%, respectively). A high-risk sub-group was identified that had ever received naloxone for an opioid overdose; they had one third of the odds of being in treatment at 30days post-intake compared with others. The intervention model holds promise as an assertive method for identifying and engaging individuals with OUD into treatment. PMID- 29415850 TI - Patterns of co-occurring addictions, posttraumatic stress disorder, and major depressive disorder in detoxification treatment seekers: Implications for improving detoxification treatment outcomes. AB - BACKGROUND AND OBJECTIVES: Poly-substance use and psychiatric comorbidity are common among individuals receiving substance detoxification services. Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are the most common co-occurring psychiatric disorders with substance use disorder (SUD). Current treatment favors a one-size-fits-all approach to treating addiction focusing on one substance or one comorbidity. Research examining patterns of substance use and comorbidities can inform efforts to effectively identify and differentially treat individuals with co-occurring conditions. METHODS: Using latent class analysis, the current study identified four patterns of PTSD, MDD, and substance use among 375 addiction treatment seekers receiving medically supervised detoxification. RESULTS: The four identified classes were: 1) a PTSD MDD-Poly SUD class characterized by PTSD and MDD occurring in the context of opioid, cannabis, and tobacco use disorders; 2) an MDD-Poly SUD class characterized by MDD and alcohol, opioid, tobacco, and cannabis use disorders; 3) an alcohol-tobacco class characterized by alcohol and tobacco use disorders; and 4) an opioid-tobacco use disorder class characterized by opioid and tobacco use disorders. The observed classes differed on gender and clinical characteristics including addiction severity, trauma history, and PTSD/MDD symptom severity. DISCUSSION AND CONCLUSIONS: The observed classes likely require differing treatment approaches. For example, people in the PTSD-MDD-Poly SUD class would likely benefit from treatment approaches targeting anxiety sensitivity and distress tolerance, while the opioid-tobacco class would benefit from treatments that incorporate motivational interviewing. Appropriate matching of treatment to class could optimize treatment outcomes for polysubstance and comorbid psychiatric treatment seekers. These findings also underscore the importance of well-developed referral networks to optimize outpatient psychotherapy for detoxification treatment-seekers to enhance long-term recovery, particularly those that include transdiagnostic treatment components. PMID- 29415849 TI - A pilot test of a motivational interviewing social network intervention to reduce substance use among housing first residents. AB - This article presents findings of a pilot test of a Motivational Interviewing social network intervention (MI-SNI) to enhance motivation to reduce high risk alcohol and other drug (AOD) use among formerly homeless individuals transitioning to housing. Delivered in-person by a facilitator trained in MI, this four-session computer-assisted intervention provides personalized social network visualization feedback to help participants understand the people in their network who trigger their alcohol and other drug (AOD) use and those who support abstinence. If ready, participants are encouraged to make changes to their social network to help reduce their own high-risk behavior. Participants were 41 individuals (33 male, 7 female, 1 other; 23 African-American, 5 non Latino White, 6 Latino, 7 other, mean age 48) who were transitioning from homelessness to permanent supportive housing. They were randomly assigned to either the MI-SNI condition or usual care. Readiness to change AOD use, AOD abstinence self-efficacy, and AOD use were assessed at baseline and shortly after the final intervention session for the MI-SNI arm and around 3-months after baseline for the control arm. Acceptability of the intervention was also evaluated. MI-SNI participants reported increased readiness to change AOD use compared to control participants. We also conducted a subsample analysis for participants at one housing program and found a significant intervention effect on readiness to change AOD use, AOD abstinence self-efficacy, and alcohol use compared to control participants. Participants rated the intervention as highly acceptable. We conclude that a brief computer-assisted Motivational Interviewing social network intervention has potential to efficaciously impact readiness to change AOD use, AOD abstinence self-efficacy, and AOD use among formerly homeless individuals transitioning to permanent supportive housing, and warrants future study in larger clinical trials. PMID- 29415851 TI - Knowledge about nutrition, eating habits and weight reduction intervention among methadone maintenance treatment patients. AB - Methadone maintenance treatment (MMT) patients are often under-nourished and overweight. The impact of a nutrition intervention program to improve knowledge about healthy food habits and losing weight was studied. Patients were screened for knowledge about nutrition and body mass index (BMI). Those with a low knowledge score or a BMI >=26 (n=89) were randomly divided into either intervention (two lectures on healthy nutrition followed by weight monitoring over 6weeks), or controls (weighed at baseline, post-lectures and at study closure). The Yale Food Addiction Scale (YFAS), eating behavior rating, and nutrition knowledge questionnaires were used. Knowledge and food habit scores improved in the intervention group (28.4+/-4.3, 37.2+/-3.1, 32.5+/-3.9 pre-, post and 6-weeks post-lectures, respectively), with no change in the controls (28.6+/ 3.4, 28.2+/-4.9, 28.1+/-5.3, repeated measured p(time)=0.001, p(group)=0.001, p(interaction)=0.001); food habit (intervention: 35.0+/-7.0, 38.4+/-5.2, 37.5+/ 5.3, controls: 34.0+/-6.9, 34.7+/-6.9, 34.6+/-7.4, p(time)=0.001, p(group)=0.04, p(interaction)=0.06). BMI scores however did not change and were similar in both groups (p=0.9). Of all patients, 10.1% met the criteria of food addiction according to the YFAS, 40.4% lost weight and 28% gained weight, with no group differences. There were more symptoms of food addiction among the patients who gained weight vs. those who lost weight (3.7+/-2.0 vs. 2.6+/-1.8, respectively, p=0.04). We concluded that although weight loss was not observed, intervention is recommended for improving knowledge about nutrition and for fostering healthy eating habits with the aim of reducing diet-related morbidity among all MMT patients. Longitudinal program combined with physical activity is needed to study if may lead to weight loss. PMID- 29415852 TI - Two brief valid measures of therapeutic alliance in counseling for tobacco dependence. AB - Behavioral counseling is effective for smoking cessation and the psychotherapy literature indicates therapeutic alliance is key to counseling effectiveness. However, no tobacco-counseling specific measures of alliance exist that are suitable in most tobacco counseling contexts. This hinders assessment of counseling components in research and clinical practice. Based on the Working Alliance Inventory, and external expert review, we developed two alliance instruments: the 12-item and 3-item Working Alliance Inventory for Tobacco (WAIT 12 and WAIT-3). Two samples of 226 daily smokers via Amazon Mechanical Turk completed measures including demographics, tobacco characteristics, working alliance scales, and quit attempts. Both WAIT-12 and WAIT-3 had good to excellent internal consistency (0.92 and 0.88 for the WAIT-3 and 0.96 for the WAIT-12). The WAIT-12 1-factor model indicated poor fit (CFI=0.83, TLI=0.79, RMSEA=0.19, SRMR=0.09). The WAIT-12 3-factor model (CFI=0.94, TLI=0.93, RMSEA=0.11, SRMR=0.04) was indicative of acceptable fit. Both the WAIT-12 and the WAIT-3 were significantly associated with participants' self-reported cigarettes per day, quit attempts, and cessation. Initial validation of the WAIT-12 and WAIT-3 indicates they are psychometrically sound measures of tobacco dependence counseling alliance. The WAIT-3 provides brevity; it can be administered in under 1min. The WAIT-12 allows for assessment of specific components of therapeutic alliance. Overall, these instruments should allow for better measurement of alliance in clinical services and research. PMID- 29415853 TI - Expected and actual fentanyl exposure among persons seeking opioid withdrawal management. AB - OBJECTIVE: Fentanyl-contaminated opioid supplies have led to rising overdose fatalities in recent years. We compared beliefs, behaviors, and risk perceptions related to fentanyl with actual toxicology reports among people who used opioids. METHOD: Participants (n=231) were patients undergoing short-term inpatient opioid withdrawal management in Fall River, Massachusetts. We compared persons testing positive and negative for fentanyl on urine toxicological testing at program entry. RESULTS: Nearly all (95.7%) participants believed that fentanyl increases risk for overdose/death, and 86.6% of participants tested positive for fentanyl. Positive fentanyl toxicology test results were associated with lower educational attainment, history of injection drug use, and self-reported lifetime use of fentanyl. Of those reporting they had never been exposed to fentanyl (intentionally or unintentionally) (n=33), two-thirds tested positive for fentanyl; among those believing their tests would be negative (n=49), 71.4% tested positive for fentanyl. Heroin use was associated with fentanyl exposure; persons who reported past month heroin use (n=213) were more likely to test positive for fentanyl (91.1%) than persons using non-heroin opioids (n=18; 33.3%). CONCLUSIONS: Nearly nine in ten participants tested positive for fentanyl, including participants who anticipated their tests would be negative. Leveraging toxicology results in opioid withdrawal settings may be helpful in educating patients about fentanyl exposure and risks. PMID- 29415854 TI - Use of web-based screening and brief intervention for unhealthy alcohol use by older adults. AB - BACKGROUND: While the number of older adults who engage in unhealthy drinking is increasing, few studies have examined the role of online alcohol screening and intervention tools for this population. The objective of this study was to describe characteristics of drinking behaviors among older adults who visited an alcohol screening and intervention website, and compare them to younger adults. METHODS: We analyzed the responses of visitors to Alcoholscreening.org in 2013 (n=94,221). The prevalence of unhealthy alcohol use, behavioral change characteristics, and barriers to changing drinking were reported by age group (ages 21-49, 50-65, 66-80). Logistic regression models were used to identify characteristics associated with receiving a plan to either help cut back or quit drinking. RESULTS: Of the entire study sample, 83% of respondents reported unhealthy drinking (exceeding daily or weekly recommended limits) with 84% among 21-49year olds, 79% among 50-65year olds, and 85% among adults over 65. Older adults reported fewer negative aspects of drinking, lower importance to change, highest confidence and fewer barriers to change, compared to younger adults. In the adjusted model, females (AOR=1.45, p<0.001) and older adults (AOR=1.55, p<0.002) were more likely to receive a plan to change drinking behaviors. DISCUSSION: An online screening and intervention tool identified many older adults with unhealthy alcohol use behaviors and most were receptive to change. Web-based screening and interventions for alcohol use have the potential to be widely used among older adults. PMID- 29415855 TI - Utilization of outpatient medical care and substance use among rural stimulant users: Do the number of visits matter? AB - Rural substance users are less likely than their urban peers to use formal substance use treatment. It is therefore important to understand how the utilization of potentially more appealing care options, such as outpatient medical care (OMC), may affect substance use over time. This study sought to examine whether the number of OMC visits, after controlling for important covariates, was associated with days of alcohol, crack and powder cocaine, and methamphetamine use among a sample of rural stimulant users over a three year period. Data were collected from a natural history study of 710 stimulant users living in rural communities in Arkansas, Kentucky, and Ohio. Participants were adults, not in drug treatment, and reporting stimulant use in the last 30days. In terms of alcohol use, for participants with higher employment-related problems, having 3 or more OMC visits (relative to none) was associated with fewer days of alcohol use. The results for days of cocaine and methamphetamine use were mixed. However, we did find that for participants reporting at least one substance use treatment or mutual help care visit in the past 6-months, having 1-2 OMC visits (compared to none) was associated with fewer days of crack cocaine use. Regarding methamphetamine use, results showed that for participants without medical insurance, having 3 or more OMC visits (compared to none) was associated with significantly fewer days of methamphetamine use if they also reported greater than or equal to a high school education. The findings from this study may help us begin to understand some of the characteristics of rural drug users, who utilize OMCs, associated with reductions in substance use. These findings may help health care administrators better plan, coordinate, and allocate resources to rural OMCs to more effectively address substance use in this population. PMID- 29415856 TI - A qualitative assessment of attitudes about and preferences for extended-release naltrexone, a new pharmacotherapy to treat opioid use disorders in Ukraine. AB - Numerous individual barriers, including negative attitudes toward opioid agonist therapies (OAT), have undermined HIV prevention efforts in Ukraine where the epidemic is concentrated in people who inject drugs (PWID). The recent availability of extended-release naltrexone (XR-NTX), an opioid antagonist, provides new opportunities for treatment and prevention, but little is known about patient preferences. We conducted qualitative analysis using focus groups (FG) of PWID recruited based on OAT experience: currently, previously, and never on OAT in five Ukrainian cities. FG included 199 PWID in 25 focus groups. Focus group transcripts were coded and analyzed using a modified grounded theory approach to identify common themes and domains related to attitudes about and preferences for XR-NTX, relative to other treatments. Interest in XR-NTX was supported if supervised opioid withdrawal and psychological support were assured. Other factors supporting XR-NTX included a focus on younger PWID early in their injection career and motivated for recovery. Perceptions of recovery included not receiving psychoactive medications like methadone or buprenorphine. With more information, XR-NTX could be a viable option for PWID in Ukraine, especially if concerns regarding withdrawal and psychological support are adequately addressed. PMID- 29415857 TI - Exploration of treatment matching of problem drinker characteristics to motivational interviewing and non-directive client-centered psychotherapy. AB - Motivational Interviewing (MI) is a known effective intervention for alcohol use disorder (AUD). MI's mechanisms of action remain inconsistently substantiated, and research in this area has been reliant on identifying relationships through strength of association rather than experimental manipulation of active ingredients. In two previous studies, a pilot and a larger replication study, we disaggregated MI into its hypothesized active ingredients by creating three conditions: MI, Spirit Only MI (SOMI, in which evocation of change talk was proscribed), and a non-therapy condition (NTC). Results from both studies yielded equivalent findings across all three conditions. In the current analyses, data from both studies were combined to test five participant characteristics as moderators of MI's component parts: 1) severity of baseline drinking, 2) severe AUD (met 6 or more criteria), 3) baseline self-efficacy to moderate drinking, 4) mean daily confidence to resist heavy drinking in the week prior to treatment initiation, and 5) depression. There were no significant findings related to baseline drinking, severe AUD, or baseline self-efficacy. Confidence yielded a significant interaction effect. When participants had high baseline confidence, drinking for those in MI increased compared to those in SOMI. Depression also yielded a significant moderating effect such that in the context of higher depressive symptoms, receipt of either therapy reduced drinking relative to NTC. Results are discussed in light of existing literature on MOBC with MI and the potential role exploring ambivalence may play for participants with particular characteristics. PMID- 29415858 TI - Identification of heavy drinking in the 10-item AUDIT: Results from a prospective study among 18-21years old non-dependent German males. AB - BACKGROUND: Alcohol consumption is pivotal for the subsequent development of alcohol use disorders (AUD). The Alcohol Use Disorders Identification Test (AUDIT) is a recommended AUD screening tool for prevention and primary care settings. The objectives of this study were to test how many participants with heavy drinking are unidentified by the AUDIT, if proportions of unidentified participants vary over time, and whether this unidentified risk group (URG) was clinically relevant in terms of drinking behavior reports and AUD risk factors, as well as future adverse outcomes, such as craving, dependence symptoms, or depression. METHODS: Our prospective cohort study followed 164 German males aged 18-19years without an alcohol dependence diagnosis over 24months. Only men were included due to higher AUD prevalence and gender-specific differences in metabolism, drinking patterns, and progression to AUD. All participants were screened via telephone interview and answered questionnaires both in person and via internet. Heavy drinking was classified using the AUDIT consumption score (AUDIT-C>=4.50). Standardized AUD diagnoses and symptoms, as well as alcohol use related outcome criteria were assessed via standardized Composite International Diagnostic Interview (CIDI), and self-report questionnaires. RESULTS: One in four participants (22-28% across all four follow-ups) reported heavy drinking but was unidentified by AUDIT total score (i.e. score<8), thus qualifying for URG status. The URG status did not fluctuate considerably across follow-ups (repeated measures ANOVA, p=0.293). URG participants identified at the six-month follow-up did not generally differ from participants without URG status in terms of AUD family history or temperament (multivariate ANOVA, p=0.114), except for anxiety sensitivity (pBonferroni<0.001). After two years, URG participants reported a similar level of adverse outcomes compared to low-risk participants (multivariate ANOVA, p=0.438), but less alcohol-related problems and less loss of control due to craving compared to high-risk participants (pBonferroni<=0.007). CONCLUSIONS: Despite the considerable number of heavy-drinking individuals unidentified by AUDIT total scores, an additional classification according to AUDIT-C values did not prove useful. Combining AUDIT and AUDIT-C scores might not be sufficient for identifying AUD risk groups among young adult German males. There is an urgent need for a replication of our findings among female participants. PMID- 29415859 TI - Effects of transdermal lidocaine or lidocaine with prilocaine or tetracaine on mechanical superficial sensation and nociceptive thermal thresholds in horses. AB - OBJECTIVE: To evaluate the transdermal local anaesthetic effect of lidocaine or lidocaine combined with prilocaine or tetracaine in horses. STUDY DESIGN: Experimental, randomized study. ANIMALS: A total of five healthy adult warmblood horses. METHODS: Horses were clipped bilaterally at the withers, cranial saddle area and caudal saddle area. Baseline measurements for mechanical superficial sensation via von Frey filaments and nociceptive thermal thresholds were performed. A 5% lidocaine patch (12 hour exposure, treatment L), a lidocaine/prilocaine cream (each 2.5%, treatment LP) and a lidocaine/tetracaine cream (each 7%, treatment LT) were applied (both 2 hour exposure). The same product was applied at the same location bilaterally, but on the right side an epidermal micro-perforation (dermaroller, 1200 needles) was performed prior to application. A total of five more measurements were performed at each location, immediately at the end of exposure time followed by hourly measurements. Thermal thresholds normalized to thermal excursion were analysed. One- or two-way anova and the Wilcoxon signed-rank test were used for statistical analysis with p<0.05 considered significant. RESULTS: Epidermal micro-perforation had no enhancing effect. Treatments L, LP, and LT resulted in increased thermal excursion (%) immediately (84.7+/-12.9; 100.0+/-0.0; 100.0+/-0.0) and 1 hour (81.7+/-66; 86.0+/ 17.7; 87.7+/-14.4) after the removal of the respective product compared to baseline (66.1+/-9.3; 69.9+/-8.3; 76.5+/-7.8). Superficial mechanical sensation was decreased by the lidocaine-and-tetracaine cream at all time points, and by the lidocaine patch and lidocaine-and-prilocaine cream for three measurements. CONCLUSIONS AND CLINICAL RELEVANCE: Eutectic mixtures of lidocaine with either prilocaine or tetracaine led to a reduction in thermal nociception and mechanical sensation for up to 2 hours. PMID- 29415860 TI - Development of an ultrasound-guided technique for retrobulbar nerve block in dromedary camels: a cadaveric study. AB - OBJECTIVE: Description of an ultrasound (US)-guided technique for retrobulbar nerve blockade in dromedary (Camelus dromedarius) cadavers. STUDY DESIGN: Prospective experimental cadaveric study that was carried out in three phases: phase I: anatomical dissection and development of US-guided technique; phase II: methylene blue (MB) injection; phase III: contrast medium (CM), US-guided injections with computed tomography (CT) control. ANIMALS: A total of 36 orbits from 18 heads were obtained from 18 dromedary cadavers. METHODS: Phase I: anatomical dissections were carried out bilaterally, using two heads to determine needle site placement. Phase II: a US-guided, lateral, in-plane approach using one of three volumes of MB (3, 6, or 9 mL) was evaluated in six heads (four orbits per volume tested) to establish the ideal injection volume. Injections of MB that strongly stained all retrobulbar nerves were considered successful, whereas insufficient MB volumes resulted in weak or no nerve staining. Phase III: US-guided retrobulbar injection with CM was carried out using 20 orbits. Computed tomography was performed after each injection trial to determine the accuracy of needle placement and CM dispersal. An injection was judged to be successful when the CT images revealed that the needle was located within the retractor bulbi muscle cone and the CM reached the target nerves at the orbitorotundum and the optic foramina. RESULTS: Only injection of 9 mL of MB stained the target nerves sufficiently, whereas there was no or only weak staining with 3 and 6 mL, respectively. Therefore, 9 mL of CM was used for the US-guided injections in phase III. Subsequent CT scans revealed satisfying CM distribution within the ocular muscle cone in 18 of 20 cases (90% success rate). CONCLUSIONS AND CLINICAL RELEVANCE: US-guided retrobulbar injection in dromedary cadavers is feasible. Further research is required to assess its practicality and usefulness in vivo. PMID- 29415861 TI - Effective plasma alfaxalone concentration to produce immobility in male neutered cats. AB - OBJECTIVE: To determine the effective plasma alfaxalone concentration for the production of immobility in cats. STUDY DESIGN: Prospective up-and-down study. ANIMALS: Sixteen 1-2 year old male castrated research cats. METHODS: Cats were instrumented with catheters in a jugular and a medial saphenous vein. Alfaxalone was administered via the medial saphenous catheter, using a target-controlled infusion system. The infusion lasted for approximately 32 minutes. A noxious stimulus (tail clamp) was applied 30 minutes after starting the alfaxalone infusion, until the cat moved or 60 seconds had elapsed, whichever occurred first. The target alfaxalone concentration was set at 5 mg L-1 in the first cat and increased or decreased by 1 mg L-1 in subsequent cats, if the previous cat had moved or not moved in response to stimulation, respectively. This was continued until six independent crossovers (different responses in pairs of subsequent cats) had been observed. Blood samples were collected before alfaxalone administration, and 15 and 31 minutes after starting the administration, for the determination of plasma alfaxalone concentration using liquid chromatography/tandem mass spectrometry. The alfaxalone concentration yielding a probability of immobility in 50% (EC50), 95% (EC95) and 99% (EC99) of the population, and their respective 95% Wald confidence intervals were calculated. RESULTS: The EC50, EC95 and EC99 for alfaxalone-induced immobility were 3.7 (2.4-4.9), 6.2 (4.7-) and 7.6 (5.5-) mg L-1, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The effective plasma alfaxalone concentration for immobility in cats was determined. This value will help in the design of pharmacokinetic-based dosing regimens. PMID- 29415862 TI - Beyond stem cells: Commitment of progenitor cells to meiosis. AB - The first step in established spermatogenesis is the production of progenitor cells by the stem cell population. The progenitor cells (undifferentiated A spermatogonia) expand in number via the formation of syncytial chains by mitosis. The mechanism by which these progenitor cells commit to meiosis and spermatogenesis is tightly controlled and results in complex morphological organization all of which is designed to efficiently achieve large numbers of spermatozoa. The major extrinsic factor that triggers the commitment to meiosis and establishes the structural complexity is retinoic acid (RA). Retinoic acid is produced from retinol via two oxidation steps in low abundance near its site of action. The action of RA on undifferentiated A spermatogonia results in the timed progression of these progenitor cells into the cycle of the seminiferous epithelium. We have utilized a drug WIN 18,446 that inhibits the second oxidation step in RA biosynthesis to block the progression of undifferentiated A spermatogonia in the mouse testis. As a result of this block the undifferentiated progenitor cells accumulate but do not differentiate into A1 spermatogonia. When the block is released and a bolus of RA is simultaneously administered the accumulated spermatogonia progress through the differentiation pathway in complete synchrony and maintain that synchrony with regard to stages of the cycle of the seminiferous epithelium for several months. This procedure allowed us to accumulate sufficient material to measure retinoic acid levels across the cycle and will allow us to isolate and analyze large number of progenitor cells proceeding synchronously down the pathway to meiosis. We have been able to show that the cycle of the seminiferous epithelium is established and maintained by pulses of RA that appear at stages VIII and IX of the cycle. PMID- 29415863 TI - [Purple urine-bag syndrome: A case report]. AB - Purple urine-bag syndrome is a rare condition that occurs in patients with indwelling urinary catheters carried over a long period and frequently associated with a urinary tract infection. It is characterized by the appearance of a violet coloration of the probe and/or the urine collection bag. We report the first case in West Africa that occurred in a 47-year-old woman in uremic encephalopathy and carrier of a urinary catheter, which presented a violet color of the tubing and urine-bag associated with a urinary tract infection. The outcome was favorable under antibiotic therapy. Many patients benefit from the installation of urinary catheters for various reasons and the occurrence of this syndrome should lead the medical team to systematically seek an underlying urinary tract infection to avoid if possible paraclinical assessments generally costly to our patients without medical coverage in our developing countries. PMID- 29415864 TI - Rickettsioses in Denmark: A retrospective survey of clinical features and travel history. AB - Rickettsia spp. can be found across the globe and cause disease of varying clinical severity, ranging from life-threatening infections with widespread vasculitis to milder, more localized presentations. Vector and, to some degree, reservoir are hematophagous arthropods, with most species harboured by ticks. In Denmark, rickettsiae are known as a cause of imported travel-related infections, but are also found endemically in ticks across the country. Data are, however, lacking on the geographical origin and clinical features of diagnosed cases. In this study, we have examined the travel history and clinical features of two groups of patients; 1) hospital-patients diagnosed with rickettsioses in the years 2010-2015 and 2) patients from primary health care (PHC) centers in Denmark having demonstrated anti-rickettsia antibodies in the years 2012-2015. The patients were identified using the Danish National Patient Registry (DNPR) and through the serological database at the State Serum Institute, where the laboratory diagnosis of rickettsioses is currently centralized. Data were collected for 86 hospital patients and 26 PHC center patients by reviewing hospital medical records and performing telephone interviews with PHC centers. Of the hospital patients, 91% (78/86) had a history of international travel 14 days prior to symptom start, with most having imported their infection from southern Africa, South Africa in particular (65%), and presenting with a clinical picture most compatible with African tick-bite fever caused by R. africae. Only two patients presented with a CRP > 100 mg/L and no mortalities were reported. At the PHC centers, most patients presented with mild flu-like symptoms and had an unknown (50%) or no history (19%) of international travel, raising the possibility of endemic rickettsioses. In view of our findings, rickettsioses do not appear to constitute a major public health problem in Denmark, with most cases being imported infections and potential endemic cases presenting as mild infections. PMID- 29415865 TI - Assessing the variability in transmission of bovine tuberculosis within Spanish cattle herds. AB - In Spain, despite years of efforts to eradicate bovine tuberculosis (bTB), the disease is still endemic, with some areas of high prevalence. In this context, the surveillance and control plans may need to be re-evaluated, and understanding the dynamics of bTB spread within Spanish herds may help to develop new strategies for reducing the time for detection of infected herds and for the elimination of bTB from the herds already infected. Here, we developed a compartmental stochastic model to simulate bTB within-herd transmission, fed it with epidemiological data from 22 herds (obtained from a previous work) and carried out parameter inference using Approximate Bayesian Computing methods We also estimated the "Within-herd transmission potential Number" (Rh), i.e. the average number of secondary cases generated by a single animal infected introduced into a totally susceptible herd, considering different scenarios depending on the frequency of controls. The median global values obtained for the transmission parameters were: for the transmission coefficient (beta), 0.014 newly infected animals per infectious individual per day (i.e. 5.2 per year), for the rate at which infected individuals become infectious (alpha), 0.01 per day (equivalent to a latent period of 97 days), and for the rate at which infected individuals become reactive to the skin test (alpha1), 0.08 per day (equivalent to a period of 12 days for an infected animal to become reactive). However, the results also evidenced a great variability in the estimates of those parameters (in particular beta and alpha) among the 22 herds. Considering a 6-month interval between tests, the mean Rh was 0.23, increasing to 0.82 with an interval of 1 year, and to 2.01 and 3.47 with testing intervals of 2 and 4 years, respectively. PMID- 29415866 TI - Idiopathic granulomatous orchitis: Ultrasound and MR imaging features. PMID- 29415867 TI - Time course of improvement after re-repair procedure for VPI management. AB - OBJECTIVES: Palatal re-repair aims to improve velar function by retro-positioning the levator veli palatini muscles. The surgery includes extensive dissection, leading to tissue edema and scar formation which may need time to remodel. Together with the change of muscle orientation and tension, it is expected that a period of time is needed to reach the final functional performance. This study attempts to determine how much time is required to reach the optimum performance of the palate after re-repair. METHODS: A retrospective chart review identified consecutive cleft patients with VPI who underwent palate re-repair procedure by a single surgeon from 2000 to 2015 and achieved normal or borderline normal VP function. Only patients who had regular postoperative follow-up visits for speech assessments until resolution of speech abnormalities were included. The percent of patients cured at each time point following surgery was recorded. RESULTS: Forty-five patients met the inclusion criteria. The mean age at surgery was 6.6 +/- 3.2 years. Speech abnormalities had resolved in 44.5% of patients within the first 6 months after surgery, 62.2% after up to 1 year, 75.6% after up to 2 years and 88.9% after up to 3 years post re-repair palatoplasty. The remaining 11.1% continued to improve after 3 years up to 6 years. CONCLUSIONS: Re-repair procedures may take a longer time than previously thought for the final outcome to manifest. Close monitoring of improvement with continued speech therapy is recommended before deciding to move to the next surgical step in management. PMID- 29415868 TI - Managing the popularity of bariatric surgery in France, comments on the editorial by Laurent Brunaud. PMID- 29415869 TI - Neotrygon indica sp. nov., the Indian Ocean blue-spotted maskray (Myliobatoidei, Dasyatidae). AB - The blue-spotted maskray, previously N. kuhlii, consists of up to eleven lineages representing separate species. Nine of these species (N. australiae, N. bobwardi, N. caeruleopunctata, N. malaccensis, N. moluccensis, N. orientale, N. vali, N. varidens, N. westpapuensis) have already been formally described and two (Indian Ocean maskray and Ryukyu maskray) remain undescribed. Here, the Indian Ocean maskray is described as a new species, Neotrygon indica sp. nov. Specimens of the new species were generally characterized on their dorsal side by a moderately large number of small ocellated blue spots, a low number of medium-sized ocellated blue spots, the absence of large ocellated blue spots, a high number of dark speckles, a few dark spots, and a conspicuous occipital mark. The new species formed a distinct haplogroup in the tree built from concatenated nucleotide sequences at the CO1 and cytochrome b loci. A diagnosis based on colour patterns and nucleotide sequences at the CO1 and cytochrome b loci is proposed. The distribution of N. indica sp. nov. includes the Indian coast of the Bay of Bengal, the Indian coast of the Laccadives Sea, and Tanzania. Considerable sampling effort remains necessary for an in-depth investigation of the phylogeographic structure of the Indian Ocean maskray. PMID- 29415870 TI - Use of primary healthcare for persons with epilepsy. AB - INTRODUCTION: In Denmark, care and treatment related to epilepsy primarily takes place at specialized hospital departments (neurology and pediatrics). The general practitioner (GP) in contrast is the primary contact and acts as a gatekeeper to the healthcare system for other disorders. The aim of the present study was to describe the utilization of services provided by the GP for children with epilepsy before and after diagnosis of epilepsy and to compare it with that of children without epilepsy. METHODS: All live born children born in Denmark between 1st of January 1996 and 1st of December 2013 were identified in the Danish National Patient Registry. Information about number and type of contact to the general practitioner was obtained from the Health Insurance Service Register. Information about epilepsy was obtained from the Danish National Patient Registry (n=10,062). For each child with epilepsy, we sampled 10 children without an epilepsy diagnosis matched on sex and age at the time of diagnosis (n=100,620). Children were followed up until 31st of December 2013. Multiple negative binomial regression analysis adjusting for relevant confounders was used to estimate the association between epilepsy and the use of GPs both before and after the time of epilepsy diagnosis. RESULTS: Children with epilepsy had a higher utilization of services provided by the GP after the diagnosis of epilepsy compared with children without epilepsy (incidence rate ratio (IRR): 1.64 (1.61-1.67)). The IRR for any contacts stayed relatively stable during the follow-up period, whereas the IRR for face-to-face contacts tended to decline and phone contacts tended to increase. The more frequent GP contacts in children with epilepsy were also evident before the time of diagnosis and for both sexes and in all age groups. For the specific services provided, children with epilepsy more often had a blood sample taken and more urine stix and CRP tests performed during the first years following diagnosis. CONCLUSION: Children with epilepsy have a higher use of services provided by the GP both before and after the epilepsy diagnosis compared with children without epilepsy. This is likely due to a higher prevalence of comorbid conditions in children with epilepsy as well as consequences of the underlying condition. PMID- 29415871 TI - Eslicarbazepine acetate as a replacement for levetiracetam in people with epilepsy developing behavioral adverse events. AB - BACKGROUND: Psychiatric and behavioral side effects (PBSEs) are a major cause of antiepileptic drug (AED) withdrawal. Levetiracetam (LEV) is a recognized first line AED with good seizure outcomes but recognized with PBSEs. Eslicarbazepine (ESL) is considered to function similarly to an active metabolite of the commonly used carbamazepine (CBZ). Carbamazepine is used as psychotropic medication to assist in various psychiatric illnesses such as mood disorders, aggression, and anxiety. AIM: The aim was to evaluate the psychiatric profile of ESL in people who had LEV withdrawn due to PBSEs in routine clinical practice to see if ESL can be used as a possible alternative to LEV. METHODS: A retrospective observational review was conducted in two UK epilepsy centers looking at all cases exposed to ESL since its licensing in 2010. The ESL group was all patients with treatment resistant epilepsy who developed intolerable PBSEs to LEV, subsequently trialed on ESL. The ESL group was matched to a group who tolerated LEV without intolerable PBSEs. Psychiatric disorders were identified from case notes. The Hamilton Depression Scale (HAM-D) was used to outcome change in mood. Clinical diagnoses of a mental disorder were compared between groups using the Fisher's exact test. Group differences in HAM-D scores were assessed using the independent samples t-test (alpha=0.05). RESULTS: The total number of people with active epilepsy in the two centers was 2142 of whom 46 had been exposed to ESL. Twenty six had previous exposure to LEV and had intolerable PBSEs who were matched to a person tolerating LEV. There was no statistical differences in the two groups for mental disorders including mood as measured by HAM-D (Chi-square test: p=0.28). CONCLUSION: The ESL was well tolerated and did not produce significant PBSEs in those who had PBSEs with LEV leading to withdrawal of the drug. Though numbers were small, the findings suggest that ESL could be a treatment option in those who develop PBSEs with LEV and possibly other AEDs. PMID- 29415872 TI - Perceived Threat and Internet Use Predict Intentions to Get Bowel Cancer Screening (Colonoscopy): Longitudinal Questionnaire Study. AB - BACKGROUND: Many people use the Internet for health-related information search, which is known to help regulate their emotional state. However, not much is known yet about how Web-based information search together with negative emotional states (ie, threat of cancer diagnosis) relate to preventive medical treatment decisions (ie, colonoscopy intentions). OBJECTIVE: The aim of this study was to investigate how frequency of health-related Internet use together with perceived threat of a possible (bowel) cancer diagnosis influences intentions to get a colonoscopy. Previous research has shown that people who experience threat preferentially process positive information in an attempt to downregulate the aversive emotional state. The Internet can facilitate this regulatory strategy through allowing self-directed, unrestricted, and thus biased information search. In the context of threat regarding a possible bowel cancer diagnosis, feelings of threat can still be effectively reduced through cancer screening (ie, colonoscopy). We, therefore, predict that in that particular context, feelings of threat should be related to stronger colonoscopy intentions, and that this relationship should be enhanced for people who use the Internet often. METHODS: A longitudinal questionnaire study was conducted among healthy participants who were approaching or just entering the bowel cancer risk group (aged 45-55 years). Perceived threat of a possible (bowel) cancer diagnosis, frequency of health related Internet use, and intentions to have a colonoscopy were assessed at 2 time points (6-month time lag between the 2 measurement points T1 and T2). Multiple regression analyses were conducted to test whether threat and Internet use at T1 together predicted colonoscopy intentions at T2. RESULTS: In line with our predictions, we found that the threat of a possible (bowel) cancer diagnosis interacted with the frequency of Internet use (both T1) to predict colonoscopy intentions (T2; B=.23, standard error [SE]=0.09, P=.01). For people who used the Internet relatively often (+1 SD), the positive relationship between threat and colonoscopy intentions was significantly stronger (B=.56, SE=0.15, P<.001) compared with participants who used the Internet less often (-1 SD; B=.17, SE=0.09, P=.07). This relationship was unique to Web-based (vs other types of) information search and independent of risk factors (eg, body mass index [BMI] and smoking). CONCLUSIONS: The results of this study suggest that health-related Internet use can facilitate emotion-regulatory processes. People who feel threatened by a possible (bowel) cancer diagnosis reported stronger colonoscopy intentions, especially when they used the Internet often. We propose that this is because people who experience threat are more likely to search for and process information that allows them to downregulate their aversive emotional state. In the present case of (bowel) cancer prevention, the most effective way to reduce threat is to get screened. PMID- 29415873 TI - Using Relational Agents to Promote Exercise and Sun Protection: Assessment of Participants' Experiences With Two Interventions. AB - BACKGROUND: Relational agents (RAs) are electronic computational figures designed to engage participants in the change process. A recent study, Project RAISE, tested the effectiveness of RAs, combined with existing computer-based interventions to increase regular exercise and sun protection behaviors. Results showed these interventions can be effective but need further development. OBJECTIVE: The purpose of this study was to examine participants' experiences using RAs to increase participant engagement and promote behavior change . METHODS: A qualitative approach was primarily utilized. A 25-question interview guide assessed different components of participants' experiences with the intervention, including motivation, engagement, satisfaction or dissatisfaction, quality of their interaction with the RA, and behavior change. Quantitative assessment of satisfaction was based on a scale of 1 to 10, with 1 representing least satisfied and 10 representing most satisfied. A summative analytic approach was used to assess individuals' qualitative responses. A single analysis of variance (ANOVA) examined levels of satisfaction by gender. RESULTS: Of the original 1354 participants enrolled in Project RAISE, 490 of 1354 (36%) were assigned to the RA group. A sample of 216 out of 490 (44%) participants assigned to the RA group completed the interventions, and follow-up assessments were contacted to participate in the semistructured interview. A total of 34 out of 216 (16%) completed the interview. Participants were motivated by, and satisfied with, the intervention. Participants viewed the RA as supportive, informative, caring, and reported positive behavior change in both exercise and sun protection. Some participants (15/34, 44%) noted the RA was less judgmental and less "overbearing" compared with a human counselor; other participants (12/34, 35%) said that the interaction was sometimes repetitive or overly general. The majority of participants (22/34, 65%) viewed the RA as an important contributor to their behavior change for exercise, sun protection, or both. Levels of satisfaction ranged between 7 and 10. There were no gender differences noted in levels of satisfaction (P=.51). CONCLUSIONS: RAs provide an innovative and attractive platform to increase exercise and sun protection behaviors and potentially other health behaviors. PMID- 29415874 TI - Confocal Laser Endomicroscopy for the Diagnosis of Urothelial Carcinoma in the Bladder and the Upper Urinary Tract: Protocols for Two Prospective Explorative Studies. AB - BACKGROUND: Visual confirmation of a suspicious lesion in the urinary tract is a major corner stone in diagnosing urothelial carcinoma. However, during cystoscopy (for bladder tumors) and ureterorenoscopy (for tumors of the upper urinary tract) no real-time histopathologic information can be obtained. Confocal laser endomicroscopy (CLE) is an optical imaging technique that allows for in vivo high resolution imaging and may allow real-time tumor grading of urothelial lesions. OBJECTIVE: The primary objective of both studies is to develop descriptive criteria for in vivo CLE images of urothelial carcinoma (low-grade, high-grade, carcinoma in situ) and normal urothelium by comparing CLE images with corresponding histopathology. METHODS: In these two prospective clinical trials, CLE imaging will be performed of suspicious lesions and normal tissue in the urinary tract during surgery, prior to resection or biopsy. In the bladder study, CLE will be performed in 60 patients using the Cystoflex UHD-R probe. In the upper urinary tract study, CLE will be performed in 25 patients during ureterorenoscopy, who will undergo radical treatment (nephroureterectomy or segmental ureter resection) thereafter. All CLE images will be analyzed frame by frame by three independent, blinded observers. Histopathology and CLE-based diagnosis of the lesions will be evaluated. Both studies comply with the IDEAL stage 2b recommendations. RESULTS: Presently, recruitment of patients is ongoing in both studies. Results and outcomes are expected in 2018. CONCLUSIONS: For development of CLE-based diagnosis of urothelial carcinoma in the bladder and the upper urinary tract, a structured conduct of research is required. This study will provide more insight in tissue-specific CLE criteria for real-time tumor grading of urothelial carcinoma. TRIAL REGISTRATION: Confocal Laser Endomicroscopy: ClinicalTrials.gov NCT03013894; https://clinicaltrials.gov /ct2/show/NCT03013894?term=NCT03013894&rank=1 (Archived by WebCite at http://www.webcitation.org/6wiPZ378I); and Dutch Central Committee on Research Involving Human Subjects NL55537.018.15; https://www.toetsingonline.nl /to/ccmo_search.nsf/fABRpop?readform&unids=6B72AE6EB0FC3C2FC125821F001B45C6 (Archived by WebCite at http://www.webcitation.org/6wwJQvqWh). Confocal Laser Endomicroscopy in the upper urinary tract: ClinicalTrials.gov NCT03013920; https://clinicaltrials.gov/ct2/show/NCT03013920? term=NCT03013920&rank=1 (Archived by WebCite at http://www.webcitation.org/6wiPkjyt0); and Dutch Central Committee on Research Involving Human Subjects NL52989.018.16; https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=D27C9C3E5 55CFECC12581690016779F (Archived by WebCite at http://www.webcitation.org/6wvy8R44C). PMID- 29415875 TI - Psychosocial Distress of Patients with Psoriasis: Protocol for an Assessment of Care Needs and the Development of a Supportive Intervention. AB - BACKGROUND: Psoriasis is a chronic inflammatory disease that is often associated with a number of somatic and mental comorbidity. Patients with psoriasis show an increased risk of depression and (social) anxiety. OBJECTIVE: The aims of this study are 1) to explore the psychosocial distress of patients with psoriasis and to assess their care needs; and 2) to develop a supportive intervention based on the prior results. METHODS: A multi-stage design with four phases combining quantitative and qualitative methodology will be used and conducted in two centers. 1) A scoping review and focus groups will be used to design a questionnaire to assess the psychosocial distress and care needs of the patients. 2) The questionnaire developed in phase 1 will be used in a cross-sectional survey to assess the extent of psychosocial distress and supportive care needs in 400 patients with psoriasis. 3) A systematic review and meta-analysis will be conducted to identify psychosocial and psychoeducational interventions for patients with psoriasis and to describe their effectiveness. 4) Based on the results of the phases 2 and 3 a manualized supportive intervention will be developed and the feasibility and acceptance of the intervention will be assessed. RESULTS: Currently, phase 1 of the project has been completed and the recruitment for phase 2 has been started. The systematic review and meta-analysis of phase 3 are conducted simultaneously to phase 2 and results are expected soon. Phase 4 has not been started yet. CONCLUSIONS: The expected results of this study will show the extent of psychosocial distress of patients with psoriasis in Germany and supplement previous research with findings about the supportive care needs of this patient group. Moreover, the developed intervention will help to address the psychosocial support needs of patients with psoriasis. Research shows that psychosocial support is strongly needed. PMID- 29415877 TI - Challenges associated with nerve conduction block using kilohertz electrical stimulation. AB - Neuromodulation therapies, which electrically stimulate parts of the nervous system, have traditionally attempted to activate neurons or axons to restore function or alleviate disease symptoms. In stark contrast to this approach is inhibiting neural activity to relieve disease symptoms and/or restore homeostasis. One potential approach is kilohertz electrical stimulation (KES) of peripheral nerves-which enables a rapid, reversible, and localized block of conduction. This review highlights the existing scientific and clinical utility of KES and discusses the technical and physiological challenges that must be addressed for successful translation of KES nerve conduction block therapies. PMID- 29415876 TI - Electric stimulus duration alters network-mediated responses depending on retinal ganglion cell type. AB - OBJECTIVE: To improve the quality of artificial vision that arises from retinal prostheses, it is important to bring electrically-elicited neural activity more in line with the physiological signaling patterns that arise normally in the healthy retina. Our previous study reported that indirect activation produces a closer match to physiological responses in ON retinal ganglion cells (RGCs) than in OFF cells (Im and Fried 2015 J. Physiol. 593 3677-96). This suggests that a preferential activation of ON RGCs would shape the overall retinal response closer to natural signaling. Recently, we found that changes to the rate at which stimulation was delivered could bias responses towards a stronger ON component (Im and Fried 2016a J. Neural Eng. 13 025002), raising the possibility that changes to other stimulus parameters can similarly bias towards stronger ON responses. Here, we explore the effects of changing stimulus duration on the responses in ON and OFF types of brisk transient (BT) and brisk sustained (BS) RGCs. APPROACH: We used cell-attached patch clamp to record RGC spiking in the isolated rabbit retina. Targeted RGCs were first classified as ON or OFF type by their light responses, and further sub-classified as BT or BS types by their responses to both light and electric stimuli. Spiking in targeted RGCs was recorded in response to electric pulses with durations varying from 5 to100 ms. Stimulus amplitude was adjusted at each duration to hold total charge constant for all experiments. MAIN RESULTS: We found that varying stimulus durations modulated responses differentially for ON versus OFF cells: in ON cells, spike counts decreased significantly with increasing stimulus duration while in OFF cells the changes were more modest. The maximum ratio of ON versus OFF responses occurred at a duration of ~10 ms. The difference in response strength for BT versus BS cells was much larger in ON cells than in OFF cells. SIGNIFICANCE: The stimulation rates preferred by subjects during clinical trials are similar to the rates that maximize the ON/OFF response ratio in in vitro testing (Im and Fried 2016a J. Neural Eng. 13 025002). Here, we determine the stimulus duration that produces the strongest bias towards ON responses and speculate that it will further enhance clinical effectiveness. PMID- 29415878 TI - Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction. AB - Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract (GIT). Cigarette smoke (CS) exposure and chronic obstructive pulmonary disease (COPD) are risk factors for CD, although the mechanisms involved are poorly understood. We employed a mouse model of CS-induced experimental COPD and clinical studies to examine these mechanisms. Concurrent with the development of pulmonary pathology and impaired gas exchange, CS-exposed mice developed CD associated pathology in the colon and ileum, including gut mucosal tissue hypoxia, HIF-2 stabilization, inflammation, increased microvasculature, epithelial cell turnover, and decreased intestinal barrier function. Subsequent smoking cessation reduced GIT pathology, particularly in the ileum. Dimethyloxaloylglycine, a pan-prolyl hydroxylase inhibitor, ameliorated CS induced GIT pathology independently of pulmonary pathology. Prior smoke exposure exacerbated intestinal pathology in 2,4,6-trinitrobenzenesulfonic acid-induced (TNBS-induced) colitis. Circulating vascular endothelial growth factor, a marker of systemic hypoxia, correlated with CS exposure and CD in mice and humans. Increased mucosal vascularisation was evident in ileum biopsies from CD patients who smoke compared with nonsmokers, supporting our preclinical data. We provide strong evidence that chronic CS exposure and, for the first time to our knowledge, associated impaired gas exchange cause systemic and intestinal ischemia, driving angiogenesis and GIT epithelial barrier dysfunction, resulting in increased risk and severity of CD. PMID- 29415879 TI - The homozygous CX3CR1-M280 mutation impairs human monocyte survival. AB - Several reports have demonstrated that mouse Cx3cr1 signaling promotes monocyte/macrophage survival. In agreement, we previously found that, in a mouse model of systemic candidiasis, genetic deficiency of Cx3cr1 resulted in increased mortality and impaired tissue fungal clearance associated with decreased macrophage survival. We translated this finding by showing that the dysfunctional CX3CR1 variant CX3CR1-M280 was associated with increased risk and worse outcome of human systemic candidiasis. However, the impact of this mutation on human monocyte/macrophage survival is poorly understood. Herein, we hypothesized that CX3CR1-M280 impairs human monocyte survival. We identified WT (CX3CR1-WT/WT), CX3CR1-WT/M280 heterozygous, and CX3CR1-M280/M280 homozygous healthy donors of European descent, and we show that CX3CL1 rescues serum starvation-induced cell death in CX3CR1-WT/WT and CX3CR1-WT/M280 but not in CX3CR1-M280/M280 monocytes. CX3CL1-induced survival of CX3CR1-WT/WT monocytes is mediated via AKT and ERK activation, which are both impaired in CX3CR1-M280/M280 monocytes, associated with decreased blood monocyte counts in CX3CR1-M280/M280 donors at steady state. Instead, CX3CR1-M280/M280 does not affect monocyte CX3CR1 surface expression or innate immune effector functions. Together, we show that homozygocity of the M280 polymorphism in CX3CR1 is a potentially novel population-based genetic factor that influences human monocyte signaling. PMID- 29415880 TI - mTOR pathway activation drives lung cell senescence and emphysema. AB - Chronic obstructive pulmonary disease (COPD) is a highly prevalent and devastating condition for which no curative treatment is available. Exaggerated lung cell senescence may be a major pathogenic factor. Here, we investigated the potential role for mTOR signaling in lung cell senescence and alterations in COPD using lung tissue and derived cultured cells from patients with COPD and from age and sex-matched control smokers. Cell senescence in COPD was linked to mTOR activation, and mTOR inhibition by low-dose rapamycin prevented cell senescence and inhibited the proinflammatory senescence-associated secretory phenotype. To explore whether mTOR activation was a causal pathogenic factor, we developed transgenic mice exhibiting mTOR overactivity in lung vascular cells or alveolar epithelial cells. In this model, mTOR activation was sufficient to induce lung cell senescence and to mimic COPD lung alterations, with the rapid development of lung emphysema, pulmonary hypertension, and inflammation. These findings support a causal relationship between mTOR activation, lung cell senescence, and lung alterations in COPD, thereby identifying the mTOR pathway as a potentially new therapeutic target in COPD. PMID- 29415882 TI - Swiprosin-1 deficiency impairs macrophage immune response of septic mice. AB - Despite the fact that many therapeutic strategies have been adopted to delay the development of sepsis, sepsis remains one of the leading causes of death in noncoronary intensive care units. Recently, sepsis-3 was defined as life threatening organ dysfunction due to a dysregulated host response to infection. Here, we report that swiprosin-1 (also known as EFhd2) plays an important role in the macrophage immune response to LPS-induced or cecal ligation and puncture induced (CLP-induced) sepsis in mice. Swiprosin-1 depletion causes higher mortality, more severe organ dysfunction, restrained macrophage recruitment in the lung and kidney, and attenuated inflammatory cytokine production (including IL-1beta, IL-6, TNF-alpha, IL-10, and IFN-gamma). The immunosuppression caused by swiprosin-1 deficiency is manifested by impaired bactericidal capacity and decreased HLA-DR expression in macrophages. Swiprosin-1 affects the activation of the JAK2/STAT1/STAT3 pathway by regulating the expression of IFN-gamma receptors in macrophages. Our findings provide a potential target for the regulation of the macrophage immune response in sepsis. PMID- 29415881 TI - TAK1 regulates skeletal muscle mass and mitochondrial function. AB - Skeletal muscle mass is regulated by a complex array of signaling pathways. TGF beta-activated kinase 1 (TAK1) is an important signaling protein, which regulates context-dependent activation of multiple intracellular pathways. However, the role of TAK1 in the regulation of skeletal muscle mass remains unknown. Here, we report that inducible inactivation of TAK1 causes severe muscle wasting, leading to kyphosis, in both young and adult mice.. Inactivation of TAK1 inhibits protein synthesis and induces proteolysis, potentially through upregulating the activity of the ubiquitin-proteasome system and autophagy. Phosphorylation and enzymatic activity of AMPK are increased, whereas levels of phosphorylated mTOR and p38 MAPK are diminished upon inducible inactivation of TAK1 in skeletal muscle. In addition, targeted inactivation of TAK1 leads to the accumulation of dysfunctional mitochondria and oxidative stress in skeletal muscle of adult mice. Inhibition of TAK1 does not attenuate denervation-induced muscle wasting in adult mice. Finally, TAK1 activity is highly upregulated during overload-induced skeletal muscle growth, and inactivation of TAK1 prevents myofiber hypertrophy in response to functional overload. Overall, our study demonstrates that TAK1 is a key regulator of skeletal muscle mass and oxidative metabolism. PMID- 29415883 TI - Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells. AB - Cancer stem cells (CSCs) - known to be resistant to genotoxic radiation and chemotherapy - are fundamental to therapy failure and cancer relapse. Here, we reveal that glioma CSCs are hypersensitive to radiation, but a temporal DNA repair mechanism converts the intrinsic sensitivity to genomic instability and treatment resistance. Transcriptome analysis identifies DNA-dependent protein kinase (DNA-PK) as a predominant DNA repair enzyme in CSCs. Notably, DNA-PK activity is suppressed after irradiation when ROS induce the dissociation of DNA PKcs with Ku70/80, resulting in delayed DNA repair and radiosensitivity; subsequently, after ROS clearance, the accumulated DNA damage and robust activation of DNA-PK induce genomic instability, facilitated by Rad50-mediated cell-cycle arrest, leading to enhanced malignancy, CSC overgrowth, and radioresistance. Finally, we show a requisite in vivo role for DNA-PK in CSC mediated radioresistance and glioma progression. These findings identify a time sensitive mechanism controlling CSC resistance to DNA-damaging treatments and suggest DNA-PK/Rad50 as promising targets for CSC eradication. PMID- 29415884 TI - TNF receptor-activated factor 2 mediates cardiac protection through noncanonical NF-kappaB signaling. AB - To elucidate the mechanisms responsible for cytoprotective effects of TNF receptor-activated factor 2 (TRAF2) in the heart, we employed genetic gain- and loss-of-function studies ex vivo and in vivo in mice with cardiac-restricted overexpression of TRAF2 (Myh6-TRAF2LC). Crossing Myh6-TRAF2LC mice with mice lacking canonical signaling (Myh6-TRAF2LC/Myh6-IkappaBalphaDeltaN) abrogated the cytoprotective effects of TRAF2 ex vivo. In contrast, inhibiting the JAK/STAT pathway did not abrogate the cytoprotective effects of TRAF2. Transcriptional profiling of WT, Myh6-TRAF2LC, and Myh6-TRAF2LC/Myh6-IkappaBalphaDeltaN mouse hearts suggested that the noncanonical NF-kappaB signaling pathway was upregulated in the Myh6-TRAF2LC mouse hearts. Western blotting and ELISA for the NF-kappaB family proteins p50, p65, p52, and RelB on nuclear and cytoplasmic extracts from naive 12-week-old WT, Myh6-TRAF2LC, and Myh6-TRAF2LC/Myh6 IkappaBalphaDeltaN mouse hearts showed increased expression levels and increased DNA binding of p52 and RelB, whereas there was no increase in expression or DNA binding of the p50 and p65 subunits. Crossing Myh6-TRAF2LC mice with RelB-/+ mice (Myh6-TRAF2LC/RelB-/+) attenuated the cytoprotective effects of TRAF2 ex vivo and in vivo. Viewed together, these results suggest that crosstalk between the canonical and noncanonical NF-kappaB signaling pathways is required for mediating the cytoprotective effects of TRAF2. PMID- 29415885 TI - RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase. AB - Renal fibrosis is a common pathogenic response to injury in chronic kidney disease (CKD). The receptor-interacting protein kinase-3 (RIPK3), a regulator of necroptosis, has been implicated in disease pathogenesis. In mice subjected to unilateral ureteral obstruction-induced (UUO-induced) or adenine diet-induced (AD induced) renal fibrosis, models of progressive kidney fibrosis, we demonstrate increased kidney expression of RIPK3. Mice genetically deficient in RIPK3 displayed decreased kidney fibrosis and improved kidney function relative to WT mice when challenged with UUO or AD. In contrast, mice genetically deficient in mixed-lineage kinase domain-like protein (MLKL), a downstream RIPK3 target, were not protected from UUO-induced kidney fibrosis. We demonstrate a pathway by which RIPK3 promotes fibrogenesis through the AKT-dependent activation of ATP citrate lyase (ACL). Genetic or chemical inhibition of RIPK3 suppressed the phosphorylation of AKT and ACL in response to TGF-beta1 in fibroblasts. Inhibition of AKT or ACL suppressed TGF-beta1-dependent extracellular matrix production and myofibroblast differentiation in fibroblasts. Pharmacological inhibition of ACL suppressed UUO-induced kidney fibrosis. RIPK3 expression was highly regulated in human CKD kidney. In conclusion, we identify a pathway by which RIPK3 promotes kidney fibrosis independently of MLKL-dependent necroptosis as a promising therapeutic target in CKD. PMID- 29415886 TI - Osteoblastic heparan sulfate regulates osteoprotegerin function and bone mass. AB - Bone remodeling is a highly coordinated process involving bone formation and resorption, and imbalance of this process results in osteoporosis. It has long been recognized that long-term heparin therapy often causes osteoporosis, suggesting that heparan sulfate (HS), the physiological counterpart of heparin, is somehow involved in bone mass regulation. The role of endogenous HS in adult bone, however, remains unclear. To determine the role of HS in bone homeostasis, we conditionally ablated Ext1, which encodes an essential glycosyltransferase for HS biosynthesis, in osteoblasts. Resultant conditional mutant mice developed severe osteopenia. Surprisingly, this phenotype is not due to impairment in bone formation but to enhancement of bone resorption. We show that osteoprotegerin (OPG), which is known as a soluble decoy receptor for RANKL, needs to be associated with the osteoblast surface in order to efficiently inhibit RANKL/RANK signaling and that HS serves as a cell surface binding partner for OPG in this context. We also show that bone mineral density is reduced in patients with multiple hereditary exostoses, a genetic bone disorder caused by heterozygous mutations of Ext1, suggesting that the mechanism revealed in this study may be relevant to low bone mass conditions in humans. PMID- 29415887 TI - Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury. AB - Neutrophils dominate the early immune response in pathogen-induced acute lung injury, but efforts to harness their responses have not led to therapeutic advancements. Neutrophil extracellular traps (NETs) have been proposed as an innate defense mechanism responsible for pathogen clearance, but there are concerns that NETs may induce collateral damage to host tissues. Here, we detected NETs in abundance in mouse models of severe bacterial pneumonia/acute lung injury and in human subjects with acute respiratory distress syndrome (ARDS) from pneumonia or sepsis. Decreasing NETs reduced lung injury and improved survival after DNase I treatment or with partial protein arginine deiminase 4 deficiency (PAD4+/-). Complete PAD4 deficiency (PAD4-/-) reduced NETs and lung injury but was counterbalanced by increased bacterial load and inflammation. Importantly, we discovered that the lipoxin pathway could be a potent modulator of NET formation, and that mice deficient in the lipoxin receptor (Fpr2-/-) produced excess NETs leading to increased lung injury and mortality. Lastly, we observed in humans that increased plasma NETs were associated with ARDS severity and mortality, and lower plasma DNase I levels were associated with the development of sepsis-induced ARDS. We conclude that a critical balance of NETs is necessary to prevent lung injury and to maintain microbial control, which has important therapeutic implications. PMID- 29415888 TI - Goblet cell loss abrogates ocular surface immune tolerance. AB - Intestinal epithelial cells condition tolerogenic properties in DCs. Aqueous deficient dry eye is associated with goblet cell (GC) loss and increased IFN gamma expression in the conjunctiva. We hypothesized that loss of GCs reduces tolerance-inducing properties of antigen presenting cells (APCs) in the conjunctiva and draining nodes. Mice lacking the SAM pointed domain containing ETS transcription factor (Spdef) that is required for GC differentiation had an increased frequency of macrophages in the conjunctiva and CD11b+CD11c+ DCs in the conjunctiva and draining nodes, and these cells had greater IL-12 expression than WT mice. Conditioned media from cultured WT conjunctival GCs suppressed LPS induced IL-12 production by conjunctival APCs. OVA antigen-specific OTII CD4+ T cells primed by Spdef-KO draining lymph node APCs showed greater proliferation, lower frequency of Foxp3+, increased frequency of IFN-gamma+ and IL-17+ cells, and greater IFN-gamma production than those primed by WT APCs. The immune tolerance to OVA antigen topically applied to the conjunctiva measured by cutaneous delayed type hypersensitivity (DTH) reaction, OVA-specific T cell proliferation, Foxp3 induction, and IFN-gamma production observed in WT mice was lost in the Spdef-KO mice. We concluded that conjunctival GCs condition tolerogenic properties in APCs that suppress IL-12 production and Th1 polarization. PMID- 29415889 TI - iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction. AB - The role of proinflammation, and specifically TNF-alpha, on downstream fibrosis and healing after cardiac injury remains unknown. Using iRhom2-deficient mice, which lack myeloid-specific shedding of TNF-alpha, we reveal increased macrophages (MPhis) that were skewed towards a more proinflammatory (M1) state at day 4, followed by more reparative, antiinflammatory (M2) state at day 7 after myocardial infarction (MI). However, associated functional cytokine expression was significantly reduced in iRhom2-mutant M1 and M2 MPhis, respectively. A dampened proinflammatory signature in iRhom2-deficient mice during the acute phase of injury and subsequent changes in MPhi polarization were associated with reduced phagocytosis and a more sparse distribution within the scar region. This resulted in impaired collagen deposition and fibrosis, and increased left ventricular remodelling and mortality in iRhom2-deficient mice after MI. Our findings reveal a requirement for an iRhom2-mediated proinflammatory response during downstream scarring and fibrosis, which is driven in part by TNF-alpha signaling. These conclusions challenge the existing model that infarct repair is determined exclusively by antiinflammatory signaling of M2 MPhis, and as such we propose an alternative view of immunomodulation to maintain effective healing after infarction. PMID- 29415890 TI - Thrombospondin-1 protects against pathogen-induced lung injury by limiting extracellular matrix proteolysis. AB - Acute lung injury is characterized by excessive extracellular matrix proteolysis and neutrophilic inflammation. A major risk factor for lung injury is bacterial pneumonia. However, host factors that protect against pathogen-induced and host sustained proteolytic injury following infection are poorly understood. Pseudomonas aeruginosa (PA) is a major cause of nosocomial pneumonia and secretes proteases to amplify tissue injury. We show that thrombospondin-1 (TSP-1), a matricellular glycoprotein released during inflammation, dose-dependently inhibits PA metalloendoprotease LasB, a virulence factor. TSP-1-deficient (Thbs1 /-) mice show reduced survival, impaired host defense, and increased lung permeability with exaggerated neutrophil activation following acute intrapulmonary PA infection. Administration of TSP-1 from platelets corrects the impaired host defense and aberrant injury in Thbs1-/- mice. Although TSP-1 is cleaved into 2 fragments by PA, TSP-1 substantially inhibits Pseudomonas elastolytic activity. Administration of LasB inhibitor, genetic disabling of the PA type II secretion system, or functional deletion of LasB improves host defense and neutrophilic inflammation in mice. Moreover, TSP-1 provides an additional line of defense by directly subduing host-derived proteolysis, with dose dependent inhibition of neutrophil elastase from airway neutrophils of mechanically ventilated critically ill patients. Thus, a host matricellular protein provides dual levels of protection against pathogen-initiated and host sustained proteolytic injury following microbial trigger. PMID- 29415891 TI - Efficacy of intracellular immune checkpoint-silenced DC vaccine. AB - BACKGROUND: DC-based tumor vaccines have had limited clinical success thus far. SOCS1, a key inhibitor of inflammatory cytokine signaling, is an immune checkpoint regulator that limits DC immunopotency. METHODS: We generated a genetically modified DC (gmDC) vaccine to perform immunotherapy. The adenovirus (Ad-siSSF) delivers two tumor-associated antigens (TAAs), survivin and MUC1; secretory bacterial flagellin for DC maturation; and an RNA interference moiety to suppress SOCS1. A 2-stage phase I trial was performed for patients with relapsed acute leukemia after allogenic hematopoietic stem cell transplantation: in stage 1, we compared the safety and efficacy between gmDC treatment (23 patients) and standard donor lymphocyte infusion (25 patients); in stage 2, we tested the efficacy of the gmDC vaccine for 12 acute myeloid leukemia (AML) patients with early molecular relapse. RESULTS: gmDCs elicited potent TAA specific CTL responses in vitro, and the immunostimulatory activity of gmDC vaccination was demonstrated in rhesus monkeys. A stage 1 study established that this combinatory gmDC vaccine is safe in acute leukemia patients and yielded improved survival rate. In stage 2, we observed a complete remission rate of 83% in 12 relapsed AML patients. Overall, no grade 3 or grade 4 graft-versus-host disease incidence was detected in any of the 35 patients enrolled. CONCLUSIONS: This study, with combinatory modifications in DCs, demonstrates the safety and efficacy of SOCS1-silenced DCs in treating relapsed acute leukemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT01956630. FUNDING: National Institute of Health (R01CA90427); the Key New Drug Development and Manufacturing Program of the "Twelfth Five-Year Plan" of China (2011ZX09102-001-29); and Clinical Application Research of Beijing (Z131107002213148). PMID- 29415892 TI - Inhibition of Wnt/beta-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. AB - Osteoarthritis (OA) is a degenerative joint disease involving both cartilage and synovium. The canonical Wnt/beta-catenin pathway, which is activated in OA, is emerging as an important regulator of tissue repair and fibrosis. This study seeks to examine Wnt pathway effects on synovial fibroblasts and articular chondrocytes as well as the therapeutic effects of Wnt inhibition on OA disease severity. Mice underwent destabilization of the medial meniscus surgery and were treated by intra-articular injection with XAV-939, a small-molecule inhibitor of Wnt/beta-catenin signaling. Wnt/beta-catenin signaling was highly activated in murine synovial fibroblasts as well as in OA-derived human synovial fibroblasts. XAV-939 ameliorated OA severity associated with reduced cartilage degeneration and synovitis in vivo. Wnt inhibition using mechanistically distinct small molecule inhibitors, XAV-939 and C113, attenuated the proliferation and type I collagen synthesis in synovial fibroblasts in vitro but did not affect human OA derived chondrocyte proliferation. However, Wnt modulation increased COL2A1 and PRG4 transcripts, which are downregulated in chondrocytes in OA. In conclusion, therapeutic Wnt inhibition reduced disease severity in a model of traumatic OA via promoting anticatabolic effects on chondrocytes and antifibrotic effects on synovial fibroblasts and may be a promising class of drugs for the treatment of OA. PMID- 29415893 TI - Thymosin alpha-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia. AB - In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel causes misfolding and premature degradation. Considering the numerous effects of the F508del mutation on the assembly and processing of CFTR protein, combination therapy with several pharmacological correctors is likely to be required to treat CF patients. Recently, it has been reported that thymosin alpha-1 (Talpha-1) has multiple beneficial effects that could lead to a single-molecule-based therapy for CF patients with F508del. Such effects include suppression of inflammation, improvement in F508del-CFTR maturation and gating, and stimulation of chloride secretion through the calcium-activated chloride channel (CaCC). Given the importance of such a drug, we aimed to characterize the underlying molecular mechanisms of action of Talpha-1. In-depth analysis of Talpha-1 effects was performed using well-established microfluorimetric, biochemical, and electrophysiological techniques on epithelial cell lines and primary bronchial epithelial cells from CF patients. The studies, which were conducted in 2 independent laboratories with identical outcome, demonstrated that Talpha-1 is devoid of activity on mutant CFTR as well as on CaCC. Although Talpha-1 may still be useful as an antiinflammatory agent, its ability to target defective anion transport in CF remains to be further investigated. PMID- 29415894 TI - Restoration of the type I IFN-IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice. AB - Type I IFN (IFN-I) dysregulation contributes to type 1 diabetes (T1D) development, and although increased IFN-I signals are pathogenic at the initiation of autoimmune diabetes, IFN-I dysregulation at later pathogenic stages more relevant for therapeutic intervention is not well understood. We discovered that 5 key antigen-presenting cell subsets from adult prediabetic NOD mice have reduced responsiveness to IFN-I that is dominated by a decrease in the tonic sensitive subset of IFN-I response genes. Blockade of IFNAR1 in prediabetic NOD mice accelerated diabetes and increased Th1 responses. Therefore, IFN-I responses shift from pathogenic to protective as autoimmunity progresses, consistent with chronic IFN-I exposure. In contrast, IL-1-associated inflammatory pathways were elevated in prediabetic mice. These changes correlated with human T1D onset associated gene expression. Prostaglandin E2 (PGE2) and prostaglandin receptor 4 (PTGER4), a receptor for PGE2 that mediates both inflammatory and regulatory eicosanoid signaling, were higher in NOD mice and drive innate immune dysregulation. Treating prediabetic NOD mice with a PTGER4 antagonist restored IFNAR signaling, decreased IL-1 signaling, and decreased infiltration of leukocytes into the islets. Therefore, innate cytokine alterations contribute to both T1D-associated inflammation and autoimmune pathogenesis. Modulating innate immune balance via signals such as PTGER4 may contribute to treatments for autoimmunity. PMID- 29415895 TI - Intracellular localization of diacylglycerols and sphingolipids influences insulin sensitivity and mitochondrial function in human skeletal muscle. AB - BACKGROUND: Accumulation of diacylglycerol (DAG) and sphingolipids is thought to promote skeletal muscle insulin resistance by altering cellular signaling specific to their location. However,the subcellular localization of bioactive lipids in human skeletal muscle is largely unknown. METHODS: We evaluated subcellular localization of skeletal muscle DAGs and sphingolipids in lean individuals (n = 15), endurance-trained athletes (n = 16), and obese men and women with (n = 12) and without type 2 diabetes (n = 15). Muscle biopsies were fractionated into sarcolemmal, cytosolic, mitochondrial/ER, and nuclear compartments. Lipids were measured using liquid chromatography tandem mass spectrometry, and insulin sensitivity was measured using hyperinsulinemic euglycemic clamp. RESULTS: Sarcolemmal 1,2-DAGs were not significantly related to insulin sensitivity. Sarcolemmal ceramides were inversely related to insulin sensitivity, with a significant relationship found for the C18:0 species. Sarcolemmal sphingomyelins were also inversely related to insulin sensitivity, with the strongest relationships found for the C18:1, C18:0, and C18:2 species. In the mitochondrial/ER and nuclear fractions, 1,2-DAGs were positively related to, while ceramides were inversely related to, insulin sensitivity. Cytosolic lipids as well as 1,3-DAG, dihydroceramides, and glucosylceramides in any compartment were not related to insulin sensitivity. All sphingolipids but only specific DAGs administered to isolated mitochondria decreased mitochondrial state 3 respiration. CONCLUSION: These data reveal previously unknown differences in subcellular localization of skeletal muscle DAGs and sphingolipids that relate to whole-body insulin sensitivity and mitochondrial function in humans. These data suggest that whole-cell concentrations of lipids obscure meaningful differences in compartmentalization and suggest that subcellular localization of lipids should be considered when developing therapeutic interventions to treat insulin resistance. FUNDING: National Institutes of Health General Clinical Research Center (RR-00036), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK089170), NIDDK (T32 DK07658), and Colorado Nutrition Obesity Research Center (P30DK048520). PMID- 29415896 TI - Virus-like infection induces human beta cell dedifferentiation. AB - Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune mediated destruction of insulin-producing pancreatic beta cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than beta cell death, suggesting loss of beta cell identity. We undertook this study to examine whether viral infection could induce human beta cell dedifferentiation. Using the functional human beta cell line EndoC-betaH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in beta cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-kappaB pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-alpha. Lastly, we identified SOX9 targets in human beta cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human beta cell dedifferentiation. PMID- 29415897 TI - Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. AB - NK cell-based immunotherapies have been gaining traction in the clinic for treatment of cancer. IL-15 is currently being used in number of clinical trials to improve NK cell expansion and function. The objective of this study is to evaluate the effect of repetitive IL-15 exposure on NK cells. An in vitro model in which human NK cells are continuously (on on on) or intermittently (on off on) treated with IL-15 was used to explore this question. After treatment, cells were evaluated for proliferation, survival, cell cycle gene expression, function, and metabolic processes. Our data indicate that continuous treatment of NK cells with IL-15 resulted in decreased viability and a cell cycle arrest gene expression pattern. This was associated with diminished signaling, decreased function both in vitro and in vivo, and reduced tumor control. NK cells continuously treated with IL-15 also displayed a reduced mitochondrial respiration profile when compared with NK cells treated intermittently with IL-15. This profile was characterized by a decrease in the spare respiratory capacity that was dependent on fatty acid oxidation (FAO). Limiting the strength of IL-15 signaling via utilization of an mTOR inhibitor rescued NK cell functionality in the group continuously treated with IL-15. The findings presented here show that human NK cells continuously treated with IL-15 undergo a process consistent with exhaustion that is accompanied by a reduction in FAO. These findings should inform IL-15-dosing strategies in NK cell cancer immunotherapeutic settings. PMID- 29415898 TI - Thyroid sclerosing mucoepidermoid carcinoma with eosinophilia distinct from the salivary type. AB - We report three cases of thyroid sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE), which is an extremely rare variant of mucoepidermoid carcinoma (MEC). The aims of this report were to describe the clinicopathological findings, including results from immunohistochemical and fluorescence in situ hybridization analysis of thyroid SMECE, as well as to discuss the distinction between thyroid SMECE and its salivary counterpart. The cases included a 63-year old female, a 44-year-old male, and a 66-year-old female, with all patients presenting with Hashimoto's thyroiditis. Nodal metastasis was not found in any of the three cases. Neither regional recurrences nor distant metastases were found in any patient during the follow-up, which was 20 years, 3 years, and 18 months, respectively. Histologically, tumors were composed of epidermoid carcinoma cells, intermediate type carcinoma cells, and goblet cell-type mucus-secreting carcinoma cells, with all tumors displaying a sclerotic stroma with eosinophilic and lymphocytic infiltration. The formation of eosinophilic abscess in the tumor nests that might be a novel characteristic finding of SMECE was observed. Immunohistochemically, the carcinoma cells were positive for cytokeratin 34betaE12, TTF-1, and PAX8, but negative for thyroglobulin. In two cases, increased IgG4-positive plasma cells were observed. Mastermind-like transcriptional coactivator 2 (MAML2), according to fluorescence in situ hybridization, was intact in all cases. In conclusion, thyroid SMECE has favorable outcomes and seems to be genetically different from salivary MEC. This is the first report to describe the presence of increased IgG4-positive plasma cells in the stroma of SMECE. PMID- 29415899 TI - Time-Dependent Changes in Increased Levels of Plasma Irisin and Muscle PGC-1alpha and FNDC5 after Exercise in Mice. AB - Exercise induces the expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1alpha) in skeletal muscle, which promotes the cleavage of fibronectin type III domain-containing protein 5 (FNDC5) to irisin. To explore the relationship between irisin and its regulators, we analyzed the plasma irisin levels and the muscle levels of FNDC5 and PGC-1alpha after exercise. Male C57BL/6J mice underwent a treadmill exercise (60% of VO2max) for 30 min or one hour (h), and blood and gastrocnemius samples were collected before exercise (pre-exercise), immediately after exercise, and during 24-h recovery after 1-h exercise. We found that plasma irisin levels were significantly increased during exercise (P < 0.05), while FNDC5 protein levels were not significantly increased. Moreover, PGC-1alpha mRNA and protein levels were significantly increased during 30-min exercise, but were decreased during 1-h exercise. After 1-h exercise, the irisin levels peaked at 6 h (20.71 +/- 0.25 ng/ml) and decreased to pre-exercise levels by 24 h (15.45 +/- 0.27 ng/ml). Likewise, PGC-1alpha mRNA and protein levels were increased at 1 h and maintained at elevated levels for 6 h; thereafter, the expression levels of PGC1-alpha protein were decreased to pre-exercise levels at 12 h. Thus, the restoration of PGC-1alpha expression to the pre-exercise levels was followed by the decrease in plasma irisin levels. By contrast, during 24-h recovery, the expression levels of FNDC5 mRNA and protein were maintained at elevated levels. These results suggest that the coordinated expression of FNDC5 and PGC-1alpha may contribute to the increased levels of plasma irisin after exercise. PMID- 29415900 TI - Identification and phase inversion of Salmonella flagellar antigens, using immuno discs. AB - Disc immuno-immobilization is a simple method for typing the flagellar phase of Salmonella enterica. We re-examined this method using commercial antisera, which contains the preservative sodium azide. Originally prepared motility agar activates bacterial motility and renders S. enterica resistant to sodium azide, resulting in the formation of immuno-immobilization lines around reactive immuno discs. Though disc immuno-immobilization serves both serotyping and phase inversion, this method is insufficient for the strains in which phase variation rarely occurs. Here, we devised a novel immuno-disc phase inversion method, and all S. enterica strains tested were identically typed. These methods would drastically simplify the task of S. enterica typing in clinical laboratories. PMID- 29415901 TI - Sexual dimorphism of craniomandibular size in the Eurasian otter, Lutra lutra, from South Korea. AB - Sexual size dimorphism of craniomandibular morphology of the Eurasian otter Lutra lutra in South Korea was analyzed using linear measurements. In total, 32 skulls (18 males and 14 females) and 22 linear measurements (16 cranial and 6 mandibular measurements) were used. Our results showed statistically significant sexual dimorphism between male and female skull size. Multivariate analyses using the cranial and mandibular traits showed significant differences between the sexes, respectively. The most dimorphic trait was ectorbital breadth (EOB), and the EOB of the male was approximately 10% greater than that of the female. This type of sexual size dimorphism, in which males are generally larger than females, is a general pattern shown in family Mustelidae. Several researchers have suggested various hypotheses about the factors causing sexual size dimorphism, i.e., 'resource partitioning model' and 'sex-specific pressure model'. Our results are consistent with these hypotheses, and we suggest that these factors would have affected the sexual size dimorphism of the Eurasian otter in Korea. PMID- 29415902 TI - Influence of changes in the intestinal microflora on the immune function in mice. AB - The composition of the intestinal microbiota is related to the health and immune function of the host. Administration of antibiotics affects the composition of the intestinal microbiota. However, the effects of immune function on the composition of the intestinal microbiota are still unclear. In this study, we investigated the lymphocyte composition and determined the relationships between lymphocyte function and the intestinal microbiota following antibiotic treatment in mice. To change the composition of the intestinal microbiota, mice were treated with or without antibiotics. Analysis of intestinal microbiota was performed by metagenomic analysis targeting 16S rRNA. Lymphocyte subsets of splenocytes were measured by flow cytometry. For functional analysis of T cells, splenocytes were stimulated with concanavalin (Con A), and cytokine gene expression was measured by real-time polymerase chain reaction. Firmicutes were predominant in the control group, whereas Bacteroidetes predominated in the antibiotic-treated group, as determined by metagenomic analysis. The diversity of the microbiota decreased in the antibiotic-treated group. Analysis of lymphocyte subsets showed that CD3+ cells decreased, whereas CD19+ cells increased in the antibiotic-treated group. All cytokine genes in splenocytes treated with Con A were downregulated in the antibiotic-treated group; in particular, genes encoding interferon-gamma, interleukin (IL)-6, and IL-13 significantly decreased. Taken together, these results revealed that changes in the composition of the intestinal microbiota by antibiotic treatment influenced the population of lymphocytes in splenocytes and affected the immune response. PMID- 29415903 TI - Infection Unit Density as an Index of Infection Potential of Arbuscular Mycorrhizal Fungi. AB - The effective use of arbuscular mycorrhizal (AM) fungal function to promote host plant phosphate uptake in agricultural practice requires the accurate quantitative evaluation of AM fungal infection potential in field soil or AM fungal inoculation material. The number of infection units (IUs), intraradical fungal structures derived from single root entries formed after a short cultivation period, may reflect the number of propagules in soil when pot soil is completely permeated by the host root. However, the original IU method, in which all AM propagules in a pot are counted, requires the fine tuning of plant growing conditions and is considered to be laborious. The objective of the present study was to test whether IU density, not the total count of IU, but the number of IUs per unit root length, reflects the density of AM fungal propagules in soil. IU density assessed after 12 d of host plant cultivation and 3,3'-diaminobenzidine (DAB) staining showed a stronger linear correlation with propagule density than the mean infection percentage (MIP). In addition, IU density was affected less by the host plant species than MIP. We suggest that IU density provides a more rapid and reliable quantitation of the propagule density of AM fungi than MIP or the original IU method. Thus, IU density may be a more robust index of AM fungal infection potential for research and practical applications. PMID- 29415904 TI - The Efficacy of Transcorneal Electrical Stimulation for the Treatment of Primary Open-angle Glaucoma: A Pilot Study. AB - The aim of this study was to evaluate the effects of transcorneal electrical stimulation in subjects with primary open-angle glaucoma. Five eyes of four male subjects with primary open-angle glaucoma (average age: 52.25 +/- 14.68 years) were enrolled. The subjects underwent transcorneal electrical stimulation every 3 months according to the following procedure. A Dawson-Trick-Litzkow electrode was placed on the cornea, and biphasic electric current pulses (10 ms, 20 Hz) were delivered using a stimulator (BPG-1,BAK Electronics) and a stimulus isolation unit (BSI-2). A current that evoked a phosphene that the subject perceived in the whole visual area was delivered continuously for 30 min. Humphrey visual field testing was performed after every third transcorneal electrical stimulation treatment. Changes in mean deviation (MD) values were evaluated with a linear regression model. Transcorneal electrical stimulation was performed 18.2 +/- 9.4 times over a period of 49.8 +/- 23.0 months. The average pretranscorneal electrical stimulation intraocular pressure, best corrected visual acuity, and MD values were 11.8 +/- 1.79 mmHg, 0.14 +/- 0.19 (logMAR) and -17.28 +/- 6.24 dB, respectively. No significant differences were observed in intraocular pressure before and after transcorneal electrical stimulation. However, there was a significant positive linear relationship between changes in MD values and the number of transcorneal electrical stimulation treatments (R2 = 0.176, P = 0.005, Spearman correlation R =0.294, P = 0.008). Transcorneal electrical stimulation treatment may improve glaucomatous visual field defects in subjects with primary open-angle glaucoma. Large-scale studies are necessary to confirm these preliminary findings. PMID- 29415905 TI - Anti-inflammatory Effects of a Small Molecule Gastrin-Releasing Peptide Receptor Antagonist on Adjuvant-Induced Rheumatoid Arthritis in Rats. AB - The anti-inflammatory effects of (R)-2-(1H-Imidazol-1-yl) ethyl-3-(1H-indol-3-yl) 2-(2-p-tolylacetamido)propanamide (RH-1402), a previous designed small molecule Gastrin releasing peptide (GRP) antagonist were evaluated in adjuvant-induced arthritic model of rats, and the inhibitory effect on neutrophil migration induced by GRP was determined by a transwell system experiment in vitro. The arthritis was induced by injection of Complete Freund's Adjuvant (CFA) containing 10 mg/mL of heat killed mycobacterium into the left hind footpad. Experimental rats were randomly divided into 6 groups, including control, placebo, positive control group, RH-1402 of low/middle/high dose group. Disease incidence and severity was evaluated through scoring of the paw edema and histologic features of joint synovial. Blood of all experimental rats was collected for interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) cytokine levels. A transwell system was used to investigate whether RH-1402 would inhibit neutrophils migrating up a gradient of GRP in vitro. RH-1402 (5 and 10 mg/kg) significantly decreased adjuvant induced increased arthritis index during the administration period (days 14-20). Significant inhibition of joint synovial histological features can be found in the RH-1402 treated group, including alleviated Hyperplasia, Inflammatory of infiltration and activation of pannus formation. It also suppressed TNF-alpha and IL-1beta level. Five and 10 mg/kg of RH-1402 significantly inhibited the effect of GRP on neutrophil migration with a dose dependent relationship. These findings indicate that RH-1402 have potential protective anti-inflammatory effects on experimental models of arthritis. PMID- 29415906 TI - Effects of Products Containing Bacillus subtilis var. natto on Healthy Subjects with Neck and Shoulder Stiffness, a Double-Blind, Placebo-Controlled, Randomized Crossover Study. AB - Neck and shoulder stiffness is a typical subjective symptom in developed countries. This stiffness is caused by factors such as muscle tension and poor blood flow, leading to reduce work efficiency and diminish QOL. NKCP(r), a natto derived dietary food supplement whose main component is bacillopeptidase F, has antithrombotic, fibrinolytic, and blood viscosity-lowering effects. Here, we investigated the effect of NKCP(r) on neck and shoulder stiffness in a double blind placebo-controlled randomized crossover study. Thirty subjects with neck and shoulder stiffness were randomly divided into 2 groups and ingested 250 mg of NKCP(r) or placebo daily for 4 weeks. Headache score significantly improved in the NKCP(r) group compared to the placebo group. Moreover, NKCP(r) significantly improved the score of visual analogue scale for neck and shoulder stiffness and pain, reduced muscle stiffness of the neck, and increased the skin surface temperature of neck and shoulders, compared to before ingestion. No adverse effects were observed during this study. These results suggest that NKCP(r) may alleviate headaches and chronic neck and shoulder stiffness and pain. PMID- 29415908 TI - Cerebrorenal Interaction and Stroke Outcome. PMID- 29415907 TI - Guidance for Pediatric Familial Hypercholesterolemia 2017. AB - This paper describes consensus statement by Joint Working Group by Japan Pediatric Society and Japan Atherosclerosis Society for Making Guidance of Pediatric Familial Hypercholesterolemia (FH) in order to improve prognosis of FH.FH is a common genetic disease caused by mutations in genes related to low density lipoprotein (LDL) receptor pathway. Because patients with FH have high LDL cholesterol (LDL-C) levels from the birth, atherosclerosis begins and develops during childhood which determines the prognosis. Therefore, in order to reduce their lifetime risk for cardiovascular disease, patients with FH need to be diagnosed as early as possible and appropriate treatment should be started.Diagnosis of pediatric heterozygous FH patients is made by LDL-C >=140 mg/dL, and family history of FH or premature CAD. When the diagnosis is made, they need to improve their lifestyle including diet and exercise which sometimes are not enough to reduce LDL-C levels. For pediatric FH aged >=10 years, pharmacotherapy needs to be considered if the LDL-C level is persistently above 180 mg/dL. Statins are the first line drugs starting from the lowest dose and are increased if necessary. The target LDL-C level should ideally be <140 mg/dL. Assessment of atherosclerosis is mainly performed by noninvasive methods such as ultrasound.For homozygous FH patients, the diagnosis is made by existence of skin xanthomas or tendon xanthomas from infancy, and untreated LDL-C levels are approximately twice those of heterozygous FH parents. The responsiveness to pharmacotherapy should be ascertained promptly and if the effect of treatment is not enough, LDL apheresis needs to be immediately initiated. PMID- 29415909 TI - Phylogenetic Diversity and Single-Cell Genome Analysis of "Melainabacteria", a Non-Photosynthetic Cyanobacterial Group, in the Termite Gut. AB - Termite guts harbor diverse yet-uncultured bacteria, including a non photosynthetic cyanobacterial group, the class "Melainabacteria". We herein reported the phylogenetic diversity of "Melainabacteria" in the guts of diverse termites and conducted a single-cell genome analysis of a melainabacterium obtained from the gut of the termite Termes propinquus. We performed amplicon sequencing of 16S rRNA genes from the guts of 60 termite and eight cockroach species, and detected melainabacterial sequences in 48 out of the 68 insect species, albeit with low abundances (0.02-1.90%). Most of the melainabacterial sequences obtained were assigned to the order "Gastranaerophilales" and appeared to form clusters unique to termites and cockroaches. A single-cell genome of a melainabacterium, designated phylotype Tpq-Mel-01, was obtained using a fluorescence-activated cell sorter and whole genome amplification. The genome shared basic features with other melainabacterial genomes previously reconstructed from the metagenomes of human and koala feces. The bacterium had a small genome (~1.6 Mb) and possessed fermentative pathways possibly using sugars and chitobiose as carbon and energy sources, while the pathways for photosynthesis and carbon fixation were not found. The genome contained genes for flagellar components and chemotaxis; therefore, the bacterium is likely motile. A fluorescence in situ hybridization analysis showed that the cells of Tpq-Mel-01 and/or its close relatives are short rods with the dimensions of 1.1+/-0.2 MUm by 0.5+/-0.1 MUm; for these bacteria, we propose the novel species, "Candidatus Gastranaerophilus termiticola". Our results provide fundamental information on "Melainabacteria" in the termite gut and expand our knowledge on this underrepresented, non-photosynthetic cyanobacterial group. PMID- 29415911 TI - Inflammatory Mechanisms of Cardiovascular Remodeling. AB - Inflammation and fibrosis play an important role in the development and progression of cardiovascular diseases. Acute coronary syndrome (ACS) is caused by rupture of inflamed atherosclerotic plaque and subsequent atherothrombosis. Recent studies have shown that inflammatory markers such as C-reactive protein (CRP) can predict ACS development and have demonstrated the effectiveness of new therapeutic approaches targeting inflammation. Studies have also shown that an enhanced inflammatory response after myocardial infarction (MI) is associated with cardiac rupture, ventricular aneurysm formation, and exacerbation of left ventricular (LV) remodeling. Inflammation is a physiological reaction in which fibrosis is induced to facilitate the healing of tissue damage. However, when an excessive inflammatory response consisting mainly of monocytes/macrophages is induced by various factors, impaired reparative fibrosis and resulting pathological remodeling processes may occur. A similar phenomenon is observed in abdominal aortic aneurysm (AAA) expansion. In contrast, myocardial diseases such as inflammatory dilated cardiomyopathy (DCMI) and valvular diseases such as aortic valve stenosis (AS) are characterized by chronic inflammation mediated mainly by T lymphocytes and the associated enhancement of reactive fibrosis. Thus, inflammation can take 2 paths (the inhibition or promotion of fibrosis), depending on the phase of inflammation, inducing pathological cardiovascular remodeling. Elucidation of the regulatory mechanisms of inflammation and fibrosis will contribute to the development of new therapeutic approaches for cardiovascular diseases. PMID- 29415910 TI - Comparative immunity of antigen recognition, differentiation, and other functional molecules: similarities and differences among common marmosets, humans, and mice. AB - The common marmoset (CM; Callithrix jacchus) is a small New World monkey with a high rate of pregnancy and is maintained in closed colonies as an experimental animal species. Although CMs are used for immunological research, such as studies of autoimmune disease and infectious disease, their immunological characteristics are less defined than those of other nonhuman primates. We and others have analyzed antigen recognition-related molecules, the development of hematopoietic stem cells (HSCs), and the molecules involved in the immune response. CMs systemically express Caja-G, a major histocompatibility complex class I molecule, and the ortholog of HLA-G, a suppressive nonclassical HLA class I molecule. HSCs express CD117, while CD34 is not essential for multipotency. CD117+ cells developed into all hematopoietic cell lineages, but compared with human HSCs, B cells did not extensively develop when HSCs were transplanted into an immunodeficient mouse. Although autoimmune models have been successfully established, sensitization of CMs with some bacteria induced a low protective immunity. In CMs, B cells were observed in the periphery, but IgG levels were very low compared with those in humans and mice. This evidence suggests that CM immunity is partially suppressed systemically. Such immune regulation might benefit pregnancy in CMs, which normally deliver dizygotic twins, the placentae of which are fused and the immune cells of which are mixed. In this review, we describe the CM immune system and discuss the possibility of using CMs as a model of human immunity. PMID- 29415912 TI - Idiopathic and Chronic Epidural Hematoma in the Lumbar Spine: A Case Report and Review of Literatures. AB - Spontaneous and chronic epidural hematoma (SSEH) in the lumbar spine is rare, and idiopathic and chronic SSEH in the lumbar spine is extremely rare disease. Most of lumbar SSEH were acute and secondary with trauma, hematologic disorders, drug, and surgical procedure. Only 20 cases of chronic SSEH in the lumbar spine have been reported and 14 cases among them were considered to be idiopathic. Definitive guidelines for management of this condition are not clear and surgical total evacuation was performed in most of the cases. Some authors reported the epidural bleeding originates in the rupture of Batson's plexus due to a rise in intra-abdominal pressure, but the mechanism is not clearly clarified. We report a surgical case of idiopathic and chronic SSEH. A 61-year-old woman suffered a sudden onset of severe lumbar pain during sleep. She had no history of trauma, spinal surgery, or hypertension. Magnetic resonance imaging revealed a lumbar chronic epidural hematoma which compressed the dural sac behind and extended from L2 to L5. This patient underwent the partial evacuation of the hematoma with partial hemilaminectomy on left at L2/3, resulting in immediate pain relief and resolution of symptoms and almost absorption of the hematoma within 1 week of the procedure. We presented this rare case and reviewed idiopathic and chronic epidural hematoma in the lumbar spine. PMID- 29415913 TI - Hybrid Method of Transvertebral Foraminotomy Combined with Anterior Cervical Decompression and Fusion for Multilevel Cervical Disease. AB - Transvertebral foraminotomy (TVF) combined with anterior cervical decompression and fusion (ACDF) can be used to treat multilevel cervical spondylotic myelopathy and radiculopathy; however, the radiological outcomes and effectiveness of this hybrid procedure are unknown. We retrospectively assessed 22 consecutive patients treated with combined TVF and ACDF between January 2007 and May 2016. The Japanese Orthopedic Association (JOA) score and Odom's criteria were analyzed. Radiological assessment included the C2-7 sagittal Cobb angle (CA) and range of motion (ROM). The tilting angle (TA), TA ROM, and disc height (DH) of segments adjacent to the ACDF were also measured. Adjacent segment degeneration, which includes disc degeneration, was evaluated. The mean postoperative follow-up was 41.7 months. All surgeries were performed at two adjacent segments, with ACDF and TVF of the upper and lower segments, respectively. The JOA scores significantly improved. There were no significant differences in the C2-7 CA, C2-7 ROM, TA, and TA ROM, but there was a statistically significant decrease in DH of the lower adjacent segment to ACDF. Progression of disc degeneration was identified in two patients, with no progression in the criterion of adjacent segment degeneration over the follow-up. The TVF combined with ACDF produced excellent clinical results and maintained spinal alignment, albeit with a reduction in DH. TVF was safely performed at the lower segment adjacent to the ACDF, although this might result in earlier degeneration. In conclusion, this hybrid method is less invasive and beneficial for reduction of the number of fused levels. PMID- 29415914 TI - High-Frequency Echocardiography - Transformative Clinical and Research Applications in Humans, Mice, and Zebrafish. AB - Echocardiography is an invaluable tool for characterizing cardiac structure and function in vivo. Technological advances in high-frequency ultrasound over the past 3 decades have increased spatial and temporal resolution, and facilitated many important clinical and basic science discoveries. Successful reverse translation of established echocardiographic techniques, including M-mode, B mode, color Doppler, pulsed-wave Doppler, tissue Doppler and, most recently, myocardial deformation imaging, from clinical cardiology into the basic science laboratory has enabled researchers to achieve a deeper understanding of myocardial phenotypes in health and disease. With high-frequency echocardiography, detailed evaluation of ventricular systolic function in a range of small animal models is now possible. Furthermore, improvements in frame rate and the advent of diastolic strain rate imaging, when coupled with the use of select pulsed-wave Doppler parameters, such as isovolumic relaxation time and E wave deceleration, have enabled nuanced interpretation of ventricular diastolic function. Comparing pulsed-wave Doppler indices of atrioventricular inflow during early and late diastole with parameters that describe the simultaneous myocardial deformation (e.g., tissue Doppler e and a, global longitudinal strain rate and global longitudinal velocity) may yield additional insights related to myocardial compliance. This review will provide a historical perspective of the development of high-frequency echocardiography and consider how ongoing innovation will help future-proof this important imaging modality for 21st century translational research. PMID- 29415915 TI - Novel Therapeutic Target of Anticoagulation Therapy in Patients With Atrial Fibrillation - Cognitive Decline and Dementia. PMID- 29415916 TI - Left Ventricular Fiber Structure and Myocardial Deformation for Assessment of Cardiotoxicity. PMID- 29415917 TI - Contiguity Between Ablation Lesions and Strict Catheter Stability Settings Assessed by VISITAGTM Module Improve Clinical Outcomes of Paroxysmal Atrial Fibrillation Ablation - Results From the VISITALY Study. AB - BACKGROUND: Our aim was to evaluate the clinical outcome of paroxysmal atrial fibrillation (AF) ablation with contact force technology, using an automated lesion tagging system (VISITAGTM module) with strict criteria of catheter stability.Methods and Results:We enrolled 200 consecutive patients who underwent pulmonary vein isolation (PVI) in 11 centers and were followed up for 12 months. The stability setting was within 3 mm for >=10 s and for >=15 s in 47% and 53% of patients, respectively. A mean of 67.2+/-21.9 VISITAGs was acquired. Freedom from atrial tachyarrhythmias at follow-up was 77.5% (155/200), and the contiguity between lesions was associated with a higher chronic success rate (96% vs. 77.1%; log-rank P=0.036). Radiofrequency (RF), fluoroscopy times, and recurrence rates at the 12-month follow-up were significantly lower than in a comparison group of 80 patients without VISITAGTM module (42.7+/-14.5 vs. 50.9+/-23.6 min; P=0.032; 11.6+/-7.8 vs. 18.4+/-12.8 min; P=0.003 and 22.5% vs. 41.2%; P=0.02). Two major complications (1 cardiac tamponade and 1 minor stroke) were observed only in the control group. CONCLUSIONS: Paroxysmal AF ablation with contact force technology and strict criteria of stability using the VISITAG module was a safe procedure, associated with an improvement in efficiency and a reduction of atrial tachyarrhythmia recurrence at the 12-month follow-up compared with manual annotation. Contiguity between lesions seemed to enhance effectiveness outcomes. PMID- 29415918 TI - Circulation Journal Awards for the Year 2017. PMID- 29415919 TI - Quantitative computed tomographic evaluation of bone mineral density in beagle dogs: comparison with dual-energy x-ray absorptiometry as a gold standard. AB - This study aimed to demonstrate the higher accuracy and reproducibility of quantitative computed tomography (QCT) compared with dual-energy X-ray absorptiometry (DXA) as a gold standard for measuring canine bone mineral density (BMD). Seven middle-aged beagle dogs underwent lumbar vertebral and bilateral femoral DXA and QCT scans. BMD (mg/cm2) was measured at the vertebral body from L2 to L6, femoral neck, and proximal and distal femoral diaphyses. The BMD values were measured 3 times and compared. The BMD value on QCT was higher than that on DXA for femoral BMD but not for vertebral BMD. The correlation was strong for the lumbar vertebrae (r=0.66) and was strongest for L3 (r=0.85). No correlation was found for the femoral neck (P=0.35), and only moderate correlations were found for the proximal and distal femoral diaphyses (r=0.43 and r=0.40, respectively). The limits of agreement were narrower for vertebral BMD than for femoral BMD, and L3 had the narrowest limits of agreement. The intraclass correlation (ICC) was higher for DXA than for QCT at all lumbar and femoral sites measured, but the ICC of QCT was higher than 0.7. In conclusion, L3 can be used to monitor changes in BMD, and relative values and sequential monitoring of femoral BMD can also be useful because of the high reproducibility of QCT measurements. QCT would be a useful technique for evaluation of BMD in veterinary practice. PMID- 29415920 TI - Neutralizing formaldehyde in chicken cadaver with urea and urea fertilizer solution. AB - This study demonstrated the potential of using urea and urea fertilizer to neutralize formaldehyde (Fd) in chicken cadavers. Initially, in vitro Fd neutralization with various concentrations of urea solution (US) and urea fertilizer solution (UFS) was conducted; subsequently, 18% US and 27% UFS were selected for infusing into the formalinized chickens. The measurement at 48 hr after infusion showed that both solutions could effectively lower Fd in chicken cadavers to below a permissible exposure limit without affecting cadaveric and histological quality. In addition, neutralizing power of 18% US was approximately 1.3 times that of 27% UFS. This is the first demonstration of neutralizing potential of US and UFS against Fd both in vitro and in vivo. PMID- 29415921 TI - Efficacy of mechanical micro-vibration in the development of bovine embryos during in vitro maturation and culture. AB - It is currently unclear how mechanical micro-vibration affects the in vitro culture of embryos in Japanese Black cow. In the experimental groups, immature oocytes and fertilized embryos were cultured using the micro-vibration culture system with the vibration set for 5 sec at intervals of 60 min and frequency of 20, 40 or 80 Hz, respectively, during in vitro maturation and in vitro development. Compared with the control group, the rate of blastocyst development significantly increased in the 40 Hz group. In addition, the number of blastocyst cells reduced significantly in the 80 Hz group. In conclusion, the development of blastocysts in cows is facilitated by providing moderate mechanical micro vibration to immature oocytes and embryos during the in vitro maturation and in vitro development. PMID- 29415923 TI - Non-work periods for a better working life. PMID- 29415922 TI - Increased expression of the stromal fibroblast-secreted periostin in canine squamous cell carcinomas. AB - Canine squamous cell carcinoma (SCC) shows highly invasive and locally destructive growth. In animal models and human cancer cases, periostin plays a critical role in the enhancement of cancer growth; however, the mechanism of involvement in canine cancers remains unknown. The aim of this study was to examine the involvement of periostin in the pathophysiology of SCC in dogs. We examined the localization of periostin and periostin-producing cells in 20 SCC and three squamous papilloma specimens. Furthermore, we focused on transforming growth factor (TGF)-beta1, which was assumed to be an inducing factor of periostin, using culture cells. By immunohistochemistry, limited periostin expression in the stroma was observed in all squamous papillomas. In SCC, periostin protein diffusely expressed at the tumor invasion front of cancer growth. In situ hybridization revealed that periostin mRNA was expressed in the stromal fibroblasts in SCC. In vitro analysis determined that canine SCC cells expressed significantly higher levels of TGF-beta1 mRNA compared with canine keratinocytes. In addition, recombinant TGF-beta1 induced secretion of periostin from cultured dermal fibroblasts. These data suggest that periostin produced by stromal fibroblasts may be involved in the pathophysiology of canine SCC. TGF beta1 derived from SCC cells may stimulate fibroblasts to produce periostin. PMID- 29415924 TI - [Technological development of alternative method to animal experiments in Japan]. AB - The alternative method to animal experiments is based on 3Rs (Replacement, Reduction, Refinement) of animal experiments. The use of an alternative method to animal experiment has become a global trend in chemical substances, pharmaceuticals, medical equipment, agrochemicals, as well as cosmetics for which animal testing within the EU area was prohibited by the EU directive. Here, the progress of alternative method research to animal experiment in Japan, and recent topics on the development of "replacement" in cell culture, non mammalian, non vertebrates and in silico as technical aspects are described. PMID- 29415925 TI - [New trends on alternative to animal testings in Japan]. AB - Non-animal alternative test methods have developed in the field of genotoxicity, endocrine disrupter, irritation and skin sensitization, and these are used the safety evaluation of chemical, pesticide, pharmaceutical and cosmetic for regulatory use. For the systemic toxicological endpoints of repeated dose toxicity, carcinogenicity, immunotoxicity and reproductive toxicity, new test methods are expected to be developed in the future worldwide. I believe Japan will make a significant contribution to these developments. PMID- 29415926 TI - [Tissue engineering-based approaches to enhance physiological relevancy of cell based assays]. AB - Animal-free and mechanism-based understanding of human body responses is the ultimate goal of alternative to animal experiments. To achieve this goal, integration of advanced cell-based assays using iPS/ES cell technologies with various numerical methods are required. In this review, from the standpoint of tissue engineering, we focused first on the enhancement of physiological relevance of tissue culture models by overcoming the problem between 3D cellular organization and oxygen/nutrient supply. Second, we summarized the concept and actual systems of microfluidic-based body/organ on-a-chip systems, also called as microphysiological system, MPS, particularly for liver on-a-chip systems. Finally, remaining issues were discussed to realize better physiological relevance in vitro. PMID- 29415927 TI - [Development of alternatives to animal experiments using pluripotent stem cells]. AB - Animal experiments have occupied an important position in the safety assessment of chemicals. However, due to the rise in animal welfare as seen in the ban of animal experiments in European cosmetic development, the development of alternative methods for animal experiments has become very important in recent years. Development of in vitro tests for local toxicity such as irritation and sensitization tests is preceded. Meanwhile, alternative tests for systemic toxicity such as chronic and developmental toxicities are under development. In developing alternative methods using cultured cells, we have been focusing on pluripotent stem cells such as ES and iPS cells and studying alternatives to developmental toxicity and neurotoxicity. As an alternative test of developmental toxicity, we developed the Hand 1-Luc EST, which is a simple test utilizing cardiomyocyte differentiation process of mouse ES cells, and Tubb 3- and Reln-Luc ESTs using nerve differentiation process. Recently, it was clarified that the combination of the Hand 1-Luc EST and the Tubb 3- and Reln-Luc ESTs improves the prediction of the developmental toxicity. In the study of in vitro neurotoxicity test using neurons derived from mouse ES cells, evaluation methods for neurite outgrowth using high-content imaging technology and for neural function using multi-electrode arrays were developed. In addition, we introduce differentiation methods for retinal tissues from human ES/iPS cells, which are the results as the collaboration with RIKEN and the present state of an in vitro phototoxicity test using retinal pigment epithelial cells (RPE) derived from human ES cells. PMID- 29415928 TI - [Animal welfare and corporate welfare in pharmaceutical R&D - the future of third party assessment]. AB - For research and development (R&D) of new drugs, animal experimentation is indispensable, and research institutes, pharmaceutical companies, or contract research organizations routinely conduct preclinical studies of efficacy, safety, or metabolism using laboratory animals. However, animal experimentation entails some organizational risks. One is the suspension of R&D of a new drug, because in the course of clinical studies it becomes apparent that the drug has limited efficacy, unexpected side effects, and/or unexpected metabolites. Another risk is damage to the company image by development of an unfavorable reputation. Society has accepted animal experimentation as a necessary evil, but if such experimentation is not conducted with adequate concern for animal welfare, social sanctions will against that institute, company or organization will result. Once this happens, it is difficult to recover a good public image. Therefore, pharmaceutical companies must conduct animal experiments so as to obtain highly useful data without sacrificing public favor. One way to maintain a good reputation is through third-party accreditation, which verifies that the institute, company or organization and its researchers value animal welfare appropriately. PMID- 29415929 TI - [Pharmacological, pharmaceutical and clinical profiles of sucroferric oxyhydroxide (P-TOL(r) Chewable Tab. 250 mg, 500 mg), a therapeutic agent for hyperphosphatemia]. AB - Sucroferric oxyhydroxide (P-TOL(r) chewable tablets, 250 and 500 mg) is a phosphate binder for oral use; it is composed of polynuclear iron (III) oxyhydroxide, sucrose, and starches, and is currently indicated for alleviating hyperphosphatemia in patients with chronic kidney disease (CKD) on dialysis. The results of non-clinical pharmacological studies have suggested that P-TOL consistently decreases serum phosphorus levels in the aqueous environment at pH levels similar to those in the gastrointestinal tract, thereby suppressing the progression of secondary hyperparathyroidism, aberrant calcification, and abnormal bone metabolism associated with hyperphosphatemia. Since the diameter of the P-TOL tablet exceeds 15 mm, it is manufactured with a doughnut-shape to minimize choking hazards. From the results of pharmaceutical studies, it was indicated that the P-TOL tablets promptly disintegrated in the gastrointestinal tract and excessive iron uptake from this product is unlikely to occur. In clinical studies, P-TOL (one tablet/dose, t.i.d.) decreased serum phosphorus levels during treatment Week 1 and allowed stable, long-term control of serum phosphorus levels. Furthermore, P-TOL was expected to reduce the tablet burden on patients and to improve medication adherence. The most common adverse reaction was diarrhea. However, in most cases, the symptoms were mild and oral administration of P-TOL could be continued. Although iron-related parameters tended to increase, iron uptake from this product was low, and the risk of iron overload was considered to be low. These findings confirm the efficacy and safety of P-TOL in CKD patients with hyperphosphatemia. Therefore, sucroferric oxyhydroxide therapy is a potentially useful treatment option for hyperphosphatemia. PMID- 29415931 TI - ? PMID- 29415930 TI - ? PMID- 29415932 TI - [Management of cardiovascular complications in CML patients treated with tyrosine kinase inhibitors]. AB - Tyrosine kinase inhibitors (TKIs) have significantly improved the clinical outcomes of patients with chronic myeloid leukemia (CML). However, patients with CML need to receive TKI therapy for several years. Hence, the safety of long-term TKI treatment warrants utmost attention. Among various adverse events caused by TKI therapy, cardiovascular events (CVEs), such as acute myocardial infarction, cerebral infarction, and pulmonary hypertension, are the most serious with high mortality. TKIs inhibit various off-target molecules involved in the occurrence of CVEs such as c-Kit, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and Tie-2/Tec. At present, nilotinib, dasatinib, and ponatinib, but not bosutinib, have been demonstrated to increase the risk of CVEs in patients with CML compared with imatinib. Conversely, patients with CML have also been shown to have high CVE risks regardless of the TKI treatment compared with non-cancer population. Hence, further analyses are required to deduce the influence of TKI treatment on CVEs. Whatever the cause may be, to prevent CVEs in patients with CML, we need to appropriately screen and monitor CVE risks such as hypertension, serum glucose, lipid levels, ankle brachial index (ABI), Electrocardiography (ECG), and echocardiography before and during TKI treatment. PMID- 29415933 TI - [Significance of upper and lower gastrointestinal endoscopy for screening small intestinal lesions in non-Hodgkin's lymphoma]. AB - The gastrointestinal tract is a common site for the occurrence of non-Hodgkin's lymphoma (NHL). NHL with gastrointestinal lesions may lead to clinically relevant intestinal complications such as obstruction, perforation, and exsanguination during the course of the disease. Consequently, patients with NHL are often examined by means of upper and lower gastrointestinal endoscopy at the initial visit. There are no clear guidelines regarding which patients should undergo capsule endoscopy (CE) and balloon enteroscopy for detecting small intestinal lesions. We retrospectively examined the feasibility of detecting small intestinal lesions in NHL using upper and lower gastrointestinal endoscopy. Between January 2007 and October 2015, 198 patients with primary NHL were admitted to our hospital. We collected data from 51 patients with NHL with gastrointestinal lesions diagnosed through upper and lower gastrointestinal endoscopy, CE, or double balloon enteroscopy (DBE). We chosed these cases that gastrointestinal lesions was doubted by an examination for image. Nineteen of these patients presented with lymphoma at the duodenal bulb/descending part when examined by upper gastrointestinal endoscopy and at the distal ileum when examined by lower gastrointestinal endoscopy. Ectopic jejunoileal lymphoma was simultaneously detected in 13 of the 19 patients (68.4%) through the use of CE or DBE. Conversely, of the 32 patients who did not exhibit lesions at the duodenal bulb/descending part or at the distal ileum, 6 patients (18.8%) presented with small intestinal lesions, indicating a smaller percentage compared to the patients with ectopic jejunoileal lymphoma. Based on these findings, a proactive search for small intestinal lesions using CE or DBE is recommended in patients with NHL presenting with lymphoma at the duodenal bulb/descending part or at the distal ileum, as examined using both upper and lower gastrointestinal endoscopy during the initial visit. PMID- 29415934 TI - [Ageing of hematopoietic stem cells]. AB - The frequency of clonal hematopoiesis in humans vastly increases with aging. Older adults may develop one or several clones and this condition is called clonal hematopoiesis of indeterminate potential (CHIP). Recent genetic analyses have identified the genes inducing CHIP. These mutant genes are detected frequently in elderly people and this condition is a precursor of hematopoietic neoplasms. The prevalence of hematopoietic neoplasms in patients with CHIP is tenfold that in those without CHIP. Consequently, the mechanism of aging and leukemogenesis of hematopoietic stem cells is being understood. Furthermore, the efficacy of senolysis, selectively removing scenescent cells from tissues, has been demonstrated in mice. The clinical application of senolysis is anticipated shortly. PMID- 29415935 TI - [Autologous peripheral blood stem cell transplantation for treating primary central nervous system lymphoma: a single-center retrospective study]. AB - Primary central nervous system lymphoma (PCNSL) is more difficult to treat than other lymphomas. Recently, it has been suggested that high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is effective for treating PCNSL. In the present study, we retrospectively analyzed 12 patients with PCNSL at our hospital. Five young patients with good performance status (PS) received upfront ASCT. The conditioning regimen prior to ASCT with busulfan + cyclophosphamide + etoposide showed good prognosis (complete remission rate of 100%). In addition, the PS improved in patients treated with high-dose chemotherapy followed by ASCT, while it worsened in those treated without ASCT. Further investigations are needed to clarify inclusion/exclusion criteria and optimize conditioning regimens for ASCT. PMID- 29415936 TI - [Recurrent invasive pneumococcal disease in a patient with IgG-kappa smoldering multiple myeloma]. AB - A 68-year-old female with smoldering multiple myeloma (IgG-kappa type) was admitted to the hospital owing to general fatigue, fever, and pain in the right leg. On the day following admission, she developed shock, and a blood culture revealed Streptococcus pneumoniae. She was diagnosed with septic shock and invasive pneumococcal disease (IPD). She received antibiotics and intravenous immunoglobulin and improved after several days. She had a history of recurrent IPD and had received the pneumococcal polysaccharide vaccine 23 (PPSV23) 2 years earlier. Therefore, we inquired with the National Institute of Infectious Diseases if the pneumococcal serotype isolated from her present IPD contained PPSV23. The results showed that her serotype was 19F, a serotype present in PPSV23. We administered pneumococcal conjugate vaccine 13 (PCV13) ; however, she was unable to mount high enough opsonophagocytic assay titers against some serotypes, including 19F. We think she was unable to mount effective humoral immune responses to PPSV23 or PCV13 owing to her underlying disease, smoldering myeloma. It should be considered how IPD can be effectively prevented in patients with multiple myeloma. PMID- 29415938 TI - [Acquisition of IgH/CCND1 translocation during the natural disease course in a patient with chronic lymphocytic leukemia]. AB - A 69-year-old man visited a doctor because of systemic lymphadenopathy. Peripheral blood examination revealed leukocytosis, anemia, and decreased platelet count (WBC, 103,060/ul; lymph, 92.2%; Hb, 8.9 g/dl; and Plt, 4.1*104/ul). Bone marrow biopsy revealed that approximately 70% of nucleated cells were small, mature lymphoid cells with positive immunostaining for CD5, CD20, and CD23. He was diagnosed with chronic lymphocytic leukemia (CLL). The IgH/CCND1 translocation and ATM locus loss in 20% and 95% peripheral cells, respectively, were detected by fluorescence in situ hybridization. Immunostaining revealed that cyclin D1 was positive in approximately 30% bone marrow cells. As the positive rate of CCND1 fusion signal was low, the diagnosis of mantle cell lymphoma was excluded. In contrast, signals of ATM locus deletion were detected in most tumor cells. Therefore, we assessed that IgH/CCND1 translocations occurred during the natural clinical course of CLL with ATM locus deletion from the onset of disease. The secondary IgH/CCND1 translocation in CLL is rare, and all reported cases with such translocations received treatments with alkylating agents. This is the first report regarding secondary IgH/CCND1 translocation during the natural clinical course of CLL and may provide insights into CLL pathogenesis. PMID- 29415937 TI - [Portal vein thrombosis associated with idiopathic hypereosinophilic syndrome]. AB - A 35-year-old man who previously underwent splenectomy for hereditary spherocytosis at age 29 visited our hospital complaining of fatigue that had started 7 days ago and right upper abdominal pain. Laboratory data showed increased white blood cell and eosinophil count accompanied by severe transaminitis and clotting abnormalities. Computed tomography scan showed multiple embolisms in the portal vein, superior mesenteric vein, right pulmonary artery, and inferior vena cava. Severe liver damage presumably caused by portal vein thrombosis was also observed. Anticoagulant therapies consisting of continuous arterial infusion of urokinase from the superior mesenteric artery and an intravenous infusion of recombinant human thrombomodulin and heparin dissolved the systemic thrombosis. Concurrently administered prednisone decreased the eosinophil count. With regard to eosinophilia, we were unable to find any connective tissue diseases, antibodies to parasites, or genetic anomalies including PDGFRA, PDGFRB, and FGFR1. Hence we diagnosed the patient with idiopathic hypereosinophilic syndrome (HES). Although thromboembolisms in patients with HES have been reported, the literature on portal vein thrombosis associated with HES is scarce. In the present case, the previous splenectomy may have contributed to the portal vein thrombosis. PMID- 29415939 TI - [Acute leukemia recurring as extramedullary tumors of the ovary following allogeneic hematopoietic stem cell transplantation]. AB - The poor prognosis of extramedullary recurrence of acute leukemia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a therapeutic challenge, and thus far no effective treatment method has been established. Here, we report two patients who presented with relapsed leukemia as extramedullary tumor in the ovary following allo-HSCT. Case 1: A 23-year-old female underwent unrelated allogeneic bone marrow transplantation during the second remission of acute myeloid leukemia. After 706 days post-transplant, bilateral ovarian tumors were detected during the pelvic ultrasound, and extramedullary recurrence in the bilateral ovaries was subsequently established on right salpingo-oophorectomy and biopsy of the left ovary. Following completed systemic chemotherapy and total body irradiation, the patient underwent unrelated cord blood transplantation (CBT) and remission was maintained without recurrence for 7 years after second transplantation. Case 2: A 49-year-old female underwent unrelated CBT during the second remission of acute lymphocytic leukemia. At 372 days post-transplant, a pelvic tumor was detected by FDG-PET/CT, and extramedullary recurrence in the right ovary was diagnosed on examination of the resected pelvic mass. Chemotherapy and radiation were performed, but the tumor recurred on day 1,027 and the patient died on day 1,603. Extramedullary recurrence of adult acute leukemia as a mass in the ovary following allo-HSCT has been rarely reported. Therefore, further accumulation of related case reports is desired. PMID- 29415940 TI - [Reduced-intensity umbilical cord blood transplantation for adult patients with fulminant aplastic anemia]. AB - Allogeneic hematopoietic stem cell transplantation is recommended as a curative treatment option for fulminant aplastic anemia with no neutrophil despite the administration of granulocyte-colony stimulating factor. In the absence of an HLA matched donor, unrelated cord blood transplantation (UCBT) is a treatment option that can be performed quickly. However, the optimal conditioning regimen of UCBT is yet to be established. We report two cases of fulminant aplastic anemia in adult patients who received UCBT. The first patient was a 52-year-old woman and the second was a 26-year-old man, both of whom received a conditioning regimen of total body irradiation (TBI; 2-4 Gy), fludarabine (Flu; 120 mg/kg), and cyclophosphamide (CY; 100 mg/kg) before UCBT. Short-term methotrexate and tacrolimus were used for prophylaxis of acute graft-versus-host disease (GVHD). Engraftments were achieved on days 26 and 19, and they exhibited complete donor chimerism by days 28 and 34. There was no evidence of acute GVHD, and therefore, the immunosuppressant drugs were discontinued. Reduced-intensity UCBT using a low dose TBI/Flu/CY conditioning regimen could be an effective treatment option for fulminant aplastic anemia in the absence of a suitable donor. PMID- 29415941 TI - [Neurolymphomatosis due to enteropathy-associated T-cell lymphoma clinically diagnosed by FDG-PET/CT and subsequently confirmed by autopsy]. AB - A 59-year-old man who complained of abdominal pain was referred to our hospital. Computed tomography (CT) revealed mesenteric lymph node swelling and intestinal perforation. Histopathological study of the resected ileum and lymph node demonstrated diffuse proliferation of medium-sized atypical lymphocytes. Immunohistochemistry results were positive for cluster of differentiation (CD) 3, CD8, and CD56 cells, negative for CD5 and CD4 cells, and negative for Epstein Barr virus-encoded RNA-fluorescent in situ hybridization (EBER-FISH). It also revealed the expression of gammadelta T-cell receptors. On the basis of these findings, enteropathy-associated T-cell lymphoma (EATL) was diagnosed. Although the patient received two courses of cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) therapy, facial nerve and lower limb paralysis manifested. Magnetic resonance imaging (MRI) and lumbar puncture revealed central nervous system invasion of the EATL. Despite intrathecal chemotherapy and high-dose cytarabine therapy, the patient's neurological symptoms deteriorated. Fluorodeoxyglucose positron emission tomography (FDG-PET) /CT scan showed the accumulation of FDG along both median and sciatic nerves, and he was diagnosed with neurolymphomatosis (NL). He died on day 120 after admission. Autopsy specimens exhibited infiltration of lymphoma cells in the median and sciatic nerves. Although only one case of suspected NL in a patient with type 2 EATL has been previously reported, we clinically diagnosed NL using FDG-PET/CT and confirmed the diagnosis by autopsy. This case is valuable in terms of the pathological diagnosis of NL. PMID- 29415942 TI - [Initial presentation of lymphoblastic crisis in a pediatric chronic myelogenous leukemia patient]. AB - A 9-year-old girl was referred to our hospital because of facial palsy. Both physical and blood examination revealed hepatosplenomegaly and leukocytosis, respectively. A bone marrow examination demonstrated marked hypercellularity involving myeloblasts and lymphoblasts. Based on these results, we suspected mixed phenotype acute leukemia. However, her leukemic blasts expressed B-cell antigens, and a chromosomal analysis of her bone marrow cells revealed the following karyotype: 46, XX, t (9;22) (q34;q11.2). All her neutrophils were positive for the breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion protein. Based on these findings, she was diagnosed with a lymphoblastic crisis of chronic myelogenous leukemia (CML). Combined chemotherapy, involving imatinib, resulted in complete molecular remission. She received cord blood transplant (CBT) during the first complete remission; she is alive and has not suffered a relapse since two years after the CBT. The sudden onset of a blastic crisis in pediatric CML is rare, and it may be difficult to distinguish such cases from de novo Ph-positive leukemia. For diagnostic purposes, it is essential to consider a patient's clinical course and blood test results. PMID- 29415944 TI - ? PMID- 29415943 TI - [Relationship between clinical features and somatic gene mutations in myelodysplastic syndrome]. AB - Recent progress in sequencing studies has suggested that somatic mutations can be used in clinical sequencing for predicting prognosis and selecting treatment options in myelodysplastic syndrome (MDS). A 48-year-old man was diagnosed with refractory cytopenia with multilineage dysplasia that is classified as a subtype of high-risk MDS based on both revised International Prognostic Scoring System and refined WHO classification based Prognostic Scoring System. He received a bone marrow transplant from an HLA-matched sibling donor at X+87 months because of disease progression. Targeted sequencing of 69 genes in bone marrow cells at X+82 months revealed mutations in BCOR and U2AF1 genes. Variant allele frequencies of these mutations were almost unchanged in the bone marrow examined from X+9 months to X+80 months, but they subsequently decreased. Neither of these mutations was detected in the bone marrow at X+88 months, a month after transplantation. The mutations often found in secondary leukemia or high-risk MDS were not detected in our patient. These serial genetic conditions may correspond to the relatively stable disease course over a long time. PMID- 29415945 TI - Validating a Selective S1P1 Receptor Modulator Syl930 for Psoriasis Treatment. AB - Psoriasis is a chronic inflammatory skin disease characterized by red, scaly and raised plaques. Thus far, T-cell infiltration is one of the most prominent pathogenic triggers, however, the exact molecular mechanisms underlying psoriasis have not been clearly established. Sphingolipid sphingosine-1-phosphate (S1P) is a lysophospholipid regulator modulating a variety of immune cell trafficking via interactions with its cognate receptors, S1P1-5. Activation of S1P signaling has recently emerged as a novel therapeutic avenue for psoriasis treatment. Here, we test a newly developed selective S1P1 modulator, Syl930, in four different psoriasis animal models. Our data reveals that oral administration of Syl930 can induce strong anti-proliferative and anti-inflammatory effects. Specifically, Syl930 decreases the pathological thickening of back skin induced by sodium lauryl sulfate (SLS), inhibits the proliferation of basal cells in a vaginal epithelium model and increases the granular layer scales in a mouse tail assay. Moreover, Syl930 can ameliorate the parakeratosis and acanthosis as well as improve granular layer composition and decrease the thickening of epidermis in a propranolol-induced guinea pig psoriasis model. Therefore, we demonstrate that Syl930 is a promising candidate for psoriasis therapy in clinical. PMID- 29415946 TI - Development of pain therapies targeting nerve growth factor signal transduction and the strategies used to resolve safety issues. AB - Therapeutic agents commonly used in the management of chronic pain have limited effectiveness and may be associated with issues of dependence and tolerability. Thus, a large unmet medical need exists for the development of safe and effective therapeutics for treatment of chronic pain. A novel approach includes identification of intracellular signals involved in the pain transduction pathway, such as nerve growth factor (NGF). Monoclonal antibodies targeting NGF, such as tanezumab, fulranumab and fasinumab, have been investigated for the treatment of chronic pain conditions. Due to unexpected joint adverse events in clinical studies and concerns about sympathetic nervous system toxicity in animals, these agents were placed on 2 separate partial clinical holds, which were subsequently lifted after rigorous evaluations were conducted to understand how inhibition of NGF impacts safety. To share learnings regarding the rigorous evaluation of clinical and nonclinical safety data which contributed to the removal of these partial clinical holds, this article reviews the rationale for developing agents that target NGF as potential treatments for chronic pain, describes nonclinical and clinical studies of these agents, and describes strategies used to evaluate whether inhibition of NGF has negative effects on joint or sympathetic nervous system safety. PMID- 29415947 TI - Neurobehavioral effects of postnatal exposure to low-level mercury vapor and/or methylmercury in mice. AB - This study examined the effects on neurobehavioral function of exposure to low level mercury vapor (Hg0), methylmercury (MeHg) in female mice and the combination of Hg0 and MeHg during postnatal development. Postnatal mice were exposed to Hg0 at a mean concentration of 0.188 mg/m3 Hg0 and supplied with food containing 3.85 MUg/g of MeHg from day 2 to day 28 after delivery. The combined exposure group was exposed to both Hg0 and MeHg, using the same procedure. When their offspring reached the age of 11 weeks, behavioral analyses were performed. The behavioral effects in mice were evaluated based on locomotive activity and rate of center entries in the open field (OPF), learning activity in the passive avoidance response (PA) and spatial learning ability in the radial maze (RM). Total locomotive activity in the OPF significantly decreased in the Hg0, MeHg and combined exposure groups compared with the control group. The proportion of entries to central area in the OPF was significantly higher in the combined exposure group than in the control group, while those in the Hg0 or MeHg exposure group did not differ from the control group. Other behavioral tests did not reveal significant differences among the groups. Behavioral anomalies were more distinctive after combined exposure compared to Hg0 or MeHg exposure alone. The brain Hg concentration of offspring, immediately after exposure, was highest in the combined exposure group, exceeding 2 MUg/g, followed by the MeHg and Hg0 exposure groups. Thus, the enhancement of neurobehavioral effects in the combined exposure group was associated with higher brain mercury concentration. PMID- 29415948 TI - Effect of gestational cadmium exposure on fetal growth, polyubiquitinated protein and monoubiqutin levels in the fetal liver of mice. AB - Cadmium (Cd) is an environmental pollutant present in contaminated water, food and soil. Cd adversely affects fetal development. We exposed pregnant mice to daily oral doses of 5 and 10 mg/kg Cd and examined fetal growth. It was demonstrated that the exposure to Cd (10 mg/kg) during gestation caused fetal growth retardation (FGR). Investigation of the ubiquitin-proteasome system in fetal livers of mice exposed to gestational Cd revealed increased polyubiquitinated protein accumulation, contrasting with decreased levels of monoubiquitin protein. Moreover, the expression level of Ubc (encoding polyubiquitin C protein) was significantly decreased in 5 and 10 mg/kg Cd-treated groups in comparison with the control group. Therefore, we propose that decrease of monoubiquitin level and accumulation of polyubiquitinated protein in the fetal liver may be important factors in Cd-induced FGR. PMID- 29415949 TI - Determination of chemical-specific IgGs in serum by an enzyme-linked immunosorbent assay with partial peptides of human serum albumin. AB - Many different types of chemicals are used in industry, and occupational allergies are becoming a serious problem in the field of industrial hygiene. In this study, we employed a novel enzyme-linked immunosorbent assay (ELISA) with partial peptides of human serum albumin (HSA) to quantify chemical-specific immunoglobulin G (IgG) in serum for evaluating exposure to chemicals. When HSA partial peptides containing lysine residues were mixed with formaldehyde (FA) or phthalic anhydride (PA), almost all lysine residues were lost. Mass spectrometry revealed that PA and FA formed imine and tertiary amine, respectively, with lysine residues in the peptides. Thus, we used FA- or PA-peptide adducts as an artificial antigen to detect FA- and PA-specific IgGs in serum. The concentrations of FA- and PA-specific IgGs in workers at plants utilizing plastic resins were significantly higher than those in general subjects. This method can estimate exposure levels to chemicals and thus be expected to contribute to the diagnosis of allergies in workers and to the prevention of health hazards due to harmful chemicals. PMID- 29415950 TI - Acute exposure to crotonaldehyde induces dysfunction of immune system in male Wistar rats. AB - Crotonaldehyde is a ubiquitous air pollutant in the environment. It is reported to be harmful to the biosystems in vivo and in vitro. The exposure to crotonaldehyde irritates the mucous membranes and induces edema, hyperemia, cell necrosis, inflammation, and acute respiratory distress syndrome in the lungs. However, the effects of crotonaldehyde on the immune system have not been reported. In the present study, 6-8 weeks old male Wistar rats were exposed to crotonaldehyde by intratracheal instillation at doses of 4, 8, and 16 MUL/kg body weight (b.w.). The general damage in the animals was investigated; the cell counting and the biochemical analysis in the peripheral blood were tested. Furthermore, we investigated the functions of alveolar macrophages (AMs), the alterations of the T-lymphocyte subsets, and the cell composition in the bronchoalveolar lavage fluid (BALF). We found that the activities of the animals were changed after exposure to crotonaldehyde, the cellular ratios and the biochemical components in the peripheral blood were altered, the ratio of mononuclear phagocytes decreased, and the ratios of lymphocytes and granulocytes elevated significantly in BALF. Meanwhile, crotonaldehyde altered the ratio of the T-lymphocyte subsets, and the phagocytic rates and indices of AMs increased obviously. In conclusion, crotonaldehyde induces dysfunction of immune system in male Wistar rats. PMID- 29415951 TI - High fructose diet feeding accelerates diabetic nephropathy in Spontaneously Diabetic Torii (SDT) rats. AB - Diabetic nephropathy (DN) is one of the complications of diabetes and is now the most common cause of end-stage renal disease. Fructose is a simple carbohydrate that is present in fruits and honey and is used as a sweetener because of its sweet taste. Fructose has been reported to have the potential to progress diabetes and DN in humans even though fructose itself does not increase postprandial plasma glucose levels. In this study, we investigated the effects of high fructose intake on the kidney of the Spontaneously Diabetic Torii (SDT) rats which have renal lesions similar to those in DN patients and compared these with the effects in normal SD rats. This study revealed that a 4-week feeding of the high fructose diet increased urinary excretion of kidney injury makers for tubular injury and accelerated mainly renal tubular and interstitial lesions in the SDT rats but not in normal rats. The progression of the nephropathy in the SDT rats was considered to be related to increased internal uric acid and blood glucose levels due to the high fructose intake. In conclusion, high fructose intake exaggerated the renal lesions in the SDT rats probably due to effects on the tubules and interstitium through metabolic implications for uric acid and glucose. PMID- 29415952 TI - Relative contribution of rat CYP isoforms responsible for stereoselective metabolism of carvedilol. AB - The relative contribution of cytochrome P450 (CYP) isoforms responsible for carvedilol (CAR) oxidation in rats were evaluated in order to compare with that of reported human CYPs responsible for the metabolism of CAR enantiomers. The depletion of CAR enantiomers by recombinant CYPs and the effects of CYP-selective inhibitors on the depletion catalyzed by rat liver microsomes (RLM) was determined. Quinine (rat CYP2D inhibitor) markedly inhibited the metabolism of both R- and S-CAR by RLM. The metabolism of S-CAR was inhibited more than that of R-CAR by furafylline, (a CYP1A2 inhibitor, 53.5% vs 11.3%), alpha-naphthoflavone (a CYP1A2 inhibitor, 64.5% vs 33.6%), and ketoconazole (a CYP3A inhibitor, 87.1% vs 51.2%). Among the CYPs examined, CYP2D2 showed the highest metabolic activities against both the enantiomers. R-CAR was mainly metabolized by CYP2D2 and CYP3A2. CYP2C11 and CYP3A1, in addition to CYP2D2 and CYP3A2 showed higher metabolic activities against S-CAR than that against R-CAR. These results suggest that CYP2D2 predominantly catalyzed R-CAR metabolism, whereas CYP2D2 and CYP3A1/2 catalyzed S-CAR metabolism in rats. PMID- 29415953 TI - Relationship between low midazolam metabolism by cytochrome P450 3A in mice and the high incidence of birth defects. AB - The use of midazolam in early stages of pregnancy has resulted in a high incidence of birth defects; however, the underlying reason is unknown. We investigated expression changes of the CYP3A molecular species and focused on its midazolam metabolizing activity from the foetal period to adulthood. CYP3A16 was the only CYP3A species found to be expressed in the liver during the foetal period. However, CYP3A11 is upregulated in adult mice, but has been found to be downregulated during the foetal period and to gradually increase after birth. When CYP3A16 expression was induced in a microsomal fraction of cells used to study midazolam metabolism by CYP3A16, its activity was suppressed. These results showed that the capacity to metabolize midazolam in the liver during the foetal period is very low, which could hence result in a high incidence of birth defects associated with the use of midazolam during early stages of pregnancy. PMID- 29415954 TI - Antiplatelet Therapy in ACS Patients: Comparing Appropriate P2Y12 Inhibition by Clopidogrel to the Use of New P2Y12 Inhibitors. AB - AIM: In percutaneous coronary intervention (PCI)-treated acute coronary syndrome (ACS) patients on clopidogrel therapy, high on-treatment platelet adenosine diphosphate (ADP) reactivity was observed in numerous studies, with significant increases in non-fatal myocardial infarction, definite/probable stent thrombosis, or cardiovascular mortality. Compared to clopidogrel, prasugrel and ticagrelor provide more potent platelet inhibition. Whether new P2Y12 inhibitors reduce thrombotic events in a similar manner compared to the rate observed with appropriate P2Y12 inhibition by clopidogrel must still be determined. This study sought to compare long-term outcomes between clopidogrel responders (platelet reactivity index [PRI] vasodilator-stimulated phosphoprotein [VASP] <61%) and patients under prasugrel or ticagrelor therapy following PCI-treated ACS. METHODS: 730 ACS patients undergoing urgent PCI were prospectively enrolled into two groups: clopidogrel responders (n=448) and those under ticagrelor or prasugrel therapy (n=282). The primary endpoint was a composite of cardiovascular death, myocardial infarction, stent thrombosis, and stroke; the secondary endpoint comprised major hemorrhagic events. RESULTS: The median follow-up was 260+/-186 days. Clopidogrel patients were older and more likely to present non-ST segment elevation myocardial infarction, cardiovascular risk factors, atrial fibrillation, or prior vascular disease. After propensity score matching, the primary endpoint was met in 7.1% of the clopidogrel group and 4.1% of the prasugrel/ticagrelor group (p=0.43). Minor bleeding events were significantly reduced in the clopidogrel group (1.1% vs. 3%; p=0.03). In a multivariate analysis, the antiplatelet treatment strategy was not an independent primary endpoint predictor. CONCLUSION: In PCI-treated ACS patients, clopidogrel therapy and PRI VASP <61% were not associated with increased risks of thrombotic events compared to prasugrel or ticagrelor therapy. PMID- 29415956 TI - [Numerical and Visual Evaluations of Compressed Sensing MRI Using 2D Cartesian Sampling]. AB - This paper describes numerical and visual evaluations of compressed sensing MRI (CS-MRI) using 2D Cartesian sampling by numerical simulation. The BrainWeb MRI Data Base was used for test images. Three brain anatomical ROIs (white matter, gray matter, cerebrospinal fluid) of a T1-weighted image (T1WI), a T2-weighted image (T2WI) and a proton density-weighted image (PDWI) were used for the numerical evaluation. Sampling ratio was 50%. Reconstruction was performed by minimizing the L1 norm of a transformed image using wavelet transform and total variation, subject to data fidelity constraints. The conjugate gradient method was used in the minimization of the object function. In the absence of noise, the root mean square error (RMSE) of T1WI was in the range of 2.99 to 3.57; that of the anatomical region of interests (ROIs) was in the range of 1.77 to 8.53; those of T2WI were 4.72 to 5.65 and 3.28 to 5.54; and those of PDWI were 1.91 to 2.36 and 1.32 to 2.09. Visual evaluation was performed by three radiologists on the basis of three categories: artifact, anatomical structure, tissue contrast. CS image quality was nearly equal to that of the original image, although a few artifacts were visible. If the noise level was assumed to be 30 dB or less, T1-CS image and PD-CS images were not significantly degraded compared to noise-free images. PMID- 29415957 TI - [Numerical and Visual Evaluations of Compressed Sensing MRI Using 2D Radial Sampling]. AB - Two-dimensional radial MRI using compressed sensing (2D radial CS) enables incoherence sampling in k space unlike conventional Cartesian MRI, however 2D radial CS has not been sufficiently investigated. Numerical and visual evaluations of 2D radial CS were performed in this paper. Three brain anatomical ROIs (white matter, gray matter, cerebrospinal fluid) of a T1-weigthted image (T1WI), a T2-weighted image (T2WI) and a proton density-weighted image (PDWI) were used for the numerical evaluation. The Brainweb MRI Data Base was used for test images. Projection of 80 spokes with linear sampling of 256 pixels was used. Reconstruction was performed by minimizing the L1 norm of a transformed image using wavelet transform and spatial finite-differences (total variation), subject to data fidelity constraint. In the absence of noise, the root mean square error (RMSE) of T1WI was in the range of 3.75 to 5.05; that of the anatomical region of interests (ROIs) was in the range of 1.54 to 10.24; those of T2WI were 8.75 to 11.65 and 4.31 to 6.99; and those of PDWI were 3.44 to 4.46 and 1.34 to 3.09. Visual evaluation was performed by three radiologists on the basis of three categories: artifact, anatomical structure, and tissue contrast. Average percent scores of the visual evaluation were 96% for T1WI, 74-81% for T2WI, and 81-89% for PDWI. PMID- 29415955 TI - Associations of Tobacco Smoking with Impaired Endothelial Function: The Circulatory Risk in Communities Study (CIRCS). AB - AIMS: Smoking impairs endothelial function as an acute effect. However, few population-based studies have examined the association between smoking status and endothelial function or the dose-response and duration-response association of smoking with endothelial function. We examined whether smoking habits were associated with impaired endothelial function depending on smoking dose and duration. METHODS: We conducted a cross-sectional study of 910 men and women aged 30-79 years from 2013 to 2016. Statistical analyses of the data were conducted between 2016 and 2017. Endothelial function was assessed by brachial artery flow mediated dilation (FMD) measurement. Low FMD was defined in two ways as the cutoff point based on the lowest quartile of %FMD (<5.1%) and median of %FMD (<6.8%), regarding as impaired endothelial function. We investigated the smoking status in terms of cigarettes consumed per day and the duration of smoking. RESULTS: Heavy and chronic smokers were associated with a high prevalence of impaired endothelial function. Those associations did not change substantially after adjustment for other cardiovascular risk factors. Among all participants, the multivariable-adjusted ORs (95% CIs) of low FMD (<5.1%) with reference to never smokers were 2.23 (1.00-5.14) for current heavy smokers of >= 30 cigarettes per day, 1.83 (1.04-3.20) for heavy smokers of >= 40 pack-years, and 2.16 (1.15 4.06) for chronic smokers of >= 40 years. For low FMD (<6.8%) those values was 2.17 (1.01-5.05), 1.70 (1.01-2.86), and 1.98 (1.07-3.69), respectively. CONCLUSIONS: Similar associations were observed among only men. Heavy or long term tobacco smoking may induce impaired endothelial function. PMID- 29415958 TI - [Evaluation of 3D Dose Distribution and Clinical Applications Using Polymer Gel Dosimeter]. AB - Evaluation of dosimetric impact of the interplay effect between multi-leaf collimator (MLC) movement and tumor respiratory motion during volumetric modulated arc therapy (VMAT) delivery using polymer gel dosimeter was taken as an example in this article. An excellent gas barrier PAN (polyacrylonitrile) bottle filled with polyacrylamide-based gel dosimeter contained magnesium chloride as a sensitizer (iPAGAT dosimeter) was set to the QUASARTM respiratory motion phantom (Modus), and was moved with motion amplitudes (peak-to-peak amplitude) of 1 and 2 cm with a 4 second period during VMAT delivery by the Novalis Tx linear accelerator (Varian/BrainLAB). Two spherical GTVs with 2 cm diameter and two PTVs were defined considering the respiratory motion and setup uncertainties. Three dimensional (3D) dose distribution in iPAGAT dosimeter was read out by the 3T MRI system, and was evaluated by the dose profiles, gamma analysis and the dose volume histogram (DVH) using in-house developed software. As a result, interplay effect was negligible since dose coverage of GTV was sufficient during VMAT delivery with simulated respiratory motion. PMID- 29415959 TI - [Polymer Gel Dosimetry for the High-Dose-Rate Brachytherapy Using Ir-192 Source]. AB - High-dose-rate (HDR) brachytherapy is performed with the remote after-loading system (RALS) to transport an Ir-192 source directly to inside or near the tumor. Quality assurance (QA) of equipment should be performed at sufficient frequency to ensuring safety and quality of HDR brachytherapy treatment. Polymer gel dosimeters have been attracting attention in recent years as a QA tools of HDR brachytherapy, because they can measure the three-dimensional steep dose gradients around HDR sources. In this paper, we introduce our preliminary results using VIPET polymer gel dosimeters for Ir-192 HDR brachytherapy dosimetry. PMID- 29415960 TI - [Accuracy Check of Monte Carlo Simulation in Particle Therapy Using Gel Dosimeters]. AB - Gel dosimeters are a three-dimensional imaging tool for dose distribution induced by radiations. They can be used for accuracy check of Monte Carlo simulation in particle therapy. An application was reviewed in this article. An inhomogeneous biological sample placing a gel dosimeter behind it was irradiated by carbon beam. The recorded dose distribution in the gel dosimeter reflected the inhomogeneity of the biological sample. Monte Carlo simulation was conducted by reconstructing the biological sample from its CT image. The accuracy of the particle transport by Monte Carlo simulation was checked by comparing the dose distribution in the gel dosimeter between simulation and experiment. PMID- 29415961 TI - [Three-Dimensional Dosimetry of Carbon Ion Beams by Gel Dosimeters]. AB - A three-dimensional dosimetry method is strongly required in the dose distribution measurement of a patient QA of a heavy ion therapy. Nanocomposite Fricke gel dosimeters are the most possible candidate for this purpose. Experimental dose distribution measurements were carried out using a scanning irradiation port of Gunma University Heavy Ion Medical Center. The result showed no significant LET dependence and indicated a possibility for a precise dosimetry of a heavy ion therapy. It also indicated the importance of three-dimensional dosimetry in the commissioning process of the treatment accelerator. PMID- 29415962 TI - [Evaluation of Three Dimensional Dose Distributions by Using Polymer Gel Dosimeters Based on HPC Gel Sheets]. AB - We have proposed a novel polymer gel dosimeter containing of 2-hydroxyethyl methacrylate (HEMA), nonaethylene glycol dimethacrylate (9G), and tetrakis (hydroxymethyl) phosphonium chloride (THPC) with radiation-crosslinked hydroxypropyl cellulose (HPC) gel sheet. The transparent sheet-type dosimeters became white and cloudy by irradiation with gamma-rays and heavy ions such as He ions (150 MeV/u), C ions (290 MeV/u), Fe ions (500 MeV/u). The cloudiness increased with increasing dose. The cloudiness distribution with the sheet-type dosimeter was obtained by using a flatbed scanner to evaluate the dose distribution. Recently, we prepared a three-dimensional dosimeter by putting the gel sheets on top of another in the glass vessel. Three-dimensional dose distribution of the dosimeter irradiated with C ions was evaluated by the reconstruction of the data of each layer. PMID- 29415963 TI - [Application of Gel Detector in Boron Neutron Capture Therapy]. AB - At present, the development of the accelerator-based irradiation system for boron neutron capture therapy (BNCT) is energetically performed by various groups in the world. Especially in Japan, BNCT using various accelerator-based irradiation systems may be carried out at plural facilities in the near future. Thus, it is the time when BNCT is shifting from a special particle therapy to a general therapy, now. In order to promote this shift, not only the development and improvement for the irradiation system but also the preparation and improvement in the physical engineering and medical physics, such as dosimetry system, etc., is important. Recently, as part of the improvement in the dosimetry method for BNCT, the estimation method of three-dimensional dose distribution using gel detector is focused. In this paper, the principle of BNCT, especially for dose deposition, is introduced, and the studies for gel detector in BNCT are introduced referring to the proceedings of the international symposium for BNCT. PMID- 29415964 TI - [Radiological Physics and Technology, Introduction of the Award (Doi Prize) and a New Goal of This Journal toward Next Decade]. PMID- 29415965 TI - [A computer simulation method for low-dose CT images by use of real high-dose images: A phantom study]. PMID- 29415966 TI - [Automatic ROI construction for analyzing time-signal intensity curve in dynamic contrast-enhanced MR imaging of the breast]. PMID- 29415967 TI - [Energy dependence measurement of small-type optically stimulated luminescence (OSL) dosimeter by means of characteristic X-rays induced with general diagnostic X-ray equipment]. PMID- 29415968 TI - ? PMID- 29415969 TI - Osteoblastic differentiating potential of dental pulp stem cells in vitro cultured on a chemically modified microrough titanium surface. AB - Titanium surface modification is critical for dental implant success. Our aim was to determine surfaces influence on dental pulp stem cells (DPSCs) viability and differentiation. Implants were divided into sandblasted/acid-etched (control) and sandblasted/acid-etched coated with calcium and magnesium ions (CaMg), supplied as composite (test). Proliferation was evaluated by MTT, differentiation checking osteoblastic gene expression, PGE2 secretion and matrix formation, inflammation by Interleukin 6 (IL-6) detection. MTT and IL-6 do not modify on test. A PGE2 increase on test is recorded. BMP2 is higher on test at early experimental points, Osterix and RUNX2 augment later. Alizarin-red S reveals higher matrix production on test. These results suggest that test surface is more osteoinductive, representing a start point for in vivo studies aiming at the construction of more biocompatible dental implants, whose integration and clinical performance are improved and some undesired effects, such as implant stability loss and further surgical procedures, are reduced. PMID- 29415970 TI - Stress distribution in tooth resin core build-ups with different post-end positions in alveolar bone level under two kinds of load directions. AB - This study aimed to evaluate influence of different post-end positions in alveolar bone level on stress distributions in resin-core build-up tooth under different load directions. Three-dimensional mathematical models of a root-filled mandibular premolar tooth were constructed. Resin post and core were built-up with six post lengths: 0, 1, 2, 3, 4, and 6 mm. Finite element analysis calculated stress distributions with oblique load of 400 N to buccal cusp 45 degree from buccal side or from lingual side. The 3 mm-post length (post-end position equal to cancellous bone level) caused highest equivalent stress of post end compared with the shorter or longer post length. When change of load direction, the direction of maximum shear stress became completely opposite at mesiodistal cervical edge of core-part without a change of the magnitude. Changing shear stress direction would increase risk of debonding at mesiodistal cervical edge. PMID- 29415971 TI - Effect of incorporation of surface pre-reacted glass ionomer filler in tissue conditioner on the inhibition of Candida albicans adhesion. AB - We investigated the effects of incorporation of surface pre-reacted glass ionomer (S-PRG) filler in tissue conditioner (TC) on Candida albicans adhesion. We prepared specimens containing 0, 5, 10, or 20 wt% of S-PRG filler, and measured the amount of C. albicans on the surface using a colony forming unit (CFU) assay and scanning electron microscopic images. In addition, we measured the consistency, penetration depth, and surface roughness (Ra). CFU values for 10 and 20 wt% were significantly lower than that for the control (p<0.05). Hyphal density on the surface was greater in the control. The 10 and 20 wt% specimens showed significantly higher consistency and Ra, lower penetration depth ratio than control (p<0.05). These results suggest that incorporation of S-PRG filler may reduce C. albicans adhesion onto TC surface; however, the optimal amount of filler is dictated by the influence of filler incorporation on mechanical and surface characters of TC. PMID- 29415972 TI - Synthesis of hybrid copper-chitosan nanoparticles with antibacterial activity against cariogenic Streptococcus mutans. AB - Hybrid nanoparticles (CuChNP) comprising of copper nanoparticles with a chitosan shell were synthesized. Antimicrobial properties of CuChNP were assessed against Streptococcus mutans (S. mutans), one of the main bacterium that causes tooth decay. Antibacterial activity of CuChNP against S. mutans was comparable to that of oral antimicrobial agents, such as chlorhexidine, and cetylpyridinium chloride. Particularly, CuChNP exhibited superior capacity to prevent the S. mutans growth on human tooth surface as well as disrupt and kill the bacterial cells in an established dental biofilm. Chitosan may interact with both tooth hydroxyapatite and bacterial cell wall, which improves the adherence of copper to the tooth surface and potentiates their anti-biofilm action. The antimicrobial properties exhibited by CuChNP could be useful for the future development of more effective treatments for the control of dental plaque biofilms. PMID- 29415973 TI - Antibacterial activity and dentin bonding ability of combined use of Clearfil SE Protect and sodium hypochlorite. AB - The aim of this study was to evaluate the antibacterial activity and dentin bonding ability of a commercial self-etch adhesive Clearfil SE Protect (Kuraray Noritake Dental, Tokyo, Japan) in combination with sodium hypochlorite (NaOCl). Agar disc diffusion tests and measurement of minimum inhibitory/bactericidal concentrations (MIC/MBC) against Streptococcus mutans were performed to evaluate antibacterial effects. The mixture solution of 5.25% NaOCl and the primer of Clearfil SE Protect demonstrated less antibacterial activity than primer only. In microtensile bond strength tests using non-carious human molars, pretreatment with 5.25% NaOCl aqueous solution had no influence on the bond strength of Clearfil SE Protect. These results indicate that pretreatment with NaOCl does not influence the bonding ability of Clearfil SE Protect, while their combined use does not enhance cavity disinfecting effects. PMID- 29415974 TI - A Case of Classical Hodgkin Lymphoma with Total Lymph Node Infarction. AB - Lymph node infarction is very rare, and is frequently associated with neoplasms, such as malignant lymphoma and non-neoplastic disease, or interventions such as fine-needle aspiration (FNA). A 76-year-old-man presented with cervical lymph node swelling. Although FNA was performed, the findings were insufficient for a definitive diagnosis. Consequently, surgical biopsy of the cervical lymph node was performed, which revealed total infarction; a diagnosis of classical Hodgkin lymphoma was made later. Both lymphoma itself and FNA may cause total lymph node infarction, which makes diagnosis confusing. Therefore, it is important to repeat the biopsy rather than repeat FNA to correctly diagnose malignant lymphoma, including Hodgkin lymphoma. PMID- 29415975 TI - Detection of Minimal Bone Marrow involvement of Blastic Plasmacytoid Dendritic Cell Neoplastic Cells - CD303 immunostaining as a diagnostic tool. AB - Blastic plasmacytoid dendritic cell (pDC) neoplasm (BPDCN) is a relatively rare hematological malignancy with significantly complex clinicopathological features that are still unclear. This study aimed to analyze the clinicopathological data of BPDCN and evaluate immunohistochemical detection of minimal bone marrow (BM) involvement. In this study, we examined skin and BM lesions from 6 patients with BPDCN. Neoplastic cells tested positive for CD303 (polyclonal, 100%; monoclonal, 40%) in the skin lesions and for CD303 (polyclonal, 100%; monoclonal, 67%) in the BM clots. Although immunostaining of CD4, CD56, CD123, CD303, and TCLl detected minimal BM involvement in 3 patients, morphological identification was challenging in the BM clots stained with hematoxylin-eosin. In conclusion, our results demonstrate the significance of observing BM smears to detect neoplastic cells and that immunohistochemical examination, including CD303 antibodies, is useful to detect minimal BM involvement. This study is the first to report the expression of thymic stromal lymphopoietin (TSLP) and its receptor in BPDCN cells. Therefore, the TSLP/TSLP receptor axis may be associated with the proliferation of BPDCN, and consequently, the survival of patients. PMID- 29415976 TI - Clinical management and outcomes of completely resected stage I follicular lymphoma. AB - Recent studies have revealed the clinical and biological features of stage I follicular lymphoma (FL), but information about patients with stage I FL who underwent total resection after tissue biopsy is limited. Among 305 FL patients diagnosed between 2001 and 2013, clinical stage I disease was observed in 36 patients. Of these, 18 patients underwent total resection after diagnostic tissue biopsy. We used 18F-fluorodeoxyglucose positron emission CT for staging assessment in 13 of 18 patients (72.2%). The median age was 56.5 years. Six patients (33.3%) were male. The soluble interleukin-2 receptor alpha concentration was significantly lower than in patients with residual disease. Among these 18 patients, 7 patients (38.9%) were treated with a "watch-and-wait" (WW) policy, 7 (38.9%) were treated with involved-field irradiation, and 4 (22.2%) received systemic chemotherapy. Patients with resected disease were treated with significantly different strategies from those with residual disease (p = 0.0026). Five patients experienced relapse during follow-up (median follow up: 48.2 months). All relapses were distant from the primary site, irrespective of treatment strategy. Among all stage I patients, disease resection was not a significant factor for survival (p = 0.9294). Collectively, the choice of treatment strategy was significantly influenced by patient status. Resection status was not significantly associated with survival after several treatment strategies. PMID- 29415978 TI - Hyaline vascular Castleman's disease representing 18 trisomy. PMID- 29415977 TI - Composite Lymphoma as Co-occurrence of Advanced Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Carrying Trisomy 12 and t(14;18) and Peripheral T-cell Lymphoma. AB - Composite lymphoma is defined as the co-occurrence of two types of lymphoma, comprising 1-4% of lymphomas, and the association of B-cell-type chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma and peripheral T-cell lymphoma (PTCL) is rare. Here, we report a case (77-year-old woman) of advanced B CLL complicated by newly appearing PTCL. Two years after the onset of B-CLL, CLL cells acquired CD38 antigen expression and the disease entity became CLL/prolymphocytic leukemia. Trisomy 12 and t(14;18) karyotypes were observed. Five years after the onset of B-CLL, large abnormal cells with convoluted nuclei appeared in the peripheral blood and rapidly increased in number. These cells were positive for CD3, CD4, CD5, CD30 (partially), CD56, and alphabeta-type T cell receptor (TCR), in which PCR demonstrated monoclonal TCR-gamma gene rearrangement. An additional diagnosis of PTCL, not otherwise specified was made. We treated her with an R-CHOP regimen, resulting in the marked reduction of B-CLL cells but progressive PTCL. Brentuximab vedotin had a transient effect, but the patient died of sepsis due to residual PTCL and pancytopenia. This case is highly informative for tumor biology of B-CLL in terms of emergence of both chromosomal abnormalities and PTCL with progression of this leukemia. PMID- 29415979 TI - Autopsy case report of intravascular large B-cell lymphoma with neoplastic PD-L1 expression. AB - Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically distinctive entity characterized by the almost exclusive growth of large cells within the lumen of blood vessels in particular capillaries. Reports of this peculiar disease, do not commonly address the PD-L1 expression on IVLBCL tumor cells. Here, we describe a 51-year-old Japanese woman who presented with rapidly progressive cognitive decline and higher brain dysfunction. CT scan and MRI revealed multiple ischemic foci in the cerebral hemispheres, ground-glass opacity in the lungs, and splenomegaly. Random skin biopsy for IVLBCL diagnosis yielded negative results. The patient experienced a rapidly deteriorating clinical course with no treatment, and died from the disease after 3 months of hospitalization. Post-mortem examination revealed systemic intravascular plugging of lymphoma cells, without mass lesions in the central nervous system or in visceral organs such as the lungs, liver, pituitary gland, ovaries, and uterus. The tumor cells were positive for CD10, CD20, BCL2, BCL6, and MUM1, but not other lineage specific markers. Notably, the tumor cells showed strong PD-L1 expression. Our case was diagnosed as IVLBCL with neoplastic PD-L1 expression. These findings suggest that PD-L1 is associated with immune evasion of IVLBCL and may play a role in the pathogenesis and peculiar biological behavior of this unique disease. Additionally, PD-L1 may represent a possible therapeutic target for immune check point inhibitors. PMID- 29415980 TI - Effect of Low-Frequency Pulsed Ultrasound on Drug Delivery, Antibacterial Efficacy, and Bone Cement Degradation in Vancomycin-Loaded Calcium Phosphate Cement. AB - BACKGROUND Calcium phosphate cement (CPC) has been applied as a biodegradable antibiotic carrier in osteomyelitis. However, the drug delivery, antibacterial efficacy, and degradation rate of CPC are insufficient and require further improvement in clinical application. MATERIAL AND METHODS Vancomycin-loaded CPC columns were prepared, and eluted in simulated body fluid. The drug delivery was assessed in the ultrasound group and control group by fluorescence polarization immunoassay. The antibacterial efficacy of vancomycin in the ultrasound group and control groups was investigated by standard plate count method. Low-frequency pulsed ultrasound (46.5 kHz, 900 mW/cm2) was used to produce a sinusoidal wave in the ultrasound groups. The percentage of residual weight was evaluated to assess the degradation of CPC. RESULTS The concentration and cumulatively released percentage of vancomycin in the ultrasound group were higher than that in the control group at each time point (p<0.05). The duration of vancomycin concentration over the level of minimum inhibitory concentration was significantly prolonged in the ultrasound group (p<0.05). Antibacterial efficacy of vancomycin in the ultrasound group was significantly greater than that in the control group with same concentration of vancomycin (p<0.05). The percentage of residual weight in the ultrasound group was significantly less than that in the control group (p<0.05). CONCLUSIONS Low-frequency pulsed ultrasound can enhance vancomycin release, prolong the duration of vancomycin concentration at high levels, and accelerate the degradation rate of vancomycin-loaded CPC. PMID- 29415981 TI - Acute Exertional Compartment Syndrome with Rhabdomyolysis: Case Report and Review of Literature. AB - BACKGROUND Acute exertional compartment syndrome (AECS) is a rare cause of leg pain often associated with a delay in diagnosis and potentially leading to irreversible muscle and nerve damage. CASE REPORT We present the case of a previously healthy, high-level athlete who presented with the acute onset of unilateral anterior leg pain and foot drop the day after a strenuous workout. He was diagnosed with compartment syndrome and rhabdomyolysis. His management included emergent fluid resuscitation, fasciotomies, debridement of necrotic muscle from his anterior compartment, and delayed primary closure. After six months of intensive outpatient physical therapy, including the use of blood flow restriction treatments, the patient returned to sports and received a NCAA Division I Football scholarship. CONCLUSIONS We describe the details of this patient's case and review the literature related to acute exertional compartment syndrome. The occurrence of acute compartment syndrome in the absence of trauma or fracture, though rare, can have devastating consequences following delays in treatment. AECS requires prompt diagnosis and surgical intervention to prevent these consequences. Diagnosis of atraumatic cases can be difficult, which is why awareness is equally as important as history and physical examination. While diagnosis is primarily clinical, it can be supported with direct intra compartmental pressure measurements and maintaining a high index of suspicion in acute presentations of exertional limb pain. PMID- 29415982 TI - Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1beta production. AB - Proteasome inhibitors have emerged as an effective therapy for the treatment of haematological malignancies; however, their efficacy can be limited by the development of tumour resistance mechanisms. Novel combination strategies including the addition of TLR adjuvants to increase cell death and augment immune responses may help enhance their effectiveness. Although generally thought to inhibit inflammatory responses and NF-kappaB activation, we found that under specific conditions proteasome inhibitors can promote inflammatory responses by mediating IL-1beta maturation and secretion after TLR stimulation. This was dependent on the timing of proteasome inhibition relative to TLR stimulation where reversal of treatment order could alternatively increase or inhibit IL 1beta secretion (P < 0.001). TLR stimulation combined with proteasome inhibition enhanced cell death in vitro and delayed tumour development in vivo in NOD SCID mice (P < 0.01). However, unlike IL-1beta secretion, cell death occurred similarly regardless of treatment order and was only partially caspase dependent, possessing characteristics of both apoptosis and necrosis as indicated by activation of caspase-1, 3, 8 and RIP3 phosphorylation. Although stimulation of various TLRs was capable of driving IL-1beta production, TLR4 stimulation was the most effective at increasing cell death in THP-1 and U937 cells. TLR4 stimulation and proteasome inhibition independently activated the RIP3 necroptotic pathway and ultimately reduced the effectiveness of caspase/necroptosis inhibitors in mitigating overall levels of cell death. This strategy of combining TLR stimulation with proteasome inhibition may improve the ability of proteasome inhibitors to generate immunogenic cell death and increase anti-tumour activity. PMID- 29415983 TI - 14-3-3zeta delivered by hepatocellular carcinoma-derived exosomes impaired anti tumor function of tumor-infiltrating T lymphocytes. AB - Increasing evidence shows that the anti-tumor functions of tumor-infiltrating T lymphocytes (TILs) were inhibited significantly, but the underlying mechanisms remain not fully understood. In this study, we found that 14-3-3zeta expression was up-regulated in hepatocellular carcinoma (HCC) cells and in TILs. TILs with 14-3-3zeta high-expression (14-3-3zetahigh) exhibited impaired activation (CD69), proliferation (Ki67) and anti-tumor functions compared to 14-3-3zeta low expression (14-3-3zetalow) TILs. Flow cytometry assay showed that compared with 14-3-3zetalow CD8+T cells, 14-3-3zetahigh ones exhibited higher frequency of exhausted phenotypes as measured by inhibitory receptors such as PD-1, TIM-3, LAG3, and CTLA-4. 14-3-3zeta overexpression inhibited the activity and proliferation of peripheral blood CD3+ T cells, deviated the differentiation of naive T cells from effector T cells to regulatory T cells. Moreover, we found that 14-3-3zeta expression levels in TILs correlated positively with those in HCC cells. Naive T cells co-cultured with HCC cells or the visible components of culture medium of HCC cells exhibited increased 14-3-3zeta expression. Stochastic optical reconstruction microscopy (STORM) and confocal assay showed that 14-3 3zeta-containing exosomes derived from HCC cells could be swallowed by T cells, suggesting that 14-3-3zeta might be transmitted from HCC cells to TILs at least partially through exosomes. In conclusion, our study for the first time demonstrated that 14-3-3zeta is up-regulated in and inhibited the anti-tumor functions of tumor-infiltrating T cells in HCC microenvironment and that 14-3 3zeta might be transmitted from HCC cells to T cells at least partially through exosomes. PMID- 29415984 TI - UHRF1 depletion sensitizes retinoblastoma cells to chemotherapeutic drugs via downregulation of XRCC4. AB - UHRF1 (ubiquitin-like with PHD and ring finger domains 1) is highly expressed in various human cancers including retinoblastoma, and associated with tumor promoting effects such as inhibition of apoptosis and high proliferation. However, the molecular mechanisms underlying tumor-promoting functions of UHRF1 in retinoblastoma still remain elusive. Here, we show that stable knockdown of UHRF1 renders retinoblastoma cells sensitized to conventional chemotherapeutic drugs such as etoposide and camptothecin, resulting in enhanced DNA damage and apoptotic cell death. We found that UHRF1-depleted retinoblastoma cells can recognize DNA damages normally but have markedly low expression of XRCC4 (X-ray repair cross complementing 4) among the components of nonhomologous end-joining (NHEJ) repair complex. Conversely, overexpression of UHRF1 increased the XRCC4 expression and stable knockdown of XRCC4 sensitized retinoblastoma cells to etoposide treatment, suggesting that XRCC4 is a key mediator for the drug sensitivity upon UHRF1 depletion in retinoblastoma cells. Consistent with the findings, chromatin association of DNA ligase IV in response to acute DNA damage was found to be significantly reduced in UHRF1-depleted retinoblastoma cells and functional complementation for XRCC4 in UHRF1-depleted cells attenuated the drug sensitivity, demonstrating that XRCC4 downregulation in UHRF1-depleted cells impaired DNA repair and consequently induced robust apoptosis upon genotoxic drug treatment. In human primary retinoblastoma, high expression of UHRF1 and XRCC4 could be detected, and elevated XRCC4 expression correlated with reduced apoptosis markers, implying that UHRF1-mediated XRCC4 upregulation under pathophysiological conditions triggered by RB1 gene inactivation may confer protection against endogenous DNA damages that arise during retinoblastoma development. Taken together, these results present a new mechanistic insight into how UHRF1 mediates its tumor-promoting functions in retinoblastoma, and also provide a basis for UHRF1 targeting to improve the efficacy of current chemotherapy for retinoblastoma treatment. PMID- 29415985 TI - Targeting deubiquitinase USP28 for cancer therapy. AB - As one of the most important post-translational modifications, ubiquitination plays versatile roles in cancer-related pathways, and is involved in protein metabolism, cell-cycle progression, apoptosis, and transcription. Counteracting the activities of the E3 ligases, the deubiquitylating enzymes have been suggested as another important mechanism to modulate the ubiquitination process, and are implicated in cancer as well. In this article, we review the emerging roles of USP28 in cancer pathways as revealed by recent studies. We discuss the major mechanisms by which USP28 is involved in the cancer-related pathways, whereby USP28 regulates physiological homeostasis of ubiquitination process, DNA damage response, and cell cycle during genotoxic stress. We further review the studies where USP28 was targeted for treating multiples cancers including non small cell lung cancer, breast cancer, intestinal cancers, gliomas, and bladder cancer. As a result, the clinical significance of targeting USP28 for cancer therapy merits further exploration and demonstration. PMID- 29415986 TI - Osteoblast-targeted delivery of miR-33-5p attenuates osteopenia development induced by mechanical unloading in mice. AB - A growing body of evidence has revealed that microRNAs (miRNAs) play crucial roles in regulating osteoblasts and bone metabolism. However, the effects of miRNAs in osteoblast mechanotransduction remain to be defined. In this study, we investigated the regulatory effect of miR-33-5p in osteoblasts and tested its anti-osteopenia effect when delivered by an osteoblast-targeting delivery system in vivo. First, we demonstrated that miR-33-5p could promote the activity and mineralization of osteoblasts without influencing their proliferation in vitro. Then our data showed that supplementing miR-33-5p in osteoblasts by a targeted delivery system partially recovered the osteopenia induced by mechanical unloading at the biochemical, microstructural, and biomechanical levels. In summary, our findings demonstrate that miR-33-5p is a key factor in the occurrence and development of the osteopenia induced by mechanical unloading. In addition, targeted delivery of the mimics of miR-33-5p is a promising new strategy for the treatment of pathological osteopenia. PMID- 29415987 TI - Oncogenic HSP60 regulates mitochondrial oxidative phosphorylation to support Erk1/2 activation during pancreatic cancer cell growth. AB - HSP60 is a mitochondrial localized quality control protein responsible for maintaining mitochondrial function. Although HSP60 is considered both a tumor suppressor and promoter in different types of cancer, the role of HSP60 in human pancreatic ductal adenocarcinoma (PDAC) remains unknown. In this study, we demonstrated that HSP60 was aberrantly expressed in human pancreatic cancer tissues and cell lines. Analysis of the Cancer Genome Atlas database revealed that HSP60 expression is positively correlated with pancreatic cancer. Further, knockdown of HSP60 attenuated pancreatic ductal cancer cell proliferation and migration/invasion, whereas ectopic expression of HSP60 increased tumorigenesis. Using an in vivo tumorigenicity assay, we confirmed that HSP60 promoted the growth of pancreatic ductal cancer cells. Functional analyses demonstrated that HSP60 plays a key role in the regulation of mitochondrial function. Mechanistically, both HSP60 knockdown and oxidative phosphorylation (OXPHOS) inhibition by metformin decreased Erk1/2 phosphorylation and induced apoptosis and cell cycle arrest, whereas Erk1/2 reactivation with EGF promoted cell proliferation. Intriguingly, in vitro ATP supplementation partially restored Erk1/2 phosphorylation and promoted proliferation in PDAC cells with HSP60 knockdown and OXPHOS inhibition. These results suggest that mitochondrial ATP is an important sensor of Erk1/2 regulated apoptosis and the cell cycle in PDAC cells. Thus, our findings indicate for the first time that HSP60 may serve as a novel diagnostic target of human pancreatic cancer, and that inhibition of mitochondrial function using drugs such as metformin may be a beneficial therapeutic strategy targeting pancreatic cancer cells with aberrant function of the HSP60/OXPHOS/Erk1/2 phosphorylation axis. PMID- 29415988 TI - Photosensitization of A2E triggers telomere dysfunction and accelerates retinal pigment epithelium senescence. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in elderly people. AMD is classified as early, intermediate, advanced non-neovascular, and advanced neovascular forms depending on the clinical features. However, the exact pathogenesis remains unclear. Retinal pigment epithelium (RPE) cells degeneration is a hallmark of AMD. With aging, lipofuscin accumulates in RPE cells. N-retinylidene-N-retinylethanolamine (named A2E), a well-known fluorophore of lipofuscin, may contribute to RPE cells degeneration. In this study, we showed that photosensitization of A2E increased DNA damage, including telomere deprotection and deletion, and triggered cellular senescence. In addition, we found that the antioxidant N-acetyl-cysteine (NAC) partially alleviated this DNA damage. Telomerase overexpression rescued A2E-mediated RPE cell senescence, indicating that telomere dysfunction plays an important role in A2E-based senescence. We further showed that the senescence induced by A2E photosensitization may affect the microenvironment of the retina by expressing several factors of the secretory phenotype (SASP) including IL1B, IL13RA2, and CXCR4 through the NF-kappaB pathway. We propose that expression of these factors create a pro-inflammatory environment that drives retina degeneration. Moreover, our findings suggest that protecting telomeres is a valuable strategy for treating retinal degeneration diseases, such as AMD. PMID- 29415989 TI - Sphingolipid de novo biosynthesis is essential for intestine cell survival and barrier function. AB - Serine palmitoyltransferase (SPT) is the rate-limiting enzyme for sphingolipid biosynthesis. SPT has two major subunits, SPTLC1 and SPTLC2. We previously found that liver Sptlc2 deficiency in early life impairs the development of adherens junctions. Here, we investigated the role of Sptlc2 deficiency in intestine. We treated Sptlc2-Flox/villin-Cre-ERT2 mice with tamoxifen (days 1, 2, and 3) to ablate Sptlc2 specifically in the intestine. At day 6 after tamoxifen treatment, Sptlc2-deficient mice had significantly decreased body weight with concurrent diarrhea and rectal bleeding. The number of goblet cells was reduced in both large and small intestine of Sptlc2-deficient mice compared with controls. Sptlc2 deficiency suppressed the level of mucin2 in the colon and increased circulating lipopolysaccharides, suggesting that SPT activity has a housekeeping function in the intestine. All Sptlc2-deficient mice died 7-10 days after tamoxifen treatment. Notably, supplementation with antibiotics and dexamethasone reduced lethality by 70%. We also found that colon specimens from patients with inflammatory bowel diseases had significantly reduced Sptlc2 expression, SPTLC2 staining, and goblet cell numbers. SPT activity is crucial for intestinal cell survival and barrier function. PMID- 29415990 TI - circHIPK3 regulates cell proliferation and migration by sponging miR-124 and regulating AQP3 expression in hepatocellular carcinoma. AB - Noncoding RNAs plays an important role in hepatocellular carcinoma (HCC). Here, we show that miR-124 was downregulated in HCC tissues and that the ectopic expression of miR-124 inhibited the proliferation and migration of HCC cells. We proposed that aquaporin 3 (AQP3) is a direct target of miR-124. AQP3 was upregulated in HCC tissues and inversely correlated with miR-124 expression. The overexpression of miR-124 decreased AQP3 expression. Indeed, AQP3 overexpression promoted cell proliferation and migration, whereas miR-124 knockdown suppressed cell proliferation and migration. Furthermore, we found that circular RNA HIPK3 (circHIPK3) acted as a miR-124 sponge and regulated the expression of the miR-124 target gene AQP3. circHIPK3 was upregulated in HCC tissues and positively correlated with AQP3 expression. Thus, silencing circHIPK3 inhibited cell proliferation and migration by downregulating AQP3 expression. Moreover, miR-124 inhibition rescued circHIPK3 knockdown induced reduction in cell proliferation and migration, as well as AQP3 expression. In vivo experiments also confirmed that circHIPK3 regulated xenograft tumor growth via the miR-124-AQP3 axis. These observations indicate a possible novel therapeutic strategy involving circular RNAs in HCC. PMID- 29415991 TI - Regulation of senescence escape by the cdk4-EZH2-AP2M1 pathway in response to chemotherapy. AB - Senescence is a tumor suppressive mechanism that induces a permanent proliferative arrest in response to an oncogenic insult or to the genotoxic stress induced by chemotherapy. We have recently described that some cells can escape this arrest, either because senescence was incomplete or as a consequence of a phenotypic adaptation. Malignant cells which resisted senescence emerged as more transformed cells that resist anoikis and rely on survival pathways activated by Akt and Mcl-1. In this study, we further characterize senescence escape, investigating how emergent cells could reproliferate. During the initial step of chemotherapy-induced senescence (CIS), we found that cyclin D1 was upregulated and that cell emergence was prevented when its main partner cdk4 was inactivated. Results indicate that this kinase induced the upregulation of the EZH2 methylase, a component of the polycomb PRC2 complex. Downregulated during the early step of treatment, the methylase was reactivated in clones that escaped senescence. The inactivation of EZH2, either by siRNA or by specific inhibitors, led to a specific inhibition of cell emergence. We used quantitative proteomic analysis to identify new targets of the methylase involved in senescence escape. We identified proteins involved in receptor endocytosis and described new functions for the AP2M1 protein in the control of chemotherapy-mediated senescence. Our results indicate that AP2M1 is involved in the transmission of secreted signals produced by senescent cells, suggesting that this pathway might regulate specific receptors involved in the control of CIS escape. In light of these results, we therefore propose that the cdk4-EZH2-AP2M1 pathway plays an important role during chemotherapy resistance and senescence escape. Since targeted therapies are available against these proteins, we propose that they should be tested in the treatment of colorectal or breast cancers that become resistant to first-line genotoxic therapies. PMID- 29415992 TI - Osteopontin promotes metastasis of intrahepatic cholangiocarcinoma through recruiting MAPK1 and mediating Ser675 phosphorylation of beta-Catenin. AB - The incidence and mortality of intrahepatic cholangiocarcinoma (ICC) are increasing worldwide in recent decades. Osteopontin (OPN) plays an important role in cancer metastasis, but its functional mechanism in ICC is not clear yet. In this study, we found that OPN level was elevated both in plasma and tumor tissues of ICC patients, which was closely related to a shorter overall survival (OS) and high probability of tumor relapse after curative resection. The gain- and loss-of function studies determined that OPN could promote ICC growth and metastasis. OPN selectively interacted with beta-Catenin and knockdown of beta-Catenin abrogated the effects induced by OPN. OPN recruited MAPK1 and activated MEK-MAPK1 pathway to mediate the S675 phosphorylation of beta-Catenin and nucleus accumulation, which induced the activation of Wnt signaling. Moreover, a significant correlation between OPN and beta-Catenin was found in ICC tissues. OPN, beta Catenin, and their combination were independent prognostic indicator for ICC patients. In conclusion, OPN promotes ICC progression through recruiting MAPK1 and activating the Wnt/beta-Catenin pathway and can serve as a novel prognostic marker and therapeutic target for ICC. PMID- 29415993 TI - Evaluation of autophagy inducers in epithelial cells carrying the DeltaF508 mutation of the cystic fibrosis transmembrane conductance regulator CFTR. AB - Cystic Fibrosis (CF) due to the DeltaF508 mutation of cystic fibrosis transmembrane conductance regulator (CFTR) can be treated with a combination of cysteamine and Epigallocatechin gallate (EGCG). Since ECGC is not a clinically approved drug, we attempted to identify other compounds that might favourably interact with cysteamine to induce autophagy and thus rescuing the function of DeltaF508 CFTR as a chloride channel in the plasma membrane. For this, we screened a compound library composed by chemically diverse autophagy inducers for their ability to enhance autophagic flux in the presence of cysteamine. We identified the antiarrhythmic Ca2+ channel blocker amiodarone, as an FDA-approved drug having the property to cooperate with cysteamine to stimulate autophagy in an additive manner. Amiodarone promoted the re-expression of DeltaF508 CFTR protein in the plasma membrane of respiratory epithelial cells. Hence, amiodarone might be yet another compound for the etiological therapy of CF in patients bearing the DeltaF508 CFTR mutation. PMID- 29415994 TI - MicroRNA-1253 suppresses cell proliferation and invasion of non-small-cell lung carcinoma by targeting WNT5A. AB - MicroRNAs (miRNA) are a class of small, noncoding RNA molecules that regulate the expression of target genes. miRNA dysregulation is involved in carcinogenesis and tumor progression. In this study, we identified microRNA-1253 (miR-1253) as being significantly down-regulated in non-small-cell lung carcinoma (NSCLC) tissues and associated with advanced clinical stage, lymph node metastasis, and poor survival. The enhanced expression of miR-1253 significantly inhibited the proliferation, migration, and invasion of NSCLC cells in vitro. Bioinformatics analyses showed that miR-1253 directly targeted WNT5A (long isoform), which was confirmed using the dual-luciferase reporter assay. The inhibitory effects of miR 1253 on the growth and metastasis of NSCLC cells were attenuated and phenocopied by WNT5A (long) overexpression and knockdown, respectively. Consistent with the in vitro results, subcutaneous tumor and metastatic NSCLC mouse models showed that miR-1253 functions as a potent suppressor of NSCLC in vivo. Taken together, our findings indicated that miR-1253 inhibited the proliferation and metastasis of NSCLC cells by targeting WNT5A (long isoform) and provided new evidence of miR 1253 as a potential therapeutic target in NSCLC. PMID- 29415995 TI - Plasma Hemopexin ameliorates murine spinal cord injury by switching microglia from the M1 state to the M2 state. AB - Spinal cord injury (SCI) is a devastating type of central nervous system (CNS) trauma with limited therapeutic treatments. The polarization of microglia into the M1 or M2 state has been documented to play important roles in the pathogenesis of SCI, although the complete repertoire of underlying factors has not been identified. Interestingly, the time point at which hematomyelia (intramedullary spinal cord hemorrhage) is alleviated coincides with a decrease in the number of M2 microglia. Here the function of Hemopexin (Hpx), a hematogenous glycoprotein, was examined in the crush model of SCI. Hpx levels were elevated at the lesion site during hematomyelia and were synchronously correlated with the level of the M2 marker Arginase-1 (Arg-1). Ablation of Hpx in vivo affected the polarization state of lipopolysaccharide (LPS)-stimulated microglia, as mirrored by a lower percentage of M2 microglia and a higher percentage of M1 microglia in the lesion site, which delayed the recovery and exacerbated the behavioral dysfunction after SCI. However, Hpx induced a rapid switch from the M1 to M2 phenotype in LPS-stimulated primary cultured microglia in a heme scavenging-independent manner. The supernant of Hpx-treated microglia ameliorated neuronal degeneration, alleviated demyelination, and promoted oligodendrocyte precursor cell (OPC) maturation. This modulatory effect of Hpx on microglia polarization was at least partially mediated by the LRP-1 receptor. Based on these results, Hpx is considered a novel modulator of the polarization of microglia during the pathogenesis of SCI and may play a crucial role in the recovery from SCI. PMID- 29415996 TI - Antitumor activity of EGFR-specific CAR T cells against non-small-cell lung cancer cells in vitro and in mice. AB - Effective control of non-small-cell lung cancer (NSCLC) remains clinically challenging, especially during advanced stages of the disease. This study developed an adoptive T-cell treatment through expression of a chimeric antigen receptor (CAR) to target human epidermal growth factor receptor (EGFR) in NSCLC. We optimized the non-viral piggyBac transposon system to engineer human T cells for the expression of EGFR-CAR, consisting of EGFR scFv, transmembrane domain, and intracellular 4-1BB-CD3zeta signaling domains. The modified CAR T cells exhibited expansion capability and anticancer efficacy in a time- and antigen dependent manner in vitro as well as regression of EGFR-positive human lung cancer xenografts in vivo. EGFR-CAR T therapy is a promising strategy to improve the efficacy and potency of the adoptive immunotherapy in NSCLC. Moreover, EGFR CAR T therapy could become a clinical application for NSCLC patients in the future. PMID- 29415997 TI - Downregulation of beta1,4-galactosyltransferase 5 improves insulin resistance by promoting adipocyte commitment and reducing inflammation. AB - Protein glycosylation is an important post-translational modification. Aberrant glycosylation has been implicated in many diseases because of associated changes in protein distribution and biological function. We showed that the expression of beta1, 4-galactosyltransferase 5 (B4GalT5) was positively correlated with diabetes and obesity. In vivo, B4GalT5 knockdown in subcutaneous adipose tissue alleviated insulin resistance and adipose tissue inflammation, and increased adipogenesis in high-fat diet (HFD)-fed mice and ob/ob mice. Downregulation of B4GalT5 in preadipocyte cells induced commitment to the adipocyte lineage in the absence of bone morphogenetic protein (BMP) 2/4 treatment, which is typically essential for adipogenic commitment. RNAi silencing experiments showed B4GalT5 knockdown activated Smad and p38 MPAK signaling pathways through both type 1A and 2 BMP receptors. Remarkably, B4GalT5 knockdown decreased BMPRIA glycosylation but increased BMPRIA stability and cellular location, thus leading to redistribution of BMPRIA and activation of the BMP signaling pathway. Meanwhile, downregulation of B4GalT5 decreased the infiltration of macrophages and the markers of M1 macrophages in subcutaneous adipose tissue of HFD mice and ob/ob mice. In bone marrow-derived macrophages (BMDMs) and RAW264.7cells, B4GalT5 knockdown also repressed the markers of M1 by reducing NFkappaB and JNK signaling. These results demonstrated B4GalT5 downregulation improved insulin resistance by promoting adipogenic commitment and decreasing M1 macrophage infiltration. PMID- 29415998 TI - Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver. AB - Elevated homocysteine (Hcy) levels have been reported to be involved in liver injury, and autophagy plays an important role in normal hepatic physiology and pathophysiology, but the mechanism underlying Hcy regulated autophagy is currently unknown. In this study, CBS+/- mice were fed with regular diet for 12 weeks to establish a hyperhomocysteinemia (HHcy) model and HL-7702 cells were treated with Hcy, we found that Hcy increases autophagy and aggravates liver injury by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo and in vitro. Overexpression of CFTR inhibited the formation of autophagosomes and the expression of autophagy-related proteins BECN1, LC3-II/I and Atg12, while the expression of p62 increased in Hcy-treated hepatocytes and CBS+/- mice injected with lentivirus expressing CFTR. Further study showed that CFTR expression is regulated by the interaction of DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), which, respectively, regulate DNA methylation and histone H3 lysine 27 trimethylation (H3K27me3). In conclusion, our study showed that Hcy activates autophagy by inhibition of CFTR expression via interaction between H3K27me3 and DNA methylation in the mouse liver. These findings provide new insight into the mechanism of Hcy-induced autophagy in liver injury. PMID- 29415999 TI - MicroRNA-27a-5p regulation by promoter methylation and MYC signaling in prostate carcinogenesis. AB - Upregulation of MYC and miRNAs deregulation are common in prostate cancer (PCa). Overactive MYC may cause miRNAs' expression deregulation through transcriptional and post-transcriptional mechanisms and epigenetic alterations are also involved in miRNAs dysregulation. Herein, we aimed to elucidate the role of regulatory network between MYC and miRNAs in prostate carcinogenesis. MYC expression was found upregulated in PCa cases and matched precursor lesions. MicroRNA's microarray analysis of PCa samples with opposed MYC levels identified miRNAs significantly overexpressed in high-MYC PCa. However, validation of miR-27a-5p in primary prostate tissues disclosed downregulation in PCa, instead, correlating with aberrant promoter methylation. In a series of castration-resistant PCa (CRPC) cases, miR-27a-5p was upregulated, along with promoter hypomethylation. MYC and miR-27a-5p expression levels in LNCaP and PC3 cells mirrored those observed in hormone-naive PCa and CRPC, respectively. ChIP analysis showed that miR-27a-5p expression is only regulated by c-Myc in the absence of aberrant promoter methylation. MiR-27a-5p knockdown in PC3 cells promoted cell growth, whereas miRNA forced expression in LNCaP and stable MYC-knockdown PC3 cells attenuated the malignant phenotype, suggesting a tumor suppressive role for miR 27a-5p. Furthermore, miR-27a-5p upregulation decreased EGFR/Akt1/mTOR signaling. We concluded that miR-27a-5p is positively regulated by MYC, and its silencing due to aberrant promoter methylation occurs early in prostate carcinogenesis, concomitantly with loss of MYC regulatory activity. Our results further suggest that along PCa progression, miR-27a-5p promoter becomes hypomethylated, allowing for MYC to resume its regulatory activity. However, the altered cellular context averts miR-27a-5p from successfully accomplishing its tumor suppressive function at this stage of disease. PMID- 29416000 TI - miR-195 targets cyclin D3 and survivin to modulate the tumorigenesis of non-small cell lung cancer. AB - miR-195 has recently been reported to function as a tumor suppressor in various cancers, including non-small cell lung cancer (NSCLC). However, the mechanisms by which miR-195 represses the tumorigenesis of NSCLC cells are not fully understood. We performed a high-throughput screen using an miRNA mimic library and confirmed the identification of miR-195 as a tumor suppressor in NSCLC. We demonstrated that overexpression or induced expression of miR-195 in lung tumors slows tumor growth and that repression of miR-195 accelerates tumor growth. In addition, we found that knockout of miR-195 promotes cancer cell growth. We demonstrated that miR-195 targets cyclin D3 to cause cell cycle arrest at the G1 phase and that miR-195 targets survivin to induce apoptosis and senescence in NSCLC cells. Overexpression of cyclin D3 or survivin reverses the effects of miR 195 in NSCLC cells. Through the analysis of data from The Cancer Genome Atlas, we confirmed that the expression of miR-195 is lower in tumors than in adjacent normal tissues and that low expression of miR-195 is associated with poor survival in both lung adenocarcinoma and squamous cell carcinoma patients. Specifically, we found that BIRC5, which codes for survivin, is upregulated in both adenocarcinoma and squamous cell carcinoma tissues and that high expression of BIRC5 is associated with poor survival in adenocarcinoma, but not squamous cell carcinoma. In addition, the ratio of miR-195 level to BIRC5 level is associated with both recurrence-free and overall survival in lung adenocarcinoma. Our results suggest that the miR-195/BIRC5 axis is a potential target for treatment of lung adenocarcinoma specifically, and NSCLC in general. PMID- 29416001 TI - LanCL1 protects prostate cancer cells from oxidative stress via suppression of JNK pathway. AB - Prostate cancer (PCa) is the most commonly diagnosed malignancy in male. Numerous studies have focused on the molecular mechanisms of carcinogenesis and progression, aiming at developing new therapeutic strategies. Here we describe Lanthionine synthase C-like protein 1 (LanCL1), a member of the LanCL family, is a potential prostate cancer susceptibility gene. LanCL1 promotes prostate cancer cell proliferation and helps protect cells from damage caused by oxidative stress. Suppression of LanCL1 by siRNA results in increased cancer cell apoptosis. Clinical data also indicate that LanCL1 upregulation in human prostate cancers correlates with tumor progression. Finally, we demonstrate that LanCL1 plays such important role through inhibiting JNK pathway. Altogether, our results suggest that LanCL1 protects cells from oxidative stress, and promotes cell proliferation. LanCL1 reduces cell death via suppression of JNK signaling pathway. PMID- 29416002 TI - EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection. AB - Enhancer of zeste homolog 2 (EZH2), a methyltransferase that di- and tri methylates lysine-27 of histone H3, largely functions as a transcriptional repressor, and plays a critical role in various kinds of cancers. Here we report a novel function of EZH2 in regulating autophagic cell death (ACD) of vascular smooth muscle cells (VSMCs) that affect aortic dissection (AD). Inhibition of EZH2 activity by UNC1999 or knockdown EZH2 resulted in VSMC loss, while overexpression of EZH2 facilitated VSMC growth, and these effects of EZH2 on VSMCs were independent of proliferation and apoptosis. Interestingly, more autophagic vacuoles and increased LC3II protein levels were identified in VSMCs with EZH2 inhibition or deficiency. Moreover, when compared with counterparts, chloroquine alone, or chloroquine with rapamycin treatment led to more LC3II accumulation in EZH2 inhibited or knockdown VSMCs, which indicated that EZH2 negatively regulated autophagosome formation. In conjunction to this, ATG5 and ATG7 protein levels were remarkably increased in EZH2 inhibited or deficient VSMCs, and ATG5 or ATG7 knockdown virtually rescued VSMC loss induced by EZH2 inhibition or knockdown. In addition, we found that the MEK-ERK1/2 signaling pathway, but not AMPKalpha, mTOR, or AKT pathway, is responsible for the impact of EZH2 on ACD of VSMCs. Additionally, the adverse effects of EZH2 inhibition or knockdown on VSMCs were largely reversed by PD98059, an inhibitor of MEK1. More importantly, decreased EZH2 expression levels in the aortic wall of patients with AD indicated its contribution to VSMC loss and AD occurrence. Overall, these findings revealed that EZH2 affects ACD of VSMCs and the pathologic process of AD via regulating ATG5 and ATG7 expression and MEK-ERK1/2 signaling. Our hitherto unrecognized findings indicate that EZH2 activation has therapeutic or preventive potential for AD. PMID- 29416003 TI - The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG. AB - Tanshinone IIA (Tan IIA), the primary bioactive compound derived from the traditional Chinese medicine (TCM) Salvia miltiorrhiza Bunge, has been reported to possess antitumor activity. However, its antitumor mechanisms are not fully understood. To resolve the potential antitumor mechanism(s) of Tan IIA, its gene expression profiles from our database was analyzed by connectivity map (CMAP) and the CMAP-based mechanistic predictions were confirmed/validated in further studies. Specifically, Tan IIA inhibited total protein kinase C (PKC) activity and selectively suppressed the expression of cytosolic and plasma membrane PKC isoforms zeta and epsilon. The Ras/MAPK pathway that is closely regulated by the PKC signaling is also inhibited by Tan IIA. While Tan IIA did not inhibit heat shock protein 90 (Hsp90), it synergistically enhanced the antitumor efficacy of the Hsp90 inhibitors 17-AAG and ganetespib in human breast cancer MCF-7 cells. In addition, Tan IIA significantly inhibited PI3K/Akt/mTOR signaling, and induced both cell cycle arrest and autophagy. Collectively, these studies provide new insights into the molecular mechanisms responsible for antitumor activity of Tan IIA. PMID- 29416005 TI - miR-27b-3p inhibits proliferation and potentially reverses multi-chemoresistance by targeting CBLB/GRB2 in breast cancer cells. AB - Drug resistance remains a major problem in the treatment of conventional chemotherapeutic agents in breast cancers. Owing to heterogeneity and complexity of chemoresistance mechanisms, most efforts that focus on a single pathway were unsuccessful, and exploring novel personalized therapeutics becomes urgent. By a system approach, we identified that microRNA-27b-3p (miR-27b), a miRNA deleted in breast cancer tissues and cell lines, has a master role in sensitizing breast cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo. Mechanistic analysis indicated that miR-27b enhanced responses to PTX by directly targeting CBLB and GRB2 to inactivate both PI3K/Akt and MAPK/Erk signaling pathways. Further, miR-27b was identified as a promising molecular biomarker in chemoresistance, clinicopathological features, and prognosis for breast cancer patients. In conclusion, we propose that combinational use of miR-27b and chemotherapeutic agents might be a promising therapeutic strategy to increase long-term drug responses in breast cancers. PMID- 29416004 TI - Regenerative potential of tonsil mesenchymal stem cells on surgical cutaneous defect. AB - As tissue engineering and regenerative medicine have evolved recently, stem cell therapy has been investigated in the field of impaired wound healing. Several studies have reported that mesenchymal stem cells derived from various tissues including bone marrow and adipose tissue can exert the regenerative efficacy in the wound healing. Previously, we have demonstrated the isolation and characterization of tonsil-derived mesenchymal stem cells (TMSCs) with excellent proliferative property. In the present study, we aimed to evaluate the regenerative efficacy of TMSCs in the wound healing process. Two distinct cutaneous surgical defects were generated in the dorsum of mice. Each wound was treated with TMSCs or phosphate-buffered saline (PBS), respectively. After sacrifice, the skin and subcutaneous tissues around the surgical defect were harvested and assessed for inflammation, re-epithelialization, dermal regeneration, and granulation tissue formation. The administration of TMSCs into wound beds significantly promoted the repair of surgical defects in mice. Especially, TMSCs efficiently contributed to the attenuation of excessive inflammation in the surgical lesion, as well as the augmentation of epidermal and dermal regeneration. To elucidate the underlying mechanisms, TMSCs were analyzed for their potency in immunomodulatory ability on immune cells, stimulatory effect on the proliferation of keratinocytes, and fibroblasts, as well as the regulation of fibroblast differentiation. TMSCs inhibited the non-specific or T-cell specific proliferation of peripheral blood mononuclear cells, as well as the M1 polarization of macrophage-like cells. Moreover, TMSCs augmented the proliferation of skin-constituting fibroblasts and keratinocytes while they suppressed the differentiation of fibroblasts into myofibroblasts. Taken together, our findings demonstrate the regenerative potential of TMSCs in wound healing process through the regulation on inflammation, proliferation, and remodeling of various skin cells, implying that TMSCs can be a promising alternative for wound repair. PMID- 29416006 TI - PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling. AB - Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDHhigh) can be quantified in a heterogeneous cell population. We confirmed high ALDH activity as surrogate marker for the CSC subpopulation in vitro and validated Wnt signaling as an essential factor for the maintenance of CSCs in SUM149 breast cancer cells. In a small molecule screen, we identified phosphodiesterase type 5 (PDE5) inhibition as potential strategy to target CSC maintenance and survival in multiple cancer cell lines. CSC elimination by PDE5 inhibition was not dependent on PKG signaling, and we suggest a novel mechanism in which PDE5 inhibition leads to elevated cGMP levels that stimulate cAMP/PKA signaling to eliminate CSCs. PMID- 29416007 TI - Genome-wide DNA methylation analysis reveals that mouse chemical iPSCs have closer epigenetic features to mESCs than OSKM-integrated iPSCs. AB - Induced pluripotent stem cells can be derived from somatic cells through ectopic expression of transcription factors or chemical cocktails. Chemical iPSCs (C iPSCs) and OSKM-iPSCs (4F-iPSCs) have been suggested to have similar characteristics to mouse embryonic stem cells (mESCs). However, their epigenetic equivalence remains incompletely understood throughout the genome. In this study, we have generated mouse C-iPSCs and 4F-iPSCs, and further compared the genome wide DNA methylomes of C-iPSCs, 4F-iPSCs, and mESCs that were maintained in 2i and LIF. Three pluripotent stem cells tend to be low methylated overall, however, DNA methylations in some specific regions (such as retrotransposons) are cell type-specific. Importantly, C-iPSCs are more hypomethylated than 4F-iPSCs. Bisulfite sequencing indicated that DNA methylation status in several known imprinted clusters, such as: Dlk1-Dio3 and Peg12-Ube3a, in C-iPSCs are closer to those of mESCs than 4F-iPSCs. Overall, our data demonstrate the reprogramming methods-dependent epigenetic differences of C-iPSCs and 4F-iPSCs and reveal that C-iPSCs are more hypomethylated than OSKM-integrated iPSCs. PMID- 29416008 TI - PHB2 interacts with LC3 and SQSTM1 is required for bile acids-induced mitophagy in cholestatic liver. AB - Mitophagy is a major pathway for clearance of injured mitochondria. However, whether mitophagy is involved in the cholestasis-induced damages of hepatic mitochondria remains unknown. We here aimed to investigate the molecular links between cholestasis and hepatic mitophagy. We show that mitophagy is increased significantly in livers of biliary atresia (BA) that is cholestatic disease in infants. The mitochondrial-toxicity bile acids treatment increases the activities of mitophagy in hepatocytes. Mechanistically, we find that the prohibitin 2 (PHB2) is crucial for cholestasis-mediated mitophagy in vitro. On the one hand, PHB2 binds the autophagosomal membrane-associated protein LC3 upon injured mitochondria via an LC3-interaction region domain. On the other hand, PHB2 forms a ternary protein complex with sequestosome 1 (SQSTM1) and LC3, leading to loading of LC3 onto the damaged mitochondria. Altogether, our study suggests that PHB2 is required for cholestasis-induced mitophagy via LC3 onto the injured mitochondria. PMID- 29416009 TI - Epigenetic inhibition of Wnt pathway suppresses osteogenic differentiation of BMSCs during osteoporosis. AB - Disrupted Wnt signaling in osteoblastic-lineage cells leads to bone formation defect in osteoporosis. However, the factors repressing Wnt signaling are unclear. In our study, we found that Wnt signaling was suppressed persistently in bone marrow-derived mesenchymal stem cells (BMSCs) during osteoporosis. Accordingly, histone acetylation levels on Wnt genes (Wnt1, Wnt6, Wnt10a, and Wnt10b) were declined in BMSCs from OVX mice. By screening the family of histone acetyltransferase, we identified that GCN5 expression increased during osteogenic differentiation of BMSCs, whereas decreased after osteoporosis. Further analysis revealed that GCN5 promoted osteogenic differentiation of BMSCs by increasing acetylation on histone 3 lysine 9 loci on the promoters of Wnt genes. Reduced GCN5 expression suppressed Wnt signaling, resulting in osteogenic defect of BMSCs from OVX mice. Moreover, restoring GCN5 levels recovered BMSC osteogenic differentiation, and attenuated bone loss in OVX mice. Taken together, our study demonstrated that disrupted histone acetylation modification in BMSCs lead to bone formation defect during osteoporosis. The findings also introduced a novel therapeutic target for osteoporosis. PMID- 29416010 TI - Role of c-Abl and nephrin in podocyte cytoskeletal remodeling induced by angiotensin II. AB - Our previous study showed that angiotensin II (Ang II) exposure diminished the interaction between nephrin and c-Abl, then c-Abl mediated SHIP2-Akt pathway in the process of podocyte injury in vivo and vitro. However, the relationship between nephrin and c-Abl was unknown. Recently, various studies showed that nephrin was required for cytoskeletal remodeling in glomerular podocytes. But its specific mechanisms remain incompletely understood. As a nonreceptor tyrosine kinase involved in cytoskeletal regulation, c-Abl may be a candidate of signaling proteins interacting with Src homology 2/3 (SH2/SH3) domains of nephrin. Therefore, it is proposed that c-Abl contributes to nephrin-dependent cytoskeletal remodeling of podocytes. Herein, we observed that nephrin-c-Abl colocalization were suppressed in glomeruli of patients with proteinuria. Next, CD16/7-nephrin and c-Abl vectors were constructed to investigate the nephrin-c Abl signaling pathway in podocyte actin-cytoskeletal remodeling. The disorganized cytoskeleton stimulated by cytochalasin D in COS7 cells was dramatically restored by co-transfection with phosphorylated CD16/7-nephrin and c-Abl full-length constructs. Further, co-immunoprecipitation showed that phosphorylated CD16/7 nephrin interacted with wild-type c-Abl, but not with SH2/SH3-defective c-Abl. These findings suggest that phosphorylated nephrin is able to recruit c-Abl in a SH2/SH3-dependent manner and detached c-Abl from dephosphorylated nephrin contributes to cytoskeletal remodeling in podocytes. PMID- 29416011 TI - Long noncoding RNA PANDAR blocks CDKN1A gene transcription by competitive interaction with p53 protein in gastric cancer. AB - Emerging evidence indicates that lncRNAs play important roles in cancer tumourigenesis and could be used as potential diagnostic biomarkers or therapeutic targets. However, the clinical significance and molecular mechanism of lncRNAs in gastric cancer (GC) is still unclear. The aim of this study was to explore the expression and role of lncRNAs in GC. The relative expression level of lncRNAs in GC samples was examined by an lncRNA microarray analysis, northern blot analysis and qRT-PCR analysis. A Kaplan-Meier survival analysis and univariate and multivariate Cox proportional hazards models were performed to evaluate the clinical and prognostic significance of PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) in GC patients. The binding activity of PANDAR with the p53 protein was analysed by an RNA immunoprecipitation analysis and RNA pull-down analysis. The depletion of PANDAR was conducted using the CRISPR/Cas9 system for PANDAR. The biological functions of PANDAR in GC cells were determined both in vitro and in vivo. Upregulated PANDAR in GC patients was positively correlated with increased tumour size, advanced TNM classification and a poor survival rate in GC patients. The ROC curves identified that the PANDAR level was a marker for discriminating the early-stage tumour group from the healthy group, the metastasis group from the non-metastasis group and the chemoresistance group from the chemosensitive group in GC patients. As a target, the CDKN1A gene was successfully downregulated by PANDAR. PANDAR controlled the transcription of the CDKN1A gene by competitively binding with p53 protein. In combination with a p53 activator (nutlin3), the knockout of PANDAR by CRISPR/Cas9 technology synergistically inhibited GC tumour growth in vivo. Our results suggest that the PANDAR is a powerful diagnostic and therapeutic marker for patients with GC and, combined with other chemotherapeutics, may have distinct antitumour effects. PMID- 29416012 TI - ROS-independent ER stress-mediated NRF2 activation promotes warburg effect to maintain stemness-associated properties of cancer-initiating cells. AB - Cancer-initiating cells (CICs) are responsible for tumor initiation, progression, and therapeutic resistance; moreover, redox homeostasis is important in regulating cancer stemness. Previously, we have identified that cancer cells containing low intracellular reactive oxygen species levels (ROSLow cells) display enhanced features of CICs. However, the specific metabolic signatures of CICs remain unclear and are required for further characterization by systemic screenings. Herein, we first showed CICs mainly relying on glycolysis that was important for the maintenance of stemness properties. Next, we revealed that NRF2, a master regulator of antioxidants, was able to maintain low intracellular ROS levels of CICs, even though in the absence of oxidative stress. We further characterized that NRF2 activation was required for the maintenance of CICs properties. Of ROSLow cells, NRF2 activation not only directly activates the transcription of genes encoding glycolytic enzymes but also inhibited the conversion of pyruvate to acetyl-CoA by directly activating pyruvate dehydrogenase kinase 1 (PDK1) to lead to inhibition of tricarboxylic acid (TCA) cycle; therefore, to promote Warburg effect. A positive regulatory ROS independent ER stress pathway (GRP78/p-PERK/NRF2 signaling) was identified to mediate the metabolic shift (Warburg effect) and stemness of CICs. Lastly, co expression of p-PERK and p-NRF2 was significantly associated with the clinical outcome. Our data show that NRF2 acting as a central node in the maintenance of low ROS levels and stemness associated properties of the CICs, which is significantly associated with the clinical outcome, but independent from ROS stress. Future treatments by inhibiting NRF2 activation may exhibit great potential in targeting CICs. PMID- 29416013 TI - miR-143-3p targeting of ITGA6 suppresses tumour growth and angiogenesis by downregulating PLGF expression via the PI3K/AKT pathway in gallbladder carcinoma. AB - Gallbladder cancer (GBC) is the most common malignant tumour of the biliary track system. Angiogenesis plays a pivotal role in the development and progression of malignant tumours. miR-143-3p acts as a tumour suppressor in various cancers. Their role in GBC is however less well defined. Here we show that the expression levels of miR-143-3p were decreased in human GBC tissues compared with the non tumour adjacent tissue (NAT) counterparts and were closely associated with overall survival. We discovered that miR-143-3p was a novel inhibitor of tumour growth and angiogenesis in vivo and in vitro. Our antibody array, ELISA and PLGF rescue analyses indicated that PLGF played an essential role in the antiangiogenic effect of miR-143-3p. Furthermore, we used miRNA target-prediction software and dual-luciferase assays to confirm that integrin alpha6 (ITGA6) acted as a direct target of miR-143-3p. Our ELISA and western blot analyses confirmed that the expression of PLGF was decreased via the ITGA6/PI3K/AKT pathway. In conclusion, miR-143-3p suppresses tumour angiogenesis and growth of GBC through the ITGA6/PI3K/AKT/PLGF pathways and may be a novel molecular therapeutic target for GBC. PMID- 29416014 TI - LncRNA NCK1-AS1 promotes proliferation and induces cell cycle progression by crosstalk NCK1-AS1/miR-6857/CDK1 pathway. AB - The purpose of this study was to develop an lncRNA signature to improve the prediction of the prognosis of cervical cancer through integration bioinformatics and analysis of TCGA RNA sequencing data. In this study, we established a set of four lncRNA signatures that was significantly associated with recurrence-free survival using the Cox regression model. Functionally, we screened the CC associated lncRNA NCK1-AS1 as a new candidate lncRNA and regulator which promotes development and progression in CC. qRT-PCR and RNA in situ hybridization (RISH) results showed that NCK1-AS1 was significantly up-regulated in 77.4% (24/31) of the CC tissue group compared with the normal group (P < 0.01). Interestingly, we demonstrated that transcription factor SP1 directly binds to the promoter to activate NCK1-AS1 expression in SiHa cells. In vitro and in vivo assays of silencing NCK1-AS1 significantly inhibited cell proliferation and invasion, with induction of cell arrest in S phase of the cell cycle. Furthermore, Human Transcriptome Array 2.0 analysis after NCK1-AS1 silencing highlighted alterations in cell proliferation and cell cycle pathways. NCK1-AS1 functioned as a molecular sponge for miR-6857, antagonizing its ability to repress CDK1/6 protein translation. In conclusion, these findings suggest that NCK1-AS1/miR-6857/CDK1 crosstalk serve as a critical effector in cervical cancer progression and may serve as a potential target in cervical cancer. PMID- 29416015 TI - Multiple molecular mechanisms form a positive feedback loop driving amyloid beta42 peptide-induced neurotoxicity via activation of the TRPM2 channel in hippocampal neurons. AB - Emerging evidence supports an important role for the ROS-sensitive TRPM2 channel in mediating age-related cognitive impairment in Alzheimer's disease (AD), particularly neurotoxicity resulting from generation of excessive neurotoxic Abeta peptides. Here we examined the elusive mechanisms by which Abeta42 activates the TRPM2 channel to induce neurotoxicity in mouse hippocampal neurons. Abeta42-induced neurotoxicity was ablated by genetic knockout (TRPM2-KO) and attenuated by inhibition of the TRPM2 channel activity or activation through PARP 1. Abeta42-induced neurotoxicity was also inhibited by treatment with TPEN used as a Zn2+-specific chelator. Cell imaging revealed that Abeta42-induced lysosomal dysfunction, cytosolic Zn2+ increase, mitochondrial Zn2+ accumulation, loss of mitochondrial function, and mitochondrial generation of ROS. These effects were suppressed by TRPM2-KO, inhibition of TRPM2 or PARP-1, or treatment with TPEN. Bafilomycin-induced lysosomal dysfunction also resulted in TRPM2-dependent cytosolic Zn2+ increase, mitochondrial Zn2+ accumulation, and mitochondrial generation of ROS, supporting that lysosomal dysfunction and accompanying Zn2+ release trigger mitochondrial Zn2+ accumulation and generation of ROS. Abeta42 induced effects on lysosomal and mitochondrial functions besides neurotoxicity were also suppressed by inhibition of PKC and NOX. Furthermore, Abeta42-induced neurotoxicity was prevented by inhibition of MEK/ERK. Therefore, our study reveals multiple molecular mechanisms, including PKC/NOX-mediated generation of ROS, activation of MEK/ERK and PARP-1, lysosomal dysfunction and Zn2+ release, mitochondrial Zn2+ accumulation, loss of mitochondrial function, and mitochondrial generation of ROS, are critically engaged in forming a positive feedback loop that drives Abeta42-induced activation of the TRPM2 channel and neurotoxicity in hippocampal neurons. These findings shed novel and mechanistic insights into AD pathogenesis. PMID- 29416016 TI - Pharmacological activation of autophagy favors the clearing of intracellular aggregates of misfolded prion protein peptide to prevent neuronal death. AB - According to the "gain-of-toxicity mechanism", neuronal loss during cerebral proteinopathies is caused by accumulation of aggregation-prone conformers of misfolded cellular proteins, although it is still debated which aggregation state actually corresponds to the neurotoxic entity. Autophagy, originally described as a variant of programmed cell death, is now emerging as a crucial mechanism for cell survival in response to a variety of cell stressors, including nutrient deprivation, damage of cytoplasmic organelles, or accumulation of misfolded proteins. Impairment of autophagic flux in neurons often associates with neurodegeneration during cerebral amyloidosis, suggesting a role in clearing neurons from aggregation-prone misfolded proteins. Thus, autophagy may represent a target for innovative therapies. In this work, we show that alterations of autophagy progression occur in neurons following in vitro exposure to the amyloidogenic and neurotoxic prion protein-derived peptide PrP90-231. We report that the increase of autophagic flux represents a strategy adopted by neurons to survive the intracellular accumulation of misfolded PrP90-231. In particular, PrP90-231 internalization in A1 murine mesencephalic neurons occurs in acidic structures, showing electron microscopy hallmarks of autophagosomes and autophagolysosomes. However, these structures do not undergo resolution and accumulate in cytosol, suggesting that, in the presence of PrP90-231, autophagy is activated but its progression is impaired; the inability to clear PrP90-231 via autophagy induces cytotoxicity, causing impairment of lysosomal integrity and cytosolic diffusion of hydrolytic enzymes. Conversely, the induction of autophagy by pharmacological blockade of mTOR kinase or trophic factor deprivation restored autophagy resolution, reducing intracellular PrP90-231 accumulation and neuronal death. Taken together, these data indicate that PrP90-231 internalization induces an autophagic defensive response in A1 neurons, although incomplete and insufficient to grant survival; the pharmacological enhancement of this process exerts neuroprotection favoring the clearing of the internalized peptide and could represents a promising neuroprotective tool for neurodegenerative proteinopathies. PMID- 29416017 TI - Fasudil increases temozolomide sensitivity and suppresses temozolomide-resistant glioma growth via inhibiting ROCK2/ABCG2. AB - Resistance to temozolomide (TMZ) is a major clinical challenge in glioma treatment, but the mechanisms of TMZ resistance are poorly understood. Here, we provided evidence that ROCK2 acted redundantly to maintain resistance of TMZ in TMZ-resistant gliomas, and as a ROCK2 phosphorylation inhibitor, fasudil significantly suppressed proliferation of TMZ-resistant gliomas in vivo and vitro via enhancing the chemosensitivity of TMZ. Additionally, the membrane translocation of ABCG2 was decreased with fasudil by ROCK2/moesin pathway. We also showed that fasudil suppressed the expression of ABCG2 via ROCK2/moesin/beta catenin pathway. Our results reveal an indispensable role for ROCK2 and provide strong evidence for the therapeutic use of fasudil in the clinical setting for TMZ-resistant gliomas. PMID- 29416018 TI - The binding landscape of a partially-selective isopeptidase inhibitor with potent pro-death activity, based on the bis(arylidene)cyclohexanone scaffold. AB - Diaryldienone derivatives with accessible beta-carbons show strong anti neoplastic properties, related to their ability to make covalent adducts with free thiols by Michael addition, and low toxicity in vivo. Accumulation of poly ubiquitylated proteins, activation of the unfolded protein response (UPR) and induction of cell death are universal hallmarks of their activities. These compounds have been characterized as inhibitors of isopeptidases, a family of cysteine-proteases, which de-conjugate ubiquitin and ubiquitin-like proteins from their targets. However, it is unclear whether they can also react with additional proteins. In this work, we utilized the biotin-conjugated diaryldienone derivative named 2c, as a bait to purify novel cellular targets of these small molecules. Proteomic analyses have unveiled that, in addition to isopeptidases, these inhibitors can form stable covalent adducts with different intracellular proteins, thus potentially impacting on multiple functions of the cells, from cytoskeletal organization to metabolism. These widespread activities can explain the ability of diaryldienone derivatives to efficiently trigger different cell death pathways. PMID- 29416019 TI - Walking and rolling of crystals induced thermally by phase transition. AB - The mechanical motion of materials has been increasingly explored in terms of bending and expansion/contraction. However, the locomotion of materials has been limited. Here, we report walking and rolling locomotion of chiral azobenzene crystals, induced thermally by a reversible single-crystal-to-single-crystal phase transition. Long plate-like crystals with thickness gradient in the longitudinal direction walk slowly, like an inchworm, by repeated bending and straightening under heating and cooling cycles near the transition temperature. Furthermore, thinner, longer plate-like crystals with width gradient roll much faster by tilted bending and then flipping under only one process of heating or cooling. The length of the crystal is shortened above the transition temperature, which induces bending due to the temperature gradient to the thickness direction. The bending motion is necessarily converted to the walking and rolling locomotion due to the unsymmetrical shape of the crystal. This finding of the crystal locomotion can lead to a field of crystal robotics. PMID- 29416020 TI - Bone morphogenetic protein 2 promotes human trophoblast cell invasion by upregulating N-cadherin via non-canonical SMAD2/3 signaling. AB - BMP2 expression is spatiotemporally correlated with embryo implantation and is crucial for endometrial decidualization and fertility in mice. BMP2 has been reported to increase the mesenchymal adhesion molecule N-cadherin and enhance cell invasion in cancer cells; moreover, studies suggest that N-cadherin promotes placental trophoblast invasion. However, whether BMP2 can promote trophoblast cell invasion during placentation remains unknown. The objective of our study was to investigate the effects of BMP2 on human trophoblast cell invasion and the involvement of N-cadherin and SMAD signaling. Primary and immortalized (HTR8/SVneo) cultures of human extravillous trophoblast (EVT) cells were used as study models. Treatment with recombinant human BMP2 increased HTR8/SVneo cell transwell Matrigel invasion as well as N-cadherin mRNA and protein levels, but had no significant effect on cell proliferation. Likewise, BMP2 treatment enhanced primary human EVT cell invasion and N-cadherin production. Basal and BMP2-induced invasion were attenuated by small interfering RNA-mediated downregulation of N-cadherin in both HTR8/SVneo and primary EVT cells. Intriguingly, BMP2 induced the phosphorylation/activation of both canonical SMAD1/5/8 and non-canonical SMAD2/3 signaling in HTR8/SVneo and primary EVT cells. Knockdown of SMAD2/3 or common SMAD4 totally abolished the effects of BMP2 on N-cadherin upregulation in HTR8/SVneo cells. Upregulation of SMAD2/3 phosphorylation and N-cadherin were totally abolished by type I receptor activin receptor-like kinases 2/3 (ALK2/3) inhibitor DMH1; moreover, knockdown of ALK2 or ALK3 inhibited N-cadherin upregulation. Interestingly, activation of SMAD2/3 and upregulation of N-cadherin were partially attenuated by ALK4/5/7 inhibitor SB431542 or knockdown of ALK4, but not ALK5. Our results show that BMP2 promotes trophoblast cell invasion by upregulating N-cadherin via non-canonical ALK2/3/4 SMAD2/3-SMAD4 signaling. PMID- 29416021 TI - Visualizing heavy fermion confinement and Pauli-limited superconductivity in layered CeCoIn5. AB - Layered material structures play a key role in enhancing electron-electron interactions to create correlated metallic phases that can transform into unconventional superconducting states. The quasi-two-dimensional electronic properties of such compounds are often inferred indirectly through examination of bulk properties. Here we use scanning tunneling microscopy to directly probe in cross-section the quasi-two-dimensional electronic states of the heavy fermion superconductor CeCoIn5. Our measurements reveal the strong confined nature of quasiparticles, anisotropy of tunneling characteristics, and layer-by-layer modulated behavior of the precursor pseudogap gap phase. In the interlayer coupled superconducting state, the orientation of line defects relative to the d wave order parameter determines whether in-gap states form due to scattering. Spectroscopic imaging of the anisotropic magnetic vortex cores directly characterizes the short interlayer superconducting coherence length and shows an electronic phase separation near the upper critical in-plane magnetic field, consistent with a Pauli-limited first-order phase transition into a pseudogap phase. PMID- 29416022 TI - Correspondence: Reply to 'Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury'. PMID- 29416024 TI - Publisher Correction: Polymorphic design of DNA origami structures through mechanical control of modular components. AB - The originally published version of this Article contained an error in Figure 5. In panel f, the right y-axis 'Strain energy (kbT)' was labelled 'Probability' and the left y-axis 'Probability' was labelled 'Strain energy (kbT)'. This error has now been corrected in both the PDF and HTML versions of the Article. PMID- 29416023 TI - A supramolecular lanthanide separation approach based on multivalent cooperative enhancement of metal ion selectivity. AB - Multivalent cooperativity plays an important role in the supramolecular self assembly process. Herein, we report a remarkable cooperative enhancement of both structural integrity and metal ion selectivity on metal-organic M4L4 tetrahedral cages self-assembled from a tris-tridentate ligand (L1) with a variety of metal ions spanning across the periodic table, including alkaline earth (CaII), transition (CdII), and all the lanthanide (LnIII) metal ions. All these M4L14 cages are stable to excess metal ions and ligands, which is in sharp contrast with the tridentate (L2) ligand and bis-tridentate (L3) ligand bearing the same coordination motif as L1. Moreover, high-precision metal ion self-sorting is observed during the mixed-metal self-assembly of tetrahedral M4L4 cages, but not on the M2L3 counterparts. Based on the strong cooperative metal ion self recognition behavior of M4L4 cages, a supramolecular approach to lanthanide separation is demonstrated, offering a new design principle of next-generation extractants for highly efficient lanthanide separation. PMID- 29416025 TI - Publisher Correction: Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer. AB - The original version of this Article contained an error in the spelling of the author Yingjie Yu, which was incorrectly given as Yu Yingjie. Furthermore, in Figure 3a, the labels 'MD | p < 0.05' incorrectly read 'MD | p > 0.05'. These errors have now been corrected in both the PDF and HTML versions of the Article. PMID- 29416026 TI - Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner. AB - Reversible post-translational modifications represent a mechanism to control tumor metabolism. Here we show that mitochondrial Sirtuin5 (SIRT5), which mediates lysine desuccinylation, deglutarylation, and demalonylation, plays a role in colorectal cancer (CRC) glutamine metabolic rewiring. Metabolic profiling identifies that deletion of SIRT5 causes a marked decrease in 13C-glutamine incorporation into tricarboxylic-acid (TCA) cycle intermediates and glutamine derived non-essential amino acids. This reduces the building blocks required for rapid growth. Mechanistically, the direct interaction between SIRT5 and glutamate dehydrogenase 1 (GLUD1) causes deglutarylation and functional activation of GLUD1, a critical regulator of cellular glutaminolysis. Consistently, GLUD1 knockdown diminishes SIRT5-induced proliferation, both in vivo and in vitro. Clinically, overexpression of SIRT5 is significantly correlated with poor prognosis in CRC. Thus, SIRT5 supports the anaplerotic entry of glutamine into the TCA cycle in malignant phenotypes of CRC via activating GLUD1. PMID- 29416027 TI - Correspondence: Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury. PMID- 29416028 TI - Inhibition of overactive TGF-beta attenuates progression of heterotopic ossification in mice. AB - Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury. The exact pathogenesis of HO remains unknown. Here we show that TGF-beta initiates and promotes HO in mice. We find that calcified cartilage and newly formed bone resorb osteoclasts after onset of HO, which leads to high levels of active TGF beta that recruit mesenchymal stromal/progenitor cells (MSPCs) in the HO microenvironment. Transgenic expression of active TGF-beta in tendon induces spontaneous HO, whereas systemic injection of a TGF-beta neutralizing antibody attenuates ectopic bone formation in traumatic and BMP-induced mouse HO models, and in a fibrodysplasia ossificans progressive mouse model. Moreover, inducible knockout of the TGF-beta type II receptor in MSPCs inhibits HO progression in HO mouse models. Our study points toward elevated levels of active TGF-beta as inducers and promoters of ectopic bone formation, and suggest that TGF-beta might be a therapeutic target in HO. PMID- 29416029 TI - Neuroglobin boosts axon regeneration during ischemic reperfusion via p38 binding and activation depending on oxygen signal. AB - Cerebral ischemia causes severe cell death or injury including axon breakdown or retraction in the brain. Axon regeneration is crucial for the functional recovery of injured neurons or brains after ischemia/reperfusion (I/R); however, this process has been proved extremely difficult in adult brains and there is still no effective therapy for it. Here we reported that neuroglobin (Ngb), a novel oxygen binding or sensor protein existing predominantly in neurons or brains, functions as a driving factor for axon regeneration during I/R. Ngb was upregulated and accumulated in growth cones of ischemic neurons in primary cultures, rat, and human brains, correlating positively to the elevation of axon-regeneration markers GAP43, neurofilament-200, and Tau-1. Ngb overexpression promoted while Ngb knockdown suppressed axon regeneration as well as GAP43 expression in neurons during oxygen-glucose deprivation/reoxygenation (OGD/Re). By using specific pharmacological inhibitors, we identified p38 MAPK as the major downstream player of Ngb-induced axon regeneration during OGD/Re. Mechanistically, Ngb directly bound to and activated p38 in neurons upon OGD/Re. Serial truncation and point mutation of Ngb revealed that the 7-105 aa fragment of Ngb was required and the oxygen-binding site (His64) of Ngb was the major regulatory site for its p38 interaction/activation. Finally, administration of exogenous TAT-Ngb peptides significantly enhanced axon regeneration in cultured neurons upon OGD/Re. Taken together, Ngb promotes axon regeneration via O2-Ngb-p38-GAP43 signaling during I/R. This novel mechanism suggests potential therapeutic applications of Ngb for ischemic stroke and other related axonopathy. PMID- 29416030 TI - Crosstalk in concurrent repeated games impedes direct reciprocity and requires stronger levels of forgiveness. AB - Direct reciprocity is a mechanism for cooperation among humans. Many of our daily interactions are repeated. We interact repeatedly with our family, friends, colleagues, members of the local and even global community. In the theory of repeated games, it is a tacit assumption that the various games that a person plays simultaneously have no effect on each other. Here we introduce a general framework that allows us to analyze "crosstalk" between a player's concurrent games. In the presence of crosstalk, the action a person experiences in one game can alter the person's decision in another. We find that crosstalk impedes the maintenance of cooperation and requires stronger levels of forgiveness. The magnitude of the effect depends on the population structure. In more densely connected social groups, crosstalk has a stronger effect. A harsh retaliator, such as Tit-for-Tat, is unable to counteract crosstalk. The crosstalk framework provides a unified interpretation of direct and upstream reciprocity in the context of repeated games. PMID- 29416031 TI - Cdk9 regulates a promoter-proximal checkpoint to modulate RNA polymerase II elongation rate in fission yeast. AB - Post-translational modifications of the transcription elongation complex provide mechanisms to fine-tune gene expression, yet their specific impacts on RNA polymerase II regulation remain difficult to ascertain. Here, in Schizosaccharomyces pombe, we examine the role of Cdk9, and related Mcs6/Cdk7 and Lsk1/Cdk12 kinases, on transcription at base-pair resolution with Precision Run On sequencing (PRO-seq). Within a minute of Cdk9 inhibition, phosphorylation of Pol II-associated factor, Spt5 is undetectable. The effects of Cdk9 inhibition are more severe than inhibition of Cdk7 and Cdk12, resulting in a shift of Pol II toward the transcription start site (TSS). A time course of Cdk9 inhibition reveals that early transcribing Pol II can escape promoter-proximal regions, but with a severely reduced elongation rate of only ~400 bp/min. Our results in fission yeast suggest the existence of a conserved global regulatory checkpoint that requires Cdk9 kinase activity. PMID- 29416032 TI - High contiguity Arabidopsis thaliana genome assembly with a single nanopore flow cell. AB - The handheld Oxford Nanopore MinION sequencer generates ultra-long reads with minimal cost and time requirements, which makes sequencing genomes at the bench feasible. Here, we sequence the gold standard Arabidopsis thaliana genome (KBS Mac-74 accession) on the bench with the MinION sequencer, and assemble the genome using typical consumer computing hardware (4 Cores, 16 Gb RAM) into chromosome arms (62 contigs with an N50 length of 12.3 Mb). We validate the contiguity and quality of the assembly with two independent single-molecule technologies, Bionano optical genome maps and Pacific Biosciences Sequel sequencing. The new A. thaliana KBS-Mac-74 genome enables resolution of a quantitative trait locus that had previously been recalcitrant to a Sanger-based BAC sequencing approach. In summary, we demonstrate that even when the purpose is to understand complex structural variation at a single region of the genome, complete genome assembly is becoming the simplest way to achieve this goal. PMID- 29416033 TI - Supramolecular aptamer nano-constructs for receptor-mediated targeting and light triggered release of chemotherapeutics into cancer cells. AB - Platforms for targeted drug-delivery must simultaneously exhibit serum stability, efficient directed cell internalization, and triggered drug release. Here, using lipid-mediated self-assembly of aptamers, we combine multiple structural motifs into a single nanoconstruct that targets hepatocyte growth factor receptor (cMet). The nanocarrier consists of lipidated versions of a cMet-binding aptamer and a separate lipidated GC-rich DNA hairpin motif loaded with intercalated doxorubicin. Multiple 2',6'-dimethylazobenzene moieties are incorporated into the doxorubicin-binding motif to trigger the release of the chemotherapeutics by photoisomerization. The lipidated DNA scaffolds self-assemble into spherical hybrid-nanoconstructs that specifically bind cMet. The combined features of the nanocarriers increase serum nuclease resistance, favor their import into cells presumably mediated by endocytosis, and allow selective photo-release of the chemotherapeutic into the targeted cells. cMet-expressing H1838 tumor cells specifically internalize drug-loaded nanoconstructs, and subsequent UV exposure enhances cell mortality. This modular approach thus paves the way for novel classes of powerful aptamer-based therapeutics. PMID- 29416034 TI - Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis. AB - Cigarette smoking is a major risk factor for atherosclerosis and other cardiovascular diseases. Increasing evidence has demonstrated that nicotine impairs the cardiovascular system by targeting vascular endothelial cells, but the underlying mechanisms remain obscure. It is known that cell death and inflammation are crucial processes leading to atherosclerosis. We proposed that pyroptosis may be implicated in nicotine-induced atherosclerosis and therefore conducted the present study. We found that nicotine resulted in larger atherosclerotic plaques and secretion of inflammatory cytokines in ApoE-/- mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with nicotine resulted in NLRP3-ASC inflammasome activation and pyroptosis, as evidenced by cleavage of caspase-1, production of downstream interleukin (IL)-1beta and IL-18, and elevation of LDH activity and increase of propidium iodide (PI) positive cells, which were all inhibited by caspase-1 inhibitor. Moreover, silencing NLRP3 or ASC by small interfering RNA efficiently suppressed nicotine-induced caspase-1 cleavage, IL-18 and IL-1beta production, and pyroptosis in HAECs. Further experiments revealed that the nicotine-NLRP3-ASC pyroptosis pathway was activated by reactive oxygen species (ROS), since ROS scavenger (N-acetyl-cysteine, NAC) prevented endothelial cell pyroptosis. We conclude that pyroptosis is likely a cellular mechanism for the pro atherosclerotic property of nicotine and stimulation of ROS to activate NLRP3 inflammasome is a signaling mechanism for nicotine-induced pyroptosis. PMID- 29416035 TI - The meniscus-guided deposition of semiconducting polymers. AB - The electronic devices that play a vital role in our daily life are primarily based on silicon and are thus rigid, opaque, and relatively heavy. However, new electronics relying on polymer semiconductors are opening up new application spaces like stretchable and self-healing sensors and devices, and these can facilitate the integration of such devices into our homes, our clothing, and even our bodies. While there has been tremendous interest in such technologies, the widespread adoption of these organic electronics requires low-cost manufacturing techniques. Fortunately, the realization of organic electronics can take inspiration from a technology developed since the beginning of the Common Era: printing. This review addresses the critical issues and considerations in the printing methods for organic electronics, outlines the fundamental fluid mechanics, polymer physics, and deposition parameters involved in the fabrication process, and provides future research directions for the next generation of printed polymer electronics. PMID- 29416036 TI - A transcriptomic atlas of aged human microglia. AB - With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia-the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer's disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEepsilon2 haplotype. APOEepsilon4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging. PMID- 29416037 TI - Design of ultra-swollen lipidic mesophases for the crystallization of membrane proteins with large extracellular domains. AB - In meso crystallization of membrane proteins from lipidic mesophases is central to protein structural biology but limited to membrane proteins with small extracellular domains (ECDs), comparable to the water channels (3-5 nm) of the mesophase. Here we present a strategy expanding the scope of in meso crystallization to membrane proteins with very large ECDs. We combine monoacylglycerols and phospholipids to design thermodynamically stable ultra swollen bicontinuous cubic phases of double-gyroid (Ia3d), double-diamond (Pn3m), and double-primitive (Im3m) space groups, with water channels five times larger than traditional lipidic mesophases, and showing re-entrant behavior upon increasing hydration, of sequences Ia3d->Pn3m->Ia3d and Pn3m->Im3m->Pn3m, unknown in lipid self-assembly. We use these mesophases to crystallize membrane proteins with ECDs inaccessible to conventional in meso crystallization, demonstrating the methodology on the Gloeobacter ligand-gated ion channel (GLIC) protein, and show substantial modulation of packing, molecular contacts and activation state of the ensued proteins crystals, illuminating a general strategy in protein structural biology. PMID- 29416039 TI - bFGF plays a neuroprotective role by suppressing excessive autophagy and apoptosis after transient global cerebral ischemia in rats. AB - Transient global cerebral ischemia (tGCI) is a cerebrovascular disorder that can cause apoptotic neuronal damage and functional deficits. Basic fibroblast growth factor (bFGF) was reported to be highly expressed in the central nervous system (CNS) and to exert neuroprotective effects against different CNS diseases. However, the effects of bFGF on tGCI have not been studied intensively. This study was conducted to investigate the effect of bFGF and its underlying mechanism in an animal model of tGCI. After intracerebroventricular (i.c.v.) injection of bFGF, functional improvement was observed, and the number of viable neurons increased in the ischemia-vulnerable hippocampal CA1 region. Apoptosis was induced after tGCI and could be attenuated by bFGF treatment via inhibition of p53 mitochondrial translocation. In addition, autophagy was activated during this process, and bFGF could inhibit activation of autophagy through the mTOR pathway. Rapamycin, an activator of autophagy, was utilized to explore the relationship among bFGF, apoptosis, and autophagy. Apoptosis deteriorated after rapamycin treatment, which indicated that excessive autophagy could contribute to the apoptosis process. In conclusion, these results demonstrate that bFGF could exert neuroprotective effects in the hippocampal CA1 region by suppressing excessive autophagy via the mTOR pathway and inhibiting apoptosis by preventing p53 mitochondrial translocation. Furthermore, our results suggest that bFGF may be a promising therapeutic agent to for treating tGCI in response to major adverse events, including cardiac arrest, shock, extracorporeal circulation, traumatic hemorrhage, and asphyxiation. PMID- 29416038 TI - Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair. AB - The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution of DNA damage but the mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha and Dicer, control the recruitment of repair factors from multiple pathways to sites of damage. Depletion of Drosha significantly reduces DNA repair by both homologous recombination (HR) and non homologous end joining (NHEJ). Drosha is required within minutes of break induction, suggesting a central and early role for RNA processing in DNA repair. Sequencing of DNA:RNA hybrids reveals RNA invasion around DNA break sites in a Drosha-dependent manner. Removal of the RNA component of these structures results in impaired repair. These results show how RNA can be a direct and critical mediator of DNA damage repair in human cells. PMID- 29416040 TI - BRE/BRCC45 regulates CDC25A stability by recruiting USP7 in response to DNA damage. AB - BRCA2 is essential for maintaining genomic integrity. BRCA2-deficient primary cells are either not viable or exhibit severe proliferation defects. Yet, BRCA2 deficiency contributes to tumorigenesis. It is believed that mutations in genes such as TRP53 allow BRCA2 heterozygous cells to overcome growth arrest when they undergo loss of heterozygosity. Here, we report the use of an insertional mutagenesis screen to identify a role for BRE (Brain and Reproductive organ Expressed, also known as BRCC45), known to be a part of the BRCA1-DNA damage sensing complex, in the survival of BRCA2-deficient mouse ES cells. Cell viability by BRE overexpression is mediated by deregulation of CDC25A phosphatase, a key cell cycle regulator and an oncogene. We show that BRE facilitates deubiquitylation of CDC25A by recruiting ubiquitin-specific processing protease 7 (USP7) in the presence of DNA damage. Additionally, we uncovered the role of CDC25A in BRCA-mediated tumorigenesis, which can have implications in cancer treatment. PMID- 29416041 TI - Structural basis for amino acid transport by the CAT family of SLC7 transporters. AB - Amino acids play essential roles in cell biology as regulators of metabolic pathways. Arginine in particular is a major signalling molecule inside the cell, being a precursor for both l-ornithine and nitric oxide (NO) synthesis and a key regulator of the mTORC1 pathway. In mammals, cellular arginine availability is determined by members of the solute carrier (SLC) 7 family of cationic amino acid transporters. Whereas CAT-1 functions to supply cationic amino acids for cellular metabolism, CAT-2A and -2B are required for macrophage activation and play important roles in regulating inflammation. Here, we present the crystal structure of a close homologue of the mammalian CAT transporters that reveals how these proteins specifically recognise arginine. Our structural and functional data provide a model for cationic amino acid transport in mammalian cells and reveals mechanistic insights into proton-coupled, sodium-independent amino acid transport in the wider APC superfamily. PMID- 29416042 TI - Stratification of TAD boundaries reveals preferential insulation of super enhancers by strong boundaries. AB - The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score. We demonstrate that higher TAD boundary insulation scores are associated with elevated CTCF levels and that they may differ across cell types. Intriguingly, we observe that super-enhancers are preferentially insulated by strong boundaries. Furthermore, we demonstrate that strong TAD boundaries and super-enhancer elements are frequently co-duplicated in cancer patients. Taken together, our findings suggest that super-enhancers insulated by strong TAD boundaries may be exploited, as a functional unit, by cancer cells to promote oncogenesis. PMID- 29416043 TI - Effects of Echo Time on IVIM Quantification of the Normal Prostate. AB - The two-compartment intravoxel incoherent motion (IVIM) theory assumes that the transverse relaxation time is the same in both compartments. However, blood and tissue have different T2 values, and echo time (TE) may thus have an effect on the quantitative parameters of IVIM. The purpose of this study was to investigate the effects of TE on IVIM-DWI-derived parameters of the prostate. In total, 17 healthy volunteers underwent two repeat examinations. IVIM-DWI data were scanned 6 times with variable TE values of 60, 70, 80, 90, 100, and 120 ms. The ADC of a mono-exponential model and the D, D*, and f parameters of the IVIM model were calculated separately for each TE. Repeat measures were assessed by calculating the coefficient of variation and Bland-Altman limits of agreement for each parameter. Spearman's rho test was used to analyse relationships between IVIM indices and TE. Our results showed that TE had an effect on IVIM quantification, which should be kept constant in the examination protocol at each individual institution. Alternatively, an extended IVIM could be used to eliminate the effect of the TE value on the quantitative parameters of IVIM. This may be helpful for guiding clinical research, especially for longitudinal studies. PMID- 29416044 TI - A small molecule inhibitor of Rheb selectively targets mTORC1 signaling. AB - The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling. NR1 potently inhibits mTORC1 driven phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) but does not inhibit phosphorylation of AKT or ERK. In contrast to rapamycin, NR1 does not cause inhibition of mTORC2 upon prolonged treatment. Furthermore, NR1 potently and selectively inhibits mTORC1 in mouse kidney and muscle in vivo. The data presented herein suggest that pharmacological inhibition of Rheb is an effective approach for selective inhibition of mTORC1 with therapeutic potential. PMID- 29416045 TI - alpha-cell glucokinase suppresses glucose-regulated glucagon secretion. AB - Glucagon secretion by pancreatic alpha-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes. Here, we show that alpha-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with alpha-cell-specific inactivation of Gck (alphaGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of KATP channels in alpha-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. alphaGckKO mice display hyperglucagonemia in the fed state, which is associated with increased hepatic gluconeogenic gene expression and hepatic glucose output capacity. In adult mice, fed hyperglucagonemia is further increased and glucose intolerance develops. Thus, glucokinase governs an alpha-cell metabolic pathway that suppresses secretion at or above normoglycemic levels; abnormal suppression of glucagon secretion deregulates hepatic glucose metabolism and, over time, induces a pre-diabetic phenotype. PMID- 29416047 TI - Low-dose x-ray tomography through a deep convolutional neural network. AB - Synchrotron-based X-ray tomography offers the potential for rapid large-scale reconstructions of the interiors of materials and biological tissue at fine resolution. However, for radiation sensitive samples, there remain fundamental trade-offs between damaging samples during longer acquisition times and reducing signals with shorter acquisition times. We present a deep convolutional neural network (CNN) method that increases the acquired X-ray tomographic signal by at least a factor of 10 during low-dose fast acquisition by improving the quality of recorded projections. Short-exposure-time projections enhanced with CNNs show signal-to-noise ratios similar to long-exposure-time projections. They also show lower noise and more structural information than low-dose short-exposure acquisitions post-processed by other techniques. We evaluated this approach using simulated samples and further validated it with experimental data from radiation sensitive mouse brains acquired in a tomographic setting with transmission X-ray microscopy. We demonstrate that automated algorithms can reliably trace brain structures in low-dose datasets enhanced with CNN. This method can be applied to other tomographic or scanning based X-ray imaging techniques and has great potential for studying faster dynamics in specimens. PMID- 29416046 TI - Ginkgolic acid, a sumoylation inhibitor, promotes adipocyte commitment but suppresses adipocyte terminal differentiation of mouse bone marrow stromal cells. AB - Sumoylation is a post-translational modification process having an important influence in mesenchymal stem cell (MSC) differentiation. Thus, sumoylation modulating chemicals might be used to control MSC differentiation for skeletal tissue engineering. In this work, we studied how the differentiation of mouse bone marrow stromal cells (mBMSCs) is affected by ginkgolic acid (GA), a potent sumoylation inhibitor also reported to inhibit histone acetylation transferase (HAT). Our results show that GA promoted the differentiation of mBMSCs into adipocytes when cultured in osteogenic medium. Moreover, mBMSCs pre-treated with GA showed enhanced pre-adipogenic gene expression and were more efficiently differentiated into adipocytes when subsequently cultured in the adipogenic medium. However, when GA was added at a later stage of adipogenesis, adipocyte maturation was markedly inhibited, with a dramatic down-regulation of multiple lipogenesis genes. Moreover, we found that the effects of garcinol, a HAT inhibitor, differed from those of GA in regulating adipocyte commitment and adipocyte maturation of mBMSCs, implying that the GA function in adipogenesis is likely through its activity as a sumoylation inhibitor, not as a HAT inhibitor. Overall, our studies revealed an unprecedented role of GA in MSC differentiation and provide new mechanistic insights into the use of GA in clinical applications. PMID- 29416048 TI - Publisher Correction: Nanoplasmonic electron acceleration by attosecond controlled forward rescattering in silver clusters. AB - The original PDF version of this Article contained an error in Equation 1. The original HTML version of this Article contained errors in Equation 2 and Equation 4. These errors have now been corrected in both the PDF and the HTML versions of the Article. PMID- 29416049 TI - Protective effect of Group B Streptococcus type-III polysaccharide conjugates against maternal colonization, ascending infection and neonatal transmission in rodent models. AB - Group B Streptococcus (GBS) is a normal inhabitant of recto-vaginal mucosae in up to 30% of healthy women. Colonization is a major risk factor for perinatal infection which can lead to severe complications such as stillbirth and neonatal invasive disease. Intra-partum antibiotic prophylaxis in colonized women is a safe and cost-effective preventive measure against early-onset disease in the first days of life, but has no effect on late-onset manifestations or on early maternal infection. Maternal immunization with capsular polysaccharide-based vaccines shows promise for the prevention of both early-onset and late-onset neonatal infections, although ability to prevent maternal colonization and ascending infection has been less studied. Here we investigated the effect of a GBS glycoconjugate vaccine since the very early stage of maternal GBS acquisition to neonatal outcome by rodent models of vaginal colonization and ascending infection. Immunization of female mice and rats with a type III glycoconjugate reduced vaginal colonization, infection of chorioamniotic/ placental membranes and bacterial transmission to fetuses and pups. Type III specific antibodies were detected in the blood and vagina of vaccinated mothers and their offspring. The obtained data support a potential preventive effect of GBS glycoconjugate vaccines during the different stages of pregnancy. PMID- 29416050 TI - Akt regulates neurite growth by phosphorylation-dependent inhibition of radixin proteasomal degradation. AB - Neurite growth is controlled by a complex molecular signaling network that regulates filamentous actin (F-actin) dynamics at the growth cone. The evolutionarily conserved ezrin, radixin, and moesin family of proteins tether F actin to the cell membrane when phosphorylated at a conserved threonine residue and modulate neurite outgrowth. Here we show that Akt binds to and phosphorylates a threonine 573 residue on radixin. Akt-mediated phosphorylation protects radixin from ubiquitin-dependent proteasomal degradation, thereby enhancing radixin protein stability, which permits proper neurite outgrowth and growth cone formation. Conversely, the inhibition of Akt kinase or disruption of Akt dependent phosphorylation reduces the binding affinity of radixin to F-actin as well as lowers radixin protein levels, resulting in decreased neurite outgrowth and growth cone formation. Our findings suggest that Akt signaling regulates neurite outgrowth by stabilizing radixin interactions with F-actin, thus facilitating local F-actin dynamics. PMID- 29416051 TI - A novel gene of Kalanchoe daigremontiana confers plant drought resistance. AB - Kalanchoe (K.) daigremontiana is important for studying asexual reproduction under different environmental conditions. Here, we describe a novel KdNOVEL41 (KdN41) gene that may confer drought resistance and could thereby affect K. daigremontiana development. The detected subcellular localization of a KdN41/Yellow Fluorescent Protein (YFP) fusion protein was in the nucleus and cell membrane. Drought, salt, and heat stress treatment in tobacco plants containing the KdN41 gene promoter driving beta-glucuronidase (GUS) gene transcription revealed that only drought stress triggered strong GUS staining in the vascular tissues. Overexpression (OE) of the KdN41 gene conferred improved drought resistance in tobacco plants compared to wild-type and transformed with empty vector plants by inducing higher antioxidant enzyme activities, decreasing cell membrane damage, increasing abscisic acid (ABA) content, causing reinforced drought resistance related gene expression profiles. The 3,3'-diaminobenzidine (DAB) and nitroblue tetrazolium (NBT) staining results also showed less relative oxygen species (ROS) content in KdN41-overexpressing tobacco leaf during drought stress. Surprisingly, by re-watering after drought stress, KdN41-overexpressing tobacco showed earlier flowering. Overall, the KdN41 gene plays roles in ROS scavenging and osmotic damage reduction to improve tobacco drought resistance, which may increase our understanding of the molecular network involved in developmental manipulation under drought stress in K. daigremontiana. PMID- 29416052 TI - Cross-Scale Molecular Analysis of Chemical Heterogeneity in Shale Rocks. AB - The organic and mineralogical heterogeneity in shale at micrometer and nanometer spatial scales contributes to the quality of gas reserves, gas flow mechanisms and gas production. Here, we demonstrate two molecular imaging approaches based on infrared spectroscopy to obtain mineral and kerogen information at these mesoscale spatial resolutions in large-sized shale rock samples. The first method is a modified microscopic attenuated total reflectance measurement that utilizes a large germanium hemisphere combined with a focal plane array detector to rapidly capture chemical images of shale rock surfaces spanning hundreds of micrometers with micrometer spatial resolution. The second method, synchrotron infrared nano-spectroscopy, utilizes a metallic atomic force microscope tip to obtain chemical images of micrometer dimensions but with nanometer spatial resolution. This chemically "deconvoluted" imaging at the nano-pore scale is then used to build a machine learning model to generate a molecular distribution map across scales with a spatial span of 1000 times, which enables high-throughput geochemical characterization in greater details across the nano-pore and micro grain scales and allows us to identify co-localization of mineral phases with chemically distinct organics and even with gas phase sorbents. This characterization is fundamental to understand mineral and organic compositions affecting the behavior of shales. PMID- 29416053 TI - Development of a mouse IgA monoclonal antibody-based enzyme-linked immunosorbent sandwich assay for the analyses of RBP4. AB - Elevated circulating Retinol-binding protein 4 (RBP4) has been associated with insulin resistance, dyslipidemia, and hypertension. However, many commonly used RBP4 ELISAs have limited dynamic range. We therefore developed an enzyme-linked immunosorbent sandwich assay (ELISA) employing a novel immunoglobulin A (IgA) type capture mAb called AG102 instead of IgG subtypes, which was selected for its stability, capture efficiency, and specificity for human RBP 4. These features of RBP4 have hampered the development of quantitative immunological assays. Molecular analysis of AG102 revealed IgA heavy and light chains and a J chain, as expected. AG102 demonstrated notable detection of both bacterial- and HEK293 expressed RBP4 in Western blots. Serial and internal deletion experiments suggested that a putative epitope may be located in the first 35 amino acids of the mature RBP4. Compared with commercial ELISAs, the AG102-based system exhibited more significant recovery of RBP4 from serum or urine at any given dilution factor. To substantiate its quantitation capacity, comparison between RBP4 measurements from quantitative western blots and the AG102-based ELISA demonstrated a significant correlation (R2 = 0.859). After measurement for those analytes, our data suggested that IgA-based ELISA could be adapted for quantitative measurement of those analytes existing as major serum proteins or as multi-protein complexes like RBP4. PMID- 29416054 TI - Evaluation of PD-L1 expression on vortex-isolated circulating tumor cells in metastatic lung cancer. AB - Metastatic non-small cell lung cancer (NSCLC) is a highly fatal and immunogenic malignancy. Although the immune system is known to recognize these tumor cells, one mechanism by which NSCLC can evade the immune system is via overexpression of programmed cell death ligand 1 (PD-L1). Recent clinical trials of PD-1 and PD-L1 inhibitors have returned promising clinical responses. Important for personalizing therapy, patients with higher intensity staining for PD-L1 on tumor biopsies responded better. Thus, there has been interest in using PD-L1 tumor expression as a criterion for patient selection. Currently available methods of screening involve invasive tumor biopsy, followed by histological grading of PD L1 levels. Biopsies have a high risk of complications, and only allow sampling from limited tumor sections, which may not reflect overall tumor heterogeneity. Circulating tumor cell (CTC) PD-L1 levels could aid in screening patients, and could supplement tissue PD-L1 biopsy results by testing PD-L1 expression from disseminated tumor sites. Towards establishing CTCs as a screening tool, we developed a protocol to isolate CTCs at high purity and immunostain for PD-L1. Monitoring of PD-L1 expression on CTCs could be an additional biomarker for precision medicine that may help in determining response to immunotherapies. PMID- 29416055 TI - Threshold-induced correlations in the Random Field Ising Model. AB - We present a numerical study of the correlations in the occurrence times of consecutive crackling noise events in the nonequilibrium zero-temperature Random Field Ising model in three dimensions. The critical behavior of the system is portrayed by the intermittent bursts of activity known as avalanches with scale invariant properties which are power-law distributed. Our findings, based on the scaling analysis and collapse of data collected in extensive simulations show that the observed correlations emerge upon applying a finite threshold to the pertaining signals when defining events of interest. Such events are called subavalanches and are obtained by separation of original avalanches in the thresholding process. The correlations are evidenced by power law distributed waiting times and are present in the system even when the original avalanche triggerings are described by a random uncorrelated process. PMID- 29416056 TI - Socio-ecological dynamics of Caribbean coral reef ecosystems and conservation opinion propagation. AB - The Caribbean coral reef ecosystem has experienced a long history of deterioration due to various stressors. For instance, over-fishing of parrotfish an important grazer of macroalgae that can prevent destructive overgrowth of macroalgae - has threatened reef ecosystems in recent decades and stimulated conservation efforts such as the formation of marine protected areas. Here we develop a mathematical model of coupled socio-ecological interactions between reef dynamics and conservation opinion dynamics to better understand how natural and human factors interact individually and in combination to determine coral reef cover. We find that the coupling opinion and reef systems generates complex dynamics that are difficult to anticipate without use of a model. For instance, instead of converging to a stable state of constant coral cover and conservationist opinion, the system can oscillate between low and high live coral cover as human opinion oscillates in a boom-bust cycle between complacency and concern. Out of various possible parameter manipulations, we also find that raising awareness of coral reef endangerment best avoids counter-productive nonlinear feedbacks and always increases and stabilizes live coral reef cover. In conclusion, an improved understanding of coupled opinion-reef dynamics under anthrogenic stressors is possible using coupled socio-ecological models, and such models should be further researched. PMID- 29416057 TI - Visuospatial asymmetries do not modulate the cheerleader effect. AB - The cheerleader effect occurs when the same individual appears to be more attractive when seen in a group, compared to alone. As observers over-attend to visual information presented in the left visual field, we investigated whether the spatial arrangement of the faces in a group would influence the magnitude of the cheerleader effect. In Experiment 1, target faces were presented twice in the centre of the display: once alone, and once in a group. Group images featured two distractor faces, which were presented in either the left or the right visual field, or on either side of the target. The location of the distractor faces did not modulate the size of the cheerleader effect, which was observed in each group configuration. In Experiment 2, we manipulated the location of the target faces, which were presented at the far left, far right, or centre of the group. Faces were again significantly more attractive in each group configuration, and the spatial location of the target face did not influence the size of the cheerleader effect. Together, our results show that the cheerleader effect is a robust phenomenon, which is not influenced by the spatial arrangement of the faces in the group. PMID- 29416058 TI - Divergent roles for antigenic drive in the aetiology of primary versus dasatinib associated CD8+ TCR-Vbeta+ expansions. AB - CD8+ T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and also occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects. However, the mechanisms that underlie the genesis and maintenance of expanded CD8+ T-cell receptor (TCR)-Vbeta+ populations in these patient groups have yet to be fully defined. In this study, we performed a comprehensive phenotypic and clonotypic assessment of expanded (TCR-Vbeta+) and residual (TCR Vbeta-) CD8+ T-cell populations in T-LGLL and dasatinib-treated chronic myelogenous leukemia (CML) patients. The dominant CD8+ TCR-Vbeta+ expansions in T LGLL patients were largely monoclonal and highly differentiated, whereas the dominant CD8+ TCR-Vbeta+ expansions in dasatinib-treated CML patients were oligoclonal or polyclonal, and displayed a broad range of memory phenotypes. These contrasting features suggest divergent roles for antigenic drive in the immunopathogenesis of primary versus dasatinib-associated CD8+ TCR-Vbeta+ expansions. PMID- 29416059 TI - Layer-specific lipid signatures in the human subventricular zone demonstrated by imaging mass spectrometry. AB - The subventricular zone is a key site of adult neurogenesis and is also implicated in neurodegenerative diseases and brain cancers. In the subventricular zone, cell proliferation, migration and differentiation of nascent stem cells and neuroblasts are regulated at least in part by lipids. The human subventricular zone is distinctly layered and each layer contains discrete cell types that support the processes of neuroblast migration and neurogenesis. We set out to determine the lipid signatures of each subventricular layer in the adult human brain (n = 4). We utilised matrix-assisted laser desorption/ionisation (MALDI) imaging mass spectrometry and liquid chromatography-mass spectrometry to characterise the lipidome of the subventricular zone, with histology and microscopy used for identifying anatomical landmarks. Our findings showed that the subventricular zone was rich in sphingomyelins and phosphatidylserines but deficient in phosphatidylethanolamines. The ependymal layer had an abundance of phosphatidylinositols, whereas the myelin layer was rich in sulfatides and triglycerides. The hypocellular layer showed enrichment of sphingomyelins. No discrete lipid signature was seen in the astrocytic ribbon. The biochemical functions of these lipid classes are consistent with the localisation we observed within the SVZ. Our study may, therefore, shed new light on the role of lipids in the regulation of adult neurogenesis. PMID- 29416060 TI - Repeated Measures of Blood and Breath Ammonia in Response to Control, Moderate and High Protein Dose in Healthy Men. AB - Ammonia physiology is important to numerous disease states including urea cycle disorders and hepatic encephalopathy. However, many unknowns persist regarding the ammonia response to common and potentially significant physiologic influences, such as food. Our aim was to evaluate the dynamic range of ammonia in response to an oral protein challenge in healthy participants. We measured blood and breath ammonia at baseline and every hour for 5.5 hours. Healthy men (N = 22, aged 18 to 24 years) consumed a 60 g protein shake (high dose); a subset of 10 consumed a 30 g protein shake (moderate dose) and 12 consumed an electrolyte drink containing 0 g protein (control). Change in blood ammonia over time varied by dose (p = 0.001). Difference in blood ammonia was significant for control versus high (p = 0.0004) and moderate versus high (p = 0.03). Change in breath ammonia over time varied by dose (p < 0.0001). Difference in breath ammonia was significant for control versus moderate (p = 0.03) and control versus high (p = 0.0003). Changes in blood and breath ammonia were detectable by fast, minimally invasive (blood) or non-invasive (breath) point-of-care ammonia measurement methods. These pilot data may contribute to understanding normal ammonia metabolism. Novel measurement methods may aid research into genetic and metabolic ammonia disorders. PMID- 29416061 TI - The lymphocyte-to-monocyte ratio is a superior predictor of overall survival compared to established biomarkers in HCC patients undergoing liver resection. AB - The aim of this study was to investigate the prognostic value of the lymphocyte to-monocyte ratio (LMR) in patients undergoing hepatectomy and to compare it to established biomarkers including the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Medical records were retrospectively analyzed for 652 HCC patients undergoing hepatectomy at the Affiliated Tumor Hospital of Guangxi Medical University and the First People's Hospital of Changde between April 2004 to April 2012. The correlation between the LMR and clinical variables were analyzed in Kaplan-Meier log-rank survival analysis and then multivariate Cox regression models trying to find relation with disease-free survival (DFS) and overall survival (OS). The area under the ROC curve (AUC) of the LMR(AUC:0.627) for predicting long-term survival was greater than that of the NLR(AUC:0.600) and the PLR(AUC:0.520).Multivariate analysis showed LMR to be an independent risk factor for OS (P = 0.002), and the NLR and PLR were not independently significant. Subgroup analysis also showed that LMR was significantly associated with poor DFS and OS in patients positive for HBsAg or with cirrhosis (both P < 0.001).Elevated preoperative LMR is an independently associated with poor OS and DFS in HCC patients following curative resection and appears to be superior to NLR and PLR. PMID- 29416062 TI - Compressive sensing for spatial and spectral flame diagnostics. AB - Combustion research requires the use of state of the art diagnostic tools, including high energy lasers and gated, cooled CCDs. However, these tools may present a cost barrier for laboratories with limited resources. While the cost of high energy lasers and low-noise cameras continues to decline, new imaging technologies are being developed to address both cost and complexity. In this paper, we analyze the use of compressive sensing for flame diagnostics by reconstructing Raman images and calculating mole fractions as a function of radial depth for a highly strained, N2-H2 diffusion flame. We find good agreement with previous results, and discuss the benefits and drawbacks of this technique. PMID- 29416064 TI - Mud Banks along the southwest coast of India are not too muddy for plankton. AB - Considering Alappuzha Mud Bank in the southern Kerala coast as a typical case of biologically productive Mud Banks that form along the southwest coast of India during the Southwest Monsoon (June - September), the present study addresses several pertinent missing links between the physical environment in Mud Banks and their influence on plankton stock. This study showed that very strong coastal upwelling prevails in the entire study domain during the Southwest Monsoon, which manifests itself in the form of significantly cool, hypoxic and nitrate-rich waters surfacing near the coast. The upwelled water persisting throughout the Southwest Monsoon period was found to have fuelled the exceptionally high phytoplankton stock in the entire study area, including the Mud Bank region. Having accepted that Mud Banks are special because of the calm sea surface conditions and relatively high turbidity level in the water column around them, the present study showed that except at points close to the sea bottom, turbidity level in the Alappuzha Mud Bank was below the critical level to inhibit the plankton stock. The suspended sediments that form in the Mud Bank occasionally could be attributed to the disturbance of the bottom fluid muddy layer and their vertical spurts. PMID- 29416063 TI - AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle. AB - Phosphatidylcholines (PC) and S-adenosylmethionine (SAM) are critical determinants of hepatic lipid levels, but how their levels are regulated is unclear. Here, we show that Pemt and Gnmt, key one-carbon cycle genes regulating PC/SAM levels, are downregulated after feeding, leading to decreased PC and increased SAM levels, but these effects are blunted in small heterodimer partner (SHP)-null or FGF15-null mice. Further, aryl hydrocarbon receptor (AhR) is translocated into the nucleus by insulin/PKB signaling in the early fed state and induces Pemt and Gnmt expression. This induction is blocked by FGF15 signaling activated SHP in the late fed state. Adenoviral-mediated expression of AhR in obese mice increases PC levels and exacerbates steatosis, effects that are blunted by SHP co-expression or Pemt downregulation. PEMT, AHR, and PC levels are elevated in simple steatosis patients, but PC levels are robustly reduced in steatohepatitis-fibrosis patients. This study identifies AhR and SHP as new physiological regulators of PC/SAM levels. PMID- 29416065 TI - Judging the position of the artificial hand induces a "visual" drift towards the real one during the rubber hand illusion. AB - When subjects look at a rubber hand being brush-stroked synchronously with their own hidden hand, they might feel a sense of ownership over the rubber hand. The perceived mislocalization of the own hand towards the rubber hand (proprioceptive drift) would reflect an implicit marker of this illusion occurring through the dominance of vision over proprioception. This account, however, contrasts with principles of multisensory integration whereby percepts result from a "statistical sum" of different sensory afferents. In this case, the most-known proprioceptive drift should be mirrored by complementary visual drift of the rubber hand in the opposite direction. We investigated this issue by designing two experiments in which subjects were not only requested to localize their own hand but also the rubber hand and further explored the subjective feeling of the illusion. In both experiments, we demonstrated a (visual) drift in the opposite direction of the proprioceptive drift, suggesting that both hands converge toward each other. This might suggest that the spatial representations of the two hands are integrated in a common percept placed in between them, contradicting previous accounts of substitution of the real hand by the rubber hand. PMID- 29416067 TI - Voluntary locomotor activity promotes myogenic growth potential in domestic pigs. AB - Self-determined physical activity is an essential behavioural need and can vary considerably between individuals of a given species. Although locomotion is suggested as a prerequisite for adequate function of skeletal muscle, domestic pigs are usually reared under limited space allowance. The aim of our study was to investigate if a different voluntary locomotor activity leads to altered properties in the muscle structure, biochemistry and mRNA expression of selected genes involved in myogenesis and skeletal muscle metabolism. Based on a video tracking method, we assigned pigs to three categories according to their total distances walked over five observed time points: long distance, medium distance, and short distance. The microstructure and biochemistry parameters of the M. semitendinosus were unaffected by the distance categories. However, we found distance-dependent differences in the mRNA expression of the genes encoding growth (IGF2, EGF, MSTN) and transcription factors (MRF4, MYOD). In particular, the IGF2/MSTN ratio appears to be a sensitive indicator, at the molecular level, for the locomotor activity of individuals. Our results indicate that the myogenic growth potential of pigs under standard rearing conditions is triggered by their displayed voluntary locomotor activity, but the covered distances are insufficient to induce adaptive changes at the tissue level. PMID- 29416066 TI - Differentially expressed host long intergenic noncoding RNA and mRNA in HIV-1 and HIV-2 infection. AB - Non-coding RNAs and mRNAs have been implicated in replication, pathogenesis and host response in HIV infection. However, the impact of long intergenic non-coding RNAs (lincRNAs) on HIV-1 and HIV-2 infection is not known. In this study, we have analyzed expression profiles of lincRNAs and mRNAs in monocyte derived macrophages (MDMs) infected with HIV-1/HIV-2 using microarrays. Our study identified many differentially expressed lincRNAs and mRNAs in MDMs infected with HIV-1/HIV-2 compared to uninfected MDMs. Genes involved in glutathione metabolism and lysine degradation were differentially regulated only in HIV-1 infected MDMs. In HIV-2 infected MDMs, CUL 2, SFRS9, and RBBP4 genes were differentially expressed. Furthermore, we found that plasma levels of lincRNA: chr2: 165509129 165519404 and lincRNA: chr12: 57761837-57762303 were better indicators of HIV-1 infection while lincRNA: chr10:128586385-128592960, XLOC_001148 and lincRNA: chr5:87580664-87583451, were better indicators of HIV-2 infection. In summary, our study has demonstrated that there is substantial alteration in lincRNA and mRNA expression in response to HIV-1/HIV-2 infection. These differentially expressed lincRNAs and mRNAs could serve as prognostic and diagnostic biomarkers of HIV infection and help in the identification of new targets for therapy. PMID- 29416068 TI - Internal noise sources limiting contrast sensitivity. AB - Contrast sensitivity varies substantially as a function of spatial frequency and luminance intensity. The variation as a function of luminance intensity is well known and characterized by three laws that can be attributed to the impact of three internal noise sources: early spontaneous neural activity limiting contrast sensitivity at low luminance intensities (i.e. early noise responsible for the linear law), probabilistic photon absorption at intermediate luminance intensities (i.e. photon noise responsible for de Vries-Rose law) and late spontaneous neural activity at high luminance intensities (i.e. late noise responsible for Weber's law). The aim of this study was to characterize how the impact of these three internal noise sources vary with spatial frequency and determine which one is limiting contrast sensitivity as a function of luminance intensity and spatial frequency. To estimate the impact of the different internal noise sources, the current study used an external noise paradigm to factorize contrast sensitivity into equivalent input noise and calculation efficiency over a wide range of luminance intensities and spatial frequencies. The impact of early and late noise was found to drop linearly with spatial frequency, whereas the impact of photon noise rose with spatial frequency due to ocular factors. PMID- 29416070 TI - Optical scheme for generating hyperentanglement having photonic qubit and time bin via quantum dot and cross-Kerr nonlinearity. AB - We design an optical scheme to generate hyperentanglement correlated with degrees of freedom (DOFs) via quantum dots (QDs), weak cross-Kerr nonlinearities (XKNLs), and linearly optical apparatuses (including time-bin encoders). For generating hyperentanglement having its own correlations for two DOFs (polarization and time bin) on two photons, we employ the effects of optical nonlinearities using a QD (photon-electron), a parity gate (XKNLs), and time-bin encodings (linear optics). In our scheme, the first nonlinear multi-qubit gate utilizes the interactions between photons and an electron of QD confined in a single-sided cavity, and the parity gate (second gate) uses weak XKNLs, quantum bus, and photon-number resolving measurement to entangle the polarizations of two photons. Finally, for efficiency in generating hyperentanglement and for the experimental implementation of this scheme, we discuss how the QD-cavity system can be performed reliably, and also discuss analysis of the immunity of the parity gate (XKNLs) against the decoherence effect. PMID- 29416069 TI - Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations. AB - Ataxia with oculomotor apraxia 2 (AOA-2) and amyotrophic lateral sclerosis (ALS4) are neurological disorders caused by mutations in the gene encoding for senataxin (SETX), a putative RNA:DNA helicase involved in transcription and in the maintenance of genome integrity. Here, using ChIP followed by high throughput sequencing (ChIP-seq), we report that senataxin is recruited at DNA double-strand breaks (DSBs) when they occur in transcriptionally active loci. Genome-wide mapping unveiled that RNA:DNA hybrids accumulate on DSB-flanking chromatin but display a narrow, DSB-induced, depletion near DNA ends coinciding with senataxin binding. Although neither required for resection nor for timely repair of DSBs, senataxin was found to promote Rad51 recruitment, to minimize illegitimate rejoining of distant DNA ends and to sustain cell viability following DSB production in active genes. Our data suggest that senataxin functions at DSBs in order to limit translocations and ensure cell viability, providing new insights on AOA2/ALS4 neuropathies. PMID- 29416071 TI - Surface ocean metabarcoding confirms limited diversity in planktonic foraminifera but reveals unknown hyper-abundant lineages. AB - Since the advent of DNA metabarcoding surveys, the planktonic realm is considered a treasure trove of diversity, inhabited by a small number of abundant taxa, and a hugely diverse and taxonomically uncharacterized consortium of rare species. Here we assess if the apparent underestimation of plankton diversity applies universally. We target planktonic foraminifera, a group of protists whose known morphological diversity is limited, taxonomically resolved and linked to ribosomal DNA barcodes. We generated a pyrosequencing dataset of ~100,000 partial 18S rRNA foraminiferal sequences from 32 size fractioned photic-zone plankton samples collected at 8 stations in the Indian and Atlantic Oceans during the Tara Oceans expedition (2009-2012). We identified 69 genetic types belonging to 41 morphotaxa in our metabarcoding dataset. The diversity saturated at local and regional scale as well as in the three size fractions and the two depths sampled indicating that the diversity of foraminifera is modest and finite. The large majority of the newly discovered lineages occur in the small size fraction, neglected by classical taxonomy. These unknown lineages dominate the bulk [>0.8 um] size fraction, implying that a considerable part of the planktonic foraminifera community biomass has its origin in unknown lineages. PMID- 29416072 TI - Adverse drug events in Chinese pediatric inpatients and associated risk factors: a retrospective review using the Global Trigger Tool. AB - Understanding the epidemiology and risk factors of adverse drug events (ADEs) in pediatric inpatient is essential if we are to prevent, reduce or ameliorate the harm experienced. The Global Trigger Tool (GTT) is a method of retrospective medical record review that measures harm in hospitalized children. We employed a three-stage retrospective chart review of random samples of 1800 pediatric inpatients discharged from January 2013 to December 2015. 31 kinds of pediatric specific triggers were made based on the previous trigger tool studies developed for use in adult or pediatric. Positive predictive value (PPV) of individual triggers, as well as ADEs detection rates were calculated. Stepwise logistic regression was performed to investigate risk factors associated with ADEs. Of 1746 patients, detected in 221 patients (12.7%) with 247 ADEs. The PPV of the trigger tool was 13.3%. Of the 247 ADEs, 82.6% were identified as category E, 11.7% category F and 5.7% category H. The pediatric-focused trigger tool is a feasible and useful tool for detecting pediatric ADEs. Especially for patients who have had more drugs, more doses or more admissions which needs to be closely monitored as triggers to improve the safety. PMID- 29416073 TI - Diagnostic Accuracy of Three-dimensional Turbo Field Echo Magnetic Resonance Imaging Sequence in Pediatric Tracheobronchial Anomalies with Congenital Heart Disease. AB - Tracheobronchial anomalies are common in congenital heart disease (CHD), including tracheobronchial stenosis, tracheal bronchus, cardiac bronchus, and bronchial isomerism, which can cause varying degrees of respiratory illness. It is necessary to assess tracheobronchial anomalies and make a preoperative airway evaluation. Multi-slice computed tomography (MSCT) and cardiac magnetic resonance imaging (MRI) are the most effective noninvasive modalities for the diagnosis of CHD and the associated tracheobronchial anomalies. However, MSCT remains an ionizing procedure despite using low dose protocols. The aim of this study was to evaluate diagnostic accuracy of tracheobronchial anomalies in patients with CHD using three-dimensional turbo field echo(3D-TFE) magnetic resonance imaging sequence for preoperative airway evaluation. The results indicated that 3D-TFE provided better image quality as compared to that of 3D-balanced turbo field echo (3D-bTFE), and it can clearly demonstrated the tracheobronchial tree and tracheobronchial anomalies in CHD. This study confirms the clinical value of 3D TFE in diagnosing tracheobronchial anomalies and supply helpful tracheobronchial information for preoperative strategies and postoperative follow-up. PMID- 29416074 TI - Molecular detection of field predation among larvae of two ladybird beetles is partially predicted from laboratory experiments. AB - Despite the fact that natural enemies can synergistically contribute to herbivore pest suppression, sometimes predators engage in intraguild predation (IGP) that might dampen trophic cascades. DNA-based gut-content analysis has become common in assessing trophic connections and biocontrol potential by predators in field systems. Here, we developed a molecular technique that can be used to unravel predation among two ladybirds, Coccinella septempunctata and Hippodamia variegata, and their shared prey, Aphis gossypii. Both ladybirds may provide effective control of the pest. Therefore, understanding their likelihood to engage in IGP is crucial for conservation biological control. Ladybird specimens were collected in melon crop. DNA extraction, primer design and evaluation were conducted. Detectability of prey DNA did not differ significantly between the two ladybirds. H. variegata exhibited higher predation on A. gossypii than C. septempunctata (90.6% vs. 70.9%) and data correction based on DNA detectability confirmed this ranking. IGP was similar among the two species, although corrected data might suggest a stronger predation by C. septempunctata. Intriguingly, IGP by C. septempunctata was lower than predicted by laboratory bioassays, possibly due to the high complexity that arises under field conditions. Implications of our results for biological control and perspectives for ecological network analysis are discussed. PMID- 29416075 TI - Efficient non-cytotoxic fluorescent staining of halophiles. AB - Research on halophilic microorganisms is important due to their relation to fundamental questions of survival of living organisms in a hostile environment. Here we introduce a novel method to stain halophiles with MitoTracker fluorescent dyes in their growth medium. The method is based on membrane-potential sensitive dyes, which were originally used to label mitochondria in eukaryotic cells. We demonstrate that these fluorescent dyes provide high staining efficiency and are beneficial for multi-staining purposes due to the spectral range covered (from orange to deep red). In contrast with other fluorescent dyes used so far, MitoTracker does not affect growth rate, and remains in cells after several washing steps and several generations in cell culture. The suggested dyes were tested on three archaeal (Hbt. salinarum, Haloferax sp., Halorubrum sp.) and two bacterial (Salicola sp., Halomonas sp.) strains of halophilic microorganisms. The new staining approach provides new insights into biology of Hbt. salinarum. We demonstrated the interconversion of rod-shaped cells of Hbt. salinarium to spheroplasts and submicron-sized spheres, as well as the cytoplasmic integrity of giant rod Hbt. salinarum species. By expanding the variety of tools available for halophile detection, MitoTracker dyes overcome long-standing limitations in fluorescence microscopy studies of halophiles. PMID- 29416076 TI - Mixing it up in the ocean carbon cycle and the removal of refractory dissolved organic carbon. AB - A large quantity of reduced carbon is sequestered in the ocean as refractory dissolved molecules that persist through several circuits of global overturning circulation. Key aspects of the cycling of refractory dissolved organic carbon (DOC) remain unknown, making it challenging to predict how this large carbon reservoir will respond to climate change. Herein we investigate mechanisms that remove refractory DOC using bioassay experiments with DOC isolated from surface, mesopelagic and deep waters of the Atlantic Ocean. The isolated DOC was refractory to degradation by native microbial communities, even at elevated concentrations. However, when the refractory DOC was introduced to a series of novel environmental conditions, including addition of a labile substrate, a microbial community from coastal waters and exposure to solar radiation, a substantial fraction (7-13%) was removed within 1.5 years. Our results suggest that while refractory molecules can persist in the ocean for millennia, removal is rapid when they encounter their fate. The observed and projected climate induced slowdown of global overturning circulation could reduce the exposure of refractory molecules to disparate removal processes. Assuming a constant rate of production, the reservoir size of refractory DOC could increase as overturning circulation slows, providing a negative feedback to rising atmospheric CO2. PMID- 29416077 TI - Prefrontal cortex modulates the correlations between brain-derived neurotrophic factor level, serotonin, and the autonomic nervous system. AB - Top-down regulation in the human brain and anatomical connections between the prefrontal cortex (PFC) and specific catecholamine-related regions have been well studied. However, the way in which the PFC modulates downstream neuro-networks in terms of serotonin and the autonomic nervous system (ANS) by variation in the level of brain-derived neurotrophic factor (BDNF) is still unclear. We recruited sixty-seven healthy subjects. Serotonin transporter (SERT) availability was examined by SPECT with [123I]ADAM analysis; heart rate variability (HRV) testing was performed, and the BDNF level was measured. The Wisconsin card-sorting test (WCST), which assesses PFC activation, was also conducted. The interactions of BDNF level and SERT availability were significant in relation to the HRV indexes of low frequency, high frequency, total power, and mean heart rate range. Moderate to significant positive correlations between SERT availability and the above-mentioned HRV indexes existed only in subjects with a low BDNF level. Furthermore, in the low BDNF level group, only those with high WCST perseveration errors or low category completions exhibited significant positive correlations between SERT availability and HRV indexes. A lower BDNF level and poorer PFC function might modulate the synergistic effects of serotonergic and ANS systems in order to maintain brain physiological and psychological homeostasis. PMID- 29416078 TI - Support vector machines for explaining physiological stress response in Wood mice (Apodemus sylvaticus). AB - Physiological stress response is a crucial adaptive mechanism for prey species survival. This paper aims to identify the main environmental and/or individual factors better explaining the stress response in Wood mice, Apodemus sylvaticus. We analyzed alterations in fecal glucocorticoid metabolite (FCM) concentration - extensively used as an accurate measure of the physiological stress response - of wild mice fecal samples seasonally collected during three years. Then, support vector machines were built to predict said concentration according to different stressors. These statistical tools appear to be particularly suitable for small datasets with substantial number of dimensions, corroborating that the stress response is an extremely complex process in which multiple factors can simultaneously partake in a context-dependent manner, i.e., the role of each potential stressor varies in time depending on other stressors. However, air humidity, temperature and body-weight allowed us to explain the FCM fluctuation in 98% of our samples. The relevance of air-humidity and temperature altering FCM level could be linked to the presence of an abundant vegetation cover and, therefore, to food availability and predation risk perception. Body-weight might be related to the stress produced by reproduction and other intraspecific relationships such as social dominance or territorial behavior. PMID- 29416079 TI - Sahel rainfall strength and onset improvements due to more realistic Atlantic cold tongue development in a climate model. AB - The simulation of Sahel rainfall and its onset during the West African Monsoon (WAM) remains a challenge for current state-of-the-art climate models due to their persistent biases, especially in the tropical Atlantic region. Here we show that improved representation of Atlantic Cold Tongue (ACT) development is essential for a more realistic seasonal evolution of the WAM, which is due to a further inland migration of the precipitation maximum. The observed marked relationship between ACT development and Sahel rainfall onset only can be reproduced by a climate model, the Kiel Climate Model (KCM), when sufficiently high resolution in its atmospheric component is employed, enabling enhanced equatorial Atlantic interannual sea surface temperature variability in the ACT region relative to versions with coarser atmospheric resolution. The ACT/Sahel rainfall relationship in the model critically depends on the correct seasonal phase-locking of the interannual variability rather than on its magnitude. We compare the KCM results with those obtained from climate models participating in the Coupled Model Intercomparison Project phase 5 (CMIP5). PMID- 29416080 TI - A compact silicon grating coupler based on hollow tapered spot-size converter. AB - A new compact silicon grating coupler enabling fibre-to-chip light coupling at a minimized taper length is proposed. The proposed coupler, which incorporates a hollow tapered waveguide, converts the spot-size of optical modes from micro- to nano-scales by reducing the lateral dimension from 15 um to 300 nm at a length equals to 60 um. The incorporation of such a coupler in photonic integrated circuit causes a physical footprint as small as 81 um * 15 um with coupling efficiency and 3-dB coupling bandwidth as high as 72% and 69 nm respectively. PMID- 29416081 TI - The yield difference between wild-type cotton and transgenic cotton that expresses IPT depends on when water-deficit stress is applied. AB - Drought is the No. 1 factor that limits agricultural production in the world, thus, making crops more drought tolerant is a major goal in agriculture. Many genes with functions in abiotic stress tolerance were identified, and overexpression of these genes confers increased drought tolerance in transgenic plants. The isopentenyltransferase gene (IPT) that encodes a rate limiting enzyme in cytokinin biosynthesis is one of them. Interestingly, when IPT-transgenic cotton was field-tested at two different sites, Texas and Arizona, different results were obtained. To explain this phenomenon, reduced irrigation experiments with different timing in applying water deficit stress were conducted. It was found that the timing of water deficit stress is critical for IPT-transgenic cotton to display its yield advantage over control plants (i.e. wild-type and segregated non-transgenic plants). If water deficit stress occurs before flowering (vegetative phase), IPT-transgenic cotton would outperform control plants; however, if water deficit stress occurs at or after flowering (reproductive phase), there would not be a yield difference between IPT transgenic and control cotton plants. This result suggests that an early induction of IPT expression (before first flowering) is needed in order to realize the benefits of IPT-expression in transgenic plants that face water deficit stress later in development. PMID- 29416082 TI - Pyrazines from bacteria and ants: convergent chemistry within an ecological niche. AB - Ants use pheromones to coordinate their communal activity. Volatile pyrazines, for instance, mediate food resource gathering and alarm behaviors in different ant species. Here we report that leaf-cutter ant-associated bacteria produce a family of pyrazines that includes members previously identified as ant trail and alarm pheromones. We found that L-threonine induces the bacterial production of the trail pheromone pyrazines, which are common for the host leaf-cutter ants. Isotope feeding experiments revealed that L-threonine along with sodium acetate were the biosynthetic precursors of these natural products and a biosynthetic pathway was proposed. PMID- 29416083 TI - SJP-L-5 inhibits HIV-1 polypurine tract primed plus-strand DNA elongation, indicating viral DNA synthesis initiation at multiple sites under drug pressure. AB - In a previous study the small molecule SJP-L-5 that inhibits HIV replication, has been shown to block uncoating of the viral capsid. Continued study showed that SJP-L-5 might hinder HIV capsid uncoating by blocking the completion of reverse transcription. However, to date, the mechanism has not been fully elucidated. Here, the effects of SJP-L-5 for reverse transcription were explored via quantitative PCR, DIG-labelled ELISA, fluorescent resonance energy transfer, and Southern blot assays. We also analyzed the resistance profile of this compound against reverse transcriptase. Our results show that SJP-L-5 preferentially inhibits PPT primed plus-strand DNA synthesis (EC50 = 13.4 +/- 3.0 MUM) over RNA primed minus-strand DNA synthesis (EC50 > 3,646 MUM), resulting in formation of five segmented plus-strand DNA and loss of HIV DNA flap, suggesting failure of both nuclear import and integration. Moreover, resistance study evidenced that SJP-L-5 requires the amino acid residues Val108 and Tyr181 to exert an inhibitory effect. These results indicate SJP-L-5 as a new non-nucleoside reverse transcriptase inhibitor that inhibits HIV-1 polypurine tract primed plus-strand DNA synthesis, initiating HIV-1 down-stream plus-strand DNA synthesis at multiple sites under drug pressure. PMID- 29416084 TI - Nuclear FAK and its kinase activity regulate VEGFR2 transcription in angiogenesis of adult mice. AB - Focal adhesion kinase (FAK) is essential in embryonic angiogenesis by regulating endothelial cell (EC) survival and barrier functions through its kinase independent and -dependent activities. Here, we generated EC-specific tamoxifen inducible FAK knockout and FAK kinase-defective (KD) mutant knockin mice to investigate the role of FAK and its kinase activity in angiogenesis of adult animals. Unlike previous observations of their differential defects in embryonic vascular development, both FAK ablation and inactivation of its kinase activity resulted in deficient angiogenesis in wound-healing as well as retinal angiogenesis models. Consistent with these phenotypes, loss of FAK or its kinase activity decreased EC proliferation and migration to similar extents, suggesting FAK primarily acts as a kinase for the regulation of adult EC-mediated angiogenesis. Further mechanistic analyses were carried out using an established mouse EC line MS1 cells. Interestingly, we found that FAK regulated the expression of VEGFR2, a central mediator of various EC functions and angiogenesis, which requires both FAK kinase activity and its translocation into the nucleus. Moreover, nuclear FAK was detected in the RNA polymerase II complex associated with VEGFR2 promoter, suggesting its direct participation in the transcriptional regulation of VEGFR2. Together, our results provide significant insights into the signaling mechanisms of FAK in angiogenesis that may contribute to future design of more effective angiogenesis related therapy. PMID- 29416085 TI - Molecular dynamic simulations reveal structural insights into substrate and inhibitor binding modes and functionality of Ecto-Nucleoside Triphosphate Diphosphohydrolases. AB - Ecto-nucleotidase enzymes catalyze the hydrolysis of extracellular nucleotides to their respective nucleosides. Herein, we place the focus on the elucidation of structural features of the cell surface located ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDase1-3 and 8). The physiological role of these isozymes is crucially important as they control purinergic signaling by modulating the extracellular availability of nucleotides. Since, crystal or NMR structure of the human isozymes are not available - structures have been obtained by homology modeling. Refinement of the homology models with poor stereo-chemical quality is of utmost importance in order to derive reliable structures for subsequent studies. Therefore, the resultant models obtained by homology modelling were refined by running molecular dynamic simulation. Binding mode analysis of standard substrates and of competitive inhibitor was conducted to highlight important regions of the active site involved in hydrolysis of the substrates and possible mechanism of inhibition. PMID- 29416086 TI - Supersaturation-controlled microcrystallization and visualization analysis for serial femtosecond crystallography. AB - Time-resolved serial femtosecond crystallography with X-ray free electron laser (XFEL) holds the potential to view fast reactions occurring at near-physiological temperature. However, production and characterization of homogeneous micron-sized protein crystals at high density remain a bottleneck, due to the lack of the necessary equipments in ordinary laboratories. We describe here supersaturation controlled microcrystallization and visualization and analysis tools that can be easily used in any laboratory. The microcrystallization conditions of the influenza virus hemagglutinin were initially obtained with low reproducibility, which was improved by employing a rapid evaporation of hanging drops. Supersaturation-controlled microcrystallization was then developed in a vapor diffusion mode, where supersaturation was induced by evaporation in hanging drops sequentially for durations ranging from 30 sec to 3 min, depending on the protein. It was applied successfully to the microcrystal formation of lysozyme, ferritin and hemagglutinin with high density. Moreover, visualization and analysis tools were developed to characterize the microcrystals observed by light microscopy. The size and density distributions of microcrystals analyzed by the tools were found to be consistent with the results of manual analysis, further validated by high-resolution microscopic analyses. Our supersaturation-controlled microcrystallization and visualization and analysis tools will provide universal access to successful XFEL studies. PMID- 29416087 TI - Broad-spectrum neutralization of avian influenza viruses by sialylated human milk oligosaccharides: in vivo assessment of 3'-sialyllactose against H9N2 in chickens. AB - Two sialylated human milk oligosaccharides (SHMOs) 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL) were accessed for their possible antiviral activity against six different subtypes of thirteen avian influenza (AI) viruses in vitro. 3'-SL exhibited promising antiviral activity against almost all subtypes of tested AI viruses in hemagglutination inhibition assay, whereas 6'-SL showed activity against few selected H1N1, H1N2, and H3N2 subtype strains. 3'-SL has minimum inhibitory concentration values of 15.62 mM or less in more than half of the viruses examined. 3'-SL also showed effective inactivation of H9N2 Korea isolate (A/Chicken/Korea/MS96/1996) at 12.5 mM concentration in Madin Darby Canine Kidney (MDCK) cell line. Thus, 3'-SL was further studied for in vivo study against H9N2 virus in pathogen free chicken experiment models. In vivo study exhibited improved clinical symptoms on H9N2 infected chickens when treated with 3'-SL. Moreover, treating chickens with 3'-SL resulted in complete elimination of H9N2 viruses within 24 h of virus infection (0.8 HAU of H9N2). Indirect ELISA assay confirmed complete wash-out of H9N2 viruses from the colon after neutralization by 3'-SL without entering the blood stream. These in vivo results open up possible applications of 3'-SL for the prevention of AI virus infections in birds by a simple cleansing mechanism. PMID- 29416088 TI - EphB2 receptor tyrosine kinase promotes hepatic fibrogenesis in mice via activation of hepatic stellate cells. AB - Hepatic fibrosis is the result of an excessive wound-healing response subsequent to chronic liver injury. A feature of liver fibrogenesis is the secretion and deposition of extracellular matrix proteins by activated hepatic stellate cells (HSCs). Here we report that upregulation of EphB2 is a prominent feature of two mouse models of hepatic fibrosis and also observed in humans with liver cirrhosis. EphB2 is upregulated and activated in mouse HSCs following chronic carbon tetrachloride (CCl4) exposure. Moreover, we show that EphB2 deficiency attenuates liver fibrosis and inflammation and this is correlated with an overall reduction in pro-fibrotic markers, inflammatory chemokines and cytokines. In an in vitro system of HSCs activation we observed an impaired proliferation and sub optimal differentiation into fibrogenic myofibroblasts of HSCs isolated from EphB2-/- mice compared to HSCs isolated from wild type mice. This supports the hypothesis that EphB2 promotes liver fibrosis partly via activation of HSCs. Cellular apoptosis which is generally observed during the regression of liver fibrogenesis was increased in liver specimens of CCl4-treated EphB2-/- mice compared to littermate controls. This data is suggestive of an active repair/regeneration system in the absence of EphB2. Altogether, our data validate this novel pro-fibrotic function of EphB2 receptor tyrosine kinase. PMID- 29416089 TI - Development of Highly Active Bifunctional Electrocatalyst Using Co3O4 on Carbon Nanotubes for Oxygen Reduction and Oxygen Evolution. AB - Replacement of precious platinum catalyst with efficient and cheap bifunctional alternatives would be significantly beneficial for electrocatalytic oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) and the application of these catalysts in fuel cells is highly crucial. Despite numerous studies on electrocatalysts, the development of bifunctional electrocatalysts with comparatively better activity and low cost remains a big challenge. In this paper, we report a nanomaterial consisting of nanocactus-shaped Co3O4 grown on carbon nanotubes (Co3O4/CNTs) and employed as a bifunctional electrocatalyst for the simultaneous catalysis on ORR, and OER. The Co3O4/CNTs exhibit superior catalytic activity toward ORR and OER with the smallest potential difference (0.72 V) between the [Formula: see text] (1.55 V) for OER and E1/2 (0.83 V) for ORR. Thus, Co3O4/CNTs are promising high-performance and cost-effective bifunctional catalysts for ORR and OER because of their overall superior catalytic activity and stability compared with 20 wt% Pt/C and RuO2, respectively. The superior catalytic activity arises from the unique nanocactus like structure of Co3O4 and the synergetic effects of Co3O4 and CNTs. PMID- 29416090 TI - Transitions to sustainable management of phosphorus in Brazilian agriculture. AB - Brazil's large land base is important for global food security but its high dependency on inorganic phosphorus (P) fertilizer for crop production (2.2 Tg rising up to 4.6 Tg in 2050) is not a sustainable use of a critical and price volatile resource. A new strategic analysis of current and future P demand/supply concluded that the nation's secondary P resources which are produced annually (e.g. livestock manures, sugarcane processing residues) could potentially provide up to 20% of crop P demand by 2050 with further investment in P recovery technologies. However, the much larger legacy stores of secondary P in the soil (30 Tg in 2016 worth over $40 billion and rising to 105 Tg by 2050) could provide a more important buffer against future P scarcity or sudden P price fluctuations, and enable a transition to more sustainable P input strategies that could reduce current annual P surpluses by 65%. In the longer-term, farming systems in Brazil should be redesigned to operate profitably but more sustainably under lower soil P fertility thresholds. PMID- 29416091 TI - Transcriptome analysis and identification of P450 genes relevant to imidacloprid detoxification in Bradysia odoriphaga. AB - Pesticide tolerance poses many challenges for pest control, particularly for destructive pests such as Bradysia odoriphaga. Imidacloprid has been used to control B. odoriphaga since 2013, however, imidacloprid resistance in B. odoriphaga has developed in recent years. Identifying actual and potential genes involved in detoxification metabolism of imidacloprid could offer solutions for controlling this insect. In this study, RNA-seq was used to explore differentially expressed genes in B. odoriphaga that respond to imidacloprid treatment. Differential expression data between imidacloprid treatment and the control revealed 281 transcripts (176 with annotations) showing upregulation and 394 transcripts (235 with annotations) showing downregulation. Among them, differential expression levels of seven P450 unigenes were associated with imidacloprid detoxification mechanism, with 4 unigenes that were upregulated and 3 unigenes that were downregulated. The qRT-PCR results of the seven differential expression P450 unigenes after imidacloprid treatment were consistent with RNA Seq data. Furthermore, oral delivery mediated RNA interference of these four upregulated P450 unigenes followed by an insecticide bioassay significantly increased the mortality of imidacloprid-treated B. odoriphaga. This result indicated that the four upregulated P450s are involved in detoxification of imidacloprid. This study provides a genetic basis for further exploring P450 genes for imidacloprid detoxification in B. odoriphaga. PMID- 29416092 TI - CD63, MHC class 1, and CD47 identify subsets of extracellular vesicles containing distinct populations of noncoding RNAs. AB - Extracellular vesicles (EVs) mediate the intercellular transfer of RNAs, which alter gene expression in target cells. EV heterogeneity has limited progress towards defining their physiological functions and utility as disease-specific biomarkers. CD63 and MHC1 are widely used as markers to purify EVs. CD47 is also present on EVs and alters their effects on target cells, suggesting that specific surface markers define functionally distinct EVs. This hypothesis was addressed by comparing Jurkat T cell EVs captured using CD47, CD63, and MHC1 antibodies. These EV subsets have similar sizes but divergent RNA contents. Apart from differences in numbers of nonannotated transcripts, CD63+, MHC1+, and CD47+ EVs have similar overall contents of most noncoding RNA classes, but the relative enrichment of specific RNAs differs. The enrichment of micro-RNAs is highly divergent, and some including miR320a are selectively concentrated in CD47+ EVs. Small nucleolar RNAs including SNORD116@ and SNHG10 are also selectively enriched in CD47+ EVs, whereas no small nuclear RNAs are enriched in CD47+ EVs. Conversely, MHC1+ EVs are selectively enriched in a subset of tRNAs including TRE CTC and TRR-CCG. This heterogeneity in RNA composition suggests multiple sorting mechanisms that direct specific RNAs into subsets of EVs that express specific surface markers. PMID- 29416093 TI - Fly ash incorporated with biocement to improve strength of expansive soil. AB - Microbially induced calcium carbonate precipitation (MICP) results in the formation of biocement (BC). This process, also known as biocementation, is recently widely used to improve the strength and durability of building materials including soils. In the present study, effectiveness of biocement as admixture with fly ash (FA) was investigated as first few studies to improve geotechnical properties of expansive soils. Biocement precipitated by Bacillus megaterium was blend with four formulations of fly ash at concentrations of 0, 10, 25 and 50%, namely 0% FABC, 10% FABC, 25% FABC, and 50% FABC, respectively. These formulations were separately added to expansive soils. Specimens with 25% FABC resulted in significant improvement in unconfined compressive strength of expansive soil that was more than two-times higher than control. Further, scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) analyses characterized microstructures of soil specimens, and depicted the process of MICP in improving strength of expansive soils. This research indicates that incorporation of biocement in fly ash is an effective means of increasing the strength of expansive soils. PMID- 29416094 TI - Traumatic Cataract in Children in Eastern China: Shanghai Pediatric Cataract Study. AB - Traumatic cataract is a main cause of visual impairment in pediatric populations and is preventable. Awareness of the causes and consequences of pediatric eye trauma play roles in health education and prevention of blindness. We conducted a retrospective chart review based on 5-year clinical data of pediatric traumatic cataract cases treated at the Eye and Ear, Nose and Throat Hospital of Fudan University, Shanghai, China. Clinical features including demographic data, injury mechanism, and causative agents were analyzed. A total of 321 eyes of 321 children (male, 74.1%) were included. Penetrating injury accounted for 76.6% of all injuries; 65% of children with such injuries underwent their first surgery on the day of injury. The average age at injury was 6.3 +/- 3.7 years, while the peak age was from two to eight years. The main causes of ocular injury were sharp metal objects, toys, and wooden sticks. The causative agent changed with increasing age; however, scissors were the leading cause within almost all age groups. Cataract surgery significantly improved visual acuity in children with traumatic cataract. These findings add information regarding the characterization of pediatric traumatic cataract in China and can help guide safety education and preventative measures. PMID- 29416095 TI - PilVax - a novel peptide delivery platform for the development of mucosal vaccines. AB - Peptide vaccines are an attractive strategy to engineer the induction of highly targeted immune responses and avoid potentially allergenic and/or reactogenic protein regions. However, peptides by themselves are often unstable and poorly immunogenic, necessitating the need for an adjuvant and a specialised delivery system. We have developed a novel peptide delivery platform (PilVax) that allows the presentation of a stabilised and highly amplified peptide as part of the group A streptococcus serotype M1 pilus structure (PilM1) on the surface of the non-pathogenic bacterium Lactococcus lactis. To show proof of concept, we have successfully inserted the model peptide Ova324-339 into 3 different loop regions of the backbone protein Spy0128, which resulted in the assembly of the pilus containing large numbers of peptide on the surface of L. lactis. Intranasal immunisation of mice with L. lactis PilM1-Ova generated measurable Ova-specific systemic and mucosal responses (IgA and IgG). Furthermore, we show that multiple peptides can be inserted into the PilVax platform and that peptides can also be incorporated into structurally similar, but antigenically different pilus structures. PilVax may be useful as a cost-effective platform for the development of peptide vaccines against a variety of important human pathogens. PMID- 29416096 TI - Characteristics of multiple Fano resonances in waveguide-coupled surface plasmon resonance sensors based on waveguide theory. AB - We observe and analyze multiple Fano resonances and the plasmon-induced transparency (PIT) arising from waveguidecoupled surface plasmon resonance in a metal-dielectric Kretschmann configuration. It is shown that the simulation results for designed structures agree well with those of the dispersion relation of waveguide theory. We demonstrate that the coupling between the surface plasmon polariton mode and multi-order planar waveguide modes leads to multiple Fano resonances and PIT. The obtained results show that the number of Fano resonances and the linewidth of resonances depend on two structural parameters, the Parylene C and SiO2 layers, respectively. For the sensing action of Fano resonance, the figure of merit for the sensitivity by intensity is estimated to be 44 times higher than that of conventional surface plasmon resonance sensors. Our research reveals the potential advantage of sensors with high sensitivity based on coupling between the SPP mode and multi-order PWG modes. PMID- 29416097 TI - Nitrogen-doped mesoporous SiC materials with catalytically active cobalt nanoparticles for the efficient and selective hydrogenation of nitroarenes. AB - Mesoporous nitrogen-doped silicon carbide catalysts with integrated cobalt nanoparticles (Co@N-SiC) were synthesized by the thermal decomposition of a microphase-separated block copolymer of polycarbosilane and polyethylene. The catalysts are highly active, reusable and offer selective hydrogenation of the nitro group in the presence of hydrogenation-sensitive functional groups. PMID- 29416098 TI - Breastfeeding moderates FTO related adiposity: a birth cohort study with 30 years of follow-up. AB - This study assessed the association of breastfeeding with body composition at 30 years, among subjects who have been prospectively followed since birth in a southern Brazilian city. We also evaluated whether breastfeeding moderated the association between the rs9939609 variant in the FTO gene and adiposity. At 30 years, total and predominant breastfeeding were positively associated with lean mass index and inversely with visceral fat thickness. Among subjects breastfed for <1 month, all outcomes showed monotonically increasing values with additional copies of the A allele in the FTO genotype (rs9939609). Associations among subjects breastfed for one month or longer tended to be in the same direction but showed lower magnitude and were less consistent; for all outcomes. Interactions had p values <= 0.05 for body mass index, fat mass index and waist circumference. Even among young adults, breastfeeding moderates the association between the FTO variant rs9939609 and body composition. PMID- 29416099 TI - Generation and characterization of a IgG monoclonal antibody specific for GM3 (NeuGc) ganglioside by immunizing beta3Gn-T5 knockout mice. AB - A murine monoclonal antibody (MAb-1) specific for GM3 has been generated by immunizing beta3Gn-T5 knockout mice with purified GM3 ganglioside. The binding specificity of MAb-1 (IgG3 subclass) was established by an enzyme-linked immunosorbent assay (ELISA) and FACS and the antibody showed high binding specificity with GM3. Cell viability assay showed that MAb-1 significantly suppressed cell growth. Immunohistochemistry analysis revealed that MAb-1 was strongly expressed in human ovarian cancer tissues, whereas it was hardly expressed in normal tissues. Finally, antibody-dependent cellular cytotoxicity (ADCC) activities were determined by measuring lactate dehydrogenase (LDH) releasing assay and the results showed high ADCC activities in two representative ovarian cancer cell lines (OVHM and ID8). All of these data indicate that MAb-1 may be potentially used as a therapeutic antibody against ovarian cancers in clinical trials. PMID- 29416100 TI - Exploring an optimal wavelet-based filter for cryo-ET imaging. AB - Cryo-electron tomography (cryo-ET) is one of the most advanced technologies for the in situ visualization of molecular machines by producing three-dimensional (3D) biological structures. However, cryo-ET imaging has two serious disadvantages-low dose and low image contrast-which result in high-resolution information being obscured by noise and image quality being degraded, and this causes errors in biological interpretation. The purpose of this research is to explore an optimal wavelet denoising technique to reduce noise in cryo-ET images. We perform tests using simulation data and design a filter using the optimum selected wavelet parameters (three-level decomposition, level-1 zeroed out, subband-dependent threshold, a soft-thresholding and spline-based discrete dyadic wavelet transform (DDWT)), which we call a modified wavelet shrinkage filter; this filter is suitable for noisy cryo-ET data. When testing using real cryo-ET experiment data, higher quality images and more accurate measures of a biological structure can be obtained with the modified wavelet shrinkage filter processing compared with conventional processing. Because the proposed method provides an inherent advantage when dealing with cryo-ET images, it can therefore extend the current state-of-the-art technology in assisting all aspects of cryo-ET studies: visualization, reconstruction, structural analysis, and interpretation. PMID- 29416101 TI - Accounting for black carbon lowers estimates of blue carbon storage services. AB - The canopies and roots of seagrass, mangrove, and saltmarsh protect a legacy of buried sedimentary organic carbon from resuspension and remineralisation. This legacy's value, in terms of mitigating anthropogenic emissions of CO2, is based on total organic carbon (TOC) inventories to a depth likely to be disturbed. However, failure to subtract allochthonous recalcitrant carbon overvalues the storage service. Simply put, burial of oxidation-resistant organics formed outside of the ecosystem provides no additional protection from remineralisation. Here, we assess whether black carbon (BC), an allochthonous and recalcitrant form of organic carbon, is contributing to a significant overestimation of blue carbon stocks. To test this supposition, BC and TOC contents were measured in different types of seagrass and mangrove sediment cores across tropical and temperate regimes, with different histories of air pollution and fire together with a reanalysis of published data from a subtropical system. The results suggest current carbon stock estimates are positively biased, particularly for low organic-content sandy seagrass environs, by 18 +/- 3% (+/-95% confidence interval) and 43 +/- 21% (+/-95% CI) for the temperate and tropical regions respectively. The higher BC fractions appear to originate from atmospheric deposition and substantially enrich the relatively low TOC fraction within these environs. PMID- 29416102 TI - Measurement of nuclear reaction cross sections by using Cherenkov radiation toward high-precision proton therapy. AB - Monitoring the in vivo dose distribution in proton therapy is desirable for the accurate irradiation of a tumor. Although positron emission tomography (PET) is widely used for confirmation, the obtained distribution of positron emitters produced by the protons does not trace the dose distribution due to the different physical processes. To estimate the accurate dose from the PET image, the cross sections of nuclear reactions that produce positron emitters are important yet far from being sufficient. In this study, we measured the cross sections of 16O(p,x)15O, 16O(p,x)13N, and 16O(p,x)11C with a wide-energy range (approximately 5-70 MeV) by observing the temporal evolution of the Cherenkov radiation emitted from positrons generated via beta+ decay along the proton path. Furthermore, we implemented the new cross sectional data into a conventional Monte Carlo (MC) simulation, so that a direct comparison was possible with the PET measurement. We confirmed that our MC results showed good agreement with the experimental data, both in terms of the spatial distributions and temporal evolutions. Although this is the first attempt at using the Cherenkov radiation in the measurements of nuclear cross sections, the obtained results suggest the method is convenient and widely applicable for high precision proton therapy. PMID- 29416103 TI - Development of a Method to Extract Opium Poppy (Papaver somniferum L.) DNA from Heroin. AB - This study is the first to report the successful development of a method to extract opium poppy (Papaver somniferum L.) DNA from heroin samples. Determining of the source of an unknown heroin sample (forensic geosourcing) is vital to informing domestic and foreign policy related to counter-narcoterrorism. Current profiling methods focus on identifying process-related chemical impurities found in heroin samples. Changes to the geographically distinct processing methods may lead to difficulties in classifying and attributing heroin samples to a region/country. This study focuses on methods to optimize the DNA extraction and amplification of samples with low levels of degraded DNA and inhibiting compounds such as heroin. We compared modified commercial-off-the-shelf extraction methods such as the Qiagen Plant, Stool and the Promega Maxwell-16 RNA-LEV tissue kits for the ability to extract opium poppy DNA from latex, raw and cooked opium, white and brown powder heroin and black tar heroin. Opium poppy DNA was successfully detected in all poppy-derived samples, including heroin. The modified Qiagen stool method with post-extraction purification and a two-stage, dual DNA polymerase amplification procedure resulted in the highest DNA yield and minimized inhibition. This paper describes the initial phase in establishing a DNA-based signature method to characterize heroin. PMID- 29416104 TI - Signs of atopic dermatitis and contact dermatitis affected by distinct H2 haplotype in the NC/Nga genetic background. AB - We recently advocated in favour of naming a novel H2-haplotype consisting of Kd, D/Ldm7, I-Ak and I-Ek in the atopic dermatitis (AD) mouse model NC/Nga as "H 2nc." The role of the H2-haplotype in AD development was investigated in H2 b congenic NC/Nga mice (NC.h2 b/b and NC.h2 b/nc ) established by backcrossing. A severe 2,4-dinitrofluorobenzene (DNFB)-induced dermatitis in NC/Nga was alleviated partially in NC.h2 b/nc and significantly in NC.h2 b/b . The AD phenotype was correlated with thymic stromal lymphopoietin (TSLP)-epidermal expression levels and serum levels of total IgE and IL-18/IL-33. Histologically, allergic contact dermatitis (ACD) was accompanied by lymphocytes and plasma cells infiltrating perivasculitis in NC.h2 b/nc and NC.h2 b/b and clearly differed from AD accompanied by neutrophils, eosinophils and macrophages-infiltrating diffuse suppurative dermatitis in NC/Nga. Interestingly, IFN-gamma/IL-17 production from autoreactive CD4+ T-cells remarkably increased in DNFB-sensitised NC.h2 b/b but not in NC/Nga. Our findings suggest that AD or ACD may depend on haplotype H-2nc or H-2b, respectively, in addition to the NC/Nga genetic background. PMID- 29416105 TI - Speciation determination of iron and its spatial and seasonal distribution in coastal river. AB - In this study, the speciation of iron (Fe), including total Fe (TFe) and acidified dissolved Fe (ADFe), was assessed by fast cathodic absorption stripping voltammetry, using a gold electrode and 2-(5-bromo-2-pyridylazo)-5 diethylaminophenol (5-Br-PADAP) as a novel complexing agent for Fe. The validity and accuracy of this method were compared with the standard spectrophotometry and tested by the standard samples. Under optimized conditions, the Fe response was linear within the range of 0.01 to 1 MUM with a detection limit of 1.2 nM. To further validate this method, the variation in concentrations of TFe and ADFe were investigated at twelve sampling stations in a local coastal river, in both the dry and wet season. Additionally, to further understand the interaction between Fe and environmental factors, the relationships between the concentration of Fe species and dissolved oxygen (DO) and salinity were also discussed. PMID- 29416107 TI - Presence of high-endothelial venules correlates with a favorable immune microenvironment in oral squamous cell carcinoma. AB - Oral squamous cell carcinomas are associated with a poor prognosis, which may be partly due to functional impairment of the immune response. Lymphocyte recruitment to the tumor site is facilitated by high-endothelial venules, whereas expression of programmed-death ligand 1 (PD-L1) can impair T-cell function. Thus, we hypothesize that these factors are important in shaping the immune response in oral squamous cell carcinoma. In the present study, we characterized the immune infiltrate in formalin-fixed, paraffin-embedded tumor samples from 75 oral squamous cell carcinoma patients. We used immunohistochemistry to determine the distribution of immune cell subsets, high-endothelial venules, and PD-L1, as well as quantitative real-time polymerase chain reaction to assess the expression of inflammatory cytokines and chemokines associated with lymphocyte trafficking. Finally, we calculated correlations between the presence of immune cell subsets, the gene expression patterns, high-endothelial venules, PD-L1, and the clinicopathological parameters, including patient survival. The presence of high endothelial venules correlated with increased number of CD3+ T cells and CD20+ B cells, higher levels of the chemokines CXCL12 and CCL21, and lower levels of CCL20, irrespective of the tumors' T stage. In univariate analysis, high levels of CD20+ B cells and CD68+ macrophages, positive high-endothelial venule status, and low T and N stages predicted longer patient survival. However, only the presence of high-endothelial venules and a low T stage were independent positive prognosticators. This indicates that high-endothelial venules are important mediators and a convenient marker of an antitumor immune response in oral squamous cell carcinoma. Our findings suggest that these vessels are a potential immunomodulatory target in this type of cancer. PD-L1 staining in tumor cells correlated with lower T stage, increased infiltration of CD4+ cells, and higher expression of several inflammation-related cytokines. Thus, oral squamous cell carcinomas rich in CD4+ cells may preferentially respond to PD-1/PD-L1 blockade therapy. PMID- 29416106 TI - Plasma homocysteine concentrations and risk of intracerebral hemorrhage: a systematic review and meta-analysis. AB - Intracerebral hemorrhage (ICH) has the highest mortality rate in all strokes. However, controversy still exists concerning the association between plasma homocysteine (Hcy) and ICH. A systematic review and meta-analysis was conducted using Pubmed, Embase, and Web of Science up to April 18, 2017. Standard mean difference (SMD) for mean differences of plasma Hcy levels with 95% confidence intervals (CI) was calculated. Seven studies including 667 ICH patients and 1821 ischemic stroke patients were identified for meta-analysis. Our results showed that Hcy levels in ICH patients were significantly higher than those in healthy controls (SMD = 0.59, 95% CI = 0.51-0.68, P < 0.001); no statistic differences were found in the comparisons of Hcy levels between ICH and ischemic stroke (SMD = -0.03, 95% CI = -0.13-0.06, P > 0.05); further subgroup analysis of ethnicity (Asians: SMD = 0.57, 95% CI = 0.48-0.66, P < 0.001; Caucasians: SMD = 0.77, 95% CI = 0.51-1.02, P < 0.001) and sample size (small samples: SMD = 0.55, 95% CI = 0.30-0.80, P < 0.001; large samples size: SMD = 0.60, 95% CI = 0.51-0.69, P < 0.001) in relation to Hcy levels between ICH and healthy controls did not change these results. In conclusion, Hcy level may be an aggravating factor in atherosclerosis, which is positively associated with high risk of ICH. Race specific differences between Asians and Caucasians have no impact on the risk of ICH. PMID- 29416108 TI - Combination of serum histidine-rich glycoprotein and uterine artery Doppler to predict preeclampsia. AB - The primary aim of this study is to determine the value of using a combination of serum histidine-rich glycoprotein (HRG) level and uterine artery pulsatility index (PI) in pregnant women at 11-13+6 weeks' gestation to predict preeclampsia. The secondary aim is to determine the association between other pregnancy complications with the use of these combined tests. Transabdominal uterine artery PI and serum HRG level were measured at the time of first-trimester aneuploidy screening at 11-13+6 weeks' gestation in 327 pregnant women. The primary outcome was preeclampsia. The predictive values of this combination test were calculated. Eighteen cases developed preeclampsia (5.5%) and four of these preeclamptic cases were early-onset preeclampsia (1.2%). The sensitivity, specificity, positive predictive value, and negative predictive value of uterine artery PI combined with serum HRG level to predict preeclampsia were 11.1%, 96.8%, 16.7%, and 94.9%, respectively. For the prediction of early-onset preeclampsia, the sensitivity, specificity, positive predictive value, and negative predictive value were 25%, 97.1%, 10%, and 99%, respectively. An abnormal uterine artery PI and abnormal serum HRG level were associated with preterm delivery and intrauterine growth restriction. Our findings reveal that the combination of uterine artery PI and serum HRG level at 11-13+6 weeks of gestation is not an effective method for predicting preeclampsia at the time of first-trimester screening. PMID- 29416109 TI - ATP2B1 Gene Silencing Increases NO Production Under Basal Conditions Through the Ca2+/calmodulin/eNOS Signaling Pathway in Endothelial Cells. AB - Emerging epidemiological and experimental evidence has shown that the ATP2B1 gene is associated with blood pressure control. Impaired eNOS activity and NO production may be among the mechanisms involved. However, little is known about how PMCA1, which is encoded by the ATP2B1 gene, regulates the activity of eNOS and NO production. In the present study, we investigated the role of the ATP2B1 gene in regulating eNOS activity and NO production under basal conditions in HUVECs and explored the mechanisms involved. Silencing ATP2B1 gene expression resulted in higher NO production and eNOS activity under basal conditions in HUVECs. Additionally, ATP2B1 gene silencing resulted in enhanced intracellular calcium concentrations compared to that in the negative siRNA-transfected HUVECs. The enhanced eNOS activity mediated by ATP2B1 gene silencing was Ca2+/calmodulin dependent, as verified by the administration of the calcium chelator BAPTA-AM or the calmodulin-specific antagonist W7. Taken together, silencing ATP2B1 gene expression results in higher NO production and eNOS activity under basal conditions in HUVECs. Furthermore, the enhanced eNOS activity induced by ATP2B1 gene silencing may be mediated via higher levels of intracellular Ca2+, and the effect was confirmed to be dependent on the eNOS-calmodulin interaction. PMID- 29416110 TI - Perforin proteostasis is regulated through its C2 domain: supra-physiological cell death mediated by T431D-perforin. AB - The pore forming, Ca2+-dependent protein, perforin, is essential for the function of cytotoxic lymphocytes, which are at the frontline of immune defence against pathogens and cancer. Perforin is a glycoprotein stored in the secretory granules prior to release into the immune synapse. Congenital perforin deficiency causes fatal immune dysregulation, and is associated with various haematological malignancies. At least 50% of pathological missense mutations in perforin result in protein misfolding and retention in the endoplasmic reticulum. However, the regulation of perforin proteostasis remains unexplored. Using a variety of biochemical assays that assess protein stability and acquisition of complex glycosylation, we demonstrated that the binding of Ca2+ to the C2 domain stabilises perforin and regulates its export from the endoplasmic reticulum to the secretory granules. As perforin is a thermo-labile protein, we hypothesised that by altering its C2 domain it may be possible to improve protein stability. On the basis of the X-ray crystal structure of the perforin C2 domain, we designed a mutation (T431D) in the Ca2+ binding loop. Mutant perforin displayed markedly enhanced thermal stability and lytic function, despite its trafficking from the endoplasmic reticulum remaining unchanged. Furthermore, by introducing the T431D mutation into A90V perforin, a pathogenic mutation, which results in protein misfolding, we corrected the A90V folding defect and completely restored perforin's cytotoxic function. These results revealed an unexpected role for the Ca2+-dependent C2 domain in maintaining perforin proteostasis and demonstrated the possibility of designing perforin with supra-physiological cytotoxic function through stabilisation of the C2 domain. PMID- 29416112 TI - Author Correction: Interplay between evanescence and disorder in deep subwavelength photonic structures. AB - This corrects the article DOI: 10.1038/ncomms12927. PMID- 29416111 TI - IRE1alpha siRNA relieves endoplasmic reticulum stress-induced apoptosis and alleviates diabetic peripheral neuropathy in vivo and in vitro. AB - Diabetic peripheral neuropathy (DPN) is mainly characterized by demyelination resulted from the apoptosis of the Schwann cell (SCs). Although the exact mechanisms underlying DPN remain unclear, endoplasmic reticulum (ER) stress is strongly implicated in the apoptosis. Under ER stress, activated inositol requiring kinase 1alpha (IRE1alpha) unregulated CHOP, phosphorylated JNK and Caspase-12 to aggravate apoptosis-mediated damage of DPN. Therefore, we tested the hypothesis that inhibition of IRE1alpha could reduce the ER stress-related apoptosis to relieve DPN. Here, we show that IRE1alpha siRNA improved the neurological morphology and function of DPN rats and rescued ER stress-related apoptosis in the sciatic nerve. Additionally, RSC96 cells transfected with IRE1alpha siRNA were used as in vitro model of DPN. It was found that IRE1alpha siRNA also decreased high glucose-induced apoptosis and inhibited ER stress related apoptosis in the cells. Altogether, our results suggest that IRE1alpha should be considered a potential therapeutic agent for DPN. PMID- 29416114 TI - Adiponectin, insulin and leptin levels in the cord plasma of the neonates from adolescent and adult mothers and their relationship with anthropometric parameters and fetal sex-gender. AB - OBJECTIVE: This cross-sectional study aimed to evaluate the association between leptin, insulin and adiponectin levels and anthropometric measurements of term newborns of adolescent and adult mothers. STUDY DESIGN: Umbilical cord plasma samples were obtained from 80 healthy term neonates (40 from teenagers and 40 from adult mothers) and adiponectin, insulin and leptin concentrations were measured. RESULTS: Cord plasma adiponectin levels were higher in the boys from adult mothers than in the boys of the adolescent (p < 0.05), while plasma leptin levels in the boys of the adults were significantly lower (p < 0.05) than those of girls from both groups. Univariate correlation analysis showed that leptin umbilical cord plasma levels were positively associated with birth weight in neonates from adolescents and adults. Multiple linear regression analysis revealed that leptin levels showed significant positive predictor for birth weight specifically in the adult mother. CONCLUSION: Gestational age, but not adipokines, showed to be a significant positive predictor factor of birth weight in adolescent pregnancy. PMID- 29416113 TI - Cryo-electron tomography reveals that dynactin recruits a team of dyneins for processive motility. AB - Cytoplasmic dynein is a protein complex that transports molecular cargo along microtubules (MTs), playing a key role in the intracellular trafficking network. Vertebrate dynein's movement becomes strikingly enhanced upon interacting with dynactin and a cargo adaptor such as BicaudalD2. However, the mechanisms responsible for increased transport activity are not well understood, largely owing to limited structural information. We used cryo-electron tomography (cryo ET) to visualize the 3D structure of the MT-bound dynein-dynactin complex from Mus musculus and show that the dynactin-cargo adaptor complex binds two dimeric dyneins. This configuration imposes spatial and conformational constraints on both dynein dimers, positioning the four motor domains in proximity to one another and oriented toward the MT minus end. We propose that grouping multiple dyneins onto a single dynactin scaffold promotes collective force production, increased processivity, and unidirectional movement, suggesting mechanistic parallels to axonemal dynein. These findings provide structural insights into a previously unknown mechanism for dynein regulation. PMID- 29416115 TI - The Baby Friendly Hospital Initiative and the ten steps for successful breastfeeding. a critical review of the literature. AB - There is no doubt regarding the multiple benefits of breastfeeding for infants and society in general. Therefore, the World Health Organization (WHO) in a conjoint effort with United Nations International Children's Emergency Fund (UNICEF) developed the "Ten Steps to Successful Breastfeeding" in 1992, which became the backbone of the Baby Friendly Hospital Initiative (BFHI). Following this development, many hospitals and countries intensified their position towards creating a "breastfeeding oriented" practice. Over the past two decades, the interest increased in the BFHI and the Ten Steps. However, alongside the implementation of the initiative, extensive research continues to evaluate the benefits and dangers of the suggested practices. Hence, it is our intention to make a critical evaluation of the current BFHI and the Ten Steps recommendations in consideration of the importance of providing an evidence-based breastfeeding supported environment for our mothers and infants. PMID- 29416116 TI - Machine learning of correlated dihedral potentials for atomistic molecular force fields. AB - Computer simulation increasingly complements experimental efforts to describe nanoscale structure formation. Molecular mechanics simulations and related computational methods fundamentally rely on the accuracy of classical atomistic force fields for the evaluation of inter- and intramolecular energies. One indispensable component of such force fields, in particular for large organic molecules, is the accuracy of molecule-specific dihedral potentials which are the key determinants of molecular flexibility. We show in this work that non-local correlations of dihedral potentials play a decisive role in the description of the total molecular energy-an effect which is neglected in most state-of-the-art dihedral force fields. We furthermore present an efficient machine learning approach to compute intramolecular conformational energies. We demonstrate with the example of alpha-NPD, a molecule frequently used in organic electronics, that this approach outperforms traditional force fields by decreasing the mean absolute deviations by one order of magnitude to values smaller than 0.37 kcal/mol (16.0 meV) per dihedral angle. PMID- 29416117 TI - Enhanced proton acceleration from an ultrathin target irradiated by laser pulses with plateau ASE. AB - We report a simulation study on proton acceleration driven by ultraintense laser pulses with normal contrast (107-109) containing nanosecond plateau amplified spontaneous emission (ASE). It's found in hydrodynamic simulations that if the thickness of the targets lies in the range of hundreds nanometer matching the intensity and duration of ASE, the ablation pressure would push the whole target in the forward direction with speed exceeding the expansion velocity of plasma, resulting in a plasma density profile with a long extension at the target front and a sharp gradient at the target rear. When the main pulse irradiates the plasma, self-focusing happens at the target front, producing highly energetic electrons through direct laser acceleration(DLA) building the sheath field. The sharp plasma gradient at target rear ensures a strong sheath field. 2D particle in-cell(PIC) simulations reveal that the proton energy can be enhanced by a factor of 2 compared to the case of using micrometer-thick targets. PMID- 29416118 TI - Increasing ambulatory pulse pressure predicts the development of left ventricular hypertrophy during long-term follow-up. AB - Ambulatory blood pressure (ABP) has been shown to have an association with left ventricular hypertrophy (LVH). We evaluated the association between ABP characteristics and the development of LVH during long-term follow-up (20 years) in 420 middle-aged subjects from OPERA cohort. ABP measurements (ABPM) were recorded and echocardiographic examinations were performed at baseline and revisit. Anthropometrics were measured and laboratory analyses performed at visit. The questionnaire presented to all participants elicited detailed information about their habits. Left ventricular mass index (LVMI) was calculated according to Troys method. Baseline LVMI was a significant independent predictor of LVMI change (p < 0.001). None of the baseline continuous ABPM predicted the change in LVMI. A greater increase in daytime and night-time systolic blood pressure (BP) (p from 0.006 to 0.048) and 24 h, daytime and night-time pulse pressure (PP) (p from 0.005 to 0.034) predicted a greater increase in LVMI. Especially the increase in night-time SBP (p = 0.006) and PP (p = 0.005) predicted a greater increase in LVMI. We also considered circadian BP profiles among subjects, whose ABPM at baseline and echocardiographic measurements both at baseline and follow-up were available. Diastolic non-dippers were observed to show a greater increase in LVMI compared to diastolic dippers (10.6 +/- 33.0 g/m2 vs. 7.0 +/- 28.8 g/m2, p = 0.032), when baseline LVMI and in-office DBP were taken account. These findings suggest that an increasing ambulatory PP increases and a diastolic non-dipping status may increase the risk for the development of LVH during later life course. PMID- 29416119 TI - Comparison of body mass index, waist circumference, conicity index, and waist-to height ratio for predicting incidence of hypertension: the rural Chinese cohort study. AB - This study compared the ability of body mass index (BMI), waist circumference (WC), conicity index, and waist-to-height ratio (WHtR) to predict incident hypertension and to identify the cutoffs of obesity indices for predicting hypertension in rural Chinese adults. This prospective cohort study recruited 9905 participants aged 18-70 years during a median follow-up of 6 years in rural China. Logistic regression and receiver operating characteristic (ROC) curve analyses were used to assess the association, predictive ability, and optimal cutoffs (in terms of hypertension risk factors) of the four obesity indices: BMI, WC, conicity index, and WHtR. The 6-year cumulative incidence of hypertension was 19.89% for men and 18.68% for women, with a significant upward trend of increased incident hypertension with increasing BMI, WC, conicity index, and WHtR (P for trend < 0.001) for both men and women. BMI and WHtR had the largest area under the ROC curve for identifying hypertension for both genders. The optimal cutoff values for BMI, WC, conicity index, and WHtR for predicting hypertension were 22.65 kg/m2, 82.70 cm, 1.20, and 0.49, respectively, for men, and 23.80 kg/m2, 82.17 cm, 1.20, and 0.52, respectively, for women. BMI, WC, conicity index, and WHtR cutoffs may offer a simple and effective way to screen hypertension in rural Chinese adults. BMI and WHtR were superior to WC and conicity index for predicting incident hypertension for both genders. PMID- 29416121 TI - In vitro activity of minocycline combined with aminoglycosides against Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. AB - This study assessed the in vitro antibacterial activity of minocycline aminoglycoside combination against Klebsiella pneumoniae carbapenemase (KPC) producing K. pneumoniae. Seventy non-duplicate clinical isolates of KPC-producing K. pneumoniae were collected from patients with bloodstream infections. The synergistic activity of minocycline-aminoglycoside combination was studied by the checkerboard method and time-kill assays in strains with different susceptibilities, and the mutant prevention concentration (MPC) and mutant selection window (MSW) of drugs alone and in combination were determined. The checkerboard method found this combination displayed synergistic and partial synergistic activity against aminoglycoside-susceptible isolates, but indifferent activity against aminoglycoside-resistant isolates. Time-kill assays further demonstrated strong synergistic and bactericidal effect of this combination existed against isolates which were susceptible to both drugs. But for resistant isolates, the time-kill assays showed no synergy. The MPCs of minocycline or aminoglycosides were 8- to 32-fold higher than the MICs, suggesting the MSWs of these drugs were quite wide. For the antibiotic combinations, the addition of 1*MIC concentration of amikacin or gentamicin could reduce the MPCs of minocycline by 4- to 16-fold. Generally, no mutants recovered in the plates containing 1*MIC concentration of minocycline and 2*MIC concentration of amikacin or gentamicin. In summary, these results suggest that minocycline-aminoglycoside combination can be an alternative for infections caused by KPC-producing K. pneumoniae because this combination displays strong synergistic and bactericidal activity in susceptible isolates, and can effectively prevent the emergence of resistant mutants. Further in vitro pharmacokinetic/pharmacodynamic studies and clinical trials should be performed to fully evaluate the efficacy of this drug combination. PMID- 29416120 TI - Relationship of serum immunoglobulin levels to blood pressure and hypertension in an adult population. AB - Evidence suggests long-term chronic inflammation, as the pathological basis of formation and development, plays an important part in atherosclerosis. Immunoglobulins (Igs) provided key information on the humoral immune status. However, few studies have evaluated the correlation between Igs and hypertension and blood pressure (BP) in a general population. We designed a cross-sectional study to evaluate whether serum Ig levels are related to BP and the prevalence of hypertension. About 12,373 participants in Tianjin, China were recruited for this study. Hypertension was diagnosed according to the criteria of the JNC 7 and serum levels of Igs were determined by the immunonephelometric technique. Multiple logistic regression analysis and analysis of covariance were used to assess relationships between serum Ig concentrations and the prevalence of hypertension and BP. The overall prevalence of hypertension was 35.5%. The means (standard deviation) of immunoglobulins [immunoglobulin G (IgG), immunoglobulin E (IgE), immunoglobulin M (IgM), and immunoglobulin A (IgA)] were 1206.0 (249.0) mg/dL, 93.8 (235.4) IU/mL, 105.3 (56.8) mg/dL, and 236.7 (98.1) mg/dL, respectively. The multivariable-adjusted odds ratios (95% confidence interval) of hypertension for the highest immunoglobulins (IgG, IgE, IgM, and IgA) quintile, when compared to the lowest quintile were 1.10 (0.96-1.26), 1.04 (0.91-1.19), 0.83 (0.72-0.96), and 1.32 (1.15-1.51), respectively. Decreased IgM and increased IgG and IgA were related to a higher prevalence of hypertension. IgM was negatively correlated with BP, while IgG and IgA were positively correlated with BP. PMID- 29416122 TI - New phenolic bisabolane sesquiterpenoid derivatives with cytotoxicity from Aspergillus tennesseensis. AB - Three new bisabolane sesquiterpenoid esters, aspertenols A-B (1-3), and six known compounds (4-9) were isolated from the fungus Aspergillus tennesseensis. The structures of new compounds were elucidated by extensive spectroscopic analysis. The cytotoxicities of 1-9 against A549, K562, and ASPC cell lines were tested by using the CCK8 method. Compounds 1, 3, 4, 6, 7, and 9 showed inhibition on K562 cell line with IC50 values in the range from 16.6 to 72.7 MUM. Compounds 1, 4, and 9 showed moderate inhibitory activity against A549 with IC50 of 43.5, 70.2, and 61.1 MUM, respectively. PMID- 29416123 TI - Lysogeny is prevalent and widely distributed in the murine gut microbiota. AB - Bacteriophages are central members and potential modulators of the gut microbiome; however, the ecological and evolutionary relationships of gut bacteria and phages are poorly understood. Here we investigated the abundance and diversity of lysogenic bacteria (lysogens) in the bacterial community of C57BL/6J mice by detecting integrated prophages in genomes reconstructed from the metagenome of commensal bacteria. For the activities of lysogens and prophages, we compared the prophage genomes with the metagenome of free phages. The majority of commensal bacteria in different taxa were identified as lysogens. More lysogens were found among Firmicutes and Proteobacteria, than among Bacteroidetes and Actinobacteria. The prophage genomes shared high sequence similarity with the metagenome of free phages, indicating that most lysogens appeared to be active, and that prophages are spontaneously induced as active phages; dietary interventions changed the composition of the induced prophages. By contrast, CRISPR-Cas systems were present in few commensal bacteria, and were rarely active against gut phages. The structure of the bacteria-phage infection networks was "nested-modular", with modularity emerging across taxonomic scales, indicating that temperate phage features have developed over a long phylogenetic timescale. We concluded that phage generalists contribute to the prevalence of lysogeny in the gut ecosystem. PMID- 29416124 TI - Phylogenetic clustering of small low nucleic acid-content bacteria across diverse freshwater ecosystems. AB - Here we used flow cytometry (FCM) and filtration paired with amplicon sequencing to determine the abundance and composition of small low nucleic acid (LNA) content bacteria in a variety of freshwater ecosystems. We found that FCM clusters associated with LNA-content bacteria were ubiquitous across several ecosystems, varying from 50 to 90% of aquatic bacteria. Using filter-size separation, we separated small LNA-content bacteria (passing 0.4 um filter) from large bacteria (captured on 0.4 um filter) and characterized communities with 16S amplicon sequencing. Small and large bacteria each represented different sub communities within the ecosystems' community. Moreover, we were able to identify individual operational taxonomical units (OTUs) that appeared exclusively with small bacteria (434 OTUs) or exclusively with large bacteria (441 OTUs). Surprisingly, these exclusive OTUs clustered at the phylum level, with many OTUs appearing exclusively with small bacteria identified as candidate phyla (i.e. lacking cultured representatives) and symbionts. We propose that LNA-content bacteria observed with FCM encompass several previously characterized categories of bacteria (ultramicrobacteria, ultra-small bacteria, candidate phyla radiation) that share many traits including small size and metabolic dependencies on other microorganisms. PMID- 29416125 TI - Life on N2O: deciphering the ecophysiology of N2O respiring bacterial communities in a continuous culture. AB - Reduction of the greenhouse gas N2O to N2 is a trait among denitrifying and non denitrifying microorganisms having an N2O reductase, encoded by nosZ. The nosZ phylogeny has two major clades, I and II, and physiological differences among organisms within the clades may affect N2O emissions from ecosystems. To increase our understanding of the ecophysiology of N2O reducers, we determined the thermodynamic growth efficiency of N2O reduction and the selection of N2O reducers under N2O- or acetate-limiting conditions in a continuous culture enriched from a natural community with N2O as electron acceptor and acetate as electron donor. The biomass yields were higher during N2O limitation, irrespective of dilution rate and community composition. The former was corroborated in a continuous culture of Pseudomonas stutzeri and was potentially due to cytotoxic effects of surplus N2O. Denitrifiers were favored over non denitrifying N2O reducers under all conditions and Proteobacteria harboring clade I nosZ dominated. The abundance of nosZ clade II increased when allowing for lower growth rates, but bacteria with nosZ clade I had a higher affinity for N2O, as defined by MUmax/Ks. Thus, the specific growth rate is likely a key factor determining the composition of communities living on N2O respiration under growth limited conditions. PMID- 29416126 TI - Microbial parasites make cyanobacteria blooms less of a trophic dead end than commonly assumed. AB - Parasites exist in every ecosystem and can have large influence on food web structure and function, yet, we know little about parasites' effect on food web dynamics. Here we investigate the role of microbial parasitism (viruses of bacteria, phytoplankton and cyanobacteria, and parasitic chytrids on cyanobacteria) on the dynamics of trophic pathways and food web functioning during a cyanobacteria bloom, using linear inverse food web modeling parameterized with a 2-month long data set (biomasses, infection parameters, etc.). We show the importance of grazing on heterotrophic bacteria (the microbial pathway: DOC -> bacteria -> consumer) and how consumers depended on bacteria during peak-cyanobacteria bloom, which abundance was partly driven by the viral activity. As bacteria become the main energy pathway to the consumers, the system takes a more web-like structure through increased omnivory, and may thereby facilitate the system's persistence to the cyanobacteria outbreak. We also showed how the killing of cyanobacteria host cells by chytrids had important impact on the food web dynamics by facilitating grazing on the cyanobacteria, and by offering alternative pathways to the consumers. This seemed to increase the system's ability to return to a mix of trophic pathways, which theoretically increases the stability of the system. PMID- 29416127 TI - Neural repair: Tagging mRNA drives regeneration. PMID- 29416130 TI - Spondyloarthritis: Effects of certolizumab pegol sustained at 4 years. PMID- 29416131 TI - Degenerative disc disease: Circular RNA reduces cell death in IVD disease. PMID- 29416132 TI - Systemic lupus erythematosus: NIKing BAFF's limelight. PMID- 29416129 TI - B cells in the pathogenesis of primary Sjogren syndrome. AB - Primary Sjogren syndrome (pSS) is a prototypical autoimmune disease. The involvement of B cells in the pathogenesis of pSS has long been suspected on the basis of clinical observations that include the presence of serum autoantibodies, hypergammaglobulinaemia, increased levels of free light chains and increased risk of B cell lymphoma. Moreover, the composition of the B cell subset is altered in pSS. In this Review, we discuss the mechanisms that support the increased activation of B cells in pSS, including genetic and epigenetic factors and environmental triggers that promote B cell activation via the innate immune system. B cell activating factor (BAFF, also known as TNF ligand superfamily member 13B) is at the crossroads of this process. An important role also exists for the target tissue (exocrine glands, namely the salivary and lachrymal glands), which promotes local B cell activation. This continuous stimulation of B cells is the main driver of lymphomatous escape. Identification of the multiple steps that support B cell activation has led to the development of promising targeted therapies that will hopefully lead to the development of an efficient therapeutic strategy for pSS. PMID- 29416128 TI - Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. AB - Acute nociceptive pain is a key defence system that enables the detection of danger signals that threaten homeostasis and survival. However, chronic pain (such as the neuropathic pain that occurs after peripheral nerve injury) is not simply a consequence of the continuity of acute nociceptive signals but rather of maladaptive nervous system function. Over recent decades, studies have provided evidence for the necessity and sufficiency of microglia for the alterations in synaptic remodelling, connectivity and network function that underlie chronic pain and have shed light on the underlying molecular and cellular mechanisms. It is also becoming clear that microglia have active roles in brain regions important for the emotional and memory-related aspects of chronic pain. Recent advances in the development of new drugs targeting microglia and the establishment of new sources of human microglia-like cells may facilitate translation of these findings from bench to bedside. PMID- 29416133 TI - Rheumatoid arthritis: Long-term mavrilimumab safe and effective. PMID- 29416135 TI - Experimental arthritis: Targeting proteolysis to halt arthritis. PMID- 29416134 TI - The B cell response to citrullinated antigens in the development of rheumatoid arthritis. AB - The immune response to citrullinated antigens is found almost exclusively in patients with rheumatoid arthritis (RA). It is a dynamic response that expands before the onset of disease and generates antibodies (anti-citrullinated protein antibodies (ACPAs)) that are extensively glycosylated in the variable domain. This feature of ACPAs is remarkable and warrants detailed investigation, as it can offer insights into the earliest immunologic mechanisms that lead up to the development of RA. The acquisition of variable domain glycans, in fact, could enable ACPA-expressing B cells to breach tolerance. Although the underlying mechanisms are still elusive, data to support this concept are emerging, owing to the reliable identification and isolation of citrullinated antigen-directed B cells from patients with RA. This technological proficiency also allows for the generation of an increasing number of well-defined monoclonal ACPAs, and provides the opportunity to test and define the mechanisms by which the citrullinated antigen-directed B cell response contributes to the onset and persistence of inflammation. Together with a revised perception of the HLA-risk effect and novel insights into how T cells can govern antibody effector functions, these developments shape an increasingly clear picture of the B cell response to citrullinated antigens in the development of RA. PMID- 29416137 TI - Acute inflammatory arthritis: Methotrexate for chronic chikungunya arthritis? PMID- 29416138 TI - Spondyloarthritis: Which composite measures to use in psoriatic arthritis? PMID- 29416139 TI - Connective tissue diseases: T cells in blood mark Sjogren syndrome activity. PMID- 29416136 TI - Proteinases and their receptors in inflammatory arthritis: an overview. AB - Proteinases are enzymes with established roles in physiological and pathological processes such as digestion and the homeostasis, destruction and repair of tissues. Over the past few years, the hormone-like properties of circulating proteinases have become increasingly appreciated. Some proteolytic enzymes trigger cell signalling via proteinase-activated receptors, a family of G protein coupled receptors that have been implicated in inflammation and pain in inflammatory arthritis. Proteinases can also regulate ion flux owing to the cross sensitization of transient receptor potential cation channel subfamily V members 1 and 4, which are associated with mechanosensing and pain. In this Review, the idea that proteinases have the potential to orchestrate inflammatory signals by interacting with receptors on cells within the synovial microenvironment of an inflamed joint is revisited in three arthritic diseases: osteoarthritis, spondyloarthritis and rheumatoid arthritis. Unanswered questions are highlighted and the therapeutic potential of modulating this proteinase-receptor axis for the management of disease in patients with these types of arthritis is also discussed. PMID- 29416140 TI - Letter to the Editor (August 24, 2017) concerning the paper "Occupational exposure to radon for underground tourist routes in Poland: Doses to lung and the risk of developing lung cancer". PMID- 29416141 TI - Authors' response (December 8, 2017) to the letter to the Editor concerning the paper "Occupational exposure to radon for underground tourist routes in Poland: Doses to lung and the risk of developing lung cancer". PMID- 29416142 TI - Adjusted fluoride concentrations and control ranges in 34 states - 2006-2010 and 2015. AB - To inform selection of a control range around the Public Health Service's recommended 0.7 mg/L drinking water fluoride concentration to prevent tooth decay, CDC's Water Fluoridation Reporting System data for 2006-2010 and 2015 were analyzed. Monthly average concentration data from 4,251 fluoride-adjusted community water systems for 191,266 of 255,060 system-months (2006-2010) were compared to control ranges 0.6 mg/L to 0.2 mg/L wide. Percentages of system months within control ranges >=0.4 mg/L wide (e.g., +/-0.2 mg/L) were >83% versus 68% for 0.2 mg/L wide (+/-0.1 mg/L). In 2015, 70% of adjusted systems maintained averages within +/-0.1 mg/L of their system's annual average for 9 of 12 months, 67% used the 0.7 mg/L target and 45% used it with a +/-0.1 mg/L control range. Adoption of the 0.7 mg/L target was underway but not completed in 2015. Control ranges narrower than +/-0.2 mg/L may be feasible for monthly average fluoride concentration. PMID- 29416143 TI - Health and Well-Being of Children in Kinship Care: Findings from the National Survey of Children in Nonparental Care. AB - This study uses nationally representative survey data to describe differences in characteristics, adverse family experiences, and child well-being among children in kinship care with varying levels of involvement with the child welfare system. Well-being is examined in the domains of physical and mental health, education, and permanency. Comparisons provide insight on kinship care arrangements inside and outside the child welfare system, as well as the variability among nonfoster kinship care arrangements. PMID- 29416144 TI - Leadership in anaesthesiology through mentoring. PMID- 29416145 TI - Clinical trial registration: A practical perspective. AB - The increase in the number of clinical trials, driven mainly for career advancement mandated by regulatory bodies such as Medical Council of India risks output of substandard publications and also wastage of resources. There are also concerns of inadequate reporting and wilful concealment of results. The quality and quantity of the output become questionable evidences for medical practice. Lack of transparency can lead to disillusionment of the public in the medical field. Clinical trials registration seeks to regulate and streamline the clinical trials by mandating registration in various registries, through free for registration sites such as Clinical Trials Registry of India (CTRI). The guidelines are based on the World Health Organisation's International Clinical Trials Registry Platform (ICTRP). This review aims to highlight the types of registries, the registration process, the data that need to be registered, the guide to use the CTRI and the search options in CTRI and ICTRP. The role of International Committee of Medical Journal Editors is also highlighted in regard to not only registration but also on the publication of trial registration number in the manuscript. PMID- 29416146 TI - Time spent by patients in a pre-anaesthetic clinic and the factors affecting it: An audit from a tertiary care teaching hospital. AB - Background and Aims: Patient satisfaction from a pre-anaesthetic clinic (PAC) visit is greatly influenced by time spent there. We aimed to determine time spent in a PAC without an appointment system and the factors affecting the same. Methods: Four hundred and eight patients coming to PAC were tracked using a time motion study model. Time spent in waiting and consultation was recorded. Independent variables potentially affecting time spent were documented. Patients were grouped based on independent variables, and the groups were compared for significant differences using appropriate statistical tests. Workload pending on physicians was calculated on an hourly basis by counting number of patients waiting and number of physicians in PAC. Results: Non-parametric statistical tests were used for analysis because the data were not normally distributed. The median and inter-quartile range for waiting time, consultation time and total time were 60 (30-90) minutes, 17 (12-26) minutes and 79 (53-111) minutes, respectively. There was considerable variation in all three. Waiting time was significantly lower in patients posted for same-day surgery or those arriving on a stretcher or wheelchair. Consultation time was correlated with American Society of Anesthesiologists physical status and grade of surgery. Most patients arrived in the morning rather than at equal intervals. Waiting time and workload were therefore maximum in the midmorning and dropped rapidly in the afternoon. Conclusion: Large variability in waiting time is linked to lack of an appointment system, and to patients being seen out of turn. PMID- 29416147 TI - Abnormal routine pre-operative test results and their impact on anaesthetic management: An observational study. AB - Background and Aims: One of the reasons for continued routine pre-operative testing practice is the identification of hidden problems which may affect perioperative management. This study was aimed to assess the prevalence of abnormal test results, their impact on perioperative management and cost effectiveness for detecting such abnormalities. Methods: This observational study was conducted by screening the files of the patients attending pre-anaesthetic check-up during December 2016-January 2017. Patients' physical status, surgery grade, normal and abnormal test results and different impacts were noted and expressed in absolute numbers/percentage. Number needed to investigate (NNI) to detect a significant abnormality was calculated. Results: Data of 414 patients (46.3% male) with mean +/- standard deviation age 43.78 +/- 17.24 years and 58.65 +/- 12.93 kg weight were analysed. Patients were mostly American Society of Anesthesiologists II and underwent National Institute of Clinical and Health Excellence Grade 3 surgeries. Totally, 345 (11.6%) test results were abnormal. Only 56 (16.2%) abnormalities had an impact in terms of referral, further investigations or delay. Twenty were significant in terms of changing perioperative anaesthetic management. Laboratory abnormalities with non significant impact resulted in median delay of 3 days (range 1 to 12 days). The NNI for a significant impact and detecting new abnormality was 21 and 28, respectively. Conclusion: Majority (57.2%) of the patients had at least one abnormal routine test result but only 1.8% abnormalities had significant impact. The NNI to find a significant impact or hidden comorbidity was more than 20. PMID- 29416148 TI - Assessment of malnutrition and enteral feeding practices in the critically ill: A single-centre observational study. AB - Background and Aims: Early identification of malnutrition among hospitalised patients is essential to institute appropriate patient-specific nutritional strategies. This study was conducted to evaluate the nutritional status of medical patients at admission to the adult intensive care unit (ICU) and to identify factors which prevent attainment of daily feeding goals in them. Methods: This was a 1 year prospective, observational study on 200 medical adult ICU patients. The study was carried out based on daily documentation. The primary outcome was the nutritional status of medical Patients at admission to the adult ICU. The tests for statistical analysis used were independent t test, Chi-square test, Fisher's exact test and multivariate logistic regression analysis. Results: Out of the 200 patients in our study, 45%, 48.5% and 9% of patients had mild, moderate and severe malnutrition, respectively, corresponding to subjective global assessment (SGA) rating A,B and C, respectively. The most common reasons for non-attainment of daily feeding goals were delayed feed procurement (17.57%), and feeds being held for procedures (16.36%). The overall mean length of ICU stay was 8.63 +/- 7.26 days, and the ICU mortality rate was 47.5% (95/200). Patients with SGA rating B and C at admission had higher risk of mortality in the ICU, with an adjusted odds ratio of 3.54 (95% confidence interval [CI]- 1.71-7.33, P = 0.001) and 11.11 (95% CI-2.26-54.66, P = 0.003), respectively. Conclusion: Malnutrition is commonly present at admission among medical ICU patients, and is associated with higher ICU mortality. PMID- 29416149 TI - Maternal and anaesthesia-related risk factors and incidence of spinal anaesthesia induced hypotension in elective caesarean section: A multinomial logistic regression. AB - Background and Aims: Although spinal anaesthesia (SA) is nowadays the preferred anaesthesia technique for caesarean section (CS), it is associated with considerable haemodynamic effects, such as maternal hypotension. This study aimed to evaluate a wide range of variables (related to parturient and anaesthesia techniques) associated with the incidence of different degrees of SA-induced hypotension during elective CS. Methods: This prospective study was conducted on 511 mother-infant pairs, in which the mother underwent elective CS under SA. The data were collected through preset proforma containing three parts related to the parturient, anaesthetic techniques and a table for recording maternal blood pressure. It was hypothesized that some maternal (such as age) and anaesthesia related risk factors (such as block height) were associated with occurance of SA induced hypotension during elective CS. Results: The incidence of mild, moderate and severe hypotension was 20%, 35% and 40%, respectively. Eventually, ten risk factors were found to be associated with hypotension, including age >35 years, body mass index >=25 kg/m2, 11-20 kg weight gain, gravidity >=4, history of hypotension, baseline systolic blood pressure (SBP) <120 mmHg and baseline heart rate >100 beats/min in maternal modelling, fluid preloading >=1000 ml, adding sufentanil to bupivacaine and sensory block height >T4in anaesthesia-related modelling (P < 0.05). Conclusion: Age, body mass index, weight gain, gravidity, history of hypotension, baseline SBP and heart rate, fluid preloading, adding sufentanil to bupivacaine and sensory block hieght were the main risk factors identified in the study for SA-induced hypotension during CS. PMID- 29416150 TI - Admission Vitamin D status does not predict outcome of critically ill patients on mechanical ventilation: An observational pilot study. AB - Background and Aims: Effect of serum 25-hydroxy vitamin D (25[OH] D) levels on the recovery of critically ill mechanically ventilated patients is unclear. Hence, this study assessed 25(OH)D levels of critically ill patients on mechanical ventilation at the time of admission to the Intensive Care Unit (ICU) and its relationship with clinical outcome. Methods: In this prospective observational pilot study, forty adult patients receiving mechanical ventilation in the ICU were included. Serum 25(OH)D was assessed within 24 h of admission. Primary outcome was 30-day mortality and secondary outcomes were days on mechanical ventilation, ICU-length of stay (ICU-LOS), days to reach spontaneous breathing trial (SBT), requirement of advanced care modality and complications. Results: Seventy-five percent patients had low serum 25(OH)D (65% deficient and 10% insufficient). Between patients with low and normal vitamin D, there was no significant difference in 30-day mortality (10% vs. 16.7%; P = 0.81), days on mechanical ventilation (16.2 +/- 8.9 vs. 19.9 +/- 8.4; P = 0.23), ICU-length of stay (18.7 +/- 8.5 vs. 23.3 +/- 11.4; P = 0.28), days to reach SBT (11.5 (0-20) vs. 21 (8-30); P = 0.78), complications developed during ICU stay (P = 0.60) and need for advanced care modalities (P = 0.72). Conclusion: Low Vitamin D level at admission did not affect 30-day mortality of critically ill patients on mechanical ventilation. PMID- 29416151 TI - Pre-procedure ultrasound-guided paramedian spinal anaesthesia at L5-S1: Is this better than landmark-guided midline approach? A randomised controlled trial. AB - Background and Aims: Routine use of pre-procedural ultrasound guided midline approach has not shown to improve success rate in administering subarachnoid block. The study hypothesis was that the routine use of pre-procedural (not real time) ultrasound-guided paramedian spinals at L5-S1 interspace could reduce the number of passes (i.e., withdrawal and redirection of spinal needle without exiting the skin) required to enter the subarachnoid space when compared to the conventional landmark-guided midline approach. Methods: After local ethics approval, 120 consenting patients scheduled for elective total joint replacements (Hip and Knee) were randomised into either Group C where conventional midline approach with palpated landmarks was used or Group P where pre-procedural ultrasound was used to perform subarachnoid block by paramedian approach at L5-S1 interspace (real time ultrasound guidance was not used). Results: There was no difference in primary outcome (difference in number of passes) between the two groups. Similarly there was no difference in the number of attempts (i.e., the number of times the spinal needle was withdrawn from the skin and reinserted). The first pass success rates (1 attempt and 1 pass) was significantly greater in Group C compared to Group P [43% vs. 22%, P = 0.02]. Conclusion: Routine use of paramedian spinal anaesthesia at L5-S1 interspace, guided by pre-procedure ultrasound, in patients undergoing lower limb joint arthroplasties did not reduce the number of passes or attempts needed to achieve successful dural puncture. PMID- 29416152 TI - A prospective observational study comparing criteria-based discharge method with traditional time-based discharge method for discharging patients from post anaesthesia care unit undergoing ambulatory or outpatient minor surgeries under general anaesthesia. AB - Background and Aims: Mostly, institutions in India have single post-anaesthesia care unit (PACU) which follows traditional time-based discharge (TBD) method. Recently, it has been classified into PACU Phase I and Phase II, and criteria based discharge (CBD) method has been used. This study primarily compares CBD versus TBD methods in moving patients through PACU, and other non-clinical factors causing delay in shifting. Methods: One hundred patients, aged 18-65 years, American Society of Anesthesiologist's physical status I and II, scheduled for elective minor surgeries under general anaesthesia were studied. White's fast track score in operating room (OR) and modified Aldrete's score (CBD time) in PACU were recorded. Patients were scheduled to discharge at 60 min based on TBD method. The mean CBD time and actual discharge time from PACU were statistically compared with TBD time. Other non-clinical factors delaying the discharge were also studied. Results: Eighty-five percent of patients achieved acceptable White's fast-track score in OR. The TBD time (60 min) was compared with the mean CBD time (10.70 +/- 2.56 min) and actual discharge time (79.75 +/- 12.98 min), which were found to be statistically significant. Primarily, anaesthesiologists' busy schedule was accountable for delay in discharge. Conclusion: The study concluded that in patients undergoing ambulatory minor surgeries, discharge times based on Criterion Based Discharge scoring systems such as modified Aldrete's and White's-fast are significantly lower in PACU Phase I as compared to the traditional Time Based Discharge method. PMID- 29416153 TI - Effect of inhaled budesonide suspension, administered using a metered dose inhaler, on post-operative sore throat, hoarseness of voice and cough. AB - Background and Aims: Post-operative sore throat (POST) is often considered an inevitable consequence of tracheal intubation. This study was performed to compare the effect of inhaled budesonide suspension, administered using a metered dose inhaler, on the incidence and severity of POST. Methods: In this prospective randomised study, 46 patients undergoing laparoscopic surgeries lasting <2 h were randomly allotted into two equal groups. Group A received 200 MUg budesonide inhalation suspension, using a metered dose inhaler, 10 min before intubation, and repeated 6 h after extubation. No such intervention was performed in Group B. The primary outcome was the incidence and severity of POST. Secondary outocomes included the incidence of post-operative hoarseness and cough. Pearson's Chi square test, Fisher's exact test and Independent sample t-test were used as applicable. Results: Compared to Group B, significantly fewer patients had POST in Group A at 2, 6, 12 and 24 h (P < 0.001). Although more patients in Group B had post-operative hoarseness of voice and cough at all-time points, the difference was statistically significant only at 12 h and 24 h for post-operative hoarseness and at 2 h and 12 h for post-operative cough. Severity as well as the incidence of POST showed downward trends in both groups over time, and by 24 h no patient in Group A had sore throat. Conclusion: Inhaled budesonide suspension is effective in significantly reducing the incidence and severity of POST. PMID- 29416154 TI - Undiagnosed intraoperative methaemoglobinaemia. AB - Methaemoglobinaemia is a rare but potentially dangerous haemoglobinopathy that is often underdiagnosed. It is one of the causes for unexplained cyanosis with dark coloured blood, especially in the absence of cardiac or pulmonary pathology. Not uncommonly so, it is an incidental perioperative finding in cases of dark coloured blood not improving with oxygen in apparently acyanotic patients. The present case report is of a child with deaf-mutism posted for cochlear implant surgery who presented with 'chocolate-coloured blood' in the surgical field, despite blood gas analysis showing a normal partial pressure of oxygen. PMID- 29416155 TI - Erector spinae plane block as an alternative to epidural analgesia for post operative analgesia following video-assisted thoracoscopic surgery: A case study and a literature review on the spread of local anaesthetic in the erector spinae plane. AB - Post-operative pain after minimally invasive video-assisted thoracoscopic surgery (VATS) in adults is commonly managed with oral and parenteral opioids and invasive regional techniques such as thoracic epidural blockade. Emerging research has shown that the novel erector spinae plane (ESP) block, can be employed as a simple and safe alternative analgesic technique for acute post surgical, post-traumatic and chronic neuropathic thoracic pain in adults. We illustrate this by presenting a paediatric case of VATS, in which an ESP block provided better analgesia, due to greater dermatomal coverage, as well as reduced side-effects when compared with a thoracic epidural that had previously been employed on the same patient for a similar procedure on the opposite side. PMID- 29416156 TI - Subcutaneous emphysema - An unexpected cause for respiratory distress during vitreoretinal surgery under peribulbar block. PMID- 29416157 TI - Use of caudal epidural catheter in a child with cerebral palsy with prior posterior spine (T1-sacrum) fusion. PMID- 29416158 TI - Keloid formation on neck after jugular central venous catheter placement: An unsightly unusual complication in a young female. PMID- 29416159 TI - Central core disease with scoliosis for congenital hip dislocation surgery: An anaesthetic demur. PMID- 29416160 TI - Sustained intraoperative bradycardia revealing Sengers syndrome. PMID- 29416161 TI - Comment on 'Sustained intraoperative bradycardia revealing Sengers syndrome'. PMID- 29416162 TI - Musculoskeletal Oncology: Finding Its Place in the Sun! PMID- 29416163 TI - Fibulectomy for Primary Proximal Fibular Bone Tumors: A Functional and Clinical Outcome in 46 Patients. AB - Background: Primary benign and malignant tumors of the proximal fibula are not very common. Upper fibula being an expendable bone; the majority of the primary bone tumors at this site are usually treated with en bloc proximal fibulectomy. There is scarce literature on functional results, difficulties faced during dissection when to preserve or sacrifice common peroneal nerve and importance of lateral collateral ligament repair after proximal fibulectomy. The present study attempts at assessing these variables. Materials and Methods: This retrospective study included 46 patients; 30 males and 16 females with age ranging from 12 to 44 years (average: 26 years) operated between 2003 and 2014. There were 34 benign and 12 malignant tumors. All were treated with proximal en bloc fibulectomy as indicated and decided by the operating surgeon keeping in view its extent on magnetic resonance imaging. Peroneal nerve sacrifice or preservation was decided as per the type (benign/malignant), its involvement by the tumor and the extent of the tumor. In 14 (for 12 malignant and two benign giant cell tumors [GCTs]) patients, the peroneal nerve required resection for the margins. Partial upper tibial resection was performed in cases of malignant tumors and three GCTs. The followup ranged between 24 and 120 months (median: 48 months). Results: Patients with peroneal nerve resection had inferior functional outcome than those without peroneal nerve resection. There was no higher risk of tibia fracture in patients with partial tibial resection. Lateral collateral reconstruction yielded better results and should be performed in all cases. Functional outcome was significantly better in patients with benign tumors than in patients with malignant tumors as these required neither resection of the peroneal nerve nor large amount of muscle excision. The functional results were evaluated using Musculoskeletal Tumor Society (MSTS) score, and clinical outcomes were evaluated using knee and ankle movements and stability. The overall average MSTS score was 26.50. Conclusions: With good reconstruction of lateral ligament we can achieve good results after proximal fibulectomy for benign as well as malignant tumor without much instability. With partial upper tibial resection (i.e., the extra articular resection of proximal tibiofibular joint) adequate margins are feasible even in malignant tumors. PMID- 29416164 TI - Retrospective Analysis of Giant Cell Tumor Lower End Radius Treated with En bloc Excision and Translocation of Ulna. AB - Background: Distal end of radius is third most common site for GCT of long bones and 1% of these metastasize mostly to lungs. Reconstruction methods commonly used are fibula (vascularized and nonvascularized), centralization of ulna, translocation of ulna, and endoprosthetic replacement. We report the outcome of series of twenty cases where we did en bloc excision of tumor with translocation of ulna. Materials and Methods: Twenty cases of giant cell tumor (GCT) of lower end of radius were included in this retrospective study. The mean age of patients was 33.15 years (range 21-55 years). We had 14 of Campanacci Grade III and 6 of Grade II. Preoperative radiographs and magnetic resonance imaging of the involved wrist and forearm were done. Results: Of all twenty patients, 14 were males and 6 were females. Mean followup duration was 3.9 years (range 1.5-17 years). Mean grip strength of involved side as a percentage of normal side was 71% (range 42% 86%) and the actual mean value for operated side was 29 kg as compared to 40 kg for normal side. The average range of forearm movement was supination 80.25 degrees (60 degrees -90 degrees ) and pronation 77.5 degrees (70 degrees -90 degrees ). No patient was dissatisfied as far as cosmesis was concerned. Discussion: In our opinion considering the propensity to recur with more aggressiveness after recurrence, en bloc excision with translocation of ulna has become a standard treatment option for GCT of lower end of radius, with advantages of better functional outcomes, retained vascularity, and elimination of risk of donor site morbidity. PMID- 29416165 TI - Distal Medullary Canal Decompression in Long Stem Hip Replacement in Long Bone Metastasis: Does it Reduce Cardiopulmonary Complications? AB - Background: The femur is the most common long bone affected by metastatic bone disease, with 25% involving the proximal third of the femur. Long stem cemented hip replacement (LHR) is an important option for cases of impending fracture. Pulmonary embolism is a critical complication that can occur. This study evaluates the effectiveness of distal femoral canal decompression in reducing the risk of cardiopulmonary events. Materials and Methods: Thirty two patients with metastatic bone disease of the proximal femur undergoing LHR were recruited and randomized. Conventional technique was used in 16 cases and distal decompression of the medullary canal was carried out for the other 16 patients. The decompression was carried out through a trocar inserted into the distal medullary canal, connected to a vacuum suction. Quantity of emboli was detected through A4 chambers transesophageal echocardiography; the blood pressure and oxygen saturation readings were also recorded. Results: The decompression group experienced significantly lower Grade 2 and Grade 3 embolic events compared to the conventional group (11 vs. 26), and the duration of the embolic phenomena was shorter. Insertion of the stem and relocating the hip gave the highest amount embolic events. There was a significant drop in systolic blood pressure (SBP) in 12 out of 16 patients (75.0%) in the conventional group and 5 out of 16 patients in the decompression group (31.3%). This is statically significant (P = 0.0124). The average drop in SBP for the conventional group is 45.8 mmHg and the decompression group was 32.9 mmHg. Oxygen saturation remained at above 96% in the decompression group. However, in the conventional group, 25% of the patients had their oxygen saturation drop to below 96% during the insertion of stem and relocation of hip joint. Conclusion: Distal femoral canal decompression is an effective method in reducing the risk of cardiopulmonary embolic events associated with LHR. PMID- 29416166 TI - Navigation in Musculoskeletal Oncology: An Overview. AB - Navigation in surgery has increasingly become more commonplace. The use of this technological advancement has enabled ever more complex and detailed surgery to be performed to the benefit of surgeons and patients alike. This is particularly so when applying the use of navigation within the field of orthopedic oncology. The developments in computer processing power coupled with the improvements in scanning technologies have permitted the incorporation of navigational procedures into day-to-day practice. A comprehensive search of PubMed using the search terms "navigation", "orthopaedic" and "oncology" yielded 97 results. After filtering for English language papers, excluding spinal surgery and review articles, this resulted in 38 clinical studies and case reports. These were analyzed in detail by the authors (GM and JS) and the most relevant papers reviewed. We have sought to provide an overview of the main types of navigation systems currently available within orthopedic oncology and to assess some of the evidence behind its use. PMID- 29416167 TI - The Values of Receptor Activator Nuclear Kappa-B Ligand Expression in Stage III Giant Cell Tumor of the Bone. AB - Background: Giant cell tumor (GCT) of bone is a benign locally aggressive primary bone tumor which is risky for local recurrences and pulmonary metastasis. Till date, there are still many uncertainties in predicting the aggressiveness of GCT. We aim to investigate whether receptor activator nuclear kappa-B ligand (RANKL) expression may determine the prognosis of the lesion. Materials and Methods: We examined RANKL expression in 39 patients (21 males, 18 females) by immunohistochemistry. Four patients (10%) were presented with tumor recurrence, eight patients (20%) were complicated with lung metastasis, and two patients (5%) were presented with both recurrence and lung metastasis. Positive RANKL expression was assessed according to a scoring system evaluating the percentage of the immunostained epithelial area and the staining intensity. The cumulative score was calculated to determine the final score value. Data were analyzed using PASW version 18.0 and independent t-test between nonrecurrence/recurrence groups, and nonlung metastasis/lung metastasis groups. Significance was set at P < 0.05. Results: Thirty-two patients (82%) scored 3 in RANKL-staining percentage from whole stromal cell population (>75%), 6 patients scored 2, and 1 patient scored 1. Nine patients (23%) scored 3 in RANKL-staining intensity (most intense), 19 patients (48%) scored 2, and 11 patients (29%) scored 1. Twenty six patients (67%) had strong RANKL expression (total score of 5-6), 12 patients (31%) showed moderate score (3-4) whereas only 1 patient (2%) showed weak RANKL expression. Together, the mean value of RANKL-staining percentage was 2.79, intensity 1.95 and the total score 4.77. The mean RANKL-staining percentage between recurrence and nonrecurrence groups was statistically significant (P = 0.009). There was no significant difference in the mean staining intensity and total score between nonrecurrence and recurrence groups, and staining percentage staining intensity and a total cumulative score of RANKL expression between lung metastasis and nonlung metastasis groups. Conclusion: RANKL expression is generally high in Stage III GCT and is a reliable prognostic marker in predicting the risk of local recurrence however not in lung metastasis. PMID- 29416168 TI - Soft-tissue Sarcomas. AB - This article discusses the epidemiology, diagnosis, and management of primary soft-tissue sarcomas (STS). These musculoskeletal tumors are a rare and heterogeneous group of malignancies, which are best managed by multidisciplinary teams in specialist sarcoma referral centers. Historically, the standard for local control of these tumors has been amputation. Evolutions in multimodality treatment have seen a shift toward preservation of the limb. Advances in limb sparing surgery have seen the quality of life in sarcoma patients to improve drastically; however, unplanned surgical excision of STS remains a major treatment dilemma in the control of local disease. PMID- 29416169 TI - Effect of Intravenous Zoledronic Acid on Histopathology and Recurrence after Extended Curettage in Giant Cell Tumors of Bone: A Comparative Prospective Study. AB - Background: Giant cell tumor (GCT) of the bone is known for its locally aggressive behavior and tendency to recur. It is an admixture of rounded or spindle-shaped mononuclear neoplastic stromal cells and multinucleated osteoclast like giant cells with their proportionate dispersion among the former. Zoledronic acid (a bisphosphonate) is being used in various cancers such as myelomas and metastasis, for osteoporosis with an aim to reduce the resorption of bone, and as an adjuvant treatment for the management of GCT of bone for reduction of local recurrence. We have carried out a prospective comparative study to assess the effect of intravenous infusion of zoledronic acid on histopathology and recurrence of GCT of bone. Materials and Methods: The study was carried out in the biopsy proven GCTs in 37 patients; 15 males and 22 females, in the age range from 17 to 55 years. They were treated with extended curettage. Of these 37 patients, 18 were given three doses of 4 mg zoledronic acid infusion at 3-week intervals and extended curettage was performed 2 weeks after the last infusion whereas the other 19 were treated with extended curettage without zoledronic infusion. The post infusion histopathology of the curetted material was compared with the histopathology of initial biopsy. All the patients were evaluated at 3 month intervals for the first 2 years and then six monthly thereafter, for local recurrence and functional outcome of limb using the Musculoskeletal Tumor Society (MSTS) score. Results: In postzoledronic infusion cases, the histopathology of samples showed abnormal stromal cells secreting matrix leading to fibrosis and calcification. The type of fibrosis and calcification was different from pathological calcification and fibrosis what is usually observed. There was a good marginalization and solidification of tumors which made surgical curettage easier in six cases in the study group. There was noticeable reduction in the number of giant cells and alteration in morphology of stromal cells to the fibroblastic-fibrocytic series type in comparison to preinfusion histopathology. Recurrence occurred in one case out of 18 patients in infusion group whereas in four cases among 19 patients in control group. The functional results were assessed, and the overall average MSTS score was 27.50 (range 24-30) and 27.00 (range 23.50-30) in the study and control groups, respectively. Conclusions: We observed that bisphosphonates reduce osteoclast activity and affects stromal cells in GCT, resulting in the reduction of their numbers and noticeable apoptosis. This results in better marginalization of the lesions and reduced recurrence. Extended curettage of friable GCT became easier and adequate which otherwise might not have been possible. PMID- 29416170 TI - Benign Aggressive Lesions of Femoral Head and Neck: Is Salvage Possible? AB - Background: Benign aggressive bone lesions of the femoral head and neck are mostly seen in young adults and warrant treatment for pain, impending fracture or established fracture, and disease clearance. It becomes challenging to treat them effectively while attempting salvage of the femoral head and yet achieving long term disease control with minimum complications. We describe our technique and experience in dealing with these lesions which can achieve the above-mentioned goals and can be easily replicated. Materials and Methods: We analyzed 15 cases of surgically treated, biopsy-proven benign, locally aggressive lesions affecting the femoral head and neck in skeletally mature individuals. All cases were treated with extended curettage through anterolateral modified Smith-Petersen approach along with tricortical iliac crest bone graft (combined with fibular graft in some cases) reconstruction with or without suitable internal fixation. Results: All, except one, patients were available for follow up. The age ranged from 18 to 43 years and the follow up ranged between 24 and 124 months (average 78 months). These included aneurysmal bone cysts (9), giant cell tumors (4), and fibrous dysplasia (2). The indication was pain (8), with impending (2) or established pathological neck femur fracture (5). In all cases, there was satisfactory healing of lesion and timely rehabilitation. Nonunion, avascular necrosis or local recurrences were not seen. The MSTS functional score was good or excellent in all (range 26-29, average 28). Conclusion: Benign aggressive lesions affecting femoral head and neck in young and middle-aged adults pose a treatment challenge. A sturdy, lasting reconstruct with acceptable functional outcome and minimal recurrence rate can be achieved by salvaging the femoral head and neck using curettage and reconstruction, obviating the need for replacement at such an early age. PMID- 29416171 TI - Methotrexate Free Chemotherapy and Limb Salvage Surgery for Paediatric Osteosarcoma in India. AB - Background: Osteosarcoma (OS) is the most common primary malignant tumor of bone. The survival of OS patients has steadily improved from <20% in the early 20th century to around 70% with current treatment. There are very few studies in pediatric OS from India analyzing various aspects of the disease. This study focuses on the clinical profile, treatment options, and their complications and survival outcomes in pediatric osteosarcoma (OS) patients. Materials and Methods: This was a retrospective observational study which included pediatric patients <14 years of age, with newly diagnosed OS confirmed by histological diagnosis. Medical records of all patients were reviewed for clinical profile, treatment data, surgical management, and treatment complications. Patients alive at the end of treatment were followed up and overall (OAS) and disease-free survival (DFS) were analyzed. Results: Sixty-two patients were diagnosed with OS during the study of whom 55 opted for treatment. Cisplatin, adriamycin, and ifosfamide (PAI) was offered as chemotherapy and was completed as planned in the majority of patients. Limb salvage surgery was performed in most patients (87%, n = 40). The local recurrence occurred in 7 patients. The 3 years overall survival for the cohort was 54.6% +/- 7.8% and DFS was 43.4% +/- 7.9%, with females and those with the localized disease having a significantly better DFS. Conclusions: High dose methotrexate free chemotherapy can give good OAS in localized disease and LSS is feasible in most of the pediatric OS patients. However the modest DFS even for localized disease with PAI chemotherapy and extremely poor outcomes in the metastatic OS, demand further research and innovations in systemic therapy to improve outcomes. PMID- 29416172 TI - Gait Analysis in Patients with Wide Resection and Endoprosthesis Replacement Around the Knee. AB - Background: Limb salvage surgery with endoprosthesis for bone tumor around the knee is reported to have good functional and oncological outcomes. However, the functional assessment using musculoskeletal tumor society (MSTS) and Toronto extremity scoring system remains subjective. We performed gait analysis as an objective assessment of their functional outcome. Materials and Methods: Gait analysis was performed in 20 patients with endoprosthesis replacement around the knee. The temporal parameters assessed during gait analysis were walking velocity, stride length, duration of stance, and goniometry of the knee. These parameters were compared with the functional outcome score of the MSTS. Results: The mean free-paced walking velocity was 0.91 m/s (normal is 1.33 m/s), which was 68% lower than normal gait. The stride length and stance phase were shorter for the affected limb compared to normal (P < 0.05). However, the gait was symmetrical with no difference in stride length (P = 0.148), velocity (P = 0.918), knee flexion (P = 0.465), and knee extension (P = 0.321) between the affected and unaffected limbs. Sixteen patients demonstrated stiff knee gait, two had a flexed knee gait, and only two patients had normal gait during the stance phase. The mean MSTS score was 21. There was significant correlation between overall MSTS scores (P = 0.023), function (P = 0.039), and walking scores (P = 0.007). Conclusion: Limb salvage surgery with endoprosthesis reconstruction around the knee gives good functional outcome, both objectively and subjectively, as evidenced by the symmetrical gait pattern and significant correlation with MSTS score. Despite decreased walking velocity, stride length, and stance phase of the operated limb, the patient still has a symmetrical gait. PMID- 29416173 TI - Does Radiotherapy after Surgery Affect Outcomes in Ewing's Sarcoma of the Pelvis? AB - Background: The impact of postoperative radiotherapy (PORT) on outcomes has been a matter of debate after adequate resection in Ewing's sarcoma of the pelvis. We evaluated our cases after surgical excision in pelvic Ewing's sarcoma and assessed local control and overall survival (OS) with respect to PORT and chemotherapy-induced percentage necrosis. Materials and Methods: Forty four surgically operated patients (June 2002-November 2014) of localized Ewing's sarcoma were retrospectively reviewed. There were 31 males and 13 females. Age ranged from 2 to 53 years. All patients received institutional chemotherapy protocol. No patient received preoperative radiotherapy. Specimen was analyzed for margins and chemotherapy-induced percentage necrosis. PORT was offered to patients on case-by-case basis. Presence of a large preoperative soft-tissue component, margin evaluation, and percentage necrosis were factors considered. At time of the last followup, 29 patients were alive, 11 died, and 4 were lost to followup. Survivors had a minimum followup of 2 years (range: 31-118 months, mean = 69 months). Results: One of twenty (5%) patients with PORT had a local recurrence as against 2 of 24 (8%) without PORT. OS of all patients was 76% at 5 years. Twelve patients with <90% necrosis had OS of 56% and 32 with >90% necrosis had OS of 83% (P = 0.040). OS of patients with PORT was 74%, without PORT was 78% (P = 0.629). Conclusions: The decision to offer PORT after surgical excision in pelvic Ewing's sarcoma is multifactorial; the absence of PORT in selected cases is not detrimental to local control. Poor responders to chemotherapy had poorer survival while PORT did not impact on outcomes. PMID- 29416174 TI - Considerations for the Long Term Treatment of Pediatric Sarcoma Survivors. AB - Sarcomas are primary malignancies of the connective tissues. They are exceedingly rare in adults, but much more common in children. The historically recent advent of cytotoxic chemotherapy for pediatric sarcomas has revolutionized the treatment of these diseases and dramatically improved their prognoses. There is thus a population of pediatric sarcoma survivors that are "coming of age" as adults. However, this progress is not without consequences. Due to aggressive treatment protocols that include various combinations of surgery, chemotherapy, and radiation therapy, pediatric sarcoma survivors are at risk of myriad physical, medical, and psychological difficulties as they enter adulthood. These include but are not limited to physical disabilities, chemotherapy-induced cardiac issues, second malignancies, and anxiety. These patients pose unique challenges to their adult primary care physicians. One possible solution to these challenges is multidisciplinary sarcoma survivorship clinics. By paying greater attention to the unique issues of pediatric sarcoma survivors, involved physicians can maximize the physical and emotional health of pediatric sarcoma survivors. PMID- 29416175 TI - Could Routine Magnetic Resonance Imaging Detect Local Recurrence of Musculoskeletal Sarcomas Earlier? A Cost-effectiveness Study. AB - Background: Current practice in our unit is to perform clinical assessment and plain film radiographs at regular intervals following treatment of a bone or soft tissue sarcoma (STS). Cross-sectional imaging is used in cases with a clinical suspicion of recurrence. We aimed to investigate the effectiveness of this protocol to determine if earlier detection may have been possible had more intensive imaging been undertaken, and whether this may have affected outcome. Materials and Methods: We reviewed clinical records and imaging of all patients with diagnosed local recurrence (LR) in the previous 5 years to investigate: how it was diagnosed, the site and size of recurrence, and management. A value judgment was then made as to whether earlier diagnosis may have altered treatment and/or outcome. Results: 161 patients with LR were identified: 87 with a STS and 74 with bone sarcoma. Median time from diagnosis to LR was 17.8 months for STS and 20.1 months for bone sarcoma. One hundred and fifteen cases (71%) were identified by the patient, 28 by routine imaging (17%), 13 by a doctor (8%), and five diagnosed by other methods. Median size of LR was 5.5 cm for STS and 5 cm for bone sarcomas. Seventy nine of the patients (49%) could have had their LR diagnosed earlier with routine imaging. Of these, 53 would have received the same treatment, but 26 (33%) could have had different treatment. Conclusion: Earlier diagnosis could have led to altered management in one-third of those patients with the potential to have their LR diagnosed earlier. If all patients had regular magnetic resonance imaging, it would cost L6987 per recurrence where management was altered in imaging costs alone. We suggest a stratified approach whereby patients at highest risk of LR and those in whom early detection of LR may be easily treatable are prioritised for more intensive followup. PMID- 29416177 TI - Legends of Indian Orthopedics: Puliyur Krishnaswamy Duraiswami. PMID- 29416176 TI - Spontaneous Conventional Osteosarcoma Transformation of a Chondroblastoma: A Case Report and Literature Review. AB - Chondroblastomas are a primary benign cartilaginous tumor that accounts for approximately 1% of all benign bone tumors. Primarily they are treated by curettage. The patient presented 4 years after a successfully treated chondroblastoma (curettage and Bone cement). Wide resection of the proximal tibia with endoprosthesis replacement was done. Lung CT showed multiple lung metastasis and despite starting chemotherapy, he succumbed to the disease. We discuss regarding the possibilities of "aggressive" chondroblastoma and more recently termed chondroblastoma-like osteosarcoma which is a separate entity from chondroblastoma. Aggressiveness in chondroblastoma can be 1 of 3 types as follows: 1. benign chondroblastoma with lung metastasis. 2. malignant chondroblastoma. 3. subsequent malignant transformation of benign chondroblastoma. We have attempted to review the literature and describe the "aggressive" chondroblastoma and chondroblastoma-like osteosarcoma in this report. PMID- 29416178 TI - Weapons, Body Postures, and the Quest for Dominance in Robberies: A Qualitative Analysis of Video Footage. AB - Objective: A small-scale exploration of the use of video analysis to study robberies. We analyze the use of weapons as part of the body posturing of robbers as they attempt to attain dominance. Methods: Qualitative analyses of video footage of 23 shop robberies. We used Observer XT software (version 12) for fine grained multimodal coding, capturing diverse bodily behavior by various actors simultaneously. We also constructed story lines to understand the robberies as hermeneutic whole cases. Results: Robbers attain dominance by using weapons that afford aggrandizing posturing and forward movements. Guns rather than knives seemed to fit more easily with such posturing. Also, victims were more likely to show minimizing postures when confronted with guns. Thus, guns, as part of aggrandizing posturing, offer more support to robbers' claims to dominance in addition to their more lethal power. In the cases where resistance occurred, robbers either expressed insecure body movements or minimizing postures and related weapon usage or they failed to impose a robbery frame as the victims did not seem to comprehend the situation initially. Conclusions: Video analysis opens up a new perspective of how violent crime unfolds as sequences of bodily movements. We provide methodological recommendations and suggest a larger scale comparative project. PMID- 29416179 TI - Foam property tests to evaluate the potential for longwall shield dust control. AB - Tests were conducted to determine properties of four foam agents for their potential use in longwall mining dust control. Foam has been tried in underground mining in the past for dust control and is currently being reconsidered for use in underground coal longwall operations in order to help those operations comply with the Mine Safety and Health Administration's lower coal mine respirable dust standard of 1.5 mg/m3. Foams were generated using two different methods. One method used compressed air and water pressure to generate foam, while the other method used low-pressure air generated by a blower and water pressure using a foam generator developed by the U.S. National Institute for Occupational Safety and Health. Foam property tests, consisting of a foam expansion ratio test and a water drainage test, were conducted to classify foams. Compressed-air-generated foams tended to have low expansion ratios, from 10 to 19, with high water drainage. Blower-air-generated foams had higher foam expansion ratios, from 30 to 60, with lower water drainage. Foams produced within these ranges of expansion ratios are stable and potentially suitable for dust control. The test results eliminated two foam agents for future testing because they had poor expansion ratios. The remaining two foam agents seem to have properties adequate for dust control. These material property tests can be used to classify foams for their potential use in longwall mining dust control. PMID- 29416181 TI - Partial least squares path modeling using ordinal categorical indicators. AB - This article introduces a new consistent variance-based estimator called ordinal consistent partial least squares (OrdPLSc). OrdPLSc completes the family of variance-based estimators consisting of PLS, PLSc, and OrdPLS and permits to estimate structural equation models of composites and common factors if some or all indicators are measured on an ordinal categorical scale. A Monte Carlo simulation (N [Formula: see text]) with different population models shows that OrdPLSc provides almost unbiased estimates. If all constructs are modeled as common factors, OrdPLSc yields estimates close to those of its covariance-based counterpart, WLSMV, but is less efficient. If some constructs are modeled as composites, OrdPLSc is virtually without competition. PMID- 29416180 TI - Molecular dynamics in germinating, endophyte-colonized quinoa seeds. AB - Aims: The pseudo-cereal quinoa has an outstanding nutritional value. Seed germination is unusually fast, and plant tolerance to salt stress exceptionally high. Seemingly all seeds harbor bacterial endophytes. This work examines mitogen activated protein kinase (MAPK) activities during early development. It evaluates possible contribution of endophytes to rapid germination and plant robustness. Methods: MAPK activities were monitored in water- and NaCl-imbibed seeds over a 4 h-period using an immunoblot-based approach. Cellulolytic and pectinolytic abilities of bacteria were assessed biochemically, and cellular movement, biofilm, elicitor and antimicrobial compound synthesis genes sequenced. GyrA based, cultivation-independent studies provided first insight into endophyte diversity. Results: Quinoa seeds and seedlings exhibit remarkably complex and dynamic MAPK activity profiles. Depending on seed origin, variances exist in MAPK patterns and probably also in endophyte assemblages. Mucilage-degrading activities enable endophytes to colonize seed surfaces of a non-host species, chia, without apparent adverse effects. Conclusions: Owing to their motility, cell wall-loosening and elicitor-generating abilities, quinoa endophytes have the potential to drive cell expansion, move across cell walls, generate damage associated molecular patterns and activate MAPKs in their host. Bacteria may thus facilitate rapid germination and confer a primed state directly upon seed rehydration. Transfer into non-native crops appears both desirable and feasible. PMID- 29416182 TI - Assessing statistical differences between parameters estimates in Partial Least Squares path modeling. AB - Structural equation modeling using partial least squares (PLS-SEM) has become a main-stream modeling approach in various disciplines. Nevertheless, prior literature still lacks a practical guidance on how to properly test for differences between parameter estimates. Whereas existing techniques such as parametric and non-parametric approaches in PLS multi-group analysis solely allow to assess differences between parameters that are estimated for different subpopulations, the study at hand introduces a technique that allows to also assess whether two parameter estimates that are derived from the same sample are statistically different. To illustrate this advancement to PLS-SEM, we particularly refer to a reduced version of the well-established technology acceptance model. PMID- 29416183 TI - The implementation of the Strategy Europe 2020 objectives in European Union countries: the concept analysis and statistical evaluation. AB - The European Union (EU), striving to create economic dominance on the global market, has prepared a comprehensive development programme, which initially was the Lisbon Strategy and then the Strategy Europe 2020. The attainment of the strategic goals included in the prospective development programmes shall transform the EU into the most competitive economy in the world based on knowledge. This paper presents a statistical evaluation of progress being made by EU member states in meeting Europe 2020. For the basis of the assessment, the authors proposed a general synthetic measure in dynamic terms, which allows to objectively compare EU member states by 10 major statistical indicators. The results indicate that most of EU countries show average progress in realisation of Europe's development programme which may suggest that the goals may not be achieved in the prescribed time. It is particularly important to monitor the implementation of Europe 2020 to arrive at the right decisions which will guarantee the accomplishment of the EU's development strategy. PMID- 29416185 TI - Coming together in a rightward direction: post-1980s changing attitudes to the British welfare state. AB - Major changes in the British welfare state were initiated during the 1980s in response to the 1970s' stagflation, rapid globalisation and the government's inability to ensure full employment: the relatively unrestricted payment of unemployment benefits was replaced by a jobseekers' allowance with applicants obliged to seek work actively and, if required, undergo training. Public support for this shift lagged behind the policy introductions, but from 1997 on there was a major change in attitudes towards welfare beneficiaries. Analysis of social attitude survey data for 1983-2011 shows this change occurred during the decade of relative prosperity under the New Labour governments. There was a growing concentration of anti-welfare attitudes across all social groups, regions and supporters of the main political parties. PMID- 29416186 TI - Who Is Doing the Housework in Multicultural Britain? AB - There is an extensive literature on the domestic division of labour within married and cohabiting couples and its relationship to gender equality within the household and the labour market. Most UK research focuses on the white majority population or is ethnicity 'blind', effectively ignoring potentially significant intersections between gender, ethnicity, socio-economic position and domestic labour. Quantitative empirical research on the domestic division of labour across ethnic groups has not been possible due to a lack of data that enables disaggregation by ethnic group. We address this gap using data from a nationally representative panel survey, Understanding Society, the UK Household Longitudinal Study containing sufficient sample sizes of ethnic minority groups for meaningful comparisons. We find significant variations in patterns of domestic labour by ethnic group, gender, education and employment status after controlling for individual and household characteristics. PMID- 29416184 TI - An overview of structural equation modeling: its beginnings, historical development, usefulness and controversies in the social sciences. AB - This paper is a tribute to researchers who have significantly contributed to improving and advancing structural equation modeling (SEM). It is, therefore, a brief overview of SEM and presents its beginnings, historical development, its usefulness in the social sciences and the statistical and philosophical (theoretical) controversies which have often appeared in the literature pertaining to SEM. Having described the essence of SEM in the context of causal analysis, the author discusses the years of the development of structural modeling as the consequence of many researchers' systematically growing needs (in particular in the social sciences) who strove to effectively understand the structure and interactions of latent phenomena. The early beginnings of SEM models were related to the work of Spearman and Wright, and to that of other prominent researchers who contributed to SEM development. The importance and predominance of theoretical assumptions over technical issues for the successful construction of SEM models are also described. Then, controversies regarding the use of SEM in the social sciences are presented. Finally, the opportunities and threats of this type of analytical strategy as well as selected areas of SEM applications in the social sciences are discussed. PMID- 29416187 TI - How to Be Modern? The Social Negotiation of 'Good Food' in Contemporary China. AB - Developing safe and sustainable food production for its population has been central to China's 'Modernisation Project'. Yet recent fieldwork in three Chinese cities suggests that there are two conflicting views on what a 'modern' agriculture should look like. For the government, modernisation implies a rational calculation of scale and a mirroring of global trends. But an alternative interpretation of modernity, promoted by civil society, has been gaining ground. For this camp, good food production is then established through a 'rhizomic' spread of new practices, which are inspired by world possibilities but are deeply rooted in the local context. Based on 14 interviews and five focus groups, this article investigates the ongoing social negotiation of 'good food' in China. It demonstrates how a non-western society responds to the twin processes of modernisation and globalisation and provides insights on the varieties of modernity in the making. PMID- 29416188 TI - Emissions of carotenoid cleavage products upon heat shock and mechanical wounding from a foliose lichen. AB - Carotenoids constitute a major target of chloroplastic photooxidative reactions, leading to the formation of several oxidized derivatives and cleavage products, some of which are volatile (VCCPs). Among them, beta-cyclocitral (beta-CC), at least, is a retrograde signaling molecule that modulates the activity of many key physiological processes. In the present work, we aimed to study whether beta-CC and other VCCPs are released into the atmosphere from photosynthetic tissues. To overcome stomatal limitations, the foliose chlorolichen Lobaria pulmonaria was used as the model system, and the emissions of biogenic volatiles, induced by heat and wounding stresses, were monitored by proton-transfer reaction time-of flight mass-spectrometry (PTR-TOF-MS) and gas-chromatography (GC-MS). Prior to stress treatments, VCCPs were emitted constitutively, accounting for 1.3 % of the total volatile release, with beta-CC being the most abundant VCCP. Heat and wounding stresses induced a burst of volatile release, including VCCPs, and a loss of carotenoids. Under heat stress, the production of beta-CC correlated positively with temperature. However the enhancement of production of VCCPs was the lowest among all the groups of volatiles analyzed. Given that the rates of carotenoid loss were three orders of magnitude higher than the release rates of VCCPs and that these compounds only represent a minor fraction in the blend of volatiles, it seems unlikely that VCCPs might represent a global stress signal capable of diffusing through the atmosphere to different neighboring individuals. PMID- 29416189 TI - An increase of intelligence measured by the WPPSI in China, 1984-2006. AB - Normative data for 5-6 year olds on the Chinese Preschool and Primary Scale of Intelligence (WPPSI) are reported for samples tested in 1984 and 2006. There was a significant increase in Full Scale IQ of 4.53 points over the 22 year period, representing a gain of 2.06 IQ points per decade. There were also significant increases in Verbal IQ of 4.27 points and in Performance IQ of 4.08 points. PMID- 29416190 TI - PLEMT: A NOVEL PSEUDOLIKELIHOOD BASED EM TEST FOR HOMOGENEITY IN GENERALIZED EXPONENTIAL TILT MIXTURE MODELS. AB - Motivated by analyses of DNA methylation data, we propose a semiparametric mixture model, namely the generalized exponential tilt mixture model, to account for heterogeneity between differentially methylated and non-differentially methylated subjects in the cancer group, and capture the differences in higher order moments (e.g. mean and variance) between subjects in cancer and normal groups. A pairwise pseudolikelihood is constructed to eliminate the unknown nuisance function. To circumvent boundary and non-identifiability problems as in parametric mixture models, we modify the pseudolikelihood by adding a penalty function. In addition, the test with simple asymptotic distribution has computational advantages compared with permutation-based test for high dimensional genetic or epigenetic data. We propose a pseudolikelihood based expectation-maximization test, and show the proposed test follows a simple chi squared limiting distribution. Simulation studies show that the proposed test controls Type I errors well and has better power compared to several current tests. In particular, the proposed test outperforms the commonly used tests under all simulation settings considered, especially when there are variance differences between two groups. The proposed test is applied to a real data set to identify differentially methylated sites between ovarian cancer subjects and normal subjects. PMID- 29416191 TI - Linear Model Selection when Covariates Contain Errors. AB - Prediction precision is arguably the most relevant criterion of a model in practice and is often a sought after property. A common difficulty with covariates measured with errors is the impossibility of performing prediction evaluation on the data even if a model is completely given without any unknown parameters. We bypass this inherent difficulty by using special properties on moment relations in linear regression models with measurement errors. The end product is a model selection procedure that achieves the same optimality properties that are achieved in classical linear regression models without covariate measurement error. Asymptotically, the procedure selects the model with the minimum prediction error in general, and selects the smallest correct model if the regression relation is indeed linear. Our model selection procedure is useful in prediction when future covariates without measurement error become available, e.g., due to improved technology or better management and design of data collection procedures. PMID- 29416192 TI - Correlates of gang involvement and health-related factors among African American females with a detention history. AB - Background: Prior studies have assessed relationships between gang membership and health-related factors. However, the existing literature has largely failed to consider how individual and broader social contextual factors might be related to such gang involvement among African American females. Thus, the aim of the present study was to identify empirically driven correlates of gang involvement and then better understand the relationship between gang membership and health related behaviors for African American females, after controlling for covariates of gang involvement. Methods: Data were collected from a convenience sample of detained African American adolescents females, between the ages of 13-17, currently incarcerated in a short-term detention facility in Atlanta, Georgia (n= 188). After obtaining written informed assent and parental permission, participants answered survey questions using A-CASI procedures that assessed socio-contextual factors and health-related behaviors. Results: Multiple logistic regression models controlling for age and SES documented that low self-esteem, emotional dysregulation, trauma history, deviant peers, low parental monitoring, infrequent parental communication, housing instability and poor neighborhood quality were correlates of gang involvement. In addition, multiple linear and logistic regression models, controlling for these constructs, revealed that gang involvement was independently associated with lower STD prevention knowledge, a higher likelihood of having a gang-involved boyfriend, a greater risk of having current casual sexual partnerships, higher rates of substance abuse, higher incidences of condom misuse and a lower likelihood of ever having been tested for HIV. Conclusions: These results provide information that can help service providers target certain profiles of African American females who may be at risk for joining gangs and address the health risk behaviors that may be associated with such memberships. PMID- 29416193 TI - Human-like object tracking and gaze estimation with PKD android. AB - As the use of robots increases for tasks that require human-robot interactions, it is vital that robots exhibit and understand human-like cues for effective communication. In this paper, we describe the implementation of object tracking capability on Philip K. Dick (PKD) android and a gaze tracking algorithm, both of which further robot capabilities with regard to human communication. PKD's ability to track objects with human-like head postures is achieved with visual feedback from a Kinect system and an eye camera. The goal of object tracking with human-like gestures is twofold : to facilitate better human-robot interactions and to enable PKD as a human gaze emulator for future studies. The gaze tracking system employs a mobile eye tracking system (ETG; SensoMotoric Instruments) and a motion capture system (Cortex; Motion Analysis Corp.) for tracking the head orientations. Objects to be tracked are displayed by a virtual reality system, the Computer Assisted Rehabilitation Environment (CAREN; MotekForce Link). The gaze tracking algorithm converts eye tracking data and head orientations to gaze information facilitating two objectives: to evaluate the performance of the object tracking system for PKD and to use the gaze information to predict the intentions of the user, enabling the robot to understand physical cues by humans. PMID- 29416194 TI - Social Security Income and Health Care Spending: Evidence from the Social Security Notch. AB - The paper exploits Social Security legislation changes to identify the causal effect of Social Security income on out-of-pocket medical expenditures of the elderly. Using the 1986-1994 Consumer Expenditure Survey and an instrumental variables strategy, the empirical results show that health care expenditures are responsive to changes in Social Security income for elderly individuals with less than a high school education. The estimated income elasticities are between 1.41 and 3.47 depending on the outcome measures and are statistically significant at conventional levels. The findings are in contrast to existing studies that find a small income elasticity at the individual/household level. PMID- 29416195 TI - Assessment of Pharmacological Responses to an Anti-diabetic Drug in a New Obese Type 2 Diabetic Rat Model. AB - Introduction: The number of diabetic patients has recently been increasing worldwide, and numerous anti-diabetic drugs have been developed to induce good glycemic control. In particular, metformin, which exhibits glucose-lowering effects by suppressing gluconeogenesis in the liver, is widely used as a first line oral anti-diabetic drug for type 2 diabetes mellitus. Material and Methods: In this study, the pharmacological effects of metformin were investigated using female and male Spontaneously Diabetic Torii (SDT) fatty rats, a new obese type 2 diabetic model. Results: Two experiments were performed: an assessment of repeated treatment with metformin in female SDT fatty rats 5 to 13 weeks of age (experiment 1), and an assessment of repeated treatment with metformin in male SDT fatty rats 6 to 10 weeks of age (experiment 2). In female SDT fatty rats, metformin treatment led to good glycemic control, increases in sensory nerve conduction velocity, and improvements in pancreatic abnormalities such as irregular boundaries and vacuole form of islets. In male SDT fatty rats, metformin decreased blood glucose levels 4 weeks after treatment. Conclusion: Metformin treatment led to maintained good glycemic control and improved neuropathy and pancreatic lesions in female SDT fatty rats. The SDT fatty rat is useful for the development of novel anti-diabetic agents that show potential to improve glucose metabolic disorders in the liver. PMID- 29416196 TI - Gender-related Histological Changes in the Thymus Gland After Pinealectomy and Short-term Melatonin Treatment in Rats. AB - Objectives: The aim of this study was to investigate the effects of pinealectomy and melatonin treatment on the rat thymus gland characteristics, taking into consideration possible gender differences. Materials and methods: Thirty adult Wistar rats of both sexes were divided into three groups. Group C and group PX served as control groups and included sham-pinealectomized and pinealectomized animals that were treated with 10% ethanol solution (0,1ml/daily, subcutaneous). Animals from third group (group PXM) underwent pinealectomy and seven days after surgery started receiving melatonin dissolved in 10% ethanol solution (3mg/kg/daily, subcutaneous). All animals were treated for 4 weeks. Results: Volume density of the thymus cortex showed statistically significant (p<0,05) decrease while the volume density of the thymus medulla was increased in the pinealectomized compared to the sham-pinealectomized female rats. Numerical density of macrophages as well as the distribution of blood vessels showed no gender differences. The numerical density of lymphocytes was statistically significantly decreased in female in comparison to the male pinealectomized rats. Melatonin treatment was proved to cause reverse effects in the sense that the results from the melatonin treated group corresponded to the results obtained from the control group of animals. Conclusion: The results of this study suggest that the pinealectomy causes gender-related changes in the rat thymus. Short-term melatonin treatment showed reverse effect, equally in both sexes. PMID- 29416197 TI - Impact of Insulin Delivery Method on Hypoglycemia Incidence in Pediatric Type 1 Diabetes Mellitus Patients. AB - Introduction: Insulin therapy of pediatric patients with type 1 diabetes mellitus (T1DM) is highly demanding due to their dynamic growth, development and different daily life activities. Goal: To determine the optimal insulin delivery method for the prevention of hypoglycemia recorded by continuous monitoring of glucose in patients with insulin pump and PEN. Material and Methods: The study included patients up to 18 years of age with diagnosed T1DM and treated with insulin pump and by insulin therapy with PEN at the Pediatric Clinic of the Clinical Center in Sarajevo. The study involved 149 patients, and lasted for 3 years. Patients were divided into two groups: group of patients on insulin pump therapy and group on insulin PEN. Results: There were 73 patients (49.6%) on insulin pump therapy and 79 patients (52.4%) on the insulin PEN therapy. There was no significant difference in the age between genders nor groups with different insulin application methods. There were no significant differences in the number of anamnestic hypoglycemia in patients with a different mode of insulin application (83.56% vs. 81.58%, p=0.114, F=2.533 < Fk=3.919). The number of hypoglycemia episodes in history is higher with the PEN therapy than in the insulin pump group. Conclusion: The number of anamnesis hypoglycemia as well as hypoglycemia from CGM records did not differ significantly in patients with IP and PEN therapy. The CGM record was significantly more valuable in the presentation of hypoglycemia compared to the history of hypoglycemia in all patients studied. Continuous monitoring of glycemia due to the ability to show glycemia variability and unrecognized hypoglycemia as well as predictive options for long-term metabolic control should be performed for all T1DM patients at least once a year. PMID- 29416198 TI - Cytogenetic Abnormalities Found in Patients with Reproductive Problems. AB - Introduction: One of the important causes of male infertility is aberration at the chromosomes. Aim: The main purpose of this study was to determine the frequency and types of chromosomal aberration in infertile/sterile men whose samples were analyzed in the Center for Cytogenetics of Faculty of Medicine University of Sarajevo in the last four years. Methods: A total of 353 infertile/sterile men, between the ages of 22-55 years, referred for cytogenetic analysis to the Center for Genetics of Faculty of Medicine during the period 2013 2016. Karyotyping was performed on peripheral blood lymphocytes by using the Giemsa trypsin banding (GTG) technique. Results: The structural and numerical chromosomal aberration in infertility/ sterility of men found with the incidence of 6% (20/353). Out of the 20 patients with abnormal cytogenetic diagnosis, structural chromosome abnormalities were observed in 17 (85%) patients and 3 (15%) with numerical aberrations. The type of aberrations mostly found were Robertsonian and reciprocal translocations (35%, 35%, respectively). Conclusions: The incidence of chromosomal abnormalities in infertile/sterile males suggests that the cytogenetics analysis is an important in male infertility, especially if it will be used for the purpose of assisted reproduction techniques. PMID- 29416199 TI - Rhythm Disturbance After Myocardial Revascularization. AB - Introduction: Heart rhythm disorders are common in the post-operative period following surgical myocardial revascularization (CABG). The incidence of any type of arrhythmia in the postoperative period can go up to 85%. While most are transient and short-term, it does not lead to deterioration of the postoperative course, in a smaller number of patients they can be predictors of various events that result in fatal outcome. Arrhythmias occur suddenly and need to be recognized and reacted in time. Standard monitoring consists of 12-channel electrocardiogram (ECG), laboratory findings and, if necessary, 24-hour HOLTER monitoring. Persistent arrhythmias increase overall morbidity and mortality, and costs treatments are increasing enormously. Patients and methods: The prospective study analyzed patients of all age groups and sexes in whom angiographically coronary arterial disease was confirmed and who underwent surgery CABG. A total of 60 patients were screened during 2016. All age groups of both sexes in whom no rhythm disorders were previously recorded were included in the study. Results: A total of 60 patients undergoing CABG were analyzed. The average age of patients was 63.56 8.55 years. The most preoperative factor was hypertension, which was recorded in 53 (88.33%) patients. The higher number of patients was operated using CPB 75.86%. The most commonly performed 3 aorto-coronary by-pass 45 (75%). The most common form of rhythm disorder was POAF, which occurred in 18 (30%) patients. In 24 patients, a change in heart rhythm was observed in the postoperative period in the group of operated ON pump techniques, while in the case of the application of Off pump technique only 5 patients were present, which was statistically significant (p <0.05). Conclusion: Preoperative patient preparation and prophylaxis with good anesthesia monitoring and minimal trauma during surgery are the main preconditions for reducing the incidence of postoperative heart rhythm disorders. PMID- 29416200 TI - Hyperlactatemia and the Importance of Repeated Lactate Measurements in Critically Ill Patients. AB - Objective: The aim of the study was to describe the prevalence of hyperlactatemia and emphasis on repeated lactate measurements in critically ill patients, and the associated mortality. Materials and methods: The study included 70 patients admitted in the Medical Intensive Care Unit at the Clinical Center, University of Sarajevo, in a 6-month period (July - December 2015). The following data were obtained: age, gender, reason for admission, Simplified Acute Physiology Score II, Acute Physiology and Chronic Health Evaluation, lactate concentrations upon admission, after 24 and 48 hours, and outcome (discharge from hospital or death). Results: Upon admission,hyperlactatemia was present in 91.4% patients with a mean concentration of lactate 4.13 +/-1.21 mmol/L. Lactate concentration at 48 hours was independently associated within creased in-hospital mortality (P = 0.018). Conclusion: Persistent hyperlactatemia is associated with adverse outcome in critically ill patients. Lactate concentration at 48 hours is independently associated within creased in-hospital mortality and it represents a statistically significant predictive marker of fatal outcomes of patients. Blood lactate concentrations > 2.25 mmol/L should be used by clinicians to identify patients at higher risk of death. PMID- 29416201 TI - Study of Echocardiographic Changes After Kidney Transplantation in End-stage Renal Disease Patients. AB - Background: Cardiovascular complications are the leading cause of mortality in end-stage renal disease (ESRD) patients. This study aimed to evaluate the efficacy of kidney transplantation on the cardiovascular status in ESRD patients. Methods: During 2012 to 2014 and in a cross-sectional study, 181 patients were randomly selected for this study. All patients were followed for periods of 6 and 12 months after kidney transplantation. The patients with ESRD and kidney transplant recipients; the patients with left ventricle ejection fraction<50%, left ventricular hypertrophy, mitral valve regurgitation and tricuspid valve regurgitation were included to study and the patients with kidney transplant rejection, myocardial infarction, high blood pressure with treatment-resistant, high blood pressure and addicted patients were censored. Results: one hundred and eighty-one patients had the mean age of 38.52 (range, 16-69 years) that 54.7% were men and the mean duration of dialysis was 3.74 years. There were significant differences after 6 and 12 months compared with before and also 6 months compared with 12 months from kidney transplantation for all echocardiographic findings. The echocardiographic findings improved after 12 months compared with 6 months and also these times compared with before kidney transplantation. Conclusions: The results of this study appeared that kidney transplantation had a positive effect on the cardiovascular status of patients with ESRD and improved the cardiac function of these patients. PMID- 29416202 TI - Prevalence of Metabolic Syndrome in the Hospitalized Psychiatric Patients. AB - Introduction: Metabolic Syndrome (MetS) is one of the most common syndromes that include a set of serious cardiovascular risk factors. MetS is highly prevalent in the high risk population and contributes to reduced lifespan. The primary goal of the study is to assess the prevalence of MetS and its relation to the treatment modalities and the psychiatric diagnosis. Methods: A cross-sectional study for the hospitalized patients in the Mental Health hospital in Taif city, Saudi Arabia that was conducted between Dec 2013 - Nov 2015. We included adult patients who were admitted to the inpatient service. We diagnosed MetS according to the new International Diabetes Federation (IDF) definition. Results: A total of 313 patients with mean age 48.4+10.8 years old, the majority were male and single, 68.3% have high school degree or less, mean BMI in the overweight range, and mean waist circumference 96.5+14.0 cm. Compared to these without MetS, those with MetS more likely to have BMI and waist circumference (P <0.001), higher SBP (P 0.028), have diabetes, hypertension and hyperlipidemia (all P <0.001), longer inpatient hospitalization (P 0.0036), report sedentary lifestyle (P 0.733), consume soft drink on a daily basis (P 0.030), and were active smoker (P 0.002). Those with MetS were less likely to be on Haloperidol and valproic acid (P 0.026). Conclusion: 39% of the participated hospitalized patients met the criteria for MetS and they tends to have significantly higher adiposity measures, cardiovascular markers, more likely to have comorbid conditions, and be active smokers. PMID- 29416203 TI - Affective and Cognitive Conditions are Stronger Predictors of Success with Community Reintegration than Gait and Balance Performance in Veterans with Mild Traumatic Brain Injury. AB - Introduction: Optimal community reintegration is an integral part of the clinical management of patients with mild traumatic brain injury. Background/Objective: We sought the contribution and inter-relation of such variables as balance, executive function, and affective regulation to the community reintegration of veterans with mTBI. Methods: We examined the statistical relationship among the above variables by conducting a series of objective evaluations to assess the balance, gait, executive function, affective regulation, and scores representing the patients' issues with community reintegration. The data were statistically analyzed for correlation and regression. Results: High correlation was found among scores for balance and gait, executive function and affective regulation. The first and second best predictors of success with patient's community reintegration were data representing affective regulation and cognitive impairments, respectively. However, the data for dynamic balance correlated weakly and insignificantly with scores for the three subsets of community reintegration. Conclusions: We revealed varying degrees of correlation among balance, executive function and affective regulation, and as they related to the community reintegration success of patients with mTBI. The strongest, intermediate and weakest predictors for these patients' success with community reintegration represented those for affective regulation, executive function, and dynamic balance and gait performance, respectively. PMID- 29416204 TI - Hemodynamic Responses to Tracheal Intubation in Elderly Patients: Intravenous or Spray of Lidocaine versus Fentanyl. AB - Introduction: Laryngoscopy and tracheal intubation are known to increase sympathetic activity that may be detrimental to patients with preexisting ischaemic or hypertensive heart disease. Aim: The aim of this study was to compare of intravenous and oropharyngeal spray of lidocaine and high dose of fentanyl on systolic and diastolic blood pressures and heart rate of patients over 65 years during tracheal intubation. Material and Methods: In this clinical trial, 160 patients over 65 yrs who were randomly divided into five groups of 32 patients. For group one lidocaine spray 10%, group two intravenous lidocaine 1.5 mg/kg, group three lidocaine spray along with intravenous lidocaine 0.75 mg/kg, and for group four fentanyl 5MUg/kg were administered and group five patients were controls which were given 1 mg of midazolam along with 2 MUg/kg fentanyl. Systolic and diastolic blood pressures and heart rate were measured before and after anesthesia and intubation. ANOVA, Scheffe's and Repeated measure tests were used for data comparison and P<0.05 was considered significant. Results: No significant difference was detected in terms of gender among the understudy groups. The mean (SD) age of patients in all groups were 69 +/-3.5 yrs. (65-80 yrs.) and there is no significant difference was detected between the mean age and other basic variables of under study groups (P<0.328). Study results showed that the kind of surgery hasn't different between groups. The table showed that no difference between male and female. No significant difference was observed between groups with different sizes of tracheal tube in terms of systolic and diastolic blood pressures and heart rate. No significant difference was detected in terms of systolic and diastolic blood pressures and heart rate among groups prior to the induction of anesthesia. Conclusion: All methods were effective for efficient blood pressure control during laryngoscopy and tracheal intubation. PMID- 29416206 TI - Introduction to Total Mesorectal Excision. AB - Colorectal cancer is the second leading cause of mortality in the West, and rectal cancer accounts for about 25% of the colon cancers. The concept of total mesothelial excision (TME) was the most important event in surgery for rectal cancer of the last two decades, because even without a curative approach, it reduced local recurrence and extended 5-year survival. PMID- 29416205 TI - Upper Urinary Tract Urothelial Cancer in Croatian and Bosnian Endemic Nephropathy Regions. AB - Objectives: Endemic nephropathy (EN) is a chronic tubulointerstitial renal disease associated with increased incidence of upper urinary tract urothelial cancer (UTUC) occurring predominantly in geographically limited areas in villages along big Danube river. Based on results obtained by the research it is confirmed that aristolochic acid is causative agent of endemic nephropathy (EN). Aim: The aim of this study was to determine characteristics of UTUC in two endemic areas and analyze trends in 5-year period. Methods: This study included all patients with UTUC with or without synchronous/metachronous urothelial cancer in urinary bladder, from Croatian and Bosnian EN and non-EN regions. We analyzed archival data bases from all patients with UTUC who were admitted and operated in Department for surgery and urology, General Hospital Josip Bencevic Slavonski Brod in the time period between 2005 and 2010. Analyzed groups of patients were divided and compared as EN group (that includes patients from Croatian and Bosnian EN region) and non-EN group (that includes patients from Croatian and Bosnian non-EN region). All surgical specimens were processed according to standardized pathological procedures. Results: Comparing patients basic characteristics from Croatian and Bosnian EN region there was no significant difference in gender (females were more frequently affected in both EN regions, p=0.99) or age (p=0.43) of patients. We found higher blood levels of urea and creatinine in group of patients from Croatian EN region when compared with group of patients from Bosnian EN region but the difference was not statistically significant (p=0.79 and p=0.44, respectively). In patients from Croatian EN group Hemoglobin levels were significantly lower than levels from Bosnian EN region patients, p=0.0049. In group of patients from Bosnian EN region ureteral tumors were more frequently observed than in Croatian group of patients, when compared with renal pelvis tumors but the difference was not statistically significant (p=0.258). Conclusion: Our data showed some differences in tumor localization between to investigated, relatively nearly situated, EN regions in Croatia and Bosnia. Statistically significant difference in hemoglobin levels between Croatian and Bosnian EN regions that should be further analyzed to give some reasonable explanation. PMID- 29416207 TI - Contribution of Arabic Medicine and Pharmacy to the Development of Health Care Protection in Bosnia and Herzegovina - the Second Part. AB - After the collapse of the Arab rule, the Arab territorial expanses and cultural heritage were taken over by the Turks. Although scientific progress in the Turkish period slowed down due to numerous unfavorable political-economic and other circumstances. Thanks to the Turks, Arabic culture and useful Islamic principles expanded to the territory of our homeland of Bosnia and Herzegovina (B&H). Significant role in the transfer of Arabic pharmaceutical knowledge was also attributed to the Sephardic Jews who, with their arrival, continued to perform their attar activities, which were largely based on Arab achievements. However, insufficiently elaborated, rich funds of oriental medical and pharmaceutical handwriting testify that Oriental science has nurtured in these areas as well, and that the Arabic component in a specific way was intertwined with other cultures and traditions of B&H. The Franciscan monasteries in Bosnia and Herzegovina have museums which contain important exhibits and libraries rich in books, among which many from the field of medicine and pharmacy. Muslim mosques, also, had small libraries with Arabic books used for spreading medical knowledge. The second category was folk doctors and practitioners who were on disposition to the people of any religion. Some of them listened to lectures in medicine during the studies of theology and philosophy. However, most did not have any medical education, but by reading books and teaching experience they made their own recipe collection. Special books, called "Ljekaruse" (Books of recipes) were also born during the study when they came into contact with an even larger number of health books. However, it should not be neglected that a lot of them contained folk medicines that were used in some environments depending on the habits and available herbs. Although it has been proven that many recipes from Ljekaruse are pharmacologically and medically justified, one should not ignore the knowledge and skill behind them. The true flowering of medicine in B&H happening thanks to graduate doctors in Italy, Austria, Hungary, Turkey, etc. Through their action, in a short time, they greatly improved health in B&H, educated the population. The Franciscans were important because they opened the first open-air clinics, the first pharmacies, and wrote the first pharmacopoeia and regulations for the work of health care institutions. Numerous works preserved in monasteries have mostly brought about the study in only one or two copies. Their contribution to the development of health care and the prevention of illness and treatment of the population in B&H during that period is very significant. PMID- 29416208 TI - Gigantic Thrombus of the Left Atrium in Mitral Stenosis. AB - Introduction: Excess dilatation of the left atrium >65 mm is known in the literature as gigantic atrium. This dilation is most commonly encountered in the mitral insufficiency of rheumatic etiology, but also in severe prolapses of the mitral valve, permanent atrial fibrillation, and at the left right shunt with cardiac insufficiency. Case report: In this paper is presented a case study of echocardiographically verified giant thrombus in left atrium in a 50 years old female patient aged 50 hospitalized because of tiredness, choking, heartburn and urinary tract symptoms. The patient had rheumatic fever at age of 18 years. At age of 35, she was diagnosed with mitral stenosis. In permanent atrial fibrillation with anamnestic data on the previous cerebrovascular stroke (CVI) and the repeated transitional ischemic seizures. Echocardiographic examination confirmed severe mitral stenosis with moderate aortic insufficiency and gigantic left atrium (LA) with gigantic thrombus. Invasive diagnostics were indicated and performed, followed by an acute cardiac surgery including left atrial thrombectomy and implantation of the mechanical aortic and mitral valve. The surgical course was without complications. Conclusion: On eleven postoperative day, after mobilization, the patient experiences stroke with motor aphasia. She was clinically recovering from stroke consequences, and remains cardiollogically stable. PMID- 29416209 TI - Effects on Glycemic Control in Impaired Wound Healing in Spontaneously Diabetic Torii (SDT) Fatty Rats. AB - Introduction: Impaired diabetic wound healing is an important issue in diabetic complications. The present study aims to evaluate the protective effect on glycemic control against impaired diabetic wound healing using a diabetic rat model. We investigated the wound healing process and effect on the impaired wound repair by glycemic control in the Spontaneously Diabetic Torii (SDT) fatty rat, which is a new animal model of obese type 2 diabetes and may be a good model for study impaired wound healing. Material and methods: Male SDT fatty rats at 15 weeks of age were administered orally with sodium glucose co-transporter (SGLT) 2 inhibitor for 3 weeks. Wounds were induced at 2 weeks after SGLT 2 inhibitor treatment, and the wound areas were periodically examined in morphological and histological analyses. Results: The SDT fatty rats showed a delayed wound healing as compared with the normal rats, but a glycemic control improved the impaired wound healing. In histological analysis in the skin of SDT fatty rats showed severe infiltration of inflammatory cell, hemorrhage and many bacterial masses in the remaining and slight fibrosis of crust on skin tissue. Thought that this results skin performance to be a delay of crust formation and regeneration of epithelium; however, these findings were ameliorated in the SGLT 2 inhibitor treated group. Conclusion: Glycemic control is effective for treatment in diabetic wounds and the SDT fatty rat may be useful to investigate pathophysiological changes in impaired diabetic wound healing. PMID- 29416210 TI - Assesment of Rhythm Disorders in Classical and Nonclassical Mitral Valve Prolapse. AB - Introduction: Mitral Valve Prolapse (MVP) is the most common cardiac valve pathology of to day. Aim of article was to identify the types and frequency of potentially malignant arrhythmia and atrial brillation in patients with MVP, to determine the differences in these arrhythmias between classical and non classical MVP, to evaluate the correlation of potentially malignant arrhythmia and atrial fibrillation with MVP with possible clinical complications of arrhythmogenic sudden cardiac death and potential risk of thromboembolic vascular incident. Patients and methods: Article has retrospective-prospective analytical character and present observational study on 239 patients (120 with MVP (66 with classical and 54 with non-classical MVP), who had a subjective feeling of palpitations and/or pain in the chest, and/or episode of syncope, and did not have ischemic heart disease or another valve pathology) and 119 healthy patients in the control group. All patients were analyzed by 24-hour ECG Holter. Results: Signifficant difference in all analyzed arrhythmias between classical MVP and control group (p <0.001) between non-classical and control group in the presence of preexcitation signs (p = 0.047), and between classical and non-classical in presence of QT prolongation and AV block of II and III degree (p = 0.023), ventricular arrhythmias of the 3rd, 4th and 5th grade at scales according to Lown (p = 0.002) and atrial brillation in favor of classical MVP (p = 0.016). Conclusion: The potential risk of cardiac death and vascular incidence is signi cantly higher in classical MVP than in non-classical MVP, implying the need for routine ECG-Holter monitoring in their diagnosis for timely prevention of clinical arrhythmogenic complications. PMID- 29416211 TI - Cardiovascular Risk Factors in Patients with Poorly Controlled Diabetes Mellitus. AB - Introduction: Diabetes mellitus(DM) is considered an independent cardiovascular risk factor. Having in mind concomitant occurence of diabetes and other cardiovascular risk factors, it is expected that patients with poor glucoregulation will have more cardiovascular risk factors and higher cardiovascular risk than patients with good glucoregulation. Aim: To compare cardiovascular risk and cardiovascular risk factors between patients with poorly controlled and patients with well-controlled Diabetes mellitus. Material and Methods: Hundered ten patients aged 40-70 years suffering from Diabetes mellitus type 2 were included. Research is designed as a retrospective, descriptive study. Patients with glycosylated hemoglobin (HbA1c) > 7% were considered to have poorly controlled diabetes. The following data and parameters were monitored: age,sex, family history, data on smoking and alcohol consumption, BMI (body mass index), blood pressure, blood glucose, total cholesterol, triglycerides, LDL, HDL, fibrinogen, uric acid. For the assessment of cardiovascular risk, the WHO / ISH (World Health Organization/International Society of hypertension) tables of the 10-year risk were used, and due to the assessment of the risk factors prevalence, the optimal values of individual numerical variables were defined. Results: Differences in the mean values of systolic, diastolic blood pressure, fasting glucose, total cholesterol, LDL cholesterol are statistically significant higher in patients with poorly controlled diabetes. Hypertension more frequently occurre in patients with poorly controlled DM. The majority of patients with well controlled DM belong to the group of low and medium cardiovascular risk, while the majority of patients with poorly controlled DM belong to the group of high and very high cardiovascular risk. In our research, there was a significant difference in cardiovascular risk in relation to the degree of DM regulation, and HbA1c proved to be an important indicator for the emergence of the CVD. Conclusion: There are significant differences in certain risk factors between patients with poorly controlled and well controlled DM. Patients with poorly controlled diabetes mellitus have a higher cardiovascular risk than patients with well controlled diabetes. The value of HbA1c should be considered when assessing cardiovascular risk. PMID- 29416212 TI - Trend Analysis and Affecting Components of Human Brucellosis Incidence During 2006 to 2016. AB - Introduction: Brucellosis is communicable between humans and animals. In spite of having an active health care system. Iran is considered as an endemic area and it stands in the fourth place in world ranking. One of the common methods for identifying the disease incidence is a regression analysis. Therefore, the aim of the study was to investigate the trend of brucellosis incidence during 2006 to 2016 and the components affecting such disease. Materials and Methods: This was a trend study which was conducted on the total of 144 brucellosis cases were recorded in the registration software in CDC of Iranian, Ministry of Health. We analyzed the changes in brucellosis incidence during 2006 to 2016 in Juybar province by the join point regression. Moreover, comparing the changes of incidence in one year intervals was also taken into account. Results: The average age of patients was 18+/-29 years. About 60% of the patients were men, and 85.4% had used non-pasteurized dairy and meat products. The contact with animals had a significant difference between the two genders (P= 0.006). During 2006 to 2016, brucellosis incidence had a decreased trend about 15%. This trend had a breakpoint in a way that during 2006 to 2008, 66.2% decrease and during 2008 to 2016, 7% increase was observed that none of these annual percentage changes (APC) were statistically significant at p= 0.05. Also, APC of brucellosis incidence in groups below 20 and between 20 to 50 years old had a decrease in a way that in groups under 20, it had 26.7% decrease and it was statistically significant. Conclusion: It is necessary to provide appropriate education training, information on the Human Brucellosis for the young and individuals with high risk professions. Moreover, some health behaviors such as not using non-pasteurized dairy, animals' vaccinations, and awareness of the disease symptoms are needed. PMID- 29416213 TI - The Role of Doppler Imaging in the Assessment of Right Ventricular Function: a Case-control Study of Acute Inferior Wall Infarction. AB - Background: Right ventricular infarction (RVI) develops in 30-50% of patients with inferior wall infarction (IWI). The rates of mortality, morbidity, and complications in these patients are greater than in the patients without RVI. We compared the tissue Doppler imaging (TDI) indices between a group of patients with IWI and RVI, with a similar group of patients who had IWI alone to investigate the application of TDI indices in the evaluation and detection of right ventricular function. Material and Methods: We studied 49 patients with first acute IWI in two groups. Group 1 (N=24) were patients with IWI and RVI while group 2 consisted of patients with IWI alone (N=25), based on standard electrocardiogram criteria. The peak systolic (Sm), peak early (Em) and late (Am) diastolic velocities, and Em/Am ratio were obtained from the apical four chamber view, at the lateral side of the tricuspid annulus. We measured trans-tricuspid early (ET) and peak (AT) filling velocity, ET/AT ratio, right ventricular end diastolic diameter (RVEDD), and tricuspid annular plane systolic excursion (TAPSE) by M-mode TDI projected at the long axis of parasternal view. Results: The RVEDD and E/Em ratio were increased, while the TAPSE was significantly decreased in the patients with RVI as compared to those without RVI (4.7+/- 0.6 vs. 3.1+/-0.2 cm; p < 0.005, 5.6+/-2.21 Vs 4.5+/-1.2; p<0.006 and 1.7+/-0.4 vs. 2.3+/-0.5 cm; p <0.0001, respectively). However, the other statistically measured parameters were not significantly different between these groups. Conclusion: The measurement of RVEDD, E/Em ratio, and TAPSE, as right ventricular myocardial systolic and diastolic parameters by pulse wave TDI could be used to objectively assess the status of RV condition in patients with first acute IWI. PMID- 29416214 TI - Prevalence of Specific Types of Human Papiloma Virus in Cervical Intraepithelial Lesions and Cervical Cancer in Macedonian Women. AB - Introduction: Cervical cancer is a malignancy originating in the transformation zone of the cervix, most commonly in the squamous cells. It is the fourth most common cancer in women worldwide, and the third most common cause of female cancer death. Genital human papilloma viruses (HPV) are sexually transmitted and approximately 630 milion people worldwide are infected. More than 200 genotypes, subtypes and variants have been reported, 13-15 being oncogenic type, which could be responsible for cervical intraepithelial lesions (CIN) or cancer. Aim: Aim of this study was to evaluate the prevalence of this infection and to identify specific types of human papiloma virus in cervical intraepithelial lesions and cervical cancer in Macedonian women. Material and methods: The study was conducted at the University Clinic for Obstetrics and Gynecology, Skopje, Macedonia, in a period of four years. The study was performed on a cohort of 1895, 18 - 73 year old patients who during primary examination had already abnormal PAP smear test. Cervical cells were collected in the lithotomy gynecological position of the patient, using endocervical cytobrush and cotton tipped swab, and both were placed in sterile test tube with phosphate buffered saline. Samples were stored at temperature of 2 - 8 degrees C and Human Pappiloma Virus (HPV) genotyping was analyzed within 7 days by multiple Polymerase Chain Reaction (PCR) methods. Results: The mean age of enrolled women was 40,8 years+/-10.36 SD(minimum of 18 and maximum 73 years. Among the patients, the presence of HPV by using PCR was detected in 40,68 % (769 patients) and was highly associated with cervical abnormalities. The prevalence of HPV was highest (82,1%) in women aged 20-years or less and it decreased with age and was lowest (19,9%) among patients older than 50 years. The prevalence of oncogenic types of the virus was higher if the cytologic diagnosis is CIN 3/Carcinoma in situ (CIS). In these patients detection of high risk HPV was in 79,1% females with CIN 3 and 97,5 % in females with CIS. The lowest prevalence was detected in patients with atypical squamous cells of undetermined significance (ASCUS) (23,9%) and CIN 1-25 (6%). Results of HPV typing show that genotypes were found either single or multiple in both single and multiple infections. We have seen that HPV 16, 18 and 31 were the most common types detected among the patients from Macedonia. HPV 16 was present even in 52,1 % of women with CIS and in 41,2% in women with CIN 3. HPV type 31 ranked second in patients wit CIN1, CIN2, CIN3 but HPV 18 ranked second in patients with CIS with (12,8%). Surprisingly, patients with mixed infection had more low grade intraepithelial squamous lesions (LSIL) and high grade squamous intraepithelial lesions (HSIL) then CIS. Conclusion: Among Macedonian women, HPV 16, 31 and 18 were HPV types strongly associated with intraepithelial cervical lesions and cervical cancers. The prevalence of high risk HPV was highest in youngest women, but the risk was highest among patients with invasive cervical cancer (ICC). Surprisingly, patients with mixed infection had more LSIL and HSIL then CIS. PMID- 29416215 TI - A Difference in Bleeding and Use of Blood and Blood Products in Patients who Were Preoperatively on Aspirin or Dual Antiplatelet Therapy Before Coronary Artery Bypass Grafting. AB - Background: Postoperative bleeding in patients who underwent elective coronary artery bypass surgery (CABG) may increase due to preoperative anticoagulant therapy indicative of their disease - acute coronary syndrome or implanted coronary artery stent. Increased bleeding in many cases requires the use of blood and blood derivatives, and sometimes even reoperation. Their use poses the risk of complications, may extend the hospitalization. Methods: Our observation retrospective study included 131 patients, 41 treated with aspirin and 90 treated with aspirin and clopidogrel. All underwent for the first time elective on-pump isolated CABG surgery at Clinic for cardiovascular surgery of Clinical Center University of Sarajevo, in period June 2016 to September 2017. The data were collected from patient's records. Results: Out of 131 patients,73.3% were male. The average age was 62. The average total drainage during the first 48 postoperative hours in ASA group was 1027.4+/-404.9ml and 1049.8+/-371.3ml in DAPT group. The mean number of whole blood transfusions in the DAPT group washigher compared to ASAgroup. The average number of fresh frozen plasma were higher in the DAPT group 0.84+/-0.51 compared to the group ASA 0.39+/-0.07, as well the average thrombocytes transfusions were slightly higher in the DAPT group. Statistical analysis suggests that there is no significant difference between the observed groups (p>0.05). Also, our study did not show a statistically significant difference between arrhythmia onset, the length of mechanical ventilation, use of protamineand tranexamic acid. Reoperation due to postoperative bleeding was recorded in 2 cases in the DAPT group as well as 2 lethal cases. Conclusion: In our study, we could not demonstrate less postoperative bleeding and use of blood and blood products in a group of patients who were preoperatively treated with aspirin compared to patients with dual antiplatelet therapy in the elective isolated CABG surgery. PMID- 29416216 TI - Characters of Nutrition Status and Energy-delivery Patterns of the University based Surgical Intensive Care Units in Thailand (Multi-center THAI-SICU Study). AB - Aim: The authors aimed to describe nutrition status and energy-delivery characters in multi-center THAI-SICU study. Material and Methods: Eligible patients admitted in SICU were 1,686 after excluding 563 of 2,249 participants owing to very short stay or non-alive within 24 hours after admission and missing data. The study was a posthoc analysis and multicenter descriptive design. The analytic methods described categorical data in percentage and the continuous data in the median with interquartile range. Variables divided into baseline characteristics and nutrition data before SICU admission, and the pattern of energy delivery in SICU. Statistical significance accepted as a p-value less than 0.05. Results: The average age was 64 (52-76) years with 57% male. The median of serum albumin level at admission (interquartile range, IQR) was 2.8 (2.2-3.4). There was 46 -47 percent of nutrition risk patient. Less than 10 percent of the patient had enteral (EN), parenteral (PN) or their combination before admission. History of weight loss and appetite loss was 27-31 percent. However, seventy percent of the patient could not define the duration of the symptom. EN was initiated early, but the tendency of full feeding was 7-10 days. At that period, supplemental PN was added around 30 percent of total calories. The composition of PN was quite low in these study which contains only 15-16 percent of total calories. The average energy delivery was 20 kcal/kg/day (the recommendation is 25-30 kcal/kg/day). Conclusion: The patient's nutrition status before SICU admission was at risk of 46-47% and weight loss and appetite loss might unreliable in ICU setting. EN is started early with gradually increase up to 7-10 days. The average total calories requirement is lower than a recommendation. PMID- 29416217 TI - Comparing Levels of Mastery Motivation in Children with Cerebral Palsy (CP) and Typically Developing Children. AB - Introduction: The present study aimed to compare motivation in school-age children with CP and typically developing children. Material and Methods: 229 parents of children with cerebral palsy and 212 parents of typically developing children participated in the present cross sectional study and completed demographic and DMQ18 forms. The rest of information was measured by an occupational therapist. Average age was equal to 127.12+/-24.56 months for children with cerebral palsy (CP) and 128.08+/-15.90 for typically developing children. Independent t-test used to compare two groups; and Pearson correlation coefficient by SPSS software applied to study correlation with other factors. Results: There were differences between DMQ subscales of CP and typically developing groups in terms of all subscales (P<0.05). The lowest motivation scores of subscales obtained in gross motor persistence (2.4870+/-.81047) and cognitive-oriented persistence (2.8529+/-.84223) in children with CP. Motivation was correlated with Gross Motor function Classification System (r= -0.831, P<0.001), Manual ability classification system (r=-0.782, P<0.001) and cognitive impairment (r=-0.161, P<0.05). Conclusion: Children with CP had lower mastery motivation than typically developing children. Rehabilitation efforts should take to enhance motivation, so that children felt empowered to do tasks or practices. PMID- 29416218 TI - The Trabecular Bone Score Predicts Spine Fragility Fractures in Postmenopausal Caucasian Women Without Osteoporosis Independently of Bone Mineral Density. AB - Introduction: The trabecular bone score (TBS) is a gray-level textural metric that can be extracted from the two-dimensional lumbar spine dual-energy X-ray absorptiometry (DXA) image. TBS is related to bone microarchitecture. Several literature data suggest that TBS predicts fracture risk as well as lumbar spine bone mineral density (LS-BMD) measurements in postmenopausal women. Objective: A retrospective case-control study assessing the ability of the TBS to predict spine fragility fractures (SFF) in postmenopausal women with or without osteoporosis (diagnosed by T-score<=-2.5). Methods: LS-BMD and the TBS were determined in the L1-L4 vertebrae. Statistical analyses were carried out in the entire group of women (entire-group) (n.699), in women both with osteoporosis (osteoporosis-subgroup) (n.253) and those without osteoporosis (non-osteoporosis subgroup) (n. 446). Results: At the unpaired t-test, both the TBS and the LS-BMD (p<=0.001) were lower in women with SFF (n.62) in the entire-group. In the non osteoporosis subgroup, the TBS (p<=0.009) was lower in women with SFF (n.29). In the osteoporosis subgroup, the LS-BMD (p<=0.003) was lower in women with SFF (n.33). Considering the TBS and LS-BMD separately in a block logistic regression, the TBS was associated with SFF in the entire-group (odds ratio (OR): 1.599, 95% confidence interval (CI): 1.021-2.128) and in the non-osteoporosis-subgroup (OR: 1.725, 95% CI:1.118-2.660) whereas LS-BMD was associated with SFF in the entire group (OR: 1.611, 95% CI: 1.187-2.187) and in the osteoporosis-subgroup (OR: 2.383, 95% CI: 1.135-5.003). According to forward logistic regression, entering the TBS, LS-BMD and confounders as predictors, the LS-BMD in the entire-group (OR: 1.620, 95% CI: 1.229-2.135) and in the osteoporosis subgroup (OR: 2.344, 95% CI: 1.194-4.600), and the TBS in the non-osteoporosis subgroup (OR: 1.685, 95% CI: 1.131-2.511) were the only predictors of SFFs. Conclusions: In the entire group, the TBS predicted SFFs almost as well as LS-BMD, but not independently of it. The TBS, but not LS-BMD, predicted SFFs in the non-osteoporosis subgroup. PMID- 29416219 TI - An Open Label Randomized Controlled Trial to Compare Low Level Pressure Support and T-piece as Strategies for Discontinuation of Mechanical Ventilation in a General Surgical Intensive Care Unit. AB - Objective: The purpose of this study was to compare the efficacy of continuous low pressure support (PSV) and T-piece as strategies for discontinuation of mechanical ventilation and extubation in a surgical ICU. Patients and Methods: This was a prospective open label randomized control study in surgical ICU patients who were intubated, mechanically ventilated, and who met criteria for a spontaneous breathing trial. Eligible, enrolled patients were randomized to receive low-level pressure supportup to 7 cmH2O (PSV) or T-piece as the mode of their spontaneous breathing trial. Results: A total of 520 patients were randomized (260 in PSV group and 260 in T-piece group). There were no differences between the groups in baseline characteristics except duration of MV before trial was longer in PSV group. There were also no differences in hemodynamic and respiratory measures between groups. The PSV had a significant higher number of SBT attempt before success and extubation. After extubation, the re-intubation within 48 hours had a lower trend in PSV group (PSV vs. T-piece: 10% vs. 14.6%; p=0.11). The pneumonia occurrence, hospital mortality, hospital and ICU length of stay were not significant different between groups. In multivariable analysis, PSV was associated with a lower risk of success at the first SBT (adjusted relative risk, RR 0.79 [95% confidence interval, CI, 0.70 - 0.88]; p<0.001], and a lower risk of re-intubation within 48 hours after extubation (adjusted RR 0.62 [95%CI 0.40 - 0.98]; p=0.04). There were no differences between groups in pneumonia after extubation and in hospital mortality rate. Conclusion: Although PSV needs a higher number of SBT trial before success and extubation, the re intubation within 48 hours is lower than T piece. However, there were no differences between the groups in term of pneumonia after extubation, hospital mortality as well as ICU and hospital length of stay. PMID- 29416220 TI - Analysis of Vitamin D Receptor Polymorphisms in Patients with Familial Multiple Sclerosis. AB - Objective: Genetic and environmental factors are important in the development of the multiple sclerosis (MS). Vitamin D shows its effects on the immune system with the vitamin D receptor (VDR) in the nucleus. Single nucleotide polymorphisms (SNPs) in the VDR gene can lead to alterations in vitamin D functions and metabolism.Taq I, Apa I, Fok I and Bsm I polymorphisms and MS associations have been investigated in many studies. VDR gene polymorphism has not been previously studied in patients with familial MS. Aim: We aimed to investigate the relationship between familial MS patients present in Turkish population and VDR genotypes Taq I, Apa I and Fok I polymorphisms. Methods: 29 patients with a family history of MS and 120 healthy control subjects were included in the present study. We studied present VDR genotypes Taq I, Apa I and Fok I polymorphisms. Results: We observed a significant difference between controls and patient group only in Taq I polymorphism (p: 0.025). Homozygousity of G allele was not seen in the patients whereas in controls frequency of that genotype was p:0.208. When gender was considered males show significant difference for GG genotype. There were no significant association for the Apa I and Fok I polymorphisms. Conclusion: Although our findings suggest association between VDR Taq I polymorphism and the familial MS, additional studies are needed to establish detailed relationships. PMID- 29416222 TI - Clinical Course and Treatment of Dilated Cardiomyopathy During Twenty Years of Follow-up. AB - Objective: Demonstration of idiopathic dilated cardiomyopathy with unusual flow, unpredictable clinical picture and complex therapy. Case report: Patient A.P., female, 38 years old, had symptoms of dilated cardiomyopathy (with possible infectious myocarditis in the background) at age 17. After hospitalization for ten months and ten days, while waiting for heart transplantation (with threatening death outcome), without a clearly pronounced threatening arrhythmia, but with a low ejection fraction and a poor general condition, remission occurred. The therapy focused primarily on the treatment of heart failure, prevention of arrhythmia and thromboembolism. Normalization of the disease by improving the function of the left ventricle (expected in 16% of patients) occurred and lasted for 4 years, followed by an exacerbation of the disease that lasted for two years. In the next few years the patient was stable, had a first child with normal pregnancy. During the second trimester of the second pregnancy, there was an exacerbation (postpartum dilatation cardiomyopathy) lasting for couple of months. At the time of case report (May 2017), the patient is stable on therapy (ACE inhibitor, beta blocker, diuretics, If channel blocker), without limitation of physical capacity, mother of two children, unemployed. Conclusion: The clinical course of dilated cardiomyopathy is extremely unpredictable and therapy is very complex and demanding. PMID- 29416221 TI - Predicting Factors of Depression and Anxiety in Mental Health Nurses: A Quantitative Cross-Sectional Study. AB - Introduction: The nursing profession is characterized as one of the most stressful and emotional dementing professions. It is widely agreed that many nurses are experiencing anxiety and depression as a results of their profession. Purpose: The purpose of this study was to assess the prevalence and associated factors of depression and anxiety among mental health nurses working in public psychiatric hospitals, in order to identify independent predictors of mental health disorders risk. Material and Methods: A descriptive, cross-sectional study was conducted in which 110 mental health nurses who were working in public psychiatric hospitals of Greece participated. The Patient Health Questionnaire-2 (PHQ-2) and the Generalized Anxiety Disorder-2 (GAD-2) questionnaire along with a sheet with basics demographic, social, and work characteristics, including gender, age, marital status, educational level, working experience in nursing, working position and shift, were used as instrument for data collection. Results: The mean age of the nurses was 42.64 years (SD = 5.87 years) and working experience in nursing 15.73 years (SD = 5.64 years). Most participants were women 64.5%, married 59.1% and nursing assistant 53.6%, while 48.2% of them held a higher education degree. A very large percentage found to be classified as depressed (52.7%) and anxious (48.2%) and factors that found to be associated were age, marital status and educational level (for depression and anxiety) and working experience (only for depression). Conclusions: Mental health nurses are in high risk for developing psychiatric disorders such as depression and anxiety. Being single, divorced or widowed, older, with many years of experience and a higher education degree can be predicting factors associated with depression and anxiety in mental health nurses. PMID- 29416223 TI - Pregnacy and Delivery in a Patient After Tetralogy of Fallot Surgery Being Undergone. AB - Aim: The aim of the paper is to present the risk of pregnancy for mother and her child in a young patient who had a surgery to repair Tetralogy of Fallot (ToF), who gave a birth to her firstborn by having a cesarean section. Case report: 23 years old patient, in 28 weeks of pregnancy was admitted to the clinic due to her medical record. She did not have any subjective complaints. She had two surgeries to repair ToF. After the surgery, she had residual ventricular septal defect (VSD). She had her first surgery 20 years ago (she was 3 years old), and second 7 years ago (she was 16). She had regular check-ups since, and her heart condition was unchanged. Due to her heart surgeries and VSD, a cardiologist indicates that she should deliver by having a c-section when she is 36 weeks pregnant. The patient's heart condition was stabilized and the patient was sent home. She was recommended to have her cardiologist check up on her as she leaves the hospital and to have a gynecological examination in 6 weeks. Conclusion: It can be concluded that team work and prenatal care, in most cases, lead to delivery without complication, both for mother and fetus. PMID- 29416224 TI - A Rare Case of Misdiagnosis: Recurrence of Dermatofibrosarcoma Protuberans That Was Treated Surgicallyas a Keloid. AB - Aim: In this report, we presented the patient with Dermatofibrosarcoma Protuberans (DFSP), removed by considering as the keloid scar in the general surgery clinic with misdiagnosis. Case report: The patient was a 19-year-old female student with no scar or previous trauma history in the lesion area. Pathology report of excisional biopsy revealed as a DFSP, reachedsubcutis and dermis. In staging by CT, there had been no distant metastases. There was a lesion with the size of 2x1.5x1.5cm. A large resection was made to include the entire mass and the lower fascia. The defect area was repaired with a Limberg flap. There was no tumor recurrence in the first 6 months following the operation with high-level aesthetics for patient satisfaction. Conclusion: DFSP should be remembered in cases of operative or spontaneous keloid scarring lesions. The surgical treatment is possible after extensive resection with flap or graft repair. PMID- 29416225 TI - NONPARAMETRIC MANOVA APPROACHES FOR NON-NORMAL MULTIVARIATE OUTCOMES WITH MISSING VALUES. AB - Between-group comparisons often entail many correlated response variables. The multivariate linear model, with its assumption of multivariate normality, is the accepted standard tool for these tests. When this assumption is violated, the nonparametric multivariate Kruskal-Wallis (MKW) test is frequently used. However, this test requires complete cases with no missing values in response variables. Deletion of cases with missing values likely leads to inefficient statistical inference. Here we extend the MKW test to retain information from partially observed cases. Results of simulated studies and analysis of real data show that the proposed method provides adequate coverage and superior power to complete case analyses. PMID- 29416226 TI - A BRIEF REVIEW ON THE MODE OF ACTION OF ANTINEMATODAL DRUGS. AB - Anthelmintics are some of the most widely used drugs in veterinary medicine. Here we review the mechanism of action of these compounds on nematode parasites. Included are the older classes of compounds; the benzimidazoles, cholinergic agonists and macrocyclic lactones. We also consider newer anthelmintics, including emodepside, derquantel and tribendimidine. In the absence of vaccines for most parasite species, control of nematode parasites will continue to rely on anthelmintic drugs. As a consequence, vigilance in detecting drug resistance in parasite populations is required. Since resistance development appears almost inevitable, there is a continued and pressing need to fully understand the mode of action of these compounds. It is also necessary to identify new drug targets and drugs for the continued effective control of nematode parasites. PMID- 29416228 TI - Between security and military identities: The case of Israeli security experts. AB - The relationship between private security professionals and the military in Israel is complex. While there is growing attention to the fact that security and military actors and their activities are becoming increasingly blurred, the Israeli case shows something different. In this ground-up analysis of the relationship between private security practices and the military, I investigate its constant negotiation by private security professionals through their identification with and differentiation from the military, whereby they reconfigure the meaning of military capital. This identity work should be understood, I propose, within the strongly militarist context of Israeli society, where military capital is highly valued. I argue that actors who exit the military system feel the need to demonstrate the added value of their work in the private sector in order for it to gain value in the light of the symbolic capital given to the military. I analyse these processes as leading to a new kind of militarism, which includes security skills and ideas about professionalism. Such an approach sheds new light on the ways in which security actors can actively reconfigure the workings of military capital in and outside the nation-state and produce a different kind of militarism. PMID- 29416227 TI - Scalable Joint Segmentation and Registration Framework for Infant Brain Images. AB - The first year of life is the most dynamic and perhaps the most critical phase of postnatal brain development. The ability to accurately measure structure changes is critical in early brain development study, which highly relies on the performances of image segmentation and registration techniques. However, either infant image segmentation or registration, if deployed independently, encounters much more challenges than segmentation/registration of adult brains due to dynamic appearance change with rapid brain development. In fact, image segmentation and registration of infant images can assists each other to overcome the above challenges by using the growth trajectories (i.e., temporal correspondences) learned from a large set of training subjects with complete longitudinal data. Specifically, a one-year-old image with ground-truth tissue segmentation can be first set as the reference domain. Then, to register the infant image of a new subject at earlier age, we can estimate its tissue probability maps, i.e., with sparse patch-based multi-atlas label fusion technique, where only the training images at the respective age are considered as atlases since they have similar image appearance. Next, these probability maps can be fused as a good initialization to guide the level set segmentation. Thus, image registration between the new infant image and the reference image is free of difficulty of appearance changes, by establishing correspondences upon the reasonably segmented images. Importantly, the segmentation of new infant image can be further enhanced by propagating the much more reliable label fusion heuristics at the reference domain to the corresponding location of the new infant image via the learned growth trajectories, which brings image segmentation and registration to assist each other. It is worth noting that our joint segmentation and registration framework is also flexible to handle the registration of any two infant images even with significant age gap in the first year of life, by linking their joint segmentation and registration through the reference domain. Thus, our proposed joint segmentation and registration method is scalable to various registration tasks in early brain development studies. Promising segmentation and registration results have been achieved for infant brain MR images aged from 2-week-old to 1-year-old, indicating the applicability of our method in early brain development study. PMID- 29416229 TI - Postoperative nausea and vomiting: The achilles heel of anesthesiologists. PMID- 29416230 TI - Etomidate derivatives: Novel pharmaceutical agents in anesthesia. AB - Etomidate is an imidazole derivative that possesses important sedative properties employed in anesthesia practice, however, etomidate has a number of well-know side effects which limit its use in certain subpopulations and over long periods of time, mostly related to dose-dependent adrenal suppression. This review focuses on novel etomidate derivatives with an emphasis on pharmacological properties which afford improved safety profile and potentially desirable clinical effects. The pharmacology and clinical investigation of some of these etomidate derivatives, e.g. cyclopropyl-methoxycarbonyl, carboetomidate metomidate, methoxycarbonyl-etomidate, cyclopropyl-methoxycarbonyl metomidate (CPMM), and dimethyl-methoxycarbonyl metomidate, are discussed in detail. The increased potency and decreased metabolite build-up of CPMM potentially makes it a very favorable drug, particularly in the setting of prolonged infusions. Further, when compared with etomidate, CPMM produces lower plasma cytokine concentration and improved survival in lipopolysaccharide inflammatory sepsis models. PMID- 29416231 TI - Anesthesia for intellectually disabled. AB - Anesthetizing an intellectually disabled patient is a challenge due to lack of cognition and communication which makes perioperative evaluation difficult. The presence of associated medical problems and lack of cooperation further complicates the anesthetic technique. An online literature search was performed using keywords anesthesia, intellectually disabled, and mentally retarded and relevant articles were included for review. There is scarcity of literature dealing with intellectually disabled patients. The present review highlights the anesthetic challenges, their relevant evidence-based management, and the role of caretakers in the perioperative period. Proper understanding of the associated problems along with a considerate and unhurried approach are the essentials of anesthetic management of these patients. PMID- 29416232 TI - The role of neurokinin-1 (substance P) antagonists in the prevention of postoperative nausea and vomiting. AB - Postoperative nausea and vomiting (PONV) can be very debilitating for surgical patients, and effective management reduces potential morbidity, aiding in patient satisfaction, and minimizing the need for unintended hospital stays. Risk factors include female sex, nonsmoker, and having a previous history of motion sickness or PONV. Anesthetic risk factors include receiving opioids, not receiving a total intravenous anesthetic (TIVA), exposure to nitrous oxide, and extended length of anesthetic. Many treatments, including serotonin antagonists, dopamine antagonists, corticosteroids, inhaled isopropyl alcohol, and anticholinergics, as well as techniques such as TIVA, have been utilized over recent decades in an attempt to reduce PONV incidence. However, it remains a problem for a significant number of surgical patients. Aprepitant is a neurokinin-1 (substance P) antagonist, which exerts its effects via a final common pathway of the emetic centers after crossing the blood brain barrier. Aprepitant is commonly used in the cancer population to help prevent cancer chemotherapy-induced nausea and vomiting and has shown great promise in both acute and delayed phase PONV. Published data has shown improved efficacy when compared with ondansetron administered prior to surgery. The use of aprepitant in combination with other antiemetics potentially may help decrease unplanned hospital admissions and potentially, reduce costs associated with PONV. PMID- 29416233 TI - Video-assisted laryngoscopic devices: Have we found the panacea for difficult airway yet? PMID- 29416234 TI - Off-label use of drugs in regional anesthesia: A need for setting up policies. PMID- 29416235 TI - The effect of intravenous infusion of N-acetyl cysteine in cirrhotic patients undergoing liver resection: A randomized controlled trial. AB - Background and Aims: Liver resection can lead to hepatocellular dysfunction. The aim was to evaluate the effect of N-acetyl cysteine (NAC) on liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), international normalized ratio (INR), C-reactive protein (CRP), and intercellular adhesion molecule 1 (ICAM 1) in cirrhotic patients undergoing liver resection. Material and Methods: A randomized controlled trial (RCT), Pan African Clinical Trial registry (PACTR201508001251260). 60 Child A patients were studied. NAC group (n = 30) received intravenous infusion of NAC 10 g/24 h in 250 ml of 5% dextrose during surgery and for 2 days. Controls (C) (n = 30) received a similar volume of 5% dextrose. All above parameter were measured during and after surgery. Results: ALT and AST were significantly elevated after surgery, but to a less extent with NAC versus C (day 3; 118.3 +/- 18.6 vs. 145.4 +/- 14.0 U/L. P < 0.01) and (121.5 +/- 19.5 vs. 146.6 +/- 15.1 U/L, P = 0.00), respectively. Lower serum CRP and ICAM 1 with NAC versus C on day 3 (44.2 +/- 13.4 vs. 68.7 +/- 48.2 mg/l, P = 0.003), (308.8 +/- 38.2 vs. 352.8 +/- 59.4 ng/ml, P = 0.002), respectively. Hospital stay was shorter with NAC versus C (6.1 +/- 0.8 vs. 6.9 +/ 1.2 days, P = 0.006). Duration of surgery, INR, and hemodynamics were comparable. Conclusion: Prophylactic NAC in hepatic patients undergoing liver surgery attenuated postoperative increase in transaminases, ICAM 1, and CRP blood levels. The impact of these findings and the cost benefit of reduced hospital stay on enhanced recovery after surgery needs to be evaluated. PMID- 29416236 TI - Dexmedetomidine as an adjunctive analgesic to ropivacaine in pectoral nerve block in oncological breast surgery: A randomized double-blind prospective study. AB - Background and Aims: Pectoral nerve block (Pecs) using local anesthetic (LA) agent is a newer analgesic technique for breast surgeries. This study further evaluates the effect of addition of dexmedetomidine to LA agent on total duration of analgesia and postoperative morphine consumption. Material and Methods: A total of 60 American Society of Anesthesiologist Grade I and II female patients with age >=18 years, scheduled for oncological breast surgery, were enrolled in the study. Patients were randomized into two equal groups of 30 each. Group R (n = 30) received ultrasound (US)-guided Pecs block with 30 ml of 0.25% ropivacaine. Group RD (n = 30 patients) received US-guided Pecs block with 30 ml of ropivacaine 0.25% and dexmedetomidine 1 MU/kg body weight. Duration of analgesia and total postoperative morphine consumption was noted in 24 h period. Unpaired t test and Chi-square test were used for statistical analysis. Results: A statistically highly significant increase in total duration of analgesia (in minutes) was recorded in Group RD as compared to Group R (469.6 +/- 81.5 in Group RD and 298.2 +/- 42.3 in Group R) (P = 0.000). Total postoperative morphine consumption in mg was also statistically significantly lower in Group RD as compared to Group R (14.8 +/- 2.4 in Group RD and 21.6 +/- 3.1 in Group R) (P = 0.000). No patient under study reported any adverse effects. Conclusion: Addition of 1 MU/kg dexmedetomidine to 0.25% ropivacaine for Pecs block increases the duration of analgesia and decreases postoperative morphine consumption. PMID- 29416237 TI - Front of neck access: A survey among anesthetists and surgeons. AB - Background and Aims: Emergency front of neck access (FONA) is the final step in a Can't Intubate-Can't Oxygenate (CICO) scenario. In view of maintaining simplicity and promoting standardized training, the 2015 Difficult Airway Society guidelines recommend surgical cricothyroidotomy using scalpel, bougie, and tube (SBT) as the preferred technique. Material and Methods: We undertook a survey over a 2-week period to evaluate the knowledge and training, preferred rescue technique, and confidence in performing the SBT technique. Data were collected from both anesthetists and surgeons. Results: One hundred and eighty-nine responses were collected across four hospitals in the United Kingdom. The majority of participants were anesthetists (55%). One hundred and eleven (59%) respondents were aware of the national guidelines (96.2% among anesthetists and 12.9% among surgeons). Only 71 (37.6%) respondents indicated that they had formal FONA training within the last one year. Seventy-five anesthetists (72.8%) knew that SBT equipment was readily available in their department, while most surgeons (81.2%) did not know what equipment available. One hundred and five (55.5%) respondents were confident in performing surgical cricothyroidotomy in a situation where the membrane was palpable and only in 33 (17.5%) where the cricothyroid membrane was not palpable. Conclusion: This survey has demonstrated that despite evidence of good training for anesthetists in FONA, there are still shortfalls in the training and knowledge of our surgical colleagues. In an emergency, surgeons may be required to assist or secure an airway in a CICO situation. Regular multidisciplinary training of all clinicians working with anesthetized patients should be encouraged and supported. PMID- 29416238 TI - I-Gel versus laryngeal mask airway (LMA) classic as a conduit for tracheal intubation using ventilating bougie. AB - Background and Aims: Supraglottic airways (SGAs) are generally used for airway management; but can also be used as a conduit for tracheal intubation. Our primary aim was to evaluate i-Gel and laryngeal mask airway (LMA) classic as conduits for tracheal intubation using ventilating bougie by assessing number of attempts and time for insertion of SGAs, ventilating bougie and endotracheal tube (ETT), and total intubation time. Material and Methods: A randomized clinical trial was carried out in 58 patients requiring general anesthesia and endotracheal intubation for planned surgery. They were randomly divided into Group I and Group C. After induction of anesthesia, i-Gel was inserted in Group I and LMA Classic in Group C; ventilating bougie was passed through SGA followed by the removal of SGA and railroading of ETT over ventilating bougie. Parameters observed were number of attempts and time taken for device insertion, total intubation time, and hemodynamic variables. Results: Twenty-nine patients were included in each group. First attempt success rate for SGA insertion (86.2% in Group I and 75.9% in Group C (P = 0.5)), ventilating bougie insertion (79.32% in Group I and 82.8% in Group C (P = 0.99)) and ETT insertion (100% in Group I and 96.5% in Group C) was not different in the two groups. Total intubation time was 93.3 +/- 9.0 s in Group I and 108. 96 +/- 16.5 s in Group C (P < 0.0001). Conclusions: i-Gel and LMA Classic both can be used as a conduit for tracheal intubation using ventilating bougie with stable hemodynamic parameters. PMID- 29416239 TI - Tracheal intubation through laryngeal mask airway CTrachTM with polyvinyl chloride tube: Comparison between two orientations of the tracheal tube. AB - Background and Aims: Higher success rate of intubation is observed with the reverse orientation of polyvinyl chloride (PVC) tracheal tube while intubating through laryngeal mask airway (LMA) FastrachTM. It is not clear whether the same is true during intubation through LMA CTrachTM visualizing the process of intubation. The primary aim of this study was to compare the influence of the PVC tracheal tube orientation on the success rate of intubation while intubating through LMA CTrachTM. Material and Methods: One-hundred and fifty patients belonging to American Society of Anesthesiologists status I-II, undergoing elective surgery under general anesthesia were randomized to either group normal orientation or group reverse orientation. A maximum of 3 intubation attempts within a span of 3 min was allowed in each group before the change over to the other group. If intubation failed with the other orientation of the tube also, then intubation through LMA CTrachTM was abandoned and intubation done by direct laryngoscopy. The success of intubation, time, maneuvers, postoperative sore throat, and hoarseness were recorded. Results: Tracheal intubation through LMA CTrachTM with PVC tube was successful in 94.5% of patients in group normal orientation and in 98.6% of patients in group reverse orientation. The first attempt success rate was 75.3% and 86.3% in group normal and group reverse orientation, respectively. The incidence of a sore throat was higher in the group normal orientation than in the reverse orientation (31.8% and 26.5%, respectively). Conclusions: Overall success rate of intubation was comparable between the two groups. Though statistically insignificant, the first attempt success rate was higher in group reverse orientation. PMID- 29416240 TI - Intensive Care Unit delirium: A wide gap between actual prevalence and psychiatric referral. AB - Background and Aims: The study aimed to assess the rates of delirium in an Intensive Care Unit (ICU) prospectively assessed with a delirium screening instrument and confirmed through psychiatrist evaluation. In addition, the referral rate to psychiatric consultation liaison services from the same ICU was assessed through the rates of psychiatric referral over the previous 10 years. Material and Methods: In the prospective part of the study, consecutive patients aged 16 years or more admitted to the ICU of a tertiary care hospital were assessed daily for delirium using confusion assessment method for the ICU, a validated instrument that can be used for both mechanically ventilated and nonventilated patient by trained heath care personnel. Retrospectively, records of patients referred to psychiatric referral team for delirium from the ICU over the last 10 years were drawn out and the referral rate was calculated. Results: In the prospective study, 109 patients were recruited of which 43 patients remained comatose throughout their ICU stay and could not be assessed for delirium. Of the 66 assessable patients, 45 (68.2% prevalence rate) patients developed delirium. Incidence rate of delirium was 59.6%. In contrast, the retrospective study showed that only 53 cases out of 3094 admissions in ICU over 10 years (1.71%) were referred to psychiatry consultation liaison team for management of delirium. In the prospective study, hypoactive delirium was the most common subtype of delirium. Conclusion: There is a mismatch between the incidence and prevalence of delirium in ICU patients prospectively diagnosed with structured, validated instruments and the diagnosis of delirium in cases referred to psychiatry consultation-liaison services. PMID- 29416241 TI - Evidence-based medicine: A survey among perioperative health care professionals in India. AB - Background and Aims: Evidence-based medicine (EBM) is defined as the use of scientifically proven evidence for delivering best possible health care to patients. Despite growing emphasis on the need for EBM-based practice, acceptability, and perceptions toward EBM might differ among health professionals. The objective of this study was to assess the attitude, knowledge, and current practices of EBM among perioperative care health professionals in India. Material and Methods: This was a single point paper-based questionnaire survey carried out in February 2014 among delegates registered for an EBM conference on "perioperative care" held at a Tertiary referral Cancer Centre in India. Participation was voluntary and respondents were given the option of remaining anonymous. Results: Out of 190 questionnaires, 123 (65%) were returned. Most respondents (98%) agreed that practicing EBM improved patient care. The need to follow departmental protocols (22%) worries about the cost of implementing new treatments (20%) and inadequate skills to critically appraise articles (16%) accounted for major barriers in implementing EBM in clinical practice, with only 15% of respondents stating reluctance to change set practice. "Randomized controlled trial" and "number needed to treat" were the best and least understood EBM terms. Regarding awareness of 10 commonly used EBM-based guidelines in perioperative medicine, the percentage of correct responses ranged from 20% to 88%. Conclusion: Although most respondents agreed that practicing EBM improved patient care, many of them showed a low level of awareness regarding fundamental aspects of EBM. In addition to encouraging implementation of EBM, there should be increased focus on training in EBM methods. PMID- 29416242 TI - The minimum dose of dexmedetomidine required for cessation of postspinal anesthesia shivering: A prospective observational study. AB - Background and Aims: Shivering is a common postanesthesia adverse event with multiple etiologies. Dexmedetomidine, a centrally acting alpha-2 adrenergic agonist, is known to reduce the shivering threshold. However, the minimum dose at which dexmedetomidine causes cessation of shivering is unknown. The aim of this prospective observational study was to find the minimum dosage of dexmedetomidine required for abolition of post-spinal anesthesia (SA) shivering. Material and Methods: Thirty patients having shivering after SA were enrolled, who received dexmedetomidine in the dosage of 1 mcg/kg over 10 min. The time-to-cessation of shivering and the dose of dexmedetomidine required were expressed as mean +/- standard deviation. Results: The mean time-to-cessation of shivering after starting dexmedetomidine infusion was 155.88 +/- 15.16 s for Grade 3 shivering and 177.71 +/- 10.87 s for Grade 4 shivering. Till that time, the mean dose of dexmedetomidine which had been infused was 0.258 +/- 0.024 mcg/kg in Grade 3 shivering and 0.295 +/- 0.018 mcg/kg in Grade 4 shivering. Conclusion: The minimum dose of dexmedetomidine required for abolition of shivering was 0.258 +/- 0.024 mcg/kg for patients with Grade 3 shivering and 0.295 +/- 0.018 mcg/kg for patients with Grade 4 shivering, which is much less than the commonly administered dose. PMID- 29416243 TI - Sevoflurane sparing effect of dexmedetomidine in patients undergoing laparoscopic cholecystectomy: A randomized controlled trial. AB - Background and Aims: Sevoflurane is an excellent but expensive anesthetic agent for laparoscopic cholecystectomy. To decrease sevoflurane consumption during surgery adjuvants like dexmedetomidine may be used. Dexmedetomidine is a recently introduced drug which alleviates the stress response of surgery, produces sedation and analgesia. We aimed to evaluate sevoflurane sparing effect of dexmedetomidine in patients undergoing laparoscopic cholecystectomy under entropy guided general anesthesia (GA). Material and Methods: In this prospective randomized control study, 100 American Society of Anesthesiologists physical status I-II adult surgical patients scheduled to undergo laparoscopic cholecystectomy were enrolled. Patients were randomly divided into two groups (n = 50). In dexmedetomidine group, patients received intravenous (IV) dexmedetomidine 0.5 MUg/kg over 10 min before induction followed by 0.5 MUg/kg/h infusion while in control group, patients received the same volume of normal saline. Results: Sevoflurane consumption was 41% lower in dexmedetomidine group as compared to control group (7.1 [1.6] vs. 12.1 [1.9] ml, P <0.001). A 40% reduction was observed in induction dose of propofol (83.0 [19.1] vs. 127.6 [24.8] mg, P <0.001). Mean Riker sedation-agitation score, visual analog score for pain and Aldrete's score were significantly lower in dexmedetomidine group as compared to control group. None of the patients experienced any significant side effects. Conclusion: A 41% reduction in sevoflurane consumption was observed in patients receiving IV dexmedetomidine as an adjuvant in patients undergoing laparoscopic cholecystectomy under GA. PMID- 29416244 TI - Comparison of maintenance, emergence and recovery characteristics of sevoflurane and desflurane in pediatric ambulatory surgery. AB - Background and Aims: Increasing number of pediatric ambulatory surgeries are being carried out in general anesthesia using supraglottic airways (SGAs). Literature comparing sevoflurane and desflurane for the maintenance of SGA-based anesthesia is limited. Hence, we planned this prospective randomized study to compare the maintenance, emergence and recovery characteristics of sevoflurane and desflurane for pediatric ambulatory surgery. Material and Methods: Sixty children aged 6 months to 6 years posted for short surgical procedures were enrolled into the study. Anesthesia was induced with intravenous propofol (maximum 4 mg/kg), SGA was inserted, and children were randomized to receive sevoflurane or desflurane for the maintenance of anesthesia. No muscle relaxants were administered, and all children received caudal block and rectal paracetamol suppository. Demographic data, perioperative hemodynamics and adverse events, emergence and recovery characteristics, postoperative pain, and emergence agitation (EA) were recorded. Data were analyzed using SPSS (version 16.0, IBM Corporation, Armonk, New York, USA). P < 0.05 was considered statistically significant. Results: Demography, perioperative hemodynamics, and duration of inhalational anesthesia were comparable between two groups. There were no respiratory adverse events in either group during maintenance. Time to awakening and time to removal of SGA were shorter with desflurane (5.3 +/- 1.4 and 5.8 +/- 1.3 min) than sevoflurane (9.1 +/- 2.4 and 10.0 +/- 1.6 min) (P < 0.0001). Recovery (steward recovery score = 6) was faster with desflurane (18 +/- 8.4 min) than sevoflurane (45.3 +/- 9.7 min) (P < 0.001). The incidence of EA was 16.7% with desflurane and 10% with sevoflurane (P = 0.226). Conclusion: Desflurane provides faster emergence and recovery in comparison to sevoflurane when used for the maintenance of anesthesia through SGA in children. Both sevoflurane and desflurane can be safely used in children for lower abdominal surgeries. PMID- 29416245 TI - Analgesic efficacy of dexamethasone as an adjuvant to caudal bupivacaine for infraumbilical surgeries in children: A prospective, randomized study. AB - Background and Aims: Provision of adequate perioperative analgesia in children is important to attenuate the stress response to surgery. Caudal analgesia using local anesthetics is a traditionally used technique but provides a limited duration of analgesia. Several adjuvants can be added to local anesthetics to increase the duration of action. This study was undertaken to evaluate the efficacy of dexamethasone added to bupivacaine for caudal block in children. Material and Methods: This was a prospective, double-blinded trial on 130 children aged between 6 months and 6 years of age allocated randomly into one of two groups for elective subumbilical surgeries. Children in Group C received caudal bupivacaine and those in Group D received caudal bupivacaine with 0.1 mg/kg of dexamethasone. Results: The mean duration of analgesia when dexamethasone was added to caudal bupivacaine was 1044.92 (+/-48.66) min, while it was 435.85 (+/-17.95) min with plain bupivacaine. The number of doses of rescue analgesics required and the mean pain score was also lesser in this group. Conclusion: The addition of 0.1 mg/kg of dexamethasone to caudal bupivacaine increases the duration of analgesia of caudal bupivacaine without any side effects in children undergoing subumbilical surgeries. PMID- 29416246 TI - Effect of lactate versus acetate-based intravenous fluids on acid-base balance in patients undergoing free flap reconstructive surgeries. AB - Background and Aims: Use of lactated intravenous fluids during long surgeries could cause lactate accumulation and lactic acidosis. Acetate-based solutions could be advantageous as they are devoid of lactate. The primary aim of the study was to assess the effect of use of an acetated solution or Ringer's lactate (RL) as intraoperative fluid on lactate levels in patients without hepatic dysfunction undergoing prolonged surgeries. Material and Methods: This was a prospective, randomized, controlled trial involving sixty patients belonging to American Society of Anesthesiologists Physical Status I to II undergoing major head and neck surgeries with free flap reconstruction. Patients were randomly allocated into two equal groups, Group sterofundin (SF) and Group RL. Group SF was started on acetate-based crystalloid solution (sterofundin B Braun(r)) and Group RL received RL intravenously at the rate of 10 ml/kg/h to maintain systolic blood pressure above 90 mmHg. Blood loss >20% was replaced with packed cells. Arterial blood gas analysis was done 2nd hourly till 8 h. Chi-square test was used to compare categorical variables. Independent sample t-test was used to compare means. Results: Intraoperative lactate levels were significantly high in RL group at 2, 4, 6, and 8 h. The pH was comparable between groups except at 8 h where RL group had a significantly lower pH than SF group (7.42 +/- 0.1 vs. 7.4 +/- 0.1). Sodium, potassium, chloride, bicarbonate, and pCO2did not show any significant difference between the groups. Conclusion: Use of acetate-based intravenous solutions reduced levels of lactate in comparison with RL in patients undergoing free flap reconstructive surgeries. PMID- 29416247 TI - Effect of the addition of rocuronium to 2% lignocaine in peribulbar block for cataract surgery. AB - Background and Aims: Peribulbar anesthesia is associated with delayed orbital akinesia compared with retrobulbar anesthesia. To test the hypothesis that rocuronium added to a mixture of local anesthetics (LAs) could improve speed of onset of akinesia in peribulbar block (PB), we designed this study. This study examined the effects of adding rocuronium 5 mg to 2% lignocaine with adrenaline to note orbital and eyelid akinesia in patients undergoing cataract surgery. Material and Methods: In a prospective, randomized, double-blind study, 100 patients were equally randomized to receive a mixture of 0.5 ml normal saline, 6 ml lidocaine 2% with adrenaline and hyaluronidase 50 IU/ml (Group I), a mixture of rocuronium 0.5 ml (5 mg), 6 ml lidocaine 2% with adrenaline and hyaluronidase 50 IU/ml (Group II). Orbital akinesia was assessed on a 0-8 score (0 = no movement, 8 = normal) at 2 min intervals for 10 min. Time to adequate anesthesia was also recorded. Results are presented as mean +/- standard deviation. Results: Rocuronium group demonstrated significantly better akinesia scores than control group at 2 min intervals post-PB (significant P value obtained). No significant complications were recorded. Rocuronium added to a mixture of LA improved the quality of akinesia in PB and reduced the need for supplementary injections. Conclusion: The addition of rocuronium 5 mg to a mixture of lidocaine 2% with adrenaline and hyaluronidase 50 IU/ml shortened the onset time of peribulbar anesthesia in patients undergoing cataract surgery without causing adverse effects. PMID- 29416248 TI - A prospective randomized study comparing recovery following anesthesia with a combination of intravenous dexmedetomidine and desflurane or sevoflurane in spinal surgeries. AB - Background and Aims: Desflurane and sevoflurane are inhalational anesthetics which provide stable intraoperative hemodynamics and rapid emergence from anesthesia. Dexmedetomidine is an alpha2-agonist with sedative and hypnotic effects. We compared recovery following anesthesia with a combination of a continuous intravenous infusion of dexmedetomidine and desflurane or sevoflurane in cases of spine surgeries because no such data are available from India. Material and Methods: It was a single-blind, prospective, randomized study. After institutional ethics committee approval, patients were randomly allocated to one of the two groups of fifty patients each. Group D received desflurane and Group S received sevoflurane, along with dexmedetomidine 0.5 MUg/kg/h IV infusion for maintenance of anesthesia. Results and Conclusions: Extubation time (ET) in Group D was shorter by 4.2 min than in Group S (10.1 +/- 2.2 and 14.2 +/- 1.3; P = 0.004). Postoperative recovery, postoperative analgesic, and antiemetic requirement between the groups were comparable The mean dial setting required to maintain the minimum alveolar concentration of 1 intraoperatively was 3.1 for desflurane and 0.7 for sevoflurane. PMID- 29416249 TI - Evaluation of effect of entropy monitoring on isoflurane consumption and recovery from anesthesia. AB - Background and Aims: Entropy monitoring entails measurement of the effect of anesthetic on its target organ rather than merely the concentration of anesthetic in the brain (indicated by alveolar concentration based on which minimum alveolar concentration [MAC] is displayed). We proposed this prospective randomised study to evaluate the effect of entropy monitoring on isoflurane consumption and anesthesia recovery period. Material and Methods: Sixty patients undergoing total abdominal hysterectomy under general anesthesia using an endotracheal tube were enrolled in either clinical practice (CP) or entropy (E) group. In group CP, isoflurane was titrated as per clinical parameters and MAC values, while in Group E, it was titrated to entropy values between 40 and 60. Data including demographics, vital parameters, alveolar isoflurane concentration, MAC values, entropy values, and recovery profile were recorded in both groups. Results: Demographic data and duration of surgery were comparable. Time to eye opening on command and time to extubation (mean +/- standard deviation) were significantly shorter, in Group E (6.6 +/- 3.66 and 7.27 +/- 4.059 min) as compared to Group CP (9.77 +/- 5.88 and 11.63 +/- 6.90 min), respectively. Mean isoflurane consumption (ml/h) was 10.81 +/- 2.08 in Group E and 11.45 +/- 2.24 in Group CP and was not significantly different between the groups. Time to readiness to recovery room discharge and postanesthesia recovery scores were also same in both groups. Conclusion: Use of entropy monitoring does not change the amount of isoflurane consumed during maintenance of anesthesia or result in clinically significant faster recovery. PMID- 29416250 TI - A study of the efficacy of stellate ganglion blocks in complex regional pain syndromes of the upper body. AB - Background and Aims: The effect of stellate ganglion blocks (SGBs) was examined in complex regional pain syndromes (CRPS) of the upper body. Material and Methods: A total of 287 SGB were given to patients with documented CRPS on medications. Spontaneous and provoked pain assessment was done with numeric pain rating scale (NPRS). The Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and range of motion (ROM) was recorded before and after each blockade. Difference between a 15-point "global rating of change" scale determined the minimal clinically important difference of the DASH score. Results: The overall mean pain reduction was 73.2% (r = 0.83, P < 0.001) considering spontaneous and 55.8% (r = 0.77, P < 0.001) on provoked pain. Mean DASH score decreased from 53 (range 36-63; P = 0.14) to 10.4 (range 10-49.2; P = 0.005). The sensitivity to change was 6.9 for spontaneous and 4.9 for provoked pain. Increase in ipsilateral limb temperature has a good correlation with Horner's syndrome (HS) and sympathetic blockade. Minor, self-limiting complications, such as hoarseness, dysphagia, local hematoma, and ipsilateral brachial plexus block occurred in 11.5%. A rare complication of contralateral HS was documented. One patient developed a small pneumothorax, but it did not require intervention. Conclusions: SGB are relatively safe and effective management in patients with neuropathic conditions already on pharmacotherapy. Serial blocks attained an average reduction in pain by >3 NPRS points from the baseline for both spontaneous and provoked pain with a decrease in mean DASH score and improvement in ROM. PMID- 29416251 TI - Aortic dissection masquerading as a bicuspid aortic valve. AB - A 37-year-old male presented to the Emergency Department with acute worsening of back pain and new onset dyspnea. Transthoracic echocardiography revealed moderate left ventricular dysfunction and a bicuspid aortic valve (BAV). In addition, he was noted to have a dilated thoracic aorta concerning for a dissection, severe aortic insufficiency (AI), and both a pericardial and pleural effusion. Magnetic resonance imaging revealed a Type A ascending aortic dissection. He was taken emergently to the operating room for repair. An intraoperative transesophageal echocardiography examination was performed which revealed a normal trileaflet AV with a Type A aortic dissection flap masquerading as a BAV. The dissection flap interfered with both the valve's function, causing severe AI, as well as the valve's appearance, causing it to look bicuspid on echocardiography. PMID- 29416252 TI - Perioperative use of transthoracic echocardiography in a patient with congenitally corrected transposition of great arteries, atrial septal defect and severe pulmonary stenosis for lower segment cesarean section. AB - A 25-year-old female with congenitally corrected transposition of great arteries (CCTGAs), atrial septal defect, and severe pulmonary stenosis underwent lower segment cesarean section at 34 weeks of gestation using combined spinal epidural anesthesia (CSEA). We used transthoracic echocardiography (TTE) for intraoperative monitoring of the cardiovascular system because these patients are reported to have a high prevalence of myocardial perfusion defects, regional wall motion abnormalities, and impaired ventricular contractility. Scanning was done at four different time intervals; preoperatively, after initiation of CSEA, after delivery of child and postoperatively (6 and 24 h postdelivery) to detect regional wall motion and valvular abnormalities, calculate ejection fractions and optimize fluid administration. In this case report, we thus discuss the anatomical defects of CCTGA, physiologic concerns and emphasize on the use of TTE for perioperative management of such cases. PMID- 29416253 TI - Anesthetic management of a patient with Takotsubo cardiomyopathy presenting for surgical clipping of intracranial aneurysm. PMID- 29416254 TI - Administration of Syntocinon by anesthetists at the time of uterine evacuation in early pregnancy. PMID- 29416255 TI - Vitamin D resistant rickets: What an anesthesiologist should know. PMID- 29416256 TI - Use of the Magill forceps as an aid for i-gel(r) removal after endotracheal intubation: A safe and simple technique. PMID- 29416257 TI - Awake fiber-optic intubation: "Stop and Think" before you act! PMID- 29416258 TI - Tramadol-induced hypoglycemia: An unusual adverse effect. PMID- 29416259 TI - Desaturation due to dislodgement of inflation line from SACETTTM - Suction Above the Cuff Endotracheal Tube. PMID- 29416260 TI - Intravenous dezocine for suppressing fentanyl-induced cough during general anesthesia induction: A potentially effective and clinically feasible method. PMID- 29416261 TI - Rigid bronchoscopic stenting in a patient of tracheobronchial gout - perioperative anesthetic concerns. PMID- 29416262 TI - Cannot intubate situation arising out of difficult mouth opening due to jaw thrust. PMID- 29416263 TI - Fiberoptic-guided intubation after awake insertion of the I-gelTM supraglottic device in a patient with predicted difficult airway. PMID- 29416264 TI - Breath-holding in Vitamin D deficiency rickets: A dilemma for the anesthetist. PMID- 29416265 TI - Subarachnoid space needle's eyelet in dural-arachnoid side-wall of lumbar cistern: Whitacre vs. Quincke. PMID- 29416267 TI - Penile-sparing modalities in the management of low-stage penile cancer. AB - Penile-sparing modalities are gaining widespread adoption for the management of low-stage penile cancer due to an increasing demonstration of sound oncologic, cosmetic, sexual, psychosocial, and quality of life outcomes. This review aims to provide a comprehensive overview of the respective treatment options in the armamentarium of the practicing urologist in dealing with this rare but problematic condition. PMID- 29416268 TI - Robot-assisted ureteral reconstruction - current status and future directions. AB - Robotic surgery in the treatment in certain urological diseases has become a mainstay. With the increasing use of the robotic platform, some surgeries which were historically performed open have transitioned to a minimally invasive technique. Recently, the robotic approach has become more utilized for ureteral reconstruction. In this article, the authors review the surgical techniques for a number of major ureteral reconstuctive surgeries and briefly discuss the outcomes reported in the literature. PMID- 29416266 TI - Aging and the Kruppel-like factors. AB - The mammalian Kruppel-like factors (KLFs) are a family of zinc-finger containing transcription factors with diverse patterns of expression and a wide array of cellular functions. While their roles in mammalian physiology are well known, there is a growing appreciation for their roles in modulating the fundamental progression of aging. Here we review the current knowledge of Kruppel-like factors with a focus on their roles in processes regulating aging and age associated diseases. PMID- 29416269 TI - Transrectal ultrasound-guided prostate rebiopsy: How many core sampling should be applied to which patient? AB - Background: We investigated the correlation between the sampled number of cores in rebiopsy and the cancer detection rate (CDR). Materials and Methods: Two hundred and twelve patients with normal rectal examination who had undergone rebiopsy in the past 5 years were examined retrospectively. Moreover, 68% of them had undergone 12 cores (Group 1) while 32% had undergone 20 cores (Group 2). Both groups were compared with respect to the CDR. Results: There was no difference between groups in terms of age, total prostate-specific antigen, and prostate volume (P > 0.05). Forty-one (19%) of 212 patients were diagnosed with cancer, and the CDR was significantly higher in Group 2 (30.9% vs. 13.9%, P = 0.004). This rate increased from 6.5% to 20% (P = 0.025) and from 0% to 33.3% (P = 0.023), respectively, with 12-core and 20-core rebiopsies in patients whose initial pathology indicated benign and high-grade prostatic intraepithelial neoplasia (HGPIN). Furthermore, cancer was detected in 24 (40%) of 60 patients who were diagnosed with atypical small acinar proliferation (ASAP) in the initial biopsy. However, despite being higher in 20-core biopsy group (47.6% vs. 35.9%), this was not statistically significant (P = 0.377). Conclusions: At least 20 cores should be sampled in rebiopsy, especially in the patients diagnosed with benign and HGPIN. However, we believe that standard systematic sampling will be sufficient for the patients diagnosed with ASAP. PMID- 29416270 TI - Evaluation of Testicular Workup for Ischemia and Suspected Torsion score in patients presenting with acute scrotum. AB - Background: Testicular torsion is one of the causes of acute scrotum and it requires timely evaluation and surgical treatment. Color Doppler is considered investigation of choice, but it may delay treatment, as, many times, it may not be available for emergency situations. Barbosa et al. created Testicular Workup for Ischemia and Suspected Torsion (TWIST) score based on clinical parameters for clinical diagnosis of testicular torsion. We have evaluated this score in our population. Materials and Methods: We retrospectively calculated TWIST score in patients of acute scrotum admitted to tertiary teaching institute. Patients without complete TWIST score were excluded from the study. The scoring system consisted of testicular swelling (2 points), hard testicle (2), absent cremasteric reflex (1), nausea/vomiting (1), and high-riding testis (1). Statistical analysis was done to evaluate the validity of scores. Results: A total of 118 patients were included in the study, out of which 45 (38%) patients had testicular torsion. The mean age of patients was 16.6 years in testicular torsion patients and 15.2 years in other patients. Cutoff for low-risk and high risk patients was two and five, respectively. Fifty percent, 26.2%, and 23.8% of patients were present in low-, intermediate-, and high-risk groups. Negative predictive value of TWIST score for low-risk patients was 96.61% while positive predictive value for high-risk patients was 92.86%. Conclusions: TWIST score has high predictive value and can be used for clinical diagnosis of testicular torsion. It can decrease the need of color Doppler in about 50% of cases and can prevent delay in treatment. PMID- 29416271 TI - Safety and efficacy of ultrasound-guided percutaneous suprapubic cystostomy in resource-poor setting: A 7-year review. AB - Introduction: Percutaneous cystostomy techniques are usually done using disposable sets in developed countries which are not affordable in poor-resource settings. However, the percutaneous technique can be done using reusable trocar or selected big size surgical blades. This is simple, safe, and cost effective in poor-resource setting. The procedure is best done under ultrasound guidance but can also be done blindly in select cases. We present our 7-year experience in ultrasound-guided percutaneous suprapubic cystostomy. Materials and Methods: This is a 7-year retrospective review of patients, who had ultrasound-guided percutaneous suprapubic cystostomy at Urology Unit of our institution from January 2010 to December 2016. Disposable cystostomy sets were used for the initial experience, but this was replaced with more cost-effective reusable metallic trocar or selected big size surgical blade methods in the later experience. Data were extracted from procedure register and patients' case notes and entered into pro forma and analyzed using Statistical Package for Social Sciences 20.0 version (2011) for windows (IBM, SPSS Incorporation, Chicago, IL, USA) 20.0 version for Windows. Results: A total number of 135 patients had percutaneous cystostomy, which was ultrasound guided in 134 patients (99.3%). The mean age of the patients was 50.5 +/- 23.3 years with a range of 2-90 years. The indications for the procedure include urine retention with failed urethral catheterization in 119 patients (88.1%), urethral injury in 14 patients (10.4%), and urethrocutaneous fistula in 2 patients (1.5%) with spinal cord injury. No major complication was recorded. Conclusion: Ultrasound-guided suprapubic cystostomy using reusable trocar or selected surgical blade is simple, safe, effective, and associated with minimal complications in poor-resource setting. PMID- 29416272 TI - Is retrograde intrarenal surgery the game changer in the management of upper tract calculi? A single-center single-surgeon experience of 131 cases. AB - Introduction: Success of any modality for stone disease needs to be evaluated in terms of Stone Free Rates (SFR), auxiliary procedures needed; complications and follow up. SFR in RIRS is subject to parameters like stone burden, location, number, hardness, composition; calyceal and ureter anatomy; use of ureteric access sheath (UAS); surgeon experience etc. Methods: The aim of this study is to evaluate the efficacy and safety of RIRS for managing upper tract stones. The objectives include evaluating SFR in RIRS in relation to stone burden, location and number. Other objectives include evaluating SFR after re RIRS in relation to stone burden, necessity of pre DJ stenting, use of UAS and post operative complication rate. 131 patients operated by single surgeon for single/multiple renal and/or upper ureteric stones were evaluated. Stone size > 3 mm on follow up CT KUB was considered as residual. Re RIRS was required for residual stones. Results: The overall SFR was 76%. SFR were statistically lower with stone burden > 1.5 cm, lower calyceal stones and single stones with stone burden > 1.5 cm. SFR was 90% after 2nd RIRS and 98.5% after 3rd RIRS procedure. No significant difference in SFR was noted between single v/s multiple stones, single calyx v/s multiple calyx stones and renal v/s upper ureteric stones. No major complication was noted. Conclusion: Larger stone burden and lower calyceal location are important factors deciding SFR in RIRS. With auxiliary procedure, RIRS is safe and effective compared to PCNL. PMID- 29416273 TI - This challenging procedure has successful outcomes: Laparoscopic nephrectomy in inflammatory renal diseases. AB - In prospective study from November 2011- November 2013, we performed 44 laparoscopic nephrectomies for benign non-functioning kidney diseases. Twenty eight patients underwent laparoscopic transperitoneal nephrectomies (63.6%), ten were laparoscopic assisted (22.7%) and six (13.6%) were converted to open. Patient's age, gender, laterality and etiology of renal failure were noted. Outcomes were measured as operative time, intraoperative and post operative complications, blood loss, pain score and hospital stay. Patients were followed up at one, three and 12 weeks and 6 monthly thereafter. Of the 44, ten (22.7%) were 15-24 years old, 32 (72%) between 25-50 years and two were more than 50 years old. Females were 54.6%. 22 patients had either right or left nephrectomy. Pelviureteric-junction (PUJ) obstruction was the commonest cause, 26 cases (59.0%). Operative time: less than two hours in 30 (68.2%) patients, more than two hours in 14 cases. Blood loss: less than 100 ml in 12 (27.3%), 100-200 ml in 20 (45.4%) and more than 200 ml in 12 (27.3%) patients. All four major complications were converted to open, two had injury to mesocolic veins and two had vascular stapler malfunction. Post-operative complications: surgical site infection (SSI), paralytic ileus and mild grade fever in six cases each and non infected benign intra abdominal collection in two cases. Maximum pain score on POD-1: four in 20 cases (45.7%), two in 24 (54%). Two had pain score between 3-4 three weeks after surgery. Oral intake started by POD-2 in 30 (68.2%) and by POD 4 in 100% cases. 22 (50%) patients were ambulating by POD-2, 16 (36.7%) by POD-4. Our study and randomized and non-randomized published literature report acceptables complication and conversion rates. In conclusion, laparoscopic nephrectomy for benign non functional kidney is a better alternative to open nephrectomy. PMID- 29416274 TI - Trend analysis of bacterial uropathogens and their susceptibility pattern: A 4 year (2013-2016) study from Aseer region, Saudi Arabia. AB - Purpose: To analyze the prevalence and resistance rates of bacterial agents causing urinary tract infections (UTIs) in Aseer, Saudi Arabia (2013-2016). Patients and Methods: This was a 4-year (2013-2016) retrospective study undertaken in Aseer Central Hospital, Saudi Arabia. A total of 49,779 urine and other UT specimens obtained from patients suspected of having a UTI were analyzed. Urine specimens were inoculated onto cystine lactose electrolyte deficient agar following standard procedures. Cultures showing significant bacteriuria were subjected to identification and sensitivity testing using VITEK 2 system. Data of patients and uropathogens were assembled, checked, and analyzed using SPSS software. Results: Culture positive samples were 49,779 (59.9% males, 40.1% females; P = 0.000). Year trend showed significant variations (P = 0.000) and the forecast trend line hypothesized a clear rise. Age groups 70-79 years were the most vulnerable group (22.3%). Gram-negative bacilli were 91.8% and the major species were Escherichia coli - 39.7%, Klebsiella pneumoniae - 15.8%; Pseudomonas aeruginosa - 13.8%, Proteus mirabilis - 10.6%, and Acinetobacter baumannii - 5%. Antimicrobials with high sensitivity rate were linezolid (99.1%), daptomycin (89.3%), vancomycin (86.7%), teicoplanin (85.5%), ertapenem (85.1%), fosfomycin (82.1%), and tigecycline (80.2%). High resistant rates to uropathogens were encountered with cephalothin (89.8%), nalidixic acid (86.7%), and ampicillin (81.9%). Conclusions: The majority of uropathogens were resistant to antibiotics commonly used in clinical practice. Linezolid, daptomycin, and vancomycin showed the lowest resistance to all uropathogens; this can be revised for empirical treatment of UTIs. Continuous surveillance of uropathogens and their susceptibility is important. PMID- 29416275 TI - Endoscopic urethral realignment of traumatic urethral disruption: A monocentric experience. AB - Introduction: The optimal management strategy for urethral injuries remains controversial. Suprapubic cystostomy followed by delayed urethral reconstruction or immediate primary urethral injury repair is associated with high complication rate. Early endoscopic realignment for urethral injuries provides early definitive procedure with low complications and avoids the need for further urethral reconstruction. Materials and Methods: Between April 2007 and March 2016, 27 patients with traumatic posterior urethral disruptions were reviewed. All patients were managed by endoscopic urethral realignment. Patients were followed up every 3 months for 18-36 months regarding incontinence, potency, and urine flow. Results: Endoscopic urethral realignment was performed immediately in 21 patients and was delayed in 6 patients. It was successful in 24/27 (88.8%) patients. During the procedure, the proximal urethral end was identified directly in four patients, and by the guidance of methylene blue injection, guidewire or endoscopic light in three, nine, and eight patients, respectively. The Foley catheter was removed after 9 weeks in 17/24 (70.8%) patients and after 12 weeks in 7/24 (29.2%) patients. Six months after realignment, minimal urethral stricture was developed in 4/24 (16.7%) patients. All of them were treated successfully with single session of internal urethrotomy without recurrence after 1-year follow-up. After 18-36-month follow-up period, all patients were potent, continent, and with satisfactory voiding pattern. Conclusions: Endoscopic primary realignment of posterior urethral rupture is less invasive and a safer procedure, without pelvic hemorrhage or additional injuries. It has low incidence of severe urethral stricture and avoids the need for delayed open urethral reconstruction. PMID- 29416277 TI - Epidemiology profile of renal cell carcinoma: A 10-year patients' experience at King Abdulaziz Medical City, National Guard Health Affairs, Saudi Arabia. AB - Purpose: The purpose of this study is to describe the epidemiological profile, histopathological features, and outcomes of patients diagnosed with renal cell carcinoma (RCC) in a tertiary referral center over 10 years. Methodology: This is a retrospective cohort of 219 Saudi patients diagnosed with RCC between June 2003 and May 2013. The variables collected included the sociodemographic details and clinical presentation. The histopathological features investigated include the tumors histological subtype, pathologic staging tumor, node, and metastasis descriptors, and lymph-vascular invasion. Patients were followed until May 2013. Bivariable analysis was calculated using Chi-square test, with level of significance set at P < 0.05. Kaplan-Meier estimate was used to calculate the survival rate. Results: The mean age of patients was 57.18 (+/-14.68 standard deviation). The trend of patients diagnosed with RCC over the past 10 years was higher among males than females (60.27% vs. 39.73%). Noticeably, more than half (57.58%) were diagnosed incidentally. The most common histological subtype was clear cell (conventional) RCC (70.44%). Patients were usually diagnosed at the pT1 stage (48.1%).The histopathological features associated with worse patient outcome were the stage of the primary tumor (P = 0.01) and lymph-vascular invasion (P = 0.003). The overall mean survival rate was 2.03 years. Conclusion: In the past 10 years, there are more patients diagnosed incidentally with RCC, which is in line with the global trend. Patients were more likely to be male and middle aged. We recommend further population-based studies in this area to establish a national epidemiological data for this common type of cancer. PMID- 29416276 TI - Role of uroflowmetry before and after hypospadias repair. AB - Aims: To study the role of uroflowmetry in the preoperative and early postoperative period in children undergoing hypospadias repair. Materials and Methods: Twenty-six cases undergoing hypospadias repair over 1 year (tubularized incised plate [TIP] Snodgrass [17 patients], TIP with Snodgraft [5 patients], Duckett's onlay flap [2 patients], and Duckett's tube [2 patients] urethroplasty) were prospectively evaluated with preoperative ultrasound and uroflowmetry and postoperative uroflowmetry at 3 months after the surgery and at 6 and 9 months interval if these dates fell within the study period on follow-up. The parameters studied were maximum flow rate (Qmax), average flow rate (Qav), total voided volume, voiding time, and type of curve. Preoperative and postoperative uroflow data were compared. Results: Twenty-six cases comprised of anterior hypospadias (n = 8), mid penile (n = 11), and posterior hypospadias (n = 7). Fourteen patients had obstructed flow rates preoperatively. While 69% patients (18/26) had obstructed flow rates at 3 months postoperatively, it dropped to 43% at 9 months. Following TIP (Snodgrass) repair, 88% (15/17) had obstructed flow rates postoperatively. Best results were seen in patients undergoing circumferentially epithelialized urethral reconstruction (TIP with Snodgraft, Duckett's onlay flap, and Duckett's tube). Conclusions: Abnormal uroflow is an inherent aspect of hypospadias in 50% of the cases. Both preoperative and postoperative uroflow evaluation is necessary for meaningful conclusion. Patients with preoperative normal flow rates but obstructed postoperative flow rates need clinical evaluation. Obstructive flow rates are more common after TIP (Snodgrass) repair. The urinary flow rates improve with time. PMID- 29416278 TI - An overview of serum prostatic surface antigen cut points for recommendation of prostatic biopsy. AB - Introduction: Patients in India frequently present with prostatic surface antigen (PSA) report and request for prostatic biopsy to rule out malignancy. With fear of harboring malignancy set in patient's mind, it becomes difficult to counsel them about absolute indications and need of biopsy. Whether serum PSA has same predictability in symptomatic patients in the Indian context for advising prostatic biopsy at same reference ranges as in western countries, remains to be answered. Materials and Methods: Symptomatic patients between 45 and 70 years of age presenting with either raised serum PSA (>4 ng/ml) reports or abnormal digital rectal examination (DRE) were considered as cases. Standard 12 core transrectal ultrasound-guided prostatic biopsy was done. Statistical analysis using optimal cut points, an R package was done to overview different PSA cut points for the recommendation of prostatic biopsy. Results: A total of 534 patients were included. Mean age was 64 years. Malignancy was detected in total 77 patients (14.42%). Malignancy was identified in 3.59% (10/279) and 30% (63/210) patients at serum PSA ranges 4-10 ng/ml and serum PSA >10 ng/ml, respectively. Both, maximum sensitivity and specificity were found at PSA cut point 9.7 ng/ml. We evaluated these patients to identify the PSA cut point above which unnecessary biopsies will be avoided. We kept power of study maximum, i.e., 1 with confidence interval of 0.95. Conclusion: PSA value 9.7 ng/ml should be considered as the cut point above which prostatic biopsy should be done to avoid unnecessary biopsies. Unless accompanied by abnormal DRE finding at PSA range 4 10 ng/ml, morbidity of prostatic biopsy procedure can be avoided using this cut point. PMID- 29416279 TI - Characteristics of bacterial colonization after indwelling double-J ureteral stents for different time duration. AB - Background: Indwelling Double-J ureteral stenting is commonly used in urological practice and has various complications. This study aimed to assess the frequency of bacterial stent colonization and stent-associated bacteriuria after indwelling it for different time durations and to evaluate the significance of urinary cultures for identification of colonizing microorganisms. Materials and Methods: A prospective cross-sectional study was conducted. Midstream urine from 72 patients undergoing J stent insertion was investigated microbiologically before stent insertion and on the day of stent removal. The stents were removed by aseptic manipulation, and 1-3 cm of the tip located in the bladder was collected for microbiological study. The urine and stent samples were cultured, and the bacterial pathogens were identified using standard microbiological methods followed by Phoenix automated system. Antimicrobial susceptibility testing was performed by Kirby-Bauer disc diffusion method. Results: Bacterial colonies were found in 47.2% (34 of 72) of the stents. Of the multiple pathogens identified, Escherichia coli (20%) was the most common, followed by Streptococcus sp. (17.5%) and Pseudomonas sp. (12.5%). The bacteria did not colonize within the first 2 weeks of stent placement. Results showed that 55% of the isolates were resistant to erythromycin, 52.5% to ampicillin, 42.5% to piperacillin, and least resistant being 17.5% for tetracycline and imipenem. However, 81.3% and 66.7% of the stents were colonized when placed for 90-120 days and 60-90 days, respectively. Conclusion: High prevalence of bacterial isolates and risk of bacteriuria and colonization was found in the DJ stent tips, with E. coli being dominant colonizer. Most of the bacteria were resistant to different classes of antibiotics. Bacteriuria and stent colonization gradually increases with the duration of stent retention in the body. PMID- 29416280 TI - STONE score versus Guy's Stone Score - prospective comparative evaluation for success rate and complications in percutaneous nephrolithotomy. AB - Purpose: The aim of the current study was to compare Guy's score and STONE score in predicting the success and complication rate of percutaneous nephrolithotomy (PCNL). Materials and Methods: A total of 445 patients were included in the study between July 2015 and December 2016. The patients were given STONE score and Guy's Stone Score (GSS) grades based on CT scan done preoperatively and intra- and post-operative complications were graded using the modified Clavien grading system. The PCNL were done by a standard technique in prone positions. Results: The success rate in our study was 86.29% and both the GSS and STONE score were significantly associated with a success rate of the procedure. Both the scoring systems correlated with operative time and postoperative hospital stay. Of the total cases, 102 patients (22.92%) experienced complications. A correlation between STONE score stratified into low, moderate, and high nephrolithometry score risk groups (low scores 4-5, moderate scores 6-8, high scores 9-13), and complication was also found (P = 0.04) but not between the GSS and complication rate (P = 0.054). Conclusion: Both GSS and STONE scores are equally effective in predicting success rate of the procedure. PMID- 29416281 TI - Comparative efficacy of tamsulosin versus tadalafil as medical expulsive therapy for distal ureteric stones. AB - Objective: The objective of this study was to compare the relative efficacy of tamsulosin and tadalafil as medical expulsive therapy for distal ureteric stones. Patients and Methods: This was a prospective study performed between December 2014 and February 2016. A total of 123 adult patients (>18 years of age) presenting with distal ureteric stones sized 6-10 mm were randomized to treatment with tamsulosin 0.4 mg once daily (Group A) or tadalafil10 mg once daily (Group B). Therapy was given for a maximum of 4 weeks. The stone expulsion rate was the primary endpoint. Time to stone expulsion, number of colic episodes, analgesic use, number of hospital visits for pain, endoscopic treatment, and adverse effects of the drugs were noted. Statistical analyses were done using Fisher's exact test and Chi-square test. Results: A total of 61 patients were included in tamsulosin group and 62 patients in tadalafil group. A statistically insignificant difference was found for stone clearance rate between both groups as a whole (Group A-73.77%, Group B-69.35%, P = 0.690) as well as when we considered both subgroups (A1-78.05%, B1-75.0%, P = 0.802; A2-65.0%, B2-55.6%, P = 0.741). All the primary and secondary outcome measures were more in favour of stones <=8 mm size than stones >8 mm size. No statistical difference was found for adverse drug effects except for retrograde ejaculation, which was significantly high in tamsulosin group (P < 0.001). Conclusion: This study showed that although tamsulosin is more effective for stone clearance than tadalafil, but this difference was not significant (P = 0.690). PMID- 29416282 TI - Incidence and characteristics of kidney stones in patients with horseshoe kidney: A systematic review and meta-analysis. AB - Introduction: The horseshoe kidney (HSK) is the most common type of renal fusion anomaly. The incidence and characteristics of kidney stones in patients with HSK are not well studied. The aim of this meta-analysis was to evaluate the incidence and types of kidney stones in patients with HSK. Methods: A systematic literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from the databases' inception through November 2016. Studies assessing the incidence and types of kidney stones in patients with HSK were included. We applied a random-effects model to estimate the incidence of kidney stones. The study protocol was registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42016052037). Results: A total of 14 observational studies with 943 patients (522 adults and 421 pediatric) with HSK were enrolled. The estimated pooled incidence of kidney stones was 36% (95% confidence interval [CI], 15%-59%) in adults with the HSK. Kidney stones were less common in pediatric patients with HSK with an estimated pooled incidence of 3% (95% CI, 2% 5%). The mean age of adult stone formers with HSK was 44.9 +/- 6.2 years, and 75% were males. Within reported studies, 89.2% of kidney stones were calcium-based stones (64.2% calcium oxalate [CaOx], 18.8% calcium phosphate [CaP], and 6.2% mixed CaOx/CaP), followed by struvite stones (4.2%), uric acid stones (3.8%), and others (2.8%). Conclusions: Kidney stones are very common in adult patients with HSK with an estimated incidence of 36%. Calcium-based stones are the most prevalent kidney stones in adults with HSKs. These findings may impact the prevention and clinical management of kidney stones in patients with HSK. PMID- 29416283 TI - Metabolic evaluation of children with urolithiasis. AB - Aim: The aim of the study is to identify the prevalence of metabolic abnormalities in children with urolithiasis. Materials and Methods: This is a prospective study; all children below 15 years who are found to have urolithiasis were prospectively evaluated with relevant history, clinical examination, and urine and serum testing. Metabolic workup includes complete urine examination, urine culture and sensitivity, and 24-h urinary analysis (lithorisk profile). Results: A total of 55 patients are included in the study. Forty-two are boys and 13 are girls aged between from 8 months to 15 years. Thirty-three patients underwent stone analysis, primary composition of calcium oxalate stones in 19 (58%), ammonium urate in 4, dahlite in 3 and uric acid in 3, silicon oxide in 2, and struvite in 2 cases. Lithorisk profile was performed in 40 cases (72.7%). The pH range is 5.6-6.2. We noted hypercalciuria in 20 patients (50%), hyperuricosuria in 23 (57.5%), hyperoxaluria in 20 (50%), hypernatriuria in 26 (65%), hypocitraturia in 9 (23%), and hypomagnesuria in 3 (7.5%). Urine calcium to-creatinine ratio >0.2 was found in 22 (55%) patients. Statistically significant association between hyperoxaluria and hyperuricosuria (P < 0.04, r = 0.32) and hypercalciuria and hyperuricosuria (P < 0.001, r = 0.51) found in this study. Hyperuricosuria is seen in 75% and 73% of patients with hypercalciuria and hyperoxaluria, respectively. Twenty-five children have both lithorisk profile and stone analysis. Hypercalciuria and hyperoxaluria were noted in 60% of calcium oxalate stone formers each. Elevated urinary calcium/creatinine ratio (>0.2) was seen in 73% of calcium oxalate stone formers. Conclusion: Because of high prevalence of metabolic risk factors and the significant risk of lifelong recurrence, all children with urolithiasis need complete evaluation with metabolic workup. PMID- 29416285 TI - A rare case of renal vein thrombosis secondary to Klebsiella pneumoniae pyelonephritis. AB - Renal vein thrombosis (RVT) is most often an implication of nephrotic syndrome. Pyelonephritis has been associated at a much lower rate, with the incidence of Klebsiella pneumoniae causation being extremely rare. In our case, a 35-year-old female patient presented with right-sided K. pneumoniae-positive acute pyelonephritis complicated by perinephric abscess and renal vein thrombosis. She was successfully treated with anticoagulation and extended antibiotic therapy. The possibility of RVT in patients with K. pneumoniae-induced pyelonephritis warrants consideration. PMID- 29416284 TI - Prolapsed ureterocele in an adult woman after endoscopic incision. AB - A 44-year-old woman underwent endoscopic incision of a right simple ureterocele with hydronephrosis discovered during gynecological assessment for stress urinary incontinence with Stage I cystocele. At the postoperative visits, she has reported a persistent flap of mucosa coming out from her urethra protruding in the vagina despite manual reduction. An endoscopic resection of the mucosa flap was programmed. After 24 months, she was asymptomatic with no history of renal colic or urinary tract infection. In patients with a history of pelvic organ prolapse, the resection of the ureterocele in the first instance may be the optimal choice. PMID- 29416286 TI - A rare case of prostatic abscess caused by Brucella organisms: First report in Saudi Arabia. AB - Brucellosis is a zoonotic infectious disease that is known endemic infection in Saudi Arabia. Yet, this infection has not been reported as evident cause of prostatic abscess. we present a new case of prostatic abscess caused by brucella organism proven using pus culture and serology. These organisms should be suspected in patients presenting with clinical picture of prostatic abscess especially in endemic areas. PMID- 29416287 TI - Hereditary leiomyomatosis and renal cell carcinoma: Case report and review of the literature. AB - Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare genetic disorder in which the affected individuals tend to develop cutaneous leiomyomas, uterine leiomyomas, and renal cell cancer (RCC). Within the spectrum of this syndromic disease, RCC is the most severe manifestation, occurring at a younger age compared to the sporadic form. Pathological suspicion or diagnosis of HLRCC is critical for appropriate clinical management and genetic counseling of the affected family members. In this study, we report the case of a 27-year-old misdiagnosed carrier of HLRCC phenotype, who presented with a large solitary Type II papillary RCC. PMID- 29416288 TI - Intravesical explosion during transurethral resection of prostate: Prevention and management. AB - The blast during transurethral surgery is a rare but known complication of transurethral resection of prostate (TURP) or transurethral resection of bladder tumors. It may lead to bladder rupture, which can be either extra- or intra peritoneal requiring urgent laparotomy. It occurs due to the generation and trapping of explosive gases under the dome of the bladder. Even though this complication is rare, but the morbidity associated with this complication is high. Here, we present an interesting case report of an intravesical explosion during TURP leading to bladder rupture to remind urologists of this rare complication with suggestions on how to manage and prevent this complication. PMID- 29416289 TI - Multiple bladder diverticula treated with robotic approach-assisted with cystoscopy. AB - A bladder diverticulum (BD) is a herniation of the bladder urothelium through the muscular bladder wall. As a result, BD presents as a thin walled bag, urine filled connected to bladder lumen through a neck or ostium. The clinical problem with bladder diverticula is their poorly empty during micturition which results in multiple lower urinary tract symptoms as well as recurrent urinary tract infections. Bladder diverticula can be grossly classified in two groups as follows: congenital or acquired with different age presentation and etiological factors in each one. Vast majority of BD occur in adults especially in men. Acquired BD, are commonly diagnosed in the setting of neurogenic dysfunction or bladder outlet obstruction, they use to be multiple, associated with trabeculated bladder and prostatic enlargement. PMID- 29416290 TI - Omphalocele, exstrophy of cloaca, imperforate anus, and spinal defect complex, multiple major reconstructive surgeries needed. AB - OEIS complex is a rare combination of serious birth defects including omphalocele, exstrophy of cloaca, imperforate anus, and spinal defects. The aim of managements has shifted from merely providing survival to improve patient outcomes and quality of life with higher level of physical and social independence. Multiple complicated reconstructive surgeries always needed for achieving the goals of treatment. In this case report, we aimed to present our surgical approach for this rare abnormality to achieve functionally and socially acceptable outcome. PMID- 29416291 TI - An alternative extragradient projection method for quasi-equilibrium problems. AB - For the quasi-equilibrium problem where the players' costs and their strategies both depend on the rival's decisions, an alternative extragradient projection method for solving it is designed. Different from the classical extragradient projection method whose generated sequence has the contraction property with respect to the solution set, the newly designed method possesses an expansion property with respect to a given initial point. The global convergence of the method is established under the assumptions of pseudomonotonicity of the equilibrium function and of continuity of the underlying multi-valued mapping. Furthermore, we show that the generated sequence converges to the nearest point in the solution set to the initial point. Numerical experiments show the efficiency of the method. PMID- 29416293 TI - The Incremental Multiresolution Matrix Factorization Algorithm. AB - Multiresolution analysis and matrix factorization are foundational tools in computer vision. In this work, we study the interface between these two distinct topics and obtain techniques to uncover hierarchical block structure in symmetric matrices - an important aspect in the success of many vision problems. Our new algorithm, the incremental multiresolution matrix factorization, uncovers such structure one feature at a time, and hence scales well to large matrices. We describe how this multiscale analysis goes much farther than what a direct "global" factorization of the data can identify. We evaluate the efficacy of the resulting factorizations for relative leveraging within regression tasks using medical imaging data. We also use the factorization on representations learned by popular deep networks, providing evidence of their ability to infer semantic relationships even when they are not explicitly trained to do so. We show that this algorithm can be used as an exploratory tool to improve the network architecture, and within numerous other settings in vision. PMID- 29416292 TI - Behavioral/Emotional Problems of Preschoolers: Caregiver/Teacher Reports From 15 Societies. AB - This study tested societal effects on caregiver/teacher ratings of behavioral/emotional problems for 10,521 preschoolers from 15 societies. Many societies had problem scale scores within a relatively narrow range, despite differences in language, culture, and other characteristics. The small age and gender effects were quite similar across societies. The rank orders of mean item ratings were similar across diverse societies. For 7,380 children from 13 societies, ratings were also obtained from a parent. In all 13 societies, mean Total Problems scores derived from parent ratings were significantly higher than mean Total Problems scores derived from caregiver/teacher ratings, although the size of the difference varied somewhat across societies. Mean cross-informant agreement for problem scale scores varied across societies. Societies were very similar with respect to which problem items, on average, received high versus low ratings from parents and caregivers/teachers. Within every society, cross informant agreement for item ratings varied widely across children. In most respects, results were quite similar across 15 very diverse societies. PMID- 29416294 TI - Online Graph Completion: Multivariate Signal Recovery in Computer Vision. AB - The adoption of "human-in-the-loop" paradigms in computer vision and machine learning is leading to various applications where the actual data acquisition (e.g., human supervision) and the underlying inference algorithms are closely interwined. While classical work in active learning provides effective solutions when the learning module involves classification and regression tasks, many practical issues such as partially observed measurements, financial constraints and even additional distributional or structural aspects of the data typically fall outside the scope of this treatment. For instance, with sequential acquisition of partial measurements of data that manifest as a matrix (or tensor), novel strategies for completion (or collaborative filtering) of the remaining entries have only been studied recently. Motivated by vision problems where we seek to annotate a large dataset of images via a crowdsourced platform or alternatively, complement results from a state-of-the-art object detector using human feedback, we study the "completion" problem defined on graphs, where requests for additional measurements must be made sequentially. We design the optimization model in the Fourier domain of the graph describing how ideas based on adaptive submodularity provide algorithms that work well in practice. On a large set of images collected from Imgur, we see promising results on images that are otherwise difficult to categorize. We also show applications to an experimental design problem in neuroimaging. PMID- 29416295 TI - Expression in retinal neurons of fukutin and FKRP, the protein products of two dystroglycanopathy-causative genes. AB - Purpose: Dystroglycanopathies are a heterogeneous group of recessive neuromuscular dystrophies that affect the muscle, brain and retina, and are caused by deficiencies in the O-glycosylation of alpha-dystroglycan. This post translational modification is essential for the formation and maintenance of ribbon synapses in the retina. Fukutin and fukutin-related protein (FKRP) are two glycosyltransferases whose deficiency is associated with severe dystroglycanopathies. These enzymes carry out in vitro the addition of a tandem ribitol 5-phosphate moiety to the so-called core M3 phosphotrisaccharide of alpha dystroglycan. However, their expression pattern and function in the healthy mammalian retina has not so far been investigated. In this work, we have addressed the expression of the FKTN (fukutin) and FKRP genes in the retina of mammals, and characterized the distribution pattern of their protein products in the adult mouse retina and the 661W photoreceptor cell line. Methods: By means of reverse transcription (RT)-PCR and immunoblotting, we have studied the expression at the mRNA and protein levels of the fukutin and FKRP genes in different mammalian species, from rodents to humans. Immunofluorescence confocal microscopy analyses were performed to characterize the distribution profile of their protein products in mouse retinal sections and in 661W cultured cells. Results: Both genes were expressed at the mRNA and protein levels in the neural retina of all mammals studied. Fukutin was present in the cytoplasmic and nuclear fractions in the mouse retina and 661W cells, and accumulated in the endoplasmic reticulum. FKRP was located in the cytoplasmic fraction in the mouse retina and concentrated in the Golgi complex. However, and in contrast to retinal tissue, FKRP additionally accumulated in the nucleus of the 661W photoreceptors. Conclusions: Our results suggest that fukutin and FKRP not only participate in the synthesis of O-mannosyl glycans added to alpha-dystroglycan in the endoplasmic reticulum and Golgi complex, but that they could also play a role, that remains to be established, in the nucleus of retinal neurons. PMID- 29416296 TI - Association of genetic variants in RAB23 and ANXA11 with uveitis in sarcoidosis. AB - Purpose: Uveitis occurs in a subset of patients with sarcoidosis. The purpose of this study was to determine whether genetic variants that have been associated previously with overall sarcoidosis are associated with increased risk of developing uveitis. Methods: Seventy-seven subjects were enrolled, including 45 patients diagnosed with sarcoidosis-related uveitis as cases and 32 patients with systemic sarcoidosis without ocular involvement as controls. Thirty-eight single nucleotide polymorphisms (SNPs) previously associated with sarcoidosis, sarcoidosis severity, or other organ-specific sarcoidosis involvement were identified. Allele frequencies in ocular sarcoidosis cases versus controls were compared using the chi-square test, and p values were corrected for multiple hypotheses testing using permutation. All analyses were conducted with PLINK. Results: SNPs rs1040461 and rs61860052, in ras-related protein RAS23 (RAB23) and annexin A11 (ANXA11) genes, respectively, were associated with sarcoidosis associated uveitis. The T allele of rs1040461 and the A allele of rs61860052 were found to be more prevalent in ocular sarcoidosis cases. These associations remained after correction for the multiple hypotheses tested (p=0.01 and p=0.02). In a subanalysis of Caucasian Americans only, two additional variants within the major histocompatibility complex (MHC) genes on chromosome 6, in HLA-DRB5 and HLA DRB1, were associated with uveitis as well (p=0.009 and p=0.04). Conclusions: Genetic variants in RAB23 and ANXA11 genes were associated with an increased risk of sarcoidosis-associated uveitis. These loci have previously been associated with overall sarcoidosis risk. PMID- 29416297 TI - The adipokines in the pathogenesis and treatment of nonalcoholic fatty liver disease. AB - Insulin resistance, abdominal obesity, and inflammation play important roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Several adipokines, particularly adiponectin but also leptin, resistin, irisin, ghrelin, and visfatin modulate these pathogenetic mechanisms and appear to play a role in the development of hepatic steatosis and the progression to steatohepatitis and cirrhosis. Accordingly, these adipokines might represent attractive targets in patients with NAFLD. Notably, both lifestyle changes and many pharmacological agents that are used in the management of NAFLD, particularly pioglitazone and statins, exert favorable effects on adipokine levels. However, it is unclear whether these effects play a role in the improvement in liver histology. Therefore, mechanistic studies are needed to clarify the contribution of changes in adipokine levels to the effects of these interventions on hepatic steatosis, inflammation, and fibrosis. In parallel, the development of novel agents that specifically target adipokine levels might offer additional insights into the potential role of adipokines as therapeutic targets in NAFLD. Hippokratia 2016, 20(4): 259-263. PMID- 29416298 TI - The Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) questionnaire: cultural adaptation and validation of the Greek version. AB - AIM: To adapt cross-culturally the Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) for use in Greek patients with atrial fibrillation (AF) and to evaluate its psychometric properties. METHODS: Professional translators were involved in the inverse translation procedure. Twenty patients with AF participated in the cultural adaptation procedure. One hundred two consecutive patients participated in the validation process that included reliability (internal consistency, test retest reliability) and validity assessment (face validity, construct validity). RESULTS: Greek AFEQT showed high internal consistency (Cronbach's alpha for overall scale: 0.97, subscales: Symptoms: 0.90, Daily Activities: 0.93, Treatment Concern: 0.91, Treatment Satisfaction: 0.83) and test-retest reliability (Spearman's rho: 0.99, p <0.001, Wilcoxon's test, p =0.959). Face validity was rated with a median of 7 by the patients. Finally, Greek AFEQT showed appropriate construct validity of demonstrating adequate convergent validity with the moderate to strong correlations of AFEQT domains with the Physical and Mental Component Summaries of SF-12 (Spearman's rho: 0.53-0.78, p <0.001). CONCLUSIONS: The Greek version of AFEQT has shown good psychometric properties and can be a useful tool in future studies on the quality of life of patients with AF. Hippokratia 2016, 20(4): 264-267. PMID- 29416299 TI - Epidemiology and outcome of elderly admitted to the ward for sepsis. AB - BACKGROUND: The elderly represent a significant cohort of patients presenting at the emergency department, especially in the developed countries. They are characterized by impaired physical condition, comorbidities, and little immune system resources and make frequent use of the healthcare system and its facilities. This study aimed to describe the features and prognostic factors of sepsis in elderly patients (>60 years old) admitted to an internal medicine ward. MATERIAL AND METHODS: Two hundred eighty eight consecutively patients aged >60 years who were admitted with sepsis during a two-year-period were retrospectively included in the study. Clinical and laboratory parameters at presentation were analyzed. Causes of sepsis and biochemical markers were compared between the healthcare facility-naive and the healthcare facility-exposed groups. The effect of comorbidities and previous exposure to the healthcare system on clinical course and outcome of the patients was analyzed. RESULTS: Among the comorbidities that were recorded and included in the analysis, the presence of chronic and acute renal impairment and neurologic disabilities were associated with a worse outcome of sepsis in the elderly. In the same cohort, a previous contact with the healthcare system was found to affect the duration of hospital stay, but not the outcome per se. Sepsis-related markers, such as inflammatory markers were not found to be associated with clinical progression and outcome. CONCLUSIONS: Timely diagnosis and accurate evaluation of the severity of sepsis is required to ensure a better outcome for the patients. Sensitive markers and accurate prognostic models are constantly pursued. The impact of living characteristics of the modern aging society is additionally addressed and their effect on sepsis outcome assessed. Hippokratia 2016, 20(4): 274-278. PMID- 29416300 TI - Home intravenous antibiotic therapy in children with cystic fibrosis: clinical outcome, quality of life and economic benefit. AB - BACKGROUND: Pediatric home care has improved therapeutic options for children with chronic disease. Home intravenous (IV) antibiotic treatment against Pseudomonas aeruginosa (PsA) in cystic fibrosis (CF) patients has offered increased flexibility to these patients and family life. A prospective clinical study was conducted to compare safety, efficacy, and cost benefits of home versus hospital IV antibiotic treatment among CF children and adolescents. METHOD: The clinical outcome, quality of life, and cost benefits of home versus hospital antibiotic treatment were assessed. The clinical outcome was evaluated with Forced Expiratory Volume in one second (FEV1) and weight gain before and one month after antibiotic treatment, while the Quality of life was evaluated using the DISABKIDS questionnaire. Cost analysis was performed to calculate cost benefits from home IV treatment. RESULTS: Thirty-five stable patients with CF (mean age: 12.6 +/- 7 years, 56 % male, mean FEV1: 83.5 +/- 26 %), colonized with PsA, were treated with IV antibiotics for two weeks either in the hospital (15 patients), or at home (20 patients) under supervision by a home care nurse. Lung function (FEV1) and weight improved significantly in both groups (DeltaFEV1% =7.7 +/- 6.1, p <0.001; DeltaWeight =1.2 +/- 0.8, p <0.001). Hospital treatment did not show a better clinical outcome, compared to home treatment (DeltaFEV1, p =0.606; DeltaWeight, p =0.608). Both improvements in the quality of life and economical savings were substantial (p <0.001) regarding patients treated at home. Also, patients treated at home did not report any significant side effects or complications. CONCLUSIONS: Home IV antibiotic therapy monitored by a home care nurse, is a safe, efficient, and cost-saving therapeutic option in CF. Hippokratia 2016, 20(4): 279-283. PMID- 29416301 TI - Prevalence and social determinants of smoking in the adult Greek Cypriot population. AB - BACKGROUND: Smoking remains a major public health concern in Europe. In the current study, we investigate the prevalence and socioeconomic factors that contribute to smoking disparities in Greek Cypriot adults. Material and methods: In 2009, using the Countrywide Integrated Noncommunicable Disease Intervention questionnaire a representative sample of Greek Cypriot adults was surveyed (response rate 100%). Socioeconomic and demographic data were collected and analyzed. RESULTS: The prevalence of smoking in Greek Cypriot adults was 50.8 % among men and 21.2 % among women. Sociodemographic disparities in smoking prevalence were identified, characterized by higher prevalence in urban vs rural centers (especially among women), and higher prevalence among employed women vs housewives. Socioeconomic inequalities in prevalent smoking were gender-specific, with occupational social class showing an inverse association among men and a direct among women, with income showing an inverse association (mostly among men), and educational attainment showing a clear inverse gradient among men and a direct gradient among women. CONCLUSION: Striking gender-specific bidirectional associations between socioeconomic factors and smoking prevalence were identified among Greek Cypriot adults, which may promote targeted intervention programmes aiming at halting and reversing smoking behaviors in Cyprus. Hippokratia 2016, 20(4): 284-291. PMID- 29416302 TI - Ultrastructural evaluation of intramuscular applied botulinum toxin type A in striated muscles of rats. AB - BACKGROUND: Botulinum toxin type A (BTX-A) is clinically utilized for therapeutic and cosmetic purposes in maxillofacial surgery as well as many other medical specialties. There is no sufficient ultrastructural research about BTX and it is controversial whether BTX-A causes muscle degeneration to some extent, in the course of therapy. The aim of this study was to evaluate the histological effects of BTX-A when injected into masseter and gluteal muscles. MATERIALS AND METHODS: A total of 30 male Sprague-Dawley rats were used and randomly divided into experimental (n =15) and control groups (n =15). Masseter and gluteal muscles were injected with a single dose of BTX-A in normal saline (0.5 U/0.1 ml), or 0.1 ml of normal saline, in the experimental and control groups, respectively. After 12 weeks all the rats were sacrificed. Gluteal, masseter muscles, and the sciatic nerves of the rats were prepared and electron microscopic, and light microscopic evaluation was performed on semi-thin sections cut from Epon embedded tissues and stained with toluidine blue. Quantitative parameters such as muscle fiber thickness and qualitative assessments including sarcosomal (striated muscle mitochondria) deformation, glycogen content, features of the triad structures and the intensity of connective tissue around the muscle fibers, and endoneurial and perineural tissue around nerve fibers were evaluated microscopically. We paired BTX- A (+) and BTX-A (-) samples statistically. Independent Samples t-test was used for the statistical analysis. RESULTS: Muscle fiber's diameter was significantly decreased in BTX-A (+) group (p <0,001). Atrophic changes in the myofibrils were characterized by a decrease in the myofibrillar diameter and changes in the sarcomere structure, and were prominent in the BTX-A (+) group. Also, some other changes like dilatation in the sarcoplasmic reticulum cisternae, mitochondrial swelling, and clearing of mitochondrial cristae associated with degeneration, were detected. No morphologic difference in the sciatic nerve fibers was detected, and myelin sheaths of axon structures were intact in both groups. CONCLUSION: BTX-A-induced muscular changes that are predominantly related to atrophy instead of degeneration. Although predominantly related to atrophy, our degeneration related findings suggest that further studies are needed focusing on detecting BTX-A effects on a cellular level. Hippokratia 2016, 20(4): 292-298. PMID- 29416303 TI - Endonasal endoscopic repair of cerebrospinal fluid leaks versus craniotomy: comparison of the outcomes. AB - BACKGROUND: Cerebrospinal fluid (CSF) leaks have been traditionally managed via craniotomy with an intradural repair. The endonasal endoscopic approach represents a minimally invasive alternative. This study aimed to compare the outcomes of the two methods. CASE SERIES: This is a prospective case series of 18 consecutive patients who underwent endonasal repair of a CSF leak. Thirteen variables were evaluated during the study, including age, gender, body mass index, site of the defect, CSF leak etiology, days of hospitalization, use of lumbar drainage, the success of repair, complications, recurrence, duration, and cost of surgery as well as patient satisfaction. The outcomes were compared with a historical cohort of 25 patients treated for CSF leaks with a craniotomy. Though we found no significant difference in the success of the repair, the endoscopic group had a significantly shorter duration of the procedure and hospitalization, a lower rate of complications, lower cost, and higher patient satisfaction. CONCLUSION: The presented data further solidify the endoscopic approach as the preferred method to address CSF leaks located in the anterior and middle skull base in cases not associated with complex intracranial pathology. Hippokratia 2016, 20(4): 299-302. PMID- 29416304 TI - Anesthesia management of a patient with a femoral neck fracture and hered-itary hemorrhagic telangiectasia. AB - BACKGROUND: The hereditary hemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu syndrome is an autosomal dominant genetic disorder affecting the small blood vessels due to mutations in specific genes that lead to angiogenesis errors. HHT represents a clinical entity with great clinical interest as severe, unpredicted, and life-threatening bleeding, sepsis, ischemia, and hemodynamic failure might occur. Literature regarding anesthesia and perioperative management of such patients is limited, with no published papers for orthopedic surgery in patients with HHT. CASE REPORT: An 82-year-old HHT female patient with femoral neck fracture was scheduled for hemiarthroplasty. Computerized tomography scan revealed an arteriovenous malformation (AVM) in the right lung. The nature of surgery in association with AVM presence suggested the use of regional anesthesia (RA) as the optimal choice. Midazolam (2 mg) was administered as premedication. Perioperatively, Levobupivacaine hydrochloride (15 mg) was administered in the subarachnoid space, at the L4-L5 lumbar intervertebral space, using a 29 Gauge needle. The patient was in lateral position with close monitoring of her blood pressure, electrocardiogram, oxygen saturation, and urine output. Two units of blood were transfused perioperatively. Her recovery was uneventful and she was discharged after ten days. CONCLUSION: Patients with HHT require careful preoperative evaluation to identify and appreciate possible symptoms as well as to assess their pulmonary and cardiac function accurately. Meticulous preoperative planning is required to minimize perioperative risks and additionally close perioperative monitoring is essential. RA was preferred to general anesthesia as positive pressure ventilation could lead to hypoxia, AVM rupture, embolism, and hemodynamic collapse, while RA offers absence of respiratory stress, excellent muscle relaxation, and decreases blood loss, lowers probability of venal thrombosis and pulmonary embolism, and assists to better perioperative management of analgesia, thus contributing to positive outcome of surgery. Hippokratia 2016, 20(4): 303-305. PMID- 29416305 TI - Multifocal splenic abscesses in immunocompetent adult due to cat-scratch disease. AB - BACKGROUND: Cat-scratch disease is caused by Bartonella henselae and transmitted to humans via the cats. Patients usually present with cutaneous lesions, regional lymphadenopathy and a brief period of fever. CASE REPORT: We report a rare case of an isolated splenic cat-scratch disease in an immunocompetent 27-year-old woman who presented with prolonged fever and multifocal splenic lesions. The patient was treated successfully with a long course of antibiotics. CONCLUSION: Isolated splenic lesions and fever is a rare manifestation of the cat-scratch disease. There is need of high suspicion index by the physicians to diagnose the disease promptly without invasive methods. Hippokratia 2016, 20(4): 306-308. PMID- 29416306 TI - Effects of radial extracorporeal shock wave therapy on hand spasticity in poststroke patient. AB - BACKGROUND: Hand spasticity after a stroke greatly increases the difficulties of the daily living activities and limits the effectiveness of rehabilitation. Radial extracorporeal shock wave therapy (RESWT) has been suggested as an alternative treatment for spasticity reduction. We demonstrate the effectiveness of RESWT regarding hand spasticity in a stroke patient. CASE DESCRIPTION: We describe the case of a 42-year-old woman with right hemiparesis after ischaemic stroke. Her right arm was plegic with increased spasticity. The patient received a total of six RESWT treatments. Clinical evaluation was performed using the Modified Ashworth Scale, passive dorsal flexion of the wrist and the Disability Assessment Scale (DAS). The measurements were made before initiation, immediately after the sixth treatment, one and three months after the RESWT. Immediately after the RESWT there was a reduction of the spasticity of the hand and fingers and increased passive range of motion of the affected wrist, as well as decreased DAS score. These effects lasted for four weeks. With time, the therapeutic effect regarding spasticity decreased, but three months following termination of treatment there was a better clinical result than before initiation of treatment. CONCLUSION: RESWT is a safe alternative treatment for hand and fingers spasticity reduction after stroke. Hippokratia 2016, 20(4): 309-312. PMID- 29416307 TI - Anal canal gastrointestinal stromal tumors - report of a rare case and review of the literature. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are considered as rare gastrointestinal tumors, and their location in the anal track is exceptionally unusual. We describe the case of a 28-year-old man with anal GIST, and a review of the cases that have been reported so far in the literature. CASE REPORT: The patient was referred for treatment of a gradually enlarging perianal mass. Clinical examination and imaging including orthosigmoidoscopy, transanal ultrasound, and magnetic resonance imaging (MRI) revealed a mass sized 7.5 cm in greatest diameter, in relation with the sphincters, which was excised under general anesthesia. His postoperative course was uneventful and he was discharged on the fourth postoperative day. Pathologic examination revealed characteristics of anal GISTs and further treatment with tyrosine kinase inhibitors was planned. CONCLUSION: Anal GISTs usually present with rectal bleeding and pain, and only sixteen cases have been reported in the literature. MRI is the radiologic examination of choice, while optimal treatment is considered surgery in combination with adjuvant therapy. Long-term follow-up is necessary. Hippokratia 2016, 20(4): 313-316. PMID- 29416308 TI - MicroRNA expression in patients with squamous cell carcinoma of the tongue. PMID- 29416309 TI - Giant hypopharyngeal fibrovascular polyp. PMID- 29416310 TI - Sarcoidosis with muscular involvement demonstrated on gallium-67 scintigraphy. PMID- 29416311 TI - Rectovaginal tear after sexual intercourse in a young woman-a case report. PMID- 29416312 TI - The relationship between neutrophil/lymphocyte and platelet/lymphocyte ratios with oxidative stress in active Crohn's disease patients. AB - BACKGROUND: This study investigated the relationship between the neutrophil-to lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) values with oxidative stress in active Crohn's disease (CD) patients. We investigated whether these parameters were useful for follow-up assessments of CD activity. METHODS: Forty-nine patients with a confirmed diagnosis of CD (24 active and 25 inactive) and 38 control subjects were enrolled in the study. We measured serum activity of superoxide dismutase (SOD) using an enzyme-linked immunosorbent assay (ELISA) and malondialdehyde (MDA) levels using a spectrophotometric method. Neutrophil, lymphocyte and platelet counts were recorded, and the NLR and PLR values were calculated from these parameters. RESULTS: Patients with active CD exhibited significantly higher serum levels of MDA (p =0.007), NLR (p =0.034), and PLR (p =0.026) than inactive CD patients. Receiver operating characteristic (ROC) curve analysis demonstrated that the optimum cut-off values of MDA, NLR, and PLR based on the differences between active and inactive patients were 0.14 umol/L, 2.58, and 192.26, respectively. The NLR value increased in active patients with elevated MDA levels as a dependent variable (B: 0.422, p =0.029). CONCLUSIONS: We suggest the use of MDA, PLR, and NLR values as a noninvasive test to evaluate disease activity in CD patients. NLR values may also reflect the presence of oxidative stress, and this value may be efficient and useful in determining CD activity. Hippokratia 2016, 20(4): 268-273. PMID- 29416313 TI - Measurement of the hypotenuse of the vertical optic nerve head cup with spectral domain optical coherence tomography for the structural diagnosis of glaucoma. AB - Purpose: To evaluate the hypotenuse of the vertical optic nerve head cup (HVOC), measured using the length and depth of the cup obtained with enhanced depth imaging spectral-domain optic coherence tomography (SD-OCT), as a biomarker for glaucoma diagnosis. Methods: This was a prospective cross-sectional study of patients with glaucoma and controls. SD-OCT was performed in all participants to assess average circumpapillary retinal nerve fiber layer (RNFL) thickness. A vertical B-scan of the optic nerve head (ONH) was obtained for HVOC measurement. The length and depth of the optic nerve cup formed the sides of a right triangle that were used to calculate the HVOC. Participants also underwent standard automated perimetry. Results: One hundred and fifty-six eyes were divided into three groups: mean deviation (MD) <-7 dB (60 eyes); MD >=-7 dB (74 eyes); and healthy subjects (22 eyes). The mean (SD) HVOC in these groups was 1,419.8 (347.2) um, 1,234.6 (258.8) um, and 685.79 (315.4) um (P<0.01), respectively. In the secondary structure-function analysis, only discs with a vertical diameter of 1.51-2.00 mm were included (120 eyes). The HVOCs were divided into four percentile groups, with the following means: 940, 1,128, 1,390, and 1,662 um. There was a significant difference in MD between percentile groups 1 and 3 (P<0.03), 1 and 4 (P<0.001), 2 and 3 (P<0.02), and 2 and 4 (P<0.001). RNFL thickness differed among all percentile groups (P<0.001). Conclusion: HVOC may provide an additional morphometric biomarker for the structural evaluation of ONH remodeling in glaucoma. PMID- 29416314 TI - Cysteamine hydrochloride eye drop solution for the treatment of corneal cystine crystal deposits in patients with cystinosis: an evidence-based review. AB - Cystinosis is a rare, autosomal recessive disorder leading to defective transport of cystine out of lysosomes. Subsequent cystine crystal accumulation can occur in various tissues, including the ocular surface. This review explores the efficacy of cysteamine hydrochloride eye drops in the treatment of corneal cystine crystal accumulation and its safety profile. PMID- 29416315 TI - Comparison of corneal biomechanics after myopic small-incision lenticule extraction compared to LASIK: an ex vivo study. AB - Purpose: To investigate ex vivo potentially different corneal biomechanical properties after small-incision lenticule extraction (SMILE) versus LASIK for myopic correction. Methods: Thirty human donor corneas were subjected to either myopic SMILE or femtosecond laser-assisted LASIK. Donor corneas were assigned to six investigative groups: Group A, -3.00 D (diopters) SMILE; Group B, -8.00 D SMILE; Group C, -3.00 D LASIK; and Group D, -8.00 D LASIK. Additionally, two control groups were formed: Group E, SMILE and Group F, LASIK. All groups consisted of five corneas, randomly allocated. The corneas in the control groups were subjected to the corresponding femtosecond-laser lamellar cuts but not to tissue removal. Evaluation of biomechanical tensile strength was conducted by biaxial force application. Primary outcome measures were stress at 10% and 15% strain, and Young's modulus at 10% and 15% strain. Results: In SMILE, the average relative difference (Delta) of the four outcome measures was -34.46% for -3.00 D correction versus control Group E and -49.34% for -8.00 D correction versus control Group E. In LASIK, average Delta was -24.88% for -3.00 D correction versus control, and -52.73% for -8.00 D correction versus control. All these differences were statistically significant; SMILE compared to LASIK for the same myopic correction appears to result in more biomechanical reduction for -3.00 D corrections by -26%, while a nonstatistically significant difference was noted in -8.00 D corrections. Conclusion: Both SMILE and LASIK procedures do substantially alter corneal biomechanical properties, and the degree of tensile strength reduction is statistically significantly correlated to the extent of myopic correction. Additionally, SMILE procedure seems to result in more tensile strength reduction in lower myopic corrections compared to LASIK, and similar tensile strength reduction to LASIK in higher myopic corrections when compared to LASIK. PMID- 29416316 TI - Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma. AB - Our expanding knowledge of immunotherapy for solid tumors has led to an explosion of clinical trials aimed at urothelial carcinoma. The primary strategy is centered on unleashing the immune system by releasing the inhibitory signals propagated by programmed cell death-1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1). Many antibody constructs have been developed to block these interactions and are used in clinical trials. The Food and Drug Administration has already approved a number of checkpoint inhibitors such as anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies including ipilimumab; anti-PD-1 monoclonal antibodies including nivolumab and pembrolizumab; anti-PD-L1 antibodies including atezolizumab, avelumab, and durvalumab. One of the latest inhibitors is durvalumab, which is a high-affinity human immunoglobulin G1 kappa monoclonal antibody and blocks the interaction of PD-L1 with PD-1 and CD80. Currently, there are a number of ongoing trials in advanced urothelial carcinoma both using durvalumab monotherapy and in combination with other targeted therapies. In addition, durvalumab is being investigated in the non-muscle-invasive urothelial carcinoma, which is centered around intravenous formulations. These exciting developments have added a significant number of therapies in a previously limited treatment landscape. PMID- 29416318 TI - Adherence to dietary recommendations in diabetes mellitus: disease acceptance as a potential mediator. AB - Background: Adherence by diabetic patients to dietary recommendations is important for effective therapy. Considering patients' expectations in case of diet is significant in this regard. The aim of this paper was to analyze the relationship between selected independent variables (eg, regular blood glucose testing) and patients' adherence to dietary recommendations, bearing in mind that the degree of disease acceptance might play a mediation role. Subjects and methods: A cross-sectional study was conducted in 91 patients treated for type 2 diabetes mellitus in a public medical facility. Paper-and-pencil interviewing was administered ahead of the planned visit with a diabetes specialist. Two measures were applied in the study: the Acceptance and Action Diabetes Questionnaire and the Patient Diet Adherence in Diabetes Scale. Additionally, data related to sociodemographic characteristics, lifestyle-related factors, and the course of the disease (management, incidence of complications, and dietician's supervision) were also collected. The regression method was used in the analysis, and Cohen's methodology was used to estimate partial mediation. Significance of the mediation effect was assessed by the Goodman test. P-values of <0.05 were considered statistically significant. Results: Patients' non-adherence to dietary recommendations was related to a low level of disease acceptance (standardized regression coefficient =-0.266; P=0.010). Moreover, failure to perform regular blood glucose testing was associated with a lack of disease acceptance (standardized regression coefficient =-0.455; P=0.000). However, the lack of regular blood glucose testing and low level of acceptance had only partially negative impacts on adherence to dietary recommendations (Goodman mediation test, Z=1.939; P=0.054). This dependence was not seen in patients treated with diet and concomitant oral medicines and/or insulin therapy. Conclusion: Effective dietary education should include activities promoting a more positive attitude toward the disease. This may be obtained by individual counseling, respecting the patient's needs, and focus on regular blood glucose testing. PMID- 29416317 TI - The influence of prebiotic or probiotic supplementation on antibody titers after influenza vaccination: a systematic review and meta-analysis of randomized controlled trials. AB - Background: Influenza infection is a common disease with a huge disease burden. Influenza vaccination has been widely used, but concerns regarding vaccine efficacy exist, especially in the elderly. Probiotics are live microorganisms with immunomodulatory effects and may enhance the immune responses to influenza vaccination. Methods: We conducted a systematic review and meta-analysis to determine the influence of prebiotics/probiotics/synbiotics supplementation on vaccine responses to influenza vaccination. Studies were systematically identified from electronic databases up to July 2017. Information regarding study population, influenza vaccination, components of supplements, and immune responses were extracted and analyzed. Twelve studies, investigating a total of 688 participants, were included in this review. Results: Patients with prebiotics/probiotics supplements were found to have higher influenza hemagglutination inhibition antibody titers after vaccination (for A/H1N1, 42.89 vs 35.76, mean difference =7.14, 95% CI =2.73, 11.55, P=0.002; for A/H3N2, 105.4 vs 88.25, mean difference =17.19, 95% CI =3.39, 30.99, P=0.01; for B strain, 34.87 vs 30.73, mean difference =4.17, 95% CI =0.37, 7.96, P=0.03). Conclusion: Supplementation with prebiotics or probiotics may enhance the influenza hemagglutination inhibition antibody titers in all A/H1N1, A/H3N2, and B strains (20%, 19.5%, and 13.6% increases, respectively). Concomitant prebiotics or probiotics supplementation with influenza vaccination may hold great promise for improving vaccine efficacy. However, high heterogeneity was observed and further studies are warranted. PMID- 29416319 TI - Medication adherence and beliefs about medication in elderly patients living alone with chronic diseases. AB - Purpose: The aim of this study was to assess medication adherence and its related factors among elderly people living alone with chronic diseases using a conceptual framework with the Belief about Medicines Questionnaire and the Adherence to Refills and Medication Scale-Korean version. Participants and methods: This was a cross-sectional study conducted in 3,326 elderly people living alone, who were enrolled in Seongnam Center for Home Health Care in South Korea. They completed validated questionnaires assessing their adherence and beliefs about medication in general. Results: In attitudinal analysis using Belief about Medicines Questionnaire, 37.0% of patients were accepting of medication (high necessity with low concerns), 49.7% were ambivalent (high necessity with high concerns), 1.9% were skeptical (low necessity with high concerns), and 11.4% were indifferent (low necessity and low concerns). In multivariable analysis, we found that adherence was related to patients' beliefs about medication; compared with patients who were accepting of medication, those in the other three attitudinal groups had significantly lower adherence (indifferent, p=0.003; skeptical, p=0.001; ambivalent, p<0.001). Also, low adherence was associated with heavy burden of drug costs (beta=0.109; 95% CI 0.03, 0.19), presence of drug side effects (beta=0.431; 95% CI 0.11, 0.75), dissatisfaction with medication (beta=-0.626; 95% CI -0.77, -0.48), perceiving health status as poor (beta=-0.151; 95% CI -0.27, -0.03), and receiving medical aid (beta=0.655; 95% CI 0.42, 0.89). Gender, age group, and number of prescribed medication were not associated with medication adherence. Conclusion: To improve medication adherence of elderly living alone, it is essential to identify barriers to adherence, including their concerns and attitudes toward medications. These factors associated with adherence should be considered in further intervention studies. PMID- 29416320 TI - Factors associated with acceptance of provider-initiated HIV testing and counseling among pregnant women in Ethiopia. AB - Introduction: The global human immunodeficiency virus (HIV) epidemic disproportionately affects sub-Saharan African countries, including Ethiopia. Provider-initiated HIV testing and counseling (PITC) is a tool to identify HIV positive pregnant women and an effective treatment and prevention strategy. However, its success depends upon the willingness of pregnant women to accept HIV testing. Objectives: To describe the level of acceptance of PITC and associated factors among pregnant women attending 8 antenatal care clinics in Adama, Ethiopia. Methods: Trained nursing students and employees from an HIV clinic conducted face-to-face structured interviews in private offices at the clinics from August to September, 2016. Results: Among the 441 respondents, 309 (70.1%) accepted PITC. Women with more antenatal care visits (odds ratio [OR] =2.59, 95% CI: 1.01-6.63), reported better quality of the PITC service (OR =1.91, 95% CI: 1.19-3.08), and higher level of knowledge on mother-to-child transmission (OR =1.82, 95% CI: 1.03-3.20), were more likely to accept PITC, while women who were older in age (OR =0.37, 95% CI: 0.19-0.74) and perceived negative attitudes from their partners toward HIV-positive results (OR =0.31, 95% CI: 0.10-0.94) were less likely to accept the PITC service. Conclusion: About one-third of pregnant women are not willing to accept PITC. When designing intervention program to improve the acceptance of PITC, we should take into consideration the personal factors, HIV-related knowledge, and attitude of women as well as institutional factors. PMID- 29416321 TI - Perioperative outcome of elderly versus younger patients undergoing major hepatic or pancreatic surgery. AB - Objective: The aim of this study was to determine the safety of elderly cancer patients (>=70 years) undergoing hepatic resection (HR) or pancreaticoduodenectomy (PD) in comparison with younger adults (<70 years). Methods: A total of 1,012 consecutive patients undergoing HR or PD were included. The incidence and severity of morbidity were documented within 30 days postoperatively and compared between elderly and younger groups. Risk factors associated with postoperative morbidity were investigated by multivariate logistic regression analysis. Results: Elderly patients (n=111, 11.0%) had more comorbidities and worse preoperative general condition and liver function versus younger patients (n=901, 89.0%), and thus were more likely to develop infectious (eg, systemic sepsis and urinary tract infection, both p<0.01) and technical associated complications (intraperitoneal bleeding and biliary/pancreatic fistula, p=0.029 and p=0.074, respectively). However, the incidence and severity of complications were comparable between elderly and younger patients in the whole cohort, and also in HR and PD surgery groups separately. Preoperative hemoglobin (odds ratio [OR] 1.4, p=0.007) and intraoperative blood transfusion (OR 1.9, p=0.002), rather than age, were independently associated with postoperative morbidity. Hepatitis (OR 2.9, p=0.001), preoperative hemoglobin (OR 1.6, p=0.036), and pancreatic versus hepatic surgery (OR 2.3, p=0.005) were independently associated with postoperative infectious. For elderly patients only, American Society of Anesthesiologists (ASA) score III (OR 2.1, p=0.033) and intraoperative blood transfusion (OR 3.2, p=0.030) were independently associated with postoperative morbidity. Conclusion: HR and PD can be safely performed in selected elderly patients versus younger patients. Elderly patients with ASA score III or above should be cautiously selected for major surgeries. PMID- 29416322 TI - Quality of life and psychological consequences in elderly patients after a hip fracture: a review. AB - Fractures due to fragility of the bone around the hip joint have become a major public health issue, presenting with an increasing incidence due to the growth of the elderly population. The purpose of this review was to evaluate the impact of hip fractures on the quality of life (QoL), health status (HS), functioning, and psychological parameters, and factors influencing the outcome and the appropriate interventions for improvement of elderly patients. A systematic electronic search of the relevant literature was carried out using the CINAHL, Cochrane, EMBASE, Medline (OvidSP), and PubMed databases spanning the time period from their establishment up to January 2017. Forty-nine randomized controlled trials or prospective cohort studies reporting the QoL and psychological outcomes were assessed by using standardized questionnaires. Patients with a hip fracture who were older than 65 years, were included in the analysis. In the majority of elderly patients, the hip fracture seriously affected physical and mental functioning and exerted a severe impact on their HS and health-related QoL (HRQoL). Moreover, most of the patients did not return to prefracture levels of performance regarding both the parameters. The levels of mental, physical, and nutritional status, prior to the fracture, comorbidity, and female gender, in addition to the postoperative pain, complications, and the length of hospital stay, were the factors associated with the outcome. Psychosocial factors and symptoms of depression could increase pain severity and emotional distress. For the displaced femoral neck fractures, the treatment with total hip arthroplasty or hemiarthroplasty, when compared to the treatment with internal fixation, provided a better functional outcome. Supportive rehabilitation programs, complemented by psychotherapy and nutritional supplementation prior to and after surgery, provided beneficial effects on the HS and the psychosocial dimension of the more debilitated patients' lives. Lack of consensus concerning the most appropriate HRQoL questionnaires to screen and identify those patients with more difficulties in the psychosocial functions, demonstrates the necessity for further research to assess the newer outcome measurement tools, which might improve our understanding for better care of patients with hip fractures. PMID- 29416323 TI - Nutritional variables predict chances of returning home and activities of daily living in post-acute geriatric care. AB - Background: Little is known about the association between malnutrition and the chances of returning home from post-acute facilities in older adult patients. This study aimed to understand whether malnutrition and malnutrition-related factors would be determinants for returning home and activities of daily living (ADL) at discharge after post-acute care. Methods: Patients aged >=65 years living at home before the onset of an acute disease and admitted to a post-acute ward were enrolled (n=207) in this prospective observational study. Malnutrition was defined based on the criteria of the European Society for Clinical Nutrition and Metabolism. Nutritional parameters included the nutritional intake at the time of admission and oral conditions evaluated by the Oral Health Assessment Tool (OHAT). The Barthel Index was used to assess daily activities. A Cox regression analysis of the length of stay was performed. Multivariable linear regression analyses to determine associations between malnutrition, returning home, and ADL at discharge were performed, after adjusting the variables of acute care setting. Results: The mean patient age was 84.7+/-6.7 years; 38% were men. European Society for Clinical Nutrition and Metabolism-defined malnutrition was observed in 129 (62.3%) patients, and 118 (57.0%) of all patients returned home. Multivariable regression analyses showed that malnutrition was a negative predictor of returning home (hazard ratio: 0.517 [0.351-0.761], p=0.001), and an increase in the nutritional intake (kcal/kg/d) was a positive predictor of the Barthel Index at discharge (coefficient: 0.34+/-0.15, p=0.021). The OHAT was not associated with returning home and ADL. Conclusion: Malnutrition and nutritional intake are associated with returning home and ADL at discharge, respectively, after post-acute care. Further studies investigating the effects of a nutritional intervention for post-acute patients would be necessary. PMID- 29416324 TI - A cross-sectional study of inpatients with late stage of dementia in Southeast China and the associations between biochemical parameters and apolipoprotein E genotypes. AB - Background: The purpose of this study was to analyze the disease distribution of patients in the late stage of dementia through a cross-sectional investigation and to clarify the association between apolipoprotein E (APOE) genotypes and the serum levels of total cholesterol, total triglycerides, and blood glucose in the late-stage Alzheimer's disease (AD) patients. Methods: Patients who were in the late stage of dementia in a mental health center were enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. The APOE genotype was determined by the multiplex amplification refractory mutation system polymerase chain reaction. The association between APOE genotype and the blood level of biochemical parameters was studied. Results: A total of 155 patients were enrolled in this study. The majority of patients had AD (67.8%), followed by vascular dementia (15.5%), mixed dementia (9%), and others (7.7%). The APOE epsilon4 allele frequency was significantly different in the different groups. The serum level of total cholesterol (TC) in APOE epsilon4 carriers was higher than in non-carriers (P<0.05). No statistically significant differences were found in the blood glucose and triglycerides (TG) levels between these two groups. Conclusion: To our knowledge, this is the first paper to study the characteristics of late-stage dementia in hospital patients in Southeast China. We found that the disease distribution was quite consistent with previous prevalence studies. Moreover, we found that the serum level of TC was higher in APOE epsilon4 carriers group. However, no association was found between the APOE epsilon4 allele and serum levels of glucose, TC and TG in the late stage of AD. PMID- 29416325 TI - Implementing Dementia Care Mapping as a practice development tool in dementia care services: a systematic review. AB - Dementia Care Mapping (DCM) is an observational tool set within a practice development process. Following training in the method, DCM is implemented via a cyclic process of briefing staff, conducting mapping observations, data analysis and report preparation, feedback to staff and action planning. Recent controlled studies of DCM's efficacy have found heterogeneous results, and variability in DCM implementation has been indicated as a potential contributing factor. This review aimed to examine the primary research evidence on the processes and the barriers and facilitators to implementing DCM as a practice development method within formal dementia care settings. PUBMED, PsycINFO, CINAHL, The Cochrane Library-Cochrane reviews, HMIC (Ovid), Web of Science and Social Care Online were searched using the term "Dementia Care Mapping". Inclusion criterion was primary research studies in any formal dementia care settings where DCM was used as a practice development tool and which included discussion/critique of the implementation processes. Assessment of study quality was conducted using the Mixed Methods Appraisal Tool. Twelve papers were included in the review, representing nine research studies. The papers included discussion of various components of the DCM process, including mapper selection and preparation; mapping observations; data analysis, report writing and feedback; and action planning. However, robust evidence on requirements for successful implementation of these components was limited. Barriers and facilitators to mapping were also discussed. The review found some consensus that DCM is more likely to be successfully implemented if the right people are selected to be trained as mappers, with appropriate mapper preparation and ongoing support and with effective leadership for DCM within the implementing organization/unit and in organizations that already have a person-centered culture or ethos. Future development of the DCM tool should consider ways to save on time taken to conduct DCM cycles. More research to understand the ingredients for effective DCM implementation is needed. PMID- 29416326 TI - Developing an assessment based on physical fitness age to evaluate motor function in frail and healthy elderly women. AB - Objectives: The purpose of this study was to identify a method for assessing physical fitness age that is easy to use with both frail and healthy elderly women and to examine its validity. Methods: Principal component analysis was used to develop a formula of physical fitness age from four motor function variables. The subjects comprised 688 (75.7+/-6.0 years) elderly women, in order to develop a physical fitness scale. The formula for calculating physical fitness age was expressed as physical fitness age =-0.419* grip strength -0.096* balancing on one leg with eyes open -0.737*30 s chair stand +0.503* figure-of-8 walking test +0.47* chronological age +52.68. Results: Measures obtained from subjects in the frail elderly (n=11, 73.0+/-2.3 years) and exercise (n=10, 70.8+/-3.1 years) groups were used to examine the validity of the assessment. The mean physical fitness age of the frail elderly group (79.0+/-3.7 years) was significantly higher than its mean chronological age (73.0+/-2.3 years, p<0.05). The mean physical fitness age of the exercise group (65.6+/-3.1 years) was significantly lower than the chronological age (70.8+/-3.1 years, p<0.05). Conclusion: These findings confirm that physical fitness age scores are applicable to frail and healthy elderly women. Physical fitness age is a valid measure of motor function in elderly women. PMID- 29416327 TI - Symptom burden and self-management in persons with chronic obstructive pulmonary disease. AB - Purpose: Self-management is crucial for effective COPD management. This study aimed at identifying associations between self-management and sociodemographic characteristics, clinical characteristics, and symptom burden in people with COPD. Patients and methods: In this cross-sectional study with 225 participants diagnosed with COPD grades II-IV, multiple linear regression analysis was conducted, using sociodemographic and clinical characteristics and symptom burden (COPD Assessment Test) as the independent variables and the eight self-management domains of the Health Education Impact Questionnaire (heiQ) as the outcome variables. Results: Higher symptom burden was significantly associated with worse scores in all self-management domains (p<0.003), except for self-monitoring and insight (p=0.012). Higher disease severity (p=0.004) and numbers of comorbidities (p<0.001) were associated with more emotional distress, and women scored higher than men on positive and active engagement in life (p=0.001). Higher score in pack-years smoking was associated with lower score in health-directed activities (p=0.006) and self-monitoring and insight (p<0.001), and participation in organized physical training was associated with higher score in health-directed activities (p<0.001). The final models explained 3.7%-31.7% of variance (adjusted R2) across the eight heiQ scales. Conclusion: A notable finding of this study was that higher symptom burden was associated with worse scores in all self management domains, except for self-monitoring and insight. In addition, sex, disease severity, comorbidity, pack-years smoking, and participation in organized physical training were associated with one or two self-management domains. The study contributes to improved understanding of self-management in COPD. However, the explained variance levels indicate that more research needs to be done to uncover what else explains self-management domains in COPD. PMID- 29416328 TI - Emphysema and bronchiectasis in COPD patients with previous pulmonary tuberculosis: computed tomography features and clinical implications. AB - Background: Pulmonary tuberculosis (PTB) is a risk factor for COPD, but the clinical characteristics and the chest imaging features (emphysema and bronchiectasis) of COPD with previous PTB have not been studied well. Methods: The presence, distribution, and severity of emphysema and bronchiectasis in COPD patients with and without previous PTB were evaluated by high-resolution computed tomography (HRCT) and compared. Demographic data, respiratory symptoms, lung function, and sputum culture of Pseudomonas aeruginosa were also compared between patients with and without previous PTB. Results: A total of 231 COPD patients (82.2% ex- or current smokers, 67.5% male) were consecutively enrolled. Patients with previous PTB (45.0%) had more severe (p=0.045) and longer history (p=0.008) of dyspnea, more exacerbations in the previous year (p=0.011), and more positive culture of P. aeruginosa (p=0.001), compared with those without PTB. Patients with previous PTB showed a higher prevalence of bronchiectasis (p<0.001), which was more significant in lungs with tuberculosis (TB) lesions, and a higher percentage of more severe bronchiectasis (Bhalla score >=2, p=0.031), compared with those without previous PTB. The overall prevalence of emphysema was not different between patients with and without previous PTB, but in those with previous PTB, a higher number of subjects with middle (p=0.001) and lower (p=0.019) lobe emphysema, higher severity score (p=0.028), higher prevalence of panlobular emphysema (p=0.013), and more extensive centrilobular emphysema (p=0.039) were observed. Notably, in patients with TB lesions localized in a single lung, no difference was found in the occurrence and severity of emphysema between the 2 lungs. Conclusion: COPD patients with previous PTB had unique features of bronchiectasis and emphysema on HRCT, which were associated with significant dyspnea and higher frequency of severe exacerbations. While PTB may have a local effect on bronchiectasis, its involvement in airspace damage in COPD may be extensive, probably through interactions with cigarette smoke. PMID- 29416329 TI - Sex-specific cardiopulmonary exercise testing indices to estimate the severity of inoperable chronic thromboembolic pulmonary hypertension. AB - Background: Sex differences in chronic thromboembolic pulmonary hypertension (CTEPH) have been revealed in few studies. Although right heart catheterization (RHC) is the gold standard for clinical diagnosis and assessment of prognosis in pulmonary hypertension (PH), cardiopulmonary exercise testing (CPET) has been a more widely used assessment of functional capacity, disease severity, prognosis, and treatment response in PH. We hypothesized that the "sex-specific" CPET indices could estimate the severity of inoperable CTEPH. Methods: Data were retrieved for 33 male (age, mean +/- standard deviation [SD] =62.5+/-13.4 years) and 40 female (age, mean +/- SD =56.3+/-11.8 years) patients with stable CTEPH who underwent both RHC and CPET at Shanghai Pulmonary Hospital from February 2010 to February 2016. Univariate and forward/backward multiple stepwise regression analysis was performed to assess the predictive value of CPET indices to hemodynamic parameters. Event-free survival was estimated using the Kaplan-Meier method and analyzed with the log-rank test. Cox proportional hazards models were performed to determine the independent event-free survival predictors. Results: Numerous CPET parameters were different between male and female patients with CTEPH and the control group. There were no significant differences in both clinical variables and RHC parameters between male and female patients with CTEPH. O2 pulse, workload, minute ventilation (VE), and end-tidal partial pressure of O2 (PETO2) at anaerobic threshold, as well as peak O2 pulse, workload, VE, and nadir VE/CO2 were significantly higher in male patients than in female patients (P<0.05). Only oxygen uptake efficiency plateau (OUEP) showed a significantly higher difference in female than male patients (P<0.05). In addition, several CPET indices correlated with hemodynamic parameters, especially pulmonary vascular resistance (PVR), which was distinctly different between the sexes. Nadir VE/CO2 was an independent predictor of PVR in male patients with CTEPH, whereas OUEP was an independent predictor of PVR in female patients with CTEPH. Conclusion: Even after confounding for age and body mass index, different CPET measurements of gas exchange efficiency correlated with PVR differently between male and female patients. This potentially could be used to estimate the severity of CTEPH. PMID- 29416330 TI - Nanomedical studies of the restoration of nitric oxide/peroxynitrite balance in dysfunctional endothelium by 1,25-dihydroxy vitamin D3 - clinical implications for cardiovascular diseases. AB - Background: Clinical studies indicate that vitamin D3 improves circulation and may have beneficial effects in hypertension. This study uses nanomedical systems to investigate the role of 1,25-dihydroxy vitamin D3 in the preservation/restoration of endothelial function in an angiotensin II (Ang II) cellular model of hypertension. Methods: 1,25-dihydroxy vitamin D3-stimulated nitric oxide (NO) and peroxynitrite (ONOO-) concentrations were measured in situ with nanosensors (200-300 mm diameter with a detection limit of 1 nM) in human umbilical vein endothelial cells of African American (AA) and Caucasian American (CA) donors exposed to Ang II. The balance/imbalance between NO and ONOO- concentrations ([NO]/[ONOO-]) was simultaneously monitored and used as an indicator of endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction. Results: [NO]/[ONOO-] imbalance in Ang II-stimulated dysfunctional endothelium was 0.20+/-0.16 for CAs and 0.11+/-0.09 for AAs. Uncoupled eNOS and overexpression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contributed to high production of ONOO-. Vitamin D3 treatment reversed [NO]/[ONOO ] to 3.0+/-0.1 in CAs and 2.1+/-0.1 in AAs - exceeding that observed in normal endothelium. Vitamin D3 restored uncoupled eNOS and endothelial function by increasing cytoprotective NO and decreasing the cytotoxic ONOO-. The beneficial effect of vitamin D3 is associated with a favorable rate of NO and ONOO- release, restoration of the [NO]/[ONOO-] and the overall decrease in the overexpression of eNOS, inducible nitric oxide synthase and NADPH oxidase. This effect of vitamin D3 may prove to be beneficial in the treatment of hypertension and other cardiovascular diseases, including heart failure, myocardial infarction, vasculopathy, stroke and diabetes. PMID- 29416331 TI - Pharmacokinetics and in vitro/in vivo antitumor efficacy of aptamer-targeted Ecoflex(r) nanoparticles for docetaxel delivery in ovarian cancer. AB - Purpose: Epithelixal ovarian cancer is the fourth cause of cancer death in developed countries with 77% of ovarian cancer cases diagnosed with regional or distant metastasis, with poor survival rates. Docetaxel (DTX) is a well-known anticancer agent, with clinically proven efficacy in several malignancies, including ovarian cancer. However, the adverse effects caused by the active ingredient or currently marketed formulations could even deprive the patient of the advantages of treatment. Therefore, in the current study, polymeric nanoparticles (NPs) equipped with aptamer molecules as targeting agents were proposed to minimize the adverse effects and enhance the antitumor efficacy through directing the drug cargo toward its site of action. Materials and methods: Electrospraying technique was implemented to fabricate poly (butylene adipate-co-butylene terephthalate) (Ecoflex(r)) NPs loaded with DTX (DTX-NPs). Afterward, aptamer molecules were added to the DTX-NPs, which bound via covalent bonds (Apt-DTX-NPs). The particle size, size distribution, zeta potential, entrapment efficiency, and release profile of the NPs were characterized. Using MTT assay and flow-cytometry analysis, the in vitro cytotoxicity and cellular uptake of the NPs were compared to those of the free drug. Following intravenous administration of Taxotere(r), DTX-NPs, and Apt-DTX-NPs (at an equivalent dose of 5 mg/kg of DTX), pharmacokinetic parameters and antitumor efficacy were compared in female Balb/c and HER-2-overexpressing tumor-bearing B6 athymic mice, respectively. Results: The obtained results demonstrated significantly enhanced in vitro cytotoxicity and cellular uptake of Apt-DTX-NPs in a HER-2 overexpressing cell line, comparing to DTX-NPs and the free drug. The results of in vivo studies indicated significant increment in pharmacokinetic parameters including the area under the plasma concentration-time curve, mean residence time, and elimination half-life. Significant increment in antitumor efficacy was also observed, probably due to the targeted delivery of DTX to the tumor site and enhanced cellular uptake as evaluated in the aforementioned tests. Conclusion: Hence, the proposed drug delivery system could be considered as an appropriate potential substitute for currently marketed DTX formulations. PMID- 29416333 TI - One-step synthesis of gene carrier via gamma irradiation and its application in tumor gene therapy. AB - Introduction: Although numerous studies have been conducted with the aim of developing drug-delivery systems, chemically synthesized gene carriers have shown limited applications in the biomedical fields due to several problems, such as low-grafting yields, undesirable reactions, difficulties in controlling the reactions, and high-cost production owing to multi-step manufacturing processes. Materials and methods: We developed a 1-step synthesis process to produce 2 aminoethyl methacrylate-grafted water-soluble chitosan (AEMA-g-WSC) as a gene carrier, using gamma irradiation for simultaneous synthesis and sterilization, but no catalysts or photoinitiators. We analyzed the AEMA graft site on WSC using 2-dimensional nuclear magnetic resonance spectroscopy (2D NMR; 1H and 13C NMR), and assayed gene transfection effects in vitro and in vivo. Results: We revealed selective grafting of AEMA onto C6-OH groups of WSC. AEMA-g-WSC effectively condensed plasmid DNA to form polyplexes in the size range of 170 to 282 nm. AEMA g-WSC polyplexes in combination with psi-hBCL2 (a vector expressing short hairpin RNA against BCL2 mRNA) inhibited tumor cell proliferation and tumor growth in vitro and in vivo, respectively, by inducing apoptosis. Conclusion: The simple grafting process mediated via gamma irradiation is a promising method for synthesizing gene carriers. PMID- 29416332 TI - Nano-biphasic calcium phosphate/polyvinyl alcohol composites with enhanced bioactivity for bone repair via low-temperature three-dimensional printing and loading with platelet-rich fibrin. AB - Background and aim: As a newly emerging three-dimensional (3D) printing technology, low-temperature robocasting can be used to fabricate geometrically complex ceramic scaffolds at low temperatures. Here, we aimed to fabricate 3D printed ceramic scaffolds composed of nano-biphasic calcium phosphate (BCP), polyvinyl alcohol (PVA), and platelet-rich fibrin (PRF) at a low temperature without the addition of toxic chemicals. Methods: Corresponding nonprinted scaffolds were prepared using a freeze-drying method. Compared with the nonprinted scaffolds, the printed scaffolds had specific shapes and well connected internal structures. Results: The incorporation of PRF enabled both the sustained release of bioactive factors from the scaffolds and improved biocompatibility and biological activity toward bone marrow-derived mesenchymal stem cells (BMSCs) in vitro. Additionally, the printed BCP/PVA/PRF scaffolds promoted significantly better BMSC adhesion, proliferation, and osteogenic differentiation in vitro than the printed BCP/PVA scaffolds. In vivo, the printed BCP/PVA/PRF scaffolds induced a greater extent of appropriate bone formation than the printed BCP/PVA scaffolds and nonprinted scaffolds in a critical-size segmental bone defect model in rabbits. Conclusion: These experiments indicate that low-temperature robocasting could potentially be used to fabricate 3D printed BCP/PVA/PRF scaffolds with desired shapes and internal structures and incorporated bioactive factors to enhance the repair of segmental bone defects. PMID- 29416334 TI - Copolymer micelles function as pH-responsive nanocarriers to enhance the cytotoxicity of a HER2 aptamer in HER2-positive breast cancer cells. AB - Efficient delivery of nucleic acids into target cells is crucial for nucleic acid based therapies. Various nucleic acid delivery systems have been developed, each with its own advantages and limitations. We previously developed a nanoparticle based delivery system for small chemical drugs using pH-responsive PEG8-PDPA100 PEG8 polymer micelles as carriers. In this study, we extend the application of these pH-responsive micelle-like nanoparticles (MNPs) to deliver oligonucleotides. We demonstrate that the MNPs efficiently encapsulate and deliver oligonucleotides of different lengths (20-100 nt) into cells. The cargo oligonucleotides are rapidly released at pH 5.0. We prepared MNPs carrying a Texas red-fluorescently labeled anti-human epidermal growth factor receptor 2 (HER2) aptamer (HApt). Compared to free HApt, the HApt-MNPs resulted in significantly better cellular uptake, reduced cell viability, and increased apoptosis in SKBR3 breast cancer cells, which overexpress HER2. Moreover, HApt MNPs were significantly less cytotoxic to MCF7 breast cancer cells, which express low levels of HER2. After cellular uptake, HApt-MNPs mainly accumulated in lysosomes; inhibition of lysosomal activity using bafilomycin A1 and LysoTracker Red staining confirmed that lysosomal activity and low pH were required for HApt MNP accumulation and release. Furthermore, HER2 protein expression declined significantly following treatment with HApt-MNPs in SKBR3 cells, indicating that HApt-induced translocation of HER2 to lysosomes exerted a potent cytotoxic effect by altering signaling downstream of HER2. In conclusion, this pH-responsive and lysosome-targeting nanoparticle system can efficiently deliver oligonucleotides to specific target cells and has significant potential for nucleic acid-based cancer therapies. PMID- 29416335 TI - Human beta-defensin 3-combined gold nanoparticles for enhancement of osteogenic differentiation of human periodontal ligament cells in inflammatory microenvironments. AB - Objective: It is a great challenge to absorb and conduct biophysicochemical interactions at the nano-bio interface. Peptides are emerging as versatile materials whose function can be programmed to perform specific tasks. Peptides combined nanoparticles might be utilized as a new approach of treatment. Human beta-defensin 3 (hBD3), possesses both antimicrobial and proregeneration properties. Gold nanoparticles (AuNPs) have shown promising applications in the field of tissue engineering. However, the coordinating effects of AuNPs and hBD3 on human periodontal ligament cells (hPDLCs) remain unknown. In this study, we systematically investigated whether AuNPs and hBD3 would be able to coordinate and enhance the osteogenic differentiation of hPDLCs in inflammatory microenvironments, and the underlying mechanisms was explored. Methods: hPDLCs were stimulated with E. coli-LPS, hBD3 and AuNPs. Alkaline phosphatase (ALP) and alizarin red S staining were used to observe the effects of hBD3 and AuNPs on the osteogenic differentiation of hPDLCs. Real-time PCR and western blot were performed to evaluate the osteogenic differentiation and Wnt/beta-catenin signaling pathway related gene and protein expression. Results: In the inflammatory microenvironments stimulated by E. coli-LPS, we found that AuNPs and hBD3 increased the proliferation of hPDLCs slightly. In addition, hBD3-combined AuNPs could significantly enhance ALP activities and mineral deposition in vitro. Meanwhile, we observed that the osteogenic differentiation-related gene and protein expressions of ALP, collagenase-I (COL-1) and runt-related transcription factor 2 (Runx-2) were remarkably upregulated in the presence of hBD3 and AuNPs. Moreover, hBD3-combined AuNPs strongly activated the Wnt/beta-catenin signaling pathway and upregulated the gene and protein expression of beta-catenin and cyclin D1. Furthermore, hBD3-combined AuNPs induced osteogenesis, which could be reversed by the Wnt/beta-catenin signaling pathway inhibitor (ICG-001). Conclusion: The present study demonstrated that hBD3 combined AuNPs could significantly promote the osteogenic differentiation of hPDLCs in inflammatory microenvironments via activating the Wnt/beta-catenin signaling pathway. PMID- 29416336 TI - Maturation of dendritic cells in vitro and immunological enhancement of mice in vivo by pachyman- and/or OVA-encapsulated poly(d,l-lactic acid) nanospheres. AB - Background: Poly lactide (PLA) was proved in the last years to be good for use in sustained drug delivery and as carriers for vaccine antigens. In our previous research, pachyman (PHY)-encapsulated PLA (PHYP) nanospheres were synthesized and their function of controlling drug release was demonstrated. Purpose: In order to modify the fast drug-release rate of PHY when inoculated alone, the maturation of bone marrow dendritic cells (BMDCs) in vitro and their immunological enhancement in vivo were explored using PHYP nanospheres. Methods: The maturation and antigen uptake of BMDCs were evaluated, both alone and with formulated antigen PHYP nanospheres, ie, ovalbumin (OVA)-loaded PHYP nanospheres, as an antigen delivery system, to investigate antigen-specific humoral and cellular immune responses. Results: The results indicated that, when stimulated by PHYP, the BMDCs matured as a result of upregulated expression of co-stimulatory molecules; the mechanism was elucidated by tracing fluorescently labeled antigens in confocal laser scanning microscopy images and observing the uptake of nanospheres by transmission electron microscopy. It was further revealed that mice inoculated with OVA-PHYP had augmented antigen-specific IgG antibodies, increased cytokine secretion by splenocytes, increased splenocyte proliferation, and activation of cluster of differentiation (CD)4+ and CD8+ T cells in vivo. Elevated immune responses were produced by OVA-PHYP, possibly owing to the activation and maturation of dendritic cells (in draining lymph nodes). Conclusion: It was corroborated that PHY- and/or OVA-encapsulated PLA nanospheres elicited prominent antigen-presenting effects on BMDCs and heightened humoral and cellular immune responses compared with other formulations. PMID- 29416337 TI - Comparative efficacy and acceptability of bibliotherapy for depression and anxiety disorders in children and adolescents: a meta-analysis of randomized clinical trials. AB - Background: Depression and anxiety are the most common mental disorders in children and adolescents. Bibliotherapy is a treatment using written materials for mental health problems. Its main advantages are ease of use, low cost, low staffing demands, and greater privacy. Yet few meta-analyses have focused on the effect of bibliotherapy on depression and anxiety disorders in children and adolescents. Methods: We included randomized controlled trials comparing bibliotherapy with control conditions for depression and anxiety in children and adolescents (aged <=18 years). Five electronic databases (PubMed, Embase, Cochrane, Web of Science, and PsycINFO) were searched from inception to January 2017. Efficacy was defined as mean change scores in depression and anxiety symptoms. Acceptability was defined as the proportion of participants who discontinued the treatment. Random effects model was used. An intention-to-treat analysis was conducted. Results: Eight studies with 979 participants were selected. At posttreatment, bibliotherapy was significantly more effective than the control conditions in reducing the symptoms of depression or anxiety (standardized mean difference, -0.52; 95% confidence interval [CI], -0.89 to 0.15). Bibliotherapy did not have statistically significantly more all-cause discontinuations than controls (risk ratios, 1.66; 95% CI, 0.93 to 2.95). We also performed subgroup analyses for efficacy outcomes in different categories (types of disorder, mean age, control conditions, and parental involvement) of studies and found that bibliotherapy has been more effective in depressive adolescents. Limitations: Limited studies were eligible in this review and hence there was potential publication bias. Conclusion: According to the findings in this review, bibliotherapy may be more beneficial in treating depression in adolescents, but shows less robust effects for anxiety in children. Further well-defined clinical studies should be performed to confirm these outcomes. PMID- 29416338 TI - Oxidative/antioxidative status, lymphocyte DNA damage, and urotensin-2 receptor level in patients with migraine attacks. AB - Background: The present study investigated the potential roles of plasma lymphocyte DNA damage, the urotensin-2 receptor (UTS2R), and oxidative changes in patients with varying degrees of migraine-related disability who were in the ictal phase and presented to our emergency department. Methods: This study enrolled 40 consecutive adult patients with migraine attack and 40 age- and sex matched healthy controls. The same health care professional determined the headache-related disability of each patient's migraine attack using the Migraine Disability Assessment Scale (MIDAS); patients were divided into three groups based on MIDAS score. Plasma lymphocyte DNA damage; UTS2R, malondialdehyde (MDA), and catalase (CAT) levels; total oxidant status (TOS); total antioxidant status (TAS); and the oxidative stress index (OSI) were used as predictors of early oxidative changes. Results: Plasma lymphocyte DNA damage, TOS, MDA levels, and OSI values were significantly higher in patients with migraine compared to controls. Conversely, TAS and CAT and UTS2R levels were markedly lower in patients with migraine compared to controls. Comparisons of the patient groups by MIDAS score revealed significant differences in plasma lymphocyte DNA damage and CAT levels but no differences in TOS, MDA levels, OSI, TAS, or UTS2R levels. MIDAS scores were positively correlated with the degree of lymphocyte DNA damage, but neither of these factors was significantly related to CAT levels. Conclusion: The present data suggest that lymphocyte DNA damage and changes in oxidative/antioxidative status may reflect an enhanced oxidative damage and an ineffective antioxidant defense system in migraineurs during headache attacks. In addition, lymphocyte DNA damage levels may be an indicator of the degree of migraine-related disability as assessed by MIDAS score. PMID- 29416339 TI - Adjustment disorder: current perspectives. AB - Adjustment disorder (AjD) is among the most often diagnosed mental disorders in clinical practice. This paper reviews current status of AjD research and discusses scientific and clinical issues associated with AjD. AjD has been included in diagnostic classifications for over 50 years. Still, the diagnostic criteria for AjD remain vague and cause difficulties to mental health professionals. Controversies in definition resulted in the lack of reliable and valid measures of AjD. Epidemiological data on prevalence of AjD is scarce and not reliable because prevalence data are biased by the diagnostic algorithm, which is usually developed for each study, as no established diagnostic standards for AjD are available. Considerable changes in the field of AjD could follow after the release of the 11th edition of International Classification of Diseases (ICD-11). A new AjD symptom profile was introduced in ICD-11 with 2 main symptoms as follows: 1) preoccupation and 2) failure to adapt. However, differences between the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and ICD-11 AjD diagnostic criteria could result in diverse research findings in the future. The best treatment approach for AjD remains unclear, and further treatment studies are needed to provide AjD treatment guidelines to clinicians. PMID- 29416340 TI - Self-stigma and treatment effectiveness in patients with anxiety disorders - a mediation analysis. AB - Goal: The goal of this study was to explore the impact of self-stigma on the treatment outcomes in patients with anxiety disorders and to find possible mediators of this relationship. Method: Two hundred and nine patients with anxiety disorders, who were hospitalized in a psychotherapeutic department, attended the study. The average age was 39.2+/-12.4 years; two-thirds were women. Most of the patients used a long-term medication. The participants underwent either cognitive behavioral therapy (CBT) or short psychodynamic therapy. The selection to the psychotherapy was not randomized. All individuals completed several scales - Beck Depression Inventory, the second edition (BDI-II), Beck Anxiety Inventory (BAI), Dissociative Experience Scale (DES), Sheehan Disability Scale (SDS), subjective Clinical Global Impression (subjCGI), and The Internalized Stigma of Mental Illness Scale (ISMI). A senior psychiatrist filled out the objective CGI (objCGI). Results: The patients significantly improved in the severity of anxiety (BAI), depression (BDI-II), and overall severity of the mental disorder (objCGI). The self-stigma predicted a lower change of the objCGI, but not a change of the anxiety and depressive symptoms severity. Anxiety, depressive symptoms, dissociation, and disability were assessed as possible mediators of the relationship between the self-stigma and the treatment change. None of them were significant. Conclusion: Self-stigma lowers the effectiveness of the combined treatment of anxiety disorders. Future research should explore other possible mediators influencing this relationship. PMID- 29416341 TI - Cognitive behavioral group therapy versus psychoeducational intervention in Parkinson's disease. AB - Objective: The aim of the current study was to evaluate whether cognitive behavioral group therapy has a positive impact on psychiatric, and motor and non motor symptoms in Parkinson's disease (PD). Methods: We assigned 20 PD patients with a diagnosis of psychiatric disorder to either a 12-week cognitive behavioral therapy (CBT) group or a psychoeducational protocol. For the neurological examination, we administered the Unified Parkinson's Disease Rating Scale and the non-motor symptoms scale. The severity of psychiatric symptoms was assessed by means of the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, the Brief Psychiatric Rating Scale, and the Clinical Global Impressions. Results: Cognitive behavioral group therapy was effective in treating depression and anxiety symptoms as well as reducing the severity of non-motor symptoms in PD patients; whereas, no changes were observed in PD patients treated with the psychoeducational protocol. Conclusion: CBT offered in a group format should be considered in addition to standard drug therapy in PD patients. PMID- 29416342 TI - Increased risk of venous thromboembolism associated with polymyositis and dermatomyositis: a meta-analysis. AB - Objective: Polymyositis and dermatomyositis (PM/DM) have been implicated in the development of venous thromboembolism (VTE). Previous studies investigating the association between PM/DM and VTE risk had yielded inconsistent findings. The aim of this study was to precisely estimate this association by meta-analysis of all available publications. Methods: Two investigators independently performed a comprehensive literature search in databases of PubMed, Embase, and the Cochrane Library for eligible studies. The strength for the association was weighed by pooled odds ratios (ORs) with 95% confidence intervals (95% CIs). Stratified analysis and sensitivity analysis were performed for further analysis. Results: Six studies including 9,045 patients with PM/DM were analyzed. The pooled OR suggested that inflammatory myositis was associated with increased risk of VTE (OR =4.31, 95% CI: 2.55-7.29, P<0.001). Besides, significantly elevated risk of VTE was related with PM and DM, respectively (for PM: OR =6.87, 95% CI: 4.12 11.46, P<0.001; for DM: OR =11.59, 95% CI: 6.54-20.55, P<0.001). In addition, inflammatory myositis could increase the risk of DVT (OR =4.85, 95% CI: 1.38 17.12, P<0.05) and PE (OR =4.74, 95% CI: 2.18-10.30, P<0.05). Sensitivity analysis did not materially alter the pooled results. Conclusion: Our study shows strong evidence that patients with inflammatory myositis have an increased risk of VTE. PMID- 29416343 TI - Biological therapy of traditional therapy-resistant adult-onset Still's disease: an evidence-based review. AB - Background: Biotherapy is becoming increasingly important in the treatment of adult-onset Still's disease (AOSD). The aim of our study was to evaluate the efficacy and safety of biological therapy for AOSD resistant to traditional therapy. Patients and methods: Database of Library of Congress, the PubMed, and Web of Science Core Collection were used to retrieve relevant articles published in English language until March 2017. Only studies published in English language were included, and the additional references quoted in these articles were also checked. Articles concerning the efficacy and safety of all the biotherapies in refractory AOSD were evaluated. Results: There were 112 articles available in total; 422 AOSD patients were given at least one biologic. We found that 293 patients (69.43%) had received TNF-alpha blocking agents (infiliximab, etanercept, and adalimumab), 194 patients (45.97%) were treated with IL-1 receptor antagonists (anakinra, rilonacept, and canakinumab), 163 patients (38.63%) were given IL-6 inhibitor (tocilizumab), and 24 patients (5.69%) received rituximab and abatacept. The efficacy of biological therapy and overall tolerance of biological therapy for refractory AOSD were good. Thirty two of 271 patients given anti-TNF-alpha therapies (11.81%), 116 patients receiving IL-1 inhibitors (65.54%), 124 patients receiving tocilizumab (76.07%), and 13 patients given other biological therapies (36.11%) achieved remission. Side effects of biologic therapy were infections such as urinary tract infections and soft tissue abscess. Conclusion: Our findings suggest that anakinra and tocilizumab may be good choices for the treatment of refractory AOSD considering the effectiveness and safety. PMID- 29416344 TI - Incidence of traumatic carotid and vertebral artery dissections: results of cervical vessel computed tomography angiogram as a mandatory scan component in severely injured patients. AB - Purpose: The aim of this study was to evaluate the true incidence of cervical artery dissections (CeADs) in trauma patients with an Injury Severity Score (ISS) of >=16, since head-and-neck computed tomography angiogram (CTA) is not a compulsory component of whole-body trauma computed tomography (CT) protocols. Patients and methods: A total of 230 consecutive trauma patients with an ISS of >=16 admitted to our Level I trauma center during a 24-month period were prospectively included. Standardized whole-body CT in a 256-detector row scanner included a head-and-neck CTA. Incidence, mortality, patient and trauma characteristics, and concomitant injuries were recorded and analyzed retrospectively in patients with carotid artery dissection (CAD) and vertebral artery dissection (VAD). Results: Of the 230 patients included, 6.5% had a CeAD, 5.2% had a CAD, and 1.7% had a VAD. One patient had both CAD and VAD. For both, CAD and VAD, mortality is 25%. One death was caused by fatal cerebral ischemia due to high-grade CAD. A total of 41.6% of the patients with traumatic CAD and 25% of the patients with VAD had neurological sequelae. Conclusion: Mandatory head-and-neck CTA yields higher CeAD incidence than reported before. We highly recommend the compulsory inclusion of a head-and-neck CTA to whole-body CT routines for severely injured patients. PMID- 29416345 TI - The role of miRNAs in the diagnosis, chemoresistance, and prognosis of pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy with late presentation, metastatic potential, chemoresistance, and poor prognosis. Therefore, there is an urgent need for novel diagnostic and prognostic biomarkers. miRNAs are small noncoding RNAs that regulate the expression of multitude number of genes. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been defined as holding promise for early diagnostics, as indicators of therapy resistance, and even as markers for prognosis in PDAC patients. In this review, we summarize the current knowledge on the role of miRNAs in diagnosis, chemoresistance, and prognosis in PDAC patients. PMID- 29416346 TI - Prediction of emergence agitation using withdrawal reaction following rocuronium injection in preschool-aged patients undergoing inguinal herniorrhaphy: a preliminary exploratory observational trial. AB - Purpose: The development of emergence agitation (EA) is associated with several factors including age, preoperative anxiety, postoperative pain, anesthesia method, and surgery type. No studies have investigated whether the withdrawal reaction following rocuronium injection can predict the occurrence of EA. Therefore, we investigated this relationship in preschool-aged children undergoing inguinal herniorrhaphy, and which grade of withdrawal reaction is appropriate for identifying patients at risk of experiencing EA. Methods: A total of 40 patients were enrolled in this study. During anesthesia induction, the withdrawal reaction after loss of consciousness following rocuronium injection was assessed using a 4-point scale. After surgery, EA was assessed using the Watcha scale. Results: There was a correlation between withdrawal reaction and EA on admission to the postanesthesia care unit (PACU). Patients with a severe withdrawal reaction (grade 3) showed a significantly higher incidence of severe EA requiring medication on admission to the PACU. Conclusion: The findings of this preliminary exploratory observational study suggest that it is possible for withdrawal movement following rocuronium injection during anesthesia induction to reflect pain sensitivity of pediatric patients, which in turn may be useful in identifying those at risk of severe EA on admission to the PACU among preschool children undergoing inguinal herniorrhaphy. Further studies with a larger sample size are required to validate these findings. The exact correlation between pain reaction following rocuronium injection and postoperative pain or pain-related phenomenon should be elucidated. PMID- 29416348 TI - Synovial sarcoma of the maxillary sinus: an extremely rare case with excellent response to chemotherapy. AB - This paper presents an extremely rare case of synovial sarcoma arising from the maxillary sinus, which resulted in a clinically complete response to chemotherapy. Synovial sarcoma is a rare soft tissue malignant tumor, most commonly affecting the extremities. While ~10% occur in the head and neck region, synovial sarcoma of the sinonasal tract is extremely rare, with only 11 cases having been reported previously. As with other sarcomas, the standard treatment is complete resection while allowing for a safe margin, but this is often difficult in the head and neck area due to the complicated anatomy there. This makes the treatment of head and neck sarcoma challenging and leads to the need for a multimodal approach in advanced cases. However, the exact efficacy of chemotherapy is not well understood. In this report, we present a case of unresectable maxillary sinus synovial sarcoma that was successfully treated by chemotherapy followed by radiation therapy. A 53-year-old Japanese man was referred to our hospital with a history of left nose obstruction over the previous couple of years. Computed tomography/magnetic resonance imaging revealed a tumor arising from the maxillary sinus that extended to adjacent tissues. A biopsy was performed, and the tumor was diagnosed as synovial sarcoma. Since the tumor was unresectable, neoadjuvant chemotherapy was administered. The response was excellent, and the tumor became undetectable under endoscopy and radiological imaging. This provided us with a clinical evaluation of "complete response". The treatment was concluded with definitive radiotherapy and two more cycles of adjuvant chemotherapy. The patient remains free of disease 12 months after treatment. Synovial sarcoma of the head and neck is a rare entity; complete resection is the treatment of choice but (neo)adjuvant chemotherapy can be considered in unresectable cases, as we show here in the present case. PMID- 29416347 TI - Total knee arthroplasty: improving outcomes with a multidisciplinary approach. AB - Total knee arthroplasty (TKA) is the most commonly performed inpatient surgical procedure within the USA and is estimated to reach 3.48 million procedures annually by 2030. As value-based care initiatives continue to focus on hospital readmission rates and patient satisfaction, it has become essential for health care providers to develop and implement a multidisciplinary approach to enhance TKA outcomes while minimizing unnecessary expenditures. Through this necessity, clinical care pathways have been developed to standardize, organize, and improve the quality and efficiency of patient care while simultaneously encouraging the collaboration among various medical care providers. Here, we review several systems based programs and specialty care practices that can be adopted into the standard orthopedic practice. PMID- 29416349 TI - ROS-dependent Bax/Bcl2 and caspase 3 pathway-mediated apoptosis induced by zineb in human keratinocyte cells. AB - There are a large number of agricultural workers who are exposed to pesticides through skin and inhalation. The best approach to identify altered molecular pathways during dermal exposure to pesticides is relevant to risk-associated concern about skin safety. In this study, we investigated the cytotoxic effect of zineb, a fungicide, in human keratinocyte (HaCaT) cells. HaCaT cells were treated with zineb (1-40 ug/mL) for 24 hours. Cellular and molecular mechanisms of cell toxicity were investigated through MTT and neutral red-uptake assays. Zineb reduced viability of HaCaT cells and induced apoptosis in a concentration dependent manner. Zineb increased levels of Bax and caspase 3 and inhibited the level of Bcl2, which subsequently induced apoptosis via the Bax/Bcl2 and caspase pathway. Therefore, zineb could have induced apoptosis through the mitochondrial pathway in HaCaT cells. Our study suggests that zineb is cytotoxic to HaCaT cells via the induction of apoptosis and oxidative stress in vitro. PMID- 29416350 TI - Prognostic role of neutrophil-lymphocyte ratio in multiple myeloma: a dose response meta-analysis. AB - Background: The neutrophil-lymphocyte ratio (NLR), a biomarker for systematic inflammation, has been recently identified as a prognostic factor for various types of both solid and hematologic malignancies. Our study presented here was the first meta-analysis assessing the prognostic role of NLR in multiple myeloma (MM). Methods: We systematically searched PubMed, Embase, and ISI Web of Science for relevant studies. Odds ratios (ORs) or hazards ratios (HRs) with corresponding 95% CIs are pooled to estimate the association between NLR and clinicopathological parameters or survival of MM patients. Results: Seven trials with 1,971 MM patients were enrolled in the meta-analysis, and the results indicated that elevated pretreatment NLR was significantly associated with advanced tumor stages (International Staging System [ISS] III vs ISS I-II: OR 2.427, 95% CI: 1.268-4.467; and Durie-Salmon III vs Durie-Salmon I-II: OR 1.738, 95% CI: 1.133-2.665). Moreover, increased NLR also predicted poorer overall survival (HR 2.084, 95% CI: 1.341-3.238) and progression-free survival (HR 1.029, 95% CI: 1.016-1.042). And two-stage dose-response meta-analysis revealed linear association between increased NLR and risk of mortality in MM patients. Conclusion: We can conclude that MM patients with higher NLR are more likely to have poorer prognosis than those with lower NLR. PMID- 29416351 TI - The prognostic role of Gas6/Axl axis in solid malignancies: a meta-analysis and literature review. AB - Background: Axl is a receptor tyrosine kinase that is involved in many pathological conditions and carcinogenesis. Gas6 is the major ligand of Axl. Activation of Gas6/Axl pathway is essential for cancer development. However, its prognostic significance in solid tumors remains unclear. Therefore, we performed this meta-analysis to elucidate the prognostic impact of Axl. Methods: Published studies on Axl or Gas6 expression and overall survival (OS) and/or disease-free survival (DFS) were searched from databases. The outcome measurement is hazard ratio (HR) for OS or DFS related to Axl/Gas6 expression. Meta-analysis was performed using RevMan. The pooled HR was calculated by fixed-/random-effect models. Results: A total of 3,344 patients from 25 studies were included. The results of meta-analysis showed that Axl overexpression was correlated with shorter OS (HR: 2.03, p<0.0001) and DFS (HR: 1.85, p<0.0001). In subgroup analysis, Axl expression was significantly correlated with poor prognosis in hepatocellular, esophageal and lung cancer. Axl expression was associated with differentiation grade, TNM stage, lymph node and distant metastasis. Conclusion: These results suggest that Axl overexpression is correlated with poor prognosis in solid tumors. This correlation varies among different types of cancers. More studies are needed to further investigate the prognostic value of Axl. PMID- 29416352 TI - The role of bevacizumab in targeted vascular endothelial growth factor therapy for epithelial ovarian cancer: an updated systematic review and meta-analysis. AB - The impact of bevacizumab (an anti-vascular endothelial growth factor therapy) remains uncertain, which has been the focus of studies on the management of epithelial ovarian cancer (EOC). To investigate the efficacy of bevacizumab combinations with different regimens in the treatment of patients with EOC, a meta-analysis of Phase III randomized controlled trials was conducted. The databases searched included PubMed, Embase, ClinicalTrials.gov, Chinese Knowledge Infrastructure, as well as the Cochrane Central Register of Controlled Trials. After evaluation of quality, a meta-analysis of valid extracted data was performed using Review Manager (RevMan) software. Five studies with 4,369 patients were included. Bevacizumab plus chemotherapy improved progression-free survival (hazard ratio [HR] =0.63; 95% confidence interval [CI], 0.51-0.77; P<0.01) and overall survival (HR =0.91; 95% CI, 0.84-0.99; P<0.05). Interestingly, in patients with a high risk of progression, the subgroups that received bevacizumab combined with different regimens of chemotherapy showed a significant improvement with paclitaxel plus carboplatin-based chemotherapy (HR =0.86; 95% CI, 0.77-0.95; P<0.01), but not with non-paclitaxel plus carboplatin based chemotherapy (HR =0.91; 95% CI, 0.77-1.07; P>0.05) in overall survival. The combination of bevacizumab and paclitaxel plus carboplatin-based regimens offers a new treatment option for women with EOC, especially in those with a high risk of progression. PMID- 29416354 TI - Nomogram for predicting survival in patients with pancreatic cancer. AB - Background: The purpose of this study was to develop a nomogram to predict cancer specific survival (CSS) in pancreatic cancer (PC). Patients and methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to analyze 53,028 patients diagnosed with PC from 2004 to 2014 and randomly divided them into the training (n=26,583) cohort and validation (n=26,445) cohort. Univariate and multivariate analyses were used to select independent prognostic factors. We used significant prognostic factors for constructing a nomogram based on Cox regression analyses. Validation of the nomogram was assessed by discrimination and calibration. Results: According to the multivariate models of training cohort, a nomogram that combined age, race, tumor location, marital status, tumor size, TNM stage, tumor grade, and surgery was constructed for predicting CSS. The internally validated and externally validated C-indexes were 0.741 and 0.734, respectively. The calibration curves showed that the nomogram was able to predict 1-, 3-, and 5-year CSS accurately. Conclusion: A nomogram effectively predicts survival in patients with PC. This prognostic model may be considered for use in clinical practice. PMID- 29416353 TI - Clinical efficacy and safety of afatinib in the treatment of non-small-cell lung cancer in Chinese patients. AB - Compared with various malignant tumors, lung cancer has high incidence and the highest mortality worldwide. Non-small-cell lung cancer (NSCLC), the most common kind of lung cancer, is still a great threat to the world, including China. Surgery, platinum-based chemotherapy, and radiotherapy are still the primary treatments for NSCLC patients in the clinic, whereas immunotherapy and targeted therapy are gradually playing more important roles. A next-generation tyrosine kinase inhibitor (TKI), afatinib, was developed as a targeted reagent for epidermal growth factor receptor (EGFR). This targeted drug was effective in a series of trials. The US Food and Drug Administration then approved afatinib as a new first-line treatment for EGFR L858R and exon 19 deletion mutant patients in 2013. This review focused on current clinical studies of afatinib. Although this TKI was not widely available in China until recently, we aim to provide a reference for its future use in China. PMID- 29416355 TI - Quantification of heart, pericardium, and left ventricular myocardium movements during the cardiac cycle for thoracic tumor radiotherapy. AB - Purpose: The purpose of this study was to quantify variations in the heart, pericardium, and left ventricular myocardium (LVM) caused by cardiac movement using the breath-hold technique. Patients and methods: In this study, the electrocardiography-gated four-dimensional computed tomography (CT) images of 22 patients were analyzed, which were sorted into 20 phases (0-95%) according to the cardiac cycle. The heart, pericardium, and LVM were contoured on each phase of the CT images. The positions, volume, dice similarity coefficient (DSC) in reference to 0% phase, and morphological parameters (max 3D diameter, roundness, spherical disproportion, sphericity, and surface area) in different phases of the heart, pericardium, and LVM were analyzed, which were presented as mean +/- standard deviation. Results: The mean values of displacements along the X, Y, and Z axes respectively were as follows: 1.2 mm, 0.6 mm, and 0.6 mm for the heart; 0.5 mm, 0.4 mm, and 0.8 mm for the pericardium; and 1.0 mm, 4.1 mm, and 1.9 mm for the LVM. The maximum variations in volume and DSC respectively were 16.49%+/ 3.85% and 10.08%+/-2.14% for the heart, 12.62%+/-3.94% and 5.20%+/-1.54% for the pericardium, and 24.23%+/-11.35% and 184.33%+/-128.61% for the LVM. The differences in the morphological parameters between the maximum and minimum DSC phases for the heart and pericardium were not significantly different (p>0.05) but were significantly different for the LVM (p<0.05). Conclusion: The volumetric and morphological variations of the heart were similar to those of pericardium, and all were significantly smaller than those of the LVM. This inconsistency in the volumetric and morphological variations between the LVM and the heart and pericardium indicates that special protection of the LVM should be considered. PMID- 29416356 TI - Clinical manifestations of pulmonary mucosa-associated lymphoid tissue lymphoma: single-center experience with 18 patients. AB - Purpose: Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is a rare entity. To date, the optimal treatment for this disease is still under debate. The aim of this study was to analyze and summarize the clinical manifestations and therapeutic experience of 18 pulmonary MALT lymphoma patients to collect information about the optimal treatment modality. Patients and methods: A retrospective analysis was performed in patients who were diagnosed with pulmonary MALT lymphoma at the Chinese People's Liberation Army General Hospital from April 1995 to April 2016. Results: Clinical data of 18 patients were available. The median age was 55 (range, 34-67) years. Also, 61.1% of the patients were male. Only 33.3% had a history of smoking and 27.8% of the patients had tuberculosis. Treatment modalities included surgery alone in 1 patient (5.6%), chemotherapy in 10 patients (55.5%), surgery in combination with chemotherapy in 6 patients (33.3%) and observation in 1 patient (5.6%). Over the median observation period of 93 months, 2 patients died, the median progression free survival was 6 years, and the estimated 5- and 10-year overall survival rates were 94.1% and 83.7%, respectively. The survival data confirmed the indolent nature of the disease. There was no difference in progression-free survival between the chemotherapy group and the surgery in combination with chemotherapy group. Conclusion: Pulmonary MALT lymphoma tended to be an indolent disease. In order to preserve the lung function and reduce the risks associated with surgery, chemotherapy might be an optimal choice for the treatment of pulmonary MALT lymphoma. PMID- 29416357 TI - A non-synonymous polymorphism in NBS1 is associated with progression from chronic hepatitis B virus infection to hepatocellular carcinoma in a Chinese population. AB - Purpose: Nijmegen breakage syndrome 1 (NBS1) has a vital role in DNA double strand break (DSB) repair, functioning as a sensor to identify and repair DNA damage and maintaining genomic stability by participating in the intra-S-phase checkpoint. Polymorphisms of NBS1 have been investigated in multiple cancers with variable results. To our best knowledge, no previous study has focused on the association between NBS1 single-nucleotide polymorphisms (SNPs) and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Patients and methods: Five NBS1 SNPs were selected based on their potential functional impact. A hospital based cohort, comprising 481 patients with HBV-related HCC, 508 patients with chronic hepatitis B virus infection (CHB), and 581 healthy controls, was recruited for genotyping analysis. Results: After quality control, four SNPs were successfully genotyped (rs10464867, rs1063053, rs1805794, and rs709816), none of which were significantly associated with HCC or CHB compared with those of healthy controls. Similarly, the combined HBV-infected group (including the HCC and CHB groups) exhibited no significant associations with these SNPs compared with healthy controls. In contrast, comparison of the frequency of rs1805794 between patients with CHB and those with HCC identified a significant association (P=2.99E-03, odds ratio =1.31, 95% confidence interval =1.10-1.56). Conclusion: These findings suggest that, as a non-synonymous SNP, the rs1805794 C/G polymorphism may play a role in the progression from CHB to HCC. PMID- 29416358 TI - miR-106b-5p promotes stem cell-like properties of hepatocellular carcinoma cells by targeting PTEN via PI3K/Akt pathway. AB - Background: The miRNA miR-106b-5p has been previously reported to be increased in hepatocellular carcinoma (HCC) tissues compared to cirrhotic tissues. The purpose of this study was to detect its expression in HCC cell lines with distinct metastatic potentials and to explore the molecular mechanisms underlying HCC stemness and migration. Methods: miR-106b-5p expression was studied in HCC tissues and cell lines. In vitro cancer stem cell (CSC)-like properties, cell migration and invasion were compared between HCC cell lines with upregulation or downregulation of miR-106b-5p. In vivo tail vein injection models were established to evaluate the role of miR-106b-5p in lung metastasis. Bioinformatics programs, luciferase reporter assay and rescue experiments were used to validate the downstream targets of miR-106b-5p. The relationship between the expression of the targeted gene and clinicopathological parameters was also analyzed. Results: miR-106b-5p expression was higher in HCC tissues and cell lines than that in non-tumor tissues and hepatocyte Chang liver, respectively. Upregulation of miR-106b-5p exhibited a promoting role in CSC properties, cell migration and activation of phosphatidylinositol-3 kinase (PI3K)/Akt signaling in vitro, as well as in lung metastasis in vivo. However, downregulation of miR-106b 5p exhibited the opposite effect. Furthermore, PTEN was verified as a direct target of miR-106b-5p. Upon clinicopathological analysis, lower level of PTEN was significantly associated with more aggressive characteristics. Patients with high PTEN expression had longer overall survival and disease-free survival. Conclusion: miR-106b-5p promotes HCC stemness maintenance and metastasis by targeting PTEN via PI3K/Akt pathway. Inhibition of miR-106b-5p might be effective therapeutic strategies to treat advanced HCC. PMID- 29416359 TI - Sputum bacteriology conversion and treatment outcome of patients with multidrug resistant tuberculosis. AB - Purpose: Multidrug-resistant tuberculosis (MDR-TB) requires long-term treatment, has a high fatality rate, and constitutes a global threat. Earlier detection of treatment failure is required to predict therapeutic efficacy. Patients and methods: We enrolled MDR-TB patients consecutively from January 2011 through December 2012 in Lianyungang, China. Sputum smear microscopy tests and sputum cultures were performed once a month for the first 6 months following initiation of antituberculosis treatment and once every 2 months thereafter until the end of therapy. The sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were used with a 95% CI to estimate the role of sputum bacteriology conversion in predicting treatment outcomes. Results: Among the 92 MDR-TB patients enrolled in this study, 40.2% had poor treatment outcomes. The median initial sputum bacteriology conversion time was 1 month. Patients having 2 month sputum smear conversions (adjusted odds ratio [OR]: 7.19, 95% CI: 2.60 19.84) or culture conversions (adjusted OR: 2.88, 95% CI: 1.11-7.45) were more likely to experience good outcomes. The sensitivity and specificity obtained when using two-month sputum smear conversions to predict treatment outcomes were 67.6% (95% CI: 50.2-82.0) and 76.4% (95% CI: 63.0-86.8), respectively. The sensitivity and specificity obtained when using 2-month culture conversions to predict treatment outcomes were 48.6% (95% CI: 32.0-65.6) and 74.5% (95% CI: 61.0-85.3), respectively. The AUC for two-month smear conversions was 0.72 (95% CI: 0.62 0.81), significantly higher than that obtained for 2-month culture conversions (0.62, 95% CI: 0.52-0.72) (chi2 = 4.18, P = 0.041). Conclusion: The prognoses of MDR-TB patients displaying persistent sputum positivity were inferior to those for whom sputum bacteriology conversion was observed. Thus, sputum smear conversion results obtained 2 months after treatment initiation may provide a potential means for predicting MDR-TB treatment outcomes. PMID- 29416360 TI - Clinical characteristics of the first cases of invasive candidiasis in China due to pan-echinocandin-resistant Candida tropicalis and Candida glabrata isolates with delineation of their resistance mechanisms. AB - Echinocandin antifungal agents have become the first-line therapy for invasive candidiasis (IC) in many countries. Despite their increasing use, resistance to this class of drug is, overall, still uncommon. Here, we report two patients from the People's Republic of China with IC, one with infection caused by pan echinocandin-resistant Candida tropicalis and the other by pan-echinocandin resistant Candida glabrata. We also describe the mechanisms of drug resistance of these isolates. The echinocandin-resistant C. glabrata isolate was cultured from ascitic fluid of a 46-year-old male patient with intra-abdominal IC developing after surgery in 2012. This patient had had no prior antifungal exposure. The echinocandin-resistant C. tropicalis isolate was cultured from chest drainage fluid of a 60-year-old female patient with severe coronary disease and lung infection. Prior to culture and identification of the isolate, the patient had received micafungin treatment for 19 days. Both isolates were cross-resistant to micafungin, anidulafungin, and caspofungin, with minimum inhibitory concentration values of >=2 ug/mL. The amino acid substitution E655K was found adjacent to the FKS2 HS1 region of the C. glabrata isolate, while the substitution S80P were found in the FKS1 HS1 region of the C. tropicalis isolate. This report highlights the emergence of echinocandin resistance in two important non-albicans Candida species. Although the overall prevalence of echinocandin resistance is low in the People's Republic of China, monitoring of antifungal susceptibility trends in all Candida species is warranted. PMID- 29416361 TI - Imported melioidosis in Japan: a review of cases. AB - Fourteen cases of reported melioidosis in Japan were reviewed. The mean age was 52.4 years (33-69 years), and all patients were male. All of the presumed exposures originated in Southeast Asia. The most common underlying disease was diabetes mellitus, including those patients with impaired glucose tolerance (n=8). As for mode of onset, 13 patients had acute infections and one had chronic infection. Of these 14 patients, the most common infection site on admission was lung (n=8), followed by bone (n=5), skin (n=4), gastrointestinal abscess formation (n=3), urinary tract (n=3), aorta (n=2), mediastinal lymph node swelling (n=1), and central nervous system (n=1). Bacteremia was observed in nine patients, and Burkholderia pseudomallei isolates were mostly susceptible to ceftazidime and carbapenem. Overall mortality was 14.3%. Melioidosis is a rare infection in Japan, with all known cases to date having been imported from Southeast Asia. Diabetes was a common risk factor. PMID- 29416362 TI - Enriched whole genome sequencing identified compensatory mutations in the RNA polymerase gene of rifampicin-resistant Mycobacterium leprae strains. AB - Despite more than three decades of multidrug therapy (MDT), leprosy remains a major public health issue in several endemic countries, including India. The emergence of drug resistance in Mycobacterium leprae (M. leprae) is a cause of concern and poses a threat to the leprosy-control program, which might ultimately dampen the achievement of the elimination program of the country. Rifampicin resistance in clinical strains of M. leprae are supposed to arise from harboring bacterial strains with mutations in the 81-bp rifampicin resistance determining region (RRDR) of the rpoB gene. However, complete dynamics of rifampicin resistance are not explained only by this mutation in leprosy strains. To understand the role of other compensatory mutations and transmission dynamics of drug-resistant leprosy, a genome-wide sequencing of 11 M. leprae strains - comprising five rifampicin-resistant strains, five sensitive strains, and one reference strain - was done in this study. We observed the presence of compensatory mutations in two rifampicin-resistant strains in rpoC and mmpL7 genes, along with rpoB, that may additionally be responsible for conferring resistance in those strains. Our findings support the role for compensatory mutation(s) in RNA polymerase gene(s), resulting in rifampicin resistance in relapsed leprosy patients. PMID- 29416364 TI - The preventive effect on respiratory tract infections of Oscillococcinum(r). A cost-effectiveness analysis. AB - Background: Anas barbariae hepatis et cordis extractum 200K (Oscillococcinum(r)) is used to treat and prevent seasonal colds and airway inflammatory affections, improve symptom control, and reduce the frequency of respiratory tract infection (RTI) episodes. The objective of this controlled observational study is to investigate, from the Italian National Health Service (NHS) point of view, the role of Anas barbariae hepatis et cordis extractum 200K in preventing RTIs and estimate the annual average cost per patient due to visits and medicines in a real-world setting, investigating whether this method of treatment can bring savings for the NHS. Methods: Data from a single center from 2002 to 2011 were used. The analysis examined 455 patients who suffered from respiratory diseases. Of the total number of patients, 246 were treated with Anas barbariae hepatis et cordis extractum 200K while 209 were not treated (Control group). All the data concerning RTI episodes, pharmacological treatments, and pneumological visits were extracted from the database. Results: It was found that, regardless of the diagnosis, the frequency of RTI episodes was always lower in patients treated with Anas barbariae hepatis et cordis extractum 200K; the difference between the numbers of events occurring was statistically significant in every class of patients (p<0.001). The costs that the NHS had to incur were significantly lower in the classes of patients treated (p<0.001). Discussion: The results indicate that Anas barbariae hepatis et cordis extractum 200K has a preventive effect on the onset of RTI episodes. The analysis shows that treating patients with Anas barbariae hepatis et cordis extractum 200K lowers costs for the NHS; this is primarily due to the fact that the medication causes fewer episodes of RTI to develop. This study suggests that the treatment with Anas barbariae hepatis et cordis extractum 200K could be helpful in preventing RTIs and improving the health status of patients who suffer from respiratory diseases, and it could lead to savings to the Italian NHS. PMID- 29416363 TI - Liver fungal infections: an overview of the etiology and epidemiology in patients affected or not affected by oncohematologic malignancies. AB - Fungal infections of the liver, most commonly caused by Candida spp., often occur in patients with hematologic malignancies treated with chemotherapy. Colonization of the gastrointestinal tract is thought to be the main origin of dissemination of Candida; mucositis and neutropenia facilitate the spread of Candida from the gastrointestinal tract to the liver. Hepatic involvement due to other fungi is a less common infectious complication in this setting. Fungal infections represent a less common cause of hepatic abscesses in non-oncohematologic population and the trend appears to be decreasing in recent years. Understanding of the etiology and epidemiology of fungal infections of the liver is indicated for an appropriate antimicrobial therapy and an overall optimal management of fungal liver infections. PMID- 29416365 TI - Systematic review of health state utility values for acute myeloid leukemia. AB - Background: Cost-utility analyses for acute myeloid leukemia (AML) require health state utility values (HSUVs) in order to calculate quality-adjusted life-years (QALYs) for each health state. Aim: This study reviewed AML-related HSUVs that could be used in economic evaluation studies. Materials and methods: EMBASE, MEDLINE, and Cochrane databases were searched from January 2000 to November 2016 for relevant studies that reported quality of life (QoL) and HSUVs in AML. Identified relevant European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 values were mapped to HSUVs. HSUVs for each health state in the AML treatment pathway were then collated. Results: Ten relevant studies were identified. Six were cost-effectiveness analyses utilizing HSUVs for calculation of QALYs, one was an effectiveness analysis (incremental QALY), and two were QoL studies reporting AML-specific utilities. An additional study reported QoL for patients undergoing stem cell transplantation (SCT). Since no study reported HSUVs for relapse, values from a study of secondary AML patients who failed prior treatment for myelodysplastic syndrome were used. Where multiple HSUVs were available, collected values were given priority over assumed values. AML treatment (induction, consolidation, or SCT) was associated with decreased HSUV, while post-treatment complete remission led to increased HSUV. Conclusion: There are some methodologically robust HSUVs that can be directly used in economic evaluations for AML. Careful interpretation is advised considering significant differences in methodologies and patient population (inclusion, size). We need to develop HSUVs with larger-sized studies, making greater use of condition-specific data. PMID- 29416366 TI - Linking care of patients with obesity to outpatient weight control clinics following acute hospitalizations. AB - Despite obesity impacting over one-third of US adults, guideline recommendations have not been effectively utilized by health care providers in hospital settings. Initiation of weight loss plans for obese patients during hospitalizations followed by linkage of care to weight control centers may improve compliance with the guidelines. Provider recognition and awareness that obesity is a chronic condition that warrants inpatient counsel and management with appropriate arrangement of postdischarge follow-up care will be critical to guideline implementation. PMID- 29416367 TI - Profile of dupilumab and its potential in the treatment of inadequately controlled moderate-to-severe atopic dermatitis. AB - Atopic dermatitis (AD) is a common inflammatory skin disorder that manifests as eczematous lesions, often associated with allergic rhinitis and asthma. Historically, moderate-to-severe disease has been managed with systemic immunosuppression, such as oral corticosteroids, which result in relapse and limiting side effects. Due to recent advancements in the identification of interleukin (IL)-4 and IL-13 as key mediators in AD, new biological agents have been developed for treatment. Dupilumab is a recently approved monoclonal antibody that targets the alpha subunit of the IL-4 receptor and, thus, downregulates activity of IL-4 and IL-13. This review discusses the profile of dupilumab and its potential for efficacy and safety in treating moderate-to severe AD by reviewing data from Phase I-III clinical trials. Results suggest that dupilumab shows great therapeutic promise for AD. Further studies investigating extended use of dupilumab and dupilumab in comparison to other agents are needed to establish long-term efficacy and safety. PMID- 29416368 TI - Antiaging efficacy of melatonin-based day and night creams: a randomized, split face, assessor-blinded proof-of-concept trial. AB - Background: Skin is a complete and independent melatoninergic system. At the skin level, melatonin (Mel) acts as a relevant antioxidant and cytoprotective substance. Topical application of Mel is considered meaningful, since it can easily penetrate the stratum corneum. Exogenous Mel can be expected to represent a potent antioxidative defense system against skin aging mechanisms. Day and night creams containing Mel, carried in lipospheres (MelatosphereTM), have been developed (Nutriage SPF 30 day cream and Nutriage night cream). Study aim: The aim of this study was to evaluate the efficacy of a Mel-based cream as antiaging treatment. Subjects and methods: In a randomized, split-face, assessor-blinded, prospective 3-month study, 22 women (mean age 55 years) with moderate-severe skin aging were enrolled (clinical trial registration number: NCT03276897). Study products were applied in the morning (Nutriage day cream) and evening (Nutriage night cream) on the right or left side of the face. Primary outcomes were: 1) clinical evaluation of wrinkles' grade (crow's feet and nasolabial folds), surface microrelief, skin tonicity (resistance to pinching and traction, recovery after pinching) and skin dryness and 2) instrumental evaluation of skin roughness and 3D photographic documentation (Vectra H1 images system). Assessments of both clinical and instrumental evaluations were performed at baseline and after 1, 2 and 3 months of treatment by an investigator unaware of treatment allocation. Results: All the subjects completed the study. Crow's feet was reduced significantly (p=0.05) by -15% with the creams in comparison with the non-treated side after 3 months. At the end of the study, surface microrelief (-26.5%), skin profilometry (-13%), skin tonicity (+30%) and skin dryness (-59.5%) significantly improved with active treatment. Both products were well tolerated. Conclusion: In women with skin aging, Mel-based creams improved significantly skin tonicity and skin hydration with a significant reduction in skin roughness, supporting the skin antiaging effect of this molecule applied topically. PMID- 29416369 TI - Rationale and design of the VISION study: a randomized, open-label study to evaluate the long-term safety of vonoprazan as maintenance treatment in patients with erosive esophagitis. AB - Erosive esophagitis (EE) occurs when the epithelial mucosa is damaged due to gastric acid reflux, and the incidence of this disease is increasing in Japan due to changes in diet and lifestyle. The condition can be treated using proton pump inhibitors (PPIs) that act by irreversibly blocking the H+,K+-ATPase responsible for acid secretion. Vonoprazan is a K+ competitive channel inhibitor, which reversibly and potently inhibits gastric acid secretion. However, long-term data on vonoprazan use are limited. The aim of the VISION trial is to investigate the long-term efficacy and safety of vonoprazan in comparison with the PPI lansoprazole. This randomized, multicenter, 5-year, open-label study has a planned recruitment of 195 participants (2:1 allocation vonoprazan:lansoprazole) from 33 sites in Japan. The study comprises an 8-week "healing" phase (vonoprazan 20 mg or lansoprazole 30 mg p.o.) and a 260-week "maintenance" phase (vonoprazan 10 mg or lansoprazole 15 mg). Safety populations in both phases are defined as participants who receive at least one dose of the study or control drug in the healing and maintenance phases, respectively. The full analysis set in both phases is defined as participants who are randomized and receive at least one dose of the study or control drug in the healing and maintenance phases, respectively. The primary endpoint of the study is the histopathological evaluation of gastric mucosa for the presence of neoplastic alteration of gastric mucosal epithelial cells. Secondary efficacy endpoints include endoscopic EE recurrence rate and EE healing rate, and secondary safety endpoints include incidence of adverse events (coded using MedDRA terminology) and endoscopic evaluation of malignant changes in the gastric mucosa. Patient recruitment started in March 2016 and is now complete. The estimated study completion date is February 2022. PMID- 29416370 TI - Prolonged-release oxycodone/naloxone reduces opioid-induced constipation and improves quality of life in laxative-refractory patients: results of an observational study. AB - Background: Opioids are an effective treatment for moderate-to-severe pain. However, they are associated with a number of gastrointestinal side effects, most commonly constipation. Laxatives do not target the underlying mechanism of opioid induced constipation (OIC), so many patients do not have their symptoms resolved. Fixed-dose prolonged-release (PR) oxycodone/naloxone (OXN) tablets contain the opioid agonist oxycodone and the opioid antagonist naloxone. Nal-oxone blocks the action of oxycodone in the gut without compromising its analgesic effects. Aim: To evaluate the effectiveness of PR OXN in patients with severe pain who had laxative-refractory OIC with their previous opioid. Methods: The study was carried out in 13 centers across the UK and Ireland, using a bespoke online tool to capture patients' data. Patients were reviewed according to normal clinical practice of each center and rated any changes in their constipation and quality of life (QoL) since starting PR OXN. Any change in patients' laxative use was also recorded. Results: One hundred and seven patients were entered into the database, and 81 went on to attend at least one review. Of these, 54 (66.7%) reported an improvement in constipation and 50 (61.7%) reported an improvement in QoL since starting PR OXN. Fifty-seven patients (70.4%) said they had reduced laxative intake; 48 (59.3%) only needed laxatives as required. Conclusion: PR OXN reduced symptoms of constipation, improved QoL and reduced laxative intake in patients with OIC. It has a potential place early in any treatment strategy for severe pain in patients using opioids, particularly in patients who may be predisposed to constipation. PMID- 29416371 TI - Survey on diabetic patients treated with insulin during the fasting month of Ramadan. AB - Aim: To estimate the proportion of diabetic patients on insulin, who interrupt fasting during Ramadan, and describe the reported reasons of this interruption. Design: This is a national observational survey of diabetic patients treated with insulin and fasting during the month of Ramadan 2013, proposed to all endocrinologists willing to participate. Consecutive patients were included until the required sample size, estimated at 498 patients, was obtained. Conducted among patients recruited by endocrinologists during the month following Ramadan 2013. Results: Five hundred twenty-six (526) patients were included, of which 51 (9.7%) had type 1 diabetes. The mean age was 36.8 +/- 11.6 and 58.3 +/- 10.0 years for type 1 and type 2 diabetes, respectively. The proportions of male subjects were 62.8% and 57.5% for type 1 and type 2 diabetes, respectively. The mean duration of diabetes was 11.0 +/- 8.8 and 14.4 +/- 7.9 years for type 1 and type 2 diabetes, respectively. During Ramadan, more than 55% (54.9% and 55.8% for type 1 and type 2 diabetes, respectively) of patients were treated with insulin analog and over a third with mixed insulin. In this study population, 71.5% reported having fasted without interruption during the month of Ramadan. The average number of non-fasted days was 3.0 +/- 6.7, mainly due to hypoglycemic episodes. Conclusion: According to this observational survey conducted in Tunisia, most patients with diabetes treated with insulin (insulin in more than half of the cases) were able to fast without interruption during Ramadan. PMID- 29416372 TI - Effect of bupivacaine and adjuvant drugs for regional anesthesia on nerve tissue oximetry and nerve blood flow. AB - Background: Nerve blood flow has a critical role in acute and chronic pathologies in peripheral nerves. Influences of local anesthetics and adjuvants on tissue perfusion and oxygenation are deemed as relevant factors for nerve damage after peripheral regional anesthesia. The link between low tissue perfusion due to local anesthetics and resulting tissue oxygenation is unclear. Methods: Combined tissue spectrophotometry and laser-Doppler flowmetry were used to assess nerve blood flow in 40 surgically exposed median nerves in pigs, as well as nerve tissue oximetry for 60 min. After baseline measurements, test solutions saline (S), bupivacaine (Bupi), bupivacaine with epinephrine (BupiEpi), and bupivacaine with clonidine (BupiCloni) were applied topically. Results: Bupivacaine resulted in significant decrease in nerve blood flow, as well as tissue oximetry values, compared with saline control. Addition of epinephrine resulted in a rapid, but nonsignificant, reduction of nerve blood flow and extensive lowering of tissue oximetry levels. The use of clonidine resulted in a reduction of nerve blood flow, comparable to bupivacaine alone (relative blood flow at T60 min compared with baseline, S: 0.86 (0.67-1.18), median (25th-75th percentile); Bupi: 0.33 (0.25-0.60); BupiCloni: 0.43 (0.38-0.63); and BupiEpi: 0.41(0.30-0.54). The use of adjuvants did not result in any relevant impairment of tissue oximetry values (saturation values in percent at T60, S: 91.5 [84-95]; Bupi: 76 [61-86]; BupiCloni: 84.5 [76-91]; and BupiEpi: 91 [56-92]). Conclusion: The application of bupivacaine results in lower nerve blood flow, but does not induce relevant ischemia. Despite significant reductions in nerve blood flow, the addition of clonidine or epinephrine to bupivacaine had no significant impact on nerve tissue oximetry compared with bupivacaine alone. Nerve ischemia due to local anesthetics is not enhanced by the adjuvants clonidine or epinephrine. PMID- 29416373 TI - As if one pain problem was not enough: prevalence and patterns of coexisting chronic pain conditions and their impact on treatment outcomes. AB - Introduction: The presence of multiple coexisting chronic pain (CP) conditions (eg, low-back pain and migraines) within patients has received little attention in literature. The goals of this observational longitudinal study were to determine the prevalence of coexisting CP conditions, identify the most frequent ones and patterns of coexistence, investigate the relationships among patients' biopsychosocial characteristics and number of CP conditions, and determine the impact of coexisting CP conditions on treatment response. Patients and methods: A total of 3,966 patients attending multidisciplinary pain-treatment centers who were enrolled in the Quebec Pain Registry were included. Patients completed self report and nurse-administered questionnaires before their first visit and 6 months later. Results were analyzed using descriptive statistics, factor and cluster analyses, negative binomials with log-link generalized linear models, and linear mixed-effect models. Results: A third of patients reported coexisting CP conditions. No specific patterns of comorbidities emerged. The presence of coexisting CP conditions was associated with longer pain duration, older age, being female, and poorer quality of life. The presence of more than one CP condition did not have a clinically significant impact on treatment responses. Discussion: The novelty of the study results relate to the heterogeneity that was found in the patterns of coexistence of CP conditions and the fact that having multiple CP conditions did not clinically impact treatment response. These results highlight the need for future research that examines causes of coexistence among CP conditions across the spectrum of CP, as opposed to focusing on specific conditions, and to examine whether multiple CP conditions impact on additional domains, such as treatment satisfaction. These results highlight the importance of studying the pathophysiological mechanisms underlying the development of coexisting CP conditions, in order eventually to prevent/minimize their occurrence and/or develop optimal treatment and management approaches. PMID- 29416374 TI - One-step nucleic acid amplification: the possible value in assessing sentinel lymph node metastasis during mastectomy. AB - Breast cancer is the most common cancer in women, worldwide, and 1,400 deaths per day are attributed to it. The success of national screening programs has seen breast cancers being diagnosed at an earlier stage. With conservative surgery to the breast demonstrating equivalent long-term outcomes, the last 10 years have seen a growing interest in the safety of less invasive management for the axilla in breast cancer patients. One-step nucleic acid amplification (OSNA) is a validated, reliable, and efficient tool in identifying micro- and macro metastases intraoperatively. It is the most widely used intraoperative analysis tool within the United Kingdom, and is employed by over 320 units across Europe and Asia. Recent evidence from the AMAROS, IBCSG 23-01, and ACOSOG Z0011 trials has changed surgical practice in managing the axilla of patients with breast cancer. We propose a clinical algorithm demonstrating the role of OSNA as an intraoperative analysis tool in today's management of breast cancer as well as prospects for the future use of OSNA. PMID- 29416376 TI - Treatment and outcomes of non-small-cell lung cancer patients with high comorbidity. AB - Background: The life expectancy of untreated non-small-cell lung cancer (NSCLC) is dismal, while treatment for NSCLC improves survival. The presence of comorbidities is thought to play a significant role in the decision to treat or not treat a given patient. We aim to evaluate the association of comorbidities with the survival of patients treated for NSCLC. Methods: We performed a retrospective study of patients aged >=66 years with invasive NSCLC between the years 2007 and 2011 in the Surveillance, Epidemiology, and End Results Kentucky Cancer Registry. Comorbidity was measured using the Klabunde Comorbidity Index (KCI), and univariate and multivariate logistic regression models were used to measure association between receiving treatment and comorbidity. Kaplan-Meier plots were constructed to estimate time-to-event outcomes. Results: A total of 4014 patients were identified; of this, 94.9% were white and 55.7% were male. The proportion of patients who did not receive any treatment was 8.7%, 3.9%, 19.1%, and 23.5% for stages I, II, III, and IV, respectively (p<0.0001). In multivariate analysis, older age, higher stage, and higher comorbidity (KCI >=3) were associated with a lower likelihood of receiving any treatment. The median overall survival (OS) for untreated and KCI=0 was 17.7 months for stages I and II, 2.3 months for stage III, and 1.3 months for stage IV. The median OS for treated and KCI=0 was 58.9 months for stages I and II, 16.8 months for stage III, and 5.8 months for stage IV (p<0.01). Treatment was an independent predictor of OS in multivariate analysis that included KCI scores. Conclusion: Our data suggest that lung cancer patients may derive a survival benefit from therapies, regardless of the presence of comorbidities, although the degree of benefit seems to decrease with higher KCI scores. PMID- 29416377 TI - Cardiovascular health status among Australian adults. AB - Background: The American Heart Association (AHA) committee recently set a guideline to define and monitor the cardiovascular health status. This study aimed to estimate cardiovascular health status among Australian adults using the guideline. Methods: We used data from a nationally representative sample of 7499 adults (age >=18 years) from 2011 to 2012 Australian Health Survey. We applied the modified AHA's definition to estimate the ideal proportions of the seven metrics and the overall cardiovascular health status. Results: Ideal status was most prevalent for fasting plasma glucose (83.6%) and least observed for dietary pattern (4.8%). The estimated percentage of ideal cardiovascular health was 0.15% in Australian adults. An estimated 0.52% of Australian adults had all four ideal cardiovascular health factors, and 16.38% had all four ideal cardiovascular health behaviors. There exist some age and sex variations for the ideal status of individual metric and the overall cardiovascular health. Conclusion: The percentage of ideal cardiovascular health in Australian adults is extremely low. Public health policies should be implemented to improve the population-wide cardiovascular health status in Australia. PMID- 29416375 TI - Solute carrier transporters: potential targets for digestive system neoplasms. AB - Digestive system neoplasms are the leading causes of cancer-related death all over the world. Solute carrier (SLC) superfamily is composed of a series of transporters that are ubiquitously expressed in organs and tissues of digestive systems and mediate specific uptake of small molecule substrates in facilitative manner. Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies. In this review, we critically summarized the recent advances in understanding the role of SLC proteins in digestive system neoplasms. We highlighted that several SLC subfamilies, including metal ion transporters, transporters of glucose and other sugars, transporters of urea, neurotransmitters and biogenic amines, ammonium and choline, inorganic cation/anion transporters, transporters of nucleotide, amino acid and oligopeptide organic anion transporters, transporters of vitamins and cofactors and mitochondrial carrier, may play important roles in mediating the initiation, progression, metastasis, and chemoresistance of digestive system neoplasms. Proteins in these SLC subfamilies may also have diagnostic and prognostic values to particular cancer types. Differential expression of SLC proteins in tumors of digestive system was analyzed by extracting data from human cancer database, which revealed that the roles of SLC proteins may either be dependent on the substrates they transport or be tissue specific. In addition, small molecule modulators that pharmacologically regulate the functions of SLC proteins were discussed for their possible application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms. PMID- 29416379 TI - Outcome of pregnancy after renal transplantation. AB - Aim: The aim of our study was to compare the outcome of pregnancy in patients who became pregnant within 24 months of renal transplantation and patients who became pregnant more than 24 months after renal transplantation. Materials and methods: The sample population of our prospective cohort study comprised of 44 patients who became pregnant following renal transplantation. In all cases, living donors were used for renal transplantation. The patients were allocated into either group A, which included 24 patients who became pregnant more than 24 months after renal transplantation, or group B, which included 20 patients who inadvertently became pregnant within 24 months of renal transplantation. Serum creatinine and 24-hour urinary protein concentration were measured each trimester. The incidences of preeclampsia and gestational diabetes, the timing and mode of delivery, the rate of preterm labor, and the mean fetal birth weight were determined. Results: The mean gestational ages in groups A and B were 35.8+/-3 weeks and 34.1+/-2.5 weeks, respectively. The mean fetal birth weights in groups A and B were 2,480+/-316 g and 2,284.5+/-262 g, respectively. These differences were statistically significant. The incidence of preterm labor was 45.8% in group A and 55% in group B. Proteinuria was significantly higher in group B during the third trimester of pregnancy. Preeclampsia occurred in 25% of the cases in group A and 30% of the cases in group B; this difference was not statistically significant. Gestational diabetes occurred in 2 out of 24 cases in group A and 2 out of 20 cases in group B. For group A and group B, normal vaginal delivery occurred in 58.3% and 55% of cases, respectively, and cesarean section was performed in 41.6% and 45% of cases, respectively. Conclusion: A longer interval between renal transplantation and pregnancy is associated with better pregnancy outcome. PMID- 29416378 TI - Replacing sedentary time with physical activity: a 15-year follow-up of mortality in a national cohort. AB - Background: Sedentary behavior is associated with health risks in adults. The potential benefits of reducing sedentary time may be dependent not only on decrease per se, but also on the type of activity it replaces. Few longitudinal studies have investigated the effects on mortality when replacing objectively assessed sedentary time with another physical activity (PA) behavior. Objective: To investigate the effects of replacing objectively assessed sedentary time with time in light-intensity PA or moderate-vigorous PA (MVPA) on all-cause mortality, cardiovascular disease (CVD) mortality or cancer mortality in a cohort with 15 years follow-up time. Methods: In total, 851 women and men from the population based Sweden Attitude Behaviour and Change study were included. Time spent sedentary, in light-intensity PA and in MVPA were assessed using an Actigraph 7164 accelerometer. Mortality data were obtained from Swedish registers. Cox proportional hazards models estimated hazard ratios (HR) of mortality with 95% confidence intervals (CI) and isotemporal substitution models were used to estimate the effect of replacing sedentary behavior with PA for the same amount of time. Results: Over a follow-up of 14.2 years (SD 1.9) with 12,117 person years at risk, 79 deaths occurred, 24 deaths from CVD, 27 from cancer, and 28 from other causes. Replacing 30 minutes/day of sedentary time with light intensity PA was associated with significant reduction in all-cause mortality risk (HR: 0.89, 95% CI: 0.81-0.98) and CVD mortality risk (HR: 0.76, 95% CI: 0.63 0.92). Replacing 10 minutes of sedentary time with MVPA was associated with reduction in CVD mortality risk (HR: 0.62, 95% CI: 0.42-0.91). No statistically significant reductions were found for cancer mortality. Conclusion: This statistical modelling study suggests that replacing sedentary time with light intensity PA could have beneficial effect on both all-cause mortality and CVD mortality. Replacing sedentary time with MVPA could reduce CVD mortality. PMID- 29416380 TI - Keratoconus treatment using femtosecond-assisted intrastromal corneal graft (FAISCG) surgery: a case series. AB - We describe an intrastromal corneal graft technique that uses femtosecond laser to create a desirable corneal lenticule with precise diameter, depth, and shape as well as an intra-stromal pocket in keratoconus patients. The technique seems to be a feasible and safe treatment option to treat keratoconic eyes with reference to the irregularity and instability of cornea. The technique can be performed easily and appears safe and effective. At 7 days postoperatively, all eyes were white and quiet, and the grafts were clear. No graft folds or interface complications were observed at the 12-month follow-up using Visante optical coherence tomography. PMID- 29416381 TI - All guns blazing: management and survival of massive valproic acid overdose - case report and literature review. AB - A 51-year-old woman, who intentionally ingested a massive dose of ~60 g of valproic acid which she was using as a mood stabilizer for bipolar affective disorder, presented within 30 minutes of ingestion to the emergency department. The patient was asymptomatic and was immediately started on decontamination therapy with activated charcoal (AC). Drug serum levels, liver functions, and ammonia levels were tested and followed up during treatment. Due to the massive ingestion and continuous rise in serum drug levels, the patient received regular multiple doses of AC, as well as l-carnitine for liver protection. The patient was started on extracorporeal therapy in the form of renal replacement therapy in the intensive care unit (ICU), followed by intermittent hemodialysis. Drug serum levels dropped significantly. Ammonia levels showed improvement with treatment. The patient was discharged from the ICU after 14 days of treatment. She was stable and in good condition with no residual hepatic or central nervous system (CNS) manifestations. PMID- 29416382 TI - High-intensity interval training versus moderate-intensity continuous training within cardiac rehabilitation: a systematic review and meta-analysis. AB - Background: Aerobic capacity has been shown to be inversely proportionate to cardiovascular mortality and morbidity and there is growing evidence that high intensity interval training (HIIT) appears to be more effective than moderate intensity continuous training (MICT) in improving cardiorespiratory fitness within the cardiac population. Previously published systematic reviews in cardiovascular disease have neither investigated the effect that the number of weeks of intervention has on cardiorespiratory fitness changes, nor have adverse events been collated. Objective: We aimed to undertake a systematic review and meta-analysis of randomized controlled trials (RCTs) within the cardiac population that investigated cardiorespiratory fitness changes resulting from HIIT versus MICT and to collate adverse events. Methods: A critical narrative synthesis and meta-analysis was conducted after systematically searching relevant databases up to July 2017. We searched for RCTs that compared cardiorespiratory fitness changes resulting from HIIT versus MICT interventions within the cardiac population. Results: Seventeen studies, involving 953 participants (465 for HIIT and 488 for MICT) were included in the analysis. HIIT was significantly superior to MICT in improving cardiorespiratory fitness overall (SMD 0.34 mL/kg/min; 95% confidence interval [CI; 0.2-0.48]; p<0.00001; I2=28%). There were no deaths or cardiac events requiring hospitalization reported in any study during training. Overall, there were more adverse events reported as a result of the MICT (n=14) intervention than the HIIT intervention (n=9). However, some adverse events (n=5) were not classified by intervention group. Conclusion: HIIT is superior to MICT in improving cardiorespiratory fitness in participants of cardiac rehabilitation (CR). Improvements in cardiorespiratory fitness are significant for CR programs of >6-week duration. Programs of 7-12 weeks' duration resulted in the largest improvements in cardiorespiratory fitness for patients with coronary artery disease. HIIT appears to be as safe as MICT for CR participants. PMID- 29416385 TI - The current practice of mentoring across Accreditation Council of Graduate Medical Education - International accredited programs in Qatar from faculty and trainees perspectives. AB - Purpose: Mentoring plays a vital role in academic productivity, personal development, and career guidance for students, residents, fellows, and junior faculty. A culture of mentoring is spreading across residency and fellowship training programs in Hamad Medical Corporation, the main teaching tertiary care facility in Qatar. However, there is insufficient knowledge about the current practice of mentoring in these programs. Methods: We conducted a cross-sectional study by surveying all faculty and trainees in all residency and fellowship training programs in Qatar. Each completed a web-based questionnaire that asked about the current experience, self-efficacy and measures of improvement of the current practice of mentoring across training programs. Results: A total of 393/650 faculty members (61%), 187/250 fellows (74%), and 405/650 residents (62%) responded to the two surveys. Most (74% of faculty members) reported being current mentors, while 67% of residents and fellows reported that they currently have mentors. Faculty who received training in mentoring and those who had an established formal mentoring program in their departments were more likely to enroll in mentoring than others (86%, P<0.01; 71%, P<0.05%, respectively). Trainees suggested that the two main areas to improve the current mentoring initiative in their departments were to develop a structured mentoring program and to train the mentors. Content analysis revealed participants' confusion differentiating between the terms mentoring and supervision. Conclusion: Based on the current study, many existing mentoring relationships have an evident confusion between supervision and mentoring roles. Developing structured mentoring program and training both faculty and trainees in mentoring is recommended to improve the current practice of mentoring within the training programs. PMID- 29416384 TI - Profile of tocilizumab and its potential in the treatment of giant cell arteritis. AB - Giant cell arteritis (GCA) remains a medical emergency due to the threat of permanent sight loss. High-dose glucocorticoids (GCs) are effective in inducing remission in the majority of patients, however, relapses are common which lengthen GC therapy. GC toxicity remains a major morbidity in this group of patients, and conventional steroid-sparing therapies have not yet shown enough of a clinical benefit to change the standard of care. As the understanding of the underlying immunopathophysiology of GCA has increased, positive clinical observations have been made with the use of IL-6 receptor inhibitor therapies, such as tocilizumab (TCZ). This has led to prospective randomized control trials that have highlighted the safety and efficacy of TCZ in both new-onset and relapsing GCA. PMID- 29416386 TI - Seven new species of the spider genus Ochyrocera from caves in Floresta Nacional de Carajas, PA, Brazil (Araneae, Ochyroceratidae). AB - Seven new species of the spider genus Ochyrocera from cave areas in Floresta Nacional de Carajas (state of Para, northern Brazil) are described: Ochyrocera varyssp. n., Ochyrocera atlachnachasp. n., Ochyrocera laracnasp. n., Ochyrocera aragoguesp. n., Ochyrocera misspidersp. n., Ochyrocera charlottesp. n., and Ochyrocera ungoliantsp. n. Two groups of the species are discussed, the quinquivittata group that include specimens with an apparently bifid retrolateral apophysis in the cymbium of the male palp and the arietina group, here proposed, that include those specimens with an entire cymbium, with no retrolateral apophysis, in the male palp. Although these species were abundant inside caves, the examined specimens do not have troglomorphic characteristics and can be classified as edaphic troglophile species, capable of completing its life cycle in soil, shallow subterranean habitats, or caves. PMID- 29416387 TI - New eurymeline leafhoppers (Hemiptera, Cicadellidae, Eurymelinae) from Eocene Baltic amber with notes on other fossil Cicadellidae. AB - Two new extinct fossil cicadellid taxa from Eocene Baltic amber, representing the subfamily Eurymelinae (sensu lato), are described and illustrated, and their relationships to modern leafhoppers are discussed. Eoidiocerus emarginatusgen. and sp. n. is the oldest known representative of the tribe Idiocerini. The new genus resembles some modern Afrotropical and Indomalayan idiocerine genera but differs in having the gena relatively narrow. Archipedionis obscurusgen. and sp. n., is the first well-preserved fossil representative of Macropsini to be described in detail. Previous reports of this tribe from Baltic amber, while credible, included too little morphological information to assess their relationships. Additional comparative notes are provided for previously described fossil taxa belonging to Idiocerini and Macropsini from the Oligocene of Germany. The new combinations Oncopsis sepultus sepultus (Statz, 1950), comb. n. and Oncopsis sepultus austerus (Statz, 1950), comb. n. are proposed for taxa previously included in Bythoscopus Germar. The previously unplaced cicadellid fossil taxon Priscacutius denticulatus Poinar & Brown, 2018 from mid-Cretaceous Myanmar amber is newly placed in subfamily Signoretiinae, tribe Phlogisini, and represents the oldest known member of this subfamily, the only one known from the fossil record and only the second modern cicadellid subfamily confirmed by direct fossil evidence to have been present during the Cretaceous period. PMID- 29416383 TI - Obstructive sleep apnea: current perspectives. AB - The prevalence of obstructive sleep apnea (OSA) continues to rise. So too do the health, safety, and economic consequences. On an individual level, the causes and consequences of OSA can vary substantially between patients. In recent years, four key contributors to OSA pathogenesis or "phenotypes" have been characterized. These include a narrow, crowded, or collapsible upper airway "anatomical compromise" and "non-anatomical" contributors such as ineffective pharyngeal dilator muscle function during sleep, a low threshold for arousal to airway narrowing during sleep, and unstable control of breathing (high loop gain). Each of these phenotypes is a target for therapy. This review summarizes the latest knowledge on the different contributors to OSA with a focus on measurement techniques including emerging clinical tools designed to facilitate translation of new cause-driven targeted approaches to treat OSA. The potential for some of the specific pathophysiological causes of OSA to drive some of the key symptoms and consequences of OSA is also highlighted. PMID- 29416388 TI - A review of the Madagascan pelican spiders of the genera Eriauchenius O. Pickard Cambridge, 1881 and Madagascarchaea gen. n. (Araneae, Archaeidae). AB - An endemic genus of Madagascan spiders (Araneae, Archaeidae, Eriauchenius) is revised. All 20 species of Eriauchenius are described and keyed, of which 14 are new species: Eriauchenius andriamanelosp. n., Eriauchenius andrianampoinimerinasp. n., Eriauchenius goodmanisp. n., Eriauchenius harveyisp. n., Eriauchenius lukemacaulayisp. n., Eriauchenius milajaneaesp. n., Eriauchenius millotisp. n., Eriauchenius rafohysp. n., Eriauchenius ranavalonasp. n., Eriauchenius rangitasp. n., Eriauchenius rixisp. n., Eriauchenius samasp. n., Eriauchenius wunderlichisp. n., Eriauchenius zirafysp. n. Additionally, six species of the new genus Madagascarchaeagen. n. are described and keyed, of which four are new species: Madagascarchaea fohysp. n., Madagascarchaea lotzisp. n., Madagascarchaea moramorasp. n., Madagascarchaea rabesahalasp. n. Diagnostic characters for the Madagascan and African genera are described, and based on these characters and previous phylogenetic analyses the following species transfers are proposed: Eriauchenius cornutus (Lotz, 2003) to Afrarchaea; Afrarchaea fisheri (Lotz, 2003) and Afrarchaea mahariraensis (Lotz, 2003) to Eriauchenius. Finally, we propose that the distribution of Afrarchaea be restricted to South Africa. While several Madagascan specimens have previously been identified as Afrarchaea godfreyi (Hewitt, 1919), we argue that these are likely misidentifications that should instead be Eriauchenius. PMID- 29416390 TI - Deep-Water Octocorals (Cnidaria, Anthozoa) from the Galapagos and Cocos Islands. Part 1: Suborder Calcaxonia. AB - Thirteen species of deep-water calcaxonian octocorals belonging to the families Primnoidae, Chrysogorgiidae, and Isididae collected from off the Galapagos and Cocos Islands are described and figured. Seven of these species are described as new; nine of the 13 are not known outside the Galapagos region. Of the four species occurring elsewhere, two also occur in the eastern Pacific, one off Hawaii, and one from off Antarctica. A key to the 22 Indo-Pacific species of Callogorgia is provided to help distinguish those species. PMID- 29416391 TI - Description of the last-instar larva and pupa of a leaf-mining hispine - Prionispa champaka Maulik, 1919 (Coleoptera, Chrysomelidae, Cassidinae, Oncocephalini). AB - The last-instar larva and pupa of Prionispa champaka Maulik, 1919 are described and figured in detail. The chaetotaxy of the head, mouthparts, legs, and dorsal and ventral surfaces of the body are given. The larva of P. champaka mine in the leaves of Pollia japonica Thunb. (Commelinaceae) and pupate in the base of the mid-ribs. The adults were also observed feeding on the leaves of Pollia siamensis (Carib.) Faden ex D. Y. Hong. The prominent diagnostic characters of immature stages of other species of the three genera of Oncocephalini (Prionispa, Chaeridiona, and Oncocephala) are discussed. PMID- 29416393 TI - A sibling species of Platythyrea clypeata Forel, 1911 in southeast Asia (Hymenoptera, Formicidae, Ponerinae). AB - A new species of the rarely collected ant genus Platythyrea Roger, 1863 closely related to Platythyrea clypeata Forel, 1911 is described and illustrated based on the worker caste under the name Platythyrea janyaisp. n. This species is distributed in southern Thailand and western Malaysia, while P. clypeata is distributed in Sri Lanka, Vietnam, Laos, and Thailand in the areas north of the Isthmus of Kra. Platythyrea clypeata is newly recorded from Thailand from dead wood on the forest floor. The type series of P. janyai was also collected from rotten wood on the forest floor. PMID- 29416389 TI - Catalogue of Tenebrionidae (Coleoptera) of North America. AB - This catalogue includes all valid family-group (8 subfamilies, 52 tribes, 14 subtribes), genus-group (349 genera, 86 subgenera), and species-group names (2825 species, 215 subspecies) of darkling beetles (Coleoptera: Tenebrionidae) known to occur in North America and their available synonyms. Data on extant, subfossil and fossil taxa are given. For each name the author and year and page number of the description are provided, with additional information (e.g., type species for genus-group names, author of synonymies for invalid taxa) depending on the taxon rank. Several new nomenclatural acts are included. One new genus, Lepidocnemeplatia Bousquet and Bouchard, is described. Spelaebiosis Bousquet and Bouchard [for Ardoinia Ozdikmen, 2004], Blapstinus marcuzzii Aalbu [for Blapstinus kulzeri Marcuzzi, 1977], and Hymenorus campbelli Bouchard [for Hymenorus oculatus Doyen and Poinar, 1994] are proposed as new replacement names. Supporting evidence is provided for the conservation of usage of Tarpela micans (Fabricius, 1798) nomen protectum over Tarpela vittata (Olivier, 1793) nomen oblitum. The generic names Psilomera Motschulsky, 1870 [= Stenomorpha Solier, 1836], Steneleodes Blaisdell, 1909 [= Xysta Eschscholtz, 1829], Ooconibius Casey, 1895 and Euconibius Casey, 1895 [= Conibius LeConte, 1851] are new synonyms (valid names in square brackets). The following 127 new synonymies of species group names, listed in their original combination, are proposed (valid names, in their current combination, placed in square brackets): Bothrasida mucorea Wilke, 1922 [= Pelecyphorus guanajuatensis (Champion, 1884)]; Parasida zacualpanicola Wilke, 1922 [= Pelecyphorus asidoides Solier, 1836]; Stenosides kulzeri Pallister, 1954, Stenosides bisinuatus Pallister, 1954, and Parasida trisinuata Pallister, 1954 [= Pelecyphorus dispar (Champion, 1892)]; Asida favosa Champion, 1884 and Asida similata Champion, 1884 [= Pelecyphorus fallax (Champion, 1884)]; Ologlyptus bicarinatus Champion, 1884 [= Pelecyphorus indutus (Champion, 1884)]; Parasida laciniata Casey, 1912 and Parasida cristata Pallister, 1954 [= Pelecyphorus liratus (LeConte, 1854)]; Parasida esperanzae Wilke, 1922 and Parasida mixtecae Wilke, 1922 [= Pelecyphorus longipennis (Champion, 1884)]; Parasida tolucana Casey, 1912 [= Pelecyphorus scutellaris (Champion, 1884)]; Parasida purpusi Wilke, 1922 [= Pelecyphorus tristis (Champion, 1884)]; Astrotus nosodermoides Champion, 1892 [= Pelecyphorus erosus (Champion, 1892)]; Astrotus seticornis var. humeralis Champion, 1884 [= Pelecyphorus seticornis (Champion, 1884)]; Pactostoma breviuscula Casey, 1912, Pactostoma exoleta Casey, 1912, Pactostoma luteotecta Casey, 1912, Pactostoma monticola Casey, 1912, Pactostoma obtecta Casey, 1912, and Pactostoma sigillata Casey, 1912 [=Pelecyphorus anastomosis (Say, 1824)]; Ologlyptus canus Champion, 1884 and Ologlyptus sinuaticollis Champion, 1884 [= Pelecyphorus graciliformis (Solier, 1836)]; Gonasida elata reducta Casey, 1912, Gonasida elata prolixa Casey, 1912, and Gonasida aucta Casey, 1912 [= Philolithus elatus compar (Casey, 1912)]; Gonasida alaticollis Casey, 1912 [= Philolithus elatus difformis (LeConte, 1854)]; Gonasida gravida Casey, 1912 [= Philolithus elatus elatus (LeConte, 1853)]; Pelecyphorus aegrotus limbatus Casey, 1912 [= Philolithus aegrotus aegrotus (LeConte, 1861)]; Pelecyphorus corporalis Casey, 1912, Pelecyphorus reptans Casey, 1912, Pelecyphorus socer Casey, 1912, Pelecyphorus abscissus Casey, 1912, Pelecyphorus fumosus Casey, 1912, Pelecyphorus parvus Casey, 1912, Pelecyphorus morbillosus pacatus Casey, 1912, Pelecyphorus morbillosus sobrius Casey, 1912, Pelecyphorus piceus Casey, 1912, Pelecyphorus piceus crudelis Casey, 1912, Pelecyphorus snowi Casey, 1912, and Pelecyphorus subtenuis Casey, 1912 [= Philolithus morbillosus (LeConte, 1858)]; Bothrasida sanctae-agnae Wilke, 1922 [= Stenomorpha funesta (Champion, 1884)]; Asida flaccida Horn, 1896 [= Stenomorpha embaphionides (Horn, 1894)]; Asida angustula Casey, 1890, Stethasida stricta Casey, 1912, Stethasida muricatula languida Casey, 1912, Stethasida pertinax Casey, 1912, Stethasida socors Casey, 1912, Stethasida angustula inepta Casey, 1912, Stethasida tenax Casey, 1912, and Stethasida vegrandis Casey, 1912 [= Stenomorpha muricatula (LeConte, 1851)]; Stethasida obsoleta expansa Casey, 1912, Stethasida obsoleta opacella Casey, 1912, Stethasida brevipes Casey, 1912, Stethasida torpida Casey, 1912, Stethasida convergens Casey, 1912, Stethasida discreta Casey, 1912, Stethasida longula Casey, 1912, Stethasida adumbrata Casey, 1912, Stethasida occulta Casey, 1912, Stethasida tarsalis Casey, 1912, Stethasida unica Casey, 1912, and Pelecyphorus laevigatus Papp, 1961 [= Stenomorpha obsoleta (LeConte, 1851)]; Trichiasida eremica Wilke, 1922 [= Stenomorpha difficilis (Champion, 1884)]; Trichiasida lineatopilosa Casey, 1912 [= Stenomorpha hirsuta (LeConte, 1851)]; Trichiasida tenella Casey, 1912 [= Stenomorpha hispidula (LeConte, 1851)]; Trichiasida duplex Casey, 1912 [= Stenomorpha villosa (Champion, 1884)]; Alaudes squamosa Blaisdell, 1919, Alaudes testacea Blaisdell, 1919, and Alaudes fallax Fall, 1928 [= Alaudes singularis Horn, 1870]; Edrotes barrowsi Dajoz, 1999 [=Edrotes ventricosus LeConte, 1851]; Nyctoporis tetrica Casey, 1907 and Nyctoporis maura Casey, 1907 [= Nyctoporis aequicollis Eschscholtz, 1831]; Nyctoporis pullata Casey, 1907 [= Nyctoporis sponsa Casey, 1907]; Eleodes tibialis forma oblonga Blaisdell, 1909 [= Eleodes tibialis Blaisdell, 1909]; Eleodes (manni var.) variolosa Blaisdell, 1917 [= Eleodes constrictus LeConte, 1858]; Eleodes cordata forma sublaevis Blaisdell, 1909, Eleodes cordata forma intermedia Blaisdell, 1909, Eleodes cordata forma oblonga Blaisdell, 1909, Eleodes cordata forma elongata Blaisdell, 1909, and Eleodes (cordata var.) adulterina Blaisdell, 1917 [= Eleodes cordata Eschscholtz, 1829]; Eleodes hornii var. monticula Blaisdell, 1918 and Eleodes manni sierra Blaisdell, 1925 [= Eleodes fuchsii Blaisdell, 1909]; Eleodes parvicollis var. squalida Blaisdell, 1918 [= Eleodes parvicollis Eschscholtz, 1829]; Eleodes reflexicollis Mannerheim, 1843 and Eleodes parvicollis forma farallonica Blaisdell, 1909 [= Eleodes planata Eschscholtz, 1829]; Eleodes indentata Blaisdell, 1935 [= Eleodes rotundipennis LeConte, 1857]; Eleodes intricata Mannerheim, 1843 [= Eleodes scabrosa Eschscholtz, 1829]; Eleodes horni fenyesi Blaisdell, 1925 [= Eleodes tenebrosa Horn, 1870]; Eleodes cordata var. horrida Blaisdell, 1918 [= Eleodes tuberculata Eschscholtz, 1829]; Eleodes oblonga Blaisdell, 1933 [= Eleodes versatilis Blaisdell, 1921]; Eleodes dentipes marinae Blaisdell, 1921 [= Eleodes dentipes Eschscholtz, 1829]; Eleodes carbonaria forma glabra Blaisdell, 1909 [= Eleodes carbonaria carbonaria (Say, 1824)]; Eleodes granosa forma fortis Blaisdell, 1909 [= Eleodes granosa LeConte, 1866]; Eleodes pilosa forma ordinata Blaisdell, 1909 [= Eleodes pilosa Horn, 1870]; Trogloderus costatus pappi Kulzer, 1960 [= Trogloderus tuberculatus Blaisdell, 1909]; Trogloderus costatus mayhewi Papp, 1961 [= Trogloderus vandykei La Rivers, 1946]; Bolitophagus cristatus Gosse, 1840 [= Bolitotherus cornutus (Fabricius, 1801)]; Eleates explanatus Casey, 1890 [= Eleates depressus (Randall, 1838)]; Blapstinus sonorae Casey, 1890 [= Blapstinus brevicollis LeConte, 1851]; Blapstinus falli Blaisdell, 1929 [= Blapstinus castaneus Casey, 1890]; Blapstinus brunneus Casey, 1890 and Blapstinus coronadensis Blaisdell, 1892 [=Blapstinus histricus Casey, 1890]; Blapstinus hesperius Casey, 1890 [=Blapstinus intermixtus Casey, 1890]; Blapstinus cinerascens Fall, 1929 [= Blapstinus lecontei Mulsant and Rey, 1859]; Blapstinus niger Casey, 1890 and Blapstinus cribricollis Casey, 1890 [= Blapstinus pimalis Casey, 1885]; Blapstinus arenarius Casey, 1890 [= Blapstinus pratensis LeConte, 1859]; Blapstinus gregalis Casey, 1890 [= Blapstinus substriatus Champion, 1885]; Blapstinus hydropicus Casey, 1890 [= Blapstinus sulcatus LeConte, 1851]; Blapstinus hospes Casey, 1890 [= Blapstinus vestitus LeConte, 1859]; Notibius reflexus Horn, 1894 [= Conibius opacus (LeConte, 1866)]; Notibius affinis Champion, 1885 [=Conibius rugipes (Champion, 1885)]; Conibius parallelus LeConte, 1851 [= Conibius seriatus LeConte, 1851]; Nocibiotes rubripes Casey, 1895 [=Nocibiotes caudatus Casey, 1895]; Nocibiotes gracilis Casey, 1895 and Nocibiotes acutus Casey, 1895 [=Nocibiotes granulatus (LeConte, 1851)]; Conibius alternatus Casey, 1890 [= Tonibius sulcatus (LeConte, 1851)]; Pedinus suturalis Say, 1824 [= Alaetrinus minimus (Palisot de Beauvois, 1817)]; Menedrio longipennis Motschulsky, 1872 [= Tenebrio obscurus Fabricius, 1792]; Hymenophorus megops Hatch, 1965 and Telesicles magnus Hatch, 1965 [= Hymenorus sinuatus Fall, 1931]; Andrimus concolor Casey, 1891 and Andrimus convergens Casey, 1891 [= Andrimus murrayi (LeConte, 1866)]; Mycetochara marshalli Campbell, 1978 [= Mycetochara perplexata Marshall, 1970]; Phaleria globosa LeConte, 1857 [= Phaleria picta Mannerheim, 1843]. The following subspecies of Trogloderus costatus LeConte, 1879 are given species rank: Trogloderus nevadus La Rivers, 1943, Trogloderus tuberculatus Blaisdell, 1909, and Trogloderus vandykei La Rivers, 1946. The following taxa, previously thought to be junior synonyms, are considered valid: Amphidora Eschscholtz, 1829; Xysta Eschscholtz, 1829; Helops confluens (Casey, 1924). Two new combinations are proposed: Stenomorpha spinimana (Champion, 1892) and Stenomorpha tenebrosa (Champion, 1892) [from the genus Parasida Casey, 1912]. The type species [placed in square brackets] of the following 12 genus-group taxa are designated for the first time: Lagriola Kirsch, 1874 [Lagriola operosa Kirsch, 1874]; Locrodes Casey, 1907 [Emmenastus piceus Casey, 1890]; Falacer Laporte, 1840 [Acanthopus cupreus Laporte, 1840 (= Helops contractus Palisot de Beauvois, 1812)]; Blapylis Horn, 1870 [Eleodes cordata Eschscholtz, 1829]; Discogenia LeConte, 1866 [Eleodes scabricula LeConte, 1858]; Metablapylis Blaisdell, 1909 [Eleodes nigrina LeConte, 1858]; Steneleodes Blaisdell, 1909 [Eleodes longicollis LeConte, 1851]; Scaptes Champion, 1886 [Scaptes squamulatus Champion, 1886 (= Asida tropica Kirsch, 1866)]; Aspidius Mulsant and Rey, 1859 [Blaps punctata Fabricius, 1792]; Cryptozoon Schaufuss, 1882 [Cryptozoon civile Schaufuss, 1882]; Halophalerus Crotch, 1874 [Phaleria rotundata LeConte, 1851]; Dignamptus LeConte, 1878 [Dignamptus stenochinus LeConte, 1878]. Two species previously known from South America [Nilio lebasi J. Thomson and Platydema erotyloides Chevrolat] are reported for the first time from North America. PMID- 29416394 TI - New records of an alien aphid species Tinocallis (Sappocallis) takachihoensis from countries in central and northern Europe (Hemiptera, Aphididae, Calaphidinae). AB - The aphid genus Tinocallis Matsumura, 1919 (Hemiptera: Aphididae: Calaphidinae) in central and northern Europe is reviewed; it includes four species. The first records of the Asian elm aphid Tinocallis takachihoensis Higuchi, 1972 are reported from the Czech Republic, Denmark, and Poland. The record in Denmark is the first in Scandinavia. Alate viviparous females and nymphs of T. takachihoensis were collected from Ulmus glabra "Pendula" (the Czech Republic and Poland) and from U. minor (Denmark) in 2017. Tinocallis takachihoensis is the fourth Tinocallis species to be recorded from Poland and together with two other species from the subgenus Sappocallis, T. nevskyi and T. saltans, is a species of alien origin. The alate viviparous females are reviewed and re-described and their affinities and distribution in central and northern Europe are discussed. A key to the European species of Tinocallis based on the characters of live and slide-mounted specimens is also given. PMID- 29416392 TI - Two new genera of metalmark butterflies of North and Central America (Lepidoptera, Riodinidae). AB - Two new genera of Riodinidae (Insecta: Lepidoptera) are described, Neoapodemia Trujano-Ortega, gen. n. (Neoapodemia nais (W. H. Edwards, 1876), comb. n., N. chisosensis Freeman, 1964, comb. n.) and Plesioarida Trujano-Ortega & Garcia Vazquez, gen. n. (Plesioarida palmerii palmerii (W. H. Edwards, 1870), comb. n., P. palmerii arizona (Austin, [1989]), comb. n., P. palmerii australis (Austin, [1989]), comb. n., P. hepburni hepburni (Godman & Salvin, 1886), comb. n., P. hepburni remota (Austin, 1991), comb. n., P. murphyi (Austin, [1989]), comb. n., P. hypoglauca hypoglauca (Godman & Salvin, 1878), comb. n., P. hypoglauca wellingi (Ferris, 1985), comb. n., P. walkeri (Godman & Salvin, 1886), comb. n., P. selvatica (De la Maza & De la Maza, 2017), comb. n.). Neoapodemia Trujano Ortega, gen. n. is distributed in the southwestern USA and northeastern Mexico, while Plesioarida Trujano-Ortega & Garcia-Vazquez, gen. n. is present from the southern USA to Central America. Species of these genera were previously classified as Apodemia C. Felder & R. Felder but molecular and morphological evidence separate them as new taxa. Morphological diagnoses and descriptions are provided for both new genera, including the main distinctive characters from labial palpi, prothoracic legs, wing venation and genitalia, as well as life history traits. A molecular phylogeny of one mitochondrial gene (COI) and two nuclear genes (EF-1a and wg) are also presented of most species of Apodemia, Neoapodemia Trujano-Ortega, gen. n., Plesioarida Trujano-Ortega & Garcia-Vazquez, gen. n., and sequences of specimens from all tribes of Riodinidae. We compare the characters of Apodemia, Neoapodemia Trujano-Ortega, gen. n. and Plesioarida Trujano-Ortega & Garcia-Vazquez, gen. n. and discuss the differences that support the description of these new taxa. This is a contribution to the taxonomy of the Riodinidae of North America of which the generic diversity is greater than previously recognized. PMID- 29416395 TI - A global checklist of the 932 fruit fly species in the tribe Dacini (Diptera, Tephritidae). AB - The correct application of the scientific names of species is neither easy nor trivial. Mistakes can lead to the wrong interpretation of research results or, when pest species are involved, inappropriate regulations and limits on trade, and possibly quarantine failures that permit the invasion of new pest species. Names are particularly challenging to manage when groups of organisms encompass a large number of species, when different workers employ different philosophical views, or when species are in a state of taxonomic flux. The fruit fly tribe Dacini is a species-rich taxon within Tephritidae and contains around a fifth of all known species in the family. About 10% of the 932 currently recognized species are pests of commercial fruits and vegetables, precipitating quarantines and trade embargos. Authoritative species lists consist largely of scattered regional treatments and outdated online resources. The checklist presented here is the first global overview of valid species names for the Dacini in almost two decades, and includes new lure records. By publishing this list both in paper and digitally, we aim to provide a resource for those studying fruit flies as well as researchers studying components of their impact on agriculture. The list is largely a consolidation of previous works, but following the results from recent phylogenetic work, we transfer one subgenus and eight species to different genera: members of the Bactrocera subgenus Javadacus Hardy, considered to belong to the Zeugodacus group of subgenera, are transferred to genus Zeugodacus; Bactrocera pseudocucurbitae White, 1999, stat. rev., is transferred back to Bactrocera from Zeugodacus; Zeugodacus arisanicus Shiraki, 1933, stat. rev., is transferred back to Zeugodacus from Bactrocera; and Z. brevipunctatus (David & Hancock, 2017), comb. n.; Z. javanensis (Perkins, 1938), comb. n.; Z. montanus (Hardy, 1983), comb. n.; Z. papuaensis (Malloch, 1939), comb. n.; Z. scutellarius (Bezzi, 1916), comb. n.; Z. semisurstyli (Drew & Romig, 2013), comb. n.; and Z. trilineatus (Hardy, 1955), comb. n. are transferred from Bactrocera to Zeugodacus. PMID- 29416396 TI - Updated checklist of the Michigan (USA) caddisflies, with regional and habitat affinities. AB - Based on examination of ~180,000 specimens from 695 collections of 443 localities collected from the 1930s to 2015 we report 295 species of caddisflies from Michigan. Of these, 41 are reported from the state for the first time. Another 18 species previously reported from Michigan are listed as doubtful. The 11 most abundant species collectively represented over half of all specimens collected. Conversely, 80 species were known from <10 specimens, and 27 species from a single specimen. The Michigan fauna is similar to those of Minnesota and Ohio, adjacent states with comparable recent collecting effort. Regional and habitat affinities for each Michigan species are reported herein. Due to the high level of species discovery over the last few years, despite a >80-year collecting history, it is likely that additional species remain undiscovered in the state. PMID- 29416397 TI - A new lineage of braconid wasps in Burmese Cenomanian amber (Hymenoptera, Braconidae). AB - A new braconid wasp from the Upper Cretaceous (Cenomanian) amber of the Hukawng Valley in Kachin State, Myanmar is described and figured from a unique female. Seneciobracon novalatus Engel & Huang, gen. et sp. n., is placed in a distinct subfamily, Seneciobraconinae Engel & Huang, subfam. n., owing to the presence of a unique combination of primitive protorhyssaline-like traits, with an otherwise more derived wing venation. The fossil is discussed in the context of other Cretaceous Braconidae. PMID- 29416398 TI - Revision of the world species of the genus Habroteleia Kieffer (Hymenoptera, Platygastridae, Scelioninae). AB - The genus Habroteleia Kieffer is revised. Seven species are recognized, three are redescribed: H. flavipes Kieffer, H. persimilis (Kozlov & Kononova), H. ruficoxa (Kieffer); and four species are described as new: H. mutabilis Chen & Talamas, sp. n., H. salebra Chen & Talamas, sp. n., H. soa Chen & Talamas, sp. n., and H. spinosa Chen & Johnson, sp. n. Four species are treated as junior synonyms of Habroteleia flavipes Kieffer: Chrestoteleia bakeri Kieffer, syn. n., Habroteleia bharatensis Saraswat, syn. n., Habroteleia browni Crawford, syn. n., and Habroteleia kotturensis (Sharma), syn. n.Habroteleia dagavia (Kozlov & Le), syn. n. is treated as junior synonym of Habroteleia persimilis (Kozlov & Kononova). Baryconus vindhiensis (Sharma), comb. n. is transferred out of Habroteleia Kieffer. Habroteleia impressa (Kieffer) and H. scapularis (Kieffer) remain valid species but their identity and status are unclear. PMID- 29416399 TI - Ten unique and charismatic new species of Microgastrinae wasps (Hymenoptera, Braconidae) from North America. AB - Ten new species within four genera of Microgastrinae parasitoid wasps (Hymenoptera: Braconidae) are described from Canada and United States: Diolcogaster ichiroi, Diolcogaster miamensis, Glyptapanteles pseudotsugae, Microgaster archboldensis, Microgaster syntopic, Microplitis altissimus, Microplitis jorgeluisi, Microplitis juanmanueli, Microplitis julioalbertoi, and Microplitis mariamargaritae. The new taxa are significant because they represent the first North American records of a tropical group (species of the basimacula group in Diolcogaster), exemplify interesting ecological cases (niche-based host selection in Glyptapanteles, syntopic species in Microgaster), and showcase unique morphological features and/or altitudinal records (Microplitis). Most of the new species were collected in protected areas or areas with strong research programs (Archbold Biological Station and hammock forests near Miami, Florida; Great Sand Dunes National Park and Preserve, and Mount Evans Wilderness Area, Colorado; Sapelo Island, Georgia; Tonto National Forest, Arizona), and thus are also of value and interest for conservation and research efforts. PMID- 29416400 TI - The Senticaudata, a suborder of the Amphipoda - A commentary on d'Udekem d'Acoz and Verheye (2017). AB - A response is given to criticisms in a recent paper of the validity of the amphipod suborder Senticaudata. The tacitly assumed status of truth implied in some molecular higher phylogenies is called in to question. PMID- 29416401 TI - On a new species of Amphilochus from deep and cold Atlantic waters, with a note on the genus Amphilochopsis (Amphipoda, Gammaridea, Amphilochidae). AB - Amphilochus manudens and Amphilochopsis hamatus are redescribed based on specimens from the BioIce, Mareano, and IceAGE programmes. The new species Amphilochus anoculussp. n. is described based on material from the IceAGE programme and the preceding BioIce programme; it is separated from the closely related Amphilochus manudens by the absence of eyes, a symmetrically bilobed labrum, four setae on the maxilla 2 outer plate, a rounded corner of epimeral plate 3, and a robust seta at the tip of the telson. There are also clear differences in depth and temperature ranges. Amphilochopsis hamatus is shown to be closely related to Amphilochus manudens and A. anoculus and transferred to Amphilochus s. str. PMID- 29416402 TI - Leucothoe vaderotti, a new Atlantic Leucothoe (Crustacea, Amphipoda) belonging to the "spinicarpa-clade" (Crustacea, Amphipoda). AB - Within the international IceAGE project (Icelandic marine Animals: Genetics and Ecology) some leucothoid amphipods (Crustacea) were collected, among them a rather small new species, belonging to the "Leucothoe spinicarpa-clade." PMID- 29416403 TI - Ampeliscidae (Crustacea, Amphipoda) from the IceAGE expeditions. AB - Ampeliscidae has been recorded extensively from Icelandic waters by many detailed reports. Material collected from the IceAGE (Icelandic marine animals: Genetics and Ecology) 1 and 2 expeditions has resulted in a reasonably expected collection of ampeliscid amphipod species and distributions. However, as seems to be the trend in amphipod systematics, there are ever-present species complexes. Resulting from this, two species new to the genus Haploops are presented. Additionally, a new species and new record and key of the genus Byblisoides is also presented. PMID- 29416405 TI - The first records of Stenobermuda Schultz, 1982 and Tenupedunculus Schultz, 1979 from Australia, with description of two new species from the Great Barrier Reef (Isopoda, Asellota, Stenetriidae). AB - The genera Tenupedunculus Schultz, 1982 and Stenobermuda Schultz, 1979 are recorded for the first time from beyond the Southern Ocean, at the Great Barrier Reef, Australia. Tenupedunculus serrulatussp. n. and Stenobermuda waroogasp. n. are described from Heron Island and Lizard Island respectively, both in the Great Barrier Reef. The genus Tenupedunculus is revised and a new diagnosis presented, with Tenupedunculus virginale Schultz, 1982, T. pulchrum (Schultz, 1982), and T. serrulatussp. n. being retained within the genus, and the remaining species here regarded as Stenetriidae incertae sedis (eight species). PMID- 29416404 TI - Revision of the genus-group Hystricella R. T. Lowe, 1855 from Porto Santo (Madeira Archipelago), with descriptions of new recent and fossil taxa (Gastropoda, Helicoidea, Geomitridae). AB - The genus-group Hystricella R. T. Lowe, 1855 is revised on the basis of conchological, anatomical and genetic characteristics. A new genus Wollastoniagen. n., two recent species, W. jessicaesp. n. and W. klausgrohisp. n., and one recent subspecies, W. jessicae monticolassp. n. are described as new to science, as well as five fossil taxa, H. microcarinatasp. n., W. beckmannisp. n., W. falknerorumsp. n., W. ripkenisp. n., and W. inexpectatasp. n. For Helix vermetiformis R. T. Lowe, 1855, H. leacockiana Wollaston, 1878, H. oxytropis R. T. Lowe, 1831, H. duplicata R. T. Lowe, 1831 and H. oxytropis var. beta subcarinulata Wollaston, 1878 lectotypes are designated. For the taxa Helix bicarinata G. B. Sowerby I, 1824, Helix bicarinata var. beta aucta Wollaston, 1878 and Discula bulverii W. Wood, 1828 neotypes are selected. The taxa aucta and subcarinulata are elevated to specific rank. For the hitherto monospecific (sub-) genus Callina R. T. Lowe, 1855 it is shown that it is not closely related to the genus Discula but to the Hystricella-group and its generic rank is confirmed. The taxon D. bulverii W. Wood, 1828 is transferred from the genus Discula s. str. to the genus Callina. A further fossil taxon C. waldenisp. n. is described as new to science. PMID- 29416406 TI - Ampithoidae (Crustacea, Amphipoda) from New Zealand. AB - Ampithoidae is a family of marine Amphipoda with approximately 230 species, belonging to 16 genera. The family has a worldwide distribution as algal dwellers. So far only five species are known from New Zealand. Recent collections and examination of historic collection material added two new species, which are described herein. An overview of and a key to the New Zealand Ampithoidae is provided. PMID- 29416407 TI - Two new species of the genus Dahlica Enderlein (Lepidoptera, Psychidae) from Korea. AB - The genus Dahlica Enderlein, 1912 is reported for the first time from Korea with two new species: Dahlica (Dahlica) somae Roh & Byun, sp. n. and Dahlica (Dahlica) ochrostigma Roh & Byun, sp. n. Adults and genitalia are illustrated, and DNA barcodes for precise identification of the species are also provided. PMID- 29416408 TI - Fishes of the Cusiana River (Meta River basin, Colombia), with an identification key to its species. AB - The Cusiana River sub-basin has been identified as a priority conservation area in the Orinoco region in Colombia due to its high species diversity. This study presents an updated checklist and identification key for fishes of the Cusiana River sub-basin. The checklist was assembled through direct examination of specimens deposited in the main Colombian ichthyological collections. A total of 2020 lots from 167 different localities from the Cusiana River sub-basin were examined and ranged from 153 to 2970 m in elevation. The highest number of records were from the piedmont region (1091, 54.0 %), followed by the Llanos (878, 43.5 %) and Andean (51, 2.5 %). 241 species distributed in 9 orders, 40 families, and 158 genera were found. The fish species richness observed (241), represents 77.7 % of the 314 estimated species (95 % CI=276.1-394.8). The use of databases to develop lists of fish species is not entirely reliable; therefore taxonomic verification of specimens in collections is essential. The results will facilitate comparisons with other sub-basins of the Orinoquia, which are not categorized as areas of importance for conservation in Colombia. PMID- 29416409 TI - The taxonomic identity of three varieties of Lecanorchis nigricans (Vanilleae, Vanilloideae, Orchidaceae) in Japan. AB - To elucidate the taxonomy of the Lecanorchis nigricans Honda, 1931 species complex, the present study investigated the detailed morphology of three L. nigricans varieties in Japan. While L. nigricans var. patipetala Y.Sawa, 1980 and L. nigricans var. yakusimensis T.Hashim., 1990 have often been treated as synonyms of L. nigricans var. nigricans, the present study demonstrates that the three varieties are morphologically distinct. More specifically, L. nigricans var. nigricans only produces complete cleistogamous flowers and is distinct from the plants currently called "L. nigricans", which are identical to the chasmogamous variety L. nigricans var. patipetala. The other chasmogamous variety L. nigricans var. yakusimensis can be easily distinguished from L. nigricans var. patipetala by its more spatulate tepals and higher cucullate lip. Therefore, the present study provides emended description of the three L. nigricans varieties based on type specimens and specimens collected from type localities. In addition, the isotype specimen of L. nigricans var. patipetala is designated as the lectotype because the holotype has been lost. PMID- 29416410 TI - A new species of Hypodematium (Hypodematiaceae) from China. AB - Hypodematium confertivillosum J.X.Li, F.Q.Zhou & X.J.Li, sp. nov., a new species of Hypodematium from Shandong, China, is described and illustrated. It is similar to H. crenatum (Forssk.) Kuhn & Decken and H. glanduloso-pilosum (Tagawa) Ohwi, but differs greatly from them by its abaxial fronds sparsely covered with rod shaped glandular hairs, its adaxial fronds without rod-shaped glandular hairs and spore reniform, with verrucate processes, surface with distinct finely lamellar rugae ornamentation. The description, photographs and a key to H. confertivillosum as well as their notes are provided. PMID- 29416411 TI - Diagnostics, taxonomy, nomenclature and distribution of perennial Sesuvium (Aizoaceae) in Africa. AB - The taxonomy of perennial Sesuvium species in Africa has been poorly investigated until now. Previously five perennial species of Sesuvium were recognised in Africa (S. congense, S. crithmoides, S. mesembryanthemoides, S. portulacastrum, and S. sesuvioides). Based on the differing number of stamens, S. ayresii is accepted here as being distinct from S. portulacastrum. Field observations in Angola also led the authors to conclude that S. crystallinum and S. mesembryanthemoides are conspecific with S. crithmoides. A new subspecies, Sesuvium portulacastrum subsp. persoonii, is described from West Africa (Cape Verde, Gambia, Guinea-Bissau, Mauritania, Senegal). The molecular phylogeny indicates the position of S. portulacastrum subsp. persoonii within the "American lineage" as a part of the Sesuvium portulacastrum complex which needs further studies. A diagnostic key and taxonomic notes are provided for the six perennial species of Sesuvium found in Africa and recognised by the authors (S. ayresii, S. congense, S. crithmoides, S. portulacastrum subsp. portulacastrum, S. portulacastrum subsp. persoonii, S. verrucosum and the facultatively short-lived S. sesuvioides). The distribution of S. crithmoides, previously considered to be endemic to Angola, is now confirmed for the seashores of Republic of Congo and DR Congo. The American species S. verrucosum is reported for the first time for Africa (the Macaronesian islands: Cape Verde and the Canaries). It is locally naturalised in Gran Canaria, being a potentially invasive species. These findings as well as new records of S. verrucosum from Asia and the Pacific Islands confirm its proneness to transcontinental introduction. Lectotypes of S. brevifolium, S. crithmoides, S. crystallinum and S. mesembryanthemoides are selected. The seed micromorphology and anatomy of the perennial African species is studied. Compared to the seeds of some annual African Sesuvium investigated earlier, those of perennial species are smooth or slightly alveolate. The aril is one-layered and parenchymatous in all species and usually tightly covers the seed. The aril detachments from the seed coat that form a white stripe near the cotyledon area easily distinguish S. verrucosum from other species under study. PMID- 29416412 TI - Taxonomic revision of Pachyptera (Bignonieae, Bignoniaceae). AB - Pachyptera DC. is a small genus of neotropical lianas included in tribe Bignonieae (Bignoniaceae). The genus has a complicated taxonomic history but currently includes species distributed from Belize to Southern Amazon. Pachyptera is characterised by four main synapomorphies, namely, a papery peeling bark, prophylls of the axillary buds organised in a series of three, patelliform glands arranged in lines in the upper portions of the calyx and corolla tube. Furthermore, members of the genus also have stems with four phloem wedges in cross-section and conspicuous extrafloral nectaries between the interpetiolar region and at the petiole apex, although these characters are also shared with other genera of tribe Bignonieae. Here, we present a taxonomic revision of Pachyptera, which includes a complete list of synonyms, detailed morphological descriptions of species and an identification key, as well as information on the habitat, distribution and phenology, nomenclatural notes, taxonomic comments and illustrations of all the species. In addition, we designate three lectotypes, propose one new combination, raise one variety to species status and describe a new species. After these adjustments, a Pachyptera with five well-defined species is recognised. PMID- 29416413 TI - Monograph of Diplachne (Poaceae, Chloridoideae, Cynodonteae). AB - Diplachne P. Beauv. comprises two species with C4 (NAD-ME) photosynthesis. Diplachne fusca has a nearly pantropical-pantemperate distribution with four subspecies: D. fusca subsp. fusca is Paleotropical with native distributions in Africa, southern Asia and Australia; the widespread Australian endemic D. f. subsp. muelleri; and D. f. subsp. fascicularis and D. f. subsp. uninervia occurring in the New World. Diplachne gigantea is known from a few widely scattered, older collections in east-central and southern Africa, and although Data Deficient clearly is of conservation concern. A discussion of previous taxonomic treatments is provided, including molecular data supporting Diplachne in its newer, restricted sense. Many populations of Diplachne fusca are highly tolerant of saline substrates and most prefer seasonally moist to saturated soils, often in disturbed areas. Some populations of Diplachne fusca in southern Asia combine nitrogen-fixation, high salinity tolerance and palatibilty to livestock, which should be pursued with further research for purposes of soil reclamation. Diplachne fusca subsp. uninervia is the most invasive of the subspecies and is becoming weedy in some non-native areas, including in the Old World. This monograph provides detailed descriptions of all taxa, a key to the species and subspecies, geographic distributions and information on the anatomy of leaves, stems, lemmatal micromorphology and discussions of the chromosome numbers. Lectotypes are designated for: Atropis carinata Grisb.; Diplachne acuminata Nash; Diplachne capensis (Nees) Nees var. concinna Nees; Diplachne capensis (Nees) Nees var. obscura Nees, Diplachne capensis (Nees) Nees var. prolifera subvar. minor Nees, Diplachne halei Nash, Diplachne maritima E.P. Bicknel, Diplachne muelleri Benth., Diplachne reverchonii Vasey, Diplachne tectoneticola Backer, Leptochloa imbricata Thurb., Leptochloa neuroglossa Peter, Leptochloa uninervia var. typica fo. abbreviata Parodi, Triodia ambigua R. Br. and Triodia parviflora R. Br. PMID- 29416414 TI - Taxonomic discoveries bridging the gap between our knowledge and biodiversity. PMID- 29416415 TI - Two new species of Trivalvaria (Annonaceae) from northern Myanmar. AB - Trivalvaria rubra and Trivalvaria casseabriae, two new species of Annonaceae from Putao, Kachin State, Myanmar, are here described and illustrated. They are morphologically similar to T. costata and T. macrophylla. The major differences between them are outlined and discussed. A diagnostic key to the species of Trivalvaria is provided. PMID- 29416416 TI - Aristolochia sinoburmanica (Aristolochiaceae), a new species from north Myanmar. AB - Aristolochia sinoburmanica Y.H.Tan & B.Yang, a new species of Aristolochiaceae from Putao, Kachin State, Myanmar, is described and illustrated. According to morphology (strongly curved perianth, 3-lobed limb, as well as 3-lobed gynostemium, anthers 6, adnate in 3 pairs to the base of gynostemium, opposite to the lobes), the species belongs to Aristolochia subgenus Siphisia. It is morphologically similar to A. faviogonzalezii, A. hainanensis, A. tonkinensis, A. saccata and A. xuanlienensis. The major differences between them are outlined and discussed. A detailed description, along with line drawings, photographs, habitat, distribution and conservation status, as well as a comparison to morphologically similar species, are also provided. PMID- 29416417 TI - Gastrodia kachinensis (Orchidaceae), a new species from Myanmar. AB - Gastrodia kachinensis, a new species of Orchidaceae, is described and illustrated from Putao, Kachin State, Myanmar. It is morphologically similar to G. gracilis, presumably its nearest relative, but can be easily distinguished from the latter by having perianth tube with punctate outer surface, verrucose outer surface of sepal lobe, orbicular petals, ovate-elliptic lip with truncate apex and auriculate-clawed base, glabrous lip apex with a pair of twin protuberance-like lamellae and column with a pair of blade-like lateral wings and acute stelidia at apex. Identification key and colour photographs are provided. A preliminary risk of-extinction assessment, according to the IUCN Red List Categories and Criteria, is given for the new species. PMID- 29416418 TI - Dendrobium naungmungense (Orchidaceae, Dendrobieae), a new species from Kachin State, Myanmar. AB - Dendrobium naungmungense, a new species from Naungmung, Kachin State, North Myanmar, is described and illustrated. It is morphologically similar to D. ciliatilabellum and D. vexabile, but the epichile is oblong with three long ciliate laminae and the column wing has significant denticulation. A preliminary risk-of-extinction assessment shows that the new species should be regarded as Critically Endangered (CR) according to the IUCN Red List Categories and Criteria. PMID- 29416419 TI - Molecular systematics and the evolution of mycoheterotrophy of tribe Neottieae (Orchidaceae, Epidendroideae). AB - Neottieae comprise about 150-200 species and are distributed mainly in temperate and subtropical zones of the northern hemisphere. Mycoheterotrophy is common in Neottieae. Based on three DNA markers and a broad sampling of Neottieae, these results indicate that Neottieae is strongly supported as monophyletic and Palmorchis is sister to the remaining genera of Neottieae. Holopogon and Neottia s.s. are deeply nested within Listera. The habit of leafless mycotrophy has independently evolved at least three times in Neottieae, one in Cephalanthera, another in Neottia s.l. and the third in the clade formed by Limodorum and Aphyllorchis. PMID- 29416420 TI - Hedychium putaoense (Zingiberaceae), a new species from Putao, Kachin State, Northern Myanmar. AB - Hedychium putaoense Y.H. Tan & H.B. Ding, a new species of Zingiberaceae from Putao, Kachin state, Northern Myanmar, is described and illustrated. It is similar to H. densiflorum Wall. and H. longipedunculatum A.R.K. Sastry & D.M. Verma, but differs by its very small bract (4-6 * 2.5-3 mm vs. 18-19 * 5-5.5 mm and ca. 11 * 7 mm, respectively), semicircle and dark red bracteole, orange flower and broadly falcate to lanceolate lateral staminodes. PMID- 29416421 TI - Rediscovery and amended descriptions of Begonia kingdon-wardii (Begoniaceae) from North Myanmar. AB - Begonia kingdon-wardii Tebbitt was rediscovered in 2014 from Myanmar after 67 years based on its last collection in 1937. Its previously unknown female flower and inaccurate morphology of leaf and ovary have been additionally described. This species belongs to Begonia sect. Sphenanthera (Hassk.) Warb. due to its dioecious habit, 3-locular ovary, berry fruits and thick placenta segments. Morphologically, it is similar to Begonia gulinqingensis S. H. Huang & Y. M. Shui in the leaf shape, placentation and fruit shape, but different in its dioecious plants, pliciform leaves, two-petalled female flowers and berry fruits. The rediscovery of this amazing living species will attract significant interest for scientific research and horticultural application. PMID- 29416422 TI - Seven new species of Begonia (Begoniaceae) in Northern Vietnam and Southern China. AB - Since 2016, KIB (Kunming Institute of Botany) and CPC (Centre for Plant Conservation of Vietnam) have conducted several surveys in the transboundary karst regions in Northern Vietnam and Southern China and seven new species in the genus Begonia Linn. (Begoniaceae) are firstly described. Amongst them, two species, Begonia albopunctata Y.M. Shui, W.H. Chen & H.Q. Nguyen and B. erectocarpa H.Q. Nguyen, Y.M. Shui & W.H. Chen, respectively belong to section Sphenanthera with berry fruits and section Leprosae with clavate berry fruits; four species, B. gulongshanensis Y.M. Shui & W. H. Chen, B. minissima H.Q. Nguyen, Y.M. Shui & W.H. Chen, B. mollissima Y.M. Shui, H.Q. Nguyen & W.H. Chen, B. rhytidophylla Y.M. Shui & W.H. Chen, belong to section Coelocentrum with parietal placentation; one species, Begonia bambusetorum H.Q. Nguyen, Y.M. Shui & W.H. Chen, belongs to section Diploclinium with 3-loculed ovary and capsules. The diagnostic characters of these species are described and illustrated in the text and photographs. PMID- 29416423 TI - Didymocarpus puhoatensis (Gesneriaceae), a new species from Vietnam. AB - Didymocarpus puhoatensis, a new species from Vietnam is described and illustrated with photographs. The new species is morphologically similar to D. brevicalyx and D. epithemoides, but can be easily distinguished by a combination of characters. So far, five species have been recorded in the genus Didymocarpus from Vietnam. PMID- 29416425 TI - Primulina malipoensis (Gesneriaceae), a new species from Sino-Vietnamese border area. AB - Primulina malipoensis, a new species from limestone areas around the Sino Vietnamese border, is described and illustrated. This new species is morphologically similar to P. maguanensis and P. lungzhouensis, but obviously differs from the latter two species by its pale greenish-yellow flowers (vs. purple, with different colour patterns). The phylogenetic affinity, illustration and photographs of this new species are provided in this paper. PMID- 29416424 TI - Two new species of Oreocharis (Gesneriaceae) from Fan Si Pan, the highest mountain in Vietnam. AB - Two new species of Oreocharis Benth. from Fan Si Pan, the highest mountain in Vietnam (Sa Pa) are described and illustrated. Oreocharis grandiflora W.H.Chen, Q.H.Nguyen & Y.M.Shui, is similar to O. flavida Merr. from Hainan province, China, but differs mainly by its larger and infundibuliform corolla, stamens adnate to the base of the corolla tube and stamens coherent in two pairs. The second, Oreocharis longituba W.H.Chen, Q.H.Nguyen & Y.M.Shui, is similar to O. hirsuta Barnett, endemic to northern Thailand, but mainly differs in its pubescence, coherent stamens and glabrous filaments. PMID- 29416426 TI - Premna grandipaniculata (Lamiaceae, Premnoideae), a remarkable new species from north Myanmar. AB - A remarkable new Premna species from Myanmar, P. grandipaniculata Y.H.Tan & Bo Li (Lamiaceae), is here described and illustrated. It differs from all known congeneric taxa by having huge complicated panicles which have tertiary branches formed by spike-like thyrses. In Premna, such a spike-like thyrse is found in P. bracteata and P. interrupta, but those species can be easily distinguished from P. grandipaniculata by their habit, indumentum, leaf size and inflorescence structure. PMID- 29416427 TI - A second contender for "world's smallest fly" (Diptera: Phoridae). AB - Background: Flies of the family Phoridae (Insecta: Diptera) are amongst the most diverse insects in the world, with an incredible array of species, structures and life histories. Wiithin their structural diversity is the world's smallest fly, Euryplatea nanaknihali Brown, 2012. New information: A second minute, limuloid female phorid parasitoid fly (Diptera: Phoridae) is described. Known from a single specimen from a site near Manaus, Brazil, Megapropodiphora arnoldigen. n., sp. n. is only 0.395 mm in body length, slightly smaller than the currently recognised smallest fly, Euryplatea nanaknihali from Thailand. The distinctive body shape of M. arnoldi, particularly the relatively enormous head, mesothorax and scutellum, the latter of which covers most of the abdomen, easily separates it from other described phorids. Most remarkably, the forelegs are extremely enlarged, whereas mid- and hind legs are reduced to small, possibly vestigial remnants. A possible male specimen, unfortunately destroyed during processing, is briefly described. PMID- 29416428 TI - A dataset on the species composition of amphipods (Crustacea) in a Mexican marine national park: Alacranes Reef, Yucatan. AB - Background: Alacranes Reef was declared as a National Marine Park in 1994. Since then, many efforts have been made to inventory its biodiversity. However, groups such as amphipods have been underestimated or not considered when benthic invertebrates were inventoried. Here we present a dataset that contributes to the knowledge of benthic amphipods (Crustacea, Peracarida) from the inner lagoon habitats from the Alacranes Reef National Park, the largest coral reef ecosystem in the Gulf of Mexico. The dataset contains information on records collected from 2009 to 2011. Data are available through Global Biodiversity Information Facility (GBIF). New information: A total of 110 amphipod species distributed in 93 nominal species and 17 generic species, belonging to 71 genera, 33 families and three suborders are presented here. This information represents the first online dataset of amphipods from the Alacranes Reef National Park. The biological material is currently deposited in the crustacean collection from the regional unit of the National Autonomous University of Mexico located at Sisal, Yucatan, Mexico (UAS-Sisal). The biological material includes 588 data records with a total abundance of 6,551 organisms. The species inventory represents, until now, the richest fauna of benthic amphipods registered from any discrete coral reef ecosystem in Mexico. PMID- 29416429 TI - Vocabulary size and speed of word recognition in very young French-English bilinguals: A longitudinal study. AB - A longitudinal study of lexical development in very young French-English bilinguals is reported. The Computerized Comprehension Test (CCT) was used to directly assess receptive vocabulary and processing efficiency, and parental report (CDI) was used to measure expressive vocabulary in monolingual and bilingual infants at 16 months, and six months later, at 22 months. All infants increased their comprehension and production of words over the six-month period, and bilingual infants acquired approximately as many new words in each of their languages as the monolinguals did. Speed of online word processing was also equivalent in both groups at each wave of data collection, and increased significantly across waves. Importantly, significant relations emerged between language exposure, vocabulary size, and processing speed, with proportion of language exposure predicting vocabulary size at each time point. This study extends previous findings by utilizing a direct measure of receptive vocabulary development and online word processing. PMID- 29416430 TI - lncRNA in HNSCC: challenges and potential. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer mortality in the world. Some progress has been made in the therapy of HNSCC, however treatment remains unsatisfactory. Recent studies have shown that different types of long non-coding RNAs (lncRNAs) are dysregulated in HNSCC and correlate with tumor progression, lymph node metastasis, clinical stage and poor prognosis. lncRNAs are a class of functional RNA molecules that can not be translated into proteins but can modulate the activity of transcription factors or regulate changes in chromatin structure. The lncRNAs might have potential of biomarker in HNSCC diagnosis, prognosis, prediction and targeted treatment. In this review we describe the potential role of lncRNAs as new biomarkers and discuss their features including source of origin, extraction methods, stability, detection methods and data normalization and potential function as biomarkers in HNSCC. PMID- 29416432 TI - Radioembolization treatment for liver metastases. AB - The liver is an organ that, due to vascularisation and functions, is prone to metastases. Most liver metastases are observed in cases of gastrointestinal cancers in: stomach, colon, gallbladder, and bile ducts. Metastatic lesions are also observed in lung, breast, thyroid, kidney, and pancreatic cancer. One of the best known and most effective ways of liver lesion treatment is Metastasectomy. Unfortunately, lesions are frequently inoperable. Apart from chemotherapy, it is possible to apply local treatment such as TACE (trans-arterial chemoembolisation), RFA (Radio Frequency Ablation), and SBRT (Stereotactic Body Radiation Therapy). One of the newest methods of inoperable lesion treatment is radioembolisation (SIRT). Intravascular administration of microspheres containing radioisotope 90Y allows delivery of a higher dose of radiation directly to the tumour than traditional radiation with an external beam, while maintaining a small dose to healthy liver methods. Conducted clinical studies confirm the efficacy and safety of SIRT. It is an interesting alternative to other ways of treatment. PMID- 29416431 TI - Immunophenotypic features of dedifferentiated skull base chordoma: An insight into the intratumoural heterogeneity. AB - Chordomas are rare and low-grade malignant solid tumours, despite their histologically benign appearance, that arise in the bone from embryonic notochordal vestiges of the axial skeleton, a mesoderm-derived structure that is involved in the process of neurulation and embryonic development. Chordomas occurring in the skull base tend to arise in the basiocciput along the clivus. Three major morphological variants have been described (classical, chondroid, and atypical/dedifferentiated). The pathogenesis and molecular mechanisms involved in chordoma development remain uncertain. From a pathological standpoint, the microenvironment of a chordoma is heterogeneous, showing a dual epithelial mesenchymal differentiation. These tumours are characterised by slow modality of biologic growth, local recurrence, low incidence of metastasis rates, and cancer stem cell (CSC) phenotype. The main molecular findings are connected with brachyury immunoexpression and activation of the downstream Akt and mTOR signalling pathways. The differentiation between typical and atypical chordomas is relevant because the tumoural microenvironment and prognosis are partially different. This review provides an insight into the recent and relevant concepts and histochemical markers expressed in chordomas, with special emphasis on dedifferentiated chordomas and their prognostic implications. PMID- 29416433 TI - Comparative genomic analysis of intracranial germ cell tumors - the preliminary study focused on Sonic Hedgehog signaling pathway. AB - Aim of the study: Examination of copy number changes in a group of intracranial germ cell tumors (GCTs) with particular focus on putative aberrations of the main genes coding SHh pathway proteins. Material and methods: The study was performed on DNA isolated from fresh-frozen tumor tissue samples from eight GCTs, including six intracranial GCTs. The intracranial group consisted of three germinomas, two mature teratomas and one mixed germ cell tumor. Comparative genomic profiling analysis was carried out using microarray-CGH method (Cytosure ISCA UPD 4*180k, OGT). The results were analyzed with Feature Extraction (Agilent Technologies) and Nexus Copy Number (BioDiscovery) softwares. Results and conclusions: Chromosomal aberrations were found in two intracranial germinomas. These tumors were characterized by complex genomic profiles encompassing chromosomes 7, 8, 9, 10, 11, 12, 16, 17 and 19. Common findings were gain at 12p13.33p11.1 of 35 Mbp and gain at 17q11.1q25.3 of 55 Mbp. In one tumor, also SHh (7q36.3), SMO (7q32.1) and GLI3 (7p14.1) copy gains occurred together with 9q21.11q34.3 loss, including PTCH1, all being elements of SHh signaling pathway. Moreover, both tumors showed various copy gain of genes being ligands, regulators, receptors or target genes of SHh (MTSS1; PRKACA and FKBP8) as well as gain of genes of SHh coopting WNT pathway (WNT3, WNT5B, WNT9B in both tumors; WNT16, WNT2 in pineal lesion). Further studies on larger group are needed to characterize SHh-related gene alterations in intracranial GCTs and for searching genotype-phenotype relations. PMID- 29416434 TI - The analysis of the long-term outcomes of sorafenib therapy in routine practice in imatinib and sunitinib resistant gastrointestinal stromal tumors (GIST). AB - Aim of the study: was to analyze the outcome of treatment and factors predicting results of sorafenib therapy in inoperable/metastatic CD117-positive GIST patients after failure on imatinib and sunitinib. Material and methods: We identified 60 consecutive patients (40 men, 20 women) with advanced inoperable/metastatic GIST after failure on at least imatinib and sunitinib treated in one sarcoma center with sorafenib at initial dose 2 * 400 mg daily in 2007-2015 (in 56 cases it was 3rd line therapy). Median follow-up time was 39 months. Results: One year progression-free survival (PFS; calculated from the date of the start of sorafenib to disease progression) rate was 23% and median PFS = 7.7 months. The median overall survival (OS) was 13.5 months calculated from sorafenib start (1-year OS rate = 57%) and 7 years from imatinib start. Three patients (5%) had objective partial responses to therapy, 31 patients (52%) had stabilization of disease > 4 months. Primary tumor mutational status was known in 43 cases (73%), but we have not identified the differences in PFS between tumors carrying different KIT/PDGFRA mutations. The most common adverse events were: diarrhoea, hand and foot syndrome, fatigue, loss of weight and skin reactions; grade 3-5 toxicity occurred in 35% of patients. 23 patients required sorafenib dose reductions due to AEs. Conclusions: We confirmed that many advanced GIST patients benefit from sorafenib therapy after imatinib/sunitinib failure with OS > 1 year. PMID- 29416435 TI - A specific controlled ovarian stimulation (COS) protocol for fertility preservation in women with breast cancer undergoing neoadjuvant chemotherapy. AB - Aim of the study: The authors present a novel and specific controlled ovarian stimulation protocol for fertility preservation in women with estrogen-positive receptor breast cancer undergoing neoadjuvant chemotherapy. The protocol foresees random start ovarian stimulation and the use of letrozole associated to tamoxifen. Material and methods: Forty breast cancer patients were included in the study. COS was performed either with recombinant FSH or hMG. Concomitantly with COS, letrozole in a dose of 5 mg and tamoxifen in a dose of 20 mg were given orally on a daily basis. The trigger was performed with 0.2 mg of triptorelin, in the presence of follicles >= 19 mm. Oocyte retrieval was scheduled 35-36 hours after triptorelin injection. Our main outcome measures were the number of oocytes collected and number of oocytes vitrified, the length of ovarian stimulation, total dose of gonadotropins administered, and levels of estradiol on the day of the trigger. Results: The mean age of patients was 30.43 +/-4.25 years. Nineteen women commenced COS in the luteal phase, eleven in the early follicular phase and ten in the late follicular phase. The mean number of collected oocytes was 11.78 +/-9.12 and the mean number of vitrified oocytes was 9.72 +/-7.36. The mean duration of COS was 10.03 +/-1.33 days. The mean estradiol concentrations on the triggering day was 623.10 +/-441.27, and the mean dose of gonadotropins administered was 2540 +/-713.10. Conclusions: The authors suggest that the protocol is efficient and may be a safe option for oocyte vitrification in these patients. PMID- 29416436 TI - Analysis of information received during treatment and adherence to tamoxifen in breast cancer patients. AB - This study examines whether women with breast cancer, who are adherent and non adherent to tamoxifen, differ in their perceptions of information received during treatment. This cross-sectional study included women receiving tamoxifen as adjuvant treatment for breast cancer recruited from a teaching hospital specialised in women's health in the state of Sao Paulo (Brazil). Women were interviewed and their records were reviewed for socio demographic data and clinical characteristics. We assessed tamoxifen adherence using the Morisky-Green Test, and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Information module (EORTC QLQ-INFO25) was used to evaluate the information received by the women. The sample contained 31 women (mean age = 55.4; SD = 11.6 years). According to the Morisky-Green Test, 74.2% of the women had suboptimal tamoxifen adherence. The global score for women's perceptions of information they received about the treatment and disease was 57.0 +/-19.1 on a scale of 0 to 100, and no significant differences in scores were observed between adherents and non-adherents. A high prevalence of suboptimal tamoxifen adherence was observed. We found no significant differences between women with breast cancer who were adherent and non-adherent to tamoxifen. PMID- 29416438 TI - Solitary breast cancer metastasis to pelvic bone treated with a unique method of surgery combined with local doxorubicin administration. AB - Treatment of bone metastasis is a major challenge for current and future orthopedic and oncology specialists. For the treatment of single metastases, there is a continuing search for effective local treatments that do not affect the whole patient. The current report describes the case of single breast cancer metastasis to the pelvic bone in a 50-year-old woman treated surgically by bone osteotomy combined with local doxorubicin application. The presence of cancer cells was confirmed by histopathological examination. After 6 months, the same defect was operated on again and a successful therapeutic result was confirmed by negative tumor pathology tests. The bone defect caused by osteotomy was reconstructed with allogenic bone grafts that healed completely over 14 months. To the best of our knowledge, this report is the first to combine the removal bone metastasis with direct local cytostatic drug administration without the use of a specific carrier, followed by successful bone reconstruction 6 months later using bone allografts. Thus, single bone metastasis may be successfully treated with resection and local cytostatic administration, enabling bone reconstruction in the postoperative period. The potential benefits of such treatments must be evaluated by considering the potential risks involved, including necrosis of surrounding soft tissues and general reactions to the chemotherapy. No data has been available until now regarding the risk of cancer disease generalization being influenced by such treatments, but patient quality of life can be improved significantly by the successful removal of a solitary bone metastasis. The present case report supports the continuation of research on improving local cytostatic drug administration during the treatment of bone metastasis. PMID- 29416437 TI - Efficacy of palifermin on oral mucositis and acute GVHD after hematopoietic stem cell transplantation (HSCT) in hematology malignancy patients: a meta-analysis of trials. AB - Aim of the study: Herein, this meta-analysis study evaluated the efficacy of palifermin after HSCT on the incidence and severity of OM or aGVHD in hematologic malignancy patients in randomized clinical trials (RCTs). Materials and methods: To compare the efficacy of palifermin on adverse events, OM and aGVHD compared with placebo, we searched databases of PubMed/Medline, Web of Science and Cochrane Library for RCTs based on a number of criteria. Results: There was no difference observed in the incidence of OM and aGVHD between two groups. The subgroup analysis didn't show significant differences in two groups for aGVHD grade 2-4 (odds ratio [OR] = 1.54, 95% confidence interval (CI): 0.70-3.39, p = 0.28), aGVHD grade 3-4 (OR = 0.97, 95% CI: 0.48-1.94, p = 0.92), OM grade 2-4 (OR = 0.76, 95% CI: 0.42-1.38, p = 0.37) and OM grade 3-4 (OR = 0.54, 95% CI: 0.25 1.15, p = 0.11], but erythema as an adverse effect in palifermin group was higher than placebo group (OR = 1.86, 95% CI: 1.10-3.15, p = 0.02]. Conclusions: This meta-analysis of six clinical trials found no statistically significant difference in OM and aGVHD grades in patients receiving 60 MUg/kg/day dose of palifermin compared with those receiving a placebo. However, oral mucosal erythema was more prevalent among patients receiving palifermin than patients receiving a placebo. PMID- 29416440 TI - Parents' time with a partner in a cross-national context: A comparison of the United States, Spain, and France. AB - BACKGROUND: Time shared with a partner is an indicator of marital well-being and couples want to spend time together. However, time with a partner depends on work and family arrangements as well as the policies, norms, and values that prevail in society. Contrary to time spent with children, couples' shared time in cross national context is relatively unstudied. Previous studies from specific countries show that dual-earner couples spend less time together and that parents spend less time alone together. OBJECTIVE: The aim of our study is to investigate partnered parents' shared time across countries to understand how social conditions, cultural norms, and policy contexts are related to the amount and nature of couples' shared time. Specifically, we compare time with a partner in the US, France, and Spain. METHODS: We use data from national time use surveys conducted in the US, France, and Spain. We leverage information about with whom activities are done to examine three types of time shared with a partner for parents with children under age 10: total time with a partner indicates the minutes per day spent in the presence of a partner; exclusive time corresponds to the minutes per day spent alone with a partner when no one else is present; and family time indicates the minutes per day spent with a partner and a child at the same time. RESULTS: Our results show that American couples spend the least time together, and Spanish couples spend the most time together. Parents in France spend the most time alone together. The most striking difference across countries is in time with a partner and children, which is much higher among Spanish families. CONCLUSION: Paid work constraints explain a small part of the differences in couples' shared time that we observe between countries. Differences in couples' shared time across countries seem to be related to social norms surrounding family and general time use. PMID- 29416439 TI - Pure hepatocellular carcinoma originates from an ectopic liver nodule located in the pancreas. AB - Ectopic liver (EL) is a rare congenital abnormality, which is localised most commonly in the wall of the gallbladder. Histoarchitectural abnormalities, which lead to impaired transfer of blood and bile, as well as well demarcation, are characteristic features of ectopic liver nodules. Both features may explain the discrepancies between hepatocellular carcinoma (HCC) cases originating from ectopic liver in comparison to HCC cases originating from orthotopic liver: the strong propensity of ectopic liver to the development of HCC. The latter feature may be linked to the better treatment prognosis in patients with HCC originating from ectopic liver tissue in comparison to those with HCC within orthotopic liver. In this paper, we discuss these differences based on a unique case of pure HCC, which developed in a small ectopic liver nodule in the pancreas. PMID- 29416441 TI - C-Phycocyanin exerts anti-cancer effects via the MAPK signaling pathway in MDA-MB 231 cells. AB - Background: Triple-negative breast cancer is a biological subtype of breast cancer, which is unresponsive to conventional chemotherapies and has a poor prognosis. C-Phycocyanin (C-PC), a marine natural purified from Spirulina platensis, has been investigated that has anti-cancer function. The mitogen activated protein kinase (MAPK) pathway plays a crucial role in the development and progression of cancer. Therefore, we would like to study the anti-cancer effects of C-phycocyanin in the treatment of triple-negative breast cancer, and explore the role of MAPK pathway in the anti-tumor effects of C-phycocyanin. Methods: Cell proliferation, cell cycle, cell apoptosis and cell migration were explored in breast cancer MDA-MB-231 cell lines. AKT, MAPK and membrane death receptor signaling were evaluated in MDA-MB-231 cell lines. Results: Our study indicated that C-phycocyanin inhibited cell proliferation and reduced colony formation ability of MDA-MB-231 cells. Furthermore, C-phycocyanin induced cell cycle G0/G1 arrest by decreasing protein expression levels of Cyclin D1 and CDK-2 and increasing protein expression levels of p21 and p27. In addition, C phycocyanin induced cell apoptotic by activating cell membrane surface death receptor pathway. Besides, C-phycocyanin down-regulated the protein expression levels of cyclooxygenase-2, and further inhibited MDA-MB-231 cells migration. We also found cell death induced by C-phycocyanin was carried through the MAPK signaling pathways. C-Phycocyanin was able to induce MDA-MB-231 cell apoptosis by activating p38 MAPK and JNK signaling pathways while inhibiting ERK pathway. Conclusions: C-Phycocyanin exerted anti-cancer activity via the MAPK signaling pathway in MDA-MB-231 cells. PMID- 29416442 TI - Young people's differential vulnerability to criminogenic exposure: Bridging the gap between people- and place-oriented approaches in the study of crime causation. AB - The overall purpose of this study is to contribute to bridging the gap between people- and place-oriented approaches in the study of crime causation. To achieve this we will explore some core hypotheses derived from Situational Action Theory about what makes young people crime prone and makes places criminogenic, and about the interaction between crime propensity and criminogenic exposure predicting crime events. We will also calculate the expected reduction in aggregate levels of crime that will occur as a result of successful interventions targeting crime propensity and criminogenic exposure. To test the hypotheses we will utilize a unique set of space-time budget, small area community survey, land use and interviewer-led questionnaire data from the prospective longitudinal Peterborough Adolescent and Young Adult Development Study (PADS+) and an artificial neural network approach to modelling. The results show that people's crime propensity (based on their personal morals and abilities to exercise self control) has the bulk of predictive power, but also that including criminogenic exposure (being unsupervised with peers and engaged in unstructured activities in residential areas of poor collective efficacy or commercial centres) demonstrates a substantial increase in predictive power (in addition to crime propensity). Moreover, the results show that the probability of crime is strongest when a crime-prone person is in a criminogenic setting and, crucially, that the higher a person's crime propensity the more vulnerable he or she is to influences of criminogenic exposure. Finally, the findings suggest that a reduction in people's crime propensity has a much bigger impact on their crime involvement than a reduction in their exposure to criminogenic settings. PMID- 29416443 TI - Low-energy Bluetooth for detecting real-world penetrance of bystander naloxone kits: a pilot study. AB - Opioid overdose is a growing public health emergency in the United States. The antidote naloxone must be administered rapidly after opioid overdose to prevent death. Bystander or "take-home" naloxone programs distribute naloxone to opioid users and other community members to increase naloxone availability at the time of overdose. However, data describing the natural history of take-home naloxone in the hands of at-risk individuals is lacking. To understand patterns of naloxone uptake in at-risk users, we developed a smart naloxone kit that uses low energy Bluetooth (BLE) to unobtrusively detect the transit of naloxone through a hospital campus. In this paper, we describe development of the smart naloxone kit and results from the first 10 participants in our pilot study. PMID- 29416444 TI - Vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract: an evidence-based review of safety, efficacy, and place in therapy. AB - Background: A systematic review and meta-analysis of the use of systemic vinflunine (VIN) in the treatment of urothelial carcinoma (UC) was performed to evaluate its efficacy based on current available clinical data. Methods: This review was prospectively registered at the International Prospective Register of Systematic Reviews, PROSPERO (registration CRD42016049294). Electronic databases including MEDLINE(r), Embase(r), Cochrane Central Register of Controlled Trials, and Web of Science were searched through December 2016. We performed a meta analysis of the published data. Primary end points were progression-free survival (PFS) and overall survival (OS). Numerous secondary clinical outcomes were analyzed including response and toxicity data. Results: We identified 382 publications, of which 35 met inclusion criteria for this review representing 29 unique studies. A total of 2,255 patients received VIN for the treatment of UC in the included studies. OS and PFS were analyzed in a pooled Kaplan-Meier analysis. Response data were available for 1,416 VIN-treated patients with random effects proportion of complete response in 1%, partial response in 18%, and overall response rate of 21%. Toxicity analysis revealed fatigue (40.1%), nausea (33.9%), constipation (34.1%), and alopecia (26.0%) as the most prevalent overall non hematologic adverse events (AEs). Most prevalent grade 3-4 AEs were fatigue (10.2%), abdominal pain (8.2%), myalgias (2.5%), and nausea (2.3%). Most common hematologic AEs of all grades were anemia (56.6%), neutropenia (46.0%), thrombocytopenia (25.5%), and febrile neutropenia (6.6%). Grade 3-4 hematologic AEs had the following pooled rates: neutropenia, 24.6%; anemia, 10.2%; febrile neutropenia, 5.4%; and thrombocytopenia, 3.0%. Conclusion: VIN has been explored as a combination first-line treatment as well as a single-agent second-line, third-line, and maintenance therapy for advanced and metastatic UC. In first-line treatment of UC, either as a maintenance agent after cisplatin or as a primary combination therapy, VIN may be a promising alternative to current treatments. Further studies are needed to compare first-line combination VIN regimens to the current standard of care in order to assess long-term survival outcomes. Second- and third-line VIN monotherapy does provide a proven, although limited, survival benefit in platinum-refractory patients. PMID- 29416445 TI - The cancer proteomic landscape and the HUPO Cancer Proteome Project. AB - The Human Cancer Proteome Project (Cancer-HPP) is an international initiative organized by HUPO whose key objective is to decipher the human cancer proteome through a coordinated effort by cancer proteome researchers around the world. The ultimate goal is to map the entire human cancer proteome to disclose tumor biology and drive improved diagnostics, treatment and management of cancer. Here we report the progress in the cancer proteomics field to date, and discuss future proteomic developments that will be needed to optimally delineate cancer phenotypes and advance the molecular characterization of this significant disease that is one of the leading causes of death worldwide. PMID- 29416446 TI - Urinary metabolic profiling of asymptomatic acute intermittent porphyria using a rule-mining-based algorithm. AB - Introduction: Metabolomic profiling combines Nuclear Magnetic Resonance spectroscopy with supervised statistical analysis that might allow to better understanding the mechanisms of a disease. Objectives: In this study, the urinary metabolic profiling of individuals with porphyrias was performed to predict different types of disease, and to propose new pathophysiological hypotheses. Methods: Urine 1H-NMR spectra of 73 patients with asymptomatic acute intermittent porphyria (aAIP) and familial or sporadic porphyria cutanea tarda (f/sPCT) were compared using a supervised rule-mining algorithm. NMR spectrum buckets bins, corresponding to rules, were extracted and a logistic regression was trained. Results: Our rule-mining algorithm generated results were consistent with those obtained using partial least square discriminant analysis (PLS-DA) and the predictive performance of the model was significant. Buckets that were identified by the algorithm corresponded to metabolites involved in glycolysis and energy conversion pathways, notably acetate, citrate, and pyruvate, which were found in higher concentrations in the urines of aAIP compared with PCT patients. Metabolic profiling did not discriminate sPCT from fPCT patients. Conclusion: These results suggest that metabolic reprogramming occurs in aAIP individuals, even in the absence of overt symptoms, and supports the relationship that occur between heme synthesis and mitochondrial energetic metabolism. PMID- 29416447 TI - A microfluidic device for the delivery of enzymes into cells by liposome fusion. AB - Liposomes are versatile carriers of drugs or biomolecules and are ideally suited to transport molecules into cells. However, mechanistic studies to understand and improve the fusion of liposomes with cell membranes and endosomes are difficult. Here, we report a method that allows for stable coimmobilization of liposomes and living cells, thereby bringing the membranes into close contact, which is essential for membrane fusion. The small unilamellar liposomes are tethered to the surface by a linker so that no modification of the liposome membrane for cell binding is required. The cells are positioned above the liposomes by posts that are integrated into the microfluidic device, and a pH drop induces the fusion of the cell-liposome membranes. Both membrane fusion and release of molecules into the cytosol are visualized by fluorescence dequenching assays. Furthermore, we proved the efficient delivery of the enzyme beta-galactosidase into the cells when a fusogenic liposome composition was used. The device could be used for fusion studies but is also a versatile means for cell transfection. PMID- 29416448 TI - Intravenous lidocaine and postextubation laryngospasm. PMID- 29416449 TI - Effect of intravenous lidocaine on the incidence of postextubation laryngospasm: A double-blind, placebo-controlled randomized trial. AB - Objectives: The study aimed to test the effect of intraoperative intravenous (IV) lidocaine on the incidence of postextubation laryngospasm in adult patients. Methods: The prospective randomized clinical trial was conducted at tertiary care hospital in Riyadh, between January and December 2012. Seventy-two patients undergoing laparoscopic cholecystectomy were randomly assigned to receive either placebo (n = 36) or IV lidocaine (n = 36), 1 mg/kg bolus after desflurane was discontinued. Laryngospasm was graded from 0 to 3 based on the absence or presence of signs and the severity of postextubation laryngospasm. Results: The study was terminated early by the data monitoring committee because of safety concerns due to an increased incidence of postextubation laryngospasm. Patient demographics were similar for both groups. The incidence of postextubation laryngospasm was 19.5% in the placebo group and 0% in the treatment (lidocaine) group; this difference was statistically significant (P = 0.017; 95% confidence interval, 4.6% to 36.0%). Conclusions: The cause of laryngospasm in our study was most likely the rapid increase in the concentration of inspired desflurane, which might have caused airway irritation. Therefore, we believe that pretreating patients at risk of developing laryngospasm with IV lidocaine could be effective. PMID- 29416450 TI - Evaluation of the neurotoxicity of intrathecal dexmedetomidine on rat spinal cord (electromicroscopic observations). AB - Background: Spinal administration of dexmedetomidine has been proposed as an adjuvant in spinal anesthesia. However, there is limited information about its possible neurotoxic effect after its neuraxial administration. Potential spinal neurotoxicity should be investigated in animals before administering drugs through the spinal cord. Our aim was to investigate the neurotoxic effects of intrathecal dexmedetomidine in rats. Methods: Two groups were performed: the dexmedetomidine (D) group (n = 10) received 10 MUg (0.5 ml), whereas the control (C) group (n = 10) received 0.9% (0.5 ml) sodium chloride through indwelling intrathecal catheter. Seven days after the injection, the medulla spinalis was extracted. Samples were withdrawn from both groups for histologic, electron microscopic examination. The histologic examination was performed separately on each of the four sites. The findings were categorized as follows: 0 - normal neuron; 1 - intermediate neuron damage; and 2 - neurotoxicity. Results: Intrathecal administration of dexmedetomidine sensorial block was seen in the dexmedetomidine group and significant differences in the dexmedetomidine group than control group in 15th and 30th min (P < 0.05). Histological examination did not show evidence suggestive of neuronal body or axonal lesion, gliosis, or myelin sheath damage in any group. In all animals, there were observed changes compatible with unspecific inflammation at the tip of the needle location. On the four-area scoring histologic examination, the scores of both groups were 0-1, and no statistical difference was observed between the groups. Conclusions: A single dose of intrathecal dexmedetomidine did not produce histologic evidence of neurotoxicity. PMID- 29416451 TI - Which is better for pain reduction during transrectal ultrasound-guided biopsy of the prostate: Intravenous diazepam, local periprostatic nerve block, or combination? controlled randomized study. AB - Background: Transrectal ultrasound-guided prostate biopsy (TRUSPB) is considered the procedure of choice for the diagnosis of prostate cancer. Men undergoing this biopsy experience high psychological stress. Different studies recommend techniques as sedation, lidocaine gel intrarectally, periprostatic nerve block alone, or nitrous oxide inhalation as effective methods of analgesia during procedural-related pain or discomfort. We evaluated three techniques for pain relief during TRUSPB and evaluated if there was any increase in the incidence of complications when employing either technique. Setting: Assiut University Hospital, Assiut, Egypt. Methods: Three hundred patients of age 43-92-year-old underwent TRUSPBs. Patients were allocated randomly into three equal groups to receive intravenous (IV) diazepam 5 mg slowly (Group I), bilateral periprostatic nerve block by 10 ml of 1% lidocaine solution injected under ultrasound guidance (Group II), or combined IV diazepam and the periprostatic nerve block (Group III). Results: The mean pain score was 4.95 for patients in Group I, 4.15 for patients in Group II, and 2.18 for patients in Group III with statistically significant findings (F = 120.27, P < 0.001). TRUSPB under combined IV sedation and local anesthesia had no significant increase in the incidence of complications. Conclusions: Patients should have analgesia during TRUSPB to decrease the procedure pain and to improve tolerance permitting proper aiming for biopsy cores without increasing the patient distress. The combined IV sedation and local periprostatic nerve block are efficient in controlling and limiting pain better than employing each technique alone with no significant increase in complications incidence. PMID- 29416452 TI - Comparative study of anatomical landmark-guided versus ultrasound-guided suprascapular nerve block in chronic shoulder pain. AB - Background: Suprascapular nerve block (SSNB) is an effective method for the treatment of shoulder disorders. The present study was conducted to evaluate and compare the effectiveness of SSNB under ultrasonographic guidance with anatomical landmark-guided (LMG) technique in the treatment of chronic shoulder pain. Materials and Methods: A total of fifty patients with shoulder pain were enrolled in the present prospective randomized study. Patients in Group I (n = 25) received SSNB using the anatomical LMG as technique described by Dangoisse, in whom a total of 6 ml of drug (5 ml of 0.25% bupivacaine and 40 mg methylprednisolone) was injected. Group II patients (n = 25) were given SSNB using the ultrasound guidance with the same amount of drug. Pain was measured using visual analog scale (VAS), range of motion and Shoulder Pain and Disability Index (SPADI) were recorded. Observations were recorded before the block, immediately after the block, and 1 and 4 weeks after the block. Results: There was no statistically significant difference between the VAS score, range of motion and SPADI before the procedure (P > 0.05) in both the groups. Both the groups showed statistically similar improvement of VAS, range of motion and SPADI at 4-week (P > 0.05) follow-up. In Group I, VAS decreased from baseline value of 6.64 +/- 1.50-2.04 +/- 0.94 at 4 weeks (P < 0.001). In Group II, the VAS decreased from 6.92 +/- 1.00 to 1.84 +/- 1.03 at 4 weeks (P < 0.01). Conclusion: In our study, both the techniques have produced comparable relief of pain, improvement in shoulder movement, and decreased SPADI 4 weeks after the block. PMID- 29416453 TI - Effect of dexmedetomidine on emergence agitation using desflurane in pediatric cataract surgery. AB - Background: In this study, we compared effectiveness of two doses of dexmedetomidine (0.15 MUg/kg and 0.3 MUg/kg) in preventing desflurane-induced emergence agitation (EA) in pediatric patients undergoing elective cataract surgery. Methods: It is a prospective double-blinded randomized study conducted on 65 American Society of Anesthesiologists 1 children (2-10 years) who underwent elective cataract surgery at our institute. They were randomized into two equal groups, who received either dexmedetomidine 0.15 MUg/kg (Group D0.15) or dexmedetomidine 0.30 MUg/kg (Group D0.3) intravenously after induction of anesthesia. An observer blinded to groups recorded heart rate (HR), arterial blood pressure, oxygen saturation, end-tidal carbon dioxide, and respiratory rate (RR) at regular intervals and evaluated preoperative anxiety, state of agitation, and postoperative pain using validated scores. Results: Both groups (Group D0.15, n = 27 vs. Group D0.3, n = 26) were demographically identical. In intraoperative period, the difference in HRs was significantly lower in Group D0.3 from 5 min till 15 min of the surgery (P < 0.05), but thereafter, from 20 min till end of surgery, the rates were comparable in both the groups, whereas RR and blood pressure fluctuations were comparable throughout. Postoperative pain scores and postoperative agitation score were significantly lower in Group D0.3 than D0.15 at all time intervals (P < 0.05). Conclusions: In our study, 0.3 MUg/kg intravenous dexmedetomidine was found to be superior to 0.15 MUg/kg group in effectively reducing EA and postoperative pain, without producing adverse effects such as hypotension or bradycardia. PMID- 29416455 TI - Fluid choice during perioperative care in children: A survey of present-day proposing practice by anesthesiologists in a tertiary care hospital. AB - Background: Perioperative fluid therapy in pediatrics has always been a challenging avenue for anesthesiologists. Inappropriate choice of fluid leads to multiple side effects, for instance iatrogenic hyponatremia. Our aim was to observe the current practice of perioperative fluid therapy in pediatric population undergoing surgery in a tertiary care hospital. Methods: After obtaining approval from the Departmental Research Review Committee, a survey form including questions was emailed to anesthesiologists from January 2015 to June 2015. Individual responses were recorded and analyzed. Results: Overall response was 100% from consultant and resident, and total 55 anesthesiologists were participated in this survey. Majority of anesthesiologist have used, 1/2 dextrose saline (52.7%) as fluid of choice in routine intraoperative maintenance, while Hartmann's solution (41.8%) and normal saline 0.9% (5.5%) were used for rest of the them. The Holliday-Segar method for maintenance fluid was mentioned by 92.7% of anesthesiologists. Conclusion: The use of hypotonic fluid in perioperative care in pediatric population is still being practiced despite the current guidelines. These results point to a considerable gap between the available evidence and practice. PMID- 29416454 TI - A randomized controlled trial comparing C Mac D Blade and Macintosh laryngoscope for nasotracheal intubation in patients undergoing surgeries for head and neck cancer. AB - Purpose: Several devices are available to take care of difficult airway, but C MAC D-Blade has scant evidence of its use in nasotracheal intubation in a difficult airway scenario. Aims and Objectives: We compared the C-MAC D-Blade videolaryngoscopeTM, and the standard Macintosh laryngoscope for nasal intubation in patients with difficult airways selected by El-Ganzouri risk index using parameters of time and attempts required for intubation, glottic view in terms of Cormack-Lehane grade, ease of intubation, success rate, use of accessory maneuvers, incidence of complications, and hemodynamic changes. Methods: One hundred American Society of Anesthesiologists (ASA) I-III patients aged 20-70 years with EGRI score 1-<=7 scheduled for head and neck surgery requiring nasal intubation. ASA IV patients, patients with mouth opening <2.5 cm, patients difficult to mask ventilate, and patients with hyperkalemia and history of malignant hyperthermia were excluded from the study. Primary outcome was time taken to intubation, and secondary outcomes were a number of attempts, glottic view in terms of C/L grade, use of accessory maneuvers, success rate, incidence of trauma, ease of intubation, and hemodynamic changes before and after intubation. Results: Time required for intubation was less (39.56 +/- 15.65 s) in Group C than in Group M (50.34 +/- 15.65 s). Cormack-Lehane Grade I and II view were more in C-MAC D-Blade group (P < 0.05). Success rate and ease of intubation were found to be more in C-MAC D-Blade group than in Macintosh group (P < 0.05). A number of attempts and incidence of complications such as trauma, bleeding, and failed intubation were greater in Macintosh group than in C-MAC D-Blade group. Hemodynamic changes were observed to be comparable in both the groups. Conclusion: C-MAC D-Blade videolaryngoscopeTM is a better tool in anesthetic management of difficult airway for nasal intubation compared to conventional Macintosh laryngoscope. PMID- 29416456 TI - Evaluation of safety and efficacy of regional anesthesia compared with general anesthesia in thoracoscopic lung biopsy procedure on patient with idiopathic pulmonary fibrosis. AB - Background: Interstitial lung diseases are diseases that need histology diagnosis or obtaining a lung biopsy to establish the diagnosis. Surgical biopsies are performed usually using the thoracoscopy technique under general anesthesia (GA) although this procedure is still associated with morbidity rate. The aim of this study is to determine the effectiveness and safety of regional anesthesia (RA) compared with GA in thoracoscopic lung biopsy procedures done on patients with idiopathic pulmonary fibrosis (IPF). Subjects and Methods: This is a retrospective qualitative study based on adult cases of video-assisted thoracoscopy (VAT) lung biopsy on patients with IPF admitted in the division of Thoracic Surgery, Department of General Surgery, King Khalid University Hospital, Riyadh, KSA. We included 67 patients with IPF, 26 with RA, and 41 with GA, who underwent this procedure from January 2008 to December 2015. Procedures performed under RA were done using three different approaches, intercostal nerve blocks, extrapleural infusion, and paravertebral block while GA was performed using double-lumen endotracheal tube placement. For statistical analysis, SPSS program, version 21.0. Software used to analyze the obtained data. The statistical significance was defined as P < 0.05. Results: Sixty-seven patients underwent the procedure of thoracoscopic lung biopsy. Twenty-six of them (38.8%) underwent the procedure under RA and 41 (61.2%) under GA. The cross tabulation of the intercostal chest tube duration showed that it was significantly longer in GA group (6.23 +/- 5.1 days) compared to RA group (3.12 +/- 1.5 days), P = 0.004. Furthermore, for the Intensive Care Unit (ICU) stay, it was significantly longer in GA group (3.38 +/- 2.1 days) compared to RA group (1.09 +/- 0.7 days), P = 0.019. Regarding the relation between the number of biopsies taken and type of anesthesia performed, the probability values for GA group as well as RA group come out to be >0.05 (statistically independent) and the results of risk estimate also show that there was no significant association found between them. The cross tabulation of the representation of biopsies taken by the two methods showed that all biopsies taken under both settings were representative of the disease. Of 41 procedures done under GA, 16 of the total showed a number of complications. Likewise, of 26 procedures under RA, five cases showed complications. The significant (two-sided) value was (P = 0.110), there was no statistical significance between the risks of complications and the two types of anesthesia. Conclusion: There was a significant decrease in chest tube duration and ICU stay in RA group compared to the GA group. There was no statistical difference between both types of anesthesia in the number of biopsy, representation, and postoperative complications although the rate of these complications was much less in the RA group. Based on this outcome, we can conclude that VAT lung biopsy procedure on patients with IPF under RA is safe, representative, and effective operation. In addition, high-risk patients for GA can go through this procedure under RA as an alternative and safe option with no added complications. PMID- 29416457 TI - Assessment of procedural skills in residents working in a research and training institute: An effort to ensure patient safety and quality control. AB - Background: To ensure patient safety, it is important to regularly assess the knowledge and practical skills of anesthesia trainees. This study was conducted to evaluate the competency of the residents and the impact of various corrective measures in the form of didactic lectures and clinical skill demonstrations on the conduct of various procedural skills by the residents. Materials and Methods: Ninety-five junior residents were enrolled in this study. Assessment of competency of 1st, 2nd, and 3rd year residents in performing various procedure skills of anesthesia was done in two stages using procedure specific checklist (PSC) and Global Rating Scales (GRSs). Preliminary results of the first assessment (Score 1) were discussed with the residents; deficiencies were identified and corrective measures suggested by didactic lectures and clinical skill demonstrations which were followed by a subsequent assessment after 3 months (Score 2). Results: There was a statistically significant improvement in the PSC and GRS scores after corrective measures for all the procedural interventions studied. Percentage increase in scores was maximum in 1st year (42.98 +/- 6.62) followed by 2nd year (34.62 +/- 5.49) and minimum in 3rd year residents (18.06 +/- 3.69). The percentage increase of scores was almost similar for all subset of procedural skills; low, intermediate, and high skill anesthetic procedures. Conclusion: For assessment of procedural skills of residents, use of PSC and GRS scores should be incorporated and the same should be used to monitor the impact of various corrective measures (didactic lectures and clinical skill demonstrations) on the conduct of various procedural skills by the resident. PMID- 29416458 TI - Randomized comparison between dexmedetomidine and midazolam for prevention of emergence agitation after nasal surgeries. AB - Background: Emergence agitation (EA) in nasal surgeries is seen in around 22% of patients, which can go to dangerous levels. Dexmedetomidine is effective in prevention of EA in such patients. Midazolam given as premedication fails to prevent EA due to its short half-life. In this study, we compared efficacy of dexmedetomidine and midazolam by intravenous infusion for prevention of EA in adult nasal surgeries. Materials and Methods: Seventy patients belonging to American society of anesthesiologist Status I and II, between 18 and 60 years of age posted for elective nasal surgeries were randomly divided into two groups. Group D received intravenous dexmedetomidine 0.5 mcg/kg over 15 min followed by 0.1 mcg/kg/h. Group M received intravenous midazolam 0.02 mg/kg over 15 min followed by 0.02 mg/kg/h. EA scores, emergence times, and hemodynamic parameters were monitored and compared between the groups. Statistical analysis was done by independent t-test, Mann-Whitney U-test, and Chi-square test as applicable. Results: Incidence of EA was comparable between the groups (P = 0.23). Two patients in midazolam group developed dangerous agitation while none in dexmedetomidine group. Patients in midazolam group (12.4%) were agitated even in postoperative period, which was not seen with dexmedetomidine group. Hypotension and bradycardia were seen more in dexmedetomidine group. Conclusion: Efficacy of midazolam when given as an intravenous infusion is comparable to dexmedetomidine in prevention of EA in nasal surgeries. PMID- 29416459 TI - Neck fat volume as a potential indicator of difficult intubation: A pilot study. AB - Background: Direct laryngoscopy is the gold standard of the airway management in patients without predicted difficulties. If unpredicted difficulties are encountered instead, different algorithms to follow have been developed. To date, no single predictor is sufficiently valid. In clinical practice, it is used a combination of them to enhance the estimate, and despite the variety of parameters used, not all the difficult intubations are predicted. The aim of this work is to retrospectively analyze neck computed tomography scans of 37 patients who have had tracheal intubation and search for anatomic neck fat compartments that correlate with the intubation difficulty, and eventually find a suitable, clinical parameter that can potentially enhance the prediction of a difficult airway when used in combination of the preexisting scores. Materials and Methods: the patients are divided by direct laryngoscopy view into two groups: Group A (n = 31): Normal airway, with a Cormack Lehane, Score I or II; Group B (n = 6): Difficult airway, with a Cormack Lehane Score III or IV. In the zone of interest, it was measured the neck volume parameter and other subparameters. Results: Despite a positive trend is shown for anterior fat volume (AFV) (P = 0.23) and fat volume (FV) (P = 0.28), statistically significant differences (P < 0.05) were not found between Group A and B in any of the measurements acquired. Conclusions: According to the literature, our results confirmed that there is still no single element that can predict a difficult intubation. Although no statistical significance was found, the AFV and FV have shown to have a potential predictive role for difficult intubation. Further studies with bigger samples are advisable to confirm this encouraging result. PMID- 29416460 TI - Endotrol tracheal tube and McGrath Mac are an effective combination for oral tracheal intubation. AB - Background: Tracheal intubation using the 2nd-generation video laryngoscope sometimes cannot be performed easily because there is no functional endotracheal tube (ETT) guide. Therefore, a rigid stylet is often required during tracheal intubation. The Endotrol(r) tracheal tube (Endotrol) is a single use ETT that whole tube can be bent and slide easily into the trachea. We studied the intubation ease of a combination of an Endtrol and the McGrath(r) video laryngoscope (McGrath), which is one of the 2nd-generation video laryngoscopes. Methods: Sixty adult patients under general anesthesia were randomized into three groups: Group A: McGrath with Endotrol, B: McGrath with a rigid stylet attached ETT, and C: Direct laryngoscope with an ETT. The primary outcome measure was intubation time. Secondary outcomes were the number of insertion attempts required and the number of patients who complained of a sore throat after the procedure. The level of significance for each test was set at P < 0.05. Results: Intubation time (median [range] in seconds) was shorter in Group A (32 [27-54]) than Group B (37 [27-49]) and C (37 [27-50]) (P = 0.01 for both comparison). There was no significant difference among groups for the number of insertion attempts required. The number of patients with a sore throat was lower in Group A (0) than Group B (5) and C (6) (P = 0.02 and 0.01, respectively). Conclusion: A combination of an Endtrol and a McGrath is effective for shortening intubation time and avoiding sore throats. PMID- 29416461 TI - Does neck circumference help to predict difficult intubation in obstetric patients? A prospective observational study. AB - Background: Failed intubation in obstetrics remains the most common cause of death directly related to anesthesia. Neck circumference has been shown to be a predictor for difficult intubation in morbidly obese patients. The aim of this study was to determine an optimal cutoff point of neck circumference for prediction of difficult intubation in obstetric patients. Methods: Ninety-four parturients scheduled for cesarean section under general anesthesia were included in the study. Preoperative airway assessment and neck circumference were measured. Difficult intubation was the primary outcome according to the intubation difficulty scale (IDS), intubation reported difficult if the IDS score was >=5. Results: Univariate analysis showed that Mallampati score and neck circumference were positive predictors for difficult intubation (P = 0.005 and P = 0.011, respectively). Mouth opening, thyromental distance, sternomental distance, and the hyomental distance ratio were not useful predictors (P = 0.68, P = 0.87, P = 0.48, and P = 0.27, respectively). Logistic regression for the Mallampati score and neck circumference negative results as independent predictors of difficult intubation in obstetric (P = 0.53). Sensitivity analysis showed that neck circumference of 33.5 cm is the cutoff point to detect difficult intubation with 100% sensitivity (95% confidence interval [CI]: 69.2-100) and 50% specificity (95% CI: 38.9-61.1). The area under the curve for neck circumference was 0.746 (95% CI: 0.646-0.830) with a positive predictive value of 19.2 (95% CI: 9.6-32.5), a negative predicative value of 100 (95% CI: 91.6-100), and a P < 0.0001. Conclusions: In obstetric patients, a neck circumference >=33.5 cm is a sensitive predictor for difficult intubation. PMID- 29416462 TI - An observational study of perioperative antibiotic-prophylaxis use at a major quaternary care and referral hospital in Saudi Arabia. AB - Context: The use of perioperative antimicrobial prophylaxis has been consistently considered an effective means of reducing the risk of surgical site infections. However, inappropriate use of surgical antibiotic prophylaxis is associated with complications such as reduced treatment efficacy, development of antibiotic resistance, and increased health-care costs. Aims: The aim of this study is to investigate the adherence to international/national guidelines regarding the use of surgical antibiotic prophylaxis in the perioperative period. Settings and Design: King Faisal Specialist Hospital and Research Centre (KFSH&RC) a 1589-bed tertiary/quaternary care and referral hospital based in Riyadh, Saudi Arabia. Subjects and Methods: A retrospective observational study, in which antibiotic prophylaxis parameters were assessed against recommendations provided by international/national guidelines in elective/emergency procedures performed at the general operating suite. Data was obtained from the medical records starting of 174 cases over a period of 2 weeks in May 2016. Results: Preoperative antibiotic prophylaxis (PAP) was prescribed for 118 (78.7%) patients, 72 (61%) of which were "recommended," whereas 46 (39%) were "not recommended." Of the 72 patients for whom the antibiotics were "recommended" and given, 19 (26.4%) received "inadequate" choice of antibiotics, 50 (69.4%) received a sub therapeutic dose, 14 (19.4%) had "improper" timing of the first dose, 11 (15.3%) were given an "inappropriate" second intraoperative dose, and 43 (59.7%) had an unnecessarily extended duration of prophylaxis. The overall compliance to guidelines was achieved in only 23 (15.3%) patients. Conclusions: A significant gap between current KFSH & RC practice and international/national guidelines regarding surgical antibiotic prophylaxis usage has been demonstrated which calls for immediate action to ensure effective guideline adoption and implementation. PMID- 29416463 TI - Effect of extended infusion of meropenem and nebulized amikacin on Gram-negative multidrug-resistant ventilator-associated pneumonia. AB - Background: Ventilator-associated pneumonia (VAP) due to multidrug-resistant organisms (MDROs) is associated with a significant mortality in the Intensive Care Unit (ICU). The aim of this study was to compare the efficacy and safety of extended infusion of meropenem and nebulized amikacin on VAP caused by Gram negative MDRO versus intravenous (IV) meropenem and amikacin alone. Methodology: A randomized nonblinded controlled trial was performed on ninety patients with VAP. Patients were randomized into three equal groups: Group I received IV amikacin 20 mg/kg/24 h and meropenem 2 g over 30 min/8 h. Group II received the same as Group I in addition to nebulized amikacin 25 mg/kg/day every 8 h. Group III received IV amikacin 20 mg/kg/24 h, nebulized amikacin 25 mg/kg/day every 8 h, and meropenem 2 g diluted in 240 ml normal saline over 3 h/8 h. The primary outcome was the clinical outcome of VAP. Secondary outcomes were microbiological outcome, VAP-related mortality, duration of MV, ICU stay, and nephrotoxicity. Results: Group II and Group III compared to Group I showed higher incidence of clinical cure (53.33% in Group II and 66.67% in Group III vs. 26.67% in Group I, P = 0.007). Group II compared to Group I showed significant reduction in ventilator days (5.32 +/- 1.86 vs. 7.3 +/- 2.1 days, respectively, P < 0.001) and reduction in ICU days (11.87 +/- 2.6 vs. 15.3 +/- 3.1 days, respectively, P < 0.001). Group III compared to Group II showed significant reduction in ventilator days (4.22 +/- 1.32 vs. 5.32 +/- 1.86, respectively, P = 0.011) and highly significant reduction in ICU days (9.21 +/- 1.17 vs. 11.87 +/- 2.6, respectively, P < 0.001). All groups were comparable as regards nephrotoxicity or mortality. Conclusions: Adding nebulized amikacin to systemic antibiotics in patients with VAP caused by Gram-negative MDRO may offer efficacy benefits, and the use of extended infusions of meropenem could improve the clinical outcomes in critically ill populations. PMID- 29416464 TI - Impact of duloxetine and dexamethasone for improving postoperative pain after laparoscopic gynecological surgeries: A randomized clinical trial. AB - Background: Patients' surgical experiences are influenced by their perception of pain management. Duloxetine (Dulox) and dexamethasone (Dex) are used in multimodal analgesia to reduce opioid use and side effects. Dulox is a selective serotonin and norepinephrine reuptake inhibitor and has efficacy in chronic pain conditions. Dex enhances postoperative (PO) analgesia and reduces PO nausea and vomiting (PONV). Methods: Seventy-five female patients were randomly allocated into one of three equal groups. GI received Dulox 60 mg orally and 100 ml 0.9% sodium chloride (normal saline [NS]) intravenous infusion (IVI) over 15 min, GII: received as GI except Dex 0.1 mg/kg was mixed with NS and GIII received identical placebo for Dulox capsule and Dex IVI, 2 h preoperatively. Patients' vitals, visual analog scale (VAS), and sedation score were assessed at 30 min, 1 h, 2 h, 6 h, and 12 h postoperatively. Total pethidine requirements, plasma cortisol, PONV, and patients satisfaction were recorded. Results: PO time for 1st rescue analgesic was significantly high in GI and GII compared to GIII and in GII compared to GI. There was a significant less VAS score, heart rate, mean arterial pressure, and a high sedation score in GI and GII compared to GIII at 30 min, 1, 2, and 6 h postoperatively. Total pethidine requirements were significantly less in GI and GII compared to GIII 12 h postoperatively. There was a significant reduction in the 2 h PO serum cortisol (MUg/dl) and a significant increase in the PO patients satisfaction score in GI and GII compared to GIII. PONV was decreased significantly in GII compared to GI and GIII. Conclusion: The use of oral Dulox 60 mg combined with Dex 0.1 mg/kg IVI is more effective than oral Dulox 60 mg alone, 2 h preoperatively, for improving PO pain by reducing the requirements for rescue analgesia and PONV. PMID- 29416466 TI - Exacerbation of chronic pain after dental extractions in a patient with post treatment Lyme disease syndrome. AB - A subset of patients who had Lyme disease experience postinfectious signs or symptoms called post-treatment Lyme disease syndrome (PTLDS). PTLDS is a chronic condition including pain in joints and muscles, neurological symptoms including demyelinating diseases, peripheral neuropathy, headaches, sleep disturbances, fatigue, and cardiac conditions. We report a case of difficult acute pain management in a patient with PTLDS who underwent dental extractions and required admission to an intensive care unit for pain control. PMID- 29416465 TI - Opioid-sparing effects of the thoracic interfascial plane blocks: A meta-analysis of randomized controlled trials. AB - Background: Thoracic interfascial plane blocks and modification (PECS) have recently gained popularity for analgesic potential during breast surgery. We evaluate/consolidate the evidence on opioid-sparing effect of PECS blocks in comparison with conventional intravenous analgesia (IVA) and paravertebral block (PVB). Materials and Methods: Prospective, randomized controlled trials comparing PECS block to conventional IVA or PVB in patients undergoing breast surgery published till June 2017 were searched in the medical database. Comparisons were made for 24-h postoperative morphine consumption and intraoperative fentanyl equivalent consumption. Results: Final analysis included nine trials (PECS vs. IVA 4 trials and PECS vs. PVB 5 trials). PECS block showed a decreased intraoperative fentanyl consumption over IVA by 49.20 mcg (95% confidence interval [CI] =42.67-55.74) (I2 = 98.47%, P < 0.001) and PVB by 15.88 mcg (95% CI = 12.95-18.81) (I2 = 95.51%, P < 0.001). Postoperative, 24-h morphine consumption with PECS block was lower than IVA by 7.66 mg (95% CI being 6.23-9.10) (I2 = 63.15, P < 0.001) but was higher than PVB group by 1.26 mg (95% CI being 0.91 1.62) (I2 = 99.53%, P < 0.001). Two cases of pneumothorax were reported with PVB, and no complication was reported in any other group. Conclusions: Use of PECS block and its modifications with general anesthesia for breast surgery has significant opioid-sparing effect intraoperatively and during the first 24 h after surgery. It also has higher intraoperative opioid-sparing effect when compared to PVB. During the 1st postoperative day, PVB has slightly more morphine sparing potential that may however be associated with higher complication rates. The present PECS block techniques show marked interstudy variations and need standardization. PMID- 29416467 TI - Apnea 6 h after a cesarean section. AB - Intrathecal narcotics have proven to be invaluable in providing pain relief following a cesarean section. They also aid in earlier mobilization. Unfortunately, they come at the risk of delayed apnea requiring close monitoring for a prolonged period of time. Physicians may sometimes underestimate the risk of these delayed complications. This especially a big concern in hospitals that cannot provide the necessary postoperative monitoring required for these women. I present a case where it took more than 6 h after injection of narcotics before the complication occurred. PMID- 29416468 TI - Nonfatal cardiac perforation after central venous catheter insertion. AB - Cardiac tamponade caused by perforation of the cardiac wall is a rare complication related to central venous catheter (CVC) placement. A 71-year-old female with a previous history of moderate aortic stenosis and kidney transplantation was admitted to hospital due to global heart failure and worsening of allograft function. Intensified hemodialysis was commenced through a CVC placed in the right subclavian vein. Chest radiography revealed catheter tip in the right atrium and no signs of pneumothorax. Thorough diagnostics outruled immediate life-threatening conditions, such as myocardial infarction and pulmonary embolism. However, not previously seen, 2 cm thick pericardial effusion without repercussion on the blood flow was visualized during echocardiography, predominantly reclining the free surface of the right atrium, with fibrin scar tissue covering the epicardium - it was the spot of spontaneously recovered cardiac wall perforation. Follow-up echocardiogram performed before the discharge showed regression of the previously found pericardial effusion. PMID- 29416469 TI - Successful removal of an intractable mucoid impaction in the bronchus using a Fogarty catheter with flexible bronchoscopy. AB - Rigid bronchoscopy is commonly used as the standard method to diagnosis and remove obstructive material from the tracheobronchial tree. However, a rigid bronchoscope has limitations when removing a foreign body with surface properties that make it difficult to grasp. We experienced a case that involved the removal of a mucoid impaction, which was accompanied by a near-total unilateral lung collapse, using a Fogarty catheter with flexible bronchoscopy. PMID- 29416470 TI - Bilateral bispectral index monitoring to detect cerebral hypoperfusion during carotid endarterectomy under general anesthesia. AB - The bilateral use of bispectral index (BIS) monitoring in a 68-year-old male who underwent right carotid endarterectomy (CEA) under general anesthesia (GA) is described. During three episodes of right internal carotid artery cross-clamping intraoperatively, the right BIS value rose relative to the left within 1 min of clamping, followed by a return to baseline within 1-2 min of clamp release. Since unilateral BIS values can decrease or increase in response to cross-clamping, a significant difference in left and right BIS values may provide a simple and easily available method to detect cerebral hypoperfusion during CEA under GA. PMID- 29416471 TI - A successful anesthetic approach in a patient with Schwartz-Jampel syndrome. AB - Schwartz-Jampel syndrome (SJS) is a rare genetic condition that is characterized by several musculoskeletal abnormalities, such as myotonia, joint contractures, and facial dysmorphisms. Patients with this syndrome can present an anesthetic challenge, due to an increased risk of developing malignant hyperthermia (MH) and the possibility of encountering a difficult airway. Several precautions must be taken when general anesthesia is required, such as the avoidance of potential triggers for MH, continuous core temperature, and end-tidal CO2 monitoring, assuring that dantrolene is readily available. It is also fundamental to prepare for a possible difficult airway, guaranteeing that difficult airway devices are available. We describe the anesthetic management of a 14-year-old boy diagnosed with SJS who was scheduled for multiple dental extractions and was successfully anesthetized with our approach. PMID- 29416472 TI - Anesthetic considerations for video-assisted thoracoscopic surgery in a child with Glenn shunt for thoracic duct ligation and pleurodesis. AB - Glenn shunt is an anastomosis between superior vena cava and right pulmonary artery to palliate patients with single ventricle physiology of the heart. Chylothorax is a frequent and troublesome complication after the creation of this shunt, which if not controlled with medical management, might require pleurodesis, and thoracic duct ligation. Video-assisted thoracoscopic surgery (VATS) causes less postoperative pain, earlier mobilization, lower overall morbidity, a shortened hospital stay with reduced cost, and a cosmetic incision. A comprehensive understanding of physiology of Glenn shunt and implications of the proposed surgical procedure (VATS) is necessary to plan the anesthetic agents, cardiovascular drugs, ventilation strategies, and other perioperative factors. PMID- 29416473 TI - Anesthetic management of a parturient with Kearns-Sayre syndrome, dual-chamber and VVI implantable defibrillator pacemaker/defibrillator, and preeclampsia for cesarean delivery: A case report and review of the literature. AB - Kearns-Sayre syndrome (KSS), a rare form of mitochondrial myopathy, is a triad of chronic progressive external ophthalmoplegia, bilateral pigmentary retinopathy, and cardiac conduction abnormalities. In this report, we show how a combined spinal epidural anesthesia can be useful for cesarean delivery, as we illustrate in a dual-chamber and VVI implantable defibrillator pacemaker/defibrillator parturient with a KSS and preeclampsia. PMID- 29416474 TI - Surgical evacuation of subdural hematoma in a patient with transplanted heart under anesthesia. PMID- 29416475 TI - Necrotizing fasciitis following spinal anesthesia: A rare and devastating complication. PMID- 29416476 TI - Fractured tracheostomy tube posted for bronchoscopic removal: An anesthetic challenge. PMID- 29416477 TI - Delayed migration of coil into the nasopharynx following embolization of internal carotid artery pseudoaneurysm: A rare complication. PMID- 29416478 TI - Hyponatremia and unexpected use of cardiopulmonary bypass. PMID- 29416479 TI - Management of a difficult-to-ventilate and difficult-to-intubate airway: Anesthetists' nightmare. PMID- 29416480 TI - Time to introduce Diameter Index Safety System for resuscitation bag!! PMID- 29416481 TI - Aspiration of severed tracheal tube: An anesthesiologist's nightmare. PMID- 29416482 TI - Painless palatal local anesthetic injection: A low-cost, effective technique. PMID- 29416483 TI - Ultrasound-guided interscalene block in a patient with halo brace. PMID- 29416484 TI - Pneumothorax in a preterm during tracheoesophageal fistula repair: Challenges in diagnosis and management. PMID- 29416485 TI - Surgical Apgar Score for predicting patient outcome after hepatopancreaticobiliary surgeries. PMID- 29416486 TI - Misplacement of central venous catheters: Was excessive length of the guide wire responsible? PMID- 29416487 TI - A reliable alternative of fiberoptic bronchoscope in unanticipated difficult airway: Flexible fiberoptic cystoscope. PMID- 29416488 TI - Bilateral greater orbital nerve block: Efficacy in postdural puncture headache. PMID- 29416489 TI - Use of high-flow nasal cannula for emergency pericardiocentesis in a case of anterior mediastinal mass. PMID- 29416490 TI - Ciproxifan in preventing inhalational anesthetic-induced neurotoxicity! PMID- 29416491 TI - Airway management in a case of large congenital ranula. PMID- 29416492 TI - Split nasopharyngeal airway as a conduit for oral fiber-optic intubation in a case of difficult airway. PMID- 29416493 TI - Anesthetic issues in pregnancy with Ebstein's anomaly, hypothyroidism, and sepsis. PMID- 29416494 TI - Ultrasound-guided lumbar transforaminal injection through interfacet approach. PMID- 29416495 TI - Radial nerve injury following lengthy general anesthesia procedure. PMID- 29416496 TI - Is homocystinuria a real challenge for anesthetist? Are we making a difference? PMID- 29416497 TI - Undiagnosed myxedema coma: Rare but life-threatening. PMID- 29416500 TI - MSA Mimic? Rare Occurrence of Anti-Hu Autonomic Failure and Thymoma in a Patient with Parkinsonism: Case Report and Literature Review. AB - Thymoma is a tumor originating from thymic gland, frequently manifesting with paraneoplastic neurological disorders. Its association with paraneoplastic dysautonomia is relatively uncommon. Here, we describe the challenging case of a 71 year-old female who developed subacute autonomic failure with digestive pseudo obstruction, dysphagia, urinary tract dysfunction and orthostatic hypotension complicating an underlying extrapyramidal syndrome that had started 3 months before hospital admission. Autonomic symptoms had 2-month course and acutely worsened just before and during hospitalization. Combination of severe dysautonomia and parkinsonism mimicked rapidly progressing multiple system atrophy. However, diagnostic exams showed thymic tumor with positive anti-Hu antibodies on both serum and cerebrospinal fluid. Complete response of dysautonomia to immunoglobulins followed by thymectomy confirmed the diagnosis of anti-Hu-related paraneoplastic neurological syndrome. With regards to extrapyramidal symptoms, despite previous descriptions of paraneoplastic parkinsonism caused by other antineuronal antibodies, in our case no relation between anti-Hu and parkinsonism could be identified. A literature review of published reports describing anti-Hu positivity in thymic neoplasms highlighted that a definite autonomic disease due to anti-Hu antibodies is extremely rare in patients with thymoma but without myasthenia gravis, with only one case published so far. PMID- 29416499 TI - A Metadata Analysis of Oxidative Stress Etiology in Preclinical Amyotrophic Lateral Sclerosis: Benefits of Antioxidant Therapy. AB - Oxidative stress, induced by an imbalance of free radicals, incites neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). In fact, a mutation in antioxidant enzyme superoxide dismutase 1 (SOD1) accounts for 20% of familial ALS cases. However, the variance among individual studies examining ALS oxidative stress clouds corresponding conclusions. Therefore, we construct a comprehensive, temporal view of oxidative stress and corresponding antioxidant therapy in preclinical ALS by mining published quantitative experimental data and performing metadata analysis of 41 studies. In vitro aggregate analysis of innate oxidative stress inducers, glutamate and hydrogen peroxide, revealed 70-90% of cell death coincides to inducer exposure equivalent to 30-50% peak concentration (p < 0.05). A correlative plateau in cell death suggests oxidative stress impact is greatest in early-stage neurodegeneration. In vivo SOD1-G93A transgenic ALS mouse aggregate analysis of heat shock proteins (HSPs) revealed HSP levels are 30% lower in muscle than spine (p < 0.1). Overall spine HSP levels, including HSP70, are mildly upregulated in SOD1-G93A mice compared to wild type, but not significantly (p > 0.05). Thus, innate HSP compensatory responses to oxidative stress are simply insufficient, a result supportive of homeostatic system instability as central to ALS etiology. In vivo aggregate analysis of antioxidant therapy finds SOD1-G93A ALS mouse survival duration significantly increases by 11.2% (p << 0.001) but insignificantly decreases onset age by 2%. Thus, the aggregate antioxidant treatment effect on survival in preclinical ALS is not sufficient to overcome clinical heterogeneity, which explains the literature disparity between preclinical and clinical antioxidant survival benefit. The aggregate effect sizes on preclinical ALS survival and onset illustrate that present antioxidants, alone, are not sufficient to halt ALS, which underscores its multi-factorial nature. Nonetheless, antioxidant-treated SOD1-G93A ALS mice have significantly increased motor performance (p < 0.05) measured via rotarod. With a colossal aggregate preclinical effect size average of 59.6%, antioxidants are promising for increasing function/quality of life in clinical ALS patients, a premise worth exploration via low-risk nutritional supplements. Finally, more direct, quantitative measures of oxidative stress, antioxidant levels and bioavailability are key to developing powerful antioxidant therapeutics that can assert measurable impacts on redox homeostasis in the brain and spinal cord. PMID- 29416498 TI - Evolving Applications, Technological Challenges and Future Opportunities in Neuromodulation: Proceedings of the Fifth Annual Deep Brain Stimulation Think Tank. AB - The annual Deep Brain Stimulation (DBS) Think Tank provides a focal opportunity for a multidisciplinary ensemble of experts in the field of neuromodulation to discuss advancements and forthcoming opportunities and challenges in the field. The proceedings of the fifth Think Tank summarize progress in neuromodulation neurotechnology and techniques for the treatment of a range of neuropsychiatric conditions including Parkinson's disease, dystonia, essential tremor, Tourette syndrome, obsessive compulsive disorder, epilepsy and cognitive, and motor disorders. Each section of this overview of the meeting provides insight to the critical elements of discussion, current challenges, and identified future directions of scientific and technological development and application. The report addresses key issues in developing, and emphasizes major innovations that have occurred during the past year. Specifically, this year's meeting focused on technical developments in DBS, design considerations for DBS electrodes, improved sensors, neuronal signal processing, advancements in development and uses of responsive DBS (closed-loop systems), updates on National Institutes of Health and DARPA DBS programs of the BRAIN initiative, and neuroethical and policy issues arising in and from DBS research and applications in practice. PMID- 29416501 TI - Function of B-Cell CLL/Lymphoma 11B in Glial Progenitor Proliferation and Oligodendrocyte Maturation. AB - B-cell CLL/lymphoma 11B (Bcl11b) - a C2H2 zinc finger transcriptional factor - is known to regulate neuronal differentiation and function in the development of the central nervous system (CNS). Although its expression is reduced during oligodendrocyte (OLG) differentiation, its biological role in OLGs remains unknown. In this study, we found that the downregulation of Bcl11b gene expression in glial progenitor cells (GPCs) by lentivirus-mediated gene knockdown (KD) causes a reduction in cell proliferation with inhibited expression of stemness-related genes, while increasing the expression of cell cyclin regulator p21. In contrast, OLG specific transcription factors (Olig1) and OLG cell markers, including myelin proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), were upregulated in Bcl11b-KD GPCs. Chromatin immunoprecipitation (ChIP) analysis indicated that Bcl11b bound to the promoters of Olig1 and PLP, suggesting that Bcl11b could act as a repressor for Olig1 and PLP, similar to its action on p21. An increase in the number of GC+- or PLP+- OLGs derived from Bcl11b-KD GPCs or OLG precursor cells was also observed. Moreover, myelin basic protein (MBP) expression in OLGs derived from Bcl11b-KD GPCs was enhanced in hippocampal neuron co-cultures and in cerebellar brain-slice cultures. The in vivo study using a lysolecithin-induced demyelinating animal model also indicated that larger amounts of MBP+-OLGs and PLP+-OLGs derived from implanted Bcl11b-KD GPCs were present at the lesioned site of the white matter than in the scramble group. Taken together, our results provide insight into the functional role of Bcl11b in the negative regulation of GPC differentiation through the repression of OLG differentiation-associated genes. PMID- 29416502 TI - Melatonin Mitigates Kainic Acid-Induced Neuronal Tau Hyperphosphorylation and Memory Deficits through Alleviating ER Stress. AB - Kainic acid (KA) exposure causes neuronal degeneration featured by Alzheimer-like tau hyperphosphorylation and memory deficits. Melatonin (Mel) is known to protect hippocampal neurons against KA-induced damage. However, the underlying mechanisms remain elusive. In the current study, we investigated the protective effect of melatonin on KA-induced tau hyperphosphorylation by focusing on endoplasmic reticulum (ER) stress-mediated signaling pathways. By using primary hippocampal neurons and mouse brain, we showed that KA treatment specifically induced ER stress and activated GSK-3beta and CDK5, two major kinases responsible for tau phosphorylation. Inhibition of ER stress efficiently inactivated GSK-3beta and CDK5. Mechanistically, we found that KA-induced ER stress significantly activated calpain, a calcium-dependent protease. Inhibition of ER stress or calpain leads to the reduction in KA-induced GSK-3beta and CDK5 activities and tau phosphorylation. Moreover, GSK-3beta or CDK5 inhibition failed to downregulate ER stress efficiently, suggesting that ER stress functions upstream of GSK-3beta or CDK5. Notably, our results revealed that melatonin acts against KA-induced neuronal degeneration and tau hyperphosphorylation via easing ER stress, further highlighting the protective role of melatonin in the KA-induced neuronal defects. PMID- 29416503 TI - Resonance Properties in Auditory Brainstem Neurons. AB - Auditory signals carry relevant information on a large range of time scales from below milliseconds to several seconds. Different stages in the auditory brainstem are specialized to extract information in specific frequency domains. One biophysical mechanism to facilitate frequency specific processing are membrane potential resonances. Here, we provide data from three different brainstem nuclei that all exhibit high-frequency subthreshold membrane resonances that are all most likely based on low-threshold potassium currents. Fitting a linear model, we argue that, as long as neurons possess active subthreshold channels, the main determinant for their resonance behavior is the steady state membrane time constant. Tuning this leak conductance can shift membrane resonance frequencies over more than a magnitude and therefore provide a flexible mechanism to tune frequency-specific auditory processing. PMID- 29416505 TI - Discounting and Digit Ratio: Low 2D:4D Predicts Patience for a Sample of Females. AB - Inter-temporal trade-offs are ubiquitous in human decision making. We study the relationship between preferences over such trade-offs and the ratio of the second digit to that of the forth (2D:4D), a marker for pre-natal exposure to sex hormones. Specifically, we study whether 2D:4D affects discounting. Our sample consists of 419 female participants of a Guatemalan conditional cash transfer program who take part in an experiment. Their choices in the convex time budget (CTB) experimental task allow us to make inferences regarding their patience (discounting), while controlling for present-biasedness and preference for smoothing consumption (utility curvature). We find that women with lower digit ratios tend to be more patient. PMID- 29416504 TI - Electrophysiological and Morphological Properties of alpha and gamma Motoneurons in the Rat Trigeminal Motor Nucleus. AB - The muscle contraction during voluntary movement is regulated by activities of alpha- and gamma-motoneurons (alphaMNs and gammaMNs, respectively). The tension of jaw-closing muscles can be finely tuned over a wide range. This excellent function is likely to be achieved by the specific populations of alphaMNs innervating jaw-closing muscles. Indeed, we have recently demonstrated that in the rat dorsolateral trigeminal motor nucleus (dl-TMN), the size distribution of alphaMNs was bimodal and the population of smaller alphaMNs showed a size distribution similar to that of gammaMNs, by immunohistochemically identifying alphaMNs and gammaMNs based on the expressions of estrogen-related receptor gamma (Err3) and neuronal DNA binding protein NeuN together with ChAT. This finding suggests the presence of alphaMNs as small as gammaMNs. However, differences in the electrophysiological membrane properties between alphaMNs and gammaMNs remain unknown also in the dl-TMN. Therefore, in the present study, we studied the electrophysiological membrane properties of MNs in the dl-TMN of infant rats at postnatal days 7-12 together with their morphological properties using whole-cell current-clamp recordings followed by immunohistochemical staining with an anti NeuN and anti-ChAT antibodies. We found that the ChAT-positive and NeuN-positive alphaMNs were divided into two subclasses: the first one had a larger cell body and displayed a 4-aminopyridine (4-AP)-sensitive current while the second one had a smaller cell body and displayed a less prominent 4-AP-sensitive current and a low-threshold spike, suitable for their orderly recruitment. We finally found that gammaMNs showing ChAT-positive and NeuN-negative immunoreactivities had smaller cell bodies and displayed an afterdepolarization mediated by flufenamate sensitive cation current. It is suggested that these electrophysiological and morphological features of MNs in the dl-TMN are well correlated with the precise control of occlusion. PMID- 29416506 TI - Asymmetric Functional Connectivity of the Contra- and Ipsilateral Secondary Somatosensory Cortex during Tactile Object Recognition. AB - In the somatosensory system, it is well known that the bilateral secondary somatosensory cortex (SII) receives projections from the unilateral primary somatosensory cortex (SI), and the SII, in turn, sends feedback projections to SI. Most neuroimaging studies have clearly shown bilateral SII activation using only unilateral stimulation for both anatomical and functional connectivity across SII subregions. However, no study has unveiled differences in the functional connectivity of the contra- and ipsilateral SII network that relates to frontoparietal areas during tactile object recognition. Therefore, we used event-related functional magnetic resonance imaging (fMRI) and a delayed match-to sample (DMS) task to investigate the contributions of bilateral SII during tactile object recognition. In the fMRI experiment, 14 healthy subjects were presented with tactile angle stimuli on their right index finger and asked to encode three sample stimuli during the encoding phase and one test stimulus during the recognition phase. Then, the subjects indicated whether the angle of test stimulus was presented during the encoding phase. The results showed that contralateral (left) SII activity was greater than ipsilateral (right) SII activity during the encoding phase, but there was no difference during the recognition phase. A subsequent psycho-physiological interaction (PPI) analysis revealed distinct connectivity from the contra- and ipsilateral SII to other regions. The left SII functionally connected to the left SI and right primary and premotor cortex, while the right SII functionally connected to the left posterior parietal cortex (PPC). Our findings suggest that in situations involving unilateral tactile object recognition, contra- and ipsilateral SII will induce an asymmetrical functional connectivity to other brain areas, which may occur by the hand contralateral effect of SII. PMID- 29416507 TI - Speed-Dependent Modulation of Muscle Activity Based on Muscle Synergies during Treadmill Walking. AB - The regulation of walking speed is easily achieved. However, the central nervous system (CNS) must coordinate numerous muscles in order to achieve a smooth and continuous control of walking speed. To control walking speed appropriately, the CNS may need to utilize a simplified system for the control of numerous muscles. Previous studies have revealed that the CNS may control walking via muscle synergies that simplify the control of muscles by modularly organizing several muscles. We hypothesized that the CNS controls the walking speed by flexibly modulating activation of muscle synergies within one gait cycle. Then, we investigated how the activation of muscle synergies depend on walking speeds using the center of activity (CoA) that indicates the center of the distribution of activation timing within one gait cycle. Ten healthy men walked on a treadmill at 14 different walking speeds. We measured the surface electromyograms (EMGs) and kinematic data. Muscle synergies were extracted using non-negative matrix factorization. Then, we calculated the CoA of each muscle synergy. We observed that the CoA of each specific synergy would shift as the walking speed changed. The CoA that was mainly activated during the heel contact phase (C1) and the activation that contributed to the double support phase (C3) shifted to the earlier phase as the walking speed increased, whereas the CoA that produced swing initiation motion (C4) and the activation that related to the late-swing phase (C5) shifted to the later phase. This shifting of the CoA indicates that the CNS controls intensive activation of muscle synergies during the regulation of walking speed. In addition, shifting the CoA might be associated with changes in kinematics or kinetics depending on the walking speed. We concluded that the CNS flexibly controls the activation of muscle synergies in regulation of walking speed. PMID- 29416508 TI - The Default Mode Network Supports Episodic Memory in Cognitively Unimpaired Elderly Individuals: Different Contributions to Immediate Recall and Delayed Recall. AB - While the neural correlates of age-related decline in episodic memory have been the subject of much interest, the spontaneous functional architecture of the brain for various memory processes in elderly adults, such as immediate recall (IR) and delayed recall (DR), remains unclear. The present study thus examined the neural correlates of age-related decline of various memory processes. A total of 66 cognitively normal older adults (aged 60-80 years) participated in this study. Memory processes were measured using the Auditory Verbal Learning Test as well as resting-state brain images, which were analyzed using both regional homogeneity (ReHo) and correlation-based functional connectivity (FC) approaches. We found that both IR and DR were significantly correlated with the ReHo of these critical regions, all within the default mode network (DMN), including the parahippocampal gyrus, posterior cingulate cortex/precuneus, inferior parietal lobule, and medial prefrontal cortex. In addition, DR was also related to the FC between these DMN regions. These results suggest that the DMN plays different roles in memory retrieval across different retention intervals, and connections between the DMN regions contribute to memory consolidation of past events in healthy older people. PMID- 29416509 TI - Decoys Selection in Benchmarking Datasets: Overview and Perspectives. AB - Virtual Screening (VS) is designed to prospectively help identifying potential hits, i.e., compounds capable of interacting with a given target and potentially modulate its activity, out of large compound collections. Among the variety of methodologies, it is crucial to select the protocol that is the most adapted to the query/target system under study and that yields the most reliable output. To this aim, the performance of VS methods is commonly evaluated and compared by computing their ability to retrieve active compounds in benchmarking datasets. The benchmarking datasets contain a subset of known active compounds together with a subset of decoys, i.e., assumed non-active molecules. The composition of both the active and the decoy compounds subsets is critical to limit the biases in the evaluation of the VS methods. In this review, we focus on the selection of decoy compounds that has considerably changed over the years, from randomly selected compounds to highly customized or experimentally validated negative compounds. We first outline the evolution of decoys selection in benchmarking databases as well as current benchmarking databases that tend to minimize the introduction of biases, and secondly, we propose recommendations for the selection and the design of benchmarking datasets. PMID- 29416510 TI - Elevated Pressure Changes the Purinergic System of Microglial Cells. AB - Glaucoma is the second cause of blindness worldwide and is characterized by the degeneration of retinal ganglion cells (RGCs) and optic nerve atrophy. Increased microglia reactivity is an early event in glaucoma that may precede the loss of RGCs, suggesting that microglia and neuroinflammation are involved in the pathophysiology of this disease. Although global changes of the purinergic system have been reported in experimental and human glaucoma, it is not known if this is due to alterations of the purinergic system of microglial cells, the resident immune cells of the central nervous system. We now studied if elevated hydrostatic pressure (EHP), mimicking ocular hypertension, changed the extracellular levels of ATP and adenosine and the expression, density and activity of enzymes, transporters and receptors defining the purinergic system. The exposure of the murine microglial BV-2 cell line to EHP increased the extracellular levels of ATP and adenosine, increased the density of ecto nucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1, CD39) and decreased the density of the equilibrative nucleotide transporter 2 as well as the activity of adenosine deaminase. The expression of adenosine A1 receptor also decreased, but the adenosine A3 receptor was not affected. Notably, ATP and adenosine selectively control migration rather than phagocytosis, both bolstered by EHP. The results show that the purinergic system is altered in microglia in conditions of elevated pressure. Understanding the impact of elevated pressure on the purinergic system will help to unravel the mechanisms underlying inflammation and neurodegeneration associated with glaucoma. PMID- 29416511 TI - Genome-Wide Identification and Expression Analysis of the KUP Family under Abiotic Stress in Cassava (Manihot esculenta Crantz). AB - KT/HAK/KUP (KUP) family is responsible for potassium ion (K+) transport, which plays a vital role in the response of plants to abiotic stress by maintaining osmotic balance. However, our understanding of the functions of the KUP family in the drought-resistant crop cassava (Manihot esculenta Crantz) is limited. In the present study, 21 cassava KUP genes (MeKUPs) were identified and classified into four clusters based on phylogenetic relationships, conserved motifs, and gene structure analyses. Transcriptome analysis revealed the expression diversity of cassava KUPs in various tissues of three genotypes. Comparative transcriptome analysis showed that the activation of MeKUP genes by drought was more in roots than that in leaves of Arg7 and W14 genotypes, whereas less in roots than that in leaves of SC124 variety. These findings indicate that different cassava genotypes utilize various drought resistance mechanism mediated by KUP genes. Specific KUP genes showed broad upregulation after exposure to salt, osmotic, cold, H2O2, and abscisic acid (ABA) treatments. Taken together, this study provides insights into the KUP-mediated drought response of cassava at transcription levels and identifies candidate genes that may be utilized in improving crop tolerance to abiotic stress. PMID- 29416513 TI - Different Training Modalities Improve Energy Cost and Performance in Master Runners. AB - Purpose: The aim of this study was to compare the effects of continuous moderate intensity and discontinuous high-intensity training on running performance in master runners. Methods: Thirty-four male master runners (47.2 +/- 7.4 years) were assigned to three different groups: continuous moderate-intensity training (CMIT), discontinuous high-intensity training (DHIT), and control group (CON). CMIT and DHIT performed 8-week of supervised training (3 session.wk-1; ~35 km.wk 1) while CON maintained their normal training habits (3-4 session.wk-1; ~50 km.wk 1). Peak oxygen consumption ([Formula: see text]O2peak) and peak running speed (vpeak) during incremental treadmill exercise, gas exchange threshold (GET), speed at GET, energy cost of running (Cr), and 5-km performance were evaluated before and after training. Results: Following the training period, both CMIT and DHIT significantly reduced Cr (-4.4 and -4.9%, respectively, P < 0.05), increased speed at GET (3.4 and 5.7%, P < 0.05) and improved 5-km time-trial performance (3.1 and 2.2%, P < 0.05) whereas no differences were found for [Formula: see text]O2peak and GET (as %[Formula: see text]O2peak). After training, vpeak improved only for DHIT (6%, P < 0.05). No differences were found in any variable for CON. Conclusions: This study indicates that both CMIT and DHIT may positively affect running performance in middle-aged master runners. This improvement was achieved despite a significant reduction of the amount of weekly training volume. PMID- 29416512 TI - Age-, Gender-, and in Vivo Different Doses of Isoproterenol Modify in Vitro Aortic Vasoreactivity and Circulating VCAM-1. AB - Different human-like cardiomyopathies associated to beta-adrenergic stimulation are experimentally modeled in animals through variations in dose, route, and duration of administration of different cardiotoxic drugs. However, associated changes in the vasculature and their relation to systemic inflammation, and the influence of cardiovascular diseases risk factors (gender and age) upon them are seldom analyzed. Here we studied the effect of age and gender on the vasoreactivity of aortas from mice subjected to in vivo repeated beta-adrenergic stimulation with different doses of isoproterenol (ISO) in association with circulating inflammatory cytokines. Young (2 months) and old (18 months) male and female mice received 0 (control), 5, 40, 80 or 160 MUg/g/d of ISO (7 days, s.c.). IL-1alpha, IL-4 and vascular cell adhesion molecule-1 (VCAM-1) were quantified in plasma. In vitro, norepinephrine-induced vasoconstriction and acetylcholine induced relaxation were measured in aortas. No differences in contraction, relaxation, IL-1alpha, and IL-4 were found between control young males and females. Age decreased contraction in males and relaxation was lower in females and abolished in males. VCAM-1 was higher in young males than in females and increased in old mice. Vasoconstriction in ISO-treated mice results as a bell shaped curve on contraction in young and old males, with lower values in the latter. In females, ISO-160 increased contraction in young females but decreased it in old females. Vasorelaxation was reduced in ISO-treated young males and females. ISO-80 and 160 reduced vasorelaxation in old females, and intermediate doses relaxed aortas from old males. VCAM-1 was higher in young and old males with ISO-80 and 160; while VCAM-1 was higher only with ISO-160 in old females. Our results demonstrate that repeated beta-adrenergic stimulation modifies vascular reactivity depending on gender, age, and dose. Females were less sensitive to alterations in vasoreactivity, and young females required a higher amount of the adrenergic stimuli than old females to show vascular alterations. Changes were independent of IL-1alpha and IL-4. VCAM-1 only changed in old females stimulated with ISO 160. Our results highlight the relevance of considering and comparing in the same study females and aged organisms to improve the accuracy of applications to clinical studies. PMID- 29416514 TI - Intramuscular Pressure of Tibialis Anterior Reflects Ankle Torque but Does Not Follow Joint Angle-Torque Relationship. AB - Intramuscular pressure (IMP) is the hydrostatic fluid pressure that is directly related to muscle force production. Electromechanical delay (EMD) provides a link between mechanical and electrophysiological quantities and IMP has potential to detect local electromechanical changes. The goal of this study was to assess the relationship of IMP with the mechanical and electrical characteristics of the tibialis anterior muscle (TA) activity at different ankle positions. We hypothesized that (1) the TA IMP and the surface EMG (sEMG) and fine-wire EMG (fwEMG) correlate to ankle joint torque, (2) the isometric force of TA increases at increased muscle lengths, which were imposed by a change in ankle angle and IMP follows the length-tension relationship characteristics, and (3) the electromechanical delay (EMD) is greater than the EMD of IMP during isometric contractions. Fourteen healthy adults [7 female; mean (SD) age = 26.9 (4.2) years old with 25.9 (5.5) kg/m2 body mass index] performed (i) three isometric dorsiflexion (DF) maximum voluntary contraction (MVC) and (ii) three isometric DF ramp contractions from 0 to 80% MVC at rate of 15% MVC/second at DF, Neutral, and plantarflexion (PF) positions. Ankle torque, IMP, TA fwEMG, and TA sEMG were measured simultaneously. The IMP, fwEMG, and sEMG were significantly correlated to the ankle torque during ramp contractions at each ankle position tested. This suggests that IMP captures in vivo mechanical properties of active muscles. The ankle torque changed significantly at different ankle positions however, the IMP did not reflect the change. This is explained with the opposing effects of higher compartmental pressure at DF in contrast to the increased force at PF position. Additionally, the onset of IMP activity is found to be significantly earlier than the onset of force which indicates that IMP can be designed to detect muscular changes in the course of neuromuscular diseases impairing electromechanical transmission. PMID- 29416516 TI - Why Don't I Help You? The Relationship between Role Stressors and Helping Behavior from a Cognitive Dissonance Perspective. AB - This paper proposes that role stressors decrease helping behavior by undermining employees' normative commitment from a cognitive dissonance perspective and social exchange theory. We also propose two competitive assumptions of the moderating effect of perceived organizational support (POS). In this paper, we first examine these hypotheses in Study 1 and then verify the cognitive dissonance perspective in Study 2. In Study 1, we collected data from 350 employees of two enterprises in China. The results indicated that role stressors had a negative link with helping behavior via the mediating role of normative commitment. The results also showed that POS strengthened the negative relationship between role stressors and normative commitment. In Study 2, we invited 104 employees to participate in a scenario experiment. The results found that role stressors had an impact on normative commitment via dissonance. Our studies verified the combination of cognitive dissonance perspective and social exchange theory to explain the impact of role stressors on helping behavior. PMID- 29416515 TI - Collective Sensing of beta-Cells Generates the Metabolic Code. AB - Major part of a pancreatic islet is composed of beta-cells that secrete insulin, a key hormone regulating influx of nutrients into all cells in a vertebrate organism to support nutrition, housekeeping or energy storage. beta-cells constantly communicate with each other using both direct, short-range interactions through gap junctions, and paracrine long-range signaling. However, how these cell interactions shape collective sensing and cell behavior in islets that leads to insulin release is unknown. When stimulated by specific ligands, primarily glucose, beta-cells collectively respond with expression of a series of transient Ca2+ changes on several temporal scales. Here we reanalyze a set of Ca2+ spike trains recorded in acute rodent pancreatic tissue slice under physiological conditions. We found strongly correlated states of co-spiking cells coexisting with mostly weak pairwise correlations widespread across the islet. Furthermore, the collective Ca2+ spiking activity in islet shows on-off intermittency with scaling of spiking amplitudes, and stimulus dependent autoassociative memory features. We use a simple spin glass-like model for the functional network of a beta-cell collective to describe these findings and argue that Ca2+ spike trains produced by collective sensing of beta-cells constitute part of the islet metabolic code that regulates insulin release and limits the islet size. PMID- 29416517 TI - Extending Situated Language Comprehension (Accounts) with Speaker and Comprehender Characteristics: Toward Socially Situated Interpretation. AB - More and more findings suggest a tight temporal coupling between (non-linguistic) socially interpreted context and language processing. Still, real-time language processing accounts remain largely elusive with respect to the influence of biological (e.g., age) and experiential (e.g., world and moral knowledge) comprehender characteristics and the influence of the 'socially interpreted' context, as for instance provided by the speaker. This context could include actions, facial expressions, a speaker's voice or gaze, and gestures among others. We review findings from social psychology, sociolinguistics and psycholinguistics to highlight the relevance of (the interplay between) the socially interpreted context and comprehender characteristics for language processing. The review informs the extension of an extant real-time processing account (already featuring a coordinated interplay between language comprehension and the non-linguistic visual context) with a variable ('ProCom') that captures characteristics of the language user and with a first approximation of the comprehender's speaker representation. Extending the CIA to the sCIA (social Coordinated Interplay Account) is the first step toward a real-time language comprehension account which might eventually accommodate the socially situated communicative interplay between comprehenders and speakers. PMID- 29416518 TI - Pleasures of the Mind: What Makes Jokes and Insight Problems Enjoyable. AB - In this paper, a parallel analysis of the enjoyment derived from humor and insight problem solving is presented with reference to a "general" Theory of the Pleasures of the Mind (TPM) (Kubovy, 1999) rather than to "local" theories regarding what makes humor and insight problem solving enjoyable. The similarity of these two cognitive activities has already been discussed in previous literature in terms of the cognitive mechanisms which underpin getting a joke or having an insight experience in a problem solving task. The paper explores whether we can learn something new about the similarities and differences between humor and problem solving by means of an investigation of what makes them pleasurable. In the first part of the paper, the framework for this joint analysis is set. Two descriptive studies are then presented in which the participants were asked to report on their experiences relating to solving visuo spatial insight problems (Study 1) or understanding cartoons (Study 2) in terms of whether they were enjoyable or otherwise. In both studies, the responses were analyzed with reference to a set of categories inspired by the TPM. The results of Study 1 demonstrate that finding the solution to a problem is associated with a positive evaluation, and the most frequent explanations for this were reported as being Curiosity, Virtuosity and Violation of expectations. The results of Study 2 suggest that understanding a joke (Joy of verification) and being surprised by it (Feeling of surprise) were two essential conditions: when they were not present, the cartoons were perceived as not enjoyable. However, this was not enough to explain the motivations for the choice of the most enjoyable cartoons. Recognizing a Violation of expectations and experiencing a Diminishment in the cleverness or awareness initially attributed to the characters in the cartoon were the aspects which were most frequently indicated by the participants to explain why they enjoyed the joke. These findings are evaluated in the final discussion, together with their limitations and potential future developments. PMID- 29416519 TI - Financial Planning for Retirement: A Psychosocial Perspective. AB - Retirement is a time of life that has grown ever longer in the developed world, and the number of pensioners has increased accordingly, questioning the strength of Social Security systems and the social safety net in general. Financial Planning for Retirement (FRP) consists of the series of activities involved in the accumulation of wealth to cover needs in the post-retirement stage of life. The negative short-, mid-, and long-term consequences of inadequate Financial Planning for Retirement do not only affect individuals, but also their extended families, homes, eventually producing an unwanted impact on the entire society. The Capacity-Willingness-Opportunity Model has been proposed to understand FPR, combined with Intentional Change Theory, a framework for understanding the process, antecedents and consequences of FPR. From this perspective, we propose this promising model, but there are a large number of variables that have not been included that offer novel ways to deepen our understanding of FPR. A focus on each dimension of the model, the role of age and psychosocial variables associated with demographic indicators such as gender, health status, and migration, allow us to provide a proposal of scientific advancement of FPR. PMID- 29416520 TI - The Experience of Couples in the Process of Treatment of Pathological Gambling: Couple vs. Individual Therapy. AB - Context: Couple treatment for pathological gambling is an innovative strategy. There are some results supporting its potential effectiveness, but little is known about the subjective experiences of the participants. Objective: The aim of this article is to document the experiences of gamblers and their partners participating in one of two treatments, namely individual or couple. Method: In a study aiming to evaluate the efficacy of the Integrative Couple Treatment for Pathological Gambling (ICT-PG), couples who were entering specialized treatment for the addiction of one member who was a pathological gambler were randomly assigned to individual or ICT-PG. Nine months after their admission to treatment, gamblers and partners (n = 21 couples; n = 13 ICT-PG; n = 8 individual treatment) were interviewed in semi-structured interviews. A sequenced thematization method was used to extract the major themes. Results: This study highlighted five major themes in the therapeutic process noted by the gamblers and their partners mainly after the couple treatment but also partly through the individual therapy. These were: (1) the gamblers' anxiety about having to reveal their gambling problems in couple therapy; (2) the wish to develop a mutually beneficial understanding of gambling and its effects on the partners in the two types of treatments; (3) the transformation of negative attributions through a more effective intra-couple communication fostered by the couple therapy; (4) the partners' contribution to changes in gambling behavior and prevention of relapses, which were both better supported in couple therapy; and (5) the interpersonal nature of gambling and its connections with the couples' relationship. However, gamblers who were in individual treatment were more likely to mention that their partners' involvement was not necessary. Participants likewise made a few recommendations about the conditions underlying the choice of one treatment method or the other. Discussion: Participants reported satisfaction with both treatment models, but their experience was more positive in couple treatment. Complementary benefits emerged from each form of treatment, which points to future treatments involving both types. Future research should explore both the couple processes associated with attempts to stop pathological gambling and the various ways of involving partners in the gamblers' treatment. PMID- 29416522 TI - Editorial: Transitions between Consciousness and Unconsciousness. PMID- 29416521 TI - Older Adults Benefit from Symmetry, but Not Semantic Availability, in Visual Working Memory. AB - Visual working memory exhibits age effects that are amongst the largest observed in the cognitive aging literature. In this research we investigated whether or not older adults can benefit from visual symmetry and semantic availability, as young adults typically do. Visual matrix pattern tasks varied in terms of the perceptual factor of symmetry (Experiment 1), as well as the availability of visual semantics, or long-term memory (LTM; Experiment 2). In Experiment 1, within a visual memory span protocol, four matrix pattern sets were employed with discrete symmetry characteristics; random, vertical, horizontal, and diagonal symmetry. Encoding time was 3 s with a 2 s maintenance interval. The findings indicated a significant difference in span level across age groups for all of the symmetry variants. More importantly, both younger and older adults could take advantage of symmetry in the matrix array in order to significantly improve task performance. In Experiment 2, two visual matrix task sets were used, with visual arrays of either low or high semantic availability (i.e., they contained stimuli with recognizable shapes that allow for LTM support). Encoding duration was 3 s with a 1 s retention interval. Here, the older adult sample was significantly impaired in span performance with both variants of the task. However, only the younger adult participants could take advantage of visual semantics. These findings show that, in the context of overall impairment in individual task performance, older adults remain capable of employing the perceptual cue of symmetry in order to improve visual working memory task performance. However, they appear less able, within this protocol, to recruit visual semantics in order to scaffold performance. PMID- 29416523 TI - A Fully Automated Pipeline for Normative Atrophy in Patients with Neurodegenerative Disease. AB - Introduction: Volumetric image analysis to detect progressive brain tissue loss in patients with multiple sclerosis (MS) has recently been suggested as a promising marker for "no evidence of disease activity." Software packages for longitudinal whole-brain volume analysis in individual patients are already in clinical use; however, most of these methods have omitted region-based analysis. Here, we suggest a fully automatic analysis pipeline based on the free software packages FSL and FreeSurfer. Materials and methods: Fifty-five T1-weighted magnetic resonance imaging (MRI) datasets of five patients with confirmed relapsing-remitting MS and mild to moderate disability were longitudinally analyzed compared to a morphometric reference database of 323 healthy controls (HCs). After lesion filling, the volumes of brain segmentations and morphometric parameters of cortical parcellations were automatically screened for global and regional abnormalities. Error margins and artifact probabilities of regional morphometric parameters were estimated. Linear models were fitted to the series of follow-up MRIs and checked for consistency with cross-sectional aging in HCs. Results: As compared to leave-one-out cross-validation in a subset of the control dataset, anomaly detection rates were highly elevated in MRIs of two patients. We detected progressive volume changes that were stronger than expected compared to normal aging in 4/5 patients. In individual patients, we also identified stronger than expected regional decreases of subcortical gray matter, of cortical thickness, and areas of reducing gray-white contrast over time. Conclusion: Statistical comparison with a large normative database may provide complementary and rater independent quantitative information about regional morphological changes related to disease progression or drug-related disease modification in individual patients. Regional volume loss may also be detected in clinically stable patients. PMID- 29416524 TI - Homozygous TBC1D24 Mutation in a Case of Epilepsia Partialis Continua. AB - TBC1D24 mutation-related epileptic syndrome includes a wide spectrum of epilepsies. We describe a case with a homozygous TBC1D24 mutation inherited from consanguineous parents. The patient manifested epilepsia partialis continua (EPC) and rare secondary generalized tonic-clonic seizure without intellectual disability or developmental delay. EPC, which involved focal limbs, came with waking and went with sleep. The genetic analysis reported a novel mutation in the TBC1D24 gene, c.229_240del (p.82_84del). The homozygous mutation was inherited from her healthy parents who were heterozygous. Morphometric analysis program (MAP), an MRI post-processing technique, was used and detected a subtle abnormality of the brain. A comprehensive analysis based on semiology, electroencephalogram, somatosensory-evoked potential, and MAP suggested a potential focal structural abnormality. This case indicates a possible correlation between the TBC1D24 mutation and brain development abnormality. PMID- 29416525 TI - Patient-Specific Alterations in CO2 Cerebrovascular Responsiveness in Acute and Sub-Acute Sports-Related Concussion. AB - Background: Preliminary studies suggest that sports-related concussion (SRC) is associated with alterations in cerebral blood flow (CBF) regulation. Here, we use advanced magnetic resonance imaging (MRI) techniques to measure CBF and cerebrovascular responsiveness (CVR) in individual SRC patients and healthy control subjects. Methods: 15 SRC patients (mean age = 16.3, range 14-20 years) and 27 healthy control subjects (mean age = 17.6, range 13-21 years) underwent anatomical MRI, pseudo-continuous arterial spin labeling (pCASL) MRI and model based prospective end-tidal targeting (MPET) of CO2 during blood oxygenation level-dependent (BOLD) MRI. Group differences in global mean resting CBF were examined. Voxel-by-voxel group and individual differences in regional CVR were examined using statistical parametric mapping (SPM). Leave-one-out receiver operating characteristic curve analysis was used to evaluate the utility of brain MRI CO2 stress testing biomarkers to correctly discriminate between SRC patients and healthy control subjects. Results: All studies were tolerated with no complications. Traumatic structural findings were identified in one SRC patient. No significant group differences in global mean resting CBF were observed. There were no significant differences in the CO2 stimulus and O2 targeting during BOLD MRI. Significant group and patient-specific differences in CVR were observed with SRC patients demonstrating a predominant pattern of increased CVR. Leave-one-out ROC analysis for voxels demonstrating a significant increase in CVR was found to reliably discriminate between SRC patients and healthy control subjects (AUC of 0.879, p = 0.0001). The optimal cutoff for increased CVR declarative for SRC was 1,899 voxels resulting in a sensitivity of 0.867 and a specificity of 0.778 for this specific ROC analysis. There was no correlation between abnormal voxel counts and Postconcussion Symptom Scale scores among SRC patients. Conclusion: Acute and subacute SRCs are associated with alterations in CVR that can be reliably detected by brain MRI CO2 stress testing in individual patients. PMID- 29416526 TI - Aldosterone Blocks Rat Stem Leydig Cell Development In Vitro. AB - Aldosterone (ALDO) is a primary endogenous mineralocorticoid, appearing as the main hormone controlling sodium and water homeostasis. Its emerging role in the development of many organs has gained interest over the past few years. In the testis, Leydig cells contain mineralocorticoid receptors and ALDO stimulates androgen synthesis via the mineralocorticoid receptors in rat adult Leydig cells. Although ALDO pharmacologically promoted the Leydig cell function, its role in Leydig cell development was unclear. In the present study, we investigated effects of ALDO on rat stem Leydig cell (SLC) proliferation and differentiation. Using an in vitro culture system of the seminiferous tubules from Leydig cell depleted testis and EdU (a modified thymidine analog) incorporation into the SLC for flurorescent labeling to judge its DNA synthesis and measurement of medium testosterone production, steroidogenesis-related gene and protein expression, we found that: (1) ALDO suppressed EdU incorporation into SLCs at 100 nM via mineralocorticoid receptor-mediated mechanism and (2) ALDO reduced Leydig cell number. In conclusion, ALDO pharmacologically blocked rat SLC development. PMID- 29416527 TI - The Impact of Type 2 Diabetes on Bone Fracture Healing. AB - Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease known by the presence of elevated blood glucose levels. Nowadays, it is perceived as a worldwide epidemic, with a very high socioeconomic impact on public health. Many are the complications caused by this chronic disorder, including a negative impact on the cardiovascular system, kidneys, eyes, muscle, blood vessels, and nervous system. Recently, there has been increasing evidence suggesting that T2DM also adversely affects the skeletal system, causing detrimental bone effects such as bone quality deterioration, loss of bone strength, increased fracture risk, and impaired bone healing. Nevertheless, the precise mechanisms by which T2DM causes detrimental effects on bone tissue are still elusive and remain poorly studied. The aim of this review was to synthesize current knowledge on the different factors influencing the impairment of bone fracture healing under T2DM conditions. Here, we discuss new approaches used in recent studies to unveil the mechanisms and fill the existing gaps in the scientific understanding of the relationship between T2DM, bone tissue, and bone fracture healing. PMID- 29416528 TI - Substrate Binding Protein DppA1 of ABC Transporter DppBCDF Increases Biofilm Formation in Pseudomonas aeruginosa by Inhibiting Pf5 Prophage Lysis. AB - Filamentous phage impact biofilm development, stress tolerance, virulence, biofilm dispersal, and colony variants. Previously, we identified 137 Pseudomonas aeruginosa PA14 mutants with more than threefold enhanced and 88 mutants with more than 10-fold reduced biofilm formation by screening 5850 transposon mutants (PLoS Pathogens5: e1000483, 2009). Here, we characterized the function of one of these 225 mutations, dppA1 (PA14_58350), in regard to biofilm formation. DppA1 is a substrate-binding protein (SBP) involved in peptide utilization via the DppBCDF ABC transporter system. We show that compared to the wild-type strain, inactivating dppA1 led to 68-fold less biofilm formation in a static model and abolished biofilm formation in flow cells. Moreover, the dppA1 mutant had a delay in swarming and produced 20-fold less small-colony variants, and both biofilm formation and swarming were complemented by producing DppA1. A whole transcriptome analysis showed that only 10 bacteriophage Pf5 genes were significantly induced in the biofilm cells of the dppA1 mutant compared to the wild-type strain, and inactivation of dppA1 resulted in a 600-fold increase in Pf5 excision and a million-fold increase in phage production. As expected, inactivating Pf5 genes PA0720 and PA0723 increased biofilm formation substantially. Inactivation of DppA1 also reduced growth (due to cell lysis). Hence, DppA1 increases biofilm formation by repressing Pf5 prophage. PMID- 29416530 TI - 'TIME': A Web Application for Obtaining Insights into Microbial Ecology Using Longitudinal Microbiome Data. AB - Realization of the importance of microbiome studies, coupled with the decreasing sequencing cost, has led to the exponential growth of microbiome data. A number of these microbiome studies have focused on understanding changes in the microbial community over time. Such longitudinal microbiome studies have the potential to offer unique insights pertaining to the microbial social networks as well as their responses to perturbations. In this communication, we introduce a web based framework called 'TIME' (Temporal Insights into Microbial Ecology'), developed specifically to obtain meaningful insights from microbiome time series data. The TIME web-server is designed to accept a wide range of popular formats as input with options to preprocess and filter the data. Multiple samples, defined by a series of longitudinal time points along with their metadata information, can be compared in order to interactively visualize the temporal variations. In addition to standard microbiome data analytics, the web server implements popular time series analysis methods like Dynamic time warping, Granger causality and Dickey Fuller test to generate interactive layouts for facilitating easy biological inferences. Apart from this, a new metric for comparing metagenomic time series data has been introduced to effectively visualize the similarities/differences in the trends of the resident microbial groups. Augmenting the visualizations with the stationarity information pertaining to the microbial groups is utilized to predict the microbial competition as well as community structure. Additionally, the 'causality graph analysis' module incorporated in TIME allows predicting taxa that might have a higher influence on community structure in different conditions. TIME also allows users to easily identify potential taxonomic markers from a longitudinal microbiome analysis. We illustrate the utility of the web-server features on a few published time series microbiome data and demonstrate the ease with which it can be used to perform complex analysis. PMID- 29416529 TI - Prebiotic Wheat Bran Fractions Induce Specific Microbiota Changes. AB - Wheat bran fibers are considered beneficial to human health through their impact on gut microbiota composition and activity. Here, we assessed the prebiotic potential of selected bran fractions by performing a series of fecal slurry anaerobic fermentation experiments using aleurone as well as total, ultrafine, and soluble wheat bran (swb) as carbon sources. By combining amplicon-based community profiling with a fluorescent in situ hybridization (FISH) approach, we found that incubation conditions favor the growth of Proteobacteria such as Escherichia and Bilophila. These effects were countered in all but one [total wheat bran (twb)] fermentation experiments. Growth of Bifidobacterium species was stimulated after fermentation using ultrafine, soluble, and twb, in the latter two as part of a general increase in bacterial load. Both ultrafine and swb fermentation resulted in a trade-off between Bifidobacterium and Bilophila, as previously observed in human dietary supplementation studies looking at the effect of inulin-type fructans on the human gut microbiota. Aleurone selectively stimulated growth of Dorea and butyrate-producing Roseburia. All fermentation experiments induced enhanced gas production; increased butyrate concentrations were only observed following soluble bran incubation. Our results open perspectives for the development of aleurone as a complementary prebiotic selectively targeting colon butyrate producers. PMID- 29416531 TI - Listeria monocytogenes Growth Kinetics in Milkshakes Made from Naturally and Artificially Contaminated Ice Cream. AB - This study assessed the growth of Listeria monocytogenes in milkshakes made using the process-contaminated ice cream associated with a listeriosis outbreak in comparison to milkshakes made with artificially contaminated ice cream. For all temperatures, growth kinetics including growth rates, lag phases, maximum populations, and population increases were determined for the naturally and artificially derived contaminants at 5, 10, 15, and 25 degrees C storage for 144 h. The artificially inoculated L. monocytogenes presented lower growth rates and shorter lag phases than the naturally contaminated populations at all temperatures except for 5 degrees C, where the reverse was observed. At 25 degrees C, lag phases of the naturally and artificially contaminated L. monocytogenes were 11.6 and 7.8 h, respectively. The highest increase in population was observed for the artificially inoculated pathogen at 15 degrees C after 96 h (6.16 log CFU/mL) of storage. Growth models for both contamination states in milkshakes were determined. In addition, this study evaluated the antimicrobial effectiveness of flavoring agents, including strawberry, chocolate and mint, on the growth of the pathogen in milkshakes during 10 degrees C storage. All flavor additions resulted in decreased growth rates of L. monocytogenes for both contamination states. The addition of chocolate and mint flavoring also resulted in significantly longer lag phases for both contamination states. This study provides insight into the differences in growth between naturally and artificially contaminated L. monocytogenes in a food product. PMID- 29416532 TI - Toll-Like Receptor 8 Agonist Strengthens the Protective Efficacy of ESAT-6 Immunization to Mycobacterium tuberculosis Infection. AB - Accumulating evidence suggests important functions for human Toll-like receptor 8 in vivo in tuberculosis and autoimmune diseases. However, these studies are limited by the lack of specific agonists and by the fact that the homology of TLR8 in human and mice is not sufficient to rely on mouse models. In this study, we examined the role of human TLR8 in the disease progression of experimental Mycobacterium tuberculosis (Mtb) infection, as well as the benefits provided by a TLR8 agonist against Mtb challenge in a human TLR8 transgenic mouse. We found that the expression of human TLR8 in C57BL/6 mice permits higher bacilli load in tissues. A vaccine formulated with ESAT-6, aluminum hydroxide, and TLR8 agonist provided protection against Mtb challenge, with a high percentage of CD44hiCD62Lhi TCM. Using ovalbumin as a model antigen, we demonstrated that the activation of TLR8 enhanced the innate and adaptive immune response, and provided a sustained TCM formation and Th1 type humoral response, which were mainly mediated by type I IFN signaling. Further research is required to optimize the vaccine formulation and seek optimal combinations of different TLR agonists, such as TLR4, for better adjuvanticity in this animal model. PMID- 29416533 TI - Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers. AB - Chronic graft versus host disease (cGVHD) is a common long-term complication after allogeneic hematopoietic stem cell transplantation. The objective of our study was to compare the metabolic profiles for allotransplant recipients and thereby identify metabolic characteristics of patients with treatment-requiring cGVHD. The study included 51 consecutive patients (29 men and 22 women; median age: 44 years, range: 15-66 years) transplanted with peripheral blood stem cells derived from human leukocyte antigen-matched family donors. All serum samples investigated by global metabolomic profiling were collected approximately 1 year posttransplant (median 358 days). Thirty-one of the 51 patients (61%) had cGVHD 1 year posttransplant. The affected organs were (number of patients) liver/bile duct (23), eyes (15), gastrointestinal tract (14), skin (13), mouth (10), lungs (3), and urogenital tract (1). We compared the metabolic profile for patients with and without cGVHD, and a Random Forrest Classification Analysis then resulted in 75% accuracy in differentiating the two groups. The 30 top-ranked metabolites from this comparison included increased levels of bile acids, several metabolites from the cytokine-responsive kynurenine pathway for tryptophan degradation, pro-inflammatory lipid metabolites, phenylalanine and tyrosine metabolites derived from the gut microbial flora, and metabolites reflecting increased oxidative stress. However, nine of these 30 top-ranked metabolites were probably altered due to cyclosporine or steroid treatment, and we therefore did a hierarchical clustering analysis including all 51 patients but only based on the other 21 cGVHD-specific metabolites. This analysis identified three patient subsets: one cluster included mainly patients without cGVHD and had generally low metabolite levels; another cluster included mainly patients with cGVHD (most patients with at least three affected organs) and high metabolite levels, and the last intermediate group including cGVHD patients with limited organ involvement. We conclude that allotransplant recipients with cGVHD have an altered metabolic profile caused both by the disease and its immunosuppressive treatment. PMID- 29416534 TI - NLRC4 Inflammasome-Driven Immunogenicity of a Recombinant MVA Mucosal Vaccine Encoding Flagellin. AB - Bacterial flagellin enhances innate and adaptive immune responses and is considered a promising adjuvant for the development of vaccines against infectious diseases and cancer. Antigen-presenting cells recognize flagellin with the extracellular TLR5 and the intracellular NLRC4 inflammasome-mediated pathway. The detailed cooperation of these innate pathways in the induction of the adaptive immune response following intranasal (i.n.) administration of a recombinant modified vaccinia virus Ankara (rMVA) vaccine encoding flagellin (rMVA-flagellin) is not known. rMVA-flagellin induced enhanced secretion of mucosal IL-1beta and TNF-alpha resulting in elevated CTL and IgG2c antibody responses. Importantly, mucosal IgA responses were also significantly enhanced in both bronchoalveolar (BAL) and intestinal lavages accompanied by the increased migration of CD8+ T cells to the mesenteric lymph nodes (MLN). Nlrc4-/- rMVA flagellin-immunized mice failed to enhance pulmonary CTL responses, IgG2c was lower, and IgA levels in the BAL or intestinal lavages were similar as those of control mice. Our results show the favorable adjuvant effect of rMVA-flagellin in the lung as well as the intestinal mucosa following i.n. administration with NLRC4 as the essential driver of this promising mucosal vaccine concept. PMID- 29416536 TI - Trichinella spiralis Excretory-Secretory Products Induce Tolerogenic Properties in Human Dendritic Cells via Toll-Like Receptors 2 and 4. AB - Trichinella spiralis, as well as its muscle larvae excretory-secretory products (ES L1), given either alone or via dendritic cells (DCs), induce a tolerogenic immune microenvironment in inbred rodents and successfully ameliorate experimental autoimmune encephalomyelitis. ES L1 directs the immunological balance away from T helper (Th)1, toward Th2 and regulatory responses by modulating DCs phenotype. The ultimate goal of our work is to find out if it is possible to translate knowledge obtained in animal model to humans and to generate human tolerogenic DCs suitable for therapy of autoimmune diseases through stimulation with ES L1. Here, the impact of ES L1 on the activation of human monocyte-derived DCs is explored for the first time. Under the influence of ES L1, DCs acquired tolerogenic (semi-matured) phenotype, characterized by low expression of HLA-DR, CD83, and CD86 as well as moderate expression of CD40, along with the unchanged production of interleukin (IL)-12 and elevated production of IL-10 and transforming growth factor (TGF)-beta, compared to controls. The interaction with DCs involved toll-like receptors (TLR) 2 and 4, and this interaction was mainly responsible for the phenotypic and functional properties of ES L1-treated DCs. Importantly, ES L1 potentiated Th2 polarizing capacity of DCs, and impaired their allo-stimulatory and Th1/Th17 polarizing properties. Moreover, ES L1-treated DCs promoted the expansion of IL-10- and TGF beta- producing CD4+CD25hiFoxp3hi T cells in indolamine 2, 3 dioxygenase (IDO)-1 dependent manner and increased the suppressive potential of the primed T cell population. ES L1-treated DCs retained the tolerogenic properties, even after the challenge with different pro-inflammatory stimuli, including those acting via TLR3 and, especially TLR4. These results suggest that the induction of tolerogenic properties of DCs through stimulation with ES L1 could represent an innovative approach for the preparation of tolerogenic DC for treatment of inflammatory and autoimmune disorders. PMID- 29416535 TI - Nutrients Mediate Intestinal Bacteria-Mucosal Immune Crosstalk. AB - The intestine is the shared site of nutrient digestion, microbiota colonization and immune cell location and this geographic proximity contributes to a large extent to their interaction. The onset and development of a great many diseases, such as inflammatory bowel disease and metabolic syndrome, will be caused due to the imbalance of body immune. As competent assistants, the intestinal bacteria are also critical in disease prevention and control. Moreover, the gut commensal bacteria are essential for development and normal operation of immune system and the pathogens are also closely bound up with physiological disorders and diseases mediated by immune imbalance. Understanding how our diet and nutrient affect bacterial composition and dynamic function, and the innate and adaptive status of our immune system, represents not only a research need but also an opportunity or challenge to improve health. Herein, this review focuses on the recent discoveries about intestinal bacteria-immune crosstalk and nutritional regulation on their interplay, with an aim to provide novel insights that can aid in understanding their interactions. PMID- 29416538 TI - Divergent Roles of Interferon-gamma and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation. AB - Aberrant interferon gamma (IFNgamma) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNgamma for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNgamma in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNgamma drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNgamma secreted by both transferred CD4 T cells and/or cells of the lymphopenic Rag1-/- recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNgamma, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNgamma-deficient mice reduced T cell mediated colitis. Intriguingly, in contrast to the anti-CD40 model of colitis, depletion of ILC in the Rag1-/- recipients of colitogenic CD4 T cells did not prevent induction of colonic inflammation. Together, our findings demonstrate that IFNgamma represents an essential, or a redundant, pro-inflammatory cytokine for the induction of intestinal inflammation, depending on the experimental mouse model used and on the nature of the critical disease inducing immune cell populations involved. PMID- 29416537 TI - Prior to Peripheral Tolerance, Newly Generated CD4 T Cells Maintain Dangerous Autoimmune Potential: Fas- and Perforin-Independent Autoimmunity Controlled by Programmed Death-1. AB - Lymphopenia can result from various factors, including viral infections, clinical interventions, or as a normal property of the fetal/neonatal period. T cells in a lymphopenic environment undergo lymphopenia-induced proliferation (LIP) to fill the available "niche" as defined by peptide-MHC and homeostatic cytokine resources. We recently reported systemic autoimmunity following reconstitution of the lymphoid compartment of Rag1-/- mice with PD-1-/- hematopoietic stem cells or by transfer of thymocytes, but not splenocytes, suggesting that programmed death 1 (PD-1) plays a crucial role in controlling recent thymic emigrants (RTE) and preventing autoimmunity upon their LIP. However, it is unclear whether RTE residing within the periphery of a lymphoreplete host maintain enhanced autoimmune generating potential or if this property only manifests if RTE experience a lymphopenic periphery immediately after export from the thymus. Furthermore, it is unclear which of a variety of T cell effector mechanisms generate pathology when control of RTE by PD-1 is lacking. Herein, we determined that PD-1 is upregulated on CD4 T cells undergoing the natural LIP characteristic of the neonatal period. Newly generated T cells lacking PD-1 maintained an enhanced autoimmune potential even after residence in a lymphoreplete periphery, emphasizing the importance of PD-1 in the establishment of peripheral tolerance. Neither Fas nor perforin-dependent killing mechanisms were required for autoimmunity, while host MHC-II expression was critical, suggesting that LIP driven autoimmunity in the absence of PD-1 may primarily result from a CD4 T cell mediated systemic cytokinemia, a feature potentially shared by other autoimmune or inflammatory syndromes associated with immune reconstitution and LIP. PMID- 29416540 TI - Induction of Short NFATc1/alphaA Isoform Interferes with Peripheral B Cell Differentiation. AB - In lymphocytes, immune receptor signals induce the rapid nuclear translocation of preformed cytosolic NFAT proteins. Along with co-stimulatory signals, persistent immune receptor signals lead to high levels of NFATc1/alphaA, a short NFATc1 isoform, in effector lymphocytes. Whereas NFATc1 is not expressed in plasma cells, in germinal centers numerous centrocytic B cells express nuclear NFATc1/alphaA. When overexpressed in chicken DT40 B cells or murine WEHI 231 B cells, NFATc1/alphaA suppressed their cell death induced by B cell receptor signals and affected the expression of genes controlling the germinal center reaction and plasma cell formation. Among those is the Prdm1 gene encoding Blimp 1, a key factor of plasma cell formation. By binding to a regulatory DNA element within exon 1 of the Prdm1 gene, NFATc1/alphaA suppresses Blimp-1 expression. Since expression of a constitutive active version of NFATc1/alphaA interfered with Prdm1 RNA expression, LPS-mediated differentiation of splenic B cells to plasmablasts in vitro and reduced immunoglobulin production in vivo, one may conclude that NFATc1/alphaA plays an important role in controlling plasmablast/plasma cell formation. PMID- 29416539 TI - Adjuvant Effect of Bacille Calmette-Guerin on Hepatitis B Vaccine Immunogenicity in the Preterm and Term Newborn. AB - Immunization is key to protecting term and preterm infants from a heightened risk of infection. However, preterm immunity is distinct from that of the term, limiting its ability to effectively respond to vaccines routinely given at birth, such as hepatitis B vaccine (HBV). As part of the Expanded Program on Immunization, HBV is often given together with the live-attenuated vaccine Bacille Calmette-Guerin (BCG), known to activate multiple pattern-recognition receptors. Of note, some clinical studies suggest BCG can enhance efficacy of other vaccines in term newborns. However, little is known about whether BCG can shape Th-polarizing cytokine responses to HBV nor the age-dependency of such effects, including whether they may extend to the preterm. To characterize the effects of BCG on HBV immunogenicity, we studied individual and combined administration of these vaccines to cord newborn and adult human whole blood and mononuclear cells in vitro and to neonatal and adult mice in vivo. Compared to either BCG or HBV alone, (BCG + HBV) synergistically enhanced in vitro whole blood production of IL-1beta, while (BCG + HBV) also promoted production of several cytokines/chemokines in all age groups, age-specific enhancement included IL-12p70 in the preterm and GM-CSF in the preterm and term. In human mononuclear cells, (BCG + HBV) enhanced mRNA expression of several genes including CSF2, which contributed to clustering of genes by vaccine treatment via principle component analysis. To assess the impact of BCG on HBV immunization, mice of three different age groups were immunized subcutaneously with, BCG, HBV, (BCG + HBV) into the same site; or BCG and HBV injected into separate sites. Whether injected into a separate site or at the same site, co-administration of BCG with HBV significantly enhanced anti-HBV IgG titers in mice immunized on day of life-0 or -7, respectively, but not in adult mice. In summary, our data demonstrate that innate and adaptive vaccine responses of preterm and term newborns are immunologically distinct. Furthermore, BCG or "BCG-like" adjuvants should be further studied as a promising adjuvantation approach to enhance immunogenicity of vaccines to protect these vulnerable populations. PMID- 29416541 TI - Herpesvirus Infection Induces both Specific and Heterologous Antiviral Antibodies in Carp. AB - IgM antibody diversity induced by viral infection in teleost fish sera remains largely unexplored despite several studies performed on their transcript counterparts in lymphoid organs. Here, IgM binding to microarrays containing ~20,000 human proteins was used to study sera from carp (Cyprinus carpio) populations having high titers of viral neutralization in vitro after surviving an experimental infection with cyprinid herpes virus 3 (CyHV-3). The range of diversity of the induced antibodies was unexpectedly high, showing CyHV-3 infection-dependent, non-specific IgM-binding activity of a ~20-fold wider variety than that found in sera from healthy carp (natural antibodies) with no anti-CyHV-3 neutralization titers. An inverse correlation between the IgM-binding levels in healthy versus infection-survivor/healthy ratios suggests that an infection-dependent feed back-like mechanism may control such clonal expansion. Surprisingly, among the infection-expanded levels, not only specific anti frgIICyHV-3 and anti-CyHV-3 IgM-binding antibodies but also antibodies recognizing recombinant fragment epitopes from heterologous fish rhabdoviruses were detected in infection-survivor carp sera. Some alternative explanations for these findings in lower vertebrates are discussed. PMID- 29416542 TI - Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection. AB - A family of transcription factors known as E proteins, and their antagonists, Id proteins, regulate T cell differentiation at critical developmental checkpoints. Id proteins promote the differentiation of conventional alphabeta T cells and suppress the expansion of innate-like alphabeta T cells known as invariant natural killer T (iNKT) cells. However, it remains to be determined whether Id proteins differentially regulate these distinct lineage choices in early stages of T cell development. In this manuscript, we report that in Id-deficient mice, uninhibited activity of the E protein family member E2A mediates activation of genes that support iNKT cell development and function. There is also biased rearrangement in Id-deficient DP cells that promotes selection into the iNKT lineage in these mice. The observed expansion of iNKT cells is not abrogated by blocking pre-TCR signaling, which is required for conventional alphabeta T cell development. Finally, E2A is found to be a key transcriptional regulator of both iNKT and gammadeltaNKT lineages, which appear to have shared lineage history. Therefore, our study reveals a previously unappreciated role of E2A in coordinating the development of the iNKT lineage at an early stage, prior to their TCR-mediated selection alongside conventional alphabeta T cells. PMID- 29416543 TI - Neutralizing Antibodies Induced by Gene-Based Hydrodynamic Injection Have a Therapeutic Effect in Lethal Influenza Infection. AB - The influenza virus causes annual epidemics and occasional pandemics and is thus a major public health problem. Development of vaccines and antiviral drugs is essential for controlling influenza virus infection. We previously demonstrated the use of vectored immune-prophylaxis against influenza virus infection. We generated a plasmid encoding neutralizing IgG monoclonal antibodies (mAbs) against A/PR/8/34 influenza virus (IAV) hemagglutinin (HA). We then performed electroporation of the plasmid encoding neutralizing mAbs (EP) in mice muscles and succeeded in inducing the expression of neutralizing antibodies in mouse serum. This therapy has a prophylactic effect against lethal IAV infection in mice. In this study, we established a new method of passive immunotherapy after IAV infection. We performed hydrodynamic injection of the plasmid encoding neutralizing mAbs (HD) involving rapid injection of a large volume of plasmid-DNA solution into mice via the tail vein. HD could induce neutralizing antibodies in the serum and in several mucosal tissues more rapidly than in EP. We also showed that a single HD completely protected the mice even after infection with a lethal dose of IAV. We also established other isotypes of anti-HA antibody (IgA, IgM, IgD, and IgE) and showed that like anti-HA IgG, anti-HA IgA was also effective at combating upper respiratory tract IAV infection. Passive immunotherapy with HD could thus provide a new therapeutic strategy targeting influenza virus infection. PMID- 29416544 TI - Whole-Cell or Acellular Pertussis Primary Immunizations in Infancy Determines Adolescent Cellular Immune Profiles. AB - Introduction: Pertussis is re-emerging worldwide, despite effective immunization programs for infants and children. Epidemiological studies show a more limited duration of protection against clinical pertussis in adolescents primed with acellular pertussis (aP) vaccines during infancy than those who have been primed with whole-cell pertussis (wP) vaccines. This study aimed to determine whether memory immune responses to aP, diphtheria, and tetanus vaccine antigens following booster vaccinations at 4 and 9 years of age differ between wP- versus aP-primed children. Methods: In a cross-sectional study, blood was collected of DTwP- or diphtheria, tetanus, and aP (DTaP)-primed children before, 1 month, and 2 years after the preschool DTaP booster administered at 4 years of age (n = 41-63 per time point). In a longitudinal study, blood was sampled of DTwP- or DTaP-primed children before, 1 month, and 1 year after a preadolescent Tdap booster at 9 years of age (n = 79-83 per time point). Pertussis, diphtheria, and tetanus vaccine antigen-specific IgG levels, B-cell and T-cell responses were determined. Results: After the preschool booster vaccination, IgG levels were significantly higher in aP-primed as compared with wP-primed children until 6 years of age. Before the preadolescent Tdap booster vaccination, humoral and cellular immune responses were similar in aP- and wP-primed children. However, the Tdap booster vaccination induced lower vaccine antigen-specific humoral, B-cell, and T-helper 1 (Th1) cell responses resulting in significantly lower Th1/Th2 ratios in aP primed compared with wP-primed children. Conclusion: The memory immune profiles at preadolescent age to all DTaP vaccine antigens are already determined by the wP or aP combination vaccines given in infancy, showing a beneficial Th1 dominated response after wP-priming. These immunological data corroborate epidemiological data showing that DTaP-primed adolescents are less protected against clinical pertussis than DTwP-primed children. PMID- 29416545 TI - Disentangling the Effects of Water Stress on Carbon Acquisition, Vegetative Growth, and Fruit Quality of Peach Trees by Means of the QualiTree Model. AB - Climate change projections predict warmer and drier conditions. In general, moderate to severe water stress reduce plant vegetative growth and leaf photosynthesis. However, vegetative and reproductive growths show different sensitivities to water deficit. In fruit trees, water restrictions may have serious implications not only on tree growth and yield, but also on fruit quality, which might be improved. Therefore, it is of paramount importance to understand the complex interrelations among the physiological processes involved in within-tree carbon acquisition and allocation, water uptake and transpiration, organ growth, and fruit composition when affected by water stress. This can be studied using process-based models of plant functioning, which allow assessing the sensitivity of various physiological processes to water deficit and their relative impact on vegetative growth and fruit quality. In the current study, an existing fruit-tree model (QualiTree) was adapted for describing the water stress effects on peach (Prunus persica L. Batsch) vegetative growth, fruit size and composition. First, an energy balance calculation at the fruit-bearing shoot level and a water transfer formalization within the plant were integrated into the model. Next, a reduction function of vegetative growth according to tree water status was added to QualiTree. Then, the model was parameterized and calibrated for a late-maturing peach cultivar ("Elberta") under semi-arid conditions, and for three different irrigation practices. Simulated vegetative and fruit growth variability over time was consistent with observed data. Sugar concentrations in fruit flesh were well simulated. Finally, QualiTree allowed for determining the relative importance of photosynthesis and vegetative growth reduction on carbon acquisition, plant growth and fruit quality under water constrains. According to simulations, water deficit impacted vegetative growth first through a direct effect on its sink strength, and; secondly, through an indirect reducing effect on photosynthesis. Fruit composition was moderately affected by water stress. The enhancements performed in the model broadened its predictive capabilities and proved that QualiTree allows for a better understanding of the water stress effects on fruit-tree functioning and might be useful for designing innovative horticultural practices in a changing climate scenario. PMID- 29416546 TI - GSHR, a Web-Based Platform Provides Gene Set-Level Analyses of Hormone Responses in Arabidopsis. AB - Phytohormones regulate diverse aspects of plant growth and environmental responses. Recent high-throughput technologies have promoted a more comprehensive profiling of genes regulated by different hormones. However, these omics data generally result in large gene lists that make it challenging to interpret the data and extract insights into biological significance. With the rapid accumulation of theses large-scale experiments, especially the transcriptomic data available in public databases, a means of using this information to explore the transcriptional networks is needed. Different platforms have different architectures and designs, and even similar studies using the same platform may obtain data with large variances because of the highly dynamic and flexible effects of plant hormones; this makes it difficult to make comparisons across different studies and platforms. Here, we present a web server providing gene set level analyses of Arabidopsis thaliana hormone responses. GSHR collected 333 RNA seq and 1,205 microarray datasets from the Gene Expression Omnibus, characterizing transcriptomic changes in Arabidopsis in response to phytohormones including abscisic acid, auxin, brassinosteroids, cytokinins, ethylene, gibberellins, jasmonic acid, salicylic acid, and strigolactones. These data were further processed and organized into 1,368 gene sets regulated by different hormones or hormone-related factors. By comparing input gene lists to these gene sets, GSHR helped to identify gene sets from the input gene list regulated by different phytohormones or related factors. Together, GSHR links prior information regarding transcriptomic changes induced by hormones and related factors to newly generated data and facilities cross-study and cross-platform comparisons; this helps facilitate the mining of biologically significant information from large-scale datasets. The GSHR is freely available at http://bioinfo.sibs.ac.cn/GSHR/. PMID- 29416547 TI - Tree Species with Photosynthetic Stems Have Greater Nighttime Sap Flux. AB - An increasing body of evidence has shown that nighttime sap flux occurs in most plants, but the physiological implications and regulatory mechanism are poorly known. The significance of corticular photosynthesis has received much attention during the last decade, however, the knowledge of the relationship between corticular photosynthesis and nocturnal stem sap flow is limited at present. In this study, we divided seven tree species into two groups according to different photosynthetic capabilities: trees of species with (Castanopsis hystrix, Michelia macclurei, Eucalyptus citriodora, and Eucalyptus grandis * urophylla) and without (Castanopsis fissa, Schima superba, and Acacia auriculiformis) photosynthetic stems, and the sap flux (Js) and chlorophyll fluorescence parameters for these species were measured. One-way ANOVA analysis showed that the Fv/Fm (Maximum photochemical quantum yield of PSII) and PhiPSII (effective photochemical quantum yield of PSII) values were lower in non-photosynthetic stem species compared to photosynthetic stem species. The linear regression analysis showed that Js,d (daytime sap flux) and Js,n (nighttime sap flux) of non-photosynthetic stem species was 87.7 and 60.9% of the stem photosynthetic species. Furthermore, for a given daytime transpiration water loss, total nighttime sap flux was higher in species with photosynthetic stems (SlopeSMA = 2.680) than in non-photosynthetic stems species (SlopeSMA = 1.943). These results mean that stem corticular photosynthesis has a possible effect on the nighttime water flow, highlighting the important eco-physiological relationship between nighttime sap flux and corticular photosynthesis. PMID- 29416548 TI - Modified Polyadenylation-Based RT-qPCR Increases Selectivity of Amplification of 3'-MicroRNA Isoforms. AB - MicroRNA (miRNA) detection by reverse transcription (RT) quantitative real-time PCR (RT-qPCR) is the most popular method currently used to measure miRNA expression. Although the majority of miRNA families are constituted of several 3' end length variants ("isomiRs"), little attention has been paid to their differential detection by RT-qPCR. However, recent evidence indicates that 3'-end miRNA isoforms can exhibit 3'-length specific regulatory functions, underlining the need to develop strategies to differentiate 3'-isomiRs by RT-qPCR approaches. We demonstrate here that polyadenylation-based RT-qPCR strategies targeted to 20 21 nt isoforms amplify entire miRNA families, but that primers targeted to >22 nt isoforms were specific to >21 nt isoforms. Based on this observation, we developed a simple method to increase selectivity of polyadenylation-based RT qPCR assays toward shorter isoforms, and demonstrate its capacity to help distinguish short RNAs from longer ones, using synthetic RNAs and biological samples with altered isomiR stoichiometry. Our approach can be adapted to many polyadenylation-based RT-qPCR technologies already exiting, providing a convenient way to distinguish long and short 3'-isomiRs. PMID- 29416549 TI - ACTN3, Morbidity, and Healthy Aging. AB - As human longevity increases, recent research has focused on the maintenance of optimal health during old age. One such area of focus is that of muscle function in the elderly, with a loss of muscle mass increasing the risk of negative outcomes such as sarcopenia and a decrease in bone mineral density. In this mini review, we focus on the impact of a single nucleotide polymorphism in ACTN3, shown to impact muscle phenotype in elite athletes, on loss of muscle function, maintenance of bone mineral density, and metabolic disorder risk in an elderly population. From the surveyed research, this polymorphism has a clear and demonstrable impact on muscle phenotype and bone mineral density in this population, and acts as a potential modulator for metabolic disorders. As such, knowledge of an individual's ACTN3 genotype may better inform the management of risk factors in the elderly, as well as driving innovations in exercise program design. Subsequently, such insights may contribute to the prolonged maintenance of health and function long into old age. PMID- 29416550 TI - The Wnt7b/beta-catenin signaling pathway is involved in the protective action of calcitonin gene-related peptide on hyperoxia-induced lung injury in premature rats. AB - Background: Calcitonin gene-related peptide (CGRP) can protect against hyperoxia induced lung injury, making the upregulation of CGRP a potential therapeutic approach for this type of injury. However, the effects of CGRP on the Wnt7b/beta catenin signaling pathway are unclear. In this study, we investigated the roles of CGRP and the Wnt7b/beta-catenin signaling pathway in hyperoxia-induced lung injury. Methods: Premature Sprague Dawley (SD) rats were exposed to 21, 40, 60 and 95% oxygen for 3, 7 and 14 days. The animals' body weights, survival rates and endogenous CGRP levels were measured. Lung samples were harvested for histological analyses and measurements of malondialdehyde (MDA) concentration and total antioxidant capacity (TAOC). We also assessed the MDA concentration and TAOC in the lung tissues after administration of 200 nmol/kg CGRP8-37 (a CGRP antagonist). Finally, alveolar epithelial type II (AEC II) cells were isolated from premature rats, exposed to 21 or 95% oxygen for 3, 7 and 14 days, and treated with 10- 8 mol/l exogenous CGRP. The protein expressions of Wnt7b and beta-catenin were assessed using western blotting, and TCF and c-myc mRNA expressions were assessed using qPCR. Results: Rats exposed to 60 and 95% oxygen had significantly lower body weights and survival rates than the 21 and 40% groups, and the decrease was time dependent. Endogenous CGRP was elevated in the lung tissues of premature rats exposed to 95% oxygen. CGRP8-37 induced apparent inflammation in the lung tissue and alveolar structural remodeling. In addition, the expression levels of Wnt7b and beta-catenin were markedly increased after exposure for 3 days. They peaked at 7 days, then declined at 14 days. The levels of TCF/c-myc in AEC II cells increased significantly after CGRP treatment when compared with cells that had only undergone hyperoxia. Conclusions: CGRP protected against hyperoxia-induced lung injury in premature rats. This process involves the Wnt7b/beta-catenin signaling pathway. PMID- 29416551 TI - Interventions to restore appropriate immune function in the elderly. AB - Advanced age is one indicator of likely immune dysfunction. As worldwide, the global population contains progressively more and more older individuals there is likelihood of an increased prevalence and incidence of infectious diseases due to common and emergent pathogens. The resultant increase in mortality and morbidity would be matched by the risk of functional decline and disability. Maintaining immune function at a plateau throughout life may therefore be associated with considerable cost savings. The aim of improving immune function in older individuals may be achieved through considering a therapeutic approach to rejuvenate, stimulate or support the indigenous immune system to perform in a more optimal manner. In terms of cost effectiveness a therapeutic approach may prove difficult because of issues associated with; identifying those who would benefit the most from this treatment, identifying the type of treatment which would suit them and identifying whether the treatment was successful. The alternative of supporting or providing a stronger stimulus through vaccination, whilst more cost effective, may be a more valuable option in the short term. Both approaches will be addressed in this review. PMID- 29416552 TI - Fructo-oligosaccharides and glucose homeostasis: a systematic review and meta analysis in animal models. AB - The aim of this systematic review was to assess the effect of fructo oligosaccharide supplementation on glucose homeostasis. The search process was based on the selection of publications listed in the Pubmed-Medline database until April 2016 to identify studies evaluating the impact of short-chain fructo oligosaccharides or oligofructose on glucose homeostasis. Twenty-nine trials were included in the systematic review and the meta-analysis was performed on twelve of these papers according to the inclusion criteria. Fasting blood concentrations of glucose and insulin were selected as pertinent criteria of glucose homeostasis for the meta-analysis. The consumption of fructo-oligosaccharides decreased fasting blood glycaemia levels, whatever the metabolic status (healthy, obese or diabetic) and diet (low-fat or high-fat) throughout the experiment. This reduction was linear with prebiotic dose (from 0 to 13% of the feed). Fasting insulinaemia also decreased linearly with fructo-oligosaccharide supplementation but the reduction was only significant in rodents fed a low-fat diet. Potential underlying mechanisms include gut bacterial fermentation of fructo oligosaccharides to short-chain fatty acids (SCFA) and bacterial modulation of bile acids, both interacting with host metabolism. This systemic review, followed by the meta-analysis, provides evidence that fructo-oligosaccharide supplementation has a significant effect on glucose homeostasis whatever the health status and diet consumed by animals. PMID- 29416553 TI - Phasing in on the cell cycle. AB - Just like all matter, proteins can also switch between gas, liquid and solid phases. Protein phase transition has claimed the spotlight in recent years as a novel way of how cells compartmentalize and regulate biochemical reactions. Moreover, this discovery has provided a new framework for the study of membrane less organelle biogenesis and protein aggregation in neurodegenerative disorders. We now argue that this framework could be useful in the study of cell cycle regulation and cancer. Based on our work on phase transitions of arginine-rich proteins in neurodegeneration, via combining mass spectroscopy with bioinformatics analyses, we found that also numerous proteins involved in the regulation of the cell cycle can undergo protein phase separation. Indeed, several proteins whose function affects the cell cycle or are associated with cancer, have been recently found to phase separate from the test tube to cells. Investigating the role of this process for cell cycle proteins and understanding its molecular underpinnings will provide pivotal insights into the biology of cell cycle progression and cancer. PMID- 29416556 TI - SWOT analysis and revelation in traditional Chinese medicine internationalization. AB - Traditional Chinese medicine (TCM) is currently the best-preserved and most influential traditional medical system with the largest number of users worldwide. In recent years, the trend of TCM adoption has increased greatly, but the process of TCM internationalization has suffered from a series of setbacks for both internal and external reasons. Thus, the process of TCM internationalization faces formidable challenges, although it also has favourable opportunities. Using SWOT analysis, this paper investigates the strengths, weaknesses, opportunities and threats for TCM. These findings can serve as references for TCM enterprises with global ambitions. PMID- 29416557 TI - Prevalence of human papillomavirus infection among Iranian women using COBAS HPV DNA testing. AB - Background: Persistent infection with High Risk Human Papillomavirus (HR HPV) typesplaysamajor role in the development of cervical cancer. Therefore, the detection of HR HPV types is an essential part of cervical cancer screening. The aim of this study was to estimate the prevalence of HR HPV infection among healthy women undergoing routine cervical cancer screening in Iran. Methods: In this cross-sectional study,the results of HPV DNA typing in 2453 normal Iranian womenwhowere referred for routine cervical cancer screening from September 2015 to March 2017 were analyzed. Participants were screened using COBAS assay for HPV DNA typing and liquid based cytology. Results: A total of 2453 healthy sexually active women were included in this study. The mean age was 35.1 +/- 8.08 years. The overall prevalence of HR HPV infection was 10.3%. HPV16 was found in 73 (3%) women. The prevalence of HPV18 and other HR HPV typeswere 16(0.7%) and166 (8.2%),respectively. Approximately, 5% of the study population had an abnormal cervical cytology (ASCUS or worse), of whom 34% were infected by HR HPV. Conclusion: The prevalence of HR HPV infection among Iranian women has increased in the recent years which indicates the need for public education and health planning toprevent this cancer through vaccination and early diagnosis using screening tests.HPV DNA typing, diagnosisand the distribution of prevalent genotypes should be considered in the development of comprehensive cervical cancer prevention programs in Iran. PMID- 29416555 TI - Raising concerns about the Sepsis-3 definitions. AB - The Global Alliance for Infections in Surgery appreciates the great effort of the task force who derived and validated the Sepsis-3 definitions and considers the new definitions an important step forward in the evolution of our understanding of sepsis. Nevertheless, more than a year after their publication, we have a few concerns regarding the use of the Sepsis-3 definitions. PMID- 29416558 TI - Organic acid production from potato starch waste fermentation by rumen microbial communities from Dutch and Thai dairy cows. AB - Background: Exploring different microbial sources for biotechnological production of organic acids is important. Dutch and Thai cow rumen samples were used as inocula to produce organic acid from starch waste in anaerobic reactors. Organic acid production profiles were determined and microbial communities were compared using 16S ribosomal ribonucleic acid gene amplicon pyrosequencing. Results: In both reactors, lactate was the main initial product and was associated with growth of Streptococcus spp. (86% average relative abundance). Subsequently, lactate served as a substrate for secondary fermentations. In the reactor inoculated with rumen fluid from the Dutch cow, the relative abundance of Bacillus and Streptococcus increased from the start, and lactate, acetate, formate and ethanol were produced. From day 1.33 to 2, lactate and acetate were degraded, resulting in butyrate production. Butyrate production coincided with a decrease in relative abundance of Streptococcus spp. and increased relative abundances of bacteria of other groups, including Parabacteroides, Sporanaerobacter, Helicobacteraceae, Peptostreptococcaceae and Porphyromonadaceae. In the reactor with the Thai cow inoculum, Streptococcus spp. also increased from the start. When lactate was consumed, acetate, propionate and butyrate were produced (day 3-4). After day 3, bacteria belonging to five dominant groups, Bacteroides, Pseudoramibacter_Eubacterium, Dysgonomonas, Enterobacteriaceae and Porphyromonadaceae, were detected and these showed significant positive correlations with acetate, propionate and butyrate levels. Conclusions: The complexity of rumen microorganisms with high adaptation capacity makes rumen fluid a suitable source to convert organic waste into valuable products without the addition of hydrolytic enzymes. Starch waste is a source for organic acid production, especially lactate. PMID- 29416554 TI - 2017 WSES guidelines for the management of iatrogenic colonoscopy perforation. AB - Iatrogenic colonoscopy perforation (ICP) is a severe complication that can occur during both diagnostic and therapeutic procedures. Although 45-60% of ICPs are diagnosed by the endoscopist while performing the colonoscopy, many ICPs are not immediately recognized but are instead suspected on the basis of clinical signs and symptoms that occur after the endoscopic procedure. There are three main therapeutic options for ICPs: endoscopic repair, conservative therapy, and surgery. The therapeutic approach must vary based on the setting of the diagnosis (intra- or post-colonoscopy), the type of ICP, the characteristics and general status of the patient, the operator's level of experience, and surgical device availability. Although ICPs have been the focus of numerous publications, no guidelines have been created to standardize the management of ICPs. The aim of this article is to present the World Society of Emergency Surgery (WSES) guidelines for the management of ICP, which are intended to be used as a tool to promote global standards of care in case of ICP. These guidelines are not meant to substitute providers' clinical judgment for individual patients, and they may need to be modified based on the medical team's level of experience and the availability of local resources. PMID- 29416559 TI - A systematic optimization of styrene biosynthesis in Escherichia coli BL21(DE3). AB - Background: Styrene is a versatile commodity petrochemical used as a monomer building-block for the synthesis of many useful polymers. Although achievements have been made on styrene biosynthesis in microorganisms, several bottleneck problems limit factors for further improvement in styrene production. Results: A two-step styrene biosynthesis pathway was developed and introduced into Escherichia coli BL21(DE3). Systematic optimization of styrene biosynthesis, such as enzyme screening, codon and plasmid optimization, metabolic flow balance, and in situ fermentation was performed. Candidate isoenzymes of the rate-limiting enzyme phenylalanine ammonia lyase (PAL) were screened from Arabidopsis thaliana (AtPAL2), Fagopyrum tataricum (FtPAL), Petroselinum crispum (PcPAL), and Artemisia annua (AaPAL). After codon optimization, AtPAL2 was found to be the most effective one, and the engineered strain was able to produce 55 mg/L styrene. Subsequently, plasmid optimization was performed, which improved styrene production to 103 mg/L. In addition, two upstream shikimate pathway genes, aroF and pheA, were overexpressed in the engineered strain, which resulted in styrene production of 210 mg/L. Subsequently, combined overexpression of tktA and ppsA increased styrene production to 275 mg/L. Finally, in situ product removal was used to ease the burden of end-product toxicity. By using isopropyl myristate as a solvent, styrene production reached a final titer of 350 mg/L after 48 h of shake-flask fermentation, representing a 636% improvement, which compared with that achieved in the original strain. Conclusions: This present study achieved the highest titer of de novo production of styrene in E. coli at shake-flask fermentation level. These results obtained provided new insights for the development of microbial production of styrene in a sustainable and environment friendly manner. PMID- 29416560 TI - Disruption of zinc finger DNA binding domain in catabolite repressor Mig1 increases growth rate, hyphal branching, and cellulase expression in hypercellulolytic fungus Penicillium funiculosum NCIM1228. AB - Background: There is an urgent requirement for second-generation bio-based industries for economical yet efficient enzymatic cocktail to convert diverse cellulosic biomass into fermentable sugars. In our previous study, secretome of Penicillium funiculosum NCIM1228 showed high commercial potential by exhibiting high biomass hydrolyzing efficiency. To develop NCIM1228 further as an industrial workhorse, one of the major genetic interventions needed is global deregulation of cellulolytic genes to achieve higher enzyme production. Mig1 orthologs found in all yeast and filamentous fungi are transcriptional regulators that maintain carbon homeostasis by negatively regulating genes of secondary carbon source utilization. Their disruption has long been known to be beneficial for increasing the production of secreted enzymes for alternate carbon source utilization. Results: Upon detailed genotypic and phenotypic analysis, we observed that NCIM1228 harbors a truncated yet functional allele of homolog of a well-known catabolite repressor, Mig1. Alleviation of carbon repression in NCIM1228 was attained by replacing functional Mig1134 allele with null allele Mig188. P. funiculosum having Mig188 null allele showed better growth characteristics and 1.75-fold better glucose utilization than parent strain. We also showed that visibly small colony size, one of the major characteristics of CCR disruptant strains in filamentous fungi, was not due to retarded growth, but altered hyphal morphology. CCR-disrupted strain PfMig188 showed profuse branching pattern in terminal hyphae resulting in small and compact colonies with compromised filamentous proliferation. We further observed that basal level expression of two major classes of cellulases, namely, cellobiohydrolase and endoglucanase, was regulated by Mig1134 in NCIM1228, whereas other two major classes, namely, xylanases and beta-glucosidase, were only marginally regulated. Finally, CCR disruption in P. funiculosum NCIM1228 led to prolonged cellulase induction in production medium resulting in twofold increased cellulase activity than the parent strain with maximum secreted protein titer being > 14 g/l. Conclusions: CCR-disrupted P. funiculosum showed better growth, enhanced carbon source utilization, profuse branching pattern in terminal hyphae, and higher cellulase activity than parent strain. Our findings are particularly important in shedding light on important functions performed by Mig1 in addition to its role as negative regulator of alternate carbon source utilization in filamentous fungi. PMID- 29416561 TI - Physico-chemical oxidative cleavage strategy facilitates the degradation of recalcitrant crystalline cellulose by cellulases hydrolysis. AB - Background: Efficient enzymatic conversion of recalcitrant crystalline cellulose is critical for enabling cost-effective industrial conversion of cellulosic biomass to biofuels and chemicals. Fully understanding enzyme digestion mechanism is paving a new way to design efficient process for biomass conversion. Accordingly, a continuing drive is inspiring to discover new routes to promote crystalline cellulose disruption. Results: Herein, a physico-chemical oxidative cleavage strategy of irradiation oxidation/post-reduction (IOPR) was employed to treat crystalline cellulose I to cleave glycosidic bonds association with some new oxidized and reduced chain ends, thus boosting downstream degradation by cellulases from Trichoderma reesei. The hydrolysis performance of treated crystalline cellulose was conducted with either T. reesei Cel7A (TrCel7A) alone, or a cellulase enzyme mixture (90% Celluclast 1.5 L, 10% beta-glucosidase). 81.6 and/or 97% of conversion efficiency have been reached for 24-h and 48-h cellulase hydrolysis, respectively. The high efficient conversion of crystalline cellulose after IOPR is mainly attributed to generating some new chain ends, which are identified by MAIDI-TOF-MS and HPLC. Furthermore, the nanoscale architectures of crystalline cellulose before and after IOPR are systematically investigated by XRD, EPR, ATR- FTIR, GPC, and XPS techniques. Together with TEM images, the results reveal a fascinating digestion mechanism of "peel-off" and "cavity formation" paradigms toward degrading crystalline cellulose by cellulase mixtures after IOPR treatment. Conclusions: This encouraging results show that the proposed IOPR approach will become a potential competitive alternative to current biomass pretreatment. It opens a new avenue toward the implementation of pretreatment and the design of enzyme cocktails in lignocellulosic biorefinery. PMID- 29416562 TI - Optimizing anaerobic growth rate and fermentation kinetics in Saccharomyces cerevisiae strains expressing Calvin-cycle enzymes for improved ethanol yield. AB - Background: Reduction or elimination of by-product formation is of immediate economic relevance in fermentation processes for industrial bioethanol production with the yeast Saccharomyces cerevisiae. Anaerobic cultures of wild-type S. cerevisiae require formation of glycerol to maintain the intracellular NADH/NAD+ balance. Previously, functional expression of the Calvin-cycle enzymes ribulose 1,5-bisphosphate carboxylase (RuBisCO) and phosphoribulokinase (PRK) in S. cerevisiae was shown to enable reoxidation of NADH with CO2 as electron acceptor. In slow-growing cultures, this engineering strategy strongly decreased the glycerol yield, while increasing the ethanol yield on sugar. The present study explores engineering strategies to improve rates of growth and alcoholic fermentation in yeast strains that functionally express RuBisCO and PRK, while maximizing the positive impact on the ethanol yield. Results: Multi-copy integration of a bacterial-RuBisCO expression cassette was combined with expression of the Escherichia coli GroEL/GroES chaperones and expression of PRK from the anaerobically inducible DAN1 promoter. In anaerobic, glucose-grown bioreactor batch cultures, the resulting S. cerevisiae strain showed a 31% lower glycerol yield and a 31% lower specific growth rate than a non-engineered reference strain. Growth of the engineered strain in anaerobic, glucose-limited chemostat cultures revealed a negative correlation between its specific growth rate and the contribution of the Calvin-cycle enzymes to redox homeostasis. Additional deletion of GPD2, which encodes an isoenzyme of NAD+-dependent glycerol-3-phosphate dehydrogenase, combined with overexpression of the structural genes for enzymes of the non-oxidative pentose-phosphate pathway, yielded a CO2-reducing strain that grew at the same rate as a non-engineered reference strain in anaerobic bioreactor batch cultures, while exhibiting a 86% lower glycerol yield and a 15% higher ethanol yield. Conclusions: The metabolic engineering strategy presented here enables an almost complete elimination of glycerol production in anaerobic, glucose-grown batch cultures of S. cerevisiae, with an associated increase in ethanol yield, while retaining near wild-type growth rates and a capacity for glycerol formation under osmotic stress. Using current genome-editing techniques, the required genetic modifications can be introduced in one or a few transformations. Evaluation of this concept in industrial strains and conditions is therefore a realistic next step towards its implementation for improving the efficiency of first- and second-generation bioethanol production. PMID- 29416563 TI - Purification of 2,3-butanediol from fermentation broth: process development and techno-economic analysis. AB - Background: 2,3-Butanediol (2,3-BDO) is a synthetic chemical compound that also can be produced by biomass fermentation, which is gaining share in the global market as an intermediate product for numerous applications, i.e. as liquid fuel or fuel additive. Several metabolic engineering fermentation strategies to enhance the production of 2,3-BDO were developed. However, the recovery of 2,3 BDO from its fermentation broth remains a challenge due to its low concentration and its solubility in water and other components. Thus, a cost-effective recovery process is required to deliver the required purity of 2,3-BDO. This paper presents a new process development and techno-economic analysis for 2,3-BDO purification from a fermentation broth. Results: Conventional distillation and hybrid extraction-distillation (HED) processes are proposed in this study with detailed optimization and economic analysis. Particularly, a systematic solvent selection method was successfully implemented to determine a good solvent for the proposed HED configuration based on numerous experimental data obtained with each solvent candidate. NRTL and UNIQUAC property methods were evaluated to obtain binary interaction parameters of 2,3-BDO through rigorous Aspen Plus regression and validated using experimental data. Total annual cost (TAC)-based optimization was performed for each proposed configuration. Even though the HED configuration required 9.5% higher capital cost than conventional distillation, placing an extraction column before the distillation column was effective in removing water from the fermentation broth and significantly improved the overall process economics. Conclusions: Oleyl alcohol was found to be the most suitable solvent for the HED of 2,3-BDO due to its high distribution coefficient and high selectivity. The proposed HED drastically reduced reboiler duty consumption and TAC by up to 54.8 and 25.8%, respectively. The proposed design is expected to be used for the commercial scale of 2,3-BDO production from fermentation process. PMID- 29416564 TI - Identification of novel genomic imbalances in Saudi patients with congenital heart disease. AB - Background: Quick genetic diagnosis of a patient with congenital heart disease (CHD) is quite important for proper health care and management. Copy number variations (CNV), chromosomal imbalances and rearrangements have been frequently associated with CHD. Previously, due to limitations of microscope based standard karyotyping techniques copious CNVs and submicroscopic imbalances could not be detected in numerous CHD patients. The aim of our study is to identify cytogenetic abnormalities among the selected CHD cases (n = 17) of the cohort using high density oligo arrays. Results: Our screening study indicated that six patients (~35%) have various cytogenetic abnormalities. Among the patients, only patient 2 had a duplication whereas the rest carried various deletions. The patients 1, 4 and 6 have only single large deletions throughout their genome; a 3.2 Mb deletion on chromosome 7, a 3.35 Mb deletion on chromosome 3, and a 2.78 Mb a deletion on chromosome 2, respectively. Patients 3 and 5 have two deletions on different chromosomes. Patient 3 has deletions on chromosome 2 (2q24.1; 249 kb) and 16 (16q22.2; 1.8 Mb). Patient 4 has a 3.35 Mb an interstitial deletion on chromosome 3 (3q13.2q13.31).Based on our search on the latest available literature, our study is the first inclusive array CGH evaluation on Saudi cohort of CHD patients. Conclusions: This study emphasizes the importance of the arrays in genetic diagnosis of CHD. Based on our results the high resolution arrays should be utilized as first-tier diagnostic tool in clinical care as suggested before by others. Moreover, previously evaluated negative CHD cases (based on standard karyotyping methods) should be re-examined by microarray based cytogenetic methods. PMID- 29416565 TI - A report of nine cases and review of the literature of infertile men carrying balanced translocations involving chromosome 5. AB - Background: Balanced translocations may cause the loss of genetic material at the breakpoints and may result in failure of spermatogenesis. However, carriers of reciprocal translocation may naturally conceive. Genetic counseling of male carriers of translocations remains challenging. This study explores the clinical features of carriers of chromosome 5 translocations, enabling informed genetic counseling of these patients. Results: Of 82 translocation carriers, 9 (11%) were carriers of a chromosome 5 translocation. One case had azoospermia, while three cases had experienced recurrent spontaneous abortions, two cases had each experienced stillbirth, and three cases produced a phenotypically normal child confirmed by amniocentesis. A literature review identified 106 patients who carried chromosome 5 translocations. The most common chromosome 5 translocation was t(4,5), observed in 13 patients. Breakpoint at 5p15 was observed in 11 patients. All breakpoints at chromosome 5 were associated with gestational infertility. Conclusion: In genetic counseling, physicians should consider chromosome 5 and its breakpoints. Carriers of chromosome 5 translocations may continue with natural conception or use assisted reproductive technologies, such as preimplantation genetic diagnosis. PMID- 29416566 TI - Can telomere shortening be the main indicator of non-viable fetus elimination? AB - Background: Telomeres are transcriptionally inactive genomic areas, which, if shortened, are associated with pathological processes, unsuccessful fertilization, aging, and death. Telomere dysfunction has also been linked to chromosomal rearrangements and genomic instability. The role of telomeres in postnatal life has been extensively studied and discussed both in physiological as well as in pathological processes. However, the role of telomere length in prenatal development is still poorly understood, and mainly concerns the preimplantation stage. The aim of this study was to estimate relative telomere length in spontaneously eliminated human embryos between 5th and 12th week of gestation. Results: Relative telomere length was measured from total genomic DNA using a real-time polymerase chain reaction approach. In this study, we examined relative telomere length in 80 spontaneously eliminated embryos and in 25 embryos eliminated due to induced abortions. Relative telomere length in spontaneous abortions was significantly lower (P = 0.000001) compared to the induced abortions. Spontaneous abortions with aneuploid anomalies (monosomy X, trisomy 21, trisomy 16 and triploidy) were characterized by shorter telomeres, compared to spontaneous abortions, subgroup with euploid (46,XN) karyotype. Conclusion: Spontaneously lost pregnancies are characterized by shortened telomeres, especially in embryos with aneuploidies. We hypothesize that the shortening of telomeres is involved in the processes leading to spontaneous abortions. PMID- 29416567 TI - Involvement of gut microbiome in human health and disease: brief overview, knowledge gaps and research opportunities. AB - The commensal, symbiotic, and pathogenic microbial community which resides inside our body and on our skin (the human microbiome) can perturb host energy metabolism and immunity, and thus significantly influence development of a variety of human diseases. Therefore, the field has attracted unprecedented attention in the last decade. Although a large amount of data has been generated, there are still many unanswered questions and no universal agreements on how microbiome affects human health have been agreed upon. Consequently, this review was written to provide an updated overview of the rapidly expanding field, with a focus on revealing knowledge gaps and research opportunities. Specifically, the review covered animal physiology, optimal microbiome standard, health intervention by manipulating microbiome, knowledge base building by text mining, microbiota community structure and its implications in human diseases and health monitoring by analyzing microbiome in the blood. The review should enhance interest in conducting novel microbiota investigations that will further improve health and therapy. PMID- 29416568 TI - The dynamic intein landscape of eukaryotes. AB - Background: Inteins are mobile, self-splicing sequences that interrupt proteins and occur across all three domains of life. Scrutiny of the intein landscape in prokaryotes led to the hypothesis that some inteins are functionally important. Our focus shifts to eukaryotic inteins to assess their diversity, distribution, and dissemination, with the aim to comprehensively evaluate the eukaryotic intein landscape, understand intein maintenance, and dissect evolutionary relationships. Results: This bioinformatics study reveals that eukaryotic inteins are scarce, but present in nuclear genomes of fungi, chloroplast genomes of algae, and within some eukaryotic viruses. There is a preponderance of inteins in several fungal pathogens of humans and plants. Inteins are pervasive in certain proteins, including the nuclear RNA splicing factor, Prp8, and the chloroplast DNA helicase, DnaB. We find that eukaryotic inteins frequently localize to unstructured loops of the host protein, often at highly conserved sites. More broadly, a sequence similarity network analysis of all eukaryotic inteins uncovered several routes of intein mobility. Some eukaryotic inteins appear to have been acquired through horizontal transfer with dsDNA viruses, yet other inteins are spread through intragenomic transfer. Remarkably, endosymbiosis can explain patterns of DnaB intein inheritance across several algal phyla, a novel mechanism for intein acquisition and distribution. Conclusions: Overall, an intriguing picture emerges for how the eukaryotic intein landscape arose, with many evolutionary forces having contributed to its current state. Our collective results provide a framework for exploring inteins as novel regulatory elements and innovative drug targets. PMID- 29416569 TI - Phylogeographic diversity and mosaicism of the Helicobacter pylori tfs integrative and conjugative elements. AB - Background: The genome of the gastric pathogen Helicobacter pylori is characterised by considerable variation of both gene sequence and content, much of which is contained within three large genomic islands comprising the cag pathogenicity island (cagPAI) and two mobile integrative and conjugative elements (ICEs) termed tfs3 and tfs4. All three islands are implicated as virulence factors, although whereas the cagPAI is well characterised, understanding of how the tfs elements influence H. pylori interactions with different human hosts is significantly confounded by limited definition of their distribution, diversity and structural representation in the global H. pylori population. Results: To gain a global perspective of tfs ICE population dynamics we established a bioinformatics workflow to extract and precisely define the full tfs pan-gene content contained within a global collection of 221 draft and complete H. pylori genome sequences. Complete (ca. 35-55kbp) and remnant tfs ICE clusters were reconstructed from a dataset comprising > 12,000 genes, from which orthologous gene complements and distinct alleles descriptive of different tfs ICE types were defined and classified in comparative analyses. The genetic variation within defined ICE modular segments was subsequently used to provide a complete description of tfs ICE diversity and a comprehensive assessment of their phylogeographic context. Our further examination of the apparent ICE modular types identified an ancient and complex history of ICE residence, mobility and interaction within particular H. pylori phylogeographic lineages and further, provided evidence of both contemporary inter-lineage and inter-species ICE transfer and displacement. Conclusions: Our collective results establish a clear view of tfs ICE diversity and phylogeographic representation in the global H. pylori population, and provide a robust contextual framework for elucidating the functional role of the tfs ICEs particularly as it relates to the risk of gastric disease associated with different tfs ICE genotypes. PMID- 29416570 TI - Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots. AB - Remodeling of the sperm epigenome by lifestyle factors before conception could account for altered metabolism in the next generation offspring. Here, we hypothesized that endurance training changes the epigenome of human spermatozoa. Using small RNA (sRNA) sequencing and reduced representation bisulfite sequencing (RRBS), we, respectively, investigated sRNA expression and DNA methylation in pure fractions of motile spermatozoa collected from young healthy individuals before, after 6 weeks of endurance training and after 3 months without exercise. Expression of 8 PIWI interacting RNA were changed by exercise training. RRBS analysis revealed 330 differentially methylated regions (DMRs) after training and 303 DMRs after the detraining period, which were, in both conditions, enriched at close vicinity of transcription start sites. Ontology analysis of genes located at proximity of DMRs returned terms related to neurological function at the trained state and, to a much lesser extent, at the detrained state. Our study reveal that short-term endurance training induces marked remodeling of the sperm epigenome, and identify genes related to the development of the central nervous system as potential hot spots for epigenetic variation upon environmental stress. PMID- 29416571 TI - A Systematic Review Regarding Tonometry and the Transmission of Infectious Diseases. AB - Tonometry has been identified as a common method for measuring the intraocular pressure in patients. The direct contact between the tonometer and the eye may contribute to the risk of cross infection, especially of viral particles, from one patient to another. A systematic review was undertaken to address the likelihood of human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, and prion diseases transmission through the use of tonometers. Additionally, a comparison of the current tonometer disinfection methods is provided to assist with identifying which technique effectively reduces the risk of disease transmission. An electronic literature search was conducted using the following databases: Web of Science, EMBASE, CINAHL, SCOPUS, Biosis Previews, Cochrane Library, PubMed, and Google Scholar. Dissertation indexes were also searched, and these included: Dissertations and Abstracts, and Dissertations and Abstracts - UK/Ireland. Additionally, the Clinicaltrials.gov trial registry was searched to identify any other relevant literature. Two independent reviewers critically appraised the articles retrieved through the literature search. In total, 11 unique studies were deemed relevant for this systematic review. The available evidence demonstrated that the use of tonometers contributes to the transmission of these infectious diseases in vitro. The results also demonstrated variability in determining the most effective tonometer sterilization technique against these infectious diseases in vitro. There was limited evidence available regarding the transmission of HIV, hepatitis B, hepatitis C, and prion diseases through the use of tonometers. Additionally, due to the variability regarding the most effective sterilization techniques, it is difficult to identify which sterilization technique is most effective or adequately effective against these infectious diseases. Future research studies regarding infectious disease transmission through tonometry and sterilization techniques should be completed to more adequately inform infectious disease control guidelines. PMID- 29416573 TI - Do All Acute Stroke Patients Receiving tPA Require ICU Admission? AB - Background: Limited resources warrant investigating models for predicting which stroke tissue-type plasminogen activator (tPA) patients benefit from admission to neurologic intensive care unit (neuroICU). Methods: This model classifies patients who on day 1 of their ICU admission are predicted to receive one or more of 30 subsequent active life supporting treatments. Two groups of patients were compared: low risk monitor (LRM) (patients who did not receive active treatment (AT) on the first day and whose risk of ever receiving active treatment was <= 10%) and AT (patients who received at least one treatment on any day of their ICU admission). Results: Compared to LRM group (21 patients), AT group (59 patients) had similar age (75 +/- 13 vs. 72 +/- 17, P = 0.4), similar gender (male: 56% vs. 52%, P = 0.8), similar National Institutes of Health stroke scale (NIHSS, 16 +/- 9 vs. 14 +/- 8, P = 0.4), and higher Acute Physiologic and Chronic Health Evaluation (APACHE) III scores (62 +/- 26 vs. 41 +/- 15, P = 0.0008). Compared to LRM group, AT group had longer ICU length of stay (4.5 +/- 4.4 vs. 2.5 +/- 1.3, P = 0.04), higher ICU mortality (22% vs. 4.7% (one patient DNR/hospice); OR: 5.6; 95% CI: 0.7 - 46.0; P = 0.1), and higher hospital mortality (36% vs. 4.7%; OR: 11; 95% CI: 1.4 - 88.0; P = 0.02). Conclusion: The outcome of LRM patients with stroke post-tPA suggests that they may not require admission to a formal neuroICU, improving resource use and reducing costs. PMID- 29416572 TI - Etiology of Cesarean Uterine Scar Defect (Niche): Detailed Critical Analysis of Hypotheses and Prevention Strategies and Peritoneal Closure Debate. AB - There is an increasing incidence of cesarean scar (CS) defect/niche and its sequelae, probably not entirely explained by better diagnosis or rising cesarean rate. Discussion of possible etiological factors has received scant attention but would be important to formulate preventive strategies. Meaningful informative studies on long-term sequelae of cesarean section are very difficult and none are available for causation of CS defect. Hence, it is crucial to identify key areas in etiology of CS defect for focused research. This practical review proposes an "ischemia and mal-apposition hypothesis for CS niche", stating that the surgical technique of uterine incision closure is the most important determinant of CS defect formation. Other factors such as cervical location incision, adhesion formation and patient specific factors seem far less important in etiology. Rather than the headline theme of "single versus double-layer closure of uterus", the finer details of surgical technique which achieve good apposition without inducing tissue ischemia seem more important. Different techniques are discussed and it is proposed that continuous, non-locking absorbable sutures in two layers, without including much of decidua and without undue tight (constricting/devasculaizing) pulling of sutures are likely to result in good healing of uterine scar. Single-layer technique may be best reserved for thin myometrial edges especially during repeat cesareans. Adhesions between uterine isthmus and bladder/abdominal wall seem common associations but not causative for CS niche. It would be desirable to prove these surgical principles by good quality prospective randomized "quantitative" studies but the wait may be very long and this should not hinder the adoption of good surgical principles. Science is much cognitive and not just empirical. To consider a related example, the current recommendation of non-suturing of peritoneal layers during cesarean is mistakenly based on short-term irrelevant surrogate outcomes like analgesic requirements and time-saving, many of which have been already disproven. Evidence is presented recommending simple quick techniques of peritoneal closure to prevent adhesions. More analytical debate in surgical techniques is needed to inspire engaged, critical and insightful practitioners rather than unquestioning dependence on weak evidence/guidance. PMID- 29416574 TI - Validation of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA). AB - Background: It has been suggested to replace the diagnosis-specific graded prognostic assessment (DS-GPA, based on performance status and number of brain metastases) for patients with primary malignant melanoma with the new Melanoma molGPA. The latter is a more complex assessment, which also includes BRAF mutation status, age and extracranial metastases. To test the performance of the Melanoma-molGPA, we performed a validation study of this new survival prediction tool. Methods: A retrospective analysis of patients treated at two different academic institutions was performed. The four-tiered Melanoma-molGPA was calculated as suggested in the original study. Results: Median overall survival was 5.4 months (95% confidence interval: 3.1 - 7.7 months). Median survival in the four prognostic classes was 2.1, 7.8, 11.8, and 18.0 months, respectively. The 1-year survival rates were 3%, 25%, 43%, and 80%, respectively. The difference between the Kaplan-Meier curves was significant (P = 0.0001, log-rank test). Conclusions: The present survival outcomes support the use of the Melanoma molGPA. However, survival was better in each of the four groups in the original study. Possible reasons include lead-time bias and different treatment policies. PMID- 29416575 TI - A Randomized Controlled Trial of a Mini Low-Carbohydrate Diet and an Energy Controlled Diet Among Japanese Patients With Type 2 Diabetes. AB - Background: Low-carbohydrate diets have been shown to effectively improve the metabolic status of patients with type 2 diabetes mellitus. However, patients may find it challenging to maintain a strict low-carbohydrate diet. The objective of this study was to determine if a one-meal, low-carbohydrate diet is as effective in improving metabolic status as a conventional, energy-restricted diet among patients with type 2 diabetes mellitus. Methods: In this 12-week randomized controlled study, the primary endpoint was differences in the changes of plasma glycosylated hemoglobin (HbA1c) levels between the two experimental groups. Since the two groups had differences in body weight, body mass index, and waist circumference, propensity score matching was used to assess HbA1c outcomes via cohort pairs according to age, sex, body weight, HbA1c level, and waist circumference. Results: There were no differences in the changes in HbA1c between the two groups (P = 0.95). In addition, there were no differences in the changes in glycated albumin, 1,5-anhydroglucitol, lipid profile, body weight, waist circumference, and fat mass between the two groups. The mini low-carbohydrate diet group had an increased protein intake (P = 0.0085), as compared with the control group. However, neither group showed changes in their Diabetes Treatment Satisfaction Questionnaire score. Conclusion: Either diet would be effective for improving the metabolic status of this study population. PMID- 29416576 TI - Association of SIRT-1 Gene Polymorphism and Vitamin D Level in Egyptian Patients With Rheumatoid Arthritis. AB - Background: We investigated SIRT-1 genetic variant and its association with vitamin D level in Egyptian patients with rheumatoid arthritis (RA). Methods: Seventy Egyptian subjects were enrolled in our study and divided into two groups: RA group (n = 50 patients) and healthy control group (n = 20 subjects). Five milliliter blood sample was withdrawn from each subject followed by laboratory investigation and DNA extraction for SIRT-1 gene polymorphism assessment (rs7895833 A>G, rs7069102 C>G and rs2273773 C>T) and vitamin D level expression. Results: There was statistically significant difference between rheumatoid cases and controls with regard to vitamin D level with 88% of cases showing insufficient vitamin D versus all controls showing sufficient level. SIRT-1 different SNPs rs2273773, rs7895833and rs7069102 genotype frequencies were statistically significant in RA compared to control group (P = 0.001). There was no statistically significant difference between different genotypes of rs2273773, rs7895833 and rs7069102 with regard to vitamin D level. Conclusion: We concluded that there is a strong association between SIRT-1 polymorphism genotyping and RA. Vitamin D level was insufficient in Egyptian patients with RA. PMID- 29416577 TI - Haptoglobin Phenotype Among Arab Patients With Mental Disorders. AB - Background: Depression, schizophrenia and panic disorder are common mental disorders in the community and hospitalized patients. These mental disorders negatively affect life quality and even expectancy of life. Haptoglobin (Hp) phenotype (Hp 1-1, 1-2, or 2-2) is associated with risk for cardiovascular diseases, but its association with psychiatric disorders, a growing concern in the modern society, has not been studied thoroughly. The aim of the study was to examine whether Hp phenotype is associated with common mental disorders such as depression, schizophrenia, and panic disorder. Methods: The study included 92 Arab patients with mental disorders, and among them 44 suffered from schizophrenia (mean age 39 +/- 1.5 years), 17 from depression (mean age 44.5 +/- 3.1 years), 31 from panic disorder (mean age of 44.9 +/- 2.7 years), and 206 healthy Arab control subjects with a mean age of 42.6 +/- 0.9 years. Beck's depression inventory assessment and Hamilton depression scale were administered for depression and panic disorder diagnosis. Schizophrenia was evaluated with positive and negative affect schedule (Panas) test. All mental disorders were evaluated by clinical review. Blood analysis for Hp phenotype was performed. Diagnosis was made using the Diagnostic and Statistical Manual of Mental Disorders axis to correlate depression with Hp phenotype. Results: In mentally healthy controls, 10.7% were Hp 1-1, 38.8% Hp 2-1, and 50.5% Hp 2-2. In patients with the studied psychiatric disorders, Hp phenotype was comparable to healthy subjects; 8.7% were Hp 1-1, 50% Hp 2-1, and 41.3% Hp 2-2. When Hp phenotyping was analyzed in the psychiatric subgroups, Hp 2-1 was more common among depressed and schizophrenic patients, as compared with healthy subjects (58.8% and 52.3% vs. 38.8%). In patients who suffer from panic disorder, Hp phenotype distribution was 6.5% Hp 1-1, 41.9% Hp 2-1, and 51.6% Hp 2-2, suggesting a lower prevalence among Hp 1-1 phenotype. Conclusions: Arab patients who carry Hp 2-1 phenotype may be at risk to develop depression or schizophrenia more than the general healthy population. In contrast, Hp 1-1 subjects have a lower prevalence of panic disorder. PMID- 29416578 TI - A Brief Survey of Public Knowledge and Stigma Towards Depression. AB - Background: The burden from depression is affected by the public's beliefs, stigma, and resulting behavior. Lack of knowledge, misunderstanding, and stigma about depressed people and their surroundings are barriers to improving their mental health. This study aimed to examine public beliefs regarding depression, especially how to recognize depression, treatment, and stigma. Methods: A self administered questionnaire was distributed to participants receiving an annual health checkup. We asked whether they agreed with four short sentences: "it is not necessary to worry about depression in a person behaving brightly" (misunderstanding about the behavior of depressed people), "rest is important for treating depression" (belief about the necessity of rest), "medicine is effective for treating depression" (belief about the effectiveness of pharmacotherapy) and "a weak personality causes depression" (stigma about the cause of depression). We also analyzed the association between these beliefs and factors such as health literacy, regularly visiting an outpatient clinic, history of depression, and demographic variables. Results: Among 1,085 respondents (75.0% response rate), 54.5%, 75.6%, 58.9%, and 70.8% responded appropriately to the "misunderstanding about the behavior of depressed people", "necessity of rest", "effectiveness of pharmacotherapy", and "stigma about the cause of depression" items, respectively. Regarding stigma about the cause of depression, 30.7% of respondents agreed that a weak personality caused depression. Female sex and younger age group were associated with appropriate answers. Health literacy was only associated with appropriate beliefs about the effectiveness of pharmacotherapy. Conclusions: Thirty percent of participants had the stigmatizing belief that a weak personality causes depression and only 58.9% believed in the effectiveness of pharmacotherapy for depression. Over 70% understood the necessity of rest and knew that depression is possible in those who act brighter. General health literacy alone might not improve knowledge and beliefs about depression. An educational intervention or campaign to reduce stigma toward depression and improve knowledge about the treatment of depression is needed. PMID- 29416579 TI - Seroepidemiology of Toxoplasma gondii Infection in Women of Reproductive Age: A Cross-Sectional Study in a Northwestern Mexican City. AB - Background: Through a cross-sectional survey, we determined the seroprevalence and correlates of Toxoplasma gondii (T. gondii) infection in women of reproductive age in Hermosillo City, Mexico. Methods: We studied 445 women of reproductive age in Hermosillo City in the northwestern Mexican state of Sonora. Women were enrolled in the University of Sonora. Sera of women were examined for IgG and IgM antibodies to T. gondii by commercially available enzyme immunoassays. The association of T. gondii seropositivity with the characteristics of the pregnant women was determined by bivariate and multivariate analyses. Results: Of the 445 women (mean age: 22.18 +/- 5.6 years) studied, 16 (3.6%) had IgG antibodies to T. gondii, and two (12.5%) were also positive for IgM antibodies to T. gondii. Of the 16 anti-T. gondii IgG-positive women, six (37.5%) had IgG levels higher than 150 IU/mL, four (25.0%) between 100 and 150 IU/mL, and six (37.5%) between 9 and 99 IU/mL. Multivariate analysis of socio-demographic and behavioral variables showed that T. gondii seropositivity was associated with older age (odds ratio (OR): 5.30; 95% confidence interval (CI): 1.37 - 20.50; P = 0.01) and boar meat consumption (OR: 6.86; 95% CI: 1.27 - 37.07; P = 0.02). Conclusions: Women of reproductive age in Hermosillo City had a low seroprevalence of T. gondii infection. However, this finding indicates that most of these women were susceptible to a primary infection. Factors associated with T. gondii infection found in this study may be useful for the optimal planning of preventive measures against T. gondii infection and its sequelae. PMID- 29416580 TI - Evaluation of Risk Factors for Second Hip Fractures in Elderly Patients. AB - Background: Hip fracture is a worldwide public health problem that primarily affects osteoporotic individuals and the elderly. A second hip fracture can occur in elderly patients who have already suffered an initial hip fracture. The aim of this study was to investigate possible risk factors for second hip fractures in elderly patients with hip fractures. Methods: Between 2010 and 2014, 230 patients who underwent uncemented bipolar hemiarthroplasty for hip fractures were retrospectively analyzed. The patients were divided into two groups: those with a first hip fracture (group 1) and those with a second hip fracture (group 2). Results: The mean time from the first hip fracture to second hip fracture was 22 months. There were no significant differences in the American Society of Anesthesiologist scores, comorbidities were observed in the two groups. The mean length of hospitalization was not significantly different between the two groups. The mean postoperative functional scores after second hip fractures were significantly lower in group 2 than in group 1. Conclusions: Although there are not certain risk factors for second hip fractures in elderly patients with hip fractures, to prevent second hip fractures, elderly patients should be provided with physical and medical therapy as well as orthotic support and their functional activity should be maintained. PMID- 29416581 TI - Prevalence of Gastroesophageal Reflux Disease in Saudi Arabia. AB - Background: Gastroesophageal reflux disease (GERD) is a common chronic gastrointestinal tract disease. The incidence is higher in Asian and Arab countries. In Saudi Arabia, there are few studies that have assessed the prevalence of GERD among some cities' communities. Hence, this study aims to study the prevalence of GERD among the general population of Saudi Arabia. Methods: A cross-sectional study was designed to determine the prevalence of GERD among the community of Saudi Arabia. The sample was randomly gathered through self-administered validated GERD questionnaire (GerdQ) to diagnose GERD, during the period from November to December 2016. The sociodemographic data was assessed for all participants. The data were analysed using Statistical Package for Social Sciences version 21.0 (SPSS); the t-test was used to assess the association of GERD and sociodemographic data. Results: The sample was comprised of 2,043 participants. Female and male were 51.8% and 48.2%, respectively. Mean age was 29.6 years with the standard deviation of 10.5 years. The GERD prevalence was 28.7%. It was found statistically significant among divorced/widow (34.9%, P = 0.003). In contrast, there was no association between GERD's prevalence and gender, age, residence status, education level, occupation, and blood group (P > 0.05). Conclusions: The prevalence of GERD among Saudi population is higher than that in Western countries and East Asia. It affects divorced/widow, obese and those with a sedentary lifestyle. It is advocated that national programs and educational campaigns for prevention of this disease and its complications should be established. PMID- 29416582 TI - Stress Factors Associated With Burnout Among Attending Physicians: A Cross Sectional Study. AB - Background: Burnout in attending physicians is a crucial issue that may negatively impact patient outcomes, as well as affect the quality of training provided to residents. To investigate the association between burnout and stress coping ability, we conducted a cross-sectional study of attending physicians. Methods: From April 2013 to March 2014, we distributed an anonymous, self administered questionnaire to 1,897 attending physicians who attended teaching related training sessions and workshops. The questionnaire included the Maslach Burnout Inventory General Survey (MBI-GS, Japanese version) to evaluate burnout; the sense of coherence scale (SOC, Japanese version) to measure stress-coping ability, with higher scores indicating higher stress-coping ability; the Brief Scales for Job Stress (BSJS) to assess stress and buffering factors; demographic factors; mean weekly working hours; and factors related to instructing residents. The MBI-GS was used to determine the presence of physician burnout. Subjects were divided into tertiles based on SOC scores. We conducted logistic regression analysis of burnout using the following independent variables: physician experience, sex, mean weekly working hours, SOC group, mental workload, and reward from work. Results: Of the 1,543 (81.3%) attending physicians who responded, 376 did not meet the inclusion criteria and 106 had missing data, thus 1,061 (55.9%) were analyzed. The prevalence of burnout was 17.2%. Physicians with burnout had significantly fewer years of experience as a doctor (P < 0.01), were more likely to be female (P < 0.01), worked more hours per week (P < 0.01), and had a lower SOC score (P < 0.01) than physicians without burnout. On the BSJS, the mean score of all stress factors was higher and that of buffering factors was lower in physicians with burnout (P < 0.01). The percentages of physicians with burnout were 35.7%, 12.8%, and 3.2% in the low, middle, and high SOC groups, respectively (P < 0.01). Using the high SOC group as a reference, the adjusted odds ratio for burnout in the low SOC group was 4.7 (95% confidence interval: 2.31 - 9.63) (P < 0.01). Conclusions: In this study, burnout among attending physicians was significantly associated with SOC scores after adjustment for stress factors and buffering factors. PMID- 29416583 TI - Assessment of Serum Vitamin B12 Levels and Other Metabolic Parameters in Subjects With Different Values of Bone Mineral Density. AB - Background: Controversial experimental and clinical evidences have raised questions regarding the role of B12 and insulin-like growth factor 1 (IGF-1) on osteoblast function and bone health. In this study, we aimed to determine if the serum levels of B12, IGF-1 and procollagen type 1 N-terminal propeptide (P1NP) are associated with different degrees of bone mineral density (BMD). Methods: A total of 287 subjects (190 women and 97 men; mean age 53 years) volunteered for evaluation of BMD and serum levels of B12, IGF-1 and P1NP; BMD at lumbar spine and proximal femur was evaluated by means of dual-energy X-ray absorption (DEXA) and expressed as T-score; serum concentrations of vitamin B12 and IGF1 were measured with a chemiluminescent immunoassay on Access II Beckman Coulter and DiaSorin Liaison XL analyzers, respectively; P1NP was assessed in 61 women and 35 men with reduced T-score on Roche Modular platform. Results: A total of 101 subjects (66 women and 35 men) had a reduced BMD (T-score < -1) or osteoporosis with a T-score < -2.5, while 186 (124 women and 62 men) had a normal BMD. No significant difference in the B12 levels was observed between the subjects with reduced BMD (mean 265.15 pg/mL, 95% CI: 236 - 294.25) and those with normal BMD (mean 243.91, 95% CI: 225.78 - 262.03) (P = 0.1990); lower levels of IGF-1 were observed in the group with reduced BMD (mean 138.7 pg/mL, 95% CI: 126.75 - 150.83) than in that with normal BMD (mean 167.34, 95% CI: 136.49 - 198.18) (P< 0.001); serum levels of P1NP were significantly lower in 22 subjects younger than 50 years (mean 44.8 ng/mL, 95% CI: 36.4 - 53.1) vs. 74 subjects > 50 years old (mean 53.3, 95% CI: 34.3 - 72.3) (P < 0.001), and in women (mean 45.3, 95% CI: 37.6 - 52.9) vs. men (mean 62, 95% CI: 23 - 101) (P < 0.001). Conclusion: We found no significant association between B12 levels and BMD, but significant associations of lower levels of IGF1 with reduced BMD and lower levels of P1NP with younger age and female sex were found; additional studies to further investigate the association of serum levels of B12, growth factors and biochemical turnover markers with human bone health are needed. PMID- 29416584 TI - The Current Conditions and Lifestyles of Obese University Students. AB - Background: The prevalence of cardiovascular diseases in Japan remains high, and the onset becomes early. Studies on the current conditions and lifestyles of obese university students may support early interventions to achieve lifestyle modification. Methods and Results: The results of periodic health examinations in 32,262 first-year university students revealed that 2,036 (6.3%) were obese. We performed a more detailed examination in 221 of these obese students (165 males and 56 females, age 19 +/- 1 years) with study agreement from 2014 to 2016. In this study cohort, the percentage of students who exercised regularly was significantly higher among males than females. Body fat in males with well exercised was lower than that in males with no exercise. In addition, serum level of high-density cholesterol in males with well-exercised was higher. Among females, there were no significant differences in these parameters between exercisers and non-exercisers. Forty-two obese students (40 males and two females) met the diagnostic criteria of metabolic syndrome (MetS). Among males, levels of body fat, uric acid, liver enzyme and insulin resistance in the MetS group were significantly higher than those in the non-MetS group. The average ratio of eicosapentaenoic acid to arachidonic acid (EPA/AA) was low (0.14). Conclusions: Although the proportions of students with obesity and/or MetS were not high, the EPA/AA ratio in obese young males was low, which may be associated with a high risk of coronary atherosclerosis. To prevent the onset of cardiovascular diseases early intervention to achieve lifestyle modification may be important. PMID- 29416585 TI - Predicting Difficult Intubation in Emergency Department by Intubation Assessment Score. AB - Background: The difficult intubation is associated with failure of emergency tracheal intubation. This study aimed to develop and validate a model for predicting difficult intubation in emergency department (ED). Methods: A cross sectional study was conducted in the ED. We collected data from all consecutive adult patients who underwent emergency tracheal intubation. Patients were excluded if they were intubated by low experience intubator. The difficult intubation was defined by grade III or IV of Cormack and Lehane classification. We used multivariable regression model to identify significant predictors of difficult intubation and weighted points proportional to the beta coefficient values. The ability to discriminate was quantified by using the area under receiver operating characteristics curve (AuROC). The bootstrapping method was used to validate the performance. Results: A total of 1,212 intubations were analyzed. One hundred and fifty-seven intubations were enrolled in difficult intubation group. Five independence predictors were identified, and each was assigned a number of points proportional to its beta coefficient: male gender (one), large tongue (two), limit mouth opening (two), poor neck mobility (two), and presence of obstructed airway (three). Intubation assessment score model was created and applied to all subjects. The AuROC was 0.81 (95% confidence interval (CI): 0.77 - 0.85) for the development dataset, and 0.80 (95% CI: 0.76 - 0.85) for the validation dataset. We defined three risk groups: low risk (zero to one points), intermediate risk (two to three points), and high risk (above three points), and the difficult intubation rate was 4.7%, 22.5%, and 53.6%, respectively. Conclusions: Intubation assessment score model was constructed from patients' simple characteristics and performed well in predicting difficult intubation and can discriminate between with and without difficult intubation. PMID- 29416586 TI - Brain Natriuretic Peptide Levels in Acute Inferior Myocardial Infarction. AB - Background: Our objective was to evaluate the relationship between initial serum brain natriuretic peptide (BNP) levels and right ventricular functions in inferior myocardial infarction (MI) with and without right ventricular involvement. Methods: The study included 61 patients, who presented with acute inferior MI. Twenty-seven patients had right ventricular involvement. Blood samples for BNP were obtained from each patient on admission. Echocardiographic assessments were performed and recorded during the first 12 h. Right ventricular involvement was determined by electrocardiography, conventional and tissue Doppler echocardiography (TDI). Results: In inferior MI with right ventricular involvement, tricuspid annulus planimetric systolic excursion (TAPSE) and right ventricular fractional area change were lower, and left ventricular E/E' ratio was higher. In the group with BNP levels above 400 pg/mL, left ventricular end diastolic diameter and left ventricular end-systolic diameter were higher, and left ventricular ejection fraction and TAPSE, indicator of right ventricular systolic function, were lower. The elevated BNP levels were negatively correlated with RSm and TAPSE, while they were positively correlated with the E/E' ratio. The systolic blood pressure and left ventricular end-diastolic diameter during admission were independent predictors of BNP levels. Conclusions: In acute inferior MI, initially increased BNP levels may be valuable in predicting the right ventricle involvement. Higher rates of hypotension, right ventricular dysfunction and increased left ventricle diameters are observed in patients with BNP levels >= 400 pg/mL. PMID- 29416587 TI - The Role of C-Peptide as Marker of Cardiometabolic Risk in Women With Polycystic Ovary Syndrome: A Controlled Study. AB - Background: The aim of this study was to examine the role of C-peptide as a biological marker of cardiometabolic risk in polycystic ovary syndrome (PCOS). Methods: This case-control study enrolled 385 PCOS patients and 240 normal cycling women. Anthropometric and clinical variables were taken at first visit. Fasting C-peptide, glucose, lipids, and hormone measurements were performed. Simple and multiple correlations between C-peptide and other variables associated with dysmetabolism and cardiovascular disease were examined. Results: C-peptide was well correlated with several anthropometric, metabolic, and endocrine parameters. In PCOS patients, stepwise multiple regression including C-peptide as the criterion variable and other predictors of cardiovascular disease risk provided a significant model in which the fasting C-peptide/glucose ratio, glucose, body weight, and free estrogen index (FEI) were retained (adjusted R2 = 0.988, F = 7.161, P = 0.008). Conclusion: C-peptide levels alone or combined with C-peptide/glucose ratio, glucose, body weight, and FEI provided a significant model to identify PCOS patients with higher risk of future cardiometabolic diseases. PMID- 29416589 TI - When Nuance Is Not an Option: Facing Prognostication Inaccuracy at Perceived End of-Life. PMID- 29416588 TI - Correlation of Clinical and Radiological Outcome After Anterior Cervical Discectomy and Fusion With a Polyetheretherketone Cage. AB - Background: Anterior cervical discectomy and fusion (ACDF) with a polyetheretherketone (PEEK) cage is considered as the gold standard for patients with cervical disc disease. However, there are limited in vivo data on the impact of ACDF on the cervical kinematics and its association with patient-reported clinical outcomes. The purpose of this study was to investigate the impact of altered cervical sagittal alignment (cervical lordosis) and sagittal range of motion (ROM) on patients' self-reported pain and functional disability, after ACDF with a PEEK cage. Methods: We prospectively studied 74 patients, who underwent single-, or consecutive two-level ACDF with a PEEK interbody cage. The clinical outcomes were assessed by using the pain numeric rating scale (NRS) and the neck disability index (NDI). Radiological outcomes included cervical lordosis and C2-C7 sagittal ROM. The outcome measures were collected preoperatively, at the day of patients' hospital discharge, and also at 6 and 12 months postoperatively. Results: There was a statistically significant reduction of the NRS and NDI scores postoperatively at each time point (P < 0.005). Cervical lordosis and also ROM significantly reduced until the last follow-up (P < 0.005). There was significant positive correlation between NRS and NDI preoperatively, as well as at 6 and 12 months postoperatively (P < 0.005). In regard to the ROM and the NDI scores, there was no correlation preoperatively (P = 0.199) or postoperatively (6 months, P = 0.322; 12 months, P = 0.476). Additionally, there was no preoperative (P = 0.134) or postoperative (6 months, P = 0.772; 12 months, P = 0.335) correlation between the NDI scores and cervical lordosis. Conclusions: In our study, reduction of cervical lordosis and sagittal ROM did not appear to significantly influence on patients' self-reported disability. Such findings further highlight the greater role of pain level over the mechanical limitations of ACDF with a PEEK cage on patients' own perceived recovery. PMID- 29416590 TI - Optimal Weight Gain During Pregnancy in Japanese Women: Is It Okay? PMID- 29416591 TI - Social Aspects of the Workplace Among Individuals With Bipolar Disorder. AB - Objective: Bipolar disorder (BD) is characterized by recurrent mood episodes and profound impairments in psychosocial functioning. Occupational disability is one of the most problematic impairments for individuals with BD due to high rates of unemployment and work impairments. Current evidence indicates that social stressors at work-such as social isolation, conflict with others, and stigmas-are common experiences for employed individuals with BD. Yet, few studies have examined the relationship between social stressors at work and overall occupational functioning, instead focusing on individual clinical features of the disorder. Method: This cross-sectional study employed logistic and linear regressions to determine which demographic variables, mood symptoms, and social aspects of the work environment (exclusion, conflict, social support, stigma) were associated with work status (working vs. not working) and work functioning for individuals with bipolar disorder I and II. Results: Greater stigma and exclusion at work (p < .05) are associated with unemployment among adult individuals with BD, and higher degrees of depression and conflict at work (p < .05) are associated with work impairments for employed individuals. Conclusions: By examining two distinct measures of work outcomes (work status and work functioning) within the same group of participants, this study provides a unique insight, revealing that predictors of occupational functioning vary based on the specific measure of work outcomes used. This study also emphasizes the need for treatments that address the clinical features of BD and intervene in the work environment to improve functioning and prevent unemployment among individuals with BD. PMID- 29416592 TI - Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy. AB - Here we present an innovative computational-based drug discovery strategy, coupled with machine-based learning and functional assessment, for the rational design of novel small molecule inhibitors of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1). Our methods resulted in the discovery of several unique molecules, of which our lead compound SSI-4 demonstrates potent anti-tumor activity, with an excellent pharmacokinetic and toxicology profile. We improve upon key characteristics, including chemoinformatics and absorption/distribution/metabolism/excretion (ADME) toxicity, while driving the IC50 to 0.6 nM in some instances. This approach to drug design can be executed in smaller research settings, applied to a wealth of other targets, and paves a path forward for bringing small-batch based drug programs into the Clinic. PMID- 29416593 TI - c-Myb and C/EBPbeta regulate OPN and other senescence-associated secretory phenotype factors. AB - Tumorigenesis results from the convergence of cell autonomous mutations and corresponding stromal changes that promote tumor cell growth. Senescent cells, which secrete a plethora of pro-tumorigenic factors termed the senescence associated secretory phenotype (SASP), play an important role in tumor formation. Investigation into SASP regulation revealed that many but not all SASP factors are subject to NF-kB and p38MAPK regulation. However, many pro-tumorigenic SASP factors, including osteopontin (OPN), are not responsive to these canonical pathways leaving the regulation of these factors an open question. We report that the transcription factor c-Myb regulates OPN, IL-6, and IL-8 in addition to 57 other SASP factors. The regulation of OPN is direct as c-Myb binds to the OPN promoter in response to senescence. Further, OPN is also regulated by the known SASP regulator C/EBPbeta. In response to senescence, the full-length activating C/EBPbeta isoform LAP2 increases binding to the OPN, IL-6, and IL-8 promoters. The importance of both c-Myb and C/EBPbeta is underscored by our finding that the depletion of either factor reduces the ability of senescent fibroblasts to promote the growth of preneoplastic epithelial cells. PMID- 29416594 TI - PINK1 suppresses alpha-synuclein-induced neuronal injury: a novel mechanism in protein phosphatase 2A activation. AB - Alpha-synuclein (alpha-Syn) and phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced putative kinase (PINK) 1 are proteins found in Lewy bodies, which are a pathological hallmark of Parkinson's disease (PD). PINK1 overexpression suppresses alpha-Syn-induced phenotypes and increases lifespan and health in an animal model of PD. It has been suggested that the two proteins regulate protein phosphatase (PP) 2A activity, but the underlying mechanisms and neuroprotective action of PP2A against PD-associated pathology are unknown. We found that alpha-Syn overexpression in SK-N-SH neuroblastoma cells and primary cortical neurons caused mitochondrial dysfunction and cell injury via phosphorylation of PP2A at Tyr307 and inhibition of its activity. Concomitant overexpression of PINK1 reversed this effect and restored the activity. The level of phospho-activated Src was increased in cells overexpressing alpha-Syn, which was reversed by co-expressing PINK1, suggesting that the latter suppressed alpha Syn-induced PP2A inactivation by inhibiting Src activity. Calmodulin/Src complex formation was also enhanced in alpha-Syn-overexpressing cells, which was reversed by co-expression of PINK1 as a result of reduced mitochondrial Ca2+ releasing. Interestingly, the protective effects of PINK1 in alpha-Syn induced models were abolished by treatment with the PP2A inhibitor okadaic acid, indicating that PP2A is a target of PINK1. These findings indicate that PINK1 protects against alpha Syn-induced neurodegeneration by promoting the dissociation of the calmodulin/Src complex and inhibiting Src, thereby enhancing PP2A activity. This was supported by the observation that PP2A activity was decreased in PD patients, which was negatively correlated with Hoehn and Yahr scores. Our results provide novel insight into the mechanisms underlying neurodegeneration in PD as well as possible avenues for therapeutic intervention in the treatment of this disease. PMID- 29416596 TI - Urine anti-PLA2R antibody is a novel biomarker of idiopathic membranous nephropathy. AB - Since urine samples more directly reflect kidney alterations and damage than blood samples, we investigated whether urine anti-PLA2R antibody (uPLA2R-Ab) could be utilized similarly to serum anti-PLA2R antibody (sPLA2R-Ab) as a noninvasive biomarker of idiopathic membranous nephropathy (IMN). In this study, we performed a qualitative analysis using an indirect immunofluorescence test (IIFT) and measured uPLA2R-Ab and sPLA2R-Ab concentrations using an enzyme-linked immunosorbent assay (ELISA) in 28 patients with biopsy-proven IMN and 12 patients with secondary membranous nephropathy (SMN). Overall, 64.3% (n=18) of patients with IMN had IIFT-positive sPLA2R-Ab, 67.9% (n=19) of patients with IMN had IIFT positive uPLA2R-Ab, and none of the SMN patients had IIFT-positive sPLA2R-Ab or uPLA2R-Ab. The titers of the anti-PLA2R antibody from the IMN patients in the urine (10.72+/-22.24 RU/MUmol, presented as uPLA2R-Ab/urine creatinine) and serum (107.36+/-140.93 RU/ml) were higher than those from the SMN patients (0.51+/-0.46 RU/MUmol, 0.008+/-0.029 RU/ml, respectively, p<0.05). Statistical analyses indicated that there were positive correlations between uPLA2R-Ab and gPLA2R, sPLA2R-Ab or urinary protein and negative correlations between uPLA2R-Ab and serum albumin in patients with IMN. In conclusion, uPLA2R-Ab is a novel biomarker of IMN. sPLA2R-Ab combined with uPLA2R-Ab might be more helpful for diagnosis and activity in PLA2R associated MN. PMID- 29416597 TI - Peptide adjacent to glycosylation sites impacts immunogenicity of glycoconjugate vaccine. AB - Glycoconjugate vaccine is composed of polysaccharides (PSs) covalently linked with carrier protein. Glycosylation site selection, as a significant factor leading to heterogeneities of glycoconjugate structure, draws more and more attentions for its impact on the immunogenicity of glycoconjugate vaccine. To elucidate the relationship between glycosylation connectivity and immunogenicity of glycoconjugate vaccine, in this study, anti-E. coli O157:H7 glycoconjugate O PS-MBP with defined connectivity, and three selected peptide segments GS1, GS2, GS3 derived from O-PS-MBP was synthesized. Immunogenicity results showed that only peptides adjacent to the glycosylation sites (GS1 and GS2) promoted the generation of PS-specific IgG antibodies and contributed to PS-specific IgG subclass distribution. Furthermore, GS1 and GS2 had significant priming effect for eliciting PS-specific IgG antibodies. These results indicated that different locations of glycosylation sites could lead to diverse presentation of peptides and glycopeptides to APCs and influence the immunogenicity of glycoconjugate vaccine, which extend the current understanding of mechanism for adaptive immune system activation by glycoconjugate vaccine, and have implications for rational glycoconjugate vaccine design. PMID- 29416595 TI - RCAN1 in the inverse association between Alzheimer's disease and cancer. AB - The inverse association between Alzheimer's disease (AD) and cancer has been reported in several population-based studies although both of them are age related disorders. However, molecular mechanisms of the inverse association remain elusive. Increased expression of regulator of calcineurin 1 (RCAN1) promotes the pathogenesis of AD, while it suppresses cancer growth and progression in many types of cancer. Moreover, aberrant RCAN1 expression is detected in both AD and various types of cancer. It suggests that RCAN1 may play a key role in the inverse association between AD and cancer. In this article, we aim to review the role of RCAN1 in the inverse association and discuss underlying mechanisms, providing an insight into developing a novel approach to treat AD and cancer. PMID- 29416598 TI - Genome-wide comparison of the protein-coding repertoire reveals fast evolution of immune-related genes in cephalochordates and Osteichthyes superclass. AB - Amphioxus is used to investigate the origin and evolution of vertebrates. To better understand the characteristics of genome evolution from cephalochordates to Osteichthyes, we conducted a genome-wide pairwise comparison of protein-coding genes within amphioxus (a comparable group) and parallel analyses within Osteichthyes (two comparable groups). A batch of fast-evolving genes in each comparable group was identified. Of these genes, the most fast-evolving genes (top 20) were scrutinized, most of which were involved in immune system. An analysis of the fast-evolving genes showed that they were enriched into gene ontology (GO) terms and pathways primarily involved in immune-related functions. Similarly, this phenomenon was detected within Osteichthyes, and more well-known and abundant GO terms and pathways involving innate immunity were found in Osteichthyes than in cephalochordates. Next, we measured the expression responses of four genes belonging to metabolism or energy production-related pathways to lipopolysaccharide challenge in the muscle, intestine or skin of B. belcheri; three of these genes (HMGCL, CYBS and MDH2) showed innate immune responses. Additionally, some genes involved in adaptive immunity showed fast evolution in Osteichthyes, such as those involving "intestinal immune network for IgA production" or "T-cell receptor signaling pathway". In this study, the fast evolution of immune-related genes in amphioxus and Osteichthyes was determined, providing insights into the evolution of immune-related genes in chordates. PMID- 29416599 TI - Quantitative assessment of HLA-DQ gene polymorphisms with the development of hepatitis B virus infection, clearance, liver cirrhosis, and hepatocellular carcinoma. AB - Hepatitis B is one of the most common infectious diseases, which leads to public health problems in the world, especially in Asian counties. In recent years, extensive human genetic association studies have been carried out to identify susceptible genes and genetic polymorphisms to understand the genetic contributions to the disease progression of HBV infection. HLA-DQ gene variations have been reported to be associated with HBV infection/clearance, disease progression and the development of hepatitis B-related complications, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC). However, the results are either inconclusive or controversial. Therefore, to derive a more precise estimation of the association, a meta-analysis was performed. Our data revealed that the HLA-DQ alleles rs2856718-G, rs7453920-A and rs9275319-G were significantly associated with decreased risk of HBV infection and HBV natural clearance. Logistic regression analyses showed that HLA-DQ alleles rs9275572-A significantly increased HBV infection clearance, and decreased HBV natural clearance. However, rs2856718-G and rs9275572-A were not associated with development of cirrhosis. The HLA-DQ polymorphisms (rs2856718 and rs9275572) were associated with a decreased HBV-related HCC risk in all genetic models, but rs9272105-A increased the risk of HBV-related HCC. In addition, no significant association was observed between HLA-DQ rs9275319-G polymorphism and HBV-related HCC. These stratified analyses were limited due to relatively modest size of correlational studies. In future, further investigation on a large population and different ethnicities are warranted. Our findings contribute to the personalized care and prognosis in hepatitis B. PMID- 29416600 TI - Impaired autophagic flux and its related inflammation in patients with adult onset Still's disease. AB - The pathogenic role of autophagic immune regulation in adult-onset Still's disease (AOSD) is unclear. We investigated the relative levels of autophagy in AOSD patients and healthy controls, its association with disease activity or course, and the change in autophagy after 6 months of therapy. Autophagosome levels were determined from the mean fluorescence intensity of autophagosomotropic dye incorporated into circulating immune cells. The fluorescent signal from lymphocytes, monocytes, and granulocytes from AOSD patients was greater than from controls. Levels of p62 fluorescence measured using flow cytometry in lymphocytes and granulocytes from AOSD patients was greater than in the corresponding cells from healthy controls. Expression of Atg5 and LC3-II mRNA and protein levels of p62 and LC3-II were elevated in AOSD patients. Moreover, AOSD activity scores correlated positively with autophagosome levels in monocytes and granulocytes, p62 levels in circulating immune cells, and levels of Beclin-1, Atg5, and LC3-II mRNA. Autophagosome levels and Atg mRNA expression decreased with disease remission in AOSD patients. Elevated autophagosome formation and p62 levels suggest impaired autophagic flux in AOSD. PMID- 29416601 TI - Genetic identification and molecular modeling characterization reveal a novel PROM1 mutation in Stargardt4-like macular dystrophy. AB - Stargardt disease-4 (STGD4) is an autosomal dominant complex, genetically heterogeneous macular degeneration/dystrophy (MD) disorder. In this paper, we used targeted next generation sequencing and multiple molecular dynamics analyses to identify and characterize a disease-causing genetic variant in four generations of a Chinese family with STGD4-like MD. We found a novel heterozygous missense mutation, c.734T>C (p.L245P) in the PROM1 gene. Structurally, this mutation most likely impairs PROM1 protein stability, flexibility, and amino acid interaction network after changing the amino acid residue Leucine into Proline in the basic helix-loop-helix leucine zipper domain. Molecular dynamic simulation and principal component analysis provide compelling evidence that this PROM1 mutation contributes to disease causativeness or susceptibility variants in patients with STGD4-like MD. Thus, this finding defines new approaches in genetic characterization, accurate diagnosis, and prevention of STGD4-like MD. PMID- 29416602 TI - The prognostic significance of nuclear expression of PHF2 and C/EBPalpha in clear cell renal cell carcinoma with consideration of adipogenic metabolic evolution. AB - Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and it has an unfavourable prognosis compared to other RCCs. Plant homeodomain finger 2 (PHF2) and CCATT/enhancer binding protein alpha (C/EBPalpha) play a role in the epigenetic regulation of adipogenesis, and their tumour suppressive functions have been elucidated. This study aimed to assess the nuclear expression of PHF2 and C/EBPalpha in ccRCC and to evaluate their role in pathogenesis and prognosis. The nuclear expression of PHF2 and C/EBPalpha was evaluated in 344 cases of ccRCC by immunohistochemistry, and adipogenesis was assessed based on cytoplasmic features. Low expression was significantly associated with a larger tumour size, higher WHO/ISUP grade, high pT, pM, and advanced pTNM stage. Additionally, the expression level was correlated with the cytoplasmic features of ccRCC. The low expression group had significantly shorter cancer-specific and progression-free survival times. Furthermore, multivariate analysis showed that the combination of PHF2 and C/EBPalpha expression as an independent prognostic factor for cancer-specific and progression-free survival. In conclusion, our results suggest that nuclear expression of PHF2 and C/EBPalpha may serve as a prognostic marker and that the oncogenic metabolic shift has progressed in ccRCC patients. PMID- 29416603 TI - Deguelin suppresses angiogenesis in human hepatocellular carcinoma by targeting HGF-c-Met pathway. AB - Angiogenesis plays a crucial role in the development of human hepatocellular carcinoma (HCC). In the present study, we found a natural compound, deguelin, has a profound anti-angiogenesis effect on HCC. Deguelin suppressed vascular endothelial growth factor (VEGF)-induced human umbilical vascular endothelial cells (HUVECs) proliferation, migration, invasion, and capillary-like tube formation in vitro and reduced tumor angiogenesis in vivo. We discovered that VEGF receptor-mediated signal transduction cascades in HUVECs were inhibited by deguelin. Deguelin decreased the autocrine of VEGF in HCC cells in a time- and dose-dependent manner. Additionally, deguelin suppressed HGF-induced activation of the c-Met signaling pathway. Knocking down c-Met or inhibition of c-Met activation impaired HGF-mediated VEGF production. Importantly, we produced patient-derived hepatocellular carcinoma xenografts to evaluate the therapeutic effect of deguelin in vivo. Taken together, these results indicate that deguelin could inhibit HCC through suppression of angiogenesis on vascular endothelial cells and reduction of proangiogenic factors in cancer cells. PMID- 29416604 TI - CUNR scoring system for the prediction of lateral lymph node metastasis in papillary thyroid carcinoma. AB - Objective: Our present study aimed to evaluate and compare the number and rate of central lymph node metastases (LNMs) for the prediction of lateral LNM (LLNM) in papillary thyroid carcinoma (PTC) and to develop a scoring system. Results: Capsule invasion, tumor location in the upper portion of the thyroid, an ipsilateral central compartment LNM number >=3, and an ipsilateral central compartment LNM rate of >=56% were identified as significant independent predictors of ipsilateral lateral LNM in PTC. The predictive ability of an ipsilateral central compartment LNM rate >=56% (area under the curve (AUC) = 0.802) was better than that of an ipsilateral central compartment LNM number >=3 (AUC = 0.755). The ROC curves identified the best index point (CUNR) to distinguish the presence or absence of ipsilateral LLNM as 11, which has a high sensitivity (0.860) and a low false-negative rate (0.100, 1-Specificity). These findings were supported by the validation cohort. Conclusions: Patients with a CUNR index point equal to or greater than 11 and ipsilateral lateral lymph node dissection should be considered for a diagnosis of LLNM. Patients and Methods: A total of 1,281 PTC patients were included and divided into two groups: those with a presence of LLNM (n = 222) and those with an absence of LLNM (n = 1059). Univariate and multivariate analyses were performed to detect the risk factors for LLNM, and receiver operating characteristic (ROC) curves were used to detect the best cutoff values of these predictors. Additionally, a scoring system for the odds ratio (OR) of independent factors was developed and validated in an independent cohort of PTC patients (n = 560). PMID- 29416606 TI - SOX9-PDK1 axis is essential for glioma stem cell self-renewal and temozolomide resistance. AB - Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor with limited therapeutic options. Glioma stem cell (GSC) is thought to be greatly responsible for glioma tumor progression and drug resistance. But the molecular mechanisms of GSC deriving recurrence and drug resistance are still unclear. SOX9 (sex-determining region Y (SRY)-box9 protein), a transcription factor expressed in most solid tumors, is reported as a key regulator involved in maintaining cancer hallmarks including the GSCs state. Previously, we have observed that silencing of SOX9 suppressed glioma cells proliferation both in vitro and in vivo. Here, we found that SOX9 was essential for GSC self-renewal. Silencing of SOX9 down-regulated a broad range of stem cell markers and inhibited glioma cell colony and sphere formation. We identified pyruvate dehydrogenase kinase 1 (PDK1) as a target gene of SOX9 using microarray analyses. PDK1 inactivation greatly inhibited glioma cell colony and sphere formation and sensitized glioma spheres to temozolomide (TMZ) toxicity. In addition, SOX9-shRNA and PDK1 inhibitor could greatly sensitize GSC to TMZ in vivo. Taken together, our data reveals that SOX9 PDK1 axis is a key regulator of GSC self-renewal and GSC temozolomide resistance. These findings may provide help for future human GBM therapy. PMID- 29416605 TI - Human DKK1 and human HSP70 fusion DNA vaccine induces an effective anti-tumor efficacy in murine multiple myeloma. AB - Dickkopf-1 (DKK1) is an ideal target for the immunotherapy of multiple myeloma. Heat Shock protein70 (HSP70) is a class of important molecular chaperone to promote antigen presentation. Homologous xenogeneic antigens can enhance immunogenicity and induce stronger anti-tumor immune response than that of allogeneic ones. Therefore, we constructed human DKK1 and human HSP70 DNA fusion vaccine (hDKK1-hHSP70), and then determined its anti-tumor immuno- genicity and anti-tumor effects on immunizing BALB/c mice already inoculated with NS-1 murine multiple myeloma cells in prophylactic and therapeutic models using cytotoxic T lymphocytes, enzyme-lined immunosorbent assay, flow cytometry, immunohistochemistry and Hochest staining. The side effects of vaccines were also monitored. We found that hDKK1-hHSP70 fusion vaccine could significantly inhibit tumor growth and prolonged the survival of the mice, whether prophylactic or therapeutic immunotherapy in vivo, by eliciting both humoral and cellular tumor specific immune responses. A significant decrease of proliferation and increase of apoptosis were also observed in the tumor tissues injected with hDKK1-hHSP70 vaccine. These findings showed the xenogeneic homologous vaccination had stronger immunogenicity and minimal toxicity. Our study may provide an effective and safety immonutheraphy strategy for multiple myeloma. PMID- 29416607 TI - A method of respiratory phase optimization for better dose sparing of organs at risks: A validation study in patients with lung cancer. AB - Background: To propose an effective and simple cost value function to determine an optimal respiratory phase for lung treatment using either respiratory gating or breath-hold technique. Results: The optimized phase was obtained at a phase close to end inhalation in 11 out of 15 patients. For the rest of patients, the optimized phase was obtained at a phase close to end exhalation indicating that optimal phase can be patient specific. The mean doses of the Organs-at-risk (OARs) significantly decreased at the optimized phase without compromising the planning target volume (PTV) coverage (about 8% for all 3 OARs considered). Materials and Methods: Fifteen lung patients were included for the feasibility test of the cost function. For all patients and all phases, delineation of the target volume and selected OARs such as esophagus, heart, and spinal cord was performed, and then cost values were calculated for all phases. After the breathing phases were ranked according to the cost values obtained, the relationship between score and dose distribution was evaluated by comparing dose volume histogram (DVH). Conclusions: The proposed cost value function can play an important role in choosing an optimal phase with minimal effort, that is, without actual plan optimization at all phases. PMID- 29416608 TI - Squamous differentiation in pT1 bladder urothelial carcinoma predicts poor response for intravesical chemotherapy. AB - The role of squamous differentiation in pT1 bladder tumors in the response to intravesical chemotherapy was unknown. We performed a retrospective analysis of 213 pT1 bladder urothelial carcinoma patients with squamous differentiation (group1), the remaining 213 pT1 pure urothelial carcinoma served as controls (group2). All cases were treated with transurethral resection of bladder tumor and subsequent intravesical chemotherapy. Within a five-year period, the tumor recurrence rate was 75.1% (160/213) in group 1 and 64.3% (137/213) in group 2. Tumor grade (HR = 2.926, P = 0.014), number of tumors (HR = 2.130, P = 0.038), tumor size (HR = 2.748, P = 0.031), and squamous differentiation (HR = 3.726, P = 0.019) were found to be important prognostic factors. Subgroup analysis for high grade tumors was performed, finding that group 1 had higher recurrence rate (50.3% vs 36.3%; for group 2). Progression was found in 32.2% (30/160) of group1 and 15.1% (11/137) of group2 (P = 0.011). Our data suggests that squamous differentiation is a predictor of poor response for intravesical chemotherapy, and that early radical cystectomy should be performed for high grade tumors, especially when dealing with recurrent cases. PMID- 29416609 TI - Alcohol and hepatitis virus-dysregulated lncRNAs as potential biomarkers for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths because of frequent late detection and poor therapeutic outcomes, necessitating the need to identify effective biomarkers for early diagnosis and new therapeutic targets for effective treatment. Long noncoding RNAs (lncRNAs) have emerged as promising molecular markers for diagnosis and treatment. Through analysis of patient samples from The Cancer Genome Atlas database, we identified putative lncRNAs dysregulated in HCC and by its risk factors, hepatitis infection and alcohol consumption. We identified 184 lncRNAs dysregulated in HCC tumors versus paired normal samples, 53 lncRNAs dysregulated in alcohol-drinking patients with hepatitis B, and 5, 456 lncRNAs dysregulated in patients with hepatitis infection. A panel of these candidate lncRNAs' expressions correlated significantly with patient survival, clinical variables, and known genomic alteration in HCC. Two most significantly dysregulated lncRNAs in our computational analysis, lnc-CFP-1:1 and lnc-CD164L2-1:1, were validated in vitro to be dysregulated by alcohol. Our findings suggest that lncRNAs dysregulated by different etiologies of HCC serve as potential disease markers and can be further investigated to develop personalized prevention, diagnosis, and treatment strategies. PMID- 29416610 TI - Altered Toll-like receptor expression and function in HPV-associated oropharyngeal carcinoma. AB - Toll-like receptors (TLRs) have been widely investigated due to their importance in the inflammatory response and possible links to tumor promotion/regression and prognosis. In cancers with an infective etiology, such as human papillomavirus (HPV)-associated Oropharyngeal Squamous Cell Carcinoma (OPSCC), TLR responses may be activated and play a role in tumorigenesis. Our aim was to assess the expression of all TLRs in OPSCC cell lines (both HPV+ and HPV-) by qPCR, Western Blot and flow cytometry and assess their response to TLR ligands lipopolysaccharide (LPS), LPS ultra-pure (LPS-UP) and peptidoglycan (PGN) by analyzing IL-8 and IL-6 production. We also immunostained 61 OPSCC tissue samples with anti-TLR4. Results showed lower TLR1 and TLR6 mRNA expression and higher TLR9 protein expression in HPV+ when compared to HPV-OPSCC cells. TLR4 expression did not vary by HPV status in OPSCC cells, but TLR4 expression was significantly lower in HPV+OPSCC tissues. After stimulation with PGN, only one cell line (HPV+) did not secrete IL-6 or IL-8. Furthermore, HPV+OPSCC lines showed no IL-6 or IL-8 production on treatment with LPS/LPS-UP. The data suggest changes in TLR4 signaling in HPV+OPSCC, since we have shown lower tissue expression of TLR4 and no pro-inflammatory response after stimulation with LPS and LPS-UP. Also, it suggests that OPSCC may respond to HPV infection by increased expression of TLR9. This study demonstrates differences in expression and function of TLRs in OPSCC, which are dependent on HPV status, and may indicate subversion of the innate immune response by HPV infection. PMID- 29416612 TI - Docking of THPDTPI: to explore P-selectin as a common target of anti-tumor, anti thrombotic and anti-inflammatory agent. AB - The impact of soluble P-selectin on tumor growth, thrombosis and inflammation has been individually documented. Whether the down-regulation of P-selectin expression can simultaneously slow the tumor growth, inhibit the thrombosis and attenuate the inflammatory response remains unknown. In this context, (2'S,5'S)- tetrahydropyrazino[1',2':1,6]-di{2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole}-1',4' dione (THPDTPI) was designed as an inhibitor of P-selectin. The suitable docking of THPDTPI towards the active site of P-selectin, the significant down-regulation of THPDTPI to P-selectin expression, and the direct action of THPDTPI on P selectin suggest that P-selectin could be a target of THPDTPI. In vivo THPDTPI possesses the anti-tumor activity, the anti-thrombotic activity and the anti inflammatory activity. This implies that targeting P-selectin is of essential importance for this triple activity. The minimal effective doses of THPDTPI inhibiting the tumor growth, the rat arterial thrombosis and the mouse ear edema are 0.01 MUmol/kg, 0.1 MUmol/kg and 0.001 MUmol/kg, respectively. Atomic force microscopy images and FT-MS spectra showed that the adhesion of THPDTPI onto the surfaces of the platelets may be the first step of P-selectin targeting. Besides, the dependence of the triple action of THPDTPI inhibiting the tumor growth, the thrombosis and the inflammation on the decrease of the soluble P-selectin led to the correlation of the soluble P-selectin with the serum TNF-alpha and serum IL 8. PMID- 29416611 TI - Three-dimensional tumor model mimics stromal - breast cancer cells signaling. AB - Tumor stroma is a major contributor to the biological aggressiveness of cancer cells. Cancer cells induce activation of normal fibroblasts to carcinoma associated fibroblasts (CAFs), which promote survival, proliferation, metastasis, and drug resistance of cancer cells. A better understanding of these interactions could lead to new, targeted therapies for cancers with limited treatment options, such as triple negative breast cancer (TNBC). To overcome limitations of standard monolayer cell cultures and xenograft models that lack tumor complexity and/or human stroma, we have developed a high throughput tumor spheroid technology utilizing a polymeric aqueous two-phase system to conveniently model interactions of CAFs and TNBC cells and quantify effects on signaling and drug resistance of cancer cells. We focused on signaling by chemokine CXCL12, a hallmark molecule secreted by CAFs, and receptor CXCR4, a driver of tumor progression and metastasis in TNBC. Using three-dimensional stromal-TNBC cells cultures, we demonstrate that CXCL12 - CXCR4 signaling significantly increases growth of TNBC cells and drug resistance through activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Despite resistance to standard chemotherapy, upregulation of MAPK and PI3K signaling sensitizes TNBC cells in co-culture spheroids to specific inhibitors of these kinase pathways. Furthermore, disrupting CXCL12 - CXCR4 signaling diminishes drug resistance of TNBC cells in co-culture spheroid models. This work illustrates the capability to identify mechanisms of drug resistance and overcome them using our engineered model of tumor-stromal interactions. PMID- 29416613 TI - Efficient inhibition of cervical cancer by dual drugs loaded in biodegradable thermosensitive hydrogel composites. AB - Background and Purpose: We aimed to explore the anti-tumor effect and mechanism of the combination of cisplatin (DDP)-containing thermosensitive hydrogel (PEG PCL-PEG, or PECE) and paclitaxel (PTX)-loaded MPEG-PCL polymeric micelles called PDMP on human cervical carcinoma (HeLa) cell. In our previous studies, we found that PDMP in situ treatment of lung cancer will be liable to have potential in Lung cancer patients. Results: Compared with other treatments, PDMP was most effective in prolonging survival time (P < 0.05), inhibiting tumor growth (P < 0.05), decreasing expression of CD133 (P < 0.05), CD31 (P < 0.05), and aldehyde dehydrogenase 1 (ALDH1) (P > 0.05), inducing G1 phase arrest (P < 0.05), increasing the apoptosis rate (P < 0.05), and in expressing ATM and gamma-H2AX (P < 0.05). Conclusions: PDMP is regarded as a promising anti-tumor reactant, when it comes to the treatment of cervical carcinoma. Methods: we used a xenograft cervical cancer model to verify the anti-tumor activity of PDMP and to explore its mechanism of action. Mice were intratumorally administered with NS, PECE, PTX+DDP or PDMP. After two days of treatment, three mice per group were sacrificed and tumor tissue was harvested. Levels of histone H2AX phosphorylation (gamma-H2AX) were determined by immunohistochemistry and ataxia telangiectasia mutated(ATM) protein levels were measured by western blot analysis. In addition, it would sacrifice each of group of three mice through 10 days' treatment, what's more, it would harvest tumor by virtue of flow cytometry and immunohistochemical analysis. It would like to use there maining mice to analyze tumor growth and survival. The remaining mice were analyzed for tumor growth and survival. PMID- 29416614 TI - Extracellular signal regulated kinase 5 and inflammasome in progression of mesothelioma. AB - Malignant mesothelioma is an aggressive cancer in desperate need of treatment. We have previously shown that extracellular signaling regulated kinase 5 (ERK5) plays an important role in mesothelioma pathogenesis using ERK5 silenced human mesothelioma cells exhibiting significantly reduced tumor growth in immunocompromised mice. Here, we used a specific ERK 5 inhibitor, XMD8-92 in various in vitro and in vivo models to demonstrate that inhibition of ERK5 can slow down mesothelioma tumorigenesis. First, we show a dose dependent toxicity of XMD8-92 to 2 human mesothelioma cell lines growing as a monolayer. We also demonstrate the inhibition of ERK5 phosphorylation in various human mesothelioma cell lines by XMD8-92. We further confirmed the toxicity of XMD8-92 towards mesothelioma cell lines grown as spheroids in a 3-D model as well as in intraperitoneal (immune-competent) and intrapleural (immune-deficient) mouse models with and without chemotherapeutic drugs. To ascertain the mechanism, we explored the role of the nod-like receptor family member containing a pyrin domain 3 (NLRP3) inflammasome in the process. We found XMD8-92 attenuated naive and chemotherapeutic-induced inflammasome priming and activation in mesothelioma cells. It can thus be concluded that ERK5 inhibition attenuates mesothelioma tumor growth and this phenomenon in part is regulated by the inflammasome. PMID- 29416615 TI - Prognostic significance of E-cadherin and ZEB1 expression in intraductal papillary mucinous neoplasm. AB - There is an urgent need to investigate the genetic changes that occur in intraductal papillary mucinous neoplasm (IPMN), which is a well-known precursor of pancreatic cancer. In this study, gene expression profiling was performed by removing unwanted variation to determine the differentially expressed genes (DEGs) associated with malignant progression of IPMN. Among the identified DEGs, zinc finger E-box binding homeobox 1 (ZEB1) and E-cadherin, a crucial regulator of epithelial-to-mesenchymal transition (EMT), was validated among identified DEGs. A total of 76 fresh-frozen tissues were used for gene expression profiling and formalin-fixed, paraffin-embedded blocks from 87 patients were obtained for immunohistochemical analysis. Loss of E-cadherin expression (p = 0.023, odd ratio [OR] = 4.923) and expression of ZEB1 in stromal cells (stromal ZEB1, p < 0.001, OR = 26.800) were significantly correlated with degree of dysplasia. The hazard of death was significantly increased in patients with loss of E-cadherin expression (hazard ratio [HR] = 13.718, p = 0.004), expression of epithelial ZEB1 (HR = 19.117, p = 0.001), and stromal ZEB1 (HR = 6.373, p = 0.043). Based on the results of this study, loss of E-cadherin and expression of stromal ZEB1 are associated with increased risk of malignant progression. Epithelial and stromal ZEB1, as well as E-cadherin may be strong predictors of survival in patients with IPMN. Our finding suggests that these EMT markers may be utilized as potential prognosticators and may be used to improve and personalize treatment of IPMN. PMID- 29416616 TI - MicroRNA-761 promotes the sensitivity of colorectal cancer cells to 5 Fluorouracil through targeting FOXM1. AB - Resistance to chemotherapy is a big challenge for treatment of patients with colorectal cancer; however; the mechanism underlying chemoresistance in colorectal cancer cell has not been elucidated. MicroRNAs (miRNAs) are new players in the development of drug chemoresistance. In our study, we indicated that overexpression of miR-761 promoted the sensitivity of colorectal cancer cells to 5-Fluorouracil (5-FU). miR-761 expression was downregulated in colorectal cancer cell lines and tissues. miR-761 expression was lower in patients with low grade than in patients with high grade. In additon, we showed that elevated expression of miR-761 suppressed colorectal cancer cell proliferation, cell cycle, colony formation and cell invasion. We identified that FOXM1 was a direct target gene of miR-761 in colorectal cancer cell. FOXM1 expression was upregulated in colorectal cancer tissues compare to the adjacent non-tumor tissues. MiR-761 expression was negatively associated with the expression of FOXM1 in colorectal cancer tissues. Elevated expression of FOXM1 suppressed the sensitivity of miR-761-overexpressing HT29 cells to 5-FU. We also indicated that FOXM1 overexpression promoted cell proliferation, cycle and invasion of miR-761-overexpressing HT29 cells. These data suggested that miR-761 played a tumor suppressor miRNA in colorectal cancer progression and reduced miR 761 expression might be a major mechanism for 5-FU resistance in colorectal cancer cell. PMID- 29416618 TI - Preclinical efficacy and biological effects of the oral proteasome inhibitor ixazomib in diffuse large B-cell lymphoma. AB - Despite advances in deciphering the molecular pathogenesis of diffuse large B cell lymphoma (DLBCL), patients with relapsed/refractory disease, particularly those with adverse genetic features (e.g., mutated p53 or double hit lymphoma (DHL)) have very poor prognoses, and effective therapies are lacking. In this study we examined the preclinical efficacy and associated biological effects of the first oral proteasome inhibitor, ixazomib, in DLBCL in vitro and in vivo models. We demonstrated that ixazomib exhibited anti-tumor activities in 28 representative DLBCL cell lines, 10 primary DLBCL samples, and a DHL xenotransplant mouse model, at clinically achievable drug concentrations. Ixazomib sensitivity in DLBCL cells is correlated with immunoproteasomal activity; stimulating lymphoma cells with interferon gamma induced immunoproteasome activity and sensitized these cells to ixazomib. In addition, we showed that ixazomib induces apoptosis and the DNA damage response pathway, through activation of the checkpoint kinase 2 (CHK2). Hence, pharmacological inhibition of CHK2 enhances the anti-tumor activity of ixazomib in DLBCL cells. Our results indicate that ixazomib is an effective proteasome inhibitor active in DLBCL, including DHL, and its combination with a CHK2 inhibitor offers a potentially more robust therapeutic regimen for treatment-resistant DLBCL. PMID- 29416619 TI - The inhibitory activity of gallic acid against DNA methylation: application of gallic acid on epigenetic therapy of human cancers. AB - Epigenome aberrations have been observed in tobacco-associated human malignancies. (-)-epigallocatechin-3-gallate (EGCG) has been proven to modulate gene expression by targeting DNA methyltransferases (DNMTs) through a proposed mechanism involving the gallate moiety of EGCG. We show that gallic acid (GA) changes the methylome of lung cancer and pre-malignant oral cell lines and markedly reduces both nuclear and cytoplasmic DNMT1 and DNMT3B within 1 week. GA exhibits stronger cytotoxicity against the lung cancer cell line H1299 than EGCG. We found that GA reactivates the growth arrest and DNA damage-inducible 45 (GADD45) signaling pathway may through the demethylation of CCNE2 and CCNB1 in H1299 cells. To improve the epigenetic anti-cancer activities of oolong tea, we identified a fungus, Aspergillus sojae which can efficiently increase the GA content in oolong tea via a 2-week fermentation process. The fungus dramatically increased GA up to 44.8 fold in the post-fermentation oolong tea extract (PFOTE), resulting in enhanced demethylation effects and a significant reduction in the nuclear abundances of DNMT1, DNMT3A, and DNMT3B in lung cancer cell lines. PFOTE also showed stronger anti-proliferation activities than oolong tea extract (OTE) and increased sensitivity to cisplatin in H1299 cells. In summary, we demonstrate the potent inhibitory effects of GA on the activities of DNMTs and provide a strong scientific foundation for the use of specialized fermented oolong tea high in GA as an effective dietary intervention strategy for tobacco-associated cancers. PMID- 29416617 TI - Low dose radiation prevents doxorubicin-induced cardiotoxicity. AB - This study aimed to develop a novel and non-invasive approach, low-dose radiation (LDR, 75 mGy X-rays), to prevent doxorubicin (DOX)-induced cardiotoxicity. BALB/c mice were randomly divided into five groups, Control, LDR (a single exposure), Sham (treated same as LDR group except for irradiation), DOX (a single intraperitoneal injection of DOX at 7.5 mg/kg), and LDR/DOX (received LDR and 72 h later received DOX). Electrocardiogram analysis displayed several kinds of abnormal ECG profiles in DOX-treated mice, but less in LDR/DOX group. Cardiotoxicity indices included histopathological changes, oxidative stress markers, and measurements of mitochondrial membrane permeability. Pretreatment of DOX group with LDR reduced oxidative damages (reactive oxygen species formation, protein nitration, and lipid peroxidation) and increased the activities of antioxidants (superoxide dismutase and glutathione peroxidase) in the heart of LDR/DOX mice compared to DOX mice. Pretreatment of DOX-treated mice with LDR also decreased DOX-induced cardiac cell apoptosis (TUNEL staining and cleaved caspase 3) and mitochondrial apoptotic pathway (increased p53, Bax, and caspase-9 expression and decreased Bcl2 expression and DeltaPsim dissipation). These results suggest that LDR could induce adaptation of the heart to DOX-induced toxicity. Cardiac protection by LDR may attribute to attenuate DOX-induced cell death via suppressing mitochondrial-dependent oxidative stress and apoptosis signaling. PMID- 29416621 TI - A prognostic score model to determine which breast cancer patients with 1-3 positive lymph nodes after modified radical mastectomy should receive radiotherapy. AB - There is no consensus on the indication for postmastectomy radiotherapy (PMRT) in breast cancer patients with one to three positive lymph nodes. To identify patients for whom PMRT may be indicated, we used a prognostic score model with the SEER database to retrospectively analyze 8049 patients with one to three positive lymph nodes who underwent mastectomy with or without PMRT between 2010 and 2013. Kaplan-Meier analysis showed that PMRT patients had better overall survival (OS) than no-PMRT patients (P < 0.001); however, there was no difference in cancer-specific survival (CSS) (P = 0.530). Multivariate analysis with Cox regression showed that grade (P < 0.001), tumor size (P < 0.001), and progesterone receptor status (P < 0.001) were independent prognostic factors for OS. To diminish bias, we used 1:1 propensity score matching analysis and prognosis score model, which revealed that PMRT patients had better OS and CSS than no-PMRT patients (P < 0.001). In a concrete subgroup analysis of PMRT patients, significant improvements in OS were observed in patients scoring 0, 1, or 2. PMRT patients scoring 2 also had improved CSS. The magnitude of the OS and CSS difference with PMRT correlated with the prognostic score (P < 0.001). These results suggest PMRT in breast cancer patients with one to three positive lymph nodes should be based on patient factors, tumor biology, and prognostic score. PMID- 29416620 TI - Iodine stimulates estrogen receptor singling and its systemic level is increased in surgical patients due to topical absorption. AB - Iodine is crucial for thyroid hormone production. However, recent epidemiologic studies have shown that breast cancer patients have an elevated risk of developing thyroid cancer and vice versa. A notable finding in this study is that iodine stimulated the transcriptional activity of estrogen receptor-alpha (ER alpha) in breast cancer cells. Iodine stimulated expression of several ER-alpha regulated gene including PS2, Cathepsin D, CyclinD1, and PR both in vitro and in nude mice, which is consistent with its stimulation of both anchorage-dependent and -independent growth of ER-alpha positive breast cancer cells and the effect to dampen tumor shrinkage of MCF-7 xenograft in ovariectomized nude mice. Analyses of clinical urine samples from breast cancer patients undergoing surgery demonstrated that urinary iodine levels were significantly higher than that in controls; and this increased level is due to the antiseptic use of iodine during breast surgery. The present study indicates that excess iodine intake may be an unfavorable factor in breast cancer by stimulation of ER-alpha transcriptional activity. PMID- 29416622 TI - MnTBAP therapy attenuates the downregulation of sodium transporters in obstructive kidney disease. AB - Ureteral obstruction is associated with reduced expressions of renal sodium transporters, which contributes to impaired urinary concentrating capacity. In this study, we employed a synthetic mitochondrial superoxide dismutase 2 (SOD2) mimic MnTBAP to investigate the role of mitochondrial oxidative stress in modulating the sodium transporters in obstructive kidney disease. Following unilateral ureteral obstruction (UUO) for 7 days, a global reduction of sodium transporters including NHE3, NCC, NKCC2, and ENaCalpha was observed as determined by qRT-PCR, Western Blotting or immunohistochemistry. Among these sodium transporters, the downregulation of NHE3, NCC, and NKCC2 was partially reversed by MnTBAP treatment. In contrast, the reduction of ENaCalpha was not affected by MnTBAP. The beta and gamma subunits of ENaC were not significantly altered by ureteral obstruction or MnTBAP therapy. To further confirm the anti-oxidant effect of MnTBAP, we examined the levels of TBARs in the urine collected from the obstructed ureters of UUO mice and bladder of sham mice. As expected, the increment of urinary TBARs in UUO mice was entirely abolished by MnTBAP therapy, indicating an amelioration of oxidative stress. Meantime, we found that three types of SOD were all reduced in obstructed kidneys determined by qRT-PCR, which was unaffected by MnTBAP. Collectively, these results demonstrated an important role of mitochondrial oxidative stress in mediating the downregulation of sodium transporters in obstructive kidney disease. PMID- 29416623 TI - HBXIP activates the PPARdelta/NF-kappaB feedback loop resulting in cell proliferation. AB - Hepatitis B X-interacting protein (HBXIP, also termed as LAMTOR5) plays a crucial role in regulation of cancer progression, while the mechanism is still unclear. Here we found that HBXIP increased the expression of PPARdelta (peroxisome proliferator-activated receptor-delta) in gene and protein levels of SW480 or HT 29 colonic cancer cells. Chromatin immunoprecipitation and luciferase reporter assays showed that HBXIP occupied the core promoter (-1079/-239 nt) regions of PPARdelta and that HBXIP activated the transcription activity of PPARdelta in an NF-kappaB (p65)-dependent manner. Moreover, Co-immunoprecipitation and immunofluorescence analysis showed that HBXIP bound to NF-kappaB/p65 in the cells. Interestingly, we found that PPARdelta could conversely increase the expression of NF-kappaB/p65 through activating its transcription activity. In addition, the clinical observations showed that both HBXIP and PPARdelta were highly expressed in colonic carcinoma, and HBXIP expression was positively associated with that of PPARdelta in the clinical specimen. Importantly, HBXIP expression levels were positively correlated with the clinical pathological parameters including lymph node metastasis and advanced TNM stage. These findings suggest that HBXIP served as a co-activator to activate the positive feedback regulations of NF-kappaB/PPARdelta, which promoted the fast proliferation of the colonic cancer cells. Therapeutically, HBXIP may serve as a potential drug target of colonic cancer cells. PMID- 29416624 TI - 1,25-Dihydroxyvitamin D3 inhibits the proliferation of rat mesangial cells induced by high glucose via DDIT4. AB - 1,25-Dihydroxyvitamin D3(1,25(OH)2 D3) is a secosteroid with antiproliferative property. It also plays a pivotal renoprotective role in diabetic nephropathy. We investigated whether 1,25(OH)2D3 could inhibit the proliferation of rat mesangial cells exposed to high glucose via the DNA-damage-inducible transcript 4/mammalian target of rapamycin(DDIT4/mTOR) pathway. The cell proliferation rate and cell cycle duration were measured using cell counting kit-8 assay and flow cytometry. Protein expression was assayed by Western blot. Glucose acted as a growth factor in rat mesangial cells, promoted cell proliferation. In parallel, the protein expression of DDIT4, TSC1/TSC2, and 4E-BP1 were decreased, and Rheb, mTOR, and p70S6K were increased. Acting via the DDIT4/mTOR signaling, 1,25(OH)2 D3 treatment reversed these pathological changes, upregulated DDIT4, TSC1/TSC2, and 4E-BP1, downregulated Rheb, mTOR, and p70S6K. The short-term overexpression of DDIT4 inhibited the proliferation of rat mesangial cells, similar to 1,25(OH)2 D3 treatment. siRNA knockdown of DDIT4 suppressed antiproliferative responses to 1,25(OH)2 D3. These results suggest that 1,25(OH)2 D3 inhibits the proliferation of rat mesangial cells induced by high glucose via the DDIT4/mTOR signaling pathway. PMID- 29416625 TI - Comparison of clinical and survival characteristics between prostate cancer patients of PSA-based screening and clinical diagnosis in China. AB - Prostate-specific antigen (PSA)-based mass screening remains the most controversial topic in prostate cancer. PSA-based mass screening has not been widely used in China yet. The aim of our study was to evaluate the effect of the PSA-based screening in China. The cohort consisted of 1,012 prostate cancer patients. Data were retrospectively collected and clinical characteristics of the cohorts were investigated. Survival was analyzed for prostatic carcinoma of both PSA screened and clinically diagnosed patients according to clinical characteristics and the National Comprehensive Cancer Network (NCCN) risk classification. Cox Proportional Hazards Model analysis was done for risk predictor identification. The median age was 71 years old. Five-year overall and prostate-cancer-specific survival in prostatic adenocarcinoma patients were 77.52% and 79.65%; 10-year survivals were 62.57% and 68.60%, respectively. Survival was significantly poorer in patients with metastases and non-curative management. T staging and Gleason score by NCCN classification effectively stratified prostatic adenocarcinoma patients into different risk groups. T staging was a significant predictor of survival by COX Proportional Hazard Model. PSA screened patients had a significantly higher percentage diagnosed in early stage. PSA screened prostatic adenocarcinoma patients had a better prognosis in both overall and prostate cancer-specific survivals. This Chinese cohort had a lower overall and prostate cancer survival rate than it is reported in western countries. The incidence of early-stage prostate cancer found in PSA-based mass screening was high and there were significant differences in both overall and prostate cancer-specific survival between the PSA-screened and clinically diagnosed patients. PMID- 29416626 TI - Utilizing glycine N-methyltransferasegene knockout mice as a model for identification of missing proteins in hepatocellular carcinoma. AB - Glycine N-methyltransferase is a tumor suppressor gene for hepatocellular carcinoma, which can activate DNA methylation by inducing the S adenosylmethionine to S-adenosylhomocystine. Previous studies have indicated that the expression of Glycine N-methyltransferase is inhibited in hepatocellular carcinoma. To confirm and identify missing proteins, the pathologic analysis of the tumor-bearing mice will provide critical histologic information. Such a mouse model is applied as a screening tool for hepatocellular carcinoma as well as a strategy for missing protein discovery. In this study we designed an analysis platform using the human proteome atlas to compare the possible missing proteins to human whole chromosomes. This will integrate the information from animal studies to establish an optimal technique in the missing protein biomarker discovery. PMID- 29416627 TI - Transcriptome evolution from breast epithelial cells to basal-like tumors. AB - In breast cancer, it is unclear the functional modifications at a transcriptomic level that are associated with the evolution from epithelial cells and ductal carcinoma in situ (DCIS) to basal-like tumors. By applying weighted gene co expression network analysis (WGCNA), we identified 17 gene co-expression modules in normal, DCIS and basal-like tumor samples. We then correlated the expression pattern of these gene modules with disease progression from normal to basal-like tumours and found eight modules exhibiting a high and statistically significant correlation. M4 included genes mainly related to cell cycle/division and DNA replication like CCNA2 or CDK1. The M7 module included genes linked with the immune response showing top hub genes such as CD86 or PTPRC. M10 was found specifically correlated to DCIS, but not to basal-like tumor samples, and showed enrichment in ubiquitination or ubiquitin-like processes. We observed that genes in some of these modules were associated with clinical outcome and/or represented druggable opportunities, including AURKA, AURKB, PLK1, MCM2, CDK1, YWHAE, HSP90AB1, LCK, or those targeting ubiquitination. In conclusion, we describe relevant gene modules related to biological functions that can influence survival and be targeted pharmacologically. PMID- 29416628 TI - Exome sequencing reveals aberrant signalling pathways as hallmark of treatment naive anal squamous cell carcinoma. AB - Anal squamous cell carcinomas (ASCC) are rare tumours in humans. The etiological role of HPV infection is now well established but little is known about the molecular landscape and signalling pathways involved in the pathogenesis of this cancer. Here we report the results from a whole exome sequencing of a homogeneous group of 20 treatment-naive ASCC. A total of 2422 somatic single nucleotide variations (SNV) were found, with an overall moderate rate of somatic mutations per tumour (median: 105 relevant SNV per tumour) but a high mutational load in 3 tumours. The mutational signatures associated with age and APOBEC were observed in 100% and 60% of tumours respectively. The most frequently mutated genes were PIK3CA (25%) followed by FBXW7 (15%), FAT1 (15%), and TRIP12 (15%), the two last ones having never been described in ASCC. The main copy number alterations were gains of chromosome 3q (affecting PIK3CA) and losses of chromosome 11q (affecting ATM). The combined analysis of somatic mutations and copy number alterations show that recurrent alterations of the PI3K/AKT/mTOR pathway are frequent (60%) in these tumours, as well as potentially targetable alterations of other signalling pathways that have never been described in ASCC such as chromatin remodelling (45%) and ubiquitin mediated proteolysis (35%). These results highlight the possible implication of these aberrant signalling pathways in anal carcinogenesis and suggest promising new therapeutic approaches in ASCC. The high somatic mutation burden found in some tumours, suggesting an elevated neoantigen load could also predict sensitivity of ASCC to immunotherapy. PMID- 29416629 TI - Homing of endogenous bone marrow mesenchymal stem cells to rat infarcted myocardium via ultrasound-mediated recombinant SDF-1alpha adenovirus in microbubbles. AB - Stem cells can promote myocardial regeneration and accelerate the formation of new blood vessels. As such, transplanted stem cells represent a promising treatment modality for acute myocardial infarction (AMI). Stem cells spontaneously home to the infarcted myocardium using chemotaxis, in which the stromal cell-derived factor (SDF-1alpha) has been shown to be one of the most important chemokines. However, spontaneously secreted SDF-1alpha is short-lived, and therefore does not meet the needs of tissue repair. In this study, adenoviruses carrying SDF-1alpha genes were loaded on microbubble carriers and the adenoviruses were released into AMI rats by ultrasound targeted microbubble destruction. The possibility of in vivo self-transplantation of bone marrow mesenchymal stem cells (BMSCs) induced by overexpression of SDF-1alpha in the infarcted myocardium was explored by detecting the number of BMSCs homing from the peripheral blood to the myocardial infarcts. The concentration of SDF-1alpha in peripheral blood was significantly higher after transfection, and the number of BMSCs was significantly higher in the peripheral blood and infarcted area. Further analyses indicated that the number of homing BMSCs increased with increased SDF-1alpha expression. In conclusion, our results suggest that ultrasound mediated transduction of exogenous SDF-1alpha genes into myocardial infarcted AMI rats can effectively promote the homing of endogenous BMSCs into the heart. Moreover, the number of homing stem cells was controlled by the level of SDF-1alpha expression. PMID- 29416630 TI - Prognostic value of quantitative ctDNA levels in non small cell lung cancer patients. AB - Background: Circulating tumor DNA (ctDNA) levels correlate well with tumor bulk. In this paper we aim to estimate the prognostic value of the dynamic quantification of ctDNA levels. Materials and Methods: A total of 251 serial plasma samples from 41 non-small-cell lung cancer patients who carried an activating EGFR mutation were analysed by digital PCR. For survival analysis, ctDNA levels were computed as a time-dependent covariate. Results: Dynamic ctDNA measurements had prognostic significance (hazard ratio for overall survival and progression free survival according to p.T790M mutant allele frequency; 2.676 and 2.71 respectively; P < 0.05). In the same way, patients with p.T790M-negative or unchanging or decreasing plasma levels of sensitizing EGFR mutation were 12 and 4.8 times more likely to maintain response or stable disease, respectively, than patients in which the opposite occurred (P < 0.05).On average, the p.T790M mutation was detected in plasma 51 days before the assessment of progression disease by CT-scan. Finally, ctDNA outperformed CTCs for assessing tumor progression (P = 0.021). Conclusions: The appearance or increase in a unit of the p.T790M allele frequency almost triples the risk of death and progression. This information can be used to design clinical trials aiming to estimate whether T790M positive patients should start second line treatment based on molecular data rather than imaging data. PMID- 29416631 TI - In vitro and in vivo anti-leukemic effects of cladoloside C2 are mediated by activation of Fas/ceramide synthase 6/p38 kinase/c-Jun NH2-terminal kinase/caspase-8. AB - We previously demonstrated that the quinovose-containing hexaoside stichoposide C (STC) is a more potent anti-leukemic agent than the glucose-containing stichoposide D (STD), and that these substances have different molecular mechanisms of action. In the present study, we investigated the novel marine triterpene glycoside cladoloside C2 from Cladolabes schmeltzii, which has the same carbohydrate moiety as STC. We assessed whether cladoloside C2 could induce apoptosis in K562 and HL-60 cells. We also evaluated whether it showed antitumor action in mouse leukemia xenograft models, and its molecular mechanisms of action. We investigated the molecular mechanism behind cladoloside C2-induced apoptosis of human leukemia cells, and examined the antitumor effect of cladoloside C2 in a HL-60 and K562 leukemia xenograft model. Cladoloside C2 dose- and time-dependently induced apoptosis in the analyzed cells, and led to the activation of Fas/ceramide synthase 6 (CerS6)/p38 kinase/JNK/caspase-8. This cladoloside C2-induced apoptosis was partially blocked by specific inhibition by Fas, CerS6, and p38 siRNA transfection, and by specific inhibition of JNK by SP600125 or dominant negative-JNK transfection. Cladoloside C2 exerted antitumor activity through the activation of Fas/CerS6/p38 kinase/JNK/caspase-8 without showing any toxicity in xenograft mouse models. The antitumor effect of cladoloside C2 was reversed in CerS6 shRNA-silenced xenograft models. Our results suggest that cladoloside C2 has in vitro and in vivo anti-leukemic effects due to the activation of Fas/CerS6/p38 kinase/JNK/caspase-8 in lipid rafts. These findings support the therapeutic relevance of cladoloside C2 in the treatment of human leukemia. PMID- 29416632 TI - HDAC inhibitor PAC-320 induces G2/M cell cycle arrest and apoptosis in human prostate cancer. AB - HDAC inhibitors (HDACis) have been demonstrated with profound antiproliferative activities in various tumor types. Previously, we screened several polyoxometalate HDACis based on our p21 luciferase promoter system and demonstrated that such HDACis have antitumor activity. Here, we further investigate the antitumor mechanism of PAC-320, a compound among the polyoxometalates, in human prostate cancer. We demonstrate that PAC-320 is a broad-spectrum HDACi and could inhibit growth of prostate cancer cells in vitro and in vivo. Furthermore, we find that PAC-320 induces cell cycle arrest at G2/M phase and apoptosis. Mechanically, PAC-320 induced cell cycle arrest is associated with an increase of p21 and decrease of cyclin A and cyclin B1, while PAC-320 induced apoptosis is mediated through mitochondria apoptotic pathway and is closely associated with increase of BH3-only proteins Noxa and Hrk. Meanwhile, we demonstrate that p38 MAPK pathway is involved in PAC-320 induced antiproliferative activities in prostate cancer. Taken together, our data indicates that PAC-320 has potent prostate cancer inhibitory activity in vitro and in vivo, which is mediated by G2/M cell cycle arrest and apoptosis. PMID- 29416633 TI - Allogeneic hematopoietic stem cell transplantation for relapsed acute myeloid leukemia in ETO positive with reduced-intensity conditioning. AB - Objective: This research is conducted under the intention of exploring the efficacy and safety of reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of relapsed ETO positive acute myeloid leukemia (AML). Materials and Methods: Treatment of 15 cases referring to recurrent ETO positive acute myeloid leukemia in an army hospital from January 2010 to January 2013 through allo-HSCT with reduced intensity conditioning. All participants belonged to the recurrent or refractory type, including 10 males and 5 females, aging from 16 to 48 years old, with the average age of 32.5 years old. Before transplantation, 6 cases were remission while 9 were not, 10 cases were HLA-identical matching and 5 cases were HLA haploidentical. Donors received G-CSF to mobilize and used peripheral blood stem cell transplantation. Patients received a combination of Fludarabine, Busulfex and cytarabine as conditioning regimen. Preventive donor peripheral blood stem cell infusion was used 3 months after transplantation in order to observe toxicity, graft versus host disease(GVHD) and disease-free survival. Results: All patients reached hematopoietic reconstitution, the average time were 15.5d and 16.8d respectively with neutrophils > 0.5 * 109/L and platelets > 20 * 109/L. Engraftment was confirmed by the evidence of 100% donor hematopoiesis and T lymphocyte subsets counts increased significantly before and after transplantation. Univariate analysis showed that the levels of CD3+, CD4+, CD8+, CD19+ significantly increased after transplantation (P < 0.05) . Until June 2016 after the duration of 27.5 months, 8 cases presented the presence of GVHD, one died of complication, another 4 died of relapse and the other three remained disease-free survival, the DFS rate of 2-year was 66.7%, with the longest DFS up to 54 months. Considering of the transplantation cases with remission into relief groups (6 cases), and not ease group (9 cases), 2 years of disease-free survival rates were 66.7% and 66.7%. The survival curves of the two groups are demonstrated with no significant statistical significance (P > 0.05). Conclusions: Reduced-intensity allogeneic hematopoietic stem cell transplantation remains effective for relapsed AML with ETO positive, with safe and effective features and can be used as the method for relapsed AML with ETO positive. PMID- 29416634 TI - Loss of epithelium-specific GPx2 results in aberrant cell fate decisions during intestinal differentiation. AB - The selenoprotein glutathione peroxidase 2 (GPx2) is expressed in the epithelium of the gastrointestinal tract, where it is thought to be involved in maintaining mucosal homeostasis. To gain novel insights into the role of GPx2, proteomic profiles of colonic tissues either derived from wild type (WT) or GPx2 knockout (KO) mice, maintained under selenium (Se) deficiency or adequate Se supplementation conditions were established and analyzed. Amongst the panel of differentially expressed proteins, the calcium-activated chloride channel regulator 1 (CLCA1) was significantly down-regulated in GPx2 KO versus WT mice regardless of the given Se status. Moreover, transcript levels of the isoforms CLCA2 and CLCA3 showed a similar expression pattern. In the intestine, CLCA1 is usually restricted to mucin-producing goblet cells. However, although -SeKO mice had the highest numbers of goblet cells as confirmed by significantly enhanced mRNA expression levels of the goblet cell marker mucin-2, the observed expression pattern suggests that GPx2 KO goblet cells might be limited in synthesizing CLCA1. Furthermore, transcript levels of differentiation markers such as chromogranin-1 (Chga) for enteroendocrine cells and leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) for stem cells were also downregulated in GPx2 KO mice. Moreover, this was accompanied by a downregulation of the mRNA expression levels of the intestinal hormones glucagon-like peptide 1 (Glp1), ghrelin (Ghrl) and somatostatin (Sst). Thus, it seems that GPx2 might be important for the modulation of cell fate decisions in the murine intestinal epithelium. PMID- 29416635 TI - OTUD7B upregulation predicts a poor response to paclitaxel in patients with triple-negative breast cancer. AB - Paclitaxel is a first-line chemotherapeutic for patients with breast cancer, particularly triple-negative breast cancer (TNBC). Molecular markers for predicting pathologic responses to paclitaxel treatment is thus urgently needed since paclitaxel resistance is still a clinical issue in treating TNBCs. We investigated the transcriptional profiling of consensus genes in HCC38 (paclitaxel-sensitive) and MDA-MB436 (paclitaxel-resistant) TNBC cells post treatment with paclitaxel. We found that OTUD7B was downregulated in HCC38 but upregulated in MDA-MB436 cells after paclitaxel treatment at cytotoxic concentrations. Moreover, our data showed that OTUD7B expression causally correlated with IC50 of paclitaxel in a panel of TNBC cell lines. Moreover, we found that OTUD7B upregulation was significantly detected in primary breast cancer tissues compared to normal breast tissues but inversely correlated with tumor growth in TNBC cells. Besides, the increased levels of OTUD7B transcript appeared to causally associate with invasive potentials in TNBC cells. In assessments of recurrence/metastasis-free survival probability, high-levels of OTUD7B transcripts strongly predicted a poor prognosis and unfavorable response to paclitaxel-based chemotherapy in patients with TNBCs. In silico analysis suggested that OTUD7B regulation, probably owing to miR-1180 downregulation, may negatively regulate the NF-kappaB-Lin28 axis which in turn triggers Let-7 microRNA-mediated caspase-3 downregulation, thereby conferring paclitaxel resistance in TNBCs. These findings suggest that OTUD7B may be a useful biomarker for predicting the anti-cancer effectiveness of paclitaxel and could serve as a new drug target for enhancing the canceridal efficiency of paclitaxel against TNBCs. PMID- 29416636 TI - Pathway-focused PCR array profiling of CAL-27 cell with over-expressed ZNF750. AB - Zinc-finger protein 750 (ZNF750) is the potential anti-cancer gene in oral squamous cell carcinoma (OSCC). The present study was to investigate the expression changes of ZNF750 in OSCC tissue and to reveal the induction of altered mRNA expression profiles caused by over-expressed ZNF750 in CAL-27 cell. The expression level of ZNF750 in tissue specimens from OSCC patients was detected by immunohistochemistry. Gene expression profiling was performed using Human Signal Transduction PathwayFinder RT2 ProfilerTM PCR Array. The expression changes of 84 key genes representing 10 signal transduction pathways in human following over-expressed ZNF750 in CAL-27 cell was examined. The expression of ZNF750 protein was reduced in OSCC tissues. The R2 PCR Array analysis revealed that 39 of the 84 examined genes that changed at least a two-fold between control and ZNF750 groups. These genes related to oxidative stress, WNT, JAK/STAT, TGFbeta, NF-kappaB (NFkappaB), p53, Notch, Hedgehog, PPAR and Hypoxia signaling. ZNF750 could inhibit the candidate genes ATF4, SQSTM1, HMOX1, CCND1, TNF-alpha, TNFSF10 and FOSL1 but activate CDKN1A and EMP1. Our studies suggest that ZNF750 can regulate signaling pathways that related to proliferation, cell cycle, inflammation and oxidative stress in CAL-27 cell. PMID- 29416637 TI - Liver X receptors agonist promotes differentiation of rat bone marrow derived mesenchymal stem cells into dopaminergic neuron-like cells. AB - Dopaminergic (DA) neurons derived from bone marrow derived mesenchymal stem cells (BMSCs) maybe a valuable source for cell replacement therapy in Parkinson disease. Recent studies showed that new functions of LXR and their ligands have been proposed to prevent PD in the adult nervous system. The present study was designed to observe the effect of liver X receptors (LXR) agonist on differentiation of rat BMSCs into DA neurons. Expressions of the neuronal markers (Tuj1 and Nestin), the specific marker of DA neurons (tyrosine hydroxylase, TH), LXR alpha and LXR beta were measured by immunocytochemical assay and TH/Tuj1 positive cells were determined by quantitative cell count analyses. mRNA expressions of LXR alpha, LXR beta, TH, DAT, Nurr1, Pitx3, En1 and Lmx1b were measured by qPCR. Compared with growth factors (GF) treated group, combined use of LXR and GF induced rat BMSCs to TH-expressing cells with 87.42% of efficiency in 6 days of period of induction. LXR agonist alone did not induce the differentiation. Compared with GF alone, combined use of LXR and GF increased expressions of LXR alpha and LXR beta protein and mRNA and TH, DAT, Nurr1, and Pitx3 mRNA, decreased expressions of En1 and Lmx1b mRNA. Our experimental results indicated that LXR activation leads to improve induction efficiency and shorten induction period of rat BMSCs into DA neuron-like cells through regulating DA development-related genes expressions and that LXR can be considered as a candidate target for drug development to improve differentiation of BMSCs into DA neurons. PMID- 29416638 TI - Nicotine-enhanced stemness and epithelial-mesenchymal transition of human umbilical cord mesenchymal stem cells promote tumor formation and growth in nude mice. AB - Cigarette smoking is a well-known risk factor in the development and progression of malignant diseases. Nicotine, the major constituent in cigarette smoke, has also shown negative effects on stem cells. Mesenchymal stem cells (MSCs) have been widely demonstrated to migrate into tumors and play key roles in cancer progression. However, the mechanisms by which nicotine impacts MSCs and tumorigenesis of lung cancer are still undetermined. In this study we investigated the effects of nicotine on human umbilical cord mesenchymal stem cells (hUC-MSCs) and the impacts of nicotine-treated hUC-MSCs on tumor formation and progression. We found that nicotine has a toxic effect on hUC-MSCs and changes the morphology, inhibits proliferation and promotes apoptosis of hUC-MSCs in a dose-dependent manner. Nicotine-treated hUC-MSCs produce higher level of IL 6. Moreover, nicotine promotes migration, stemness and epithelial-mesenchymal transition (EMT) of hUC-MSCs by inhibiting E-cadherin expression and upregulating mesenchymal markers such as N-cadherin and Vimentin, leading to the induction of stem cell markers Sox2, Nanog, Sall4, Oct4 and CD44. Migration and proliferation of non-small cell lung cancer A549 cells and breast cancer MCF-7 cells are promoted after their coculture with nicotine-treated hUC-MSCs in a cell-cell contact-independent manner. Furthermore, nicotine-treated hUC-MSCs promote tumor formation and growth of A549 cells in nude mice. These studies demonstrated that the enhanced stemness and EMT of hUC-MSCs induced by nicotine are critical for the development of tobacco-related cancers. PMID- 29416639 TI - Expression of ANO1/DOG1 is associated with shorter survival and progression of breast carcinomas. AB - The expression of ANO1 is considered to have diagnostic specificity for gastrointestinal stromal tumors. However, its function as a calcium-activated chloride channel suggests that the expression of ANO1 is not restricted to gastrointestinal stromal tumors. Recently, it has been reported that ANO1 has roles in the progression of human malignant tumors. However, the role of ANO1 in breast carcinoma has been controversial. Therefore, we investigated the expression of ANO1 in 139 breast carcinoma patients and the role of ANO1 in vitro. The immunohistochemical expression of ANO1 was significantly associated with the expression of beta-catenin, cyclin D1, MMP9, snail, and E-cadherin. Especially, ANO1 expression was an independent indicator of poor prognosis of shorter overall survival and relapse-free survival of breast carcinoma patients by multivariate analysis. In MCF7 and MDA-MB-231 breast carcinoma cells, inhibition of ANO1 with T16Ainh-A01 or siRNA for ANO1 significantly suppressed the proliferation of cells. Knock-down of ANO1 with siRNA induced G0/G1 cell cycle arrest and significantly inhibited the invasiveness of breast carcinoma cells. Knock-down of ANO1 decreased the expression of beta-catenin, cyclin D1, MMP9, snail, and N-cadherin, and increased the expression of E-cadherin. In conclusion, this study demonstrates that ANO1 expression is an indicator of poor prognosis of breast carcinoma patients and suggests that ANO1 might be a therapeutic target for breast carcinoma patients with ANO1-positive tumors and poor prognosis. PMID- 29416640 TI - Development of suspension cell culture model to mimic circulating tumor cells. AB - Circulating tumor cells (CTCs) are essential for the establishment of distant metastasis. Numerous studies have characterized CTCs as metastatic precursors; however, the molecular nature of CTCs has not been completely revealed yet due to the low number of CTCs in the blood stream. As an alternative approach, we developed a long-term suspension cell culture model using human breast cancer cell lines to mimic CTCs. We found that more than 40 passaged suspension cells acquired the ability to enhance metastasis like cancer stem cells. To identify molecular changes acquired during the suspension cell culture, we analyzed metabolic and lipidomic profiles as well as transcriptome in MDA-MB-468 suspension cells. Glutamate and leucine levels increased in suspension cells, and cholesterol synthesis pathway was altered. The inhibition of glutamate metabolic pathway decreased the proliferation of suspension cells compared to that of adherent cells. In the lipidomic profile, PC species containing long chain and polyunsaturated fatty acids increased in suspension cells and these species could be authentic and specific biomarkers for highly metastatic cancers. As this CTC mimicking suspension cell culture model may easily apply to various types of cancer, we suggest this model as a great tool to develop therapeutic targets and drugs to eradicate metastatic cancer cells. PMID- 29416641 TI - PD-L1 (CD274) and PD-L2 (PDCD1LG2) promoter methylation is associated with HPV infection and transcriptional repression in head and neck squamous cell carcinomas. AB - Background: DNA methylation of the immune checkpoint gene PD-L1 has recently been shown to be associated with PD-L1 mRNA expression in various malignancies. This study aimed to investigate the association of PD-L1 and PD-L2 methylation with mRNA expression, immune cell infitration, protein expression and human papilloma virus (HPV) infection in head and neck squamous cell carcinoma (HNSCC) patients. Results: DNA methylation of PD-L1 and PD-L2 correlates inversely with mRNA expression (PD-L1: p <= 0.002; PD-L2: p <= 0.014). Methylation of specific CpG sites of both PD-L1 and PD-L2 were further significantly associated with HPV infection in the TCGA cohort. Immune cell infiltrates correlated significantly with PD-L1 and PD-L2 methylation. In the validation cohort, PD-L1 protein expression was associated with PD-L1 hypomethylation (p = 0.012). Conclusions: DNA methylation of PD-L1 and PD-L2 is associated with transcriptional silencing and HPV infection in HNSCCs. Additional studies are warranted to test PD-L1 and PD-L2 methylation as predictive biomarkers for response to immunotherapies (e.g. pembrolizumab and nivolumab) that target the PD-L1/PD-L2/PD-1 immune checkpoint axis. Materials and Methods: PD-L1 and PD-L2 promoter methylation and its mRNA expression were analyzed based on Infinium HumanMethylation450 BeadChip and RNA Seq (both Illumina, Inc.) data in a representative HNSCC patient cohort (n = 528) enrolled by The Cancer Genome Atlas (TCGA) Research Network. A validation cohort consisting of 168 HNSCC patients treated at the University Hospital Bonn was analyzed regarding PD-L1 and PD-L2 promoter methylation by means of methylation specific quantitative real-time PCR. PD-L1 protein expression in the validation cohort was quantified via immunohistochemistry (PD-L1 antibody clone 22C3, Dako/Agilent Technologies, Inc.). PMID- 29416642 TI - Progesterone inhibits contraction and increases TREK-1 potassium channel expression in late pregnant rat uterus. AB - Objective: The aim of this study was to investigate the effect and mechanism by which progesterone regulates uterine contraction in late pregnant rats. Results: Progesterone caused concentration-dependent relaxation of uterine strips that was enhanced compared with control nontreated uterine strips. Uterine strips incubated with progesterone showed a significant increase in TREK-1 mRNA expression and protein level. TREK-1 inhibitor L-methionine partly reversed uterine relaxation caused by the progesterone, while TREK-1 activator arachidonic acid did not cause significant change in progesterone-induced relaxation. Conclusions: Progesterone inhibits uterine contraction and induces uterine relaxation in late pregnancy. The progesterone-induced inhibition of uterine contraction appears to partly involve increased potassium channel TREK-1 expression/activity. Materials and Methods: Uterus from late-pregnant rats (gestational day 19) was isolated, and uterine strips were prepared for isometric contraction measurement. Oxytocin-induced contraction was compared in uterine strips pretreated with different concentration of progesterone. TREK-1 potassium channel inhibitor L-methionine and TREK-1 agonist arachidonic acid were used to determine whether the changes caused by progesterone involve changes in TREK-1 activity. The mRNA and protein expression of TREK-1 in uterine tissues were measured using qPCR and Western blot. PMID- 29416643 TI - Clinical validation of serum endocan (ESM-1) as a potential biomarker in patients with renal cell carcinoma. AB - To determine the suitability of serum endocan (ESM-1) levels for diagnosing and monitoring renal cell carcinoma (RCC), we measure serum ESM-1 levels in 56 RCC patients who had undergone radical or partial nephrectomies and 56 age- and sex matched healthy kidney donors. Measurements were made before and 1 month and 3 months after surgery. The areas under the curve (AUCs) were determined from receiver operating characteristic (ROC) analyses. RCC patients had higher mean serum ESM-1 levels than control subjects (0.59 +/- 0.07 vs. 0.52 +/- 0.08 ng/mL, P < 0.001), with an AUC of 0.721 (95% CI: 0.628-0.817). In patients with tumors larger than 2 cm (n = 40) and those with clear-cell histology (n = 44), the AUCs for ESM-1 were 0.771 and 0.721, respectively. In control subjects, serum ESM-1 levels were higher in older (>50 years) individuals (P < 0.001). Among the study cohort, the AUCs for ESM-1 were 0.813 in individuals 50 years of age or younger (n = 55) and 0.637 in individuals older than 50 years (n = 57). In RCC patients, serum ESM-1 levels were reduced 1 month (P = 0.047) and 3 months (P = 0.009) after surgery. These results suggest serum ESM-1 can serve as a serologic biomarker for diagnosing and monitoring RCC, particularly in patients younger than 50 years. PMID- 29416644 TI - C-MYC and BCL-2 mediate YAP-regulated tumorigenesis in OSCC. AB - Transcriptional co-activator Yes-associated protein (YAP) is a key oncogene in mammalian cells. The present understanding of YAP in oral squamous cells carcinoma (OSCC) remains unclear. The purpose of this study is to investigate the effects of YAP on proliferation and apoptosis in OSCC and the molecular mechanism. The results showed the expression level of YAP was higher in OSCC tissues than that in adjacent normal tissues. Knockdown of YAP in CAL27 cell lines prohibited cell proliferation while augmented apoptosis. Conversely, overexpression of YAP protected cells from apoptosis and promoted cell proliferation. Moreover, C-MYC and BCL-2 mRNA and protein levels were altered due to the differential expression of YAP. Subsequent Verteporfin treatment in CAL27 cells revealed that the transcription and translation of BCL-2 and C-MYC both decreased. In a tumor xenograft model, knockdown of YAP suppressed tumor growth of CAL27 in vivo, while YAP overexpression promoted the tumor growth. These results suggest that YAP is a crucial regulator that exerts pro-proliferation and anti-apoptosis effects in OSCC through actions affecting the cell cycle and intrinsic apoptotic signaling. Thus YAP could potentially serve as a valuable molecular biomarker or therapeutic target in the treatment of OSCC. PMID- 29416645 TI - PGK1 and GRP78 overexpression correlates with clinical significance and poor prognosis in Chinese endometrial cancer patients. AB - The aim of this study was to measure the expression patterns of PGK1 and GRP78 in normal endometrial tissues and endometrial carcinoma, and associations between their combined effects and the pathological features of endometrial carcinoma. We used 30 normal endometrial tissue samples and 130 endometrial carcinoma samples, and separately evaluated PGK1 and GRP78 protein expression by immunohistochemistry. Scores ranging from 0 to 9 were obtained by multiplying the percentage of positive cells by the staining intensity (0-3). Immunohistochemical analysis revealed increased PGK1 and GRP78 expression in the cytoplasm of endometrial carcinoma cells compared with that in normal endometrial tissues. High PGK1 expression positively correlated with the FIGO stage (P < 0.001), histological grade (P = 0.002), and lymph node status (P < 0.001). High GRP78 expression positively correlated with the pathological type (P = 0.0125), FIGO stage (P < 0.001), and lymph node status (P < 0.001). In addition, PGK1 overexpression was positively correlated with GRP78 overexpression in endometrial carcinoma patients (P < 0.001), and the concurrent expression of both oncogenes in endometrial carcinoma patients correlated significantly with the lymph node status (P < 0.001) and FIGO stage (P < 0.001). Patients with high PGK1 and GRP78 expression levels had poorer overall survival rates than those with low expression levels of both proteins (P < 0.001). Our results suggested that the co occurrence of PGK1 and GRP78 expression is potentially an unfavorable factor for endometrial carcinoma progression. PMID- 29416646 TI - Radiation-induced alternative transcripts as detected in total and polysome-bound mRNA. AB - Alternative splicing is a critical event in the posttranscriptional regulation of gene expression. To investigate whether this process influences radiation-induced gene expression we defined the effects of ionizing radiation on the generation of alternative transcripts in total cellular mRNA (the transcriptome) and polysome bound mRNA (the translatome) of the human glioblastoma stem-like cell line NSC11. For these studies, RNA-Seq profiles from control and irradiated cells were compared using the program SpliceSeq to identify transcripts and splice variations induced by radiation. As compared to the transcriptome (total RNA) of untreated cells, the radiation-induced transcriptome contained 92 splice events suggesting that radiation induced alternative splicing. As compared to the translatome (polysome-bound RNA) of untreated cells, the radiation-induced translatome contained 280 splice events of which only 24 were overlapping with the radiation-induced transcriptome. These results suggest that radiation not only modifies alternative splicing of precursor mRNA, but also results in the selective association of existing mRNA isoforms with polysomes. Comparison of radiation-induced alternative transcripts to radiation-induced gene expression in total RNA revealed little overlap (about 3%). In contrast, in the radiation induced translatome, about 38% of the induced alternative transcripts corresponded to genes whose expression level was affected in the translatome. This study suggests that whereas radiation induces alternate splicing, the alternative transcripts present at the time of irradiation may play a role in the radiation-induced translational control of gene expression and thus cellular radioresponse. PMID- 29416648 TI - Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2. AB - Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo, despite elevated expression levels of COX-2 in Nf2-deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms. PMID- 29416647 TI - The dual PI3K/mTOR inhibitor dactolisib elicits anti-tumor activity in vitro and in vivo. AB - Glioblastomas (GBMs) are among the most malignant of all human tumors and have poor prognosis. The current standard of care (SOC) includes maximal surgical tumor resection followed by adjuvant temozolomide (TMZ) and concomitant radiotherapy (RT). However, even with this treatment, the 5-year survival rate is less than 10%, and thus, follow-up treatment is required to improve efficacy. In GBMs as well as many other solid cancers, PI3K/mTOR signaling is overactivated. Therefore, multiple tumor-based PI3K inhibitors have been studied in various cancers. In the current study, we investigated the effect of the dual PI3K/mTOR inhibitor dactolisib on TMZ+RT treatment in three human GBM cell lines and a orthotopic xenograft model. Dactolisib alone induced cytotoxicity and pro apoptotic effects, which act as antitumor factors. Combined with SOC treatment, dactolisib inhibited cell viability, induced enhanced pro-apoptotic effect, and attenuated migration/invasion in all three cell lines, thereby enhancing the SOC therapeutic effect. Protein microarray analysis showed that A172 cells treated with TMZ+RT+dactolisib had higher p27 and lower Bcl-2 expression than other groups. Moreover, in the xenograft model, oral dactolisib combined with TMZ+RT inhibited tumor growth and prolonged survival. Thus, SOC combined with dactolisib shows potent anti-tumor activity and has promising potential for solid tumor treatment. PMID- 29416649 TI - Cooperation between ZEB2 and Sp1 promotes cancer cell survival and angiogenesis during metastasis through induction of survivin and VEGF. AB - Epithelial-mesenchymal transition (EMT) is a process implicated in tumor invasion and metastasis. During EMT, epithelial cells undergo molecular changes to acquire mesenchymal phenotypes, which are mediated by EMT-inducing transcription factors. Previously, we showed that ZEB2 cooperates with the transcription factor Sp1 to function as a transcriptional activator of vimentin, integrin alpha5, and cadherin-11, which promotes cancer cell invasion. We hypothesized that ZEB2, through cooperation with Sp1, would mediate diverse cellular functions beyond EMT and invasion during metastasis. ZEB2 upregulated the expression of Sp1-regulated genes such as survivin, bcl-2, cyclin D1, and vascular endothelial growth factor in an Sp1-dependent manner, resulting in increased cancer cell survival and proliferation and endothelial cell activation in vitro, and increased circulating tumor cell survival and tumor angiogenesis in vivo. In addition, Sp1 enhanced ZEB2 stability, suggesting the presence of a positive feedback loop between ZEB2 and Sp1. Clinical data showed that ZEB2 expression was positively associated with Sp1 expression, and that the expression of both of these factors had prognostic significance for predicting survival in cancer patients. This study suggests that invasion is linked to cancer cell survival and angiogenesis by ZEB2 during cancer progression, and increases our understanding of the pathways via which EMT inducing transcription factors regulate the complex process of metastasis. PMID- 29416650 TI - Organic cation transporter 3 mediates cisplatin and copper cross-resistance in hepatoma cells. AB - Platinum-based drugs are first-line compounds in the treatment of many solid cancers. Major obstacles are tumors that become resistant and toxic side effects, both largely due to the expression of transporters that mediate the cellular processing of platinum. In this study, we addressed the establishment of cisplatin resistance in the absence of copper transporter ATP7B that has been previously found to be overexpressed in various resistant cells. Cisplatin sensitivity, induction of apoptosis, drug accumulation, and transporter gene expression were determined in hepatoma cell lines. Knockout or overexpression of copper transporter ATP7B did not affect cisplatin sensitivity. Cisplatin resistant cells showed a stably reduced cisplatin accumulation and a downregulation of organic cation transporter 3 (OCT3). In contrast, OCT3 overexpression could reverse resistance. Reduced MT1 expression was detected in the resistant cell line, however transient and highly dependent on the presence of cisplatin. Cross-resistance to copper was also associated with OCT3 downregulation. Our results suggest that a decreased level of OCT3 expression results in resistance to cisplatin and copper. OCT3 may represent a novel target for improved prognosis and anticancer therapy, including HCC. PMID- 29416651 TI - Jazf1 promotes prostate cancer progression by activating JNK/Slug. AB - Juxtaposed with another zinc finger protein 1 (Jazf1) is a zinc finger protein and is known to affect both prostate cancer and type 2 diabetes. Jazf1 inhibits testicular nuclear receptor 4 (TR4) activation through protein-protein interaction, which results in weight loss and alleviates diabetes. However, the role of Jazf1 in prostate cancer is still poorly understood. Hence, we investigated whether the expression of Jazf1 is associated with prostate cancer progression. We confirmed the upregulation of Jazf1 expression in human prostate tissue samples. In addition, using Jazf1 overexpressing prostate cancer cell lines, DU145 and LNCaP, we found Jazf1 promoted cell proliferation and colony formation ability. We also observed that Jazf1 dramatically enhanced cell migration and invasion in transwell assays. Additionally, we checked the upregulation of vimentin and downregulation of E-cadherin expression in Jazf1 overexpressing DU145 and LNCaP cells. Moreover, we found that Slug, which is known to be regulated by JNK/c-Jun phosphorylation, was upregulated in the microarray analysis of two prostate cancer cell lines. Jazf1 promotes the phosphorylation of JNK/c-Jun, likely promoting cell proliferation and invasion through Slug. In a xenograft model, tumors overexpressing Jazf1 were larger than control tumors, and tumors with decreased Jazf1 were smaller. These data indicated that Jazf1 enhances prostate cancer progression and metastasis via regulating JNK/Slug signaling. Taken together, these results suggest that Jazf1 plays an important role in both androgen dependent and independent prostate cancer. PMID- 29416652 TI - Phase II study of rituximab given in conjunction with standard chemotherapy in primary central nervous system lymphoma (PCNSL): a trial of the ECOG-ACRIN cancer research group (E1F05). AB - Background: Therapy of primary CNS lymphoma (PCNSL) has focused on multi-agent chemotherapy designed to cross the blood brain barrier. Rituximab has demonstrated activity in PCNSL. E1F05 is an ECOG-ACRIN multicenter phase 2 prospective trial of rituximab with high-dose methotrexate (HD-MTX)-based chemotherapy similar to the RTOG 93-10 regimen, omitting radiotherapy. Methods: Immunocompetent patients with newly diagnosed PCNSL received HD-MTX 3.5g/m2 with vincristine every two weeks for 5 doses; procarbazine for 7 days in weeks 1, 5, and 9; cytarabine 3g/m2/day IV for 2 days in weeks 11 and 14; a dexamethasone taper over 6 weeks; and rituximab 375mg/m2 IV infusion 3 times per week for weeks 1-4. Subjects with CSF involvement received intrathecal methotrexate 12mg every two weeks. Results: Twenty-six patients were enrolled; median age was 57. Sixteen subjects (65%) completed treatment per protocol; the most common reason for discontinuation was adverse events, and 2 subjects discontinued due to progressive disease (PD). Complete response (CR) + unconfirmed CR (CRu) was 16/25 (64%), overall response rate was 20/25 (80%), and 4/25(16%) had PD as best response. Median progression free survival (PFS) was 34 months, and median overall survival has not been reached at 40 months' median follow up. Two year PFS was 63%. The most common grade 3-4 toxicities were hematologic. Conclusion: The addition of rituximab to multi-agent chemotherapy is well tolerated. Outcomes are comparable to or better than those seen in RTOG 93-10, which included RT. These and other results suggest rituximab has activity in the CNS. [ECOG-ACRIN E1F05]. Clinical Trial Registration: NCT00335140, clinicaltrials.gov. PMID- 29416653 TI - Thyroid cancer risk in the Swedish AMORIS study: the role of inflammatory biomarkers in serum. AB - Chronic inflammation is one of the underlying risks associated with thyroid cancer. We ascertained the association between commonly measured serum biomarkers of inflammation and the risk of thyroid cancer in Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. 226,212 subjects had baseline measurements of C reactive protein, albumin and haptoglobin. Leukocytes were measured in a subgroup of 63,845 subjects. Associations between quartiles and dichotomized values of inflammatory markers and risk of thyroid cancer were analysed using multivariate Cox proportional hazard models. 202 individuals were diagnosed with thyroid cancer during a mean follow-up of 19.6 years. There was a positive association between lower albumin levels and risk of developing thyroid cancer [Hazard Ratio for albumin <= 40 g/L: 1.50 (95% Confidence Interval = 1.04-2.16)]. When stratified by a metabolic score, we observed similar association for albumin with higher HR among those with metabolic score >= 1, as compared to those with metabolic score of 0 [HR 1.98 (95% CI = 1.11-3.54) vs 1.17 (95% CI = 0.72-1.89)] (P = 0.19). Apart from albumin, none of the serum markers of inflammation studied showed a link with the risk of developing thyroid cancer-suggesting that the role of inflammation may be more complicated and requires assessment of more specialised measurements of inflammation. PMID- 29416654 TI - Down-regulation of long non-coding RNA ESCCAL_1 inhibits tumor growth of esophageal squamous cell carcinoma in a xenograft mouse model. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignant cancers with high incidence and mortality. Current reliable effective diagnostic and prognostic biomarkers are very limited in clinic. Emerging evidence indicates that dysregulated expression of the long non-coding RNAs (lncRNAs) was examined in various types of cancer including ESCC. ESCC associated lncRNA _1 (ESCCAL_1) was first time identified to be increased expression in ESCC, and therefore named by our research team. However, its potential function in the progression of ESCC remains unclear. In this study, we investigated the effect of ESCCAL_1 knockdown on ESCC tumorigenicity using a xenograft mouse model and explored the underlying molecular mechanism. Here we showed that ESCCAL_1 knockdown significantly inhibited EC9706 cell growth in nude mice. Interestingly, we also found that reduced expression of ESCCAL_1 resulted in distinct alterations of relative phosphorylation level of kinases (p-p38alpha, p-JNK, p-FAK and p-Src), and significant changes of the expression level of apoptosis-related proteins (p53, BAX, Bcl-2 and Caspase-3). In summary, our results suggest that lncRNA ESCCAL_1 is a potential diagnostic and prognostic target of ESCC. PMID- 29416655 TI - Folate receptor-alpha targeted near-infrared fluorescence imaging in high-risk endometrial cancer patients: a tissue microarray and clinical feasibility study. AB - Objective: Detection and resection of all malignant lesions is pivotal in staging and cytoreductive surgery (CRS) of endometrial cancer (EC). Intraoperative EC detection could be enhanced using OTL-38, a fluorescent-labelled folate receptor alpha (FRalpha) targeted imaging agent. The objectives of this study were to investigate which subgroups of high-risk EC patients express FRalpha and assess feasibility of intraoperative EC detection using OTL-38. Results: FRalpha expression on TMA was significantly correlated with tumor type (p < 0.01). Eighty two percent of serous and clear cell carcinomas showed FRalpha expression. Four patients were enrolled in the clinical study. Using fluorescence imaging all omental (n = 3) and lymph node (LN) metastases (n = 16) could be clearly identified, including one otherwise undetected omental metastasis. However, false positive fluorescence was identified in 17/50 non-metastatic LNs, caused by OTL 38 targeting of FRbeta, expressed by tumor-associated activated macrophages. Conclusions: This study describes high FRalpha expression in serous and clear cell EC and demonstrates the first experience of intraoperative FRalpha-targeted tumor detection in patients with these subtypes of EC. Although all metastases could be clearly identified using OTL-38, the role of tumor-associated macrophages should be further evaluated. Methods: Immunohistochemical (IHC) staining of FRalpha expression was performed on tissue micro arrays (TMA) of 116 patients with high-risk EC features. Patients with either serous or clear cell EC, planned for staging or CRS, were eligible for inclusion in the clinical study and received an intravenous dose of 0.0125 mg/kg OTL-38, 2-3 hours prior to surgery. Resected lesions, identified by standard-of-care and/or fluorescence imaging, were histopathologically assessed for FRalpha and tumor status. PMID- 29416656 TI - Propranolol enhanced the anti-tumor effect of sunitinib by inhibiting proliferation and inducing G0/G1/S phase arrest in malignant melanoma. AB - Both sunitinib, a multi-target tyrosine kinase inhibitor (TKI) and propranolol, a non-selective beta-blocker, have proven therapeutic effects on malignant melanoma (MM). This study reports a synergistic effect of propranolol and sunitinib upon A375, P8 MM cell lines and mice xenografts. Cell viability assays detected a significant decrease of sunitinib IC50 in combination with propranolol, which was confirmed by a colony formation assay. Western blot showed that propranolol and sunitinib combination significantly down-regulated phospho-Rb, phospho-ERK, Cyclin D1, and Cyclin E, but had no effect on Bax, Bcl-2, or cleaved PARP expression. The average tumor size of propranolol and low-dose sunitinib (Sun L) combination treated mice was reduced and similar to high-dose sunitinib treated A375 xenografts. The Ki67 index was significantly reduced in propranolol and Sun L combination treated group compared with single Sun L treated group. This synergistic effect between propranolol and sunitinib to inhibit MM proliferation was through suppressing ERK/Cyclin D1/Rb/Cyclin E pathways and inducing G0/G1/S phase arrest, rather than by inducing tumor cell apoptosis. PMID- 29416657 TI - Efficient leukocyte depletion by a novel microfluidic platform enables the molecular detection and characterization of circulating tumor cells. AB - RT-qPCR is a highly sensitive approach to detect rare transcripts, as derived from circulating tumor cells (CTCs) in the blood of cancer patients. However, the presence of unwanted leukocytes often leads to false positive results. Here, we evaluated whether the micro-fluidic ParsortixTM technology is appropriate to remove these leukocytes and thereby finally to improve the overall approach. In this study, we established a workflow including the micro-fluidic ParsortixTM technology for the molecular detection of CTC related transcripts. Background levels of EpCAM, PPIC, TUSC3, and MAL2 were efficiently removed due to an up to 106-fold depletion of leukocytes. The presence of these gene markers was observed in ParsortixTM-enriched blood samples from patients with primary and recurrent gynecological cancer (32% and 14%), as well as in 86% of the metastatic breast cancer samples, at a very high specificity. In the ovarian cancer samples, PPIC was the most prominent gene marker, contributing to all positive cases and at least to 70% of the positive cases after pre-amplification of the respective target genes. Expanding the analytical panel up to 29 gene markers further increased the positivity rate (primary gynecological cancer: 95%, recurrent gynecological cancer: 100%, metastatic breast cancer: 92%). The established workflow strongly improved the overall molecular analysis of the target cells by the efficient removal of contaminating cells, and, thereby offers great promise for the molecular characterization of CTCs. PMID- 29416658 TI - Frizzled-10 and cancer progression: Is it a new prognostic marker? AB - Frizzled (FZD) proteins, a family of Wnt receptors, are involved in carcinogenesis in different organs. One interesting FZD protein is FZD-10 highly expressed in embryogenesis but completely absent in the membrane or cytosol of healthy proliferated cells. We studied in detail the expression level and the location of Frizzled-10 protein in different cancerous tissues, such as colon, melanoma and gastric cancer and in function of different staging of the tumor and in metastases. We observed a correlation between cancer evolution and FZD-10 expression, and localization of protein during carcinogenesis. In colon, we have an increase of cytoplasmic FZD-10 expression from hyperplastic mucosa to metastatic tissues, while the amount in the nucleus decreases significantly in T3 and T4 staging tumors as well as in metastases. In melanoma and gastric cancer, we observed the opposite trend of FZD-10 protein in the cytosol but both show a decrease in the T3 and T4 stage of the tumor and in metastases. However, the decrease is less prominent in gastric cancer. Our findings indicate an important role of FZD-10 in tumor progression especially in the later stages of tumor. The nuclear expression of FZD-10 or its absence can give a new tool for tumor staging to pathologists. For target therapy, at least for colon cancer, the high presence of FZD-10 in the later stages of tumor progression and the absence in healthy tissue present a promising new approach. PMID- 29416659 TI - Recombinant rabies virus with the glycoprotein fused with a DC-binding peptide is an efficacious rabies vaccine. AB - Our previous studies demonstrated that recruiting and/or activating dendritic cells (DCs) enhanced the immunogenicity of recombinant rabies viruses (rRABV). In this study, rRABV LBNSE with a small DC-binding peptide (designated as rLBNSE DCBp) or a negative control peptide (designated as rLBNSE-DCCp) fused to the glycoprotein (G) was constructed and rescued. As expected, significantly more activated DCs were detected in rLBNSE-DCBp-immunized mice than those immunized with rLBNSE or rLBNSE-DCCp. Subsequently, significantly more generation of TFH and GC B cells were observed in rLBNSE-DCBp immunized mice than those in rLBNSE or rLBNSE-DCCp-immunized mice. In addition, significantly higher levels of virus neutralizing antibodies (VNAs) were observed in mice immunized with rLBNSE-DCBp than those immunized with rLBNSE or rLBNSE-DCCp, resulting in a better protection of rLBNSE-DCBp immunized mice against the lethal challenge. Taken together, our results suggest that rRABV with G fused with DCBp is a promising rabies vaccine candidate. PMID- 29416660 TI - FoxM1 is a promising candidate target in the treatment of breast cancer. AB - Forkhead box protein M1(FoxM1) is a member of forkhead superfamily transcription factors. Emerging evidences have progressively contributed to our understanding on a central role of FoxM1 in human cancers. However, perspectives on the function of FoxM1 in breast cancer (BC) remain conflicting, and mostly were from basic research. Here, we explored the expression profile and prognostic values of FoxM1 based on analysis of pooled clinical datasets derived from online accessible databases, including ONCOMINE, Breast Cancer Gene-Expression Miner v4.0, and Kaplan-Meier plotter. It was found that, FoxM1 mRNA expression was significantly higher in breast tumor versus normal control. FoxM1expression profile presented a distinct pattern in different molecular subtypes of BC patients. Higher expression of FoxM1 was correlated to low mRNA expression of estrogen receptor 1 (ESR1), erb-B2 receptor tyrosine kinase 2 (ERBB2), and was inversely associated with the expression of classical luminal regulators forkhead box protein A1 (FoxA1) and GATA binding protein 3 (GATA3). Elevated FoxM1 expression predicted shorter distance metastasis free survival (DMFS) in BC patients, particularly with estrogen receptor (ER) positive and Luminal A, Luminal B subtypes of BC. More interestingly, elevated FoxM1 expression predicted poor survival in breast cancer patients, especially in the ER (+), progesterone receptor (PR) (+) subgroups and BC patients received adjuvant chemotherapy only or treated with tamoxifen only. These results implied that FoxM1 is an essential prognostic factor and promising candidate target in the treatment of breast cancer. PMID- 29416661 TI - Gli is activated and promotes epithelial-mesenchymal transition in human esophageal adenocarcinoma. AB - Esophageal adenocarcinoma (EAC) accounts for the most esophageal cancer cases in the US, and is notoriously aggressive. This study examines the role of Sonic Hedgehog (SHh)/Gli signaling in the regulation of epithelial-mesenchymal transition (EMT), a process tied to invasion and metastasis, in EAC. Gli/EMT protein expression levels were examined by western blot in paired EAC patient tissues (n = 24) and cell lines (OE19, OE33). Functional analyses were performed (siRNA, treatment with Gli-inhibitor, AKT-inhibitor, and N-Shh recombinant proteins) to investigate SHh/Gli signaling and EMT, cell cycle, and prognostic markers in EAC cell lines. MTS, luciferase reporter, qRT-PCR, western blot, wound healing, and transwell assays were executed to analyze pathway activity, cell migration, and invasion. Aberrant Gli1/2 expression was found in EAC patient tissues, and was significantly associated with increased EMT and AKT pathway activity. Stimulation of SHh/Gli resulted in EMT signaling, including expression of E-cadherin, N-cadherin, Vimentin, beta-catenin, Snail, and Slug, as well as cell cycle progression at mRNA and protein levels in EAC cell lines. Gli inhibition via small molecule administration and siRNA significantly reduced EMT, decreasing cell mobility and invasion. Both Gli and AKT inhibition rescued E cadherin expression and suppressed AKT phosphorylation. This study provides evidence for a strong association between aberrant Gli1/2 expression and AKT/EMT markers in EAC; activated SHh/Gli signaling may be a critical component in promoting cell survival, metastases, and resistance to chemotherapy, and represents a promising avenue to target tumor proliferation and mobility. PMID- 29416662 TI - Xanthohumol prevents dextran sulfate sodium-induced colitis via inhibition of IKKbeta/NF-kappaB signaling in mice. AB - Xanthohumol (XN), a prenylated chalcone isolated from the hop plant, has been reported to exhibit multiple biological functions including anti-inflammation. However, the pharmacological function of XN on colitis remains unknown. In this study, we investigated the anti-inflammatory effect of synthesized XN and molecular mechanism on dextran sulfate sodium (DSS)-induced experimental colitis. XN attenuated the colitis symptoms along with the prevention of colonic lesions after DSS challenge. XN inhibited the production of pro-inflammatory cytokines, oxidative stress and cyclooxygenase-2 expression in DSS-treated mice. Moreover, XN inhibited the phosphorylation of IkappaBalpha, the nuclear translocation of NF kappaB subunits and the transcriptional activity of NF-kappaB in vivo and in vitro. In contrast to XN, isoXN showed much less effects on the kinase activity of IKKbeta and IkappaBalpha phosphorylation induced by XN in this study, suggesting that an electrophilic carbon center present in XN is critical for the anti-inflammation in colitis, especially inhibition of IKKbeta/NF-kappaB signaling pathway. Consistently, our docking analysis revealed that XN could bind to the active site, presumably at the Cys99 of IKKbeta. Taken together, these findings demonstrate a new function of XN to inhibit IKKbeta/NF-kappaB signaling, suggesting XN could be the potential therapeutic agent for the prevention of colitis. PMID- 29416663 TI - Genetic variation in CDH13 gene was associated with non-small cell lung cancer (NSCLC): A population-based case-control study. AB - Cadherin 13 (CDH13, T-cadherin, H-cadherin) has been identified as an anti oncogene in various cancers. Recent studies have reported that downregulation of H-cadherin in cancers is associated with CDH13 promoter hypermethylation, which could be affected by the single nucleotide polymorphisms (SNPs) near CpG sites in the CDH13 promoter. In the current study, we investigated and analyzed the association of seven SNPs (rs11646213, rs12596316, rs3865188, rs12444338, rs4783244, rs12051272 and rs7195409) with non-small cell lung cancer (NSCLC) using logistic regression analysis. SNPs rs11646213, rs12596316, rs3865188 and rs12444338 are located in the promoter region, rs4783244 and rs12051272 are located in intron 1, and rs7195409 is located in intron 7. A total of 454 patients with NSCLC were placed into a NSCLC group and 444 healthy controls were placed into a control group, all participants were recruited to genotype the SNPs using Taqman assay. Our results showed that the allelic frequencies of rs11646213 were significantly different between NSCLC and control groups (P = 0.006). In addition, the association analysis of these SNPs stratified into NSCLC pathologic stages I+II and III+IV showed that the allelic frequencies rs7195409 had a significant difference between NSCLC pathologic stages I+II and III+IV (P = 0.006). Our results indicated that the rs11646213 and rs7195409 in CDH13 could be associated with NSCLC or its pathologic stages in the Chinese Han population. PMID- 29416664 TI - Direct bilirubin levels are prognostic in non-small cell lung cancer. AB - We investigated the prognostic value of serum bilirubin levels in stage I-II non small cell lung cancer (NSCLC) patients and evaluated the relationship between bilirubin levels and response to first-line platinum-based chemotherapy. We divided 634 NSCLC patients from a single hospital in China into retrospective training (n = 307) and prospective validation (n = 327) cohorts. X-tile was used to identify the optimal serum bilirubin cutoff value for sorting retrospective cohort patients into low and high overall survival (OS) groups. TNM stage and serum bilirubin levels were associated with OS on univariate analysis. Direct bilirubin (DBIL) levels were correlated with tumor progression and response to first-line platinum-based chemotherapy, and were associated with OS after adjusting for TNM stage. Our findings indicate a DBIL-based prognostic nomogram is more accurate than the TNM staging system in predicting clinical outcomes, and that the DBIL level is an independent predictor of OS in NSCLC. Thus, an index that combines DBIL with TNM stage may better predict patient outcomes than TNM stage alone. PMID- 29416665 TI - Baicalin hydrate inhibits cancer progression in nasopharyngeal carcinoma by affecting genome instability and splicing. AB - Baicalin hydrate (BH), a natural compound, has been investigated for many years because of its traditional medicinal properties. However, the anti-tumor activities of BH and its epigenetic role in NPC have not been elucidated. In this study, we identified that BH inhibits NPC cell growth in vivo and in vitro by inducing apoptosis and cell cycle arrest. BH epigenetically regulated genome instability by up-regulating the expression of satellite 2 (Sat2), alpha satellite (alpha-Sat), and major satellite (Major-Sat). BH also increased the level of IKKalpha, Suv39H1, and H3K9me3 and decreased LSH expression. Interestingly, BH promoted the splicing of Suv39H1 via the enhancement of m6A RNA methylation, rather than DNA methylation. Taken together, our results demonstrated that BH has an anti-tumor role in NPC and revealed a unique role of BH in genome instability and splicing in response to DNA damage. PMID- 29416666 TI - Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models. AB - Melanoma is a recalcitrant disease. Melanoma patients with the BRAF-V600E mutation have been treated with the drug vemurafenib (VEM) which targets this mutation. However, we previously showed that VEM is not very effective against a BRAF-V600E melanoma mutant in a patient-derived orthotopic xenograft (PDOX) model. In contrast, we demonstrated that recombinant methioninase (rMETase) which targets the general metabolic defect in cancer of methionine dependence, was effective against the BRAF-V600E mutant melanoma PDOX model. In the present study, we demonstrate that rMETase is effective against a BRAF-V600E-negative melanoma PDOX which we established. Forty BRAF-V600E-negative melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); temozolomide (TEM) (25 mg/kg, p.o., 14 consecutive days, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); TEM + rMETase (TEM: 25 mg/kg, p.o., rMETase: 100 units, i.p., 14 consecutive days, n = 10). All treatments inhibited tumor growth compared to untreated control (TEM: p = 0.0003, rMETase: p = 0.0006, TEM/rMETase: p = 0.0002) on day 14 after initiation. Combination therapy of TEM and rMETase was significantly more effective than either mono therapy (TEM: p = 0.0113, rMETase: p = 0.0173). The present study shows that TEM combined with rMETase is effective for BRAF-V600E-negative melanoma PDOX similar to the BRAF-V600E-positive mutation melanoma. These results suggest rMETase in combination with first-line chemotherapy can be highly effective in both BRAF V600E-negative as well as BRAF-V600E-positive melanoma and has clinical potential for this recalcitrant disease. PMID- 29416667 TI - Discovery of a FLT3 inhibitor LDD1937 as an anti-leukemic agent for acute myeloid leukemia. AB - FMS-like receptor tyrosine kinase-3 (FLT3) belongs to the family of receptor tyrosine kinase (RTK), and the FLT3 mutation is observed in 1/3 of all acute myeloid leukemia (AML) patients. Potential FLT3 inhibitors have been investigated as potential therapeutic agents of AML. In this study, we identified a potent FLT3 inhibitor LDD1937 containing an indirubin skeleton. The potent inhibitory activity of LDD1937 against FLT3 was shown with an in vitro kinase assay (IC50 = 3 nM). The LDD1937 compound selectively inhibited the growth of MV-4-11 cells (GI50 = 1 nM) and induced apoptotic cell death. LDD1937 caused cell cycle arrest at the G2/M phase and increased the cell population at the sub-G1 phase. Phosphorylation of STAT5, which is the downstream signaling of FLT3, was significantly reduced by LDD1937 in a dose-dependent manner. The pharmacokinetic properties of LDD1937 were investigated in mice. Then, the in vivo anti-tumor effect was investigated using a MV-4-11 xenograft. With the intravenous administration of 5 and 10 mg/kg in nu/nu mice, the tumor volume and weight were significantly reduced compared to the control. LDD1937 is a promising therapeutic candidate to treat AML patients because of its ability to suppress tumor cell growth in vitro and in vivo. PMID- 29416668 TI - Molecular mechanisms of cardioprotective effects mediated by transplanted cardiac ckit+ cells through the activation of an inflammatory hypoxia-dependent reparative response. AB - The regenerative effects of cardiac ckit+ stem cells (ckit+CSCs) in acute myocardial infarction (MI) have been studied extensively, but how these cells exert a protective effect on cardiomyocytes is not well known. Growing evidences suggest that in adult stem cells injury triggers inflammatory signaling pathways which control tissue repair and regeneration. Aim of the present study was to determine the mechanisms underlying the cardioprotective effects of ckit+CSCs following transplantation in a murine model of MI. Following isolation and in vitro expansion, cardiac ckit+CSCs were subjected to normoxic and hypoxic conditions and assessed at different time points. These cells adapted to hypoxia as showed by the activation of HIF-1alpha and the expression of a number of genes, such as VEGF, GLUT1, EPO, HKII and, importantly, of alarmin receptors, such as RAGE, P2X7R, TLR2 and TLR4. Activation of these receptors determined an NFkB-dependent inflammatory and reparative gene response (IRR). Importantly, hypoxic ckit+CSCs increased the secretion of the survival growth factors IGF-1 and HGF. To verify whether activation of the IRR in a hypoxic microenvironment could exert a beneficial effect in vivo, autologous ckit+CSCs were transplanted into mouse heart following MI. Interestingly, transplantation of ckit+CSCs lowered apoptotic rates and induced autophagy in the peri-infarct area; further, it reduced hypertrophy and fibrosis and, most importantly, improved cardiac function. ckit+CSCs are able to adapt to a hypoxic environment and activate an inflammatory and reparative response that could account, at least in part, for a protective effect on stressed cardiomyocytes following transplantation in the infarcted heart. PMID- 29416669 TI - Association of DNA repair gene polymorphisms with the risk of radiation pneumonitis in lung cancer patients. AB - A total of 149 lung cancer patients were recruited to receive intensity modulated radiation therapy (IMRT). The association of developing radiation pneumonitis (RP) with genetic polymorphism was evaluated. The risks of four polymorphic sites in three DNA repair related genes (ERCC1, rs116615:T354C and rs3212986:C1516A; ERCC2, rs13181:A2251C; XRCC1, rs25487:A1196G) for developing grade >= 2 RP were assessed respectively. It was observed that ERCC1 T354C SNP had a significant effect on the development of grade >= 2 RP (CT/TT vs. CC, adjusted HR = 0.517, 95% CI, 0.285-0.939; adjusted P = 0.030). It is the first time demonstrating that CT/TT genotype of ERCC1 354 was significantly associated with lower RP risk after radio therapy. PMID- 29416670 TI - Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling. AB - Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, known as colitis-associated cancer (CAC). It is still unclear what driver mutations are caused by chronic inflammation and lead to CAC development. To get insight into this issue, we investigated somatic alterations in CAC. We performed exome sequencing of 22 fresh CACs and targeted sequencing of 43 genes on 90 archive specimens from Japanese CAC patients, of which 58 were ulcerative colitis (UC) and 32 were Crohn's disease (CD). Consistently with the previous reports, TP53 was commonly mutated (66%) whereas APC, KRAS and SMAD4 were mutated less frequently (16%, 11% and 11%, respectively). Mucinous CD-CACs in the anus, an Asian-specific subtype of CD-CAC, had less somatic mutations in our target genes. We also found that RNF43, a negative regulator of the Wnt signaling, was somatically mutated in a significant fraction of CACs (10 of 90; 11%). Two lines of evidence indicated that somatic mutations of RNF43 were related to chronic inflammation. First, somatic mutations of RNF43 were significantly associated with longer duration of IBD. Second, clinico-pathological features suggested many of the APC-mutated CACs were actually sporadic colorectal cancer whereas RNF43 mutated CACs did not have this tendency. RNA-Seq analysis showed that RNF43 mutated CACs had elevated expression of c-Myc and its target genes, suggesting that RNF43 is a bona fide driver of CAC development. This study provides evidence that somatic mutation of RNF43 is the driver genetic alteration that links chronic inflammation and cancer development in about 10% of CACs. PMID- 29416671 TI - Prostaglandin receptor EP3 regulates cell proliferation and migration with impact on survival of endometrial cancer patients. AB - Background: Prostaglandin E2 (PGE2) receptor 3 (EP3) regulates tumor cell proliferation, migration, and invasion in numerous cancers. The role of EP3 as a prognostic biomarker in endometrial cancer remains unclear. The primary aim of this study was to analyze the prognostic significance of EP3 expression in endometrial cancer. Methods: We analyzed the EP3 expression of 140 endometrial carcinoma patients by immunohistochemistry. RL95-2 endometrial cancer cell line was chosen from four endometrial cancer cell lines (RL95-2, Ishikawa, HEC-1-A, and HEC-1-B) according to EP3 expression level. Treated with PGE2 and EP3 antagonist, RL95-2 cells were investigated by MTT, BrdU, and wound healing assay for functional assessment of EP3. Results: EP3 staining differed significantly according to WHO tumor grading in both whole cohort (p = 0.01) and the subgroup of endometrioid carcinoma (p = 0.01). Patients with high EP3 expression in their respective tumors had impaired progression-free survival as well as overall survival in both cohorts above. EP3 expression in the overall cohort was identified as an independent prognostic marker for progression-free survival (HR 1.014, 95%CI 1.003-1.024, p = 0.01) when adjusted for age, stage, grading, and recurrence. Treatment with EP3 antagonists induced upregulation of estrogen receptor beta and decreased activity of Ras and led to attenuated proliferation and migration of RL95-2 cells. Conclusions: EP3 seems to play a crucial role in endometrial cancer progression. In the context of limited systemic treatment options for endometrial cancer, this explorative analysis identifies EP3 as a potential target for diagnostic workup and therapy. PMID- 29416672 TI - Mitochondrial dysfunction activates lysosomal-dependent mitophagy selectively in cancer cells. AB - Molecules designed to target and accumulate in the mitochondria are an emerging therapeutic approach for cancer and other indications. Mitochondria-targeted redox agents (MTAs) induce mitochondrial damage and autophagy in cancer cells. However, the mechanisms for these molecules to induce mitophagy, the clearance of damaged mitochondria, are largely unknown. Using breast derived cell lines and a series of targeted molecules, mitochondrial dysfunction and autophagy was established to be selective for MDA-MB-231 cancer cells as compared to the non cancerous MCF-12A cells. Kinetic analyses revealed that mitochondrial dysfunction precedes the activation of autophagy in these cancer cells. To determine the onset of mitophagy, stably expressing mitochondrial mKeima, a mitochondrial pH sensor, cell lines were generated and revealed that these drugs activate lysosomal dependent mitochondrial degradation in MDA-MB-231 cells. Mitophagy was confirmed by identifying the accumulation of a PINK1, mitochondria located in autophagosomes, and the formation of an autophagosome-mitochondria protein (MFN2 LC3-II) complex. These results are the first to demonstrate that mitochondrial redox agents selectively induce mitophagy in a breast cancer cell line and their potential application both as tools for investigating mitochondrial biomechanics and as therapeutic strategies that target mitochondrial metabolism. PMID- 29416673 TI - Splice variants of the endonucleases XPF and XPG contain residual DNA repair capabilities and could be a valuable tool for personalized medicine. AB - The two endonucleases XPF and XPG are essentially involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. Defects in these two proteins result in severe diseases like xeroderma pigmentosum (XP). We applied our newly CRISPR/Cas9 generated human XPF knockout cell line with complete loss of XPF and primary fibroblasts from an XP-G patient (XP20BE) to analyze until now uncharacterized spontaneous mRNA splice variants of these two endonucleases. Functional analyses of these variants were performed using luciferase-based reporter gene assays. Two XPF and XPG splice variants with residual repair capabilities in NER, as well as ICL repair could be identified. Almost all variants are severely C-terminally truncated and lack important protein-protein interaction domains. Interestingly, XPF-202, differing to XPF-003 in the first 12 amino acids only, had no repair capability at all, suggesting an important role of this region during DNA repair, potentially concerning protein-protein interaction. We also identified splice variants of XPF and XPG exerting inhibitory effects on NER. Moreover, we showed that the XPF and XPG splice variants presented with different inter-individual expression patterns in healthy donors, as well as in various tissues. With regard to their residual repair capability and dominant-negative effects, functionally relevant spontaneous XPF and XPG splice variants present promising prognostic marker candidates for individual cancer risk, disease outcome, or therapeutic success. This merits further investigations, large association studies, and translational research within clinical trials in the future. PMID- 29416674 TI - SNHG16/miR-140-5p axis promotes esophagus cancer cell proliferation, migration and EMT formation through regulating ZEB1. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies. Long noncoding RNAs (lncRNAs) have been identified to be associated with many diseases including tumors, and involved in the regulation of a wide array of pathophysiological processes. Small nucleolar RNA host gene 16 (SNHG16), also known as noncoding RNA expressed in aggressive neuroblastoma, was newly identified as a potential oncogene in many cancers. However, its role in ESCC has not been investigated. In the current study, the level of SNHG16 in the ESCC tissues and cell lines was measured by quantitative real-time PCR (qRT-PCR). Then loss-of-function assays were performed to explore the biological effects of SNHG16 in ESCC cell. Based on the online database analysis tools, we uncovered that miR-140-5p could interact with SNHG16 and the level of miR-140-5p was inverse correlated with SNHG16 in ESCC specimens. Moreover, RIP, RNA pulldown system and dual luciferase reporter assay further provided evidence that SNHG16 directly targets miR-140-5p by binding with microRNA binding site harboring in the SNHG16 sequence. Furthermore, bioinformatics analysis revealed that ZEB1 is a target of miR-140-5p in ESCC. Collectively, our findings suggested that SNHG16 could act as an oncogenic lncRNA that promotes tumor progression through acting as an endogenous 'sponge' by competing with miR-140-5p, thereby regulating target ZEB1. PMID- 29416675 TI - Phosphorylation of caspase-9 at Thr125 directs paclitaxel resistance in ovarian cancer. AB - Although paclitaxel is routinely prescribed for the treatment of epithelial ovarian cancer (EOC), paclitaxel resistance is common in EOC and correlates with short survival of patients. A previous pharmacogenomic study revealed the importance of cyclin-dependent kinase 1 (CDK1) activity in a response on paclitaxel. However, a subsequent research showed that the expression level of CDK1 failed to show significant correlation with delayed apoptosis and patient survival. Rather, the expression and phosphorylation of capase-9, the downstream target molecule of CDK1, appeared to determine drug resistance. Our results suggest that treatment with the CDK1 inhibitor alsterpaullone reduces phosphorylation of caspase-9. Its phosphorylation level was dependent on CDK1 activity and it directs paclitaxel resistance. This observation was reproducible in xenografted tumors. Thus, the regulation of caspase-9 may be a novel therapeutic strategy to reverse paclitaxel-induced resistance in ovarian cancer cells. PMID- 29416676 TI - Long non-coding RNA GAS5 and ZFAS1 are prognostic markers involved in translation targeted by miR-940 in prostate cancer. AB - Identification of prognostic biomarkers helps facilitate the prediction of patient outcomes as well as guide treatments. Accumulating evidence now suggests that long non-coding RNAs (lncRNAs) play key roles in tumor progression with diagnostic and prognostic values. However, little is known about the biological functions of lncRNAs and how they contribute to the pathogenesis of cancer. Herein, we performed weighted correlation network analysis (WGCNA) on 380 RNA-seq samples from prostate cancer patients to create networks comprising of microRNAs, lncRNAs, and protein-coding genes. Our analysis revealed expression modules that associated with pathological parameters. More importantly, we identified a gene module that is involved in protein translation and is associated with patient survival. In this gene module, we explored the regulation axis involving GAS5, ZFAS1, and miR-940. We show that GAS5, ZFAS1, and miR-940 are up-regulated in tumors relative to normal prostate tissues, and high expression of either lncRNA is an indicator of poor patient outcome. Finally, we constructed a co-expression network involving GAS5, ZFAS1, and miR-940, as well as the targets of miR-940. Our results show that GAS5 and ZFAS1 are targeted by miR-940 via NAA10 and RPL28. Taken together, co-expression analysis of gene expression profiling from RNA-seq can accelerate the identification and functional characterization of novel prognostic markers in prostate cancer. PMID- 29416677 TI - Identification of human age-associated gene co-expressions in functional modules using liquid association. AB - Aging is a major risk factor for age-related diseases such as certain cancers. In this study, we developed Age Associated Gene Co-expression Identifier (AAGCI), a liquid association based method to infer age-associated gene co-expressions at thousands of biological processes and pathways across 9 human tissues. Several hundred to thousands of gene pairs were inferred to be age co-expressed across different tissues, the genes involved in which are significantly enriched in functions like immunity, ATP binding, DNA damage, and many cancer pathways. The age co-expressed genes are significantly overlapped with aging genes curated in the GenAge database across all 9 tissues, suggesting a tissue-wide correlation between age-associated genes and co-expressions. Interestingly, age-associated gene co-expressions are significantly different from gene co-expressions identified through correlation analysis, indicating that aging might only contribute to a small portion of gene co-expressions. Moreover, the key driver analysis identified biologically meaningful genes in important function modules. For example, IGF1, ERBB2, TP53 and STAT5A were inferred to be key genes driving age co-expressed genes in the network module associated with function "T cell proliferation". Finally, we prioritized a few anti-aging drugs such as metformin based on an enrichment analysis between age co-expressed genes and drug signatures from a recent study. The predicted drugs were partially validated by literature mining and can be readily used to generate hypothesis for further experimental validations. PMID- 29416678 TI - MiR-27a as a predictor for the activation of hepatic stellate cells and hepatitis B virus-induced liver cirrhosis. AB - Circulating microRNAs (miRNAs) can be employed as biomarkers to diagnose liver and other diseases. Noninvasive approaches are needed to complement and improve the current strategies for screening for biomarkers liver cirrhosis. We determined whether the serum levels of miRNAs can distinguish between chronic hepatitis B (CHB) and CHB-induced cirrhosis (HBC) and investigated the potential mechanisms involved. We found that serum miR-27a was significantly up-regulated in HBC, distinguishing HBC from CHB and healthy controls (Ctrl) (P<0.0001, the area of under the curve (AUC) =0.82 and 0.87, respectively). Specifically, when miR-27a was combined with miR-122, HBC was differentiated from CHB with an AUC=0.94. The serum miR-27a level in HBC patients with hepatic decompensation was significantly higher than that in patients with compensated HBC (P=0.0009). MiR 27a was also significantly up-regulated in the serum of rats with DMN-induced liver cirrhosis compared to that in saline-treated rats (P<0.0001). Furthermore, the down-regulation of miR-27a inhibited the proliferation and overexpression of miR-27a in activated hepatic stellate cells (HSCs) through the up-regulation of alpha-SMA and COL1A2 expression by targeting PPARgamma, FOXO1, APC, P53 and RXRalpha. Our study demonstrated that circulating miR-27a can be used as a predictor for the activation of HSCs and the occurrence and development of HBC. PMID- 29416679 TI - CONCORD biomarker prediction for novel drug introduction to different cancer types. AB - Many cancer therapeutic agents have shown to be effective for treating multiple cancer types. Yet major challenges exist toward introducing a novel drug used in one cancer type to different cancer types, especially when a relatively small number of patients with the other cancer type often benefit from anti-cancer therapy with the drug. Recently, many novel agents were introduced to different cancer types together with companion biomarkers which were obtained or biologically assumed from the original cancer type. However, there is no guarantee that biomarkers from one cancer can directly predict a therapeutic response in another. To tackle this challenging question, we have developed a concordant expression biomarker-based technique ("CONCORD") that overcomes these limitations. CONCORD predicts drug responses from one cancer type to another by identifying concordantly co-expressed biomarkers across different cancer systems. Application of CONCORD to three standard chemotherapeutic agents and two targeted agents demonstrated its ability to accurately predict the effectiveness of a drug against new cancer types and predict therapeutic response in patients. PMID- 29416680 TI - Elevated transgelin/TNS1 expression is a potential biomarker in human colorectal cancer. AB - Transgelin is an actin-binding protein that regulates cell motility and other important cellular functions. Previous studies have suggested that transgelin expression is associated with cancer development and progression, but its specific role in colorectal cancer (CRC) remains controversial. We analyzed expression of transgelin and its candidate downstream target, tensin 1 (TNS1), in CRC patients using the ONCOMINE, Protein Atlas, and OncoLnc databases. Transgelin and TNS1 mRNA and protein levels were higher in CRC patients and CRC cell lines than in normal tissues and cells. Survival analyses using the OncoLnc database revealed that elevated TAGLN/TNS1 levels were associated with a poor overall survival in CRC patients. Transgelin suppression using siRNA decreased TNS1 expression in CRC cells, demonstrating that transgelin induces the TNS1 expression. Importantly, suppression of transgelin or TNS1 using siRNA decreased proliferation and invasiveness of CRC cells. These results suggest that transgelin/TNS1 signaling promotes CRC cell proliferation and invasion, and that transgelin/TNS1 expression levels could potentially serve as a prognostic and therapeutic target in CRC patients. PMID- 29416681 TI - Changes in metabolism affect expression of ABC transporters through ERK5 and depending on p53 status. AB - Changes in metabolism require the efflux and influx of a diverse variety of metabolites. The ABC superfamily of transporters regulates the exchange of hundreds of substrates through the impermeable cell membrane. We show here that a metabolic switch to oxidative phosphorylation (OXPHOS), either by treating cells with dichloroacetate (DCA) or by changing the available substrates, reduced expression of ABCB1, ABCC1, ABCC5 and ABCG2 in wild-type p53-expressing cells. This metabolic change reduced histone changes associated to active promoters. Notably, DCA also inhibited expression of these genes in two animal models in vivo. In contrast, OXPHOS increased the expression of the same transporters in mutated (mut) or null p53-expressing cells. ABC transporters control the export of drugs from cancer cells and render tumors resistant to chemotherapy, playing an important role in multiple drug resistance (MDR). Wtp53 cells forced to perform OXPHOS showed impaired drug clearance. In contrast mutp53 cells increased drug clearance when performing OXPHOS. ABC transporter promoters contain binding sites for the transcription factors MEF2, NRF1 and NRF2 that are targets of the MAPK ERK5. OXPHOS induced expression of the MAPK ERK5. Decreasing ERK5 levels in wtp53 cells increased ABC expression whereas it inhibited expression in mutp53 cells. Our results showed that the ERK5/MEF2 pathway controlled ABC expression depending on p53 status. PMID- 29416682 TI - Mechanism of action and efficacy of LY2109761, a TGF-beta receptor inhibitor, targeting tumor microenvironment in liver cancer after TACE. AB - TACE (transcatheter arterial chemoembolization) has been recognized as an effective palliative treatment option for patients with HCC, however, the medium long term efficacy of it remains modest. LY2109761, a TGF-beta receptor inhibitor, was confirmed to reduce tumor cell growth, intravasation, and metastatic dissemination of HCC cells through different molecular mechanisms. This study aims to investigate the treatment effect of combining TACE therapy with LY2109761- a TGF-beta receptor I kinase inhibitor on suppressing tumor growth and metastasis in a rabbit VX2 tumor model. The molecular mechanisms underlying the biological activities of LY2109761 was also evaluated through an in vitro model. And we found that LY2109761 could inhibit cell proliferation by down-regulating the phosphorylation of Smad-2 as well as improved the therapeutic effect of TACE in a VX2 hepatocellular carcinoma model. And we further found that LY2109761 may play a modulating role in the process of T cell transformation. Hence, based on those obsevations in our research, we concluded that combing LY2109761 with TACE for the treatment of VX2 rabbit liver cancer can help inhibit tumor growth as well as increase the tumor cell necrosis after TACE. PMID- 29416683 TI - CCAR2 negatively regulates IL-8 production in cervical cancer cells. AB - Cell cycle and apoptosis regulator 2 (CCAR2) is a multifaceted protein that controls diverse cellular functions; however, its function in cancer is unclear. To better understand its potential role in cancer, we examined gene expression patterns regulated by CCAR2 in cervical cancer cells. Cytokine and chemokine production by CCAR2-deficient cells increased under oxidative conditions. In particular, H2O2-treated CCAR2-depleted cells showed a significant increase in interleukin-8 (IL-8) production, indicating a negative regulation of IL-8 by CCAR2. Upregulation of IL-8 expression in CCAR2-deficient cells occurred via activation of transcription factor AP-1. The negative correlation between CCAR2 and IL-8 expression was confirmed by examining mRNA and protein levels in tissues from cervical cancer patients. Furthermore, CCAR2-regulated IL-8 expression is associated with a shorter survival of cervical cancer patients. Overall, the data suggest that CCAR2 plays a critical role in controlling both the cancer secretome and cancer progression. PMID- 29416684 TI - Downregulation of long non-coding RNA LET predicts poor prognosis and increases Notch signaling in non-small cell lung cancer. AB - Long non-coding RNAs (lncRNAs) have been found to be dysregulated in a variety of tumors. The lncRNA-Low Expression in Tumor (LET) is a recently identified lncRNA, but its expression pattern and biological significance in human non-small cell lung cancer (NSCLC) are still largely unknown. In this study, we found that lncRNA-LET was significantly downregulated in human NSCLC lung tissues and cell lines. Decreased lncRNA-LET expression was strongly associated with advanced tumor stages and poorer overall survival of NSCLC patients. Functionally, overexpression of lncRNA-LET in NSCLC H292 cells significantly suppressed cell proliferation, migration and invasion, and promoted cell cycle arrest and apoptosis, while knockdown of lncRNA-LET in NSCLC H1975 cells showed an opposite effect, pointing to a tumor-suppressive role for lncRNA-LET in NSCLC. Mechanistically, we demonstrated that lncRNA-LET overexpression significantly reduced the expression of Notch1 intracellular Domain (NICD1) in H292 cells while knockdown of lncRNA-LET increased NICD1 expression in H1975 cells. Similarly, NSCLC lung tissues with high levels of lncRNA-LET had lower NICD1 expression. Thus, our results provide a strong rationale for lncRNA-LET to be used as a prognostic indicator and a potent therapeutic target for NSCLC patients, and highlight a novel lncRNA-LET/Notch axis in regulating NSCLC cell fate and tumor progression. PMID- 29416685 TI - Estrogen/ERalpha signaling axis participates in osteoblast maturation via upregulating chromosomal and mitochondrial complex gene expressions. AB - Estrogen deficiency usually leads to bone loss and osteoporosis in postmenopausal women. Osteoblasts play crucial roles in bone formation. However, osteoblast functions are influenced by mitochondrial bioenergetic conditions. In this study, we investigated the roles of the estrogen and estrogen receptor alpha (ERalpha) axis in mitochondrial energy metabolism and subsequent osteoblast mineralization. Exposure of rat calvarial osteoblasts to estradiol caused substantial improvements in alkaline phosphatase activities and cell calcification. In parallel, treatment of human osteoblast-like U2OS cells, derived from a female osteosarcoma patient, with estradiol specifically augmented ERalpha levels. Sequentially, estradiol stimulated translocation of ERalpha to nuclei in human osteoblasts and induced expressions of genomic respiratory chain complex NDUFA10, UQCRC1, cytochrome c oxidase (COX)8A, COX6A2, COX8C, COX6C, COX6B2, COX412, and ATP12A genes. Concurrently, estradiol stimulated translocation of ERalpha to mitochondria from the cytoplasm. A bioinformatic search found the existence of four estrogen response elements in the 5'-promoter region of the mitochondrial cox i gene. Interestingly, estradiol induced COX I mRNA and protein expressions in human osteoblasts or rat calvarial osteoblasts. Knocking-down ERalpha translation concurrently downregulated estradiol-induced COX I mRNA expression. Consequently, exposure to estradiol led to successive increases in the mitochondrial membrane potential, the mitochondrial enzyme activity, and cellular adenosine triphosphate levels. Taken together, this study showed the roles of the estradiol/ERalpha signaling axis in improving osteoblast maturation through upregulating the mitochondrial bioenergetic system due to induction of definite chromosomal and mitochondrial complex gene expressions. Our results provide novel insights elucidating the roles of the estrogen/ERalpha alliance in regulating bone formation. PMID- 29416686 TI - Exosomes released by metabotropic glutamate receptor 1 (GRM1) expressing melanoma cells increase cell migration and invasiveness. AB - Exosomes are naturally occurring membrane-bound nanovesicles generated constitutively and released by various cell types, and often in higher quantities by tumor cells. Exosomes may facilitate communication between the primary tumor and its local microenvironment, supporting cell invasion and other early events in metastasis. A neuronal receptor, metabotropic glutamate receptor 1 (GRM1), when ectopically expressed in melanocytes, induces in vitro melanocytic transformation and spontaneous malignant melanoma development in vivo in a transgenic mouse model. Our earlier studies showed that genetic modulation in GRM1 expression by siRNA or disruption of GRM1-mediated glutamate signaling interfere with downstream effectors resulting in a decrease in both cell proliferation in vitro and tumor progression in vivo. In this study, we sought to determine whether exosome formation might play a role in GRM1 mediated melanoma development and progression. To test this, we utilized in vitro cultured cells in which GRM1 expression and function could be modulated by pharmacological and genetic means and determined effects on exosome production. We also tested the effects of exosomes from GRM1 expressing melanoma cells on growth, migration and invasion of GRM1 negative cells. Our results show that although GRM1 expression has no influence on exosome quantity, exosomes produced by GRM1-positive cells modulate the ability of the recipient cell to migrate, invade and exhibit anchorage-independent cell growth. PMID- 29416688 TI - KSHV LANA upregulates the expression of epidermal growth factor like domain 7 to promote angiogenesis. AB - Kaposi's sarcoma (KS) is a highly-vascularized tumor characterized by inflammation and extensive neo-angiogenesis. The KS tumor microenvironment is rich in inflammatory and pro-angiogenic cytokines. Here, we report that the expression of Epidermal growth factor-like domain 7 (EGFL7) is upregulated in Kaposi's sarcoma-associated herpes virus (KSHV) infected cells. EGFL7 is a secreted pro-angiogenic cytokine that has been implicated in angiogenesis and the proliferation of endothelial cells during many pathological conditions. Our data show that KS tumors as well as primary effusion lymphoma cells have increased levels of EGFL7 compared to the uninfected cells. We determined that the expression of a KSHV latent protein, LANA (latency-associated nuclear antigen), is the main viral factor responsible for this upregulation. The modulation of EGFL7 expression by LANA involves sequestration of death domain-associated protein 6 (Daxx) from the EGFL7 promoter. Daxx acts as a suppressor of promoter activity by binding to the avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1), which is the core transcription factor required for the expression of EGFL7. We additionally show that the upregulation of EGFL7 by LANA contributes to the promotion of angiogenesis since siRNA-mediated knockdown of EGFL7 reduced in vitro tubulogenesis in LANA-expressing HUVEC cells. EGFL7 promotes angiogenesis through autocrine as well as paracrine mechanisms as the supernatant from LANA expressing cells depleted of EGFL7 showed reduced tubulogenesis. This study for the first time demonstrates EGFL7 to be an important angiogenic molecule secreted during KSHV infection that could be exploited for blocking KSHV associated malignancies in conjugation with other anti-angiogenic therapies. PMID- 29416687 TI - No differences in brain microstructure between young KIBRA-C carriers and non carriers. AB - KIBRA rs17070145 polymorphism is associated with variations in memory function and the microstructure of related brain areas. Diffusion kurtosis imaging (DKI) as an extension of diffusion tensor imaging that can provide more information about changes in microstructure, based on the idea that water diffusion in biological tissues is heterogeneous due to structural hindrance and restriction. We used DKI to explore the relationship between KIBRA gene polymorphism and brain microstructure in young adults. We recruited 100 healthy young volunteers, including 53 TT carriers and 47 C allele carriers. No differences were detected between the TT homozygotes and C-allele carriers for any diffusion and kurtosis parameter. These results indicate KIBRA rs17070145 polymorphism likely has little or no effect on brain microstructure in young adults. PMID- 29416689 TI - Molecular regulation of ERK5 in development of diabetic retinopathy. AB - Diabetic retinopathy (DR) is a major complication of diabetes, and causes pathological changes in retina blood vessels, as the most common cause of vision loss. Extracellular-signal-regulated kinase 5 (ERK5) is the newest discovered member in the mitogen-activated protein kinases (MAPKs) family, and recent evidence demonstrates an essential role of ERK5 signaling in the angiogenesis. However, whether ERK5 signaling may regulate DR development is unknown. Here, we used a streptozocin (STZ)-induce mouse DR model to investigate this question. We detected significant increases in the phosphorylation of ERK5, a signature of ERK5 activation in the purified retinal endothelial cells in DR mice, compared to control mice. In vivo suppression of ERK5 phosphorylation through administration of a specific inhibitor of ERK5 activation, BIX02189, did not prevent the occurrence of STZ-induced diabetes in mice, but significantly alleviated the severity of DR, seemingly through attenuating the retina neovascularization. Thus, our study suggests a previously unappreciated role of ERK5 signaling in DR development. PMID- 29416690 TI - High mobility group protein A2 overexpression indicates poor prognosis for cancer patients: a meta-analysis. AB - Overexpression of the high mobility group protein A2 (HMGA2), an architectural transcription factor, has been linked to poor prognosis in many malignancies, although this remains controversial. Herein, we conducted a meta-analysis to investigate whether HMGA2 has prognostic value, and evaluated the association between HMGA2 and clinicopathologic factors in malignancies. A total of 29 studies involving 4114 patients were included in this meta-analysis. The pooled results demonstrated that elevated HMGA2 predicted a poor overall survival (OS) (hazard ratio [HR] = 1.82; 95% confidence interval [CI] = 1.62-2.05; P < 0.001) and disease-free survival/progression-free survival/recurrence-free survival (HR = 1.94; 95% CI = 1.27-2.98; P = 0.002). Subgroup analysis conducted by study region, sample size, detection method, and analysis method indicated that HMGA2 overexpression correlated with poor OS. Furthermore, HMGA2 overexpression was found to be linked to poor OS in various cancers except ovarian cancer (pooled HR = 1.14; 95% CI = 0.62-2.09; P = 0.673). High HMGA2 expression level also correlated with advanced TNM stage (OR = 2.44; 95% CI =1.87-3.2; P < 0.001), lymphovascular invasion (OR = 2.46, 95% CI = 1.67-3.64; P < 0.001), distant metastasis (OR = 2.66; 95% CI =1.51-4.69; P < 0.001), and lymph node metastasis (OR = 1.83; 95% CI =1.27-2.64; P = 0.001). In conclusion, HMGA2 overexpression indicates a worse prognosis and may serve as a prognostic predictor in cancer patients. PMID- 29416691 TI - Chinese C allele carriers of the ERCC5 rs1047768 polymorphism are more sensitive to platinum-based chemotherapy: a meta-analysis. AB - It is suspected that ERCC5 rs1047768 and rs17655 polymorphisms influence the response to platinum-based chemotherapy. This meta-analysis was performed to summarize the scattered evidence regarding the association between these two polymorphisms and sensitivity to platinum-based treatment. Thirteen studies were included after a comprehensive literature search. The pooled odds ratios and 95% confidence intervals suggested that the C allele of the ERCC5 rs1047768 polymorphism is associated with elevated sensitivity to platinating agents, especially for Chinese patients. However, no difference among rs17655 genotypes could be detected. PMID- 29416692 TI - The prognostic value of NRF2 in solid tumor patients: a meta-analysis. AB - Nuclear factor E2-related factor 2 (NRF2), a transcription factor, is known as a potential therapeutic target of solid tumor for that it is a master regulator of the injury and inflammation response, including controlling antioxidant cell progress. Recent studies showed that NRF2 played significant roles in tumorigenesis and tumor progression, however no association and relationship between NRF2 expression and different clinical manifestation of solid tumor had been accurately evaluated. The present meta-analysis picked up 17 suitable articles from EMBASE, PubMed, and ISI Web of Science databases, including 2238 patients. Combined with results of hazard ratios (HRs) and 95% confidence intervals (CIs), we concluded that a higher expression of NRF2 would have worse impact on overall survival (HR = 2.29, 95% CI 1.80-2.91, P < 0.05) and disease free survival (HR = 2.34, 95% CI 1.36-4.00, P < 0.05) by a random-effect model. Moreover, further results were positively correlated to the clinical diagnosis, curative effect observation and prognosis, including tumor differentiation, lymph node metastasis, distant metastasis and clinical stage. Consequently, our data shown that NRF2 is a potential poor prognostic factor in a variety of solid tumors. PMID- 29416694 TI - Prognostic and clinicopathological significance of microRNA-494 overexpression in cancers: a meta-analysis. AB - MicroRNA-494 was revealed as an attractive prognostic biomarker in recent studies. Nevertheless, the prognostic value of microRNA-494 in cancers remains controversial. Current meta-analysis aims to elucidate the precise predictive value of microRNA-494 in various cancers. Eligible studies were identified through multiple search strategies, the hazard ratios (HRs) and their confidence interval (CI) for patient prognostic outcomes were extracted and estimated. The pooled results of fifteen studies indicated that elevated expression of microRNA 494 implies a good overall survival of cancer patients (HR = 0.58, 95% CI: 0.36 0.91); While no significant association was found between the high expression of microRNA-494 and clinicopathological characteristic. Additionally, subgroup analysis revealed that overexpression of microRNA-494 predicted a worse overall survival in non-small cell lung cancer (HR = 2.35, 95% CI: 1.05-5.24) and colorectal cancer (HR = 2.59, 95% CI: 1.62-4.14). As per the subgroup analysis, the cancer type, the anatomy system classification and the ethnic background had influence on the overall survival result. Our findings indicate that elevated expression of microRNA-494 might predict a good overall survival in most cancers, while in non-small cell lung cancer and colorectal cancer, overexpression of microRNA-494 might predict a worse overall survival. PMID- 29416695 TI - Association between hypertensive disorders of pregnancy and risk of autism in offspring: a systematic review and meta-analysis of observational studies. AB - Background: Autism spectrum disorder (ASD) is a common severe pervasive neurodevelopmental disorder of undetermined etiology. Environmental exposures, especially pregnancy complications, have been increasingly recognized as a potential risk factor for ASD. Our aim was to (1) systematically evaluate the association between hypertensive disorders of pregnancy (HDP) and the risk of ASD in offspring, (2) specifically draw a subgroup analysis of disease severity in patients with HDP to achieve more sufficient evidence on this issue. Results: A total of 21 studies were identified with more than 6.5 million participants, including 31,027 ASD probands. A comparative meta-analysis established that offspring born premature to HDP were significantly associated with ASD than matched controls (OR = 1.42, 95% CI: 1.34-1.50). Subgroup analysis of clinical classification include: (1) gestational hypertension, (2) pre-eclampsia, (3) chronic hypertension complicating pregnancy (CHP). The offspring of mothers with pre-eclampsia and CHP have slightly higher risk (OR = 1.43; OR = 1.48, respectively) of ASD than those of mothers with gestational hypertension (OR = 1.37). In consistence with most previous researches, higher ASD prevalence was observed in male than female (OR = 1.38), indicating a potential role for gender in the pathophysiology of ASD. Materials and Methods: We conducted a systematic literature search on PubMed, EMBASE, Web of Science, PsycINFO database and China National Knowledge Infrastructure up to Jun. 2017. Statistical analysis was performed using Stata 10.0. Conclusions: This meta-analysis implies a possible link between HDP and the risk of ASD in offspring. However, further investigation should be conducted to confirm this conclusion, and intensive prenatal surveillance and early prediction for ASD is needed. PMID- 29416693 TI - Serum levels of adipokines and cytokines in psoriasis patients: a systematic review and meta-analysis. AB - Purpose: To evaluate the association of serum levels of adipokines and cytokines with psoriasis. Materials and Methods: A comprehensive literature search was performed in PubMed, ScienceDirect and Web of Science for the available relevant studies published before December 1, 2016. Differences in serum marker levels between patients and controls were pooled as standardized mean differences (SMDs) with 95% confidence interval to combine the effect estimations. We also conducted stratified analysis, meta-regression analysis and sensitivity analysis. Results: Sixty-three studies containing 2876 psoriasis patients and 2237 healthy controls were included in this meta-analysis. The pooled serum levels of TNF-alpha, IFN gamma, IL-2, IL-6, IL-8, IL-18, IL-22, chemerin, lipocalin-2, resistin, sE selectin, fibrinogen and C3 were higher in psoriasis patients compared with healthy controls (all P < 0.05). In contrast, adiponectin levels were lower. Serum levels of IL-1beta, IL-4, IL-10, IL-12, IL-17, IL-21, IL-23, visfatin and omentin were not significantly different between psoriasis patients and controls (all P > 0.05). However, increased serum levels of IL-17 correlated with psoriasis in men. For other biomarkers, age, gender and psoriasis area and severity index did not explain the differences in effect size between the studies. Conclusions: Serum levels of TNF-alpha, IFN-gamma, IL-2, IL-6, IL-8, IL 18, IL-22, chemerin, lipocalin-2, resistin, sE-selectin, fibrinogen, complement 3, and adiponectin correlate with psoriasis and can be used as potential biomarkers for psoriasis and response to the treatment. Future studies are needed to identify additional players involved in the pathogenesis of psoriasis and to fully decipher the underlying mechanism. PMID- 29416696 TI - TNFR/TNF-alpha signaling pathway regulates apoptosis of alveolar macrophages in coal workers' pneumoconiosis. AB - We explored the role of TNFR/TNF-alpha signalingin apoptosis among alveolar macrophages (AM) and its relevance to the development of coal workers' pneumoconiosis (CWP). Purified alveolar macrophages (AMs) were prepared from bronchoalveolar lavage fluid harvested from 366 CWP patients and 120 healthy subjects enrolled inthe study. The purified AMs were then divided into control, SOD, anti-TNFR, TNFR and NFkB inhibitor groups and analyzed for apoptosis usingflow cytometry (sub-diploid peak) and western blotting (Bcl-2, Caspase-3 and Caspase-8 expression). We found thatAM apoptosis washigher amongCWP patients than thehealthycontrols. Expression ofBcl-2, Caspase-3 and Caspase-8 was higher inAMs from CWP patientsthan in those from the controlsand correlated with increased AM apoptosis. Univariate and multivariate analyses suggested that CWP grade, initial exposure time, exposure time inyears, and CWP onset agewereall associated with altered levels of Bcl-2, Caspase-3 and Caspase-8. Inhibition of TNFR/TNF-alpha signaling usinganti-TNFR antibody, SOD or NFkB inhibitionreduced AM apoptosisand decreased Bcl-2, Caspase-3 and Caspase-8 expression. These data suggestinhibition of a TNFR/TNF-alpha signaling pathway is a potentiallyeffective means ofalleviating CWP by inhibiting AM apoptosis. PMID- 29416697 TI - Mid-arm muscle circumference as a substantial factor against mortality among people with elevated gamma gaps. AB - Gamma gap is the difference in total serum proteins and albumin and an elevated gamma gap is related to infections, malignancy, and rheumatic diseases. An elevated gamma gap is also associated with higher mortality due to the correlation with inflammatory status. The study aimed to utilize mid-arm muscle circumference (MAMC) to assist in predicting all-cause mortality, cancer mortality, and cardiovascular mortality in people with elevated gamma gaps. Data were obtained from the third U.S. National Health and Nutrition Examination Survey (1988-1994), which contained 14,011 adults aged 20 to 90 years during up to 14.3 years of follow-up. The Primary analysis examined MAMC in tertiles and revealed the demographic and characteristics of the study population. Receiver operating characteristic curve analysis was used and the most suitable cut-off point of gamma gap was 3.65 g/dl. The secondary analysis employed Cox proportional hazards models stratified by age, gender and body mass index to evaluate the hazard ratios for all-cause mortality, cancer mortality, and cardiovascular mortality associated with the MAMC. As the MAMC tertiles increased in group with gamma gap >= 3.65 g/dl, individuals with elder age (60-90 years), normal range of body mass index (19-24.9 kg/m2), and male gender tended to have lower hazard ratios for all-cause mortality, cancer mortality, and cardiovascular mortality. These substantial findings indicate that higher MAMC may be a protective factor of all cause-mortality, cancer mortality, and cardiovascular mortality among older male with normal body mass index and elevated gamma gaps. PMID- 29416699 TI - LGR5 and LGR6 in stem cell biology and ovarian cancer. AB - Wnt signaling plays a fundamental role in patterning of the embryo and maintenance of stem cells in numerous epithelia. Epithelial stem cells are closeted in niches created by surrounding differentiated cells that express secreted Wnt and R-spondin proteins that influence proliferation rate and fate determination of stem cell daughters. R-spondins act through the LGR receptors to enhance Wnt signaling. This close association of stem cells with more differentiated regulatory cells expressing Wnt-pathway ligands is a feature replicated in all of the epithelial stem cell systems thus far examined. How the stem cell niche operates through these short-range interactions is best understood for the crypts of the gastrointestinal epithelium and skin. Less well understood are the stem cells that function in the ovarian surface epithelium (OSE) and fallopian tube epithelium (FTE). While the cuboidal OSE appears to be made up of a single cell type, the cells of the FTE progress through a life cycle that involves differentiation into ciliated and secretory subtypes that are eventually shed into the lumen in a manner similar to the gastrointestinal epithelium. Available evidence suggests that high grade serous ovarian carcinoma (HGSOC) originates most often from stem cells in the FTE and that Wnt signaling augmented by LGR6 supports tumor development and progression. This review summarizes current information on LGR5 and LGR6 in the OSE and FTE and how their niches are organized relative to that of the gastrointestinal epithelium and skin. PMID- 29416700 TI - Equine infectious anemia virus in China. AB - Equine infectious anemia is an equine disease caused by equine infectious anemia virus, which was first reported in 1840. Equine infectious anemia virus research in China started in the 1960s, focusing on etiology, pathology, diagnosis, and immunology. Notably, in 1978 an attenuated vaccine was successfully developed for equine infectious anemia virus, effectively preventing equine infectious anemia virus in China. This article will review equine infectious anemia virus in China, including past and recent research, and commemorate scientists who have made great contributions to equine infectious anemia virus prevention. PMID- 29416698 TI - 3D modeling of cancer stem cell niche. AB - Cancer stem cells reside in a distinct microenvironment called niche. The reciprocal interactions between cancer stem cells and niche contribute to the maintenance and enrichment of cancer stem cells. In order to simulate the interactions between cancer stem cells and niche, three-dimensional models have been developed. These in vitro culture systems recapitulate the spatial dimension, cellular heterogeneity, and the molecular networks of the tumor microenvironment and show great promise in elucidating the pathophysiology of cancer stem cells and designing more clinically relavant treatment modalites. PMID- 29416701 TI - Exploring the molecular aspects associated with testicular germ cell tumors: a review. AB - Testicular germ cell tumors (TGCTs) represent the most common solid tumors affecting young men. They constitute a distinct entity because of their embryonic origin and their unique biological behavior. Recent preclinical data regarding biological signaling machinery as well as genetic and epigenetic mechanisms associated with molecular patterns of tumors have contribute to explain the pathogenesis and the differentiation of TGCTs and to understand the mechanisms responsible for the development of resistance to treatment. In this review, we discuss the main genetic and epigenetic events associated with TGCTs development in order to better define their role in the pathogenesis of these tumors and in cisplatin-acquired resistance. PMID- 29416702 TI - Drug resistance related to aberrant glycosylation in colorectal cancer. AB - Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths in the world. Drug resistance of tumour cells remains the main challenge toward curative treatments efficiency. Several epidemiologic studies link emergence and recurrence of this cancer to metabolic disorders. Glycosylation that modifies more than 80% of human proteins is one of the most widepread nutrient-sensitive post-translational modifications. Aberrant glycosylation participates in the development and progression of cancer. Thus, some of these glycan changes like carbohydrate antigen CA 19-9 (sialyl Lewis a, sLea) or those found on carcinoembryonic antigen (CEA) are already used as clinical biomarkers to detect and monitor CRC. The current review highlights emerging evidences accumulated mainly during the last decade that establish the role played by altered glycosylations in CRC drug resistance mechanisms that induce resistance to apoptosis and activation of signaling pathways, alter drug absorption and metabolism, and led to stemness acquisition. Knowledge in this field of investigation could aid to the development of better therapeutic approaches with new predictive biomarkers and targets tied in with adapted diet. PMID- 29416703 TI - Current research on head and neck cancer-associated long noncoding RNAs. AB - Head and neck cancers (HNC) are one of the ten leading cancers worldwide, including a range of malignant tumors arising from the upper neck. Due to the complex mechanisms of HNC and lack of effective biomarkers, the 5-year survival rate of HNC has been low and the mortality rate has been high in recent decades. Long noncoding RNAs (lncRNAs), noncoding RNAs longer than 200 bps, are a focus of current cancer research, closely related to tumor biology. LncRNAs have been revealed to be aberrantly expressed in various types of HNC, and the dysregulated lncRNAs participate in HNC progression and induce malignant behavior by modulating gene expression at diverse levels. This review will focus on the functions and molecular mechanisms of dysregulated lncRNAs in HNC tumorigenesis and progression, as well as their diagnostic, therapeutic or prognostic implications in HNC. PMID- 29416704 TI - LncRNAs regulate cancer metastasis via binding to functional proteins. AB - Cancer is one of the leading causes of death worldwide, and metastasis is a crucial characteristic of malignancy. Recent studies have shown that lncRNAs play an important role in regulating cancer metastasis through various molecular mechanisms. We briefly summarize four known molecular functions of lncRNAs, including their role as a signal, decoy, guide and scaffold. No matter which pattern lncRNAs follow to carry out their functions, the proteins that lncRNAs bind to are important for them to exhibit their gene-regulating properties. We further illustrate that lncRNAs regulate the localization, stabilization or modification of their binding proteins to realize the binding role of lncRNAs. In this review, we focus on the interactions between lncRNAs and their binding proteins; moreover, we focus on the mechanisms of the collaborative work of lncRNAs and their binding proteins in cancer metastasis, thus evaluating the potential of lncRNAs as prospective novel therapeutic targets in cancer. PMID- 29416705 TI - Circular RNAs: clinical relevance in cancer. AB - Circular RNAs, as recently discovered new endogenous non-coding RNAs, are important gene modulators with critical roles in tumor initiation and malignant progression. With the development of RNA sequencing and microarray technologies, numerous of functional circRNAs have been identified in cancerous tissues and cell lines. Mechanistically, circRNAs function as miRNA sponges, miRNA reservoirs or parental gene expression regulators. In this review, we discuss the properties and functions of circRNAs and their clinical implication as promising biomarkers for cancer research. Moreover, some emerging fields, such as exosome-loaded and immune response-associated circRNAs, are also discussed, suggesting novel insights into the carcinogenesis and therapy associated with these molecules. PMID- 29416708 TI - Targeting altered Nme heterooligomerization in disease? PMID- 29416706 TI - Troponin through the looking-glass: emerging roles beyond regulation of striated muscle contraction. AB - Troponin is a heterotrimeric Ca2+-binding protein that has a well-established role in regulating striated muscle contraction. However, mounting evidence points to novel cellular functions of troponin, with profound implications in cancer, cardiomyopathy pathogenesis and skeletal muscle aging. Here, we highlight the non canonical roles and aberrant expression patterns of troponin beyond the sarcomeric milieu. Utilizing bioinformatics tools and online databases, we also provide pathway, subcellular localization, and protein-protein/DNA interaction analyses that support a role for troponin in multiple subcellular compartments. This emerging knowledge challenges the conventional view of troponin as a sarcomere-specific protein exclusively involved in muscle contraction and may transform the way we think about sarcomeric proteins, particularly in the context of human disease and aging. PMID- 29416707 TI - Protein dysregulation in graft versus host disease. AB - Allogeneic hematopoietic stem cell transplantation is a well-established treatment for many malignant and non-malignant hematological disorders. As a frequent complication in up to 50% of all patients, graft-versus-host disease is still the main cause for morbidity and non-relapse mortality. Diagnosis is usually done clinically, even though confirmation by pathology is often used to support the clinical findings. Effective treatment requires intensified immunosuppression as early as possible. Although several promising biomarkers have been proposed for an early diagnosis, no internationally-recognized consensus has yet been established. Protein-based biomarkers represent an interesting tool since they have been recently reported to be an important regulator of various cells, including immune cells such as T cells. Therefore, we assume that protein dysregulation is important in the pathogenesis of acute graft versus host disease and their detection might be an possibility in the early diagnosis and monitoring. In this review, we aim to summarize the previous reports of protein biomarkers, focusing on the pathogenesis of the disease and possible implications in diagnostic approaches. PMID- 29416709 TI - Low-dose statin treatment increases prostate cancer aggressiveness. AB - Prostate cancer is diagnosed late in life, when co-morbidities are frequent. Among them, hypertension, hypercholesterolemia, diabetes or metabolic syndrome exhibit an elevated incidence. In turn, prostate cancer patients frequently undergo chronic pharmacological treatments that could alter disease initiation, progression and therapy response. Here we show that treatment with anti cholesterolemic drugs, statins, at doses achieved in patients, enhance the pro tumorigenic activity of obesogenic diets. In addition, the use of a mouse model of prostate cancer and human prostate cancer xenografts revealed that in vivo simvastatin administration alone increases prostate cancer aggressiveness. In vitro cell line systems supported the notion that this phenomenon occurs, at least in part, through the direct action on cancer cells of low doses of statins, in range of what is observed in human plasma. In sum, our results reveal a prostate cancer experimental system where statins exhibit an undesirable effect, and warrant further research to address the relevance and implications of this observation in human prostate cancer. PMID- 29416710 TI - Developmental and light regulation of tumor suppressor protein PP2A in the retina. AB - Protein phosphatases are a group of universal enzymes that are responsible for the dephosphorylation of various proteins and enzymes in cells. Cellular signal transduction events are largely governed by the phosphorylation of key proteins. The length of cellular response depends on the activation of protein phosphatase that dephosphorylates the phosphate groups to halt a biological response, and fine-tune the defined cellular outcome. Dysregulation of these phosphatase(s) results in various disease phenotypes. The retina is a post-mitotic tissue, and oncogenic tyrosine and serine/ threonine kinase activities are important for retinal neuron survival. Aberrant activation of protein phosphatase(s) may have a negative effect on retinal neurons. In the current study, we characterized tumor suppressor protein phosphatase 2 (PP2A), a major serine/ threonine kinase with a broad substrate specificity. Our data suggest that PP2A is developmentally regulated in the retina, localized predominantly in the inner retina, and expressed in photoreceptor inner segments. Our findings indicate that PKCalpha and mTOR may serve as PP2A substrates. We found that light regulates PP2A activity. Our studies also suggest that rhodopsin regulates PP2A and its substrate(s) dephosphorylation. PP2A substrate phosphorylation is increased in mice lacking the A-subunit of PP2A. However, there is no accompanying effect on retina structure and function. Together, our findings suggest that controlling the activity of PP2A in the retina may be neuroprotective. PMID- 29416711 TI - Comprehensive transcriptional landscape of porcine cardiac and skeletal muscles reveals differences of aging. AB - Aging significantly affects the cardiac muscle (CM) and skeletal muscles (SM). Since the aging process of CM and SM may be different, high throughput RNA sequencing was performed using CM and SM in different age conditions to evaluate the expression profiles of messenger RNA (mRNA), long non-coding RNA (lncRNA), micro RNA (miRNA), and circular (circRNA). Several mRNAs, lncRNAs, and miRNAs were highly expressed and consistently appeared in both ages in one of the two muscle tissues. Gene ontology (GO) annotation described that these genes were required for maintaining normal biological functions of CM and SM tissues. Furthermore, 26 mRNAs, 4 lncRNAs, 22 miRNAs, and 26 circRNAs were differentially expressed during cardiac muscle aging. Moreover, 81 mRNAs, 5 lncRNAs, 79 miRNAs, and 62 circRNAs were differentially expressed during aging of skeletal muscle. When comparing the expression profiles of CM and SM during aging, the senescence process in CM and SM was found to be fundamentally different. In addition, we assessed multi-group cooperative control relationships and constructed circRNA miRNA-mRNA co-expression networks in muscular aging. In conclusion, our findings will contribute to the understanding of muscular aging and provide a foundation for future studies on the molecular mechanisms underlying muscular aging. PMID- 29416712 TI - B7-H3 promoted proliferation of mouse spermatogonial stem cells via the PI3K signaling pathway. AB - Objective: We found seminal B7-H3 was associated with human sperm concentration. However, the mechanism is unclear. The purpose of this study was to investigate the expression of B7-H3 in mouse testis and determine the effects of B7-H3 on the proliferation of mouse spermatogonial stem cells (SSCs) and the underlying mechanisms. Methods: B7-H3 expression in the testis of mice at different ages (3 weeks, 8 weeks, 4 months and 9 months) was detected by western blot and immunohistochemistry. CCK-8 were used to measure mouse SSCs proliferation after incubation with different concentrations of B7-H3 for 1-72 h in vitro. Flow cytometry was used to analyze the cell cycle of mouse SSCs after incubation with different concentrations of B7-H3 for 48 and 72 h. The signaling pathways involved were assessed by western blot. Results: Four-month-old mice had the highest expression of B7-H3 in the testis, while 3-week-old mice had the lowest expression of B7-H3. B7-H3 was predominantly detected on the membrane and in the cytoplasm of Sertoli cells. Furthermore, B7-H3 promoted mouse SSCs proliferation and increased the percentage of cells in S+G2/M phase in a time- and dose dependent manner in vitro. These effects were inhibited by LY294002, indicating the involvement of the phosphoinositide 3-kinase signaling pathway. Conclusions: The expression of B7-H3 in mouse testis, especially Sertoli cells, was associated with mouse age. In vitro, B7-H3 promoted the proliferation and accelerated the cell cycle of mouse SSCs via the PI3K pathway, indicating a critical role of B7 H3 expressed by Sertoli cells in mouse spermatogenesis. PMID- 29416713 TI - Associations of TAP1 genetic polymorphisms with atopic diseases: asthma, rhinitis and dermatitis. AB - Controversial findings have been reported regarding to the effect of the transporter associated with antigen processing 1 (TAP1) polymorphisms exerted on the atopic diseases susceptibility. To gain a better understanding of the effects of TAP1 polymorphisms on the risk of atopic diseases, a retrospective study was carried out to evaluate the association of the most common TAP1 polymorphisms, rs1057141 and rs1135216, with the risk of atopic diseases. From studies published in PubMed, Embase, and Web of Science up to July 2017, ten eligible studies were selected for meta-analysis. The pooled results from rs1135216 polymorphism showed increased risk of atopic diseases in homozygote and recessive comparison. From the subgroup analysis by ethnicity, it was found that rs1135216 polymorphism contributed to atopic diseases susceptibility among Africans in all the five genetic models. Subgroup analysis by atopic types indicated significant association of TAP1 polymorphism rs1135216 with asthma in the allele, dominant and recessive models and with allergic rhinitis in the recessive model. As to rs1057141, increased risk of atopic disease in the allelic, dominant and heterozygous model was found in African population. Overall, this meta-analysis study demonstrated that rs1135216 polymorphism may contribute to atopic diseases susceptibility in Asians and Africans as assessed in this study. However, well designed large-scale case-control studies are needed to confirm such preliminary findings. PMID- 29416714 TI - Mitosis-specific phosphorylation of Mis18alpha by Aurora B kinase enhances kinetochore recruitment of polo-like kinase 1. AB - Mis18alpha, a component of Mis18 complex comprising of Mis18alpha, Mis18beta, and M18BP1, is known to localize at the centromere from late telophase to early G1 phase and plays a priming role in CENP-A deposition. Although its role in CENP-A deposition is well established, the other function of Mis18alpha remains unknown. Here, we elucidate a new function of Mis18alpha that is critical for the proper progression of cell cycle independent of its role in CENP-A deposition. We find that Aurora B kinase phosphorylates Mis18alpha during mitosis not affecting neither centromere localization of Mis18 complex nor centromere loading of CENP A. However, the replacement of endogenous Mis18alpha by phosphorylation-defective mutant causes mitotic defects including micronuclei formation, chromosome misalignment, and chromosomal bridges. Together, our data demonstrate that Aurora B kinase-mediated mitotic phosphorylation of Mis18alpha is a crucial event for faithful cell cycle progression through the enhanced recruitment of polo-like kinase 1 to the kinetochore. PMID- 29416715 TI - Long-term follow-up and novel splice donor mutation in MEN1 in a Chinese family. AB - Heterozygous germline mutation of the MEN1 tumor suppressor gene is responsible for multiple endocrine neoplasia type 1. Parathyroid and thoracic neuroendocrine tumor specimens and DNA from two Han Chinese MEN1 family patients were analyzed using whole exome and Sanger sequencing. The proband (II-3) was sequentially diagnosed with pituitary adenoma, pancreatic tumor, adrenal cortical tumor, abdominal lipoma, and parathyroid adenoma during the 6-year follow-up. The son of the proband (III-6) was also diagnosed with a thoracic neuroendocrine tumor and a parathyroid adenoma during this period. Splice alterations were studied by RT-PCR and sequencing. The mutation impact was evaluated using bioinformatics. Sequence analysis revealed a novel splice donor mutation, MEN1 IVS9 + 1G > C, that changed the splicing mode of MEN1 to halt translation before two nuclear localization signals in the menin protein. Novel somatic mutations, MEN1 c.1402_1405delGAGG and c.286 C > T, were identified in the parathyroid adenoma of II-3 and thoracic neuroendocrine tumor of III-6, respectively, indicating a two-hit etiology of MEN1 syndrome. Our study revealed the clinical and genetic basis of MEN1 in this Han Chinese family and provides insight into MEN1 mechanisms, diagnosis, and management. PMID- 29416717 TI - Phosphorylated heat shock protein 27 as a potential biomarker to predict the role of chemotherapy-induced autophagy in osteosarcoma response to therapy. AB - Autophagy is a catabolic process involved in cellular homeostasis. Autophagy is increased above homeostatic levels by chemotherapy, and this can either promote or inhibit tumor growth. We previously demonstrated that aerosol gemcitabine (GCB) has a therapeutic effect against osteosarcoma (OS) lung metastases. However, some tumor cells failed to respond to the treatment and persisted as isolated lung metastasis. Here, we examined the mechanisms underlying the dual role of chemotherapy-induced autophagy in OS and sought to identify biomarkers to predict OS response to treatment. In this study, we demonstrate that treatment of various OS cells with GCB induced autophagy. We also showed that GCB reduces the phosphorylation of AKT, mTOR and p70S6K and that GCB-induced autophagy in OS can lead to either cell survival or cell death. Blocking autophagy enhanced the sensitivity of LM7 OS cells and decreased the sensitivity of CCH-OS-D and K7M3 OS cells to GCB. Using a kinase array, we also demonstrated that differences in the phosphorylated heat shock protein 27 (p-HSP27) expression in the various OS cell lines after treatment with GCB, correlates to whether chemotherapy-induced autophagy will lead to increase or decrease OS cells sensitivity to therapy. Increased p-HSP27 was associated with increased sensitivity to anticancer drug treatment when autophagy is inhibited. The results of this study reveal a dual role of autophagy in OS cells sensitivity to chemotherapy and suggest that p HSP27 could represent a predictive biomarker of whether combination therapy with autophagy modulators and chemotherapeutic drugs will be beneficial for OS patients. PMID- 29416716 TI - Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super enhancer-driven EWSR1-ETS targets. AB - Ewing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4-, BCOR-CCNB3-, EWSR1 NFATc2-, and EWSR1-ETS-translocated sarcomas are distinct entities, and revealed that ATP1A1, BCL11B, and GLG1 constitute specific markers for Ewing sarcoma. Their high expression was validated by immunohistochemistry and proved to depend on EWSR1-FLI1-binding to highly active proximal super-enhancers. Automated cut off-finding and combination-testing in a tissue-microarray comprising 174 samples demonstrated that detection of high BCL11B and/or GLG1 expression is sufficient to reach 96% specificity for Ewing sarcoma. While 88% of tested Ewing-like sarcomas displayed strong CD99-immunoreactivity, none displayed combined strong BCL11B- and GLG1-immunoreactivity. Collectively, we show that ATP1A1, BCL11B, and GLG1 are EWSR1-FLI1 targets, of which BCL11B and GLG1 offer a fast, simple, and cost-efficient way to diagnose Ewing sarcoma by immunohistochemistry. These markers may significantly reduce the number of misdiagnosed patients, and thus improve patient care. PMID- 29416718 TI - ING5 differentially regulates protein lysine acetylation and promotes p300 autoacetylation. AB - ING5 belongs to the Inhibitor of Growth (ING) candidate tumor suppressor family. Previously, we have shown that ING5 inhibits invasiveness of lung cancer cells by downregulating EMT-inducing genes. However, the underlying mechanisms remain unclear. The aim of the study was to use integrated approach involving SILAC labeling and mass spectrometry-based quantitative proteomics to quantify dynamic changes of acetylation regulated by ING5 in lung cancer cells. Here, we have found that ING5 has a profound influence on protein lysine acetylation with 163 acetylation peptides on 122 proteins significantly upregulated and 100 acetylation peptides on 72 proteins downregulated by ING5 overexpression. Bioinfomatic analysis revealed that the acetylated proteins upregulated by ING5 located preferentially in nucleus to cytoplasm and were significantly enriched in transcription cofactor activity, chromatin binding and DNA binding functions; while those downregulated by ING5 located preferentially in cytoplasm rather than nucleus and were functionally enriched in metabolism, suggesting diverse functions of ING5 through differentially regulating protein acetylation. Interestingly, we found ING5 overexpression promotes p300 autoacetylation at K1555, K1558 and K1560 within p300 HAT domain, and two novel sites K1647 and K1794, leading to activation of p300 HAT activity, which was confirmed by accelerated acetylation of p300 target proteins, p53 at k382 and histone H3 at K18. A specific p300 HAT inhibitor C646 impaired ING5-increased acetylation of H3K18 and p53K382, and subsequent expression of p21 and Bax. In conclusion, our results reveal the lysine acetylome regulated by ING5 and provide new insights into mechanisms of ING5 in the regulation of gene expression, metabolism and other cellular functions. PMID- 29416719 TI - Response to stereotactic ablative radiotherapy in a novel orthotopic model of non small cell lung cancer. AB - Stereotactic ablative radiotherapy (SABR) is the main treatment for inoperable early-stage non-small cell lung cancer (NSCLC). Despite the widespread use of SABR, the biological determinants of response to SABR remain poorly investigated. We developed an orthotopic NSCLC animal model to study the response to clinically relevant doses of SABR. Image-guided intra-thoracic injection of NSCLC cells was performed in the right lung of nude rats. A highly conformal dose of 34 Gy was delivered in a single fraction using clinical photon energies. Animals were sacrificed 10-60 days post treatment. Lung tumors were assessed for tumor differentiation, proliferation and invasiveness. An analysis of 770 cancer related genes was performed on tumor-derived cell lines from treated animals at early and late time points after SABR. The majority of animals receiving SABR demonstrated complete response (67%), while 33% demonstrated local failure. 50% of animals with complete response failed distantly. Analysis of cancer-related genes revealed significant differences between tumors treated with SABR and untreated tumors. SABR significantly modulated expression of genes involved in adhesion, migration and angiogenesis. In particular, interleukin-8 (IL8) which plays a critical role in promoting tumor invasion was found to be secreted at high levels after SABR. In vitro invasion assays confirmed SABR-induced invasion and demonstrated induction of IL-8 secretion in multiple NSCLC cell lines. Our findings underscore the importance of developing targeted therapies that can circumvent the pro-invasive effects of SABR in NSCLC. PMID- 29416720 TI - Targeting the Golgi apparatus to overcome acquired resistance of non-small cell lung cancer cells to EGFR tyrosine kinase inhibitors. AB - Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) were demonstrated to provide survival benefit in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR; however, emergence of acquired resistance to EGFR-TKIs has been shown to cause poor outcome. To overcome the TKI resistance, drugs with different mode of action are required. We previously reported that M-COPA (2-methylcoprophilinamide), a Golgi disruptor, suppressed the growth of gastric cancers overexpressing receptor tyrosine kinases (RTKs) such as hepatocyte growth factor receptor (MET) via downregulating their cell surface expression. In this study, we examined the antitumor effect of M COPA on NSCLC cells with TKI resistance. As a result, M-COPA effectively downregulated cell surface EGFR and its downstream signals, and finally exerted in vivo antitumor effect in NSCLC cells harboring secondary (T790M/del19) and tertiary (C797S/T790M/del19) mutated EGFR, which exhibit acquired resistance to first- and third generation EGFR-TKIs, respectively. M-COPA also downregulated MET expression potentially involved in the acquired resistance to EGFR-TKIs via bypassing the EGFR pathway blockade. These results provide the first evidence that targeting the Golgi apparatus might be a promising therapeutic strategy to overcome the vicious cycle of TKI resistance in EGFR-mutated NSCLC cells via downregulating cell surface RTK expression. PMID- 29416721 TI - Collagen XVII/laminin-5 activates epithelial-to-mesenchymal transition and is associated with poor prognosis in lung cancer. AB - Epithelial-to-mesenchymal transition (EMT) is associated with tumor metastasis and tumorigenesis in lung cancer stem-like cells (CSCs). However, the exact mechanism underlying this is not clear. We used microarray analysis to identify candidate genes responsible for EMT in spheroid and monolayer cultures of lung cancer cells. We found increased expression of a variety of adhesion molecules in CSCs. One of these molecules, Collagen XVII (Col XVII), was demonstrated to be required for maintenance of EMT phenotypes and metastasis ability in lung CSCs. We showed that Col XVII stabilized laminin-5 to activate the FAK/AKT/GSK3beta pathway, thereby suppressing Snail ubiquitination-degradation. The function of Col XVII was mainly dependent on shedding by ADAM9 and ADAM10. Patients who underwent surgical resection for lung cancer, and displayed overexpression of both Col XVII and laminin-5, had the worst prognosis of all expression types. Moreover, blockage of the Col XVII/laminin-5 pathway reduced the EMT phenotypes of lung CSCs in vitro and decreased the potential of lung metastasis in vivo. Our findings suggested that targeting Col XVII and laminin-5 could be novel therapeutic strategies for treating lung cancer patients, and warrant further investigation. PMID- 29416722 TI - The pharmacokinetic-pharmacodynamic modeling and cut-off values of tildipirosin against Haemophilus parasuis. AB - The goal of this study was to establish the epidemiological, pharmacodynamic cut off values, optimal dose regimens for tildipirosin against Haemophilus parasuis. The minimum inhibitory concentrations (MIC) of 164 HPS isolates were determined and SH0165 whose MIC (2 MUg/ml ) were selected for PD analysis. The ex vivo MIC in plasma of SH0165 was 0.25 MUg/ml which was 8 times lower than that in TSB. The bacteriostatic, bactericidal and elimination activity (AUC24h/MIC) in serum were 26.35, 52.27 and 73.29 h based on the inhibitory sigmoid Emax modeling. The present study demonstrates that 97.9% of the wild-type (WT) isolates were covered when the epidemiological cut-off value (ECV) was set at 8 MUg/ml. The parameters including AUC24h, AUC, T1/2, Cmax, CLb and MRT in PELF were 19.56, 60.41, 2.32, 4.02, 56.6, and 2.63 times than those in plasma, respectively. Regarding the Monte Carlo simulation, the COPD was defined as 0.5 MUg/ml in vitro, and the optimal doses to achieve bacteriostatic, bactericidal and elimination effect were 1.85, 3.67 and 5.16 mg/kg for 50% target, respectively, and 2.07, 4.17 and 5.78 mg/kg for 90% target, respectively. The results of this study offer a more optimised alternative for clinical use and demonstrated that 4.17 mg/kg of tildipirosin by intramuscular injection could have an effect on bactericidal activity against HPS. These values are of great significance for the effective treatment of HPS infections, but it also be deserved to be validated in clinical practice in the future research. PMID- 29416723 TI - TLR1 polymorphisms are significantly associated with the occurrence, presentation and drug-adverse reactions of tuberculosis in Western Chinese adults. AB - Background: Obtaining further knowledge regarding single nucleotide polymorphisms in the Toll-like receptor1 gene is of great importance to elucidate immunopathogenesis and management of tuberculosis. Results: Rs5743565 and rs5743557 were significantly associated with reduced predisposition to TB regarding the mutant allele in additive and dominant models with odds ratios (ORs) ranging from 0.61 to 0.83. There was increased tuberculosis risk associated with the haplotype CAG (rs4833095/rs76600635/rs5743596) [OR (95% CI) = 1.33 (1.07 1.65)] and with haplotype GG (rs56357984/rs5743557) [OR = 1.21 (1.02-1.43)]. The erythrocyte and hemoglobin levels were significantly higher in TB patients with the rs5743557 GG genotype than for AA and/or AG genotype carriers (p = 0.006 and 0.020, respectively). The occurrence rates of chronic kidney damage and hepatotoxicity were 21.56% and 10.32%, respectively. Rs5743565 seemed to pose a higher risk of anti-TB-induced hepatotoxicity under the dominant model [OR = 2.17 (1.17-4.05)], and rs76600635 GG/AG genotypes were clearly correlated with the development of thrombocytopenia [OR = 2.98 (1.26-7.09)]. Conclusions: Rs5743565 and rs5743557 in the TLR1 gene may contribute to decreased risk for tuberculosis susceptibility in a Western Chinese population. Rs5743565 and rs76600635 are potential risk factors for adverse reactions to anti-TB drugs. Methods: We enrolled 646 tuberculosis patients and 475 healthy controls from West China. Six single nucleotide polymorphisms in Toll-like receptor1 gene were genotyped in every individual and were analyzed for their association with tuberculosis susceptibility and clinical presentation. The prospective follow-up was performed to determine whether these single nucleotide polymorphisms are associated with adverse reactions to anti-tuberculosis drugs. PMID- 29416724 TI - Cancer preventive effect of recombinant TRAIL by ablation of oncogenic inflammation in colitis-associated cancer rather than anticancer effect. AB - The potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in inducing apoptosis is a hallmark in cancer therapeutics, after which its selective ability to achieve cell death pathways against cancer cells led to hope for recombinant TRAIL in cancer therapeutics. The present data from azoxymethane initiated, dextran sulfate sodium-promoted colitis associated cancer (CAC) model strongly indicate the potential of rTRAIL in cancer prevention rather than in cancer therapeutics. Early treatment of rTRAIL significantly reduced colitis and CAC by inhibiting the recruitment of macrophages into the damaged mucosa and activating the scavenger activity with efferocytosis and the production of several growth factors. In contrast, late administration of rTRAIL as for anti cancer effect did not decrease the initiation and development of CAC at all. Significant cancer preventing mechanisms of rTRAIL were identified. In the CAC model, anti-inflammation, regeneration, and efferocytosis was induced by treatment of TRAIL for 6 days, significant inhibitory activity was evident at 4 weeks and anti-oxidative and anti-inflammatory induction were noted at 12 weeks. Most importantly, TRAIL promoted tissue regeneration by enhancing the resolution of pathological inflammation through the activation of the NLRP3 inflammasome pathway. The results indicate that TRAIL reduces the induction of colitis and the initiation of CAC by inhibiting pro-inflammatory signaling and promoting tissue repair to maintain intestinal homeostasis through activation of the NLRP3 inflammasome. Therefore, TRAIL can be used as a chemopreventive agent against CAC, rather than as a therapeutic drug endowing apoptosis. PMID- 29416725 TI - Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma. AB - Hepatitis C virus (HCV) is a single-stranded RNA virus that not only affects hepatocytes, by B cells as well. It is thought that HCV is involved in the onset of B-cell lymphoma. The clinicopathological characteristics of HCV-positive diffuse large B-cell lymphoma (DLBCL) and HCV-positive splenic marginal zone lymphoma (SMZL) are known, but there has been no report on HCV-positive follicular lymphoma (FL). In this study, the clinicopathological characteristics of HCV-positive FL were examined in 263 patients with FL who were classified into a HCV-positive group with HCV antibody and negative groups without one. The number of patients with HCV-positive FL and HCV-negative FL was 10 (3.8%) and 253 (96.2%), respectively. The patients with HCV-positive FL commonly had more than one region of lymphadenopathy, Ann Arbor stage III/IV, hemoglobin <120 g/l, elevated lactate dehydrogenase level, and high-risk categorization of Follicular Lymphoma International Prognostic Index (FLIPI) than in patients with HCV negative FL. Overall survival and progression-free survival were poorer in patients with HCV-positive FL than in those with HCV-negative FL (p < 0.0001 and 0.006, respectively). Also, multivariate analysis revealed that positive HCV antibody was a poor prognostic factor of OS. In conclusion, HCV-positive FL has unique clinical features and may have a great impact on the overall survival of affected patients. PMID- 29416726 TI - Outcomes of radiation therapy for resectable M0 gastric cancer. AB - Background: The role of radiaotion therapy in resectable gastric cancer patients without distant metastases remains controversial. This retrospective analysis was performed to identify whether resectable gastric cancer patients without distant metastases might benefit from radiation. Results: The results of the Kaplan-Meier analysis and log-rank test showed that a total of 3309 patients had a MST of 29.0 months, a 1-year survival rate of 74.7%, and a 3-year survival rate of 45.5%. Among them, the MST of the "RPS" group and the "RAS" group were significantly longer compared with that of the "No Radiation" group (32.7vs 32.9 vs 25.3 months, P < 0.05). The 1-year survival rates were 83.7%, 83.5% and 65.6% for the "RPS", "RAS" and "No radiation" groups, respectively (P < 0.05) and the 3-year survival rates were 52.6%, 63.6% and 44.9%, respectively (P < 0.05). The multivariate Cox proportional hazard regression analysis showed that radiation was an independent prognostic factor. Materials and Methods: A total of 5744 patients from the SEER database who were initially diagnosed with histologically confirmed gastric cancer without distant metastases from 2010 to 2013 were included. Patients were divided into three groups as follows: patients who underwent radiation after surgery ("RAS" group), patients who underwent radiation prior to surgery ("RPS" group) and patients who did not undergo radiation ,only surgery performed ("No radiation'"group). Conclusions: This retrospective analysis demonstrated that "RPS" or "RAS"alone were independent prognostic factors for survival improvement in selected gastric cancer patients without distant metastases. PMID- 29416727 TI - Evaluation of predictive models for delayed graft function of deceased kidney transplantation. AB - Background: This study aimed to evaluate the predictive power of five available delayed graft function (DGF)-prediction models for kidney transplants in the Chinese population. Results: Among the five models, the Irish 2010 model scored the best in performance for the Chinese population. Irish 2010 model had an area under the receiver operating characteristic (ROC) curve of 0.737. Hosmer-Lemeshow goodness-of-fit test showed that the Irish 2010 model had a strong correlation between the calculated DGF risk and the observed DGF incidence (p = 0.887). When Irish 2010 model was used in the clinic, the optimal upper cut-off was set to 0.5 with the best positive likelihood ratio, while the lower cut-off was set to 0.1 with the best negative likelihood ratio. In the subgroup of donor aged <= 5, the observed DGF incidence was significantly higher than the calculated DGF risk by Irish 2010 model (27% vs. 9%). Materials and Methods: A total of 711 renal transplant cases using deceased donors from China Donation after Citizen's Death Program at our center between February 2007 and August 2016 were included in the analysis using the five predictive models (Irish 2010, Irish 2003, Chaphal 2014, Zaza 2015, Jeldres 2009). Conclusions: Irish 2010 model has the best predictive power for DGF risk in Chinese population among the five models. However, it may not be suitable for allograft recipients whose donor aged <= 5-year-old. PMID- 29416728 TI - Crucial role of pro-inflammatory cytokines from respiratory tract upon PM2.5 exposure in causing the BMSCs differentiation in cells and animals. AB - Fine particulate matter exposure may cause health risk, including cardiovascular diseases and cancer. Bone marrow mesenchymal stem cell (BMSC), a typical model for evaluating pollutant toxicity, has been closely linked to these diseases, due to its characteristics of differentiation. We therefore studied the BMSCs differentiation and its roles in inflammatory activation in the respiratory tract upon PM2.5 exposure using both in vitro and in vivo models. BMSCs differentiation into endothelial-like cells (ELCs) and cancer-associated fibroblasts cells (CAFs) was enhanced in response to conditioned medium from PM2.5-treated 16HBE cells. PM2.5 elevated inflammatory cytokines' expression and secretion in 16HBE cells. However, induction of differentiation markers was reduced when IL-1beta, IL-6 and COX-2 neutralizing antibodies were added to the conditioned medium. Furthermore, PM2.5 induced ROS formation and NADPH oxidase (NOX) expression in 16HBE cells. DPI (inhibitor of ROS from NOX) or NAC (inhibitor of ROS) supplement reduced PM2.5-induced inflammatory activation and BMSCs differentiation. Likewise, a concomitant disorder of mitochondrial morphology and respiratory chain was observed. In addition, Rot or AA (inhibitor of mitochondrial complex I or III) supplement restored PM2.5-induced toxic effects. Moreover, the results coincided with the in vitro data obtained from SD rats post-exposed to different doses of PM2.5 for 30 days. PM2.5 enhanced the BMSCs differentiation and inflammatory cytokines' expression in respiratory organs of SD rats, including lung and trachea tissue. This study uncovers that PM2.5 promotes the BMSCs differentiation via inflammatory activation mediated by ROS induction from NOX and mitochondria in the respiratory tract. PMID- 29416729 TI - Multicomponent analysis of the tumour microenvironment reveals low CD8 T cell number, low stromal caveolin-1 and high tenascin-C and their combination as significant prognostic markers in non-small cell lung cancer. AB - The complex interplay of the tumour microenvironment (TME) and its role in disease progression and response to therapy is poorly understood. The majority of studies to date focus on individual components or molecules within the TME and so lack the power correlative analysis. Here we have performed a multi-parameter analysis of the TME in 62 resectable non-small cell lung cancer (NSCLC) specimens detailing number and location of immune infiltrate, assessing markers of cancer associated fibroblasts, caveolin-1 and tenascin-C, and correlating with clinicopathological details, as well as markers of disease progression such as epithelial-to-mesenchymal transition (EMT). The influence of individual parameters on overall survival was determined in univariate and multivariate analysis and the combination of risk factors and interplay between components analysed. Low numbers of CD8 T cells, low stromal levels of caveolin-1 or high levels of tenascin-C were significant prognostic markers of decreased overall survival in both univariate and multivariate analysis. Patients with two or more risk factors had dramatically reduced overall survival and those with all three a median survival of just 7.5 months. In addition, low levels of tumour E-cadherin correlated with reduced immune infiltrate into the tumour nests, possibly linking EMT to the avoidance of CD8 T cell control. The multicomponent approach has allowed identification of the dominant influences on overall survival, and exploration of the interplay between different components of the TME in NSCLC. PMID- 29416730 TI - Neutrophil extracellular traps contribute to the pathogenesis of acid-aspiration induced ALI/ARDS. AB - Background: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a manifestation of systemic inflammation in the lungs, but the factors that trigger inflammation in ALI/ARDS are unclear. We hypothesized that neutrophil extracellular traps (NETs) contribute to the pathogenesis of acid aspiration induced ALI/ARDS. Results: Analysis of bronchial aspirates from ARDS patients showed that NETs were significantly correlated with the degree of ARDS (r = 0.5846, p = 0.0359). NETs in bronchoalveolar lavage fluid of acid-aspiration mice were significantly higher (141.6 +/- 23.08) at 3 h after injury than those in the sham group (1234 +/- 101.9; p = 0.003, n = 5 per group). Exogenous NETs aggravated lung injury, while alvelestat and DNase markedly attenuated the intensity of ARDS. Materials and Methods: We investigated whether NETs are involved in the severity of gastric aspiration-induced ARDS. Then, a hydrochloric acid aspiration-induced ALI murine model was used to assess whether NETs are pathogenic and whether targeting NETs is protective. Exogenous NETs were administered to mice. Alvelestat can inhibit neutrophil elastase (NE), which serves an important role in NET formation, so we investigated whether alvelestat could protect against ALI in cell and mouse models. Conclusions: NETs may contribute to ALI/ARDS by promoting tissue damage and systemic inflammation. Targeting NETs by alvelestat may be a potential therapeutic strategy. PMID- 29416731 TI - Comparative proteomics as a tool for identifying specific alterations within interferon response pathways in human glioblastoma multiforme cells. AB - An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where oncolytic virus therapy would be most effective. We quantified changes in protein abundances in two glioblastoma multiforme (GBM) cell lines that differ in the ability to induce resistance to vesicular stomatitis virus (VSV) infection in response to type I interferon (IFN) treatment. In IFN-treated samples we observed an up-regulation of protein products of some IFN-regulated genes (IRGs). In total, the proteome analysis revealed up to 20% more proteins encoded by IRGs in the glioblastoma cell line, which develops resistance to VSV infection after pre-treatment with IFN. In both cell lines protein-protein interaction and signaling pathway analyses have revealed a significant stimulation of processes related to type I IFN signaling and defense responses to viruses. However, we observed a deficiency in STAT2 protein in the VSV-sensitive cell line that suggests a de-regulation of the JAK/STAT/IRF9 signaling. The study has shown that the up-regulation of IRG proteins induced by the IFNalpha treatment of GBM cells can be detected at the proteome level. Similar analyses could be applied for revealing functional alterations within the antiviral mechanisms in glioblastoma samples, accompanying by acquisition of sensitivity to oncolytic viruses. The approach can be useful for discovering the biomarkers that predict a potential sensitivity of individual glioblastoma tumors to oncolytic virus therapy. PMID- 29416732 TI - Gene amplification in mesenchymal stem cells and during differentiation towards adipocytes or osteoblasts. AB - Gene amplifications are an attribute of tumor cells and have for long time been overlooked in normal cells. A growing number of investigations describe gene amplifications in normal mammalian cells during development and differentiation. Possibly, tumor cells have rescued the gene amplification mechanism as a physiological attribute of stem cells. Here, we investigated human mesenchymal stem cells (hMSCs) for gene amplification using array-CGH, single cell fluorescence in situ hybridization and qPCR. Gene amplifications were detected in mesenchymal stem cells and in mesenchymal stem cells during differentiation towards adipocytes and osteoblasts. Undifferentiated hMSCs harbor 12 amplified chromosomal regions, hMSCs that differentiated towards adipocytes 18 amplified chromosome regions, and hMSCs that differentiate towards osteoblasts 19 amplified regions. Specifically, hMSCs that differentiated towards adipocytes or osteoblasts harbor CDK4 and MDM2 amplifications both of which frequently occur in osteosarcoma and liposarcoma that are both of same cell origin. Beside the amplifications, we identified 36 under-replicated regions in undifferentiated and in differentiating hMSC cells. PMID- 29416733 TI - Genome-wide profiling identifies the THYT1 signature as a distinctive feature of widely metastatic Papillary Thyroid Carcinomas. AB - Background: Papillary Thyroid Carcinomas (PTCs) are generally indolent tumors. However, a small but significant percentage of PTCs behaves aggressively, progressing to a diffuse metastatic spreading and leading to patient's death. The lack of reliable markers for predicting the metastatic behavior of these tumors prevents a correct risk based stratification of the disease, thus contributing to the issue of patients' overtreatment. In this study we aimed at identifying genetic features associated with the development of distant metastasis in PTCs. Results: We showed that DM PTCs are characterized by a moderate degree of copy number alterations but display low level of microsatellite instability and a low mutational burden. We identified duplication of Chr1q, duplication of Chr5p harboring the TERT genomic locus and mutations of TERT promoter as distinctive features of DM PTCs. These three genetic variables defined a signature (THYT1) that was significantly associated with a metastatic behavior and a shortened survival. We analyzed the THYT1 signature in PTCs fine needle aspirate biopsies (FNAB) and we demonstrating the applicability of this signature as a molecular marker in the pre-operative diagnostic setting of PTCs. Materials and Methods: A consecutive series of 2,937 thyroid malignancies, diagnosed at the Arcispedale S. Maria Nuova - IRCCS, Italy between 1978 and 2015 were searched to retrieve those who developed distant metastasis (DM, n = 50). We performed a deep profiling to explore the genomic landscape of these tumors. Conclusions: Overall our data identify the first genetic signature that independently predicts metastasis and negative outcome of PTCs, and lay the basis for the possible application of the THYT1 as prognostic marker to improve risk-based stratification and management of PTC patients. PMID- 29416734 TI - SSCMDA: spy and super cluster strategy for MiRNA-disease association prediction. AB - In the biological field, the identification of the associations between microRNAs (miRNAs) and diseases has been paid increasing attention as an extremely meaningful study for the clinical medicine. However, it is expensive and time consuming to confirm miRNA-disease associations by experimental methods. Therefore, in recent years, several effective computational models for predicting the potential miRNA-disease associations have been developed. In this paper, we proposed the Spy and Super Cluster strategy for MiRNA-Disease Association prediction (SSCMDA) based on known miRNA-disease associations, integrated disease similarity and integrated miRNA similarity. For problems of mixed unknown miRNA disease pairs containing both potential associations and real negative associations, which will lead to inaccurate prediction, spy strategy is adopted by SSCMDA to identify reliable negative samples from the unknown miRNA-disease pairs. Moreover, the super-cluster strategy could gather as many positive samples as possible to improve the accuracy of the prediction by overcoming the shortage of lacking sufficient positive training samples. As a result, the AUCs of global leave-one-out cross validation (LOOCV), local LOOCV and 5-fold cross validation were 0.9007, 0.8747 and 0.8806+/-0.0025, respectively. According to the AUC results, SSCMDA has shown a significant improvement compared with some previous models. We further carried out case studies based on various version of HMDD database to test the prediction performance robustness of SSCMDA. We also implemented case study to examine whether SSCMDA was effective for new diseases without any known associated miRNAs. As a result, a large proportion of the predicted miRNAs have been verified by experimental reports. PMID- 29416735 TI - Long non-coding RNA n326322 promotes the proliferation and invasion in nasopharyngeal carcinoma. AB - Long non-coding RNAs (lncRNAs) have been reported to perform significant roles in cancer development and progression. Our research has found that a novel lncRNA n326322 was higher in nasopharyngeal carcinoma (NPC) cells. Moreover, the gain and loss of functional approaches revealed that the overexpression of lncRNA n326322 promoted NPC cell proliferation and invasion, whereas the downregulation of lncRNA-n326322 suppressed cell proliferation and invasion. Further experiments demonstrated that potential mechanism may be associated with the activation of PI3K/AKT and ERK/MAPK pathways. Taken together, these results indicate that lncRNA-n326322 is associated with tumorigenesis of NPC. PMID- 29416736 TI - Prognostic and histogenetic roles of gene alteration and the expression of key potentially actionable targets in salivary duct carcinomas. AB - The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53, 68%; PIK3CA, 18%; H-RAS, 16%; BRAF, 4%; and AKT1, 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC. PMID- 29416737 TI - Hypericin targets osteoclast and prevents breast cancer-induced bone metastasis via NFATc1 signaling pathway. AB - Bone is the most common target organ of metastasis of breast cancers. This produces considerable morbidity due to skeletal-related events, and severely reduces the quality of life. Increased osteoclast activity is implicated in breast cancer outgrowth in the bone microenvironment. Our previous observation of an anti-osteoclastic activity of hypericin, a natural plant compound, led us to investigate whether hypericin could inhibit bone metastasis and osteolysis caused by breast cancer. We find that hypericin inhibited the upregulation of osteoclasts stimulated by breast cancer cells. The activity of hypericin on osteoclasts and breast cancer-mediated osteoclastogenesis was associated with the inhibition of NFATc1 signaling pathway and attenuation of Ca2+ oscillation. Furthermore, hypericin suppresses invasion and migration in breast cancer cells, but has little effect on breast cancer-cell induced RANKL/OPG ratio in osteoblast or the expression of osteoclast-activating factors. Administration of hypericin could reduce tumor burden, osteolysis induced by direct inoculation of MDA-MB-231 cells into the bone marrow cavity of the tibia as well as metastasis of bone and improve survival in an experimental metastasis model by intracardiac injection of MDA-MB-231 breast cancer cells. Taken together, these results suggest that hypericin may be a potential natural agent for preventing and treating bone destruction in patients with bone metastasis due to breast cancer. PMID- 29416739 TI - Protective role of STVNa in myocardial ischemia reperfusion injury by inhibiting mitochondrial fission. AB - It has been reported that isosteviol, a widely known sweeteners, can protect against myocardial ischemia-reperfusion (IR) injury in isolated guinea pig heart. Here, we aim to confirm the cardioprotective effect of its sodium salt, isosteviol sodium (STVNa), against IR injury and its potential molecular mechanism in H9c2 cardiomyocytes. STVNa significantly improved cell viability, restored mitochondrial membrane potential, decreased cellular reactive oxygen species generation, and inhibited cell apoptosis. Furthermore, STVNa treatment changed the morphology of mitochondria from fragmented, discontinuous forms to normal elongated, tubular forms. Cyto-immunofluorescence and western blot analysis revealed that STVNa inhibited mitochondrial fission proteins dynamin related protein 1 (Drp1), and mitochondrial fission 1 (Fis1), thus plays a key role in cardioprotection. These findings, for the first time, suggest that STVNa can protect against myocardial IR injury through reverse mitochondrial fission. PMID- 29416738 TI - PARP-1 inhibitors sensitize HNSCC cells to APR-246 by inactivation of thioredoxin reductase 1 (TrxR1) and promotion of ROS accumulation. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for HNSCC patients with mutations in the TP53 gene although patients are responsive to surgery, irradiation, and chemotherapy early in the treatment. p53 Reactivation and Induction of Massive Apoptosis-1 (PRIMA-1) and its methylated analogue PRIMA-1Met (also known as APR-246) are quinuclidine compounds that rescue the DNA-binding activity of mutant p53 (mut-p53) and restore the potential of wild-type p53. In the current report, we demonstrated that inhibition of poly (ADP-ribose) polymerase-1 (PARP-1) with 6(5H)-phenanthridinone (PHEN) and N-(6 Oxo-5,6-dihydrophenanthridin-2-yl)-(N, N-dimethylamino) acetamide hydrochloride (PJ34) sensitizes UMSCC1, UMSCC14, and UMSCC17A, three HNSCC cell lines to the treatment of APR-246. PHEN enhances APR-246-induced apoptosis, but not programmed necrosis or autophagic cell death in HNSCC cells. The PARP-1 inhibition-induced sensitization of HNSCC cells to APR-246 is independent of TP53 mutation. Instead, PARP-1 inhibition promotes APR-246-facilitated inactivation of thioredoxin reductase 1 (TrxR1), leading to ROS accumulation and DNA damage. Overexpression of TrxR1 or application of antioxidant N-acetyl-L-cysteine (NAC) depletes the ROS increase, reduces DNA damage, and decreases cell death triggered by APR-246/PHEN in HNSCC cells. Thus, we have characterized a new function of PARP-1 inhibitor in HNSCC cells by inactivation of TrxR1 and elevation of ROS and provide a novel therapeutic strategy for HNSCC by the combination of PARP-1 inhibitors and APR 246. PMID- 29416740 TI - Prognostic value of histogram analysis in advanced non-small cell lung cancer: a radiomic study. AB - Introduction: Quantitative assessment of heterogeneity by histogram analysis (HA) of tumor images can potentially provide a non-invasive prognostic biomarker. We assessed the prognostic value of HA and evaluated a correlation with molecular signature. Results: CT scans performed between July 2009 and January 2015 from 692 patients were reviewed. HA was performed on scans from 313 patients in the training dataset and 108 in the validation dataset. Median follow-up were 33.7 months [range: 1.7 - 65.5] and 29 months [range: 1.1 - 35.6] with a median overall survival (OS) of 11.7 months [95%CI: 10.7 - 13.1] and 9.5 months [95%CI: 7.9 - 12.7] respectively. Primary mass entropy in coarse texture with spatial filter 3.3 was prognostic for OS in a multivariate Cox analysis (HR: 1.3 [95%CI: 1.1 - 1.5], p=0.001). Results were not reproduced in our validation set and no correlation with molecular signature was identified. Materials and Methods: HA using filtration-histogram method was applied to the region of interest on the primary tumor in enhanced-CT acquired as diagnostic/staging routine, from a cohort of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. The resultants parameters were prospectively applied to a validation dataset. CT scans, clinical and molecular data were retrospectively collected. Cox proportional hazard models were used for survival analysis and Wilcoxon test for correlations. Conclusion: Primary mass entropy was significantly associated with survival in the training set but was not validated in the validation cohort, raising doubt over the reliability of published data from small cohorts. PMID- 29416741 TI - Long noncoding RNA DANCR is activated by SALL4 and promotes the proliferation and invasion of gastric cancer cells. AB - Long noncoding RNAs (LncRNAs) play important roles in tumor development and progression. The expression of lncRNAs is frequently dysregulated in human cancer. DANCR (anti-differentiation noncoding RNA) is a newly identified lncRNA in human cancer, however, its functional roles and clinical value in gastric cancer (GC) remains unknown. In this study, we investigated the expression of DANCR in the tumor tissues and serum of GC patients and analyzed the correlation between DANCR expression levels and the clinicopathological characteristics. Our results showed that the expression of DANCR was higher in the tumor tissues than that in the adjacent non-cancerous tissues. The expression level of DANCR was also elevated in the serum of GC patients compared to that of healthy controls. The expression levels of DANCR were significantly associated with tumor size, TNM stage, lymphatic metastasis and invasion depth. DANCR knockdown inhibited the proliferation of GC cells by inducing cell cycle arrest and cell apoptosis. In addition, DANCR knockdown suppressed gastric cancer growth in vivo. Moreover, DANCR knockdown inhibited the migration and invasion of GC cells via the suppression of epithelial-mesenchymal transition (EMT). However, DANCR overexpression had the opposite effect. DANCR is activated by SALL4 in gastric cancer cells and exerted its oncogenic activities through the activation of beta catenin pathway. Taken together, our findings suggest that DANCR promotes the progression of gastric cancer and have the potential to serve as a novel diagnostic biomarker. PMID- 29416742 TI - MicroRNA-19a acts as a prognostic marker and promotes prostate cancer progression via inhibiting VPS37A expression. AB - Prostate cancer (PCa) is a leading cause of cancer-related deaths among males worldwide. However, the molecular mechanisms underlying the progression of PCa remain unclear. Despite several reported miRNAs in prostate cancer, these reports lacked system-level identification of differentially expressed miRNAs in large sample size. Moreover, it's still largely unknown how miRNAs result in tumorigenesis and progression of PCa. Therefore, by analyzing three public databases, we identified 16 upregulated miRNAs and 13 downregulated miRNAs, and validated miR-19a was one of the most upregulated miRNAs using qRT-PCR. The dual luciferase reporter assays indicated VPS37A was a potential target of miR-19a. Functional assays revealed miR-19a served as an oncogene by inhibiting VPS37A. Notably, a significant inverse correlation of miR-19a and VPS37A expression was observed in PCa specimens. Moreover, miR-19a-high and VPS37A-low phenotypes were associated with poor prognosis with biochemical recurrence-free probability. In this study, we confirmed the oncogenic role of miR-19a via targeting VPS37A in PCa, identifying miR-19a and VPS37A as diagnosis and therapeutic biomarkers for PCa. PMID- 29416743 TI - DHSpred: support-vector-machine-based human DNase I hypersensitive sites prediction using the optimal features selected by random forest. AB - DNase I hypersensitive sites (DHSs) are genomic regions that provide important information regarding the presence of transcriptional regulatory elements and the state of chromatin. Therefore, identifying DHSs in uncharacterized DNA sequences is crucial for understanding their biological functions and mechanisms. Although many experimental methods have been proposed to identify DHSs, they have proven to be expensive for genome-wide application. Therefore, it is necessary to develop computational methods for DHS prediction. In this study, we proposed a support vector machine (SVM)-based method for predicting DHSs, called DHSpred (DNase I Hypersensitive Site predictor in human DNA sequences), which was trained with 174 optimal features. The optimal combination of features was identified from a large set that included nucleotide composition and di- and trinucleotide physicochemical properties, using a random forest algorithm. DHSpred achieved a Matthews correlation coefficient and accuracy of 0.660 and 0.871, respectively, which were 3% higher than those of control SVM predictors trained with non optimized features, indicating the efficiency of the feature selection method. Furthermore, the performance of DHSpred was superior to that of state-of-the-art predictors. An online prediction server has been developed to assist the scientific community, and is freely available at: http://www.thegleelab.org/DHSpred.html. PMID- 29416744 TI - Experimental evidence of good efficacy and reduced toxicity with peptide doxorubicin to treat gastric cancer. AB - Background: To compare the efficacy and toxicity of peptide-doxorubicin (PDOX) and doxorubicin (DOX) on nude mice models of human gastric cancer. Results: Both PDOX and DOX could significantly inhibit tumor growth compared with Control (P < 0.05) in both subcutaneous and orthotopic models. Animal survival was much better in PDOX group than DOX group. In peripheral blood test, PDOX group had significantly higher levels of platelets than the Control (P < 0.05), and lymphocyte lower than Control (P < 0.05). There were no significant differences on liver, kidney and cardiac function parameters among three groups (P > 0.05). Immunohistochemistry showed that treatment groups had much higher Tunel than Control (P < 0.05), and PDOX had significantly lower Ki-67 than doxorubicin and Control group (P < 0.01). Western blotting showed that PDOX caused much higher expressions of P53, P21, Aparf-1, pro- and cleaved-caspase 3, compared with DOX. Conclusion: Compared with DOX, PDOX has increased effects but much decreased toxicity in treating animal model of gastric cancer. Materials and Methods: Animals in subcutaneous model were randomized into Control, doxorubicin, PDOX-L, PDOX-M, and PDOX-H groups. Animals in surgical orthotopic implantation model were randomized into Control, doxorubicin and, peptide-doxorubicin groups. The animals were treated, monitored and examined following a set protocol. PMID- 29416745 TI - iTRAQ analysis of a mouse acute myocardial infarction model reveals that vitamin D binding protein promotes cardiomyocyte apoptosis after hypoxia. AB - The proteome profile changes after acute myocardial infarction (AMI) and the roles played by important protein species remain poorly understood. Here, we constructed a mouse AMI model by ligating the left coronary artery of male C57B/6J mice to investigate the molecular changes after AMI on the protein level. Total proteins of the left ventricle were extracted and quantitatively analyzed by isobaric tags using relative and absolute quantitation (iTRAQ) technologies. The transcript and protein levels of important genes were further validated using quantitative polymerase chain reaction and western blot. An oxygen and glucose deprivation/reperfusion cell model was constructed using H9C2 cells to further validate the expression patterns and functions of important proteins after hypoxia. Seven hundred seventy-six proteins were identified as differentially abundant proteins after AMI, of which 406 were accumulated, and 370 were reduced. Gene ontology enrichment analysis showed that the most enriched molecular function category terms were binding, including calcium ion biding, GTP binding, actin binding and lipid binding. The expression levels of vitamin D binding protein (VDBP) and its related proteins were increased in both left ventricular tissue and H9C2 cells after ischemia-hypoxia. Overexpression of VDBP in H9C2 cells reduced vitamin D receptor and promoted the cell apoptosis rate after hypoxia. Our data provided new insights into proteome profile changes after AMI and indicated that VDBP could promote cardiomyocyte apoptosis after hypoxia. PMID- 29416746 TI - miR-518f-5p decreases tetraspanin CD9 protein levels and differentially affects non-tumourigenic prostate and prostate cancer cell migration and adhesion. AB - Tetraspanin CD9 is generally considered to be a metastasis suppressor, with decreased levels associated with progression and metastasis in many advanced stage cancers. Little is known about the cause of CD9 dysregulation in prostate cancer, however there are several miRNA-binding sites in the 3'UTR of the transcript suggesting it could be post-transcriptionally regulated. Using microarrays and luciferase assays in tumourigenic and non-tumourigenic prostate cell lines we identified miR-518f-5p as a regulator of the CD9 3'UTR gene expression, and decreased expression of endogenous CD9 in non-tumorigenic prostate RWPE1 and prostate cancer DU145 cells. This resulted in differential functional effects, in which RWPE1 cells showed increased migration and decreased adhesion to extracellular matrix substrates, whereas DU145 cells showed decreased migration and increased adhesion. Moreover, overexpression of miR-518f-5p significantly increased proliferation between 48h and 72h in normal RWPE1 cells, with no effect on tumourigenic DU145 cell proliferation. These results show that tetraspanin CD9 is regulated by miRNAs in prostate cell lines and that due to differential functional effects in non-tumourigenic versus tumourigenic prostate cells, miR-518f-5p may be an effective biomarker and/or therapeutic target for prostate cancer progression. PMID- 29416747 TI - CD34- human placenta-derived mesenchymal stem cells protect against heat stroke mortality in rats. AB - CD34 is a transmembrane phosphoglycoprotein used to selectively enrich bone marrow in hematopoietic stem cells for transplantation. Treating rats with CD34+ cells derived from human umbilical cord blood before or after heat stroke has been shown to promote survival. We investigated whether CD34- human placenta derived stem cells (PDMSCs) could improve survival following heat stroke in rats. Rats were subjected to heat stress (42 degrees C for 98 min) to induce heat stroke. Intravenous administration of PDMSCs 1 day before or immediately after the onset of heat stroke improved survival by 60% and 20%, respectively. Pre treatment with CD34- PDMSCs protected against heat stroke injury more effectively than that treatment after injury. PDMSCs treatment attenuated cerebrovascular dysfunction, the inflammatory response, and lipid peroxidation. These data suggest human PDMSCs protect against heat stroke injury in rats. Moreover, these effects do not require the presence of CD34+ cells. PMID- 29416748 TI - SIRT1 contributes to neuroendocrine differentiation of prostate cancer. AB - The epigenetic factor SIRT1 can promote prostate cancer progression, but it is unclear whether SIRT1 contributes to neuroendocrine differentiation. In this study, we showed that androgen deprivation can induce reactive oxygen species production and that reactive oxygen species, in turn, activate SIRT1 expression. The increased SIRT1 expression induces neuroendocrine differentiation of prostate cancer cells by activating the Akt pathway. In addition, the interaction between Akt and SIRT1 is independent of N-Myc and can drive the development of neuroendocrine prostate cancer when N-Myc is blocked. Furthermore, SIRT1 facilitates tumor maintenance, and targeting SIRT1 may reduce the tumor burden during androgen deprivation. Our findings suggest that SIRT1 is a potential target for therapeutic intervention. PMID- 29416749 TI - microRNA-19a protects osteoblasts from dexamethasone via targeting TSC1. AB - Activation of mTOR complex 1 (mTORC1) could protect human osteoblasts from dexamethasone. Tuberous sclerosis complex 1 (TSC1) is mTORC1 upstream inhibitory protein. We demonstrate here that microRNA-19a ("miR-19a", -3p) targets the 3' untranslated regions of TSC1 mRNA. Expression of miR-19a downregulated TSC1 in OB 6 osteoblastic cells and primary human osteoblasts. miR-19a activated mTORC1 and protected human osteoblasts from dexamethasone. mTORC1 inhibition, by RAD001 or Raptor shRNA, almost completely abolished miR-19a-induced osteoblast cytoprotection against dexamethasone. Knockdown of TSC1 by targeted shRNA similarly induced mTORC1 activation and protected osteoblasts. Moreover, miR-19a activated mTORC1-dependent NF-E2-related factor 2 (Nrf2) signaling and inhibited dexamethasone-induced reactive oxygen species production in osteoblasts. Together, miR-19a protects human osteoblasts from dexamethasone possibly via targeting TSC1-mTORC1 signaling. PMID- 29416750 TI - Pharmacological targeting of ROS reaction network in myeloid leukemia cells monitored by ultra-weak photon emission. AB - Acute myeloid leukemia (AML) is a blood cancer that is caused by a disorder of the process that normally generates neutrophils. Function and dysfunction of neutrophils are key to physiologic defense against pathogens as well as pathologies including autoimmunity and cancer. A major mechanism through which neutrophils contribute to health and disease is oxidative burst, which involves rapid release of reactive oxygen species (ROS) generated by a chemical reaction network catalyzed by enzymes including NADPH oxidase and myeloperoxidase (MPO). Due to the involvement of neutrophil-derived reactive oxygen species in many diseases and importance of NADPH oxidase and MPO-mediated reactions in progression and treatment of myeloid leukemia, monitoring this process and modulating it by pharmacological interventions is of great interest. In this work, we have evaluated the potential of a label-free method using ultra-weak photon emission (UPE) to monitor ROS production in neutrophil-like HL60 myeloid leukemia cells. Suppression of ROS was achieved by several drug candidates that target different parts of the reaction pathway. Our results show that UPE can report on ROS production as well as suppression by pharmacological inhibitors. We find that UPE is primarily generated by MPO catalyzed reaction and thus will be affected when an upstream reaction is pharmacologically modulated. PMID- 29416751 TI - Trichostatin A resistance is facilitated by HIF-1alpha acetylation in HeLa human cervical cancer cells under normoxic conditions. AB - Trichostatin A (TSA) is an anticancer drug that inhibits histone deacetylases (HDACs). Hypoxia-inducible factor 1 (HIF-1) participates in tumor angiogenesis by upregulating target genes, such as vascular endothelial growth factor (VEGF). In the present study, we investigated whether TSA treatment increases HIF-1alpha stabilization via acetylation under normoxic conditions, which would lead to VEGF upregulation and resistance to anticancer drugs. TSA enhanced total HIF-1alpha and VEGF-HRE reporter activity under normoxic conditions. When cells were transfected with GFP-HIF-1alpha, treatment with TSA increased the number of green fluorescence protein (GFP)-positive cells. TSA also enhanced the nuclear translocation of HIF-1alpha protein, as assessed by immunoblotting and as evidenced by increased nuclear localization of GFP-HIF-1alpha. An increase in the interaction between HIF-1alpha and the VEGF promoter, which was assessed by a chromatin immunoprecipitation (ChIP) assay, led to activation of the VEGF promoter. TSA acetylated HIF-1alpha at lysine (K) 674, which led to an increase in TSA-induced VEGF-HRE reporter activity. In addition, TSA-mediated cell death was reduced by the overexpression of HIF-1alpha but it was rescued by transfection with a HIF-1alpha mutant (K674R). These data demonstrate that HIF 1alpha may be stabilized and translocated into the nucleus for the activation of VEGF promoter by TSA-mediated acetylation at K674 under normoxic conditions. These findings suggest that HIF-1alpha acetylation may lead to resistance to anticancer therapeutics, such as HDAC inhibitors, including TSA. PMID- 29416752 TI - Fanconi Anemia germline variants as susceptibility factors in aplastic anemia, MDS and AML. AB - Using next generation sequencing we have systematically analyzed a large cohort of 489 patients with bone marrow failure (BMF), including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), aplastic anemia (AA), and related conditions for the presence of germline (GL) alterations in Fanconi Anemia (FA) and telomerase genes. We have detected an increased frequency of heterozygous FA gene mutations in MDS and to lesser degree in AML suggesting that the presence of one normal allele may not be completely protective and indeed heterozygous FA lesions may have a long latency period before hematologic manifestation. In contrast, GL telomerase gene mutations were not associated with increased disease risk. When compared to large control cohorts, we have not detected an increased frequency of damaging variants among telomerase complex genes, including those previously believed to be involved in the pathogenesis of AA. Our results may suggest that while low penetrance and delayed disease onset can confound identification of genetic predisposition factors, GL FA alterations can be also associated with MDS. PMID- 29416753 TI - Co-targeting of Tiam1/Rac1 and Notch ameliorates chemoresistance against doxorubicin in a biomimetic 3D lymphoma model. AB - Lymphoma is a heterogeneous disease with a highly variable clinical course and prognosis. Improving the prognosis for patients with relapsed and treatment resistant lymphoma remains challenging. Current in vitro drug testing models based on 2D cell culture lack natural tissue-like structural organization and result in disappointing clinical outcomes. The development of efficient drug testing models using 3D cell culture that more accurately reflects in vivo behaviors is vital. Our aim was to establish an in vitro 3D lymphoma model that can imitate the in vivo 3D lymphoma microenvironment. Using this model, we explored strategies to enhance chemosensitivity to doxorubicin, an important chemotherapeutic drug widely used for the treatment of hematological malignancies. Lymphoma cells grown in this model exhibited excellent biomimetic properties compared to conventional 2D culture including (1) enhanced chemotherapy resistance, (2) suppressed rate of apoptosis, (3) upregulated expression of drug resistance genes (MDR1, MRP1, BCRP and HIF-1alpha), (4) elevated levels of tumor aggressiveness factors including Notch (Notch-1, -2, -3, and -4) and its downstream molecules (Hes-1 and Hey-1), VEGF and MMPs (MMP-2 and MMP-9), and (5) enrichment of a lymphoma stem cell population. Tiam1, a potential biomarker of tumor progression, metastasis, and chemoresistance, was activated in our 3D lymphoma model. Remarkably, we identified two synergistic therapeutic oncotargets, Tiam1 and Notch, as a strategy to combat resistance against doxorubicin in EL4 T and A20 B lymphoma. Therefore, our data suggest that our 3D lymphoma model is a promising in vitro research platform for studying lymphoma biology and therapeutic approaches. PMID- 29416755 TI - Sperm-egg fusion disorder in a Chinese male patient was associated with a rare ADAM20 variant. AB - We report here a 28-year-old male with infertility. No abnormality was found in his semen examination. The couple achieved a successful pregnancy under the help of intracytoplasmic sperm injection during which we found that sperm could enter the zona pellucida, but could not fuse with the egg within the short insemination period. We then performed whole-exome sequencing technology on this patient and found a rare variant (c.641A>C:p.D214A) in ADAM20, which encoded a disintegrin and metalloprotease 20 protein. To further verify the pathogenicity of this variant, we analyzed ADAM20 protein expression in spermatozoa by immunostaining analysis, which showed a mis-localization of ADAM20 in the patient's spermatozoa. Therefore, we concluded that mutation in ADAM20 may be associated with sperm-egg fusion disorder in this patient. PMID- 29416754 TI - Targeted deep sequencing of circulating tumor DNA in metastatic pancreatic cancer. AB - Purpose: Precision medicine in pancreatic ductal adenocarcinoma (PDAC) could be substantially supported by tools that allow to establish and monitor the molecular setup of the tumor. In particular, noninvasive approaches are desirable, but not validated. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Experimental Design: Blood samples from patients with metastatic PDAC prior to and during palliative treatment were collected. ctDNA and corresponding tumor tissue were analyzed by targeted next generation sequencing and droplet digital PCR for the 7 most frequently mutated genes in PDAC (TP53, SMAD4, CDKN2A, KRAS, APC, ATM, and FBXW7). Findings were correlated with clinical and imaging data. Results: A total of 20 patients (therapy naive n = 11; pretreated n = 9) were included. All therapy naive patients (n = 11/11) presented with detectable ctDNA at baseline. In pretreated patients, 3/7 (prior to 2nd line treatment) and 2/2 (prior to 3rd line chemotherapy) had detectable ctDNA. The combined mutational allele frequency (CMAF) of KRAS and TP53 was chosen to reflect the amount of ctDNA. The median CMAF level significantly decreased during treatment (P = 0.0027) and increased at progression (P = 0.0104). CA19-9 analyses did not show significant differences. In treatment naive patients, the CMAF levels during therapy significantly correlated with progression-free survival (Spearman, r = -0.8609, P = 0.0013). Conclusions: Monitoring of ctDNA and its changes during treatment may enable to adapt therapeutic strategies to the specific molecular changes present at a certain time during treatment of mPDAC. PMID- 29416757 TI - The functional mechanism of miR-125b in gastric cancer and its effect on the chemosensitivity of cisplatin. AB - Numerous studies have shown drug resistance of gastric cancer cells could be modulated by abnormal expression of microRNAs. Cisplatin (DDP) is one of the most commonly used drugs for chemotherapy of gastric cancer. In this study, the potential function of miR-125b on DDP resistance in gastric cancer cells was investigated. Sixteen miRNAs significantly differential expressed in gastric tumor tissues and adjacent tissues were characterized and their corresponding putative target genes were also screened. MiR-125b was selected as our focus for its evident down-regulated expression among candidate genes. Real-time polymerase chain reaction assay indicated that miR-125b was significantly down-regulated in gastric cancer tissues and various cell lines. HER2 was identified as a target gene of miR-125b by dual luciferase reporter assay and Western blot. Moreover, miR-125b overexpression inhibited not only the proliferation, migration, and invasion abilities of HGC-27 and MGC-803 cells, but also in vivo tumor growth of MGC-803 cells by an intratumoral delivery approach. Notably, we observed up regulated miR-125b contributed to the chemosensitivity of DDP in HGC-27 and MGC 803 cells at different concentrations and also possessed sensibilization for DDP at different times. MiR-125b expression was found to be related to lymph node metastasis, HER2 expression and overall survival of patients through correlation analysis. Collectively, these results indicate miR-125b may regulate DDP resistance as a promising therapeutic target for gastric cancer treatment in future. PMID- 29416756 TI - A miRNA-based classification of renal cell carcinoma subtypes by PCR and in situ hybridization. AB - Renal cell carcinoma (RCC) constitutes an array of morphologically and genetically distinct tumors the most prevalent of which are clear cell, papillary, and chromophobe RCC. Accurate distinction between the typically benign behaving renal oncocytoma and RCC subtypes is a frequent challenge for pathologists. This is critical for clinical decision making. Subtypes also have different survival outcomes and responses to therapy. We extracted RNA from ninety formalin-fixed paraffin-embedded (FFPE) tissues (27 clear cell, 29 papillary, 19 chromophobe, 4 unclassified RCC and 11 oncocytomas). We quantified the expression of six miRNAs (miR-221, miR-222, miR-126, miR-182, miR-200b and miR-200c) by qRT-PCR, and by in situ hybridization in an independent set of tumors. We developed a two-step classifier. In the first step, it uses expression of either miR-221 or miR-222 to distinguish the clear cell and papillary subtypes from chromophobe RCC and oncocytoma (miR-221 AUC: 0.96, 95% CI: 0.9132-1.014, p < 0.0001 and miR-222 AUC: 0.91, 95% CI: 0.8478-0.9772, p < 0.0001). In the second step, it uses miR-126 to discriminate clear cell from papillary RCC (AUC: 1, p < 0.0001) and miR-200b to discriminate chromophobe RCC from oncocytoma (AUC: 0.95, 95% CI: 0.8933-1.021, p < 0.0001). In situ hybridization showed a nuclear staining pattern. miR-126, miR-222 and miR-200b were significantly differentially expressed between the subtypes by in situ hybridization. miRNA expression could distinguish RCC subtypes and oncocytoma. miRNA expression assessed by either PCR or in situ hybridization can be a clinically useful diagnostic tool to complement morphologic renal tumor classification, improving diagnosis and patient management. PMID- 29416758 TI - Duration-response association between exercise and HDL in both male and female Taiwanese adults aged 40 years and above. AB - Background: Exercise is an important cardiovascular risk reducing therapy. Objective: The aim of this study was to assess the relationship between weekly exercise duration and high-density lipoprotein cholesterol (HDL-c) in Taiwanese men and women. Methods: Data were retrieved from the dataset of the national adult preventive medical services which is recorded under the Health Promotion Administration (HPA). The lipid profiles of 194528 eligible participants aged 40 years and above who completed a questionnaire on recent health behavior including smoking, drinking, exercise and other factors in 2014 were determined. Weekly exercise durations of 0.0, <2.5 and >=2.5 hours were classified as no, below recommended and recommended, respectively. The relationship between exercise and HDL-c was determined using linear regression. Results: After multivariate adjustments, a duration-response association existed between exercise and HDL-c (P-trend <0.0001) in both sexes. Weekly exercise durations of <2.5 and >=2.5 hours were both positively associated with HDL-c (P <0.0001) in both sexes. However, the associations were stronger in males than females in both exercise groups. Smoking (P <0.05) and BMI (P <0.0001) were negatively associated while drinking was positively associated with HDL-c in both sexes. Conclusion: This study demonstrated a duration-response association between exercise and HDL-c. Exercise at durations below the minimum weekly recommendation of 2.5 hours was positively associated with HDL-c. PMID- 29416759 TI - SNHG1 promotes cell proliferation by acting as a sponge of miR-145 in colorectal cancer. AB - ncRNAs are important regulatory molecules and involve in many physiological cellular processes. Small nucleolar RNA host gene 1 (SNHG1) is a host to 8 snoRNAs and is located in 11q12.3 region of the chromosome. It has been reported to be involved in several cancers. However, the role of SNHG1 in the tumorigenesis of colorectal cancer is still unknown. In this study, SNHG1 was upregulated in colorectal cancers, and SNHG1 expression was correlated with advanced colorectal cancer stage and tumor recurrence. We found that SNHG1 promoted cell proliferation by acting as a sponge of miR-145, a well known tumor suppressor of colorectal cancer. Furthermore, the survival analysis indicated that colorectal cancer patients with higher expression of SNHG1 had a worse prognosis. These findings suggested that SNHG1 may act as a potential therapeutic target for the treatment of colorectal cancer. PMID- 29416760 TI - Combination therapy of 7-O-succinyl macrolactin A tromethamine salt and temozolomide against experimental glioblastoma. AB - 7-O-succinyl macrolactin A has shown anti-inflammatory, anti-angiogenesis, and anti-metastatic effects. It also exhibits strong suppression of tumor growth. In our previous study, we assessed the anti-neoplastic effects of 7-O-succinyl macrolactin A tromethamine salt (SMA salt) on a glioma cell line. Moreover, according to our data, SMA salt might be contributed to the inhibitory effects on migration and invasion, as well as a cytotoxic effect on the glioblastoma cell lines. In the present study, we investigated the anti-tumor effects of combination therapy with SMA salt and temozolomide (TMZ) in glioblastoma cell lines. The combination therapy affected cell viability significantly, decreasing in glioblastoma cell lines. In cell migration assays, combination therapy showed more inhibitory effects than TMZ in these cell lines. The tumor volume was significantly decreased in the combination group compared with both TMZ and control groups by using the orthotopic mouse model. The effects of combination therapy with SMA salt and TMZ attributed to the inhibition of migration, invasion activities and anti-tumor effects. SMA salt could be one of the promising candidates for combination therapy in clinical settings. PMID- 29416761 TI - Increased risk of Parkinson's disease following tension-type headache: a nationwide population-based cohort study. AB - Purpose: Previous studies have suggested associations between primary headache and neurodegenerative diseases; however, the relationship between tension-type headache (TTH), which is the most common type of primary headache, and Parkinson's disease (PD) remains controversial. Hence, in this nationwide, population-based, retrospective cohort study, we explored the temporal association between TTH and PD. Methods: Using claims data in the National Health Insurance Research Database of Taiwan, we evaluated 12,309 subjects aged >=20 years who were newly diagnosed with TTH from 2000 to 2005. The non-TTH group included 49,236 randomly selected sex- and age-matched patients without TTH. Subjects were followed up until the end of 2011, diagnosis of PD, or death. The incidence of PD was compared between the two groups. A Cox multivariable proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate the risk of PD. Results: The overall incidence of PD (per 1,000 person-years) in the TTH and non-TTH groups was 3.01 and 1.68, respectively. After adjustment for sex, age, and comorbidities, the association between TTH and PD remained statistically significant (adjusted HR = 1.37, 95% CI = 1.19-1.57). The TTH group had a higher risk of PD than the non-TTH group did, regardless of subjects' sex, age, and comorbidity status. Conclusions: These findings demonstrate that patients diagnosed with TTH exhibit an increased risk of PD. Additional studies should investigate the potential shared pathophysiological mechanisms of TTH and PD. Clinicians should be aware that TTH is a potential risk factor for PD. PMID- 29416762 TI - Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models. AB - Acquired resistance to chemo-drugs remains a major obstacle to successful cancer therapy. Metformin, a well-documented drug for treating type II diabetes, was recently proposed as a novel agent for tumor treatment. In this study, we found that metformin suppressed MCF7/ADR, a doxorubicin-resistant breast cancer cell line, and acted synergistically with doxorubicin by reversing drug-resistant phenotypes both in vitro and in vivo. Metformin alone dose-dependently inhibited tumor growth, especially the stressful tumor microenvironment of glucose deficiency, and the cytotoxicity of metformin was markedly enhanced by increasing ROS production and ATP depletion. In addition, we found that metformin showed synergistic activity with doxorubicin against MCF7/ADR. Metformin increased nuclear doxorubicin accumulation and overcame drug resistance by down-regulating drug-resistant genes such as P-glycoprotein (Pgp). Metformin alone markedly inhibited MCF7/ADR tumor xenografts and demonstrated synergistic activity with doxorubicin in vivo by eliminating Ki67-positive cancer cells. In addition, metformin suppressed Pgp expression in vivo. In conclusion, our results suggested that metformin could potentially be used in the treatment of chemo-resistant tumors and could restore doxorubicin sensitivity. PMID- 29416763 TI - Dysregulation of YAP by the Hippo pathway is involved in intervertebral disc degeneration, cell contact inhibition, and cell senescence. AB - The Hippo pathway plays important roles in wound healing, tissue repair and regeneration, and in the treatment of degenerative diseases, by regulating cell proliferation and apoptosis in mammals. Intervertebral disc degeneration (IDD) is one of the major causes of low back pain, a widespread issue associated with a heavy economic burden. However, the mechanism underlying how the Hippo pathway regulates IDD is not well understood. Here, we demonstrate that the Hippo pathway is involved in natural IDD. Activation and dephosphorylation of yes-associated protein (YAP) were observed in younger rat discs, and decreased gradually with age. Surprisingly, Hippo pathway suppression was accompanied by overexpression of YAP, caused by acute disc injury, suggesting a limited ability for self-repair in IDD. We also demonstrated that YAP is inhibited by cell-to-cell contact via the Hippo pathway in vitro. Phosphorylation by large tumor suppressor kinases 1/2 (LATS1/2) led to cytoplasmic translocation and inactivation of YAP. YAP dephosphorylation was mainly localized in the nucleus and regulated by the Hippo pathway, whereas YAP dephosphorylation occurred in the cytoplasm and was associated with nucleus pulposus cell (NPC) senescence. Moreover, NPCs were transfected with shYAP and it accelerates the premature senescence of cells by interfered Hippo pathway through YAP. Therefore, our results indicate that the Hippo pathway plays an important role in maintaining the homeostasis of intervertebral discs and controlling NPC proliferation. PMID- 29416764 TI - Characterization of the effects of defined, multidimensional culture conditions on conditionally reprogrammed primary human prostate cells. AB - The inability to propagate human prostate epithelial cells indefinitely has historically presented a serious impediment to prostate cancer research. The conditionally reprogrammed cell (CRC) approach uses the combination of irradiated J2 mouse fibroblasts and a Rho kinase inhibitor such as Y27632 to support the continuous culture of cells derived from most epithelial tissues, including the prostate. Due to their rapid establishment and overall ease of use, CRCs are now widely used in a variety of basic and preclinical settings. In addition, CRCs were successfully used to clinically treat respiratory papillomatosis. Although both normal and tumor-derived prostate CRCs have been used to study the basic biology of prostate cancer and to test new therapies, certain limitations exist. We have previously reported that prostate CRCs form functional prostate glands when implanted under the mouse renal capsule. However in conventional culture, the prostate CRCs exist in an adult stem-like, transient amplifying state and consequently do not adequately recapitulate several important features of a differentiated prostate epithelium. To address these limitations, we previously described a transwell dish-based model that supported the culturing of prostate CRCs and the collection of cells and cell extracts for molecular and genetic analyses. Using normal and tumor-derived prostate CRCs, we describe the combined effects of the multi-dimensional transwell platform and defined culture media on prostate cellular proliferation, differentiation and signaling. PMID- 29416765 TI - Elevated level of D-dimer increases the risk of stroke. AB - The aim of this study was to systematically evaluate the association between D dimer level and the risk of stroke through performing a meta-analysis. PubMed, Web of Science, EMBASE and Cochrane Library were searched for potentially eligible literature. Prospective observational studies or case-control studies were included. The study characteristics and relevant data were extracted. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to estimate the association between D-dimer level and the risk of stroke. Seven prospective studies with 22,207 patients and three case-control studies with 2,248 patients were included. For the prospective studies, the pooled HRs of higher D-dimer level for all types of stroke, ischemic stroke and hemorrhagic stroke were 1.55 (95% CI, 1.28- 1.87), 1.62 (95% CI, 1.18-2.22) and 1.30 (95% CI, 0.63-2.68), respectively. The pooled HRs per SD increase in log D-dimer for all types of stroke, ischemic stroke and hemorrhagic stroke were 1.16 (95% CI, 1.06 1.26), 1.11 (95% CI, 1.03-1.21) and 1.11 (95% CI, 0.95-1.30), respectively. For the case-control studies, the pooled OR of higher D-dimer level for acute ischemic stroke was 2.06 (95% CI, 1.08-3.96). No significant publication bias was found in the meta-analysis. In conclusion, our results suggested that higher D dimer level was associated with higher risk of stroke, especially ischemic stroke. PMID- 29416767 TI - The prevalence and association of chronic kidney disease and diabetes in liver cirrhosis using different estimated glomerular filtration rate equation. AB - Background: Chronic kidney disease (CKD) in cirrhosis is one of the dreaded complications associated with a steep rise in mortality and morbidity, including diabetes. There are limited data on the prevalence of CKD and the association with diabetes in outpatients with cirrhosis. Methodology: This is a cross sectional study of 7,440 adult liver cirrhosis patients enrolled from August 2001 to April 2010 in a medical center. Case control matching by age and sex with 1,967 pairs, and conditional logistic regression for odds of diabetes was analyzed using adjusted model. Results: CKD was present in 46.0%, 45.7% and 45.6% of the study population using the MDRD-6, CKD-EPI and MDRD-4 estimated glomerular filtration rate (eGFR) equations, respectively. Using a conditional logistic regression model after adjusting for other risk factors, odds for diabetes increased significantly compared with non-CKD in CKD stage 3 to 5 (stage 3~5) based on MDRD-6-adjusted model, ORs were: stage 3~5, 2.34 (95% CI, 1.78-3.01); MDRD-4-adjusted model, ORs were: stage 3~5, 8.51 (95% CI, 5.63-11.4); CKD-EPI adjusted model, ORs were: stage 3~5, 8.61 (95% CI, 5.13-13.9). Conclusion: In cirrhosis patients, prevalence of diabetes was higher in patients with advanced stage of CKD. For patients with cirrhosis, patients with CKD stages 3~5 defined by MDRD-4, MDRD-6, and CKD-EPI eGFR equations had increased risk for diabetes. More severe cirrhosis, indicated by the Child-Turcott-Pugh classification was also accompanied by an increased risk for diabetes. PMID- 29416766 TI - Cell surface expression of nucleolin mediates the antiangiogenic and antitumor activities of kallistatin. AB - Kallistatin is a unique serine proteinase inhibitor and heparin-binding protein. A previous study conducted by our group indicated that kallistatin has antiangiogenic and antitumoral activities. In the present study, we report that kallistatin specifically binds to membrane surface-expressed nucleolin with high affinity. Antibody-mediated neutralization or siRNA-induced nucleolin knockdown results in loss of kallistatin suppression of endothelial cell proliferation and migration in vitro and tumor angiogenesis and growth in vivo. In addition, we show that kallistatin is internalized and transported into cell nuclei of endothelial cells via nucleolin. Within the nucleus, kallistatin inhibits the phosphorylation of nucleolin, which is a critical step required for cell proliferation. Thus, we demonstrate that nucleolin is a novel functional receptor of kallistatin that mediates its antiangiogenic and antitumor activities. These findings provide mechanistic insights into the inhibitory effects of kallistatin on endothelial cell growth, tumor cell proliferation, and tumor-related angiogenesis. PMID- 29416768 TI - Variants in the APOB gene was associated with Ischemic Stroke susceptibility in Chinese Han male population. AB - Background: Stroke is an extremely complicated disease caused by multiple factors. Epidemiological studies have shown that genetic factors contribute to the pathogenesis of stroke. There is still little research on the effect of ApoB gene on stroke in Chinese Han population. The purpose of our research was to explore the effect of ApoB gene polymorphism on the genetic susceptibility to Ischemic Stroke in Chinese Han male population. Materials and methods: 7 polymorphisms in ApoB gene were selected and genotyped using Sequenom MassARRAY in 325 ischemic stroke male patients and 399 healthy male controls in Chinese Han population. The association between ApoB gene and genetic susceptibility to Ischemic Stroke was performed by the chi2 test, genetic model analysis and haplotype analysis. Results: In the allele model, ApoB rs1042034 "T" allele and rs673548 "G" allele increased the risk of the Ischemic Stroke (rs1042034: OR=1.29, 95%CI: 1.02-1.63, p=0.030; rs673548: OR=1.28, 95%CI: 1.02-1.62, p=0.034). Logistic regression analysis found that ApoB rs1042034 and rs673548 increased the risk of Ischemic Stroke in the log-additive model, the odds of having Ischemic Stroke would be 1.28-fold and 1.27-fold with the variant allele, respectively. We also found that the risk of individuals carrying the ApoB rs693 "AA-AG" genotype had Ischemic Stroke risk of 1.52-fold of carrying "GG" genotype in the dominant model. The haplotype analysis shown that "TAG" haplotype raised the risk of Ischemic Stroke (OR=1.52, 95%CI: 1.02-2.27, p=0.0042). Conclusion: The polymorphisms of the ApoB gene may affect Ischemic Stroke occurrence. PMID- 29416769 TI - Roles of MALAT1 in development and migration of triple negative and Her-2 positive breast cancer. AB - Background: As a type of new targets for prognosis of malignancies, long non coding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcription 1) is associated with proliferation and metastatic abilities of several malignancies. However, its relations to development and migration of triple negative and human epidermal growth factor receptor 2 (Her-2) positive breast cancers haven't been reported. Objectives: In this paper, we aimed to discuss how MALAT1 is connected with and affects proliferation and invasion abilities of cells in Her-2 positive and triple-negative breast cancers (TNBC). Methods: The expression of MALAT1 in clinical samples with TNBC and Her-2 positive breast cancers was tested by qRT PCR. The statistical analysis was performed to unveil the potential relationships between the expression of MALAT1 and prognostic factors of breast cancer such as OS (overall survival), RFS (relapse-free survival), number of metastatic lymph nodes and pTNM staging in patients with TNBC or Her-2 positive breast cancer. MALAT1 and XBP1 were knockdown respectively in Her-2 positive cell line MDA-MB 231, and MALAT1 and Her-2 were knockdown respectively in TNBC cell line MDA-MD 435 using siRNA. The alterations of expressions of MALAT1 and related genes were detected by qRT-PCR in two breast cancer cell lines. The changes of proliferation abilities in two cell lines were observed using CCK8 assays. Furthermore, transwell assays were performed to detect changes to invasion abilities of the cells. Results: The expression of MALAT1 in triple negative and Her-2 positive breast cancers was positively correlated to the number of metastatic lymph nodes in patients with breast cancer. MALAT1 promotes proliferation and invasion abilities of breast cancer cells through XBP1 (X-box binding protein 1)-HIF (hypoxia-inducible factor)-1alpha pathway in MDA-MB-231 and through Her-2 pathway in MDA-MD-435. Moreover, MALAT1 could possibly be involved in regulation of MYC gene and CD47 (an immune checkpoint gene) in both cell lines. Conclusions: Our study suggested that MALAT1 is a core signaling molecule for promoting development and migration of triple negative and Her-2 positive breast cancers. It would be employed as common markers for prognosis of the two types of breast cancer mentioned above and potential targets for treating them. PMID- 29416770 TI - HPRT1 activity loss is associated with resistance to thiopurine in ALL. AB - Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Thiopurine is a widely used drug in the maintaining treatment of ALL. After a period of chemotherapy, 20% of pediatric patients and over 50% of adult patients will relapse. To investigate the mechanisms of drug resistance in vitro, we established the thiopurine resistant cell lines Reh-6MPR (6-MP Resistant cell) and Reh-6TGR (6-TG Resistant cell) by stepwise selection of the ALL cell line Reh. Cell viability assay revealed that 6MPR and 6TGR cells were almost 1000-fold more resistant to thiopurine comparing with the control Reh cells, and thiopurine conversion was significantly impaired in the resistant cells. Mechanistically, a same novel hypoxanthine phosphoribosyl transferase 1 (HPRT1) mutation c.495_496insA (p.V165fs) was found by whole exome sequencing in both resistant cells. The HPRT1 mutation dramaticly decreased the production of [13C5,15N4]-IMP from [13C5,15N4] hypoxanthine (HX), showed a loss-of-funciton mechanism. Notably, re-expression the wildtype HPRT1 in Reh-6MPR cell can reverse the drug resistance and thiopurine conversion in Reh-6MPR cells. These results highlight the importance of HPRT1's activity in thiopurine resistance. PMID- 29416771 TI - Menopause and adipose tissue: miR-19a-3p is sensitive to hormonal replacement. AB - Tissue-specific effects of 17beta-estradiol are delivered via both estrogen receptors and microRNAs (miRs). Menopause is known to affect the whole-body fat distribution in women. This investigation aimed at identifying menopause- and hormone replacement therapy (HRT)-associated miR profiles and miR targets in subcutaneous abdominal adipose tissue and serum from the same women. A discovery phase using array technology was performed in 13 women, including monozygotic twin pairs discordant for HRT and premenopausal young controls. Seven miRs, expressed in both adipose tissue and serum, were selected for validation phase in 34 women from a different cohort. An age/menopause-related increase of miRs-16 5p, -451a, -223-3p, -18a-5p, -19a-3p,-486-5p and -363-3p was found in the adipose tissue, but not in serum. MiR-19a-3p, involved in adipocyte development and estrogen signaling, resulted to be higher in HRT users in comparison with non users. Among the identified targets, AKT1, BCL-2 and BRAF proteins showed lower expression in both HRT and No HRT users in comparison with premenopausal women. Unexpectedly, ESR1 protein expression was not modified although its mRNA was lower in No HRT users compared to premenopausal women and HRT users. Thus, both HRT and menopause appear to affect adipose tissue homeostasis via miR-mediated mechanism. PMID- 29416772 TI - Identification of a novel MYO7A mutation in Usher syndrome type 1. AB - Usher syndrome (USH) is an autosomal recessive disease characterized by deafness and retinitis pigmentosa. In view of the high phenotypic and genetic heterogeneity in USH, performing genetic screening with traditional methods is impractical. In the present study, we carried out targeted next-generation sequencing (NGS) to uncover the underlying gene in an USH family (2 USH patients and 15 unaffected relatives). One hundred and thirty-five genes associated with inherited retinal degeneration were selected for deep exome sequencing. Subsequently, variant analysis, Sanger validation and segregation tests were utilized to identify the disease-causing mutations in this family. All affected individuals had a classic USH type I (USH1) phenotype which included deafness, vestibular dysfunction and retinitis pigmentosa. Targeted NGS and Sanger sequencing validation suggested that USH1 patients carried an unreported splice site mutation, c.5168+1G>A, as a compound heterozygous mutation with c.6070C>T (p.R2024X) in the MYO7A gene. A functional study revealed decreased expression of the MYO7A gene in the individuals carrying heterozygous mutations. In conclusion, targeted next-generation sequencing provided a comprehensive and efficient diagnosis for USH1. This study revealed the genetic defects in the MYO7A gene and expanded the spectrum of clinical phenotypes associated with USH1 mutations. PMID- 29416773 TI - Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma. AB - Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile. We investigated the effect of the novel MDM2 small molecular inhibitor, DS-3032b, on viability, proliferation, senescence, migration, cell cycle arrest and apoptosis in a panel of six neuroblastoma cell lines with different TP53 and MYCN genetic backgrounds, and assessed efficacy in a murine subcutaneous model for high-risk neuroblastoma. Re-analysis of existing expression data from 476 primary neuroblastomas showed that high-level MDM2 expression correlated with poor patient survival. DS-3032b treatment enhanced TP53 target gene expression and induced G1 cell cycle arrest, senescence and apoptosis. CRISPR-mediated MDM2 knockout in neuroblastoma cells mimicked DS-3032b treatment. TP53 signaling was selectively activated by DS-3032b in neuroblastoma cells with wildtype TP53, regardless of the presence of MYCN amplification, but was significantly reduced by TP53 mutations or expression of a dominant-negative TP53 mutant. Oral DS-3032b administration inhibited xenograft tumor growth and prolonged mouse survival. Our in vitro and in vivo data demonstrate that DS-3032b reactivates TP53 signaling even in the presence of MYCN amplification in neuroblastoma cells, to reduce proliferative capacity and cause cytotoxicity. PMID- 29416775 TI - The DNA methyl-transferase protein DNMT1 enhances tumor-promoting properties of breast stromal fibroblasts. AB - The activation of breast stromal fibroblasts is a crucial step toward tumor growth and spread. Therefore, it is extremely important to understand the molecular basis of this activation and determine the molecules and the mechanisms responsible for its sustainability. In the present report we have shown that the DNA methyl-transferase protein DNMT1 is critical for the activation of breast stromal fibroblasts as well as the persistence of their active status. Indeed, we have first revealed DNMT1 up-regulation in most cancer-associated fibroblasts relative to their corresponding adjacent normal fibroblasts. This effect resulted from HuR-dependent stabilization of the DNMT1 mRNA. Furthermore, ectopic expression of DNMT1 activated primary normal breast fibroblasts and promoted their pro-carcinogenic effects, both in vitro and in orthotopic tumor xenografts. By contrast, specific DNMT1 knockdown normalized breast myofibroblasts and repressed their cancer-promoting properties. These effects were sustained through inhibition of the IL-6/STAT3/NF-kappaB epigenetic cancer/inflammation positive feedback loop. Furthermore, we have shown that DNMT1-related activation of breast fibroblasts is mediated through upregulation of the RNA binding protein AUF1, which is also part of the loop. The present data demonstrate the critical function of DNMT1 in breast cancer-related sustained activation of breast stromal fibroblasts. PMID- 29416774 TI - Flow cytometric characterization of acute leukemia reveals a distinctive "blast gate" of murine T-lymphoblastic leukemia/lymphoma. AB - Immunophenotypic analysis using multiparameter flow cytometry is an indispensable tool for diagnosis and management of acute leukemia. Mouse models have been widely used for medical research for more than 100 years and are indispensable for leukemia research. However, immunophenotypic analysis of murine leukemia was not always performed in published studies, and blast gating for isolation of blasts was shown only in very few studies. No systemic characterization of all types of murine acute leukemia in large cohorts by flow cytometry has been reported. In this study, we used flow cytometry to comprehensively characterize murine acute leukemia in a large cohort of mice. We found that murine T lymphoblastic leukemia/lymphoma (T-ALL) exhibits a distinctive "blast gate" (CD45bright) with CD45/side scatter gating that differs from the "blast gate" (CD45dim) of human T-ALL. By contrast, murine B-lymphoblastic leukemia and acute myeloid leukemia show the same blast region (CD45dim) as human leukemia. Using blast cell gating, we for first time detected T-ALL development in FLT3-ITD knock in mice (incidence: 23%). These leukemic cells were selectively killed by the FLT3 inhibitors crenolanib and midostaurin in vitro. These data suggest that FLT3 ITD plays a potential role in the pathogenesis of T-ALL and that FLT3-ITD inhibition is a therapeutic option in the management of patients with T-ALL. Our gating strategy for immunophenotypic analysis can be used for leukemogenesis and preclinical gene therapy studies in mice and may improve the quality of such analyses. PMID- 29416776 TI - Monoclonal gammopathy of renal significance (MGRS) increases the risk for progression to multiple myeloma: an observational study of 2935 MGUS patients. AB - Purpose: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignancy preceding multiple myeloma (MM) or related disorders. In MGUS, renal impairment caused by deposition of the monoclonal immunoglobulins or free light-chains monoclonal gammopathy of renal significance (MGRS) is often associated with high morbidity and mortality. We analysed the prevalence of renal impairment, clinical features and the long-term outcome in 2935 patients with MGUS. Methods: Between 1/2000 and 8/2016, 2935 adult patients with MGUS were identified in our database. Results: In 44/2935 (1.5%) patients MGRS was diagnosed. In MGRS patients, significantly more progressions to MM were observed than in MGUS patients (18% vs. 3%; P<0.001). MGRS patients showed a higher risk for progression (HR 3.3 [1.5-7.4]) in the Cox model. Median time to progression was 23 years for MGUS and 18.8 years for MGRS patients. Corresponding progression rate was 8.8 [7.2-10.7] per 1000 patient-years (py) for MGUS patients and 30.6 [15.3-61] for the MGRS group. Risk for progression within the first year after diagnosis was 1% [0.6-1.4] in the MGUS group and 10% [4-29] among MGRS patients. Conclusion: The significantly higher risk for progression to MM means MGRS patients should be monitored carefully and treated in a specialized centre. PMID- 29416777 TI - Staging of rat liver fibrosis using monoexponential, stretched exponential and diffusion kurtosis models with diffusion weighted imaging- magnetic resonance. AB - Early diagnosis of liver fibrosis is important. The objective of this study was to explore the characteristics and to assess the accuracy of monoexponential, stretched exponential models (SEM), and diffusion kurtosis imaging (DKI) with diffusion-weighted imaging (DWI)-magnetic resonance imaging (MRI) in various stages of liver fibrosis in two standard rat models induced by carbon tetrachloride (CCl4) and biliary duct ligation (BDL). Parameters (ADC, Dapp, Kapp, DDC, alpha) were measured with a 3.0T MRI. Liver fibrosis stages (F0-F4) were defined by METAVIR scoring. Parameters (ADC, Dapp, DDC) were found to be negatively associated (r: -0.675~-0.789; P<0.05) with advancement of fibrosis stage. The analysis of receiver operating characteristic (ROC) curves illustrated that the areas under the curves (AUC) for ADC, Dapp, and DDC were 0.687~0.957, 0.805~0.938 and 0.876~1.000, respectively. The study showed that (ADC, Dapp, Kapp, DDC, alpha) from various diffusion models reflected pathological and physiological tissue changes. We conclude that SEM and DKI may provide more accurate information about diffusion, and non-Gaussian diffusion analysis may be a complementary tool for the assessment of liver fibrosis. PMID- 29416778 TI - Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1. AB - Despite advances in colon cancer treatments, resistance and recurrence remain a significant challenge in treating patients. Novel therapeutic strategies are in urgent need to overcome resistance and improve patient outcomes. MicroRNA based therapeutics have potential to help combat resistance. In this study, we have shown that low miR-15a expression correlates with poor patient prognosis. We have demonstrated the therapeutic potential of miR-15a in colon cancer. miR-15a inhibits several important genes (BCL2, BMI1, YAP1 and DCLK1), decreasing cancer progression and resistance. Additionally, by replacing uracil in miR-15a with 5 fluorouracil, we created a novel miR-15a mimic with enhanced therapeutic potential. This mimic maintains target specificity and is more potent than unmodified miR-15a in vitro and inhibits colon tumor metastasis in vivo. This mimic has great potential for therapeutic development for treating colon cancer patients. This novel modification has potential to advance the development of other microRNA based therapeutics beyond miR-15a. PMID- 29416779 TI - The sphingosine kinase 2 inhibitor ABC294640 inhibits cervical carcinoma cell growth. AB - ABC294640 is a specific sphingosine kinase 2 (SphK2) inhibitor. The anti-cervical carcinoma activity by ABC294640 was tested in this study. ABC294640 inhibited in vitro growth of the established (C33A and HeLa lines) and primary human cervical carcinoma cells. The SphK2 inhibitor also induced G1-S arrest and apoptosis in cervical carcinoma cells. It was yet non-cytotoxic to SphK2-low human cervical epithelial cells. ABC294640 inhibited SphK activation, causing sphingosine-1 phosphate depletion, signal transducer and activator of transcription 3 in activation and ceramide production. Bcl-2 is a key resistance factor of ABC294640. Pharmacological Bcl-2 inhibition or Bcl-2 shRNA potentiated ABC294640 induced C33A cell growth inhibition and apoptosis. On the other hand, exogenous over-expression of Bcl-2 attenuated ABC294640's cytotoxicity against C33A cells. In vivo, ABC294640 administration inhibited C33A xenograft tumor growth in mice. Co-administration of the Bcl-2 inhibitor GDC-0199 further potentiated ABC294640's anti-tumor activity. Together, we suggest that ABC294640 might have translational value for the treatment of human cervical carcinoma. PMID- 29416780 TI - LncRNA NEAT1 enhances the radio-resistance of cervical cancer via miR-193b 3p/CCND1 axis. AB - LncRNAs have become a hot topic in various cancer-related researches. Radio resistance is a great threat for cancer therapy. However, how lncRNAs affect the radio-resistance in cervical cancer is masked. As for our paper, it was discovered that NEAT1 was highly expressed in cervical cancer tissues and non sensitive tissues as well as radio-resistant cell lines. And the overexpression of NEAT1 accelerated proliferation, while the knockdown of NEAT1 had the opposite result. The effect of NEAT1 on cell proliferation was dependent on the dose of ionizing radiation. And the silence of NEAT1 also caused cell cycle arrest in G0/G1 phase, and triggered more apoptosis, indicating the oncogenic role of NEAT1 in cervical cancer. Next, mechanistic assays affirmed that NEAT1 could function as a ceRNA to regulate cyclin D1 through sponging miR-193b-3p in cervical cancer. Rescue assays were employed to validate that miR-193b-3p and cyclin D1 could inhibit NEAT1-mediated suppressive effect on proliferation, and its stimulative effect on cell cycle arrest and apoptosis. In general, this article disclosed that NEAT1 could facilitate the radio-resistance of cervical cancer via competitively binding miR-193b-3p to up-regulate the expression of cyclin D1. PMID- 29416781 TI - Gene master regulators of papillary and anaplastic thyroid cancers. AB - We hypothesize that distinct cell phenotypes are governed by different sets of gene master regulators (GMRs) whose strongly protected (by the homeostatic mechanisms) abundance modulates most cell processes by coordinating the expression of numerous genes from the corresponding functional pathways. Gene Commanding Height (GCH), a composite measure of gene expression control and coordination, is introduced to establish the gene hierarchy in each phenotype. If the hypothesis is true, than one can selectively destroy cancer nodules from a heterogeneous tissue by altering the expression of genes whose GCHs are high in cancer but low in normal cell phenotype. Here, we test the hypothesis and show its utility for the thyroid cancer (TC) gene therapy. First, we prove that malignant and cancer free surrounding areas of a surgically removed papillary TC (PTC) tumor are governed by different GMRs. Second, we show that stable transfection of a gene induces larger transcriptomic alterations in the cells where it has higher GCH than in other cells. For this, we profiled the transcriptomes of the papillary BCPAP and anaplastic 8505C TC cell lines before and after stable transfection with NEMP1, DDX19B, PANK2 or UBALD1. The four genes were selected to have similar expression levels but significantly different GCH scores in the two cell lines before transfection. Indeed, each of the four genes triggered larger alterations in the cells where they had larger GCH. Our results prove the feasibility of a personalized gene therapy approach that selectively targets the cancer cells from a tissue. PMID- 29416782 TI - Nomogram predicting pulmonary metastasis of hepatocellular carcinoma after liver transplantation. AB - A novel prognostic nomogram predicting post-transplant pulmonary metastasis was established with a primary cohort of 308 HCC patients who received liver transplantation between 2007 and 2011 at Ren Ji Hospital. The C-indexes for predicting pulmonary metastasis was 0.85. The calibration curves fitted well between the predicted and actual outcomes. The decision curve analysis indicated that our nomogram was the optimal decision-making strategy for PM prediction compared to Milan, University of California San Franscisco, and up-to-seven criteria. These results were further validated by data from 103 patients who underwent liver transplantation between 2011 and 2012 at the same institution. In conclusion, our nomogram could be used as an effective tool to predict PM after liver transplantation. PMID- 29416783 TI - Study on polymorphisms in CHRNA5/CHRNA3/CHRNB4 gene cluster and the associated with the risk of non-small cell lung cancer. AB - CHRNA5/CHRNA3/CHRNB4 gene cluster is located on chromosome 15q25.1 and was reported to be associated with risk of lung cancer. So far, the effect of three single nucleotide polymorphisms rs6495309, rs8040868, rs1948 in this gene cluster was unclear about lung cancer risk. The aim of the present study was to evaluate the associations of rs6495309, rs8040868, rs1948 polymorphism, smoking exposure and the interaction with non-small cell lung cancer risk in Chinese population. In this hospital-based case-control study, 306 lung cancer patients and 306 cancer-free controls were interviewed to collect demographic data and exposure status of smoking, and then donate 2ml venous blood which was used to be genotyped by Taqman allelic discrimination method. Our study found that subjects carrying rs1948 CT genotype stated to be a risk factor in Chinese Han population (adjusted OR = 1.594, 95% CI = 1.066-2.383, P = 0.023) and in non-smoking population (adjusted OR = 1.896, 95%CI = 1.069-3.362, P = 0.029). rs8040868 CC genotype indicated a higher risk for lung cancer in non-smokers in a recessive model (adjusted OR = 2.496, 95%CI = 1.044-5.965, P = 0.040) and in age-based stratified analysis (age <= 60, adjusted OR = 4.213, 95%CI = 1.062-16.708, P = 0.041). All smoking interaction were positive in the multiplicative interaction of the SNPs and smoking status (-/+) compared with recessive model. Overall, these finding suggested that rs1948(C > T) and rs8040868(T > C) could be meaningful as genetic markers for lung cancer risk in Chinese Han population. PMID- 29416785 TI - Predictors of lymphovascular invasion identified from pathological factors in Chinese patients with breast cancer. AB - This study aimed to evaluate correlations between lymphovascular invasion (LVI) and the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2), Ki-67, CK5/6, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), E-cadherin, BCL11A and P53 in invasive breast cancer and to identify predictors of LVI based on these pathological factors. In all, 392 paraffin-embedded tissues from consecutive patients with primary operable invasive breast cancer were included. Immunohistochemistry (IHC) was retrospectively performed using a tissue microarray (TMA) of the paraffin-embedded tissues. LVI-positive rates were compared using the chi2 test. Correlations between pathological factors were assessed using Spearman's test. Binary logistic regression was employed in multivariate analyses of statistically significant factors. The results showed that LVI positivity was significantly higher in patients with HER-2-positive expression or high Ki-67 expression. HER-2 expression was weakly positively correlated with Ki-67 expression. HER-2-positive expression and high Ki-67 expression were found to be risk factors for LVI, and associations between LVI and other pathological factors were not significant. Therefore, HER-2-positive expression and high Ki-67 expression are predictors of LVI, whereas the expression of ER, PR, CK5/6, EGFR, VEGF, E-cadherin, BCL11A and P53 is not associated with LVI in invasive breast cancer. PMID- 29416784 TI - Differential expression profile of CXCR3 splicing variants is associated with thyroid neoplasia. Potential role in papillary thyroid carcinoma oncogenesis? AB - Papillary thyroid cancer (PTC) is the most prevalent endocrine neoplasia. The increased incidence of PTC in patients with thyroiditis and the frequent immune infiltrate found in PTC suggest that inflammation might be a risk factor for PTC development. The CXCR3-ligand system is involved in thyroid inflammation and CXCR3 has been found upregulated in many tumors, suggesting its pro-tumorigenic role under the inflammatory microenvironment. CXCR3 ligands (CXCL4, CXCL9, CXCL10 and CXCL11) trigger antagonistic responses partly due to the presence of two splice variants, CXCR3A and CXCR3B. Whereas CXCR3A promotes cell proliferation, CXCR3B induces apoptosis. However, the relation between CXCR3 variant expression with chronic inflammation and PTC development remains unknown. Here, we characterized the expression pattern of CXCR3 variants and their ligands in benign tumors and PTC. We found that CXCR3A and CXCL10 mRNA levels were increased in non-metastatic PTC when compared to non-neoplastic tissue. This increment was also observed in a PTC epithelial cell line (TPC-1). Although elevated protein levels of both isoforms were detected in benign and malignant tumors, the CXCR3A expression remained greater than CXCR3B and promoted proliferation in Nthy-ori-3 1 cells. In non-metastatic PTC, inflammation was conditioning for the CXCR3 ligands increased availability. Consistently, CXCL10 was strongly induced by interferon gamma in normal and tumor thyrocytes. Our results suggest that persistent inflammation upregulates CXCL10 expression favoring tumor development via enhanced CXCR3A-CXCL10 signaling. These findings may help to further understand the contribution of inflammation as a risk factor in PTC development and set the basis for potential therapeutic studies. PMID- 29416786 TI - Identification of differentially expressed genes in human breast cancer cells induced by 4-hydroxyltamoxifen and elucidation of their pathophysiological relevance and mechanisms. AB - While tamoxifen (TAM) is used for treating estrogen receptor (ER)a-positive breast cancer patients, its anti-breast cancer mechanisms are not completely elucidated. This study aimed to examine effects of 4-hydroxyltamoxifen (4-OH-TAM) on ER-positive (ER+) breast cancer MCF-7 cell growth and gene expression profiles. MCF-7 cell growth was inhibited by 4-OH-TAM dose-dependently with IC50 of 29 MUM. 332 genes were up-regulated while 320 genes were down-regulated. The mRNA levels of up-regulated genes including STAT1, STAT2, EIF2AK2, TGM2, DDX58, PARP9, SASH1, RBL2 and USP18 as well as down-regulated genes including CCDN1, S100A9, S100A8, ANXA1 and PGR were confirmed by quantitative real-time PCR (qRT PCR). In human breast tumor tissues, mRNA levels of EIF2Ak2, USP18, DDX58, RBL2, STAT2, PGR, S1000A9, and CCND1 were significantly higher in ER+- than in ER- breast cancer tissues. The mRNA levels of EIF2AK2, TGM2, USP18, DDX58, PARP9, STAT2, STAT1, PGR and CCND1 were all significantly higher in ER+-tumor tissues than in their corresponding tumor-adjacent tissues. These genes, except PGR and CCND1 which were down-regulated, were also up-regulated in ER+ MCF-7 cells by 4 OH-TAM. Total 14 genes mentioned above are involved in regulation of cell proliferation, apoptosis, cell cycles, and estrogen and interferon signal pathways. Bioinformatics analysis also revealed other novel and important regulatory factors that are associated with these genes and involved in the mentioned functional processes. This study has paved a foundation for elucidating TAM anti-breast cancer mechanisms in E2/ER-dependent and independent pathways. PMID- 29416787 TI - Upregulation of ALDH1B1 promotes tumor progression in osteosarcoma. AB - Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood and adolescence with poor prognosis. The mechanism underlying tumorigenesis and development of OS is largely unknown. ALDH1B1 has been reported to involve in many kinds of human cancers and functions as an oncogene, but the role of ALDH1B1 in OS has not been investigated comprehensively. In the present study, we aimed to examine clinical value and biological function of ALDH1B1 in OS. Firstly, we investigated the roles of ALDH1B1 on an OS tissue microarray (TMA) as well as two OS cohorts from GEO database. We found that ALDH1B1 was significantly up regulated in OS tissues and was independently associated with poor prognosis. Moreover, ALDH1B1 silencing could suppress the proliferation, migration, invasion in vitro and inhibit the growth of xenograft tumor and of OS cells in vivo. Additional, ALDH1B1 knockdown increased the apoptosis rate and lead to cell cycle arrest in G1 stage of OS cell in vitro. More importantly, the inhibition of ALDH1B1 expression could increase the sensitivity of OS cells to chemotherapy, which suggested that ALDH1B1 might be served as a therapeutic target to reverse drug resistance in chemotherapy in OS patients. Taken together, our founding suggested that ALDH1B1 contributes to OS tumor progression and drug resistance, which may represent a novel prognostic marker and potential therapeutic target for OS patients. PMID- 29416788 TI - Improved anti-tumor efficacy via combination of oxaliplatin and fibrin glue in colorectal cancer. AB - Colorectal cancer is very common worldwide and advanced colorectal cancer exhibited very poor clinical outcome. Oxaliplatin (OXP) is one of the principal chemotherapeutic agents in colorectal cancer treatment presenting impressive anti tumor ability, limited by adverse effect in clinical practice. Fibrin glue (FG) is a biocompatible formulation made of fibrinogen and thrombin, extensively used in surgery for hemostasis, tissue adhesion and sealing. In this study, FG was innovatively applied as OXP delivery system and results showed enhanced anti tumor performance in subcutaneous model and abdominal metastasis model of murine colorectal cancer compared with that of OXP used alone. It is revealed that combination of OXP and FG could increase activated CD8+ T cells, reduce regulatory T (Treg) cells and increase interferon-gamma (IFN-gamma). Furthermore, results showed promoted tumor apoptosis, decreased proliferation and inhibited tumor angiogenesis by OXP and FG combination. No obvious systemic toxicity was observed in this study. Finally, our findings provided basis for promising application of OXP and FG combination in colorectal cancer treatment. PMID- 29416789 TI - Significance of cyclin D1 overexpression in progression and radio-resistance of pediatric ependymomas. AB - Due to the limited efficacy of chemotherapy, the applications of adjuvant irradiation play an important role for ependymoma treatment. However, in the young ages, the resistance of residual and recurrent tumor, and long-term intellectual sequelae remain the major obstacles of radiotherapy. Understanding the mechanism of therapeutic failure caused by radio-resistance is, therefore, crucial in ependymoma treatment. Here we retrospectively analyze clinic pathological factors in 82 cases of ependymoma less than 20 years old and identify radio-resistant genes through gene expression microarray followed by qRT PCR validation and immunohistochemistry staining. Thirty-one out of 82 (37.8%) patients are under 3-year-old. The 10 years PFS and OS are 38% and 60%. Gross total resection is the single significant prognostic factor for longer 10 years PFS and OS in the multivariant analysis (p<0.05). According to the microarray analysis, CCND1 is up-regulated in supratentorial and infratentorial ependymomas and is associated with DNA repair. We demonstrated that 24 primary and 16 recurrent ependymomas were up-regulated, and 5 out of 7 paired samples exhibited higher CCND1 expression in recurrent tumors. We also found RAD51, another DNA repair gene, was up-regulated in supratentorial and infratentorial ependymomas. Knocking down CCND1 reduced cell proliferation and repressed several genes associated with S-phase and DNA repair. Homologous recombination activities of DNA repair were significantly decreased in CCND1-deficient cells while the level of gammaH2AX was increased after irradiation. In summary, these observations suggest a robust role of CCND1 in regulating cell proliferation and radio resistance in ependymomas, providing a potential therapeutic target for pediatric ependymomas. PMID- 29416791 TI - Combined use of preoperative lymphocyte counts and the post/preoperative lymphocyte count ratio as a prognostic marker of recurrence after curative resection of stage II colon cancer. AB - Purpose: Diagnostic markers for recurrence of colorectal cancer have not been established. The aim of the present study was to identify new diagnostic markers for recurrence after curative surgery of stage II colon cancer. Materials and Methods: In this study, the prognostic values of the preoperative lymphocyte count and the post/preoperative lymphocyte count ratio (PPLR) were evaluated in 142 patients with localized colon cancer treated with surgery at a single medical center. The associations of patient demographics, blood chemistry, and serum biochemical indices with recurrence-free survival (RFS) and cancer-specific survival (CSS) were examined by univariate and multivariate analyses. Results: Receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off values of the lymphocyte count and PPLR were, respectively, 1555.2/MUl and 1.151 for RFS. On univariate analysis, tumor depth of invasion, carbohydrate antigen 19-9 (CA19-9), and preoperative low lymphocyte count (<=1555.2/MUl) were all correlated with poorer RFS (p < 0.05). On multivariate analysis, T4, low lymphocyte count, and low PPLR were independent predictors of poor RFS. Furthermore, the patients were categorized into four categories based on preoperative lymphocyte count high/low and PPLR high/low. Patients with a low preoperative lymphocyte count and low PPLR had the poorest RFS and CSS compared to the other patients. Conclusion: The combination of the preoperative lymphocyte count and the PPLR appears to be a potential marker for predicting recurrence of stage II colon cancer. PMID- 29416790 TI - Dihydroartemisinin-regulated mRNAs and lncRNAs in chronic myeloid leukemia. AB - Chronic myelocytic leukemia (CML) is characterized by increased and unregulated growth of predominantly myeloid cells in the bone marrow, and accumulation of these cells in blood. We investigated the effects of an anti-malarial drug, dihydroartemisinin (DHA), on K562 CML cells. We identified 34 mRNAs and eight lncRNAs dysregulated following DHA treatment in pure and hemin-induced K562 cells. Up- or downregulation of these potential DHA targets increased with increasing DHA concentration. We also constructed and analyzed a DHA-related mRNA lncRNA regulation network in K562 cells, and found that four DHA-modulated mRNAs regulated by four lncRNAs participated in the steroid biosynthesis pathway. Some estrogen-related drugs, such as tamoxifen, shared common targets with DHA. We inferred that DHA exerted anti-cancer effects on K562 cells by influencing estrogen levels. Our findings indicate that DHA has potential not only as an anti malarial drug, but also as an anti-CML chemotherapeutic. PMID- 29416792 TI - CancerDiscover: an integrative pipeline for cancer biomarker and cancer class prediction from high-throughput sequencing data. AB - Accurate identification of cancer biomarkers and classification of cancer type and subtype from High Throughput Sequencing (HTS) data is a challenging problem because it requires manual processing of raw HTS data from various sequencing platforms, quality control, and normalization, which are both tedious and time consuming. Machine learning techniques for cancer class prediction and biomarker discovery can hasten cancer detection and significantly improve prognosis. To date, great research efforts have been taken for cancer biomarker identification and cancer class prediction. However, currently available tools and pipelines lack flexibility in data preprocessing, running multiple feature selection methods and learning algorithms, therefore, developing a freely available and easy-to-use program is strongly demanded by researchers. Here, we propose CancerDiscover, an integrative open-source software pipeline that allows users to automatically and efficiently process large high-throughput raw datasets, normalize, and selects best performing features from multiple feature selection algorithms. Additionally, the integrative pipeline lets users apply different feature thresholds to identify cancer biomarkers and build various training models to distinguish different types and subtypes of cancer. The open-source software is available at https://github.com/HelikarLab/CancerDiscover and is free for use under the GPL3 license. PMID- 29416793 TI - Dose- and time-dependence of the host-mediated response to paclitaxel therapy: a mathematical modeling approach. AB - It has recently been suggested that pro-tumorigenic host-mediated processes induced in response to chemotherapy counteract the anti-tumor activity of therapy, and thereby decrease net therapeutic outcome. Here we use experimental data to formulate a mathematical model describing the host response to different doses of paclitaxel (PTX) chemotherapy as well as the duration of the response. Three previously described host-mediated effects are used as readouts for the host response to therapy. These include the levels of circulating endothelial progenitor cells in peripheral blood and the effect of plasma derived from PTX treated mice on migratory and invasive properties of tumor cells in vitro. A first set of mathematical models, based on basic principles of pharmacokinetics/pharmacodynamics, did not appropriately describe the dose dependence and duration of the host response regarding the effects on invasion. We therefore provide an alternative mathematical model with a dose-dependent threshold, instead of a concentration-dependent one, that describes better the data. This model is integrated into a global model defining all three host mediated effects. It not only precisely describes the data, but also correctly predicts host-mediated effects at different doses as well as the duration of the host response. This mathematical model may serve as a tool to predict the host response to chemotherapy in cancer patients, and therefore may be used to design chemotherapy regimens with improved therapeutic outcome by minimizing host mediated effects. PMID- 29416794 TI - MELK is a novel therapeutic target in high-risk neuroblastoma. AB - Maternal embryonic leucine zipper kinase (MELK) is known to modulate intracellular signaling and control cellular processes. However, the role of MELK in oncogenesis is not well defined. In this study, using two microarray datasets of neuroblastoma (NB) patients, we identified that MELK expression is significantly correlated to poor overall survival, unfavorable prognosis, and high-risk status. We found that MELK is a direct transcription target of MYCN and MYC in NB, and MYCN increases MELK expression via direct promoter binding. Interestingly, knockdown of MELK expression significantly reduced the phosphorylation of target protein Retinoblastoma (pRb) and inhibited NB cell growth. Furthermore, pharmacological inhibition of MELK activity by small molecule inhibitor OTSSP167 significantly inhibited cell proliferation, anchorage independent colony formation, blocked cell cycle progression, and induced apoptosis in different NB cell lines including a drug-resistant cell line. Additionally, OTSSP167 suppressed NB tumor growth in an orthotopic xenograft mouse model. Overall, our data suggest that MELK is a novel therapeutic target for NB and its inhibitor OTSSP167 is a promising drug for further clinical development. PMID- 29416795 TI - Treatment-associated TP53 DNA-binding domain missense mutations in the pathogenesis of secondary gliosarcoma. AB - Background: Gliosarcoma is a rare variant of glioblastoma (GBM) that exhibits frequent mutations in TP53 and can develop in a secondary fashion after chemoradiation of a primary GBM. Whether temozolomide (TMZ)-induced mutagenesis of the TP53 DNA-binding domain (DBD) can drive the pathogenesis of gliosarcoma is unclear. Methods: We identified a case of a primary GBM that rapidly progressed into secondary gliosarcoma shortly after chemoradiation was initiated. Bulk tumor was collected and gliomasphere cultures derived from both the pre- and post treatment tumors. We performed targeted DNA sequencing and transcriptome analyses of the specimens to understand their phylogenetic relationship and identify differentially expressed gene pathways. Gliomaspheres from the primary GBM were treated with TMZ and then analyzed to compare patterns of mutagenesis in vivo and ex vivo. Results: The pre- and post-treatment tumors shared EGFR, CDKN2A, and PTEN mutations, but only the secondary gliosarcoma exhibited TP53 DBD missense mutations. Two mutations, R110C, and R175H, were identified, each in distinct clones. Both were base transitions characteristic of TMZ mutagenesis. Gene expression analysis identified increased JAK-STAT signaling in the gliosarcoma, together with reduced expression of microRNAs known to regulate epithelial mesenchymal transition. Ex vivo treatment of the GBM spheres with TMZ generated numerous variants in cancer driver genes, including TP53 and CDH1, which were mutated in the post-treatment tumor. Conclusions: TMZ-induced TP53 gain-of function mutations can have a driving role in secondary gliosarcoma pathogenesis. Analysis of variants identified in ex vivo TMZ-treated gliomaspheres may have utility in predicting GBM evolutionary trajectories in vivo during standard chemoradiation. PMID- 29416796 TI - CD44/CD24 and aldehyde dehydrogenase 1 in estrogen receptor-positive early breast cancer treated with tamoxifen: CD24 positivity is a poor prognosticator. AB - CD44+/CD24- or aldehyde dehydrogenase 1 (ALDH1) has been suggested as a potential marker for breast cancer stem cells. In the cohort of 819 patients with resected ER-positive breast cancer, the '5-year relapse group' within 5 years postsurgery during adjuvant tamoxifen treatment and the 'non-relapse group' longer than 9 years postsurgery were defined. Paraffin-embedded tumor tissues were available in 31 patients from 5-year relapse group and 68 from the non-relapse group. CD44/ CD24 and ALDH1 expression was evaluated by immunohistochemical staining. Phenotypes of CD44/CD24 were CD44+/CD24- in one patient (1%), CD44+/CD24+in one patient (1%), CD44-/CD24+ in 12 patients (12%), and CD44-/CD24- in 67 patients (68%). Four patients (4%) showed ALDH1-positivity. Due to the rarity of CD44 positivity or ALDH1-positivity, we dichotomized the patients into CD24-positive status (13%, 13/99 patients) and CD24-negative status (87%, 86/99 patients) only based on CD24 status, and only the status of CD24 was further analyzed. CD24 positivity was higher in the 5-year relapse group (32%) than in the non-relapse group (4%). CD24-positivity was associated with negative PR (P=0.026), higher N stage (P=0.029), and higher histologic grade (P=0.034). However, in the multivariate logistic regression adjusted for the known prognostic factors, CD24 positivity was still a significant predictive factor for 5-year relapse (hazard ratio=8.5; P=0.006). Our results indicated that the expression of CD24 was a significant poor prognostic factor in ER-positive early breast cancer treated with adjuvant tamoxifen. CD24 is worth further investigation as a novel biomarker for tamoxifen resistance beyond general aggressiveness of cancer cells. PMID- 29416797 TI - Hydrogen protects against liver injury during CO2 pneumoperitoneum in rats. AB - The aim of the current study was to identify the protective effect of hydrogen gas against liver injury during CO2 pneumoperitoneum. Rats were randomly divided into three groups: control group (C group), pneumoperitoneum group (P15 group) and hydrogen group (H2 group). Rats in the C group were subjected to anesthesia for 90 min. Rats in the P15 group received an abdominal insufflation of CO2 for 90 min at an intra-abdominal pressure of 15 mmHg. Rats in the H2 group received a hypodermic injection of hydrogen gas (0.2 mL/kg) and after 10 min they received an abdominal insufflation of CO2 for 90 min at an intra-abdominal pressure of 15 mmHg. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured to evaluate liver function. Malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) content were measured to evaluate oxidative stress. Nuclear factor E2-related factor 2 (Nrf2) and Nrf2 downstream target genes, apoptosis-related genes and inflammatory cytokine mRNA and protein expression were detected. Liver injury was detected under the microscope. Our results revealed that liver function, antioxidants content, inflammation and liver injury were improved after hydrogen preconditioning in H2 group compared with P15 group. Overall, our results revealed that subcutaneous hydrogen injection could exert a protective effect against liver injury during CO2 pneumoperitoneum through reducing oxidative stress, cell apoptosis and inflammatory cytokines release. PMID- 29416798 TI - RUNX2 promotes epithelial differentiation of ADSCs and burn wound healing via targeting E-cadherin. AB - Epithelial differentiation of adipose-derived stem cells (ADSCs) is mediated by sophisticated interactions of various molecular functions and biological processes, including transcriptional regulation. Runt-related transcription factor 2 (RUNX2) increases osteoblast and adipocyte differentiation of ADSCs. However, the role of RUNX2 in epithelial differentiation of ADSCs is unknown. We first showed that ADSCs possess the potential to differentiate into epithelial lineage. Then, we employed the effect of RUNX2 on epithelial differentiation of ADSCs. Our data showed that RUNX2 promoted epithelial differentiation of ADSCs. Overexpression or knockdown of RUNX2 resulted in increase or decrease of E cadherin expression, respectively. Abatement of E-cadherin in ADSCs attenuated RUNX2-activated epithelial conversion of ADSCs and epithelial markers cytokeratin 18 (CK18) and zonula occludens protein-1 (ZO-1). We also evaluated the effect of RUNX2 on burn wound healing in vivo. The wound re-epithelialization were accelerated by RUNX2. The wound closure indexs, demis regeneration and revascularization were all improved. Furthermore, RUNX2 binding directly to the E cadherin promoter region was characterized in ADSCs by chromatin immunoprecipitation (ChIP) and luciferase promoter reporter assays. Taken together, the study demonstrates the role of RUNX2 in epithelial differentiation of ADSCs and suggests that RUNX2 promotes E-cadherin expression, at least in part, through its direct binding to the promoter. PMID- 29416799 TI - Correlation among genetic variations of c-MET in Chinese patients with non-small cell lung cancer. AB - Background: The purpose of our research was to determine the correlation of amplification, protein expression and somatic mutation of c-MET in IIIb-IV stage NSCLC (Non-small cell lung cancer). We also explored correlation of c-MET variation with clinical outcome. Results: c-MET expression was observed in 28.6% (56/196) cases, and among those 13.8% (27/196) were shown to be FISH positive. Only 2.67% patients in this study carried the c-MET mutation. Cases with c-MET FISH positive were all IHC positive ,but in IHC positive cases, only half were FISH positive. Among patients with IHC2+ staining, 35.5% was FISH positive, while cases with IHC3+ staining,64% was FISH positive. Both protein expression and copy number of c-MET did not significantly correlate with clinical prognosis in these patients treated with EGFR-TKIs. Conclusions: IHC could be used as a preliminary screening method for c-MET copy number amplification and should be confirmed by FISH only in IHC positive case which facilitate selection of ALK or MET inhibitor therapy. Methods: c-MET gene copy number, protein expression and somatic mutation for exon 14 were detected by fluorescent- In-Situ-Hybridization (FISH), Immunohistochemistry (IHC), and Denaturing-High-Performance-Liquid-Chromatography (DHPLC), respectively, in 196 NSCLC patients. The relationship between c-MET abnormalities and clinical outcome of targeted therapy was analyzed by McNemar's test. PMID- 29416800 TI - Ultrasonic RF time series for early assessment of the tumor response to chemotherapy. AB - Ultrasound radio-frequency (RF) time series have been shown to carry tissue typing information. To evaluate the potential of RF time series for early prediction of tumor response to chemotherapy, 50MCF-7 breast cancer-bearing nude mice were randomized to receive cisplatin and paclitaxel (treatment group; n = 26) or sterile saline (control group; n = 24). Sequential ultrasound imaging was performed on days 0, 3, 6, and 8 of treatment to simultaneously collect B-mode images and RF data. Six RF time series features, slope, intercept, S1, S2, S3, and S4, were extracted during RF data analysis and contrasted with microstructural tumor changes on histopathology. Chemotherapy administration reduced tumor growth relative to control on days 6 and 8. Compared with day 0, intercept, S1, and S2 were increased while slope was decreased on days 3, 6, and 8 in the treatment group. Compared with the control group, intercept, S1, S2, S3, and S4 were increased, and slope was decreased, on days 3, 6, and 8 in the treatment group. Tumor cell density decreased significantly in the latter on day 3. We conclude that ultrasonic RF time series analysis provides a simple way to noninvasively assess the early tumor response to chemotherapy. PMID- 29416801 TI - Metabolomic alterations in invasive ductal carcinoma of breast: A comprehensive metabolomic study using tissue and serum samples. AB - Invasive ductal carcinoma (IDC) is the most common type of breast cancer and the leading cause of breast cancer related mortality. In the present study, metabolomic profiles of 72 tissue samples and 146 serum samples were analysed using targeted liquid chromatography multiple reaction monitoring mass spectrometry (LC-MRM/MS) and untargeted gas chromatography mass spectrometry (GC MS) approaches. Combination of univariate and multivariate statistical treatment identified significant alterations of 42 and 32 metabolites in tissue and serum samples of IDC, respectively when compared to control. Some of the metabolite changes from tissue were also reflected in serum, indicating a bi-directional interaction of metabolites in IDC. Additionally, 8 tissue metabolites and 9 serum metabolites showed progressive change from control to benign to IDC suggesting their possible role in malignant transformation. We have identified a panel of three metabolites viz. tryptophan, tyrosine, and creatine in tissue and serum, which could be useful in screening of IDC subjects from both control and benign. The metabolomic alterations in IDC showed perturbations in purine and pyrimidine metabolism, amino sugar metabolism, amino acid metabolism, fatty acid biosynthesis etc. Comprehensively, this study provides valuable insights into metabolic adaptations of IDC, which can help to identify diagnostic markers as well as potential therapeutic targets. PMID- 29416802 TI - Prognostic impact of AnxA1 and AnxA2 gene expression in triple-negative breast cancer. AB - Objective: Previous studies have shown Annexin A1 (AnxA1) and Annexin A2 (AnxA2) association with the aggressive behavior of Triple Negative Breast Cancer (TNBC). Our aim was to determine the correlation of AnxA1 and AnxA2 with poor prognosis of TNBC patients. Methods: We analyzed the gene expression of the human annexin family from microarray datasets and correlated with clinical outcomes to determine their ability to predict prognosis. Results: Within a mean follow-up time of 57.2 months in our TNBC cohort, high AnxA1 expression was an independent indicator of poor overall survival (OS) [hazard ratio (HR), 2.14; 95% confidence interval (CI), 1.22-3.78] and relapse-free survival (RFS) prognosis [HR, 1.66; 95% CI, 1.28-2.17]. Additionally, high AnxA2 expression was an independent indicator of poor OS [HR, 2.66; 95% CI, 1.14-6.25], RFS [HR, 1.45; 95% CI, 1.12 1.89], RFS [HR, 1.45; 95% CI, 1.12-1.89), and distant metastasis free survival (DMFS) prognosis [HR, 1.5; 95% CI, 1.16-1.95]. Analyses of TNBC patients with both high AnxA1 and AnxA2, demonstrates a significant decrease in OS (P=0.0017) and RFS (P=0.0002) when compared to the expression of genes independently. Furthermore, AnxA1 prognostic impact relies on high AnxA2 expression and both are preferential for TNBC when compared to other breast cancer subtypes. Conclusion: Together these findings indicate that AnxA1 and AnxA2 are preferential dual prognostic predictors among TNBC patients. PMID- 29416803 TI - Clinical significance of detecting CSF-derived tumor cells in breast cancer patients with leptomeningeal metastasis. AB - Despite marked advances in breast cancer therapy, breast cancer-associated leptomeningeal metastasis (LM), a particularly aggressive syndrome with multifocal seeding of the leptomeninges by tumor cells, still carries an abysmal prognosis. A major problem with breast cancer LM surveillance is the lack of an effective and sensitive means to track dynamic changes of the disease. Cytology detection of cerebrospinal fluid (CSF) is considered the gold standard for LM diagnosis but has a high false-negative rate with a limited sensitivity. Here we applied subtraction enrichment and immunostaining-fluorescence in situ (SE i*FISH) method, a technique previously used for isolating circulating tumor cells (CTCs) from the peripheral blood, to detect, enumerate, and track cerebrospinal fluid-derived tumor cells (CSFTCs) in CSF samples from 8 breast cancer patients. Comparing with cytology test, we found SE-i*FISH method can accurately and feasibly detect CSFTCs for the diagnosis of breast cancer-associated LM and monitor the disease progression. We also isolated and cultured CSFTCs from these cancer patients and performed genomic sequencing on CSFTCs of two patients. Genomic analysis of CSFTCs against corresponding archival primary breast tumors revealed clonal relationships with some ongoing evolution. Further drug sensitivity test on cultured CSFTCs based on genomic analysis data helped identify promising treatment options for the patient tested. Together, our results suggest that CSFTCs detection using SE-i*FISH platform could serve as a sensitive and accurate method to make the diagnosis and a promising approach to monitor tumor dynamics and treatment response for breast cancer-associated LM. PMID- 29416804 TI - Clinicopathological features and prognosis of intestinal hepatoid adenocarcinoma: evaluation of a pooled case series. AB - Backgroud: Intestinal hepatoid adenocarcinoma (IHA) is a very rare and unique intestinal malignancy. Due to the lack of case series specifically pertaining to IHA, the clinicopathological features and prognosis of it remain unclear. Results: Of the 42 patients enrolled in this study, 30 (71.4%) were male. Twenty one cases (50.0%) were located in the colon. Eight cases (19.0%) had accompanying inflammatory bowel disease (IBD). Elevated serum alpha-fetoprotein (AFP) was detected for most patients (25/33, 84.8%). Twenty-five (59.5%) patients received complete resections. Vascular invasion (22/36, 61.1%), lymph node metastasis (28/36, 77.8%) and distant metastasis (21/42, 50.0%) were common. The 1-year progression-free survival (PFS) and disease-specific survival (DSS) of IHA were 26.9% and 30.6%, respectively. Multivariate analysis showed that only pTNM stage was an independent risk factor for PFS and DSS. PFS and DSS in patients with IHA were significantly lower than those with colorectal adenocarcinoma (CA) and hepatoid adenocarcinoma of the stomach (HAS). Conclusions: IHA most commonly occurred in the colon and accompanied by IBD in several cases. pTNM stage was an independent factor for prognosis. The prognosis of IHA was significantly worse than that of CA and HAS. Patients and Methods: Clinical data of IHA from four patients managed at our institution between January 2010 and December 2016, and 38 cases from research databases prior to 2017 were retrospectively studied. PMID- 29416805 TI - Pro-apoptotic effect of doxycycline and hydroxychloroquine on B-cell lymphoma induced by C. burnetii. PMID- 29416806 TI - Glucose transporter-1 as an independent prognostic marker for cancer: a meta analysis. AB - Objective: Glucose transporter-1 (GLUT-1) as the major glucose transporter present in human cells is found overexpressed in a proportion of human malignancies. This meta-analysis is attempted to assess the prognostic significance of GLUT-1 for survival in various cancers. Materials and Methods: We conducted an electronic search using the databases PubMed, Embase and Web of Science, from inception to Oct 20th, 2016. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Results: Fourty-one studies with a total of 4794 patients were included. High GLUT-1 expression was significantly associated with poorer prognosis [overall survival: HR = 1.833 (95% CI: 1.597 2.069, P < 0.0001); disease-free survival: HR = 1.838 (95% CI: 1.264-2.673, P < 0.0001); progression-free survival: HR = 2.451 (95% CI: 1.668-3.233, P < 0.0001); disease specific survival: HR = 1.96 (95% CI: 1.05-2.871, P < 0.0001)]. Conclusions: High GLUT-1 expression may be an independent prognostic marker to predict poor survival in various types of cancers. Further clinical trials with high quality need to be conducted to confirm our conclusion. PMID- 29416807 TI - Survival and time to initiation of adjuvant chemotherapy among breast cancer patients: a systematic review and meta-analysis. AB - The relationship between survival and time to the start of adjuvant chemotherapy (AC) among breast cancer patients is unclear. In order to illustrate the effect of delaying the initiation of AC on survival we have undertaken a systematic review and meta-analysis. We identified 12 available studies in the meta-analysis including 15 independent analytical groups. This meta-analysis showed that a 4 week delay before AC was associated with a significantly worse overall survival (OS)(HR=1.13; 95% confidence interval [CI], 1.08-1.19) and disease free survival (DFS)(HR=1.14; 95%CI, 1.05-1.24). Two studies categorized patients into hormone receptor-positive, ERBB2-positive, and triple-negative breast cancer (TNBC) patients according to the clinicopathological features of breast cancer. The HRs for OS between waiting time (WT) <=30 days and 31-60 days in the subgroups were extracted and analyzed. The analysis demonstrated that a WT of 31-60 days was related to worse OS among patients with TNBC (HR, 1.26; 95% CI, 1.08-1.48), but had no significant effect on OS among those with hormone receptor-positive (HR, 1.02; 95% CI, 0.89-1.15) or ERBB2-postive (HR, 0.95; 95%CI, 0.79-1.14) tumors. In this meta-analysis of the eligible literatures reviewing the time to AC, a longer waiting time to adjuvant chemotherapy may lead to worse survival in breast cancer patients, especially in TNBC patients. PMID- 29416808 TI - Increased risk of cerebrovascular accident related to non-alcoholic fatty liver disease: a meta-analysis. AB - Recent published studies on the association between non-alcoholic fatty liver disease (NAFLD) and cerebrovascular accident (CVA) risk have yielded conflicting findings. The aim of our study was to identify the potential association by pooling all available publications. A total of nine independent studies were included into our study. The pooled odd ratio (OR) with 95% confidence interval (95% CI) was calculated to weigh the strength for the relationship between NAFLD and CVA risk. We also conducted stratified analyses by study design, ethnicity and disease classification for further elucidation. The pooled results of the present meta-analysis showed that NAFLD was related to increased risk of CVA (OR = 2.32, 95% CI 1.84-2.93, P < 0.001). Besides, NAFLD is associated with increased risk of CVA among both Caucasians (OR = 2.27, 95% CI 1.77-2.90, P < 0.001) and Asians (OR = 2.81, 95% CI 1.43-5.51, P = 0.003). Moreover, the significant association was also observed in case-control studies (OR = 2.73, 95% CI 1.67 4.48, P < 0.001) and cohort studies (OR = 2.22, 95% CI 1.71-2.89, P < 0.001), respectively. In addition, NAFLD was shown to correlate with increased risk of cerebral hemorrhage (OR = 1.85, 95% CI 1.05-3.27, P = 0.034) and the ischemic stroke (OR = 2.51, 95% CI 1.92-3.28, P < 0.001). In conclusion, our findings firstly provide strong evidence for a risk effect of NAFLD on CVA development. PMID- 29416809 TI - Meta-analysis of the prognostic value of p-4EBP1 in human malignancies. AB - Phosphorylated 4E-binding protein 1 (p-4EBP1) is the inactivated form of 4EBP1, which is a downstream mediator in the mTOR signaling pathway and a vital factor in the synthesis of some oncogenic proteins. This meta-analysis was conducted to assess the predicative value of p-4EBP1 expression in human malignancies. The PubMed and Embase databases were carefully searched. Articles comparing the prognostic worthiness of different p-4EBP1 levels in human malignancies were collected for pooled analyses and methodologically appraised using the Newcastle Ottawa Scale (NOS). A total of 39 retrospective cohorts with an overall sample size of 3,980 were selected. Patients with lower p-4EBP1 expression had better 3 year (P < 0.00001), 5-year (P < 0.00001), and 10-year (P = 0.03) overall survival and better 3-year (P < 0.0001) and 5-year (P = 0.0005) disease-free survival. Subgroup analyses confirmed the unfavorable prognosis associated with p-4EBP1 overexpression. These findings were further validated by sensitivity analyses. Harbord and Peters tests revealed no publication bias within the included studies. It thus appears higher expression of p-4EBP1 indicates a poor prognosis in human malignancies. PMID- 29416810 TI - G protein beta 3(GNbeta3) C825T polymorphism and irritable bowel syndrome susceptibility: an updated meta-analysis based on eleven case-control studies. AB - Several studies have reported an association between GNbeta3 C825T polymorphism and irritable bowel syndrome (IBS). However, the results remain inconclusive and controversial, particularly for the data derived from different ethnicities and IBS subtypes. Therefore, we performed an updated meta-analysis to evaluate this association. All eligible case-control studies that met the search criteria were retrieved from multiple databases, and eleven case-control studies were included for detailed evaluation. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strengths of the association between GNbeta3 C825T polymorphism and susceptibility to IBS and its subtypes. Our meta-analysis found no significantly associations of GNbeta3 C825T polymorphism with IBS risk in all populations. Whereas the C allele was demonstrated to be a decreased risk factor for constipation predominant IBS (IBS C) in allele model. Additionally, the CC genotype was found to be associated with increased diarrhea predominant IBS (IBS-D) risk in recessive model. Subgroup analysis by ethnicity revealed that these associations held true for the Asian subpopulation. In conclusion, this meta-analysis suggests the C allele of GNbeta3 C825T might be associated with a decreased risk of IBS-C, and the CC genotype of GNbeta3 might be associated with increased IBS-D risk. PMID- 29416811 TI - Risk factors, follow-up, and treatment of urethral recurrence following radical cystectomy and urinary diversion for bladder cancer: a meta-analysis of 9498 patients. AB - Purpose: Patients frequently undergo radical cystectomy and urinary diversion for treatment of bladder cancer. However, they remain at risk of urethral recurrence (UR). Studies have determined various risk factors leading to urethral recurrence. However, no publications have weighed the predictive values of these factors. Materials and Methods: Studies published between 1971 and 2016 were retrieved from PubMed, EMBASE and MEDLINE. We used STATA software (Version 12.0) to estimate the pooled risk ratio. Results: Twenty-five publications with 9498 patients were included. Overall, male patients, especially those with concomitant carcinoma in situ, superficial or intravesical bladder cancer, non-orthotopic diversion, prostatic involvement, bladder neck involvement, positive urethral margins or multifocal bladder cancer were at higher risk of urethral recurrence. The overall risks of recurrence, reported as risk ratios, varied widely. Among all 25 studies, 118 (60.2%) cases in 9 studies were diagnosed through routine follow-up. Another 82 (40.8%) patients in 11 studies first reported symptomatic abnormalities. Prognoses were worse for patients with symptomatic recurrence. Urethral cytology was the most common diagnostic method. Treatment after UR was reported for 272 cases in 14 publications, and 190 patients underwent urethrectomy and 52 underwent urethra-sparing treatments. Outcomes after UR were described in 12 studies reporting 180 cases, and 41 patients were alive through the end of follow-up and 65 patients died of bladder cancer. Conclusions: UR following radical cystectomy for bladder cancer was closely related to risk factors. Precautions, strict follow-up protocols and rational therapies were critical to patients with high risks of urethral recurrences. PMID- 29416812 TI - Prognostic value of resected lymph nodes numbers for Siewert II gastroesophageal junction cancer. AB - We aim to evaluate whether resected lymph nodes (RLNs) numbers have prognostic value in patients with gastroesophageal junction cancers (GEJ, Siewert type II). Patients with gastroesophageal junction cancers were identified from the Surveillance Epidemiology and End Results (SEER) registry between 1988 to 2013. Multivariate Cox regression analyses and Kaplan-Meier method were performed to analyze risk factors for overall survival (OS) and cause-specific survival(CSS). A total of 8396 patients who underwent surgeries and had reginal lymph nodes examined were identified. Kaplan-Meier analysis indicated that more numbers of resected lymph nodes (RLNs) were associated with better survival. The five-year OS rates for 1-20 and 21-90 RLNs were 26.8% and 32.4%, with a median survival time of 62 and 72 months, respectively (P < 0.001). The five-year CSS rates were 32.2% and 37.2% in each group, with median survival time of 90 and 101 months, respectively (P < 0.001). Cox regression multivariate analysis showed that year of diagnosis, age, sex, marital status, grade, seer histology, tumor histology, lymph node ratio (LNR) and RLNs as a categorical variable were all significant prognostic factors for both OS and CSS. RLN count is an independent prognostic factor for Siewert type II GEJ cancer patients and patients can achieve better overall and cancer-specific survival with more than 20 RLNs dissected. PMID- 29416813 TI - The prognostic value of negative lymph node count for patients with cervical cancer after radical surgery. AB - Negative lymph node (NLN) count has been recognized as a prognostic indicator in various cancers. However, the relationship between NLN count and the prognosis of cervical cancer is still unknown. In this study, 10, 500 cervical cancer patients after radical surgery were selected from Epidemiology and End Results Program (SEER) data. Clinicopathological characteristics were collected for analysis, including year of diagnosis, age, race, grade, primary site, FIGO stage and cause specific survival (CSS). Univariate and multivariate Cox proportional hazards model was used to assess risk factors for survival of patients. X-tile plots identified 6 as the optimal cutoff value of NLN count to divide patients into high and low risk subsets in terms of CSS (chi2 = 183.95, P < 0.001). The rate of 5-year CCS of cervical cancer patients was improved with an increase in NLN count from 0 to 23 (all P < 0.001). NLN count was validated as an independently prognostic factor by the multivariate Cox analysis (HR: 1.571, 95% CI: 1.370~1.801, P < 0.001). Subgroup analysis showed that NLN count was a prognosis factor in FIGO stage I (chi2=35.023, P < 0.001), stage II (chi2 = 12.910, P < 0.001), stage III + IV (chi2 = 9.732, P = 0.002) and unknown stage (chi2 = 16.654, P < 0.001). Conclusively, this study demonstrated the NLN count was an independent prognostic factor for cervical cancer patients. PMID- 29416814 TI - Association of conventional ultrasound, elastography and clinicopathological factors with axillary lymph node status in invasive ductal breast carcinoma with sizes > 10 mm. AB - Background: To evaluate whether conventional ultrasound, elastography [conventional strain elastography of elasticity imaging, acoustic radiation force impulse induced strain elastography of virtual touch tissue imaging, and a novel two-dimensional shear wave elastography of virtual touch tissue imaging quantification] and clinicopathological factors are associated with axillary lymph node metastasis in invasive ductal breast carcinoma with sizes > 10 mm. Materials and Methods: We evaluated 150 breast lesions from 148 patients using the above methods and the clinicopathological factors. Univariate and multivariate logistic regression analysis were performed to determine the axillary lymph node metastasis risk factors. Diagnostic performance was evaluated using receiver operating characteristic curve analysis. Results: Sixty-three tumors (42%) were node-positive, 87 (58%) were node-negative. Aspect ratio, virtual touch tissue imaging grade, shear wave velocity, pathological invasive tumor size, and histological grade maintained independent significance in predicting nodal involvement. The mean tumor shear wave velocitys (4.60, 6.49, 7.16) increased in proportion to metastatic node number (0, 1-3, >= 4, respectively; P < 0.001). For all tumors in this study, the cut-off shear wave velocity was 6.16 m/s and was associated with 64.1% sensitivity, 78.0% specificity and an area under the ROC curve of 0.799 (95% confidence interval, 0.731-0.868). Conclusions: Aspect ratio, virtual touch tissue imaging grade, shear wave velocity, pathological invasive tumor size and histological grade are independently associated with axillary lymph node metastasis in invasive ductal breast carcinoma with sizes > 10 mm. PMID- 29416815 TI - Increased risk of malignancy in patients with an aortic aneurysm: a nationwide population-based retrospective study. AB - Background: Cardiovascular disease and malignancy have numerous similarities and possible interactions, as these diseases share several risk factors, epidemiological features and biological signaling pathways. Data regarding the risk of malignancy in patients with aortic aneurysm (AA) are scarce. We aimed to determine whether patients with AA have an increased risk of malignancy. Materials and Methods: The data for the nationwide population-based retrospective cohort study described herein were obtained from the Taiwan National Health Insurance Research Database (NHIRD). We selected adult patients who had been newly diagnosed with AA and were followed up between 2000 and 2010. We excluded patients who had been diagnosed with AA and malignancy prior to the date of the AA diagnosis. The control cohort was selected from individuals who had no history of AA and was selected with 1:4 matching according to co-morbidities and medication history. The outcome was a diagnosis of malignancy and the cumulative incidence of AA. Results: A total of 10,933 patients diagnosed with AA were identified. The patients with an AA had a significantly higher cumulative risk of developing malignancies in subsequent years than the patients without an AA (log rank test < 0.001). Similarly, patients with malignancies had a significantly higher cumulative risk of developing an AA in subsequent years than patients without malignancies (log rank test < 0.001). Conclusions: Patients with an AA were shown to have a substantially increased risk of developing a variety of malignancies compared with patients without AAs. Healthcare professionals should be aware of this increased risk when treating patients with AAs. PMID- 29416816 TI - Comprehensive immunotherapy combined with intratumoral injection of zoledronate pulsed dendritic cells, intravenous adoptive activated T lymphocyte and gemcitabine in unresectable locally advanced pancreatic carcinoma: a phase I/II trial. AB - Dendritic cell (DC)-based vaccines prepared using various antigen loading methods have been studied for cancer immunotherapy. The in vivo provocation of immunity by the direct injection of DCs without using tumor-specific antigens into tumors after apoptosis-inducing chemotherapy is more applicable. We previously reported that zoledronate-pulsed DCs (Zol-DCs) may induce tumor-antigen-specific CD8+ T cells by activating Vgamma9gammadeltaT cells. In this report, we studied the feasibility, safety, and efficacy of a comprehensive immunotherapy involving the combined intratumoral injection of Zol-DC, gemcitabine (GEM) and alphabetaT cells in locally advanced pancreatic carcinoma. Seven of 15 patients showed a stable disease (SD) and most of the patients showed long-term clinical responses. The FACT-BRM score was significantly higher in the patients with SD. Additionally the CD8+/Treg ratio significantly increased in SD patients after treatment. The median over-all survival and progression-free-survival of 15 patients were 12.0 months and 5.5 months, respectively. Patients with a pretreatment neutrophil/lymphocyte ratio (NLR) lower than 5.0 showed significantly longer survival. Even in an analysis limited to the patients with an NLR lower than 5.0, the patients whose CD8+/Treg ratio increased more than twofold tended to survive longer. In conclusion, the comprehensive immunotherapy using Zol-DCs, systemic alphabetaT cells, and GEM may synergistically show a therapeutic effect on locally advanced pancreatic carcinoma. By using appropriate and precise biomarkers, such as NLR and CD8+/Treg ratio, the present comprehensive immunotherapy could be more beneficial for patients with pancreatic carcinoma. PMID- 29416817 TI - Transplants of unrelated cord blood or sibling allogeneic peripheral blood stem cells/bone marrow in adolescent and young adults with chronic myeloid leukemia: comparable outcomes but better chronic GVHD-free and relapse-free survival among survivors with cord blood. AB - Adolescent and young adult (AYA) patients with hematological malignancy aged 15 to 39 years are recognized as a separate entity, and the efficacy and safety of unrelated cord blood transplantation (CBT) for chronic myeloid leukemia (CML) in AYA patients has not been reported. From March 2002 to June 2015, total of 106 CML patients received allogeneic hematopoietic cell transplantation (allo-HCT) in our center. Included in the present study were CML patients aged 15 to 39 years who received unrelated CBT or sibling allo-HCT, and 74 consecutive AYA patients with CML enrolled in this analysis. The day-100 cumulative incidences of grade 2 4 aGVHD and grade 3-4 aGVHD were similar following CBT and sibling-PBSCT/BMT. The cumulative incidences of cGVHD and extensive cGVHD were 21.7% and 5.3% in the CBT cohort, which were significantly lower than those in the sibling-PBSCT/BMT cohort (58.0% and 45.5%), respectively (p = 0.046, 0.008). There was no significant difference between the two cohorts in terms of transplant-related mortality (TRM), relapse, and long-term survival (overall survival and leukemia-free survival). The 5-year probability of GVHD-free/relapse-free survival (GRFS) was 47.9% and 33.4% in the CBT and the sibling-PBSCT/BMT cohorts, respectively (p = 0.632); among patients who survived more than 100 days after transplantation (n = 61), the 5-year probability of chronic GVHD-free, relapse-free survival (CRFS) was 66.2% in the CBT cohort, which was significantly higher than that in the sibling-PBSCT/BMT cohort (37.4%) (p = 0.037). Our study suggests that for AYA patients with CML, transplantation using unrelated CB offers comparable outcomes to sibling -PBSCT/BMT, including similar aGVHD, TRM, relapse, and long-term survival; however, from the perspective of quality of life, unrelated CBT have a lower incidence of cGVHD and a higher CRFS among survivors. PMID- 29416818 TI - Clinical features and prognostic factors of ten patients with renal failure caused by IgG4-related retroperitoneal fibrosis. AB - IgG4-related retroperitoneal fibrosis (IgG4-RPF) is a newly recognized entity which often mimics cancer. We aimed to investigate the clinical features and the causes of renal failure, as well as to explore the factors affecting the prognosis of renal function by analysis of the clinical data of patients with IgG4-RPF. We reviewed clinical features of 10 patients with renal failure caused by IgG4-RPF, which was confirmed by pathology review and clinic-pathologic correlations. All patients were male, and the mean age at onset was 64.2 +/- 10.0 years. Five patients were revealed with acute renal failure (ARF), while the other five ones with ARF on chronic kidney disease (CKD) (A on C) at diagnosis. Initial favorable responses obtained in 90% of the patients who underwent steroid therapy. The serum creatinine (SCr) level returned to normal in six patients including five with ARF and one with A on C, while those of the rest four patients with A on C restored to baseline levels (GFR remained below 60 ml/min/1.73 m2 however) after therapy. These four unrecovered patients had a history of CKD, a longer period of persistently elevated SCr, a thinner total renal parenchyma thickness, and continuous elevated serum IgG4 levels after steroid therapy, compared with those recovered patients (P < 0.05). We concluded that recovery and long-term prognosis of the disease were primarily associated with timely diagnosis and proper treatment. PMID- 29416819 TI - Chemoradiotherapy in combination with radical surgery is associated with better outcome in cervical cancer patients. AB - Objectives: To retrospectively assess the influence of radical surgery following concurrent chemoradiotherapy (CCRT) on outcomes in cervical cancer (CC) patients. Methods: Patients diagnosed with cervical squamous cell carcinoma or adenocarcinoma (FIGO stages IB2 to IIB) at the Yinbin Second People's Hospital between September 2008 and September 2013, were included in this study. Patients were classified into 2 groups based on the treatment received: surgery group (CCRT plus radical surgery) and non-surgery groups (CCRT only). In addition to clinical information, inter-group differences with respect to local control rate (LCR), local recurrence rate (LRR), metastasis rate, overall survival (OS), progress free survival(PFS) and complications were assessed. Results: A total of 314 patients were included in the analysis. Parametrial invasion, pelvic lymph node metastasis, tumor diameter > 4 cm and presence of residual disease were risk factors for recurrence in the non-surgery group. In patients with risk factors, radical surgery significantly improved their clinical outcome. The 3-year/5-year LCR in the surgery and non-surgery groups was 88.3%/87.4% and 82.3%/77.5%, respectively (P = 0.04). The 3-year/5-year OS rate in the two groups was 87.1%/81.7% and 72.8%/67.3%, respectively (P = 0.001). The 3-year/5-year LRR in the two groups were 11.7%/12.6% and 17.7%/22.5%, respectively (P = 0.04). The metastasis rates in the two groups were 19.9% and 24.8%, respectively (P = 0.09). Conclusions: Surgery following CCRT could improve overall survival and progressfree survival. Radical surgery following CCRT appears to confer significant benefits including an increase in LCRs and decrease in LRR in CC patients with risk factors. PMID- 29416820 TI - Predictive factors for 6 vs 12 cycles of Folfiri-Bevacizumab in metastatic colorectal cancer. AB - Early switching to de-intensified maintenance regimen is still a matter of debate in metastatic colorectal cancer (mCRC). The MARTHA trial, a S.I.C.O.G. phase III randomized trial, compared FOLOFIRI+bevacizumab (B) for 12 cycles (6 months) followed by B for up to 12 months (FOLFIRI +B*12 arm) vs FOLFIRI+B for 6 cycles (3 months) followed by capecitabine+B for 4 cycles followed by B for up to 12 months (FOLFIRI+B*6 arm). Chemotherapy-naive mCRC patients were randomized, primary endpoint was progression free survival (PFS), with overall survival (OS) as a secondary endpoint. A novel analysis, the Death Pace Analysis (DPA), was performed to identify patients who benefited from a specific treatment. No PFS difference was seen in 198 enrolled patients (101 in FOLFIRI+B*12, 97 in FOLFIRI+B*6). A non-significant superior OS was observed for FOLFIRI+B*6 (HR 0.74, p 0.098). The DPA demonstrated that 14% of patients were identifiable as FOLFIRI+B*6-benefiting patients. According to a logistic regression analysis including 23 clinicopathological variables, baseline Hb was the only independent predictor of DPA-defined FOLFIRI+B*6-benefit status. Among patients with Hb <= 11.1 gr/dL a statistically significant prolonged OS was observed for FOLFIRI+B*6 over FOLFIRI+B*12 (median OS: 20.7 vs 12.6 months, respectively, HR 0.54, p 0.048). No survival difference was observed between arms in patients with Hb > 11.1. mCRC patients with low baseline Hb levels are better treated with FOLFIRI+B*6 first-line strategy. Possible biological explanations for this finding are being investigated. PMID- 29416821 TI - Dendritic cells loaded with tumor derived exosomes for cancer immunotherapy. AB - Exosomes are vesicles that can be secreted by many types of cell and released into the extracellular space. Studies have found that tumor derived exosomes (TEXs) can promote tumor growth and metastasis, as well as inhibit immune response through transferring their genetic information to the recipient cells. Given their functions in tumor progression, TEXs are considered as promising biomarkers for early detection of human malignancy. Dendritic cells (DCs), a type of antigen presenting cells, can induce tumor-specific T cell immune responses in carcinogenesis. Growing evidences have demonstrated that the matured DCs induced by TEXs exhibit enhanced anti-tumor effects that may be applied for cancer immunotherapy. Thus in this review, according to the previous studies, we summarized the effects of DCs loaded with TEXs in cancer immunotherapy. PMID- 29416822 TI - IL-36 cytokines in autoimmunity and inflammatory disease. AB - The inteleukin-36 (IL-36) cytokines include IL-36alpha, IL-36beta, IL-36gamma and IL-36Ra, which belong to the IL-1 family and exert pro-inflammatory effects on various target cells such as keratinocytes, synoviocytes, dendritic cells and T cells. Emerging evidence has suggested a role of IL-36 in the pathogenesis of many inflammatory diseases. Here, we provide a brief review on the activation of IL-36 family cytokines and their involvement in autoimmunity and inflammatory diseases, which will provide further insights in understanding the functions of IL-36 family cytokines in the pathophysiology of autoimmunity and inflammatory diseases. PMID- 29416823 TI - Dichotomous roles of co-stimulatory molecules in diabetes mellitus. AB - Numerous studies have established the importance of immune dysfunction in the development of diabetes mellitus, including typ1 and typ2 diabetes, and it is worth noting that T cell activation acts a key role in the pathogenesis of loss of beta cell mass, adipose inflammation and insulin resistance. Regarding as an important checkpoint in the process of T cell activation, co-stimulatory molecules interaction between antigen present cells and T cells have been identified the critical role in the development of diabetes mellitus. Thus, blockage of co-stimulatory dyads interaction between antigen present cells and T cells was supposed to a potential of therapeutic strategies. However, studies also showed that inhibition or deletion of some co-stimulatory molecules do not always reduce the development of diabetes, and even exacerbate the disease activity. Here, in this context, we highlight the dichotomous role of co stimulatory molecules interaction in the pathogenesis of diabetes. PMID- 29416824 TI - The dawn of the liquid biopsy in the fight against cancer. AB - Cancer is a molecular disease associated with alterations in the genome, which, thanks to the highly improved sensitivity of mutation detection techniques, can be identified in cell-free DNA (cfDNA) circulating in blood, a method also called liquid biopsy. This is a non-invasive alternative to surgical biopsy and has the potential of revealing the molecular signature of tumors to aid in the individualization of treatments. In this review, we focus on cfDNA analysis, its advantages, and clinical applications employing genomic tools (NGS and dPCR) particularly in the field of oncology, and highlight its valuable contributions to early detection, prognosis, and prediction of treatment response. PMID- 29416825 TI - Prognosis of men with penile metastasis and malignant priapism: a systematic review. AB - Introduction: Metastases to the penis are rare, but can have severe consequences. The aim of this study was to systematically review the literature in order to gain more information on the presentation and prognosis of this metastatic disease. We reviewed the literature relating to all case reports, series and reviews about penile metastasis, from 2003 to 2013, through a Medline search. We identified 63 articles and 69 patients. Metastases were located on the root (38.8%), the shaft (38.8%) or the glans (22.2%) of the penis. The diagnosis of penile metastasis was made after the primary cancer had been diagnosed. The most common presentation was a single small penile nodule. Ten patients reported priapism. The median survival time after diagnosis of penile metastasis was 10 months (range 6-18 months). A Kaplan-Meier analysis has shown that the patients presenting with priapism and those with metastases from non-urologic tumors have a significantly worse prognosis (age adjusted Log Rank: p=0.037 for priapism vs. no priapism and p=0.045 for urologic vs. non urologic). There are prognostic differences based on the presentation of penile metastases. Survival is substantial and treatment should therefore take into account symptoms improvement and quality of life. PMID- 29416826 TI - Role of ginsenosides in reactive oxygen species-mediated anticancer therapy. AB - Cancer is still a global public health problem, which is the leading cause of death in most countries. Ginseng has been used for centuries all over the world as a panacea that promotes longevity. As the king of herb plants, ginseng holds great promise as a new treatment option which is used either by itself or in combination with other medicinal ingredients that is widely accepted as complementary and alternative medicine in cancer therapy. Ginsenosides, the major pharmacologically active ingredients of ginseng, have been shown to have multiple medicinal effects including prominent anticancer activity. The purpose of this review is to give our perspective about the roles of ginsenosides in reactive oxygen species (ROS)-mediated anticancer therapy. Additionally, to provide new sheds light for further improvement and carry out pre-clinical and clinical trials to develop it successfully into a potential anticancer agent. Panax herbs and their derivate/metabolites ginsenosides exert beneficial effects for treating various types of cancers. The mechanism of ROS-mediated anticancer activities of ginsenosides varies depending on the specific type of cancer cells involved. Ginsenosides may suppress cancer cell proliferation through anti-oxidation on tumor initiation and induce apoptosis, paraptosis or autophagy via generation of ROS on tumor progression, promotion, angiogenesis, invasion and metastasis by various signaling pathways e.g., activation of AMPK, MEK, ASK-1/JNK, ESR2-NCF1 ROS, ER-dependent PI3K/Akt/Nrf2, P53-CHOP, ROS-JNK-autophagy, and/or inhibition of PI3K/Akt signaling pathways. These multiple effects rather than a single may play a crucial role in emerging ginsenosides as a successful anticancer drug. PMID- 29416828 TI - Asymmetrically enlarged parietal foramina in a rare case of Goldenhar syndrome with a possible etiopathogenesis. AB - Goldenhar's syndrome (GS) also known as oculo-auriculo-vertebral spectrum (OAVS) is a relatively rare condition. GS is of multifactorial etiology that includes environmental and/or genetic factors, in addition to teratogens that disturb the blastogenesis. A 5-year-old girl from Saudi Arabia, was a member of dizygotic twins conceived by assisted reproductive technology (ART), and born with features of GS. She had asymmetrical face, cleft lip and palate, right microphthalmia and microtia. Radiological imaging showed right maxillary and mandibular bone hypoplasia, asymmetrically enlarged parietal foramina, a persistent midline occipital foramen, abnormal bone arising from occipital bone, extending along tentorium cerebelli, and a lipoma at the right tentorium cerebelli. A rudimentary right eye with dermoid cyst and pseudotumor as well as bilateral atresia of external auditory canals were present. Karyotyping was normal. ART and the risk of manipulation of ovum/embryo, was shown to be associated with multiple gestation and an increased risk of major birth defects. Given that our patient was from Eastern-province close to the South of Iraq, where Gulf wars took place and the reported incidence of birth defects, including orofacial malformation, jumped there to about seven-folds, after war, thus, environmental contamination, and the possible teratogenic effect of depleted uranium could not be excluded. In conclusion, our case of GS, disclosed a rare radiological finding in calvarial anatomy, and asserted that, careful clinical evaluation is recommended in cases of GS. ART fertilization risk along with the possible parental environmental exposure were regarded as the potential cooperators of multifactorial etiology in our case. PMID- 29416827 TI - Aptamer: A potential oligonucleotide nanomedicine in the diagnosis and treatment of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. Late diagnosis and poor prognosis are still a major drawback since curative therapies such as liver resection and liver transplantation are effective only for an early stage HCC. Development of novel molecular targeting therapies against HCC may provide new options that will improve the efficiency of the diagnosis and the success of the therapy, thus ameliorating the life expectancy of the patients. The aptamer is an oligonucleotide nanomedicine that has high binding affinity and specificity to small and large target molecules in the intracellular and extracellular environment with agonist or antagonist function. Currently, several aptamers for diagnostic and therapeutic purposes are under development to recognize different molecules of HCC. In in vitro models, the aptamer has been shown to be able to reduce the growth of HCC cells and increase the sensitivity to conventional chemotherapies. In in vivo mouse models, aptamer could induce cell apoptosis with antitumor activity. Overall data had shown that aptamer has limited toxicity and might be safe in clinical application. This review summarizes recent information of aptamer as a potential oligonucleotide nanomedicine tool, in diagnostics, targeted therapy, and as drug delivery nano-vehicles. PMID- 29416829 TI - Evolutionary insight on localization of 18S, 28S rDNA genes on homologous chromosomes in Primates genomes. AB - We explored the topology of 18S and 28S rDNA units by fluorescence in situ hybridization (FISH) in the karyotypes of thirteen species representatives from major groups of Primates and Tupaia minor (Gunther, 1876) (Scandentia), in order to expand our knowledge of Primate genome reshuffling and to identify the possible dispersion mechanisms of rDNA sequences. We documented that rDNA probe signals were identified on one to six pairs of chromosomes, both acrocentric and metacentric ones. In addition, we examined the potential homology of chromosomes bearing rDNA genes across different species and in a wide phylogenetic perspective, based on the DAPI-inverted pattern and their synteny to human. Our analysis revealed an extensive variability in the topology of the rDNA signals across studied species. In some cases, closely related species show signals on homologous chromosomes, thus representing synapomorphies, while in other cases, signal was detected on distinct chromosomes, leading to species specific patterns. These results led us to support the hypothesis that different mechanisms are responsible for the distribution of the ribosomal DNA cluster in Primates. PMID- 29416830 TI - Nursing students' perceptions of teachers' uncivil behaviors: a qualitative research. AB - One of the main issues in nursing education that teachers and students frequently encounter is uncivil behaviors. This type of behavior is destructive for the teaching and learning environment. As teachers play an important role in nursing students' education and are ultimately their role models, the identification of these behaviors in nursing teachers appears to be essential. This study was conducted to determine nursing students' perceptions of their teachers' uncivil behaviors. The present study was conducted using a qualitative approach and content analysis. A total of 13 nursing students were selected through purposive sampling, and deep and semi-structured interviews were conducted with them. Content analysis was performed using an inductive approach. Three main categories were obtained through data analysis; disruptive behaviors affecting communication climate (subthemes: humiliation, the lack of supportiveness, and distrust), disruptive behaviors affecting ethical climate (subthemes: self-centeredness, coercion and aggression, and harassment), and disruptive behaviors affecting learning climate (subthemes: poor teaching skills, poor time management, and indiscipline). Given that human dignity takes precedence over education, any action causing humiliation and embarrassment can have inverse effects on the students and may harm them. These behaviors taint the educational role. Since students select their teachers as their role models, the impact of teachers' uncivil behaviors on students cannot be neglected. Neglecting these behaviors might lead to their persistence in the clinical setting and irreparable damage to patients, who are the ultimate recipients of care. PMID- 29416831 TI - Is past life regression therapy ethical? AB - Past life regression therapy is used by some physicians in cases with some mental diseases. Anxiety disorders, mood disorders, and gender dysphoria have all been treated using life regression therapy by some doctors on the assumption that they reflect problems in past lives. Although it is not supported by psychiatric associations, few medical associations have actually condemned it as unethical. In this article, I argue that past life regression therapy is unethical for two basic reasons. First, it is not evidence-based. Past life regression is based on the reincarnation hypothesis, but this hypothesis is not supported by evidence, and in fact, it faces some insurmountable conceptual problems. If patients are not fully informed about these problems, they cannot provide an informed consent, and hence, the principle of autonomy is violated. Second, past life regression therapy has the great risk of implanting false memories in patients, and thus, causing significant harm. This is a violation of the principle of non malfeasance, which is surely the most important principle in medical ethics. PMID- 29416832 TI - Consanguineous marriages in the genetic counseling centers of Isfahan and the ethical issues of clinical consultations. AB - Consanguineous marriage, which is common in many regions in the world, has absorbed much attention as a causative factor in raising the incidence of genetic diseases. The adverse effects may be attributed to the expression of the genes received from common ancestors and mortality and morbidity of the offspring. Iran has a high rate of consanguineous marriages. In recent years genetic counseling has come to be considered in health care services. This cross-sectional study was conducted in order to determine the prevalence and types of consanguineous marriages in the genetic clinics in Isfahan. We aimed to define the different types of marriages, specific categories of genetic disorders associated with consanguineous marriages, and mode of inheritance in the family tree. We also narratively reviewed the ethical aspects of the issue. The data were collected using a simple questionnaire. A total number of 1535 couples from urban and rural areas formed the study population. The marriages were classified according to the degree of the relationship between couples, including: double cousin, first cousin, first cousin once removed, second cousin and beyond second cousin. The SPSS software version 16 was used for data analysis. Data obtained through genetic counseling offered during a 5-year period revealed that 74.3% had consanguineous relationships, 62.3% were first cousins, 1% were double cousins and 7.8% were second cousins. In addition, 76% of the couples had at least one genetic disease in their family tree. Related ethical issues were also considered in this study, including autonomy and informed decision making, benefit and harm assessment, confidentiality, ethics in research, justice in access to counseling services, financial problems ethics, and the intellectual property of scientific success. PMID- 29416833 TI - Consumption of a Low Fermentable Oligo-, Di-, Mono-saccharides, and Polyols Diet and Irritable Bowel Syndrome: A Systematic Review. AB - Consumption of low dietary fermentable carbohydrates, including fermentable oligo , di-, mono-saccharides, and polyols (FODMAP) has been hypothesized to improve symptoms of irritable bowel syndrome (IBS). This study was done to summarize findings from earlier evidence on the effect of a low FODMAP diet (LFD) on the symptoms of IBS. We searched in ISI Web of Knowledge, PubMed, Scopus, and Google Scholar using the following keywords: "FODMAP" OR "oligosaccharides" OR "disaccharides" OR "Monosaccharaides" in combination with "irritable bowel syndrome" or "IBS" or "Gastrointestinal Disease." The reference lists of the relevant papers were also examined to avoid missing any publication. No time and language restrictions were applied. The relevant studies were selected through an independent search by two investigators. Overall, 778 relevant articles were found in our initial search. After reviewing title and abstracts, 763 papers were excluded from this review and 15 studies were included. All published studies were interventional studies in which patients with IBS had been recommended or randomized to receive a LFD. Three studies had quasi-experimental design, 9 were parallel randomized clinical trial and 3 studies were of randomized cross-over trials. These studies were conducted between 2009 and 2016. Nine studies were done in Europe, 2 in US, 3 in Australia, and one in Asia. Sample sizes of these studies were varied from 12 to 182. All studies had been conducted on both sexes, with the majority of participants as women (>70%). The age range was between 11 and 74 years in different studies. One study was performed on children, 9 on adults, and 5 others were in young-to-middle age groups. Duration of intervention was varied from 2 days to 16 months (2 studies with <1 week, and others with more than 2 weeks). Eight studies had suggested a significant effect of LFD on the improvement of all IBS symptoms, and 1 study had reported improvement in all symptoms except for constipation. One study had not found a significant difference between LFD and lactobacillus GG on IBS symptoms. Another paper had reported no significant effect of an LFD on IBS compared with the traditional IBS diet. The other paper had reported LFD improved 75% of diarrhea. Adherence to an LFD was not associated with the severity of symptoms. It is concluded that consumption of an LFD might reduce symptoms of IBS; however, further studies are required to shed light on inconsistencies in this field. PMID- 29416834 TI - Soy Protein and Chronic Kidney Disease: An Updated Review. AB - Chronic kidney disease (CKD) is a serious universal problem that is the main risk for several diseases including cardiovascular disease. Dietary factors are important to prevent and control the kidney disease. Some evidence has shown that modifying the amount and the types of dietary protein exert a major effect on renal failure so limiting dietary protein and substituting animal protein with soy protein has suggested. However, there is a lot of controversy about it, especially in human. Thus, this paper will review the clinical trial studies conducted on the effects of soy protein intake on CKD in both animal and human and its effect mechanism. PMID- 29416835 TI - Improving Participants' Retention in a Smoking Cessation Intervention Using a Community-based Participatory Research Approach. AB - Background: This study compares participant' sretention in three phases of smoking cessation interventions, one provided in a health clinic and the subsequent two in community-based settings. Methods: Smoking cessation interventions were conducted in three phases from 2008 to 2015 in two underserved urban communities with low socioeconomic profiles and high rates of smoking (n = 951). Phase I was conducted in a clinic; Phases II and III were conducted in community venues. In Phases II and III, incremental changes were made based on lessons learned from the previous phases. Retention (attending six or more sessions) was the primary predictor of cessation and was analyzed while controlling for associated factors including age, gender, race, employment, education, and nicotine dependence. Results: Retention increased substantially over the three phases, with rates for attending six or more sessions of 13.8%, 51.9%, and 67.9% in Phases I, II, and III, respectively. Retention was significantly higher in community settings than in the clinic setting (adjusted odds ratio [OR] = 6.7; 95% confidence intervals [CI] = 4.6, 9.8). In addition to the intervention in community venues, predictors of retention included age and unemployment. Higher retention was significantly associated with higher quit rates (adjusted OR = 2.4; 95% CI = 1.5, 3.8). Conclusions: Conducting the intervention in community settings using trained peer motivators rather than health-care providers resulted in significantly higher retention and smoking cessation rates. This was due in part to the ability to tailor cessation classes in the community for specific populations and improving the quality of the intervention based on feedback from participants and community partners. PMID- 29416836 TI - Methodology of the Comprehensive Program on Prevention and Control of Overweight and Obesity in Iranian Children and Adolescents: The IRAN-Ending Childhood Obesity (IRAN-ECHO) Program. AB - Background: The World Health Organization program on Ending Childhood Obesity (WHO-ECHO) has developed a comprehensive and integrated package of recommendations to address childhood obesity. The present study, entitled IRAN ECHO, was designed and implemented in the framework of the WHO-ECHO program. Methods: The IRAN-ECHO program is implementing multicomponent interventions by considering life course dimensions. The program has two parts: a population approach and an individual approach. The population approach considers different periods in life, including prenatal, infancy, childhood, and adolescence, as well as family and society. The individual approach targets those children or adolescents with overweight or obesity; this part is conducted as a referral system that is now integrated in the current national health system. As part of the population approach, a quasi-experimental study was conducted in six provinces to compare the status before and after implementing parts of the interventions. By intersectoral collaboration with different organizations, multicomponent interventions are conducted for different age groups. Results: The IRAN-ECHO program is being conducted in six provinces, and will be considered in all provinces in the near future. Its main effects could be assessed in future years. Part of this program that was conducted as a quasi-experimental survey comprised 7149 students and showed that a high percentage of students had acceptable knowledge about adverse health effects of overweight and obesity. However, the knowledge about the low nutritional value of unhealthy snacks such as potato chips, puffs, industrial juices, and carbonated drinks was not appropriate. Many participants had the undesirable attitude of skipping one of the main meals when attempting to lose weight. Conclusions: The IRAN-ECHO program is presenting the feasibility of conducting the WHO-ECHO recommendations in Iran. The scope of potential policy recommendations to decrease childhood obesity is extensive and includes various elements. This program considers multisectoral interventions through population and individual approaches. The multicomponent interventions of this program address the obesogenic environment by considering the life course dimensions. It is expected that, by its life course interventions, it could help in primordial and primary prevention of noncommunicable diseases. PMID- 29416837 TI - A Comprehensive Health Plan: The Lifestyle Affecting Factors in Iranian Youth. AB - Background: Factors affecting lifestyle become one of the most priorities of the research field, especially in adolescents and youth. Using a qualitative approach, this study aimed to understand what factors are affecting young people's healthy lifestyle. Methods: Using the conventional content analysis, and used the semi-structured in-depth interviews, we conducted a qualitative study to elicit the youth opinion considering their lifestyle affecting factors. Initially, purposeful sampling method was considered for data collection. Participants were selected from volunteered youths 18-30 years whom were selected from the Tehran city. Inclusion criteria for the participants were; (a) willingness to participate in the study, and (b) ability to express experiences. Results: According to findings, although the majority of participants agreed on the important role of lifestyle related behaviors in their healthy life, the lack of essential motivation and the pressure of educational assignments remove it from their daily program priorities. The most important barrier to observing the healthy lifestyle was expressed as; the acceptance of the concept by the individual and the social and economic potential of the individual. It was also suggested that practical interventions should focus on improving more participator engagement of all of the related stakeholders. Conclusions: We proposed the participatory strategies for youth healthy lifestyle promotion. Through which based on a specific needs the assessment of different target groups, designing, development, and implementation of health programs led to more effective interventions. PMID- 29416838 TI - Investigating the Role of Interpersonal Sensitivity, Anger, and Perfectionism in Social Anxiety. AB - Background: The investigation of personality characteristics and emotional experiences of the people suffering from anxiety disorders is one of the most important issues which are considered by researchers and clinicians. Perfectionism, sensitivity to interpersonal rejection, and anger are personality traits related to social anxiety. In social anxiety disorder, it has also been focused on anger as a personality characteristic and as an emotional condition. The main purpose of this work is to investigate the role of these variables in predicting social anxiety among a nonclinical group of Iranian students. Methods: In this cross-sectional study, 131 students completed the self-report version of Liebowitz Social Anxiety Scale Self-Report version (LSAS-SR), Frost Multidimensional Perfectionism Scale (FMPS), Interpersonal Sensitivity Measure (IPSM), and State and Trait Anger Expression Inventory. Multiple linear regressions were conducted to examine the concurrent associations between perfectionism, interpersonal sensitivity and quality of emotional experience, and expression of anger with severity of self-report social anxiety. Results: Greater levels of FMPS total were significantly associated with a greater level of LSAS total, fear, and avoidance of social and functional situations (P = 0.022, P = 0.024, and P = 0.006). Moreover, a significant positive correlation between IPSM total (P = 0.015) with fear and also between anger expression index (P = 0.009) with avoidance subscale were found. Conclusions: In accordance to the previous researches, we found that perfectionism, interpersonal sensitivity, anger experience, and anger expression skills are related to social anxiety. How these personality traits are related to fear and avoidance of social situations and their concurrent effects on predicting social anxiety were discussed. PMID- 29416839 TI - Lead Poisoning in Opium Abuser in Iran: A Systematic Review. AB - Substance abuse and its consequences are major health hazards in the world. Opium addiction is a common form of substance abuse in Iran. Adulteration of illegal substances in the process of production and distribution of the drug in black market with many types of materials have been reported. One of the main goals of the adulteration of illegal substances is cutting of the substance for deal and increase of the weight for more benefit. However, adding of adulterating agents to illegal drugs could be considered as a cause of nonspecific and rare toxicity during substance abuse. Although the presence of lead in street-level heroin, marijuana, and amphetamines has been reported from some countries previously, recently, several reports suggested lead poisoning in Iranian opium addicts. Adulteration of opium with lead is a new source of lead poisoning in Iran in which the opium abuse is frequent and it could be a new health problem in the future. In this regard, evaluation of blood lead level would be important for early diagnosis of lead poisoning in opium addicts. PMID- 29416840 TI - Educational intervention on knowledge of cervical cancer and uptake of Pap smear test among market women in Niger State, Nigeria. AB - Cervical cancer is the most common female genital tract carcinoma worldwide. It is increasingly becoming the leading carcinoma seen among women in the developing world. The aim of our study was to showcase the effect of educational intervention on the knowledge of cervical cancer and subsequently the uptake of Pap smear test amongst market women in Niger state, Nigeria. The state has a rich network of markets in all the local government areas because of the fishing activities, bountiful agricultural produce yearly and its situation to the North of the national capital, Abuja. This was a quasi-experimental study conducted in two groups with pre and post intervention data collection. Sample size was determined based on a previous similar study done in Nigeria. Multi stage sampling technique was used for recruiting the study participants. SPSS statistical software was used for data entry, editing and analysis. Respondents' knowledge of cervical cancer were comparable at pre-intervention but were statistically significantly better (P<0.0001) at post-intervention in the intervention group compared to the control group for every variable measured. However, there was only a (Fisher's exact, P=0.621) compared to the control group. This study showed an increase in knowledge about cervical cancer and Pap smear test however the uptake of Pap smear test remained low even after intervention. This underscores the need for sustained intervention programs to eventually translate knowledge acquired to habitual practice. PMID- 29416841 TI - Effects of mother related factors on perinatal outcomes-a study of mothers seeking antenatal care at public and non-public health facilities in Kisii County, Kenya. AB - The study sought to determine clientlevel and facility-level factors that affect perinatal outcomes among women attending comparable public (government owned) and non-public health facilities (non-government owned) in Kisii County-Kenya in the context of free maternity care. A total of 365 pregnant mothers recruited in 4 health facilities during their ANC visit and followed up to 2 weeks post-delivery but only 287 attended all follow-up visits. Study subjects were recruited proportionate to number of deliveries each of the facilities had conducted in the preceding 6 months. The dependent variable was perinatal outcome; independent variables were demographic and clinical factors. Analysis was done using chi2, logistic regression, paired t and McNemar's tests. Maternal BMI and a mother's parity were statistically correlated with perinatal outcome (chi2= 8.900, d.f =3, P=0.031 and (chi2= 13.232, d.f =4, P=0.039) respectively. Mothers with 1 parity were 4.5 times more likely to have normal perinatal outcomes (OR =4.5, 95% CI 2.25-14.29, P=0.012). There was a significant relationship between a mother's knowledge of pregnancy-related issues and the baby's weight (t=-67.8 d.f. 213 P<0.001). Mothers' knowledge on pregnancy issues and spousal involvement influences perinatal outcomes. Dietary Diversity Score (DDS) of a mother does not have a direct influence on the outcome of a pregnancy. There is need to focus on maternal factors that affect perinatal outcomes besides free maternity care. PMID- 29416842 TI - Caesarean section in a primary health facility in Ghana: Clinical indications and feto-maternal outcomes. AB - There is great concern about the increasing rise in the rate of caesarean section in both developed and developing countries. This study was to ascertain the prevalence and compare outcomes of elective and emergency caesarean sections among women who deliver at the University of Cape Coast Hospital, Ghana. This retrospective study reviewed records of 645 women who delivered through caesarean sections during the period of January 2014 and December 2015. The prevalence of caesarean section was 26.9%. There was a significantly higher rate of adverse fetal outcomes (P=0.016) among babies born through emergency caesarean section. There were 12 (1.9%) women who had caesarean section done based on maternal request. The caesarean section rate found in this study was high. The lack of availability of technology for diagnosing fetal distress found in this study could possibly lead to over diagnosis of fetal distress. Thus availability of such diagnostic technology could reduce the high caesarean section rate. The high numbers of women requesting caesarean section without medical indication should be investigated and the motivation factors identified so as to curb the practice. PMID- 29416843 TI - Perceptions and practice of health care workers regarding hepatitis B vaccination, Bouake, Cote d'Ivoire, 2016. AB - Barriers to immunization are seen in both the general population and the health care workforce. We conducted this study to determine the perception of health workers on vaccination and the immunization of their patients. This cross sectional descriptive analytical study was carried out among the medical staff in Bouake, from 10 January to 07 March 2016. The data collected from the interviews were analyzed using Epi info 2000 software and SPSS 17.0. The Chi-2 test and logistic regression were performed and the significance threshold of the tests was 5%. The vaccination status of the 291 health care workers (HCWs) for the hepatitis B virus (HBV) was statistically related to their participation in the course in vaccination during their training (ORa = 1.69, 95% CI: 1.04-2.75 P<0.05) and the systematic verification of the vaccination status of the patient was statistically related to the vaccination status of the HCW (ORa = 4.33, 95% CI: 2.97-8.18, P<0.05). Promoting the vaccination among the population should be dependent on the promotion among HCWs. PMID- 29416844 TI - Negative peri-donation events among whole blood donors in a blood bank in Ibadan, Nigeria. AB - The existence and sustenance of the blood bank depends on blood donors. It is imperative that the donation experience is satisfactory for the donors. Therefore this study was carried out to determine the frequency of undesirable events experienced by the blood donor as part of donor haemovigilance. This was a retrospective descriptive study of the events that occurred amongst the blood donors of the blood bank of a tertiary institution. The blood donor incident book was reviewed for the period of six months. Negative undesirable events occurred in 2% of the donor populations, of which 45.8% could not complete the blood donation process while only 16.7% completed the blood donation process. Mild vasovagal attack occurred in 0.2% of the donor population. Undisclosed deferrable risk factors/ behaviours were identified by the phlebotomist in the bleeding room which made donors unfit for donation even though they had passed the donor screening criteria. This accounted for 20.8% of those with negative experience. Guidelines are required to identify donors that are not likely to complete donation to avoid wastage of time, blood, resources and reduce undesirable experiences. PMID- 29416845 TI - EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction. AB - Background: Genetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism. Methods: Three adults (two males, one female) with a genetically confirmed diagnosis of EHMT1 mosaicism were examined by means of a battery of tests and observational instruments covering both neurocognitive and psychiatric features. The battery included the following instruments: the Autism Diagnostic Observation Schedule (ADOS), the mini Psychiatric Assessment Schedules for Adults with Developmental Disabilities (mini PAS-ADD), the Vineland Adaptive Behavior Scales (VABS), and the Cambridge Neuropsychological Test Automated Battery (CANTAB). These measures were compared with our previously reported data from Kleefstra syndrome patients with confirmed (germline) EHMT1 defects. Results: All three subjects achieved maximum total scores on the VABS, indicative of adequate (adaptive) functioning. In all, scores above cutoff were found on the ADOS for ASD and on the mini PAS-ADD for major depressive disorder (lifetime). Finally, results on the CANTAB showed impaired cognitive flexibility in all subjects. Conclusion: Individuals with EHMT1 mosaicism seem to have increased vulnerability for developing severe psychopathology, especially ASD and mood disorders. Although at first glance they appear to be well-adapted in their daily functioning, they may experience significant psychiatric symptoms and show reduced cognitive flexibility in comparison to the general population. PMID- 29416847 TI - Development and validation of a standardized double-blind, placebo-controlled food challenge matrix for raw hazelnuts. AB - Background: Double-blind, placebo-controlled food challenge (DBPCFC) is considered the gold standard for food allergy diagnosis. However, this test is rarely performed routinely in clinical practice because of various practical issues, e.g. the lack of a standardized matrix preparation. The aim of this study was to develop and validate a convenient DBPCFC matrix, that can easily be implemented in daily clinical practice. The focus of this study was the blinding of hazelnuts, whereby the hazelnuts retained as much as possible their allergenicity and could be mixed homogenously in low-doses to the matrices. Methods: A basophil-activation test (BAT), microbial tests and an LC-MS/MS test were performed to assess respectively the allergenicity of the used hazelnuts, the microbial stability of the novel developed matrices and the homogeneity of the hazelnuts in the matrices. A sensory test was conducted to validate the blinding of the hazelnuts in the matrices. A pilot DBPCFC study included eight patients as proof of concept. Results: The BAT-test gave the first insights concerning the retained allergenicity of the hazelnuts. The microbial safety could be assured after 12 months of storage. Sufficient masking was assessed by several sensory tests. Homogeneous hazelnut distribution could be achieved for the different hazelnut concentrations. The DBPCFC's results showed diverse allergic responders (from no reactions to distinct objective symptoms). Conclusion: A novel stable and validated DBPCFC matrix using raw hazelnuts has been developed that allows easy preparation in a standardized way for convenient use in daily clinical practice.Trial registration EC Project number: EC/2015/0852; Date of registration: 13 Oct 2015; End date: 01 Feb 2017. PMID- 29416848 TI - Correction to: Better recognition, diagnosis and management of non-IgE-mediated cow's milk allergy in infancy: iMAP-an international interpretation of the MAP (Milk Allergy in Primary Care) guideline. AB - [This corrects the article DOI: 10.1186/s13601-017-0162-y.]. PMID- 29416846 TI - PML: Regulation and multifaceted function beyond tumor suppression. AB - Promyelocytic leukemia protein (PML) was originally identified as a fusion partner of retinoic acid receptor alpha in acute promyelocytic leukemia patients with the (15;17) chromosomal translocation, giving rise to PML-RARalpha and RARalpha-PML fusion proteins. A body of evidence indicated that PML possesses tumor suppressing activity by regulating apoptosis, cell cycle, senescence and DNA damage responses. PML is enriched in discrete nuclear substructures in mammalian cells with 0.2-1 MUm diameter in size, referred to as alternately Kremer bodies, nuclear domain 10, PML oncogenic domains or PML nuclear bodies (NBs). Dysregulation of PML NB formation results in altered transcriptional regulation, protein modification, apoptosis and cellular senescence. In addition to PML NBs, PML is also present in nucleoplasm and cytoplasmic compartments, including the endoplasmic reticulum and mitochondria-associated membranes. The role of PML in tumor suppression has been extensively studied but increasing evidence indicates that PML also plays versatile roles in stem cell renewal, metabolism, inflammatory responses, neural function, mammary development and angiogenesis. In this review, we will briefly describe the known PML regulation and function and include new findings. PMID- 29416849 TI - The effects of the Er:YAG laser on trabecular bone micro-architecture: Comparison with conventional dental drilling by micro-computed tomographic and histological techniques. AB - Background: The use of lasers has become increasingly common in the field of medicine and dentistry, and there is a growing need for a deeper understanding of the procedure and its effects on tissue. The aim of this study was to compare the erbium-doped yttrium aluminium garnet (Er:YAG) laser and conventional drilling techniques, by observing the effects on trabecular bone microarchitecture and the extent of thermal and mechanical damage. Methods: Ovine femoral heads were employed to mimic maxillofacial trabecular bone, and cylindrical osteotomies were generated to mimic implant bed preparation. Various laser parameters were tested, as well as a conventional dental drilling technique. The specimens were then subjected to micro-computed tomographic (MUCT) histomorphometic analysis and histology. Results: Herein, we demonstrate that mCT measurements of trabecular porosity provide quantitative evidence that laser-mediated cutting preserves the trabecular architecture and reduces thermal and mechanical damage at the margins of the cut. We confirmed these observations with histological studies. In contrast with laser-mediated cutting, conventional drilling resulted in trabecular collapse, reduction of porosity at the margin of the cut and histological signs of thermal damage. Conclusions: This study has demonstrated, for the first time, that mCT and quantification of porosity at the margin of the cut provides a quantitative insight into damage caused by bone cutting techniques. We further show that with laser-mediated cutting, the marrow remains exposed to the margins of the cut, facilitating cellular infiltration and likely accelerating healing. However, with drilling, trabecular collapse and thermal damage is likely to delay healing by restricting the passage of cells to the site of injury and causing localized cell death. PMID- 29416850 TI - People who report anomalous information reception have higher dissociation symptom scores. AB - Background: Dissociative states exist on a continuum from nonpathological expressions, such as highway hypnosis and day-dreaming, to pathological states of derealization and depersonalization. Claims of anomalous information reception (AIR) are often dismissed as symptoms of dissociation disorder, despite other studies that show otherwise. This study examined the relationship of dissociation symptoms and AIR in a large convenience sample (n= 3,984). Methods: These secondary analyses of cross-sectional survey data were examined. The survey included demographics, the Dissociation Experience Scale Taxon, and AIR data. Summary statistics and linear and logistic regressions evaluated dissociation variables and AIR endorsement relationships with and without covariates. Results: 3023 respondents with complete data were included. Participants were mostly middle aged (51 years +/- 16; range 17-96), female (70%), Caucasian (85%), college educated (88%), had an annual income over $50,000 (55%), were raised Christian (71%), and now affiliated as Spiritual but not Religious (60%). AIR ability was endorsed by 42% of participants, with their first experience starting in childhood (81%), and 53% having family members with similar experiences. The mean dissociation score was 14.4 +/- 17.3 (range 0-100) for all participants and was significantly higher for AIR claimants (18.2 +/- 19.3), as compared to non claimants (11.8 +/- 15.2; t = -10.3, p<0.000). In total, 11% of AIR non-endorsers and 22% of AIR endorsers had a cut-off score greater than 30 ( X2 = 63.0, p=<0.000). Conclusions: Both AIR claimants and non-claimants scored lower than the clinical cutoff for dissociation, with the claimants having significantly higher scores. Future studies comparing AIR claimants versus non-claimants may benefit by incorporating comprehensive dissociation symptom measurement, as well as their effects on the person's functionality, to discern the pathological versus non-pathological nature of purported AIR experiences. PMID- 29416851 TI - Effects of stress or infection on rat behavior show robust reversals due to environmental disturbance. AB - Background: The behavior of animals is intricately linked to the environment; a relationship that is often studied in laboratory conditions by using environmental perturbations to study biological mechanisms underlying the behavioral change. Methods: This study pertains to two such well-studied and well-replicated perturbations, i.e., stress-induced anxiogenesis and Toxoplasma induced loss of innate fear. Here, we demonstrate that behavioral outcomes of these experimental manipulations are contingent upon the ambient quality of the wider environment where animal facilities are situated. Results: During late 2014 and early 2015, a building construction project started adjacent to our animal facility. During this phase, we observed that maternal separation stress caused anxiolysis, rather than historically observed anxiogenesis, in laboratory rats. We also found that Toxoplasma infection caused an increase, rather than historically observed decrease, in innate aversion to predator odors in rats. Conclusion: These observations suggest that effects of stress and Toxoplasma are dependent on variables in the environment that often go unreported in the published literature. PMID- 29416852 TI - Recent advances in understanding evolution of the placenta: insights from transcriptomics. AB - The mammalian placenta shows an extraordinary degree of variation in gross and fine structure, but this has been difficult to interpret in physiological terms. Transcriptomics offers a path to understanding how structure relates to function. This essay examines how studies of gene transcription can inform us about placental evolution in eutherian and marsupial mammals and more broadly about convergent evolution of viviparity and placentation in vertebrates. Thus far, the focus has been on the chorioallantoic placenta of eutherians at term, the reproductive strategies of eutherians and marsupials, and the decidual response of the uterus at implantation. Future work should address gene expression during early stages of placental development and endeavor to cover all major groups of mammals. Comparative studies across oviparous and viviparous vertebrates have centered on the chorioallantoic membrane and yolk sac. They point to the possibility of defining a set of genes that can be recruited to support commonalities in reproductive strategies. Further advances can be anticipated from single-cell transcriptomics if those techniques are applied to a range of placental structures and in species other than humans and mice. PMID- 29416853 TI - New insights in chemokine signaling. AB - Chemokine signaling is essential for coordinated cell migration in health and disease to specifically govern cell positioning in space and time. Typically, chemokines signal through heptahelical, G protein-coupled receptors to orchestrate cell migration. Notably, chemokine receptors are highly dynamic structures and signaling efficiency largely depends on the discrete contact with the ligand. Promiscuity of both chemokines and chemokine receptors, combined with biased signaling and allosteric modulation of receptor activation, guarantees a tightly controlled recruitment and positioning of individual cells within the local environment at a given time. Here, we discuss recent insights in understanding chemokine gradient formation by atypical chemokine receptors and how typical chemokine receptors can transmit distinct signals to translate guidance cues into coordinated cell locomotion in space and time. PMID- 29416854 TI - Regulation of plasma von Willebrand factor. AB - Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays a central role in the initiation of blood coagulation. Through interactions between its specific functional domains, the vascular wall, coagulation factor VIII, and platelet receptors, VWF maintains hemostasis by binding to platelets and delivering factor VIII to the sites of vascular injury. In the healthy human population, plasma VWF levels vary widely. The important role of VWF is illustrated by individuals at the extremes of the normal distribution of plasma VWF concentrations where individuals with low VWF levels are more likely to present with mucocutaneous bleeding. Conversely, people with high VWF levels are at higher risk for venous thromboembolic disease, stroke, and coronary artery disease. This report will summarize recent advances in our understanding of environmental influences and the genetic control of VWF plasma variation in healthy and symptomatic populations and will also highlight the unanswered questions that are currently driving this field of study. PMID- 29416855 TI - Recent advances in understanding vertebrate segmentation. AB - Segmentation is the partitioning of the body axis into a series of repeating units or segments. This widespread body plan is found in annelids, arthropods, and chordates, showing it to be a successful developmental strategy for growing and generating diverse morphology and anatomy. Segmentation has been extensively studied over the years. Forty years ago, Cooke and Zeeman published the Clock and Wavefront model, creating a theoretical framework of how developing cells could acquire and keep temporal and spatial information in order to generate a segmented pattern. Twenty years later, in 1997, Palmeirim and co-workers found the first clock gene whose oscillatory expression pattern fitted within Cooke and Zeeman's model. Currently, in 2017, new experimental techniques, such as new ex vivo experimental models, real-time imaging of gene expression, live single cell tracking, and simplified transgenics approaches, are revealing some of the fine details of the molecular processes underlying the inner workings of the segmentation mechanisms, bringing new insights into this fundamental process. Here we review and discuss new emerging views that further our understanding of the vertebrate segmentation clock, with a particular emphasis on recent publications that challenge and/or complement the currently accepted Clock and Wavefront model. PMID- 29416857 TI - GLP1 and GIP are involved in the action of synbiotics in broiler chickens. AB - Background: In order to discover new strategies to replace antibiotics in the post-antibiotic era in meat-type chicken production, two new synbiotics were tested: (Lactobacillus salivarius IBB3154 plus galactooligosaccharide (Syn1) and Lactobacillus plantarum IBB3036 plus raffinose family oligosaccharides (Syn2). Methods: The synbiotics were administered via syringe, using a special automatic system, into the egg air chamber of Cobb 500 broiler chicks on the 12th day of egg incubation (2 mg of prebiotics + 105 cfu bacteria per egg). Hatched roosters (total 2,400) were reared on an experimental farm, kept in pens (75 animals per pen), with free access to feed and water. After 42 d animals were slaughtered. Blood serum, pancreas, duodenum and duodenum content were collected. Results: Syn2 increased trypsin activity by 2.5-fold in the pancreas and 1.5-fold in the duodenal content. In the duodenum content, Syn2 resulted in ca 30% elevation in lipase activity and 70% reduction in amylase activity. Syn1 and Syn2 strongly decreased expression of mRNA for GLP-1 and GIP in the duodenum and for GLP-1 receptors in the pancreas. Simultaneously, concentrations of the incretins significantly diminished in the blood serum (P < 0.05). The decreased expression of incretins coincides with changed activity of digestive enzymes in the pancreas and in the duodenal content. The results indicate that incretins are involved in the action of Syn1 and Syn2 or that they may even be their target. No changes were observed in key hormones regulating metabolism (insulin, glucagon, corticosterone, thyroid hormones, and leptin) or in metabolic indices (glucose, NEFA, triglycerides, cholesterol). Additionally, synbiotics did not cause significant changes in the activities of alanine and aspartate aminotransferases in broiler chickens. Simultaneously, the activity of alkaline phosphatase and gamma glutamyl transferase diminished after Syn2 and Syn1, respectively. Conclusion: The selected synbiotics may be used as in ovo additives for broiler chickens, and Syn2 seems to improve their potential digestive proteolytic and lipolytic ability. Our results suggest that synbiotics can be directly or indirectly involved in incretin secretion and reception. PMID- 29416858 TI - A data infrastructure for the assessment of health care performance: lessons from the BRIDGE-health project. AB - The integration of different administrative data sources from a number of European countries has been shown useful in the assessment of unwarranted variations in health care performance. This essay describes the procedures used to set up a data infrastructure (e.g., data access and exchange, definition of the minimum common wealth of data required, and the development of the relational logic data model) and, the methods to produce trustworthy healthcare performance measurements (e.g., ontologies standardisation and quality assurance analysis). The paper ends providing some hints on how to use these lessons in an eventual European infrastructure on public health research and monitoring. Although the relational data infrastructure developed has been proven accurate, effective to compare health system performance across different countries, and efficient enough to deal with hundred of millions of episodes, the logic data model might not be responsive if the European infrastructure aims at including electronic health records and carrying out multi-cohort multi-intervention comparative effectiveness research. The deployment of a distributed infrastructure based on semantic interoperability, where individual data remain in-country and open access scripts for data management and analysis travel around the hubs composing the infrastructure, might be a sensible way forward. PMID- 29416859 TI - Applying realistic medicine to intrathecal opioid utilisation in Scotland: do we have a standardised approach? AB - Intrathecal opioids (ITOs) are commonly administered as part of a multimodal anaesthetic strategy for a variety of surgical procedures. The evolution of laparoscopic surgical techniques has seen the popularity of ITOs increase as they are effective, well tolerated and lack the cardiovascular side effects associated with epidural infusions. The risk of delayed respiratory depression remains a concern; therefore, high-quality post-operative monitoring is vital. The evidence regarding the practicalities of ITO administration such as opioid dose, type, side effect prevalence and ideal post-operative care arrangements are sparse. As such, a variety of clinical opinion has been generated. In order to quantify this variation within Scotland, we devised a short telephone questionnaire regarding ITO utilisation. We contacted 16 acute surgical sites. Of these, 14 confirmed regular utilisation of ITOs. Our survey demonstrated significant variability in practice. Both diamorphine and morphine are utilised, but no centre could provide a reason to justify the choice of one over the other. The commonly administered dose range for both agents ranged between 100 and 1100 ug. Most centres employed post-operative monitoring geared towards the detection of delayed respiratory depression but this was not unanimous. Each centre had a variation on what observations nursing staff were expected to complete in the post-operative period. Itch and nausea were not encountered frequently. Two centres experienced at least one episode of delayed respiratory depression which was detected and treated with no patient harm. In the report to the Scottish Government, 'Realistic Medicine', by the Chief Medical Officer, the need to reduce unnecessary variation in practice and outcomes is highlighted. We believe that a national sprint audit would gather sufficient prospective data to further determine whether a correlation exists between side effect profile and ITO utilisation practice. We hope this would help form a consensus and guide a standardised approach. PMID- 29416856 TI - Effects of Bacillus coagulans supplementation on the growth performance and gut health of broiler chickens with Clostridium perfringens-induced necrotic enteritis. AB - Background: The poultry industry is in need of effective antibiotic alternatives to control outbreaks of necrotic enteritis (NE) due to Clostridium perfringens. Methods: This study was conducted to investigate the effects of feeding Bacillus coagulans on the growth performance and gut health of broiler chickens with C. perfringens-induced NE. Two hundred and forty 1-day-old broiler chicks were randomly assigned to a 2 * 2 factorial arrangement with two dietary B. coagulans levels (0 or 4 * 109 CFU/kg of diet) and two disease challenge statuses (control or NE challenged). Results: NE-induced reduction in body weight gain was relieved by the addition of B. coagulans into broiler diets compared with the NE-infected birds. NE infection damaged intestinal morphological structure, promoted intestinal C. perfringens growth and liver invasion, and enhanced anti-C. perfringens specific sIgA concentrations in the gut and specific IgG levels in serum compared with the uninfected birds. NE infection significantly (P < 0.05) decreased mucin-2 (at 14 d post-infection (DPI), toll -like receptor 2 (TLR2, at 7 and 14 DPI), TLR4 (at 7 and 14 DPI), tumor necrosis factor super family 15 (TNFSF15, at 7 and 14 DPI), lysozyme (LYZ, at 14 DPI) and fowlicidin-2 (at 7 and 14 DPI) mRNA levels, whereas it dramatically (P = 0.001) increased IFN-gamma mRNA levels at 7 DPI. However, challenged birds fed diets supplemented with B. coagulans showed a significant (P < 0.01) decrease in gut lesion scores, decreased C. perfringens numbers in the cecum and liver, and an increase in fowlicidin-2 mRNA levels in compared with the uninfected birds. In addition, compared with the non-supplemented group, dietary inclusion of B. coagulans improved intestinal barrier structure, further increased specific sIgA levels and alkaline phosphatase (IAP) activity in the jejunum, enhanced the expression of jejunum lysozyme mRNA, and inhibited the growth, colonization, and invasion of C. perfringens; in contrast, it reduced serum-specific IgG concentrations and jejunum IFN-gamma mRNA levels. Conclusion: These results indicated that dietary B. coagulans supplementation appeared to be effective in preventing the occurrence and reducing the severity of C. perfringens-induced NE in broiler chickens. PMID- 29416860 TI - Better safe than sorry? Frequent attendance in a hospital emergency department: an exploratory study. AB - Introduction: Pain accounts for the majority of attendances to the Emergency Department (ED), with insufficient alleviation of symptoms resulting in repeated attendance. People who frequently attend the ED are typically considered to be psychologically and socially vulnerable in addition to experiencing health difficulties. This service development study was commissioned to identify the defining characteristics and unmet needs of frequent attenders (FAs) in a UK acute district general hospital ED, with a view to developing strategies to meet the needs of this group. Methods: A mixed-methods multi-pronged exploratory approach was used, involving staff interviews, focus groups, business data and case note analysis. Results: Findings reflect an absence of a coherent approach to meeting the needs of FAs in the ED, especially those experiencing pain. FAs to this ED tend to be vulnerable, complex and report significant worry and anxiety. Elevated anxiety on the part of the patient may be contributing to a 'better safe than sorry' culture within the ED and is reported to bear some influence on the clinical decision-making process. Discussion: It is recommended that a systemic approach is taken to improve the quality and accessibility of individualised care plans, provision of patient education, psychological care and implementation of policies and procedures. Change on an organisational level is likely to improve working culture, staff satisfaction and staff relationships with this vulnerable group of patients. A structured care pathway and supportive changes are likely to lead to economic benefits. Further research should build on findings to implement and test the efficacy of these interventions. PMID- 29416861 TI - Prevalence and management of intrathecal morphine-induced pruritus in New Zealand Maori healthcare recipients. AB - Aims and objectives: The aim of this article was to determine whether the incidence of intrathecal morphine-induced pruritus (ITMI) was influenced by ethnicity, age or gender in relation to orthopaedic versus caesarean surgeries. Background: The use of intrathecal morphine for patients undergoing total hip and knee joint replacements and for lower segment caesarean sections (LSCS) has gained popularity worldwide since its introduction over 30 years ago. Several international studies show that morphine delivered via the intrathecal route is an effective and safe method of pain relief. However, while the beneficial effects of intrathecal morphine have been clearly documented in many studies, so also have the adverse effects, predominantly being nausea and vomiting, pruritus and respiratory depression. Pruritus is described as one of the most common adverse effects, with a reported incidence of 30-100%. Design: A retrospective study was conducted using data collected over a 21-month period on post-operative patients who had received intrathecal morphine as their post-operative pain management. Methods: A two-phased approach was undertaken. The study was conducted to determine the incidence of ITMI pruritus among two patient groups, New Zealand Maori and New Zealand European, 96 subjects in total, and if treatment was received. Results: The findings revealed significant ethnic disparities whereas New Zealand Maori had a significantly higher rate of ITMI pruritus than New Zealand European, New Zealand Maori experienced the pruritus with more intensity and are less likely to be treated for it. Conclusion: Increased international knowledge and awareness for health professionals around the diversities of ethnicity and associated pharmacogenetics playing a significant role in patient response to opioid therapy can lead to improved overall care and patient satisfaction. PMID- 29416862 TI - Tramadol sparing effect of dexmedetomidine as an adjuvant with lignocaine in preoperative stellate ganglion block for postoperative pain relief following upper limb surgeries. AB - Background: Recent literature has established the role of stellate ganglion block (SGB) for management of acute postoperative pain. The effects of dexmedetomidine as an adjuvant to lignocaine in a preoperative SGB for postoperative pain relief have not been evaluated so far. Methods: The following randomised, double blinded, control trail included 54 patients scheduled for upper limb orthopaedic surgery under general anaesthesia. Preoperative ultrasound-guided (USG) SGB was performed in all patients. Group I (n = 18) received 3.5 mL of a solution (3 mL 2% lignocaine + 0.5 MUg/kg dexmedetomidine for SGB) and 15 mL of intravenous (IV) normal saline (NS). Group II (n = 18) received 3.5 mL of a solution (3 mL 2% lignocaine + 0.5 mL NS for SGB) and 15 mL of IV NS. Group III (n = 18) received 3.5 mL of a solution (3 mL 2% lignocaine + 0.5 mL of NS for SGB) and 0.5 MUg/kg dexmedetomidine in 15 mL of IV NS. Postoperatively tramadol consumption and Visual Analogue Scale (VAS) score were recorded up to 48 hours. Results: The cumulative tramadol consumption at the end of 48 hours (p = 0.01) was significantly reduced in the group I as compared to group II. In group I, postoperative VAS at rest was significantly reduced up to 12 hours postoperatively as compared to group II (p = 0.05). The cumulative tramadol consumption was not reduced significantly in group III compared to group II (p = 0.51). Conclusion: Dexmedetomidine as an adjuvant to SGB along with lignocaine produced a significant tramadol sparing effect and superior analgesia as compared to IV dexmedetomidine and control group.1. PMID- 29416863 TI - Dimension of pain-related quality of life and self-reported mental health in men and women of the European Prospective Investigation into Cancer-Norfolk cohort: a population-based cross-sectional study. AB - Both cognitive and behavioural factors are linked to the experience of pain as well as its interference with quality of life. Psychological distress has been shown to be associated to several emotional and social impairments. Although, the association between pain and mental health has been widely discussed, the understanding of life interference and outcome is not fully understood. This study examined the association of pain dimension and mental health domain in 16,051 participants of the EPIC-Norfolk cohort (mean age = 58.9 +/- 9.1 years). Study outcomes were depressive or anxious behaviour and limitations due to emotional problems and impairments in social functioning (mental functional health components of the Short Form-36 (SF-36)). Logistic regression models were constructed controlling for the potentially confounding factors including socio economic variables (occupational social class, deprivation, marital status, education), lifestyle behaviour (physical activity, smoking, alcohol, dietary) and previous medical history. Strong interference in quality of life due to pain (bottom 20% of pain dimension score of SF-36) was significantly associated with poor MH in men and women (odds ratios (ORs) (95% confidence intervals (CIs)): 1.35 (1.19, 1.54) and 1.39 (1.25, 1.55), respectively; p < 0.0001) in fully adjusted models. Moreover, strong interference due to pain was also significantly associated with poor overall MH including emotional and social functioning (ORs (95% CIs): 1.42 (1.25, 1.62) and 1.39 (1.25, 1.55) respectively; p < 0.0001) in fully adjusted models; subsidiary analysis using linear regression models demonstrated similar results for these domains. Although a strong association has been shown, further research is needed to provide information on the different site and/or causes of pain which would allow stratification. Moreover, assuming a bi-directional nature of both domains, systematic assessment and management of pain have a lot of potential to improve the MH-related quality of life in the general population and vice versa. PMID- 29416864 TI - A national survey of pain clinics within the United Kingdom and Ireland focusing on the multidisciplinary team and the incorporation of the extended nursing role. AB - Inconsistencies in the availability and quality of pain service provision have been noted nationally, as have lengthy waiting times for appointments and lack of awareness of the Pain Clinic role. The 2013 NHS England report stated that specialist pain services must offer multispecialty and multidisciplinary pain clinics. This national survey of multidisciplinary pain service provision in the United Kingdom and Ireland provides a snapshot of pain service provision in order to review and highlight what variations exist in multidisciplinary team (MDT) provision and working patterns. A common perception among clinicians is that financial pressures have led to alternate ways of staff utilisation with variable degrees of success. The survey included 143 pain clinics, focusing principally on MDT working patterns, MDT composition and adoption of the extended role. The results identified that the majority of Pain Clinics utilise the MDT approach. However, provision of critical components such as regular MDT meetings is highly variable as is the composition of the MDT itself and also working patterns of the individual clinicians. The survey reports the successful use of the extended roles for specialist nurses in follow up clinics. In contrast, the survey highlights that a large proportion of clinicians surveyed have reservations about both the effectiveness and the safety of utilising specialist nurses in the extended role to see new referrals of complex pain patients to pain clinics. This survey underlines the essential requirement for incorporation of greater MDT working locally and nationally and allocation of appropriate resources to facilitate this. PMID- 29416865 TI - A week of pain in the emergency department. AB - Background: Pain is a common complaint in patients attending the emergency department (ED), and historically, it is under-assessed and undertreated. Previous research is heterogeneous and does not well describe pain in EDs over time. Our aim was to describe pain in a UK ED using a sample that included every adult attendance over the course of 1 week. Methods: We retrospectively reviewed every adult attendance (N = 1872) over 1 week to the ED of a large English NHS District General Hospital. We noted the initial pain score and, if the initial score was >=5, the final recorded pain score. We categorised attendances as 'illness' or 'injury'. Results: In all, 62.1% of patients had a pain score recorded, of whom 50.7% had a pain score of zero. Median pain score was 6/10 in patients with pain; 58% had a second score recorded. More patients with illness than injury had a second score recorded. Most patients had an improvement in their pain; however, around one-third had no change or worse pain at the end of their ED stay. Conclusion: We have defined the incidence, severity and change in pain in an ED over 1 week. This information will underpin the design of future studies aimed at improving patient care in this important area of emergency medicine practice. PMID- 29416866 TI - The evolution of fibrin-specific targeting strategies. AB - Fibrin-specific targeting capabilities have been highly sought for over 50 years due to their implications for bio-molecule delivery, diagnostics, and regenerative medicine. Yet only recently has our full knowledge of fibrin's complex polymerization dynamics and biological interactions begun to be fully exploited in pursuit of this goal. This highlight will discuss the range of rapidly changing strategies for specifically targeting fibrin over the precursor fibrinogen and the advantages and disadvantages of these approaches for various applications. PMID- 29416867 TI - Onco-testicular sperm extraction (Onco-TESE) from a single testis with metachronous bilateral testicular cancer: a case report. AB - Background: Although oncologic testicular sperm extraction (onco-TESE) has been increasingly practiced, the evidence of onco-TESE performed in patients with testicular cancer is insufficient. Furthermore, in bilateral testicular cancer, accounting for 0.5%-1% of testicular cancers, onco-TESE is more challenging and has been insufficiently reported. Case presentation: Here we report the case of a 25-year-old man who underwent onco-TESE from his residual single testis with a nonseminomatous germ cell tumor that occurred 5 years after orchiectomy of the contralateral testis. A second orchiectomy and simultaneous TESE from the noncancerous testicular tissue were performed. The pathological diagnosis was germ cell tumors, tumors of more than one histological type (embryonal carcinoma, immature teratoma, yolk sac tumor, seminoma, and choriocarcinoma; pT1N0M0). The patient subsequently married and hoped for fatherhood 3 years later. Whereas histological diagnosis of the normal testicular tissue was Johnsen score 6 (maturation arrest), morphologically normal and motile sperms were successfully retrieved from thawed TESE samples and used for multiple cycles of intracytoplasmic sperm injection. Although the conception has not been succeeded to date, ICSI attempts have been continuing. Conclusion: This case demonstrates the effectiveness of onco-TESE for challenging cases such as bilateral and nonseminmatous testicular cancer. PMID- 29416868 TI - Clinical outcomes of patients undergoing primary percutaneous coronary intervention for acute myocardial infarction requiring the intensive care unit. AB - Background: Outcomes for patients with ST-segment elevation myocardial infarction continue to improve, largely due to timely provision of reperfusion by primary percutaneous coronary intervention (PPCI). However, despite prompt and successful PPCI, a small proportion of patients require ventilatory and hemodynamic support in an intensive care unit (ICU). The outcome of these patients remains poorly defined. Methods: A retrospective review of all consecutive admissions post-PPCI pathway to a single ICU between January 2009 and May 2014 was performed. Patients were analysed based on survival and indication for admission. Preadmission characteristics and ICU course were reviewed. Univariate and multivariable regression analysis was performed to determine predictors of outcome. Results: During the study period 2902 PPCI were performed and 101 patients were admitted to ICU following PPCI (incidence 3.5%). ICU mortality post-PPCI was 33.7%. Pre ICU admission factors in a multivariable logistic regression analysis associated with increased mortality included requirement for an intra-aortic balloon pump and a high SOFA score. Conclusions: ICU admission post PPCI is associated with significant mortality. Mortality was related to high presenting SOFA score and need for IABP. These results provide important prognostic information and an acceptable method for risk-stratifying patients with acute myocardial infarction requiring intensive care. PMID- 29416869 TI - Cultural differences in food and shape related attitudes and eating behavior are associated with differences of Body Mass Index in the same food environment: cross-sectional results from the Seafarer Nutrition Study of Kiribati and European seafarers on merchant ships. AB - Background: Overweight and obesity is quite prevalent among seafarers. The present study examined differences in BMI and their association with weight, shape and nutrition related attitudes and perceptions among seafarer from Kiribati, a Pacific Island Group, and European origin. Methods: The Seafarer Nutrition Study compared 48 Kiribati and 33 European male seafarers from 4 commercial merchant ships. BMI was calculated from measured weight and height. Attitudes to weight, shape and nutrition and disinhibition of control as a characteristic of eating behavior were assessed in a structured interview. Differences between the two groups were examined using t-tests and Chi-square tests as appropriate. Associations between the variables were examined using Multiple Regression Analysis (MRA) and correlations. Results: Kiribati seafarer had significantly higher BMI than Europeans (30.3 +/- 4.2 vs. 25.6 +/- 3.4; p < 0.001). However, MRA indicated that Kiribati were choosing thinner shapes as being "most similar" to their appearance than Europeans with the same BMI (B = - 1.14; p < 0.05). In addition, Kiribati had significantly higher scores of disinhibition than Europeans (5.6 +/- 2.2 vs. 4.3 +/- 2.1; p < 0.01), and disinhibition correlated with BMI in the Kiribati (r = 0.39; p < 0.01), but not in the European group (r = 0.17; n.s.). Conclusions: For Kiribati seafarers the nutrition situation on board represents a highly tempting westernized food environment. Their tendency to disinhibited eating facilitates overconsumption and weight gain, and self-evaluation of their shapes as being thinner than comparable Europeans may hamper appropriate weight control behavior. PMID- 29416871 TI - Anesthesiology Control Tower: Feasibility Assessment to Support Translation (ACT FAST)-a feasibility study protocol. AB - Background: Major postoperative morbidity and mortality remain common despite efforts to improve patient outcomes. Health information technologies have the potential to actualize advances in perioperative patient care, but failure to evaluate the usability of these technologies may hinder their implementation and acceptance. This protocol describes the usability testing of an innovative telemedicine-based intra-operative clinical support system, the Anesthesiology Control Tower, in which a team led by an attending anesthesiologist will use a combination of established and novel information technologies to provide evidence based support to their colleagues in the operating room. Methods: Two phases of mixed-methods usability testing will be conducted in an iterative manner and will evaluate both the individual components of the Anesthesiology Control Tower and their integration as a whole. Phase I testing will employ two separate "think aloud" protocol analyses with the two groups of end users. Segments will be coded and analyzed for usability issues. Phase II will involve a qualitative and quantitative in situ usability and feasibility analysis. Results from each phase will inform the revision and improvement of the Control Tower prototype throughout our testing and analysis process. The final prototype will be evaluated in the form of a pragmatic randomized controlled clinical trial. Discussion: The Anesthesiology Control Tower has the potential to revolutionize the standard of care for perioperative medicine. Through the thorough and iterative usability testing process described in this protocol, we will maximize the usefulness of this novel technology for our clinicians, thus improving our ability to implement this innovation into the model of care for perioperative medicine. Trial registration: The study that this protocol describes has been registered in clinicaltrials.gov as NCT02830126. PMID- 29416870 TI - A research protocol for a pilot randomized controlled trial designed to examine the feasibility of a couple-based mind-body intervention for patients with metastatic lung cancer and their partners. AB - Background: Given the generally incurable nature of metastatic non-small cell lung cancer (mNSCLC), patients and their romantic partners are at risk for existential/spiritual distress. Although a handful of dyadic psychosocial interventions for lung cancer patients and their caregivers exist, none of them target spiritual well-being. Informed by the mindfulness-based intervention literature and our pilot work in couples affected by lung cancer, we developed a brief couple-based mind-body (CBMB) intervention. The primary aim of this research protocol is to determine the feasibility of implementing the CBMB intervention versus an active control (AC) or wait list control (WLC) group in patients with mNSCLC and their partners using a randomized controlled trial design. Methods: Seventy-five patients with mNSCLC receiving treatment and their partners are randomized to the CBMB intervention, an AC or a WLC group. Those in the CBMB intervention and AC groups receive four intervention sessions of 60 min each over 4 weeks and complete weekly homework assignments. The first session is delivered in person, and the remaining sessions are delivered via videoconference. The dyads in the AC group discuss cancer-related and personal growth concerns with the interventionist but are not taught coping skills. Patients and partners in all groups complete baseline assessments of quality of life (QOL) prior to randomization. Follow-up assessments are performed 4 weeks and then again 3 months later. The primary outcome is feasibility (i.e., >= 30% of eligible couples consent, >= 70% of enrolled couples are retained, and >= 50% of all CBMB and AC sessions are attended). We will also perform primarily descriptive analyses of the self-reported outcomes (e.g., spiritual well-being and psychological distress) and explore potential intervention mediators (i.e., compassion, communication, mindfulness, and closeness) to inform a larger, future trial. Discussion: This trial will provide important information regarding the feasibility of a behavioral intervention in a vulnerable yet understudied population using videoconferencing and descriptive data regarding spiritual well being and other indices of QOL in both mNSCLC patients and their partners. Trial registration: ClinicalTrials.gov NCT02596490. PMID- 29416872 TI - Feasibility of using risk prompts to prevent falls, dehydration and pulmonary aspiration in nursing homes: a clinical study protocol. AB - Background: Evidence has shown a relationship between dehydration, falls, and pulmonary aspiration among older adults in nursing homes, all of which contribute to loss of independence and quality of life. It is believed that improving communication among healthcare professionals in nursing homes (physicians, nurses, rehabilitation team, psychologist, social workers, dieticians and medical assistants) decreases the number of adverse events in institutionalized patients. This study will evaluate the feasibility of using a set of written signs, designed to caution against the risk of falls, dehydration, and pulmonary aspiration, and will enable the proposal of tailored interventions to manage these events in nursing homes. Methods/Design: All patients from Campus Neurologico Senior (CNS) nursing home, at risk of falls and/ordysphagia and/or dehydration will be invited to participate in the study. Patients will undertake a screeningrisk assessment and the corresponding risk prompts will be attributed. Study duration will be a minimum ofthree months per participant, including daily record of falls, dehydration and pulmonary aspiration eventsand monthly interview assessments, conducted by a member of the research team. Data of the events that occur will be compared with historical data extracted retrospectively from medical and nursing charts. This study has been approved by the Ethics Committee of the Medical Academic Center of Lisbon, Faculty of Medicine, University of Lisbon (Ref. 176/15). All participants will give their written informed consent before entering the study. Discussion: This study is unique in evaluating the feasibility of a communication system in preventing the three major risks in nursing home. Thoughtful selection and display of proper risk prompts in nursing homes could be an essential step along a path toward efficient communication of risks among healthcare teams. We expect that the displays will be easily applicable given their simplicity, low complexity, and minimal physical requirements. Trial registration: NCT03123601. March 7, 2017. Retrospectively registered. PMID- 29416874 TI - Optimization of commercially available Zika virus antibodies for use in a laboratory-developed immunohistochemical assay. AB - Zika virus (ZIKV) infection during pregnancy can cause adverse fetal outcomes and severe irreversible congenital birth defects including microcephaly. Immunohistochemistry (IHC) is a valuable diagnostic tool for detecting ZIKV antigens in tissues from cases of fetal loss in women infected with ZIKV, and for providing insights into disease pathogenesis. As a result, there is increasing demand for commercially available ZIKV antibodies for use in IHC assays. ZIKV antibodies were selected and obtained from commercial sources to include both mouse and rabbit hosts, and a variety of antigenic targets. Pretreatment conditions and antibody concentrations resulting in optimal immunohistochemical staining were determined using ZIKV cell control and polymerase chain reaction (PCR)-confirmed ZIKV case control material (fetal brain tissue). Cross-reactivity of the antibodies against other flaviviruses (dengue virus serogroups 1-4, yellow fever virus, Japanese encephalitis virus, West Nile virus) and chikungunya virus was also evaluated. Immunostaining using the commercially available antibodies was compared to a previously validated ZIKV IHC assay used for primary diagnosis. Four antibodies demonstrated optimal staining similar to the previously validated ZIKV IHC assay. Two of the four antibodies cross-reacted with dengue virus, while the other two antibodies showed no cross-reactivity with dengue, other flaviviruses, or chikungunya virus. Differences in the cross-reactivity profiles could not be entirely explained by the antigenic target. Commercially available ZIKV antibodies can be optimized for use in IHC testing to aid in ZIKV diagnostic testing and an evaluation of tissue tropism. PMID- 29416875 TI - Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma. AB - Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ~50% of patients. The tumour suppressor BAP1 is considered to be key in UM progression. Herein, we present the largest study to date investigating cellular expression patterns of BAP1 protein in 165 UMs, correlating these patterns to prognosis. Full clinical, histological, genetic, and follow-up data were available for all patients. BAP1 gene sequencing was performed on a subset of 26 cases. An independent cohort of 14 UMs was examined for comparison. Loss of nuclear BAP1 (nBAP1) protein expression was observed in 54% (88/165) UMs. nBAP1 expression proved to be a significant independent prognostic parameter: it identified two subgroups within monosomy 3 (M3) UM, which are known to have a high risk of metastasis. Strikingly, nBAP1-positiveM3 UMs were associated with prolonged survival compared to nBAP1-negative M3 UMs (Log rank, p = 0.014). nBAP1 protein loss did not correlate with a BAP1 mutation in 23% (6/26) of the UMs analysed. Cytoplasmic BAP1 protein (cBAP1) expression was also observed in UM: although appearing 'predominantly diffuse' in most nBAP1 negative UM, a distinct 'focal perinuclear' expression pattern - localized immediately adjacent to the cis Golgi - was seen in 31% (18/59). These tumours tended to carry loss-of-function BAP1 mutations. Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression. Our data suggest that non-genetic mechanisms account for nBAP1 loss in a small number of UMs. In addition, we describe a subset of nBAP1-negative UM, in which BAP1 is sequestered in perinuclear bodies, most likely within Golgi, warranting further mechanistic investigation. PMID- 29416873 TI - Biomarker discovery for renal cancer stem cells. AB - Characterised by high intra- and inter-tumor heterogeneity, metastatic renal cell carcinoma (RCC) is resistant to chemo- and radiotherapy. Therefore, the development of new prognostic and diagnostic markers for RCC patients is needed. Cancer stem cells (CSCs) are a small population of neoplastic cells within a tumor which present characteristics reminiscent of normal stem cells. CSCs are characterised by unlimited cell division, maintenance of the stem cell pool (self renewal), and capability to give rise to all cell types within a tumor; and contribute to metastasis in vivo (tumourigenicity), treatment resistance and recurrence. So far, many studies have tried to establish unique biomarkers to identify CSC populations in RCC. At the same time, different approaches have been developed with the aim to isolate CSCs. Consequently, several markers were found to be specifically expressed in CSCs and cancer stem-like cells derived from RCC such as CD105, ALDH1, OCT4, CD133, and CXCR4. However, the contribution of genetic and epigenetic mechanisms, and tumor microenvironment, to cellular plasticity have made the discovery of unique biomarkers a very difficult task. In fact, contrasting results regarding the applicability of such markers to the isolation of renal CSCs have been reported in the literature. Therefore, a better understanding of the mechanism underlying CSC may help dissecting tumor heterogeneity and drug treatment efficiency. PMID- 29416876 TI - Histological scoring of immune and stromal features in breast and axillary lymph nodes is prognostic for distant metastasis in lymph node-positive breast cancers. AB - The prognostic importance of lymph node (LN) status and tumour-infiltrating lymphocytes (TILs), is well established, particularly TILs in triple negative breast cancers (TNBCs). So far, few studies have interrogated changes in involved and uninvolved LNs and evaluated if their morphological patterns add valuable information for the prediction of disease progression in breast cancer. In a cohort of 309 patients enriched for TNBCs (170/309), we histologically characterised immune and stromal features in primary tumours and associated involved and uninvolved axillary LNs on routine haematoxylin and eosin stained sections. Of the 309 patients, 143 had LN-positive disease. Twenty-five histopathological features were assessed, including the degree of TIL presence, quantitative and qualitative assessment of germinal centres (GCs) and sinus histiocytosis. Multivariate and cross-validated proportional hazard regression analyses were used to identify optimal covariate sets for prediction of distant metastasis-free survival (DMFS). The degree of intratumoural and peritumoural immune infiltrate was associated with architectural changes in both uninvolved and involved LNs. By including clinicopathological characteristics as well as tumour and LN histopathological features in L2-regularised proportional hazard models, the prediction of 5-year DMFS was improved by 3-15% over the baseline in all cancers and in TNBCs. In LN-positive cancers, the combination of Salgado's classification, lymphocytic lobulitis, size and number of GCs in the uninvolved LNs and location of GCs in the involved LNs carried significant prognostic information. From these features, a multivariate cross-validation-stable risk signature was constructed, which identified low-risk groups within both LN positive breast cancers and the LN-positive TNBCs group with a 10-year DMFS probability of 78 and 87%, respectively. This study illustrates that, by incorporating histopathological patterns of involved and uninvolved LNs combined with primary tumour immune and stromal features, the prediction of developing distant metastasis in LN-positive breast cancers can be estimated more accurately. PMID- 29416877 TI - IDK1 is a rat monoclonal antibody against hypoglycosylated bone sialoprotein with application as biomarker and therapeutic agent in breast cancer skeletal metastasis. AB - Changes in glycosylation are salient features of cancer cells. Here, we report on the diagnostic and therapeutic properties of IDK1, an antibody against tumour associated, hypoglycosylated bone sialoprotein (hypo-BSP). The affinity of the rat monoclonal antibody IDK1 for hypo-BSP, as determined by microscale thermophoresis, was three orders of magnitude higher than for mature BSP, whereas the mouse monoclonal antibody used had similar affinity for both BSP forms. IDK1 showed no activity against the proliferation or migration of normal or cancer cells growing in vitro. In vivo, however, IDK1 caused dose-dependent regression of soft tissue and skeletal lesions in nude rats harbouring human MDA-MB-231 cells. At optimal dose, 80% of the treated rats showed complete remission of all tumour lesions. Analysis of BSP expression in vitro by fluorescence-activated cell sorting (FACS) and immunocytochemistry showed basal levels of this protein, which were visible only in a fraction of these cells. Cells of the metastatic cell lines MDA-MB-231 and PC-3 were more often positive for hypo-BSP. In addition, there was co-expression of both forms in some cells, but almost no co localization; rather, hypo-BSP was present in the nucleus, and mature BSP was detected extra-cellularly. Normal osteoblasts and osteoclasts were negative for hypo-BSP. Breast cancer tissue, however, showed strong expression of mature BSP, which was present intra-cellularly as well as in vesicles outside cells. Hypo-BSP was present mainly in lesions from skeletal sites, thus explaining the antineoplastic activity of IDK1, which was high in lesions growing in the vicinity of the skeleton but low in lesions growing subcutaneously. Finally, hypo BSP was detected in specimens from breast cancer patients, with a significantly greater intensity in skeletal metastases as compared to the respective primary cancers. In conclusion, IDK-1 is an antibody with diagnostic and therapeutic applications in skeletal metastases of breast cancer. PMID- 29416878 TI - Genomic profiling identifies GPC5 amplification in association with sarcomatous transformation in a subset of uterine carcinosarcomas. AB - Uterine carcinosarcoma, also known as Malignant Mixed Mullerian Tumour, is a high grade biphasic neoplasm composed of sarcomatous elements thought to originate via transdifferentiation from high-grade endometrial carcinoma. To identify molecular factors contributing to the histogenesis of this tumour, we analyzed DNA extracted from matched carcinoma and sarcoma components from 12 cases of carcinosarcoma by a molecular inversion probe microarray to assess genomic copy number alterations (CNAs) and allelic imbalances. Widespread CNAs were identified in tumours with serous histology in the carcinoma component (9/12), while the remaining three cases with endometrioid carcinoma were near-diploid. Quantification of the extent of genomic aberrations revealed a significant increase in sarcoma relative to carcinoma in tumours with well-delineated histologic components. Focal amplification of 13q31.3 was identified in 6/12 profiled tumours, of which four harboured the aberration exclusively in the sarcoma component. This result was verified by fluorescence in situ hybridization against GPC5, the only gene situated within the minimal region of amplification. In a validation cohort composed of 97 carcinosarcomas and other uterine sarcomas, amplification of GPC5 (GPC5/CEP13 ratio >= 2.2) was identified in 11/97 (11.3%) cases (9/64 carcinosarcoma, 1/3 rhabdomyosarcoma, 1/21 leiomyosarcoma, 0/8 adenosarcoma, 0/1 undifferentiated endometrial sarcoma) and an additional 4 (2.8%) cases had low level gains (GPC5/CEP13 ratio >=1.5 but <2.2). The functional relevance of Glypican-5, the gene product of GPC5, in regulating differentiation and lineage commitment was demonstrated in an endometrial carcinoma cell line in vitro. In conclusion, we identified GPC5 amplification as a molecular event mediating epithelial-mesenchymal transdifferentiation in a subset of uterine carcinosarcomas. PMID- 29416879 TI - Establishing research priorities relating to the long-term impact of TIA and minor stroke through stakeholder-centred consensus. AB - Plain English summary: What is the problem and why is this important? Mini strokes are similar to full strokes, but symptoms last less than 24 h. Many people (up to 70%) have long-term problems after a mini-stroke, such as anxiety; depression; problems with brain functioning (like memory loss); and fatigue (feeling tired). However, the current healthcare pathway only focuses on preventing another stroke and care for other long-term problems is not routinely given. Without proper treatment, people with long-term problems after a mini stroke could have worse quality of life and may find it difficult to return to work and their social activities. What is the aim of the research? We wanted to understand the research priorities of patients, health care professionals and key stakeholders relating to the long-term impact of mini-stroke. How did we address the problem? We invited patients, clinicians, researchers and other stakeholders to attend a meeting. At the meeting people discussed the issues relating to the long-term impact of mini-stroke and came to an agreement on their research priorities. There were three stages: (1) people wrote down their individual research suggestions; (2) in smaller groups people came to an agreement on what their top research questions were; and (3) the whole group agreed final research priorities. What did we find? Eleven people attended who were representatives for patients, GPs, stroke consultants, stroke nurses, psychologists, the Stroke Association (charity) and stroke researchers, The group agreed on eleven research questions which they felt were the most important to improve health and well being for people who have had a mini-stroke.The eleven research questions encompass a range of categories, including: understanding the existing care patients receive (according to diagnosis and geographical location); exploring what optimal care post-TIA/minor stroke should comprise (identifying and treating impairments, information giving and support groups) and how that care should be delivered (clinical setting and follow-up pathway); impact on family members; and education/training for health care professionals. Abstract: Background Clinical management after transient ischaemic attack (TIA) and minor stroke focuses on stroke prevention. However, evidence demonstrates that many patients experience ongoing residual impairments. Residual impairments post-TIA and minor stroke may affect patients' quality of life and return to work or social activities. Research priorities of patients, health care professionals and key stakeholders relating to the long-term impact of TIA and minor stroke are unknown.Methods Our objective was to establish the top shared research priorities relating to the long-term impact of TIA and minor stroke through stakeholder-centred consensus. A one-day priority setting consensus meeting took place with representatives from different stakeholder groups in October 2016 (Birmingham, UK). Nominal group technique was used to establish research priorities. This involved three stages: (i) gathering research priorities from individual stakeholders; (ii) interim prioritisation in three subgroups; and (iii) final priority setting.Results The priority setting consensus meeting was attended by 11 stakeholders. The individual stakeholders identified 34 different research priorities. During the interim prioritisation exercise, the three subgroups generated 24 unique research priorities which were discussed as a whole group. Following the final consensus discussion, 11 shared research priorities were unanimously agreed.The 11 research questions encompass a range of categories, including: understanding the existing care patients receive (according to diagnosis and geographical location); exploring what optimal care post-TIA/minor stroke should comprise (identifying and treating impairments, information giving and support groups) and how that care should be delivered (clinical setting and follow-up pathway); impact on family members; and education/training for health care professionals.Conclusions Eleven different research priorities were established through stakeholder-centred consensus. These research questions could usefully inform the research agenda and policy decisions for TIA and minor stroke. Inclusion of stakeholders in setting research priorities is important to increase the relevance of research and reduce research waste. PMID- 29416880 TI - Crystal structure of 8-(4-methyl-phen-yl)-2'-de-oxy-adenosine hemihydrate. AB - In the asymmetric unit, equalling the unit cell (triclinic, P1, Z = 1), two mol ecules of the title compound, 8-(4-methyl-phen-yl)-d-2'-de-oxy-adenosine, C17H19N5O3, are present, with distinct conformations of the two sugar moieties, together with one solvent water mol-ecule. All three ribose O atoms are involved in hydrogen bonding and the crystal packing is largely determined by hydrogen bonding or hydrogen-heteroatom inter-actions (O-H?O, O-H?N, N-H?O, C-H?O and C H?N) with one independent mol-ecule directly linked to four neighbouring mol ecules and the other mol-ecule directly linked to six neighbouring mol-ecules. The two independent mol-ecules of the asymmetric unit display three weak intra molecular C-H-to-heteroatom contacts, two of which are very similar despite the different conformations of the deoxyribosyl moieties. The aromatic ring systems of both mol-ecules are in proximity to each other and somehow aligned, though not coplanar. The absolute structures of the two mol-ecules were assumed with reference to the reactant 8-bromo-d-2'-de-oxy-adenosine as they could not be determined crystallographically. PMID- 29416881 TI - Crystal structure of a Zn complex with tereph-thalate and 1,6-bis-(1,2,4-triazol 1-yl)hexa-ne. AB - A new zinc coordination polymer with rigid benzene-1,4-di-carboxyl-ate (bdc) and flexible 1,6-bis-(1,2,4-triazol-1-yl)hexane (btrh), namely poly[[(MU2-benzene-1,4 di-carboxyl-ato)[MU2-1,6-bis-(1,2,4-triazol-1-yl)hexa-ne]zinc] di-methyl-form amide monosolvate], [Zn(C8H4O4)(C10H16N6)].C3H7NO, was synthesized. According to the single-crystal XRD analysis, the product crystallizes in the P-1 space group and has a layered structure. Analysis of the layered structure reveals {Zn(bdc)} chains which are connected by pairs of btrh ligands. The layers are packed tightly perpendicular to the [1-22] direction, separated by one non-disordered di methyl-formamide solvent mol-ecule per formula unit. According to thermogravimetric analysis, the product completely loses this solvent at 453 K; the desolvated compound is stable up to 503 K. As a result of the lack of hydrogen-donor groups, hydrogen bonds are not observed in the structure of the complex; however, an inter-molecular C-H?pi contact of 3.07 A occurs. PMID- 29416882 TI - Crystal structure of 3-benzyl-2-[(E)-2-(furan-2-yl)ethen-yl]-2,3-di-hydro quinazolin-4(1H)-one and 3-benzyl-2-[(E)-2-(thio-phen-2-yl)ethen-yl]-2,3-di-hydro quinazolin-4(1H)-one from synchrotron X-ray diffraction. AB - The chiral title compounds, C21H18N2O2, (I), and C21H18N2OS, (II) - products of the three-component reaction between benzyl-amine, isatoic anhydride and furyl- or thienyl-acrolein - are isostructural and form isomorphous racemic crystals. The tetra-hydro-pyrimidine ring in (I) and (II) adopts a sofa conformation. The amino N atom has a trigonal-pyramidal geometry [sum of the bond angles is 347.0 degrees for both (I) and (II)], whereas the amido N atom is flat [sum of the bond angles is 359.3 degrees for both (I) and (II)]. The furyl- and thienylethenyl substituents in (I) and (II) are planar and the conformation about the bridging C=C bond is E. These bulky fragments occupy the axial position at the quaternary C atom of the tetra-hydro-pyrimidine ring, apparently, due to steric reasons. In the crystals, mol-ecules of (I) and (II) form hydrogen-bonded helicoidal chains propagating along [010] by strong inter-molecular N-H?O hydrogen bonds. PMID- 29416883 TI - Crystal structures of bis-[4-(di-methyl-amino)-pyridinium] tetra-kis-(thio cyanato-kappaN)manganate(II) and tris-[4-(di-methyl-amino)-pyridinium] penta kis(thio-cyanato-kappaN)manganate(II). AB - The crystal structures of the title salts, (C7H11N2)2[Mn(NCS)4] (1) and (C7H11N2)3[Mn(NCS)5] (2), consist of manganese(II) cations that are tetra hedrally (1) or trigonal-bipyramidally (2) coordinated to four or five terminal N bonded thio-cyanate ligands, respectively, into discrete anionic complexes. The negative charge is compensated by two (1) or three (2) 4-(di-methyl-amino) pyridinium cations, which are protonated at the pyridine N atom. The asymmetric unit of compound 1 consists of one anionic complex and two 4-(di-methyl-amino) pyridinium cations, whereas that of compound 2 consists of two anionic complexes and six 4-(di-methyl-amino)-pyridinium cations, all of them located in general positions. These complexes are linked by N-H?S, C-H?S and C-H?N hydrogen-bonding inter-actions between the 4-(di-methyl-amino)-pyridinium cations and the thio cyanate ligands into three-dimensional network structures. PMID- 29416884 TI - 3-{(E)-[4-(4-Hy-droxy-3-meth-oxy-phen-yl)butan-2-yl-idene]amino}-1-phenyl-urea: crystal structure and Hirshfeld surface analysis. AB - Two independent mol-ecules (A and B) comprise the asymmetric unit of the title compound, C18H21N3O3. The urea moiety is disubstituted with one amine being linked to a phenyl ring, which is twisted out of the plane of the CN2O urea core [dihedral angles = 25.57 (11) (A) and 29.13 (10) degrees (B)]. The second amine is connected to an imine (E conformation), which is linked in turn to an ethane bridge that links a disubstituted benzene ring. Intra-molecular amine-N H?N(imine) and hydroxyl-O-H?O(meth-oxy) hydrogen bonds close S(5) loops in each case. The mol-ecules have twisted conformations with the dihedral angles between the outer rings being 38.64 (81) (A) and 48.55 (7) degrees (B). In the crystal, amide-N-H?O(amide) hydrogen bonds link the mol-ecules A and B via an eight membered {?HNCO}2 synthon. Further associations between mol-ecules, leading to supra-molecular layers in the ac plane, are hydrogen bonds of the type hydroxyl-O H?N(imine) and phenyl-amine-N-H?O(meth-oxy). Connections between layers, leading to a three-dimensional architecture, comprise benzene-C-H?O(hy-droxy) inter actions. A detailed analysis of the calculated Hirshfeld surfaces shows mol ecules A and B participate in very similar inter-molecular inter-actions and that any variations relate to conformational differences between the mol-ecules. PMID- 29416885 TI - Assembly of ZnII and CdII coordination polymers with different dimensionalities based on the semi-flexible 3-(1H-benzimidazol-2-yl)propanoic acid ligand. AB - Two new coordination polymers, namely, poly[[MU3-3-(1H-benzimidazol-2 yl)propionato]zinc(II)], [Zn(C10H8N2O2)] n , (1), and poly[bis-[MU2-3-(1H benzimid-azol-2-yl)propionato]cadmium(II)], [Cd(C10H8N2O2)2] n , (2) have been synthesized from 3-(1H-benzoimidazol-2-yl)propanoic acid ligands through a mixed ligand synthetic strategy under a solvothermal environment, and studied by single crystal X-ray diffraction. Complex 1 crystallizes in the ortho-rhom-bic space group Pbca and features a two-dimensional structure formed by a binuclear Zn2O4 core. Complex 2, however, crystallizes in the monoclinic space group P21/c and forms a one-dimensional chain structure. The ZnII and CdII ions have different coordination numbers and the 3-(1H-benzoimidazol-2-yl)propano-ate ligands display different coordination modes. The structures reported here show the importance of the selection of metal ions and suitable ligands. PMID- 29416886 TI - Crystal structure of the eta4-ketimine titanium complex (di-phenyl-amido kappaN){3-methyl-6-[(4-methyl-phen-yl)(phenyl-aza-nid-yl)methyl-idene]cyclo-hexa 2,4-dien-1-yl-kappa2N,C1}(eta5-penta-methyl-cyclo-penta-dien-yl)titanium(IV). AB - The mol-ecular structure of the title titanium(IV) half-sandwich complex, [Ti(eta5-C10H15)(eta4-C21H19N)(C12H10N)], shows a three-legged piano-stool geometry at the central TiIV atom, comprising of one penta-methyl-cyclo-penta dienyl ligand, one bidentate ketimine ligand in an eta4-coordination mode and one monodentate di-phenyl-amide ligand. Except for van der Waals forces, there are no significant inter-molecular inter-actions in the crystal. PMID- 29416887 TI - Bis{MU-2,2'-[(3,4-di-thia-hexane-1,6-di-yl)bis-(nitrilo-methanylyl-idene)]bis-(4 bromo-phenolato)-kappa4O,N,N',O'}dicopper(II). AB - The crystal structure of the title compound, [Cu2(C18H12Br2N4O2S2)2], consists of binuclear complex units which lie across inversion centres and are connected by weak Cu-O coordination bonds forming chains along the b axis. The CuII ion is five-coordinated by two N atoms and two O atoms of the chelating ligand and one symmetry-related O atom forming a square-pyramidal coordination geometry. In the crystal, short S?Br contacts connect neighbouring chains into a two-dimensional network parallel to (101). PMID- 29416888 TI - Crystal structure of 2,3-dimeth-oxy-N-(4-nitro-phen-yl)benzamide. AB - In the title compound, C15H14N2O5, the benzene rings are nearly coplanar, making a dihedral angle of 4.89 (8) degrees . An intra-molecular N-H?O hydrogen bond occurs between the imino and meth-oxy groups. In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into supra-molecular chains propagating along the a axis direction. pi-pi stacking is observed between parallel benzene rings of neighbouring chains, the centroid-to-centroid distance being 3.6491 (10) A. Three dimensional Hirshfeld surface analyses and two-dimensional fingerprint plots have been used to analyse the inter-molecular inter-actions present in the crystal. PMID- 29416889 TI - Crystal structure and Hirshfeld surface analysis of aqua-bis-(nicotinamide kappaN)bis-(4-sulfamoylbenzoato-kappaO1)copper(II). AB - In the crystal of the title complex, [Cu(C7H6NO4S)2(C6H6N2O)2(H2O)], the CuII cation and the O atom of the coordinated water mol-ecule reside on a twofold rotation axis. The CuII ion is coordinated by two carboxyl-ate O atoms of the two symmetry-related 4-sulfamoylbenzoate (SB) anions and by two N atoms of the two symmetry-related nicotinamide (NA) mol-ecules at distances of 1.978 (2) and 2.025 (3) A, respectively, forming a slightly distorted square-planar arrangement. The distorted square-pyramidal coordination environment is completed by the water O atom in the axial position at a distance of 2.147 (4) A. In the crystal, the mol ecules are linked via O-H?O and N-H?O hydrogen bonds with R22(8) and R22(18) ring motifs, forming a three-dimensional architecture. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H?O/O?H (42.2%), H?H (25.7%) and H?C/C?H (20.0%) inter actions. PMID- 29416890 TI - Crystal structure of (S)-5-chloro-N-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phen yl]oxazolidin-5-yl}meth-yl)thio-phene-2-carboxamide. AB - The asymmetric unit of the crystal of the title compound (common name rivaroxaban), C19H18ClN3O5, contains two rivaroxaban mol-ecules with different conformations; the C-C-N-C torsion angles between the oxazolidine and thio-phene rings are -171.1 (7) and -106.8 (9) degrees in the two independent mol-ecules. In the crystal, classical N-H?O hydrogen bonds and weak C-H?O hydrogen bonds link the mol-ecules into a three-dimensional supra-molecular architecture. PMID- 29416891 TI - Crystal structure of 5,15-bis-(4-methyl-phen-yl)-10,20-bis-(4-nitro-phen yl)porphyrin nitro-benzene disolvate. AB - The whole mol-ecule of the title porphyrin, C46H32N6O4.2C6H5NO2, which crystallized as a nitro-benzene disolvate, is generated by inversion symmetry. The porphyrin macrocycle is almost planar, the maximum deviation from the mean plane of the non-hydrogen atoms is 0.097 (2) A. The aryl rings at the meso positions are inclined to this mean plane by 74.84 (6) degrees for the nitro phenyl rings and 73.37 (7) degrees for the tolyl rings. In the crystal, the porphyrin mol-ecules are linked by C-H?O hydrogen bonds, forming chains along [100]. The solvent mol-ecules are also linked by C-H?O hydrogen bonds, forming chains along [100]. Inter-digitation of the p-tolyl groups along the c axis creates rectangular channels in which the solvent mol-ecules are located. PMID- 29416892 TI - Crystal structure of (E)-2-(furan-2-yl-methyl-idene)-2,3,4,9-tetra-hydro-1H carbazol-1-one. AB - The title compound, C17H13NO2, crystallizes with two conformationally very similar independent mol-ecules (A and B) in the asymmetric unit. In the crystal, the individual mol-ecules are linked by pairs of N-H?O hydrogen bonds forming A-A and B-B inversion dimers, with R22(10) rings. They stack alternately up the a axis direction and are linked by C-H?pi inter-actions, forming sheets parallel to the ab plane. PMID- 29416893 TI - Crystal structure of 6,7-de-hydro-royleanone isolated from Taxodium distichum (L.) Rich. AB - The title compound, 6,7-de-hydro-royleanone, C20H26O3 [systematic name: (4bS)-3 hy-droxy-2-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a-hexa-hydro-phenanthrene-1,4 dione] was isolated from Taxodium distichum (L.) Rich. The compound crystallizes in the space group P21. The crystal structure features two O-H?O hydrogen bonds, forming chains along the [010] direction. PMID- 29416894 TI - Crystal structure of ethyl 2-cyano-2-(1,3-di-thian-2-yl-idene)acetate. AB - The title compound, C9H11NO2S2, contains a 1,3-di-thiane ring which has a twist boat conformation. The dihedral angle between the mean planes of the ethyl acetate group and the di-thiane ring is 17.56 (13) degrees . In the crystal, mol ecules stack in layers up the a-axis direction, however, there are no significant inter-molecular inter-actions present. PMID- 29416895 TI - Acetonyltri-phenyl-phospho-nium 2,3,5-tri-phenyl-tetra-zolium tetra-chlorido cuprate(II). AB - The title compound, (C21H20OP)(C19H15N4)[CuCl4], was obtained by reacting CuCl2.2H2O with a mixture of one equivalent of acetonyltri-phenyl-phospho-nium chloride and one equivalent of 2,3,5-tri-phenyl-tetra-zolium chloride in aceto nitrile. In the structure, the Cu centre in the dianion is bonded to four chloride ligands and adopts a distorted tetra-hedral geometry. The phospho-nium cation likewise adopts the expected tetra-hedral geometry. The tetra-zolium ring forms dihedral angles of 77.68 (10), 26.85 (11) and 66.48 (10) degrees with the planes of the benzene rings of the substituent groups. In the crystal, weak C H?Cl hydrogen-bonding inter-actions involving both cations and the anion give rise to a three-dimensional supra-molecular structure. PMID- 29416896 TI - Crystal structure and hydrogen bonding in N-(1-de-oxy-beta-d-fructo-pyranos-1-yl) 2-amino-isobutyric acid. AB - The title compound, alternatively called d-fructose-2-amino-isobutyric acid (FruAib), C10H19NO7, (I), crystallizes exclusively in the beta-pyran-ose form, with two conformationally non-equivalent mol-ecules [(IA) and (IB)] in the asymmetric unit. In solution, FruAib establishes an equilibrium, with 75.6% of the population consisting of beta-pyran-ose, 10.4% beta-furan-ose, 10.1% alpha furan-ose, 3.0% alpha-pyran-ose and <0.7% the acyclic forms. The carbohydrate ring in (I) has the normal 2C5 chair conformation and the amino acid portion is in the zwitterion form. Bond lengths and valence angles compare well with the average values from related pyran-ose structures. All carboxyl, hy-droxy and ammonium groups are involved in hydrogen bonding and form a three-dimensional network of infinite chains that are connected through homodromic rings and short chains. Intra-molecular hydrogen bonds bridge the amino acid and sugar portions in both mol-ecules. A comparative Hirshfeld surfaces analysis of FruAib and four other sugar-amino acids suggests an increasing role of intra-molecular heteroatom inter-actions in crystal structures with an increasing proportion of C-H bonds. PMID- 29416897 TI - Crystal structures and Hirshfeld surfaces of two 1,3-benzoxa-thiol-2-one derivatives. AB - The crystal structures of 6-meth-oxy-1,3-benzoxa-thiol-2-one, C9H8O3S, (I), and 2 oxo-1,3-benzoxa-thiol-6-yl acetate, C9H6O4S, (II), are described. Compound (I) is almost planar (r.m.s. deviation for the non-H atoms = 0.011 A), whereas (II) shows a substantial twist between the fused-ring system and the acetate substituent [dihedral angle = 74.42 (3) degrees ]. For both structures, the bond distances in the heterocyclic ring suggest that little if any conjugation occurs. In the crystal of (I), C-H?O hydrogen bonds link the mol-ecules into [1-11] chains incorporating alternating R22(8) and R22(12) inversion dimers. The extended structure of (II) features C(7) [201] chains linked by C-H?O hydrogen bonds, with further C-H?O bonds and weak pi-pi stacking inter-actions connecting the chains into a three-dimensional network. Hirshfeld fingerprint analyses for (I) and (II) are presented and discussed. PMID- 29416898 TI - Crystal structure of 4'-allyl-4,5,6,7,2',7'-hexa-chloro-fluorescein allyl ester unknown solvate. AB - In the title compound, 4'-allyl-4,5,6,7,2',7'-hexa-chloro-fluorescein allyl ester {systematic name: prop-2-en-1-yl 2,3,4,5-tetra-chloro-6-[2,7-di-chloro-6-hy-droxy 3-oxo-4-(prop-2-en-1-yl)-3H-xanthen-9-yl]benzoate}, C26H14Cl6O5, accompanied by unknown solvate molecules, the dihedral angle between the xanthene ring system (r.m.s. deviation = 0.046 A) and the penta-substituted benzene ring is 71.67 (9) degrees . Both allyl groups are disordered over two sets of sites in statistical ratios. The scattering contributions of the disordered solvent mol-ecules (both Ph2O and CHCl3, as identified by NMR) were removed with the PLATON SQUEEZE algorithm [Spek (2015 ?). Acta Cryst. C71, 9-18]. In the crystal, tetra-meric supra-molecular aggregates linked by O-H?O hydrogen bonds occur; these further inter-act with neighboring aggregates through C-Cl?pi inter-actions arising from the benzene rings, forming infinite two-dimensional sheets. Each C6Cl4 ring shifts in the direction perpendicular to the two-dimensional sheet, exhibiting a helical chain in which every C6Cl4 ring is utilized as both a donor and an acceptor of Cl?pi contacts. Thus, these two-dimensional sheets pack in a helical fashion, constructing a three-dimensional network. PMID- 29416900 TI - Ketamine Differentially Attenuates Alcohol Intake in Male Versus Female Alcohol Preferring (P) Rats. AB - Background: Although various pharmacological tools in combating addiction to alcohol are available, their efficacy is limited. Hence, there is a critical need for development of more effective medications. Recent advances in the field have identified the glutamatergic system as a potential novel target for intervention in addictive behaviors. Purpose: Hence, we evaluated the effects of acute administration of low (subanesthetic) doses of ketamine, an NMDA receptor antagonist, on alcohol intake and alcohol preference in both male and female rats. Study design: Adult alcohol preferring (P) rats were exposed to two-bottle choice (ethanol 10% and water) for at least three weeks following a nine-day training period and the effects of various doses of ketamine (5 mg/kg, 7.5 mg/kg, and 10 mg/kg, injected subcutaneously, SC) on consumption of alcohol over various time periods during a 24 h interval were measured. Results: Our results indicate that ketamine treatment significantly reduced both alcohol intake and preference in a time- and dose-dependent manner in both sexes. Moreover, a differential sensitivity between the sexes was observed. Thus, although alcohol intake was higher in males, female rats responded much more strongly to the highest dose of ketamine than males in the initial time periods. Conclusion: It is concluded that glutamatergic receptor manipulations may be of therapeutic potential in addiction to alcohol and that different sexes may respond differentially to such treatments. PMID- 29416899 TI - Genotypic characterization and comparison of Streptococcus mutans in American Indian and Southeast Iowa children. AB - Early childhood caries is a complex health care issue that has a multifactorial etiology. One aspect of this etiology is the colonization and propagation of acidogenic bacteria at an early age. There have been several bacterial species associated with caries but 1 common species is Streptococcus mutans. Here, we describe genotypic diversity and commonality of Streptococcus mutans recovered from children representing 2 groups with similar socioeconomic demographics: a Northern Plains American Indian Tribe and a Southeast Iowa population. Forty 36 month-old American Indian children were selected from a cohort of 239 mothers and children, and forty 2- to 5-year-old children from Southeast Iowa were selected to compare the genotypic profiles of Streptococcus mutans recovered from each child's plaque. S. mutans isolates were selected from whole mouth plaque samples; DNA was extracted and amplified via AP-PCR to show specific genotype patterns. These patterns were compared with GelComparIIv6.5 gel analysis software. We found 18 distinct genotypes from 524 isolates; 13 of which were common between the 2 communities. Five genotypes were unique to only the American Indian children while the Southeast Iowa children harbored no unique genotypes. Although the American Indian children had some genotypes that were not present in the Southeast Iowa children, these were not widely distributed among the community. Furthermore, the levels of genotypic diversity and commonality were similar between the 2 populations. This study sets the groundwork for a comprehensive comparison of genotypes and caries among larger subsections of both populations. PMID- 29416902 TI - Applying robust design to study the effects of stratigraphic characteristics on brittle failure and bump potential in a coal mine. AB - Bumps and other types of dynamic failure have been a persistent, worldwide problem in the underground coal mining industry, spanning decades. For example, in just five states in the U.S. from 1983 to 2014, there were 388 reportable bumps. Despite significant advances in mine design tools and mining practices, these events continue to occur. Many conditions have been associated with bump potential, such as the presence of stiff units in the local geology. The effect of a stiff sandstone unit on the potential for coal bumps depends on the location of the stiff unit in the stratigraphic column, the relative stiffness and strength of other structural members, and stress concentrations caused by mining. This study describes the results of a robust design to consider the impact of different lithologic risk factors impacting dynamic failure risk. Because the inherent variability of stratigraphic characteristics in sedimentary formations, such as thickness, engineering material properties, and location, is significant and the number of influential parameters in determining a parametric study is large, it is impractical to consider every simulation case by varying each parameter individually. Therefore, to save time and honor the statistical distributions of the parameters, it is necessary to develop a robust design to collect sufficient sample data and develop a statistical analysis method to draw accurate conclusions from the collected data. In this study, orthogonal arrays, which were developed using the robust design, are used to define the combination of the (a) thickness of a stiff sandstone inserted on the top and bottom of a coal seam in a massive shale mine roof and floor, (b) location of the stiff sandstone inserted on the top and bottom of the coal seam, and (c) material properties of the stiff sandstone and contacts as interfaces using the 3 dimensional numerical model, FLAC3D. After completion of the numerical experiments, statistical and multivariate analysis are performed using the calculated results from the orthogonal arrays to analyze the effect of these variables. As a consequence, the impact of each of the parameters on the potential for bumps is quantitatively classified in terms of a normalized intensity of plastic dissipated energy. By multiple regression, the intensity of plastic dissipated energy and migration of the risk from the roof to the floor via the pillars is predicted based on the value of the variables. The results demonstrate and suggest a possible capability to predict the bump potential in a given rock mass adjacent to the underground excavations and pillars. Assessing the risk of bumps is important to preventing fatalities and injuries resulting from bumps. PMID- 29416901 TI - Alcohol-Induced Increases in Inflammatory Cytokines Are Attenuated by Nicotine in Region-Selective Manner in Male Rats. AB - Background: Heavy use of alcohol is commonly associated with heavy smoking (nicotine intake). Although many factors, including mood effects of these two drugs may contribute to their co-use, the exact neurobiological underpinnings are far from clear. It is well known that chronic alcohol exposure induces neuroinflammation that may precipitate depressive-like behavior, which is considered an important factor in alcohol relapse. Nicotine, on the other hand, possesses anti-inflammatory and antidepressant effects. Purpose: In this study, we sought to determine which proinflammatory markers may be associated with the depressogenic effects of chronic alcohol and whether nicotine pretreatment may normalize these changes. Study design: For this purpose, we treated adult male Wistar rats with alcohol (1.0 g/kg, IP), nicotine (0.3 mg/kg, IP) or their combination once daily for 14 days. Two prominent proinflammatory cytokines (IL 1beta and TNF-alpha) in two primary brain regions, namely the hippocampus and frontal cortex that are intimately involved in mood regulation, were evaluated. Results: Chronic alcohol resulted in increases in both cytokines in both regions as determined by Western blot. Nicotine completely blocked alcohol-induced effects in the hippocampus, but not in the frontal cortex. These data suggest that nicotine may mitigate the inflammatory effects of alcohol in brain-selective region. Hence, the previously observed depressogenic effects of alcohol and the antidepressant effects of nicotine may at least be partially mediated through manipulations of proinflammatory cytokines in the hippocampus. Conclusion: These findings suggest possible therapeutic potential of anti-inflammatory cytokines in combating alcohol-induced depression and/or relapse. PMID- 29416903 TI - Giant vertebral aneurysm: A case report detailing successful treatment with combined stenting and surgery. AB - Background: Giant aneurysms (>25 mm) arising from the vertebral artery (VA) often present with slow progression of symptoms and signs because of gradual brainstem and cranial nerve compression. The underlying pathophysiology is not well understood, and treatment, wherever possible, is tailored to each singular case. Endovascular management does not usually solve the problem of mass compression, whereas surgical treatment involves several complications. Case Description: A 58 year-old woman presented with a continuously growing giant right VA aneurysm, partially thrombosed, even after endovascular treatment (placement of two diversion flow stents). Operative partial aneurysmectomy and intraoperative placement of an endovascular balloon allowed removal from circulation without significant bleeding with a good neurological outcome. Conclusions: The variability of VA thrombosed giant aneurysms implies a customized therapeutic strategy. Combined endovascular techniques and surgical clipping allow safe and successful trapping and aneurysmectomy. This case highlights the benefits of treating similar pathologies with a combination of both techniques. PMID- 29416904 TI - Vasospasm in the setting of traumatic bilateral carotid-cavernous fistulas and its effect on treatment. AB - Background: Direct, Type A, cavernous-carotid fistulas (CCFs) are predominantly caused by head trauma, especially when basilar skull fractures are present. Transarterial endovascular treatment of direct CCFs is the preferred method of treatment. Bilateral CCFs are estimated to be present in 1-2% of the cases. The treatment of bilateral CCFs is difficult often requiring a combination of endovascular and open surgical approaches. Case Description: We present a case of traumatic bilateral CCFs presenting with vasospasm of the anterior circulation seen on the initial angiogram on day 1 and our treatment paradigm. Conclusion: This case illustrates the challenges in managing bilateral CCFs as well as the changes in collateral circulation because of cerebral vasospasm which affected our treatment paradigm. PMID- 29416905 TI - Man-in-the-barrel syndrome: Case report of ventral epidural abscess and review of the literature. AB - Background: Man-in-the-barrel syndrome (MBS) is an uncommon clinical condition for which patients present with bilateral brachial diplegia but intact lower extremity strength. This syndrome is typically attributed to a cranial/cortical injury rather than a spinal pathology. Case Description: A 62-year-old diabetic male presented with bilateral upper extremity paresis attributed to a ventral cervical epidural abscess diagnosed on magnetic resonance imaging. Emergent cervical decompression resulted in slight improvement of upper extremity strength. However, he later expired due to sepsis and respiratory compromise. Conclusion: Establishing the correct diagnosis via clinical examination and proceeding with appropriate management of MBS attributed to a cervical epidural abscess is critical to achieve a good outcome. PMID- 29416906 TI - Space-brain: The negative effects of space exposure on the central nervous system. AB - Journey to Mars will be a large milestone for all humankind. Throughout history, we have learned lessons about the health dangers associated with exploratory voyages to expand our frontiers. Travelling through deep space, the final frontier, is planned for the 2030s by NASA. The lessons learned from the adverse health effects of space exposure have been encountered from previous, less lengthy missions. Prolonged multiyear deep space travel to Mars could be encumbered by significant adverse health effects, which could critically affect the safety of the mission and its voyagers. In this review, we discuss the health effects of the central nervous system by space exposure. The negative effects from space radiation and microgravity have been detailed. Future aims and recommendations for the safety of the voyagers have been discussed. With proper planning and anticipation, the mission to Mars can be done safely and securely. PMID- 29416907 TI - Aneurysm trapping by both direct and endovascular surgery for vertebral artery dissection: A case report. AB - Background: Although vertebral artery (VA) dissecting aneurysms are treated by direct or endovascular surgery, some disadvantages are associated with each surgery. Therefore, the type of surgery should be selected based on the condition of the aneurysm. We performed aneurysm trapping by endovascular surgery via the contralateral VA after proximal direct ligation with bypass to prevent complications as well as achieve complete treatment. Case Description: We attempted to insert a distal clip to achieve complete trapping of the ruptured VA dissecting aneurysm after proximal ligation with occipital artery-posterior inferior cerebellar artery (PICA) anastomosis; however, the operative field was limited by the existence of lower cranial nerves, brain swelling, and tortuosity of VA. Therefore, we performed the aneurysmal trapping by endovascular surgery via contralateral VA just after the direct surgery. Conclusions: This technique can provide complete resolution without any complications, particular in the case of bleeding VA dissecting aneurysms that have a PICA origin and are located in the high or contralateral position. PMID- 29416908 TI - Acute tetraplegia following laryngotracheal reconstruction surgery. AB - Background: Paraplegia following thoracic spinal surgery or abdominal operations is usually attributed to spinal cord ischemia due to interruption of the segmental spinal vascular supply. Alternatively, the etiology of spinal cord ischemia following cervical surgery is less clear. Case Description: A 14-year old male became acutely tetraplegic with a C4 sensory level and sphincteric dysfunction 12 h following surgery for tracheal stenosis due to prior intubation. Signs included loss of pain and temperature below the level of C4 with preservation of deep sensations (position and vibration) and mute plantar responses. The cervical magnetic resonance imaging revealed diffuse intramedullary cord swelling between C2-C7 and hyperintense signal changes in the anterior and posterior columns of the cord on T2-weighted images. Various etiologies for this finding included a cervical hyperextension or hyperflexion injury vs. anterior spinal artery syndrome. Conclusions: Postoperative treatment of spinal cord ischemia attributed to cervical and thoracoabdominal surgery is largely ineffective in reversing major neurological deficits. Therefore, it is critical to prevent ischemia during these procedures by the avoidance of coagulopathies, anemia, hypotension, and hyperflexion/hyperextension maneuvers. PMID- 29416909 TI - Success rate of elective lumbar puncture at a major Melbourne neurology unit. AB - Background: Lumbar puncture remains an important diagnostic and therapeutic procedure in clinical neurology. Failed lumbar punctures can result in a delay in diagnosis. Ultrasound may have a role in increasing successful lumbar puncture rates. Methods: Data was collected retrospectively from patient notes who had an elective lumbar puncture from January 2012 to August 2015. Results: During this four-year period, 74 patients underwent a neurologic outpatient lumbar puncture. Of these 74 lumbar punctures, 53 were successful (28% failure rate). Conclusions: This study found a 28% failure rate of conventional palpation-guided lumbar puncture. Ultrasound may provide an exciting opportunity to optimize lumbar puncture procedures and improve patient experience and diagnostic outcomes. PMID- 29416910 TI - High cord signals on magnetic resonance and other factors predict poor outcomes of cervical spine surgery: A review. AB - Background: High cord signals (HCS) on preoperative/postoperative T1, T1 gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), and T2 magnetic resonance (MR) studies, postoperative failure of HCS to regress and/or cord re expansion, and a triangular cord configuration are poor prognostic factors for surgical patients with cervical spondylotic myelopathy (CSM). Methods: Here, we reviewed the negative prognostic import of high Grades/Types and more extensive locations of preoperative/postoperative HCS on T1, T1 Gd-DTPA, and T2 MR studies in surgical patients with CSM. Additional predictors of poor operative outcomes included postoperative failure of HCS to regress, cord re-expansion at the site of a HCS, and the triangular vs. teardrop or boomerang cord configuration. The Types/Grades of HCS on MR follow:Type/Grade 0 - no/absent signal changes; Type/Grade 1 - mild/light/fuzzy/obscure/low cord signal (LCS) changes; Type/Grade 2 - sharp/intense/well-defined HCS; and Type/Grade 3 - mixed/HCS. The definitions of location/extent of LCS/HCS were: focal (1 level), multifocal (with skip areas), and multisegmental (continuous over >1 segment), while cord configuration was categorized as triangular, teardrop, or boomerang. Results: On MR studies, preoperative/postoperative Types/Grades 0-1 changes correlated with better prognoses (e.g., improved Japanese Orthopedic Association (JOA) scores or Nurick Grades), while Types/Grades 2-3 correlated with poorer outcomes. Multiple poor prognostic indicators also included; failure of postoperative HCS on MR to regress (particularly if multisegmental), postoperative cord re-expansion at the site of a prior HCS, and triangular cord configuration. Conclusions: Grade/Types 2-3 HCS on T1, T1 Gd-DTPA, and T2-weighted MR images on preoperative/postoperative MR studies, failure of HCS to regress (multisegmental), cord re-expansion at the site of a prior HCS, and a triangular cord configuration (atrophy) all contributed to poorer outcomes for CSM surgery. PMID- 29416911 TI - Application of Text Information Extraction System for Real-Time Cancer Case Identification in an Integrated Healthcare Organization. AB - Background: Surgical pathology reports (SPR) contain rich clinical diagnosis information. The text information extraction system (TIES) is an end-to-end application leveraging natural language processing technologies and focused on the processing of pathology and/or radiology reports. Methods: We deployed the TIES system and integrated SPRs into the TIES system on a daily basis at Kaiser Permanente Southern California. The breast cancer cases diagnosed in December 2013 from the Cancer Registry (CANREG) were used to validate the performance of the TIES system. The National Cancer Institute Metathesaurus (NCIM) concept terms and codes to describe breast cancer were identified through the Unified Medical Language System Terminology Service (UTS) application. The identified NCIM codes were used to search for the coded SPRs in the back-end datastore directly. The identified cases were then compared with the breast cancer patients pulled from CANREG. Results: A total of 437 breast cancer concept terms and 14 combinations of "breast"and "cancer" terms were identified from the UTS application. A total of 249 breast cancer cases diagnosed in December 2013 was pulled from CANREG. Out of these 249 cases, 241 were successfully identified by the TIES system from a total of 457 reports. The TIES system also identified an additional 277 cases that were not part of the validation sample. Out of the 277 cases, 11% were determined as highly likely to be cases after manual examinations, and 86% were in CANREG but were diagnosed in months other than December of 2013. Conclusions: The study demonstrated that the TIES system can effectively identify potential breast cancer cases in our care setting. Identified potential cases can be easily confirmed by reviewing the corresponding annotated reports through the front-end visualization interface. The TIES system is a great tool for identifying potential various cancer cases in a timely manner and on a regular basis in support of clinical research studies. PMID- 29416912 TI - Commentary: Improving the Efficiency of the Ova and Parasite Examination Using Cloud-Based Image Analysis. PMID- 29416913 TI - Preconceived Stakeholders' Attitude Toward Telepathology: Implications for Successful Implementation. AB - Introduction: Telepathology is a subdiscipline of telemedicine. It has opened new horizons to pathology, especially to the field of organizing consultations. This study aims to determine the capabilities and equipment required for the implementation of telepathology from the viewpoints of managers, IT professionals, and pathologists of the hospitals of West Azerbaijan, Iran. Methods: This is a descriptive-analytical study conducted as a cross-sectional study in 2015. All public and private hospitals of West Azerbaijan were selected as the study sites. The population of the study was the managers, directors, pathologists, and IT professionals of the hospitals. The study population was considered as the study sample. Data were collected using questionnaires. The validity and reliability of the questionnaires were assessed, and data were analyzed using SPSS (Statistical Product and Services Solutions, version 16.0, SPSS Inc, Chicago, IL, USA). Results: The mean awareness of the study population of telepathology in the studied hospitals was 2.43 with a standard deviation of 0.89. According to analysis results (F = 7.211 and P = 0.001), in the studied hospitals, the mean awareness of pathologists, managers, directors, and IT professionals' of telepathology is significant. In addition, the mean awareness of pathologists is higher than that of managers, directors, and IT professionals, and this relation is significant (P = 0.001). According to IT professionals, among the influential dimensions of the implementation of telepathology in the studied hospitals, the effect of all dimensions, except hardware capabilities, was above moderate level. Conclusion: According to our findings, stakeholders believe that the implementation of telepathology promotes the quality of health care services and caring patients on the one hand and decreases health-care costs on the other hand. Therefore, it crucial and important to consider users' viewpoints into the process of implementing such systems as they play a vital role in the success or failure, and the accurate estimation of required sources, of the systems. PMID- 29416914 TI - Routine Digital Pathology Workflow: The Catania Experience. AB - Introduction: Successful implementation of whole slide imaging (WSI) for routine clinical practice has been accomplished in only a few pathology laboratories worldwide. We report the transition to an effective and complete digital surgical pathology workflow in the pathology laboratory at Cannizzaro Hospital in Catania, Italy. Methods: All (100%) permanent histopathology glass slides were digitized at *20 using Aperio AT2 scanners. Compatible stain and scanning slide racks were employed to streamline operations. eSlide Manager software was bidirectionally interfaced with the anatomic pathology laboratory information system. Virtual slide trays connected to the two-dimensional (2D) barcode tracking system allowed pathologists to confirm that they were correctly assigned slides and that all tissues on these glass slides were scanned. Results: Over 115,000 glass slides were digitized with a scan fail rate of around 1%. Drying glass slides before scanning minimized them sticking to scanner racks. Implementation required introduction of a 2D barcode tracking system and modification of histology workflow processes. Conclusion: Our experience indicates that effective adoption of WSI for primary diagnostic use was more dependent on optimizing preimaging variables and integration with the laboratory information system than on information technology infrastructure and ensuring pathologist buy-in. Implementation of digital pathology for routine practice not only leveraged the benefits of digital imaging but also creates an opportunity for establishing standardization of workflow processes in the pathology laboratory. PMID- 29416915 TI - Working together to make AJCR stronger. PMID- 29416916 TI - Genotyping and mRNA profiling reveal actionable molecular targets in biliary tract cancers. AB - Biliary tract cancer (BTC) represents a heterogeneous disease with dismal outcome. Herein, we examined genotype and angiogenesis features in BTC. We applied genotyping (Sanger, qPCR, 101-gene panel NGS), mRNA relative quantification methods, and beta-catenin immunohistochemistry in 84 FFPE BTC (55 gallbladder [GBC], 14 intrahepatic [ICC], 15 extrahepatic [ECC] carcinomas). We identified 541 mutations in 68 (81%) tumors. Top mutated genes were CTNNB1 (36%); PTEN (33%); TP53 (31%); PIK3R1 (29%); PIK3CA (13%); BRCA2 and KRAS (12%); BRCA1 (11%). Six GBCs were hypermutated [hm] displaying a distinct mutational pattern. Mutations in TP53 and PI3K, Wnt and RAS components were prevalent among non hypermutated tumors. All hmGBCs carried mutations in BRCA2 and other homologous recombination repair (HRR) genes, in PD1, but not in CTNNB1 and KRAS. None of the pathogenic BRCA2 p.D2723G and BRCA1 p.Q563* and c.5266dupC was present at frequencies expected for germline mutations. We observed copy gains (>6 copies) in EGFR (9% of informative tumors), PRKAR1A (7%), PIK3CA (6%), ERBB2 (5%) and MET (4%). TP53 mutations were prevalent in GBC (P<0.001) and PRKAR1A copy gains in ICC (P=0.007). PTEN was frequently co-mutated with CTNNB1 (P<0.001). Unrelated to CTNNB1 mutations, nuclear beta-catenin was detected in 45% of tumors, among them in 5/6 hmGBC. We observed strong mRNA expression correlation of the two neuropilins (NRP1 and NRP2) with each other (Spearman's rho 0.59) and with the endothelin receptor (NRP2 rho 0.66; NRP2 rho 0.51), and between VEGFA and its receptors (FLT1 rho 0.49; KDR rho 0.45). All PIK3CA mutated tumors expressed endothelin 1 mRNA (P=0.010). Most tumors expressing nuclear beta-catenin were negative for VEGFC (P=0.009) and FLT4 (P=0.002) mRNA expression. In conclusion, we confirmed the presence of known genomic aberrations in BTC and different genotypes between BTC subsets. Novel findings are the coexistence of PI3K and WNT pathway gene alterations in BTC, their association with angiogenesis, and the hypermutated GBCs with HRR gene mutations, all of which may be considered for new treatment options in this difficult to treat disease. PMID- 29416918 TI - MicroRNA-149 sensitizes colorectal cancer to radiotherapy by downregulating human epididymis protein 4. AB - Human epididymis protein 4 (HE4) was significantly up-regulated in colorectal cancer (CRC), while the potential relevance to radiation resistance of this phenomenon is still elusive. Relative expressions of target genes were quantified by real-time PCR. The protein level was determined by Western blot. The regulatory effect of miR-149 on WFDC2 (gene encoding HE4 protein) expression was analyzed by luciferase reporter assay. The response to radiation was evaluated by clonogenic assay in vitro and xenograft growth in vivo. WFDC2 was aberrantly up regulated and miR-149 was down-regulated in CRC. MiR-149 repressed WFDC2 expression via directly targeting its 3'UTR region. The ectopic expression of miR 149 significantly sensitized CRC to radiation both in vitro and in vivo. Likewise, we further demonstrated that WFDC2-deficiency remarkably improved the radiation resistance in CRC. Simultaneously, WFDC2 rescue completely abolished the radiation sensitivity imposed by miR-149. Our data suggested that miR-149 sensitized CRC to radiation via directly inhibiting WFDC2/HE4, which would hold great promise for future therapeutic exploitations. PMID- 29416917 TI - cAMP induces cell apoptosis in multiple myeloma and overcomes bortezomib resistance. AB - The acquired resistance to bortezomib represents a major obstacle for multiple myeloma (MM) treatment. Studies revealed that the treatment with cyclic adenosine monophosphate (cAMP) may be a promising strategy for MM therapy. Therefore, the present study aimed to explore the mechanism of action of cAMP in MM cells. Our results showed that 8-CPT-cAMP and bortezomib synergistically induced growth inhibition and apoptosis in MM bortezomib-resistant cell lines and primary MM cells, in which protein kinase A (PKA) activation was involved. Furthermore, 8 CPT-cAMP induced the degradation of cyclinD1 and downregulation of myeloid cell leukemia-1 (Mcl-1). Moreover, 8-CPT-cAMP enhanced endoplasmic reticulum stress caused by bortezomib. A synergy between bortezomib and cAMP was also revealed in a murine MOPC315 xenograft model, which was evidenced by the significantly inhibited tumor growth and the improved multiple cancer-related parameters by the combination of the cAMP-elevating compound forskolin and bortezomib. Taken together, this study suggests that the treatment with cAMP may be a promising strategy for enhancing the therapeutic efficacy of bortezomib in MM treatment. PMID- 29416919 TI - Mechanism of action of the atypical retinoid ST1926 in colorectal cancer: DNA damage and DNA polymerase alpha. AB - Despite advances in therapeutic strategies, colorectal cancer (CRC) remains the third cause of cancer-related deaths with a relatively low survival rate. Resistance to standard chemotherapy represents a major hurdle in disease management; therefore, developing new therapeutic agents demands a thorough understanding of their mechanisms of action. One of these compounds is ST1926, an adamantyl retinoid that has shown potent antitumor activities in several human cancer models. Here, we show that ST1926 selectively suppressed the proliferation of CRC cells while sparing normal counterparts, and significantly reduced tumor volume in a xenograft cancer mouse model. Next, we investigated the effects of ST1926 in CRC cells and observed early DNA damage, S-phase arrest, dissipation of mitochondrial membrane potential, and apoptosis induction, in a p53 and p21 independent manner. To address the underlying mechanism of resistance to ST1926, we generated ST1926-resistant HCT116 cells and sequenced DNA polymerase alpha (POLA1), which was reported to be a direct target to the drug's parent molecule, CD437. We identified similar mutations in POLA1 that conferred resistance to ST1926 and CD437. These mutations were absent in 5-fluorouracil-resistant HCT116 cells, clearly validating the specificity of these mutations to the lack of DNA damage and acquired resistance to ST1926. ST1926 also inhibited POLA1 activity and reduced its protein expression levels. Further, in silico analysis of normal and malignant tissue expression data demonstrated that POLA1 levels are elevated in CRC cells and tissues compared to normal counterparts as well as to other cancer types. Our findings highlight previously uncharacterized mechanisms of action of ST1926 in CRC and suggest that elevated POLA1 expression is a pertinent molecular feature and an attractive target in CRC. PMID- 29416920 TI - Everolimus following 5-aza-2-deoxycytidine is a promising therapy in paclitaxel resistant clear cell carcinoma of the ovary. AB - Our previous study showed that 5-aza-2-deoxycytidine (5-aza-dC) could inhibit tumor growth by enhancing the susceptibility of ovarian clear cell carcinoma (OCCC) to paclitaxel through decreasing AKT/mTOR expressions. The objective of the study is to evaluate the antitumor efficacy of everolimus (RAD001) and 5-aza 2-deoxycytidine (5-aza-dC) by targeting AKT/mTOR and EZH2 in OCCC. Paclitaxel sensitive and resistant OCCC cell lines were established. In vitro proliferative and apoptotic assays and flow cytometry were performed. The expressions of EZH2, PIK3IP1, phospho-AKT, phospho-mTOR and phospho-Rictor in the OCCC cell lines were evaluated by Western blotting. In vivo animal experiments with RAD001 and 5-aza dC were performed. RAD001 alone showed significant in vitro antitumor activity and inhibited in vivo tumor growth in paclitaxel-sensitive and resistant OCCC cells. In addition, 5-aza-dC enhanced the antitumor effects when combined with paclitaxel or RAD001 in both paclitaxel-sensitive and resistant tumors. Activation of phospho-AKT ser473 and PIK3IP1 was observed in RAD001-treated paclitaxel-sensitive and resistant OCCC cells. In contrast, inhibition of phospho AKT ser473 and EZH2 was observed with RAD001 following 5-aza-dC treatment of paclitaxel-sensitive and resistant OCCC cells. Furthermore, RAD001 following 5 aza-dC enhanced apoptosis of paclitaxel-sensitive and resistant OCCC cells. RAD001 following 5-aza-dC may be a promising treatment strategy for the treatment of both chemo-sensitive and resistant OCCC. Further clinical studies are warranted. PMID- 29416921 TI - Inhibition of Rac family protein impairs colitis and colitis-associated cancer in mice. AB - The prevalence of inflammatory bowel disease (IBD) has increased worldwide and IBD has been demonstrated to promote the development of colorectal cancer. The Rac family of proteins are involved in key mitogenic pathways. However, to the best of our knowledge, no prior studies have investigated the expression and role of Rac on colitis and colitis-associated cancer (CAC). In the current study, Rac expression in patients with colitis was analyzed according to the expression value from NCBI GEO database (GDS3268). EHT-1864, the specific inhibitor of Rac, was intraperitoneally injected to treat mice with dextran sulfate sodium (DSS) induced acute and chronic colitis and mice with azoxymethane (AOM)/DSS-induced CAC. Furthermore, immune cell infiltration and the expression of several inflammatory cytokines in colon tissues were analyzed by flow cytometry, immunofluorescence, and ELISAs. We demonstrated the upregulation of the Rac family of proteins in colitis. Inhibition of Rac by EHT-1864 treatment was found to have an efficient inhibitory effect on DSS-induced acute and chronic colitis and AOM/DSS-induced CAC development. We also observed that downregulation of Rac family protein expression markedly prevented macrophage and myeloid-derived suppressor cell (MDSC) infiltration in colon tissues and suppressed pro inflammatory cytokine expression. Our study established a foundation for understanding the role of Rac in colitis and CAC and to provide a novel strategy and target for colitis and CAC therapy. PMID- 29416922 TI - Long noncoding RNA NEAT1 promotes the metastasis of osteosarcoma via interaction with the G9a-DNMT1-Snail complex. AB - Osteosarcoma (OS) is the most common histological form of primary bone cancer. Long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) functions as an oncogene in some cancers. However, the functional role of NEAT1 in OS metastasis remains elusive. In the present study, we found that NEAT1 expression was significantly increased in OS tissues and cell lines. Overexpression of NEAT1 in OS tissues was correlated with higher clinical stage, distant metastasis and poorer prognosis. Loss- and gain-of-function assays showed that NEAT1 positively regulated metastasis in vitro and in vivo. In addition, ectopic expression of NEAT1 also induced epithelial-mesenchymal transition (EMT). Mechanistic studies revealed that NEAT1 epigenetically suppresses E-cadherin expression through association with G9a-DNMT1-Snail complex. Taken together, our study reveals a critical epigenetic mechanism underlying NEAT1-mediated metastasis. PMID- 29416923 TI - Bispecific tumor-penetrating protein anti-EGFR-iRGD efficiently enhances the infiltration of lymphocytes in gastric cancer. AB - Efficient trafficking of lymphocytes to the tumor microenvironment is crucial for the success of an effective antitumor immunotherapy. A major challenge to achieve effective adoptive immunotherapy is poor tumor penetration and inefficient migration of T cells to the tumor site. Several approaches to facilitate the trafficking of lymphocytes to the tumor microenvironment have been suggested to overcome these obstacles. Here, we address this issue with a focus on the tumor penetrating peptide iRGD, which can specifically increase the permeability of the tumor vasculature and tumor tissue, enhancing drug penetration. We previously constructed a bispecific tumor-penetrating protein, anti-EGFR-iRGD, which consists of the variable region of the heavy chain of anti-EGFR antibody and a tumor-penetrating peptide iRGD, and verified its ability to improve the penetration of antitumor drugs. Herein, we introduce a novel method of co administering T cells and anti-EGFR-iRGD to enhance the trafficking, penetration and antitumoral activity of T cells. Our results provide new insights for effectively enhancing T-cell infiltration in tumors and demonstrate a preclinical translational approach for the use of anti-EGFR-iRGD as a therapeutic modifier of cancer immunotherapy to improve clinical outcomes. PMID- 29416925 TI - MiR-382 targets GOLM1 to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival. AB - Accumulating evidences have illuminated that an amount of microRNAs are involved in human diseases including hepatocellular carcinoma (HCC). In this study, we found that the expression of miR-382 in HCC tissues was down-regulated compared with the non-cancerous tissues. Over-expression of miR-382 could significantly inhibit the migration and invasion of HCC cells in vitro and in vivo. Bioinformatic algorithms and luciferase reporter assays suggested that Golgi Membrane Protein 1 (GOLM1) was a direct target of miR-382. Interestingly, we found the down-regulation of GOLM1 in HCC cells could rescue these cells from miR 382-mediated suppression of migration and invasion. Our findings might demonstrate that miR-382 inhibited the metastasis of HCC by targeting GOLM1. Furthermore, cox proportional hazards analyses suggested that low expression of miR-382 was an independent prognostic factor for the HCC patients. In conclusion, our results highlighted that miR-382, a novel prognostic factor, target GOLM1 to inhibit metastasis of hepatocellular carcinoma. PMID- 29416924 TI - Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models. AB - New immunotherapeutic approaches are urgently needed for gastric cancer due to its poor survival and unsatisfactory treatment. Here we applied the humanized chA21 scfv based chimeric antigen receptor (CAR) modified T cells approach to the HER2 overexpressing gastric cancer treatment. The chA21-4-1BBz CAR T cells specifically exerted Th1 skewed cytokine response and efficient cytolysis of HER2 overexpressing human gastric cancer cells in vitro. Both the cytokine production and cytotoxicity levels were correlated with the level of HER2 surface expression by tumor cells. In established subcutaneous xenograft and peritoneal metastasis models, chA21-4-1BBz CAR T cells dramatically facilitated regression of HER2 overexpressing tumor and prolonged survival of tumor-bearing mice, whereas spared the progression of HER2 low-expressing tumor. Additionally, the capability of these CAR T cells to persist in circulation, as well as specifically home to, and accumulate in tumor sites were identified. Taken together, these results provide the basis for the future clinical investigation of the humanized chA21 scFv based, 4-1BB costimulated CAR T cells for the treatment of gastric cancer, and other HER2-expressing solid tumors. PMID- 29416926 TI - ARRDC1 and ARRDC3 act as tumor suppressors in renal cell carcinoma by facilitating YAP1 degradation. AB - The alpha-arrestins domain-containing 1 and 3 (ARRDC1 and ARRDC3) are two members of the alpha-arrestins family. Yes-associated protein 1 (YAP1) is a key downstream transcription co-activator of the Hippo pathway essential for cancer initiation, progression, or metastasis in clear cell renal cell carcinoma (ccRCC). The aim of this work was to elucidate the role of the alpha-arrestins in ccRCC tumorigenesis by identifying molecular interacting factors and exploring potential mechanisms. In this study, we identified YAP1 as a novel ARRDC3 interacting protein in RCC cells through tandem affinity purification and mass spectrometry. We confirmed that ARRDC1 and ARRDC3, but not other alpha-arrestin family proteins, interact with YAP1. Binding of ARRDC1/3 to YAP1 is mediated through the WW domains of YAP1 and the PPXY motifs of ARRDC1/3. Functional analysis of ARRDC1/3 by lentiviral shRNA revealed a role for ARRDC1/3 in suppression of cell growth, migration, invasion and epithelial-mesenchymal transition in ccRCC cells, and these effects were mediated, at least in part, through YAP1. Mechanically, ARRDC1/3 negatively regulates YAP1 protein stability by facilitating E3 ubiquitin ligase Itch-mediated ubiquitination and degradation of YAP1. Moreover, ARRDC1/3 mRNA levels were significantly downregulated in ccRCC specimens. A negative correlation was identified between ARRDC3 and YAP1 expression in ccRCC specimens by immunohistochemistry. This study revealed a novel mechanism for ARRDC1/3 in the regulation of YAP1 stability and provided insight in understanding the relationship between ARRDC1/3 downregulation and aberrant Hippo-YAP1 pathway activation in ccRCC. PMID- 29416927 TI - Herniation of crypts in hyperplastic polyp and sessile serrated adenoma: a prospective study. AB - Presence of colonic crypts in submucosa was previously termed as herniation of crypts, pseudoinvasion, epithelial-misplacement, or inverted hyperplastic-polyp. It is considered as an important criterion for diagnosing sessile serrated adenoma (SSA), which links to a higher risk of synchronous and future colorectal cancers compared with hyperplastic polyp (HP). Here, we aimed to study the frequencies, diagnostic specificity and synchronous neoplasms of herniation of crypts in HP and SSA. We prospectively included all HP and SSA cases and 514 randomly-selected colorectal polyps of normal histology diagnosed from 2013 to 2015 at our institution. We calculated the frequencies of herniation of crypts by histology, sex, age, size, race, location, prior polyp-history and synchronous neoplasms (including colorectal cancers and adenomas). Binary and ordinal (ordered) logistic regression analyses were used to identify potential associations. Among the 2,560 colorectal polyps in the subjects with average-risk of colorectal cancer, the frequencies of herniation of crypts were 1.79% (10/559) in SSA, 0.2% (3/1487) in HP and 0% (0/514) in polypoid normal tissue. The specificity of herniation of crypts for diagnosing serrated polyp (HP and SSA versus normal tissue) was 100% (514/514), but its sensitivity was 0.64% (13/2046), while the specificity of herniation of crypts for diagnosing SSA (versus HP and polypoid normal tissue) was 99.85% (1998/2001) and its sensitivity was 1.79% (10/559). Our multivariate analyses identified an independent association between herniation of crypts and diagnosis of SSA (Odds ratio [OR]=9.37, P=0.015 for versus HP and normal tissue, and OR=11.47, P=0.009 for versus HP). We also found that herniation of crypts in SSA and HP did not independently link to race or synchronous neoplasms (including cancers and adenomas). In summary, our data show that, while herniation of crypts is rare, its presence is highly suggestive of SSA. PMID- 29416928 TI - Isocorydine suppresses doxorubicin-induced epithelial-mesenchymal transition via inhibition of ERK signaling pathways in hepatocellular carcinoma. AB - Doxorubicin (DOX) is a conventional and effective chemotherapeutic used in the treatment of hepatocellular carcinoma (HCC). However, doxorubicin administration may induce EMT, which results in the development of chemoresistance in HCC. Recent studies report that Isocorydine (ICD) selectively inhibits human cancer stem cells (CSCs), which have an important role in the development of chemoresistance. In this study, we observed that ICD co-administration enhanced DOX cytotoxicity in HCC cells, enabling the inhibition of DOX-induced epithelial mesenchymal transition (EMT). Microarray data analysis revealed substantially decreased ERK signaling after ICD treatment. Additionally, we observed decreased IC50 for DOX upon ERK knockdown. Finally, we confirmed the enhanced efficacy of treatment with a combination of DOX and ICD in xenograft models. Collectively, the present study unveils the benefit of using DOX in combination with ICD for chemotherapy against HCC, revealing a novel potential anti-cancer strategy. PMID- 29416929 TI - A novel dysfunctional germline P53 mutation identified in a family with Li Fraumeni syndrome. AB - Li-Fraumeni Syndrome (LFS), which is a rare dominantly inherited cancer predisposition syndrome, is associated with germline P53 mutations. Mutations of the tumor suppressor protein P53 are associated with more than 50% of human cancers; however, almost 30% of P53 mutations occur rarely and this has raised questions about their significance. It therefore appeared of particular interest that we identified a novel mutation in a patient suffering from breast cancer and fulfilling the diagnostic criteria of LFS. In this study, a patient with remarkable family history developed breast cancer and was diagnosed with LFS. By performing next-generation sequencing on the patient and subsequent verification by Sanger sequencing among other family members, a new germ-line P53 replication error, a trinucleotide repeat mutation in the coding region, was identified in two generations of this Li-Fraumeni family. PMID- 29416930 TI - HOXD-AS1 promotes cell proliferation, migration and invasion through miR-608/FZD4 axis in ovarian cancer. AB - Evidence is accumulating that long non-coding RNAs (lncRNAs) exert crucial roles in the incidence and progression of tumors. HOXD cluster antisense RNA 1 (HOXD AS1), a cancer-related lncRNA, has been frequently reported to be involved in tumorigenesis and dysregulated in multiple types of human cancers; however, little is known about its role in ovarian cancer (OC). This study aimed to explore the role of HOXD-AS1 in OC and elucidate the potential mechanism involved. In the current study, HOXD-AS1 was observed to be upregulated in both OC tissues and cell lines. Besides, elevated expression of HOXD-AS1 was found to be associated with poor prognosis of OC patients. Furthermore, functional studies demonstrated that HOXD-AS1 promoted OC cell proliferation and colony formation, and enhanced the migration and invasion capabilities of OC cells. Mechanistically, HOXD-AS1 was detected to positively regulate the expression of frizzled family receptor 4 (FZD4) by competitively binding to miR-608. Taken together, HOXD4-AS1 exerts tumor-promoting functions through miR-608/FZD4 axis in OC. Our findings indicate that HOXD-AS1 may be used as a promising therapeutic target and a novel prognostic biomarker for OC. PMID- 29416931 TI - Single oral dose acute and subacute toxicity of a c-MET tyrosine kinase inhibitor and CDK 4/6 inhibitor combination drug therapy. AB - c-MET inhibitor, crizotinib, and CDK 4/6 inhibitor, palbociclib, have been evaluated in combination as cancer treatment in vitro. Because the toxicological data for the combination of these drugs is limited, we investigated the toxicity of the crizotinib and palbociclib combination in 80 ICR (CD-1) mice (average age = ~20 weeks). Treatments were arranged as a 2 * 2 * 2 factorial and included sex (female vs. male), crizotinib (0 or 4 mg), and palbociclib (0 or 1 mg). Drugs were administered to mice by oral gavage 24 hours (n = 40) and 7 days (n = 40) prior to the collection of blood and tissue samples to determine serum chemistry, hematology, and histopathology. After dosing, each study group of mice was observed acutely (24 hrs) and subacutely (7 days) for any clinical changes associated with toxicity from the drugs. Serum chemistry, hematological effects, and selected histological tissue samples of each animal immediately after euthanasia were analyzed at the end of the study. No significant abnormalities or changes in the clinical signs, body and organ weight, or gross and histopathological evaluations were observed. Although within the normal reference range, there was an elevation in the red blood cells (P = 0.05) from 24-hour crizotinib- and palbociclib-treated mice (both males and females), which contrasted with the typical anemia observed in palbociclib-treated patients. Administration of the crizotinib and palbociclib combination resulted in an elevation in the ALT liver enzyme (P = 0.05) in the 24-hour treated group (both male and female), but the levels were within the normal ranges of the mice. Overall, serum chemistry and hematology did not reach significant abnormal levels in any of the acute- or subacute-treated groups. The results of this study confirmed that the combination of crizotinib and palbociclib at the given doses did not cause significant treatment-related toxicities in mice. PMID- 29416932 TI - Long noncoding RNA CNALPTC1 promotes cell proliferation and migration of papillary thyroid cancer via sponging miR-30 family. AB - Several somatic copy number variations (CNVs) have been identified in papillary thyroid cancer (PTC). However, the functional roles of CNVs and the genes responsible for the roles of CNVs are largely unknown. In this study, we identified a novel long noncoding RNA (lncRNA) CNALPTC1 (copy number amplified long noncoding RNA in papillary thyroid cancer 1). The genomic copy number of CNALPTC1 is amplified and CNALPTC1 expression level is up-regulated in PTC. Increased expression of CNALPTC1 is associated with aggressive clinicopathological characteristics. Gain-of-function and loss-of-function assays revealed that CNALPTC1 promotes proliferation and migration of PTC cells, and inhibits apoptosis of PTC cells. Mechanistically, we found that CNALPTC1 physically associates to miR-30 family and down-regulates miR-30 expression. Furthermore, CNALPTC1 up-regulates the expression of miR-30 targets, such as BCL9, SNAI1, and VIM. The mutation of miR-30 binding site on CNALPTC1 or overexpression of miR-30 abrogates the oncogenic roles of CNALPTC1 in PTC. Collectively, our results suggested that the copy number amplified lncRNA CNALPTC1 promotes PTC progression via sponging miR-30 family. Our data also implied that CNALPTC1 may be a novel therapeutic target for PTC. PMID- 29416933 TI - Prevalence and Risk Factors of Elevated Blood Lead in Children in Gold Ore Processing Communities, Zamfara, Nigeria, 2012. AB - Background: In March 2010, Medecins Sans Frontieres/Doctors Without Borders detected an outbreak of acute lead poisoning in Zamfara State, northwestern Nigeria, linked to low-technology gold ore processing. The outbreak killed more than 400 children <=5 years of age in the first half of 2010 and has left more than 2,000 children with permanent disabilities. Objectives: The aims of this study were to estimate the statewide prevalence of children <=5 years old with elevated blood lead levels (BLLs) in gold ore processing and non-ore-processing communities, and to identify factors associated with elevated blood lead levels in children. Methods: A representative, population-based study of ore processing and non-ore-processing villages was conducted throughout Zamfara in 2012. Blood samples from children, outdoor soil samples, indoor dust samples, and survey data on ore processing activities and other lead sources were collected from 383 children <=5 years old in 383 family compounds across 56 villages. Results: 17.2% of compounds reported that at least one member had processed ore in the preceding 12 months (95% confidence intervals (CI): 9.7, 24.7). The prevalence of BLLs >=10 ug/dL in children <=5 years old was 38.2% (95% CI: 26.5, 51.4) in compounds with members who processed ore and 22.3% (95% CI: 17.8, 27.7) in compounds where no one processed ore. Ore processing activities were associated with higher lead concentrations in soil, dust, and blood samples. Other factors associated with elevated BLL were a child's age and sex, breastfeeding, drinking water from a piped tap, and exposure to eye cosmetics. Conclusions: Childhood lead poisoning is widespread in Zamfara State in both ore processing and non-ore-processing settings, although it is more prevalent in ore processing areas. Although most children's BLLs were below the recommended level for chelation therapy, environmental remediation and use of safer ore processing practices are needed to prevent further exposures. Patient consent: Obtained. Ethics approval: The study protocol was approved by the US Centers for Disease Control Institutional Review Board-A and the National Health Research Ethics Committee of Nigeria. Competing Interests: The authors declare no competing financial interests. PMID- 29416934 TI - Getting Data Right - and Righteous to Improve Hispanic or Latino Health. AB - Hispanics or Latinos constitute the largest racial/ethnic minority in the United States. They are also a very diverse population. Latino/Hispanic's health varies significantly for subgroups defined by national origin, race, primary language, and migration-related factors (place of birth, immigration status, years of residence in the United States). Most Hispanics speak Spanish at home, and one third have limited English proficiency (LEP). There is growing awareness on the importance for population health monitoring programs to collect those data elements (Hispanic subgroup, primary language, and migration-related factors) that better capture Hispanics' diversity, and to provide language assistance (translation of data collection forms, interpreters) to ensure meaningful inclusion of all Latinos/Hispanics in national health monitoring. There are strong ethical and scientific reasons for such expansion of data collection by public health entities. First, expand data elements can help identify otherwise hidden Hispanic subpopulations' health disparities. This may promote a more just and equitable distribution of health resources to underserved populations. Second, language access is needed to ensure fair and legal treatment of LEP individuals in federally supported data collection activities. Finally, these strategies are likely to improve the quality and representativeness of data needed to monitor and address the health of all Latino/Hispanic populations in the United States. PMID- 29416936 TI - Characterization and Treatment of Unilateral Facial Muscle Spasm in Linear Scleroderma: A Case Report. AB - Background: Linear scleroderma has been associated with muscle spasms ipsilateral to skin lesions. Typically, spasms are located in trigeminal innervated muscles, leading to hemimasticatory spasm (HMS). Case Report: We report a case of linear scleroderma associated with spasm of muscles innervated not only by the trigeminal but also by the facial nerve. Discussion: We review the patient's successful treatment with incobotulinumtoxinA, a formulation of botulinum toxin that has not been reported for use in this condition. PMID- 29416935 TI - Familial Cortical Myoclonic Tremor and Epilepsy, an Enigmatic Disorder: From Phenotypes to Pathophysiology and Genetics. A Systematic Review. AB - Background: Autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE) is characterized by distal tremulous myoclonus, generalized seizures, and signs of cortical reflex myoclonus. FCMTE has been described in over 100 pedigrees worldwide, under several different names and acronyms. Pathological changes have been located in the cerebellum. This systematic review discusses the clinical spectrum, treatment, pathophysiology, and genetic findings. Methods: We carried out a PubMed search, using a combination of the following search terms: cortical tremor, myoclonus, epilepsy, benign course, adult onset, familial, and autosomal dominant; this resulted in a total of 77 studies (761 patients; 126 pedigrees) fulfilling the inclusion and exclusion criteria. Results: Phenotypic differences across pedigrees exist, possibly related to underlying genetic differences. A "benign" phenotype has been described in several Japanese families and pedigrees linked to 8q (FCMTE1). French patients (5p linkage; FCMTE3) exhibit more severe progression, and in Japanese/Chinese pedigrees (with unknown linkage) anticipation has been suggested. Preferred treatment is with valproate (mind teratogenicity), levetiracetam, and/or clonazepam. Several genes have been identified, which differ in potential pathogenicity. Discussion: Based on the core features (above), the syndrome can be considered a distinct clinical entity. Clinical features may also include proximal myoclonus and mild progression with aging. Valproate or levetiracetam, with or without clonazepam, reduces symptoms. FCMTE is a heterogeneous disorder, and likely to include a variety of different conditions with mutations of different genes. Distinct phenotypic traits might reflect different genetic mutations. Genes involved in Purkinje cell outgrowth or those encoding for ion channels or neurotransmitters seem good candidate genes. PMID- 29416937 TI - Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype. AB - Background: Spinocerebellar ataxia (SCA) is an uncommon form of progressive cerebellar ataxia with multiple genetic causes and marked variability in phenotypic expression even across patients with identical genetic abnormalities. SCA27 is a recently identified SCA caused by mutations in the Fibroblast Growth Factor 14 gene, with a phenotypic expression that is only beginning to be fully appreciated. We report here a case of a 70-year-old male who presented with slowly worsening tremor and gait instability that began in his early adulthood along with additional features of parkinsonism on examination. Work-up revealed a novel pathogenic mutation in the Fibroblast Growth Factor 14 gene, and symptoms improved with amantadine and levodopa. We also provide a review of the literature in order to better characterize the phenotypic expression of this uncommon condition. Methods: Case report and review of the literature. Results: Review of the literature revealed a total of 32 previously reported clinical cases of SCA27. Including our case, we found that early-onset tremor (12.1 +/- 10.5 years) was present in 95.8%, while gait ataxia tended to present later in life (23.7 +/- 16.7 years) and was accompanied by limb ataxia, dysarthria, and nystagmus. Other features of SCA27 that may distinguish it from other SCAs include the potential for episodic ataxia, accompanying psychiatric symptoms, and cognitive impairment. Discussion: Testing for SCA27 should be considered in individuals with ataxia who report tremor as an initial or early symptom, as well as those with additional findings of episodic ataxia, neuropsychiatric symptoms, or parkinsonism. PMID- 29416938 TI - Complete response in advanced breast cancer patient treated with a combination of capecitabine, oral vinorelbine and dasatinib. AB - Background: Currently, there are no data available on the best choice of treatment in heavily pretreated patients with advanced breast cancer. However, the combination of oral vinorelbine and capecitabine has been demonstrated to be effective and safe in patients with advanced breast cancer pretreated with anthracycline. Furthermore, some studies assessed the activity of dasatinib, an oral tyrosine kinase inhibitor that inhibits five oncogenic tyrosine kinase families, alone or in combination with different chemotherapy in patients affected with advanced breast cancer. Case presentation: A patient with metastatic breast cancer, hormone receptor positive and human epidermal grow factor receptor 2 negative, pretreated with epirubicine, taxanes and nab paclitaxel, was submitted to third line chemotherapy with vinorelbine 60 mg/m2 on day 1, 8 plus capecitabine 1000 mg/m2 twice daily from day 1 to day 14 every 21 days. The patient was taking also dasatinib 100 mg once daily for chronic myeloid leukemia. The treatment was well tolerated and, after 15 months, computed tomography scan showed a complete response of liver metastases and bone stable disease. After another 28 months, a 18-fluorodeoxyglucose positron emission tomography scan showed a metabolic response of bone metastases without other site of disease. Conclusions: This is the first case in literature about activity of dasatinib in combination with a chemotherapy schedule of oral vinorelbine and capecitabine in advanced breast cancer. This treatment showed both good tolerability and great activity with a long progression free survival of 54 months. PMID- 29416941 TI - Development and Maintenance of Standardized Cross Setting Patient Assessment Data for Post-Acute Care: Summary Report of Findings from Alpha 1 Pilot Testing. AB - The Centers for Medicare & Medicaid Services (CMS) contracted with the RAND Corporation to identify and/or develop standardized items to include in the post acute care patient assessment instruments. RAND was tasked by CMS with developing and testing items to measure seven areas of health status for Medicare beneficiaries: (1) vision and hearing; (2) cognitive status; (3) depressed mood; (4) pain; (5) care preferences; (6) medication reconciliation; and (7) bladder and bowel continence. This article presents results of the first Alpha 1 feasibility test of a proposed set of items for measuring each of these health status areas. Conducted between August and October 2016, the test is one of two Alpha tests that will be completed by mid-2017 to assess the feasibility of proposed items. The results of these small-scale feasibility tests will inform a national Beta test designed to determine how well the measures perform when implemented in post-acute care settings. The Alpha 1 testing phase was successfully completed, in that all items were pilot tested among 133 patients. Items from all content areas were assessed on interrater reliability and feasibility; items from some content areas were assessed on other metrics. Items have now been revised, when necessary, based on the findings of the Alpha 1 test. Alpha 2 testing is under way with the updated, revised items. PMID- 29416940 TI - Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma. AB - The immune contexture, a composition of the tumor microenvironment, plays multiple important roles in cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT), and hence critically influences tumor initiation, progression and patient outcome. Tumor-associated macrophages (TAMs) are abundant in immune contexture, however their roles in CSC, EMT and prognosis of colorectal cancer (CRC) have not been elucidated. In 419 colorectal carcinomas, immune cell types (CD68+ macrophages, CD3+, CD4+ or CD8+ T lymphocytes, CD20+ B lymphocytes), EMT markers (E-cadherin and Snail) as well as the stem cell marker (CD44v6) were detected in tumor center (TC) and tumor invasive front (TF) respectively by immunohistochemistry. Tumor buds, that represent EMT phenotype, were also counted. It was found CD68+ macrophages were the most infiltrating immune cells in CRC. By correlation analysis, more CD68+TF macrophages were associated with more CD44v6 expression (p < 0.001), lower SnailTF expression (p = 0.08) and fewer tumor buds (p < 0.001). More CD68+TF macrophages were significantly related to more CD3+TF T lymphocytes (p = 0.002), CD8+TF T lymphocytes (p < 0.001) and CD20+TF B lymphocytes counts (p = 0.004). Strong CD68+TF macrophages infiltration also predicted long term overall survival. CRC patients with more tumor buds had worse survival. However, strong CD68+TF macrophages infiltration could reverse the unfavorable results since patients with more tumor buds but increasing CD68+TF macrophages infiltration had the favorable outcome, similar to lower tumor buds groups. This study provided direct morphological evidence that tumor associated macrophages in the invasive front play critical roles in fighting with the unfavorable results of tumor buds, thus resulting favorable outcomes for CRC patients. PMID- 29416939 TI - Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer. AB - Tertiary lymphoid structures (TLS) are associated with favorable outcome in non metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: [1] Early TLS, composed of dense lymphocytic aggregates without FDCs, [2] Primary follicle-like TLS, having FDCs but no GC reaction, and [3] Secondary follicle like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence. PMID- 29416942 TI - Nurse-Designed Care Models and Culture of Health: Review of Three Case Studies. AB - The Robert Wood Johnson Foundation (RWJF) recently made a commitment to advancing a national culture of health (COH)-an action framework developed by RWJF that focuses on well-being and equity with the goal of empowering and supporting people to lead healthier lives where they live, learn, work, and play, now and in generations to come. Nurses are well positioned to provide care that is consistent with, and contributes to, a COH in their communities. RWJF contracted with the American Academy of Nursing (the Academy) with a subcontract to the RAND Corporation to explore the ways that innovative nurse-designed models of care are currently advancing a COH. This article presents findings from case studies of three nurse-designed care models that have been recognized as innovative by the Academy's Edge Runner program, which identifies nurses who have designed innovations to remedy challenges in the delivery of health care or address an unmet health need of a population, and who can demonstrate positive clinical and financial outcomes. Findings indicate that nurse-designed models of care focus extensively on activities in the four different "action areas" set forth in RWJF's COH framework: making health a shared value; fostering cross-section collaboration to improve well-being; creating healthier, more equitable communities; and strengthening integration of health services and systems. Strong leadership and broad community support were key to the success of each of these models. A persistent challenge was identifying a sustainable funding mechanism for community-level efforts aimed at addressing social determinants of health most of these efforts are currently grant-funded. PMID- 29416943 TI - Understanding value in health data ecosystems: A review of current evidence and ways forward. AB - The potential of health data to improve the efficiency and effectiveness of health research and development, healthcare delivery, and health systems more widely is substantial. There are many initiatives across the EU that are experimenting with ways to capture value and address the nexus of technical, legal, ethics-related, governance and data protection-related, and cultural challenges to delivering potential benefits for society and the economy. The field of health data research and policy is highly dynamic and there is a need for further reflection, thematic learning and evaluation to better understand how to create and connect receptive places, to inform future interventions and to identify transferable lessons. Our research emphasises that realising the benefits of health data at scale will require: a simultaneous focus on the technological and structural conditions that are required; collaboration and coordination to transform working cultures and build health and care workforce and citizen capacity to engage with data; and efforts to ensure that policy, industry, and research communities respond to public concerns, needs, and expectations in a timely and sustained manner. The global community of individuals and organisations with a stake in health data will also need to consider how progress can benefit different populations across the world in an equitable manner. PMID- 29416944 TI - Mid-Term Assessment of the EU Drugs Strategy 2013-2020 and Final Evaluation of the Action Plan on Drugs 2013-2016: Final report. AB - The aim of the EU Drugs Strategy 2013-2020 is to contribute to a reduction in drug demand and drug supply within the EU. The Strategy has so far been implemented by an Action Plan covering the period 2013-2016. This article sets out the findings of an evaluation that assesses the degree of implementation of the Strategy and the Action Plan in terms of outputs and, where possible, impacts. It looks at the extent to which the objectives of the Strategy have been achieved. The evaluation aims to provide evidence to support the European Commission's decision about whether to propose a new Action Plan for the period 2017-2020 and, if so, what changes would be needed compared to the current plan. Through applying a mixed-methods approach, the evaluation examined the effectiveness, efficiency, relevance and coherence of the actions undertaken on the basis of the EU Drugs Strategy and the Action Plan, as well as their EU added value. The evaluation makes 20 recommendations, addressed to the European Commission, Member States, the European Council and other stakeholders. The key recommendation for the Commission is that a new Action Plan should be implemented for the period 2017-2020. This should be an updated version of the current Action Plan, rather than taking a new approach or introducing more new actions. PMID- 29416945 TI - How Cultural Alignment and the Use of Incentives Can Promote a Culture of Health: Stakeholder Perspectives. AB - In 2013, the Robert Wood Johnson Foundation embarked on a pioneering effort to advance a Culture of Health. This report focuses on two questions that are central to understanding how individuals and sectors think about health and are motivated to promote it: How can the commonly understood concepts of cultural identity (e.g., ethnic or religious; lesbian, gay, bisexual, transgender plus; military) and organizational culture be harnessed to develop a Culture of Health? How can incentives be used to promote individual health and engage investors and leaders within organizations or governments to promote health and well-being broadly? This study draws on 43 one-hour semistructured interviews that RAND researchers conducted with stakeholders whose work focused on cultural alignment, incentives, or both to learn how organizations are addressing and leveraging culture and incentives to promote health and well-being, as well as to identify facilitators, barriers, potential best practices, and lessons learned. Key findings include the following: Equity is often addressed in silos, which impedes progress toward a unified goal of health equity for all; members of specific cultural groups need to be given a voice in health-related activities; systems are built around prevailing cultural norms, making it challenging for those working with specific cultures to make cultural adaptations; and not all incentives are monetary. Recommendations include institutionalizing practices that ensure ongoing input from marginalized populations, identifying ways to help smaller organizations overcome structural inequalities, and institutionalizing health promotion efforts in sectors other than public health or health care to sustain collaborative efforts. PMID- 29416946 TI - Workplace Wellbeing Charter: Analysis of take-up and impact. AB - There is strong and growing evidence that work and health and wellbeing are closely and strongly linked and need to be addressed together. In June 2014, Public Health England (PHE) published a set of national standards for workplace health for the first time-the Workplace Wellbeing Charter (WWC or Charter), which was developed with the charity Health@Work and Liverpool County Council and was based on their scheme and others from around the country. The national standards aimed to introduce a level of coherence and consistency across the country to support local authorities that had different programmes, with their own standards and reporting requirements, or were planning to introduce them. The national standards provide a universal baseline for local areas to commission or provide their schemes against, harmonising the core of existing schemes and allowing other elements to be tailored to local needs and interests. The WWC is designed to provide employers with a systematic, evidence-based approach to workplace health improvement. While the need for employers to act on workplace health and wellbeing is unequivocal and the practice of bringing together resources within a coherent approach is valid, there has been limited research into the impact of the WWC as a method. This study investigates the take-up and impact of the WWC, maps available data on the number of organisations accredited with the Charter across England and provides insights into a diverse range of organisations that have invested in the wellbeing of staff in their workplaces. PMID- 29416947 TI - Student Access to Mental Health Information on California College Campuses. AB - Two surveys of California public college students provide insight into the preliminary impact of the California Mental Health Services Authority's activities on college students' receipt of information about mental health issues and support services. PMID- 29416948 TI - Fit for Duty?: Evaluating the Physical Fitness Requirements of Battlefield Airmen. AB - Military occupations can be physically demanding, yet few attempts have been made to determine the physical readiness of today's airmen to perform their jobs. Although the Air Force conducts fitness testing of all its airmen, these tests and standards are not based on validated job requirements. As part of a broader Air Force effort to measure the physical readiness of airmen to perform their jobs, this study describes a methodology for establishing physical fitness standards for four physically demanding Air Force occupational specialties-combat controller, pararescue, special operations weather team, and tactical air control party. Airmen in these specialties are collectively known as battlefield airmen. The authors sought to identify the physically demanding tasks required of battlefield airmen and ways in which fitness standards might be established to ensure that individuals in these specialties are able to perform these tasks. They reviewed the research literature and relevant military documents, conducted focus groups and interviews with battlefield airmen and other subject matter experts, and analyzed the movement patterns and physical abilities associated with each task. They found a high demand across the four specialities for strength and muscular and cardiovascular endurance, followed by agility, anaerobic power, and equilibrium, whereas they found flexibility to be less critically important. The authors recommend that a validation study be conducted next, to (a) ensure that tests measure important physical abilities required for successful mission or job performance, (b) ensure that performance on tests is a good indicator of mission or job performance, and PMID- 29416950 TI - Letter from the Editor. PMID- 29416949 TI - Improving Support for America's Hidden Heroes: A Research Blueprint. AB - The United States is home to more than 21 million veterans, many of whom deployed to support combat operations around the globe during their military service and sustained service-related conditions or disabilities. Supporting these wounded, ill, and injured warriors once home are millions of informal caregivers individuals who provide unpaid support with activities that enable the service member or veteran to live in a noninstitutionalized setting. In this study, researchers describe elements of a research blueprint to inform future efforts to improve support for military and veteran caregivers. To construct this blueprint, researchers inventoried currently available research on caregiving for disabled adults and children and gathered stakeholder input by conducting a survey and facilitating an online panel. The study highlights the need for more studies that examine how military and veteran caregiver needs evolve over time, how programs are working, and how caregiving affects specific subgroups. The resulting blueprint should serve as a guide for the caregiver support community to use in prioritizing and facilitating future research. PMID- 29416951 TI - Functional MRI for Treatment Evaluation in Patients with Head and Neck Squamous Cell Carcinoma: A Review of the Literature from a Radiologist Perspective. AB - Purpose of review: To show the role of functional MRI in patients treated for head and neck squamous cell carcinoma. Recent findings: MRI is commonly used for treatment evaluation in patients with head and neck tumors. However, anatomical MRI has its limits in differentiating between post-treatment effects and tumor recurrence. Recent studies showed promising results of functional MRI for response evaluation. Summary: This review analyzes possibilities and limitations of functional MRI sequences separately to obtain insight in the post-therapy setting. Diffusion, perfusion and spectroscopy show promise, especially when utilized complimentary to each other. These functional MRI sequences aid in the early detection which might improve survival by increasing effectiveness of salvage therapy. Future multicenter longitudinal prospective studies are needed to provide standardized guidelines for the use of functional MRI in daily clinical practice. PMID- 29416952 TI - Advanced Imaging Techniques in Skull Base Osteomyelitis Due to Malignant Otitis Externa. AB - Purpose of Review: To give an up-to-date overview of the strengths and weaknesses of current imaging modalities in diagnosis and follow-up of skull base osteomyelitis (SBO). Recent Findings: CT and MRI are both used for anatomical imaging, and nuclear techniques aid in functional process imaging. Hybrid techniques PET-CT and PET-MRI are the newest modalities which combine imaging strengths. Summary: No single modality is able to address the scope of SBO. A combination of functional and anatomical imaging is needed, in the case of newly suspected SBO we suggest the use of PET-MRI (T1, T2, T1-FS-GADO, DWI) and separate HRCT for diagnosis and follow-up. PMID- 29416953 TI - Redescription of Calyptosuchus (Stagonolepis) wellesi (Archosauria: Pseudosuchia: Aetosauria) from the Late Triassic of the Southwestern United States with a discussion of genera in vertebrate paleontology. AB - Calyptosuchus wellesi is a medium-sized desmatosuchian aetosaur common in Adamanian (early to middle Norian) age rocks from the Chinle Formation and Dockum Group of the Western United States. Known chiefly from osteoderms, this taxon has never been fully described and non-osteoderm material assigned to Calyptosuchus has been done so based on questionable criteria. Mapping of aetosaurian elements from the Placerias Quarry allows for the recognition of associated material providing support for referrals of non-osteoderm material. Furthermore, another previously undescribed specimen from the Chinle Formation of Arizona provides more details about this taxon. Presently Calyptosuchus lacks discrete autapomorphies, but can be distinguished from other aetosaurs based on a unique combination of characters supported by a phylogenetic analysis. Calyptosuchus is one of the most common aetosaurians in the Western United States and an index taxon of the early Adamanian biozone. The name Calyptosuchus is retained and encouraged as the applicable genus name for the species wellesi rather than the often used Stagonolepis because assignments of taxa to multi-species genus names are problematic and in this case provides a proposed taxonomic relationship that cannot be unambiguously supported, even by phylogenetic analyses. Because of the inherent limitations of the fossil record, referral of specimens and species to species and genera respectively is an epistemological problem in vertebrate paleontology. PMID- 29416955 TI - Molecular systematics of the subfamily Limenitidinae (Lepidoptera: Nymphalidae). AB - We studied the systematics of the subfamily Limenitidinae (Lepidoptera: Nymphalidae) using molecular methods to reconstruct a robust phylogenetic hypothesis. The molecular data matrix comprised 205 Limenitidinae species, four outgroups, and 11,327 aligned nucleotide sites using up to 18 genes per species of which seven genes (CycY, Exp1, Nex9, PolII, ProSup, PSb and UDPG6DH) have not previously been used in phylogenetic studies. We recovered the monophyly of the subfamily Limenitidinae and seven higher clades corresponding to four traditional tribes Parthenini, Adoliadini, Neptini, Limenitidini as well as three additional independent lineages. One contains the genera Harma + Cymothoe and likely a third, Bhagadatta, and the other two independent lineages lead to Pseudoneptis and to Pseudacraea. These independent lineages are circumscribed as new tribes. Parthenini was recovered as sister to rest of Limenitidinae, but the relationships of the remaining six lineages were ambiguous. A number of genera were found to be non-monophyletic, with Pantoporia, Euthalia, Athyma, and Parasarpa being polyphyletic, whereas Limenitis, Neptis, Bebearia, Euryphura, and Adelpha were paraphyletic. PMID- 29416954 TI - A 250 plastome phylogeny of the grass family (Poaceae): topological support under different data partitions. AB - The systematics of grasses has advanced through applications of plastome phylogenomics, although studies have been largely limited to subfamilies or other subgroups of Poaceae. Here we present a plastome phylogenomic analysis of 250 complete plastomes (179 genera) sampled from 44 of the 52 tribes of Poaceae. Plastome sequences were determined from high throughput sequencing libraries and the assemblies represent over 28.7 Mbases of sequence data. Phylogenetic signal was characterized in 14 partitions, including (1) complete plastomes; (2) protein coding regions; (3) noncoding regions; and (4) three loci commonly used in single and multi-gene studies of grasses. Each of the four main partitions was further refined, alternatively including or excluding positively selected codons and also the gaps introduced by the alignment. All 76 protein coding plastome loci were found to be predominantly under purifying selection, but specific codons were found to be under positive selection in 65 loci. The loci that have been widely used in multi-gene phylogenetic studies had among the highest proportions of positively selected codons, suggesting caution in the interpretation of these earlier results. Plastome phylogenomic analyses confirmed the backbone topology for Poaceae with maximum bootstrap support (BP). Among the 14 analyses, 82 clades out of 309 resolved were maximally supported in all trees. Analyses of newly sequenced plastomes were in agreement with current classifications. Five of seven partitions in which alignment gaps were removed retrieved Panicoideae as sister to the remaining PACMAD subfamilies. Alternative topologies were recovered in trees from partitions that included alignment gaps. This suggests that ambiguities in aligning these uncertain regions might introduce a false signal. Resolution of these and other critical branch points in the phylogeny of Poaceae will help to better understand the selective forces that drove the radiation of the BOP and PACMAD clades comprising more than 99.9% of grass diversity. PMID- 29416956 TI - Complete mitochondrial genome sequence of the "copper moss" Mielichhoferia elongata reveals independent nad7 gene functionality loss. AB - The mitochondrial genome of moss Mielichhoferia elongata has been sequenced and assembled with Spades genome assembler. It consists of 100,342 base pairs and has practically the same gene set and order as in other known bryophyte chondriomes. The genome contains 66 genes including three rRNAs, 24 tRNAs, and 40 conserved mitochondrial proteins genes. Unlike the majority of previously sequenced bryophyte mitogenomes, it lacks the functional nad7 gene. The phylogenetic reconstruction and scrutiny analysis of the primary structure of nad7 gene carried out in this study suggest its independent pseudogenization in different bryophyte lineages. Evaluation of the microsatellite (simple sequence repeat) content of the M. elongata mitochondrial genome indicates that it could be used as a tool in further studies as a phylogenetic marker. The strongly supported phylogenetic tree presented here, derived from 33 protein coding sequences of 40 bryophyte species, is consistent with other reconstructions based on a number of different data sets. PMID- 29416957 TI - A Staufen1-mediated decay pathway influences the local transcriptome in axons. AB - Local translation is critical for diverse aspects of neuronal function, including mediating responses of elongating axons to guidance cues and other signaling molecules. A major determinant of the protein synthetic capacity of axons and growth cones is the specific set of mRNAs that are trafficked to these sites. However, recently it has become clear that the axonal transcriptome can also be shaped by local RNA degradation mechanisms, such as nonsense-mediated decay. Here we show that Staufen1-mediated decay can also occur within axons and mediate degradation of specific axonal transcripts. We show that Staufen1 and Upf1, which function together in Staufen1-mediated decay, are localized in growth cones. Selective depletion of Staufen1 from neurons results in a complex pattern of transcriptional alterations, with a subset of transcripts showing increased expression and increased RNA half-life consistent with their regulation by Staufen1-mediated decay. Additionally, we show certain transcripts, such as Rac1, are regulated by Staufen1 within axons and growth cones. The functional significance of Staufen1 in growth cones is supported by morphological alterations in growth cones following Staufen1 knockdown. Together these data point to Staufen1-mediated decay as a novel mechanism to control mRNA expression levels in axons and growth cones through local RNA degradation. PMID- 29416958 TI - Antimicrobial properties of lactic acid bacteria isolated from traditional yogurt and milk against Shigella strains. AB - Background: Lactic acid bacteria (LAB) are normal flora of the mouth, intestines and the female genital tract. They are also frequently found in meat, vegetables, and dairy products. Most of probiotic bacteria belong to the LAB group. Some probiotic LAB are useful in prevention and treatment of diarrheal diseases. The aim of this study was to investigate the antimicrobial properties of LAB isolated from traditional yogurt and milk against Shigella strains. Materials and methods: Forty LAB strains were isolated from traditional yogurt and milk. The antimicrobial activity of LAB against Shigella strains (eight S. flexneri, four S. sonnei) was examined using the agar-well diffusion assay. LAB strains with antimicrobial effect against all Shigella strains were identified by 16S rRNA gene sequencing. Results: Six LAB strains inhibited the growth of all 12 Shigella strains. Lb. paracasei Y1-3, Lb. paracasei Y8-1 and Lb. fermentum Y2-2 were isolated from yogurt. Lb. paracasei M18-1, Lb. parelimentarius M4-3 and Lb. plantarum M19-1 were isolated from milk. Conclusion: This study showed that Lactobacillus strains with good inhibitory activity against S. flexneri and S. sonnei could be isolated from traditional yogurt and milk. PMID- 29416960 TI - Changes in profile of patients seeking alcohol treatment and treatment outcomes following policy changes. AB - Aim: In 2007, the legal obligation to deliver alcohol treatment to the public was transferred to the 98 municipalities of Denmark. This resulted in changes in how alcohol treatment centers in Denmark work. The aim of the present study was to describe the patient profiles and treatment outcomes in the alcohol treatment centers regarding regional variation and changes over time. Subjects and methods: This is a descriptive, register-based study of patients enrolled in alcohol treatment centers from 2006-2014 in Denmark. Only patients above the age of 15 years and with a valid postal code were included. The sample was restricted to the patients' first contact with the alcohol treatment register (n = 44,516). Results: Patients who initiated treatment in the period 2006-2014 and were registered in the National Alcohol Treatment Register were primarily males (69 70%) with an average age between 46 and 49 years. Most had a vocational education (38-41%) on top of their primary education. The number of years with excessive alcohol use started out as being quite different in the five regions, but became more homogeneous over the study period. Treatment duration in the various regions followed a similar pattern, with all five of them having a similar treatment duration time of 160-230 days by 2014. Conclusion: We found that treatment for alcohol use disorder became more homogeneous across the regions in Denmark over time and that by 2014 it was difficult to identify any differences across the country. PMID- 29416959 TI - Socioeconomic status, health inequalities and non-communicable diseases: a systematic review. AB - Aim: A comprehensive approach to health highlights its close relationship with the social and economic conditions, physical environment and individual lifestyles. However, this relationship is not exempt from methodological problems that may bias the establishment of direct effects between the variables studied. Thus, further research is necessary to investigate the role of socioeconomic variables, their composition and distribution according to health status, particularly on non-communicable diseases. Subjects and methods: To shed light on this field, here a systematic review is performed using PubMed, the Cochrane Library and Web of Science. A 7-year retrospective horizon was considered until 21 July 2017. Results: Twenty-six papers were obtained from the database search. Additionally, results from "hand searching" were also included, where a wider horizon was considered. Five of the 26 studies analyzed used aggregated data compared to 21 using individual data. Eleven considered income as a study variable, while 17 analyzed the effect of income inequality on health status (2 of the studies considered both the absolute level and distribution of income). The most used indicator of inequality in the literature was the Gini index. Conclusion: Although different types of analysis produce very different results concerning the role of health determinants, the general conclusion is that income distribution is related to health where it represents a measure of the differences in social class in the society. The effect of income inequality is to increase the gap between social classes or to widen differences in status. PMID- 29416961 TI - German claims data analysis to assess impact of different intraocular lenses on posterior capsule opacification and related healthcare costs. AB - Aim: Cataract extraction is one of the most frequent surgeries in Germany. In most cases, the clouded natural lens is replaced by a hydrophobic or hydrophilic acrylic intraocular lens (IOL) implant. The most common long-term complication after cataract surgery is the development of a posterior capsule opacification (PCO). Although no precise real world data are available, published evidence suggests a lower risk for PCO development for hydrophobic acrylic IOLs compared to hydrophilic acrylic IOLs. Therefore, in the present study we assessed real world data on the impact of different IOL material types on the incidence of post operative PCO treatment. Subject and methods: In this retrospective study, we included 3,025 patients who underwent cataract extraction and implantation of either an acrylic hydrophobic or hydrophilic IOL in 2010. We assessed clinical outcomes and direct costs in a 4-year follow-up period after cataract surgery from a statutory health insurance (SHI) perspective in Germany. Results: PCO that required capsulotomies occurred significantly (p < 0.0001) less frequent in patients who had received a hydrophobic IOL (31.57% of 2,078 patients) compared to the group with hydrophilic IOL implants (56.6% of 947 patients) and costs per patient for postoperative treatment in a 4-year follow-up were 50.03 ? vs. 87.81 ? (i.e. 75% higher in the latter group, p < 0.0001). Conclusion: Considering the high prevalence of cataract, the economic burden associated with adverse effects of cataract extraction is of great relevance for the German SHI. Hydrophobic lenses seem to be superior regarding both medical and economic results. PMID- 29416962 TI - Internal Suture Augmentation Technique to Protect the Anterior Cruciate Ligament Reconstruction Graft. AB - The anterior cruciate ligament suture augmentation technique is a method to augment anterior cruciate ligament reconstruction (ACLR) with autologous hamstring tendons using a braided ultrahigh-molecular weight polyester or polyethylene suture or suture tape and fixed on both the femoral and tibial sides independent of the graft to act as a backup or secondary stabilizer until complete integration and ligamentization of the graft take place. The technique is proposed to allow early rehabilitation and return to sports after ACLR and may be advantageous in patients with a high body mass index and in cases with small grafts (7 or 7.5 mm in diameter). In such situations the technique is supposed to decrease the risk of reinjury, as well as the degree of postoperative lengthening or stretching of the graft, in the early postoperative avascular phase. We describe graft preparation with the internal suture augmentation technique in arthroscopic ACLR using a cortical button system on the femoral side and a Bio Interference Screw (Arthrex, Naples, FL) on the tibial side. PMID- 29416963 TI - The PASTA Bridge: A Technique for the Arthroscopic Repair of PASTA Lesions. AB - PASTA (partial articular supraspinatus tendon avulsion) lesions of greater than 50% thickness are usually repaired, whereas those of less than 50% thickness receive subacromial decompression and debridement. However, tears of greater than 25% thickness of the tendon result in increased strain of the adjacent, intact tendon fibers. Re-creating the tendon footprint at the greater tuberosity is the goal of a repair. Transtendon repairs have been considered the gold standard in repair but have shown varying outcomes and are technically difficult procedures. This report details the PASTA bridge-a technique for the arthroscopic, percutaneous repair of PASTA lesions. The PASTA bridge uses a spinal needle to ensure the repair includes the leading edge of the good tissue and is at the appropriate angle and area. Most procedures use a knife or trocar blindly to access the joint to place anchors, which has the potential to damage surrounding tissues and result in poor anchor and suture placement. The PASTA bridge is a safe, reliable procedure that is easily reproducible and appropriate for surgeons of all experience levels and should be strongly considered when repairing PASTA lesions. PMID- 29416964 TI - Arthroscopic Rotator Cuff Repair With Mini-open Subpectoral Biceps Tenodesis. AB - With a range of tear characteristics such as chronicity, degree of fatty atrophy, and number of tendons involved as well as varying patient-specific characteristics including age, injury mechanism, and expectations after treatment to consider, proper and successful treatment of a rotator cuff tear is multifactorial and, consequently, challenging. Although conservative management of a rotator cuff tear may be successful, a more severe tear with involvement of more tendons may warrant surgical intervention. Furthermore, additional pathology including biceps tendinopathy may result in greater patient morbidity and an even more complex treatment decision-making process and surgical technique. The purpose of this Technical Note is to describe our preferred surgical technique for the treatment of a rotator cuff tear involving 2 rotator cuff tendons in conjunction with a lesion of the long head of the biceps tendon. PMID- 29416965 TI - Vertical Lasso and Horizontal Lasso Sutures for Repair of Horizontal Cleavage and Horizontal Oblique Meniscal Tears: Surgical Technique and Indications. AB - Horizontal cleavage and horizontal oblique meniscal tears have traditionally been treated with partial meniscectomy. Recent research has shown the deleterious long term effects of meniscectomy in these patients regarding the development of osteoarthritis. Meniscal preservation is thus the preferred method of surgical treatment in patients with these tears. However, traditional repair techniques using inside-out sutures or suture anchor-based devices do not address the horizontally aligned nature of these particular tears and thus do not compress the meniscal tissue in the correct plane. The recent development of an arthroscopic suture-passing system now allows surgeons to place arthroscopic sutures in any pattern or direction. This allows surgeons to treat tears of any type with sutures ideally placed to repair the given tears. This Technical Note describes and demonstrates 2 all-suture, all-inside, arthroscopic meniscus repair techniques to treat these challenging horizontal tear types. The repair techniques are named the vertical lasso and horizontal lasso. PMID- 29416966 TI - Superior Capsular Reconstruction With Superimposition of Rotator Cuff Repair for Massive Rotator Cuff Tear. AB - Massive rotator cuff tears are particularly challenging to treat and severely limit the function of the shoulder. Compared with a small rotator cuff tear, massive tears are more unpredictable and usually present with low tendon quality. When performing an anatomical repair of the rotator cuff, the surgical treatment is often associated with failure of the construct. An alternative procedure that can be performed in the setting of a massive tear is superior capsular reconstruction (SCR), using an autograft or allograft. This procedure has been shown to be effective and is associated with positive treatment outcomes. Moreover, the combination of an SCR with an anatomic repair of the rotator cuff tendon may provide a stronger fixation for the rotator cuff and ultimately lead to a lower likelihood of retear and failure. The purpose of this Technical Note is to describe our preferred procedure for the treatment of a massive rotator cuff tear through SCR with superimposition of the repair of the native rotator cuff tendons. PMID- 29416967 TI - Arthroscopic Intra-articular Spinoglenoid Cyst Resection Following SLAP Repair. AB - Spinoglenoid cyst (SGC) is a ganglion arising in the spinoglenoid notch and is thought to be related to SLAP lesion. This cyst often compresses the suprascapular nerve in the spinoglenoid notch. Symptomatic cysts require surgical treatment when conservative treatment fails. In particular, arthroscopic decompression through the torn labral tissue when the cyst is extending into the joint cavity is easy and convenient. However, if the cyst is confined to the spinoglenoid notch, arthroscopic approach through the torn labral tissue is challenging. Thus, we present our preferred technique of addressing the SGC through an additional superior capsular window after completing SLAP repair. We believe that our technique is easy, reproducible, and reasonable. PMID- 29416968 TI - Suture Repair of Full Radial Posterior Lateral Meniscus Tears Using a Central Midline Portal. AB - Full radial posterior lateral meniscus root tears are frequently associated with injuries to the anterior cruciate ligament. Left unrepaired, they result in loss of the meniscus hoop stress function and can lead to overload of the lateral compartment and early degenerative changes. Arthroscopic suture repairs show successful results with long-term follow-up. However, previously described suture repair techniques have often required special instrumentation and can be technically demanding. This Technical Note describes the use of an accessory portal through the patellar tendon as a safe and easy method for repairing full posterior radial tears of the lateral meniscus. PMID- 29416969 TI - "In-Round" Labral Repair After Acetabular Recession Using Intermittent Traction. AB - The prevalence of hip arthroscopy has increased exponentially with the advent of arthroscopic labral repair techniques for femoroacetabular impingement. The goal of arthroscopic labral repair is to re-create the anatomic suction seal of the labrum against the femoral head. This important anatomic relationship has been demonstrated in several biomechanical studies. Performing the acetabular recession and evaluating the congruity of labral repairs during surgery is difficult with the application of traction distracting the femoral head from the chondrolabral junction. Additionally, prolonged traction risks nerve injury during hip arthroscopy. The purpose of this technique article is to describe a method of using traction only for central compartment work, and releasing the traction to allow the femoral head to reduce the labrum to its anatomic position for acetabular recession, anchor placement, and suture fixation. In this manner, the presented technique prevents an "out-of-round" or everted repair. This technique re-creates the native anatomy and biomechanics of the hip after acetabular recession and labral repair while decreasing traction time. PMID- 29416970 TI - Combined Anterior Cruciate Ligament and Medial Collateral Ligament Reconstruction Using a Single Achilles Tendon Allograft. AB - Approaches to management of combined anterior cruciate ligament (ACL) and high grade medial collateral ligament (MCL) injuries remain controversial. Some studies suggest that with grade III MCL injuries, patients may benefit from concurrent MCL reconstruction to restore stability and prevent increased stress on the ACL graft. We present a technique for simultaneous ACL/MCL reconstructions using a single Achilles tendon allograft. PMID- 29416971 TI - Biologic and Mechanical Augmentation in Anterior Cruciate Ligament Reconstruction: Fibrin Clot Augmentation of 5-Strand Hamstring Autograft. AB - Hamstring autografts in anterior cruciate ligament reconstruction have an excellent clinical track record, but some patients have hamstring tendons that yield grafts of smaller diameter, which has been shown to be a significant risk factor for worse outcomes and graft failure. Some authors have advocated augmentation with allograft in these patients. Tripling the semitendinosus yields a completely autogenous 5-strand graft with a larger diameter but still of sufficient length. In addition, imaging studies still show signal heterogeneity within grafts, even autografts, after the healing process, which correlates with worse biomechanical properties. Recent animal studies have shown improved incorporation and better remodeling of soft tissue grafts with the use of an endogenous fibrin clot. We present our technique of biologic and mechanical augmentation of hamstring autografts with fibrin clot and a 5-strand graft. PMID- 29416972 TI - Fibular Intra-articular Resection During Arthroscopic Ankle Arthrodesis: The Surgical Technique. AB - Ankle arthrodesis is still considered the gold standard in the treatment of advanced painful ankle osteoarthritis. More than 3 decades ago, it was performed under arthroscopy; thereafter, many authors have reported excellent results and a low complication rate. Despite the significant improvements in surgical techniques, nonunion remains a problematic and relatively frequent event. This is one of the reasons the research is constantly active in this field. Ten years ago, a fibular resection during ankle arthrodesis was, for the first time, described in the literature as a means to correct malalignment in varus cases. Nowadays, we perform a similar technique during all arthroscopic ankle arthrodeses, regardless of the kind of preoperative deformity (varus, valgus, or normal alignment). In this article, we describe the arthroscopic technique to perform a fibular intra-articular resection during arthroscopic ankle arthrodesis, joining the benefits of arthroscopic minimal invasiveness to the full joint contact gained after such a fibular osteotomy. In our opinion, this would be the only way through which full contact between the talar and tibial surfaces may be achieved. PMID- 29416973 TI - Transmedial All-inside TriLink Posterior Cruciate Ligament Reconstruction. AB - Posterior cruciate ligament (PCL) injuries usually constitute part of a multiligament injury. Isolated PCL injuries account for only approximately 3% of all ligament injuries. No consensus on optimal surgical reconstruction exists. The PCL is a double-bundle structure that functions in an anisometric manner. Biomechanical studies have shown that re-creating the PCL femoral double-bundle configuration provides greater stability. We present a 3-socket approach for an anatomic "all-inside" double-bundle PCL reconstruction using our preferred option of a FiberTape (Arthrex, Naples, FL)-reinforced peroneus longus allograft fashioned to create a trifurcate graft: the TriLink technique. Cortical suspensory fixation devices are used, allowing differential tensioning of the anterolateral and posteromedial bundles. This enables more accurate replication of the native PCL and its biomechanical properties. PMID- 29416974 TI - Arthroscopic Chondral Debridement Using Radiofrequency Ablation for Patellofemoral Compartment Pathology. AB - The purpose of this Technical Note is to introduce a surgical technique using a fluid pressure pump, mid-lateral portal, and radiofrequency ablation for visualization, assessment, and subsequent, accurate/adequate removal of patellofemoral articular lesions for the treatment of patellofemoral compartment pathology. With the patient in the supine position, and an inflated thigh tourniquet, standard lateral and medial portals are made. The medial-femoral compartment, notch, lateral-femoral compartment, and patellofemoral compartments are assessed. If pathology is seen within the patellofemoral compartment, a mid lateral portal is made if chondral pathology cannot be addressed thoroughly. Addressing chondral pathology to achieve chondral stability is then performed using a combination of the radiofrequency ablator and chondrotome. This technique provides greater visibility and access to accurately and thoroughly smooth chondral pathology. PMID- 29416975 TI - All-inside Arthroscopic Meniscal Repair Technique Using a Midbody Accessory Portal. AB - Treatment of symptomatic meniscal tears continues to evolve as we improve our understanding of the biomechanical role of the meniscus and its long-term importance to the health of the knee joint. Suture repair of meniscal tears is challenging, yet the incidence of repairs among our colleagues continues to rise as we aim to preserve meniscal tissue. Many elements of performing a repair are tedious and difficult, including proper meniscal preparation, reduction, mattress suture placement, and fixation. The tear pattern and location present another layer of difficulty. The most widely used all-inside repair devices are harpoon style devices and present their own challenges in using them without causing harm to the meniscus and surrounding cartilage. In this article, we describe a simple all-inside meniscal repair technique to improve the reproducibility and reliability of meniscal repairs using an accessory midbody meniscal portal and a surgical probe. This ensures proper placement of mattress sutures in a reduced meniscus, with a reduced risk of collateral injury to the meniscus and articular cartilage. Furthermore, this surgical technique is adaptable to any meniscal fixation method to the medial or lateral meniscus. PMID- 29416976 TI - Graft Transfer Technique in Arthroscopic Posterior Glenoid Reconstruction With Distal Tibia Allograft. AB - Posterior glenoid reconstruction using distal tibia allograft is an available technique for the treatment of posterior shoulder instability with glenoid bone loss. A key aspect to this procedure relies on maintaining complete control of the graft during insertion and securement to the posterior glenoid. Although there are commercially available products to aid with graft control, we describe a novel graft transfer technique that is compatible with all cannulated systems for maintaining positive graft control. This technique allows the surgery to be performed in an arthroscopic manner using current instrumentation for open glenoid reconstruction. PMID- 29416977 TI - The "Parachute" Technique: A Simple and Effective Single-Row Procedure to Achieve an Increased Contact Area Between the Cuff-Tendon and Its Footprint. AB - Many techniques of arthroscopic rotator cuff repair have been described. No significant differences in clinical outcomes or rerupture rates have been observed when comparing single-row with double-row methods. Not all single- and double-row repairs are the same. The details of the technique used are crucial. It has been shown that the suture-tendon interface is the weakest point of the reconstruction. Therefore, the biomechanical properties of rotator cuff repairs might be influenced more by the suture configuration than by the number of anchors or by the number of rows involved. Techniques that secure less amount of tendon over a smaller area of the healing zone might be expected to have higher failure rates. The way the sutures of the "parachute technique" are configured represents a quadruple mattress that increases the contact and pressure between the tendon and its footprint and increases the primary load to failure of the repair. We present a simple and effective single-row technique that involves the biomechanical and biological advantages related to the increased contact area and pressure between the cuff and its footprint. PMID- 29416978 TI - Arthroscopic Transfer of the Long Head of the Biceps Brachii for Anterior Shoulder Instability. AB - In the treatment of anterior shoulder instability, there are various conditions in which a sling effect is needed to enhance anterior stability. The traditional Latarjet procedure provides a sling effect but destroys the coracoacromial arch, which may result in superior instability. To preserve the coracoacromial arch and create a sling to enhance the anterior-inferior side of the shoulder, we introduce an arthroscopic technique to transfer the long head of the biceps (LHB) brachii. Indications of LHB transfer are patients younger than 45 years of age who participate in competitive sports, require forceful external rotation and abduction movement of the shoulder, and/or have capsule-ligament insufficiency, as well as patients 45 years o or older who have combined SLAP lesions (type II or IV). The main steps of this procedure include detaching the LHB, retrieving and braiding the LHB, creating a glenoid tunnel, placing a guide suture through the subscapularis and glenoid tunnel, passing the LHB through the subscapularis and into the glenoid tunnel, and suspension fixation of the LHB. PMID- 29416979 TI - Posterior Lateral Meniscus Root Reattachment With Suture Anchors: An Arthroscopic Technique. AB - The posterior lateral meniscus root (PLMR) provides the circumferential tension required to stabilize the lateral meniscus. Thus, preservation of the PLMR is important to prevent an increase in tibiofemoral contact pressure, which could result in osteoarthritis. We describe an all-arthroscopic approach to the fixation of PLMR using suture anchors through associated posterolateral arthroscopic portals that result in a more favorable inclination of the anchors. Initially, the anatomical insertion site of the root on the tibial plateau is debrided, 1 to 2 anchors are placed through the posterolateral portals into the root's footprint area, and the meniscus is finally sutured from the posterolateral portals. Compression of the meniscus is achieved with bone contact. This technique achieves lateral meniscus root fixation, reducing the risk of subluxation of the meniscus and subsequent osteoarthritis. PMID- 29416980 TI - Arthroscopic Technique to Reduce Suture Button Migration During Anterior Cruciate Ligament Reconstruction Procedure. AB - Suture button-based femoral cortical suspension constructs of anterior cruciate ligament grafts can facilitate a fast and secure fixation. However, there are several case reports showing button malpositioning resulting from the inability to visualize the "flipped" button. Many current surgical techniques do not allow direct visualization of EndoButtons (Smith & Nephew, Andover, MA) in their final position, making it difficult to ensure that both buttons are fully flipped and that there is no soft-tissue interposition between the button and femur. We describe an arthroscopic technique for making femoral tunnels through the outside in method that reduces the migration of the EndoButton through a lateral femoral portal. This technique may assist surgeons in understanding how to deal with and potentially avoid EndoButton migration during anterior cruciate ligament reconstruction. PMID- 29416981 TI - Consolidated Proximal Biceps Tenodesis and Subscapularis Repair. AB - Pathologic changes to the biceps tendon including subluxation are frequently encountered in patients with subscapularis tears. Operatively managing these combined lesions can be difficult depending on the status of the subscapularis tendon and the degree of biceps medialization. The presented technique is an effective and relatively simple method that simultaneously and efficiently provides for secure tenodesis of the biceps and fixation of subscapularis tendon detachment. PMID- 29416982 TI - Medial Patella Femoral Ligament Reconstruction With Periosteal Tunnels and Suture Fixation. AB - Lateral patellar dislocations can damage the medial patella femoral ligament. Nonoperative care is preferred but some tears may require a surgical intervention. Patella fractures are considered a risk factor after surgery. The technique described in this Technical Note avoids any bone tunnel drilling, which may eliminate the possibility of a patella fracture. The surgical procedure uses periosteal fibro-osseous tunnels to a double-limbed gracilis graft to reconstruct the upper and lower borders as conventionally used for medial patella femoral ligament reconstruction. Once the graft is tensioned, it is sutured to the periosteal fibro-osseous tunnel with 2 sutures on the medial side and at least 1 suture on the lateral side of each periosteal fibro-osseous sleeve. Each of the 2 periosteal fibro-osseous tunnels has 3 to 4 sutures securing the graft. After surgery, the patients complete 5 phases of rehabilitation to reduce swelling and to regain their strength and range of motion. PMID- 29416983 TI - Mosaicplasty Using Grafts From the Upper Tibiofibular Joint. AB - Autologous mosaicplasty has been widely used for the treatment of focal, full thickness, articular cartilage lesions of the knee and ankle joints. Commonly, the autografts are harvested from non-weight-bearing areas of the knee joint, leading to associated donor-site morbidity and representing a considerable disadvantage. This Technical Note presents a mosaicplasty procedure for harvesting autologous osteochondral plugs from the upper tibiofibular joint to repair articular cartilage defects. With this technique, it is possible to achieve low or no risk of donor-site morbidity, being therefore a safe and favorable option to treat large cartilage defects. Because of its minimal size related restrictions, it enables harvesting larger plugs (filling an area up to 5 cm2) without any additional iatrogenic complications. Hence, mosaicplasty using the upper tibiofibular joint autografts can overcome many of the reported complications associated with osteochondral autograft harvesting. Thus, the upper tibiofibular joint articular surface should be considered as a safe and reliable autograft source for harvesting osteochondral plugs. PMID- 29416984 TI - Single Working Portal Technique for Knotless Arthroscopic Bankart Repair. AB - Arthroscopic Bankart repair is widely accepted as the method of choice in restoring the labrum to the glenoid rim. It has been shown to have comparable outcomes with open stabilization. This usually involves the use of 2 portals anteriorly: one anterosuperior accessory portal and another anteroinferior working portal. The aim of this Technical Note is to present a simple and reproducible technique for Bankart repair using a single working portal anteriorly without an accessory portal. PMID- 29416985 TI - Posterior Tibial Tendon Endoscopic Debridement for Stage I and II Posterior Tibial Tendon Dysfunction. AB - Adult acquired flatfoot deformity (AAFD), formerly known as posterior tibial tendon (PTT) dysfunction, is one of the most common problems of the foot and ankle. It was first described as tendon failure but has since been revealed as ligamentous failure in addition. AAFD is a spectrum of deformities that ranges from tenosynovitis (stage I) to AAFD (stages II-IV). Regarding mild stage I and stage II disease, it was once standard to perform an open synovectomy completely removing the inflamed synovium; this procedure required a large 6-cm medial ankle incision. Postoperative management included plaster cast immobilization for 3 weeks, followed by a boot with controlled ankle movement for another 3 weeks. Now, the standard is shifting to PTT endoscopy, which has proved to be an efficient way to treat tenosynovitis in stage I and II AAFD with a shorter postoperative period. Using this technique, we can achieve 360 degrees visualization of the PTT within the tendon sheath, allowing for a complete exploration and debridement. We hope that by using this video description, practitioners could avoid the increased morbidity associated with open procedures, as well as help patients return to activity sooner after surgery. PMID- 29416986 TI - Neoadjuvant Treatment of Stage IIB/III Triple Negative Breast Cancer with Cyclophosphamide, Doxorubicin, and Cisplatin (CAP Regimen): A Single Arm, Single Center Phase II Study (GBECAM 2008/02). AB - Background: The DNA damaging platinum salts have been explored in the treatment of triple negative breast cancer (TNBC) based on preclinical, and, more recently, clinical evidence of specific susceptibility of TNBC to these agents. Despite the increased toxicity, treatment intensification with polychemotherapy improves response and might be of interest in patients presenting with large primaries. In this trial, we aimed at exploring the efficacy and tolerability of the addition of cisplatin to standard anthracycline-cyclophosphamide backbone in patients with stage IIB/III TNBC. Patients and methods: This is a single arm, single center, non-randomized, phase II trial of stage IIB/III TNBC. Patients received neoadjuvant chemotherapy with cisplatin (50 mg/m2) in combination with doxorubicin (50 mg/m2) and cyclophosphamide (500 mg/m2) every 21 days and for a total of six cycles (CAP). After surgery, adjuvant chemotherapy consisting of docetaxel (75 mg/m2) every 21 days was further provided for four cycles. Primary outcome was pathological complete response in the breast and axilla (pCR; ypT0ypN0). Secondary outcomes were safety, disease-free survival (DFS), and overall survival (OS). Results: Eight (19.5%) out of 41 patients reached a pCR and 35 (85.4%) had a clinical complete or partial response. After a median follow up of 47.4 months (interquartile range 30.9-61.9), the proportion of patients free of recurrence or death at 3 years was of 51.8% [95% confidence interval (CI) 34.6-66.5%], while the proportion of patients alive at 3 years was of 55.5% (95% CI 37.8-70.1%). Patients with a pCR rate or family history of breast and/or ovarian cancer showed a numerical but statistically non-significant trend for improved DFS and OS. The majority of patients received six cycles of CAP (82.9%). The three most common grade >=3 adverse events were nausea (16.3%), vomiting (14.0%), and neutropenia (9.3%). Febrile neutropenia occurred in three patients (7.0%). Conclusion: Cisplatin in association with doxorubicin and cyclophosphamide was associated with a pCR rate of 19.5% in a cohort of patients with predominantly stage III tumors. The tolerability profile of this combination poses clinical challenges to its general use in clinical practice. Unique Identifier Number: GBECAM 2008/02. NCT Identifier Number: NCT03304756. PMID- 29416987 TI - Streptococcal Cysteine Protease-Mediated Cleavage of Desmogleins Is Involved in the Pathogenesis of Cutaneous Infection. AB - Streptococcus pyogenes is responsible for a wide variety of cutaneous infections ranging from superficial impetigo to fulminant invasive necrotizing fasciitis. Dysfunction of desmosomes is associated with the pathogenesis of cutaneous diseases. We identified streptococcal pyrogenic exotoxin B (SpeB) as a proteolytic factor that cleaves the extracellular domains of desmoglein 1 and 3. In an epicutaneous infection model, lesional skin infected with an speB deletion mutant were significantly smaller as compared to those caused by the wild-type strain. Furthermore, immunohistological analysis indicated cleavage of desmogleins that developed around the invasion site of the wild-type strain. In contrast, the speB mutant was preferentially found on the epidermis surface layer. Taken together, our findings provide evidence that SpeB-mediated degradation of desmosomes has a pathogenic role in development of S. pyogenes cutaneous infection. PMID- 29416988 TI - Pattern of health promises for Indian democracy: A qualitative review of political manifestos. AB - Introduction: India is a multiparty parliamentary democracy and second most populous country in the world. In spite of pressing needs of the population, healthcare is still not considered a driving electoral mobilizer as compared to the older democracies such as the UK and USA. Only three National Health Policies (1983, 2002 and 2017) have been promulgated by the respective governments during the past 70 years of India's independence. National policies are often preceded by commitment of political parties documented in the manifestos. Type and nature of promises in the manifesto of National Political Parties (NPPs) are reflective of vision and intentions of parties. The present study was done to qualitatively analyze the pattern of expressed intensions in terms of health promises made for 16th Lok Sabha (people house) elections of India in the year 2014 by its NPPs. Methods: Manifestos of NPP, as notified by election commission of India, were retrieved from their respective website and effort was also made with an online search. Manifesto of five out of total seven NPPs could be accessed and analyzed. Consensus-based criteria of assessment were developed by public health experts and each manifesto was assessed independently by two experts. In a case of difference in scoring, independent opinion was sought from the third expert for adjudication. Results: Two NPPs mentioned majority of statements as goals and rest focused for health strategies. The focus of statements was for public health problems (11.5%), public health financing (9.0%), and improving infrastructure (9.0%). All parties were committed for improving health services as it shared 30.8% space as statements in all five manifestos. All statements were of primary or secondary prevention in nature and focused more on improving processes (47.4%) and increasing inputs (31.6%). Whereas, Communist Party of India focused only on inputs (60.0%) and outputs (40.0%). Conclusion: Promises made by all NPPs were quite progressive, inclusive, and comprehensive in nature; however, much of these do not find space in public debates on television and election speeches. PMID- 29416989 TI - Policy and System Approach (PSA): A primer. AB - A number of public health challenges have emerged at global and national level in the last two decades. The response to these challenges has rarely been swift and often "knee-jerk." The national and state level program officials responsible for the activities often apportion the blame on weak health systems or fragmented health service delivery mechanisms, amongst other. In India, the viral illnesses (including those due to dengue and chikungunya) are becoming the increasing realities. The Public health response of early identification, disease surveillance, reporting and the preventive and curative measures, remains suboptimal. The health challenges which require multidimensional interventions are usuallyattempted to be resolved through piece meal solutions. This article proposes "policy and system approach (PSA)," combining concepts of "Health in all policies" for intersectoral coordination and "health system approach" for intra sectoral tackling of the emerging and existing health challenges. PMID- 29416990 TI - Politics of Ebola and the critical role of global health diplomacy for the CARICOM. AB - The 2014 Ebola epidemic was the largest in history, affecting Guinea, Liberia, Sierra Leone, Nigeria, and Mali in West Africa. The International Health Regulations are legally binding in 194 countries including all the member states of WHO "to prevent, protect against, control, and provide a public health response to the international spread of disease." Since the Caribbean Community region heavily depends on tourism, a single case of the disease anywhere in the region could have serious negative consequences for the rest of the region's tourism industry. Global health diplomacy brings together the disciplines of public health, international affairs, management, law, and economics and focuses on negotiations that shape and manage the global policy environment for health. The regional institutes such as Caribbean Public Health Agency should play a more proactive and pivotal role in the creation of regional response teams in all the island nations collaborating with the departments of public health and epidemiology at the regional campuses of The University of the West Indies. The role of global health diplomacy and its practice should be encouraged to reach a consensus among the stakeholders considering the threat to the health security in the region. There is a need for the cadre of global health diplomats who has a critical understanding of health and also the practice of diplomacy since such serious health issues have implications at the global level in this globalized world. PMID- 29416991 TI - Adolescent health in urban India. AB - Adolescence is the period in human growth and development that occurs after childhood and before adulthood, from ages 10 to 19 years. It is a period of dynamic brain development. During this period, adolescents learn from the social behavior and environmental surroundings of their community. Because of rapid urbanization without accounting for the basic health-care amenities, health disparities tend to arise. In this review, we have tried to describe the health profile of adolescents in urban India. Relevant articles were extracted from PubMed and related websites. Adolescents in urban areas perceive their physical environment as very poor. Social capital and social cohesion are very important in their development. Increasing child marriage and poor antenatal care among adolescents are key challenges in improving the reproductive and sexual health. More than half of adolescents are undernourished. About 56% of adolescent girls are anemic. At this time of fighting against under-nutrition, burden of overweight and obesity is increasing among the urban adolescents. Mass media use and increased sedentary lifestyle increase the risk factors for noncommunicable diseases. Labile mental and emotional behavior makes them prone to suicide and intentional self-harm. Another avoidable key challenge among adolescents is addiction. Urban living and regular media exposure are positively associated with smoking and alcohol consumption. Among unintentional injuries, road traffic accidents dominate the picture. Various health programs targeting adolescent health have been launched in the recent past. PMID- 29416992 TI - Evaluation of Janani Shishu Suraksha Karyakram scheme and out of pocket expenditure in a rural area of Northern India. AB - Introduction: The stagnant performance of countries with regard to maternal and child health is linked to low investment in health and out of pocket expenditure (OOP). To address issue of OOP expenses related to maternal and newborn care, Janani Shishu SUraksha Karyakram (JSSK) was launched in the year 2011 in Mewat district of Haryana with the objective to eliminate OOP expenses of obstetric women and sick infants. Methods: A community based cross-sectional study was undertaken in rural area of Haryana to know the utilization of JSSK scheme and OOP expenditure. A total of 200 delivered mothers were included as study subjects. The study was conducted from July 20113 to September 2014. Results: Out of 200, 134 subjects delivered in government institutions and hence were eligible for benefits of JSSK scheme. Twenty nine percent of deliveries occurred in private facilities and 17% newborns were sick within 30 days of birth. OOP expenditure was done by 83.5% subjects with median amount Rs. 1100. Most common suggestions given by subjects were the availability of ultrasound facility, cooperative staff and crowd management in hospitals. Conclusion: For reducing OOP expenses, up-gradation and constant supervision is required to maintain the adequacy of services. More evaluation studies need to be conducted to know the utilization pattern of JSSK so as to improve the coverage and removing the bottlenecks to further increase the utilization of JSSK scheme. PMID- 29416993 TI - Factors affecting antiretroviral treatment adherence among people living with human immunodeficiency virus/acquired immunodeficiency syndrome: A prospective study. AB - Context: Antiretroviral adherence is the second strongest predictor of progression to acquired immunodeficiency syndrome (AIDS) and death, after CD4 count. Adherence to antiretroviral therapy (ART) has been strongly correlated with human immunodeficiency virus (HIV) viral suppression, reduced rates of resistance, an increase in survival, and improved quality of life. Aims: To determine the adherence rates and factors affecting adherence to ART among people living with HIV/AIDS (PLWHA). Settings and Design: A Prospective study for 1 year was conducted among PLWHA, aged between 15 and 49 years, visiting ART center. Subjects and Methods: 242 PLWHAs were included in the study. Structured questionnaire was used to obtain data on sociodemographic profile, factors affecting adherence. Adherence was assessed through self-reports, routine and random pill counts, and assessment of medical records. Statistical Analysis Used: Descriptive statistics, logistic regression, and Chi-square tests were computed using Epi Info 7 version CDC (Centers for Disease Control and Prevention) U.S. Department of Health and Human Services. Results: Adherence to ART was finally assessed on 242 PLWHAs. Mean age of subjects was 35 +/- 7.8 years. One hundred percent adherence rate (consistent adherers) for the whole 6 month period was seen only in 31.6% patients. Lower 6 month averages of 95-100%, 80-95%, and <80% were noted in 49.8%, 9.1%, and 9.5% patients, thus resulting in optimal adherence rate of >95% in 81.4%. Earning member (odds ratio [OR] =0.404) and weight difference (OR = 0.818) were most associated with the adherent individuals. Most common psychological reason was forgetfulness in 44.9%. Conclusions: Adherence rate was poor among PLWHA and economic factors play an important role in adherence. PMID- 29416994 TI - A study on awareness about breast carcinoma and practice of breast self examination among basic sciences' college students, Bengaluru. AB - Background: In India, the number of new breast cancer cases is about 115,000 per year and this is expected to rise to 250,000 new cases per year by 2015. It needs to be noted that breast cancer is leading in the age groups of 15-34 years which is a cause of concern as this denotes the need for educative and awareness programs targeting younger members of the society, to implement early practices of breast examination. This study was carried out with the intention of assessing the level of knowledge and awareness of carcinoma breast and breast self examination (BSE) in female college students. Materials and Methods: This cross sectional study was carried out in a well-known basic sciences college. After the pretest questionnaire was given, an awareness talk was given about breast cancer and BSE. A posttest questionnaire was administered. The data of pre- and post test were collected and analyzed using SPSS. Results: Pretest and posttest were collected from 1030 students. The age of the study participants was ranged between 18 and 23 years. Most of them were aware of breast carcinoma, but half of them thought breast cancer affects the elderly. Regarding different aspects studied, 58% had a knowledge of at least one of the symptoms and 59% knew at least one of the risk factors for breast carcinoma. Only 185 (18%) women knew about BSE and 107 women practice it. Conclusions: This study concluded that the awareness of the breast cancer was good but the knowledge of signs and BSE was poor, which is utmost important for early detection and in reduction of mortality. PMID- 29416995 TI - Prevalence of risk factors of noncommunicable diseases in a rural population of district Gautam-Budh Nagar, Uttar Pradesh using the World Health Organization STEPS approach. AB - Context: Globally, it is estimated that by 2020, noncommunicable diseases (NCDs) will account for 73% of deaths and 60% of disease burden. India is in the midst of an epidemiological transition leading to increasing the prevalence of NCDs. Targeting the risk factors for NCDs is recognized as an essential preventive strategy. Aims: The rationale of this study was to decipher the baseline data on the prevalence of NCD risk factors among the rural population. Settings and Design: A community-based cross-sectional study was conducted among 207 adults in the rural catchment area of the Department of Community Medicine. Subjects and Methods: The World Health Organization STEPS approach was employed which includes three sequential phases: Collection of information on sociodemographic variables and behavioral risk factors (STEP 1), obtaining physical measurements (STEP 2), and acquiring biochemical measurements (STEP 3). Statistical Analysis: Data were analyzed using the SPSS version 16. P < 0.05 was considered to be statistically significant. Results: Among the study subjects, the prevalence of smoking, smokeless tobacco use, alcohol use, and sedentary lifestyle was 26.0%, 35.1%, 16.9%, and 9.6%, respectively, in males and 4.6%, 15.4%, 0.0%, and 19.0%, respectively, in females. The prevalence of hypertension and diabetes was 15.6% and 13.0% respectively among males and 20.0% and 7.7% respectively among females. Hypercholesterolemia and Hypertriglyceridemia were observed in 5.2% men and 13.8% women and 22.1% men and 16.9% women, respectively. Conclusions: The study reveals high burden of NCD risk factors in rural areas as well and reiterates the need to take preventive measures. PMID- 29416996 TI - Combined steroid and lignocaine injection in resistant cases of tennis elbow: A prospective, interventional study from India. AB - Background: Tennis elbow or lateral epicondylitis is a chronic, painful condition and is often resistant to conventional therapy. We evaluated the benefits of a combined steroid and lignocaine injection in resistant cases of tennis elbow. Materials and Methods: In this prospective, interventional study, we included chronic lateral epicondylitis patients resistant to analgesics and physiotherapy. The pain was assessed by visual analog scale (VAS), and we included patients with a baseline VAS >4. All patients were given local infiltration at the painful site with methylprednisolone (1 ml) and lignocaine (1 ml) by the peppering technique. The primary outcome was the change in VAS from the baseline at the end of 7 and 28 days. The improvement is classified as good, moderate, or mild based on the reduction in VAS score by 3, 2, 1, respectively. Descriptive statistics and appropriate tests were used to analyze the results. Results: The study population (n = 63; male: female - 33:30) had a mean age of 36.2 +/- 4.5 years and disease duration of 17.4 +/- 5.8 weeks. After 1 week, 55 patients showed good improvement, three patients showed moderate improvement, two patients showed mild improvement, and three patients had no improvement. The improvement persisted till 28 days in all the patients and one patient who had not improved after 7 days did not report for 28 days follow-up. Conclusion: Local infiltration with steroids and lignocaine is a useful modality of therapy for tennis elbow, especially in patients where ultrasonic therapy and conservative measures have failed. PMID- 29416997 TI - Acute coronary syndrome-related mortality audit in a teaching hospital at Port Blair, India. AB - Background: India has a growing trend of acute myocardial infarction (AMI) due to shifting lifestyle. Objective: To study the profile of patients died due to AMI and to find its risk correlates. Methods: A study was conducted on consecutive AMI cases admitted in the teaching hospital at Port Blair from April 2011 to March 2016. During inpatients management, outcomes were followed up from admission till discharge or expiry. Results: Of the total 491 cases, majority (75.99%) had ST-elevated myocardial infarction (STEMI); mean age of 73 deaths was 58.01 +/- 13.60, mortality probability among females was less; in the age group 41-50 years the case fatality rate was the lowest (7.58%). Mean age of survival was 56.75 +/- 10.47; great majorities were males across all age groups in cases and deaths; highest number of cases were in the age group 51-60 (34.21%); reportedly 83.10% had some physical activities; 6.52% were vegetarian; 34.22% were smokers; 10.39% had family history of AMI, majority (59.06%) were from white collar profession (teacher, clerical, etc.); 52.95% were diabetics; and 47.45% were hypertensives. Lifestyle-related risk factors, physical activity, and vegetarian diet were not protective; family history and addiction to smoking were significantly associated with AMI deaths. Thrombolytic intervention helped the survival of 73.68%, and the odds ratio of survival showed benefit. Conclusions: Acute STEMI had male and middle-age predominance with a common risk factor of family history, smoking, diabetes, and hypertension. PMID- 29416998 TI - Association of personal hygiene with common morbidities among upper primary school children in rural Odisha. AB - Context: In India, children of upper primary school receive less attention from health-care providers. The majority of their health problems are preventable through hygienic practices. Aims: The aim of this study was to find out the association of personal hygiene with common morbidities among upper primary school children. Settings and Design: A cross-sectional study conducted in a rural upper primary school of Odisha. Subjects and Methods: A semi-structured schedule based on the Global School Health Survey Questionnaire and necessary instruments for clinical examination were used. Statistical Analysis Used: Data were entered in Microsoft Excel 2007 and analyzed by SPSS version 20 software. Results: Of 90 participants, 58 (64.4%) were girls. The mean age was 11.8 (+/ 1.01) years. The mean body mass index of females was significantly higher than males (16.95 vs. 14.72; P = 0.001). More than 90% of children maintained good personal hygiene such as clean tongue, clean hair, handwashing, and using footwear. The most common morbidities found were dental caries (38.9%), history of worms in stool and lethargy (20%). A mean score of 6.14 +/- 0.11 (out of 8) was seen for personal hygiene and not associated with any particular morbidity or gender. Brushing daily was significantly associated with reduced dental caries (chi2 = 8.7; P < 0.005) and foul-smelling breath (chi2 = 4.93; P < 0.05). Fungal infections were significantly less in children who bathed daily (chi2 = 28.7; <0.005) and wore clean clothes (chi2 = 5.06; P < 0.05). Conclusion: Dental caries, foul-smelling breath, and fungal infections were significantly associated with poor personal hygiene. School health services should also focus on upper primary school children for improvement of personal hygiene. PMID- 29416999 TI - Female married illiteracy as the most important continual determinant of total fertility rate among districts of Empowered Action Group States of India: Evidence from Annual Health Survey 2011-12. AB - Background: District level determinants of total fertility rate in Empowered Action Group states of India can help in ongoing population stabilization programs in India. Objective: Present study intends to assess the role of district level determinants in predicting total fertility rate among districts of the Empowered Action Group states of India. Material and Methods: Data from Annual Health Survey (2011-12) was analysed using STATA and R software packages. Multiple linear regression models were built and evaluated using Akaike Information Criterion. For further understanding, recursive partitioning was used to prepare a regression tree. Results: Female married illiteracy positively associated with total fertility rate and explained more than half (53%) of variance. Under multiple linear regression model, married illiteracy, infant mortality rate, Ante natal care registration, household size, median age of live birth and sex ratio explained 70% of total variance in total fertility rate. In regression tree, female married illiteracy was the root node and splits at 42% determined TFR <= 2.7. The next left side branch was again married illiteracy with splits at 23% to determine TFR <= 2.1. Conclusion: We conclude that female married illiteracy is one of the most important determinants explaining total fertility rate among the districts of an Empowered Action Group states. Focus on female literacy is required to stabilize the population growth in long run. PMID- 29417000 TI - Trends and complications of ear piercing among selected Nigerian population. AB - Background: The reported health and socioeconomic consequences of ear piercing, especially in modern day society, underscore the need to further research into this subject. In this study, we determine the trends and complications of ear piercing among selected Nigerian population. Aim and Objectives: The aim and objective of this study was to draw attention to the trends and complications of ear piercing with a view to prevent its associated complications. Methodology: It is a descriptive cross-sectional study carried out between February and May 2015 among selected Nigerian population from two of its six geo-political zones. A self-administered semi-structured questionnaire which had been pretested was used to collect data from 458 respondents who consented using multistage sampling technique. Results: Of 480 respondents enumerated, 458 completed the questionnaires and gave their biodata. The male:female ratio was 1:6.2. Their ages ranged from 18 to 75 years with a mean of 35.56 +/- 10.16. About 35.4% of the respondents were within the age group of 31-40 years. Majority of the respondents, i.e.,79.3% practiced ear piercing on their children. Most of them (86.8%) preferred single piercing. Ear piercing was performed within the 1st week of birth in 37.2% of the respondents. Large percentage (93.2%) of the respondents will not encourage ear piercing in male children. Nearly 20.5% of the respondents observed complications. Conclusion: Ear piercing remained a common practice in Nigeria, with respondents preferring it on females. Majority of the piercings are done in childhood and by untrained personnel. Keloid formation was the notable complication observed by the respondents. There is a need to increase awareness about the hazards of ear piercings and to enact laws that regulate ear piercings particularly in children which is hereby stretched. PMID- 29417001 TI - Locomotor problems among rural elderly population in a District of Aligarh, North India. AB - Introduction: Locomotor functions decline with the age along with other physiological changes. This results in deterioration of the quality of life with decreased social and economic role in the society, as well as increased dependency, for the health care and other basic services. The demographic transition resulting in increased proportion of elderly may pose a burden to the health system. Objectives: To find the prevalence of locomotor problems among the elderly population, and related sociodemographic factors. Materials and Methods: The study was a community-based cross-sectional study done at field practice area of Rural Health Training Centre, JN Medical College, AMU, Aligarh, Uttar Pradesh, India. A sample of 225 was drawn from 1018 elderly population aged 60 years and above using systematic random sampling with probability proportionate to size. Sociodemographic characteristics were obtained using pretested and predesigned questionnaire. Locomotor problems were assessed using the criteria used by National Sample Survey Organization. Data were analyzed using SPSS version 20. Chi-square test was used to test relationship of locomotor problems with sociodemographic factors. P <0.05 was considered statistically significant. Results: The prevalence of locomotor problems among the elderly population was 25.8%. Locomotor problems were significantly associated with age, gender, and working status whereas no significant association with literacy status and marital status was observed. Conclusion: The study concluded that approximately one-fourth of the elderly population suffered from locomotor problems. The sociodemographic factors related to locomotor problems needs to be addressed properly to help them lead an independent and economically productive life. PMID- 29417002 TI - Antibiotic prescribing knowledge, attitudes, and practice among physicians in teaching hospitals in South India. AB - Background: Antibiotic overuse is a major public health challenge worldwide. Data from India related to physician antibiotic prescribing patterns are limited. Aims: We assessed antibiotic prescribing knowledge, attitudes, and practices among physicians in Mangalore, South India. Materials and Methods: Using a cross sectional descriptive study design, physicians at academic tertiary hospitals completed an anonymous on-site survey. The survey items incorporated Likert scales, and data were analyzed using SPSS version 15.0. Results: Of the 350 physicians approached using a convenient sampling method, 230 (66%) consented and interviewed. The physician's knowledge of resistance patterns of common bacteria was related to receiving periodic updates on resistance patterns of bacteria (P = 0.019) and participation in courses on antibiotics (P = 0.026). Individuals with more number of years of experience (mean of 11 years) were less likely to justify antibiotic use for uncomplicated bronchitis (P = 0.015) and acute gastroenteritis (P = 0.001). Most respondents (n = 204, 89%) believed that physicians overprescribed antibiotics in routine clinical practice. Forty-five percent (n = 104) stated that their hospitals did not have an infection control policy in place. Conclusions: This study provides some understanding of physician's antibiotic prescribing patterns from teaching hospitals in India. Judicious antimicrobial use through educational and antimicrobial stewardship programs remains critical to control the spread of antibiotic resistance. PMID- 29417003 TI - Neglected health literacy undermining fluorosis control efforts: A pilot study among schoolchildren in an endemic village of rural Rajasthan, India. AB - Background: Ingestion of excess fluoride can cause fluorosis which adversely affects teeth and bones. Fluorosis is a major public health problem in the state of Rajasthan with all its 32 districts having variable fluoride contamination, and many initiatives are currently implemented in this region to mitigate the fluorosis burden. Objective: The objective of this study was to assess fluorosis, its risk factors, and the awareness among school students and teachers in endemic villages of Jodhpur district, Rajasthan. Materials and Methods: A representative sample of 300 students of age 12-15 years were enrolled for cross-sectional study in selected villages. Data were collected regarding awareness, behavioral and preventive practices about fluorosis and clinical assessment and fluoride estimation in water and urine samples was done. Results: Dental fluorosis through Dean's index was observed in 24.5% of students. The awareness and practices for fluorosis prevention and its risk factors were poor among both students and teachers. Intake of piped water supply was reported by majority of students (95.8%). High fluoride concentration was found in 35 (81.3%) out of 43 urine samples. Conclusion: Improvement in drinking water supply in the endemic village of Rajasthan has decreased the burden of fluorosis, but low level of awareness and prevailing dietary and behavioral practices still pose them at risk of high fluoride intake. This signifies the need to address nonconventional sources of fluoride intake (diet and toothpaste) and early screening of disease by involving teachers and family physicians in fluoride mitigation efforts. PMID- 29417004 TI - Quality of medication services for morbidities in a rural health center in Puducherry, India. AB - Background: Client satisfaction on quality of medication services perceived by the patients is an important measure of the health services and needs to be addressed to improve the utilization of primary health-care services. Methods: This is a descriptive study on quality of medication services perceived by the patients attending a rural health center in Puducherry. The data were collected with pretested semi-structured questionnaire. The study population consisted of 365 patients. Results: The mean age of the study population was 44.73 years and 61.6% were females. Majority of the participants (340, 93.2%) had visited the clinic at least six times in the last 6 months. The main presenting conditions included hypertension (22.7%), pregnancy (11.8%), bronchial asthma (9%), diabetes (12%), skin infections (7%), myalgia (7%), and other ailments. Average waiting time to collect drugs was 11 min (ranging from 3 to 30 min). Around half of them were advised to consume medications regularly and on time as per prescriptions (n = 199, 54.5%). Around one-fourth of the participants were advised regarding the timing of medication with respect to food (n = 96, 26.3%). Overall satisfaction was moderate in 73% participants and extremely satisfied in 25%. Around 86% of the participants told that their doubts regarding medication use were clarified by the pharmacist at the counters while 5% felt that it was not addressed. Around two-thirds were highly satisfied with the quality of drugs received (65%) and availability of drugs (64.4%). Around 52% were highly satisfied with the behavior of the pharmacy staff and 55% were moderately satisfied with timing of the pharmacy facility. Around 60% of the participants were moderately satisfied with the discipline in the queue system. Conclusions: The quality of medication services perceived by the participants is high in comparison with other studies. However, a few areas of dissatisfaction have been noted. There is a need to improve the services at the rural health centers with more satisfaction of patients availing such public health facilities. PMID- 29417005 TI - Refractive errors among patients attending the ophthalmology department of a medical college in North-East India. AB - Purpose: To determine the magnitude and pattern of refractive errors among patients attending the ophthalmology department of a new medical college in North East India. Materials and Methods: A prospective study of the new patients (age >=5 years), who were phakic and whose unaided visual acuities were worse than 20/20 but improved with pinhole, was done. Complete ophthalmic examination and refraction with appropriate cycloplegia for age were done for the 4582 eligible patients. Spherical equivalents (SE) of refractive errors of the right eyes were used for analysis. Results: Of the 4582 eligible patients, 2546 patients had refractive errors (55.56%). The proportion of emmetropia (SE - 0.50-+0.50 diopter sphere [DS]), myopia (SE <-0.50 DS), high myopia (SE >-5.0 DS), and hypermetropia (>+0.50 DS for adults and >+2.0 DS for children) were 53.1%, 27.4%, 2.6%, and 16.9%, respectively. The proportion of hyperopia increased till 59 years and then decreased with age (P = 0.000). The proportion of myopia and high myopia decreased significantly with age after 39 years (P = 0.000 and P = 0.004, respectively). Of the 1510 patients with astigmatism, 17% had with-the-rule (WTR), 23.4% had against-the-rule (ATR), and 19% had oblique astigmatisms. The proportion of WTR and ATR astigmatisms significantly decreased (P = 0.000) and increased (P = 0.000) with age, respectively. Conclusions: This study has provided the magnitude and pattern of refractive errors in the study population. It will serve as the initial step for conducting community-based studies on the prevalence of refractive errors in this part of the country since such data are lacking from this region. Moreover, this study will help the primary care physicians to have an overview of the magnitude and pattern of refractive errors presenting to a health-care center as refractive error is an established and significant public health problem worldwide. PMID- 29417006 TI - Depression and its associated factors among people living with HIV/AIDS: Can it affect their quality of life? AB - Introduction: Depression, being the most common neuropsychiatric complication of HIV, is also associated with increased health-care utilization, decreased quality of life (QOL), and poor adherence to antiretroviral therapy (ART). Depression is a multidimensional disorder affected by a variety of biological, psychological, and social determinants and this relation becomes more complicated in HIV patients. The current study therefore aimed to investigate the sociodemographic and clinical determinants of depression and assess difference in the QOL of HIV patients not having depression and those suffering from depression. Materials and Methods: A cross-sectional study was conducted at an ART center in a tertiary care hospital in HIV/AIDS patients of 18 years of age. Sociodemographic and clinical characteristics were studied, depression anxiety and stress scale-21 was used to assess depression, and QOL assessment was done using WHOQOL-HIV BREF questionnaire. Results and Conclusions: Out of 754 study subjects, 377, i.e., 50% suffered from depression and nearly 75.9% of them were in the age group of 25-44 years. The prevalence of depression was higher in females, illiterates, and unemployed HIV patients as compared to males, literates, and employed subjects, respectively. HIV patients who were depressed had significantly lower QOL than the subjects not suffering from depression, more so in the environment and social relationships domains. PMID- 29417007 TI - Practices and attitudinal behavior about drinking water in an urban slum of district Rohtak, Haryana: A community-based study. AB - Background: Globally, approximately, one billion people lack access to safe drinking water and 1.59 million deaths per year are because of contaminated water, primarily in children age <5 years. WHO reported that more than 90% of diarrhea cases can be prevented by enhancing the availability of clean water and improving hygiene measures. Methodology: The study was conducted in an urban slum of Rohtak district. Investigator interviewed the mothers at their home having children age less than 5 years using study tools in their vernacular language. Study Design: The study was a community based epidemiological study with cross sectional design. Study Participants: 400 mothers having children less than 5 years. Results: Most of subjects (59%) were in the age group of 15-25 years followed by in 25-35 years. One third of subjects belonged to upper caste and 29% of subjects from backward class. The study found that 80% of mother store water in earthen pitcher followed by plastic jug (14%). 78% of mothers said that their source of drinking water was tap while 12% had Hand pump. 83.5% of subjects said that they drink water as such ie without filtering, boiling or chlorination. Conclusion and Recommendations: The study concluded that the prevalence of diarrhea is more among children < 5 years this is because of poor knowledge, poor attitude and inadequate storage water practices of water. The study recommends creating awareness how to diminish contamination of water at household level, creating community groups for women to learn about treatment of water at household level. PMID- 29417008 TI - Drug abuse: Uncovering the burden in rural Punjab. AB - Introduction: Drug abuse is a global phenomenon, affecting almost every country, but its extent and characteristics differ from region to region. India too is caught in this vicious circle of drug abuse, and the numbers of drug addicts are increasing day by day. The bane of drug abuse in Punjab has acquired the proportions of a pestilence that has shaken the entire society in the state. It is observed that in Punjab "drug abuse" is a raging epidemic, especially among the young. Methodology: The present cross-sectional study was conducted on 400 adolescents and young adults (11-35 years) from 15 villages of Jalandhar District. Systematic sampling (probability proportionate to size) was used for the selection of study subjects. A preformed, semi-structured questionnaire was used to collect information on type and frequency of drugs abused and other sociodemographic variables. The statistical evaluation of the data was performed using SPSS software, version 21.0. Results: The prevalence of substance abuse among study group was 65.5% and most common substance abused was alcohol (41.8%), followed by tobacco (21.3%). A high prevalence of heroin abusers was noted among study subjects (20.8%). The prevalence of nonalcohol and nontobacco substance abuse was 34.8%. A significant association of drug abuse was observed with male gender, illiteracy, and age above 30 years. Conclusions: The problem of drug abuse in youth of Punjab is a matter of serious concern as every third person is hooked to drugs other than alcohol and tobacco. The other striking observations were the high prevalence of heroin and intravenous drug abuse. PMID- 29417009 TI - Hepatobiliary dysfunction in Type-2 diabetes mellitus. AB - Objective: Nonalcoholic fatty liver disease (NAFLD) and gallstones are frequently present in diabetics, but its exact prevalence is not well studied in India. We have done a prevalence study of hepatobiliary involvement in Type-2 diabetes mellitus (T2DM) and also studied the other risk factors of NAFLD. Materials and Methods: Two hundred diabetics and 200 controls underwent anthropometric measurements, abdominal ultrasonography, (USG) and biochemical tests at a tertiary care hospital. Univariate and multivariate logistic regression analyses were done. Results: One hundred and thirty (65%) diabetics and 47 (23.50%) controls were having USG evidence of fatty liver (odds ratio [OR] = 6.046, 95% confidence interval [CI]: 3.904-9.363 [P < 0.0001]). Raised liver enzymes were present in 42 (21%) diabetics and 16 (8%) controls [OR = 3.057, 95% CI: 1.654 5.648 [P < 0.004]). Gallstones were present in 32 (16%) diabetics and 10 (5%) controls (OR = 2.825; 95% CI: 1.850-4.315 P < 0.0001). In addition, waist circumference (WC) and body mass index (BMI) were significantly more in diabetics, but lipid profile was not significantly deranged as compared to controls. Then, all patients with fatty liver were compared with patients with normal liver, and we found that fatty liver group was having raised BMI, WC, liver enzymes, and more dyslipidemia. Multivariate analysis was done which shows the presence of T2DM, elevated liver enzymes, obesity, and elevated WC as independent risk factors of fatty liver. Conclusion: The prevalence of NAFLD and gallstones was higher in diabetics as compared to healthy population. In addition, the presence of T2DM, elevated liver enzymes, obesity, and elevated WC are independent predictors of NAFLD. PMID- 29417010 TI - Reproductive behavior of newly married women in rural Punjab, India: A longitudinal study. AB - Introduction: In India, little is known about the reproductive behavior during earlier years of married life of women, when they are more vulnerable to reproductive ill health and early child bearing with very few interventions available. Objective: The objective of this study is to follow a cohort of newly married women immediately after marriage until their first pregnancy outcome to gain an insight into their reproductive behavior so that important opportunities could be identified for intervention. Subjects and Methods: A community-based longitudinal study was carried out in 15 villages of Ludhiana District under the Rural Health Training Centre of Department of Community Medicine, Dayanand Medical College and Hospital, Ludhiana, Punjab. All marriages of the male residents that took place in these villages from January 1, 2013, to December 31, 2013 were enrolled. Thus, a cohort of 195 newly married women was identified over a period of 1 year and followed every month till first pregnancy outcome. The analysis was performed using SPSS version 20 statistical software. Results: Mean age at marriage for newly married women was 22.9 +/- 3.0 years. Majority of them conceived within 1st year of marriage (79.5%) while 10.8% of women did not conceive till the end of follow-up period. Mean age at first pregnancy was 23.4 +/- 3.1 years with mean interval between marriage and first pregnancy of 5.4 +/- 6.1 months. Nearly, three-fourth of pregnancies resulted in live births while adverse pregnancy outcome including still births and abortions was seen in 15.9% of the study cohort. Conclusions: Overall findings indicate optimistic picture for married young women, but critical opportunities should be utilized to promote health of these women in a journey toward safe motherhood. PMID- 29417011 TI - Relationship of antioxidant system and reactive oxygen species with clinical semen parameters in infertile men. AB - Aims and Objectives: To determine the correlation of antioxidant system and reactive oxygen species with clinical parameters in infertile semen samples. Materials and Methods: Semen sample of fifty infertile men were divided into three groups: (1) Group I - Normospermic (count >15 million/ml), Group II - Asthenospermic (motility <32%), and Group III - Oligospermic (counts <15 million/ml) subjects based on the sperm count and sperm motility. The samples were also divided into two groups: (1) Group IV with semen pH >7.2 (25 samples) and Group V - Semen pH <7.2 (25 samples). The grouping was based on the WHO guideline for semen analysis (12). The semen antioxidant parameters like glucose 6-phosphate dehydrogenase (G-6-PDH) (spectrophotometric method Kornberg and Horecker, 1955). Catalase (Maehly and Chance 1954), glutathione peroxidase (GPX) (Rotruck method), glutathione (GSH) (dithiobisnitro-benzoate method), superoxide dismutase (SOD) (direct method), and malondialdehyde (MDA) (thiobarbituric acid reactive substances assay kit method) were investigated. Mann-Whitney U-test was applied to compare the findings. Results: Of fifty semen samples there were 12 normospermic (sperm concentration >=15 * 106/ml of ejaculates), 24 asthenospermic (sperm motility <=32%), and 14 oligospermic (sperm concentration <=15 * 106/ml of ejaculates) subjects. Results suggested that all asthenospermic males were found to have reduced motility and viability when compared with normospermic and oligospermic subjects. Activity of antioxidant parameters such as G-6-PDH, GPX, GSH, and SOD was decreased in case of asthenospermic subjects. The concentration of MDA was increased significantly (P < 0.001) in semen of asthenospermic subjects compared to normospermic and oligospermic subjects. Conclusion: The current study concludes that there is a significant relationship of ROS and semen parameters. Further studies will be needed in such subjects regarding role of effectiveness of dietary antioxidants in improving semen qualities. PMID- 29417012 TI - The reliability and validity of using the urine dipstick test by patient self assessment for urinary tract infection screening in spinal cord injury patients. AB - Aims: The aim of this is to evaluate the reliability of the urine dipstick test by patients' self-assessment for urinary tract infection (UTI) screening and to determine the validity of urine dipstick test. Settings: Rehabilitation Department, Srinagarind Hospital, Thailand. Study Design: A diagnostic study. Subjects and Methods: This study compared the urine dipstick test (index test) with the National Institute on Disability and Rehabilitation Research (NIDRR) criteria (gold standard test) in spinal cord injury (SCI) patients. The urine dipstick test informed positive and negative results. Besides the NIDRR criteria classified as UTI and no UTI. The interrater reliability was measured in the sense of Kappa whereas the validity of urine dipstick test was reported in terms of sensitivity, specificity, positive likelihood ratio (LR) (+LR), negative LR ( LR), positive predictive value (PPV), and negative predictive value (NPV). Results: Out of the 56 participants, the kappa of urine dipstick test for leukocyte esterase, nitrite, and combined leukocyte esterase and nitrite were 0.09, 0.21, and 0.52, respectively. The nitrite urine dipstick test showed the highest sensitivity (90%). The combined leukocyte esterase and nitrite urine dipstick test gave the highest specificity (87%), PPV (60%), NPV (93%), and +LR (5.63). Conclusions: The interrater reliability of combined leukocyte esterase and nitrite urine dipstick test was moderate agreement. The combined leukocyte esterase and nitrite urine dipstick test showed high level of both sensitivity and specificity. The combined leukocyte esterase and nitrite urine dipstick test should be promoted for patients' self-assessment for UTI screening in SCI patients. PMID- 29417013 TI - Determinants of menstrual hygiene among school going adolescent girls in a rural area of West Bengal. AB - Background: Menstrual hygiene is a neglected issue in rural India. Lack of menstrual hygiene in adolescent girls can make them susceptible to various morbidities, for example, reproductive tract infection and urinary tract infection and their long-term consequences, for example, cervical cancer, infertility, and ectopic pregnancy. This study aims to find out the determinants of menstrual hygiene among the school going adolescent girls in a rural area of West Bengal. Objectives: To elicit the menstrual hygiene practices among the study population and to find out the association of poor menstrual hygiene practices with sociodemographic factors, such as age, occupation and education of the parents, housing, and presence of sanitary toilet. Materials and Methods: A descriptive, cross-sectional study was conducted among 307 school going adolescent girls of 12-17 years age group in a rural area of West Bengal. Results: Majority of the students in both schools (62.9%) were Hindu, general caste (54.1%) and belonged to nuclear family (69.7%). Most of the parents in both schools had completed their education up to primary level. Bivariate analyses were done, and the significant factors predicting good menstrual hygiene were entered into the multivariable logistic regression model. It revealed that good menstrual hygiene was more among those whose mothers were educated (adjusted odds ratios [AOR] 2.3 [1.06-5.01]), and who were homemakers (AOR 2.3 [1.06-5.01]). Conclusions: Menstrual hygiene among the study population was found to be poor. The improving education level of the mothers can go a long way in improving menstrual hygiene practice. PMID- 29417014 TI - Knowledge of hepatitis B among healthy population: A community-based survey from two districts of Gujarat, India. AB - Background: Hepatitis B is the world's most common blood-borne viral infection, accounting for 2 billion infections, 350 million carriers, and 6 lakh deaths annually. Country like India still harbors approximately 30-60 million hepatitis B virus (HBV) carriers. A modest estimate would put the number of deaths occurring due to HBV infection per year in India to around 100,000. To prevent transmission and progression of the disease, proper community awareness including prevention is necessary. Therefore, this study aims to study the knowledge awareness among the healthy population about hepatitis B including knowledge regarding vaccine. Methodology: A community-based cross-sectional study was undertaken in two districts of Gujarat. Cluster sampling (30 clusters) was used, and pretested questionnaire was administered to 600 (with a prevalence rate of 5% in Gujarat having design effect of 2 within 95% confidence interval and 10% nonrespondent) healthy individuals, who heard about hepatitis B. Data handled and analyzed in EpiData Analysis V2.2.2.183. Results: Majority of the participants knew about symptoms whereas only 41% knew about prevention methods and few 34% knew about the mode of transmission. Although 40% sample has knowledge about the availability of vaccination, only 20% were self-vaccinated. The common reason for nonvaccination was lack of awareness. Conclusions: Only one-third of the populations in study districts are aware about hepatitis B and its vaccine. Less than one-fifth of the populations are vaccinated for hepatitis B. Important knowledge deficits about the routes of hepatitis B transmission/prevention were identified. Continued efforts should be made to develop and implement hepatitis B educational campaigns/health promotion for these communities. PMID- 29417015 TI - Prevalence of osteoporosis and osteopenia in stable patients of chronic obstructive pulmonary disease in Sub-Himalayan region of Himachal Pradesh, India. AB - Background: Chronic obstructive pulmonary disease (COPD) is a lifestyle-related chronic inflammatory pulmonary disease and a major cause of morbidity and mortality globally. Osteoporosis and osteopenia are common observations in COPD and degree of the loss of bone mineral density (BMD) has been found to be proportionate to the severity of the disease. Objectives: Our objective was to study the prevalence of osteoporosis and osteopenia in stable COPD patients in Indian Sub-Himalayan population. Materials and Methods: This study was performed on 84 patients of COPD attending as outpatient in the Pulmonary Medicine Department after application of inclusion and exclusion criteria. A control group of 60 healthy controls was selected for comparison with COPD group. Spirometry was done on patients to stage the severity of COPD according to global initiative for chronic obstructive lung disease criteria. Dual-energy X-ray absorptiometry scan of the lumbar spine was done using bone densitometer to determine the severity of reduced BMD. The patients were categorized according to the World Health Organization criterion for definition of reduced BMD. Results: In the present study, a total of 45.2% patients had osteoporosis, 41.6% patients had osteopenia while the rest 13% patients had normal bone density in the COPD group. The prevalence of low bone density was about 4 times higher in COPD group as compared to control group. There were 15.48 times higher chances of low BMD in COPD patients as compared to healthy controls. Conclusions: Reduced BMD is a common comorbid entity in COPD patients which leads to increase in bone fragility and susceptibility to fracture. It is recommended that all the patients with COPD should be screened for osteoporosis to initiate the treatment for the disorder before they develop fractures. PMID- 29417016 TI - Risk factor of type 2 diabetes mellitus among adolescents from rural area of India. AB - Context: Health system is likely to encounter more adolescents with Type 2 diabetes mellitus (T2DM) as a consequence of obesity and sedentary lifestyle. Intervention at various stages of the life cycle is needed as cumulative effect of risk factors accumulated from fetal life to adult increases risk of noncommunicable disease. Aims: The aim of this study was to find out awareness regarding T2DM and distribution of risk factor for T2DM in adolescents from the rural areas of Wardha district, India. Methodology: A cross-sectional study conducted in the rural area of India involves 412 adolescent boys and girls selected by systematic random sampling technique. Data collected by a face-to face interview and waist-hip ratio (WHR), body mass index, random capillary blood glucose (RCBG) were estimated. Results: 65.1% were aware of T2DM. Girls, older adolescents, higher education were associated with awareness (P < 0.001). Totally, 204 (49.51%) had some risk factors for T2DM, of these 191 (46.6%) had sedentary lifestyle, 153 (31.7%) adolescents had nutritional risk factors, 69 (43.4%) boys had WHR >0.90 and 113 (71.1%) girls had WHR >0.85, 103 (25%) adolescents had RCBG >=110 mg/dl, and 77 (18.7%) participants reported family history of DM. Conclusions: Considering the risk factors of T2DM among adolescents from the rural area, there is a need for prevention programs for creating awareness related to T2DM, early identification of risk factor for T2DM, and targeted interventions. The study may serve as a formative research for developing and testing interventions aimed at primary prevention of T2DM among adolescents from rural India. PMID- 29417017 TI - How much do persons with diabetes in a rural area of South India know about diabetes management? A step toward person-centered care. AB - Introduction: The burden of diabetes mellitus is increasing worldwide, more so in developing countries. Optimal diabetes care depends on adherence to management protocol, which can be brought about by shared decision-making. Patient's knowledge on life-threatening complications and preventive strategies for the same is a prerequisite for shared decision-making. Hence, this study was carried out among diabetes patients to assess the level of knowledge on different aspects of diabetes management. Methodology: A facility-based cross-sectional study was conducted among patients registered and seeking care from a Rural Primary Health Centre in Puducherry, South India. All the individuals with diabetes were included in the study. Trained MBBS interns interviewed the patients after obtaining informed consent. A semi-structured interview schedule was used to capture information on sociodemographic profile, disease characteristics, knowledge on different aspects of diabetes management, and prevention of diabetic complications. Data were entered and analyzed using EpiData software. Knowledge on each item was expressed as percentages. Results: Of the total 172 participants, 58% were females, 63% were aged between 31 and 60 years. About half of the participants had diabetes for more than 5 years. Of the total, about 83% knew that there is a need for lifelong treatment. About 51%, 44%, 21%, and 9% were aware that diabetes can cause complications to eye, renal, foot, and heart, respectively. Of the total, about 74%, 78%, 17%, 15%, 35%, and 56% knew the correct frequency for monitoring of blood sugars, blood pressure, renal function, lipid profile, fundus, and foot, respectively. Conclusion: This study shows that knowledge on few components of diabetes management is still limited, and there is a need to impart knowledge through health education to patients. Adequate knowledge on diabetes management principles is important for implementing patient centered care in primary care setting. PMID- 29417018 TI - Lacunae in noncommunicable disease control program: Need to focus on adherence issues! AB - Introduction: Chronic non communicable diseases in India have increased in magnitude with earlier onset and more likelihood of complications. Much emphasis is given to early diagnosis and timely treatment. Additionally, tertiary prevention through medication adherence is needed to limit disability and prevent early onset of complications. This study was aimed to assess the magnitude of medication and lifestyle adherence among elderly patients suffering from diabetes and hypertension in rural areas of Punjab. Methodology: This was a clinic based study in district Fatehgarh Sahib, Punjab. Patients were subjected to regular blood pressure and blood glucose monitoring. Thereafter they were offered free medications through weekly clinic held at Community Health Center, Bassi Pathana. Along with treatment, Public Health Nurse conducted counselling on diet and lifestyle. Frequency and process of taking medications was explained in local language and records duly maintained during visits. Results: Nearly 70% of study subjects were more than 50 years old. Males constituted 26% of the sample and 60% of subjects were illiterate. Large majority of study subjects did not consumed tobacco (98.08%) or alcohol (89.42%) in past thirty days. In-sufficient physical activity and poor compliance to diet was reported by 10.5% (Males: 7.4%, Females: 11.7%) and 23.5% (Males: 31.5%, Females: 20.8%) subjects. Nearly 46.15% of study subjects reported missing prescribed medications. Nearly 61.54% of study subjects were very sure that they will be able to take medicines as directed by physician. Conclusion: National Program for Control of Diabetes, Cardio-vascular Disease and Stroke relies on early diagnosis and treatment non- communicable diseases. However, with reported levels of adherence to medication and lifestyle interventions, there is an urgent need of exploring innovative ways to ensure compliance and improve treatment outcomes. PMID- 29417019 TI - Barriers and enablers to adoption of intrauterine device as a contraceptive method: A multi-stakeholder perspective. AB - Background: Promoting family planning practices aid considerably in attaining Millennium Development Goals by various mechanisms. Despite concerted health system efforts, adoption of especially reversible contraceptive methods such as intrauterine devices (IUDs) has remained negatively skewed in India, which is the pioneer country to implement Family Planning programme way back in 1952. Although few studies in India have looked into the reasons for its nonacceptance, literature from Odisha was scant and hence the study was undertaken. Methodology: A cross-sectional study using qualitative methods was done in the Mahanga Tehsil of Cuttack district. In-depth interviews were conducted with women of reproductive age (WRA) and focused group discussions (FGDs) among health workers and health professionals were held separately. Data analysis was done using thematic framework approach supported by Atlas Ti software. Results: There were 31 in-depth interviews with WRA, two FGDs with health workers, and one FGD with health professionals. Availability of IUD services was low and wherever available, being located far away affected its physical accessibility. Most women were reluctant to ask health workers about services owing to their shyness while many women felt using IUDs breached their autonomy and privacy. The existence of fear and misconceptions regarding its use rooting from lack of knowledge and poor service quality also impeded its adoption by women. Conclusion: There is a pressing need to enhance the demand of IUDs by dispelling the myths among women through effective information, education, and communication and also to improve the availability of IUDs. PMID- 29417021 TI - Prevalence and determinants of delay in diagnosis of pulmonary tuberculosis in Darjeeling district of West Bengal. AB - Background: Delayed diagnosis of tuberculosis (TB) is a significant problem both in individual as well as community level. Different studies around globe revealed that these diagnostic delays are attributed to both patient delay and health system-related delay. Aims: This study aims to assess the magnitude of delay in diagnosis and the association with sociodemographic profile among new sputum positive pulmonary TB patients in Darjeeling district. Materials and Methods: A cross-sectional study was conducted among 374 TB patients from October 2011 to March 2012 using a predesigned pretested schedule by face-to-face interview. Statistical Analysis: Logistic regression analysis, odds ratios (OR), adjusted ORs. Results: Patient delay, health system delay and total diagnostic delay were 27 days, 20.1 days, and 20.6 days; mean delays were 23.64, 5.71, and 29.46 days, and median delays were 25, 5, and 32 days, respectively. Risk factors associated with patient delay were female gender, rural residence, illiteracy, smoking, alcohol consumption, taking two, or more alternate treatments; for health system delay were female sex, rural residence, time to reach health facility, time spent per visit; and for total diagnostic delay were female sex, alcoholism, and seeking more than two alternate treatment. Conclusions: The risk factors for delay identified may be the subject of future interventions. PMID- 29417020 TI - Prevalence of left ventricular dysfunction in rheumatoid arthritis. AB - Background: Rheumatoid arthritis (RA) is a polyarticular disorder with many extra articular features. Cardiovascular disorders, including heart failure (HF), are the leading causes of mortality in RA patients. We studied the prevalence of left ventricular dysfunction (LVD) in patients with RA. Materials and Methods: In this cross-sectional study, we evaluated 100 consecutive patients with RA (aged >18 years and duration >1 year) for the presence of LVD. We excluded patients with known cardiac and systemic disorders that may contribute to LVD. LVD is defined by the presence of either left ventricular systolic dysfunction (LVSD) or left ventricular diastolic dysfunction (LVDD), evaluated by the echocardiography. Descriptive statistics and relevant tests were used to analyze the results. Results: The study participants (n = 100; 80F and 20M) had a mean age of 45 +/- 11.8 years, duration of disease 7.4 +/- 5.4 years, and disease activity score of 3.5 +/- 1.1. A total of 46 patients had symptoms of HF, but only 14% of them had signs of HF. LVD was seen in 59 (LVSD-4, LVDD-50, and both together in 5) patients, and none of the participants had severe grades of LVSD and LVDD. LVD showed no relation to the age of the patients (P = 0.186) and it was more with increasing duration of RA (P < 0.001) and higher disease activity (P = 0.042). Conclusion: LVD is more common in RA patients, which increases the associated morbidity and mortality. Higher threshold is required by the family practitioners to perform a screening echocardiography in long-standing RA patients. PMID- 29417023 TI - Diagnostic delay and associated factors among patients with pulmonary tuberculosis in Kerala. AB - Introduction: Delay in the diagnosis of tuberculosis (TB) can lead to an increased infectivity period, delayed treatment, and increased severity of the disease. The objective of this study was to estimate the diagnostic delay and factors associated with the delay in diagnosis among the newly diagnosed smear positive pulmonary TB patients in Kerala, India. Materials and Methods: A cross sectional study was conducted among TB patients who were in the intensive phase of directly observed treatment short-course treatment in four randomly selected TB units in a district in Kerala during the years 2012-2013. Diagnostic delay was defined as the delay between the onset of symptoms and diagnosis. Data collection using a modified World Health Organization questionnaire was done by interviewing 302 participants. Results: Mean age of the participants was 48.6 +/- 14.5 years. Males constituted 76.5% of the study population. The mean diagnostic delay was 43.5 +/- 29.1 days (median: 37 days). The median patient and health system delays were 16 days and 15 days, respectively. Patient delay (55.6%) contributed more than health system delay (44.4%). Poor knowledge about TB, first consulting a private physician, and increased number of consultations were found to be significantly associated with diagnostic delay. Conclusion: The diagnostic delay in tuberculosis reported in this study was lower than other studies in India but it needs further reduction. Both patients and health providers play a role in a delay in diagnosis, and poor knowledge about the disease among the patients was one of the main risk factors. Interventions to improve knowledge and awareness of the disease and to increase the suspicion of chest symptomatic by health-care providers in the private sector are vital to reduce diagnostic delay. PMID- 29417022 TI - A study of knowledge, attitude and practice regarding administration of pediatric dosage forms and allied health literacy of caregivers for children. AB - Context: Caregivers of sick children have to be careful with medicine dosing and giving medicines to a reluctant child can be challenging. Aim: To assess the knowledge, attitude, and practices of caregivers regarding pediatric medicine administration and health literacy allied to this task. Settings and Design: This cross-sectional study was carried out on outpatient and inpatient basis in the pediatrics department of a teaching hospital over 6 months. Subjects and Methods: Data regarding sociodemographic profile of patient and caregiver, idea regarding pediatric dosage forms, dosing of medicines, and medication errors during administration were recorded from 377 caregivers. Reconstitution of dry powder and measurement of 5 mL liquid medicine using measuring cup of the medicine phial was demonstrated by the caregivers. Statistical Analysis: Association assessed by point biserial correlation and Spearman's rank correlation. Results: Majority of the primary caregivers surveyed were young, educated, homemaker mothers. Liquid medicines were used maximally (88.9%). Majority (87.3%) of the caregivers used standardized dosing instruments to measure liquids and reconstitution (85.9%), and teaspoon measurement task (91%) was performed satisfactorily by most. Some potentially wrong practices (e.g., adding medicine to milk, redilution of reconstituted medicine, and storing beyond the recommended period) were recorded. Medication errors were reported by 44.5% caregivers, significantly more in the outpatient setting. Although the statistical correlation was weak, the chance of medication error was less, and the precision of measurement was better with increasing education of the caregiver. Conclusions: Physicians need to be aware of the limitations of knowledge and the possibility of wrong administration practices among caregivers of children. Remedial measures in this regard can reduce the risk of medication errors. PMID- 29417024 TI - Fulminant hepatitis E in an infant. AB - Hepatitis E virus (HEV) is an enterically transmitted infection that is typically self-limited. It spreads by fecally contaminated water within endemic areas. Hepatitis E infection occurs in both sporadic and epidemic forms in developing countries. HEV infection is usually subclinical in children but in a pregnant woman, it manifests commonly as fulminant hepatic failure. A few cases of acute liver failure caused primarily by HEV infection in children have been reported. We present a case of fulminant hepatitis E in a 1-year-old child. She showed positive signs of hepatic encephalopathy, jaundice, and coagulopathy and was given symptomatic treatment for the same. She recovered due to the self-limiting nature of HEV infection and prompt symptomatic relief. PMID- 29417025 TI - Fracture neck of femur in Factor XIII deficiency: Was better outcome possible? AB - The fracture in a Factor XIII deficiency patient is being reported for the first time in the literature. We report a displaced fracture neck of femur in a 17-year old boy with Factor XIII deficiency. Open reduction and internal fixation was done 8 days after the following the initial injury. Two units each of fresh frozen plasma and cryoprecipitate were given perioperatively to prevent excessive bleeding. No perioperative bleeding complications were encountered. At 18-months follow-up, the fracture had united with evidence of avascular necrosis. The fracture neck of femur in a child or young adult needs to be reduced and stabilized at the earliest to prevent devastating complications. Its occurrence in a patient with Factor XIII deficiency is to be managed like in a normal patient, but with extra perioperative care. Undue delay in fixation as happened in this case should be avoided for a better outcome. PMID- 29417026 TI - Duchenne muscular dystrophy: Case report and review. AB - Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations. PMID- 29417027 TI - Back pain: An unusual manifestation of acute lymphoblastic leukemia - A case report and review of literature. AB - Acute lymphoblastic leukemia (ALL) presented with bone pain and leukopenia is a well-recognized complex. Bone and joint pain are seen as presenting symptoms in 25% of patients with acute leukemia, but generalized osteopenia and vertebral complications are less common. Back pain due to vertebral changes as an early feature has been infrequently reported. We report a case of a 9-year-old female child who presented with back pain for 3 weeks. Blood counts and peripheral smear were normal. X-ray of the spine showed wedge-shaped deformity in L3-L5 vertebrae. Magnetic resonance imaging of the spine confirmed the lytic lesions of L3-L5 vertebrae. Infective etiological evaluation was normal. Bone marrow aspiration revealed pre-B-cell lymphoblastic leukemia. She was started on ALL protocol and pain subsided within a week, and remodeling of the bony lesions could be seen 2 months later. This case highlights that spinal involvement may be a presenting feature despite normal peripheral blood counts. PMID- 29417028 TI - Annular cutaneous sarcoidosis with systemic involvement. AB - Sarcoidosis is a granulomatous disease involving multiple systems. Cutaneous involvement is present in 25% of patients. A 42-year-old woman presented with itchy skin lesions on her face for 5 years duration. She was found to have annular and discoid plaques with prominent overlying telangiectasia. A biopsy from the plaque was suggestive of sarcoidosis. On further evaluation, she was found to have both pulmonary and ocular involvements. Annular sarcoidosis is a rare variant of cutaneous sarcoidosis. We report this case to highlight this rare variant of sarcoidosis and discuss the various cutaneous manifestations of sarcoidosis. PMID- 29417029 TI - A rare case report of Strychnos nux-vomica poisoning with bradycardia. AB - Strychnine poisoning is a rare method of deliberate self-harm in adults. Poisoning with strychnine leaves is a rare form of strychnine poisoning, as the usual plant parts used are nuts, bark, and seeds. Although the common cardiac manifestations of strychnine positioning include tachycardia and hypertension, we report a patient with mild strychnine poisoning with bradycardia. PMID- 29417030 TI - Hansen's disease: An unusual presentation. AB - Hansen's disease can present with varied and subtle symptoms which can be missed. A middle-aged gentleman presented with swelling of face and hands. Detailed examination and investigations confirmed borderline tuberculoid leprosy with lepra reaction. A high index of suspicion with vigilance can help to make an early diagnosis in this potentially treatable condition. PMID- 29417031 TI - Atypical preeclampsia - Gestational proteinuria. AB - There are many rural areas where obstetric care is predominately performed by family medicine physicians. As such, it is important for family medicine physicians to stay up to date with the latest obstetric guidelines. Preeclampsia is a well-established disorder and the guidelines for screening and treatment are well known. However, atypical presentations of preeclampsia have been less studied. Notably, what constitutes atypical preeclampsia and when to be concerned for increased morbidity and mortality in the mother and neonate. This report describes a unique case in which a woman with proteinuria of pregnancy developed atypical preeclampsia with severe features. This report discusses the care that was given by a practicing family medicine physician and the reasoning behind it. PMID- 29417032 TI - Paraquat poisoning: Case report of a survivor. AB - N, N'-dimethyl-4, 4'-bipyridinium dichloride (paraquat) is a widely used synthetic, nonselective contact herbicide. Ingestion of toxic doses of paraquat can be fatal with life-threatening effects on the lungs, gastrointestinal (GI) tract, kidney, liver, heart, and other organs. Till date, there are no specific antidotes and none of the current treatments have proven efficacious. The prognosis is uniformly poor worldwide, including those who treat aggressively with multimodal therapies. Long-term survivors are few, and have GI and pulmonary complications. Hence, prevention needs to be the utmost priority, and on exposure, aggressive decontamination should be initiated. Although it is a very common herbicide, there are very few cases reported from India and awareness among people needs to be widened. PMID- 29417033 TI - Abdominal cocoon - A rare etiology of intestinal obstruction. AB - Abdominal cocoon is one of the rare causes of intestinal obstruction. It is referred as complete or partial small bowel encapsulation caused by the thick fibrocollagenous membrane. It is most common in young adolescent girls. We present a 40-year-old male patient with idiopathic abdominal cocoon. Few cases of male patients suffering from idiopathic abdominal cocoon have been reported in literature. PMID- 29417034 TI - Giant bilateral keloids of the ear lobule: Case report and brief review of literature. AB - Keloids are abnormal tissue response to cutaneous injury. They are benign fibrocollagenous growth that rise above the skin surface and extend beyond the borders of the original wound. They may also rarely regress spontaneously and show a high level of recurrence after treatment. They usually arise after cutaneous insult, but idiopathic spontaneous etiology is also reported. Their high recurrence creates nuisance not only for the patient but also for the doctors. Bilateral keloids of ear lobules are rare. We report one such case of giant keloids of bilateral ear lobules in a 42-year-old male patient. Keloids have known to be notorious for their poor response to treatment owing to complex and ill-deciphered pathophysiology. Recent studies indicate that transforming growth factor beta and platelet-derived growth factor play an integral role in the formation of keloids. In this article, we have reviewed the available literature to discuss the pathophysiology and treatment modalities that may be used to prevent the recurrence of keloids. PMID- 29417035 TI - A misplaced intramuscular injection and limb-threatening ischemia. AB - Femoral artery thrombosis is a rare complication of intramuscular (IM) injection in children. A 12-month-old boy presented with right lower limb ischemia and digital gangrene 3 days after an injection of ceftriaxone administered to his medial aspect of the right thigh. Successful thrombolysis and partial limb salvage was possible with enoxaparin despite a late presentation. Unnecessary and unsafe IM injection in community practice might lead to such devastating outcome which should be avoided. PMID- 29417036 TI - Rhabdomyosarcoma mimicking as pleural effusion. AB - Rhabdomyosarcoma (RMS), a malignant neoplasm of skeletal muscle origin, is the most common soft tissue sarcoma caused by infectious disease etiology, especially in nondeveloped countries. Despite being a relatively rare cancer, it accounts for approximately 40% of all recorded soft tissue sarcomas. Alveolar RMSs are seen to occur in children, while around 80% cases occur in the first three decades of life. We present here, a case of a 12-year-old child having alveolar RMS, presenting clinically and radiologically with pleural effusion. PMID- 29417037 TI - Neurological effects of an unusual insecticide poison: Amitraz. AB - Amitraz is a triazapentadiene compound belonging to amidine family. As an insecticide and acaricide, it has been used to control red spider mites, scale insects, aphids, leaf worms, whitefly, bollworms, and pear psylla on Oregon pear crops. Poisoning is secondary to accidental or suicidal inhalation and ingestion of the compound. The toxicity profile is mostly in the form of alteration of the nervous system resulting in various clinical manifestations. We describe a case report of amitraz poisoning presenting with coma. PMID- 29417038 TI - Miliary tuberculosis with pulmonary and extrapulmonary component complicated with acute respiratory distress syndrome. AB - Miliary tuberculosis results from the lymphohematogenous spread of the tubercle bacilli to the vascular beds in the lungs and other organs. Diagnosis is made by clinical judgment and chest X-ray showing miliary mottling of the lung fields. Another imaging study like computed tomography imaging of the lungs and abdomen can also be supportive in diagnosing miliary tuberculosis. We present a case of miliary tuberculosis in an immunocompetent young male with atypical manifestation of a left-sided pleural effusion and a life-threatening complication of acute respiratory distress syndrome during hospital stay which required noninvasive mechanical ventilation and steroids therapy, along with antitubercular medication. PMID- 29417039 TI - Our experience of utilizing community-based health assistants in delivering primary eye care services in a resource-poor setting of Rural Bengaluru, Karnataka, South India. PMID- 29417040 TI - Diagnostic criteria for drug rash and eosinophilia with systemic symptoms. PMID- 29417041 TI - "Need for a rethink:" Questions raised by the "clarifications" issued by the Medical Council of India for academic promotions. PMID- 29417042 TI - Sample size for cluster sampling. PMID- 29417043 TI - Leukemoid reaction in megaloblastic anemia of the puerperium: An unusual cause. PMID- 29417044 TI - Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer. AB - Phosphatidylserine (PS) is a negatively charged phospholipid in all eukaryotic cells that is actively sequestered to the inner leaflet of the cell membrane. Exposure of PS on apoptotic cells is a normal physiological process that triggers their rapid removal by phagocytic engulfment under noninflammatory conditions via receptors primarily expressed on immune cells. PS is aberrantly exposed in the tumor microenvironment and contributes to the overall immunosuppressive signals that antagonize the development of local and systemic antitumor immune responses. PS-mediated immunosuppression in the tumor microenvironment is further exacerbated by chemotherapy and radiation treatments that result in increased levels of PS on dying cells and necrotic tissue. Antibodies targeting PS localize to tumors and block PS-mediated immunosuppression. Targeting exposed PS in the tumor microenvironment may be a novel approach to enhance immune responses to cancer. PMID- 29417045 TI - Urothelial carcinoma: the evolving landscape of immunotherapy for patients with advanced disease. AB - Urothelial carcinoma is the sixth most common malignancy in the US. While most patients present with non-muscle-invasive disease, many will develop recurrent disease including some progressing to muscle invasive metastatic cancer. Treatment outcomes have remained poor and stagnant for those with more advanced illness, with typical 5-year survival rates in the range of <=15%. While first line, platinum-based chemotherapy remains the current standard for those eligible, the recent incorporation of checkpoint inhibitors into the management of advanced bladder cancer has resulted in an expansion of treatment options for a difficult-to-treat disease. This review will discuss the historic standard treatment options, followed by the more recent evolving role immune therapy has in the management of bladder cancer. PMID- 29417047 TI - A Computed Microtomography Method for Understanding Epiphyseal Growth Plate Fusion. AB - The epiphyseal growth plate is a developmental region responsible for linear bone growth, in which chondrocytes undertake a tightly regulated series of biological processes. Concomitant with the cessation of growth and sexual maturation, the human growth plate undergoes progressive narrowing, and ultimately disappears. Despite the crucial role of this growth plate fusion "bridging" event, the precise mechanisms by which it is governed are complex and yet to be established. Progress is hindered by the current methods for growth plate visualization; these are invasive and largely rely on histological procedures. Here, we describe our non-invasive method utilizing synchrotron X-ray computed microtomography for the examination of growth plate bridging, which ultimately leads to its closure coincident with termination of further longitudinal bone growth. We then apply this method to a dataset obtained from a benchtop micro computed tomography scanner to highlight its potential for wide usage. Furthermore, we conduct finite element modeling at the micron-scale to reveal the effects of growth plate bridging on local tissue mechanics. Employment of these 3D analyses of growth plate bone bridging is likely to advance our understanding of the physiological mechanisms that control growth plate fusion. PMID- 29417048 TI - Antibiotic Prophylaxis in Prostate Biopsies: Contemporary Practice Patterns in Germany. AB - Purpose: Prostate biopsy (pbx) is the most common outpatient procedure in urology. Complications are urinary tract infections, including hospitalization and sepsis. Recommendations on antibiotic prophylaxis (apx) are scarce, and healthcare data are not available. The study addressed the following endpoints: the duration and spectrum of antimicrobial prophylaxis in transrectal and transperineal pbx in the hospital and the practice setting. Methods: A questionnaire compiled data about age, gender, board certification, and place of work. Information about the frequency of pbx, duration and type of apx, usage of disinfecting lubricant, and urine or rectal swab cultures was collected. The study refers to German urologists. Results: Overall 478 urologists answered the questionnaire. 15.5% (74) of respondents were residents. 50.8% (243) of urologists work in a practice; the rest in a hospital. Only 4.8% do not perform pbx. Transrectal pbx are performed a median of two times a week. The majority (446, 98%) prescribe an apx, mostly fluoroquinolones (407, 89.5%). In total, 10.1% (46) of the participants use a single-shot-apx. apx has a median duration of 4 days. One-third uses a disinfecting lubricant. Urine and rectal swab cultures are analyzed by 45.5% (207) and 24.4% (111), respectively. Conclusion: Most urologists prescribe an extended apx for both transrectal and transperineal pbx. Perineal pbx is still a deviation from everyday practice and not an established alternative to transrectal pbx. Urologists are aware of the increasing fluoroquinolone-resistance and are adapting with rectal swab and urine cultures. Further studies need to evaluate alternatives to 5-day apx and results should be addressed in our guidelines. This is of importance in light of the increasing resistance rates and fluoroquinolone side effects. PMID- 29417046 TI - Subversion of the Endocytic and Secretory Pathways by Bacterial Effector Proteins. AB - Intracellular bacteria have developed numerous strategies to hijack host vesicular trafficking pathways to form their unique replicative niches. To promote intracellular replication, the bacteria must interact with host organelles and modulate host signaling pathways to acquire nutrients and membrane for the growing parasitophorous vacuole all while suppressing activation of the immune response. To facilitate host cell subversion, bacterial pathogens use specialized secretion systems to deliver bacterial virulence factors, termed effectors, into the host cell that mimic, agonize, and/or antagonize the function of host proteins. In this review we will discuss how bacterial effector proteins from Coxiella burnetii, Brucella abortus, Salmonella enterica serovar Typhimurium, Legionella pneumophila, Chlamydia trachomatis, and Orientia tsutsugamushi manipulate the endocytic and secretory pathways. Understanding how bacterial effector proteins manipulate host processes not only gives us keen insight into bacterial pathogenesis, but also enhances our understanding of how eukaryotic membrane trafficking is regulated. PMID- 29417049 TI - Stress Resilience of Spermatozoa and Blood Mononuclear Cells without Prion Protein. AB - The cellular prion protein PrPC is highly expressed in neurons, but also present in non-neuronal tissues, including the testicles and spermatozoa. Most immune cells and their bone marrow precursors also express PrPC. Clearly, this protein operates in highly diverse cellular contexts. Investigations into putative stress protective roles for PrPC have resulted in an array of functions, such as inhibition of apoptosis, stimulation of anti-oxidant enzymes, scavenging roles, and a role in nuclear DNA repair. We have studied stress resilience of spermatozoa and peripheral blood mononuclear cells (PBMCs) derived from non transgenic goats that lack PrPC (PRNPTer/Ter) compared with cells from normal (PRNP+/+) goats. Spermatozoa were analyzed for freeze tolerance, DNA integrity, viability, motility, ATP levels, and acrosome intactness at rest and after acute stress, induced by Cu2+ ions, as well as levels of reactive oxygen species (ROS) after exposure to FeSO4 and H2O2. Surprisingly, PrPC-negative spermatozoa reacted similarly to normal spermatozoa in all read-outs. Moreover, in vitro exposure of PBMCs to Doxorubicin, H2O2 and methyl methanesulfonate (MMS), revealed no effect of PrPC on cellular survival or global accumulation of DNA damage. Similar results were obtained with human neuroblastoma (SH-SY5Y) cell lines stably expressing varying levels of PrPC. RNA sequencing of PBMCs (n = 8 of PRNP+/+ and PRNPTer/Ter) showed that basal level expression of genes encoding DNA repair enzymes, ROS scavenging, and antioxidant enzymes were unaffected by the absence of PrPC. Data presented here questions the in vitro cytoprotective roles previously attributed to PrPC, although not excluding such functions in other cell types or tissues during inflammatory stress. PMID- 29417050 TI - D-Amino Acid Oxidase-pLG72 Interaction and D-Serine Modulation. AB - pLG72 is a small, primate-specific protein of 153 amino acids. It is the product of the G72 gene, expressed in testis, spinal cord, and brain. The presence of G72 transcript and pLG72 has recurrently been called into question, however G72 mRNA and pLG72 protein levels were higher in blood and brain of patients with schizophrenia than in healthy controls. On the one hand, the SNP rs2391191 corresponding to the R30K substitution in pLG72 was genetically linked to schizophrenia, reduced thickness of the brain cortex in schizophrenia-affected individuals, and altered memory function. Various lines of evidence indicated that pLG72 is a mitochondrial protein, specifically an extrinsic protein bound on the outer membrane. Over the years, pLG72 was proposed to be involved in different functions: (a) overexpression induces mitochondria fragmentation, increasing the numbers of shorter and more mobile ones which could be delivered faster to regions of intense growth and facilitating the dendritic complexity; (b) it might induce oxidative stress by interacting with methionine-R-sulfoxide reductase B2; and (c) it binds and modulates the activity of FMN-containing oxidoreductase of the respiratory complex I. The main role of this protein, however, is related to its binding to the human flavoenzyme D-amino acid oxidase (hDAAO), i.e., the main catabolic enzyme for D-enantiomer of serine. This D-amino acid is a main endogenous coagonist of the N-methyl-D-aspartate type glutamate receptor (NMDAR) involved in main functions such as synaptic plasticity, learning, memory, and excitotoxicity. For this work, we reviewed the recent literature concerning the hDAAO-pLG72 interaction, focusing on the molecular details of the interaction, the effect of hDAAO function and stability, and the cellular effects, especially on D-serine concentration. The main effects related to the pathological R30K substitution are also reported. We have highlighted the gaps in our knowledge of this human protein as well as the relevance of clarifying the molecular details of hDAAO-pLG72 interaction in order to design molecules to modulate hDAAO activity/stability and thus NMDAR function acting at the D-serine cellular level. PMID- 29417052 TI - Comparison of Four Diagnostic Methods for Detection and Relative Quantification of Haemonchus contortus Eggs in Feces Samples. AB - We compared four methods for identification of Haemonchus contortus eggs. With increased trade in animals within and between countries and continents, it has become important to correctly identify H. contortus eggs in fecal samples. To validate the outcome of diagnostic tests, sheep feces (n = 38) were collected from naturally infected flocks in Sweden. Subsamples were analyzed with (a) McMaster egg counting; (b) differential counting of eggs after staining with peanut agglutinin (PNA); (c) detection of DNA following amplification by real time quantitative polymerase chain reaction (qPCR); and (d) loop-mediated isothermal amplification (LAMP). Differences between similar tests (microscopic and molecular) and SD (+/-SD) were analyzed with Bland-Altman plots and Spearman rank correlation. Strongylid egg counts ranged from 200 to 12,100 eggs per gram (epg) (mean epg +/- SD = 1,278 +/- 2,049). Microscopy showed presence of H. contortus eggs in 27 (73%) unstained samples and in 28 (76%) samples stained with PNA, whereas 29 samples (78%) tested positive in LAMP and 34 (91%) in qPCR analysis. The cycle threshold (Ct) values with LAMP ranged between 13 and 38 (mean +/- SD = 21 +/- 7), and those in qPCR between 25 and 49 (mean +/- SD = 33 +/- 6). In the LAMP and qPCR analyses, seven (19%) and three (8%) samples, respectively, had a cycle threshold (Ct) >35, whereas no reactions were observed in eight (22%) and three (8%) samples, respectively. There was good agreement between the diagnostic tests based on microscopic examination and DNA detection, although the molecular tests were more sensitive. The bias between the microscopy methods (-4.2 +/- 11) was smaller than for the molecular tests (-9.8 +/- 10). The observed ranking in terms of test sensitivity was: McMaster counting by conventional microscopy < PNA < LAMP < qPCR. In conclusion, H. contortus can be identified by McMaster counting, without major mistakes regarding false positive results. However, molecular methods provide the capacity to diagnose H. contortus eggs with increased accuracy. This is essential when animals are investigated in quarantine or in studies evaluating anthelmintic treatment efficacy. These methods could also be applied to fecal samples from wildlife to investigate nematode transmission between wildlife and livestock. PMID- 29417053 TI - Highly Pathogenic Avian Influenza H5N8 Clade 2.3.4.4b in Germany in 2016/2017. AB - Here, we report on the occurrence of highly pathogenic avian influenza (HPAI) H5Nx clade 2.3.4.4b in Germany. Between November 8, 2016, and September 30, 2017, more than 1,150 cases of HPAI H5Nx clade 2.3.4.4b in wild birds and 107 outbreaks in birds kept in captivity (92 poultry holdings and 15 zoos/animal parks) were reported in Germany. This HPAI epidemic is the most severe recorded in Germany so far. The viruses were apparently introduced by migratory birds, sparking an epidemic among wild birds across Germany with occasional incursions into poultry holdings, zoos and animal parks, which were usually rapidly detected and controlled by stamping out. HPAI viruses (mainly subtype H5N8, in a few cases also H5N5) were found in dead wild birds of at least 53 species. The affected wild birds were water birds (including gulls, storks, herons, and cormorants) and scavenging birds (birds of prey, owls, and crows). In a number of cases, substantial gaps in farm biosecurity may have eased virus entry into the holdings. In a second wave of the epidemic starting from February 2017, there was epidemiological and molecular evidence for virus transmission of the infections between commercial turkey holdings in an area of high poultry density, which caused approximately 25% of the total number of outbreaks in poultry. Biosecurity measures in poultry holdings should be adapted. This includes, inter alia, wearing of stable-specific protective clothing and footwear, cleaning, and disinfection of equipment that has been in contact with birds and prevention of contacts between poultry and wild water birds. PMID- 29417051 TI - Inflammation in Vein Graft Disease. AB - Bypass surgery is one of the most frequently used strategies to revascularize tissues downstream occlusive atherosclerotic lesions. For venous bypass surgery the great saphenous vein is the most commonly used vessel. Unfortunately, graft efficacy is low due to the development of vascular inflammation, intimal hyperplasia and accelerated atherosclerosis. Moreover, failure of grafts leads to significant adverse outcomes and even mortality. The last couple of decades not much has changed in the treatment of vein graft disease (VGD). However, insight is the cellular and molecular mechanisms of VGD has increased. In this review, we discuss the latest insights on VGD and the role of inflammation in this. We discuss vein graft pathophysiology including hemodynamic changes, the role of vessel wall constitutions and vascular remodeling. We show that profound systemic and local inflammatory responses, including inflammation of the perivascular fat, involve both the innate and adaptive immune system. PMID- 29417054 TI - Aujeszky's Disease and Hepatitis E Viruses Transmission between Domestic Pigs and Wild Boars in Corsica: Evaluating the Importance of Wild/Domestic Interactions and the Efficacy of Management Measures. AB - Wildlife species as reservoirs of infectious pathogens represent a serious constraint in the implementation of disease management strategies. In the Mediterranean island of Corsica, the dynamics of hepatitis E virus (HEV) and Aujeszky's disease virus (ADV) are suspected to be influenced by interactions between wild and domestic pigs. To improve our understanding of these influences, we first compared the seroprevalences of both viruses in domestic pig populations from different locations with contrasted levels of wild-domestic interactions, ADV vaccination, biosafety, and farm husbandry. Second, we performed an analysis at a more restricted geographical scale, to assess the matching of ADV or HEV prevalence between sympatric wild boar and outdoor pig farms most exposed to interactions with wildlife. Logistic models were adjusted to the observed data. A high seroprevalence of HEV (>80%) and ADV (40%) in pigs, with no significant difference according to the region, confirms that both pathogens are enzootic in Corsica. Vaccination against ADV had a strong protective effect, even when performed voluntarily by farmers. Farm biosafety had an additional effect on pigs' exposure, suggesting that contact between wild boars and pigs were involved in disease transmission. A strong correlation in HEV seroprevalence was observed between pigs and wild boars that were in close contact, and significantly lower seroprevalence was observed in pigs when they had little contact with wild boars due to spatial segregation. These results suggest a regular HEV circulation between sympatric wild boar and domestic pigs. The high HEV seroprevalence observed in domestic pigs (>80%) suggests a spillover of the virus from domestic to wild populations through environmental contamination, but this hypothesis has to be confirmed. Conversely, even though avoiding sows' release on pasture during estrus showed some protecting effect in the free ranging pig farms regarding ADV, ADV seroprevalence was not dependent on the swine populations (wild or domestic) or on the wild-domestic spatial overlap, suggesting two quasi-separate enzootic cycles. This information will prove useful for designing more efficient disease management strategies in Corsica and similar contexts. PMID- 29417055 TI - Ras signalling in pathogenic yeasts. AB - The small GTPase Ras acts as a master regulator of growth, stress response and cell death in eukaryotic cells. The control of Ras activity is fundamental, as highlighted by the oncogenic properties of constitutive forms of Ras proteins. Ras also plays a crucial role in the pathogenicity of fungal pathogens where it has been found to regulate a number of adaptions required for virulence. The importance of Ras in fungal disease raises the possibility that it may provide a useful target for the development of new treatments at a time when resistance to available antifungals is increasing. New findings suggest that important regulatory sequences found within fungal Ras proteins that are not conserved may prove useful in the development of new antifungals. Here we review the roles of Ras protein function and signalling in the major human yeast pathogens Candida albicans and Cryptococcus neoformans and discuss the potential for targeting Ras as a novel approach to anti-fungal therapy. PMID- 29417056 TI - Untargeted metabolomics confirms and extends the understanding of the impact of aminoimidazole carboxamide ribotide (AICAR) in the metabolic network of Salmonella enterica. AB - In Salmonella enterica, aminoimidazole carboxamide ribotide (AICAR) is a purine biosynthetic intermediate and a substrate of the AICAR transformylase/IMP cyclohydrolase (PurH) enzyme. When purH is eliminated in an otherwise wild-type strain, AICAR accumulates and indirectly inhibits synthesis of the essential coenzyme thiamine pyrophosphate (TPP). In this study, untargeted metabolomics approaches were used to i) corroborate previously defined metabolite changes, ii) define the global consequences of AICAR accumulation and iii) investigate the metabolic effects of mutations that restore thiamine prototrophy to a purH mutant. The data showed that AICAR accumulation led to an increase in the global regulator cyclic AMP (cAMP) and that disrupting central carbon metabolism could decrease AICAR and/or cAMP to restore thiamine synthesis. A mutant (icc) blocked in cAMP degradation that accumulated cAMP but had wild-type levels of AICAR was used to identify changes in the purH metabolome that were a direct result of elevated cAMP. Data herein describe the use of metabolomics to identify the metabolic state of mutant strains and probe the underlying mechanisms used by AICAR to inhibit thiamine synthesis. The results obtained provide a cautionary tale of using metabolite concentrations as the only data to define the physiological state of a bacterial cell. PMID- 29417058 TI - Yeast quiescence exit swiftness is influenced by cell volume and chronological age. AB - Quiescence exit swiftness is crucial not only for micro-organisms in competition for an environmental niche, such as yeast, but also for the maintenance of tissue homeostasis in multicellular species. Here we explore the effect of replicative and chronological age on Saccharomyces cerevisiae quiescence exit efficiency. Our study reveals that this step strongly relies on the cell volume in quiescence but is not influenced by cell replicative age, at least for cells that have undergone less than 10 divisions. Furthermore, we establish that chronological age strongly impinges on cell's capacities to exit quiescence. This effect is not related to cell volume or due to cell's inability to metabolize external glucose but rather seems to depend on intracellular trehalose concentration. Overall, our data illustrate that the quiescent state is a continuum evolving with time, early and deep quiescence being distinguishable by the cell's proficiency to re-enter the proliferation cycle. PMID- 29417059 TI - New perspectives from South-Y-East, not all about death. A report of the 12th lnternational Meeting on Yeast Apoptosis in Bari, Italy, May 14th-18th, 2017. PMID- 29417057 TI - Fat storage-inducing transmembrane (FIT or FITM) proteins are related to lipid phosphatase/phosphotransferase enzymes. AB - Fat storage-inducing transmembrane (FIT or FITM) proteins have been implicated in the partitioning of triacylglycerol to lipid droplets and the budding of lipid droplets from the ER. At the molecular level, the sole relevant interaction is that FITMs directly bind to triacyglycerol and diacylglycerol, but how they function at the molecular level is not known. Saccharomyces cerevisiae has two FITM homologues: Scs3p and Yft2p. Scs3p was initially identified because deletion leads to inositol auxotrophy, with an unusual sensitivity to addition of choline. This strongly suggests a role for Scs3p in phospholipid biosynthesis. Looking at the FITM family as widely as possible, we found that FITMs are widespread throughout eukaryotes, indicating presence in the last eukaryotic common ancestor. Protein alignments also showed that FITM sequences contain the active site of lipid phosphatase/phosphotransferase (LPT) enzymes. This large family transfers phosphate-containing headgroups either between lipids or in exchange for water. We confirmed the prediction that FITMs are related to LPTs by showing that single amino-acid substitutions in the presumptive catalytic site prevented their ability to rescue growth of the mutants on low inositol/high choline media when over-expressed. The substitutions also prevented rescue of other phenotypes associated with loss of FITM in yeast, including mistargeting of Opi1p, defective ER morphology, and aberrant lipid droplet budding. These results suggest that Scs3p, Yft2p and FITMs in general are LPT enzymes involved in an as yet unknown critical step in phospholipid metabolism. PMID- 29417060 TI - Burkholderia gladioli strain NGJ1 deploys a prophage tail-like protein for mycophagy. AB - Fungal pathogens are responsible for approximately two third of the infectious plant diseases. Historically they have been associated with several devastating famines, causing death and disabilities in humans. Mostly fungal diseases are being controlled by using fungicides which otherwise have adverse side effects on the health of consumers as well as environment. Due to extensive usages, pathogens have evolved resistance against most of the commonly used fungicides and rendered them ineffective. Controlling fungal disease in a sustainable and eco-friendly fashion remains a challenge. The antifungal biocontrol agents are being considered as potent, alternative and ecofriendly approach to manage fungal diseases. In our recent work, we have identified a rice associated bacterium; Burkholderia gladioli strain NGJ1 which demonstrates broad spectrum fungal eating (mycophagous) property. We determined that the bacterium utilizes its type III secretion system (Injectisome) machinery to deploy a prophage tail-like protein (Bg_9562) into fungal cells to devour them. The purified Bg_9562 protein from over-expressing recombinant E. coli strain demonstrates broad spectrum antifungal activity. Overall our study opens up a new opportunity to exploit prophage tail like protein as potent antifungal compound to control plant as well as animal fungal diseases. PMID- 29417061 TI - Nursing students plan after graduation: A qualitative study. AB - BACKGROUND: Identifying nursing students' plan after graduation is necessary to maintain the profession in line with their nursing education. This study was conducted to explore the career plans of diploma nursing students after graduation and factors influencing their plans. MATERIALS AND METHODS: This was a qualitative descriptive study using focus group discussion, conducted in Academy of Nursing of Belitung, Indonesia. Twenty diploma nursing students at the beginning of their 1st year of study were recruited. Data were analyzed using content analysis model. RESULTS: The plan of diploma nursing students after graduation: becoming a civil servant and its influencing factors (fixed and higher salary, fair remuneration and incentives, and retirement fund); becoming a bedside nurse and its influencing factors (helping others and gaining experiences); and continuing higher education in nursing and its influencing factors (recognition as professional nurse, financial support, family responsibilities, and location of nursing schools). CONCLUSION: It is suggested that nurse educators should change the mindset of the students not to focus only becoming a civil servant, and the government should open bachelor program in nursing in Belitung and provide educational support for those who would like to continue studying nursing. PMID- 29417062 TI - Developing a pilot curriculum to foster humanism among graduate medical trainees. AB - BACKGROUND: Humanism is a central tenant of professionalism, a required competency for all residency programs. Yet, few residencies have formal curriculum for teaching this critical aspect of medicine. Instead, professionalism and humanism are often taught informally through role-modeling. With increased burnout, faculty professionalism may suffer and may compromise resident role-modeling. The objective of this study was to design a pilot curriculum to foster humanism in among residents and assess its ability to do so. MATERIALS AND METHODS: Two-phase exploratory sequential mixed methods study. Phase 1: a qualitative analysis of residents' narratives regarding challenges to humanistic behavior, and identified themes of compassion, fatigue, communication challenges, and work-life balance. Themes used as needs assessment to build curriculum. Phase 2: three sessions with themes taken from faculty development course. Participants and controls completed baseline and 60-day follow-up questionnaires assessing burnout, compassion, satisfaction, and ability to practice psychological medicine. Phase one included Obstetrics/Gynecology and internal medicine residents. Phase two included residents from the above programs, who attended at least 2/3 interactive sessions designed to address the themes identified above. RESULTS: Twelve participants began and ten completed curriculum (83%). The curriculum met course objectives and was well-received (4.8/5). Burnout decreased (-3.1 vs. 2.5, P = 0.048). A trend toward improved compassion (4.4 vs.-0.6, P = 0.096) for participants compared to controls was noted. CONCLUSION: A pilot humanism curriculum for residents was well-received. Participants showed decreased burnout and trended to improved compassion scores. Development and evaluation of an expanded curriculum would further explore feasibility and effectiveness of the intervention. PMID- 29417063 TI - The Effect of aerobic exercise on primary dysmenorrhea: A clinical trial study. AB - INTRODUCTION: Primary dysmenorrhea without pelvic pathology is one of the most common complaints in women's medicine. Primary dysmenorrhea can affect the quality of life of women. Aerobic exercise is one of the ways to reduce the severity of primary dysmenorrhea. The present study aimed to determine the effect of 8 weeks of aerobic exercise on the severity of primary dysmenorrhea. METHODS: This is a clinical trial study performed on 70 students with primary dysmenorrhea in dormitories of Mashhad University of Medical Sciences in 2015. Participants were randomly assigned to intervention and control groups. The instrument was a visual pain questionnaire completed by the two groups in the first 3 days of the menstrual cycle. The exercise protocol included aerobic exercise, which performed the intervention group for 8 weeks, three times a week, and each time for 30 min. Data were analyzed by Fisher and Chi-square tests. RESULTS: The control and intervention groups were homogeneous in terms of demographic characteristics. Results showed that the severity of primary dysmenorrhea at the beginning of the study was not significantly correlated with the two groups. At the end of the 4 weeks after the intervention, the intervention group did not show any significant changes in the control group (P = 0.423) but At the end of 8 weeks after the study, the intervention group showed significant changes compared to the control group (P = 0.041). CONCLUSION: The results of this study showed that performing aerobic exercise can improve primary dysmenorrhea. Therefore, aerobic exercise can be used to treat primary dysmenorrhea. PMID- 29417064 TI - Cross-cultural adaptation and psychometric evaluation of oral health impact profile among school teacher community. AB - AIM: To translate OHIP-14 into Hindi and test its psychometric properties among school teacher community. METHODS: The OHIP-14 was translated to OHIP-14-H using WHO recommended translation protocol. During pre-testing, an expert panel assessed content validity of the questionnaire. Face validity was assessed on a sample of 10 individuals. The OHIP-14-H was administered on a random sample of 170 primary school teachers. Internal consistency and test-retest reliability were assessed using Cronbach's alpha and Intra-class correlation coefficient (ICC) respectively, with 2 weeks interval. Predictive validity was tested by comparing OHIP-14-H scores with clinical parameters. The concurrent validity was assessed using self-reported oral health and discriminant validity was ascertained through negative association with sociodemographic variables. RESULTS: The mean OHIP-14-H score was 9.57 (S.D = 4.58). ICC and Cronbach's alpha for OHIP-14-H was 0.96 and 0.92 respectively. Concurrent validity using binomial regression model indicated that good (OR = 0.56, 95% CI = 0.55 - 4.47) and moderate (OR = 0.25, 95% CI = 0.17 - 1.87) OHIP-14-H scores were negative but significant risk indicators of poor self reported oral health (P < 0.009). Significant predictive validity was observed between OHIP-14-H scores and clinical parameters (P < 0.000). CONCLUSION: Translated and culturally adapted OHIP-14-H indicates good reliability and validity among primary school teachers. PMID- 29417065 TI - Predictors of public transportation in Mashhad: A population-based study. AB - BACKGROUND: The development of public transportation (PT) is a crucial issue in the modern societies. The aim of this study was to assess the status of PT usage among the population residing in Mashhad. MATERIALS AND METHODS: In a cross sectional design, 464 citizens of Mashhad filled a checklist about PT-use (i.e., bus, taxi, and metro) to find their supporting and opposing factors in 2014. Chi square, Mann-Whitney, Student's t-test, and logistic regressions were used for inferential analysis in SPSS 11.5. RESULTS: Mean age was 30.02 +/- 11.24 years and 57% (263) were female. Bus (169, 50%) was the most popular PT means, followed by metro (98, 29%) and taxi (74, 21%). Most transportations were happened at morning (248, 35%) and evening (221, 31%). Increasing age (odds ratio [OR] =1.04, confidence interval [CI] 95% = 1.008-1.07), higher education (OR = 2.91, CI 95% = 1.14-7.38), being homemaker (OR = 2.97, CI 95% = 1.19-7.36), or student (OR = 2.91, CI 95% = 1.14-7.38) were predictors of PT-use. CONCLUSION: Individual preference between PT and driving is associated with social, economic, and cultural aspects of a population. Recognizing the influencing factors can help to design population-oriented services. PMID- 29417066 TI - A comparison of face to face and group education on informed choice and decisional conflict of pregnant women about screening tests of fetal abnormalities. AB - BACKGROUND AND GOAL: Screening of fetal anomalies is assumed as a necessary measurement in antenatal cares. The screening plans aim at empowerment of individuals to make the informed choice. This study was conducted in order to compare the effect of group and face-to-face education and decisional conflicts among the pregnant females regarding screening of fetal abnormalities. METHODS: This study of the clinical trial was carried out on 240 pregnant women at <10 week pregnancy age in health care medical centers in Mashhad city in 2014. The form of individual-midwifery information and informed choice questionnaire and decisional conflict scale were used as tools for data collection. The face-to face and group education course were held in two weekly sessions for intervention groups during two consecutive weeks, and the usual care was conducted for the control group. The rate of informed choice and decisional conflict was measured in pregnant women before education and also at weeks 20-22 of pregnancy in three groups. The data analysis was executed using SPSS statistical software (version 16), and statistical tests were implemented including Chi-square test, Kruskal Wallis test, Wilcoxon test, Mann-Whitney U-test, one-way analysis of variance test, and Tukey's range test. The P < 0.05 was considered as a significant. RESULTS: The results showed that there was statically significant difference between three groups in terms of frequency of informed choice in screening of fetal abnormalities (P = 0.001) in such a way that at next step of intervention, 62 participants (77.5%) in face-to-face education group, 64 members (80%) in group education class, and 20 persons (25%) in control group had the informed choice regarding screening tests, but there was no statistically significant difference between two individual and group education classes. Similarly, during the postintervention phase, there was a statistically significant difference in mean score of decisional conflict scale among pregnant women regarding screening tests in three groups (P = 0.001). DISCUSSION AND CONCLUSION: With respect to effectiveness of group and face-to-face education methods in increasing the informed choice and reduced decisional conflict in pregnant women regarding screening tests, each of these education methods may be employed according to the clinical environment conditions and requirement to encourage the women for conducting the screening tests. PMID- 29417067 TI - Hepatitis C: Knowledge and awareness of private dental practitioners of a tricity in India. AB - BACKGROUND: Dental health-care personnel are at an increased risk toward infections caused by various microorganisms including hepatitis B and hepatitis C viruses (HCV). A dentist can play an important role in the prevention of HCV by considering every patient as a potential carrier for hepatitis. Therefore, the present study was conducted to assess the knowledge and awareness of dental health-care professionals regarding various aspects of HCV. MATERIALS AND METHODS: A cross-sectional study was conducted among 247 private dental practitioners of tricity. A close-ended self-structured questionnaire was administered which contained 12 questions on knowledge and awareness regarding HCV infection keeping in view the time constraints. Categorization of knowledge scores was done at three levels - poor, moderate, and good. Statistical analysis was done using ANOVA and Student's t-test. RESULTS: Nearly 96% (102) of postgraduates and 84% (117) of graduates had heard about HCV. 45.5% (112) had poor knowledge scores, 33.6% (83) had moderate knowledge scores, and only 21% (52) of participants had good knowledge scores. On the opinion of treating an HCV infected patient by a dentist, only 61% (65) of postgraduates and 46% (64) of graduates agreed. There was statistically significant association of mean knowledge scores with gender, education level, and experience (P < 0.05). CONCLUSION: Majority of the dental professionals lacked knowledge regarding HCV infection and were not fully aware regarding certain aspects. Therefore, there is an urgent need for modification of the existing dental curriculum so that knowledge regarding these diseases can be imparted during graduation. PMID- 29417068 TI - Internationalization or globalization of higher education. AB - INTRODUCTION: Studies about globalization and internationalization demonstrate different attitudes in explaining these concepts. Since there is no consensus among Iranian specialists about these concepts, the purpose of this study is to explain the concepts of internationalization and globalization in Iran. MATERIALS AND METHODS: This study is a systematic review done in the first half of 2016. To explain the concept of globalization and internationalization, articles in Scientific Information D atabase, Magiran database, and Google Scholar were searched with the keywords such as globalization, scientific exchange, international cooperation, curriculum exchange, student exchange, faculty exchange, multinational cooperation, transnational cooperation, and collaborative research. Articles, used in this study, were in Persian and were devoted to internationalization and globalization between 2001 and 2016. The criterion of discarding the articles was duplicity. RESULTS: As many as 180 Persian articles were found on this topic. After discarding repetitive articles, 64 remained. Among those, 39 articles mentioned the differences between globalization and internationalization. Definitions of globalization were categorized in four categories, including globalization, globalizing, globalization of higher education, and globalizing of higher education. Definitions about internationalization were categorized in five categories such as internationalization, internationalization of higher education, internationalization of the curriculum, internationalization of curriculum studies, and internationalization of curriculum profession. CONCLUSION: The spectrum of the globalization of higher education moves from dissonance and multipolarization to unification and single polarization of the world. One end of the spectrum, which is unification and single polarization of the world, is interpreted as globalization. The other side of the spectrum, which is dissonance and multipolarization, is interpreted as globalizing. The definition of internalization is the same as that of globalizing. In other words, it is possible to say that internalization is similar to globalizing but different from globalization. PMID- 29417069 TI - Assessment of readiness to quit tobacco among patients with oral potentially malignant disorders using transtheoretical model. AB - BACKGROUND: Tobacco use is a disease of addiction and a behavior choice. It is valuable to understand the psychosocial dimension of disease. OBJECTIVES: The research aimed to assess the (I) behavioral determinants and pattern of tobacco use (II) readiness to quit tobacco among patients with oral potentially malignant disorders (OPMDs) using transtheoretical model (TTM) approach visiting the dental college in Goa, India. MATERIALS AND METHODS: This cross-sectional analytical study was conducted among 300 patients over 3 months. Information about sociodemographics, determinants including age and reason of onset, behavioral stages, and the presence of OPMDs was collected using specially designed pro forma. Descriptive and inferential statistics were performed using SPSS 18.0. RESULTS: Smokeless form of tobacco 199 (66.34%) was most prevalent followed by smoking 79 (26.33%) and dual tobacco use 22 (07.33%) in males. Majority belonged to low socioeconomic class. Peer influence was the most-cited reason. Around 1/3rd of the participants had OPMDs associated with tobacco use. Significant association was observed between the presence of OPMDs and TTM behavioral stages. Patients with OPMDs are more motivated for tobacco cessation (odd's ratio = 2.30, P = 0.002), that is, they are more in preparation and action stages. CONCLUSION: The findings reflect that smokeless tobacco use is more prevalent in males with low level of education and socioeconomic class. Readiness to quit tobacco increases among patients with OPMDs using TTM. PMID- 29417070 TI - Utilizing mobile health method to emergency nurses' knowledge about Emergency Severity Index triage. AB - BACKGROUND: Mobile health has the potential to revolutionize the role of educators by empowering nurses to take more responsibility for their own learning. Hence, this study was designed to examine the effect of mobile health method to emergency nurses' knowledge about Emergency Severity Index triage. MATERIALS AND METHODS: A two groups' pool blind quasi-experimental study was performed on emergency department nurses working in hospitals affiliated with Isfahan University of Medical Sciences. The study was conducted from September to November 2014. Sample size was calculated as 35 participants in each group (a total of seventy participants). Participants were divided into two groups of mobile health and workshop, randomly. Participants' knowledge score was collected according to researcher-made questionnaire with twenty questions. SPSS version 11.5 was used to conduct statistical tests such as independent t-test and paired t-test for analyzing the data with the significant level <0.05. RESULTS: The results show that there was not any significant difference between the knowledge scores of mobile health and workshop group before intervention, but there was a significant difference after 2-week intervention (P = 0.012). CONCLUSION: The electronic program was an attractive education method for emergency nurses because in these method educators by empowering nurses to take more responsibility for their own learning. Hence, it is suggested that mobile health is used by authorities along with routine training, due to its less cost and spending less time. PMID- 29417071 TI - Research self-efficacy and its relationship with academic performance in postgraduate students of Tehran University of Medical Sciences in 2016. AB - BACKGROUND: Research self-efficacy is one of the main factors influencing the successful conduction of research and following it in students. This study was performed with the aim of determining the research self-efficacy and its relationship with academic performance in postgraduate students of Tehran University of Medical Sciences (TUMS) in 2016. MATERIALS AND METHODS: This cross sectional study was performed on 320 postgraduate students of TUMS in 2016. Proportional stratified sampling was done with simple random sampling from each school. The data were gathered with Phillips and Russell's research self-efficacy questionnaire, demographic questions, and grade point average (GPA) and were analyzed with independent t-tests, ANOVA, Pearson's correlation, and multiple linear regressions in SPSS 18. RESULTS: Out of 320 students participating in this study, 152 patients (47.5%) were male and 168 (52.5%) were female with the mean age of 27.83 +/- 4.3 years. The mean of research self-efficacy score was 186.18 +/- 59.5 which was significant depended on college degrees and was significantly higher in doctorate students (P = 0.0001). However, no significant difference was seen in research self-efficacy score of students due to gender (P = 0.754) and school (P = 0.364). There was a significant direct relationship between students' GPA and research self-efficacy score (r = 0.393, P = 0.0001). CONCLUSIONS: Results of this study showed that the research self-efficacy score of TUMS postgraduate students is at an acceptable level, except the quantitative and computer skills that need appropriate educational interventions. As a direct and significant relationship existed between research self-efficacy score and student's academic performance, improving the research self-efficacy will also increase students' academic performance. PMID- 29417072 TI - Knowledge regarding anesthesiologist and anesthesiology among patients and attendants attending a rural hospital of New Delhi. AB - INTRODUCTION: Anesthesia has become one of the most advanced specialties in modern medicine with tremendous growth in knowledge and substances available for use. However, public awareness toward anesthesiologist and anesthesiology is limited. It is important for us to make people aware about the role played by an anesthesiologist in medical setup. The present study was conducted among patients and attendants to assess the knowledge regarding the anesthesiologist and anesthesiology. MATERIALS AND METHODS: The study was carried out at a rural hospital of New Delhi, on 250 adult patients and attendants visiting outpatient departments to assess their knowledge regarding anesthesiologists and anesthesiology. An interview in their local language with the help of a prestructured questionnaire was carried out over a 3 month period. The participants on the basis of their answers were classified as aware or unaware. The data were analyzed using SPSS version 17. RESULTS: Most of the patients in our study were not aware of the role of anesthesiologists, their role in OT and postoperative period, and about anesthesiology as a separate discipline. They were aware of the general and regional anesthesia techniques. Only half of the participants had good knowledge (55.6%), and it was significantly associated with age, sex, and education (P < 0.001). CONCLUSION: There is ignorance among the general population regarding the role played by anesthesiologists. We need newer initiatives for educating public and professionals for future progress. PMID- 29417073 TI - Factors influencing the results of faculty evaluation in Isfahan University of Medical Sciences. AB - OBJECTIVE: This study aimed to explore factors influencing the results of faculty member evaluation from the viewpoints of faculty members affiliated with Isfahan University of Medical Sciences, Isfahan, Iran. MATERIALS AND METHODS: This qualitative study was done using a conventional content analysis method. Participants were faculty members of Isfahan University of Medical Sciences who, considering maximum variation in sampling, were chosen with a purposive sampling method. Semi-structured interviews were held with 11 faculty members until data saturation was reached. The interviews were transcribed verbatim and analyzed with conventional content analysis method for theme development. Further, the MAXQDA software was used for data management. RESULTS: The data analysis led to the development of two main themes, namely, "characteristics of the educational system" and "characteristics of the faculty member evaluation system." The first main theme consists of three categories, i.e. "characteristics of influential people in evaluation," "features of the courses," and "background characteristics." The other theme has the following as its categories: "evaluation methods," "evaluation tools," "evaluation process," and "application of evaluation results." Each category will have its subcategories. CONCLUSIONS: Many factors affect the evaluation of faculty members that should be taken into account by educational policymakers for improving the quality of the educational process. In addition to the factors that directly influence the educational system, methodological problems in the evaluation system need special attention. PMID- 29417074 TI - The effect of religious-spiritual support on childbirth self-efficacy. AB - BACKGROUND: Childbirth self-efficacy is one of the most important factors causing a shift in mothers do vaginal delivery. If the mother feels that she can cope well with stress, will be protected from the harmful effects of stress on your health. Self-efficacy contained individual's assessment of her ability to deal with stressful situations. Strengthen the spiritual beliefs of the patient causes her to be a good result every situation even incurable condition. This study aimed to determine the effect of religious-spiritual support on childbirth self efficacy in primiparous women. METHODS: This is a quasi-experimental study carried on seventy primiparous women; participants were randomly divided into two intervention and control groups. The intervention group received the e-learning package based on religious-spiritual content. Self-efficacy questionnaire by both groups before and 4 weeks after it was completed. Collected data were entered into SPSS version 11 descriptive statistics, independent t-test, and paired t test which were used for analysis of data. The significant level was considered <0.05. RESULTS: The results showed that the mean self-efficacy score before and after intervention in case group was 105.2 (27.01) and 110.12 (21.2), respectively, and in control group; 111.2 (23.12) and 116.9 (24.43). Paired t test in two groups was significant (P = 0.042, P = 0.045) but independent t-test showed no significant difference in scores of childbirth self-efficacy before and after intervention in two groups (P = 0.061). CONCLUSION: In prenatal periods, religious-spiritual support through electronic package method can increase childbirth self-efficacy, so the planning and establishment of this training are recommended as an effective training. PMID- 29417075 TI - Meta-evaluation of published studies on evaluation of health disaster preparedness exercises through a systematic review. AB - OBJECTIVE: Exercise evaluation is one of the most important steps and sometimes neglected in designing and taking exercises, in this stage of exercise, it systematically identifying, gathering, and interpreting related information to indicate how an exercise has fulfilled its objectives. The present study aimed to assess the most important evaluation techniques applied in evaluating health exercises for emergencies and disasters. METHODS: This was meta-evaluation study through a systematic review. In this research, we searched papers based on specific and relevant keywords in research databases including ISI web of science, PubMed, Scopus, Science Direct, Ovid, ProQuest, Wiley, Google Scholar, and Persian database such as ISC and SID. The search keywords and strategies are followed; "simulation," "practice," "drill," "exercise," "instrument," "tool," "questionnaire," " measurement," "checklist," "scale," "test," "inventory," "battery," "evaluation," "assessment," "appraisal," "emergency," "disaster," "cricise," "hazard," "catastrophe,: "hospital", "prehospital," "health centers," "treatment centers," were used in combination with Boolean operators OR and AND. RESULTS: The research findings indicate that there are different techniques and methods for data collection to evaluate performance exercises of health centers and affiliated organizations in disasters and emergencies including debriefing inventories, self-report, questionnaire, interview, observation, shooting video, and photographing, electronic equipment which can be individually or collectively used depending on exercise objectives or purposes. CONCLUSION: Taking exercise in the health sector is one of the important steps in preparation and implementation of disaster risk management programs. This study can be thus utilized to improve preparedness of different sectors of health system according to the latest available evaluation techniques and methods for better implementation of disaster exercise evaluation stages. PMID- 29417076 TI - Forecasting the shortage of neurosurgeons in Iran using a system dynamics model approach. AB - CONTEXT: Shortage of physicians particularly in specialty levels is considered as an important issue in Iran health system. Thus, in an uncertain environment, long term planning is required for health professionals as a basic priority on a national scale. AIMS: This study aimed to estimate the number of required neurosurgeons using system dynamic modeling. SETTING AND DESIGN: System dynamic modeling was applied to predict the gap between stock and number of required neurosurgeons in Iran up to 2020. SUBJECTS AND METHODS: A supply and demand simulation model was constructed for neurosurgeons using system dynamic approach. The demand model included epidemiological, demographic, and utilization variables along with supply model-incorporated current stock of neurosurgeons and flow variables such as attrition, migration, and retirement rate. STATISTICAL ANALYSIS USED: Data were obtained from various governmental databases and were analyzed by Vensim PLE Version 3.0 to address the flow of health professionals, clinical infrastructure, population demographics, and disease prevalence during the time. RESULTS: It was forecasted that shortage in number of neurosurgeons would disappear at 2020. The most dominant determinants on predicted number of neurosurgeons were the prevalence of neurosurgical diseases, the rate for service utilization, and medical capacity of the region. CONCLUSIONS: Shortage of neurosurgeons in some areas of the country relates to maldistribution of the specialists. Accordingly, there is a need to reconsider the allocation system for health professionals within the country instead of increasing the overall number of acceptance quota in training positions. PMID- 29417077 TI - Ciprofloxacin Use in Hospitalized Children: Approved or Off-label? AB - Objective: Fluoroquinolones are not routinely used as the first-line antimicrobial therapy in pediatrics. The American Academy of Pediatrics (AAP) and the United States Food and Drug Administration (FDA) approved fluoroquinolones on certain indications in children. The aim of this study was to evaluate to what extent and how ciprofloxacin is used on approved indication or as off-label. Besides, dose adequacy and treatment duration were assessed. Methods: In a 10 month observational study, all children receiving systemic ciprofloxacin were assessed. We classified ciprofloxacin prescription to an AAP/FDA or off-label indication. The off-label prescriptions were further categorized to justified and unjustified therapy subgroups. The AAP/FDA category and the justified subgroup constituted the appropriate prescriptions. Findings: During the study period, 32 patients were prescribed ciprofloxacin. In general, 37% (12) of prescriptions determined to be appropriate. Of the appropriate prescriptions, 7 were AAP/FDA approved indications. Children with Crohn's disease with abdominal abscess and children with infectious bloody diarrhea constituted the off-label; justified therapy subgroup. Unjustified prescriptions mainly occurred in the presence of a suitable alternative antibiotic for ciprofloxacin. Mean +/- SD of ciprofloxacin dose (mg/kg/day) and duration (days) were 21.25 +/- 6.35 and 13.56 +/- 8.48, respectively. Of the appropriate prescriptions, 41% were underdosed. Underdosing was more encountered in patients with cystic fibrosis. Duration of treatment of the appropriate prescriptions was determined to be appropriate. Conclusion: The majority of children were receiving ciprofloxacin off-label and in an inappropriate manner. This issue emphasizes that antimicrobial stewardship program on ciprofloxacin use in pediatric hospitals should be implemented. Further studies evaluating clinical and microbiological outcomes of these programs in children are needed. PMID- 29417078 TI - Efficacy of Intense-pulsed Light Therapy with Topical Benzoyl Peroxide 5% versus Benzoyl Peroxide 5% Alone in Mild-to-moderate Acne Vulgaris: A Randomized Controlled Trial. AB - Objective: Acne vulgaris is a disease of pilosebaceous unit with multifactorial pathogenesis and threats patients' social functioning. There is a growing research to find faster, more effective, and easy to use treatments. The aim of this study is to evaluate the efficacy of benzoyl peroxide 5% (BP) with and without concomitant intense-pulsed light (IPL) therapy in mild-to-moderate acne vulgaris. Methods: In this controlled trial, 58 eligible patients with mild-to moderate acne and Fitzpatrick skin phototype III and IV were randomly allocated to two groups. All patients were asked to use a thin layer of BP every night. The IPL therapy was administered at the end of first, 2nd, and 3rd months. Acne Global Severity Scale (AGSS), Acne Severity Index (ASI), and total lesion counting (TLC) along with patient satisfaction were recorded. Patients were also examined 1 month after the final therapeutic visit. Findings: The IPL group showed greater reduction in AGSS (P < 0.001) and TLC (P = 0.005) than the control group. However, the difference in ASI was not significant (P = 0.12). Patients in IPL groups were more satisfied than control group (P < 0.001). Conclusion: Adding IPL to BP can result better response to BP alone. In acne treatment, combination therapy such as IPL and other topical agents should be kept in mind. PMID- 29417080 TI - New Indications for Dabigatran: A Suggestion from a Drug Use Evaluation Study. AB - Objective: Dabigatran etexilate is a novel oral anticoagulant with several advantages over warfarin such as no need for routine monitoring and fewer drug interactions. This drug was added to our hospital's formulary in 2012. The objective of this study was to assess the rational drug use of dabigatran at a large teaching hospital. Methods: A prospective cross-sectional study was performed from November to June 2015 at Alzahra teaching hospital, Isfahan, Iran. All patients who received at least one dose of dabigatran were eligible for inclusion. Data were collected on patient demographics, indication, dosing regimen, adverse events, concurrent anticoagulant therapy, and laboratory data (including renal function). Findings: A total of sixty patients were included in our study. The majority of patients (n = 40, 66.7%) was prescribed dabigatran for deep vein thrombosis prophylaxis. Only one patient received dabigatran with appropriate indication, dose, and duration. Thirty-six (60%) of our patients had thrombocytopenia at the time of dabigatran initiation. We also detected that ten patients (16.7%) received this drug for heparin-induced thrombocytopenia (HIT). In 32 patients, platelet levels increased after dabigatran initiation. Only seven patients received the appropriate dose of dabigatran (regarding both indication and renal function). Conclusion: Unlabeled use and incorrect dosing of dabigatran in this study emphasize the need to develop a hospital protocol for dabigatran use within our facility. We suggest proper education of clinicians about novel drugs, pharmacist interventions, and further studies about the safety and efficacy of dabigatran for the new indication (such as HIT). PMID- 29417079 TI - Prescription Pattern Analysis of Nonsteroidal Anti-inflammatory Drugs in the Northeastern Iranian Population. AB - Objective: Inappropriate nonsteroidal anti-inflammatory drugs (NSAIDs) therapy is a common cause of actual and potential adverse effects, such as bleeding and gastrointestinal ulceration, which exacerbates the patient's medical condition and might even be life threatening. We aimed to evaluate and analyze the prescription pattern of NSAIDs in Northeastern Iranian population and also provide suggestions for a more rational prescription behavior for such drugs. Methods: In this cross-sectional retrospective study, pattern of 1-year prescriptions was inspected based on 9.3 million prescriptions from two insurance companies. Type of NSAIDs, all dispensed doses and the number of NSAIDs ordered per prescription, and the route of administration for each patient were extracted from the databases. The prescription pattern of NSAIDs was analyzed seasonally. Findings: Out of 9,303,585 prescriptions, 19.3% contained at least one NSAID. Diclofenac was the most commonly prescribed NSAID (49.21%). At least two NSAIDs were simultaneously prescribed in 7% of prescriptions. General practitioners prescribed NSAIDs more frequently (67%) than specialists. Orthopedic surgeons and internists more frequently prescribed NSAIDs in comparison with other physicians (6% and 4%, respectively). Gastroprotective agents (GPAs) were coprescribed to only 7.62% of prescriptions. Conclusion: The frequency of NSAIDs prescription was relatively high in Northeast of Iran. A significant number of prescriptions were associated with irrational prescribing in both coadministration of NSAIDs and GPAs and NSAIDs combination. A strategy must be developed and implemented for prescribing and rational use of medications, e.g., continuing medical education regarding the potential risks of NSAIDs, importance of their appropriate and rational use, and necessity of appropriate prescription writing regarding both content and indication. PMID- 29417081 TI - Pharmacokinetic Behavior of Phenytoin in Head Trauma and Cerebrovascular Accident Patients in an Iranian Population. AB - Objective: Acute brain injury is one of the leading causes of morbidity and mortality worldwide. Phenytoin has been commonly used as an anticonvulsant agent for the treatment or prophylaxis of seizures following acute brain injury. After a severe head injury, several pharmacokinetic changes occur. The aim of this study is the comparative evaluation of phenytoin serum concentration in patients with traumatic and nontraumatic brain injury (TBI). Methods: This prospective observational study was performed on twenty adult brain injury patients who were admitted to an Intensive Care Unit and required phenytoin for the treatment or prophylaxis of postinjury seizures. For all the patients, phenytoin serum concentration was determined in three scheduled time points. Phenytoin serum concentration and pharmacokinetic parameters were compared between patients with TBI and cerebrovascular accident (CVA). Findings: The Vmaxand Kmwere significantly higher in head trauma (HT) patients than the CVA group. The phenytoin concentration (Cp) and the Cp/dose ratio were significantly higher in the CVA group patients during the first sampling (P < 0.05). The Acute Physiology and Chronic Health Evaluation P (APACHE P) score was significantly lower than the baseline at the end of the study in each group of patients (P < 0.05). In addition, no significant correlation was observed between Vmax, Km, Cp, Cp/dose ratio, and APACHE II scores at the time of sampling. Conclusion: Due to significant differences in phenytoin plasma concentration and pharmacokinetic parameters between HT and CVA patients, close attention must be paid to the pharmacokinetic behavior of phenytoin in the efforts to improve the patient's outcome after a severe HT. PMID- 29417082 TI - Comparison of Subacromial Ketorolac Injection versus Corticosteroid Injection in the Treatment of Shoulder Impingement Syndrome. AB - Objective: Subacromial impingement syndrome is the most common cause of shoulder pain and restriction in range of motion in the world. The aim of this study was to compare the efficacy of subacromial injection of ketorolac with the injection of corticosteroid for the treatment of subacromial impingement syndrome. Methods: A total of forty patients were randomly allocated into two groups. Group A received 40 mg of methylprednisolone and Group B received 60 mg of ketorolac as a subacromial injection along with lidocaine. Each patient was evaluated in terms of visual analog scale (VAS) for evaluating pain and Constant's score for function evaluation (pain, activity level, and range of motion with standard goniometry). The patients were re-examined 1 and 3 months after intervention. All the patients educated for simple home exercise. Findings: At 1 and 3 months of follow-up, both treatment arms resulted in an increased range of motion and decreased pain. The difference between the groups was not statistically significant (P > 0.05). In ketorolac group, mean pre- and post-treatment (at 12 weeks) VAS scores were 8.6 (range, 3-9) and 4.5 (range 2-4), respectively. In steroid group, mean pre- and post-treatment (at 12 weeks) VAS scores were 8.3 (range, 3-10) and 3.9 (range, 0-7), respectively. The difference was statistically significant within groups at baseline and 1 (P < 0.001) and 3 (P < 0.001) months after the injection. Conclusion: Subacromial injection of ketorolac has an equivalent outcome to subacromial injection of corticosteroid. The use of ketorolac injections can substantially decrease the pain and increase the range of motion of the shoulder and could be a reasonable alternative in case of corticosteroid contraindications. PMID- 29417083 TI - The Efficacy of Crocin of Saffron (Crocus sativus L.) on the Components of Metabolic Syndrome: A Randomized Controlled Clinical Trial. AB - Objective: Metabolic syndrome is a set of cardiac risk factors with increased risk of chronic diseases. The aim of this study is to evaluate the efficacy of crocin of saffron on metabolic syndrome. Methods: This double-blind, randomized clinical trial was conducted on metabolic syndrome patients who were randomly assigned to crocin of saffron or control (placebo) groups. The intervention group received 100 mg/day crocin tablets (a constituent of saffron) for 6 weeks. Then, the changes in metabolic syndrome component were compared between two groups. The trial was registered in the Iranian Registry of Clinical Trials. Data were entered to SPSS 15. Chi-square, Fisher's exact, paired t-test, and independent t test were used to analyze data. P < 0.05 was defined as statistical significant level. Findings: Totally, 48 patients included in the trial (24 intervention and 24 placebo participants). There were significant reductions from baseline measurements in the levels of total cholesterol (P < 0.001) and triglyceride (P = 0.003) after the 6-week crocin administration. However, this decrease in lipid profile was not significant when compared with placebo group. There was no significant change in other laboratory values, blood pressure, and anthropometric measures. Conclusion: The present study indicated that the dose of about 100 mg crocin of saffron was well tolerated and has no complication for 6 weeks of oral administration. However, the dosage used in our study had no effect on metabolic syndrome. Further studies are required to assess this effect with the higher dosages of crocin as well as long time effects of its administration on metabolic syndrome patients. PMID- 29417084 TI - Comparing the Efficacy of Low Dose and Conventional Dose of Oral Isotretinoin in Treatment of Moderate and Severe Acne Vulgaris. AB - Objective: This study was conducted to compare the effect of low-dose isotretinoin with its conventional dose in patients with moderate and severe acne. Methods: This was a clinical trial conducted on 60 male and female patients with moderate and severe acne vulgaris. The patients were divided into two treatment groups: 0.5 mg/kg/day isotretinoin capsule and low-dose isotretinoin capsule (0.25 mg/kg/day). Patients in both groups received 6-month treatment. At the end of the 6th month and 12th month (6 months after the end of the treatment), they were examined again, and their improvement was determined and compared. Findings: The average severity of acne in the two treatment groups did not differ significantly within any of the study periods. The most common side effects were nose dryness in the low-dose group (17%) and hair thinning and loss in the conventional-dose group (33.2%), although all the patients had dry lips. Conclusion: According to the same severity of the acne in two groups in different study periods, as well as fewer side effects and more patients' satisfaction, the low-dose isotretinoin can be considered in the treatment of acne. PMID- 29417085 TI - In silico design and expression of a novel fusion protein of HBHA and high antigenic region of FAP-P of Mycobacterium avium subsp. paratuberculosis in Pichia pastoris. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of Johne's disease in ruminants and there has been a shift in the public health approach to MAP and human diseases like Crohn's disease. The prevention of infection by MAP in ruminants is thought to deter the high impact of economic losses in the level of dairy industry and possible spreading of this pathogen in dairy products. The present study was done to investigate the construction and expression of the soluble form of a novel fusion protein, consisting of Heparin binding hemagglutinin (HBHA) and high antigenic region of Fibronectin Attachment Protein-P (FAP-P), in order to introduce as a Th1 inducer subunit vaccine against MAP. HBHA is a mycobacterial adhesin and it has been demonstrated that a HBHA specific IFN-gamma response, in latent M. tuberculosis infection, depends on the methylation of the antigen. Further, FAP-P induces Th1 polarization. Because methylation of HBHA was not performed in E. coli, Pichia pastoris was chosen as the host. The desired fusion protein had a similar 3D structure to that of HBHA with its native form and post-translational methylation in C-terminal. Hence, the uptake of the purified fusion protein will be done by M cells because of HBHA, and cell-mediated immunity will be induced because of both antigens. Eventually, successful construction and expression of the newly-designed chimeric protein under the mentioned conditions is reported in this article. PMID- 29417086 TI - Biotic elicitation for scopolamine production by hairy root cultures of Datura metel. AB - The (-)-hyoscyamine, atropine and scopolamine (hyoscine) are three valuable tropane alkaloids while scopolamine is the most important member of this group for the pharmaceutical industry due to its higher demand compared to hyoscyamine and atropine. Scopolamine is an anticholinergic reagent with several therapeutic applications. In the current study, the hairy roots culture of Daturametel was used as an advantageous method for production of scopolamine. The hairy roots are formed by Agrobacterium rhizogenes and have genetic stability, high growth rate and lateral branching. In this study, the effect of Bacillus cereus and Staphylococcus aureus as biotic elicitors on the production of scopolamine in D.metel hairy roots was investigated. The amount of scopolamine in the hairy roots was detected by HPLC analysis and compared with control samples after 0, 12 and 24 hours. Results showed that, B. cereus and S. aureus enhanced scopolamine production in the culture while the atropine content was decreased. Although in the control samples with no bacterial elicitation no scopolamine was detected, elicitation by B. cereus caused production of scopolamine and about 0.03 gram and 0.017 gram of it was detected in 100 gram dried D.metel hairy roots after 12 and 24 hours respectively. In S. aureus elicited hairy roots, scopolamine was not produced after 12 hours. However, about 0.025 gram of this tropane alkaloid was detected in 100 gram dried hairy roots after 24 hours. In conclusion, S. areus and B. cereus induced the scopolamine production in D. metel hairy roots. PMID- 29417087 TI - Fundamentals of Presbyopia: visual processing and binocularity in its transformation. AB - Background: The accommodation has considerable interactions with the pupil response, vergence response and binocularity. The transformation of visual reception processing and the changes of the binocular cooperation during the presbyopia development are still poorly studied. So, the regularities of visual system violation in the presbyopia formation need to be characterized. This study aims to reveal the transformation of visual reception processing and to determine the role of disturbances in binocular interactions in presbyopia formation. Methods: This study included 60 people with emmetropic refraction, uncorrected distance visual acuity 1.0 or higher (decimal scale), normal color perception, without concomitant ophthalmopathology. The first group consisted of 30 people (from 18 to 27 years old) without presbyopia, the second cohort comprised 30 patients (from 45 to 55 years old) with presbyopia. The eyeball anatomy and optics were evaluated using ultrasound biomicroscopy, aberrometry, and pupillometry. The functional state of the visual system was investigated under monocular and binocular conditions. The registration of the disparate fusional reflex limits was performed by the original technic using a diploptic device which facilitated investigation of the binocular interaction under natural conditions without the accommodation response, but with the different vergence load. The disparate fusional reflex was analyzed using the proximal and distal fusion borders, and the convergence and divergence fusion borders. The calculation of the area of binocularity field was performed in cm2. Results: The presbyopia formation is characterized by a change in an intraocular anatomy, optics, visual processing, and binocularity. The processes of binocular interaction inhibition make a significant contribution to the misalignment of the visual perception. The modification of the proximal, distal and convergence fusion borders was determined. It was revealed that 87% of the presbyopic patients had binocularity shortage, whereas the reduction of binocularity field area in extreme grade was seen in 6% of cases. Conclusions: The presbyopia formation is accompanied by a significant reorganization of the visual system activity and by the creation of the new visual processing interactions. These data may be useful in presbyopia surgery. PMID- 29417088 TI - The art of nomograms. AB - Background: To retrospectively analyse strategies for adjusting refractive surgery plans with reference to the preoperative manifest refraction. Methods: We constructed seven nomograms based on the refractive outcomes (sphere, cylinder, axis [SCA]) of 150 consecutive eyes treated with laser in situ keratomileusis for myopic astigmatism. We limited the initial data to the SCA of the manifest refraction. All nomograms were based on the strategy: if for x diopters (D) of attempted metric, y D is achieved; we can reverse this sentence and state for achieving y D of change in the metric, x D will be planned. The effects of the use of plus or minus astigmatism notation, spherical equivalent, sphere, principal meridians notation, cardinal and oblique astigmatism, and astigmatic axis were incorporated. Results: All nomograms detected subtle differences in the spherical component (p < 0.0001). Nomograms 5 and 7 (using power vectors) and 6 (considering axis shifts) detected significant astigmatic differences (nomogram 5, p < 0.001; nomogram 6, p < 0.05; nomogram 7, p < 0.005 for cardinal astigmatism, p = 0.1 for oblique astigmatism). We observed mild clinically relevant differences (~ 0.5 D) in sphere or astigmatism among the nomograms; differences of ~ 0.25 D in the proposals for sphere or cylinder were not uncommon. All nomograms suggested minor improvements versus actual observed outcomes, with no clinically relevant differences among them. Conclusions: All nomograms anticipated minor improvements versus actual observed outcomes without clinically relevant differences among them. The minimal uncertainties in determining the manifest refraction (~ 0.6 D) are the major limitation to improving the accuracy of refractive surgery nomograms. PMID- 29417089 TI - Social Support, Sexual Violence, and Transactional Sex Among Female Transnational Migrants to South Africa. AB - Objectives: To examine the relationship between sexual violence and transactional sex and assess the impact of social support on this relationship among female transnational migrants in Cape Town, South Africa. Methods: In 2012 we administered a behavioral risk factor survey using respondent-driven sampling to transnational migrant women aged between 16 and 39 years, born outside South Africa, living in Cape Town, and speaking English, Shona, Swahili, Lingala, Kirundi, Kinyarwanda, French, or Somali. Results: Controlling for study covariates, travel-phase sexual violence was positively associated with engagement in transactional sex (adjusted prevalence ratio [APR] = 1.38; 95% confidence interval [CI] = 1.07, 1.77), and social support was shown to be a protective factor (APR = 0.84; 95% CI = 0.75, 0.95). The interaction of experienced sexual violence during migration and social support score was APR = 0.85 (95% CI = 0.66, 1.10). In the stratified analysis, we found an increased risk of transactional sex among the low social support group (APR = 1.56; 95% CI = 1.22, 2.00). This relationship was not statistically significant among the moderate or high social support group (APR = 1.04; 95% CI = 0.58, 1.87). Conclusions: Programs designed to strengthen social support may reduce transactional sex among migrant women after they have settled in their receiving communities. PMID- 29417090 TI - Real-time Analysis of Auxin Response, Cell Wall pH and Elongation in Arabidopsis thaliana Hypocotyls. AB - The rapid auxin-triggered growth of the Arabidopsis hypocotyls involves the nuclear TIR1/AFB-Aux/IAA signaling and is accompanied by acidification of the apoplast and cell walls (Fendrych et al., 2016). Here, we describe in detail the method for analysis of the elongation and the TIR1/AFB-Aux/IAA-dependent auxin response in hypocotyl segments as well as the determination of relative values of the cell wall pH. PMID- 29417091 TI - Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. AB - Objective: To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs). Methods: We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup. Results: The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis. Conclusions: Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases. PMID- 29417092 TI - Cognitive Behavioral Therapy for Children with Dental Anxiety: A Randomized Controlled Trial. AB - Dental anxiety affects approximately 9% of children and is associated with poor oral health, pain, and psychosocial problems. The objective of this study was to investigate the efficacy of cognitive behavioral therapy (CBT) for children with dental anxiety in specialist pediatric dentistry. The study used a parallel-group superiority randomized controlled trial design. The primary outcome measure was the behavioral avoidance test; assessors were blind to treatment allocation. Participants were 8 boys and 22 girls 7 to 18 y old (mean +/- SD, 10 +/- 3.1). Children fulfilling the diagnostic criteria for dental anxiety were randomized to CBT (n = 13) or treatment as usual (n = 17), such as various sedation methods. Psychologists provided 10 h of CBT based on a treatment manual. Treatments were conducted in a naturalistic real-world clinical setting. Assessments were conducted before the treatment, 3 mo after the start of treatment, and at 1-y follow-up. The analyses of the primary outcome measure by repeated-measures analysis of variance and independent t test showed that children receiving CBT made superior, statistically significant improvements at follow-up (16.8 +/- 2.4) compared with treatment as usual (11.4 +/- 3.1, P < 0.01). A large between-group effect size (Cohen's d = 1.9) was found. Following treatment, 73% of those in the CBT group managed all stages of the dental procedures included in the behavioral avoidance test compared with 13% in the treatment-as-usual group. Furthermore, 91% in the CBT group compared with 25% in the treatment-as-usual group no longer met the diagnostic criteria for dental anxiety at the 1-y follow-up according to the secondary outcome measure. Measures of dental anxiety and self-efficacy showed larger improvements in the CBT group compared with controls. We conclude that CBT is an efficacious treatment for children and adolescents with dental anxiety and should be made accessible in pediatric dentistry (ClinicalTrials.gov: NCT01798355). Knowledge transfer statement: The results of this study can be used by decision makers and clinicians when planning to implement evidence-based treatment in pediatric dentistry and give children and adolescents access to methods for treating dental anxiety. The results can also be used by parents of children with dental anxiety when asking dentists to cooperate with psychologists using cognitive behavioral therapy. PMID- 29417093 TI - Does the University-Industry Link Affect Solving Challenges of the Job Market? Lessons From Teacher Education and the Ministry of Education in Malawi. AB - About half of the secondary school teachers in Malawi are professionally unqualified. Furthermore, the net enrolment of eligible pupils in secondary schools is at 36% per year. Hence, this study sought to establish factors affecting access to quality and relevant secondary education in Malawi with reference to coordination, collaboration, and feedback between secondary school teacher education institutions and the Ministry of Education. Officials from the Ministry of Education and secondary school teacher training colleges participated in the study. Findings suggest that there is weak collaboration, coordination, and feedback between teacher training institutions and the Ministry of Education which is affecting the quality and relevance of education in Malawi. The study has also established that the weak linkage has resulted into perceived mismatches between expectations of the ministry and those of the education institutions about the problem in question. Theoretical and practical implications of this study are discussed in this article. PMID- 29417095 TI - Knockdown of Laminin gamma-3 (Lamc3) impairs motoneuron guidance in the zebrafish embryo. AB - Background: Previous work in the zebrafish embryo has shown that laminin gamma-3 ( lamc3) is enriched in endothelial cells marked by expression of fli1a, but the role of Lamc3 has been unknown. Methods: We use antisense morpholino oligonucleotides, and CRISPR/Cas9 mutagenesis of F0 embryos, to create zebrafish embryos in which lamc3 expression is compromised. Transgenic imaging, immunofluorescence, and in situ hybridisation reveal that Lamc3 loss-of-function affects the development of muscle pioneers, endothelial cells, and motoneurons. Results: Lamc3 is enriched in endothelial cells during zebrafish development, but it is also expressed by other tissues. Depletion of Lamc3 by use of antisense morpholino oligonucleotides perturbs formation of the parachordal chain and subsequently the thoracic duct, but Lamc3 is not required for sprouting of the cardinal vein. F0 embryos in which lamc3 expression is perturbed by a CRISPR/Cas9 approach also fail to form a parachordal chain, but we were unable to establish a stable lamc3 null line. Lamc3 is dispensable for muscle pioneer specification and for the expression of netrin-1a in these cells. Lamc3 knockdown causes netrin-1a up-regulation in the neural tube and there is increased Netrin-1 protein throughout the trunk of the embryo. Axonal guidance of rostral primary motoneurons is defective in Lamc3 knockdown embryos. Conclusions: We suggest that knockdown of Lamc3 perturbs migration of rostral primary motoneurons at the level of the horizontal myoseptum, indicating that laminin gamma3 plays a role in motoneuron guidance. PMID- 29417096 TI - The effectiveness and safety of antifibrinolytics in patients with acute intracranial haemorrhage: statistical analysis plan for an individual patient data meta-analysis. AB - Introduction: The Antifibrinolytic Trialists Collaboration aims to increase knowledge about the effectiveness and safety of antifibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of antifibrinolytics for acute intracranial haemorrhage. Methods: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42016052155). We will conduct an individual patient data meta-analysis of randomised controlled trials with 1000 patients or more assessing the effects of antifibrinolytics in acute intracranial haemorrhage. We will assess the effect on two co-primary outcomes: 1) death in hospital at end of trial follow-up, and 2) death in hospital or dependency at end of trial follow-up. The co-primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of antifibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of antifibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. Conclusions: This IPD meta-analysis will examine important clinical questions about the effects of antifibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice. PMID- 29417094 TI - Fine-scale spatial and temporal heterogeneities in insecticide resistance profiles of the malaria vector, Anopheles arabiensis in rural south-eastern Tanzania. AB - Background: Programmatic monitoring of insecticide resistance in disease vectors is mostly done on a large scale, often focusing on differences between districts, regions or countries. However, local heterogeneities in residual malaria transmission imply the need for finer-scale data. This study reports small-scale variations of insecticide susceptibility in Anopheles arabiensis between three neighbouring villages across two seasons in Tanzania, where insecticidal bed nets are extensively used, but malaria transmission persists. Methods: WHO insecticide susceptibility assays were conducted on female and male An. arabiensis from three proximal villages, Minepa, Lupiro, and Mavimba, during dry (June-December 2015) and wet (January-May 2016) seasons. Adults emerging from wild-collected larvae were exposed to 0.05% lambda-cyhalothrin, 0.05% deltamethrin, 0.75% permethrin, 4% DDT, 4% dieldrin, 0.1% bendiocarb, 0.1% propoxur, 0.25% pirimiphos-methyl and 5% malathion. A hydrolysis probe assay was used to screen for L1014F ( kdr-w) and L1014S ( kdr-e) mutations in specimens resistant to DDT or pyrethroids. Synergist assays using piperonly butoxide (PBO) and triphenol phosphate (TPP) were done to assess pyrethroid and bendiocarb resistance phenotypes. Results: There were clear seasonal and spatial fluctuations in phenotypic resistance status in An. arabiensis to pyrethroids, DDT and bendiocarb. Pre-exposure to PBO and TPP, resulted in lower knockdown rates and higher mortalities against pyrethroids and bendiocarb, compared to tests without the synergists. Neither L1014F nor L1014S mutations were detected. Conclusions: This study confirmed the presence of pyrethroid resistance in An. arabiensis and showed small-scale differences in resistance levels between the villages, and between seasons. Substantial, though incomplete, reversal of pyrethroid and bendiocarb resistance following pre exposure to PBO and TPP, and absence of kdr alleles suggest involvement of P450 monooxygenases and esterases in the resistant phenotypes. We recommend, for effective resistance management, further bioassays to quantify the strength of resistance, and both biochemical and molecular analysis to elucidate specific enzymes responsible in resistance. PMID- 29417097 TI - Segmentation of Craniomaxillofacial Bony Structures from MRI with a 3D Deep Learning Based Cascade Framework. AB - Computed tomography (CT) is commonly used as a diagnostic and treatment planning imaging modality in craniomaxillofacial (CMF) surgery to correct patient's bony defects. A major disadvantage of CT is that it emits harmful ionizing radiation to patients during the exam. Magnetic resonance imaging (MRI) is considered to be much safer and noninvasive, and often used to study CMF soft tissues (e.g., temporomandibular joint and brain). However, it is extremely difficult to accurately segment CMF bony structures from MRI since both bone and air appear to be black in MRI, along with low signal-to-noise ratio and partial volume effect. To this end, we proposed a 3D deep-learning based cascade framework to solve these issues. Specifically, a 3D fully convolutional network (FCN) architecture is first adopted to coarsely segment the bony structures. As the coarsely segmented bony structures by FCN tend to be thicker, convolutional neural network (CNN) is further utilized for fine-grained segmentation. To enhance the discriminative ability of the CNN, we particularly concatenate the predicted probability maps from FCN and the original MRI, and feed them together into the CNN to provide more context information for segmentation. Experimental results demonstrate a good performance and also the clinical feasibility of our proposed 3D deep-learning based cascade framework. PMID- 29417098 TI - Simultaneous drug delivery and cellular imaging using graphene oxide. AB - Graphene oxide (GO), a derivative of graphene, and its related nanomaterials have attracted much attention in recent years due to the excellent biocompatibility and large surface area of GO with abundant oxygen functional groups, which further enable it to serve as a nano-bio interface. Herein, we demonstrate the induction of blue fluorescence in GO suspensions via a mild thermal annealing procedure. Additionally, this procedure preserves the oxygen functional groups on the graphene plane which enables the conjugation of cancer drugs without obvious cytotoxicity. Consequently, we demonstrate the capability of GO to simultaneously play the dual-role of a: (i) cellular imaging agent and (ii) drug delivery agent in CT26 cancer cells without the need for additional fluorescent protein labeling. Our method offers a simple, controllable strategy to tune and enhance the fluorescence property of GO, which shows potential for biomedical applications and fundamental studies. PMID- 29417099 TI - Arrested disproportionation in trivalent, mononuclear, and non-metallocene complexes of Zr(iii) and Hf(iii). AB - Reduction of the group 4 transition metal precursors [(PN)2MCl2] (M = Zr (1), and Hf (2)); PN- = (N-(2-(diisopropylphosphino)-4-methylphenyl)-2,4,6 trimethylanilide), both readily prepared by transmetallation of 2 LiPN with [MCl4(THF)2], with a slight excess of KC8, resulted in the isolation of the trivalent complexes [(PN)2MCl] (M = Zr (3), and Hf (4)). Complexes 1-4 were all identified by solid-state X-ray diffraction analysis, whereas in the case of 3 and 4 low temperature X-band EPR spectroscopy allowed for the identification of these metal-centered d1 radicals. A comparison with the isostructural and isoelectronic but more stable [(PN)2TiCl] is also presented. PMID- 29417100 TI - Monitoring photo-induced population dynamics in metastable linkage isomer crystals: a crystallographic kinetic study of [Pd(Bu4dien)NO2]BPh4. AB - We present a detailed kinetic study of photo-induced solid state linkage isomerism in the compound [Pd(Bu4dien)NO2]BPh4 (Bu4dien = N,N,N',N' tetrabutyldiethylenetriamine) using in situ photocrystallographic techniques. We explore the key variables that influence the photoconversion and develop a detailed kinetic model for the excitation and decay processes and the temperature dependence of the conversion rates. We show that by varying the temperature the lifetime of the excited state can be varied over orders of magnitude, making these systems ideal test cases for the development of new time-resolved X-ray diffraction methods. The kinetic model is used to build a numerical-simulation tool, which we use to explore the practicalities of pump-probe single-crystal diffraction experiments with minute and second time-resolution. PMID- 29417101 TI - Ionic liquids in cross-coupling reactions: "liquid" solutions to a "solid" precipitation problem. AB - To alleviate the problem of solid salt precipitation when using inorganic bases in cross-coupling reactions, basic anions were combined with the trihexyl(tetradecyl)phosphonium ([P66614]+) cation to ensure an ionic liquid byproduct. If the starting base is also an ionic liquid, as is the case for [P66614][OH].4MeOH, it can be used as both base and solvent. PMID- 29417102 TI - Molecular dynamics simulations of energy dissipation and non-thermal diffusion on amorphous solid water. AB - Molecules in space are synthesized via a large variety of gas-phase reactions, and reactions on dust-grain surfaces, where the surface acts as a catalyst. Especially, saturated, hydrogen-rich molecules are formed through surface chemistry where the interstellar grains act as a meeting place and absorbing energy. Here we present the results of thousands of molecular dynamics simulations to quantify the outcome of an energy dissipation process. Admolecules on top of an amorphous solid water surface have been given translational energy between 0.5 and 5 eV. Three different surface species are considered, CO2, H2O and CH4, spanning a range in binding energies, number of internal degrees of freedom and molecular weight. The results are compared against a previous study using a crystalline water ice surface. Possible outcomes of a dissipation process are adsorption - possibly after long-range diffusion-, desorption and desorption of a surface molecule. The three admolecules were found to bind at different locations on the surface, particularly in terms of height. Water preferably binds on top of the surface, whereas methane fills the nanopores on the surface. This has direct consequences for desorption, travelled distance, and kick-out probabilities. The admolecules are found to frequently travel several tens of angstroms before stabilizing on a binding site, allowing follow-up reactions en route. We present kick-out probabilities and we have been able to quantify the desorption probability which depends on the binding energy of the species, the translational excitation, and a factor that accounts for difference in binding site height. We provide expressions that can be incorporated in astrochemical models to predict grain surface formation and return into the gas phase of these products. PMID- 29417103 TI - On the regioselectivity of the Diels-Alder cycloaddition to C60 in high spin states. AB - Controlling the regioselectivity in the exohedral functionalization of fullerenes and endohedral metallofullerenes is essential to produce specific desired fullerene derivatives. In this work, using density functional theory (DFT) calculations, we show that the regioselectivity of the Diels-Alder (DA) cycloaddition of cyclopentadiene to 2S+1C60 changes from the usual [6,6] addition in the singlet ground state to the [5,6] attack in high spin states of C60. Changes in the aromaticity of the five- and six-membered rings when going from singlet to high spin C60 provide a rationale to understand this regioselectivity change. Experimentally, however, we find that the DA cycloaddition of isoindene to triplet C60 yields the usual [6,6] adduct. Further DFT calculations and computational analysis give an explanation to this unanticipated experimental result by showing the presence of an intersystem crossing close to the formed triplet biradical intermediate. PMID- 29417104 TI - Gas phase kinetics of the OH + CH3CH2OH reaction at temperatures of the interstellar medium (T = 21-107 K). AB - Ethanol, CH3CH2OH, has been unveiled in the interstellar medium (ISM) by radioastronomy and it is thought to be released into the gas phase after the warm up phase of the grain surface, where it is formed. Once in the gas phase, it can be destroyed by different reactions with atomic and radical species, such as hydroxyl (OH) radicals. The knowledge of the rate coefficients of all these processes at temperatures of the ISM is essential in the accurate interpretation of the observed abundances. In this work, we have determined the rate coefficient for the reaction of OH with CH3CH2OH (k(T)) between 21 and 107 K by employing the pulsed and continuous CRESU (Cinetique de Reaction en Ecoulement Supersonique Uniforme, which means Reaction Kinetics in a Uniform Supersonic Flow) technique. The pulsed laser photolysis technique was used for generating OH radicals, whose time evolution was monitored by laser induced fluorescence. An increase of approximately 4 times was observed for k(21 K) with respect to k(107 K). With respect to k(300 K), the OH-reactivity at 21 K is enhanced by two orders of magnitude. The obtained T-expression in the investigated temperature range is k(T) = (2.1 +/- 0.5) * 10-11 (T/300 K)-(0.71+/-0.10) cm3 molecule-1 s-1. In addition, the pressure dependence of k(T) has been investigated at several temperatures between 21 K and 90 K. No pressure dependence of k(T) was observed in the investigated ranges. This may imply that this reaction is purely bimolecular or that the high-pressure limit is reached at the lowest total pressure experimentally accessible in our system. From our results, k(T) at usual IS temperatures (~10-100 K) is confirmed to be very fast. Typical rate coefficients can be considered to range within about 4 * 10-11 cm3 molecule-1 s-1 at 100 K and around 1 * 10-10 cm3 molecule-1 s-1 at 20 K. The extrapolation of k at the lowest temperatures of the dense molecular clouds of ISM is also discussed in this paper. PMID- 29417105 TI - Nanopore-mediated ultrashort laser-induced formation and erasure of volume nanogratings in glass. AB - Ultrashort laser nanostructuring of glasses has attracted increasing interest over the last few decades due to numerous applications in three-dimensional nanofabrication, optical data storage, and development of nanofluidic and polarization-sensitive devices. The knowledge of the influence of laser parameters on the nanostructure formation/erasure is still lacking. In this work, laser-induced modifications and mechanisms of glass decomposition in fused silica are numerically investigated. Cavitation is shown to be the primary mechanism responsible for void formation at the center of the heat-affected zone. Multipulse accumulation processes providing higher local temperatures/pressures lead to the rapid formation of cavitation nanopores, lying in the origin of self organized nanogratings. Femtosecond laser-interaction threshold conditions required for nanograting formation/erasure are defined in agreement with the available experimental findings. For this, a detailed multi-physical modeling is performed taking into account laser pulse propagation in nonlinear and dispersive media, electronic relaxation/excitation processes, electron-ion heat transfer and thermal diffusion. Based on the calculated temperatures, classical nucleation theory, viscoelastic energy conservation law and the Rayleigh-Plesset model, threshold conditions leading to nanopore formation, stability and growth are investigated as a function of laser energy, pulse duration and repetition rate. The performed numerical study not only contributes to a better fundamental understanding of ultrashort laser-induced modifications on the nanoscale but should also be helpful in defining the optimal laser parameters for nanostructuring or avoiding nanostructure organization and in developing techniques for nanograting rewriting. PMID- 29417106 TI - Nanoparticle-triggered in situ catalytic chemical reactions for tumour-specific therapy. AB - Tumour chemotherapy employs highly cytotoxic chemodrugs, which kill both cancer and normal cells by cellular apoptosis or necrosis non-selectively. Catalysing/triggering the specific chemical reactions only inside tumour tissues can generate abundant and special chemicals and products locally to initiate a series of unique biological and pathologic effects, which may enable tumour specific theranostic effects to combat cancer without bringing about significant side effects on normal tissues. Nevertheless, chemical reaction-initiated selective tumour therapy strongly depends on the advances in chemistry, materials science, nanotechnology and biomedicine. This emerging cross-disciplinary research area is substantially different from conventional cancer-theranostic modalities in clinics. In response to the fast developments in cancer theranostics based on intratumoural catalytic chemical reactions, this tutorial review summarizes the very-recent research progress in the design and synthesis of representative nanoplatforms with intriguing nanostructures, compositions, physiochemical properties and biological behaviours for versatile catalytic chemical reaction-enabled cancer treatments, mainly by either endogenous tumour microenvironment (TME) triggering or exogenous physical irradiation. These unique intratumoural chemical reactions can be used in tumour-starving therapy, chemodynamic therapy, gas therapy, alleviation of tumour hypoxia, TME-responsive diagnostic imaging and stimuli-responsive drug release, and even externally triggered versatile therapeutics. In particular, the challenges and future developments of such a novel type of cancer-theranostic modality are discussed in detail to understand the future developments and prospects in this research area as far as possible. It is highly expected that this kind of unique tumour specific therapeutics by triggering specific in situ catalytic chemical reactions inside tumours would provide a novel but efficient methodology for benefiting personalized biomedicine in combating cancer. PMID- 29417107 TI - Direct measurement of OH and HO2 formation in R + O2 reactions of cyclohexane and tetrahydropyran. AB - Formation of the key general radical chain carriers, OH and HO2, during pulsed photolytic Cl-initiated oxidation of tetrahydropyran and cyclohexane are measured with time-resolved infrared absorption in a temperature-controlled Herriott multipass cell in the temperature range of 500-750 K at 20 Torr. The experiments show two distinct timescales for HO2 and OH formation in the oxidation of both fuels. Analysis of the timescales reveals striking differences in behavior between the two fuels. In both cyclohexane and tetrahydropyran oxidation, a faster timescale is strongly related to the "well-skipping" (R + O2 -> alkene + HO2 or cyclic ether + OH) mechanism and is expected to have, at most, a weak temperature dependence. Indeed, the fast HO2 formation timescale is nearly temperature independent both for cyclohexyl + O2 and for tetrahydropyranyl + O2 below 700 K. A slower HO2 formation timescale in cyclohexane oxidation is shown to be linked to the sequential R + O2 -> ROO -> alkene + HO2 pathway, and displays a strong temperature dependence mainly from the final step (with energy barrier ~32.5 kcal mol-1). In contrast, the slower HO2 formation timescale in tetrahydropyran oxidation is surprisingly temperature insensitive across all measured temperatures. Although the OH formation timescales in tetrahydropyran oxidation show a temperature dependence similar to the cyclohexane oxidation, the temperature dependence of OH yield is opposite in both cases. This significant difference of HO2 formation kinetics and OH formation yield for the tetrahydropyran oxidation can arise from contributions related to ring-opening pathways in the tetrahydropyranyl + O2 system that compete with the typical R + O2 reaction scheme. This comparison of two similar fuels demonstrates the consequences of differing chemical mechanisms on OH and HO2 formation and shows that they can be highlighted by analysis of the eigenvalues of a system of simplified kinetic equations for the alkylperoxy-centered R + O2 reaction pathways. We suggest that such analysis can be more generally applied to complex or poorly known oxidation systems. PMID- 29417108 TI - Light-initiated reversible conversion of macrocyclic endoperoxides derived from half-sandwich rhodium-based metallarectangles. AB - Although reversible photo-dimerization or oxygenation of anthracene and its derivatives is a common reaction, light-initiated reversible conversion of endoperoxide organometallic frameworks has only rarely been addressed. Herein, a series of tetranuclear organometallic macrocycles, [Cp*2Rh2(MU-C2O4 kappaO)]2(BP4VA)2(OTf)4 (4), [Cp*2Rh2(BiBzIm)]2(BP4VA)2(OTf)4 (5), and [Cp*2Rh2(DHBQ)]2(BP4VA)2(OTf)4 (6), were obtained in good yields from the reactions of the binuclear half-sandwich rhodium precursors [Cp*2Rh2(MU-C2O4 kappaO)Cl2] (1), [Cp*2Rh2(BiBzIm)Cl2] (2), and [Cp*2Rh2(DHBQ)Cl2] (3) with the 9,10-bis((E)-2-(pyrid-4-yl)vinyl)anthracene (BP4VA) ligand. The photochemical reaction of these metallarectangles was investigated by NMR and UV/vis spectroscopy. We have demonstrated that complexes 4, 5, and 6 can be reversibly and nearly quantitatively converted to the macrocyclic endoperoxides 4-O2, 5-O2, and 6-O2. Meanwhile, the structure of the endoperoxide photoproducts was unambiguously confirmed by 1H/13C NMR spectroscopy, IR spectroscopy, elemental analyses, and X-ray crystallography. PMID- 29417109 TI - Three Zn(ii)-based MOFs for luminescence sensing of Fe3+ and Cr2O72- ions. AB - Three zinc metal-organic frameworks (MOFs), {ZnL(chd)}n (1), {[Zn(L)0.5(oba)].DMF.H2O}n (2) and {[Zn(L)0.5(sdb)].H2O}n (3) [L = E,E-2,5 dihexyloxy-1,4-bis-(2-pyridin-vinyl)-benzene; H2chd = 1,4-cyclohexanedicarboxylic acid, H2oba = 4,4'-oxybisbenzoic acid, H2sdb = 4,4'-sulfonyldibenzoic acid], have been hydrothermally synthesized. We explored their applications in detecting ions, and the result shows that they all show highly selective sensing for Fe3+ and Cr2O72- ions. PMID- 29417110 TI - Neuroprotective alpha-cleavage of the human prion protein significantly impacts Cu(ii) coordination at its His111 site. AB - The cellular prion protein (PrPC) is a copper binding protein that undergoes post translational modifications, such as endoproteolytic alpha cleavage, which occurs in the vicinity of the His111 Cu binding site. Alpha cleavage processing of PrPC is considered to be neuroprotective since the cleavage site is located in a region that is key to the conversion of PrPC into the infectious scrapie isoform (PrPSc), yielding a membrane bound C1 fragment of PrPC that still contains His111. In this work, we use hPrP(111-115) fragment as a model peptide to evaluate the impact of alpha cleavage processing of PrPC in its ability to coordinate Cu(ii) ions at His111. By using different spectroscopic techniques such as electronic absorption, circular dichroism, nuclear magnetic resonance, and electron paramagnetic resonance, this study demonstrates that Cu(ii) binding to the cleaved His111 site is highly dependent on Cu and proton concentrations. The imidazole group of His111 and its free NH2 terminus emerge as the main anchoring sites for Cu(ii) coordination, yielding very different complexes from those characterized for the intact His111 site in the full protein. Different Cu(ii) coordination modes that could form with the alpha cleaved PrPC under physiological conditions are identified and characterized. Overall, this study contributes to understand how alpha cleavage processing of PrPC impacts its Cu(ii) binding properties at His111. While the functional implications of Cu binding to the cleaved PrPC remain to be discovered, proteolytic processing of PrPC and its Cu binding features appear to be molecular events that might be strongly linked to its cellular function. PMID- 29417111 TI - Interactions between wine phenolic compounds and human saliva in astringency perception. AB - Astringency is a complex perceptual phenomenon involving several sensations that are perceived simultaneously. The mechanism leading to these sensations has been thoroughly and controversially discussed in the literature and it is still not well understood since there are many contributing factors. Although we are still far from elucidating the mechanisms whereby astringency develops, the interaction between phenolic compounds and proteins (from saliva, oral mucosa or cells) seems to be most important. This review summarizes the recent trends in the protein phenol interaction, focusing on the effect of the structure of the phenolic compound on the interaction with salivary proteins and on methodologies based on these interactions to determine astringency. PMID- 29417112 TI - Versatile synthesis of functionalized beta- and gamma-carbolines via Pd-catalyzed C-H addition to nitriles/cyclization sequences. AB - The first example of versatile synthesis of functionalized beta-carbolines and gamma-carbolines via redox-free Pd-catalyzed C-H addition of indole to nitrile/cyclization sequences is reported. A wide range of functionalized beta carbolines and gamma-carbolines can be prepared from readily accessible indoles and nitriles in good to excellent yields under the optimal conditions. PMID- 29417113 TI - The contradictory effect of the methoxy-substituent in palladium-catalyzed ethylene/methyl acrylate cooligomerization. AB - Two new nonsymmetric bis(aryl-imino)acenaphthene ligands (Ar,Ar'-BIAN) and one symmetric Ar2-BIAN were studied. The three ligands share the presence of at least one methoxy group on one of the two aryl rings. These ligands were used for the synthesis of neutral and monocationic palladium(ii) complexes of general formula [Pd(CH3)Cl(N-N)] and [Pd(CH3)(L)(N-N)][PF6] (N-N = Ar,Ar'-BIAN, Ar2-BIAN; L = CH3CN, dmso). Due to the nonsymmetric nature of the ligands and their coordination to palladium in a nonsymmetric chemical environment, cis and trans isomers are possible for the three series of complexes with Ar,Ar'-BIANs. Both a detailed NMR investigation in solution and the X-ray characterization in the solid state point out that the trans isomer is the preferred species for the neutral derivatives, whereas for the cationic compounds a decrease in the stereoselectivity of the coordination is observed. One of the new Ar,Ar'-BIANs differs from an already reported nonsymmetric alpha-diimine for the replacement, on one aryl ring, of a methyl group with a methoxy substituent, thus allowing a comparison of the structural features of the relevant complexes. The monocationic complexes were tested as precatalysts for the ethylene/methyl acrylate copolymerization under mild reaction conditions. Despite the structural similarities observed in solution with the already known precatalysts, the present compounds demonstrated a remarkable decrease in the productivity values associated with a higher affinity for the polar monomer. PMID- 29417114 TI - The effects of whey and soy proteins on growth performance, gastrointestinal digestion, and selected physiological responses in rats. AB - The objective of this work was to identify the nutritional and physiological effects of commercial soy and whey protein preparations. Wistar rats were fed with soy (S), whey (W), or casein (C) preparations as the sole dietary protein source. The nitrogen balance, body composition, changes in caecal microbiota, mucosal and bacterial enzyme activities, and allergenic potential of the preparations were analysed. The whey diet elicited greater skeletal muscle anabolism than the soy diet. Rats from the S group had the lowest values of body weight, fat, and lean mass gain. Compared to casein, soy and whey preparations decreased the protein efficiency ratio, increased N in the urine, and triggered the reduction of ammonia levels in the caecum. Changes in beta-glucuronidase and beta-galactosidase activities in the small intestine, caecum, and colon between experimental groups were observed. Significant differences were noted in the total counts of anaerobic bacteria and sulphite reducing bacteria during soy and whey treatments. This probably affected the short chain fatty acid level in caecal digesta resulting in the lowest propionic acid and total putrefactive short chain fatty acid levels during S treatment. Generally, whey preparations are a good choice for rapid bodybuilding (skeletal muscles), whereas soy preparations are more helpful during mass reduction. PMID- 29417115 TI - Evolution of surface catalytic sites on thermochemically-tuned gold-palladium nanoalloys. AB - Nanoscale alloying constitutes an increasingly-important pathway for design of catalysts for a wide range of technologically important reactions. A key challenge is the ability to control the surface catalytic sites in terms of the alloying composition, thermochemical treatment and phase in correlation with the catalytic properties. Herein we show novel findings of the nanoscale evolution of surface catalytic sites on thermochemically-tuned gold-palladium nanoalloys by probing CO adsorption and oxidation using in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) technique. In addition to the bimetallic composition and the support, the surface sites are shown to depend strongly on the thermochemical treatment condition, demonstrating that the ratio of three fold vs. bridge or atop Pd sites is greatly reduced by thermochemical treatment under hydrogen in comparison with that under oxygen. This type of surface reconstruction is further supported by synchrotron high-energy X-ray diffraction coupled to atomic pair distribution function (HE-XRD/PDF) analysis of the nanoalloy structure, revealing an enhanced degree of random alloying for the catalysts thermochemically treated under hydrogen. The nanoscale alloying and surface site evolution characteristics were found to correlate strongly with the catalytic activity of CO oxidation. These findings have significant implications for the nanoalloy-based design of catalytic synergy. PMID- 29417116 TI - New reactivity at the silicon bridge in sila[1]ferrocenophanes. AB - We describe two new types of reactivity involving silicon-bridged [1]ferrocenophanes. In an attempt to form a [1]ferrocenophane with a bridging silyl cation, the reaction of sila[1]ferrocenophane [Fe(eta-C5H4)2Si(H)TMP] (12) (TMP = 2,2,6,6-tetramethylpiperidyl) towards the hydride-abstraction reagent trityl tetrakis(pentafluorophenyl)borate ([CPh3][B(C6F5)4]) was explored. This yielded the unusual dinuclear species [Fe(eta-C5H4)2Si(TMP.H)(eta-C5H3)Fe(eta C5H4)Si(H)TMP][B(C6F5)4] [13][B(C6F5)4] in low yield. The formation of [13]+ is proposed to involve abstraction of hydride from the silicon bridge in 12 with subsequent C-H bond cleavage of a cyclopentadienyl group by the resulting electrophilic transient silyl cation intermediate. We also explored the reaction of dimethylsila[1]ferrocenophane [Fe(eta-C5H4)2SiMe2] (1) with the Au(i) species AuCl(PMe3). This was found to result in addition of the Au-Cl bond across the Cpipso-Si bond to yield the ring-opened species [1'-(chlorodimethylsilyl) ferrocenyl](trimethylphosphine)gold(i), [Fe(C5H4SiMe2Cl){C5H4Au(PMe3)}] (14). This represents the first example of ring-opening addition of a metallocenophane with a reagent possessing a transition metal-halogen bond. PMID- 29417117 TI - Mg2+ incorporated Co-based MOF precursors for hierarchical CNT-containing porous carbons with ORR activity. AB - In this paper, we introduced light and abundant metal magnesium into a cobalt based metal organic framework (Co-MOF, [(CH3)2NH2]2[Co3(bpdc)4].5DMF.4CH3OH) (1, H2bpdc = 4,4'-biphenyldicarboxylic acid, DMF = N,N-dimethylformamide) as a heteroatom to synthesize Mg-Co bimetallic MOFs, namely [(CH3)2NH2]2[MgCo2(bpdc)4].4DMF.5CH3OH (2) and [(CH3)2NH2]2[Mg1.2Co1.8(bpdc)4] 4DMF.4CH3OH.6H2O (3). Based on the formation of a rather low density framework after the introduction of the light Mg2+, such bimetallic MOFs exhibited higher gas adsorption abilities than the isostructural Co-based MOF 1. N2 adsorption measurements demonstrate that the BET surface area of 3 is 305.4 m2 g-1, exhibiting three times that of 1 (104.4 m2 g-1). Significantly, due to the introduction of the low-melting Mg2+, the Mg-Co MOFs could be further utilized as precursors for porous carbons only by calcination at a mild temperature of 600 degrees C which could exhibit a BET surface as high as 712.78 m2 g-1. Furthermore, after post-synthetic modification with a N/S heteroatom at 900 degrees C, the obtained hierarchical carbons exhibit superior activity in the oxygen reduction reaction (ORR) that is comparative to the commercial Pt/C catalyst. TEM results indicate that Co-embedded carbon nanotube (CNT)-containing hierarchically nanoporous carbons have been obtained. This study may offer a new avenue to prepare porous carbons utilizing Mg-containing bimetallic MOFs as sacrificial templates. PMID- 29417118 TI - Occurrence, biological activity and metabolism of 6-shogaol. AB - As one of the main bioactive compounds of dried ginger, 6-shogaol has been widely used to alleviate many ailments. It is also a major pungent flavor component, and its precursor prior to dehydration is 6-gingerol, which is reported to be responsible for the pungent flavor and biological activity of fresh ginger. Structurally, gingerols including 6-gingerol have a beta-hydroxyl ketone moiety and is liable to dehydrate to generate an alpha,beta-unsaturated ketone under heat and/or acidic conditions. The conjugation of the alpha,beta-unsaturated ketone skeleton in the chemical structure of 6-shogaol explicates its higher potency and efficacy than 6-gingerol in terms of antioxidant, anti-inflammatory, anticancer, antiemetic and other bioactivities. Research on the health benefits of 6-shogaol has been conducted and results have been reported recently; however, scientific data are scattered due to a lack of systematic collection. In addition, action mechanisms of the preventive and/or therapeutic actions of 6 shogaol remain obscurely non-collective. Herein, we review the preparations, biological activity and mechanisms, and metabolism of 6-shogaol as well as the properties of 6-shogaol metabolites. PMID- 29417119 TI - Mono- and dinuclear oxidovanadium(v) complexes of an amine-bis(phenolate) ligand with bromo-peroxidase activities: synthesis, characterization, catalytic, kinetic and computational studies. AB - The mono- and dinuclear oxidovanadium(v) complexes [VVO(L1)(Cl)] (1) and [L1VVO(MU2-O)VO(L1)] (2) of ONNO donor amine-bis(phenolate) ligand (H2L1) were readily synthesized by the reaction between H2L1 and VCl3.(THF)3 or VO(acac)2 in MeOH or MeCN, respectively, and then characterized through mass spectroscopy, 1H NMR and FTIR techniques. Both the complexes possess distorted octahedral geometry around each V centre. Upon the addition of 1 equivalent or more acid to a MeCN solution of complex 1, it immediately turned into the protonated form, which might be in equilibrium as: [L1ClVV[double bond, length as m-dash]OH]+ <-> [L1ClVV-OH]+ (in the case of [L1ClVV[double bond, length as m-dash]OH]+ oxo-O is just protonated, whereas in [L1ClVV-OH]+ it is a hydroxo species), with the shift in lambdamax from 610 nm to 765 nm. Similar was the case for complex 2. The complexes 1 and 2 could efficiently catalyze the oxidative bromination of salicylaldehyde in the presence of H2O2 to produce 5-bromo salicylaldehyde as the major product with TONs of 405 and 450, respectively, in the mixed solvent system (H2O : MeOH : THF = 4 : 3 : 2, v/v). The kinetic analysis of the bromide oxidation reaction indicated a first-order mechanism in the protonated peroxidovanadium complex and a bromide ion and limiting first-order mechanism on [H+]. The evaluated kBr and kH values were 5.78 +/- 0.20 and 11.01 +/- 0.50 M-1 s 1 for complex 1 and 6.21 +/- 0.13 and 20.14 +/- 0.72 M-1 s-1 for complex 2, respectively. The kinetic and thermodynamic acidities of the protonated oxido species of complexes 1 and 2 were pKa = 2.55 (2.35) and 2.16 (2.19), respectively, which were far more acidic than those reported by Pecoraro et al. for peroxido-protonation instead of oxido protonation. On the basis of the chemistry observed for these model compounds, a mechanism of halide oxidation and a detailed catalytic cycle are proposed for the vanadium haloperoxidase enzyme and these were substantiated by detailed DFT calculations. PMID- 29417120 TI - Formation of Fe3O4@C/Ni microtubes for efficient catalysis and protein adsorption. AB - In the recent years, the fabrication of functional nanostructures with multicomponent has received considerable attention due to their exceptional properties. Herein, we report a facile approach for the preparation of Fe3O4@C/Ni microtubes, which could be used as both a catalyst and the adsorbents. During the synthetic process, a layer of nickel ion-doped polydopamine (PDA-Ni2+) was polymerized in situ on the surface of the MoO3@FeOOH by an extended stober method using MoO3 microrods as the sacrificing templates. Notably, the PDA-Ni2+ coating and the removal of the MoO3 cores were carried out simultaneously during the coating of the PDA-Ni2+ in an ammonia solution. Then the prepared FeOOH@PDA-Ni2+ microtubes were converted to Fe3O4@C/Ni hybrid microtubes through a pyrolysis with a thermochemical reduction process. The resulting Fe3O4@C/Ni hybrid microtubes were used as a novel catalyst towards the reduction of 4-nitrophenol (4-NP) in the presence of NaBH4. Moreover, they also exhibited highly selective adsorption on His-rich proteins (BHb). Moreover, the Fe3O4@C/Ni hybrid microtubes can be conveniently separated by an external magnetic field due to the presence of Ni and Fe3O4. Furthermore, they show good cyclic stability, which is important for the practical applications. PMID- 29417121 TI - Observation of a low temperature n-p transition in individual titania nanotubes. AB - Manipulating the transport properties of titania nanotubes (NTs) is paramount in guaranteeing the material's successful implementation in various solid state applications. Here we present the unique semiconducting properties of individual titania NTs as revealed from thermoelectric and structural studies performed on the same individual NTs. The NTs were in the anatase phase fabricated by anodic oxidation and doped with intrinsic defects created by reducing the lattice thermally. Despite their polycrystalline nature and nanoscale walls, the doped NTs were found to be 4-5 orders of magnitude more electrically conducting than TiO2 nanowires and thin films, with values approaching the bulk single crystal conductivity. The reason for the high conductivity was found to be the high carrier concentration on the order of 1022 cm-3, which counteracted the low mobility values ~0.006 cm2 V-1 s-1. Furthermore, this high level of carrier concentration transitioned the NTs to a degenerate state, which is the first such example in thermally doped titania NTs. More importantly, our study showed the creation of acceptor states along with donor states in individual nanotubes upon lattice reduction. These acceptor levels were found to be active at low temperatures when donor states were not ionized, shifting the Fermi level (Ef) from the conduction band to the valence band. PMID- 29417122 TI - Encoding matter with regiospecific 12C/13C isotopic labels. AB - Society suffers due to an inability to regulate matter. This study presents a practical tool for the encryption of materials by adjusting the levels of 13C at regiospecific atoms within a molecule to generate a stable-isotopically encoded signature. This system is demonstrated by securing a document by adapting natural product chemistry as an encryption device. This approach delivers a complex signal that would be difficult to intercept due to the need for access to extraction protocols, sophisticated NMR instrumentation and a vital level of prior knowledge. Overall, this discovery offers an important tool to monitor and track valuable entities on our planet. PMID- 29417123 TI - Preferential horizontal growth of tungsten sulfide on carbon and insight into active sulfur sites for the hydrogen evolution reaction. AB - Transition metal dichalcogenides (TMDs) have attracted considerable attention as active electrocatalysts for the hydrogen evolution reaction (HER). Since TMD catalysts are commonly supported on carbon to endow electrical conductivity, understanding the growth behaviour of TMDs on carbon surfaces is crucial, and yet remains to be explored. In this work, we investigated the growth behaviour of tungsten sulfide (WSx) on carbon surfaces inside the confined nanopores. Experimental and computational studies revealed the preferential bonding between the basal planes of WSx and carbon surfaces, as well as the subsequent horizontal growth of WSx. As a result, subnanometer WSx clusters were formed at a low WSx loading, and grew into monolayer WS2 nanoplates with increased WSx loadings. In contrast, a TMD analogue, MoS2, favors edge plane bonding with carbon surfaces and subsequent stacking of nanoplate layers, leading to multilayer MoS2 nanoplates with increased MoS2 loadings. A time-dependent growth of WSx further corroborated the formation of WS2 nanoplates at the expense of ultrasmall WSx nanoclusters. Interestingly, the sample prepared with a short sulfidation time, which was mainly comprised of WSx nanoclusters, showed higher HER activity compared to the sample prepared with a prolonged sulfidation time, which mostly contained WS2 nanoplates. The higher HER activity of WSx nanoclusters is attributed to the larger density of active bridging S22- sites, compared to the WS2 nanoplates. These findings may provide important insights into the growth behaviour of layered TMD materials at the nanoscale, as well as potential active species in WSx for the HER. PMID- 29417124 TI - Edible oleogels: an opportunity for fat replacement in foods. AB - The scientific and industrial communities have been giving great attention to the development of new bio-based materials with potential use in innovative technological applications. Among these materials are the structures with gel like behavior that can be used in the cosmetic, pharmaceutical and food industries, aiming at controlling the physical properties of the final products. In the past ten years, words like oleogels and organogels have been increasingly used, the existing number of manuscripts and patents being proof of this tendency. In the food industry, oleogels can be used to control phase separation, and decrease the mobility and migration of the oil phase, providing solid-like properties without using high levels of saturated fatty acids as well as to be a carrier of bioactive compounds. In most cases, their main features are related to the reorganization process of gelators after an increase of the temperature, above the melting or glass transition temperature of the materials, known as the direct method, but it is also possible to develop oleogels by indirect methods, such as emulsification and the solvent exchange technique. In the direct methods, the reorganization is able to physically entrap oil leading to different physicochemical properties, the rheological behavior and texture properties being the frequently most studied ones. This review overviews the use of food grade and bio-based structurants to produce edible oleogels, aiming at fat replacement and structure-tailoring. Gelation mechanisms and oil phases used during oleogel production are discussed, as well as the current food applications and future trends for this kind of structure. PMID- 29417128 TI - A fluorescent 3,7-bis-(naphthalen-1-ylethynylated)-2'-deoxyadenosine analogue reports thymidine in complementary DNA by a large emission Stokes shift. AB - The new environmentally responsive fluorescent nucleosides, 3,7-bis-(naphthalen-1 ylethynyl)-8-aza-3,7-dideaza-2'-deoxyadenosine (3n7nzA, 1) and 7-(naphthalen-1 ylethynyl)-8-aza-3,7-dideaza-2'-deoxyadenosine (37nzA, 2), have been synthesized. Both 3n7nzA (1) and 37nzA (2) possess large pi-conjugated systems which extend into both the minor and major grooves or the major groove alone, respectively. The nucleosides exhibited large solvatochromic shifts (3n7nzA: Deltalambda = 45 nm, 37nzA: Deltalambda = 78 nm) and were examined for their ability to fluorimetrically report hybridization events. When incorporated into ODN probes, the bis-substituted 3n7nzA (1) selectively recognized thymidine on target strands which was reported by a distinct change in its emission wavelength in the long wavelength region, whereas 37nzA (2) showed a preference for pairing to cytidine and a smaller wavelength shift. Thus, 3n7nzA (1) has the potential for use as a fluorescent probe for structural studies of DNAs/RNAs including the detection of single-base alterations in target DNA sequences. PMID- 29417129 TI - Incorrect Spelling of Coauthor Surname. PMID- 29417131 TI - Erosive Patches on Bilateral Nipples. PMID- 29417132 TI - Evaluating Industry Payments Among Dermatology Clinical Practice Guideline Authors-Reply. PMID- 29417130 TI - The Origin of Spousal Resemblance for Alcohol Use Disorder. AB - Importance: Although spouses strongly resemble one another in their risk for alcohol use disorder (AUD), the causes of this association remain unclear. Objectives: To examine longitudinally, in first marriages, the association of a first registration for AUD in one spouse with risk of registration in his or her partner and to explore changes in the risk for AUD registration in individuals with multiple marriages as they transition from a spouse with AUD to one without or vice versa. Design, Setting, and Participants: Population-wide Swedish registries were used to identify individuals born in Sweden between 1960 and 1990 who were married before the end of study follow-up on December 31, 2013. The study included 8562 marital pairs with no history of AUD registration prior to their first marriage and an AUD registration in 1 spouse during marriage and 4891 individuals with multiple marriages whose first spouse had no AUD registration and second spouse did or vice versa. Final statistical analyses were conducted from August 15 to September 1, 2017. Exposures: A spousal onset or history of AUD registration. Main Outcomes and Measures: Alcohol use disorder registration in national medical, criminal, or pharmacy registries. Results: Among the 8562 marital pairs (5883 female probands and 2679 male probands; mean [SD] age at marriage, 29.2 [5.7] years) in first marriages, the hazard ratio of AUD registration in wives immediately after the first AUD registration in their husbands was 13.82, which decreased 2 years later to 3.75. The hazard ratio of AUD registration in husbands after the first AUD registration in their wives was 9.21, which decreased 2 years later to 3.09. Among the 4891 individuals with multiple marriages (1439 women and 3452 men; mean [SD] age at first marriage, 25.5 [4.2] years), when individuals transitioned from a first marriage to a spouse with AUD to a second marriage to a spouse without AUD, the hazard ratio for AUD registration was 0.50 (95% CI, 0.42-0.59) in women and 0.51 (95% CI, 0.44 0.59) in men. After a first marriage to a spouse without AUD, the hazard ratio for AUD with a second marriage to a spouse with AUD was 7.02 (95% CI, 5.34-9.23) in women and 9.06 (95% CI, 7.55-10.86) in men. These patterns were modestly attenuated when moving from second to third marriages. Controlling for AUD registration prior to first marriage or between first and second marriages produced minimal changes in risk. Conclusions and Relevance: The increase in risk for AUD registration in a married individual following a first AUD registration in the spouse is large and rapid. When an individual with serial spouses is married, in either order, to partners with vs without an AUD registration, the risk for AUD registration is substantially increased when the partner has an AUD registration and decreased when the partner does not have an AUD registration. These results suggest that a married individual's risk for AUD is directly and causally affected by the presence of AUD in his or her spouse. PMID- 29417133 TI - Evaluating Industry Payments Among Dermatology Clinical Practice Guideline Authors. PMID- 29417134 TI - Opioid Prescribing Patterns and Complications in the Dermatology Medicare Population. AB - Importance: The ongoing opioid epidemic in the United States has been fueled by prescription opioids. Increases in opioid-related deaths and complications mandate clinicians in all fields to scrutinize their prescribing patterns. Objective: To characterize the current status and potential complications of opioid prescribing practices among dermatologists for Medicare beneficiaries. Design, Setting, and Participants: A cross-sectional study used Medicare Part D prescriber data to evaluate opioid prescriptions by dermatologists from January 1 to December 31, 2014. The number of prescribers, opioid claims, beneficiaries, and days supplied as well as the type of opioid and geographic location of prescribers were extracted and analyzed. The top 1% of dermatologists prescribing opioids were identified and compared with a random sample of the same size among the remaining dermatologists based on sex, geographic location, type of practice, and time in practice. A systematic literature review was conducted to estimate the outcome of opioid prescribing practices on the exposed population. Main Outcome and Measures: Practice characteristics, epidemiologic factors, and consequences of opioids prescribed by dermatologists. Results: Of the 12 537 dermatologists in the study, 5305 (42.3%) prescribed no opioid claims, 5408 (43.1%) prescribed 1 to 10 opioid claims, and 1824 (14.5%) prescribed more than 10 opioid claims. Among dermatologists prescribing at least 10 opioid claims, a mean of 1.0 opioid claims was given to each beneficiary, with a supply lasting a mean of 4.4 days. A total of 108 dermatologists (93.9%) in the top 1% of opioid prescribers (n = 115) work in a surgical practice. Estimates suggest that opioids prescribed by dermatologists could annually lead to 3877 to 7602 beneficiaries continuing to use opioids at 1 year and 1825 to 4209 continuing to use opioids at 3 years. A total of 9882 to 22 806 beneficiaries could experience gastrointestinal tract or central nervous system adverse effects and 588 to 999 could experience fractures. Conclusions and Relevance: Opioid prescribing among dermatologists is limited and concentrated in the surgical setting, but it may be associated with a substantial number of adverse events that serve as a reminder to emphasize nonopioid pain medications in the postoperative setting. PMID- 29417135 TI - Efficacy and Safety of Guselkumab, an Anti-interleukin 23 Monoclonal Antibody, for Palmoplantar Pustulosis: A Randomized Clinical Trial. AB - Importance: Palmoplantar pustulosis (PPP) is a recalcitrant skin disease with no biologics currently approved for treatment. The involvement of interleukin 23 (IL 23) and cytokines of the type 17 helper T cell lineage in the pathogenesis of PPP has been recently postulated. Objective: To evaluate the efficacy and safety of guselkumab, an anti-IL-23 monoclonal antibody, in Japanese patients with PPP. Design, Setting, and Participants: This double-blind, randomized, placebo controlled, parallel-group, 24-week trial was conducted between May 14, 2013, and September 27, 2014, at 11 centers in Japan. Participants were patients with moderate to severe PPP that did not respond adequately to conventional treatments. Interventions: Patients were randomized 1:1 to receive guselkumab, 200 mg, by subcutaneous injection or matching placebo at weeks 0 and 4. Main Outcomes and Measures: Changes in total scores of skin-related outcomes from baseline at the end of week 16 (primary clinical cutoff) and through week 24 were measured. Serum biomarker analyses were performed at baseline, week 4, and week 16, and safety was monitored through week 24. Results: Of 49 randomized patients (35 [71%] women; median [range] age, 52 [28-77] years), 41 completed the study at week 24. Mean (SD) PPP severity index total scores (primary end point) improved significantly from baseline in guselkumab-treated patients (-3.3 [2.43]) vs placebo (-1.8 [2.09]) (least squares mean difference, -1.5; 95% CI, -2.9 to -0.2; P = .03). At week 16, PPP area and severity index scores (least squares mean difference, -5.65; 95% CI, -9.80 to -1.50; P = .009) and proportion of patients achieving 50% reduction in these scores (difference in proportion, 39.2; 95% CI, 14.0-64.3; P = .009) improved significantly. A numerically higher proportion of patients had a physician's global assessment score of 1 or less in the guselkumab group vs placebo. Improvement in efficacy scores was maintained through week 24 in the guselkumab group. Significant reductions from baseline in serum IL-17A and IL-17F cytokine levels were observed at weeks 4 and 16. Frequency of treatment emergent adverse events was comparable between the guselkumab group (19 of 25 patients [76%]) and the placebo group (18 of 24 patients [75%]). Frequent adverse effects included nasopharyngitis (14 patients [29%]), headache (3 patients [6%]), contact dermatitis (3 patients [6%]), and injection site erythema (3 patients [6%]). No major safety concerns emerged during the study. Conclusions and Relevance: Targeting IL-23 and its associated immune cascade with guselkumab may be a safe and useful therapeutic option for treatment of PPP. Trial Registration: clinicaltrials.gov Identifier: NCT01845987. PMID- 29417137 TI - Myocardial Infarction After Vascular Surgery: A Systematic Troponin Surveillance and a Uniform Definition Is Needed. PMID- 29417136 TI - A Novel Severity Assessment Scoring System for Hidradenitis Suppurativa. AB - Importance: The variation in both clinical appearance and responses to diverse treatment options emphasize the importance of an accurate, clinically relevant, yet easy-to-use scoring system in hidradenitis suppurativa. Objective: To propose and provide validation data for the newly designed Severity Assessment of Hidradenitis Suppurativa score. Design, Setting, and Participants: We prospectively assessed disease severity using Hurley staging and the modified Hidradenitis Suppurativa Score in 355 patients referred to Ruhr-University Bochum Department of Dermatology between March 2016 and June 2017. We also assessed disease severity via the Severity Assessment of Hidradenitis Suppurativa score. Main Outcomes and Measures: Evaluation and assessment of convergent validity and responsiveness to treatment of the Severity Assessment of Hidradenitis Suppurativa score. Results: Eighty-eight of the 355 patients (134 [37.7%] men and 221 [62.3%] women with a median [IQR] age of 40 [30-49] years) were classified as Hurley stage I, 221 were Hurley stage II, and 46 were Hurley stage III, with an overall median modified Hidradenitis Suppurativa Score of 31 (interquartile range [IQR], 19.3-53). The median total Severity Assessment of Hidradenitis Suppurativa score was 6 (IQR, 4-9), significantly different among the 3 Hurley groups. The median SAHS score for patients in Hurley stage I was 5 (IQR, 3-6), 6 (IQR, 5-9) for patients in Hurley stage II, and 9 (IQR, 7-12) for patients in Hurley stage III (P < .001, Kruskal-Wallis test). Correlation analysis showed a significant correlation between the modified Hidradenitis Suppurativa Score and the Severity Assessment of Hidradenitis Suppurativa score (r = 0.79, P < .001). Disease severity assessment before and after 3 months of conservative systemic treatment showed a significant correlation between the Severity Assessment of Hidradenitis Suppurativa score and modified Hidradenitis Suppurativa Score. Both the mHSS (P = .001) and the SAHS score (P < .001) significantly differed between the baseline visit (median mHSS, 33 [IQR, 24-52]; median SAHS score, 6 [IQR, 5-9]) and the 3 month visit (median mHSS, 28 [IQR, 15-43.5]; median SAHS score, 5 [IQR, 4-6.3]). The 2 patient-reported items demonstrated excellent test-retest reliability with intraclass correlation coefficient values greater than 0.8. Conclusions and Relevance: Our validation data demonstrated that the Severity Assessment of Hidradenitis Suppurativa score is a disease severity instrument that significantly correlates with Hurley staging and the modified Hidradenitis Suppurativa Score, and is responsive enough to measure treatment outcome. PMID- 29417138 TI - Severe Abdominal Pain With Hypotension. PMID- 29417139 TI - Addressing Potential Conflicts of Interest in Dermatology Clinical Practice Guidelines. PMID- 29417140 TI - Virtual and Augmented Reality Put a Twist on Medical Education. PMID- 29417142 TI - Myocardial Infarction After Vascular Surgery-Reply. PMID- 29417141 TI - Nonculprit Plaque Characteristics in Patients With Acute Coronary Syndrome Caused by Plaque Erosion vs Plaque Rupture: A 3-Vessel Optical Coherence Tomography Study. AB - Importance: Patients with culprit plaque rupture are known to have pancoronary plaque vulnerability. However, the characteristics of nonculprit plaques in patients with acute coronary syndromes caused by plaque erosion are unknown. Objective: To investigate the nonculprit plaque phenotype in patients with acute coronary syndrome according to culprit plaque pathology (erosion vs rupture) by 3 vessel optical coherence tomography imaging. Design, Setting, and Participants: In this observational cohort study, between August 2010 and May 2014, 82 patients with acute coronary syndrome who underwent preintervention optical coherence tomography imaging of all 3 major epicardial coronary arteries were enrolled at the Massachusetts General Hospital Optical Coherence Tomography Registry database. Analysis of the data was conducted between November 2016 and July 2017. Patients were classified into 2 groups based on the culprit lesion pathology: 17 patients with culprit plaque erosion and 34 patients with culprit plaque rupture. Thirty-one patients with the absence of culprit rupture or erosion were excluded from further analysis. Exposures: Preintervention 3-vessel optical coherence tomography imaging. Main Outcomes and Measures: Plaque characteristics at the culprit and nonculprit lesions evaluated by optical coherence tomography. Results: In 51 patients (37 men; mean age, 58.7 years), the characteristics of 51 culprit plaques and 216 nonculprit plaques were analyzed. In patients with culprit erosion, the mean (SD) number of nonculprit plaques per patient was smaller (3.4 [1.9] in erosion vs 4.7 [2.1] in rupture, P = .05). Patient-based analysis showed that none of 17 patients with culprit plaque erosion had nonculprit plaque rupture, whereas 26% of the patients (9 of 34) with culprit plaque rupture had nonculprit plaque rupture (P = .02). Plaque-based analysis showed that, compared with the culprit rupture group (n = 158), the culprit erosion group (n = 58) had lower prevalence of plaque rupture (0% vs 8%; P < .001), macrophage accumulation (29% vs 53%; P = .01), microvessels (21% vs 42%; P = .003), and spotty calcium (5% vs 22%; P = .006) in the nonculprit lesions. The prevalence of lipid-rich plaque, thin-cap fibroatheroma, and thrombus did not differ between the groups. Conclusions and Relevance: Compared with those with culprit plaque rupture, patients with acute coronary syndrome caused by culprit plaque erosion had a smaller number of nonculprit plaques and the lower levels of panvascular instability, affirming that distinct pathophysiologic mechanisms operate in plaque erosion and plaque rupture. PMID- 29417144 TI - Omitted Disclosure of Potential Conflicts of Interest. PMID- 29417143 TI - Accuracy of Predictions of Patients With Breast Cancer of Future Well-being After Immediate Breast Reconstruction. AB - Importance: Making a good decision about breast reconstruction requires predicting how one would feel after the procedure, but people tend to overestimate the impact of events on future well-being. Objective: To assess how well patients predict future well-being after mastectomy, with or without immediate reconstruction, with the following a priori hypotheses: Patients will overestimate the negative impact of mastectomy and positive impact of reconstruction, and prediction accuracy will be associated with decision satisfaction and decision regret. Design, Setting, and Participants: This prospective cohort survey study was conducted at a single, multidisciplinary academic oncology clinic from July 2012 to February 2014. Adult women undergoing mastectomy for stage 1, 2, or 3 invasive ductal or lobular breast cancer, ductal carcinoma in situ, or prophylaxis were invited to participate. Data analysis was conducted from September 2015 to October 2017. Exposures: Mastectomy only or mastectomy with immediate reconstruction. Main Outcomes and Measures: Preoperative measures predicted were 12-month happiness (Cantril Ladder) and quality of life, predicted satisfaction with breasts, sexual attractiveness, breast numbness, and pain (measured with BreastQ single items). Measures at 12 months postoperative added the Decision Regret Scale and Satisfaction With Decisions Scale. Results: Of 214 eligible patients, 182 consecutive patients were approached, and 145 enrolled (80%). Of these 145 patients, 131 returned surveys (72%) and 111 of these remained at 12 months (88%). Fifteen who had delayed reconstruction were excluded from analysis, leaving a final cohort of 96 women; 54 had not had reconstruction and 42 had had reconstruction. The mean (SD) age of the cohort was 53.9 (12.1) years; 73 (76%) were white; 50 (52%) were college graduates; 54 (56%) were privately insured; 69 (72%) had disease at stages 0, 1, or 2; and 31 (32%) received adjuvant radiation. Patients having mastectomy without reconstruction underestimated future well-being in all domains. Differences were significant for quality of life scores (mean predicted, 68 vs mean actual, 74; t50, -2.47; P = .02) and satisfaction with breasts-clothed (mean predicted, 2.4 vs mean actual, 2.8; t49, -2.11; P = .04). Patients undergoing mastectomy with reconstruction overestimated future well-being in all but 1 domain. Differences were significant for satisfaction with breasts-unclothed (mean predicted, 3.1 vs mean actual, 2.6; t41, 2.70; P = .01); sexual attractiveness-clothed (mean predicted, 3.7 vs mean actual, 3.3; t39, 2.29; P = .03); sexual attractiveness-unclothed (mean predicted, 3.3 vs mean actual, 2.3; t40, 5.57; P < .001). Both groups experienced more numbness than predicted (mean predicted, 2.79 and 2.72 for mastectomy only and mastectomy with reconstruction groups, respectively; mean actual, 3.52 and 3.56, respectively; t47, -3.4 and t38, -2.9, respectively; P < .01). Patients who were less happy (beta = 6.3; P = .02) or had greater pain (beta = 8.7; P < .001) than predicted had greater regret. Conclusions and Relevance: Patients underestimated future well-being after mastectomy and overestimated well-being after reconstruction. Misprediction was associated with regret. Decision support for breast reconstruction should address expectations about well-being. PMID- 29417145 TI - Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis? AB - Purpose: Stargardt disease (STGD) is the most common form of inherited juvenile macular degeneration. It is inherited as autosomal recessive trait (STGD1), although STGD3 and STGD4 are inherited as autosomal dominant inheritance pattern. STGD3 is caused by mutations in the elongation of very long-chain fatty acids like 4 (ELOVL4) gene encoding for a very long-chain fatty acid elongase. Mutations lead to a truncated Elovl4, lacking of a dilysine motif necessary for retention of transmembrane proteins in the endoplasmic reticulum. STGD occurs due to altered synthesis of very long-chain polyunsaturated fatty acids (VLC-PUFA). Our work investigates the role of two variants in the ELOVL4 gene promoter region, c.-236 C>T (rs240307) and c.-90 G>C (rs62407622), identified in a patient with STGD in transconfiguration. Methods: Their effects on ELOVL4 expression were examined by Dual-Luciferase Reporter assay. Results: rs62407622 and rs240307 variants caused 14% and 18% of expression reduction, respectively, compared with wild-type promoter. A very strong decreased gene expression was caused by coexistence of both variants. Conclusions: A highly reduced activity of the ELOVL4 promoter was registered due to combination of two variants. Decrease of ELOVL4 enzymatic activity could lead to a deficiency of VLC-PUFA, essential components for rods function and longevity, which are among the parameters involved in the etiopathogenesis of STGD. PMID- 29417146 TI - Associations of Distance to Trauma Care, Community Income, and Neighborhood Median Age With Rates of Injury Mortality. AB - Importance: Rural, low-income, and historically underrepresented minority communities face substantial barriers to trauma care and experience high injury incidence and mortality rates. Characteristics of injury incident locations may contribute to poor injury outcomes. Objective: To examine the association of injury scene characteristics with injury mortality. Design, Setting, and Participants: In this cross-sectional study, data from trauma center and emergency medical services provided by emergency medical services companies and designated trauma centers in the state of Maryland from January 1, 2015, to December 31, 2015, were geocoded by injury incident locations and linked with injury scene characteristics. Participants included adults who experienced traumatic injury in Maryland and were transported to a designated trauma center or died while in emergency medical services care at the incident scene or in transit. Exposures: The primary exposures of interest were geographic characteristics of injury incident locations, including distance to the nearest trauma center, designation level and ownership status of the nearest trauma center, and land use, as well as community-level characteristics such as median age and per capita income. Main Outcomes and Measures: Odds of death were estimated with multilevel logistic regression, controlling for individual demographic measures and measures of injury and health. Results: Of the 16 082 patients included in this study, 8716 (52.4%) were white, and 5838 (36.3%) were African American. Most patients were male (10 582; 65.8%) and younger than 65 years (12 383; 77.0%). Odds of death increased by 8.0% for every 5-mile increase in distance to the nearest trauma center (OR, 1.08; 95% CI, 1.01-1.15; P = .03). Compared with privately owned level 1 or 2 centers, odds of death increased by 49.9% when the nearest trauma center was level 3 (OR, 1.50; 95% CI, 1.06-2.11; P = .02), and by 80.7% when the nearest trauma center was publicly owned (OR, 1.81; 95% CI, 1.39-2.34; P < .001). At the zip code tabulation area level, odds of death increased by 16.0% for every 5-year increase in median age (OR, 1.16; 95% CI, 1.03-1.30; P = .02), and decreased by 26.6% when the per capita income was greater than $25 000 (OR, 0.73; 95% CI, 0.54-0.99; P = .05). Conclusions and Relevance: Injury scene characteristics are associated with injury mortality. Odds of death are highest for patients injured in communities with higher median age or lower per capita income and at locations farthest from level 1 or 2 trauma centers. PMID- 29417148 TI - What Is an Addictive Disorder? PMID- 29417147 TI - Direct Oral Anticoagulants in Addition to Antiplatelet Therapy for Secondary Prevention After Acute Coronary Syndromes: A Systematic Review and Meta-analysis. AB - Importance: Patients with acute coronary syndrome (ACS) remain at high risk for experiencing recurrent ischemic events. Direct oral anticoagulants (DOAC) have been proposed for secondary prevention after ACS. Objective: To evaluate the safety and efficacy of DOAC in addition to antiplatelet therapy (APT) after ACS, focusing on treatment effects stratified by baseline clinical presentation (non ST-segment elevation ACS [NSTE-ACS] vs ST-segment elevation myocardial infarction [STEMI]). Data Sources: PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched from inception to March 1, 2017. Study Selection: Randomized clinical trials on DOAC after ACS were evaluated for inclusion. Overall, 473 studies were screened, 19 clinical trials were assessed as potentially eligible, and 6 were included in the meta-analysis. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used to abstract data and assess quality and validity. The risk of bias tool, version 2.0 (Cochrane) was used for risk of bias assessment. Data were pooled using random-effects models. Main Outcomes and Measures: The prespecified primary efficacy end point was the composite of cardiovascular death, myocardial infarction, and stroke. The prespecified primary safety end point was major bleeding. Results: Six trials that included 29 667 patients were identified (14 580 patients [49.1%] with STEMI and 15 036 [50.7%] with NSTE-ACS). The primary efficacy end point risk was significantly lower in patients who were treated with DOAC as compared with APT alone (odds ratio [OR], 0.85; 95% CI, 0.77-0.93; P < .001). This benefit was pronounced in patients with STEMI (OR, 0.76; 95% CI, 0.66-0.88; P < .001), while no significant treatment effect was observed in patients with NSTE-ACS (OR, 0.92; 95% CI, 0.78-1.09; P = .36; P for interaction = .09). With respect to safety, DOACs were associated with a higher risk of major bleeding as compared with APT alone (OR, 3.17; 95% CI, 2.27-4.42; P < .001), with consistent results in patients with STEMI (OR, 3.45; 95% CI, 1.95-6.09; P < .001) and NSTE-ACS (OR, 2.19; 95% CI, 1.38-3.48; P < .001; P for interaction = .23). Conclusions and Relevance: To our knowledge, these findings are the first evidence to support differential treatment effects of DOAC in addition to APT according to ACS baseline clinical presentation. In patients with NSTE-ACS, the risk-benefit profile of DOAC appears unfavorable. Conversely, DOAC in addition to APT might represent an attractive option for patients with STEMI. PMID- 29417150 TI - Knowledge and beliefs in a selected group of parents of children aged 2 and less concerning preventive vaccination AB - OBJECTIVE: The objective of this research was to get to know the level of knowledge and beliefs concerning preventive vaccination among parents of children up to 2 years of age MATERIAL AND METHODS: The survey was carried out in 2015 in a group of 120 parents of children aged 2 or less in the capital city of Warsaw and its vicinity. An original survey questionnaire was applied. Descriptive statistics methods were applied RESULTS: The most numerous researched group were people aged 20-40 (79.2%) with higher education (76.8%). The majority of respondents declared their positive attitude to rationality of vaccination (76.7%). Only 1.7% of respondents declared that they remained unconvinced as to giving their children preventive vaccination. Women were convinced about the usefulness and preventive effectiveness of preventive vaccination. Among all the respondents 11.7% claimed they did not get enough information on preventive vaccination from medical staff. According to 7.5% of the respondents, the information provided by medical personnel is incomprehensible and insufficient. According to 50.8% of the respondents the effectiveness of parents' education in the scope of preventive vaccination administered to children should be improved CONCLUSIONS: The parents of children aged 2 or less point out to lack of sufficient information on preventive vaccination. It is therefore necessary to involve medical personnel more in order to increase the effectiveness of education of small children's parents in the discussed field PMID- 29417149 TI - Association of DSM-5 Betel-Quid Use Disorder With Oral Potentially Malignant Disorder in 6 Betel-Quid Endemic Asian Populations. AB - Importance: Betel-quid (BQ) is the fourth most popular psychoactive agent worldwide. An emerging trend across Asia is the addictive consumption of BQ, which is associated with oral cancer and other health consequences. Objective: To investigate the validity and pattern of DSM-5-defined BQ use disorder (BUD) and its association with oral potentially malignant disorder (OPMD) among Asian populations. Design, Setting, and Participants: In-person interviews were conducted from January 1, 2009, to February 28, 2010, among a random sample of 8922 noninstitutionalized adults from the Asian Betel-quid Consortium study, an Asian representative survey of 6 BQ-endemic populations. Statistical analysis was performed from January 1, 2015, to December 31, 2016. Main Outcomes and Measures: Participants were evaluated for BUD using DSM-5 criteria for substance use disorder and for OPMD using a clinical oral examination. Current users of BQ with 0 to 1 symptoms were classified as having no BUD, those with 2 to 3 symptoms as having mild BUD, those with 4 to 5 symptoms as having moderate BUD, and those with 6 or more symptoms as having severe BUD. Results: Among the 8922 participants (4564 women and 4358 men; mean [SD] age, 44.2 [0.2] years), DSM-5 symptoms showed sufficient unidimensionality to act as a valid measure for BUD. The 12-month prevalence of DSM-5-defined BUD in the 6 study populations was 18.0% (mild BUD, 3.2%; moderate BUD, 4.3%; and severe BUD, 10.5%). The 12-month proportion of DSM-5-defined BUD among current users of BQ was 86.0% (mild BUD, 15.5%; moderate BUD, 20.6%; and severe BUD, 50.0%). Sex, age, low educational level, smoking, and drinking were significantly associated with BUD. Among individuals who used BQ, family use, high frequency of use, and amount of BQ used were significantly linked to moderate to severe BUD. Compared with individuals who did not use BQ, those who used BQ and had no BUD showed a 22.0-fold (95% CI, 4.3-112.4) risk of OPMD (P < .001), whereas those with mild BUD showed a 9.6-fold (95% CI, 1.8-56.8) risk (P = .01), those with moderate BUD showed a 35.5-fold (95% CI, 4.3-292.3) risk (P = .001), and those with severe BUD showed a 27.5-fold (95% CI, 1.6-461.4) risk of OPMD (P = .02). Individuals with moderate to severe BUD who used BQ and had the symptom of tolerance had a 153.4-fold (95% CI, 33.4 703.6) higher risk of OPMD than those who did not use BQ, and those with moderate to severe BUD who used BQ and had a larger amount or longer history of BQ use had an 88.9-fold (95% CI, 16.6-476.5) higher risk of OPMD than those who did not use BQ. Conclusions and Relevance: This international study gathered data about BQ users across 6 Asian populations, and it demonstrates that DSM-5 symptoms could fulfill a BUD construct. Most current Asian users of BQ already have BUD, which is correlated with risk of OPMD. Among individuals with moderate to severe BUD who used BQ, tolerance and a larger amount or longer history of BQ use are the key symptoms that correlated with enhanced risk of OPMD. These findings play an important role in providing a new indication of an additional psychiatric management plan for users of BQ who have BUD. PMID- 29417151 TI - Error in Data Presentation in Figure. PMID- 29417154 TI - Frankfurt is Calling! PMID- 29417155 TI - Diagnosing Neoplastic Hematoma: Role of MR Perfusion. AB - BACKGROUND: The imaging appearance of neoplastic hematoma can be complicated by the presence of a large hematoma, even on magnetic resonance imaging (MRI). We describe the role of MR perfusion (MRP) in detecting neoplastic hematomas in patients with intraparenchymal hematoma (IPH). MATERIAL AND METHODS: A retrospective review was performed for consecutive patients with IPH, where MRP was performed. Routine, post-gadolinium MRI and MRP were analyzed. All patients were either operated on for evacuation of IPH or followed up on imaging. The MRP parameters of cerebral blood volume (CBV) and cerebral blood flow (CBF) and pattern of enhancement (peripheral linear vs. nodular) were recorded. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated for these parameters for diagnosing neoplastic hematoma. RESULTS: Of 116 patients with MRP, 16 patients (male 8; mean age-65.5 years) had IPH on their initial MRI. For diagnosing neoplastic hematoma, the sensitivity, specificity, PPV and NPV for increased CBF and CBV were 100%, 88.9%, 87.5%, and 100%; for peripheral linear enhancement were 100%, 28.6%, 50%, 100% and for nodular enhancement were 85.7%, 77.8%, 75% and 12.5%, respectively. The combination of peripheral linear enhancement and increased CBF and CBV showed 100% sensitivity, specificity, PPV and NPV. CONCLUSION: In our small series, the combination of peripheral linear enhancement and increased CBF and CBV showed 100% sensitivity, specificity, PPV and NPV for diagnosing a neoplastic hematoma. These findings need to be validated in a larger study. PMID- 29417156 TI - ? PMID- 29417157 TI - [Prevalence of dermatomycoses in professional football players : A study based on data of German Bundesliga fitness check-ups (2013-2015) compared to data of the general population]. AB - BACKGROUND: The prevention, early diagnosis and treatment of onychomycosis is of great importance for professional athletes to avoid physical limitations by complications. So far, there is only little data on the prevalence of dermatomycosis in professional athletes. OBJECTIVES: The aim of the study was to detect the prevalence of dermatomycosis in professional football players compared to the general population. MATERIALS AND METHODS: The prospective, non interventional, controlled study on the prevalence of dermatomycosis in professional football players was carried out on football players of a German Bundesliga team compared with a previously studied, equivalently aged German working population. A questionnaire survey, a dermatological check-up and a microbiological detection of pathogens in cases of suspicion were performed. RESULTS: Data of 84 football players (n = 45 in 2013; n = 39 in 2015) were compared to data of n = 8186 male employees between 17 and 35 years of age. In the group of athletes, there were findings of 60.7% onychomycosis, 36.9% of tinea pedis and 17.8% of pityriasis versicolor. In the group of the age-equivalent general German working population the findings were: onychomycosis 3.3%, tinea pedis 3.2%, pityriasis versicolor 1.4%. CONCLUSION: Our study shows a clearly higher risk for fungal diseases of the skin especially on the feet of professional football players. The results show a necessity for elucidation within prevention and the establishment of an appropriate therapy of dermatomycosis for professional football players. PMID- 29417158 TI - Operative treatment algorithm for foot deformities in Charcot-Marie-Tooth disease. AB - The present article presents a short summary concerning the pathomechanisms and clinical presentation of foot deformities in Charcot-Marie-Tooth syndrome. Furthermore, a classification system is introduced and based on a recently performed review of the literature an operative treatment algorithm is provided. The operative technique of the following surgical procedures is described in more detail: 1. dorsiflexion osteotomy at the base of the 1st metatarsus, 2. dorsiflexion osteotomy at the base of a lesser metatarsal bone, 3. claw hallux correction including fusion of the first phalangeal joint, 4. claw toe correction, 5. transfer of extensor digitorum longus tendons to the peroneal tendons and finally 6. tibialis posterior tendon transfer to the dorsiflexors of the foot. PMID- 29417159 TI - [Digital volume tomography : Dedicated scanner and cone beam CT with C-arm systems]. AB - CLINICAL/METHODICAL ISSUE: Digital volume tomography (DVT) and cone-beam computed tomography (CT) with C-arm systems have become established three-dimensional imaging systems as an alternative to CT in some application areas. STANDARD RADIOLOGICAL METHODS: The technology of the systems is well developed so that they have become a competing method to CT imaging in terms of image quality and radiation exposure. PERFORMANCE: An advantage is the better spatial resolution, preferably with dedicated scanner systems, especially in the z direction. The radiation exposure of CT, cone beam CT and DVT are comparable, if the exposure parameter in CT imaging can be adjusted to the lower exposure levels. ACHIEVEMENTS: Advantages of these systems are that they can be used for imaging in a better workflow or to acquire images under conditions not possible in CT, e. g. imaging under stress in orthopedics or to take images in the corona technique with a horizontal gantry in cone-beam CT mammography PRACTICAL RECOMMENDATIONS: The use of three-dimensional imaging is becoming more frequent and will replace planar radiography in additional clinical situations. The three-dimensional imaging without superpositioning of structures has advantages in the visibility of structures and the spatial relation to other organs and structures. In guidelines and recommendations, the number of recommendations given for the use of three-dimensional imaging is increasing. This leads to a small increase in the radiation exposure of patients, a trend which is reflected in the annual reports of the Federal Office for Radiation Protection. PMID- 29417160 TI - Bioaccumulation Patterns of Perfluoroalkyl Acids in an Estuary of the Ariake Sea, Japan. AB - To evaluate the bioaccumulation potential of perfluoroalkyl acids (PFAAs) in an aquatic food web, we measured the concentrations of nine PFAAs in the water and aquatic organisms from an estuary of the Omuta River, Japan. Average log bioaccumulation factors for all PFAAs ranged from 2.0 to 2.8. There was no positive correlation observed between PFAA carbon chain length and there was no evidence of trophic magnification demonstrated among the sample types collected. These results differed from the findings of previous studies in enclosed bodies of water, perhaps because river mouth-estuarine ecotones are more variable spatially and temporally and include some fish that are highly migratory. Further investigations of bioaccumulation factors will be needed to elucidate the tendency of amphiphilic chemicals to bioaccumulate in these river mouth-estuarine ecotones. PMID- 29417161 TI - Comment on "Hysteropreservation versus hysterectomy in the surgical treatment of uterine prolapse: systematic review and meta-analysis". PMID- 29417162 TI - Single and multiple phenotype QTL analyses of downy mildew resistance in interspecific grapevines. AB - KEY MESSAGE: Downy mildew resistance across days post-inoculation, experiments, and years in two interspecific grapevine F1 families was investigated using linear mixed models and Bayesian networks, and five new QTL were identified. Breeding grapevines for downy mildew disease resistance has traditionally relied on qualitative gene resistance, which can be overcome by pathogen evolution. Analyzing two interspecific F1 families, both having ancestry derived from Vitis vinifera and wild North American Vitis species, across 2 years and multiple experiments, we found multiple loci associated with downy mildew sporulation and hypersensitive response in both families using a single phenotype model. The loci explained between 7 and 17% of the variance for either phenotype, suggesting a complex genetic architecture for these traits in the two families studied. For two loci, we used RNA-Seq to detect differentially transcribed genes and found that the candidate genes at these loci were likely not NBS-LRR genes. Additionally, using a multiple phenotype Bayesian network analysis, we found effects between the leaf trichome density, hypersensitive response, and sporulation phenotypes. Moderate-high heritabilities were found for all three phenotypes, suggesting that selection for downy mildew resistance is an achievable goal by breeding for either physical- or non-physical-based resistance mechanisms, with the combination of the two possibly providing durable resistance. PMID- 29417163 TI - [Profit center analysis of esophagectomy : Economical analysis of transthoracic esophagectomy depending on postoperative complications]. AB - Due to increasing medical costs and yet limited financial resources, medical treatment and economic analyses can no longer be separated; therefore, direct costing and cost unit accounting become more and more relevant as controlling tools in hospital management. Transthoracic esophagectomy is an integral part of the current treatment concept in patients with esophageal carcinoma. The question of the present study was whether the present diagnosis-related groups (DRG) system is a cost-effective tool to represent transthoracic esophagectomy. In this retrospective study at a high-volume center, 161 consecutive patients with esophageal carcinoma were included. All patients were surgically treated according to the current S3 guidelines by a transthoracic esophagectomy. Detailed and standardized documentation of the postoperative complications was made according to the classification of Clavien-Dindo and the guidelines of the Esophagectomy Complications Consensus Group (ECCG). For each individual patient, the respective actual costs were analyzed according to the Institute for the Remuneration System in Hospitals (InEK) cost accounting approach comparing DRG payments (DRG G03A) on a case level including all extra fees per DRG catalogue. The mean costs per case of all included 161 patients were 24,338 ? (median: 19,210 ?, range: 12,149-127,376 ?), while mean payments per case of 22,591 ? were recorded. For the entire study population, the profit margin was -281,330 ? (mean: -1747 ?). Only patients with an uncomplicated course (Clavien-Dindo 0) yielded a slightly positive profit margin of 2514 ?. With increasing complication score the profit margin became increasingly negative (Clavien-Dindo I: -2878 ?, Clavien-Dindo IVb: -58,543 ?). Within the analysis of the InEK target cost matrix, main cost drivers can be identified as medical services (22.3%) and non medical infrastructure (18.7%). Surgical treatment according to the existing guidelines of patients with esophageal carcinoma is not cost-covering in high volume centers and cannot be solely financed by existing DRG revenues. PMID- 29417164 TI - Bacteriocinogenic properties of Escherichia coli P2C isolated from pig gastrointestinal tract: purification and characterization of microcin V. AB - The aim of this study was to isolate and investigate the bacteriocinogenic and probiotic potential of new Gram-negative isolates. Of 22 bacterial isolates from pig intestine and chicken crops, ten isolates had demonstrated a good activity, and the most potent five strains were identified as four E. coli and one as Proteus sp. No virulence factors were detected for E. coli strains isolated from pig intestine. The semi-purified microcins proved to be resistant to temperature and pH variation, but sensitive to proteolytic enzymes. Of particular interest, strain E. coli P2C was the most potent, free of virulence genes and sensitive to tested antibiotics. Purification procedure revealed the presence of a single pure peak having a molecular mass of 8733.94 Da and matching microcin V (MccV). The sequence obtained by LC-MS/MS confirmed the presence of MccV. Purified MccV showed a good activity against pathogenic coliforms, especially E. coli O1K1H7 involved in avian colibacillosis. The present study provides evidence that E. coli strains isolated from pig intestine produce microcin-like substances. E. coli P2C is a safe MccV producer that could be a good candidate for its application as novel probiotic strain to protect livestock and enhance growth performance. PMID- 29417165 TI - Changes in signal intensity in the dentate nucleus at unenhanced T1-weighted magnetic resonance imaging depending on class of previously used gadolinium-based contrast agent. AB - BACKGROUND: Signal increase on T1-weighted magnetic resonance imaging (MRI) in the dentate nucleus has been reported in adults after multiple injections of gadolinium-based contrast agents. Linear contrast agents are more prone to cause this increase. Studies in children are still rare and focus mostly on the analysis of one single agent. OBJECTIVE: To compare signal intensity chances in children after more than four injections of either only linear or only macrocyclic contrast agents. MATERIALS AND METHODS: Seventy children (examined from October 2001 to February 2016) were included in this retrospective study. Signal intensities in the dentate nucleus and pons were measured on non-enhanced T1-weighted images from the first and last MRI scans. A two-sample t-test compared the dentate nucleus-to-pons signal intensity ratio differences for linear versus macrocyclic gadolinium-based contrast agent applications and also the number of applications (4-8, 9-12 or >12). Patients' charts were analysed to evaluate potentially associated neurological symptoms. RESULTS: Patients had contrast-enhanced MRI using either only linear (n=16) or only macrocyclic (n=54) gadolinium-based contrast agents. In patients with >12 injections, dentate nucleus-to-pons signal intensity ratio was statistically different concerning the contrast agent class (0.16+/-0.125 for macrocyclic vs. 0.0005+/-0.13 for linear agents). For linear agents, a statistically significant increase was found between 4-8 injections (-0.051+/-0.087) and >12 injections (0.16+/-0.125). No neurological symptoms were recorded in patients with signal changes. CONCLUSION: Multiple injections of linear gadolinium-based contrast agents lead to a signal increase of the dentate nucleus in children. Signal intensity increases depend on the number of injections of linear contrast agents. PMID- 29417166 TI - Diffusion pseudonormalization and clinical outcome in term neonates with hypoxic ischemic encephalopathy. AB - BACKGROUND: Pseudonormalization of diffusion-weighted magnetic resonance imaging (MRI) can lead to underestimation of brain injury in newborns with hypoxic ischemic encephalopathy (HIE), posing a significant problem. We have noticed that some neonates show pseudonormalization negativity on diffusion-weighted imaging. OBJECTIVE: To compare pseudonormalization negativity with clinical outcomes. MATERIALS AND METHODS: Seventeen term neonates with moderate or severe HIE underwent therapeutic hypothermia. They were examined by MRI twice at mean ages of 3 days and 10 days. We evaluated the presence of restricted diffusion, and also the presence or absence of pseudonormalization, by diffusion-weighted imaging at the time of the second MRI, and correlated the results with clinical outcome. RESULTS: DWI demonstrated no abnormality in seven neonates. Among the 10 neonates with abnormal diffusion-weighted imaging findings, 2 were positive for pseudonormalization and 8 were negative. Among neonates with normal diffusion weighted imaging findings and with positivity for pseudonormalization, none had major disability. Among the eight neonates with pseudonormalization negativity, all but one, who was lost to follow-up, had major disability. CONCLUSION: Abnormal diffusion-weighted imaging with pseudonormalization negativity might be predictive of severe brain injury and major disability. The second-week MRI is important for the judgment of pseudonormalization. PMID- 29417167 TI - Maternal NO2 exposure induces cardiac hypertrophy in male offspring via ROS-HIF 1alpha transcriptional regulation and aberrant DNA methylation modification of Csx/Nkx2.5. AB - Maternal exposure to nitrogen dioxide (NO2) poses a risk for morbidity and mortality in infantile congenital heart diseases and even adult cardiovascular diseases. However, the experimental evidence supporting these effects is insufficient, and the related regulatory mechanisms are unknown. In the present study, we aimed to determine whether maternal NO2 exposure causes cardiac hypertrophy-related consequences in offspring, and if so, how these adverse effects occur in the postnatal heart. The results indicate that in mice, maternal NO2 exposure causes cardiac hypertrophy in male offspring. This altered phenotype was accompanied by increased expression of atrial natriuretic peptide, B-type natriuretic peptide, bone morphogenetic protein 10 and beta-myosin heavy chain and elevated activities of cardiomyocyte injury markers, including serum glutamate-oxaloacetate transaminase, lactate dehydrogenase and kinases creatine phosphokinase (CK-MB) in serum. The cardiac-specific transcription factor Csx/Nkx2.5 played an important role in the induction of cardiac hypertrophy and cardiomyocyte injury, and the action was associated with ROS-HIF-1alpha transcriptional regulation and DNA hypomethylation modification. PMID- 29417168 TI - Patient-reported outcome metrics following total knee arthroplasty are influenced differently by patients' body mass index. AB - PURPOSE: This study investigated the impact of body mass index (BMI) on improvement in patient outcomes (pain, function, joint awareness, general health and satisfaction) following total knee arthroplasty (TKA). METHODS: Data were obtained for primary TKAs performed at a single centre over a 12-month period. Data were collected pre-operatively and 12-month postoperatively with the Oxford Knee Score (OKS) measuring pain and function, the EQ-5D-3L measuring general health status, the Forgotten Joint Score-12 (FJS-12) measuring joint awareness and a single question on treatment satisfaction. Change in scores following surgery was compared across the BMI categories identified by the World Health Organization (< 25.0, 25.0-29.9, 30.0-34.9, 35.0-39.9 and >= 40.0). Differences in postoperative improvement between the BMI groups were analysed with an overall Kruskal-Wallis test, with post hoc pairwise comparisons between BMI groups with Mann-Whitney tests. RESULTS: Of 402 patients [mean age 70.7 (SD 9.2); 55.2% women] 15.7% were normal weight (BMI < 25.0), 33.1% were overweight (BMI 25.0 29.9), 28.2% had class I obesity (BMI 30.0-34.9), 16.2% had class II obesity (BMI 35.0-39.9), and 7.0% had class III obesity (BMI >= 40.0). Postoperative change in OKS (n.s.) and EQ-5D-3L (n.s.) was not associated with BMI. Higher BMI group was associated with less improvement in FJS-12 scores (p = 0.010), reflecting a greater awareness of the operated joint during activity in the most obese patients. Treatment satisfaction was associated with BMI category (p = 0.029), with obese patients reporting less satisfaction. CONCLUSIONS: In TKA patients, outcome parameters are influenced differently by BMI. Our study showed a negative impact of BMI on postoperative improvement in joint awareness and satisfaction scores, but there was no influence on pain, function or general health scores. This information may be useful in terms of setting expectations expectation in obese patients planning to undergo TKA. LEVEL OF EVIDENCE: Level 1. PMID- 29417169 TI - The flexion space is more reliably balanced when using the transepicondylar axis as compared to the posterior condylar line. AB - PURPOSE: The purpose of this study was to evaluate the differences in flexion space balance when the femoral component is implanted parallel to the surgical transepicondylar axis (TEA) or with 3 degrees of external rotation from the posterior condylar line (PoCoLi). It was hypothesized that implantation parallel to the TEA will produce a more reliably balanced flexion space. METHODS: Forty eight consecutive patients with a varus deformity were prospectively randomized to undergo total knee arthroplasty with a femoral component implanted parallel the TEA, or with 3 degrees of external rotation from the PoCoLi. The posterior condylar angle (PCA) was measured. Intraoperative load measurements were taken at 10 degrees , 45 degrees , and 90 degrees of flexion. RESULTS: The PCA was similar between groups (TEA group: 4.2 degrees +/- 1.5 degrees and PoCoLi group: 4.0 degrees +/- 1.3 degrees ; n.s.). The mean difference in load values between the medial and lateral compartments was significantly lower in the TEA group than in the PoCoLi group at the 45 (0 +/- 8 vs. 9 +/- 13 lbs; respectively, p = 0.008) and 90 degrees flexion angles (1 +/- 9 vs. 10 +/- 15 lbs; respectively, p = 0.01). The PoCoLi group had a linear increase in the difference of load values between the medial and lateral compartments with increasing magnitude of the posterior condylar angle (45 degrees , p = 0.0013; 90 degrees , p = 0.0006), but this was not observed in the TEA group. CONCLUSION: Femoral component implantation parallel to the TEA resulted in a more balanced flexion gap as compared to implantation at 3 degrees of external rotation from the PoCoLi. The intraoperative use of the TEA rather than the PoCoLi to set femoral component rotation may provide a more balanced flexion space and decrease the need for extensive soft tissue releases. LEVEL OF EVIDENCE: II. PMID- 29417171 TI - Absence of Exertional Oscillatory Ventilation During Exercise Related to Late Adverse Outcome in Fontan Patients. PMID- 29417170 TI - In Vitro Anti/Pro-oxidant Activities of R. ferruginea Extract and Its Effect on Glioma Cell Viability: Correlation with Phenolic Compound Content and Effects on Membrane Dynamics. AB - Rapanea ferruginea antioxidant and antitumoral properties were not explored before in literature. This study aimed to investigate these biological activities for the R. ferruginea leaf extract and correlate them with its phenolic content and influence in biological membrane dynamics. Thus, in this study, anti/pro oxidative properties of R. ferruginea leaf extract by in vitro DPPH and TBARS assays, with respect to the free radical reducing potential and to its activity regarding membrane free radical-induced peroxidation, respectively. Furthermore, preliminary tests related to the extract effect on in vitro glioma cell viability were also performed. In parallel, the phenolic content was detected by HPLC-DAD and included syringic and trans-cinnamic acids, quercetrin, catechin, quercetin, and gallic acid. In an attempt to correlate the biological activity of R. ferruginea extract and its effect on membrane dynamics, the molecular interaction between the extract and a liposomal model with natural-sourced phospholipids was investigated. Location and changes in vibrational, rotational, and translational lipid motions, as well as in the phase state of liposomes, induced by R. ferruginea extract, were monitored by Fourier-transform infrared spectroscopy, nuclear magnetic resonance, differential scanning calorimetry, and UV-visible spectroscopy. In its free form, the extract showed promising in vitro antioxidant properties. Free-form extract (at 1000u g/mL) exposure reduced glioma cell in vitro viability in 40%, as evidenced by MTT tests. Pro-oxidant behavior was observed when the extract was loaded into liposomes. A 70.8% cell viability reduction was achieved with 500 ug/mL of liposome-loaded extract. The compounds of R. ferruginea extract ordered liposome interface and disorder edits a polar region. Phenolic content, as well as membrane interaction and modulation may have an important role in the oxidative and antitumoral activities of the R. ferruginea leaf extract. PMID- 29417172 TI - Axial reflexes are present in older subjects and may contribute to balance responses. AB - We studied the response to axial taps (mini-perturbations) of a group of 13 healthy older subjects (mean age 63 +/- 12 years, 7 females, 6 males), 12 of whom were also studied using larger applied (macro-) perturbations requiring active postural responses. The mini-perturbation consisted of a brief impulsive force produced by a mini-shaker applied to the trunk at the level of the shoulders and anteriorly at the upper sternum which was perceived as a tap. Acceleration, force platform, and EMG measurements were made. The average peak accelerations for the mini-perturbations were 108 mG (anterior) and - 78.9 mG (posterior). Responses overall were very similar to those previously reported for younger subjects: the perturbation evoked short latency responses in leg muscles, modulated by degree and direction of lean, and were largest for the muscle most relevant for the postural correction. The increases in the amplitude for the main agonist were greater than the increase in tonic activity. With both anterior and posterior lean, co-contraction responses were present. The size of the EMG response to the mini-perturbations correlated with the corresponding earliest EMG responses (0 100, 100-200 ms intervals) to the larger postural perturbations, timing which corresponds to balance responses. The balance responses evoked by the larger imposed postural perturbations may, therefore, receive a contribution through the reflex pathway mediating the axial tap responses, whose efferent limb appears to be the reticulospinal tract. PMID- 29417173 TI - CTA/V detection of bilateral sigmoid sinus dehiscence and suspected idiopathic intracranial hypertension in unilateral pulsatile tinnitus. AB - PURPOSE: This aimed to evaluate the prevalence and extent of bilateral sigmoid sinus dehiscence (SSD) and to explore the presence of idiopathic intracranial hypertension (IIH) in patients with unilateral pulsatile tinnitus (PT) with CTA/V. METHODS: Sixty PT patients (52 females; 40.4 +/- 11.6 years [20-72]) who underwent CTA/V and 30 non-PT patients (27 females; 38.4 +/- 14.7 years [12-62]) were enrolled in this study. The primary outcome measure was the radiographic presence of SSD. The index of transverse sinus stenosis (ITSS) was obtained by multiplying the stenosis scale values for each transverse sinus, and once was >= 4, the presence of IIH was suspected. RESULTS: The prevalence and extent of SSD on symptomatic side (78%; maximum transverse diameter, MTD 0.49 +/- 0.23; maximum vertical diameter, MVD 0.50 +/- 0.26 cm) were significantly higher and larger than those on asymptomatic side (50%, P < 0.001; MTD 0.35 +/- 0.18, P = 0.006; MVD 0.30 +/- 0.15 cm, P < 0.001) in the study group and those (20%, P < 0.001; MTD 0.36 +/- 0.18, P = 0.073; MVD 0.30 +/- 0.22 cm, P < 0.048) in the control group. The presence of SSD showed significant correlation with both PT (logistic regression analysis, OR 4.167 [1.450-11.97]; P = 0.008) and suspected IIH (OR 16.25 [1.893-139.5]; P = 0.011). CONCLUSION: In PT patients, SSD has a significant correlation with PT and a potential correlation with IIH. PMID- 29417174 TI - Reply to comment on Andrei et al.: The variability of vertebral body volume and pain associated with osteoporotic vertebral fractures: conservative treatment versus percutaneous transpedicular vertebroplasty. PMID- 29417175 TI - The steady state pharmacokinetics of trientine in Wilson disease patients. AB - PURPOSE: To determine the steady state pharmacokinetics of trientine in children (>= 12 years of age) and adult patients who had been receiving trientine dihydrochloride therapy prior to the study. METHODS: Twenty patients were exposed to trientine (trientine dihydrochloride capsules supplied by Univar) after standard oral dosing as part of ongoing therapy. Plasma trientine concentration was determined pre-dose and at 30 min, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 h post dose. Concentrations of trientine in plasma were determined by LC-MS/MS using a validated bioanalytical method with stable labelled trientine as the internal standard. RESULTS: Trientine was generally absorbed fairly rapidly with a median Tmax of 1.49 h (range, 0.48-4.08 h). There was some variability in exposure, with a 10-fold range in Cmax, and a 13.8-fold range in AUC0-t. This variability was slightly lower when PK parameters were dose-normalised (6.7-fold range in Cmax/D and an 11.6-fold range in AUC0-t/D). The terminal half-life, which could be defined in 14 of the 20 patients, was broadly consistent between patients (range of 2.33 to 6.99 h). There was no marked difference in pharmacokinetics between adult patients (n = 16) and children (n = 4). The Cmax range was 506 to 3100 ng/mL in adults and 309 to 1940 ng/mL in children-the equivalent ranges for AUC0 t were 1240 to 17,100 ng/mL h and 1500 to 8060 ng/mL h. When PK parameters were normalised for administered dose, the Cmax/D and AUC0-t/D for children were contained within the ranges for the adult patients. CONCLUSIONS: The steady state pharmacokinetics of trientine in Wilson disease patients were broadly similar to that reported in healthy subjects. PMID- 29417177 TI - Stem cells from human apical papilla decrease neuro-inflammation and stimulate oligodendrocyte progenitor differentiation via activin-A secretion. AB - Secondary damage following spinal cord injury leads to non-reversible lesions and hampering of the reparative process. The local production of pro-inflammatory cytokines such as TNF-alpha can exacerbate these events. Oligodendrocyte death also occurs, followed by progressive demyelination leading to significant tissue degeneration. Dental stem cells from human apical papilla (SCAP) can be easily obtained at the removal of an adult immature tooth. This offers a minimally invasive approach to re-use this tissue as a source of stem cells, as compared to biopsying neural tissue from a patient with a spinal cord injury. We assessed the potential of SCAP to exert neuroprotective effects by investigating two possible modes of action: modulation of neuro-inflammation and oligodendrocyte progenitor cell (OPC) differentiation. SCAP were co-cultured with LPS-activated microglia, LPS-activated rat spinal cord organotypic sections (SCOS), and LPS-activated co cultures of SCOS and spinal cord adult OPC. We showed for the first time that SCAP can induce a reduction of TNF-alpha expression and secretion in inflamed spinal cord tissues and can stimulate OPC differentiation via activin-A secretion. This work underlines the potential therapeutic benefits of SCAP for spinal cord injury repair. PMID- 29417176 TI - Mechanisms of autophagy and relevant small-molecule compounds for targeted cancer therapy. AB - Autophagy is an evolutionarily conserved, multi-step lysosomal degradation process for the clearance of damaged or superfluous proteins and organelles. Accumulating studies have recently revealed that autophagy is closely related to a variety of types of cancer; however, elucidation of its Janus role of either tumor-suppressive or tumor-promoting still remains to be discovered. In this review, we focus on summarizing the context-dependent role of autophagy and its complicated molecular mechanisms in different types of cancer. Moreover, we discuss a series of small-molecule compounds targeting autophagy-related proteins or the autophagic process for potential cancer therapy. Taken together, these findings would shed new light on exploiting the intricate mechanisms of autophagy and relevant small-molecule compounds as potential anti-cancer drugs to improve targeted cancer therapy. PMID- 29417180 TI - [Cervical decompression surgery]. PMID- 29417179 TI - The DNA double-strand "breakome" of mouse spermatids. AB - De novo germline mutations arise preferentially in male owing to fundamental differences between spermatogenesis and oogenesis. Post-meiotic chromatin remodeling in spermatids results in the elimination of most of the nucleosomal supercoiling and is characterized by transient DNA fragmentation. Using three alternative methods, DNA from sorted populations of mouse spermatids was used to confirm that double-strand breaks (DSB) are created in elongating spermatids and repaired at later steps. Specific capture of DSB was used for whole-genome mapping of DSB hotspots (breakome) for each population of differentiating spermatids. Hotspots are observed preferentially within introns and repeated sequences hence are more prevalent in the Y chromosome. When hotspots arise within genes, those involved in neurodevelopmental pathways become preferentially targeted reaching a high level of significance. Given the non-templated DNA repair in haploid spermatids, transient DSBs formation may, therefore, represent an important component of the male mutation bias and the etiology of neurological disorders, adding to the genetic variation provided by meiosis. PMID- 29417181 TI - Analysis of quality of life after major trauma: a spanish follow-up cohort study. AB - PURPOSE: Study objectives are to determine whether quality of life is recovered completely after major injury and to identify determinants associated with a worse quality of life. METHODS: Prospective 12-month follow-up of injured patients admitted to the intensive care unit in a Spanish level 1 trauma centre. The main outcome (quality of life) was measured using the EQ-5D-5L. The relationships between sociodemographic factors, injury severity and location, and quality of life scores were evaluated. Mean comparison analysis (95% confidence interval) was performed with the student "t" test for quantitative variables and with chi-squared for proportion comparison (qualitative variables). A multivariate logistic regression (odds ratio and 95% confidence interval) was performed to identify determinants of each dimension, and a multivariate linear regression (regression coefficient and 95% confidence interval) to identify the determinants of EQus and EQvas. RESULTS: Over a 2-year period, 304 patients who met the inclusion criteria were identified, and 200 patients (65.8%) were finally included. Most of patients suffered blunt trauma (91.5%), 72.5% were men, mean age was 47.8, mean ISS was 15.2. The overall health index (EQvas) improved slightly, but its mean value at 12 months was below the Spanish population norm (P < 0.001). In the multivariate analysis, age >= 55, female gender and unskilled employment were risk factors for a lower EQvas. Also in the multivariate analysis, having a severe extremity injury was associated with a lower score on the mobility dimension (OR 6.56 95% CI 2.00, 21.55) while age >= 55 years was associated with a lower score on the usual activities dimension (OR 3.52 95% CI 1.17, 10.57). Female gender was the most important factor associated with suffering pain (OR 4.54, 95% CI 2.01, 10.27) and depression/anxiety (OR 4.04, 95% CI 1.88, 8.65). In the univariate and multivariate analyses, female gender, age >= 55 years, ISS >= 25 and severe extremity injury were associated with a lower EQ utility score (EQus). CONCLUSIONS: The quality of life score improves during the first year after major trauma. However, it does not return to the reference levels for the normal population. Female gender and age >= 55 years are statistically significant determinants of poorer EQvas and EQus. PMID- 29417178 TI - Cellular and molecular mechanisms of HIV-1 integration targeting. AB - Integration is central to HIV-1 replication and helps mold the reservoir of cells that persists in AIDS patients. HIV-1 interacts with specific cellular factors to target integration to interior regions of transcriptionally active genes within gene-dense regions of chromatin. The viral capsid interacts with several proteins that are additionally implicated in virus nuclear import, including cleavage and polyadenylation specificity factor 6, to suppress integration into heterochromatin. The viral integrase protein interacts with transcriptional co activator lens epithelium-derived growth factor p75 to principally position integration within gene bodies. The integrase additionally senses target DNA distortion and nucleotide sequence to help fine-tune the specific phosphodiester bonds that are cleaved at integration sites. Research into virus-host interactions that underlie HIV-1 integration targeting has aided the development of a novel class of integrase inhibitors and may help to improve the safety of viral-based gene therapy vectors. PMID- 29417182 TI - Simultaneous common bile duct clearance and laparoscopic cholecystectomy: experience of a one-stage approach. AB - INTRODUCTION: The timing and optimal method for common bile duct (CBD) clearance and laparoscopic cholecystectomy remains controversial. Several different approaches are available in clinical practice. The current study presents the experience of two European hospitals of simultaneous laparoscopic cholecystectomy (LC) and intra-operative endoscopic retrograde cholangiopacreatography (IO-ERCP) done by surgeons. METHODS: Retrospective analysis of all consecutive patients subjected to LC + IO-ERCP during their index admission between 4/2014 and 9/2016. Data accrued included patient demographics, laboratory markers, operation time (min) reported as mean (+/- SD) and hospital length of stay (LOS) reported as median (lower quartile, upper quartile). RESULTS: During the 29-month study, a total of 201 consecutive LC + IO-ERCPs were performed. The mean age of patients was 55 +/- 19 years and 67% were female. The mean intervention time was 105 +/- 44 min. The total LOS was 4 (3, 7) days and the post-operative LOS was 2 (1, 3) days. A total of 6 (3%) patients experienced post-interventional pancreatitis and two (1%) patients suffered a Strasberg type A bile leak. All patients were successfully discharged. CONCLUSION: Simultaneous LC + IO-ERCP is associated with few complications. Further studies investigating cost-benefit and patient satisfaction are warranted. PMID- 29417183 TI - Impaired hypoglycaemia awareness in type 1 diabetes: lessons from the lab. AB - Hypoglycaemia remains the most common metabolic adverse effect of insulin and sulfonylurea therapy in diabetes. Repeated exposure to hypoglycaemia leads to a change in the symptom complex that characterises hypoglycaemia, culminating in a clinical phenomenon referred to as impaired awareness of hypoglycaemia (IAH). IAH effects approximately 20-25% of people with type 1 diabetes and increases the risk of severe hypoglycaemia. This review focuses on the mechanisms that are responsible for the much higher frequency of hypoglycaemia in people with diabetes compared with those without, and subsequently how repeated exposure to hypoglycaemia leads to the development of IAH. The mechanisms that result in IAH development are incompletely understood and likely to reflect changes in multiple aspects of the counterregulatory response to hypoglycaemia, from adaptations within glucose and non-glucose-sensing cells to changes in the integrative networks that govern glucose homeostasis. Finally, we propose that the general process that incorporates many of these changes and results in IAH following recurrent hypoglycaemia is a form of adaptive memory called 'habituation'. PMID- 29417184 TI - Galectin-3 is independently associated with progression of nephropathy in type 2 diabetes mellitus. AB - AIMS/HYPOTHESIS: Galectin-3 has been implicated in cardiac and renal fibrosis and serves as a prognostic clinical indicator in heart failure. The aim of the present study was to evaluate whether serum galectin-3 level is associated with progressive kidney disease in type 2 diabetes. METHODS: Galectin-3 was measured in baseline samples by ELISA in 1320 participants with type 2 diabetes with eGFR >=30 ml min-1 1.73 m-2. The primary outcome was defined as doubling of serum creatinine and/or initiation of renal replacement therapy during follow-up. The secondary outcome was progression to macroalbuminuria in individuals with normo- or microalbuminuria at baseline. RESULTS: Serum galectin-3 levels were significantly increased in a random subgroup of 270 type 2 diabetic individuals with eGFR >60 ml min-1 1.73 m-2 compared with an age- and sex-matched non diabetic control group (7.58 +/- 2.29 ng/ml vs 6.10 +/- 1.91 ng/ml, respectively, p < 0.01). In the whole diabetic cohort, after a mean follow-up of 9 years, galectin-3 was independently associated with doubling of serum creatinine (HR 1.19; 95% CI 1.14, 1.24, p < 0.001) and incident macroalbuminuria (HR 1.20; 95% CI 1.12, 1.30, p < 0.001), even after adjusting for traditional risk factors, baseline eGFR and albuminuria status. Individuals with galectin-3 levels in the highest quartile had a fourfold risk of renal function loss and threefold risk of incident macroalbuminuria. CONCLUSIONS/INTERPRETATION: Serum galectin-3 was independently associated with progressive renal disease in type 2 diabetes. Further mechanistic studies are warranted to determine whether galectin-3 is simply a disease biomarker or is also a mediator of the development and progression of diabetic nephropathy. PMID- 29417186 TI - A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes. AB - AIMS/HYPOTHESIS: Identifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies. METHODS: We studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS. RESULTS: Of the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p < 0.0001). Age of diabetes diagnosis and type 1 diabetes GRS combined to be highly discriminatory of monogenic autoimmunity (receiver operating characteristic AUC: 0.88). Most individuals without a mutation in a known gene had a high type 1 diabetes GRS, suggesting that they have polygenic clustering of type 1 diabetes and additional autoimmunity and should not be included in gene discovery studies. CONCLUSIONS/INTERPRETATION: We have shown that the type 1 diabetes GRS can identify individuals likely to have monogenic autoimmunity, helping both diagnostic testing and novel monogenic autoimmunity gene discovery. Individuals with monogenic autoimmunity have a different clinical course to those with polygenic type 1 diabetes and can respond well to therapies targeting the underlying genetic defect. PMID- 29417185 TI - Diabetes in the older patient: heterogeneity requires individualisation of therapeutic strategies. AB - Owing to the worldwide increase in life expectancy, the high incidence of diabetes in older individuals and the improved survival of people with diabetes, about one-third of all individuals with diabetes are now older than 65 years. Evidence is accumulating that type 2 diabetes is associated with cognitive impairment, dementia and frailty. Older people with diabetes have significantly more comorbidities, such as myocardial infarction, stroke, peripheral arterial disease and renal impairment, compared with those without diabetes. However, as a consequence of the increased use of multifactorial risk factor intervention, a considerable number of older individuals can now survive for many years without any vascular complications. Given the heterogeneity of older individuals with type 2 diabetes, an individualised approach is warranted, which must take into account the health status, presence or absence of complications, and life expectancy. In doing so, undertreatment of otherwise healthy older individuals and overtreatment of those who are frail may be avoided. Specifically, overtreatment of hyperglycaemia in older patients is potentially harmful; in particular, insulin and sulfonylureas should be avoided or, if necessary, used with caution. Instead, glucose-dependent drugs that do not induce hypoglycaemia are preferable since older patients with diabetes and impaired kidney function are especially vulnerable to this adverse event. PMID- 29417187 TI - Responses of Aquatic Hyphomycetes to Temperature and Nutrient Availability: a Cross-transplantation Experiment. AB - Aquatic hyphomycetes represent a large component of the microbial assemblage that decomposes submerged leaf-litter in fluvial ecosystems. The structure and activity of these fungal decomposers depend on environmental factors. Fungal communities may adapt to local habitat conditions; however, little is known about how fungal communities respond to abrupt changes in factors such as nutrient availability and temperature. To respond to this question, we carried out a cross transplantation experiment, which assessed the decomposer activity and structure of this microbial community on decaying leaves transplanted from a cold and oligotrophic stream (S1) to a warmer and nitrogen-richer one (S2) and vice versa. Results were compared to those from untransplanted leaves decomposing either at S1 or at S2. In terms of days, untransplanted leaves were decomposed at a similar rate in both streams; the change to warmer and nitrogen-richer waters (S1 ? S2) significantly enhanced the decomposition process while the reciprocal transplantation (S2 ? S1) did not alter decomposition rate. However, when standardizing the temperature effects by using degree-days, microbial decomposers under colder conditions were more efficient in terms of accumulated heat, independent of the initial or final incubation site. Regarding community structure, taxa richness and diversity of aquatic hyphomycetes appear to be favoured under warmer and richer conditions, increasing after transplantation to S2 but with little effect on the predominant taxa. However, the reciprocal transplantation (S2 ? S1) yielded a clear decline of the dominant taxa at S2 (Lunulospora curvula) in favour of the local dominant ones. Thus, effects of environmental changes on activity and community structure can be highly variable and not always clearly linked or reciprocal. Therefore, results from simplified experimental designs (e.g. artificial assemblages under laboratory conditions) must be taken with caution. Additional field studies and manipulative experimentation dealing with natural communities are required when trying to extend individual results to complex scenarios such as those projected by global change. PMID- 29417189 TI - ? PMID- 29417188 TI - Assessment of Bacterial Community Composition of Anaerobic Granular Sludge in Response to Short-Term Uranium Exposure. AB - The effect of 10-50 MUM uranium (U(VI)) on the bacterial community of anaerobic granular sludge was investigated by 24-h exposure tests, after which the bacterial community was analyzed by high-throughput sequencing. The specific U(VI) reducing activity of the anaerobic granular sludge ranged between 3.1 to 19.7 MUM U(VI) g-1(VSS) h-1, independently of the initial U(VI) concentration. Alpha diversity revealed that microbial richness and diversity was the highest for anaerobic granular sludge upon 10 MUM uranium exposure. Compared with the original biomass, the phylum of Euryarchaeota was significantly affected, whereas the Bacteroidetes, Firmicutes, and Synergistetes phyla were only slightly affected. However, the abundance of Chloroflexi and Proteobacteria phyla clearly increased after 24 h uranium exposure. Based on the genus level analysis, significant differences appeared in the bacterial abundance after uranium exposure. The proportions of Pseudomonas, Acinetobacter, Parabacteroides, Brevundimonas, Sulfurovum, and Trichococcus increased significantly, while the abundance of Paludibacter and Erysipelotrichaceae incertae sedis decreased dramatically. This study shows a dynamic diversification of the bacterial composition as a response to a short time (24 h) U(VI) exposure (10-50 MUM). PMID- 29417190 TI - [Tinnitus - New challenge and therapeutic approaches. German version]. PMID- 29417191 TI - [New clinical applications for laser Doppler vibrometry in otology]. AB - BACKGROUND: An instrument to measure vibration in the middle ear needs to be sensitive enough to detect displacement on a nanometer scale, yet not affect the vibration itself. Numerous techniques have been described in the literature, but laser Doppler vibrometry (LDV) has nowadays become established as the standard method in hearing research. OBJECTIVE: This article aims to present possible clinical applications of an LDV system in otology. MATERIALS AND METHODS: A commercially available single-point vibrometer was used. Measurements were carried out both with the sensor head mounted on an operating microscope and as a handheld device with the sensor head manually inserted in the ear canal. For the latter, a custom-made unit containing an electrically tunable lens was attached to the sensor head. Middle ear vibrations were measured in a temporal bone model as well as in patients during and after implantation of a Vibrant Soundbridge (VSB; MED-EL Corp., Durham/NC, USA). RESULTS: Different types of middle ear pathologies can be distinguished by the frequency response of the umbo. The LDV technique can be used for intraoperative quantification of the coupling quality of the VSB's Floating Mass Transducer (FMT; MED-EL) to the ossicle chain during VSB implantation. Postoperatively, the method serves as a follow-up testing tool if a deterioration in aided hearing threshold occurs. The measurement can reveal changes in the umbo transfer function, e. g., due to middle ear scarring or dislocation of the FMT. CONCLUSION: Many clinical questions in otology can be addressed by LDV. However, due to the high acquisition costs of an LDV system, the relatively large instrumental setup, and the large inter-ear variability of middle-ear function, the technique has not (yet) become established in clinical routine. PMID- 29417192 TI - [Current aspects of tinnitus and depression]. AB - Health authorities underestimate the negative influence of emotional factors such as depression, anxiety disorders, or somatoform disorders in the development of tinnitus and their contribution to a poor prognosis. This can lead to underestimation of the impairment suffered by tinnitus patients and, consequently, a possibly incorrect treatment approach or belated initiation of therapy. Mental disorders play a large role in the S3AWMF "Tinnitus" guidelines. Thus, the somatic and psychiatric approaches for treatment of chronic tinnitus patients are combined. Starting with taking chronic tinnitus patients' case history, special attention should be paid to comorbid mental disorders. PMID- 29417193 TI - [Smartphone app-supported approaches to tinnitus therapy]. AB - In recent years, applications (apps) for medical purposes have been developed and introduced, including apps that perform diagnostics and documentation for hearing loss and tinnitus in combination with smartphones. Even therapeutic apps, particularly for chronic tinnitus, have been launched. This review discusses the existing scientific literature for these smartphone applications. For tinnitus, Internet-based cognitive behavioral therapy has been developed and evaluated. For tinnitus therapy, introduced apps combine acoustic stimulation and music, or serve acoustic stimulation of cortical regions around the tinnitus frequency. Although these apps appear very innovative, their effectiveness has not yet been scientifically proven. A general problem associated with using smartphone apps lies in their safety in terms of possible side effects and personal data protection. However, Internet programs and apps can be a useful supplement to multimodal tinnitus therapies. PMID- 29417194 TI - [Sphincter and corpus cavernosum prostheses as components of endoprosthetics in urology]. AB - Artificial urinary sphincters and penile corpus cavernosum prostheses are effective for patients who are not adequately treated by conservative treatment or pharmacotherapy. Both of these devices show good results concerning functional outcome if used within the correct patient selection. Penile prostheses are meant to be the last line of treatment for severe erectile dysfunction after failure of conventional treatment. Artificial urinary sphincters are the treatment of choice for severe urinary stress incontinence. Although the surgical procedure is an easy one, only highly experienced centers should perform the implantation due to minimization of infections and loss of function. Because of the hydraulic working principle of both devices, check-ups on a regular basis are strongly recommended. In the case of a loss of function or infections, a rapid and targeted treatment is the key to make new implantations possible in the future. PMID- 29417196 TI - Engineering of the Trichoderma reesei xylanase3 promoter for efficient enzyme expression. AB - The GH10 xylanase XYNIII is expressed in the hyper-cellulase-producing mutant PC 3-7, but not in the standard strain QM9414 of Trichoderma reesei. The GH11 xylanase gene xyn1 is induced by cellulosic and xylanosic carbon sources while xyn3 is induced only by cellulosic carbon sources in the PC-3-7 strain. In this study, we constructed a modified xyn3 promoter in which we replaced the cis acting region of the xyn3 promoter by the cis-acting region of the xyn1 promoter. The resulting xyn3 chimeric promoter exhibited improved inductivity against cellulosic carbon over the wild-type promoter and acquired inductivity against xylanosic carbon. Furthermore, PC-3-7 expressing the heterologous beta glycosidase gene, Aspergillus aculeatus bgl1, under the control of the xyn3 chimeric promoter, showed enhanced saccharification ability through increased cellobiase activity. We also show that the xyn3 chimeric promoter is also functional in the QM9414 strain. Our results indicate that the xyn3 chimeric promoter is very efficient for enzyme expression. PMID- 29417197 TI - Modulation of gut microbiota by dietary supplementation with tuna oil and algae oil alleviates the effects of D-galactose-induced ageing. AB - Previous studies have shown that dietary supplementation with tuna oil and algae oil can alleviate the effects of ageing on learning and memory in mouse models, but the mechanism of this effect remains unknown. This study aimed to determine whether dietary oil supplementation alters the composition of the gut microbiota during the prevention of age-related effects on cognition. Ageing mice received dietary oil supplementation continuously for 12 weeks. The supplementation was found to improve the animals' learning and cognition, and this effect was most marked in the TO200AO400 group, which received a 1:2 mixture of tuna oil and algae oil at 600 mg kg-1 day-1. Next-generation sequencing of the 16S rRNA gene present in faecal samples showed that the gut microbiota varied in the groups that received different oil treatments; the TO200AO400 treatment most closely restored the composition of the D-galactose-altered gut microbiota to that of the control. Moreover, 83 altered operational taxonomic units (OTUs) responsive to dietary oil supplementation were identified; five of these differed in one or more parameters associated with host ageing. In conclusion, this study confirmed the effect of dietary oil supplementation on the alleviation of age-related decline in cognitive function and showed that oil supplementation results in alterations in the composition of the gut microbiota. Further research will be needed to elucidate the causal relationship between the reversal of age-related cognitive decline and gut microbiota modulation and to explore the potential of gut microbial communities as a diagnostic biomarker and a therapeutic target in ageing. PMID- 29417198 TI - New cost-effective bioconversion process of palm kernel cake into bioinsecticides based on Beauveria bassiana and Isaria javanica. AB - The present study aimed to add value to palm oil by-products as substrates to efficiently produce conidia of Beauveria bassiana and Isaria javanica (Hypocreales: Cordycipitaceae) for biological control of the whitefly Bemisia tabaci (Hemiptera: Aleyrodidae), through a solid-state fermentation process using palm kernel cake and palm fiber as nutrient source and solid matrix, respectively. The optimum culture conditions yielded high concentrations of viable conidia after air-drying, when the fungi were grown on palm kernel cake (B. bassiana 7.65 * 109 and I. javanica 2.91 * 109 conidia g-1 dry substrate) after 6 days under optimal growth conditions set to 60% substrate moisture and 32 degrees C. Both fungal strains exhibited high efficacy against third-instar whitefly nymphs, inducing mortality up to 62.9 and 56.6% by B. bassiana and I. javanica, respectively, assessed after 9 days post-application in a screenhouse. Furthermore, we noted that insect mortality was strongly correlated with high atmospheric moisture, while B. bassiana appeared to require shorter accumulative hours under high moisture to kill whitefly nymphs compared to I. javanica. Our results underpin a feasible and cost-effective mass production method for aerial conidia, using palm kernel as the main substrate in order to produce efficacious fungal bioinsecticides against an invasive whitefly species in Brazil. Finally, our fermentation process may offer a sustainable and cost-effective means to produce eco-friendly mycoinsecticides, using an abundant agro-industrial by product from Brazil that will ultimately assist in the integrated management of agricultural insect pests. PMID- 29417199 TI - Role and mechanism of cell-surface hydrophobicity in the adaptation of Sphingobium hydrophobicum to electronic-waste contaminated sediment. AB - Sphingomonads are isolated at exceptionally high frequency from organic polluted environments and assumed to be more hydrophobic than other Gram-negative bacteria. However, the potential roles of cell-surface hydrophobicity (CSH) in the cell survival in polluted environment, as well as the mechanisms underlying the CSH of sphingomonads, remain unclear. Sphingobium hydrophobicum C1T is a highly hydrophobic sphingomonad isolated from electronic-waste contaminated sediment. In this study, we found that exposure to the typical pollutants in electronic-waste contaminated sediment, such as the heavy metal ion Pb and the organic compound deca-brominated diphenyl ether (deca-BDE), resulted in the development of even higher CSH of the hydrophobic strain C1T; but no significant change was observed in the low CSH of its hydrophilic variant C2. The hydrophobic strain C1T achieved higher biomass yield in standing conditions and adsorbed more amounts of hydrophobic deca-BDE than its hydrophilic variant C2, suggesting that the high CSH potentially enhanced the adaptation of hydrophobic strain to colonize in sediment and adsorb hydrophobic nutrients. The identification of the bacterial cell-surface constituents showed that the high CSH of S. hydrophobicum was contributed greatly by outer-membrane proteins, particularly membrane transporters functioning as enhancers for nutrient uptake and stress sustainment. This study will enhance our understanding of the adaptive strategies of sphingomonads in contaminated environments. It will be of great importance to enhance the CSH of sphingomonads and utilize them in cleaning up the environment from organic pollution. PMID- 29417200 TI - Production of extracellular heterologous proteins in Streptomyces rimosus, producer of the antibiotic oxytetracycline. AB - Among the Streptomyces species, Streptomyces lividans has often been used for the production of heterologous proteins as it can secrete target proteins directly into the culture medium. Streptomyces rimosus, on the other hand, has for long been used at an industrial scale for oxytetracycline production, and it holds 'Generally Recognised As Safe' status. There are a number of properties of S. rimosus that make this industrial strain an attractive candidate as a host for heterologous protein production, including (1) rapid growth rate; (2) growth as short fragments, as for Escherichia coli; (3) high efficiency of transformation by electroporation; and (4) secretion of proteins into the culture medium. In this study, we specifically focused our efforts on an exploration of the use of the Sec secretory pathway to export heterologous proteins in a S. rimosus host. We aimed to develop a genetic tool kit for S. rimosus and to evaluate the extracellular production of target heterologous proteins of this industrial host. This study demonstrates that S. rimosus can produce the industrially important enzyme phytase AppA extracellularly, and analogous to E. coli as a host, application of His-Tag/Ni-affinity chromatography provides a simple and rapid approach to purify active phytase AppA in S. rimosus. We thus demonstrate that S. rimosus can be used as a potential alternative protein expression system. PMID- 29417201 TI - CD19 targeted CAR-T therapy versus chemotherapy in re-induction treatment of refractory/relapsed acute lymphoblastic leukemia: results of a case-controlled study. AB - Chimeric antigen receptor modified T cells against CD19 (CART19s) have potent anti-leukemia activities in patients with refractory/relapsed acute lymphoblastic leukemia (R/R ALL). This study was designed to investigate the correlation between safety/efficacy and therapeutic modalities including chemotherapy and CART19 therapy. Total 23 and 69 patients were enrolled in the CART19 group and in the chemotherapy group, respectively. The safety and efficacy profiles of 66 and 22 patients in the 2 groups were evaluated. The complete remission (CR) rate was higher in the CART19 group than that in the chemotherapy group (90.9 vs 37.9%, P = 0.000). For patients relapsed after allo-HSCT and chemotherapy, CR rates were 100% (8/8) vs 48.0% (12/25) (P = 0.009) and 85.7% (12/14) vs 31.7% (13/41) (P = 0.000), respectively. Moreover, a higher percentage in the CART19 group had results below the threshold for minimal residual disease (100 vs 7.58%, P = 0.000). In survival analysis, the overall survival rate at 12 months was higher in the CART19 group than that in the chemotherapy group (60.9 vs 10.1%, P = 0.000). For post-transplant patients achieving CR, 25.0% (2/8) and 75.0% (9/12) complicated with GVHD (P = 0.04) in the CART19 group and chemotherapy group, respectively. For all CR patients, the median duration of absolute neutrophil count less than 500/MUL and platelet count less than 20,000/MUL were longer in the CART19 group than in the chemotherapy group (p = 0.0047 and 0.0003, respectively). Our data demonstrated that patients with CART19s therapy acquired higher rates of remission and longer survival, confirming the encouraging application of CART19 therapy in R/R ALL. PMID- 29417202 TI - Sequential development of monoclonal B cell lymphocytosis-derived small lymphocytic lymphoma and plasma cell leukemia. PMID- 29417203 TI - Reciprocal Regulation of OmpR and Hfq and Their Regulatory Actions on the Vi Polysaccharide Capsular Antigen in Salmonella enterica Serovar Typhi. AB - Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of human typhoid fever. S. Typhi expresses a major virulence determinant called Vi polysaccharide capsular antigen, which is encoded by the viaB locus containing 10 consecutive genes including tviA and tviB. Expression of Vi antigen is regulated by the two-component regulatory system EnvZ/OmpR and the global RNA-binding factor Hfq. In this study, we show that OmpR coordinates with Hfq to regulate the transcription of Vi antigen genes under osmotic stress conditions. OmpR binds to the promoters of tviA and its own genes to activate their transcription; however, it positively regulates tviB and negatively regulates hfq in an indirect manner. Moreover, Hfq reversely inhibits ompR, tviA and tviB, and positively regulates its own gene expression. Thus, we report of a complex gene regulatory network involving the reciprocal regulation and autoregulation of OmpR and Hfq, and their regulatory actions on Vi polysaccharide capsular antigen genes in S. Typhi. PMID- 29417204 TI - The influence of gestational age, mode of delivery and abdominal wall closure method on the surgical outcome of neonates with uncomplicated gastroschisis. AB - AIM OF THE STUDY: To evaluate if gestational age (GA), mode of delivery and abdominal wall closure method influence outcomes in uncomplicated gastroschisis (GTC). METHODS: Retrospective review of NICU admissions for gastroschisis, August 2008-July 2016. Primary outcomes were: time to start enteral feeds (on-EF), time to discontinue parenteral nutrition (off-PN), and length of stay (LOS). MAIN RESULTS: A total of 200 patients with GTC were admitted to our NICU. Patients initially operated elsewhere (n = 13) were excluded. Patients with medical/surgical complications (n = 62) were analyzed separately. The study included 125 cases of uncomplicated GTC. There were no statistically significant differences in the outcomes of patients born late preterm (34 0/7-36 6/7; n = 70) and term (n = 40): on-EF 19 (5-54) versus 17 (7-34) days (p = 0.29), off-PN 32 (12-101) versus 30 (16-52) days (p = 0.46) and LOS 40 (18-137) versus 37 (21-67) days (p = 0.29), respectively. Patients born before 34 weeks GA (n = 15) had significantly longer on-EF, off-PN and LOS times compared to late preterm patients: 26 (12-50) days (p = 0.01), 41 (20-105) days (p = 0.04) and 62 (34-150) days (p < 0.01), respectively. There were no significant differences in outcomes between patients delivered by C-section (n = 62) and patients delivered vaginally (n = 63): on-EF 20 (5-50) versus 19 (7-54) days (p = 0.72), off-PN 32 (12-78) versus 33 (15-105) days (p = 0.83), LOS 42 (18-150) versus 41 (18-139) days (p = 0.68), respectively. There were significant differences in outcomes between patients who underwent primary reduction (n = 37) and patients who had a silo (88): on-EF 15 (5-37) versus 22 (6-54) days (p < 0.01), off-PN 28 (12-52) versus 34 (15-105) days (p = 0.04), LOS 36 (18-72) versus 44 (21-150) days (p = 0.04), respectively. CONCLUSION: In our experience, late preterm delivery did not affect outcomes compared to term delivery in uncomplicated GTC. Outcomes were also not influenced by the mode of delivery. Patients who underwent primary reduction had better outcomes than patients who underwent silo placement. PMID- 29417205 TI - Localised cutaneous microvascular adaptation to exercise training in humans. AB - PURPOSE: Exercise training induces adaptation in conduit and resistance arteries in humans, partly as a consequence of repeated elevation in blood flow and shear stress. The stimuli associated with intrinsic cutaneous microvascular adaptation to exercise training have been less comprehensively studied. METHODS: We studied 14 subjects who completed 8-weeks cycle ergometer training, with partial cuff inflation on one forearm to unilaterally attenuate cutaneous blood flow responses during each exercise-training bout. Before and after training, bilateral forearm skin microvascular dilation was determined using cutaneous vascular conductance (CVC: skin flux/blood pressure) responses to gradual localised heater disk stimulation performed at rest (33, 40, 42 and 44 degrees C). RESULTS: Cycle exercise induced significant increases in forearm cutaneous flux and temperature, which were attenuated in the cuffed arm (2-way ANOVA interaction-effect; P < 0.01). We found that forearm CVC at 42 and 44 degrees C was significantly lower in the uncuffed arm following 8-weeks of cycle training (P < 0.01), whereas no changes were apparent in the contralateral cuffed arm (P = 0.77, interaction effect P = 0.01). CONCLUSIONS: Lower limb exercise training in healthy young men leads to lower CVC-responses to a local heating stimulus, an adaptation mediated, at least partly, by a mechanism related to episodic increases in skin blood flow and/or skin temperature. PMID- 29417206 TI - Depressive residual symptoms are associated with illness course characteristics in a sample of outpatients with bipolar disorder. AB - Rates of 50-70% of residual symptoms referring to subsyndromal manifestations between episodes that do not meet the required criteria for episode definition were reported in bipolar disorder (BD). However, the specific role of these symptoms on the course of BD patients is poorly understood; thus, we aimed to investigate factors associated with depressive residual symptoms. Overall, 255 currently euthymic BD outpatients on maintenance treatment, including 95 (37.2%) males and 160 (62.8%) females, were consecutively recruited at the Section of Psychiatry, Department of Neuroscience, University of Genoa (Italy) and underwent detailed structured interviews, comprehensive clinical interviews, and clinical record reviews for assessment/collection of relevant information concerning the course of illness and clinical status including cross-referral of all available information. After categorizing subjects according to the presence/absence of residual symptoms, groups were compared along clinical variables and variables associated with residual symptoms were analyzed using multivariate analyses. Subjects with residual symptoms were less likely to report substance abuse (chi2(2) = 11.937, p <= 0.005) and lifetime psychotic symptoms (chi2(2) = 10.577, p = 0.005), and more likely to report higher illness episodes, longer duration of illness (t253 = 67.282, p <= 0.001; t253 = 10.755, p <= 0.001), and longer duration of current illness episode (t253 = 7.707, p <= 0.001) than those without residual symptoms. After multivariate analyses, a significant positive contribution to residual symptoms was given only by duration of current illness episode (beta = 0.003; p <= 0.05), and lifetime psychotic symptoms (beta = 1.094; p <= 0.005). Clinicians have to pay attention to minimize residual symptoms that may significantly impact on the course of BD and achievement of full remission between episodes. PMID- 29417207 TI - Gradual fibular transfer by ilizarov external fixator in post-traumatic and post infection large tibial bone defects. AB - INTRODUCTION: Several reconstructive procedures have been used in management of large tibial bone defects including bone graft, bone transport (distraction osteogenesis) using various external fixators, and vascularized bone graft. Each of these procedures has its limitations and complications. The study describes gradual medial fibular transfer using Ilizarov external fixators in management of patients with large tibial defect, either following infection or trauma. PATIENTS AND METHODS: Between May 2011 and June 2013, 14 patients were prospectively included in the current study. The inclusion criteria were large tibial defect due to trauma or infection with severe soft tissue compromise, and small or poor tibial bone remnants making bone lengthening difficult. Exclusion criteria were patients with vascular or nerve injuries. The average age of the patients was 31.64 (+/- 6.5) years. Medial fibular transfer was done for all patients using Ilizarov at a rate of 0.5 mm twice daily. Iliac bone graft was used in all patients after the transfer. RESULTS: The average segmental bone defect of the tibia was (13.2 +/- 2.6), ranging between 8 and 18.6 cm. Union was achieved in all patients with average fixator time was 32.42 (+/- 4.32) weeks. Average follow up after removal of the fixator was 40.5 (+/- 6.9) months. CONCLUSION: Gradual fibular transfer by Ilizarov external fixator is a reliable technique in management of post-traumatic and post-infection large tibial bone defects with good clinical outcome, and with few complications. PMID- 29417208 TI - Novel pathomorphologic classification of capsulo-articular lesions of the pubic symphysis in athletes to predict treatment and outcome. AB - INTRODUCTION: Radiographic abnormalities of the symphysis as well as the formation of accessory clefts, indicating injury at the rectus-adductor aponeurosis, reportedly relate to longstanding groin pain in athletes. However, yet, no systematic classification for clinical and scientific purposes exists. We aimed to (1) create a radiographic classification based on symphysography; (2) test intra- and interobserver reliability; (3) characterise clinical significance of the morphologic patterns by evaluating success of injection therapy. PATIENTS AND METHODS: We retrospectively reviewed symphysography, AP radiographs, and MRI of the pelvis from 70 consecutive competitive athletes, with chronic groin pain. Symphysographs were evaluated for intra- and interobserver variance using cohen's kappa statistics. Morphologic studies of the different contrast distribution patterns and their clinical and radiological correlation with symptom relief were investigated. All patients were followed up to evaluate immediate and long-term response to the initial therapeutic injection with steroid. RESULTS: Four reproducible symphysographic patterns were identified: type 0, no changes; type 1, symphyseal disk degeneration; types 2a with unilateral clefts, bilateral clefts (2b), suprapubic clefts (2c); and type 3, with expanded or multidirectional clefts. Analysis revealed excellent intra (0.94)-and interobserver (0.90) reliability. Our findings showed that 78.6% of our patients had significant short-term improvement enabling early resumption of physiotherapy, only in types 1 and 2 (p = 0.001), while type 0 and 3 did not respond. At follow-up, only 21.8% had permanent pain relief. Regarding the detection of pathologic clefts with symphysography, sensitivity (88%) and specifity (77%) were superior to that of MRI. CONCLUSIONS: A reproducible symphysography-based classification of distinct morphologic patterns is proposed. It serves as a predictive tool for response to injection therapy in a select group of pathologic lesions. Complete recovery after injection can only be expected in a lesser percentage, as this might indicate surgical treatment for long-term non-responders. PMID- 29417209 TI - Rapidly progressive interstitial lung disease due to anti-MDA5 antibodies without skin involvement: a case report and literature review. AB - Anti-MDA5 antibodies have been strongly associated with rapidly progressive interstitial lung disease (RP-ILD) in dermatomyositis (DM) patients, especially in the clinically amyopathic subset (CADM). We present a case of anti-MDA5 antibody-associated RP-ILD in a patient with arthritis but with no other clinical signs suggestive of DM or CADM successfully treated with a combination of cyclophosphamide, cyclosporine and corticoids. A review of the literature was also done. Despite its rarity, anti-MDA5 antibody-associated ILD should be suspected in cases of RP-ILD even without other signs of DM or CADM as prompt and aggressive treatment could improve prognosis. PMID- 29417210 TI - Standards of care and quality indicators for multidisciplinary care models for psoriatic arthritis in Spain. AB - To define and give priority to standards of care and quality indicators of multidisciplinary care for patients with psoriatic arthritis (PsA). A systematic literature review on PsA standards of care and quality indicators was performed. An expert panel of rheumatologists and dermatologists who provide multidisciplinary care was established. In a consensus meeting group, the experts discussed and developed the standards of care and quality indicators and graded their priority, agreement and also the feasibility (only for quality indicators) following qualitative methodology and a Delphi process. Afterwards, these results were discussed with 2 focus groups, 1 with patients, another with health managers. A descriptive analysis is presented. We obtained 25 standards of care (9 of structure, 9 of process, 7 of results) and 24 quality indicators (2 of structure, 5 of process, 17 of results). Standards of care include relevant aspects in the multidisciplinary care of PsA patients like an appropriate physical infrastructure and technical equipment, the access to nursing care, labs and imaging techniques, other health professionals and treatments, or the development of care plans. Regarding quality indicators, the definition of multidisciplinary care model objectives and referral criteria, the establishment of responsibilities and coordination among professionals and the active evaluation of patients and data collection were given a high priority. Patients considered all of them as important. This set of standards of care and quality indicators for the multidisciplinary care of patients with PsA should help improve quality of care in these patients. PMID- 29417211 TI - Predicting morbidity of liver resection. AB - PURPOSE: Multiple models have attempted to predict morbidity of liver resection (LR). This study aims to determine the efficacy of American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) surgical risk calculator and the Physiological and Operative Severity Score in the enUmeration of Mortality and Morbidity (POSSUM) in predicting post-operative morbidity in patients who underwent LR. METHODS: A retrospective analysis was conducted on patients who underwent elective LR. Morbidity risk was calculated with the ACS NSQIP surgical risk calculator and POSSUM equation. Two models were then constructed for both ACS-NSQIP and POSSUM-(1) the original risk probabilities from each scoring system and (2) a model derived from logistic regression of variables. Discrimination, calibration, and overall performance for ACS-NSQIP and POSSUM were compared. Sub-group analysis was performed for both primary and secondary liver malignancies. RESULTS: Two hundred forty-five patients underwent LR. Two hundred twenty-three (91%) had malignant liver pathologies. The post operative morbidity, 90-day mortality, and 30-day mortality rate were 38.3%, 3.7%, and 2.4% respectively. ACS-NSQIP showed superior discriminative ability, calibration, and performance to POSSUM (p = 0.03). Hosmer-Lemeshow plot demonstrated better fit of the ACS-NSQIP model than POSSUM in predicting morbidity. CONCLUSION: In patients undergoing LR, the ACS-NSQIP surgical risk calculator was superior to POSSUM in predicting morbidity risk. PMID- 29417213 TI - The effect of trabeculectomy on serum brain-derived neurotrophic factor levels in primary open-angle glaucoma. AB - PURPOSE: We aimed to investigate the effect of trabeculectomy on serum brain derived neurotrophic factor (BDNF) levels. Our secondary goal was to compare serum and aqueous humor (AH) BDNF levels in primary open-angle glaucoma (POAG) and control subjects. METHODS: This prospective, cross-sectional study consists of 20 eyes of with advanced-stage POAG who had trabeculectomy and 19 eyes of age- and sex-matched control healthy subjects who had cataract surgery. Serum and AH samples were obtained preoperatively in trabeculectomy group and control subjects. Serum samples were obtained at the third postoperative month in both groups. RESULTS: The aqueous humor and serum levels of BDNF at the surgery day were found to be strongly positive correlated (r = 0.868; p < 0.001). Serum and AH BDNF levels of POAG cases were significantly lower than control subjects at the surgery day (respectively p = 0.038, p = 0.011). In POAG cases, serum BDNF levels significantly increased at the third month after trabeculectomy while there was not a significant difference in control subjects with cataract surgery (p < 0.001; p = 0.717 respectively). CONCLUSION: Trabeculectomy was found to have a positive effect on serum BDNF levels in POAG cases. PMID- 29417214 TI - Trends in treatment strategies for suspected bacterial endophthalmitis. AB - PURPOSE: To describe how vitreoretinal specialists have incorporated the Endophthalmitis Vitrectomy Study (EVS) findings into current practice, to highlight divergences from the EVS recommendations, and address the role of microbial culture in guiding additional treatments. METHODS: This is a cross sectional survey of vitreoretinal specialists regarding indications used for performing a pars plana vitrectomy (PPV), selection of antibiotics for treatment, utilization of cultures, and treatment strategies for treatment-refractory patients with bacterial endophthalmitis. RESULTS: Of 681 physicians contacted, 149 (21.9%) responded. For patients with visual acuity of light perception or less, 75% of respondents utilized PPV. Intravitreal vancomycin and ceftazidime were used by 100% and 96% of participants respectively. Vitreal cultures were obtained more than 50% of the time by 86.5% of participants, and were used to influence retreatment less than 50% of the time by 77.8% of respondents. For patients with worsening clinical signs 48 hours after initial treatment, 69.8% of participants performed PPV with intravitreal antibiotics. CONCLUSIONS: Although most respondents followed the EVS guidelines, a minority deviated, and the majority generalized their strategy to other forms of endophthalmitis. There is significant variation in retreatment strategies, and while cultures are frequently obtained to help guide these treatments, they are utilized infrequently. PMID- 29417215 TI - Organ and tissue donation in a regional paediatric intensive care unit: evaluation of practice. AB - : Approximately 2% of those on the organ transplant list in the UK are children. Early identification of donors and referral to organ donation teams (ODT) has proven to increase both the success rate of gaining consent and the number of organs actually retrieved. To evaluate the practice relating to organ donation for children receiving end-of-life care on a paediatric intensive care unit (PICU) measured against the National Guidelines. All children 0-18 who received their end-of-life care and died on the PICU. A retrospective cohort study of organ donation patterns including referral, approach, consent and donation. This involved a review of case notes on PICU between the years 2009 and 2014. One hundred five deaths were identified and 100 notes were examined and data analysed to ascertain if religion, age and length of stay on PICU impacted on practice. Eighty-six children met the early identification criteria for potential donors, 40 (46.5%) children were referred to the ODT and 33 (38.3%) families were approached regarding donation. Twenty-one (24.4%) families consented to donation. Seventeen donations took place with a total of 41 sets of organs/tissues retrieved. Despite the majority of children meeting early identification for potential donors, many were not being referred. CONCLUSIONS: All children on end of-life care should be referred for potential organ donation. Organ donation needs to be seen as a priority for hospitals as a part of routine end-of-life care to help increase referral rates and give families the opportunity to donate. Many paediatric deaths are not referred for consideration of organ donation, despite guidelines stating that this process should be standard of care. Further optimization of referral rates may aid in increasing the number of organs available for donation. What is Known: * Shortage of organs continues to be a national problem. * NICE guidelines state that all patients who are on end-of life care should have the option of organ donation explored. * Required referral both increases the number of donors and organs donated. What is New: * The process of identifying and referring children for paediatric organ donation. * Identifies that children are still not being referred for organ donation. * Organ donation is still not a priority for hospitals. PMID- 29417216 TI - Respiratory hospital admissions and weather changes: a retrospective study in Charlottesville, Virginia, USA. AB - In most midlatitude locations, human morbidity and mortality are highly seasonal, with winter peaks driven by respiratory disease and associated comorbidities. But the transition between high and low mortality/morbidity months varies spatially. We use a measure of the thermal biophysical strain imposed on the respiratory system-the Acclimatization Thermal Strain Index (ATSI)-to examine respiratory hospital admissions in Charlottesville, VA. Daily respiratory admissions to the University of Virginia over a 19-year period are compared to ATSI values derived from hourly surface weather data acquired from the Charlottesville airport. Negative ATSI values (associated with transitions from warm (and humid) to cold (and dry) conditions) are related to admission peaks at seasonal and weekly timescales, whereas positive ATSI values (cold to warm) exhibit weaker relationships. This research marks the first application of the ATSI to human morbidity, and results suggest that respiratory strain may account for how people who are acclimated to different climates respond to short-term weather changes. PMID- 29417217 TI - Dew point temperature affects ascospore release of allergenic genus Leptosphaeria. AB - The genus Leptosphaeria contains numerous fungi that cause the symptoms of asthma and also parasitize wild and crop plants. In search of a robust and universal forecast model, the ascospore concentration in air was measured and weather data recorded from 1 March to 31 October between 2006 and 2012. The experiment was conducted in three European countries of the temperate climate, i.e., Ukraine, Poland, and the UK. Out of over 150 forecast models produced using artificial neural networks (ANNs) and multivariate regression trees (MRTs), we selected the best model for each site, as well as for joint two-site combinations. The performance of all computed models was tested against records from 1 year which had not been used for model construction. The statistical analysis of the fungal spore data was supported by a comprehensive study of both climate and land cover within a 30-km radius from the air sampler location. High-performance forecasting models were obtained for individual sites, showing that the local micro-climate plays a decisive role in biology of the fungi. Based on the previous epidemiological studies, we hypothesized that dew point temperature (DPT) would be a critical factor in the models. The impact of DPT was confirmed only by one of the final best neural models, but the MRT analyses, similarly to the Spearman's rank test, indicated the importance of DPT in all but one of the studied cases and in half of them ranked it as a fundamental factor. This work applies artificial neural modeling to predict the Leptosphaeria airborne spore concentration in urban areas for the first time. PMID- 29417218 TI - Experience of Immediate Ambulation and Early Discharge After Tumescent Anesthesia and Propofol Infusion in Cosmetic Breast Augmentation. PMID- 29417219 TI - Robust identification of mosaic variants in congenital heart disease. AB - Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (n = 715) and a cohort of healthy individuals (n = 416). This is a novel application of the somatic variant caller designed for cancer to WES trio data. We identified two cases with mosaic KMT2D mutations that are likely pathogenic for CHD, but conclude that, overall, mosaicism detectable in peripheral blood or saliva does not account for a significant portion of CHD etiology. PMID- 29417221 TI - Reevaluation of established and new criteria in differential diagnosis of Spitz nevus and melanoma. AB - The histopathologic differentiation between Spitz nevus and melanoma is of particular interest in routine diagnostic procedures of melanocytic tumors. Atypical Spitz nevi are sometimes difficult to distinguish from melanoma. There is still no single criterion that ensures a distinction of melanoma and atypical Spitz nevus. The aim of this study was to reevaluate established and new criteria to differentiate Spitz nevus from melanoma more reliably. We analyzed 25 melanomas with a Breslow index >= 1 mm and 18 classical compound Spitz nevi concerning their histopathologic, immunohistochemical and molecular genetic characteristics. Moreover, clinical follow-up data for 5 years were collected. We found statistically significant differences between Spitz nevus and melanoma for the following features: pagetoid spread, atypia, maturation, elastosis, Kamino bodies, p16 expression, and the staining pattern of HMB45. BRAF was positive in 7/21 melanomas and in 1/14 Spitz nevi. Fluorescence in situ hybridization confirmed the histopathologic diagnosis in 36/37 cases. The established clinical, histopathologic, and immunohistochemical criteria to differentiate Spitz nevus and melanoma could be reproduced in our collective. Especially, the expression of p16, BRAF analysis and fluorescence in situ hybridization proved to be helpful tools to improve the differentiation of Spitz nevus and melanoma in our study. Nevertheless, there is-until now-no reliable histopathologic and immunohistochemical parameter which can discriminate Spitz nevus and melanoma with absolute certainty. PMID- 29417220 TI - Ubiquitin-like activating enzymes BcAtg3 and BcAtg7 participate in development and pathogenesis of Botrytis cinerea. AB - In eukaryotes, the ubiquitin-like (UBL) protein-activating enzymes play a crucial role in autophagy process, however, it is poorly characterized in filamentous fungi. Here, we investigated the functions of two UBL activating enzymes, BcAtg3 (E2) and BcAtg7 (E1) in the plant pathogenic fungus Botrytis cinerea. The physical interaction of BcAtg3 with BcAtg7 was demonstrated by yeast two-hybrid system. Subcellular localization assays showed that BcAtg3 diffused in cytoplasm, and BcAtg7 localized in cytoplasm as pre-autophagosomal structures (PAS). Target gene deletion experiments revealed that both BcATG3 and BcATG7 are essential for autophagy pathway. Notably, the single deletion mutant of BcATG3 and BcATG7 displayed similar biological phenotypes, including the defects in mycelial growth, conidiation and sclerotial formation. Infection tests showed that both BcATG3 and BcATG7 were required for full virulence of B. cinerea. All of these defective phenotypes were rescued by gene complementation. These results indicate that BcATG3 and BcATG7 are necessary for autophagy to regulate fungal development and pathogenesis in B. cinerea. PMID- 29417222 TI - Aspartic acid introduce the functional amine groups on the surface of superparamagnetic Fe(OH)3@Fe3O4 nanoparticles for efficient immobilization of Penaeus vannamei protease. AB - In this study, we synthesized super magnetic Fe(OH)3@Fe3O4 nanoparticles (SPIONs) by the co-precipitation method and introduction of amine groups via chemisorption of L-aspartic acid (LAA) on the surface of SPIONs. Penaeus vannamei protease (PVP) was immobilized onto amine-functionalized supermagnetic nanoparticles (ASPIONs), and conditions affecting PVP immobilization were investigated. PVP immobilized onto ASPIONs exhibited shifts in both working optimum pH and temperature with an increase from pH 7 to pH 8, and increased optimum temperature by 10 degrees C compared to free enzyme. Similarly, the thermal, pH, and storage stabilities of the immobilized PVP were superior to those of free form of the enzyme. In comparison to the free enzyme, the immobilized enzyme was reusable for 15 cycles while retaining 73% of its initial activity. The Michaelis-Menten kinetic constant (Km) and maximum reaction velocity (Vmax) for free PVP were 2.3 uM and 88 uM min-1, respectively, whereas Km and Vmax values of immobilized enzyme were 2.5 uM and 85 uM min-1, respectively. These results indicated that immobilized PVP was efficient in terms of catalytic activity and can be applied to continuous casein processing applications in the different industries. PMID- 29417225 TI - [Rheumatology in the public eye : From the perspective of a (former) politician]. PMID- 29417223 TI - Relationship between blood urea nitrogen-to-creatinine ratio at hospital admission and long-term mortality in patients with acute decompensated heart failure. AB - Although elevated blood urea nitrogen (BUN)-to-creatinine (BUN/Cr) ratio at hospital admission has been reported to be associated with poor short-term prognosis, its association to long-term mortality in patients with acute decompensated heart failure (ADHF) remains to be elucidated. Moreover, an additive prognostic value to preexisting renal markers including creatinine and BUN has not been well described. A cohort of 557 consecutive ADHF patients admitted to the cardiac intensive care unit was studied. All cohorts were divided into high and low BUN/Cr ratios according to the median value of BUN/Cr ratio at admission. Association between admission BUN/Cr ratio and long-term all-cause mortality was assessed. There were 145 deaths (27%) observed during the follow-up period of 1.9 years in median. Patients with high BUN/Cr ratio showed with higher mortality compared to low BUN/Cr ratio (log-rank: P = 0.006). In the multivariable analysis, patients with high BUN/Cr ratio at admission were associated with high mortality independently from other covariates including BUN and creatinine (HR 1.81, 95% CI 1.16-2.80, P = 0.009). In patients with ADHF, there is a relationship between admission BUN-to-creatinine ratio and long-term mortality. PMID- 29417224 TI - Influence of dietary iron intake restriction on the development of hypertension in weanling prehypertensive rats. AB - Hypertension is a major public health problem leading to death. To reduce the morbidity and mortality in patients with hypertension, it is crucial to develop a novel strategy for prevention of hypertension. We have currently reported an attempt at dietary iron intake restriction as non-pharmacological treatment of hypertension in patients with hypertension. However, it remains fully unknown whether dietary iron restriction prevents the development of hypertension. We investigated the influence of dietary iron restriction on the development of hypertension in weanling pre-hypertensive model rats. 3-week-old male stroke prone spontaneously hypertensive rats (SHR-SP) were randomly divided into two groups and were given an ad libitum normal diet or an iron-restricted diet for 12 weeks. Blood pressure was progressively increased in SHR-SP according to growth, while dietary iron restriction attenuated the development of hypertension. Proteinuria was also increased in SHR-SP according to growth, whereas dietary iron restriction suppressed the increment of proteinuria. SHR-SP exhibited glomerulosclerosis and exacerbated renal interstitial fibrosis at 15 weeks old, indicating that SHR-SP developed hypertensive nephropathy in the adult stage; however, these changes were attenuated by dietary iron restriction. Gelatin zymography showed dietary iron restriction decreased both renal MMP-2 and MMP-9 activities in SHR-SP at 15 weeks old. Of interest, dietary iron restriction suppressed renal TGFbeta-RI expression and Smad2 phosphorylation in SHR-SP. Furthermore, dietary iron restriction decreased renal fibrosis, renal MMP-2 and MMP-9 activities, renal TGFbeta-RI expression, and Smad2 phosphorylation in rats with unilateral ureteral obstruction. Dietary iron restriction prevented the development of hypertension in weanling pre-hypertensive rats. PMID- 29417226 TI - [Interdisciplinary multimodal pain therapy 2020 : Appropriate structures and performance-related reimbursement]. PMID- 29417227 TI - Risk of de novo aneurysm formation in patients with unruptured intracranial aneurysms. AB - BACKGROUND AND PURPOSE: The rate of de novo aneurysm formation in patients with unruptured aneurysm without history of subarachnoid hemorrhage is scarcely defined in literature. We report the incidence of de novo aneurysm formation in a large contemporary series of patients with unruptured intracranial aneurysm (UIA) undergoing serial neurovascular imaging. METHODS: Neurovascular imaging studies of 321 consecutive UIA patients with no prior history of subarachnoid hemorrhage, with at least 3 years of follow-up imaging, were reviewed by a neuroradiologist and a neurosurgeon. Rate of de novo aneurysm formation was reported on a per patient and per-patient-year basis. RESULTS: Of the 321 included patients, three patients (0.9%) developed a de novo aneurysm over a mean follow-up period of 5.2 years, for an incidence rate of 0.18% per patient-year. No de novo aneurysms ruptured and all three were 2 mm in size. CONCLUSIONS: The rate of de novo aneurysm formation in patients with unruptured aneurysms and no history of subarachnoid hemorrhage is very low. These data are useful to advice patients with unruptured aneurysms from another aneurysm and to plan imaging follow-ups in these patients. PMID- 29417228 TI - Comparison of long-term clinical outcomes between endoscopic and surgical resection for early-stage adenocarcinoma of the esophagogastric junction. AB - BACKGROUND: The aim of this study was to analyze long-term clinical and oncologic outcomes in patients with early-stage adenocarcinoma of the esophagogastric junction (AEG) managed with either endoscopic resection (ER) or surgery. METHODS: The inclusion criteria were AEG, meeting classic or expanded indications for ER of early gastric cancer, and complete resection. A total of 66 patients with Siewert type II AEG were included (ER group, n = 38; vs. surgery group, n = 28). RESULTS: The mean age of the ER group was greater than that of the surgery group (mean +/- SD, 66.9 +/- 9.7 vs. 58.5 +/- 10.4 years, respectively; p = 0.001). Compared to the ER group, macroscopically flat or depressed-type lesions were more common (47.4 vs. 89.3%; p = 0.001), and mean lesion size was larger in the surgery group (13.3 +/- 8.4 vs. 18.6 +/- 11.0 mm; p = 0.039). One intensive care unit admission and subsequent surgery-related death occurred in the surgery group (1/28 vs. 0/38 in the ER group; p = 0.424). During follow-up, recurrence was detected in both groups (4/38 vs. 1/28; p = 0.385). Overall survival and 5-year disease-free survival did not differ between the groups (93.3 vs. 92.9%; p = 0.282 and 88.0 vs. 100.0%; p = 0.066). CONCLUSIONS: Once complete resection is achieved in patients with AEG who met the expanded criteria for endoscopic submucosal dissection of gastric cancer, there was no significant difference in clinical outcomes between ER and surgery. PMID- 29417229 TI - Endoscopic submucosal dissection for early gastric cancer on the lesser curvature in upper third of the stomach is a risk factor for postoperative delayed gastric emptying. AB - BACKGROUND: Advances in Endoscopic submucosal dissection (ESD) technology have established ESD for early gastric cancer as a safe and stable technique. However, ESD may induce delayed gastric emptying and the cause of food residue retention in the stomach after ESD is not clear. This study aimed to clarify risk factors for delayed gastric emptying with food retention after gastric ESD. METHODS: We retrospectively examined for food residue in the stomach 1 week after ESD was performed for early gastric carcinoma at Osaka Saiseikai Nakatsu Hospital from February 2008 to November 2016. RESULTS: Food residue was observed in 68 (6.1%) of 1114 patients who underwent gastric ESD. The percentage of lesions located on the lesser curvature of the upper third of the stomach was 45.6% (31/68) in the food residue group and 3.5% (37/1046) in the non-food residue group, which was significantly different (P < 0.01). Multivariate logistic regression analysis revealed that lesions on the lesser curvature of the upper third of the stomach (Odds ratio [OR] 23.31, 95% confidence interval [CI] 12.60-43.61, P < 0.01), post ESD bleeding (OR 4.25, 95%CI 1.67-9.80, P < 0.01), submucosal invasion (OR 2.80, 95%CI 1.34-5.63, P < 0.01), and age over 80 years (OR 2.34, 95%CI 1.28-4.22, P < 0.01) were independent risk factors for food retention after gastric ESD. Of the 68 patients, 3 had food residue in the stomach on endoscopic examination for follow-up observation after the ESD ulcer had healed. CONCLUSIONS: Delayed gastric emptying with food retention after gastric ESD was associated with lesions located in the lesser curvature of the upper stomach, submucosal invasion of the lesion, age older than 80 years, and post-ESD bleeding, though it was temporary in most cases. PMID- 29417230 TI - Identification of megakaryocytes as a target of advanced glycation end products in diabetic complications in bone marrow. AB - AIMS: To define the possible effect of diabetic conditions on megakaryocytes, the long-know precursors of platelets and lately characterized modulator of hematopoietic stem quiescence-activation transition. METHODS: Megakaryoblastic MEG-01 cell culture and TPO/SCF/IL-3-induced differentiation of human umbilical blood mononuclear cells toward megakaryocytes were used to test effects of glycated bovine serum albumin (BSA-AGEs). The ob/ob mice and streptozotocin treated mice were used as models of hyperglycemia. MTT was used to measure cell proliferation, FACS for surface marker and cell cycle, and RT-qPCR for the expression of interested genes. Megakaryocytes at different stages in marrow smear were checked under microscope. RESULTS: When added in MEG-01 cultures at 200 MUg/ml, BSA-AGEs increased proliferation of cells and enhanced mRNA expression of RAGE, VEGFalpha and PF4 in the cells. None of cell cycle distribution, PMA-induced platelet-like particles production, expression of GATA1/NF-E2/PU-1/IL-6/OPG/PDGF in MEG-01 cells nor TPO/SCF/IL-3 induced umbilical cord blood cells differentiation into megakaryocyte was affected by BSA-AGEs. In the ob/ob diabetic mice, MKs percentages in marrow cells and platelets in peripheral blood were significantly increased compared with control mice. In streptozotocin-induced diabetic mice, however, MKs percentage in marrow cells was decreased though peripheral platelet counts were not altered. Gene expression assay showed that the change in MKs in these two diabetic conditions might be explained by the alteration of GATA1 and NF-E2 expression, respectively. CONCLUSIONS: Diabetic condition in animals might exert its influence on hematopoiesis via megakaryocytes-the newly identified modulator of hematopoietic stem cells in bone marrow. PMID- 29417231 TI - The effect of technogenic emissions on the heavy metals accumulation by herbaceous plants. AB - The effect of technogenic emissions on the input of Pb, Zn, Cd, Cu, Mn, Cr, and Ni into plants from the Poaceae and Asteraceae families has been studied. Soil and plant contamination by anthropogenic emissions from industrial enterprises leads the decreasing of crop quality; therefore, the monitoring investigation of plants and soils acquires special importance. The herbaceous plants may be used as bioindicators for main environmental changes. It was found that the high level of anthropogenic load related to atmospheric emissions from the power plant favors the heavy metal (HM) accumulation in herbaceous plants. Contamination with Pb, Cd, Cr, and Ni was revealed in plants growing near the power plant. Heavy metals arrive to plants from the soil in the form of mobile compounds. Plant family is one of the main factors affecting the HM distribution in the above- and underground parts of plants. Plants from the Poaceae family accumulate less chemical elements in their aboveground parts than the Asteraceae plants. Ambrosia artemisiifolia and Artemisia austriaca are HM accumulators. For assessing the stability of plants under contamination with HMs, metal accumulation by plants from soil (the bioconcentration factor) and metal phytoavailability from plants above- and underground parts (the acropetal coefficient) were calculated. According to the bioconcentration factor and translocation factor values, Poaceae species are most resistant to technogenic contamination with HMs. The translocation factor highest values were found for Tanacetum vulgare; the lowest bioconcentration factor values were typical for Poa pratensis. PMID- 29417233 TI - Non-profit Drug Research and Development at a Crossroads. AB - In wealthy nations, non-profit drug R&D has been proposed to reduce the prices of medicines. We sought to review the ethical and economic issues concerning non profit drug R&D companies, and the possible impact that their pricing strategy may have on the innovation efforts from for-profit companies targeting the same segment of the pharmaceutical market. There are two possible approaches to pricing drugs developed by non-profit R&D programs: pricing that maximises profits and "affordable" pricing that reflects the cost of manufacturing and distribution, plus a margin that ensures sustainability of the drug supply. Overall, the non-profits face ethical challenges - due to the lack of resources, they are unable to independently commercialize their products on a large scale; however, the antitrust law does not permit them to impose prices on potential licensees. Also, reduced prices for the innovative products may result in drying the for-profit R&D in the area. PMID- 29417232 TI - A new Em-like protein from Lactuca sativa, LsEm1, enhances drought and salt stress tolerance in Escherichia coli and rice. AB - Late embryogenesis abundant (LEA) proteins are closely related to abiotic stress tolerance of plants. In the present study, we identified a novel Em-like gene from lettuce, termed LsEm1, which could be classified into group 1 LEA proteins, and shared high homology with Cynara cardunculus Em protein. The LsEm1 protein contained three different 20-mer conserved elements (C-element, N-element, and M element) in the C-termini, N-termini, and middle-region, respectively. The LsEm1 mRNAs were accumulated in all examined tissues during the flowering and mature stages, with a little accumulation in the roots and leaves during the seedling stage. Furthermore, the LsEm1 gene was also expressed in response to salt, dehydration, abscisic acid (ABA), and cold stresses in young seedlings. The LsEm1 protein could effectively reduce damage to the lactate dehydrogenase (LDH) and protect LDH activity under desiccation and salt treatments. The Escherichia coli cells overexpressing the LsEm1 gene showed a growth advantage over the control under drought and salt stresses. Moreover, LsEm1-overexpressing rice seeds were relatively sensitive to exogenously applied ABA, suggesting that the LsEm1 gene might depend on an ABA signaling pathway in response to environmental stresses. The transgenic rice plants overexpressing the LsEm1 gene showed higher tolerance to drought and salt stresses than did wild-type (WT) plants on the basis of the germination performances, higher survival rates, higher chlorophyll content, more accumulation of soluble sugar, lower relative electrolyte leakage, and higher superoxide dismutase activity under stress conditions. The LsEm1-overexpressing rice lines also showed less yield loss compared with WT rice under stress conditions. Furthermore, the LsEm1 gene had a positive effect on the expression of the OsCDPK9, OsCDPK13, OsCDPK15, OsCDPK25, and rab21 (rab16a) genes in transgenic rice under drought and salt stress conditions, implying that overexpression of these genes may be involved in the enhanced drought and salt tolerance of transgenic rice. Thus, this work paves the way for improvement in tolerance of crops by genetic engineering breeding. PMID- 29417234 TI - Diel and seasonal nitrous oxide fluxes determined by floating chamber and gas transfer equation methods in agricultural irrigation watersheds in southeast China. AB - Agricultural nitrate leaching and runoff incurs high nitrogen loads in agricultural irrigation watersheds, constituting one of important sources of atmospheric nitrous oxide (N2O). Two independent sampling campaigns of N2O flux measurement over diel cycles and N2O flux measurements once a week over annual cycles were carried out in an agricultural irrigation watershed in southeast China using floating chamber (chamber-based) and gas transfer equation (model based) methods. The diel and seasonal patterns of N2O fluxes did not differ between the two measurement methods. The diel variation in N2O fluxes was characterized by the pattern that N2O fluxes were greater during nighttime than daytime periods with a single flux peak at midnight. The diel variation in N2O fluxes was closely associated with water environment and chemistry. The time interval of 9:00-11:00 a.m. was identified to be the sampling time best representing daily N2O flux measurements in agricultural irrigation watersheds. Seasonal N2O fluxes showed large variation, with some flux peaks corresponding to agricultural irrigation and drainage episodes and heavy rainfall during the crop growing period of May to November. On average, N2O fluxes calculated by model based methods were 27% lower than those determined by the chamber-based techniques over diel or annual cycles. Overall, more measurement campaigns are highly needed to assess regional agricultural N2O budget with low uncertainties. PMID- 29417235 TI - The impact of anaemia, transfusion dependency, comorbidities and polypharmacy in elderly patients with low-risk myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) are heterogeneous clonal disorders ranging from indolent conditions with a near-normal life expectancy to forms approaching acute myeloid leukaemia. Comorbid conditions have rarely been systematically studied among patients with MDS. Older age per se has a negative impact on survival of MDS patients, in particular of those with lower risk. However, age indirectly affects also the survival of higher-risk patients by limiting their eligibility to intensive treatments. In addition, ageing is associated with an increasingly high risk of developing comorbidity, and a high prevalence of comorbid diseases has indeed been reported in MDS patients. The impact of multi morbidities/comorbidities and polypharmacy in patients with low-risk MDS patients is a poorly explored topic. We focused on medications, multi-morbidities and comorbidities of 155 low-risk MDS patients followed in the haematological outpatients clinics or in medical/oncology wards of our University Hospital. One or more comorbidities were present at diagnosis in 24 younger patients with MDS syndromes (31%), whereas 56 older patients with MDS (75%) presented 1 or more comorbidities (P < 0.001).The most frequent comorbidity was cardiac comorbidity 18% in younger patients and 25% in older patients. With no statistical significance between older and younger patients, congestive heart failure was the most frequent observed disease. Our study has shown a statistical correlation between transfusion dependency and polypathology (P = 0.0014). These data were also confirmed in a subanalysis of the younger group of patients. Our study has shown that comorbidity is very common among patients with MDS, potentially affecting the clinical course and outcome of MDS patients. PMID- 29417236 TI - Working across species down on the farm: Howard S. Liddell and the development of comparative psychopathology, c. 1923-1962. AB - Seeking a scientific basis for understanding and treating mental illness, and inspired by the work of Ivan Pavlov, American physiologists, psychiatrists and psychologists in the 1920s turned to nonhuman animals. This paper examines how new constructs such as "experimental neurosis" emerged as tools to enable psychiatric comparison across species. From 1923 to 1962, the Cornell "Behavior Farm" was a leading interdisciplinary research center pioneering novel techniques to experimentally study nonhuman psychopathology. Led by the psychobiologist Howard Liddell, work at the Behavior Farm formed part of an ambitious program to develop new preventative and therapeutic techniques and bring psychiatry into closer relations with physiology and medicine. At the heart of Liddell's activities were a range of nonhuman animals, including pigs, sheep, goats and dogs, each serving as a proxy for human patients. We examine how Pavlov's conceptualization of 'experimental neurosis' was used by Liddell to facilitate comparison across species and communication between researchers and clinicians. Our close reading of his experimental system demonstrates how unexpected animal behaviors and emotions were transformed into experimental virtues. However, to successfully translate such behaviors from the animal laboratory into the field of human psychopathology, Liddell increasingly reached beyond, and, in effect, redefined, the Pavlovian method to make it compatible and compliant with an ethological approach to the animal laboratory. We show how the resultant Behavior Farm served as a productive "hybrid" place, containing elements of experiment and observation, laboratory and field. It was through the building of close and more naturalistic relationships with animals over extended periods of time, both normal and pathological, and within and outside of the experimental space, that Liddell could understand, manage, and make useful the myriad behavioral complexities that emerged from the life histories of experimental animals, the researchers who worked with them, and their shared relationships to the wider physical and social environments. PMID- 29417237 TI - Prediction of Quantum Anomalous Hall Effect in MBi and MSb (M:Ti, Zr, and Hf) Honeycombs. AB - The abounding possibilities of discovering novel materials has driven enhanced research effort in the field of materials physics. Only recently, the quantum anomalous hall effect (QAHE) was realized in magnetic topological insulators (TIs) albeit existing at extremely low temperatures. Here, we predict that MPn (M =Ti, Zr, and Hf; Pn =Sb and Bi) honeycombs are capable of possessing QAH insulating phases based on first-principles electronic structure calculations. We found that HfBi, HfSb, TiBi, and TiSb honeycomb systems possess QAHE with the largest band gap of 15 meV under the effect of tensile strain. In low-buckled HfBi honeycomb, we demonstrated the change of Chern number with increasing lattice constant. The band crossings occurred at low symmetry points. We also found that by varying the buckling distance we can induce a phase transition such that the band crossing between two Hf d-orbitals occurs along high-symmetry point K2. Moreover, edge states are demonstrated in buckled HfBi zigzag nanoribbons. This study contributes additional novel materials to the current pool of predicted QAH insulators which have promising applications in spintronics. PMID- 29417238 TI - Options for Adjuvant Therapy for Uterine Leiomyosarcoma. AB - OPINION STATEMENT: Uterine leiomyosarcoma (uLMS) is a rare disease; in the data from the SEER database, 3165 cases of uLMS were diagnosed between January 2000 and December 2012. While a majority of patients (60%) are diagnosed with early stage disease, recurrence rates are high. Five-year disease-specific survival is 76% for patients with FIGO stage I and 60% for patients with FIGO stage II disease. Adjuvant treatments, including radiation therapy, chemotherapy, and combined modality approaches, have been explored with the goal of demonstrating improved survival. However, heterogeneous patient populations, small sample sizes, and lack of no-treatment control arms have limited the interpretation and reliability of the results from these studies. A randomized trial of adjuvant pelvic radiation compared to no additional treatment showed that adjuvant radiation did not improve recurrence or survival outcomes for early-stage uterine LMS. To date, no prospective, randomized trial has been completed comparing adjuvant chemotherapy to observation. A recent well-designed retrospective study showed that women treated with adjuvant gemcitabine-docetaxel had no improvement in progression-free or overall survival compared to women who received no additional treatment. Thus, current data support our recommendation against adjuvant radiation or chemotherapy treatment for patients with non-morcellated, completely resected, and uterine-confined leiomyosarcoma. We recommend that these patients be observed with periodic surveillance imaging and physical examinations. PMID- 29417239 TI - Correction to: The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. AB - The published article contains an error in Figure 5. The term "Atu027" should be substituted by "Patisiran" in figure and legend. PMID- 29417240 TI - Allexiviruses may have acquired inserted sequences between the CP and CRP genes to change the translation reinitiation strategy of CRP. AB - Allexiviruses are economically important garlic viruses that are involved in garlic mosaic diseases. In this study, we characterized the allexivirus cysteine rich protein (CRP) gene located just downstream of the coat protein (CP) gene in the viral genome. We determined the nucleotide sequences of the CP and CRP genes from numerous allexivirus isolates and performed a phylogenetic analysis. According to the resulting phylogenetic tree, we found that allexiviruses were clearly divided into two major groups (group I and group II) based on the sequences of the CP and CRP genes. In addition, the allexiviruses in group II had distinct sequences just before the CRP gene, while group I isolates did not. The inserted sequence between the CP and CRP genes was partially complementary to garlic 18S rRNA. Using a potato virus X vector, we showed that the CRPs affected viral accumulation and symptom induction in Nicotiana benthamiana, suggesting that the allexivirus CRP is a pathogenicity determinant. We assume that the inserted sequences before the CRP gene may have been generated during viral evolution to alter the termination-reinitiation mechanism for coupled translation of CP and CRP. PMID- 29417241 TI - Myxovirus resistance protein A inhibits hepatitis C virus replication through JAK STAT pathway activation. AB - The interferon-inducible dynamin-like GTPase myxovirus resistance protein A (MxA) exhibits activity against multiple viruses. However, its role in the life cycle of hepatitis C virus (HCV) is unclear, and the mechanisms underlying the anti-HCV activity of MxA require further investigation. In this study, we demonstrated that exogenous MxA expression in the Huh7 and Huh7.5.1 hepatoma cell lines significantly decreased the levels of HCV RNA and core proteins, whereas MxA knockdown exerted the opposite effect. MxA-mediated inhibition of HCV replication was found to involve the JAK-STAT pathway: STAT1 phosphorylation and the expression of IFN-stimulated genes (ISGs) such as guanylate-binding protein 1 and 2'-5'-oligoadenylate synthetase 1 were augmented by MxA overexpression and reduced by endogenous MxA silencing. Treatment with the JAK inhibitor ruxolitinib abrogated the MxA-mediated suppression of HCV replication and activation of the JAK-STAT pathway. Additionally, transfection with an MxA mutant with disrupted GTP-binding consensus motifs abrogated activation of the JAK-STAT pathway and resistance to HCV replication. This study shows that MxA inhibits HCV replication by activating the JAK-STAT signaling pathway through a mechanism involving its GTPase function. PMID- 29417242 TI - Reductive transformation of profenofos with nanoscale Fe/Ni particles. AB - Profenofos is an abundantly used organophosphate pesticide in agriculture but its excessive use may lead to hazardous effects on environment. Thus, the present study focused on the reductive transformation of this pesticide in the presence of Fe/Ni bimetallic nanoparticles by optimizing the process parameters such as stirring time, nanoparticles dose, pH, and initial pesticide concentration. The results of reductive transformation were compared with photodegradation studies. It was found that with the increase in UV irradiation time, the percent degradation was increased. After 660 min, a 78% photodegradation of 100 MUM solution of pesticide was observed. On increasing the initial pesticide concentration to 200 MUM, the maximum degradation was achieved in 570 min, but here, only 73% degradation was observed. The rates of photodegradation observed with 100 to 400 MUM solutions were 1.4 * 10-3, 1.5 * 10-3, 1.5 * 10-3, and 5 * 10 4 min-1 respectively.In case of reductive transformation carried out in the presence of Fe/Ni bimetallic nanoparticles, the degradation was observed to be increased from 78 to 93.9% in only 180 min. A further increase in pesticide concentration led to a decrease in degradation. Under these conditions, the rate of reaction was found to be 1.09 * 10-2 min-1. A 93% degradation of profenofos was further increased to 98% when the quantity of nanoparticles was increased twice; hence, a significant reduction in time of irradiation was observed. Reductive transformation of pesticide thus provided an efficient and cheaper method for reducing the burden of profenofos from the environment. PMID- 29417243 TI - One-Step Ball Milling Preparation of Nanoscale CL-20/Graphene Oxide for Significantly Reduced Particle Size and Sensitivity. AB - A one-step method which involves exfoliating graphite materials (GIMs) off into graphene materials (GEMs) in aqueous suspension of CL-20 and forming CL 20/graphene materials (CL-20/GEMs) composites by using ball milling is presented. The conversion of mixtures to composite form was monitored by scanning electron microscopy (SEM) and powder X-ray diffraction (XRD). The impact sensitivities of CL-20/GEM composites were contrastively investigated. It turned out that the energetic nanoscale composites based on CL-20 and GEMs comprising few layers were accomplished. The loading capacity of graphene (reduced graphene oxide, rGO) is significantly less than that of graphene oxide (GO) in CL-20/GEM composites. The formation mechanism was proposed. Via this approach, energetic nanoscale composites based on CL-20 and GO comprised few layers were accomplished. The resulted CL-20/GEM composites displayed spherical structure with nanoscale, epsilon-form, equal thermal stabilities, and lower sensitivities. PMID- 29417244 TI - Secondary Raynaud's Phenomenon and Skin Necrosis of Toes in the Paraplegic Patient with Hypertension. AB - We present two cases of paraplegic patients who developed secondary Raynaud's phenomenon. A 43-year-old man with paraplegia presented with dark purple discoloration and skin defects on his left second and third toes and complained of a cold sensation in both feet for a period of 1 year. He had been taking diuretics for 4 years. The capillary refilling time for both affected toes was delayed. His antihypertensive drug was changed to a calcium channel blocker under suspicion of Raynaud's phenomenon aggravated by hydrochlorothiazide, and the capillary refilling time normalized within 3 days. The toe skin defect was covered with a skin graft. A 51-year-old man with paraplegia presented with cyanotic color change and recurrent unstable wounds on his toes. He was also taking diuretics for hypertension. Suspecting secondary Raynaud's phenomenon aggravated by diuretics, we changed the diuretics to olmesartan medoxmil 20 mg and amlodipine besylate 2.5 mg per day. Subsequently, he has had no unstable wounds for 30 months. If hypertensive patients with paraplegia complain of skin discoloration in their extremities, Raynaud's phenomenon should be considered and the antihypertensive drug may need to be stopped in order to improve the wound healing process. PMID- 29417245 TI - Laparoscopic Versus Open Approach for Formal Right and Left Hepatectomy: A Propensity Score Matching Analysis. AB - BACKGROUND: Laparoscopic liver surgery is expanding worldwide, but further evidence is needed to assess safety and efficacy of laparoscopic major hepatectomy. The study analyzes perioperative outcomes of pure laparoscopic versus open major hepatectomies matched by the propensity score method. METHODS: From 2005 to 2017, 268 major hepatectomies were performed of which 73 were laparoscopic. After a 1:1 propensity score matching, 59 laparoscopic right and left hepatectomies were compared to 59 open. The matching was based on age, gender, year of procedure, BMI, ASA score, underlying liver disease, previous abdominal surgery, type of hepatectomy, preoperative chemotherapy, number, dimension and nature of lesions. An intention-to-treat analysis and a per protocol analysis were carried out. RESULTS: Mean surgical time was 315 min in the laparoscopic group and 292.5 min in the open group (p = 0.039); conversion rate in laparoscopy was 20.3%; blood loss was 480 ml (50-3000) versus 550 ml (50 2600), respectively, for laparoscopic and open (p = 0.577). Lengths of postoperative analgesia and hospital stay were shorter in the laparoscopic group (p = 0.0001 and 0.024, respectively). Postoperative complications occurred in 11.9% of laparoscopic cases and in 25.4% of open cases (p = 0.098). Median Comprehensive Complication Index was 26.2 (8.7-54.2) in the open group versus 20.9 (8.7-66.2) in open (p = 0.368). Per-protocol analysis showed a better trend in favor of laparoscopy concerning surgical time. CONCLUSIONS: Laparoscopic major hepatectomies are safe and feasible procedures allowing a similar complication rate with a shorter hospital stay and diminished postoperative pain with respect to the standard approach. PMID- 29417246 TI - Necrotizing Soft Tissue Infections at a Tertiary Referral Hospital in Rwanda: Epidemiology and Risk Factors for Mortality. AB - BACKGROUND: Necrotizing soft tissue infections (NSTI) are emergency surgical conditions with severe physiologic and metabolic derangement. These infections are associated with increased rates of mortality and morbidity worldwide, particularly in developing countries if not diagnosed and treated early. METHODS: This prospective, observational cohort study includes all patients aged 12 and above who presented at Department of Surgery, University Teaching Hospital of Kigali from April 2016 to January 2017 with NSTI. We describe epidemiology, operative management, and outcomes of care. We determined risk factors for mortality using multivariate logistic regression. RESULTS: We identified 175 patients with confirmed diagnosis of NSTI. The majority of patients (53%) were male, and the mean age was 44 years. The median duration of symptoms was 8 days [interquartile range (IQR) 5-14]. The median length of hospital stay was 23 days (IQR 8-41). The overall mortality was 26%. Multivariate regression analysis revealed four independent predictors of mortality: presence of shock at admission [odds ratio (OR) 14.15, 95% confidence interval (CI) 0.96-208.01, p = 0.050], renal failure (OR 8.92, 95% CI 1.55-51.29, p = 0.014), infection located on the trunk (OR 5.60, 95% CI 0.99-31.62, p = 0.050), and presence of skin gangrene (OR 4.04, 95% CI 1.18-13.76, p = 0.026). CONCLUSION: In Rwanda, NSTI mortality is high and associated with advanced disease. It is imperative that efforts are focused on early consultation, diagnosis, and surgical management to prevent adverse outcomes. PMID- 29417247 TI - Predicting Conversion from Laparoscopic to Open Cholecystectomy: A Single Institution Retrospective Study. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the standard surgical treatment for benign gallbladder disease. Nevertheless, conversion to open cholecystectomy (OC) is needed in some cases. The aim of this study is to calculate our institutional conversion rate and to identify the variables that are implicated in increasing the risk of conversion (LC-OC). MATERIALS AND METHODS: We carried out a retrospective study of all cases of LC performed at the American University of Beirut Medical Center between 2000 and 2015. Each (LC-OC) case was randomly matched to a laparoscopically completed case by the same consultant within the same year of practice, as the LC-OC case, in a 1:5 ratio. Forty-eight parameters were compared between the two study groups. RESULTS: Forty-eight out of 4668 LC were converted to OC over the 15-year study period; the conversion rate in our study was 1.03%. The variables that were found to be most predictive of conversion were male gender, advanced age, prior history of laparotomy, especially in the setting of prior gunshot wound, a history of restrictive or constrictive lung disease and anemia (Hb < 9 g/dl). The most common intraoperative reasons for conversion were perceived difficult anatomy or obscured view secondary to severe adhesions or significant inflammation. Patients who were in the LC-OC arm had a longer length of hospital stay. CONCLUSION: Advance age, male gender, significant comorbidities and history of prior laparotomies have a high risk of conversion. Patients with these risk factors should be counseled for the possibility of conversion to open surgery preoperatively. Further research is needed to determine whether these high risks patients should be operated on by surgeons with more extensive experience in minimal invasive surgery. PMID- 29417248 TI - Recycling of phenolic compounds in Borneo's tropical peat swamp forests. AB - BACKGROUND: Tropical peat swamp forests (TPSF) are globally significant carbon stores, sequestering carbon mainly as phenolic polymers and phenolic compounds (particularly as lignin and its derivatives) in peat layers, in plants, and in the acidic blackwaters. Previous studies show that TPSF plants have particularly high levels of phenolic compounds which inhibit the decomposition of organic matter and thus promote peat accumulation. The studies of phenolic compounds are thus crucial to further understand how TPSF function with respect to carbon sequestration. Here we present a study of cycling of phenolic compounds in five forests in Borneo differing in flooding and acidity, leaching of phenolic compounds from senescent Macaranga pruinosa leaves, and absorption of phenolics by M. pruinosa seedlings. RESULTS: The results of the study show that total phenolic content (TPC) in soil and leaves of three species of Macaranga were highest in TPSF followed by freshwater swamp forest and flooded limestone forest, then dry land sites. Highest TPC values were associated with acidity (in TPSF) and waterlogging (in flooded forests). Moreover, phenolic compounds are rapidly leached from fallen senescent leaves, and could be reabsorbed by tree roots and converted into more complex phenolics within the leaves. CONCLUSIONS: Extreme conditions-waterlogging and acidity-may facilitate uptake and synthesis of protective phenolic compounds which are essential for impeded decomposition of organic matter in TPSF. Conversely, the ongoing drainage and degradation of TPSF, particularly for conversion to oil palm plantations, reverses the conditions necessary for peat accretion and carbon sequestration. PMID- 29417250 TI - Using coronary CT angiography for guiding invasive coronary angiography: potential role to reduce intraprocedural radiation exposure. AB - OBJECTIVES: We investigated the potential reduction of patient exposure during invasive coronary angiography (ICA) if the procedure had only been directed to the vessel with at least one >= 50% stenosis as described in the CT report. METHODS: Dose reports of 61 patients referred to ICA because of at least one >= 50% stenosis on coronary CT angiography (CCTA) were included. Dose-area product (DAP) was documented separately for left (LCA) and right coronary arteries (RCA) by summing up the single DAP for each angiographic projection. The study population was subdivided as follows: coronary intervention of LCA (group 1) or RCA (group 2) only, or of both vessels (group 3), or further bypass grafting (group 4), or no further intervention (group 5). RESULTS: 57.4% of the study population could have benefitted from reduced exposure if catheterization had been directly guided to the vessel of interest as described on CCTA. Mean relative DAP reductions were as follows: group 1 (n = 18), 11.2%; group 2 (n = 2), 40.3%; group 3 (n = 10), 0%; group 4 (n = 3), 0%; group 5 (n = 28), 28.8%. CONCLUSIONS: Directing ICA to the vessel with stenosis as described on CCTA would reduce intraprocedural patient exposure substantially, especially for patients with single-vessel stenosis. KEY POINTS: * Patients with CAD can benefit from decreased radiation exposure during coronary angiography. * ICA should be directed solely to significant stenoses as described on CCTA. * Severely calcified plaques remain a limitation of CCTA leading to unnecessary ICA referrals. PMID- 29417251 TI - Dedicated computer-aided detection software for automated 3D breast ultrasound; an efficient tool for the radiologist in supplemental screening of women with dense breasts. AB - OBJECTIVES: To determine the effect of computer-aided-detection (CAD) software for automated breast ultrasound (ABUS) on reading time (RT) and performance in screening for breast cancer. MATERIAL AND METHODS: Unilateral ABUS examinations of 120 women with dense breasts were randomly selected from a multi-institutional archive of cases including 30 malignant (20/30 mammography-occult), 30 benign, and 60 normal cases with histopathological verification or >= 2 years of negative follow-up. Eight radiologists read once with (CAD-ABUS) and once without CAD (ABUS) with > 8 weeks between reading sessions. Readers provided a BI-RADS score and a level of suspiciousness (0-100). RT, sensitivity, specificity, PPV and area under the curve (AUC) were compared. RESULTS: Average RT was significantly shorter using CAD-ABUS (133.4 s/case, 95% CI 129.2-137.6) compared with ABUS (158.3 s/case, 95% CI 153.0-163.3) (p < 0.001). Sensitivity was 0.84 for CAD-ABUS (95% CI 0.79-0.89) and ABUS (95% CI 0.78-0.88) (p = 0.90). Three out of eight readers showed significantly higher specificity using CAD. Pooled specificity (0.71, 95% CI 0.68-0.75 vs. 0.67, 95% CI 0.64-0.70, p = 0.08) and PPV (0.50, 95% CI 0.45-0.55 vs. 0.44, 95% CI 0.39-0.49, p = 0.07) were higher in CAD-ABUS vs. ABUS, respectively, albeit not significantly. Pooled AUC for CAD-ABUS was comparable with ABUS (0.82 vs. 0.83, p = 0.53, respectively). CONCLUSION: CAD software for ABUS may decrease the time needed to screen for breast cancer without compromising the screening performance of radiologists. KEY POINTS: * ABUS with CAD software may speed up reading time without compromising radiologists' accuracy. * CAD software for ABUS might prevent non-detection of malignant breast lesions by radiologists. * Radiologists reading ABUS with CAD software might improve their specificity without losing sensitivity. PMID- 29417249 TI - Post-contrast acute kidney injury. Part 2: risk stratification, role of hydration and other prophylactic measures, patients taking metformin and chronic dialysis patients : Recommendations for updated ESUR Contrast Medium Safety Committee guidelines. AB - OBJECTIVES: The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) has updated its 2011 guidelines on the prevention of post-contrast acute kidney injury (PC-AKI). The results of the literature review and the recommendations based on it, which were used to prepare the new guidelines, are presented in two papers. AREAS COVERED IN PART 2: Topics reviewed include stratification of PC-AKI risk, the need to withdraw nephrotoxic medication, PC-AKI prophylaxis with hydration or drugs, the use of metformin in diabetic patients receiving contrast medium and the need to alter dialysis schedules in patients receiving contrast medium. KEY POINTS: * In CKD, hydration reduces the PC-AKI risk * Intravenous normal saline and intravenous sodium bicarbonate provide equally effective prophylaxis * No drugs have been consistently shown to reduce the risk of PC-AKI * Stop metformin from the time of contrast medium administration if eGFR < 30 ml/min/1.73 m 2 * Dialysis schedules need not change when intravascular contrast medium is given. PMID- 29417252 TI - Dynamic contrast-enhanced ultrasonography (D-CEUS) for the early prediction of bevacizumab efficacy in patients with metastatic colorectal cancer. AB - OBJECTIVES: To investigate early changes in tumour perfusion parameters by dynamic contrast-enhanced ultrasonography (D-CEUS) and to identify any correlation with survival and tumour response in patients with metastatic colorectal cancer (CRC) treated with bevacizumab (B). METHODS: Thirty-seven patients randomized to either chemotherapy (C) plus B or C alone were considered for this study. D-CEUS was performed at baseline and after the first treatment cycle (day 15). Four D-CEUS perfusion parameters were considered: derived peak intensity (DPI), area under the curve (AUC), slope of wash-in (A) and time to peak intensity (TPI). RESULTS: In patients treated with C plus B, a >=22.5 % reduction in DPI, >=20 % increase in TPI and >=10 % reduction in AUC were correlated with higher progression-free survival in the C+B arm (p = 0.048, 0.024 and 0.010, respectively) but not in the C arm. None of the evaluated parameter modifications had a correlation with tumour response or overall survival. CONCLUSIONS: D-CEUS could be useful for detecting and quantifying dynamic changes in tumour vascularity as early as 15 days after the start of B-based therapy. Although these changes may be predictive of progression-free survival, no correlation with response or overall survival was found. KEY POINTS: * D-CEUS showed early changes in liver metastasis perfusion in colorectal cancer. * A decrease in tumour perfusion was associated with longer progression-free survival. * The decrease in perfusion was not correlated with higher overall survival. PMID- 29417253 TI - Ablation of colorectal liver metastasis: Interaction of ablation margins and RAS mutation profiling on local tumour progression-free survival. AB - OBJECTIVES: To investigate effects of ablation margins on local tumour progression-free survival (LTPFS) according to RAS status in patients with colorectal liver metastases (CLM). METHODS: This two-institution retrospective study from 2005-2016 included 136 patients (91 male, median age 60 years) with 218 ablated CLM. LTPFS was performed using the Kaplan-Meier method and evaluated with the log-rank test. Uni/multivariate analyses were performed using Cox regression models. RESULTS: Three-year LTPFS rates for CLM with minimal ablation margin <=10 mm were significantly worse than those with >10 mm in both mutant-RAS (29% vs. 48%, p=0.038) and wild-type RAS (70% vs. 94%, p=0.039) subgroups. Three year LTPFS rates of mutant-RAS were significantly worse than wild-type RAS in both CLM subgroups with minimal ablation margin <=10 mm (29% vs. 70%, p<0.001) and >10 mm (48% vs. 94%, p=0.006). Predictors of worse LTPFS were ablation margins <=10 mm (HR: 2.17, 95% CI 1.2-4.1, p=0.007), CLM size >=2 cm (1.80, 1.1 2.8, p=0.017) and mutant-RAS (2.85, 1.7-4.6, p<0.001). CONCLUSIONS: Minimal ablation margin and RAS status interact as independent predictors of LTPFS following CLM ablation. While minimal ablation margins >10 mm should be always the procedural goal, this becomes especially critical for mutant-RAS CLM. KEY POINTS: * RAS and ablation margins are predictors of local tumour progression free survival. * Ablation margin >10 mm, always desirable, is crucial for mutant RAS metastases. * Interventional radiologists should be aware of RAS status to optimize LTPFS. PMID- 29417254 TI - Assessment and comparison of phytochemical constituents and biological activities of bitter bean (Parkia speciosa Hassk.) collected from different locations in Malaysia. AB - BACKGROUND: Parkia speciosa seeds are a common ingredient in Malay cuisine with traditional interest because of its medicinal importance and content of health promoting phytochemicals. This study evaluated the phytochemical constituents and biological activities (antioxidant and antibacterial activities) of Parkia speciosa Hassk seeds collected from three different regions of Malaysia (Perak, Negeri Sembilan and Johor). Phytochemical constituents (total flavonoid and total phenolic) were measured using the spectrophotometric method, and individual flavonoids and phenolic acids were identified using ultra-high-performance liquid chromatography. Ferric reducing antioxidant potential (FRAP) assay and 2,2 diphenyl-1-picrylhydrazyl (DPPH) assay we used in order to evaluation of antioxidant activities. Disc diffusion method was employed for the evaluation of antibacterial activity of extracts against Gram-positive and Gram-negative bacterial strains. RESULTS: The primary screening of phytochemicals showed that P. speciosa seeds contain alkaloids, terpenoids, flavonoids, and phenolics. Samples collected from Perak contained the highest levels of the phytochemical constituents, with highest DPPH and FRAP activity followed by Negeri sembilan and Johor. From the identified compounds, quercetin and gallic acid were identified as the most abundant compounds. Seeds collected from the Perak location exhibited potent antibacterial activity, against both Gram-positive and Gram-negative bacteria strains. Staphylococcus aureus and Bacillus subtilis were recorded as the bacterial strains most sensitive to P. speciosa seed extracts. Correlation analysis showed that flavonoid compounds are responsible for the antioxidant activities of the P. speciosa seeds studied, while antibacterial activity showed a high correlation with the levels of gallic acid. CONCLUSIONS: Parkia speciosa seed grown in Perak exhibit the highest concentrations of phytochemicals, as well as the highest biological activity. It may also be recommended for the food industry to use seeds from this area for their products, which are going to compete in the expanding functional food markets. PMID- 29417255 TI - On chronic fatigue syndrome and nosological categories. AB - Chronic fatigue syndrome (CFS) is a heterogeneous disease which presents with pronounced disabling fatigue, sleep disturbances, and cognitive impairment that negatively affects patients' functional capability. CFS remains a poorly defined entity and its etiology is still in question. CFS is neither a novel diagnosis nor a new medical condition. From as early as the eighteenth century, a constellation of perplexing symptoms was observed that resembled symptoms of CFS. Commencing with "febricula" and ending with CFS, many names for the disease were proposed including neurocirculatory asthenia, atypical poliomyelitis, Royal Free disease, effort syndrome, Akureyri disease, Tapanui disease, chronic Epstein-Barr virus syndrome, and myalgic encephalitis. To date, it remains unclear whether CFS has an autoimmune component or is a condition that precedes a full-blown autoimmune disease. Research suggests that CFS may overlap with other diseases including postural orthostatic tachycardia syndrome (POTS), autoimmune syndrome induced by adjuvants (ASIA), and Sjogren's syndrome. Additionally, it has been postulated that the earliest manifestations of some autoimmune diseases can present with vague non-specific symptoms similar to CFS. Sometimes only when exposed to a secondary stimulus (e.g., antigen) which could accelerate the natural course of the disease would an individual develop the classic autoimmune disease. Due to the similarity of symptoms, it has been postulated that CFS could simply be an early manifestation of an autoimmune disease. This paper will provide a historical background review of this disease and a discussion of CFS as an entity overlapping with multiple other conditions. PMID- 29417256 TI - Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation. AB - The effect of direct oral anticoagulants (DOACs) on turbidimetric measurements of plasma clot formation and susceptibility to fibrinolysis may facilitate a comparison between different classes of anticoagulants in plasma samples. We obtained 424 citrate plasma samples from 226 atrial fibrillation patients on anticoagulation and 24 samples without anticoagulation serving as controls. As comparators, we measured the international normalized ratio (INR) for phenprocoumon samples (N = 166), anti-Xa for low molecular weight heparin (LMWH) samples (N = 42), and DOAC levels with mass spectrometry (dabigatran N = 40, rivaroxaban N = 110, apixaban N = 42). Plasma clot formation and lysis were recorded continuously on a photometer after addition of an activation mix (tissue factor 2 pmol/l and tissue plasminogen activator 333 ng/ml). We used linear regression and ANCOVA for correlation analysis. Clot formation lag phase was prolonged in the presence of anticoagulants in a concentration-dependent manner for DOACs (dabigatran Spearman r = 0.74; rivaroxaban r = 0.78; apixaban r = 0.72, all p < 0.0001), INR dependent for phenprocoumon (r = 0.59, p < 0.0001), anti-Xa level dependent in LMWH samples (r = 0.90, p < 0.0001). Maximum rate of clot formation and peak clot turbidity were reduced in the presence of anticoagulants, but correlated only moderately with the comparator measures of anticoagulation. The clot lysis time was inversely correlated with DOAC concentrations in the presence of recombinant thrombomodulin. A direct ex vivo comparison between the effects of different classes of anticoagulants is possible with turbidimetric measurement of plasma clot formation and lysis. Anticoagulation inhibited clot formation in a plasma concentration manner for DOACs, INR dependent for phenprocoumon, and anti-Xa dependent for LMWH. Susceptibility to fibrinolysis increased with increasing DOAC concentrations. PMID- 29417257 TI - Oncological effect of palliative transurethral resection of the prostate in patients with advanced prostate cancer: a propensity score matching study. AB - PURPOSE: We investigated the oncologic effect of palliative transurethral resection of the prostate (pTURP) in patients with prostate cancer who received primary androgen deprivation therapy. METHODS: We reviewed 614 patients, including 83 who underwent pTURP; those with incidental prostate cancer were excluded. Patients were divided into the TURP group and non-TURP group. Propensity score matching was performed for comorbidity, initial prostate specific antigen (PSA), TNM stage, and Gleason score (GS). The Kaplan-Meier method was used to confirm castration-resistant prostate cancer (CRPC), cancer specific survival (CSS), and overall survival (OS). Cox regression was performed to confirm factors affecting CSS. RESULTS: Before matching, the TURP group had a worse TNM stage (p < 0.01) and GS (p = 0.028) and larger prostate volume (50.1 vs. 39.0 cc, p = 0.005) than the non-TURP group. The most common reason for pTURP was acute urinary retention. After matching, the TURP group showed worse outcomes in CRPC (p = 0.003), CSS (p = 0.003), and OS (p = 0.026). In multivariate analysis, factors for predicting CSS were a positive core percent [hazard ratio (HR) 1.015, p = 0.0272], GS (10 vs. <=8; HR 6.716, p = 0.0008), and TURP within 3 months after biopsy (HR 2.543, p = 0.0482). The resection weight (HR 1.000, p = 0.9730), resection time (HR 1.000, p = 0.3670), and blood transfusion (HR 0.630, p = 0.1860) were not associated with CSS. CONCLUSIONS: The oncologic effect of pTURP as cytoreductive operation seems to be limited. Patients who had to receive pTURP due to cancer-related symptoms, especially early necessity of pTURP (within 3 months after biopsy), showed worse clinical courses; therefore, they should be treated more carefully and actively. PMID- 29417258 TI - Impact of comorbidities at diagnosis on prostate cancer treatment and survival. AB - BACKGROUND: The aim of this study was to assess the associations of comorbidities with primary treatment of prostate cancer (PCa) patients and of comorbidities with PCa-specific mortality (PCSM) compared to other-cause mortality (OCM) in Switzerland. PATIENTS AND METHODS: We included 1527 men diagnosed with PCa in 2000 and 2001 in the canton of Zurich. Multiple imputation methods were applied to missing data for stage, grade and comorbidities. Multinomial logistic regression analyses were used to explore the associations of comorbidities with treatment. Cox regression models were used to estimate all-cause mortality, and Fine and Gray competing risk regression models to estimate sub-distribution hazard ratios for the outcomes PCSM and OCM. RESULTS: Increasing age was associated with a decreasing probability of receiving curative treatment, whereas an increasing Charlson Comorbidity Index (CCI) did not influence the treatment decision as strongly as age. The probability of OCM was higher for patients with comorbidities compared to those without comorbidities [CCI 1: hazard ratio 2.07 (95% confidence interval 1.51-2.85), CCI 2+: 2.34 (1.59-3.44)]; this was not observed for PCSM [CCI 1: 0.79 (0.50-1.23), CCI 2+: 0.97 (0.59-1.59)]. In addition, comorbidities had a greater impact on the patients' mortality than age. CONCLUSIONS: The results of the current study suggest that chronological age is a stronger predictor of treatment choices than comorbidities, although comorbidities have a larger influence on patients' mortality. Hence, inclusion of comorbidities in treatment choices may provide more appropriate treatment for PCa patients to counteract over- or undertreatment. PMID- 29417260 TI - Visualization of endothelial cell cycle dynamics in mouse using the Flt-1/eGFP anillin system. AB - Endothelial cell proliferation is a key process during vascular growth but its kinetics could only be assessed in vitro or ex vivo so far. To enable the monitoring and quantification of cell cycle kinetics in vivo, we have generated transgenic mice expressing an eGFP-anillin construct under control of the endothelial-specific Flt-1 promoter. This construct labels the nuclei of endothelial cells in late G1, S and G2 phase and changes its localization during the different stages of M phase, thereby enabling the monitoring of EC proliferation and cytokinesis. In Flt-1/eGFP-anillin mice, we found eGFP+ signals specifically in Ki67+/PECAM+ endothelial cells during vascular development. Quantification using this cell cycle reporter in embryos revealed a decline in endothelial cell proliferation between E9.5 to E12.5. By time-lapse microscopy, we determined the length of different cell cycle phases in embryonic endothelial cells in vivo and found a M phase duration of about 80 min with 2/3 covering karyokinesis and 1/3 cytokinesis. Thus, we have generated a versatile transgenic system for the accurate assessment of endothelial cell cycle dynamics in vitro and in vivo. PMID- 29417259 TI - Generation of erythroid cells from polyploid giant cancer cells: re-thinking about tumor blood supply. AB - INTRODUCTION: During development and tumor progression, cells need a sufficient blood supply to maintain development and rapid growth. It is reported that there are three patterns of blood supply for tumor growth: endothelium-dependent vessels, mosaic vessels, and vasculogenic mimicry (VM). VM was first reported in highly aggressive uveal melanomas, with tumor cells mimicking the presence and function of endothelial cells forming the walls of VM vessels. The walls of mosaic vessels are randomly lined with both endothelial cells and tumor cells. We previously proposed a three-stage process, beginning with VM, progressing to mosaic vessels, and eventually leading to endothelium-dependent vessels. However, many phenomena unique to VM channel formation remain to be elucidated, such as the origin of erythrocytes before VM vessels connect with endothelium-dependent vessels. RESULTS: In adults, erythroid cells are generally believed to be generated from hematopoietic stem cells in the bone marrow. In contrast, embryonic tissue obtains oxygen through formation of blood islands, which are largely composed of embryonic hemoglobin with a higher affinity with oxygen, in the absence of mature erythrocytes. Recent data from our laboratory suggest that embryonic blood-forming mechanisms also exist in cancer tissue, particularly when these tissues are under environmental stress such as hypoxia. We review the evidence from induced pluripotent stem cells in vitro and in vivo to support this previously underappreciated cell functionality in normal and cancer cells, including the ability to generate erythroid cells. We will also summarize the current understanding of tumor angiogenesis, VM, and our recent work on polyploid giant cancer cells, with emphasis on their ability to generate erythroid cells and their association with tumor growth under hypoxia. CONCLUSION: An alternative embryonic pathway to obtain oxygen in cancer cells exists, particularly when they are under hypoxic conditions. PMID- 29417262 TI - Thirty Years of Research on Gay Men and HIV Prevention in France: A Narrative Review of the Literature. AB - Research on homosexuality and HIV/AIDS in the social sciences has evolved into a vast and multiform field of study since the beginning of the epidemic in the Global North. Studies from France in this domain have remained relatively unknown at the international level. This article offers a narrative review of publications that resulted from research on homosexuality and HIV/AIDS, from 1985 to 2016. It offers an analysis of how the constitution of a field of research conditions the ways scientific questions are asked (and answered). This epistemological concern is addressed through a sociohistorical contextualization of the main issues surrounding prevention and how they have been addressed by researchers in France. A review of French publications on HIV prevention among gay men reveals certain specificities. In terms of the social science disciplines, psychology and psychoanalysis are much less present in this domain, whereas epidemiology, sociology, and anthropology are the most represented. The works analyzed in this article also reveal the circulation and local adaptations of risk categories imported from the English-speaking world, such as "relapse" and "bareback." Regardless, research on HIV prevention in France largely evolved contemporaneously in the same way that it did elsewhere. PMID- 29417261 TI - The ratio of ADSCs to HSC-progenitors in adipose tissue derived SVF may provide the key to predict the outcome of stem-cell therapy. AB - BACKGROUND: Stromal vascular fraction (SVF) represents an attractive source of adult stem cells and progenitors, holding great promise for numerous cell therapy approaches. In 2017, it was reported that 1524 patients received autologous SVF following the enzymatic digestion of liposuction fat. The treatment was safe and effective and patients showed significant clinical improvement. In a collaborative study, we analyzed SVF obtained from 58 patients having degenerative, inflammatory, autoimmune diseases, and advanced stage cancer. RESULTS: Flow analysis showed that freshly isolated SVF was very heterogeneous and harbored four major subsets specific to adipose tissue; CD34high CD45- CD31- CD146- adipose-derived stromal/stem cells (ADSCs), CD34low CD45+ CD206+CD31- CD146- hematopoietic stem cell-progenitors (HSC-progenitors), CD34high CD45- CD31+CD146+ adipose tissue-endothelial cells and CD45-CD34-CD31-CD146+ pericytes. Culturing and expanding of SVF revealed a homogenous population lacking hematopoietic lineage markers CD45 and CD34, but were positive for CD90, CD73, CD105, and CD44. Flow cytometry sorting of viable individual subpopulations revealed that ADSCs had the capacity to grow in adherent culture. The identity of the expanded cells as mesenchymal stem cells (MSCs) was further confirmed based on their differentiation into adipogenic and osteogenic lineages. To identify the potential factors, which may determine the beneficial outcome of treatment, we followed 44 patients post-SVF treatment. The gender, age, clinical condition, certain SVF-dose and route of injection, did not play a role on the clinical outcome. Interestingly, SVF yield seemed to be affected by patient's characteristic to various extents. Furthermore, the therapy with adipose-derived and expanded-mesenchymal stem cells (ADE-MSCs) on a limited number of patients, did not suggest increased efficacies compared to SVF treatment. Therefore, we tested the hypothesis that a certain combination, rather than individual subset of cells may play a role in determining the treatment efficacy and found that the combination of ADSCs to HSC-progenitor cells can be correlated with overall treatment efficacy. CONCLUSIONS: We found that a 2:1 ratio of ADSCs to HSC progenitors seems to be the key for a successful cell therapy. These findings open the way to future rational design of new treatment regimens for individuals by adjusting the cell ratio before the treatment. PMID- 29417263 TI - Superselective Transcatheter Artery Embolization in Patients with Non-ischemic Priapism. AB - PURPOSE: To investigate the efficacy and safety of superselective transcatheter artery embolization in patients with non-ischemic priapism. MATERIALS AND METHODS: We retrospectively reviewed a cohort of 17 consecutive patients with non ischemic priapism from September 2006 to August 2017. The median follow-up time was 8 months. RESULTS: Sixteen patients underwent superselective transcatheter artery embolization, and all had complete resolution of non-ischemic priapism. Fifteen of 16 patients (93.7%) underwent a single embolization without recurrence. A secondary embolization was required in one patient (6.3%) as a result of recurrence. Two of 16 patients (12.5%) had a decrease in their erectile function; one of the two patients had premorbid erectile dysfunction. Excluding the patient with premorbid erectile dysfunction, 14 of 15 patients (93.3%) maintained premorbid normal erectile function after embolization; the incidence of decrease in quality of erection is 6.7% (1/15). One patient did not undergo artery embolization because of negative findings of cavernous fistula by angiography. No angiography-related complications were found. CONCLUSION: Superselective transcatheter artery embolization is an effective and safe procedure for non-ischemic priapism. PMID- 29417264 TI - Polidocanol Sclerotherapy Combined with Transarterial Embolization Using n-Butyl Cyanoacrylate for Extracranial Arteriovenous Malformations. AB - PURPOSE: To assess the safety and effectiveness of polidocanol sclerotherapy combined with transarterial embolization using a liquid adhesive agent (n-butyl cyanoacrylate, NBCA) for treatment of extracranial arteriovenous malformations (AVMs). MATERIALS AND METHODS: Twenty-three patients with symptomatic AVMs in the head and neck (6), upper (7) and lower extremity (10) with a mean age of 42 years (range 4-74) treated with polidocanol sclerotherapy were retrospectively assessed. AVMs were classified according to the angiographic morphology of the nidus. There were 2 type I, 6 type II, 6 type IIIa and 9 type IIIb. Arterial embolization using NBCA was performed to reduce arterial flow before sclerotherapy. Polidocanol mixed with contrast material or carbon dioxide was delivered by percutaneous direct puncture. RESULTS: Treatment was successfully performed in all patients. In the mean follow-up period of 38 months, symptoms resolved or improved in 20/23 patients (87.0%). AVMs were devascularized 100% in 2 patients, 76-99% in 13, 50-75% in 7 and < 50% in 1. More than 50% devascularization was seen in 22 patients (95.6%). Two (8%) patients had complete remission, 17 (74%) had partial remission and 3 (13%) had no remission. There was no aggravation. Treatment was considered effective (complete and partial remission) in 20 patients (87.0%). Minor complications including localized arterial thrombosis (2) and spontaneously healing skin ulcer (1) were seen in 2 patients (8.7%). There were no major procedure-related complications. CONCLUSION: Polidocanol sclerotherapy combined with transarterial embolization using NBCA is safe and effective for treating extracranial AVMs with an acceptable risk of minor complications. PMID- 29417265 TI - Embolization of the Thoracic Duct by Direct Injection of N-Butyl-2-Cyanoacrylate Glue via a Puncture Needle. AB - PURPOSE: To report embolization of the thoracic duct by direct injection of N butyl-2-cyanoacrylate (NBCA) glue via a puncture needle. MATERIALS AND METHODS: Two cases of high output chylothorax were successfully treated with direct injection of N-butyl-2-cyanoacrylate (NBCA) glue via a puncture needle. In them, conventional thoracic duct embolization (TDE) was attempted, but the cisterna chyli was absent on intranodal lymphangiography, and probably for this reason catheterization of the thoracic duct was unsuccessful. Contrast material injection via a puncture needle, however, clearly showed a leak from the thoracic duct, prompting us to attempt embolization of the thoracic duct by direct injection of NBCA glue via the needle. RESULTS: Thoracic duct embolization by direct injection of NBCA glue via a puncture needle was technically successful in both patients. No minor or major complication occurred. Both patients disappeared chylothorax after this treatment. CONCLUSION: This embolization method can be useful for treatment of chylothorax when conventional TDE is not achievable. PMID- 29417266 TI - Comparison of Patient Skin Dose Evaluated Using Radiochromic Film and Dose Calculation Software. AB - PURPOSE: To compare, in an interventional radiology setting, peak skin doses (PSDs) delivered as calculated using a dedicated software tool and as measured using radiochromic film. To assess the utility of this dose calculation software tool in routine clinical practice. MATERIALS AND METHODS: First, radiochromic films were positioned on the examination table in the back of an adult anthropomorphic phantom to measure PSD, and X-ray examinations were simulated. Then, films were again positioned in the patient's back for 59 thoracic or abdominopelvic endovascular interventions. The results obtained with the radiochromic films were taken as a reference and were statistically compared with those of the software. RESULTS: With measured PSDs ranging from 100 to 7000 mGy, the median software-film difference was 8.5%. Lin's concordance coefficient was 0.98 [0.97; 0.99] (p < 0.001), meaning that concordance was excellent between the two methods. For the films where PSD exceeded 1000 mGy, the median difference in the measured value was 8.7% [- 1.3; 21.1], with a maximum discrepancy of 34%. Lin's concordance coefficient was 0.98 [0.96; 1] (p < 0.001), meaning that concordance was excellent between the two methods. CONCLUSION: Comparison between radiochromic films and the software tool showed that the software is a suitable tool for a simple and reliable estimation of PSD. The software seems to be a good alternative to films, whose use remains complex. PMID- 29417267 TI - Modified Balloon-Occluded Retrograde Transvenous Obliteration (BRTO) Techniques for the Treatment of Gastric Varices: Vascular Plug-Assisted Retrograde Transvenous Obliteration (PARTO)/Coil-Assisted Retrograde Transvenous Obliteration (CARTO)/Balloon-Occluded Antegrade Transvenous Obliteration (BATO). AB - Gastric varices in the setting of portal hypertension occur less frequently than esophageal varices but occur at lower portal pressures and are associated with more massive bleeding events and higher mortality rate. Balloon-occluded retrograde transvenous obliteration (BRTO) of gastric varices has been well documented as an effective therapy for portal hypertensive gastric varices. However, BRTO requires lengthy, higher-level post-procedural monitoring and can have complications related to balloon rupture and adverse effects of sclerosing agents. Several modified BRTO techniques have been developed including vascular plug-assisted retrograde transvenous obliteration, coil-assisted retrograde transvenous obliteration, and balloon-occluded antegrade transvenous obliteration. This article provides an overview of various modified BRTO techniques. PMID- 29417268 TI - Retrospective Single-Arm Cohort Study of Patients with Hepatocellular Adenomas Treated with Percutaneous Thermal Ablation. AB - PURPOSE: To assess the safety and efficacy of percutaneous thermal ablation for the treatment of hepatocellular adenomas. MATERIALS AND METHODS: This is an ethics board-approved, single-arm, retrospective, cohort study of patients with pathologically proven hepatocellular adenomas treated with percutaneous thermal ablation at a tertiary referral center from 1999 to 2016. Demographic, procedural, and outcome data were collected and summarized with appropriate measures of central tendency and dispersion. Complications were graded per the Society of Interventional Radiology reporting guidelines. Determination of primary and secondary technique efficacies was based on post-procedural imaging. RESULTS: Thirty-six patients (4 male, 32 female) with a median age of 35 years had 44 procedures for the treatment of 58 tumors. Twenty-two percent of patients had prior history of adenoma-related hemorrhage. The median tumor size was 2.1 cm (range 0.6-6.0). The majority of treatments were done on an outpatient basis, under moderate sedation, using radiofrequency ablation with ultrasound guidance. The median procedure time was 85 min. There were two immediate post-procedural hemorrhages (4.5% per procedure). During a median follow-up of 1.7 years (95% CI 0.2-8.0), there were no instances of malignant transformation, adenoma-related hemorrhages, or deaths. The primary and secondary technique efficacy rates were 88 and 100%, respectively. CONCLUSION: Thermal ablation for the treatment of hepatocellular adenoma had a primary and secondary efficacy of 88 and 100%, respectively. The major complication rate was 4.5%. The clinical efficacy during a median follow-up of 1.7 year was 100%. PMID- 29417269 TI - Transcriptome-wide identification and functional prediction of novel and flowering-related circular RNAs from trifoliate orange (Poncirus trifoliata L. Raf.). AB - MAIN CONCLUSION: A total of 558 potential circular RNAs (circRNAs) were identified in citrus, and these were analyzed and compared. One hundred seventy six differentially expressed circRNAs were identified in two genotypes of trifoliate orange. Circular RNAs (circRNAs) play diverse roles in transcriptional control and microRNA (miRNA) function. However, little information is known about circRNAs in citrus. To identify citrus circRNAs and investigate their functional roles, high-throughput sequencing of precocious trifoliate orange (an early flowering trifoliate orange mutant, Poncirus trifoliata L. Raf.) and its wild type was performed. A total of 558 potential circRNAs were identified by bioinformatic analysis, and 86.02% of these were sense-overlapping circRNAs. Their sequence features, alternative circularization, and other characteristics were investigated in this study. Compared with the wild type, 176 circRNAs were identified as differentially expressed circRNAs, 61 were significantly up regulated and 115 were down-regulated in precocious trifoliate orange, indicating that they may play an important role in the early flowering process. Alternative circularization and differential expression of some circRNAs were verified by Sanger sequencing and real-time polymerase chain reaction. The functions of differentially expressed circRNAs and their host genes were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We found that many differentially expressed circRNAs had abundant miRNA binding sites: 29 circRNAs were found to act as the 16 miRNA targets. Overall, these results will help to reveal the biological functions of circRNAs in growth and development of citrus. PMID- 29417270 TI - Involvement of S-nitrosothiols modulation by S-nitrosoglutathione reductase in defence responses of lettuce and wild Lactuca spp. to biotrophic mildews. AB - MAIN CONCLUSION: Resistant Lactuca spp. genotypes can efficiently modulate levels of S-nitrosothiols as reactive nitrogen species derived from nitric oxide in their defence mechanism against invading biotrophic pathogens including lettuce downy mildew. S-Nitrosylation belongs to principal signalling pathways of nitric oxide in plant development and stress responses. Protein S-nitrosylation is regulated by S-nitrosoglutathione reductase (GSNOR) as a key catabolic enzyme of S-nitrosoglutathione (GSNO), the major intracellular S-nitrosothiol. GSNOR expression, level and activity were studied in leaves of selected genotypes of lettuce (Lactuca sativa) and wild Lactuca spp. during interactions with biotrophic mildews, Bremia lactucae (lettuce downy mildew), Golovinomyces cichoracearum (lettuce powdery mildew) and non-pathogen Pseudoidium neolycopersici (tomato powdery mildew) during 168 h post inoculation (hpi). GSNOR expression was increased in all genotypes both in the early phase at 6 hpi and later phase at 72 hpi, with a high increase observed in L. sativa UCDM2 responses to all three pathogens. GSNOR protein also showed two-phase increase, with highest changes in L. virosa-B. lactucae and L. sativa cv. UCDM2-G. cichoracearum pathosystems, whereas P. neolycopersici induced GSNOR protein at 72 hpi in all genotypes. Similarly, a general pattern of modulated GSNOR activities in response to biotrophic mildews involves a two-phase increase at 6 and 72 hpi. Lettuce downy mildew infection caused GSNOR activity slightly increased only in resistant L. saligna and L. virosa genotypes; however, all genotypes showed increased GSNOR activity both at 6 and 72 hpi by lettuce powdery mildew. We observed GSNOR mediated decrease of S-nitrosothiols as a general feature of Lactuca spp. response to mildew infection, which was also confirmed by immunohistochemical detection of GSNOR and GSNO in infected plant tissues. Our results demonstrate that GSNOR is differentially modulated in interactions of susceptible and resistant Lactuca spp. genotypes with fungal mildews and uncover the role of S nitrosylation in molecular mechanisms of plant responses to biotrophic pathogens. PMID- 29417271 TI - Purinergic signaling modulates the splenic inflammatory response in silver catfish naturally infected with Ichthyophthirius multifiliis. AB - The spleen is an immune lymphatic organ linked with control of the immune response, which is important to fish health. Recent evidence has suggested the involvement of purinergic signaling in the modulation of immune and inflammatory responses through the nucleotide adenosine triphosphate (ATP) and the nucleoside adenosine (Ado), which are regulated by the enzymes nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase, and adenosine deaminase (ADA). Thus, the aim of this study was to evaluate whether purinergic signaling can modulate the immune and inflammatory responses in the spleen of silver catfish (Rhamdia quelen) naturally infected with Ichthyophthirius multifiliis. Splenic NTPDase and 5'-nucleotidase activities increased in infected animals compared with uninfected animals, while the splenic ADA activity decreased. These data indicate that purinergic signaling can modulate the splenic immune and inflammatory responses through the regulation of ATP and Ado levels, which are known to participate in the physiological and pathological responses as pro inflammatory and anti-inflammatory molecules, respectively. In summary, modulation of the splenic purinergic cascade has an anti-inflammatory role in reducing or preventing inflammatory damage. PMID- 29417272 TI - Morphological and molecular genetic characterization of Kudoa konishiae n. sp. (Myxosporea: Multivalvulida) in the muscle of Japanese Spanish mackerel (Scomberomorus niphonius). AB - The Japanese Spanish mackerel (Scomberomorus niphonius; Perciformes: Scombridae) is widely distributed in the continental shelves of the northwestern Pacific Ocean around Japan, Sea of Japan, and East China Sea. In the present study, small, spindle-shaped myxosporean plasmodia (0.15-0.53 mm by 0.04-0.13 mm) were frequently encountered in the myofiber of trunk muscles of two Japanese Spanish mackerels; one fished in the Sea of Japan off western Japan and the other in the northwestern Pacific Ocean off southern Japan in the autumn of 2016. Isolated myxospores of Kudoa konishiae n. sp. (Myxosporea: Multivalvulida) from these two fish were stellate with six equal shell valves and polar capsules, 8.1-9.7 MUm in width, 7.1-8.8 MUm in thickness, and 7.1-8.8 MUm in length. The polar capsules were teardrop-shaped, 2.7-4.7 MUm by 1.2-2.5 MUm. The lateral view of spores revealed a drawstring-pouch shape. The nucleotide sequences of the 18S and 28S ribosomal RNA gene (rDNA) were distinct from any recorded species. Phylogenetic trees demonstrated a close relationship of the present new species with Kudoa spp. with stellate spores with five or more shell valves/polar capsules, recorded in scombrid fishes. To clarify the phylogenetic relationships between three closely related species, i.e., Kudoa konishiae n. sp., Kudoa hexapunctata, and Kudoa neothunni, three mitochondrial DNA genes (cytochrome c oxidase subunit 1 gene (cox-1) and the small and large subunits of the ribosomal RNA gene (rns rnl)) of two isolates of the new species, six isolates of K. hexapunctata, and 13 isolates of K. neothunni were sequenced. The interspecific and intraspecific variations of the newly obtained cox-1 and rns-rnl nucleotide sequences of K. hexapunctata, K. neothunni, and K. konishiae n. sp. were clarified for the first time. PMID- 29417273 TI - Borrelia burgdorferi in small mammal reservoirs in Kentucky, a traditionally non endemic state for Lyme disease. AB - The incidence of tick-borne zoonoses such as Lyme disease has steadily increased in the southeastern United States. Southeastern states accounted for 1500 of over 28,000 confirmed cases of Lyme disease reported in the United States during 2015. Borrelia burgdorferi, the etiologic agent of Lyme disease, is maintained in small mammal reservoirs and vectored to new hosts by ixodid ticks. This study examined ecological relationships of the B. burgdorferi/vector/reservoir system in order to understand the dynamics of Lyme disease risk in Kentucky. Small mammals were captured using live traps from November 2014 to October 2015. Ticks were removed and blood and tissue collected from small mammals were screened for B. burgdorferi DNA by PCR with primers specific to the OspA gene. Prevalence of B. burgdorferi (21.8%) in Kentucky small mammals was comparable to the lowest recorded prevalence in regions where Lyme disease is endemic. Moreover, infestation of small mammals by Ixodes scapularis, the primary vector of B. burgdorferi, was rare, while Dermacentor variabilis comprised the majority of ticks collected. These findings provide ecological insight into the relative paucity of Lyme disease in Kentucky. PMID- 29417274 TI - Molecular evidence of Chlamydiales in ticks from wild and domestic hosts in Sardinia, Italy. AB - Ticks are well known to be important vectors for a wide range of bacteria, viruses and protozoa affecting human and animal health. Ixodid ticks are widely distributed in Sardinia, and an increasing number of tick-borne bacteria have been documented in the island. A growing number of evidence are supporting the hypothesis of alternative transmission routes for chlamydial bacteria such as the involvement of vectors. This study was conducted to provide possible molecular detection of members belonging to the Chlamydiales order in Sardinian ticks and to update information concerning the presence of new ectoparasite-borne bacteria in ticks collected from domestic and wild hosts in a typical Mediterranean environment. A total of 378 ticks were individually screened with a pan Chlamydiales specific primers targeting the 16S rRNA gene. Chlamydiales DNA was detected in 28% of the total ticks analyzed. The analyses of sequences highlighted that Rhipicephalus sanguineus sensu lato, Rhipicephalus bursa, Rhipicephalus annulatus, Haemaphysalis sulcata, Haemaphysalis punctata and Dermacentor marginatus ticks exhibited DNA of Chlamydiaceae and Parachlamydiaceae members. Our results revealed that DNA of zoonotic microorganisms such as C. psittaci, C. abortus and the emerging pathogen Parachlamydia acanthamoebae are present in Sardinian ticks. Since routes of Chlamydia transmission are yet to be fully defined, the role of ticks as possible vectors for Chlamydiales remains the most challenging and interesting question to be addressed in future research. Continued monitoring of these pathogens in tick vectors is needed to provide strategies for controlling of possible chlamydial infections and disease outbreaks in the island. PMID- 29417275 TI - Cochlear implantation using the underwater technique: long-term results. AB - INTRODUCTION: The opening of the round window and the insertion of the electrode array into the scala tympani during cochlear implant surgery can lead to a pressure shock of the delicate inner ear structures. By filling the tympanic cavity with Ringer Solution during these surgical steps (underwater technique), the hydrostatic pressure of the fluid acts as a smooth pressure stabilizer, avoiding a pressure shock of the inner ear structures. The aim of this retrospective study was to present long-term results of this new method of cochlear implantation in underwater technique. METHODS: Altogether, 47 implantations in 43 patients with residual hearing at the frequencies 250, 500 and 1000 Hz in the unaided preoperative pure tone audiometry were included. A cochlear implantation via round window with a conventional full-length electrode was performed in underwater technique. Changes of residual hearing 7 weeks and 24 months after surgery were analyzed. RESULTS: Overall postimplant hearing preservation 7 weeks after implantation was achieved in 22 ears (47%). Subsequent follow-up was performed on average 24 months after surgery (range 12 months-4.2 years) in all patients. At this late postoperative evaluation, preservation of hearing was recorded in 18 ears (38%). Neither the follow-up time nor the type of electrode had a significant impact on the postoperative hearing loss. CONCLUSION: The underwater technique is an atraumatic cochlear implantation technique with hearing preservation rates comparable to results in literature and a very small hearing preservation decline rate over time even when using full-length CI electrodes. PMID- 29417276 TI - Preliminary experience in transoral laryngeal surgery with a flexible robotic system for benign lesions of the vocal folds. AB - PURPOSE: This purpose of this case series is to present the first four cases utilizing micro-phonosurgical instrumentation designed specifically for use with a semi-flexible 'robotic' system-the Medrobotics Flex system and to evaluate the accessibility and feasibility of this platform in the context of transoral robotic surgery (TORS) for laryngeal surgery. METHODS: Four patients (3 female, 1 male; age range 49-79 years) were operated by the senior author at CHL-a tertiary hospital centre between 2016 and 2017. The 'robot' was deployed in all cases to assess its accessibility and ability to perform surgery in the larynx. RESULTS: All four patients were successfully treated using the system along with newly developed instrumentation specifically focused on phonosurgery. CONCLUSION: This series has demonstrated accessibility and ability for laryngeal surgery using a novel semi-rigid operator-controlled 'robotic' system. We encountered no device failures and were able to perform all the selected cases uneventfully. PMID- 29417277 TI - Radiological comparison of inferior turbinate hypertrophy between allergic and non-allergic rhinitis: does allergy really augment turbinate hypertrophy? AB - BACKGROUND: Inferior turbinate hypertrophy could be a result of allergic rhinitis (AR) that leads to nasal congestion and nasal airway obstruction, which is the most bothersome complaint in patients with AR. However, evidence regarding whether patients with AR have a more hypertrophied inferior turbinate than do patients with non-AR is lacking. OBJECTIVE: We aimed to evaluate the degree of inferior turbinate hypertrophy according to the presence of AR using radiological measurements of the inferior turbinate. METHODS: For evaluating the inferior turbinate, which contributes to nasal obstruction in patients with AR, we enrolled 90 adult patients with septal deviation and divided them into two groups (AR group: n = 49; non-AR group: n = 41). Allergic rhinitis was diagnosed according to the presence of an allergic history, positive multiple allergen simultaneous test, and serological total immunoglobulin E level (>= 100 kU/L). We analyzed the minimal cross-sectional area on acoustic rhinometry for both groups. The bilateral total width as well as medial mucosa and nasal cavity space in the anterior and posterior portions of the inferior turbinate were measured using computed tomography. RESULTS: We could not find any significant differences in the anterior and posterior dimensions of the inferior turbinate, intranasal space, and choanal spaces between the AR and non-AR groups. Instead, the anterior part of the inferior turbinate in both the groups showed significant differences between the deviated and contralateral sides. The contralateral side had a larger width than did the deviated side, but no significant difference was noted in the posterior portion of the inferior turbinate. CONCLUSION: The degree of inferior turbinate hypertrophy showed no difference between patients with and without AR. Therefore, we suggest that surgical treatment for reducing the size of the inferior turbinate hypertrophy should be considered when performing septoplasty in patients with symptoms of nasal obstruction, regardless of the presence of AR. PMID- 29417278 TI - Validation of the second version of the LittlEARS(r) Early Speech Production Questionnaire (LEESPQ) in German-speaking children with normal hearing. AB - INTRODUCTION: The introduction of neonatal hearing screening and the increasingly early age at which children can receive a cochlear implant has intensified the need for a validated questionnaire to assess the speech production of children aged 0-18. Such a questionnaire has been created, the LittlEARS(r) Early Speech Production Questionnaire (LEESPQ). This study aimed to validate a second, revised edition of the LEESPQ. METHODS AND MATERIALS: Questionnaires were returned for 362 children with normal hearing. Completed questionnaires were analysed to determine if the LEESPQ is reliable, prognostically accurate, internally consistent, and if gender or multilingualism affects total scores. RESULTS: Total scores correlated positively with age. The LEESPQ is reliable, accurate, and consistent, and independent of gender or lingual status. A norm curve was created. DISCUSSION: This second version of the LEESPQ is a valid tool to assess the speech production development of children with normal hearing, aged 0-18, regardless of their gender. As such, the LEESPQ may be a useful tool to monitor the development of paediatric hearing device users. CONCLUSION: The second version of the LEESPQ is a valid instrument for assessing early speech production of children aged 0-18 months. PMID- 29417279 TI - Tumors of the parapharyngeal space: the VU University Medical Center experience over a 20-year period. AB - BACKGROUND: Tumors of the parapharyngeal space (PPS) are rare, accounting for 0.5 1.5% of all head and neck tumors. The anatomy of the PPS is responsible for a wide variety of tumors arising from the PPS. This series of 99 PPS tumors provides an overview of the clinical course and management of PPS tumors. MATERIALS AND METHODS: This retrospective study included clinical data from patients treated for PPS tumors from 1991 to 2012 (warranting at least a 4-year follow-up) at the VU University Medical Center, Amsterdam, The Netherlands. RESULTS: Fifty percent were salivary gland tumors, 41% were neurogenic and 9% had a different origin. 18.2% of the PPS tumors were malignant. The most reported symptom at presentation was swelling of the neck and throat. In 14%, the PPS tumor was an accidental finding following imaging for other diagnostic reasons. Cytology showed an accuracy rate of 73.1% (19/26). The positive predictive value of a malignant cytology result was 86% (95% CI 42.1-99.6%). Surgery was performed in 55 patients (56%). The most frequently performed approach (56%) was the cervical-transparotid approach, followed by the cervical (25%), transmandibular (16%) and transoral (2%) approach. Nine patients died of the disease, of which seven patients had a malignant salivary gland tumor, one patient had a pleomorphic adenoma at first diagnosis which degenerated into carcinoma ex pleomorphic adenoma and one patient died of metastatic renal cell carcinoma. CONCLUSION: This large single-centre report on PPS tumors shows that careful diagnostic work up and proper surgical planning are important in this specific and rare group of head and neck tumors. Surgery was the main treatment (56%) for parapharyngeal tumors. Management of parapharyngeal neurogenic neoplasms generally consists of active surveillance due to peri-operative risk for permanent cranial nerve damage. The histopathological diagnoses were consistent with previous reports. PMID- 29417281 TI - Morbidity, fertility and pregnancy outcomes after myoma enucleation by laparoscopy versus laparotomy. AB - OBJECTIVES: Myomas are defined as benign tumours that arise from smooth muscle cells of the uterus. Clinically, they are found in 5-77% of women of reproductive age. The prevalence rate varies considerably in the literature and a large number of fibroids do not cause symptoms. The lifetime risk of acquiring myomas is 70% for Caucasian women and >= 80% for African American women. MATERIALS/METHODS: The data of 265 patients undergoing surgery for symptomatic myomas by laparoscopy or laparotomy, performed in the gynaecological department of Hannover Medical School, Hannover, Germany, between 2009 and 2013, were retrospectively analysed in this retrospective design study. RESULTS: High pregnancy rates (up to 70%) and birth rates (up to 86%) after myomectomy, regardless of the surgical approach adopted, were found in the current study. The trend was that >= 3 myomas and those that were >= 6 cm in size were almost always removed by laparotomy in our clinic. It was possible to remove up to 42 myomas without having to perform a hysterectomy. A statistically significant negative correlation was observed in relation to the association between the size of the largest myoma extracted and the pregnancy rate (p = 0.02). A statistically significant correlation between the number of removed myomas and the pregnancy rate was observed for patients who wished to bear children (p = 0.010). Elevated complication rates (of up to 50%) were reported for more than three extracted myomas with a statistically significance (p = 0.0471). CONCLUSIONS: It is necessary to ensure sound preoperative selection of the surgical approach in order to achieve the most optimal results, especially for those patients who wished to bear children. PMID- 29417280 TI - Coexistence of frontal sinus hypoplasia with maxillary sinus hypoplasia: a radiological study. AB - The goal of this study was to determine whether frontal sinus hypoplasia coexists with maxillary sinus hypoplasia. Analyzing paranasal CT scans retrospectively, we included 86 patients who had a hypoplastic maxillary sinus at least on one side and 80 patients with bilateral normal maxillary sinuses (control group). We classified hypoplastic maxillary sinuses using the classification system previously defined by Bolger et al. (Otolaryngol Head Neck Surg 103(5):759-765, 1990). We classified the frontal sinuses as aplastic, hypoplastic, medium-sized, and hyperplastic; as previously defined by Guerram et al. (Am J Phys Anthropol 154(4):621-627, 2014). We compared the presence of frontal sinus hypoplasia using Chi-square test between the groups. The mean age of the maxillary sinus group was 43.2 (range 18-84) years. Of 86 patients, 33 (38.4%) had unilateral and 53 (61.6%) had bilateral maxillary sinus hypoplasia. Of 139 maxillary sinuses totally included, 73 (52.5%) were type 1, 51 (36.7%) were type 2 and 15 (10.8%) were type 3 hypoplastic maxillary sinuses. Of 332 frontal sinuses totally included, 25 (7.5%) were aplastic, 32 (9.6%) were hypoplastic, 172 (51.9%) were medium-sized, and 103 (31%) were hyperplastic. Of 86 patients with a hypoplastic maxillary sinus at least on one side, 29 (33.7%) had a hypoplastic and/or aplastic frontal sinus, while 10 (12.5%) had a hypoplastic and/or aplastic frontal sinus at least on one side in control group. Incidence of frontal sinus hypoplasia and/or aplasia was significantly higher in patients with maxillary sinus hypoplasia compared to the patients with bilaterally normal maxillary sinuses (chi2 = 10.384, P = 0.001). Maxillary sinus hypoplasia has a significantly higher coexistence with frontal sinus hypoplasia. This study may have an implication for anatomical studies about the development of the paranasal sinuses and paranasal sinus surgery as well as further morphological studies. PMID- 29417282 TI - Conventional in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI): which is preferred for advanced age patients with five or fewer oocytes retrieved? AB - PURPOSE: To investigate the clinical outcomes of conventional IVF and ICSI in female patients aged 40 years and over with no more than five oocytes retrieved and non-male factor infertility. METHODS: A retrospective study of a cohort of 644 patients undergoing IVF/ICSI treatment. The 534 female patients aged ? 40 years with no more than five oocytes retrieved and non-male factor infertility undergoing their first conventional IVF cycles were assigned in IVF group. The rest of 110 patients aged 40 years and over with no more than five oocytes retrieved and non-male factor infertility undergoing first ICSI cycles were recruited in ICSI group. RESULTS: Our results showed the clinical pregnancy, live birth and miscarriage rates were similar between the IVF and ICSI groups (21.59% vs. 13.25%, P > 0.05; 12.16% vs. 6.02%, P > 0.05; 43.68% vs. 54.55%, P > 0.05; respectively), however, the implantation and cumulative live-birth rates were significantly higher in the IVF compared to the ICSI group (15.11% vs. 7.75%, 14.59% vs. 5.56%, P < 0.05), though the IVF group had a lower normal fertilization rate (61.56% vs. 76.00%, P < 0.001). CONCLUSIONS: Our study provides strong evidences that the conventional IVF exhibits advantages over the ICSI method in non-male factor infertility for advanced age patients with five or fewer oocytes retrieved. PMID- 29417283 TI - Depleted lamin B1: a possible marker of the involvement of senescence in endometriosis? AB - PROPOSE: Endometriosis is a benign disease characterized by implantation and the growth of endometrial tissue outside the uterine cavity and it shares similarities with cancer. Lamin B1, p16 and p21 play a role on cell cycle regulation, development, cell repair and its activities are related to cancers. Considering the similarities between endometriosis and cancer, the aim of the present cross-sectional study is to detect p16, p21 and Lamin B1 in the ectopic endometrium of patients with endometriosis (n = 8) with eutopic (n = 8) and control endometrium (n = 8) and relate them to the maintenance and development of endometriosis. METHODS: Biopsies were obtained from both eutopic and ectopic, from deep infiltrating lesions, endometrium frozen and used for immunofluorescent (p16) or immunohistochemistry procedures (p16, p21, lamin B1). RESULTS: Detected higher lamin B1 in the eutopic endometrium when compared with ectopic endometrium, with no differences between endometriosis tissue with control endometrium. Similar presence of p16 in all groups of patients and no p21 detection was observed. CONCLUSION: We observed reduced detection of lamin B1 in the ectopic endometrium raising the possibility that the presence of senescent cells might be contributing to the maintenance and progression of endometriosis by apoptosis resistance and peritoneal stress inherent of the disease. PMID- 29417284 TI - Biologic meshes and synthetic meshes in cancer patients: a double-edged sword: differences in production of IL-6 and IL-12 caused by acellular dermal matrices in human immune cells. AB - PURPOSE: In 2005, Breuing et al. first described the use of acellular dermal matrices (ADMs) in breast cancer patients. ADMs are assumed to be safe to use in an oncologic setting, but data from controlled studies are still needed. Here, we investigate the effects of ADMs on the production of interleukin (IL)-6 and IL 12, key regulators of immune suppression and activation. METHODS: Strattice (ST), CollaMend (CM), and Biodesign (BD) biologic meshes and TiLoop, a synthetic mesh (TL), were used in this study. We isolated myeloid dendritic cells (MDCs), untouched plasmacytoid dendritic cells (pDCs), naive B cells, and CD8+ T cells and co-cultured these cells with either the biologic meshes or TL. As positive controls, we used CpG ODN 2216 or lipopolysaccharide (LPS). The cytokine concentrations of IL-12p70 and IL-6 were determined after 7 days using sandwich ELISA sets. RESULTS: There were highly significant differences between the ADMs and TL in terms of their ability to stimulate immunologic responses. IL-6 expression was significantly increased in B cells (p = 0.0006131) and T cells (p = 0.00418) when comparing TL and ADMs. We also identified significant differences in IL-12 production by B cells (p = 0.0166) and T cells (p = 0.003636) when comparing TL and ADMs. CONCLUSIONS: Despite the assumed lack of an immunological response to ADMs, in our experimental study, human immune cells reacted with significantly different cytokine profiles. These findings may have implications for the potential activation or suppression of effector cells in cancer patients and could explain some of the post clinical post surgical signs of ADMS like skin rush and seroma. PMID- 29417285 TI - Surgical laparoscopic treatment of bowel endometriosis with transvaginal resection of the rectum using ultrasonically activated shears: a retrospective cohort study with description of technique. AB - BACKGROUND: To asses the results of laparoscopic surgical treatment of bowel endometriosis with transvaginal resection of the rectum employing ultrasonic energy retrospective study. METHOD: 100 patients with symptoms of narrowing or partial obstruction of colon were submitted to laparoscopic resection of rectosigmoid tract through a vaginal route. Length of surgery, blood loss, histopathological extent of rectal invasion, surgical complications, and length of hospital stay were the main analyzed outcomes. RESULTS: Mean operative time was 281 min, blood loss was 250 ml on average, length of stay was 8 days, bowel movements were after 3.5 days, the mean length of bowel-resected segments was 13.3 cm, the disease was multifocal in 64% and multicentric in 36% of surgical specimens. CONCLUSION: Laparoscopically assisted vaginal resection of rectosigmoid colon affected by endometriosis using ultrasonically activated shears with mechanical intestinal anastomoses tension free is a safe and effective procedure for surgical management of severe pelvic endometriosis with bowel involvement. PMID- 29417286 TI - Does post-operative radiochemotherapy improve survival in high-grade endometrial cancer patients? Results of a population-based cohort analysis of a cancer registry. AB - PURPOSE: Adjuvant treatment of high-grade endometrial cancer varies greatly due to the lack of definitive results from controlled randomized trials on the subject. In a retrospective study, we sought to investigate the influence of post operative radio-, chemo, and radiochemotherapy on survival time and recurrence rates among high-grade endometrial cancer patients. METHODS: 284 high-grade endometrial cancer patients (FIGOI-III, or unknown classification) diagnosed between 1998 and 2015 were retrospectively analyzed. All patients underwent surgery. Overall survival (OS), recurrence-free survival (RFS), and recurrence rates were compared for post-operative treatment modalities of radiotherapy alone (RT), chemotherapy alone (CTX), radiochemotherapy (RCT), and observation (OBS). RESULTS: Post-operative RCT and RT resulted in a significantly improved 5-year OS of 94.1% (HR 0.104, CI 0.013-0.809) and 62.1% (HR 0.615, CI 0.390-0.969), respectively, compared to 43.6% for OBS. CTX did not significantly improve OS leading to a 5-year OS of 56.5% (HR 0.783, CI 0.224-2.740). 5-year recurrence rate was lowest for patients treated with RCT (5.3%). 5-year RFS was 94.1% for the RCT group and proved to be significantly superior to 58.8% for RT (HR 9.034, CI 1.184-68.948), 56% for CTX (HR 12.738, CI 1.337-121.346), and 37.4% for OBS (HR 16.407, CI 2.127-126.575), respectively. In comparison with OBS, RT alone resulted in a significant improvement in RFS (HR 0.551, CI 0.354-0.856). CONCLUSIONS: Our retrospective population-based study indicates a survival benefit from treating high-grade endometrial cancer with post-operative RCT. Randomized controlled trials are needed to minimize potential confounding parameters and further clarify the subject. PMID- 29417287 TI - Preoperative chronic kidney disease before radical cystectomy as predictor of oncological outcomes: a pick of the iceberg? PMID- 29417288 TI - Antimicrobial lubricant reduces rectal bacteria at transrectal prostate biopsy: results from a prospective randomized trial. AB - PURPOSE: Antibiotic resistance may lead to increasing infection rates at transrectal prostate biopsy. Local antimicrobial agents might help to reduce bacterial load. The aim of this study was to test the potency of antimicrobial lubricants to reduce local bacterial loads and specifically fluoroquinolone resistant strains. PATIENTS AND METHODS: Overall, 384 prostate biopsy (PBx) patients of a larger prospective randomized trial (n = 1000) were included. Patients were randomized for biopsy with pre-interventional instillation of an antimicrobial lubricant (intervention group n = 256) or with the standard lubricant (control group n = 128). Bacteria were recovered on pre- and post biopsy rectal swab cultures from both patient groups. Bacterial colonization was semi-quantitatively recorded and analyzed for the presence of ciprofloxacin resistant isolates. RESULTS: Within the intervention group, where antimicrobial lubricant was instilled for PBx, the post-biopsy bacterial count was statistically significantly lower compared to prior biopsy bacterial count (p < 0.001), while in the control group, no statistically significant difference was shown. Moreover, our results demonstrated the tendency for reduction in ciprofloxacin-resistant bacteria growth when instillation of antimicrobial lubricant was used (9.4% versus 5.9%, p = 0.5 prior- and post-biopsy). No reduction in ciprofloxacin-resistant bacterial growth was demonstrated for the control group. Ciprofloxacin-resistance was shown in overall 30 (7.8%) patients. CONCLUSION: Our data demonstrated that the antimicrobial lubricant prior biopsy leads to reduced bacterial load. Moreover, our data show the tendency for reduced ciprofloxacin-resistant bacteria growth when antimicrobial lubricant was instilled prior biopsy. However, the incidence of ciprofloxacin-resistant bacteria is low in our patient population. Rectal swabs should assess fluoroquinolone-resistance rates at prostate biopsy. PMID- 29417290 TI - Secondary coiling after incomplete surgical clipping of cerebral aneurysms: a rescue strategy or a treatment option for complex cases? Institutional series and systematic review. AB - Residual and recurrent intracranial aneurysms after surgical clipping present a persistent risk of bleeding. Secondary coiling after incomplete clipping represents a strategy to occlude the residual sac: feasibility, bleeding risk and outcome were evaluated through a systematic review of literature along with the series of two tertiary referral neurovascular centres. Demographics, ruptured status, aneurysm morphology, topography, exclusion at surgery, timing of secondary coiling, complications, occlusion rate and outcome were analysed. Percentage of incidence and 95% CI were calculated for all variables. T test was used for continue variables, whereas Fisher's test (two-sided) is for categorical ones. Overall, 102 patients (92 cases from literature and 10 cases from institutional series) were included. Mean age at diagnosis was 52.94 +/- 12.17 years, and male/female ratio 0.5; 3/4 of aneurysms involved the anterior circulation, whereas 1/4 the posterior circulation. An aneurysmal neck remnant was described in 58.43% of cases, an aneurysmal sac remnant in 29.21% and a regrowth in 12.36%. Residual aneurysm rupture was reported in 22% of cases. Complete/near-complete occlusion after secondary coiling was observed in 70% of cases, a partial in 25.56% and a failure in 4.44%. Only one case of perforation was reported. Complications were comparable to standard endovascular procedures. Aneurysms remnants after clipping are often observed in cases difficult anatomical locations. Their bleeding risk is not negligible. Secondary coiling is a rescue strategy to effectively and safely secure the aneurysm remnant. Only in a minority of cases, it is a staged treatment after 'remodelling' of the aneurysm neck. PMID- 29417289 TI - Thromboprophylaxis and the route of administration of chemotherapy in testicular cancer patients in German-speaking countries. AB - PURPOSE: Due to the excellent cure rates for testicular cancer (TC), focus has shifted towards decreasing therapy-related morbidities. Thrombosis is a frequent complication of cisplatin chemotherapy. Furthermore, the optimal route of administration for chemotherapy is still under debate. The purpose of this study was to assess the patterns of care concerning dosing and duration of thromboprophylaxis currently utilized in TC patients in German-speaking countries as well as the route of chemotherapy administration. METHODS: A standardized questionnaire was sent to all members of the German TC Study Group (GTCSG) and to all the urological university hospitals in Germany. The questionnaire was also sent to the oncologic clinics at those universities where urologists do not administer chemotherapy. RESULTS: The response rate was 87% (55/63). Prophylactic anticoagulation with low-molecular-weight heparin (LMWH) was administered in 94% of the clinics. The dosing of LMWH was prophylactic (85%), high prophylactic (adjusted to bodyweight) (7%), or risk adapted (9%). After completion of chemotherapy, anticoagulation was continued in 15 clinics (33%) for 2 to 24 weeks, while the remainder stopped the LMWH upon cessation of chemotherapy. Chemotherapy was administered via central venous access in 59%, peripheral IV in 27%, or both in 14% of the clinics. CONCLUSIONS: Most of the institutions performed some form of thromboprophylaxis, although the modes of application varied by institution type and amongst the urologists and oncologists. Prospective studies are needed to evaluate the incidence, date of occurrence, and risk factors of venous thrombosis during TC chemotherapy to provide a recommendation concerning prophylactic anticoagulation. PMID- 29417291 TI - Management and survival analysis of elderly patients with a cancer in the digestive system who refused to receive anticancer treatments. AB - Treatment and management of cancers in elderly patients require some special considerations. A better understanding of how cancers progress in those elderly patients who have not received any anticancer treatments could better help us in treating these patients and in making end-of-life decisions. Over the past years, we had encountered 57 elderly patients, aged 75 to 94 years (87.6 on average), with a cancer in the digestive system, who refused to accept anticancer treatment but who did receive the best available supportive and palliative care. Clinicopathological data of these patients were analyzed. Of these 57 cases, 49 were at an advanced or late stage, while the remaining eight were at an early stage at the time of diagnosis. The median overall survival time of all the patients was 11 months, and almost the entire cohort manifested multiple-organ impairments. The average number of malfunctioning organs per patient was 3.68. After carefully predicting, and then preventing or managing complications, only 54.4% of the patients eventually died of multiple-organ functional failure. Nearly 18% of the single organ dysfunctions were finally well-controlled. Our data provide the first statistical information on the survival time and the direct cause of death of the elderly patients with a cancer in the digestive system not treated with chemotherapy or other direct anticancer interventions, but who did receive the best available supportive and palliative cares. During their struggle with cancer, elderly patients clearly could benefit from prophylactic interventions on organ dysfunction. PMID- 29417292 TI - Treatment toxicities and their impact on oral intake following non-surgical management for head and neck cancer: a 3-year longitudinal study. AB - PURPOSE: Patients who receive (chemo)radiotherapy [(C)RT] for head and neck cancer (HNC) experience multiple treatment effects. However, the presence and recovery of treatment toxicities and how these impact on oral intake over time post-treatment are not fully understood. The primary aim of this study was to examine patient perceptions of the toxicities present and which are barriers to oral intake, up to 3 years post (C)RT. The secondary aim was to identify mealtime strategies used to optimise oral intake. METHODS: A prospective cohort of 96 patients after completion of (C)RT for HNC reported the presence of toxicities, if they were barriers to oral intake, and use of any mealtime strategies at the end of treatment (EoT), and at 3, 6, 12, 24, and 36 months post-treatment. RESULTS: All toxicities and reported barriers changed over time (p < 0.05) except trismus. Odynophagia, reduced appetite, and fatigue improved (p < 0.05) by 3 months. Significantly less patients reported xerostomia and dysgeusia as barriers to oral intake at 3 months despite no improvement in their presence. No change in the presence of any toxicity or its impact on oral intake occurred from 12 to 36 months, with exception of dentition problems which significantly increased at 36 months. Alternating food/fluids was the most frequently used mealtime swallowing strategy at all time points beyond the EoT. CONCLUSIONS: The dysphagia and associated toxicities HNC patients experience are chronic in nature. Rehabilitation should include mealtime strategies and support with adjusting to the changing presence and impact of toxicities on oral intake. PMID- 29417293 TI - Enhancing evaluation of sarcopenia in patients with non-small cell lung cancer (NSCLC) by assessing skeletal muscle index (SMI) at the first lumbar (L1) level on routine chest computed tomography (CT). AB - PURPOSE: Ongoing cancer cachexia trials evaluate sarcopenia by skeletal muscle index (SMI) at the L3 vertebrae level, commonly used as a standard. Routine chest CT institutional protocols widely differ in including L3. We investigated whether SMI at L1 assessment, rather than L3, would be reliable and more practicable for non-small cell lung cancer (NSCLC). METHODS: NSCLC patients with routine CT chest had SMI measurements performed at L1 using Slice-O-Matic software. Accuracy of including L1 level, imaging quality, and ability to detect sarcopenia was collected and correlation of L1 SMI with body mass index (BMI) was performed. RESULTS: Thirty-seven patients with NSCLC (73 CT assessments) were enlisted at three institutions. Characteristics: 47% female; medians: age 59, KPS 80%; BMI 25.49, weight 72.97 kg, SMI 59.24. Sarcopenia was detected in 14.7% of patients; 20% had sarcopenic obesity. Of the 73 CTs, 94.5% included L1 (95% CI 86.6-98.5%). Three images (4%) were difficult to evaluate. Inclusion of L1 was similar among the three participating institutions (90.4 to 96.7% inclusion). BMI correlation with SMI was weak (r = 0.329). CONCLUSIONS: SMI assessment at L1 is achievable in patients with NSCLC receiving routine chest CT, with 96% having acceptable quality evaluations. Similar to results previously reported at L3, BMI showed poor correlation and low sensitivity to detect muscle mass loss. The use of CT at L1 is reliable and presents the opportunity for easier patient evaluation of sarcopenia in patients with lung cancer without the need for additional testing or radiation exposure. PMID- 29417294 TI - A pilot investigation on impact of participation in a long-term follow-up clinic (LTFU) on breast cancer and cardiovascular screening among women who received chest radiation for Hodgkin lymphoma. AB - BACKGROUND: Women treated with chest radiation for Hodgkin lymphoma (HL) are at significantly increased risk of breast cancer and cardiovascular disease. HL survivors are recommended to have annual dual screening with mammogram (MMG) and breast magnetic resonance imaging (MRI). They are also recommended to undergo echocardiogram (echo) 5 years after completion of radiation. We performed a pilot study to characterize the women who are and are not receiving proper dual screening for breast cancer and baseline echo, and to examine the impact of a LTFU clinic consultation on screening. METHODS: A retrospective chart review of 114 women treated for HL at University of Minnesota (UMN) between 1993 and 2009 was performed. Demographics, disease and treatment history (age at diagnosis, stage, radiation dose and field, chemotherapy, recurrence) were assessed, as well as screening practices (MMG, MRI, both and echo), participation in LTFU clinic, and recommendations from providers. Data was summated in yes/no (y/n) format; statistical analysis was performed using chi-squared and Fisher's exact tests. Breast cancer and cardiovascular screening outcomes were compared by participation in the LTFU clinic (y/n) using Fisher's exact tests. P values < 0.05 were considered statistically significant. RESULTS: Forty-one of 114 women met inclusion criteria and had follow-up data for analysis. Median age at diagnosis was 29 years; 67.6% were diagnosed at stage IIa. Median dose of radiation was 3570 cGy. 56.1% participated in the LTFU clinic at the UMN. 36.6% had dual screening with both MMG and MRI, 41.5% had screening with only MMG, and 19.5% had no screening performed. Women were more likely to have dual screening if they were seen in LTFU clinic vs not seen in LTFU clinic (52.2 vs 16.7%, p = 0.02). 67.5% of women were screened with echo; women were also more likely to have screening with echo if seen in LTFU clinic vs not seen (86.4 vs 44.4%, p = 0.007). CONCLUSION: Many women are not getting the proper dual screening for breast cancer despite their increased risk, with only 36.6% of our study sample getting dual screening. Having a consultation in a LTFU clinic increases dual screening for breast cancer and echo screening for cardiovascular disease. Proper screening allows for detection of secondary breast cancer at earlier stages where treatment can be local therapy. Diagnosing CV disease early could allow for proper preventative treatment or intervention. PMID- 29417295 TI - The effect of a medication reconciliation program in two intensive care units in the Netherlands: a prospective intervention study with a before and after design. AB - BACKGROUND: Medication errors occur frequently in the intensive care unit (ICU) and during care transitions. Chronic medication is often temporarily stopped at the ICU. Unfortunately, when the patient improves, the restart of this medication is easily forgotten. Moreover, temporal ICU medication is often unintentionally continued after ICU discharge. Medication reconciliation could be useful to prevent such errors. Therefore, the aim of this study was to determine the effect of medication reconciliation at the ICU. METHODS: This prospective 8-month study with a pre- and post-design was carried out in two ICU settings in the Netherlands. Patients were included when they used >= 1 chronic medicine and when the ICU stay exceeded 24 h. The intervention consisted of medication reconciliation by pharmacists at the moment of ICU admission and prior to ICU discharge. Medication transfer errors (MTEs) were collected and the severity of potential harm of these MTEs was measured, based on a potential adverse drug event score (pADE = 0; 0.01; 0.1; 0.4; 0.6). Primary outcome measures were the proportions of patients with >= 1 MTE at ICU admission and after discharge. Secondary outcome measures were the proportions of patients with a pADE score >= 0.01 due to these MTEs, the severity of the pADEs and the associated costs. Odds ratio and 95% confidence intervals were calculated, by using a multivariate logistic regression analysis. RESULTS: In the pre-intervention phase, 266 patients were included and 212 in the post-intervention phase. The proportion of patients with >= 1 MTE at ICU admission was reduced from 45.1 to 14.6% (ORadj 0.18 [95% CI 0.11-0.30]) and after discharge from 73.9 to 41.2% (ORadj 0.24 [95% CI 0.15-0.37]). The proportion of patients with a pADE >= 0.01 at ICU admission was reduced from 34.8 to 8.0% (ORadj 0.13 [95% CI 0.07-0.24]) and after discharge from 69.5 to 36.2% (ORadj 0.26 [95% CI 0.17-0.40]). The pADE reduction resulted in a potential net cost-benefit of ? 103 per patient. CONCLUSIONS: Medication reconciliation by pharmacists at ICU transfers is an effective safety intervention, leading to a significant decrease in the number of MTE and a cost effective reduction in potential harm. Trial registration Dutch trial register: NTR4159, 5 September 2013, retrospectively registered. PMID- 29417296 TI - Participatory implementation science to increase the impact of evidence-based cancer prevention and control. AB - It is critical to accelerate the integration of evidence-based programs, practices, and strategies for cancer prevention and control into clinical, community, and public health settings. While it is clear that effective translation of existing knowledge into practice can reduce cancer burden, it is less clear how best to achieve this. This gap is addressed by the rapidly growing field of implementation science. Given that context influences and is influenced by implementation efforts, engaging stakeholders in the co-production of knowledge and solutions offers an opportunity to increase the likelihood that implementation efforts are useful, scalable, and sustainable in real-world settings. We argue that a participatory implementation science approach is critical, as it supports iterative, ongoing engagement between stakeholders and researchers to improve the pathway between research and practice, create system change, and address health disparities and health equity. This article highlights the utility of participatory implementation science for cancer prevention and control research and addresses (a) the spectrum of participatory research approaches that may be of use, (b) benefits of participatory implementation science, and PMID- 29417297 TI - HOTAIR induces the ubiquitination of Runx3 by interacting with Mex3b and enhances the invasion of gastric cancer cells. AB - BACKGROUND: Long non-coding RNAs (LncRNAs) exert their functions mainly by binding to their corresponding proteins. Runt-related transcription factor 3 (Runx3) is an important transcription factor that functions as a tumor suppressor in gastric cancer. Whether there is an interplay between LncRNAs and Runx3 remains unclear. METHODS: RPISeq was applied to screen the LncRNAs that potentially bind to Runx3. The interaction between LncRNA HOX antisense intergenic RNA (HOTAIR) and Runx3 was validated by RNA Immunoprecipitation and RNA pull-down assays. The role of Mex3b in the ubiquitination of Runx3 induced by HOTAIR was assessed by immunoprecipitation. Pearson's correlation between HOTAIR mRNA expression and Runx3 protein expression was analyzed. Cell migration and invasion were explored by transwell assays. RESULTS: We found that HOTAIR was bound to Runx3 protein and identified the fragment of HOTAIR spanning 1951-2100 bp as the specific binding site. In addition, mex-3 RNA binding family member B (Mex3b) was an E3 ligase involved in HOTAIR-induced ubiquitous degradation of Runx3. Silencing the expression of HOTAIR or Mex3b attenuated the degradation of Runx3. In human gastric cancer tissues, HOTAIR was negatively associated with the expression level of Runx3 protein (Pearson coefficient - 0.501, p = 0.025). Inhibition of HOTAIR significantly suppressed gastric cancer cell migration and invasion through upregulating claudin1, which could be reversed by co-deficiency of Runx3. CONCLUSIONS: These results uncovered the novel interaction between HOTAIR and Runx3, and provided potential therapeutic targets on the metastasis of gastric cancer. PMID- 29417298 TI - Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. AB - PURPOSE: Triple-negative breast cancer (TNBC) accounts for approximately 20% of breast cancer cases. Although there have been advances in the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancers, targeted therapies for TNBC remain unavailable. In this narrative review, we summarize recent discoveries related to the underlying biology of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway in TNBC, examine clinical progress to date, and suggest rational future approaches for investigational therapies in TNBC. RESULTS: As with other subtypes of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are common in TNBC. Preclinical data support the notion that these aberrations predict TNBC inhibition by targeted agents. In a recently published phase 2 clinical trial, an AKT inhibitor (ipatasertib) improved outcomes in a subset of patients with metastatic TNBC when combined with paclitaxel in the first-line setting. In addition, new compounds with distinct specificity and potency targeting different PI3K/AKT/mTOR components and cognate molecules (e.g., mitogen activated protein kinase) are being developed. These agents present a wide range of toxicity profiles and early efficacy signals, which must be considered prior to the advancement of new agents in later-phase clinical trials. CONCLUSIONS: The development of drugs targeting the PI3K/AKT/mTOR pathway for the treatment of TNBC is an evolving field that should take into account the efficacies and toxicities of new agents in addition to their interactions with different cancer pathways. PMID- 29417300 TI - Stress influenced the aerotolerance of Lactobacillus rhamnosus hsryfm 1301. AB - OBJECTIVE: To investigate the aerotolerance of Lactobacillus rhamnosus hsryfm 1301 and its influencing factors. RESULTS: The growth rate of L. rhamnosus hsryfm 1301 weakened noticeably when the concentration of supplemented H2O2 reached 1 mM, and only 2% of all L. rhamnosus hsryfm 1301 cells survived in MRS broth supplemented with 2 mM H2O2 for 1 h. After pretreatment with 0.5 mM H2O2, the surviving cells of L. rhamnosus hsryfm 1301 in the presence of 5 mM H2O2 for 1 h increased from 3.7 to 7.8 log CFU. Acid stress, osmotic stress, and heat stress at 46 degrees C also enhanced its aerotolerance, while heat stress at 50 degrees C reduced the tolerance of L. rhamnosus hsryfm 1301 to oxidative stress. Moreover, treatment with 0.5 mM H2O2 increased the heat stress tolerance of L. rhamnosus hsryfm 1301 by approximately 150-fold. CONCLUSIONS: Lactobacillus rhamnosus hsryfm 1301 possesses a stress-inducible defense system against oxidative stress, and the cross-adaptation to different stresses is a promising target to increase the stress tolerance of L. rhamnosus hsryfm 1301 during probiotic food and starter culture production. PMID- 29417299 TI - First international TNBC conference meeting report. AB - Recently, Georgia State University's Centennial Hall was the premier location for the 2017 International Conference on Triple Negative Breast Cancer (TNBC): Illuminating Actionable Biology, which was held from Sept. 18 to 20, 2017, in Atlanta, USA. The conference featured a stellar line-up of domestic and international speakers and diverse participants including TNBC survivors, luminaries in breast cancer research, medical students and fellows, clinicians, translational researchers, epidemiologists, biostatisticians, bioinformaticians, and representatives from the industry. This report distills the burning questions that spiked the event and summarizes key themes, findings, unique opportunities and future directions that emerged from this confluence of thought leaders. PMID- 29417301 TI - Light energy partitioning, photosynthetic efficiency and biomass allocation in invasive Prunus serotina and native Quercus petraea in relation to light environment, competition and allelopathy. AB - This study addressed whether competition under different light environments was reflected by changes in leaf absorbed light energy partitioning, photosynthetic efficiency, relative growth rate and biomass allocation in invasive and native competitors. Additionally, a potential allelopathic effect of mulching with invasive Prunus serotina leaves on native Quercus petraea growth and photosynthesis was tested. The effect of light environment on leaf absorbed light energy partitioning and photosynthetic characteristics was more pronounced than the effects of interspecific competition and allelopathy. The quantum yield of PSII of invasive P. serotina increased in the presence of a competitor, indicating a higher plasticity in energy partitioning for the invasive over the native Q. petraea, giving it a competitive advantage. The most striking difference between the two study species was the higher crown-level net CO2 assimilation rates (Acrown) of P. serotina compared with Q. petraea. At the juvenile life stage, higher relative growth rate and higher biomass allocation to foliage allowed P. serotina to absorb and use light energy for photosynthesis more efficiently than Q. petraea. Species-specific strategies of growth, biomass allocation, light energy partitioning and photosynthetic efficiency varied with the light environment and gave an advantage to the invader over its native competitor in competition for light. However, higher biomass allocation to roots in Q. petraea allows for greater belowground competition for water and nutrients as compared to P. serotina. This niche differentiation may compensate for the lower aboveground competitiveness of the native species and explain its ability to co-occur with the invasive competitor in natural forest settings. PMID- 29417302 TI - Balancing animal welfare and assisted reproduction: ethics of preclinical animal research for testing new reproductive technologies. AB - In the field of medically assisted reproduction (MAR), there is a growing emphasis on the importance of introducing new assisted reproductive technologies (ARTs) only after thorough preclinical safety research, including the use of animal models. At the same time, there is international support for the three R's (replace, reduce, refine), and the European Union even aims at the full replacement of animals for research. The apparent tension between these two trends underlines the urgency of an explicit justification of the use of animals for the development and preclinical testing of new ARTs. Considering that the use of animals remains necessary for specific forms of ART research and taking account of different views on the moral importance of helping people to have a genetically related child, we argue that, in principle, the importance of safety research as part of responsible innovation outweighs the limited infringement of animal wellbeing involved in ART research. PMID- 29417305 TI - Anti-NMDA receptor encephalitis presenting as postpartum psychosis-a clinical description and review. AB - Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is increasingly being recognised to be associated with protean neuropsychiatric manifestations. Anti-NMDAR encephalitis is considered to be the most common amongst the autoimmune-mediated encephalitic disorders. It is caused by the autoantibodies against GluN1 subunits of N-methyl-D-aspartate (NMDA) receptor and manifests with prominent psychiatric symptoms, especially during the initial phase of illness. Literature anti-NMDAR encephalitis presenting with postpartum psychosis is scant. In this report, we present a 28-year-old lady with postpartum psychosis as presenting manifestation of anti-NMDAR encephalitis and discuss the neuropsychiatric manifestations of this emerging entity. PMID- 29417304 TI - Systemic Complications Following Status Epilepticus. AB - PURPOSE OF REVIEW: Status epilepticus (SE) is a multisystem disorder. Initially, complications of a massive catecholamine release followed by the side effects of medical therapies, impact patients' outcomes. The aim of this article is to provide an updated summary of the systemic complications following SE. RECENT FINDINGS: In recent years, the importance of the multifaceted nature of SE and its relationship with clinical outcomes has been increasingly recognized. The cumulative systemic effects of prolonged seizures and their treatment contribute to morbidity and mortality in this condition. Most systemic complications after SE are predictable. Anticipating their occurrence and respecting a number of simple guidelines may improve the prognosis of these patients. PMID- 29417303 TI - Pseudohypoparathyroidism type 1B in a patient conceived by in vitro fertilization: another imprinting disorder reported with assisted reproductive technology. AB - Pseudohypoparathyroidism type 1B (PHP1B) is characterized by renal tubular resistance to parathyroid hormone (PTH) leading to hyperphosphatemia, hypocalcemia, elevated PTH, and hyperparathyroid bone changes. PHP1B is an imprinting disorder that results from loss of methylation at the maternal GNAS gene, which suppresses transcription of the alpha subunit of the stimulatory G protein of the PTH receptor. Emerging evidence supports an association between assisted reproductive technologies (ART) and imprinting disorders; however, there is currently little evidence linking PHP1B and ART. We present a twin boy conceived by ART to parents with no history of subfertility who presented at age 12 with bilateral slipped capital femoral epiphysis and bilateral genu valgum deformity. Clinical and laboratory investigation revealed markedly elevated PTH, low ionized calcium, elevated phosphorus, TSH resistance, and skeletal evidence of hyperparathyroidism, leading to the diagnosis of PHP1B. A partial loss of methylation at the GNAS exon A/B locus was observed. The patient's dizygotic twin sibling was asymptomatic and had normal laboratory evaluation. This is the second reported case of a child with PHP1B conceived by ART, further supporting the possibility that ART may lead to an increased risk for imprinting defects. PMID- 29417306 TI - Editorial : Neuroendocrine neoplasms. PMID- 29417307 TI - Caregiving for Relatives with Psychiatric Disorders vs. Co-Occurring Psychiatric and Substance Use Disorders. AB - Despite the high comorbidity of psychiatric and substance use disorders, extremely little research has examined the experience of caregiving for relatives with co-occurring psychiatric and substance use disorders (COD). The primary objective of the present article is to identify characteristics pertaining to care recipients, family caregivers, and the experience of providing caregiving associated with care recipients having COD vs. only having psychiatric disorders (PD). A U.S. community recruited sample of 1394 family caregivers of persons with COD or PD was employed. Chi-square and Mann-Whitney-Wilcoxon tests were conducted. Compared to caregivers of persons with only PD, caregivers of persons with COD provided slightly less caregiving but experienced significantly greater negative effects from providing care. Caregivers of persons with COD were also more likely to fear care recipients would engage in multiple problematic behaviors. Most significant differences found in providing care to recipients with COD vs. only PD persisted when examining care recipients with severe psychiatric disorders or more moderate psychiatric disorders. Additional findings and treatment implications are described. PMID- 29417309 TI - IL-33 Can Promote the Process of Pulmonary Fibrosis by Inducing the Imbalance Between MMP-9 and TIMP-1. AB - IL-33 played an important role in inflammatory diseases as evidenced by their high levels of expression in diseased tissues. Previous studies showed that IL 33/ST2L signal transduction pathway participated in epithelial-mesenchymal transition (EMT) of A549 cells. Cytokine IL-1beta can increase the expression of MMPs by activating NF-kB. The excessive or inappropriate expression of MMP-9 may randomly and non-selectively destroy the extracellular matrix. TIMP-1 (tissue inhibitor of MMP-9) effects on ebb and flow of ECM by inhibiting activation of MMP-9. Therefore, IL-33 may take part in the process of pulmonary fibrosis by regulating expressions of MMP-9 and TIMP-1. To explore the acting mechanism of IL 33 in pulmonary fibrosis, proliferation of the human embryonic lung fibroblasts and expressions of related signal molecules was analyzed in vitro. We cultured HELF cells and stimulated HELF with rhIL-33 at different time points (24, 48, 72 h) and different concentrations respectively. The expression of the receptor ST2L was analyzed by RT-PCR and the proliferative rate of HELF was tested by MTT. The expressions of collagen IV, MMP-9, TIMP-1, and critical signal transducer TRAF-6 and NF-kappaB were tested by Western blotting. The rhIL-33 can promote proliferation of HELF and the concentration of 10 ng/ml was most significant at 72 h (P < 0.05). Hence, this experiment chose 10 ng/ml as stimulated concentration at following experiments. The expressions of collagen IV, MMP-9, TIMP-1, TRAF-6, and NF-kappaB increased and then reduced in protein levels at different time points (0, 6, 12, 24, 48, 72 h) (P < 0.05). IL-33 participates in the production of profibrotic cytokines and formation of mesenchymal substances in early inflammatory responses of pulmonary fibrosis. IL-33 can regulate deposition of ECM and promote the process of pulmonary fibrosis by inducing the imbalance between MMP-9 and TIMP-1. PMID- 29417308 TI - Burn-Induced Multiple Organ Injury and Protective Effect of Lutein in Rats. AB - Thermal injury may lead to multiple organ dysfunction through release of proinflammatory mediators and reactive oxygen radicals. This study investigated the effects of thermal injury on remote organs of rats and the possible protective effect of lutein. Thermal trauma was induced in the back of rats by exposing them to 90 degrees C bath for 10 s. Rats were sacrificed 48 h after burn, and blood samples were collected to monitor liver and kidney functions. Tissue samples from liver, kidneys, and lungs were taken for studying oxidative stress parameters, gene expressions of TNF-alpha and Casp-3, besides histopathological examination. Skin scald injury caused significant elevations of liver and kidney function biomarkers in the serum. In tissue samples, increments of MDA, GPx, and 8-OHdG were recorded while GSH level and the activities of CAT and SOD were suppressed. The expressions of TNF-alpha and caspase-3 mRNA were increased, and histopathological results revealed remote organ injury. Oral administration of lutein (250 mg/kg) resulted in amelioration of the biochemical and molecular changes induced by burn as well as the histopathological alterations. According to the findings of the present study, lutein possesses anti-oxidant, anti-inflammatory, and anti-apoptotic effects that protect against burn-induced damage in remote organs. PMID- 29417310 TI - Human papillomavirus genotype and viral load agreement between paired first-void urine and clinician-collected cervical samples. AB - The performance and acceptability of first-void urine as specimen for the detection of HPV DNA in a Belgian referral population was evaluated using an optimized sample collection and processing protocol. One hundred ten first-void urine and cervical samples were collected from 25- to 64-year-old women who were referred for colposcopy (January-November 2016). Paired samples were analyzed by the Riatol qPCR HPV genotyping assay. Acceptability data were gathered through questionnaires (NCT02714127). A higher high-risk HPV DNA prevalence was observed in first-void urine (n = 76/110) compared to cervical samples (n = 73/110), with HPV31 and HPV16/31 being most prevalent correspondingly. For both any and high risk HPV DNA, good agreement was observed between paired samples (Cohen's Kappa of 0.660 (95% CI: 0.486-0.833) and 0.688 (95% CI: 0.542-0.835), respectively). In addition, significant positive correlations in HPV copies (per microliter of DNA extract) between paired samples were observed for HPV16 (rs = 0.670; FDR (false discovery rate)-adjusted p = 0.006), HPV18 (rs = 0.893; FDR-adjusted p = 0.031), HPV31 (rs = 0.527; FDR-adjusted p = 0.031), HPV53 (rs = 0.691; FDR-adjusted p = 0.017), and HPV68 (rs = 0.569; FDR-adjusted p = 0.031). First-void urine sampling using a first-void urine collection device was preferred over a clinician collected cervical sample. And mostly, first-void urine sampling at home was favored over collection at the clinic or the general practitioner's office. First void urine sampling is a highly preferred, non-invasive method that ensures good agreement in HPV DNA (copies) with reference cervical samples. It is particularly interesting as a screening technique to reach non-participants, and its clinical performance should be further evaluated. PMID- 29417311 TI - Genotypic diversity of Streptococcus suis strains isolated from humans in Thailand. AB - The purpose of this study is to characterize Streptococcus suis isolates recovered from human infections regarding serotype distribution, genotypic profile, clinical manifestations, and epidemiology. A total of 668 S. suis isolates recovered from human infections in Thailand were characterized based on serotyping by multiplex PCR and co-agglutination, genotypic profiles by multilocus sequence typing, and PCR for virulence-associated genes, as well as review of medical records. Serotype 2 (94.6%) was predominant, followed by serotype 14 (4.5%), 24 (0.45%), 5 (0.3%), and 4 (0.15%). Multilocus sequence typing analyses revealed seven clonal complexes (CC): CC1 (56.43%), CC104 (31.74%), CC233/379 (5.4%), CC25 (4.5%), CC28 (0.9%), CC221/234 (0.6%), CC94 (0.15%), and two singletons. The CC1 group contained serotype 2 and 14 isolates, while CC25, 28, 104, and 233/379 consisted of serotype 2 isolates only. CC221/234 contained serotype 5 and 24 isolates, whereas the single serotype 4 isolate belonged to CC94. Two singletons contained serotype 5 (ST235) and 2 (ST236) isolates. Our data showed that ST1 isolates were more associated with meningitis than those of other STs (p < 0.001). The major route of infection was shown to be close contact with infected pigs or contaminated raw pork-derived products, including occupational exposure and recent consumption of raw pork products. This study revealed a relatively large number of CCs of S. suis causing human infection in Thailand. Among them, CC1 followed by CC104, with serotype 2 isolates, are predominant. Food safety campaigns and public health interventions would be important for controlling the S. suis infection in humans. PMID- 29417312 TI - Lessons learned from splenic infarcts with fever of unknown origin (FUO): culture negative endocarditis (CNE) or malignancy? AB - Culture negative endocarditis (CNE) is a common concern in patients with fever, heart murmur, cardiac vegetation, and negative blood cultures. The diagnosis of CNE is not based only on negative blood cultures and a cardiac vegetation. The clinical definition of CNE is based on negative blood cultures plus the findings of culture positive infective endocarditis (IE), e.g., fever, cardiac vegetation, splenomegaly, peripheral manifestations. Because embolic splenic infarcts may occur with culture positive IE, some may assume that splenic infarcts are a sign of CNE. Previously, CNE was due to fastidious and non-culturable organisms. With current diagnostic methods, fastidious organisms grow in 2-3 days. Therefore, fastidious IE are a subset of culture positive IE, but do not represent true CNE. We describe a case of an elderly female who presented with a fever of unknown origin (FUO) and multiple splenic infarcts thought by some to represent CNE. An extensive workup for CNE pathogens was negative. The final cause of her splenic infarcts was a diffuse large B-cell lymphoma (DLBCL). Review of the literature, as well as this case, confirms that splenic infarcts are not a feature of CNE. In patients with fever, splenic infarcts, and negative blood cultures, physicians should search for an alternate explanation rather than CNE, e.g., malignancy and hypercoaguable state (lupus anticoagulant). PMID- 29417313 TI - Sweetening Inhaled Antibiotic Treatment for Eradication of Chronic Respiratory Biofilm Infection. AB - PURPOSE: The failure of chronic therapy with antibiotics to clear persistent respiratory infection is the key morbidity and mortality factor for patients with chronic lung diseases, primarily due to the presence of biofilm in the lungs. It is hypothesised that carbon sources, such as mannitol, could stimulate the metabolic activity of persister cells within biofilms and restore their susceptibility to antibiotics. The aims of the current study are to: (1) establish a representative in vitro model of Pseudomonas aeruginosa biofilm lung infection, and (2) investigate the effects of nebulised mannitol on antibiotic efficacy, focusing on ciprofloxacin, in the eradication of biofilm. METHOD: Air interface biofilm was cultured onto Snapwell inserts incorporated into a modified pharmacopeia deposition apparatus, the Anderson Cascade Impactor (ACI). Three different formulations including mannitol only, ciprofloxacin only and combined ciprofloxacin and mannitol were nebulised onto the P. aeruginosa biofilm using the modified ACI. Antibacterial effectiveness was evaluated using colony-forming units counts, biofilm penetration and scanning electron microscopy. RESULTS: Nebulised mannitol promotes the dispersion of bacteria from the biofilm and demonstrated a synergistic enhancement of the antibacterial efficacy of ciprofloxacin compared to delivery of antibiotic alone. CONCLUSIONS: The combination of ciprofloxacin and mannitol may provide an important new strategy to improve antibiotic therapy for the treatment of chronic lung infections. Furthermore, the development of a representative lung model of bacterial biofilm could potentially be used as a platform for future new antimicrobial pre-clinical screening. PMID- 29417314 TI - Exploring Molecular Speciation and Crystallization Mechanism of Amorphous 2 Phenylamino Nicotinic Acid. AB - PURPOSE: Molecular understanding of phase stability and transition of the amorphous state helps in formulation and manufacturing of poorly-soluble drugs. Crystallization of a model compound, 2-phenylamino nicotinic acid (2PNA), from the amorphous state was studied using solid-state analytical methods. Our previous report suggests that 2PNA molecules mainly develop intermolecular COOH???pyridine N (acid-pyridine) interactions in the amorphous state. In the current study, the molecular speciation is explored with regard to the phase transition from the amorphous to the crystalline state. METHODS: Using spectroscopic techniques, the molecular interactions and structural evolvement during the recrystallization from the glassy state were investigated. RESULTS: The results unveiled that the structurally heterogeneous amorphous state contains acid-pyridine aggregates - either as hydrogen-bonded neutral molecules or as zwitterions - as well as a population of carboxylic acid dimers. Phase transition from the amorphous state results in crystal structures composed of carboxylic acid dimer (acid-acid) synthon or acid-pyridine chains depending on the crystallization conditions employed. CONCLUSIONS: The study underlines the structural evolvement, as well as its impact on the metastability, of amorphous samples from local, supramolecular assemblies to long-range intermolecular ordering through crystallization. PMID- 29417315 TI - Physical activity and telomere length in American Indians: the Strong Heart Study. AB - Telomere length, a marker of biological aging, has been associated with many chronic diseases, but its relations with physical activity remains unclear. The purpose of this study was to examine the association of objectively measured ambulatory activity with leukocyte telomere length (LTL), a marker of biological aging, among American Indians. This cross-sectional study included 2312 AI participants from the Strong Heart Family Study. Steps per day were measured using Accusplit AE120 pedometers. Quantitative PCR was used to measure LTL. Generalized estimating equations were used to examine the associations of steps per day with LTL. The median steps per day over a 1 week period was 5118 steps (interquartile range = 3163-7576 steps). Compared to participants in the lowest quartile of steps per day, participants in the upper three quartiles of steps per day had longer LTL: beta +/- SE = 0.0195 +/- 0.0144, 0.0273 +/- 0.0139, and 0.0375 +/- 0.0143 T/S ratio units longer (p trend = 0.010) after adjustment for potential confounders. These data suggest that ambulatory activity is associated with LTL. Further studies are needed to determine the mechanism by which ambulatory activity influences LTL. PMID- 29417316 TI - Body mass index, abdominal fatness, and the risk of sudden cardiac death: a systematic review and dose-response meta-analysis of prospective studies. AB - Although overweight and obesity are established risk factors for some types of heart disease including ischemic heart disease, heart failure and atrial fibrillation, less is known about the association between adiposity and sudden cardiac death. We conducted a systematic review and meta-analysis of prospective studies to clarify the association between adiposity and risk of sudden cardiac death. PubMed and Embase databases were searched up to July 20th 2017. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random effects models. The summary RR was 1.16 (95% CI 1.05-1.28, I2 = 68%, n = 14) per 5 unit increment in BMI, and 1.82 (95% CI 1.61-2.07, I2 = 0%, n = 3) per 0.1 unit increase in waist-to-hip ratio, and 1.03 (95% CI 0.93-1.15, I2 = 0%, n = 2) per 10 cm increase in waist circumference. The heterogeneity in the analysis of BMI and sudden cardiac death persisted across most subgroup analyses. The association was stronger among studies with longer follow-up compared to short follow-up and was observed in the European and American studies, but not in the Asian studies. There was a J-shaped association between BMI and sudden cardiac death and the lowest risk was observed in the normal weight range, however, the increased risk with a low BMI was attenuated among studies with a longer duration of follow-up. This meta-analysis suggest an increased risk of sudden cardiac death with increasing BMI and waist-to-hip ratio, however, further studies with stratification for smoking status are needed of waist circumference, weight changes and adiposity at younger ages. PMID- 29417317 TI - Tobacco smoking and the risk of sudden cardiac death: a systematic review and meta-analysis of prospective studies. AB - Smoking is an established risk factor for cardiovascular disease including coronary heart disease and stroke, however, data regarding smoking and sudden cardiac death have not been summarized in a meta-analysis previously. We therefore conducted a systematic review and meta-analysis to clarify this association. We searched the PubMed and Embase databases for studies of smoking and sudden cardiac death up to July 20th 2017. Prospective studies were included if they reported adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for smoking and sudden cardiac death. Summary RRs were estimated by use of a random effects model. Twelve prospective studies were included. The summary RR was 3.06 (95% CI 2.46-3.82, I2 = 41%, pheterogeneity = 0.12, n = 7) for current smokers and 1.38 (95% CI 1.20-1.60, I2 = 0%, pheterogeneity = 0.55, n = 7) for former smokers compared to never smokers. For four studies using non current (never + former) smokers as the reference category the summary RR among current smokers was 2.08 (95% CI 1.70-2.53, I2 = 18%, pheterogeneity = 0.30). The results persisted in most of the subgroup analyses. There was no evidence of publication bias. These results confirm that smoking increases the risk of sudden cardiac death. Any further studies should investigate in more detail the effects of duration of smoking, number of cigarettes per day, pack-years, and time since quitting smoking and sudden cardiac death. PMID- 29417319 TI - Retraction Note: Enhanced Emission of Quantum System in Si-Ge Nanolayer Structure. AB - RETRACTION NOTE: The Editor has retracted this article [1] due to significant overlap in text and figures with a previous article published in another journal [2]. The authors do not agree with the retraction. PMID- 29417318 TI - Gastrointestinal and hepatic enzyme activities in juvenile silvery-black porgy (Sparidentex hasta) fed essential amino acid-deficient diets. AB - As amino acids (AAs) are vital molecules in the metabolism of all living organisms and are the building blocks of enzymes, a 6-week feeding trial was conducted for determining the influence of dietary essential amino acid (EAA) deficiencies on pancreatic, plasma, and hepatic enzyme activities in silvery black porgy (initial weight 4.7 +/- 0.01 g) juveniles. Eleven isoproteic (ca. 47%) and isoenergetic (ca. 20.5 MJ kg-1) diets were formulated including a control diet, in which 60% of dietary nitrogen were provided by intact protein (fish meal, gelatin, and wheat meal) and 40% by crystalline AA. The other 10 diets were formulated by 40% reduction in each EAA from the control diet. At the end of the experiment, fish fed with threonine-deficient diet showed the lowest survival rate (P < 0.05), whereas growth performance decreased in fish fed all EAA-deficient diets, although the reduction in body growth varied depending on the EAA considered. Pancreatic enzymes (trypsin, lipase, alpha-amylase, and carboxypeptidase A) activities significantly decreased in fish fed the EAA deficient diets in comparison with fish fed the control diet (P < 0.05). Fish fed with the arginine-deficient diet had the highest plasma and liver alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels (P < 0.05). Plasma and liver lactate dehydrogenase and superoxide dismutase showed the highest and lowest values, respectively, in fish fed the arginine and lysine deficient diets (P < 0.05). Plasma metabolites were significantly affected by dietary EAA deficiencies (P < 0.05). The results of this study suggesting dietary EAA deficiencies led to reduction in growth performance as well as pancreatic and liver malfunction. Furthermore, arginine and lysine are the most limited EAA for digestive enzyme activities and liver health in silvery-black porgy. PMID- 29417320 TI - Bridging the Gap Towards Awareness Detection in Disorders of Consciousness: An Experimental Study on the Mirror Neuron System. AB - Advanced functional neuroimaging approaches dealing with motor imagery have disclosed covert cognitive processes in patients with disorders of consciousness (DoC). However, motor impairment and cognitive-motor dissociation can bias such approaches. Fourteen patients with post-traumatic DoC and ten healthy controls (HC) were provided with three motor tasks related to mirror neuron system (MNS) activation (movement observation, movement execution, and passive motor imagery of a movement) while recording electroencephalographic (EEG) metrics [EEG power and Granger Casualty Index (GCI)] to detect residual signs of conscious awareness. The most relevant finding was that all HCs, all patients with Minimally Conscious State and one with Unresponsive Wakefulness Syndrome demonstrated an event-related synchronization in the gamma range over left frontal regions, with high GCI values, in the passive motor imagery condition. These data significantly correlated with the level of behavioral responsiveness measured by the Coma Recovery Scale-Revised. Thus, our findings may indicate that motor tasks related to MNS can activate frontoparietal networks, although leading to different conscious processes. Hence, MNS assessment can be usefully employed to differentiate among patients with DoC. PMID- 29417322 TI - Sagittal imbalance treated with L5 pedicle subtraction osteotomy with short lumbar fusion from L4 to sacrum using four screws into L4 for enhanced fixation two additional vertebral screws: a technical note. AB - PURPOSE: To report on suggested technique with four screws in a single vertebra (two pedicle screws and two direct vertebral body screws) for enhanced fixation with just one level cranially to a pedicle subtraction osteotomy (PSO). METHODS: A 60-year-old woman underwent L4/5 fusion surgery for degenerative spondylolisthesis. Two years later, she was unable to stand upright even for a short time because of lumbar kyphosis caused by subsidence of the fusion cage and of Baastrup syndrome in the upper lumbar spine [sagittal vertical axis (SVA) of 114 mm, pelvic incidence of 75 degrees , and lumbar lordosis (LL) of 41 degrees ]. She underwent short-segment fusion from L4 to the sacrum with L5 pedicle subtraction osteotomy. We reinforced the construct with two vertebral screws at L4 in addition to the conventional L4 pedicle screws. RESULTS: After the surgery, her sagittal parameters were improved (SVA, 36 mm; LL, 54 degrees ). Two years after the corrective surgery, she maintained a low sagittal vertical axis though high residual pelvic tilt indicated that the patient was still compensating for residual sagittal misalignment. CONCLUSION: PSO surgery for sagittal imbalance usually requires a long fusion at least two levels above and below the osteotomy site to achieve adequate stability and better global alignment. However, longer fixation may decrease the patients' quality of life and cause a proximal junctional failure. Our novel technique may shorten the fixation area after osteotomy surgery. These slides can be retrieved under Electronic Supplementary Material. PMID- 29417321 TI - Shared and Disorder-Specific Event-Related Brain Oscillatory Markers of Attentional Dysfunction in ADHD and Bipolar Disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) often present with overlapping symptoms and cognitive impairments, such as increased fluctuations in attentional performance measured by increased reaction-time variability (RTV). We previously provided initial evidence of shared and distinct event-related potential (ERP) impairments in ADHD and BD in a direct electrophysiological comparison, but no study to date has compared neural mechanisms underlying attentional impairments with finer-grained brain oscillatory markers. Here, we aimed to compare the neural underpinnings of impaired attentional processes in ADHD and BD, by examining event-related brain oscillations during a reaction-time task under slow-unrewarded baseline and fast incentive conditions. We measured cognitive performance, ERPs and brain oscillatory modulations of power and phase variability in 20 women with ADHD, 20 women with BD (currently euthymic) and 20 control women. Compared to controls, both ADHD and BD groups showed increased RTV in the baseline condition and increased RTV, theta phase variability and lower contingent negative variation in the fast-incentive condition. Unlike controls, neither clinical group showed an improvement from the slow-unrewarded baseline to the fast-incentive condition in attentional P3 amplitude or alpha power suppression. Most impairments did not differ between the disorders, as only an adjustment in beta suppression between conditions (lower in the ADHD group) distinguished between the clinical groups. These findings suggest shared impairments in women with ADHD and BD in cognitive and neural variability, preparatory activity and inability to adjust attention allocation and activation. These overlapping impairments may represent shared neurobiological mechanisms of attentional dysfunction in ADHD and BD, and potentially underlie common symptoms in both disorders. PMID- 29417323 TI - Georg Schmorl Prize of the German Spine Society (DWG) 2017: correction of spino pelvic alignment with relordosing mono- and bisegmental TLIF spondylodesis. AB - INTRODUCTION: A balanced ratio of the main parameters of lumbar lordosis (LL) and pelvic incidence (PI) has high clinical relevance. A postoperative mismatch of LL and PI has been described in the literature to be associated with an inferior clinical outcome and higher postoperative revision rates. The aim of this retrospective, radiological study is to evaluate the magnitude of relordosing in mono-/bisegmental TLIF spondylodesis affecting the spino-pelvic alignment and the main contributing factors. MATERIALS AND METHODS: 164 patients (pat.) underwent monosegmental (n = 115, G1) and bisegmental (n = 49, G2) TLIF spondylodesis, respectively, for different indications in 2016 in our hospital. Pelvic incidence, lumbar lordosis (preop., postop., 3 months postop.), implanted cage sizes, and the use of additional Smith-Petersen osteotomies were analysed retrospectively. Patients were divided into three groups depending on match of LL/PI (PI-LL < 10 degrees green, PI-LL = 10-20 degrees yellow, PI-LL > 20 degrees red). Furthermore, a differentiation was made between surgeons with more than or less than 10 years of spinal surgery experience, respectively. RESULTS: 29.6% of pat. in G1 and 16.3% in G2 showed a highly pronounced preoperative spino pelvic mismatch (red). A high grade of mismatch (yellow) between LL/PI was seen in 29.6% in G1 and in 38.8% in G2. The remaining patients already had a balanced ratio of LL/PI (green). Through relordosing TLIF the LL could be corrected significantly (p < 0.05). Therefore, the number of patients with a balanced sagittal alignment (green) increased from 40.9% preop. to 70.4% postoperative in G1 and from 44.9 to 85.7% in G2 (p < 0.05). The number of pat. with highly pronounced preoperative mismatch (red) could be lowered in G1 from 29.6 to 13.9% and in G2 from 16.3 to 2% postoperative (p < 0.05). In G1, the preoperative LL could be corrected from 46.3 degrees to 53.8 degrees (yellow) and 35.7 degrees to 45.8 degrees (red), while in G2, a correction was possible from 43.4 degrees to 51.5 degrees (yellow) and 36.6 degrees to 50.1 degrees (red) (p < 0.05). No significant difference of segmental/complete LL was found between radiologic measurement immediately postoperative and at the 3-month follow-up. In monosegmental fusion higher cages sizes lead to a better match of LL/PI (p < 0.05). The specific cage lordosis (5 degrees vs. 10 degrees ) had no influence on the extent of relordosing. Experienced surgeons had significant higher postoperative matches of LL/PI (p < 0.05) and accomplished more osteotomies (p < 0.05). DISCUSSION: This retrospective study demonstrates that significant relordosing and, therefore, correction of the spino-pelvic alignment are possible with mono-/bisegmental TLIF spondylodesis. Positive influence of higher cage sizes and surgeon's experience was shown. We conclude that the ratio of LL/PI should be taken into account preoperatively in lumbar fusion surgery when planning mono-/bisegmental TLIF spondylodesis to optimize spino-pelvic alignment. These slides can be retrieved under Electronic Supplementary Material. PMID- 29417324 TI - Radiological severity of hip osteoarthritis in patients with adult spinal deformity: the effect on spinopelvic and lower extremity compensatory mechanisms. AB - PURPOSE: Sagittal spinal deformity (SSD) patients utilize pelvic tilt (PT) and their lower extremities in order to compensate for malalignment. This study examines the effect of hip osteoarthritis (OA) on compensatory mechanisms in SSD patients. METHODS: Patients >= 18 years with SSD were included for analysis. Spinopelvic, lower extremity, and cervical alignment were assessed on standing full-body stereoradiographs. Hip OA severity was graded by Kellgren-Lawrence scale (0-4). Patients were categorized as limited osteoarthritis (LOA: grade 0-2) and severe osteoarthritis (SOA: grade 3-4). Patients were matched for age and T1 pelvic angle (TPA). Spinopelvic [sagittal vertical axis (SVA), T1-pelvic angle, thoracic kyphosis (TK), pelvic tilt (PT), lumbar lordosis (LL), pelvic incidence minus lumbar lordosis (PI-LL), T1-spinopelvic inclination (T1SPi)] and lower extremity parameters [sacrofemoral angle, knee angle, ankle angle, posterior pelvic shift (P. Shift), global sagittal axis (GSA)] were compared between groups using independent sample t test. RESULTS: 136 patients (LOA = 68, SOA = 68) were included in the study. SOA had less pelvic tilt (p = 0.011), thoracic kyphosis (p = 0.007), and higher SVA and T1Spi (p < 0.001) than LOA. SOA had lower sacrofemoral angle (p < 0.001) and ankle angle (p = 0.043), increased P. Shift (p < 0.001) and increased GSA (p < 0.001) compared to LOA. There were no differences in PI-LL, LL, knee angle, or cervical alignment (p > 0.05). CONCLUSIONS: Patients with coexisting spinal malalignment and SOA compensate by pelvic shift and thoracic hypokyphosis rather than PT, likely as a result of limited hip extension secondary to SOA. As a result, SOA had worse global sagittal alignment than their LOA counterparts. These slides can be retrieved under Electronic Supplementary Material. PMID- 29417325 TI - Preoperative Right-Sided Cardiac Congestion Is Associated with Gastrointestinal Bleeding in Patients with Continuous-Flow Left Ventricular Assist Devices. AB - BACKGROUND: Large scale data on preoperative risk stratification for gastrointestinal bleeding (GIB) following continuous-flow left ventricular assist device (CF-LVAD) implantation are scarce. AIMS: To identify independent predictors for GIB following CF-LVAD implantation. METHODS: We conducted a retrospective cohort study of consecutive 243 patients who underwent CF-LVAD implantation (HeartMateII) from January 2009 to March 2015 at the University of Chicago Medical Center. GIB was defined as the presence of overt bleeding or occult GIB with >= 2 g/dl drop in hemoglobin (Hgb) from recorded baseline values and hemoccult-positive stool. The preoperative and postoperative data were reviewed. RESULTS: Within a median follow-up duration of 408 (IQR 113-954) days, 83 (34%) patients developed GIB after a median of 149 (IQR 27-615) days after implantation of CF-LVAD. There were no significant differences between the groups of GIB and non-GIB with respect to preoperative demographics and comorbidity except for ethnicity. The source of bleeding was identified in 39 (47%) patients and arteriovenous malformation or submucosal streaming vessel was the most frequent cause of bleeding (18/39, 46%). Multivariate-adjusted analysis demonstrated preoperative central venous pressure (CVP) >= 18 mmHg (HR 3.56; 95% CI 1.16-10.9; p = 0.026), mean pulmonary artery pressure (mPA) >= 36 mmHg (HR 4.14; 95% CI 1.35-12.7; p = 0.013), and the presence of moderate/severe tricuspid valve disease (HR 1.01; 95% CI 1.01-3.86; p = 0.046) were associated with the risk of GIB. CONCLUSIONS: In this study, preoperative right-sided cardiac congestion (i.e., increased CVP, mPA and the presence of moderate/severe tricuspid valve disease) was associated with GIB in patients with CF-LVAD. PMID- 29417326 TI - Role of Esophageal Metal Stents Placement and Combination Therapy in Inoperable Esophageal Carcinoma: A Systematic Review and Meta-analysis. AB - INTRODUCTION: More than 50% of patients with esophageal cancer already have inoperable disease at the time of diagnosis. Controversy surrounds the outcomes of patients with advanced esophageal cancer who receive palliative care by either stent alone or stent plus an additional modality. We set out to perform a systematic review and meta-analysis of studies assessing the use of metal stents as treatment options for symptomatic improvement, survival, and adverse events. METHODS: We searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception until January 14, 2016, as well as other databases for randomized controlled trials (RCTs) comparing esophageal stent versus either esophageal stent plus brachytherapy, radiotherapy, or chemotherapy. For quality assurance purposes throughout the systematic review, multiple independent extractions were performed, and the process was executed as per the standards of the Cochrane collaboration. Primary outcomes were mean change in dysphagia score, overall survival, and quality of life. Secondary outcomes were adverse events including fever, severe pain, aspiration, fistula, stent migration, perforation, and restenosis. RESULTS: Eight RCTs enrolling 732 patients were included with three distinct comparisons: stents combination therapy vs stents alone (5 studies, n = 417), stents alone versus brachytherapy alone (2 studies, n = 274), and stents + brachytherapy vs brachytherapy alone (1 study, n = 41). Stents combination therapy was defined as stents plus radiotherapy, chemotherapy, or both. Mean change in dysphagia scores favored stents combination therapy versus stents alone, and the effect was seen in patients surviving longer than 3 months. Stents combination therapy was also associated with a more favorable overall survival. The risks of stent migration, aspiration pneumonia, and restenosis were lower in the stents combination group compared to stents alone, while the risks of severe pain, hemorrhage, and fistula formation were higher. Changes in dysphagia scores and overall survival did not differ significantly in the brachytherapy-alone vs stents-alone comparison. The risk of fistula formation and hemorrhage were higher in the stents-alone group, while the risk of perforation was lower, compared to brachytherapy alone. Quality of life improvements were seen in all treatment groups, but were not pooled in analysis due to differing methods of measurement. DISCUSSION: While there appears to be no immediate short-term differences, those who live longer than 3 months experience a significant improvement in dysphagia score using a stents combination therapy approach vs stents alone. The combination therapy significantly improves the overall survival as well as showed improvements in quality of life scores. Larger randomized controlled trials are needed to assess improvements in dysphagia score, overall survival, quality of life, and adverse events. PMID- 29417327 TI - Infliximab Versus Adalimumab in Patients with Biologic-Naive Crohn's Disease: Is the Difference Real? PMID- 29417328 TI - Identification of Small Proteins and Peptides in the Differentiation of Patients with Intraductal Mucinous Neoplasms of the Pancreas, Chronic Pancreatitis and Pancreatic Adenocarcinoma. AB - BACKGROUND: There are a limited number of studies investigating the type of serum proteins capable of differentiating intraductal papillary mucinous neoplasms from benign or malignant diseases of the pancreas. AIMS: To select proteins able to differentiate intraductal papillary mucinous neoplasms from benign and malignant pancreatic disease using semiquantitative proteomics. METHODS: Serum samples were obtained from 74 patients (19 with type II intraductal papillary mucinous neoplasms, 8 with type I/III intraductal papillary mucinous neoplasms, 24 with chronic pancreatitis, 23 with pancreatic ductal adenocarcinomas) and 21 healthy subjects. Small proteins and peptides were assayed by matrix-assisted laser desorption/ionization for the detection of differentially abundant species possibly related to tumor onset. Serum pancreatic amylase, lipase, carcinoembryonic antigen and carbohydrate antigen 19-9 (CA 19-9) were also assayed. RESULTS: Twenty-six of 84 peaks detected were dysregulated (7 more abundant and 19 less abundant in the type II intraductal papillary mucinous neoplasms, p < 0.05). Of the differentially abundant peaks, 17 were commonly dysregulated (3 peaks more abundant and 13 less abundant in type II intraductal papillary mucinous neoplasms, and one at m/z = 9961 at variance), indicating a protein fingerprint shared by types I/III and type II intraductal papillary mucinous neoplasms and pancreatic ductal adenocarcinomas. CONCLUSIONS: These results suggest that our approach can be used to differentiate type II intraductal papillary mucinous neoplasms from type I/III neoplasms, and type II intraductal papillary mucinous neoplasms from pancreatic ductal adenocarcinomas. PMID- 29417329 TI - Concise Commentary: Presurgical Evaluation of IPMNs-Eight Is Enough. PMID- 29417330 TI - IgG4-Related Disease Mimicking Crohn's Disease: A Case Report and Review of Literature. PMID- 29417331 TI - Risk Factors for Clostridium difficile Isolation in Inflammatory Bowel Disease: A Prospective Study. AB - INTRODUCTION: Clostridium difficile is the most commonly isolated stool pathogen in inflammatory bowel disease (IBD). Traditional risk factors for C. difficile may not exist in patients with IBD, and no prior studies have assessed the risk factors for the isolation of C. difficile in both symptomatic and asymptomatic IBD outpatients. METHODS: We prospectively recruited consecutive IBD patients presenting to our outpatient clinic between April 2015 and February 2016. We excluded patients with a diverting ostomy or ileoanal pouch. Demographics, healthcare exposures, medical therapies and disease activity were recorded from medical charts or surveys. A rectal swab was performed from which toxigenic culture and PCR analysis for the presence of toxin and fluorescent PCR ribotyping were performed. The primary outcome of interest was isolation of toxigenic C. difficile. RESULTS: A total of 190 patients were enrolled in this prospective study including 137 (72%) with Crohn's disease and 53 (28%) with ulcerative colitis. At the time of enrollment, 69 (36%) had clinically active disease. Sixteen (8.4%) patients had toxigenic C. difficile isolated on rectal swab at enrollment and four (2.1%) patients had non-toxigenic C. difficile cultured. Mixed infection with more than one toxigenic isolate was present in 5/16 (31.3%) individuals. Patients with CD with a toxin positive isolate were more likely to have a history of CDI in the past 12 months (40 vs. 11.02%, p = 0.027) and an emergency department visit in the past 12 weeks (50 vs. 20.63%, p = 0.048). In UC, individuals with isolation of C. difficile were more likely to be hospitalized within the past 12 months (66.6 vs. 8.51%, p = 0.003). C. difficile isolation at the time of presentation was not associated with a subsequent disease relapse over a 6-month period in CD (p = 0.557) or UC (p = 0.131). CONCLUSION: Healthcare exposures remain a significant risk factor for C. difficile isolation in the IBD population; however, this was not associated with relapse of disease. Further studies assessing the clinical significance of C. difficile isolation is warranted in IBD. PMID- 29417332 TI - Left-Sided Colectomy: One of the Important Risk Factors of Metachronous Colorectal Adenoma After Colectomy for Colon Cancer. AB - BACKGROUND: Patients with a history of colonic resection for cancer have an increased risk for the development of metachronous malignant lesions. However, there is a lack of data on the detection rates of premalignant lesions during colonoscopy surveillance in these patients, and the few existing studies have shown conflicting results. AIMS: To identify the risk factor of metachronous premalignant lesions after colon cancer surgery. METHODS: We retrospectively screened consecutive patients who had undergone colonic surgery to treat colon cancer at the Chungnam National University Hospital between September 2009 and April 2014. We measured polyp, adenoma, and advanced adenoma detection rates (PDR, ADR, AADR) from the second surveillance colonoscopy in patients with left sided colectomy (LCR) or right-sided colectomy (RCR). Multivariate analysis was performed to adjust for other confounding factors. RESULTS: A total of 348 patients were enrolled (220 LCR patients and 128 RCR patients). The PDR, ADR, and AADR in patients in the LCR and RCR groups were 56.4, 43.6, and 11.8% and 35.9, 26.6, and 9.4%, respectively. PDR and ADR in the LCR group were significantly higher than those in the RCR group. A multivariate analysis showed that male sex, hypertension, body mass index higher than 25, and LCR (odds ratio 2.090; 95% confidence interval 1.011-4.317) were associated with adenoma recurrence. CONCLUSIONS: The LCR group had a higher adenoma recurrence rate than the RCR group. Further studies are required to determine the optimal surveillance intervals according to the type of colonic resection. PMID- 29417333 TI - Preparation of virus-like particles for porcine circovirus type 2 by YeastFab Assembly. AB - Porcine circovirus type 2 (PCV2) poses a genuine threat to pig industry. An effective vaccine production against the pandemic is desirable. The aim of this study was to construct recombination yeast strains with PCV2 Cap protein. We adopt to YeastFab Assembly method to synthesize transcriptional units in a single tube by piecing up promoter, open reading frame, and terminator in S. cerevisiae. Two yeast recombinants were successfully constructed using GPD and TEF2 promoters, respectively, to express PCV2 by secreting Cap protein in vitro. Electronic microscope observation demonstrated that the yeast-derived PCV2 Cap protein could self-assembles into 18-nm-diameter virus-like particles (VLPs). The yield of two different recombination yeasts containing GPD and TEF2 promoters were 12, 25 MUg/ml, respectively. Our results showed that it is feasible to use S. cerevisiae as a safe and simple system to produce PCV2 virus-like particles. This indicated that there is possibility of obtaining PCV2 VLP vaccine by homologous recombination in yeast genome, and Cap protein was secreted into the cultural supernatant which can be used as a potential oral vaccine to protect pigs from PCV2-infection. PMID- 29417334 TI - Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson's disease. AB - The era of MAO-B inhibitors dates back more than 50 years. It began with Kalman Magyar's outstanding discovery of the selective inhibitor, selegiline. This compound is still regarded as the gold standard of MAO-B inhibition, although newer drugs have also been introduced to the field. It was revealed early on that selective, even irreversible inhibition of MAO-B is free from the severe side effect of the non-selective MAO inhibitors, the potentiation of tyramine, resulting in the so-called 'cheese effect'. Since MAO-B is involved mainly in the degradation of dopamine, the inhibitors lack any antidepressant effect; however, they became first-line medications for the therapy of Parkinson's disease based on their dopamine-sparing activity. Extensive studies with selegiline indicated its complex pharmacological activity profile with MAO-B-independent mechanisms involved. Some of these beneficial effects, such as neuroprotective and antiapoptotic properties, were connected to its propargylamine structure. The second MAO-B inhibitor approved for the treatment of Parkinson's disease, rasagiline also possesses this structural element and shows similar pharmacological characteristics. The preclinical studies performed with selegiline and rasagiline are summarized in this review. PMID- 29417335 TI - Dopamine receptors: homomeric and heteromeric complexes in L-DOPA-induced dyskinesia. AB - The current standard treatment for Parkinson disease focuses on restoring striatal dopamine levels using L-3,4-dihydroxyphenylalanine (L-DOPA). However, disease progression and chronic treatment are associated with motor side effects such as L-DOPA-induced dyskinesia (LID). Dopamine receptor function is strongly associated with the mechanisms underlying LID. In fact, increased D1R signaling is associated with this motor side effect. Compelling evidence demonstrates that dopamine receptors in the striatum can form heteromeric complexes, and heteromerization can lead to changes in the functional and pharmacological properties of receptors compared to their monomeric subtypes. Currently, the most promising strategy for therapeutic intervention in dyskinesia originates from investigations of the D1R-D3R heteromers. Interestingly, there is a correlation between the expression of D1R-D3R heteromers and the development of LID. Moreover, D3R stimulation can potentiate the D1R signaling pathway. The aim of this review is to summarize current knowledge of the distinct roles of heteromeric dopaminergic receptor complexes in LID. PMID- 29417337 TI - Natriuretic peptide receptor-C activation attenuates angiotensin II-induced enhanced oxidative stress and hyperproliferation of aortic vascular smooth muscle cells. AB - We showed previously that natriuretic peptide receptor-C (NPR-C) agonist, C-ANP4 23, attenuated the enhanced expression of Gialpha proteins in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) through the inhibition of enhanced oxidative stress. Since the enhanced levels of endogenous angiotensin II (Ang II) contribute to the overexpression of Gialpha proteins and augmented oxidative stress in VSMC from SHR, the present study was undertaken to investigate if C-ANP4-23 could also attenuate angiotensin II (Ang II)-induced oxidative stress and associated signaling. Ang II treatment of aortic VSMC augmented the levels of superoxide anion (O2-), NADPH oxidase activity, and the expression of NADPH oxidase subunits and C-ANP4-23 treatment attenuated all these to control levels. In addition, Ang II-induced enhanced levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyl content were also attenuated toward control levels by C-ANP4-23 treatment. On the other hand, Ang II inhibited the levels of nitric oxide (NO) and augmented the levels of peroxynitrite (OONO-) in VSMC which were restored to control levels by C-ANP4-23 treatment. Furthermore, C-ANP4-23 treatment attenuated Ang II-induced enhanced expression of Gialpha proteins, phosphorylation of p38, JNK, and ERK 1,2 as well as hyperproliferation of VSMC as determined by DNA synthesis, and metabolic activity. These results indicate that C-ANP4-23, via the activation of NPR-C, attenuates Ang II-induced enhanced nitroxidative stress, overexpression of Gialpha proteins, increased activation of the p38/JNK/ERK 1,2 signaling pathways, and hyperproliferation of VSMC. It may be suggested that C-ANP4-23 could be used as a therapeutic agent in the treatment of vascular remodeling associated with hypertension and atherosclerosis. PMID- 29417339 TI - Abdominal wall reconstruction following resection of large abdominal aggressive neoplasms using tensor fascia lata flap with or without mesh reinforcement. AB - PURPOSE: Abdominal wall defects caused by neoplasms with large extended resection defects remain a challenging problem. Autologous flaps, meshes, and component separation techniques are effective in reconstructing these defects. We retrospectively reviewed and assessed the success of reconstruction using tensor fascia lata flap with or without meshes. METHODS: 18 patients with abdominal wall neoplasms were identified during the period from 2007 to 2016. A retrospective review of office charts and hospital records was performed. RESULTS: A total of 18 patients received corresponding treatment according to the degree of defects, with a mean age of 53.89 +/- 14.56 years old, a mean body mass index (BMI) of 22.89 +/- 4.09 kg/m2, and a mean American Society of Anesthesiologist (ASA) score of 2.18 +/- 0.75. Operative details included the mean defect size (303.44 +/- 175.67 cm2), the mean mesh size (265.92 +/- 227.99 cm2), and the mean operative time (382.33 +/- 180.38 min). Postoperative wound complications were identified in 7 (39%) patients, including incisional infection, edema and thrombus. Neoplasm recurrence was observed in 2 (13%) primary neoplasms patients. No hernias were present in any patient. CONCLUSIONS: Abdominal wall defects caused by neoplasms should be repaired by autologous flaps combined with or without mesh reinforcement. Most type I defects should be primary sutured; type II or III defects should be repaired well by flaps, with or without mesh; if the incision is infected or contaminated, biological mesh or flaps are the best choice. PMID- 29417341 TI - Acknowledgment of Reviewers of Volume 38. PMID- 29417336 TI - Prion-like properties of disease-relevant proteins in amyotrophic lateral sclerosis. AB - The hallmark of age-related neurodegenerative diseases is the appearance of cellular protein deposits and spreading of this pathology throughout the central nervous system. Growing evidence has shown the involvement and critical role of proteins with prion-like properties in the formation of these characteristic cellular aggregates. Prion-like domains of such proteins with their proposed function in the organization of membraneless organelles are prone for misfolding and promoting further aggregation. Spreading of these toxic aggregates between cells and across tissues can explain the progression of clinical phenotypes and pathology in a stereotypical manner, characteristic for almost every neurodegenerative disease. Here, we want to review the current evidence for the role of prion-like mechanisms in classical neurodegenerative diseases and ALS in particular. We will also discuss an intriguingly central role of the protein TDP 43 in the majority of cases of this devastating disease. PMID- 29417338 TI - Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment. AB - Cancer remains a global health problem and approximately 1.7 million new cancer cases are diagnosed every year worldwide. Although diverse molecules are currently being explored as targets for cancer therapy the tumor treatment and therapy is highly tricky. Secondary messengers are important for hormone-mediated signaling pathway. Cyclic AMP (cAMP), a secondary messenger responsible for various physiological processes regulates cell metabolism by activating Protein kinase A (PKA) and by targeting exchange protein directly activated by cAMP (EPAC). EPAC is present in two isoforms EPAC1 and EPAC2, which exhibit different tissue distribution and is involved in GDP/GTP exchange along with activating Rap1- and Rap2-mediated signaling pathways. EPAC is also known for its dual role in cancer as pro- and anti-proliferative in addition to metastasis. Results after perturbing EPAC activity suggests its involvement in cancer cell migration, proliferation, and cytoskeleton remodeling which makes it a potential therapeutic target for cancer treatments. PMID- 29417340 TI - Trans-umbilical two-port laparoscopic suturing of the inguinal hernia defect with percutaneous assistance: a safe and efficient scarless surgery for pediatric inguinal hernia repair. AB - PURPOSE: This study was aimed to describe the technique of the modified trans umbilical two-port laparoscopic suturing (M-TTLS), and show its feasibility and efficacy to treat pediatric inguinal hernia (PIH). METHODS: After general anesthesia, the patient was placed in the Trendelenburg position. Two trocars were set on umbilicus and a pneumoperitoneum was established at 8-12 mmHg. Under direct vision, a long syringe needle was punctured into the preperitoneal space above the internal inguinal ring (IIR). After the peritoneum separated by hydrodissection, the syringe needle was left in peritoneal cavity. A suture needle with 2-0 silk suture was periced into abdomen, and its tip was then inserted into the syringe needle hole by laparoscopic needle holder. Under the syringe's guidance, the peritoneum on the surface of the vessels and vas was sutured intactly by a single stitch. Subsequently, the rest peritoneum was sutured continuously in a clockwise direction. After a purse-string suture completed, the orifice of hernia sac was closed intracorporeally by a single instrument tie technique. RESULTS: Overall, 139 patients with PIH underwent M TTLS, including 130 boys and 9 girls. Median age was 46.8 months. All procedures were performed uneventfully without conversion. Median operation time was 12 min for unilateral and 17 min for bilateral operations. There were three minor extraperitoneal hematomas occurred during the operation. After a median follow-up of 13 months, no common complications developed and no visible scars were observed on the abdominal wall. CONCLUSIONS: M-TTLS is a safe and efficient scarless surgery for PIH repair. PMID- 29417342 TI - Morphofunctional diversity of equine of varied genetic compositions raised in the Pantanal biome of Brazil. AB - Evaluating phenotypic diversity makes it possible to identify discrepancies in aptitudes among animals of different genetic bases, which is an indicator of adaptive or selective differences between populations. The objective of this work was to evaluate the morphofunctional diversity of 452 male and female adult equines (Arabian, Quarter Mile, Pantaneiro, and Criollo breeds, and undefined crossbreeds of horses and mules) raised in the Pantanal biome (Brazil). Linear measurements were performed to estimate conformation indexes. Initially, a discriminant analysis was performed, regardless of the animal's size, followed by factor analysis. The factors were characterized and used as new variables. The diversity among equines and their relationship with the factors were evaluated using multivariate analysis. The factors were classified according to their decreasing importance: balance, rusticity, and robustness for the measurement factors; and load, ability, conformation, and equilibrium for the index factors. The genetic groups of equines have well-defined morphofunctional characteristics. The main differences are based on the rusticity and ability typologies in relation to those based on performance. Equines introduced to the Pantanal biome presented a more robust and compact body with good conformation. As a result, these horses may have superior athletic performance during equestrian activities when compared to the Pantaneiro local breed. However, this biotype may represent less rusticity (less adaptive capacity). Therefore, the regional breed can be equal or better in equestrian activities than breeds introduced to the Pantanal biome. Thus, breeders may cross horses from local breeds as an alternative to those introduced. Undefined crossbred male equines presented a different profile from the Pantaneiro breed, which may indicate little use of crossbreeds in breeding. PMID- 29417343 TI - Expansion of the concept of the Opistholebetinae Fukui, 1929 (Digenea: Opecoelidae Ozaki, 1925), with Magnaosimum brooksae n. g., n. sp. from Tripodichthys angustifrons (Hollard) (Tetraodontiformes: Triacanthidae) in Moreton Bay, Australia. AB - The Opecoelidae Ozaki, 1925, the largest trematode family, currently lacks an adequate subfamilial organisation. In particular, recent analyses have shown that the sequenced representatives of the Opistholebetinae Fukui, 1929 are nested among taxa currently recognised in the Plagioporinae Manter, 1947, which itself is polyphyletic. The concept of the Opistholebetinae persists because its 25 or so species are united by a distinctive morphology and a narrow host range; species are known only from tetraodontiform fishes, specifically of the Tetraodontidae and Diodontidae, and possess a muscular post-oral ring, unusual pigmented granules throughout the body and a ventral sucker positioned more posteriorly than is typical for other opecoelids. Here we report on Magnaosimum brooksae n. g., n. sp. from a tetraodontiform, Tripodichthys angustifrons (Hollard) (Triacanthidae), collected in Moreton Bay, Australia. The new species has a longer forebody than hindbody, but lacks a post-oral ring and pigmented granules. It resolves to the plagioporine clade containing the Opistholebetinae, but does not form a monophyletic grouping with those taxa. We propose to expand the concept of the Opistholebetinae to include Magnaosimum, as well as Gaevskajatrema Gibson & Bray, 1982, Macvicaria Gibson & Bray, 1982, Pachycreadium Manter, 1954, Peracreadium Nicoll, 1909, Pinguitrema Siddiqi & Cable, 1960, Propycnadenoides Fishcthal & Kuntz, 1964, Pseudopycnadena Saad-Fares & Maillard, 1986, Pycnadena Linton, 1911 and Pycnadenoides Yamaguti, 1938. PMID- 29417344 TI - Two species of Phyllodistomum Braun, 1899 (Trematoda: Gorgoderidae) from Moreton Bay, Australia. AB - Two species of the trematode genus Phyllodistomum Braun, 1899 (Gorgoderidae) are reported infecting teleost fishes from Moreton Bay, Queensland, Australia. Phyllodistomum hyporhamphi n. sp. is described from two species of garfishes (Hemiramphidae), Hyporhamphus regularis ardelio (Whitley) and H. australis (Steindachner). The new species differs from other marine species of Phyllodistomum in possessing a forebody length less than half that of the body, a body length to width ratio < 4:1, an oral sucker width to ventral sucker width ratio > 1:1 and < 2:1, 7-9 strong, marginal undulations on each side of the body and large, slightly lobed vitelline masses. Phyllodistomum pacificum Yamaguti, 1951 is reported, for the first time in Australian waters, from Pantolabus radiatus (MacLeay) (Carangidae). The new material agrees closely with the original description of P. pacificum, in Carangoides equula (Temminck & Schlegel) off Hamazima, Mie Prefecture, Japan, although the specimens from Moreton Bay are larger than those of the original description (4,575-5,338 * 1,111-1,328 vs 2,200 3,100 * 570-930 MUm). Cetiotrema carangis (Manter, 1947) Manter, 1970 is found to be a synonym of Cetiotrema carangis (MacCallum, 1913) Williams & Bunkley Williams, 1996 and the species is formally moved to Phyllodistomum as P. carangis (MacCallum, 1913) n. comb. Phylogenetic analyses of 28S rDNA data showed that the six marine species of Phyllodistomum for which molecular data are available form a strongly-supported clade. PMID- 29417347 TI - Unspoken Plea. PMID- 29417345 TI - Nucleosomes positioning around transcriptional start site of tumor suppressor (Rbl2/p130) gene in breast cancer. AB - Dynamic positioning of nucleosomes is pivotal in determining level of genes expression especially on or around transcription start site (TSS) of a gene. Purpose of the current study was to determine nucleosome position around TSS of Rbl2/p130. We investigated Rbl2/p130 expression in connection to nucleosome positions around its TSS among breast tumors and their adjacent normal control tissues (ANCT) using micrococcal nuclease (MNAse) digestion assay and ChIP-PCR analysis. Three fold reduced Rbl2/p130 expression in these tumor tissues were noticed compared to their control tissues. DNA obtained from MNAse digested chromatin was used as PCR template. Region between - 137 to + 140 around TSS was scanned using 3 primer pairs (P1 = - 137 to + 69; P2 = - 90 to + 69; P3 = - 33 to + 140). ~ 66% breast tumors and ~ 26% ANCT samples were positive for P1. The difference was found statistically significant (p = 0.000) with an odd ratio (OD) of 9.143, suggesting that nucleosome formation in this region is ~ 9 times more probable in tumor samples. ~ 73% of the tumor and 60% ANCT were positive for P2, which although is significant (p = 0.035) with OD = 3.250, but less preferable than P1. However, P3 was not found to be a preferred area for nucleosome occupancy (p = 0.670; OD = 1.2). Negative correlations for nucleosome positions were observed especially for P1. Our results indicate that nucleosome are present slightly downstream of TSS in routine, while in case of breast carcinogenesis nucleosomes slides 55 bases upstream of the TSS, aligning + 1 position at the center of nucleosome, hence hindering access to the transcriptional machinery. PMID- 29417346 TI - Transcript profiling and gene expression analysis under drought stress in Ziziphus nummularia (Burm.f.) Wright & Arn. AB - Drought is one of the prime abiotic stresses responsible for limiting agricultural productivity. A number of drought responsive genes have been isolated and functionally characterized but these studies have been restricted to a few model plant systems. Very few drought responsive genes have been reported till date from non model drought tolerant plants. The present study aimed at identifying differentially expressed genes from a drought tolerant, non-model plant, Ziziphus nummularia (Burm.f.) Wight & Arn. One month old seedlings of Z. nummularia were subjected to drought stress by 30% Polyethylene glycol (PEG 6000) treatment for 6, 12, 24, 48 and 72 h. A significant reduction in RWC and increase in proline was observed at 24 h and 48 h of treatment. Suppression subtractive hybridization (SSH) library was constructed with drought stressed seedlings after 24 h and 48 h of PEG 6000 treatment. A total of 142 and 530 unigenes from 24 h and 48 h library were identified respectively. Gene ontology studies revealed that about 9.78% and 15.07% unigenes from 24 h and 48 h SSH libraries were expressed in "response to stress". Fifteen putative drought responsive genes identified in SSH library were validated for drought responsive differential expression by RT-qPCR. Significant changes in fold expressions were observed with time in the treated samples compared to the control. A heat map revealing the expression profile of genes was constructed by hierarchical clustering. Various genes identified in SSH libraries can serve as a resource for marker discovery and selection of candidate genes to improve drought tolerance in other susceptible crops. PMID- 29417348 TI - Perioperative management of external fixation in staged protocols: an international survey. AB - INTRODUCTION: Despite the frequent use of external fixation, various regimes of antibiotic prophylaxis, surgical technique and postoperative pin care exist and underline the lack of current evidence. The aim of the study was to assess the variability or consensus in perioperative protocols to prevent implant-associated infections for temporary external fixation in closed fractures of the extremities. MATERIALS AND METHODS: A 26-question survey was sent to 170 members of the Traumaplatform. The survey included questions concerning demographics, level of training, type of training and perioperative protocols as: antibiotic prophylaxis, intraoperative management, disinfection and postoperative pin site care. All responses were statistically analysed, and intraoperative measures rated on a 5-point Likert scale. RESULTS: The responses of fifty orthopaedic trauma and general surgeons (response rate, 29.4%) were analysed. The level of experience was more than 5 years in 92% (n = 46) with up to 50 closed fractures of the extremities annually treated with external fixation in 80% (n = 40). Highest consensus could be identified in the following perioperative measures: preoperative antibiotic prophylaxis with a second-generation cephalosporin (86%, n = 43), changing gloves if manipulation of the external fixator is necessary during surgery (86%, n = 43; 4.12 points on the Likert scale), avoid overlapping of the pin sites with the definitive implant site (94%, n = 47; 4.12 points on the Likert scale) and soft tissue protection with a drill sleeve (83.6%, n = 41). CONCLUSION: Our survey could identify some general principles, which were rated as important by a majority of the respondents. Futures studies' focus should elucidate the role of perioperative antibiotics and different disinfection protocols on implant-associated infections after temporary external fixation in staged protocols. LEVEL OF EVIDENCE: This study provides Level IV evidence according to Oxford centre for evidence-based medicine. PMID- 29417350 TI - The Relationship Between Stigma and Health-Related Quality of Life in People Living with HIV Who Have Full Access to Antiretroviral Treatment: An Assessment of Earnshaw and Chaudoir's HIV Stigma Framework Using Empirical Data. AB - The aim was to empirically test the tenets of Earnshaw and Chaudoir's HIV stigma framework and its potential covariates for persons living with HIV in Sweden. Partial least squares structural equation modelling was used on survey data from 173 persons living with HIV in Sweden. Experiencing stigma was reported to a higher extent by younger persons and by women who had migrated to Sweden. As expected, anticipated stigma was related to lower Physical functioning, and internalized stigma to lower Emotional wellbeing. In contrast to that hypothesized by the HIV stigma framework, enacted stigma was not related to Physical functioning and no relationships were found between HIV-related stigma and antiretroviral adherence. These results indicate that the HIV stigma framework may need to be revised for contexts where a very high proportion of persons living with HIV are diagnosed and under efficient treatment. PMID- 29417351 TI - HIV Stigma and Its Relation to Mental, Physical and Social Health Among Black Women Living with HIV/AIDS. AB - Black women living with HIV/AIDS (LWHA) are a subgroup with the highest growing rates of HIV infection in the United States. Stigma and co-occurring mental and physical health problems have been reported among Black women LWHA, and research on the benefits of social and religious support, often major protective factors among Black women, has been met with mixed findings. The current study examined the relation between anticipated HIV stigma and mental and physical health symptoms and risk and protective factors (discrimination, coping, social support) among Black women LWHA (N = 220). Results showed that greater anticipated stigma was significantly related to poorer mental health status, greater discrimination, and greater use of negative coping strategies. Stigma was not related to physical health, perceived social support or use of positive coping strategies. This study lends support to the need for psychosocial interventions that reduce anticipated stigma among individuals LWHA, particularly Black women LWHA. PMID- 29417349 TI - Histopathological analysis of the posterior cruciate ligament in primary osteoarthritis. AB - BACKGROUND: According to some authors, the indication of an arthroplasty maintaining the posterior cruciate ligament (PCL) demands adequate structural preservation and proprioceptive function of this ligament. The nervous fibers contained in the synovial neurovascular bundle (NVB) around the PCL are involved in proprioception. A study evaluating the grade of PCL and NVB degeneration by using clinical, radiological, and perioperative parameters in knee arthritis patients, in theory, could help surgeons in the decision of preserving or not preserving the PCL in a particular patient. QUESTIONS: (1) Can the degree of the PCL collagen fibers degeneration be predicted by clinical, radiographic, and perioperative parameters in knee arthritis patients? (2) Is the NVB histological degeneration status predictable using clinical, radiographic, and perioperative parameters in the same subset of patients? (3) Is there a correlation between the degree of the PCL collagen fibers degeneration and NVB status in knee arthritis patients? METHODS: Eighty-nine PCLs (85 patients) obtained from total knee replacement surgery were studied. The histologic degeneration of PCL collagen fibers and the NVB status (preserved, degenerated, not detected) were evaluated. These histological degeneration patterns were correlated with clinical and radiographic parameters and with anterior cruciate ligament (ACL) status. RESULTS: A small prevalence of preserved NVB was related to Grades IV and V of Ahlback's classification, ACL absence, and severe PCL degeneration. The clinical and radiological parameters studied were not able to predict the grade of histological degeneration of the PCL. CONCLUSIONS: Ahlback's classification and ACL status provided useful information about NVB integrity. LEVEL OF EVIDENCE: Basic Science Level IV. PMID- 29417352 TI - UROKIN: A Software to Enhance Our Understanding of Urogenital Motion. AB - Transperineal ultrasound (TPUS) allows for objective quantification of mid sagittal urogenital mechanics, yet current practice omits dynamic motion information in favor of analyzing only a rest and a peak motion frame. This work details the development of UROKIN, a semi-automated software which calculates kinematic curves of urogenital landmark motion. A proof of concept analysis, performed using UROKIN on TPUS video recorded from 20 women with and 10 women without stress urinary incontinence (SUI) performing maximum voluntary contraction of the pelvic floor muscles. The anorectal angle and bladder neck were tracked while the motion of the pubic symphysis was used to compensate for the error incurred by TPUS probe motion during imaging. Kinematic curves of landmark motion were generated for each video and curves were smoothed, time normalized, and averaged within groups. Kinematic data yielded by the UROKIN software showed statistically significant differences between women with and without SUI in terms of magnitude and timing characteristics of the kinematic curves depicting landmark motion. Results provide insight into the ways in which UROKIN may be useful to study differences in pelvic floor muscle contraction mechanics between women with and without SUI and other pelvic floor disorders. The UROKIN software improves on methods described in the literature and provides unique capacity to further our understanding of urogenital biomechanics. PMID- 29417353 TI - Perioperative management with phosphodiesterase type 5 inhibitor and prostaglandin E1 for moderate portopulmonary hypertension following adult-to adult living-donor liver transplantation: a case report. AB - BACKGROUND: Portopulmonary hypertension (PPH) is a relatively rare but well recognized complication of end-stage liver disease. Moderate or severe PPH (mean pulmonary artery pressure [mPAP] >= 35 mmHg) is usually a contraindication for liver transplantation due to high operation-related mortality. Here, we report on a patient with moderate PPH whose condition was successfully managed with a phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) and prostaglandin E1, who experienced rapid improvement of PPH after living-donor liver transplantation (LDLT). CASE PRESENTATION: A 63-year-old woman with alcoholic decompensated cirrhosis was referred to our hospital for LDLT. She had mild dyspnea on exertion as well as fatigue. Echocardiography and subsequent cardiac catheterization revealed a high mPAP (35 mmHg), and she was diagnosed with moderate PPH. We commenced treatment with oral tadalafil for the PPH. A second preoperative echocardiography demonstrated improved PPH, and she underwent LDLT. An intravenous infusion of prostaglandin E1 was introduced instead of tadalafil during and after the operation. The mPAP value showed a rapid decrease in mPAP value to 22 mmHg in 2 days. After discontinuation of the prostaglandin E1, the mPAP value remained 23 mmHg. Postoperative catheterization 2 months after LDLT showed no exacerbation of PPH. She was discharged on foot 70 days after LDLT in good condition and has shown a good clinical condition more than 2 years after LDLT. CONCLUSION: LDLT could be a radical treatment for PPH with careful management and adequate patient selection. PDE5 inhibitor and PGE1 is effective and feasible for perioperative management of the patient with moderate portopulmonary hypertension in LDLT. PMID- 29417354 TI - Clonal dynamics in a case of acute monoblastic leukemia that later developed myeloproliferative neoplasm. AB - In acute myeloid leukemia (AML), patients may harbor pre-leukemic hematopoietic stem cells (HSCs) containing some, but not all, of the mutations observed in the leukemic cells. These pre-leukemic HSCs may survive induction chemotherapy and contribute to AML relapse by obtaining additional mutations. We report here an acute monoblastic leukemia (AMoL) patient who later developed an unclassifiable myeloproliferative neoplasm (MPN-U). Whole-exome sequencing and cluster analysis demonstrated the presence of three distinct major clones during the clinical course: (1) an AMoL clone with ASXL1, CBL, and NPM1 somatic mutations, likely associated with the pathogenesis, and GATA2, SRSF2, and TET2 mutations, (2) an AMoL remission clone, with mutated GATA2, SRSF2, and TET2 only (possibly the founding clone (pre-leukemic HSC) that survived chemotherapy), (3) a small subclone which had JAK2 mutation during the AMoL remission, appearing at MPN-U manifestation with additional mutations. These findings suggest that pre-leukemic HSCs in AML patients may give rise to non-AML myeloid malignancies. This is the first report to analyze the clonal evolution from AMoL to MPN-U, which may provide new insight into the development of myeloid malignancies. PMID- 29417356 TI - Evaluation of Hepatitis B Virus Screening, Vaccination, and Linkage to Care Among Newly Arrived Refugees in Four States, 2009-2011. AB - Many U.S.-bound refugees originate from countries with intermediate or high hepatitis B virus (HBV) infection prevalence and have risk for severe liver disease. We evaluated HBV screening and vaccination of newly arrived refugees in four states to identify program improvement opportunities. Data on HBV testing at domestic health assessments (1/1/2009-12/31/2011) were abstracted from state refugee health surveillance systems. Logistic regression identified correlates of infection. Over 95% of adults aged >=19 years (N = 24,647) and 50% of children (N = 12,249) were tested. Among 32,107 refugees with valid results, the overall infection prevalence was 2.9% (0.76-9.25%); HBV prevalence reflected the burden in birth countries. Birth in the Western Pacific region carried the greatest infection risk (adjusted prevalence ratio = 4.8, CI 2.9, 7.9). Care linkage for infection was unconfirmed. Of 7409 susceptible persons, 38% received 3 doses of hepatitis B vaccine. Testing children, documenting care linkage, and completing 3 dose vaccine series were opportunities for improvement. PMID- 29417355 TI - Kalman filter-based EM-optical sensor fusion for needle deflection estimation. AB - PURPOSE: In many clinical procedures such as cryoablation that involves needle insertion, accurate placement of the needle's tip at the desired target is the major issue for optimizing the treatment and minimizing damage to the neighboring anatomy. However, due to the interaction force between the needle and tissue, considerable error in intraoperative tracking of the needle tip can be observed as needle deflects. METHODS: In this paper, measurements data from an optical sensor at the needle base and a magnetic resonance (MR) gradient field-driven electromagnetic (EM) sensor placed 10 cm from the needle tip are used within a model-integrated Kalman filter-based sensor fusion scheme. Bending model-based estimations and EM-based direct estimation are used as the measurement vectors in the Kalman filter, thus establishing an online estimation approach. RESULTS: Static tip bending experiments show that the fusion method can reduce the mean error of the tip position estimation from 29.23 mm of the optical sensor-based approach to 3.15 mm of the fusion-based approach and from 39.96 to 6.90 mm, at the MRI isocenter and the MRI entrance, respectively. CONCLUSION: This work established a novel sensor fusion scheme that incorporates model information, which enables real-time tracking of needle deflection with MRI compatibility, in a free-hand operating setup. PMID- 29417357 TI - Emergency medicine summary code for reporting CT scan results: implementation and survey results. AB - PURPOSE: The purpose of the study was to assess the emergency department (ED) providers' interest and satisfaction with ED CT result reporting before and after the implementation of a standardized summary code for all CT scan reporting. MATERIALS AND METHODS: A summary code was provided at the end of all CTs ordered through the ED from August to October of 2016. A retrospective review was completed on all studies performed during this period. A pre- and post-survey was given to both ED and radiology providers. RESULTS: A total of 3980 CT scans excluding CTAs were ordered with 2240 CTs dedicated to the head and neck, 1685 CTs dedicated to the torso, and 55 CTs dedicated to the extremities. Approximately 74% CT scans were contrast enhanced. Of the 3980 ED CT examination ordered, 69% had a summary code assigned to it. Fifteen percent of the coded CTs had a critical or diagnostic positive result. CONCLUSIONS: The introduction of an ED CT summary code did not show a definitive improvement in communication. However, the ED providers are in consensus that radiology reports are crucial their patients' management. There is slightly increased satisfaction with the providers with less than 5 years of experience with the ED CT codes compared to more seasoned providers. The implementation of a user-friendly summary code may allow better analysis of results, practice improvement, and quality measurements in the future. PMID- 29417358 TI - Sediminibacillus massiliensis sp. nov., a moderately halophilic, Gram-positive bacterium isolated from a stool sample of a young Senegalese man. AB - A Gram-positive, moderately halophilic bacterium, referred to as strain Marseille P3518T, was isolated from a stool sample with 2% NaCl concentration from a healthy 15-year-old male living in Dielmo, a village in Senegal. Cells are aerobic, rod-shaped and motile and display endospore formation. Strain Marseille P3518T can grow in a medium with 0-20% (w/v) sodium chloride (optimally at 5-7.5% w/v). The major fatty acids were 12-methyl-tetradecanoic acid (45.8%), 13-methyl tetradecanoic acid (26.9%) and 12-methyl-tridecanoic acid (12.8%). The genome is 4,347,479 bp long with 42.1% G+C content. It contains 4282 protein-coding and 107 RNA genes. Phylogenetic analysis based on 16S rRNA gene sequence comparisons showed that strain Marseille-P3518T is a member of the Bacillaceae family and is closely related to Sediminibacillus albus (97.4% gene sequence similarity). Strain Marseille-P3518T was clearly differentiated from its phylogenetic neighbors on the basis of phenotypic and genotypic features. Strain Marseille P3518T is, therefore, considered to be a novel representative of the genus Sediminibacillus, for which the name Sediminibacillus massiliensis sp. nov. is proposed, and the type strain is Marseille-P3518T (CSUR P3518T, DSM69894). PMID- 29417359 TI - Crossing the Age Divide: Cross-Age Collaboration Between Programs Serving Transition-Age Youth. AB - Programs that serve transition-age youth with serious mental health conditions typically reside in either the child or the adult system. Good service provision calls for interactions among these programs. The objective of this research was to discover programmatic characteristics that facilitate or impede collaboration with programs serving dissimilar age groups, among programs that serve transition age youth. To examine this "cross-age collaboration," this research used social network analysis methods to generate homophily and heterophily scores in three communities that had received federal grants to improve services for this population. Heterophily scores (i.e., a measure of cross-age collaboration) in programs serving only transition-age youth were significantly higher than the heterophily scores of programs that served only adults or only children. Few other program markers or malleable program factors predicted heterophily. Programs that specialize in serving transition-age youth are a good resource for gaining knowledge of how to bridge adult and child programs. PMID- 29417360 TI - 42,573 cases of hepatectomy in China: a multicenter retrospective investigation. AB - Hepatectomy is currently routinely performed in most hospitals in China. China owns the largest population of liver diseases and the biggest number of liver resection cases. A nationwide multicenter retrospective investigation involving 112 hospitals was performed, and focused on liver resection for patients with hepatocellular carcinoma (HCC). 42,573 cases of hepatectomy were enrolled, and 18,275 valid cases of liver resection for HCC patients were selected for statistical analysis. The epidemiology of HCC, distribution of hepatectomy, postoperative complications and prognosis were finally analyzed. In the 18,275 HCC patients, 81% had hepatitis B virus infection and 10% had hepatitis C virus infection. 38% of the HCC patients had normal Alphafetoprotein (AFP) level, and other 35% had an AFP level lower than 400 ng mL-1. In the study period, 97% of the hepatectomy for HCC were treated with open surgery, and 23.81% had vascular exclusion techniques. The operation time was (191.7+/-105.6) min, the blood loss was (546.0+/-562.8) mL, and blood transfusion was (543.0+/-1,035.2) mL. The median survival for HCC patients was 631 days, with 1-, 3-, and 5-year overall survival of 73.2%, 28.8% and 19.6%, respectively. Liver cirrhosis, multiple nodules, tumor thrombosis and high AFP level were risk factors that affect postoperative survival. PMID- 29417361 TI - Sexually Transmitted Diseases Among Pregnant Women: 5 States, United States, 2009 2011. AB - Introduction Screening for specific sexually transmitted diseases (STDs) during pregnancy has been a longstanding public health recommendation. Prior studies have described associations between these infections and socioeconomic factors such as race/ethnicity and education. Objectives We evaluated the prevalence of STDs and the correlation socioeconomic factors have with the presence of these infections among pregnant women in the United States. Methods We conducted an analysis using self-reported data from 12,948 recently pregnant women from the Pregnancy Risk Assessment Monitoring System (PRAMS) in 5 states during 2009-2011. Responses to questions about curable STDs (chlamydia, gonorrhea, syphilis, trichomoniasis) diagnosed during pregnancy were utilized to calculate weighted STD prevalence estimates and 95% confidence intervals (CI). A logistic regression was also conducted to identify maternal socioeconomic characteristics significantly associated with STDs; results are displayed as adjusted prevalence ratios (aPR). The PRAMS protocol was approved at PRAMS participating sites and by CDC's Institutional Review Board. Results Overall, 3.3% (CI 2.9-3.7) reported >= 1 curable STD during her most recent pregnancy. The adjusted STD prevalence was higher among women with younger age (aPR, 2.4; CI 1.8-3.4), non-Hispanic black race/ethnicity (aPR, 3.3; CI 2.4-4.1), unmarried status (aPR, 2.1; CI 1.4-3.0), no college education (aPR, 1.4; CI 1.0-1.9), annual income < $25,000 (aPR, 2.0; CI 1.3-3.2), and no pre-pregnancy health insurance (aPR, 1.4; CI 1.1-1.8). Conclusions for Practice This is the largest study of prevalence of self-reported curable STDs among U.S. pregnant women. Differences in STD prevalence highlight the association between certain socioeconomic factors and the presence of STDs. PMID- 29417362 TI - Association of Maternal Depressive Symptoms and Offspring Physical Health in Low Income Families. AB - Objectives The present study sought to examine the association between maternal depressive symptoms and characteristics of offspring physical health, including health status, health behaviors, and healthcare utilization, among low-income families. Maternal engagement was explored as a mediator of observed effects. Methods Cross-sectional survey data from a community sample of 4589 low-income women and their preschool-age children participating in the WIC program in Los Angeles County were analyzed using logistic, Poisson, and zero-inflated negative binomial regression. Mediation was tested via conditional process analyses. Results After controlling for the effects of demographic characteristics including maternal health insurance coverage, employment status, education, and preferred language, children of depressed women (N = 1025) were significantly more likely than children of non-depressed women (N = 3564) to receive a "poor" or "fair" maternal rating of general health (OR 2.34), eat fewer vegetables (IRR: 0.94) more sweets (IRR: 1.20) and sugary drinks daily (IRR: 1.32), and consume fast food more often (OR 1.21). These children were also less likely to have health insurance (OR 1.59) and more likely to receive medical care from a public medical clinic or hospital emergency room (OR 1.30). Reduced maternal engagement partially mediated associations between maternal depressive symptoms and several child health outcomes including poor diet, health insurance coverage, and use of public medical services. Conclusions for Practice Maternal depressive symptoms are associated with poor health among preschool-age children in low-income families. Prevention, screening, and treatment efforts aimed at reducing the prevalence of maternal depression may positively affect young children's health. PMID- 29417363 TI - Motivating Smoking Cessation Text Messages: Perspectives from Pregnant Smokers. AB - OBJECTIVES: The purpose of this research is to analyze cessation text-messages written by pregnant smokers to elucidate the target population's preferred content and message attributes. To achieve this goal, the objectives of this study are three-fold; to qualitatively code messages written by pregnant smokers for frame, type of appeal, and intended target. METHODS: Study participants were recruited as part of a larger trial of pregnant smokers who were enrolled in a text-messaging program or control group and surveyed 1 month post-enrollment. Each participant was asked to write a brief message to another pregnant smoker and two independent coders qualitatively analyzed responses. RESULTS: User generated messages (N = 51) were equally loss and gain framed, and the most common appeals were: fear, guilt, cognitive, hope and empathy, in order of most to least frequent. The target of the majority of the messages was the baby. CONCLUSIONS FOR PRACTICE: Allowing pregnant smokers to write cessation text messages for other pregnant women can provide relevant insight into intervention content. Specifically, pregnant smokers appear to equally promote gain and loss frames, but may prefer messages that include components of fear and guilt related to the impact of smoking on their baby. Additional research is needed to systematically uncover perspectives of pregnant smokers to ensure interventions are optimally effective. PMID- 29417364 TI - Maternal Care Providers' Barriers Regarding Influenza and Pertussis Vaccination During Pregnancy in Catalonia, Spain. AB - Objective Maternal care providers (MCPs), obstetrician-gynaecologists and midwives are uniquely placed to increase maternal vaccination acceptance. We aimed to assess their knowledge, attitudes and practices regarding influenza and pertussis vaccination during pregnancy. Methods We conducted an online survey among MCPs working at "Attention to Sexual and Reproductive Health" (ASSIR) Units in Catalonia region. The survey included questions about current recommendations of influenza and pertussis immunization during pregnancy, reasons for not routinely recommending vaccination and several strategies to increase vaccination uptake. Results A total of 194 MCPs completed the survey, 178 (91.8%) were female and 145 (70%) were midwives. Only 61 (31.4%) stated they vaccinated themselves annually against influenza with a significant lower uptake among midwives (26.9%) than obstetrician-gynaecologists (44.9%) (p = 0.03). Overall, 53.6% of MCPs knew influenza vaccine was indicated during first trimester but only 43.3% stated they prescribed it. Almost all MCPs (98.5%) knew pertussis vaccine was recommended and 97.4% stated they prescribed it. The most important vaccination barrier found was the concern related to vaccine adverse events (25.9%) and more midwives than obstetrician-gynaecologists expressed this concern (30.8 vs. 10%) (p = 0.02). The most popular strategies were: including vaccine recommendations in the pregnancy booklet (93.8%) and receiving vaccination training (92.3%). In the adjusted analysis, the only factor significantly associated with MCPs' prescription of influenza vaccine during second/third trimester was having been vaccinated themselves (odds ratio 3.70, 95% confidence interval 1.3-13.2). Conclusions for Practice Implementation of practical tools, continuous training and clear definition of responsibilities regarding vaccination among MCPs may have a significant impact on maternal vaccination coverage. PMID- 29417365 TI - Integrating Obstetrical Care and WIC Nutritional Services to Address Maternal Obesity and Postpartum Weight Retention. AB - OBJECTIVE: This pilot study evaluated a cost neutral, integrated Special Supplemental Nutrition Program for Women Infants and Children (WIC) and obstetrical service model designed to prevent postpartum weight retention in obese women. METHODS: A sample of women who received benefits from the Johns Hopkins (JH) WIC program and prenatal care from the JH Nutrition in Pregnancy Clinic, which provides obstetrical care for women with a BMI >= 30 kg/m2, participated in the WICNIP randomized clinical trial. Intervention participants received enhanced nutrition services and education at five visits and during one phone call between delivery and 6 months postpartum. Control participants received standard WIC services. Weight data was collected for all participants at multiple time points: pre-pregnancy, delivery, and postpartum at 4, 6 weeks, 4, and 6 months. Maternal socio-demographic factors, obesity class and the number of education contacts received were also recorded. RESULTS: Fifty-three African American women were randomized into the intervention and control groups. Intervention participants retained significantly less gestational weight gain than control participants (3.0 +/- 11.8 vs. 12.6 +/- 20.4, p < 0.05). In both groups, participants with Class III obesity retained significantly less weight than participants in Classes I and II (p = 0.02). CONCLUSIONS FOR PRACTICE: An integrated WIC and obstetrical service model is feasible and can limit postpartum weight retention in obese women. Weight retention at 6 months postpartum between intervention and control participants was statistically significant. Further research should explore targeted interventions by obesity class to address weight retention for low-income, African American women who participate in WIC. PMID- 29417366 TI - Implementation of Steps 1-9 to Successful Breastfeeding Reduces the Frequency of Mild and Severe Episodes of Diarrhea and Respiratory Tract Infection Among 0-6 Month Infants in Democratic Republic of Congo. AB - INTRODUCTION: Global initiatives to improve breastfeeding practices have focused on the Ten Steps to Successful Breastfeeding. The aim of this study was to assess the effect of implementing Baby-Friendly Hospital Initiative (BFHI) steps 1-9 and BFHI steps 1-10 on incidence of diarrhea and respiratory illnesses in the first 6 months of life. METHODS: We reanalyzed a cluster randomized trial in which health care clinics in Kinshasa, Democratic Republic of Congo, were randomly assigned to standard care (control group), BFHI steps 1-9, or BFHI steps 1-10. Outcomes included episodes of diarrhea and respiratory illness. Piecewise Poisson regression with generalized estimation equations to account for clustering by clinic was used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI). RESULTS: Steps 1-9 was associated with a decreased incidence of reported diarrhea (IRR 0.72, 95% CI 0.53, 0.99) and respiratory illness (IRR 0.48, 95% CI 0.37, 0.63), health facility visits due to diarrhea (IRR 0.60, 95% CI 0.42, 0.85) and respiratory illness (IRR 0.47, 95% CI 0.36, 0.63), and hospitalizations due to diarrhea (IRR 0.42, 95% CI 0.17, 1.06) and respiratory illness (IRR 0.33, 95% CI 0.11, 0.98). Addition of Step 10 attenuated this effect: episodes of reported diarrhea (IRR 1.24, 95% CI 0.93, 1.68) and respiratory illness (IRR 0.77, 95% CI 0.60, 0.99), health facility visits due to diarrhea (IRR 0.76, 95% CI 0.54, 1.08) and respiratory illness (IRR 0.75 95% CI 0.57, 0.97), and hospitalizations due to respiratory illness (IRR 0.48 95% CI 0.16, 1.40); but strengthened the effect against hospitalizations due to diarrhea (IRR 0.14, 95% CI 0.03, 0.60). CONCLUSIONS: Implementation of steps 1-9 significantly reduced incidence of mild and severe episodes of diarrhea and respiratory infection in the first 6 months of life, addition of step 10 appeared to lessen this effect. TRIAL REGISTRATION: NCT01428232. PMID- 29417367 TI - Chlamydia trachomatis and Adverse Pregnancy Outcomes: Meta-analysis of Patients With and Without Infection. AB - OBJECTIVES: We conducted a meta-analysis to determine the association between Chlamydia trachomatis and adverse perinatal outcomes. METHODS: Electronic databases were searched between 1970 and 2013. Included studies reported perinatal outcomes in women with and without chlamydia. Summary odds ratios were calculated using fixed- and random-effects models. Study bias was assessed using a Funnel Plot and Begg's test. RESULTS: Of 129 articles identified, 56 studies met the inclusion criteria encompassing 614,892 subjects. Chlamydia infection in pregnancy was associated with preterm birth (OR = 1.27, 95% CI 1.05, 1.54) with a large quantity of heterogeneity (I2 = 61%). This association lost significance when limiting the analysis to high-quality studies based on the Newcastle-Ottawa Scale. Chlamydia infection in pregnancy was also associated with preterm premature rupture of membranes (OR = 1.81, 95% CI 1.0, 3.29), endometritis (OR 1.69, 95% CI 1.20, 2.38), low birthweight (OR 1.34, 95% CI 1.21, 1.48), small for gestational age (OR 1.14, 95% CI 1.05, 1.25) and intrauterine fetal demise (OR 1.44, 95% CI 1.06, 1.94). CONCLUSIONS: This review provides evidence that chlamydia in pregnancy is associated with a small increase in the odds of multiple adverse pregnancy outcomes. The literature is complicated by heterogeneity and the fact that the association may not hold in higher quality and prospective studies or those that use more contemporary nucleic acid testing. PMID- 29417368 TI - Pilot Study of a Novel Partnership for Installing Smoke Alarms. AB - Objectives To demonstrate the feasibility of partnering fire department personnel and home visiting nurses to increase the number of low-income homes protected by smoke alarms. Methods During a regularly scheduled home visit, nurses at the Nurse-Family Partnership of Maricopa County (NFP) informed their clients about an opportunity to have smoke alarms installed in their homes for free. For interested families, nurses sent a referral to the Phoenix Fire Department (PFD), scheduled an appointment, and accompanied the PFD volunteers during the installation. During the appointment, PFD personnel installed alarms and provided safety education. Clients completed a follow-up survey 1-3 months after the installation visit. In-depth interviews were completed with key informants from NFP and PFD to solicit feedback on the program. Results Fifty-two smoke alarm installation visits were completed. Before the fire department arrived, 55% of homes had no working smoke alarm. Almost all (94%) homes received at least one new smoke alarm, and every home had at least one working smoke alarm at the end of the fire department visit. At follow-up, all homes maintained at least one working smoke alarm. Members from both organizations were enthusiastic about, and supportive of the project. NFP nurses appreciated the skill and knowledge of the firefighters; PFD representatives noted that the nurses' relationships with clients made it easier for them to gain access to families who are often described as "hard-to-reach". Conclusions Partnering home visiting nurses and fire departments can be successful to increase the number of vulnerable homes with smoke alarms. PMID- 29417369 TI - Mental Health of Mothers of Infants with Neonatal Abstinence Syndrome and Prenatal Opioid Exposure. AB - BACKGROUND: The prevalence of opioid use during pregnancy is increasing. Two downstream effects are neonatal abstinence syndrome (NAS), a postnatal withdrawal syndrome, and long-term prenatal opioid exposure (LTPOE) without documented withdrawal symptoms in the infant. Mental health characteristics of mothers of infants with NAS and LTPOE have not been described. METHODS: Using linked maternal and infant Medicaid claims and birth certificate data, we analyzed 15,571 infants born to Medicaid-insured women 15-24 years old in a mid-Atlantic city from 2007 to 2010. Pairwise comparisons with multinomial logistic regression, adjusting for maternal and infant covariates, were performed. We compared four mental health conditions among mothers of infants with NAS, infants with LTPOE without NAS, and controls: depression, anxiety, bipolar disorder, and schizophrenia. RESULTS: The prevalence of depression among mothers of infants with NAS, infants with LTPOE, and controls was 26, 21.1, and 5.5% respectively. Similar results were found for anxiety. In multivariable analysis, mothers of infants with NAS and LTPOE had approximately twice the depression risk as controls, while mothers of infants with LTPOE had 2.2 times the bipolar disorder risk and 4.6 times the schizophrenia risk as controls. The overall risk of mental health conditions in mothers of infants with NAS and LTPOE was similar. DISCUSSION: Mothers of infants with LTPOE who did not develop NAS are at similarly high risk for mental health conditions as mothers of infants with NAS, and both are at higher risk than controls. Therefore, those mothers of infants who did not develop symptoms of NAS despite LTPOE may be a vulnerable population that needs additional mental health support in the post-partum period. PMID- 29417371 TI - A randomized general population study of the effects of repeated health checks on incident diabetes. AB - BACKGROUND: It is not clear whether offering health checks to the general population can be used to prevent diabetes. Few randomized studies have had a long-term follow-up. We used a randomly selected population cohort as a randomized trial to examine the effect of repeated health checks on the 30-year incidence of diabetes. METHODS: The study included all persons from 11 municipalities in Copenhagen aged 30, 40, 50, and 60 years (n = 17845). An age stratified and gender-stratified random sample (N = 4789) was invited to participate in a maximum of three health checks between 1982 and 1994 ('intervention group'). The remaining 12994 persons were defined as the 'control group'. The health checks included a questionnaire, a physical examination including assessment of overweight and blood pressure, and blood sampling with determination of serum lipid levels. Based on the person's answers and test results, the participants were given individual information about the results, disease risk and lifestyle. Their general practitioner, too, was provided with written information on the test results. Both groups were followed in the Danish Civil Registration System, the Danish National Diabetes Register, the Cause of Death Registry, and the National Patient Registry until 31 December 2012. FINDINGS: There were 2636 incident cases of diabetes and a mean follow-up time of 24.1 years. The age-adjusted and gender-adjusted hazard ratio (HR) (95% confidence interval, CI) for the intervention group versus the control group was HR = 1.07 (95% CI: 0.98, 1.16, p = 0.153). INTERPRETATION: Offering repeated general health checks to the general population had no preventive effect on the development of diabetes during 30 years of follow-up. PMID- 29417370 TI - Treatment of adult growth hormone deficiency with human recombinant growth hormone: an update on current evidence and critical review of advantages and pitfalls. AB - Adult-onset growth-hormone (GH) deficiency (GHD) is a rare disorder, which most commonly results from pituitary or peripituitary tumors and their treatment, and is characterized by alterations in body composition, carbohydrate and lipid metabolism, bone mineral density, cardiovascular risk profile and quality of life, all of which may contribute to an increased morbidity and mortality. Since recombinant human GH (rhGH) became available in 1985, several studies have provided evidence of its beneficial effects, despite the potential risk of developing adverse effects, and much clinical experience has been accumulated. However, in adults, the precise therapeutic role of GH replacement therapy and the individual response to it remains highly variable and is still a matter of debate. In this article, we present a critical review of the available evidence on rhGH replacement therapy in GHD adults, emphasizing the pitfalls clinicians encounter in the diagnosis of GHD and monitoring of rhGH replacement therapy. We will cover all the relevant aspects regarding the potential usefulness of GH treatment, including the hot topic of mortality. PMID- 29417372 TI - Adipose tissue, but not skeletal muscle, sirtuin 1 expression is decreased in obesity and related to insulin sensitivity. AB - PURPOSE: Sirtuin 1 may regulate glucose and lipid metabolism. We aimed to assess adipose tissue and skeletal muscle sirtuin 1 expression in relation to insulin sensitivity, the expression of proinflammatory and metabolic genes, and to study the regulation of sirtuin 1 expression by hyperinsulinemia and circulating free fatty acids elevation. METHODS: We examined 60 normal-weight, 42 overweight and 15 obese young subjects. The hyperinsulinemic-euglycemic clamp technique was applied throughout to measure insulin sensitivity. In 20 subjects, two 6 h clamps were performed, one of them with concurrent Intralipid/heparin infusion. Biopsies of subcutaneous adipose tissue and skeletal muscle were collected for the measurement of gene and protein expression. RESULTS: Obese subjects had lower adipose sirtuin 1 in comparison with normal-weight and overweight participants. Muscle sirtuin 1 did not differ between the groups. Adipose tissue sirtuin 1 was related to insulin sensitivity, adipose tissue SLC2A4. The relationship between adipose tissue sirtuin 1 and insulin sensitivity was still present after controlling for BMI, however, it disappeared after controlling for adipose tissue SLC2A4. Muscle sirtuin 1 was not related to insulin sensitivity. Hyperisulinemia decreased adipose tissue and increased muscle sirtuin 1 expression. Intralipid/heparin infusion negated these effects. CONCLUSIONS: Adipose tissue, but not muscle, sirtuin 1 is associated with insulin sensitivity in humans, possibly because of its correlation with adipose tissue SLC2A4 expression. Insulin differentially regulates adipose tissue and skeletal muscle sirtuin 1 expression in the short-term and circulating free fatty acids elevation negates these effects, which may be associated with lipid-induced insulin resistance. PMID- 29417373 TI - Practical issues for the management of hyponatremia in oncology. AB - Hyponatremia is common in cancer patients and has a negative impact on outcomes and survival. Both the diagnosis and treatment of hyponatremia are challenging. Easy-to-use, practical guidelines are needed. The aim of this article is to discuss practical issues related to the diagnostic workup and management of hyponatremia, with particular attention to complex patients, such as those affected by neoplastic diseases. Admittedly, these patients may present several comorbidities, which may cause sodium alterations. In addition, multidrug therapy may precipitate serum sodium fall. An algorithm for the diagnosis and treatment of hyponatremia was also developed, based on the discussion of the results of a questionnaire completed by the authors and of the published recommendations/guidelines on hyponatremia. The goal was to produce an algorithm that was as simple as possible but still comprehensive, without compromising information completeness. Many explanatory notes were added with the aim of guiding clinicians throughout the management of complex patients with hyponatremia, such as those with cancer. The resulting algorithm and supporting literature are presented. PMID- 29417374 TI - Influence of different dynamic sporting disciplines on right ventricular Structure and function in elite male athletes. AB - Our objective was to assess the influence of different levels of exposure to dynamic training on right ventricular (RV) structure, function and mechanics in elite male athletes. We recruited 492 male elite athletes aged between 18 and 30 years old. Athletes were grouped according to their sporting discipline using the Mitchell Classification as Low Dynamic (LD), Moderate Dynamic (MD) or High Dynamic (HD). All participants underwent 2D, Doppler, tissue Doppler and strain (epsilon) echocardiography with a focused and comprehensive assessment of the right heart. Athletes involved in MD sports had the largest absolute RV chamber size and when scaled to body size RVOT PLAX, RVOT2, RVD1 and RVD3 were larger in HD compared to MD and LD athletes. There were no between group differences in conventional RV functional indices as well as global RV epsilon (LD: - 23.4 +/- 3.1 vs. MD: - 22.7 +/- 2.7 vs. HD: - 23.5 +/- 2.6, %) and strain rate (P > 0.01). The base to apex epsilon gradient in the RV septum was lower in the MD athletes compared to HD and LD due to a lower apical septal epsilon which significantly correlated with absolute RV chamber size. After scaling for body size there was evidence of larger RV cavities in both MD and HD athletes compared to LD athletes. Global RV function, epsilon and strain rate were not different between groups. MD athletes had lower apical septal epsilon that contributed to a smaller base-to-apex epsilon gradient that is partially associated with larger absolute RV chamber dimensions. PMID- 29417376 TI - Complications of a poly-L-lactic acid and polyglycolic acid osteosynthesis device for internal fixation in maxillofacial surgery. AB - The purpose of this study was to retrospectively evaluate and examine the incidence of complications using poly-L-lactic acid and polyglycolic acid (PLLA/PGA) copolymer plate system in maxillofacial osteosynthesis. The retrospective study included 87 patients (50 men, 37 women), who needed maxillofacial surgery. We examined the proportion of complications and their factors from clinical data. A comparison was also made for plate decomposition using the molecular weight of the plate without plate exposure and complications. Osteosynthesis sites healed in all patients. Ten cases (11.5%) showed plate exposure-related complications, with all occurring at intraoral surgical sites. There was no significant difference in molecular weight changes of plates in resorbable process. Statistical analysis of study variables between patients with and without exposed plates showed that the plate thickness was significantly associated with the risk of exposed plates (p < 0.05). The commercially available PLLA/PGA device could be a useful rapid resorbable material for maxillofacial osteosynthesis. When thick plates are used on the intraoral site, it may be necessary to pay attention to the complication of plate exposure. Even if exposure-related complications have occurred, resorption and degradation of this material proceeds, suggesting the ease of appropriate risk management. PMID- 29417377 TI - Better agonist for the opioid receptors. AB - This commentary highlights the recent work published in journal Nature on the structural based discovery of novel analgesic compounds for opioid receptors with minimal effects. Manglik et al. selectively targeted the Gi based MUOR pathway instead of the beta-arrestin pathway of the opioids. The computational screening of millions of compounds showed a list of several competent ligands. From these ligands they synthesized the compounds with the best docking score, which were further optimized by adding side residues for better interaction with the MUOR. A promising compound, PZM21, was a selective agonist of MUOR. It has better analgesic properties with minimal side effects of respiratory depression and constipation. This work is a step towards better drug designing and synthesizing in terms of efficacy, specificity with least side effects of targeted GPCR proteins present in the human proteome. PMID- 29417375 TI - Dependence of Nanoparticle Toxicity on Their Physical and Chemical Properties. AB - Studies on the methods of nanoparticle (NP) synthesis, analysis of their characteristics, and exploration of new fields of their applications are at the forefront of modern nanotechnology. The possibility of engineering water-soluble NPs has paved the way to their use in various basic and applied biomedical researches. At present, NPs are used in diagnosis for imaging of numerous molecular markers of genetic and autoimmune diseases, malignant tumors, and many other disorders. NPs are also used for targeted delivery of drugs to tissues and organs, with controllable parameters of drug release and accumulation. In addition, there are examples of the use of NPs as active components, e.g., photosensitizers in photodynamic therapy and in hyperthermic tumor destruction through NP incorporation and heating. However, a high toxicity of NPs for living organisms is a strong limiting factor that hinders their use in vivo. Current studies on toxic effects of NPs aimed at identifying the targets and mechanisms of their harmful effects are carried out in cell culture models; studies on the patterns of NP transport, accumulation, degradation, and elimination, in animal models. This review systematizes and summarizes available data on how the mechanisms of NP toxicity for living systems are related to their physical and chemical properties. PMID- 29417379 TI - A snapshot of type two diabetes mellitus management in general practice prior to the introduction of diabetes Cycle of Care. AB - BACKGROUND: Diabetes is associated with complications, including coronary heart disease, stroke, kidney failure, blindness and amputation, and ultimately is a major cause of disability and death worldwide. Adherence to best practice guidelines is limited in unstructured diabetes management in primary care settings. AIMS: This study aims to establish what data was being collected in general practice prior to the introduction of the Cycle of Care, which is a proactive model of diabetes management introduced in Ireland. METHODS: Medical students in general practices with the University of Limerick Graduate Entry Medical School and their supervisors used practice software to collect quantitative data from the clinical records of patients with T2DM. RESULTS: The sample included 2696 patients with T2DM who had visited their GP in the previous year. During the 12 months studied, 18.5% of patients with T2DM attended an emergency department and 24% were admitted to hospital. The results of the documentation of three modifiable risk factors associated with T2DM were as follows: 49.5% had BMI documented, 51.7% had smoking status documented and 33.9% had alcohol consumption documented. Two hundred and fifty people were diagnosed with T2DM in the previous 12 months. Of these, 19% had been referred to a chiropodist and 23% to a dietician. CONCLUSIONS: This study provides a comprehensive snapshot of care in Irish general practice for patients with T2DM prior to the introduction of the Cycle of Care. Future research must investigate the impact of Cycle of Care on patient care in general practice. PMID- 29417378 TI - In Vitro Screening of Indigenous Lactobacillus Isolates for Selecting Organisms with Better Health-Promoting Attributes. AB - Lactobacilli have several attributes that provide health benefits to the host. The aim of this study was to screen indigenous lactobacilli from human gut and fermented foods for such attributes as production of beta- and alpha galactosidase and also their ability to reduce serum cholesterol. Lactobacilli were cultured on MRS broth and beta-galactosidase activity was determined using o nitrophenyl-beta-D-galactopyranoside (ONPG) as a substrate. Three isolates Lactobacillus fermentum GPI-3 and L. fermentum GPI-6 and Lactobacillus salivarius GPI-1(S) showed better beta-galactosidase activity than the standard strains Lactobacillus rhamnosus GG (LGG) and Lactobacillus plantarum ATCC 8014. The isolates showed variability in assimilating cholesterol during growth. Several isolates showed excellent cholesterol-lowering ability compared to standard strains LGG and L. plantarum ATCC 8014. Isolate L. rhamnosus SCB being the highest acid producer (pH 4.38) also showed the highest cholesterol reduction compared to other strains including standard strains. The ability of these isolates to produce alpha-galactosidase was also studied and the maximum alpha galactosidase activity was found in isolate L. salivarius GPI-1(S) followed by L. fermentum FA-5 and Lactobacillus helveticus FA-7. This study therefore reports Lactobacillus isolates that have superior probiotic properties when compared to the standard strains; hence, they could be considered as potential probiotic strains, which can provide health benefits to the Indian population. PMID- 29417381 TI - Pancreatic cancer: risk and preventive factors. PMID- 29417382 TI - Squamous Cell Carcinoma of Colon-an Etiopathological Surprise. PMID- 29417380 TI - Assessing long-term neuroinflammatory responses to encephalopathy using MRI approaches in a rat endotoxemia model. AB - Sepsis-associated encephalopathy (SAE) induces neuroinflammation, which is associated with cognitive impairment (CI). CI is also correlated with aging. We used contrast-enhanced magnetic resonance imaging (MRI), perfusion MRI, and MR spectroscopy to assess long-term alterations in BBB permeability, microvascularity, and metabolism, respectively, in a rat lipopolysaccharide induced SAE model. Free radical-targeted molecular MRI was used to detect brain radical levels at 24 h and 1 week post-LPS injection. CE-MRI showed increased Gd DTPA uptake in LPS rat brains at 24 h in cerebral cortex, hippocampus, thalamus, and perirhinal cortex regions. Increased MRI signal intensities were observed in LPS rat brains in cerebral cortex, perirhinal cortex, and hippocampus regions 1 week post-LPS. Long-term BBB dysfunction was detected in the cerebral cortex at 6 weeks post-LPS. Increased relative cerebral blood flow (rCBF) in cortex and thalamus regions at 24 h, decreased cortical and hippocampal rCBF at 6 weeks, decreased cortical rCBF at 3 and 12 weeks, and increased thalamus rCBF at 6 weeks post-LPS, were detected. MRS indicated that LPS-exposed rat brains had decreased: NAA/Cho metabolite ratios at 1, 3, 6, and 12 weeks; Cr/Cho at 1, 3, and 12 weeks; and Myo-Ins/Cho at 1, 3, and 6 weeks post-LPS. Free radical imaging detected increased radical levels in LPS rat brains at 24 h and 1 week post-LPS. LPS exposed rats were compared to saline-treated controls. We clearly demonstrated BBB dysfunction, impaired vascularity, and decreased brain metabolites, as measures of long-term neuroinflammatory indicators, as well as increased free radicals in a LPS-induced rat SAE model. PMID- 29417383 TI - Targeted heat activation of HSP promoters in the skin of mammalian animals and humans. AB - The use of highly inducible HSP promoters for exerting spatial and/or temporal control over the expression of therapeutic transgenes has long been discussed. Localized and time-limited induction of the heat shock response may potentially also be of medical interest. However, such applications would require targeted delivery of heat doses capable of activating HSP promoters in tissues or organs of interest. Accessible areas, including the skin and tissues immediately underneath it, may be most readily targeted. A few applications for heat-directed or heat-controlled therapy in the skin might involve expression of proteins to restore or protect normal skin function, protein antigens for vaccination/immunotherapy, vaccine viruses or even systemically active proteins, e.g., cytokines and chemokines. A review of the literature relating to localized heat activation of HSP promoters and HSP genes in the skin revealed that a multitude of different technologies has been explored in small animal models. In contrast, we uncovered few publications that examine HSP promoter activation in human skin. None of these publications has a therapeutic focus. We present herein two, clinically relevant, developments of heating technologies that effectively activate HSP promoters in targeted regions of human skin. The first development advances a system that is capable of reliably activating HSP promoters in human scalp, in particular in hair follicles. The second development outlines a simple, robust, and inexpensive methodology for locally activating HSP promoters in small, defined skin areas. PMID- 29417384 TI - Effects of Agave fructans (Agave tequilana Weber var. azul) on Body Fat and Serum Lipids in Obesity. AB - Obesity affects millions of people worldwide, constituting a public health problem associated with premature mortality. Agave fructans decrease fat mass, body and liver weight, and generate satiety in rodents. In the present study the effects of agave fructans on weight control, lipid profile, and physical tolerability were evaluated in obese people. Twenty-eight obese volunteers were randomly divided into two groups. In the first group, 96 mg/bw of agave fructans was administered for 12 weeks; in the second group, maltodextrin as a placebo was administered for 12 weeks. All participants consumed a low-calorie diet of 1500 kcal/day. Anthropometric and biochemical measurements were taken at baseline and at the end of the study. The body mass index (BMI) of the agave fructans treated group was reduced significantly from the baseline to the final measurements. Hip and waist circumferences decreased statistically in both groups. A decrease of 10% in total body fat was observed in the agave fructans treated group, resulting in a statistically significant difference in the final versus baseline measurements between the Agave fructans treated group and the placebo treated group. Triglycerides were reduced significantly in the agave fructans treated group. Glucose values did not change in either group. Agave fructans intake was safe and well tolerated throughout the study. The results showed that the ingestion of agave fructans enhanced the decrease in BMI, the decrease in total body fat, and the decrease in triglycerides in obese individuals who consume a low-calorie diet. PMID- 29417386 TI - Vimentin-positive gastric adenocarcinoma arising in a hyperplastic polyp. AB - We report a case of vimentin-positive early gastric adenocarcinoma arising in a hyperplastic polyp (HP). A 72-year-old Japanese man was admitted for the detailed examination of a gastric polyp. He had a subtotal gastrectomy due to acute abdomen 12 years ago. Upper endoscopy revealed a pedunculated polyp measuring approximately 2 cm on the greater curvature of upper body of the remnant stomach. Magnifying endoscopy revealed that the microsurface pattern was irregular and partially absent accompanied with irregular microvessels at the upper end of the polyp. We speculated that the lesion was an adenocarcinoma arising in the HP. Endoscopic submucosal dissection (ESD) was performed. Histological examination of the ESD specimen revealed that the lesion consisted of well- to poorly differentiated adenocarcinoma at the protruding lesion and foveolar hyperplastic epithelia at the base of the polyp. Immunohistochemically, most of tumor cells that comprised poorly-differentiated adenocarcinoma were positive for both cytokeratin and vimentin. Although carcinomas have occasionally been found in HPs, the histological features of the present case are considered extremely unusual. To the best of our knowledge, this is the first case of vimentin positive early gastric carcinoma arising in a HP. PMID- 29417388 TI - Comparison Between Folic Acid and gH625 Peptide-Based Functionalization of Fe3O4 Magnetic Nanoparticles for Enhanced Cell Internalization. AB - A versatile synthetic route based on magnetic Fe3O4 nanoparticle (MNP) prefunctionalization with a phosphonic acid monolayer has been used to covalently bind the gH625 peptide on the nanoparticle surface. gH625 is a membranotropic peptide capable of easily crossing the membranes of various cells including the typical human blood-brain barrier components. A similar synthetic route was used to prepare another class of MNPs having a functional coating based on PEG, rhodamine, and folic acid, a well-known target molecule, to compare the performance of the two cell-penetrating systems (i.e., gH625 and folic acid). Our results demonstrate that the uptake of gH625-decorated MNPs in immortalized human brain microvascular endothelial cells after 24 h is more evident compared to folic acid-functionalized MNPs as evidenced by confocal laser scanning microscopy. On the other hand, both functionalized systems proved capable of being internalized in a brain tumor cell line (i.e., glioblastoma A-172). These findings indicate that the functionalization of MNPs with gH625 improves their endothelial cell internalization, suggesting a viable strategy in designing functional nanostructures capable of first crossing the BBB and, then, of reaching specific tumor brain cells. PMID- 29417387 TI - Fitz-Hugh-Curtis syndrome in a man positive for Chlamydia trachomatis. AB - Fitz-Hugh-Curtis syndrome (FHCS) is characterized by perihepatic and pelvic inflammation and occurs mostly in women of childbearing age. Here, we report a case of FHCS caused by Chlamydia trachomatis in a 50-year-old man. The patient presented to our hospital with right upper quadrant abdominal pain, and enhanced computed tomography revealed perihepatic and pelvic free fluid and early-phase hepatic capsular enhancement. A urine specimen was positive for Chlamydia trachomatis. The patient was diagnosed with FHCS due to Chlamydia trachomatis infection. In conclusion, FHCS cannot be excluded when men present with right upper quadrant abdominal pain without significant signs of biliary tract disease. PMID- 29417389 TI - Vocational activity and health insurance type among patients with end-stage renal disease: association with outcomes. AB - It is widely thought that patients with end-stage renal disease who remain vocationally active and/or commercially insured following dialysis initiation have better clinical outcomes and higher quality of life than those who do not. However, scientifically robust data are lacking. Here, we examined whether vocational status (active, N = 1848; inactive, N = 10,001) and, separately, insurance status (commercial, N = 4858; Medicare/self-pay, N = 13,329; Medicaid, N = 3528) were associated with clinical outcomes and Kidney Disease Quality of Life (KDQOL) scores among a cohort of patients who initiated dialysis at a large US dialysis organization during 2015-2016. Outcomes were considered from the day after index (31 days after dialysis initiation for vocational status and 1 day after initiation for insurance status) until the earliest of death, discontinuation of dialysis, transplant, loss to follow-up, or end of study (30 September 2016). Comparisons were made using intention-to-treat principles and generalized linear models adjusted for imbalanced patient characteristics, including sociodemographic variables. Vocational inactivity (vs. vocational activity) was independently associated with higher rates of mortality and hospitalization, lower rates of transplant, and lower KDQoL scores in 4 of 5 domains. Similar trends were observed when comparing Medicare/self-pay or Medicaid insurance to commercial insurance. Vocational activity, and separately, commercial insurance, were independently associated with better clinical and quality of life outcomes compared to other insurance and vocational categories. These findings may inform patient and physician education, and guide advocacy efforts. PMID- 29417390 TI - Urban Neighborhood and Residential Factors Associated with Breast Cancer in African American Women: a Systematic Review. AB - Residential characteristics in urban neighborhoods impact health and might be important factors contributing to health disparities, especially in the African American population. The purpose of this systematic review is to understand the relationship between urban neighborhood and residential factors and breast cancer incidence and prognosis in African American women. Using PubMed and Web of Science, the existing literature was reviewed. Observational, cross-sectional, cohort, and prospective studies until February 2017 were examined. Studies including populations of African American women, setting in "urban" areas, and a measure of a neighborhood or residential factor were reviewed. Four parameters related to neighborhood or residential factors were extracted including: neighborhood socioeconomic status (nSES), residential segregation, spatial access to mammography, and residential pollution. Our analysis showed that African American women living in low nSES have greater odds of late stage diagnosis and mortality. Furthermore, African American women living in segregated areas (higher percentage of Blacks) have higher odds of late stage diagnosis and mortality compared to White and Hispanic women living in less segregated areas (lower percentage of Blacks). Late stage diagnosis was also shown to be significantly higher in areas with poor mammography access and areas with higher Black residential segregation. Lastly, residential pollution did not affect breast cancer risk in African American women. Overall, this systematic review provides a qualitative synthesis of major neighborhood and residential factors on breast cancer outcomes in African American women. PMID- 29417391 TI - Teaching Responsible Research and Innovation: A Phronetic Perspective. AB - Across the European research area and beyond, efforts are being mobilized to align research and innovation processes and products with societal values and needs, and to create mechanisms for inclusive priority setting and knowledge production. A central concern is how to foster a culture of "Responsible Research and Innovation" (RRI) among scientists and engineers. This paper focuses on RRI teaching at higher education institutions. On the basis of interviews and reviews of academic and policy documents, it highlights the generic aspects of teaching aimed at invoking a sense of care and societal obligation, and provides a set of exemplary cases of RRI-related teaching. It argues that the Aristotelian concept of phronesis can capture core properties of the objectives of RRI-related teaching activities. Teaching should nurture the students' capacity in terms of practical wisdom, practical ethics, or administrative ability in order to enable them to act virtuously and responsibly in contexts which are often characterized by uncertainty, contention, and controversy. PMID- 29417392 TI - Neutrophil-to-lymphocyte ratio decreases in obstructive sleep apnea treated with mandibular advancement devices. AB - PURPOSE: Obstructive sleep apnea has been associated with chronic inflammation triggered by nocturnal hypoxemia. The neutrophil-to-lymphocyte ratio (NLR) is a measure of subclinical systemic inflammation. We hypothesize that NLR levels would improve as chronic inflammation diminishes in obstructive sleep apnea (OSA) patients treated with mandibular advancement devices (MADs). METHODS: We studied patients with OSA who were treated with MAD as a first-line treatment or because they could not tolerate CPAP. We obtained pre-treatment and post-treatment complete blood counts. NLR was calculated by dividing the number of neutrophils by the number of lymphocytes obtained from the CBCs. Patients with other conditions known to affect NLR were excluded from the study. RESULTS: We compared the values of NLR and oxygen desaturation index (ODI) before and after treatment with MAD in 22 patients who met inclusion criteria and completed the study protocol. There was a significant difference in NLR before and after treatment (p = 0.01). There was also a significant difference in the 3% ODI and 4% ODI before and after treatment with MAD (p = 0.014, 0.007), respectively. A subgroup analysis compared NLR in two groups of patients, the optimally treated and suboptimally treated. There was a significant decrease in the NLR in the optimally treated group (n = 10) (p < 0.01), whereas it did not change in the suboptimally treated group (n = 12) (p = 0.349). CONCLUSION: The neutrophil-to lymphocyte ratio may be useful in documenting improvement in inflammation for OSA patients treated with mandibular advancement devices. Our results specifically suggest that the NLR values are associated with the decrease in the ODI. PMID- 29417393 TI - Introductory TORS training in an otolaryngology residency program. AB - Transoral robotic surgery (TORS) is becoming an integral part of the otolaryngology resident experience. While there is widespread agreement that a formal, validated curriculum for TORS training is needed for residents, none presently exists. The primary objective of this study is to evaluate an introductory resident curriculum for TORS training that could be easily adopted at other institutions. This is a prospective study of otolaryngology residents (PGY1-5) in an academic medical center from 2015 to 2016. Trainees completed an introductory TORS training program consisting of online modules, logistic training, and hands-on training consisting of 12 tasks on the da Vinci Skills Simulator (dVSS). The primary outcomes were completion of training and time to completion. The secondary outcomes included resident attitudes regarding TORS as reflected on post-training survey. A total of 20 resident trainees participated in the study. 85% of trainees completed the hands-on robotic training in the allotted 3-h time limit. The average time to completion for those who finished was 91.53 min (SD 33.59 min). There was no statistically significant correlation between time to completion and PGY, number of robotic first assists, or total number of robotic cases. An introductory, resident-directed TORS training curriculum using the dVSS on an active surgical console is feasible in an academic medical center and may contribute to basic robotic competency among residents. Institutions with a dVSS may replicate this training in a resource efficient manner prior to implementation of more comprehensive training. Robotic skills are likely trainable and independent from surgical skills learned during residency. PMID- 29417394 TI - Total extraperitoneal robot assisted laparoscopic renal transplant recipient surgery. AB - INTRODUCTION: Renal transplant recipient surgery is conventionally performed using open technique which is total extra-peritoneal in approach whereas robot assisted renal transplant recipient surgery is performed through a transperitoneal approach. We present a case where a total extraperitoneal robot assisted renal transplant recipient surgery was performed. MATERIALS AND METHODS: A 30 year old gentleman with Ig A nephropathy and diffuse glomerulosclerosis underwent total extra-peritoneal robot assisted renal transplant recipient surgery (TERT) with sister as donor. Renal allograft was introduced through Pfannensteil incision. Alexis wound retractor was used to minimize trauma while positioning the allograft. RESULTS: There was good urine output on release of vascular clamps. Nadir creatinine was attained in three days. Patient was discharged on post-operative day six. CONCLUSION: TERT is a technically demanding procedure that closely resemble open technique while imparting the benefits of minimally invasive surgery to the patient. PMID- 29417395 TI - Islamic Considerations on the Application of Patient's Autonomy in End-of-Life Decision. AB - In end-of-life situation, the need for patient's preference comes into the picture with the intention of guiding physicians in the direction of patient care. Preference in medical directive is made by a person with full mental capacity outlining what actions should be taken for his health should he loses his competency. This is based on the reality of universal paradigm in medical practice that emphasises patient's autonomy. A specific directive is produced according to a patient's wish that might include some ethically and religiously controversial directives such as mercy killing, physician-assisted suicide, forgoing life-supporting treatments and do-not-resuscitate. In the future, patient autonomy is expected to become prevalent. The extent of patient autonomy has not been widely discussed among Muslim scholars. In Islam, there are certain considerations that must be adhered to. PMID- 29417396 TI - Black Male Mental Health and the Black Church: Advancing a Collaborative Partnership and Research Agenda. AB - This article explores the role the Black Church could play in facilitating spiritually sensitive, culturally relevant and gender-specific services to address the mental health and well-being of Black males. The help-seeking behaviors of Black men are examined as the authors offer two theories: the body, mind, spirit, environment, social, transcendent, and health, illness, men, and masculinities that may assist the Black Church in functioning as an effective support networks for healthy Black male mental health. Next, the authors discuss implications for practice, research, and education, and lastly, eight recommendations for Black Church leadership, social workers, and mental health professionals are also discussed. PMID- 29417397 TI - Cancer Immunotherapy: Factors Important for the Evaluation of Safety in Nonclinical Studies. AB - The development of novel therapies that can harnass the immune system to eradicate cancer is an area of intensive research. Several new biopharmaceuticals that target the immune system rather than the tumor itself have recently been approved and fundamentally transformed treatment of many cancer diseases. This success has intensified the search for new targets and modalities that could be developed as even more effective therapeutic agents either as monotherapy or in combination. While great benefits of novel immunotherapies in oncology are evident, the safety of these therapies has to also be addressed as their desired pharmacology, immune activation, can lead to "exaggerated" effects and toxicity. This review is focused on the unique challenges of the nonclinical safety assessment of monoclonal antibodies that target immune checkpoint inhibitors and costimulatory molecules. This class of molecules represents several approved drugs and many more drug candidates in clinical development, for which significant experience has been gained. Their development illustrates challenges regarding the predictivity of the animal models for assessing safety and setting starting doses for first-in-human trials as well as the translatability of nonclinical in vitro and in vivo data to the human findings. Based on learnings from the experience to date, factors to consider and novel approaches to explore are discussed to help address the unique safety issues of immuno-oncology drug development. PMID- 29417398 TI - Effects of central FGF21 infusion on the hypothalamus-pituitary-thyroid axis and energy metabolism in rats. AB - The aim of this study was to evaluate the impact of intracerebroventricular chronic fibroblast growth factor 21 (FGF21) infusion on hypothalamic-pituitary thyroid (HPT) axis, energy metabolism, food intake and body weight. Thirty male Wistar albino rats were used and divided into three groups including control, sham (vehicle) and FGF21 infused groups (n = 10). Intracerebroventricularly, FGF21 and vehicle groups were infused for 7 days with FGF21 (0.72 ug/day) and artificial cerebrospinal fluid, respectively. During the experimental period, changes in food intake and body weight were recorded daily. Serum thyroid stimulating hormone (TSH), Triiodothyronine (T3) and thyroxine (T4) levels were measured using ELISA. TRH and uncoupling protein 1 (UCP1) gene expressions were analyzed by using RT-PCR in hypothalamus and adipose tissues, respectively. Chronic infusion of FGF21 significantly increased serum TSH (p < 0.05), T3 (p < 0.05) and T4 (p < 0.001) levels. Additionally, hypothalamic TRH (p < 0.05) and UCP1 gene expressions (p < 0.05) in white adipose tissue were found to be higher than in the vehicle and control groups. While FGF21 infusion did not cause a significant change in food consumption, it caused a reduction in the body weight of rats (p < 0.05). Our findings indicate that FGF21 may have an effect on energy metabolism via the HPT axis. PMID- 29417399 TI - Melanoma Brain Metastases: Local Therapies, Targeted Therapies, Immune Checkpoint Inhibitors and Their Combinations-Chances and Challenges. AB - Recent phase II trials have shown that BRAF/MEK inhibitors and immune checkpoint inhibitors are active in patients with melanoma brain metastases (MBM), reporting intracranial disease control rates of 50-75%. Furthermore, retrospective analyses suggest that combining stereotactic radiosurgery with immune checkpoint inhibitors or BRAF/MEK inhibitors prolongs overall survival. These data stress the need for inter- and multidisciplinary cooperation that takes into account the individual prognostic factors in order to establish the best treatment for each patient. Although the management of MBM has dramatically improved, a substantial number of patients still progress and die from brain metastases. Therefore, there is an urgent need for prospective studies in patients with MBM that focus on treatment combinations and sequences, new treatment strategies, and biomarkers of treatment response. Moreover, further research is needed to decipher brain specific mechanisms of therapy resistance. PMID- 29417400 TI - Pediatric neuro-oncology survival disparities in California. AB - The objective of this study was to investigate racial/ethnic differences in survival for pediatric high-grade glioma (HGG) and medulloblastoma in the state of California. We obtained data from the California Cancer Registry on 552 high grade glioma patients (110 brainstem, 442 non-brainstem) and 648 medulloblastoma patients ages 0-19 years from 1988 to 2012. Using multivariate Cox proportional hazards regression, we examined the impact of individual and neighborhood characteristics on survival. Socioeconomic quintile and insurance status differed significantly by race for both diagnoses. Hispanic children with non-brainstem HGG had worse survival than non-Hispanic white children: hazard ratio (HR) 1.62; 95% confidence interval (CI) 1.24-2.11, but the difference was mitigated some by accounting for socioeconomic status (HR 1.48, CI 1.10-1.99). Racial/ethnic differences in survival exist for children with high-grade glioma, particularly Hispanic children with non-brainstem high-grade glioma, and are likely related to sociologic factors. PMID- 29417401 TI - Factors affecting early versus late remission in acromegaly following stereotactic radiosurgery. AB - Stereotactic radiosurgery (SRS) is a well-established treatment modality for patients with acromegaly. Our previously published study demonstrated a median time to remission of 29 months. This study aims to identify factors affecting the timing of remission and also to quantify the rate of late remission. This is a retrospective analysis of acromegaly patients who underwent SRS between 1988 and 2016. Early and late remissions were defined based on our prior median remission time of 29 months. The median imaging and endocrine follow-ups are 66 and 104.8 months, respectively. Multivariate analysis was conducted to analyze factors leading to late remission. A total number of 157 patients, of those 102 (64.9%) patients achieved remission. of those 102 patients, 62 patients (60.7%) had remission in less than 29 months (early remission) whereas 40 patients (39.3%) achieved remission later than (late remission) 29 months. The two groups differed significantly in the time interval between the last resection and the first SRS (p = 0.040) whole sella radiosurgery (p = 0.025) or radiosurgery to the cavernous sinus (p = 0.041). Competing risk analysis showed the interval between resection and SRS was significantly longer in the late remission group (HR 1.013, 95% CI 1.004-1.02; p = 0.007). Fifty-one of 157 patients (32.5%) developed a new endocrine deficiency following SRS. Those with shorter time between resection and SRS were more likely to achieve early remission. While most patients achieve remission in less than 4 years, the latency of effect with SRS yields a small percentage of patients achieving remission beyond that time point. PMID- 29417403 TI - Implementing a Program of Talimogene laherparepvec. AB - BACKGROUND: Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in cancer cells without harming normal cells. Talimogene laherparepvec (Imlygic(r)), the first oncolytic viral therapy approved for treatment of cancer, was approved for treatment of locally advanced melanoma in October 2015. PURPOSE: As a biologic product, use of T. laherparepvec in the clinical setting requires pretreatment planning and a unique systematic approach to deliver the therapy. The processes we describe herein could be adopted by other centers that choose to prescribe T. laherparepvec. METHODS: We studied our clinical trial experience with T. laherparepvec before we embarked on using commercially available T. laherparepvec. We created a standard operating procedure (SOP) with multidisciplinary buy-in and oversight from leadership in Infection Control at our institution. We reflected on clinical cases and the actual procedures of administering T. laherparepvec to create the SOP. RESULTS: The preimplementation planning, patient selection, identification of lesions to treat, the actual procedure, and ongoing assessment of patients are described. Tumoral-related factors that lead to unique challenges are described. CONCLUSIONS: A process to ensure safe and responsible implementation of a program to administer T. laherparepvec for treatment of melanoma may improve the quality of treatment for patients who suffer from advanced melanoma. PMID- 29417402 TI - Cost Effectiveness of Routine Laryngoscopy in the Surgical Treatment of Differentiated Thyroid Cancer. AB - BACKGROUND: Some surgeons perform flexible fiberoptic laryngoscopy (FFL) in all patients prior to thyroid cancer operations. Given the low likelihood of recurrent laryngeal nerve (RLN) or aerodigestive invasion in clinically low-risk thyroid cancers, the value of routine FFL in this group is controversial. We hypothesized that routine preoperative FFL would not be cost effective in low risk differentiated thyroid cancer (DTC). METHODS: A decision model was constructed comparing preoperative FFL versus surgery without FFL in a clinical stage T2 N0 DTC patient without voice symptoms. Total thyroidectomy and definitive hemithyroidectomy were both modeled as possible initial surgical approaches. Outcome probabilities and their corresponding utilities were estimated via literature review, and costs were estimated using Medicare reimbursement data. Sensitivity analysis was conducted to examine the uncertainty of cost, probability, and utility estimates in the model. RESULTS: When the initial surgical strategy was total thyroidectomy, routine preoperative FFL produced an incremental cost of $183 and an incremental effectiveness of 0.000126 quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) for routine FFL prior to total thyroidectomy was $1.45 million/QALY, exceeding the $100,000/QALY threshold for cost effectiveness. Routine FFL became cost effective if the preoperative probability of asymptomatic vocal cord paralysis increased from 1.0% to 4.9%, or if the cost of preoperative FFL decreased from $128 to $27. Changing the extent of initial surgery to hemithyroidectomy produced a higher ICER for routine FFL of $1.7 million/QALY. CONCLUSION: Routine preoperative FFL is not cost effective in asymptomatic patients with sonographically low-risk DTC, regardless of the initial planned extent of surgery. PMID- 29417404 TI - Solitary Pulmonary Lesion in Patients with History of Malignancy: Primary Lung Cancer or Metastatic Cancer? AB - BACKGROUND: Defining the status of solitary pulmonary lesion (SPL) in patients with history of malignancy is important because primary lung cancer (PLC) or intrapulmonary metastasis might indicate different surgical strategies. The aim of this study is to identify factors related to the status of these lesions and construct a clinical model to estimate the pretest probability of PLC. METHODS: From January 2005 to January 2016, 104 patients with previous malignancy and suitable for surgery were retrospectively studied. Univariate and multivariate analyses were performed to identify possible factors related to SPLs. A nomogram was constructed to differentiate PLC from intrapulmonary metastasis. RESULTS: Ninety-seven (93.3%) patients were diagnosed as malignant postoperatively, including 61 patients with intrapulmonary metastasis and 36 patients with PLC. Multivariate analysis showed that site of primary tumor [head and neck squamous cell cancer: odds ratio (OR) = 28.509, P = 0.006; genitourinary cancer: OR = 23.928, P = 0.012], negative lymph node status of primary tumor (OR = 3.154, P = 0.038), spiculation of SPL (OR = 3.972, P = 0.022), and central location of SPL (OR = 4.679, P = 0.026) were four independent factors differentiating PLC from intrapulmonary metastasis. All of these were included in the nomogram. The C index of the nomogram for predicting probability was 0.82. CONCLUSIONS: Incidence of malignant SPLs was fairly high in patients with history of malignancy. A nomogram including site and lymph node status of primary tumor, and spiculation and location of SPL might be a good tool for differentiating PLC from intrapulmonary metastasis preoperatively and guiding treatment. PMID- 29417405 TI - Salvage Surgery for Esophageal Cancer: How to Improve Outcomes? AB - BACKGROUND: Locoregional recurrence rates after definitive chemoradiotherapy (dCRT) for locally advanced esophageal cancer (EC) are high. Salvage surgery (SALV) is considered the best treatment option in case of persistent or recurrent disease for operable patients, but SALV has been associated with increased morbidity and mortality. The aim of this study is to identify factors linked to outcomes after SALV to better select candidates and to optimize perioperative care. STUDY DESIGN: We retrospectively analyzed data from 308 consecutive SALV patients from a large multicenter European cohort. Univariate and multivariate analyses were performed to identify factors associated with in-hospital postoperative morbidity, anastomotic leakage (AL), and overall survival (OS). RESULTS: The in-hospital postoperative mortality and morbidity rates were 8.4 and 34.7%, respectively. Squamous cell histology (p = 0.040) and radiation dose >= 55 Gy (p = 0.047) were independently associated with major morbidity. The AL rate was 12.7%, and cervical anastomosis was independently associated with AL (p = 0.002). OS at 5 years was 34.0%. Radiation dose >= 55 Gy (p = 0.003), occurrence of postoperative complications (p = 0.006), ypTNM stage 3 (p = 0.019), and positive surgical margins (p < 0.001) were linked to poor prognosis. CONCLUSIONS: SALV is a valuable option for patients with persistent or recurrent disease after dCRT and offers long-term survival. Factors such as radiation dose and anastomosis location identified here will help to optimize outcomes after SALV, which may be considered a standard treatment in the EC therapeutic armamentarium. PMID- 29417406 TI - A Review of Interleukin-1 in Heart Disease: Where Do We Stand Today? AB - Cardiovascular diseases are the leading cause of death worldwide. Research in the last two decades has emphasized the inflammatory process as a key component in the pathogenesis of many of them. The Interleukin-1 family is a pivotal element of inflammation and has been well studied as a therapeutic target in various inflammatory states. Recent trials have explored the effect of Interleukin-1 blockade in cardiovascular diseases and initial evidence of the relevance of such treatment in this field of medicine accumulate. This review will describe the role of Interleukin-1 in heart diseases and the potential therapeutic effect of its blockade in such diseases. PMID- 29417407 TI - A systematic review of ultrasound-accelerated catheter-directed thrombolysis in the treatment of deep vein thrombosis. AB - To review the clinical evidence for ultrasound-accelerated catheter-directed thrombolysis (UACDT) using the EKOS system in the treatment of deep vein thrombosis (DVT) in terms of case selection, procedural outcomes, clinical outcomes and safety outcomes. A systematic literature search strategy was used to identify the use of the EKOS system in the treatment of DVT using the following electronic databases: MEDLINE, EMBASE, the Cochrane databases and the Web of Science. The references in the relevant literature were also screened. Our literature search identified a total of 16 unique clinical studies. Twelve of the sixteen studies were retrospective case series studies. To date, only one randomised controlled trial (RCT) is available. Overall, UACDT using the EKOS system was performed 548 times in 512 patients. Among all cases, 77-100% achieved substantial lysis (> 50%) based on the different definitions of the individual studies. This treatment modality appears to be safe, as there were no reported procedure-related pulmonary embolisms (PE) and only one procedure-related death was reported. Bleeding events were reported in 14 of the 16 studies, and 3.9% (20/512) of the cases of bleeding were considered major. During the follow-up, post-thrombotic syndrome was observed in 17.1% (20/117) of cases. UACDT using the EKOS system is an effective, safe and promising treatment modality for DVT, but the existing clinical evidence is inadequate to make UACDT using the EKOS system the first-line choice for DVT. Additional prospective large-sample RCTs with long term follow-ups are warranted to define the role of UACDT using the EKOS system in the treatment of DVT. PMID- 29417408 TI - Comparative outcomes of thrombocytopenic acute leukemic patients with venous thromboembolism at a Comprehensive Cancer Center. AB - Patients with hematological malignancies often have severe thrombocytopenia, which poses problems when making thrombosis management decisions. A retrospective study was conducted to analyze the clinical outcomes associated with different management options in acute leukemic patients with thrombocytopenia (<= 50 * 109/L) following an acute venous thromboembolic event. A total of 74 patients were divided into three treatment groups: observation only (n = 30); anticoagulation (n = 23); or inferior vena cava placement (n = 21). Multivariate analysis showed that anticoagulant administration was significantly associated with improved overall survival without an increased rate of clinical relevant bleeding events when compared to other thrombosis management modalities. This study notes that dose adjusted-anticoagulant therapy may offer a safe and clinical advantageous strategy for the treatment and secondary prevention of recurrent venous thrombosis in thrombocytopenic patients with hematologic malignancies. PMID- 29417409 TI - A new method of CT for the cardiac measurement: correlation of computed tomography measured cardiac parameters and pulmonary obstruction index to assess cardiac morphological changes in acute pulmonary embolism patients. AB - Acute pulmonary embolism (APE) is a serious disease which is life-threatening. Since it is crucial for APE patients to assess the changes of cardiac function safely and timely, the imaging research of cardiac morphology and function is becoming more and more important. The correlation of computed tomography (CT) measured cardiac parameters and pulmonary obstruction index (POI) was analyzed to discuss the morphological changes of the heart of APE patients in order to provide a new method to evaluate cardiac functions accurately and effectively. 118 APE patients confirmed with CT pulmonary angiography (CTPA) were divided into high-risk group (47 cases, POI >= 20) and low-risk group (71 cases, POI < 20) according to the Qanadli Score. The left to right diameter (RL) and the anteroposterior diameter (AP) of the cardiac chambers were compared among the high-risk group, the low-risk group, and the normal group (60 cases). The correlation between CT measured cardiac parameters and the POI was analyzed. Except for left ventricular AP and right atrial AP, there were statistically significant differences (P < 0.05) in the RL and AP of the each cardiac cavity, these parameters meant that right hearts were enlarged and the left hearts were decreased in size. The ratio of right/left heart diameter was statistically significant among the three groups, a < b < c (P < 0.05). Moreover, the POI of 118 APE patients was 14.29 +/- 9.53, and there was significant linear correlation between CT measured cardiac parameters and the POI (P < 0.05), excluding the left ventricular AP and right atrial AP. The correlation coefficient reached 0.5 or more in terms of the right atrial LR, the right ventricular LR, the ratio of right/left atrial diameter and the ratio of right/left ventricular diameter. With the increasing value of POI, the right atrium and right ventricular of APE patients were enlarged, and the left atrium and left ventricular were decreased in size. These heart changes can be observed by using CTPA, even non-enhanced chest CT. PMID- 29417410 TI - Cardiovascular disease in the literature: A selection of recent original research papers. PMID- 29417411 TI - A quick glance at selected topics in this issue. AB - A quick glance at selected topics in this issue aims to highlight contents of the Journal and provide a quick review to the readers. PMID- 29417412 TI - Radiopharmaceuticals for cardiac imaging: Current status and future trends. PMID- 29417413 TI - What is This Image? 2018: Image 5 Result : Insidious disease. PMID- 29417414 TI - Development of an inflammation imaging tracer, 111In-DOTA-DAPTA, targeting chemokine receptor CCR5 and preliminary evaluation in an ApoE-/- atherosclerosis mouse model. AB - BACKGROUND: Chemokine receptor 5 (CCR5) plays an important role in atherosclerosis. Our objective was to develop a SPECT tracer targeting CCR5 for imaging plaque inflammation by radiolabeling D-Ala-peptide T-amide (DAPTA), a CCR5 antagonist, with 111In. METHODS: 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid (DOTA) conjugated DAPTA (DOTA-DAPTA) was labeled with 111In. Cell uptake studies were conducted in U87-CD4-CCR5 and U87-MG cells. Biodistribution was determined in C57BL/6 mice. Autoradiography, en face and Oil Red O (ORO) imaging studies were performed in ApoE-/- mice. RESULTS: DOTA-DAPTA was radiolabeled with 111In with high radiochemical purity (> 98%) and specific activity (70 MBq.nmol). 111In-DOTA-DAPTA exhibited fast blood and renal clearance and high spleen uptake. The U87-CD4-CCR5 cells had significantly higher uptake in comparison to the U87-MG cells. The cell uptake was reduced by three times with DAPTA, indicating the receptor specificity of the uptake. Autoradiographic images showed significantly higher lesion uptake of 111In-DOTA-DAPTA in ApoE-/- mice than that in C57BL/6 mice. The tracer uptake in 4 month old ApoE-/- high fat diet (HFD) mice with blocking agent was twofold lower than the same mice without the blocking agent, demonstrating the specificity of the tracer for the CCR5 receptor. CONCLUSION: 111In-DOTA-DAPTA, specifically targeting chemokine receptor CCR5, is a potential SPECT agent for imaging inflammation in atherosclerosis. PMID- 29417415 TI - Provocative testing for low-risk chest pain patients, must we continue? PMID- 29417416 TI - Testing our tests: Do clinical studies of diagnostic performance truly inform patient management? PMID- 29417417 TI - Arterial inflammation in young patients with human immunodeficiency virus infection: A cross-sectional study using F-18 FDG PET/CT. AB - BACKGROUND: HIV infection is associated with the risk of development of atherosclerosis at a younger age. We compared arterial inflammation in HIV infected and HIV-uninfected patients with otherwise low-risk factors for cardiovascular disease (CVD) using FDG PET/CT. METHODS: 242 patients aged 18-40 years with low-risk factors for CVD consisting of 121 HIV-infected patients and 121 HIV-uninfected age- and gender-matched controls were studied, mean age = 34.95 +/- 5.46 years. We calculated and compared the target-to-background ratio of FDG uptake in ascending aorta of HIV-infected and non-infected patients. RESULTS: Median CD4 count and viral load were 375.5 cells/mm3 (range 2-1094) and 6391.00 copies/mL (range 24-1,348,622), respectively. There was slightly higher but significant overlap in the TBR between HIV-infected group compared with control (1.22, 0.87-2.02 vs. 1.12, 0.38-1.40, P < 0.001). TBR was neither affected by CD4 count levels nor the presence or absence of detectable viremia. We also found no significant difference in TBR between male and female patients with HIV infection. We found a weak positive correlation between TBR and CD4 count, TBR and duration of HIV infection, and a very weak negative correlation between TBR and viral load. There was no significant difference in TBR between patients on HAART and those not yet commenced on therapy. CONCLUSION: Marginally higher TBR with a significant overlap exist in HIV-infected patients compared with control. Arterial F-18 FDG uptake is not affected by the CD 4 count, viral load, gender, or duration of HIV infection. PMID- 29417418 TI - Future growth and success of nuclear cardiology. PMID- 29417419 TI - Summed thickening score by myocardial perfusion imaging: A risk factor of left ventricular remodeling in patients with myocardial infarction. AB - BACKGROUND: Left ventricular (LV) remodeling has adverse effects on the prognosis of patients with myocardial infarction (MI). The aim of this study is to identify the risk factors of LV remodeling in MI patients by radionuclide myocardial imaging. METHODS AND RESULTS: This retrospective study consisted of 92 patients who had a history of definite prior MI on ECG and underwent both resting gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) and positron emission tomography (PET) myocardial metabolism imaging. LV remodeling was defined as > mean + 2SD of LV end-diastolic volume index (LVEDVi) in the normal database. LV enlargement, cardiac dysfunction, wall thickening abnormalities expressed as summed thickening score (STS) were more severe in the old MI patients as compared to those with subacute MI. STS (Odds ratio, 1.296; P = .004) and the proportion of segments with reduced wall thickening in segments with normal perfusion (Odds ratio, 1.110; P = .001) were identified as the independent factors of LV remodeling in subacute and old MI patients in the multivariate binary regression model. Total perfusion deficit (TPD), viable myocardium, scar, and the proportion of segments with reduced wall thickening in segments with decreased perfusion showed strong correlation with LV remodeling in the univariate regression model as well. CONCLUSIONS: LV remodeling in old MI patients is more extensive and severe than that in subacute MI patients. LV wall thickening abnormalities as expressed by STS and the proportion of segments with reduced wall thickening in segments with normal perfusion are the independent risk factors of LV remodeling in MI patients. PMID- 29417420 TI - Comparison of the AHA/ACC vs ESC guidelines for management of patients with non ST-elevation acute coronary syndromes: Are the differences clinically different? PMID- 29417421 TI - Myocardial perfusion imaging prior to coronary revascularization: From risk stratification to procedure guidance. PMID- 29417422 TI - Unmet Patient Need in Statin Intolerance: the Clinical Characteristics and Management. AB - PURPOSE: A substantial percentage of patients report intolerance or side effects of statin treatment leading to treatment changes or discontinuation. The purpose of this study was to examine statin therapy changes and subsequent effects on low density lipoprotein cholesterol (LDL-C) among patients with statin intolerance (SI). METHODS: We identified 45,037 adults from Kaiser Permanente Southern California with SI documented between 2006 and 2012. Changes in statin therapy in the year before and after the SI index date were examined. We categorized patients into those who initiated statin therapy, discontinued, up-titrated, down titrated, or did not switch therapy. We calculated the percentage change in LDL-C from the year before to the year after SI, and the percentage of patients attaining LDL-C < 100 and < 70 mg/dL. RESULTS: In the year prior to the SI date, 77.8% of patients filled a statin prescription. Following SI, 44.6% had no treatment change, 25.5% discontinued, and 30.0% altered their statin therapy. Of those who altered statin therapy, 52.6% down-titrated and 17.2% up-titrated their dose. Rhabdomyolysis was documented in < 1% of the cohort. The largest changes in LDL-C were experienced by patients who were on a high-intensity statin then discontinued treatment (35.6% increase) and those who initiated a high-intensity statin (25.5% decrease). The proportion of patients achieving LDL-C < 100 mg/dL and LDL-C < 70 mg/dL was the lowest among those who discontinued therapy. CONCLUSIONS: Although adjustments to the statin dosage may be appropriate upon documentation of SI, many of these patients will have high LDL-C. Strategies for LDL-C reduction in patients with SI may be necessary. PMID- 29417423 TI - Dysphagia in myasthenia gravis: the tip of the Iceberg. AB - We evaluated swallowing function in patients with myasthenia gravis (MG) with or without dysphagia symptoms using different evaluation parameters and compared the results with those of healthy subjects. A total of 36 patients with MG and 25 healthy volunteers were included in the study. The subjects were classified into three groups; patients without dysphagia (group 1), patients with dysphagia (group 2), and healthy participants (group 3). The presence and severity of dysphagia, the oropharyngeal, pharyngeal, pharyngoesophageal, and esophageal phases were assessed using a screening test, manometric test, electrophysiologic studies [electroneuromyography (EMG)], fiberoptic endoscopic evaluation of swallowing (FEES), and barium swallow pharyngeal esophagography (BSPE), respectively. There was a significant difference between group 1 and group 3 in terms of BSPE (p = 0.001) and manometry tests (p = 0.001). A significant difference was found in all methods between group 2 and group 3 (p = 0.001, for all). In the comparison of the patient groups, although the number of patients with dysphagia in group 2 was significantly higher in the clinical tests (p = 0.007), FEES (p = 0.001), and EMG (p = 0.043) than in group 1, no difference was detected for BSPE (p = 0.119) and manometry (p = 0.644). Swallowing functions in patients with MG may be affected even without symptoms. This condition should be considered in their follow-up. PMID- 29417424 TI - KIAA2022-related disorders can cause Jeavons (eyelid myoclonia with absence) syndrome. PMID- 29417426 TI - Association of midlife value priorities with health-related quality of life, frailty and mortality among older men: a 26-year follow-up of the Helsinki Businessmen Study (HBS). AB - PURPOSE: Personal values influence behavior and decision making, but their long term associations with health-related quality of life (HRQoL), frailty, and mortality are less clear. We studied these associations from midlife to old age in a 26-year follow-up of the Helsinki Businessmen Study (HBS) cohort. METHODS: In 1974, 1320 clinically healthy men (born 1919-1934) reported in a 12-item questionnaire their personal values. In 2000, a mailed questionnaire, including assessment of HRQoL with RAND-36 (SF-36) instrument, was sent to survivors, and 1025 men responded. In 2000, the presence of phenotypic frailty was assessed using modified Fried criteria including indicators of shrinking, physical weakness, exhaustion, and physical inactivity. Mortality through December 31, 2000 was verified from national registries. RESULTS: Using a factor analysis, the data of the 12-item questionnaire of personal values were loaded in 3 factors: valuing health ("Health"), enjoyable and varying life ("Enjoyment"), and comfort and work-oriented life ("Work-life-balance"). Adjusted for age, we found a significant positive association between valuing "Health" in midlife and RAND-36 domains of Physical functioning (p = .032) and Vitality (p = .005) in old age. "Health" also predicted less frailty (p = .008), and "Enjoyment" was associated with higher mortality (p = .017). CONCLUSIONS: Value priorities of men assessed in midlife had long-term associations with HRQoL and frailty in old age, and they may also predict mortality. PMID- 29417425 TI - The association between post-diagnosis health behaviors and long-term quality of life in survivors of ductal carcinoma in situ: a population-based longitudinal cohort study. AB - PURPOSE: Women diagnosed with ductal carcinoma in situ (DCIS) often experience adverse changes in health-related behaviors following diagnosis. The impact of health behaviors on long-term quality of life (QoL) in DCIS survivors has not been investigated. METHODS: We examined the association of post-diagnosis body mass index (BMI), physical activity, alcohol, and smoking with QoL among 1448 DCIS survivors aged 20-74 enrolled in the population-based Wisconsin in situ Cohort from 1997 to 2006. Health behaviors and QoL were self-reported during biennial post-diagnosis interviews. Physical and mental QoL were measured using the validated SF-36 questionnaire. Generalized linear regression was used to determine the association between behaviors and QoL with adjustment for confounders. Lagged behavior variables were used to predict QoL during follow-up and avoid reverse causation. RESULTS: Women reported 3,536 QoL observations over an average 7.9 years of follow-up. Women maintaining a healthy BMI had on average a significantly higher summary measure score of physical QoL than obese women (normal versus obese: beta = 3.02; 2.18, 3.85). Physical QoL scores were also elevated among those who were physically active (5 + h/week vs. none: beta = 1.96; 0.72, 3.20), those consuming at least seven drinks/week of alcohol (vs. none; beta = 1.40; 0.39, 2.41), and nonsmokers (vs. current smokers: beta = 1.80; 0.89, 2.71). Summary measures of mental QoL were significantly higher among women who were moderately physically active (up to 2 h/week vs. none: beta = 1.11; 0.30, 1.92) and nonsmokers (vs. current smokers: beta = 1.49;0.45, 2.53). CONCLUSIONS: Our results demonstrate that maintaining healthy behaviors following DCIS treatment is associated with modest improvements in long-term QoL. These results inform interventions aimed at promoting healthy behaviors and optimizing QoL in DCIS survivors. PMID- 29417427 TI - Computer assistive technology and associations with quality of life for individuals with spinal cord injury: a systematic review. AB - STUDY DESIGN: Systematic review. OBJECTIVE: The purpose of the study was to identify and organize evidence regarding quality of life influenced by assistive technology related to computers for people with traumatic and non-traumatic spinal cord injury (SCI). SETTING: Distrito Federal, Brazil. METHODS: A search strategy was conducted on the PubMed, PEDro, LILACS, PsycINFO, and SCIELO. All types of study designs considering assistive technology to improve quality of life for individuals with SCI were included. After search strategy procedures, ten references were included to review. The methodologic quality of each study was evaluated using the Level of Evidence proposed by the Oxford Centre for Evidence-based Medicine. RESULTS: Most of the studies showed that devices for computer access improve the quality of life of people with SCI, regardless of the level of injury and type of resource. However, the positive outcomes in the quality of life should be interpreted with caution, as several methodological limitations were observed in the articles. CONCLUSIONS: Despite the scarcity of studies and their methodological limitations, there is evidence that assistive technology for computer access favors the quality of life of people with tetraplegia due to SCI, since it improves participation, independence, and self esteem. PMID- 29417428 TI - Diel Periodicity of 3-Methyl-2-Butenyl Butyrate Emissions by Bronze Bug Males Is Suppressed in the Presence of Females. AB - The bronze bug, Thaumastocoris peregrinus Carpintero & Dellape (Heteroptera: Thaumastocoridae), is an exotic emerging pest in Eucalyptus commercial forests in South America, Africa, and southern Europe. Information on the chemical communication system and reproductive ecology of this insect is scant, and it may be relevant for designing management strategies for eucalypt plantations. Males emit large amounts of 3-methyl-2-butenyl butyrate, which attracts conspecific adult males but not females. To learn more about the biological function of this putative male-produced pheromone, we quantified this compound in volatile emissions collected from males, females, and couples, in three 4-h collecting periods during the morning, afternoon, and night of a single 24-h cycle. Our results showed that virgin males emit 3-methyl-2-butenyl butyrate in a diel time pattern, with an almost sevenfold difference between the afternoon emission peak compared to morning or night hours. In addition, we show that in the presence of females, males emit the compound in the same amounts throughout the photocycle. While a definite function cannot yet be attributed to the emission of 3-methyl-2 butenyl butyrate by T. peregrinus males, our findings point to an intraspecific function, possibly one related to male-male competition. PMID- 29417429 TI - Effect of the Shellfish Proteinase K Digestion Method on Norovirus Capsid Integrity. AB - Norovirus outbreaks are associated with the consumption of contaminated shellfish, and so efficient methods to recover and detect infectious norovirus in shellfish are important. The Proteinase K digestion method used to recover norovirus from shellfish, as described in the ISO 15216, would be a good candidate but its impact on the virus capsid integrity and thus infectivity was never examined. The aim of this study was to assess the impact of the Proteinase K digestion method, and of the heat treatment component of the method alone, on norovirus (genogroups I and II) and MS2 bacteriophage capsid integrity. A slightly modified version of the ISO method was used. RT-qPCR was used for virus detection following digestion of accessible viral RNA using RNases. MS2 phage infectivity was measured using a plaque assay. The effect of shellfish digestive glands (DG) on recovery was evaluated. In the presence of shellfish DG, a reduction in MS2 phage infectivity of about 1 log10 was observed after the Proteinase K digestion method and after heat treatment component alone. For norovirus GII and MS2 phage, there was no significant loss of genome following the Proteinase K digestion method but there was a significant 0.24 log10 loss of norovirus GI. In the absence of shellfish DG, the reduction in MS2 phage infectivity was about 2 log10, with the addition of RNases resulting in a significant loss of genome for all tested viruses following complete Proteinase K digestion method and the heat treatment alone. While some protective effect from the shellfish DG on viruses was observed, the impact on capsid integrity and infectivity suggests that this method, while suitable for norovirus genome detection, may not completely preserve virus infectivity. PMID- 29417430 TI - Effect of Discontinuation or Initiation of Methotrexate or Glucocorticoids on Tofacitinib Efficacy in Patients with Rheumatoid Arthritis: A Post Hoc Analysis. AB - INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the effect of concomitant methotrexate (MTX) or glucocorticoid (GC) use on tofacitinib clinical efficacy. METHODS: Data were pooled from two open-label, long-term extension studies of tofacitinib 5 or 10 mg twice daily in patients with RA. Response according to Clinical Disease Activity Index (CDAI) was assessed separately in patients who discontinued (no MTX/GC use within 30 days prior to year-3 visit; assessment at month 3/year 3) or initiated (on/before year 3; assessment at initiation and year 3) MTX/GC. RESULTS: By year 3, among patients receiving background MTX at baseline, 186/1608 (11.6%) discontinued MTX, and 319/1434 (22.2%) patients receiving GC at baseline discontinued GC. Overall, 70.4/69.1% of patients who discontinued/continued MTX and 72.7/65.9% who discontinued/continued GC achieved CDAI remission or low disease activity (LDA) at year 3. Month 3 remission/LDA rates were maintained at year 3 in the majority of patients, irrespective of MTX/GC discontinuation/continuation. By year 3, 6.2% of patients receiving tofacitinib without MTX at baseline had initiated concomitant MTX, and 25.1% receiving tofacitinib without GC initiated GC; 69.0% and 45.4% initiating MTX or GC, respectively, had a CDAI-defined incomplete response prior to initiation. RA signs/symptoms improved following MTX initiation; only modest improvement was observed with GC initiation. CONCLUSIONS: Patients achieving remission/LDA with tofacitinib may discontinue MTX or GC and maintain treatment response. Patients with an incomplete response may benefit from adding concomitant MTX. FUNDING: Pfizer Inc. TRIAL REGISTRATION: Study A3921024 [NCT00413699] and Study A3921041 [NCT00661661]. PMID- 29417431 TI - Epoetin Biosimilars in the Treatment of Chemotherapy-Induced Anemia: 10 Years' Experience Gained. AB - High-quality, safe, and effective biosimilars have the potential to increase access to biological therapies worldwide and to reduce cancer care costs. The European Medicines Agency (EMA) was the first regulatory authority to establish legislative procedures for the approval of biosimilars when they published their guidelines on similar biological medicinal products in 2005. Biosimilar epoetins were first approved in 2007, and a wealth of data has been collected over the last decade. Two biosimilar epoetins (under five commercial names) have been approved by the EMA so far. The availability of epoetin biosimilars generated discussion among the oncology community regarding prescribing these products, their efficacy, and their safety. These agents are approved only if they are shown in extensive analytical and clinical testing to have comparable quality, safety, and efficacy to the reference medicine, and real-world studies provide further data that biosimilar epoetins are an effective and well-tolerated option for the treatment of chemotherapy-induced anemia in patients with cancer. Other countries have adopted similar regulatory pathways to those in Europe and have approved epoetin biosimilars. The now extensive European experience with biosimilar epoetins should reassure regulators from other territories. PMID- 29417432 TI - Sensory Subtypes in Preschool Aged Children with Autism Spectrum Disorder. AB - Given the heterogeneity of autism spectrum disorder (ASD), research has investigated how sensory features elucidate subtypes that enhance our understanding of etiology and tailored treatment approaches. Previous studies, however, have not integrated core developmental behaviors with sensory features in investigations of subtypes in ASD. Therefore, we used latent profile analysis to examine subtypes in a preschool aged sample considering sensory processing patterns in combination with social-communication skill, motor performance, and adaptive behavior. Results showed four subtypes that differed by degree and quality of sensory features, age and differential presentation of developmental skills. Findings partially align with previous literature on sensory subtypes and extends our understanding of how sensory processing aligns with other developmental domains in young children with ASD. PMID- 29417433 TI - Brief Report: Effects of Video-Based Group Instruction on Spontaneous Social Interaction of Adolescents with Autism Spectrum Disorders. AB - Four adolescents with autism spectrum disorder (ASD) were taught to interact with peers by asking social questions or commenting about others during game play or group activities. Participants were shown a video model and then given an opportunity to perform the social behavior depicted in the model when playing a game with one another. All participants demonstrated an increase in both social interaction skills, replicating previous research on video-based group instruction for adolescents with ASD. The results suggest the procedure may be useful for teaching social skills that occur under natural conditions. PMID- 29417434 TI - Mothers' Experiences of a Women's Health and Empowerment Program for Mothers of a Child with a Disability. AB - Substantial research identifies mothers of children with a disability as a vulnerable group with compromised health outcomes and restrictions for their own self-care, social, economic and leisure participation. This study investigated perceptions and experiences of mothers following attendance at health education and empowerment workshops (Healthy Mothers Healthy Families). Mixed methods evaluated mothers' experiences. A pragmatic qualitative approach was applied to data analysis of interviews with mothers (N = 19). Four themes emerged: Changes for me; Changes for my family; Wisdom gained; and Worthwhile workshops. Mothers described feeling validated and empowered in this facilitated group intervention and valued education about women's health, tailored research findings, individualised goal setting, time to learn and share with other mothers, and the workshop environment. PMID- 29417436 TI - Paraprofessional-Delivered Video Prompting to Teach Academics to Students with Severe Disabilities in Inclusive Settings. AB - Video prompting is effective for teaching a variety of skills (e.g., daily living, communication) to students with autism and intellectual disability; yet, little research exists on the efficacy of these strategies on academic skills, in inclusive settings, and with typical intervention agents. Authors collaborated with paraprofessionals to select socially important academic skills (i.e., literacy, social studies, science, and math) aligned with students' IEPs and content taught in their inclusive classes. Results from the multiple probe across participants and skills design indicated a functional relation between the paraprofessional-delivered video prompting and correct responding to academic tasks for all three elementary students with autism and intellectual disability. Implications for practitioners, study limitations, and recommendations for future research are discussed. PMID- 29417435 TI - Evaluating Sensory Processing in Fragile X Syndrome: Psychometric Analysis of the Brain Body Center Sensory Scales (BBCSS). AB - Individuals with fragile X syndrome (FXS), especially those co-diagnosed with autism spectrum disorder (ASD), face many sensory processing challenges. However, sensory processing measures informed by neurophysiology are lacking. This paper describes the development and psychometric properties of a parent/caregiver report, the Brain-Body Center Sensory Scales (BBCSS), based on Polyvagal Theory. Parents/guardians reported on 333 individuals with FXS, 41% with ASD features. Factor structure using a split-sample exploratory-confirmatory design conformed to neurophysiological predictions. Internal consistency, test-retest, and inter rater reliability were good to excellent. BBCSS subscales converged with the Sensory Profile and Sensory Experiences Questionnaire. However, data also suggest that BBCSS subscales reflect unique features related to sensory processing. Individuals with FXS and ASD features displayed more sensory challenges on most subscales. PMID- 29417437 TI - Brief Report: Adults with Autism are Less Accurate at Predicting How Their Personality Traits are Evaluated by Unfamiliar Observers. AB - Social cognitive impairments in autism spectrum disorder (ASD) are well documented, yet little research has examined whether ASD is also characterized by difficulties in meta-perception, or the ability to gauge how one is perceived. In this study, ASD and TD adults (N = 22) largely did not differ on the self perception of their personality traits or on how they expected to be perceived by unfamiliar observers. However adults with ASD were rated less favorably by TD observers (N = 412) on 19 out of 20 personality items, and adults with ASD were less accurate at predicting how they would be perceived. These findings suggest impaired meta-perception in ASD that may serve as a potential mechanism through which reduced social cognitive ability contributes to social impairment. PMID- 29417438 TI - Correction to: SEOM clinical guidelines for endometrial cancer (2017). AB - In the original version of this article Figure 1 was shown incorrectly. The correct Figure 1 is shown here. PMID- 29417439 TI - Antioxidants Reverse the Changes in the Cholinergic System Caused by L-Tyrosine Administration in Rats. AB - Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in the activity of the enzyme tyrosine aminotransferase, leading to tyrosine accumulation in the body. Although the mechanisms involved are still poorly understood, several studies have showed that higher levels of tyrosine are related to oxidative stress and therefore may affect the cholinergic system. Thus, the aim of this study was to investigate the effects of chronic administration of L-tyrosine on choline acetyltransferase activity (ChAT) and acetylcholinesterase (AChE) in the brain of rats. Moreover, we also examined the effects of one antioxidant treatment (N-acetylcysteine (NAC) + deferoxamine (DFX)) on cholinergic system. Our results showed that the chronic administration of L-tyrosine decreases the ChAT activity in the cerebral cortex, while the AChE activity was increased in the hippocampus, striatum, and cerebral cortex. Moreover, we found that the antioxidant treatment was able to prevent the decrease in the ChAT activity in the cerebral cortex. However, the increase in AChE activity induced by L-tyrosine was partially prevented the in the hippocampus and striatum, but not in the cerebral cortex. Our results also showed no differences in the aversive and spatial memory after chronic administration of L-tyrosine. In conclusion, the results of this study demonstrated an increase in AChE activity in the hippocampus, striatum, and cerebral cortex and an increase of ChAT in the cerebral cortex, without cognitive impairment. Furthermore, the alterations in the cholinergic system were partially prevented by the co administration of NAC and DFX. Thus, the restored central cholinergic system by antioxidant treatment further supports the view that oxidative stress may be involved in the pathophysiology of tyrosinemia type II. PMID- 29417440 TI - Caffeine Protects Against Anticonvulsant-Induced Impaired Neurogenesis in the Developing Rat Brain. AB - In preterm infants, phenobarbital is the first-line antiepileptic drug for neonatal seizures while caffeine is used for the treatment of apnea. Data from experimental animals suggest that phenobarbital and other anticonvulsants are toxic for the developing brain, while neuroprotective effects have been reported for caffeine both in newborn rodents and preterm human infants. To characterize the interaction of phenobarbital and caffeine in the hippocampus of the developing rodent brain, we examined the effects of both drugs given separately or together on postnatal neurogenesis after administration to neonatal rats throughout postnatal day (P) 4 to P6. Phenobarbital treatment (50 mg/kg) resulted in a significant decrease of proliferative capacity in the dentate gyrus. Phenobarbital also reduced expression of neuronal markers (doublecortin (DCX), calretinin, NeuN), neuronal transcription factors (Pax6, Sox2, Tbr1/2, Prox1), and neurotrophins (NGF, BDNF, NT-3) up to 24 h after the last administration. The phenobarbital-mediated impairment of neurogenesis was largely ameliorated by preconditioning with caffeine (10 mg/kg). In contrast, caffeine alone reduced proliferative capacity and expression of the neuronal markers DCX and NeuN at 6 h, but increased expression of neurotrophins and neuronal transcription factors at 6 and 12 h. These results indicate that administration of phenobarbital during the vulnerable phase of brain development negatively interferes with neuronal development, which can be prevented in part by co-administration of caffeine. PMID- 29417443 TI - The outcomes of subtotal vitrectomy in macular surgeries: a single surgeon case series. AB - PURPOSE: To investigate the outcomes of subtotal vitrectomy in epiretinal membrane (ERM) and idiopathic macular hole (IMH) surgeries. METHODS: The patients who underwent vitrectomy for primary ERM and IMH were included. After the truncation of posterior hyaloid, cortical vitreous was incompletely removed and anterior vitreous was left in place. The main outcome measure was the complications of the surgical technique during the postoperative 12 months of follow-up. RESULTS: Fifty-two eyes were included. Thirty-seven eyes had ERM, and 15 had IMH. During the 12 months of follow-up period, 33% of the phakic patients showed progression in the lens opacities and required cataract surgery. Other postoperative complications were listed as follows: transient intraocular pressure increase in 3 (5.9%), endophthalmitis in 1 (2.0%), and retinal detachment in 1 patient (2.0%). CONCLUSION: Subtotal vitrectomy seems as an effective and safe surgical technique in the treatment of macular diseases. PMID- 29417442 TI - Combination treatment of all-trans retinoic acid (ATRA) and gamma-secretase inhibitor (DAPT) cause growth inhibition and apoptosis induction in the human gastric cancer cell line. AB - Current medication for gastric cancer patients has a low success rate with resistance and side effects. According to recent studies, gamma-secretase inhibitors is used as therapeutic drugs in cancer. Moreover, all-trans retinoic acid (ATRA) is a natural compound proposed for the treatment/chemo-prevention of cancers. The aim of this study was to explore the effects of ATRA in combination with N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT) as gamma-secretase inhibitor on viability and apoptosis of the AGS and MKN-45 derived from human gastric cancer. AGS and MKN-45 gastric cancer cell lines were treated with different concentrations of ATRA or DAPT alone or ATRA plus DAPT. The viability, death detection and apoptosis of cells was examined by MTT assay and Ethidium bromide/acridine orange staining. The distribution of cells in different phases of cell cycle was also evaluated through flow cytometry analyses. In addition, caspase 3/7 activity and the expression of caspase-3 and bcl-2 were examined. DAPT and ATRA alone decreased gastric cancer cells viability in a concentration dependent manner. The combination of DAPT and ATRA exhibited significant synergistic inhibitory effects. The greater percentage of cells were accumulated in G0/G1 phase of cell cycle in combination treatment. The combination of DAPT and ATRA effectively increased the proportion of apoptotic cells and the level of caspase 3/7 activities compared to single treatment. Moreover, augmented caspase-3 up-regulation and bcl-2 down-regulation were found following combined application of DAPT and ATRA. The combination of DAPT and ATRA led to more reduction in viability and apoptosis in respect to DAPT or ATRA alone in the investigated cell lines. PMID- 29417441 TI - Glycotoxins: Dietary and Metabolic Origins; Possible Amelioration of Neurotoxicity by Carnosine, with Special Reference to Parkinson's Disease. AB - There is a strong association between neurodegeneration and protein glycation; possible origins of neurotoxic glycated protein, also called glycotoxins, include (i) diet (i.e., proteins cooked at high temperatures), (ii) protein glycation in the gut, and (iii) intracellular reaction of proteins with deleterious aldehydes, especially methylglyoxal (MG). It is likely that excessive glycolysis provokes increased generation of dihydroxyacetone phosphate which decomposes into MG due to activity-induced deamidation of certain asparagine residues in the glycolytic enzyme triose-phosphate isomerase (TPI). It is suggested that, following hyperglycemia, erythrocytes (i) possibly participate in MG distribution throughout the body and (ii) could provide a source of glycated alpha-synuclein which also accumulates in PD brains as Lewy bodies. The dipeptide carnosine, recently shown to be present in erythrocytes, could help to protect against MG reactivity by scavenging the reactive bicarbonyl, especially if glyoxalase activity is insufficient, as often occurs during aging. By reacting with MG, carnosine may also prevent generation of the neurotoxin 1-acetyl-6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline (ADTIQ), which accumulates in PD and diabetic brains. It is suggested that carnosine's therapeutic potential could be explored via nasal administration in order to avoid the effects of serum carnosinase. The possibility that some glycated proteins (e.g., alpha-synuclein) could possess prion-like properties is also considered. PMID- 29417444 TI - Corneal perforation after noncontact tonometry in patients with active recurrent herpes simplex keratitis: case report. AB - PURPOSE: To report iatrogenic complications and to review the potential complications caused by noncontact tonometry (NCT) in related literature. METHODS: This case report describes two cases of active recurrent herpes simplex keratitis (HSK) on top of a thin corneal scar. The cornea was perforated by the air pulse from the NCT, resulting in an air bubble in the anterior chamber. RESULTS: Both patients were diagnosed with active recurrent necrotizing stromal HSK on top of a thinned corneal scar after previous therapeutic treatment involving tissue adhesive glue with a bandage contact lens (BCL) to treat a perforated cornea. During a follow-up visit, both patients reported similar symptoms of acute pain and fluid exuding from their eyes immediately after undergoing NCT. Slit-lamp examination revealed a perforated cornea with an intracameral air bubble. Treatment involved use of tissue adhesive glue and BCL in both cases. CONCLUSION: NCT may not be sufficiently safe in patients with active infectious keratitis, particularly in cases where the cornea is relatively thin and necrotic. PMID- 29417445 TI - A rating scale is a proper method to evaluate changes in quality of life due to dry eye symptoms. AB - PURPOSE: To determine which utility value assessment method is more suitable to evaluate changes in the quality of life due to dry eye symptoms. METHODS: Dry eye outpatients with a presenting visual acuity of 20/25 or better in the worse seeing eye were recruited. Presenting distance visual acuity, tear film break-up time, Schirmer I test and fluorescein were assessed. The severity of dry eye symptoms was assessed using the Ocular Surface Disease Index (OSDI), and utility values were measured using the time trade-off (TTO), standard gamble (SG1 and SG2) and rating scale (RS) methods. Different utility values were compared with each other. The most appropriate utility value method to evaluate quality-of-life changes solely due to dry eye symptoms is determined by calculating the correlation between the OSDI score and different utility values. RESULTS: A total of 104 patients were enrolled. The three sections of OSDI in the order of high to low scores were as follows: "environmental trigger," "eye discomfort" and "visual function." The utility scores measured with TTO, SG1, SG2 and RS were 0.95 +/- 0.11, 0.96 +/- 0.10, 0.99 +/- 0.07 and 0.89 +/- 0.10, respectively. The utility scores evaluated by the TTO, SG1, SG2 and RS methods were significantly different from each other (p < 0.05). Only the utility scores measured with RS were significantly correlated with the composite OSDI score, "environmental trigger" and "eye discomfort" section scores (p < 0.05). CONCLUSIONS: RS is more sensitive than TTO and SG for the evaluation of altered quality of life due to dry eye symptoms. PMID- 29417447 TI - Maternal and Family Processes in Different Subgroups of Youth with Autism Spectrum Disorder. AB - We compared the maternal reports on mothering and family processes between 160 youth with autism spectrum disorder (ASD) and 160 age and gender-matched typically developing (TD) youth stratified by personal characteristics from Taiwan. The ASD groups consisted of 51 'typical autism' (TA), 52 'high functioning autism' (HFA), and 57 'Asperger syndrome (AS).' Maternal reports showed that youth with ASD obtained less affection and more protection from the mother, and had less active mother-child interactions and more behavioral problems at home. Their mothers perceived less family support when compared to mothers of TD youth. Moreover, both TA and AS groups had more maternal protection and less maternal perceived family support, whereas HFA and co-occurring ADHD were only associated with more behavioral problems at home. The maternal and family process may vary across different ASD subgroups. PMID- 29417446 TI - Linking the Gut Microbiota to Bone Health in Anorexia Nervosa. AB - PURPOSE OF REVIEW: The purpose of this review is to examine the anorexia nervosa microbiota-bone relationship, offering a compilation of the relevant human and animal studies that may contribute to a more comprehensive understanding of potential mechanisms involved. RECENT FINDINGS: Recent studies have implicated fermentation by-products of the gut microbiota in bone metabolism. Compromised bone health often accompanies anorexia nervosa due to energy deficiency and hypoestrogenism. The gut microbiome has been implicated as a link between these conditions and impaired bone growth phenotypes. Current research supports decrements in Firmicutes and short-chain fatty acids with increases in Methanobrevibacter smithii and Proteobacteria in anorexia nervosa. A potential mechanism for microbiome-regulated bone growth is through modulation of insulin like growth factor-1. Future research should aim to examine short-chain fatty acids, probiotics, and prebiotics as alternative therapies to treat low bone density in anorexia nervosa. PMID- 29417448 TI - Atorvastatin Attenuates Cognitive Deficits and Neuroinflammation Induced by Abeta1-42 Involving Modulation of TLR4/TRAF6/NF-kappaB Pathway. AB - Inflammatory damage aggravates the progression of Alzheimer's disease (AD) and the mechanism of inflammatory damage may provide a new therapeutic window for the treatment of AD. Toll-like receptor 4 (TLR4)-mediated signaling can regulate the inflammatory process. However, changes in TLR4 signaling pathway induced by beta amyloid (Abeta) have not been well characterized in brain, especially in the hippocampus. In the present study, we explored the changes of TLR4 signaling pathway induced by Abeta in the hippocampus and the role of atorvastatin in modulating this signal pathway and neurotoxicity induced by Abeta. Experimental AD rats were induced by intrahippocampal injection of Abeta1-42, and the rats were treated with atorvastatin by oral gavage from 3 weeks before to 6 days after injections of Abeta1-42. To determine the spatial learning and memory ability of rats in the AD models, Morris water maze (MWM) was performed. The expression of the glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule-1 (Iba-1), TLR4, tumor necrosis factor receptor-associated factor 6 (TRAF6), and nuclear transcription factor (NF)-kappaB (NF-kappaB) protein in the hippocampus was detected by immunohistochemistry and Western blot. Compared to the control group, increased expression of TLR4, TRAF6, and NF-kappaB was observed in the hippocampus at 7 days post-injection of Abeta (P < 0.01). Furthermore, atorvastatin treatment significantly ameliorated cognitive deficits of rats, attenuated microglia and astrocyte activation, inhibited apoptosis, and down-regulated the expression of TLR4, TRAF6, and NF-kappaB, both at the mRNA and protein levels (P < 0.01). TLR4 signaling pathway is thus actively involved in Abeta-induced neuroinflammation and atorvastatin treatment can exert the therapeutic benefits for AD via the TLR4 signaling pathway. PMID- 29417449 TI - Varying acoustic-phonemic ambiguity reveals that talker normalization is obligatory in speech processing. AB - The nondeterministic relationship between speech acoustics and abstract phonemic representations imposes a challenge for listeners to maintain perceptual constancy despite the highly variable acoustic realization of speech. Talker normalization facilitates speech processing by reducing the degrees of freedom for mapping between encountered speech and phonemic representations. While this process has been proposed to facilitate the perception of ambiguous speech sounds, it is currently unknown whether talker normalization is affected by the degree of potential ambiguity in acoustic-phonemic mapping. We explored the effects of talker normalization on speech processing in a series of speeded classification paradigms, parametrically manipulating the potential for inconsistent acoustic-phonemic relationships across talkers for both consonants and vowels. Listeners identified words with varying potential acoustic-phonemic ambiguity across talkers (e.g., beet/boat vs. boot/boat) spoken by single or mixed talkers. Auditory categorization of words was always slower when listening to mixed talkers compared to a single talker, even when there was no potential acoustic ambiguity between target sounds. Moreover, the processing cost imposed by mixed talkers was greatest when words had the most potential acoustic-phonemic overlap across talkers. Models of acoustic dissimilarity between target speech sounds did not account for the pattern of results. These results suggest (a) that talker normalization incurs the greatest processing cost when disambiguating highly confusable sounds and (b) that talker normalization appears to be an obligatory component of speech perception, taking place even when the acoustic phonemic relationships across sounds are unambiguous. PMID- 29417451 TI - Interactions of Climate Change, Air Pollution, and Human Health. AB - PURPOSE OF REVIEW: I review literature on the impacts of climate change on air quality and human health, with a focus on articles published from 2013 on ozone and airborne particles. Selected previous literature is discussed where relevant in tracing the origins of our current knowledge. RECENT FINDINGS: Climate and weather have strong influences on the spatial and temporal distribution of air pollution concentrations. Emissions of ozone and PM2.5 precursors increase at higher ambient temperatures. The reactions that form ozone occur faster with greater sunlight and higher temperatures. Weather systems influence the movement and dispersion of air pollutants in the atmosphere through the action of winds, vertical mixing, and precipitation, all of which are likely to alter in a changing climate. Recent studies indicate that, holding anthropogenic air pollution emissions constant, ozone concentrations in populated regions will tend to increase in future climate scenarios. For the USA, the climate impact on ozone is most consistently seen in north-central and north-eastern states, with the potential for many thousands of additional ozone-related deaths. The sensitivity of anthropogenic PM2.5 to climate is more variable across studies and regions, owing to the varied nature of PM constituents, as well as to less complete characterization of PM reaction chemistry in available atmospheric models. However, PM emitted by wildland fires is likely to become an increasing health risk in many parts of the world as climate continues to change. The complex interactions between climate change and air quality imply that future policies to mitigate these twin challenges will benefit from greater coordination. Assessing the health implications of alternative policy approaches towards climate and pollution mitigation will be a critical area of future work. PMID- 29417450 TI - Zebrafish as a Model for Toxicological Perturbation of Yolk and Nutrition in the Early Embryo. AB - PURPOSE OF REVIEW: Developmental toxicity assessments often focus on structural outcomes and overlook subtle metabolic differences which occur during the early embryonic period. Deviant embryonic nutrition can result in later-life disease, including diabetes, obesity, and cardiovascular disease. Prior to placenta mediated nutrient exchange, the human embryo requires maternally supplied nutritional substrates for growth, called yolk. Here, we compare the biology of the human and zebrafish yolk and review examples of toxicant-mediated perturbation of yolk defects, composition, and utilization. RECENT FINDINGS: Zebrafish embryos, like human embryos, have a protruding yolk sac that serves as a nutritional cache. Aberrant yolk morphology is a common qualitative finding in fish embryotoxicity studies, but quantitative assessment and characterization provides an opportunity to uncover mechanistic targets of toxicant effects on embryonic nutrition. The zebrafish and the study of its yolk sac is an excellent model for uncovering toxicant disruptions to early embryonic nutrition and has potential to discover mechanistic insights into the developmental origins of health and disease. PMID- 29417452 TI - Unfamiliar Accented English Negatively Affects EFL Listening Comprehension: It Helps to be a More Able Accent Mimic. AB - In this study, EFL learners who listened to four short context-rich audio files each delivered in an unfamiliar English accent were required to produce best attempt transcriptions and accent imitation recordings. Results indicate that exposure alone does not suffice to eliminate accent impact on EFL listeners. Importantly, results from one-way ANOVA analyses reveal between-participants differences in residual accent impact, vocabulary knowledge, and quality of accent imitation. Results from a linear mixed-effects model analysis, while suggesting that other unidentified factors may also assist EFL listeners in processing unfamiliar accented English, demonstrate that the more able mimics cope more successfully with unfamiliar accents than the less able mimics. Counter intuitively, vocabulary knowledge is rejected as a predictor for success in reducing accent impact. A logical explanation for this particular finding is that a larger vocabulary repertoire aids listeners where there is no interference from unfamiliar accents. Given these findings, to better prepare EFL listeners for the English-as-an-International-Language world, training should include both listening to a variety of native and non-native accents and performing accent imitation (reproduction) exercises to further expand listeners' phonological phonetic flexibility. PMID- 29417453 TI - Non-Selective Lexical Access in Late Arabic-English Bilinguals: Evidence from Gating. AB - Previous research suggests that late bilinguals who speak typologically distant languages are the least likely to show evidence of non-selective lexical access processes. This study puts this claim to test by using the gating task to determine whether words beginning with speech sounds that are phonetically similar in Arabic and English (e.g., [b,d,m,n]) give rise to selective or non selective lexical access processes in late Arabic-English bilinguals. The results show that an acoustic-phonetic input (e.g., [bae]) that is consistent with words in Arabic (e.g., [baedrun] "moon") and English (e.g., [baed] "bad") activates lexical representations in both languages of the bilingual. This non-selective activation holds equally well for mixed lists with words from both Arabic and English and blocked lists consisting only of Arabic or English words. These results suggest that non-selective lexical access processes are the default mechanism even in late bilinguals of typologically distant languages. PMID- 29417454 TI - Autoregressive Generalized Linear Mixed Effect Models with Crossed Random Effects: An Application to Intensive Binary Time Series Eye-Tracking Data. AB - As a method to ascertain person and item effects in psycholinguistics, a generalized linear mixed effect model (GLMM) with crossed random effects has met limitations in handing serial dependence across persons and items. This paper presents an autoregressive GLMM with crossed random effects that accounts for variability in lag effects across persons and items. The model is shown to be applicable to intensive binary time series eye-tracking data when researchers are interested in detecting experimental condition effects while controlling for previous responses. In addition, a simulation study shows that ignoring lag effects can lead to biased estimates and underestimated standard errors for the experimental condition effects. PMID- 29417455 TI - A Review of Photodynamic Therapy for Neoplasms of the Head and Neck. AB - Photodynamic therapy (PDT) involves the use of a phototoxic drug which is activated by low powered laser light to destroy neoplastic cells. Multiple photosensitizers have been studied and tumors have been treated in a variety of head and neck sites over the last 30 years. PDT can effectively treat head and neck tumors, particularly those of the superficial spreading type, and the classic application of this technology has been in the patient with a wide field of dysplastic change and superficial carcinomatosis. Interstitial treatment has been used to treat more invasive cancer. Data is available from case series and institutional experiences, but very little randomized data is available. We review the mechanisms of action, historical development, available data, and current knowledge regarding PDT for the various head and neck subsites, and discuss possible future directions, with an emphasis on clinical application. PMID- 29417456 TI - BCGosis in Infants with Severe Combined ImmunoDeficiency (SCID). PMID- 29417457 TI - Clinical Outcome at One Year of Age Following Device Closure of Patent Ductus Arteriosus (PDA) in Small Babies. PMID- 29417458 TI - Human Milk Banking and Challenges in Quality Control. PMID- 29417459 TI - Streptococcus pneumoniae-associated Hemolytic Uremic Syndrome. PMID- 29417460 TI - Outcome of Early Stage Pediatric Non-Lymphoblastic Non-Hodgkin Lymphoma. AB - There is lack of data on outcome of limited stage pediatric non-Hodgkin lymphoma (NHL) from south Asia. In view of this lacuna, authors evaluated patients of early stage (stage 1 and 2) non-lymphoblastic pediatric NHL patients treated with uniform short course, reduced-intensity protocol from Jan 2003 through Dec 2016. Of the total 280 subjects with pediatric NHL, 50 were of early stage of which 42 received uniform protocol. B-cell subtype was observed in 83% patients. Event free-survival (EFS) and overall-survival (OS) were 85% and 90% respectively at 5 y (median-not reached). Age > 13 y emerged as the only poor risk factor for EFS (p = 0.05) on univariate analysis and same had a trend toward inferior prognosis in OS (p = 0.09). Vincristine-induced neuropathy occurred in five patients. Febrile neutropenia was observed in 16% subjects with one patient requiring hospitalization. There was no treatment-related death. This largest data of limited stage pediatric non-lymphoblastic NHL from south Asia highlights that good outcomes may be achieved with less intense short course therapy without hospitalization, and that adolescent age is the only poor prognostic factor for outcome. PMID- 29417461 TI - Individualizing PSA Monitoring Among Older Prostate Cancer Survivors. PMID- 29417462 TI - Chronic Hepatitis C in Elderly Patients: Current Evidence with Direct-Acting Antivirals. AB - Since the introduction of direct-acting antivirals (DAAs), the outcomes of hepatitis C (HCV) treatment have shown an improvement in cure rates with minimal side effects. However, to date, the safety and efficacy of DAAs have not been specifically examined in elderly patients. The treatment of HCV in the era of pegylated interferon and ribavirin was more challenging among elderly patients due to the increased prevalence of multiple comorbid conditions associated with an increased risk of side effects, including anemia, and high rates of discontinuation, likely as a result of poor tolerability, resulting in lower rates of sustained virologic response (SVR). The advent of highly efficacious all oral DAA agents with minimal adverse events has provided more data on the outcomes of treatment in the elderly population. The current evidence shows that DAA agents have been effective and safe in the elderly population, with comparable rates of SVR. The aim of this article was to review the safety and efficacy of commonly prescribed DAA agents in the management of chronic HCV in the elderly population. PMID- 29417463 TI - Drug Interchangeability of Generic and Brand Products of Fixed Dose Combination Tablets of Sofosbuvir and Ledipasvir (400/90 mg): Employment of Reference Scaled Average Bioequivalence Study on Healthy Egyptian Volunteers. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to apply the reference scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence and to investigate the pharmacokinetic properties of two formulations of fixed dose combination (FDC) tablet of sofosbuvir (SOF) and ledipasvir (LED) (400/90 mg) in 36 healthy Egyptian volunteers. METHODS: The study was performed in single-dose, randomized-sequence, open-label, reference-replicated, 3-period crossover design (RTR, TRR, RRT), with a washout period of 2 weeks. A rapid and simple LC-MS/MS method was developed and validated for the simultaneous estimation of SOF and LED using eplerenone as an internal standard (IS). RESULTS: The results showed that the 90% confidence intervals (CIs) for natural log-transformed ratios of Cmax, AUClast and AUCinfinity of SOF (89.95-115.31, 98.77-109.75 and 98.79-109.75) were within the RSABE acceptance limits. The 90% CIs for natural log-transformed ratios of Cmax and AUClast of LED (87.33-115.15 and 83.82-112.26) were within the FDA bioequivalence limits (80.00-125.00). In addition, the in vitro dissolution study was done and both formulations released > 85% of drug within 15 min in the proposed dissolution medium. CONCLUSIONS: In conclusion, bioequivalence between the two fixed-dose combination products was demonstrated for both active ingredients. PMID- 29417464 TI - Cost Effectiveness of Daclatasvir Plus Asunaprevir Therapy for Chinese Patients with Chronic Hepatitis C Virus Genotype 1b. AB - BACKGROUND AND OBJECTIVES: Daclatasvir plus asunaprevir has shown superior efficacy and safety for treating hepatitis C virus genotype 1b infection in comparison with pegylated interferon and ribavirin. The objective of this analysis is to investigate the cost effectiveness of daclatasvir plus asunaprevir compared with interferon-alpha-based therapies from the perspective of the Chinese healthcare system. METHODS: A Markov model was established to measure economic and health outcomes of daclatasvir plus asunaprevir compared with general interferon-alpha plus ribavirin and pegylated interferon plus ribavirin for hepatitis C virus genotype 1b infection. We also considered the two following scenarios: 24 weeks of daclatasvir plus asunaprevir used as a second-line treatment for ineligible/intolerant and non-responding patients with HCV during 48 weeks of first-line interferon-alpha plus ribavirin (interferon-alpha plus ribavirin and daclatasvir plus asunaprevir) or pegylated interferon plus ribavirin (pegylated interferon plus ribavirin and daclatasvir plus asunaprevir) treatment. Clinical costs and utility inputs were derived from the published literature. The incremental cost-effectiveness ratio was shown as costs in US dollars per quality-adjusted life-years gained. Uncertainty was examined by one way and probabilistic sensitivity analyses. RESULTS: Compared with interferon alpha plus ribavirin, pegylated interferon and ribavirin, interferon-alpha plus ribavirin plus daclatasvir plus asunaprevir, and pegylated interferon plus ribavirin plus daclatasvir plus asunaprevir strategies, daclatasvir plus asunaprevir gained an additional 0.62, 0.32, 0.20, and 0.15 quality-adjusted life year with increasing costs of US$11,950, US$671, US$8366, and -$3783, respectively. The incremental cost-effectiveness ratios of pegylated interferon and ribavirin, daclatasvir plus asunaprevir, interferon-alpha plus ribavirin and daclatasvir plus asunaprevir, and pegylated interferon plus ribavirin and daclatasvir plus asunaprevir against the baseline interferon-alpha plus ribavirin strategy were US$37,930, US$19,233, US$8495, and US$33,031 per quality-adjusted life-year gained. Daclatasvir plus asunaprevir and interferon-alpha plus ribavirin plus daclatasvir plus asunaprevir were presented as the cost-effective alternatives, and pegylated interferon plus ribavirin and pegylated interferon plus ribavirin and daclatasvir plus asunaprevir strategies dominated. The model outputs were sensitive to a patient's age, discount rate, and the risk ratio between pegylated interferon plus ribavirin and interferon-alpha plus ribavirin. CONCLUSIONS: Daclatasvir plus asunaprevir in the Chinese setting is likely to be cost effective for treating hepatitis C virus genotype 1b infection. PMID- 29417465 TI - Reply to comments: duration of antimicrobial therapy for Gram-negative bacteremia secondary to urinary source of infection. PMID- 29417466 TI - Lanostane triterpenoids from Fomitopsis officinalis and their trypanocidal activity. AB - Fomitopsis officinalis is a medicinal fungus, known as 'Agarikon', and is used traditionally in the treatment of asthma and rheumatism in Mongolia. The investigation of the chemical constituents of F. officinalis led to the isolation of 4 new lanostane triterpenoids together with 4 known triterpenoids. Inhibitory activity against Trypanosoma congolense, which causes fatal diseases in animals including livestock, was estimated for the isolated compounds. Compounds 2-5 and 8 exhibited moderate inhibition activities with IC50 values ranging from 7.0-27.1 uM. PMID- 29417467 TI - Pulmonary Vascular Disease: Hemodynamic Assessment and Treatment Selection-Focus on Group II Pulmonary Hypertension. AB - PURPOSE OF REVIEW: Pulmonary hypertension due to left heart disease (PH-LHD) is the most common cause of pulmonary hypertension worldwide, yet therapies used to treat pulmonary arterial hypertension have failed to show efficacy in this population. Proper hemodynamic assessment and differentiation of pulmonary hypertension phenotypes is therefore critical for both current clinical practice and future research and therapeutic efforts. RECENT FINDINGS: Substantial recent efforts have sought to improve the hemodynamic characterization of pulmonary hypertension for both diagnostic and prognostic purposes. These efforts include identifying occult LHD using provocative maneuvers as well as sub-classifying PH LHD based on the presence or absence of a pre-capillary component. How to best define the pre-capillary component remains controversial as several studies have drawn conflicting conclusions. The lack of standardization of hemodynamic measurements as well as measurement fidelity concerns may explain some of the discrepant results. Non-hemodynamic methods of PH-LHD classification may also have an emerging role. Despite recent advances, therapeutic studies have largely remained disappointing. In this review, we discuss the nuances and controversies surrounding diagnostic and prognostic hemodynamic characterization of PH-LHD as well as summarize the recent therapeutic efforts and ongoing challenges in this population. PMID- 29417468 TI - Antibody response of growing German Holstein bulls to a vaccination against bovine viral diarrhea virus (BVDV) is influenced by Fusarium toxin exposure in a non-linear fashion. AB - The Fusarium toxin deoxynivalenol (DON) is a frequent contaminant of feedstuffs and is supposed to interfere with immune responses. As the relevance for growing bulls is less clear than for other livestock, the trial was designed according to the dose-response principal with a control group fed a diet with background contamination (CON, 0.36 mg DON per kilogram dry matter [DM]) and three groups with increasing concentrations of DON (mg/kg DM); FUS I, 3.01; FUS II, 5.66; FUS III, 8.31. Half of each treatment group was vaccinated against BVDV at days 1 and 21 of the 70 days lasting experiment. Sequential blood samples were collected for determination of antibody titers to BVDV and for hematological and clinical chemical traits. Antibody response was strongest in group FUS II while group FUS III responded weakest. This group showed the lowest proportion of CD4+ T cells, but also the highest levels of liver lesion indicating enzyme activities in blood. BVDV-vaccination induced a pronounced decrease in red blood count indices, which occurred dose-dependently at a higher level in the FUS-fed groups. The obvious interactions between DON exposure and BVDV-vaccination require further elucidation. PMID- 29417469 TI - Association between systemic leptin and neurotensin concentration in adult individuals with and without type 2 diabetes mellitus. AB - PURPOSE: Leptin is an adipokine which regulates appetite and energy balance through a mechanism partially mediated by neurotensin (NT) in central nervous system. Besides acting as a neurotransmitter, NT is expressed in human intestine where it promotes fat absorption and its circulating levels associate with obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Whether a relation exists between circulating leptin and NT levels has not been investigated yet. The aim of this study was to test the hypothesis of an association between plasma leptin and NT concentration in adults with or without T2DM. METHODS: We recruited a population of 72 subjects (M/F: 39/33; age: 49.5 +/ 10.6 years; BMI: 26.5 +/- 4.7 kg/m2) including individuals with T2DM (n = 32) referring to our Diabetes Outpatient Clinics, Sapienza University of Rome, and healthy controls. Study participants underwent metabolic characterization; plasma leptin was measured by MILLIPLEX, Luminex, and proneurotensin (proNT), a stable precursor of NT, by chemiluminometric sandwich immunoassay. RESULTS: Circulating median (25 degrees -75 degrees ) leptin levels were 2.75 (1.27-4.93) ng/mL and did not differ between T2DM and non-diabetic subjects. Leptin concentration directly correlated with proNT (r = 0.41; p = 0.015); higher leptin levels were also associated with age, male gender, obesity, higher HOMA-IR, systolic blood pressure and C-reactive protein. Belonging to the highest pro-NT quartile correlated with greater leptin levels independent of age, gender and other confounders (r2 = 0.82, p = 0.02). CONCLUSIONS: Circulating leptin is associated with higher proNT levels independent of diabetes, obesity and metabolic syndrome components; besides its effects on central leptin signaling, NT may influence energy balance by modulating circulating leptin concentration likely through a mechanism involving gut fat absorption. PMID- 29417470 TI - Involvement of Ventral Periaqueductal Gray Dopaminergic Neurons in Propofol Anesthesia. AB - : It has been reported that central dopaminergic system is implicated in the mechanism underlying general anesthesia. Whether dopamine (DA) neurons in midbrain ventral periaqueductal gray (vPAG) are involved in general anesthesia and how general anesthetics affect these neurons remain sparsely documented. To determine the role of vPAG DA neurons in propofol-induced anesthesia, we performed microinjection of 6-hydroxydopamine (6-OHDA) into vPAG to damage DA neurons and investigated the alteration in somatosensory electroencephalogram (EEG), as well as the induction and recovery time of propofol anesthesia. Subsequently, we examined the effect of propofol on the electrophysiological activity of DA neurons in vPAG using whole-cell patch clamp. Two weeks after 6 OHDA microinfusion, DA neurons in the vPAG were markedly reduced by 63.6% in the 6-OHDA-treated rats compared with vehicle rats. This lesion significantly shortened the induction time (7.15 +/- 3.97 s vs. 11.18 +/- 2.83 s, P < 0.05) and prolonged the recovery time of propofol anesthesia (780.26 +/- 150.86 s vs. 590.68 +/- 107.97 s, P < 0.05). Meanwhile, EEG in somatosensory cortex revealed that delta power (0-4 Hz) was significantly higher in 6-OHDA-treated rats than vehicle rats. In the electrophysiological experiment, propofol decreased the frequency of spontaneous excitatory postsynaptic currents rather than the amplitude and decay time. In addition, propofol preferentially increased the frequency and prolonged the decay time of spontaneous inhibitory postsynaptic currents without affecting the amplitude. SIGNIFICANCE: Propofol can promote presynaptic GABA release, inhibit presynaptic glutamate release and increase postsynaptic GABAA receptor sensitivity, which eventually inhibits the activity of vPAG DA neurons and thereby influences the state of consciousness. PMID- 29417471 TI - Neuroprotective Effects of Phenolic and Carboxylic Acids on Oxidative Stress Induced Toxicity in Human Neuroblastoma SH-SY5Y Cells. AB - An increase in oxidative stress is a key factor responsible for neurotoxicity induction and cell death leading to neurodegenerative diseases including Parkinson's and Alzheimer's diseases. Plant phenolics exert diverse bioactivities i.e., antioxidant, anti-inflammatory, and neuroprotective effects. Herein, phenolic compounds, namely protocatechuic aldehyde (PCA) constituents of Hydnophytum formicarum Jack. including vanillic acid (VA) and trans-ferulic acid (FA) found in Spilanthes acmella Murr., were explored for anti-neurodegenerative properties using an in vitro model of oxidative stress-induced neuroblastoma SH SY5Y cells. Exposure of the neuronal cells with H2O2 resulted in the decrease of cell viability, but increasing in the level of reactive oxygen species (ROS) together with morphological changes and inducing cellular apoptosis. SH-SY5Y cells pretreated with 5 uM of PCA, VA, and FA were able to attenuate cell death caused by H2O2-induced toxicity, as well as decreased ROS level and apoptotic cells after 24 h of treatment. Pretreated SH-SY5Y cells with phenolic compounds also helped to upregulate H2O2-induced depletion of the expressions of sirtuin-1 (SIRT1) and forkhead box O (FoxO) 3a as well as induce the levels of antioxidant (superoxide dismutase (SOD) 2 and catalase) and antiapoptotic B-cell lymphoma 2 (Bcl-2) proteins. The findings suggest that these phenolics might be promising compounds against neurodegeneration. PMID- 29417472 TI - Gastrodin Suppresses Pentylenetetrazole-Induced Seizures Progression by Modulating Oxidative Stress in Zebrafish. AB - Pentylenetetrazole (PTZ)-induced seizures in Zebrafish models are now widely accepted for investigating human disease epilepsy. In epilepsy, the generation of oxidative stress contributes to the brain injury. Although Gastrodin (GAS) has been reported to have anticonvulsant activities, its effects on zebrafish seizure models and the underlying mechanism remain unclear. In this study, we evaluated the effects of GAS pretreatment on PTZ-induced seizures in zebrafish larvae and investigated the underlying mechanism related to its anti-oxidative defense. We found for the first time that GAS significantly decreased seizure-like behavior and extended the latency period to the onset of seizures. In addition, after exposure to GAS, anti-oxidative activity was observed in PTZ-induced seizures by measurement of antioxidant enzymes activities and oxidative stress-related genes expression. The overall results indicate that GAS attenuates PTZ-induced seizures in a concentration-dependent manner and modulates oxidative stress to potentially protect larval zebrafish from further seizures. Furthermore, our results have provided novel insights into GAS related therapy of seizures and associated neurological disorders. PMID- 29417474 TI - The Impact of Fellowship in Dietetics on Clinical Practice. AB - Medical nutrition therapy (MNT) in pediatric cancer treatment is essential. The Nutrition Department and the International Outreach Program at St. Jude Children's Research Hospital in Memphis, TN have worked together from 2005 to 2013 to develop and implement a training program for international dietitians working with pediatric oncology patients. During that time, St. Jude hosted 15 dietitians from various countries for this 3-week-long program. The curriculum provided experience in nutrition risk screening, nutrition care process, nutrition for cancer prevention, palliative care, and exposure to nutrition support. Monthly online meetings were established through the Cure4Kids website to continue collaboration and training. Learning outcomes were developed, and the impact of the program was evaluated based on changes made by former fellows in clinical practice, research, management, and food service upon return to their country. In addition, the program was evaluated based on recognition by the medical team, professional growth/networking, and personal growth. The survey return rate was 100%: responses revealed that 80% of participants continued working in pediatric oncology, 67% participated in monthly meetings, 47% collaborated on research, 100% advanced their competency in clinical practice, 93% broadened their competency in research, 67% became increasingly competent in management, 60% implemented changes in food service, 100% were recognized for participating in the program, and 100 and 93% noted that participation in the fellowship program helped their professional and personal growth, respectively. The psychological impact of the training on healthcare providers was as important as the impact of the program on patient care. PMID- 29417475 TI - Enterocin M and its Beneficial Effects in Horses-a Pilot Experiment. AB - Probiotic bacteria or their antimicrobial proteinaceous substances called bacteriocins (enterocins) hold promising prophylactic potential for animal breeding. This study present the results achieved after application of Enterocin M in horses. Enterocin M has never been applied to horses before. Clinically healthy horses (10) were involved in this pilot experiment. They were placed in the stables of the University of Veterinary Medicine and Pharmacy, Kosice, Slovakia, with the approval of the University Ethics Committee. The animals were fed twice a day with hay and oats, or alternatively grazed with access to water ad libitum. The experiment lasted 6 weeks. Sampling was performed at the start of the experiment, at day 0-1, at day 21 (3 weeks of Enterocin M application), and at day 42 (3 weeks of cessation). Feces were sampled directly from the rectum and blood from the vena jugularis; the samples were immediately treated and/or stored for analyses. Each horse itself represented a control animal (compared to its status at the start of the experiment, day 0-1). After initial sampling, the horses were administered 100 MUl of Ent M (precipitate, 12,800 AU/ml) in a small feed bolus to ensure it was consumed; Ent M was applied for 3 weeks (21 days). Fecal samples were treated using the standard microbial dilution method; phagocytic activity was assessed with standard and flow cytometry; biochemistry and metabolic profiles were tested using commercial kits and standard methods. Administration of Ent M led to mathematical reduction of coliforms, campylobacters (abP < 0.05), and significant reduction of Clostridium spp. (abP < 0.001, bcP < 0.001); increase of PA values was noted (P < 0.05, P < 0.0001); no negative influence on hydrolytic enzyme profile or biochemical blood parameters was noted. PMID- 29417473 TI - Impact of Coffee and Cacao Purine Metabolites on Neuroplasticity and Neurodegenerative Disease. AB - Increasing evidence suggests that regular consumption of coffee, tea and dark chocolate (cacao) can promote brain health and may reduce the risk of age-related neurodegenerative disorders. However, the complex array of phytochemicals in coffee and cacao beans and tea leaves has hindered a clear understanding of the component(s) that affect neuronal plasticity and resilience. One class of phytochemicals present in relatively high amounts in coffee, tea and cacao are methylxanthines. Among such methylxanthines, caffeine has been the most widely studied and has clear effects on neuronal network activity, promotes sustained cognitive performance and can protect neurons against dysfunction and death in animal models of stroke, Alzheimer's disease and Parkinson's disease. Caffeine's mechanism of action relies on antagonism of various subclasses of adenosine receptors. Downstream xanthine metabolites, such as theobromine and theophylline, may also contribute to the beneficial effects of coffee, tea and cacao on brain health. PMID- 29417476 TI - Qi Fu Yin-a Ming Dynasty Prescription for the Treatment of Dementia. AB - The Traditional Chinese Medicine (TCM) theory that "kidneys give rise to marrow, and the brain is the sea of marrow" has been a guide for the clinical application of kidney, qi and blood tonics for prevention and treatment of dementia and improvement in memory. As low resistance end-organs, both the brain and the kidneys are subjected to blood flow of high volumes throughout the cardiac cycle. Alzheimer's disease and vascular dementia are two common causes of dementia, and it is increasingly recognized that many older adults with dementia have both AD and vascular pathologies. The underlying molecular mechanisms are incompletely understood, but may involve atherosclerosis, vascular dysfunction, hypertension, type 2 diabetes, history of cardiac disease and possibly, kidney dysfuntion, leading to reduced erythropoietin production, anemia, brain energy deficit and slow excitotoxicity. During the Ming Dynasty, Zhang Jing-Yue used Qi Fu Yin (seven blessings decoction), comprising Panax ginseng, Rehmannia glutinosa, Angelica polymorpha, Atractylodes macrocephala, Glycyrrhiza uralensis, Ziziphus jujube, and Polygala tenuifolia to boost qi and blood circulation, strengthen the heart, and calm the spirit-skillfully linking heart, spleen, kidney, qi, blood and brain as a whole to treat age-related dementia. The purpose of this review is to outline TCM concepts for the treatment of dementia and illustrated with a historical prescription for the treatment of the condition, with the hope that this description may lead to advances in its management. PMID- 29417478 TI - Modeling the exposure time in a tidal system: the impacts of external domain, tidal range, and inflows. AB - Exposure time is an important characteristic for hydrodynamics that has simultaneous impacts on the biochemical processes in tidal systems. To eliminate man-made errors, decrease computational effort, and increase simulation efficiency, exposure time was evaluated under different hydrodynamic conditions for a bay to investigate the impact of the external domain on the accuracy of the computational results for exposure time. The exposure time was explicitly defined and computed using a hydrodynamic model and tracer experiments for a set of ten external domain sizes (EDS), five external domain lengths (EDL), and three special hydrodynamic conditions. The results indicated that the external domain had a significant influence on the exposure time, and the intensity of this influence was related to hydrodynamic conditions. The sensitivity of the exposure time to the external domain increased with increasing tidal range, while freshwater inflows decreased this sensitivity. However, the variation trends for exposure time with different EDS and EDL were independent of the hydrodynamic conditions. Considering the computational efficiency (maximum), the calculated error (minimum) of the exposure time, and the impact of the boundary conditions (minimum), the recommended EDS and EDL range from 9 to 13 times the initial domain size and 1.30 to 1.45 times the length in the bay, respectively. The research regarding exposure time and external domains not only helps to eliminate the errors caused by man-made factors and reduce the computational effort but also provides a reference for understanding the interrelationship between coastal waters, reciprocating flow, and the water environment. PMID- 29417477 TI - MicroRNA-34 Contributes to the Stress-related Behavior and Affects 5-HT Prefrontal/GABA Amygdalar System through Regulation of Corticotropin-releasing Factor Receptor 1. AB - Recent studies show that microRNA-34 (miR-34) family is critical in the regulation of stress response also suggesting that it may contribute to the individual responsiveness to stress. We have recently demonstrated that mice carrying a genetic deletion of all miR-34 isoforms (triple knockout, TKO) lack the stress-induced serotonin (5-HT) and GABA release in the medial prefrontal cortex (mpFC) and basolateral amygdala (BLA), respectively. Here, we evaluated if the absence of miR-34 was also able to modify the stress-coping strategy in the forced swimming test. We found that the blunted neurochemical response to stress was associated with lower levels of immobility (index of active coping behavior) in TKO compared to WT mice. Interestingly, among the brain regions mostly involved in the stress-related behaviors, the miR-34 displayed the strongest expression in the dorsal raphe nuclei (DRN) of wild-type (WT) mice. In the DRN, the corticotropin-releasing factor receptors (CRFR) 1 and 2, contribute to determine the stress-coping style and the CRFR1 is a target of miR-34. Thus, we hypothesized that the miR-34-dependent modulation of CRFR1 expression may be involved in the DRN regulation of stress-coping strategies. In line with this hypothesis, we found increased CRFR1 levels in the DNR of TKO compared to WT mice. Moreover, infusion of CRFR1 antagonist in the DRN of TKO mice reverted their behavioral and neurochemical phenotype. We propose that miR-34 modulate the mpFC 5-HT/BLA GABA response to stress acting on CRFR1 in the DRN and that this mechanism could contribute to determine individual stress-coping strategy. PMID- 29417479 TI - Association of urinary phthalate metabolites concentrations with body mass index and waist circumference. AB - This study aims to investigate the association of urinary concentration of phthalate metabolites with body mass index (BMI) and waist circumference (WC) in 2016 on 242 children and adolescents, aged 6-18 years living in Isfahan, Iran. Urinary concentration of mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), mono-2-ethylhexyl phthalate (MEHP), mono-methyl phthalate (MMP), mono (2 ethyl-5-exohexyl) phthalate (MEOHP), and mono (2-ethyl-5hydroxyhexyl) phthalate (MEHHP) metabolites were determined. For comparison of means, t test and to evaluate the association of analytes in different groups according to weight ANOVA was used. The correlation was applied to determine the association between phthalate metabolites with age, sex, WC, BMI, and BMI z-score. The univariate and multivariate regression models were used to determine the association of metabolites concentration with BMI z-score and WC. Mean (SD) BMI, BMI z-score and WC were 23.89 (4.41) kg/m2, 1.37 (1.3), and 82.37 (12.71) cm, respectively. There was a significant correlation between boys' age with BMI z-score (p value = 0.03) and WC (p value = 0.01), while the corresponding figures were not statistically significant in girls (p value = 0.48, and 0.4, respectively). Of the total population, 37 participants (15.3%) were obese. MMP, MBP, and MBzP metabolites were observed in all samples while MEHP, MEOHP, and MEHHP in 99.6, 95.86, and 96.28% of the studied population. Mean concentration of MMP (64.38 MUg/L) and MBzP (268 MUg/L) had the lowest and highest concentrations of metabolites, respectively. A significant relationship was observed among all studied metabolites and weight groups (p value <= 0.02). After adjustment for potential confounders, all metabolites (except MMP) showed a low-to-moderate positive and significant relationship with BMI z-score (beta = 0.17-0.3). A weak to moderate positive and significant relationship was observed between all phthalate metabolites and WC (beta = 0.14-0.39). The concentration of phthalate metabolites was much higher in the population living in Isfahan-Iran than in some other populations, indicating a high exposure to contaminants. Therefore, further studies and preventive measures are required for improving the environmental health. PMID- 29417480 TI - Cadmium and lead accumulations and agronomic quality of a newly bred pollution safe cultivar (PSC) of water spinach. AB - Breeding for pollution-safe cultivars (PSCs) can reduce pollutant accumulation in crops. However, the PSC breeding would face the risk of nutritional quality reduction, which is usually ignored in conventional breeding programs targeting to increase crop yield or nutritional quality. Thus, the doubt whether the risk would exist has to be clarified for supporting the PSC breeding. In the present study, a newly bred Cd/Pb-PSC of water spinach (Ipomoea aquatic Forsk.) and its parents (QLQ with low-Cd/Pb accumulation ability and T308 with high yield) of water spinach were employed to clarify the above-mentioned issue. Yields, and concentrations of Cd, Pb, nitrite, and organic and inorganic nutrients in shoots of the three experimental lines were determined. There were no significant differences in Cd/Pb concentration between the new PSC and QLQ, in nitrite content between the new PSC and its two parents and in yield between the new PSC and T308. It is decisively significant that shoot concentrations of organic and inorganic nutrients in the Cd/Pb-PSC were as high as those in one of its parents. It is affirmed that the breeding operations (crossing and consequently continuous selfing) for lowering Cd/Pb accumulation capacity of water spinach would not lower the nutritional values of the obtained Cd/Pb-PSCs from the breeding, which should be a pillar that supports the feasibility to minimize Cd/Pb pollution in vegetables using PSC-breeding method. PMID- 29417481 TI - Effect of planting density and harvest protocol on field-scale phytoremediation efficiency by Eucalyptus globulus. AB - The phytoremediation efficiency of multi-metal-polluted sites in an electronic waste recycling town by Eucalyptus globulus was evaluated through a series of 2 year field experiments. Different initial planting densities (2500, 5000, and 10,000 plants per ha), coppice rotations, and harvesting position (5 or 30 cm above the ground) protocols were designed to improve the remediation potential of the species. There were unnoticeable variations in metal concentrations and distribution characteristics in plant tissues in a low and medium planting density field during the experimental period. At the end of the experiment, total biomass production per hectare in different protocols displayed a wide range with maximum yield produced in high density, moderate harvesting, and coppice rotation protocol being 2.9 times higher than the minimum yield. The moderate harvest protocol performed with medium planting density was the optimal Cd and Cu decontamination technique. Although the high planting-density field without coppice rotation had the strongest potential for Pb decontamination, it would take more time to remove other metals for the multi-metal-polluted soil decontamination. Considering the remediation efficiency and maintainability of the cultivation system, the moderate harvest protocol performed with the medium planting density was commended for phytoremediation of e-waste recycling impacted area. PMID- 29417482 TI - Fullerene C60 for enhancing phytoremediation of urea plant wastewater by timber plants. AB - Phytoremediation has been applied as a promising and cost-effective technique for removing nutrient pollutants from wastewater. In this study, the effect of fullerene C60 was assessed on enhancing the phytoremediation efficiency of teak plants over a period of 1 month. Teak plants were supplied with fullerene C60 (0, 25, or 50 mg L-1) and fed daily with two types of urea plant wastewater (with and without adding optimum ratio of phosphorus and potassium). The required volume of wastewater by the teak plants, nitrogen removal percentage, plant growth parameters (plant height, number of leaves, leaf surface area, and dry biomass), and nutrient content was recorded throughout the study. The results showed that addition of 25 mg L-1 fullerene C60 to urea plant wastewater could increase water uptake and nitrogen recovery of the teak plants. Plant growth and nutrient contents of teak plants were also increased in the presence of 25 mg L-1 fullerene C60. However, addition of 50 mg L-1 fullerene C60 to the wastewater decreased the values for water uptake and nitrogen recovery. The findings indicated that addition of proper amount of fullerene C60 to the teak-based remediation system can increase the efficiency of the plants for nitrogen removal. PMID- 29417483 TI - Risk assessment of occupational exposure to benzene using numerical simulation in a complex geometry of a reforming unit of petroleum refinery. AB - There has been an increasing concern about the continuous and the sudden release of volatile organic pollutants from petroleum refineries and occupational and environmental exposures. Benzene is one of the most prevalent volatile compounds, and it has been addressed by many authors for its potential toxicity in occupational and environmental settings. Due to the complexities of sampling and analysis of benzene in routine and accidental situations, a reliable estimation of the benzene concentration in the outdoor setting of refinery using a computational fluid dynamics (CFD) could be instrumental for risk assessment of occupational exposure. In the present work, a computational fluid dynamic model was applied for exposure risk assessment with consideration of benzene being released continuously from a reforming unit of a refinery. For simulation of benzene dispersion, GAMBIT, FLUENT, and CFD post software are used as preprocessing, processing, and post-processing, respectively. Computational fluid dynamic validation was carried out by comparing the computed data with the experimental measurements. Eventually, chronic daily intake and lifetime cancer risk for routine operations through the two seasons of a year are estimated through the simulation model. Root mean square errors are 0.19 and 0.17 for wind speed and concentration, respectively. Lifetime risk assessments of workers are 0.4-3.8 and 0.0096-0.25 per 1000 workers in stable and unstable atmospheric conditions, respectively. Exposure risk is unacceptable for the head of shift work, chief engineer, and general workers in 141 days (38.77%) in a year. The results of this study show that computational fluid dynamics is a useful tool for modeling of benzene exposure in a complex geometry and can be used to estimate lifetime risks of occupation groups in a refinery setting. PMID- 29417484 TI - Health and environmental risks associated with emerging pollutants and novel green processes. PMID- 29417485 TI - "Upper Gastrointestinal Endoscopy Prior to Bariatric Surgery. Mandatory or Expendable? An Analysis of 801 Cases". PMID- 29417486 TI - The Change in the Percent of Android and Gynoid Fat Mass Correlated with Increased Testosterone After Laparoscopic Sleeve Gastrectomy in Chinese Obese Men: a 6-Month Follow-Up. AB - OBJECTIVE: The study was designed to examine changes of body fat distribution after laparoscopic sleeve gastrectomy (LSG) in obese male patients and to confirm whether these changes are correlated with increased testosterone. METHODS: A total of 30 obese male patients with body mass index (BMI) 30-45 kg/m2 were enrolled in this study. Data on demographic characteristics, anthropometry, metabolic parameters, and body fat distribution were collected at baseline and 6 months after LSG. Body fat distribution was assessed by dual-energy X-ray absorptiometry (DXA). RESULTS: Six months after surgery, the BMI of participants (age 33.0 +/- 9.5) decreased from 40.2 +/- 5.2 to 30.8 +/- 4.4 kg/m2, total testosterone increased from 2.4 +/- 1.2 to 4.5 +/- 1.8 ng/mL, and the percentage of testosterone deficiency in these patients decreased from 82.7 to 23.1%. Fat mass was significantly decreased in all regions, but the loss of fat mass in the android region was more than that in any other body region. After adjusting age and the BMI, the changes in android FM% and gynoid FM% were significantly correlated with an increase in total testosterone concentration (R2 = 0.187, R2 = 0.282, respectively). CONCLUSION: In obese male patients with BMI 30-45 kg/m2, an increase of total testosterone correlated to the changes in android FM% and gynoid FM% at the sixth month after LSG surgery. PMID- 29417487 TI - Perioperative Outcomes of Laparoscopic and Robotic Revisional Bariatric Surgery in a Complex Patient Population. AB - BACKGROUND: Utilization of the robotic platform has become more common in bariatric applications. We aim to show that robotic revisional bariatric surgery (RRBS) can be safely performed in a complex patient population with perioperative outcomes equivalent to laparoscopic revisional bariatric surgery (LRBS). METHODS: Retrospective review was conducted of adult patients undergoing laparoscopic revisional bariatric surgery (LRBS) or robotic revisional bariatric surgery (RRBS) at our institution from September 2007 to December 2016. Patients undergoing planned two-stage bariatric procedures were excluded. RESULTS: A total of 84 patients who underwent LRBS (n = 66) or RRBS (n = 18) were included. The index operation was adjustable gastric banding (AGB) in 39/84 (46%), sleeve gastrectomy (VSG) in 23/84 (27%), Roux-en-Y gastric bypass (RYGB) in 13/84 (16%), and vertical banded gastroplasty (VBG) in 9/84 (11%). For patients undergoing conversion from AGB (n = 39), there was no difference in operative time, length of stay, or complications by surgical approach. For patients undergoing conversion from a stapled procedure (n = 45), the robotic approach was associated with a shorter length of stay (5.8 +/- 3.3 vs 3.7 +/- 1.7 days, p = 0.04) with equivalent operative time and post-operative complications. There were three leaks in the LRBS group and none in the RRBS group (p = 0.36). Major complications occurred in 3/39 (8%) of patients undergoing conversion from AGB and 2/45 (4%) of patients undergoing conversion from a stapled procedure (p = 0.53) with no difference by surgical approach. CONCLUSIONS: RRBS is associated with a shorter length of stay than LRBS in complex procedures and has at least an equivalent safety profile. Long-term follow-up data is needed. PMID- 29417488 TI - Trends in Early Morbidity and Mortality after Sleeve Gastrectomy in Patients over 60 Years : Retrospective Review and Data Analysis of the German Bariatric Surgery Registry. AB - BACKGROUND: The population are getting older and obesity is growing. Laparoscopic sleeve gastrectomy (LSG) is increasingly used worldwide but is still used with skepticism in the elderly. The purpose of our analysis is to judge the security of LSG in patients older than 60 years compared to patients younger than 60 years. METHODS: This retrospective review included data of all patients in Germany who underwent LSG between January 2005 and December 2016.The data were published online in the German Bariatric Surgery Registry. A total of 21,571 operations were gathered and divided into two groups: group I, patients < 60 years old; and group II, patients >= 60 years old. RESULTS: The total number of patients and the mean body mass index of group I and group II was 19,786, 51.7 +/ 9.5 kg/m2 and 1771, 49.2 +/- 8.1 kg/m2, respectively. Regarding comorbidities, group II suffered statistically significantly more comorbidities than group I (p < 0.001). The general postoperative complications were 4.9% in group I and 7.8% in group II (p < 0.001). There was no significant difference in special postoperative complications (p = 0.048) and a slightly higher intraoperative complication rate in group II (2.2% vs. 1.6%, p = 0.048). Thirty-day mortality rate for group I versus II was 0.22% and 0.23% (p = 0.977), respectively. CONCLUSIONS: LSG is a low-risk operation and safe surgical method with acceptable, not elevated perioperative morbidity and mortality rates in patients >= 60 years of age. PMID- 29417489 TI - Problematic Eating Behaviors Predict Outcomes After Bariatric Surgery. AB - BACKGROUND: There are no clear psychosocial predictors of weight loss following bariatric surgery. The purpose of this study was to investigate whether preoperative problematic eating behaviors predict weight loss outcomes following bariatric surgery. METHODS: Clinical records were utilized to examine outcomes of 101 patients who completed a pre-surgical psychosocial evaluation and underwent gastric bypass or sleeve gastrectomy. Information analyzed included binge eating history and scores from the Hospital Anxiety and Depression Scale, Yale Food Addiction Scale, and Emotional Eating Scale. Measures of weight loss 1 year post surgery were compared to pre-surgical assessments. RESULTS: One-year follow-up data were available for 60 patients. Patients with higher levels of eating in response to anger/frustration (p = .02), anxiety (p = .01), or depression (p = .05) were more likely to miss the 1-year follow-up appointment. Eating in response to anger/frustration and depression were related to poorer weight loss outcomes. There was a trend for binge eating to predict greater %EWL (p = .06). A higher number of food addiction symptoms increased the likelihood that patients would experience less weight loss (p = .01). Psychiatric symptoms were not related to weight loss outcomes. CONCLUSIONS: Patients who endorsed higher levels of pre-surgical emotional eating and food addiction symptoms had poorer weight loss 1 year post-surgery. Providers should consider screening patients for these behaviors during the pre-surgical psychosocial evaluation which would allow opportunities for psychotherapy and potential improvement in weight loss outcomes. Future research should examine which interventions are successful at improving problematic eating behaviors. PMID- 29417490 TI - Motor and extra-motor gray matter integrity may underlie neurophysiologic parameters of motor function in amyotrophic lateral sclerosis: a combined voxel based morphometry and transcranial stimulation study. AB - The association between gray matter (GM) density and neurophysiologic changes is still unclear in amyotrophic lateral sclerosis (ALS). We evaluated the relationship between GM density and motor system integrity combining voxel-based morphometry (VBM) and transcranial magnetic stimulation (TMS) in ALS. We included 17 ALS patients and 22 healthy controls (HC) who underwent 3D-T1-weighted imaging. Among the ALS group, we applied left motor cortex single-pulse TMS. We used whole-brain VBM comparing ALS and HC in GM density. We also conducted regression analysis to examine correlations between GM density and the following TMS parameters: motor evoked potential (MEP)/M ratio and central motor conduction time (CMCT). We found significantly decreased GM density in ALS patients in several frontal, temporal, parietal/occipital and cerebellar regions (p < 0.001 uncorrected; cluster-extent threshold k = 100 voxels per cluster). With regards to TMS parameters, ALS patients showed mostly increased MEP/M ratio and modest prolongation of CMCT. MEP/M ratio was associated with GM density in (a) rolandic operculum/inferior frontal gyrus/precentral gyrus; anterior cingulate gyrus; inferior temporal gyrus; superior parietal lobule; cuneus; superior occipital gyrus and cerebellum (positive association) and (b) paracentral lobule/supplementary motor area (negative association). CMCT was associated with GM density in (a) inferior frontal gyrus and middle cingulated gyrus (positive association) and (b) superior parietal lobule; cuneus and cerebellum (negative association). Our findings support a significant interaction between motor and extra-motor structural and functional changes and highlight that motor and extra motor GM integrity may underlie TMS parameters of motor function in ALS patients. PMID- 29417491 TI - Meditation and yoga practice are associated with smaller right amygdala volume: the Rotterdam study. AB - To determine the association between meditation and yoga practice, experienced stress, and amygdala and hippocampal volume in a large population-based study. This study was embedded within the population-based Rotterdam Study and included 3742 participants for cross-sectional association. Participants filled out a questionnaire assessing meditation practice, yoga practice, and experienced stress, and underwent a magnetic resonance scan of the brain. 2397 participants underwent multiple brain scans, and were assessed for structural change over time. Amygdala and hippocampal volumes were regions of interest, as these are structures that may be affected by meditation. Multivariable linear regression analysis and mixed linear models were performed adjusted for age, sex, educational level, intracranial volume, cardiovascular risk, anxiety, depression and stress. 15.7% of individuals participated in at least one form of practice. Those who performed meditation and yoga practices reported significantly more stress (mean difference 0.2 on a 1-5 scale, p < .001) and more depressive symptoms (mean difference 1.03 on CESD, p = .015). Partaking in meditation and yoga practices was associated with a significantly lower right amygdala volume (beta = - 31.8 mm3, p = .005), and lower left hippocampus volume (beta = - 75.3 mm3, p = .025). Repeated measurements using linear mixed models showed a significant effect over time on the right amygdala of practicing meditation and yoga (beta = - 24.4 mm3, SE 11.3, p = .031). Partaking in meditation and yoga practice is associated with more experienced stress while it also helps cope with stress, and is associated with smaller right amygdala volume. PMID- 29417492 TI - Quantitative susceptibility mapping as a biomarker for evaluating white matter alterations in Parkinson's disease. AB - Myelinated white matter showing diamagnetic susceptibility is important for information transfer in the brain. In Parkinson's disease (PD), the white matter is also suffering degenerative alterations. Quantitative susceptibility mapping (QSM) is a novel technique for noninvasive assessment of regional white matter ultrastructure, and provides different information of white matter in addition to standard diffusion tensor imaging (DTI). In this study, we used QSM to detect spatial white matter alterations in PD patients (n = 65) and age- and sex-matched normal controls (n = 46). Voxel-wise tract-based spatial statistics were performed to analyze QSM and DTI data. QSM showed extensive white matter involvement-including regions adjacent to the frontal, parietal, and temporal lobes-in PD patients, which was more widespread than that observed using DTI. Both QSM and DTI showed similar alterations in the left inferior longitudinal fasciculus and right cerebellar hemisphere. Further, alterations in the white matter were correlated with motor impairment and global disease severity in PD patients. We suggest that QSM may provide a novel approach for detecting white matter alterations and underlying network disruptions in PD. Further, the combination of QSM and DTI would provide a more complete evaluation of the diseased brain by analyzing different biological tissue properties. PMID- 29417494 TI - MALDI Mass Spectral Imaging of Bile Acids Observed as Deprotonated Molecules and Proton-Bound Dimers from Mouse Liver Sections. AB - Bile acids (BAs) play two vital roles in living organisms, as they are involved in (1) the secretion of cholesterol from liver, and (2) the lipid digestion/absorption in the intestine. Abnormal bile acid synthesis or secretion can lead to severe liver disorders. Even though there is extensive literature on the mass spectrometric determination of BAs in biofluids and tissue homogenates, there are no reports on the spatial distribution in the biliary network of the liver. Here, we demonstrate the application of high mass resolution/mass accuracy matrix-assisted laser desorption/ionization (MALDI)-Fourier-transform ion cyclotron resonance (FTICR) to MS imaging (MSI) of BAs at high spatial resolutions (pixel size, 25 MUm). The results show chemical heterogeneity of the mouse liver sections with a number of branching biliary and blood ducts. In addition to ion signals from deprotonation of the BA molecules, MALDI-MSI generated several further intense signals at larger m/z for the BAs. These signals were spatially co-localized with the deprotonated molecules and easily misinterpreted as additional products of BA biotransformations. In-depth analysis of accurate mass shifts and additional electrospray ionization and MALDI-FTICR experiments, however, confirmed them as proton-bound dimers. Interestingly, dimers of bile acids, but also unusual mixed dimers of different taurine conjugated bile acids and free taurine, were identified. Since formation of these complexes will negatively influence signal intensities of the desired [M - H]- ions and significantly complicate mass spectral interpretations, two simple broadband techniques were proposed for non-selective dissociation of dimers that lead to increased signals for the deprotonated BAs. Graphical Abstract ?. PMID- 29417496 TI - [Peripheral arterial disease]. PMID- 29417497 TI - ? PMID- 29417493 TI - Depression in Multiple Sclerosis: Epidemiology, Aetiology, Diagnosis and Treatment. AB - Depressive disorders are common in patients with multiple sclerosis, influencing their quality of life and adherence to treatments, as well as becoming more frequent with the progression of the disease and in the secondary progressive form of multiple sclerosis. Patients with multiple sclerosis often experience a typical cluster of symptoms in association with depression, such as fatigue, pain and cognitive impairment. However, the pathogenesis of multiple sclerosis-related depression remains partially unclear, even though genetic, immune-inflammatory and psychosocial factors might be seen to play a role, in addition to the brain structural alterations documented by magnetic resonance imaging studies. The high incidence and burden of depression in people affected with multiple sclerosis are matters of crucial importance. Despite such importance, the efficacy of pharmacologic treatments has been poorly studied and, for the most part, the access to non-pharmacological treatments is partially dependent on the local health system availability. It has been determined that interferon-beta and glatiramer acetate do not cause depressive symptoms; however, no definitive data in this regard are avaible for the newer disease-modifyng medications. In this review, we discuss the diagnosis, prevalence, pathogenesis, clinical aspects, magnetic resonance imaging findings and treatments available in patients experiencing multiple sclerosis-related depression. PMID- 29417495 TI - Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. AB - INTRODUCTION: Carbohydrate restriction markedly improves glycemic control in patients with type 2 diabetes (T2D) but necessitates prompt medication changes. Therefore, we assessed the effectiveness and safety of a novel care model providing continuous remote care with medication management based on biometric feedback combined with the metabolic approach of nutritional ketosis for T2D management. METHODS: We conducted an open-label, non-randomized, controlled, before-and-after 1-year study of this continuous care intervention (CCI) and usual care (UC). Primary outcomes were glycosylated hemoglobin (HbA1c), weight, and medication use. Secondary outcomes included fasting serum glucose and insulin, HOMA-IR, blood lipids and lipoproteins, liver and kidney function markers, and high-sensitivity C-reactive protein (hsCRP). RESULTS: 349 adults with T2D enrolled: CCI: n = 262 [mean (SD); 54 (8) years, 116.5 (25.9) kg, 40.4 (8.8) kg m2, 92% obese, 88% prescribed T2D medication]; UC: n = 87 (52 (10) years, 105.6 (22.15) kg, 36.72 (7.26) kg m2, 82% obese, 87% prescribed T2D medication]. 218 participants (83%) remained enrolled in the CCI at 1 year. Intention-to-treat analysis of the CCI (mean +/- SE) revealed HbA1c declined from 59.6 +/- 1.0 to 45.2 +/- 0.8 mmol mol-1 (7.6 +/- 0.09% to 6.3 +/- 0.07%, P < 1.0 * 10-16), weight declined 13.8 +/- 0.71 kg (P < 1.0 * 10-16), and T2D medication prescription other than metformin declined from 56.9 +/- 3.1% to 29.7 +/- 3.0% (P < 1.0 * 10-16). Insulin therapy was reduced or eliminated in 94% of users; sulfonylureas were entirely eliminated in the CCI. No adverse events were attributed to the CCI. Additional CCI 1-year effects were HOMA-IR - 55% (P = 3.2 * 10-5), hsCRP - 39% (P < 1.0 * 10-16), triglycerides - 24% (P < 1.0 * 10-16), HDL-cholesterol + 18% (P < 1.0 * 10-16), and LDL-cholesterol + 10% (P = 5.1 * 10 5); serum creatinine and liver enzymes (ALT, AST, and ALP) declined (P <= 0.0001), and apolipoprotein B was unchanged (P = 0.37). UC participants had no significant changes in biomarkers or T2D medication prescription at 1 year. CONCLUSIONS: These results demonstrate that a novel metabolic and continuous remote care model can support adults with T2D to safely improve HbA1c, weight, and other biomarkers while reducing diabetes medication use. CLINICALTRIALS. GOV IDENTIFIER: NCT02519309. FUNDING: Virta Health Corp. PMID- 29417498 TI - ? PMID- 29417499 TI - ? PMID- 29417501 TI - ? PMID- 29417500 TI - ? PMID- 29417503 TI - ? PMID- 29417502 TI - ? PMID- 29417504 TI - ? PMID- 29417505 TI - ? PMID- 29417506 TI - ? PMID- 29417507 TI - ? PMID- 29417508 TI - [What do migraine apps offer?] PMID- 29417510 TI - ? PMID- 29417509 TI - [Changes to cervical cancer screening in Germany]. PMID- 29417511 TI - [Spoiled party]. PMID- 29417512 TI - [Gastroesophageal reflux disease beyond PPI]. PMID- 29417513 TI - [Prescription of PPI in Germany: too often, too long, too much?] PMID- 29417514 TI - ? PMID- 29417516 TI - ? PMID- 29417515 TI - ? PMID- 29417517 TI - ? PMID- 29417518 TI - ? PMID- 29417520 TI - ? PMID- 29417519 TI - ? PMID- 29417521 TI - ? PMID- 29417523 TI - ? PMID- 29417522 TI - ? PMID- 29417524 TI - ? PMID- 29417526 TI - ? PMID- 29417525 TI - ? PMID- 29417527 TI - ? PMID- 29417528 TI - ? PMID- 29417529 TI - ? PMID- 29417530 TI - ? PMID- 29417531 TI - ? PMID- 29417533 TI - ? PMID- 29417532 TI - ? PMID- 29417534 TI - ? PMID- 29417535 TI - ? PMID- 29417537 TI - ? PMID- 29417536 TI - ? PMID- 29417538 TI - ? PMID- 29417540 TI - ? PMID- 29417539 TI - ? PMID- 29417541 TI - ? PMID- 29417543 TI - ? PMID- 29417544 TI - ? PMID- 29417545 TI - ? PMID- 29417546 TI - ? PMID- 29417547 TI - A mixed-methods evaluation of the Association of Anaesthetists of Great Britain and Ireland Uganda Fellowship Scheme. AB - The Association of Anaesthetists of Great Britain and Ireland and the then Uganda Society of Anaesthesia established the Uganda Fellowship Scheme in 2006, to provide scholarships to encourage doctors to train in anaesthesia in Uganda. We conducted an evaluation of this programme using online questionnaires and face-to face semi-structured interviews with trainees who received scholarships, as well as with senior surgeons and anaesthetists. Focus group discussions were held to assess changes in attitudes towards anaesthesia over the last 10 years. Interviews were recorded, transcribed and analysed using the constant comparative method. A total of 54 Ugandan doctors have received anaesthesia scholarships since 2006 (median funding per trainee (IQR [range]) L5520 (L5520-L6750 [L765 L9000]). There has been a four-fold increase in the number of physician anaesthetists in Uganda during this time. All those who received funding remain in the region. The speciality of anaesthesia is undergoing a dramatic transformation led by this group of motivated young anaesthetists. There is increased access to intensive care, and this has allowed surgical specialities to develop. There is greater understanding and visibility of anaesthesia, and the quality of education in anaesthesia throughout the country has improved. The Uganda Fellowship Scheme provided a relatively small financial incentive to encourage doctors to train as anaesthetists. Evaluation of the project shows a wide-ranging impact that extends beyond the initial goal of simply improving human resource capacity. Financial incentives combined with strong 'north-south' links between professional organisations can play an important role in tackling the shortage of anaesthesia providers in a low-income country and in improving access to safe surgery and anaesthesia. PMID- 29417548 TI - Caseating granulomas manifesting as aseptic abscesses in the setting of ulcerative colitis. PMID- 29417549 TI - Treatment efficacy of probiotics on atopic dermatitis, zooming in on infants: a systematic review and meta-analysis. AB - Probiotic treatment of atopic dermatitis is widely studied with controversial results. The objective of this study is to review the efficacy of probiotics for the treatment of atopic dermatitis in infants. PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, and reference lists were searched up to July 2017. Double-blinded randomized clinical trials were included. The primary outcome was the Scoring Atopic Dermatitis index. Subgroups analyses were conducted on probiotic species, treatment duration, participant age, and disease severity. Eight clinical trials (741 infants) were included in the quantitative synthesis. The overall pooled change in Scoring Atopic Dermatitis index (95% CI) in infants was -5.71 (-8.37, -3.04), P < 0.01. Subgroup analysis revealed that the effect was protective in moderate-to-severe patients 8.32 (-16.35, -0.28), with preparations containing Lactobacillus -5.76 (-9.21, 2.30). Probiotics for the treatment of infantile atopic dermatitis is beneficial. PMID- 29417550 TI - Socially accountable anaesthesia: matching human resources with community need for safe care. PMID- 29417552 TI - Validation of the Swedish version of Quality of Recovery score -15: a multicentre, cohort study. AB - BACKGROUND: Quality of recovery (QoR) after surgery is often focused on morbidity, mortality and physiological changes, while well-being and emotional state are other important aspects that are often ignored. QoR is poorly investigated in clinical settings and a psychometrically tested questionnaire, QoR-15, has recently been developed. QoR-15 has not been validated for Swedish conditions. The aim of this study was to translate, adapt and validate QoR-15 to Swedish conditions (QoR-15swe). METHODS: A translation and cultural adaption was performed resulting in a Swedish version of the instrument, QoR-15swe. Patients answered the QoR-15swe before surgery, 24 and 48 h after surgery. Feasibility, validity, reliability and responsiveness of the QoR-15swe were evaluated. RESULTS: The QoR-15swe was feasible in 85.5% of the eligible patients. Construct validity was good, with significant correlations between QoR-15swe score and, ASA PS class, grade of surgery, length of surgery and time in the post-anaesthesia care unit. The instrument demonstrated good internal consistency with an inter item Cronbach's alpha of 0.83-0.87, and inter-dimension Cronbach's alpha was acceptable 0.71-0.76. Test-retest repeatability was also good with Cronbach's alpha > 0.99 and an interclass correlation coefficient of 0.992 (CI: 0.981 0.997). There were no floor and ceiling effects. Responsiveness assessed by Cliff's effect size was -0.23 indicating a moderate ability to detect change at 24 h postoperatively. CONCLUSION: We have translated and culturally adapted the QoR-15 into Swedish. The score demonstrated acceptable validity, reliability and responsiveness. The QoR-15swe is a clinically acceptable and feasible outcome measure after surgery in a Swedish population. PMID- 29417553 TI - Glycogen synthase kinase-3beta regulation: another kinase gets in on the AKT. PMID- 29417554 TI - Toxicity and growth inhibition potential of vetiver, cinnamon, and lavender essential oils and their blends against larvae of the sheep blowfly, Lucilia sericata. AB - BACKGROUND: Myiasis induced by the sheep blowfly, Lucilia sericata, represents a public health problem widely distributed throughout the world. L. sericata larval stages feed on both humans and animals. L. sericata adults and larvae can play a role in spreading agents of mycobacterial infections. OBJECTIVES: It is critical to establish new and safe alternative methods of controlling L. sericata. METHODS: The insecticidal effectiveness and growth inhibition potential of three commercially available essential oils (EOs), vetiver (Chrysopogon zizanioides), cinnamon (Cinnamomum zeylanicum), and lavender (Lavandula angustifolia), as well as their blends, were tested against the second (L2) and third (L3) larval stages of L. sericata. Sunflower (Helianthus annuus) oil was used as a carrier and tested on L2 and L3 larvae. To the best of our knowledge, all applied essential oils, except lavender, and oil blends were tested against L. sericata for the first time. RESULTS: All applied oils did not repel L2 from the treated liver but adversely affected their development. Contact treatments on L. sericata L3 indicated that vetiver and cinnamon oils significantly affected treated larvae. Total mortality rates were 93.33 and 95.56%, respectively. Furthermore, oil blends tested through contact assays killed larvae when used at higher concentrations; adult emergence was eliminated post-treatment with doses >30% for oil blend 1 and >10% for oil blend 2. CONCLUSION: Overall, cinnamon and vetiver oils (5%) were selected as reliable and cheap biopesticides for controlling larvae of L. sericata. The tested oils are inexpensive and represent new promising botanical insecticides in the fight against blowflies causing myiasis. PMID- 29417555 TI - The immediate and short-term effects of bilateral intrahippocampal depth electrodes on verbal memory. AB - In contrast to previous studies, Ljung et al. provide evidence of permanent cognitive consequences of bilateral intrahippocampal depth electrodes for verbal memory in patients who were not operated or operated in the right temporal lobe. Stimulated by this, we provide historical confirmatory and supplementary evidence of the detrimental effect of bilateral depth electrodes implanted along the longitudinal axis of the hippocampus on verbal learning and especially on delayed verbal memory and recognition performance. This is demonstrated in 31 patients with memory assessments before implantation, after explantation, and 3 months later after left/right temporal lobe surgery. After surgery, significant recovery from postimplantation impairment is found in right temporal patients. Left temporal resection patients stay on the level seen after implantation and do not recover. Surgery, however, has its own effects in addition to the implantation. Intracranial electrodes for electroencephalographic monitoring or electrical stimulation are commonly and increasingly used for diagnosis or treatment in pharmacoresistant epilepsies. Thus, the monitoring of invasive stereotactic approaches is recommended to find safe procedures for the patients. In response to the findings, we restricted indications and used different implantation schemes, different trajectories, and targets to minimize the risk of additional damage. PMID- 29417556 TI - Identification of a novel lethal form of autosomal recessive ichthyosis caused by UDP-glucose ceramide glucosyltransferase deficiency. PMID- 29417557 TI - Multiple bilateral adnexal tumours of the ear: Dermoscopic clues. PMID- 29417558 TI - Management of tone in children and young people with cerebral palsy. What is the evidence? PMID- 29417559 TI - Imatinib-induced diffuse hyperpigmentation of the oral mucosa, the skin, and the nails in a patient affected by chronic myeloid leukemia: report of a case and review of the literature. AB - BACKGROUND: Imatinib mesylate is a tyrosine-kinase inhibitor used as the first line treatment in chronic myeloid leukemia patients, but it is also indicated for other hematological diseases and solid tumors. Imatinib treatment is often associated with hypopigmentation, but only a few cases of hyperpigmentation are described in literature. METHODS: We are reporting the first case of imatinib related hyperpigmentation involving the oral mucosa, skin, and nails in a patient affected by chronic myeloid leukemia and treated with imatinib since 2002. A review of all the available literature regarding the imatinib-related hyperpigmentation was performed, and one additional case was analyzed. Due to the possibility of a post-inflammatory hyperpigmentation, all cases of pigmentary changes previously characterized by a rash and/or pruritus in the same body areas were excluded. RESULTS: Thirty cases of well-documented imatinib-related hyperpigmentation were described in literature. In our case, imatinib therapy was well tolerated for several years, and it led to an excellent hematological and cytogenetic response. However, the patient gradually developed a blue-gray pigmentation that involved the nose, fingernails, toenails, pretibial regions, posterior axillary folds, and hard palate. Other causes of pigmentary changes were excluded, and histopathological examination confirmed the clinical suspicion of imatinib-related hyperpigmentation. CONCLUSIONS: Hyperpigmentation induced by imatinib is an adverse reaction rarely described in literature. The underlying pathogenetic mechanisms are not yet completely clear, and further studies are necessary to elucidate them. Currently, no treatment is required for this condition, and there is no indication to discontinue imatinib treatment. PMID- 29417560 TI - Education and Knowledge in Pharmacogenomics: Still a Challenge? AB - A number of barriers exist for adoption of pharmacogenomics into practice. Physicians, pharmacists, and nurses report limited knowledge about pharmacogenomics and its use in patient care. Lack of pharmacogenomics education curricula as part of professional schools or postgraduate training programs has been reported as a potential cause. Understanding pharmacogenomics is further complicated by a complex and nonstandard lexicon, limited medication guidelines, rapidly changing evidence, and insufficient awareness of test availability and utility. PMID- 29417561 TI - Outcomes for dermatology inpatients treated with a simplified short-contact wet wrap protocol. PMID- 29417562 TI - Novel Biomarkers of Drug-Induced Kidney Injury. AB - There is an expanding body of literature regarding the utility of novel biomarkers in drug-induced kidney injury (DIKI) and other forms of acute kidney injury (AKI). The authors could not thoroughly review this topic without referring to and acknowledging this work. Included is a list of additional articles (see Supplementary Reading List) that have been referenced, but not cited within the body of the text. These references have provided data used within this article and have allowed the authors to discuss the epidemiology of DIKI, its classification, the utility of specific biomarkers, and the impact that comorbid illness and medications can have on their levels. PMID- 29417567 TI - Breaking Down Barriers to Effective Patient Care. AB - The theme for the 2018 ASCPT Annual Meeting is "Breaking Down Barriers to Effective Patient Care." This theme refers to the essential contributions of clinical pharmacology to the development of today's discovery into tomorrow's medicine. The various subdisciplines within clinical pharmacology serve to move molecules through the various stages of drug development and also refine or expand use of the drug postapproval. The wide range of topics covered by the 2018 Annual Meeting scientific program demonstrates the breadth of clinical pharmacology's impact. Because of new methods being developed to identify drug targets, medicines are being developed for patients with rare diseases. Biomarkers and diagnostic tools are advancing the development of drugs for neurodegenerative disorders, cancer, and many other diseases. Preclinical data are playing a key role in informing the quantitative clinical pharmacology of drugs, especially antimicrobials, and animal efficacy data are pivotal for drugs that are developed and approved under the animal rule. The use of pharmacogenomics, model-based drug development, informatics, and identification and evaluation of subgroups are key topics. With our focus on the patient, the Annual Meeting, and this issue of Clinical Pharmacology & Therapeutics, will highlight the many innovative ways that current clinical pharmacology investigations are attempting to dissolve barriers to effective patient care. PMID- 29417569 TI - Evolution of self-care and functional mobility after single-event multilevel surgery in children and adolescents with spastic diplegic cerebral palsy. AB - AIM: To explore the evolution of self-care and functional mobility after multilevel surgery in children and adolescents with spastic diplegic cerebral palsy and to identify factors affecting these outcomes. METHOD: Thirty-four participants (22 males, 12 females) were evaluated before surgery, and at 2 months, 6 months, 1 year, 18 months, and 2 years after surgery. Self-care was assessed with the Pediatric Evaluation of Disability Inventory Dutch edition. The Mobility Questionnaire47 (MobQues47) and Functional Mobility Scale (FMS) were used to measure functional mobility. RESULTS: All outcomes revealed a significant decrease 2 months after single-event multilevel surgery (SEMLS) (p-value between <0.001 and 0.02) followed by a significant increase at 6 months (p<0.001 and p=0.045). Between 6 months and 1 year, a significant increase was also revealed for Mobques47 (p<0.001), FMS (p<=0.008), and the Pediatric Evaluation of Disability Inventory Functional Skills Scale (PEDI-FSS) (p=0.001). Improvement continued until 18 months for the PEDI-FSS. Initial score, initial muscle strength, Gross Motor Function Classification System level, age, and number of surgical interventions significantly influenced time trends for self-care and/or functional mobility. INTERPRETATION: Most preoperative scores are regained at 6 months after SEMLS. Further improvement is seen until 18 months. Participants with a higher functional level before surgery will temporarily lose more than participants with lower initial functional ability, but they also fast regain their function. WHAT THIS PAPER ADDS: Self-care and functional mobility decrease significantly in the first months after single-event multilevel surgery (SEMLS). Six months after SEMLS most preoperative scores are regained. Impact of SEMLS is more pronounced for functional mobility than for self-care. Muscle strength and functionality at baseline are important influencing factors on the evolution after SEMLS. PMID- 29417568 TI - N-terminal B-type natriuretic peptide (NT-proBNP) is associated with disease severity in multiple myeloma. AB - BACKGROUND: Elevated levels of cardiovascular markers including N-terminal B-type natriuretic peptide (NT-proBNP) have been shown to be associated with disease severity and mortality in an unselected population of cancer patients without cardiac disease. The aim of this study was to investigate whether NT-proBNP levels are related to disease severity in multiple myeloma (MM) and to assess the natural course of NT-proBNP levels throughout disease progression. MATERIALS AND METHODS: We retrospectively analysed a total of 118 patients with MM, who were followed up routinely. NT-proBNP, beta-2-microglobulin (B2M) and levels of plasma cell-derived light chains were measured at baseline and follow-up (FUP) visits. All-cause mortality was defined as primary study endpoint, and the correlation between NT-proBNP and disease severity reflected by B2M and the International Staging System (ISS) was assessed. RESULTS: During a median FUP of 845 (IQR:683 978) days, 31 patients (26%) died. NT-proBNP showed a highly significant positive correlation with B2M at first presentation [r = .65, P < .001] and increased significantly with progressing MM disease stage [133.3 pg/mL (IQR:51.5-282.0) for ISS stage 1, 487.4 pg/mL (IQR:123.8-738.3) for ISS stage 2 and 969.1 pg/mL (IQR:472.8-3748.0) for ISS stage 3, P < .001 between all groups]. During FUP, NT proBNP levels rose significantly alongside other MM disease severity markers for patients experiencing the primary outcome [356.6 pg/mL (IQR:142.9-782.3) vs 862.9 pg/mL (IQR:338.8-4215.0), P < .001], whereas no significant changes in laboratory parameters could be detected for survivors. CONCLUSIONS: Elevated levels of the cardiovascular marker NT-proBNP are associated with disease severity in patients with MM. PMID- 29417570 TI - Onychoscopy of trachyonychia: an analysis of 30 patients and comparison with onychomycosis. PMID- 29417571 TI - Multiple extensive malacoplakia mimicking metastatic carcinoma. PMID- 29417572 TI - Key Design Considerations When Calculating Cost Savings for Population Health Management Programs in an Observational Setting. AB - OBJECTIVE: To illustrate the impact of key quasi-experimental design elements on cost savings measurement for population health management (PHM) programs. DATA SOURCES: Population health management program records and Medicaid claims and enrollment data from December 2011 through March 2016. STUDY DESIGN: The study uses a difference-in-difference design to compare changes in cost and utilization outcomes between program participants and propensity score-matched nonparticipants. Comparisons of measured savings are made based on (1) stable versus dynamic population enrollment and (2) all eligible versus enrolled-only participant definitions. Options for the operationalization of time are also discussed. DATA COLLECTION/EXTRACTION METHODS: Individual-level Medicaid administrative and claims data and PHM program records are used to match study groups on baseline risk factors and assess changes in costs and utilization. PRINCIPAL FINDINGS: Savings estimates are statistically similar but smaller in magnitude when eliminating variability based on duration of population enrollment and when evaluating program impact on the entire target population. Measurement in calendar time, when possible, simplifies interpretability. CONCLUSION: Program evaluation design elements, including population stability and participant definitions, can influence the estimated magnitude of program savings for the payer and should be considered carefully. Time specifications can also affect interpretability and usefulness. PMID- 29417573 TI - Smile Aesthetics Satisfaction Scale: development and validation of a new brief five-item measure of satisfaction with smile aesthetics in adults and the elderly. AB - OBJECTIVE: To create and validate a brief questionnaire designed for the assessment of satisfaction with smile aesthetics and to test its efficiency as a patient-centred outcome measure of aesthetic interventions in dentistry. MATERIALS AND METHODS: A team of three specialists - two from prosthodontics and one psychologist - used a self-evaluation scale consisting of five elements in order to rate self-perceived smile aesthetics. A total of 671 subjects (63% female), 18-86 years of age, were included in the investigation. The internal consistency, validity and stability of the questionnaire, along with the responsiveness induced by the tooth-whitening procedure, were evaluated. The relationship between self-perceived satisfaction with the smile aesthetics and the clinical status of the dentition was assessed. RESULTS: The questionnaire had one dimension accounting for 64.3% of variance and showed a high level of reliability (Cronbach alpha = 0.859). It measured a construct similar to concern with tooth appearance and the desire to improve this appearance (r = -0.403 and r = -0.353, respectively; P < 0.001). High test-retest reliability was demonstrated (intraclass correlation coefficient = 0.985). The questionnaire was able to detect an increase in satisfaction with smile aesthetics as a result of the tooth whitening procedure (P = 0.016). Clinical predictors of greater satisfaction with smile aesthetics were greater tooth display when smiling, decreased chroma and the absence of gingivitis, as well as absence of crowded, fractured and restored teeth in the anterior segment. CONCLUSIONS: A new questionnaire, titled the Smile Aesthetics Satisfaction Scale (SASS), showed good psychometric properties and its use can be recommended. PMID- 29417574 TI - Medicare Payment Penalties and Safety Net Hospital Profitability: Minimal Impact on These Vulnerable Hospitals. AB - OBJECTIVE: To examine relationships between penalties assessed by Medicare's Hospital Readmission Reduction Program and Value-Based Purchasing Program and hospital financial condition. DATA SOURCES/STUDY SETTING: Centers for Medicare and Medicaid Services, American Hospital Association, and Area Health Resource File data for 4,824 hospital-year observations. STUDY DESIGN: Bivariate and multivariate analysis of pooled cross-sectional data. PRINCIPAL FINDINGS: Safety net hospitals have significantly higher HRRP/VBP penalties, but, unlike nonsafety net hospitals, increases in their penalty rate did not significantly affect their total margins. CONCLUSIONS: Safety net hospitals appear to rely on nonpatient care revenues to offset higher penalties for the years studied. While reassuring, these funding streams are volatile and may not be able to compensate for cumulative losses over time. PMID- 29417575 TI - Patient and surgeon factors explain variation in the frequency of frontal sinus surgery. AB - OBJECTIVES/HYPOTHESIS: Ethmoidectomy may be sufficient to address frontal sinus disease, but some surgeons may perform frontal recess dissection initially. Our objectives were to describe patient-associated factors with frequency of frontal sinus surgery and analyze the association with provider volume. STUDY DESIGN: Retrospective cohort analysis. METHODS: The 2013 State Ambulatory Surgery Databases of New Jersey, Florida, and Kentucky were queried to identify adults who underwent anterior ethmoidectomy or total ethmoidectomy using standard Current Procedural Terminology codes. Univariate and multivariate logistic regression was performed to determine the odds of undergoing concurrent frontal sinus exploration along with ethmoidectomy, adjusting for age, gender, race, insurance type, median income, and the metropolitan designation by zip code. We also examined provider and center volume, use of image guidance, and total charges. RESULTS: There were 10,564 ethmoidectomies, of which 4,726 had concurrent frontal sinus surgery. Women were less likely to have frontal sinus surgery (P = .0011), as were patients with Medicare (P = .007). Hispanics were more likely to have frontal sinus surgery (P = .0003). Surgeons with higher surgical volumes were more likely to perform frontal sinus surgery; it was also more likely to be performed in centers where more sinus procedures occurred (P < .0001, both). CONCLUSIONS: Variation in the utilization of frontal sinus surgery is associated with patient sex, ethnicity, insurance status, geography, as well as provider and hospital volumes. These data support the idea that nonclinical factors may influence the treatment of frontal sinus disease. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2008-2014, 2018. PMID- 29417577 TI - A New Solution for Confined-Unconfined Flow Toward a Fully Penetrating Well in a Confined Aquifer. AB - Transient confined-unconfined flow conversion caused by pumping in a confined aquifer (i.e., piezometric head drops below the top confined layer) is complicated, partly due to different hydraulic properties between confined and unconfined regions. For understanding mechanism of the transient confined unconfined conversion, this paper develops a new analytical solution for the transient confined-unconfined flow toward a fully penetrating well in a confined aquifer. The analytical solution is used to investigate the impacts on drawdown simulation by differences of hydraulic properties, including transmissivity, storativity, and diffusivity defined as a ratio of transmissivity and storativity, between the confined and unconfined regions. It is found that neglecting the transmissivity difference may give an overestimation of drawdown. Instead, neglecting the diffusivity difference may lead to an underestimation of drawdown. The shape of drawdown-time curve is sensitive to the change of storativity ratio, S/Sy , between the confined and unconfined regions. With a series of drawdown data from pumping tests, the analytical solution can also be used to inversely estimate following parameters related to the transient confined unconfined conversion: radial distance of conversion interface, diffusivity, and specific yield of the unconfined region. It is concluded that using constant transmissivity and diffusivity in theory can result in biased estimates of radial distance of the conversion interface and specific yield of the unconfined region in practice. The analytical solution is useful to gain insight about various factors related to the transient confined-unconfined conversion and can be used for the design of mine drainage and groundwater management in the mining area. PMID- 29417576 TI - Olfactory and middle meatal cytokine levels correlate with olfactory function in chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: The etiology of chronic rhinosinusitis (CRS)-associated olfactory loss is unclear, but may result from inflammatory changes in the olfactory epithelium that result in signaling dysfunction or loss of olfactory neurons. Several proinflammatory cytokines have been associated with CRS, but their expression within the olfactory cleft microenvironment and association with olfactory function is unknown. STUDY DESIGN: Prospective case-control study. METHODS: Mucus was collected from the olfactory cleft and middle meatus of 31 CRS without nasal polyps subjects, 36 CRS with nasal polyps (CRSwNP) subjects, and 12 healthy controls. Olfactory function was assessed using the validated Smell Identification Test (SIT). Site-specific levels of 14 cytokines/chemokines (interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17A, tumor necrosis factor-alpha, Eotaxin, RANTES [regulated on activation, normal T cell expressed and secreted]) were assessed using a multiplex flow cytometric bead assay and correlated with SIT scores. RESULTS: Mucus cytokine levels in the olfactory cleft were strongly or moderately correlated with levels in the middle meatus for all but one measured inflammatory mediators. SIT scores were inversely correlated with levels of IL-2 (P = .006), IL-5 (P < .0001), IL-6 (P = .0009), IL-10 (P < .0001), and IL-13 (P < .0001), with significance largely driven by CRSwNP patients. CONCLUSIONS: The inflammatory microenvironment within the olfactory cleft mirrors that within the middle meatus. Elevated levels of IL 2, IL-5, IL-6, IL-10, and IL-13 in olfactory cleft mucus are associated with reduced olfactory identification scores in CRS patients. Altered levels of select olfactory mucus cytokines could potentially have deleterious effects on olfactory neuron function and turnover. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E304-E310, 2018. PMID- 29417578 TI - Sensory, digestion, and texture quality of commercial gluten-free bread: Impact of broken rice flour type. AB - : This research investigated the effects of two varieties of broken rice (Khouzestan and Lenjan) from warm and dry regions, and two (Hashemi and Tarom) from mild and humid regions on different parameters including dough rheology, digestibility, and quality (color, specific volume, textural properties, and sensorial properties) of a commercial gluten-free bread (GFB). Furthermore, the rice varieties' hydration properties, gelatinization temperatures, and starch granule morphology were assessed. Significant differences were observed in the varieties' proximate composition and hydration properties from both climate zones. The granules' average size was 3.17-4.9 um. The specific volume of the breads showed no correlation with either the damaged starch content or the amylose content, but had a significant negative correlation with hardness (r = .923, p < .05). The crumb hardness of bread was positively correlated with water binding capacity and was affected by elastic modulus of dough. Results of predicted glycemic index were in accordance with total carbohydrates. Khouzestan received the highest score in sensory evaluation test. Based on the outcomes for bread-quality attributes, Khouzestan from the warm and dry region, which is a cheaper rice variety in Iran, was the most appropriate variety for GFB production. Moreover, it was determined that the rice varieties currently used in commercial manufacture of gluten-free bread do not necessarily yield the highest quality bread. PRACTICAL APPLICATIONS: Gluten-free breads (GFBs) are generally used by Coeliac patients. In comparison to wheat bread, the quality of GFBs is lower. Rice is one of the main ingredients of GFBs' formulation, thence by determining the quality-related features of the rice, improvement in the final product could be achieved. In addition, by implementing the cheap and the broken rice variety, the price of the final product could be decreased and be more affordable for the patients. PMID- 29417579 TI - Two pivotal RNA editing sites in the mitochondrial atp1mRNA are required for ATP synthase to produce sufficient ATP for cotton fiber cell elongation. AB - RNA editing is a post-transcriptional maturation process affecting organelle transcripts in land plants. However, the molecular functions and physiological roles of RNA editing are still poorly understood. Using high-throughput sequencing, we identified 692 RNA editing sites in the Gossypium hirsutum mitochondrial genome. A total of 422 editing sites were found in the coding regions and all the edits are cytidine (C) to uridine (U) conversions. Comparative analysis showed that two editing sites in Ghatp1, C1292 and C1415, had a prominent difference in editing efficiency between fiber and ovule. Biochemical and genetic analyses revealed that the two vital editing sites were important for the interaction between the alpha and beta subunits of ATP synthase, which resulted in ATP accumulation and promoted cell growth in yeast. Ectopic expression of C1292, C1415, or doubly edited Ghatp1 in Arabidopsis caused a significant increase in the number of trichomes in leaves and root length. Our results indicate that editing at C1292 and C1415 sites in Ghatp1 is crucial for ATP synthase to produce sufficient ATP for cotton fiber cell elongation. This work extends our understanding of RNA editing in atp1 and ATP synthesis, and provides insights into the function of mitochondrial edited Atp1 protein in higher plants. PMID- 29417580 TI - In vivo characterization of brain metabolism by 1 H MRS, 13 C MRS and 18 FDG PET reveals significant glucose oxidation of invasively growing glioma cells. AB - Glioblastoma are notorious for their highly invasive growth, diffusely infiltrating adjacent brain structures that precludes complete resection, and is a major obstacle for cure. To characterize this "invisible" tumor part, we designed a high resolution multimodal imaging approach assessing in vivo the metabolism of invasively growing glioma xenografts in the mouse brain. Animals were subjected longitudinally to magnetic resonance imaging (MRI) and 1 H spectroscopy (MRS) at ultra high field (14.1 Tesla) that allowed the measurement of 16 metabolic biomarkers to characterize the metabolic profiles. As expected, the neuronal functionality was progressively compromised as indicated by decreasing N-acetyl aspartate, glutamate and gamma-aminobutyric acid and reduced neuronal TCA cycle (-58%) and neurotransmission (-50%). The dynamic metabolic changes observed, captured differences in invasive growth that was modulated by re-expression of the tumor suppressor gene WNT inhibitory factor 1 (WIF1) in the orthotopic xenografts that attenuates invasion. At late stage mice were subjected to 13 C MRS with infusion of [1,6-13 C]glucose and 18 FDG positron emission tomography (PET) to quantify cell-specific metabolic fluxes involved in glucose metabolism. Most interestingly, this provided the first in vivo evidence for significant glucose oxidation in glioma cells. This suggests that the infiltrative front of glioma does not undergo the glycolytic switch per se, but that environmental triggers may induce metabolic reprograming of tumor cells. PMID- 29417581 TI - VEGF, FGF-2 and TGFbeta expression in the normal and regenerating epidermis of geckos: implications for epidermal homeostasis and wound healing in reptiles. AB - The skin is a bilayered organ that serves as a key barrier between an organism and its environment. In addition to protecting against microbial invasion, physical trauma and environmental damage, skin participates in maintaining homeostasis. Skin is also capable of spontaneous self-repair following injury. These functions are mediated by numerous pleiotrophic growth factors, including members of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor beta (TGFbeta) families. Although growth factor expression has been well documented in mammals, particularly during wound healing, for groups such as reptiles less is known. Here, we investigate the spatio-temporal pattern of expression of multiple growth factors in normal skin and following a full-thickness cutaneous injury in the representative lizard Eublepharis macularius, the leopard gecko. Unlike mammals, leopard geckos can heal cutaneous wounds without scarring. We demonstrate that before, during and after injury, keratinocytes of the epidermis express a diverse panel of growth factor ligands and receptors, including: VEGF, VEGFR1, VEGFR2, and phosphorylated VEGFR2; FGF-2 and FGFR1; and phosphorylated SMAD2, TGFbeta1, and activin betaA. Unexpectedly, only the tyrosine kinase receptors VEGFR1 and FGFR1 were dynamically expressed, and only during the earliest phases of re-epithelization; otherwise all the proteins of interest were constitutively present. We propose that the ubiquitous pattern of growth factor expression by keratinocytes is associated with various roles during tissue homeostasis, including protection against ultraviolet photodamage and coordinated body-wide skin shedding. PMID- 29417582 TI - Activating biochar by manipulating the bacterial and fungal microbiome through pre-conditioning. AB - Biochar can enhance plant growth and reduce diseases, but frequently the optimal doses for these two benefits do not coincide. An approach is needed that will extend the range of biochar doses resulting in a concurrence of maximum benefits for both plant productivity and disease suppression. A biochar-amended growth medium was pre-conditioned by pre-planting fertigation in order to enhance the indigenous microbial community structure and activity. Cucumber plant performance and resistance against damping-off caused by Pythium aphanidermatum were monitored. Soil microbial activity, as well as bacterial and fungal community structure, were assessed by high-throughput 16S rRNA and ITS1 gene amplicon sequencing. Pre-conditioning enhanced the efficacy of biochar for improving plant performance and suppressing soilborne disease through enriching the medium in beneficial soil microorganisms, increasing microbial and fungal diversity and activity, and eliminating biochar phytotoxic compounds. The pre-conditioning process brought dose-response curves for both growth and disease resistance into sync, resulting in maximum benefits for both. These findings suggest that pre conditioning should be incorporated as an important stage during biochar application in soil and soilless media. PMID- 29417583 TI - The use of specific immunoglobulin E in nasal secretions for the diagnosis of allergic rhinitis. AB - OBJECTIVE: Although local specific immunoglobulin (sIgE) has been employed as a diagnostic criterion for allergic rhinitis (AR), the use of local sIgE has not been fully evaluated in the diagnosis of allergic rhinitis. The aim of this study was to evaluate the use of nasal secretion sIgE in the diagnosis of allergic rhinitis. METHODS: A total of 51 patients (27 males and 24 females, mean age = 33.3 years) with rhinitis symptoms were enrolled consecutively from the allergy rhinology clinic of Beijing TongRen Hospital (Beijing, People's Republic of China). Questionnaires were completed by each participant at recruitment to record demographic data, nasal symptom severity, and physician-diagnosed comorbid asthma. The severity of nasal obstruction, rhinorrhea, sneezing, and nasal/eye itching was recorded according to a visual analogue scale (VAS) of 10 cm. Sensitization to Dermatophagoides pteronyssinus, Dermatophagoides farinae, mugwort, Candida albicans, Penicillium notatum, Alternaria, Cladosporium, and Aspergillus were assessed according to presence of sIgE antibodies to these allergens in serum and nasal secretions. RESULTS: VAS scores of the participants ranged from 11 to 25 (mean = 17), and 14 (27.5%) patients had comorbid asthma. Based on serum sIgE, 31 (60.8%) patients were allergic to mugwort, 14 (27.5%) to Dermatophagoides, and three (5.9%) to fungal allergens. Based on nasal secretion sIgE, 32 (62.7%) patients were allergic to mugwort, 12 (23.5%) to Dermatophagoides, and three (5.9%) to fungal allergens. The local mugwort sIgE level and serum mugwort sIgE level were positively correlated with each other and with VAS scores. CONCLUSION: sIgE level in nasal secretions of subjects with rhinitis is a reliable noninvasive alternative to serum sIgE for diagnosis of allergic rhinitis. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:E311-E315, 2018. PMID- 29417584 TI - The use of a combination of instrumental methods to assess change in sensory crispness during storage of a "Honeycrisp" apple breeding family. AB - : Loss of crispness in apple fruit during storage reduces the fruit's fresh sensation and consumer acceptance. Apple varieties that maintain crispness thus have higher potential for longer-term consumer appeal. To efficiently phenotype crispness, several instrumental methods have been tested, but variable results were obtained when different apple varieties were assayed. To extend these studies, we assessed the extent to which instrumental measurements correlate to and predict sensory crispness, with a focus on crispness maintenance. We used an apple breeding family derived from a cross between "Honeycrisp" and "MN1764," which segregates for crispness maintenance. Three types of instrumental measurements (puncture, snapping, and mechanical-acoustic tests) and sensory evaluation were performed on fruit at harvest and after 8 weeks of cold storage. Overall, 20 genotypes from the family and the 2 parents were characterized by 19 force and acoustic measures. In general, crispness was more related to force than to acoustic measures. Force linear distance and maximum force as measured by the mechanical-acoustic test were best correlated with sensory crispness and change in crispness, respectively. The correlations varied by apple genotype. The best multiple linear regression model to predict change in sensory crispness between harvest and storage of fruit of this breeding family incorporated both force and acoustic measures. PRACTICAL APPLICATIONS: This work compared the abilities of instrumental tests to predict sensory crispness maintenance of apple fruit. The use of an instrumental method that is highly correlated to sensory crispness evaluation can enhance the efficiency and reduce the cost of measuring crispness for breeding purposes. This study showed that sensory crispness and change in crispness after storage of an apple breeding family were reliably predicted with a combination of instrumental measurements and multiple variable analyses. The strategy potentially can be applied to other apple varieties for more accurate interpretation of crispness maintenance measured instrumentally. PMID- 29417585 TI - The Anatomical Society core anatomy syllabus for pharmacists: outcomes to create a foundation for practice. AB - The Anatomical Society has developed a series of learning outcomes that 'experts' within the field would recommend as core knowledge outputs for a Master's Degree Programme in Pharmacy (MPharm) within the UK. Using the Anatomical Society core gross anatomy syllabus for medical anatomy as a foundation, a modified Delphi technique was used to develop outcomes specific to pharmacy graduates. A Delphi panel consisting of medical practitioners, pharmacists and anatomists (n = 39) was created and involved 'experts' representing 20 UK Higher Education Institutions. The output from this study was 49 pharmacy-specific learning outcomes that are applicable to all pharmacy programmes. The new MPharm anatomy syllabus offers a basic anatomical framework upon which pharmacy educators can build the necessary clinical practice and knowledge. These learning outcomes could be used to develop anatomy teaching within an integrated curriculum as per requirements of the General Pharmaceutical Council (GPhC). PMID- 29417586 TI - Office-based esophageal dilation in head and neck cancer: Safety, feasibility, and cost analysis. AB - OBJECTIVE: To review experience, safety, and cost of office-based esophageal dilation in patients with history of head and neck cancer (HNCA). METHODS: The medical records of patients undergoing esophageal dilation in the office were retrospectively reviewed between August 2015 and May 2017. Patients were given nasal topical anesthesia. Next, a transnasal esophagoscopy (TNE) was performed. If the patient tolerated TNE, we proceeded with esophageal dilation using Seldinger technique with the CRETM Boston Scientific (Boston Scientific Corp., Marlborough, MA) balloon system. Patients were discharged directly from the outpatient clinic. RESULTS: Forty-seven dilations were performed in 22 patients with an average of 2.1 dilations/patient (range 1-10, standard deviation [SD] +/- 2.2). Seventeen patients (77%) were male. The average age was 67 years (range 35 78 years, SD +/- 8.5). The most common primary site of cancer was oral cavity/oropharynx (n = 10), followed by larynx (n = 6). All patients (100%) had history of radiation treatment. Four patients were postlaryngectomy. The indication for esophageal dilation was esophageal stricture and progressive dysphagia. All dilations occurred in the proximal esophagus. There were no major complications. Three focal, superficial lacerations occurred. Two patients experienced mild, self-limited epistaxis. One dilation was poorly tolerated due to discomfort. One patient required pain medication postprocedure. Office-based esophageal dilation generated $15,000 less in health system charges compared to traditional operating room dilation on average per episode of care. CONCLUSION: In patients with history of HNCA and radiation, office-based TNE with esophageal dilation appears safe, well-tolerated, and cost-effective. In a small cohort, the technique has low complication rate and is feasible in an otolaryngology outpatient office setting. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2261-2267, 2018. PMID- 29417588 TI - Targeting the CXCL12/CXCR4 pathway and myeloid cells to improve radiation treatment of locally advanced cervical cancer. AB - Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide. Approximately half of cervical cancer patients present with locally advanced disease, for which surgery is not an option. These cases are nonetheless potentially curable with radiotherapy and cisplatin chemotherapy. Unfortunately, some tumours are resistant to treatment, and lymph node and distant recurrences are major problems in patients with advanced disease at diagnosis. New targeted treatments that can overcome treatment resistance and reduce metastases are urgently needed. The CXCL12/CXCR4 chemokine pathway is ubiquitously expressed in many normal tissues and cancers, including cervical cancer. Emerging evidence indicates that it plays a central role in cervical cancer pathogenesis, malignant progression, the development of metastases and radiation treatment response. Pre-clinical studies of standard-of care fractionated radiotherapy and concurrent weekly cisplatin plus the CXCR4 inhibitor Plerixafor (AMD3100) in patient-derived orthotopic cervical cancer xenografts have shown improved primary tumour response and reduced lymph node metastases with no increase in early or late side effects. These studies have pointed the way forward to future clinical trials of radiotherapy/cisplatin plus Plerixafor or other newly emerging CXCL12 or CXCR4 inhibitors in women with cervical cancer. PMID- 29417587 TI - Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development. AB - Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation-associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour-associated TLSs remain ill defined. Here, we observed tumour-associated TLSs in a preclinical mouse model (gp130F/F ) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL-6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell-rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130-driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3-dependent, but independent of the cytokine IL-17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour-associated TLSs were also observed in patients with intestinal-type gastric cancer, and a gene signature linked with TLS development in gp130F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130-STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis. PMID- 29417590 TI - Association between intimate partner violence during pregnancy and maternal pregnancy complications among recently delivered women in Bangladesh. AB - Intimate partner violence (IPV), an actual or threatened physical, sexual, or psychological abuse by a current or former partner or spouse, is a common global public health issue. Understanding both the prevalence of IPV during pregnancy and its potential impact on the health of pregnant women is important for the development and implementation of interventions to prevent maternal morbidity and mortality. The purpose of this study was to explore the association between maternal experiences of IPV during pregnancy and pregnancy complications. A health-facility-based cross-sectional study was conducted from July 2015 to April 2016 among 400 randomly selected women who were admitted to the postnatal wards of Rajshahi Medical College Hospital for delivery. Data were collected through face-to-face interviews using a structured questionnaire. Multivariable logistic regressions were performed to assess relationships between variables of interest after controlling for potential confounders. Results indicated that 39.0% of women reported physical IPV and 26.3% of women reported sexual IPV during pregnancy. Additionally, 69.5% of women experienced medical complications (MCs); of this group, 44.3% experienced obstetric complications (OCs) and 79.3% experienced any pregnancy complication (AC) during their last pregnancy. The experience of physical IPV during pregnancy was significantly associated with the experience of MCs (adjusted odds ratio (AOR): 2.05, 95% confidence interval (CI): 1.15-4.01), OCs (AOR: 4.23, 95% CI: 2.01-7.12) and AC (AOR: 5.26, 95% CI: 2.98 10.52). Women who experienced sexual IPV during pregnancy were also at increased risk of suffering from any MC, any OC, and AC. Maternal experience of IPV during pregnancy is positively associated with pregnancy complications. Preventing IPV directed at pregnant women might reduce maternal morbidity and mortality in Bangladesh. PMID- 29417589 TI - Capillary response to skeletal muscle contraction: evidence that redundancy between vasodilators is physiologically relevant during active hyperaemia. AB - KEY POINTS: The current theory behind matching blood flow to metabolic demand of skeletal muscle suggests redundant interactions between metabolic vasodilators. Capillaries play an important role in blood flow control given their ability to respond to muscle contraction by causing conducted vasodilatation in upstream arterioles that control their perfusion. We sought to determine whether redundancies occur between vasodilators at the level of the capillary by stimulating the capillaries with muscle contraction and vasodilators relevant to muscle contraction. We identified redundancies between potassium and both adenosine and nitric oxide, between nitric oxide and potassium, and between adenosine and both potassium and nitric oxide. During muscle contraction, we demonstrate redundancies between potassium and nitric oxide as well as between potassium and adenosine. Our data show that redundancy is physiologically relevant and involved in the coordination of the vasodilator response during muscle contraction at the level of the capillaries. ABSTRACT: We sought to determine if redundancy between vasodilators is physiologically relevant during active hyperaemia. As inhibitory interactions between vasodilators are indicative of redundancy, we tested whether vasodilators implicated in mediating active hyperaemia (potassium (K+ ), adenosine (ADO) and nitric oxide (NO)) inhibit one another's vasodilatory effects through direct application of pharmacological agents and during muscle contraction. Using the hamster cremaster muscle and intravital microscopy, we locally stimulated capillaries with one vasodilator in the absence and the presence of a second vasodilator (10-7 m S-nitroso-N acetylpenicillamine (SNAP), 10-7 m ADO, 10 mm KCl) applied sequentially and simultaneously, and observed the response in the associated upstream 4A arteriole controlling the perfusion of the stimulated capillary. We found that KCl significantly attenuated SNAP- and ADO-induced vasodilatations by ~49.7% and ~128.0% respectively and ADO significantly attenuated KCl- and SNAP-induced vasodilatations by ~94.7% and ~59.6%, respectively. NO significantly attenuated KCl vasodilatation by 93.8%. Further, during muscle contraction we found that inhibition of NO production using l-NG -nitroarginine methyl ester and inhibition of ADO receptors using xanthine amine congener was effective at inhibiting contraction-induced vasodilatation but only in the presence of K+ release channel inhibition. Thus, only when the inhibiting vasodilator K+ was blocked was the second vasodilator, NO or ADO, able to produce effective vasodilatation. Therefore, we show that there are inhibitory interactions between specific vasodilators at the level of the capillary. Further, these inhibitions can be observed during muscle contraction indicating that redundancies between vasodilators are physiologically relevant and influence vasodilatation during active hyperaemia. PMID- 29417591 TI - Clinically Practical Approach for Screening of Low Muscularity Using Electronic Linear Measures on Computed Tomography Images in Critically Ill Patients. AB - BACKGROUND: Computed tomography (CT) scans performed during routine hospital care offer the opportunity to quantify skeletal muscle and predict mortality and morbidity in intensive care unit (ICU) patients. Existing methods of muscle cross sectional area (CSA) quantification require specialized software, training, and time commitment that may not be feasible in a clinical setting. In this article, we explore a new screening method to identify patients with low muscle mass. METHODS: We analyzed 145 scans of elderly ICU patients (>=65 years old) using a combination of measures obtained with a digital ruler, commonly found on hospital radiological software. The psoas and paraspinal muscle groups at the level of the third lumbar vertebra (L3) were evaluated by using 2 linear measures each and compared with an established method of CT image analysis of total muscle CSA in the L3 region. RESULTS: There was a strong association between linear measures of psoas and paraspinal muscle groups and total L3 muscle CSA (R2 = 0.745, P < 0.001). Linear measures, age, and sex were included as covariates in a multiple logistic regression to predict those with low muscle mass; receiver operating characteristic (ROC) area under the curve (AUC) of the combined psoas and paraspinal linear index model was 0.920. Intraclass correlation coefficients (ICCs) were used to evaluate intrarater and interrater reliability, resulting in scores of 0.979 (95% CI: 0.940-0.992) and 0.937 (95% CI: 0.828-0.978), respectively. CONCLUSIONS: A digital ruler can reliably predict L3 muscle CSA, and these linear measures may be used to identify critically ill patients with low muscularity who are at risk for worse clinical outcomes. PMID- 29417592 TI - Nurturing Nature: Exploring Ecological Self-of-the-Therapist Issues. AB - Much has been written about the systemic effects of families and culture on individual well-being. Seldom discussed, however, are the systemic effects of our relationship with the larger ecological system in which all families and cultures are embedded. A case is made for the importance of nature in family therapy. Furthermore, before therapists can effectively address ecological issues in therapy, they need to address various ecological self-of-the-therapist issues that will influence their clinical practice. A series of questions are asked to help guide therapists in this exploration, and practical suggestions for incorporating nature into MFT clinical practice, training, and research are made. PMID- 29417593 TI - Medical findings in 1,026 consecutive adult inpatient-residential eating disordered patients. AB - OBJECTIVE: Eating disorders are associated with multiple medical complications. We report contemporary medical data, for newly admitted adult inpatient and residential level of care patients. METHOD: Medical records of a transdiagnostic sample of 1,026 patients, with eating disorders, were retrospectively reviewed for the presence of a broad array of medical complications at time of admission. The prevalence of physiologically relevant medical complications was assessed across major eating disorder categories. RESULTS: Of the patients, 93.6% were female, and they had an average age of 28.1 (SD = 10.1, range 17-69). The average admission body mass index was 16.1 (SD = 2.3). The prevalence of abnormal laboratory values varied by eating disorder subtype. In patients with anorexia nervosa-restricting subtype, 51.4% had low prealbumin, 36.1% were leukopenic, 34.3% had osteoporosis, 30.0% vitamin D deficiency, 16.8% metabolic alkalosis, 16.0% had hyponatremia, 14.2% hypokalemia, and 7.1% hypoglycemia. These patients had normal average QTc intervals. In patients with anorexia nervosa-binge purging subtype, 42.4% had hypokalemia, 33.3% metabolic alkalosis, osteoporosis in 21.1%, and they had longer QTc intervals (433.9 ms, p < .001). Only 6.0% of patients with anorexia nervosa had hypophosphatemia. Patients with bulimia nervosa demonstrated hypokalemia in 26.2%, and metabolic alkalosis in 23.4%; the QTc interval was longer than in AN-R patients (437.9 ms, p < .001), but still in the normal range. DISCUSSION: Numerous medical complications are associated with severe eating disorders. As the severity increases, the number of complications increase and are related to the presence or absence of purging behaviors. PMID- 29417594 TI - Feasibility of a parent education and skills workshop for improving response to family-based treatment of adolescent anorexia nervosa. AB - OBJECTIVE: Early response to family-based treatment (FBT) is a robust predictor of positive outcomes for adolescents with anorexia nervosa (AN). We introduced a parent education and skills workshop in the first 4 weeks of treatment with the aim of improving changes in parent self-efficacy in FBT and, in turn, patient weight gain. METHOD: Forty-five families who had at least one parent attend the workshop were compared to a matched control of families who did FBT before the workshop was introduced. RESULTS: Among adolescents who were underweight at baseline, weight gain by Week 4 of treatment was higher for adolescents whose parents attended the workshop (M = 90.84% median BMI) than those who did not (M = 88.54% mBMI, p < .05). There was no significant difference in weight at Week 12 or at end of treatment, nor was there a difference in self-efficacy as measured by the Parent Versus Anorexia Scale. Participants reported a high level of satisfaction with the workshop and significant improvements in knowledge and confidence. DISCUSSION: Overall, the workshop was a feasible adjunct for improving early response to FBT. PMID- 29417595 TI - Aggression is associated with greater subsequent alcohol consumption: A shared neural basis in the ventral striatum. AB - Alcohol use and abuse (e.g., binge drinking) are among the most reliable causes of aggressive behavior. Conversely, people with aggressive dispositions (e.g., intermittent explosive disorder) are at greater risk for subsequent substance abuse. Yet it remains unknown why aggression might promote subsequent alcohol use. Both aggressive acts and alcohol use are rewarding and linked to greater activity in neural reward circuitry. Through this shared instantiation of reward, aggression may then increase subsequent alcohol consumption. Supporting this mechanistic hypothesis, participants' aggressive behavior directed at someone who had recently rejected them, was associated with more subsequent beer consumption on an ad-lib drinking task. Using functional MRI, both aggressive behavior and beer consumption were associated with greater activity in the bilateral ventral striatum during acts of retaliatory aggression. These results imply that aggression is linked to subsequent alcohol abuse, and that a mechanism underlying this effect is likely to be the activation of the brain's reward circuitry during aggressive acts. PMID- 29417596 TI - Accelerated SDS depletion from proteins by transmembrane electrophoresis: Impacts of Joule heating. AB - SDS plays a key role in proteomics workflows, including protein extraction, solubilization and mass-based separations (e.g. SDS-PAGE, GELFrEE). However, SDS interferes with mass spectrometry and so it must be removed prior to analysis. We recently introduced an electrophoretic platform, termed transmembrane electrophoresis (TME), enabling extensive depletion of SDS from proteins in solution with exceptional protein yields. However, our prior TME runs required 1 h to complete, being limited by Joule heating which causes protein aggregation at higher operating currents. Here, we demonstrate effective strategies to maintain lower TME sample temperatures, permitting accelerated SDS depletion. Among these strategies, the use of a magnetic stir bar to continuously agitate a model protein system (BSA) allows SDS to be depleted below 100 ppm (>98% removal) within 10 min of TME operations, while maintaining exceptional protein recovery (>95%). Moreover, these modifications allow TME to operate without any user intervention, improving throughput and robustness of the approach. Through fits of our time-course SDS depletion curves to an exponential model, we calculate SDS depletion half-lives as low as 1.2 min. This promising electrophoretic platform should provide proteomics researchers with an effective purification strategy to enable MS characterization of SDS-containing proteins. PMID- 29417598 TI - The price of abandoning diagnostic testing for cell-free fetal DNA screening. PMID- 29417597 TI - Acute Ethanol Inhibition of Adult Hippocampal Neurogenesis Involves CB1 Cannabinoid Receptor Signaling. AB - BACKGROUND: Chronic ethanol (EtOH) exposure has been found to inhibit adult hippocampal neurogenesis in multiple models of alcohol addiction. However, acute EtOH inhibition of adult neurogenesis is not well studied. Although many abused drugs have been found to inhibit adult neurogenesis, few have studied cannabinoids or cannabinoids with EtOH, although human use of both together is becoming more common. We used an acute binge alcohol drinking model in combination with select cannabinoid receptor agonists and antagonists to investigate the actions of each alone and together on hippocampal neurogenesis. METHODS: Adult male Wistar rats were treated with an acute binge dose of EtOH (5 g/kg, i.g.), cannabinoid 1 receptor (CB1R) or cannabinoid 2 receptor (CB2R) agonists, as well as selective cannabinoid (CB) antagonists, alone or combined. Hippocampal doublecortin (DCX), Ki67, and activated cleaved caspase-3 (CC3) immunohistochemistry were used to assess neurogenesis, neuroprogenitor proliferation, and cell death, respectively. RESULTS: We found that treatment with EtOH or the CB1R agonist, arachidonoyl-2'-chloroethylamide (ACEA), and the combination significantly reduced DCX-positive neurons (DCX + IR) in dentate gyrus (DG) and increased CC3. Further, using an inhibitor of endocannabinoid metabolism, for example, JZL195, we also found reduced DCX + IR neurogenesis. Treatment with 2 different CB1R antagonists (AM251 or SR141716) reversed both CB1R agonist and EtOH inhibition of adult neurogenesis. CB2R agonist HU-308 treatment did not produce any significant change in DCX + IR. Interestingly, neither EtOH nor CB1R agonist produced any alteration in cell proliferation in DG as measured by Ki67 + cell population, but CC3-positive cell numbers increased following EtOH or ACEA treatment suggesting an increase in cell death. CONCLUSIONS: Together, these findings suggest that acute CB1R cannabinoid receptor activation and binge EtOH treatment reduce neurogenesis through mechanisms involving CB1R. PMID- 29417599 TI - Obstetricians' views on the ethics of cardiac surgery for newborns with common aneuploidies. AB - OBJECTIVE: To examine whether obstetricians think that cardiac surgery is ethical in babies with common aneuploidies and whether insurance companies should be required to pay for these surgeries. STUDY DESIGN: A survey was e-mailed to 2897 OB-GYNs, and 898 (31%) actively practicing obstetricians responded to the survey. Respondents were asked whether it is ethical to offer cardiac surgery for babies with heart defects diagnosed with trisomies 21, 18, and 13 and Turner syndrome and whether insurance companies should be required to pay for such surgeries in cases of trisomy 18 or 13. Chi-square tests were utilized to compare responses by using an alpha level of .05. RESULTS: Most obstetricians thought that offering cardiac surgery was ethical if the baby had trisomy 21 or Turner syndrome (94%), but not trisomy 18 or 13 (75%). Most obstetricians (69%) thought that insurance companies should not be legally required to pay for cardiac surgery for the latter group. CONCLUSION: Obstetricians were more likely to think cardiac surgery was ethical if the prognosis or the outcome was good. Most respondents did not think that insurance companies should be required to subsidize the cost of cardiac surgeries for all babies with trisomy 18 or 13. PMID- 29417600 TI - A critical narrative review of transfer of basic science knowledge in health professions education. AB - CONTEXT: 'Transfer' is the application of a previously learned concept to solve a new problem in another context. Transfer is essential for basic science education because, to be valuable, basic science knowledge must be transferred to clinical problem solving. Therefore, better understanding of interventions that enhance the transfer of basic science knowledge to clinical reasoning is essential. This review systematically identifies interventions described in the health professions education (HPE) literature that document the transfer of basic science knowledge to clinical reasoning, and considers teaching and assessment strategies. METHODS: A systematic search of the literature was conducted. Articles related to basic science teaching at the undergraduate level in HPE were analysed using a 'transfer out'/'transfer in' conceptual framework. 'Transfer out' refers to the application of knowledge developed in one learning situation to the solving of a new problem. 'Transfer in' refers to the use of previously acquired knowledge to learn from new problems or learning situations. RESULTS: Of 9803 articles initially identified, 627 studies were retrieved for full text evaluation; 15 were included in the literature review. A total of 93% explored 'transfer out' to clinical reasoning and 7% (one article) explored 'transfer in'. Measures of 'transfer out' fostered by basic science knowledge included diagnostic accuracy over time and in new clinical cases. Basic science knowledge supported learning - 'transfer in' - of new related content and ultimately the 'transfer out' to diagnostic reasoning. Successful teaching strategies included the making of connections between basic and clinical sciences, the use of commonsense analogies, and the study of multiple clinical problems in multiple contexts. Performance on recall tests did not reflect the transfer of basic science knowledge to clinical reasoning. CONCLUSIONS: Transfer of basic science knowledge to clinical reasoning is an essential component of HPE that requires further development for implementation and scholarship. PMID- 29417601 TI - Erratum. PMID- 29417602 TI - Body mass index and motor coordination: Non-linear relationships in children 6-10 years. AB - BACKGROUND: Given the concern for health-related consequences of an elevated body mass index (BMI; obesity), the potential consequences of a low BMI in children are often overlooked. The purpose was to evaluate the relationship between the BMI across its entire spectrum and motor coordination (MC) in children 6-10 years. METHODS: Height, weight, and MC (Korperkoordinationstest fur Kinder, KTK test battery) were measured in 1,912 boys and 1,826 girls of 6-10 years of age. BMI (kg/m2 ) was calculated. KTK scores for each of the four tests were also converted to a motor quotient (MQ). One-way ANOVA was used to test differences in the BMI, individual test items, and MQ among boys and girls within age groups. Sex-specific quadratic regressions of individual KTK items and the MQ on the BMI were calculated. Girls and boys were also classified into four weight status groups using International Obesity Task Force criteria: thin, normal, overweight, and obese. Differences in specific test items and MQ between weight status groups were evaluated by age group in each sex. RESULTS: Thirty-one percent of the sample was overweight or obese, whereas 5% was thin. On average, normal weight children had the highest MQ in both sexes across the age range with few exceptions. Overweight/obese children had a lower MQ than normal weight and thin children. The quadratic regression lines generally presented an inverted parabolic relationship between the BMI and MC and suggested a decrease in MC with an increase in the BMI. CONCLUSION: In general, BMI shows a curvilinear, inverted parabolic relationship with MC in children 6-10 years. PMID- 29417604 TI - Effects of Alcohol on the Brain in Cirrhosis: Beyond Hepatic Encephalopathy. AB - Recent advances have led to a greater understanding of how alcohol alters the brain, both in acute stages (intoxication and alcohol withdrawal) and in chronic misuse. This review focuses on the current understanding of how alcohol affects the brain in cirrhosis patients with and without hepatic encephalopathy (HE). Chronic alcohol use is associated with nutritional deficiencies, dementia, cirrhosis, and decompensating events such as HE. Direct toxicity on brain tissue, induction of neuro-inflammation, and alcohol's alterations of the gut microbiome are possible mechanisms for the clinical features of HE associated with alcohol use. Acute management of the alcoholic cirrhosis patient with altered mental status should focus on ruling out other causes, best intensive care, and use of gut-based therapies such as lactulose and rifaximin. Long-term management centers on optimizing treatment of concurrent mood disorders, nutritional support, and medical management of complications associated with cirrhosis. Future studies are needed to clarify mechanisms of brain injury in concomitant alcohol misuse and HE in addition to designing treatment interventions in order to improve outcomes in these patients. PMID- 29417603 TI - A 10-session cognitive-behavioral therapy (CBT-T) for eating disorders: Outcomes from a case series of nonunderweight adult patients. AB - OBJECTIVE: Existing forms of evidence-based cognitive behavior therapy for eating disorders (CBT-ED) are relatively effective for nonunderweight cases. However, they are also expensive compared to CBT for other disorders. This study reports the first outcomes for a shorter, 10-session form of CBT-ED (CBT-T) for such cases, designed to be less demanding of resources. METHOD: A case series of 106 nonunderweight eating disordered cases were considered for this effectiveness study. A protocolized 10-session version of CBT-ED was delivered by clinical assistants, under supervision. Measures assessed eating attitudes and behaviors, anxiety, depression, personality pathology, and the working alliance. Intention to-treat analyses were used. RESULTS: Suitability, acceptability, working alliance ratings, and retention were all positive. Outcomes by the end of therapy and at three-month follow-up were positive for all symptoms, with levels of change, abstinence and remission that were comparable to those from effectiveness studies of longer forms of CBT. Higher levels of pretreatment anxiety predicted retention in treatment, but no factors predicted poorer response. Early change in eating attitudes and the working alliance were the strongest predictors of a positive response. DISCUSSION: This 10-session form of CBT-ED for nonunderweight eating disorders performed at a level that is comparable to versions of CBT-ED that are twice as long, despite being delivered by nonspecialist therapists. Replication and longer-term follow-ups are needed to ensure retained effects. However, CBT-T has promise as a therapy for use in a range of healthcare settings, to enhance access to treatment for such eating disorders. PMID- 29417605 TI - Efficacy of a novel neem oil formulation (RP03TM) to control the poultry red mite Dermanyssus gallinae. AB - Dermanyssus gallinae (Mesostigmata: Dermanyssidae) is the most harmful ectoparasite of laying hens, represents an occupational hazard for poultry workers, and a growing threat to medical science per se. There is increasing demand for alternative products, including plant-derived acaricides, with which to control the mite. The present study investigated the efficacy of neem oil against D. gallinae on a heavily infested commercial laying hen farm. A novel formulation of 20% neem oil, diluted from a 2400-p.p.m. azadirachtin-concentrated stock (RP03TM), was administered by nebulization three times in 1 week. Using corrugated cardboard traps, mite density was monitored before, during and after treatment and results were statistically analysed. Mite populations in the treated block showed 94.65%, 99.64% and 99.80% reductions after the first, second and third product administrations, respectively. The rate of reduction of the mite population was significantly higher in the treated block (P < 0.001) compared with the control and buffer blocks. The results suggest the strong bioactivity of neem, and specifically of the patented neem-based formulation RP03TM, against D. gallinae. The treatment was most effective in the 10 days following the first application and its effects persisted for over 2 months. Further studies will aim to overcome observed side effects of treatment represented by an oily layer on equipment and eggs. PMID- 29417606 TI - Impact of laser therapy for twin-to-twin transfusion syndrome on subsequent pregnancy. AB - OBJECTIVES: The objective of our study was to determine the impact of laser therapy for twin-to-twin transfusion syndrome (TTTs) on subsequent pregnancies. METHODS: This was a monocentric retrospective observational study. Women treated by laser fetoscopy for TTTs were asked to answer a postal questionnaire about subsequent pregnancies. The primary outcome was fecundity (number of pregnancies and time to pregnancy). We also assessed pregnancy complications, birth weight, and gestational age at delivery. Pregnancy complications included the following: threatened preterm labor, preeclampsia, placenta accreta, postpartum hemorrhage, and psychological disorders. Our study population was compared with an external control group made up of mothers of monochorionic twins without TTTs. RESULTS: We included 122 cases managed at the Necker Hospital between 2008 and 2012 and 39 controls. The median conception time was longer in the TTTs group (6.4 +/- 11.1 versus 2 +/- 1.6 months, P = .03). The numbers of live childbirths at the end of those pregnancies were equivalent (77.6% versus 66.7%, P = .56). Birth weight (3317 +/- 726 versus 3240 +/- 382 g, P = .81) and gestational age at delivery (38.2 +/- 6.8 WG versus 39.5 +/- 1.2 WG, P = .64) were similar, with no increase of obstetrical complications compared with the control group. DISCUSSION: Twin-to twin transfusion syndrome and its treatment do not seem to impact subsequent pregnancies. PMID- 29417607 TI - Fetal pulmonary valve stenosis or atresia with intact ventricular septum: Predictors of need for neonatal intervention. AB - OBJECTIVES: To compare the fetal echocardiographic measurements and neonatal outcome of fetuses with diagnosis of critical pulmonary stenosis (CPS/IVS) and pulmonary atresia with intact ventricular septum (PA/IVS) to identify the predictors of neonatal ductus dependence and the need for neonatal intervention. METHODS: Forty-four fetuses with a diagnosis of membranous PA/IVS or CPS/IVS referred to Shanghai Xinhua Hospital Affiliated to Shanghai Jiaotong University between June 2009 and November 2014 were respectively analyzed. We analyzed their fetal and pediatric echocardiographic features and clinical features after birth. RESULTS: Among the 29 infants in the final analysis, 19 were ductal dependent and were diagnosed as CPS/IVS or PA/IVS after birth. Ten patients with fetal CSP/IVS were ductal independent and were diagnosed as pulmonary stenosis after birth. In midtrimester, significance was only detected in pulmonary valve (PV) regurgitation between 2 groups (P = .009). The fetuses with PV regurgitation in midtrimester were more likely to be ductal independent (odds ratio = 6.67; P = .010) than those with absence of PV regurgitation in the midtrimester scan. In late trimester, the infants in ductus-independent group had better fetal right ventricular development than those in ductus dependent group. The right ventricle over left ventricle length ratio in last scan over 0.86 had the best capability in predicting ductus independence during neonatal period with help of receiver operating characteristic curve and the logistic regression analysis. CONCLUSION: Among fetuses with pulmonary valve stenosis and right ventricle dysplasia at the time of first fetal echo in midtrimester, use of pulmonary valve regurgitation can identify who will be ductal dependent at births. In late trimester, right ventricle over left ventricle length ratio less than 0.86 had the best capability of predicting neonatal ductal dependence. Fetuses with reversed ductus arteriosus flow direction in late trimester were more likely to be ductus dependent after birth. PMID- 29417608 TI - Current controversies in prenatal diagnosis 2: Cell-free DNA prenatal screening should be used to identify all chromosome abnormalities. AB - Noninvasive prenatal testing (NIPT) using cell-free DNA (cfDNA) from maternal serum has been clinically available since 2011. This technology has revolutionized our ability to screen for the common aneuploidies trisomy 21 (Down syndrome), trisomy 18, and trisomy 13. More recently, clinical laboratories have offered screening for other chromosome abnormalities including sex chromosome abnormalities and copy number variants (CNV) without little published data on the sensitivity, specificity, and positive predictive value. In this debate, the pros and cons of performing prenatal screening via cfDNA for all chromosome abnormalities is discussed. At the time of the debate in 2017, the general consensus was that the literature does not yet support using this technology to screen for all chromosome abnormalities and that education is key for both providers and the patients so that the decision-making process is as informed as possible. PMID- 29417609 TI - How many individuals achieve symptom abstinence following psychological treatments for bulimia nervosa? A meta-analytic review. AB - OBJECTIVES: It is unclear how many patients with bulimia nervosa (BN) completely abstain from the core behavioral symptoms after receiving psychological treatment. The present meta-analysis of randomized controlled trials (RCTs) aimed to (a) estimate the prevalence of patients who abstain from binge eating and/or purging following all psychological treatments for BN, and (b) test whether these abstinence estimates are moderated by the type of treatment modality delivered, the definition of abstinence applied, and trial quality. METHOD: Forty-five RCTs were included, with 78 psychotherapy conditions. Pooled event rates were calculated using random effects models. RESULTS: At post-treatment, the total weighted percentage of treatment-completers who achieved abstinence was 35.4% (95% CI = 29.6, 41.7), while the total weighted percentage of abstinence for all randomized patients (intention-to-treat) was 29.9% (95% CI = 25.7, 33.2). Abstinence estimates were highest in trials that used behavioral-based treatments (e.g., cognitive-behavioral therapy, behavior therapy). There was also evidence that guided self-help interventions produced the lowest post-treatment abstinence rates, but with no difference at follow-up from clinician-led treatments, and studies that used a shorter timeframe for defining abstinence (i.e., 14 days symptom-free compared to 28-days symptom-free) produced the highest abstinence rates. Abstinence estimates at follow-up for both the completer (34.6%; 95% CI = 29.3, 40.2) and intention-to-treat (28.6%; 95% CI = 25.1, 32.3) analyses were essentially the same as the post-treatment estimates. DISCUSSION: Over 60% of patients fail to fully abstain from core BN symptoms even after receiving our most empirically-supported treatments. The present findings highlight the urgency toward improving the effectiveness of psychological treatments for BN. PMID- 29417610 TI - Drinking Level Versus Drinking Pattern and Cigarette Smoking Among Older Adults. AB - BACKGROUND: There is a lack of research on the role of alcohol consumption in cigarette smoking among older adults, and the few studies on alcohol use and smoking with older adults have failed to distinguish between average level and pattern of drinking as predictors of smoking. The main purpose of this study was to examine the independent contributions of average level versus pattern of drinking as predictors of cigarette smoking among older adults. A subsidiary purpose was to examine the link between continued smoking and mortality among older smokers. METHODS: We investigated average level and pattern of drinking as predictors of current smoking among 1,151 older adults at baseline and of continued smoking and mortality among the subset of 276 baseline smokers tracked across 20 years. We used multiple linear and logistic regression analyses and, to test mediation, bias-corrected bootstrap confidence intervals. RESULTS: A high level of average drinking and a pattern of episodic heavy drinking were concurrently associated with smoking at baseline. However, only episodic heavy drinking was prospectively linked to continued smoking among baseline smokers. Continued smoking among baseline smokers increased the odds of 20-year mortality and provided an indirect pathway through which heavy episodic drinking related to mortality. CONCLUSIONS: Smokers who misuse alcohol are a challenging population for smoking cessation efforts. Older adults who concurrently misuse alcohol and smoke cigarettes provide a unique target for public health interventions. PMID- 29417611 TI - Longitudinal detection of DNMT3AR882H transcripts in patients with acute myeloid leukemia. PMID- 29417612 TI - Diabetes stigma is associated with negative treatment appraisals among adults with insulin-treated Type 2 diabetes: results from the second Diabetes MILES - Australia (MILES-2) survey. AB - AIM: To explore factors associated with negative insulin appraisals among adults with Type 2 diabetes, including perceived and experienced diabetes stigma. METHODS: The second Diabetes MILES - Australia study (MILES-2) is a national survey of adults with diabetes, focused on behavioural and psychosocial issues. Subgroup analyses were conducted on the responses of 456 adults with insulin treated Type 2 diabetes (38% women; mean +/- sd age: 61.2 +/- 8.8 years; diabetes duration: 14.5 +/- 7.5 years; years using insulin: 6.4 +/- 5.5). Participants completed validated measures of perceived and experienced diabetes stigma (Type 2 Diabetes Stigma Assessment Scale), insulin appraisals [Insulin Treatment Appraisal Scale (ITAS)] and known correlates of insulin appraisals: diabetes specific distress (Problem Areas In Diabetes scale) and diabetes-specific self efficacy (Confidence in Diabetes Self-care scale). A multiple linear regression was conducted (N = 279) to determine the contribution of those variables found to be associated with ITAS Negative scores. RESULTS: Univariable analyses revealed negative insulin appraisals were associated with demographic and self-care characteristics (age, employment status, BMI, years using insulin, injections per day), self-efficacy, diabetes-specific distress and diabetes stigma (all P < 0.01). Number of injections per day [regression coefficient [95% confidence interval]: 0.74 [0.08, 1.40]; P = 0.028], self-efficacy [-0.12 [-0.19, -0.06]; P < 0.001] and diabetes stigma [0.39 (0.31, 0.46); P < 0.001) significantly and independently contributed to the final multivariable model, explaining 58% of the variance in ITAS Negative scores. The independent contribution of diabetes specific distress was suppressed following the inclusion of diabetes stigma. CONCLUSIONS: This study represents the first step in understanding the relationship between perceived and experienced diabetes stigma and negative insulin appraisals, and provides quantitative evidence for the strong, independent relationship between these two important constructs. PMID- 29417613 TI - Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. PMID- 29417614 TI - Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial. AB - Few trials have examined rates of hypersensitivity reactions (HSRs) with intravenous iron formulations used to treat iron deficiency anemia (IDA). This randomized, multicenter, double-blind clinical trial compared the safety, and efficacy of ferumoxytol versus ferric carboxymaltose (FCM), focusing on rates of HSRs and hypotension as the primary end point. Patients with IDA of any etiology in whom oral iron was unsatisfactory or intolerable received ferumoxytol (n = 997) or FCM (n = 1000) intravenously over >=15 minutes on days 1 and 8 or 9 for total respective doses of 1.02 g and 1.50 g. Composite incidences of moderate-to severe HSRs, including anaphylaxis, or moderate-to-severe hypotension from baseline to week 5 (primary safety end point) were 0.6% and 0.7% in the ferumoxytol and FCM groups, respectively, with ferumoxytol noninferior to FCM. No anaphylaxis was reported in either group. The secondary safety end point of incidences of moderate-to-severe HSRs, including anaphylaxis, serious cardiovascular events, and death from baseline to week 5 were 1.3% and 2.0% in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Least-squares mean changes in hemoglobin at week 5 were 1.4 g/dL and 1.6 g/dL in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Incidence of hypophosphatemia was 0.4% for ferumoxytol and 38.7% for FCM. PMID- 29417615 TI - The effect of handover location on trauma theatre start time: An estimated cost saving of L131 000 per year. AB - BACKGROUND: The National Health Service was estimated to be in L2.45 billion deficit in 2015 to 2016. Trauma theatre utilization and efficiency has never been so important as it is estimated to cost L15/minute. METHODS: Structured questionnaires were given to 23 members of staff at our Trust who are actively involved in the organization or delivery of orthopaedic trauma lists at least once per week. This was used to identify key factors that may improve theatre efficiency. Following focus group evaluation, the location of the preoperative theatre meeting was changed, with all staff involved being required to attend this. Our primary outcome measure was mean theatre start time (time of arrival in the anaesthetic room) during the 1 month immediately preceding the change and the month following the change. RESULTS: Theatre start time was improved on average 24 minutes (1 month premeeting and postmeeting change). This equates to a saving of L360 per day, or L131 040 per year. CONCLUSION: Changing the trauma meeting location to a venue adjacent to the trauma theatre can improve theatre start times, theatre efficiency, and therefore result in significant cost savings. PMID- 29417617 TI - The relationship between socio-economic status and diagnosed Type 2 diabetes is changing with economic growth in Nanjing, China. AB - AIM: In developed countries, the relationship between socio-economic status (SES) and Type 2 diabetes was positive several decades ago but is now negative. However, in developing societies such as China the relationship remains positive. It is likely that at some stage of economic development the SES-Type 2 diabetes association will become negative in developing communities. This study aimed to examine whether this inflexion is approaching in China. METHODS: Two cross sectional surveys were undertaken in Nanjing, China, in 2000 and 2011. The same sampling approach was used to randomly select participants. Diagnosed Type 2 diabetes was the outcome variable. SES was measured using monthly family average income and divided into thirds. Mixed-effects models were used to calculate the association between SES and Type 2 diabetes. RESULTS: There were 19 861 (response rate, 90.1%) and 7824 (response rate, 82.8%) participants in 2000 and 2011, respectively. A 2.6-fold increase in Type 2 diabetes prevalence was observed from 3.0% (95% confidence interval 2.8%, 3.3%) in 2000 to 8.2% (7.7%, 8.8%) in 2011 (P < 0.01). After controlling for potential confounders, the odds ratios of having Type 2 diabetes decreased from 2.06 (95% CI 1.55, 2.73) and 1.83 (1.40, 2.37) in 2000 to 1.58 (1.23, 2.02) and 1.35 (1.06, 1.74) in 2011 for the higher and middle SES groups respectively, compared with those in the lower SES category. CONCLUSIONS: The SES-Type 2 diabetes association remained positive in Nanjing, China, in 2011 but the disparity diminished significantly compared with 2000. These results can inform the delivery of appropriate interventions to people at risk of developing Type 2 diabetes. PMID- 29417616 TI - Alcohol mixed with energy drink (AMED): A critical review and meta-analysis. AB - The purpose of this systematic review and meta-analysis was to critically review the (1) prevalence of alcohol mixed with energy drink (AMED) consumption, (2) motives for AMED consumption, (3) correlates of AMED consumption, and (4) whether AMED consumption has an impact on (a) alcohol consumption, (b) subjective intoxication, and (c) risk-taking behavior. Overall a minority of the population consumes AMED, typically infrequently. Motives for AMED consumption are predominantly hedonistic and social. Meta-analyses revealed that AMED consumers drink significantly more alcohol than alcohol-only (AO) consumers. Within-subject comparisons restricted to AMED consumers revealed that alcohol consumption does not significantly differ between typical AMED and AO occasions. On past month heaviest drinking occasions, AMED users consume significantly less alcohol on AMED occasions when compared to AO occasions. AMED consumers experience significantly fewer negative consequences and risk-taking behavior on AMED occasions compared with AO occasions. Meta-analyses of subjective intoxication studies suggest that AMED consumption does not differentially affect subjective intoxication when compared to AO consumption. In conclusion, when compared to AO consumption, mixing alcohol with energy drink does not affect subjective intoxication and seems unlikely to increase total alcohol consumption, associated risk-taking behavior, nor other negative alcohol-related consequences. Further research may be necessary to fully reveal the effects of AMED. PMID- 29417618 TI - Evaluation of vitamin D receptor gene polymorphisms (Fok-I and Bsm-I) in T1DM Saudi children. AB - BACKGROUND: Vitamin D deficiency conferred strongest susceptibility to pathogenesis of type 1 diabetes mellitus (T1DM). Altered gene expression and function have strong effect on VDR gene polymorphism. OBJECTIVES: We aimed to check for the association of two single nucleotide polymorphisms (SNPs) in VDR gene (Fok-I and Bsm-I) with T1DM in Saudi children. SUBJECTS AND METHODS: Cross sectional study included 100 T1DM Saudi children, plus 102 unrelated healthy subjects. PCR technique was used for detection of Fok-I and Bsm-I SNPs in VDR gene. RESULTS: Regarding the Fok-I polymorphisms, T1DM cases showed a significant increased frequency of the heterozygous genotype (Ff) than controls (33% vs 21%, OR = 1.9, 95% CI = 1.006-3.587, P = .04). In the meantime, they showed significantly lower frequency of the homozygous (ff) genotype (64% vs 79%, OR = 0.51, 95% CI = 0.28-0.96, P = .03). Cases showed also a significantly lower frequency of the (f) allele than controls (80.5% vs 87.7%, OR = 0.57, 95% CI = 0.33-0.995, P = .04). On the other hand, cases showed significantly higher frequency of the Bsm-I homozygous (bb) and heterozygous (Bb) genotypes (25% vs 11.8%, P = .01, OR = 2.5, 95% CI = 1.18-5.31) & (45% vs 27.5%, P = .0, OR = 2.1, 95 % CI = 1.20-3.89, respectively). Cases showed also significantly higher frequency of (b) allele compared to control (47.5% vs 25.5%, P = .0, OR = 2.6, 95% CI = 1.74-4.02). Haplotype analysis showed an increased risk with the fB and fb haplotypes. CONCLUSION: This study emphasizes a positive association between SNPs (Fok-I and Bsm-I) and T1DM among Saudi children with increased risk with the Fok-I F and Bsm-I b alleles. PMID- 29417619 TI - "There is always a better way": Managing uncertainty in decision making about new cancer drugs in Canada. AB - Policy decisions about the approval and funding of new cancer drugs must often be made in an environment of complex uncertainty about clinical and cost effectiveness data. The focus of this article is on the results from qualitative interviews with senior officials (n = 16) who make decisions about or influence cancer drug policy in various organizations in the Canadian cancer control system. Most participants identified the use of a limited number of informal approaches to address uncertainty, such as grounding decisions in evidence and advice from expert groups. People tended to focus on evidence informed decisions including price negotiations, the ability to implement policy changes, and stakeholder values. Lessons from the Canadian context related to continuing efforts to build a public culture of understanding into how policy decisions like cancer drug funding are made may result in greater acceptance and increased confidence in health policy decision-making processes across multiple sectors internationally. PMID- 29417620 TI - HER2 Ile655Val polymorphism is negatively associated with breast cancer susceptibility. AB - BACKGROUND: The HER2 (human epidermal growth factor receptor-2) Ile655Val (rs1136201) genetic polymorphism can alter the receptor structure and its auto activation, which can modify the signal transduction and, consequently, the cell cycle regulation. For this reason, this polymorphism has been extensively investigated as a candidate marker for breast cancer (BC). In this context, the aim of this study was to evaluate the possible influence of HER2 Ile655Val in BC susceptibility and prognostic factors in a Brazilian population. METHODS: Polymorphism genotype was assessed through RFLP-PCR in 107 BC patients with clinicopathological data available and in 150 women with no evidence of neoplasia and with no familial history of BC as control group. Association between this polymorphism and BC susceptibility and clinical parameters was evaluated through odds ratio (OR) and chi-squared or Fisher's exact test, respectively. RESULTS: A significant negative association between valine allele and BC susceptibility in dominant model was found (OR 0.5; 95% CI 0.27-0.93, P = .036). No significant association was found in relation to BC clinicopathological features (tumor size, lymph nodes commitment, histological grade, HER2 overexpression, hormonal receptors, p53, and Ki-67). CONCLUSION: Although this polymorphism did not demonstrate potential as a prognostic marker, it may be a suitable susceptibility marker for BC. PMID- 29417621 TI - Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A second experience. PMID- 29417622 TI - Mad About States. PMID- 29417623 TI - Serum levels of interleukin 6 in schizophrenic patients during treatment augmentation with sarcosine (results of the PULSAR study). AB - OBJECTIVE: Augmentation of sarcosine, a natural inhibitor of the glycine transporter type I, normalizes glutamatergic neurotransmission, having beneficial impact on primary negative symptoms in schizophrenia and may also influence immune system and interleukin 6 (IL-6) levels. AIM: Finding a relationship between initial IL-6 serum concentrations or its changes and severity of symptoms as a result of sarcosine addition to stable antipsychotic treatment. METHOD: Fifity-eight individuals with schizophrenia with predominantly negative symptoms completed a 6-month randomized, double-blind placebo-controlled prospective study. Patients received 2 g of sarcosine (n = 29) or placebo (n = 30) daily per os. We measured IL-6 levels and severity of symptoms at the beginning, after 6 weeks and 6 months. As main clinical tools, we used Positive and Negative Syndrome Scale (PANSS) and Calgary depression scale for schizophrenia (CDSS). RESULTS: Augmentation with sarcosine had no effect on IL-6 serum levels in all time points. We noted significant improvements in negative symptoms, general psychopathology, and total PANSS score in the sarcosine group. We found correlation of initial serum IL-6 with severity of positive symptoms and negative association between IL-6 levels reduction and positive symptoms reduction. CONCLUSIONS: Sarcosine does not significantly affect IL-6 concentrations but IL-6 may be involved in mechanisms related to the presence of positive symptoms. PMID- 29417624 TI - Letter: innovative use of the alfapump system to treat a small hepatocellular carcinoma. PMID- 29417625 TI - Editorial: looking for patients at risk of cirrhosis in the general population many needles in a haystack. PMID- 29417627 TI - Editorial: a novel technology for the assessment of non-alcoholic fatty liver disease. PMID- 29417626 TI - Editorial: weighing the global risk of cancer with thiopurines in inflammatory bowel disease-Authors' reply. PMID- 29417628 TI - Letter: nutritional benefits of rifaximin in cirrhotic patients. PMID- 29417629 TI - Editorial: weighing the global risk of cancer with thiopurines in inflammatory bowel disease. PMID- 29417631 TI - Letter: what gastroenterologists should know about VSL#3. PMID- 29417630 TI - Letter: innovative use of the alfapump system to treat small hepatocellular carcinoma - authors' reply. PMID- 29417632 TI - Letter: the efficacy and safety of rifaximin for the prophylaxis of spontaneous bacterial peritonitis in cirrhotic patients. PMID- 29417633 TI - Mutations and prognosis in myelodysplastic syndromes: karyotype-adjusted analysis of targeted sequencing in 300 consecutive cases and development of a genetic risk model. AB - To develop a genetic risk model for primary myelodysplastic syndromes (MDS), we queried the prognostic significance of next-generation sequencing (NGS)-derived mutations, in the context of the Mayo cytogenetic risk stratification, which includes high-risk (monosomal karyotype; MK), intermediate-risk (non-MK, classified as intermediate/poor/very poor, per the revised international prognostic scoring system; IPSS-R), and low-risk (classified as good/very good, per IPSS-R). Univariate analysis in 300 consecutive patients with primary MDS identified TP53, RUNX1, U2AF1, ASXL1, EZH2, and SRSF2 mutations as "unfavorable" and SF3B1 as "favorable" risk factors for survival; for the purposes of the current study, the absence of SF3B1 mutation was accordingly dubbed as an "adverse" mutation. Analysis adjusted for age and MK, based on our previous observation of significant clustering between MK and TP53 mutations, confirmed independent prognostic contribution from RUNX1, ASXL1, and SF3B1 mutations. Multivariable analysis that included age, the Mayo cytogenetics risk model and the number of adverse mutations resulted in HRs (95% CI) of 5.3 (2.5-10.3) for presence of three adverse mutations, 2.4 (1.6-3.7) for presence of two adverse mutations, 1.5 (1.02-2.2) for presence of one adverse mutation, 5.6 (3.4-9.1) for high-risk karyotype, 1.5 (1.1-2.2) for intermediate-risk karyotype and 2.4 (1.8 3.3) for age >70 years; HR-weighted risk point assignment generated a three tiered genetic risk model: high (N = 65; 5-year survival 2%), intermediate (N = 100; 5-year survival 18%), and low (N = 135; 5-year survival 56%). The current study provides a practically simple risk model in MDS that is based on age, karyotype, and mutations only. PMID- 29417634 TI - Building hospital capacity planning mechanisms in Poland: The impact of 2016/2017 regulatory changes. AB - Capacity planning is a crucial component of modern health care governance. The aim of this paper is to analyze the requirements that need to be met to build effective hospital capacity planning mechanisms in Poland. In this context, the recent regulatory changes strongly influencing hospital sector functioning, including introduction of health care needs maps, capital investment assessment, and hospital network regulations, are analyzed. Some possible ways forward, based on review of international experiences in hospital capacity planning, are discussed. Applied methods include literature review and analysis of statistical data as well as desk analysis of key national regulations related to hospital sector. Results indicate that at the system level, the process of capacity planning involves 4 elements: capital investment in facilities, equipment, and technology; service delivery; allocation of staff; and financial resources. For hospital capacity planning to be effective, the strategic decision at the macrolevel must be complemented by appropriate management of individual hospitals. The major challenge of building hospital capacity planning mechanism in Poland is imbedding it into the overall health system strategy. Because of the lack of such a strategy, the practical implementation of the ad hoc changes, which have been introduced, shows some inconsistencies. The regulations implemented between 2016 and 2017 provided a basis for hospital capacity planning, yet still need evaluation and adjustments. Also, including a mechanism for human resources planning is of crucial importance. The regulations should provide incentives for reducing oversized hospital infrastructure with simultaneous development of the long-term and coordinated care models. PMID- 29417635 TI - Magnetic resonance imaging following regional limb perfusion of gadolinium contrast medium in 26 horses. AB - BACKGROUND: Systemic administration of gadolinium contrast medium is common in small animals to increase lesion conspicuity and determine vascularisation of lesions identified with magnetic resonance imaging (MRI); however, the large volume required for systemic administration limits its use in horses. OBJECTIVES: The purpose of this study was to assess the feasibility of administering a low dose of contrast medium via venous regional limb perfusion. STUDY DESIGN: Prospective clinical study. METHODS: Distal limbs of 26 horses (one limb per horse) were imaged with MRI before and after administration of 5 mL of gadopentetate dimeglumine (Magnevist(r) ) diluted with 5 mL of physiological saline via a palmar/plantar digital vein with a tourniquet in place at the level of the mid aspect of the third metacarpal/metatarsal bone. Commonly assessed structures of the equine distal limb were examined for normal and abnormal contrast enhancement. RESULTS: Twenty-five of 26 horses had adequate contrast enhancement of their distal limb. The lack of adequate contrast enhancement in one limb was likely associated with failure of the tourniquet. No adverse reactions were identified in any horse. One hundred thirty-two lesions were detected, of which, 69 contrast enhanced. Twelve lesions were detected exclusively following contrast enhancement. MAIN LIMITATIONS: Case numbers and lesion variability yielded insufficient data to perform statistical analyses. Histopathology was not performed on sound horses to determine if the imaged structures were normal. CONCLUSIONS: Regional limb perfusion is a feasible method to administer gadolinium contrast material to the equine distal limb for MRI. The enhancement pattern of the equine distal limb in sound horses is described. Contrast enhanced MRI of the distal equine limb helps to further characterise lesions identified with precontrast images, including adhesions and deep digital flexor tendinopathy. Contrast enhanced MRI also aids in identification of additional lesions, such as neovascularisation. PMID- 29417636 TI - Modifying oligoalanine conformation by replacement of amide to ester linkage. AB - Oligo(lactic acid) is an ester-analogue of short oligoalanine sequence and adopts a rigid left-handed helical structure. In this study, oligo(lactic acid) was incorporated into oligoalanine sequences and their conformations were studied by vibrational circular dichroism and electronic circular dichroism spectroscopy. The results suggested that oligo(lactic acid) moiety in these sequences maintains a left-handed helix and increases the conformational propensity of the oligoalanine moiety to form a left-handed polyproline type II-like helix. The importance of the chirality of oligo(lactic acid) moiety for the oligoalanine conformation was also studied. The results obtained in this study should be useful in developing ester-containing oligopeptides that function better than normal peptides. PMID- 29417637 TI - On the chiroptical properties of racemic crystals. AB - In a recent letter on the "Optical activity from racemates", discussed at the 16th International Conference on Chiroptical Spectroscopy in Rennes (June 2017), scientists claimed to have measured the circular dichroism of colored, racemic crystals of two transition metal complexes, observations that "serve to correct a clear deficit in our understanding of the optical properties of racemates." In fact, there is no deficit in our understanding of the optical properties of racemates. Moreover, the measurements presented are unconvincing as evidence of circular dichroism measured in anisotropic crystals and therefore do not inform our understanding of the specific crystals investigated, or racemates generally speaking. PMID- 29417638 TI - Spontaneous reduction of native kidney size involving angiomyolipoma lesions in a kidney transplant recipient with tuberous sclerosis complex. PMID- 29417639 TI - Synthesis of EU-1/ZSM-48 Co-Crystalline Zeolites from High-Silica EU-1 Seeds: Tailoring Phase Proportions and Promoting Long Crystalline-Phase Stability. AB - A facile, specific, seed-assisted strategy for the synthesis of EU-1/ZSM-48 co crystalline zeolites in the presence of hexamethonium ions (HM2+ ) has been developed. EU-1/ZSM-48 co-crystalline zeolites with various phase proportions, with EU-1 in the range of 25 wt %-86 wt %, were obtained by adding high-silica EU 1 seeds (SiO2 /Al2 O3 ratio of 300) and adjusting the synthesis parameters. Not only can the phase proportions of EU-1/ZSM-48 co-crystalline zeolites be controlled, but also the stability period for co-crystallization of the two phases can be extended through varying the amount of EU-1 seeds and the HM2+ template. Moreover, with the increase of the EU-1 proportion in the EU-1/ZSM-48 co-crystalline, the framework SiO2 /Al2 O3 ratios of EU-1 phase promotes steadily. Major differences in acidity and textural properties of the EU-1/ZSM-48 co-crystalline zeolites (Coz) were found with varying phase proportions, due to their distinct topological structures, crystal morphology and asymmetry between the EU-1 and ZSM-48 phases. For instance, the EU-1/ZSM-48 zeolite containing 75 wt % of EU-1 (Coz-75) possesses specific acidity and mesoporous characteristics, showing an excellent catalytic activity and stability in n-hexane cracking reaction. Compared to EU-1, ZSM-48, and a mechanical mix of the two zeolites (Mix 75), Coz-75 resulted in the highest hexane conversion and yields of light olefins, with a propylene yield, in particular, up to 38.3 wt %, which is 6.3 % more than that of the Mix-75 sample. PMID- 29417640 TI - Dynamic Protein-Metal Ion Networks: A Unique Approach to Injectable and Self Healable Metal Sulfide/Protein Hybrid Hydrogels with High Photothermal Efficiency. AB - A new strategy is proposed to fabricate adaptable protein-based hydrogel networks with both injectable and self-healable properties. By mixing proteins and metal ions under alkaline conditions, the metal ions can crosslink proteins into protein-metal ion dynamic networks. Subsequently, the metal ions can react with the cysteine residues of protein to in situ form corresponding metal sulfide NPs with ultra-small size, which leads to nanocomposite hydrogels with adaptable structures. This approach is general and a series of metal sulfide NP in situ embedded nanocomposite hydrogels were obtained. As an example, a Bi2 S3 -BSA hydrogel with tunable networks is shown to serve as an injectable, self-healable photothermal agent for the treatment of tumors. Our finding paves a new avenue for the preparation of injectable and self-healable hydrogels with potential applications in biomedicine. PMID- 29417641 TI - Role of computed tomography-calculated intraparenchymal tumor volume in assessment of patients undergoing partial nephrectomy. AB - OBJECTIVES: To determine the complexity of renal masses by using an objective novel imaging parameter (intraparenchymal tumor volume) based on computed tomography scans, to correlate this parameter to perioperative outcomes and to the RENAL nephrometry score. METHODS: After institutional review board approval, 87 patients who underwent partial nephrectomy between 2012 and 2016 at Singapore General Hospital, Singapore, were retrospectively analyzed. Preoperative computed tomography intravenous pyelogram scans were reviewed by a single senior radiologist who calculated the intraparenchymal tumor volume. Once the intraparenchymal tumor volume scores were obtained, they were compared with perioperative renal and surgical outcomes, and nephrometry scores. Furthermore, intraparenchymal tumor volume was subdivided into two categories, low and high intraparenchymal tumor volume, both using the 89th percentile. RESULTS: The mean patient age was 60 years, and the mean tumor size was 2.9 cm. The mean nephrometry score was 7.8, and the mean intraparenchymal tumor volume score was 12.7 cm3. The cut-off for high intraparenchymal tumor volume was >27.26 cm3. As a continuous variable, intraparenchymal tumor volume showed a significant relationship with the percentage of creatinine change (P = 0.009) and nephrometry scores (P < 0.001). As a categorical variable, high intraparenchymal tumor volume showed significance when compared with absolute creatinine change (P = 0.018), percentage of creatinine change (P = 0.004) and nephrometry score (P < 0.001). CONCLUSIONS: Intraparenchymal tumor volume represents a novel objective tool based on computed tomography imaging to determine the complexity of a renal mass. This tool correlates with renal functional outcomes of partial nephrectomy, and it also shows good correlation with RENAL nephrometry score. PMID- 29417642 TI - Carvacrol induces cytotoxicity in human cervical cancer cells but causes cisplatin resistance: Involvement of MEK-ERK activation. AB - Carvacrol has been shown to possess anticancer activity, but the mechanism is unknown, as well as the possibility of interaction with anticancer drugs. The aim of this study was to investigate the role of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling in carvacrol induced human cervical cancer HeLa cell cytotoxicity. In addition, we studied sensitization of HeLa cells to cisplatin (CP) by carvacrol. Both carvacrol and CP showed dose-dependent cytotoxicity against HeLa cells and activated ERK1/2. The MEK inhibitor PD325901 suppressed ERK expression and further increased cytotoxicity of carvacrol but increased viability of CP-treated cells by modulating apoptosis. The MEK inhibitor also increased microtubule-associated protein 1A/1B-light chain 3 beta expression in CP treatment. Cotreatment with CP and carvacrol resulted in increased viability of the cancer cells compared with CP treatment, which was associated with the suppression of apoptosis. MEK inhibition decreased the cell viability, without changes in apoptosis. Concomitantly, carvacrol increased CP-induced expression of light chain 3 beta, which was enhanced by MEK inhibition. The results of the current study suggest the opposite role of ERK1/2 in carvacrol and CP-induced HeLa cell cytotoxicity. Interestingly, carvacrol induced CP resistance in HeLa cells through ERK1/2 independent suppression of apoptosis and ERK1/2-dependent modulation of autophagy. PMID- 29417643 TI - High throughput image cytometry micronucleus assay to investigate the presence or absence of mutagenic effects of cold physical plasma. AB - Promising cold physical plasma sources have been developed in the field of plasma medicine. An important prerequisite to their clinical use is lack of genotoxic effects in cells. During optimization of one or even different plasma sources for a specific application, large numbers of samples need to be analyzed. There are soft and easy-to-assess markers for genotoxic stress such as phosphorylation of histone H2AX (gammaH2AX) but only few tests are accredited by the OECD with regard to mutagenicity detection. The micronucleus (MN) assay is among them but often requires manual counting of many thousands of cells per sample under the microscope. A high-throughput MN assay is presented using image flow cytometry and image analysis software. A human lymphocyte cell line was treated with plasma generated with ten different feed gas conditions corresponding to distinct reactive species patterns that were investigated for their genotoxic potential. Several millions of cells were automatically analyzed by a MN quantification strategy outlined in detail in this work. Our data demonstrates the absence of newly formed MN in any feed gas condition using the atmospheric pressure plasma jet kINPen. As positive control, ionizing radiation gave a significant 5-fold increase in micronucleus frequency. Thus, this assay is suitable to assess the genotoxic potential in large sample sets of cells exposed chemical or physical agents including plasmas in an efficient, reliable, and semiautomated manner. Environ. Mol. Mutagen. 59:268-277, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29417644 TI - Pregnancy and herbal medicines: An unnecessary risk for women's health-A narrative review. AB - The indiscriminate use of herbal medicines to prevent or to heal diseases or even the use for questionable purposes such as weight loss has received both interest and scrutiny from the scientific community and general public alike. An increasing number of women put their own and the unborn child's health at risk due to a lack of knowledge about the phytochemical properties and adequate use of herbal medicine (phytomedicines or herbal supplements) and lack of communication with their healthcare provider. The purpose of this narrative review was to summarize the use of herbal medicines during pregnancy and their potential toxic effects to highlight the importance of caution when prescribing herbal medicines or supplements for women, because, in addition to suffering interactions and a great amount of information obtained in preclinical predictive studies, assessment of nephrotoxicity, neurotoxicity, hepatotoxicity, genotoxicity, and teratogenicity of traditional medicinal herbs still remains scarce in the clinical setting. PMID- 29417645 TI - Profiling of miRNAs in neonatal cloned bovines with collapsed lungs and respiratory distress. AB - Neonatal respiratory distress is a major mortality factor in cloned animals; however, the pathogenesis of this disease has rarely been investigated. Previous studies have shown that miRNAs regulate critical genes related to lung development, cell differentiation, surfactant synthesis, secretion and lung disease. This study aimed to examine differentially expressed miRNAs in collapsed lungs of cloned bovine neonates and normal lungs in order to identify key pathways and functions that might be related to the pathogenesis of neonatal respiratory distress. In this study, miRNA transcriptomes of collapsed lungs of neonatal cloned bovines and normal lungs were analysed by next-generation sequencing and the results were validated using quantitative real-time PCR (qRT PCR). A total of 177 differentially expressed miRNAs were identified in the two groups (fold change > 2, RPM >= 5), some of which were associated with type II cell differentiation, for example, mmu-miR-29a-5p_L-2R+1, hsa-miR-200c-5p_L-1R+1 and mmu-miR-18a-3p_R+1. The differentially expressed miRNAs were predicted to 6,031 target genes. By Gene Ontology (GO) and Kyoto Encyclopeida of Genes and Genomes (KEGG) DATA base, 133 significant GO terms (p < .05) and 13 significant KEGG pathways (p < .05) were obtained. Many of them were associated with lung development and surfactant homoeostasis, such as lipid biosynthetic processes, protein transport, endocytosis, lysosome, endosome, Golgi apparatus and membrane. Our results of miRNAs express profiles may partially explain the respiratory distress and lung collapse in neonatal bovine clones and could provide novel insights into roles of miRNAs in regulation of lung collapse and neonatal respiratory distress in cloned farm animals. PMID- 29417646 TI - Heavy drinkers of Ilex paraguariensis beverages show lower lipid profiles but higher body weight. AB - Obesity is a widely recognized risk factor for several diseases, reaching an epidemic magnitude worldwide. Natural polyphenols may improve blood lipids and body weight, but their clinical relevance in the general population remains unclear. Thus, we aimed to analyze the relationship of intake of Ilex paraguariensis (I. paraguariensis) beverages to lipid profiles and body weight in a large patient population. Patients were recruited to participate in an educational program to change habits to a healthy lifestyle. Anamnesis, clinical and laboratory assessments were conducted at study enrollment and during follow up. I. paraguariensis beverages were defined according to preparation as obtained by repeated cold water extraction (CWE), hot water infusions, or water and sugar decoction. Heavy drinkers were defined as those persons consuming >1 L/day of one or more preparation types. Participants (N = 18,287) aged >=18 years entered the study. Overall prevalence of I. paraguariensis consumption was 91.2%. All three forms were drunk by 35.7%, whereas CWE + hot water infusion and CWE alone by 28.4% and 14.5% participants, respectively. Heavy CWE drinkers had lower total cholesterol (191.4 +/- 49.4 vs. 194.6 +/- 48.3 mg/dl, p = .02) and lower low density lipoprotein cholesterol (118.6 +/- 38.9 vs. 121.2 +/- 47.1 mg/dl, p = .001), but body weight was higher (81.1 +/- 16.8 vs. 77.2 +/- 16.4 kg, p < .0001) compared with moderate drinkers. Fasting glucose was lower (104.5 +/- 48.7 vs. 107.2 +/- 49.5 mg/dl, p < .001), and consumption of carbohydrates was higher (36.3% vs. 28.7%, p < .001). A low-lipids high-body-weight paradox could be observed in a population of heavy drinkers of I. paraguariensis beverages. Induced hypoglycemia and compensatory higher intake of refined carbohydrates may represent a possible cause. PMID- 29417647 TI - Fracture Resistance of Titanium-Based Lithium Disilicate and Zirconia Implant Restorations. AB - PURPOSE: To evaluate the fracture resistance of a newer lithium disilicate abutment material. MATERIALS AND METHODS: A premolar-shaped implant crown was designed using CAD/CAM software, and four groups of implant and crown combinations were milled: (1) lithium-disilicate hybrid-abutment crown; (2) "screwmentable" lithium-disilicate hybrid abutment/lithium-disilicate crown with screw channel; (3) lithium-disilicate hybrid abutment/lithium-disilicate crown; and (4) zirconia hybrid abutment/lithium-disilicate crown (control). The specimens were cemented to a titanium-base implant system, subjected to thermocycling and cyclic loading, and fractured in a material testing device. RESULTS: The lithium-disilicate hybrid-abutment crown had significantly greater fracture load than all the other groups, which were not significantly different from each other. CONCLUSIONS: Based on fracture load, the new lithium-disilicate hybrid-abutment material may serve as a viable alternative to the use of zirconia as a hybrid-abutment material. PMID- 29417648 TI - Depletion of amyloid-beta peptides from solution by sequestration within fibril seeded hydrogels. AB - Aggregation of amyloid-beta (Abeta) peptides in brain tissue leads to neurodegeneration in Alzheimer's disease (AD). Regardless of the kinetics or detailed mechanisms of Abeta aggregation, aggregation can only occur if Abeta concentrations exceed their local equilibrium solubility values. We propose that excess Abeta peptides can be removed from supersaturated solutions, including solutions in biological fluids, by the addition of hydrogels that are seeded with Abeta fibril fragments. Fibril growth within the hydrogels then sequesters excess peptides until equilibrium concentrations are reached. Experiments with 40- and 42-residue Abeta peptides (Abeta40 and Abeta42) in phosphate buffer at 24 degrees C and in filtered fetal bovine serum at 37 degrees C, using crosslinked polyacrylamide hydrogels, demonstrate the validity of this concept. Abeta sequestration in fibril-seeded hydrogels (or other porous media) may prove to be a useful technique in experiments with animal models of AD and may represent a possible approach to preventing or slowing the progression of AD in humans. PMID- 29417649 TI - 'Addressed to you not as a smoker... but as a doctor': doctor-targeted cigarette advertisements in JAMA. AB - BACKGROUND AND AIM: During the mid-20th century tobacco companies placed advertisements in medical journals to entice physicians to smoke their brand and, more importantly, to recommend it to their patients. They have been little studied, in part because advertising sections in medical journals are almost universally discarded before binding. This study aimed to define the themes and techniques used in doctor-targeted tobacco advertisements that appeared in American medical journals in the mid-20th century and determine the motivations and tactics of the tobacco industry in engaging the medical profession in this way. METHODS: Doctor-targeted tobacco advertisements from JAMA and the New York State Medical Journal appearing between 1936 and 1953 were studied. These were obtained from the New York Academy of Medicine and the UCSF Truth database of tobacco industry documents. Content analysis of advertising slogans and imagery was conducted. Using internal tobacco industry documents, we examined the relationship between tobacco advertisers and medical journals. RESULTS: Among the 519 doctor-targeted advertisements, 13 brands were represented, with two (Philip Morris and Camel) accounting for 84%. Correspondence between tobacco advertisers and medical journal editors reveals the potent influence of revenue to the sponsoring society and personal compensation derived from consulting arrangements. Content analysis of the advertisements revealed much flattery of doctors and arguments professing the harmlessness of the company's brand. CONCLUSIONS: Analysis of doctor-targeted tobacco advertisements in American medical journals from 1936 to 1953 suggest that tobacco companies targeted physicians as a potential sales force to assuage the public's fear of health risks and to recruit them as allies against negative publicity. Tobacco companies also appeared to try, through the substantial advertising revenue passed by journals to their parent medical societies, to temper any possible opposition by organized medicine. PMID- 29417651 TI - Thyroidectomy in patients who have undergone gastric bypass surgery. AB - BACKGROUND: Morbid obesity is a chronic condition that may be challenging to treat. Gastric bypass surgery is used to treat morbid obesity and its complications. Hypocalcemia, a known complication after thyroidectomy, is usually transient and treatable. There is a growing body of literature indicating that patients with previous gastric bypass surgery are at an increased risk for recalcitrant, symptomatic hypocalcemia after thyroidectomy. The management of hypocalcemia in patients with prior gastric bypass surgery may be exceedingly difficult. METHODS: Relevant articles published between 2008 and January 2017 were reviewed by topic. The review of literature was conducted using a systematic search of database resources, such as PubMed and EMBASE. RESULTS: Prior gastric bypass surgery may be an independent risk factor for developing profound hypocalcemia after thyroid surgery. CONCLUSION: Refractory hypocalcemia in patients who have undergone gastric bypass surgery is underreported. Careful consideration should be given to performing staged thyroidectomy and, in some cases, reversal of the bariatric surgery. PMID- 29417652 TI - Persistence of self-injury, aggression and property destruction in children and adults with tuberous sclerosis complex. AB - BACKGROUND: Individuals with tuberous sclerosis complex (TSC) are at increased risk of developing self-injurious behaviour. The persistence of this deleterious behaviour over years is reported in aetiologically heterogeneous samples to be between 60% and 80% but is unknown for TSC. METHOD: In this study, we determined the 3-year persistence of self-injury in a sample (n = 52) of children (with and without ID) and adults (with ID) with TSC and examined characteristics associated with persistence. RESULTS: Findings for self-injury were contrasted to those for aggression and property destruction to examine the specificity of results to this behaviour. Self-injury was persistent in 84.6% of those with TSC who showed this behaviour, in contrast to 66.7% both for aggression and destruction. Persistent self-injury was associated with poor self-help skills, greater overactivity/impulsivity and more behavioural indicators of pain. These latter two characteristics were also associated with persistent aggression. No characteristics were associated with persistence of property destruction. CONCLUSION: These findings suggest that self-injurious behaviours in individuals with TSC, together with aggressive and destructive behaviours, are highly persistent and would benefit from targeted intervention. Poor adaptive skills, overactivity/impulsivity and painful health conditions may differentiate those at most risk for persistent self-injury or aggression. PMID- 29417650 TI - A peptide-display protein scaffold to facilitate single molecule force studies of aggregation-prone peptides. AB - Protein aggregation is linked with the onset of several neurodegenerative disorders, including Parkinson's disease (PD), which is associated with the aggregation of alpha-synuclein (alphaSyn). The structural mechanistic details of protein aggregation, including the nature of the earliest protein-protein interactions, remain elusive. In this study, we have used single molecule force spectroscopy (SMFS) to probe the first dimerization events of the central aggregation-prone region of alphaSyn (residues 71-82) that may initiate aggregation. This region has been shown to be necessary for the aggregation of full length alphaSyn and is capable of forming amyloid fibrils in isolation. We demonstrate that the interaction of alphaSyn71-82 peptides can be studied using SMFS when inserted into a loop of protein L, a mechanically strong and soluble scaffold protein that acts as a display system for SMFS studies. The corresponding fragment of the homolog protein gamma-synuclein (gammaSyn), which has a lower aggregation propensity, has also been studied here. The results from SMFS, together with native mass spectrometry and aggregation assays, demonstrate that the dimerization propensity of gammaSyn71-82 is lower than that of alphaSyn71-82 , but that a mixed alphaSyn71-82 : gammaSyn71-82 dimer forms with a similar propensity to the alphaSyn71-82 homodimer, slowing amyloid formation. This work demonstrates the utility of a novel display method for SMFS studies of aggregation-prone peptides, which would otherwise be difficult to study. PMID- 29417654 TI - Prevalence of adverse pathological features in 1 to 4 cm low-risk differentiated thyroid carcinoma. AB - BACKGROUND: The American Thyroid Association (ATA) recommends thyroid lobectomy for 1 to 4 cm tumors without adverse features. We studied the prevalence of adverse pathological features in patients eligible for unilateral lobectomy. METHODS: We conducted a retrospective study of patients who underwent total thyroidectomy. Patients with differentiated thyroid cancer (DTC) with tumors measuring 1 to 4 cm with no known preoperative adverse features were included in this study. Patients with nodal and distant metastasis, tumors <1 cm to > 4 cm, age < 17 years old, and gross extrathyroidal extension were excluded. Patients with bilateral nodularity on imaging were excluded from the final analysis on adverse features. RESULTS: There were 59.1% of patients undergoing thyroidectomy with tumors measuring 1 to 4 cm and no preoperatively known adverse features who were eligible for lobectomy under current ATA guidelines who would have needed a completion thyroidectomy after pathological analysis of the index tumor. CONCLUSION: Two thirds of the patients may require a completion thyroidectomy if unilateral lobectomy is done in tumors measuring 1 to 4 cm based on adverse pathological features. PMID- 29417655 TI - Glycan distribution and density in native skin's stratum corneum. AB - BACKGROUND: The glycosylation of proteins on the surface of corneocytes is believed to play an important role in cellular adhesion in the stratum corneum (SC) of human skin. Mapping with accuracy the localization of glycans on the surface of corneocytes through traditional methods of immunohistochemistry and electron microscopy remains a challenging task as both approaches lack enough resolution or need to be performed in high vacuum conditions. MATERIALS AND METHODS: We used an advanced mode of atomic force microscope (AFM), with simultaneous topography and recognition imaging to investigate the distribution of glycans on native (no chemical preparation) stripped samples of human SC. The AFM cantilever tips were functionalized with anti-heparan sulfate antibody and the lectin wheat germ agglutinin (WGA) which binds specifically to N-acetyl glucosamine and sialic acid. RESULTS: From the recognition imaging, we observed the presence of the sulfated glycosaminoglycan, heparan sulfate, and the glycans recognized by WGA on the surface of SC corneocytes in their native state. These glycans were found associated with bead-like domains which represent corneodesmosomes in the SC layers. Glycan density was calculated to be ~1200 molecules/MUm2 in lower layers of SC compared to an important decrease, (~106 molecules/MUm2 ) closer to the surface due probably to corneodesmosome degradation. CONCLUSION: Glycan spatial distribution and degradation is first observed on the surface of SC in native conditions and at high resolution. The method used can be extended to precisely localize the presence of other macromolecules on the surface of skin or other tissues where the maintenance of its native state is required. PMID- 29417653 TI - Functional proteomic analysis of crossbred (Holstein Friesian * Sahiwal) bull spermatozoa. AB - Male infertility is one of the prime concerns of dairy cattle production. The study was designed to find out differentially expressed proteins in categorized crossbred (Holstein Friesian * Sahiwal) bull semen to serve as potential biomarkers for male infertility. Frozen crossbred bull semen with satisfactory phenotypic records were defined as "good" and "poor" based on their fertility rates. A total of 1,547 proteins were detected in bull spermatozoa using liquid chromatography-mass spectrometer (LC-MS/MS) analysis. Results revealed that 558 (36.1%) and 653 (42.2%) proteins were expressed to good and poor quality bull spermatozoa, respectively. A total of 336 proteins (21.7%) were reported to be unique for both good and poor quality bull semen, and among the common proteins, 224 (66.7%) and 112 (33.3%) were up- and downregulated in good and poor quality categorized bull semen, respectively. Gene Ontology analysis of global proteomes identified different signalling pathways, and most of them were related to cellular motility, immune systems as well as cellular metabolisms. The distinctive presence of some of the proteins may provide an insight into the molecular mechanistic role played by these proteins in crossbred bull infertility. PMID- 29417656 TI - Quality of life during the first year after partial laryngectomy: Longitudinal study. AB - BACKGROUND: This prospective study was conducted to assess changes in quality of life (QOL) of patients who undergo a partial laryngectomy. METHODS: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires Core and Head and Neck (EORTC-QLQ-C30, QLQ-H&N35) were used preprocedure (n = 218), 1 week (n = 159), 3 months (n = 122), and 1 year after partial laryngectomy (n = 88). Changes over time were analyzed with the Wilcoxon signed rank test and the Holm-Bonferroni method, and interpreted regarding clinical relevance. RESULTS: Most subscales worsened 1 week postprocedure, but many recovered to baseline level after 1 year. Dyspnea and cognitive functioning deteriorated over time, with worst scores recorded after 1 year. Financial difficulties and fatigue increased after surgery and maintained that level throughout the follow-up period; sticky saliva remained worse than at baseline, despite some improvements over time. CONCLUSION: The discovered limitations of QOL should be observed more closely during follow-up treatment, and patients should be informed about these potential effects before partial laryngectomy. PMID- 29417657 TI - Digit ratio (2D:4D) in Chinese women with gastric cancer. AB - OBJECTIVES: Digit ratio, especially the second-to-fourth digit ratio (2D:4D), is a proxy indicator for prenatal exposure and sensitivity to sexual hormones which may influence the susceptibility to certain cancers. The aim of the present study was to investigate whether there is a possible association between 2D:4D and gastric cancer (GCA) in north Chinese women. METHODS: Photographs of the left and right hands of 167 women (controls: 113; patients: 54) were collected. Left hand, right hand, and right minus left hand (Dr-l) 2D:4D were analyzed and compared. RESULTS: The GCA group presented significantly lower 2D:4D than controls (left: P < .01; right: P < .05). No significant difference was observed in Dr-l between the two groups. In patients, there were no correlations between 2D:4D and age at GCA or tumor staging. CONCLUSIONS: Decreased 2D:4D (especially of the left hand) may suggest a higher prenatal testosterone (lower prenatal estrogen) exposure in north Chinese women with GCA. PMID- 29417658 TI - Reductions in complexity of mitochondrial genomes in lichen-forming fungi shed light on genome architecture of obligate symbioses. AB - Symbioses among co-evolving taxa are often marked by genome reductions such as a loss of protein-coding genes in at least one of the partners as a means of reducing redundancy or intergenomic conflict. To explore this phenomenon in an iconic yet under-studied group of obligate symbiotic organisms, mitochondrial genomes of 22 newly sequenced and annotated species of lichenized fungi were compared to 167 mitochondrial genomes of nonlichenized fungi. Our results demonstrate the first broad-scale loss of atp9 from mitochondria of lichenized fungi. Despite key functions in mitochondrial energy production, we show that atp9 has been independently lost in three different lineages spanning 10 of the 22 studied species. A search for predicted, functional copies of atp9 among genomes of other symbionts involved in each lichen revealed the full-length, presumably functional copies of atp9 in either the photosynthetic algal partner or in other symbiotic fungi in all 10 instances. Together, these data yield evidence of an obligate symbiotic relationship in which core genomic processes have been streamlined, likely due to co-evolution. PMID- 29417659 TI - Ethical challenges to research in the criminal justice system. PMID- 29417660 TI - Do terrorists suffer from alexithymia? PMID- 29417661 TI - Shining lights in dark corners of people's lives: Reaching consensus for people with complex mental health difficulties who are given a diagnosis of personality disorder. PMID- 29417662 TI - Reticular rash in a neonate. PMID- 29417663 TI - Reticular rash in a neonate. PMID- 29417664 TI - Discussions on limiting life-sustaining treatment for newborns. PMID- 29417666 TI - Pulmonary and hepatic cystic lesions in a child. PMID- 29417665 TI - Pulmonary and hepatic cystic lesions in a child. PMID- 29417667 TI - Meningococcal Meningitis Complicated by Ventriculitis in an Infant. PMID- 29417668 TI - Teaching children health literacy. PMID- 29417669 TI - 'Babble': A smartphone app for parents who have a baby in the neonatal unit. PMID- 29417671 TI - Perplexing perinatal practices. PMID- 29417670 TI - A Case of the Stomach Flu. PMID- 29417672 TI - Unintentional fatal child drowning in the bath: A 12-year Australian review (2002 2014). AB - AIM: To establish the prevalence of unintentional fatal drowning in baths involving children <18 years in Australia and to identify causal factors to underpin prevention. METHODS: We report a total population study of all childhood (0-17 years) unintentional drowning fatalities in baths (bathtubs, spa baths and showers) in Australia between 1 July 2002 and 30 June 2014. Demographic, forensic and aetiological data (including co-bathing, use of bath aids, supervision and enactment of cardiopulmonary resuscitation) were documented for each victim. RESULTS: Seventy-eight children were identified; two thirds (66.7%) were under 2 years old, of which 43.6% were aged less than 1 year (1.0/100 000/annum) and 23.1% 1-2 years (0.27/100 000/annum). Nine older children (10-17 years) also drowned. Common causes included: infants and children unable to hold their head out of water while unsupervised and associated pre-existing medical conditions, including epilepsy. All children who drowned were left without adult supervision. No child drowned in a bath with water deeper than 40 cm (M = 19.4 cm). Custodian reported 'time left unsupervised' ranged from 30 s to 60 min. Children with pre existing medical conditions were, on average, older (9.9 years; confidence interval: 7.9-11.9) and left unsupervised for longer (M = 15.4 min; confidence interval: 3.8-27.1) than those without. CONCLUSIONS: On average, 6.5 children drown every year in baths in Australia. Children aged younger than 1 year are most affected, with both genders equally represented. Infants and toddlers left unsupervised, false confidence in the preventive role of bath aids, unrealistic expectations in the supervisory capabilities of co-bathing children and epilepsy remain threats to children in the bath. PMID- 29417673 TI - Autism Spectrum Disorder. PMID- 29417674 TI - Screening for obesity in children and adolescents. PMID- 29417675 TI - Evie. PMID- 29417676 TI - Diagnostic Outcomes of Children Referred for Multidisciplinary Assessment. PMID- 29417677 TI - Quik-Wee. PMID- 29417678 TI - Re: Low-molecular-weight heparin associated with reduced fetal fraction and subsequent false- negative cell-free DNA test result for trisomy 21. PMID- 29417679 TI - Re: Monochorionic diamniotic twin pregnancy with selective fetal growth restriction Type II: sonographic and fetoscopic findings of poor prognosis. PMID- 29417681 TI - Erratum. PMID- 29417680 TI - Re: Validation of prediction model for successful vaginal birth after Cesarean delivery based on sonographic assessment of hysterotomy scar. A. Baranov, K. A. Salvesen and O. Vikhareva. Ultrasound Obstet Gynecol 2018; 51: 189-193. PMID- 29417682 TI - Re: Placental histopathology associated with pre-eclampsia: a systematic review and meta-analysis. PMID- 29417683 TI - Re: International Endometrial Tumor Analysis (IETA) terminology in women with postmenopausal bleeding and sonographic endometrial thickness >= 4.5 mm: agreement and reliability study. P. Sladkevicius, A. Installe, T. Van den Bosch, D. Timmerman, B. Benacerraf, L. Jokubkiene, A. Di Legge, A. Votino, L. Zannoni, B. De Moor, B. De Cock, B. Van Calster and L. Valentin. Ultrasound Obstet Gynecol 2018; 51: 259-268. PMID- 29417684 TI - Reply. PMID- 29417685 TI - Reply. PMID- 29417686 TI - Reply. PMID- 29417687 TI - Role of adjuvant chemoradiotherapy in T4N0 stage IV head and neck cancer: A National Cancer Database analysis. AB - BACKGROUND: The purpose of this study was to evaluate the role of postoperative adjuvant radiotherapy (surgery + adjuvant RT) versus adjuvant chemoradiotherapy (surgery + adjuvant CRT) in patients with T4N0M0, stage IV head and neck squamous cell carcinoma (HNSCC). METHODS: Between 1998 and 2011, 3518 and 885 patients were treated with surgery + adjuvant RT and surgery + adjuvant CRT, respectively. Three-year overall survival (OS) rates were determined and crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were computed. RESULTS: Median follow-up was 41.8 months with 2193 reported deaths. The 3-year OS was 67.5% for surgery + adjuvant RT and 70.5% for surgery + adjuvant CRT (P = .013). For negative margins, the corresponding 3-year OS was 70.1% and 74.9% (P = .005). For positive margins, the corresponding 3-year OS was 56.0% and 60.6% (P = .079). On multivariate analysis, the beneficial effect for adjuvant CRT over adjuvant RT was not significant (HR 0.90; CI 0.79-1.03; P = .124). CONCLUSION: In this cohort of patients with T4N0 HNSCC treated with surgery, there was no observed survival benefit of adjuvant CRT over adjuvant RT on multivariate analysis. PMID- 29417688 TI - PAGANI Toolkit: Parallel graph-theoretical analysis package for brain network big data. AB - The recent collection of unprecedented quantities of neuroimaging data with high spatial resolution has led to brain network big data. However, a toolkit for fast and scalable computational solutions is still lacking. Here, we developed the PArallel Graph-theoretical ANalysIs (PAGANI) Toolkit based on a hybrid central processing unit-graphics processing unit (CPU-GPU) framework with a graphical user interface to facilitate the mapping and characterization of high-resolution brain networks. Specifically, the toolkit provides flexible parameters for users to customize computations of graph metrics in brain network analyses. As an empirical example, the PAGANI Toolkit was applied to individual voxel-based brain networks with ~200,000 nodes that were derived from a resting-state fMRI dataset of 624 healthy young adults from the Human Connectome Project. Using a personal computer, this toolbox completed all computations in ~27 h for one subject, which is markedly less than the 118 h required with a single-thread implementation. The voxel-based functional brain networks exhibited prominent small-world characteristics and densely connected hubs, which were mainly located in the medial and lateral fronto-parietal cortices. Moreover, the female group had significantly higher modularity and nodal betweenness centrality mainly in the medial/lateral fronto-parietal and occipital cortices than the male group. Significant correlations between the intelligence quotient and nodal metrics were also observed in several frontal regions. Collectively, the PAGANI Toolkit shows high computational performance and good scalability for analyzing connectome big data and provides a friendly interface without the complicated configuration of computing environments, thereby facilitating high-resolution connectomics research in health and disease. PMID- 29417689 TI - Efficacy of high-dose steroids for bronchiolitis obliterans syndrome post pediatric hematopoietic stem cell transplantation. AB - BOS is the pulmonary manifestation of cGvHD post-allogeneic HSCT. Survival and treatment of this often fatal complication have not improved over the last 20 years and there is no clear standard of care. For the past 10 years, BOS was treated in our center with monthly cycles of HDPS. We reviewed the outcomes of patients with post-HSCT BOS who met the diagnostic criteria for BOS as per the NIH consensus and were treated with at least one cycle of methylprednisolone at a dose of 10-30 mg/kg/d*3 d. We collected demographic and clinical data, responses to treatment and results of pulmonary function tests at several time points. Between January 2007 and January 2014, 12 patients were treated with HDPS for post-HSCT BOS. Five patients (42%) had a good response to treatment; four patients (33%) stabilized with moderate lung disease; and three patients (25%) progressed to end-stage disease. No significant acute side effects attributable to the HDPS treatment were identified. HDPS may be an effective treatment option for all but the most severely ill patients with post-HSCT BOS. PMID- 29417691 TI - Incidence, risk factors, and outcomes related with neurological events after liver transplantation in adult and pediatric recipients. AB - Controversy exists whether NE after LT are more frequently observed in children or adults. We aimed to compare the incidence and outcomes for NE after LT in pediatric and adult recipients. A single-center cohort study, including all LT between 2001 and 2013, was performed. Definition of NE included impaired consciousness, delirium, seizures, focal neurologic deficit, visual impairment, or slurred speech. A cohort of 443 consecutive LT recipients was included: 307 adults and 136 children. Cumulative incidence of NE was similar between adults 15% (n = 41) and children 16% (n = 20; P = .73) with a complete neurological recovery in 62% and 95% of the patients, respectively (P < .0001). Adults with NE had significantly lower survival (70% vs 76%; P = .015) with a HR of 2.36; this was similarly observed in children (45% vs 66%; HR 2.05, CI 0.66; 6.34). Independent risk factors for NE in adults were pre-LT ascites, delta sodium, and post-LT hypomagnesemia, whereas in children pre-LT encephalopathy >=II and serum albumin were associated with NE. Although a similar incidence of NE after LT was observed, children were more likely to achieve neurological recovery. Risk factors for the development of NE are difficult to assess in both populations. PMID- 29417692 TI - Advantages of different care services for reducing neuropsychiatric symptoms in dementia patients. AB - BACKGROUND: It is assumed that care services effectively reduce behavioural and psychological symptoms of dementia (BPSD). However, it is unclear which care services are effective for reducing specific BPSD. The aim of this study was to clarify which care services were recognized by care specialists as being effective for reducing each of 11 BPSD. METHODS: We sent unsigned questionnaires to care specialists in Japan. The questionnaires asked specialists to choose from 12 kinds of care services the most, second-most, and third-most effective service for reducing each of 11 BPSD. The most effective service was scored as 3 points, the second-most was 2 points, and the third-most was 1 point. Specialists were also asked to describe why they chose each service. The 12 kinds of care services were categorized into four categories: (i) home-visit; (ii) outpatient; (iii) short-stay; and (iv) facility. Total scores for each category were analyzed using a two-way anova. The reasons care specialists chose each service were analyzed using morphological analysis, and representative reasons were extracted. RESULTS: A total of 103 questionnaires were returned. Of the four service categories, outpatient services yielded the highest score for reducing apathy (P < 0.001) due to the effectiveness of participating in recreation and receiving stimulation. Facility services yielded the highest score for reducing aberrant motor behaviour (P < 0.001). Short-stay services yielded the lowest score for reducing depression (P < 0.001). For eight other kinds of BPSD, there were no significant differences between home-visit and facility services or between outpatient and facility services. CONCLUSIONS: Care specialists reported that effective care services for reducing BPSD differed among types of BPSD. In-home care services might be effective at reducing many BPSD except for aberrant motor behaviour, suggesting that greater use of in-home care services might enable people with BPSD to live in their homes for longer. PMID- 29417690 TI - Metastatic ability and the epithelial-mesenchymal transition in induced cancer stem-like hepatoma cells. AB - Cancer stem cells (CSCs) are thought to play important roles in cancer malignancy. Previously, we successfully induced sphere cancer stem-like cells (CSLCs) from several cell lines and observed the property of chemoresistance. In the present study, we examined the metastatic potential of these induced CSLCs. Sphere cancer stem-like cells were induced from a human hepatoma cell line (SK HEP-1) in a unique medium containing neural survival factor-1. Splenic injection of cells into immune-deficient mice was used to assess hematogenous liver metastasis. Transcriptomic strand-specific RNA-sequencing analysis, quantitative real-time PCR, and flow cytometry were carried out to examine the expression of epithelial-mesenchymal transition (EMT)-related genes. Splenic injection of CSLCs resulted in a significantly increased frequency of liver metastasis compared to parental cancer cells (P < .05). In CSLCs, a mesenchymal marker, Vimentin, and EMT-promoting transcription factors, Snail and Twist1, were upregulated compared to parental cells. Correspondingly, significant enrichment of the molecular signature of the EMT in CSLCs relative to parental cancer cells was shown (q < 0.01) by RNA-sequencing analysis. This analysis also revealed differential expression of CD44 isoforms between CSLCs and parental cancer cells. Increasing CD44 isoforms containing an extra exon were observed, and the standard CD44 isoform decreased in CSLCs compared to parental cells. Interestingly, another CD44 variant isoform encoding a short cytoplasmic tail was also upregulated in CSLCs (11.7-fold). Our induced CSLCs possess an increased liver metastatic potential in which promotion of the EMT and upregulation of CD44 variant isoforms, especially short-tail, were observed. PMID- 29417693 TI - Mutations in the signal transducer and activator of transcription family of genes in cancer. AB - In recent years, it has become clear that members of the signal transducer and activator of transcription (STAT) family of genes play an important role in cancer. The STAT family consists of seven genes, STAT1-4, STAT5A, STAT5B and STAT6, that are involved in regulating cellular proliferation, apoptosis, angiogenesis and the immune system response. Constitutive activation of STAT3, via mutational changes, is important in oncogenesis in both solid and hematopoietic cancers. In the case of hematopoietic neoplasms, STAT3 driver mutations have been described in T-cell large granular lymphocytic (T-LGL) leukemia and chronic natural killer lymphoproliferative disorders (CLPD-NK) and are seen in 30%-40% of T-LGL leukemia patients. STAT5B is also mutated in T-LGL leukemia and CLPD-NK, but in a much smaller proportion. Here we review past and current research on STAT genes in hematopoietic and solid cancers with emphasis on STAT3 and STAT5B and their roles in the pathogenesis of hematopoietic malignancies, particularly T-LGL leukemia and CLPD-NK. PMID- 29417694 TI - Inferring distinct mechanisms in the absence of subjective differences: Placebo and centrally acting analgesic underlie unique brain adaptations. AB - Development and maintenance of chronic pain is associated with structural and functional brain reorganization. However, few studies have explored the impact of drug treatments on such changes. The extent to which long-term analgesia is related to brain adaptations and its effects on the reversibility of brain reorganization remain unclear. In a randomized placebo-controlled clinical trial, we contrasted pain relief (3-month treatment period), and anatomical (gray matter density [GMD], assessed by voxel-based morphometry) and functional connectivity (resting state fMRI nodal degree count [DC]) adaptations, in 39 knee osteoarthritis (OA) patients (22 females), randomized to duloxetine (DLX, 60 mg once daily) or placebo. Pain relief was equivalent between treatment types. However, distinct circuitry (GMD and DC) could explain pain relief in each group: up to 85% of variance for placebo analgesia and 49% of variance for DLX analgesia. No behavioral measures (collected at entry into the study) could independently explain observed analgesia. Identified circuitry were outside of nociceptive circuitry and minimally overlapped with OA-abnormal or placebo response predictive brain regions. Mediation analysis revealed that changes in GMD and DC can influence each other across remote brain regions to explain observed analgesia. Therefore, we can conclude that distinct brain mechanisms underlie DLX and placebo analgesia in OA. The results demonstrate that even in the absence of differences in subjective pain relief, pharmacological treatments can be differentiated from placebo based on objective brain biomarkers. This is a crucial step to untangling mechanisms and advancing personalized therapy approaches for chronic pain. PMID- 29417695 TI - Visual perceptual skills and visual motor integration in children and adolescents after allogeneic hematopoietic stem cell transplantation. AB - The aim of the study was to study visual acuity, visual perceptual, and VMI skills in patients after HSCT in childhood. Tests of visual perceptual skills, VMI, and visual acuity were performed in 102 children/adolescents (age range 4.3 20.9 years). Mean time from HSCT to testing was 6.0 years (0.9-17.5 years). Visual acuity was median 1.0 decimal (range 0.16-1.6). Visual perceptual skills (memory, form constancy, visual sequential memory) and VMI were low compared to age-equivalent normative data with, respectively, 36%, 45%, 60%, and 46% of all patients performing below the 25 percentile. All patients performed significantly lower than the 50 percentile in the reference material in visual sequential memory, P < .001 (boys P < .001 and girls P < .05). All patients also performed significantly lower than the 50 percentile in VMI (P < .01) (boys P < .05). Pretransplant conditioning regimen did not affect outcome if the results were corrected for age at HSCT. Visual perceptual skill problems and VMI problems frequently occur in patients after HSCT in childhood. Age at HSCT and original diagnosis influence the outcome. Neuropsychological assessment including visual perception is recommended in children after HSCT. PMID- 29417696 TI - Structure and function of the bacillithiol-S-transferase BstA from Staphylococcus aureus. AB - Bacillithiol is a low-molecular weight thiol produced by many gram-positive organisms, including Staphylococcus aureus and Bacillus anthracis. It is the major thiol responsible for maintaining redox homeostasis and cellular detoxification, including inactivation of the antibiotic fosfomycin. The metal dependent bacillithiol transferase BstA is likely involved in these sorts of detoxification processes, but the exact substrates and enzyme mechanism have not been identified. Here we report the 1.34 A resolution X-ray crystallographic structure of BstA from S. aureus. Our structure confirms that BstA belongs to the YfiT-like metal-dependent hydrolase superfamily. Like YfiT, our structure contains nickel within its active site, but our functional data suggest that BstA utilizes zinc for activity. Although BstA and YfiT both contain a core four helix bundle and coordinate their metal ions in the same fashion, significant differences between the protein structures are described here. PMID- 29417697 TI - About why there is a shift from cardinal to ordinal processing in the association with arithmetic between first and second grade. AB - Digit comparison is strongly related to individual differences in children's arithmetic ability. Why this is the case, however, remains unclear to date. Therefore, we investigated the relative contribution of three possible cognitive mechanisms in first and second graders' digit comparison performance: digit identification, digit-number word matching and digit ordering ability. Furthermore, we examined whether these components could account for the well established relation between digit comparison performance and arithmetic. As expected, all candidate predictors were related to digit comparison in both age groups. Moreover, in first graders, digit ordering and in second graders both digit identification and digit ordering explained unique variance in digit comparison performance. However, when entering these unique predictors of digit comparison into a mediation model with digit comparison as predictor and arithmetic as outcome, we observed that whereas in second graders digit ordering was a full mediator, in first graders this was not the case. For them, the reverse was true and digit comparison fully mediated the relation between digit ordering and arithmetic. These results suggest that between first and second grade, there is a shift in the predictive value for arithmetic from cardinal processing and procedural knowledge to ordinal processing and retrieving declarative knowledge from memory; a process which is possibly due to a change in arithmetic strategies at that age. A video abstract of this article can be viewed at: https://youtu.be/dDB0IGi2Hf8. PMID- 29417698 TI - Pervasive migration across rainforest and sandy coastal plain Aechmea nudicaulis (Bromeliaceae) populations despite contrasting environmental conditions. AB - Understanding the colonization of extreme marginal habitats and the relative roles of space and environment in maintaining peripheral populations remains challenging. Here, we leverage a system of pairs of rainforest and sandy coastal plain communities that allow us to decouple spatial and environmental effects in the population structure and migration rates of the bromeliad Aechmea nudicaulis. Structure and gene flow between populations were estimated from Bayesian clustering and coalescent-based migration models applied to chloroplast sequence and nuclear microsatellite data. Contrary to our initial expectation, the sharp environmental gradient between rainforest and sandy plains does not seem to have affected the colonization and migration dynamics in A. nudicaulis. Our analyses uncover pervasive gene flow between neighbouring habitats in both chloroplast and nuclear data despite the striking differences in environmental conditions. This result is consistent with a scenario of repeated colonization of the sandy coastal plains from forest populations through seed dispersal, as well as the maintenance of gene flow between habitats through pollination. We also recovered a broad north/south population structure that has been found in other Atlantic rainforest groups and possibly reflects older phylogeographic dynamics. PMID- 29417699 TI - Effectiveness of Faradic and Russian currents on plantar flexor muscle spasticity, ankle motor recovery, and functional gait in stroke patients. AB - BACKGROUND AND PURPOSE: Spasticity is a major disabling symptom in patients post stroke. Though studies have demonstrated that electrical stimulation (ES) can reduce spasticity and improve passive ankle range of motion (ROM), not many studies have evaluated the effectiveness of ES on active ankle ROM. The purpose of this study was to determine the effectiveness of Faradic and Russian currents in the reduction of ankle plantar-flexor spasticity and improving motor recovery in patients post stroke. METHODS: Eighty-three patients (29 females and 54 males; mean age of 57.12 years) were randomly assigned to Group 1 (task-oriented exercises), Group 2 (Faradic current for 10 min and task-oriented exercises), and Group 3 (Russian current for 10 min and task-oriented exercises) for a period of 5 sessions per week for 6 weeks. All patients were assessed for soleus and gastrocnemius muscles spasticity measured by modified modified Ashworth scale; active and passive range ROM measured by goniometer; and functional ambulation measured by modified Emory Functional Ambulation Profile at the time of recruitment to study and after 6 weeks. RESULTS: Both the types of stimulation and exercises were not associated with improvements in modified Emory Functional Ambulation Profile (p > 0.05). The results showed that all the groups are effective in improving passive ankle ROM (p < 0.05) and reducing soleus and gastrocnemius muscles spasticity (p < 0.05). Though all the groups were effective in improving active ankle ROM, no group was found to be superior to another after treatment CONCLUSION: Adding ES to exercises are associated with low to medium effect sizes (<0.5) in reducing spasticity and improving ankle ROM. PMID- 29417700 TI - Postoperative chemoradiotherapy in patients with head and neck cancer aged 70 or older with positive margins or extranodal extension and the influence of nodal classification. AB - BACKGROUND: Postoperative concomitant chemoradiotherapy (CRT) improves outcomes for younger adults with head and neck squamous cell carcinoma (HNSCC) and positive margins or extranodal extension (ENE), but its benefit for older adults is not well established. METHODS: Patients from the National Cancer Data Base (NCDB) with HNSCC undergoing curative-intent resection, neck dissection, and postoperative radiation with positive margins or ENE were identified. RESULTS: This analysis included 1199 patients aged >= 70 years with median follow-up of 42.6 months. Postoperative concurrent CRT was associated with improved overall survival (OS; hazard ratio [HR] 0.752; 95% confidence interval [CI] 0.638-0.886) compared to radiation alone in multivariable analysis. Three-year OS was 52.4% with CRT versus 43.4% with radiation (P = .012) in propensity-score matched cohorts. The survival impact of CRT varied by N classification (P = .002 for interaction), with benefit seen only in those with N2 to N3 disease. CONCLUSION: Postoperative concurrent CRT may benefit older patients with HNSCC with positive margins or ENE, particularly those with higher nodal burden. PMID- 29417702 TI - Ethnic differences in spirometry measurements in China: Results from a large community-based epidemiological study. AB - BACKGROUND AND OBJECTIVE: No previous studies have examined differences in spirometry measurements among ethnic populations in China, and factors which may influence ethnic differences are unclear. Our study aimed to investigate whether forced expiratory volume in 1 s (FEV1 ) and forced vital capacity (FVC) differ among Han Chinese and other ethnic minorities in China. METHODS: We recruited 7137 individuals aged 35-70 years from four areas of China inhabited by ethnic minority groups between 2007 and 2009. We conducted spirometry tests for all available participants, and compared FEV1 and FVC among Uygur, Hui, Mongolian, Dai and Han Chinese ethnicities, using nonlinear multiplicative regression models. RESULTS: A total of 2005 healthy never-smokers were enrolled in the analysis. For all ethnicities, spirometry values increased with height and decreased with age; FEV1 and FVC were consistently higher in males than in females. Compared with Han Chinese, FEV1 was 4.42% (95% CI: 2.11-6.78%) higher in Mongolians, 4.08% (95% CI: 1.33-6.76%) lower in Uygurs, 4.39% (95% CI: 1.33 7.35%) lower in Hui people and 4.72% (95% CI: 1.80-7.55%) lower in Dai people, after adjusted for potential confounders including height, age, sex and place of residence. We observed similar differences for FVC. CONCLUSIONS: We detected significant differences in spirometry measurements among ethnic populations in China. Such differences cannot be fully explained by demographic, anthropometric or socioeconomic factors, but may also be attributed to genetic background as well as indoor and outdoor environmental exposures that need further investigation. PMID- 29417701 TI - Impact of novel oncogenic pathways regulated by antitumor miR-451a in renal cell carcinoma. AB - Recent analyses of our microRNA (miRNA) expression signatures obtained from several types of cancer have provided novel information on their molecular pathology. In renal cell carcinoma (RCC), expression of microRNA-451a (miR-451a) was significantly downregulated in patient specimens and low expression of miR 451a was significantly associated with poor prognosis of RCC patients (P = .00305) based on data in The Cancer Genome Atlas. The aims of the present study were to investigate the antitumor roles of miR-451a and to identify novel oncogenic networks it regulated in RCC cells. Ectopic expression of miR-451a significantly inhibited cancer cell migration and invasion by RCC cell lines, suggesting that miR-451a had antitumor roles. To identify oncogenes regulated by miR-451a in RCC cells, we analyzed genome-wide gene expression data and examined information in in silico databases. A total of 16 oncogenes and were found to be possible targets of miR-451a regulation. Interestingly, high expression of 9 genes (PMM2, CRELD2, CLEC2D, SPC25, BST2, EVL, TBX15, DPYSL3, and NAMPT) was significantly associated with poor prognosis. In this study, we focused on phosphomannomutase 2 (PMM2), which was the most strongly associated with prognosis. Overexpression of PMM2 was detected in clinical specimens and Spearman's rank test indicated a negative correlation between the expression levels of miR-451a and PMM2 (P = .0409). Knockdown of PMM2 in RCC cells inhibited cancer cell migration and invasion, indicating overexpression of PMM2 could promote malignancy. Analytic strategies based on antitumor miRNAs is an effective tool for identification of novel pathways of cancer. PMID- 29417703 TI - Factors associated with intention of Israeli-born women and immigrant women from the Former Soviet Union to take folic acid before and during pregnancy. AB - AIM: Folic acid supplementation before and during pregnancy decreases rates of neural tube defects. However, many women fail to adhere to folic acid supplementation recommendations. This study explored factors associated with women's intention to take folic acid before and during pregnancy, using the Theory of Planned Behaviour, with an emphasis on differences between Israeli-born women and immigrant women from the Former Soviet Union. METHODS: In this cross sectional study, 100 Israeli born-women and 100 women from the Former Soviet Union of childbearing age completed a questionnaire, based on the Theory of Planned Behaviour. RESULTS: The findings indicated a significant difference in the rates at which Israeli-born and FSU-born women took folic acid before and during pregnancy, as well as a significant difference in their intention to take folic acid supplementation in future pregnancies. The theoretical model explained 88.7% of variance in women's intention to take folic acid, with the most influential variable being behavioural attitudes towards taking folic acid. CONCLUSION: The study emphasizes the need to increase knowledge and change attitudes and beliefs about folic acid supplementation among women and their significant others, as well as the importance of cultural, language, and economic barriers when treating Former Soviet Union immigrant populations. PMID- 29417704 TI - Cognitive impairment in Parkinson's disease, Alzheimer's dementia, and vascular dementia: the role of the clock-drawing test. AB - AIM: Cognitive impairment is present in several neurodegenerative disorders. The clock-drawing test (CDT) represents a useful screening instrument for assessing the evolution of cognitive decline. The aim of this study was to investigate the sensitivity of the CDT in monitoring and differentiating the evolution of cognitive decline in Alzheimer's dementia (AD), vascular dementia (VaD), and Parkinson's disease (PD). METHODS: This study involved 139 patients, including 39 patients with PD and mild cognitive impairment, 16 demented PD patients, 21 VaD patients with mild cognitive impairment, 17 patients with VaD, 33 patients with mild cognitive impairment due to AD, and 13 patients with probable AD. All participants completed the CDT. The Mini-Mental State Examination was administered to establish patients' cognitive functioning. RESULTS: Comparisons of quantitative and qualitative CDT scores showed significant differences between the various diseases. Impairment of executive functioning seems to be more pronounced in PD and VaD than in AD. Patients with AD committed more errors related to a loss of semantic knowledge, indicating a severely reduced capacity in abstract and conceptual thinking. CONCLUSION: Results support the usefulness and sensitivity of the CDT in the detection of different dementia subtypes. Qualitative error analysis of the CDT may be helpful in differentiating PD, VaD, and AD, even in the early stages of each disease. PMID- 29417705 TI - Functional connectivity corresponding to the tonotopic differentiation of the human auditory cortex. AB - Recent research has demonstrated that resting-state functional connectivity (RS FC) within the human auditory cortex (HAC) is frequency-selective, but whether RS FC between the HAC and other brain areas is differentiated by frequency remains unclear. Three types of data were collected in this study, including resting state functional magnetic resonance imaging (fMRI) data, task-based fMRI data using six pure tone stimuli (200, 400, 800, 1,600, 3,200, and 6,400 Hz), and structural imaging data. We first used task-based fMRI to identify frequency selective cortical regions in the HAC. Six regions of interest (ROIs) were defined based on the responses of 50 participants to the six pure tone stimuli. Then, these ROIs were used as seeds to determine RS-FC between the HAC and other brain regions. The results showed that there was RS-FC between the HAC and brain regions that included the superior temporal gyrus, dorsolateral prefrontal cortex (DL-PFC), parietal cortex, occipital lobe, and subcortical structures. Importantly, significant differences in FC were observed among most of the brain regions that showed RS-FC with the HAC. Specifically, there was stronger RS-FC between (1) low-frequency (200 and 400 Hz) regions and brain regions including the premotor cortex, somatosensory/-association cortex, and DL-PFC; (2) intermediate-frequency (800 and 1,600 Hz) regions and brain regions including the anterior/posterior superior temporal sulcus, supramarginal gyrus, and inferior frontal cortex; (3) intermediate/low-frequency regions and vision-related regions; (4) high-frequency (3,200 and 6,400 Hz) regions and the anterior cingulate cortex or left DL-PFC. These findings demonstrate that RS-FC between the HAC and other brain areas is frequency selective. PMID- 29417706 TI - High-throughput environmental sequencing reveals high diversity of litter and moss associated protist communities along a gradient of drainage and tree productivity. AB - Although previous studies, mostly based on microscopy analyses of a few groups of protists, have suggested that protists are abundant and diverse in litter and moss habitats, the overall diversity of moss and litter associated protists remains elusive. Here, high-throughput environmental sequencing was used to characterize the diversity and community structure of litter- and moss-associated protists along a gradient of soil drainage and forest primary productivity in a temperate rainforest in British Columbia. We identified 3262 distinct protist OTUs from 36 sites. Protists were strongly structured along the landscape gradient, with a significant increase in alpha diversity from the blanket bog ecosystem to the zonal forest ecosystem. Among all investigated environmental variables, calcium content was the most strongly associated with the community composition of protists, but substrate composition, plant cover and other edaphic factors were also significantly correlated with these communities. Furthermore, a detailed phylogenetic analysis of unicellular opisthokonts identified OTUs covering most lineages, including novel OTUs branching with Discicristoidea, the sister group of Fungi, and with Filasterea, one of the closest unicellular relatives to animals. Altogether, this study provides unprecedented insight into the community composition of moss- and litter-associated protists. PMID- 29417708 TI - The effect of the heights and thicknesses of the remaining root segments on buccal bone resorption in the socket-shield technique: An experimental study in dogs. AB - BACKGROUND: To date only a few studies have been done on the use of the socket shield technique for preserving the resorption of the buccal bone in aesthetically sensitive sites. Besides, there have been no further studies on the effect of the heights and thicknesses of the remaining root segments on buccal bone resorption when using this method. PURPOSE: The aim of this study was to evaluate the effect of different heights and thicknesses of the remaining root segments on bone resorption in the socket-shield technique. MATERIALS AND METHODS: Four healthy female beagle dogs were used in this study. The third premolar (P3) and the fourth premolar (P4) on both sides of the mandible were hemisected in the buccal-lingual direction, and the clinical crown of the distal root was beheaded. In the experimental groups, the roots were worn down in the apical direction until they were located at the buccal crestal level (Group A) or 1 mm higher than that level (Group B). In the control group, the distal root segments were extracted. Then, implant placement was performed into the distal root. After 3 months of healing, the specimens were prepared for histological diagnosis. RESULTS: There was no difference between Group A and Group B when using the socket-shield technique, but the results of both groups were better than those of the control group. CONCLUSIONS: The height of the root segments has little effect on the bone absorption of alveolar bone, while the bone absorption was strongly influenced by the thickness of the root segments. More precisely, the absorption may decrease if the thickness of the root fragment increases, when the thickness of the root plate is in the 0.5-1.5 mm range. PMID- 29417709 TI - Semiconducting Polymer Nanoenzymes with Photothermic Activity for Enhanced Cancer Therapy. AB - Regulation of enzyme activity is fundamentally challenging but practically meaningful for biology and medicine. However, noninvasive remote control of enzyme activity in living systems has been rarely demonstrated and exploited for therapy. Herein, we synthesize a semiconducting polymer nanoenzyme with photothermic activity for enhanced cancer therapy. Upon near-infrared (NIR) light irradiation, the activity of the nanoenzyme can be enhanced by 3.5-fold to efficiently digest collagen in the tumor extracellular matrix (ECM), leading to enhanced nanoparticle accumulation in tumors and consequently improved photothermal therapy (PTT). This study thus provides a promising strategy to remotely regulate enzyme activity for cancer therapy. PMID- 29417707 TI - Increased carotid intima-media thickness in African American pediatric kidney transplant recipients. AB - Early signs of subclinical CV dysfunction can be detected by ultrasound for CIMT. Although A-A are at high risk for CV disease, CIMT of A-A kidney transplant recipients has not been previously investigated. The aim of this prospective, controlled, longitudinal study was to investigate determinants of CIMT in a multiracial pediatric kidney transplant population, with a focus on A-A. Transplant recipients (n = 42) had BMI, waist-to-height ratio, fasting glucose, lipid panel, HbA1c%, and CIMT measured at 1, 18, and 30 months post-transplant. Twenty-four healthy children (14 A-A) served as controls. CIMT of A-A transplant (0.49, 0.49, and 0.48 mm) was higher than non-AA transplant (0.43, 0.44, and 0.44 mm) at 1, 18, and 30 months and higher than A-A controls (0.47 mm). Hyperparathyroidism prior to transplant predicted high CIMT-for-race. A-A race was associated with 10% higher CIMT vs non-A-A transplant. Metabolic syndrome was associated with 0.03 +/- 0.01 mm increase in CIMT among A-A transplant recipients only. In conclusion, A-A kidney transplant recipients have increased CIMT. Metabolic syndrome disproportionately affects CIMT of A-A children post transplant. Identification of subclinical CV damage, detected by CIMT, may provide an opportunity for early detection of CV risk in this vulnerable population. PMID- 29417710 TI - Gcn5-dependent histone H3 acetylation and gene activity is required for the asexual development and virulence of Beauveria bassiana. AB - Gcn5 is a core histone acetyltransferase that catalyzes histone H3 acetylation on N-terminal lysine residues in yeasts and was reported to catalyze H3K9/K14 acetylation required for activating asexual development in Aspergillus. Here, we report a localization of Gcn5 ortholog in the nucleus and cytoplasm of Beauveria bassiana, a fungal insect pathogen. Deletion of gcn5 led to hypoacetylated H3 at K9/14/18/27 and 97% reduction in conidiation capacity as well as severe defects in colony growth and conidial thermotolerance. Two master conidiation genes, namely brlA and abaA, were transcriptionally repressed to undetectable level in Deltagcn5, but sharply upregulated in wild-type, at the beginning time of conidiation. Based on chromatin immunoprecipitation, both DNA and acetylation levels of the distal and proximal fragments of the brlA promoter bound by acetylated H3K14 alone were upregulated in wild-type, but not in Deltagcn5, at the mentioned time. In Deltagcn5, normal cuticle infection was abolished while virulence through cuticle-bypassing infection was greatly attenuated, accompanied by drastically reduced activities of putative cuticle-degrading enzymes, retarded dimorphic transition and transcriptional repression of associated genes. These findings unveil a novel mechanism by which Gcn5 activates asexual development pathway by acetylating H3K14 and regulates the virulence-related cellular events in B. bassiana. PMID- 29417711 TI - Design of a Short Thermally Stable alpha-Helix Embedded in a Macrocycle. AB - Although helices play key roles in peptide-protein and protein-protein interactions, the helical conformation is generally unstable for short peptides (10-15 residues) in aqueous solution in the absence of their binding partners. Thus, stabilizing the helical conformation of peptides can lead to increases in binding potency, specificity, and stability towards proteolytic degradation. Helices have been successfully stabilized by introducing side chain-to-side chain crosslinks within the central portion of the helix. However, this approach leaves the ends of the helix free, thus leading to fraying and exposure of the non hydrogen-bonded amide groups to solvent. Here, we develop a "capped-strapped" peptide strategy to stabilize helices by embedding the entire length of the helix within a macrocycle, which also includes a semirigid organic template as well as end-capping interactions. We have designed a ten-residue capped-strapped helical peptide that behaves like a miniprotein, with a cooperative thermal unfolding transition and Tm ~70 degrees C, unprecedented for helical peptides of this length. The NMR structure determination confirmed the design, and X-ray crystallography revealed a novel quaternary structure with implications for foldamer design. PMID- 29417712 TI - Structure and cis-regulatory analysis of a Drosophila grainyhead neuroblast enhancer. AB - Evolutionary analysis of cis-regulatory DNA reveals that enhancers consist of clusters of conserved sequence blocks (CSBs) that are made up of both unique and repeated sequence elements. This study seeks to address the basis for spatial and temporal regulation of neuroblas. A search for temporally restricted CNS NB enhancers identified one within the transcription factor grainyhead (grh) gene locus. The intronic enhancer, grh-15, contains two separable semi-autonomous activities, one that drives expression predominantly within the developing brain NBs and another in ventral cord NBs. To gain insight into the function of the CSBs constituting the brain-specific enhancer, we have systematically deleted each CSB and compared the activity of the altered enhancer to that of the full brain-specific enhancer. While our results indicate that information regulating enhancer activity is highly redundant, we have found that individual CSBs convey expression in subsets of larval lineages that are generated from either Type I or Type II NBs. These studies also highlight how evolutionary sequence conservation can be used as a guide the functional analysis of cis-regulatory DNA. PMID- 29417713 TI - Person-centred care in nurse-led outpatient rheumatology clinics: Conceptualization and initial development of a measurement instrument. AB - BACKGROUND: Person-centred care (PCC) is considered a key component of effective illness management and high-quality care. However, the PCC concept is underdeveloped in outpatient care. In rheumatology, PCC is considered an unmet need and its further development and evaluation is of high priority. The aim of the present study was to conceptualize and operationalize PCC, in order to develop an instrument for measuring patient-perceived PCC in nurse-led outpatient rheumatology clinics. METHODS: A conceptual outpatient PCC framework was developed, based on the experiences of people with rheumatoid arthritis (RA), person-centredness principles and existing PCC frameworks. The resulting framework was operationalized into the PCC instrument for outpatient care in rheumatology (PCCoc/rheum), which was tested for acceptability and content validity among 50 individuals with RA attending a nurse-led outpatient clinic. RESULTS: The conceptual framework focuses on the meeting between the person with RA and the nurse, and comprises five interrelated domains: social environment, personalization, shared decision-making, empowerment and communication. Operationalization of the domains into a pool of items generated a preliminary PCCoc/rheum version, which was completed in a mean (standard deviation) of 5.3 (2.5) min. Respondents found items easy to understand (77%) and relevant (93%). The Content Validity Index of the PCCoc/rheum was 0.94 (item level range, 0.87 1.0). About 80% of respondents considered some items redundant. Based on these results, the PCCoc/rheum was revised into a 24-item questionnaire. CONCLUSIONS: A conceptual outpatient PCC framework and a 24-item questionnaire intended to measure PCC in nurse-led outpatient rheumatology clinics were developed. The extent to which the questionnaire represents a measurement instrument remains to be tested. PMID- 29417714 TI - Crystalline-Sponge-Based Structural Analysis of Crude Natural Product Extracts. AB - Characterization of complex natural product mixtures to the absolute structural level of their components often requires significant amounts of starting materials and lengthy purification process, followed by arduous structure elucidation efforts. The crystalline sponge (CS) method has demonstrated utility in the absolute structure elucidation of isolated organic compounds at miniscule quantities compared to conventional methods. In this work, we developed a new CS based workflow that greatly expedites the in-depth structural analysis of crude natural product extracts. Using a crude extract of the red alga Laurencia pacifica, we showed that CS affinity screening prior to compound isolation enables prioritization of analytes present in the extract, and we subsequently resolved the molecular structures of six sesquiterpenes with stereochemical clarity from around 10 mg crude extract. This study demonstrates a new chemotyping workflow that can greatly accelerate natural product discovery from complex samples. PMID- 29417715 TI - Competing for blood: the ecology of parasite resource competition in human malaria-helminth co-infections. AB - Ecological theory suggests that co-infecting parasite species can interact within hosts directly, via host immunity and/or via resource competition. In mice, competition for red blood cells (RBCs) between malaria and bloodsucking helminths can regulate malaria population dynamics, but the importance of RBC competition in human hosts was unknown. We analysed infection density (i.e. the concentration of parasites in infected hosts), from a 2-year deworming study of over 4000 human subjects. After accounting for resource-use differences among parasites, we find evidence of resource competition, priority effects and a competitive hierarchy within co-infected individuals. For example reducing competition via deworming increased Plasmodium vivax densities 2.8-fold, and this effect is limited to bloodsucking hookworms. Our ecological, resource-based perspective sheds new light into decades of conflicting outcomes of malaria-helminth co-infection studies with significant health and transmission consequences. Beyond blood, investigating within-human resource competition may bring new insights for improving human health. PMID- 29417716 TI - Gamma-oryzanol for behavioural and psychological symptoms of dementia. PMID- 29417717 TI - Influence of cleaning methods on resin bonding to saliva-contaminated zirconia. AB - OBJECTIVE: The aim of this study was to investigate the influence of different cleaning methods on the shear bond strengths of 2 resin cements to saliva contaminated zirconia. METHODS: After saliva contamination, alumina-blasted zirconia specimens were cleaned with 1 of 5 methods of water-rinsing (SA), K etchant GEL phosphoric acid (PA), Ivoclean (IC), AD Gel (ADG), or additional alumina-blasting (AB). Alumina-blasted zirconia without saliva contamination was used as control group (Cont). Composite cylinders were bonded to the zirconia with 1 of 2 dual-cured resin cements. The bond strengths were measured by shear testing after 24 hours (TC0) and after thermal cycling at 4 degrees C-60 degrees C (TC10 000) and specimen surfaces were evaluated using X-ray photoelectron spectroscopy (XPS). Data were statistically analyzed using 3-way analysis of variance and Tukey test (alpha = 0.05). RESULTS: There were no significant differences in the bond strengths of 2 resin cements between the Cont ADG, and AB groups before and after TCs (P > .05). SA, PA, and IC groups did not exhibit durable resin bonding to zirconia. XPS showed that carbon and nitrogen increased in the SA group in comparison to the Cont group. The concentration of carbon in other 4 groups returned to the concentration range of the Cont group; however, nitrogen was not detected in the only AB group. CONCLUSIONS: Saliva contamination significantly reduced the bond strength of 2 resin cements to zirconia. Additional AB or cleaning with ADG resulted in effective cleaning of saliva contamination and preserved resin cement bond strength to zirconia. CLINICAL SIGNIFICANCE: Saliva contamination occurs during clinical procedures for adjustment of zirconia ceramic restorations in the oral environment. AD Gel application is effective for removing saliva contaminants on the alumina-blasted zirconia surface beforehand by the dental laboratory instead of additional AB since AD Gel application and AB had a similar effect on the removal of organic components of saliva. PMID- 29417718 TI - The educational needs of patients with undifferentiated spondyloarthritis: Validation of the ENAT questionnaire and needs assessment. AB - OBJECTIVES: The aim of the present study was to validate the Swedish version of the educational needs assessment tool (SwENAT) in undifferentiated spondyloarthritis (USpA) and use it to study the educational needs of patients with USpA. METHODS: This was a cross-sectional study, recruiting a random sample of patients with USpA from a hospital register in Sweden. Educational needs data were collected, together with disease activity and function indices (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] and Bath Ankylosing Spondylitis Functional Index [BASFI]). Rasch analysis was utilized to evaluate the construct validity, internal consistency and unidimensionality of the SwENAT before studying differences in educational needs between patient subgroups (gender, age and disease severity). RESULTS: Complete responses were obtained from 77 patients (48 women), with a mean age (standard deviation [SD]) of 50 (12) years, a disease duration of 16 (11) years, a BASDAI score of 4.9 (1.9) and a BASFI score of 3.1 (2.3). The SwENAT satisfied the requirements of the Rasch model (chi2 = 11.488; p = 0.119), including strict unidimensionality. Overall, the mean (SD) SwENAT score was 86 (32). Women reported higher needs than men in the domains of pain (mean [SD] 13.1 [6.8] versus 10.1 [6.0]; p = 0.05); movement (mean [SD] 13.0 [5.5] versus 9.9 [5.7]; p = 0.02) and self-help (mean [SD] 17.0 [5.8] versus 14.1 [5.0]; p = 0.03). Higher disease activity (BASDAI >4) was associated with higher educational needs (mean [SD] 92.6 [31.9] versus 73.7 [29.4]; p = 0.02). CONCLUSIONS: These data suggest that the SwENAT is valid in USpA. Women and patients with higher disease activity are more likely to have high levels of educational needs, so special attention and strategies to target patient education are warranted. PMID- 29417719 TI - The role of mate-choice copying in speciation and hybridization. AB - Mate-choice copying, a social, non-genetic mechanism of mate choice, occurs when an individual (typically a female) copies the mate choice of other individuals via a process of social learning. Over the past 20 years, mate-choice copying has consistently been shown to affect mate choice in several species, by altering the genetically based expression of mating preferences. This behaviour has been claimed by several authors to have a significant role in evolution. Because it can cause or increase skews in male mating success, it seems to have the potential to induce a rapid change of the directionality and rate of sexual selection, possibly leading to divergent evolution and speciation. Theoretical work has, however, been challenging this view, showing that copying may decelerate sexual selection and that linkage disequilibrium cannot be established between the copied preference and the male trait, because females copy from unrelated individuals in the population, making an invasion of new and potentially fitter male traits difficult. Given this controversy, it is timely to ask about the real impact of mate-choice copying in speciation. We propose that a solution to this impasse may be the existence of some degree of habitat selection, which would create a spatial structure, causing scenarios of micro allopatry and thus overcoming the problem of the lack of linkage disequilibrium. As far as we are aware, the potential role of mate-choice copying on fostering speciation in micro-allopatry has not been tackled. Also important is that the role of mate-choice copying has generally been discussed as being a barrier to gene flow. However, in our view, mate-choice copying may actually play a key role in facilitating gene flow, thereby fostering hybridization. Yet, the role of mate choice copying in hybridization has so far been overlooked, although the conditions under which it might occur are more likely, or less restricted, than those favouring speciation. Hence, a conceptual framework is needed to identify the exact mechanisms and the conditions under which speciation or hybridization are expected. Here, we develop such a framework to be used as a roadmap for future research at the intersection of these research areas. PMID- 29417720 TI - Global environmental costs of China's thirst for milk. AB - China has an ever-increasing thirst for milk, with a predicted 3.2-fold increase in demand by 2050 compared to the production level in 2010. What are the environmental implications of meeting this demand, and what is the preferred pathway? We addressed these questions by using a nexus approach, to examine the interdependencies of increasing milk consumption in China by 2050 and its global impacts, under different scenarios of domestic milk production and importation. Meeting China's milk demand in a business as usual scenario will increase global dairy-related (China and the leading milk exporting regions) greenhouse gas (GHG) emissions by 35% (from 565 to 764 Tg CO2eq ) and land use for dairy feed production by 32% (from 84 to 111 million ha) compared to 2010, while reactive nitrogen losses from the dairy sector will increase by 48% (from 3.6 to 5.4 Tg nitrogen). Producing all additional milk in China with current technology will greatly increase animal feed import; from 1.9 to 8.5 Tg for concentrates and from 1.0 to 6.2 Tg for forage (alfalfa). In addition, it will increase domestic dairy related GHG emissions by 2.2 times compared to 2010 levels. Importing the extra milk will transfer the environmental burden from China to milk exporting countries; current dairy exporting countries may be unable to produce all additional milk due to physical limitations or environmental preferences/legislation. For example, the farmland area for cattle-feed production in New Zealand would have to increase by more than 57% (1.3 million ha) and that in Europe by more than 39% (15 million ha), while GHG emissions and nitrogen losses would increase roughly proportionally with the increase of farmland in both regions. We propose that a more sustainable dairy future will rely on high milk demanding regions (such as China) improving their domestic milk and feed production efficiencies up to the level of leading milk producing countries. This will decrease the global dairy related GHG emissions and land use by 12% (90 Tg CO2eq reduction) and 30% (34 million ha land reduction) compared to the business as usual scenario, respectively. However, this still represents an increase in total GHG emissions of 19% whereas land use will decrease by 8% when compared with 2010 levels, respectively. PMID- 29417721 TI - Npom-Protected NONOate Enables Light-Triggered NO/cGMP Signalling in Primary Vascular Smooth Muscle Cells. AB - Diazeniumdiolates (NONOates) are a class of nitric-oxide-releasing substances widely used in studies of NO/cGMP signalling. Because spatiotemporal control is highly desirable for such purposes, we have synthesised a new Npom-caged pyrrolidine NONOate. A kinetic analysis together with a Griess assay showed the photodependent release of NO with high quantum yield (UV light). In primary vascular smooth muscle cells (VSMCs), our compound was reliably able to induce fast increases in cGMP, as measured with a genetically encoded FRET-based cGMP sensor and further validated by the phosphorylation of the downstream target vasodilator-stimulated phosphoprotein (VASP). Thanks to their facile synthesis, good decaging kinetics and capability to activate cGMP signalling in a fast and efficient manner, Npom-protected NONOates allow for improved spatiotemporal control of NO/cGMP signalling. PMID- 29417722 TI - Is there a case for eculizumab for pediatric renal transplantation? PMID- 29417723 TI - Health status of older adults living in the community in Japan: Recent changes and significance in the super-aged society. AB - As of 2017, the total Japanese population was 126.7 million, which included 35 million who were aged >=65 years (27.6%) and 17.3 million aged >=75 years (13.7%). From now, the old-old aged >=75 years will increase rapidly in Japan compared with the young-old aged 65-74 years. The characteristics of the old-old include deterioration of activities of daily living (ADL) functions and an increase of chronic diseases, which are unavoidable consequences of advanced age. In the present review article, secular changes of the health status and functional capacity of older people living in communities are described based on representative longitudinal studies on aging in Japan. The author also discusses the importance and implication of two major strategies related to health promotion, and prevention of both lifestyle-related diseases and long-term care dependence in the super-aged society. Among the old-old people, prevention of long-term care dependence becomes a much higher priority than disease prevention. In regard to evidence-based prevention of long-term care dependence, various geriatric syndromes, such as undernutrition, falling, incontinence and decline of cognitive function, are the major targets for prevention. Many randomized controlled trials on the prevention of geriatric syndromes have been carried out in Japan, targeting high-risk older people living in the community, and have attained many excellent achievements so far. Finally, the author introduces a new index of competence for older people (the Japan Science and Technology Agency Index of Competence), which can accurately measure high-level competence and higher functioning needed to execute the activities of more sophisticated living of today and in the future. Geriatr Gerontol Int 2018; 18: 667-677. PMID- 29417724 TI - Hydrogen-Bonded Organic Aromatic Frameworks for Ultralong Phosphorescence by Intralayer pi-pi Interactions. AB - Ultralong organic phosphorescence (UOP) based on metal-free porous materials is rarely reported owing to rapid nonradiative transition under ambient conditions. In this study, hydrogen-bonded organic aromatic frameworks (HOAFs) with different pore sizes were constructed through strong intralayer pi-pi interactions to enable ultralong phosphorescence in metal-free porous materials under ambient conditions for the first time. Impressively, yellow UOP with a lifetime of 79.8 ms observed for PhTCz-1 lasted for several seconds upon ceasing the excitation. For PhTCz-2 and PhTCz-3, on account of oxygen-dependent phosphorescence quenching, UOP could only be visualized in N2 , thus demonstrating the potential of phosphorescent porous materials for oxygen sensing. This result not only outlines a principle for the design of new HOFs with high thermal stability, but also expands the scope of metal-free luminescent materials with the property of UOP. PMID- 29417725 TI - Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism. AB - BACKGROUND: To assess the utility of whole-exome sequencing (WES) for mutation detection in maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI). MODY and CHI are the two commonest monogenic disorders of glucose-regulated insulin secretion in childhood, with 13 causative genes known for MODY and 10 causative genes identified for CHI. The large number of potential genes makes comprehensive screening using traditional methods expensive and time consuming. METHODS: Ten subjects with MODY and five with CHI with known mutations underwent WES using two different exome capture kits (Nimblegen SeqCap EZ Human v3.0 Exome Enrichment Kit, Nextera Rapid Capture Exome Kit). Analysis was blinded to previously identified mutations, and included assessment for large deletions. The target capture of five exome capture technologies was also analyzed using sequencing data from >2800 unrelated samples. RESULTS: Four of five MODY mutations were identified using Nimblegen (including a large deletion in HNF1B). Although targeted, one mutation (in INS) had insufficient coverage for detection. Eleven of eleven mutations (six MODY, five CHI) were identified using Nextera Rapid (including the previously missed mutation). On reconciliation, all mutations concorded with previous data and no additional variants in MODY genes were detected. There were marked differences in the performance of the capture technologies. CONCLUSIONS: WES can be useful for screening for MODY/CHI mutations, detecting both point mutations and large deletions. However, capture technologies require careful selection. PMID- 29417726 TI - Reversible Clustering of Gold Nanoparticles under Confinement. AB - A limiting factor of solvent-induced nanoparticle self-assembly is the need for constant sample dilution in assembly/disassembly cycles. Changes in the nanoparticle concentration alter the kinetics of the subsequent assembly process, limiting optical signal recovery. Herein, we show that upon confining hydrophobic nanoparticles in permeable silica nanocapsules, the number of nanoparticles participating in cyclic aggregation remains constant despite bulk changes in solution, leading to highly reproducible plasmon band shifts at different solvent compositions. PMID- 29417727 TI - COMP report: CPQR technical quality control guidelines for brachytherapy remote afterloaders. AB - The Canadian Organization of Medical Physicists (COMP), in close partnership with the Canadian Partnership for Quality Radiotherapy (CPQR) has developed a series of Technical Quality Control (TQC) guidelines for radiation treatment equipment. These guidelines outline the performance objectives that equipment should meet in order to ensure an acceptable level of radiation treatment quality. The TQC guidelines have been rigorously reviewed and field tested in a variety of Canadian radiation treatment facilities. The development process enables rapid review and update to keep the guidelines current with changes in technology (the most updated version of this guideline can be found on the CPQR website). This particular TQC details recommended quality control testing of brachytherapy remote afterloaders. PMID- 29417729 TI - Stress and coping mechanisms among adolescents living in orphanages: An experience from Klang Valley, Malaysia. AB - INTRODUCTION: Health issues often differ from one population to another. Assessing different aspects of the health condition is a vital step toward developing and designing appropriate prevention and treatment programs to reduce health problems in any group or population. This study aimed to assess both the prevalence of stress and the coping mechanisms as well as identify the predictors of stress levels among adolescents in Malaysian orphanages. METHODS: Overall, 307 male and female adolescents (aged 13-18 y old) living in 9 private orphanages located in Klang Valley, Malaysia, participated in this cross-sectional study. Brief COPE scale and Depression, Anxiety and Stress Scale-21 were used as the main instruments in the current study. RESULTS: The results of the current study showed female adolescents and participants with a higher level of education were more likely to experience stress. The results also showed significant differences between boys and girls in using of coping mechanisms in self-distraction (t = 2.39, P = .01), substance use (t = 2.12, P = .03), use of emotional support (t = 2.70, P = .001), humor (t = 2.28, P = .02), and religion (t = -2.19, P = .02). Denial, venting, religion, humor, planning, and active coping were identified as predictors of stress among participants. DISCUSSION: The results showed a high prevalence of stress and a negative coping pattern among participants. The finding of the current study also showed the urgency of taking immediate action to reduce stress and improve coping methods among Malaysian institutional adolescents. PMID- 29417728 TI - Comparison of four techniques for spine stereotactic body radiotherapy: Dosimetric and efficiency analysis. AB - PURPOSE: The aim of this study is to compare the dosimetric differences between four techniques for spine stereotactic body radiotherapy (SBRT): CyberKnife (CK), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT) with dynamic jaws (HT-D) and fixed jaws (HT-F). MATERIALS/METHODS: Data from 10 patients were utilized. All patients were planned for 24 Gy in two fractions, with the primary objectives being: (a) restricting the maximum dose to the cord to <= 17 Gy and/or cauda equina to <= 20 Gy, and (b) to maximize the clinical target volume (CTV) to receive the prescribed dose. Treatment plans were generated by separate dosimetrists and then compared using velocity AI. Parameters of comparison include target volume coverage, conformity index (CI), gradient index (GI), homogeneity index (HI), treatment time (TT) per fraction, and monitor units (MU) per fraction. RESULTS: PTV D2 and D5 were significantly higher for CK compared to VMAT, HT-F, and HT-D (P < 0.001). The average volume of CTV receiving the prescription dose (CTV D95) was significantly less for VMAT compared to CK, HT-F and HT-D (P = 0.036). CI improved for CK (0.69), HT-F (0.66), and HT-D (0.67) compared to VMAT (0.52) (P = 0.013). CK (41.86) had the largest HI compared to VMAT (26.99), HT-F (20.69), and HT-D (21.17) (P < 0.001). GI was significantly less for CK (3.96) compared to VMAT (6.76) (P = 0.001). Likewise, CK (62.4 min, 14059 MU) had the longest treatment time and MU per fraction compared to VMAT (8.5 min, 9764 MU), HT-F (13 min, 10822 MU), and HT-D (13.5 min, 11418 MU) (P < 0.001). CONCLUSION: Both CK and HT plans achieved conformal target coverage while respecting cord tolerance. Dose heterogeneity was significantly larger in CK. VMAT required the least treatment time and MU output, but had the least steep GI, CI, and target coverage. PMID- 29417730 TI - Role of poor sleep in determining distress in caregivers of individuals with early psychosis. AB - AIM: Looking after someone in the early stages of psychosis can have a negative impact on caregivers, but there is little clarity about which interventions, if any, caregivers should be offered. This study investigated sleep disturbances in early psychosis caregivers and the relationship between their sleep quality and distress. METHOD: In all, 79 caregivers of patients with a recent first episode of psychosis completed self-report measures including the Pittsburgh Sleep Quality Index (PSQI), the RAND 36-item Health Survey 1.0 (SF-36) and the Experiences of Caregiving Inventory (ECI). RESULTS: All caregivers were living with their relatives with psychosis and had been providing support since the onset of illness (mean duration = 92.5 weeks, SD = 84.0); 60% (47/79) obtained a global PSQI score that exceeded the established cut-off score for clinically significant sleep problems (>5). Low "sleep duration" and "sleep disturbances" contributed the most to elevated PSQI scores, with 17.7% of participants reporting regular wakening at night due to "stress" or "worries." When predicting psychological distress (SF-36) from negative appraisals of caregiving (ECI) and poor sleep (PSQI), a significant unadjusted regression model was obtained, F(2,73) = 29.440, P = .000, R2 of .447. An estimation of the indirect effect of negative thoughts about caregiving on mental distress through poor sleep was also significant (ab = -.05, 95% CI [-.09, -.02], PM = .39). CONCLUSION: Caregivers of people with psychosis may have significant problems with sleep, which relates to distress and negative appraisals about caregiving. Health services need to ask caregivers directly about such issues and consider offering brief interventions to improve sleep quality. PMID- 29417731 TI - Super High-Flux Continuous Venovenous Hemodialysis Using Regional Citrate Anticoagulation: Long-Term Stability of Middle Molecule Clearance. AB - Continuous renal replacement therapy is a standard treatment in critically ill patients with acute kidney injury. All CRRT techniques provide a high low molecular weight clearance but even with hemofiltration, clearance of middle molecules is low. We investigated whether a new super high-flux hemofilter provides effective and sustained middle molecule clearance during citrate anticoagulated continuous venovenous hemodialysis for up to 72 h. We included 14 critically ill patients with AKI-KDIGO-III in a prospective observational trial. We measured/calculated blood and urine concentrations, clearances and sieving coefficients of eight molecules with molecular weights from 60 to 66 kDa, hemodynamic parameters and SAPS-II scores. All filters were patent at 72 h. Clearance and sieving coefficients of small solutes were high and sustained over time, those for larger solutes decreased over 72 h but remained high enough to decrease blood concentrations of solutes up to 25 kDa. Albumin serum levels remained unaffected. Catecholamine doses and SAPS-II scores decreased significantly. This new hemofilter may improve blood purification in critically ill patients with AKI. PMID- 29417732 TI - The Sydney Triage to Admission Risk Tool (START): A prospective validation study. AB - OBJECTIVE: The present study aims to prospectively validate the Sydney Triage to Admission Risk Tool (START) to predict ED disposition. METHODS: This was a prospective validation study at two metropolitan EDs in Sydney, Australia. Consecutive triage encounters were observed by a trained researcher and START scores calculated. The primary outcome was patient disposition (discharge or inpatient admission) from the ED. Multivariable logistic regression was used to estimate area under curve of receiver operator characteristic (AUC ROC) for START scores as well as START score in combination with other variables such as frailty, general practitioner referral, overcrowding and major medical comorbidities. RESULTS: There were 894 patients analysed during the study period. The START score when applied to the data had AUC ROC of 0.80 (95% CI 0.77-0.83). The inclusion of other clinical variables identified at triage did not improve the overall performance of the model with an AUC ROC of 0.81 (95% CI 0.78-0.84) in the present study. CONCLUSION: The overall performance of the START tool with respect to model discrimination and accuracy has been prospectively validated. Further clinical trials are required to test the clinical effectiveness of the tool in improving patient flow and overall ED performance. PMID- 29417733 TI - A Naturally Encoded Dipeptide Handle for Bioorthogonal Chan-Lam Coupling. AB - Manipulation of biomacromolecules is ideally achieved through unique and bioorthogonal chemical reactions of genetically encoded, naturally occurring functional groups. The toolkit of methods for site-specific conjugation is limited by selectivity concerns and a dearth of naturally occurring functional groups with orthogonal reactivity. We report that pyroglutamate amide N-H bonds exhibit bioorthogonal copper-catalyzed Chan-Lam coupling at pyroglutamate histidine dipeptide sequences. The pyroglutamate residue is readily incorporated into proteins of interest by natural enzymatic pathways, allowing specific bioconjugation at a minimalist dipeptide tag. PMID- 29417734 TI - Incidence and immediate management of genitourinary injuries in pelvic and acetabular trauma: a 10-year retrospective study. AB - OBJECTIVE: To report the incidence of genitourinary (GU) injuries in pelvic and acetabular (P + A) fractures, to investigate associations between P + A fractures and GU injury patterns, and, as a secondary objective, to evaluate prospectively P + A fracture referrals with regard to adherence to the British Orthopaedic Association Standards for Trauma (BOAST) guidelines over a 12-month period. METHODS: A retrospective review of GU injuries associated with P + A fractures was performed for the period January 2006 to December 2016 in a national pelvic trauma centre in Ireland. Patient demographics, mechanism of injury and details of injuries were recorded. In addition, P + A fracture referrals were prospectively monitored in 2016 and reviewed for adherence to guidelines. RESULTS: The incidence of urological trauma in P + A fractures was 2.4% (n = 28/1 141). The median (range) patient age was 45 (19-85) years and the male to female ratio was 2.1:1. Urethral injuries occurred most frequently (n = 12, 43%), followed by bladder (n = 9, 32%), combined bladder and urethral (n = 3, 11%) and kidney (n = 4, 14%). Bladder and urethral injuries were associated with high energy pelvic trauma. Renal injuries were associated with acetabular fractures in isolation and in combination with pelvic trauma (P = 0.01). In 2016, there were 175 P + A fracture referrals and 19 patients had suspected urotrauma (visible haematuria, n = 5; non-visible haematuria, n = 2; trauma imaging, n = 11); 9 of these 19 patients had no urological investigations performed. CONCLUSION: In P + A trauma cases GU injuries may be underreported because of inadequate evaluation and diagnostic investigations in these patients. We advocate robust, uniform and guideline-based evaluation of GU injuries in P + A trauma to avoid the significant long-term morbidities that are associated with misdiagnosis. PMID- 29417735 TI - Foetal bovine serum can reduce toxicity of indocyanine green, brilliant blue G and trypan blue in ARPE-19 cellular model that suggests new surgical staining protocols for internal limiting membrane peeling procedure. AB - BACKGROUND: To investigate and compare the cytotoxicity of indocyanine green (ICG), brilliant blue G (BBG) and trypan blue (TB) using ARPE-19 cells that have been pre-treated/post-treated with balanced salt solution (BSS) or foetal bovine serum (FBS). METHODS: The cultured human retina pigment epithelium ARPE-19 cells were pre-treated/post-treated with BSS or FBS (represent the autologous serum in clinic) in parallel with cells being soaked with various concentrations of ICG, BBG and TB. The cells were then assessed for viability, growth rate, reactive oxygen species (ROS) level, mitochondrial membrane potential (Deltapsi) and mitochondrial mass as cytotoxic indices. For the FBS pre-treated cells, only ROS was examined. RESULTS: Using the MTT assay, cytotoxicity seemed to appear when the dye concentration was above 2.5 mg/mL for ICG but no cytotoxicity for BBG and TB at the concentrations used. Cell growth was arrested at a concentration 1 mg/mL when ICG or BBG were present but no arrest at any of the tested concentrations was found for TB with the cell-growth curve was slowest for ICG. Cellular ROS levels increased at all concentrations of all dyes, but the increasing slopes were decreased after FBS post-treatment washout. CONCLUSIONS: As a rinse buffer FBS performs much better than BSS in terms of cell rescue, which agrees with a clinical report when autologous whole blood was applied to macular hole surgery. However, FBS pre-treatment seems to be much better than FBS use as washout buffer in post-treatment. PMID- 29417736 TI - mRNA-Independent way to regulate translation elongation rate in eukaryotic cells. AB - The question of what governs the translation elongation rate in eukaryotes has not yet been completely answered. Earlier, different availability of different tRNAs was considered as a main factor involved, however, recent data revealed that the elongation rate does not always depend on tRNA availability. Here, we offer another, codon-independent approach to explain specific tRNA-dependence of the elongation rate in eukaryotes. We hypothesize that the exit rate of eukaryotic translation elongation factor 1A (eEF1A)*GDP from the 80S ribosome depends on the protein affinity to specific aminoacyl-tRNA remaining on the ribosome after GTP hydrolysis. Subsequently, a slower dissociation of eEF1A*GDP from certain aminoacyl-tRNAs in the ribosome can negatively influence the ribosomal elongation rate in a tRNA-dependent and mRNA-independent way. The specific tRNA-dependent departure rate of eEF1A*GDP from the ribosome is suggested to be a novel factor contributing to the overall translation elongation control in eukaryotic cells. (c) 2018 IUBMB Life, 70(3):192-196, 2018. PMID- 29417737 TI - Drug-induced enterocolitis: Prevention and management in primary care. AB - Drug-induced enterocolitis is a condition diagnosed with increasing frequency. It includes a variety of morphological and functional alterations of the small and large intestine as a consequence of exposure to pharmacological active compounds. A number of factors play a key role in this condition or participate in the onset of enterocolitis, which is the result of an interplay between the effect of the drug molecule and the tolerance of the bowel to damaging insults. The patient's age, gender, dose of drug, time of exposure, pharmaceutical preparation, drug drug and drug-food interactions, gut barrier integrity, underlying intestinal conditions, and gut microbiota composition are all involved in the occurrence and extent of the injury. This review approaches the topic from the viewpoint of primary care, and focuses on epidemiology, mechanisms of damage, protective systems and diagnostic tools. Although the first-line therapeutic measure is the discontinuation of the drug, some options for prevention and treatment are discussed. PMID- 29417739 TI - Seventeen-Year Nationwide Trends in Use of Long-acting Bronchodilators and Inhaled Corticosteroids among Adults - A Danish Drug Utilization Study. AB - Long-acting bronchodilators and inhaled corticosteroids (ICS) are the cornerstones in treatment of chronic obstructive and inflammatory pulmonary diseases. However, non-adherence to guidelines is widespread. Detailed information on real-life treatment patterns is needed to promote rational use. We aimed to investigate nationwide time trends in individual-level treatment patterns of long-acting bronchodilators and ICS. Using nationwide Danish health registries, we identified all Danish adults with a prescription for long-acting bronchodilators and/or ICS from 2000 to 2016. We investigated the total use of long-acting bronchodilators and ICS, the proportion of current users and the rate of new users over time. Finally, we assessed treatment persistence. We included 23,061,681 prescriptions for long-acting bronchodilators and ICS issued to 805,860 individuals from 2000 to 2016. Over this period, the total annual amount of prescribed long-acting bronchodilators and ICS increased by 39%. Similarly, the proportion of adult users increased from 2.6% to 4.5%, mainly driven by the introduction of combination therapy and long-acting muscarinic antagonist (LAMA). Although the rate of new users of fixed-dose combination drugs increased substantially over time, the overall rate of new users was stable. In general, the proportion of patients on therapy after 1 year was low (25-53%), especially among young individuals and users of ICS. We document a pronounced increase in the total use of long-acting bronchodilators and ICS over time, mainly driven by the introduction of combination drugs and LAMA. Special attention should be paid to the low level of persistence, especially among young individuals and users of ICS. PMID- 29417738 TI - Genetic variants in sex hormone pathways and the risk of type 2 diabetes among African American, Hispanic American, and European American postmenopausal women in the US. AB - BACKGROUND: Sex hormones are implicated in the development of diabetes. However, whether genetic variations in sex hormone pathways (SHPs) contribute to the risk of type 2 diabetes mellitus (T2DM) remains to be determined. This study investigated associations between genetic variations in all candidate genes in SHPs and T2DM risk among a cohort of women participating in the Women's Health Initiative (WHI). METHODS: Single nucleotide polymorphisms (SNPs) located within 30 kb upstream and downstream of SHP genes were comprehensively examined in 8180 African American, 3498 Hispanic American, and 3147 European American women in the WHI. In addition, whether significant SNPs would be replicated in independent populations was examined. RESULTS: After adjusting for age, region, and ancestry estimates and correcting for multiple testing, seven SNPs were significantly associated with the risk of T2DM among Hispanic American women were identified in the progesterone receptor (PGR) gene, with rs948516 showing the greatest significance (odds ratio 0.67; 95% confidence interval 0.57-0.78; P = 8.8 * 10-7 ; false discovery rate, Q = 7.8 * 10-4 ). These findings were not replicated in other ethnic groups in the WHI or in sex-combined analyses in replication studies. CONCLUSION: Significant signals were identified implicating the PGR gene in T2DM development in Hispanic American women in the WHI, which are consistent with genome-wide association studies findings linking PGR to glucose homeostasis. Nevertheless, the PGR SNPs-T2DM association was not statistically significant in other ethnic populations. Further studies, especially sex-specific analyses, are needed to confirm the findings and clarify the role of SHPs in T2DM. PMID- 29417740 TI - The clinical educator and complexity: a review. AB - BACKGROUND: Complexity science perspectives have helped in examining fundamental assumptions about learning and teaching in the health professions. The implications of complexity thinking for how we understand the role and development of the clinical educator is less well articulated. This review article outlines: the key principles of complexity science; a conceptual model that situates the clinical educator in a complex system; and the implications for the individual, organisation and the system. KEY FINDINGS: Our conceptual model situates the clinical educator at the centre of a complex and dynamic system spanning four domains and multiple levels. The four domains are: personal (encompassing personal/professional needs and expectations); health services (health agencies and their consumers); educational (educational institutions and their health students); and societal (local community/region and government). The system also comprises: micro or individual, meso or organisational, and macro or socio-political levels. CONCLUSION: Our model highlights that clinical educators are situated within a complex system comprising different agents and connections. It emphasises that individuals, teams and organisations need to recognise and be responsive to the unpredictability, interconnectedness and evolving nature of this system. Importantly, our article also calls for an epistemological shift from faculty development to capacity building in health professions education, aimed at developing individual, team, organisational and system capabilities to work with(in) complexity. Clinical educators are situated within a complex system comprising different agents and connections. PMID- 29417741 TI - How Can Omic Science be Improved? AB - One of the promises of multiomic analysis was to transform the clinical diagnostics to deliver much more exact phenotyping of disease states. However, despite enormous investments, the transformation of clinical routine has not taken place. There are many reasons for this lack of success but one is the failure to deliver quantitative and reproducible data. This failure is not only impeding progress in clinical phenotyping but also in the application of omic science in systems biology. The focus in this Viewpoint will be on lipidomics but the lessons learned are generally applicable. PMID- 29417742 TI - Physiological differences between a noncontinuous and a continuous endurance training protocol in recreational runners and metabolic demand prediction. PMID- 29417743 TI - Cardiac adaptation to hypertension in adult female Dahl salt-sensitive rats is dependent on ovarian function, but loss of ovarian function does not predict early maladaptation. AB - Aim of study was to examine experimentally the adult female hypertensive heart in order to determine the role of ovary function in the response of the heart to salt-dependent hypertension. Dahl salt-sensitive rats, age 12 weeks, with/without ovariectomy were fed a standard (0.3% NaCl) or high-salt diet (8%) for 16 weeks. Mean arterial blood pressure monitored noninvasively in conscious state increased significantly by high salt. Echocardiography was performed at baseline and endpoint. Heart function and molecular changes were evaluated at endpoint by left ventricle catheterization, by sirius red staining for collagen and by gene expression using quantitative RT-PCR for selected genes. At endpoint, significant concentric hypertrophy was present with high salt. Increase in relative wall thickening with high salt compared to normal diet was more pronounced with intact ovaries (0.33 +/- 0.02 and 0.57 +/- 0.04 vs. 0.29 +/- 0.00 and 0.46 +/- 0.03) as was the reduction in midwall fractional shortening (20 +/- 0.6 and 14 +/- 2 vs. 19 +/- 0.9 and 18 +/- 1). Ovariectomy increased stroke volume and decreased the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E') (E/E' ratio) when compared to hearts from intact rats. High salt increased expression of collagen I and III genes and perivascular collagen in the heart slightly, but % interstitial collagen by sirius red staining remained unchanged in intact rats and decreased significantly by ovariectomy. Added volume load but not deterioration of function or structure characterized the nonfailing hypertensive heart of salt-sensitive females ovariectomized at mature age when compared to corresponding intact females. PMID- 29417744 TI - First detection and molecular identification of Neospora caninum from naturally infected cattle and sheep in North Africa. AB - Neosporosis, caused by the protozoan Neospora caninum, is a major cause of reproductive failure in ruminants causing enormous economic losses. The objective of this study was to estimate the infection rate and molecular identification of N. caninum in Tunisian cattle and sheep. A total number of 348 meat samples were collected from 150 cows and 198 ewes slaughtered in the regional slaughterhouse of Beja (North-west Tunisia) and tested for the presence of N. caninum ITS1 gene using PCR followed by sequencing of some PCR products. A phylogenetic tree was then constructed to compare the partial sequences of the ITS1 gene with GenBank sequences. The overall molecular infection prevalence of N. caninum was significantly higher in cattle than in sheep (22 and 10.6%, respectively, p = .003). In sheep, the highest prevalence was observed in the northern Beja locality (31.2 +/- 16.1), with the Noire de Thibar breed as the most infected sheep breed (31.7 +/- 14.2%) (p < .001). In cattle, there were no differences in the molecular prevalence of N. caninum according to breeds and localities. The association between age and N. caninum molecular prevalence was statistically significant in both species; the highest prevalence was observed in sheep of more than one year of age (19.4 +/- 9.1%), and in cattle between two and eight years of age (28.8 +/- 10.9%). Comparison of the partial sequences of the ITS1 gene revealed 96%-100% similarity among our N. caninum amplicon and those deposited in GenBank. To our knowledge, this is the first detection and molecular identification of N. caninum in sheep and cattle in North Africa. This information is pertinent in designing control programmes that would reduce economic losses in the livestock industry. PMID- 29417745 TI - Effect of speed endurance training and reduced training volume on running economy and single muscle fiber adaptations in trained runners. AB - The aim of the present study was to examine whether improved running economy with a period of speed endurance training and reduced training volume could be related to adaptations in specific muscle fibers. Twenty trained male (n = 14) and female (n = 6) runners (maximum oxygen consumption (VO2 -max): 56.4 +/- 4.6 mL/min/kg) completed a 40-day intervention with 10 sessions of speed endurance training (5 10 * 30-sec maximal running) and a reduced (36%) volume of training. Before and after the intervention, a muscle biopsy was obtained at rest, and an incremental running test to exhaustion was performed. In addition, running at 60% vVO2 -max, and a 10-km run was performed in a normal and a muscle slow twitch (ST) glycogen depleted condition. After compared to before the intervention, expression of mitochondrial uncoupling protein 3 (UCP3) was lower (P < 0.05) and dystrophin was higher (P < 0.05) in ST muscle fibers, and sarcoplasmic reticulum calcium ATPase 1 (SERCA1) was lower (P < 0.05) in fast twitch muscle fibers. Running economy at 60% vVO2 -max (11.6 +/- 0.2 km/h) and at v10-km (13.7 +/- 0.3 km/h) was ~2% better (P < 0.05) after the intervention in the normal condition, but unchanged in the ST glycogen-depleted condition. Ten kilometer performance was improved (P < 0.01) by 3.2% (43.7 +/- 1.0 vs. 45.2 +/- 1.2 min) and 3.9% (45.8 +/- 1.2 vs. 47.7 +/- 1.3 min) in the normal and the ST glycogen-depleted condition, respectively. VO2 -max was the same, but vVO2 -max was 2.0% higher (P < 0.05; 19.3 +/- 0.3 vs. 18.9 +/- 0.3 km/h) after than before the intervention. Thus, improved running economy with intense training may be related to changes in expression of proteins linked to energy consuming processes in primarily ST muscle fibers. PMID- 29417747 TI - Hyperbaric oxygen therapy and intermittent ischaemia in the treatment of chronic wounds. PMID- 29417748 TI - Depression in schizophrenia - A good or bad omen? PMID- 29417749 TI - Identification of the novel HLA-B*40:333 allele by polymerase chain reaction sequence-based typing. AB - HLA-B*40:333 differs from HLA-B*40:01:01 by a single nucleotide substitution at position 380 T>C. PMID- 29417746 TI - Nomenclature for factors of the HLA system, update November 2017. PMID- 29417752 TI - Silver linings on the horizon: highlights from the 10th Cachexia Conference. AB - This article highlights the updates from preclinical and clinical studies into the field of wasting disorders that were presented at the 10th Cachexia Conference held in Rome, Italy, in December 2017. This year's conference saw some interesting results of larger-scale studies and clinical trials and new therapeutic targets. Herein, we summarize the biological and clinical significance of different markers and new diagnostic tools and cut-offs for the detection of skeletal muscle wasting, including micro RNAs, the ubiquitin proteasome system, mTOR signalling, news in body composition analysis including the D3-creatine dilution method, and new biomarkers. Clinical studies investigated novel nutritional approaches, trials of elamipretide, enobosarm, and urolithin A. It remains a fact, however, that effective treatments of cachexia and wasting disorders are urgently needed in order to improve patients' quality of life and their survival. PMID- 29417750 TI - Does gradual change in head positioning affect cerebrovascular physiology? AB - We studied cerebral blood velocity (CBV), and associated hemodynamic parameters during gradual changes in head positioning in a nonstroke group. CBV (transcranial Doppler ultrasound), beat-to-beat blood pressure (BP, Finometer), and end-tidal carbon dioxide (ETCO2 , capnography) were recorded between lying flat (0 degrees ) and sitting up (30 degrees ) head positions, in 18 volunteers (10 female, mean age, 57 +/- 16 years), at two visits (12 +/- 8 days). A significant reduction was found between 5-min FLAT (0 degrees ) and 5-min SIT (30 degrees ) positions in CBV (visit 1: 4.5 +/- 3.3%, P = 0.006; visit 2: 4.1 +/- 3.5%, P = 0.003), critical closing pressure (CrCP; visit 1: 15.5 +/- 14.0%, P = 0.0002; visit 2: 14.1 +/- 7.8%, P = 0.009) and BP (visit 1: 8.3 +/- 7.4%, P = 0.001; visit 2: 11.0 +/- 11.3%, P < 0.001). For 5 min segments of data, the autoregulation index and other hemodynamic parameters did not show differences either due to head position or visit. For 30 sec time intervals, significant differences were observed in the following: (BP, P < 0.001; dominant hemisphere (DH) CBV, P < 0.005; nondominant hemisphere (NDH) CBV, P < 0.005; DH CrCP, P < 0.001; NDH CrCP, P < 0.001; DH resistance area product (RAP), P = 0.002; NDH RAP, P = 0.033). Significant static changes in BP, CBV and CrCP, and large transient changes in key hemodynamic parameters occur during 0 degrees to 30 degrees , and vice versa, with reproducible results. Further studies are needed following acute ischemic stroke to determine if a similar responses is present. PMID- 29417753 TI - Strain- and sex-dependent pulmonary toxicity of waterpipe smoke in mouse. AB - Waterpipe smoking is emerging as a form of tobacco smoking, but its lung health/risks is not known. It has been shown that different mouse strains show differences in susceptibility to tobacco smoke. However, the effect of waterpipe smoke (WPS) exposure and strain differences in susceptibility to oxidative and inflammatory responses is not known. Here, we showed acute WPS exposure induced oxidative stress and inflammatory response in C57BL/6J and BALB/cJ mouse strains. WPS exposure induced inflammatory cell influx (neutrophils and T-lymphocytes) in bronchoalveolar lavage fluid (BAL fluid), which varied among mouse strains. Proinflammatory cytokines release differed among both the strains, but was significantly increased in C57BL/6J mice. Myeloperoxidase levels in BAL fluid were increased significantly in both the strains. Total reduced glutathione (GSH) level was decreased, whereas the level of oxidized or glutathione disulfide (GSSG) increased in lungs of both the strains. Similarly, the level of lipid peroxidation markers, 15-isoprostane (plasma), malondialdehyde and 4-hydroxy-2 nonenal (lung homogenates) were increased by WPS. Our data suggest that, oxidative stress and inflammatory responses are influenced by strain characteristics during acute WPS exposure. Overall, C57BL/6J mice showed more susceptibility to oxidative stress and inflammatory responses compared to BALB/cJ mice. Acute WPS mediated pulmonary toxicity is differentially regulated in different mouse strains. PMID- 29417754 TI - Facile Photoinduced Generation of Hydroxyl Radical on a Nitrocellulose Membrane Surface and its Application in the Degradation of Organic Pollutants. AB - A simple, clean, and efficient method has been developed for generating hydroxyl radicals on a nitrocellulose membrane (NCM) under light of wavelengths greater than 280 nm. Hydroxyl radicals formed on the NCM surface, diffusing into the bulk solution under irradiation. Radical generation was shown to be dependent on the nature of the NCM and light, and independent of the properties of the bulk solution. The quantum yield for hydroxyl radicals from the NCM was 1.72*10-4 , which is approximately 2.46 times that from TiO2 . This hydroxyl radical generation method was preliminarily applied in the photodegradation of organic pollutants, in which electrostatic interactions between the pollutant molecules and the NCM surface were found to play a key role. Further applications of this hydroxyl radical generation method should be assessed. PMID- 29417756 TI - Darrell R. Abernethy (1949-2017). PMID- 29417755 TI - Safety signal detection and evaluation in clinical development programs: A case study of tofacitinib. AB - Adverse events are anticipated during a clinical development program. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We describe here the process undertaken by Pfizer to investigate a safety signal for pancreatic cancer with tofacitinib. Potential cases of pancreatic cancer across indications from Pfizer's clinical trials and safety databases were identified and underwent in-depth case review and external expert consultation. The magnitude of the signal was quantified. The feasibility of formal signal evaluation via a hypothesis-testing study was explored. As of July 2016, 14 cases of potential pancreatic cancer were identified: eight cases in clinical development trials (psoriasis n = 6; RA n = 1; psoriatic arthritis n = 1), four cases in a postmarketing study in RA patients in Japan, and two spontaneous reports. Incidence rates (95% confidence intervals) per 100 patient-years ranged from 0 (0, 0.02) to 0.14 in RA, 0.05 (0.01, 0.15) to 0.07 (0.02, 0.16) in psoriasis, and 0.25 (0.01, 1.37) in psoriatic arthritis. The majority of patients had established risk factors for pancreatic cancer. The pharmaceutical industry's rapid and transparent response to safety signals is essential for ensuring patient safety and enabling physicians and patients to adequately assess a drug's risk:benefit. Safety signals emerging through pharmacovigilance may be true or false indicators of a causative association with drug exposure. In this example, it was determined that tofacitinib exposure was unlikely to be related to induction and promotion of pancreatic cancer; however, a relationship with pancreatic cancer promotion could not be excluded. PMID- 29417757 TI - Natriuretic peptide receptor-C-mediated attenuation of vascular smooth muscle cell hypertrophy involves Gqalpha/PLCbeta1 proteins and ROS-associated signaling. AB - Hypertension is associated with vascular remodeling due to hyperproliferation and hypertrophy of vascular smooth muscle cells (VSMC). Recently, we showed the implication of enhanced expression of Gqalpha and PLCbeta1 proteins in hypertrophy of VSMCs from 16-week-old spontaneously hypertensive rats (SHR). The aim of this study was to investigate whether C-ANP4-23 , a natriuretic peptide receptor-C (NPR-C) ligand that was shown to inhibit vasoactive peptide-induced enhanced protein synthesis in A10 VSMC could also attenuate hypertrophy of VSMC isolated from rat model of cardiac hypertrophy and to further explore the possible involvement of Gqalpha/PLCbeta1 proteins and ROS-mediated signaling in this effect. The protein synthesis and cell volume, markers of hypertrophy were significantly enhanced in VSMC from 16-week-old SHR compared with age-matched WKY rats and C-ANP4-23 treatment attenuated both to WKY levels. In addition, C-ANP4 23 treatment also attenuated the enhanced expression of AT1 receptor, Gqalpha, PLCbeta1, Nox4, and p47phox proteins, the enhanced activation of EGFR, PDGFR, IGF 1R, enhanced phosphorylation of ERK1/2/AKT and c-Src in VSMC from SHR. Furthermore, the enhanced levels of superoxide anion and NADPH oxidase activity exhibited by VSMC from SHR were also attenuated to control levels by C-ANP4-23 treatment. These results indicate that C-ANP4-23 via the activation of NPR-C attenuates VSMC hypertrophy through decreasing the overexpression of Gqalpha/PLCbeta1 proteins, enhanced oxidative stress, increased activation of growth factor receptors, and enhanced phosphorylation of MAPK/AKT signaling pathways. Thus, it can be suggested that C-ANP4-23 may be used as a therapeutic agent for the treatment of vascular complications associated with hypertension and atherosclerosis. PMID- 29417758 TI - Protective effect of carvedilol alone and coadministered with diltiazem and prednisolone on doxorubicin and 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. AB - This study investigated the protective effects of carvedilol alone and coadministered with prednisolone and diltiazem on doxorubicin (DOX) and 5 fluorouracil (5-FU)-induced toxicity. Each of 2 pools of 70 female rats were randomly allotted into 10 groups of 7 animals each and treated as follows: Group 1: normal saline (10 mL/kg); Group 2: normal saline and DOX (40 mg/kg)/5-FU (20 mg/kg) alone; Group 3: gallic acid (200 mg/kg) and DOX/5-FU; Group 4: carvedilol (0.075 mg/kg) and DOX/5-FU; Group 5: carvedilol (0.15 mg/kg) and DOX/5-FU; Group 6: carvedilol (0.30 mg/kg) and DOX/5-FU; Group 7: diltiazem (3.43 mg/kg) and DOX/5-FU; Group 8: diltiazem (3.43 mg/kg), carvedilol (0.15 mg/kg), and DOX/5-FU; Group 9: prednisolone (0.57 mg/kg) and DOX/5-FU; and Group 10: prednisolone (0.57 mg/kg), carvedilol (0.15 mg/kg), and DOX/5-FU. Treatments were done p.o. for 16/14 days for the DOX/5-FU models. DOX/5-FU was administered i.p. to the rats in Groups 2-10 on day 14/10-14. On day 17/15 (DOX/5-FU), blood samples were collected, and liver and kidneys of rats were harvested for antioxidant and histopathological assessments. Carvedilol alone and coadministered with prednisolone significantly (P < .05) decreased alanine aminotransferase level compared with administration of DOX alone. Carvedilol alone and coadministered with diltiazem significantly (P < .05) decreased creatinine level compared with administration of DOX/5-FU alone. Carvedilol alone and coadministered with diltiazem and prednisolone significantly (P < .05) increased the level of hepatic superoxide dismutase and catalase, and decreased malondialdehyde compared with DOX administration alone. Histopathological observations correlated with results of biochemical and antioxidant analyses. Carvedilol administered alone and coadministered with diltiazem and prednisolone reduced the effect of DOX/5-FU induced hepatic and renal toxicities due to enhanced in vivo antioxidant activity. The protective effect was more prominent in the doxorubicin model compared with the 5-fluorouracil test. Coadministration of carvedilol with either diltiazem or prednisolone did not show better protection relative to carvedilol alone. PMID- 29417759 TI - Anxiety- and activity-related effects of paracetamol on healthy and neuropathic rats. AB - Paracetamol has recently been suggested to affect emotion processing in addition to alleviating pain in humans. We investigated in adult male Hannover-Wistar rats whether acute intraperitoneally administrated paracetamol affects behavior in tests measuring anxiety, mood, motor activity, and memory. Unoperated rats received saline or a low (50 mg/kg) or high (300 mg/kg) dose of paracetamol, while rats with a spared nerve injury (SNI) model of neuropathy and sham-operated rats received saline or the low dose of paracetamol. Rats were tested on open field (OFT), elevated plus-maze (EPM), light-dark box (LDB), novel-object recognition (NOR), sucrose preference, rotarod, and monofilament tests. In unoperated rats, both the low and high dose of paracetamol reduced line crossings, and grooming time in the OFT, and novel preference in NOR. The high dose of paracetamol increased the time spent in the closed arm in EPM, reduced the number of rearings and leanings in OFT, the time spent in the light box in LDB, and sucrose preference. Paracetamol had no significant effect on the rotarod test measuring motor activity. The low dose of paracetamol suppressed mechanical pain hypersensitivity in SNI rats, without influencing pain behavior in sham operated rats. Saline- but not paracetamol-treated SNI rats spent more time than sham-operated rats in the closed arm in the EPM test. Together the results suggest that a high dose of paracetamol increases anxiety-like and anhedonic behavior, and impairs recognition memory in unoperated controls, while in neuropathy, a low dose of paracetamol reduces nerve injury-associated anxiety probably by reducing neuropathic pain. PMID- 29417760 TI - Fosfomycin as a potential therapy for the treatment of systemic infections: a population pharmacokinetic model to simulate multiple dosing regimens. AB - Fosfomycin has emerged as a potential therapy for multidrug-resistant bacterial infections. In most European countries, the oral formulation is only approved as a 3 g single dose for treatment of uncomplicated cystitis. However, for the treatment of complicated systemic infections, this dose regimen is unlikely to reach efficacious serum and tissue concentrations. This study aims to investigate different fosfomycin-dosing regimens to evaluate its rationale for treatment of systemic infections. Serum concentration-time profiles of fosfomycin were simulated using a population pharmacokinetic model based on published pharmacokinetic parameter values, their uncertainty, inter-individual variability and covariates. The model was validated on published data and used to simulate a wide range of dosing regimens for oral and intravenous administration of fosfomycin. Finally, based on the minimum inhibitory concentration for E. coli, surrogate pharmacodynamic indices were calculated for each dosing regimen. This is the first population pharmacokinetic model to describe the oral pharmacokinetics of fosfomycin using data from different literature sources. The model and surrogate pharmacodynamic indices provide quantitative evidence that a dosing regimen of 6-12 g per day divided in 3 doses is required to obtain efficacious exposure and may serve as a first step in the treatment of systemic multi-drug-resistant bacterial infections. PMID- 29417761 TI - Pharmacokinetic equivalence, comparable safety, and immunogenicity of an adalimumab biosimilar product (M923) to Humira in healthy subjects. AB - The aims of this randomized, double-blind, three-arm, single-dose study were to demonstrate pharmacokinetic (PK) equivalence of the adalimumab biosimilar M923 (hereafter referred to as "M923") to each of 2 reference products, and to assess M923's safety and immunogenicity. Primary PK endpoints were maximum observed concentration (Cmax ), area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf ), and AUC from time 0 to 336 hours (AUC0-336 ). Secondary endpoints included safety and immunogenicity assessments. Healthy subjects were randomized 1:1:1 to receive a 40-mg dose of M923 (n = 107); adalimumab US Humira (n = 105), hereafter referred to as "US Humira"; or adalimumab EU Humira (n = 103), hereafter referred to as "EU Humira." PK equivalence was demonstrated for all primary PK endpoints. Geometric least squares means ratios (GMRs) for Cmax , AUC0-inf , and AUC0-336 were 99.4, 100.9, and 100.5, respectively, between the M923 and EU Humira arms and 102.6, 104.2, and 102.9 between the M923 and US Humira arms. The 90% confidence intervals of the GMRs for all PK endpoints were within prespecified confidence bounds of 80%-125%. Adverse event rates were similar across the M923 (47.7%), US Humira (50.9%), and EU Humira (53.3%) arms and were generally mild (73.7%) or moderate (22.0%). The proportion of subjects with a confirmed antidrug antibody (ADA) response was similar across study arms. This study demonstrated bioequivalent PK among M923, US Humira, and EU Humira and demonstrated that the PK parameters were consistent with similar safety and tolerability profile and ADA response rates. PMID- 29417762 TI - Improving the assessment of adverse drug reactions using the Naranjo Algorithm in daily practice: The Japan Adverse Drug Events Study. AB - It is difficult to determine adverse drug reactions (ADRs) in daily complicated clinical practice in which many kinds of drugs are prescribed. We evaluated how well the Naranjo Algorithm (NA) categorized ADRs among suspected ADRs. The Japan Adverse Drug Events (JADE) study was a prospective cohort study of 3459 inpatients. After all suspected ADRs were reported from research assistants, a single physician reviewer independently assigned an NA score to each. After all NA score of suspected ADRs were scored, two physician reviewers discussed and determined ADRs based on the literature. We investigated the sensitivity and specificity of NA and each component to categorize ADRs among suspected ADRs. A total of 1579 suspected ADRs were reported in 962 patients. Physician reviewers determined 997 ADRs. The percentage of ADRs was 94% if the total NA score reached 5. The modified NA consisted of 5 components that showed high classification abilities; its area under the curve (AUC) was 0.92 for categorizing ADRs, the same as the original. When we set the total NA score cut-off value to 5, specificity was 0.95 and sensitivity was 0.59. When we reclassified NA components as binary variables, the specificity increased to 0.98 with a cut-off value of 4 and yielded an AUC of 0.93. In conclusion, we showed that both NA and modified NA could categorize ADRs among suspected ADRs with a high likelihood in daily clinical practice. PMID- 29417763 TI - Combined treatment with a selective PDE10A inhibitor TAK-063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic like effects without affecting plasma prolactin levels and cataleptic responses in rodents. AB - Activation of indirect pathway medium spiny neurons (MSNs) via promotion of cAMP production is the principal mechanism of action of current antipsychotics with dopamine D2 receptor antagonism. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl] 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a novel phosphodiesterase 10A inhibitor that activates both direct and indirect pathway MSNs through increasing both cAMP and cGMP levels by inhibition of their degradation. The activation of indirect pathway MSNs through the distinct mechanism of action of these drugs raises the possibility of augmented pharmacological effects by combination therapy. In this study, we evaluated the potential of combination therapy with TAK-063 and current antipsychotics, such as haloperidol or olanzapine after oral administration. Combined treatment with TAK 063 and either haloperidol or olanzapine produced a significant increase in phosphorylation of glutamate receptor subunit 1 in the rat striatum. An electrophysiological study using rat corticostriatal slices showed that TAK-063 enhanced N-methyl-D -aspartic acid receptor-mediated synaptic responses in both direct and indirect pathway MSNs to a similar extent. Further evaluation using pathway-specific markers revealed that coadministration of TAK-063 with haloperidol or olanzapine additively activated the indirect pathway, but not the direct pathway. Combined treatment with TAK-063 and either haloperidol or olanzapine at subeffective doses produced significant effects on methamphetamine- or MK-801-induced hyperactivity in rats and MK-801-induced deficits in prepulse inhibition in mice. TAK-063 at 0.1 mg/kg did not affect plasma prolactin levels and cataleptic response from antipsychotics in rats. Thus, TAK-063 may produce augmented antipsychotic-like activities in combination with antipsychotics without effects on plasma prolactin levels and cataleptic responses in rodents. PMID- 29417764 TI - Prospective evaluation of Ceftriaxone use in medical and emergency wards of Gondar university referral hospital, Ethiopia. AB - Ceftriaxone is among the most commonly utilized antibiotics owing to its high potency, wide spectrum of activity, and low risk of toxicity. It is used to treat different types of bacterial infections including pneumonia, bone infections, abdominal infections, Skin and soft tissue infections, urinary tract infections. However, evidence around the globe shows the misuse of Ceftriaxone. This study aimed at evaluating the appropriateness of ceftriaxone use in medical and emergency wards of Gondar university referral hospital (GURH), Northwest Ethiopia. A prospective, cross-sectional study design was employed to evaluate the use of ceftriaxone. The medical records of patients who received ceftriaxone were reviewed prospectively between January 1 and March 30, 2017. Appropriateness of ceftriaxone use was evaluated as per the protocol developed from current treatment guidelines. A total of 390 patients' medical records were reviewed. The utilization rate of ceftriaxone was found to be high with a point prevalence of 59%. Ceftriaxone was empirically used in 79.5% of cases. The most common indications of Ceftriaxone were respiratory tract infections (29.3%), central nervous system infections (24.1%), and prophylactic indications (16.4%). The mean duration of ceftriaxone therapy in our study was 11.47 days, with a range of 1-52 days. More than two-thirds (80.2%) of ceftriaxone use were found to be inappropriate and majority of unjustified ceftriaxone use emanated from inappropriate frequency of administration (78.3%), absence of culture and sensitivity test (68.7%), and duration of therapy (47%). Empiric treatment with ceftriaxone and the presence of coadministered drugs was significantly associated with its inappropriate use. The present study revealed a very high rate of inappropriate use of ceftriaxone which may potentially lead to emergence of drug resistant microorganisms and ultimately exposes the patient to treatment failure and increased cost of therapy. PMID- 29417765 TI - Conflicting evidence for the role of JNK as a target in breast cancer cell proliferation: Comparisons between pharmacological inhibition and selective shRNA knockdown approaches. AB - As a target, the JNK pathway has been implicated in roles including cell death, proliferation, and inflammation in variety of contexts which span cardiovascular disease, neurodegenerative pathologies, and cancer. JNK1 and JNK2 have recently been demonstrated to function independently, highlighting a new parameter in the study of the JNK pathway. In order for JNK1 and JNK2-specific roles to be defined, better tools need to be employed. Previous studies have relied upon the broad spectrum JNK inhibitor, SP600125, to characterize the role of JNK signaling in a number of cell lines, including the breast cancer cell line MCF-7. In line with previous literature, our study has demonstrated that SP600125 treatment inhibited c-Jun and JNK phosphorylation and MCF-7 proliferation. However, in addition to targeting JNK1, JNK2, and JNK3, SP600125 has been previously demonstrated to suppress the activity of a number of other serine/threonine kinases, making SP600125 an inadequate tool for JNK isoform-specific roles to be determined. In this study, lentiviral shRNA was employed to selectively knockdown JNK1, JNK2, and JNK1/2 in MCF-7 cells. Using this approach, JNK phosphorylation was fully inhibited following stable knockdown of respective JNK isoforms. Interestingly, despite suppression of JNK phosphorylation, MCF-7 cell proliferation, cell cycle progression, or cell death remained unaffected. These findings raise the question of whether JNK phosphorylation really is pivotal in MCF-7 cell growth and death or if suppression of these events is a result of one of the many off-targets cited for SP600125. PMID- 29417766 TI - Limiting glioma development by photodynamic therapy-generated macrophage vaccine and allo-stimulation: an in vivo histological study in rats. AB - Immunotherapy of brain tumors involves the stimulation of an antitumor immune response. This type of therapy can be targeted specifically to tumor cells thus sparing surrounding normal brain. Due to the presence of the blood-brain barrier, the brain is relatively isolated from the systemic circulation and, as such, the initiation of significant immune responses is more limited than other types of cancers. The purpose of this study was to show that the efficacy of tumor primed antigen presenting macrophage (MaF98) vaccines can be increased by: (1) photodynamic therapy (PDT) of the priming tumor cells and (2) intracranial injection of allogeneic glioma cells directly into the tumor site. Experiments were conducted in an in vivo brain tumor development model using Fischer rats and F98 (syngeneic) and BT4C (allogeneic) glioma cells. The results showed that immunization with Ma (acting as antigen-presenting cells), primed with PDT treated tumor cells (MaF98), significantly slowed but did not prevent the growth of F98-induced tumors in the brain. Complete suppression of tumor development was obtained via MaF98 inoculation combined with direct intracranial injection of allogeneic glioma cells. No deleterious effects were noted in any of the animals during the 14-day observation period. PMID- 29417767 TI - [Reasonable and standard usage to spinal intervertebral fusion]. PMID- 29417768 TI - [Clinical study of application minimally invasive expandable channel in lumbar discectomy and interbody fusion and internal fixation]. AB - OBJECTIVE: To explore the advantages of minimally invasive expandable in surgery of lumbar discectomy and interbody fusion and internal fixation. METHODS: The clinical data of 48 patients who underwent lumbar discectomy and interbody fusion and internal fixation from January 2010 to March 2016 was retrospectively analyzed. According to the admission queue, the patients were randomly assigned into channel group (26 cases) or traditional group (22 cases). In channel group, surgical approach of minimally invasive expandable channel was applied, and in traditional group, open posterior operation approach (including posterior lumbar interbody fusion and transforaminal lumbar interbody fusion, etc.) was applied. In channel group, there were 20 males and 6 females, aged from 43 to 74 years with an average of(56.6+/-5.1) years; course of disease was ranged from 4 to 22 months with an average of (6.7+/-1.8) months; 1 case was complicated with diabetes, 6 cases were complicated with hypertensive disease, and 2 cases were complicated with arrhythmia. In traditional group, there were 15 males and 7 females, aged from 43 to 73 years with an average of(55.9+/-4.6) years; course of disease was ranged from 4 to 26 months with an average of (6.2+/-2.1) months; 2 cases were complicated with diabetes, 5 cases were complicated with hypertensive disease, and 1 case was complicated with arrhythmia. Operation time, bleeding volume, and hospitalization time were compared between two groups and visual analogue scale(VAS), Oswestry Disability Index(ODI), bone fusion information, and complications correlated with incision were observed in two groups. RESULTS: All 48 patients were followed up for more than 6 months. Postoperative VAS and ODI were significantly improved (P<0.01), but 3 and 6 months after operation, there was no significant difference in VAS between two groups, and ODI score of channel group was lower than that of traditional group(P<0.01). Operation time, bleeding volume, hospitalization time in channel group respectively were (167.3+/-30.2) min, (786.8+/-147.8) ml, (12.3+/-2.4) d, and in traditional group were (197.5+/ 48.7) min, (786.8+/-147.8) ml, (16.5+/-3.8) d, there was significant differences between two groups. There was no significant difference in fusion rate and fusion time between two groups. There were 4 cases and 7 cases developed incision related complications in channel group and traditional group, respectively. The difference between two groups was significant(P<0.01). CONCLUSIONS: Compared with conventional surgery minimally invasive lumbar discectomy and interbody fusion and internal fixation has advantages of less trauma, shorter operative time and better functional recovery. PMID- 29417769 TI - [Case control study of interbody fusion with simple decompression bone block in treating degenerative lumbar instability and spinal stenosis]. AB - OBJECTIVE: To explore the value of the self-decompression bone block in interbody fusion. METHODS: From April 2014 to May 2015, 42 patients with degenerative lumbar instability and spinal stenosis were treated by posterior vertebral lamina decompression and pedicle nail-rod fixation and unilateral modified transforaminal lumbar interbody fusion, including 18 males and 24 females. The treatment group had 24 cases with autologous pure decompression bone block as single interbody fusion material and the control group had 18 cases with cage and autologous bone as interbody fusion material. Clinical data, bone healing time, interbody fusion rate, intervertebral height and curative effect were analyzed in two groups. RESULTS: All the patients were followed up for 12 to 24 months with an average of 16 months. There was no significant difference in age, sex ratio, degree of lumbar instability, or follow-up time between two groups(P>0.05); and there was no significant difference in curative effect, intervertebral height loss, or interbody fusion rate between two groups(P>0.05). CONCLUSIONS: Using self-decompression bone block fusion can get high fusion rate, maintain good intervertebral height, obtain satisfactory curative effect. Its design was scientific and reasonable with less complication, which provide an effective, economic, and practical method for degenerative lumbar instability and spinal stenosis. PMID- 29417770 TI - [Debridement, internal fixation, and reconstruction with titanium mesh for the surgical treatment of lumbar tuberculosis via a posterior-only approach in adults]. AB - OBJECTIVE: To investigate the clinical effects, indications and key techniques of debridement, internal fixation, and reconstruction with titanium mesh in lumbar tuberculosis via a posterior-only approach in adults. METHODS: The clinical data of 26 patients with monosegment lumbar tuberculosis treated with surgery from March 2012 to March 2014 was retrospectively analyzed. Among them, 15 cases were male and 11 cases were female, and patients' age ranged from 21 to 68 years old (average, 44.7 years old). All patients suffered from back pain and/or pain with radiation to the legs. The clinical efficacy was evaluated based on the complications, erythrocyte sedimentation rate (ESR), imaging examination, and back and leg pain score of visual analogue scale (VAS). RESULTS: All operations were successful in 26 patients with an average operation time of (2.4+/-0.8) h (range from 2 to 4 h), with an average blood loss of (320+/-86) ml(range from 200 to 700 ml) .VAS was decreased from (5.7+/-1.4) points preoperatively to (1.6+/ 0.5) points 2 weeks postoperatively (P<0.01); and ESR was decreased from (42.8+/ 10.4)mm/h preoperatively to (12.1+/-5.6)mm/h 3 months after surgery (P<0.01). All the patients were followed up for 24 to 48 months with an average of(28.3+/-5.8) months. One patients suffered from the recurrence of TB and sinus tract formation at 2 months after surgery, and was cured by stronger anti-tuberculosis drugs, local debridement with drainage, and sinus tract healed at 3 months after operation. All intervertebral bone graft obtained fusion within 1 year after operation and no local recurrence of TB was found at final follow-up. CONCLUSIONS: Debridement, internal fixation, and reconstruction with titanium mesh via a posterior-only approach is a effective and safe method for the treatment of monosegment lumbar tuberculosis, especially for the patients with secondary spinal stenosis. PMID- 29417771 TI - [Comparison of clinical effects between anterior cervical Zero-incision fusion system and traditional nail plate system in the treatment of cervical spondylotic myelopathy]. AB - OBJECTIVE: To compare the short-term efficacy of anterior cervical discectomy and fusion(ACDF) with traditional nail plate system and Zero-profile device in the treatment of cervical spondylotic myelopathy(CSM). METHODS: The clinical data of 45 patients with CSM treated from July 2014 to August 2015 was retrospectively analyzed. There were 23 males and 22 females with an average age of 53.7 years old(range, 32 to 71 years old). The course of disease was 5 months to 2 years. All the patients were treated with ACDF with 24 cases by traditional nail plate system fixation(group A) and 21 cases by Zero-P system fixation(group B). Operation time and intraoperative bleeding were compared between two groups. Neurological function and cervical pain were evaluated by Japanese Orthopaedic Association scores (JOA) and visual analogue scale (VAS), respectively. Cervical curvature(Cobb angle) change and intervertebral fusion were evaluated by X-rays and CT. And associated complications were analyzed in two groups. RESULTS: All the patients were followed up for 12 to 16 months with an average of 14 months. Operation time of group A and B was(87.6+/-23.2) min and (62.7+/-17.3) min respectively, and the difference was significant between two groups; and intraoperative bleeding was (80.2+/-36.8) ml and (78.4+/-29.6) ml respectively, and the difference was not significant. At final follow-up, JOA and VAS of all patients were obvious improved, but there was no significant difference between two groups. Preoperative Cobb angle in group A and B was (8.7+/-4.3) degrees and (8.6+/-4.2) degrees respectively, and the difference was significant. The Cobb angle at final follow-up was (14.5+/-6.4) degrees and (17.4+/-8.6) degrees respectively, and the difference between two groups was significant. The incidence of dysphagia in group A and B were 29.17% and 9.52% respectively, and there was significant difference between two groups. All intervertebral spaces got fusion at final follow-up. No tracheo-asophageal injury and recurrent laryngeal nerve damage or other complications were found. No fusional migration, subsidence, loosening, breakage, etc. were found. CONCLUSIONS: The clinical comparison of Zero-P interbody fixation system and cervical plate internal fixation for the treatment of cervical spondylosis was quite fair, but Zero-P showed a better therapeutic effect with improvement of life quality. PMID- 29417772 TI - [Case control study on two different surgical approaches combined fixation with lumbar interbody fusion for the treatment of single segmental lumbar vertebra diseases]. AB - OBJECTIVE: To discuss the advantages and disadvantages of two different surgical approaches combined fixation with lumbar interbody fusion in treating single segmental lumbar vertebra diseases. METHODS: The clinical data of 86 patients with single segmental lumbar vertebra diseases treated from June 2011 to June 2013 was retrospectively analyzed. There were 33 males and 53 females, aged from 28 to 76 years old with an average of 53.0 years. Among them, there were 39 cases of lumbar disc degeneration, 22 cases of lumbar disc herniation complicated with spinal canal stenosis, 9 cases of huge lumbar disc herniation and 16 cases of lumbar degenerative spondylolisthesis (Meyerding degree I ). Lesion sites contained L3, 4 in 5 cases, L4, 5 in 70 cases and L5S1 in 11 cases. All the patients were treated with internal fixation and lumbar interbody fusion with 45 cases by midline incision approach (median incision group) and the other 41 cases by channel-assisted by muscle-splitting approach(channel group). Incision length, operation time, intraoperative bleeding and postoperative drainage were recorded in two groups. Visual analogue scale(VAS) was used to assess lumbar incision pain 72 h after operation. Depended on imaging results to compare the changes of the disc space height in lesion in preoperative, postoperative and final follow-up, the coronal and sagittal Cobb angle in preoperative and final follow-up, the area of multifidus and the degree of multifidus fat deposition before and after operation between two groups. Loosening or fragmentation of internal fixation, displacement of intervertebral cage and interbody fusion were observed in each group. Japanese Orthopedic Association (JOA) scoring system was used to evaluate the function before operation and at the final follow-up. RESULTS: The channel group was superior to the median incision group in incision length and postoperative drainage while the median incision group was less than the channel group in the operation time and intraoperative bleeding. The average VAS score of lumbar incision 72 h after operation was 1.50 points in median incision group and 0.97 points in channel group, and there was significant difference between two groups(P<0.05). No incision infection was found, but there were 4 cases of incisional epidermal necrosis, 1 case of incision healed badness, and 3 cases of nerve injury in channel group. The incidence of cacothesis of pedicle screw were 5.0% and 3.6% in median incision group and channel group respectively, and there was no significant difference between two groups(P>0.05). The incidence of cacothesis of translaminar facet screw were 6.6% and 12.2% in median incision group and channel group respectively, and there was significant difference between two groups(P<0.05). All the patients were followed up for 12 to 36 months with a mean of 22.8 months. The changes of disc space height had statistical difference between preoperative and postoperative(P<0.05) in all patients, but there was no significant difference between postoperative and final follow up(P>0.05), however, there was no significant difference 3 days after operation and final follow-up between two groups(P>0.05). At final follow-up, coronal and sagittal Cobb angle were obviously improved in all patients(P<0.05), but there was no significant difference between two groups(P>0.05). One year after operation, the area of multifidus in median incision group was (789.00+/-143.15) mm2 less than preoperative(1 066.00+/-173.55) mm2 (P<0.05), and in channel group, was(992.00+/-156.75) mm2 at 1 year after operation and(1 063.00+/-172.13) mm2 preoperatively, there was no significant difference between them(P>0.05), however, there was significant difference one year after operation between two groups (P<0.05) . About the degree of multifidus fat deposition, there was significant difference between one year after operation and preoperation in median incision group (P<0.05), but there was no significant difference between one year after operation and preoperation in channel group (P>0.05), and there was significant difference at one year after operation between two groups(P<0.05). During the follow-up period, neither pedicle screw and/or translaminar facet screw loosening, displacement or fragmentation nor displacement of intervertebral cage were found. The lumbar interbody fusion rate was 95.6% in median incision group and was 95.1% in channel group, and there was no significant difference between two groups(P>0.05). No obvious adjacent segmental degeneration was observed in fixed position. JOA score in median incision group was significantly increased from 8-16 points (average: 12.77+/ 2.56) preoperative to 21-29 points (average: 25.20+/-2.43) at final follow up(P<0.05); and in channel group was significantly increased from 8-16 points (average: 12.64+/-2.37) preoperative to 23-29 points(average: 26.7+/-1.82) at final follow-up(P<0.05); there was also significant difference between two groups at final follow-up. CONCLUSIONS: Compared to the median incision approach, unilateral pedicle screw combined with contralateral translaminar facet screw fixation using channel-assisted by muscle-splitting approach has advantages of small incision, less trauma, fast recovery and so on. However, it also has shortages such as high surgical complications incidence, especially in cases that. PMID- 29417773 TI - [Mid and long-term clinical effects of percutaneous kyphoplasty with two methods for vertebral fragility fracture in the elderly]. AB - OBJECTIVE: To evaluate the middle-long-term clinical effects of unilateral and bilateral percutaneous kyphoplasty(PKP) for vertebral fragility fracture in the elderly. METHODS: The clinical data in elderly patients with vertebral fragility fracture treated by unilateral and bilateral PKP between January 2008 and January 2010 was retrospective analyzed. According to a unified criteria to divided into two groups for 104 patients(44 males and 60 females), of them, 50 cases were divided in unilateral group using unilateral pedicle surgical approach for PKP and 54 cases were in bilateral group using bilateral pedicle approach. VAS score, Cobb angle, and the height of anterior and posterior vertebral body were respectively analyzed peroperatively and at 3 d, 3 months, 1 year, 3 years postoperatively and final follow-up. Clinical effects and safety were assessed in two groups. RESULTS: All the operations were successful. Operative time and bone cement injection volume in unilateral group were less than those of bilateral group(P<0.05). Postoperative VAS scores, Cobb angle, and the height of anterior and posterior vertebral body were obviously improved in two groups(P<0.05), and there was no significant difference between two groups(P>0.05). Bone cement leakage occurred in 12 cases(11.5%), recurrent fracture of vertebral body occurred in 5 cases(4.8%), cerebrospinal leak occurred in 2 cases(1.9%), and nerve root irritation occurred in 3 cases(2.9%). The above complications were transient and released after symptomatic treament. CONCLUSIONS: Middle-long-term clinical effects of unilateral and bilateral percutaneous kyphoplasty for vertebral fragility fracture are safe and satisfactory, and may be extended as a minimally invasive method. Unilateral approach for PKP has advantages of short operation time, relative less trauma, thus is a more ideal method. PMID- 29417774 TI - [Risk factors of cubitus varus in humeral condylar fracture after conservative treatment in child]. AB - OBJECTIVE: To further investigate the risk factors of cubitus varus in humeral condylar fracture after conservative treatment in children through Logistic regression analysis, so as to guide the clinical treatment. METHODS: Children with humeral condylar fracture who were treated by manipulative reduction and plaster fixation in our hospital from March 2008 to December 2014 were studied. The clinical data including age, gender, BMI, time from injury to reduction, direction of displacement, rotation displacement, fixed position, and epiphyseal injury were collected. First, preliminary screen the risk factors through univariate analysis of the above data, then determine the risk factors of cubitus varus through multivariate Logistic regression analysis of the significant factors from univariate analysis. RESULTS: Univariate analysis showed that time from injury to reduction, direction of displacement, rotation displacement and epiphyseal injury were significantly correlated with the cubitus varus. Multivariate Logistic regression analysis showed that time from injury to reduction which was longer than 8 h [P=0.017, OR=3.303(1.243-8.774)], ulnar displacement [P=0.001, OR=11.951(2.895-49.335)], rotation displacement [P=0.003, OR=4.190(1.643-10.685)]and epiphyseal injury [P=0.000, OR=7.092(2.557-19.671)] were independent risk factors of cubitus varus. CONCLUSIONS: Time from injury to reduction, ulnar displacement, rotation displacement and epiphyseal injury are independent risk factors of cubitus varus. So it need corresponding treatment according to different risk factors. PMID- 29417775 TI - [Mechanical complications with self-made, antibiotic-loaded cement articulating spacers in the treatment of the infected hip replacement]. AB - OBJECTIVE: To study the complications and efficacy of self-made, antibiotic loaded cement articulating spacers in the treatment of the infected hip replacement. METHODS: Between January 2006 and July 2016, 265 patients (266 hips) received a self-made, antibiotic-loaded cement articulating spacer as part of a two-stage protocol. Among those patients, there were 143 males(144 hips) and 122 females(122 hips). The cement articulating spacers with vancomycin and two Steinman pins were made by a self-made mold system. Meanwhile, another antibiotic was added to the spacers according to the drug sensitivity test. Record if the infected prosthesis was removed, related complication with spacer(breakage and dislocation), Harris score, and control rate of infection. RESULTS: The mean age of two-stage revision operation was(57.4+/-14.2) years. Thirty-nine patients(14.7%) used extended trochanteric osteotomy(ETO) to remove the infected prosthesis. And 38 patients occurred mentioned complications(14.3%). Spacer breakage occurred in 28 cases(10.5%) and dislocation occurred in 10 cases(3.8%). The mean follow-up time was(83.4+/-14.6) months. The Harris hip score was from 47.56+/-14.23 preoperatively to 86.43+/-12.84 at final follow-up(P<0.05). The infection of 256 cases(96.6%) got control after revision operation. However, during postoperative follow-up, 4 cases occurred re-infection, and they were reoperated, and the infections obtained effective control after the operation. Thus total infection control rate was 95.1%(252/265). CONCLUSIONS: Antibiotic loaded cement articulating spacer made by a self-made mold system is effective in controling infection caused by hip replacement. Related complication is less with spacer by a mould enclosing two Steinman pins. Using metallic internal fixation or allograft bone combined with spacer does not affect infection control. PMID- 29417776 TI - [Clinical outcomes Tight rope versus traditional screw fixation for the treatment of injury of distal tibiofibular syndesmosis in ankle fracture]. AB - OBJECTIVE: To compare the clinical effectiveness for Tight rope fixation and traditional screw fixation in treating injury of distal tibiofibular syndesmosis in ankle fractures. METHODS: A retrospective study was carried out in patients with injury of distal syndesmosis in ankle fractures who received 2 surgical operations(observation group: 33 cases with Tight rope fixation; control group: 35 cases with traditional screw fixation) from May 2014 to February 2016. There were 18 males and 15 females, aged from 20 to 55 years old with an average of(32.4+/-5.2) years old in observation group; of them, 19 cases were caused by traffic accidents, 10 by sprain, and 4 by falling; according to Lauge-Hansen typing of ankle fractures, all of the 33 cases were pronation-extorsion fracture, 12 cases were III degree and 21 cases were IV degree. There were 19 males and 16 females, aged from 21 to 54 years old with an average of (32.8+/-5.5) years old in control group; of them, 20 cases were caused by traffic accidents, 11 by sprain, 4 by falling; according to Lauge-Hansen typing of ankle fractures, 1 case was with pronation-outreach, 34 cases with pronation-extorsion, 13 cases were III degree and 21 cases were IV degree. Fixation time and complication were compared between two groups and AOFAS scores were observed in two groups 3 and 6 months after the operation as well as final follow-up. RESULTS: All the patients were followed up from 8 to 24 months with an average of (16.3+/-3.8) months. Fixation time of observation group and control group were (10.1+/-2.8) min and (9.5+/-2.3) min(P>0.05) respectively. There were significant difference in complication and AOFAS of 3, 6 months postoperatively between two groups(P<0.05). In observation group, 23 case got excellent result, 9 good, 1 fair; and in control group, 18 cases got excellent results, 12 good, 5 fair; there was no significant difference between two groups(P>0.05). CONCLUSIONS: Tight rope for the treatment of injury of distal tibiofibular ligament union in ankle fractures has advantages such as easier techniques, earlier weight-bearing exercises without risk of screw breakage, thus is a new choice. However, it is still necessary to further study the angle, direction and tension of button steel plate. PMID- 29417777 TI - [Effect of different bone cement dispersion types in the treatment of osteoporotic vertebral compression fracture]. AB - OBJECTIVE: To observe different bone cement dispersion types of PVP, PKP and manipulative reduction PVP and their effects in the treatment of senile osteoporotic vertebral compression fractures and the bone cement leakage rate. METHODS: The clinical data of patients with osteoporotic vertebral compression fractures who underwent unilateral vertebroplasty from January 2012 to January 2015 was retrospectively analyzed. Of them, 56 cases including 22 males and 34 females aged from 60 to 78 years old were treated by PVP operation; Fouty-eight cases including 17 males and 31 females aged from 61 to 79 years old were treated by PKP operation; Forty-three cases including 15 males and 28 females aged from 60 to 76 years old were treated by manipulative reduction PVP operation. AP and lateral DR films were taken after the operation; the vertebral bone cement diffusion district area and mass district area were calculated with AutoCAD graphics processing software by AP and lateral DR picture, then ratio(K) of average diffusion area and mass area were calculated, defining K<50% as mass type, 50%<=K<=100% as mixed type and K>100% as diffusion type. Different bone cement dispersion types of PVP, PKP and manipulative reduction PVP operation were analyzed. According to bone cement dispersion types, patients were divided into diffusion type, mixed type and mass type groups.Visual analogue scale (VAS), vertebral body compression rate, JOA score and bone cement leakage rate were observed. RESULTS: All patients were followed up for 12-24 months with an average of 17.2 months. There was significant difference in bone cement dispersion type among three groups (P<0.05). The constituent ratio of diffusion type, mixed type and mass type in PVP operation was 46.43%, 35.71%, 17.86%, in PKP was 16.67%, 37.50% , 45.83%, and in manipulative reduction PVP was 37.21%, 44.19% and 18.60%, respectively. PVP operation and manipulative reduction PVP were mainly composed of diffusion type and mixed type, while PKP was mainly composed of mass type and mixed type. There was no significant difference in VAS score, JOA score and bone cement leakage rate among three groups. There was statistically significant difference in postoperative vertebral body compression rate among three bone cement dispersion types(P<0.05), postoperative vertebral body compression rate in diffusion type group at 24 h postoperatively and final follow-up was (17.31+/ 5.06)% and(18.58+/-4.91)%, respectively. In mixed type group, it was(14.21+/ 5.15)% and(14.59+/-5.07)%, respectively. In mass type group, it was(13.89+/ 5.02)% and(14.28+/-4.94)%, respectively. CONCLUSIONS: Bone cement dispersion type is different in PVP, PKP and manipulative reduction PVP operation. The bone cement dispersion of mass type and mixed type to recovery of compressed vertebral body is better than diffusion type, and there is no obvious difference in clinical effect in different bone cement dispersion type early and middle term. PMID- 29417778 TI - [Unilateral Wiltse intermuscular approach and contralateral decompression for the treatment of thoracolumbar burst fracture]. AB - OBJECTIVE: To compare the clinical effects and multifidus muscle injury of different approaches, including unilateral Wiltse intermuscular approach and intramuscular approach combined with contralateral decompression, in treating thoracolumbar burst fracture. METHODS: Forty-three patients with thoracolumbar burst fracture were enrolled in the study from January 2010 to December 2014, including 29 males and 14 females with an average age of 42.3 years old(ranged from 21 to 64 years old). The patients were treated with posterior pedicle screw fixation and unilateral decompression and were divided into Wiltse intermuscular approach group (group A) and intramuscular approach group (group B) according to surgical approach. Operation time and intraoperative bleeding were recorded for all patients; visual analogue scale(VAS) was compared 1 d preoperatively, 1 week, 12 months postoperatively between two groups; preoperation and 12 months postoperatively, the fractured vertebral canal and two-sides multifidus muscle of the same section were observed and compared by CT measure between two groups. RESULTS: All the patients were follow-up for 14 to 21 months with an average of 16.3 months. Partial wound non-healing occurred in 3 patients and the wound ultimately healing after debridgement suture and change dressings. No screw breakage was found. There was significant difference in operation and intraoperative bleeding operation between two groups (P<0.05), while there was no significant difference in VAS score of 1 d preoperatively, 1 week, 12 months postoperatively between two groups(P>0.05). As for CT measurement results, postoperative vertebral canal narrow ratio was significant decreased in all patients(P<0.05), while perioperative changes of the two-sides multifidus muscle cross section area and density were significant in group A (P<0.05), but there was no significant difference in group B (P>0.05). Neurologic status of all patients got recovery at final follow-up. CONCLUSIONS: The method of unilateral Wiltse intermuscular approach combined with contralateral decompression for the treatment of thoracolumbar burst fracture has good clinical effects, also it is less invasive and less damage to multifidus muscle compared with intramuscular approach. PMID- 29417779 TI - [Correlation analysis between position of head, cervical curvature classification and balance of cervical spine through lateral plain radiograph measurement]. AB - OBJECTIVE: To analyze the relationship between position of head, cervical curvature type and associated cervical balance parameters in a neutral looking forward posture. METHODS: Cervical lateral X-rays of 60 patients with cervical spondylosis were selected from January to December 2015. There were 22 males and 38 females with an average age of (35.5+/-10.9) years old. The measured parameters included cervical curvature type, McGregor slope, C2 lower end plate slope, T1 slope, center of gravity to C7 sagittal vertical offset (CG-C7 SVA), and C2 to C7 sagittal vertical offset (C2-C7 SVA). The parameters were analyzed using Spearman correlation. RESULTS: The cervical curvature type was significantly correlated with C2 lower endplate slope, C0-C2 angle (total degree of C2 lower endplate slope plus McGregor slope), CG-C7 SVA and T1 slope (P<0.05), but it was not significantly correlated McGregor slope (P>0.05). C2 lower endplate slope and C2-C7 SVA (r=0.87) were significantly (P<0.05) correlated with CG-C7 SVA (P<0.05). CONCLUSIONS: There was certain some relationship among position of head, cervical curvature type and associated cervical balance parameters in a neutral looking-forward posture. The center of gravity of the head would backwards shift following faced upward. A position of extension with posterior-shifting of the head would suggest that it may be accompanied with a relatively normal lordosis of the cervical spine. Some patients with abnormal curvature showed slightly bended head in the natural posture. Health education toward these people would be meaningful to restore the balance of their neck. PMID- 29417780 TI - [Subculture, cryopreservation and recovery of osteoclasts]. AB - OBJECTIVE: To explore the feasibility of passage, cryopreservation, and recovery of osteoclasts in order to develop new techniques facilitating osteoclast research. METHODS: Passage of osteoclasts: adult male SD rat(SPF grade, weight of 250 g) was sacrificed and the abdominal aorta was exposed for blood draw. Monocytes isolated from peripheral circulation was treated with RANKL and M-CSF for 2 weeks. After formation of osteoclasts, they were trypsinized with pipetting, centrifuged, re-suspended with alpha-MEM containing RANKL and M-CSF, and cultured in 6 well-plates and 35 mm culture dishes. Freezing of osteoclasts: trypsinized osteoclasts were centrifuged and resuspended with DMSO, FBS, alpha MEM (1:2:7), and were stored in liquid nitrogen(-196 degrees C). Recovery of osteoclasts: frozen osteoclasts were taken out of liquid nitrogen tank and thawed quickly at 37 degrees C in water bath. After wash with PBS, the cells were resuspended with alpha-MEM containing RANKL and M-CSF, and were cultured in 6 well dishes and 35 mm culture dishes. Meanwhile, cells were checked with inverted phase contrast microscope and observed in the live cell station for real time imaging. TRAP staining was performed 3 days after plating. RESULTS: Trypsinization together with pipetting and shaking can detach the adherent osteoclasts, and the resuspended cells can be used for passage and storage in liquid nitrogen. The passaged cells became fully attached to the culture dishes in 2 hours, and the multinucleated feature could be clearly seen. The osteoclasts recovered from liquid nitrogen could completely spread out for 2 to 3 hours so that the multinucleated cells were clearly seen. These cells were still TRAP positive. CONCLUSIONS: Although osteoclasts strongly adhere to the bottom of culture dishes, a large majority of the osteoclasts can be detached after appropriate digestion with trypsin, pipetting and shaking. These cells can be used for passage and cryopreservation. After recovering from liquid nitrogen, these cells still preserve the viability and the feature of osteoclasts. The results provide a new and powerful tool for future study of osteoclast biology. PMID- 29417781 TI - [Surgical treatment for talar neck fracture of Hawkins III, IV type with compression hollow screws combined with external fixator]. AB - OBJECTIVE: To investigate the clinical effects of compression hollow screws combined with external fixator in treating talar neck fracture of Hawkins III, IV type. METHODS: From March 2010 to August 2014, 15 patients with talar neck fractures of Hawkins III, IV type were treated by open reduction and compression hollow screws fixation complicated with external fixator fixation. Including 9 males and 6 females, aged from 17 to 65 years old with an average of 37.5 years old. There were 9 cases of Hawkins III and 6 cases of Hawkins IV type. Postoperative radiographs and CT of ankle were used to evaluate the fracture healing and talar necrosis. The function of ankle and foot were evaluated by American Society of Ankle and Foot Surgery(AOFAS). RESULTS: All the patients were followed up for 8 to 55 months with an average of 23.5 months and all fractures got bone healing from 13 to 38 weeks with an average of (17.99+/-6.81) weeks. Traumatic arthritis occurred in 7 cases and talar necrosis in 6 cases (2 cases of type III and 4 cases of type IV) after operation. The average AOFAS score was 61.80+/-18.75, including excellent in 4 cases, good in 2 cases, fair in 4 cases and poor in 5 cases. CONCLUSIONS: Talar neck fracture with Hawkins III, IV type has large possibility to develop avascular necrosis. Hollow compression screw combined with external fixation may late weight-bearing for ankle and can sufficiently guarantee bone healing time, and achieve good results for the treatment of talar neck fracture. PMID- 29417782 TI - [Posterior debridement, interbody fusion, internal fixation for treatment of lumbar discitis]. AB - OBJECTIVE: To evaluate the clinical effects of posterior debridement, interbody fusion with internal fixation in the treatment of lumbar discitis. METHODS: The clinical data of 13 patients with lumbar discitis treated from January 2005 to June 2012 was retrospectively analyzed. There were 9 males and 4 females, aged from 31 to 68 years old with an average of 56 years old. There were 2 cases on L3, 4, 4 cases on L4, 5, and 7 cases on L5S1. Two cases complicated with diabetes, 4 cases with hypertension, and 1 case with obsolete pulmonary tuberculosis. ESR level of 13 cases was 12-89 mm/h with an average of 42 mm/h; and C reactive protein fluctuations level was level 8-114 ng/L with an average of 47 ng/L. All the patients denied history of operation or injection, and the main symptom was severe pain and limitation of motion in lumbar, with no efficacy for conservative methods. Preoperative VAS was from 5 to 10 points with an average of 7.8 points. All patients were treated with posterior debridement, interbody fusion, and internal fixation. RESULTS: All the patients left hospital after wound healing, and the effective antibiotics were continuously used for 4 weeks intravenously and 2 weeks for orally. All patients were followed up from 7 to 24 months with an average of 18 months. VAS decreased for 0-1 point. No internal fixation breakage, and recurrence were found. Bone graft got fusion, and postoperative pathology showed phlogistic changes. CONCLUSIONS: One-stage posterior debridement, interbody fusion with internal fixation was an effective method in treating lumbar discitis, and it lead to quicker relived pain relief and earlier mobilization. PMID- 29417783 TI - [Lumbar spinal canal stenosis complicated with lumbar ligamentum flavum cyst: a case report]. PMID- 29417784 TI - [Progress on propionibacterium acnes and degenerative intervertebral disc]. AB - The mechanism of degenerative intervertebral disc is very complex, which may be associated with multiple factors such as the mechanical stress force injury of intervertebral disc, nutritional deficiency, inflammatory stimulation, etc. Recently, many studies detected propionibacterium acnes(P. acnes) in degenerative intervertebral disc and supposed P. acnes was associated with degenerative intervertebral disc. Here, the papers related to P. acnes and degenerative intervertebral disc were reviewed. Further, we deduced the approach of P. acnes enterring into the intervertebral disc as well as the mechanism of P. acnes aggravating the disc degeneration. These may provide suggestions for treating degenerative intervertebral disc. PMID- 29417785 TI - [Therapeutic progress in lumbar spinal stenosis]. AB - Along with the population aging in China, patients with lumbar spinal stenosis(LSS) caused by recessive change incessantly increase. At present, there is no adequate evidence to recommend any specific nonoperative treatment for LSS, and surgery is still an effective method. The cilincal symptoms of the patients without conservative treatment got improvement after surgery, which is the strongest evidence base. Spinal instability after simple decompression promotes the development of fusion technique, and the accelerated adjacent segment degeneration and no relief in symptoms after fusion lead to dynamic fixation technology emerge as the times require. Patients with spinal canal decompression whether need bone fusion or not is still controversial. For the past few years, the operation of simple decompression for LSS obviously decreased, whereas the decompression plus fusion surgery showed sustainable growth. Decompression complicated with fusion was more and more adopted in LSS, in order to reduce the hidden risk of spinal instability and deformity. Although decompressive operation has determinate effect, now it is still unclear if the therapeutic effect of decompression complicated with fusion is better than simple decompression. This article reviews the current studies to explore whether decompression plus bone fusion is applicable for LSS. To further explore the best choice of surgical treatment for LSS, we focused on evidence-based therapeutic options. PMID- 29417786 TI - What mother know about vaccine preventable diseases? AB - INTRODUCTION AND OBJECTIVE: The improving epidemiological situation of the most of communicable diseases causes, that the real and potential risks attributable to them have been forgotten. The aim of study was to determine the mothers knowledge about vaccine preventable diseases MATERIALS AND METHODS: A survey was conducted among 177 randomly selected mothers. The interviews with mothers hospitalized after childbearing in two hospitals in Krakow and Myslenice were conducted at the end of 2014 and in 2015 RESULTS: The assessment of risk to develop an infectious diseases in unvaccinated children significantly varied among mothers. Individual respondents claimed that the risk does not exist regarding each of considered disease. The highest percentage of that kind of answers was related to poliomyelitis - 3.9% of mothers assessed that unvaccinated children have no risk to become ill. The similar percentage of respondents assessed a risk as remote probable regarding poliomyelitis, pertussis and hepatitis A - 16.8%, 15.2% and 16.3%, respectively. The highest risk was attributed to varicella - 50.6% mothers gave that answers. Mothers could not state a risk of disease developing mostly with regard to poliomyelitis, diphtheria, hepatitis A and pertussis - 42.7%, 38.2%, 33.7% and 33.2%, respectively. Relatively high percentage of respondents stated a mild course of that kind of diseases like varicella, mumps, rubella, infectious diarrhea and measles - from 17.4% with respect to measles to 34.3% regarding varicella. To life-threating category mothers primarily included sepsis (74.2%), meningitis and tick-borne encephalitis (each obtained 68.5% answers) CONCLUSIONS: Mothers knowledge about vaccine preventable diseases varied depending on the type of disease. The lack of awareness of the risk related to communicable diseases regarded not only those diseases which have not been occurred in Poland for many years but also those ones that still represent significant epidemiological problem. The society too often has an opinion that some diseases like varicella, mumps or rubella are the mild diseases what can conduce to easy withdrawal from those vaccinations PMID- 29417787 TI - Fluoride compounds in dental caries prophylaxis in children and adolescents - review of Polish literature AB - Dental caries is a process that leads to the destruction of the tooth structure. Statistics about dental caries in Poland are alarming. That is why preventive measures are so important. Fluoride compounds are commonly used in dental prophylaxis. They support the remineralization, inhibit the demineralization of the enamel and reduce the cariogenic effect of bacteria on the teeth. Fluoride in lower concentration enables the constant repositionof mineral compounds which are lost during acids attacks on the enamel and the formation of fluorapatites which are less susceptible to acids. Higher concentration of fluoride leads to calcium fluoride formation which is a reservoir of that element. It is now believed that the most important is the topical (exogenous) action of fluoride. The basic method of caries prevention is brushing teeth twice a day with fluoride toothpaste. It should be emphasized that special attention ought to be paid to the thorough removal of the dental plaque during brushing the teeth. The other methods of topical fluoridation are for example fluoride varnishes or mouthrinses containing fluoride. Fluoride mouthrinsesin most cases can be used by patient at home. Whereas fluoride varnishes should be applied by a professional at a dental clinic. There are also glass-ionomer restorations available which release fluoride ions. According to current knowledge, dental prophylaxis should be adjusted to each patient individually. Based on the literature reviewed, it can be concluded that fluoride compounds play the important role in dental caries prophylaxis and,if only used deliberately, can bring great benefits. However, it should be underlined that in excess - as everything - may be not good for health. PMID- 29417788 TI - Evaluation of dental state in 6-year-old children from the Skierniewice region AB - INTRODUCTION: Caries is a social disease and a serious problem, especially in the childhood. The effects of untreated caries can cause not only disorders of the stomatognathic system, but also have a negative impact on the overall health and development of the child THE AIM OF THE STUDY: The aim of this study was to evaluate the state of dentition of 6-year-old children from the Skierniewice region MATERIALS AND METHODS: A total of 140 children (6-year-old) were included to the study - 74 from a small town (Skierniewice) and 66 from a village. Caries prevalence, caries intensity (dmf, DMF) and dental treatment index (DTI) were assessed. The results were analyzed statistically RESULTS: The caries prevalence in the study group was 88.6%. The caries intensity in the deciduous dentition (dmf) was statistically significantly higher (p=0.021) in rural areas (7.45) than in the city (6.32). The mean dmf value was mainly determined as the number of filled teeth. In permanent dentition, higher values of DMF were found in children from rural areas (2.30) than urban areas (1.93). The dental treatment index for the deciduous dentition amounted to 0.67 and for the permanent dentition to 0.4. Both for deciduous and permanent teeth, this index was higher in urban than rural children CONCLUSIONS: High rates of caries prevalence and intensity in 6-year-old children from the Skierniewice region confirm that caries is still a serious problem, especially in the village. The high value of the treatment index for deciduous dentition demonstrates the efficacy of treatment in this field. It is necessary to carry out preventive programs and make parents aware that they should early take care of their children's dentition PMID- 29417789 TI - Prevalence of dental caries in overweight school going children of 12-15 years in and around Jaipur city, Rajasthan, India AB - INTRODUCTION: Dental caries and obesity are both multifactorial disease with a complex etiology and both are associated with dietary habits. Prevalence of dental caries and an association between body mass index (BMI) and dental caries among school children METHODS: The present was done on 1500 school going children to assess the prevalence of dental caries in 12-15 year old overweight children. Weight and height were measured in light clothing and without shoes using an electronic weighing scale. Subjects' heights were measured using a stadiometre. Subjects were examined on an upright chair in adequate natural daylight and dental caries was measured by using DMF index. Chi-square test was used to analyze and compare qualitative data whereas unpaired 't' test was used to analyze and compare quantative data RESULTS: Amongst 1500 children, 156 were found to be overweight, 443 were normal weight. When mean BMI between overweight and normal weight were compared a highly significant difference was observed. When DMFT of overweight and normal weight were compared no significant difference was observed CONCLUSION: Dental caries was observed more in females as compared to males and no significant difference was observed between dental caries and weight gain PMID- 29417790 TI - Knowledge of family medicine trainers concerning HIV/AIDS - pilot study AB - AIM: The objective of the study was to assess knowledge of doctors during their residency training in family medicine about HIV infection, routes of transmission and diagnosis of AIDS METHODS: We developed an anonymous questionnaire with questions concerning knowledge about routes of infection, possibility of diagnosis of HIV infection based on presenting symptoms, risk of vertical transmission, risk of acquiring of HIV infection during occupational activities RESULTS: The obtained results revealed insufficient knowledge about routes of transmission as well as about symptoms which should prompt a general practitioner to suspect an HIV infection. Almost 20% of doctors regarded their risk of acquiring the HIV infection during their professional activities as quite high, while 10% of them stated that they would refuse to help an HIV-positive patient or that they did not know what they would do in such a situation. Majority (71.4%) of the respondents claimed that within the last 2 years they had undertaken a training oncerningHIV/AIDS CONCLUSIONS: The results of our study suggest that still more training is needed PMID- 29417791 TI - Traumatic stress in the work of paramedics AB - Paramedics are a new group of professionals among the medical professions aimed to save lives and health of the injured. The nature of the work, intensity of the actions, decision-making, struggle for life and health of the patients often in difficult and extreme conditions exposes this group to stress and broadly understood trauma. The paper describes the nature of work in the profession of a paramedic and outlines both negative and positiveconsequences, that may result from frequent experience of traumatic events connected with performing work PMID- 29417792 TI - Clinical guidelines development process in Poland AB - Clinical practice guidelines are set of recommendations for cliniciansa bout the care of patients. The aim of clinical practice guidelines is to support clinical decision-making, rationalize diagnostic and therapeutic procedures and provide high-quality healthcare. Development of clinical practice guidelines should be a systematic process based on evidence based medicine (EBM). However, as practice shows, they are not always reliable and are not developed according to the recommended world-wide methodology. The purpose of this article is to provide an outline of the clinical guidelines development process and to present international instruments for guidance development, evaluation and adaptation PMID- 29417793 TI - Novel combination for the treatment of acne differentiated based on gender: a new step towards personalized treatment. AB - BACKGROUND: The aim of this study is to evaluate efficacy and tolerability of a complete skin care line consisting of an oral supplement in two distinct formulations for males and females, and a topical cream device in the treatment of mild and moderate acne. Oral supplements contain biotin, probiotic, vitamin E, zinc, nicotinamide; in the formulation for males beta sitosterol and Boswellia serrata were added, the oral supplement for females contains myo-inositol and folic acid. The topical cream device is represented by the association between active plant agents (verbascoside, Ocimum gratissimum) and keratolytic molecules (salicylic acid, gluconolactone, complex alpha-hydroxy acids). METHODS: An equal number of male and female patients with mild to moderate acne were enrolled in a double-blinded clinical trial. Efficacy and tolerability evaluations were performed at week 4 (T1) and week 12 (T2) by Global acne Grading System (GAGs). RESULTS: Most of patients had satisfactory therapeutic response, in terms of GAGs reduction. All the four groups presented a statistically significant improvement of the mean GAGs at T2 but those assuming the oral supplement improved more, as expected. CONCLUSIONS: Our data suggest that this association can be considered a new effective option for mild and moderate acne. This therapeutic line differs from others in the gender matched oral treatment. PMID- 29417794 TI - Efficacy of a detergent combined with a moisturiser for the treatment of pruritus associated with xerosis in an elderly population affected by Kaposi's sarcoma. AB - BACKGROUND: Xerosis is common among patients with Kaposi's sarcoma (KS). The aim of our study was to evaluate the efficacy of a detergent containing dihydroavenanthramide D 5% combined with a moisturiser containing 1% of menthol for the treatment of chronic pruritus associated with xerosis in elderly KS patients. METHODS: We conducted a prospective, open-label, intra-individual, right/left comparative study. During the 4-week treatment study, patients used the test products on the right lower limb, and a basic skin cleanser plus basic cream on their left lower limb, in a predefined protocol. A 10 cm Visual Analogue Scale (VAS), the hydration index (HI) of the stratum corneum and the Overall Dry Skin Score (ODSS) were used to assess pruritus and xerosis severity on admission, at 2 and 4 weeks. RESULTS: Thirty patients (24 males, 6 females, mean age: 76.6 +/- 6.8 years) were enrolled. At the end of 4 weeks, the mean pruritus VAS score declined from 4.2+/-2.2 to 1.7+/-1.4 on the right side, and from 4.2+/-2.2 to 2.3+/-1.5 on the left side. The HI score increased from 25.6+/-15.0 to 46.1+/ 12.3 on the right side, and from 26.0+/-15.2 to 35.4+/-12.6 on the left side. Differences between the right and left limbs were significant for VAS score (p=0.0064), HI (p<0.0001) and ODSS values (p=0.0049). There was no adverse reaction to the test products. CONCLUSIONS: Daily use of a detergent containing dihydroavenanthramide D 5% combined with a moisturiser containing 1% of menthol improves chronic pruritus associated with xerosis in elderly adults with KS. PMID- 29417795 TI - Telomere shortening and tnf-alpha: gateway for psoriasis in celiac disease? PMID- 29417796 TI - Angiomatoid melanoma: a dermoscopic and pathologic challenge. PMID- 29417797 TI - Verrucous mycosis fungoides. PMID- 29417798 TI - Neglected skin carcinomas and Vismodegib: our experience. PMID- 29417799 TI - A synthesis of the world's guidelines on photodynamic therapy for non-melanoma skin cancer. AB - Photodynamic therapy (PDT), using topically administered photosensitizing agents, is widely approved as a treatment for certain nonmelanoma skin cancers. As a tissue-sparing non-surgical modality, there is great potential for PDT to enhance the choice of therapies available to treat, and potentially prevent, skin cancer. Treatment-specific guidelines have assessed the evidence for various photosensitizing agents and light sources, dosimetry, and evaluate reported adverse effects. Discomfort is frequently experienced during treatment but no analgesia was required in most pivotal lesion-directed studies. Durability of response has been assessed with studies of PDT for basal cell carcinomas (BCC) extending to 5 years and beyond, 2 years for Bowen's disease and up to 1 year for actinic keratoses (AK). Disease-specific guidelines consider the place for topical PDT in routine clinical practice recognizing that PDT is typically office/clinic-based and usually initiated by specialists. Where updated guidelines are awaited, national and international consensus publications offer recommendations, including on the use of daylight to activate the photosensitizer for treating AK. Reviewed studies indicate equivalent efficacy of daylight PDT, but greatly reduced pain compared with conventional PDT. Guidelines and consensus publications also consider the place of PDT in treating skin lesions arising in organ transplant recipients and in the potential for PDT to delay/prevent the development of nonmelanoma skin cancers. There is now a substantial evidence-base to support the use of topical PDT in routine clinical practice with daylight PDT indicated for AK, providing suitable outside climate, whilst conventional PDT remains suitable for AK, Bowen's Disease, superficial and certain thin nodular BCC. PMID- 29417800 TI - Cutaneous larva migrans and tungiasis: infestations of the affluent society. PMID- 29417801 TI - Rapid response to cyclosporine in a rare case of pityriasis rubra pilaris with autoantibodies and systemic symptoms. PMID- 29417802 TI - Can daylight-PDT be performed indoor? AB - Natural DayLight-mediated PhotoDynamic Therapy (NDL-PDT) is an efficacious treatment option for thin actinic keratosis that offers advantages over conventional PDT in terms of tolerability and cost. It is now accepted that the minimum criteria required for effective NDL-PDT is a dose of 4 J/cm2 with a treatment time of 2 hours and a minimum temperature of 10 degrees C, corresponding to a minimum illuminance of 11,000 lux. This value is easily achievable: 20,000 lux can be obtained during a typical overcast day at midday. It can reach 110,000 lux with a bright sunlight. However, it is limited to certain times of the year at our latitude. However rain and cold temperatures appear the main limitations of NDL-PDT. Greenhouses make possible to perform the illumination even in harsh weather conditions. Furthermore, it is difficult to install a greenhouse everywhere. Several solutions are now proposed to carry out indoor illumination so-called artificial white light or simulated daylight (SDL PDT). Illumination sources installed at the ceiling of the treatment room is one option. Several lamp pairs can be combined to illuminate groups of patients simultaneously. A surgical theatre light can be used or dedicated systems using white LEDs can be used to deliver the required illumination dose. In conclusion, Indoor lightning (or simulated daylight: SDL-PDT or Artificial White Light: AWL) could offer an interesting alternative to NDL-PDT. PMID- 29417803 TI - Cutaneous tuberculosis, a reemerging dermatologic diagnostic challenge. PMID- 29417804 TI - Past and present history of cholera epidemics. Hundred years of operation of National Institute of Hygiene for the prevention and control of cholera AB - BACKGROUND: Cholera is an infectious disease that in the epidemic form should not continue to appear now, as is known from the experience of developed countries AIM: The aim of this work is to bring to memory the epidemics of cholera, that were introduced to the territory of Poland, in the past and the role of National Institute of Hygiene (PZH) in the fight against them and to demonstrate contemporary danger from cholera outbreaks that still exists in the world MATERIAL AND METHODS: The information from the historic publications were analyzed, the results Polish research performed in National Institute of Hygiene in the second half of the XX century were collected and demonstrated the most recent information from in the world science publications on the subject of cholera and the conditions that were in the origin of the recent outbreaks of cholera mentioned RESULTS: The data available for the number of cholera victims in the epidemics of XIX century is concerning the persons ill with characteristic clinical symptoms, but the data for XX century is concerning only patients that were infected with by the strain Vibrio cholerae O1 classic type, the bacteria that were described by R. Koch, but from the 70-years of XX century mostly the cases infected with Vibrio cholerae O1 type El-Tor, that was the etiologic agent of the seventh cholera pandemic SUMMARY AND CONCLUSIONS: The origin of the epidemic cholera is depending on several conditions :appearance in water the infectious agent with the toxin producing character, ecological conditions of the surface waters, and on living conditions of human society which might be infected from the source of infection in water. The presence of the infectious agent in the natural waters should be always taken under special consideration car any worsening of living condition of the human population like natural disaster or war, may still create the dangers of the epidemic of infectious disease, as recently has happened with the outbreak of epidemic of cholera in Yemen PMID- 29417805 TI - Technical assistants at the Department of Epidemiology of National Institute of Hygiene in Warsaw PMID- 29417807 TI - Novel Magnetic Microprobe with Benzoboroxole-Modified Flexible Multisite Arm for High-Efficiency cis-Diol Biomolecule Detection. AB - With regard to regulating a variety of biological events, including molecular recognition, signal transduction, cell adhesion, and immune response, cis-diol biomolecules, such as saccharides and glycoproteins, play vital roles. However, saccharides and glycoproteins in living systems usually exist in very low abundance, along with abundant interfering components. High-efficiency detection of saccharides and glycoproteins is a challenging yet highly impactful area of research. Herein, we reported a novel magnetic microprobe with a benzoboroxole modified flexible multisite arm (PEG 2000-grafted PAMAM dendrimers; the microprobe was denoted as BFMA-MNP) for high-efficiency saccharides detection. The extraction capacity was significantly improved by ~2 orders of magnitude, because of the integration of the enhanced hydrophilicity and multivalency effects in benzoboroxoles and the enhanced accessibility of the binding sites within the PEG 2000-grafted PAMAM dendrimers. As a result, the proposed approach possessed several advantages, compared with previous boronic acid-based methods, including ultrahigh sensitivity (limit of detection was <1 ng/mL), wide linear range (ranged from 0.5 MUM to 2000 MUM), and applicable in physiological pH condition. Furthermore, we established a general BFMA-MNP/glycoproteins/AuNPs sandwich assay to realize the visual glycoprotein qualitative screening for the first time. The unique sandwich assay possessed the dual nature of the magnetic separation by BFMA-MNPs and specific coloration by citrate-coated AuNPs. This visual sandwich assay enabled fast differentiation of the existence of glycoproteins in complicated samples without any advanced instruments. We believe the proposed BFMA-MNP microprobe herein will advance the ideas to detect and identify trace saccharides and glycoproteins in important fields such as glycomics and glycoproteomics. PMID- 29417806 TI - Scalable 9-Step Synthesis of the Splicing Modulator NVS-SM2. AB - NVS-SM2, the first activator of pre-mRNA splicing, displays remarkable pharmacological in vivo activities in models of spinal muscular atrophy. Herein we describe an improved approach to the synthesis of this compound, which features a convenient introduction of sterically encumbered amine moiety onto a fluoropyridazine intermediate. PMID- 29417808 TI - In Situ Formation of Cobalt Nitrides/Graphitic Carbon Composites as Efficient Bifunctional Electrocatalysts for Overall Water Splitting. AB - Developing cost-effective and highly efficient bifunctional electrocatalysts for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is of great interest for overall water splitting but still remains a challenging issue. Herein, a self-template route is employed to fabricate a unique hybrid composite constructed by encapsulating cobalt nitride (Co5.47N) nanoparticles within three dimensional (3D) N-doped porous carbon (Co5.47N NP@N-PC) polyhedra, which can be served as a highly active bifunctional electrocatalyst. To afford a current density of 10 mA cm-2, the as-fabricated Co5.47N NP@N-PC only requires overpotentials as low as 149 and 248 mV for HER and OER, respectively. Moreover, an electrolyzer with Co5.47N NP@N-PC electrodes as both the cathode and anode catalyst in alkaline solutions can drive a current density of 10 mA cm-2 at a cell voltage of only 1.62 V, superior to that of the Pt/IrO2 couple. The excellent electrocatalytic activity of Co5.47N NP@N-PC can be mainly ascribed to the high inherent conductivity and rich nitrogen vacancies of the Co5.47N lattice, the electronic modulation of the N-doped carbon toward Co5.47N, and the hierarchically porous structure design. PMID- 29417809 TI - High-Performance Graphene Sponges Reinforced with Polyimide for Room-Temperature Piezoresistive Sensing. AB - The bulk materials of three-dimensional graphene (3DG) with high network structure and excellent electrical conductivity have many potential applications in flexible electronics, but the network structure is not very stable due to weak bonding between graphene nanosheets. Here, a polyimide (PI) layer was introduced on the as-prepared 3DG sponge by vacuum infiltration-curing method. The resulting 3DG/PI composite sponges with robust 3D network structure exhibited an excellent electrical conductivity (3.7 S/cm), compression strength (175 kPa), elasticity, and flexibility, as well as outstanding compression sensitivity to resistance and stable piezoresistance effect; namely, they possess a large change in resistance in response to application of small strain and low density, and the resistance change remains favorably stable after performing 300 compress-release cycles, which means that the prepared composite sponges can find wide applications in pressure-sensing or stimulus-responsive graphene system. PMID- 29417811 TI - Morphology and Magnetic Structure of the Ferritin Core during Iron Loading and Release by Magnetooptical and NMR Methods. AB - Ferritins are proteins, which serve as a storage and transportation capsule for iron inside living organisms. Continuously charging the proteins with iron and releasing it from the ferritin is necessary to assure proper management of these important ions within the organism. On the other hand, synthetic ferritins have great potential for biomedical and technological applications. In this work, the behavior of ferritin during the processes of iron loading and release was examined using multiplicity of the experimental technique. The quality of the protein's shell was monitored using circular dichroism, whereas the average size and its distribution were estimated from dynamic light scattering and transmission electron microscopy images, respectively. Because of the magnetic behavior of the iron mineral, a number of magnetooptical methods were used to gain information on the iron core of the ferritin. Faraday rotation and magnetic linear birefringence studies provide evidence that the iron loading and the iron release processes are not symmetrical. The spatial organization of the mineral within the protein's core changes depending on whether the iron was incorporated into or removed from the ferritin's shell. Magnetic optical rotatory dispersion spectra exclude the contribution of the Fe(II)-composed mineral, whereas joined magnetooptical and nuclear magnetic resonance results indicate that no mineral with high magnetization appear at any stage of the loading/release process. These findings suggest that the iron core of loaded/released ferritin consists of single-phase, that is, ferrihydrite. The presented results demonstrate the usefulness of emerging magnetooptical methods in biomedical research and applications. PMID- 29417812 TI - Selective Orientation of Chiral Molecules by Laser Fields with Twisted Polarization. AB - We explore a pure optical method for enantioselective orientation of chiral molecules by means of laser fields with twisted polarization. Several field implementations are considered, including a pair of delayed, cross-polarized laser pulses, an optical centrifuge, and polarization-shaped pulses. We show that these schemes lead to out-of-phase time-dependent dipole signals for different enantiomers, and we also predict a substantial permanent molecular orientation persisting long after the laser fields are over. The underlying classical orientation mechanism common to all of these fields is discussed, and its operation is demonstrated for a range of chiral molecules of various complexity: hydrogen thioperoxide (HSOH), propylene oxide (CH3CHCH2O), and ethyl oxirane (CH3CH2CHCH2O). The presented results demonstrate generality, versatility, and robustness of this optical method for manipulating molecular enantiomers in the gas phase. PMID- 29417810 TI - Enantioselective Synthesis of Trisubstituted Allenyl-B(pin) Compounds by Phosphine-Cu-Catalyzed 1,3-Enyne Hydroboration. Insights Regarding Stereochemical Integrity of Cu-Allenyl Intermediates. AB - Catalytic enantioselective boron-hydride additions to 1,3-enynes, which afford allenyl-B(pin) (pin = pinacolato) products, are disclosed. Transformations are promoted by a readily accessible bis-phosphine-Cu complex and involve commercially available HB(pin). The method is applicable to aryl- and alkyl substituted 1,3-enynes. Trisubstituted allenyl-B(pin) products were generated in 52-80% yield and, in most cases, in >98:2 allenyl:propargyl and 92:8-99:1 enantiomeric ratio. Utility is highlighted through a highly diastereoselective addition to an aldehyde, and a stereospecific catalytic cross-coupling process that delivers an enantiomerically enriched allene with three carbon-based substituents. The following key mechanistic attributes are elucidated: (1) Spectroscopic and computational investigations indicate that low enantioselectivity can arise from loss of kinetic stereoselectivity, which, as suggested by experimental evidence, may occur by formation of a propargylic anion generated by heterolytic Cu-C cleavage. This is particularly a problem when trapping of the Cu-allenyl intermediate is slow, namely, when an electron deficient 1,3-enyne or a less reactive boron-hydride reagent (e.g., HB(dan) (dan = naphthalene-1,8-diaminato)) is used or under non-optimal conditions (e.g., lower boron-hydride concentration causing slower trapping). (2) With enynes that contain a sterically demanding o-aryl substituent considerable amounts of the propargyl-B(pin) isomer may be generated (25-96%) because a less sterically demanding transition state for Cu/B exchange becomes favorable. (3) The phosphine ligand can promote isomerization of the enantiomerically enriched allenyl-B(pin) product; accordingly, lower ligand loading might at times be optimal. (4) Catalytic cross-coupling with an enantiomerically enriched allenyl-B(pin) compound might proceed with high stereospecificity (e.g., phosphine-Pd-catalyzed cross-coupling) or lead to considerable racemization (e.g., phosphine-Cu catalyzed allylic substitution). PMID- 29417813 TI - Promising Anodic Electrochemiluminescence of Nontoxic Core/Shell CuInS2/ZnS Nanocrystals in Aqueous Medium and Its Biosensing Potential. AB - Copper indium sulfide (CuInS2, CIS) nanocrystals (NCs) are a promising solution to the toxic issue of Cd- and Pb-based NCs. Herein, electrochemiluminescence (ECL) of CIS NCs in aqueous medium is investigated for the first time with l glutathione and sodium citrate-stabilized water-soluble CIS/ZnS NCs as model. The CIS/ZnS NCs can be oxidized to hole-injected states via electrochemically injecting holes into valence band at 0.55 and 0.94 V (vs Ag/AgCl), respectively. The hole-injected state around 0.94 V can bring out efficient oxidative-reduction ECL with a similar color to Ru(bpy)32+ in the presence of tri- n-propylamine (TPrA) and enable CIS/ZnS NCs promising ECL tags with l-glutathione as linker for labeling. The ECL of CIS/ZnS NCs/TPrA can be utilized to determine vascular endothelial growth factor (VEGF) from 0.10 to 1000 pM with the limit of detection at 0.050 pM (S/N = 3). Although the hole-injected state around 0.55 V is generated ahead of oxidation of TPrA and fails to bring out coreactant ECL, annihilation ECL proves that both hole-injected states generated, at 0.55 and 0.94 V, can be involved in electrochemical redox-induced radiative charge transfer by directly stepping CIS/ZnS NCs from electron-injecting potential to hole-injecting potential. CIS/ZnS NCs are promising nontoxic electrochemiluminophores with lowered ECL triggering potential around 0.55 V for less electrochemical interference upon the development of coreactant. PMID- 29417814 TI - Total Biosynthesis of Antiangiogenic Agent (-)-Terpestacin by Artificial Reconstitution of the Biosynthetic Machinery in Aspergillus oryzae. AB - The total biosynthesis of (-)-terpestacin was achieved by heterologous expression of four biosynthetic enzyme genes ( tpcA- D) in Aspergillus oryzae. After construction of preterpestacin I by the action of bifunctional terpene synthase (TpcA), two cytochrome P450s (TpcBC) activate inert C-H bond to install three hydroxyl groups on the A-ring in stereo- and regioselective manners. Subsequently, a flavin-dependent oxidase (TpcD) catalyzes oxidation of the vicinal diol moiety to give a alpha-diketone, which undergoes an enolization to furnish terpestacin. The successful synthesis of structurally elaborated terpestacin showed that a reconstitution approach that harnesses several biosynthetic enzyme genes in A. oryzae could be a promising alternative to the current chemical synthesis of natural terpenoids. PMID- 29417815 TI - Self-Healing Phenomenon Observed During Capacity-Control Cycling of Freestanding Si-Based Composite Paper Anodes for Li-Ion Batteries. AB - A different strategy of capacity-control cycling under fixed upper and lower capacity/voltage limits is used in an attempt to seek an extended cycle life for Si nanoparticle-multiwalled carbon nanotube (Si-MW) electrodes for Li-ion batteries. For cells using Si-MW 1:1 (w/w) electrodes in the electrolyte of ethylene carbonate-diethyl carbonate-fluoroethylene carbonate (EC-DEC-FEC, 45:45:10 w/w/w) tested at a current of 1 mA, stable 326 charge/discharge cycles at a designated capacity of 506 mA h g-1 are attained. The new cycling protocol allows for the observation of a self-healing phenomenon by studying the specific capacities and charge/discharge end voltages. Prolonged cycling under capacity control (500 mA h g-1) and the interesting pattern of variations in the discharge/charge end voltage are successfully reproduced under different electrode/electrolyte and current conditions: Si-MW 3:2 in the electrolyte of DEC FEC (1:1 w/w) at 1 mA (490 cycles), Si-MW 3:2 in DEC-FEC at 0.5 mA (483 cycles), and Si-MW 1:1 in DEC-FEC at 0.5 mA (576 cycles), which can be explained by applying the proposed self-healing mechanism as well. PMID- 29417816 TI - Interface Engineering of Anchored Ultrathin TiO2/MoS2 Heterolayers for Highly Efficient Electrochemical Hydrogen Production. AB - An efficient self-standing hydrogen evolution electrode was prepared by in situ growth of stacked ultrathin TiO2/MoS2 heterolayers on carbon paper (CP@TiO2@MoS2). Owing to the high overall conductivity, large electrochemical surface area and abundant active sites, this novel electrode exhibits an excellent performance for hydrogen evolution reaction (HER). Remarkably, the composite electrode shows a low Tafel slope of 41.7 mV/dec, and an ultrahigh cathodic current density of 550 mA/cm2 at a very low overpotential of 0.25 V. This work presents a new universal strategy for the construction of effective, durable, scalable, and inexpensive electrodes that can be extended to other electrocatalytic systems. PMID- 29417817 TI - Visible-Light-Enhanced Ring Opening of Cycloalkanols Enabled by Bronsted Base Tethered Acyloxy Radical Induced Hydrogen Atom Transfer-Electron Transfer. AB - A metal-free ring opening/halogenation of cycloalkanols, which combines both PPO/TBAX oxidant system and blue LEDs irradiation, is presented. This method produces diverse gamma, delta, and even more remotely halogenated ketones in moderate to excellent yields under mild conditions. Interestingly, experimental and computational studies demonstrate the novel ring size-dependent concerted/stepwise (four-/five- to eight-membered rings) hydrogen atom transfer electron transfer induced by Bronsted base-tethered acyloxy radical, which indicates distinct advantages brought by the cyclic structure of diacyl peroxides. PMID- 29417818 TI - Asymmetric and Site-Selective [3 + 2]-Annulations for the Synthesis of High-Value Bicyclic Lactams. AB - Asymmetric and site-selective formal [3 + 2]-annulations of gamma-alkyl beta,gamma-unsaturated gamma-lactams with alpha,beta-unsaturated aldehydes have been developed. These organocatalysed transformations yield high value enantioenriched bicyclic gamma-lactams with up to four new stereocenters (sometimes including a quarternary carbon). The overall transformation starts from simple and readily accessible furans and oversees a rapid, controlled, and dramatic enhancement in 3D complexity. PMID- 29417819 TI - Iodosobenzene-Mediated alpha-Acyloxylation of 1,3-Dicarbonyl Compounds with Carboxylic Acids and Insight into the Reaction Mechanism. AB - A highly efficient direct alpha-acyloxylation of 1,3-dicarbonyl compounds with carboxylic acids mediated by hypervalent iodine reagent is presented. Treatment of a variety of 1,3-dicarbonyl compounds with carboxylic acids in the presence of iodosobenzene provides the corresponding alpha-acyloxylated products in good to excellent yields. The mechanistic investigation by means of NMR spectroscopy reveals that the in situ-generated phenyliodine biscarboxylate proves to be the key intermediate for the alpha-acyloxylation, and the loading sequence of reactants and oxidant is crucial for the generation of the active species. The mild reaction conditions, wide substrate scope, short reaction time, good yields, high chemoselectivity, excellent functional group tolerance, and metal catalyst free conversion make this acyloxylation a significant synthetic protocol. PMID- 29417820 TI - Bidirectional Electrochemiluminescence Color Switch: An Application in Detecting Multimarkers of Prostate Cancer. AB - A selective excitation of [Ir(df-ppy)2(pic)] and [Ru(bpy)3]2+ through tuning the electrode potential is reported in this work. Bidirectional color change from blue-green to red could be observed along with increase and decrease of the potential, which was ascribed to the dual-potential excitation property of [Ir(df ppy)2(pic)]. Similar to the three-electrode system, selective excitation of ECL could be achieved at the anode of the bipolar electrode (BPE). Both increase and decrease of the faradic reactions at the cathode of the BPE could induce ECL reporting color at the other pole switched from blue-green to red. We applied a closed BPE device for the bioanalysis of multicolor ECL since the organic solvent containing electrochemiluminophores could be separated from the bioanalytes. On the basis of BPE arrays coupled with the ECL switch, the detection of three biomarkers of prostate cancer, PSA, microRNA-141, and sarcosine were integrated in a same device. The cutoff values of the biomarkers could be recognized directly by the naked eye. Such a device holds great potential in the early diagnosis of prostate cancer. PMID- 29417821 TI - Comparative Toxicokinetics and Plasma Protein Binding of Ochratoxin A in Four Avian Species. AB - Ochratoxin A (OTA, 0.25 mg/kg body weight) was absorbed rapidly ( Tmax = 0.31 1.88 h) in all avian species (broiler chickens, laying hens, turkeys, and Muscovy ducks) but more slowly in broiler chickens ( Tmax = 1.43-4.63 h). The absolute oral bioavailability was complete in these bird species (88.0-109.6%). Ducks have a significantly higher volume of distribution ( Vd) and turkeys a lower Vd compared to chickens and layers (broiler chickens, 0.27 +/- 0.12 L/kg; layers, 0.23 +/- 0.08 L/kg; turkeys, 0.18 +/- 0.04 L/kg; ducks, 0.76 +/- 0.44 L/kg). This difference in Vd can be attributed to the species-dependent differences in plasma protein binding of OTA, namely ranging between 82.2 and 88.9% in ducks and between 96.5 and 98.8% in turkeys. No significant gender differences were found in toxicokinetics or plasma protein binding. PMID- 29417822 TI - Go with the (back) flow: what can retrograde perfusion teach us about arterial remodeling in pulmonary arterial hypertension? PMID- 29417824 TI - Metallocyclodextrins in medicinal chemistry. AB - This review focuses on metal complexes of cyclodextrin (CyD) derivatives designed for application as therapeutics or diagnostics. We discuss examples of metalloprotein models (hemoglobin, superoxide dismutase and catalase) based on cyclodextrins. The hydrophobic microenvironment of CyDs stabilizes the Fe(II) porphyrin system that can reversibly bind O2 or CO in water. Superoxide dismutase/catalase mimetics exploit functionalization with CyDs, which increase their solubility and biological activity. Furthermore, CyDs have been used as scaffolds to obtain multicenter metal complexes: paramagnetic systems act as high performance contrast agents for magnetic resonance imaging applications. Finally, we review CyD ligands, whose use appears promising in metal chelation therapy, as CyD moiety confers additional properties to the ligands. PMID- 29417825 TI - A case for identifying smoking in presentations to the emergency department with suicidality. AB - OBJECTIVES: The aim of this study was to identify mental health and lifestyle factors predicting smoking among people at high risk of suicidal behaviour. METHODS: Participants ( n = 363) completed self-report mental health and lifestyle measures at first appointment in a hospital clinic following presentation to the emergency department for deliberate self-harm or suicidal ideation. RESULTS: The rate of daily smoking in this group, 61.4%, is more than four times the rate observed in the general population. Those with a history of previous deliberate self-harm were twice as likely to be smokers. Each one-point increase in poor health behaviours increased the odds of smoking by 22%. CONCLUSIONS: Identifying and managing smoking and related lifestyle behaviours are important considerations in routine clinical assessments. PMID- 29417823 TI - Drug-induced pulmonary arterial hypertension: a primer for clinicians and scientists. AB - Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization Group 1 pulmonary hypertension (PH) defined by severe small vessel loss and obstructive vasculopathy, which leads to progressive right heart failure and death. To date, 16 different compounds have been associated with D-PAH, including anorexigens, recreational stimulants, and more recently, several Food and Drug Administration-approved medications. Although the clinical manifestation, pathology, and hemodynamic profile of D-PAH are indistinguishable from other forms of pulmonary arterial hypertension, its clinical course can be unpredictable and to some degree dependent on removal of the offending agent. Because only a subset of individuals develop D-PAH, it is probable that genetic susceptibilities play a role in the pathogenesis, but the characterization of the genetic factors responsible for these susceptibilities remains rudimentary. Besides aggressive treatment with PH-specific therapies, the major challenge in the management of D-PAH remains the early identification of compounds capable of injuring the pulmonary circulation in susceptible individuals. The implementation of pharmacovigilance, precision medicine strategies, and global warning systems will help facilitate the identification of high-risk drugs and incentivize regulatory strategies to prevent further outbreaks of D-PAH. The goal for this review is to inform clinicians and scientists of the prevalence of D-PAH and to highlight the growing number of common drugs that have been associated with the disease. PMID- 29417826 TI - Indolylarylsulfones, a fascinating story of highly potent human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors. AB - Indolylarylsulfones are a potent class of human immunodeficiency virus type 1 non nucleoside reverse transcriptase inhibitors. In this review, the structure activity relationship (SAR) studies to improve the profile of sulfone L-737,126 discovered by Merck AG have been analysed with focus on introduction of the 3',5' dimethyl groups at the 3-phenylsulfonyl moiety, the 2-hydroxyethyl tail at the indole-2-carboxamide nitrogen, coupling of the carboxamide nitrogen with one or two glycinamide and alaninamide units, a fluorine atom at position 4 of the indole ring and correlation between configuration of the asymmetric centre and linker length. IAS derivatives look like promising drug candidates for the treatment of AIDS and related infections in combination with other antiretroviral agents. PMID- 29417828 TI - Early heart attack care as a prehospital programme designed to supplement the established chest pain unit concept in Germany. PMID- 29417827 TI - Validating the total illness burden index for prostate cancer (TIBI-CaP) in men with castration-resistant prostate cancer: data from TRUMPET. AB - AIM: To validate the total illness burden index for prostate cancer (TIBI-CaP) in castration-resistant prostate cancer (CRPC) patients. PATIENTS & METHODS: Baseline comorbidity scores collected using the TIBI-CaP were compared with the baseline patient-reported health-related quality of life using the SF-12v2 and FACT-P questionnaires in 302 patients enrolled in the Treatment Registry for Outcomes in CRPC Patients (TRUMPET). RESULTS: Baseline TIBI-CaP scores were negatively correlated with all baseline SF-12v2 domain/composite (p < 0.001) and FACT-P subscale/total (p < 0.020) scores. There was a significant decreasing linear trend in SF12v2 and FACT-P scores over the categories based on TIBI-CaP quartiles of comorbidity burden (from 'least' to 'severe'). CONCLUSION: The TIBI CaP is a valid measure of comorbidity burden in patients with CRPC in the real world. PMID- 29417829 TI - Identifying characteristics and practices of multidisciplinary team reviews for patients with severe mental illness: a systematic review. AB - OBJECTIVES: Multidisciplinary teams in mental health receive limited guidance, leading to inconsistent practices. We undertook a systematic review of the characteristics and practices of multidisciplinary team reviews for patients with severe mental illness or in relevant mental health service settings. METHODS: Sources published since 2000 were located via academic database and web searches. Results were synthesised narratively. RESULTS: A total of 14 sources were analysed. Important characteristics and practices identified included routine monitoring and evaluation, good communication, equality between team members, and clear documentation practices. Success factors included defined leadership and clear team goals. Four sources described considerations for patients with complex clinical needs, including allocating sufficient time for discussion, maintaining connections with community providers, and ensuring culturally sensitive practices. CONCLUSIONS: No single best practice model was found, due to variations in team caseload, casemix, and resourcing levels. However, key ingredients for success were proposed. Sources were mostly descriptive; there remains a lack of evidence-based guidance regarding multidisciplinary team review characteristics and practices. PMID- 29417830 TI - The benefits of sensory modulation on levels of distress for consumers in a mental health emergency setting. AB - OBJECTIVES: This paper reports a pilot study exploring the benefits of offering sensory modulation within a mental health emergency setting for consumers experiencing distress during a psychiatric presentation. METHODS: Seventy-four consumers with a mental health presentation reported on their sensory modulation use experiences during their stay in a South Australian tertiary teaching hospital emergency department. An evaluation form was used to document use of items, self-reported distress pre and post sensory modulation use, and other consumer experiences. RESULTS: Consumers used between one and six sensory items for a median duration of 45 min. There was a statistically significant reduction ( t(73) = 15.83, p < .001) in self-reported distress post sensory modulation use, and consumers also reported that use was helpful, distracting, calming and assisted in managing negative emotions and thoughts. CONCLUSIONS: The results demonstrate the potential value of sensory-based interventions in reducing behavioural and emotional dysregulation in an emergency setting whilst also promoting consumer self-management strategies. PMID- 29417831 TI - Effectiveness of aquatic exercises compared to patient-education on health status in individuals with knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To compare the effectiveness of aquatic exercises with patient education in individuals with knee osteoarthritis. DESIGN: Randomized controlled trial with blinded assessor and intention-to-treat analysis. SETTING: Aquatic Physiotherapy Centre and Primary Health Care Unit. SUBJECTS: A total of 60 patients, aged 68.3 (SD = 4.8) with clinical symptoms and radiographic grading (Kellgren-Lawrence 1-4) of knee osteoarthritis were included. INTERVENTIONS: An eight-week treatment protocol of aquatic exercise ( n = 31) (16 individual sessions, twice a week) and an educational program (group sessions, once a week) ( n = 29). MAIN MEASURES: Before, after eight-week intervention, and a three month follow-up with results for the following outcome measures: pain, function, quality of life, functional mobility, and depression. RESULTS: At the end of treatment, the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) functional capacity values reduced in favour of the aquatic exercise group for both the total score MD (mean difference) = -14.2; 95% CI (confidence interval) (-18; -10.5), P = 0.04 and the pain domain MD = -3.8 points; 95% CI ( 8.71; -1), P = 0.021. The total score also reduced in the follow-up: MD = -12.3 points; 95% CI (-24.7; -6.1), P = 0.017. No differences were found for the outcomes functional mobility or depression. CONCLUSION: Aquatic exercise improved pain and function after eight weeks, and function at the three-month follow-up compared to the patient-education program. PMID- 29417832 TI - The effects of Internet-based exercise compared with supervised group exercise in people with type 2 diabetes: a randomized controlled study. AB - OBJECTIVES: To compare the effects of Internet-based exercise on glycaemic control, blood lipids, body composition, physical activity level, functional capacity, and quality of life with supervised group exercise in patients with type 2 diabetes. DESIGN: Single-blind, randomized controlled study. SETTING: A Faculty of Health Sciences. SUBJECTS: A total of 65 patients with type 2 diabetes (47 women, 18 men). INTERVENTION: Group A ( n = 22), control group - physical activity counselling once with a brochure. Group B ( n = 22), supervised group based exercise, three days per week for eight weeks. Group C ( n = 21), Internet based exercise following the same programme via a website. MAIN MEASURES: Primary outcomes - glycosylated haemoglobin, fasting blood glucose, high-density and low density lipoprotein, triglyceride, and cholesterol. Secondary outcomes - waist and hip circumferences, body mass index, number of steps, six-minute walking test, and Euro-Quality of Life-5 Dimension. RESULTS: After treatment, glycaemic control (mean change for Group B; Group C; -0.80%, -0.91%, P = 0.003), waist circumference (-4.23 cm, 5.64 cm, P = 0.006), and quality of life (0.26, 0.15, P = 0.013) significantly improved in both training groups compared with the control group. Fasting blood glucose (-46.86 mg/dL, P = 0.009) and hip circumference ( 2.7 cm, P = 0.011) were significantly decreased in Group B and total cholesterol (-16.4 mg/dL, P = 0.028), six-minute walking distance (30.5 m, P = 0.01), and number of steps (1258.05, P = 0.023) significantly improved in Group C compared with control group. Group B and Group C changed with equal magnitude. CONCLUSION: In type 2 diabetes, supervised group-based and Internet-based exercise can improve equally glycaemic control, waist circumference, and quality of life, and both are better than simply counselling. PMID- 29417833 TI - Clinical response to treatment in inpatients with depression correlates with changes in activity levels and psychomotor speed. AB - BACKGROUND: Monitoring clinical response to treatment in depressed inpatients, particularly identifying early improvement, may be sub-optimal. This may impact adversely on patients through longer admissions and sub-optimal pharmacotherapy. Psychomotor speed is a prominent neuropsychological function which changes as recovery occurs. This study examines simple techniques used to quantify psychomotor change and their potential to contribute to monitoring recovery. METHODS: Activity levels were continuously monitored in patients diagnosed with a major depressive episode from four acute psychiatric wards using two actigraphs (commercial and scientific) for 3 weeks and linear regression used to calculate a gradient to express rate of change. Psychomotor speed was assessed using the simple Coin Rotation Task. Mood and functioning were rated using the Quick Inventory of Depressive Symptoms, Clinical Global Impression Scale and Functioning Assessment Short Test. The assessments were completed at baseline and follow-up (3 weeks), and correlations were calculated for all change measures. RESULTS: In all, 24 inpatients were recruited but not all completed baseline and follow-up measures. Change in activity count ( N = 16) and psychomotor speed ( N = 13) correlated significantly with improvement in clinical measures of depressive symptoms. Actigraphs were acceptable to hospital inpatients. LIMITATIONS: The limited size of this pilot study precludes the analysis of predictive power or the influence of other variables such as depression subtypes, age, gender or variations related to medications. CONCLUSION: Early change in simple activity and psychomotor speed warrant further investigation for utility in measuring treatment response in depressed inpatients. PMID- 29417835 TI - Corrigendum. PMID- 29417834 TI - Helping adolescents to better support their peers with a mental health problem: A cluster-randomised crossover trial of teen Mental Health First Aid. AB - BACKGROUND: teen Mental Health First Aid (tMHFA) is a classroom-based training programme for students aged 15-18 years to improve supportive behaviours towards peers, increase mental health literacy and reduce stigma. This research evaluated tMHFA by comparing it to a matched emergency Physical First Aid (PFA) training programme. METHODS: A cluster-randomised crossover trial matched four public schools in two pairs and then randomised each to first receive tMHFA or PFA for all Year 10 students. In the subsequent calendar year, the new Year 10 cohort received the opposite intervention, giving eight cohorts. Online surveys were administered at baseline and 1 week post-training, measuring quality of first aid intentions, mental health literacy, problem recognition and stigmatising beliefs, towards fictional adolescents with depression and suicidality (John) and social anxiety (Jeanie). RESULTS: A total of 1942 students were randomised (979 received tMHFA, 948 received PFA), 1605 (84%) analysed for the John vignette at baseline and 1116 (69% of baseline) provided post-training data. The primary outcomes, 'helpful first aid intentions' towards John/Jeanie, showed significant group-by time interactions with medium effect sizes favouring tMHFA ( ds = 0.50-0.58). Compared to PFA, tMHFA students also reported significantly greater improvements in confidence supporting a peer ( ds = 0.22-0.37) and number of adults rated as helpful ( ds = 0.45-0.46) and greater reductions in stigmatising beliefs ( ds = 0.12-0.40) and 'harmful first aid intentions' towards John/Jeanie ( ds = 0.15 0.41). CONCLUSIONS: tMHFA is an effective and feasible programme for increasing supportive first aid intentions and mental health literacy in adolescents in the short term. tMHFA could be widely disseminated to positively impact on help seeking for adolescent mental illness. PMID- 29417836 TI - Heart Rate Variability as a Marker of Distress and Recovery: The Effect of Brief Supportive Expressive Group Therapy With Mindfulness in Cancer Patients. AB - OBJECTIVES: We aimed to investigate the effects of brief supportive expressive group therapy with mindfulness for cancer patients and to assess the utility of heart rate variability (HRV) as a biomarker of distress and treatment effect. METHODS: A total of 28 female patients with nonmetastatic cancer at a university hospital in South Korea received a 4-week modified group therapy for distress reduction. The BESTMIND (Brief Expression and Support Therapy with Mindfulness) program consisted of supportive-expressive group therapy and mindfulness-based stress reduction. The subjective outcomes of distress, anger, sleep quality, and sense of well-being and the physiological outcome of HRV were assessed before and after the program. RESULTS: After the program, patients showed significantly reduced distress, perceived stress, anger, and sleep disturbance and increased quality of life. No significant change was observed in the degree of mindfulness. A significantly increased SD in the normal beat-to-beat intervals and normalized high-frequency (HF 0.15-0.4 Hz) power from spectral analysis were observed after treatment. According to the correlation analyses, HF power correlated with depression scores, and normalized HF power was associated with depression, anxiety, perceived stress, and anger at baseline. The pretreatment and posttreatment comparison indicated that an increase in HF power was associated with a decrease in anger. CONCLUSIONS: These results suggest the effectiveness of this modified group-based program for distress reduction and also provide preliminary evidence for the use of HRV as a biomarker of distress and recovery. HF power from HRV variables may serve as a quantitative biomarker of the treatment response of distress management, including anger. PMID- 29417837 TI - Diuretic activity of ethanolic extract of Panicum repens L. roots and rhizomes. AB - The diuretic activity of ethanolic extract of Panicum repens was investigated in rats. A single oral dose of 500 mg/kg of P. repens extract were given to rats, after 24 h, urine volume, its sodium and potassium concentrations were estimated. Treatment with P. repens extract caused a significant increase in tested parameters as compared to their corresponding controls, p < 0.05. PMID- 29417838 TI - Lung cancer: a brief review of epidemiology and screening. AB - The global burden of lung cancer has been increasing over the past years, and is still a major threat to public health worldwide, leading to disabilities and premature mortality. Despite multifactorial cause, smoking remains as the major etiological factor, followed by occupational exposure to carcinogens, genetic predisposition and other concomitant diseases. In order to reduce the individual and social burden due to the direct and indirect costs related to the lung cancer treatment, accurate methods of screening are needed. Among those, x-ray with cytological analysis of sputum was first proposed. Nowadays, more sensitive methods such as low-dose computed tomography are being used to improve the early detection. In the future, molecular biomarkers may complement low-dose computed tomography and improve the robustness of early lung cancer detection. PMID- 29417840 TI - What makes decision-making difficult for oncologists faced with critical situations? The socio-affective side of the physician-patient relationship. AB - The aim of this qualitative study based on a Social Representations approach was to explore experienced oncologists' representations of difficult decision-making situations. In total, 22 semi-structured interviews with oncologists were conducted and analysed by performing a thematic content analysis. The thematic content analysis brought to light the main medical problem involved such as uncertainty, the lethal nature of cancer and physicians' specialties, as well as the psychosocial ones, such as patients' non-medical characteristics and the patient-physician relationships. This analysis also showed the painful tensions experienced by specialists in the context of decision-making situations when the medical arguments conflict with the psychosocial ones. These findings suggest that in order to understand more clearly the complex processes involved in difficult medical decision-making situations, studies on physicians' expertise should include the socio-affective climate involved in each patient-physician relationship. PMID- 29417839 TI - Mechanical thrombectomy - is time still brain? The DAWN of a new era. AB - PURPOSE: The purpose of this study is to review the history of treatments for acute ischemic stroke, examine developments in endovascular therapy, and discuss the future of the management of acute ischemic stroke. METHODS: A selective review of recent clinical trials for the treatment of acute ischemic stroke was conducted. RESULTS: We reviewed completed trials of the management of acute ischemic stroke including intravenous thrombolytics, intraarterial thrombolytics, and thrombectomy. We also assessed the future direction of research by reviewing ongoing clinical trials. CONCLUSIONS: The advancement of endovascular treatment for stroke has led to improved morbidity and mortality for patients. Future challenges include delivering these treatments to stroke centers worldwide. PMID- 29417841 TI - Chemical composition of essential oil from plants of abandoned mining site of Elba island. AB - The essential oil composition of three spontaneous species growing in an abandoned mining of Elba island was analyzed by GC-MS. A total of 194 compounds were identified representing 73.7-100% of the whole oil composition. The essential oils of Cistus salvifolius and Dittrichia viscosa from this site showed different profiles in comparison with those from not polluted area, where oxygenated sesquiterpenes were the main class. Volatiles from D. viscosa growing in ex-mining area presented 10-epi-gamma-eudesmol and alpha-eudesmol as main compounds while beta-caryophyllene and limonene were the main ones in not polluted area. Ambroxide and ambrial were the most important compounds in the essential oil from C. salvifolius harvested in polluted area while nonanal and tridecanal were the main compounds in control samples. Oxygenated monoterpenes were the most abundant class from both Lavandula stoechas samples, with fenchone and camphor as main compounds. PMID- 29417842 TI - Development of food emulsions containing an advanced performance xanthan gum by microfluidization technique. AB - Gums are often used to increase the viscosity of the continuous phase of oil-in water emulsions in order to reduce or inhibit some destabilization processes such as creaming. A new type of xanthan gum, advanced performance xanthan gum, which possesses improved rheological properties, has been used as a stabilizer. The addition of advanced performance xanthan gum to egg protein-based emulsions prepared at different homogenization pressures in Microfluidizer was studied. These emulsions showed different droplet size distributions and flocculation degrees. However, all the emulsions studied exhibited the same viscoelastic properties, characterized by a crossover point in the mechanical spectra. This work demonstrates the essential role of this novel gum in the rheology of emulsions. In addition, there is a direct relation between homogenization pressure and flocculation degree. This flocculation led to destabilization by coalescence in these emulsions, being the emulsion processed at the smallest homogenization pressure the most stable. PMID- 29417843 TI - Microneedles containing cross-linked hyaluronic acid particulates for control of degradation and swelling behaviour after administration into skin. AB - Microneedles (MN) containing cross-linked hyaluronic acid (X-linked HA) particulates were prepared to control the degradation and swelling behaviour after transdermal drug delivery. The X-linked HA particulates were prepared by cross-linking HA chains and then passing the particulates through a sieve. Then, microneedles were prepared by micromolding method. The rheological properties of X-linked HA were studied. The penetration success rate, mechanical failure and dissolution rate of microneedles containing only hyaluronic acid (HA MN) and microneedles containing X-linked HA were compared. The delivery of fluorescein into the skin with X-linked HA MN was also observed using a confocal microscope. The size of the pulverised particulates in water ranged between 29 and 82 MUm in diameter. The HA MN and X-linked HA MN were 270 MUm in length. X-linked HA MN with fluorescein was inserted to a depth of 90% of the microneedle length successfully. There was no decrease in the penetration success rate for MN with up to 20% content of X-linked HA particulates. X-linked HA MN with up to 20% of particulate content did not change the dissolution time. Delay in degradation of HA, sustained drug release, and swelling behaviour of the skin layer can be obtained by X-linked HA MN. PMID- 29417844 TI - Taurine reduces blue light-induced retinal neuronal cell apoptosis in vitro. AB - BACKGROUND: The massive uptake of organic compatible osmolytes is a self protective response to multiple stressors. OBJECTIVE: This study aimed to determine the protective effects of the osmolyte taurine against blue light induced apoptosis in retinal neuronal cells in vitro. METHODS: Real-time PCR was used to measure osmolyte transport. Radioimmunoassays were performed to measure osmolyte uptake. Cell Counting Kit-8 assays were conducted to measure cellular viability. Flow cytometry analysis was used to measure apoptosis. RESULTS: Compared with normotonic stress, hypertonic stress-induced uptake of osmolytes, including betaine, myoinositol, and taurine, into the retinal neuronal cells. Blue light increased osmolyte transporter mRNA expression together with osmolyte uptake. Furthermore, taurine significantly suppressed blue light-induced retinal neuronal cell apoptosis. CONCLUSION: The compatible osmolyte taurine may have an important role in cell resistance to blue light and cell survival. PMID- 29417845 TI - Acanthus mollis L. leaves as source of anti-inflammatory and antioxidant phytoconstituents. AB - This work expands the phytochemical composition knowledge of Acanthus mollis and evaluates antioxidant and anti-inflammatory activities which could be related with its traditional uses. Extracts from leaves, obtained by sequential extraction, were screened using TLC and HPLC-PDA. The ethanol extract was the most active on DPPH assay (IC50 = 20.50 MUg/mL) and inhibited nitric oxide (NO) production in RAW 264.7 macrophages (IC50 = 48.31 MUg/mL). Significant amounts of cyclic hydroxamic and phenolic acids derivatives were detected. A lower antioxidant effect was verified for a fraction enriched with DIBOA derivatives (IC50 = 163.02 MUg/mL), suggesting a higher contribution of phenolic compounds for this activity in ethanol extract. However, this fraction exhibited a higher inhibition of NO production (IC50 = 32.32 MUg/mL), with absence of cytotoxicity. These results support the ethnomedical uses of this plant for diseases based on inflammatory processes. To our knowledge, it is the first report to the anti inflammatory activity for DIBOA derivatives. PMID- 29417846 TI - Fall Hazards Within Senior Independent Living: A Case-Control Study. AB - AIM:: The main purpose of this research was to identify significant relationships between environmental hazards and older adults' falling. BACKGROUND:: Falls can present a major health risk to older persons. Identifying potential environmental hazards that increase fall risks can be effective for developing fall prevention strategies that can create safer residential environments for older adults. METHODS:: The research included a retrospective analysis of 449 fall incident reports in two case-control buildings. In the homes of 88 older adults residing in independent living, an observational study was conducted to identify environmental hazards using two assessment tools including Westmead Home Safety Assessment (WeHSA) and resident interviews. RESULTS:: A fall history analysis indicated that falls occurred in the bathroom were significantly associated with hospitalization. The observational study revealed that the bathroom was the most common place for environmental hazards. The research showed, with increasing age and use of mobility assistive aids, there was a corresponding increase in the total number of environmental hazards. Home hazards were significantly and independently associated with the incidence rate of falls. In other words, the high fall rate building included more environmental hazards compared to the low fall rate building while controlling for residents' age and mobility. CONCLUSION:: The current study provides empirical evidence of the link between environmental hazards and older adults' falling, which is useful for developing effective fall intervention design strategies. PMID- 29417847 TI - Clinical outcomes of endoscopic versus microscopic trans-sphenoidal surgery for large pituitary adenoma. AB - OBJECTIVE: To compare clinical outcomes of large pituitary adenomas (>=3 cm in maximum diameter), operated on by Endoscopic Transsphenoidal Surgery (ETS), versus Microscopic Transsphenoidal Surgery (MTS). METHODS: Medical records and MRI Scans of patients with a diagnosis of pituitary adenoma for whom transphenoidal surgery was done were reviewed. Complete pre and post-operative data were available for 121 patients. Thirty five patients had large pituitary adenoma and were enrolled in this study. ETS was done in 16 patients, and 19 underwent MTS. All patients were followed for at least six months. Clinical and imaging characteristics were reported in details. Post-operative clinical outcomes were defined as clinical outcomes persisted 6 months after surgery. RESULTS: The average tumor size was 36.3 +/- 4.4 mm in ETS group, and 34.0 +/- 4.6 mm in MTS group, (p = .46). Six months after surgery, tumor size was 4.6 +/- 6.6 mm in ETS and 17.7 +/- 12.2 mm in MTS group, (p = .002). Gross total resection (GTR) was observed in the 81.2% of the patient in the ETS group. In the MTS group, GTR was observed in 15.8%. Post-operative clinical outcomes including new onset hypopituitarism, visual impairment, and permanent diabetes insipidus (DI) were comparable between the two groups. CONCLUSION: ETS is superior to MTS in treatment of large pituitary adenomas with comparable post-operative complications. PMID- 29417848 TI - Triiodothyronine stimulates VEGF expression and secretion via steroids and HIF 1alpha in murine Leydig cells. AB - : Leydig cells are the principal steroidogenic cells of the testis. Leydig cells also secrete a number of growth factors including vascular endothelial growth factor (VEGF) which has been shown to regulate both testicular steroidogenesis and spermatogenesis. The thyroid hormone, T3, is known to stimulate steroidogenesis in Leydig cells. T3 has also been shown to stimulate VEGF production in a variety of cell lines. However, studies regarding the effect of T3 on VEGF synthesis and secretion by the Leydig cells were lacking. Therefore, we investigated the effect of T3 on VEGF synthesis and secretion in a mouse Leydig tumour cell line, MLTC-1. The effect of T3 was compared with that of LH/cAMP and hypoxia, two known stimulators of Leydig cell functions. The cells were treated with T3, 8-Br-cAMP (a cAMP analogue), or CoCl2 (a hypoxia mimetic) and VEGF secreted in the cell supernatant was measured using ELISA. The mRNA levels of VEGF were measured by quantitative RT-PCR. In the MLTC-1 cells, T3, 8 Br-cAMP, and CoCl2 stimulated VEGF mRNA levels and the protein secretion. T3 also increased steroid secretion as well as HIF-1alpha protein levels, two well established upstream regulators of VEGF. Inhibitors of steroidogenesis as well as HIF-1alpha resulted in inhibition of T3-stimulated VEGF secretion by the MLTC-1 cells. This suggested a mediatory role of steroids and HIF-1alpha protein in T3 stimulated VEGF secretion by MLTC-1 cells. The mediation by steroids and HIF 1alpha were independent of each other. ABBREVIATIONS: 8-Br-cAMP: 8-bromo - 3', 5' cyclic adenosine monophosphate; CoCl2: cobalt chloride; HIF-1alpha: hypoxia inducible factor -1alpha; LH: luteinizing hormone; T3: 3, 5, 3'-L triiodothyronine; VEGF: vascular endothelial growth factor. PMID- 29417849 TI - A new sulphated flavone and other phytoconstituents from the leaves of Tetracera indica Merr. and their alpha-glucosidase inhibitory activity. AB - The bioactivity guided fractionation of Tetracera indica leaves crude ethanolic extract has afforded the isolation and characterization of six compounds including a new natural product viz., 5,7-dihydroxyflavone-O-8-sulphate (1) and five known flavonoids (2-6). The structures of the compounds were elucidated using 1D and 2D NMR and HRESIMS spectroscopic analyses. All the isolated compounds were evaluated for their in vitro inhibitory activity against alpha glucosidase. Compound 1, 5 and 6 showed strong alpha-glucosidase inhibitory activity, 3 and 4 displayed weak activity while compound 2 was inactive. The interactions of the active compounds with alpha-glucosidase were further investigated using molecular docking to confirm their antidiabetic potential. PMID- 29417851 TI - Psychosocial interventions enhance HIV medication adherence: A systematic review and meta-analysis. AB - About 40 per cent of people living with HIV do not sufficiently adhere to their medication regimen, which adversely affects their health. The current meta analysis investigated the effect of psychosocial interventions on medication adherence in people living with HIV. Databases were systematically searched, resulting in 43 included randomized controlled trials. Study and intervention characteristics were investigated as moderators. The overall effect size indicates a small to moderate positive effect (Hedges' g = 0.37) of psychosocial interventions on medication adherence in people living with HIV. No evidence for publication bias was found. This meta-analysis study concludes that various psychosocial interventions can improve medication adherence and thereby the health of people living with HIV. PMID- 29417852 TI - The Role of Environmental Design in Cancer Prevention, Diagnosis, Treatment, and Survivorship: A Systematic Literature Review. AB - The purpose of this literature review is to provide a better understanding of the impact that environmental design can have on the process of cancer prevention, diagnosis, treatment, and survivorship. Cancer is considered a chronic disease in the United States, and more than 1.6 million new cases are diagnosed annually. New strategies of cancer care propose patient-centered services to achieve the best outcome, and researchers have found that environmental design can be an important part of improving this care. Searches were conducted in the PubMed and Google Scholar databases as well as in specific healthcare design journals such as Health Environments Research & Design, Environmental Psychology, and Environment and Behavior. The criteria for articles included in the review were (a) English-language articles related to facility design, which addressed (b) the topics of built environment in relation to cancer diagnosis, treatment, and survivorship, and were (c) published in peer-reviewed journals between 2000 and 2017. Finally, 10 articles were selected, and the contents were analyzed. The selected articles demonstrate that environmental design is one of the critical factors for success throughout the whole continuum of cancer care from diagnosis to end-of-treatment. Some of the specific conclusions from the review are that "neighborhood-oriented" design strategies can be beneficial (by providing accessibility to all facilities along the patient's path), that access to nature for patients, staff, and visitors alike is associated with better outcomes, and that provisions for natural lighting and noise reduction are associated with cancer patients' well-being. PMID- 29417850 TI - Efficacy of Ginger in Ameliorating Acute and Delayed Chemotherapy-Induced Nausea and Vomiting Among Patients With Lung Cancer Receiving Cisplatin-Based Regimens: A Randomized Controlled Trial. AB - Nausea and vomiting are among the most common and distressing side effects of chemotherapy. Additional antiemetic drugs are urgently needed to effectively manage and ameliorate chemotherapy-induced nausea and vomiting (CINV). The efficacy of ginger as an antiemetic modality for ameliorating CINV has not been established in previous studies. The aim of this study was to examine the efficacy of ginger, as an adjuvant drug to standard antiemetic therapy, in ameliorating acute and delayed CINV in patients with lung cancer receiving cisplatin-based regimens. In this randomized, double-blind, placebo-controlled clinical trial, 140 patients with lung cancer receiving cisplatin-based regimens were enrolled and allocated to receive either ginger root powder or a placebo. Ginger root powder was administered orally (0.5 g, 2 capsules per day, 0.25 g per capsule, every 12 hours) for 5 days beginning on the first day of chemotherapy. The incidence and severity of acute and delayed nausea and vomiting were assessed using the MASCC (Multinational Association for Supportive Care in Cancer) Antiemesis Tool (MAT). Adverse effects and patient adherence were also assessed in this study. No significant difference was observed between the ginger and control groups in the reduction of the incidence and severity of nausea and vomiting ( P > .05). No significant difference in adverse events was observed between the 2 groups ( P > .05). No study-treatment-related adverse events were observed in this study. As an adjuvant drug to standard antiemetic therapy, ginger had no additional efficacy in ameliorating CINV in patients with lung cancer receiving cisplatin-based regimens. PMID- 29417853 TI - Challenges in the diagnosis of acute cyanide poisoning. AB - OBJECTIVE: The aim of this systematic review was to identify isolated acute cyanide poison cases and to identify reported signs, symptoms, and laboratory findings. METHODS: We searched MEDLINE, Cochrane Reviews, and Web of Science case reports and series using a number of MeSH descriptors pertaining to cyanide, toxicity, and poisonings. We excluded studies on plants, laboratory analyses, smoke inhalation poisonings, animals as well as non-English language articles and those in which data were not available. Data extracted included demographics, exposure characteristics, acute signs/symptoms, and medical management and outcome. RESULTS: From the initial 2976 articles retrieved, 65 articles (52 case reports, 13 case series) met inclusion criteria and described 102 patients. Most patients were unresponsive (78%), hypotensive (54%), or had respiratory failure (73%); other signs and symptoms included cardiac arrest (20%), seizures (20%), cyanosis (15%), cherry red skin (11%), and had an odor present (15%). Medical management included cyanide antidote kit (20%), sodium thiosulfate (40%), and hydroxocobalamin (29%). The majority of cases (66%) required intubation with mechanical ventilation and a substantial number (39%) developed refractory hypotension requiring vasopressor support. CONCLUSIONS: Contrary to general reviews published on cyanide toxicity, reports of cherry red skin and bitter almond odor were rare among published cyanide cases. Consistent with other studies, metabolic acidosis with significant lactic acidosis were the laboratory values consistently associated with cyanide toxicity. Healthcare providers may overlook cyanide toxicity in the differential diagnosis, if certain expected characteristics, such as the odor of almonds or a cherry red color of the skin are absent on physical examination. PMID- 29417854 TI - Coming of age in a conflict area: Mental health, education, employment, migration and family formation in the southernmost provinces of Thailand. AB - OBJECTIVES: Three southern provinces of Thailand - Pattani, Yala and Narathiwat - have been involved in a long period of unrest. Young people in these provinces have lived with this violence for many years. The objectives of this article are to assess the prevalence of psychiatric symptoms of young adults aged 18-24 years and to examine the perceived effects of the conflict on education, employment, social and religious life. METHODS: Data were drawn from a probability sample of 2,053 Muslim adults aged 18-59 years conducted in 2014. Mental health was assessed using World Health Organization's (WHO) Self Reporting Questionnaire (SRQ) of 20 questions, the Thai Mental Health questionnaire and a Happiness scale. In-depth interviews with 30 respondents were also used to assess the perceived effects of the conflict on daily life, education, employment and settlement. RESULTS: Most respondents reported low levels of psychiatric symptoms, though a small proportion reported a large high enough number to be of concern. Most of them also reported high levels of happiness. Respondents who wished to migrate to work in another area reported more psychiatric symptoms and lower levels of happiness. Many respondents reported concerns about the violence in their daily lives, although some may have become habituated to its effects. There were many obstacles reported toward obtaining education including the threat of violence, financial cost and drug use. Male respondents had concerns about consequences of being suspected to be involved in the violence and drug use. The limited employment and the threat of violence were related to the plan to migrate or to settle in the three provinces. CONCLUSION: In summary, most young people in the area move forward with their lives and many display some habituation to the violence. However, the economic depression due to the violence and the threat of violence often affected their daily lives. PMID- 29417855 TI - Intra-articular application of pulsed radiofrequency combined with viscosupplementation for improvement of knee osteoarthritis symptoms: a single centre prospective study. AB - OBJECTIVES: To prospectively evaluate the effectiveness of intra-articular application of pulsed radiofrequency (PRF) combined with viscosupplementation in patients with knee osteoarthritis suffering from chronic pain refractory to conservative therapies. METHODS: During a 30-month period, PRF combined with viscosupplementation was performed on 53 cases of knee osteoarthritis (45 patients, 8/45 with bilateral knee osteoarthritis). Pre-operational imaging included standard knee X-rays on anterior-posterior and lateral views used to evaluate patients according to the Kellgren-Lawrence classification. Pain, prior, one week/one, 6 and 12 months post were compared by means of a numeric visual scale (NVS) questionnaire. RESULTS: Mean pain score prior to PRF was 8.19 +/- 1.4 NVS units. This score was reduced to a mean value of 2.47 +/- 2.5 NVS units at 1 week after, 2.55 +/- 2.6 at 1 month, 3.1 +/- 2.8 at 6 months and 5.02 +/- 3.09 at 12 months of follow-up (p < 0.01). Overall mobility improved in 47/53 (88.6%) patients. No complication was observed. CONCLUSIONS: Combining PRF with viscous supplementation is an effective and safe technique for palliative management of chronic pain in patients with knee osteoarthritis. Results seem to be reproducible and long lasting. There seems to be a need of repeating the session at 1 year. PMID- 29417856 TI - Gastrointestinal safety and tolerability of oral non-aspirin over-the-counter analgesics. AB - Over-the-counter (OTC) analgesics are routinely used worldwide for self management of various painful conditions. Despite this, there has been little in depth review of the safety of non-aspirin analgesics at OTC doses. This paper reviews the available literature on the gastrointestinal (GI) and hepatic safety of non-aspirin OTC analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs; ibuprofen, ketoprofen, diclofenac, and naproxen) and acetaminophen; safety in overdose is also reviewed. Each non-aspirin OTC analgesic has a distinct adverse event (AE) profile, with GI AE rates for OTC dosing in one study ranging from 37% for diclofenac to 7.2% for ibuprofen and 7.6% for acetaminophen; GI effects accounted for 75% of total AEs in the study. Across all studies reviewed here, the risk of serious GI toxicity, including upper GI bleeding and peptic ulcers, was low at OTC doses. By contrast, while both NSAIDs and acetaminophen may be associated with hepatotoxicity and acute liver failure (ALF), the risks associated with acetaminophen are somewhat higher and better documented. Reports of NSAID-associated hepatotoxicity rarely make distinctions by dose, making the risk at OTC doses difficult to assess. Liver injury due to acetaminophen, however, can occur at doses < 4000 mg. Case reports of NSAID associated overdose are rare, while acetaminophen-containing drugs are a leading cause of overdose and are implicated in up to 97% of ALFs leading to transplant involving overdose. OTC analgesics are effective for self-management of pain; however, they are associated with a low but important rate of GI and hepatic events, as well as a risk of intentional and non-intentional overdose. Given the widespread use of this class of drugs, it is important for healthcare professionals to be mindful of their patients' use of OTC analgesics. PMID- 29417857 TI - Radiofrequency ablation for the treatment of knee osteoarthritis: present status and future perspectives. PMID- 29417858 TI - The Year That Was 2017: Highlights in Pediatric Exercise Research. PMID- 29417859 TI - Newborn Screening for Hemoglobinopathies and Red Cell Enzymopathies in Tripura State: A Malaria-Endemic State in Northeast India. AB - Hemoglobinopathies are a group of inherited single gene disorders. There are reports on hemoglobin (Hb) variants identified in the tribal and non-tribal populations of Tripura State in northeastern India. This study aimed to determine the spectrum of hemoglobinopathies and enzymopathies by newborn screening in Tripura State and assess the extent of neonatal jaundice. A total of 2400 cord blood samples were collected and analyzed by high performance liquid chromatography (HPLC). Further confirmation of any abnormal HPLC was done by DNA analysis. The samples were also screened for deficiency of enzymopathies, glucose 6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase. Of 2400 cord blood samples screened, 225 (9.3%) were Hb E (HBB: c.79G>A) heterozygotes, 80 (3.3%) were Hb E homozygotes and one carried Hb E-beta-thalassemia (beta-thal). Other Hb abnormalities were also detected including 15 Hb S (HBB: c.20A>T) heterozygotes, two Hb D-Punjab (HBB: c.364G>C) heterozygotes and two compound heterozygotes for Hb D-Punjab and Hb E. Of the 80 homozygous Hb E babies, four were non-tribal and 76 babies were tribal, and 225 patients carried Hb E trait, 141 were tribal, while 84 were non-tribal. Of 40 G6PD deficient babies identified, 13 had coinherited Hb E and two babies had pyruvate kinase deficiency. alpha Genotyping was performed in 162 affected babies, 50 of them carried alpha gene deletions. Newborn screening programs for Hb E, other hemoglobinopathies and G6PD deficiency must be encouraged in the malaria-endemic northeastern region of India. Drug-induced hemolysis can also be avoided by screening for G6PD deficiency at birth. PMID- 29417860 TI - An insight into frequency and predictors leading psychiatric patients to visit faith healers: A hospital-based cross-sectional survey, Karachi, Pakistan. AB - BACKGROUND: Psychiatric illnesses have recently escalated in numbers, with patients resorting to various forms of healthcare providers, including faith healers. This delays early psychiatric treatment, resulting in further mental health deterioration of the patient. Various factors impact the mode of treatment preferred by psychiatric patients. AIMS: To determine the frequency of psychiatric patients visiting faith healers, presenting at the outpatient department of Liaquat National Hospital, Karachi, Pakistan, and to explore the predictors that direct them toward visiting faith healers. METHODS: This cross sectional survey was conducted using a semi-structured pre-tested questionnaire, employing a total of 219 male and female psychiatric patients. Patients were recruited through non-random consecutive sampling technique. SPSS 18 was used for statistical analysis. RESULTS: About 32% of the patients had visited a faith healer in their lifetime. Frequency of current visitors declined; the most frequent reason being stated was no relief from their treatment. Students, patients of upper middle class and those coming for initial visit to a psychiatrist were more likely to visit a faith healer. Patients who knew of someone previously visiting a faith healer were less likely to have visited a faith healer. CONCLUSION: This study highlights the importance of a multisectoral approach to dealing with psychiatric patients to help in bridging the treatment gap in mental health. PMID- 29417861 TI - The potential of AR-V7 as a therapeutic target. AB - INTRODUCTION: The androgen receptor variant AR-V7 is gaining attention as a potential predictive marker for as well as one of the resistance mechanisms to the most current anti-androgen receptor (AR) therapies in castration-resistant prostate cancer (CRPC). Accordingly, development of next-generation drugs that directly or indirectly target AR-V7 signaling is urgently needed. Areas covered: We review proposed mechanisms of drug resistance in relation to AR-V7 status, the mechanisms of generation of AR-V7, and its transcriptome, cistrome, and interactome. Pharmacological agents that interfere with these processes are being developed to counteract pan AR and AR-V7-specific signaling. Also, we address the current status of the preclinical and clinical studies targeting AR-V7 signaling. Expert opinion: AR-V7 is considered a true therapeutic target, however, it remains to be determined if AR-V7 is a principal driver or merely a bystander requiring heterodimerization with co-expressed full-length AR or other variants to drive CRPC progression. While untangling AR-V7 biology, multiple strategies are being developed to counteract drug resistance, including selective blockade of AR-V7 signaling as well as inhibition of pan-AR signaling. Ideally anti-AR therapies will be combined with agents preventing activation and enrichment of AR negative tumor cells that are otherwise depressed by AR activity axis. PMID- 29417862 TI - Nanomaterials in dentistry: a cornerstone or a black box? AB - AIM: The studies on tooth structure provided basis for nanotechnology-based dental treatment approaches known as nanodentistry which aims at detection and treatment of oral pathologies, such as dental caries and periodontal diseases, insufficiently being treated by conventional materials or drugs. This review aims at defining the role of nanodentistry in the medical area, its potential and hazards. MATERIALS & METHODS: To validate these issues, current literature on nanomaterials for dental applications was critically reviewed. RESULTS: Nanomaterials for teeth restoration, bone regeneration and oral implantology exhibit better mechanical properties and provide more efficient esthetic outcome. However, still little is known about influence of long-term function of such biomaterials in the living organism. CONCLUSION: As application of nanomaterials in industry and medical-related sciences is still expanding, more information is needed on how such nano-dental materials may interfere with oral cavity, GI tract and general health. PMID- 29417863 TI - Marmoset cytochrome P450 2B6, a propofol hydroxylase expressed in liver. AB - The common marmoset (Callithrix jacchus) is a useful experimental animal to evaluate the pharmacokinetics of drug candidates. Cytochrome P450 (P450) 2B enzyme in marmoset livers has been identified; however, only limited information on the enzymatic properties and distribution has been available. Marmoset P450 2B6 amino acids showed high sequence identities (>86%) with those of primates including humans and cynomolgus monkeys. Phylogenetic analysis using amino acid sequences indicated that marmoset P450 2B6 was closer to human and cynomolgus monkey P450 2B6 than to P450 2B orthologs of other species, including pigs, dogs, rabbits and rodents. Quantitative polymerase chain reaction analysis using specific primers showed P450 2B6 mRNA predominantly expressed in livers among the five marmoset tissues, similar to those of humans and cynomolgus monkeys. Marmoset P450 2B6 heterologously expressed in Escherichia coli membranes oxidized 7-ethoxycoumarin, pentoxyresorufin, propofol and testosterone, at roughly similar rates to those of humans and/or cynomolgus monkeys. A high capacity of marmoset P450 2B6 with propofol 4-hydroxylation (at low ionic strength conditions) with a low Km value was relatively comparable to that for marmoset livers. These results collectively indicated a high propofol 4-hydroxylation activity of P450 2B6 expressed in marmoset livers. PMID- 29417864 TI - Enhanced silver loaded antibacterial titanium implant coating with novel hierarchical effect. AB - In this study, we present a novel strategy for hierarchical antibacterial implant coating by controlling structural and componential features as regulators of surface bactericidal property. Anodized titanium dioxide nanotubes and self polymerized polydopamine were both used as preliminary antibacterial agents with a significant positive effect on surface bioactivity. At the same time, the storage capacity of nanotubes and the in situ reduction activity of polydopamine can introduce large amounts of strong attached silver nanoparticles for enhanced stable antibacterial performance. The surface morphology, chemical composition, and hydrophilicity had been thoroughly characterized. The sustained silver release performances were continuously monitored. The successively in vitro inhibition on Staphylococcus aureus growth of titanium dioxide nanotube, polydopamine layer and silver nanoparticles demonstrated the hierarchical antibacterial property of the final silver nanoparticles-incorporated polydopamine-modified titanium dioxide nanotube coating (silver/polydopamine/nanotube). Moreover, the bioactivity investigation indicated the vital role of polydopamine-modified titanium dioxide nanotube coating on preserving healthy osteoblast activity at the implant interface. The unique hierarchical coating for titanium implant may be a promising method to maximize antibacterial capacity and maintain good cellular activity at the same time. PMID- 29417865 TI - Advanced diffusion-weighted imaging in patients with optic neuritis deficit - value of reduced field of view DWI and readout-segmented DWI. AB - Objective The objective of this article is to evaluate advanced techniques of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) measurements of the optic nerve in patients with optic neuritis. Methods In this prospective and institutional review board-approved trial, we examined 15 patients with acute visual loss and clinical signs of optic neuritis including thin-slice multi-shot segmented readout of long variable echo trains (rs-EPI, RESOLVE) DWI and reduced field-of view DWI using a parallel transmit system (rFOV EPI). Conventional single-shot echo-planar DWI (ss-EPI) of the whole brain was available in 13 patients. Subjective image quality was compared using a four point scale and objective ADC measurements were performed in comparison with the non-affected side. Results In the intraorbital segment, subjective image quality was significantly higher in rFOV-EPI (score 3.3 +/- 0.8) compared with rs-EPI (score 2.1 +/- 0.8) and ss-EPI (score 0.9 +/- 0.8). Diagnosis was hampered in the canalicular segment ( n = 3) and the intracranial segment ( n = 1) in all applied DWI techniques. ADC measurements of the affected side differed significantly in all DWI sequences ss-EPI (sensitivity 54%, accuracy 77%), rs-EPI (sensitivity 71%, accuracy 86%), and rFOV-EPI (sensitivity 73%, accuracy 87%). Conclusion Optic neuritis in the intraorbital segment can be detected with high sensitivity without the need for contrast application. Using rFOV-EPI improves subjective image quality compared with rs-EPI and ss-EPI. Due to its higher spatial resolution, rFOV-EPI was the preferred technique in our study and can ensure the diagnosis in the intraorbital segment. However, artefacts occur in the canalicular and intracranial segment of the optic nerve, therefore contrast enhanced T1-weighted images must still be considered as the gold standard. PMID- 29417866 TI - Insulin-like growth factor-1 regulation of retinal progenitor cell proliferation and differentiation. AB - Strategies to improve retinal progenitor cell (RPC) capacity to yield proliferative and multipotent pools of cells that can efficiently differentiate into retinal neurons, including photoreceptors, could be vital for cell therapy in retinal degenerative diseases. In this study, we found that insulin-like growth factor-1 (IGF-1) plays a role in the regulation of proliferation and differentiation of RPCs. Our results show that IGF-1 promotes RPC proliferation via IGF-1 receptors (IGF-1Rs), stimulating increased phosphorylation in the PI3K/Akt and MAPK/Erk pathways. An inhibitor experiment revealed that IGF-1 induced RPC proliferation was inhibited when the PI3K/Akt and MAPK/Erk pathways were blocked. Furthermore, under the condition of differentiation, IGF-1 pretreated RPCs prefer to differentiate into retinal neurons, including photoreceptors, in vitro, which is crucial for visual formation and visual restoration. These results demonstrate that IGF-1 accelerates the proliferation of RPCs and IGF-1 pretreated RPCs may have shown an increased potential for retinal neuron differentiation, providing a novel strategy for regulating the proliferation and differentiation of retinal progenitors in vitro and shedding light upon the application of RPCs in retinal cell therapy. PMID- 29417867 TI - Bioinformatic analyses of microRNA-targeted genes and microarray-identified genes correlated with Barrett's esophagus. AB - Barrett's esophagus (BE) is defined as a metaplasia condition in the distal esophagus, in which the native squamous epithelium lining is replaced by a columnar epithelium with or without intestinal metaplasia. It is commonly accepted that BE is a precancerous lesion for esophageal adenocarcinoma. The aim of this study was to investigate the aberrant microRNAs (miRNAs) and differentially expressed genes (DEGs) associated with BE based on online microarray datasets. One miRNA and five gene expression profiling datasets were retrieved from the Gene Expression Omnibus Database. Aberrant microRNAs and DEGs were obtained using R/Bioconductor statistical analysis language and software. 23 dysregulated miRNAs and 632 DEGs demonstrating consistent expression tendencies in the five gene microarrays were identified in BE. Moreover, 1962 target genes of aberrant miRNAs were predicted using three bioinformatic tools, namely TargetScan, RNA22-HSA and miRDB. Ultimately, 93 target DEGs were obtained, after which functional annotation was performed on DAVID Bioinformatics Resources. Among Gene Ontology (GO) biological processes, digestive tract development and epithelial cell differentiation have demonstrated significant associations with BE pathogenesis. In addition, analysis of the KEGG pathways has revealed associations with cancer. To enable further study, one miRNA-target DEGs regulatory network was constructed using Cytoscape. 6 target DEGs demonstrated higher-degree distributions in the network, and ROC analysis indicated that FNDC3B may be the best potential biomarker for BE diagnosis. The data presented herein may provide new perspectives for exploring BE pathogenesis and may offer hits with regard to potential biomarkers in BE diagnosis, prediction and therapeutic evaluation. PMID- 29417868 TI - Non-coding RNAs as therapeutic targets for preventing myocardial ischemia reperfusion injury. AB - INTRODUCTION: New treatments are required to improve clinical outcomes in patients with acute myocardial infarction (AMI), for reduction of myocardial infarct (MI) size and preventing heart failure. Following AMI, acute ischemia/reperfusion injury (IRI) ensues, resulting in cardiomyocyte death and impaired cardiac function. Emerging studies have implicated a fundamental role for non-coding RNAs (microRNAs [miRNA], and more recently long non-coding RNAs [lncRNA]) in the setting of acute myocardial IRI. Areas covered: In this article, we discuss the roles of miRNAs and lncRNAs as potential biomarkers and therapeutic targets for the detection and treatment of AMI, review their roles as mediators and effectors of cardioprotection, particularly in the settings of interventions such as ischemic pre- and post-conditioning (IPC & IPost) as well as remote ischemic conditioning (RIC), and highlight future strategies for targeting ncRNAs to reduce MI size and prevent heart failure following AMI. Expert opinion: Investigating the roles of miRNAs and lncRNAs in the setting of AMI has provided new insights into the pathophysiology underlying acute myocardial IRI, and has identified novel biomarkers and therapeutic targets for detecting and treating AMI. Pharmacological and genetic manipulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients. PMID- 29417869 TI - A biomechanical model of the human defecatory system to investigate mechanisms of continence. AB - This article presents a method to fabricate, measure and control a physical simulation of the human defecatory system to investigate individual and combined effects of anorectal angle and sphincter pressure on continence. To illustrate the capabilities and clinical relevance of the work, the influence of a passive assistive artificial anal sphincter (FENIXTM) is evaluated. A model rectum and associated soft tissues, based on geometry from an anonymised computed tomography dataset, was fabricated from silicone and showed behavioural realism to the biological system and ex vivo tissue. Simulated stool matter with similar rheological properties to human faeces was developed. Instrumentation and control hardware were used to regulate injection of simulated stool into the system, automate balloon catheter movement through the anal canal, define the anorectal angle and monitor stool flow rate, intra-rectal pressure, anal canal pressure and puborectalis force. Studies were conducted to examine the response of anorectal angles at 80 degrees , 90 degrees and 100 degrees with simulated stool. Tests were then repeated with the inclusion of a FENIX device. Stool leakage was reduced as the anorectal angle became more acute. Conversely, intra-rectal pressure increased. Overall inclusion of the FENIX reduced faecal leakage, while combined effects of the FENIX and an acute anorectal angle showed the greatest resistance to faecal leakage. These data demonstrate that the anorectal angle and sphincter pressure are fundamental in maintaining continence. Furthermore, it demonstrates that use of the FENIX can increase resistance to faecal leakage and reduce anorectal angles required to maintain continence. Physical simulation of the defecatory system is an insightful tool to better understand, in a quantitative manner, the effects of the anorectal angle and sphincter pressure on continence. This work is valuable in helping improve our understanding of the physical behaviour of the continence mechanism and facilitating improved technologies to treat severe faecal incontinence. PMID- 29417870 TI - Elite Youth Sports-The Year That Was 2017. AB - In 2017, considerable attention has been paid by researchers on early sports specialization for youth athletes. Issues related to injury, burnout, and talent development to name a few have been debated, particularly when contrasted against other opposing youth development approaches, such as a multisport approach. The increasing professionalization of young athletes, a particular concern of this author, is coupled with the ensuing physical and mental pressures on these youngsters, as highlighted by the 2 highlighted publications in this commentary. Moreover, the financial costs to parents to support talented youngsters lead me to conclude that we must not treat them as "mini-adult athletes." Trying to predict too far into the sporting future of a 9- or 10-year athlete can lead us to forgetting that they are just a 9 year, who typically wants to play, have fun, and be with their friends. Embarking on concentrated training programs, endless travel for tournaments, and an overemphasis on winning can be detrimental to participation rates as shown by recent data in the United States. Therefore, the challenge for researchers in elite youth sports is to ensure that practices we pursue with our young charges promote their health and well-being and that sports is for the benefit of the athlete and not the other way around. PMID- 29417871 TI - Restructuring of a Textile Manufacturing Company and Workers' Health. AB - Organizational restructuring is associated with greater mortality and morbidity of the workers affected by it. We examined the quality of workers' health at a textile manufacturing company after restructuring, comparing three groups of workers: workers who remained (survivors), workers who lost their jobs and later found new jobs (the reemployed), and unemployed workers. A total of 1046 workers participated in a telephonic survey. The data were processed using SPSS and the R package version 1.2 of prLogistic. The differences between groups were calculated using the chi-square test and adjusted prevalence ratios. The comparison between the three groups shows significantly poorer mental health of the unemployed, who more often than survivors and the reemployed reported depression, as well as significant differences in elevated blood pressure, cholesterol level, and cardiac disorders. The reemployed, who were nonetheless in better health compared to the unemployed, reported poor mental health or depression more often in comparison to survivors. Higher morbidity of the unemployed and reemployed could be influenced by numerous factors associated with restructuring. PMID- 29417872 TI - Physical Activity, Inactivity, and Health During Youth-The Year That Was 2017. AB - It is well known that physical activity is important for children's current and future mental and physical health. Despite this, there appears to be a secular decline in children's physical activity (Cameron et al. [ 2 ]; Dalene et al. [ 3 ]). Furthermore, (frustratingly) interventions aiming to increase children's physical activity have limited success (Metcalf et al. [ 10 ]), demonstrating a need for more information on the amenability of activity levels to change. PMID- 29417873 TI - Simple discrimination of sub-cycling cells by propidium iodide flow cytometric assay in Jurkat cell samples with extensive DNA fragmentation. AB - Human leukemia Jurkat T cells were analyzed for apoptosis and cell cycle by flow cytometry, using the Annexin V/propidium iodide (PI) standard assay, and a simple PI staining in Triton X-100/digitonin-enriched PI/RNase buffer, respectively. Cells treated with doxorubicin or menadione displayed a very strong correlation between the apoptotic cell fraction measured by the Annexin V/PI assay, and the weight of a secondary cell population that emerged on the forward scatter (FS)/PI plot, as well as on the side scatter (SS)/PI and FL1/PI plots generated from parallel cell cycle recordings. In both cases, the Pearson correlation coefficients were >0.99. In cell cycle determinations, PI fluorescence was detected on FL3 (620/30 nm), and control samples exhibited the expected linear dependence of FL3 on FL1 (525/40 nm) signals. However, increasing doses of doxorubicin or menadione generated a growing subpopulation of cells displaying a definite right-shift on the FS/FL3, SS/FL3 and FL1/FL3 plots, as well as decreased PI fluorescence, indicative of ongoing fragmentation and loss of nuclear DNA. By gating on these events, the resulting fraction of presumably sub cycling cells (i.e. cells with cleaved DNA, counting sub-G0/G1, sub-S and sub G2/M cells altogether) was closely similar to the apoptotic rate assessed by Annexin V/PI labeling. Taken together, these findings suggest a possible way to recognize the entire population of cells undergoing apoptotic DNA cleavage and simultaneously determine the cell cycle distribution of non-apoptotic cells in PI labeled cell samples with various degrees of DNA fragmentation, using a simple and reproducible multiparametric analysis of flow cytometric recordings. PMID- 29417874 TI - Adaptive Working Memory Training Reduces the Negative Impact of Anxiety on Competitive Motor Performance. AB - Optimum levels of attentional control are essential to prevent athletes from experiencing performance breakdowns under pressure. The current study explored whether training attentional control using the adaptive dual n-back paradigm, designed to directly target processing efficiency of the main executive functions of working memory (WM), would result in transferrable effects on sports performance outcomes. A total of 30 tennis players were allocated to an adaptive WM training or active control group and underwent 10 days of training. Measures of WM capacity as well as performance and objective gaze indices of attentional control in a tennis volley task were assessed in low- and high-pressure posttraining conditions. Results revealed significant benefits of training on WM capacity, quiet eye offset, and tennis performance in the high-pressure condition. Our results confirm and extend previous findings supporting the transfer of cognitive training benefits to objective measures of sports performance under pressure. PMID- 29417875 TI - A DP-like transcription factor protein interacts with E2fl1 to regulate meiosis in Tetrahymena thermophila. AB - Evolutionarily conserved E2F family transcription factors regulate the cell cycle via controlling gene expression in a wide range of eukaryotes. We previously demonstrated that the meiosis-specific transcription factor E2fl1 had an important role in meiosis in the model ciliate Tetrahymena thermophila. Here, we report that expression of another E2F family transcription factor gene DPL2 correlates highly with that of E2FL1. Similar to e2fl1Delta cells, dpl2Delta cells undergo meiotic arrest prior to anaphase I, with the five chromosomes adopting an abnormal tandem arrangement. Immunofluorescence staining and immunoprecipitation experiments demonstrate that Dpl2 and E2fl1 form a complex during meiosis. We previously identified several meiotic regulatory proteins in T. thermophila. Cyc2 and Tcdk3 may cooperate to initiate meiosis and Cyc17 is essential for initiating meiotic anaphase. We investigate the relationship of these regulators with Dpl2 and E2fl1, and then construct a meiotic regulatory network by measuring changes in meiotic genes expression in knockout cells. We conclude that the E2fl1/Dpl2 complex plays a central role in meiosis in T. thermophila. PMID- 29417876 TI - Towards clinical application of non-invasive imaging to detect bacterial infections. AB - In vivo imaging technologies offer a great potential for the diagnosis of difficult-to-treat bacterial infections. A major limitation of conventional imaging modalities is the lack of specificity to distinguish the site of bacterial infection from sterile inflammation. Targeted approaches like antibiotics linked to imaging tracers for detection of various bacterial pathogens or species-specific antibodies combined with anatomical imaging modalities are currently being evaluated to overcome this problem. Considering the recent progress in optical and targeted imaging that may accelerate preclinical development programs, clinical implementation of in vivo imaging modalities to detect bacterial infection foci becomes realistic in the future. PMID- 29417877 TI - Children's Compliance With Wrist-Worn Accelerometry Within a Cluster-Randomized Controlled Trial: Findings From the Healthy Lifestyles Programme. AB - PURPOSE: The purpose of this study was to assess children's compliance with wrist worn accelerometry during a randomized controlled trial and to examine whether compliance differed by allocated condition or gender. METHODS: A total of 886 children within the Healthy Lifestyles Programme trial were randomly allocated to wear a GENEActiv accelerometer at baseline and 18-month follow-up. Compliance with minimum wear-time criteria (>=10 h for 3 weekdays and 1 weekend day) was obtained for both time points. Chi-square tests were used to determine associations between compliance, group allocation, and gender. RESULTS: At baseline, 851 children had usable data, 830 (97.5%) met the minimum wear-time criteria, and 631 (74.1%) had data for 7 days at 24 hours per day. At follow-up, 789 children had usable data, 745 (94.4%) met the minimum wear-time criteria, and 528 (67%) had complete data. Compliance did not differ by gender (baseline: chi2 = 1.66, P = .2; follow-up: chi2 = 0.76, P = .4) or by group at follow-up (chi2 = 2.35, P = .13). CONCLUSION: The use of wrist-worn accelerometers and robust trial procedures resulted in high compliance at 2 time points regardless of group allocation, demonstrating the feasibility of using precise physical activity monitors to measure intervention effectiveness. PMID- 29417878 TI - Newton in China: Translating the Principia into Chinese (c. 1855-2015). AB - This paper provides an account of Chinese translations of Newton's Principia produced over the past century and a half within the larger context of the dissemination of Newtonian philosophy in China. Given its fundamental importance in the history of science, the Principia, originally penned in Latin, has been translated into a number of other languages. While in all these languages no more than two full translations have appeared, as many as four complete versions in Chinese have been produced since the 1850s, when first attempts were made to translate the Principia in late imperial China. They include a 1931 version in semi-classical Chinese completed during the Republican era and three rival versions in modern Chinese published in contemporary China. This rich history of translating the Principia into Chinese, which remains little known to scholars in the West, is for the first time reconstructed and presented in English. This account is based on a meticulous scrutiny of manuscripts, historical records, secondary literature and interviews with some of the contemporary translators. It demonstrates that Chinese translation of the Principia is a complex process that involves scientific traditions, linguistic peculiarities, translators' subjectivity, readers' expectations and even the role of the market. PMID- 29417879 TI - 'Pure' drug users, commercial sex workers and 'ordinary girls': gendered narratives of HIV risk and prevention in post-Soviet Ukraine. AB - International best practices call for a gender-responsive approach to HIV prevention for women, including those who use drugs and those who engage in sex work. This paper draws on multiple qualitative data sources collected over five years in Ukraine to explore the notions of gender, women and family that buttress HIV-related programmes for women. Our analysis reveals that service providers often cast women as hapless victims of unfortunate family circumstances and troubled personal relationships that produce sudden poverty, or social strivers who seek access to wealth and privilege at the expense of their health. Women are portrayed as most vulnerable to HIV when they lack a male 'protector'. We argue that the programmes constituted around these stereotypes of women and their vulnerabilities reflect new forms of institutional power that deflect attention away from gendered socio-economic processes that contribute to women's HIV vulnerability, including job insecurity and unemployment, workplace discrimination, unreliable social benefits and power imbalances within their relationships. We explore how to transform HIV prevention efforts to better address the causes of women's increased vulnerability to HIV in Ukraine and in Eastern Europe more generally. PMID- 29417880 TI - General self-efficacy in the Norwegian population: Differences and similarities between sociodemographic groups. AB - AIMS: General self-efficacy (GSE) refers to optimistic self-beliefs of being able to perform and control behaviors, and is linked with various physical and mental health outcomes. Measures of self-efficacy are commonly used in health research with clinical populations, but are less explored in relationship to sociodemographic characteristics in general populations. This study investigated GSE in relation to sociodemographic characteristics in the general population in Norway. METHODS: As part of a larger national survey, the GSE scale was administered to a general population sample, and 1787 out of 4961 eligible participants (response rate 36%) completed the scale. Group comparisons were conducted using independent t-tests and one-way analyses of variance. Linear regression analysis was used to examine factors independently associated with GSE. RESULTS: GSE was lower for older compared to younger participants ( p < 0.001). It was higher for men compared to women ( p < 0.001), higher for those with higher levels of education compared to those with lower levels ( p < 0.001) and higher for those in work compared to their counterparts ( p < 0.001). Controlling for all variables, male gender and employment were independently associated with higher GSE. Age moderated the associations between gender and employment on one hand, and GSE on the other. The association between being male and having higher GSE was more pronounced in younger age, as was the association between being employed and having higher GSE. CONCLUSIONS: Male gender and being employed were related to higher GSE among persons in the general population in Norway, and these associations were stronger among persons of younger age. The findings are considered fairly representative for the Norwegian population. PMID- 29417881 TI - Influencing factors and kinetic studies of imidacloprid degradation by ozonation. AB - Batch kinetic tests in ozonation of imidacloprid from water were performed in this study. The pseudo-first-order rate constant of imidacloprid degradation was increased from 0.079 to 0.326 min-1 with the increasing pH from 6.02 to 8.64 at an average ozone dose of 1.149 mg L-1. When the alkalinity was increased from 0 to 250 mg L-1 NaHCO3, the pseudo-first-order rate constants decreased from 0.121 to 0.034 min-1. These results suggested that the predominant oxidant gradually switched from ozone to hydroxyl radicals ([Formula: see text]) with the increase in solution pH. The secondary rate constant [Formula: see text] (10.92 +/- 0.12 M 1s-1) for the reaction of imidacloprid and molecular ozone was determined at pH 2.0 and in the presence of 50 mM ter-butyl alcohol (p-chlorobenzoic acid, pCBA), respectively. An indirect competition method was used to determine the secondary rate constant for [Formula: see text] oxidation of imidacloprid in the presence of pCBA as the reference compound. The rate constants [Formula: see text] were estimated to range 2.65-3.79 M-1s-1 at pH 6.02-8.64. Results obtained from this study demonstrate that ozonation appears to be an effective method to remove imidacloprid from water. PMID- 29417882 TI - Exploring the Effects of Working Memory on Time Perception in Attention Deficit Hyperactivity Disorder. AB - Children with attention deficit hyperactivity disorder (ADHD) are often reported to have deficits of time perception. However, there is a strong relation between performance on tasks of working memory and time perception. Thus, it is possible that the poor performance of children with ADHD on time perception results from their deficit of working memory. In this study, the working memory of participants was separately assessed; therefore, we could explore the relationship between working memory and time perception of children with ADHD. Fifty-six children with ADHD and those of healthy controls completed tasks measuring working memory and time perception. The results showed that the time discrimination ability of children with ADHD was poorer than that of controls. However, there was a strong association between time perception and working memory. After controlling working memory and intelligence, the time discrimination ability of children with ADHD was not significantly poorer than that of controls. We suggest that there is an interdependent relationship between time perception and working memory for children with ADHD. PMID- 29417883 TI - Patent highlights October-November 2017. AB - A snapshot of noteworthy recent developments in the patent literature of relevance to pharmaceutical and medical research and development. PMID- 29417887 TI - Calcium phosphate precipitation in nitrified wastewater from the potato processing industry. AB - Increasing environmental concerns and the awareness of the finite nature of natural resources make the valorization of waste materials to become a real challenge. The objective of the current research is to investigate the possibility of phosphate recovery as calcium phosphate salts from the wastewater from the potato-processing industry. Batch tests demonstrated that at high pH, struvite and calcium carbonate precipitations are competitive processes and that bicarbonate inhibits the precipitation of calcium phosphate salts. A biological nitrification of the wastewater removed the buffering capacity, the competitive formation of struvite and paved the way for phosphate precipitation as calcium phosphate salts as it also led to the simultaneous removal of (bi)carbonates. It is demonstrated that 75% of the phosphate precipitated as calcium phosphate at a [Ca2+]/[P] ratio of 2.5 at pH 8.5 and as such it provides a convenient alternative for the currently applied struvite processes in the agro-industrial industry. PMID- 29417888 TI - Prior art takes new shapes: relying on non-traditional prior art to invalidate a patent. PMID- 29417889 TI - Female Mate Choice Based on Male Nuptial Coloration in Pale Chub, Zacco platypus. AB - Males of many animals exhibit conspicuous secondary sexual traits, which are often the result of sexual selection. During the breeding period of the pale chub (Pisces: Cyprinidae), males show various sexual traits, such as long anal fins, breeding tubercles on the head, and/or conspicuous red and greenish-blue nuptial colorations. Although these conspicuous sexual dimorphisms and dichromatisms indicate that this can serve as a model species for understanding sexual selection, it is unclear whether these male sexual traits are related to female mate choice. This study examined the relationships between female mate choice and male sexual traits under laboratory conditions. In a dichotomous choice experiment, no relationship was found between female preference and male body size, anal fin length or number of breeding tubercles. In addition, female preference was not detected for traits related to the greenish-blue nuptial color of males. Instead, females chose males based on the degree of expression of red nuptial coloration. Such female preference may be useful for selecting high quality males with good foraging abilities or good immune function related to carotenoids and sexual hormones. The present study suggests that red nuptial coloration of the male pale chub evolved in part through female mate choice. PMID- 29417890 TI - Characterization of the Adaptive Morphology of Japanese Stream Toad (Bufo torrenticola) Using Geometric Morphometrics. AB - The order Anura (frogs and toads) is a group of amphibians and contains over 6500 extant species living in a variety of environments. Each frog species evolved body form adaptive for living and breeding in their own habitats. In Japan, four taxa of Bufo are living: Western-Japanese common toad (Bufo japonicus japonicus), Eastern-Japanese common toad (B. japonicus formosus), Miyako toad (B. gargarizans miyakonis) and Japanese stream toad (B. torrenticola). The former three taxa breed in still water as many other species of Bufo do. In contrast, B. torrenticola breeds in running water such as streams in mountainous area. Corresponding to their breeding in a stream environment, both adult and larva of B. torrenticola acquired unique morphological characters. However, few study have explored differences in the body form between B. torrenticola and closely-related Bufo species quantitatively, remaining the details about the morphological adaptation to a stream environment in this toad species poorly understood. In this study, we quantitatively compared the shape of the foot and skull between the adult male of B. torrenticola and its close relative B. j. formosus using landmark-based geometric morphometrics. Our analyses revealed that B. torrenticola has relatively longer toe phalanges with relatively larger foot webs and relatively shorter metatarsals and a narrower and more streamlined skull, compared to closely-related B. j. formosus. These morphological characteristics are considered adaptive for their breeding in mountain torrents. PMID- 29417891 TI - A Comparison of Food Habits Between Japanese Marten and Raccoon Dog in Western Tokyo with Reference to Fruit Use. AB - We studied the food habits of the Japanese marten (Martes melampus) and the raccoon dog (Nyctereutes procionoides) at the Tama Forest Science Garden, western Tokyo, Japan by fecal analysis in 2014/15. Martens were dependent on fruits throughout the year and showed less marked seasonal changes. Raccoon dogs were less dependent on fruits than martens were, and more dependent on mammals in spring, insects in summer and winter, and seeds throughout the year. Martens fed on more fruits containing tiny seeds, such as Actinidia arguta and Stachyurus praecox, whereas raccoon dogs fed on more large-seeded fruits, such as Ginkgo biloba and Diospyros kaki. Martens fed on more fruits that grew at the forest edges, whereas raccoon dogs fed on more fruits growing inside the forest. PMID- 29417892 TI - Drosophila Peptide Hormones Allatostatin A and Diuretic Hormone 31 Exhibiting Complementary Gradient Distribution in Posterior Midgut Antagonistically Regulate Midgut Senescence and Adult Lifespan. AB - Enteroendocrine cells (EEs) are evolutionarily conserved gastrointestinal secretory cells that show scattered distribution in the intestinal epithelium. These cells classified into several subtypes based on the hormones they produce in both mammals and insects. In the fruit fly Drosophila, it has been suggested that nearly equal numbers of two subtypes of EEs (Allatostatin A: AstA and Diuretic hormone 31 : Dh31) are alternately produced from the intestinal stem cells in the posterior midgut. However, we found that these two subtypes are not always present in this manner, but are rather distributed in a complementary frequency gradient along the posterior midgut. We show that midgut-preferential RNA knockdown of the peptide hormones AstA or Dh31 respectively results in decreased or increased adult lifespan. This effect on longevity is apparently correlated with the midgut senescence phenotypes as a result of direct hormone action through both hormone receptors expressed in the enteroblasts or other midgut cell types. However, gut senescence does not appear to be the direct cause for longevity regulation, as knockdown of both hormone receptors did not affect adult lifespan. Furthermore, these senescence phenotypes appear to be independent of insulin signaling and manifest in an organ-specific manner. These results indicate that the two intestinal secretory peptides antagonistically regulate adult lifespan and intestinal senescence through multiple pathways, irrespective of insulin, which implicates a complementary gradient distribution of each of the hormone-producing EEs, consistent with local requirements for cell activity along the posterior midgut. PMID- 29417893 TI - Post-Embryonic Development and Genital-Complex Formation in Three Species of Polyclad Flatworms. AB - Without the establishment of effective culturing systems, little can be known about the late developmental stages of polyclad flatworms. Here, we report a laboratory culturing system for three polyclad species: Comoplana pusilla, Notocomplana koreana, and Pseudostylochus obscurus, and we describe changes in their morphology from hatching to reproductive maturity. These species hatch out as lobe-less larvae with four eyespots, but the number of eyespots increases in later development. Cross-like and triangularly shaped larvae are observed in N. koreana and P. obscurus, respectively. After settlement, a pale area appears on the body of juveniles and then develops into the copulatory complexes. All three species could be successfully reared on brine shrimp, but only C. pusilla and N. koreana achieved reproductive maturation in such a culturing system. In P. obscurus, switching the food to the gastropod Monodonta labio induced sexual maturation. PMID- 29417894 TI - Strong Heterogeneity in Advances in Cryopreservation Techniques in the Mammalian Orders. AB - Between 1970 and 2012, vertebrate abundance has declined by 58% with an average annual decline of 2%, calling for serious action to prevent a mass extinction and an irreversible loss of biodiversity. Cryobanks and cryopreservation have the potential to assist and improve ex situ and in situ conservation strategies by storing valuable genetic material. A great deal of studies concerning cryopreservation have been performed within the class Mammalia, although no systematic overview has previously been presented. The objective of this study is therefore to evaluate the status, pattern and future of cryopreservation within Mammalia. A strong disproportional distribution of studies in examined orders is displayed. For the majority of examined orders less than 10% of species has been examined. However, the cryopreservation of germplasm has in several cases been successful and resulted in successful applications of assisted reproductive techniques (ARTs). Various obstacles are associated with the development of cryopreservation protocols, and among them the most prominent is interspecific differences in cryotolerance. Extrapolation of protocols in closely related species is considered the most applicable procedure, and a future supplement to overcome this problem is the examination and comparison of cryobiological traits. Successful protocols have been developed for the vast majority of domesticated mammals, which gives incentive for the further extrapolation of protocols in threatened species. PMID- 29417895 TI - Dumbbell-Shaped Ossicles Discovered in Pedicellaria of Flower Sea Urchins. AB - Sea urchins have a globiferous pedicellaria that stands from a test with a stalk on which lies a head made of three movable jaws with venom-injecting teeth. The globiferous pedicellariae of the flower sea urchin Toxopneustes pileolus, one of the most developed among sea urchins, are unique in that the jaws are provided with a jaw membrane that gives the pedicellaria an appearance of a flower when the jaws are open. We observed this membrane in an ionic liquid that does not require processes, such as fixation, dehydration, or coating with conductive materials, for observation with a scanning electron microscope. Using this technique, we discovered dumbbell-shaped ossicles, which consist of two spheres of similar size connected by a cylinder. The diameter of the sphere is 4-8 um, and the total length of the ossicle is 10-20 um. The jaw membrane is trimmed with an edge zone. The ossicles were found sparsely in the connective tissue of general part of the membrane, but in the edge zone their density was so high that neighboring ossicles were in close contact with each other. Some neighboring ossicles crossed their cylinders and some inserted one of their spheres to snugly fit in the gap between the spheres of neighboring ossicles. Their structural role is very likely in strengthening the jaw membrane, probably serving as fillers in the general part of the membrane; in the edge zone the interlocking of adjacent ossicles forms a loose network providing a firm frame for the head of the globiferous pedicellaria. When opened, the stiff frame prevents the membrane from sagging. When clasped, it works as a closed door, firmly keeping prey trapped. PMID- 29417896 TI - Reflectance Spectra of Peacock Feathers and the Turning Angles of Melanin Rods in Barbules. AB - I analyzed the association between the reflectance spectra and melanin rod arrangement in barbules of the eyespot of peacock feathers. The reflectance spectra from the yellow-green feather of the eyespot indicated double peaks of 430 and 540 nm. The maximum reflectance spectrum of the blue feather was 480 nm, and that of the dark blue feather was 420 nm. The reflectance spectra from brown feathers indicated double peaks of 490 and 610 nm. Transmission electron microscopic analysis confirmed that melanin rods were arranged fanwise in the outer layer toward the barbule tips. In addition, using polarized light microscope, I attempted to determine whether the turning angles of melanin rods in the barbules reflected different colors. The turning angle of the polarizing axis of the barbules was supported by that of the melanin rods, observed using transmission electron microscopic images. To compare the turning angle of melanin rods in the respective barbules, I calculated the opening width of the fanwise melanin rods by dividing the width of the barbules by the turning angle of the polarizing axis of barbules and obtained a positive correlation between the reflectance spectra and opening width of the fanwise melanin rods. Moreover, the widely spreading reflection from the barbules may occur because of the fanwise melanin rod arrangement. PMID- 29417897 TI - Two New Species of Ansonia from Thailand (Anura: Bufonidae). AB - The taxonomic status of two populations of stream toads of the genus Ansonia from Thailand, previously suspected to be specifically distinct on the basis of molecular data, are assessed using morphological and additional genetic data. In mtDNA phylogeny, each of the two Thai lineages, one from Pilok Subdistrict, Kanchanaburi, and another from Phuket Island, are separated from other congenerics from the Thai-Malay Peninsula by large genetic distances, comparable with those observed between other species in the genus. Although each of the two lineages is superficially similar to other species morphologically, they are distinguishable in several morphological traits and are considered to represent valid, independently evolving species. We therefore describe them as A. pilokensis sp. nov. and A. phuketensis sp. nov. PMID- 29417898 TI - Food and Feeding Habits of Gaur (Bos gaurus) in Highlands of Central India: A Case Study at Pench Tiger Reserve, Madhya Pradesh (India). AB - Indian gaur (Bos gaurus) is one of nine species of wild oxen found in the world. They are largely confined to evergreen, semi-evergreen, and moist deciduous forests, but also occur in dry deciduous forest areas at the periphery of their range. According to the IUCN Red List ( 2017 ), the estimated population of gaur in India is between 15,000 and 35,000 individuals, and probably due to this, despite the gaur's vast range of distribution, they are listed as a vulnerable species by IUCN and listed as schedule-I of the Indian Wildlife Protection Act ( 1972 ) as well as in appendix-I in CITES ( 2003 ). Gaur is not a well studied species, and baseline data are thus needed to support conservation efforts. We studied the feeding habits of gaur in Pench Tiger Reserve. Pench Tiger Reserve is the 19th tiger reserve in India, situated in the Seoni and Chhindwara districts of MP, India (21 degrees 41'35"N 79 degrees 14'54"E). Diet composition of gaur was studied by micro-histological examination of 32 dung piles collected from different sampling plots in different seasons. For this purpose, 169 sampling plots were established at an interval of 200 m. To locate gaur faecal matter, a circular plot of 10 m radius was laid within each sampling plot. Eighty-eight permanent reference slides of available plants were prepared and used for plant fragment identification from the dung piles. A total of 29 plant species were identified from dung piles of gaur. On average, 44.51% of grass-fragments were detected in the diet of gaur, suggesting that gaurs are primarily grazers in the Pench Tiger Reserve. PMID- 29417899 TI - Maternal Effects Via Resting eggs in Predator Defense of the Rotifer Brachionus calyciflorus. AB - Maternal effects play important evolutionary and ecological roles. Amictic female mothers of monogonont rotifer Brachionus calyciflorus can transmit predatory information of Asplanchna brightwellii in their environment to their offspring by changing the offspring's defensive morphology to increase their fitness. However, it remains unclear whether such maternal effects also exist during sexual reproduction of a mictic mother. This study explored the maternal effect in mictic mothers using the B. calyciflorus and A. brightwellii as a prey-predator model. We collected resting eggs from two groups of mictic mothers that previously experienced environments with (P environment) or without (NP environment) Asplanchna kairomones. Stem females from the resting eggs of each maternal group were also hatched and reared in P and NP environments. The population growth rate of offspring who experienced the same environment as their mictic mothers was significantly higher than those that experienced a different environment. When exposed to a gradient of predator kairomone levels, the posterolateral spine of the offspring elongated with increasing kairomone concentration. Offspring from the P mictic mother showed significantly shorter posterolateral spines than those from the NP mictic mother at each predator kairomone level. Offspring originating from NP mictic mothers clearly elongated their posterolateral spines at low concentrations of predator kairomones, while those from P mothers elongated their posterolateral spines only at the highest levels of predator kairomone. Our findings highlight the existence of anticipatory maternal effects during the sexual process via resting eggs of B. calyciflorus in response to predator kairomone. PMID- 29417900 TI - Catalytic gasification of phenol in supercritical water over bimetallic Co-Ni/AC catalyst. AB - Solid-solution bimetallic alloy catalysts containing no noble metals were developed via both simultaneous and sequential deposition in supercritical water (SCW). These bimetallic nano-catalysts were analyzed by Brunauer-Emmett-Teller, X ray diffraction, X-ray photoelectron spectroscopy and transmission electron microscopy. Obvious downward shifts are observed in diffraction peaks, situated between the peak (1 1 1) for Co and the peak (1 1 1) for Ni. The shifts indicate the formation of NiCo solid-solution bimetallic alloy(s). The bimetallic nanoparticles show high activity for supercritical water gasification of phenol to produce gaseous fuels. The carbon gasification efficiency (CGE) of phenol in SCW can reach 95% on the Co-Ni/AC catalyst at conditions of 500 degrees C and 30 min, showing nearly the same CGE as the commercial noble-metal-based catalyst, such as Ru/C (5 wt% Ru) from Sigma-Aldrich. The Co-Ni/AC catalyst also shows high stability. Therefore, deposition in SCW provides an effective way to create noble metal-free solid-solution bimetallic alloy catalysts. PMID- 29417901 TI - Editorial - Tribute to Neville Moray (1935-2017) - Ergonomics and Global Issues. PMID- 29417902 TI - Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections. AB - AIM: This study aimed to evaluate the safety and therapeutic potential of autologous human adipose-derived mesenchymal stem cells (haMSCs) in patients with osteoarthritis. MATERIALS & METHODS: Safety and efficacy of haMSCs were preclinically assessed in vitro and in BALB/c-nu nude mice. 18 patients were enrolled and divided into three dose groups: the low-dose, mid-dose and high-dose group (1 * 107, 2 * 107 and 5 * 107 cells, respectively), provided three injections and followed up for 96 weeks. RESULTS & CONCLUSION: The preclinical study established the safety and efficacy of haMSCs. Intra-articular injections of haMSCs were safe and improved pain, function and cartilage volume of the knee joint, rendering them a promising novel treatment for knee osteoarthritis. The dosage of 5 * 107 haMSCs exhibited the highest improvement (ClinicalTrials.gov Identifier: NCT01809769). PMID- 29417903 TI - [The Role of Internet Parenting for the Internet use of Children in Pre-, Primary and Secondary School]. AB - The Role of Internet Parenting for the Internet use of Children in Pre-, Primary and Secondary School The present study analyzes the relationship between mothers' and fathers' Internet parenting and children's Internet use across different age groups (1-15 years). Especially, we looked at the influencing factors of parental mediation strategies and the interplay of mothers' and fathers' Internet parenting. Based on data of the DJI-survey "Growing up in Germany" (Aufwachsen in Deutschland: Alltagswelten, AID:A II 2015, N = 1,196), dyadic structural equation models have shown that across all age groups shared parent-child online activities were important influencing factors of regulating the children's Internet use. Also, the self-perceived Internet education competence of mothers and fathers has been confirmed as a relevant factor influencing a more intense use of parental mediation strategies for school-aged children. While the amount of Internet use among young children (1-6 years) was exclusively influenced by features and strategies of mothers' Internet parenting, the transition to elementary school not only marked changes in the frequency of children's Internet use, but also in the ICT parenting of mothers and fathers. For school-aged children, we indeed found an influence of fathers as well as, in case of the oldest age group, a reduced use of parental mediation strategies. However, parents' attitudes, competences and strategies regarding Internet parenting still stayed important during adolescence. PMID- 29417904 TI - [Adolescent Use of Digital Media and Parental Mediation - A Research Review]. AB - Adolescent Use of Digital Media and Parental Mediation - A Research Review Digital media are wide spread, frequently used, and highly relevant in the lives of children, adolescents and their parents. Because parents aim to reduce or prevent potential risks of media use for their children, many parents apply different strategies of parental mediation of children's media use: restrictive parental mediation, active parental mediation, co-media use, technical monitoring, and participatory learning. These forms of parental mediation have differential impact on children and adolescents. Different types of media (e. g. television, video games, internet, and mobile phones) have common features but also specific characteristics that lead to partially inconsistent research findings that are not only due to age differences of children and adolescents. Concerning an impact model of parental mediation, the current contribution presents overarching and divergent empirical findings, approaches the effectiveness of parental mediation for cyberbullying, and discusses practical implications as well as research gaps in the analysis of parental mediation. PMID- 29417906 TI - [Editorial]. PMID- 29417907 TI - [Interrelations Between Adolescent Problematic Internet Use and Parental Internet Mediation]. AB - Interrelations Between Adolescent Problematic Internet Use and Parental Internet Mediation Everyday life of adolescents and their parents is increasingly characterized by digital media usage (also referred to as "process of mediatization"). In the current study, associations between problematic Internet use of the adolescents (as a possible consequence of the process of mediatization) and parental media education were explored. For this purpose, throughout Germany 1,095 family dyads (an adolescent and a related parent) were investigated with a standardized questionnaire measuring different aspects of parental media education and adolescent problematic Internet use. We conducted two multiple linear regression analyses (dimensional approach) with adolescent problematic Internet use based on self-ratings (model 1, corrected R2 = 0.18) and parental assessment (model 2, corrected R2 = 0.24) as response variables. Consistently for self- and parental ratings, adolescent problematic Internet use was statistically significant related to male gender (of the adolescent), a more frequent inconsistent media education (adolescents' and parents' perspective) and a stronger monitoring (parents' perspective). Additionally, we observed associations between the parental rating of adolescent problematic Internet use and a less frequent active and restrictive Internet Mediation (parents' perspective). The findings of the present study show the importance of parental media education for problematic Internet use in adolescence and especially, the role of inconsistent media education should be investigated again in further studies. PMID- 29417912 TI - [Friend or Foe in the Pocket? - The Role of the Individual, Peergroup and Parents for (dys)functional Mobile Phone Use]. AB - Friend or Foe in the Pocket? - The Role of the Individual, Peergroup and Parents for (dys)functional Mobile Phone Use In order to provide consultative support to parents as well as to children and young people, background knowledge regarding the motives of mobile phone use, functions of usage, comprehension of the attraction of this all-round medium also as knowledge about potential hazards are essential. This study offers empirical results about potentials and risks. The peergroup plays an important role for riskful and problematic mobile phone involvement. Parents function as a role model and the explicit parental mediation practices and their impact on the child are in focus. Data was acquired from a quota-sample survey with 500 children between the age of 8 and 14 years and one of their parents, qualitative interviews (20 children and their parents) and eight peergroup-discussions (52 participants). The present paper illuminates the above mentioned aspects and derives implications for guidance practice. PMID- 29417913 TI - [Parents' and Children's Perspectives of Parental Mediation Strategies in Association with Children's Internet Skills]. AB - Parents' and Children's Perspectives of Parental Mediation Strategies in Association with Children's Internet Skills The purpose of this study was to examine the association of parental mediation strategies (from parents' and children's perspective) and children's internet skills. In total 194 parent-child dyads were questioned about their parent's mediation strategies. The children (fifth to ninth grade) additionally answered questions about their internet skills and the amount of time they spent daily on the internet. Parents' and children's ratings of the parental mediation strategies showed moderate associations. Parents reported to use more often mediation strategies than was perceived by their children. The mediation strategies had only limited value for the prediction of the children's internet skills. Parents' and children's perspective about restrictive content mediation were both negatively associated to children's internet skills. After controlling for children's age, sex and time spent daily on the internet, results showed that only congruencies between children's and parental perspectives regarding the parental restrictive content mediation were associated with decreased technical and social internet skills. Additionally, discrepancies between the children's and parental perspectives regarding the parental use of technical mediation were associated with decreased technical internet skills. Discrepancies regarding the parental mediation strategy monitoring were related to increased information navigation skills. PMID- 29417914 TI - Primary care practitioner perceptions and attitudes of complementary medicine: a content analysis of free-text responses from a survey of non-metropolitan Australian general practitioners. AB - : AimThis study examines GP perceptions, attitudes and knowledge of complementary medicine (CM), and to understand contextual factors that influence these perceptions, attitudes and knowledge. BACKGROUND: CM use is increasing, and its influence on primary care becoming increasingly significant. Although general practitioners (GPs) often have central primary care gate-keeper roles within health systems, few studies have looked specifically at GPs' perceptions, attitudes and knowledge of CM. METHODS: A questionnaire was mailed to all 1486 GPs registered as practicing in non-metropolitan areas of New South Wales. The survey included one free-text qualitative question, where respondents were invited to highlight issues associated with CM in their own words. Free-text responses were analyzed qualitatively using thematic analysis.FindingsIn total, 585 GPs responded to the survey (adjusted response rate 40.1%), with 152 (26.0%) filling in the free-text question. Central themes which emerged were risk as a primary concern; opposition to, resistance to and the inappropriateness of complementary therapies; struggles with complexity and ambivalent tolerance. CONCLUSION: GPs in Australia have a wide variety of perceptions toward CM. A minority of GPs have absolute views on CM, with most GPs having numerous caveats and qualifications of individual CM. Efficacy is only one aspect of CM critically evaluated by GPs when gauging support for individual therapies - risk, alignment with medical principles and an openness to exploring new avenues of treatment where others have failed, all appear to be equally important considerations when GPs form their views around CM. PMID- 29417915 TI - Competition in health care: lessons from the English experience. AB - The use of competition and the associated increase in choice in health care is a popular reform model, adopted by many governments across the world. Yet it is also a hotly contested model, with opponents seeing it, at best, as a diversion of energy or a luxury and, at worst, as leading to health care inequality and waste. This paper subjects the use of competition in health care to scrutiny. It begins by examining the theoretical case and then argues that only by looking at evidence can we understand what works and when. The body of the paper examines the evidence for England. For 25 years the United Kingdom has been subject to a series of policy changes which exogenously introduced and then downplayed the use of competition in health care. This makes England a very useful test bed. The paper presents the UK reforms and then discusses the evidence of their impact, examining changes in outcomes, including quality, productivity and the effect on the distribution of health care resources across socio-economic groups. The final section reflects on what can be learnt from these findings. PMID- 29417916 TI - Prestige Asymmetry in American Physics: Aspirations, Applications, and the Purloined Letter Effect. AB - Argument Why do similar scientific enterprises garner unequal public approbation? High energy physics attracted considerable attention in the late-twentieth century United States, whereas condensed matter physics - which occupied the greater proportion of US physicists - remained little known to the public, despite its relevance to ubiquitous consumer technologies. This paper supplements existing accounts of this much remarked-upon prestige asymmetry by showing that popular emphasis on the mundane technological offshoots of condensed matter physics and its focus on human-scale phenomena have rendered it more recondite than its better-known sibling field. News reports about high energy physics emphasize intellectual achievement; reporting on condensed matter physics focuses on technology. And whereas frontier-oriented rhetoric of high energy physics communicates ideals of human potential, discoveries that smack of the mundane highlight human limitations and fail to resonate with the widespread aspirational vision of science - a consequence I call "the purloined letter effect." PMID- 29417917 TI - Disciplining Physiological Psychology: Cinematographs as Epistemic Devices in the Work of Henri Bergson and Charles Scott Sherrington. AB - Argument This paper arrives at a normative position regarding the relevance of Henri Bergson's philosophy to historical enquiry. It does so via experimental historical analysis of the adaptation of cinematographic devices to physiological investigation. Bergson's philosophy accorded well with a mode of physiological psychology in which claims relating to mental and physiological existence interacted. Notably however, cinematograph-centered experimentation by British physiologists including Charles Scott Sherrington, as well as German-trained psychologists such as Hugo Munsterberg and Max Wertheimer, contributed to a cordoning-off of psychological from physiological questioning during the early twentieth century. Bergson invested in a mode of intellectual practice in which psychological claims had direct relevance to the interpretation of physiological nature. The in-part cinematograph-inspired breakdown of this mode had significance for subsequent interpretations of his philosophy. It is suggested that this experimental particularization of Bergson's contentions indicates that any adaptation of his thought for historical enquiry must be disciplinarily specific. PMID- 29417918 TI - Ruggiero Boscovich and "the Forces Existing in Nature". AB - Argument According to a long-standing interpretation which traces back to Max Jammer's Concepts of Force (1957), Ruggiero G. Boscovich would have developed a concept of force in the tradition of Leibniz's dynamics. In his variation on the theme, basic properties of matter such as solidity or impenetrability would be derived from an interplay of some "active" force of attraction and repulsion that any primary element of nature ("point of matter" in Boscovich's theory) would possess. In the present paper I discuss many flaws of this interpretation and argue for an alternative point of view, according to which the crucial aspect in the development of Boscovich's natural philosophy is his early definition of forces as "mathematical determinations" to have a certain state of motion. This is consistent with a Newtonian background and has as its epistemological consequence a certain agnosticism about the nature of forces and a "mathematical neutralism" (mathematics as a neutral tool, allowing for a plurality of interpretations). PMID- 29417919 TI - Multistate Outbreak of an Emerging Burkholderia cepacia Complex Strain Associated With Contaminated Oral Liquid Docusate Sodium. PMID- 29417920 TI - Emergency Airway Management in a Simulation of Highly Contagious Isolated Patients: Both Isolation Strategy and Device Type Matter. AB - OBJECTIVE To compare 6 airway-management devices in 3 isolation scenarios regarding their effect on airway management: portable isolation unit (PIU), personal protective equipment (PPE), and standard protection measures METHODS In total, 30 anesthesiologists working in emergency medical services performed airway management on mannequins in 3 isolation settings using 6 different airway management devices (in random order): (1) standard Macintosh laryngoscope; (2) Airtraq SP-video-laryngoscope; (3) i-gel; (4) LMA-Fastrach; (5) Ambu fiberoptic aScope; and (6) Melker cricothyrotomy-set. Each was assessed regarding time-to ventilate (primary outcome) and rating of difficulty handling the device. RESULTS In 86% (standard protection) and 85% (PPE) of attempts, airway management was achieved in <60 seconds, irrespective of the device used. In the PIU setting, only 69% of attempts succeeded within this time frame (P<.05). Median time-to ventilate was shorter for standard protection (23 seconds) and PPE (25 seconds) compared to the PIU (38 seconds; P<.001). In the PIU setting, the fiberscope took the longest (median, 170 seconds), while i-gel was the quickest (median, 13 seconds). The rating of difficulty (visual analogue scale [VAS], 0-100) differed significantly between the isolation scenarios: Airway management was most difficult with PIU (VAS, 76), followed by PPE (VAS, 35), and standard protection (VAS, 9) (P<.01). CONCLUSION Wearing PPE produced similar times-to-ventilate as standard protection among anesthesiologists, but it was subjectively rated more difficult. The portable isolation unit permitted acceptable times-to-ventilate when excluding fiberscope and cricothyrotomy. Supraglottic airway devices allowed the fastest airway management in all isolation scenarios, thus being highly recommendable if a portable isolation unit is used and emergency airway management becomes necessary. Infect Control Hosp Epidemiol 2018;39:145-151. PMID- 29417921 TI - Setting a Research Agenda in Prevention of Healthcare-Associated Infections (HAIs) and Multidrug-Resistant Organisms (MDROs) Outside of Acute Care Settings. PMID- 29417922 TI - Quasi-experimental Studies in the Fields of Infection Control and Antibiotic Resistance, Ten Years Later: A Systematic Review. AB - OBJECTIVE A systematic review of quasi-experimental studies in the field of infectious diseases was published in 2005. The aim of this study was to assess improvements in the design and reporting of quasi-experiments 10 years after the initial review. We also aimed to report the statistical methods used to analyze quasi-experimental data. DESIGN Systematic review of articles published from January 1, 2013, to December 31, 2014, in 4 major infectious disease journals. METHODS Quasi-experimental studies focused on infection control and antibiotic resistance were identified and classified based on 4 criteria: (1) type of quasi experimental design used, (2) justification of the use of the design, (3) use of correct nomenclature to describe the design, and (4) statistical methods used. RESULTS Of 2,600 articles, 173 (7%) featured a quasi-experimental design, compared to 73 of 2,320 articles (3%) in the previous review (P<.01). Moreover, 21 articles (12%) utilized a study design with a control group; 6 (3.5%) justified the use of a quasi-experimental design; and 68 (39%) identified their design using the correct nomenclature. In addition, 2-group statistical tests were used in 75 studies (43%); 58 studies (34%) used standard regression analysis; 18 (10%) used segmented regression analysis; 7 (4%) used standard time series analysis; 5 (3%) used segmented time-series analysis; and 10 (6%) did not utilize statistical methods for comparisons. CONCLUSIONS While some progress occurred over the decade, it is crucial to continue improving the design and reporting of quasi-experimental studies in the fields of infection control and antibiotic resistance to better evaluate the effectiveness of important interventions. Infect Control Hosp Epidemiol 2018;39:170-176. PMID- 29417923 TI - A Bundle of Measures to Control an Outbreak of Pseudomonas aeruginosa Associated With P-Trap Contamination. AB - OBJECTIVE To describe an outbreak of multidrug-resistant Pseudomonas aeruginosa in which the hospital waste-pipe system was the likely source of contamination and to report the bundle of measures that facilitated the long-term control of the outbreak. DESIGN Outbreak investigation. SETTING The hematology unit of a tertiary-care referral center. PATIENTS Patients who were colonized or infected with P. aeruginosa belonging to the clonal outbreak. METHODS Patients admitted to our 15-bed stem-cell transplantation hematology unit were screened for P. aeruginosa carriage. Pseudomonas aeruginosa isolates were also obtained from diagnostic samples. We assessed the microbiological contamination of P-traps, water and toilets for 42 months. Extended-spectrum beta-lactamases (ESBLs) and metallo-beta-lactamases (MBLs) were screened and identified by polymerase chain reaction (PCR) and sequencing. Molecular typing of ESBL- or MBL-producing isolates was carried out using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). RESULTS From 2009 to 2013, a biclonal outbreak of IMP-19-producing ST235 (11 cases) and IMP-29-producing ST111 (10 cases) of P. aeruginosa occurred. The environmental investigation strongly suggested that P traps were the reservoirs for the outbreak strains. A bundle of infection control measures, including engineering interventions on water outlets and disinfection of P-traps, controlled the outbreak. CONCLUSIONS We report a prolonged outbreak of IMP-producing high-risk clones of P. aeruginosa, for which P-traps seems to play a major role in cross-transmission. It appears essential to implement proactive measures to limit the bacterial load in water fittings of high-risk units. Infect Control Hosp Epidemiol 2018;39:164-169. PMID- 29417924 TI - Research Agenda for Microbiome Based Research for Multidrug-resistant Organism Prevention in the Veterans Health Administration System. PMID- 29417925 TI - Research Agenda for Antimicrobial Stewardship in the Veterans Health Administration. PMID- 29417926 TI - Setting the Research Agenda for Preventing Infections From Multidrug-Resistant Organisms in the Veterans Health Administration. PMID- 29417927 TI - Establishing a Research Agenda for Preventing Transmission of Multidrug-Resistant Organisms in Acute-Care Settings in the Veterans Health Administration. PMID- 29417928 TI - S. aureus Infections in Chicago, 2006-2014: Increase in CA MSSA and Decrease in MRSA Incidence - ERRATUM. PMID- 29417929 TI - Challenges in validating candidate therapeutic targets in cancer. AB - More than 30 published articles have suggested that a protein kinase called MELK is an attractive therapeutic target in human cancer, but three recent reports describe compelling evidence that it is not. These reports highlight the caveats associated with some of the research tools that are commonly used to validate candidate therapeutic targets in cancer research. PMID- 29417931 TI - 3D printed Lego(r)-like modular microfluidic devices based on capillary driving. AB - The field of how to rapidly assemble microfluidics with modular components continuously attracts researchers' attention, however, extra efforts must be devoted to solving the problems of leaking and aligning between individual modules. This paper presents a novel type of modular microfluidic device, driven by capillary force. There is no necessity for a strict seal or special alignment, and its open structures make it easy to integrate various stents and reactants. The key rationale for this method is to print different functional modules with a low-cost three-dimensional (3D) printer, then fill the channels with capillary materials and assemble them with plugs like Lego(r) bricks. This rapidly reconstructed modular microfluidic device consists of a variety of common functional modules and other personalized modules, each module having a unified standard interface for easy assembly. As it can be printed by a desktop 3D printer, the manufacturing process is simple and efficient, with controllable regulation of the flow channel scale. Through diverse combinations of different modules, a variety of different functions can be achieved, without duplicating the manufacturing process. A single module can also be taken out for testing and analysis. What's more, combined with basic circuit components, it can serve as a low-cost Lego(r)-like modular microfluidic circuits. As a proof of concept, the modular microfluidic device has been successfully demonstrated and used for stent degradation and cell cultures, revealing the potential use of this method in both chemical and biological research. PMID- 29417932 TI - Stepped surfaces. PMID- 29417930 TI - MELK expression correlates with tumor mitotic activity but is not required for cancer growth. AB - The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (Lin et al., 2017). Here, we generate several additional knockout clones of MELK and demonstrate that across cancer types, cells lacking MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. By combining our MELK-knockout clones with a recently described, highly specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies. PMID- 29417933 TI - Completely flat 2D Zn3O2 monolayer with triangle and pentangle coordinated networks. AB - Two-dimensional (2D) materials with strictly planar hyper-coordinated motifs are of great importance in fundamental science and potential applications but extremely rare. Here we theoretically design a novel 2D IIB-VIA inorganic system, namely Zn3O2 monolayer, by comprehensive first-principles computations. This Zn3O2 monolayer is composed from highly symmetrical tri-coordinated oxygen and tetra-coordinated zinc, featuring planar and peculiar triangle and pentangle combined bonded network. The newly predicted Zn3O2 monolayer possesses excellent dynamic and thermal stabilities and is also the lowest-energy structure of its 2D space indicated by particle swarm search, supporting its experimentally synthetic viability. A relatively wide band gap of 4.46 eV means it has potential applications in electronics and optoelectronics. The present findings provide a new field of hyper-coordinated 2D nanomaterials for study. PMID- 29417934 TI - Functionalized thermosensitive hydrogel combined with tendon stem/progenitor cells as injectable cell delivery carrier for tendon tissue engineering. AB - Thermosensitive hydrogels have been studied for potential application as promising alternative cell carriers in cell-based regenerative therapies. In this study, a thermosensitive butane diisocyanate (BDI)-collagen hydrogel (BC hydrogel) was designed as an injectable cell delivery carrier of tendon stem/progenitor cells (TSPCs) for tendon tissue engineering. We functionalized the BDI hydrogel with the addition of 20% (v/v) collagen I gel to obtain the thermosensitive BC hydrogel, which was then seeded with TSPCs derived from human Achilles tendons. The BC hydrogel compatibility and TSPC behavior and molecular response to the 3D hydrogel were investigated. Collagen (COL) I gel served as a control group. Our findings demonstrated that the BC hydrogel was thermosensitive, and hardened above 25 degrees C. It supported TSPC survival, proliferation, and metabolic activity with satisfactory dimension stability and biocompatibility, as revealed by gel contraction assay, live/dead staining, DNA quantification, and resazurin metabolic assay. Phalloidin-based visualization of F-actin demonstrated that the TSPCs were stretched within COL I gel with classical spindle cell shapes; similar cell morphologies were also found in the BC hydrogel. The gene expression profile of TSPCs in the BC hydrogel was comparable with that in COL I gel. Moreover, the BC hydrogel supported capillary like structure formation by human umbilical vein endothelial cells (HUVECs) in the hydrogel matrix. Taken together, these results suggest that the thermosensitive BC hydrogel holds great potential as an injectable cell delivery carrier of TSPCs for tendon tissue engineering. PMID- 29417935 TI - Hydroxysafflor-Yellow A Induces Human Gastric Carcinoma BGC-823 Cell Apoptosis by Activating Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma). AB - BACKGROUND Anti-tumor properties of hydroxysafflor-yellow A (HSYA) have been recently revealed, as a series of apoptotic factors were confirmed to be regulated by HSYA and associated with peroxisome proliferator-activated receptor Gamma (PPARgamma). In this study, we investigated the cell apoptosis mechanism of HSYA via activated PPARgamma signal in human gastric carcinoma cells. MATERIAL AND METHODS BGC-823 cells were cultured and divided into 5 independent groups: Tumor, HSYA, HSYA+PPARgamma inhibitor (GW9662), and PPARg agonist (RGZ), RGZ+GW9662. Cell proliferative activity was measured by MTT. Apoptosis and cell cycle were detected by flow cytometry. The nuclear translocation of PPARgamma was detected by immunofluorescence staining chemistry, and mRNA levels of PPARgamma and caspase-3 were measured by real-time qPCR. RESULTS Compared to the RGZ group, the HSYA group (100 uM) showed a similar inhibitory effect on the proliferation process of BGC-823 cells, inducing their apoptosis. As a result, the transition of BGC-823 cells from G0/G1 phase to S phase was blocked. HSYA was also found to promote the nuclear translocation of PPARgamma, leading to increased expression of PPARgamma and caspase-3. The regulatory effect of HSYA on BGC-823 cells could be further inhibited by PPARgamma inhibitor in group GW9662. CONCLUSIONS We report the inhibitory effect of HSYA on the proliferation of BGC-823 cells, which results in activating PPARg-dependent cell cycle blocking and cell apoptosis, suggesting that PPARg is a specific type of HSYA that can induce apoptosis of BGC 823 cells. PMID- 29417936 TI - Rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at the least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation. In this Primer, we discuss the epidemiology, pathophysiology, diagnosis and management of RA. PMID- 29417938 TI - Rheology and the Eye: blood, tears and other humours. PMID- 29417937 TI - Advances in lipid-lowering therapy through gene-silencing technologies. AB - New treatment opportunities are emerging in the field of lipid-lowering therapy through gene-silencing approaches. Both antisense oligonucleotide inhibition and small interfering RNA technology aim to degrade gene mRNA transcripts to reduce protein production and plasma lipoprotein levels. Elevated levels of LDL, remnant lipoproteins, and lipoprotein(a) all cause cardiovascular disease, whereas elevated levels of triglyceride-rich lipoproteins in some patients can cause acute pancreatitis. The levels of each of these lipoproteins can be reduced using gene-silencing therapies by targeting proteins that have an important role in lipoprotein production or removal (for example, the protein products of ANGPTL3, APOB, APOC3, LPA, and PCSK9). Using this technology, plasma levels of these lipoproteins can be reduced by 50-90% with 2-12 injections per year; such dramatic reductions are likely to reduce the incidence of cardiovascular disease or acute pancreatitis in at-risk patients. The reported adverse effects of these new therapies include injection-site reactions, flu-like symptoms, and low blood platelet counts. However, newer-generation drugs are more efficiently delivered to liver cells, requiring lower drug doses, which leads to fewer adverse effects. Although these findings are promising, robust evidence of cardiovascular disease reduction and long-term safety is needed before these gene-silencing technologies can have widespread implementation. Before the availability of such evidence, these drugs might have roles in patients with unmet medical needs through orphan indications. PMID- 29417939 TI - Apolipoprotein J as a predictive biomarker for restenosis after carotid endarterectomy: a retrospective study. AB - Carotid endarterectomy (CEA) is an effective surgical option for stroke prophylaxis in most patients. Restenosis after CEA can lead to re-intervention and adverse events, but the factors predicting restenosis are poorly understood. Apolipoprotein J (ApoJ) is considered to be a novel predictive factor of vascular restenosis and is associated with a large number of processes related to atherosclerosis and cell-cycle phases. The aim of this study was to elucidate the predictive value of Apo J in internal carotid artery (ICA) restenosis following CEA. This retrospective study examined all prospectively collected data for patients who underwent CEA at our surgical department over a 2-year period. The serum ApoJ levels of 100 patients were examined; 56 patients who underwent CEA comprised the vascular group (VG), and 44 patients who underwent minor surgery comprised the control group (CG). ApoJ samples were obtained preoperatively, 24 h after the surgical procedure and at 1, 6 and 12 months thereafter during the follow-up. The preoperative difference in ApoJ levels between the CG and VG was statistically signifcant; the mean values were 39.11+/-14.16 and 83.03+/-35.35 MUg/mL, respectively. In the VG, the serum ApoJ levels were 112.09+/-54.40, 71.20+/-23.70, 69.92+/-25.76 and 62.25+/-19.17 MUg/mL at postoperative day 1 and at 1, 6 and 12 months post-operatively, respectively, while the ApoJ concentrations of patients in the CG remained unchanged. Further subdivision of the VG into patients with or without restenosis revealed that restenosis patients presented signifcantly higher mean ApoJ values than non-restenosis VG patients. In summary, ApoJ seems to be an important predictor for carotid restenosis at 6 and 12 months postoperatively. PMID- 29417940 TI - Inverse changes in plasma tetranectin and titin levels in patients with type 2 diabetes mellitus: a potential predictor of acute myocardial infarction? AB - An early intervention using biomarkers to predict acute myocardial infarction (AMI) will effectively reduce global heart attack incidence, particularly among high-risk patients with type 2 diabetes mellitus (T2DM). This study attempted to identify potential biomarkers by detecting changes in the levels of plasma proteins in T2DM patients following onset of AMI in comparison with those without AMI. Volunteer T2DM patients without AMI (control; n=10) and T2DM patients with AMI (n=10) were recruited. Plasma samples from these patients were evaluated via two-dimensional gel electrophoresis (2DE) to screen for proteins with level changes between the two groups. The abundance of spots on gel images was analyzed using Progenesis SameSpots and subjected to false discovery rate (FDR) analysis. Protein spots with statistically significant changes of at least 1.5 fold were selected for mass spectrometry (MS) analysis. Due to strong cardiac connections, tetranectin and titin were evaluated by enzymelinked immunosorbent assay (ELISA). The adjusted P-values and fold changes between the two groups resulted in identification of 34 protein spots with significantly altered abundance. Upon MS analysis, 17 plasma proteins were identified: tetranectin, titin, clusterin, haptoglobin, myosin-13, zinc fnger protein 445, DNA repair protein RAD50, serum albumin, apolipoprotein A-IV, caspase-6, aminoacyl tRNA synthase complex interacting multifunctional protein 1, serotransferrin, retinol-binding protein 4, transthyretin, alpha-1-antitrypsin, apolipoprotein A-I and serum amyloid A. Comparable patterns of changes in tetranectin and titin between the control and AMI groups were confirmed using ELISA. In summary, tetranectin and titin in plasma appeared to be closely associated with the onset of AMI among T2DM patients and can be used as potential biomarkers for prediction of a cardiac event, though this requires validation in a prospective cohort study. PMID- 29417941 TI - CTC clusters induced by heparanase enhance breast cancer metastasis. AB - Aggregated metastatic cancer cells, referred to as circulating tumor cell (CTC) clusters, are present in the blood of cancer patients and contribute to cancer metastasis. However, the origin of CTC clusters, especially intravascular aggregates, remains unknown. Here, we employ suspension culture methods to mimic CTC cluster formation in the circulation of breast cancer patients. CTC clusters generated using these methods exhibited an increased metastatic potential that was defined by the overexpression of heparanase (HPSE). Heparanase induced FAK- and ICAM-1-dependent cell adhesion, which promoted intravascular cell aggregation. Moreover, knockdown of heparanase or inhibition of its activity with JG6, a heparanase inhibitor, was sufficient to block the formation of cell clusters and suppress breast cancer metastasis. Our data reveal that heparanase mediated cell adhesion is critical for metastasis mediated by intravascular CTC clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression. PMID- 29417942 TI - Full genetic analysis for genome-wide association study of Fangji: a powerful approach for effectively dissecting the molecular architecture of personalized traditional Chinese medicine. AB - Elucidation of the systems biology foundation underlying the effect of Fangji, which are multi-herbal traditional Chinese medicine (TCM) formulas, is one of the major aims in the field. The numerous bioactive ingredients of a Fangji deal with the multiple targets of a complex disease, which is influenced by a number of genes and their interactions with the environment. Genome-wide association study (GWAS) is an unbiased approach for dissecting the genetic variants underlying complex diseases and individual response to a given treatment. GWAS has great potential for the study of systems biology from the point of view of genomics, but the capacity using current analysis models is largely handicapped, as evidenced by missing heritability. Recent development of a full genetic model, in which gene-gene interactions (dominance and epistasis) and gene-environment interactions are all considered, has addressed these problems. This approach has been demonstrated to substantially increase model power, remarkably improving the detection of association of GWAS and the construction of the molecular architecture. This analysis does not require a very large sample size, which is often difficult to meet for a GWAS of treatment response. Furthermore, this analysis can integrate other omic information and allow for variations of Fangji, which is very promising for Fangjiomic study and detection of the sophisticated molecular architecture of the function of Fangji, as well as for the delineation of the systems biology of personalized medicine in TCM in an unbiased and comprehensive manner. PMID- 29417943 TI - Inhibition of the G9a/GLP histone methyltransferase complex modulates anxiety related behavior in mice. AB - Epigenetic gene-regulation abnormalities have been implicated in various neuropsychiatric disorders including schizophrenia and depression, as well as in the regulation of mood and anxiety. In addition, epigenetic mechanisms are involved in the actions of psychiatric drugs. Current anxiolytic drugs have significant shortcomings, and development of new medications is warranted. Two proteins, G9a (also known as EHMT2 or KMT1C) and GLP (G9a-like protein, also known as EHMT1 or KMT1D), which methylate lysine 9 of histone H3 (H3K9), could be promising anxiolytic targets. Postnatal genetic knock-out of G9a reduces anxiety related behavior, consistent with the reduction of G9a levels by some medications used to treat anxiety (amitriptyline, imipramine and paroxetine). Conversely, there is increased anxiety-like behavior in mice with GLP haplodeficiency. We sought to determine whether two pharmacological inhibitors of G9a/GLP, UNC0642 and A-366, would have similar effects to genetic G9a/GLP insufficiency. We found that G9a/GLP inhibition with either compound reduced anxiety-like behaviors when administered to adult mice, in conjunction with decreased H3K9 methylation in the brain. In contrast, exposure to these compounds from embryonic day 9.5 (E9.5) until birth increased anxiety-like behaviors and decreased social interaction in adulthood, while H3K9 methylation was at normal levels in the brains of the adult mice. These findings reinforce genetic evidence that G9a/GLP has different effects on anxiety-like behavior at different stages of brain development, and suggest that targeting this histone methyltransferase pathway could be useful for developing new anxiolytic drugs. These data also suggest that antidepressant exposure in utero could have negative effects in adulthood, and further investigation of these effects is warranted. PMID- 29417945 TI - Emodin alleviates alternatively activated macrophage and asthmatic airway inflammation in a murine asthma model. AB - Alternatively activated macrophages (AAMs) are not only associated with asthma but also lead to asthmatic airway inflammation and remodeling. Inhibition of AAMs is an alternative therapeutic strategy for treating asthma. In this study we investigated whether emodin (1,3,8-trihydroxy-6-methylanthraquinone), isolated from the rhizome of Rheum palmatum, alleviated asthmatic airway inflammation and reduced AAM polarization in a murine asthma model. Mice were sensitized with a triple allergen mix containing dust mite, ragweed and aspergillus (DRA). In mice with DRA-induced asthma, asthmatic inflammation was significantly enhanced. Intraperitoneal injection of emodin (20 mg.kg-1.d-1, ip) 1 h prior to DRA challenge on days 12-14 significantly decreased pulmonary eosinophil and lymphocyte infiltration, mucus secretion and serum IgE production, as well as IL 4 and IL-5 production in bronchoalveolar lavage fluid. In response to emodin treatment, activated markers of AAM Ym-1, Fizz-1 and arginase-1 in the lung tissues were remarkably decreased. In mouse bone marrow-derived macrophages (BMDMs) in vitro, emodin (2-50 MUmol/L) dose-dependently inhibited IL-4-induced AAM polarization and STAT6 phosphorylation. Collectively, our results suggest that emodin effectively ameliorates asthmatic airway inflammation and AAM polarization, and it may therefore become a potential agent for the treatment of asthma. PMID- 29417944 TI - Epicatechin potentiation of glucose-stimulated insulin secretion in INS-1 cells is not dependent on its antioxidant activity. AB - Epicatechin (EC) is a monomeric flavan-3-ol. We have previously demonstrated that glucose-intolerant rats fed flavan-3-ols exhibit improved pancreatic islet function corresponding with an increase in circulating EC-derived metabolites. Thus, we speculate that EC may act as a cellular signaling molecule in vivo to modulate insulin secretion. In this study we further examined the effects of different concentrations of EC on H2O2 or hyperglycemia-induced ROS production, as well as on saturated fatty acid (SFA)-impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cell line in vitro. We showed that EC at a high concentration (30 MUmol/L), but not a low concentration (0.3 MUmol/L), significantly decreased H2O2 or hyperglycemia-induced ROS production in INS-1 cells. However, EC (0.3 MUmol/L) significantly enhanced SFA-impaired GSIS in INS 1 cells. Addition of KN-93, a CaMKII inhibitor, blocked the effect of EC on insulin secretion and decreased CaMKII phosphorylation. Addition of GW1100, a GPR40 antagonist, significantly attenuated EC-enhanced GSIS, but only marginally affected CaMKII phosphorylation. These results demonstrate that EC at a physiological concentration promotes GSIS in SFA-impaired beta-cells via activation of the CaMKII pathway and is consistent with its function as a GPR40 ligand. The findings support a role for EC as a cellular signaling molecule in vivo and further delineate the signaling pathways of EC in beta-cells. PMID- 29417946 TI - MicroRNAs as biomarkers for human glioblastoma: progress and potential. AB - Glioblastoma multiforme (GBM) is the most common malignant glioma. Despite innovative research efforts in tumor therapy, the outcome for most diagnosed patients remains poor; therefore, early diagnosis of GBM is the most effective method for achieving better patient outcomes. In recent years, combined research efforts including cellular, molecular, genetic, and bioinformatics methods have been used to investigate GBM, and the results show that variations in miRNA expression occur in GBM tissues and biological fluids. Some highly stable miRNAs circulate in the blood and cerebrospinal fluid (CSF) of both healthy individuals and diagnosed patients, thus raising the possibility that miRNAs may serve as novel diagnostic markers. In addition, increased understanding of the miRNA and mRNA interactions involved in GBM progression may lead to discovering predictive biomarkers, some of which are clinically relevant for targeted therapy and predicting prognosis. However, as this field is relatively new, some studies have yielded conflicting results. To progress in the field, different advanced techniques must be combined, including bioinformatics methods and molecular and cellular techniques. In addition, we must overcome the various challenges in non invasive GBM biomarker detection. Here, we discuss the progress and potential of miRNAs as biomarkers for GBM and related signaling pathways. Studying the clinical relevance and applicability of these biomarkers may alter GBM patient diagnosis and treatment. PMID- 29417948 TI - Different network pharmacology mechanisms of Danshen-based Fangjis in the treatment of stable angina. AB - Danshen (Salvia miltiorrhiza) preparations such as Danhong injection, Danshen injection, Salvianolate injection, compound Danshen injection and Sodium Tanshinone IIA Sulfonate (STS) injection are widely used in China to treat stable angina (angina pectoris) caused by coronary heart disease. In this study we compared the network pharmacological mechanisms of the 5 Danshen preparations. Following a literature search performed in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI) database, China Biology Medicine (CBM) database, China Conference Paper Database, Wanfang Database, VIP Database and Conference Proceedings Citation Index (through January 2015), 444 randomized controlled trial publications detailing the use of the 5 Danshen-based injections for treating stable angina were identified, and their combined data were analyzed using a network meta-analysis. All of the 5 Danshen-based preparations were effective in treating stable angina with clinical improvement rates of 72.4% 91.6% and electrocardiogram (ECG) improvement rates of 54.5%-71.6%. According to both clinical improvement and ECG improvement, the 5 Danshen-based preparations were ranked as follows: Danhong injection > Salvianolate injection > STS injection > compound Danshen injection > Danshen injection. There were no significant differences among the safety profiles of the 5 Danshen preparations. The meta-analysis results were further examined using a network pharmacology approach and functional enrichment analysis, which revealed that Danshen and Danhong injections affected 4 and 15 signaling pathways, respectively, and that the 4 signaling pathways affected by Danshen were a subset of those influenced by Danhong. Therefore, Danhong injection affected some unique signaling pathways that might regulate lipoprotein metabolism, oxidation, and inflammation, and protect vascular endothelia, reflecting the multi-component and multi-target characteristics of this traditional formula and its strengths in treating complex diseases. PMID- 29417949 TI - Charactering the metabolism of cryptotanshinone by human P450 enzymes and uridine diphosphate glucuronosyltransferases in vitro. AB - Cryptotanshinone (CT) is the main active component in the root of Salvia miltiorrhiza Bunge (SMB) that displays antibacterial, anti-inflammatory and anticancer activities. In this study, we characterized phase I and phase II metabolism of CT in human liver microsomes in vitro and identified the metabolic enzymes (CYPs and UGTs) involved. The metabolites of CT generated by CYPs were detected using LC-MS/MS and the CYP subtypes involved in the metabolic reactions were identified using chemical inhibitors of CYP enzymes and recombinant human CYP enzymes (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Glucuronidation of CT was also examined, and the UGT subtypes involved in the metabolic reactions were identified using recombinant human UGT enzymes (1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17). After adding NADPH to the human liver microsomes incubation system, CT was transformed into 6 main dehydrogenation and hydroxylation metabolites. CYP2A6, CYP3A4 and CYP2C19 were the major contributors to the transformation of its hydroxylation metabolites. CYP2C19, CYP1A2 and CYP3A4 were the major contributors to the transformation of its hydrogenation metabolites in human liver microsomes. This study showed that the metabolites at m/z of 473 were mediated by UGT1A9 and that the metabolites at m/z of 489 were mediated by UGT2B7 and UGT2B4. CT was extensively metabolized by UGTs following metabolism by CYPs in the liver. PMID- 29417947 TI - Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools. AB - Exosomes are nano-sized vesicles that serve as mediators for intercellular communication through the delivery of cargo, including protein, lipids, nucleic acids or other cellular components, to neighboring or distant cells. Exosomal cargo may vary in response to different physiological or pathological conditions. The endosomal sorting complex required for transport (ESCRT) family has been widely accepted as a key mechanism in biogenesis and cargo sorting. On the other hand, accumulating evidence show that ESCRT-independent pathways exist. Due to the critical role of exosomes in intercellular communications in delivering cargo to recipient cells, exosomes have been investigated as a vector for the delivery of endogenous or exogenous cargo for therapeutic purposes. But the number of exosomes produced by cells is limited, which hampers their application. Synthetic exosome-mimics have been fabricated and investigated as a therapeutic tool for drug delivery. This review focuses on ESCRT-independent regulation of cargo loading into exosomes, including lipid raft and ceramide-mediated mechanisms, and reported exosomes or exosome-mimics with therapeutic effects. PMID- 29417950 TI - Rheumatoid arthritis. PMID- 29417951 TI - Erratum: Characterization of lymphopenia in patients with MS treated with dimethyl fumarate and fingolimod. AB - [This corrects the article on p. e432 in vol. 5, PMID: 29296636.]. PMID- 29417952 TI - Beyond journalism: Theorizing the transformation of journalism. AB - Journalism has enjoyed a rich and relatively stable history of professionalization. Scholars coming from a variety of disciplines have theorized this history, forming a consistent body of knowledge codified in national and international handbooks and canonical readers. However, recent work and analysis suggest that the supposed core of journalism and the assumed consistency of the inner workings of news organizations are problematic starting points for journalism studies. In this article, we challenge the consensual (self )presentation of journalism - in terms of its occupational ideology, its professional culture, and its sedimentation in routines and organizational structures (cf. the newsroom) in the context of its reconfiguration as a post industrial, entrepreneurial, and atypical way of working and of being at work. We outline a way beyond individualist or institutional approaches to do justice to the current complex transformation of the profession. We propose a framework to bring together these approaches in a dialectic attempt to move through and beyond journalism as it has traditionally been conceptualized and practiced, allowing for a broader definition and understanding of the myriad of practices that make up journalism. PMID- 29417953 TI - Consensus dynamics in online collaboration systems. AB - Background: In this paper, we study the process of opinion dynamics and consensus building in online collaboration systems, in which users interact with each other following their common interests and their social profiles. Specifically, we are interested in how users similarity and their social status in the community, as well as the interplay of those two factors, influence the process of consensus dynamics. Methods: For our study, we simulate the diffusion of opinions in collaboration systems using the well-known Naming Game model, which we extend by incorporating an interaction mechanism based on user similarity and user social status. We conduct our experiments on collaborative datasets extracted from the Web. Results: Our findings reveal that when users are guided by their similarity to other users, the process of consensus building in online collaboration systems is delayed. A suitable increase of influence of user social status on their actions can in turn facilitate this process. Conclusions: In summary, our results suggest that achieving an optimal consensus building process in collaboration systems requires an appropriate balance between those two factors. PMID- 29417954 TI - IDH1 R132H predicts sensitivity to Bcl-xL inhibition-mediated programmed cell death. PMID- 29417955 TI - Reporting the methods used in public health research and practice. AB - The methods section of a scientific article often receives the most scrutiny from journal editors, peer reviewers, and skeptical readers because it allows them to judge the validity of the results. The methods section also facilitates critical interpretation of study activities, explains how the study avoided or corrected for bias, details how the data support the answer to the study question, justifies generalizing the findings to other populations, and facilitates comparison with past or future studies. In 2006, the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Programme began collecting and disseminating guidelines for reporting health research studies. In addition, guidelines for reporting public health investigations not classified as research have also been developed. However, regardless of the type of study or scientific report, the methods section should describe certain core elements: the study design; how participants were selected; the study setting; the period of interest; the variables and their definitions used for analysis; the procedures or instruments used to measure exposures, outcomes, and their association; and the analyses. Specific requirements for each study type should be consulted during the project planning phase and again when writing begins. We present requirements for reporting methods for public health activities, including outbreak investigations, public health surveillance programs, prevention and intervention program evaluations, research, surveys, systematic reviews, and meta analyses. PMID- 29417956 TI - iLid: Low-power Sensing of Fatigue and Drowsiness Measures on a Computational Eyeglass. AB - The ability to monitor eye closures and blink patterns has long been known to enable accurate assessment of fatigue and drowsiness in individuals. Many measures of the eye are known to be correlated with fatigue including coarse grained measures like the rate of blinks as well as fine-grained measures like the duration of blinks and the extent of eye closures. Despite a plethora of research validating these measures, we lack wearable devices that can continually and reliably monitor them in the natural environment. In this work, we present a low-power system, iLid, that can continually sense fine-grained measures such as blink duration and Percentage of Eye Closures (PERCLOS) at high frame rates of 100fps. We present a complete solution including design of the sensing, signal processing, and machine learning pipeline; implementation on a prototype computational eyeglass platform; and extensive evaluation under many conditions including illumination changes, eyeglass shifts, and mobility. Our results are very encouraging, showing that we can detect blinks, blink duration, eyelid location, and fatigue-related metrics such as PERCLOS with less than a few percent error. PMID- 29417957 TI - Erratum: Progressive inner nuclear layer dysfunction in non-optic neuritis eyes in MS. AB - [This corrects the article on p. e427 in vol. 5, PMID: 29259999.]. PMID- 29417958 TI - Comparison of Impact Performance between Youth and Varsity Football Helmets. AB - Current youth football helmets, intended for players under the age of 14 years old, are similar in design and are tested under the same standard as varsity football helmets. This study evaluated the impact performance of matched youth and adult varsity football helmets. Eight helmet models were evaluated using an impact pendulum, with a modified National Operating Committee on Standards for Athletic Equipment (NOCSAE) medium sized headform mounted on a Hybrid III 50th percentile neck. Four locations on the helmet shell at three impact velocities were tested for three trials, for a total of 576 impact tests. Linear acceleration, rotational acceleration, and a concussion correlate were recorded for each test and a comparison between the youth and varsity helmets were made. It was found that the age group the helmet is intended for did not have a significant effect on the impact performance of the helmet in either linear acceleration, rotational acceleration, or concussion correlate. These results are likely due to the similarities in helmet design resulting from being tested to the same standard. Although it is unknown how a youth helmet should differ from a varsity helmet, differences in impact exposure, anthropometry, physiology, and injury tolerance are factors to consider. These data serves as a reference point for future youth-specific helmet design and helmet standards. PMID- 29417959 TI - Corrigendum: Dusp16 Deficiency Causes Congenital Obstructive Hydrocephalus and Brain Overgrowth by Expansion of the Neural Progenitor Pool. AB - [This corrects the article on p. 372 in vol. 10, PMID: 29170629.]. PMID- 29417961 TI - Pretreatment of Wheat Bran for Suitable Reinforcement in Biocomposites. AB - Wheat bran, abundant but underutilized, was investigated for its potential as a reinforcement in biocomposites through different pretreatment methods. Pretreatment methods included were dilute sodium hydroxide (NaOH), dilute sulfuric acid (H2SO4), liquid hot water (LHW), calcium hydroxide (CaOH), organosolv such as aqueous ethanol (EtOH), and methyl isobutyl ketone (MIBK). Changes in chemical composition and fiber characteristics of the treated bran were studied using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Cellulose content increased to 35.1% and 29.6% in brans treated with H2SO4 and NaOH, respectively. The SEM micrographs showed surface cleaning of treated bran while maintaining sufficient surface roughness for the H2SO4, NaOH, and MIBK treated brans. Crystallinity index increased slightly for all treatments except H2SO4. NaOH and H2SO4 pretreated brans achieved important fiber characteristics, which could be useful for making thermoplastic biocomposites. Innovative use of bran in thermoplastic will create more opportunities for growers while enhancing biodegradability. PMID- 29417962 TI - Development and testing of a novel micro-Raman probe and application of calibration method for the quantitative analysis of microfluidic nitric acid streams. AB - To simplify and improve the safety of reprocessing used nuclear fuel, an initial assessment was made of Raman microscopy applied to microfluidic volumes with a view toward the on-line spectroscopic measurement of highly radioactive solutions. This study compares a microscopic Raman probe (excitation focal point diameter 70 MUm) to a larger, well studied probe (excitation focal point diameter 125 MUm) used in prior investigations. This was done by chemometrically modeling and predicting concentrations of HNO3 solutions (0 M to 8 M) as they flowed through microfluidic cells based upon spectra from each probe. Spectra recorded for each probe using the same static HNO3 solution set contained in 2 dram glass vials were used as training sets to produce models for the respective probes. Modeling required baseline, normalization and smoothing preprocessing to compensate for a reduced path length between the static glass vial training set (4 cm) and the reduced path length flow cell (1 cm), wide ranging solution concentrations, and the associated non-linear spectral changes, and abrupt and uneven concentration changes of flowing solutions. The micro-Raman probe is able to produce spectra that may be analyzed chemometrically to accurately predict the concentration of flowing HNO3 solutions down to microliter volumes. Based upon RMSECV and RMSEP modeling statistics concentration predictions of the micro-Raman probe are comparable to those obtained for a macro-Raman on identical samples. PMID- 29417960 TI - The graphical brain: Belief propagation and active inference. AB - : This paper considers functional integration in the brain from a computational perspective. We ask what sort of neuronal message passing is mandated by active inference-and what implications this has for context-sensitive connectivity at microscopic and macroscopic levels. In particular, we formulate neuronal processing as belief propagation under deep generative models. Crucially, these models can entertain both discrete and continuous states, leading to distinct schemes for belief updating that play out on the same (neuronal) architecture. Technically, we use Forney (normal) factor graphs to elucidate the requisite message passing in terms of its form and scheduling. To accommodate mixed generative models (of discrete and continuous states), one also has to consider link nodes or factors that enable discrete and continuous representations to talk to each other. When mapping the implicit computational architecture onto neuronal connectivity, several interesting features emerge. For example, Bayesian model averaging and comparison, which link discrete and continuous states, may be implemented in thalamocortical loops. These and other considerations speak to a computational connectome that is inherently state dependent and self-organizing in ways that yield to a principled (variational) account. We conclude with simulations of reading that illustrate the implicit neuronal message passing, with a special focus on how discrete (semantic) representations inform, and are informed by, continuous (visual) sampling of the sensorium. Author Summary: This paper considers functional integration in the brain from a computational perspective. We ask what sort of neuronal message passing is mandated by active inference-and what implications this has for context-sensitive connectivity at microscopic and macroscopic levels. In particular, we formulate neuronal processing as belief propagation under deep generative models that can entertain both discrete and continuous states. This leads to distinct schemes for belief updating that play out on the same (neuronal) architecture. Technically, we use Forney (normal) factor graphs to characterize the requisite message passing, and link this formal characterization to canonical microcircuits and extrinsic connectivity in the brain. PMID- 29417967 TI - An electrically conducting crystal composed of an octahedrally ligated porphyrin complex with high-spin iron(iii). AB - A porphyrin-based octahedrally ligated complex with high-spin iron(iii) was designed, and the resulting electrically conducting crystal TPP[FeIII(tbp)Br2]2 (TPP = tetraphenylphosphonium and tbp = tetrabenzoporphyrin) was synthesised. Although TPP[Fe(tbp)Br2]2 was isostructural to the reported TPP[Fe(Mc)L2]2 systems (Mc = macrocyclic ligands such as phthalocyanine (Pc) or tbp; and L = CN, Cl, or Br), the bond lengths between Fe and ligands in the [Fe(tbp)Br2] unit were evidently longer than those in the other units, because of the different spin states of Fe: high-spin in TPP[Fe(tbp)Br2]2 and low-spin in others. The magnetic anisotropy observed in the low-spin state vanished when the Fe is in the high spin state. Based on reports for Pc-based systems, the negative magnetoresistance (MR) effect for TPP[Fe(tbp)Br2]2 was expected to be smaller than that for TPP[Fe(tbp)(CN)2]2. However, the former showed a giant negative MR effect similar to or larger than the latter, suggesting that the nature of iron is a crucial factor for the electrical properties of porphyrin-based materials. PMID- 29417969 TI - NMR and experimental reinvestigation of the condensation reaction between gamma methylene-alpha,beta-unsaturated aldehydes and propargyl aldehydes. AB - The condensation reaction between a gamma-methylene-alpha,beta-unsaturated aldehyde and phenylpropargyl aldehyde was revisited and, guided by extensive DFT calculations of NMR shifts, was found to afford a deconjugative aldol condensation product. In this manner, a simple protocol for the preparation of valuable cross-conjugated oxatrienes was uncovered. PMID- 29417972 TI - Relevance of copper transporter 1 and organic cation transporters 1-3 for oxaliplatin uptake and drug resistance in colorectal cancer cells. AB - Oxaliplatin is a routinely used drug in the treatment of colorectal cancer. However, development of resistance is a major hurdle of the chemotherapy success. Defects in cellular accumulation represent a frequently reported feature of cells with acquired resistance to platinum drugs. Nevertheless, the mechanisms of oxaliplatin uptake and their role in oxaliplatin resistance remain poorly elucidated. The aim of this study was to investigate the relevance of copper transporter 1 (CTR1) and organic cation transporters 1-3 (OCT1-3) for oxaliplatin uptake and resistance to the drug in sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cells. Co-incubation with copper(ii) sulfate, a CTR1 substrate, significantly decreased oxaliplatin accumulation but not cytotoxicity in both cell lines. Pre- as well as co-incubation with the OCT1 inhibitor atropine led to a significant reduction in oxaliplatin accumulation in sensitive but not in resistant cells. However, oxaliplatin cytotoxicity was also decreased in the presence of atropine in both cell lines. Cimetidine, an inhibitor of OCT2, induced a significant reduction in the cellular accumulation and potency of oxaliplatin in sensitive and resistant cells. An inhibitor of OCT3, decynium-22, had no influence on oxaliplatin accumulation and cytotoxicity in either cell line. No differences in the transporter expressions were observed between the cell lines, drug-treated or not, either at the mRNA or protein levels. A fluorescent oxaliplatin derivative CFDA-oxPt co-localized with CTR1, OCT1 and OCT2 in sensitive cells, but only with CTR1 and OCT2 in the resistant cell line. Our results suggest that oxaliplatin is transported into the cell by CTR1 in both cell lines. However, contribution of CTR1-mediated uptake to resistance seems unlikely. Uptake of oxaliplatin via OCT1 appears to take place in the sensitive but not in the resistant cell line underscoring the transporter relevance for oxaliplatin resistance. OCT2 is likely to be involved in the uptake of oxaliplatin to a similar extent in both cell lines suggesting no major contribution of this transporter to resistance. In contrast, OCT3 appears to be irrelevant for oxaliplatin transport into the cell and resistance. PMID- 29417971 TI - In situ sulfur loading in graphene-like nano-cell by template-free method for Li S batteries. AB - Carbon nanomaterials with 3D structures as sulfur hosts have been widely developed in lithium-sulfur batteries because of their high specific surface area, high conductivity and structural stability. However, sulfur, loaded by melting-diffusion method, is usually attached to the outside surface of carbon host, resulting in weak adsorption to expose polysulfide. Herein, we report a template-free method for synthesizing graphene-like nano-cell (GLC) with high in situ sulfur loading (S@GLC). The GLC is expected to provide physical adsorption by enclosed graphene cell architecture and chemical adsorption by pyridinic N doping and oxygen functional group. With these merits, the S@GLC cathode owned high sulfur content (72%) and also, it exhibited a reversible specific capacity of 1253 mA h g-1 at 0.2C, excellent rate performance, and long cycling stability (502 mA h g-1 after 400 cycles at 1C). PMID- 29417968 TI - Engineering functional inorganic-organic hybrid systems: advances in siRNA therapeutics. AB - Cancer treatment still faces a lot of obstacles such as tumor heterogeneity, drug resistance and systemic toxicities. Beyond the traditional treatment modalities, exploitation of RNA interference (RNAi) as an emerging approach has immense potential for the treatment of various gene-caused diseases including cancer. The last decade has witnessed enormous research and achievements focused on RNAi biotechnology. However, delivery of small interference RNA (siRNA) remains a key challenge in the development of clinical RNAi therapeutics. Indeed, functional nanomaterials play an important role in siRNA delivery, which could overcome a wide range of sequential physiological and biological obstacles. Nanomaterial formulated siRNA systems have potential applications in protection of siRNA from degradation, improving the accumulation in the target tissues, enhancing the siRNA therapy and reducing the side effects. In this review, we explore and summarize the role of functional inorganic-organic hybrid systems involved in the siRNA therapeutic advancements. Additionally, we gather the surface engineering strategies of hybrid systems to optimize for siRNA delivery. Major progress in the field of inorganic-organic hybrid platforms including metallic/non-metallic cores modified with organic shells or further fabrication as the vectors for siRNA delivery is discussed to give credit to the interdisciplinary cooperation between chemistry, pharmacy, biology and medicine. PMID- 29417970 TI - Total synthesis of complex terpenoids employing radical cascade processes. AB - Covering: 2011-2017Radical cyclizations have a rich history in organic chemistry and have been particularly generous to the field of natural product synthesis. Owing to their ability to operate in highly congested molecular quarters, and with significant functional group compatibility, these transformations have enabled the synthesis of numerous polycyclic terpenoid natural products over the past several decades. Moreover, when programmed accordingly into a synthetic plan, radical cascade processes can be used to rapidly assemble molecular complexity, much in the same way nature rapidly constructs terpene frameworks through cationic cyclization pathways. This review highlights recent total syntheses of complex terpenoids (from 2011-2017) employing C-C bond-forming radical cascade sequences. PMID- 29417973 TI - Boron-phil and boron-phob structure units in novel borides Ni3Zn2B and Ni2ZnB: experiment and first principles calculations. AB - The crystal structures of two novel borides in the Ni-Zn-B system, tau5-Ni3Zn2B and tau6-Ni2ZnB, were determined by single crystal X-ray diffraction (XRSC) in combination with selected area electron diffraction in a transmission electron microscope (SAED-TEM) and electron probe microanalysis (EPMA). Both compounds crystallize in unique structure types (space group C2/m, a = 1.68942(8) nm, b = 0.26332(1) nm, c = 0.61904(3) nm, beta = 111.164(2) degrees , RF = 0.0219 for Ni3Zn2B, and space group C2/m, a = 0.95296(7) nm, b = 0.28371(2) nm, c = 0.59989(1) nm, beta = 93.009(4) degrees , RF = 0.0163 for Ni2ZnB). Both compounds have similar building blocks: two triangular prisms centered by boron atoms are arranged along the c-axis separated by Zn layers, which form empty octahedra connecting the boron centered polyhedra. Consistent with the (Ni+Zn)/B ratio, isolated boron atoms are found in tau5-Ni3Zn2B, while B-B pairs exist in tau6 Ni2ZnB. The crystal structure of Ni2ZnB is closely related to that of tau4 Ni3ZnB2, i.e. Ni2ZnB can be formed by removing the nearly planar nickel layer in Ni3ZnB2 and shifting the origin of the unit cell to the center of the B-B pair. The electrical resistivity and specific heat of tau5-Ni3Zn2B reveal the metallic behavior of this compound with an anomaly at low temperature, possibly arising from a Kondo-type interaction. Further analysis on the lattice contribution of the specific heat reveals similarity with tau4-Ni3ZnB2 with some indications of lattice softening in tau5-Ni3Zn2B, which could be related to the increasing metal content and the absence of B-B bonding in tau5-Ni3Zn2B. For the newly found phases, tau5-Ni3Zn2B and tau6-Ni2ZnB as well as for tau3-Ni21Zn2B20 and tau4 Ni3ZnB2 density functional theory (DFT) calculations were performed by means of the Vienna Ab initio Simulation Package (VASP). Total energies and forces were minimized in order to determine the fully relaxed structural parameters, which agree very well with experiment. Energies of formations in the range of -25.2 to 26.9 kJ mol-1 were calculated and bulk moduli in the range of 179.7 to 248.9 GPa were derived showing hardening by increasing the B concentration. Charge transfer is discussed in terms of Bader charges resulting in electronic transfer from Zn to the system and electronic charge gain by B. Ni charge contributions vary significantly with crystallographic position depending on B located in the neighbourhood. The electronic structure is presented in terms of densities of states, band structures and contour plots revealing Ni-B and Ni-Zn bonding features. PMID- 29417974 TI - Facile synthesis of ultrathin two-dimensional nanosheets-constructed MCo2O4 (M = Ni, Cu, Zn) nanotubes for efficient photocatalytic oxygen evolution. AB - Hierarchical nanosheets-assembled nanotubes are of great interest for their unique physicochemical properties as well as their potential applications in a variety of fields. However, the synthesis of hierarchical mixed transition-metal oxides-based nanosheets-assembled nanotubes for highly efficient photocatalytic oxygen evolution is rarely reported. Herein, a simple and versatile approach was developed to synthesize hierarchical nanosheets-constructed MCo2O4 (M = Ni, Cu, Zn) nanotubes. Core-shell polyacrylonitrile (PAN)/M-cobalt hydroxide ultrathin nanosheet composite nanofibers were first synthesized by hydroxylation reaction between PAN/M-cobalt acetate hydroxide precursors and NaBH4. After calcination, these nanofibers as precursors were easily transformed into the corresponding hierarchical nanosheets-constructed MCo2O4 nanotubes. By applying a photocatalyst, the resultant MCo2O4 nanotubes, particularly the CuCo2O4 nanotubes, exhibited high photocatalytic activity and cycle stability toward water oxidation reaction with O2 generation rates of 51.1 mmol g-1 h-1 under visible light irradiation, which is higher than most reported catalysts. This approach is very versatile and can be applied to synthesize other hierarchical multi-element oxides-based nanosheets-constructed nanotubes for advanced applications. PMID- 29417975 TI - Bromination and iodination of diphosphane dichalcogenides. AB - The diphosphane dichalcogenides dppmSe2, dppeSe2, diprpmSe2, diprpeSe2, dppmS2 and dppeS2, [dppm = bis(diphenylphosphano)methane, dppe = bis(diphenylphosphano)ethane, diprpm = bis(diisopropylphosphano)methane, diprpe = bis(diisopropylphosphano)ethane] have been treated with elemental bromine or iodine and the products 1-15 characterized by single crystal X-ray diffraction. DppeSe2 with bromine or iodine gives the simple (and previously known) adducts dppe(SeBr2)21 or dppe(SeI2)22 respectively; diprpeSe2 reacts similarly to give diprpe(SeBr2)23 (at 0 degrees C) or diprpe(SeI2)24. The bromine derivatives display a T-shaped geometry at selenium, whereas the iodine derivatives involve linear Se-I-I groups. With dppmSe2 and bromine, a product was formed at -50 degrees C, but could not be isolated; at room temperature the reaction leads to a mixture of products, from which only [dppmBr2]2+ [Se2Br10]2-5 (the anion involving a dibromine molecule coordinating to a Se centre) could be isolated. Reaction of dppeSe2 with excess bromine at room temperature leads to [dppeBr2]2+.1/2[SeBr6]2-.[SeBr2.Br2.Br3]-6. The reaction of dppmSe2 with iodine gives the 1 : 2 adduct [dppmSe2I]+ [I3]-7, the cation of which contains a novel five-membered CP2Se2 heterocycle. In a 1 : 1 ratio the same reaction gives another 1 : 2 adduct, [I2Se(dppm)Se-I-Se(dppm)SeI2]+ [I3]-8. DiprpmSe2 with iodine gives [diprpmSe2I]+ [I3]-9, analogous to 7, and with bromine at 0 degrees C the corresponding product [diprpmSe2Br]+ [Br3]-10. At room temperature, diprpeSe2 reacts with bromine to give a mixture of [diprpe(SeBr2)Br]+ Br-11 and [diprpeBr2]2+ [SeBr4]2-12, whereas diprpmSe2 forms [diprpmBr2]2+ [SeBr4]2-13, analogous to 12. The disulfides dppmS2 and dppeS2 react with bromine to give [dppmSBr]+ [Br3]-14 and [dppeSBr]+ [Br3]-15. PMID- 29417976 TI - Serum cortisol levels and neuropsychological impairments in patients diagnosed with Fibromyalgia. AB - OBJECTIVE: To describe the relationship between neuropsychological variables and serum cortisol levels as a measure of physiological stress in patients with fibromyalgia. METHODOLOGY: A sample of 60 women was intentionally selected: 30 with Fibromyalgia diagnosis and 30 with normal controls. Cortisol levels were determined using two blood samples (AM and PM) and a neuropsychological and emotional battery was applied with a standardized protocol in Colombian population to evaluate different cognitive domains. Comparative and correlational non-parametric analyzes were performed, a multiple regression analysis to determine influences between variables. RESULTS: Significant differences between the study groups in the neuropsychological variables (attention, memory, language, visual-constructive praxis and executive functions (EF), (p<0.05) were found, obtaining better scores in the control group. Significant correlations between the cortisol profile, with false acknowledgments of Rey auditory- verbal learning test, and with perseverative errors of the Wisconsin test were found. Multiple regression analysis predicts the influence of memory and EF variables on the cortisol profile in an 88.7%. CONCLUSIONS: The findings show that, in patients with FM, there are neuropsychological alterations, mainly in executive functioning (cognitive flexibility) and episodic memory (evocation and storage). Likewise, executive dysfunction is related to physiological stress reciprocally and in turn are conditioned by emotional alterations such as symptoms of depression, which supports the neurophysiological model that compromises the hypothalamic-pituitary-adrenal axis and the prefrontal cortex, rich in corticosteroid receptors. PMID- 29417977 TI - Descriptive study of evolution experienced by users of mental health residence, after 10 years of operation. AB - INTRODUCTION: The transformation of the social-health benefits system must demonstrate efficiency. The objective of the current work is to evaluate the evolution of those living in a residence during the first 10 years of its operation. METHOD: Of the 205 patients used in the assessment, 93 were admitted. The evolutionary study was done with the 62 patients that were cared for between 2002-2012. The variables studied include the ENAR-CPB Scale, days hospitalized, community activities, a satisfaction survey and QOL. RESULTS: After the assessment process only 45% of those proposed for admission were actually admitted. Resident rotation is 3.4% annually. Many leave the program after being referred to a long-term psychiatric hospital; 14.5% leave the residence in order to have a more autonomous life. After living 2 years in the residence there is a general improvement in the majority of residents, which is maintained after 5 years as well. This improvement is maintained even after 10 years, however a general loss of capacities is experienced. CONCLUSIONS: Living in a Residence favors improvement in the quality of life, both subjectively as well as objectively. Institutional treatment consists of working with the patients in a way that treats them as individuals, so they can go about their lives and perform their tasks with creativity. In order for this to be possible, an individualized and flexible model is required. PMID- 29417978 TI - Analysis of the effectiveness of a training program for parents of children with ADHD in a hospital environment. AB - INTRODUCTION: Regarding the Attention Deficit Hyperactivity Disorder (ADHD), treatments combined with pharmacological, psychoeducational and parents training programs interventions are recommended. Parenting programs have been proven efficacy in the experimental area, but there is few data about their effectiveness and feasibility in the professional area. The objective of the study is to analyze the effectiveness of a parenting program implemented in a hospital setting to improve internalized and externalized behaviors as well as parenting styles in a sample of ADHD children. METHODOLOGY: A training program for behavior management was applied to parents of 21 children with ADHD in a quasi-experimental pretest-posttest design, using measures from Child Behavior Checklist (CBCL) and Parenting Scale. RESULTS: Post-treatment data showed significant improvements specially on emotional, anxiety and oppositional defiant disorder measures. A significant but moderate improvement was found on ADHD, and non-significant on conduct problem measure. Additionally, there were moderate but significant improvements in parenting styles. CONCLUSIONS: Data support the effectiveness and feasibility of parent training programs for children with ADHD applied in hospital settings as they improve a large part of associated symptoms and parenting styles. PMID- 29417979 TI - Facial and bilateral leg edema in a patient using quetiapine. PMID- 29417980 TI - Gender violence and mental health: a gap between clinical assistance and research. PMID- 29417981 TI - Immunoexpression of IgA receptors (CD89, CD71) in dermatitis herpetiformis. AB - INTRODUCTION: The role of IgA receptors in dermatitis herpetiformis (DH) pathogenesis is still unknown. CD89 and CD71 may be associated with immune response during DH development. The purpose of this study was to perform semiquantitative analysis of simultaneous immunoexpression of CD89 and CD71 in DH and IgA/neutrophil-mediated non-DH dermatoses (IgAN) in relation to specific IgA autoantibodies/antibodies (tissue and epidermal transglutaminases, nonapeptides of gliadin - eTG/tTG/npG) as well neutrophil activation via the release of neutrophil elastase (NE). MATERIAL AND METHODS: In total, 48 patients were studied. The study was conducted on skin lesions and sera obtained from DH and IgAN patients. DH and IgAN served as mutually positive control groups. We used immunohistochemical technique with semiquantitative digital morphometry and ELISA to measure serum levels of anti-eTG/tTG/npG IgA. RESULTS: CD89 showed a significantly higher expression in DH than in IgAN. CD71 was overexpressed in DH and IgAN. CD89 immunoexpression correlated negatively with CD71 in IgAN. A positive correlation was revealed between CD89 immunoexpression and anti-npG IgA in DH. No statistically significant correlations were found in DH between the CD89/CD71 and NE immunoexpression, between CD71 immunoexpression and anti tTG/eTG/npG IgA, or between CD89 immunoexpression and anti-eTG/tTG IgA serum levels. CONCLUSIONS: CD89 is probably a key IgA Fc receptor in DH development, where it is associated with immune response to gluten. CD71 may be linked with inflammation in DH and IgAN. We suggest that interaction between CD89 and CD71 can modulate the inflammation in IgAN. PMID- 29417982 TI - How or When Samples Are Collected Affects Measured Arsenic Concentration in New Drinking Water Wells. AB - Naturally occurring arsenic can adversely affect water quality in geologically diverse aquifers throughout the world. Chronic exposure to arsenic via drinking water is a human health concern due to risks for certain cancers, skin abnormalities, peripheral neuropathy, and other negative health effects. Statewide in Minnesota, USA, 11% of samples from new drinking water wells have arsenic concentrations exceeding 10 MUg/L; in certain counties more than 35% of tested samples exceed 10 MUg/L arsenic. Since 2008, Minnesota well code has required testing water from new wells for arsenic. Sample collection protocols are not specified in the well code, so among 180 well drillers there is variability in sampling methods, including sample collection point and sample collection timing. This study examines the effect of arsenic sample collection protocols on the variability of measured arsenic concentrations in water from new domestic water supply wells. Study wells were drilled between 2014 and 2016 in three regions of Minnesota that commonly have elevated arsenic concentrations in groundwater. Variability in measured arsenic concentration at a well was reduced when samples were (1) filtered, (2) collected from household plumbing instead of from the drill rig pump, or (3) collected several months after well construction (instead of within 4 weeks of well installation). Particulates and fine aquifer sediments entrained in groundwater samples, or other artifacts of drilling disturbance, can cause undesirable variability in measurements. Establishing regulatory protocols requiring sample filtration and/or collection from household plumbing could improve the reliability of information provided to well owners and to secondary data users. PMID- 29417983 TI - Rare, genetically conditioned forms of rickets: Differential diagnosis and advances in diagnostics and treatment. AB - Apart from the classic forms of rickets, there are rare genetic disorders from the group of vitamin D-resistant rickets where the clinical picture is very similar to the classic forms. Diagnosis of genetically conditioned rickets is often delayed. It is very important to know that a disorder of genetic background may be the cause of the failure of classic treatment in patients with rachitic symptoms. In the group of genetically conditioned rickets there are, among others, congenital hypophosphatemic rickets and vitamin D-dependent rickets type I and II. Congenital hypophosphatemic rickets is characterised by bone mineralisation disturbances related to hypophosphatemia secondary to renal loss of phosphates. The term "hypophosphatemic rickets" covers a group of diseases with similar phenotype but with different genotypes, inheritance models and etiopathogeneses. Mutation of at least 10 genes underlying this disease entity has been described. Vitamin D-dependent rickets are caused by defects of vitamin D metabolism. There are 4 forms described in literature that are distinguished by their genetic causes: type 1A (vitamin D-dependent rickets type IA), type 1B (vitamin D-dependent rickets type IB) and type 2A (vitamin D-dependent rickets type 2A), type 2B (vitamin D-dependent rickets type 2B). A detailed family history in combination with a physical examination, biochemistry and X-ray imaging helps in differential diagnostics of rare forms of rickets. PMID- 29417984 TI - [18 F]Fluorodeoxyglucose PET/CT and prediction of histopathological response to neoadjuvant chemotherapy for adenocarcinoma of the oesophagus and oesophagogastric junction. AB - BACKGROUND: The aim of this prospective study was to assess whether [18 F]fluorodeoxyglucose PET can be used to predict histopathological response early in the course of neoadjuvant chemotherapy in patients with adenocarcinoma of the oesophagus and oesophagogastric junction. METHODS: Following the PET response criteria in solid tumours (PERCIST 1.0) as a standardized method for semiquantitative assessment of metabolic response, FDG-PET/CT was performed before (PET1) and after (PET2) initiation of the first cycle of chemotherapy. The relative changes in the peak standardized uptake value (DeltaSUL) and total lesion glycolysis (DeltaTLG) between PET1 and PET2 were correlated with histopathological response, defined as less than 50 per cent viable tumour cells in the resection specimen. A receiver operating characteristic (ROC) curve analysis was used to identify the optimal cut-off value with the highest accuracy of histopathological response prediction. RESULTS: PET2 was performed a median of 16 (range 12-22) days after the start of chemotherapy. Some 27 of 90 patients who underwent surgery had a histopathological response. There was no association between the median DeltaSUL or median DeltaTLG and the histopathological response. A post hoc analysis in 47 patients with PET2 performed 16 days or less after the start of chemotherapy showed that DeltaTLG, but not DeltaSUL, was associated with the histopathological response (P = 0.009). The optimal cut-off value of DeltaTLG was 66 per cent or more. CONCLUSION: FDG-PET/CT after the first cycle of chemotherapy does not predict histopathological response in patients with adenocarcinoma of the oesophagus and oesophagogastric junction. PMID- 29417985 TI - Nationwide analysis of risk factors for in-hospital mortality in patients undergoing abdominal aortic aneurysm repair. AB - BACKGROUND: There is increasing awareness that women may have worse outcomes following repair of abdominal aortic aneurysm (AAA). The aim of this study was to analyse the association between sex, age and in-hospital mortality after AAA using hospital episode data collected routinely at the nationwide level. METHODS: Data were extracted from the nationwide statutory Diagnosis Related Group statistics provided by the German Federal Statistical Office. Patients with a diagnosis of intact (non-ruptured) AAA (ICD-10 GM I71.4) and procedure codes (OPS; 2005-2013) for endovascular aneurysm repair (EVAR) (5-38a.1*) or open aneurysm repair (5-384.5, 5-384.7), treated from 2005 to 2013, were included. A multilevel multivariable regression model was applied to adjust for medical risk (using the Elixhauser co-morbidity score), type of procedure, type of admission, and to account for clustering of patients within centres. The primary outcome was in-hospital mortality. RESULTS: Some 84 631 patients were identified, of whom 10 039 (11.9 per cent) were women. Women were significantly older than men at admission (median 74 (i.q.r. 69-80) versus 72 (66-77) years; P < 0.001). EVAR was used less frequently in women (48.1 versus 54.7 per cent; P < 0.001). The in hospital mortality rate was higher in women, overall (5.0 versus 3.1 per cent; relative risk 1.60, 95 per cent c.i. 1.45 to 1.75), and for EVAR (2.8 versus 1.5 per cent; RR 1.90, 1.60 to 2.30) and open repair (6.8 versus 5.0 per cent; RR 1.36, 1.22 to 1.52). In-hospital mortality increased with age and was highest in patients aged over 80 years. In multivariable regression analysis, female sex (RR 1.20, 1.07 to 1.35) and age per 10-year increase (RR 1.83, 1.73 to 1.95) were independent risk factors for higher in-hospital mortality. CONCLUSION: In Germany, women were older when undergoing AAA repair and were less likely to receive EVAR. Mortality rates were higher in older patients and in women, irrespective of the surgical technique used. PMID- 29417986 TI - Three-dimensional anatomy of the anthropoid bony pelvis. AB - OBJECTIVES: Pelvic form is hypothesized to reflect locomotor adaptation in anthropoids. Most observed variation is found in the ilium, which traditionally is thought to reflect thoracic and shoulder morphology. This article examines the articulated bony pelvis of anthropoids in three dimensions (3D) to test hypothesized variation in pelvic anatomy related to overall torso form. MATERIALS AND METHODS: Sixty landmarks were collected on articulated pelves from 240 anthropoid individuals. Landmark data were subjected to a Generalized Procrustes Analysis. Principal Components Analysis was used to identify trends among taxa. Linear metrics were extracted, and bivariate allometric analysis was used to compare intergroup differences and scaling trends of specific dimensions. RESULTS: The combination of 3D and bivariate allometric analysis demonstrates a complex pattern of locomotor/phylogenetic and allometric influences on pelvic morphology. Apes have relatively narrower dorsal interiliac spacing than do most monkeys, with relatively smaller spinal muscle attachment areas but only minimally wider ventral bi-iliac breadths. Hylobatids and atelids have a relatively more cranial position of their sacra than do other taxa, and hylobatids and cercopithecids relatively more retroflexed ischia. Within groups, the three pelvic joints (lumbosacral, sacroiliac, and hip) become relatively closer together with increasing body size. CONCLUSIONS: A three-dimensional consideration of the articulated pelvis in anthropoids reveals determinants of pelvic variation not previously appreciated by studies of isolated hipbones. This study provides no support for the hypothesis that the ape pelvis is mediolaterally broader than that of monkeys in relative terms, as would be expected if iliac shape is related to hypothesized differences in thoracic breadth and shoulder orientation. Instead, apes, especially great apes, have relatively narrow sacra and longer lower pelves, related to their shorter, stiffer lumbar spines and torsos. This difference, coupled with strong positive allometry of iliac breadth and negative allometry of key pelvic lengths, along with some variation in ischial morphology in certain taxa, explains much of the variation in pelvic form among anthropoid primates. PMID- 29417987 TI - Psychosocial stress differentially affects emotional empathy in women with borderline personality disorder and healthy controls. AB - OBJECTIVE: Deficits in empathy, an important part of social cognition, have been described in patients with borderline personality disorder (BPD). Importantly, psychosocial stress enhances emotional empathy in healthy participants. However, it remains unknown whether stress affects empathy in BPD. METHOD: We randomized 47 women with BPD and 47 healthy women to either the Trier Social Stress Test or a control condition. Subsequently, all participants underwent the Multifaceted Empathy Test (MET), a measure of cognitive and emotional facets of empathy. RESULTS: Across groups, stress resulted in a significant increase in cortisol and stress ratings. There was a significant stress * group interaction for emotional empathy (Fdf1,92 = 5.12, P = 0.04, etap2 = 0.05). While there was no difference between patients with BPD and healthy participants after the control condition, patients with BPD had significantly lower emotional empathy scores after stress compared to healthy individuals. There were no effects for cognitive empathy. CONCLUSION: The current finding provides first evidence that stress differentially affects emotional empathy in patients with BPD and healthy individuals such that patients with BPD showed reduced emotional empathy compared to healthy women after stress. Given the strong impact of stress on acute psychopathology in patients with BPD, such a response may exacerbate interpersonal conflicts in stress contexts and may be an important target for therapeutic interventions. PMID- 29417988 TI - Eco-geographic adaptations in the human ribcage throughout a 3D geometric morphometric approach. AB - OBJECTIVES: According to eco-geographic rules, humans from high latitude areas present larger and wider trunks than their low-latitude areas counterparts. This issue has been traditionally addressed on the pelvis but information on the thorax is largely lacking. We test whether ribcages are larger in individuals inhabiting high latitudes than in those from low latitudes and explored the correlation of rib size with latitude. We also test whether a common morphological pattern is exhibited in the thorax of different cold-adapted populations, contributing to their hypothetical widening of the trunk. MATERIALS AND METHODS: We used 3D geometric morphometrics to quantify rib morphology of three hypothetically cold-adapted populations, viz. Greenland (11 individuals), Alaskan Inuit (8 individuals) and people from Tierra del Fuego (8 individuals), in a comparative framework with European (Spain, Portugal and Austria; 24 individuals) and African populations (South African and sub-Saharan African; 20 individuals). RESULTS: Populations inhabiting high latitudes present longer ribs than individuals inhabiting areas closer to the equator, but a correlation (p < 0.05) between costal size and latitude is only found in ribs 7-11. Regarding shape, the only cold adapted population that was different from the non-cold adapted populations were the Greenland Inuit, who presented ribs with less curvature and torsion. CONCLUSIONS: Size results from the lower ribcage are consistent with the hypothesis of larger trunks in cold-adapted populations. The fact that only Greenland Inuit present a differential morphological pattern, linked to a widening of their ribcage, could be caused by differences in latitude. However, other factors such as genetic drift or specific cultural adaptations cannot be excluded and should be tested in future studies. PMID- 29417989 TI - Dentine morphology of Atapuerca-Sima de los Huesos lower molars: Evolutionary implications through three-dimensional geometric morphometric analysis. AB - OBJECTIVES: This study aims to explore the affinities of the Sima de los Huesos (SH) population in relation to Homo neanderthalensis, Arago, and early and contemporary Homo sapiens. By characterizing SH intra-population variation, we test current models to explain the Neanderthal origins. MATERIALS AND METHODS: Three-dimensional reconstructions of dentine surfaces of lower first and second molars were produced by micro-computed tomography. Landmarks and sliding semilandmarks were subjected to generalized Procrustes analysis and principal components analysis. RESULTS: SH is often similar in shape to Neanderthals, and both groups are generally discernible from Homo sapiens. For example, the crown height of SH and Neanderthals is lower than for modern humans. Differences in the presence of a mid-trigonid crest are also observed, with contemporary Homo sapiens usually lacking this feature. Although SH and Neanderthals show strong affinities, they can be discriminated based on certain traits. SH individuals are characterized by a lower intra-population variability, and show a derived dental reduction in lower second molars compared to Neanderthals. SH also differs in morphological features from specimens that are often classified as Homo heidelbergensis, such as a lower crown height and less pronounced mid-trigonid crest in the Arago fossils. DISCUSSION: Our results are compatible with the idea that multiple evolutionary lineages or populations coexisted in Europe during the Middle Pleistocene, with the SH paradigm phylogenetically closer to Homo neanderthalensis. Further research could support the possibility of SH as a separate taxon. Alternatively, SH could be a subspecies of Neanderthals, with the variability of this clade being remarkably higher than previously thought. PMID- 29417991 TI - Nocturnal behavior by a diurnal ape, the West African chimpanzee (Pan troglodytes verus), in a savanna environment at Fongoli, Senegal. AB - OBJECTIVES: I report on the nocturnal behavior of Fongoli chimpanzees in a savanna mosaic during different seasons and lunar phases and test the hypothesis that hot daytime temperatures influence activity at night. I predicted that apes would be more active at night during periods of greater lunar illuminosity given diurnal primates' lack of visual specializations for low-light conditions and in dry season months when water scarcity exacerbated heat stress. MATERIALS AND METHODS: I observed chimpanzees for 403 hrs on 40 nights between 2007 and 2013 and categorized their activity as social, movement, or vocalization. I scored their activity as occurring after moonrise or before moonset and considered the influence of moon phase (fuller versus darker phases) as well as season on chimpanzee nocturnal behavior in the analyses. RESULTS: Results indicate that apes were more active after moonrise or before moonset during fuller moon phases in the dry season but not the wet season. Most night-time activity involved movement (travel or forage), followed by social behavior, and long-distance vocal communication. DISCUSSION: Animals in highly seasonal habitats often exhibit thermoregulatory adaptations but, like other primates, chimpanzees lack physiological mechanisms to combat thermal stress. This study provides evidence that they may exhibit behaviors that allow them to avoid high temperatures in a savanna environment, such as feeding and socializing at night during the hottest time of year and in the brightest moon phases. The results support theories invoking thermal stress as a selective pressure for hominins in open environments where heat would constrain temporal foraging niches, and suggest an adaptability of sleeping patterns in response to external factors. PMID- 29417990 TI - Interbirth intervals in wild baboons: Environmental predictors and hormonal correlates. AB - OBJECTIVES: Interbirth intervals (IBIs) are a key metric of female reproductive success; understanding how they are regulated by environmental, social, and demographic factors can provide insight into sources of variance in female fitness. MATERIALS AND METHODS: Using 36 years of reproductive data on 490 IBIs for 160 wild female baboons, we identified sources of variance in the duration of IBIs and of their component phases: postpartum amenorrhea (PPA), sexual cycling, and pregnancy. We also examined how body fat and fecal hormone concentrations varied during female IBIs. RESULTS: We found that IBIs tended to be shorter (reproduction was accelerated) when female traits and environmental variables promoted energy acquisition, but with different specific effects for different component phases of the IBI. We also found that females lost a substantial amount of body fat during PPA, indicating that PPA imposes accumulating energetic costs as it progresses. Prior to cycle resumption females began to regain body fat; body fat was stable across the cycling phase and increased throughout most of pregnancy. However, body fat scores per se were not associated with the duration of any of the component phases. Finally, we found that fecal glucocorticoid concentrations decreased as PPA progressed, suggesting a decline in energetic stress over this phase. Fecal progestogen and estrogen concentrations changed over time during sexual cycling; the direction of these changes depended on the phase of the sexual cycle (luteal versus early or late follicular phases). DISCUSSION: Our study lends insight into the energetic constraints on female primate reproduction, revealing how female environments, changes in body fat, and steroid hormone concentrations relate to IBI duration and to reproductive readiness. PMID- 29417992 TI - Crystal clear: Vibrational spectroscopy reveals intrabone, intraskeleton, and interskeleton variation in human bones. AB - OBJECTIVES: Vibrational spectroscopy is a valuable tool for the study of burned skeletal remains. Nonetheless, most investigations have been focused on a limited number of samples as well as on faunal bones rather than human bones. Conclusions based on those investigations may lack representativeness, namely about the intrabone, intra- and interskeleton variability of several chemometric indices. We aimed to investigate this issue on a large sample of human bones. MATERIAL AND METHODS: Powder samples were collected from 168 bones from four human skeletons. The sampling targeted 47 long bones, 72 short bones, and 49 tarsal bones as well as different bone regions in a total of 638 powder samples. Bones were experimentally burned in an electric muffle furnace for two hours to maximum temperatures ranging from 400 degrees C to 1000 degrees C. Another 623 burned samples were then collected totaling 1261 samples subjected to FTIR-ATR analysis. The CI, BPI, C/C, and OH/P indices were calculated. RESULTS: An important intrabone, intra- and interskeleton variation was observed, especially for the BPI. The CI, C/C, and OH/P indices revealed much less variation so site-specific sampling may not be as critical in these cases. Clear differences between our results and those from previous investigations were observed, namely on the temperature increment evolution of the CI and C/C indices. DISCUSSION: The relatively large heterogeneity, especially at the intrabone level, is possibly the consequence of microstructural bone differences. The dissimilarities observed between our investigation and other published studies are probably due to the fact that the samples used here came from human rather than faunal bones. Also, our samples were buried previously to the experimental burning so this may also partly explain our contrasting results, since previous research was mostly performed on fresh bone. Future inferences based on vibrational spectroscopy analyses should take into account the possible effect of all these sources. PMID- 29417993 TI - Related herbivore species show similar temporal dynamics. AB - Within natural communities, different taxa display different dynamics in time. Why this is the case we do not fully know. This thwarts our ability to predict changes in community structure, which is important for both the conservation of rare species in natural communities and for the prediction of pest outbreaks in agriculture. Species sharing phylogeny, natural enemies and/or life-history traits have been hypothesized to share similar temporal dynamics. We operationalized these concepts into testing whether feeding guild, voltinism, similarity in parasitoid community and/or phylogenetic relatedness explained similarities in temporal dynamics among herbivorous community members. Focusing on two similar datasets from different geographical regions (Finland and Japan), we used asymmetric eigenvector maps as temporal variables to characterize species and community-level dynamics of specialist insect herbivores on oak (Quercus). We then assessed whether feeding guild, voltinism, similarity in parasitoid community and/or phylogenetic relatedness explained similarities in temporal dynamics among taxa. Species-specific temporal dynamics varied widely, ranging from directional decline or increase to more complex patterns. Phylogeny was a clear predictor of similarity in temporal dynamics at the Finnish site, whereas for the Japanese site, the data were uninformative regarding a phylogenetic imprint. Voltinism, feeding guild and parasitoid overlap explained little variation at either location. Despite the rapid temporal dynamics observed at the level of individual species, these changes did not translate into any consistent temporal changes at the community level in either Finland or Japan. Overall, our findings offer no direct support for the notion that species sharing natural enemies and/or life-history traits would be characterized by similar temporal dynamics, but reveal a strong imprint of phylogenetic relatedness. As this phylogenetic signal cannot be attributed to guild, voltinism or parasitoids, it will likely derive from shared microhabitat, microclimate, anatomy, physiology or behaviour. This has important implications for predicting insect outbreaks and for informing insect conservation. We hope that future studies will assess the generality of our findings across plant-feeding insect communities and beyond, and establish the more precise mechanism(s) underlying the phylogenetic imprint. PMID- 29417994 TI - Bacterial diversity and community structure in Chongqing radish paocai brines revealed using PacBio single-molecule real-time sequencing technology. AB - BACKGROUND: Traditional Chongqing radish paocai fermented with aged brine is considered to have the most intense flavor and authentic taste. Eight 'Yanzhi' (red, RRPB group) and 'Chunbulao' (white, WRPB) radish paocai brine samples were collected from Chongqing peasant households, and the diversity and community structures of bacteria present in these brines were determined using PacBio single-molecule real-time sequencing of their full-length 16S rRNA genes. RESULTS: In total, 30 phyla, 218 genera, and 306 species were identified from the RRPB group, with 20 phyla, 261 genera, and 420 species present in the WRPB group. Obvious differences in bacterial profiles between the RRPB and WRPB groups were found, with the bacterial diversity of the WRPB group shown to be greater than that of the RRPB group. This study revealed several characteristics of the bacteria composition, including the predominance of heterofermentative lactic acid bacteria, the species diversity of genus Pseudomonas, and the presence of three opportunistic pathogenic species. CONCLUSION: This study provides detailed information on the bacterial diversity and community structure of Chongqing radish paocai brine samples, and suggests it may be necessary to analyze paocai brine for potential sources of bacterial contamination and take appropriate measures to exclude any pathogenic species. (c) 2018 Society of Chemical Industry. PMID- 29417995 TI - Change in the color of heat-treated, vacuum-packed broccoli stems and florets during storage: effects of process conditions and modeling by an artificial neural network. AB - BACKGROUND: Vacuum-packed broccoli stems and florets were subjected to heat treatment (60-99 degrees C) for various time intervals. The activity of peroxidase was measured after processing. Thermally processed samples were then stored at 4 degrees C for 35 days, and the color of the samples was measured every 7 days. Effects of parameters (heating temperature and duration, storage time) on the color of broccoli were modeled and simulated by an artificial neural network (ANN). RESULTS: Simulations confirmed that stems were predicted to be more prone to changes than florets. More color loss was observed with longer processing or storage combinations. The simulations also confirmed that higher temperatures during heat processing could retard color changes during storage. For stems treated at 80 degrees C for short durations, color loss was more predominant than both 65 and 99 degrees C, probably due to the incomplete inactivation of enzymes besides more tissue damage, with increased enzyme access to the substrate. CONCLUSION: The greenness of both stems and florets during storage can be better preserved at higher temperatures (99 degrees C) and short times. The simulation results revealed that the ANN method could be used as an effective tool for predicting and analyzing the color values of heat-treated broccoli. (c) 2018 Society of Chemical Industry. PMID- 29417996 TI - Issues and Options in the Delineation of Well Capture Zones under Uncertainty. AB - The delineation of wellhead protection areas (WHPAs) under uncertainty is still a challenge for heterogeneous porous media. For granular media, one option is to combine particle tracking (PT) with the Monte Carlo approach (PT-MC) to account for geologic uncertainties. Fractured porous media, however, require certain restrictive assumptions under this approach. An alternative for all types of media is the capture probability (CP) approach, which is based on the solution of the standard advection-dispersion equation in a backward mode, making use of the analogy between forward and backward transport processes. Within this context, we review the current controversy about the correct form of the conceptual model for transport, finding that the advection-diffusion model, which represents the diffusive interchange between streamtubes with differing velocities, is more physically realistic than the conventional advection-dispersion model. For mildly to moderately heterogeneous materials, stochastic theories and simulation experiments show that this process converges at the field scale to an effective advection-dispersion process that can be simulated with conventional transport models using appropriate macrodispersivity values. For highly heterogeneous materials, stochastic theories do not yet exist but there is no reason why the process should not converge naturally as well. Macrodispersivities appear to be formation-specific. The advection-dispersion model can be used for capture zone delineation in heterogeneous granular media. For fractured porous systems, hybrid equivalent porous medium and discrete fracture network or CP-based approaches may have potential. In general, capture zones delineated by PT without MC will always be too small and should not be used as a basis for land-use decisions. PMID- 29417997 TI - Sexual signal loss: The link between behaviour and rapid evolutionary dynamics in a field cricket. AB - Sexual signals may be acquired or lost over evolutionary time, and are tempered in their exaggeration by natural selection. In the Pacific field cricket, Teleogryllus oceanicus, a mutation ("flatwing") causing loss of the sexual signal, the song, spread in <20 generations in two of three Hawaiian islands where the crickets have been introduced. Flatwing (as well as some normal-wing) males behave as satellites, moving towards and settling near calling males to intercept phonotactic females. From 2005 to 2012, we surveyed crickets and their responses to conspecific song, noting the morph and number of males and females before and after experimental playbacks. The three Hawaiian islands consistently contained different proportions of flatwing crickets, ranging from about 90% of males on Kauai to 50% on Oahu to rare on the Big Island of Hawaii. Flatwing and normal-wing males do not appear to differ in responsiveness to playback, a behaviour that should influence the likelihood of a male encountering a phonotactic female. Instead, male and female crickets from populations in which little to no calling song is perceptible during development tended to seek out callers more readily than crickets that developed in noisier environments. Such increased phonotaxis makes females more likely to find either the caller to which they are responding or to encounter a flatwing (or normal male satellite) that has also been attracted to the song. Our evidence suggests that pre-existing behavioural plasticity (manifest as flexible responses to social-particularly acoustic-information in the environment) is associated with the rapid spread of the flatwing trait. Different social environments select for differential success of flatwing or normal-wing males, which in turn alters the social environment itself. PMID- 29417998 TI - Preparation of konjac glucomannan/casein blending gels optimized by response surface methodology and assessment of the effects of high-pressure processing on their gel properties and structure. AB - BACKGROUND: In order to improve the compatibility of polysaccharide-protein mixtures and enhance their performance, a response surface methodology was used to optimize the preparation conditions of konjac glucomannan/casein blend gel. Moreover, the effects of high-pressure processing (HPP) on the gel properties and structure were also investigated. RESULTS: The optimal preparation parameters were a temperature of 60 degrees C, a total concentration 40 g kg-1 , and a dietary alkali concentration 5 g kg-1 . Under these conditions, the experimental value of hardness was 38.7 g, which was close to the predicted value. HPP increased gel hardness by 161-223% and led to a more compact structure at 200-600 MPa/10 min, while a hardness increase of ~120% and damaged structure were observed at 600 MPa/30 min. Fourier transform infrared spectroscopy showed that noncovalent interactions are likely the most important factor in the modification of gel hardness; indeed, hydrogen bonding interactions in the gels are enhanced when subjected to HPP, but are weakened at 600 MPa/30 min. COUCLUSION: Protein polysaccharide complexes with excellent properties could be obtained through this method, with broad application prospects in the food industry. (c) 2018 Society of Chemical Industry. PMID- 29417999 TI - Evaluation of phenolic profiles and antioxidant capacity of maqui (Aristotelia chilensis) berries and their relationships to drying methods. AB - BACKGROUND: Five drying methods (freeze, convective, sun, infrared, and vacuum drying) were applied to maqui berries to establish their effect on phenolic compounds and antioxidant capacity. Total phenolic, total flavonoid, and total anthocyanin contents were measured by spectrophotometry, anthocyanin and phenolic profiles were analyzed by chromatography, and the antioxidant capacity was determined. This study is probably the first to demonstrate the variation and stability of bioactive compounds from maqui berries after applying different drying methods. RESULTS: The highest content of phenolic and antioxidant compounds was obtained by using the freeze-drying method compared with fresh samples (P < 0.05). Eight anthocyanins were identified in all dehydrated maqui samples. Compared with fresh maqui, freeze-dried samples retained 73% and 64% of delphinidin and cyanidin derivatives respectively. Sun- and vacuum-dried samples conserved some phenolic acids. Vacuum-dried maqui retained a higher amount of free flavonols. CONCLUSION: This study demonstrated that the application of any drying method results in a final product with good levels of phenolic compounds. (c) 2018 Society of Chemical Industry. PMID- 29418000 TI - Cellulose synthesis during cell plate assembly. AB - The plant cell wall surrounds and protects the cells. To divide, plant cells must synthesize a new cell wall to separate the two daughter cells. The cell plate is a transient polysaccharide-based compartment that grows between daughter cells and gives rise to the new cell wall. Cellulose constitutes a key component of the cell wall, and mutants with defects in cellulose synthesis commonly share phenotypes with cytokinesis-defective mutants. However, despite the importance of cellulose in the cell plate and the daughter cell wall, many open questions remain regarding the timing and regulation of cellulose synthesis during cell division. These questions represent a critical gap in our knowledge of cell plate assembly, cell division and growth. Here, we review what is known about cellulose synthesis at the cell plate and in the newly formed cross-wall and pose key questions about the molecular mechanisms that govern these processes. We further provide an outlook discussing outstanding questions and possible future directions for this field of research. PMID- 29418002 TI - Long distance RNA movement. AB - Contents Summary 29 I. Introduction 29 II. Phloem as a conduit for macromolecules 30 III. Classes of phloem transported RNAs and their function 32 IV. Mode of RNA transport 35 V. Conclusions 37 Acknowledgements 37 References 37 SUMMARY: In higher plants, small noncoding RNAs and large messenger RNA (mRNA) molecules are transported between cells and over long distances via the phloem. These large macromolecules are thought to get access to the sugar-conducting phloem vessels via specialized plasmodesmata (PD). Analyses of the phloem exudate suggest that all classes of RNA molecules, including silencing-induced RNAs (siRNAs), micro RNAs (miRNAs), transfer RNAs (tRNAs), ribosomal RNA (rRNAs) and mRNAs, are transported via the vasculature to distant tissues. Although the functions of mobile siRNAs and miRNAs as signalling molecules are well established, we lack a profound understanding of mobile mRNA function(s) in recipient cells and tissues, and how they are selected for transport. A surprisingly high number of up to thousands of mRNAs were described in diverse plant species such as cucumber, pumpkin, Arabidopsis and grapevine to move long distances over graft junctions to distinct body parts. In this review, we present an overview of the classes of mobile RNAs, the potential mechanisms facilitating RNA long-distance transport, and the roles of mobile RNAs in regulating transcription and translation. Furthermore, we address potential function(s) of mobile protein-encoding mRNAs with respect to their characteristics and evolutionary constraints. PMID- 29418001 TI - Evidence for Reverse Hoogsteen Hairpin Intermediates in the Photocrosslinking of Human Telomeric DNA Sequences. AB - UVB irradiation of human telomeric d(GGGTTA)3 GGG sequences in potassium ion solution crosslinks the first and third TTA segments through anti cyclobutane pyrimidine dimer (CPD) formation. The photocrosslinking reaction was first proposed to occur through a form 3 two-tetrad G-quadruplex in which the lateral four-nucleotide GTTA loop can interact with an adjacent TTA loop. Curiously, the reaction does not occur with sodium ion, which was explained by the formation of a basket structure which only has three-nucleotide TTA loops that cannot interact. Sequences known or expected to favor the two-tetrad basket did not show enhanced photocrosslinking, suggesting that some other structure was the reactive intermediate. Herein, we report that anti CPDs form in human telomeric DNA sequences with lithium ion that is known to disfavor G-quadruplex formation, as well as with potassium ion when the bases are modified to interfere with G quartet formation. We also show that anti CPDs form in sequences containing A's in place of G's that cannot form Hoogsteen hairpins, but can form reverse Hoogsteen hairpins. These results suggest that reverse Hoogsteen hairpins may play a hitherto unrecognized role in the biology and photoreactivity of DNA in telomeres, and possibly in other purine-rich sequences found in regulatory regions. PMID- 29418003 TI - In vitro evaluation of chitosan copper chelate gels as a multimicronutrient feed additive for cattle. AB - BACKGROUND: Effective micronutrient supplementation strategies are critical to ensure optimal health and productivity in livestock. The objective of this study was to develop a copper and vitamin (multimicronutrient) delivery system based on chitosan gel beads, and test its suitability, in vitro, for use as a cattle feed additive. RESULTS: Chitosan was chelated with copper sulfate to produce millimetre-scale gel matrices (~2 mm). The copper content was significantly increased (from 61 to 95 mg g by adjusting pH to alkaline conditions post bead formation. The beads could subsequently be loaded with the model vitamin riboflavin to levels as high as 324 ug g-1 beads. Restricted rehydration of the dried gel matrices in simulated rumen fluid led to a sustained release of riboflavin with no copper released in these neutral conditions for up to 24 h, demonstrating copper rumen bypass. Moreover, sustained release of the mineral was observed in abomasal conditions of pH 2 over a 3 h period. CONCLUSIONS: The matrices showed rumen bypass for copper yet supplied nutritionally relevant levels of the free mineral in abomasal conditions, as required for effective supplementation in cattle. The controlled-release properties demonstrated by the matrices indicate their potential as a multimicronutrient functional feed additive to enhance cattle nutrition and productivity. (c) 2018 Society of Chemical Industry. PMID- 29418004 TI - Spectral resolution and high-flux capability tradeoffs in CdTe detectors for clinical CT. AB - PURPOSE: Photon-counting detectors using CdTe or CZT substrates are promising candidates for future CT systems but suffer from a number of nonidealities, including charge sharing and pulse pileup. By increasing the pixel size of the detector, the system can improve charge sharing characteristics at the expense of increasing pileup. The purpose of this work is to describe these considerations in the optimization of the detector pixel pitch. METHODS: The transport of x rays through the CdTe substrate was simulated in a Monte Carlo fashion using GEANT4. Deposited energy was converted into charges distributed as a Gaussian function with size dependent on interaction depth to capture spreading from diffusion and Coulomb repulsion. The charges were then collected in a pixelated fashion. Pulse pileup was incorporated separately with Monte Carlo simulation. The Cramer-Rao lower bound (CRLB) of the measurement variance was numerically estimated for the basis material projections. Noise in these estimates was propagated into CT images. We simulated pixel pitches of 250, 350, and 450 microns and compared the results to a photon counting detector with pileup but otherwise ideal energy response and an ideal dual-energy system (80/140 kVp with tin filtration). The modeled CdTe thickness was 2 mm, the incident spectrum was 140 kVp and 500 mA, and the effective dead time was 67 ns. Charge summing circuitry was not modeled. We restricted our simulations to objects of uniform thickness and did not consider the potential advantage of smaller pixels at high spatial frequencies. RESULTS: At very high x-ray flux, pulse pileup dominates and small pixel sizes perform best. At low flux or for thick objects, charge sharing dominates and large pixel sizes perform best. At low flux and depending on the beam hardness, the CRLB of variance in basis material projections tasks can be 32%-55% higher with a 250 micron pixel pitch compared to a 450 micron pixel pitch. However, both are about four times worse in variance than the ideal photon counting detector. The optimal pixel size depends on a number of factors such as x-ray technique and object size. At high technique (140 kVp/500 mA), the ratio of variance for a 450 micron pixel compared to a 250 micron pixel size is 2126%, 200%, 97%, and 78% when imaging 10, 15, 20, and 25 cm of water, respectively. If 300 mg/cm2 of iodine is also added to the object, the variance ratio is 117%, 91%, 74%, and 72%, respectively. Nonspectral tasks, such as equivalent monoenergetic imaging, are less sensitive to spectral distortion. CONCLUSIONS: The detector pixel size is an important design consideration in CdTe detectors. Smaller pixels allow for improved capabilities at high flux but increase charge sharing, which in turn compromises spectral performance. The optimal pixel size will depend on the specific task and on the charge shaping time. PMID- 29418005 TI - Phosphorus- and nitrogen-acquisition strategies in two Bossiaea species (Fabaceae) along retrogressive soil chronosequences in south-western Australia. AB - During long-term ecosystem development and its associated decline in soil phosphorus (P) availability, the abundance of mycorrhizal plant species declines at the expense of non-mycorrhizal species with root specialisations for P acquisition, such as massive exudation of carboxylates. Leaf manganese (Mn) concentration has been suggested as a proxy for such a strategy, Mn concentration being higher in non-mycorrhizal plants that release carboxylates than in mycorrhizal plants. Shifts in nitrogen (N)-acquisition strategies also occur; nodulation in legumes is expected at low N availability, when sufficient P is available. We investigated whether two congeneric legume species (Bossiaea linophylla and Bossiaea eriocarpa) occurring along two long-term chronosequences on the south-western Australian coast and grown in a glasshouse at varying N and P supply exhibited plasticity in nutrient-acquisition strategies. We hypothesised that the shifts in nutrient limitation and nutrient-acquisition strategies at the community level would also be found at the species level. Leaf N: P ratios and the responses to nutrient availability suggested that growth of both species exhibited P-limitation in all treatments, due to the very high leaf [N] of legumes afforded by symbiotic N-fixation. Mycorrhizal colonisation was not greater at higher P supply, and root exudation of carboxylates was not stimulated at low P supply; both were unrelated to leaf [Mn]. However, nodule production declined with increasing N supply. We conclude that intraspecific variation in nutrient-acquisition and use is low in these species, and that the variation at the community level, observed in previous studies, is likely driven by high species turnover. PMID- 29418006 TI - Light-based methods for whole blood bacterial inactivation enabled by a recirculating flow system. AB - Light of certain wavelengths can be used to inactivate pathogens. Whole blood is opaque; thus, the penetration of light is reduced. Here, we overcame this limitation using a thin transparent tube that is illuminated from all angles. Three light-based techniques were evaluated: photodynamic therapy (PDT) using a 660-nm light and antibody-photosensitizer conjugates, ultraviolet, and violet light. We observed a reduction of 55-71% of Staphylococcus aureus after 5 h of exposure (starting concentration 107 CFU mL-1 ) and an 88-97% reduction in methicillin-resistant Staphylococcus aureus (MRSA) (starting 104 CFU mL-1 ). An 83-92% decrease for S. aureus and 98-99.9% decrease for MRSA were observed when combined with an immunocapture approach. Complete blood count with differential analysis did not reveal any significant changes in the blood cell numbers. Genotoxicity studies showed that violet and ultraviolet did not induce any significant level of single strand breaks and alkali labile sites in the peripheral blood mononuclear cells (PBMC). In contrast, ultraviolet did induce a very low level of cyclobutane pyrimidine dimers, a UV damage indicator. PDT generated a significant level of single strand breaks and 8-oxoGua in these cells. The approaches showed promise for whole blood pathogen inactivation with minimal collateral damage to PBMC. PMID- 29418007 TI - Blood reflux to the lymphatic vessels after lymphaticovenous anastomosis. PMID- 29418008 TI - Double-barrel vascularized dual fibula transfer with epiphyseal growth plate for hip reconstruction: A case report. AB - We present a case report of a 10-year-old girl diagnosed with Ewing sarcoma treated with intra-articular wide resection of the right femur and reconstruction with a series-connected double-barrel bilateral vascularized fibula graft (db BVFG), including fibular head for articulation with the acetabulum of the pelvic bone and preservation of the epiphyseal growth plates for eventual limb growth. No postoperative complications were observed and bone union was achieved with fibular graft hypertrophy, allowing for full weight bearing. Neither local recurrence nor metastasis was observed at 17-year follow-up. Range of motion degrees at last follow up: hip flexion 90 degree, extension 12 degree, abduction 31 degree, rotation 25 degree. Right versus left limb discrepancy was 60 mm. Db BVFG may be an option for reconstruction of long femoral defects and hip joint restoration following tumor resection and inclusion of epiphysis within the graft is a viable option in pediatric patients to restore longitudinal growth of the reconstructed long bone. PMID- 29418009 TI - Multidisciplinary approach in a case of Hand-Schuller-Christian disease with maxillary involvement. AB - Langerhans cell histiocytosis (LCH) is a childhood pathology with a peak of incidence ranging from 1 to 4 years of age, though diagnosis is often made in adult age. LCH is clinically classified into three types: eosinophilic granuloma, Hand-Schuller-Christian disease and Abt-Letterer-Siwe disease. We report a case of Hand-Schuller-Christian disease with diabetes insipidus, skull and maxillary involvement in a 16-year-old boy referred to our observation for gradual increase in mobility of the teeth and subsequent gradual loss of the second premolars and the first molars of the upper jaw. Due to the extension of the lesion and the age of the patient, surgery, and chemotherapy was chosen as the more fit treatment according to the current protocol. The clinical and radiological evaluation at the end of the therapy and after 5 years showed complete remission. The absence of relapse has allowed to initiate a fixed orthodontic dental alignment treatment with a good response to orthodontic treatment despite the underlying disease. The present case exemplifies the importance of close multidisciplinary dental and medical collaboration including general dentistry, periodontology, oral medicine, oral and maxillofacial pathology, oral radiology, orthodontics and hematology oncology for diagnosis, management, treatment monitoring, and decision-making. PMID- 29418010 TI - Tissue models for RF exposure evaluation at frequencies above 6 GHz. AB - Exposures to radiofrequency (RF) energy above 6 GHz are characterized by shallow energy penetration, typically limited to the skin, but the subsequent increase in skin temperature is largely determined by heat transport in subcutaneous layers. A detailed analysis of the energy reflection, absorption, and power density distribution requires a knowledge of the properties of the skin layers and their variations. We consider an anatomically detailed model consisting of 3 or 4 layers (stratum corneum, viable epidermis plus dermis, subcutaneous fat, and muscle). The distribution of absorbed power in the different tissue layers is estimated based on electrical properties of the tissue layers inferred from measurements of reflected millimeter wavelength energy from skin, and literature data for the electrical properties of fat and muscle. In addition, the thermal response of the model is obtained using Pennes bioheat equation as well as a modified version incorporating blood flow rate-dependent thermal conductivity that provides a good fit to experimentally-found temperature elevations. A greatly simplified 3-layer model (Dermis, Fat, and Muscle) that assumes surface heating in only the skin layer clarifies the contribution of different tissue layers to the increase in surface skin temperature. The model shows that the increase in surface temperature is, under many circumstances, determined by the thermal resistance of subcutaneous tissues even though the RF energy may be deposited almost entirely in the skin layer. The limits of validity of the models and their relevance to setting safety standards are briefly discussed. Bioelectromagnetics. 39:173-189, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418011 TI - Health status and most distressing concerns at admission and discharge reported by patients cared for at an internal medical care ward. AB - BACKGROUND: To promote patients' ability to regain health during hospitalisation, care should not only focus on disease but also on how patients perceive health. There is a lack of studies on how patients admitted for inpatients care perceive their health. AIM: To investigate self-reported health at admission and discharge perceived by patients admitted to an internal medicine ward; and, further, to explore the most distressing concerns at admission and discharge and the factors that influence low health status at discharge. DESIGNS AND METHODS: One hundred and forty-seven patients completed EQ-5D and an open-ended question 'What concerns distress you the most?' at admission and discharge. Descriptive, parametric and nonparametric analyses were used. Subset analyses were performed between three groups based on health change. Factors influencing low health status at discharge were tested in a logistic regression. To analyse most distressing concerns, an inductive content analysis was performed. RESULTS: There was a significant increase in self-rated health for patients with gastrointestinal disorders. At discharge, 50% was identified with improved and 30% with unaltered health. Twenty per cent reported a significant deterioration of health and had the highest frequency of severe problems in all EQ-5D dimensions. Several patients left hospital with distressing symptoms, uncertainty and concerns that had persisted throughout their hospitalisation. Vulnerable patients were characterised by an acute admission, unemployment and longer hospitalisation. Low EQ VAS at admission predicted poor health at discharge. CONCLUSIONS: Many patients had low health status at admission. For some, this did not improve during hospital stay, and for some, it got worse. Our findings highlight a group, whose care can be improved, through information, support and follow-up routines within and outside the hospital. Identifying these patients, efforts to better support patients in their self-care, including relief of pain and worries, at discharge can be established. PMID- 29418012 TI - Human leucocyte antigens coeliac haplotypes and primary autoimmune hypophysitis in caucasian patients. AB - PURPOSE: Primary hypophysitis is a rare disease, with an autoimmune aetiology. As few papers have investigated genetic of hypophysitis, our aim was to evaluate HLA status in a single-centre series of patients. PATIENTS AND METHOD: A retrospective, longitudinal and cross-sectional study was conducted. In consecutive Caucasian patients, clinically or histologically diagnosed for primary autoimmune hypophysitis (PAH), the HLA genotype having been determined. This cohort was compared with a control group. Anti-pituitary and anti hypothalamus auto-antibodies evaluation was included. RESULTS: 16 patients were enrolled. Fourteen patients were female (87.5%). According to HLA-DR status, we found the following: 9 of 16 patients (56.3%) haplotypes that were associated with coeliac disease (CD). Among these, 5 carried the DR7-DQ2 heterozygote haplotype (55.5%) while the remaining ones only the following haplotypes: DR3-DQ2 homozygote (25%), DR4-DQ2 heterozygote (25%), DR4-DQ8 heterozygote (50%) and DR4 DQ8 homozygote (25%), respectively. A total of 12 CD-associated haplotypes were identified. In PAH, we found a significantly higher frequency of patients carrying CD-associated HLA haplotypes as compared to the control group (respectively, 75% vs 48% P = .03; OR: 3.25 95%IC:1.1-10.3), particularly, for DQ2 and DQ8 haplotypes. DQ2 haplotype was detected in 50% of PAH and 38.4% of the control group (P = .3), while DQ8 haplotype in 25% of PAH and 7.2% of the control group (P = .01 OR:4.3 95%IC:1.3-14.7). CONCLUSION: Our data suggest that PAH and CD share some HLA haplotypes, reinforcing the knowledge of their association. HLA haplotypes, particularly DQ8, may play a role in PAH management and diagnosis, also suggesting the predisposition to other autoimmune diseases. PMID- 29418013 TI - Transcriptional profiles of pulmonary innate immune responses to isogenic antibiotic-susceptible and multidrug-resistant Pseudomonas aeruginosa. AB - The virulence of an isogenic pair of Pseudomonas aeruginosa strains was studied under similar experimental conditions in two animal infection models. The time to death was significantly longer for the multidrug resistant (MDR) than the wild type strain. The transcriptional profiles of 84 innate immune response genes in the lungs of immune competent Balb/C mice were further compared. Significantly weaker expression of genes involved in production of soluble pattern recognition receptor and complement were observed in animals infected with the MDR strain. Altered patterns of innate immune system activation may explain the attenuated virulence in MDR bacteria. PMID- 29418014 TI - Transformation of cellobiose during the interaction of cellobiose dehydrogenase and beta-glucosidase of Cerrena unicolor. AB - This work investigated the regulatory role of the interaction between cellobiose dehydrogenase (CDH) and beta-glucosidase (beta-GLU) in the conversion of cellobiose into cellobionolactone or glucose in vitro. To study the regulation, the two enzymes were isolated from the culture medium of the fungus Cerrena unicolor grown on a medium with microcrystalline cellulose. The enzymes were obtained in an electrophoretically homogeneous state. Their properties were studied. Both enzymes had acidic pH optima and were more stable in the acidic pH range. CDH was moderately thermostable, while beta-GLU had a low thermostability. Both enzymes efficiently catalyzed the transformation of cellobiose. A mixture of CDH and beta-GLU transformed cellobiose to glucose or cellobionolactone in the presence of various concentrations of laccase and hydroquinone. Formation of glucose and cellobionolactone in vitro during the competition between CDH and beta-GLU for cellobiose depended on the availability of quinones, formed as a result of the interaction of laccase and hydroquinone, for CDH. At low laccase and hydroquinone concentrations, the formation of glucose was found to predominate over that of cellobionolactone. The possible physiological role of the enzymes' interaction is discussed. PMID- 29418015 TI - Inverted follicular keratoses of the buttocks. PMID- 29418016 TI - Bone mineral density in young adults with Prader-Willi syndrome: A randomized, placebo-controlled, crossover GH trial. AB - CONTEXT: The prevalence of osteoporosis is increased in adults with Prader-Willi syndrome (PWS). In children with PWS, growth hormone (GH) treatment has beneficial effects on bone mineral density (BMD). BMD might deteriorate after cessation of GH at adult height (AH), while continuing GH might maintain BMD. OBJECTIVE: To investigate the effects of GH vs placebo, and furthermore the effects of sex steroid replacement therapy (SSRT), on BMD in GH-treated young adults with PWS who had attained AH. DESIGN: Two-year, randomized, double-blind, placebo-controlled, crossover GH study. PATIENTS: Twenty-seven young adults with PWS were stratified for gender and BMI and then randomly and blindly assigned to receive GH (0.67 mg/m2 /day) or placebo for 1 year, after which they crossed over to the alternative treatment for another year. MEASUREMENTS: Bone mineral density of the total body (BMDTB ) and lumbar spine (BMDLS ) SDS were measured by dual energy x-ray absorptiometry. RESULTS: At AH, BMDTB SDS was significantly lower compared to healthy peers (P < .01), while BMADLS SDS was similar. Both BMDTB SDS and BMADLS SDS were similar during 1 year of GH vs 1 year of placebo. In hypogonadal young adults without SSRT, BMDTB SDS and BMADLS SDS decreased during the 2-year study (P = .11 and P = .01), regardless of GH or placebo, while BMDTB SDS increased in those with SSRT (P < .01). CONCLUSIONS: Compared to GH treatment, 1 year of placebo after attainment of AH does not deteriorate BMD SDS in young adults with PWS. In addition, our data suggest that GH is not able to prevent the decline in BMD SDS in hypogonadal young adults with PWS, unless it is combined with SSRT. PMID- 29418017 TI - Periodontal condition in relation to the adherence to nutrient recommendations in daily smokers. AB - AIM: To examine whether a healthy diet based on nutrient recommendations is associated with periodontal condition in smokers. MATERIAL AND METHODS: Daily smokers from the cross-sectional Health 2000 Survey (BRIF 8901) in Finland were analysed in two age groups (30-49 and 50-79 years, n = 704 and 267) and according to the level of oral hygiene. Periodontal condition was measured as the number of sextants with gingival bleeding and teeth with >=4 mm deepened periodontal pockets. Information on nutrition was collected by a validated food frequency questionnaire and measured using the Baltic Sea Diet Score (BSDS) and the Recommended Finnish Diet Score (RFDS). RESULTS: In the total study population, no association between the scores and periodontal condition was observed. Among 30- to 49-year-old participants with good oral hygiene, diet scores associated inversely with the number of teeth with deepened periodontal pockets (p = .078 (BSDS) and p = .027 (RFDS)). CONCLUSIONS: In a representative sample of Finnish adults who smoke, a healthy diet was not associated with periodontal condition. Among a younger age group with good oral hygiene, a healthy diet associated with better periodontal condition. Age and oral hygiene appeared to modify the association between diet and periodontal condition. PMID- 29418018 TI - At a crossroads: Revisiting mild cognitive impairment in Parkinson's disease. PMID- 29418020 TI - What is Vipp1 good for? AB - While Vipp1 (also known as IM30) clearly is essential for proper biogenesis of thylakoid membranes in chloroplasts and cyanobacteria, the exact function of Vipp1/IM30 still remains unclear. The recent in vivo study of Gutu et al. now demonstrates that Vipp1/IM30 forms localized puncta specifically at highly curved membrane regions at the cell periphery. These Vipp1/IM30 puncta were found being highly dynamic under normal growth conditions, while it has recently been shown that they stably associate with membranes under high-light conditions. These observations, together with the observation that other Vipp1/IM30 homologous proteins also form puncta under stress conditions, indicate a protective function of these proteins at stressed membrane regions. However, Gutu et al. additionally show that Vipp1/IM30 is of special importance when growing cells are shifted from dark to light growth conditions, which could be explained by light stress, by thylakoid membrane dynamics and/or by photosystem biogenesis, which is being discussed in this article. PMID- 29418021 TI - Association between serum hepcidin level and restless legs syndrome. AB - BACKGROUND: To better understand the role of iron homeostasis dysregulation in restless legs syndrome, we compared serum hepcidin and ferritin levels in drug free patients with primary restless legs syndrome and healthy controls and studied the relationship between hepcidin level and restless legs syndrome severity. METHODS: One hundred and eight drug-free patients with primary restless legs syndrome (65 women; median age, 61.5 years) and 45 controls (28 women; median age, 53.9 years) were enrolled. Inclusion criteria were: normal ferritin level (>50 ng/mL) and absence of iron disorders, chronic renal or liver failure, and inflammatory or neurological diseases. Each subject underwent a thorough clinical examination and a polysomnography assessment. Serum hepcidin-25 was quantified using a validated mass spectrometry method. Restless legs syndrome severity was evaluated according to the International Restless Legs Syndrome Study Group. RESULTS: Despite no group difference between normal ferritin levels and demographic features, serum hepcidin level and hepcidin/ferritin ratio were higher in patients than in controls. Hepcidin level and hepcidin/ferritin ratio, but not ferritin level, were positively correlated with periodic leg movements during sleep and wakefulness in the whole sample. Hepcidin level seem to be associated with restless legs syndrome severity in a complex U-shaped relationship, without relationship with age at restless legs syndrome onset, positive family history, sleep and depressive symptoms, genetic background, and polysomnographic measurements. No relationship was found between ferritin level and restless legs syndrome severity. CONCLUSION: In drug-free patients with primary restless legs syndrome, hepcidin level is higher than in controls and may be associated with restless legs syndrome clinical severity. This result emphasizes the complex peripheral iron metabolism deregulation in restless legs syndrome, opening potential perspectives for a personalized approach with a hepcidin antagonist. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29418022 TI - Acute anti-obesity effects of intracerebroventricular 11beta-HSD1 inhibitor administration in diet-induced obese mice. AB - The hypothalamus is the regulatory centre of both appetite and energy balance and endoplasmic reticulum (ER) stress in the hypothalamus is involved in the pathogenesis of obesity. Recently, inhibition of 11 beta hydroxysteroid dehydrogenase type1 (11beta-HSD1) was reported to have an anti-obesity effect by reducing fat mass. However, the link between the role of 11beta-HSD1 in the hypothalamus and obesity has yet to be determined. In the present study, embryonal primary hypothalamic neurones and high-fat diet (HFD) fed mice were used to investigate the anorexigenic effects of 11beta-HSD1 inhibitors both in vitro and in vivo. In hypothalamic neurones, carbenoxolone (a non selecitve 11beta-HSD inhibitor) alleviated ER stress and ER stress-induced neuropeptide alterations. In HFD mice, i.c.v. administration of carbenoxolone or KR67500 (nonselective and selective 11beta-HSD1 inhibitors, respectively) was associated with less weight gain compared to control mice for 24 hours after treatment, presumably by reducing food intake. Furthermore, glucose regulated protein (Grp78), spliced X-box binding protein (Xbp-1s), c/EBP homologous protein (chop) and ER DnaJ homologue protein (Erdj4) expression was decreased in the hypothalami of mice administrated 11beta-HSD1 inhibitors compared to controls. Conversely, the phosphorylation of protein kinase B (PKB/Akt), signal transducer and activator of transcription 3 (Stat3), mitogen-activated protein kinase (MAPK/ERK) and S6 kinase1 (S6K1) in the hypothalamus was induced more in mice treated using the same regimes. In conclusion, acute 11beta-HSD1 inhibition in the hypothalamus could reduce food intake by decreasing ER stress and increasing insulin, leptin, and mammalian target of rapamycin complex 1 (mTORC1) signalling. PMID- 29418019 TI - New Developments in Genetic rat models of Parkinson's Disease. AB - Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD-linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD. Emerging research tools include "knockout" rats with disruption of genes in which mutations have been causally linked to PD, including LRRK2, alpha-synuclein, Parkin, PINK1, and DJ-1. Rats have also been increasingly used for transgenic and viral-mediated overexpression of genes relevant to PD, particularly alpha-synuclein. It may not be realistic to obtain a single animal model that completely reproduces every feature of a human disease as complex as PD. Nevertheless, compared with mice with the same mutations, many genetic rat animal models of PD better reproduce key aspects of PD including progressive loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits, and age-dependent formation of abnormal alpha synuclein protein aggregates. Here we briefly review new developments in genetic rat models of PD that may have greater potential for identifying underlying mechanisms, for discovering novel therapeutic targets, and for developing greatly needed treatments to slow or halt disease progression. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29418023 TI - A noble pathological role for alpha-synuclein in triggering neurodegeneration of Parkinson's disease. PMID- 29418024 TI - Light Regulation of DNA Minicircle Dimerization by Utilizing Azobenzene C Nucleosides. AB - Although DNA has the ability to form almost every desired shape, the usability of DNA nanostructures can be limited due to the lack of functionality. To functionalize nanoscale structures, light-responsive moieties like photoswitchable azobenzenes can be introduced into DNA. Upon UV irradiation, the isomerization of the azobenzene moiety causes destabilization of the neighboring base pairs leading to decreased binding ability. The linker strategy of the azobenzene to the DNA alters the performance of the switching behavior significantly. We hereby report the utilization of four different azobenzene C nucleosides and compare their features in a nanoarchitecture model with the help of gel-electrophoresis and atomic force microscope-imaging. PMID- 29418025 TI - A simple and effective method to optimize limb position after complex lower limb free flap reconstruction with concurrent external fixation. PMID- 29418026 TI - Transcriptional profiling of primary endometrial epithelial cells following acute HIV-1 exposure reveals gene signatures related to innate immunity. AB - PROBLEM: Genital epithelial cells (GECs) line the mucosal surface of the female genital tract (FGT) and are the first cells that interface with both commensal microbiota and sexually transmitted pathogens. Despite the protective barrier formed by GECs, the FGT is a major site of HIV-1 infection. This highlights the importance of studying the interaction of HIV-1 and GECs. METHOD OF STUDY: Using microarray analysis, we characterized the transcriptional profile of primary endometrial GECs grown in the presence or absence of physiological levels of E2 (10-9 mol/L) or P4 (10-7 mol/L) following acute exposure to HIV-1 for 6 hours. RESULTS: Acute exposure of primary endometrial GECs to HIV-1 resulted in the expression of genes related to inflammation, plasminogen activation, adhesion and diapedesis and interferon response. Interestingly, exposure to HIV-1 in the presence of E2 and P4 resulted in differential transcriptional profiles, suggesting that the response of primary endometrial GECs to HIV-1 exposure is modulated by female sex hormones. CONCLUSION: The gene expression signature of endometrial GECs indicates that the response of these cells may be key to determining host susceptibility to HIV-1 and that sex hormones modulate these interactions. This study allows us to explore possible mechanisms that explain the hormone-mediated fluctuation of HIV-1 susceptibility in women. PMID- 29418027 TI - Emerging role of the Jun N-terminal kinase interactome in human health. AB - The c-Jun N-terminal kinases (JNKs) are located downstream of Ras-mitogen activated protein kinase signaling cascades. More than 20 years of study has shown that JNKs control cell fate and many cellular functions. JNKs and their interacting proteins form a complicated network with diverse biological functions and physiological effects. Members of the JNK interactome include Jun, amyloid precursor protein, and insulin receptor substrate. Recent studies have shown that the JNK interactome is involved in tumorigenesis, neuron development, and insulin resistance. In this review, we summarize the features of the JNK interactome and classify its members into three groups: upstream regulators, downstream effectors, and scaffold partners. We also highlight the unique cellular signaling mechanisms of JNKs and provide more insights into the roles of the JNK interactome in human diseases. PMID- 29418028 TI - Stabilization and translation of synthetic operon-derived mRNAs in chloroplasts by sequences representing PPR protein-binding sites. AB - The chloroplast is a prime target for genetic engineering in plants, offering various advantages over nuclear transformation. For example, chloroplasts allow the expression of polycistronic transcripts and thus to engineer complex metabolic pathways. Each cistron within such a longer transcript needs its own expression elements. Within the 5'-UTR, such expression elements are needed for stabilizing mRNAs and for translation of the downstream reading frame. One of the few effective expression elements used so far in transplastomic approaches is the intercistronic expression element (IEE). The IEE is derived from the psbT-psbH intergenic region and includes a target sequence of the RNA binding protein HCF107. We here show that excessive expression of the IEE can lead to specific defects of endogenous chloroplast mRNA stabilization, likely via depletion of HCF107. Key players in chloroplast transcript stabilization and translation are pentatricopeptide repeat (PPR) proteins, which are structurally related to HCF107. PPR proteins that stabilize mRNAs leave behind short RNA footprints that are indicators of their activity. We identified such sRNAs in tobacco, and demonstrate that they are sufficient to stabilize and stimulate translation of mRNAs from synthetic dicistronic transgenes in chloroplasts. Thus, minimal sequence elements are generally adequate to support key steps in chloroplast gene expression, i.e. RNA stability and translation. Furthermore, our analysis expands the repertoire of available expression elements to facilitate the assembly and expression of multi-gene ensembles in the chloroplast. PMID- 29418029 TI - Procedural and obstetrical outcomes after embryo reduction or fetal reduction in multifetal pregnancies: a retrospective study. AB - OBJECTIVES: Few studies have compared embryo reduction (ER) and fetal reduction (FR) for multifetal pregnancy reduction (MPR). This study investigated the procedure-related adverse events and the obstetrical outcomes in women with multifetal pregnancies (MPs) in whom MPRs to twins or a single fetus were performed at different gestational ages. METHODS: We retrospectively analyzed the data from MPs on which transvaginal ER (n = 181) at a mean gestational age of 7.6 weeks or transabdominal FR (n = 115) at a mean gestational age of 12.9 weeks were performed between December 2006 and January 2017. The groups were compared with respect to the procedure-related and obstetrical outcomes. RESULTS: Compared with that in the ER group, the proportion of procedure-related fetal losses was lower in the FR group (7.2% vs. 0.9%; P = 0.039; odds ratio [OR], 0.12; 95% confidence interval [CI], 0.02 to 0.89). The mean gestational ages at delivery for twins were 34.2 weeks in the ER group and 35.7 weeks in the FR group (P = 0.014). Compared with those in the ER group, the FR group had lower miscarriage (8.8% vs. 2.6%; P = 0.045; OR, 0.28; 95% CI, 0.08 to 0.97) and overall fetal loss (13.3% vs. 5.2%; P = 0.031; OR, 0.36; 95% CI, 0.14 to 0.91) rates. CONCLUSION: The FR procedure is overall a better and safer approach to reducing morbidity and mortality in MPs. Spontaneous demise of one fetus may occur after ER, and FR has advantages because chorionic villus sampling and ultrasound screening for nuchal translucency and anatomical defects can be conducted before the procedure. The ER approach is still reasonable when a patient's religious or other ethical concerns are of primary importance. PMID- 29418030 TI - Bifunctional glycosyltransferases catalyze both extension and termination of pectic galactan oligosaccharides. AB - Pectins are the most complex polysaccharides of the plant cell wall. Based on the number of methylations, acetylations and glycosidic linkages present in their structures, it is estimated that up to 67 transferase activities are involved in pectin biosynthesis. Pectic galactans constitute a major part of pectin in the form of side-chains of rhamnogalacturonan-I. In Arabidopsis, galactan synthase 1 (GALS1) catalyzes the addition of galactose units from UDP-Gal to growing beta 1,4-galactan chains. However, the mechanisms for obtaining varying degrees of polymerization remain poorly understood. In this study, we show that AtGALS1 is bifunctional, catalyzing both the transfer of galactose from UDP-alpha-d-Gal and the transfer of an arabinopyranose from UDP-beta-l-Arap to galactan chains. The two substrates share a similar structure, but UDP-alpha-d-Gal is the preferred substrate, with a 10-fold higher affinity. Transfer of Arap to galactan prevents further addition of galactose residues, resulting in a lower degree of polymerization. We show that this dual activity occurs both in vitro and in vivo. The herein described bifunctionality of AtGALS1 may suggest that plants can produce the incredible structural diversity of polysaccharides without a dedicated glycosyltransferase for each glycosidic linkage. PMID- 29418031 TI - Fitness variation among host species and the paradox of ineffective rhizobia. AB - Legumes can preferentially select beneficial rhizobial symbionts and sanction ineffective strains that fail to fix nitrogen. Yet paradoxically, rhizobial populations vary from highly beneficial to ineffective in natural and agricultural soils. Classic models of symbiosis focus on the single dimension of symbiont cost-benefit to sympatric hosts, but fail to explain the widespread persistence of ineffective rhizobia. Here, we test a novel framework predicting that spatio-temporal and community dynamics can maintain ineffective strains in rhizobial populations. We used clonal and multistrain inoculations and quantitative culturing to investigate the relative fitness of four focal Bradyrhizobium strains varying from effective to ineffective on Acmispon strigosus. We found that an ineffective Bradyrhizobium strain can be sanctioned by its native A. strigosus host across the host's range, forming fewer and smaller nodules compared to beneficial strains. But the same ineffective Bradyrhizobium strain exhibits a nearly opposite pattern on the broadly sympatric host Acmispon wrangelianus, forming large nodules in both clonal and multistrain inoculations. These data suggest that community-level effects could favour the persistence of ineffective rhizobia and contribute to variation in symbiotic nitrogen fixation. PMID- 29418032 TI - Birth-weight differences at term are explained by placental dysfunction and not by maternal ethnicity. AB - OBJECTIVE: To investigate the influence of ethnicity, fetal gender and placental dysfunction on birth weight (BW) in term fetuses of South Asian and Caucasian origin. METHODS: This was a retrospective study of 627 term pregnancies assessed at two public tertiary hospitals in Spain and Sri Lanka. All fetuses underwent biometry and Doppler examinations within 2 weeks of delivery. The influences of fetal gender and ethnicity, gestational age (GA) at delivery, cerebroplacental ratio (CPR) and maternal age, height, weight and parity on BW were evaluated by multivariable regression analysis. RESULTS: Fetuses born in Sri Lanka were smaller than those born in Spain (mean BW = 3026 +/- 449 g vs 3295 +/- 444 g; P < 0.001). Multivariable regression analysis demonstrated that GA at delivery, maternal weight, CPR, maternal height and fetal gender (estimates = 0.168, P < 0.001; 0.006, P < 0.001; 0.092, P = 0.003; 0.009, P = 0.002; 0.081, P = 0.01, respectively) were associated significantly with BW. Conversely, no significant association was noted for maternal ethnicity, age or parity (estimates = -0.010, P = 0.831; 0.005, P = 0.127; 0.035, P = 0.086, respectively). The findings were unchanged when the analysis was repeated using INTERGROWTH-21st fetal weight centiles instead of BW (log odds, -0.175, P = 0.170 and 0.321, P < 0.001, respectively for ethnicity and CPR). CONCLUSION: Fetal BW variation at term is less dependent on ethnic origin and better explained by placental dysfunction. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29418034 TI - In search of atrial fibrillation driver sites: Is temporally stable frequency mapping a new armamentarium? PMID- 29418033 TI - When the BRANCHED network bears fruit: how carpic dominance causes fruit dimorphism in Aethionema. AB - Life in unpredictably changing habitats is a great challenge, especially for sessile organisms like plants. Fruit and seed heteromorphism is one way to cope with such variable environmental conditions. It denotes the production of distinct types of fruits and seeds that often mediate distinct life-history strategies in terms of dispersal, germination and seedling establishment. But although the phenomenon can be found in numerous species and apparently evolved several times independently, its developmental time course or molecular regulation remains largely unknown. Here, we studied fruit development in Aethionema arabicum, a dimorphic member of the Brassicaceae family. We characterized fruit morph differentiation by comparatively analyzing discriminating characters like fruit growth, seed abortion and dehiscence zone development. Our data demonstrate that fruit morph determination is a 'last minute' decision happening in flowers after anthesis directly before the first morphotypical differences start to occur. Several growth experiments in combination with hormone and gene expression analyses further indicate that an accumulation balance of the plant hormones auxin and cytokinin in open flowers together with the transcript abundance of the Ae. arabicum ortholog of BRANCHED1, encoding a transcription factor known for its conserved function as a branching repressor, may guide fruit morph determination. Thus, we hypothesize that the plasticity of the fruit morph ratio in Ae. arabicum may have evolved through the modification of a preexisting network known to govern correlative dominance between shoot organs. PMID- 29418035 TI - Digging their own macroevolutionary grave: fossoriality as an evolutionary dead end in snakes. AB - The tree of life is highly asymmetrical in its clade wise species richness, and this has often been attributed to variation in diversification rates either across time or lineages. Variations across lineages are usually associated with traits that increase lineage diversification. Certain traits can also hinder diversification by increasing extinction, and such traits are called evolutionary dead ends. Ecological specialization has usually been considered as an evolutionary dead end. However, recent analyses of specializations along single axes have provided mixed support for this model. Here, we test if fossoriality, a trait that forces specialization at multiple axes, acts as an evolutionary dead end in squamates (lizards and snakes) using recently developed phylogenetic comparative methods. We show that fossoriality is an evolutionary dead end in snakes but not in lizards. Fossorial snakes exhibit reduced speciation and increased extinction compared to nonfossorial snakes. Our analysis also indicates that transition rates from fossoriality to nonfossoriality in snakes are significantly lower than transition rates from nonfossoriality to fossoriality. Overall our results suggest that broad-scale ecological interactions that lead to specialization at multiple axes limit diversification. PMID- 29418036 TI - In memory of Dr. Koji Koyama. PMID- 29418039 TI - Topical Tranexamic Acid for Epistaxis in Patients on Antiplatelet Drugs: A New Use for an Old Drug. PMID- 29418037 TI - Constitutive overexpression of periostin delays wound healing in mouse skin. AB - Periostin is a matricellular protein involved in development, maintenance, and regulation of tissues and organs via by binding to cell surface integrin receptors. Pathologically, periostin plays an important role in the process of wound healing: as a deficiency of the Postn gene delays wound closure and periostin is consistently up-regulated in response to injury and skin diseases. However, the functional role of elevated periostin in the process of wound healing has not been tested. In this study, we generated Postn-transgenic mice under the control of the CAG promoter/enhancer to investigate the effects of constitutive overexpression of full length periostin during its pathophysiological roles. Transgenic mice showed significant overexpression of periostin in skin, lung, and heart, but no morphological changes were observed. However, when these transgenic mice were injured, periostin overexpression delayed the closure of excisional wounds. Expression of IL-1beta and TNFalpha, pro-inflammatory cytokines important for wound healing, was significantly decreased in the transgenic mice, prior to delayed healing. Infiltration of neutrophils and macrophages, the main sources of IL-1beta and TNFalpha, was also down-regulated in the transgenic wound sites. From these data, we conclude that enforced expression of periostin delays wound closure due to reduced infiltration of neutrophils and macrophages followed by down-regulation of IL-1beta and TNFalpha expression. This suggests that regulated spatiotemporal expression of periostin is important for efficient wound healing and that constitutive periostin overexpression interrupts the normal process of wound closure. PMID- 29418038 TI - Imaging in gynecological disease (13): clinical and ultrasound characteristics of endometrioid ovarian cancer. AB - OBJECTIVE: To describe the clinical and ultrasound characteristics of ovarian pure endometrioid carcinomas. METHODS: This was a retrospective multicenter study of patients with a histological diagnosis of pure endometrioid carcinoma. We identified 161 patients from the International Ovarian Tumor Analysis (IOTA) database who had undergone preoperative ultrasound examination by an experienced ultrasound examiner between 1999 and 2016, and another 78 patients from the databases of the departments of gynecological oncology in the participating centers. All tumors were described using IOTA terminology. In addition, one author reviewed all available ultrasound images and described them using pattern recognition. RESULTS: Median age of the 239 patients was 55 years (range, 19-88 years). On ultrasound examination, two (0.8%) endometrioid carcinomas were described as unilocular cysts, three (1.3%) as multilocular cysts, 37 (15.5%) as unilocular-solid cysts, 115 (48.1%) as multilocular-solid cysts and 82 (34.3%) as solid masses. Median largest tumor diameter was 102.5 mm (range, 20-300 mm) and median largest diameter of the largest solid component was 63 mm (range, 9-300 mm). Papillary projections were present in 70 (29.3%) masses. Most cancers (188 (78.7%)) were unilateral. In 49 (20.5%) cases, the cancer was judged by the pathologist to develop from endometriosis. These cancers, compared with those without evidence of tumor developing from endometriosis, more often manifested papillary projections on ultrasound (46.9% (23/49) vs 24.7% (47/190)), were less often bilateral (8.2% (4/49) vs 24.7% (47/190)) and less often associated with ascites (6.1% (3/49) vs 28.4% (54/190)) and fluid in the pouch of Douglas (24.5% (12/49) vs 48.9% (93/190)). Retrospective analysis of available ultrasound images using pattern recognition revealed that many tumors without evidence of tumor developing from endometriosis (36.3% (41/113)) had a large central solid component entrapped within locules, giving the tumor a cockade-like appearance. CONCLUSIONS: Endometrioid cancers are usually large, unilateral, multilocular solid or solid tumors. The ultrasound characteristics of endometrioid carcinomas developing from endometriosis differ from those without evidence of tumor developing from endometriosis, the former being more often unilateral cysts with papillary projections and no ascites. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29418040 TI - Male gender, school attendance and sports participation are positively associated with health-related quality of life in children and adolescents with congenital bleeding disorders. AB - BACKGROUND: This study assesses health-related quality of life (HRQOL), and variables associated with HRQOL, in children and adolescents with haemophilia and congenital bleeding disorders (CBD) in the Netherlands. METHODS: Patients <18 years with CBD under treatment at the Hemophilia Comprehensive Care Center of the Academic Medical Center were included. Participants completed generic HRQOL questionnaires (TAPQOL 0-5 years; PedsQL 6-18 years). Differences and effect sizes in HRQOL compared to healthy peers, and between hemophilia severity groups, were tested using Mann Whitney U-tests. Multivariate regression analyses were performed to assess variables associated with HRQOL. RESULTS: Data of 145 patients (81%) were analyzed (N = 32 with severe haemophilia). Children (0-12 years) show no significant impairments in HRQOL compared to healthy peers. Adolescent boys (13-18 years) with CBD report a slightly higher HRQOL on the total and emotional functioning scales than healthy peers (small-moderate effect sizes). In contrast, adolescent girls experience lower HRQOL on total, social functioning and psychosocial health scales compared to healthy peers (moderate effect sizes). No differences between severity groups were found in HRQOL, but more problem behaviour was found in young boys (0-5 years) with severe haemophilia. Male gender, participation in sports and school attendance are positively associated with HRQOL. Parental country of birth, type of treatment and number of bleeds are not associated with HRQOL. CONCLUSION: Continuing monitoring HRQOL in daily clinical practice for children with CBD is important, since possible influencing psychosocial factors can change over time, with special focus on adolescent girls, sports participation and school absence. PMID- 29418041 TI - Intrageneric Variability Between the Chloroplast Genomes of Trachelomonas grandis and Trachelomonas volvocina and Phylogenomic Analysis of Phototrophic Euglenoids. AB - The latest studies of chloroplast genomes of phototrophic euglenoids yielded different results according to intrageneric variability such as cluster arrangement or diversity of introns. Although the genera Euglena and Monomorphina in those studies show high syntenic arrangements at the intrageneric level, the two investigated Eutreptiella species comprise low synteny. Furthermore Trachelomonas volvocina show low synteny to the chloroplast genomes of the sister genera Monomorphina aenigmatica, M. parapyrum, Cryptoglena skujae, Euglenaria anabaena, Strombomonas acuminata, all of which were highly syntenic. Consequently, this study aims at the analysis of the cpGenome of Trachelomonas grandis and a comparative examination of T. volvocina to investigate whether the cpGenomes are of such resemblance as could be expected for a genus within the Euglenaceae. Although these analyses resulted in almost identical gene content to other Euglenaceae, the chloroplast genome showed significant novelties: In the rRNA operon, we detected group II introns, not yet found in any other cpGenome of Euglenaceae and a substantially heterogeneous cluster arrangement in the genus Trachelomonas. The phylogenomic analysis with 84 genes of 19 phototrophic euglenoids and 18 cpGenome sequences from Chlorophyta and Streptophyta resulted in a well-supported cpGenome phylogeny, which is in accordance to former phylogenetic analyses. PMID- 29418042 TI - The importance of ABO blood group in pharmacokinetic studies in haemophilia A. PMID- 29418043 TI - Advantage of recombinant von Willebrand factor for peri-operative management in paediatric acquired von Willebrand syndrome. PMID- 29418044 TI - Vacuolar ATPase is required for ERK-dependent wound healing in the Drosophila embryo. AB - Epithelia have the ability to repair injuries through an evolutionary conserved wound healing mechanism. Wound healing events can be classified into the transcription-independent signals involving mobilization of ionic currents and cytoskeletal rearrangements or the transcription-dependent response with activation of repair genes. The vacuolar H+ -ATPase (V-ATPase) has been implicated in the regeneration of vertebrate structures, but the underlying cellular mechanisms remain unclear. Here, we use wounding assays on the epidermis of Drosophila embryos to assess the role of the V-ATPase in the healing response. We show that a deficient V-ATPase induces a defective wound healing response by delaying re-epithelialization and preventing the ERK-dependent transcriptional activation of repair around the wound site. Our data suggests that the V-ATPase plays an evolutionary conserved role in the activation of genes necessary for the wound healing response. PMID- 29418045 TI - Laboratory monitoring issues in recombinant porcine FVIII replacement in acquired haemophilia A. PMID- 29418046 TI - Management of brothers with haemophilia A and familial cerebral cavernous malformations. PMID- 29418047 TI - The role of mitochondria in the female germline: Implications to fertility and inheritance of mitochondrial diseases. AB - Mitochondria play a fundamental role during development of the female germline. They are fragmented, round, and small. Despite these characteristics suggesting that they are inactive, there is accumulating evidence that mitochondrial dysfunctions are a major cause of infertility and generation of aneuploidies in humans. In addition, mitochondria and their own genomes (mitochondrial DNA-mtDNA) may become damaged with time, which might be one reason why aging leads to infertility. As a result, mitochondria have been proposed as an important target for evaluating oocyte and embryo quality, and developing treatments for female infertility. On the other hand, mutations in mtDNA may cause mitochondrial dysfunctions, leading to severe diseases that affect 1 in 4,300 people. Moreover, very low levels of mutated mtDNA seem to be present in every person worldwide. These may increase with time and associate with late-onset degenerative diseases such as Parkinson disease, Alzheimer disease, and common cancers. Mutations in mtDNA are transmitted down the maternal lineage, following a poorly understood pattern of inheritance. Recent findings have indicated existence in the female germline of a purifying filter against deleterious mtDNA variants. Although the underlying mechanism of this filter is largely unknown, it has been suggested to rely on autophagic degradation of dysfunctional mitochondria or selective replication/transmission of non-deleterious variants. Thus, understanding the mechanisms regulating mitochondrial inheritance is important both to improve diagnosis and develop therapeutic tools for preventing transmission of mtDNA encoded diseases. PMID- 29418048 TI - A brief survey of clinicians' perceptions of parent preferences for involvement in obstetrical and perinatal management decisions in haemophilia. PMID- 29418049 TI - Effectiveness of a Specialized Brief Intervention for At-risk Drinkers in an Emergency Department: Short-term Results of a Randomized Controlled Trial. AB - BACKGROUND: Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have been developed, evaluated, and shown to be effective, particularly in primary care and general practice. Nevertheless, effectiveness of SBIRT in emergency departments (EDs) has not been clearly established. OBJECTIVE: We aimed to evaluate the feasibility and efficacy of an SBIRT program conducted by highly specialized professionals in the ED of a tertiary hospital. METHODS: We conducted a randomized controlled trial to study the feasibility and efficacy of an SBIRT program conducted by alcohol specialists for at-risk drinkers presenting to the ED, measured with the three-item version of the Alcohol Use Disorder Identification Test (AUDIT-C). Patients were randomized to two groups, with the control group receiving two leaflets-one regarding alcohol use and the other giving information about the study protocol. The intervention group received the same leaflets as well as a brief motivational intervention on alcohol use and, where appropriate, a referral to specialized treatment. The primary outcomes were the proportion of at-risk alcohol use measured by AUDIT-C scale and the proportion of patients attending specialized treatment at 1.5 months. RESULTS: Of 3,027 patients presenting to the ED, 2,044 (67%) were potentially eligible to participate, 247 (12%) screened positive for at-risk drinking, and 200 agreed to participate. Seventy-two percent of the participating sample were men, and the mean (+/-SD) age was 43 (+/-16.7) years. Follow-up rates were 76.5%. At 1.5 months, the intervention group showed greater reductions in alcohol consumption and fewer patients continuing with at-risk alcohol use (27.8% vs. 48.1%; p = 0.01). The SBIRT program also increased the probability of attending specialized treatment, compared to the control condition (23% vs. 9.8%, p = 0.0119) CONCLUSION: The SBIRT program in the ED was found to be feasible and effective in identifying at-risk drinkers, reducing at-risk alcohol use, and increasing treatment for alcohol problems. PMID- 29418051 TI - A Pericyclic Reaction Cascade in Leporin Biosynthesis. AB - All roads lead to Rome: The biosynthesis of the leporins in Aspergillus sp. involves an unprecedented pericyclic reaction cascade. The enzyme LepI directs the periselectivity of a [4+2] cycloaddition towards a hetero-Diels-Alder reaction outcome to give the leporin molecular scaffold. The Diels-Alder side product is morphed into the leporin core structure by a LepI-catalyzed retro Claisen rearrangement, culminating in efficient kinetic side product recycling. PMID- 29418050 TI - The process of incorporating insulin pumps into the everyday lives of people with Type 1 diabetes: A critical interpretive synthesis. AB - BACKGROUND: Insulin pump therapy (IPT) is a technological advancement that has been developed to help people manage Type 1 diabetes (T1D). However, ways of managing diabetes requiring the implementation of health technologies bring new complexities and a need to understand the factors which enable people with T1D to incorporate a novel device. This new comprehension could provide an exemplar for people with long-term conditions to incorporate new technologies more generally. OBJECTIVE: To determine what influences the incorporation, adaptation and use of IPT into the everyday lives of people living with diabetes. DESIGN: Critical interpretive synthesis (CIS) using systematic searches undertaken in 7 electronic databases of literature, published 2008 onwards. RESULTS: A total of 4998 titles were identified, 274 abstracts reviewed, 39 full articles retrieved and 22 papers selected for analysis. Three themes emerged which were of relevance to the introduction and use of IPT; Tensions between expectations and experiences in adoption and early adaptation; Negotiation of responsibility and accessing support; Reflexivity, active experimentation and feedback. CONCLUSIONS: This CIS builds on earlier reviews on lived experiences of IPT. Novel insights are offered through examination of the experiences of pump users from children through to adults, their families and health-care professionals. Expectations of what the device can do to improve self-management impacts on the early stages of adoption as the reality of the technology requires substantial thought and action. Areas for intervention to improve IPT incorporation include establishing who is responsible for management tasks of the device and enabling navigation to further means of support and resources. PMID- 29418052 TI - Publication ethics from the ground up. AB - It is relatively easy to begin policy documents with a general assertion that ethics will be followed. Less obvious is how to ensure that day-to-day activities are consonant with ethical standards. We suggest that using day-to-day publication activities as the driver for building policies and procedures can promote ethical practices from the ground up. Although basic principles of ethical publication practice may seem straightforward to some, for others this information may require explanation, interpretation and context. Effective policy development includes big-picture items as well as more day-to-day tactical responsibilities such as those discussed below. Research questions, disciplinary practices, applications and team structures may vary. Thus, no single publication plan or policy solution is right for all teams. It is up to team members to review guidelines for best practices and find the optimal implementation for their situations. Experts in publication management, planning and writing can help large teams manage publication activities. These experts have an obligation to maintain and enhance their skills continually. A strong acumen in publication best practices will allow these publication professionals to better address any possible ethical dilemmas in the future. PMID- 29418053 TI - Preparing researchers for patient and public involvement in scientific research: Development of a hands-on learning approach through action research. AB - BACKGROUND: Acquiring the theoretical and practical knowhow of conducting patient and public involvement (PPI) in research is not part of the traditional curriculum of researchers. Zuyd University of Applied Sciences and Huis voor de Zorg, a regional umbrella patient organization, therefore started a 1.5-year coaching programme. OBJECTIVE: To establish a community of practice by developing a PPI coaching programme for senior and junior health services researchers of Zuyd University. The context consisted of research projects conducted by the participants. METHODS: A participatory action research methodology. Data were collected from reports of thematic group meetings and individual sessions with participants, field notes and regular reflection meetings with the project team. Data were analysed by reflexive deliberation. FINDINGS: The programme comprised a kick-off meeting (52 attendees), followed by 7 group meetings with 11 junior and 9 senior researchers. The project team constructed a serious game based on the concept of the participation ladder. Questions and concerns differed for junior and senior researchers, and separate tailored meetings were organized for both groups. Between group meetings, participants received individual assignments. Group meetings were accompanied by individual coaching sessions to provide tailor made feedback. The programme concluded with a combined meeting with all stakeholders. CONCLUSION: Building a community of PPI practice through action research facilitates the development of a coaching programme that fosters social learning, empowerment and the development of a shared identity concerning PPI. The role and responsibilities of senior researchers should be distinguished from those of junior researchers. PMID- 29418054 TI - Evaluation of treatment outcomes of patients with MRSA bacteremia following antimicrobial stewardship programs with pharmacist intervention. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) is associated with high mortality and implementing an appropriate antimicrobial stewardship (AS) program with treatment intervention is essential. The aim of this study was to evaluate the impact of AS with pharmacist intervention on patients with MRSA-B. METHODS: Patients who were diagnosed with MRSA-B between January 2012 and April 2013 were defined as the pre-intervention group, while those diagnosed between May 2013 and December 2015 were defined as the intervention group (ie, AS with pharmacist intervention). The factors affecting bundle compliance rates and mortality were analysed. RESULT: The pre-intervention group comprised 43 patients and the intervention group comprised 51 patients. Bundle compliance rates were estimated as follows in the intervention group: an increase was observed in the appropriate duration of therapy (from 44.8% to 72.1%, P = .027), incidences of the early use of anti-MRSA drugs (from 62.3% to 82.4%, P = .038), and the number of negative follow-up blood cultures (from 40.0% to 80.0%, P < .001), and a decrease was observed for 30-day mortality (from 41.8% to 21.6%, P = .044) and hospital mortality (from 58.1% to 27.5%, P = .003). In multivariate analysis, the intervention group was independent of 30-day mortality and hospital mortality risk reduction factors (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.12-0.86, and OR, 0.20; 95% CI, 0.07-0.53). CONCLUSIONS: AS programs with pharmacist intervention improve mortality in patients with MRSA-B. PMID- 29418055 TI - Activating CoOOH Porous Nanosheet Arrays by Partial Iron Substitution for Efficient Oxygen Evolution Reaction. AB - Iron-substituted CoOOH porous nanosheet arrays grown on carbon fiber cloth (denoted as Fex Co1-x OOH PNSAs/CFC, 0<=x<=0.33) with 3D hierarchical structures are synthesized by in situ anodic oxidation of alpha-Co(OH)2 NSAs/CFC in solution of 0.01 m (NH4 )2 Fe(SO4 )2 . X-ray absorption fine spectra (XAFS) demonstrate that CoO6 octahedral structure in CoOOH can be partially substituted by FeO6 octahedrons during the transformation from alpha-Co(OH)2 to Fex Co1-x OOH, and this is confirmed for the first time in this study. The content of Fe in Fex Co1 x OOH, no more than 1/3 of Co, can be controlled by adjusting the in situ anodic oxidation time. Fe0.33 Co0.67 OOH PNSAs/CFC shows superior OER electrocatalytic performance, with a low overpotential of 266 mV at 10 mA cm-2 , small Tafel slope of 30 mV dec-1 , and high durability. PMID- 29418056 TI - Micropolarity and Hydrogen-Bond Donor Ability of Environmentally Friendly Anionic Reverse Micelles Explored by UV/Vis Absorption of a Molecular Probe and FTIR Spectroscopy. AB - In the present work we show how two biocompatible solvents, methyl laurate (ML) and isopropyl myristate (IPM), can be used as a less toxic alternative to replace the nonpolar component in a sodium 1,4-bis-2-ethylhexylsulfosuccinate (AOT) reverse micelles (RMs) formulation. In this sense, the micropolarity and the hydrogen-bond ability of the interface were monitored through the use of the solvatochromism of a molecular probe (1-methyl-8-oxyquinolinium betaine, QB) and Fourier transform infrared spectroscopy (FTIR). Our results demonstrate that the micropolarity sensed by QB in ML RMs is lower than in IPM RMs. Additionally, the water molecules form stronger H-bond interactions with the polar head of AOT in ML than in IPM. By FTIR was revealed that more water molecules interact with the interface in ML/AOT RMs. On the other hand, for AOT RMs generated in IPM, the weaker water-surfactant interaction allows the water molecules to establish hydrogen bonds with each other trending to bulk water more easily than in ML RMs, a consequence of the dissimilar penetration of nonpolar solvents into the interfacial region. The penetration process is strongly controlled by the polarity and viscosity of the external solvents. All of these results allow us to characterize these biocompatible systems, providing information about interfacial properties and how they can be altered by changing the external solvent. The ability of the nontoxic solvent to penetrate or not into the AOT interface produces a new interface with attractive properties. PMID- 29418057 TI - Highly Enantioselective Tandem Michael Addition of Tryptamine-Derived Oxindoles to Alkynones: Concise Synthesis of Strychnos Alkaloids. AB - A highly enantioselective tandem Michael addition of tryptamine-derived oxindoles to alkynones was developed by taking advantage of a chiral N,N'-dioxide Sc(OTf)3 catalyst. The reaction enables the facile preparation of enantioenriched spiro[pyrrolidine-3,3'-oxindole] compounds, which provides a novel strategy for the synthesis of monoterpenoid indole alkaloids. As a demonstration, the asymmetric synthesis of strychnos alkaloids [(-)-tubifoline, (-)-tubifolidine, ( )-dehydrotubifoline] was achieved in 10-11 steps. PMID- 29418058 TI - Evolutionary conservation of the allosteric activation of factor VIIa by tissue factor in lamprey. AB - : Essentials Tissue factor (TF) enhances factor VIIa (FVIIa) activity through structural and dynamic changes. We analyzed conservation of TF-activated FVIIa allosteric networks in extant vertebrate lamprey. Lamprey Tf/FVIIa molecular dynamics show conserved Tf-induced structural/dynamic FVIIa changes. Lamprey Tf activation of FVIIa allosteric networks follows molecular pathways similar to human. SUMMARY: Background Previous studies have provided insight into the molecular basis of human tissue factor (TF) activation of activated factor VII (FVIIa). TF-induced allosteric networks of FVIIa activation have been rationalized through analysis of the dynamic changes and residue connectivities in the human soluble TF (sTF)/FVIIa complex structure during molecular dynamics (MD) simulation. Evolutionary conservation of the molecular mechanisms for TF induced allosteric FVIIa activation between humans and extant vertebrate jawless fish (lampreys), where blood coagulation emerged more than 500 million years ago, is unknown and of considerable interest. Objective To model the sTf/FVIIa complex from cloned Petromyzon marinus lamprey sequences, and with comparisons to human sTF/FVlla investigate conservation of allosteric mechanisms of FVIIa activity enhancement by soluble TF using MD simulations. Methods Full-length cDNAs of lamprey tf and f7 were cloned and characterized. Comparative models of lamprey sTf/FVIIa complex and free FVIIa were determined based on constructed human sTF/FVIIa complex and free FVIIa models, used in full-atomic MD simulations, and characterized using dynamic network analysis approaches. Results Allosteric paths of correlated motion from Tf contact points in lamprey sTf/FVIIa to the FVIIa active site were determined and quantified, and were found to encompass residue residue interactions along significantly similar paths compared with human. Conclusions Despite low conservation of residues between lamprey and human proteins, 30% TF and 39% FVII, the structural and protein dynamic effects of TF activation of FVIIa appear conserved and, moreover, present in extant vertebrate proteins from 500 million years ago when TF/FVIIa-initiated extrinsic pathway blood coagulation emerged. PMID- 29418060 TI - Ectopic nephrogenic rests in children: A series of 13 cases in a single institution. AB - PURPOSE: Ectopic nephrogenic rests (ENR) are extremely rare, and their diagnosis and treatment have not yet been standardized. Our study aimed to analyze the clinical and pathological features of ENR in children and explore the optimal methods for diagnosis and treatment. METHODS: A retrospective, single-center, case series study of 13 children with ENR was performed. Clinical manifestations, work-up, pathological features, and treatment methods were analyzed, and the postoperative status was evaluated at follow-up. RESULTS: The study cohort included seven males and six females aged 1/4-19 months, who were divided into two subgroups: group 1 (pure ENR, cases 1-3) and group 2 (ENR associated with teratoma, cases 4-13). The patients commonly presented with a painless mass or an incidental finding in surgery. The ENR were detected in the lumbosacral and sacrococcygeal region (five cases), retroperitoneal area (five cases), testis (one case), gubernaculum testis (one case), and stomach (one case). Radiological findings showed a mixed-density mass or a mixed-signal-intensity lesion in group 2. All the patients underwent surgical resection, and all except two were event free in a follow-up period of 2-154 months. Case 8 showed recurrence, and extended surgery was performed. Case 7 developed metastases and received chemotherapy. CONCLUSIONS: ENR are rare among children and have no specific clinical manifestations, lab tests, and radiological features. Different treatment strategies may be adopted based on the diagnosis. Complete resection can generally be achieved, and the prognosis is excellent in most cases. However, relapse or metastasis may occur in a small subset of patients. Close follow-up is mandatory to detect recurrence and metastasis early. PMID- 29418061 TI - Platelets couple inflammation to tumorigenesis, a bridge too far. PMID- 29418059 TI - The extraordinary challenge of treating patients with congenital rhabdoid tumors a collaborative European effort. AB - BACKGROUND: Congenital rhabdoid tumors are rare and highly aggressive malignancies. In general, patients are considered to be incurable and are often treated using an exclusive, primarily palliative approach. METHODS: A prospective and retrospective collection of 42 patients from the European Rhabdoid Registry (EU-RHAB), France and Moscow (2006-2016) diagnosed within the first 28 days of life was evaluated. Genetic and clinical reference evaluation included SMARCB1 and/or SMARCA4 (fluorescence-in-situ-hybridization, multiplex ligation-dependent probe amplification, and sequencing) mutation analysis and immunohistochemistry. Forty-eight percent (20/42) of patients were treated according to the EU-RHAB therapy, 7% (3/42) according to the pilot approach Rhabdoid 2007, 33% (14/42) with individual schedules, and 12% (5/42) received no chemotherapy at all. RESULTS: Forty point five percent (17/42) of patients presented with extracranial rhabdoid tumors, 33.5% (14/42) with rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumor), and the remainder 26% (11/42) demonstrated synchronous tumors. Metastases at diagnosis were present in 52% (22/42) of patients. A germline mutation was detected in 66% (25/38) and was associated with a poor prognosis (4.2 +/- 4.1% vs. 48 +/- 16.4%, P < 0.00005). A gross total resection (GTR) was realized in 17%. A GTR (42.9 +/- 18.7% vs. 4.9 +/- 4.3%, P = 0.04), therapy according to a standardized approach (20.9 +/- 8.7% vs. 7.1 +/- 6.9 %, P = 0.0018), and a complete remission (CR) (23.6 +/- 9.8% vs. 1.3 +/- 3.6%, P = 0.04) were significant prognostic factors. CONCLUSIONS: The management of patients with congenital rhabdoid tumors requires a major multidisciplinary effort. In many instances, cure is not possible and a palliative approach is warranted. Our data indicate a positive impact of standardized therapeutic approaches on survival, making a tailored approach toward affected patients and their families mandatory. PMID- 29418062 TI - 2D Nanostructured Metal Hydroxides with Gene Delivery and Theranostic Functions; A Comprehensive Review. AB - Layered double hydroxides (LDHs) with two dimensional structure have been attracted considerable interest in exploring new intercalative nanohybrids, such as inorganic-LDHs, organic-LDHs and bio-LDHs ones, which often exhibit extraordinarily synergetic effects and complementary performances. More recently, bio-related nanotechnology becomes one of the most essential research field in the viewpoint of the health and safety of human being. In this regard, LDHs have been focused as an important inorganic material for gene and drug delivery carriers with imaging and targeting functions. In the present review, an attempt has been made to describe gene delivery systems based on LDH nanoparticles in terms of synthetic routes of gene-LDH nanohybrids, their physico-chemical properties, intercellular uptake mechanisms, intracellular trafficking pathways and drug resistance, and passive and active targeting functions in in-vitro and in-vivo, and finally imaging functions. And recent studies of gene-therapies with LDHs are also discussed from the viewpoint of state-of-the-art nanohybrids technology. PMID- 29418063 TI - Perceptions of barriers and facilitators to early integration of pediatric palliative care: A national survey of pediatric oncology providers. AB - OBJECTIVES: The goal of this study was to assess pediatric oncology providers' perceptions of palliative care in order to validate previously identified barriers and facilitators to early integration of a pediatric palliative care team (PCT) in the care of children with cancer. METHODS: A 36-question survey based on preliminary, single-institution data was electronically distributed to pediatric oncology physicians, nurse practitioners, nurses, and social workers nationally. The principal outcomes measured included perceived barriers and facilitators to early integration of pediatric palliative care. Data were analyzed using Rv3.1.2 statistical software. RESULTS: Most respondents agreed that the PCT does not negatively impact the role of the oncologist; however, there were concerns that optimal patient care may be limited by pediatric oncologists' need to control all aspects of patient care (P < 0.001). Furthermore, oncologists, more than any provider group, identified that the emotional relationship they form with the patients and families they care for, influences what treatment options are offered and how these options are conveyed (P < 0.01). Education and evidence-based research remain important to all providers. Respondents reached consensus that early integration of a PCT would provide more potential benefits than risks and most would not limit access to palliative care based on prognosis. CONCLUSIONS: Overall, providers endorse early integration of the PCT for children with cancer. There remains a continued emphasis on provider and patient education. Palliative care is generally accepted as providing a benefit to children with cancer, though barriers persist and vary among provider groups. PMID- 29418064 TI - Acute lymphoblastic leukemia and lymphoblastic lymphoma in adolescents and young adults. AB - Compared to younger and older age groups, the incidence of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) has increased more in the adolescent and young adult (AYA) population, the cause of which is unknown. As of the last decade, only half of the AYA patients with these diseases were surviving 10 years. Strong evidence exists that favors "pediatric" treatment regimens for AYAs compared to "adult" treatment regimens in terms of survival rates, hospitalization time, toxicities, late effects, and quality of life both during and after treatment. Targeted agents are clinically accessible for certain subsets of patients with Philadelphia-like ALL, the incidence of which peaks in AYAs. Treatment teams must appreciate the complex psychosocial underpinnings in these patients in order to maximize compliance with the prolonged and complex treatment plans during the AYA years. PMID- 29418065 TI - Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease. AB - BACKGROUND & AIMS: In Wilson disease (WD), copper accumulates in the liver and other tissues because of mutations in the ATP7B copper transporter gene. Early and effective anticopper treatment is crucial. However, routine diagnostic methods based on clinical findings, copper metabolism tests, liver biopsies and DNA analyses do not always provide a conclusive diagnosis. The aim was to evaluate radioactive copper incorporation as a diagnostic test. METHODS: We included cases with a diagnosis of WD supported by radiocopper testing and later, when available, confirmed by DNA analysis. Incorporation of 64 Cu was measured at 2, 24 and 48 hours following intravenous injection. Diagnostic accuracy (area under the receiver operating characteristic curve [AUC]), sensitivity, specificity and predictive value were assessed for 24 hours/2 hours and 48 hours/2 hours 64 Cu ratios and compared with serum measurements of ceruloplasmin, copper, non-ceruloplasmin-bound copper and urinary 24-hours copper excretion. RESULTS: Patients having two pathogenic ATP7B mutations (homozygotes/compound heterozygotes) (n = 74) had significantly lower 24 hours/2 hours and 48 hours/2 hours 64 Cu ratios than heterozygote controls (n = 21) (mean 0.14 and 0.12 vs 0.49 and 0.63, respectively; both P < .001). Of note, 24 hours/2 hours and 48 hours/2 hours 64 Cu ratios had excellent diagnostic accuracy, with AUCs approaching 1, and only 24-hours urinary copper excretion displayed similar positive features. Other copper metabolism tests studied had lower accuracy, specificity and sensitivity. CONCLUSIONS: The radioactive copper test had excellent diagnostic accuracy and may be useful in the evaluation of new therapies aimed at restoring ATP7B function. PMID- 29418066 TI - Integrating environmental monitoring with cumulative effects management and decision making. AB - Cumulative effects (CE) monitoring is foundational to emerging regional and watershed CE management frameworks, yet monitoring is often poorly integrated with CE management and decision-making processes. The challenges are largely institutional and organizational, more so than scientific or technical. Calls for improved integration of monitoring with CE management and decision making are not new, but there has been limited research on how best to integrate environmental monitoring programs to ensure credible CE science and to deliver results that respond to the more immediate questions and needs of regulatory decision makers. This paper examines options for the integration of environmental monitoring with CE frameworks. Based on semistructured interviews with practitioners, regulators, and other experts in the Lower Athabasca, Alberta, Canada, 3 approaches to monitoring system design are presented. First, a distributed monitoring system, reflecting the current approach in the Lower Athabasca, where monitoring is delegated to different external programs and organizations; second, a 1-window system in which monitoring is undertaken by a single, in-house agency for the purpose of informing management and regulatory decision making; third, an independent system driven primarily by CE science and understanding causal relationships, with knowledge adopted for decision support where relevant to specific management questions. The strengths and limitations of each approach are presented. A hybrid approach may be optimal-an independent, nongovernment, 1 window model for CE science, monitoring, and information delivery-capitalizing on the strengths of distributed, 1-window, and independent monitoring systems while mitigating their weaknesses. If governments are committed to solving CE problems, they must invest in the long-term science needed to do so; at the same time, if science-based monitoring programs are to be sustainable over the long term, they must be responsive to the more immediate, often shorter term needs and CE information requirements of decision makers. Integr Environ Assess Manag 2018;14:407-417. (c) 2018 SETAC. PMID- 29418067 TI - Effects of Bioreactor-Oxygenation During Extracorporeal Granulocytes Treatment in Septic Patients. AB - A granulocyte bioreactor for the extracorporeal treatment was developed to enhance the immune cell function in patients with severe sepsis. The influence of oxygenation on the used cells was tested in a prospective clinical study. Ten patients with severe sepsis were treated twice with the granulocyte bioreactor. The used cells were screened for functionality; values of blood gases, glucose and lactate were obtained from the recirculating bioreactor circuit. Five patients were treated with an oxygenator setup (Oxy group), five without oxygenator (Non-Oxy group). The overall in-hospital mortality was 50%. Significantly lower values of oxygen saturation, partial oxygen pressure, lactate, oxyburst and phagocytosis were seen in the Non-Oxy group compared with the Oxy group in the bioreactor circuit. Further studies with this approach are encouraged and should focus on the influence of oxygenation on production of reactive oxygen species and cytokines of used cells. PMID- 29418068 TI - Isolation, Synthesis and AChE Inhibitory Potential of Some Novel Cinnamyl Esters of Taraxerol, the Major Metabolite of the Mangrove Bruguiera cylindrica. AB - Systematic chemical screening of the leaves of Bruguiera cylindrica, the tree mangrove of Rhizophoraceae family, afforded five single and pure compounds. The structures of the isolated compounds were established by their spectroscopic data as taraxerol (1), 3beta-(E)-coumaroyltaraxerol (2), 3beta-(Z)-coumaroyltaraxerol (3), beta-sitosterol (4), and eicosanol (5). In view of significant accumulation and interesting biological activities, taraxerol (1) was chemically transformed to synthesize a series of ten cinnamyl esters in very good to excellent yields. The synthesized analogues along with the parent compound were evaluated for their AChE inhibitory potential, BBB permeability and cytotoxicity against Neuro 2A cell line. Among the tested samples, compound 9 showed promising AChE inhibition with significantly low IC50 values, low cytotoxicity and high BBB permeability. Hence, compound 9 can be considered as a lead molecule for further development as potent AChE inhibitor. PMID- 29418069 TI - Factors that influence public awareness of domestic waste characteristics and management in rural areas. AB - Public awareness of domestic waste characteristics and management (PADWCM) is a prerequisite for a domestic waste management (DWM) plan. In this study, we considered China as a typical example of developing countries to investigate the public perception of environmental pollution (PEP), its PADWCM, and its socioeconomic factors, using questionnaires and statistical methods. The results indicated that the public PEP was mainly due to obvious environmental contamination in local villages, and the PADWCM is still inadequate in rural areas. However, 83.9% of the respondents agreed that DWM is highly necessary. The PADWCM, including the hazard, recyclability, and characteristic pollution caused by domestic waste, was learned mainly from people's direct PEP, experiences, and repurchasing by recyclers. Education period had highly significant positive correlations and regressions with PEP and PADWCM, respectively. Additionally, education directly affected public awareness in different income and age groups. Demonstration projects had a significant positive effect on the awareness of characteristic pollution caused by domestic waste, which was readily perceived. Propaganda had a significant positive influence on the awareness of treatment necessity. Age and gender had no obvious effects on public PEP and PADWCM. Some aspects of PADWCM requiring a deep understanding became stronger as income increased; however, the PADWCM located close to poor people became weaker. Some aspects of PEP could significantly influence the awareness of characteristic pollution caused by domestic waste and awareness of treatment necessity. Therefore, improving environmental education, performing demonstration projects and effective environmental propaganda, increasing people's income, and attracting young people to participate in DWM will be important for enhancing environmental awareness and DWM in rural areas. Integr Environ Assess Manag 2018;14:395-406. (c) 2018 SETAC. PMID- 29418070 TI - Children with sickle cell disease migrating to the United States from sub-Saharan Africa. AB - Sickle cell disease (SCD) is an inherited red blood cell disorder that occurs worldwide and results in significant morbidity and mortality. In addition to affected children who are born in the US, an increasing number of children with SCD are migrating to the US with their families or through international adoption. Children arriving as immigrants or refugees have unique medical and psychosocial challenges that require a multidisciplinary team approach which takes into account the family's primary language, culture, and health beliefs. This review focuses on the special challenges for children with SCD who emigrate from sub-Saharan Africa to the US. PMID- 29418071 TI - Sodium Butyrate Inhibits Colorectal Cancer Cell Migration by Downregulating Bmi-1 Through Enhanced miR-200c Expression. AB - SCOPE: Short-chain fatty acid sodium butyrate (NaB) is the byproduct of bacterial anaerobic fermentation of dietary fiber in the colon, and has been shown to have an antitumor effect on colorectal cancer (CRC). The miR-200 family is a key regulator of the epithelial-mesenchymal transition (EMT). We investigate the role of miR-200s expression on cell migration in NaB-treated CRC cells. METHODS AND RESULTS: HCT116 and LOVO CRC cells treated with NaB depicted reduced cell proliferation, enhanced apoptosis, and cell cycle arrest. NaB inhibited cell migration in the wound healing and transwell assays, and in spheriod cultures while regulating EMT-related protein expression. NaB reciprocally increased miR 200s but reduced expression of their target genes (Bmi-1, Zeb1, EZH2). Cells transfected with miR-200c shRNA displayed a significant blockade of NaB-induced anti-invasive activity. Upregulation of Bmi-1 expression partially reversed the effect of NaB. In addition to inhibition of tumor growth in vivo, qRT-PCR results showed that NaB increased miR-200c/200b/492 expression in the tumor tissues. Immunohistochemistry and Western blotting results demonstrated that NaB decreased Bmi-1 expression in vivo. CONCLUSION: NaB inhibits CRC cell migration by enhancing miR-200c expression-mediated downregulation of Bmi-1. These findings support the utility of NaB in colorectal cancer therapy. PMID- 29418072 TI - Effects of MiR-137 genetic risk score on brain volume and cortical measures in patients with schizophrenia and controls. AB - Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R2 = 0.008, Beta = -0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure. PMID- 29418073 TI - A Flexible High-Performance Photoimaging Device Based on Bioinspired Hierarchical Multiple-Patterned Plasmonic Nanostructures. AB - In insect eyes, ommatidia with hierarchical structured cornea play a critical role in amplifying and transferring visual signals to the brain through optic nerves, enabling the perception of various visual signals. Here, inspired by the structure and functions of insect ommatidia, a flexible photoimaging device is reported that can simultaneously detect and record incoming photonic signals by vertically stacking an organic photodiode and resistive memory device. A single layered, hierarchical multiple-patterned back reflector that can exhibit various plasmonic effects is incorporated into the organic photodiode. The multiple patterned flexible organic photodiodes exhibit greatly enhanced photoresponsivity due to the increased light absorption in comparison with the flat systems. Moreover, the flexible photoimaging device shows a well-resolved spatiotemporal mapping of optical signals with excellent operational and mechanical stabilities at low driving voltages below half of the flat systems. Theoretical calculation and scanning near-field optical microscopy analyses clearly reveal that multiple patterned electrodes have much stronger surface plasmon coupling than flat and single-patterned systems. The developed methodology provides a versatile and effective route for realizing high-performance optoelectronic and photonic systems. PMID- 29418074 TI - Relationship Between Glucocerebrosidase Activity and Clinical Response to Enzyme Replacement Therapy in Patients With Gaucher Disease Type I. AB - The quantification of enzyme activity in the patient treated with enzyme replacement therapy (ERT) has been suggested as a tool for dosage individualization, so we conducted a study to evaluate the relationship between glucocerebrosidase activity and clinical response in patients with Gaucher disease type I (GD1) to ERT. The study included patients diagnosed with GD1, who were being treated with ERT, and healthy individuals. Markers based on glucocerebrosidase activity measurement in patients' leucocytes were studied: enzyme activity at 15 min. post-infusion (Act75 ) reflects the amount of enzyme that is distributed in the body post-ERT infusion, and accumulated glucocerebrosidase activity during ERT infusion (Act75-0 ) indicates the total drug exposure during infusion. The clinical response was evaluated based on criteria established by Pastores et al. and Gaucher Severity Score Index. Statistical analysis included ROC analysis and area under the curve test. Act75 and Act75-0 were found to be moderate predictive markers of an optimal clinical response (area under the ROC of Act75 was 0.733 and Act75-0 was 0.817). Act75-0 showed statistical significance in its discriminative capacity (p < 0.05) for obtaining an optimal response to ERT. The cut-off point was 58% (RR = 1.800; 95% CI: 1.003-3.229; p < 0.05). Moreover, Act75 showed a significant and inverse correlation with the Gaucher Severity Score Index, and Act75 and Act75-0 presented a significant correlation with residual enzyme activity at diagnosis. Markers based on glucocerebrosidase activity have a good correlation with clinical response to ERT. Therefore, it could provide supporting clinical data for dose management in GD1 patients. PMID- 29418075 TI - Infant multiple breath washout using a new commercially available device: Ready to replace the previous setup? AB - INTRODUCTION: Multiple breath washout (MBW) is a sensitive test to measure lung volumes and ventilation inhomogeneity from infancy on. The commonly used setup for infant MBW, based on ultrasonic flowmeter, requires extensive signal processing, which may reduce robustness. A new setup may overcome some previous limitations but formal validation is lacking. AIM: We assessed the feasibility of infant MBW testing with the new setup and compared functional residual capacity (FRC) values of the old and the new setup in vivo and in vitro. METHODS: We performed MBW in four healthy infants and four infants with cystic fibrosis, as well as in a Plexiglas lung simulator using realistic lung volumes and breathing patterns, with the new (Exhalyzer D, Spiroware 3.2.0, Ecomedics) and the old setup (Exhalyzer D, WBreath 3.18.0, ndd) in random sequence. RESULTS: The technical feasibility of MBW with the new device-setup was 100%. Intra-subject variability in FRC was low in both setups, but differences in FRC between the setups were considerable (mean relative difference 39.7%, range 18.9; 65.7, P = 0.008). Corrections of software settings decreased FRC differences (14.0%, -6.4; 42.3, P = 0.08). Results were confirmed in vitro. CONCLUSION: MBW measurements with the new setup were feasible in infants. However, despite attempts to correct software settings, outcomes between setups were not interchangeable. Further work is needed before widespread application of the new setup can be recommended. PMID- 29418076 TI - Viral-based nanomaterials for plasmonic and photonic materials and devices. AB - Over the last decade, viruses have established themselves as a powerful tool in nanotechnology. Their proteinaceous capsids benefit from biocompatibility, chemical addressability, and a variety of sizes and geometries, while their ability to encapsulate, scaffold, and self-assemble enables their use for a wide array of purposes. Moreover, the scaling up of viral-based nanotechnologies is facilitated by high capsid production yield and speed, which is particularly advantageous when compared with slower and costlier lithographic techniques. These features enable the bottom-up fabrication of photonic and plasmonic materials, which relies on the precise arrangement of photoactive material at the nanoscale to control phenomena such as electromagnetic wave propagation and energy transfer. The interdisciplinary approach required for the fabrication of such materials combines techniques from the life sciences and device engineering, thus promoting innovative research. Materials with applications spanning the fields of sensing (biological, chemical, and physical sensors), nanomedicine (cellular imaging, drug delivery, phototherapy), energy transfer and conversion (solar cells, light harvesting, photocatalysis), metamaterials (negative refraction, artificial magnetism, near-field amplification), and nanoparticle synthesis are considered with exclusive emphasis on viral capsids and protein cages. This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures. PMID- 29418077 TI - Case of advanced pulmonary squamous cell carcinoma cured by resection through preoperative induction of immune checkpoint inhibitor. AB - The options for lung cancer treatment have increased due to the development of immune checkpoint inhibitors, but there has been no report of inoperable cases whereby the treatment effects rendered the case operable, an operation was subsequently performed, and histological assessment of the surgical specimen was carried out. Here, we report a 67-year-old man who was given pembrolizumab for T3N0 lung squamous cell carcinoma suspected of pericardial infiltration and judged inoperable. Treatment effect was evaluated after four courses. Computed tomography indicated a partial response, and operability was feasible. Therefore, thoracoscopic left upper lobectomy was performed after six courses of pembrolizumab, and histological assessment of the treatment effect was determined to be Ef 3, a complete response. The postoperative course was uneventful and he was discharged on the third postoperative day. We encountered a case that could be surgically treated after pembrolizumab administration. This treatment was safe and effective for advanced lung cancer. PMID- 29418078 TI - A model-based solution for observational errors in laboratory studies. AB - Molecular techniques for detecting microorganisms, macroorganisms and infectious agents are susceptible to false-negative and false-positive errors. If left unaddressed, these observational errors may yield misleading inference concerning occurrence, prevalence, sensitivity, specificity and covariate relationships. Occupancy models are widely used to account for false-negative errors and more recently have even been used to address false-positive errors, too. Current modelling options assume false-positive errors only occur in truly negative samples, an assumption that yields biased inference concerning detection because a positive sample could be classified as such not because the target agent was successfully detected, but rather due to a false-positive test result. We present an extension to the occupancy modelling framework that allows false-positive errors in both negative and positive samples, thereby providing unbiased inference concerning occurrence and detection, as well as reliable conclusions about the efficacy of sampling designs, handling protocols and diagnostic tests. We apply the model to simulated data, showing that it recovers known parameters and outperforms other approaches that are commonly used when confronted with observation errors. We then apply the model to an experimental data set on Batrachochytrium dendrobatidis, a pathogenic fungus that is implicated in the global decline or extinction of hundreds of amphibian species. The model-based approach we present is not only useful for obtaining reliable inference when data are contaminated with observational errors, but also eliminates the need for establishing arbitrary thresholds or decision rules that have hidden and unintended consequences. PMID- 29418080 TI - Insights from Ion Binding Site Network Analysis into Evolution and Functions of Proteins. AB - Many biological phenomena can be represented as complex networks. Using a protein binding site comparison approach, we generated a network of ion binding sites on the scale of all known protein structures from the Protein Data Bank. We found that this ion binding site similarity network is scale-free, indicating a network in which a few ion binding site scaffolds are the network hubs, and these are connected to hundreds of nodes, whereas the vast majority of nodes have only a few neighbors. Enrichment and statistical analysis of the network components and communities yielded insights into underlying processes from the functional and the structural perspective. Largest components and communities were observed to be closely related to basic metabolic processes and some of the most common structural folds, which, from the evolutionary point of view, indicates that they may be the oldest ones. Further, we derived the first comprehensive map of ion interchangeability, based on binding site similarity. Several highly interchangeable protein-ion binding site pairs emerged (e.g., Ca2+ and Mg2+ ), as well as structurally distinct ones. The constructed network of ion binding site similarities will aid in understanding the general principles of protein-ion binding sites structure, function and evolution. We demonstrate potential uses of the network on proteins involved in cancer development and immune response, where individual ions play prominent roles in disease development. PMID- 29418081 TI - Cutaneous disorders characterized by elastolysis or loss of elastic tissue. AB - Along with collagen, elastic fibers are integral components of cutaneous connective tissue. A decrease in elastic fibers or loss thereof has been described in a number of clinically distinct skin diseases, both hereditary and acquired. In disorders associated with inflammation, elastophagocytosis is an important histological hallmark. Treatment is generally difficult. PMID- 29418082 TI - Basalzellkarzinom des Mamillen-Areola-Komplexes mit multiplen Lasionen: Bestrahlung als mogliche Ursache. PMID- 29418079 TI - Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment. AB - Nowadays, more than 90% of patients affected by chronic myeloid leukemia (CML) survive with a good quality of life, thanks to the clinical efficacy of tyrosine kinase inhibitors (TKIs). Nevertheless, point mutations of the ABL1 pocket occurring during treatment may reduce binding of TKIs, being responsible of about 20% of cases of resistance among CML patients. In addition, the presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance. LSCs express stem cell markers, including active efflux pumps and genetic and epigenetic alterations together with deregulated cell signaling pathways involved in self-renewal, such as Wnt/beta catenin, Notch, and Hedgehog. Moreover, the interaction with the bone marrow microenvironment, also known as hematopoietic niche, may influence the phenotype of surrounding cells, which evade mechanisms controlling cell proliferation and are less sensitive or frankly resistant to TKIs. This Review focuses on the role of LSCs and stem cell niche in relation to response to pharmacological treatments. A literature search from PubMed database was performed until April 30, 2017, and it has been analyzed according to keywords such as chronic myeloid leukemia, stem cell, leukemic stem cells, hematopoietic niche, tyrosine kinase inhibitors, and drug resistance. Stem Cells Translational Medicine 2018;7:305 314. PMID- 29418083 TI - S2k guideline: HPV-associated lesions of the external genital region and the anus - anogenital warts and precancerous lesions of the vulva, the penis, and the peri and intra-anal skin (short version). PMID- 29418084 TI - Pleomorphes Lipom. PMID- 29418085 TI - Generalized maculopapular and vesicular rash. PMID- 29418087 TI - Erythematose and hypopigmentierte Streifen mit Atrophie entlang der Blaschko Linien. PMID- 29418086 TI - Molecular diagnosis of skin infections using paraffin-embedded tissue - review and interdisciplinary consensus. AB - Nucleic acid amplification techniques (NATs), such as PCR, are highly sensitive and specific methods that have become valuable supplements to culture and serology in the diagnosis of infectious disorders. However, especially when using formalin-fixed and paraffin-embedded tissue, these techniques are associated with both false-negative and false-positive results, a pitfall that is frequently misjudged. Representatives of the German Society of Hygiene and Microbiology (DGHM) and the German Society of Dermatology (DDG) therefore set out to develop a consensus - in the form of a review article - on the appropriate indications for NATs using paraffin-embedded tissue, its contraindications, and the key points to be considered in the pre- and post-analytical phase. Given that fresh, naive tissue is preferably to be used in the workup of a suspected infection, PCR analysis on paraffin sections represents an exception. The latter may be considered if an infection is suspected at a later point in time and fresh tissue has not been preserved or can no longer be obtained. Potential indications include confirmation of histologically suspected infections with Leishmania spp., Bartonella spp., Rickettsia spp., or in case of ecthyma contagiosum. Infections with, for example, mycobacteria or RNA viruses, on the other hand, are not considered useful indications for NATs using paraffin sections. In order to avoid misinterpretation of test results, it is essential that laboratory reports on NATs using paraffin-embedded tissue contain information on the indication/diagnostic circumstances, the required and chosen pre-analytical steps, the limitations of the method, and on diagnostic alternatives. PMID- 29418088 TI - Verleihung der Schaudinn-Hoffmann-Plakette an Prof. Dr. Helmut Schofer (Frankfurt am Main) im Rahmen der 49. Tagung der Deutschen Dermatologischen Gesellschaft in Berlin am 26. April 2017. PMID- 29418089 TI - Kutane Granulome bei einem Patienten mit variablem Immundefektsyndrom. PMID- 29418091 TI - Biosimilars und Patientenversorgung. PMID- 29418090 TI - S2k-Leitlinie: HPV-assoziierte Lasionen der aubetaeren Genitalregion und des Anus - Genitalwarzen und Krebsvorstufen der Vulva, des Penis und der peri- und intraanalen Haut (Kurzfassung). PMID- 29418092 TI - Tumorgeschwulst an der linken Fubetasohle bei einem Mann mittleren Alters. PMID- 29418093 TI - Spalthauttransplantation zur Defektdeckung am Ohr: eine statistische Analyse. AB - HINTERGRUND UND ZIELE: Die Rekonstruktion nach Entfernung ausgedehnter maligner Hauttumoren am Ohr ist eine Herausforderung. Verschiedene Methoden der Defektdeckung wurden beschrieben. Lappenplastiken, langere Anasthesiezeiten, geringe Compliance und Antikoagulation stellen bei den oft alteren Patienten zusatzliche Risiken dar. Eine rasch, effizient und unkompliziert durchfuhrbare Methode der Defektdeckung ist daher wunschenswert. Ziel der Studie war die Beurteilung des asthetischen Resultats, des Heilungsprozesses, der Komplikations- und Rezidivrate nach Transplantation ungenetzter Spalthaut (SPHT) zur Defektdeckung nach knorpelerhaltender Resektion maligner Tumoren am Ohr. PATIENTEN UND METHODIK: 32 Patienten wurden nach Entfernung von Hauttumoren am Ohr einer Defektdeckung mittels SPHT unterzogen. ERGEBNISSE: Die durchschnittliche Defektgrobetae betrug 8,0 cm2 . Eine vollstandige Einheilung des Transplantates erfolgte in allen Fallen innerhalb von zwei Wochen. Wesentliche Komplikationen traten nicht auf. Das asthetische Resultat wurde sowohl von den Patienten als auch von einem Dermatochirurgen und zwei plastischen Chirurgen als gut bewertet. SCHLUSSFOLGERUNGEN: Die SPHT am Ohr ist eine zuverlassige Methode zur Deckung ausgedehnter Hautdefekte. Selbst bei grobetaen Tumoren des aubetaeren Ohres ist der Ohrknorpel nicht immer infiltriert. Eine knorpelschonende Tumorresektion mit anschliebetaender Defektdeckung mittels SPHT ist eine ausgezeichnete und rasch durchfuhrbare Technik mit hoher Patientenzufriedenheit. PMID- 29418095 TI - Kongresskalender 2018. PMID- 29418094 TI - Lokalisiertes pratibiales bulloses Pemphigoid bei einer Patientin unter Pembrolizumab-Therapie wegen eines metastasierten Melanoms. PMID- 29418096 TI - Ara-C ears: an actual drug-induced reaction or a distinctive manifestation of a neutrophilic dermatosis? PMID- 29418097 TI - Hyalinosis cutis et mucosae: eine klinische Fallvorstellung mit besonderer Berucksichtigung von Schleimhautveranderungen. PMID- 29418098 TI - Stellenwert der Dermatoskopie in Deutschland - Ergebnisse aus der Pan-Euro Dermoscopy-Querschnittsstudie. PMID- 29418099 TI - Elastolysen und Hauterkrankungen mit Verlust der elastischen Fasern. AB - Die elastischen Fasern sind neben den kollagenen Fasern der wichtigste Bestandteil des Bindegewebsgerustes der Haut. Eine Verminderung oder ein Verlust der elastischen Fasern ist bei einer Vielzahl von klinisch sich unterschiedlich prasentierenden Erkrankungen, hereditar oder erworben, beschrieben. Bei den Erkrankungen, die mit einer Entzundung einhergehen ist die Elastophagozytose ein wichtiges histologisches Merkmal. Die Therapie der Erkrankungen dieser Gruppe ist grundsatzlich schwierig. PMID- 29418101 TI - "Creeping eruption" und eosinophile Follikulitis: Atypische kutane Larva migrans. PMID- 29418100 TI - Molekulare Diagnostik von Hautinfektionen am Paraffinmaterial - Ubersicht und interdisziplinarer Konsensus. AB - Nukleinsaure-Amplifikations-Techniken (NAT), wie die PCR, sind hochsensitiv sowie selektiv und stellen in der mikrobiologischen Diagnostik wertvolle Erganzungen zur kulturellen Anzucht und Serologie dar. Sie bergen aber gerade bei formalinfixiertem und in Paraffin eingebettetem Gewebe ein Risiko fur sowohl falsch negative als auch falsch positive Resultate, welches nicht immer richtig eingeschatzt wird. Daher haben Vertreter der Deutschen Gesellschaft fur Hygiene und Mikrobiologie (DGHM) und der Deutschen Dermatologischen Gesellschaft (DDG) einen Konsensus in Form einer Ubersichtsarbeit erarbeitet, wann eine NAT am Paraffinschnitt angezeigt und sinnvoll ist und welche Punkte dabei in der Praanalytik und Befundinterpretation beachtet werden mussen. Da bei Verdacht auf eine Infektion grundsatzlich Nativgewebe genutzt werden soll, ist die PCR am Paraffinschnitt ein Sonderfall, wenn beispielsweise bei erst nachtraglichaufgekommenem Verdacht auf eine Infektion kein Nativmaterial zur Verfugung steht und nicht mehr gewonnen werden kann. Mogliche Indikationen sind der histologisch erhobene Verdacht auf eine Leishmaniose, eine Infektion durch Bartonellen oder Rickettsien, oder ein Ecthyma contagiosum. Nicht sinnvoll ist oder kritisch gesehen wird eine NAT am Paraffinschnitt zum Beispiel bei Infektionen mit Mykobakterien oder RNA-Viren. Die Konstellation fur eine NAT aus Paraffingewebe sollte jeweils benannt werden, die erforderliche Pra-Analytik, die jeweiligen Grenzen des Verfahrens und die diagnostischen Alternativen bekannt sein. Der PCR-Befund sollte entsprechend kommentiert werden, um Fehleinschatzungen zu vermeiden. PMID- 29418103 TI - Lokalisierte subepidermale Blasenbildung: nicht immer ein bulloses Pemphigoid, sondern eine diagnostische Herausforderung. PMID- 29418104 TI - Leserbrief zu Menzer C et al. Afrikanisches Zeckenstichfieber - Ein unliebsames Souvenir aus Sudafrika [1]. PMID- 29418105 TI - AraC-Ohren - durch Medikamente ausgelost oder Manifestation einer neutrophilen Dermatose? PMID- 29418107 TI - Exanthematische makulopapulose Hautveranderungen und Vesikel am gesamten Integument. PMID- 29418106 TI - Biosimilars in der Dermatologie - Theorie wird Realitat. AB - Biosimilars sind biologische Medikamente, bei denen es sich um Nachbildungen eines spezifischen Referenzprodukts handelt. Biosimilars der Tumornekrosefaktor alpha-Inhibitoren Infliximab und Etanercept sind bereits zugelassen und stehen fur dermatologische Indikationen zur Verfugung. Die Aufsichtsbehorden verlangen eine eingehende Analyse der physikochemischen und funktionellen Eigenschaften dieser hochkomplexen Molekule sowie klinische Daten hinsichtlich ihrer gleichwertigen Wirksamkeit und Sicherheit anhand mindestens einer klinischen Studie mit einer sensitiven und homogenen Population. Fur die Zulassung in einem regulierten Arzneimittelmarkt muss daher nachgewiesen werden, dass die Biosimilars praktisch gleichwertig mit dem jeweiligen Originalpraparat sind. Demzufolge werden diese Daten von einem Molekul (dem Originator) auf das andere (das Biosimilar) extrapoliert und die resultierende Zulassung umfasst die gleichen Indikationen wie beim Originalpraparat. Die Extrapolation ist zwar gut akzeptiert und reguliert, es fehlen jedoch klare Empfehlungen hinsichtlich der Austauschbarkeit von Originator und Biosimilar ebenso wie Daten uber mehrmalige aufeinanderfolgende Umstellungen. Die aktuellen wissenschaftlichen Erkenntnisse stehen einer Anwendung von Biosimilars bei dermatologischen Indikationen nicht entgegen. Eine mehrmalige Umstellung der Biosimilars sollte jedoch sorgfaltig uberdacht werden. Um das Vertrauen in Biosimilars zu festigen und ihre Evidenz zu verbessern, ist es essentiell das spezifische Produkt, das jeder Patient erhalt, moglichst genau und moglichst im Rahmen von Patientenregister zu dokumentieren. PMID- 29418108 TI - Hautfarbene Papeln an den Ellenbogen mit Granuloma-anulare-ahnlichem histologischen Muster. PMID- 29418109 TI - Pruritische papulovesikulose Dermatose mit retikularer Hyperpigmentierung. PMID- 29418110 TI - Stevens-Johnson-Syndrom/toxische epidermale Nekrolyse Overlap bei einem NSCLC Patienten unter Afatinib-Behandlung. PMID- 29418111 TI - Scaling of Primate Forearm Muscle Architecture as It Relates to Locomotion and Posture. AB - It has been previously proposed that distal humerus morphology may reflect the locomotor pattern and substrate preferred by different primates. However, relationships between these behaviors and the morphological capabilities of muscles originating on these osteological structures have not been fully explored. Here, we present data about forearm muscle architecture in a sample of 44 primate species (N = 55 specimens): 9 strepsirrhines, 15 platyrrhines, and 20 catarrhines. The sample includes all major locomotor and substrate use groups. We isolated each antebrachial muscle and categorized them into functional groups: wrist and digital extensors and flexors, antebrachial mm. that do not cross the wrist, and functional combinations thereof. Muscle mass, physiological cross sectional area (PCSA), reduced PCSA (RPCSA), and fiber length (FL) are examined in the context of higher taxonomic group, as well as locomotor/postural and substrate preferences. Results show that muscle masses, PCSA, and RPCSA scale with positive allometry while FL scales with isometry indicating that larger primates have relatively stronger, but neither faster nor more flexible, forearms across the sample. When accounting for variation in body size, we found no statistically significant difference in architecture among higher taxonomic groups or locomotor/postural groups. However, we found that arboreal primates have significantly greater FL than terrestrial ones, suggesting that these species are adapted for greater speed and/or flexibility in the trees. These data may affect our interpretation of the mechanisms for variation in humeral morphology and provide information for refining biomechanical models of joint stress and movement in extant and fossil primates. Anat Rec, 301:484-495, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418112 TI - The Anatomical Record Stretches Its Legs and Pumps Its Arms in Part II of Our Special Issue Examining Behavioral Adaptations in Muscle Functional Morphology. PMID- 29418113 TI - The Search for the Intersection of Form and Function: Looking for Clues into What Has Determined How, Why, and When Animals Came to Move the Way They Do. PMID- 29418114 TI - Anatomical Basis of Differences in Locomotor Behavior in Martens: A Comparison of the Forelimb Musculature Between Two Sympatric Species of Martes. AB - Arboreal locomotion imposes selective pressures that may affect the evolution of the locomotor apparatus. The limbs have to be mobile to reach across discontinuities, yet at the same time need to be forceful to move against gravity during climbing. However, as intermediaries between the arboreal and terrestrial environment, semi-arboreal mammals appear not extremely specialized and, thus, anatomical adaptations may be less evident than expected for arboreal climbers. Here, we present quantitative data on the muscle anatomy of the forelimbs (N = 14) of two closely related species of Mustelidae and relate the findings to their locomotor habits. The arboreal pine marten (Martes martes) and the more terrestrial stone marten (Martes foina) are the most similar sympatric carnivores in Europe, but distinctly differ in habitat selection and locomotor mode. Via dissections muscle architectural variables including muscle mass, pennation angle, and fiber length were measured and the physiological cross-sectional area and maximum isometric force were estimated for each muscle. The results reveal that the force-generating capacity of the limb flexor and retractor muscles and the excursion capability of the adductor muscles are greater in the pine marten compared to the stone marten. Since the two sympatric martens are very similar in terms of overall appearance, body size, intra-limb proportions, phylogenetic relationships and predation behavior, the differences in forelimb musculature are interpreted to reflect the greater climbing ability of the pine marten. The functional properties appear to facilitate locomotion in a three-dimensionally complex arboreal environment. Anat Rec, 301:449-472, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418115 TI - How the Brain May Have Shaped Muscle Anatomy and Physiology: A Preliminary Study. AB - Skeletal muscle fibers are often used to evaluate functional differences in locomotion. However, because there are energetic differences among muscle fiber cells, muscle fiber composition could be used to address evolutionary questions about energetics. Skeletal muscle is composed of two main types of fibers: Type I and II. The difference between the two can be reduced to how these muscle cells use oxygen and glucose. Type I fibers convert glucose to ATP using oxygen, while Type II fibers rely primarily on anaerobic metabolic processes. The expensive tissue hypothesis (ETH) proposes that the energetic demands imposed on the body by the brain result in a reduction in other expensive tissues (e.g., gastrointestinal tract). The original ETH dismisses the energetic demands of skeletal muscle, despite skeletal muscle being (1) an expensive tissue when active and (2) in direct competition for glucose with the brain. Based on these observations we hypothesize that larger brained primates will have relatively less muscle mass and a decrease in Type I fibers. As part of a larger study to test this hypothesis, we present data from 10 species of primates. We collected body mass, muscle mass, and biopsied four muscles from each specimen for histological procedures. We collected endocranial volumes from the literature. Using immunohistochemistry, a muscle fiber composition profile was created for each species sampled. Results show that larger brained primates have less muscle and fewer Type I fibers than primates with smaller brains. Results clarify the relationship between muscle mass and brain mass and illustrate how muscle mass could be used to address energetic questions. Anat Rec, 301:528-537, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418116 TI - Does the Morphology of the Forelimb Flexor Muscles Differ Between Lizards Using Different Habitats? AB - Lizards are an interesting group to study how habitat use impacts the morphology of the forelimb because they occupy a great diversity of ecological niches. In this study, we specifically investigated whether habitat use impacts the morphology of the forelimb flexor muscles in lizards. To do so, we performed dissections and quantified the physiological cross sectional area (PCSA), the fiber length, and the mass of four flexor muscles in 21 different species of lizards. Our results show that only the PCSA of the m. flexor carpi radialis is different among lizards with different ecologies (arboreal versus non-arboreal). This difference disappeared, however, when taking phylogeny into account. Arboreal species have a higher m. flexor carpi radialis cross sectional area likely allowing them to flex the wrist more forcefully which may allow them climb and hold on to branches better. In contrast, other muscles are not different between arboreal and non-arboreal species. Further studies focusing on additional anatomical features of the lizard forelimb as well as studies documenting how lizards use the arboreal niche are needed to fully understand how an arboreal life style may constrain limb morphology in lizards. Anat Rec, 301:424-433, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418117 TI - Functional Morphology and Behavioral Correlates to Postcranial Musculature. AB - In this the second issue of a two-volume set of the Anatomical Record on the relationship between muscle functional morphology and behavior, the focus is on the postcranial musculature. Traditionally, when talking of the postcranium we think of the skeletal parts that primarily provide the lever system necessary for body movements. However, without the force produced by muscle, the postcranial skeleton could not perform these or most other tasks. In this special issue, our colleagues present ten papers that focus on postcranial muscle morphology and function from different perspectives. They include papers on forelimb and hindlimb muscle functional morphology of vertebrates, including lizards, bats, primates, a carnivoran and a rodent, and involved in different substrate use (arboreal, terrestrial, and flying) and locomotion behavior (quadrupedal, leaper, and suspensory) along with a historical overview to help bookend the contextualization of the issues. The picture that these papers provide is one of great liveliness in the field of muscle functional morphology where both young students and affirmed professors continue to contribute with both traditional approaches and new techniques to further our knowledge of muscle morphology and its relationship with animal behavior. Anat Rec, 301:419-423, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418118 TI - Innervation of the Long Head of the Triceps Brachii in Humans-A Fresh Look. AB - The triceps brachii muscle occupies the posterior compartment of the arm in humans and has three heads. The lateral and medial heads originate from the humerus and the long head arises from the infraglenoid tubercle of the scapula. All heads form a common tendon that inserts onto the olecranon and the deep antebrachial fascia on each side of it. Each head receives its own motor branch, which all are thought to originate from the radial nerve. However, several studies reported that the motor branch of the long head of the triceps (LHT) arises from the axillary nerve or the posterior cord. Here, we dissected 27 triceps in 15 cadavers to analyze the innervation of the LHT and found only radial innervation, which contradicts those studies. We examined studies reporting that the motor branch to the LHT in humans does not arise from the radial nerve as well as studies of the triceps in primates. Occasional variations of the innervation of skeletal muscles are normal, but a change of principal motor innervation from radial to axillary nerve has important implications. This is because the axillary nerve is often involved during shoulder injuries. The precise identification of the prevalence of axillary versus radial innervation is therefore clinically relevant for surgery, nerve drafting, and occupational and physical therapy. We conclude that the primary motor branch to the LHT arises from the radial nerve but axillary/posterior cord innervations occur occasionally. We suggest the development of a standard methodology for further studies. Anat Rec, 301:473-483, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418119 TI - Leg Muscle Architecture in Primates and Its Correlation with Locomotion Patterns. AB - Bone biomechanical studies indicate that leg bone structure can be related to different locomotor patterns. The osteological correlates of extant primates' locomotion patterns and substrate use are important to consider when estimating corresponding behaviors of extinct primates. Here, we test if these same patterns are seen in the differences in leg muscular architecture. Muscle mass, fascicle lengths (FL), physiological cross-sectional area (PCSA), reduced PCSA (RPCSA) and tendon-to-muscle belly ratio were studied in 33 primate species (6 strepsirrhines, 14 platyrrhines and 13 catarrhines). Muscles were grouped into toe and ankle flexors and extensors and studied for phylogenetic and functional signals. All variables strongly correlate with body mass: strength variables (mass, PCSA and RPCSA) scale with positive allometry, whereas the speed/stretch measure (FL) trend toward negative allometry. Thus, larger primates are relatively stronger than smaller species, but they have relatively shorter leg muscle fibers than smaller primates. The strongest functional signal emerged when comparing belly-muscle tendon unit (MTU) length ratio in leaping and non-leaping primates. Leapers show significantly smaller plantarflexor belly-MTU ratio. Surprisingly, no significant results reflect a correlation between muscle architecture and substrate and locomotor groups. However, several trends suggest that a larger sample and more fine-grained defined categories could produce significant results. These results show the complex relation between leg bone biomechanics and muscle architecture and demand for further studies on this topic. Anat Rec, 301:515-527, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418120 TI - Assessment of the Hindlimb Membrane Musculature of Bats: Implications for Active Control of the Calcar. AB - The striking postcranial anatomy of bats reflects their specialized ecology; they are the only mammals capable of powered flight. Bat postcranial adaptations include a series of membranes that connect highly-modified, or even novel, skeletal elements. While most studies of bat postcranial anatomy have focused on their wings, bat hindlimbs also contain many derived and functionally important, yet less studied, features. In this study, we investigate variation in the membrane and limb musculature associated with the calcar, a neomorphic skeletal structure found in the hindlimbs of most bats. We use diffusible iodine-based contrast-enhanced computed tomography and standard histological techniques to examine the calcars and hindlimb membranes of three bat species that vary ecologically (Myotis californicus, a slow-flying insectivore; Molossus molossus, a fast-flying insectivore; and Artibeus jamaicensis, a slow-flying frugivore). We also assess the level of mineralization of the calcar at muscle attachment sites to better understand how muscle contraction may enable calcar function. We found that the arrangement of the calcar musculature varies among the three bat species, as does the pattern of mineral content within the calcar. M. molossus and M. californicus exhibit more complex calcar and calcar musculature morphologies than A. jamaicensis, and the degree of calcar mineralization decreases toward the tip of the calcar in all species. These results are consistent with the idea that the calcar may have a functional role in flight maneuverability. Anat Rec, 301:441-448, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418121 TI - Mouse Hind Limb Skeletal Muscle Functional Adaptation in a Simulated Fine Branch Arboreal Habitat. AB - The musculoskeletal system is remarkably plastic during growth. The purpose of this study was to examine the muscular plasticity in functional and structural properties in a model known to result in significant developmental plasticity of the postcranial skeleton. Fifteen weanling C57BL/6 mice were raised to 16 weeks of age in one of two enclosures: a climbing enclosure that simulates a fine branch arboreal habitat and is traversed by steel wires crossing at 45 degrees relative to horizontal at multiple intersections, and a control enclosure that resembles a parking deck with no wires but the same volume of habitable space. At killing, ex vivo contractility properties of the soleus (SOL) and extensor digitorum longus (EDL) muscles were examined. Our results demonstrate that EDL muscles of climbing mice contracted with higher specific forces and were comprised of muscle fibers with slower myosin heavy chain isoforms. EDL muscles also fatigued at a higher rate in climbing mice compared to controls. SOL muscle function is not affected by the climbing environment. Likewise, mass and architecture of both EDL and SOL muscles were not different between climbing and control mice. Our data demonstrate that functional adaptation does not require concomitant architectural adaptation in order to increase contractile force. Anat Rec, 301:434-440, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418122 TI - Muscle Functional Morphology in Paleobiology: The Past, Present, and Future of "Paleomyology". AB - Our knowledge of muscle anatomy and physiology in vertebrates has increased dramatically over the last two-hundred years. Today, much is understood about how muscles contract and about the functional meaning of muscular variation at multiple scales. Progress in muscle anatomy has profited from the availability of broad comparative samples, advances in microscopy have permitted comparisons at increasingly finer scales, and progress in muscle physiology has profited from many carefully designed and executed experiments. Several avenues of future work are promising. In particular, muscle ontogeny (growth and development) is poorly understood for many vertebrate groups. We consider which types of advances in muscle functional morphology are of use to paleobiologists. These are only a modest subset for muscle anatomy and a very small subset for muscle physiology. The relationship between muscle and bone - spatially and mechanically-is critical to any future advances in "paleomyology". Anat Rec, 301:538-555, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418124 TI - The Value of Disinfectants. PMID- 29418123 TI - Why Do Knuckle-Walking African Apes Knuckle-Walk? AB - Among living mammals, only the African apes and some anteaters adopt knuckle walking as their primary locomotor behavior. That Pan and Gorilla both knuckle walk has been cited as evidence of their common ancestry and a primitive condition for a combined Homo, Pan, and Gorilla clade. Recent research on forelimb ontogeny and anatomy, in addition to recently described hominin fossils, indicate that knuckle-walking was independently acquired after divergence of the Pan and Gorilla lineages. Although the large-bodied, largely suspensory orangutan shares some aspects of the African ape bauplan, it does not regularly knuckle walk when terrestrial. While many anatomical correlates of knuckle-walking have been identified, a functional explanation of this unusual locomotor pattern has yet to be proposed. Here, we argue that it was adopted by African apes as a means of ameliorating the consequences of repetitive impact loadings on the soft and hard tissues of the forelimb by employing isometric and/or eccentric contraction of antebrachial musculature during terrestrial locomotion. Evidence of this adaptation can be found in the differential size and fiber geometry of the forearm musculature, and differences in torso shape between the knuckle-walking and non-knuckle-walking apes (including humans). We also argue that some osteological features of the carpus and metacarpus that have been identified as adaptations to knuckle-walking are consequences of cartilage remodeling during ontogeny rather than traits limiting motion in the hand and wrist. An understanding of the functional basis of knuckle-walking provides an explanation of the locomotor parallelisms in modern Pan and Gorilla. Anat Rec, 301:496-514, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29418125 TI - Passing Events and Topics. PMID- 29418126 TI - The Value of Disinfectants. PMID- 29418127 TI - The Sweating Sicknesses. PMID- 29418129 TI - Vaccination and Smallpox: Memorandum by the Ministry of Health. PMID- 29418128 TI - The Disqualification of Marriage. PMID- 29418130 TI - Quarantine. PMID- 29418132 TI - Edward Jenner-I: The Discoverer of Vaccination. PMID- 29418131 TI - The Training of Health Visitors. PMID- 29418133 TI - Difficulties at Burton. PMID- 29418134 TI - Notes and Comments. PMID- 29418135 TI - A Leaflet Competition. PMID- 29418136 TI - The Purpose of the Hospital. PMID- 29418138 TI - Hospital Finance. PMID- 29418137 TI - Are Doctors Becoming Unpopular? PMID- 29418139 TI - Safeguarding the Milk Supply. PMID- 29418140 TI - Hospital Officials' Pensions. PMID- 29418142 TI - Milk Purity: The Distributor's View. PMID- 29418141 TI - The Decline and Fall (?) of Tuberculosis.-II. PMID- 29418143 TI - Notes and Comments. PMID- 29418144 TI - Public Health and Emigration. PMID- 29418145 TI - The Norfolk and Norwich Hospital. PMID- 29418147 TI - Approved Societies and Hospital Treatment. PMID- 29418146 TI - Hospital News. PMID- 29418148 TI - King Edward's Hospital Fund: Annual Meeting and Report. PMID- 29418149 TI - Approved Societies and Hospital Treatment. PMID- 29418150 TI - The British Medical Association and the Voluntary Hospitals. PMID- 29418151 TI - The Decline and Fall (?) of Tuberculosis.-III. PMID- 29418152 TI - Hospital News. PMID- 29418153 TI - Notes and Comments. PMID- 29418154 TI - The Public Health: Does It Matter? PMID- 29418155 TI - The Great Drought of 1921 : Chlorination of Impure Water Supplies. PMID- 29418156 TI - Hospital Finance. PMID- 29418157 TI - The Change in Hospital Finance. PMID- 29418158 TI - Advertising a Contribution Scheme. PMID- 29418160 TI - The Effects of the Drought of 1921 on Water Supply. PMID- 29418159 TI - The Treatment of Tonsils and Adenoids. PMID- 29418161 TI - The Control of Diphtheria. PMID- 29418162 TI - The Period of Infectivity of Venereal Disease. PMID- 29418163 TI - Passing Events and Topics. PMID- 29418165 TI - Prevention and Cure. PMID- 29418166 TI - The Sussex Provident Scheme and Its Critics. PMID- 29418164 TI - The Late Sir Arthur Pearson. PMID- 29418168 TI - Notes and Comments. PMID- 29418167 TI - The Treatment of Chronic Otorreoea in School Children. PMID- 29418169 TI - The Renewal of Vision in Hospital Administration. PMID- 29418171 TI - The Government and the Voluntary System. PMID- 29418170 TI - The Great Plague. PMID- 29418172 TI - A New Year's Appeal. PMID- 29418173 TI - News in Brief: Personal Notes-What the Hospitals are Doing. PMID- 29418174 TI - Health with Economy: The Position on the South Coast: Eastbourne. PMID- 29418175 TI - Tobacco and the Worker. PMID- 29418176 TI - The Fundamental Biological Factors Underlying the Incidence of Tuberculosis.-II. PMID- 29418177 TI - Passing Events and Topics. PMID- 29418178 TI - Notes and Comments. PMID- 29418179 TI - Edward Jenner. PMID- 29418180 TI - Hospital Planning in America. PMID- 29418181 TI - Hospital Officials' Pensions. PMID- 29418182 TI - Medical Education and the Public Health. PMID- 29418183 TI - Medicine in Ancient Egypt and Ethiopia. PMID- 29418184 TI - Hospital Officials' Pensions. PMID- 29418185 TI - The Training of Male Nurses. PMID- 29418186 TI - The Orthopaedic Hospital at Shepherd's Bush. PMID- 29418187 TI - Notes and Comments. PMID- 29418189 TI - The Future of the Voluntary Hospitals. PMID- 29418188 TI - The A.B.C. of Vitamins.-II. PMID- 29418190 TI - Hospital News. PMID- 29418192 TI - Other News. PMID- 29418191 TI - The Decline and Fall (?) of Tuberculosis.-I. PMID- 29418193 TI - Edinburgh Royal Infirmary and Approved Societies. PMID- 29418194 TI - Is the Panel Doctor Doing His Job? PMID- 29418196 TI - Hospital Finance. PMID- 29418195 TI - The Lister Ward at Glasgow Royal Infirmary. PMID- 29418197 TI - Health with Economy: The Position on the South Coast: Folkstone. PMID- 29418198 TI - Isolation Hospital Consultants' Fees. PMID- 29418199 TI - The Toxicity of Putrid Food. PMID- 29418200 TI - Public Health Education. PMID- 29418201 TI - The Voluntary Hospitals. PMID- 29418202 TI - The Chlorination of Water: Circular of the Ministry of Health. PMID- 29418203 TI - The Black Death. PMID- 29418204 TI - Women in National Life. PMID- 29418205 TI - Hospital Representation on the King's Fund. PMID- 29418207 TI - Food Poisoning. PMID- 29418206 TI - Notes and Comments. PMID- 29418208 TI - The Medical Aspects of Dried Milk. PMID- 29418209 TI - Medical Correspondents. PMID- 29418210 TI - The Value of Disinfectants. PMID- 29418212 TI - Local Committees. PMID- 29418211 TI - Passing Events and Topics. PMID- 29418213 TI - Help for Armenia. PMID- 29418215 TI - The Royal Institute of Public Health: Plymouth Congress. PMID- 29418214 TI - Eugenics and Public Health. PMID- 29418217 TI - Notes and Comments. PMID- 29418216 TI - Hospital Finance. PMID- 29418218 TI - Lunacy Reform. PMID- 29418219 TI - The British Hospitals Association Conference. PMID- 29418220 TI - Hospital and Other News. PMID- 29418222 TI - Preventive and Rescue Work: A Forward Move in London. PMID- 29418221 TI - A Hospital's Water Supply. PMID- 29418223 TI - The Need of Maternity Homes: (Communicated). PMID- 29418224 TI - The Public Health: Interviews with Local Authorities: Liverpool. PMID- 29418225 TI - Approved Societies and Hospital Treatment. PMID- 29418226 TI - The Voluntary Hospital: A Retrospect and a Prospect. PMID- 29418227 TI - The Health Ministry's Progress. PMID- 29418228 TI - The British Medical Association and the Voluntary Hospitals. PMID- 29418229 TI - Co-Operation in a Contributory Scheme. PMID- 29418230 TI - Another Contributory Scheme. PMID- 29418232 TI - Physical Education for Girls. PMID- 29418231 TI - The Hospital Management and Treatment of Infectious Diseases.-II. PMID- 29418233 TI - The Hospital Saturday Committee. PMID- 29418234 TI - The Report of the War Office Committee on "Shell-Shock". PMID- 29418235 TI - Hospital News. PMID- 29418236 TI - The Smoke Nuisance. PMID- 29418237 TI - Hospital Finance. PMID- 29418238 TI - Conference of Sanitary Inspectors' Association at Buxton: Presidential Address. PMID- 29418239 TI - The Public Health: Interviews with Local Authorities: The City of Sheffield. PMID- 29418240 TI - Our Penal and Prison System.-II. PMID- 29418241 TI - Notes and Comments. PMID- 29418242 TI - The Work of the Panel Committees. PMID- 29418243 TI - Medicines and Meddlesomeness.-I. PMID- 29418245 TI - The Value of Disinfectants. PMID- 29418244 TI - The Wrong Turning in Public Health. PMID- 29418246 TI - The Future of the Hospitals: The Cave Committee and after. PMID- 29418247 TI - He Wants to Know. PMID- 29418248 TI - The Treatment of Tonsils and Adenoids. PMID- 29418249 TI - The Conditional Grant. PMID- 29418250 TI - Passing Events and Topics. PMID- 29418251 TI - Smallpox and Vaccination. PMID- 29418252 TI - A Christmas Appeal for the Hospitals. PMID- 29418253 TI - A Layman's Opinion. PMID- 29418254 TI - Smallpox at Nottingham. PMID- 29418256 TI - A Pageant for Hospitals. PMID- 29418255 TI - Belladonna and Blethers. PMID- 29418258 TI - Notes and Comments. PMID- 29418257 TI - Folk-Lore in Medicine. PMID- 29418259 TI - The Health of London. PMID- 29418261 TI - International Union against Tuberculosis. PMID- 29418260 TI - Edward Jenner-II: The Discoverer of Vaccination. PMID- 29418262 TI - The Combined Appeal for London Hospitals. PMID- 29418263 TI - Highland Folk Medicine: Some Strange Customs. PMID- 29418264 TI - Hospital Finance. PMID- 29418265 TI - Maternity Homes: The Henry Saxon Snell Prize. PMID- 29418266 TI - Lunacy Reform.-II. PMID- 29418267 TI - A Central Fund for Provincial Hospitals. PMID- 29418268 TI - International Conference on Birth Control. PMID- 29418269 TI - Notes and Comments. PMID- 29418270 TI - Do the Approved Societies Seek to Control the Doctors? PMID- 29418272 TI - The Public Health: Interviews with Local Authorities: The County of Durham. PMID- 29418271 TI - The Hospital Problem. PMID- 29418274 TI - National Baby Week. PMID- 29418273 TI - Hospital Economies. PMID- 29418275 TI - Home Nursing of Insured Persons. PMID- 29418276 TI - Hospital News. PMID- 29418277 TI - The Conversion of Pail Closets. PMID- 29418278 TI - The History of Medical Attendance on the Poor. PMID- 29418280 TI - Hospital News. PMID- 29418279 TI - Do the Approved Societies Seek to Control the Doctors? PMID- 29418281 TI - Course of Study for Trained Hospital Nurses: To Qualify for Positions under Local Health Authorities (Approved by the Scottish Board of Health). PMID- 29418282 TI - Notes and Comments. PMID- 29418283 TI - Our Penal and Prison System.-I. PMID- 29418284 TI - On the State of Public Health. PMID- 29418285 TI - The Hospital Management and Treatment of Infectious Diseases.-I. PMID- 29418286 TI - The Public Health: Interviews with Local Authorities: The City of Birmingham. PMID- 29418287 TI - The Surgery Queue. PMID- 29418288 TI - Salisbury and District Infirmary and Hospital League. PMID- 29418289 TI - The Voluntary Hospitals Commission. PMID- 29418290 TI - Hospital Finance. PMID- 29418291 TI - The Medical Curriculum. PMID- 29418292 TI - Unemployment and Health. PMID- 29418293 TI - Home Nursing for Insured Persons. PMID- 29418294 TI - King Edward's Hospital Fund. PMID- 29418295 TI - Hospitals and Unemployment: The King's Fund and the Cabinet Committee. PMID- 29418296 TI - The Safety of Public Water Supplies: With Special Reference to the "Wallace Tiernan" Chlorinator. PMID- 29418297 TI - The Influenza of 1918-1919. PMID- 29418298 TI - Diphtheria in Bristol, 1921. PMID- 29418299 TI - Voluntary Hospitals. PMID- 29418300 TI - The A B C of Vitamins. PMID- 29418301 TI - An Appeal. PMID- 29418302 TI - A Profession for the Blind. PMID- 29418303 TI - Sheffield Voluntary Hospitals Committee. PMID- 29418305 TI - Passing Events and Topics. PMID- 29418304 TI - Notes and Comments. PMID- 29418306 TI - The Fundamental Biological Factors Underlying the Incidence of Tuberculosis. PMID- 29418308 TI - News in Brief: What the Provinces Are Doing-Personal Notes-Christmas Festivities. PMID- 29418307 TI - Public Health Legislation in 1921: A General Review. PMID- 29418310 TI - Notes and Comments. PMID- 29418309 TI - Notes from the Conference of Educational Associations. PMID- 29418311 TI - A Visit to Sheffield's Remarkable Sewage Works. PMID- 29418312 TI - King Edward's Hospital Fund for London: The Statistical Report for 1921. PMID- 29418313 TI - The Dentists' Act, 1921. PMID- 29418314 TI - Stopping the Panel Doctor's Pay. PMID- 29418315 TI - The Voluntary Hospitals Commission on Hospital Management. PMID- 29418316 TI - The Dentists' Register. PMID- 29418317 TI - National Health Insurance Notes and Comments. PMID- 29418318 TI - Hospital News. PMID- 29418319 TI - Effect of Unemployment and the Dole on the Health and Habit of the Nation. PMID- 29418320 TI - What We Stand for in Public Health. PMID- 29418321 TI - Insulin and Diabetes: The Types for Which Cure Is in Sight. PMID- 29418322 TI - The Town Planning Acts, 1909 and 1919: Some Difficulties. PMID- 29418323 TI - The Public Health: Interviews with Local Authorities: Portsmouth: Safety First. PMID- 29418324 TI - Hospital Finance. PMID- 29418326 TI - Labour's Health Policy. PMID- 29418325 TI - Sir Napier Burnett's Report on the Voluntary Hospitals outside London. PMID- 29418327 TI - Raising Money for Hospitals. PMID- 29418328 TI - Housing and the Cost of Land. PMID- 29418329 TI - Hospital and Health News. PMID- 29418330 TI - Artificial Legs for Civilians. PMID- 29418331 TI - Humane Slaughtering of Animals. PMID- 29418332 TI - No. PMID- 29418333 TI - A Clean Milk Opportunity: Effects of the New Regulations. PMID- 29418334 TI - Boys and Girls in Secondary Schools. PMID- 29418335 TI - Echoes of the Month. PMID- 29418336 TI - The Organisation of Panel Practice. PMID- 29418337 TI - Hospital Finance. PMID- 29418338 TI - Raising Money for Hospitals. PMID- 29418339 TI - Health and the Roof Tree. PMID- 29418340 TI - The Public Health-Child Welfare in the West Riding. PMID- 29418341 TI - The Future of Voluntary Hospitals: What the New Finance May Do. PMID- 29418342 TI - Notes and Comments. PMID- 29418343 TI - Yes. PMID- 29418344 TI - National Health Insurance Notes. PMID- 29418345 TI - Regional Planning for Health and Beauty-A Vision of a New South Yorkshire. PMID- 29418346 TI - The Humour and Tragedy of Hospital Life. PMID- 29418347 TI - Hospital Needs and Hospital Appeals: Hospitals with 150 Beds and Upwards. PMID- 29418348 TI - Mass Contributions in London: The Hospitals Savings Association Scheme. PMID- 29418349 TI - Raising Money for Hospitals. PMID- 29418350 TI - Our Hospitals-To-Day and To-Morrow. PMID- 29418351 TI - Co-Operation in a Contributory Scheme. PMID- 29418352 TI - Hospital Finance. PMID- 29418353 TI - National Health Insurance Notes and Comments. PMID- 29418354 TI - Regular Contributions in South London. PMID- 29418355 TI - Hospital and Other News. PMID- 29418356 TI - Hospital Co-Operation in Westminster. PMID- 29418357 TI - Notes and Comments. PMID- 29418358 TI - The "New Movement" in Hospital Appeals: What the Marylebone Group Has Done. PMID- 29418359 TI - Report of Committee of the Wilts Branch of the British Medical Association on County Medical Service. PMID- 29418360 TI - Hospital Accounts and Finance: Real Economy and How to Secure It. PMID- 29418361 TI - Nursing for the Insured. PMID- 29418363 TI - The Conquest of Disease. PMID- 29418362 TI - Panelphobia and Its Cure. PMID- 29418365 TI - Tuberculosis and Housing in the West Riding. PMID- 29418364 TI - Facts about Gas Poisoning. PMID- 29418366 TI - The Maintenance of Voluntary Hospitals. PMID- 29418367 TI - Physically Defective Children. PMID- 29418368 TI - The Lady Almoner. PMID- 29418370 TI - Combating Venereal Diseases. PMID- 29418369 TI - Bread and Dirt. PMID- 29418371 TI - Cadet Corps as Health Centres. PMID- 29418372 TI - Opening of Maudsley Hospital-A New Departure in the Treatment of Insanity. PMID- 29418373 TI - A Fair Chance for the Panel System. PMID- 29418374 TI - Hospital Progress and Finance. PMID- 29418375 TI - Hospital and Health News. PMID- 29418376 TI - The Hospital Saving Scheme-Provincial Success and London Promise. PMID- 29418377 TI - Drugs of Addiction. PMID- 29418378 TI - The Virus of Influenza. PMID- 29418379 TI - Notes and Comments. PMID- 29418380 TI - A Hospital Social Evening. PMID- 29418381 TI - Echoes of the Month. PMID- 29418382 TI - Central Surgeries. PMID- 29418383 TI - National Health Insurance Notes. PMID- 29418385 TI - Points from Hospital Reports. PMID- 29418384 TI - Asylum Reform. PMID- 29418386 TI - Notes and Comments. PMID- 29418387 TI - Rhyl Sanitary Congress: Smoke and Scavenging. PMID- 29418389 TI - Hospital Progress and Finance. PMID- 29418388 TI - National Health Insurance Notes. PMID- 29418390 TI - The Hospital Needs of Swindon: Mr. Orde's Report. PMID- 29418391 TI - The National Health: The Cost of Progress. PMID- 29418392 TI - Hospital Co-Operation: What Westminster Is Doing. PMID- 29418393 TI - The Reformed Public House. PMID- 29418394 TI - Work of the Red Cross. PMID- 29418395 TI - The Hartshill Orthopaedic Hospital. PMID- 29418396 TI - Echoes of the Month. PMID- 29418397 TI - A Dustless and Washable Hospital: New Ideas in Paint and Colours. PMID- 29418398 TI - The Public Health: Interviews with Local Authorities-The County of Leicester. PMID- 29418399 TI - Contributory Schemes at Work: Voluntary Hospitals Commission Report. PMID- 29418400 TI - Spiritual Healing. PMID- 29418401 TI - The Ministry and Its Ministers. PMID- 29418402 TI - Responsibility for Dirty Milk. PMID- 29418404 TI - Hospital and Health News. PMID- 29418403 TI - If the Doctors Refuse? PMID- 29418405 TI - Hospitals and Their Milk Supply: An Ideal Method. PMID- 29418407 TI - National Health Insurance Notes and Comments. PMID- 29418406 TI - The Sterilisation of Undesirable Citizens. PMID- 29418408 TI - An Open-Air Hospital Ward. PMID- 29418409 TI - The Health of the School Child. PMID- 29418411 TI - Milk: The Administration of the Law Relating to Milk Pure and Clean Milk. PMID- 29418410 TI - Nursing in India. PMID- 29418412 TI - The National Institute for the Blind. PMID- 29418413 TI - Medicines and Meddlesomeness.-II. PMID- 29418414 TI - Notes and Comments. PMID- 29418415 TI - Mosquitoes and Malaria in England. PMID- 29418416 TI - The Future of Hospitals. PMID- 29418417 TI - Hospital Finance. PMID- 29418418 TI - The Milk Supply in America. PMID- 29418419 TI - The Public Health: Interviews with Local Authorities: Nottingham: An Industrial Health Resort. PMID- 29418420 TI - The Control of Hospital Expenditure: The Budget or Estimate System. PMID- 29418421 TI - Hospital News. PMID- 29418422 TI - Home Nursing for Insured Persons. PMID- 29418423 TI - Internationalising Health: Work of the Rockefeller Foundation. PMID- 29418424 TI - An East Coast Convalescent Home. PMID- 29418425 TI - The Pay of Medical Officers. PMID- 29418426 TI - The Medical Curriculum. PMID- 29418427 TI - Unoccupied Beds in Cottage Hospitals. PMID- 29418428 TI - The Head-To-Foot Way: New Dormitory Method. PMID- 29418429 TI - Health Insurance Notes. PMID- 29418430 TI - The Army Medical Service. PMID- 29418431 TI - The Medical Officer: His Professional Education and Training. PMID- 29418432 TI - Notes and Comments. PMID- 29418433 TI - Why Not Clean Milk? PMID- 29418434 TI - The Nation's Health: Sanitary Congress at Hull. PMID- 29418435 TI - Metropolitan Asylums Board Report: Its Varied Activities. PMID- 29418436 TI - Talking Health and Acting Health. PMID- 29418437 TI - Hospital and Health News. PMID- 29418438 TI - September and the Panel Doctor. PMID- 29418439 TI - First Aid for the Cinema "Artist". PMID- 29418440 TI - Hospital Progress and Finance. PMID- 29418441 TI - The Public Health: Interviews with Local Authorities-Leicester. PMID- 29418442 TI - Echoes of the Month. PMID- 29418443 TI - How a Hospital Saves Premature Infants: A Manchester Experiment. PMID- 29418444 TI - Echoes of the Month. PMID- 29418445 TI - An English Patient in a German Hospital. PMID- 29418446 TI - Standard Bread. PMID- 29418447 TI - The Voluntary Hospitals Commission. PMID- 29418448 TI - Tinkering with Tuberculosis. PMID- 29418449 TI - A Conference on Day Nursery Schools. PMID- 29418451 TI - Hospital and Health News. PMID- 29418450 TI - The Heritage of Health. PMID- 29418452 TI - Panel Pay and Extended Services.-I. PMID- 29418453 TI - The Evolution of the Voluntary Hospital: Lecture By Mr. Godfrey Hamilton. PMID- 29418454 TI - Dirty Money. PMID- 29418455 TI - Health Insurance Notes. PMID- 29418456 TI - Ministry of Health Estimates. PMID- 29418457 TI - The Bottle of Medicine Habit. PMID- 29418458 TI - Sheltering the People. PMID- 29418459 TI - Jubilee of the Hospital Saturday Fund: Raising a Million for Hospitals. PMID- 29418461 TI - Hospital Progress and Finance. PMID- 29418460 TI - Hospital Accounts and Finance: Getting Value for Money. PMID- 29418462 TI - A Local Committee Urged to Continue. PMID- 29418463 TI - Notes and Comments. PMID- 29418464 TI - The Middle Classes in Hospital. PMID- 29418465 TI - The Hospital and Nursing Exhibition: Lectures and Conferences. PMID- 29418466 TI - The Public Health: Interviews with Local Authorities: Bradford. PMID- 29418467 TI - Wasting Money on Neurotics: What a Consultant Thinks. PMID- 29418468 TI - A Medical Utopia. PMID- 29418469 TI - Prescribing for the Eye. PMID- 29418470 TI - St. Bartholomew's Octocentenary: Fair and Pageant. PMID- 29418471 TI - Scarborough Health Conference. PMID- 29418472 TI - British Hospital Association: The Sheffield Conference. PMID- 29418473 TI - Hospital and Health News. PMID- 29418474 TI - Panel Pay and Extended Services-II. PMID- 29418476 TI - Smoke and Health. PMID- 29418475 TI - The Middle Classes in Hospital. PMID- 29418477 TI - Incipient Insanity. PMID- 29418478 TI - Red Tape in Nursing Homes. PMID- 29418479 TI - Echoes of the Month. PMID- 29418480 TI - Notes and Comments. PMID- 29418481 TI - Health Insurance Notes. PMID- 29418482 TI - Work of Medical Missions. PMID- 29418483 TI - The Mental Treatment Bill: Interview with Sir F. Willis. PMID- 29418484 TI - Hospital Progress and Finance. PMID- 29418485 TI - A Laundry Maid and a Hospital Epidemic. PMID- 29418486 TI - Heatherwood Hospital, Ascot: Healing by Natural Conditions. PMID- 29418487 TI - The Future of Voluntary Hospitals. PMID- 29418488 TI - Sheffield Hospital Conference: An Impression by a Rank=and=File Member. PMID- 29418489 TI - Health Insurance Notes. PMID- 29418490 TI - Slaughter-House Horrors. PMID- 29418491 TI - Women's Holiday Fund. PMID- 29418492 TI - The Venereal Disease Inquiry. PMID- 29418494 TI - Echoes of the Month. PMID- 29418493 TI - The Hospital's Paying Guest. PMID- 29418495 TI - The Years That Count. PMID- 29418496 TI - The Public Health: Interviews with Local Authorities-Norwich. PMID- 29418497 TI - Hospital Progress and Finance. PMID- 29418498 TI - Extension of University College Hospital: The King and the Rockefeller Gift. PMID- 29418499 TI - Panel Pay and Extended Services. PMID- 29418501 TI - Notes and Comments. PMID- 29418500 TI - Voluntary Hospital Finance: A Study of Contributory Schemes. PMID- 29418502 TI - Hospital and Health News. PMID- 29418503 TI - St. Bartholomew's Octo-Centenary: Celebrations Grave and Gay. PMID- 29418504 TI - The Retort Courteous. PMID- 29418505 TI - Are We Over-Drugging Ourselves ? PMID- 29418506 TI - Hospital and Health News. PMID- 29418507 TI - Echoes of the Month. PMID- 29418508 TI - The Ministry and Its Ministers. PMID- 29418509 TI - Neglect of Minor Disease. PMID- 29418511 TI - Hospital Tablets and Memorials. PMID- 29418510 TI - The Reformed Public House. PMID- 29418512 TI - Reformed Public Houses. PMID- 29418513 TI - Homes for Aged Nurses. PMID- 29418514 TI - An Overburdened Ministry. PMID- 29418515 TI - The Need for Consultation. PMID- 29418516 TI - Dustless and Washable Hospitals. PMID- 29418517 TI - Notes and Comments. PMID- 29418518 TI - The Re-Naming of Wards. PMID- 29418519 TI - Financial Position of the London Hospitals: Statistics of Income and Expenditure. PMID- 29418521 TI - The Cost of Collection. PMID- 29418520 TI - Nerves and Communications. PMID- 29418522 TI - Popular Lectures on Cancer. PMID- 29418523 TI - Hospital Progress and Finance. PMID- 29418524 TI - National Health Insurance: A Momentous Decision. PMID- 29418526 TI - The Co-Ordination of Local Health Services: Wanted, a Plea for the Public Health. PMID- 29418525 TI - The Art of Living: The Work of the Health Visitor. PMID- 29418528 TI - A "Live Hospital": Newcastle Royal Victoria Infirmary. PMID- 29418527 TI - The High Grade Mental Defective. PMID- 29418529 TI - Middlesex Hospital School: Portraits of Founders. PMID- 29418530 TI - Points from Hospital Reports. PMID- 29418531 TI - The Public Health: Interviews with Local Authorities-Essex. PMID- 29418533 TI - Hospital Needs and Hospital Appeals: Hospitals with 150 Beds and Upwards. PMID- 29418532 TI - The Reformed Public House. PMID- 29418534 TI - League of Remembrance. PMID- 29418536 TI - Notes and Comments. PMID- 29418535 TI - London and Liverpool Hospitals. PMID- 29418537 TI - The Prince in His Principality: A Hospital Tour. PMID- 29418538 TI - The Outlawry of Disease: Controlling Contagion. PMID- 29418539 TI - The London Hospitals: Analysis of the Statistical Report. PMID- 29418540 TI - Echoes of the Month. PMID- 29418541 TI - The Price of Radium. PMID- 29418542 TI - Modern "Bills of Mortality". PMID- 29418543 TI - Health Exhibition at Leeds. PMID- 29418544 TI - Hospital Progress and Finance. PMID- 29418545 TI - "Abolishing" the Slums. PMID- 29418547 TI - Hospital and Health News. PMID- 29418546 TI - Health of the School Child: Sir George Newman's Report. PMID- 29418548 TI - Hospitals and Country Annexes. PMID- 29418549 TI - The Panel Difficulty. PMID- 29418550 TI - Hospitals and Approved Societies. PMID- 29418551 TI - Clothing and Health: Lecture by Professor Leonard Hill. PMID- 29418552 TI - Notes and Comments. PMID- 29418553 TI - The Apotheosis of the Tomato. PMID- 29418554 TI - Health Insurance Notes. PMID- 29418555 TI - The Horrors of Sanitation. PMID- 29418556 TI - Points from Hospital Reports. PMID- 29418557 TI - Is Vaccination Any Use? PMID- 29418559 TI - Hospital Progress and Finance. PMID- 29418558 TI - The Nemesis of Folly. PMID- 29418560 TI - The Prince of Wales at Guy's Hospital. PMID- 29418561 TI - The Public Health: Interviews with Local Authorities-Yarmouth. PMID- 29418562 TI - Echoes of the Month. PMID- 29418564 TI - The Voluntary Hospitals Report: Sir Napier Burnett's Report. PMID- 29418563 TI - Hospital Accounts and Finance: A New System of Accounting Control. PMID- 29418565 TI - Curing and Teaching. PMID- 29418566 TI - Zoning the Worker: A Deeside Regional Planning Scheme. PMID- 29418567 TI - How a Country Hospital Was Saved: Let the People Know. PMID- 29418568 TI - The League of Remembrance: Its Work for Hospitals. PMID- 29418569 TI - Pity the Poor Panel Patient. PMID- 29418570 TI - Hospital and Health News. PMID- 29418572 TI - Hospital Progress and Finance. PMID- 29418571 TI - Lavender for Hospitals. PMID- 29418573 TI - Ambulance Work in Bombay. PMID- 29418574 TI - Ophthalmia in Lying-In Hospitals. PMID- 29418575 TI - Replanting the Black Country. PMID- 29418577 TI - Sussex County Hospital: Report of the Inquiry Committee. PMID- 29418576 TI - Echoes of the Month. PMID- 29418578 TI - Certificated Blind Masseurs. PMID- 29418579 TI - Voluntary Hospitals Commission: An Encouraging Report. PMID- 29418580 TI - The Public Health: Interviews with Local Authorities-Middlesex. PMID- 29418581 TI - The Hospital and Nursing Exhibition: An Attractive Programme. PMID- 29418582 TI - The Romance of Cod-Liver Oil. PMID- 29418583 TI - Mr. Neville Chamberlain's Opportunity. PMID- 29418584 TI - An Open-Air School. PMID- 29418585 TI - The New Housing Policy. PMID- 29418586 TI - The Bottle of Medicine Habit. PMID- 29418587 TI - Future of the Voluntary Hospitals. PMID- 29418588 TI - Public Health Services in Southern Ireland. PMID- 29418589 TI - Insurance Scraps of Paper. PMID- 29418591 TI - Insurance Notes. PMID- 29418590 TI - Notes and Comments. PMID- 29418592 TI - Hospital and Health News. PMID- 29418593 TI - The Blind Man at Work. PMID- 29418594 TI - The Reformed Public House. PMID- 29418595 TI - Hospital Men of Mark: Colonel D. J. Mackintosh and Mr. J. Matheson Johnston. PMID- 29418596 TI - The Life and Doctrine of Sir Edwin Chadwick. PMID- 29418597 TI - The Reformed Public House. PMID- 29418598 TI - Echoes of the Month. PMID- 29418599 TI - Spiritual Healing. PMID- 29418600 TI - Notes and Comments. PMID- 29418601 TI - Sir Napier Burnett: An Appreciation. PMID- 29418602 TI - Satellite Towns. PMID- 29418603 TI - Hospital Progress and Finance. PMID- 29418604 TI - The Public Health: Interviews with Local Authorities: Brighton. PMID- 29418606 TI - Voluntary Hospitals and Poor Law Infirmaries. PMID- 29418605 TI - Some Medical Benefit Changes. PMID- 29418607 TI - Hospital and Health News. PMID- 29418608 TI - Useless Disinfection. PMID- 29418609 TI - Health for the Middle-Aged Artisan: The Soul of the Worker. PMID- 29418610 TI - Hospitals for the Middle Classes. PMID- 29418611 TI - Echoes of the Month. PMID- 29418613 TI - Prince Tafari at St. Thomas's Hospital. PMID- 29418612 TI - A Haven of Peace. PMID- 29418614 TI - Notes and Comments. PMID- 29418616 TI - A Transformed Hospital. PMID- 29418615 TI - The District Nurse. PMID- 29418617 TI - Hospital Men of Mark: Mr. Thomas Hayes. PMID- 29418618 TI - A Ward for Indian Seamen. PMID- 29418619 TI - Exhibition by International Tennis Players. PMID- 29418620 TI - National Health Insurance Notes: Appointment of Royal Commission. PMID- 29418621 TI - The Citizen of the Future: Conference on Infant Welfare. PMID- 29418622 TI - The Public Health: Interviews with Local Authorities: Tuberculosis in Lancashire. PMID- 29418623 TI - Beginning at the Beginning. PMID- 29418624 TI - Points from Hospital Reports. PMID- 29418625 TI - The Dust Cart, Some Wind, and the Baby. PMID- 29418626 TI - Hospital and Health News. PMID- 29418627 TI - Hospital Progress and Finance. PMID- 29418628 TI - The Health of the Workless. PMID- 29418630 TI - Papworth Village Settlement: The Consumptive as Wage Earner. PMID- 29418629 TI - Concerning Memorials. PMID- 29418631 TI - Medical Staffs of Voluntary Hospitals: Should They Be Paid ? PMID- 29418632 TI - League of Remembrance. PMID- 29418633 TI - Points from Hospital Reports. PMID- 29418634 TI - Echoes of the Month. PMID- 29418635 TI - The Hospital, Nursing, and Midwifery Exhibition. PMID- 29418636 TI - Hospital Officers Conference. PMID- 29418637 TI - Health and Comfort at Wembley. PMID- 29418639 TI - Reducing Venereal Disease in Belgium. PMID- 29418638 TI - Notes and Comments. PMID- 29418640 TI - The Hospital Almoner: What She Is and What She Does. PMID- 29418641 TI - The Finger of the State. PMID- 29418642 TI - An East End Hospital. PMID- 29418643 TI - Gift to University College Hospital. PMID- 29418644 TI - The Reformed Public House. PMID- 29418645 TI - Accounting in Relation to Hospital Administration. PMID- 29418646 TI - How Glands Influence Character: A New Conception in Physiology. PMID- 29418647 TI - International Health. PMID- 29418649 TI - Hospital Men of Mark: Mr. J. Courtney Buchanan, C.B.E. PMID- 29418648 TI - Chinese Foot Binding. PMID- 29418650 TI - Hospital Progress and Finance. PMID- 29418651 TI - Change and Monotony in the Factory: Their Effect on the Human Machine. PMID- 29418652 TI - Hospital and Health News. PMID- 29418654 TI - Hospital Men of Mark: Col. A. C. Dawson, C.B.E., and Mr. Frank Inch. PMID- 29418653 TI - Can the Voluntary System Continue ?: Conference on Hospital Problems. PMID- 29418655 TI - A Model Abattoir at Liverpool. PMID- 29418656 TI - Hospital and Health News. PMID- 29418657 TI - Hospital Cookery. PMID- 29418658 TI - Hospital Progress and Finance. PMID- 29418659 TI - Health Work in the States: A British Medical Officer's Notes. PMID- 29418661 TI - Education in Health. PMID- 29418660 TI - An Ambitious Hospital Scheme: Enlarging the Royal Gwent. PMID- 29418662 TI - A New Hospital System. PMID- 29418663 TI - Smallpox in England and Wales. PMID- 29418664 TI - Scarcity of Hospital Almoners. PMID- 29418666 TI - Learning the Way of Health: Hygiene for Schools. PMID- 29418665 TI - The Problem of Cancer: A Plea for Immediate Action. PMID- 29418667 TI - Notes and Comments. PMID- 29418668 TI - Hospitals and Dangerous Drugs. PMID- 29418669 TI - Population and Unemployment: The Purpose of the Universe. PMID- 29418670 TI - Pensions for Nurses. PMID- 29418671 TI - Points from Hospital Reports. PMID- 29418672 TI - Parochial Beds. PMID- 29418673 TI - Echoes of the Month. PMID- 29418674 TI - A Hospital Chapel. PMID- 29418675 TI - Manchester Royal Infirmary. PMID- 29418677 TI - Seamen and Tuberculosis: King George's Sanatorium for Sailors. PMID- 29418676 TI - The Lost Art of Hospital Ventilation. PMID- 29418679 TI - The Conditions of Health: Can We Secure Them ? PMID- 29418678 TI - The Majesty of Motherhood: The Russell Institute at Paisley. PMID- 29418680 TI - Hospital and Health News. PMID- 29418682 TI - Echoes of the Month. PMID- 29418681 TI - The Reformed Public House. PMID- 29418683 TI - Qualifications of a Hospital Secretary. PMID- 29418684 TI - The Public Health: Interviews with Local Authorities: Bristol. PMID- 29418685 TI - A Mission Hospital in Assam: In the Khasi Hills. PMID- 29418686 TI - Rural Housing and Rural Sickness. PMID- 29418687 TI - Hospital Officers' Association. PMID- 29418688 TI - Defects of the Lunacy Law. PMID- 29418689 TI - The Earliest Report. PMID- 29418690 TI - Hospital Men of Mark: Sir Edward Pearson and Mr. C. M. Power. PMID- 29418691 TI - Points from Hospital Reports. PMID- 29418692 TI - Hospital Progress and Finance. PMID- 29418693 TI - The Care of the Baby. PMID- 29418694 TI - St. Thomas's Hospital Armorial Bearings. PMID- 29418696 TI - What Manner of Man Is the Murderer ?: Physique and Intelligence. PMID- 29418695 TI - Health in the Irish Free State. PMID- 29418697 TI - The Convalescent Mental Patient. PMID- 29418698 TI - Notes and Comments. PMID- 29418699 TI - Medical Service Afloat: A Career for the Newly Qualified. PMID- 29418700 TI - Drugs from Venezuela. PMID- 29418701 TI - Hospital and Health News. PMID- 29418702 TI - The Comradeship of Science: Work of the Rockefeller Foundation. PMID- 29418703 TI - Making a Practice. PMID- 29418704 TI - Longevity and Disability. PMID- 29418705 TI - When Labour Moves. PMID- 29418706 TI - Hospital Men of Mark: Lord Armstrong and Mr. S. Dunstan. PMID- 29418707 TI - Hospital Progress and Finance. PMID- 29418708 TI - New Medical Schools. PMID- 29418709 TI - The Public Health: Interviews with Local Authorities: Marylebone. PMID- 29418710 TI - Notes and Comments. PMID- 29418712 TI - Heartbeats by Radio: A New Use for Wireless. PMID- 29418711 TI - Clean Milk without Expense. PMID- 29418713 TI - The Medical Curriculum. PMID- 29418714 TI - Echoes of the Month. PMID- 29418715 TI - First Aid for the Hop-Picker. PMID- 29418716 TI - The Tuberculous Child: Sheffield's Little Cripples. PMID- 29418717 TI - The Reformed Public House. PMID- 29418718 TI - The Search for a Policy. PMID- 29418719 TI - Extending the Seamen's Hospital: Curing the Sick Sailor. PMID- 29418720 TI - The Bordeaux Conference. PMID- 29418722 TI - Voluntary Hospitals and Municipal Authorities: Their Future Relations. PMID- 29418721 TI - Hospital and Health News. PMID- 29418723 TI - Hospital Men of Mark: Mr. Wade Deacon, C.B.E., and Captain William Rutter. PMID- 29418724 TI - Tom George. PMID- 29418725 TI - Opening of Biddulph Grange. PMID- 29418726 TI - British Hospitals Association Conference: An Impression. PMID- 29418727 TI - A Syrian Mental Hospital. PMID- 29418728 TI - The Voluntary Hospitals Conference. PMID- 29418729 TI - Ice in Hospitals: Distribution of Low Temperatures. PMID- 29418730 TI - Echoes of the Month. PMID- 29418731 TI - Points from Hospital Reports. PMID- 29418732 TI - The London School of Hygiene: What It Will Do. PMID- 29418733 TI - Health of the Empire. PMID- 29418734 TI - Notes and Comments. PMID- 29418735 TI - Approved Societies in Relation to Voluntary Hospitals. PMID- 29418736 TI - Hospital Progress and Finance. PMID- 29418737 TI - What Is the Voluntary Principle ? PMID- 29418738 TI - Sheffield Hospital News. PMID- 29418739 TI - The Training of Nurses. PMID- 29418740 TI - The Healing Waters of Buxton. PMID- 29418741 TI - The Worker and His Hour of Need. PMID- 29418742 TI - The Battle for Infant Life. PMID- 29418743 TI - Echoes of the Month. PMID- 29418744 TI - Hospital Progress and Finance. PMID- 29418745 TI - Public Health: Interviews with Local Authorities: Cardiff. PMID- 29418746 TI - Notes and Comments. PMID- 29418747 TI - Hospital Men of Mark: Mr. Frederick Action and Mr. Peter McColl. PMID- 29418749 TI - Sunday Afternoon with the Wounded: Work of the Adair Fund. PMID- 29418748 TI - Death Rate in Childhood: The Decline before Five. PMID- 29418750 TI - The Earliest Report. PMID- 29418751 TI - Blackburn Royal Infirmary. PMID- 29418752 TI - The Hospital and Nursing Exhibition. PMID- 29418754 TI - National Health Insurance Notes. PMID- 29418753 TI - Hospitals and Income Tax. PMID- 29418755 TI - Hospital and Health News. PMID- 29418756 TI - Defects of the Lunacy Law. PMID- 29418757 TI - The Queen at the New Nurses' Hostel, Windsor. PMID- 29418758 TI - Closing the Gap. PMID- 29418759 TI - Our Health Week Competition: The Winning Papers: A Close Contest. The Prize Divided.-Four Consolation Prizes. PMID- 29418760 TI - Welfare Work in the Malay States. PMID- 29418761 TI - Artificial Heat in Hospitals. PMID- 29418762 TI - The School in the Sun: A Day at Les Noisetiers. PMID- 29418764 TI - Liverpool Babies. PMID- 29418763 TI - Lack of Food Standards: What Other Countries Are Doing. PMID- 29418766 TI - Hospital and Health News. PMID- 29418765 TI - Hospital Progress and Finance. PMID- 29418767 TI - Hospital Cookery. PMID- 29418768 TI - Alton Cottage Hospital Extension. PMID- 29418769 TI - Wireless and Health: Talks with the Million. PMID- 29418770 TI - Recovery of the Voluntary Hospitals: First Post-War Surplus. PMID- 29418771 TI - The Vindication of Voluntaryism. PMID- 29418772 TI - Homoeopathy at Bristol: A Very Modern Hospital. PMID- 29418773 TI - The Removel of Bethlem Hospital. PMID- 29418774 TI - A Sprightly Acrobat: The Ubiquitous Pulex Irritans. PMID- 29418775 TI - Notes and Comments. PMID- 29418776 TI - Echoes of the Month. PMID- 29418777 TI - Points from Hospital Reports. PMID- 29418778 TI - Hospital Men of Mark: Mr. Reginald B. Loder and Mr. Carrington S. Risbee. PMID- 29418779 TI - Nurses for Public Health Work. PMID- 29418780 TI - Preservatives and Food. PMID- 29418781 TI - Echoes of the Month. PMID- 29418782 TI - Research at Great Ormond Street. PMID- 29418783 TI - The Smoke We Breathe. PMID- 29418784 TI - Points from Hospital Reports. PMID- 29418785 TI - Hospital and Health News. PMID- 29418787 TI - Zoning a Great City: Town-Planning at Sheffield. PMID- 29418786 TI - Cripples at Biddulph Grange. PMID- 29418788 TI - The Final Vindication. PMID- 29418790 TI - Recovery of the London Hospitals: An Aggregate Surplus. PMID- 29418789 TI - Quantity Statistics and Internal Control. PMID- 29418792 TI - To Lighten a Burden. PMID- 29418791 TI - Notes and Comments. PMID- 29418793 TI - Public Health Administration: Interview with Dr. Lyster. PMID- 29418794 TI - The Causation of Cancer. PMID- 29418795 TI - Where London Takes the Air: The Ozone of the Parks. PMID- 29418797 TI - Hospital Men of Mark: Brigadier-General Brownlow and Mr. Lancaster-Gaye. PMID- 29418796 TI - A Miniature Town from Hospital Waste: The Work of Crippled Children. PMID- 29418798 TI - Hospital Needs and Hospital Appeals: Hospitals with 150 Beds and Upwards. PMID- 29418799 TI - Hospital Progress and Finance. PMID- 29418800 TI - The Reformed Public House. PMID- 29418802 TI - Hospital and Health News. PMID- 29418801 TI - Catching Disease. PMID- 29418804 TI - Health of the World. PMID- 29418803 TI - Blackburn and a Clean Milk Supply. PMID- 29418805 TI - A Hospital Pageant. PMID- 29418806 TI - Panel Fees: A Question of Ethics. PMID- 29418807 TI - Hospital Men of Mark. PMID- 29418809 TI - Public Health and Preventive Medicine: Rockefeller Foundation Report. PMID- 29418808 TI - Health Week and Its Objects: A Story of Progress. PMID- 29418810 TI - Exchequer Grants and the Public Health. PMID- 29418812 TI - A Cure for Leprosy at Last. PMID- 29418811 TI - Sheffield White and Sheffield Black: The Tragedy of Monday. PMID- 29418814 TI - Points from Hospital Reports. PMID- 29418813 TI - Salisbury Infirmary and Contributory Organisations. PMID- 29418815 TI - Co-Ordination of Local Health Services: The Poor Law under Sentence of Death. PMID- 29418817 TI - Hospital Problems in Canada: Work of 1923. PMID- 29418816 TI - Echoes of the Month. PMID- 29418818 TI - Houses and Slums. PMID- 29418819 TI - The Beacon Light. PMID- 29418820 TI - Health and Ventilation: Artificial Methods Condemned. PMID- 29418821 TI - Hospital Progress and Finance. PMID- 29418822 TI - Notes and Comments. PMID- 29418824 TI - Pensions and Health. PMID- 29418823 TI - The Care and Cure of Cripple Children: Development of the Hospital School. PMID- 29418826 TI - The Panel Fee Inquiry. PMID- 29418825 TI - Health Weeks in London: Their Usefulness and Prospects. PMID- 29418827 TI - The Reformed Public House. PMID- 29418828 TI - Middlesex Hospital Reception. PMID- 29418829 TI - Centenary of Medical Missions: Work of the Jerusalem Hospital. PMID- 29418830 TI - King's College Hospital Pageant. PMID- 29418831 TI - The American Small Hospital: A Competition in Design and Planning. PMID- 29418832 TI - Notes and Comments. PMID- 29418833 TI - Hospital Men of Mark: Mr. E. W. Morris, C.B.E. PMID- 29418835 TI - Insanity and Crime. PMID- 29418834 TI - Doctors and Colonial Income Tax. PMID- 29418836 TI - Hospitals for the Middle Classes. PMID- 29418838 TI - East Suffolk and Ipswich Hospital: Nurses' Prize Day. PMID- 29418837 TI - A New Welfare Centre at Liverpool. PMID- 29418840 TI - Hospital Progress and Finance. PMID- 29418839 TI - The Hospitals' Handmaid. PMID- 29418841 TI - Clean Milk for Consumptives: Hospital Milk from a Garden City. PMID- 29418842 TI - Hospital History of Cape Town. PMID- 29418843 TI - Echoes of the Month. PMID- 29418844 TI - The Truth about Poisoning with Furs. PMID- 29418845 TI - Hospital and Health News. PMID- 29418846 TI - Experiences in Relation to Cholera in India from 1842 to 1879. PMID- 29418847 TI - Back-to-Back Houses. PMID- 29418848 TI - Diphtheria in Older and Newer Bristol: Notified Cases for the Five Years, 1890 94. PMID- 29418849 TI - Infectious Sore-Throat and Diphtheria. PMID- 29418850 TI - Edward Jenner. PMID- 29418851 TI - On Post-Scarlatinal Diphtheria in the Hospitals of the Metropolitan Asylums Board. PMID- 29418852 TI - An Outbreak of Typhoid Fever in Beyrout, Syria. PMID- 29418853 TI - Puerperal Mortality. PMID- 29418854 TI - Considerations in Respect to "Return" Cases of Scarlatina. PMID- 29418855 TI - Remarks on the Topography and Diseases of the Gold Coast; West Coast of Africa. PMID- 29418857 TI - Report of the Diphtheria Committee. PMID- 29418856 TI - On the Theory of Zymosis. PMID- 29418858 TI - Suggestions for Utilising the Statistics of Disease among the Poor. PMID- 29418859 TI - President's Address. PMID- 29418860 TI - Further Observations on Scarlet Fever. PMID- 29418862 TI - The Influence of Contagion on the Rise and Spread of Epidemic Diseases. PMID- 29418861 TI - On the Recent Introduction of Yellow Fever into Port Royal, Jamaica. PMID- 29418863 TI - On Fever in the Zambesi: A Note from Dr. Livingstone to Dr. M'William. PMID- 29418864 TI - Notices of the Appearance of Syphilis in Scotland, in the Last Years of the Fifteenth Century. PMID- 29418866 TI - President's Address. PMID- 29418865 TI - On Yellow Fever in the West Indies and West Coast of America. PMID- 29418867 TI - On the Recent Introduction of Fever into Liverpool by the Crew of an Egyptian Frigate. PMID- 29418868 TI - Notes on the Epidemy of Cholera-Morbus at the Island of St. Jago, Cape De Verds, in 1856. PMID- 29418869 TI - Observations on the Climatology, Topography, and Diseases of Hong-Kong, and the Canton-River Station. PMID- 29418870 TI - On Diseases and Injuries of Artisans and Labourers Traceable to Their Respective Occupations. PMID- 29418872 TI - Note on Diphtheria in Peru. PMID- 29418871 TI - On the Spotted-Haemorrhagic Yellow Fever of the Peruvian Andes, in 1853-57. PMID- 29418873 TI - Vital Statistics of Tasmania in 1861. PMID- 29418874 TI - On the Recent Epidemic of Diphtheria. PMID- 29418875 TI - On an Indian Remedy for Small-Pox. PMID- 29418876 TI - Notes on the Recent Prevalence of Yellow Fever in Several of H.M. Ships on the West India Station; and the Recent Introduction of the Disease into the Port of Halifax, with Remarks on the Climate, Etc., of Halifax. PMID- 29418877 TI - Report of the Council. PMID- 29418878 TI - On Dr. A. Hirsch's "Handbook of Historico-Geographical Pathology." PMID- 29418879 TI - History of an Outbreak of Fever at over Darwen in the Autumn of 1861. PMID- 29418880 TI - Part I. Geography of Certain Epidemics Abroad in 1861-2. PMID- 29418882 TI - Part II. The State of Epidemic, Epizootic, and Epiphytic Disease in Great Britain, in 1861-62. PMID- 29418881 TI - Report on Epidemics, 1861-2. PMID- 29418883 TI - On the Outbreak of Cerebro-Spinal Meningitis in the Province of Dantzic. PMID- 29418885 TI - The President's (Dr. Milroy's) Address, Session 1865-66. PMID- 29418884 TI - On Diphtheria in Bermuda. PMID- 29418886 TI - On Recent Additions to Our Knowledge of Epidemics in England during the Sixteenth and Seventeenth Centuries. PMID- 29418887 TI - On Vaccination in Tasmania. PMID- 29418888 TI - On Scurvy in the Mercantile Marine. PMID- 29418889 TI - On Epidemic Cerebro-Spinal Meningitis at Rochester. PMID- 29418890 TI - On the State of Disease in Sweden during 1862 and 1863. PMID- 29418891 TI - On a Case of Presumed Delhi Boil. PMID- 29418892 TI - On the Prevalence, Distribution, and Limitation of Scarlet Fever in England. PMID- 29418893 TI - The President's (Dr. Milroy's) Address on Vacating the Chair. PMID- 29418894 TI - On Pettenkofer's Theory of the Mode of the Propagation of Cholera. PMID- 29418896 TI - The President's (Dr. Milroy's) Address, Session 1864-65. PMID- 29418895 TI - On Epidemic Varioloid Varicella in Jamaica, 1863. PMID- 29418897 TI - On an Outbreak of Dysentery on Board H.M.S. Conqueror. PMID- 29418898 TI - Remarks on the Epidemic Fever of Scotland during the Years 1863-64-65; and on the Epidemics of Fever Which Have Prevailed in Scotland during the past Quarter of a Century. PMID- 29418899 TI - Suggestions for the Limitation of Syphilis among the Civil Population. PMID- 29418900 TI - On the Epidemiology of Cape Colony and Natal in 1865. PMID- 29418901 TI - On the Epidemiology of Cape Colony and Natal in 1864. PMID- 29418902 TI - On the Epidemiology of Cape Colony and Natal in 1862-63. PMID- 29418903 TI - Note on Diphtheria in Peru. PMID- 29418904 TI - On Scarlatina Rheumatica, Break-Bone Fever, or Dengue. PMID- 29418905 TI - On the Cattle-Plague in Its Epidemiological Aspects. PMID- 29418906 TI - On the Laws of Pestilence. PMID- 29418907 TI - On the Theory and Mode of Propagation of Cholera. PMID- 29418908 TI - On an Anomalous Form of Eruptive Disorder, Which It Is Proposed to Designate Rubeola Notha. PMID- 29418909 TI - The Present Position and Prospects of Epidemiological Science: Being the Opening Address of the Thirteenth Session of the Epidemiological Society. PMID- 29418910 TI - Report of the Trial of Sarracenia Purpurea, or the Pitcher Plant, in Small-Pox. PMID- 29418911 TI - On an Anomalous Exanthem: Rosalia Idiopathica. PMID- 29418912 TI - On the Cause, Malignancy, and Persistence of Yellow Fever Aboard Ship. PMID- 29418913 TI - Remarks on the Enthetic Diseases Affecting the Health of the Troops Serving in the United Kingdom during the Years 1837-46, 1859, 1860, and 1861. PMID- 29418914 TI - On Certain Endemic Cutaneous Affections Observed in Schools, Factories, and Workhouses. PMID- 29418915 TI - On an Epidemic of Jaundice at Rotherham, in Yorkshire. PMID- 29418917 TI - On Recent Typhus in Lancashire. PMID- 29418916 TI - On the Prevention of Syphilis in the Navy. PMID- 29418919 TI - Address of Dr. Babington, F.R.S., on Vacating the Chair. PMID- 29418918 TI - Erratum. AB - [This corrects the article on p. 336 in vol. 2.]. PMID- 29418920 TI - On Epidemic Pleuropneumonia, in the Mediterranean Fleet. PMID- 29418922 TI - Report on Epidemics in Great Britain, 1863. PMID- 29418921 TI - Notes on the Epidemic and Other Diseases of the Natives of India. PMID- 29418923 TI - On the Yellow Fever Epidemics of Bermuda. PMID- 29418924 TI - On an Outbreak of Typhoid Fever at Wing, Bucks. PMID- 29418926 TI - Notices of the Epidemics of 1719-20 and 1759 in Peru; Also of the Mexican Haemorrhagic Disease of 1736 and 1855. PMID- 29418925 TI - On the Epidemic Diseases of Tasmania. PMID- 29418927 TI - Results of Re-Vaccination in the British and Some of the Continental Armies. PMID- 29418928 TI - Observations on the Influence of Pandemic Causes in the Production of Fever. PMID- 29418930 TI - On Some Arithmetical Questions Involved in the Rise and Progress of Epidemics. PMID- 29418929 TI - On the Relations of Scarlet Fever and Diphtheria. PMID- 29418931 TI - On Errors in the Usual Method of Investigating Epidemics. PMID- 29418932 TI - Remarks on the Conditions of Propagation of Small-Pox and Cholera. PMID- 29418933 TI - On the Alleged Spontaneous Production of the Poison of Enteric Fever. PMID- 29418935 TI - Introductory Address, Session 1874-75. PMID- 29418934 TI - Introductory Address, Session 1873-74. PMID- 29418937 TI - On Recent Re-Appearances of Plague. PMID- 29418936 TI - A Brief Account of the Proceedings of the International Sanitary Conference at Vienna, in 1874. PMID- 29418938 TI - Further Remarks on the Period of Infection in Epidemic Diseases. PMID- 29418939 TI - On the Prevailing Epidemics of the Last Three Years: An Address to the Epidemiological Society, Nov. 9th, 1871, on Taking the Chair. PMID- 29418940 TI - On the Distribution of Asiatic Cholera in Africa. PMID- 29418941 TI - Observations on Outbreaks of Cholera in Ships at Sea. PMID- 29418942 TI - Notes on the Cholera Epidemics in East Africa. PMID- 29418943 TI - On the Concurrence of Epidemics. PMID- 29418945 TI - Medical Statistics, with Especial Reference to Cholera and Syphilis. PMID- 29418944 TI - Address at the Opening of Session, 1872-73. PMID- 29418946 TI - On Cholera in Persia, 1866-68. PMID- 29418947 TI - The Period of Infection in Epidemic Disease. PMID- 29418948 TI - The Influence of Vaccination. PMID- 29418949 TI - On the Reported Outbreak of Plague at Kerbela. PMID- 29418950 TI - On Yellow Fever in Relation to the Home Population. PMID- 29418951 TI - Notes of Epidemics in South Africa in 1866. PMID- 29418952 TI - Report on the Recent Epidemic of Cholera (1865-1866). PMID- 29418953 TI - On the Malignant Purple Fever Epidemic in Ireland. PMID- 29418954 TI - Remarks on the Outbreak of Cholera in Broad Street, Golden Square, London, in 1854. PMID- 29418955 TI - The Medical Topography of Mauritius, with an Account of the Fever Which Prevailed There in 1867. PMID- 29418956 TI - On the Recent Outbreak of Pernicious Fever in Mauritius. PMID- 29418957 TI - On the Early Seats of Cholera in India and in the East, with Reference to the Past and the Present. PMID- 29418959 TI - On the International Sanitary Conference, and the Preservation of Europe from Cholera. PMID- 29418958 TI - Further Observations on the Influence of Pandemic Waves in the Production of Fevers and Cholera. PMID- 29418960 TI - On the Outbreak of Cholera at Theydon Bois, Essex, in 1865, with Special Reference to the Propagation of Cholera by Water as a Medium. PMID- 29418961 TI - Address Delivered at the Opening of the Session 1866-67. PMID- 29418963 TI - Notes on the Epidemic of Malarial Fever Which Appeared in Mauritius in 1866-1867. PMID- 29418962 TI - On the Prevention of Disease by the Reconstruction of the Dwellings of the Poor. PMID- 29418964 TI - Experiments Connected with Small-Pox, Inoculation, and Vaccination. PMID- 29418965 TI - On the So-Called Epidemic of "Malignant" Purpuric Fever in Ireland, as It Occurred Amongst the Troops. PMID- 29418966 TI - The Mauritius Epidemic of 1867. PMID- 29418967 TI - On the Epidemic of Cholera in the Punjaub, the North-West and Central Provinces of Bengal, 1867. PMID- 29418968 TI - On Small Pox and Vaccination in the Island of Antigua. PMID- 29418970 TI - On Measles in Fiji. PMID- 29418969 TI - On Endemic and Epidemic Influences in Peru. PMID- 29418971 TI - Notes on the Recent History of the Plague in the Province of Baghdad. PMID- 29418972 TI - On Medical Statistics in the Public Health Section of the Ninth International Statistical Congress, Held in Buda-Pesth, Hungary, in September 1876. PMID- 29418973 TI - On the Introduction of Asiatic Cholera into the United States in 1873. PMID- 29418974 TI - Remarks on the Cholera Epidemic of 1875 in India. PMID- 29418976 TI - On Infantile Diarrhoea. PMID- 29418975 TI - On Coco: A Fijian Disease. PMID- 29418977 TI - On Yellow Fever. PMID- 29418978 TI - On the Study of Medical Meteorology, Especially in Its Relation to Epidemic Maladies. PMID- 29418979 TI - On Dengue. PMID- 29418980 TI - A Sketch of the Recent Cholera Epidemic in Syria. PMID- 29418981 TI - The Etiology of Summer Diarrhoea. PMID- 29418982 TI - Infantile Diarrhoea. PMID- 29418983 TI - On Infection Considered from a Darwinian Point of View. PMID- 29418984 TI - Remarks on the Origin of Infection. PMID- 29418985 TI - On the Characters of Epidemic Plague in Mesopotamia in 1876-1877. PMID- 29418986 TI - Comparison of Small-Pox Statistics, Epidemics of 1871 and 1876. PMID- 29418987 TI - Remarks on the Diagnosis and Cause of Yellow Fever. PMID- 29418988 TI - On the Relation of Filaria Sanguinis Hominis to the Endemic Diseases of India. PMID- 29418989 TI - Details of Experiments on the Vaccination and Subsequent Removal of Supernumerary Fingers, Apparently Showing the Imperfect Protection Afforded by Vaccination When the Vesicles Are Removed before Their Full Maturity. PMID- 29418990 TI - On Plague and Typhus Fever in India. PMID- 29418991 TI - On Certain Points Connected with the Epidemic of Plague in the Province of Astrakhan, Russia, in the Winter of 1878-79. PMID- 29418992 TI - Inaugural Address, Session 1879-80. PMID- 29418993 TI - The Report of the Imperial German Medical Commission on the Plague Which Prevailed in the Province of Astrakhan during the Winter of 1878 and 1879. PMID- 29418994 TI - Remarks on Epidemic Diseases-Men and Animals-In the Colony of Natal. PMID- 29418995 TI - Enteric Fever in India, with Some Observations on Its Probable Etiology in That Country. PMID- 29418996 TI - On the Endemic Continued Fevers of Sub-Tropical Latitudes. PMID- 29418997 TI - On Certain Views Regarding Fever in India. PMID- 29418998 TI - On Endemic Plague in India. PMID- 29418999 TI - Notes on the Relapsing Fever of India. PMID- 29419000 TI - On Some Statistical Indications of a Relationship between Scarlatina, Puerperal Fever, and Certain Other Diseases. PMID- 29419001 TI - On Removal in Epidemic Cholera. PMID- 29419002 TI - Report by Leon Colin, M.D., on the Deaths of Esquimaux from Small-Pox, in Paris, in January 1881. PMID- 29419004 TI - On Scrofula, Tuberculosis, and Phthisis in India. PMID- 29419003 TI - Certain Considerations Regarding Cholera and Fever. PMID- 29419005 TI - Report on "Dengue" Fever. PMID- 29419006 TI - On the Transmissibility of Diphtheria from Animals to Man. PMID- 29419007 TI - Inaugural Address, Session 1880-81. PMID- 29419008 TI - The "Woolsorters' Disease", or Anthrax Fever. PMID- 29419009 TI - On the Outbreak of Plague in the Province of Astrakhan. PMID- 29419010 TI - On the Influence of Fairs, Floods, Famine, and Season, on the Development and Dissemination of Cholera. PMID- 29419011 TI - On Certain Appearances of Cholera in the Countries Lying between Europe and India Since the Year 1874. PMID- 29419012 TI - On Certain Points in Connection with Malarial Fevers in India. PMID- 29419013 TI - On the Use of Detached Floating Barracks for Small-Pox or Fever Hospitals. PMID- 29419014 TI - Contribution to the History of the Epidemic Fever Prevailing in the Country Districts of the Bombay Presidency during the Famine-Period of 1876-78. PMID- 29419015 TI - The Nature and Origin of Climatic Fever. PMID- 29419017 TI - Some Evidence Respecting Tubercular Infective Areas. PMID- 29419016 TI - A Review of the past Year, with Some Reminiscences of Cholera and Tropical Fevers: Inaugural Address of Session 1886-87. PMID- 29419018 TI - The History of Cholera in the East. PMID- 29419019 TI - Diphtheria. PMID- 29419020 TI - Diphtheria in Connection with Damp and Mould-Fungi. PMID- 29419021 TI - Preventive Inoculations. PMID- 29419022 TI - Record of Cases Treated in Hospital during the Small-Pox Epidemic in West Ham in 1884 and 1885. PMID- 29419023 TI - Typho-Malarial Fever. PMID- 29419024 TI - Further Observations on the Filaria Sanguinis Hominis in South Formosa. PMID- 29419026 TI - Observations on a Certain Malady Occurring among Cows at a Time When the Milk Produced by Them Disseminated Scarlet-Fever. PMID- 29419025 TI - Diphtheria as a Chronic Malady in Particular Individuals, with Liability in Them to Recrudescence. PMID- 29419027 TI - The German Vaccination Commission. PMID- 29419028 TI - Report of the Vaccination Committee. PMID- 29419029 TI - Notes on Some Recent Epidemics at Home and Abroad. Inaugural Address of Session 1885-86. PMID- 29419030 TI - On Asiatic Cholera in Our Fleets and Ships. PMID- 29419031 TI - On Certain Supposed Injuries by Vaccination in North Germany in 1885. PMID- 29419032 TI - On the Results of the International Sanitary Conference of Rome, 1885. PMID- 29419033 TI - Hydrophobia Statistics. PMID- 29419035 TI - Notes on Diphtheria. PMID- 29419034 TI - On Some Specific Febrile Diseases of Malarious Origin, and on the Necessity of the Existence of Germs for Their Production. PMID- 29419036 TI - The Condition as to Vaccination of Persons Scarred by Small-Pox. PMID- 29419037 TI - Age, Sex, and Season in Relation to Scarlet-Fever. PMID- 29419038 TI - The Dangers of Water-Contamination during Distribution in Mains and Service Pipes. PMID- 29419039 TI - Some of the Infectious Diseases Common to Man and the Lower Animals. PMID- 29419040 TI - On the Progress of Preventive Medicine during the Victorian Era. Inaugural Address of Session 1887-88. PMID- 29419042 TI - On the Prevalence and Fatality of Scarlatina as Influenced by Sex, Age, and Season. PMID- 29419043 TI - On the Microbian Doctrine of Yellow Fever. PMID- 29419041 TI - Epidemic Cerebro-Spinal Fever in the Fiji Islands, 1885. PMID- 29419045 TI - The Origin of the Cholera Epidemic of 1883 in Egypt. PMID- 29419044 TI - The Re-Vaccination of School Children. PMID- 29419046 TI - Some Observations on the Etiology of Diphtheria. PMID- 29419047 TI - The Colonisation of the Sub-Himalayas and Neilgherries, with Remarks on the Management of European Children in India. PMID- 29419048 TI - Scurvy, in Its Bearings on Explorations by Sea. PMID- 29419049 TI - The Etiology and Pathology of Cholera. PMID- 29419050 TI - The Behaviour of Certain Epidemic Diseases in Natives of Polynesia, with Especial Reference to the Fiji Islands. PMID- 29419051 TI - Epidemiological Notes during the Autumn of 1883 in Beyrout, Syria. PMID- 29419053 TI - Notes on the Death-Rate from Small-Pox in the City of Chester in 1774. PMID- 29419052 TI - Medico-Topographical and Health Histories for Districts and Towns: Inaugural Address of Session 1883-84. PMID- 29419054 TI - Remarks on Outbreaks of Cholera in Ships Carrying Coolies from Calcutta, and in Other Ships with Troops: Shewing the Period of These Occurrences, and the Ships' Positions at the Time. PMID- 29419056 TI - The Constitutional Requirements for Tropical Climates, with Especial Reference to Temperaments. PMID- 29419057 TI - The Seasonal Prevalence of Continued Fevers in London. PMID- 29419055 TI - The Prevention of Heat Apoplexy. PMID- 29419058 TI - On Some Rare Epidemics and Endemics. Inaugural Address of Session 1884-85. PMID- 29419059 TI - Ventilation with Air from Superior Layers in Place of Inferior Layers. PMID- 29419060 TI - Variola and the Varioloid Diseases of Animals. PMID- 29419061 TI - On Some Special Arrangements for the Isolation of Infectious Diseases. PMID- 29419062 TI - On Old London: Its Insanitary Conditions and Its Epidemic Diseases. PMID- 29419063 TI - On the Prevalence of Epidemic Roseola in Calcutta. PMID- 29419064 TI - Observations on Filaria Sanguinis Hominis in South Formosa. PMID- 29419065 TI - On the Form of the Epidemic Wave and Some of Its Probable Causes. PMID- 29419066 TI - On Filaria Sanguinis Hominis, Lymphocele, Lymphuria, and Other Associated Morbid Disorders. PMID- 29419067 TI - Observations on the Pre-Eruptive Stage in Small-Pox, with History of Cases. PMID- 29419068 TI - Aids to Epidemiological Knowledge-Inaugural Address of the Session 1881-82. PMID- 29419069 TI - The Progress of Zymotic Micro-Pathology. PMID- 29419070 TI - On Filariae and Other Parasites in Relation to Endemics and Epizootics. PMID- 29419071 TI - Malaria. PMID- 29419072 TI - On the Probability That the Infection of Diphtheria Is Sometimes Transported by the Wind. PMID- 29419073 TI - Is the Climate of Indian Hill Sanitaria Beneficial in Scrofula, Tuberculosis, and Phthisis? PMID- 29419074 TI - The Policy and Practice of Glasgow in the Management of Epidemic Diseases, with Results. PMID- 29419075 TI - Conversazione: Demonstration of Micro-Organisms of Disease. PMID- 29419076 TI - The So-Called Epidemics of Seamen, More Particularly with Reference to Fevers. PMID- 29419077 TI - The Influence of Small-Pox Hospitals. PMID- 29419078 TI - The Delhi and Oriental Sore. PMID- 29419079 TI - The Sanitary Lessons of Indian Epidemics. PMID- 29419080 TI - A Glance at the Sanitary Defects of the Site of London and Its Environs. PMID- 29419081 TI - Causes of Excessive Mortality among Women and Children of the European Soldiers Serving in India. PMID- 29419082 TI - Phthisis, Bronchitis, and Pneumonia: Are They Epidemic Diseases? PMID- 29419084 TI - The Sanitary State of the British Troops in Northern India. PMID- 29419083 TI - On the Planning and Construction of Hospitals for Infectious Diseases. PMID- 29419086 TI - Memorandum Concerning Cholera. PMID- 29419085 TI - The Use of Tents in the Treatment of Small-Pox. PMID- 29419087 TI - Is Influenza in Man and in Animals AEtiologically Distinct? PMID- 29419088 TI - Inaugural Address of Session 1891-92. PMID- 29419089 TI - On the Manifestations of Cholera in Ships at Sea, and Their Connections with Outbreaks on Land. PMID- 29419090 TI - Bacteriology of Vaccine Lymph. PMID- 29419091 TI - Famine: Its Effects and Relief. PMID- 29419092 TI - What Is Efficient Vaccination? PMID- 29419093 TI - The Seasonal Prevalence of Enteric Fever. PMID- 29419094 TI - Measles: An Epidemiological Study. PMID- 29419095 TI - Is the Colonisation of Tropical Africa by Europeans Possible? PMID- 29419096 TI - The Relation of Modification of Function of Micro-Organisms to the Virulence and Spread of Specific Infective Diseases. PMID- 29419097 TI - Retrospect of the Successive Epidemics of Cholera in Europe and America, from 1830 to 1890. PMID- 29419098 TI - The Relations of Saprophytic to Parasitic Micro-Organisms. PMID- 29419100 TI - Notes on an Epidemic of Typhoid Fever in South-East Essex in 1890. PMID- 29419099 TI - On the Spread of Influenza by Contagion. PMID- 29419101 TI - A Brief Review of Recent Sanitary Legislation. The Inaugural Address of Session 1890-91. PMID- 29419102 TI - On the Cause of Enteric Fever in India. PMID- 29419103 TI - Analysis of 118 Cases of Leprosy in the Tarntaran Asylum (Punjab). PMID- 29419104 TI - On an Epidemic of Dengue Fever in Fiji in 1885. PMID- 29419105 TI - Epidemic Influenza in France. PMID- 29419106 TI - Notes on an Outbreak of Typhus Fever. PMID- 29419107 TI - On Malta Fever. PMID- 29419108 TI - Malaria versus More Recognisable Causes of Disease. PMID- 29419109 TI - Enteric Fever in India: Its Increase, Causes, Remedies, and Probable Consequences. PMID- 29419110 TI - Notes on an Outbreak of Influenza in a Poor-Law School. PMID- 29419111 TI - On the Arrest and Cure of Leprosy by the External and Internal Use of the Gurjun and Chaulmoogra Oils. PMID- 29419112 TI - On the Use of the Oil of Eucalyptus Globulus in Scarlet Fever and Other Infectious Diseases. PMID- 29419113 TI - Inaugural Address of Session 1889-90. PMID- 29419114 TI - The Sanitary Administration of Dairy Farms. PMID- 29419116 TI - A Brief Review of Our Knowledge of the Relation of Micro-Organisms to Diseases in Man. PMID- 29419115 TI - On the Epidemic of Cholera in Malta during 1887. PMID- 29419117 TI - On Rabies: Its Treatment by M. Pasteur, and on the Means of Detecting It in Suspected Cases. PMID- 29419118 TI - Leprosy: A Review of Some Facts and Figures. PMID- 29419119 TI - The Prevention of Phthisis. PMID- 29419120 TI - Abstract of Paper on Beri-Beri by Staff-Surgeon T. D. Gimlette, R.N. PMID- 29419121 TI - The Increase of Leprosy in India: Its Causes, Probable Consequences, and Remedies. PMID- 29419122 TI - Scarlatina in Its Relation to Cow's Milk, at Wimbledon and Merton, 1886-7. PMID- 29419123 TI - On Beri-Beri. PMID- 29419124 TI - The History of Typhoid Fever in Munich. PMID- 29419126 TI - On the Physical and Ethnological Conditions under Which Leprosy Occurs in China, the Malay Peninsula, the East Indian Archipelago, and the Islands of the Pacific. PMID- 29419125 TI - International Sanitary Conferences of the Victorian Era. Inaugural Address of Session 1897-98. PMID- 29419127 TI - On an Outbreak of Milk-Borne Enteric Fever in Clifton, in Relation to Distribution of the Disease, Incidence of Attack, and General Character of the Outbreak; with Some Reference to the Use of the Serum Test (Widal) in Public Health Work. PMID- 29419128 TI - Seasonal Variations in Age-Distribution and Fatality. PMID- 29419129 TI - The Jenner Memorial Medal. PMID- 29419130 TI - The Relation of Variations in the Level of the Ground-Water to the Incidence and Seasonal Distribution of Malarial Fevers in India. PMID- 29419131 TI - Enteric Fever at Norwich: A Triennium of Typhoid. Statistics Relating to the Home Surroundings of 656 Cases Notified during the Years 1895-6-7. PMID- 29419133 TI - Notes on Cerebrospinal Fever. PMID- 29419132 TI - The Prospect of Abolishing Tuberculosis. PMID- 29419134 TI - The Relations of Bacteriology to Epidemiology. PMID- 29419135 TI - Epidemic Cerebrospinal Meningitis. PMID- 29419136 TI - A Study of Enteric Fever in the Netherlands during the Period 1875-1894. PMID- 29419137 TI - Blackwater Fever. PMID- 29419138 TI - Half a Century of Sanitary Progress, and Its Results. Inaugural Address of Session 1898-99. PMID- 29419140 TI - On the Endemic Prevalence of Infective Diseases in the Tropics. Inaugural Address of Session 1896-97. PMID- 29419139 TI - Ten Years' Experience of Enteric Fever in a Midland Town, and Its Lessons. PMID- 29419141 TI - The Seasonal Fluctuations of Epidemic Diseases. PMID- 29419143 TI - The Prevention of Tuberculosis. PMID- 29419142 TI - The Spread of Plague. PMID- 29419144 TI - The Report of the Royal Commission on Vaccination: A Review of the Dissentients' Statement. PMID- 29419146 TI - The Jenner Memorial Medal. PMID- 29419145 TI - Age-Incidence in Relation with Cycles of Disease-Prevalence. PMID- 29419147 TI - Resolution in Reference to Re-Vaccination. PMID- 29419148 TI - Some Observations on the Infectivity of Diphtheria, and on the Relation of Diphtheria Prevalence to School-Closure. PMID- 29419149 TI - The Commemoration Dinner. PMID- 29419151 TI - Plague in Britain in the Nineteenth Century. PMID- 29419150 TI - Account of the Foundation of the Society, and List of Officers of the Society from 1850-1900. PMID- 29419152 TI - Principles Determining the Geographical Distribution of Disease. PMID- 29419153 TI - Remarks on the Diagnosis of Plague. PMID- 29419154 TI - The Epidemiology of Scarlet Fever in Relation to the Utility of Isolation Hospitals. PMID- 29419155 TI - Enteric Fever Mortality in Copenhagen. PMID- 29419156 TI - A Suggested Method of Preventing Water-Borne Enteric Fever among Armies in the Field. PMID- 29419158 TI - Some Problems in Tropical Epidemiology. Inaugural Address of Session 1900-1901. PMID- 29419157 TI - Soil and Typhoid Fever: Effect of Sewerage and Water-Supply on the Behaviour of Enteric Fever in Buenos Ayres. PMID- 29419159 TI - The Supposed Infectivity of Desquamation in Scarlet Fever. PMID- 29419160 TI - Small-Pox Hospitals and the Spread of Infection. PMID- 29419161 TI - Dysentery in Asylums. PMID- 29419162 TI - An Outbreak of Syphilis in an Indigenous Tribe in India. PMID- 29419163 TI - The Etiology of Beri-Beri. Inaugural Address of Session 1901-1902. PMID- 29419164 TI - Filariasis in the West Indies and Its Prevention. PMID- 29419165 TI - Infantile Mortality in the Tropics. PMID- 29419166 TI - A Doubtful Case of Haemorrhagic Small-Pox. PMID- 29419167 TI - On Immunity and Resistance as Factors in the Epidemicity of Infective Diseases. PMID- 29419168 TI - Measures Taken at Tor and Suez against Ships Coming from the Red Sea and the Far East. PMID- 29419169 TI - Seasonal Variations in Age-Distribution of Deaths from Certain Infectious Diseases. PMID- 29419170 TI - Some Preventive Measures Adopted in the Presidency of Madras during the Late Epidemic Prevalence of Plague in India. PMID- 29419171 TI - The Utility of Bacteriological Examination in a Diphtheria Epidemic in a School; with Special Reference to the Diphtheria in the Poplar Union Schools at Forest Gate, in 1898-1899. PMID- 29419172 TI - Introduction to a Discussion on the Infectivity of Enteric Fever. PMID- 29419173 TI - On the Comparative Mortality of English Districts. Inaugural Address of Session 1899-1900. PMID- 29419174 TI - Measles: Its Distribution and Control: Being the Experience of an Epidemic of over 2,000 Cases. PMID- 29419176 TI - Insanitary Property and Workmen's Dwellings in Liverpool. PMID- 29419177 TI - Plague at Oporto. PMID- 29419175 TI - Advantages of Bacteriological Diagnosis as Instanced by the History of an Outbreak of Diphtheria in a Large School. PMID- 29419178 TI - Use of Eucalyptus Oil as a Disinfectant in Scarlet Fever. PMID- 29419179 TI - On the Study of Epidemiology. Inaugural Address of Session of 1894-95. PMID- 29419180 TI - Epidemic Disease in the Royal Navy. PMID- 29419181 TI - Immunity. PMID- 29419182 TI - The Relation of Bacteria and Their Toxines. PMID- 29419183 TI - A Treatise on Foot Vapour (Distemper). PMID- 29419185 TI - Chapter I. Of the Plague and Its Cause, with Something Concerning Former Plagues. PMID- 29419184 TI - The Influence of Soil as a Factor in the Production of Disease, Especially in Hot Climates. PMID- 29419187 TI - Chapter XVIII. Of Passions and Affections. PMID- 29419186 TI - Chapter XXIV. The Cure of Carbuncles. PMID- 29419188 TI - Chapter XXVIII. Some Observations That Could Not Bee Conveniently Put into the Foregoeing Chapters. PMID- 29419189 TI - Chapter XVII. Of Sleeping and Exercise. PMID- 29419190 TI - Chapter XXII. The Cure of Concomitant Symptomes Joyned to the Plague, and First of the Feaver. PMID- 29419191 TI - Chapter XX. Of Cure in Generall. PMID- 29419192 TI - Chapter XXI. The Method of Cures. PMID- 29419194 TI - Chapter VII. Of Tokens, Carbuncles, Buboes, & Blains. PMID- 29419193 TI - Chapter VIII. Of Tokens. PMID- 29419195 TI - Chapter XXIII. The Method of Cureing Buboes as Much as Concerns Outward Cures. PMID- 29419196 TI - Chapter XXVI. Medicines for Expelling the Plague. PMID- 29419197 TI - Chapter II. Of Prognosticks. PMID- 29419198 TI - Chapter IV. Evil Signes or Presagers of the Plague. PMID- 29419199 TI - Chapter X. Of Buboes or Risings. PMID- 29419200 TI - Chapter XIV. What Is to Bee Done? First, of Flight. PMID- 29419201 TI - Chapter XII. Of Prophylacticks or Preservative Means. PMID- 29419202 TI - Chapter III. Diagnosticks. PMID- 29419203 TI - Chapter XV. Preservatives and Means for Those Who Stay behind. PMID- 29419205 TI - Chapter IX. Of Carbuncles. PMID- 29419204 TI - Chapter XI. Of Blaines. PMID- 29419206 TI - Chapter VI. Good Signes in the Plague. PMID- 29419207 TI - Chapter XIII. What Things Are to Be Avoyded. PMID- 29419208 TI - Chapter V. Further Comments on Evil Signs in the Plague. PMID- 29419210 TI - Chapter XIX. Of Medicinal Preservatives. PMID- 29419209 TI - Chapter XVI. Of Meat and Drink, Fullness and Fasting. PMID- 29419212 TI - Chapter XXVII. Of the Many Evill Reliques and Consequent Diseases Which Follow a Plague. PMID- 29419211 TI - Chapter XXV. The Cure of Blains. PMID- 29419213 TI - Considerations Regarding the Nature of Infection, with Special Reference to the Action of Bacterial Poisons. PMID- 29419214 TI - On the Co-Existence, or the Occurrence in Close Succession, of More Than One Infectious Disease in the Same Individual. PMID- 29419215 TI - On Certain Affections of the Mucous Surfaces and Their Relation to Diphtheria. PMID- 29419216 TI - On the Distribution of the Mortality from Influenza in England and Wales during Recent Years. PMID- 29419218 TI - The Outbreak of Cholera in Mesopotamia and Syria in 1889, 1890, and 1891. PMID- 29419217 TI - A Contribution to the Epidemiology of Cholera in Russia. PMID- 29419219 TI - On the Recent Outbreak of Cholera in Persia. PMID- 29419220 TI - On the History of Epidemiology in England. Inaugural Address of Session 1893-94. PMID- 29419221 TI - The Aerial Convection of Small-Pox from Hospitals. PMID- 29419222 TI - On Tuberculosis as an Endemic Disease. Inaugural Address of Session 1892-93. PMID- 29419223 TI - Measles Epidemics, Major and Minor. PMID- 29419224 TI - On African Haemoglobinuric Fever. PMID- 29419225 TI - Epidemic Dropsy. PMID- 29419226 TI - Post-Scarlatinal Diphtheria: A Statistical and Etiological Study. PMID- 29419227 TI - Variola and Vaccinia: Their Manifestations and Inter-Relations in the Lower Animals. An Experimental Research. PMID- 29419228 TI - The Etiology of Leprosy. PMID- 29419229 TI - The Seasonal Incidence of Typhoid Fever and of Diarrhoea: The Seasonal Consumption of Shellfish Probably One of the Chief Factors as Regards the Former, and the Seasonal Prevalence of Flies as Regards the Latter. PMID- 29419230 TI - The Relation of the Panama Canal to the Introduction of Yellow Fever into Asia. PMID- 29419231 TI - Bovine and Human Tuberculosis in India. PMID- 29419233 TI - Remarks on the Causation of Epidemic Diarrhoea, Introducing the Discussion on Professor Delepine's Paper. PMID- 29419232 TI - The Prevention of Diphtheria Outbreaks in Hospitals for Children. PMID- 29419234 TI - What Is Climatic Disease? PMID- 29419236 TI - Some of the Dangers of Boracic Acid and Formaldehyde as Food Preservatives. PMID- 29419235 TI - The Bearing of Outbreaks of Food-Poisoning upon the Etiology of Epidemic Diarrhoea. PMID- 29419237 TI - On the Etiology of Scurvy. PMID- 29419238 TI - The Elucidation of Sleeping Sickness. PMID- 29419239 TI - The Epidemiology of Enteric Fever and Cholera in Hamburg. PMID- 29419240 TI - Some Remarks on the Epidemiology of Plague. PMID- 29419241 TI - Five Years of Cholera Prevalence in the Turkish Empire. PMID- 29419242 TI - Industrial Anthrax, 1899-1903. PMID- 29419243 TI - The Prevalence of Enteric Fever in Prussia during the Decade 1893 to 1901: Together with Remarks on Its Origin, Spread, and Control. PMID- 29419244 TI - Studies Concerning Ship Beri-Beri. - On the Etiology of Scurvy. PMID- 29419245 TI - On Tuberculosis: Inaugural Address of Session 1906-1907. PMID- 29419246 TI - Variations in the Age-Incidence of Mortality from Certain Diseases. PMID- 29419247 TI - Recent Researches into the Epidemiology of Malta Fever. PMID- 29419248 TI - Studies Concerning Ship Beri-Beri. - Polyneuritis of Poultry. PMID- 29419249 TI - Some Recent Manifestations of Cerebro-Spinal Fever. PMID- 29419250 TI - The Distribution and Nature of Sprue, with Notes on the Pathology of Intestinal Dyscrasias. PMID- 29419251 TI - Real and Apparent Differences in the Incidence of Cancer. PMID- 29419252 TI - An Outbreak Simulating Influenza in an Institution. PMID- 29419253 TI - Clinical Notes on Cerebro-Spinal Fever. PMID- 29419254 TI - The Yellow Fever Epidemic in New Orleans in 1905. PMID- 29419256 TI - Evolution in Relation to Disease. PMID- 29419255 TI - A Study of the Typhoid Fever Epidemics in the United States Volunteer Encampments in 1898. PMID- 29419257 TI - The Distribution, Spread and Prophylaxis of "Sleeping Sickness" in the Congo Free State: From the Expedition to the Congo of the Liverpool School of Tropical Medicine, Consisting of the Late J. Everett Dutton, M.B.Vict., and John L. Todd, B.A., M.D.McGill, Walter Myers Fellow, Liverpool University. PMID- 29419258 TI - The Infectivity of Cerebro Spinal Fever. PMID- 29419259 TI - The Relative Importance of the Constituent Factors Involved in the Control of Pulmonary Tuberculosis. PMID- 29419260 TI - Glanders in Horse and Man. PMID- 29419261 TI - Ancient Theories of Causation of Fever by Mosquitoes. PMID- 29419262 TI - Ankylostomiasis. PMID- 29419263 TI - The Epidemiological Aspects of Industrial Diseases: Inaugural Address of Session 1904-1905. PMID- 29419265 TI - On the Spread of Small-Pox Occasioned by Small-Pox Hospitals during the Epidemic Period, 1900-1904; and Its Relation to Atmospheric Convection. PMID- 29419264 TI - A Contribution to the Etiology of Rheumatic Fever. PMID- 29419266 TI - Phthisis Rates: Their Significance and Their Teaching. PMID- 29419267 TI - On the Relation of the Parasitic Protozoa to Each Other and to Human Disease. PMID- 29419268 TI - Ticks and Tick-Transmitted Diseases. PMID- 29419269 TI - ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes. PMID- 29419270 TI - ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes. PMID- 29419271 TI - ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes. PMID- 29419272 TI - Effects of Spaceflight on Astronaut Brain Structure. PMID- 29419273 TI - Effects of Spaceflight on Astronaut Brain Structure. PMID- 29419274 TI - Nutritional Management of Chronic Kidney Disease. PMID- 29419275 TI - Nutritional Management of Chronic Kidney Disease. PMID- 29419276 TI - Nutritional Management of Chronic Kidney Disease. PMID- 29419277 TI - Acute Graft-versus-Host Disease. PMID- 29419278 TI - Maternal Health in the United States. PMID- 29419279 TI - Teaching the New HIM: Educators Integrating Informatics, Data Analytics, and Information Governance Into HIM Programs. PMID- 29419280 TI - Building a Talent Pipeline: AHIMA Foundation Apprenticeships Help Connect Prospective HIM Professionals With First-Time Jobs. PMID- 29419281 TI - Light-Activated Proteomic Labeling via Photocaged Bioorthogonal Non-Canonical Amino Acids. AB - This work introduces light-activated bioorthogonal noncanonical amino acid tagging (laBONCAT) as a method to selectively label, isolate, and identify proteins newly synthesized at user-defined regions in tissue culture. By photocaging l-azidohomoalanine (Aha), metabolic incorporation into proteins is prevented. The caged compound remains stable for many hours in culture, but can be photochemically liberated rapidly and on demand with spatial control. Upon directed light exposure, the uncaged amino acid is available for local translation, enabling downstream proteomic interrogation via bioorthogonal conjugation. Exploiting the reactive azide moiety present on Aha's amino acid side chain, we demonstrate that newly synthesized proteins can be purified for quantitative proteomics or visualized in synthetic tissues with a new level of spatiotemporal control. Shedding light on when and where proteins are translated within living samples, we anticipate that laBONCAT will aid in understanding the progression of complex protein-related disorders. PMID- 29419282 TI - Construction of Axially Chiral Compounds via Asymmetric Organocatalysis. AB - Axially chiral compounds have received much attention from chemists because of their widespread appearance in natural products, biologically active compounds, and useful chiral ligands in asymmetric catalysis. Because of the importance of this structural motif, the catalytic enantioselective construction of axially chiral scaffolds has been intensively investigated, and great progress has been accomplished. However, the majority of methodologies in this field focus on the use of metal catalysis, whereas approaches involving organocatalysis have started to emerge only recently. This Account describes certain advances in the organocatalytic asymmetric synthesis of axially chiral compounds involving the following strategies: kinetic resolution, desymmetrization, cyclization/addition, direct arylation, and so on. We began our investigation by developing a highly efficient strategy for the kinetic resolution of axially chiral BINAM derivatives involving a chiral Bronsted acid-catalyzed imine formation and transfer hydrogenation cascade process, thereby providing a convenient route to generate chiral BINAM derivatives in high yields with excellent enantioselectivities. The desymmetrization of 1-aryltriazodiones (ATADs) through an organocatalyzed tyrosine clicklike reaction wherein a nucleophile was added to the ATAD afforded an interesting type of axially chiral N-arylurazole in an excellent remote enantiocontrolled manner. We then focused on a direct construction strategy involving cyclization and the addition strategy given the inherent limitations of the kinetic resolution in terms of the chemical yield and the desymmetrization in terms of the substrate scope. By utilizing the catalytic enantioselective Paal Knorr reaction, we disclosed a general and efficient cyclization method to access enantiomerically pure arylpyrroles. The direct heterocycle formation and the stepwise method, which was executed in a one-pot fashion containing enantioselective cyclization and subsequent aromatization, were successfully applied for the construction of diverse axially chiral arylquinazolinones catalyzed by chiral Bronsted acids. We discovered the asymmetric organocatalytic approach to construct axially chiral styrenes through the 1,4-addition of arylalkynals in good chemical yields and enantioselectivities. Such structural motifs are important precursors for further transformations into biologically active compounds and useful synthetic intermediates and may have potential applications in asymmetric syntheses as olefin ligands or organocatalysts. To further tackle this challenge, we accomplished the phosphoric acid-catalyzed enantioselective direct arylative reactions of 2-naphthol and 2-naphthamine with quinone derivatives to deliver efficient access to a class of axially chiral BINOL and NOBIN derivatives in good yields with excellent enantioselectivities under mild reaction conditions. Most importantly, we discovered that the azo group can effectively perform as a directing and activating group for organocatalytic formal aryl C-H functionalization via formal nucleophilic aromatic substitution of azobenzene derivatives. Thus, a wide range of axially chiral arylindoles were synthesized in good yields with excellent enantioselectivities. We anticipate that this strategy will foster the development of many other transformations and motivate a new enthusiasm for organocatalytic enantioselective aryl functionalization. Moreover, SPINOLs are fundamental synthetic precursors in the construction of other chiral organocatalysts and ligands. We have successfully developed a phosphoric acid catalyzed enantioselective approach for SPINOLs. This approach is highly convergent and functional-group-tolerant for the efficient generation of SPINOLs with good results, thus delivering practical access to this privileged structure. PMID- 29419283 TI - Trading off Aircraft Fuel Burn and NO x Emissions for Optimal Climate Policy. AB - Aviation emits pollutants that affect the climate, including CO2 and NO x, NO x indirectly so, through the formation of tropospheric ozone and reduction of ambient methane. To improve the fuel performance of engines, combustor temperatures and pressures often increase, increasing NO x emissions. Conversely, combustor modifications to reduce NO x may increase CO2. Hence, a technology trade-off exists, which also translates to a trade-off between short-lived climate forcers and a long-lived greenhouse gas, CO2. Moreover, the NO x-O3-CH4 system responds in a nonlinear manner, according to both aviation emissions and background NO x. A simple climate model was modified to incorporate nonlinearities parametrized from a complex chemistry model. Case studies showed that for a scenario of a 20% reduction in NO x emissions the consequential CO2 penalty of 2% actually increased the total radiative forcing (RF). For a 2% fuel penalty, NO x emissions needed to be reduced by >43% to realize an overall benefit. Conversely, to ensure that the fuel penalty for a 20% NO x emission reduction did not increase overall forcing, a 0.5% increase in CO2 was found to be the "break even" point. The time scales of the climate effects of NO x and CO2 are quite different, necessitating careful analysis of proposed emissions trade offs. PMID- 29419284 TI - DNA's Encounter with Ultraviolet Light: An Instinct for Self-Preservation? AB - Photochemical modification is the major class of environmental damage suffered by DNA, the genetic material of all free-living organisms. Photolyases are enzymes that carry out direct photochemical repair (photoreactivation) of covalent pyrimidine dimers formed in DNA from exposure to ultraviolet light. The discovery of catalytic RNAs in the 1980s led to the "RNA world hypothesis", which posits that early in evolution RNA or a similar polymer served both genetic and catalytic functions. Intrigued by the RNA world hypothesis, we set out to test whether a catalytic RNA (or a surrogate, a catalytic DNA) with photolyase activity could be contemplated. In vitro selection from a random-sequence DNA pool yielded two DNA enzymes (DNAzymes): Sero1C, which requires serotonin as an obligate cofactor, and UV1C, which is cofactor-independent and optimally uses light of 300-310 nm wavelength to repair cyclobutane thymine dimers within a gapped DNA substrate. Both Sero1C and UV1C show multiple turnover kinetics, and UV1C repairs its substrate with a quantum yield of ~0.05, on the same order as the quantum yields of certain classes of photolyase enzymes. Intensive study of UV1C has revealed that its catalytic core consists of a guanine quadruplex (G quadruplex) positioned proximally to the bound substrate's thymine dimer. We hypothesize that electron transfer from photoexcited guanines within UV1C's G quadruplex is responsible for substrate photoreactivation, analogous to electron transfer to pyrimidine dimers within a DNA substrate from photoexcited flavin cofactors located within natural photolyase enzymes. Though the analogy to evolution is necessarily limited, a comparison of the properties of UV1C and Sero1C, which arose out of the same in vitro selection experiment, reveals that although the two DNAzymes comparably accelerate the rate of thymine dimer repair, Sero1C has a substantially broader substrate repertoire, as it can repair many more kinds of pyrimidine dimers than UV1C. Therefore, the co-opting of an amino acid-like cofactor by a nucleic acid enzyme in this case contributes functional versatility rather than a greater rate enhancement. In recent work on UV1C, we have succeeded in shifting its action spectrum from the UVB into the blue region of the spectrum and determined that although it catalyzes both repair and de novo formation of thymine dimers, UV1C is primarily a catalyst for thymine dimer repair. Our work on photolyase DNAzymes has stimulated broader questions about whether analogous, purely nucleotide-based photoreactivation also occurs in double-helical DNA, the dominant form of DNA in living cells. Recently, a number of different groups have reported that this kind of repair is indeed operational in DNA duplexes, i.e., that there exist nucleotide sequences that actively protect, by way of photoreactivation (rather than by simply preventing their formation), pyrimidine dimers located proximal to them. Nucleotide-based photoreactivation thus appears to be a salient, if unanticipated, property of DNA and RNA. The phenomenon also offers pointers in the direction of how in primordial evolution-in an RNA world-early nucleic acids may have protected themselves from structural and functional damage wrought by ultraviolet light. PMID- 29419285 TI - Increased Degree of Unsaturation in the Lipid of Antifungal Cationic Amphiphiles Facilitates Selective Fungal Cell Disruption. AB - Antimicrobial cationic amphiphiles derived from aminoglycosides act through cell membrane permeabilization but have limited selectivity for microbial cell membranes. Herein, we report that an increased degree of unsaturation in the fatty acid segment of antifungal cationic amphiphiles derived from the aminoglycoside tobramycin significantly reduced toxicity to mammalian cells. A collection of tobramycin-derived cationic amphiphiles substituted with C18 lipid chains varying in degree of unsaturation and double bond configuration were synthesized. All had potent activity against a panel of important fungal pathogens including strains with resistance to a variety of antifungal drugs. The tobramycin-derived cationic amphiphile substituted with linolenic acid with three cis double bonds (compound 6) was up to an order of magnitude less toxic to mammalian cells than cationic amphiphiles composed of lipids with a lower degree of unsaturation and than the fungal membrane disrupting drug amphotericin B. Compound 6 was 12-fold more selective (red blood cell hemolysis relative to antifungal activity) than compound 1, the derivative with a fully saturated lipid chain. Notably, compound 6 disrupted the membranes of fungal cells without affecting the viability of cocultured mammalian cells. This study demonstrates that the degree of unsaturation and the configuration of the double bond in lipids of cationic amphiphiles are important parameters that, if optimized, result in compounds with broad spectrum and potent antifungal activity as well as reduced toxicity toward mammalian cells. PMID- 29419286 TI - Colloidal Plasmonic Nanocomposites: From Fabrication to Optical Function. AB - Plasmonic nanostructures are extensively used building blocks for engineering optical materials and device architectures. Plasmonic nanocomposites (pNCs) are an emerging class of materials that integrate these nanostructures into hierarchical and often multifunctional systems. These pNCs can be highly customizable by modifying both the plasmonic and matrix components, as well as by controlling the nano- to macroscale morphology of the composite as a whole. Assembly at the nanoscale plays a particularly important role in the design of pNCs that exhibit complex or responsive optical function. Due to their scalability and tunability, pNCs provide a versatile platform for engineering new plasmonic materials and for facile integration into optoelectronic device architectures. This review provides a comprehensive survey of recent achievements in pNC structure, design, fabrication, and optical function, along with some examples of their application in optoelectronics and sensing. PMID- 29419287 TI - Enhanced Electron Transfer Mediated by Conjugated Polyelectrolyte and Its Application to Washing-Free DNA Detection. AB - Direct electron transfer between a redox label and an electrode requires a short working distance (<1-2 nm), and in general an affinity biosensor based on direct electron transfer requires a finely smoothed Au electrode to support efficient target binding. Here we report that direct electron transfer over a longer working distance is possible between (i) an anionic pi-conjugated polyelectrolyte (CPE) label having many redox-active sites and (ii) a readily prepared, thin polymeric monolayer-modified indium-tin oxide electrode. In addition, the long CPE label (~18 nm for 10 kDa) can approach the electrode within the working distance after sandwich-type target-specific binding, and fast CPE-mediated oxidation of ammonia borane along the entire CPE backbone affords high signal amplification. PMID- 29419288 TI - Deciphering the Role of Dipolar Interactions in Magnetic Layered Double Hydroxides. AB - Layered double hydroxides (LDHs) exhibit unparalleled anion exchange properties and the ability to be exfoliated into 2D nanosheets, which can be used as a building block to fabricate a wide variety of hybrid functional nanostructured materials. Still, if one wants to use LDHs as a magnetic building blocks in the design of complex architectures, the role played by the dipolar magnetic interactions in these layered materials needs to be understood. In this work, we synthesized and characterized a five-membered CoAl-LDH series with basal spacing ranging from 7.5 to 34 A. A detailed experimental characterization allows us to conclude that the main factor governing the dipolar interactions between magnetic layers cannot be the interlayer spacing. Supporting theoretical modeling suggests instead a relevant role for spin correlation size, which, in the limit, is related to the lateral dimension of the layer. These results highlight the importance of cation ordering in the magnetic behavior of LDHs, and underpin the differences with homometallic-layered hydroxides. PMID- 29419289 TI - A Ruthenium Hydrido Dinitrogen Core Conserved across Multielectron/Multiproton Changes to the Pincer Ligand Backbone. AB - A series of ruthenium(II) hydrido dinitrogen complexes supported by pincer ligands in different formal oxidation states have been prepared and characterized. Treating a ruthenium dichloride complex supported by the pincer ligand bis(di-tert-butylphosphinoethyl)amine (H-PNP) with reductant or base generates new five-coordinate cis-hydridodinitrogen ruthenium complexes each containing different forms of the pincer ligand. Further ligand transformations provide access to the first isostructural set of complexes featuring all six different forms of the pincer ligand. The conserved cis-hydridodinitrogen structure facilitates characterization of the pi-donor, pi-acceptor, and/or sigma donor properties of the ligands and assessment of the impact of ligand-centered multielectron/multiproton changes on N2 activation. Crystallographic studies, infrared spectroscopy, and 15N NMR spectroscopy indicate that N2 remains weakly activated in all cases, providing insight into the donor properties of the different pincer ligand states. Ramifications on applications of (pincer)Ru species in catalysis are considered. PMID- 29419290 TI - Unique Zigzag-Shaped Buckling Zn2C Monolayer with Strain-Tunable Band Gap and Negative Poisson Ratio. AB - Designing new materials with reduced dimensionality and distinguished properties has continuously attracted intense interest for materials innovation. Here we report a novel two-dimensional (2D) Zn2C monolayer nanomaterial with exceptional structure and properties by means of first-principles calculations. This new Zn2C monolayer is composed of quasi-tetrahedral tetracoordinate carbon and quasi linear bicoordinate zinc, featuring a peculiar zigzag-shaped buckling configuration. The unique coordinate topology endows this natural 2D semiconducting monolayer with strongly strain tunable band gap and unusual negative Poisson ratios. The monolayer has good dynamic and thermal stabilities and is also the lowest-energy structure of 2D space indicated by the particle swarm optimization (PSO) method, implying its synthetic feasibility. With these intriguing properties the material may find applications in nanoelectronics and micromechanics. PMID- 29419291 TI - Tailoring the Electronic Structure of Uranium Mono(imido) Species through Ligand Variation. AB - Uranium mono(imido) species have been prepared via the oxidation of Cp*U(MesPDIMe)(THF) (1-Cp*) and [CpPU(MesPDIMe)]2 (1-CpP), where Cp* = eta5 1,2,3,4,5-pentamethylcyclopentadienide, CpP = 1-(7,7 dimethylbenzyl)cyclopentadienide, MesPDIMe = 2,6-[(Mes)N?CMe]2C5H3N, and Mes = 2,4,6-trimethylphenyl, with organoazides. Treating either with N3DIPP (DIPP = 2,6 diisopropylphenyl) formed uranium(IV) mono(imido) complexes, CpPU(NDIPP)(MesPDIMe) (2-CpP) and Cp*U(NDIPP)(MesPDIMe) (2-Cp*), featuring reduced [MesPDIMe]-. The addition of electron-donating 1-azidoadamantane (N3Ad) to 1-Cp* generated a dimeric product, [Cp*U(NAd)(MesHPDIMe)]2 (3), from radical coupling at the p-pyridine position of the pyridine(diimine) ligand and H-atom abstraction, formed through a monomeric intermediate that was observed in solution but could not be isolated. To support this, Cp*U(tBu-MesPDIMe)(THF) (1 tBu), which has a tert-butyl group protecting the para position, was also treated with N3Ad, and the monomeric product, Cp*U(NAd)(tBu-MesPDIMe) (2-tBu), was isolated. All isolated complexes were analyzed spectroscopically and structurally, and the dynamic solution behavior was examined using electronic absorption spectroscopy. PMID- 29419292 TI - Vinylogous Elimination/Heck Coupling/Allylation Domino Reactions: Access to 2 Substituted 2,3-Dihydrobenzofurans and Indolines. AB - A highly regio- and stereoselctive palladium-catalyzed domino reaction of functionalized aryl allyl ethers has been developed. Various aryl allyl ethers derived from the phosphine-catalyzed addition of electron-deficient allenes with phenol are found to be efficient substrates for the synthesis of 2-substituted 2,3-dihydrobenzofurans and indolines. It is the first example of aryl allyl ether used as an ideal and practical precursor of hard to get functionalized 1,3 butadiene for the heterocyclic compound synthesis. PMID- 29419293 TI - Origin of Xylitol in Chewing Gum: A Compound-Specific Isotope Technique for the Differentiation of Corn- and Wood-Based Xylitol by LC-IRMS. AB - The sugar replacement compound xylitol has gained increasing attention because of its use in many commercial food products, dental-hygiene articles, and pharmaceuticals. It can be classified by the origin of the raw material used for its production. The traditional "birch xylitol" is considered a premium product, in contrast to xylitol produced from agriculture byproducts such as corn husks or sugar-cane straw. Bulk stable-isotope analysis (BSIA) and compound-specific stable-isotope analysis (CSIA) by liquid-chromatography isotope-ratio mass spectrometry (LC-IRMS) of chewing-gum extracts were used to determine the delta13C isotope signatures for xylitol. These were applied to elucidate the original plant type the xylitol was produced from on the basis of differences in isotope-fractionation processes of photosynthetic CO2 fixation. For the LC-IRMS analysis, an organic-solvent-free extraction protocol and HPLC method for the separation of xylitol from different artificial sweeteners and sugar-replacement compounds was successfully developed and applied to the analysis of 21 samples of chewing gum, from which 18 could be clearly related to the raw-material plant class. PMID- 29419294 TI - Rhodamine-Platinum Diimine Dithiolate Complex Dyads as Efficient and Robust Photosensitizers for Light-Driven Aqueous Proton Reduction to Hydrogen. AB - Three new dyads consisting of a rhodamine (RDM) dye linked covalently to a Pt diimine dithiolate (PtN2S2) charge transfer complex were synthesized and used as photosensitizers for the generation of H2 from aqueous protons. The three dyads differ only in the substituents on the rhodamine amino groups, and are denoted as Pt-RDM1, Pt-RDM2, and Pt-RDM3. In acetonitrile, the three dyads show a strong absorption in the visible region corresponding to the rhodamine pi-pi* absorption as well as a mixed metal-dithiolate-to-diimine charge transfer band characteristic of PtN2S2 complexes. The shift of the rhodamine pi-pi* absorption maxima in going from Pt-RDM1 to Pt-RDM3 correlates well with the HOMO-LUMO energy gap measured in electrochemical experiments. Under white light irradiation, the dyads display both high and robust activity for H2 generation when attached to platinized TiO2 nanoparticles (Pt-TiO2). After 40 h of irradiation, systems containing Pt-RDM1, Pt-RDM2, and Pt-RDM3 exhibit turnover numbers (TONs) of 33600, 42800, and 70700, respectively. Ultrafast transient absorption spectroscopy reveals that energy transfer from the rhodamine 1pi-pi* state to the singlet charge transfer (1CT) state of the PtN2S2 chromophore occurs within 1 ps for all three dyads. Another fast charge transfer process from the rhodamine 1pi pi* state to a charge separated (CS) RDM(0*)-Pt(+*) state is also observed. Differences in the relative activity of systems using the RDM-PtN2S2 dyads for H2 generation correlate well with the relative energies of the CS state and the PtN2S23CT state used for H2 production. These findings show how one can finely tune the excited state energy levels to direct excited state population to the photochemically productive states, and highlight the importance of judicious design of a photosensitizer dyad for light absorption and photoinduced electron transfer for the photogeneration of H2 from aqueous protons. PMID- 29419295 TI - Relationships between Product Ratios in Ambimodal Pericyclic Reactions and Bond Lengths in Transition Structures. AB - Ambimodal reactions involve a single transition state leading to multiple products. In such reactions, transition state theory gives no information about the ratio of products that are formed, and molecular dynamics must be performed to predict this ratio. Understanding the relationship between the transition structure and the product ratio is a long-standing problem in molecular dynamics. We have studied 15 ambimodal pericyclic reactions and investigated the relationship between the TS bond lengths in the saddle points and the product ratios from trajectory simulations. A linear correlation, ln(B:A) = -9.4(Bond 3 - Bond 2), is found with R2 = 0.92, where A and B refer to the products formed upon formation of bonds 2 and 3, respectively. The correlation shows that the ratio of products formed after the bifurcation is related to the partial bond lengths, and corresponding bond orders, in the transition state. PMID- 29419296 TI - Differentiating Organically Farmed Rice from Conventional and Green Rice Harvested from an Experimental Field Trial Using Stable Isotopes and Multi Element Chemometrics. AB - Chemometric methods using stable isotopes and elemental fingerprinting were used to characterize organically grown rice from green and conventionally grown rice in experimental field trials in China. Carbon, nitrogen, hydrogen, and oxygen stable isotopes as well as 26 other elements were determined. Organic rice was found to be more depleted in 13C than green or conventionally grown rice because of the uptake of enriched 13C from carbon dioxide and methane respiring bacteria and more enriched in 15N because of the volatilization of the nitrogen from the urea and ammonium of the animal manures used to manufacture the organic composts. Chemometrics (principal-component analysis and linear-discriminant analysis) were used to separate the three farming methods and provided a promising scientific tool to authenticate the farming methods of different rice cultivars fertilized with animal manures, green composts, and synthetic fertilizers in China or elsewhere. PMID- 29419297 TI - Distinguishing the Dynamic Fingerprints of Two- and Three-Dimensional Chemical Waves in Microbeads. AB - Spatiotemporal oscillations confined to quasi-2D surface layers or 3D volumes play an important role for wave-based information relay and global oscillations in living systems. Here, we describe experiments with the Belousov-Zhabotinsky reaction confined to microbeads, in which the catalyst is selectively loaded either onto the surface or into the body of the spherical beads. We find that the dynamics of global oscillations, traveling reaction fronts, and rotating spiral waves under surface confinement are strikingly different from those in the bead volume. Our results establish a useful model system for the study of geometrical effects on nonlinear chemical processes and provide diagnostic features that allow the distinction of membrane-mediated 2D and cytosolic 3D processes in biological cells. PMID- 29419298 TI - Stretch-Induced Interdigitation of a Phospholipid/Cholesterol Bilayer. AB - The interdigitated gel (LbetaI) phase is one of the membrane phases of phospholipid molecules in which the hydrophobic tails of the phospholipid molecules penetrate the opposite leaflet of the bilayer. Recent molecular dynamics (MD) simulations have shown that interdigitation can take place as a phase transition from the liquid-ordered (Lo) phase to the LbetaI phase under stretching. However, there is still no conclusive experimental evidence for this process, so its existence remains controversial. In this study, to explain the transition from energy balance, we propose a free-energy model. The model consists of three energy components: the elastic deformation energy, surface energy at the bilayer-water interface, and interphase boundary energy. To determine the parameters of the model, we perform MD simulations of a stretched 1,2-dipalmitoyl- sn-glycero-3-phosphocholine/cholesterol bilayer. The phase diagrams from our model are in good agreement with those obtained from MD simulations. The energy balance among the components in the stretched bilayer quantitatively explains the stretch-induced transition. In the model, increasing the system size to that used in experiments shows that interdigitation is favorable for rigid bilayers under stretching or in alcohol solutions. These results suggest that the stretch-induced interdigitation might be observed in microscopic experiments. PMID- 29419299 TI - Acid Dissociation Equilibrium and Singlet Molecular Oxygen Quantum Yield of Acetylated 6,8-Dithioguanosine in Aqueous Buffer Solution. AB - 2',3',5'-Tri- O-acetyl-6,8-dithioguanosine (taDTGuo) is a nucleoside derivative of drug 6-thioguanine and under further development as a potential photochemotherapeutic agent due to its desirable properties of photosensitivity to UVA light and singlet molecular oxygen generation. The photochemical characteristics of taDTGuo under biological conditions (namely in aqueous solution) were intensively investigated by the steady-state absorption and emission, time-resolved near-infrared emission measurements, and quantum chemical calculations. taDTGuo was found to be held in sequential acid dissociation equilibria within pH 3.79-11.93. With the global fitting analysis of the absorption spectra at various pHs, two p Ka values of the equilibria were determined to be 7.02 +/- 0.01 and 9.79 +/- 0.01. Quantum chemical calculations suggested that its mono- and dianionic species in the ground state should be 1 imide anionic form (N1-taDTGuo-) and 1,7-di-imide anionic form (taDTGuo2-). taDTGuo generates a singlet molecular oxygen effectively and has pH-dependent quantum yields. In conclusion, taDTGuo would be very useful as a potent agent for photochemotherapy under certain carcinomatous pH conditions. PMID- 29419300 TI - Convergent Total Synthesis of Paecilomycin B and 6'- epi-Paecilomycin B by a Barbier-Type Reaction Using 2,4,6-Triisopropylphenyllithium. AB - The convergent total synthesis of the natural product paecilomycin B and its 6' epimer was investigated. The aryl- C-glycoside skeleton was constructed by an intramolecular Barbier-type reaction using 2,4,6-triisopropylphenyllithium and subsequent deoxygenation of the resulting anomeric hydroxy group. Starting from aryl iodide 24, the addition reaction afforded the thermodynamically stable C beta macrocyclic adduct 41a in 29% yield and the C-alpha adduct 41b in 1% yield. Meanwhile, aryl iodide 43 (6'-epimer of 24) gave only the C-alpha adduct 44 in 76% yield. The stereoselectivities of these nucleophilic addition reactions are also discussed. PMID- 29419301 TI - Identification of Rare Lewis Oligosaccharide Conformers in Aqueous Solution Using Enhanced Sampling Molecular Dynamics. AB - Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free-energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling, and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 MUs trajectories; these simulations find a predominance of closed conformer and a range of low-occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the 4C1 form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 MUs unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation. PMID- 29419302 TI - All Inkjet-Printed Amperometric Multiplexed Biosensors Based on Nanostructured Conductive Hydrogel Electrodes. AB - Multiplexing, one of the main trends in biosensors, aims to detect several analytes simultaneously by integrating miniature sensors on a chip. However, precisely depositing electrode materials and selective enzymes on distinct microelectrode arrays remains an obstacle to massively produced multiplexed sensors. Here, we report on a "drop-on-demand" inkjet printing process to fabricate multiplexed biosensors based on nanostructured conductive hydrogels in which the electrode material and several kinds of enzymes were printed on the electrode arrays one by one by employing a multinozzle inkjet system. The whole inkjet printing process can be finished within three rounds of printing and only one round of alignment. For a page of sensor arrays containing 96 working electrodes, the printing process took merely ~5 min. The multiplexed assays can detect glucose, lactate, and triglycerides in real time with good selectivity and high sensitivity, and the results in phosphate buffer solutions and calibration serum samples are comparable. The inkjet printing process exhibited advantages of high efficiency and accuracy, which opens substantial possibilities for massive fabrication of integrated multiplexed biosensors for human health monitoring. PMID- 29419303 TI - Asymmetric Diels-Alder Reaction of alpha,beta-Unsaturated Oxazolidin-2-one Derivatives Catalyzed by a Chiral Fe(III)-Bipyridine Diol Complex. AB - An asymmetric FeIII-bipyridine diol catalyzed Diels-Alder reaction of alpha,beta unsaturated oxazolidin-2-ones has been developed. Among various FeII/FeIII salts, Fe(ClO4)3.6H2O was selected as the Lewis acid of choice. The use of a low catalyst loading (2 mol % of Fe(ClO4)3.6H2O and 2.4 mol % of Bolm's ligand) afforded high yields (up to 99%) and high enantiomeric excesses (up to 98%) of endo-cycloadducts for the Diels-Alder reaction between cyclopentadiene and substituted acryloyloxazolidin-2-ones. Other noncyclic dienes led to decreased enantioselectivities. A proposed model supports the observed stereoinduction. PMID- 29419304 TI - Asymmetric Construction of Fluoroalkyl Tertiary Alcohols through a Three Component Reaction of (Bpin)2, 1,3-Enynes, and Fluoroalkyl Ketones Catalyzed by a Copper(I) Complex. AB - An asymmetric three-component reaction of Bis(pinacolato)diboron ((BPin)2), 1,3 enynes, and fluoroalkyl ketones was carried out by using a copper(I)-Ph-BPE complex as the catalyst, which afforded a series of chiral fluoroalkyl diols in good to high yield, good to high diastereoselectivity, and high enantioselectivity after an oxidative workup. The reaction exhibits advantages that include a broad substrate scope, high functional group compatibility, high stereoselectivity, and an easy reaction protocol. The synthetic utility of the reaction was showcased by several transformations. PMID- 29419305 TI - Peptide-Functionalized Phase-Transformation Nanoparticles for Low Intensity Focused Ultrasound-Assisted Tumor Imaging and Therapy. AB - In this study, we successfully developed novel tumor homing-penetrating peptide functionalized drug-loaded phase-transformation nanoparticles (tLyP-1-10-HCPT-PFP NPs) for low intensity focused ultrasound (LIFU)-assisted tumor ultrasound molecular imaging and precise therapy. With the nanoscale particle size, tLyP-1 10-HCPT-PFP NPs could pass through the tumor vascular endothelial cell gap. Induced by tLyP-1 peptide with targeting and penetrating efficiency, tLyP-1-10 HCPT-PFP NPs could increase tumor accumulation and penetrate deeply into the extravascular tumor tissue, penetrating through extracellular matrix and the cellular membrane to the cytoplasm. With LIFU assistance, tLyP-1-10-HCPT-PFP NPs could phase-transform into microbubbles and enhance tumor ultrasound molecular imaging for tumor diagnosis. Furthermore, after further irradiation by LIFU, an intracellular "explosion effect" caused by acoustic droplet vaporization, ultrasound targeted microbubble destruction, and release of 10-HCPT could realize physicochemical synergistic antitumor therapy. PMID- 29419306 TI - Highly Site-Selective Metal-Free C-H Acyloxylation of Stable Enamines. AB - A highly site-selective acyloxylation of stable enamines with PhI(OAc)2 under metal-free conditions to afford (E)-vinyl acetate derivatives in good to excellent yields is described. Depending on the judicious choice of the solvent system, either the alpha- or beta-site-selective product could be obtained with high selectivity. For the alpha-site-selective product, the rearranged amide compound is obtained as the major product. This reaction proceeds under mild reaction conditions (room temperature, metal-free, and open-flask) and features a broad substrate scope. PMID- 29419308 TI - Changes in psychiatric symptoms and psychological processes among veterans participating in a therapeutic adventure program. AB - When veterans need effective mental health treatment, many are reluctant to engage in traditional treatment modalities because of stigma. Therapeutic adventure shows promise as a way to engage veterans and enact positive changes in functioning, but little is known about how therapeutic adventure impacts mental health symptoms among veterans. This study examined changes in mental health symptoms and related psychological processes over the course of a 6-day Outward Bound for Veterans (OB4V) program and at a 1-month follow-up. This study examined data from 77 U.S. military veterans with psychiatric diagnoses. The authors hypothesized that participants would report significant reductions in mental health symptoms over the course of the program and following its completion, as well as significant improvements in psychological processes that included initiative for psychological growth, psychological attitudes, attitudes toward help-seeking, psychological mindedness, and emotional suppression. A repeated measures analysis of variance was performed on each of the dependent variables. Results showed that, from pre- to postprogram, participants reported significant improvement in life purpose satisfaction and self-confidence during stressful situations. Further, from preprogram to 1-month postprogram, veterans reported increased psychological mindedness, increased engagement to promote personal growth, decreased mental health symptomology, decreased emotional suppression, and an increase in positive attitude toward seeking professional psychological help. These improvements were significant during the OB4V program and even continued to improve after the program ended, showing the promise of therapeutic adventure as a modality to address veterans' mental health issues. (PsycINFO Database Record PMID- 29419307 TI - False memories, false preferences: Flexible retrieval mechanisms supporting successful inference bias novel decisions. AB - Prior research suggests that episodic memory can guide value-based decisions when single episodes are encoded in relation to the specific reward-context in which they were experienced. The current experiments examine the role that a flexible recombination-related retrieval mechanism that allows one to link together distinct events plays in the misattribution of specific reward-contexts across distinct episodes. To determine whether the same recombination-related retrieval mechanism supports both successful inference and transfer of reward-context across episodes, we developed a modified version of an associative inference paradigm in which participants encoded overlapping associations (AB, BC) that could later be linked to support inferential retrieval (AC), where one element ("A") was tied to reward. Our key experimental manipulation concerned whether value memory (Experiments 1 and 2) or decision bias tests (Experiment 3) were probed before or after the associative inference test, thereby allowing us to assess whether false value transfer and decision bias scores increased after as compared to before successful versus unsuccessful inference. Results revealed that participants more frequently misattributed the specific reward-context ("A") to unrewarded items ("C;" Experiments 1 and 2) and showed higher decision bias scores when asked to choose between two previously unrewarded items ("C;" Experiment 3) for successful compared with unsuccessful inference, but only when the value memory and decision bias tests were given after the associative inference test. These results suggest that a recombination-related retrieval mechanism that supports successful inference also contributes to the misattribution of reward-context in memory and further biases participants' novel value-based decisions. (PsycINFO Database Record PMID- 29419309 TI - Barriers to the use of Veterans Affairs health care services among female veterans who served in Iraq and Afghanistan. AB - The study investigated barriers to the utilization of Veterans Affairs (VA) health care services among female veterans who served in served in Iraq and Afghanistan, including reasons for not choosing VA health care, reasons for not seeking mental health treatment, and types of desired VA services. Female respondents to a survey assessing Operation Enduring Freedom/Operation Iraqi Freedom veterans' needs and health (N = 186) completed measures of military history, posttraumatic stress disorder, depression, barriers to VA health care, and preferences for services. Barriers to use of VA health care endorsed by female veterans included receiving care elsewhere and logistical issues. Barriers to utilization of mental health services among female veterans who screened positive for depression or posttraumatic stress disorder included negative treatment biases and concerns about stigma, privacy, and cost. Female veterans endorsed preferences for services related to eligibility education, nonprimary care physical health services, vocational assistance, and a few behavioral/mental health services. Findings highlight the need for ongoing outreach and education regarding eligibility and types of resources for physical and mental health problems experienced by female veterans who served in Iraq and Afghanistan, as well as inform types of VA programming and services desired by female veterans. (PsycINFO Database Record PMID- 29419312 TI - Traditional Chinese medicine: perspectives on and treatment of menopausal symptoms. PMID- 29419310 TI - Validation and psychometric properties of the Alcohol Positive and Negative Affect Schedule: Are drinking emotions distinct from general emotions? AB - People vary in experiences of positive and negative emotions from consuming alcohol, but no validated measurement instrument exclusively devoted to assessing drinking emotions exists in the literature. The current research validated and evaluated the psychometric properties of an alcohol affect scale based on adjectives from the Positive and Negative Affect Schedule (PANAS) and tested the extent that emotions incurred from drinking were distinct from general trait based emotions. Three studies tested independent samples of adult alcohol users. In Study 1 (N = 494), exploratory factor analyses of the Alcohol PANAS revealed that both the 20-item model and the 9-parcel model (represented by similar mood content) supported the 2-factor dimensionality of alcohol positive and negative affect. In Study 2 (N = 302), confirmatory factor analyses corroborated the measurement structure of alcohol positive and negative affect, and both constructs evidenced statistical independence from general positive and negative affect. In Study 3 (N = 452), alcohol positive and negative affect exhibited discriminant, convergent, and criterion validity with established alcohol scales. Incremental validity tests demonstrated that alcohol positive and negative affect uniquely contributed (beyond general positive and negative affect) to alcohol expectancies, use, and problems. Findings support that alcohol emotions are conceptually distinct from trait emotions, and underscore the necessity of an assessment instrument tailored to the former to examine associations with alcohol beliefs and behaviors. The Alcohol PANAS confers theoretical and practical applications to understand the emotional consequences of drinking. (PsycINFO Database Record PMID- 29419311 TI - Revisiting the Drinker Inventory of Consequences: An extensive evaluation of psychometric properties in two alcohol clinical trials. AB - Alcohol-related consequences are linked directly to the diagnostic criteria for alcohol use disorder (AUD). However, alcohol consumption outcome variables (e.g., percent days abstinent, heavy drinking days) remain the dominant outcome in AUD treatment research. Two reasons AUD treatment researchers have not shifted to include alcohol-related consequences as a primary outcome may be that previous studies have failed to provide convincing evidence of (1) the psychometric properties of measures of alcohol-related consequences, and (2) whether consequences measures are sensitive to change following treatment. The present study directly addresses these two concerns via psychometric evaluation and sensitivity/specificity testing of the Drinker Inventory of Consequences (DrInC; Miller, Tonigan, & Longabaugh, 1995) in two of the largest multisite clinical trials ever conducted (COMBINE Study, Anton, et al., 2006; and Project MATCH, Project MATCH Research Group, 1997). Results indicated that the five subscales commonly used for the DrInC had poor construct validity and were noninvariant across time. A newly developed three-factor model consisting of mild, moderate, and severe consequences had excellent psychometrics, including good internal consistency reliability, construct validity, and measurement invariance over time. The three-factor model of the DrInC was also sensitive and specific for detecting consumption outcomes in both COMBINE and MATCH and had convergent validity with measures of consumption and wellbeing. In conclusion, the three factor DrInC may be a useful tool for defining AUD treatment success in a clinically meaningful way that aligns with diagnostic criteria. (PsycINFO Database Record PMID- 29419313 TI - Beyond ulcers and osteomyelitis: imaging of less common musculoskeletal complications in diabetes mellitus. AB - Metabolic perturbations in diabetes mellitus affect various organ systems and can lead to end-organ failure. Though most musculoskeletal (MSK) complications of diabetes mellitus are usually not life-threatening, they are often the cause of significant morbidity. While some of the MSK complications have a proven association with diabetes mellitus, others have been loosely associated because of their frequent coexistence, as are the rheumatologic complications. While many of these conditions are well-known, some are overlooked in routine clinical practice. This article focuses on highlighting key imaging features of less common MSK complications and associations of diabetes mellitus. PMID- 29419315 TI - Decision-making about mammographic screening: pursuing informed choice. AB - For decades, persuasive techniques have been used to communicate to women about breast cancer screening with the aim of maximizing screening uptake. However, more recently this has shifted to an approach which recognizes that it is important for women to be aware of harms, such as overdiagnosis, as well as benefits of breast screening. There is a lack of consensus in the literature around whether benefits clearly outweigh harms for population-based breast cancer screening. In light of this, the gold standard for communication about breast cancer screening is now to try and support informed decision-making - that is, to help women understand both the advantages and disadvantages of screening, allowing them to make individual decisions about their screening participation that reflect their informed preferences. In this review, we summarize relevant research to identify theoretical and practical aspects of improving communication and decision-making about breast cancer screening, and discuss future implications. PMID- 29419314 TI - Psychiatry in Portugal: Key actors and conceptual history (1884-1924). AB - The aim of this article is the study of psychiatry in Portugal between 1884 and 1924, the period when it became institutionalized, and when works that marked its scientific evolution were published. This paper summarizes the various historiographical approaches, and its approach to the subject is closest to the conceptual history carried out by German Berrios in Cambridge. The study attempts to correlate the key actors and their works with the history of different scientific ideas, its differences, and the influences of foreign authors. The diseases, syndromes, symptoms and pathologizations in this historical period were also studied, justifying a constructionist perspective. Finally, the various therapies are discussed, from institutional to pharmacological and psychotherapeutical. PMID- 29419317 TI - Effects of Menthol-Containing Artificial Tears on Tear Stimulation and Ocular Surface Integrity in Normal and Dry Eye Rat Models. AB - PURPOSE: To evaluate the effects of menthol-containing artificial tears on tear stimulation and ocular surface integrity in normal and dry eye rat models. METHODS: A total of 54 male Lewis rats were used. The levels of tear secretion and tear MUC5AC concentrations were compared between the menthol-containing artificial tear-treated group (menthol group) and the vehicle-treated group (vehicle group). The groups were compared after a single instillation to evaluate the immediate effects, and after repeated instillation (five times a day for 5 days) to evaluate the longer-term effects. Tear lactate dehydrogenase (LDH) activity was measured to evaluate eye drop instillation-induced ocular surface damage. The effects of menthol-containing artificial tears were also evaluated in a dry eye rat model. RESULTS: After a single instillation of menthol-containing artificial tears, tear secretion increased from 4.37 (+/-0.75) mm at baseline to 7.37 (+/-1.60) mm. However, after repeated instillations, the effects of tear stimulation decreased. The tear MUC5AC concentration was significantly lower in the menthol group than in the vehicle group after a single instillation, but not after repeated instillation. However, the tear LDH concentration was significantly increased in the menthol group after repeated instillation. In the dry eye rat model, the extent of menthol-induced tear stimulation was reduced. CONCLUSIONS: Menthol-containing artificial tears increased tear secretion, but lowered the tear MUC5AC concentration. Menthol-induced tear stimulation was reduced after repeated instillation for 5 days and in the dry eye rat model. Conversely, repeated instillation of menthol-induced ocular surface damage, resulting in increased tear LDH activity. PMID- 29419318 TI - The Relationship Between Sexual Concordance and Orgasm Consistency in Women. AB - Sexual concordance (the relationship between genital and self-reported sexual responses) may be associated with orgasm consistency (OC; the proportion of sexual acts leading to orgasm) during penile-vaginal intercourse (PVI) in women. We investigated the relationship between women's sexual concordance (assessed using different stimulus modalities and self-reported sexual arousal methods) and OC during various sexual activities (assessed using different types of questions). For Study 1 (n = 51), when sexual concordance was assessed using audiovisual sexual stimuli, we did not find a statistically significant relationship between OC and poststimulus self-reports of sexual arousal or genital sensations, raw values of OC, or ranges of OC. For Study 2 (n = 44), where sexual concordance was assessed using audionarrative sexual stimuli, we did find a statistically significant relationship between PVI OC and sexual concordance using change in self-reported sexual arousal, and ranges of orgasm consistency. Two findings were inconsistent with previous research. First, OC varied significantly by activity type in both studies; masturbation yielded the highest OC. Second, PVI OC was significantly related to oral sex and masturbation OC (Study 2). We discuss the need for further research and various factors that may affect women's orgasm consistency and sexual concordance. PMID- 29419319 TI - Synthesis and biological evaluation of ferrocene-based cannabinoid receptor 2 ligands. AB - Ferrocene analogs of known fatty acid amide hydrolase inhibitors and CB2 ligands have been synthesized and characterized spectroscopically and crystallographically. The resulting bio-organometallic isoxazoles were assayed for their effects on CB1 and CB2 receptors as well as on fatty acid amide hydrolase. None had any fatty acid amide hydrolase activity but compound 3, 5-(2 (pentyloxy)phenyl)-N-ferrocenylisoxazole-3-carboxamide, was found to be a potent CB2 ligand (Ki = 32.5 nM). PMID- 29419320 TI - Using the Clear Communication Index to Improve Materials for a Behavioral Intervention. AB - Ensuring that written materials used in behavioral interventions are clear is important to support behavior change. This study used the Clear Communication Index (CCI) to assess the original and revised versions of three types of written participant materials from the SIPsmartER intervention. Materials were revised based on original scoring. Scores for the entire index were significantly higher among revised versions than originals (57% versus 41%, p < 0.001); however, few revised materials (n = 2 of 53) achieved the benchmark of >=90%. Handouts scored higher than worksheets and slide sets for both versions. The proportion of materials scored as having "a single main message" significantly increased between versions for worksheets (7% to 57%, p = 0.003) and slide sets (33% to 67%, p = 0.004). Across individual items, most significant improvements were in Core, with four-items related to the material having a single main message. Findings demonstrate that SIPsmartER's revised materials improved after CCI informed edits. They advance the evidence and application of the CCI, suggesting it can be effectively used to support improvement in clarity of different types of written materials used in behavioral interventions. Implications for practical considerations of using the tool and suggestions for modifications for specific types of materials are presented. PMID- 29419321 TI - The potential role of variations in juvenile hip geometry on the development of Legg-Calve-Perthes disease: a biomechanical investigation. AB - Legg-Calve-Perthes disease (LCP) is one of the most poorly understood diseases in paediatric orthopaedics. One common trait of LCP is the marked morphological difference between healthy and pathological hips, early deviations of which (i.e. prior to disease onset) have been suggested to lead to the overload and collapse of the epiphysis. Here, the impact of common variations in geometry is investigated with a finite element model of a juvenile femur under single leg standing and landing. Here, the impact of typical variations in geometry is investigated with a finite element model of a juvenile femur under single leg standing and landing. The variations appear to have only a limited effect on the stress distribution in the femoral epiphysis even during high impact activities. This suggests that, for this individual at least, they would be unlikely to cause epiphyseal overload and collapse, even in the presence of a skeletally immature epiphysis. PMID- 29419322 TI - What Theories and Methods From Relationship Research Can Contribute to Sex Research. AB - Sexual and relationship satisfaction tend to be closely linked in the context of romantic relationships. Understanding how sexual processes influence relationships and how aspects of the relationship influence a couple's sex life can provide insight into the maintenance of sexual desire and satisfaction over time. In this article, we review how theories and methods that form the foundation for relationship research have made-and will continue to make sexuality research a stronger, more theoretical, and methodologically sophisticated science. We discuss the key theories that have been used to advance our understanding of who is more likely to be sexually satisfied in relationships, when sex is most satisfying, and how couples can have more satisfying sex lives and relationships. We then provide an overview of dyadic and repeated-measures designs and demonstrate how the use of these types of research methods allows relationship and sexuality researchers to answer novel and nuanced questions about how romantic partners influence each other, as well as how sexual processes unfold in couples' daily lives and over time. Throughout the review, we highlight what we see as fruitful directions for future research at the intersection of sexuality and relationships. PMID- 29419323 TI - Increasing Organ Donation for Children Who Need Transplants. AB - Editor-in-chief emeritus professor Alan Glasper from the University of Southampton discusses how children's and young people's nurses can improve the rates of organ donation for children in need of transplants. PMID- 29419324 TI - Accuracy and precision of manual segmentation of the maxillary sinus in MR images a method study. AB - OBJECTIVE: To assess the accuracy and precision of segmentation of the maxillary sinus in MR images to evaluate the potential usefulness of this modality in longitudinal studies of sinus development. METHODS: A total of 15 healthy subjects who had been both craniofacial CT and MR scanned were included and the 30 maxillary sinus volumes were evaluated using segmentation. Two of the authors did segmentation of MRI and one of these authors did double segmentation. Agreement in results between CT and MRI as well as inter- and intraexaminer errors were evaluated by statistical and three-dimensional analysis. RESULTS: The intraclass correlation coefficient for volume measurements for both method error, inter- and intraexaminer agreement were > 0.9 [maximal 95% confidence interval of 0.989-0.997, p < 0.001] and the limit of agreement for all parameters were < 5.1%. Segmentation errors were quantified in terms of overlap [Dice Coefficient (DICE) > 0.9 = excellent agreement] and border distance [95% percentile Hausdorff Distance (HD) < 2 mm = acceptable agreement]. The results were replicable and not influenced by systematic errors. CONCLUSION: We found a high accuracy and precision of manual segmentation of the maxillary sinus in MR images. The largest mean errors were found close to the orbit and the teeth. Advances in knowledge: MRI can be used for 3D models of the paranasal sinuses with equally good results as CT and allows longitudinal follow-up of sinus development. PMID- 29419325 TI - Anatomic distribution of hematoma following pelvic fracture. AB - OBJECTIVE: To assess the extent of pelvic hemorrhage on CT and to estimate its significance on outcome in patients with blunt high-energy pelvic trauma. METHODS: 576 patients with blunt high-energy pelvic fractures in 2005-2011 were identified in the hospital's Trauma Registry (a major Trauma Center). 60 of these met our further inclusion criteria of initial systolic blood pressure <=100 mmHg and pelvic-related hemorrhage. CT scans of the patients were reviewed with regard to pelvic and abdominal retroperitoneal hemorrhage, type of fracture (Tile classification) and associated injuries. Extent of hemorrhage was correlated to 30-day mortality, transfusion requirements and need of angiography. Statistical methods include Pearson's Chi2 test and Fisher's exact test. RESULTS: Pelvic hemorrhage extended beyond the pelvis to the abdominal area in 47% of the patients, to the thighs in 25% and to the gluteal areas in 81%. The extent of hemorrhage was significantly associated with the need for blood transfusions (p = 0.011) and angiography (p < 0.001), but not with 30-day mortality. CONCLUSION: Traumatic pelvic bleeding frequently extends beyond the true pelvis. Extrapelvic hemorrhage correlates with an increased need of transfusions, but not with 30-day mortality. Further studies are needed to assess whether present techniques to control pelvic bleeding need to be modified in order to further reduce mortality in traumatic pelvic hemorrhage. Advances in knowledge: The study shows localization of pelvic hemorrhage in trauma patients. It may help to select patients in need of further interventions to control bleeding. PMID- 29419326 TI - Horse Husbandry and Preventive Health Practices in Australia: An Online Survey of Horse Guardians. AB - Little is known about the horse health management practices of Australian horse caregivers (owners). This article presents findings from a convenience sample of 505 horse owners who participated in an online survey. No large-scale welfare issues were identified, but there were some areas of potential concern, including owners who did not regularly deworm their horses (4%), a lack of strategic parasite control (3.1%), and a lack of regular dental care (11%). Several participants did not have their horse's hooves regularly shod or trimmed (2%), and 14% had an unqualified person maintain their horse's hooves. One in five owners (19%) did not vaccinate their horses against tetanus. The findings are discussed in relation to current Australian horse health guidelines and traditional sources of horse health information, together with recommendations for providing horse owners with relevant information in relevant forms. PMID- 29419327 TI - Evaluation of principal component analysis-based data-driven respiratory gating for positron emission tomography. AB - OBJECTIVE: Respiratory motion can degrade PET image quality and lead to inaccurate quantification of lesion uptake. Such motion can be mitigated via respiratory gating. Our objective was to evaluate a data-driven gating (DDG) technique that is being developed commercially for clinical PET/CT. METHODS: A data-driven respiratory gating algorithm based on principal component analysis (PCA) was applied to phantom and FDG patient data. An anthropomorphic phantom and a NEMA IEC Body phantom were filled with 18F, placed on a respiratory motion platform, and imaged using a PET/CT scanner. Motion waveforms were measured using an infrared camera [the Real-time Position ManagementTM system (RPM)] and also extracted from the PET data using the DDG algorithm. The waveforms were compared via calculation of Pearson's correlation coefficients. PET data were reconstructed using quiescent period gating (QPG) and compared via measurement of recovery percentage and background variability. RESULTS: Data-driven gating had similar performance to the external gating system, with correlation coefficients in excess of 0.97. Phantom and patient images were visually clearer with improved contrast when QPG was applied as compared to no motion compensation. Recovery coefficients in the phantoms were not significantly different between DDG- and RPM-based QPG, but were significantly higher than those found for no motion compensation (p < 0.05). CONCLUSION: A PCA-based DDG algorithm was evaluated and found to provide a reliable respiratory gating signal in anthropomorphic phantom studies and in example patients. Advances in knowledge: The prototype commercial DDG algorithm may enable reliable respiratory gating in routine clinical PET-CT. PMID- 29419329 TI - Understanding gastroschisis and its clinical management: where are we? AB - INTRODUCTION: Gastroschisis is the commonest developmental defect of the anterior abdominal wall in both developed and developing countries. The past 30 years have seen transformational improvements in outcome due to advances in neonatal intensive care and enhanced integration between the disciplines of maternal fetal medicine, neonatology and pediatric surgery. A review of gastroschisis, which emphasizes its epidemiology, multidisciplinary care strategies and contemporary outcomes is timely. Areas covered: This review discusses the current state of knowledge related to prevalence and causation, and postulated embryopathologic mechanisms contributing to the development of gastroschisis. Using relevant, current literature with an emphasis on high level evidence where it exists, we review modern techniques of prenatal diagnosis, pre and postnatal risk stratification, preferred timing and method of delivery, options for abdominal wall closure, nutritional management, and short and long term clinical and neurodevelopmental follow-up. Expert commentary: This section explores controversies in contemporary management which contribute to practice and cost variation and discusses the benefits of novel nutritional therapies and care standardization that target unnecessary practice variation and improve overall cost-effectiveness of gastroschisis care. The commentary concludes with a review of fertile areas of gastroschisis research, which represent opportunities for knowledge synthesis and further outcome improvement. PMID- 29419328 TI - Brain-focussed ultrasound: what's the "FUS" all about? A review of current and emerging neurological applications. AB - MR-guided focussed ultrasound surgery (MRgFUS) allows for precise non-invasive thermal ablation of target tissues for a wide range of clinical applications. It is an innovative and rapidly expanding technology, which has already established itself as an effective and safe incisionless alternative in the treatment of various soft tissue tumours, with many more research studies underway to extend its therapeutic envelope. The non-invasiveness of the procedure makes FUS particularly attractive in functional neurosurgery, where existing treatment options are not suitable for all patients. Several clinical trials have demonstrated the feasibility and favourable safety profile of MR-guided focused ultrasound surgery in essential tremor, Parkinson's disease and other neurological conditions. This article reviews the existing evidence base for the neurological applications of FUS and the evidence for its emerging roles in the treatment of a range of brain disorders. PMID- 29419330 TI - Organ-based drug delivery. AB - The phenomenal advances in pharmaceutical sciences over the last few decades have led to the development of new therapeutics like peptides, proteins, RNAs, DNAs and highly potent small molecules. Fruitful applications of these therapeutics have been challenged by several anatomical and physiological barriers that limit adequate drug disposition at the site-of-action and by off-target drug distribution to undesired tissues, which together result in the reduced effectiveness and increased side effects of therapeutic agents. As such, the development of drug delivery and targeting systems has been recognised as a cornerstone for future drug development. Research in pharmaceutical sciences is now devoted to tackling delivery challenges through engineering delivery systems that move beyond conventional dosage forms and regimens into state-of-the-art targeted drug delivery tailored toward specific therapeutic needs. Modern drug delivery systems comprise passive and active targeting approaches. While passive targeting relies on the natural course of distribution of drugs or drug carriers in the body, as governed by their physicochemical properties, active targeting often exploits targeting moieties that home preferentially into target tissues. Here, we provide an overview of theories of and approaches to passive and active drug delivery. As the design of drug delivery is dependent on the unique structure of target tissues and organs, we present our discussion in an organ specific manner with the aim to inspire the development of new strategies for curing disease with high accuracy and efficiency. PMID- 29419331 TI - (ICORG 05-03): prospective randomized non-inferiority phase III trial comparing two radiation schedules in malignant spinal cord compression (not proceeding with surgical decompression); the quality of life analysis. AB - BACKGROUND: The optimal primary external beam radiation therapy (EBRT) radiation schedule for malignant epidural spinal cord compression (MSCC) remains to be determined. The ICORG 05-03 trial assessed if a 10 Gy single fraction radiation schedule was not inferior to one with 20 Gray (Gy) in five daily fractions, in terms of functional motor outcome, for the treatment of MSCC in patients not proceeding with surgical decompression. This article reports on two of the secondary endpoints, Quality of life (QoL), assessed according to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0 (EORTC Data Center, Brussels, Belgium) and pain control assessed using a visual analog scale. METHODS: A randomized, parallel group, multicenter phase III trial was conducted by Cancer Trials Ireland (formerly All-Ireland Cooperative Oncology Research Group, ICORG), across five hospital sites in Ireland and Northern Ireland. Patients were randomized to 10 Gy single fraction of EBRT or 20 Gy in five fractions in a 1:1 ratio. Patients with baseline and 5-week follow up QoL data are included in this analysis. FINDINGS: From 2006 to 2014, 112 eligible patients were enrolled for whom 57 were evaluated for this secondary analysis. After adjusting for pre intervention scores, there was no statistically significant difference in post treatment Summary scores (excl. FI and QL), or pain scores between the two RT schedules at 5 weeks and 3 months following EBRT. There was a statistically significant relationship between the pretreatment and post-treatment Summary scores (p = .002) but not between the pre-treatment and post-treatment pain scores. INTERPRETATION: Primary radiotherapy for the treatment of MSCC significantly improves QoL in patients not proceeding with surgical decompression. After adjusting for pre-intervention scores, there was no statistically significant difference between a 10 Gy single fraction radiation schedule and one with 20 Gy in five daily fractions on post-treatment QoL Summary scores. For most patients, an effective treatment with low burden would be desirable. A single fraction schedule should be considered for this group of patients. PMID- 29419332 TI - Alcohol as a Factor in 911 Calls in Denver. AB - BACKGROUND: Excessive alcohol consumption is associated with a substantial number of emergency department visits annually and is responsible for a significant number of lives lost each year in the United States. However, a minimal amount is known about the impact of alcohol on the EMS system. OBJECTIVES: The primary objective was to determine the proportion of 9-1-1 calls in Denver, Colorado in which (1) alcohol was a contributing factor or (2) the individual receiving EMS services had recently ingested alcohol. The secondary objectives were to compare the characteristics of EMS calls and to estimate the associated costs. METHODS: This was a prospective observational cohort study of EMS calls for adults from July 1, 2012, to June 30, 2014. Primary outcomes for the study were alcohol as a contributing factor to the EMS call and recent alcohol consumption by the patient receiving EMS services. Logistic regression was utilized to determine the associations between EMS call characteristics and the outcomes. Cost was estimated using historic data. RESULTS: During the study period, 169,642 EMS calls were completed by the Denver Health Paramedic Division. Of these 71% were medical and 29% were trauma-related. The median age was 45 (interquartile range [IQR] 29-59) years, and 55% were male. 50,383 calls (30%) had alcohol consumption, and 49,165 (29%) had alcohol as a contributing factor. Alcohol related calls were associated with male sex, traumatic injuries including head trauma, emergent response, use of airway adjuncts, cardiac monitoring, glucose measurement, use of restraints, use of spinal precautions, and administration of medications for sedation. Estimated costs to the EMS system due to alcohol intoxication exceeded $14 million dollars over the study period and required in excess of 37 thousand hours of paramedic time. CONCLUSIONS: Compared to 9-1-1 calls that do not involve alcohol, alcohol-related calls are more likely to involve male patients, emergent response, traumatic injuries, advanced monitoring, airway adjuncts, and medications for sedation. This represents a significant burden on the emergency system and society. Further studies are needed to evaluate whether additional interventions such as social services could be used to lessen this burden. PMID- 29419333 TI - An interprofessional initiative aimed at creating a common learning resource for the operating room ward. AB - Every semester, the operating room (OR) ward receives students from different educational programmes. Although interprofessional knowledge is essential for OR teamwork, students have traditionally been prepared in an uniprofessional manner, with no focus on interprofessional learning outcomes. This report describes the work process of an interprofessional initiative undertaken to create a common learning resource aimed at preparing students for OR practice. With a focus on interprofessional learning, shared and profession-specific learning outcomes, which are needed to prepare for practice, were identified by an interprofessional faculty. To avoid timetabling and geographic barriers, learning outcomes and constructed learning activities were packaged into an e-module and delivered on line as an adjunct to existing lectures and workshops. A survey was administered to 4th year medical (n = 42) and 1st year OR nurse students (n = 4) to evaluate their perceptions of the e-module. We found that most learning outcomes from the different syllabuses were common for all professions. The overall response rate of the survey was 59% (27 of 46 students). Eighteen of the 27 responding students had used the learning resource, of which 15 students considered it to be of 'high' or 'very high' value. In summary, this interprofessional initiative resulted in a new common learning resource for the OR, which was used and perceived valuable by a majority of the students. The learning outcomes needed to prepare students from different educational programmes for OR practice are, to a great extent, generic and interprofessional and we thus argue that the interprofessional nature of the faculty was essential for the success of the initiative. PMID- 29419334 TI - Survey of Four Groups of Cumulative Pesticide Residues in 12 Vegetables in 15 Provinces in China. AB - The present study investigated the concentrations of residues of four groups of pesticides in the People's Republic of China: organophosphorus, carbamate, pyrethroid, and triazine pesticides. Twenty-six pesticides were examined using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry in 2,169 samples of 12 typical vegetables collected from 15 provinces in China. The results showed that 908 (41.9%) samples were positive, with 133 (6.1%) samples exceeding the limit legal in China. Leafy vegetables showed higher positive rates than fruits and root vegetables. Organophosphorus, carbamate, pyrethroid, and triazine pesticides were found in 11.8, 7.7, 13.9, and 10.9% of the samples, respectively, which provided important information on current concentrations of cumulative assessment group pesticide residues for vegetables in China. Of the positive samples, a slight violation rate of 1.9% for the organophosphorus pesticide category exceeded China's maximum residue limits. Positive rates for chlorpyrifos in celery, pak-choi, and leeks were higher, but fewer exceeded China's maximum residue limits. PMID- 29419335 TI - Differential Effect of Food Sanitizers on Formation of Viable but Nonculturable Salmonella enterica in Poultry. AB - A method for microscopic enumeration of viable Salmonella enterica in meat samples was developed by using the LIVE/DEAD BacLight kit technology. A two-step centrifugation and wash process was developed to clean the samples from food and chemical impurities that might otherwise interfere with the appropriate staining reactions. The accuracy of the BacLight kit-based viability assessments was confirmed with various validation tests that were conducted by following the manufacturer's instructions. For the biocide challenge tests, chicken parts each bearing around 8.5 log of S. enterica were sprayed with common food sanitizers such as 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), lactic acid (LA), and peracetic acid (PAA). The log reduction (LR) of S. enterica for each test biocide was evaluated by microscopic and conventional culture plate methods. The results show that both LA and PAA treatments generated a greater number of microscopic counts compared with the corresponding plate counts with differences being around half a log. This discrepancy is believed to occur when cells enter a so-called viable but nonculturable (VBNC) state, and to our knowledge, this is the first report documenting the presence of VBNC in PAA- and LA-treated food samples. In contrast, the BacLight-based viable counts were comparable to the culture-based enumerations of all DBDMH-treated samples. Therefore, we concluded that DBDMH treated meat did not contain significant VBNC populations of S. enterica. A detailed description of our spray system, the dye validation, and the treatment reproducibility are also provided in this work. PMID- 29419336 TI - Case report of four siblings in southeast Turkey with a novel RAB3GAP2 splice site mutation: Warburg micro syndrome or Martsolf syndrome? AB - BACKGROUND: Warburg micro syndrome is a very rare autosomal recessive disorder characterized by a mutation in the RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 genes. Warburg Micro syndrome 2 and Martsolf syndrome are clinically overlapping conditions characterized by variable clinical signs counting postnatal growth retardation, cataract, intellectual deficiency, contractures, and central nervous system abnormalities due to RAB3GAP2 gene mutations. The RAB3GAP2 gene encodes a member of the Rab3 protein family, which is involved in regulated exocytosis of neurotransmitters and hormones. CASE PRESENTATION: We describe four siblings from healthy consanguineous Turkish parents with developmental delay, congenital cataract, and speech delay. In this study, we performed whole exom sequencing (WES) in a index patient. WES analyses in proposita showed a homozygous c.1998 + 1 G > A mutation in RAB3GAP2 gene. After the Sanger confirmation, the same mutation was detected in the other three siblings. CONCLUSION: The four siblings had a novel splice site mutation in RAB3GAP2. This report compares the symptoms and features of the our patients with clinical summary of Warburg Micro syndrome 2 and Martsolf syndrome. Further reports will make possible knowing of the genetic and clinical backgrounds of this orphan diseases. Abbreviation: MRI: Magnetic resonance imaging. PMID- 29419337 TI - Multidimensional Improvements in Health Following Hatha Yoga for Individuals with Diabetic Peripheral Neuropathy. AB - The purpose of this study was to understand the lived experience of ten individuals with diabetic peripheral neuropathy (DPN) who completed an 8-week Hatha Yoga trial. The International Classification of Function, Disability, and Health (ICF) provided the framework for this study. Two focus groups were conducted following a twice-weekly, 60-minute yoga intervention that was designed for people with DPN. Interpretative phenomenological analysis was employed to analyze the data. Themes in the data emerged related to improvements in body functions, specifically neuromuscular and movement-based function and sensory functions, as well as stress management and sleep improvement via breathwork, and social support was an essential environmental factor. These data support the bidirectionality of the ICF and demonstrate that in individuals with DPN, yoga may affect health holistically by improving body functions, activities, participation, and environmental factors. Yoga may be a tool to improve general well-being in individuals with DPN. A larger, randomized trial should be conducted to extend the findings from the present trial. PMID- 29419338 TI - Bridging Body and Mind: Considerations for Trauma-Informed Yoga. AB - Individuals who suffer from trauma-related symptoms are a unique population that could benefit from the mind-body practice of yoga-or have their symptoms reactivated by it, depending on the type of yoga. Trauma-informed yoga (TIY), that is, yoga adapted to the unique needs of individuals working to overcome trauma, may ameliorate symptoms by creating a safe, tailored practice for students to learn how to respond, rather than react, to symptoms and circumstances. Yoga not thus adapted, on the other hand, may increase reactivity and activate symptoms such as hyperarousal or dissociation. This article reports on expert input about adapting yoga for individuals with trauma, with special considerations for military populations. Eleven experts, recruited based on literature review and referrals, were interviewed in person or via telephone and asked seven questions about trauma-informed yoga. Verbatim transcripts were subjected to open-coding thematic analysis and a priori themes. Findings revealed that TIY needs to emphasize beneficial practices (e.g., diaphragmatic breath and restorative postures), consider contraindications (e.g., avoiding sequences that overly engage the sympathetic nervous system), adapt to limitations and challenges for teaching in unconventional settings (e.g., prisons, VA hospitals), and provide specialized training and preparation (e.g., specialized TIY certifications, self-care of instructors/therapists, adaptions for student needs). TIY for veterans must additionally consider gender- and culture-related barriers, differing relationships to pain and injury, and medication as a barrier to practice. PMID- 29419339 TI - Emphysema induced by elastase alters the mRNA relative levels from DNA repair genes in acute lung injury in response to sepsis induced by lipopolysaccharide administration in Wistar rats. AB - : Purpose/Aim of the study: Patients suffering from chronic obstructive pulmonary disease (COPD) in association with acute respiratory distress syndrome (ARDS) present oxidative stress in lung cells, with production of free radicals and DNA lesions in pulmonary and adjacent cells. Once the DNA molecule is damaged, a set of enzymatic mechanisms are trigged to preserve genetic code integrity and cellular homeostasis. These enzymatic mechanisms include the base and the nucleotide excision repair pathways, as well as telomere regulation. Thus, the aim of this work was to evaluate the mRNA levels from APEX1, ERCC2, TP53, and TRF2 genes in lung tissue from Wistar rats affected by acute lung injury in response to sepsis and emphysema. MATERIALS AND METHODS: Adult male Wistar rats were randomized into 4 groups (n = 6, for each group): control, emphysema, sepsis, and emphysema with sepsis. Pulmonary emphysema was induced by intratracheal instillation of elastase (12 IU/animal) and sepsis induced by intraperitoneal Escherichia coli lipopolysaccharide (LPS) injection (10 mg/kg). Lungs were removed, and samples were withdrawn for histological analysis and total RNA extraction, cDNA synthesis, and mRNA level evaluation by real time quantitative polymerase chain reaction. RESULTS: Data show acute lung injury by LPS and emphysema by elastase and that APEX1, ERCC2, TP53, and TRF2 mRNA levels are increased significantly (p < 0.01) in emphysema with sepsis group. CONCLUSION: Our results suggest that alteration in mRNA levels from DNA repair and genomic stability could be part of cell response to acute lung injury in response to emphysema and sepsis. PMID- 29419340 TI - Alpha-1-antitrypsin: a novel predictor for long-term recovery of chronic disorder of consciousness. AB - BACKGROUND: The aim of this manuscript was to explore the molecular basis and identify novel biomarkers for the diagnosis and prognosis of patients with chronic disorder of consciousness. METHODS: A coupled isobaric tag for relative and absolute quantitation-based approach was used to screen differentially expressed proteins (DEPs) between patients with chronic disorder of consciousness and healthy individuals. Candidate proteins were identified and measured. The Coma Recovery Scale-Revised (CRS-R) score was used to quantify the severity, and long-term recovery was assessed by Glasgow Outcome Scale (GOS). RESULTS: Between patients and controls, a total of 77 DEPs were identified. Based on the DEPs, a network containing 50 nodes and 207 edges was built, and alpha-1-antitrypsin was marked as the hub protein. The results indicated that alpha-1-antitrypsin correlated with the CRS-R score with a correlation coefficient of 0.631, and an outcome at 12 months (8.5 +/- 2.1 ng/ml in patients with GOS 1-2 vs. 6.8 +/- 1.6 ng/ml in those with GOS 3-5, p = 0.002). CONCLUSIONS: The data confirm the diagnostic and prognostic potential of alpha-1-antitrypsin in chronic disorder of consciousness, which may contribute to the development of novel therapeutic agents. PMID- 29419341 TI - Comparing the Validity of Self-Report and Urinalysis for Substance Use among Former Inmates in the Northeastern United States. AB - BACKGROUND: Problems with self-reported drug use include difficulties with recall and recognition as well as the desire to respond to questions in a socially desirable manner. Various methods have been developed to improve and/or validate estimates based on direct questioning of individuals regarding their substance use. For this study, we were interested in validating self-reported use of: 1) tobacco, 2) marijuana, and 3) other substances (i.e., heroin, cocaine, opiates, oxycodone, benzodiazepines, methamphetamine, phencyclidine, and barbiturates) employing urinalysis among inmates who participated in a randomized controlled trial of a smoking abstinence intervention in a tobacco-free prison located in the northeastern United States. METHODS: Two-hundred and seven men and women with a mean age of 34.9 (standard deviation = 9.0) completed questions regarding their substance use on a 7-day Timeline Follow-Back and provided urine specimens three weeks following prison release. RESULTS: Self-reported tobacco and marijuana use were highly consistent with urine drug testing in terms of overall agreement and Kappa (93.7% and.804 for tobacco, respectively; and 90.3% and.804 for marijuana, respectively); however, consistency was much lower for other drug use grouped together (62.7% and.270). DISCUSSION: Although some former inmates may not accurately report substance use, our findings indicate that they are in the minority, suggesting that self-report is valid for tobacco and marijuana use but much less so for other drugs grouped together. Future research should be conducted with a larger and more diverse sample of former inmates to establish the generalizability of our findings from this study. PMID- 29419342 TI - A shot taxonomy in the era of tracking data in professional tennis. AB - Shots are an essential part of the language of tennis yet little is known about the distinct types of shots in the professional game. In this study, we build a taxonomy of shots for elite tennis players using tracking data from multiple years of men's and women's matches at the Australian Open. Our taxonomy is constructed using model-based multi-stage functional data clustering, an unsupervised machine learning approach. Among 270,023 men's and 178,136 women's shots, we found 13 distinct types of serves to both the Ad and Deuce court for male players and 17 and 15 types to the Ad and Deuce for female players. More variety was found among serve returns and rally shots compared to the serve; with less variety on the backhand than forehand. There was also more overlap in the physical characteristics of groundstroke shots between male and female players than on serve. Shot type was strongly associated with winning points and shots in the highest speed and lowest net clearance categories tended to be the most effective. This data-driven dictionary of shots provides a framework for analysis of elite player performance, characterizing playing style, and designing more representative practice. PMID- 29419343 TI - Telemonitoring in subjects with newly diagnosed heart failure with reduced ejection fraction: From clinical research to everyday practice. AB - Introduction Heart failure is increasingly common, and characterised by frequent admissions to hospital. To try and reduce the risk of hospitalisation, techniques such as telemonitoring (TM) may have a role. We wanted to determine if TM in patients with newly diagnosed heart failure and ejection fraction <40% reduces the risk of readmission or death from any cause in a 'real-world' setting. Methods This is a retrospective study of 124 patients (78.2% male; 68.6 +/- 12.6 years) who underwent TM and 345 patients (68.5% male; 70.2 +/- 10.7 years) who underwent the usual care (UC). The TM group were assessed daily by body weight, blood pressure and heart rate using electronic devices with automatic transfer of data to an online database. Follow-up was 12 months. Results Death from any cause occurred in 8.1% of the TM group and 19% of the UC group ( p = 0.002). There was no difference between the two groups in all-cause hospitalisation, either in the number of subjects hospitalised ( p = 0.7) or in the number of admissions per patient ( p = 0.6). There was no difference in the number of heart-failure related readmissions per person between the two groups ( p = 0.5), but the number of days in hospital per person was higher in the UC group ( p = 0.03). Also, there were a significantly greater number of days alive and out of hospital for the patients in the TM group compared with the UC group ( p = 0.0001). Discussion TM is associated with lower any-cause mortality and also has the potential to reduce the number of days lost to hospitalisation and death. PMID- 29419346 TI - Increasing Inequality in Physical Activity Among Minnesota Secondary Schools, 2001-2010. AB - BACKGROUND: Two Healthy People 2020 goals are to increase physical activity (PA) and to reduce disparities in PA. We explored whether PA at the school level changed over time in Minnesota schools and whether differences existed by demographic and socioeconomic factors. METHODS: We examine self-reported PA (n = 276,089 students; N = 276 schools) for 2001-2010 from the Minnesota Student Survey linked to school demographic data from the National Center for Education Statistics and the Rural-Urban Commuting Area Codes. We conducted analyses at the school level using multivariable linear regression with cluster-robust recommendation errors. RESULTS: Overall, students who met PA recommendations increased from 59.8% in 2001 to 66.3% in 2010 (P < .001). Large gains in PA occurred at schools with fewer racial/ethnic minority students (0%-60.1% in 2001 to 67.5% in 2010, P < .001), whereas gains in PA were comparatively small at schools with a high proportion of racial/ethnic minority students in 2001 (30% 59.2% in 2001 to 62.7% in 2010). CONCLUSIONS: We found increasing inequalities in school-level PA by racial/ethnic characteristics of their schools and communities among secondary school students. Future research should monitor patterns of PA over time and explore mechanisms for patterns of inequality. PMID- 29419345 TI - Validation of the Expanded Versions of the Adult ADHD Self-Report Scale v1.1 Symptom Checklist and the Adult ADHD Investigator Symptom Rating Scale. AB - OBJECTIVE: The aim of this study is to validate the Adult ADHD Self-Report Scale (ASRS) and Adult ADHD Investigator Symptom Rating Scale (AISRS) expanded versions, including executive function deficits (EFDs) and emotional dyscontrol (EC) items, and to present ASRS and AISRS pilot normative data. METHOD: Two patient samples (referred and primary care physician [PCP] controls) were pooled together for these analyses. RESULTS: Final analysis included 297 respondents, 171 with adult ADHD. Cronbach's alphas were high for all sections of the scales. Examining histograms of ASRS 31-item and AISRS 18-item total scores for ADHD controls, 95% cutoff scores were 70 and 23, respectively; histograms for pilot normative sample suggest cutoffs of 82 and 26, respectively. CONCLUSION: (a) ASRS and AISRS-expanded versions have high validity in assessment of core 18 adult ADHD Diagnostic and Statistical Manual of Mental Disorders ( DSM) symptoms and EFD and EC symptoms. (b) ASRS (31-item) scores 70 to 82 and AISRS (18-item) scores from 23 to 26 suggest a high likelihood of adult ADHD. PMID- 29419344 TI - Mitochondrial autophagosomes as a mechanism of drug resistance in breast carcinoma. AB - We have previously described the process by which mitochondria donate their membranes for the formation of autophagosomes, and in this study we show that the same process could be involved in drug sequestration and exocytosis resulting in multidrug-resistant cancerous cells. We examine the implications of mitochondrial vesicle formation of mitoautophagosomes (MAPS) in response to the cytotoxic drug MKT-077, which targets mortalin, in a drug-resistant breast carcinoma cell line overexpressing P-glycoprotein (P-gp). The breast cancer cell line MCF-7Adr is derived from MCF-7, but differs from its ancestral line in tolerance of MKT-077 induced mitochondrial toxicity. Our ultrastructural observations suggest that autophagy in the MCF-7Adr cells entails regional sequestration of MKT077 in multilamellar LC3-labeled MAPS, which then separate from their mitochondria, and fuse with or engulf each other. MAPS appeared to be migrating through the cytoplasm and fusing with the plasma membrane, thus carrying out exocytotic secretion. This mechanism, which seems ineffective in the ancestral cell line, provides a resistance mechanism for MKT-077 by enhancing the efflux process of the cells. After 8 hr of MKT-077 exposure, a fraction of the resistant cells appeared viable and contained larger number of smaller sized mitochondria. Mitoautophagosomes, therefore, provide a potentially novel model for multidrug resistance in cancerous cells and may contribute to the P-gp efflux process. PMID- 29419347 TI - The prognosis of pulmonary arterial hypertension associated with primary Sjogren's syndrome: a cohort study. AB - Pulmonary arterial hypertension (PAH) is a rare and severe complication of primary Sjogren's syndrome (pSS). Cohort studies indicate that the underlying diseases of PAH associated with connective tissue disease (CTD-PAH) in Asian countries are different from that in the United States and in Europe. This study investigated the clinical characteristics, survival, and prognostic factors of pSS-PAH in Chinese patients. We enrolled 29 patients with pSS-PAH who visited our referral center during August 2007 and May 2015. PAH was confirmed by right heart catheterization (RHC). Baseline demographic data, clinical manifestations, laboratory tests, autoantibody results, hemodynamics data, and treatment regimens were analyzed. All patients were followed up at the Department of Rheumatology, Peking Union Medical College Hospital (PUMCH) every three to six months. All patients were female. Mean age of pSS onset was 34.4 +/- 11.1 years. Mean age of PAH diagnosed by RHC was 40.6 +/- 9.0 years. There was no significant difference in age, disease duration, and hemodynamic findings between the survivors and the non-survivors in this cohort. The overall one-, three-, and five-year survival rates were 80.2%, 74.8%, and 67.4%, respectively. Prognostic factors of mortality were time between pSS onset and PAH onset (HR 1.102, 95% CI 1.017-1.185, p = 0.018) and cardiac index < 2 l/min/m2 (HR 5.497, 95% CI 1.063-28.434, p = 0.042). In contrast, the use of immunosuppressants (HR 0.110, 95% CI 0.024-0.495, p = 0.004) was related to better survival. This study demonstrates that the predictors of mortality in patients with pSS-PAH include delayed onset of PAH in pSS and worse cardiac function. Immunosuppressants can improve the prognosis of pSS-PAH. PMID- 29419348 TI - A pilot study on the reproductive risks of maternal exposure to magnetic fields from electronic article surveillance systems. AB - PURPOSE: We investigated the feasibility of a large-scale epidemiological study on reproductive effects of intermediate frequency (IF) magnetic field (MF) exposure among cashiers working near electronic article surveillance (EAS) systems. MATERIALS AND METHODS: The study cohort included 4157 women who had worked as cashiers in supermarkets with EAS devices (considered as exposed) or grocery stores without EAS devices (considered as unexposed) between 2008 and 2015. 536 births and 38 miscarriages occurred among these women during the study period, based on information from nationwide health registries. Measurements were also performed to characterize the MF exposure of cashiers. RESULTS: Cashiers were found to be exposed to 8.2 MHz MFs only when passing by the gates at short distance. Static fields of about 0.1 mT were observed at cashier's seat. Extremely low frequency MFs were higher at stores without EAS devices. No differences on the risk of miscarriage, reduced birth weight or preterm birth were observed between cashiers in different store types. CONCLUSIONS: Any further studies should attempt to include study subjects working near EAS systems that produce stronger IF MFs at kHz frequencies. Exposure to ELF MFs should be assessed as a possible confounding factor. PMID- 29419349 TI - Autophagy precedes apoptosis among at risk cerebellar Purkinje cells in the shaker mutant rat: an ultrastructural study. AB - Cerebellar Purkinje cell (PC) death has been shown to occur in essential tremor, ataxia, and many other neurodegenerative diseases in humans. Shaker mutant rats have an X-linked recessive mutation that causes hereditary degeneration of "at risk" cerebellar PCs. This defect can occur in the restricted anterior (ADC) and posterior (PDC) vermal degeneration compartments postnatally within 7 to 14 weeks of age as a natural phenotype in the shaker mutant rat. "Secure" PCs persist in a flocculonodular survival compartment (FNSC). Because we have previously shown that "at risk" PCs die due to apoptosis in the shaker mutant rat, we hypothesized that the PC death observed in the hereditary shaker mutant rat may be due to the activation of more than one type of death pathway. This ultrastructural investigation suggests that "at risk" PCs die due to apoptosis as a result of autophagic activation. Moreover, our data suggest that both apoptosis and autophagy must be simultaneously inhibited to rescue "at risk" PCs from death. PMID- 29419350 TI - Swim exercise training ameliorates hepatocyte ultrastructural alterations in rats fed on a high fat and sugar diet. AB - Excessive consumption of carbohydrate and fat increases the risk of liver disease. We hypothesized that swim exercise can protect hepatocytes from ultra structural damage induced by high cholesterol and fructose diets (HCFD). Rats were either fed with HCFD (model group) or a standard laboratory chow (control group) for 15 weeks before being sacrificed. Swim exercise trained rats started the treatment from the 11th week until the sacrifice day, end of week 15. Blood samples were assayed for biomarkers of liver injury and adiponectin. The harvested liver tissues were examined using transmission electron microscopy (TEM). TEM images revealed substantial damage and accumulation of lipid droplets (steatosis) in the hepatocytes of the model group that was inhibited by swim exercise. In addition, HCFD significantly (p < 0.0005) increased insulin resistance index (HOMA-IR), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), which were effectively (p < 0.02) decreased by a swim exercise to levels comparable to control group. Whereas, swim exercise increased adiponectin levels in HCFD group (p < 0.03). These results show that HCFD-induced hepatic injury is ameliorated by swim training exercise possibly via restoration of a normal blood sugar and lipid, induction of adiponectin and inhibition of inflammatory, and liver injury biomarkers. PMID- 29419351 TI - Ultrastructure of colorectal adenocarcinoma and peritumoral tissue in untreated patients. AB - In this study, we describe, compare, and discuss several subcellular alterations found in Colorectal Adenocarcinoma and peritumoral tissue using transmission electron microscopy, morphometry, and statistical analysis. Tissue samples from anterior resections were collected from patients diagnosed with Colorectal Adenocarcinoma in the University Hospital of Caracas. Samples were processed according to the typical protocol for their observation through transmission electron microscopy. The resulting images were analyzed using specialized software for the collection of morphometric data. Several anomalies were common for both tissues, including but not limited to, rough endoplasmic reticulum and mitochondrial swelling, nuclear invagination, nuclear enlargement, and cellular swelling. In general, alterations within the tumor were more frequent and intense. Extensive organellar degradation and other evidences of cellular damage seemed to extend past the edge of the tumor into the peritumoral tissue. There seems to be a clear process of lateral cancerization present in the peritumoral area. The tissue layers composed of smooth muscle cells, probably due to their structural features, may allow greater diffusion of harmful substances produced by the tumor. A more in-depth analysis of peritumoral tissue considering organellar damage and morphometric data may provide relevant insight about the changing microenvironment promoted by the close proximity of a tumor. PMID- 29419352 TI - Betel Quid Chewing, Personality and Mood: Betel Quid Chewing Associated with Low Extraversion and Negative Mood. AB - BACKGROUND: Betel quid (BQ), chewed by about 600 million people worldwide, is one of the most widely used addictive substances. Little is known about psychological factors in BQ chewers. OBJECTIVES: The present study was the first attempt to explore the relationships between BQ chewing, personality, and mood. METHODS: A survey was conducted with a purposive sample to assess BQ chewing habits in four subgroups: BQ-only users, BQ users who smoke and/or drink, smokers and/or drinkers only, and substance nonusers. A total of 494 participants were recruited from the civilian, non-institutionalized population in Taiwan. Habitual consumption of BQ, smoking and drinking; socio-demographic variables; extraversion; and mood (tension, depression, anger, vigor, fatigue, confusion, and self-esteem). All BQ chewers were evaluated on BQ dependence domains using DSM IV and ICD-10 criteria. RESULTS: The 6-month BQ dependency rate among BQ chewers, defined by either DSM-IV or ICD-10 criteria, ranged from 42.9 to 45.6%. BQ-only users had significantly lower scores on extraversion than substance nonusers. BQ-only users had statistically significant higher scores on confusion and total mood than substance nonusers. BQ-only users had significantly higher scores on fatigue, anger, tension, and depression, than substance nonusers, BQ users who smoke and/or drink, and smokers and/or drinkers only. The number of BQ dependence domains correlated significantly negatively with total mood scores. Conclusions/Importance: The results supported the two hypotheses: (a) BQ chewing is associated with low extraversion; and (b) BQ chewing is related to negative mood. PMID- 29419353 TI - Characteristics of Suicide Attempters and Ideators in a Clinical Sample of Substance Users. AB - There is little research to distinguish those who attempt suicide and those who only consider suicide, and the role that substance use plays in this progression. We aim to describe clinical correlates of suicide attempters versus ideators in substance users. We examined characteristics of substance users (N = 185) that had either a suicide attempt within the last 6 months (n = 94) or were suicide ideators (n = 91). Suicide attempters displayed significant different clinical profiles to that of non-attemptors. Relative to ideators, attempters had greater scores on impulsivity, the brief psychiatric scale and more likely to be female and a recent psychostimulant user. Logistic regression revealed that male gender was associated with a decreased odds of a previous suicide attempt (OR = 0.37, p < 0.05) and greater impulsivity scores were associated with increased odds of an attempt (OR = 1.15, p < 0.05), although entering interaction terms diminished the role of impulsivity and revealed a significant interaction of alcohol use x depression. While impulsivity was a significant predictor of suicide attempt relative to depression or alcohol use alone, this reduced when considering interactions between psychological characteristics and substance use, whereby the effect of alcohol use on the likelihood of a recent suicide attempt varied at different levels of depression. PMID- 29419354 TI - Blocking incidental frustration during bargaining. AB - The current study examined the effects of an intervention aimed at blocking the transfer of frustration from a previous experience (i.e. recall task) to a subsequent and unrelated task (i.e. ultimatum bargaining task). Participants who went through the intervention were more likely to accept unfair offers in the ultimatum bargaining task than those who did not go through the intervention. These results show that participants who were blocked from transferring their feelings of frustration from the recall task to the subsequent bargaining task (no-transfer condition) more likely accepted unfair offers than those who inadvertently transferred their feelings of frustration (transfer condition). The effect of conditions on accept-reject decisions in the ultimatum bargaining was mediated by reported feelings of frustration. PMID- 29419355 TI - The Impact of Agentic and Communal Exercise Messages on Individuals' Exercise Class Attitudes, Self-Efficacy Beliefs, and Intention to Attend. AB - We tested the effects of advertisements about a fictitious exercise class-derived using the theoretical constructs of agency and communion-on recipients' perceptions about, and interest in, the class. The final sample consisted of 150 adults (Mage = 44.69, SD = 15.83). Results revealed that participants who received a communal-oriented message reported significantly greater exercise task self-efficacy and more positive affective attitudes relative to those who received an agentic-oriented message. Communal (relative to agentic) messages were also indirectly responsible for greater intentions to attend the class, via more positive self-efficacy beliefs and affective attitudes. These findings were obtained despite the use of another manipulation to orient participants to either agency or communion goals. The results indicate that the primacy of communion over agency for message recipients may extend to exercise settings and may occur irrespective of whether participants are situationally oriented toward agency or communion. PMID- 29419356 TI - Developmental differences in approaches to nonsymbolic comparison tasks. AB - Nonsymbolic comparison tasks are widely used to measure children's and adults' approximate number system (ANS) acuity. Recent evidence has demonstrated that task performance can be influenced by changes to the visual characteristics of the stimuli, leading some researchers to suggest it is unlikely that an ANS exists that can extract number information independently of the visual characteristics of the arrays. Here, we analysed 124 children's and 120 adults' dot comparison accuracy scores from three separate studies to investigate individual and developmental differences in how numerical and visual information contribute to nonsymbolic numerosity judgements. We found that, in contrast to adults, the majority of children did not use numerical information over and above visual cue information to compare quantities. This finding was consistent across different studies. The results have implications for research on the relationship between dot comparison performance and formal mathematics achievement. Specifically, if most children's performance on dot comparison tasks can be accounted for without the involvement of numerical information, it seems unlikely that observed correlations with mathematics achievement stem from ANS acuity alone. PMID- 29419357 TI - HIV and syphilis epidemic among MSM and non-MSM aged 50 and above in Shanghai, China: A yearly cross-sectional study, 2008-2014. AB - The magnitude of the HIV and syphilis epidemic among Chinese men ages 50 and older is unclear. In this study, we aimed to characterise and compare the prevalence of HIV and syphilis infections; linkage to care among those infected with HIV; and the geographic distribution of the two epidemics among elderly men who have sex with men (MSM) and non-MSM in Shanghai, China. This cross-sectional study involved 12,910 men ages 50 and above who participated in the HIV voluntary and counselling testing programme each year from 2008 to 2014. HIV prevalence among MSM in our sample ranged between 4.9% and 15.4%, while syphilis frequency among non-MSM decreased from 26.0% to 18.7%. Further, in 2014, MSM participants had a higher HIV prevalence than non-MSM (4.9% vs 1.8%), whereas syphilis was higher in older non-MSM compared to MSM (18.7% vs 12.4%). Among those infected with HIV, 121/211 (53.75%) of participants were linked to HIV treatment, where the linkage rate was comparable to that in Kunming [Zhao, S., Zhao, G., Zhang, W., liao, B., Chu C., Wang J., & Li, L. (2015). Compare the difference of efficiency between voluntary counseling testing and provider-initiated testing counseling for identifying HIV/AIDS in Kunming. Chinese Journal of AIDS & STD, 21(7), 623-625]. The high burden of HIV and syphilis among men ages 50 and older in Shanghai, China highlights the need to target older Chinese men, both MSM and non-MSM, with prevention efforts. PMID- 29419358 TI - 'Hold on' (Bambelela)! Lyrical interpretations of participation in an HIV prevention clinical trial. AB - During a five-day workshop, former clinical trial participants and local musicians wrote the lyrics and recorded a song about an HIV prevention trial. Born of concerns about misconceptions regarding experimental drug trials, the aim was to engender engagement with medical researchers and open dialogue about the risks and benefits of trial participation. Composing lyrics that highlighted their credibility as communicators of medical scientific knowledge and their selfless sacrifice to stem the transmission of HIV, women performed their social positioning and cultural authority in contrast to men as well as other women not part of the trial. While involvement in HIV prevention initiatives often attracts stigma, scorn and criticism, the song's lyrics highlighted women's new-found identities as heroines searching for a solution to the spread of HIV, challenging these stereotypes. Methodologically, the paper describes a novel approach that uses artistic expression for public engagement with biomedical research. PMID- 29419359 TI - Minimising failure in critical lower limb ischaemia intervention: Adjuvant capillary bed recruitment is the missed opportunity. AB - Critical limb ischaemia is the end stage of peripheral arterial disease before limb loss. Contemporary interventions to restore blood flow have high morbidity and mortality and fail to provide sustained restoration of peripheral circulation. Cell-based therapies designed to promote neovascularisation or angiogenesis have been shown in trials to be safe but clinically ineffective. Notwithstanding endless research in the area, no headway has been made in identifying a successful therapy designed specifically to target muscle disease in critical lower limb ischaemia. Thus, the quest to find an effective, lasting solution for critical lower limb ischaemia continues and requires more innovative therapeutic tactics. Our aim is to highlight the crucially interlinked role of the capillary bed, skeletal muscle mass and mitochondria in critical lower limb ischaemia patients and to identify novel therapeutic mechanisms that the vascular interventionalist can add to their armamentarium. PMID- 29419360 TI - The prevalence of restless legs syndrome and its relationship with demographic characteristics and medical disorders in postmenopausal Iranian women. AB - This study was conducted to evaluate the prevalence of restless legs syndrome (RLS) and its relationship with demographic factors and medical disorders on 980 postmenopausal women. Data was gathered using a demographic questionnaire and the International Restless Legs Syndrome Scale. The prevalence of RLS was 16.02% (157/980). Women with poor economic status were 3.37 and 2.33 times more likely to have RLS than women with a good economic situation and moderate economic status (CI:2.041-5.579, P <= 0.0001) and (CI: 1.540-3.551, P <= 0.0001) respectively. The risk of RLS was 64% greater in women who smoked than in non smokers. Women with history of hypertension, diabetes and anemia were 2.82, 2.09 and 2.19 times, respectively, more likely to have RLS than those without (P < 0.001). Also women with higher body mass index were more likely to have RLS and women taking hormone replacement therapy were less likely to have RLS. The prevalence of RLS among postmenopausal Iranian women is quite high and there is a relationship between RLS and factors such as age at menopause, education level, a history of smoking, hypertension, anemia and diabetes. PMID- 29419361 TI - Mental health literacy, stigma, and help-seeking behaviors among male college students. AB - OBJECTIVE: Mental health literacy (MHL) is low in college-aged men potentially resulting in impaired mental wellbeing. This study assessed MHL, psychosocial determinants, and help-seeking behaviors among male university students. PARTICIPANTS: Male undergraduate and graduate students were surveyed in Spring 2017 (n = 1,242) at a large southeastern university in the United States. METHODS: Preexisting validated scales for MHL, psychosocial determinants, and help-seeking intention were used in measurement and demographic variables were collected. T-tests and one-way ANOVA were performed to measure differences between groups. RESULTS: Participants showed low scores for all constructs with statistically significant differences between undergraduate and graduate students, as well as between races and major classifications. Undergraduate men had moderate MHL and low intentions to seek professional care. CONCLUSIONS: Interventions focusing on increasing mental health knowledge and improving beliefs can improve MHL among male college students. Further, interventions should be tailored for racial groups and major classifications. PMID- 29419362 TI - Effectiveness of self-management program on arthritis symptoms among older women: A randomized controlled trial study. AB - We aimed to determine the effectiveness of a self-management program amongst older women with rheumatoid arthritis. The intervention group (n = 40) received a six-week arthritis self-management program. Assessments were recorded prior to and after the program using a demographic questionnaire, Visual Analogue Scale, Arthritis Self-Efficacy Scale, and self- reported questions regarding mobility. Significant improvements in self-efficacy for functional ability and pain management were found in the intervention group compared to those before the intervention and the control group. Our trial indicates that the program used in conjunction with exercise interventions for aged patients may lead to benefits perceived self-efficacy. PMID- 29419363 TI - Longitudinal predictors of cigarette use among students from 24 Texas colleges. AB - OBJECTIVE: The purpose of this study is to examine differences between current and non-current cigarette users, focusing on sociodemographic factors, non cigarette tobacco product use, parental and friend use, and alcohol and marijuana use; and to identify predictors of cigarette use sixmonths later. PARTICIPANTS: Participants included young adults (n = 4,296) from 24 Texas colleges, participating in a young adult cohort study, beginning in fall 2014. METHODS: Mixed effects logistic regressions were conducted accounting for school-level variability. RESULTS: Cigarette users were older, more likely to report use of non-cigarette tobacco products and peer use of cigarettes than non-current users. Wave 1 cigarette and non-cigarette tobacco product use, marijuana use and binge drinking, and peer use all uniquely predicted cigarette use at wave 2. CONCLUSIONS: Colleges need prevention programs targeting multiple tobacco products, because non-cigarette tobacco use and other risky behaviors appear to be independent risk factors for cigarette use in young adults. PMID- 29419364 TI - Perspectives and Insights from Vietnamese American Mental Health Professionals on How to Culturally Tailor a Vietnamese Dementia Caregiving Program. AB - OBJECTIVE: Little is known about dementia and caregiving among the rapidly growing Vietnamese American population. This qualitative study elicited insights on culturally tailoring an intervention to address mental health needs in Vietnamese American dementia caregivers from Vietnamese American mental health professionals. METHODS: Eight Vietnamese American mental health professionals were interviewed to explore: experiences working with and needs of the community; Vietnamese attitudes toward treatment; and acculturation in Vietnamese caregiving. Participants provided recommendations on tailoring a program for Vietnamese dementia caregivers. Content analysis of their responses was conducted. RESULTS: Themes included: a) caregivers' unique needs and experiences; b) different waves of immigration and acculturation levels affect views on mental health, treatment, and caregiving; c); traditions and beliefs on caregiving; d) mental health, help-seeking and health services; e) how to culturally tailor a program for Vietnamese dementia caregivers; and f) cultural acceptance of the program. CONCLUSIONS: An intervention to reduce stress and depression among Vietnamese American dementia caregivers should recognize the special risks of the experiences of war and immigration of the caregivers as well as the pressure of the expectations of the Vietnamese culture on family care. For the program to be acceptable and effective, it needs to consider all aspects of caregivers' health, and incorporate Vietnamese cultural values/beliefs. CLINICAL IMPLICATIONS: A successful Vietnamese dementia caregiver intervention should include traditional Vietnamese values/beliefs, holistic experiences, spirituality, and background/immigration experiences. Evidence-based programs may be used with this population if they are culturally tailored. PMID- 29419366 TI - Optimising collaboration in science and clinical practice. PMID- 29419365 TI - Meek micrografting history, indications, technique, physiology and experience: a review article. AB - AIMS: Traumatic loss of skin, particularly in major burns, requires skin grafting to repair the tissue. For a large burn, where donor sites are limited, the skin graft may need to be expanded. In addition, rapid wound closure is a large factor in successful recovery and is usually achieved by debridement and skin grafting. Micrografting was introduced by Meek and involved dividing the skin into small pieces, allowing for up to a tenfold skin expansion. METHODS: We conducted a review of the literature, searched via Medline, Pubmed and Embase (from 1958 to June 2017), searching to identify studies and reports of micrografting. We searched using the Medical Subject Headings (MeSH) 'micrograft', 'micrograft technique', 'Meek', 'Meek technique', 'Parker Cicero', 'major burn treatment' and 'mesh skin graft'. RESULTS: We analysed 24 articles in which the description and modifications presented by the micrograft technique were presented, along with evidence that supports or rejects its use. The consensus was for the use of micrografting in burns of >30% total body surface area (TBSA). On poor wound beds, the evaluation of re-epithelialisation had greater success due to low metabolic demands and greater skin coverage compared with control groups (p<0.005). Comparing the 'mesh' with 'Meek' group, the micrograft group had fewer surgeries (10 versus 19.75), shorter average length of hospital stay (51 days versus 120.5 days; p<0.05). CONCLUSIONS: Micrografting can be used where there is poor bed vascularity (such as in patients with diabetes), with higher success due to low metabolic demand. This is recommended for major burns, >30% TBSA, with inadequate donor sites and comorbidities, such as diabetes. However, disadvantages include a 'polka dot' appearance on healing and the fact the initial surgeries, creating the micrograft squares, are labour-intensive. PMID- 29419367 TI - Biological effects of amniotic membrane on diabetic foot wounds: a systematic review. AB - OBJECTIVE: The amniotic membrane has biological properties that are beneficial to the wound healing process of diabetic foot ulcers (DFU). Our aim is to analyse the scientific evidence found in literature on the use of the amniotic membrane to stimulate DFU healing. METHOD: A systematic review of amniotic membrane's influence was undertaken, using the search terms 'placenta' 'diabetic foot' 'amnion' and biological dressing', assessing the outcomes 'wound healing' and 'wound healing time', in DFU. Following the inclusion and exclusion criteria, randomised controlled trials (RCT) were identified, and the risk of bias was analysed according to the Cochrane risk of bias tool. We conducted a meta analysis of the two outcomes to evaluate the level of evidence. RESULTS: We identified six clinical trials, with a total of 331 patients. The most common risks of bias in the studies were selection, attrition, and detection biases. From the meta-analysis, although the result difference of the intervention group (amnion) in relation to the control group was not statistically significant, we found that wound healing in the group treated with amniotic membrane occurs 2.32 times more often and is 32 days faster in comparison with the group that used conventional dressings. CONCLUSION: There is no statistical evidence to support the effectiveness of amniotic membrane in comparison with other conventional dressings. However, there is a clear tendency for the use of amniotic membrane treatment to result in a larger number of DFUs healing at a quicker rate. PMID- 29419368 TI - A histological analysis of chronic wounds treated with negative pressure wound therapy to aid healing: a case series. AB - OBJECTIVE: Our aim was to examine histopathological changes in three chronic wounds, and to assess whether the application of negative pressure wound therapy (NPWT) changes the wound bed environment. METHOD: - Results: We recruited three patients were recruited who had a non-healing wounds in excess of eight weeks. Histopathological changes in the wound bed supported the evidence that NPWT changes the wound bed environment by reducing inflammatory damage and facilitating wound bed perfusion with angiogenesis. CONCLUSION: We suggest that NPWT is a valuable adjunct to aid chronic wound healing. In this case series, we observed histopathological changes and improvement in the wounds, following one week's treatment with NPWT. Further analysis should be done to demonstrate any interaction between the cells involved in the wound healing process is enhanced, growth factor performance is optimised and cell migration is achieved following NPWT, in order to facilitate the healing process. PMID- 29419369 TI - Risks and prevalence of pressure ulcers among patients in an acute hospital in Finland. AB - OBJECTIVE: To quantify pressure ulcer (PU) prevalence and to describe and identify the PU risk factors in acute hospital wards. METHOD: A descriptive quantitative study was performed in 13 wards in a central hospital in Finland. The study included PU risk evaluation using the Braden risk assessment method, and full skin and medical assessment of consenting adult patients. Patients in paediatric, maternity and psychiatric wards, and in the intensive care unit were excluded. Patient's PUs were examined on the ward, and evaluated and classified using the international European Pressure Ulcer Advisory Panel and National Pressure Ulcer Advisory Panel (EPUAP/NPUAP) Pressure Ulcer Classification System. Demographic data, the Braden risk assessment scale, skin assessment, and the location and severity of PUs were also recorded. RESULTS: A sample of 229 inpatients was examined for signs of PUs on one day in 2013. The overall PU prevalence was 8.7% (20 patients). Of those assessed as 'at risk of developing PUs', four patients (1.7%) were considered at 'very high risk', 39 patients (17.0%) at 'high risk', and 60 patients (26.2%) with a 'moderate risk'. The patient's age and length of treatment period were associated with PU risk, while only length of treatment period was associated with PU prevalence. Older patients had a higher risk of PUs than younger ones. The longer the hospital stay, the higher the PU risk was. In addition, patients with a long hospital stay more often had a PU. CONCLUSION: According to the study, PUs occur with significant frequency in acute hospital wards. It is important to carry out PU prevention actions among all patient groups, but risk increases among older patients and those who, for any reason, stay in hospital for a longer period of time. PMID- 29419370 TI - Working Together for the Future of Implant Dentistry. PMID- 29419371 TI - An NMRA-Like Protein Regulates Gene Expression in Phytophthora capsici to Drive the Infection Cycle on Tomato. AB - Phytophthora spp. cause devastating disease epidemics on important crop plants and pose a grave threat to global crop production. Critically, Phytophthora pathogens represent a distinct evolutionary lineage in which pathogenicity has been acquired independently. Therefore, there is an urgent need to understand and disrupt the processes that drive infection if we aspire to defeat oomycete pathogens in the field. One area that has received little attention thus far in this respect is the regulation of Phytophthora gene expression during infection. Here, we characterize PcNMRAL1 (Phyca11_505845), a homolog of the Aspergillus nidulans nitrogen metabolite repression regulator NMRA and demonstrate a role for this protein in progression of the Phytophthora capsici infection cycle. PcNmrAL1 is coexpressed with the biotrophic marker gene PcHmp1 (haustorial membrane protein 1) and, when overexpressed, extends the biotrophic infection stage. Microarray analyses revealed that PcNmrAL1 overexpression in P. capsici leads to large-scale transcriptional changes during infection and in vitro. Importantly, detailed analysis reveals that PcNmrAL1 overexpression induces biotrophy associated genes while repressing those associated with necrotrophy. In addition to factors controlling transcription, translation, and nitrogen metabolism, PcNMRAL1 helps regulate the expression of a considerable effector repertoire in P. capsici. Our data suggests that PcNMRAL1 is a transcriptional regulator that mediates the biotrophy to necrotrophy transition. PcNMRAL1 represents a novel factor that may drive the Phytophthora disease cycle on crops. This study provides the first insight into mechanisms that regulate infection-related processes in Phytophthora spp. and provides a platform for further studies aimed at disabling pathogenesis and preventing crop losses. PMID- 29419373 TI - From the Editor. PMID- 29419372 TI - SNARE-Encoding Genes VdSec22 and VdSso1 Mediate Protein Secretion Required for Full Virulence in Verticillium dahliae. AB - Proteins that mediate cellular and subcellular membrane fusion are key factors in vesicular trafficking in all eukaryotic cells, including the secretion and transport of plant pathogen virulence factors. In this study, we identified vesicle-fusion components that included 22 soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), four Sec1/Munc18 (SM) family proteins, and 10 Rab GTPases encoded in the genome of the vascular wilt pathogen Verticillium dahliae Vd991. Targeted deletion of two SNARE-encoding genes in V. dahliae, VdSec22 and VdSso1, significantly reduced virulence of both mutants on cotton, relative to the wild-type Vd991 strain. Comparative analyses of the secreted protein content (exoproteome) revealed that many enzymes involved in carbohydrate hydrolysis were regulated by VdSec22 or VdSso1. Consistent with a role of these enzymes in plant cell-wall degradation, pectin, cellulose, and xylan utilization were reduced in the VdSec22 or VdSso1 mutant strains along with a loss of exoproteome cytotoxic activity on cotton leaves. Comparisons with a pathogenicity-related exoproteome revealed that several known virulence factors were not regulated by VdSec22 or VdSso1, but some of the proteins regulated by VdSec22 or VdSso1 displayed different characteristics, including the lack of a typical signal peptide, suggesting that V. dahliae employs more than one secretory route to transport proteins to extracellular sites during infection. PMID- 29419374 TI - Autistic Traits and Executive Functions in Children and Adolescents with Gender Dysphoria. AB - OBJECTIVE: We aimed to examine the autistic traits and executive functions that may require clinical attention in children and adolescents with gender dysphoria (GD). METHOD: The study sample consisted of 25 patients with GD, and 50 controls (aged 5-17 years). The instruments were Social Responsiveness Scale (SRS), and the Behavior Rating Inventory of Executive Function (BRIEF). RESULTS: The GD (mean age: 11.56+/-4.15 years) and control (mean age: 11.42+/-3.91 years) groups were similar with respect to age and sex; around 50% of the GD group (n=13) and control groups were male (n=26). The BRIEF metacognitive index (t= 7.023, p<0.001), behavioral regulation index (t= 6.340, p<0.001), and global executive composite (t= 7.268, p<0.001) scores were significantly higher in the GD group when compared with the controls. Similarly, mean SRS scores were significantly higher in the GD group (t= 4.978, p<0.001). The GD group had statistically significant higher BRIEF global scores even after controlling for SRS-key autism scores (p<0.001). CONCLUSION: Young people with GD had relatively more disturbed behavior related to executive functions and social impairment associated with autistic traits when compared with their control counterparts. Although preliminary, our results may indicate a possible neurodevelopmental background for individuals with GD. PMID- 29419375 TI - Tri-phasic fever in dengue fever. AB - Dengue fever is an acute febrile illness with a duration of 2-12 days. Our observational study observed the 24-h continuous tympanic temperature pattern of 15 patients with dengue fever and compared this with 26 others with fever due to a non-dengue aetiology. A tri-phasic fever pattern was seen among two-thirds of dengue fever patients, but in only one with an inflammatory disease. One-third of dengue fever patients exhibited a single peak temperature. Continuous temperature monitoring and temperature pattern analysis in clinical settings can aid in the early differentiation of dengue fever from non-dengue aetiology. PMID- 29419376 TI - Orphan receptor GPR158 controls stress-induced depression. AB - Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid dependent manner. Viral overexpression of GPR158 in the PFC induced depressive like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression. PMID- 29419378 TI - Does ursodeoxycholic acid improve perinatal outcomes in women with intrahepatic cholestasis of pregnancy? PMID- 29419379 TI - GPs to judge which patients deserve an NHS prescription. PMID- 29419377 TI - Bipolar filaments of human nonmuscle myosin 2-A and 2-B have distinct motile and mechanical properties. AB - Nonmusclemyosin 2 (NM-2) powers cell motility and tissue morphogenesis by assembling into bipolar filaments that interact with actin. Although the enzymatic properties of purified NM-2 motor fragments have been determined, the emergent properties of filament ensembles are unknown. Using single myosin filament in vitro motility assays, we report fundamental differences in filaments formed of different NM-2 motors. Filaments consisting of NM2-B moved processively along actin, while under identical conditions, NM2-A filaments did not. By more closely mimicking the physiological milieu, either by increasing solution viscosity or by co-polymerization with NM2-B, NM2-A containing filaments moved processively. Our data demonstrate that both the kinetic and mechanical properties of these two myosins, in addition to the stochiometry of NM-2 subunits, can tune filament mechanical output. We propose altering NM-2 filament composition is a general cellular strategy for tailoring force production of filaments to specific functions, such as maintaining tension or remodeling actin. PMID- 29419381 TI - How to estimate the effect of treatment duration on survival outcomes using observational data. PMID- 29419380 TI - Evaluating Rapid Rule-out of Acute Myocardial Infarction Using a High-Sensitivity Cardiac Troponin I Assay at Presentation. AB - BACKGROUND: Low concentrations of cardiac troponin (cTn) have been recommended for rapid rule-out of acute myocardial infarction (AMI). We examined the Beckman Coulter Access high-sensitivity cardiac troponin I (hs-cTnI) assay to identify a single test threshold that can safely rule out AMI. METHODS: This analysis used stored samples collected in 2 prospective observational studies. In all, 1871 patients presenting to a tertiary emergency department with symptoms of acute coronary syndrome had blood taken for measurement of cTnI on presentation. The endpoint was type 1 myocardial infarction (T1MI). Sensitivity and negative predictive value (NPV) were calculated for hs-cTnI values below the 99th percentile. RESULTS: Ninety-eight patients had T1MI (5.2%), and 638 (34.1%) patients had an hs-cTnI <2 ng/L (limit of detection), with sensitivity of 99.0% (95% CI, 94.4%-100%) and NPV of 99.8% (95% CI, 99.1%-100%). No hs-cTnI value above a concentration of 2 ng/L achieved sensitivity of 99%. However, an NPV of 99.5% was achieved at values <6 ng/L. A cutoff <6 ng/L enabled 1475 (78.8%) patients to be ruled out on presentation with sensitivity of 93.9% (95% CI, 87.1% 97.7%). CONCLUSIONS: A single baseline cTn <2 ng/L measured with the Access hs cTnI assay performed well for rule-out of AMI. This cutoff concentration identified 99% of patients with AMI and could reduce the number of patients requiring lengthy assessment. A cutoff of <6 ng/L yielded a high NPV but missed more cases of AMI than would be acceptable to clinicians. PMID- 29419382 TI - Fear and infertility research. PMID- 29419383 TI - Fund IVF fully to lower rates of multiple pregnancies, says royal college. PMID- 29419384 TI - Call for duty of candour in Northern Ireland after doctors found unwilling to admit errors. PMID- 29419385 TI - Should action take priority over further research on public health? PMID- 29419386 TI - Bright side of life with Parkinson's. PMID- 29419387 TI - Trump promises cheaper drugs and experimental treatments for terminally ill people. PMID- 29419388 TI - Criminalising doctors. PMID- 29419391 TI - Correction: An alternative surgical approach reduces variability following filament induction of experimental stroke in mice (doi: 10.1242/dmm.029108). PMID- 29419390 TI - Dyslipidemia and Risk of Cardiovascular Events in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Therapy: Insights From the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) Trial. AB - BACKGROUND: Dyslipidemia is a major risk factor for cardiovascular events. The prognostic importance of lipoproteins in patients with atrial fibrillation is not well understood. We aimed to explore the association between apolipoprotein A1 (ApoA1) and B (ApoB) and cardiovascular events in patients with atrial fibrillation receiving oral anticoagulation. METHODS AND RESULTS: Using data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, ApoA1 and ApoB plasma levels were measured at baseline in 14 884 atrial fibrillation patients. Median length of follow-up was 1.9 years. Relationships between continuous levels of ApoA1 and ApoB and clinical outcomes were evaluated using Cox models adjusted for cardiovascular risk factors, medication including statins, and cardiovascular biomarkers. A composite ischemic outcome (ischemic stroke, systemic embolism, myocardial infarction, and cardiovascular death) was used as the primary end point. Median (25th, 75th) ApoA1 and ApoB levels were 1.10 (0.93, 1.30) and 0.70 g/L (0.55, 0.85), respectively. In adjusted analyses, higher levels of ApoA1 were independently associated with a lower risk of the composite ischemic outcome (hazard ratio, 0.81; P<0.0001). Similar results were observed for the individual components of the composite outcome. ApoB was not significantly associated with the composite ischemic outcome (P=0.8240). Neither apolipoprotein was significantly associated with major bleeding. There was no interaction between lipoproteins and randomized treatment for the primary outcome (both P values >=0.2448). CONCLUSIONS: In patients with atrial fibrillation on oral anticoagulation, higher levels of ApoA1 were independently associated with lower risk of ischemic cardiovascular outcomes. Investigating therapies targeting dyslipidemia may thus be useful to improve cardiovascular outcomes in patients with atrial fibrillation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. PMID- 29419392 TI - Correction: Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia (doi: 10.1242/dmm.030502). PMID- 29419389 TI - Role of Monocytes in Heart Failure and Atrial Fibrillation. PMID- 29419393 TI - A keen eye for risk. PMID- 29419394 TI - Peripheral artery disease. PMID- 29419395 TI - Seven days in medicine: 24 to 30 January 2018. PMID- 29419397 TI - Heavy use of agency staff linked to worse patient and staff experiences. PMID- 29419398 TI - Substantia Nigra Free Water Increases Longitudinally in Parkinson Disease. AB - BACKGROUND AND PURPOSE: Free water in the posterior substantia nigra obtained from a bi-tensor diffusion MR imaging model has been shown to significantly increase over 1- and 4-year periods in patients with early-stage idiopathic Parkinson disease compared with healthy controls, which suggests that posterior substantia nigra free water may be an idiopathic Parkinson disease progression biomarker. Due to the known temporal posterior-to-anterior substantia nigra degeneration in idiopathic Parkinson disease, we assessed longitudinal changes in free water in both the posterior and anterior substantia nigra in patients with later-stage idiopathic Parkinson disease and age-matched healthy controls for comparison. MATERIALS AND METHODS: Nineteen subjects with idiopathic Parkinson disease and 19 age-matched healthy control subjects were assessed on the same 3T MR imaging scanner at baseline and after approximately 3 years. RESULTS: Baseline mean idiopathic Parkinson disease duration was 7.1 years. Both anterior and posterior substantia nigra free water showed significant intergroup differences at baseline (P < .001 and P = .014, respectively, idiopathic Parkinson disease versus healthy controls); however, only anterior substantia nigra free water showed significant longitudinal group * time interaction increases (P = .021, idiopathic Parkinson disease versus healthy controls). There were no significant longitudinal group * time interaction differences found for conventional diffusion tensor imaging or free water-corrected DTI assessments in either the anterior or posterior substantia nigra. CONCLUSIONS: Results from this study provide further evidence supporting substantia nigra free water as a promising disease-progression biomarker in idiopathic Parkinson disease that may help to identify disease-modifying therapies if used in future clinical trials. Our novel finding of longitudinal increases in anterior but not posterior substantia nigra free water is potentially a result of the much longer disease duration of our cohort compared with previously studied cohorts and the known posterior-to anterior substantia nigra degeneration that occurs over time in idiopathic Parkinson disease. PMID- 29419399 TI - Spinal Angiogram: A Treacherous Criterion Standard.... PMID- 29419396 TI - Expanding primary cells from mucoepidermoid and other salivary gland neoplasms for genetic and chemosensitivity testing. AB - Restricted availability of cell and animal models is a rate-limiting step for investigation of salivary gland neoplasm pathophysiology and therapeutic response. Conditionally reprogrammed cell (CRC) technology enables establishment of primary epithelial cell cultures from patient material. This study tested a translational workflow for acquisition, expansion and testing of CRC-derived primary cultures of salivary gland neoplasms from patients presenting to an academic surgical practice. Results showed that cultured cells were sufficient for epithelial cell-specific transcriptome characterization to detect candidate therapeutic pathways and fusion genes, and for screening for cancer risk associated single nucleotide polymorphisms (SNPs) and driver gene mutations through exome sequencing. Focused study of primary cultures of a low-grade mucoepidermoid carcinoma demonstrated amphiregulin-mechanistic target of rapamycin-protein kinase B (AKT; AKT1) pathway activation, identified through bioinformatics and subsequently confirmed as present in primary tissue and preserved through different secondary 2D and 3D culture media and xenografts. Candidate therapeutic testing showed that the allosteric AKT inhibitor MK2206 reproducibly inhibited cell survival across different culture formats. By contrast, the cells appeared resistant to the adenosine triphosphate competitive AKT inhibitor GSK690693. Procedures employed here illustrate an approach for reproducibly obtaining material for pathophysiological studies of salivary gland neoplasms, and other less common epithelial cancer types, that can be executed without compromising pathological examination of patient specimens. The approach permits combined genetic and cell-based physiological and therapeutic investigations in addition to more traditional pathologic studies, and can be used to build sustainable bio-banks for future inquiries.This article has an associated First Person interview with the first author of the paper. PMID- 29419400 TI - High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1 Weighted MR Images: Comparison between Gadobutrol and Linear Gadolinium-Based Contrast Agents. AB - BACKGROUND AND PURPOSE: In view of the recent observations that gadolinium deposits in brain tissue after intravenous injection, our aim of this study was to compare signal changes in the globus pallidus and dentate nucleus on unenhanced T1-weighted MR images in patients receiving serial doses of gadobutrol, a macrocyclic gadolinium-based contrast agent, with those seen in patients receiving linear gadolinium-based contrast agents. MATERIALS AND METHODS: This was a retrospective analysis of on-site patients with brain tumors. Fifty-nine patients received only gadobutrol, and 60 patients received only linear gadolinium-based contrast agents. Linear gadolinium-based contrast agents included gadoversetamide, gadobenate dimeglumine, and gadodiamide. T1 signal intensity in the globus pallidus, dentate nucleus, and pons was measured on the precontrast portions of patients' first and seventh brain MRIs. Ratios of signal intensity comparing the globus pallidus with the pons (globus pallidus/pons) and dentate nucleus with the pons (dentate nucleus/pons) were calculated. Changes in the above signal intensity ratios were compared within the gadobutrol and linear agent groups, as well as between groups. RESULTS: The dentate nucleus/pons signal ratio increased in the linear gadolinium-based contrast agent group (t = 4.215, P < .001), while no significant increase was seen in the gadobutrol group (t = 1.422, P = .08). The globus pallidus/pons ratios followed similarly, with an increase in the linear gadolinium-based contrast agent group (t = 2.931, P < .0001) and no significant change in those receiving gadobutrol (t = 0.684, P = .25). CONCLUSIONS: Successive doses of gadobutrol do not result in T1 shortening compared with changes seen in linear gadolinium-based contrast agents. PMID- 29419401 TI - Optimization of DARTEL Settings for the Detection of Alzheimer Disease. AB - BACKGROUND AND PURPOSE: Although Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) has been introduced as an alternative to conventional voxel-based morphometry, there are scant data available regarding the optimal image-processing settings. The aim of this study was to optimize image-processing and ROI settings for the diagnosis of Alzheimer disease using DARTEL. MATERIALS AND METHODS: Between May 2002 and August 2014, we selected 158 patients with Alzheimer disease and 198 age-matched healthy subjects; 158 healthy subjects served as the control group against the patients with Alzheimer disease, and the remaining 40 served as the healthy data base. Structural MR images were obtained in all the participants and were processed using DARTEL-based voxel based morphometry with a variety of settings. These included modulated or nonmodulated, nonsmoothed or smoothed settings with a 4-, 8-, 12-, 16-, or 20-mm kernel size. A z score was calculated for each ROI, and univariate and multivariate logistic regression analyses were performed to determine the optimal ROI settings for each dataset. The optimal settings were defined as those demonstrating the highest chi2 test statistics in the multivariate logistic regression analyses. Finally, using the optimal settings, we obtained receiver operating characteristic curves. The models were verified using 10-fold cross validation. RESULTS: The optimal settings were obtained using the hippocampus and precuneus as ROIs without modulation and smoothing. The average area under the curve was 0.845 (95% confidence interval, 0.788-0.902). CONCLUSIONS: We recommend using the precuneus and hippocampus as ROIs without modulation and smoothing for DARTEL-based voxel-based morphometry as a tool for diagnosing Alzheimer disease. PMID- 29419402 TI - Deep Learning in Neuroradiology. AB - Deep learning is a form of machine learning using a convolutional neural network architecture that shows tremendous promise for imaging applications. It is increasingly being adapted from its original demonstration in computer vision applications to medical imaging. Because of the high volume and wealth of multimodal imaging information acquired in typical studies, neuroradiology is poised to be an early adopter of deep learning. Compelling deep learning research applications have been demonstrated, and their use is likely to grow rapidly. This review article describes the reasons, outlines the basic methods used to train and test deep learning models, and presents a brief overview of current and potential clinical applications with an emphasis on how they are likely to change future neuroradiology practice. Facility with these methods among neuroimaging researchers and clinicians will be important to channel and harness the vast potential of this new method. PMID- 29419403 TI - Neuroradiology Fellowship Case Requirements Need Reform. PMID- 29419404 TI - Quantitative Analysis of Conebeam CT for Delineating Stents in Stent-Assisted Coil Embolization. AB - BACKGROUND AND PURPOSE: Innovative techniques and device-related advances have improved the outcomes of neuroendovascular treatment. 3D imaging has previously used 2 * 2 binning, but 1 * 1 binning has recently been made available. The aim of this study was to evaluate the quantitative ability of conebeam CT for stent delineation and to investigate its effectiveness in the clinical environment. MATERIALS AND METHODS: Four acquisition groups of 3D MIP images acquired using conebeam CT with varying conditions (acquisition time, 10 or 20 seconds and binning, 1 * 1 or 2 * 2) were compared. Two methods of analysis were performed, a phantom study and an analysis of 28 randomly selected patients. The phantom study assessed the contrast-to-noise ratio and full width at half maximum values in conebeam CT images of intracranial stent struts. In the clinical subjects, we assessed contrast-to-noise ratio, full width at half maximum, and dose-area product. RESULTS: In the phantom study, the contrast-to-noise ratio was not considerably different between 10- and 20-second acquisition times at equivalent binning settings. Additionally, the contrast-to-noise ratio at equivalent acquisition times did not differ considerably by binning setting. For the full width at half maximum results, equivalent acquisition times differed significantly by binning setting. In the clinical analyses, the 10-second/1 * 1 group (versus 20 second/2 * 2) showed a higher contrast-to-noise ratio (P < .05) and a dose-area product reduced by approximately 70% (P < .05), but the difference in full width at half maximum was not significant (P = .20). CONCLUSIONS: For stent-assisted coil embolization, quantitative assessment of conebeam CT showed that 10 second/1 * 1 was equivalent to 20 second/2 * 2 for imaging deployed intracranial stents. Furthermore, the 10-second/1 * 1 settings resulted in a much smaller DAP. PMID- 29419405 TI - Muscle Contraction. AB - Muscle cells are designed to generate force and movement. There are three types of mammalian muscles-skeletal, cardiac, and smooth. Skeletal muscles are attached to bones and move them relative to each other. Cardiac muscle comprises the heart, which pumps blood through the vasculature. Skeletal and cardiac muscles are known as striated muscles, because the filaments of actin and myosin that power their contraction are organized into repeating arrays, called sarcomeres, that have a striated microscopic appearance. Smooth muscle does not contain sarcomeres but uses the contraction of filaments of actin and myosin to constrict blood vessels and move the contents of hollow organs in the body. Here, we review the principal molecular organization of the three types of muscle and their contractile regulation through signaling mechanisms and discuss their major structural and functional similarities that hint at the possible evolutionary relationships between the cell types. PMID- 29419406 TI - Microglial Phenotypes and Functions in Multiple Sclerosis. AB - Microglia are the resident immune cells that constantly survey the central nervous system. They can adapt to their environment and respond to injury or insult by altering their morphology, phenotype, and functions. It has long been debated whether microglial activation is detrimental or beneficial in multiple sclerosis (MS). Recently, the two opposing yet connected roles of microglial activation have been described with the aid of novel microglial markers, RNA profiling, and in vivo models. In this review, microglial phenotypes and functions in the context of MS will be discussed with evidence from both human pathological studies, in vitro and in vivo models. Microglial functional diversity-phagocytosis, antigen presentation, immunomodulation, support, and repair-will also be examined in detail. In addition, this review discusses the emerging evidence for microglia-related targets as biomarkers and therapeutic targets for MS. PMID- 29419407 TI - Hyperoxia Causes Mitochondrial Fragmentation in Pulmonary Endothelial Cells by Increasing Expression of Pro-Fission Proteins. AB - OBJECTIVE: We explored mechanisms that alter mitochondrial structure and function in pulmonary endothelial cells (PEC) function after hyperoxia. APPROACH AND RESULTS: Mitochondrial structures of PECs exposed to hyperoxia or normoxia were visualized and mitochondrial fragmentation quantified. Expression of pro-fission or fusion proteins or autophagy-related proteins were assessed by Western blot. Mitochondrial oxidative state was determined using mito-roGFP. Tetramethylrhodamine methyl ester estimated mitochondrial polarization in treatment groups. The role of mitochondrially derived reactive oxygen species in mt-fragmentation was investigated with mito-TEMPOL and mitochondrial DNA (mtDNA) damage studied by using ENDO III (mt-tat-endonuclease III), a protein that repairs mDNA damage. Drp-1 (dynamin-related protein 1) was overexpressed or silenced to test the role of this protein in cell survival or transwell resistance. Hyperoxia increased fragmentation of PEC mitochondria in a time dependent manner through 48 hours of exposure. Hyperoxic PECs exhibited increased phosphorylation of Drp-1 (serine 616), decreases in Mfn1 (mitofusion protein 1), but increases in OPA-1 (optic atrophy 1). Pro-autophagy proteins p62 (LC3 adapter binding protein SQSTM1/p62), PINK-1 (PTEN-induced putative kinase 1), and LC3B (microtubule-associated protein 1A/1B-light chain 3) were increased. Returning cells to normoxia for 24 hours reversed the increased mt-fragmentation and changes in expression of pro-fission proteins. Hyperoxia-induced changes in mitochondrial structure or cell survival were mitigated by antioxidants mito TEMPOL, Drp-1 silencing, or inhibition or protection by the mitochondrial endonuclease ENDO III. Hyperoxia induced oxidation and mitochondrial depolarization and impaired transwell resistance. Decrease in resistance was mitigated by mito-TEMPOL or ENDO III and reproduced by overexpression of Drp-1. CONCLUSIONS: Because hyperoxia evoked mt-fragmentation, cell survival and transwell resistance are prevented by ENDO III and mito-TEMPOL and Drp-1 silencing, and these data link hyperoxia-induced mt-DNA damage, Drp-1 expression, mt-fragmentation, and PEC dysfunction. PMID- 29419408 TI - Distinct Pathogenesis of Pancreatic Cancer Microvesicle-Associated Venous Thrombosis Identifies New Antithrombotic Targets In Vivo. AB - OBJECTIVE: Cancer patients are at high risk of developing deep venous thrombosis (DVT) and venous thromboembolism, a leading cause of mortality in this population. However, it is largely unclear how malignant tumors drive the prothrombotic cascade culminating in DVT. APPROACH AND RESULTS: Here, we addressed the pathophysiology of malignant DVT compared with nonmalignant DVT and focused on the role of tumor microvesicles as potential targets to prevent cancer associated DVT. We show that microvesicles released by pancreatic adenocarcinoma cells (pancreatic tumor-derived microvesicles [pcMV]) boost thrombus formation in a model of flow restriction of the mouse vena cava. This depends on the synergistic activation of coagulation by pcMV and host tissue factor. Unlike nonmalignant DVT, which is initiated and propagated by innate immune cells, thrombosis triggered by pcMV was largely independent of myeloid leukocytes or platelets. Instead, we identified externalization of the phospholipid phosphatidylethanolamine as a major mechanism controlling the prothrombotic activity of pcMV. Disrupting phosphatidylethanolamine-dependent activation of factor X suppressed pcMV-induced DVT without causing changes in hemostasis. CONCLUSIONS: Together, we show here that the pathophysiology of pcMV-associated experimental DVT differs markedly from innate immune cell-promoted nonmalignant DVT and is therefore amenable to distinct antithrombotic strategies. Targeting phosphatidylethanolamine on tumor microvesicles could be a new strategy for prevention of cancer-associated DVT without causing bleeding complications. PMID- 29419409 TI - Anticoagulant Protein S Targets the Factor IXa Heparin-Binding Exosite to Prevent Thrombosis. AB - OBJECTIVE: PS (protein S) is a plasma protein that directly inhibits the coagulation FIXa (factor IXa) in vitro. Because elevated FIXa is associated with increased risk of venous thromboembolism, it is important to establish how PS inhibits FIXa function in vivo. The goal of this study is to confirm direct binding of PS with FIXa in vivo, identify FIXa amino acid residues required for binding PS in vivo, and use an enzymatically active FIXa mutant that is unable to bind PS to measure the significance of PS-FIXa interaction in hemostasis. APPROACH AND RESULTS: We demonstrate that PS inhibits FIXa in vivo by associating with the FIXa heparin-binding exosite. We used fluorescence tagging, immunohistochemistry, and protein-protein crosslinking to show in vivo interaction between FIXa and PS. Importantly, platelet colocalization required a direct interaction between the 2 proteins. FIXa and PS also coimmunoprecipitated from plasma, substantiating their interaction in a physiological milieu. PS binding to FIXa and PS inhibition of the intrinsic Xase complex required residues K132, K126, and R170 in the FIXa heparin-binding exosite. A double mutant, K132A/R170A, retained full activity but could not bind to PS. Crucially, Hemophilia B mice infused with FIXa K132A/R170A displayed an accelerated rate of fibrin clot formation compared with wild-type FIXa. CONCLUSIONS: Our findings establish PS as an important in vivo inhibitor of FIXa. Disruption of the interaction between PS and FIXa causes an increased rate of thrombus formation in mice. This newly discovered function of PS implies an unexploited target for antithrombotic therapeutics. PMID- 29419410 TI - 2017 George Lyman Duff Memorial Lecture: Fat in the Blood, Fat in the Artery, Fat in the Heart: Triglyceride in Physiology and Disease. AB - Cholesterol is not the only lipid that causes heart disease. Triglyceride supplies the heart and skeletal muscles with highly efficient fuel and allows for the storage of excess calories in adipose tissue. Failure to transport, acquire, and use triglyceride leads to energy deficiency and even death. However, overabundance of triglyceride can damage and impair tissues. Circulating lipoprotein-associated triglycerides are lipolyzed by lipoprotein lipase (LpL) and hepatic triglyceride lipase. We inhibited these enzymes and showed that LpL inhibition reduces high-density lipoprotein cholesterol by >50%, and hepatic triglyceride lipase inhibition shifts low-density lipoprotein to larger, more buoyant particles. Genetic variations that reduce LpL activity correlate with increased cardiovascular risk. In contrast, macrophage LpL deficiency reduces macrophage function and atherosclerosis. Therefore, muscle and macrophage LpL have opposite effects on atherosclerosis. With models of atherosclerosis regression that we used to study diabetes mellitus, we are now examining whether triglyceride-rich lipoproteins or their hydrolysis by LpL affect the biology of established plaques. Following our focus on triglyceride metabolism led us to show that heart-specific LpL hydrolysis of triglyceride allows optimal supply of fatty acids to the heart. In contrast, cardiomyocyte LpL overexpression and excess lipid uptake cause lipotoxic heart failure. We are now studying whether interrupting pathways for lipid uptake might prevent or treat some forms of heart failure. PMID- 29419411 TI - Correlation of immunohistochemical mismatch repair protein status between colorectal carcinoma endoscopic biopsy and resection specimens. AB - BACKGROUND: Microsatellite instability is reflective of a deficient mismatch repair system (dMMR), which may be due to either sporadic or germline mutations in the relevant mismatch repair (MMR) gene. MMR status is frequently determined by immunohistochemistry (IHC) for mismatch repair proteins (MMRPs) on colorectal cancer (CRC) resection specimens. However, IHC testing performed on endoscopic biopsy may be as reliable as that performed on surgical resections. AIM: We aimed to evaluate the reliability of MMR IHC staining on preoperative CRC endoscopic biopsies compared with matched-surgical resection specimens. METHODS: A retrospective search of our institution's histopathology electronic database was performed. Patients with CRC who had MMR IHC performed on both their preoperative endoscopic biopsy and subsequent resection from January 2010 to January 2016 were included. Concordance of MMR staining between biopsy and resection specimens was assessed. RESULTS: From 2000 to 2016, 53 patients had MMR IHC performed on both their preoperative colorectal endoscopic biopsy and resection specimens; 10 patients (18.87%) demonstrated loss of >=1 MMRP on their initial endoscopic tumour biopsy. The remainder (81.13%) showed preservation of staining for all MMRPs. There was complete agreement in MMR IHC status between the preoperative endoscopic biopsies and corresponding resection specimens in all cases (kappa=1.000, P<0.000) with a sensitivity of 100% (95% CI 69.15 to 100) and specificity of 100% (95% CI 91.78 to 100) for detection of dMMR. CONCLUSION: Endoscopic biopsies are a suitable source of tissue for MMR IHC analysis. This may provide a number of advantages to both patients and clinicians in the management of CRC. PMID- 29419412 TI - Neural and neurogenic tumours of the gastroenteropancreaticobiliary tract. AB - Neural lesions occur uncommonly in the gastroenteropancreaticobiliary tract. However, due to the growing number of screening colonoscopy procedures, polypoid neural lesions of the colon are being recognised increasingly and range from benign tumours to high-grade malignant neoplasms. Morphological variability of neural tumours can be wide, although some entities share pathological features, and, as such, these lesions can be diagnostically challenging. We review the spectrum of pathology of neural tumours in the gastroenteropancreaticobiliary tract, with the goal of providing a practical approach for practising surgical pathologists. PMID- 29419414 TI - Motor neuron degeneration correlates with respiratory dysfunction in SCA1. AB - Spinocerebellar ataxia type 1 (SCA1) is characterized by adult-onset cerebellar degeneration with attendant loss of motor coordination. Bulbar function is eventually impaired and patients typically die from an inability to clear the airway. We investigated whether motor neuron degeneration is at the root of bulbar dysfunction by studying SCA1 knock-in (Atxn1154Q/+ ) mice. Spinal cord and brainstem motor neurons were assessed in Atxn1154Q/+ mice at 1, 3 and 6 months of age. Specifically, we assessed breathing physiology, diaphragm histology and electromyography, and motor neuron histology and immunohistochemistry. Atxn1154Q/+ mice show progressive neuromuscular respiratory abnormalities, neurogenic changes in the diaphragm, and motor neuron degeneration in the spinal cord and brainstem. Motor neuron degeneration is accompanied by reactive astrocytosis and accumulation of Atxn1 aggregates in the motor neuron nuclei. This observation correlates with previous findings in SCA1 patient tissue. Atxn1154Q/+ mice develop bulbar dysfunction because of motor neuron degeneration. These findings confirm the Atxn1154Q/+ line as a SCA1 model with face and construct validity for this understudied disease feature. Furthermore, this model is suitable for studying the pathogenic mechanism driving motor neuron degeneration in SCA1 and possibly other degenerative motor neuron diseases. From a clinical standpoint, the data indicate that pulmonary function testing and employment of non-invasive ventilator support could be beneficial in SCA1 patients. The physiological tests used in this study might serve as valuable biomarkers for future therapeutic interventions and clinical trials.This article has an associated First Person interview with the first author of the paper. PMID- 29419415 TI - Spliceosomal components protect embryonic neurons from R-loop-mediated DNA damage and apoptosis. AB - RNA splicing factors are essential for the viability of all eukaryotic cells; however, in metazoans some cell types are exquisitely sensitive to disruption of splicing factors. Neuronal cells represent one such cell type, and defects in RNA splicing factors can lead to neurodegenerative diseases. The basis for this tissue selectivity is not well understood owing to difficulties in analyzing the consequences of splicing factor defects in whole-animal systems. Here, we use zebrafish mutants to show that loss of spliceosomal components, including splicing factor 3b, subunit 1 (sf3b1), causes increased DNA double-strand breaks and apoptosis in embryonic neurons. Moreover, these mutants show a concomitant accumulation of R-loops, which are non-canonical nucleic acid structures that promote genomic instability. Dampening R-loop formation by conditional induction of ribonuclease H1 in sf3b1 mutants reduced neuronal DNA damage and apoptosis. These findings show that splicing factor dysfunction leads to R-loop accumulation and DNA damage that sensitizes embryonic neurons to apoptosis. Our results suggest that diseases associated with splicing factor mutations could be susceptible to treatments that modulate R-loop levels. PMID- 29419413 TI - Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures. AB - OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. DESIGN: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. METHODS: Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). RESULTS: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 * 10-11) or controls (18%, P = 5.5 * 10-12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 * 10 7). CONCLUSIONS: Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty. PMID- 29419418 TI - Correction: Control of Cdc6 accumulation by Cdk1 and MAPK is essential for completion of oocyte meiotic divisions in Xenopus (doi:10.1242/jcs.166553). PMID- 29419416 TI - Lymphoblastoid cell lines as a model to understand amyotrophic lateral sclerosis disease mechanisms. AB - In the past, amyotrophic lateral sclerosis (ALS) has been considered a 'neurocentric' disease; however, new evidence suggests that it should instead be looked at from a 'multisystemic' or 'non-neurocentric' point of view. From 2006, we focused on the study of non-neural cells: ALS patients' peripheral blood mononuclear cells (PMBCs) and lymphoblastoid cell lines (LCLs). Here, we characterize LCLs of sporadic ALS (sALS) and patients carrying SOD1, TARDBP and FUS mutations to identify an ALS biologically relevant molecular signature, and determine whether and how mutations differentially affect ALS-linked pathways. Although LCLs are different from motor neurons (MNs), in LCLs we found some features typical of degenerating MNs in ALS, i.e. protein aggregation and mitochondrial dysfunction. Moreover, different gene mutations have different effects on ALS cellular mechanisms. TARDBP and FUS mutations imbalance mitochondrial dynamism toward increased fusion, whereas sALS and SOD1 mutations mainly affect fission. With regards to protein aggregation and/or mislocalization, TARDBP and SOD1 mutations show the presence of aggregates, whereas FUS mutation does not induce protein aggregation and/or mislocalization. Finally, all LCLs, independently from mutation, are not able to work in a condition of excessive energy request, suggesting that mitochondria from ALS patients are characterized by a significant metabolic defect. Taken together, these data indicate that LCLs could be a valid cellular model in ALS research in the identification and study of specific pathological pathways. PMID- 29419419 TI - Learning from an exceptional boy. PMID- 29419420 TI - Diaphragmatic flutter. AB - A 78-year-old woman presented with involuntary movements of her abdomen, which started after a right hemispheric stroke. She had irregular, variable, hyperkinetic predominantly right-sided abdominal wall movements. MR scan of brain confirmed a recent infarct in the right occipitotemporal lobe and the right cerebellum. Diaphragmatic fluoroscopy confirmed high-frequency flutter as the cause of her abdominal movements and confirmed the diagnosis of van Leeuwenhoek's disease. Anthonie van Leeuwenhoek first described this condition in 1723 and had the condition himself. He was a Dutch businessman who is often acknowledged as the first microscopist and microbiologist. He disagreed with his physician who attributed his ailment as being of cardiac origin. Diaphragmatic flutter is a rare disorder that requires a high index of suspicion with symptoms including abnormal abdominal wall movements, dyspnoea and respiratory distress. Despite medical treatment, the patient was still highly symptomatic, so she is currently being considered for a phrenic nerve crush. PMID- 29419421 TI - Deemed consent: assessing the new opt-out approach to organ procurement in Wales. AB - In December 2015, Wales became the first country in the UK to move away from an opt-in system in organ procurement. The new legislation introduces the concept of deemed consent whereby a person who neither opt in nor opt out is deemed to have consented to donation. The data released by the National Health Service (NHS) in July 2017 provide an excellent opportunity to assess this legislation in light of concerns that it would decrease procurement rates for living and deceased donation, as well as sparking an increase in family refusals. None of these concerns have come to pass, with Wales experiencing more registered donors, fewer family refusals and more living donations. However, as the number of actual donors has dropped slightly from a high level, the situation must be monitored closely in the years to come. PMID- 29419417 TI - The central role of DNA damage and repair in CAG repeat diseases. AB - Diseases such as Huntington's disease and certain spinocerebellar ataxias are caused by the expansion of genomic cytosine-adenine-guanine (CAG) trinucleotide repeats beyond a specific threshold. These diseases are all characterised by neurological symptoms and central neurodegeneration, but our understanding of how expanded repeats drive neuronal loss is incomplete. Recent human genetic evidence implicates DNA repair pathways, especially mismatch repair, in modifying the onset and progression of CAG repeat diseases. Repair pathways might operate directly on repeat sequences by licensing or inhibiting repeat expansion in neurons. Alternatively, or in addition, because many of the genes containing pathogenic CAG repeats encode proteins that themselves have roles in the DNA damage response, it is possible that repeat expansions impair specific DNA repair pathways. DNA damage could then accrue in neurons, leading to further expansion at repeat loci, thus setting up a vicious cycle of pathology. In this review, we consider DNA damage and repair pathways in postmitotic neurons in the context of disease-causing CAG repeats. Investigating and understanding these pathways, which are clearly relevant in promoting and ameliorating disease in humans, is a research priority, as they are known to modify disease and therefore constitute prevalidated drug targets. PMID- 29419422 TI - Occupational health and valid work exposure tools are keys to improving the health of ageing workers. PMID- 29419423 TI - Neurobehavioural symptoms and acute pesticide poisoning: a cross-sectional study among male pesticide applicators selected from three commercial farming systems in Ethiopia. AB - OBJECTIVE: To estimate prevalence of acute pesticide poisoning (APP) and its association with neurobehavioural symptoms in Ethiopian pesticide applicators. METHODS: We performed a cross-sectional survey among 256 pesticide applicators from small-scale irrigated farms, a large-scale open farm and large-scale greenhouses. APP was ascertained using a modified WHO case definition, and neurobehavioural symptoms were collected with a standardised questionnaire (Q16). Exposure to pesticides was estimated using detailed exposure algorithms specifically developed for Ethiopian farms. Multiple logistic regression models were used to estimate risk of APP and its association with neurobehavioural symptoms. RESULTS: Overall APP prevalence was 16%. Working as an applicator in greenhouses was strongly associated with APP (OR 3.00, 95% CI 1.38 to 6.54). Estimated annual pesticide exposure was also associated with APP (OR 1.14, 95% CI 1.00 to 1.20). Longer duration of employment appeared to be negatively associated with APP. Having had an APP was strongly associated with reporting more neurobehavioural symptoms (OR 2.15, 95% CI 1.01 to 4.58) independent of cumulative pesticide exposure. Cumulative exposure to pesticides appeared to be associated with neurobehavioural symptoms among applicators without and with APP. CONCLUSIONS: We showed a substantial prevalence of APP that differed between farming systems and was strongly associated with neurobehavioural symptoms. Intensity of exposure was also clearly associated with these symptoms. Reduction and control of occupational exposure to pesticides is urgently needed in Ethiopia. PMID- 29419424 TI - Levels of the erythropoietin-responsive hormone erythroferrone in mice and humans with chronic kidney disease. PMID- 29419425 TI - Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results. AB - Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cells that can be harvested for transduction or gene editing. We therefore performed a phase I dose-escalation study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34+ cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and ten were on hydroxyurea. Of eight patients who achieved a CD34+ cell concentration >30 cells/MUL, six were on hydroxyurea. There was no clear dose response to increasing plerixafor dosage. There was a low rate of serious adverse events; two patients developed vaso-occlusive crises, at the doses of 80 MUg/kg and 240 MUg/kg. Hydroxyurea may have contributed to the limited CD34+ mobilization by affecting baseline peripheral blood CD34 counts, which correlated strongly with peak peripheral blood CD34 counts. Plerixafor administration did not induce significant increases in the fraction of activated neutrophils, monocytes, or platelets. However, increased neutrophils positive for activated beta2 integrin and Mac-1 were associated with serious adverse events. In summary, plerixafor was well tolerated but did not achieve consistent CD34+ cell mobilization in this cohort of patients, most of whom were being actively treated with hydroxyurea and only one was chronically transfused. The study will continue with escalation of the dose of plerixafor and modification of hydroxyurea administration. Clinicaltrials.gov identifier: NCT02193191. PMID- 29419426 TI - Heterozygous carriers of germline c.657_661del5 founder mutation in NBN gene are at risk of central nervous system relapse of B-cell precursor acute lymphoblastic leukemia. PMID- 29419427 TI - A defined culture method enabling the establishment of ring sideroblasts from induced pluripotent cells of X-linked sideroblastic anemia. PMID- 29419428 TI - Ibrutinib for chronic lymphocytic leukemia: international experience from a named patient program. PMID- 29419430 TI - Cytogenetic aberrations in multiple myeloma are associated with shifts in serum immunoglobulin isotypes distribution and levels. PMID- 29419431 TI - Sequential loss of tumor surface antigens following chimeric antigen receptor T cell therapies in diffuse large B-cell lymphoma. PMID- 29419429 TI - Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. AB - Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect(r) Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure. PMID- 29419432 TI - The contribution of platelet glycoprotein receptors to inflammatory bleeding prevention is stimulus and organ dependent. PMID- 29419433 TI - Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT. AB - We investigated extramedullary disease in newly diagnosed multiple myeloma patients and its impact on outcome following first-line autologous stem cell transplantation. We identified 3744 adult myeloma patients who received up-front single (n=3391) or tandem transplantation (n=353) between 2005 and 2014 with available data on extramedullary involvement at diagnosis. The overall incidence of extramedullary disease was 18.2% (n=682) and increased per year from 6.5% (2005) to 23.7% (2014). Paraskeletal involvement was found in 543 (14.5%) and extramedullary organ involvement in 139 (3.7%). More patients with extramedullary organ involvement had multiple involved sites (>=2; P<0.001). In a comparison of patients with single sites with patients without the disease, up-front transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: P=0.86, and extramedullary organ: P=0.88). In single paraskeletal involvement, this translated less clearly into worse 3-year overall survival (P=0.07) while single organ involvement was significantly worse (P=0.001). Multiple organ sites were associated with worse outcome (P<0.001 and P=0.01). First-line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (P=0.13 for both). PMID- 29419434 TI - Deep sequencing and flow cytometric characterization of expanded effector memory CD8+CD57+ T cells frequently reveals T-cell receptor Vbeta oligoclonality and CDR3 homology in acquired aplastic anemia. AB - Oligoclonal expansion of CD8+ CD28- lymphocytes has been considered indirect evidence for a pathogenic immune response in acquired aplastic anemia. A subset of CD8+ CD28- cells with CD57 expression, termed effector memory cells, is expanded in several immune-mediated diseases and may have a role in immune surveillance. We hypothesized that effector memory CD8+CD28-CD57+ cells may drive aberrant oligoclonal expansion in aplastic anemia. We found CD8+CD57+ cells frequently expanded in the blood of aplastic anemia patients, with oligoclonal characteristics by flow cytometric Vbeta usage analysis: skewing in 1-5 Vbeta families and frequencies of immunodominant clones ranging from 1.98% to 66.5%. Oligoclonal characteristics were also observed in total CD8+ cells from aplastic anemia patients with CD8+CD57+ cell expansion by T-cell receptor deep sequencing, as well as the presence of 1-3 immunodominant clones. Oligoclonality was confirmed by T-cell receptor repertoire deep sequencing of enriched CD8+CD57+ cells, which also showed decreased diversity compared to total CD4+ and CD8+ cell pools. From analysis of complementarity-determining region 3 sequences in the CD8+ cell pool, a total of 29 sequences were shared between patients and controls, but these sequences were highly expressed in aplastic anemia subjects and also present in their immunodominant clones. In summary, expansion of effector memory CD8+ T cells is frequent in aplastic anemia and mirrors Vbeta oligoclonal expansion. Flow cytometric Vbeta usage analysis combined with deep sequencing technologies allows high resolution characterization of the T-cell receptor repertoire, and might represent a useful tool in the diagnosis and periodic evaluation of aplastic anemia patients. (Registered at clinicaltrials.gov identifiers: 00001620, 01623167, 00001397, 00071045, 00081523, 00961064). PMID- 29419435 TI - Outcomes of a large cohort of individuals with clinically ascertained high-count monoclonal B-cell lymphocytosis. PMID- 29419436 TI - Trametinib inhibits RAS-mutant MLL-rearranged acute lymphoblastic leukemia at specific niche sites and reduces ERK phosphorylation in vivo. PMID- 29419437 TI - Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. AB - MABLE investigated the efficacy and safety of rituximab plus bendamustine or rituximab plus chlorambucil in fludarabine-ineligible patients with chronic lymphocytic leukemia. Patients received rituximab plus bendamustine or rituximab plus chlorambucil every four weeks for six cycles. Rituximab plus chlorambucil treated patients without a complete response after Cycle 6 received chlorambucil monotherapy for at least six additional cycles or until complete response. The primary endpoint was complete response rate (confirmed by bone marrow biopsy) after Cycle 6 in first-line patients. Secondary endpoints included progression free survival, overall survival, minimal residual disease, and safety. Overall, 357 patients were randomized (rituximab plus bendamustine, n=178; rituximab plus chlorambucil, n=179; intent-to-treat population), including 241 first-line patients (n=121 and n=120, respectively); 355 patients received treatment (n=177 and n=178, respectively; safety population). In first-line patients, complete response rate after Cycle 6 (rituximab plus bendamustine, 24%; rituximab plus chlorambucil, 9%; P=0.002) and median progression-free survival (rituximab plus bendamustine, 40 months; rituximab plus chlorambucil, 30 months; P=0.003) were higher with rituximab plus bendamustine than rituximab plus chlorambucil. Overall response rate and overall survival were not different. In first-line patients with a complete response, minimal residual disease-negativity was higher with rituximab plus bendamustine than rituximab plus chlorambucil (66% vs 36%). Overall adverse event incidence was similar (rituximab plus bendamustine, 98%; rituximab plus chlorambucil, 97%). Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible patients with chronic lymphocytic leukemia. PMID- 29419438 TI - Clonal evolution in the transition from cutaneous disease to acute leukemia suggested by liquid biopsy in blastic plasmacytoid dendritic cell neoplasm. PMID- 29419439 TI - Safety and efficacy of exposure to bedaquiline-delamanid in multidrug-resistant tuberculosis: a case series from France and Latvia. PMID- 29419441 TI - Markers of cardiovascular autonomic dysfunction predict COPD in middle-aged subjects. AB - Autonomic dysfunction is commonly observed in chronic obstructive pulmonary disease (COPD) and may relate to the known comorbidity with coronary artery disease (CAD). We hypothesised that clinical markers of cardiovascular autonomic dysfunction predict COPD in the population, independently of CAD.In a population based cohort of 24 768 subjects (mean age 45 years) without baseline airflow obstruction, we analysed the cross-sectional relationship of one-minute orthostatic systolic (SBP) and diastolic (DBP) blood pressure changes, and resting heart rate with forced vital capacity (FVC) and forced expiratory volume (FEV1). Cox-regression-models were used to analyse the association of orthostatic SBP and DBP changes (SBP/DBP-decrease) and resting heart rate with incident COPD over 32-year follow-up.Baseline orthostatic SBP-decrease (p=0.020) and DBP decrease (p=0.001) associated with reduced FVC, whereas resting heart rate associated with reduced FVC and FEV1 (p<0.001). After adjustment for smoking and baseline lung function, SBP-decrease predicted COPD (Hazard ratio [HR] 1.10 per 10 mmHg; 95% confidence interval [CI]:1.03-1.18). Resting heart rate predicted COPD among smokers (HR 1.11 per 10 beats-per-minute increase; 95%CI:1.05-1.18). Results were similar in subjects without CAD.Subtle signs of cardiovascular autonomic dysfunction may precede development of COPD in middle-aged subjects. This association is independent of the relationship between cardiovascular autonomic dysfunction and CAD. PMID- 29419440 TI - Effect modification of perinatal exposure to air pollution and childhood asthma incidence. AB - Perinatal exposure to ambient air pollution has been associated with childhood asthma incidence, however, less is known regarding the potential effect modifiers in this association. We examined whether maternal and infant characteristics modified the association between perinatal exposure to air pollution and development of childhood asthma.761 172 births occurring between 2006 and 2012 were identified in the province of Ontario, Canada. Associations between exposure to ambient air pollutants and childhood asthma incidence (up to age 6) were estimated using Cox regression models.110,981 children with asthma were identified. In models adjusted for postnatal exposures, second trimester exposures to particulate matter with a diameter <=2.5 MUm (PM2.5) (Hazard Ratio (HR) per interquartile (IQR) increase=1.07, 95% CI: 1.06-1.09) and nitrogen dioxide (NO2) (HR per IQR increase=1.06, 95% CI: 1.03-1.08) were associated with childhood asthma development. Enhanced impacts were found among children born to mothers with asthma, those who smoked during pregnancy, boys, those born preterm, of low birth weight and among those born to mothers living in urban areas during pregnancy.Prenatal exposure to air pollution may have a differential impact on the risk of asthma development according to maternal and infant characteristics. PMID- 29419442 TI - Cross border, highly individualised treatment of a patient with challenging extensively drug-resistant tuberculosis. PMID- 29419443 TI - Inhaled granulocyte-macrophage colony-stimulating factor for Mycobacterium abscessus in cystic fibrosis. PMID- 29419445 TI - Do Recent Trends in RA Surgery Reflect Success in Disease Management? PMID- 29419444 TI - Impact of the mitochondria-targeted antioxidant MitoQ on hypoxia-induced pulmonary hypertension. AB - Increased mitochondrial reactive oxygen species (ROS), particularly superoxide have been suggested to mediate hypoxic pulmonary vasoconstriction (HPV), chronic hypoxia-induced pulmonary hypertension (PH) and right ventricular (RV) remodelling.We determined ROS in acute, chronic hypoxia and investigated the effect of the mitochondria-targeted antioxidant MitoQ under these conditions.The effect of MitoQ or its inactive carrier substance, decyltriphenylphosphonium (TPP+), on acute HPV (1% O2 for 10 minutes) was investigated in isolated blood free perfused mouse lungs. Mice exposed for 4 weeks to chronic hypoxia (10% O2) or after banding of the main pulmonary artery (PAB) were treated with MitoQ or TPP+ (50 mg/kg/day).Total cellular superoxide and mitochondrial ROS levels were increased in pulmonary artery smooth muscle cells (PASMC), but decreased in pulmonary fibroblasts in acute hypoxia. MitoQ significantly inhibited HPV and acute hypoxia-induced rise in superoxide concentration. ROS was decreased in PASMC, while it increased in the RV after chronic hypoxia. Correspondingly, MitoQ did not affect the development of chronic hypoxia-induced PH, but attenuated RV remodelling after chronic hypoxia as well as after PAB.Increased mitochondrial ROS of PASMC mediate acute HPV, but not chronic hypoxia-induced PH. MitoQ may be beneficial under conditions of exaggerated acute HPV. PMID- 29419446 TI - Underestimation of Risk of Carotid Subclinical Atherosclerosis by Cardiovascular Risk Scores in Patients with Psoriatic Arthritis: How Far Are We from the Truth? PMID- 29419447 TI - Challenges and Advances in Targeting Remission in Axial Spondyloarthritis. PMID- 29419448 TI - The Sex Influence on Response to Tumor Necrosis Factor-alpha Inhibitors and Remission in Axial Spondyloarthritis. AB - OBJECTIVE: The aim of this study was to evaluate the influence of sex on response to treatment and disease remission in patients with axial spondyloarthritis (axSpA). METHODS: In this retrospective multicenter study, patients with axSpA, according to the Assessment of Spondyloarthritis international Society (ASAS) criteria for axSpA, and treated with adalimumab, etanercept, golimumab, or infliximab, were studied. We compared clinical characteristics, patient-reported outcomes, disease activity, function, and response to treatment in male and female patients with this disease. RESULTS: Three hundred forty patients with axSpA (270 with ankylosing spondylitis, 19 with psoriatic arthritis with axial involvement, and 51 with nonradiographic axSpA) were studied. Male subjects had a significantly higher prevalence of grade IV sacroiliitis, higher levels of serum C-reactive protein, lower Maastricht Ankylosing Spondylitis Enthesitis Score, and fatigue when compared with females. Further, Kaplan-Meier survival curves showed that the rate of partial remission, ASAS40 response, and Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement, but not ASDAS inactive disease, were significantly lower in female patients. CONCLUSION: Our data suggest that female sex was associated with a lower rate of response to treatment and of disease remission in patients with axSpA treated with antitumor necrosis factor alpha drugs. PMID- 29419449 TI - Histoplasma Tenosynovitis Revealed by Fungal Culture in a Patient Treated with Infliximab. PMID- 29419450 TI - Candida albicans Pyomyositis in a Patient with Systemic Lupus Erythematosus. PMID- 29419451 TI - Does Pulmonary Involvement Play a Role in Right Ventricular Dysfunction of Patients with Idiopathic Inflammatory Myopathies? PMID- 29419452 TI - Dr. Guerra, et al reply. PMID- 29419454 TI - Safety and Efficacy of Golimumab Administered Intravenously in Adults with Ankylosing Spondylitis: Results through Week 28 of the GO-ALIVE Study. PMID- 29419453 TI - Prevalence and Clinical Significance of Anti-DFS70 in Antinuclear Antibody (ANA) positive Patients Undergoing Routine ANA Testing in a New Zealand Public Hospital. PMID- 29419455 TI - 2018 Southern Regional Meeting. PMID- 29419456 TI - Errata. PMID- 29419457 TI - AACR/SNMMI State-of-the-Art Molecular Imaging in Cancer Biology and Therapy: Abstracts. PMID- 29419458 TI - Survey of Programs About the ABR 16-Month Nuclear Radiology Pathway for Diagnostic Radiology Residents. PMID- 29419459 TI - SNMMI Leadership Update: Strengthening Outreach to Patients and the Medical Community. PMID- 29419461 TI - 2017 SNMMI Highlights Lecture: Oncology, Part 2. PMID- 29419463 TI - HLA-DRB1 Analysis Identified a Genetically Unique Subset within Rheumatoid Arthritis and Distinct Genetic Background of Rheumatoid Factor Levels from Anticyclic Citrullinated Peptide Antibodies. AB - OBJECTIVE: HLA-DRB1 is the most important locus associated with rheumatoid arthritis (RA) and anticitrullinated protein antibodies (ACPA). However, fluctuations of rheumatoid factor (RF) over the disease course have made it difficult to define fine subgroups according to consistent RF positivity for the analyses of genetic background and the levels of RF. METHODS: A total of 2873 patients with RA and 2008 healthy controls were recruited. We genotyped HLA-DRB1 alleles for the participants and collected consecutive data of RF in the case subjects. In addition to RF+ and RF- subsets, we classified the RF+ subjects into group 1 (constant RF+) and group 2 (seroconversion). We compared HLA-DRB1 alleles between the RA subsets and controls and performed linear regression analysis to identify HLA-DRB1 alleles associated with maximal RF levels. Omnibus tests were conducted to assess important amino acid positions. RESULTS: RF positivity was 88%, and 1372 and 970 RF+ subjects were classified into groups 1 and 2, respectively. RF+ and RF- showed similar genetic associations to ACPA+ and ACPA- RA, respectively. We found that shared epitope (SE) was more enriched in group 2 than 1, p = 2.0 * 10-5, and that amino acid position 11 showed a significant association between 1 and 2, p = 2.7 * 10-5. These associations were independent of ACPA positivity. SE showed a tendency to be negatively correlated with RF titer (p = 0.012). HLA-DRB1*09:01, which reduces ACPA titer, was not associated with RF levels (p = 0.70). CONCLUSION: The seroconversion group was shown to have distinct genetic characteristics. The genetic architecture of RF levels is different from that of ACPA. PMID- 29419464 TI - Muscle Strength and Muscle Endurance During the First Year of Treatment of Polymyositis and Dermatomyositis: A Prospective Study. AB - OBJECTIVE: To investigate muscle impairment (isometric and dynamic) and disease activity during the first year after diagnosis of polymyositis (PM) and dermatomyositis (DM), and to study the relationship between muscle impairment, patient-reported health, and disease activity. METHODS: Seventy-two patients enrolled in the Swedish Myositis Register, 2003-2010, were followed prospectively. The Manual Muscle test (MMT-8; isometric muscle strength), the Functional Index of myositis test (FI-2; dynamic, repetitive muscle function), and disease activity (6-item core set) were retrieved at the time of diagnosis, and after 6 and 12 months. Self-reported health (Medical Outcomes Study Short Form-36; SF-36) was retrieved at 12 months. RESULTS: At the time of diagnosis, median (Q1-Q3) for the FI-2 was 27.2% (7.9-60.5%) of maximal score compared to 93.8% (92.5-98.8%) of maximal MMT-8. At 12 months, the FI-2 and the MMT-8 improved to 29.4% (16.5-60.7%; p < 0.05) and 96.1% (88.1-99.4%), respectively (p < 0.01). At 12 months, 45% of patients improved >= 20%, and 27% worsened >= 20% in FI-2 score, while 10% improved >= 20% in MMT-8. Physician's global visual analog scale (VAS), Health Assessment Questionnaire, and creatine phosphokinase levels improved significantly at 12 months (p < 0.05-0.001) while patient's global and extramuscular VAS remained unchanged. The SF-36 physical function correlated strongly with the FI-2 (rs = 0.74; CI 0.55-0.85) and moderately with the MMT (rs = 0.54; CI 0.27-0.73), with lower correlations between muscle function and other SF-36 domains. CONCLUSION: Patients with PM/DM were characterized by impaired dynamic repetitive muscle function (DRMF) that correlated well with patient-reported physical function. Assessment of DRMF adds information regarding muscle impairment in these patients. PMID- 29419462 TI - Gaps in Diagnosis and Treatment of Cardiovascular Risk Factors in Patients with Psoriatic Disease: An International Multicenter Study. AB - OBJECTIVE: We aimed to estimate the proportion of underdiagnosis and undertreatment of cardiovascular risk factors (CVRF) in an international multicenter cohort of patients with psoriasis and psoriatic arthritis (PsA). METHODS: A cross-sectional analysis was conducted of patients with psoriatic disease from the International Psoriasis and Arthritis Research Team cohort. The presence of modifiable CVRF [diabetes, hypertension (HTN), dyslipidemia, smoking, elevated body mass index, and central obesity] and the use of appropriate therapies for HTN and dyslipidemia were determined. The 10-year CV risk was calculated according to the Framingham Risk Score. Physician adherence with guidelines for the treatment of dyslipidemia and HTN was assessed. Regression analysis was used to assess predictors of undertreatment of HTN and dyslipidemia. RESULTS: A total of 2254 patients (58.9% PsA, 41.1% psoriasis) from 8 centers in Canada, the United States, and Israel were included. Their mean age was 52 +/- 13.8 years and 53% were men. Of the patients, 87.6% had at least 1 modifiable CVRF, 45.1% had HTN, 49.4% dyslipidemia, 13.3% diabetes, 75.3% were overweight or obese, 54.3% central obesity, and 17.3% were current smokers. We found 59.2% of patients with HTN and 65.6% of patients with dyslipidemia were undertreated. Undertreatment was associated with younger age (<= 50 yrs), having psoriasis, and male sex. CONCLUSION: In real-world settings, a large proportion of patients with psoriasis and PsA were underdiagnosed and undertreated for HTN and dyslipidemia. Strategies to improve the management of CVRF in psoriatic patients are warranted. PMID- 29419465 TI - Safety, and Humoral and Cell-mediated Immune Responses to Herpes Zoster Vaccine in Patients with Rheumatoid Arthritis. AB - OBJECTIVE: To examine humoral and cellular immune responses induced by a live attenuated herpes zoster (HZ) vaccine in patients with rheumatoid arthritis (RA) compared with osteoarthritis (OA) patients. METHODS: This was an observational study of a live attenuated HZ vaccine in 41 patients with RA receiving conventional disease-modifying antirheumatic drugs (cDMARD) and/or low-dose glucocorticoids (GC) and in 28 patients with OA. Blood samples were obtained before and at 12 weeks after HZ vaccination. Immunogenicity was assessed using varicella zoster virus (VZV)-specific interferon gamma ELISA and an in-house ELISA. Clinical outcomes, including adverse events, HZ occurrence, and RA flares, were analyzed. RESULTS: No patients developed vaccination-induced HZ during the followup period (median = 1.6 yrs). The HZ vaccine induced a significant increase in the VZV-specific enzyme-linked immunospot spot-forming units and anti-VZV immunoglobulin G antibodies in patients with RA and OA. The number of spot forming units was lower in patients with RA than in patients with OA both at baseline and at 12 weeks after vaccination. The disease activity index for patients with RA was similar at baseline and at 12 weeks after vaccination. However, 6 patients with RA (14.6%) experienced a flare during the 12 weeks. Overall, 17 (24.6%) participants reported a mild adverse event such as an injection site reaction (11.6%). CONCLUSION: The HZ vaccine induced VZV-specific cellular and humoral responses in patients with RA. Although patients with RA showed a weaker vaccine-induced VZV-specific cellular immune response than patients with OA, the vaccine may be considered in patients with RA receiving cDMARD and/or low dose GC. PMID- 29419466 TI - Sclerostin and Antisclerostin Antibody Serum Levels Predict the Presence of Axial Spondyloarthritis in Patients with Inflammatory Bowel Disease. AB - OBJECTIVE: The early diagnosis of inflammatory bowel disease (IBD)-associated spondyloarthritis (SpA/IBD) in patients affected by IBD represents a major topic in clinical practice; in particular, to date there are no available serum biomarkers revealing the presence of joint inflammation in these patients. Sclerostin (SOST), an antagonist of the Wnt/beta-catenin pathway, and antisclerostin-immunoglobulin G (anti-SOST-IgG) have been recently studied in patients with ankylosing spondylitis (AS) as a putative marker of disease activity. METHODS: SOST and anti-SOST-IgG serum levels were assayed in 125 patients with IBD, 85 with axial or peripheral SpA, and in control groups (patients with AS and rheumatoid arthritis, and healthy individuals). The diagnostic performance in discriminating the presence of SpA/IBD was assessed for both candidate biomarkers. RESULTS: Patients affected by SpA/IBD with axial involvement displayed significantly lower levels of SOST and higher levels of anti-SOST-IgG compared to patients with only peripheral arthritis, IBD, and controls. Moreover, SOST and anti-SOST-IgG serum levels were inversely correlated and were associated with the duration of articular symptoms. Both biomarkers showed good accuracy in predicting the presence of axial SpA in patients with IBD. CONCLUSION: We demonstrated that in patients with IBD, SOST and anti-SOST IgG might represent novel biomarkers to assess the presence of axial joint involvement. Moreover, the development of anti-SOST-IgG and the subsequent decrease of SOST serum levels could play a role in the pathogenesis of SpA/IBD. PMID- 29419468 TI - Disparities in Outcomes for Blacks versus Whites Undergoing Total Hip Arthroplasty: A Systematic Literature Review. AB - OBJECTIVE: Total hip replacement (THA) surgery is a successful procedure, yet blacks in the United States undergo THA less often and reflect poorer outcomes than whites. The purpose of this study is to systematically review the literature on health-related quality of life after THA, comparing blacks and whites. METHODS: A librarian-assisted search was performed in Medline through PubMed, Embase, and Cochrane Library on February 27, 2017. Original cohort studies examining pain, function, and satisfaction in blacks and whites 1 year after elective THA were included. Using the Patient/Population-Intervention Comparison/Comparator-Outcome (PICO) process format, our population of interest was US black adults, our intervention was elective THA, our comparator was white adults, and our outcomes of interest were pain, function, and satisfaction after elective THA. The protocol was registered under the PROSPERO international register, and the Preferred Reporting Items for Systematic reviews and Meta Analyses (PRISMA) guidelines were followed. RESULTS: Of the articles, 4739 were screened by title, 180 by abstract, 25 by full text, and 4 remained for analysis. The studies represented 1588 THA patients, of whom 240 (15%) were black. All studies noted more pain and worse function for blacks; although differences were statistically significant, they were not clinically significant. One study sought and identified less satisfaction for blacks after THA, and 1 study showed worse fear and anxiety scores in blacks. CONCLUSION: When measured, there are small differences in THA outcomes between blacks and whites, but most studies do not analyze/collect race. Future studies should address the effect of race and socioeconomic factors on healthcare disparities. PMID- 29419467 TI - Barriers to Adherence in Juvenile Idiopathic Arthritis: A Multicenter Collaborative Experience and Preliminary Results. AB - OBJECTIVE: Nonadherence is currently an underrecognized and potentially modifiable obstacle to care in juvenile idiopathic arthritis (JIA). The purpose of our study was to design and implement a standardized approach to identifying adherence barriers for youth with JIA across 7 pediatric rheumatology clinics through the Pediatric Rheumatology Care and Outcomes Improvement Network (PR COIN) and to assess the frequency of adherence barriers in patients and their caregivers across treatment modalities. METHODS: An iterative process using coproduction among parents and providers of patients with JIA was used to design the Barriers Assessment Tool to screen for adherence barriers across 4 treatment modalities (i.e., oral medications, injectable medications, infusions, and physical/occupational therapy). This tool was implemented in 7 rheumatology clinics across the United States and patient responses were collected for analysis. RESULTS: Data were collected from 578 parents and 99 patients (n = 44 parent-child dyads). Seventy-seven percent (n = 444) of caregivers and 70% (n = 69) of patients reported at least 1 adherence barrier across all treatment components. The most commonly reported adherence barriers included worry about future consequences of therapy, pain, forgetting, side effects, and embarrassment related to the therapy. There was no significant difference between endorsement of barriers between parents and adolescents. CONCLUSION: Implementing a standardized tool assessing adherence barriers in the JIA population across multiple clinical settings is feasible. Systematic screening sheds light on the factors that make adherence difficult in JIA and identifies targets for future adherence interventions in clinical practice. PMID- 29419470 TI - Occupation, Physical Workload Factors, and Disability Retirement as a Result of Hip Osteoarthritis in Finland, 2005-2013. AB - OBJECTIVE: To identify occupations with a high risk of disability retirement as a result of hip osteoarthritis (OA), and to examine the effect of physical workload factors on the occupational differences in disability retirement. METHODS: A total of 1,135,654 (49.4% women) Finns aged 30-60 years in gainful employment were followed from 2005 to 2013 for full disability retirement as a result of hip OA. Information on pensions, occupation, and education were obtained from national registers. Physical workload was assessed by a sex-specific job exposure matrix. We calculated age-adjusted incidence rates and examined the associations of occupation, education, and physical workload factors with disability retirement using a competing risk regression model. RESULTS: Age-adjusted incidence rate was 25 and 22 per 100,000 person-years in men and women, respectively. Both men and women working in lower-level nonmanual and manual occupations had an elevated age-adjusted risk of disability retirement as a result of hip OA. A very high risk of disability retirement was found among male construction workers, electricians, and plumbers (HR 12.7, 95% CI 8.4-19.7), and female professional drivers (HR 15.2, 95% CI 7.5-30.8) as compared with professionals. After adjustment for age and education, the observed occupational differences in disability retirement were largely explained by physical workload factors among men and to a smaller extent, among women. CONCLUSION: Our results suggest that education and physical workload factors appear to be the major reasons for excess disability retirement as a result of hip OA in manual occupations, particularly among men. PMID- 29419469 TI - Risk Factors for Relapse of Antineutrophil Cytoplasmic Antibody-associated Vasculitis in Japan: A Nationwide, Prospective Cohort Study. AB - OBJECTIVE: The aim was to elucidate the prognosis and risk factors associated with relapse during longterm remission maintenance therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Patients with newly diagnosed AAV (n = 156) were registered in the Remission Induction Therapy in Japanese patients with ANCA-associated Vasculitides (RemIT-JAV) study, and among them, 83 patients who achieved remission were enrolled and followed up for 24 additional months in our nationwide, prospective cohort study (Co-RemIT-JAV; registration number UMIN 000006373). Patterns of maintenance therapy, effectiveness, and safety were evaluated from months 25 to 48 after the RemIT JAV. The primary outcome measure was the rate of relapse. Secondary outcome measures included overall and renal survival, risk factors associated with relapse, and incidence rates of serious infections. RESULTS: The patients comprised 35 men and 48 women aged 65.3 +/- 12.6 years. Between months 25 and 48, the survival rate was 95% (79/83). Causes of death included 1 thyroid cancer, 1 infection, and 2 unknown reasons. Four patients had developed endstage renal disease (ESRD) by Month 24; 1 developed ESRD beyond Month 25. The relapse rate was 24% (20/83) from months 25 to 48. Multivariable analysis revealed that oral prednisolone <= 2.5 mg/day at Month 24 was a significant risk factor for relapse between months 25 and 48 (HR = 3.1, 95% CI 1.1-8.5). CONCLUSION: One-quarter of patients with AAV relapsed during maintenance therapy, and relapse was associated with the dose of oral prednisolone 24 months after the initiation of remission induction therapy in Japan. PMID- 29419471 TI - Increased Levels of Soluble Programmed Death Ligand 1 Associate with Malignancy in Patients with Dermatomyositis. AB - OBJECTIVE: To investigate the levels of soluble programmed death ligand 1 (sPD L1) and evaluate its association with malignancy in patients with dermatomyositis (DM). METHODS: Levels of sPD-L1 were measured in serum from 88 DM patients without malignancies (sDM), 40 with cancer-related DM (CRDM), and 30 healthy controls (HC) using ELISA. The CRDM subjects were divided into new-onset cancers (nCRDM) and stable cancers (sCRDM). Receiver-operating characteristic (ROC) curve analysis was performed to determine the cutoff sPD-L1 value that distinguished patients with nCRDM from those who were sDM. Serum antitranscriptional intermediary factor 1-gamma (TIF1-gamma) antibodies were detected using immunoblot, and the diagnostic values for malignancy were compared with sPD-L1 levels in patients with DM. RESULTS: Serum sPD-L1 levels were significantly higher in sDM [median 12.3 ng/ml, interquartile range (IQR) 8.4-16.2] than in HC (median 1.3 ng/ml, IQR 0.4-2.2, p = 0.0001). Extremely high sPD-L1 levels were seen in nCRDM (median 18.5 ng/ml, IQR 13.8-22.4), much higher than those in sCRDM (median 8.5 ng/ml, IQR 6.8-11.8, p = 0.0001). The sPD-L1 levels in 4 patients with nCRDM decreased after curative cancer treatment (p = 0.013). ROC curve analysis revealed that the sPD-L1 value distinguishing nCRDM from sDM was 16.1 ng/ml, with an area under the curve value of 0.72 +/- 0.04 (p = 0.0001). The combination of sPD-L1 and anti-TIF1-gamma antibodies yielded greater specificity and positive predictive value in diagnosing cancer, reaching values of 95% and 70%, respectively. CONCLUSION: Serum sPD-L1 levels increased significantly in sDM, and markedly high sPD-L1 levels could be a diagnostic indicator for malignancies in patients with DM, especially in those with anti-TIF1-gamma antibodies. PMID- 29419472 TI - Application of Recommendations Regarding the Use of Subcutaneous Tumor Necrosis Factor Inhibitors in Spondyloarthritis by Rheumatologists in Daily Practice. AB - OBJECTIVE: To assess the implementation of European recommendations for use of TNF inhibitors for spondyloarthritis (SpA), rheumatologists' level of knowledge of and adherence to the recommendations, and potential barriers to the application of recommendations. METHODS: We conducted a retrospective study among 42 rheumatologists who initiated a first subcutaneous TNF inhibitor for SpA in 2013 or 2014. Thirty items from national and international recommendations were separated into 3 domains: indication, pretherapeutic monitoring, and management under TNF inhibitors. A standardized data collection procedure was used to gather data from medical files to assess the application of each recommendation. Questionnaires assessing the knowledge, level of adherence to each recommendation, and potential barriers to their implementation were sent to rheumatologists. RESULTS: Rheumatologists applied a mean of 60% of items from domains A and B, but less than 50% from domain C items. Recommendations regarding the search for previous infection and the prevention of future infections were the ones most often applied. However, < 60% of rheumatologists assessed cancer and other diseases before TNF inhibitor initiation. More than 95% of rheumatologists knew of the recommendations and had a high level of adherence. Lack of time, difficulties accessing specialized consultations, and lack of flexibility in the recommendations explained rheumatologists' difficulties in applying the recommendations. CONCLUSION: Despite high levels of knowledge of, and adherence to, recommendations for using TNF inhibitors for SpA, rheumatologists' application was limited because of a lack of human and material resources. PMID- 29419474 TI - Frequency, Diagnosis, Treatment, and Outcome of Gastrointestinal Disease in Granulomatosis with Polyangiitis and Microscopic Polyangiitis. AB - OBJECTIVE: Involvement of the gastrointestinal (GI) tract is a rare complication of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The aim was to describe frequency, diagnosis, treatment, and outcome of GI disease in a large series of patients in a single center. METHODS: A database that includes all patients with GPA and MPA diagnosed since 1997 in a defined area of southeastern Sweden as well as prevalent older cases and tertiary referral patients was screened for patients with GI disease. Data were retrieved from the patient's medical records, and GI manifestations of vasculitis were defined as proposed by Pagnoux, et al in 2005. RESULTS: Fourteen (6.5%) of 216 consecutive patients with GPA/MPA had GI manifestations. Abdominal pain and GI bleeding were the most common symptoms. Radiology was important for detection of GI disease, while endoscopy failed to support the diagnosis in many patients. Because of perforation, 5 patients underwent hemicolectomy or small intestine resection. Primary anastomosis was created in 2/5 and enterostomy in 3/5 patients. One patient had a hemicolectomy because of lower GI bleeding. One sigmoid abscess was treated with drainage, and 1 intraabdominal bleeding condition with arterial coiling. Two patients died from GI disease. GPA and MPA patients with and without GI disease exhibited a similar overall survival. CONCLUSION: GI disease was found in 6.5% among 216 patients with GPA or MPA. Surgery was judged necessary only in cases with GI perforation or severe bleeding. Multidisciplinary engagement is strongly recommended. PMID- 29419473 TI - Feasibility, Validity, and Reliability of the 10-item Patient Reported Outcomes Measurement Information System Global Health Short Form in Outpatients with Systemic Lupus Erythematosus. AB - OBJECTIVE: To assess the feasibility, validity, and reliability of the Patient Reported Outcomes Measurement Information System Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE). METHODS: SLE outpatients completed PROMIS10, Medical Outcomes Study Short Form-36 (SF-36), LupusQoL-US, and selected PROMIS computerized adaptive tests (CAT) at routine visits at an SLE Center of Excellence. Construct validity was evaluated by correlating PROMIS10 physical and mental health scores with PROMIS CAT, legacy instruments, and physician-derived measures of disease activity and damage. Test retest reliability was determined among subjects reporting stable SLE activity at 2 assessments 1 week apart using intraclass correlation coefficients (ICC). RESULTS: A diverse cohort of 204 out of 238 patients with SLE (86%) completed survey instruments. PROMIS10 physical health scores strongly correlated with physical function, pain, and social health domains in PROMIS CAT, SF-36, and LupusQoL, while mental health scores strongly correlated with PROMIS depression CAT, SF-36, and LupusQoL mental health domains (Spearman correlations >= 0.70). Active arthritis, comorbid fibromyalgia (FM), and anxiety were associated with worse PROMIS10 scores, but sociodemographic factors and physician-assessed flare status were not. Test-retest reliability for PROMIS10 physical and mental health scores was high (ICC >= 0.85). PROMIS10 required < 2 minutes to complete. CONCLUSION: PROMIS10 is valid and reliable, and can efficiently screen for impaired physical function, pain, and emotional distress in outpatients with SLE. With strong correlations to LupusQoL and SF-36 but significantly reduced responder burden, PROMIS10 is a promising tool for measuring patient-reported outcomes in routine SLE clinical care and value-based healthcare initiatives. PMID- 29419475 TI - Biochemical Recurrence of Prostate Cancer: Initial Results with [18F]PSMA-1007 PET/CT. AB - Biochemical recurrence (BCR) is a concern for prostate cancer patients after local treatment. 68Ga-labeled prostate-specific membrane antigen (PSMA) ligands have significantly improved prostate cancer imaging. However, several 18F-labeled ligands that were developed as fluorinated tracers might present advantages. In this study, we analyzed the potential of 18F-PSMA-1007 in patients with BCR. Methods: Twelve patients with BCR after local treatment underwent PET/CT scans 1 and 3 h after injection of 18F-PSMA-1007. Results:18F-PSMA-1007 PET/CT detected lesions in 9 of 12 patients (75%). A significant difference was observed when comparing the tracer uptake in 18F-PSMA-1007-positive lesions 1 and 3 h after injection (median SUVmax, 7.00 vs. 11.34; P < 0.001; n = 76). Forty-four (88%) of 50 18F-PSMA-1007-positive lymph nodes had a short-axis diameter of less than 8 mm. Conclusion: In this pilot study, 18F-PSMA-1007 PET/CT presented high potential for localization of recurrent disease in prostate cancer patients with BCR. PMID- 29419476 TI - Reply: Staging, Restaging, and Treatment Response Assessment in Lymphomas: What We Should Know. PMID- 29419477 TI - Imaging for Pulmonary Embolism in Sickle Cell Disease: A 17-Year Experience. AB - Sickle cell disease, a complex disorder with known pulmonary complications, has the potential to confound the diagnosis of pulmonary embolism. We hypothesized that when the choice of imaging is guided by chest radiographic results, CT pulmonary angiography (CTPA) and ventilation-perfusion (V/Q) scintigraphy have comparable diagnostic performance in sickle cell disease. Methods: A retrospective cohort of adults with sickle cell disease who were imaged for suspected pulmonary embolism with either CTPA or V/Q, from 2000 to 2016 at our institution, was established. To reduce radiation exposure, our practice recommends V/Q for stable patients with normal chest radiographs. Results of index pulmonary embolism imaging, 90-d follow-up, and results of chest radiography were recorded. Results: Two hundred forty-five adults with sickle cell disease comprised the cohort. The mean age (+/-SD) was 33 +/- 10.5 y, and 58% (141) were men. Index imaging was V/Q in 62.9% (n = 154) and CTPA in 37.1% (n = 91). Chest radiographs, performed in 96.3% (n = 236), were normal in 72.9% (n = 172). Imaging results for pulmonary embolism were negative in 88.2% (n = 216), positive in 4.1% (n = 10), and indeterminate in 7.8% (n = 19) with no difference between V/Q and CTPA (P = 0.63). Reimaging within 90 d occurred in 9.8% (n = 24), 14.7% (20/136) after initial V/Q, and 5% (4/109) after initial CTPA (P = 0.08). Reimaging revealed a pulmonary embolism diagnosis after negative/indeterminate results in 0.7% (1/149) of V/Qs and 1.2% of (1/86) CTPAs (P = 0.69). Over the 17 y study period, 47% (114/245) underwent repeated imaging, and 11% (27/245) were diagnosed with pulmonary embolism at least once. Conclusion: In sickle cell disease patients with suspected pulmonary embolism, positive imaging rates were low for any given clinical presentation, but 11% of the cohort was diagnosed with pulmonary embolism over the 17-y study period. CTPA and V/Q performed comparably for pulmonary embolism diagnosis when the choice of imaging was guided by results of chest radiography. Hence, V/Q is a reasonable first choice for sickle cell disease patients with normal chest radiographs. PMID- 29419478 TI - 18F-Fludarabine PET for Lymphoma Imaging: First-in-Humans Study on DLBCL and CLL Patients. AB - This was the first-in-humans clinical study of 18F-fludarabine, which is a radiopharmaceutical for PET imaging in lymphoma, for which many issues remain controversial with the standard radiotracer 18F-FDG. Methods:18F-fludarabine PET or PET/CT was performed on 10 patients: 5 with diffuse large B-cell lymphoma (DLBCL) and 5 with chronic lymphocytic leukemia. The tumor uptake, biodistribution, and radiation dosimetry of 18F-fludarabine were evaluated. Six successive partial-body PET scans were acquired for 250 min after an intravenous 4 MBq/kg bolus of 18F-fludarabine. SUVs were recorded for each involved lymph node territory and for several extranodal sites, with particular reference to the liver. To assess the time-related uptake profile of 18F-fludarabine, PET images were analyzed by delineating volumes of interest over the uptake sites on the optimal scan for visual observation and were projected onto all coregistered scans of the same subject. Physical examination, laboratory studies, and contrast enhanced CT were performed on all patients. For the DLBCL group, 18F-FDG PET was also considered. Results: In DLBCL patients, increased 18F-fludarabine uptake was observed in sites considered abnormal by CT or 18F-FDG, with SUVs significantly higher in involved lesions than in physiologic nontarget sites. Nonetheless, the comparison of 18F-fludarabine and 18F-FDG PET showed discrepancies in 2 patients. In chronic lymphocytic leukemia patients, the uptake of 18F-fludarabine coincided with sites expected to be involved (including splenic invasion) according to conventional clinical and CT staging and was significant in hematopoietic bone marrow. No uptake was observed, whatever the disease group, in cardiac muscle or brain. The mean effective dose from a mean injected 18F-fludarabine activity of 305 +/- 76 MBq was 3.07 +/- 0.81 mSv. Conclusion:18F-fludarabine PET might well be a promising tool for lymphoproliferative diseases. The radiation dose of this radiopharmaceutical is below that of 18F-FDG. The specificity of this PET probe for lymphoid cells, its absence of accumulation in reactive tissues, and its feasibility for detection of bone marrow infiltration might play an innovative role in lymphoma imaging. PMID- 29419479 TI - The Effect of Total Tumor Volume on the Biologically Effective Dose to Tumor and Kidneys for 177Lu-Labeled PSMA Peptides. AB - The aim of this work was to simulate the effect of prostate-specific membrane antigen (PSMA)-positive total tumor volume (TTV) on the biologically effective doses (BEDs) to tumors and organs at risk in patients with metastatic castration resistant prostate cancer who are undergoing 177Lu-PSMA radioligand therapy. Methods: A physiologically based pharmacokinetic model was fitted to the data of 13 patients treated with 177Lu-PSMA I&T (a PSMA inhibitor for imaging and therapy). The tumor, kidney, and salivary gland BEDs were simulated for TTVs of 0.1-10 L. The activity and peptide amounts leading to an optimal tumor-to-kidneys BED ratio were also investigated. Results: When the TTV was increased from 0.3 to 3 L, the simulated BEDs to tumors, kidneys, parotid glands, and submandibular glands decreased from 22 +/- 15 to 11.0 +/- 6.0 Gy1.49, 6.5 +/- 2.3 to 3.7 +/- 1.4 Gy2.5, 11.0 +/- 2.7 to 6.4 +/- 1.9 Gy4.5, and 10.9 +/- 2.7 to 6.3 +/- 1.9 Gy4.5, respectively (where the subscripts denote that an alpha/beta of 1.49, 2.5, or 4.5 Gy was used to calculate the BED). The BED to the red marrow increased from 0.17 +/- 0.05 to 0.32 +/- 0.11 Gy15 For patients with a TTV of more than 0.3 L, the optimal amount of peptide was 273 +/- 136 nmol and the optimal activity was 10.4 +/- 4.4 GBq. Conclusion: This simulation study suggests that in patients with large PSMA-positive tumor volumes, higher activities and peptide amounts can be safely administered to maximize tumor BEDs without exceeding the tolerable BED to the organs at risk. PMID- 29419480 TI - Comparative In Vitro and In Vivo Quantifications of Pathologic Tau Deposits and Their Association with Neurodegeneration in Tauopathy Mouse Models. AB - Fibrillary tau aggregates in Alzheimer disease and allied neurodegenerative disorders have been visualized in vivo by PET, whereas mechanistic links between PET-detectable tau deposits and neurotoxicity remain elusive. Here, we took advantage of transgenic mouse models of tauopathies to evaluate associations between PET and postmortem measures of tau probe binding and their relation to neuronal loss. Methods: PET with a tau probe, 11C-PBB3 (2-((1E,3E)-4-(6-(11C methylamino)pyridine-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol), and volumetric MRI were performed for transgenic rTg4510 mice and nontransgenic mice. Binding of 11C-PBB3 and its blockade by another tau binding compound, AV-1451 (-(6 fluoropyridine-3-yl)-5H-pyrido[4,3-b]indole), in homogenized brains of tauopathy patients and rTg4510 and PS19 mice were quantified, and 11C-PBB3-positive and phosphorylated tau lesions in sectioned brains of these mice were assessed. Results: In vivo 11C-PBB3 binding to the rTg4510 neocortex/hippocampus was increased relative to controls and correlated with local atrophy. In vitro 11C PBB3 binding in the neocortex/hippocampus also correlated well with in vivo radioligand binding and regional atrophy in the same individual rTg4510 mice. By contrast, in vitro 11C-PBB3 binding was elevated in the brain stem but not hippocampus of PS19 mice, despite a pronounced loss of neurons in the hippocampus rather than brain stem. Finally, 11C-PBB3 and AV-1451 showed similar binding properties between mouse models and tauopathy patients. Conclusion: The present findings support the distinct utilities of 11C-PBB3 PET and MRI in rTg4510 and PS19 mice for quantitatively pursuing mechanisms connecting PET-detectable and PET-undetectable tau aggregations to neuronal death, which recapitulate 2 different modes of tau-provoked neurotoxicity. PMID- 29419481 TI - Noninvasive Whole-Body Imaging of Phosphatidylethanolamine as a Cell Death Marker Using 99mTc-Duramycin During TNF-Induced SIRS. AB - Systemic inflammatory response syndrome (SIRS) is an inflammatory state affecting the whole body. It is associated with the presence of pro- and antiinflammatory cytokines in serum, including tumor necrosis factor (TNF). TNF has multiple effects and leads to cytokine production, leukocyte infiltration, and blood pressure reduction and coagulation, thereby contributing to tissue damage and organ failure. A sterile mouse model of sepsis, TNF-induced SIRS, was used to visualize the temporal and spatial distribution of damage in susceptible tissues during SIRS. For this, a radiopharmaceutical agent, 99mTc-duramycin, that binds to exposed phosphatidylethanolamine on dying cells was longitudinally visualized using SPECT/CT imaging. Methods: C57BL/6J mice were challenged with intravenous injections of murine TNF or vehicle, and necrostatin-1 was used to interfere with cell death. Two hours after vehicle or TNF treatment, mice received 99mTc duramycin intravenously (35.44 +/- 3.80 MBq). Static whole-body 99mTc-duramycin SPECT/CT imaging was performed 2, 4, and 6 h after tracer injection. Tracer uptake in different organs was quantified by volume-of-interest analysis using PMOD software and expressed as SUVmean After the last scan, ex vivo biodistribution was performed to validate the SPECT imaging data. Lastly, terminal deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining was performed to correlate the obtained results to cell death. Results: An increased 99mTc-duramycin uptake was detected in mice injected with TNF, when compared with control mice, in lungs (0.55 +/- 0.1 vs. 0.34 +/- 0.05), intestine (0.75 +/- 0.13 vs. 0.56 +/- 0.1), and liver (1.03 +/- 0.14 vs. 0.64 +/- 0.04) 4 h after TNF and remained significantly elevated until 8 h after TNF. The imaging results were consistent with ex vivo gamma-counting results. Significantly increased levels of tissue damage were detected via TUNEL staining in the lungs and intestine of mice injected with TNF. Interestingly, necrostatin 1 pretreatment conferred protection against lethal SIRS and reduced the 99mTc duramycin uptake in the lungs 8 h after TNF (SUV, 0.32 +/- 0.1 vs. 0.51 +/- 0.15). Conclusion: This study demonstrated that noninvasive 99mTc-duramycin SPECT imaging can be used to characterize temporal and spatial kinetics of injury and cell death in susceptible tissues during TNF-induced SIRS, making it useful for global, whole-body assessment of tissue damage during diseases associated with inflammation and injury. PMID- 29419482 TI - Reply: Molecular Imaging of Bacteria in Patients Is an Attractive Fata Morgana, Not a Realistic Option. PMID- 29419483 TI - Development and Evaluation of mini-EXPLORER: A Long Axial Field-of-View PET Scanner for Nonhuman Primate Imaging. AB - We describe a long axial field-of-view (FOV) PET scanner for high-sensitivity and total-body imaging of nonhuman primates and present the physical performance and first phantom and animal imaging results. Methods: The mini-EXPLORER PET scanner was built using the components of a clinical scanner reconfigured with a detector ring diameter of 43.5 cm and an axial length of 45.7 cm. National Electrical Manufacturers Association (NEMA) NU-2 and NU-4 phantoms were used to measure sensitivity and count rate performance. Reconstructed spatial resolution was investigated by imaging a radially stepped point source and a Derenzo phantom. The effect of the wide acceptance angle was investigated by comparing performance with maximum acceptance angles of 14 degrees -46 degrees . Lastly, an initial assessment of the in vivo performance of the mini-EXPLORER was undertaken with a dynamic 18F-FDG nonhuman primate (rhesus monkey) imaging study. Results: The NU-2 total sensitivity was 5.0%, and the peak noise-equivalent count rate measured with the NU-4 monkey scatter phantom was 1,741 kcps, both obtained using the maximum acceptance angle (46 degrees ). The NU-4 scatter fraction was 16.5%, less than 1% higher than with a 14 degrees acceptance angle. The reconstructed spatial resolution was approximately 3.0 mm at the center of the FOV, with a minor loss in axial spatial resolution (0.5 mm) when the acceptance angle increased from 14 degrees to 46 degrees . The rhesus monkey 18F-FDG study demonstrated the benefit of the high sensitivity of the mini-EXPLORER, including fast imaging (1-s early frames), excellent image quality (30-s and 5-min frames), and late-time-point imaging (18 h after injection), all obtained at a single bed position that captured the major organs of the rhesus monkey. Conclusion: This study demonstrated the physical performance and imaging capabilities of a long axial FOV PET scanner designed for high-sensitivity imaging of nonhuman primates. Further, the results of this study suggest that a wide acceptance angle can be used with a long axial FOV scanner to maximize sensitivity while introducing only minor trade-offs such as a small increase in scatter fraction and slightly degraded axial spatial resolution. PMID- 29419484 TI - Vitamin D shows in vivo efficacy in a placebo-controlled, double-blinded, randomised clinical trial on canine atopic dermatitis. AB - Atopic dermatitis (AD) in dogs is among the most common skin diseases in small animal practice. It is an inflammatory disease based on a genetic predisposition to develop hypersensitivity against environmental and food allergens and typical clinical signs up exposure. Treatment sometimes can be difficult and associated with adverse effects. Previous studies evaluating cholecalciferol as treatment for human AD have shown promising results. With canine AD being a good animal model for its human counterpart, it was hypothesised that cholecalciferol might have beneficial clinical effects in dogs, too. In this randomised, placebo controlled, double-blinded eight-week cross-over study, 23 client-owned dogs received either systemic cholecalciferol (n=16), a vitamin D receptor analogue (n=8) or placebo (n=13). Blood samples for ionised calcium were obtained regularly during the study, and Canine Atopic Dermatitis Extent and Severity Index and pruritus scores, blood levels of vitamin D metabolites, measurements of skin pH and transepidermal water loss were determined before and after. Pruritus and lesion scores decreased significantly in the cholecalciferol group versus placebo. No differences in water loss or skin pH were observed. An increase in serum 25-hydroxycholecalciferol strongly correlated with a reduction in pruritus. Systemic cholecalciferol may be a viable treatment option for canine AD. PMID- 29419485 TI - Recurrent pyoderma and its underlying primary diseases: a retrospective evaluation of 157 dogs. AB - Bacterial pyoderma is common in small animal practice. Usually there is an associated underlying disease, but little is known about the prevalence of underlying diseases in dogs with recurrent pyoderma. The aim of this study was to analyse the frequency of the different underlying diseases in dogs with recurrent pyoderma. In total, 157 animals with recurrent pyoderma were identified in hospital records from 2008 to 2013 and the data analysed for primary diseases. The time between recurrences, the type of clinical signs and the age at pyoderma onset were also evaluated. At least one primary disease was found in 107 dogs. Allergies were the primary cause in 63 dogs, environmental allergy was the most frequent (n=45) and was often associated with other allergies, followed by hypothyroidism (n=12) and hyperadrenocorticism (n=6). Sixteen dogs with recurrent pyoderma suffered from demodicosis. In young dogs with recurrent pyoderma an allergy work-up combined with deep skin scrapings should lead to a diagnosis of the underlying disease in most of the cases. In dogs in which pyoderma began in middle or old age, hormonal testing and ruling out a possible flea infestation should be the first steps. PMID- 29419486 TI - Occurrence of dysentery-like diarrhoea associated with Brachyspira suanatina infection in a German fattening pig farm. AB - The anaerobic intestinal spirochaete Brachyspira (B.) suanatina was first described in 2007 but since then no further isolates have been reported from pigs. Accordingly, when the species was validly published in 2016, the overall occurrence and clinical relevance in pigs were unknown. In a fattening farm in southern Germany, mucohaemorrhagic diarrhoea was observed in 60 per cent (750 animals) of the finisher pigs. A diagnostic workup including Brachyspira culture, Salmonella culture, Lawsonia intracellularis-specific, B. hyodysenteriae-specific and B. pilosicoli-specific multiplex PCR and postmortem examination of severely affected pigs was performed. Tests for Salmonella species, Lawsonia intracellularis and B. hyodysenteriae were all negative. Gross and microscopic lesions were in agreement with dysentery and spirochaetes could be demonstrated by silver staining in tissue samples of the caecum at the ileal papilla. B. suanatina was cultured from faeces or colon of all (five) animals sampled and identified using nox-RFLP, partial nox-gene-sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). According to the initial report from Scandinavia, B. suanatina can be isolated from birds and cross-species infection could be demonstrated infecting pigs with an avian isolate. Thus outdoor production as in the case presented here and international trade may pose a risk for infection of naive herds. PMID- 29419488 TI - Dual use of electronic nicotine delivery systems (ENDS) and smoked tobacco: a qualitative analysis. AB - INTRODUCTION: Electronic nicotine delivery systems (ENDS) arguably pose fewer health risks than smoking, yet many smokers adopt ENDS without fully relinquishing smoking. Known as 'dual use', this practice is widespread and compromises the health benefits that ENDS may offer. To date, few studies have explored how dual use practices arise and manifest. METHODS: We conducted in depth, semi-structured interviews with 20 current ENDS users from New Zealand who reported smoking tobacco at least once a month. We explored participants' smoking history, their recent and current smoking, trial, uptake and patterns of ENDS use, and future smoking and vaping intentions. We managed the data using NVivo V.11 and used a thematic analysis approach to interpret the transcripts. RESULTS: Dual use practices among participants evolved in four ways. First, as an attempt to manage the 'inauthenticity' of vaping relative to smoking and to retain meaningful rituals. Second, as complex rationalisations that framed decreased tobacco use, rather than smoking cessation, as 'success'. Third, as a means of alleviating the financial burden smoking imposed and to circumvent smoke-free policies. Lastly, dual use reflected attempts to comply with social group norms and manage stigma. CONCLUSIONS: Dual use reflects both social and physical cues. It assisted participants to navigate smoking restrictions and allowed them to manage divergent norms. Policies that discourage smoking, particularly excise tax increases on smoked tobacco and smoke-free space restrictions, appear important in prompting ENDS use. Future research could explore whether these policies also help foster complete transition from smoking to exclusive ENDS use. PMID- 29419489 TI - Taking the pet out of petrified. PMID- 29419490 TI - International pay league table: where does the UK fit on the global scale? PMID- 29419491 TI - Data protection: fines last resort for practices. PMID- 29419487 TI - Genetically engineered pigs as models for human disease. AB - Genetically modified animals are vital for gaining a proper understanding of disease mechanisms. Mice have long been the mainstay of basic research into a wide variety of diseases but are not always the most suitable means of translating basic knowledge into clinical application. The shortcomings of rodent preclinical studies are widely recognised, and regulatory agencies around the world now require preclinical trial data from nonrodent species. Pigs are well suited to biomedical research, sharing many similarities with humans, including body size, anatomical features, physiology and pathophysiology, and they already play an important role in translational studies. This role is set to increase as advanced genetic techniques simplify the generation of pigs with precisely tailored modifications designed to replicate lesions responsible for human disease. This article provides an overview of the most promising and clinically relevant genetically modified porcine models of human disease for translational biomedical research, including cardiovascular diseases, cancers, diabetes mellitus, Alzheimer's disease, cystic fibrosis and Duchenne muscular dystrophy. We briefly summarise the technologies involved and consider the future impact of recent technical advances. PMID- 29419492 TI - No brachys here, says New Zealand website. PMID- 29419494 TI - Summit delegates clash over antibiotic use. PMID- 29419495 TI - Tackling the prevalence of bovine TB in Ethiopia. AB - Farming activity in Ethiopia is being stepped up in a bid to increase the country's economy, but what effect will this have on disease transmission? Georgina Mills explains. PMID- 29419497 TI - Disease surveillance in England and Wales, January 2018. PMID- 29419498 TI - PRRS diagnoses in Great Britain 2016/17. AB - This article was prepared by Susanna Williamson (APHA), Jean-Pierre Frossard (APHA) and Jill Thomson (SAC C VS) of the GB Pig Expert Group. PMID- 29419499 TI - Forensic entomology in the veterinary context. PMID- 29419501 TI - First-opinion practice needs evidence-based policies. PMID- 29419502 TI - Extreme breeding in cats. PMID- 29419503 TI - Me too. PMID- 29419505 TI - Editor's response. PMID- 29419504 TI - Protecting poultry from avian influenza. PMID- 29419506 TI - Infectious disease communications. PMID- 29419508 TI - Should vets use gallows humour at work? PMID- 29419520 TI - Depth dependant element analysis of PbMg1/3Nb2/3O3 using muonic X-rays. AB - The relaxor PbMg1/3Nb2/3O3 (PMN) has received attention due to its potential applications as a piezoelectric when doped with PbTiO3 (PT). Previous results have found that there are two phases existing in the system, one linked to the near-surface regions of the sample, the other in the bulk. However, the exact origin of these two phases is unclear. In this paper, depth dependant analysis results from negative muon implantation experiments are presented. It is shown that the Pb content is constant throughout all depths probed in the sample, but the Mg and Nb content changes in the near surface region below 100MUm. At a implantation depth of 60MUm, it is found that there is a 25% increase in Mg content, with a simultaneous 5% decrease in Nb content in order to maintain charge neutrality. These results show that the previously observed skin effects in PMN are due to a change in concentration and unit cell. PMID- 29419521 TI - Electronic transport property in Weyl semimetal with local Weyl cone tilt. AB - In realistic materials of Weyl semimetal (WSM), the Weyl cone tilt (WCT) is allowed due to the absence of Lorentz invariance in condensed matter physics. In this context, we theoretically study the electronic transport property in WSM with the local WCT as the scattering mechanism. In so doing, we establish an electronic transport structure of WSM with the WCT occurring only in the central region sandwiched between two pieces of semi-infinite WSM without the WCT. By means of two complementary theoretical approaches, i.e. the continuum-model method and the lattice-model method, the electronic transmission probability, the conductivity and the Fano factor as functions of the incident electron energy are calculated respectively. We find that the WCT can give rise to nontrivial intervalley scattering, as a result, the Klein tunneling is notably suppressed. More importantly, the minimal conductivity of a WSM shifts in energy from the Weyl nodal point. The Fano factor of the shot noise deviates obviously from the sub-Poissonian value in a two dimensional WSM with the WCT. PMID- 29419522 TI - Gender differences in mortality among ST elevation myocardial infarction patients in Malaysia from 2006 to 2013. AB - BACKGROUND: Coronary artery disease (CAD) is one of the leading causes of death in Malaysia. However, the prevalence of CAD in males is higher than in females and mortality rates are also different between the two genders. This suggest that risk factors associated with mortality between males and females are different, so we compared the clinical characteristics and outcome between male and female STEMI patients. OBJECTIVES: To identify the risk factors associated with mortality for each gender and compare differences, if any, among ST-elevation myocardial infarction (STEMI) patients. DESIGN: Retrospective analysis. SETTINGS: Hospitals across Malaysia. PATIENTS AND METHODS: We analyzed data on all STEMI patients in the National Cardiovascular Database-Acute coronary syndrome (NCVD ACS) registry for the years 2006 to 2013 (8 years). We collected demographic and risk factor data (diabetes mellitus, hypertension, smoking status, dyslipidaemia and family history of CAD). Significant variables from the univariate analysis were further analysed by a multivariate logistic analysis to identify risk factors and compare by gender. MAIN OUTCOME MEASURES: Differential risk factors for each gender. RESULTS: For the 19484 patients included in the analysis, the mortality rate over the 8 years was significantly higher in females (15.4%) than males (7.5%) (P < .001). The univariate analysis showed that the majority of male patients < 65 years while females were >=65 years. The most prevalent risk factors for male patients were smoking (79.3%), followed by hypertension (54.9%) and diabetes mellitus (40.4%), while the most prevalent risk factors for female patients were hypertension (76.8%), followed by diabetes mellitus (60%) and dyslipidaemia (38.1%). The final model for male STEMI patients had seven significant variables: Killip class, age group, hypertension, renal disease, percutaneous coronary intervention and family history of CVD. For female STEMI patients, the significant variables were renal disease, smoking status, Killip class and age group. CONCLUSION: Gender differences existed in the baseline characteristics, associated risk factors, clinical presentation and outcomes among STEMI patients. For STEMI females, the rate of mortality was twice that of males. Once they reach menopausal age, when there is less protection from the estrogen hormone and there are other risk factors, menopausal females are at increased risk for STEMI. LIMITATION: Retrospective registry data with inter hospital variation. PMID- 29419523 TI - Association between the mode of transport and in-hospital medical complications in trauma patients: findings from a level-I trauma center in Saudi Arabia. AB - BACKGROUND: In Saudi Arabia, injury is the leading cause of death. Even if nonfatal, the impact of injuries on population health is enormous, as thousands of young patients suffer permanent disabilities every year. Unlike in developed countries, private transportation (PT) is a common means to transport trauma patients. Outcome differences between patients transported via PT relative to emergency medical services (EMS) has not been previously explored. OBJECTIVES: To evaluate the association between transportation mode and in-hospital complications among trauma patients. DESIGN: Retrospective. SETTING: Tertiary care center. PATIENTS AND METHODS: The study included all patients (>=16 years), who were admitted following trauma. MAIN OUTCOME MEASURES: The main outcome in the study was the occurrence of any medical complications including stroke, sepsis, myocardial infarction, pulmonary embolism, pneumonia, renal failure, acute respiratory distress syndrome, and cardiac arrest. RESULTS: The 493 patients were relatively young (over two-thirds of the sample were 45 years old or younger) and over half the population sustained injuries due traffic crashes. More than half (58%) of patients arrived via private transportation. Regression analyses revealed that in-hospital complications following injuries were significantly lower among those who arrived via PT. However, after incorporating propensity score matching, we found no difference in hospital complications (OR=0.55, 95% CI 0.25-1.17). CONCLUSION: Multiple factors may influence this unexpected finding, such as distance to health care set.tings, the belief that PT is faster or lack of knowledge of the EMS contact number. Further efforts are needed to raise awareness of the importance of using EMS to transport trauma patients to hospitals. Prevention programs to reduce traffic crashes may facilitate reduction in traumatic injuries and associated complications. LIMITATIONS: Retrospective and conducted in one center only. PMID- 29419524 TI - Delirium and correlates of delirium among newly admitted elderly patients: a cross-sectional study in a Saudi general hospital. AB - BACKGROUND: Delirium is a common, often undiagnosed disorder in elderly patients, but no studies have been conducted in Saudi Arabia. OBJECTIVES: To determine the prevalence of delirium among elderly patients on admission and to identify associated factors. DESIGN: A cross-sectional study. SETTING: Tertiary care hospital, Saudi Arabia. PATIENTS AND METHODS: Elderly patients were evaluated for delirium within 24 hours of admission using the Confusion Assessment Method (CAM). The medical records were also reviewed to identify associated factors and whether the diagnosis of delirium was documented by the admitting physician. MAIN OUTCOME MEASURES: Prevalence of delirium. RESULTS: Of 147 patients aged 60 or over screened for delirium within 24 hours of admission, 32 (21.8%) patients were identified with delirium. Seven (21.9%) of the 32 patients with delirium had documentation of their diagnosis in the patient chart by the attending physician. Univariate logistic regression identified greater age (OR=2.70, 95%-CI: 1.21 6.02), higher unemployment rate (OR=3.30, 95%-CI: 1.43-7.61), more often had 3-5 co-morbidities (OR=2.69, 95%-CI: 1.14-6.33), and more cognitive impairment (OR=38.90, 95%-CI: 8.78-172.34) as risk factors for delirium on admission. Multivariate logistic regression analysis identified greater age (OR=2.53, 95% CI: 1.08-5.88), higher unemployment rate (OR=3.73, 95%-CI: 1.52-9.13) and 3-5 co morbidities (OR=3.31, 95%-CI: 1.30-8.46) as risk factors for delirium. CONCLUSIONS: Delirium was common and frequently not recognized in elderly patients admitted to the hospital. Administration of the CAM was very helpful in identifying delirium at admission. LIMITATIONS: The main limitation of our study was the relatively small number of patients which might have limited the power to detect some associations. PMID- 29419525 TI - Psychometric Arabic Sino-Nasal Outcome Test-22: validation and translation in chronic rhinosinusitis patients. AB - BACKGROUND: The Sino-Nasal Outcome Test (SNOT)-22 has multiple items that reflect how nasal disease affects quality of life. Currently, no validated Arabic version of the SNOT-22 is available. OBJECTIVE: . To develop an Arabic-validated version of SNOT-22. DESIGN: Prospective. SETTING: Tertiary care center. PATIENT AND METHODS: This single-center validation study was conducted between 2015 and 2017 at King Abdul-Aziz University Hospital, Riyadh, Saudi Arabia. The SNOT-22 English version was translated into Arabic by the forward and backward method. The test and retest reliability, internal consistency, responsiveness to surgical treatment, discriminant validity, sensitivity and specificity all were tested. MAIN OUTCOME MEASURES: Validated Arabic version of the SNOT-22. RESULTS: Of 265 individuals, 171 were healthy volunteers and 94 were chronic rhinosinusitis patients. The Arabic version showed high internal consistency (Cronbach's of 0.94), and the ability to differentiate between diseased and healthy volunteers (P < .001). The translated versions demonstrated the ability to detect the change scores significantly in response to intervention (P < .001). CONCLUSION: This is the first validated Arabic version of SNOT-22. The instrument can be used among the Arabic population. LIMITATIONS: No subjects from other Arab countries. PMID- 29419526 TI - Descemet stripping automated endothelialkeratoplasty (DSAEK) versus repeat penetrating keratoplasty (PKP) to manage eyes with failed corneal graft. AB - BACKGROUND: Failed corneal graft management is a challenge. Descemet stripping automated endothe.lial keratoplasty (DSAEK) and repeat penetrating keratoplasty (PKP) are two options. Only two studies have compared outcomes of DSAEK and PKP in the management of a failed graft. OBJECTIVE: To compare the visual outcomes, changes in intraocular pressure (IOP) and complications in eyes with failed corneal grafts that were subsequently managed with DSAEK and PKP. DESIGN: Retrospective cohort study. SETTINGS: Tertiary eye hospital of central Saudi Arabia. PATIENTS AND METHODS: A retrospective chart review was performed for cases managed between 2007 and 2012. Data were collected on the best-corrected visual acuity (BCVA) before and at day 1, 1 week, 4 weeks, 12 weeks, and 24 weeks after intervention. BCVA was compared in patients managed with DSAEK or PKP. Intra- and postoperative complications were compared in both groups. MAIN OUTCOME MEASURES: Clear graft, vision at last follow up, complications. RESULTS: There were 15 eyes in the DSAEK group and 30 in the PKP group. The causes of previously failed PKP differed between groups. BCVA at 6 months after repeat surgeries was 20/20 to 20/40 in 4 (27%) eyes in the DSAEK group and in 8 (27%) eyes in the PKP group. The IOP at 6 months was statistically significantly higher in the DSAEK group than the PKP group (P=.006). In DSAEK group, one graft rejection occurred in one eye and graft dislocation in another eye. Seven eyes in PKP group had signs of graft rejection that regressed in 5 eyes following medical management. CONCLUSIONS: DSAEK and PKP for previously failed corneal graft resulted in similar BCVA 6 months after repeat surgery. However, the visual outcomes were less promising with both types of surgeries. The lower complication rate and surgical ease may favor DSAEK over PKP in managing failed grafts. LIMITATIONS: Small sample, retrospective study. PMID- 29419527 TI - Nonmelanoma skin cancer in Saudi Arabia: single center experience. AB - BACKGROUND: Skin cancer is the most common cancer worldwide; one in every three diagnosed malignancies is a skin cancer. However, skin cancer is rarely reported in Saudi Arabia so we conducted this study to highlight these underreported neoplasms. OBJECTIVES: Determine the prevalence and patterns of basal cell carcinoma (BCC) and primary squamous cell carcinoma (SCC), the most common types of nonmelanoma skin cancer (NMSC) with respect to age, sex, and anatomic location and to identify potentially associated risk factors. DESIGN: Retrospective, descriptive medical record review. SETTING: A tertiary care centre. PATIENTS AND METHODS: We did a retrospective chart review of all patients diagnosed with basal cell carcinoma and primary squamous cell carcinoma between 2003-2016. MAIN OUTCOME MEASURES: Prevalence and pattern of BCC and SCC with respect to age, sex, and anatomic location. RESULTS: Of 593 cases reviewed, 279 had NMSC. Most (95%) were diagnosed with BCC or SCC or both in a few cases. The mean age at diagnosis was 59 (19.5) years. Sixty-two percent of the patients were males. However, 24.3% (n=68) of skin cancers occurred in patients younger than 50 years. The frequency of BCC and SCC was 50.2% and 44.8%, respectively. The head and neck was the most common location (79.6%). In patients younger than 50 years, xeroderma pigmentosum and previously treated solid malignancies were the major factors. CONCLUSIONS: BCC and SCC are uncommon but not rare. However, skin cancers are underreported in our population. NMSC in individuals younger than 50 years of age requires more careful evaluation of possible risk factors. LIMITATIONS: Retrospective in a single tertiary care setting. PMID- 29419528 TI - Sleep disorders as primary and secondary factors in relation with daily functioning in medical students. AB - BACKGROUND: College students experience various types of sleep disorders that impact daily functioning. Previous studies have focused on the effect of one sleep disorder. OBJECTIVE: Examine factors that might relate to several sleep disorders and the impacts of sleep disorders on the daily functioning in medical students. DESIGN: Cross-sectional study. SETTING: Medical college. SUBJECTS AND METHODS: A random sample of medical students from a public university was invited to participate in a cross-sectional study using the structured SLEEP-50 self reported questionnaire. The sleep disorders covered by the questionnaire were insomnia, sleep apnea, restless legs syndrome, sleep walking, circadian rhythm sleep disorder, nightmares, narcolepsy, and factors impacting sleep, effects of sleep complaints on daily functioning, and sleeping duration. MAIN OUTCOME MEASURE: Sleep duration, sleep disorders. RESULTS: Of 317 participants, 165 (50.2%) reported having less than 7 hours sleep and apart from hyper-somnia, had various kinds of sleep disorders. Various factors such as having no pleasure and entertainment, feeling sadness, alcohol drinking, amount of sleeping hours, smoking, age, a noisy or light bedroom, and substance abuse were related to different sleep disorders. Moreover, students with sleep disorders felt tired arising, felt sleepy during the day, were easily irritated, had difficulty in concentration, had concerns about amount of sleep, and slept badly at college. CONCLUSIONS: Insufficient sleep is a common issue in medical students and a number of sleep disorders were found. The results suggest that sleep disorders could have negative impacts on the daily functioning of students. LIMITATIONS: The study findings may not be generalizable because sociocultural characteristics of the sample may differ from the general population. PMID- 29419529 TI - The endangered clinician-investigator profession in Saudi Arabia: curricular attention is required. PMID- 29419530 TI - Challenges and Opportunities for High-grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangement (Double-hit Lymphoma). AB - The most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma, is cured in approximately two thirds of patients after initial therapy. The remaining one-third of patients who suffer relapse or become refractory have very poor survival outcomes despite salvage chemotherapy with or without stem cell transplantation. A considerable proportion of relapsed or refractory large B cells belong to the WHO subtype known as high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and/or BCL6, also known as double-hit lymphoma (DHL). Most DHL patients present with Ann Arbor's stage III/IV, a comparatively higher rate of extranodal involvement including bone marrow and central nervous system infiltration, high levels of lactate dehydrogenase, and an elevated Ki67 expression in the tumor cells. Newer therapeutic approaches, including targeted therapy against BCL2, MYC, or other associated pathways, are needed. In addition, recent therapies that harness the immune system, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, are changing the paradigm of treatment for non-Hodgkin lymphoma and could impact the outcome of DHL. PMID- 29419531 TI - Differential Prognostic Impact of Strong PD-L1 Expression and 18F-FDG Uptake in Triple-negative Breast Cancer. AB - OBJECTIVES: Triple-negative breast cancers (TNBC) is an aggressive disease and often associated with early distant metastases, which negate the role of adjuvant radiotherapy. We studied the clinical utility of programmed death ligand-1 (PD L1) and other available factors in predicting clinical outcome in TNBC. METHODS: Of the 539 patients with newly diagnosed TNBC between 2004 and 2011, we analyzed 117 patients who had both tumor samples which PD-L1 protein expression could be evaluated using immunohistochemistry and initial staging F-fluorodeoxyglucose (FDG) positron emission tomography (PET) data to find available immunologic or metabolic factors. Median follow-up duration was 53 months. RESULTS: Strong PD-L1 expression was significantly associated with increased risk of recurrence along with tumor hypermetabolism. The systemic recurrence rate was significantly higher in the strong PD-L1 group than the weak PD-L1 group (35% vs. 11%; P=0.002); whereas there was no difference in locoregional failures (8% vs. 8%). Meanwhile, tumor hypermetabolism seemed to relate with an increase in overall recurrences (26% vs. 8%; P=0.019), not with specific type (locoregional, 9% vs. 3% [P=0.289]; systemic, 22% vs. 8% [P=0.051]). The relationship between PD-L1 expression and survival outcomes retained significance even after adjusting potential risk factors. CONCLUSIONS: PD-L1 and tumor metabolism might have role of predicting an increase in treatment failures. Especially, strong PD-L1 expression status was related to distant metastasis-dominant recurrence pattern which needs for intensive systemic therapy. PMID- 29419532 TI - Management of Menopausal Symptoms for Women Who Are at High Risk of Thrombosis. AB - For women at elevated risk of thrombosis, clinicians are challenged to relieve menopausal symptoms without increasing the risk of thrombosis. Oral menopausal hormone therapy increases the risk of venous thromboembolism by 2-fold to 3-fold. Observational studies suggest less thrombotic risk with transdermal therapies and with progesterone over synthetic progestogens (progestins), but the data are limited. Beneficial nonpharmacologic therapies include cognitive behavioral therapy and clinical hypnosis, whereas beneficial nonhormonal pharmacologic therapies include selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors. For treatment of the genitourinary syndrome of menopause, vaginal lubricants and moisturizers, low-dose vaginal estrogen, and intravaginal dehydroepiandrosterone are options. PMID- 29419533 TI - Effect of Treating Vitamin D Deficiency in Uncontrolled Type 2 Diabetes: A Randomized, Placebo-Controlled Study. AB - BACKGROUND: Literature increasingly supports the inverse relationship of vitamin D (VitD) level and type 2 diabetes (T2DM). Proposed protective mechanisms of VitD include its anti-inflammatory effects, increased insulin secretion via pancreatic beta-cell stimulation, and downregulation of parathyroid hormone levels. Interventional studies show mixed results of VitD therapy in prediabetic patients with VitD deficiency or diabetic patients with normal VitD levels. STUDY QUESTION: Does high-dose VitD replacement improve glycemic control and microalbuminuria (MAU) in uncontrolled T2DM and concurrent VitD deficiency? STUDY DESIGN: This placebo-controlled, double-blinded study randomized 30 subjects aged 30-65 years with an elevated HbA1c level of 7.5%-10% and a low total 25 hydroxyvitamin-D value of <20 ng/mL to either placebo (n = 16) or ergocalciferol 50,000 IU (n = 14) once weekly for 8 weeks then once monthly for 4 months. MEASURES AND OUTCOMES: Primary outcome was difference in HbA1c from baseline to month 6 between the VitD-intervention group and the placebo-controlled group. Secondary end points were differences in total 25-hydroxyvitamin-D and MAU. Paired t tests and linear mixed-effects models were used for statistical analysis. RESULTS: No significant differences were seen in HbA1c or MAU between baseline versus postintervention visits within the placebo group (HbA1c: 8.4% +/- 0.2 vs. 8.1% +/- 0.3, P = 0.088; MAU: 94.1 mg/g +/- 43.9 vs. 45.9 mg/g +/- 20.2, P = 0.152) and the intervention group (HbA1c: 8.8% +/- 0.3 vs. 8.7% +/- 0.4, P = 0.692; MAU: 167.8 mg/g +/- 70.1 vs. 108.5 mg/g +/- 39.9, P = 0.356). The difference between placebo-slope and intervention-slope was nonsignificant for MAU (beta = -0.1 mg/g +/- 0.4, P = 0.835) but was significant for total 25 hydroxyvitamin-D (beta = 11.7 ng/mL +/- 2.5, P <= 0.001). Greater HbA1c reduction occurred unexpectedly in the placebo group (beta = -0.4% +/- 0.2) than in the intervention group (beta = -0.2% +/- 0.4), although the difference in slopes was not significant (beta = 0.2% +/- 0.4, P = 0.640). CONCLUSIONS: Our proof-of concept study found no benefit of high-dose VitD therapy in glycemic control and MAU in uncontrolled T2DM and VitD deficiency. Post hoc analyses raise concerns for high-dose VitD therapy to delay glycemic improvement. Large-scale interventional trials are much needed in this patient population to substantiate our findings and elucidate VitD's mechanisms on glucose metabolism. PMID- 29419534 TI - Duloxetine Uses in Patients With Kidney Disease: Different Recommendations From the United States Versus Europe and Canada. PMID- 29419535 TI - Electromagnetic Interference Between Left Ventricular Assist Device and a Three Dimensional Mapping System Overcome by "Hot Mapping". AB - The number of patients with implanted left ventricular assist devices is constantly increasing. Numerous patients suffer from drug-resistant ventricular tachycardias. Only a few studies and reports about ablation therapy in this cohort of patients are available. Electromagnetic interferences between the left ventricular assist device and the three-dimensional mapping system which is used for ablation has been described as disabling the investigator to create a proper map of the left ventricle. We observed that this interference is interrupted by "hot mapping" meaning that one pretends an ablation with only 5 W, permitting the creation of a clear map in areas of interference. PMID- 29419536 TI - Extracorporeal Membrane Oxygenation in a Patient with Biliary Atresia: Case and Review of Extracorporeal Life Support Organization Data. AB - Biliary atresia is a newborn cholangiopathy that may lead to portopulmonary hypertension and cirrhosis-induced cardiomyopathy while awaiting liver transplantation. Extracorporeal life support and hepatic toxin filtration are life-saving interventions that provide cardiopulmonary support and hepatic dialysis to allow resolution of a child's illness. We utilized a combination of these extreme measures to bridge an infant with biliary atresia to transplantation. We reviewed cases of extracorporeal life support utilization in transplantation recipients in the Extracorporeal Life Support Organization database and determined that ours was the only use of pretransplant extracorporeal life support in biliary atresia. PMID- 29419537 TI - Modification of a Ventricular Assistance Device for a Hemiplegic Left Ventricular Assist Device Patient. AB - Neurologic events occur in up to 18% of patients with continuous-flow left ventricular assist devices (LVAD) and is associated with significant morbidity and mortality. The current form of the LVAD equipment is not suited to serve patients who are impaired by a stroke. By creating an assistance device for the LVAD equipment, we have been able to greatly improve the quality of life and self dependence of a hemiplegic LVAD patient. PMID- 29419538 TI - Percutaneous Mechanical Circulation Support Combined with Extracorporeal Membrane Oxygenation (oxyRVAD) in Secondary Right Heart Failure. AB - Right heart failure (RHF) because of pulmonary hypertension (PH) is a frequently encountered clinical problem with high mortality. The last resort, if pharmacological therapy fails, is mechanical circulatory support. There is a lack of percutaneous systems to support the right ventricle (RV). Venoarterial extracorporeal membrane oxygenation is widely used as a bailout in acute RHF in non-left ventricular assist device patients. Venoarterial extracorporeal membrane oxygenation does not unload the left ventricle and may cause failure of the left ventricle if used for a longer period of time. We report the long-term use of an ECMO-based percutaneous right ventricular assist system (oxyRVAD) capable to deliver up to 6 L/min of blood flow with a returning cannula placed in the main pulmonary artery used in RHF originating from PH with poor oxygenation. We present a series of four patients on oxyRVAD (mean treatment duration 15 +/- 7.6 days). Patients benefited from the system clinically; however, two patients eventually died while on oxyRVAD. Nevertheless, we provide a proof-of-concept of this system in PH patients, which is feasible and might provide a useful "bridge to-recovery" or "bridge-to-transplant" option in the management of patients with severe RHF because of PH. PMID- 29419539 TI - ASDS International Surgical Fellowship Venues Being Established in New Program. PMID- 29419540 TI - Basal Cell Adenoma of the Upper Lip Treated With Mohs Micrographic Surgery. PMID- 29419541 TI - Plaque-Type Syringoma Coexisting With Basal Cell Carcinoma. PMID- 29419542 TI - Reduction of Submental Fat Continues Beyond 28 Days After ATX-101 Treatment: Results From a Post hoc Analysis. PMID- 29419543 TI - Evaluation of MITF, SOX10, MART-1, and R21 Immunostaining for the Diagnosis of Residual Melanoma In Situ on Chronically Sun-Damaged Skin. AB - BACKGROUND: Melanocytic immunostains can assist in margin evaluation of melanoma in situ (MIS) excisions; however, their accuracy and reliability relative to hematoxylin & eosin (H&E) is yet to be determined. OBJECTIVE: The objective of this study was to evaluate the sensitivity, specificity, and concordance of 4 melanocyte-specific immunostains for diagnosing MIS occurring on chronically sun damaged skin. MATERIALS AND METHODS: Serial permanent sections from representative areas of negative margin and residual tumor were stained using H&E, MITF, MART-1, SOX10, and R21 and examined in a blinded fashion. The study set included 100 digital microscopy images from 10 cases of MIS excisions from the face. Two board-certified dermatopathologists, 4 fellowship-trained Mohs surgeons, 2 Mohs fellows, and 2 dermatology residents independently reviewed the 100 images. RESULTS: The average melanocyte density was 11 versus 28 melanocytes per 0.5 mm for chronically sun-damaged skin versus residual MIS on H&E, respectively. Statistically significantly higher melanocyte densities were observed using MITF, MART-1, and SOX10 on negative margins. The sensitivity and interobserver concordance was highest using MITF and SOX10. The intraobserver agreement on 4 duplicate images was 85%. CONCLUSION: In conclusion, the nuclear immunostains (MITF and SOX10) show the most promise for improving the diagnosis of MIS in chronically sun-damaged skin. PMID- 29419544 TI - Neurapraxia Not Neuropraxia. PMID- 29419545 TI - Significance, Errors, Power, and Sample Size: The Blocking and Tackling of Statistics: Erratum. PMID- 29419546 TI - Characteristics of Successful Internal Medicine Resident Research Projects: Predictors of Journal Publication Versus Abstract Presentation. AB - PURPOSE: To identify the characteristics of successful research projects at an internal medicine residency program with an established research curriculum. METHOD: The authors collected data about all research projects initiated by or involving medicine residents from 2006 to 2013 at Baystate Medical Center, using departmental files and institutional review board applications. Resident and mentor characteristics were determined using personnel files and Medline searches. Using multivariable models, the authors identified predictors of successful completion of projects using adjusted prevalence ratios (PRs). The primary outcome was manuscript publication, and secondary outcome was publication or regional/national presentation. Finally, residents were surveyed to identify barriers and/or factors contributing to project completion. RESULTS: Ninety-four research projects were identified: 52 (55.3%) projects achieved the primary outcome and 72 (76.5%) met the secondary outcome, with overlap between categories. Most study designs were cross-sectional (41; 43.6%) or retrospective cohort (30; 31.9%). After adjustment, utilization of the epidemiology/biostatistical core (PR = 2.09; 95% CI: 1.36, 3.21), established publication record of resident (PR = 1.54; 95% CI: 1.14, 2.07), and resident with U.S. medical education (PR = 1.39; 95% CI: 1.02, 1.90) were associated with successful project completion. Mentor publication record (PR = 3.13) did not retain significance because of small sample size. Most respondents (65%) cited "lack of time" as a major project barrier. CONCLUSIONS: Programs seeking to increase resident publications should consider an institutional epidemiology/biostatistical core, made available to all residency research projects, and residents should choose experienced mentors with a track record of publications. PMID- 29419547 TI - Navigating the Complexities of Undergraduate Medical Curriculum Change: Change Leaders' Perspectives. AB - PURPOSE: Changing an undergraduate medical curriculum is a recurring, high-stakes undertaking at medical schools. This study aimed to explore how people leading major curriculum changes conceived of the process of enacting change and the strategies they relied on to succeed in their efforts. METHOD: The first author individually interviewed nine leaders who were leading or had led the most recent undergraduate curriculum change in one of the eight medical schools in the Netherlands. Interviews were between December 2015 and April 2016, using a semistructured interview format. Data analysis occurred concurrently with data collection, with themes being constructed inductively from the data. RESULTS: Leaders conceived of curriculum change as a dynamic, complex process. They described three major challenges they had to deal with while navigating this process: the large number of stakeholders championing a multitude of perspectives, dealing with resistance, and steering the change process. Additionally, strategies for addressing these challenges were described. The authors identified an underlying principle informing the work of these leaders: being and remaining aware of emerging situations, and carefully constructing strategies for ensuring that the intended outcomes were reached and contributed to the progress of the change process. DISCUSSION: This empirical, descriptive study enriches the understanding of how institutional leaders navigate the complexities of major medical curriculum changes. The insights serve as a foundation for training and coaching future change leaders. To broaden the understanding of curriculum change processes, future studies could investigate the processes through alternative stakeholder perspectives. PMID- 29419548 TI - Implications for the Dental Care of Vulnerable Populations if Medicaid Is Cut Back. AB - Good oral health affects academic performance, employability and annual earnings, military readiness, overall health care costs, and general health status and well being. The Affordable Care Act (ACA) has enhanced the ability of many Americans to receive dental care through the expansion of Medicaid and the inclusion of pediatric oral health as 1 of the 10 "essential health benefits." Almost all of the proposals presented by the current Congress and Administration to modify the ACA call for changes to Medicaid that would cut back funding and/or give states more control over programs. Limiting federal support to Medicaid will eventually increase the pressure on states to cut costs, and dental care is usually one of the first benefits on the chopping block. If this happens, all of the gains that have been realized as a result of the Medicaid expansion would be diminished or lost, with a significant impact on the overall health, well-being, and success of those who will suffer the consequences of a lack of access to dental care. PMID- 29419549 TI - The Couples Match: Navigating the Trail Together. PMID- 29419550 TI - Are They Ready to Be Senior Residents? PMID- 29419551 TI - What to Do About the Transition to Residency? Exploring Problems and Solutions From Three Perspectives. AB - Transitions are both a blessing and a curse for learning and professional development. While transitions can afford valuable opportunities for growth, they can also burden learners in ways that stymie performance and development. In this Invited Commentary, the author focuses on the transition from medical school to residency-a transition that many believe has tipped too far toward burden. The commentary explores three ways of problematizing the transition to residency. The first is as a transaction problem involving a complex exchange of information among programs and people. The second is as a transfer problem in which learners must apply knowledge in new contexts. The third is a trajectory problem concerning each learner's progression through medical education. The author describes current efforts aligned with each framing of the problem and discusses potential gaps in these efforts that might be addressed through an overarching framing of transitions in medical education as transformative processes. This framing may help the medical educational community think more holistically about the problems and solutions with transitions. PMID- 29419552 TI - Is Speed a Desirable Difficulty for Learning Procedures? An Initial Exploration of the Effects of Chronometric Pressure. AB - PURPOSE: To determine whether "chronometric pressure" (i.e., a verbal prompt to increase speed) could predictably alter medical learners' speed-accuracy trade off during a simulated surgical task, thus modifying the challenge. METHOD: The authors performed a single-task, interrupted time-series study, enrolling surgery residents and medical students from two institutions in September and October 2015. Participants completed 10 repetitions of a simulated blood vessel ligation (placement of two ligatures 1 cm apart). Between repetitions 5 and 6, participants were verbally encouraged to complete the next repetition 20% faster than the previous one. Outcomes included time and accuracy (ligature tightness, placement distance). Data were analyzed using random-coefficients spline models. RESULTS: The authors analyzed data from 78 participants (25 medical students, 16 first-year residents, 37 senior [second-year or higher] residents). Overall, time decreased from the 1st (mean [standard deviation] 39.8 seconds [18.4]) to the 10th (29.6 [12.5]) repetition. The spline model showed a decrease in time between repetitions 5 and 6 of 8.6 seconds (95% confidence interval: -11.1, -6.1). The faster time corresponded with declines in ligature tightness (unadjusted difference -19%; decrease in odds 0.86 [0.76, 0.98]) and placement accuracy (unadjusted difference -5%; decrease in odds 0.86 [0.75, 0.99]). Significant differences in the speed-accuracy trade-off were seen by training level, with senior residents demonstrating the greatest decline in accuracy as speed increased. CONCLUSIONS: Chronometric pressure influenced the speed-accuracy trade off and modified the challenge level in a simulated surgical task. It may help unmask correctable deficiencies or false plateaus in learners' skill development. PMID- 29419553 TI - Malpractice Litigation in Cornea and Refractive Surgery: A Review of the WestLaw Database. AB - PURPOSE: To report and analyze the causes and outcomes of malpractice litigation in cornea and refractive surgery. METHODS: The WestLaw database was reviewed for all malpractice litigation related to ophthalmology in the United States between 1930 and 2014. Search terms included ophthalmology or ophthalmologist and malpractice anywhere in the retrieved results. All cases involving cornea and refractive surgery were included in this analysis, and results were compared with ophthalmology as a whole. RESULTS: One hundred fifty-nine cornea and refractive surgery cases between the years 1964 and 2014 were included. Ninety-three cases (58.5%) were resolved through a jury trial, 21.5% of which were associated with plaintiff verdicts with a median adjusted jury award of $588,896 (mean $1,518,686). Nineteen cases (11.9%) resulted in settlements with a median adjusted indemnity of $782,533 (mean $761,963). Commonly litigated scenarios included laser-assisted in situ keratomileusis (74.2%) and corneal transplantation (8.2%). Overall, 88.7% of cases involved surgical or procedural claims, 8.8% involved noninterventional claims, and 2.5% involved medical claims only. CONCLUSIONS: Cornea and refractive surgery is a high-risk subspecialty of ophthalmology. Laser-assisted in situ keratomileusis and corneal transplant claims were the most commonly litigated entities in this series. Many cases focus on failure to achieve patients' desired expectations after elective refractive procedures or the negligent performance of refractive surgery on patients with contraindications to surgery, both highlighting the importance of detailed informed consent discussions, realistic goal setting with patients, and thorough examinations and preoperative evaluation. PMID- 29419554 TI - Lamina Cribrosa Thickness in Patients With Keratoconus. PMID- 29419555 TI - Engaging Alumni as Mentors for Nursing Students. PMID- 29419556 TI - Determining the Upper and Lower Limits of Cerebral Autoregulation With Cerebral Oximetry Autoregulation Curves: A Case Series. AB - OBJECTIVE: Critical care guidelines recommend a single target value for mean arterial blood pressure in critically ill patients. However, growing evidence regarding cerebral autoregulation challenges this concept and supports individualizing mean arterial blood pressure targets to prevent brain and kidney hypo- or hyperperfusion. Regional cerebral oxygen saturation derived from near infrared spectroscopy is an acceptable surrogate for cerebral blood flow and has been validated to measure cerebral autoregulation. This study suggests a novel mechanism to construct autoregulation curves based on near-infrared spectroscopy measured cerebral oximetry. DESIGN: Case-series study. SETTING: Neurocritical care unit in a tertiary medical center. PATIENTS: Patients with acute neurologic injury and Glasgow coma scale score less than or equal to 8. MEASUREMENTS AND MAIN RESULTS: Autoregulation curves were plotted using the fractional-polynomial model in Stata after multimodal continuous monitoring of regional cerebral oxygen saturation and mean arterial blood pressure. Individualized autoregulation curves of seven patients exhibited varying upper and lower limits of autoregulation and provided useful clinical information on the autoregulation trend (curves moving to the right or left during the acute coma period). The median lower and upper limits of autoregulation were 86.5 mm Hg (interquartile range, 74-93.5) and 93.5 mm Hg (interquartile range, 83-99), respectively. CONCLUSIONS: This case-series study showed feasibility of delineating real trends of the cerebral autoregulation plateau and direct visualization of the cerebral autoregulation curve after at least 24 hours of recording without manipulation of mean arterial blood pressure by external stimuli. The integration of multimodal monitoring at the bedside with cerebral oximetry provides a noninvasive method to delineate daily individual cerebral autoregulation curves. PMID- 29419557 TI - Development and Evaluation of an Automated Machine Learning Algorithm for In Hospital Mortality Risk Adjustment Among Critical Care Patients. AB - OBJECTIVES: Risk adjustment algorithms for ICU mortality are necessary for measuring and improving ICU performance. Existing risk adjustment algorithms are not widely adopted. Key barriers to adoption include licensing and implementation costs as well as labor costs associated with human-intensive data collection. Widespread adoption of electronic health records makes automated risk adjustment feasible. Using modern machine learning methods and open source tools, we developed and evaluated a retrospective risk adjustment algorithm for in-hospital mortality among ICU patients. The Risk of Inpatient Death score can be fully automated and is reliant upon data elements that are generated in the course of usual hospital processes. SETTING: One hundred thirty-one ICUs in 53 hospitals operated by Tenet Healthcare. PATIENTS: A cohort of 237,173 ICU patients discharged between January 2014 and December 2016. DESIGN: The data were randomly split into training (36 hospitals), and validation (17 hospitals) data sets. Feature selection and model training were carried out using the training set while the discrimination, calibration, and accuracy of the model were assessed in the validation data set. MEASUREMENTS AND MAIN RESULTS: Model discrimination was evaluated based on the area under receiver operating characteristic curve; accuracy and calibration were assessed via adjusted Brier scores and visual analysis of calibration curves. Seventeen features, including a mix of clinical and administrative data elements, were retained in the final model. The Risk of Inpatient Death score demonstrated excellent discrimination (area under receiver operating characteristic curve = 0.94) and calibration (adjusted Brier score = 52.8%) in the validation dataset; these results compare favorably to the published performance statistics for the most commonly used mortality risk adjustment algorithms. CONCLUSIONS: Low adoption of ICU mortality risk adjustment algorithms impedes progress toward increasing the value of the healthcare delivered in ICUs. The Risk of Inpatient Death score has many attractive attributes that address the key barriers to adoption of ICU risk adjustment algorithms and performs comparably to existing human-intensive algorithms. Automated risk adjustment algorithms have the potential to obviate known barriers to adoption such as cost-prohibitive licensing fees and significant direct labor costs. Further evaluation is needed to ensure that the level of performance observed in this study could be achieved at independent sites. PMID- 29419558 TI - Monitoring the Relationship Between Changes in Cerebral Oxygenation and Electroencephalography Patterns During Cardiopulmonary Resuscitation: A Feasibility Study. AB - OBJECTIVES: To date, no studies have examined real-time electroencephalography and cerebral oximetry monitoring during cardiopulmonary resuscitation as markers of the magnitude of global ischemia. We therefore sought to assess the feasibility of combining cerebral oximetry and electroencephalography in patients undergoing cardiopulmonary resuscitation and further to evaluate the electroencephalography patterns during cardiopulmonary resuscitation and their relationship with cerebral oxygenation as measured by cerebral oximetry. DESIGN: Extended case series of in-hospital and out-of-hospital cardiac arrest subjects. SETTING: Tertiary Medical Center. PATIENTS: Inclusion criteria: Convenience sample of 16 patients undergoing cardiopulmonary resuscitation during working hours between March 2014 and March 2015, greater than or equal to 18 years. A portable electroencephalography (Legacy; SedLine, Masimo, Irvine, CA) and cerebral oximetry (Equanox 7600; Nonin Medical, Plymouth, MN) system was used to measure cerebral resuscitation quality. INTERVENTIONS: Real-time regional cerebral oxygen saturation and electroencephalography readings were observed during cardiopulmonary resuscitation. The regional cerebral oxygen saturation values and electroencephalography patterns were not used to manage patients by clinical staff. MEASUREMENTS AND MAIN RESULTS: In total, 428 electroencephalography images from 16 subjects were gathered; 40.7% (n = 174/428) were artifactual, therefore 59.3% (n = 254/428) were interpretable. All 16 subjects had interpretable images. Interpretable versus noninterpretable images were not related to a function of time or duration of cardiopulmonary resuscitation but to artifacts that were introduced to the raw data such as diaphoresis, muscle movement, or electrical interference. Interpretable data were able to be obtained immediately after application of the electrode strip. Seven distinct electroencephalography patterns were identified. Voltage suppression was commonest and seen during 78% of overall cardiopulmonary resuscitation time and in 15 of 16 subjects at some point during their cardiopulmonary resuscitation. Other observed patterns and their relative prevalence in relation to overall cardiopulmonary resuscitation time were theta background activity 8%, delta background activity 5%, bi frontotemporal periodic discharge 4%, burst suppression 2%, spike and wave 2%, and rhythmic delta activity 1%. Eight of 16 subjects had greater than one interpretable pattern. At regional cerebral oxygen saturation levels less than or equal to 19%, the observed electroencephalography pattern was exclusively voltage suppression. Delta background activity was only observed at regional cerebral oxygen saturation levels greater than 40%. The remaining patterns were observed throughout regional cerebral oxygen saturation categories above a threshold of 20%. CONCLUSIONS: Real-time monitoring of cerebral oxygenation and function during cardiac arrest resuscitation is feasible. Although voltage suppression is the commonest electroencephalography pattern, other distinct patterns exist that may correlate with the quality of cerebral resuscitation and oxygen delivery. PMID- 29419559 TI - Clinical Practice Recommendations for Continuation and Maintenance Electroconvulsive Therapy for Depression: Outcomes From a Review of the Evidence and a Consensus Workshop Held in Australia in May 2017. AB - OBJECTIVES: Continuation or maintenance electroconvulsive therapy (ECT) is often provided as a strategy for post-ECT relapse prevention. However, the evidence has been insufficient until recently to produce clear consensus on what best practice maintenance ECT (mECT) should be like in a real world ECT clinical service. The aims of this article are to help fill this gap and to provide a comprehensive set of practical, clinically-based recommendations for ECT clinicians and services. METHODS: A workshop was held at the Royal Australian and New Zealand College of Psychiatry Congress in Adelaide on April 30, 2017. This workshop was hosted by the authors. After a presentation on the state of the evidence, the 30 participants were asked to work in small groups to develop consensus recommendations on different aspects of mECT. These were then collated into one comprehensive set of clinical recommendations for the practice of mECT. RESULTS: These best practice recommendations are set out below. CONCLUSIONS: These recommendations will assist ECT services and clinicians to provide best practice mECT according to currently available evidence. PMID- 29419560 TI - Implications of the New National Guidelines for Hypertension. AB - Automated validated devices should be used for measuring blood pressure (BP). A systolic BP between 120 and 129 mm Hg with a diastolic BP < 80 mm Hg should be treated by lifestyle measures. Lifestyle measures plus BP lowering drugs should be used for secondary prevention of recurrent cardiovascular disease (CVD) events in persons with clinical CVD (coronary heart disease, congestive heart failure, and stroke) and an average systolic BP of >=130 mm Hg or an average diastolic BP >= 80 mm Hg. Lifestyle measures plus BP lowering drugs should be used for primary prevention of CVD in persons with an estimated 10-year risk of atherosclerotic CVD >= 10% and an average systolic BP >=130 mm Hg or an average diastolic BP >= 80 mm Hg. Lifestyle measures plus BP lowering drugs should be used for primary prevention of CVD in persons with an estimated 10-year risk of atherosclerotic CVD of <10% and an average systolic BP >= 140 mm Hg or an average diastolic BP >= 90 mm Hg. Initiate antihypertensive drug therapy with 2 first-line drugs from different classes either as separate agents or in a fixed-dose combination in persons with a BP >= 140/90 mm Hg or with a BP > 20/10 mm Hg above their BP target. White coat hypertension must be excluded before initiating treatment with antihypertensive drugs in persons with hypertension at low risk for atherosclerotic CVD. Antihypertensive drug treatment for different disorders is discussed. PMID- 29419561 TI - Impact of Improved Survival in Congenital Heart Disease on Incidence of Disease. AB - Survival rates and life expectancies for patients with congenital heart disease (CHD) have dramatically increased, and these patients are now reaching reproductive age. As they reproduce, questions pertaining to recurrent risk of disease and the impact on incidence rates have emerged. Recurrence rates for CHD have been estimated at 3% to 5%, although, due to the complex genetics underlying CHD, this range may represent an underestimation of the true risk. Debate still exists on whether the impact of recurrence of disease has been reflected in incidence rates. Although incidence rates have undoubtedly increased, the mechanism underlying this remains unclear; improved detection likely accounts for the majority of the observed increase; however, a true increase may be present simultaneously. Concurrently, certain factors, including improved fetal detection and elective terminations, infertility, increased rates of spontaneous abortion and intrauterine fetal demise in women with CHD, and folic acid supplementation, are leading to decreases in the incidence of CHD. It is likely that the full impact of improved survival and heritability of CHD on incidence rates remains to be seen and will likely be attenuated by other factors acting to decrease incidence. PMID- 29419562 TI - Acupuncture and Cardiovascular Disease: Focus on Heart Failure. AB - Symptomatic heart failure is managed with interdisciplinary approaches to reduce acute exacerbations and to improve mortality. Acupuncture is a standardized treatment of Traditional Chinese Medicine that has been shown to have beneficial effects on the cardiovascular system via a neurohumoral pathway known as the long loop pathway. This article serves to examine recent evidence supporting the long loop pathway as the physiologic mechanism of acupuncture and the sympatholytic, vasodilatory, and cardioprotective effects of acupuncture that could specifically improve cardiac function and quality of life measures in the management of congestive heart failure. PMID- 29419563 TI - A Nonsurgical Approach to Mesenteric Vascular Disease. AB - Mesenteric ischemia is a rare disorder, with considerably high morbidity and mortality rates. It can manifest in several ways, including acute mesenteric ischemia, chronic mesenteric ischemia, nonocclusive mesenteric ischemia, mesenteric venous thrombosis, and colonic ischemia. Of these, acute mesenteric ischemia is the most severe form of intestinal ischemia, with a high mortality rate. The mainstay of therapy for mesenteric ischemia is surgical exploration and resection of infarcted bowel; however, medical therapy can play an important adjunctive role. When diagnosed early, before bowel infarction, endovascular therapy can be used as the primary treatment option. Endovascular therapy includes catheter-based thrombolysis, thromboembolectomy, and stenting. Vasodilators also play an important role in the early management of mesenteric ischemia. Anticoagulation is the main form of therapy in mesenteric venous thrombosis. PMID- 29419564 TI - Patient factors and outcomes associated with the withdrawal or withholding of life-sustaining therapies in mechanically ventilated brain-injured patients: An observational multicentre study. AB - BACKGROUND: Knowledge of the factors associated with the decision to withdraw or withhold life support (WWLS) in brain-injured patients is limited. However, most deaths in these patients may involve such a decision. OBJECTIVES: To identify factors associated with the decision to WWLS in brain-injured patients requiring mechanical ventilation who survive the first 24 h in the ICU, and to analyse the outcomes and time to death. DESIGN: A retrospective observational multicentre study. SETTINGS: Twenty French ICUs in 18 university hospitals. PATIENTS: A total of 793 mechanically ventilated brain-injured adult patients. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Decision to WWLS within 3 months of ICU admission, and death or Glasgow Outcome Scale (GOS) score at day 90. RESULTS: A decision to WWLS was made in 171 patients (22%), of whom 89% were dead at day 90. Out of the 247 deaths recorded at day 90, 153 (62%) were observed after a decision to WWLS. The median time between admission and death when a decision to WWLS was made was 10 (5 to 20) days vs. 10 (5 to 26) days when no end-of-life decision was made (P < 0.924). Among the 18 patients with a decision to WWLS who were still alive at day 90, three patients (2%) had a GOS score of 2, nine patients (5%) had a GOS score of 3 and five patients (3%) a GOS score of 4. Older age, presence of one nonreactive and dilated pupil, Glasgow Coma Scale less than 7, barbiturate use, acute respiratory distress syndrome and worsening lesions on computed tomography scans were each independently associated with decisions to WWLS. CONCLUSION: Using a nationwide cohort of brain-injured patients, we observed a high proportion of deaths associated with an end-of-life decision. Older age and several disease severity factors were associated with the decision to WWLS. PMID- 29419565 TI - Safety and efficacy of peri-operative administration of hydroxyethyl starch in children undergoing surgery: A systematic review and meta-analysis. AB - BACKGROUND: Hydroxyethyl starch (HES) solutions have shown their efficiency for intravascular volume expansion. A safety recommendation limiting their use in adult patients has recently been made. OBJECTIVE: To assess the efficacy and adverse effects of HES when administered intra-operatively to paediatric patients. DESIGN: Systematic review with meta-analyses. Data were analysed using classical mean differences [and their 95% confidence intervals (CIs)] and trial sequential analysis. A Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification was performed for all outcomes. Reviewers extracted valid data, including perioperative total fluid intakes, mortality, renal function, coagulation tests, blood loss and length of hospital and ICU stay. DATA SOURCES: Searches were performed in databases (Pubmed, Embase, Cochrane central register of controlled trials), clinical trials register, and open access journals not indexed in major databases. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) published before December 2016 involving paediatric patients who received 6% low molecular weight HES. RESULTS: Nine RCTs involving 530 peri-operative paediatric patients were analysed. Compared with other fluids, HES did not significantly modify the amount of peri-operative fluid administered [mean difference 0.04; 95% CI (-1.76 to 1.84) ml kg], urine output [mean difference -33; 95% CI (-104 to 38) ml kg] or blood loss [mean difference 0.09; (-0.32 to 0.15) ml kg]. Trial sequential analysis determined that the outcomes for peri-operative fluid and urine output were underpowered. All results were graded as very low quality of evidence. CONCLUSION: Intravascular volume expansion with low molecular weight 6% HES did not appear to modify renal function, blood loss or transfusion when administered to children during the peri operative period. However, given the lack of statistical power and the very low GRADE quality of evidence, more high-quality RCTs are needed to explore these outcomes. PMID- 29419566 TI - Risk Factors for Adverse Events in Patients With Breast, Colorectal, and Lung Cancer. AB - OBJECTIVE: The aim of the study was to identify risk factors associated with medical errors and iatrogenic injuries during an initial course of cancer directed treatment. METHODS: In this retrospective cohort study of 400 patients 18 years or older undergoing an initial course of treatment for breast, colorectal, or lung cancer at a comprehensive cancer center, we abstracted patient, disease, and treatment-related variables from the electronic medical record. We examined adverse events (AEs) and preventable AEs by risk factor using the chi or Fisher exact tests. We estimated the association between risk factors and the relative risk of an additional AE or preventable AE in multivariable negative binomial regression models with backwards selection (P < 0.1). RESULTS: There were 304 AEs affecting 136 patients (34%) and 97 preventable AEs affecting 53 patients (13%). In multivariable analyses, AEs were overrepresented in those with lung cancer compared with patients with breast cancer (incident rate ratio = 1.9, 95% confidence interval = 1.1-3.2). Nonwhite race (1.6, 1.0-2.6), Hispanic or Latino ethnicity (2.0, 0.9-4.1), advanced disease (1.7, 1.1-2.6), use of each additional class of high-risk nonchemotherapy medication (1.6, 1.3-1.9), and chemotherapy (2.1, 1.3-3.3) were all associated with risk of an additional AE. Preventable AEs were associated with lung cancer (7.4, 2.4-23.2), Hispanic or Latino ethnicity (5.5, 1.7-17.9), and high-risk nonchemotherapy medications (1.5, 1.2-2.0). CONCLUSIONS: Risk factors for AEs among patients with cancer reflected patients' underlying disease, cancer-directed therapy, and high-risk noncancer medications. The association of AEs with ethnicity merits further research. Risk factor models could be used prospectively to identify patients with cancer at increased risk of harm. PMID- 29419567 TI - Brief Report: Recent Methamphetamine Use Is Associated With Increased Rectal Mucosal Inflammatory Cytokines, Regardless of HIV-1 Serostatus. AB - BACKGROUND: Methamphetamine use increases the risk of HIV-1 infection among seronegative users and can exacerbate disease progression in HIV-positive users. The biological mechanisms underlying these associations remain unclear. In this cross-sectional pilot study, we examine the associations between recent methamphetamine use and inflammation in the rectal mucosa and peripheral blood compartments in HIV-1 seropositive and seronegative men who have sex with men. METHODS: HIV-seronegative and HIV-seropositive men who have sex with men participants were enrolled (N = 24). Recent methamphetamine use was determined by urine drug screen. Cytokines were quantified using multiplex arrays from collected plasma and rectal sponge samples, and peripheral blood T-cell activation was assessed by flow cytometry. RESULTS: Methamphetamine use was associated with consistently increased rectal inflammatory cytokines, specifically interleukin-6 and tumor necrosis factor-alpha, regardless of HIV-1 serostatus in this pilot study. This association was significant after adjusting for age, HIV-serostatus, and receptive anal intercourse frequency using regression analysis. Similar increases were not uniformly observed in peripheral blood. CONCLUSIONS: Methamphetamine use is associated with increased local mucosal inflammatory cytokine production. These findings may help explain the increased HIV-1 risk seen in methamphetamine users and contribute to increased inflammation among HIV-seropositive users. PMID- 29419570 TI - Brief Report: HIV Postexposure Prophylaxis-in-Pocket ("PIP") for Individuals With Low-Frequency, High-Risk HIV Exposures. AB - BACKGROUND: On-demand preexposure prophylaxis may reduce one's risk of HIV acquisition; however, it is unclear if individuals with a very low frequency of HIV exposures are conferred adequate protection. We evaluated a novel approach dubbed HIV postexposure prophylaxis-in-pocket ("PIP"), for individuals with a low frequency of high-risk HIV exposures. SETTING: Two HIV clinics in Toronto, Canada, managing HIV prevention cases. METHODS: A retrospective evaluation of patients referred to HIV clinics for preexposure prophylaxis between January 1, 2013, and September 30, 2017, inclusive. After counseling and education, selected patients were initiated on PIP if they were having very infrequent HIV exposures. RESULTS: Thirty patients were prescribed PIP. Four patients (13.3%) used PIP during this study. There were no HIV seroconversions in 21.8 cumulative patient years of PIP. CONCLUSIONS: PIP may be a useful HIV prevention modality for individuals with a very low frequency of HIV exposures. PMID- 29419569 TI - Brief Report: Statin Effects on Myocardial Fibrosis Markers in People Living With HIV. AB - BACKGROUND: In observational studies, patients with HIV have higher levels of soluble ST2 (sST2), galectin-3, and growth differentiation factor-15 (GDF-15) than non-HIV controls. As statins exert pleiotropic immunomodulatory effects that may affect markers of myocardial fibrosis, the objective of the current study is to determine whether biomarkers of myocardial fibrosis reflecting subclinical pathology may be modified by statin therapy in patients with HIV. SETTING AND METHODS: Forty HIV+ men and women participated in a single center 12-month randomized, double-blind placebo-controlled trial of atorvastatin 40 mg every day vs. placebo. At baseline and 12-months, sST2, GDF-15, galectin-3 were measured. RESULTS: The changes in sST2 were -0.310 (-4.195, 2.075) vs. 1.163 (0.624, 4.715) ng/mL, median (interquartile range) atorvastatin vs. placebo (P = 0.04). The change in sST2 was significantly related to changes in monocyte activation marker sCD14 (r = 0.63, P < 0.0001) and MCP (r = 0.52, P = 0.0009), markers of generalized inflammation hs-IL-6 (r = 0.58, P = 0.0002), oxLDL (r = 0.49, P = 0.002), and GDF-15 (r = 0.54, P = 0.0008). CONCLUSIONS: sST2, a member of the IL 1 receptor family and a marker of fibrosis and inflammation increases over time among patients with HIV and this increase is attenuated by statin therapy in HIV. This effect may relate to immunomodulatory mechanisms of statins. PMID- 29419571 TI - Ameliorative Effect of Epigallocatechin Gallate on Cardiac Hypertrophy and Fibrosis in Aged Rats. AB - The objective of the present study is to evaluate the effect of epigallocatechin gallate (EGCG) on aging-mediated cardiac hypertrophy, fibrosis, and apoptosis. The Wistar albino rats were divided into 4 groups (n = 18). Group I: young (3 months), group II: aged (24-26 months), group III: aged + EGCG (200 mg/kg for 30 days), and group IV: young + EGCG. At the end of 30 days, EGCG administration to the aged animals showed significant (P < 0.001) reduction of low-density lipoprotein, very low-density lipoprotein, triglyceride, total cholesterol with concomitant increase of high-density lipoprotein (P < 0.001) when compared with aged rats. Increased (P < 0.001) heart volume, weight with concomitant increase of left ventricular wall thickness, and reduced ventricular cavity were observed in aged rats supplemented with EGCG compared with aged animals. Histology and histomorphometry study of aged animals treated with EGCG showed marked increases in the diameter and volume of cardiomyocytes with concomitant reduction of numerical density when compared with aged animals. Reduced reactive oxygen species (P < 0.001) production with association of increased antioxidant defense system (P < 0.001) in aged hearts supplemented with EGCG when compared with aged animals. TUNEL staining and fibrosis showed a marked increase in apoptotic cell death (P < 0.001) and collagen deposition (P < 0.001) in aged animals treated with EGCG when compared with aged animals. Aged animals treated with EGCG showed a marked increase in protein expression of TGFbeta, TNFalpha, and nuclear factor kappa B (NF-kappaB) and significant (P < 0.001) alteration in the gene expression of TGFbeta, TNFalpha, NF-kappaB, alpha-SMA, and Nrf2 when compared with aged animals. Taken together, it is evident that EGCG may potentially inhibit aging induced cardiac hypertrophy, fibrosis, and apoptosis, thereby preserving cardiac function. The proposed mechanism would be inhibition of reactive oxygen species dependent activation of TGFbeta1, TNFalpha, and NF-kappaB signaling pathway. Hence, the present study suggests that EGCG can be useful to fight against aging induced cardiac hypertrophy, fibrosis, and apoptosis. PMID- 29419568 TI - Recent Abacavir Use Increases Risk of Type 1 and Type 2 Myocardial Infarctions Among Adults With HIV. AB - BACKGROUND: There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV. METHODS: Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence. RESULTS: Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17 2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08 4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome. CONCLUSIONS: Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs. PMID- 29419572 TI - Preconditioning and Postconditioning by Cardiac Glycosides in the Mouse Heart. AB - Ouabain preconditioning (OPC) initiated by low concentrations of the cardiac glycoside (CG) ouabain binding to Na/K-ATPase is relayed by a unique intracellular signaling and protects cardiac myocytes against ischemia/reperfusion injury. To explore more clinically applicable protocols based on CG properties, we tested whether the FDA-approved CG digoxin could trigger cardioprotective effects comparable with those of ouabain using PC, preconditioning and PostC, postconditioning protocols in the Langendorff-perfused mouse heart subjected to global ischemia and reperfusion. Ouabain or digoxin at 10 MUmol/L inhibited Na/K-ATPase activity by approximately 30% and activated PKCepsilon translocation by approximately 50%. Digoxin-induced PC (DigPC), initiated by a transient exposure before 40 minutes of ischemia, was as effective as OPC as suggested by the recovery of left ventricular developed pressure, end diastolic pressure, and cardiac Na/K-ATPase activity after 30 minutes of reperfusion. DigPC also significantly decreased lactate dehydrogenase release and reduced infarct size, comparable with OPC. PostC protocols consisting of a single bolus injection of 100 nmoles of ouabain or digoxin in the coronary tree at the beginning of reperfusion both improved significantly the recovery of left ventricular developed pressure and decreased lactate dehydrogenase release, demonstrating a functional and structural protection comparable with the one provided by OPC. Given the unique signaling triggered by OPC, these results suggest that DigPostC could be considered for patients with risk factors and/or concurrent treatments that may limit effectiveness of ischemic PostC. PMID- 29419573 TI - Important Role of Endothelial Caveolin-1 in the Protective Role of Endothelium dependent Hyperpolarization Against Nitric Oxide-Mediated Nitrative Stress in Microcirculation in Mice. AB - AIMS: Nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) play important roles in maintaining cardiovascular homeostasis. We have previously demonstrated that endothelial NO synthase (eNOS) plays diverse roles depending on vessel size, as a NO generating system in conduit arteries and an EDH-mediated system in resistance arteries, for which caveolin-1 (Cav-1) is involved. However, the physiological role of endothelial Cav-1 in microvessels remains to be elucidated. METHODS AND RESULTS: We newly generated endothelium-specific Cav-1 knockout (eCav-1-KO) mice. eCav-1-KO mice showed loss of endothelial Cav-1/eNOS complex and had cardiac hypertrophy despite normal blood pressure. In eCav-1-KO mice, as compared to wild-type controls, the extent of eNOS phosphorylation at inhibitory Thr495 was significantly reduced in mesenteric arteries and the heart. Isometric tension and Langendorff-perfused heart experiments showed that NO mediated responses were enhanced, whereas EDH-mediated responses were reduced in coronary microcirculation in eCav-1-KO mice. Immunohistochemistry showed increased level of 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), a marker of nitrative stress, in the heart from eCav-1-KO mice. S-guanylation of cardiac H-Ras in eCav-1-KO mice was also significantly increased compared with wild-type controls. CONCLUSIONS: These results suggest that eCav-1 is involved in the protective role of EDH against nitrative stress caused by excessive NO to maintain cardiac microvascular homeostasis. PMID- 29419574 TI - NACNS Newsletter: President's Message. PMID- 29419575 TI - Publishing Evidence-Based Practice Projects. PMID- 29419576 TI - Intensive Care Unit Diaries: The Importance of Exploring the Literature Before Implementation. PMID- 29419577 TI - Social Media: The Next Research Frontier. PMID- 29419578 TI - From the Bedside to Serving on the Board: Nurses Are Changing the Face of Healthcare. PMID- 29419579 TI - Role Transition After Clinical Nurse Specialist Education. AB - PURPOSE: This study explored the transition of clinical nurse specialists into new roles after completion of their graduate education. DESIGN: A quantitative longitudinal survey was used to measure certification, employment, career commitment, and the imposter phenomenon. METHODS: An online survey was sent to 113 participants from a previous national study that agreed to follow-up. The Student Nurse Anesthetist Experience Questionnaire and Clance Imposter Phenomenon Scale instruments were used. Each case (N = 68) was matched with data from the primary study, and 2 comparison groups were formed based on employment status as a clinical nurse specialist. RESULTS: The advanced practice certification rate was 66.7%, and 48.5% were employed as a clinical nurse specialist. The employed group perceived more autonomy, a more positive view of the clinical nurse specialist lifestyle, and upset life plans if not able to practice in the role when compared with the not-employed group. Self-image was significantly different based on employment, but career commitment was not particularly strong regardless of employment status. The prevalence of imposter phenomenon experiences was 74.6% in this sample. CONCLUSION: Recent graduates are struggling with their transition into practice as clinical nurse specialists. PMID- 29419580 TI - Self-monitoring Lifestyle Behavior in Overweight and Obese Pregnant Women: Qualitative Findings. AB - BACKGROUND: Excessive maternal gestational weight gain increases pregnancy and infant complications. Self-monitoring has been shown to be an effective strategy in weight management. Literature, however, is limited in describing pregnant women's engagement in self-monitoring. AIM: This qualitative study explored the experiences of overweight and obese pregnant women who self-monitored their eating, walking, and weight as participants in an intervention for excessive gestational weight gain prevention. METHODS: Thirteen overweight and obese pregnant women participated in semistructured interviews. Reflexive iteration data analysis was conducted. FINDINGS: Five themes were identified: making self monitoring a habit, strategies for self-monitoring, barriers to self-monitoring, benefits of self-monitoring, and drawbacks of self-monitoring. The women viewed self-monitoring as a "habit" that could foster a sense of self-control and mindfulness. Visual or tracing aids were used to maintain the self-monitoring habit. Forgetting, defective tracking aids, complexities of food monitoring, and life events could impede self-monitoring. Being unable to keep up with self monitoring or to achieve goals created stress. CONCLUSIONS: Self-monitoring is a promising approach to weight management for overweight and obese pregnant women. However, healthcare providers should be aware that, although women may identify several benefits to self-monitoring, for some women, consistently trying to track their behaviors is stressful. PMID- 29419581 TI - Outcomes of Clinical Nurse Specialist Practice in the Implementation of Video Monitoring at an Academic Medical Center. AB - PURPOSE/OBJECTIVES: The purpose of this project was to design and implement a program that utilizes video cameras with the goal of monitoring for and preventing unsafe patient events that can lead to poor outcomes. DESCRIPTION OF THE PROJECT: The Concerns-Based Adoption Model was utilized to address users' concerns in different stages of diffusion of the new technology. Clinical nurse specialists, as part of a Constant Observation Workgroup, addressed these concerns during initial development and subsequent implementation of video monitoring on adult inpatient units. Establishing initiation criteria for video monitoring and documentation in the electronic health record was critical to success of the project. OUTCOMES: Video monitoring was successfully implemented on 8 inpatient units. A decline in full-time employment numbers for 1:1 sitters was demonstrated with no increase in fall numbers. CONCLUSIONS: Clinical nurse specialists were successful in collaborating with interdisciplinary colleagues to support the development of a Constant Observation Program that included video monitoring. In addition, clinical nurse specialists developed documentation, policies, and procedures to support this new technology. Success was evidenced by support of and growth of the program over time. PMID- 29419582 TI - Resilience and Coping After Hospital Mergers. AB - OBJECTIVE: The aim of this study was to explore the relationship between resilience and coping in frontline nurses working in a healthcare system that has recently undergone a merger. BACKGROUND: Hospital mergers are common in the current healthcare environment. Mergers can provide hospital nurses the opportunity to use and develop positive coping strategies to help remain resilient during times of change. METHODS: An anonymous-survey, quantitative, exploratory, descriptive study design was used. Data were obtained from an electronic survey that was made available to all nurses working in a 3-hospital system located in the northeast. RESULTS: Overall, the results showed that, when nurses reported using positive coping strategies, they report higher levels of resilience. The levels of resilience also varied from campus to campus. The campus that has been through 2 recent mergers reported the highest levels of resilience. CONCLUSION: This study suggests that, during times of change in the workplace, if nurses are encouraged to use positive coping strategies, they may have higher levels of resilience. This changing environment provides the clinical nurse specialists/clinical nurse educators the opportunity to foster and support frontline nurses in the use of healthy coping strategies and to help improve and maintain a high level of resilience, which is critical in today's healthcare environment. PMID- 29419583 TI - Tagore on the Language of Joy. PMID- 29419584 TI - Recurrence of Giant Cell Tumor of The Larynx. AB - Giant cell tumor of the larynx is a rare tumor. It was first reported by Wessely et al in 1940. Thirty-nine cases have been reported until now and together with the current case 2 recurrences were encountered. In this case report, our aim was to discuss conservative management because of the suspicion of recurrence. A 70 year-old male patient was admitted to our clinic with the complaint of hoarseness. A tumor measuring 1 * 1 cm located in the anterior half right vocal fold and extending to the anterior comissure was found on laryngeal endoscopy. Direct laryngoscopy and biopsy of the mass revealed giant cell tumor on histopathological examination. Tumor resection with cordectomy through laryngofissure and subsequently medialization thyroplasty were performed. Horaseness of the patient improved. On 2-year follow-up, a tumoral lesion suggesting recurrence was found on the vocal cord. Direct laryngoscopy and biopsy confirmed recurrence. Total laryngectomy was performed. This is the second case of recurrent giant cell tumor of the larynx. The therapy of choice should be selected considering the possibility of recurrence. PMID- 29419585 TI - Application of Digital Diagnosis and Treatment Technique in Benign Mandibular Diseases. AB - PURPOSE: To explore the feasibility of preoperative planning for treatment of benign mandibular lesions (BML) using digital technologies such as three dimensional (3D) reconstruction, measurement, visualization as well as image contrast and design of neural positioning protection template (NPPT) in combination with 3D printing technology in the BML diagnosis and treatment. METHODS: The 3D models of BML and inferior alveolar nerves (IAN) of 10 BML patients were reconstructed based on their digital imaging and communications in medicine (DICOM) data using MIMICS16.0 software. The models were used to visualize lesions and nerve contrast measurement and guide design of personalized NPPT and osteotomy after operation modality was determined in order to achieve accurate, minimally invasive operation with shortened intraoperative time. RESULTS: Intraoperative NPPT application could accurately locate lesions and their scope and assist osteotomy. The measurement results were consistent with those of preoperative reconstruction and measurement. The BML were curetted completely without damage IAN. The 10 BML patients had no numbness and other discomforts in the lower lip and mandibular teeth after operation. CONCLUSIONS: The digital diagnosis and treatment technology is an effective method for functional treatment of BML patients and its application could achieve personalized, minimally invasive and precise treatment and save intraoperation time. PMID- 29419586 TI - Comparison of Three Methods Used for Estimating Area of Foramen Magnum. AB - OBJECTIVE: To compare whether there are any differences between the 3 methods used for measure area of foramen magnum (FM) in skulls. METHODS: The FMs of 150 skulls were examined. Antero-posterior diameter, transverse diameter were measured using by Vernier caliper. The area of the FM was calculated by using 2 different formulas as described previously by Radinsky and Teixeira.The authors also applied stereological assessment method for estimating the surface area of FMs. The area was calculated 3 times manually using stereological point grid system for each skull.The authors compared the mean surface area of FMs obtained from each of these 3 methods estimating surface area of FMs whether there were any significant differences in between their results. RESULTS: The mean areas of the FMs estimated according to Teixeria formula, Radinsky formula, and Cavalieri stereological method were respectively as follows: 790.47 +/- 99.86 mm, 783.66 +/ 99.34 mm, and 748.06 +/- 100.19 mm. The authors observed significant differences (P < 0.05) in between the mean surface areas of FMs obtained from each of these 3 methods used for estimating the area. CONCLUSION: There were significant differences (P < 0.05) in between the mean surface areas of FMs obtained from each of these 3 methods used for estimating the area. PMID- 29419587 TI - Evaluation of the Characteristics and Association Between Schneiderian Membrane Thickness and Nasal Septum Deviation. AB - OBJECTIVE: Nasal septum deviation (NSD) is an anomaly that disturbs normal mucus drainage in sinuses, leading to recurrent sinusitis. Sinusitis, infections, and mucosal irritations are the potential causes of Schneiderian membrane thickening (SMT). The aim of this study was to evaluate the characteristics and association between NSD and SMT along with factors such as age, gender, and tooth groups using cone-beam computed tomography (CBCT) imaging. METHODS: The maxillary sinus and nasal cavity of 249 patients (136 females and 113 males) were examined retrospectively using CBCT. The statistical analysis was performed to determine the association between SMT, NSD, gender, and age. RESULTS: No statistically significant relation was detected between NSD and SMT. The NSD was found in 50.6% of patients without gender predilection. Age was not associated with the presence of NSD. The mean thickness of the membrane was least in the third molar region and highest in the first molar region. The average SMT was found to be higher in males for all the examined tooth areas (P <= 0.05). CONCLUSION: A retrospective evaluation of CBCT images emphasized the concept that NSD was not a factor that affected the thickening of maxillary sinus mucosa. The CBCT imaging could be used for evaluating the maxillary sinuses and nasal septum. PMID- 29419588 TI - Heritability of Facial Skeletal and Dental Characteristics of Monozygotic and Dizygotic Twins Using Cephalometric Analysis and Falconer's Method. AB - The purpose of this study was to investigate the heritability of facial skeletal and dental characteristics of the monozygotic (MZ) and dizygotic (DZ) twins. The samples consisted of Korean MZ and DZ twins (n = 13 pairs/each twin; 7 pairs of males and 6 pairs of females; mean age, 39 years, respectively). The linear, angular, and ratio variables, which could describe the size and shape of the facial horizontal and vertical, dental, mandible and cranial base structure, were measured. The Falconer's method was used to calculate the heritability (h; close to or below 0, low heritability; close to or above 1, high heritability). In the facial horizontal and vertical aspects, the highest h values were shown at SNA (degree, 1.53), SNB (degree, 2.12), SN-Pog (degree, 2.19), SN-palatal plane angle (degree, 1.29), SN-mandibular plane angle (degree, 1.59), N-ANS/ANS-Me (1.66), and ANS-Me/N-Me (1.62). In the dental aspects, although L1-occlusal plane angle (degree, 1.38) and SN-occlusal plane angle (degree, 2.09) showed high h values, most of the dental variables showed low h values. In the mandible and cranial base, lower gonial angle, mandibular body length, and cranial base angle showed high h values (N-Go-Gn [degree], 1.07; Go-Pog [mm], 0.92; N-S-Ba [degree], 1.51). The descending order of the overall mean h values was the facial horizontal (1.10), facial vertical (0.71), mandible (0.59), cranial base (0.37), and dental characteristics (-0.11). The shape of facial skeletal structure and location of the occlusal plane within skeletal framework was more influenced by genetic factors than environmental factors. PMID- 29419589 TI - Merkel Cell Carcinoma of the Cheek. AB - Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a neuroendocrine phenotype. Here, the authors reported a case of MCC, presented as a rapidly growing, asymptomatic, erythematous nodule measuring 3.8 cm * 2.8 cm in diameter on the right cheek of an 85-year-old Caucasian woman. After resection of the nodule, the defect was repaired with cutaneous graft taken from the supraclavicular area and healed uneventfully. Histopathologic examination confirmed the diagnosis of MCC. PMID- 29419590 TI - Extended Release Liposomal Bupivacaine Injection (Exparel) for Early Postoperative Pain Control Following Pharyngoplasty. AB - BACKGROUND: Liposomal bupivacaine (LB, Exparel) is a long-acting local anesthetic reported to decrease postoperative. The authors demonstrate the first safe use of LB in pediatric patients with improved pain control following pharyngoplasty. METHODS: Retrospective case-control of all the patients who underwent pharyngoplasty at a tertiary craniofacial center from March 2010 to June 2016. Treatment group (TG) administered 1.3% LB and 0.5% bupivacaine and 1:200,000 epinephrine. Control group (CG) administered 0.5% lidocaine with 1:200,000 epinephrine. Pain scores, oral intake, opioids administered, and duration of hospitalization were measured. RESULTS: Sixty patients (30 males, 30 females; average age 6.2 +/- 2.4 years, weight 20.9 +/- 6.8 kg) were evenly divided into a TG that received 3.5 +/- 2.1 mL (2.6 +/- 1.9 mg/kg) LB and 2.0 +/- 2.3 mL 0.5% bupivacaine and a CG that received 2.7 +/- 3.2 mL lidocaine. Treatment group patients had lower initial face, legs, activity, cry, consolability pain scale scores (0.1 +/- 0.55/10, P = 0.0049; CG 4.5 +/- 1.1/10, P = 0.00061) and no significant inpatient pain score difference 0 to 36 hours postoperative (P = 0.32 0.53). Oral intake was tolerated 0.21 +/- 0.12 days (P < 0.0001) earlier by the TG and with greater first 24-hour average volume (377.6 +/- 351.9 cc, P < 0.0001). Treatment group patients were discharged 1.8 +/- 0.87 days (P = 0.00023) earlier and required lower average opioids (15.1 +/- 11.2 mg hydrocodone equivalents) than CG (27.5 +/- 19.1 mg hydrocodone-equivalents; P = 0.0017). CONCLUSIONS: Liposomal bupivacaine is safe in pediatric patients, associated with less opioids, increased and earlier oral intake, and shorter hospital stay. PMID- 29419591 TI - Application of Micromirror in Microsurgical Clipping to the Intracranial Aneurysms. AB - OBJECTIVE: The aim of the study was to explore the values and disadvantages of micromirror in the intracranial aneurysm clipping surgery. METHODS: Micromirror was used to assist microsurgical clipping to 36 intracranial aneurysms in 31 patients, of which 3 were carotid-ophthalmic artery aneurysms, 3 were anterior choroidal artery aneurysms, 11 were posterior communicating artery aneurysms, 7 were middle cerebral artery aneurysms, 10 were anterior communicating artery or anterior cerebral artery aneurysms, and the rest were a posterior cerebral artery aneurysm and a posterior inferior cerebellar artery aneurysm. The micromirror was used before and after clipping to observe the anatomic features of necks hidden behind and medial to aneurysms, to visualize surrounding neurovascular structures, and to verify the optimal clipping position. Intraoperative indocyanine green fluorescein angiography, postoperative computerized tomography angiography, and digital subtraction angiography confirmed the success of sufficient clipping. RESULTS: Intraoperative indocyanine green angiography, postoperative computerized tomography angiography , or digital subtraction angiography were performed and showed no case of wrong or insufficient clipping of aneurysm. CONCLUSIONS: Micromirror-assisted microsurgical clipping to the intracranial aneurysm is safe, sufficient, convenient, and practical. PMID- 29419592 TI - Refinements in Elevation of the Reconstructed Auricle: The "Zigzag Incision". AB - OBJECTIVE: Auricular elevation with superficial temporal fascia and skin graft is widely used in microtia reconstruction using costal cartilage. However, in some patients, there has been occurrence of contraction of skin graft, which led to insufficient projection of the elevated auricle and diminished auriculocephalic angle with unfavorable long-term results. In this article, the authors introduce their multiple triangular flaps with zigzag incision to maintain stable projection and natural retroauricular sulcus appearance in auricular reconstruction patients. METHODS: The authors have designed zigzag incision along the lateral margin of the ear framework to prepare triangular flaps targeting the root of the helix or inferior half of the auricle. Depending on the extent of remnant skin coverage, the number of triangular flaps is varied. The posterior raw surface of the ear framework was covered with triangular flaps and full thickness skin graft. RESULTS: Zigzag incision was conducted in 22 microtia patients who underwent auricular elevation using superficial temporal fascia and skin graft. Mean follow-up period was 2 years and there were no reports of occurrence of surgery-related complications, specifically skin necrosis, infection, or hematoma. The auricular projections were well maintained and auriculocephalic angle of the constructed auricles was similar to the healthy ears. CONCLUSIONS: The author's method comprises comparatively easy techniques and leads to good projection of the auricular angle. A zigzag incision using the triangular flaps could be an attractive surgical option for preventing shrinkage of grafted site and in achieving sufficient projection in autologous reconstructed auricle. PMID- 29419593 TI - Three-Dimensional Finite Element Analysis of Different Plating Techniques for Unfavorable Mandibular Angle Fractures. AB - The purpose of the current study was to assess the biomechanical behavior of 5 different fixation schemes for unfavorable mandibular angle fractures using the three-dimensional finite element analysis method. Five different miniplate fixation schemes were modeled for the fixation of unfavorable mandibular angle fractures. A double parallel miniplate (M1), which was placed at the halfway point of the mandibular angle height; a 1/3 superior-positioned miniplate (M2); a single miniplate (M3), which was placed at the halfway point of the mandibular angle height (1/2 middle-positioned); a 1/3 inferior-positioned miniplate (M4); and an X-miniplate which was placed at the halfway point of the mandibular angle height (M5). The lowest mechanical stresses were detected in the double miniplate model when compared with the other schemes, whereas 1/3 inferior-positioned miniplate had the highest stress and displacement values. The authors suggest that the double miniplate is an adequate rigid fixation technique, whereas the 1/3 inferior-positioned miniplate configuration should not be used in case of unfavorable mandibular angle fracture. PMID- 29419594 TI - Rate of Relapse After Enucleation of Solid/Multicystic Ameloblastoma Followed by Piezoelectric or Conventional Peripheral Ostectomy. AB - The use of piezo surgery is characterized by a good cutting ability associated with a higher soft tissues respect. Such skills have led to an increment of the use of such systematic in the clinical practice. The aim of this study was to figure out whether the use of piezo surgery may show clinical advantages when enucleation is followed by peripheral ostectomy for the treatment of solid/multicystic ameloblastoma. A retrospective case-control study was performed, including patients treated with piezo surgery or conventional drilling in a single center in Italy. Results of this investigation revealed a lower rate of relapse, at 5 years' follow-up for patients treated with piezo surgery. Although characterized by low power of evidences, the results of this investigation encourage the development of further studies related to the use of piezo surgery for the treatment of solid/multicystic ameloblastoma. PMID- 29419595 TI - Endoscopic Approach for Excision of Venous Malformation of the Orbital Apex. AB - INTRODUCTION: Venous malformation is a common tumor of the orbit, presenting with visual impairment and proptosis. These lesions can be excised via an external or transcranial approach, but recent advances in minimally invasive surgery have led to increased popularity of endoscopic approach. PATIENT: The authors report a 62 year-old female presenting with diplopia and proptosis, found to have a 1.7-cm venous malformation of the orbital apex. An endoscopic trans-nasal approach was undertaken for surgical resection. RESULTS: The tumor was successfully removed in a single specimen, without injury to the nearby orbital anatomy. The patient experienced resolution of her presenting symptoms 3 weeks after the procedure, with no adverse effects. A review of the literature demonstrates increasing reports of similar successful cases. CONCLUSION: A minimally invasive, endoscopic resection of orbital venous malformation is possible and provides a reasonably safe and effective approach. Further large-scale studies are needed to fully explore its outcomes relative to traditional approaches. PMID- 29419596 TI - Orbital Cavernous Hemangioma Causing Spontaneous Compressive Hemorrhage. AB - Cavernous hemangiomas are the most common tumors of the posterior cone of the orbit in adults. They are discovered in a fortuitous manner or in front of the appearance of a progressive exophthalmia.The authors report through a complete literature review (PubMed) patients of retro-orbital cavernous hemangioma revealed by spontaneous compressional hemorrhage from 1984 to 2017.This review is illustrated by a case of sharp decrease in visual acuity secondary to orbital cavernous hemangioma hemorrhage.The authors detail the management and the evolution of all these patients. PMID- 29419597 TI - Orbital Schwannoma With Atypical Presentation. AB - Orbital schwannomas are characteristically slow-growing benign tumors arising from peripheral sensory nerves. However, the authors' case illustrates the atypical presentation of such a tumor.A 71-year-old male presented with proptosis, visual loss, and periorbital inflammation. Sequential imaging showed continuous and rapid growth of an intraconal mass arising from the medial rectus. Excision of the mass was performed and it was histopathologically proven to be an orbital schwannoma.This patient demonstrates the atypical presentation of an orbital schwannoma, arising from an extraocular muscle with rapid progressive growth and inflammation, indicating it should be considered a differential diagnosis in orbital masses presenting as such. PMID- 29419598 TI - Occlusion-Fit Three-Dimensional-Printed Zygoma Repositioner. AB - Reduction malarplasty is utilized to reshape the facial form into an oval shape. However, complications and unfavorable results in reduction malarplasty have been reported. Reoperation of a nonunion malar complex is difficult relative to the achievement of a satisfactory outcome using the intraoral approach with a narrow surgical field because the normal anatomy has been destroyed, and previous surgery may have caused asymmetry. In this situation, computer-aided simulation surgery and surgical guides can serve as effective solutions to overcome the limitations of reoperative malarplasty using the intraoral approach.In this report, the authors present a case with successful treatment outcomes for a nonunion malar complex using a three-dimensional-printed zygoma repositioner. PMID- 29419600 TI - PCNA News. PMID- 29419601 TI - Transition Planning. PMID- 29419602 TI - New Hypertension Guideline Emphasizes the Benefits of Lower Blood Pressure. PMID- 29419603 TI - Characteristics of Infants With Congenital Diaphragmatic Hernia Who Need Follow Up of Pulmonary Hypertension. AB - OBJECTIVES: Pulmonary hypertension is one of the main causes of mortality and morbidity in patients with congenital diaphragmatic hernia. Currently, it is unknown whether pulmonary hypertension persists or recurs during the first year of life. DESIGN: Prospective longitudinal follow-up study. SETTING: Tertiary university hospital. PATIENTS: Fifty-two congenital diaphragmatic hernia patients admitted between 2010 and 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pulmonary hypertension was measured using echocardiography and electrocardiography at 6 and 12 months old. Characteristics of patients with persistent pulmonary hypertension were compared with those of patients without persistent pulmonary hypertension. At follow-up, pulmonary hypertension persisted in four patients: at 6 months old, in three patients (patients A-C), and at 12 months old, in two patients (patients C and D). Patients with persistent pulmonary hypertension had a longer duration of mechanical ventilation (median 77 d [interquartile range, 49-181 d] vs median 8 d [interquartile range, 5-15 d]; p = 0.002) and hospital stay (median 331 d [interquartile range, 198-407 d) vs median 33 d (interquartile range, 16-59 d]; p = 0.003) than patients without persistent pulmonary hypertension. The proportion of patients with persistent pulmonary hypertension (n = 4) treated with inhaled nitric oxide (100% vs 31%; p = 0.01), sildenafil (100% vs 15%; p = 0.001), and bosentan (100% vs 6%; p < 0.001) during initial hospital stay was higher than that of patients without persistent pulmonary hypertension (n = 48). At 6 months, all patients with persistent pulmonary hypertension were tube-fed and treated with supplemental oxygen and sildenafil. CONCLUSIONS: Less than 10% of congenital diaphragmatic hernia patients had persistent pulmonary hypertension at ages 6 and/or 12 months. Follow-up for pulmonary hypertension should be reserved for congenital diaphragmatic hernia patients with echocardiographic signs of persistent pulmonary hypertension at hospital discharge and/or those treated with medication for pulmonary hypertension at hospital discharge. PMID- 29419604 TI - Assessment of Recovery Following Pediatric Traumatic Brain Injury. AB - OBJECTIVES: We analyzed a prospective database of pediatric traumatic brain injury patients to identify predictors of outcome and describe the change in function over time. We hypothesized that neurologic status at hospital discharge would not reflect the long-term neurologic recovery state. DESIGN: This is a descriptive cohort analysis of a single-center prospective database of pediatric traumatic brain injury patients from 2001 to 2012. Functional outcome was assessed at hospital discharge, and the Glasgow Outcome Scale Extended Pediatrics or Glasgow Outcome Scale was assessed on average at 15.8 months after injury. SETTING: Children's Medical Center Dallas, a single-center PICU and Level 1 Trauma Center. PATIENTS: Patients, 0-17 years old, with complicated-mild/moderate or severe accidental traumatic brain injury. MEASUREMENTS AND MAIN RESULTS: Dichotomized long-term outcome was favorable in 217 of 258 patients (84%), 80 of 82 patients (98%) with complicated-mild/moderate injury and 133 of 172 severe patients (77%). In the bivariate analysis, younger age, motor vehicle collision as a mechanism of injury, intracranial pressure monitor placement, cardiopulmonary resuscitation at scene or emergency department, increased hospital length of stay, increased ventilator days (all with p < 0.01) and occurrence of seizures (p = 0.03) were significantly associated with an unfavorable outcome. In multiple regression analysis, younger age (p = 0.03), motor vehicle collision (p = 0.01), cardiopulmonary resuscitation (p < 0.01), and ventilator days (p < 0.01) remained significant. Remarkably, 28 of 60 children (47%) with an unfavorable Glasgow Outcome Scale at hospital discharge improved to a favorable outcome. In severe patients with an unfavorable outcome at hospital discharge, younger age was identified as a risk factor for remaining in an unfavorable condition (p = 0.1). CONCLUSIONS: Despite a poor neurologic status at hospital discharge, many children after traumatic brain injury will significantly improve at long-term assessment. The factors most associated with outcomes were age, cardiopulmonary resuscitation, motor vehicle collision, intracranial pressure placement, days on a ventilator, hospital length of stay, and seizures. The factor most associated with improvement from an unfavorable neurologic status at discharge was being older. PMID- 29419605 TI - Ceftaroline for Suspected or Confirmed Invasive Methicillin-Resistant Staphylococcus aureus: A Pharmacokinetic Case Series. AB - OBJECTIVES: To describe the ceftaroline pharmacokinetics in critically ill children treated for suspected or confirmed methicillin-resistant Staphylococcus aureus infections, including blood stream infection and describe the microbiological and clinical outcomes. DESIGN: Retrospective electronic medical record review. SETTINGS: Free-standing tertiary/quaternary pediatric children's hospital. PATIENTS: Critically ill children receiving ceftaroline monotherapy or combination therapy for suspected or confirmed methicillin-resistant S. aureus infections in the PICU. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Seven patients, three females (43%), and four males (57%), accounted for 33 ceftaroline samples for therapeutic drug management. A median of four samples for therapeutic drug management was collected per patient (range, 2-9 samples). The median age was 7 years (range, 1-13 yr) with a median weight of 25.5 kg (range, 12.6-40.1 kg). Six of seven patients (86%) demonstrated an increase in volume of distribution, five of seven patients (71%) demonstrated an increase in clearance, and 100% of patients demonstrated a shorter half-life estimate as compared with the package insert estimate. Six of seven patients (85.7%) had documented methicillin-resistant S. aureus growth from a normally sterile site with five of six (83.3%) having documented BSI, allowing six total patients to be evaluated for the secondary objective of microbiological and clinical response. All six patients achieved a positive microbiological and clinical response for a response rate of 100%. CONCLUSIONS: These data suggest the pharmacokinetics of ceftaroline in PICU patients is different than healthy pediatric and adult patients, most notably a faster clearance and larger volume of distribution. A higher mg/kg dose and a more frequent dosing interval for ceftaroline may be needed in PICU patients to provide appropriate pharmacodynamic exposures. Larger pharmacokinetic, pharmacodynamic, and interventional treatment trials in the PICU population are warranted. PMID- 29419607 TI - Editorial introduction. PMID- 29419606 TI - In Vitro Adsorption of Analgosedative Drugs in New Extracorporeal Membrane Oxygenation Circuits. AB - OBJECTIVE: Evaluate drug disposition of sedatives and analgesics in the Xenios/Novalung extracorporeal membrane oxygenation circuits. DESIGN: In vitro experimental study. SETTING: Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. SUBJECTS: Nine closed-loop extracorporeal membrane oxygenation circuits, made up of the iLA Activve console with four different iLA Activve kits: two X-lung kits, two iLA-Activve iLA kits, two MiniLung kits, and three MiniLung petite kits. INTERVENTIONS: The circuits were primed with fresh whole blood and maintained under physiologic conditions (pH/temperature) throughout 24 hours. Paracetamol, morphine, midazolam, fentanyl, and sufentanil were injected as standard age-related doses into nine closed-loop extracorporeal membrane oxygenation circuits. MEASUREMENTS AND MAIN RESULTS: Pre-membrane (P2) blood samples were obtained prior to drug injection and after injection at 2, 10, 30, 180, 360 minutes, and at 24 hours. A control sample at 2 minutes was collected for spontaneous drug degradation testing at 24 hours. Two hundred sixteen samples were analyzed. After correction for the spontaneous drug degradation, the mean drug loss at 24 hours was paracetamol 49%, morphine 51%, midazolam 40%, fentanyl 84%, sufentanil 83%. Spontaneous degradation was paracetamol 6%, morphine 0%, midazolam 11%, fentanyl 4%, and sufentanil 0%. The decline of drug concentration over time was more pronounced for the more lipophilic drugs. CONCLUSIONS: Loss of highly lipophilic drugs in the extracorporeal membrane oxygenation circuits at 24 hours was remarkable. Drug loss is comparable with other hollow fiber extracorporeal membrane oxygenation systems but less than in silicone-based membranes especially in the first hours after injection. PMID- 29419609 TI - Systematic searching?...well, we had a bit of a look. PMID- 29419611 TI - Reliability, validity and relevance of needs assessment instruments for informal dementia caregivers: a psychometric systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this psychometric review is to identify needs assessment instruments for informal dementia caregivers which are:More specifically, the aim is to present an overview and an evaluation of the available needs assessment instruments, including: i) their psychometrics (reliability and validity) when available, and ii) their relevance according to the instrument characteristics, namely, their purpose, application method, administration burden, number of items and domain structure. PMID- 29419610 TI - Vision loss in Indigenous peoples of the world: a systematic review protocol. AB - REVIEW OBJECTIVE/QUESTION: The objectives of this review are. PMID- 29419612 TI - Effectiveness of universal hyperbilirubinemia screening on newborn health: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to assess the effectiveness of the universal hyperbilirubinemia screening program on common newborn health outcomes.Specifically, the review will assess: the incidence of severe hyperbilirubinemia/kernicterus/exchange transfusion, rate of readmission due to jaundice, length of hospital stay on birth admission, rate and utilization of phototherapy during birth hospitalization, and jaundice related emergency visits. PMID- 29419613 TI - Effectiveness of interventions to prevent medication errors: an umbrella systematic review protocol. AB - REVIEW QUESTION: What is the effectiveness of interventions designed to prevent medication error on medication administration errors, medication-related harms and medication-related death in acute care patients? PMID- 29419614 TI - Phytochemicals and cognitive/behavioral function in patients with Alzheimer's disease: a scoping review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to explore the existing literature related to phytochemicals and cognitive/behavioral function in patients with Alzheimer's disease, to examine and conceptually map the evidence, and to identify any gaps.The question of this review is: what is the evidence on phytochemicals and cognitive/behavioral function in patients with Alzheimer's disease? PMID- 29419615 TI - Effectiveness of pain management educational interventions on nurses' knowledge and attitudes regarding postoperative pain management: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify the effectiveness of pain management education programs (PMEPs) in improving the level of knowledge and the attitudes of nurses working in adult surgical departments and intensive care units on postoperative pain management. PMID- 29419616 TI - Effectiveness of primary surgery versus primary radiotherapy on unknown primary head and neck squamous cell carcinoma: a systematic review protocol. AB - REVIEW QUESTION: The review question is: what is the effectiveness of primary surgery versus primary radiotherapy on disease-free survival and quality of life in adults with an unknown primary, head and neck squamous cell carcinoma? PMID- 29419617 TI - Psychometric properties of health related quality of life measures in acute coronary syndrome patients: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to evaluate the psychometric properties and clinical utility of patient-reported outcome measures that assess health-related quality of life in patients with a clinical diagnosis of acute coronary syndrome. PMID- 29419618 TI - Sexuality and intimacy among people with serious mental illness in hospital and community settings: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The aim of this review is to synthesize the best available qualitative evidence on the experiences and support needs of people with serious mental illness (SMI) regarding sexuality and intimacy within hospital and community settings. The objectives of the present study are. PMID- 29419619 TI - Second trimester ultrasound detection of fetal anomalies in the obese obstetrical population: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify, appraise and synthesize the best available evidence on the impact of maternal obesity on mid second trimester ultrasound detection of fetal anomalies in pregnancy. PMID- 29419620 TI - Cost-effectiveness of the antimicrobial treatment for inpatients infected with Klebsiella pneumoniae carbapenemase: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to evaluate the cost effectiveness of antimicrobial therapy treatment for inpatients infected with Klebsiella pneumoniae carbapenemase.More specifically, the review question is: What is the best evidence on the cost-effectiveness of the antimicrobial treatment for inpatients infected with Klebsiella Pneumoniae Carbapenemase?" PMID- 29419621 TI - The impact of transitional care programs on health services utilization in community-dwelling older adults: a systematic review. AB - OBJECTIVE: The objective was to identify and synthesize the best available evidence on the impact of transitional care programs on various forms of health services utilization in community-dwelling older adults. INTRODUCTION: There is growing evidence that transitional care programs can help address important challenges facing health care systems and our increasing older adult population in many countries by reducing unnecessary health service utilization. There is a need for a systematic review of the research evaluating the impact of transitional care programs on hospital and other health service usage. INCLUSION CRITERIA: The review included studies on community-dwelling adults age 60 and over with at least one medical diagnosis, and which evaluated the outcomes of transitional care programs on health system utilization of older adults. The outcomes for this review were hospital usage including admissions and readmissions, emergency department usage, primary care/physician usage, nursing home usage, and home health care usage. The review considered experimental and epidemiological study designs including randomized controlled trials, non randomized controlled trials, quasi-experimental studies, before and after studies, prospective and retrospective cohort studies, and case-control studies. METHODS: A three-step search was utilized to find published and unpublished studies conducted in any country but reported in English. Six electronic databases were searched from inception of the database to May, 2016. A search for unpublished studies was also conducted. Methodological quality was assessed independently by two reviewers using the Joanna Briggs Institute critical appraisal checklist for systematic reviews and research synthesis. Quantitative data were extracted from included studies independently by the two reviewers using the standardized Joanna Briggs Institute data extraction tools. Due to the methodological heterogeneity of the included studies, a comprehensive meta analysis for all outcomes was not possible. Meta-analysis was conducted for rehospitalization at 30, 90 and 180 days. A narrative summary of other quantitative findings was conducted. RESULTS: Twenty-three studies met the inclusion criteria and were included in the review. Nineteen of the studies were randomized controlled trials and four were case control studies, involving 20,997 participants in total with a mean age of 76. Meta-analysis found that transitional care significantly reduced hospital readmission rates at 30 days (odds ratio [OR] 0.75, 95% confidence intervals [CIs] 0.62-0.91, p < 0.01), 90 days (OR 0.77, 95% CIs 0.59-1.02, p = 0.04), and 180 days (OR 0.67, 95% CIs 0.46 0.99, p < 0.01). Narrative synthesis indicated little impact of transitional care on emergency department and nursing home usage, increased use of primary care/physician usage, and decreased home health care usage. CONCLUSIONS: Based on a review of 23 studies conducted in the USA, Hong Kong, Canada, Germany, the Netherlands, Sweden and Switzerland, we identified four major conclusions. First, transitional care reduces rehospitalization rates over time, with the largest effects seen at 30 days. Second, transitional care may increase the utilization of primary care services and thus have a favourable impact on preventative care. Third, transitional care may reduce home health usage. Fourth, transitional care interventions of one month or less appear to be as effective as longer interventions in reducing hospital usage. PMID- 29419622 TI - Experiences and cessation needs of Indigenous women who smoke during pregnancy: a systematic review of qualitative evidence. AB - OBJECTIVES: The aim of this review was to identify and synthesize the best available evidence to address two questions: i) what is the experience of smoking during pregnancy for Indigenous women? and ii) what are the smoking cessation needs of Indigenous women who smoke during pregnancy? INTRODUCTION: Smoking during pregnancy not only affects pregnant women's general health but also causes such serious problems as pre-term delivery, low birth weight, and sudden infant death. Rates of smoking during pregnancy are particularly high among Indigenous women. Learning about Indigenous women's experiences of smoking during pregnancy and associated smoking cessation needs is important to providing informed health care to them. INCLUSION CRITERIA: The participants of interest were Indigenous women who smoked during a current or past pregnancy. The phenomena of interest were the experiences of smoking during pregnancy for Indigenous women and the smoking cessation needs of Indigenous women during pregnancy. The context was any community worldwide where pregnant Indigenous women live. Studies considered for this review were those in which qualitative data were gathered and analysed on the phenomena of interest, including mixed methods research. METHODS: A comprehensive search was conducted for published studies in academic databases (i.e. PubMed, CINAHL, PsycINFO, Embase, Sociological Abstracts, SocINDEX, and Web of Science), unpublished studies in sources of gray literature (i.e. ProQuest Dissertations and Theses, OAIster, LILACS, MedNar, Google, Google Scholar, OpenGrey and relevant websites), and any additional studies in reference lists. Language and date limiters were not applied. The searches included all studies globally and were carried out on October 31, 2016. Studies that met the inclusion criteria were assessed for methodological quality by two reviewers independently, using the criteria of the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Qualitative Research. Descriptive details of each study accepted for this review were extracted in accordance with the elements of the JBI Data Extraction Form for Qualitative Research. The research findings that were relevant to the phenomena of interest and had participant voice were extracted from each included study and synthesized using the JBI meta-aggregative approach. The synthesized findings were assigned confidence scores in accordance with the JBI ConQual approach. RESULTS: Thirteen studies were included in this review following careful consideration of the methodological quality of each study. The studies yielded a total of 116 research findings, which were grouped into 19 categories and then aggregated to form five synthesized findings. Confidence in the findings was determined to be low to very low (see ConQual Summary of Findings). CONCLUSION: There is a small body of research evidence on Indigenous women's experiences of smoking during pregnancy and their smoking cessation needs. Confidence in the synthesized findings is constrained due to methodological limitations in many of the primary studies included in this review, along with mixed credibility of the research findings from across primary studies. PMID- 29419624 TI - Intermittent fasting interventions for treatment of overweight and obesity in adults: a systematic review and meta-analysis. AB - OBJECTIVE: To examine the effectiveness of intermittent energy restriction in the treatment for overweight and obesity in adults, when compared to usual care treatment or no treatment. INTRODUCTION: Intermittent energy restriction encompasses dietary approaches including intermittent fasting, alternate day fasting, and fasting for two days per week. Despite the recent popularity of intermittent energy restriction and associated weight loss claims, the supporting evidence base is limited. INCLUSION CRITERIA: This review included overweight or obese (BMI >=25 kg/m) adults (>=18 years). Intermittent energy restriction was defined as consumption of <=800 kcal on at least one day, but no more than six days per week. Intermittent energy restriction interventions were compared to no treatment (ad libitum diet) or usual care (continuous energy restriction ~25% of recommended energy intake). Included interventions had a minimum duration of 12 weeks from baseline to post outcome measurements. The types of studies included were randomized and pseudo-randomized controlled trials. The primary outcome of this review was change in body weight. Secondary outcomes included: i) anthropometric outcomes (change in BMI, waist circumference, fat mass, fat free mass); ii) cardio-metabolic outcomes (change in blood glucose and insulin, lipoprotein profiles and blood pressure); and iii) lifestyle outcomes: diet, physical activity, quality of life and adverse events. METHODS: A systematic search was conducted from database inception to November 2015. The following electronic databases were searched: MEDLINE, Embase, CINAHL, Cochrane Library, ClinicalTrials.gov, ISRCTN registry, and anzctr.org.au for English language published studies, protocols and trials. Two independent reviewers evaluated the methodological quality of included studies using the standardized critical appraisal instruments from the Joanna Briggs Institute. Data were extracted from papers included in the review by two independent reviewers using the standardized data extraction tool from the Joanna Briggs Institute. Effect sizes were expressed as weighted mean differences and their 95% confidence intervals were calculated for meta-analyses. RESULTS: Six studies were included in this review. The intermittent energy restriction regimens varied across studies and included alternate day fasting, fasting for two days, and up to four days per week. The duration of studies ranged from three to 12 months. Four studies included continuous energy restriction as a comparator intervention and two studies included a no treatment control intervention. Meta-analyses showed that intermittent energy restriction was more effective than no treatment for weight loss (-4.14 kg; 95% CI -6.30 kg to -1.99 kg; p <= 0.001). Although both treatment interventions achieved similar changes in body weight (approximately 7 kg), the pooled estimate for studies that investigated the effect of intermittent energy restriction in comparison to continuous energy restriction revealed no significant difference in weight loss (-1.03 kg; 95% CI -2.46 kg to 0.40 kg; p = 0.156). CONCLUSIONS: Intermittent energy restriction may be an effective strategy for the treatment of overweight and obesity. Intermittent energy restriction was comparable to continuous energy restriction for short term weight loss in overweight and obese adults. Intermittent energy restriction was shown to be more effective than no treatment, however, this should be interpreted cautiously due to the small number of studies and future research is warranted to confirm the findings of this review. PMID- 29419625 TI - Use of a standardized care communication checklist during multidisciplinary rounds in pediatric cardiac intensive care: a best practice implementation project. AB - OBJECTIVES: This project aimed to improve thoroughness and continuity of care of patients in a pediatric cardiac intensive care unit. Specific objectives were to increase support of clinical nurse and family participation in multidisciplinary rounds (MDR), as well as full use of a multi-component Complex Care Checklist (CCC) by all nurses in this unit. INTRODUCTION: Communication and collaboration are paramount for safe care and positive outcomes of critically ill patients hospitalized in intensive care units. Nurse participation in daily patient rounding enhances individualized goal-setting. Concomitant use of a communication checklist promotes comprehensive delivery of care. METHODS: Evidence-based audit criteria were developed for this project which used the Joanna Briggs Institute Practical Application of Clinical Evidence System (JBI PACES) and Getting Research into Practice (GRiP) tools for promoting change in health practice. Direct observation of MDR processes was used to conduct a baseline and post implementation audit. Intervention strategies relied primarily on nurse education tactics. RESULTS: Although attending physicians' and charge nurses' support and facilitation of clinical nurse presence during MDR rose substantially to 95% compliance, only moderate compliance (67%) was demonstrated for clinical nurses' attendance at and participation in MDR. Compliance with nurses' report of the patient's daily care plan and completion of CCC components during MDR improved moderately (52% and 54%). Family attendance at MDR did not improve. CONCLUSIONS: Project aims of enhanced thoroughness and continuity of care of patients with congenital heart defects were realized through an improved MDR process enhanced with a care communication checklist and clinical nurse participation. With the support of attending physicians and charge nurses, clinical nurses felt more empowered to address care concerns during MDR. The project outcomes indicated further activities are needed to assist nurses with a higher level of participating in MDR and using the CCC to its full potential. Continued evolution of the rounding process is imperative to adapting to patient needs and improving care. PMID- 29419626 TI - Effect of a patency bundle on central venous catheter complications among hospitalized adult patients: a best practice implementation project. AB - OBJECTIVES: The aim of this project was to improve continuity of care by decreasing central catheter occlusions in adults in two acute care units with high use of central venous catheters. Specific objectives were to introduce a patency bundle and train nurses on thrombolytic administration for timely resolution of catheter occlusions. INTRODUCTION: Central venous catheters are a vital component of medical care of acutely ill hospitalized patients. Occluded catheters delay treatment and can increase infection risk. There are bundles of best practices on catheter insertion, dressing and removal. However, a gap exists in nursing guidance for maintaining and restoring catheter patency. METHODS: The project used the Joanna Briggs Institute's tools for promoting practice change. Getting Research into Practice (GRiP) and Practical Application of Clinical Evidence System (PACES) assisted with strategy formation and data analysis. Direct observation and medical record review were used for baseline and follow-up audits. Several teaching strategies were employed to educate direct care nurses. RESULTS: Occlusion rates fluctuated greatly above and below baseline rates. Infection rates did not increase with thrombolytic administration. Nurses' compliance with catheter access and flushing techniques doubled. Timeliness of thrombolytic administration increased to 100% compliance. However, patency documentation did not improve. CONCLUSIONS: Multi-modal education reached all nurses and contributed to significantly improved compliance with patency best practice. Nurses were empowered to expediently troubleshoot occlusions by using thrombolytics. However, three months of post-implementation data was not enough to demonstrate a continued downward trend in occlusion rates. Thrombolytic administration by nurses on the other adult units and improved patency documentation are in the planning stages. PMID- 29419623 TI - Clinical effectiveness of decongestive treatments on excess arm volume and patient-centered outcomes in women with early breast cancer-related arm lymphedema: a systematic review. AB - OBJECTIVE: To identify the effect of decongestive lymphedema treatment on excess arm volume or patient-centered outcomes in women presenting within either 12 months or a mean nine months of developing arm lymphedema following breast cancer treatment. INTRODUCTION: Lymphedema is a common consequence of breast cancer treatment requiring life-long treatment to reduce symptoms and prevent complications. Currently, evidence to inform the optimal decongestive lymphedema treatment package is lacking. INCLUSION CRITERIA: The review included studies on women who received lymphedema treatment within either 12 months or a mean of nine months of developing unilateral breast cancer-related arm lymphedema. The intervention was any decongestive lymphedema treatment delivered with the purpose of reducing arm lymphedema, compared to another form of lymphedema treatment (whether self or practitioner-administered), placebo or no treatment. The clinical outcome was excess arm volume; patient-centered outcomes were health related quality of life, arm heaviness, arm function, patient-perceived benefit and satisfaction with treatment. Experimental study designs were eligible, including randomized and non-randomized controlled trials, quasi-experimental, prospective and retrospective before and after studies were considered. METHODS: A three-step search strategy was utilized to find published and unpublished studies. The search identified studies published from the inception of each database to July 6, 2016. Reference lists were scanned to identify further eligible studies. Studies were critically appraised using appropriate standardized critical appraisal instruments from the Joanna Briggs Institute. Details describing each study and treatment results regarding outcomes of interest were extracted from papers included in the review using appropriate standardized data extraction tools from the Joanna Briggs Institute. Due to heterogeneity in included studies, results for similar outcome measures were not pooled in statistical meta-analysis. A narrative and tabular format was used to synthesize results from identified and included studies. RESULTS: Seven studies reporting results for outcomes of interest were critically appraised and included in the review: five randomized controlled trials and two descriptive (uncontrolled) studies. Reported outcomes included excess arm volume (five studies), health-related quality of life (three studies), arm heaviness (one study), arm function (two studies) and patient-perceived benefit (two studies). There was some evidence that decongestive treatments were effective for women presenting within either 12 months or a mean of nine months of developing breast cancer-related arm lymphedema, but the wide range of data prevented comparison of treatment findings which limited our ability to answer the review questions. CONCLUSIONS: Weak evidence (grade B) for the impact of decongestive lymphedema treatment on women with early lymphedema (i.e. less than 12 months duration of BCRL symptoms) did not allow any conclusions to be drawn about the most effective treatment to be offered when these women first present for treatment. Findings provided no justification to support change to current practice.Future primary research needs to focus on the most effective treatment for women when they first present with lymphedema symptoms, e.g. treatment provided within 12 months of developing symptoms. Studies should be adequately powered and recruit women exclusively with less than 12 months duration of breast cancer-related lymphedema symptoms, provide longer follow-up to monitor treatment effect over time, with comparable treatment protocols, outcome measures and reporting methods. PMID- 29419627 TI - Complex Regional Pain Syndrome After Distal Radius Fracture Is Uncommon and Is Often Associated With Fibromyalgia. AB - BACKGROUND: Complex regional pain syndrome (CRPS) is frequently diagnosed in patients recovering from surgery or injury. The symptoms and signs included in consensus diagnostic criteria for CRPS are expected after injury. Categorizing symptoms and signs that occur on a continuum as disproportionate or not is subjective and prone to bias. Psychiatrists and psychologists do not diagnose CRPS and instead measure and treat anxiety and catastrophic thinking on its continuum. Given the expected variation in subjective diagnoses such as CRPS, this study addresses factors associated with use of this diagnosis and how it influences care. QUESTIONS/PURPOSES: (1) Among patients recovering from fracture of the distal radius, what factors are associated with the diagnosis of CRPS? (2) Are patients diagnosed with CRPS after distal radius fractures, as opposed to those without CRPS, more likely to have a bone scan, stellate ganglion block, therapy, or subsequent surgery? METHODS: Using the Truven database, we identified 59,765 patients treated for a distal radius fracture from 2012 to 2014, of whom 114 (0.19%) were diagnosed with CRPS. The Truven Health MarketScan database is an administrative claims data set of commercially insured patients and this analysis only included patients with complete enrollment from 2012 through 2014. Bivariate analyses sought differences between patients diagnosed with and patients not diagnosed with CRPS. All factors with p < 0.05 were included in a multivariable logistic regression model. RESULTS: The covariates older age (odds ratio [OR], 1.029; 95% confidence interval [CI], 1.011-1.048; p = 0.002), gender (women at greater risk, OR, 3.86; CI, 1.99-7.49; p < 0.001), concomitant fracture of the distal ulna (OR, 1.54; CI, 1.05-2.23; p = 0.029), open fracture (OR, 0.414; CI, 0.192-0.895; p = 0.025), and comorbid fibromyalgia (OR, 16.0; CI, 4.92-51.8; p < 0.001) were independently associated with a diagnosis of CRPS among patients recovering from a fracture of the distal radius. Patients diagnosed with CRPS are more likely than other patients with a distal radius fracture to have had a bone scan (OR, 66.0; CI, 8.19-532; p < 0.001), physical or occupational therapy (OR, 3.89; CI, 2.68-5.67; p < 0.001), and subsequent wrist surgery (OR, 2.52; CI, 1.65 3.84; p < 0.001). No one had a stellate ganglion injection. CONCLUSIONS: We found that a coded diagnosis of CPRS is uncommonly applied to patients on the higher range of pain, stiffness, and limitations after fracture of the distal radius most commonly in women and in association with another nonspecific, objectively unverifiable diagnosis (fibromyalgia)-and that this label may lead to more testing and invasive treatment. Future research should address the utility and value of diagnoses that create subjective categories for aspects of human illness that occur on a continuum. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 29419628 TI - Floor Effect of PROMIS Depression CAT Associated With Hasty Completion in Orthopaedic Surgery Patients. AB - BACKGROUND: The Patient Reported Outcomes Measurement Information System (PROMIS) was developed to provide valid, reliable, and standardized measures to gather patient-reported outcomes for many health domains, including depression, independent of patient condition. Most studies confirming the performance of these measures were conducted with a consented, volunteer study population for testing. Using a study population that has undergone the process of informed consent may be differentiated from the validation group because they are educated specifically as to the purpose of the questions and they will not have answers recorded in their permanent health record. QUESTIONS/PURPOSES: (1) When given as part of routine practice to an orthopaedic population, do PROMIS Physical Function and Depression item banks produce score distributions different than those produced by the populations used to calibrate and validate the item banks? (2) Does the presence of a nonnormal distribution in the PROMIS Depression scores in a clinical population reflect a deliberately hasty answering of questions by patients? (3) Are patients who are reporting minimal depressive symptoms by scoring the minimum score on the PROMIS Depression Computer Adaptive Testing (CAT) distinct from other patients according to demographic data or their scores on other PROMIS assessments? METHODS: Univariate descriptive statistics and graphic histograms were used to describe the frequency distribution of scores for the Physical Function and Depression item banks for all orthopaedic patients 18 years or older who had an outpatient visit between June 2015 and December 2016. The study population was then broken into two groups based on whether they indicated a lack of depressive symptoms and scored the minimum score (34.2) on the Depression CAT assessment (Floor Group) or not (Standard Group). The distribution of Physical Function CAT scores was compared between the two groups. Finally, a time-per-question value was calculated for both the Physical Function and Depression CATs and was compared between assessments within each group as well as between the two groups. Bivariate statistics compared the demographic data between the two groups. RESULTS: Physical Function CAT scores in musculoskeletal patients were normally distributed like the distribution calibration population; however, the score distribution of the Depression CAT in musculoskeletal patients was nonnormal with a spike in the floor score. After excluding the floor spike, the distribution of the Depression CAT scores was not different from the population control group. Patients who scored the floor score on the Depression CAT took slightly less time per question for Physical Function CAT when compared with other musculoskeletal patients (floor patients: 11 +/- 9 seconds; normally distributed patients: 12 +/- 10 seconds; mean difference: 1 second [0.8-1.1]; p < 0.001 but not clinically relevant). They spent a substantially shorter amount of time per question on the Depression CAT (Floor Group: 4 +/- 3 seconds; Standard Group: 7 +/- 7 seconds; mean difference: 3 [2.9 3.2]; p < 0.001). Patients who scored the minimum score on the PROMIS Depression CAT were younger than other patients (Floor Group: 50 +/- 18 SD; Standard Group: 55 +/- 16 SD; mean difference: 4.5 [4.2-4.7]; p < 0.001) with a larger percentage of men (Floor Group: 48.8%; Standard Group 40.0%; odds ratio 0.6 [0.6-0.7]; p < 0.001) and minor differences in racial breakdown (Floor Group: white 85.2%, black 11.9%, other 0.03%; Standard Group: white 83.9%, black 13.7%, other 0.02%). CONCLUSIONS: In an orthopaedic surgery population that is given PROMIS CAT as part of routine practice, the Physical Function item bank had a normal performance, but there is a group of patients who hastily complete Depression questions producing a strong floor effect and calling into question the validity of those floor scores that indicate minimal depression. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 29419629 TI - Classifications in Brief: Thoracolumbar Injury Classification and Injury Severity Score System. PMID- 29419630 TI - Classifications in Brief: Regan-Morrey Classification of Coronoid Fractures. PMID- 29419631 TI - The Rothman Index Is Associated With Postdischarge Adverse Events After Hip Fracture Surgery in Geriatric Patients. AB - BACKGROUND: The Rothman Index is a comprehensive measure of overall patient status in the inpatient setting already in use at many medical centers. It ranges from 100 (best score) to -91 (worst score) and is calculated based on 26 variables encompassing vital signs, routine laboratory values, and organ system assessments from nursing rounds from the electronic medical record. Past research has shown an association of Rothman Index with complications, readmission, and death in certain populations, but it has not been evaluated in geriatric patients with hip fractures, a potentially vulnerable patient population. QUESTIONS/PURPOSES: (1) Is there an association between Rothman Index scores and postdischarge adverse events in a population aged 65 years and older with hip fractures? (2) What is the discriminative ability of Rothman Index scores in determining which patients will or will not experience these adverse events? (3) Are there Rothman Index thresholds associated with increased incidence of postdischarge adverse outcomes? METHODS: One thousand two hundred fourteen patients aged 65 years and older who underwent hip fracture surgery at an academic medical center between 2013 and 2016 were identified. Demographic and comorbidity characteristics were characterized, and 30-day postdischarge adverse events were calculated. The associations between a 10-unit change in Rothman Index scores and postdischarge adverse events, mortality, and readmission were determined. American Society of Anesthesiologists (ASA) class was used as a measure of comorbidity because prior research has shown its performance to be equivalent or superior to that of calculated comorbidity measures in this data set. We assessed the ability of Rothman Index scores to determine which patients experienced adverse events. Finally, Rothman Index thresholds were assessed for an association with increased incidence of postdischarge adverse outcomes. RESULTS: We found a strong association between Rothman Index scores and postdischarge adverse events (lowest score: odds ratio [OR] = 1.29 [1.18-1.41], p < 0.001; latest score: OR = 1.37 [1.24-1.52], p < 0.001) after controlling for age, sex, body mass index, ASA class, and surgical procedure performed. The discriminative ability of lowest and latest Rothman Index scores was better than those of age, sex, and ASA class for any adverse event (lowest value: area under the curve [AUC] = 0.641; 95% confidence interval [CI], 0.601-0.681; latest value: AUC = 0.640; 95% CI, 0.600-0.680); age (0.534; 95% CI, 0.493-0.575, p < 0.001 for both), male sex (0.552; 95% CI, 0.518-0.585, p = 0.001 for both), and ASA class (0.578; 95% CI, 0.542-0.614; p = 0.004 for lowest Rothman Index, p = 0.006 for latest Rothman Index). There was never a difference when comparing lowest Rothman Index value and latest Rothman Index value for any of the outcomes (Table 5). Patients experienced increased rates of postdischarge adverse events and mortality with a lowest Rothman Index of <= 35 (p < 0.05) or latest Rothman Index of <= 55 (p < 0.05). CONCLUSIONS: The Rothman Index provides an objective method of assessing perioperative risk in the setting of hip fracture surgery in patients older than age 65 years and is more accurate than demographic measures or ASA class. Furthermore, there are Rothman Index thresholds that can be used to identify patients at increased risk of complications. Physicians can use this tool to monitor the condition of patients with hip fracture, recognize patients at high risk of adverse events to consider changing their plan of care, and counsel patients and families. Further investigation is needed to determine whether interventions based on Rothman Index values contribute to improved outcomes or value of hip fracture care. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 29419632 TI - CORR Insights(r): What Is the State of Quality Measurement in Spine Surgery? PMID- 29419633 TI - CORR Insights(r): What Is the Diagnostic Accuracy of the Duck Walk Test in Detecting Meniscal Tears? PMID- 29419634 TI - Are There Age- and Sex-related Differences in Spinal Sagittal Alignment and Balance Among Taiwanese Asymptomatic Adults? AB - BACKGROUND: Sagittal spinopelvic balance and proper sagittal alignment are important when planning corrective or reconstructive spinal surgery. Prior research suggests that people from different races and countries have moderate divergence; to the best of our knowledge, the population of Taiwan has not been studied with respect to this parameter. QUESTIONS/PURPOSES: To investigate normal age- and sex-related differences in whole-spine sagittal alignment and balance of asymptomatic adults without spinal disorders. METHODS: In this prospective study, we used convenience sampling to recruit asymptomatic volunteers who accompanied patients in the outpatient orthopaedic department. One hundred forty males with a mean age of 48 +/- 19 years and 252 females with a mean age of 53 +/- 17 years underwent standing lateral radiographs of the whole spine. For analysis, participants were divided in three groups by age (20 to 40 years, 41 to 60 years, and 61 to 80 years) and analyzed by sex (male and female). The following eight radiologic parameters were measured: sacral slope, pelvic tilt, pelvic incidence, thoracic kyphosis, lumbar lordosis, cervical lordosis, C2-C7 sagittal vertical axis, and C7-S1 sagittal vertical axis. Three observers performed estimations of the sagittal parameters twice, and the intraclass correlation coefficients for inter- and intraobserver variability were 0.81 and 0.83. RESULTS: The mean pelvic incidence was 49 degrees +/- 12 degrees ; lumbar lordosis was smaller in the group that was 61 to 80 years old than in the groups that were 20 to 40 years and 41 to 60 years (95% CI of the difference, 4.50-13.64 and 1.00- 9.60; p < 0.001), while cervical lordosis was greater in the 61 to 80 years age group than the other two groups (95% CI of the difference, -14.64 to -6.57 and -11.57 to -3.45; p < 0.001). The mean C7-S1 sagittal vertical axis was 30 +/- 29 mm, and there was no difference among the three groups and between males and females. Pelvic tilt was greater in the group 61 to 80 years old than the 20 to 40 years and 41 to 60 years age groups (95% CI of the difference, -10.81 to -5.42 and -7.15 to -2.08; p < 0.001), while sacral slope was larger in 61 to 80 years age group than in the 41 to 60 years group (95% CI of the difference, 0.79-6.25; p = 0.006). C7 slope was greater in 61 to 80 years age group than in the 20 to 40 years group (95% CI of the difference, -7.49 to -1.26; p = 0.002) and larger in 41 to 60 years age group than in 20 to 40 years group (95% CI of the difference, -6.31 to -0.05; p = 0.045). C2-C7 sagittal vertical axis was greater in males than in females (95% CI of the difference, 2.84-7.74; p < 0.001). C7 slope was negatively correlated with thoracic kyphosis (95% CI of the difference, -0.619 to 0.468; p < 0.001) and lumbar lordosis (95% CI of the difference, -0.356 to -0.223; p < 0.001), and positively correlated with pelvic incidence (95% CI of the difference, 0.058- 0.215; p < 0.001) and cervical lordosis (95% CI of the difference, 0.228 - 0.334; p < 0.001). CONCLUSIONS: Normal values of the spinopelvic sagittal parameters vary by age and sex in Taiwanese individuals. CLINICAL RELEVANCE: Pelvic incidence and sacral slope observed in this population seemed smaller than those reported in other studies of white populations; this seems important when considering spine surgery in Taiwanese patients. Future studies should include collection of whole body sagittal parameters of larger and more-diverse populations, and assessments of patients with symptomatic spinal disorders. PMID- 29419635 TI - Pearls: Early Removal of Posterior Osteophytes in TKA. PMID- 29419636 TI - CORR Insights(r): Does Extracorporeal Irradiation and Reimplantation After Acetabulum Resections Result in Adequate Hip Function? A Preliminary Report. PMID- 29419638 TI - Permanent Versus Bioresorbable Implants in Orbital Floor Blowout Fractures. AB - PURPOSE: To compare the outcomes of bioresorbable and permanent implants in the reconstruction of isolated orbital floor blowout fractures. METHODS: Retrospective series of all patients who had orbital floor fracture repair in a single tertiary trauma center from January 2005 to December 2014. The authors reviewed the case notes and CT scans of patients with orbital floor fracture repair with either bioresorbable or permanent implants. Main outcome measures were enophthalmos, diplopia, and ocular motility restriction 1.5 years after fracture repair. Implant-related complications were collected for analysis. RESULTS: There were a total of 88 patients in our study. Bioresorbable implants were used in 48 patients (54.5%) while 40 patients had permanent implants (45.5%). The authors analyzed the implants used in various sizes of orbital fractures: small (<13.3 mm), medium (13.3-20 mm), and large (>20 mm). One and a half years after fracture repair, both groups had comparable clinical outcomes (n = 2 and n = 0 for diplopia for permanent and bioresorbable implant groups, respectively, n = 0 for enophthalmos for both groups and n = 1 for ocular motility limitation for both groups) overall and across all fracture sizes. CONCLUSION: Bioresorbable implants degrade after fracture healing through hydrolysis and promote the gradual transfer of functional forces to healing bone during its disintegration. The clinical outcomes of diplopia, enophthalmos, and ocular motility restriction associated with the use of resorbable implants are comparable to that of permanent implants for all fracture sizes. Their study shows that bioresorbable and permanent implants are equally safe and effective for the treatment of patients with isolated orbital floor blowout fractures. PMID- 29419639 TI - The Development of Defense Mechanisms During the Latency Period. AB - The developmental period of latency, during middle childhood, has not been previously studied for possible change in the use of defense mechanisms. Using a validated narrative method to assess defenses, the present research examines change in children's defense use during this period. As predicted from theory, there was a significant increase in the use of the defense of Identification. This finding is consistent with theory that posits a shift at this time from defense against anxiety that is based on lack of impulse control to defense that is based on anxiety due to violation of conscience. PMID- 29419640 TI - A Mixed Program of Psychoeducational and Psychological Rehabilitation for Patients With Bipolar Disorder in a Day Hospital Setting. AB - The present study describes a new mixed program of psychoeducational and psychological interventions for bipolar patients, applicable during everyday practice. Thirty-two bipolar patients recruited at a psychiatric day-hospital service have been admitted to a program consisting of 30 meetings and 2 follow ups at 6 and 12 months. The psychoeducational support determined a general improvement of all included patients. At baseline, patients with residual depression had higher Hamilton Depression Rating Scale (HDRS) scores than euthymic patients (mean score +/- SD: 21.25 +/- 3.92 vs. 7.00 +/- 2.95, respectively). After psychoeducation sessions, the HDRS scores of euthymic patients remained stable (mean +/- SD: 7.00 +/- 3.74), whereas the HDRS scores of depressed patients demonstrated a statistically significant improvement (mean +/- SD: 14.00 +/- 6.72, t = 2.721, p = 0.03). Results of the Connor-Davidson Resilience scale and specifically constructed questionnaire Questionario per la Valutazione della Conoscenza e dell'Apprendimento per il Disturbo Bipolare showed a statistically significant improvement in resilience and insight in all recruited patients. Psychoeducational intervention as adjunctive treatment to pharmacotherapy seems to be very effective in bipolar patients, not only for those in the euthymic phase, but this model could also be extended to patients with an ongoing mild or moderate depressive episode. PMID- 29419641 TI - Epidemiology of Exfoliation Syndrome. AB - BACKGROUND: From a historical standpoint the epidemiology of exfoliation syndrome (XFS) is one of the most controversial subjects in ophthalmic literature. Current literature abounds with studies on the prevalence of XFS in various ethnic populations and clearly XFS is a common condition, but its true prevalence is difficult to ascertain. Overall, XFS is considered to be the most common identifiable cause of glaucoma worldwide. PURPOSE: This review critically examines the published literature documenting the epidemiological features of XFS and attempts to provide a unified concept concerning existing controversy. METHODS: A critical review of selected literature pertaining to the epidemiology of XFS. RESULTS: It is well established that XFS and the ensuing exfoliative glaucoma have a worldwide prevalence and a progressively increasing age-related incidence. The prevalence of the condition is significantly underestimated. Many past studies have proposed clear geographic variations within and between ethnic groups. In contrast, there has also been some epidemiological evidence suggesting that the prevalence of XFS is similar within various ethnic groups. Published literature fails to address the potential role and impact of suspected exfoliation cases in the reported prevalence figures of the condition. Incidence figures for the condition are limited and vary extensively. Cumulative data have indicated that several, as yet partly understood genetic, ethnic, and environmental factors contribute to the varied prevalence of this condition. CONCLUSIONS: Further understanding on XFS epidemiology is needed. Only a future large prospective study conducted by the same investigators, using similar methodologies for different ethnic populations will prove beyond doubt the hypothesis that significant geographic variations exist. Since patients with exfoliative glaucoma are at significant risk of losing vision it is vital to elucidate the causes and the risk of developing XFS. To reach this goal, it is important to better delineate the early changes of XFS and to focus research efforts on modifiable factors for XFS development. PMID- 29419643 TI - Exfoliation Syndrome: A Historical Perspective. AB - The discoverer of exfoliation was John Lindberg of Helsinki, Finland. He conducted his research as a young ophthalmology resident with the aim of elucidating 2 types of age-related degenerations of the iris and presenting it as an academic thesis. To this end, he had to construct a slit lamp, because they were not commercially available. During this investigation, he paid attention to greyish flakes and fringes on the anterior lens capsule and the pupillary border, which had not been previously described. His material consisted of 202 patients. The findings were recorded by time-consuming skillful drawings. His conclusions that the condition was age-related and often linked to chronic glaucoma and cataract are still valid today. The work was accepted as an academic thesis at the University of Helsinki in 1917. PMID- 29419642 TI - Reduced Retinal Vessel Density in Primary Angle Closure Glaucoma: A Quantitative Study Using Optical Coherence Tomography Angiography. AB - PURPOSE: The purpose of this article is to investigate the changes in the retinal vasculature in different parts of the fundus in eyes with primary angle closure glaucoma (PACG). METHODS: Healthy subjects and those with PACG were enrolled. Optical coherence tomography and a split-spectrum amplitude decorrelation angiography algorithm were used to quantify the retinal vessel densities in the parafoveal and peripapillary areas. RESULTS: Thirty-nine eyes from 24 PACG patients and 39 eyes from 20 age-matched and sex-matched healthy subjects were included. The retinal vessel densities in the parafoveal and peripapillary areas and every sector of the 2 areas were significantly lower in the PACG eyes than in the healthy eyes. The difference was greater in the peripapillary area (11.75%) than in the parafoveal area (7.55%, P<0.05). In the PACG eyes, the vessel density in the peripapillary area correlated closely with the intraocular pressure, but that in the parafoveal area did not. When the PACG eyes were divided into groups with well-controlled and not well-controlled intraocular pressure (<=21 mm Hg or not), the vessel density and retinal nerve fiber layer thickness in the peripapillary area were much lower in the not well-controlled eyes (P<0.05), whereas the vessel density in the parafovea and the ganglion cell complex thickness were similar in the 2 subgroups. CONCLUSION: Retinal vessel density was significantly reduced in PACG eyes. The magnitude of this difference varied between the fundus areas, and was greater in the peripapillary area. PMID- 29419644 TI - Laser Management of Glaucoma in Exfoliation Syndrome. AB - Argon laser trabeculoplasty as well as selective laser trabeculoplasty can be used in patients with exfoliation syndrome with similar safety and efficacy. However, treatment effect may abruptly reverse and patients need to be followed regularly to monitor intraocular pressure control. Newer laser treatment modalities including micropulse laser trabeculoplasty, titanium sapphire laser trabeculoplasty and pattern scanning trabeculoplasty show promising results but need to be studied in exfoliation patients. For exfoliation patients with angle closure, peripheral iridectomy, iridoplasty or cataract extraction can be very helpful. For refractory exfoliation glaucoma, transscleral diode laser cyclophotocoagulation offers a reasonable option to lower intraocular pressure. Other approaches to cyclophotocoagulation such as micropulse transcleral diode laser need to be studied further in exfoliation patients. PMID- 29419645 TI - Current Concepts in True Exfoliation Syndrome. AB - True exfoliation syndrome is characterized by the peeling of a translucent membrane from the anterior lens capsule. The condition increases with age and despite the classic association with occupations involving intense heat, most cases are idiopathic. We have proposed a new clinical classification system dividing true exfoliation syndrome into 4 successive stages based on characteristic changes in the anterior capsule. We have also proposed a new mechanism related to iris movement and aqueous flow accounting for the capsular delamination. We have found that a detached flap occurs exclusively in areas that lack the anterior zonules. In our series of 259 consecutive patients, 47 (19.5%) patients developed primary open-angle glaucoma, 26 (10.0%) had primary angle closure glaucoma, and 15 (5.8%) were primary angle-closure suspects. Twenty-six (10.0%) patients demonstrated spontaneous phacodonesis or anterior lens dislocation, of whom 14 also had secondary angle-closure and 2 had open-angle glaucoma. Histologic studies have shown that the lens dislocation is associated with a lack of anterior zonular support. All patients developed cataracts, predominantly nuclear sclerosis. The double-ring sign frequently occurs during capsulorhexis. PMID- 29419646 TI - Lysyl Oxidases: Functions and Disorders. AB - Lysyl oxidases (LOX) are copper-dependent enzymes that oxidize lysyl and hydroxylysyl residues in collagen and elastin, as a first step in the stabilization of these extracellular matrix proteins through the formation of covalent cross-linkages, an essential process for connective tissue maturation. Five different LOX enzymes have been identified in mammals, LOX and LOX-like (LOXL) 1 to 4, being genetically different protein products with a high degree of homology in the catalytic carboxy terminal end and a more variable amino terminal proregion. Intensive investigation in the last years has delineated the main biological functions of these enzymes and their involvement in several pathologies including fibrosis, cancer, and ocular disorders. This review article summarizes the major findings on the role of LOX isoforms, with particular focus on their contribution to the development and progression of human disorders. PMID- 29419648 TI - Vascular Dysfunction in Exfoliation Syndrome. AB - Both exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) are associated with systemic vascular diseases and abnormalities. Although no uniform relationship between XFS/XFG and clinical systemic vascular diseases has been established across various populations, vascular dysfunction with or without clinically significant consequences has been repeatedly detected with both epidemiological and pathophysiological methods. Elevated plasma homocysteine, reduced cutaneous capillary flow reactions, damaged conduit artery dysfunction, impaired baroreflex sensitivity, parasympathetic cardiovascular neuropathy, and pathologic heart rate variability indices have all been shown in XFS and XFG. These pathophysiological alterations exceed the normal age-dependent decline and are considered strongly related to systemic elastosis and increased oxidative stress, but are not direct consequences of the presence of the risk alleles of the lysyl oxydase-like 1 gene. The mechanisms of the development of the clinically significant consequences (eg, increased frequency of myocardial dysfunction, stroke, aorta aneurism, and white matter lesions) are only partially understood. The current knowledge on vascular dysfunction in XFS/XFG is summarized in this article. PMID- 29419647 TI - Update on Animal Models of Exfoliation Syndrome. AB - Animal models are powerful tools for studying diseases that affect the eye, such as exfoliation syndrome (XFS). Two types of animal models have been used to investigate the pathophysiology of XFS and glaucoma. One class of models is engineered to have key features of a disease by alteration of their genome (genotype-driven animal models). LOXL1 is the first gene known to increase the risk for developing XFS in humans. Two transgenic mouse models with altered Loxl1 genes have been generated to study XFS. One strain of mice, Loxl1 deficient mice, also known as Loxl1 knockout mice, have had the Loxl1 gene removed from their genomes. Another strain has been engineered to produce excess amounts of the protein produced by the Loxl1 gene, or Loxl1 overexpression. A second class of animal models includes naturally occurring strains of mice that exhibit key clinical features of a disease. Studies of these phenotype-driven animal models may identify genes that cause disease and may also provide a valuable resource for investigating pathogenesis. One strain of mice, B6-Lyst, has several key features of human XFS, including ocular production of exfoliation-like material, and stereotypical iris abnormalities. Studies of this range of mice and other public mouse genetic resources have provided some important insights into the biology of XFS and may be useful for future studies to test the efficacy of drug therapies. PMID- 29419649 TI - Molecular Biology of Exfoliation Syndrome. AB - Exfoliation syndrome (XFS) is a common age-related matrix process resulting from excessive production and disordered assembly of elastic microfibrillar components into highly cross-linked fibrillary aggregates throughout the anterior eye segment and various organ systems. The underlying molecular pathophysiology involves a complex interplay of profibrotic protagonists including growth factors, proteolytic enzymes and inhibitors, proinflammatory cytokines, chaperones, and dysregulated stress response pathways including insufficient autophagy. Interaction between individual genetic predisposition and stress factors is a plausible theory explaining the development of XFS in the aging individual. Genome-wide association studies have identified robust genetic associations with LOXL1, CACNA1A, and 5 additional genes including POMP and TMEM136, which provide new biological insights into the pathology of XFS and highlight a role for abnormal matrix cross-linking processes, Ca channel deficiency, blood-aqueous barrier dysfunction, and abnormal ubiquitin-proteasome signaling in XFS pathophysiology. However, the exact pathophysiological mechanisms, the functional role of genetic risk variants, and gene-environment interactions still remain to be characterized. PMID- 29419650 TI - Functional imaging in microfluidic chambers reveals sensory neuron sensitivity is differentially regulated between neuronal regions. AB - Primary afferent sensory neurons are incredibly long cells, often traversing distances of over 1 m in humans. Cutaneous sensory stimuli are transduced in the periphery by specialised end organs or free nerve endings, which code the stimulus into electrical action potentials that propagate towards the central nervous system. Despite significant advances in our knowledge of sensory neuron physiology and ion channel expression, many commonly used techniques fail to accurately model the primary afferent neuron in its entirety. In vitro experiments often focus on the cell somata and neglect the fundamental processes of peripheral stimulus transduction and action potential propagation. Despite this, these experiments are commonly used as a model for cellular investigations of the receptive terminals. We demonstrate that ratiometric calcium imaging performed in compartmentalised sensory neuron cultures can be used to directly and accurately compare the sensitivity and functional protein expression of isolated neuronal regions in vitro. Using microfluidic chambers, we demonstrate that the nerve terminals of cultured dorsal root ganglion neurons can be depolarised to induce action potential propagation, which has both tetrodotoxin resistant and tetrodotoxin-sensitive components. Furthermore, we show that there is a differential regulation of proton sensitivity between the sensory terminals and somata in cultured sensory neurons. We also demonstrate that capsaicin sensitivity is highly dependent on embryonic dissection age. This approach enables a comprehensive method to study the excitability and regional sensitivity of cultured sensory neurons on a single-cell level. Examination of the sensory terminals is crucial to further understand the properties and diversity of dorsal root ganglion sensory neurons. PMID- 29419651 TI - Perceived diagnostic uncertainty in pediatric chronic pain. PMID- 29419654 TI - Interventions for attentional disruption in pain: cognition-general, mechanism specific, or exercise-based? PMID- 29419652 TI - Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. AB - Development of chemotherapy-induced neuropathic pain (CINP) compromises the use of chemotherapy and greatly impacts thousands of lives. Unfortunately, there are no Food and Drug Administration-approved drugs to prevent or treat CINP. Neuropathological changes within CNS, including neuroinflammation and increased neuronal excitability, are driven by alterations in neuro-glia communication; but, the molecular signaling pathways remain largely unexplored. Adenosine is a potent neuroprotective purine nucleoside released to counteract the consequences of these neuropathological changes. Adenosine signaling at its adenosine receptors (ARs) is dictated by adenosine kinase (ADK) in astrocytes, which provides a cellular sink for the removal of extracellular adenosine. We now demonstrate that chemotherapy (oxaliplatin) in rodents caused ADK overexpression in reactive astrocytes and reduced adenosine signaling at the A3AR subtype (A3AR) within the spinal cord. Dysregulation of ADK and A3AR signaling was associated with increased proinflammatory and neuroexcitatory interleukin-1beta expression and activation of nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, but not putative oxaliplatin-associated GSK3beta transcriptional regulation. Intrathecal administration of the highly selective A3AR agonist MRS5698 attenuated IL-1beta production and increased the expression of potent anti-inflammatory and neuroprotective IL-10. The effects of MRS5698 were blocked by attenuating IL-10 signaling in rats with intrathecal neutralizing IL-10 antibody and in IL-10 knockout mice. These findings provide new molecular insights implicating astrocyte-based ADK-adenosine axis and nucleotide-binding oligomerization domain-like receptor protein 3 in the development of CINP and IL 10 in the mechanism of action of A3AR agonists. These findings strengthen the pharmacological rationale for clinical evaluation of A3AR agonists already in advanced clinical trials as anticancer agents as an adjunct to chemotherapy. PMID- 29419653 TI - Long-term use of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: a randomized, double-blind, placebo controlled phase 3 study. AB - The long-term safety of naldemedine, a peripherally acting u-opioid receptor antagonist, was evaluated in patients with opioid-induced constipation and chronic noncancer pain in a 52-week, randomized, double-blind, phase 3 study. Eligible adults who could be on a routine laxative regimen were randomized 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 623) or placebo (n = 623). The primary endpoint was summary measures of treatment-emergent adverse events (AEs). Additional endpoints included opioid withdrawal on the Clinical Opiate Withdrawal Scale and the Subjective Opiate Withdrawal Scale, pain intensity on Numeric Rating Scale, frequency of bowel movements, and constipation-related symptoms and quality of life on the Patient Assessment of Constipation Symptoms and Patient Assessment of Constipation Quality of Life scales, respectively. Treatment emergent AEs (naldemedine, 68.4% vs placebo, 72.1%; difference: -3.6% [95% confidence interval: -8.7 to 1.5]) and treatment-emergent AEs leading to study discontinuation (6.3% vs 5.8%; difference: 0.5% [-2.2 to 3.1)] were reported for similar proportions of patients. Diarrhea was reported more frequently with naldemedine (11.0%) vs placebo (5.3%; difference: 5.6% [2.6-8.6]). There were no meaningful differences between groups in opioid withdrawal or pain intensity. Sustained significant improvements in bowel movement frequency and overall constipation-related symptoms and quality of life were observed with naldemedine (P <= 0.0001 vs placebo at all time points). Naldemedine was generally well tolerated for 52 weeks and did not interfere with opioid-mediated analgesia or precipitate opioid withdrawal. Naldemedine significantly increased bowel movement frequency, improved symptomatic burden of opioid-induced constipation, and increased patients' quality of life vs placebo. PMID- 29419655 TI - Correlates and importance of neglect-like symptoms in complex regional pain syndrome. AB - Neglect-like symptoms (NLS) are frequently observed in complex regional pain syndrome (CRPS). The clinical meaning of NLS, however, is largely unknown. Therefore, this study sets out to assess the importance of NLS for patient outcome and to explore their clinical correlates. We assessed NLS in a group of 53 patients with CRPS and compared the results to 28 healthy volunteers. To define the origin of the NLS reports, we tested the subjective visual midline, performed a limb-laterality recognition test, and quantitative sensory testing. In addition, psychological and pain assessment scales were completed. Tests were analyzed with univariate and multivariate approaches. After 6 months, patients were reassessed and the influence of NLS on pain outcome was determined. Most patients reported NLS in the questionnaire, whereas subjective visual midline and limb-laterality recognition test in contrast to previous studies did not reveal perceptual disturbances. Neglect-like symptom scores were associated with pain and pain catastrophizing in acute CRPS and anxiety and thermal sensory loss in chronic CRPS. Furthermore, high NLS scores had a negative impact on pain outcome after 6 months. Our results indicate that NLS have a different meaning in acute and chronic CRPS and might be of prognostic value. Possibly, treatment should focus on reducing NLS. PMID- 29419656 TI - Psychological factors predict an unfavorable pain trajectory after hysterectomy: a prospective cohort study on chronic postsurgical pain. AB - Chronic postsurgical pain (CPSP) is a well-recognized potential complication with negative personal, social, and health care consequences. However, limited data exist on CPSP and on the course of pain over time after hysterectomy. Using data from a prospective cohort study on a consecutive sample assessed at 4 time points, presurgery (T1), 48 hours (T2), 4 months (T3), and 5 years postsurgery (T4), we sought to examine women's PSP trajectories using assessments of pain at T3 and T4. In addition, this study aimed to investigate presurgical and postsurgical risk factors associated with an unfavourable pain trajectory (PT). Based on pain data collected at T3 and T4, 3 distinct trajectories of PSP emerged: no CPSP (PT1; n = 88), prolonged PSP (PT2; n = 53), and CPSP (PT3; n = 29). Moreover, reported CPSP prevalence at 5 years was 17.1%. Multinomial logistic regression models controlling for age, presurgical pain, and type of hysterectomy tested for baseline and acute postsurgical predictive variables. Membership in PT2 and PT3 was predicted by presurgical anxiety (odds ratio [OR] = 1.131, P = 0.015; OR = 1.175, P = 0.009, respectively), emotional representation of the surgical disease (OR = 1.155, P = 0.034; OR = 1.213, P = 0.020, respectively), and pain catastrophizing (OR = 1.079, P = 0.043; OR = 1.143, P = 0.001, respectively). Furthermore, acute PSP intensity and frequency determined membership of women in PT3 (OR = 1.211, P = 0.033; OR = 3.000, P = 0.029, respectively), and postsurgical anxiety (OR = 1.182, P = 0.026) also played a key predictive role. This study identified factors that can be easily screened before and after surgery and are amenable to change through carefully designed timely and tailored interventions for women at risk of an unfavorable PSP trajectory posthysterectomy. PMID- 29419658 TI - Finding our way in human genetic research on neuropathic pain. PMID- 29419657 TI - Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients. AB - Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (eg, microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far, the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared with healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18 kDa translocator protein, in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients' clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared with both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared with more superior segments). Furthermore, the neuroforaminal translocator protein signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients. PMID- 29419659 TI - Validation of prognostic biomarker scores for predicting progression of dementia in patients with amnestic mild cognitive impairment. AB - OBJECTIVE: The objective of this study was to develop and validate a practical computerized prognostic model that uses baseline psychometric and imaging data, including results of PET imaging of amyloid deposition, to predict the progression to dementia in patients at risk for Alzheimer's disease (AD). PATIENTS AND METHODS: Data from patients in a phase II trial of [F]flutemetamol for PET imaging of brain amyloid and from the Alzheimer's Disease Neuroimaging Initiative were used to train the prognostic model to yield a disease state index (DSI), a measure of the similarity of an individual patient's data to data from patients in specific diagnostic groups. Inputs to the model included amyloid PET results, MRI measurements of hippocampal volume, and the results of psychometric tests. The model was subsequently validated by using data from a prospective study of an independent cohort of patients with mild cognitive impairment. RESULTS: In total, data from 223 patients of the 233 enroled were suitable for analysis. The DSI predicted by the model and the risk of progression to AD dementia within 3 years were higher for patients with amyloid deposition and neurodegeneration than for patients with amyloid deposition without neurodegeneration. Rates of non-AD dementia among patients with neurodegeneration at baseline were consistent with the results of other studies. The results were consistent with the Jack model of AD progression. CONCLUSION: The DSI from the model that included psychometric, MRI, and PET amyloid data provides useful prognostic information in cases of mild cognitive impairment. PMID- 29419660 TI - Continuous cervical epidural block: Treatment for intractable hiccups. AB - Intractable hiccups, although rare, may result in severe morbidity, including sleep deprivation, poor food intake, respiratory muscle fatigue, aspiration pneumonia, and death. Despite these potentially fatal complications, the etiology of intractable hiccups and definitive treatment are unknown. This study aimed to evaluate the effectiveness of continuous cervical epidural block in the treatment of intractable hiccups.Records from 28 patients with a history of unsuccessful medical and invasive treatments for hiccups were evaluated. Continuous cervical epidural block was performed with a midline approach at the C7-T1 or T1-T2 intervertebral space with the patient in the prone position. The epidural catheter was advanced through the needle in a cephalad direction to the C3-C5 level. Catheter placement was confirmed using contrast radiography. A 6-mL bolus of 0.25% ropivacaine was injected, and a continuous infusion of 4 mL/h of ropivacaine was administered through the epidural catheter using an infuser containing 0.75% ropivacaine (45 mL ropivacaine and 230 mL normal saline). When the hiccups stopped and did not recur for 48 hours, the catheter was removed.Cumulative complete remission rates were 60.71% after the first cervical epidural block, 92.86% after the second, and 100% after the third. One patient complained of dizziness that subsided. No other adverse effects were reported.Continuous C3-C5 level cervical epidural block has a successful remission rate. We suggest that continuous cervical epidural block is an effective treatment for intractable hiccups. PMID- 29419661 TI - Hyperglycemia is associated with cardiac complications in elderly nondiabetic patients receiving total parenteral nutrition. AB - Adverse outcomes have been associated with hyperglycemia in patients receiving total parenteral nutrition (TPN). The relationship may be characteristic in elderly patients. However, limited data are available about the relationship between TPN-related hyperglycemia and cardiac adverse outcome in elderly patients without previously known diabetes. This study aims to identify whether there is an association between hyperglycemia and 45-day cardiac adverse outcomes in critically and noncritically ill elderly nondiabetic patients receiving TPN.Outcome measures of 45-day cardiac complications after receiving TPN were recorded from a retrospective review of 1517 medical and surgical elderly patients. The mean glucose levels were significantly higher in patients with cardiac complications than in patients without cardiac complications (P < .001). In multivariate logistic regression analysis adjusting for age, gender, comorbidities, and medications, higher mean blood glucose levels were independently associated with increased 45-day cardiac complications (odds ratio, 1.62; 95% confidence interval, 1.453-1.816; P < .001). Furthermore, Kaplan-Meier event-free survival curves demonstrated that patients with mean blood glucose level >=11.1 mmol/L had worse cardiac complications event-free survival compared with those mean blood glucose level <11.1 mmol/L during 45 days after receiving TPN.This study showed that TPN-induced hyperglycemia was associated with increased risk of cardiac complications in both critically and noncritically ill elderly patients without a history of diabetes. PMID- 29419662 TI - The role of postmastectomy radiation therapy in patients with immediate prosthetic breast reconstruction: A meta-analysis. AB - OBJECTIVE: The controversy remains as to whether immediate prosthetic breast reconstruction with postmastectomy radiation therapy (PMRT) is associated with acceptable complications and aesthetic outcomes. The aim of this meta-analysis was to provide a pooled analysis of comparative clinical studies that evaluated breast cancer patients who were treated with a mastectomy and an immediate prosthetic breast reconstruction to compare the complications and satisfaction of those who underwent or did not undergo PMRT. METHODS: According to the recommendations of the Cochrane Collaboration, we established a rigorous study protocol. We performed a systematic electronic search of the PubMed and Embase databases to identify articles for inclusion in our meta-analysis. Reconstruction failure, overall complications, capsular contracture, and patient satisfaction were analyzed individually. RESULTS: Fifteen controlled trials were included, comprising 5314 patients (1069 PMRT vs 4245 non-PMRT). Primary outcomes revealed a statistically significant increase in overall complications [odds ratio (OR) 3.45; 95% confidence interval (95% CI) 2.62-4.54; P < .00001], reconstruction failure (OR: 2.59; 95% CI 1.46-4.62; P = .001), and capsular contracture (OR: 5.26, 95% CI: 2.73-10.13, P < .00001) after receiving PMRT. CONCLUSION: Our review found that PMRT for patients who underwent immediate implant-based breast reconstruction led to higher risks of reconstruction failure, overall complications, and capsular contracture. However, it is still the standard adjuvant therapy for mastectomy patients who have opted for immediate implant based breast reconstruction. PMID- 29419663 TI - Emphysematous endocarditis caused by AmpC beta-lactamase-producing Escherichia coli: A case report. AB - RATIONALE: Infective endocarditis (IE) is a life-threatening disease, mostly caused by gram-positive bacteria. Gram-negative bacteria were identified as a causative organism in relatively small number of cases. Although, antibiotic resistant Escherichia coli is common cause of gram-negative endocarditis, AmpC beta-lactamase (BL)-harboring E coli is very rare cause of IE. Furthermore, emphysematous endocarditis is also a very rare manifestation of E coli infection. PATIENT CONCERNS: We report a case of 80-year-old female patient presenting with dizziness, fever, and altered mental status, who was finally diagnosed with emphysematous endocarditis caused by E coli harboring an AmpC BL gene. DIAGNOSIS: Her chest computed tomography revealed air bubbles surrounding the annulus of a mitral valve and a transesophageal echocardiogram revealed a hyperechogenic mass fixed on the posteromedial side of the mitral annulus with 2 eccentric mitral regurgitation jets. Blood cultures grew E coli which harbored the DHA-type AmpC BL. The organism belonged to a B2 phylogenic group, and multilocus sequence typing analyses revealed that the strains were of ST-95. INTERVENTIONS: She was treated with meropenem following the resistant profiles, and surgery was recommended by the healthcare professional, but denied by the patient's guardians. She was transferred to another hospital due to a refusal for further treatment. LESSONS: Emphysematous endocarditis is an uncommon complication of E coli bacteremia. Certain phylogenetic groups may be associated with development of E coli endocarditis. PMID- 29419664 TI - Effect of Zhizhu Kuanzhong capsule on functional dyspepsia: Protocol for a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Functional dyspepsia (FD) is a gastrointestinal disorder affecting people in the globe. Spleen-deficiency syndrome is one of its basic syndromes. Zhizhu Kuanzhong capsule was the most frequent Chinese herbal formula used in the spleen-deficiency researches. We aim to assess the effectiveness and safety of Zhizhu Kuanzhong capsule on FD. METHODS: A systematic literature search for randomized controlled trials (RCTs) from their inception until December 31, 2017 will be conducted using 7 databases: PubMed, Cochrane Library, Embase, VIP Database, Chinese National Knowledge Infrastructure, Wanfang Data, and Chinese BioMedical Database. Inclusion the trials of Zhizhu Kuanzhong capsule which evaluate motilin level, clinical syndrome, and side effect in people with FD. The primary outcome measures will be motilin level, clinical syndrome integral, and clinical total effective rate. Data extraction and risk of bias assessments will be performed by 2 reviewers independently. Methodological and reporting quality of included studies will be assessed by the consolidated standards of reporting trials for Chinese herbal medicine formulas. All statistical analyses will be conducted using RevMan V.5.3 software. Funnel plots, Begg's test, and Egger's test will be developed to evaluate reporting bias. RESULTS: This review will assess the effect of Zhizhu Kuanzhong capsule on clinical total effective rate, symptom remission rate, plasma motilin level, and safety of FD in patients. CONCLUSION: The conclusion of our study will provide updated evidence to judge whether Zhizhu Kuanzhong capsule is an effective intervention for patients with FD. PMID- 29419665 TI - The effects of physical therapy with neuromuscular electrical stimulation in patients with septic shock: Study protocol for a randomized cross-over design. AB - INTRODUCTION: Septic shock is a potentially fatal organ dysfunction caused by an imbalance of the host response to infection. The changes in microcirculation during sepsis can be explained by the alterations in the endothelial barrier function. Endothelial progenitor cells (EPCs) are a potential recovery index of endothelial function and it an increase in response to neuromuscular electrical stimulation (NMES) was demonstrated. Therefore, the objective of this study is to investigate the effects of NMES in patients with septic shock. METHODS AND ANALYSIS: It is a study protocol for a randomized cross-over design in an intensive care unit of a tertiary University hospital. Thirty-one patients aged 18 to 65 years. The study will be divided in 2 phases: the phase one will be held in the first 72 hours of septic shock and the phase two after 3 days of first assessment. Patients will be randomly selected to the intervention protocol (decubitus position with the limbs raised and NMES) and control protocol (decubitus position with the limbs raised without NMES). After this procedure, the patients will be allocated in group 1 (intervention and control protocol) or group 2 (control and intervention protocol) with a wash-out period of 4 to 6 hours between them. The main outcome is mobilization of EPCs. The secondary outcome is metabolic and hemodynamic data. A linear mixed model will be used for analysis of dependent variables and estimated values of the mean of the differences of each effect. PMID- 29419666 TI - A comparative study of the incidence of in-hospital cardiopulmonary resuscitation on Monday-Wednesday and Thursday-Sunday: Retrospective analysis in a tertiary care hospital. AB - Because most medical staff work from Monday-Friday, it is possible that they are relatively more fatigued and less capable of providing emergency supportive services on Thursday-Sunday (Thu-Sun) than on Monday-Wednesday (Mon-Wed). In this study, we aimed to analyze the incidence of in-hospital cardiopulmonary resuscitation (CPR) to determine if it differed between Thu-Sun and Mon-Wed.This retrospective observational study of in-hospital CPR was performed during 2012 to 2016 among inpatients at the Seoul National University Bundang Hospital. The primary outcome was the incidence of in-hospital CPR per 1000 inpatients in the Mon-Wed and Thu-Sun periods. Secondary outcomes included differences in the CPR incidence by time of day and season.In the study, 1195 cases of in-hospital CPR were included. The incidence of in-hospital CPR per 1000 inpatients was significantly higher on Thu-Sun (mean: 0.595, 95% confidence interval [CI]: 0.564 0.626) than on Mon-Wed (mean: 0.505, 95% CI: 0.474-0.536, P < .001). There were no seasonal variations in the incidence of in-hospital CPR. However, in-hospital CPR was most frequently performed between 16:00 and 24:00, and the return of spontaneous circulation (ROSC) rate was the lowest among cases that occurred between 0:00 and 8:00. In addition, the ROSC rate was lowest among female patients, patients with cardiac arrest, and after in-hospital CPR performed on a Sunday.The incidence of in-hospital CPR per 1000 inpatients was significantly higher on Thu-Sun than on Mon-Wed. No seasonal variations were observed in the incidence of in-hospital CPR, but the data suggest circadian variations and differences in ROSC rates. PMID- 29419667 TI - Comparison of intravenous and oral acetaminophen for pain control after total knee and hip arthroplasty: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the efficacy between intravenous and oral acetaminophen as adjunct to multimodal analgesia regimens for pain management after total knee and hip arthroplasties. METHODS: We conduct electronic searches of Medline (1966 2017.09), PubMed (1966-2017.09), Embase (1980-2017.09), ScienceDirect (1985 2017.09), and the Cochrane Library. Only randomized controlled trials (RCTs) are included. The quality assessment is performed according to the Cochrane systematic review method. Fixed/random effect model is adopted according to the heterogeneity tested by I statistic. Meta-analysis is performed using Stata 11.0 software. RESULTS: Two RCTs are included involving 236 patients. The present meta analysis demonstrated that there were no significant differences between groups regarding pain scores at 12, 24, or 48 hours. No significant differences were observed in terms of opioid consumption at 12, 24, or 48 hours after arthroplasties. CONCLUSION: Intravenous acetaminophen to multimodal analgesia dose not demonstrate a significant benefit in reducing pain and opioid consumption compared oral formulation after total knee arthroplasty and total hip arthroplasty. Higher-quality RCTs are required for further research. PMID- 29419668 TI - Disordered high-frequency oscillation in face processing in schizophrenia patients. AB - Schizophrenia is a complex disorder characterized by marked social dysfunctions, but the neural mechanism underlying this deficit is unknown. To investigate whether face-specific perceptual processes are influenced in schizophrenia patients, both face detection and configural analysis were assessed in normal individuals and schizophrenia patients by recording electroencephalogram (EEG) data. Here, a face processing model was built based on the frequency oscillations, and the evoked power (theta, alpha, and beta bands) and the induced power (gamma bands) were recorded while the subjects passively viewed face and nonface images presented in upright and inverted orientations. The healthy adults showed a significant face-specific effect in the alpha, beta, and gamma bands, and an inversion effect was observed in the gamma band in the occipital lobe and right temporal lobe. Importantly, the schizophrenia patients showed face-specific deficits in the low-frequency beta and gamma bands, and the face inversion effect in the gamma band was absent from the occipital lobe. All these results revealed face-specific processing in patients due to the disorder of high-frequency EEG, providing additional evidence to enrich future studies investigating neural mechanisms and serving as a marked diagnostic basis. PMID- 29419669 TI - Assessment of the association between serum uric acid levels and the incidence of hypertension in nonmetabolic syndrome subjects: A prospective observational study. AB - The purpose of this study was to examine the association between serum uric acid (sUA) and the incidence of hypertension in nonmetabolic syndrome (non-MetS) subjects.This was a prospective observational study including 23,525 subjects who had been followed up for at least 5 years. A logistic regression model was used to assess independent risk factors associated with hypertension. An area under the receiver operating characteristic curve (auROC) was generated, and a nomogram was developed to assess diagnostic ability of sUA and the sUA-based score.We enrolled 11,642 subjects, and 763 (6.55%) were diagnosed with hypertension at the 5-year follow-up. Subjects were classified into 4 groups based on the sUA quarter. Using Q1 as the reference group, Q2, Q3, and Q4 were found to show a higher risk for the development of hypertension with odds ratio of 1.51 (1.15, 1.98), 1.72 (1.30, 2.27), and 2.27 (1.68, 3.06), respectively (P < .001) after adjusting for other known confounding variables. Interaction analysis showed that there was no significant difference between subgroups stratified on the basis of sex, age, body mass index, fasting plasma glucose, and high-density lipoprotein cholesterol except triglycerides (P = .006). The auROCs for sUA and the sUA-based score were 0.627 (0.607, 0.647) and 0.760 (0.742, 0.777), respectively. A nomogram comprising independent risk factors was developed to predict the 5-year risk of hypertension for each subject.High sUA was significantly associated with the incidence of hypertension in non-MetS subjects adjusting for confounders. PMID- 29419670 TI - Improved detectability of thromboses of the lower limb using low kilovoltage computed tomography. AB - To determine the utility of low kilovoltage computed tomographic venography (CTV) for the detection of deep venous thrombus in the lower limbs.Twenty-one thrombi in 19 enrolled patients were investigated in this retrospective study. Patients were initially scanned using CTV at 100 kVp, at the femur level, followed by an immediate switch to 80 kVp. We assessed the CT values of thrombi and veins and performed subjective evaluation for detecting thrombi using a 5-point scoring system: 1, unable to evaluate due to noise or artifacts; 2, equivocal venous thrombus; 3, possible venous thrombus; 4, probable venous thrombus; and 5, definite venous thrombus.Venous density on 100-kVp images (mean +/- SD [standard deviation]: 122 +/- 23 HU, 95% confidence interval [CI]: 111-133 Hounsfield unit [HU]) was significantly lower than that on 80-kVp images (136 +/- 24 HU, 95% CI: 125-147 HU, P < .001). There was no significant difference in thrombi between 100 kVp images (55 +/- 14 HU, 95% CI: 49-61 HU) and 80-kVp images (57 +/- 16, 95% CI: 50-64 HU, P = .168). The thrombus to vein ratio on 100-kVp images (0.47 +/- 0.20, 95% CI: 0.39-0.56) was significantly higher than that on 80-kVp images (0.44 +/- 0.16, 95% CI: 0.37-0.51, P = .048). The mean 5-point score was significantly higher on the 80-kVp images (4.76) than on the 100-kVp images (4.45, P = .016).Lower kilovoltage CTV significantly improved thrombotic to venous contrasts in the lower limbs. PMID- 29419671 TI - Assessment of liver fibrosis in Egyptian chronic hepatitis B patients: A comparative study including 5 noninvasive indexes. AB - Fibrosis assessment in chronic hepatitis B (CHB) is essential for prediction of long-term prognosis and proper treatment decision. This study was conducted to assess predictability of 5 simple noninvasive fibrosis indexes in comparison to liver biopsy in CHB patients.A total of 200 CHB adult Egyptian patients were consecutively included in this study, all were subjected to liver biopsy with staging of fibrosis using METAVIR scoring system. Fibrosis indexes including S index, red cell distribution width to platelets ratio index (RPR), fibrosis-4 index (Fib-4), AST to platelets ratio index (APRI), and AST/ALT ratio index (AAR) were compared to biopsy result and their predictabilities for the different fibrosis stages were assessed using area under receiver operating characteristic curve (AUROC) analysis.S-index showed the highest AUROCs for predicting fibrosis among the studied indexes. AUROCs of S-index, RPR, Fib-4, APRI, and AAR were: 0.81, 0.67, 0.70, 0.68, and 0.60 for prediction of significant fibrosis (F2-F4), 0.90, 0.66, 0.68, 0.67, and 0.57 for advanced fibrosis (F3-F4), and 0.96, 0.62, 0.61, 0.57, and 0.53 for cirrhosis (F4), respectively. The optimal S-index cutoff for ruling in significant fibrosis was >=0.3 with 94% specificity, 87% PPV, and 68% accuracy, while that for ruling out significant fibrosis was <0.1 with 96% sensitivity, 91% NPV, and 67% accuracy. Accuracy of S-index was higher for predicting cirrhosis (91%) than that for predicting advanced fibrosis (79%) and significant fibrosis (68%).S-index has the highest predictability for all fibrosis stages among the studied fibrosis indexes in HBeAg-negative CHB patients, with higher accuracy in cirrhosis than in the earlier fibrosis stages. PMID- 29419672 TI - Pulse pressure and diabetes treatments: Blood pressure and pulse pressure difference among glucose lowering modality groups in type 2 diabetes. AB - Type 2 diabetes is associated with higher pulse pressure. In this study, we assessed and compared effects of classic diabetes treatments on pulse pressure (PP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in patients with type 2 diabetes.In a retrospective cohort study, 718 non hypertensive patients with type 2 diabetes were selected and divided into 4 groups including metformin, insulin, glibenclamide+metformin, and metformin+insulin. They were followed for 4 consecutive visits lasting about 45.5 months. Effects of drug regimens on pulse and blood pressure over time were assessed separately and compared in regression models with generalized estimating equation method and were adjusted for age, duration of diabetes, sex, smoking, and body mass index (BMI).Studied groups had no significant change in PP, SBP, and DBP over time. No significant difference in PP and DBP among studied groups was observed (PP:P = 0.090; DBP:P = 0.063). Pairwise comparisons of PP, SBP, and DBP showed no statistically significant contrast between any 2 studied groups. Interactions of time and treatment were not different among groups.Our results demonstrate patients using metformin got higher PP and SBP over time. Averagely, pulse and blood pressure among groups were not different. Trends of variation in pulse and blood pressure were not different among studied diabetes treatments. PMID- 29419673 TI - Aromatherapy for managing menopausal symptoms: A protocol for systematic review and meta-analysis. AB - BACKGROUND: Aromatherapy is often used as a complementary therapy for women's health. This systematic review aims to evaluate the therapeutic effects of aromatherapy as a management for menopausal symptoms. METHODS: Eleven electronic databases will be searched from inception to February 2018. Randomized controlled trials that evaluated any type of aromatherapy against any type of control in individuals with menopausal symptoms will be eligible. The methodological quality will be assessed using the Cochrane risk of bias tool. Two authors will independently assess each study for eligibility and risk of bias and to extract data. RESULTS: This study will provide a high quality synthesis of current evidence of aromatherapy for menopausal symptoms measured with Menopause Rating Scale, the Kupperman Index, the Greene Climacteric Scale, or other validated questionnaires. CONCLUSIONS: The conclusion of our systematic review will provide evidence to judge whether aromatherapy is an effective intervention for patient with menopausal women. ETHICS AND DISSEMINATION: Ethical approval will not be required, given that this protocol is for a systematic review. The systematic review will be published in a peer-reviewed journal. The review will also be disseminated electronically and in print. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017079191. PMID- 29419674 TI - Expression of TP53 and IL-1alpha in unicystic ameloblastoma predicts the efficacy of marsupialization treatment. AB - In this study, we evaluated the effects of marsupialization in treating unicystic ameloblastoma (UA) and investigated the relationship between TP53 and interleukin 1 alpha (IL-1alpha) expression and the clinical outcome of UA treated with marsupialization.Consecutive patients treated with marsupialization and curettage at Shanghai Ninth People's Hospital were included. According to the unified standard, 48 patients were included in this study. Of these, 20 showed a good response, 10 a partial response, and 18 no response, based on the outcome of the marsupialization procedure. The expression of proteins TP53 and IL-1alpha was detected with immunohistochemistry (IHC). The clinical and pathological characteristics of the patients were analyzed.Analysis of the clinical and pathological characteristics showed that the effects of marsupialization treatment were significantly associated with lesion location (P < .001) and tumor diameter (P = .01). IHC showed that TP53 expression was significantly higher in the good-response group than in the partial- or no-response group (P = .02), and IL-1alpha expression was significantly higher in the good-response group than in the partial- and no-response groups (P = .03).Marsupialization is an effective preliminary procedure for treating UA before curettage and peripheral ostectomy. The expression of the TP53 and IL-1alpha proteins correlates directly with the outcome of UA treated with marsupialization. PMID- 29419675 TI - The precision and reliability evaluation of 3-dimensional printed damaged bone and prosthesis models by stereo lithography appearance. AB - Recently, clinical application of 3D printed model was increasing. However, there was no systemic study for confirming the precision and reliability of 3D printed model. Some senior clinical doctors mistrusted its reliability in clinical application. The purpose of this study was to evaluate the precision and reliability of stereolithography appearance (SLA) 3D printed model.Some related parameters were selected to research the reliability of SLA 3D printed model. The computed tomography (CT) data of bone/prosthesis and model were collected and 3D reconstructed. Some anatomical parameters were measured and statistical analysis was performed; the intraclass correlation coefficient (ICC) was used to was used to evaluate the similarity between the model and real bone/prosthesis. the absolute difference (mm) and relative difference (%) were conducted. For prosthesis model, the 3-dimensional error was measured.There was no significant difference in the anatomical parameters except max height (MH) of long bone. All the ICCs were greater than 0.990. The maximum absolute and relative difference were 0.45 mm and 1.10%; The 3-dimensional error analysis showed that positive/minus distance were 0.273 mm/0.237 mm.The application of SLA 3D printed model in diagnosis and treatment process of complex orthopedic disease was reliable and precise. PMID- 29419676 TI - Gastrointestinal involvement by mantle cell lymphoma identified by biopsy performed during endoscopy: A case report. AB - RATIONALE: Primary gastrointestinal mantle cell lymphoma is rare, and histopathological examination and specific immunohistochemical staining are still the gold standard for diagnosis. Therefore, it is necessary to find a new way to improve positive biopsy rates. PATIENT CONCERNS: A 58-year-old man was admitted to our hospital with epigastric pain, abdominal distension, nausea, and melena. Endoscopy identified submucosal neoplasms and diffuse gastrointestinal tract involvement including the esophagus. DIAGNOSES: A false-negative diagnosis was first determined by ordinary endoscopy. However, a large tissue biopsy was subsequently performed using endoscopic mucosal resection based on endoscopic ultrasonography (EUS). Pathological examination of the biopsy specimens taken from the lesions of the duodenum and rectum revealed diffuse lymphocytic proliferation and obscure nodular and small cleaved cells with irregularly shaped nuclei. Immunohistochemistry showed that the cells were positive for CyclinD1, BCL-2, CD20, CD21, and CD5; however, they were negative for CD3, CD6, CD10, and CD43. INTERVENTIONS: The patient refused to receive further treatment. OUTCOMES: Mantle cell lymphoma was conclusively diagnosed. CONCLUSIONS: EUS has an important role in the diagnosis and management of gastrointestinal submucosal tumors. Performing a pathological biopsy including EUS may be useful for identifying the unknown nature of tumors of the digestive tract. PMID- 29419678 TI - Tour leaders with detailed knowledge of travel-related diseases play a key role in disease prevention. AB - In Taiwan, group tours are a popular mode of international travel; hence, group tour leaders must ensure traveler safety and health. This study identified factors influencing tour leaders' willingness to recommend pretravel medical consultation and vaccination.A cross-sectional questionnaire survey was administered to tour leaders from January 2011 to December 2012. Multivariate logistic regression analyses were performed to estimate the odds ratios of having a positive attitude and willingness based on different knowledge scores of the tour leaders after adjustments for age, sex, education level, and seniority.Tour leaders with a more detailed knowledge of both travel-related infectious and noninfectious diseases demonstrated a higher willingness to receive vaccination. They believed that consultation at travel clinics before travel can improve travelers' health (P < .05).This study supports the importance and effectiveness on educating tour leaders' knowledge about travel-related diseases to improve health care for travelers. PMID- 29419677 TI - Risk of major comorbidities among workers with hemophilia: A 14-year population based study. AB - Multiple comorbidities, especially musculoskeletal dysfunction and cerebrovascular disease, remain barriers to normal social participation among persons with hemophilia (PWH). However, the relative health effects of such comorbidities on workers with hemophilia have seldom been explored. In this study, we investigated the incidence of comorbidities and their risk factors among workers with hemophilia.The study compared the incidence and risk factors of the major comorbidities of 411 workers with hemophilia enrolled in Taiwan's National Health Insurance Research Database between 1997 and 2010 with an age- and sex-matched general population.Compared with the general population, workers with hemophilia had higher risks for hemorrhagic stroke, arthritis/arthropathy, and knee/hip replacement among workers with hemophilia after multivariate adjustment, with hazard ratios (95% CI) of 4.60 (2.81-7.53), 4.03 (3.34-4.87), and 1.29 (1.10-1.41), respectively.Disorder of joints, hemophilia-related arthritis/arthropathy, hemorrhagic stroke, and knee/hip replacement remain significant comorbidities among workers with hemophilia, which will result in increased social burden. Policymakers and employers should apply appropriate interventions to help prevent productivity losses, reduced workforce participation, sick leave, and work disability among hemophilia workers. PMID- 29419679 TI - The efficacy and safety of using cooled radiofrequency in treating chronic sacroiliac joint pain: A PRISMA-compliant meta-analysis. AB - BACKGROUND: Cooled radiofrequency procedure is a novel minimally invasive surgical technique and has been occasionally utilized in managing chronic sacroiliac joint (SIJ) pain. A meta-analysis was conducted to systematically assess the efficacy and safety of using cooled radiofrequency in treating patients with chronic SIJ pain in terms of pain and disability relief, patients' satisfaction degree as well as complications. METHODS: Studies of using cooled radiofrequency procedure in managing SIJ pain were retrieved from Medline and Web of Science according to inclusion and exclusion criteria. Quality evaluation was conducted using Cochrane collaboration tool for randomized controlled trials and MINORS quality assessment for noncomparative trials. Statistics were managed using Review Manager 5.3. RESULTS: Totally 7 studies with 240 eligible patients were enrolled. The overall pooled results demonstrated that pain intensity decreased significantly after cooled radiofrequency procedure compared with that measured before treatment. The mean difference (MD) was 3.81 [95% confidence intervals (95% CIs): 3.29-4.33, P < .001] and 3.78 (95% CIs: 3.31-4.25, P < .001) as measured by the Numerical Rating Scale (NRS) and Visual Analog Scale (VAS), respectively. Disability also relieved significantly after treatment compared with that measured before treatment. The MD was 18.2 (95% CIs: 12.22-24.17, P < .001) as measured by the Oswestry Disability Index (ODI). Seventy-two percent of the patients presented positive results as measured by the Global Perceived Effect (GPE). The OR was 0.01 (95% CIs: 0.00-0.05, P < .001). Only mild complications were observed in the 7 studies, including transient hip pain, soreness, and numbness. CONCLUSION: Cooled radiofrequency procedure can significantly relieve pain and disability with no severe complications, and majority of patients are satisfied with this technique. Thus, it is safe and effective to use this procedure in managing patients with chronic SIJ pain. More high-quality and large-scale randomized controlled trials (RCTs) are required to validate our findings. LIMITATIONS: The sample size of the included studies was small and various heterogeneity existed. PMID- 29419680 TI - MiR-664a-3p expression in patients with obstructive sleep apnea: A potential marker of atherosclerosis. AB - The early prediction of atherosclerosis (AS) is important in the management of obstructive sleep apnea patients (OSA). MicroRNA (miRNA) plays a vital role in the evolution of OSA and AS. Its differential expression may therefore serve as a diagnostic and prognostic biomarker of AS in OSA. The aim of this study was to identify specific serum miRNAs that could serve as a novel screening signature of AS in OSA patients. The specificity and sensitivity of these miRNAs in the early diagnosis of AS in OSA patients were then determined.The 128 participants in this study underwent maximum carotid intima-media thickness (CIMT) measurements and polysomnography and were divided into 4 groups: 27 healthy volunteers with normal max-CIMT, 31 healthy volunteers with increased max-CIMT, 35 OSA patients with normal max-CIMT, and 35 OSA patients with iCIMT. MiRNA was extracted from the 12 participants' serum (3 participants each groups) and used to establish miRNA libraries for deep sequencing. A total of 116 participants were quantified by qRT PCR. Correlations between differential expression of miRNAs and CIMT were assessed using the Spearman correlation coefficient. Our study was approved by the Ethics Committee of our hospital and was conducted in line with the Helsinki Declaration.MiR-664a-3p expression was quantified by qRT-PCR. Correlations between miR-664a-3p expression and CIMT were assessed using the Spearman correlation coefficient. The results showed that the miR-664a-3p was downregulated in the OSA, OSA with iCMIT, and nCIMT groups compared with the control group.The demonstrated potential of circulating miR-664a-3p as a noninvasive marker of AS in essential OSA patients should be confirmed in further studies. PMID- 29419681 TI - Shear wave sonoelastography in infants with congenital muscular torticollis. AB - Congenital muscular torticollis (CMT) is characterized by shortening or excessive contraction of the sternocleidomastoid muscle (SCM). The main purpose of this study was to evaluate the feasibility of quantifying SCM stiffness using acoustic radiation force impulse (ARFI) sonoelastography in infants with CMT. Twenty infants with an SCM thickness greater than 10 mm with or without involvement of the entire SCM length (limitation of neck rotation passive range of motion [PROM]: group 1S >30 degrees , group 1M = 15 degrees -30 degrees ) and 12 infants with an SCM thickness smaller than 10 mm with or without involvement of any part of SCM (group 2) were included. The SCM thickness was measured using real time B mode ultrasound, and the local SCM shear wave velocity (SWV) and subcutaneous fat layer using ARFI sonoelastography. The neck rotation PROM was significantly greater in group 1S (36.5 degrees +/- 5.3 degrees ) than in group 1M (18.8 degrees +/- 4.9 degrees ; P < .01); the SWV of the SCM in the affected side (2.96 +/- 0.99 m/s) was significantly higher than that in the unaffected side (1.50 +/- 0.30 m/s; P < .01) in group 1. The SWV of the SCM was significantly higher in group 1S than in group 1M. There was significant correlation between the degree of PROM deficit of neck rotation and the SWV of the affected SCM (r = .75; P < .01) in all infants. This study revealed a difference in the SWV of the affected SCM in relationship to the limitation of neck rotation PROM in infants with CMT, if there was no difference in SCM thickness among infants. PMID- 29419682 TI - Acupuncture for management of lower urinary tract symptoms in Parkinson's disease: A protocol for the systematic review of randomized controlled trials. AB - BACKGROUND: Acupuncture is claimed to improve the lower urinary tract symptoms (LUTS). Currently, no systematic reviews are performed for acupuncture on LUTS in patients with Parkinson's diseases (PD). This review aims to evaluate the current evidence on the efficacy of acupuncture for the management of LUTS in PD. METHODS AND ANALYSES: Eleven databases will be searched from their inception. These include PubMed, AMED, EMBASE, the Cochrane Library, 6 Korean medical databases, and 1 Chinese medical database. Study selection, data extraction, and assessment will be performed independently by 2 researchers. Risk of bias will be assessed with the Cochrane risk of bias assessment tool. ETHICS AND DISSEMINATION: Ethical approval will not be required, given that this protocol is for a systematic review. The systematic review will be published in a peer-reviewed journal and disseminated both electronically and in print. The review will be updated to inform and guide healthcare practice and policy. TRIAL REGISTRATION NUMBER: PROSPERO 2018 CRD42018083857. PMID- 29419683 TI - A 10-year monitoring of the eyesight in patients after kidney transplantation. AB - A pilot study of a 10-year analysis of the eyesight characteristics in patients after renal transplantation with a view to a later wider study of the same population.The study encompassed 50 eyes in 25 patients who underwent renal transplantation in the years 2007 and 2008. All patients underwent: visual acuity measurement, tonometry, slit lamp examination, and spectroscopic optical coherence tomography.Changes in the eyes observed during the 10-year observation period included mostly: cataract (48%), hypertensive angiopathy (28%), diabetic macular edema (16%), and glaucoma (16%). Ten years after the renal transplant visual acuity declined in 15 patients (60%). In 67% of those with eyesight deterioration the cause was cataract, while in patients with no changes in the eyesight (n = 10) cataract was diagnosed only in one. Patients with cataracts had been more often treated with cyclosporine, and that difference was statistically significant (73% vs 21%; P < .05). Comparing patients with hypertensive angiopathy with controls has shown that in the first group creatinine levels were statistically significantly higher (1.6 vs 1.16 mg/dL; P < .05). Patients with angiopathy had been also longer on renal replacement therapy before transplant (57 vs 26 months, P > .05), and this group included also statistically more persons after retransplantation (43% vs 5%, P < .05).Most frequent ophthalmological diagnoses in patients after a kidney transplant include cataract, diabetic retinopathy, and hypertensive angiopathy. Visual acuity deterioration was seen in 60% of patients and was mainly the effect of cataract progress. The effect of cyclosporine on cataract progress was significant. The diagnosis of hypertensive angiopathy corresponded with poorer function of the transplanted kidney. PMID- 29419684 TI - Phylogenetic and temporal dynamics of human immunodeficiency virus type 1 CRF01_AE and CRF07_BC among recently infected antiretroviral therapy-naive men who have sex with men in Jiangsu province, China, 2012 to 2015: A molecular epidemiology-based study. AB - The prevalence and incidence of human immunodeficiency virus type 1 (HIV-1) among men who have sex with men (MSM) are on the rise throughout China. With a large population of MSM, Jiangsu Province is facing an escalating HIV-1 epidemic.The aim of this study was to explore the phylogenetic and temporal dynamics of HIV-1 CRF01_AE and CRF07_BC among antiretroviral therapy (ART)-naive MSM recently infected with HIV-1 in Jiangsu Province.We recruited MSM in Jiangsu Province (Suzhou, Wuxi, Nantong, Taizhou and Yancheng) 2012 to 2015. We collected information on demographics and sexual behaviors and a blood sample for HIV genome RNA extraction, RT-PCR amplification, and DNA sequencing. Multiple alignments were made using Gene Cutter, with the selected reference sequences of various subtypes/recombinants from the Los Alamos HIV-1 database. Phylogenetic and Bayesian evolutionary analysis was performed by MEGA version 6.0, Fasttree v2.1.7. and BEAST v1.6.2. Categorical variables were analyzed using chi test (or Fisher exact test where necessary). chi test with trend was used to assess the evolution of HIV-1 subtype distribution over time. All data were analyzed using SPSS20.0 software package (IBM Company, New York, NY).HIV-1 phylogenetic analysis revealed a broad viral diversity including CRF01_AE (60.06%), CRF07_BC (22.29%), subtype B (5.88%), CRF67_01B (5.26%), CRF68_01B (2.79%), CRF55_01B (1.55%), CRF59_01B (0.93%), and CRF08_BC (0.62%). Two unique recombination forms (URFs) (0.62%) were also detected. Four epidemic clusters and 1 major cluster in CRF01_AE and CRF07_BC were identified. The introduction of CRF01_AE strain (2001) was earlier than CRF07_BC strain (2004) into MSM resided in Jiangsu based on the time of the most recent common ancestor.Our study demonstrated HIV-1 subtype diversity among ART-naive MSM recently infected with HIV-1 in Jiangsu. We first depicted the spatiotemporal dynamics, traced the dates of origin for the HIV-1 CRF01_AE/07_BC strains and made inference for the effective population size among newly infected ART-naive MSM in Jiangsu from 2012 to 2015. A real-time surveillance of HIV-1 viral diversity and phylodynamics of epidemic cluster would be of great value to the monitoring of the epidemic and control of transmission, improvement of antiretroviral therapy strategies, and design of vaccines. PMID- 29419685 TI - The adaptive change of patellofemoral joint after arthroscopic discoid lateral meniscus plasty: An observational study. AB - The purpose of this study was to investigate the patellofemoral joint adaptive changes after discoid lateral meniscus (DLM) plasty.Forty-one patients with unilateral complete type DLM tears were included in this study. Demographic variables, including gender, age, body mass index (BMI), injury to operation interval, type of injury, and follow-up time, were recorded. The evolution of physical examination, imaging index, and functional score were analyzed by Chi squared test, Wilcoxon signed ranks test, and Friedman test. Mann-Whitney test was used to analyze the difference at different time points between group PFI > 1.6 and PFI < 1.6.After the patients received arthroscopic DLM plasty, the positive rate of Patella grinding test increased from 19.5% to 29.3%, and it showed significant increased at last follow-up time point (48.8%) (P = .005). Mechanical axis deviation (MAD) significant decreased from -0.7 +/- 2.1 mm to 9.4 +/- 3.2 mm (P < .001). Lateral patellofemoral angle (LPFA) and lateral shift distance (LSD), respectively, decreased from 11.9 +/- 5.8 degrees and 1.0 +/- 4.0 mm to 7.2 +/- 4.5 degrees and -0.5 +/- 3.3 mm (P < .001). Patellofemoral index (PFI) increased from 1.7 +/- 0.3 to 1.9 +/- 0.4 (P < .001). Kujala score and Lysholm score, respectively, increased from 65.9 +/- 10.0 and 85.2 +/- 6.4 mm to 61.8 +/- 10.2 and 89.5 +/- 5.0 (P < .001). Only LSD in group > 1.6 were significant lower than those in group < 1.6 (>1.6: -1.5 +/- 2.8, -1.6 +/- 2.7, 1.5 +/- 2.6; <1.6: 0.8 +/- 3.4, 0.4 +/- 3.6, 0.6 +/- 2.8. P = .010,.038,.011) at the 3 postoperative follow-up time points.After arthroscopic plasty for complete type DLM which decreased the thickness and width of the residual meniscus, in turn causing the varus deformity significantly decreased or a valgus inclination developed. Moreover, the consequent changes of patellofemoral joint caused a certain amount of patellar tilt and patellar dislocation, might aggravated the symptomatic anterolateral knee pain or the lateral patellar compression syndrome. PMID- 29419686 TI - The clinical efficacy of epalrestat combined with alpha-lipoic acid in diabetic peripheral neuropathy: Protocol for a systematic review and meta-analysis. AB - BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common long-term complication of diabetes mellitus, affecting patients in the world. Epalrestat combined with alpha-lipoic acid (ALA) is the most frequent combine therapy used in the DPN researches. We aim to assess the effectiveness and safety of epalrestat combined with ALA in patients with DPN, compare with epalrestat alone. METHODS: We will search Cochrane Library, PubMed, Wanfang Data, China National Knowledge Infrastructure, VIP Chinese Science and Technology Journals Database, and Chinese Biomedical Database from inception until October 31th, 2017. Inclusion the randomized controlled trials and clinical control trials of combine therapy which evaluate clinical efficacy and side effect in people with DPN. Data extraction and risk of bias assessments will be independently conducted by 2 reviewers. The primary outcome measures will be total effective rate, motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), Toronto clinical scoring system (TCSS), and total symptom score (TSS). All statistical analyses will be performed using RevMan V.5.3 software. RESULTS: This review will evaluate the total effective rate, nerve conduction velocity, TCSS, TSS, and safety of ALA combined with epalrestat for patients with DPN, compare with epalrestat alone. CONCLUSION: Our study will provide evidence to assess whether epalrestat combined with ALA is an optional treatment for patients with DPN. PMID- 29419687 TI - Synchronous papillary thyroid cancer and non-Hodgkin lymphoma: Case report. AB - RATIONALE: Differentiated thyroid cancer is the most common endocrine malignancy with concomitant hematological malignancy in 7%. PATIENT CONCERNS: We present a case of a synchronous papillary thyroid cancer and a follicular variant of non Hodgkin lymphoma and discuss the possible diagnostic and treatment dilemmas. DIAGNOSIS: A 48-year-old female was reffered to our hospital with diagnosis "thyroid cancer". Due to a history compatable of synchronous lymphoproliferative disease we performed a computed tomography, which revealed multiple enlarged lymph nodes in the neck, mediastinum, axilla and abdomen. INTERVENTIONS: A total thyroidectomy with dissection of the central compartment was performed. The microscopic examination of thyroid gland revealed multifocal papilary thyroid cancer and metastaes from the same cancer plus aggressive follicular B-cell non Hodgkin lymphoma in the lymph nodes. Despite the classic approach "solid cancer first", due to the advanced stage of lymphoma we first started the chemotherapy of NHL. She received 8 cycles of CHOP and I therapy with 129 mCi. Because of incomplete response 4 cycles Mabthera plus Bendamustin were added. The follow-up PET scan revealed complete remission of lymphoma and bilaterally enlarged single cervical lymph nodes, previously known to be iodine positive on I-SPECT/CT. She was sheduled for bilateral radical neck LND. OUTCOMES: Complete remission of NHL and residual single metastatic cervical lymph nodes requiring bilateral radical neck LND. LESSONS: The synchronous DTC and NHL is rare. To date, there is no standardized approach due to lack of experience. We suggest lymphoma first approach with synchronized and tailored multidisciplinary efforts. The molecular mechanisms of this link are poorly understood and yet remain to be elucidated. PMID- 29419688 TI - Impact of dialysis dependence on prognosis in patients with myocardial infarction: An 11-year population-based study. AB - In this study we aimed to directly compare the short and long-term prognosis of nondialysis patients with chronic kidney disease (CKD), dialysis patients, and patients with preserved renal function after acute myocardial infarction (AMI).AMI in patients with CKD is a catastrophic event associated with high medical expenditures and dismal survival. However, there is little research comparing post-AMI outcomes between patients with CKD who were and were not receiving dialysis.The retrospective cohort study included patients with AMI (n = 158,125) in the Taiwan's National Health Insurance Research Database who were treated March 1998 and December 2009. Patients were classified into a nondialysis CKD group (n = 6300), dialysis group (n = 5140), and a control group (n = 146,685). The clinical characteristics, in-hospital events, and long-term outcomes of these 3 groups were compared separately using a multivariable Cox proportional hazard model.The risks of in-hospital death and 2-year all-cause mortality were the highest in the dialysis group, followed by the nondialysis CKD group, and were the lowest in the control group. The 1-year risk of myocardial infarction did not differ among the 3 study groups, but the 2-year risk of myocardial infarction was higher in the dialysis group than in the control group (hazard ratio, 1.13; 95% confidence interval, 1.03-1.24; P = .010).Patients with CKD experienced adverse short- and long-term outcomes after acute myocardial infarction. Patients with CKD, especially those who are dialysis dependent, may require more intensive management to improve their post-AMI clinical outcomes. PMID- 29419689 TI - Surgical reconstruction of the fascia lata and posterior tibial artery perforator flap to treat children with simultaneous injury to the Achilles tendon and heel skin. AB - Children with simultaneous injury to the Achilles tendon and heel skin remain a challenge for clinicians. The purpose of this study is to evaluate a combined surgical procedure involving use of the fascia lata to reconstruct the Achilles tendon, and the posterior tibial artery perforator flap to cover the accompanying heel skin injury.Between February 2010 and February 2013, 8 children (3 females and 5 males) between 3 and 12 years of age, with a median age of 7.5 years, were hospitalized in the First Affiliated Hospital of Shantou University Medical College. All injuries involved damage to an Achilles tendon and heel skin. In all patients, the fascia lata was transplanted to reconstruct the Achilles tendon and the posterior tibial artery perforator flap transplanted to cover the skin injury.Hospitalization was 11 to 15 days (mean 13.5 days). Local necrosis (15% of the area) occurred in 1 flap, but healed after changing dressing. All other flaps survived well. At follow-up after 1 to 2 years, all children had recovered good plantar-flexion and supported their weight while walking. Use of the Arner Lindholm standard to rate clinical efficacy revealed that of the 8 cases, 6 cases showed excellent recovery and 2 were good, with 0 cases ranking moderate or poor. The excellent and good rate was 100%.Child patients with Achilles tendon injury accompanied by heel skin injury are still a challenge for clinicians. Use of the fascia lata, combined with a posterior tibial artery perforator flap, to reconstruct the Achilles tendon and heel skin for children is a feasible, safe, effective method, faster than other methods for recovery, and should be widely applied in the clinic. PMID- 29419690 TI - Association between paced QRS duration and atrial fibrillation after permanent pacemaker implantation: A retrospective observational cohort study. AB - Right ventricular pacing often results in prolonged QRS duration (QRSd) as the result of right ventricular stimulation, and atrial fibrillation (AF) may result. The association of pacing-induced prolonged QRSd and AF in patients with permanent pacemakers is unknown.We selected 180 consecutive patients who underwent pacemaker implantation for complete/advanced atrioventricular block. All of the patients were paced from the right ventricular septum. Electrocardiography recordings were obtained at the beginning and the end of pacemaker implantation. QRSd was measured in all 12 leads. The QRSd variation was calculated by subtracting the preimplantation QRSd from the postimplantation QRSd.The occurrence of AF was observed in 64 (35.56%) patients (follow-up 33.62 +/- 21.47 mo). No significant differences in preimplantation QRSd were observed between the AF occurrence and nonoccurrence groups. The QRSd variation in leads V4 (54.22 +/- 29.03 vs 42.66 +/- 33.79 ms, P = .022), and V6 (64.62 +/- 23.16 vs 48.45 +/- 34.40 ms, P = .001) differed significantly between the occurrence and nonoccurrence groups. More QRSd variation in lead V6 (P = .005, HR = 1.822, 95% CI 1.174-2.718, interval scale of QRSd was 40 ms) and left atrial diameter (P = .045, HR = 1.042, 95% CI 1.001-1.086) were independent risk factors for AF occurrence. Receiver operating characteristic curve suggested that QRSd variation in lead V6 could predict AF occurrence, especially for patients with long preimplantation QRSd (>=120 ms, area under the curve was 0.826, 95% CI 0.685 0.967).QRSd variation in lead V6 might be positively correlated with postimplantation AF occurrence. In patients with pacemaker implantation, QRSd could be a complementary criterion for optimizing the right ventricular septal pacing site, and smallest QRSd might be worth pursuing. PMID- 29419692 TI - Comparison of surgical or nonsurgical treatment outcomes in patients with thoracolumbar fracture with Score 4 of TLICS: A randomized, single-blind, and single-central clinical trial. AB - BACKGROUND: Thoracolumbar fractures are among the most common types of damages caused to the spinal cord .Therefore, the aim of this study was the comparison of surgical or nonsurgical treatment outcomes in patients with thoracolumbar fracture with score 4 of the thoracolumbar injury classification and severity (TLICS) METHODS:: This study was clinical trial and double blind. Patients with thoracolumbar fracture with score 4 of TLICS entered at this research. We divided patients in 2 groups randomly (each group 25 patients) and then we followed patients for 1 year after start of treatment. We checked duration of bedridden and absence work, pain every 3 months for 1 year and radiography every 3 months for 1 year. RESULTS: Pain in operative group was lower than nonoperative group (P = .02). Regional sagittal angles (RSA) in operative group was lower than nonoperative group in all time (P = .0001). Mean of time of return to work in operative group was lower than nonoperative group (P = .001). CONCLUSIONS: Pain and mean of time of return to work and RSA in operative group was lower than nonoperative group. The present data suggest the use of operative method in patients with thoracolumbar fracture with score 4 of TLICS. PMID- 29419691 TI - Sigmoid colon translocation of an intrauterine device misdiagnosed as a colonic polyp: A case report. AB - RATIONALE: Intrauterine contraceptive devices (IUDs) are recommended as a means of contraception. Translocation of IUD is a rare and serious complication. Colonic inflammatory mass caused by translocated IUD initially misdiagnosed as a colonic polyp is extremely rare and has not been reported yet. PATIENT CONCERNS: This report presents a case of sigmoid colon translocation of intrauterine device on a 37-year-old female patient. Colonoscopy was performed due to her complain of repeated blood in stools and subsequently the patient was misdiagnosed as a sigmoid colon polyp. Nonetheless, the "polyp" was not able to be removed endoscopically. DIAGNOSES: Sigmoid colon translocation of an intrauterine device. INTERVENTIONS: To further clarify the diagnosis, computed tomography (CT) scan was performed and the "polyp" was confirmed to be caused by a translocated IUD. OUTCOMES: The translocated IUD was removed easily by surgery, and the patient recovered soon after the operation. LESSONS: The present case indicates that an annual gynaecologic examination is necessary to determine the position of the IUD, and a CT examination may help confirm an ectopic IUD. PMID- 29419693 TI - Organ damage mitigation with the Baskent Sickle Cell Medical Care Development Program (BASCARE). AB - The Eastern Mediterranean is among the regions where sickle cell disease (SCD) is common. The morbidity and mortality of this disease can be postponed to adulthood through therapies implemented in childhood. The present study focuses on the organ damage-reducing effects of the Baskent Sickle Cell Medical Care Development Program (BASCARE), which was developed by a team who lives in this region and has approximately 25 years of experience. The deliverables of the program included the development of an electronic health recording system (PRANA) and electronic vaccination system; the use of low citrate infusion in routine prophylactic automatic erythrocyte exchange (ARCE) programs including pregnant women; the use of leukocyte-filtered and irradiated blood for transfusion; the use of magnetic resonance imaging methods (T2) for the management of transfusion-related hemosiderosis; and the implementation of an allogeneic hematopoietic stem cell transplantation protocol for adult patients. The sample was composed of 376 study subjects and 249 control subjects. The hospital's Data Management System and the central population operating system were used for data collection. BASCARE enabled better analysis and interpretation of complication and mortality data. Vaccination rates against influenza and pneumococcal disease improved (21.5% vs 50.8% and 21.5% vs 49.2%, respectively). Effective and safe ARCE with low citrate infusion were maintained in 352 subjects (1003 procedures). Maternal and fetal mortality was prevented in 35 consecutive pregnant patients with ARCE. Chelating therapy rates reduced from 6.7% to 5%. Successful outcomes could be obtained in all 13 adult patients who underwent allogeneic peripheral stem cell transplantation from a fully matched, related donor. No patients died by day 100 or after the first year. Cure could be achieved without graft loss, grades III to IV acute graft versus host disease, extensive chronic graft versus host disease, or other major complications. The BASCARE program significantly improved patient care and thereby prolonged the life span of SCD patients (42 +/- 13 years vs 29 +/- 7 years, P < .001). We may recommend using such individualized programs in centers that provide health care for patients with SCD, in accordance with holistic approach due to the benign nature but malignant course of the disease. PMID- 29419694 TI - Akinetic mutism following prefrontal injury by an electrical grinder a case report: A diffusion tensor tractography study. AB - RATIONALE: A 72-year-old male had suffered from head trauma resulting from injury to his frontal area by an electrical grinder while working at his home. PATIENT CONCERNS: He lost consciousness for approximately 10 minutes and experienced continuous post-traumatic amnesia. DIAGNOSES: He was diagnosed as traumatic intracerebral hemorrhage in both frontal lobes, intraventricular hemorrhage, and subarachnoid hemorrhage, and underwent decompressive craniectomy and hematoma removal. INTERVENTIONS: The patient's Glasgow Coma Scale score was 5. At 2 months after onset, when starting rehabilitation, he showed no spontaneous movement or speech; he remained in a lying position all day with no spontaneous activity. OUTCOMES: On 2-month diffusion tensor tractography, decreased neural connectivity of the caudate nucleus to the medial prefrontal cortex (PFC, Broadmann area [BA]: 10 and 12) and orbitofrontal cortex (BA 11 and 13) was observed in both hemispheres. LESSONS: Akinetic mutism following prefrontal injury. PMID- 29419695 TI - Association of microRNA-423 rs6505162 C>A polymorphism with susceptibility and metastasis of colorectal carcinoma. AB - Studies have evaluated the association between the SNP miRNA-423 rs6505162 C>A and cancer risk in several cancers with contradictory outcomes. It was reported that miRNA-423 rs6505162 C>A polymorphism was associated with the overall survival and the recurrence-free survival of colorectal carcinoma. However, no studies have reported the association between miRNA-423 rs6505162 C>A polymorphism and susceptibility of colorectal carcinoma.In this study, we investigated the association between miRNA-423 polymorphism with risk and clinicopathological parameters of colorectal carcinoma. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to genotype 117 colorectal carcinoma patients and 84 healthy controls.Our data indicated the frequencies of rs6505162 genotypes and alleles were significantly different between colorectal carcinoma patients and controls. Compared with CC homozygote, the AC heterozygote exhibited a significantly decreased risk of colorectal carcinoma; and the combination of AC and AA genotype was associated with decreased risk of colorectal carcinoma. The allele distribution of rs6505162 was significantly different between cases and controls. Furthermore, miR-423 rs6505162 C>A genotype showed a significant association with metastasis in patients (P = .022).Our study suggested that miR-423 rs6505162 C>A polymorphism was associated with the susceptibility and metastasis of colorectal carcinoma, and that miR-423 rs6505162 C>A polymorphism might be a potential biomarker for colorectal carcinoma. PMID- 29419696 TI - Lower likelihood of cardiac procedures after acute coronary syndrome in patients with human immunodeficiency virus/acquired immunodeficiency syndrome. AB - Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected adults; however, this population may be less likely to receive interventions during hospitalization for acute coronary syndrome (ACS). The degree to which this disparity can be attributed to poorly controlled HIV infection is unknown.In this large cohort study, we used the National Inpatient Sample (NIS) to compare rates of cardiac procedures among patients with asymptomatic HIV-infection, symptomatic acquired immunodeficiency syndrome (AIDS), and uninfected adults hospitalized with ACS from 2009 to 2012. Multivariable analysis was used to compare procedure rates by HIV status, with appropriate weighting to account for NIS sampling design including stratification and hospital clustering.The dataset included 1,091,759 ACS hospitalizations, 0.35% of which (n = 3783) were in HIV-infected patients. Patients with symptomatic AIDS, asymptomatic HIV, and uninfected patients differed by sex, race, and income status. Overall rates of cardiac catheterization and revascularization were 53.3% and 37.4%, respectively. In multivariable regression, we found that relative to uninfected patients, those with symptomatic AIDS were less likely to undergo catheterization (odds ratio [OR] 0.48, confidence interval [CI] 0.43-0.55), percutaneous coronary intervention (OR 0.69, CI 0.59-0.79), and coronary artery bypass grafting (0.75, CI 0.61-0.93). No difference was seen for those with asymptomatic HIV relative to uninfected patients (OR 0.93, CI 0.81-1.07; OR 1.06, CI 0.93-1.21; OR 0.88, CI 0.72-1.06, respectively).We found that lower rates of cardiovascular procedures in HIV infected patients were primarily driven by less frequent procedures in those with AIDS. PMID- 29419697 TI - Frail and pre-frail phenotype is associated with pain in older HIV-infected patients. AB - As HIV-infected patients grow older, some accumulate multiple health problems earlier than the noninfected ones in particular frailty phenotypes. Patients with frailty phenotype are at higher risk of adverse outcomes (worsening mobility, disability, hospitalization, and death within three years).Our study aimed to evaluate prevalence of frailty in elderly HIV-infected patients and to assess whether frailty is associated with HIV and geriatric factors, comorbidities, and precariousness in a French cohort of older HIV infected.This 18-month cross sectional multicenter study carried in 2013 to 2014 had involved 502 HIV-infected patients aged 50 years and older, cared in 18 HIV-dedicated hospital medical units, located in South of France.Prevalence of frailty was 6.3% and of pre frailty 57.2%. Low physical activity and weakness were the main frailty markers, respectively 49.4% and 19.9%. In univariate models, precariousness, duration of HIV antiretroviral treatment >15 years, 2 comorbidities or more, risk of depression, activities of daily living disability, and presence of pain were significantly associated with frail and pre-frail phenotype. Multivariate logistic regression analyses showed that only pain was significantly different between frail and pre frail phenotype versus non frail phenotype (odds ratio = 1.2; P = .002).Our study is the first showing a significant association between pain and frailty phenotype in older patients infected by HIV. As frailty phenotype could be potentially reversible, a better understanding of the underlying determinant is warranted. Further studies are needed to confirm these first findings. PMID- 29419698 TI - Next-generation sequencing diagnostics of bacteremia in sepsis (Next GeneSiS Trial): Study protocol of a prospective, observational, noninterventional, multicenter, clinical trial. AB - BACKGROUND: Sepsis remains a major challenge, even in modern intensive care medicine. The identification of the causative pathogen is crucial for an early optimization of the antimicrobial treatment regime. In this context, culture based diagnostic procedures (e.g., blood cultures) represent the standard of care, although they are associated with relevant limitations. Accordingly, culture-independent molecular diagnostic procedures might be of help for the identification of the causative pathogen in infected patients. The concept of an unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) has recently been identified to be a promising diagnostic platform for critically ill patients suffering from bloodstream infections. Although this new approach might be more sensitive and specific than culture-based state-of-the-art technologies, additional clinical trials are needed to exactly define the performance as well as clinical value of a NGS-based approach. METHODS: Next GeneSiS is a prospective, observational, noninterventional, multicenter study to assess the diagnostic performance of a NGS-based approach for the detection of relevant infecting organisms in patients with suspected or proven sepsis [according to recent sepsis definitions (sepsis-3)] by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard (culture-based) microbiological diagnostics. The clinical value of this NGS-based approach will be estimated by a panel of independent clinical specialists, retrospectively identifying potential changes in patients' management based on NGS results. Further subgroup analyses will focus on the clinical value especially for patients suffering from a failure of empiric treatment within the first 3 days after onset [as assessed by death of the patient or lack of improvement of the patient's clinical condition (in terms of an inadequate decrease of SOFA-score) or persistent high procalcitonin levels]. DISCUSSION: This prospective, observational, noninterventional, multicenter study for the first time investigates the performance as well as the clinical value of a NGS-based approach for the detection of bacteremia in patients with sepsis and may therefore be a pivotal step toward the clinical use of NGS in this indication. TRIAL REGISTRATION: DRKS-ID: DRKS00011911 (registered October 9, 2017) https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS000 1911; ClinicalTrials.gov Identifier: NCT03356249 (registered November 29, 2017) https://clinicaltrials.gov/ct2/show/NCT03356249. PMID- 29419699 TI - Spontaneous retroperitoneal hemorrhage in Menkes disease: A rare case report. AB - RATIONALE: Menkes disease (MD), also known as Menkes kinky hair disease, is a fatal neurodegenerative disease caused by a defect in copper metabolism. The symptoms involve multiple organ systems, such as the brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. There is currently no cure for this disease entity, and patients with the classic form of MD usually die from complications between 6 months and 3 years of age. Intracranial hemorrhage secondary to tortuous intracranial arteries is a well known complication of MD, but spontaneous retroperitoneal hemorrhage, to the best of our knowledge, has never been reported in a patient with MD. Herein, we describe the first case of retroperitoneal hematoma as a complication of MD in a 4-year-old boy. PATIENT CONCERNS: A 4-year-old Taiwanese male patient with MD was referred to the hospital and presented with a palpable epigastric mass. DIAGNOSES: On the basis of the findings of ultrasonography and enhanced computed tomography, the diagnosis was retroperitoneal hematoma. INTERVENTIONS: Interventions included laparotomy with evacuation of the hematoma, manual compression, and suture of the bleeding vessels. OUTCOMES: There were no postoperative complications. LESSONS: This case emphasizes that bleeding in patients with MD is possible at any site in the body owing to the unstable structure of the connective tissues. Timely diagnosis with proper imaging studies can lead to prompt and appropriate management and save patients from this life threatening condition. PMID- 29419700 TI - Deep femoral artery branch pseudoaneurysm formation and injury after hip fracture surgery: A case series and a literature review. AB - INTRODUCTION: Complications involving vascular injuries after hip fracture are rare, and the diagnosis and management of deep femoral artery (DFA) injuries are challenging. We reported 4 cases of DFA injuries after hip fracture surgery and aimed to discuss their early detection, treatment, and prevention. METHODS: We reviewed 4 cases of deep femoral injury after hip fracture. Case 1: a 71-year-old woman suffered a fracture around a prosthesis. Cases 2-4: 2 men and 1 woman suffered subtrochanteric or intertrochanteric fracture. DFA branch pseudoaneurysm formation and injury were found via arteriography after surgery. All the patients were diagnosed with DFA branch pseudoaneurysm formation and injury. Percutaneous intervention therapy was used to block the pseudoaneurysms with coil or gel. RESULTS: Among the cases, the main symptoms were severe pain or swelling with large-scale ecchymosis in the thigh or perineum. We used arterial duplex to diagnose pseudoaneurysm and treated the injury using interventional intravascular embolization. In Case 1, damage by the guide wire used during surgery, and over treatment with anticoagulants, may have occurred. In Case 2, the guide wire was a possible contributing factor to injuries. In Case 3, the displaced lesser trochanter fragment may have damaged the vessel. Lastly, a drill bit was a contributing factor to the injuries in Case 4. CONCLUSION: There are many definitive causes of DFA pseudoaneurysm formation and injuries. Such injuries can be diagnosed via digital subtraction angiography or CT angiography, and a thorough understanding of the anatomy of the femur and damages from reductions is important. PMID- 29419701 TI - Quantitative assessment of the relationship between Fas/FasL genes polymorphisms and head and neck cancer risk. AB - BACKGROUND: Molecular epidemiological studies have demonstrated a closer association between Fas/FasL polymorphisms and head and neck cancer (HNC) risk, and the results of these published studies were inconsistent. We therefore performed this meta-analysis to explore the associations between Fas/FasL polymorphisms and HNC risk. METHODS: Four online databases (PubMed, Embase, CNKI, and Wanfang) were searched. Odds ratios (ORs) with 95% confidence interval (95% CIs) were calculated to assess the association between Fas -670A>G, Fas -1377G>A, and FasL -844C>T polymorphisms and HNC risk. In addition, heterogeneity, accumulative/sensitivity analysis, and publication bias were conducted to check the statistical power. RESULTS: Overall, 9 related publications (20 independent case-control studies) involving 3179 patients and 4217 controls were identified. Significant association of protective effects was observed between FasL -844C>T polymorphism and HNC risk in codominant and dominant model models (CT vs CC: OR = 0.89, 95% CI = 0.79-1.00, P = .05, I = 38.3%, CT+TT vs CC: OR = 0.88, 95% CI = 0.79-0.98, P = .02, I = 35.8%). Furthermore, the similar protective effects were observed the subgroup analysis of in Asian population and population-based controls group. CONCLUSION: Our meta-analysis indicated that FasL -844C>T polymorphism plays a protective role against HNC development, but the Fas -670A>G and Fas -1377G>A polymorphisms maybe not associated with HNC risk. PMID- 29419702 TI - Unilateral ectopic breast tissue on vulva in postpartum woman: A case report. AB - RATIONALE: Ectopic mammary gland tissues occur in about 2% to 6% of women in general population. Vulva is considered a rare site for the ectopic breast tissue. PATIENT CONCERNS: We report a rare case of a 27 year-old woman, para 2 and presenting as a vulvar mass in the postpartum period. DIAGNOSES: Ectopic mammary tissue in vulva. INTERVENTIONS: The mass was removed by wide local excision. Histopathological assessment revealed features of ectopic mammary tissue CONCLUSION:: The vulvar region is one of the reported sites for ectopic breast tissue in the body. The presence of a rapidly enlarging, well-encapsulated mass in the vulvar region associated with recent delivery or lactation is suggestive of ectopic breast tissue. LESSONS: It is important for clinicians to get a good history and consider ectopic breast tissue on vulva in postpartum women and confirm diagnosis via biopsy with histopathological examination. PMID- 29419703 TI - The association between CCND1 G870A polymorphism and colorectal cancer risk: A meta-analysis: Erattum. PMID- 29419704 TI - A new clinical decision support tool for improving the adequacy of anticoagulant therapy and reducing the incidence of stroke in nonvalvular atrial fibrillation: A randomized clinical trial in primary care: Erratum. PMID- 29419705 TI - Relationship Between Sever Disease and Skeletal Maturity. AB - BACKGROUND: Sever disease is a common condition in active, growing children. This condition presents as pain in the heel and is thought to be an overuse condition of the calcaneal apophysis. There are currently no defined radiographic diagnostic criteria for evaluation of Sever disease, with radiographs generally showing normal appearance of the calcaneal apophysis. A better understanding of the relationship of Sever disease and skeletal maturity may allow for improved interpretation of radiographs when trying to diagnose this condition. METHODS: ICD-9 code 732.5 was used to search for patients diagnosed with Sever disease from 2007 to 2015 at a single hospital. For every patient with Sever disease with available calcaneal imaging within 40 days of diagnosis, heel x-rays were staged for calcaneal maturity score using a previously described calcaneal skeletal maturity assessment system. Controls matched by age, race, and sex were evaluated for calcaneal stage to compare with the Sever patients. RESULTS: The chart review yielded 78 patients diagnosed with Sever disease by the orthopaedic attending, 39 of which have x-rays around the time of diagnosis. Calcaneal scores averaged 2.2+/-0.8 for all patients, 2.1+/-0.9 for male individuals, and 2.3+/-0.8 for female individuals. The average age for male individuals was 10.4+/-1.9 years and for female individuals, 9.2+/-2.2 years. The ages of diagnosis were similar for patients with and without x-rays. Twenty-two of 39 patients with Sever disease were calcaneal stage 2, and 37 of 39 were stages 1, 2, or 3. We calculated the absolute difference from stage 2 for the Sever and control groups. Mean difference from stage 2 was 0.51+/-0.68 for the Sever patients and 0.95+/-0.79 for control patients (P=0.01). CONCLUSION: Sever disease occurs in a very narrow range of skeletal maturity, as measured by the calcaneal skeletal maturity assessment system and our observations with chronological age. When compared with age-matched and race-matched controls, stage 2 was seen more frequently in the Sever patients. If a child is not within calcaneal stages 1, 2, or 3, then a different diagnosis should be considered. LEVEL OF EVIDENCE: Level III retrospective case-control study. PMID- 29419706 TI - Rehabilitation Reduced Readmission and Mortality Risks in Patients With Stroke or Transient Ischemic Attack: A Population-based Study. AB - BACKGROUND: It remains unclear whether rehabilitation has an impact on reducing the long-term risk of mortality or readmission following stroke or transient ischemic attack (TIA). OBJECTIVES: To investigate the association between the dosage and continuation of rehabilitation and the risk of outcome events (OEs) after stroke or TIA. RESEARCH DESIGN: A retrospective cohort study using Taiwan's National Health Insurance database. SUBJECTS: In total, 4594 patients admitted with first-ever acute stroke or TIA were followed-up for 32 months. MEASURES: The occurrence of 3 OEs: (1) vascular readmissions/all-cause mortality [vascular event (VE)], (2) all-cause readmissions/mortality (OE1), and (3) all-cause mortality (OE2), in model 1: none, low-intensity, and high-intensity rehabilitation; and model 2: inpatient plus/or outpatient rehabilitation. RESULTS: Comparing with patients without rehabilitation, in model 1, patients receiving low-intensity rehabilitation had a lower risk of VE [Hazard ratio (HR), 0.77; 95% CI, 0.68-0.87] and OE1 (HR, 0.77; CI, 0.71-0.84), but not OE2 (HR, 0.91; CI, 0.77-1.07). Patients receiving high-intensity rehabilitation had lower risks of all VE (HR, 0.68; CI, 0.58-0.79), OE1 (HR, 0.79; CI, 0.71-0.88), and OE2 (HR, 0.56; CI, 0.44-0.71). In model 2, patients receiving inpatient plus outpatient rehabilitation had a lowest risk of VE (HR, 0.55; CI, 0.47-0.65), OE1 (HR, 0.65; CI, 0.58-0.72), and OE2 (HR, 0.45; CI, 0.35-0.59). Sensitivity analysis with TIA excluded rendered the similar trend. Subgroup analyses found that the positive effect was not demonstrated in hemorrhagic stroke patients. CONCLUSIONS: Rehabilitation use was associated with reduction of readmissions/mortality risks following stroke or TIA. The optimal intensity and duration of rehabilitation and the discrepancy shown in hemorrhagic stroke need further clarification. PMID- 29419708 TI - Intravenous Calcium-/Zinc-Diethylene Triamine Penta-Acetic Acid in Patients With Presumed Gadolinium Deposition Disease: A Preliminary Report on 25 Patients. AB - OBJECTIVES: The aim of this study was to report the use of intravenous calcium (Ca)-/zinc (Zn)-diethylene triamine penta-acetic acid (DTPA) for the treatment of 25 symptomatic patients diagnosed with gadolinium deposition disease (GDD). MATERIALS AND METHODS: Written informed consent was obtained. Twenty-five patients (18 women; mean age, 46.8 +/- 15.3 years) with a diagnosis of GDD were included. All patients had received at least 1 administration of a gadolinium (Gd)-based contrast agent. Patients received 3 treatment sessions with Ca-/Zn DTPA, 15 with treatments spaced 1 month apart, and 10 with treatments spaced 1 week apart. In all cases, every treatment consisted of an application of Ca-DTPA and Zn-DTPA separated by 24 hours. Measurements of 24-hour urine Gd content before dosing and on the first and second days of therapy were performed. Symptomatic improvement of patients was determined by use of a 10-point scale of patient symptoms. Serum electrolytes were quantified. RESULTS: Gadolinium content increased in the urine, with an overall mean of 30.3-fold increase in the monthly regimen (P < 0.001) and 12.9-fold in the weekly regimen (P < 0.001). Eleven patients experienced transient worsening of at least some of their symptoms, termed a "flare-up" phenomenon, in most of whom symptoms improved or receded. Overall, symptoms improved in 13 patients, unchanged in 10, and worse in 2. Significant clinical improvement was present for headache, brain fog, and bone pain for the monthly regimen and arm pain and leg pain for the weekly regimen. There were no significant changes in major serum electrolytes. CONCLUSIONS: Three courses of intravenous Ca-/Zn-DTPA therapy results in significantly increased urine content of Gd after treatment and moderate symptomatic improvement. PMID- 29419707 TI - Assessing Variation in Implantable Cardioverter Defibrillator Therapy Guideline Adherence With Physician and Hospital Patient-sharing Networks. AB - BACKGROUND: Implantable cardioverter defibrillator (ICD) therapy is used for primary prevention of death among people with heart failure, and new evidence in 2005 on its effectiveness changed practice guidelines in the United States. OBJECTIVES: The objective of this study is to examine how the connectedness of physicians and hospitals, measured using network analysis, relates to guideline consistent ICD implantation. RESEARCH DESIGN: We constructed physician and hospital networks for cardiovascular disease. Physicians were linked if they shared cardiovascular disease patients; these links were aggregated by hospital affiliation to construct a hospital network. SUBJECTS: Medicare beneficiaries who underwent ICD therapy for primary prevention from 2007 to 2011. MEASURES: The clinical outcome of interest was guideline-consistent ICD implantation, calculated using the National Cardiovascular Data Registry. The exposure variables of interest were the network measures of the ICD surgeon, the referring hospital, and the hospital where the ICD surgery occurred. RESULTS: We focused on patients who were referred between hospitals for ICD implantation because they were more likely influenced by the hospital network (n=28,179). Patients were less likely to meet guidelines if their referring hospital had more connections to other hospitals (OR, 0.49; 95% confidence interval, 0.25-0.96) and more likely to meet guidelines if their ICD surgery hospital had more connections (OR, 1.61; 95% confidence interval, 0.98-2.64). The ICD surgeon's network measures were not associated with guideline-consistent implantation. CONCLUSIONS: Associations between the hospital network measures and guideline adherence suggests new approaches to better disseminate clinical guidelines across health systems. PMID- 29419709 TI - Efficacy of a Clinic-Based Safer Sex Program for Human Immunodeficiency Virus Uninfected and Human Immunodeficiency Virus-Infected Young Black Men Who Have Sex With Men: A Randomized Controlled Trial. AB - OBJECTIVE: To test the efficacy of a single-session, clinic-based intervention designed to promote condom use among young black men who have sex with men (YBMSM). METHODS: Six hundred YBMSM were enrolled in a randomized controlled trial, using a 12-month observation period. An intent-to-treat analysis was performed, with multiple imputation for missing data. RESULTS: Compared with the reference group, human immunodeficiency virus (HIV)-infected men in the intervention group had 64% greater odds of reporting consistent condom use for anal receptive sex over 12 months (estimated odds ratio, 1.64; 95% confidence interval, 1.23-2.17, P = 0.001). Also, compared with the reference group, HIV uninfected men in the intervention group had more than twice the odds of reporting consistent condom use for anal receptive sex over 12 months (estimated odds ratio, 2.14; 95% confidence interval, 1.74-2.63, P < 0.001). Significant intervention effects relative to incident sexually transmitted diseases were not observed. CONCLUSIONS: A single-session, clinic-based, intervention may help protect HIV-uninfected YBMSM against HIV acquisition and HIV-infected YBMSM from transmitting the virus to insertive partners. PMID- 29419710 TI - Screening for Chlamydia trachomatis and Neisseria gonorrhoeae Infections in Men Who Have Sex With Men: Diagnostic Accuracy of Nucleic Acid Amplification Test on Pooled Urine, Anorectal, and Pharyngeal Specimens. AB - Neisseria gonorrhoeae and Chlamydia trachomatis screening was performed in a cohort of 100 men who have sex with men. A nucleic acid amplification test on a pooled sample of first-pass urine, pharyngeal, and anorectal specimens was compared with results on nonpooled samples. Despite an excellent agreement (Cohen kappa, 0.932), pooling specimens reduced test sensitivity to 89.5%. PMID- 29419711 TI - Erratum: Assessing the Performance of Three HIV Incidence Risk Scores in a Cohort of Black and White MSM in the South. PMID- 29419712 TI - TO THE EDITOR. PMID- 29419713 TI - Exploration of the Inter-Relationships Between Obesity, Physical Inactivity, Inflammation, and Low Back Pain. AB - STUDY DESIGN: Retrospective analysis wherein 103 patients were considered, and 76 patients were included: 49 were classified as chronic non-specific low back pain (CNSLBP) (Study group) and 27 had identifiable cases of specific chronic low back pain (LBP) (Control group). OBJECTIVE: Elucidate markers of systemic inflammation in patients with CNSLBP. SUMMARY OF BACKGROUND DATA: Mechanisms of LBP are poorly understood. Pro-inflammatory cytokines are increased in obesity and involved with pain modulation; we previously proposed a theoretical model of their mediating role in LBP. METHODS: Demographic information was acquired via questionnaire, chart review, and blood test data. Univariate analysis identified factors associated with CNSLBP and markers of systemic inflammation. A receiver operating curve and Youden Index were used to select optimal cut-off points for elevated C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Multivariable logistic regression analysis calculated the adjusted strength of relationship between factors that were proposed in our theoretical model for CNSLBP. RESULTS: Unadjusted CRP was significantly correlated with ESR (R = 0.63, P < 0.0001) and body mass index (BMI) (R = 0.38, P = 0.0015). Physically inactive patients had significantly higher CRP (6.1 vs. 1.2, P = 0.0050). ESR was significantly correlated with number of comorbidities (R = 0.34, P = 0.0047), BMI (R = 0.38, P = 0.0014), and age (R = 0.36, P = 0.0026). Physically inactive patients (10.4 vs. 3.6, P = 0.0001) and females (11.2 vs. 6.4, P = 0.0422) had significantly higher ESR. Adjusted analyses indicated significant relationships between physical inactivity and markers of systemic inflammation (adjusted odds ratios for ESR and CRP: 15.9, P = 0.0380; 15.2, P = 0.0272, respectively), and between elevated CRP and CNSLBP (adjusted odds ratio: 8.0, P = 0.0126). CONCLUSION: Systemic inflammation may act as a mediator for physical inactivity and obesity in the pathogenesis of CNSLBP. LEVEL OF EVIDENCE: 2. PMID- 29419714 TI - The Impact of Comorbid Mental Health Disorders on Complications Following Adult Spinal Deformity Surgery With Minimum 2-Year Surveillance. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To compare long-term outcomes between patients with and without mental health comorbidities who are undergoing surgery for adult spinal deformity (ASD). SUMMARY OF BACKGROUND DATA: Recent literature reveals that one in three patients admitted for surgical treatment for ASD has comorbid mental health disorder. Currently, impacts of baseline mental health status on long-term outcomes following ASD surgery have not been thoroughly investigated. METHODS: Patients admitted from 2009 to 2013 with diagnoses of ASD who underwent more than or equal to 4-level thoracolumbar fusion with minimum 2-year follow-up were retrospectively reviewed using New York State's Statewide Planning and Research Cooperative System (SPARCS). Patients were stratified by fusion length (short: 4-8-level; long: >=9 level). Patients with comorbid mental health disorder (MHD) at time of admission were selected for analysis (MHD) and compared against those without MHD (no-MHD). Univariate analysis compared demographics, complications, readmissions, and revisions between cohorts for each fusion length. Multivariate binary logistic regression models identified independent predictors of outcomes (covariates: fusion length, age, female sex, and Deyo score). RESULTS: Six thousand twenty patients (MHD: n = 1631; no-MHD: n = 4389) met inclusion criteria. Mental health diagnoses included disorders of depression (59.0%), sleep (28.0%), anxiety (24.0%), and stress (2.3%). At 2-year follow-up, MHD patients with short fusion had significantly higher complication rates (P = 0.001). MHD patients with short or long fusion also had significantly higher rates of any readmission and revision (all P <= 0.002). Regression modeling revealed that comorbid MHD was a significant predictor of any complication (odds ratio [OR]: 1.17, P = 0.01) and readmission (OR: 1.32, P < 0.001). MHD was the strongest predictor of any revision (OR: 1.56, P < 0.001). Long fusion most strongly predicted any complication (OR: 1.87, P < 0.001). CONCLUSION: ASD patients with comorbid depressive, sleep, anxiety, and stress disorders were more likely to experience surgical complications and revision at minimum of 2 years following spinal fusion surgery. Proper patient counseling and psychological screening/support is recommended to complement ASD treatment. LEVEL OF EVIDENCE: 3. PMID- 29419715 TI - Spine Trauma From Personal Watercraft Usage. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To identify patient characteristics and associated injuries in those sustaining a spine fracture from personal watercraft (PWC) usage. SUMMARY OF BACKGROUND DATA: There are few studies regarding PWC use and injuries, and even more scarce are studies evaluating PWC usage and spine injuries. Identifying high-risk actions and individuals can help to effectively treat them, reduce mortality, and possibly avoid certain spine fractures. METHODS: Retrospective analysis of 142 patients admitted from the emergency department with PWC-related injuries at a single level I trauma center from January 1, 2004 to May 1, 2017. Twenty-six (18.3%) sustained a spine fracture, totaling 71 fractures. Statistical analysis was used to investigate the patient characteristics, specific mechanisms of injury, injury severity score (ISS), and associated injuries. Patients expiring (12) had incomplete evaluations and were excluded from most reported results. RESULTS: Spine fractures were not associated with age, race, or sex, but were associated with a higher ISS, intensive care unit length, in-patient length of stay, cerebral injury, and abdominal/genitourinary (GU) injury. There were 8 cervical fractures, 22 thoracic fractures, 33 lumbar, and 8 sacral fractures. Axial load injuries were associated with vertebral body fractures and specifically burst fractures. Being a driver or passenger did not influence likelihood of a spine fracture, but did correlate with abdominal/GU injury. Five (19.2%) of patients with spine fractures required eight spine surgeries during admission. Mortality was associated with females, severe systemic injuries (ISS >= 15), direct collision mechanism of injury, and the spring season. CONCLUSION: PWC usage may result in spine fractures with a moderate percentage requiring orthopedic surgery. Additional studies should examine how hull or seat modifications can lessen the risk of axial loads leading to spine fractures. PWC patients with spine fractures should also be evaluated for abdominal/GU and cerebral injuries at presentation. LEVEL OF EVIDENCE: 4. PMID- 29419716 TI - Authorship Trends in Spine Publications From 2000 to 2015. AB - STUDY DESIGN: Literature review. OBJECTIVE: To examine changes in authorship characteristics for Spine publications from the year 2000 to 2015. SUMMARY OF BACKGROUND DATA: Scientific publications are considered an indication of academic achievement for physicians. Recently, authorship trends have been investigated; however, limited information is available on this topic within spine-specific literature. METHODS: Original research articles published in Spine in the years 2000, 2005, 2010, and 2015 were evaluated. Authorship characteristics were collected for each article, including the number of authors and institutions per publication, first and last authors' sex, publication origin, and highest degree held by the first and last author. Trends over time were analyzed using numeric and visual descriptive analyses including percentages, means, standard deviations, and graphs. RESULTS: An average of 506 articles per year was published in Spine during the years 2000, 2005, 2010, and 2015. The number of articles written by 10 or more authors increased during this time (0.9%-14.4%). There was a substantial increase in the number of multiple institutional affiliations (33.6%-68.7%) and articles originating from outside North America (47.6%-55.7%) from 2000 to 2015. The percentage of first authors with bachelor's degrees was higher in 2015 (6.6%) as compared to 2000 (1.4%), and more last authors were identified as MD/PhDs in 2015 (19.2%) than in 2000 (10.0%). Similar female representation was noted for first and last authorship for all years evaluated. CONCLUSION: The results of this study demonstrate increases in authors per article published in Spine from 2000 to 2015. In addition, first authors were more likely to hold bachelor's degrees over time. This may be attributed to increasing competition in spine-related fields, necessitating earlier research exposure to aid in academic achievement. Interestingly, the percentage of female authorship has not changed significantly over time, in contrast with much of the previous literature. LEVEL OF EVIDENCE: 2. PMID- 29419717 TI - The Efficacy of Brace Treatment for Thoracolumbar Kyphosis in Patients With Achondroplasia. AB - STUDY DESIGN: A retrospective study. OBJECTIVES: The aim of this study was to evaluate the outcome of brace treatment in the correction of thoracolumbar kyphosis (TLK) for patients with achondroplasia and to determine the factors associated with bracing efficacy. SUMMARY OF BACKGROUND DATA: Brace treatment has been used to correct TLK in patients with achondroplasia. However, there was a paucity of knowledge concerning its effectiveness. METHODS: A total of 33 achondroplasic patients treated by bracing were included in this study. Radiographic parameters including TLK, lumbar lordosis, curve magnitude, apical vertebral translation (AVT), percentage of apical vertebral wedging, pelvic tilt (PT), and pelvic incidence were recorded for each patient at the visit. Comparison of these parameters between the initial visit and the final visit was performed using the Student t test. Factors associated with the correction of TLK were evaluated using the logistic regression analysis. RESULTS: The mean age at presentation was 27.5 +/- 13.4 months. The mean period of treatment was 32.2 +/- 15.7 months, and the mean period of follow-up was 25.7 +/- 11.3 months. At the initial visit, the mean value of TLK and the percentage of apical vertebral wedging were 41.7 +/- 15.4 degrees and 61.4% +/- 16.2%, respectively. At the final visit, the TLK and apical vertebral wedging were remarkably reduced to 29.5 +/- 20.8 degrees and 52.1% +/- 18.7%, respectively. The logistic regression analysis showed that initial TLK, AVT, percentage of apical vertebral wedging, and PT were independent factors associated with the correction of TLK. CONCLUSION: Brace treatment can effectively correct TLK and restore the morphology of apical vertebral body for patients with achondroplasia. Large TLK, severe apical vertebral wedging, presence of AVT, and low PT may be indicative of an unfavorable outcome, which should be taken into account at the initiation of bracing. LEVEL OF EVIDENCE: 4. PMID- 29419718 TI - Delayed Fatal Lumbar Artery Bleeding Following Less Invasive Posterolateral Decompression and Fusion. AB - STUDY DESIGN: A case report. OBJECTIVE: The aim of this study was to outline the potential risks of late bleeding from the segmental vessels following less invasively dorsolateral approaches to the thoracolumbar spine. SUMMARY OF BACKGROUND DATA: A low risk of major intraoperative bleeding, associated traditional dorsolateral approach to the lumbar spine is reported, but segmental arteries and great vessels may be rarely damaged. Spine surgeons who are involved with these approaches should be aware of this rare but potential dangerous vascular complication because it could be life-threatening, particularly in elderly patients with increased morbidity, and/or metastatic disease to the spine. METHODS: A 76-year-old white woman with a comminuted osteoporotic fracture of the L1-vertebrae with spinal canal encroachment underwent a corpectomy and a 360 degrees fusion with the use of a titanium mesh cage, through a less invasively dorsolateral approach. RESULTS: Despite the lack of visible intraoperative bleeding and uneventful postoperative period, the patient died on the seventh postoperative day as a result of massive bleeding from a segmental artery at the level of L3 vertebrae body, two levels below our intervention area. CONCLUSION: This article describes a rare complication of delayed and fatal bleeding of the segmental L3 left vertebral artery following less invasively L1 corpectomy, mesh cage insertion, and pedicle screw fixation in a elderly female patient with history of two malignancies. Although injury to large vessels must always be prevented during these procedures, an injury to the segmental vessels occurs more frequently. The dorsolateral approach and other retroperitoneal approaches to the thoracolumbar region are established methods for the surgical stabilization of comminuted vertebral body fractures, especially on the hands of experienced spine surgeons. Great care should be given postoperatively for signs of bleeding and hematoma and the surgeon should be aware for these life threatening complications. LEVEL OF EVIDENCE: 5. PMID- 29419719 TI - Incidence, Risk Factors, and Evolution of Proximal Junctional Kyphosis After Posterior Hemivertebra Resection and Short Fusion in Young Children With Congenital Scoliosis. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To investigate the incidence, risk factors, and evolution of proximal junctional kyphosis (PJK) in young children who underwent posterior hemivertebra resection and short fusion. SUMMARY OF BACKGROUND DATA: PJK is an undesired, but common complication following posterior spinal fusion. However, there is a paucity of data on PJK in young children after posterior hemivertebra resection and short fusion. METHODS: This study included 189 children who had undergone posterior hemivertebra resection and short fusion (<=4 vertebra) from January 2008 and May 2015 at a single institution. Medical records were reviewed and radiographic assessments were made preoperatively and throughout the follow-up period. Risk factors for PJK were evaluated by correlation analysis and logistic regression analysis. RESULTS: The mean age at surgery was 4.5 years (range, 3-10 yr) and the average follow-up was 48.4 months (range, 24-87 mo). Twenty-two (11.6%) patients experienced PJK. PJK was identified within 6 months after surgery in 21 cases (95%), and the most common type was ligamentous failure. In comparison with the non-PJK group, the PJK group had greater preoperative segmental kyphosis (26.9 degrees vs. 16.7 degrees , P < 0.01), longer fusion levels (3.4 vs. 2.5, P < 0.01), and larger postoperative sagittal vertical axis (SVA; 18.9 vs. 8.6 mm, P < 0.01). Preoperative segmental kyphosis >30 degrees (odds ratio, 4.426), and postoperative SVA of more than 20 mm (odds ratio, 3.580) were identified as independent risk factors for PJK. In PJK group, the average proximal junctional angle increased from 4.9 degrees to 18.5 degrees at 6 months postoperatively, but significantly decreased to 14.8 degrees at final follow-up. Eleven patient received brace treatment, and no patients required revision surgery. CONCLUSION: Despite the incidence of PJK in 11.6% of young children undergoing posterior hemivertebra resection and short fusion, no significant deterioration of proximal junctional angle were found till the last follow-up. Its risk factors include preoperative segmental kyphosis, a larger postoperative SVA and ligamentous failure. Early detection and active management may be helpful for minimizing the progression of PJK. LEVEL OF EVIDENCE: 3. PMID- 29419720 TI - Minimally Invasive Surgery for Neuromuscular Scoliosis: Results and Complications in a Series of One Hundred Patients. AB - STUDY DESIGN: A retrospective review. OBJECTIVE: To report the results of an alternative technique using a minimally invasive fusionless surgery. The originality is based on the progressive correction of the deformities with proximal and distal fixation and on the reliability of the pelvic fixation using iliosacral screws on osteoporotic bones. SUMMARY OF BACKGROUND DATA: Spinal deformities are common in neuromuscular diseases. Conventional treatment involves bracing, followed by spinal instrumented fusion. Growing rod techniques are increasingly advocated but have a high rate of complications. METHODS: The technique relies on a bilateral double rod sliding construct anchored proximally by four hooks claws and distally to the pelvis by iliosacral screws through a minimally invasive approach. Hundred patients with neuromuscular scoliosis underwent the same fusionless surgery extended from T1 to the pelvis. The average age at initial surgery was 11 + 6 years. Diagnoses included cerebral palsy (61), spinal muscular atrophy (22), muscular dystrophy (10), and other neurological etiologies (7). Cobb angle and pelvic obliquity were measured before and after initial surgery, and at final follow-up. Complications were reviewed. RESULTS: At latest follow-up 3 + 9 years (range 2 yr-6 + 3 yr), the mean Cobb angle improved from 89 degrees to 35 degrees which corresponds to 61% correction. Mean pelvic obliquity improved from 29 degrees to 5 degrees , which corresponds to 83% correction. Mean T1-S1 length increased from 30.02 to 37.28 cm. Mean preoperative hyper kyphosis was reduced from 68.44 degrees to 33.29 degrees . Complications occurred in 26 patients including mechanical complications (12) and wound infections (16). No arthrodesis was required at last follow-up. CONCLUSION: This original fusionless technique is safe and effective, preserving spinal and thoracic growth. It provides a significant correction of spinal deformities and pelvic obliquity with a reduced complications rate. The strength and stability of this modular construct over time allow the avoidance of final arthrodesis. LEVEL OF EVIDENCE: 4. PMID- 29419721 TI - Intersurgeon Cost Variability in Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: Retrospective review of prospective patient outcomes and cost data. OBJECTIVE: To analyze the contribution of surgeon-specific variability in cost and patient-reported outcomes (PROs) to overall variability in anterior cervical discectomy and fusion (ACDF), whereas adjusting for patient comorbidities. SUMMARY OF BACKGROUND DATA: Cost reduction in surgical care has received increased attention. Patient factors contributing to cost variability in ACDF have been described; however, intersurgeon cost and outcome variability has received less attention in the literature. METHODS: Adult patients undergoing elective primary ACDF by five different surgeons were analyzed from a prospective registry database. Direct and indirect 90-day costs were compared across each surgeon, along with PROs. Predicted costs were calculated based on patient co morbidities, and an "observed versus expected" cost differential was measured for each surgeon; this O/E cost ratio was then compared with PROs. RESULTS: A total of 431 patients were included in the analysis. There were no differences in comorbidities, age, smoking status, or narcotic use. There was significant variation between surgeons in total 90-day costs, as well as variation between each surgeon's observed versus expected cost ratio. Despite these surgeon specific cost variations, there were no differences in PROs across the participating surgeons. CONCLUSION: Intersurgeon cost variation in elective ACDF persists even after adjusting for patient comorbidities. There was no apparent correlation between increased surgeon-specific costs and 90-day PROs. These findings show there is opportunity for improvement in inter-surgeon cost variation without compromise in PROs. LEVEL OF EVIDENCE: 3. PMID- 29419722 TI - Detection of Drug-Exposed Newborns. AB - Maternal substance abuse during pregnancy is a growing problem with major public health and legal concerns. In utero substance exposure may adversely affect neonatal development; pregnancy outcome; and the long-term behavioral, cognitive, and developmental abilities of the child. Also, serious legal implications are associated with substance abuse during pregnancy, including charges of child abuse and neglect that may result in the removal of the neonate from parental care and loss of custodial rights. Timely detection of in utero drug exposure is necessary for early identification and effective management of exposed newborns. Accurate identification of drug-exposed newborns relies on maternal history; clinical presentation of the newborn; and laboratory testing of biological maternal matrices (ie, urine, blood, oral fluid, sweat, hair, and breast milk), neonatal matrices (ie, urine, meconium, hair, and umbilical cord blood and tissue), and/or matrices from both the mother and neonate (ie, placenta and amniotic fluid). Evaluation of biological matrices can account for in utero exposure at various stages of gestation and approximate the period (recent versus chronic use) of substance exposure. Each matrix has its own unique advantages and limitations in terms of ease of collection, the window of gestational exposure represented, and sensitivity for different parent drug analytes and metabolites, which must be carefully considered for accurate interpretation of results. Analytical approaches to sample preparation and analysis vary based on the complexity of these biological matrices. Immunoassays are routinely used for screening, and chromatographic separation coupled to mass spectrometry detection method is commonly used for definitive (confirmatory) testing. Some laboratories use a single technology for all testing. This review provides a discussion on approaches used to detect drug-exposed newborns, biological specimens that have been studied to identify and characterize drug exposures, example analytical methods for meconium and umbilical cord tissue as well as considerations surrounding the interpretation of results. A possible algorithm for testing is also proposed. PMID- 29419723 TI - Development and Validation of a Bioanalytical Method to Quantitate Enzalutamide and its Active Metabolite N-Desmethylenzalutamide in Human Plasma: Application to Clinical Management of Patients With Metastatic Castration-Resistant Prostate Cancer. AB - BACKGROUND: Enzalutamide is a potent androgen-signaling receptor inhibitor and is licensed for the treatment of metastatic castration-resistant prostate cancer. N desmethylenzalutamide is the active metabolite of enzalutamide. A method to quantitate enzalutamide and its active metabolite was developed and validated according to the European Medicine Agency guidelines. METHODS: Enzalutamide and N desmethylenzalutamide were extracted by protein precipitation, separated on a C18 column with gradient elution and analyzed with tandem quadrupole mass spectrometry in positive ion mode. A stable deuterated isotope (D6-enzalutamide) was used as an internal standard. The method was tested and stability was studied in real-life patients with metastatic castration-resistant prostate cancer patients treated with enzalutamide. RESULTS: The calibration curve covered the range of 500-50,000 ng/mL. Within- and between-day precisions were <8% and accuracies were within 108% for both enzalutamide and N-desmethylenzalutamide. Precisions for lower limit of quantification level were <10% and accuracies within 116% for enzalutamide and N-desmethylenzalutamide. Enzalutamide and N desmethylenzalutamide stability was proven for 24 hours for whole blood at ambient temperature and 23 days for plasma at both ambient temperature and 2-8 degrees C. Long-term patient plasma stability was shown for 14 months at -40 degrees C. CONCLUSIONS: This bioanalytical method was successfully validated and applied to determine plasma concentrations of enzalutamide and N desmethylenzalutamide in clinical studies and in routine patient care. PMID- 29419725 TI - Effect of Facility Ownership on Utilization of Arthroscopic Shoulder Surgery. AB - INTRODUCTION: We examined practice patterns and surgical indications in the management of common shoulder procedures by surgeons practicing at physician owned facilities. METHODS: This study was a retrospective analysis of 501 patients who underwent arthroscopic shoulder procedures performed by five surgeons in our practice at one of five facilities during an 18-month period. Two of the facilities were physician-owned, and three of the five surgeons were shareholders. Demographics, insurance status, symptom duration, time from injury/symptom onset to the decision to perform surgery (at which time surgical consent is obtained), and time to schedule surgery were studied to determine the influence of facility type and physician shareholder status. RESULTS: Median duration of symptoms before surgery was significantly shorter in workers' compensation patients than in non-workers' compensation patients (47% less; P < 0.0001) and in men than in women (31% less; P < 0.001), but was not influenced by shareholder status or facility ownership (P > 0.05). Time between presentation and surgical consent was not influenced by facility ownership (P = 0.39) or shareholder status (P = 0.50). Time from consent to procedure was 13% faster in physician-owned facilities than in non-physician-owned facilities (P = 0.03) and 35% slower with shareholder physicians than with nonshareholder physicians (P < 0.0001). DISCUSSION: The role of physician investment in private healthcare facilities has caused considerable debate in the orthopaedic surgery field. To our knowledge, this study is the first to examine the effects of shareholder status and facility ownership on surgeons' practice patterns, surgical timing, and measures of nonsurgical treatment before shoulder surgery. CONCLUSIONS: Neither shareholder status nor facility ownership characteristics influenced the speed with which surgeons determined that shoulder surgery was indicated or surgeons' use of preoperative nonsurgical treatment. After the need for surgery was determined, patients underwent surgery sooner at physician-owned facilities than at non-physician-owned facilities and with nonshareholder physicians than with shareholder physicians. LEVEL OF EVIDENCE: Level III. PMID- 29419724 TI - Clinical Outcomes After Reverse Shoulder Arthroplasty With and Without Subscapularis Repair: The Importance of Considering Glenosphere Lateralization. AB - INTRODUCTION: Recent biomechanical data suggests that repairing the subscapularis during reverse shoulder arthroplasty (RSA) can increase the force required by the posterior rotator cuff and deltoid to elevate the arm. METHODS: We retrospectively studied patients who underwent primary RSA and had baseline and minimum 2-year postoperative American Shoulder and Elbow Surgeons (ASES) shoulder scores, stratified them according to subscapularis management, then subgrouped them according to lateralization of the glenosphere component. RESULTS: Patients with subscapularis repair and a lateralized glenosphere had significantly less improvement in ASES scores than did those without lateralization (P = 0.016) and patients without subscapularis repair (P = 0.006). Individually, subscapularis management (P = 0.163) and glenosphere lateralization (P = 0.847) had no significant effect on the change in ASES score but in combination did have a significant effect on the change in ASES score (P = 0.002). DISCUSSION: The combination of subscapularis repair and glenosphere implant lateralization in RSA translates to significantly less clinical improvement. CONCLUSIONS: Patients who underwent both subscapularis repair and glenosphere lateralization had significantly less improvement in ASES scores. LEVEL OF EVIDENCE: Level III. PMID- 29419726 TI - The Effect of Door Opening on Positive Pressure and Airflow in Operating Rooms. AB - INTRODUCTION: Door openings and increased foot traffic in operating rooms (ORs) during total joint arthroplasty are thought to increase the risk of surgical site infection. METHODS: Digital manometers were used to collect pressure data during off-hours at the thresholds of both the outer door (ie, the door to the common OR hallway) and the inner substerile door, which opens to the substerile hallway, of six empty ORs used for total joint arthroplasty. Airflow patterns were visualized with smoke studies to determine whether outside air entered the ORs during single or multiple door openings. Data were analyzed using the Student t-test and one way analysis of variance. RESULTS: Positive pressure was not defeated during any door-opening event. The average time for recovery of the initial pressurization in the OR regardless of the door used was between 14 and 15 seconds (P = 0.462). No differences in the degree of room depressurization were noted between entry of personnel through the outer door, passing of a surgical tray through the outer door, and entry of personnel through the inner door (P = 0.312). Smoke studies confirmed that no contaminated outside air entered the OR with single door opening. Outside air entered the OR if two doors were open simultaneously. CONCLUSION: Single door opening does not defeat OR positive pressure, but simultaneous opening of two doors allows contaminated air to flow into the OR. OR traffic should continue to be limited during surgical procedures. OR personnel should be educated about the danger to the sterile field that can result from simultaneous door openings and should be discouraged from such activity. PMID- 29419727 TI - Identification of Differentially Methylated Sites with Weak Methylation Effects. AB - Deoxyribonucleic acid (DNA) methylation is an epigenetic alteration crucial for regulating stress responses. Identifying large-scale DNA methylation at single nucleotide resolution is made possible by whole genome bisulfite sequencing. An essential task following the generation of bisulfite sequencing data is to detect differentially methylated cytosines (DMCs) among treatments. Most statistical methods for DMC detection do not consider the dependency of methylation patterns across the genome, thus possibly inflating type I error. Furthermore, small sample sizes and weak methylation effects among different phenotype categories make it difficult for these statistical methods to accurately detect DMCs. To address these issues, the wavelet-based functional mixed model (WFMM) was introduced to detect DMCs. To further examine the performance of WFMM in detecting weak differential methylation events, we used both simulated and empirical data and compare WFMM performance to a popular DMC detection tool methylKit. Analyses of simulated data that replicated the effects of the herbicide glyphosate on DNA methylation in Arabidopsis thaliana show that WFMM results in higher sensitivity and specificity in detecting DMCs compared to methylKit, especially when the methylation differences among phenotype groups are small. Moreover, the performance of WFMM is robust with respect to small sample sizes, making it particularly attractive considering the current high costs of bisulfite sequencing. Analysis of empirical Arabidopsis thaliana data under varying glyphosate dosages, and the analysis of monozygotic (MZ) twins who have different pain sensitivities-both datasets have weak methylation effects of <1% show that WFMM can identify more relevant DMCs related to the phenotype of interest than methylKit. Differentially methylated regions (DMRs) are genomic regions with different DNA methylation status across biological samples. DMRs and DMCs are essentially the same concepts, with the only difference being how methylation information across the genome is summarized. If methylation levels are determined by grouping neighboring cytosine sites, then they are DMRs; if methylation levels are calculated based on single cytosines, they are DMCs. PMID- 29419729 TI - Effect of Air Abrasion on the Number of Particles Embedded in Zironia. AB - : Background: Determination of the number of abrasive particles embedded in the zirconia surface after variable parameters of treatment. METHODS: One hundred thirty cylindrical disks made from zirconia were divided into 7 groups (n = 10): one control and six test groups treated by air abrasion using Al2O3 or SiC with grain sizes: 60, 110, 250 MUm with a working pressure of 0.2 or 0.35 MPa. The SEM images were observed in BSE and BSE 3D. The chemical composition was determined by means of X-ray microanalysis with EDS. The surface was determined by quantitative metallography methods. Surfaces (%) depending on the particle type were compared using the Mann-Whitney test, depending on the pressure were compared using the Mann-Whitney test, and depending on the grain size were compared using the Kruskal-Wallis test as well as the Jonckheere-Terpstra trend test as well as the Dunn post-hoc testA probability. Value of p < 0.05 was deemed significant, while a p-value of p < 0.01 was regarded as highly significant. RESULTS: After blasting aluminium and silicon particles were embedded in zirconia surface. When blasted with Al2O3, the average amount of embedded grain was higher, while in the case of SiC. Highly significant differences were observed in the surface share of the abrasive depending on the grain size. At a pressure of 0.20 MPa the quantity of embedded abrasive amounted to 6.63, and at the pressure of 0.35 MPa rose to 7.17. Most particles of abrasive material became embedded when sandblasting with grain size 60 MUm grain. No significant difference was observed in the surface share of the abrasive depending on the pressure. CONCLUSION: The quantity of embedded abrasive depends on its type and grain size, and the pressure applied. PMID- 29419728 TI - DNA Methylation and All-Cause Mortality in Middle-Aged and Elderly Danish Twins. AB - Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55-90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate ( FDR ) < 0.05 ), of which 24 had an association p-value below 10 - 7 . This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35%, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross validation, but did not perform very well in independent samples. PMID- 29419730 TI - Influential Effects of Intrinsic-Extrinsic Incentive Factors on Management Performance in New Energy Enterprises. AB - Background: New energy has become a key trend for global energy industry development. Talent plays a very critical role in the enhancement of new energy enterprise competitiveness. As a key component of talent, managers have been attracting more and more attention. The increase in job performance relies on, to a certain extent, incentive mechanism. Based on the Two-factor Theory, differences in influences and effects of different incentives on management performance have been checked in this paper from an empirical perspective. Methods: This paper selects the middle and low level managers in new energy enterprises as research samples and classifies the managers' performance into task performance, contextual performance and innovation performance. It uses manager performance questionnaires and intrinsic-extrinsic incentive factor questionnaires to investigate and study the effects and then uses Amos software to analyze the inner link between the intrinsic-extrinsic incentives and job performance. Results: Extrinsic incentives affect task performance and innovation performance positively. Intrinsic incentives impose active significant effects on task performance, contextual performance, and innovation performance. The intrinsic incentive plays a more important role than the extrinsic incentive. Conclusions: Both the intrinsic-extrinsic incentives affect manager performance positively and the intrinsic incentive plays a more important role than the extrinsic incentive. Several suggestions to management should be given based on these results. PMID- 29419731 TI - Inflammatory Alteration of Human T Cells Exposed Continuously to Asbestos. AB - Asbestos is a known carcinogen and exposure can lead to lung cancer and malignant mesothelioma. To examine the effects of asbestos fibers on human immune cells, the human T cell leukemia/lymphoma virus (HTLV)-1 immortalized human T cell line MT-2 was employed. Following continuous exposure to asbestos fibers for more than eight months, MT-2 sublines showed acquisition of resistance to asbestos-induced apoptosis with decreased death signals and increased surviving signals. These sublines showed various characteristics that suggested a reduction in anti-tumor immunity. On the other hand, inflammatory changes such as expression of MMP7, CXCR5, CXCL13 and CD44 was found to be markedly higher in sublines continuously exposed to asbestos compared with original MT-2 cells. All of these molecules contribute to lung inflammation, T and B cell interactions and connections between mesothelial cells and T cells. Thus, further investigation focusing on these molecules may shed light on the role of chronic inflammation caused by asbestos exposure and the occurrence of malignant mesothelioma. Finally, regarding peripheral T cells from healthy donors (HD) and asbestos-exposed patients with pleural plaque (PP) or malignant pleural mesothelioma (MPM), following stimulation of CD4+ T cells, T cells from MPM patients showed reduced potential of interferon (IFN)-gamma expression. Moreover, levels of interleukin (IL)-6, one of the most important cytokines in chronic inflammation, in cultured supernatants were higher in PP and MPM patients compared with HD. Overall, asbestos-induced chronic inflammation in the lung as well as the pleural cavity may facilitate the onset of asbestos-induced cancers due to alterations in the interactions among fibers, immune cells such as T and B cells and macrophages, and mesothelial and lung epithelial cells. Further investigations regarding chronic inflammation caused by asbestos fibers may assist in identifying molecular targets for preventive and therapeutic strategies related to the effects of asbestos exposure. PMID- 29419732 TI - Dissection of the Mechanism for Compatible and Incompatible Graft Combinations of Citrus grandis (L.) Osbeck ('Hongmian Miyou'). AB - 'Hongmian miyou' (Citrus grandis L. Osbeck) is mutated from 'Guanxi miyou', with a different spongy layer coloration. Trifoliate orange (Poncirus trifoliata) is widely used as rootstocks in 'Guanxi miyou' grafting, whereas 'Hongmian miyou' is incompatible with available trifoliate orange rootstocks. To explore the reasons for the etiolation of leaves of 'Hongmian miyou'/trifoliate orange, anatomical differences among different graft unions, gene expression profiles, and auxin levels of scion were investigated in this study. A histological assay indicated that there was no significant difference in anatomical structure between the compatible and incompatible combinations. A total of 1950 significant differentially-expressed genes (DEGs) were identified and analyzed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that genes involved in carbohydrate metabolism, energy metabolism, amino acid metabolism, and plant hormone signal transduction were significantly enriched. Moreover, the expression of nine genes in the auxin pathway were upregulated and three were downregulated in compatible combinations compared with those in the incompatible group. Further experiments verified that indole-3-acetic acid (IAA) content increases in the compatible graft combination, which suggests that IAA might promote graft compatibility. PMID- 29419733 TI - High Add Valued Application of Turpentine in Crop Production through Structural Modification and QSAR Analysis. AB - Turpentine is a volatile component of resin, which is an abundant forest resource in Southern China. As one of the most important components, the integrated application of beta-pinene has been studied. The broad-spectrum evaluation of beta-pinene and its analogues has, therefore, been necessary. In an attempt to expand the scope of agro-activity trials, the preparation and the evaluation of the herbicidal activity of a series of beta-pinene analogues against three agricultural herbs were carried out. In accordance with the overall herbicidal activity, it is noteworthy that compounds 6k, 6l, and 6m demonstrated extreme activity with IC50 values of 0.065, 0.065, and 0.052 mol active ingredients/hectare against E. crus-galli. The preliminary structure-activity relationship (SAR) was analyzed and the compounds with the appropriate volatility and substituent type that had beneficial herbicidal activity were analyzed. Simultaneously, the quantitative structure-activity relationship (QSAR) model was built and the most important structural features were indicated, which was, to a certain extent, in line with the SAR study. The study aimed to study the application of the forest resource turpentine in agriculture as a potential and alternative approach for comprehensive utilization. PMID- 29419734 TI - Exploring Interventions for Sleep Disorders in Adolescent Cannabis Users. AB - This review summarizes the available literature on the intersection of adolescent cannabis use and sleep disturbances, along with interventions for adolescent cannabis users who suffer sleep impairments. Adolescents are susceptible to various sleep disorders, which are often exacerbated by the use of substances such as cannabis. The relationship between cannabis and sleep is bidirectional. Interventions to improve sleep impairments among adolescent cannabis users to date have demonstrated limited efficacy, although few studies indicating the benefits of behavioral interventions-such as Cognitive Behavior Therapy for Insomnia or Mindfulness Based Stress Reduction-appear promising in the treatment of sleep disorders, which are present for users of cannabis. Further research is necessary to elucidate the precise mechanisms by which cannabis use coexists with sleep impairments, along with effective interventions for those users who suffer sleep difficulties. PMID- 29419735 TI - Bauerenol Acetate, the Pentacyclic Triterpenoid from Tabernaemontana longipes, is an Antitrypanosomal Agent. AB - The Latin American plant Tabernaemontana longipes was studied in this work as a potential source of antiparasitic agents. The chloroform extract of T. longipes leaves was separated into several fractions, and tested for antitrypanosomal activity. One of the fractions displayed significant growth inhibitory activity against Trypanosoma brucei. The active principle in the fraction was isolated, purified, and characterized by NMR and mass spectrometry. The antitrypanosomal agent in the CHCl3 extract of T. longipes leaves is the pentacyclic triterpenoid bauerenol acetate. A metabolite profiling assay suggest that the triterpenoid influences cholesterol metabolism. The molecular target(s) of bauerenol and its acetate, like many other antiparasitic pentacyclic triterpenoids is/are unknown, but they present privileged structural scaffolds that can be explored for structure-based activity optimization studies using phenotypic assays. PMID- 29419736 TI - Crambescidin 800, Isolated from the Marine Sponge Monanchora viridis, Induces Cell Cycle Arrest and Apoptosis in Triple-Negative Breast Cancer Cells. AB - Triple negative breast cancer (TNBC) is currently the only group of breast cancers without an effective targeted therapy. Marine sponges have historically been a source of compounds with anticancer activity. In this study, we screened extracts from twenty marine sponges collected off the coast of Western Australia for cytotoxic activity against TNBC cells. One very active extract derived from the sponge Monanchora viridis was selected for bioactivity-guided fractionation. Through multiple steps of purification, we isolated a potent cytotoxic compound, which was identified as crambescidin 800 (C800). We found that C800 exhibited cytotoxic potency in a panel of breast cancer cells, of which TNBC and luminal cancer cell models were the most sensitive. In addition, C800 induced cell cycle arrest at the G2/M phase, resulting in a decline in the expression of cyclin D1, CDK4, and CDK6 in TNBC cells. This effect was associated with the inhibition of phosphorylation of Akt, NF-kappaB, and MAPK pathways, resulting in apoptosis in TNBC cells. PMID- 29419737 TI - Development of Volatile Compounds during Hydrolysis of Porcine Hemoglobin with Papain. AB - There is a growing market for the use of hydrolysates from animal side-streams for production of high-protein supplements. However, there can be issues with development of off-flavors, either due to the raw material in question or due to the hydrolysis process itself. This study examined the development of volatile compounds during hydrolysis of hemoglobin. Briefly, porcine hemoglobin was hydrolyzed by 0.5% papain for up to 5 h, and the development of volatile compounds was analyzed via gas chromatography-mass spectrometry. The results showed that there was significant development of a number of volatile compounds with time, e.g., certain Maillard reaction and lipid oxidation products, which are likely candidates for the aroma development during hydrolysis. Furthermore, it was shown that development of a number of the volatiles was due to the hydrolysis process, as these compounds were not found in a control without enzyme. PMID- 29419738 TI - Candida-Epithelial Interactions. AB - A plethora of intricate and dynamic molecular interactions occur between microbes and the epithelial cells that form the mucosal surfaces of the human body. Fungi, particularly species of Candida, are commensal members of our microbiota, continuously interacting with epithelial cells. Transient and localised perturbations to the mucosal environment can facilitate the overgrowth of fungi, causing infection. This minireview will examine the direct and indirect mechanisms by which Candida species and epithelial cells interact with each other, and explore the factors involved in the central processes of adhesion, invasion, and destruction of host mucosal surfaces. PMID- 29419739 TI - Transcytosis Involvement in Transport System and Endothelial Permeability of Vascular Leakage during Dengue Virus Infection. AB - The major role of endothelial cells is to maintain homeostasis of vascular permeability and to preserve the integrity of vascular vessels to prevent fluid leakage. Properly functioning endothelial cells promote physiological balance and stability for blood circulation and fluid components. A monolayer of endothelial cells has the ability to regulate paracellular and transcellular pathways for transport proteins, solutes, and fluid. In addition to the paracellular pathway, the transcellular pathway is another route of endothelial permeability that mediates vascular permeability under physiologic conditions. The transcellular pathway was found to be associated with an assortment of disease pathogeneses. The clinical manifestation of severe dengue infection in humans is vascular leakage and hemorrhagic diatheses. This review explores and describes the transcellular pathway, which is an alternate route of vascular permeability during dengue infection that corresponds with the pathologic finding of intact tight junction. This pathway may be the route of albumin transport that causes endothelial dysfunction during dengue virus infection. PMID- 29419740 TI - Tea Polysaccharide Prevents Colitis-Associated Carcinogenesis in Mice by Inhibiting the Proliferation and Invasion of Tumor Cells. AB - The imbalance between cell proliferation and apoptosis can lead to tumor progression, causing oncogenic transformation, abnormal cell proliferation and cell apoptosis suppression. Tea polysaccharide (TPS) is the major bioactive component in green tea, it has showed antioxidant, antitumor and anti inflammatory bioactivities. In this study, the chemoprophylaxis effects of TPS on colitis-associated colon carcinogenesis, especially the cell apoptosis activation and inhibition effects on cell proliferation and invasion were analyzed. The azoxymethane/dextran sulfate sodium (AOM/DSS) was used to induce the colorectal carcinogenesis in mice. Results showed that the tumor incidence was reduced in TPS-treated AOM/DSS mice compared to AOM/DSS mice. TUNEL staining and Ki-67 immunohistochemistry staining showed that the TPS treatment increased significantly the cell apoptosis and decreased cell proliferation among AOM/DSS mice. Furthermore, TPS reduced the expression levels of the cell cycle protein cyclin D1, matrix metalloproteinase (MMP)-2, and MMP-9. In addition, in vitro studies showed that TPS, suppressed the proliferation and invasion of the mouse colon cancer cells. Overall, our findings demonstrated that TPS could be a potential agent in the treatment and/or prevention of colon tumor, which promoted the apoptosis and suppressed the proliferation and invasion of the mouse colon cancer cells via arresting cell cycle progression. PMID- 29419741 TI - Intrinsic Properties of tRNA Molecules as Deciphered via Bayesian Network and Distribution Divergence Analysis. AB - The identity/recognition of tRNAs, in the context of aminoacyl tRNA synthetases (and other molecules), is a complex phenomenon that has major implications ranging from the origins and evolution of translation machinery and genetic code to the evolution and speciation of tRNAs themselves to human mitochondrial diseases to artificial genetic code engineering. Deciphering it via laboratory experiments, however, is difficult and necessarily time- and resource-consuming. In this study, we propose a mathematically rigorous two-pronged in silico approach to identifying and classifying tRNA positions important for tRNA identity/recognition, rooted in machine learning and information-theoretic methodology. We apply Bayesian Network modeling to elucidate the structure of intra-tRNA-molecule relationships, and distribution divergence analysis to identify meaningful inter-molecule differences between various tRNA subclasses. We illustrate the complementary application of these two approaches using tRNA examples across the three domains of life, and identify and discuss important (informative) positions therein. In summary, we deliver to the tRNA research community a novel, comprehensive methodology for identifying the specific elements of interest in various tRNA molecules, which can be followed up by the corresponding experimental work and/or high-resolution position-specific statistical analyses. PMID- 29419742 TI - Spatial Cognition and Range Use in Free-Range Laying Hens. AB - Radio-frequency identification tracking shows individual free-range laying hens vary in range use, with some never going outdoors. The range is typically more environmentally complex, requiring navigation to return to the indoor resources. Outdoor-preferring hens may have improved spatial abilities compared to indoor preferring hens. Experiment 1 tested 32 adult ISA Brown hens in a T-maze learning task that showed exclusively-indoor birds were slowest to reach the learning success criterion (p < 0.05). Experiment 2 tested 117 pullets from enriched or non-enriched early rearing treatments (1 pen replicate per treatment) in the same maze at 15-16 or 17-18 weeks. Enriched birds reached learning success criterion faster at 15-16 weeks (p < 0.05) but not at 17-18 weeks (p > 0.05), the age that coincided with the onset of lay. Enriched birds that were faster to learn the maze task showed more range visits in the first 4 weeks of range access. Enriched and non-enriched birds showed no differences in telencephalon or hippocampal volume (p > 0.05). Fear may reduce spatial abilities but further testing with more pen replicates per early rearing treatments would improve our understanding of the relationship between spatial cognitive abilities and range use. PMID- 29419743 TI - Preparation of Monoclonal Antibody for Brevetoxin 1 and Development of Ic-ELISA and Colloidal Gold Strip to Detect Brevetoxin 1. AB - Brevetoxin-1 (BTX-1), a marine toxin mostly produced by the dinoflagellatae Karenia brevis, has caused the death of marine organisms and has had numerous toxicological effects on human health. Hence, it is very necessary to develop a rapid, economical, and reliable immunoassay method for BTX-1 detection. In this study, two kinds of complete antigen were synthesized using the succinic anhydride and isobutyl chloroformate two-step methods. Conjugate BTX-1-OVA was used as an antigen for mice immunization, and BTX-1-BSA for measuring the titer of the produced antibodies. A hybridoma cell line 6C6 stably secreting monoclonal antibody (mAb) against BTX-1 was obtained by fusing SP2/0 myeloma cells with the spleen cells from the immunized mouse. The hybridoma 6C6 was injected into the abdomen of BALB/c mice to obtain ascites, and the anti-BTX-1 mAb was harvested from ascites by precipitation with caprylic acid/ammonium sulfate (CA-AS). The anti-BTX-1 mAb was identified as an IgG1 subtype, and the cross-reactivity results showed that anti-BTX-1 mAb was highly specific to BTX-1 with the affinity of 1.06 * 108 L/mol. The indirect competitive ELISA results indicated that the linear range for BTX-1 detection was 14-263 ng/mL with IC50 of 60 ng/mL, and a detection limit of 14 ng/mL. The average recovery rate from the spiked samples was 88 +/- 2% in intra-assay and 89 +/- 2% in inter-assay. The limit of detection (LOD) using the colloidal gold strip was 200 ng/mL with high specificity. Therefore, the anti-BTX-1 mAb can be used to detect BTX-1 in shellfish and other related samples. PMID- 29419745 TI - Optical Fiber Sensors Based on Fiber Ring Laser Demodulation Technology. AB - A review for optical fiber sensors based on fiber ring laser (FRL) demodulation technology is presented. The review focuses on the principles, main structures, and the sensing performances of different kinds of optical fiber sensors based on FRLs. First of all, the theory background of the sensors has been discussed. Secondly, four different types of sensors are described and compared, which includes Mach-Zehnder interferometer (MZI) typed sensors, Fabry-Perot interferometer (FPI) typed sensors, Sagnac typed sensors, and fiber Bragg grating (FBG) typed sensors. Typical studies and main properties of each type of sensors are presented. Thirdly, a comparison of different types of sensors are made. Finally, the existing problems and future research directions are pointed out and analyzed. PMID- 29419746 TI - The Impact of Excluding Food Guarding from a Standardized Behavioral Canine Assessment in Animal Shelters. AB - Many shelters euthanize or restrict adoptions for dogs that exhibit food guarding while in the animal shelter. However, previous research showed that only half the dogs exhibiting food guarding during an assessment food guard in the home. So, dogs are often misidentified as future food guarders during shelter assessments. We examined the impact of shelters omitting food guarding assessments. Nine shelters conducted a two-month baseline period of assessing for food guarding followed by a two-month investigative period during which they omitted the food guarding assessment. Dogs that guarded their food during a standardized assessment were less likely to be adopted, had a longer shelter stay, and were more likely to be euthanized. When the shelters stopped assessing for food guarding, there was no significant difference in the rate of returns of food guarding dogs, even though more dogs were adopted because fewer were identified with food guarding behavior. Additionally, the number of injuries to staff, volunteers, and adopters was low (104 incidents from a total of 14,180 dogs) and did not change when the food guarding assessment was omitted. These results support a recommendation that shelters discontinue the food guarding assessment. PMID- 29419744 TI - Extracellular Matrix Metalloproteinase Inducer EMMPRIN (CD147) in Cardiovascular Disease. AB - The receptor EMMPRIN is involved in the development and progression of cardiovascular diseases and in the pathogenesis of myocardial infarction. There are several binding partners of EMMPRIN mediating the effects of EMMPRIN in cardiovascular diseases. EMMPRIN interaction with most binding partners leads to disease progression by mediating cytokine or chemokine release, the activation of platelets and monocytes, as well as the formation of monocyte-platelet aggregates (MPAs). EMMPRIN is also involved in atherosclerosis by mediating the infiltration of pro-inflammatory cells. There is also evidence that EMMPRIN controls energy metabolism of cells and that EMMPRIN binding partners modulate intracellular glycosylation and trafficking of EMMPRIN towards the cell membrane. In this review, we systematically discuss these multifaceted roles of EMMPRIN and its interaction partners, such as Cyclophilins, in cardiovascular disease. PMID- 29419747 TI - Voluntary Physical Exercise Improves Subsequent Motor and Cognitive Impairments in a Rat Model of Parkinson's Disease. AB - BACKGROUND: Parkinson's disease (PD) is typically characterized by impairment of motor function. Gait disturbances similar to those observed in patients with PD can be observed in animals after injection of neurotoxin 6-hydroxydopamine (6 OHDA) to induce unilateral nigrostriatal dopamine depletion. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegenerative disease. METHODS: In this study, we investigated the long-term effects of voluntary running wheel exercise on gait phenotypes, depression, cognitive, rotational behaviors as well as histology in a 6-OHDA-lesioned rat model of PD. RESULTS: We observed that, when compared with the non-exercise controls, five-week voluntary exercise alleviated and postponed the 6-OHDA induced gait deficits, including a significantly improved walking speed, step/stride length, base of support and print length. In addition, we found that the non-motor functions, such as novel object recognition and forced swim test, were also ameliorated by voluntary exercise. However, the rotational behavior of the exercise group did not show significant differences when compared with the non-exercise group. CONCLUSIONS: We first analyzed the detailed spatiotemporal changes of gait pattern to investigate the potential benefits after long-term exercise in the rat model of PD, which could be useful for future objective assessment of locomotor function in PD or other neurological animal models. Furthermore, these results suggest that short-term voluntary exercise is sufficient to alleviate cognition deficits and depressive behavior in 6-OHDA lesioned rats and long-term treatment reduces the progression of motor symptoms and elevates tyrosine hydroxylase (TH), Brain-derived neurotrophic factor (BDNF), bone marrow tyrosine kinase in chromosome X (BMX) protein expression level without affecting dopaminergic (DA) neuron loss in this PD rat model. PMID- 29419748 TI - Lipid Supplement in the Cultural Condition Facilitates the Porcine iPSC Derivation through cAMP/PKA/CREB Signal Pathway. AB - Large numbers of lipids exist in the porcine oocytes and early embryos and have the positive effects on their development, suggesting that the lipids may play an important role in pluripotency establishment and maintenance in pigs. However, the effects of lipids and their metabolites, such as fatty acids on reprogramming and the pluripotency gene expression of porcine-induced pluripotent stem cells (iPSCs), are unclear. Here, we generated the porcine iPSCs that resemble the mouse embryonic stem cells (ESCs) under lipid and fatty-acid-enriched cultural conditions (supplement of AlbuMAX). These porcine iPSCs show positive for the ESCs pluripotency markers and have the differentiation abilities to all three germ layers, and importantly, have the capability of aggregation into the inner cell mass (ICM) of porcine blastocysts. We further confirmed that lipid and fatty acid enriched condition can promote the cell proliferation and improve reprogramming efficiency by elevating cAMP levels. Interestingly, this lipids supplement promotes mesenchymal-epithelial transition (MET) through the cAMP/PKA/CREB signal pathway and upregulates the E-cadherin expression during porcine somatic cell reprogramming. The lipids supplement also makes a contribution to lipid droplets accumulation in the porcine iPSCs that resemble porcine preimplantation embryos. These findings may facilitate understanding of the lipid metabolism in porcine iPSCs and lay the foundation of bona fide porcine embryonic stem cell derivation. PMID- 29419750 TI - Carotid Artery Calcification: A Digital Panoramic-Based Study. AB - OBJECTIVE: The aim of this study was to estimate the incidence of carotid artery calcification (CAC) in a sample of Lebanese population using digital panoramic radiographs. MATERIALS AND METHODS: Panoramic radiographs of 500 patients (281 females and 219 males), aged between 18 and 88 years (mean: 47.9 years), were assessed for CAC. Data collected were analyzed statistically using IBM(r) SPSS(r) for Windows version 20.0 (SPSS, Chicago, IL, USA). RESULTS: CAC were found in 34 cases (6.8%), among them, 23 females (8.18%) and 11 males (5.02%). Six of all the calcifications were on the right side, against six on the left side, and 22 on both sides. The mean age of patients affected with CAC was 60.9 years (ranging from 18 to 88 years). Chi-square test showed no statistical significance between gender and CAC, while Spearman correlation analysis showed positive low correlation with age (r = 0.179). CONCLUSION: CAC can be found on routine panoramic radiographs taken in dental clinics; dentists should automatically refer the patients in question for specialized medical evaluation. PMID- 29419749 TI - Deficiency of Invariant Natural Killer T Cells Does Not Protect Against Obesity but Exacerbates Atherosclerosis in Ldlr-/- Mice. AB - Obesity is a chronic inflammatory state characterized by altered levels of adipose tissue immune cell populations. Natural killer T (NKT) cells are CD1d restricted lymphocyte subsets that recognize lipid antigens whose level decreases in obese adipose tissue. However, studies in mice with deficiency or increased levels of NKT cells have yielded contradictory results, so the exact role of these cells in obesity and adipose tissue inflammation is not yet established. We previously showed that Ldlr-/- mice with excess invariant NKT (iNKT) cells demonstrate significant weight gain, adiposity, metabolic abnormalities, and atherosclerosis. The current study evaluates the effects of NKT cell deficiency on obesity, associated metabolic changes, and atherosclerosis in Jalpha18-/-Ldlr /- (lacking iNKT cells) and Cd1d-/-Ldlr-/- (lacking invariant and type II NKT cells) mice, and control mice were fed an obesogenic diet (high fat, sucrose, cholesterol) for 16 weeks. Contrary to expectations, Ja18-/-Ldlr-/- mice gained significantly more weight than Ldlr-/- or Cd1d-/-Ldlr-/- mice, developed hypertriglyceridemia, and had worsened adipose tissue inflammation. All the mice developed insulin resistance and hepatic triglyceride accumulation. Ja18-/-Ldlr-/ mice also had increased atherosclerotic lesion area. Our findings suggest that iNKT cells exacerbates the metabolic, inflammatory, and atherosclerotic features of diet-induced obesity. Further work is required to unravel the paradox of an apparently similar effect of iNKT cell surplus and depletion on obesity. PMID- 29419751 TI - Accurate Initial State Estimation in a Monocular Visual-Inertial SLAM System. AB - The fusion of monocular visual and inertial cues has become popular in robotics, unmanned vehicles and augmented reality fields. Recent results have shown that optimization-based fusion strategies outperform filtering strategies. Robust state estimation is the core capability for optimization-based visual-inertial Simultaneous Localization and Mapping (SLAM) systems. As a result of the nonlinearity of visual-inertial systems, the performance heavily relies on the accuracy of initial values (visual scale, gravity, velocity and Inertial Measurement Unit (IMU) biases). Therefore, this paper aims to propose a more accurate initial state estimation method. On the basis of the known gravity magnitude, we propose an approach to refine the estimated gravity vector by optimizing the two-dimensional (2D) error state on its tangent space, then estimate the accelerometer bias separately, which is difficult to be distinguished under small rotation. Additionally, we propose an automatic termination criterion to determine when the initialization is successful. Once the initial state estimation converges, the initial estimated values are used to launch the nonlinear tightly coupled visual-inertial SLAM system. We have tested our approaches with the public EuRoC dataset. Experimental results show that the proposed methods can achieve good initial state estimation, the gravity refinement approach is able to efficiently speed up the convergence process of the estimated gravity vector, and the termination criterion performs well. PMID- 29419753 TI - Kinetic Phase Diagrams of Ternary Al-Cu-Li System during Rapid Solidification: A Phase-Field Study. AB - Kinetic phase diagrams in technical alloys at different solidification velocities during rapid solidification are of great importance for guiding the novel alloy preparation, but are usually absent due to extreme difficulty in performing experimental measurements. In this paper, a phase-field model with finite interface dissipation was employed to construct kinetic phase diagrams in the ternary Al-Cu-Li system for the first time. The time-elimination relaxation scheme was utilized. The solute trapping phenomenon during rapid solidification could be nicely described by the phase-field simulation, and the results obtained from the experiment measurement and/or the theoretical model were also well reproduced. Based on the predicted kinetic phase diagrams, it was found that with the increase of interface moving velocity and/or temperature, the gap between the liquidus and solidus gradually reduces, which illustrates the effect of solute trapping and tendency of diffusionless solidification. PMID- 29419752 TI - A Novel Computational Method for Detecting DNA Methylation Sites with DNA Sequence Information and Physicochemical Properties. AB - DNA methylation is an important biochemical process, and it has a close connection with many types of cancer. Research about DNA methylation can help us to understand the regulation mechanism and epigenetic reprogramming. Therefore, it becomes very important to recognize the methylation sites in the DNA sequence. In the past several decades, many computational methods-especially machine learning methods-have been developed since the high-throughout sequencing technology became widely used in research and industry. In order to accurately identify whether or not a nucleotide residue is methylated under the specific DNA sequence context, we propose a novel method that overcomes the shortcomings of previous methods for predicting methylation sites. We use k-gram, multivariate mutual information, discrete wavelet transform, and pseudo amino acid composition to extract features, and train a sparse Bayesian learning model to do DNA methylation prediction. Five criteria-area under the receiver operating characteristic curve (AUC), Matthew's correlation coefficient (MCC), accuracy (ACC), sensitivity (SN), and specificity-are used to evaluate the prediction results of our method. On the benchmark dataset, we could reach 0.8632 on AUC, 0.8017 on ACC, 0.5558 on MCC, and 0.7268 on SN. Additionally, the best results on two scBS-seq profiled mouse embryonic stem cells datasets were 0.8896 and 0.9511 by AUC, respectively. When compared with other outstanding methods, our method surpassed them on the accuracy of prediction. The improvement of AUC by our method compared to other methods was at least 0.0399 . For the convenience of other researchers, our code has been uploaded to a file hosting service, and can be downloaded from: https://figshare.com/s/0697b692d802861282d3. PMID- 29419754 TI - Antifungal Activity of Natural Volatile Organic Compounds against Litchi Downy Blight Pathogen Peronophythora litchii. AB - Litchi (Litchi chinensis Sonn.) is a commercially important fruit but its production and quality are restricted by litchi downy blight, caused by the oomycete pathogen Peronophythora litchii Chen. Volatile substances produced by a biocontrol antinomycetes Streptomyces fimicarius BWL-H1 could inhibited P. litchii growth and development both in vitro and in detached litchi leaf and fruit infection assay. Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM) analyses indicated that volatile organic compounds (VOCs) from BWL-H1 resulted in severe damage to the endomembrane system and cell wall of P. litchii cells in vitro and abnormal morphology of appressoria, as well as deformed new hyphae in infection process. VOCs could suppress mycelial growth, sporulation, while with no obvious effect on sporangia germination. Based on gas chromatography-mass spectrophotometric analyses, 32 VOCs were identified from S. fimicarius BWL-H1, the most abundant of which was phenylethyl alcohol. Eight VOCs, including phenylethyl alcohol, ethyl phenylacetate, methyl anthranilate, alpha-copaene, caryophyllene, humulene, methyl salicylate and 4-ethylphenol, that are commercially available, were purchased and their bioactivity was tested individually. Except for humulene, the other seven tested volatile compounds shown strong inhibitory activity against mycelial growth, sporulation, sporangia germination and germ-tube growth of P. litchii. Especially, 4-ethylphenol showed the highest inhibitory effect on sporulation at a very low concentration of 2 uL/L. Overall, our results provided a better understanding of the mode of action of volatiles from BWL-H1 on P. litchii, and showed that volatiles from BWL-H1 have the potential for control of postharvest litchi downy blight. PMID- 29419755 TI - Rapid Detection of Flusilazole in Pears with Au@Ag Nanoparticles for Surface Enhanced Raman Scattering. AB - Residual pesticides in vegetables or fruits have been become one of the world's most concerned food safety issues. Au-Ag core-shell nanoparticles (Au@Ag NPs) coupled with surface-enhanced Raman spectroscopy (SERS) was used for analysis of flusilazole which was widely applied in pears. Three different diameters of Au@Ag NPs were prepared to select the best SERS substrate for analyzing flusilazole. The Au@Ag NPs sizes of 90 +/- 7 nm showed the highest enhancement effect and could be detected flusilazole standard solution and the minimum detectable concentration was 0.1 mg/L. Flusilazole in pear could also identified at as low as 0.1 MUg/g. The amount of adsorbent is critical in the sample preparation process and the best amount of each absorber dosage was 0.6 g MgSO4, 0.2 g C18 and 0.2 g primary secondary amine (PSA). The experimental results indicated a good linear relationship between the Raman intensities of chief peaks and the concentrations of flusilazole solutions (R2 = 0.924-0.962). This study shows that Au@Ag as SERS substrate has great potential to analyze of flusilazole in food matrices. PMID- 29419756 TI - Dietary Cholesterol Intake and Risk of Lung Cancer: A Meta-Analysis. AB - Multiple epidemiologic studies have evaluated the relationship between dietary cholesterol and lung cancer risk, but the association is controversial and inconclusive. A meta-analysis of case-control studies and cohort studies was conducted to evaluate the relationship between dietary cholesterol intake and lung cancer risk in this study. A relevant literature search up to October 2017 was performed in Web of Science, PubMed, China National Knowledge Infrastructure, Sinomed, and VIP Journal Integration Platform. Ten case-control studies and six cohort studies were included in the meta-analysis, and the risk estimates were pooled using either fixed or random effects models. The case-control studies with a total of 6894 lung cancer cases and 29,736 controls showed that dietary cholesterol intake was positively associated with lung cancer risk (Odds Ratio = 1.70, 95% Confidence Interval: 1.43-2.03). However, there was no evidence of an association between dietary cholesterol intake and risk of lung cancer among the 241,920 participants and 1769 lung cancer cases in the cohort studies (Relative Risk = 1.08, 95% Confidence Interval: 0.94-1.25). Due to inconsistent results from case-control and cohort studies, it is difficult to draw any conclusion regarding the effects of dietary cholesterol intake on lung cancer risk. Carefully designed and well-conducted cohort studies are needed to identify the association between dietary cholesterol and lung cancer risk. PMID- 29419759 TI - A Novel Method for Remote Depth Estimation of Buried Radioactive Contamination. AB - Existing remote radioactive contamination depth estimation methods for buried radioactive wastes are either limited to less than 2 cm or are based on empirical models that require foreknowledge of the maximum penetrable depth of the contamination. These severely limits their usefulness in some real life subsurface contamination scenarios. Therefore, this work presents a novel remote depth estimation method that is based on an approximate three-dimensional linear attenuation model that exploits the benefits of using multiple measurements obtained from the surface of the material in which the contamination is buried using a radiation detector. Simulation results showed that the proposed method is able to detect the depth of caesium-137 and cobalt-60 contamination buried up to 40 cm in both sand and concrete. Furthermore, results from experiments show that the method is able to detect the depth of caesium-137 contamination buried up to 12 cm in sand. The lower maximum depth recorded in the experiment is due to limitations in the detector and the low activity of the caesium-137 source used. Nevertheless, both results demonstrate the superior capability of the proposed method compared to existing methods. PMID- 29419757 TI - Environmental Intolerance, Symptoms and Disability Among Fertile-Aged Women. AB - The purpose was to study the prevalence of environmental intolerance (EI) and its different manifestations, including behavioral changes and disability. Fertile aged women (n = 680) of the Kuopio Birth Cohort Study were asked about annoyance to 12 environmental factors, symptoms and behavioral changes. We asked how much the intolerance had disrupted their work, household responsibilities or social life. We chose intolerance attributed to chemicals, indoor molds, and electromagnetic fields to represent typical intolerance entities. Of the respondents, 46% reported annoyance to chemicals, molds, or electromagnetic fields. Thirty-three percent reported symptoms relating to at least one of these three EIs, 18% reported symptoms that included central nervous system symptoms, and 15% reported behavioral changes. Indicating disability, 8.4% reported their experience relating to any of the three EIs as at least "somewhat difficult", 2.2% "very difficult" or "extremely difficult", and 0.9% "extremely difficult". Of the latter 2.2%, all attributed their intolerance to indoor molds, and two thirds also to chemicals. As the number of difficulties increased, the number of organ systems, behavioral changes and overlaps of the three EIs also grew. EI is a heterogeneous phenomenon and its prevalence depends on its definition. The manifestations of EI form a continuum, ranging from annoyance to severe disability. PMID- 29419758 TI - Sensitivity to Social Contingency in Adults with High-Functioning Autism during Computer-Mediated Embodied Interaction. AB - Autism Spectrum Disorder (ASD) can be understood as a social interaction disorder. This makes the emerging "second-person approach" to social cognition a more promising framework for studying ASD than classical approaches focusing on mindreading capacities in detached, observer-based arrangements. According to the second-person approach, embodied, perceptual, and embedded or interactive capabilities are also required for understanding others, and these are hypothesized to be compromised in ASD. We therefore recorded the dynamics of real time sensorimotor interaction in pairs of control participants and participants with High-Functioning Autism (HFA), using the minimalistic human-computer interface paradigm known as "perceptual crossing" (PC). We investigated whether HFA is associated with impaired detection of social contingency, i.e., a reduced sensitivity to the other's responsiveness to one's own behavior. Surprisingly, our analysis reveals that, at least under the conditions of this highly simplified, computer-mediated, embodied form of social interaction, people with HFA perform equally well as controls. This finding supports the increasing use of virtual reality interfaces for helping people with ASD to better compensate for their social disabilities. Further dynamical analyses are necessary for a better understanding of the mechanisms that are leading to the somewhat surprising results here obtained. PMID- 29419760 TI - Comparative Evaluation of Soluble and Insoluble-Bound Phenolics and Antioxidant Activity of Two Chinese Mistletoes. AB - Mistletoes are used medicinally in order to treat various human illnesses. Few studies have reported on the phenolic content and antioxidant properties of Chinese mistletoes (CMs). In this work, the total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activities of soluble and insoluble bound phenolic extracts from CMs hosted by Camellia assamica (Mast.) Chang (CMC) and Pyrus, i, f. (CMP) were compared. Phenolic compounds in CMC and CMP were identified and quantified using high-performance liquid chromatography (HPLC). The results indicated that the TPC of soluble phenolic extracts was higher than insoluble-bound phenolic counterparts in both CMC and CMP. In addition, the TPC of soluble, insoluble-bound and total phenolic fractions (9.91 +/- 0.23, 4.59 +/- 0.27 and 14.50 +/- 0.35 MUmol ferulic acid equivalents per gram (FAE/g) dry sample) extracted from CMP were higher than those extracted from CMC. The soluble phenolic extracts in CMP showed higher antioxidant activities than those in CMC. Eighteen phenolic compounds from soluble and insoluble-bound phenolic extracts from the CMs were identified and quantified by HPLC. This study indicates that CMC and CMP, especially the latter, could be sources of antioxidants in human health care. PMID- 29419761 TI - A-Kinase Anchoring Protein-Lbc: A Molecular Scaffold Involved in Cardiac Protection. AB - Heart failure is a lethal disease that can develop after myocardial infarction, hypertension, or anticancer therapy. In the damaged heart, loss of function is mainly due to cardiomyocyte death and associated cardiac remodeling and fibrosis. In this context, A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that facilitate the spatiotemporal activation of the cyclic adenosine monophosphate (AMP)-dependent protein kinase (PKA) and other transduction enzymes involved in cardiac remodeling. AKAP-Lbc, a cardiac enriched anchoring protein, has been shown to act as a key coordinator of the activity of signaling pathways involved in cardiac protection and remodeling. This review will summarize and discuss recent advances highlighting the role of the AKAP-Lbc signalosome in orchestrating adaptive responses in the stressed heart. PMID- 29419762 TI - Roles of Two Sox9 Genes during Gonadal Development in Japanese Flounder: Sex Differentiation, Spermatogenesis and Gonadal Function Maintenance. AB - The transcription factor sox9 has been implicated in cartilage formation and testis determination in mammals. Here, two duplicates of sox9 were found in Japanese flounder (Paralichthys olivaceus) named Posox9a and Posox9b, respectively. Phylogenetic and gene structure analyses revealed that Posox9a and Posox9b were homologous to that of teleosts and tetrapods. Quantitative real-time polymerase chain reaction (qRT-PCR) showed that both Posox9a and Posox9b expressed higher in testis than in ovary of adult tissues. The in situ hybridization (ISH) analysis of gonads showed that Posox9a and Posox9b mRNA were both detected in oocytes, Sertoli cells and spermatocytes. During sex differentiation, the expression of Posox9a exhibited obvious sexual dimorphic expression from 60 days after hatch (dah) with higher expression in male preferred individuals than female preferred individuals and increased gradually from 30 to 100 dah. A similar pattern was detected in Posox9b expression. After injection of androgen (17alpha-methyltestosterone) of different concentrations, the expression level of Posox9b increased significantly, whereas Posox9a did not change obviously. These results indicated that the two sox9 genes of Japanese flounder had converse functions in sex differentiation, whereas their differences in 17alpha-methyltestosterone administration were obvious and worthwhile for exploring evolutionary and adaptive significance. This study provided a foundation for further exploration of the roles of Posox9 genes during the sex determination and differentiation, spermatogenesis and gonadal function maintenance of Japanese flounder. PMID- 29419764 TI - Differential Regulation of Immune Signaling and Survival Response in Drosophila melanogaster Larvae upon Steinernema carpocapsae Nematode Infection. AB - Drosophila melanogaster is an excellent model to dissect the molecular components and pathways of the innate anti-pathogen immune response. The nematode parasite Steinernema carpocapsae and its mutualistic bacterium Xenorhabdus nematophila form a complex that is highly pathogenic to insects, including D. melanogaster. We have used symbiotic (carrying X. nematophila) and axenic (lacking X. nematophila) nematodes to probe the regulation of genes belonging to different immune signaling pathways in D. melanogaster larvae and assess the survival response of certain mutants to these pathogens. We found that both types of S. carpocapsae upregulate MyD88 (Toll), but not PGRP-LE (Imd); whereas axenic S. carpocapsae strongly upregulate Wengen (Jnk), Domeless (Jak/Stat), Dawdle (TGFbeta, Activin), and Decapentaplegic (TGFbeta, BMP). We further found that inactivation of Wengen and Decapentaplegic confers a survival advantage to larvae infected with axenic S. carpocapsae, whereas mutating PGRP-LE promotes the survival of larvae infected with symbiotic nematodes. PMID- 29419765 TI - Hinfinity Robust Control of a Large-Piston MEMS Micromirror for Compact Fourier Transform Spectrometer Systems. AB - Incorporating linear-scanning micro-electro-mechanical systems (MEMS) micromirrors into Fourier transform spectral acquisition systems can greatly reduce the size of the spectrometer equipment, making portable Fourier transform spectrometers (FTS) possible. How to minimize the tilting of the MEMS mirror plate during its large linear scan is a major problem in this application. In this work, an FTS system has been constructed based on a biaxial MEMS micromirror with a large-piston displacement of 180 MUm, and a biaxial Hinfinity robust controller is designed. Compared with open-loop control and proportional-integral derivative (PID) closed-loop control, Hinfinity robust control has good stability and robustness. The experimental results show that the stable scanning displacement reaches 110.9 MUm under the Hinfinity robust control, and the tilting angle of the MEMS mirror plate in that full scanning range falls within +/-0.0014 degrees . Without control, the FTS system cannot generate meaningful spectra. In contrast, the FTS yields a clean spectrum with a full width at half maximum (FWHM) spectral linewidth of 96 cm-1 under the Hinfinity robust control. Moreover, the FTS system can maintain good stability and robustness under various driving conditions. PMID- 29419766 TI - "I Always Feel Like I Have to Rush..." Pet Owner and Small Animal Veterinary Surgeons' Reflections on Time during Preventative Healthcare Consultations in the United Kingdom. AB - Canine and feline preventative healthcare consultations can be more complex than other consultation types, but they are typically not allocated additional time in the United Kingdom (UK). Impacts of the perceived length of UK preventative healthcare consultations have not previously been described. The aim of this novel study was to provide the first qualitative description of owner and veterinary surgeon reflections on time during preventative healthcare consultations. Semi-structured telephone interviews were conducted with 14 veterinary surgeons and 15 owners about all aspects of canine and feline preventative healthcare consultations. These qualitative data were thematically analysed, and four key themes identified. This paper describes the theme relating to time and consultation length. Patient, owner, veterinary surgeon and practice variables were recalled to impact the actual, versus allocated, length of a preventative healthcare consultation. Preventative healthcare consultations involving young, old and multi-morbid animals and new veterinary surgeon-owner partnerships appear particularly susceptible to time pressures. Owners and veterinary surgeons recalled rushing and minimizing discussions to keep consultations within their allocated time. The impact of the pace, content and duration of a preventative healthcare consultation may be influential factors in consultation satisfaction. These interviews provide an important insight into the complex nature of preventative healthcare consultations and the behaviour of participants under different perceived time pressures. These data may be of interest and relevance to all stakeholders in dog and cat preventative healthcare. PMID- 29419767 TI - Application of Polymerization Activator in the Course of Synthesis of N Isopropylacrylamide Derivatives for Thermally Triggered Release of Naproxen Sodium. AB - Poly-N-isopropylacrylamide (polyNIPA) is an extensively studied polymer in the field of controlled drug delivery. PolyNIPA contains carbonyl and amide groups along a hydrophobic chain. In an aqueous environment, crosslinked polyNIPA forms a gel characterized by a reversible volume phase transition temperature (VPTT), in response to changes in the external environment excited by the temperature factor. NIPA-based polymers were synthesized by a surfactant-free precipitation polymerization (SFPP) method at a temperature of 70 degrees C using the free radical initiator potassium persulfate (KPS) and at 35 degrees C using redox initiator system KPS with N,N,N',N'-tetramethylethylenediamine (TEMED). The synthesized products were evaluated via dynamic light scattering (DLS), nuclear magnetic resonance (NMR) and Fourier-transform infrared spectroscopy (FTIR). The chemical structure, molecular mass, and hydrodynamic diameter of obtained particles, as well as the effects of synthesized polymers on the release of the active substance, naproxen sodium (NS), from hydroxypropyl methyl cellulose (HPMC)-based hydrogels were assessed. The use of the TEMED activator affected the particle size, as well as the release kinetics of NS. The insertion of TEMED into reactant mixtures may be applied to modify the release kinetics of NS from hydrogel preparations. PMID- 29419763 TI - The Regulation of Translation in Alphavirus-Infected Cells. AB - Sindbis virus (SINV) contains an RNA genome of positive polarity with two open reading frames (ORFs). The first ORF is translated from the genomic RNA (gRNA), rendering the viral non-structural proteins, whereas the second ORF is translated from a subgenomic mRNA (sgRNA), which directs the synthesis of viral structural proteins. SINV infection strongly inhibits host cell translation through a variety of different mechanisms, including the phosphorylation of the eukaryotic initiation factor eIF2alpha and the redistribution of cellular proteins from the nucleus to the cytoplasm. A number of motifs have been identified in SINV sgRNA, including a hairpin downstream of the AUG initiation codon, which is involved in the translatability of the viral sgRNA when eIF2 is inactivated. Moreover, a 3' UTR motif containing three stem-loop structures is involved in the enhancement of translation in insect cells, but not in mammalian cells. Accordingly, SINV sgRNA has evolved several structures to efficiently compete for the cellular translational machinery. Mechanistically, sgRNA translation involves scanning of the 5'-UTR following a non-canonical mode and without the requirement for several initiation factors. Indeed, sgRNA-directed polypeptide synthesis occurs even after eIF4G cleavage or inactivation of eIF4A by selective inhibitors. Remarkably, eIF2alpha phosphorylation does not hamper sgRNA translation during the late phase of SINV infection. SINV sgRNA thus constitutes a unique model of a capped viral mRNA that is efficiently translated in the absence of several canonical initiation factors. The present review will mainly focus in the non canonical mechanism of translation of SINV sgRNA. PMID- 29419768 TI - Enrichment of OpenStreetMap Data Completeness with Sidewalk Geometries Using Data Mining Techniques. AB - Tailored routing and navigation services utilized by wheelchair users require certain information about sidewalk geometries and their attributes to execute efficiently. Except some minor regions/cities, such detailed information is not present in current versions of crowdsourced mapping databases including OpenStreetMap. CAP4Access European project aimed to use (and enrich) OpenStreetMap for making it fit to the purpose of wheelchair routing. In this respect, this study presents a modified methodology based on data mining techniques for constructing sidewalk geometries using multiple GPS traces collected by wheelchair users during an urban travel experiment. The derived sidewalk geometries can be used to enrich OpenStreetMap to support wheelchair routing. The proposed method was applied to a case study in Heidelberg, Germany. The constructed sidewalk geometries were compared to an official reference dataset ("ground truth dataset"). The case study shows that the constructed sidewalk network overlays with 96% of the official reference dataset. Furthermore, in terms of positional accuracy, a low Root Mean Square Error (RMSE) value (0.93 m) is achieved. The article presents our discussion on the results as well as the conclusion and future research directions. PMID- 29419769 TI - Ionizing Radiation Measurement Solution in a Hospital Environment. AB - Ionizing radiation is one of the main risks affecting healthcare workers and patients worldwide. Special attention has to be paid to medical staff in the vicinity of radiological equipment or patients undergoing radioisotope procedures. To measure radiation values, traditional area meters are strategically placed in hospitals and personal dosimeters are worn by workers. However, important drawbacks inherent to these systems in terms of cost, detection precision, real time data processing, flexibility, and so on, have been detected and carefully detailed. To overcome these inconveniences, a low cost, open-source, portable radiation measurement system is proposed. The goal is to deploy devices integrating a commercial Geiger-Muller (GM) detector to capture radiation doses in real time and to wirelessly dispatch them to a remote database where the radiation values are stored. Medical staff will be able to check the accumulated doses first hand, as well as other statistics related to radiation by means of a smartphone application. Finally, the device is certified by an accredited calibration center, to later validate the entire system in a hospital environment. PMID- 29419770 TI - Energy Efficient Data Transmission for Sensors with Wireless Charging. AB - This paper studies the problem of maximizing the energy utilization for data transmission in sensors with periodical wireless charging process while taking into account the thermal effect. Two classes of problems are analyzed: one is the case that wireless charging can process for only a limited period of time, and the other is the case that wireless charging can process for a long enough time. Algorithms are proposed to solve the problems and analysis of these algorithms are also provided. For the first problem, three subproblems are studied, and, for the general problem, we give an algorithm that can derive a performance bound of ( 1 - 1 2 m ) ( O P T - E ) compared to an optimal solution. In addition, for the second problem, we provide an algorithm with 2 m 2 m - 1 O P T + 1 performance bound for the general problem. Simulations confirm the analysis of the algorithms. PMID- 29419771 TI - A Dynamic Approach to Rebalancing Bike-Sharing Systems. AB - Bike-sharing services are flourishing in Smart Cities worldwide. They provide a low-cost and environment-friendly transportation alternative and help reduce traffic congestion. However, these new services are still under development, and several challenges need to be solved. A major problem is the management of rebalancing trucks in order to ensure that bikes and stalls in the docking stations are always available when needed, despite the fluctuations in the service demand. In this work, we propose a dynamic rebalancing strategy that exploits historical data to predict the network conditions and promptly act in case of necessity. We use Birth-Death Processes to model the stations' occupancy and decide when to redistribute bikes, and graph theory to select the rebalancing path and the stations involved. We validate the proposed framework on the data provided by New York City's bike-sharing system. The numerical simulations show that a dynamic strategy able to adapt to the fluctuating nature of the network outperforms rebalancing schemes based on a static schedule. PMID- 29419772 TI - Effect of C and N Addition on Thermoelectric Properties of TiNiSn Half-Heusler Compounds. AB - We investigated the thermoelectric properties of the ternary half-Heusler compound, TiNiSn, when introducing C and N. The addition of C or N to TiNiSn leads to an enhanced power factor and a decreasing lattice thermal conductivity by point defect phonon scattering. The thermoelectric performances of TiNiSn alloys are significantly improved by adding 1 at. % TiN, TiC, and figure of merit (ZT) values of 0.43 and 0.34, respectively, can be obtained at 723 K. This increase in thermoelectric performance is very helpful in the commercialization of thermoelectric power generation in the mid-temperature range. PMID- 29419773 TI - The Influence of the Interlayer Distance on the Performance of Thermally Reduced Graphene Oxide Supercapacitors. AB - In this paper, cationic surfactant cetyltrimethylammonium bromide (CTAB) was employed to prevent the restack of the thermally reduce graphene oxide (TRG) sheets. A facile approach was demonstrated to effectively enlarge the interlayer distance of the TRG sheets through the ionic interaction between the intercalated CTAB and ionic liquids (ILs). The morphology of the composites and the interaction between the intercalated ionic species were systematically characterized by SEM, SAXS, XRD, TGA, and FTIR. In addition, the performance of the EDLC cells based on these TRG composites was evaluated. It was found that due to the increased interlayer distance (0.41 nm to 2.51 nm) that enlarges the accessible surface area for the IL electrolyte, the energy density of the cell can be significantly improved (23.1 Wh/kg to 62.5 Wh/kg). PMID- 29419774 TI - A Naturally Occurring Antioxidant Complex from Unripe Grapes: The Case of Sangiovese (v. Vitis vinifera). AB - The wine industry is well known for its production of a large amount of wastes and by-products. Among them, unripe grapes from thinning operations are an undervalued by-product. Grapes are an interesting source of natural antioxidants such as flavonoids, non-flavonoids and stilbenes. A potential strategy to exploit unripe grapes was investigated in this study. Juice from unripe grapes, v. Sangiovese, was obtained by an innovative technique of solid-liquid extraction without the use of solvents. The juice was dried by a spray-drying technique with the addition of arabic gum as support to obtain powder; juice and powder were characterized for antioxidant activity, phenolic concentration and profile. Phenolic acids, flavonols, flava-3-ols, procyanidins and resveratrol were detected in the juice and powder. The powder was used as anti-browning additive in white wine to test the potential re-use of the unripe grapes in the wine industry. The results indicated that the antioxidant complex from unripe grapes contributed to increasing the anti-browning capacity of white wine. Other applications, such as food and nutraceutical products development, can be considered for the antioxidant complex extracted from unripe grapes. In conclusion, the method proposed in this study may contribute to the exploitation of unripe grapes as a by-product of the winemaking process. PMID- 29419775 TI - TiO2, SiO2 and ZrO2 Nanoparticles Synergistically Provoke Cellular Oxidative Damage in Freshwater Microalgae. AB - Metal-based nanoparticles (NPs) are the most widely used engineered nanomaterials. The individual toxicities of metal-based NPs have been plentifully studied. However, the mixture toxicity of multiple NP systems (n >= 3) remains much less understood. Herein, the toxicity of titanium dioxide (TiO2) nanoparticles (NPs), silicon dioxide (SiO2) NPs and zirconium dioxide (ZrO2) NPs to unicellular freshwater algae Scenedesmus obliquus was investigated individually and in binary and ternary combination. Results show that the ternary combination systems of TiO2, SiO2 and ZrO2 NPs at a mixture concentration of 1 mg/L significantly enhanced mitochondrial membrane potential and intracellular reactive oxygen species level in the algae. Moreover, the ternary NP systems remarkably increased the activity of the antioxidant defense enzymes superoxide dismutase and catalase, together with an increase in lipid peroxidation products and small molecule metabolites. Furthermore, the observation of superficial structures of S. obliquus revealed obvious oxidative damage induced by the ternary mixtures. Taken together, the ternary NP systems exerted more severe oxidative stress in the algae than the individual and the binary NP systems. Thus, our findings highlight the importance of the assessment of the synergistic toxicity of multi-nanomaterial systems. PMID- 29419777 TI - Mitigating Toxic Planktonic Cyanobacterial Blooms in Aquatic Ecosystems Facing Increasing Anthropogenic and Climatic Pressures. AB - Toxic planktonic cyanobacterial blooms are a pressing environmental and human health problem. Blooms are expanding globally and threatening sustainability of our aquatic resources. Anthropogenic nutrient enrichment and hydrological modifications, including water diversions and reservoir construction, are major drivers of bloom expansion. Climatic change, i.e., warming, more extreme rainfall events, and droughts, act synergistically with human drivers to exacerbate the problem. Bloom mitigation steps, which are the focus of this review, must consider these dynamic interactive factors in order to be successful in the short and long-term. Furthermore, these steps must be applicable along the freshwater to marine continuum connecting streams, lakes, rivers, estuarine, and coastal waters. There is an array of physical, chemical, and biological approaches, including flushing, mixing, dredging, application of algaecides, precipitating phosphorus, and selective grazing, that may arrest and reduce bloom intensities in the short-term. However, to ensure long term, sustainable success, targeting reductions of both nitrogen and phosphorus inputs should accompany these approaches along the continuum. Lastly, these strategies should accommodate climatic variability and change, which will likely modulate and alter nutrient bloom thresholds. PMID- 29419776 TI - Modulation of miRNAs by Vitamin C in Human Bone Marrow Stromal Cells. AB - MicroRNAs (miRNAs) are small (18-25 nucleotides), noncoding RNAs that have been identified as potential regulators of bone marrow stromal cell (BMSC) proliferation, differentiation, and musculoskeletal development. Vitamin C is known to play a vital role in such types of biological processes through various different mechanisms by altering mRNA expression. We hypothesized that vitamin C mediates these biological processes partially through miRNA regulation. We performed global miRNA expression analysis on human BMSCs following vitamin C treatment using microarrays containing human precursor and mature miRNA probes. Bioinformatics analyses were performed on differentially expressed miRNAs to identify novel target genes and signaling pathways. Our bioinformatics analysis suggested that the miRNAs may regulate multiple stem cell-specific signaling pathways such as cell adhesion molecules (CAMs), fatty acid biosynthesis and hormone signaling pathways. Furthermore, our analysis predicted novel stem cell proliferation and differentiation gene targets. The findings of the present study demonstrate that vitamin C can have positive effects on BMSCs in part by regulating miRNA expression. PMID- 29419778 TI - Chemoselective Polymerization of Polar Divinyl Monomers with Rare-Earth/Phosphine Lewis Pairs. AB - This work reports the chemoselective polymerization of polar divinyl monomers, including allyl methacrylate (AMA), vinyl methacrylate (VMA), and 4-vinylbenzyl methacrylate (VBMA), by using simple Lewis pairs comprised of homoleptic rare earth (RE) aryloxide complexes RE(OAr)3 (RE = Sc (1), Y (2), Sm (3), La (4), Ar = 2,6-tBu2C6H3) and phosphines PR3 (R = Ph, Cy, Et, Me). Catalytic activities of polymerizations relied heavily upon the cooperation of Lewis acid and Lewis base components. The produced polymers were soluble in common organic solvents and often had a narrow molecular weight distribution. A highly syndiotactic poly(allyl methacrylate) (PAMA) with rr ~88% could be obtained by the scandium complex 1/PEt3 pair at -30 degrees C. In the case of poly(4-vinylbenzyl methacrylate) (PVBMA), it could be post-functionalized with PhCH2SH. Mechanistic study, including the isolation of the zwitterionic active species and the end group analysis, revealed that the frustrated Lewis pair (FLP)-type addition was the initiating step in the polymerization. PMID- 29419780 TI - Differential Enzymatic Activity of Rat ADAR2 Splicing Variants Is Due to Altered Capability to Interact with RNA in the Deaminase Domain. AB - In mammals, adenosine (A) to inosine (I) RNA editing is performed by adenosine deaminases acting on RNA (ADAR), ADAR1 and ADAR2 enzymes, encoded by mRNAs that might undergo splicing process. In rat, two splicing events produce several isoforms of ADAR2, called ADAR2a, ADAR2b, ADAR2e, and ADAR2f, but only ADAR2a and ADAR2b are translated into an active protein. In particular, they differ for ten amino acids located in the catalytic domain of ADAR2b. Here, we focused on these two isoforms, analyzing the splicing pattern and their different function during rat neuronal maturation. We found an increase of editing levels in cortical neurons overexpressing ADAR2a compared to those overexpressing ADAR2b. These results indicate ADAR2a isoform as the most active one, as reported for the homologous human short variant. Furthermore, we showed that the differential editing activity is not due to a different dimerization of the two isoforms; it seems to be linked to the ten amino acids loop of ADAR2b that might interfere with RNA binding, occupying the space volume in which the RNA should be present in case of binding. These data might shed light on the complexity of ADAR2 regulations. PMID- 29419781 TI - Recent Advances of Malaria Parasites Detection Systems Based on Mathematical Morphology. AB - Malaria is an epidemic health disease and a rapid, accurate diagnosis is necessary for proper intervention. Generally, pathologists visually examine blood stained slides for malaria diagnosis. Nevertheless, this kind of visual inspection is subjective, error-prone and time-consuming. In order to overcome the issues, numerous methods of automatic malaria diagnosis have been proposed so far. In particular, many researchers have used mathematical morphology as a powerful tool for computer aided malaria detection and classification. Mathematical morphology is not only a theory for the analysis of spatial structures, but also a very powerful technique widely used for image processing purposes and employed successfully in biomedical image analysis, especially in preprocessing and segmentation tasks. Microscopic image analysis and particularly malaria detection and classification can greatly benefit from the use of morphological operators. The aim of this paper is to present a review of recent mathematical morphology based methods for malaria parasite detection and identification in stained blood smears images. PMID- 29419782 TI - Nuclear Radiation Degradation Study on HD Camera Based on CMOS Image Sensor at Different Dose Rates. AB - In this work, we irradiated a high-definition (HD) industrial camera based on a commercial-off-the-shelf (COTS) CMOS image sensor (CIS) with Cobalt-60 gamma rays. All components of the camera under test were fabricated without radiation hardening, except for the lens. The irradiation experiments of the HD camera under biased conditions were carried out at 1.0, 10.0, 20.0, 50.0 and 100.0 Gy/h. During the experiment, we found that the tested camera showed a remarkable degradation after irradiation and differed in the dose rates. With the increase of dose rate, the same target images become brighter. Under the same dose rate, the radiation effect in bright area is lower than that in dark area. Under different dose rates, the higher the dose rate is, the worse the radiation effect will be in both bright and dark areas. And the standard deviations of bright and dark areas become greater. Furthermore, through the progressive degradation analysis of the captured image, experimental results demonstrate that the attenuation of signal to noise ratio (SNR) versus radiation time is not obvious at the same dose rate, and the degradation is more and more serious with increasing dose rate. Additionally, the decrease rate of SNR at 20.0, 50.0 and 100.0 Gy/h is far greater than that at 1.0 and 10.0 Gy/h. Even so, we confirm that the HD industrial camera is still working at 10.0 Gy/h during the 8 h of measurements, with a moderate decrease of the SNR (5 dB). The work is valuable and can provide suggestion for camera users in the radiation field. PMID- 29419779 TI - MiRNAs at the Crossroads between Innate Immunity and Cancer: Focus on Macrophages. AB - Innate immune cells form an integrative component of the tumor microenvironment (TME), which can control or prevent tumor initiation and progression, due to the simultaneous processing of both anti- and pro-growth signals. This decision making process is a consequence of gene expression changes, which are in part dependent on post-transcriptional regulatory mechanisms. In this context, microRNAs have been shown to regulate both recruitment and activation of specific tumor-associated immune cells in the TME. This review aims to describe the most important microRNAs that target cancer-related innate immune pathways. The role of exosomal microRNAs in tumor progression and microRNA-based therapeutic strategies are also discussed. PMID- 29419783 TI - Inner Leaf Gel of Aloe striata Induces Adhesion-Reducing Morphological Hyphal Aberrations. AB - Fungi, particularly molds that are cosmopolitan in soils, are frequent etiologic agents of opportunistic mycoses. Members of the Fusarium solani and Fusarium oxysporum species complexes are the most commonly implicated etiologic agents of opportunistic fusarial infections in mammals, while Paecilomyces variotii is one of the most frequently encountered Paecilomyces species in human infections. Prevention and treatment of these mycoses are problematic because available antimycotics are limited and often have toxic side effects. Popular folk medicines, such as the inner leaf gel from Aloe spp., offer potential sources for novel antimycotic compounds. To screen for antifungal properties of Aloe striata, we treated conidia of three strains each of F. solani, F. oxysporum, and P. variotii with homogenized and filtered inner leaf gel. Exposure to gel homogenates caused minimal inhibition of conidial germination in tested strains. However, it significantly increased the frequency of hyphal aberrations characterized by increased hyphal diameters that resulted in intervals of non parallel cell walls. Non-parallel cell walls ostensibly reduce total hyphal surface area available for adhesion. We found a significant decrease in the ability of aberrated P. variotii hyphae to remain adhered to microscope slides after repeated washing with reverse osmosis water. Our results suggest that treatment with A. striata contributes to a decrease in the adhesion frequency of tested P. variotii strains. PMID- 29419784 TI - Mutual-Information-Based Incremental Relaying Communications for Wireless Biomedical Implant Systems. AB - Network lifetime maximization of wireless biomedical implant systems is one of the major research challenges of wireless body area networks (WBANs). In this paper, a mutual information (MI)-based incremental relaying communication protocol is presented where several on-body relay nodes and one coordinator are attached to the clothes of a patient. Firstly, a comprehensive analysis of a system model is investigated in terms of channel path loss, energy consumption, and the outage probability from the network perspective. Secondly, only when the MI value becomes smaller than the predetermined threshold is data transmission allowed. The communication path selection can be either from the implanted sensor to the on-body relay then forwards to the coordinator or from the implanted sensor to the coordinator directly, depending on the communication distance. Moreover, mathematical models of quality of service (QoS) metrics are derived along with the related subjective functions. The results show that the MI-based incremental relaying technique achieves better performance in comparison to our previous proposed protocol techniques regarding several selected performance metrics. The outcome of this paper can be applied to intra-body continuous physiological signal monitoring, artificial biofeedback-oriented WBANs, and telemedicine system design. PMID- 29419785 TI - Macronutrient Composition and Food Form Affect Glucose and Insulin Responses in Humans. AB - Glycaemic index (GI) is used as an indicator to guide consumers in making healthier food choices. We compared the GI, insulin index (II), and the area under the curve for blood glucose and insulin as glucose (GR) and insulin responses (IR) of a newly developed liquid nutritional formula with one commercially available liquid product with different types of carbohydrates. We then evaluated the glucose and insulin responses of two test foods with comparable energy density and protein percentage but presented in different food forms (liquid vs. solid). Fourteen healthy women participated in the study. GI, II, GR, and IR were assessed after (independent) consumption of two liquid products and a solid breakfast meal. The two liquid foods showed comparable GI, whilst the liquid form appeared to produce lower median GI (25 vs. 54), and II (52 vs. 98) values compared to the solid breakfast (p < 0.02). The median GR and IR for solid breakfast were respectively 44% and 45% higher compared to the liquid product (p < 0.02). Liquid formulas with different carbohydrate qualities produced comparable glucose responses, while foods with comparable energy density and protein percentage but different food form elicited differential effects on GI, II, GR, and IR. Nutrient quality and food form need to be taken into consideration when developing low GI products to manage glycaemic responses. PMID- 29419786 TI - Disease and Economic Burden of Hospitalizations Attributable to Diabetes Mellitus and Its Complications: A Nationwide Study in Brazil. AB - Diabetes is associated with a significant burden globally. The costs of diabetes related hospitalizations are unknown in most developing countries. The aim of this study was to estimate the total number and economic burden of hospitalizations attributable to diabetes mellitus (DM) and its complications in adults from the perspective of the Brazilian Public Health System in 2014. Data sources included the National Health Survey (NHS) and National database of Hospitalizations (SIH). We considered diabetes, its microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary heart disease, cerebrovascular disease, and peripheral arterial disease), respiratory and urinary tract infections, as well as selected cancers. Assuming that DM patients are hospitalized for these conditions more frequently that non-DM individuals, we estimated the etiological fraction of each condition related to DM, using the attributable risk methodology. We present number, average cost per case, and overall costs of hospitalizations attributable to DM in Brazil in 2014, stratified by condition, state of the country, gender and age group. In 2014, a total of 313,273 hospitalizations due to diabetes in adults were reported in Brazil (4.6% of total adult hospitalization), totaling (international dollar) Int$264.9 million. The average cost of an adult hospitalization due to diabetes was Int$845, 19% higher than hospitalization without DM. Hospitalizations due to cardiovascular diseases related to diabetes accounted for the higher proportion of costs (47.9%), followed by microvascular complications (25.4%) and DM per se (18.1%). Understanding the costs of diabetes and its major complications is crucial to raise awareness and to support the decision-making process on policy implementation, also allowing the assessment of prevention and control strategies. PMID- 29419788 TI - The Impact of Sustainable Development Technology on a Small Economy-The Case of Energy-Saving Technology. AB - We investigated the impact of a sustainable development technology on the macroeconomic variables in a small economy utilizing a case study with a stochastically improving energy saving technology and a stochastically increasing energy price. The results show the technological displacement effects of energy saving technology are stronger, but there are more ambiguous instantaneous returns to physical capital. However, the energy saving technology's displacement effects might not affect the conditions under which the Harberger-Laursen-Metzler (HLM) effect holds. The effects of rising energy prices on bonds are stronger, and there are more ambiguous instantaneous returns, but the conditions under which the HLM effect holds are different. PMID- 29419787 TI - Biomarkers' Responses to Reductive Dechlorination Rates and Oxygen Stress in Bioaugmentation Culture KB-1TM. AB - Using mRNA transcript levels for key functional enzymes as proxies for the organohalide respiration (OHR) rate, is a promising approach for monitoring bioremediation populations in situ at chlorinated solvent-contaminated field sites. However, to date, no correlations have been empirically derived for chlorinated solvent respiring, Dehalococcoides mccartyi (DMC) containing, bioaugmentation cultures. In the current study, genome-wide transcriptome and proteome data were first used to confirm the most highly expressed OHR-related enzymes in the bioaugmentation culture, KB-1TM, including several reductive dehalogenases (RDases) and a Ni-Fe hydrogenase, Hup. Different KB-1TM DMC strains could be resolved at the RNA and protein level through differences in the sequence of a common RDase (DET1545-like homologs) and differences in expression of their vinyl chloride-respiring RDases. The dominant strain expresses VcrA, whereas the minor strain utilizes BvcA. We then used quantitative reverse transcriptase PCR (qRT-PCR) as a targeted approach for quantifying transcript copies in the KB-1TM consortium operated under a range of TCE respiration rates in continuously-fed, pseudo-steady-state reactors. These candidate biomarkers from KB-1TM demonstrated a variety of trends in terms of transcript abundance as a function of respiration rate over the range: 7.7 * 10-12 to 5.9 * 10-10 microelectron equivalents per cell per hour (MUeeq/cell?h). Power law trends were observed between the respiration rate and transcript abundance for the main DMC RDase (VcrA) and the hydrogenase HupL (R2 = 0.83 and 0.88, respectively), but not transcripts for 16S rRNA or three other RDases examined: TceA, BvcA or the RDase DET1545 homologs in KB1TM. Overall, HupL transcripts appear to be the most robust activity biomarker across multiple DMC strains and in mixed communities including DMC co-cultures such as KB1TM. The addition of oxygen induced cell stress that caused respiration rates to decline immediately (>95% decline within one hour). Although transcript levels did decline, they did so more slowly than the respiration rate observed (transcript decay rates between 0.02 and 0.03 per hour). Data from strain-specific probes on the pangenome array strains suggest that a minor DMC strain in KB-1TM that harbors a bvcA homolog preferentially recovered following oxygen stress relative to the dominant, vcrA-containing strain. PMID- 29419789 TI - Aged Oolong Tea Reduces High-Fat Diet-Induced Fat Accumulation and Dyslipidemia by Regulating the AMPK/ACC Signaling Pathway. AB - While oolong tea (OT) has been shown to induce weight loss and reduce fat accumulation, the mechanisms remain poorly defined, especially for aged OT. In this study, five groups of mice (n = 9/group) were used including a normal diet with vehicle treatment, and a high-fat diet (HFD) with vehicle or the water extracts from aged OTs (EAOTs, three different storage years) by oral gavage at 1000 mg/kg.BW for 6 weeks. Body weight, fat accumulation, and serum biochemical parameters were used to evaluate obesity. The morphology of hepatocytes and adipocytes was analyzed by being stained with hematoxylin and eosin. The levels of p-AMPK, p-ACC (and non-phosphorylated versions), CPT-1 and FAS were determined by Western blotting and immunohistochemistry. EAOTs decreased HFD-induced body weight, fat accumulation, serum levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol, while enhancing the serum high-density lipoprotein cholesterol level. At the same time, EAOTs clearly alleviated fatty liver and reduced the size of adipocytes in the epididymal fat, especially in the 2006 group. Most importantly, EAOTs increased the phosphorylation of AMPK and ACC, and up-regulated the expression of CPT-1 but down-regulated the expression of fatty acid synthase, TNF-alpha and iNOS. Thus, EAOTs may inhibit obesity by up regulating energy expenditure and fatty acid oxidation while inhibiting fatty acid synthesis and inflammation. PMID- 29419791 TI - Unintentional Childhood Injuries in Urban and Rural Ujjain, India: A Community Based Survey. AB - Injuries are a major global public health problem. There are very few community based studies on childhood injury from India. The objective of this cross sectional, community-based survey was to identify the incidence, type, and risk factors of unintentional childhood injuries. The study was done in seven villages and ten contiguous urban slums in Ujjain, India. World Health Organization (WHO) tested tools and definitions were used for the survey, which included 2518 households having 6308 children up to 18 years of age, with 2907 children from urban households and 3401 from rural households. The annual incidence of all injuries was 16.6%, 95% Confidence Interval 15.7-17.5%, (n = 1049). The incidence was significantly higher among boys compared to girls (20.2% versus 12.7%, respectively), was highest in age group 6-10 years of age (18.9%), and in urban locations (17.5%). The most commonly identified injury types were: physical injuries (71%), burns (16%), poisonings (10%), agriculture-related injuries (2%), near drowning (2%), and suffocations (2%). The most common place of injury was streets followed by home. The study identified incidence of different types of unintentional childhood injuries and factors associated with increased risk of unintentional injuries. The results can help in designing injury prevention strategies and awareness programs in similar settings. PMID- 29419792 TI - Revealing Subtle Functional Subgroups in Class A Scavenger Receptors by Pattern Discovery and Disentanglement of Aligned Pattern Clusters. AB - A protein family has similar and diverse functions locally conserved as aligned sequence segments. Further discovering their association patterns could reveal subtle family subgroup characteristics. Since aligned residues associations (ARAs) in Aligned Pattern Clusters (APCs) are complex and intertwined due to entangled function, factors, and variance in the source environment, we have recently developed a novel method: Aligned Residue Association Discovery and Disentanglement (ARADD) to solve this problem. ARADD first obtains from an APC an ARA Frequency Matrix and converts it to an adjusted statistical residual vectorspace (SRV). It then disentangles the SRV into Principal Components (PCs) and Re-projects their vectors to a SRV to reveal succinct orthogonal AR groups. In this study, we applied ARADD to class A scavenger receptors (SR-A), a subclass of a diverse protein family binding to modified lipoproteins with diverse biological functionalities not explicitly known. Our experimental results demonstrated that ARADD can unveil subtle subgroups in sequence segments with diverse functionality and highly variable sequence lengths. We also demonstrated that the ARAs captured in a Position Weight Matrix or an APC were entangled in biological function and domain location but disentangled by ARADD to reveal different subclasses without knowing their actual occurrence positions. PMID- 29419790 TI - The Roles of Three Types of Knowledge and Perceived Uncertainty in Explaining Risk Perception, Acceptability, and Self-Protective Response-A Case Study on Endocrine Disrupting Surfactants. AB - The ubiquitous surfactants nonylphenol (NP) and its ethoxylates (NPEOs), which are known as endocrine disrupters, have appeared in the lists of restricted chemical substances, monitoring programs, and environmental quality standards of many countries due to their adverse effects. Recent studies have reported alarming levels of NP, as the final metabolite of NPEOs, in Vietnamese urban waters, whilst response to this issue is negligible. With the aim of addressing how the public perceives and expects to avoid the risk of endocrine disrupting surfactants (EDSs), the study tested the hypothesized roles of specific knowledge, general knowledge, and perceived uncertainty using structural equation modelling. The findings revealed that different types of knowledge played certain roles in explaining risk perception, risk acceptability, and self-protective response, which are distinguished by experience amongst the public. Evidence of the mediating role that perceived uncertainty may play in the decrease of risk perception and the increase of risk unacceptance has been provided. The insights gained from the study may help answer why the public are in favor of taking non diet-related self-protective measures rather than changing their dietary habits, which illustrates a comparison with the basis of health belief model. The needs for building cognitive capacity amongst the public, particularly pregnant women and young mothers, and risk communication concerning endocrine disrupting contamination linked to reproductive health are highlighted. PMID- 29419793 TI - Microbiological Values of Rainwater Harvested in Adelaide. AB - In Australia, rainwater is an important source of water for many households. Unlike municipal water, rainwater is often consumed untreated. This study investigated the potential contamination of rainwater by microorganisms. Samples from 53 rainwater tanks across the Adelaide region were collected and tested using ColilertTM IDEXX Quanti-Tray*/2000. Twenty-eight out of the 53 tanks (53%) contained Escherichia coli. Samples collected from ten tanks contained E. coli at concentrations exceeding the limit of 150 MPN/100 mL for recreational water quality. A decline in E. coli was observed in samples collected after prolonged dry periods. Rainwater microbiological values depended on the harvesting environment conditions. A relationship was found between mounted TV antenna on rooftops and hanging canopies; and E. coli abundance. Conversely, there was no relationship between seasonality and E. coli or roof and tank structure materials and E. coli. In several tanks used for drinking water, samples collected prior to and after filtration showed that the filtration systems were not always successful at completely removing E. coli. These results differed from a study undertaken in the laboratory that found that a commercially available in-bench 0.45 um filter cartridge successfully reduced E. coli in rainwater to 0 MPN/100 mL. After running a total of 265 L of rainwater which contained high levels of E. coli through the filter (half of the advertised filter lifespan), the filter cartridge became blocked, although E. coli remained undetected in filtered water. The difference between the laboratory study and field samples could be due to improper maintenance or installation of filters or recontamination of the faucet after filtration. The presence of E. coli in water that is currently used for drinking poses a potential health concern and indicates the potential for contamination with other waterborne pathogens. PMID- 29419794 TI - Gene Expression Profile Analysis is Directly Affected by the Selected Reference Gene: The Case of Leaf-Cutting Atta Sexdens. AB - Although several ant species are important targets for the development of molecular control strategies, only a few studies focus on identifying and validating reference genes for quantitative reverse transcription polymerase chain reaction (RT-qPCR) data normalization. We provide here an extensive study to identify and validate suitable reference genes for gene expression analysis in the ant Atta sexdens, a threatening agricultural pest in South America. The optimal number of reference genes varies according to each sample and the result generated by RefFinder differed about which is the most suitable reference gene. Results suggest that the RPS16, NADH and SDHB genes were the best reference genes in the sample pool according to stability values. The SNF7 gene expression pattern was stable in all evaluated sample set. In contrast, when using less stable reference genes for normalization a large variability in SNF7 gene expression was recorded. There is no universal reference gene suitable for all conditions under analysis, since these genes can also participate in different cellular functions, thus requiring a systematic validation of possible reference genes for each specific condition. The choice of reference genes on SNF7 gene normalization confirmed that unstable reference genes might drastically change the expression profile analysis of target candidate genes. PMID- 29419795 TI - Non-Orthogonal Multiple Access for Ubiquitous Wireless Sensor Networks. AB - Ubiquitous wireless sensor networks (UWSNs) have become a critical technology for enabling smart cities and other ubiquitous monitoring applications. Their deployment, however, can be seriously hampered by the spectrum available to the sheer number of sensors for communication. To support the communication needs of UWSNs without requiring more spectrum resources, the power-domain non-orthogonal multiple access (NOMA) technique originally proposed for 5th Generation (5G) cellular networks is investigated for UWSNs for the first time in this paper. However, unlike 5G networks that operate in the licensed spectrum, UWSNs mostly operate in unlicensed spectrum where sensors also experience cross-technology interferences from other devices sharing the same spectrum. In this paper, we model the interferences from various sources at the sensors using stochastic geometry framework. To evaluate the performance, we derive a theorem and present new closed form expression for the outage probability of the sensors in a downlink scenario under interference limited environment. In addition, diversity analysis for the ordered NOMA users is performed. Based on the derived outage probability, we evaluate the average link throughput and energy consumption efficiency of NOMA against conventional orthogonal multiple access (OMA) technique in UWSNs. Further, the required computational complexity for the NOMA users is presented. PMID- 29419796 TI - Tuning the Stiffness Balance Using Characteristic Frequencies as a Criterion for a Superconducting Gravity Gradiometer. AB - Tuning the stiffness balance is crucial to full-band common-mode rejection for a superconducting gravity gradiometer (SGG). A reliable method to do so has been proposed and experimentally tested. In the tuning scheme, the frequency response functions of the displacement of individual test mass upon common-mode accelerations were measured and thus determined a characteristic frequency for each test mass. A reduced difference in characteristic frequencies between the two test masses was utilized as the criterion for an effective tuning. Since the measurement of the characteristic frequencies does not depend on the scale factors of displacement detection, stiffness tuning can be done independently. We have tested this new method on a single-component SGG and obtained a reduction of two orders of magnitude in stiffness mismatch. PMID- 29419797 TI - Infrared Thermography as a Non-Invasive Tool to Explore Differences in the Musculoskeletal System of Children with Hemophilia Compared to an Age-Matched Healthy Group. AB - Recurrent joint bleeds and silent bleeds are the most common clinical feature in patients with hemophilia. Every bleed causes an immediate inflammatory response and is the leading cause of chronic crippling arthropathy. With the help of infrared thermography we wanted to detect early differences between a group of clinical non-symptomatic children with hemophilia (CWH) with no history of clinically detected joint bleeds and a healthy age-matched group of children. This could help to discover early inflammation and help implement early treatment and preventative strategies. It could be demonstrated that infrared thermography is sensitive enough to detect more signs of early inflammatory response in the CWH than in healthy children. It seems to detect more side differences in temperature than clinical examination of silent symptoms detects tender points. Silent symptoms/tender points seem to be combined with early local inflammation. Using such a non-invasive and sensor-based early detection, prevention of overloading and bleeding might be achieved. PMID- 29419798 TI - Determination of Odour Interactions in Gaseous Mixtures Using Electronic Nose Methods with Artificial Neural Networks. AB - This paper presents application of an electronic nose prototype comprised of eight sensors, five TGS-type sensors, two electrochemical sensors and one PID type sensor, to identify odour interaction phenomenon in two-, three-, four- and five-component odorous mixtures. Typical chemical compounds, such as toluene, acetone, triethylamine, alpha-pinene and n-butanol, present near municipal landfills and sewage treatment plants were subjected to investigation. Evaluation of predicted odour intensity and hedonic tone was performed with selected artificial neural network structures with the activation functions tanh and Leaky rectified linear units (Leaky ReLUs) with the parameter a = 0.03 . Correctness of identification of odour interactions in the odorous mixtures was determined based on the results obtained with the electronic nose instrument and non-linear data analysis. This value (average) was at the level of 88% in the case of odour intensity, whereas the average was at the level of 74% in the case of hedonic tone. In both cases, correctness of identification depended on the number of components present in the odorous mixture. PMID- 29419799 TI - Inhibition of Phosphodiesterase 4 by FCPR03 Alleviates Lipopolysaccharide-Induced Depressive-Like Behaviors in Mice: Involvement of p38 and JNK Signaling Pathways. AB - Inflammatory responses induced by peripheral administration of lipopolysaccharide (LPS) triggers depressive-like behavioral syndrome in rodents. Inhibition of phosphodiesterase 4 (PDE4) produces a robust anti-inflammatory effect in inflammatory cells. Unfortunately, archetypal PDE4 inhibitors cause intolerable gastrointestinal side-effects, such as vomiting and nausea. N-isopropyl-3 (cyclopropylmethoxy)-4-difluoromethoxy benzamide (FCPR03) is a novel, selective PDE4 inhibitor with little, or no, emetic potency. Our previous studies show that FCPR03 is effective in attenuating neuroinflammation in mice treated with LPS. However, whether FCPR03 could exert antidepressant-like effect induced by LPS is largely unknown. In the present study, mice injected intraperitoneally (i.p.) with LPS was established as an in vivo animal model of depression. The antidepressant-like activities of FCPR03 were evaluated using a tail suspension test, forced swimming test, and sucrose preference test. We demonstrated that administration of FCPR03 (1 mg/kg) produced antidepressant-like effects in mice challenged by LPS, as evidenced by decreases in the duration of immobility in the forced swim and tail suspension tests, while no significant changes in locomotor activity were observed. FCPR03 also increased sucrose preference in mice treated with LPS. In addition, treatment with FCPR03 abolished the downregulation of brain-derived neurotrophic factor induced by LPS and decreased the level of corticosterone in plasma. Meanwhile, periphery immune challenge by LPS induced enhanced phosphorylation of p38-mitogen activated protein kinase (p38) and c-Jun N-terminal kinase (JNK) in both the cerebral cortex and hippocampus in mice. Interestingly, treatment with FCPR03 significantly blocked the role of LPS and reduced the levels of phosphorylated p38 and JNK. Collectively, these results indicate that FCPR03 shows antidepressant-like effects in mice challenged by LPS, and the p38/JNK signaling pathway is possibly involved in this process. Our findings suggest that FCPR03 is a potential compound for the prevention or treatment of depression. PMID- 29419800 TI - Intestinal Permeability and Cellular Antioxidant Activity of Phenolic Compounds from Mango (Mangifera indica cv. Ataulfo) Peels. AB - Mango (Mangifera indica cv. Ataulfo) peel contains bound phenolics that may be released by alkaline or acid hydrolysis and may be converted into less complex molecules. Free phenolics from mango cv. Ataulfo peel were obtained using a methanolic extraction, and their cellular antioxidant activity (CAA) and permeability were compared to those obtained for bound phenolics released by alkaline or acid hydrolysis. Gallic acid was found as a simple phenolic acid after alkaline hydrolysis along with mangiferin isomers and quercetin as aglycone and glycosides. Only gallic acid, ethyl gallate, mangiferin, and quercetin were identified in the acid fraction. The acid and alkaline fractions showed the highest CAA (60.5% and 51.5%) when tested at 125 ug/mL. The value of the apparent permeability coefficient (Papp) across the Caco-2/HT-29 monolayer of gallic acid from the alkaline fraction was higher (2.61 * 10-6 cm/s) than in the other fractions and similar to that obtained when tested pure (2.48 * 10-6 cm/s). In conclusion, mango peels contain bound phenolic compounds that, after their release, have permeability similar to pure compounds and exert an important CAA. This finding can be applied in the development of nutraceuticals using this important by-product from the mango processing industry. PMID- 29419802 TI - Neurotropin(r) Accelerates the Differentiation of Schwann Cells and Remyelination in a Rat Lysophosphatidylcholine-Induced Demyelination Model. AB - Neurotropin(r) (NTP), a non-protein extract of inflamed rabbit skin inoculated with vaccinia virus, is clinically used for the treatment of neuropathic pain in Japan and China, although its effect on peripheral nerve regeneration remains to be elucidated. The purpose of this study was to investigate the effects of NTP on Schwann cells (SCs) in vitro and in vivo, which play an important role in peripheral nerve regeneration. In SCs, NTP upregulated protein kinase B (AKT) activity and Krox20 and downregulated extracellular signal-regulated kinase1/2 activity under both growth and differentiation conditions, enhanced the expression of myelin basic protein and protein zero under the differentiation condition. In a co-culture of dorsal root ganglion neurons and SCs, NTP accelerated myelination of SCs. To further investigate the influence of NTP on SCs in vivo, lysophosphatidylcholine was injected into the rat sciatic nerve, leading to the focal demyelination. After demyelination, NTP was administered systemically with an osmotic pump for one week. NTP improved the ratio of myelinated axons and motor, sensory, and electrophysiological function. These findings reveal novel effects of NTP on SCs differentiation in vitro and in vivo, and indicate NTP as a promising treatment option for peripheral nerve injuries and demyelinating diseases. PMID- 29419803 TI - Antibacterial Activities of Azole Complexes Combined with Silver Nanoparticles. AB - Growing antimicrobial resistance is considered a potential threat for human health security by health organizations, such as the WHO, CDC and FDA, pointing to MRSA as an example. New antibacterial drugs and complex derivatives are needed to combat the development of bacterial resistance. Six new copper and cobalt complexes of azole derivatives were synthesized and isolated as air-stable solids and characterized by melting point analyses, elemental analyses, thermogravimetric analyses (TGA), and infrared and ultraviolet/visible spectroscopy. The analyses and spectral data showed that the complexes had 1:1 (M:L) stoichiometries and tetrahedral geometries, the latter being supported by DFT calculations. The antibacterial activities of the metal complexes by themselves and combined with silver nanoparticles (AgNPs; 2 MUg mL-1) were assessed in vitro by broth microdilution assays against eight bacterial strains of clinical relevance. The results showed that the complexes alone exhibited moderate antibacterial activities. However, when the metal complexes were combined with AgNPs, their antibacterial activities increased (up to 10-fold in the case of complex 5), while human cell viabilities were maintained. The minimum inhibitory concentration (MIC50) values were in the range of 25-500 MUg mL-1. This study thus presents novel approaches for the design of materials for fighting bacterial resistance. The use of azole complexes combined with AgNPs provides a new alternative against bacterial infections, especially when current treatments are associated with the rapid development of antibiotic resistance. PMID- 29419801 TI - Plant Responses to Pathogen Attack: Small RNAs in Focus. AB - Small RNAs (sRNA) are a significant group of gene expression regulators for multiple biological processes in eukaryotes. In plants, many sRNA silencing pathways produce extensive array of sRNAs with specialized roles. The evidence on record advocates for the functions of sRNAs during plant microbe interactions. Host sRNAs are reckoned as mandatory elements of plant defense. sRNAs involved in plant defense processes via different pathways include both short interfering RNA (siRNA) and microRNA (miRNA) that actively regulate immunity in response to pathogenic attack via tackling pathogen-associated molecular patterns (PAMPs) and other effectors. In response to pathogen attack, plants protect themselves with the help of sRNA-dependent immune systems. That sRNA-mediated plant defense responses play a role during infections is an established fact. However, the regulations of several sRNAs still need extensive research. In this review, we discussed the topical advancements and findings relevant to pathogen attack and plant defense mediated by sRNAs. We attempted to point out diverse sRNAs as key defenders in plant systems. It is hoped that sRNAs would be exploited as a mainstream player to achieve food security by tackling different plant diseases. PMID- 29419805 TI - Hypoxia Enhances Differentiation of Adipose Tissue-Derived Stem Cells toward the Smooth Muscle Phenotype. AB - Smooth muscle differentiated adipose tissue-derived stem cells are a valuable resource for regeneration of gastrointestinal tissues, such as the gut and sphincters. Hypoxia has been shown to promote adipose tissue-derived stem cells proliferation and maintenance of pluripotency, but the influence of hypoxia on their smooth myogenic differentiation remains unexplored. This study investigated the phenotype and contractility of adipose-derived stem cells differentiated toward the smooth myogenic lineage under hypoxic conditions. Oxygen concentrations of 2%, 5%, 10%, and 20% were used during differentiation of adipose tissue-derived stem cells. Real time reverse transcription polymerase chain reaction and immunofluorescence staining were used to detect the expression of smooth muscle cells-specific markers, including early marker smooth muscle alpha actin, middle markers calponin, caldesmon, and late marker smooth muscle myosin heavy chain. The specific contractile properties of cells were verified with both a single cell contraction assay and a gel contraction assay. Five percent oxygen concentration significantly increased the expression levels of alpha-smooth muscle actin, calponin, and myosin heavy chain in adipose-derived stem cell cultures after 2 weeks of induction (p < 0.01). Cells differentiated in 5% oxygen conditions showed greater contraction effect (p < 0.01). Hypoxia influences differentiation of smooth muscle cells from adipose stem cells and 5% oxygen was the optimal condition to generate smooth muscle cells that contract from adipose stem cells. PMID- 29419804 TI - Alpha-Difluoromethylornithine, an Irreversible Inhibitor of Polyamine Biosynthesis, as a Therapeutic Strategy against Hyperproliferative and Infectious Diseases. AB - The fluorinated ornithine analog alpha-difluoromethylornithine (DFMO, eflornithine, ornidyl) is an irreversible suicide inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme of polyamine biosynthesis. The ubiquitous and essential polyamines have many functions, but are primarily important for rapidly proliferating cells. Thus, ODC is potentially a drug target for any disease state where rapid growth is a key process leading to pathology. The compound was originally discovered as an anticancer drug, but its effectiveness was disappointing. However, DFMO was successfully developed to treat African sleeping sickness and is currently one of few clinically used drugs to combat this neglected tropical disease. The other Food and Drug Administration (FDA) approved application for DFMO is as an active ingredient in the hair removal cream Vaniqa. In recent years, renewed interest in DFMO for hyperproliferative diseases has led to increased research and promising preclinical and clinical trials. This review explores the use of DFMO for the treatment of African sleeping sickness and hirsutism, as well as its potential as a chemopreventive and chemotherapeutic agent against colorectal cancer and neuroblastoma. PMID- 29419807 TI - Barriers and Facilitators of Partner Treatment of Chlamydia: A Qualitative Investigation with Prescribers and Community Pharmacists. AB - Chlamydia trachomatis is the most frequently-notified sexually transmitted infection in Australia. Effective and timely partner treatment of chlamydia is essential to reduce overall prevalence and the burden of infection. Currently in most of Australia, the only avenue for partner treatment of chlamydia ("standard partner therapy") is a tedious, and often inconvenient, process. The barriers and facilitators of standard partner therapy, and newer models of accelerated partner therapy (APT), need to be identified in the Australian setting. Additionally, the potential role of community pharmacists need to be explored. Semi-structured interview guides for two key stakeholder groups (prescribers and pharmacists) were developed and piloted. Eleven prescribers (general practitioners, sexual health clinicians and nurse practitioners) and twelve pharmacists practicing in the Perth metropolitan region were interviewed. Key reported barriers to standard partner therapy were lack of or delayed chlamydia testing. Key facilitators included ability to test and educate sexual partner. Key barriers for APT included prescribers' legal responsibility and potential for medication-related adverse effects. Healthcare provider consultation and chlamydia testing were seen as potential facilitators of APT. Pharmacists were receptive to the idea of expanding their role in chlamydia treatment, however, barriers to privacy must be overcome in order to be acceptable to prescribers and pharmacists. PMID- 29419808 TI - Fine-Tuning of Gene Expression by tRNA-Derived Fragments during Abiotic Stress Signal Transduction. AB - When plants are subjected to unfavorable environmental conditions, overall gene expression in stressed cells is altered from a programmed pattern for normal development to an adaptive pattern for survival. Rapid changes in plant gene expression include production of stress responsive proteins for protection as well as reduction of irrelevant proteins to minimize energy consumption during growth. In addition to the many established mechanisms known to modulate gene expression in eukaryotes, a novel strategy involving tRNA-derived fragments (tRFs) was recently reported to control gene expression. In animals, tRFs are shown to play a certain role in infected or cancer cells. However, tRFs are expected to function in the regulation of gene expression against abiotic stress conditions in plants. Moreover, the underlying mechanism linking up-regulation of tRFs under stress conditions with the stress tolerant response remains unknown. In this review, the biogenesis and putative function of diverse tRFs in abiotic stress signaling are discussed with a focus on tRFs as a transcriptional/post transcriptional/translational regulator. PMID- 29419809 TI - Live Dynamics of 53BP1 Foci Following Simultaneous Induction of Clustered and Dispersed DNA Damage in U2OS Cells. AB - Cells react differently to clustered and dispersed DNA double strand breaks (DSB). Little is known about the initial reaction to simultaneous induction of DSBs with different complexities. Here, we used live cell microscopy to analyse the behaviour of 53BP1-GFP (green fluorescence protein) foci formation at DSBs induced in U2OS cells by alpha particles, X-rays or mixed beams over a 75 min period post irradiation. X-ray-induced foci rapidly increased and declined over the observation interval. After an initial increase, mixed beam-induced foci remained at a constant level over the observation interval, similarly as alpha induced foci. The average areas of radiation-induced foci were similar for mixed beams and X-rays, being significantly smaller than those induced by alpha particles. Pixel intensities were highest for mixed beam-induced foci and showed the lowest level of variability over time as compared to foci induced by alphas and X-rays alone. Finally, mixed beam-exposed foci showed the lowest level of mobility as compared to alpha and X-ray exposure. The results suggest paralysation of chromatin around foci containing clustered DNA damage. PMID- 29419806 TI - Neuroprotective Effects of Bioactive Compounds and MAPK Pathway Modulation in "Ischemia"-Stressed PC12 Pheochromocytoma Cells. AB - This review surveys the efforts taken to investigate in vitro neuroprotective features of synthetic compounds and cell-released growth factors on PC12 clonal cell line temporarily deprived of oxygen and glucose followed by reoxygenation (OGD/R). These cells have been used previously to mimic some of the properties of in vivo brain ischemia-reperfusion-injury (IRI) and have been instrumental in identifying common mechanisms such as calcium overload, redox potential, lipid peroxidation and MAPKs modulation. In addition, they were useful for establishing the role of certain membrane penetrable cocktails of antioxidants as well as potential growth factors which may act in neuroprotection. Pharmacological mechanisms of neuroprotection addressing modulation of the MAPK cascade and increased redox potential by natural products, drugs and growth factors secreted by stem cells, in either undifferentiated or nerve growth factor-differentiated PC12 cells exposed to ischemic conditions are discussed for future prospects in neuroprotection studies. PMID- 29419810 TI - De Novo Assembly and Characterization of the Xenocatantops brachycerus Transcriptome. AB - Grasshoppers are common pests but also have high nutritional and commercial potential. Xenocatantops brachycerus Willemse (Orthoptera: Acrididae) is an economically important grasshopper species that is reared in China. Using the IlluminaHiSeqTM 4000 platform, three transcriptomes of the adult male, adult female, and nymph of X. brachycerus were sequenced. A total of 133,194,848 clean reads were obtained and de novo assembled into 43,187 unigenes with an average length of 964 bp (N50 of 1799 bp); of these, 24,717 (57.23%) unigenes matched known proteins. Based on these annotations, many putative transcripts related to X. brachycerus growth, development, environmental adaptability, and metabolism of nutritional components and bioactive components were identified. In addition, the expression profiles of all three transcriptome datasets were analyzed, and many differentially expressed genes were detected using RSEM and PossionDis. Unigenes. Unigenes with functions associated with growth and development exhibited higher transcript levels at the nymph stage, and unigenes associated with environmental adaptability showed increased transcription in the adults. These comprehensive X. brachycerus transcriptomic data will provide a useful molecular resource for gene prediction, molecular marker development, and studies on signaling pathways in this species and will serve as a reference for the efficient use of other grasshoppers. PMID- 29419812 TI - Attenuation of Glucose-Induced Myoglobin Glycation and the Formation of Advanced Glycation End Products (AGEs) by (R)-alpha-Lipoic Acid In Vitro. AB - : High-carbohydrate containing diets have become a precursor to glucose-mediated protein glycation which has been linked to an increase in diabetic and cardiovascular complications. The aim of the present study was to evaluate the protective effect of (R)-alpha-lipoic acid (ALA) against glucose-induced myoglobin glycation and the formation of advanced glycation end products (AGEs) in vitro. METHODS: The effect of ALA on myoglobin glycation was determined via the formation of AGEs fluorescence intensity, iron released from the heme moiety of myoglobin and the level of fructosamine. The extent of glycation-induced myoglobin oxidation was measured via the levels of protein carbonyl and thiol. RESULTS: The results showed that the co-incubation of ALA (1, 2 and 4 mM) with myoglobin (1 mg/mL) and glucose (1 M) significantly decreased the levels of fructosamine, which is directly associated with the decrease in the formation of AGEs. Furthermore, ALA significantly reduced the release of free iron from myoglobin which is attributed to the protection of myoglobin from glucose-induced glycation. The results also demonstrated a significant protective effect of ALA on myoglobin from oxidative damage, as seen from the decreased protein carbonyls and increased protein thiols. CONCLUSION: The anti-glycation properties of ALA suggest that ALA supplementation may be beneficial in the prevention of AGEs mediated diabetic and cardiovascular complications. PMID- 29419814 TI - An Improved Adaptive Received Beamforming for Nested Frequency Offset and Nested Array FDA-MIMO Radar. AB - For the conventional FDA-MIMO (frequency diversity array multiple-input-multiple output) Radar with uniform frequency offset and uniform linear array, the DOFs (degrees of freedom) of the adaptive beamformer are limited by the number of elements. A better performance-for example, a better suppression for strong interferences and a more desirable trade-off between the main lobe and side lobe can be achieved with a greater number of DOFs. In order to obtain larger DOFs, this paper researches the signal model of the FDA-MIMO Radar with nested frequency offset and nested array, then proposes an improved adaptive beamforming method that uses the augmented matrix instead of the covariance matrix to calculate the optimum weight vectors and can be used to improve the output performances of FDA-MIMO Radar with the same element number or reduce the element number while maintain the approximate output performances such as the received beampattern, the main lobe width, side lobe depths and the output SINR (signal-to interference-noise ratio). The effectiveness of the proposed scheme is verified by simulations. PMID- 29419813 TI - Biodegradable and Biocompatible Polyhydroxy-alkanoates (PHA): Auspicious Microbial Macromolecules for Pharmaceutical and Therapeutic Applications. AB - Polyhydroxyalkanoates (PHA) are bio-based microbial biopolyesters; their stiffness, elasticity, crystallinity and degradability are tunable by the monomeric composition, selection of microbial production strain, substrates, process parameters during production, and post-synthetic processing; they display biological alternatives for diverse technomers of petrochemical origin. This, together with the fact that their monomeric and oligomeric in vivo degradation products do not exert any toxic or elsewhere negative effect to living cells or tissue of humans or animals, makes them highly stimulating for various applications in the medical field. This article provides an overview of PHA application in the therapeutic, surgical and tissue engineering area, and reviews strategies to produce PHA at purity levels high enough to be used in vivo. Tested applications of differently composed PHA and advanced follow-up products as carrier materials for controlled in vivo release of anti-cancer drugs or antibiotics, as scaffolds for tissue engineering, as guidance conduits for nerve repair or as enhanced sutures, implants or meshes are discussed from both a biotechnological and a material-scientific perspective. The article also describes the use of traditional processing techniques for production of PHA based medical devices, such as melt-spinning, melt extrusion, or solvent evaporation, and emerging processing techniques like 3D-printing, computer-aided wet-spinning, laser perforation, and electrospinning. PMID- 29419815 TI - 23rd International Symposium on Infections in the Critically Ill Patient. AB - This 23rd International Symposium on Infections in the Critically Ill Patient aims to review current concepts, technology and present advances in infections in critically ill patient [...]. PMID- 29419811 TI - Plant and Mammal Aquaporins: Same but Different. AB - Aquaporins (AQPs) constitute an ancient and diverse protein family present in all living organisms, indicating a common ancient ancestor. However, during evolution, these organisms appear and evolve differently, leading to different cell organizations and physiological processes. Amongst the eukaryotes, an important distinction between plants and animals is evident, the most conspicuous difference being that plants are sessile organisms facing ever-changing environmental conditions. In addition, plants are mostly autotrophic, being able to synthesize carbohydrates molecules from the carbon dioxide in the air during the process of photosynthesis, using sunlight as an energy source. It is therefore interesting to analyze how, in these different contexts specific to both kingdoms of life, AQP function and regulation evolved. This review aims at highlighting similarities and differences between plant and mammal AQPs. Emphasis is given to the comparison of isoform numbers, their substrate selectivity, the regulation of the subcellular localization, and the channel activity. PMID- 29419816 TI - Structural prediction of protein models using distance restraints derived from cross-linking mass spectrometry data. AB - This protocol describes a workflow for creating structural models of proteins or protein complexes using distance restraints derived from cross-linking mass spectrometry experiments. The distance restraints are used (i) to adjust preliminary models that are calculated on the basis of a homologous template and primary sequence, and (ii) to select the model that is in best agreement with the experimental data. In the case of protein complexes, the cross-linking data are further used to dock the subunits to one another to generate models of the interacting proteins. Predicting models in such a manner has the potential to indicate multiple conformations and dynamic changes that occur in solution. This modeling protocol is compatible with many cross-linking workflows and uses open source programs or programs that are free for academic users and do not require expertise in computational modeling. This protocol is an excellent additional application with which to use cross-linking results for building structural models of proteins. The established protocol is expected to take 6-12 d to complete, depending on the size of the proteins and the complexity of the cross linking data. PMID- 29419817 TI - Investigation of the spatial structure and interactions of the genome at sub kilobase-pair resolution using T2C. AB - Chromosome conformation capture (3C) and its derivatives (e.g., 4C, 5C and Hi-C) are used to analyze the 3D organization of genomes. We recently developed targeted chromatin capture (T2C), an inexpensive method for studying the 3D organization of genomes, interactomes and structural changes associated with gene regulation, the cell cycle, and cell survival and development. Here, we present the protocol for T2C based on capture, describing all experimental steps and bio informatic tools in full detail. T2C offers high resolution, a large dynamic interaction frequency range and a high signal-to-noise ratio. Its resolution is determined by the resulting fragment size of the chosen restriction enzyme, which can lead to sub-kilobase-pair resolution. T2C's high coverage allows the identification of the interactome of each individual DNA fragment, which makes binning of reads (often used in other methods) basically unnecessary. Notably, T2C requires low sequencing efforts. T2C also allows multiplexing of samples for the direct comparison of multiple samples. It can be used to study topologically associating domains (TADs), determining their position, shape, boundaries, and intra- and inter-domain interactions, as well as the composition of aggregated loops, interactions between nucleosomes, individual transcription factor binding sites, and promoters and enhancers. T2C can be performed by any investigator with basic skills in molecular biology techniques in ~7-8 d. Data analysis requires basic expertise in bioinformatics and in Linux and Python environments. PMID- 29419819 TI - A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers. AB - PURPOSE: Peroxisome biogenesis disorders-Zellweger spectrum disorders (PBD-ZSD) are metabolic diseases with multisystem manifestations. Individuals with PBD-ZSD exhibit impaired peroxisomal biochemical functions and have abnormal levels of peroxisomal metabolites, but the broader metabolic impact of peroxisomal dysfunction and the utility of metabolomic methods is unknown. METHODS: We studied 19 individuals with clinically and molecularly characterized PBD-ZSD. We performed both quantitative peroxisomal biochemical diagnostic studies in parallel with untargeted small molecule metabolomic profiling in plasma samples with detection of >650 named compounds. RESULTS: The cohort represented intermediate to mild PBD-ZSD subjects with peroxisomal biochemical alterations on targeted analysis. Untargeted metabolomic profiling of these samples revealed elevations in pipecolic acid and long-chain lysophosphatidylcholines, as well as an unanticipated reduction in multiple sphingomyelin species. These sphingomyelin reductions observed were consistent across the PBD-ZSD samples and were rare in a population of >1,000 clinical samples. Interestingly, the pattern or "PBD-ZSD metabolome" was more pronounced in younger subjects suggesting studies earlier in life reveal larger biochemical changes. CONCLUSION: Untargeted metabolomics is effective in detecting mild to intermediate cases of PBD-ZSD. Surprisingly, dramatic reductions in plasma sphingomyelin are a consistent feature of the PBD ZSD metabolome. The use of metabolomics in PBD-ZSD can provide insight into novel biomarkers of disease. PMID- 29419818 TI - SCYL1 variants cause a syndrome with low gamma-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN). AB - PURPOSE: Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure. The occurrence of SCYL1 deficiency among patients with previously undetermined infantile cholestasis or acute liver failure has not been studied; furthermore, little is known regarding the hepatic phenotype. METHODS: We aimed to identify patients with SCYL1 variants within an exome-sequencing study of individuals with infantile cholestasis or acute liver failure of unknown etiology. Deep clinical and biochemical phenotyping plus analysis of liver biopsies and functional studies on fibroblasts were performed. RESULTS: Seven patients from five families with biallelic SCYL1 variants were identified. The main clinical phenotype was recurrent low gamma glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy and a variable neurological phenotype of later onset (CALFAN syndrome). Liver crises were triggered by febrile infections and were transient, but fibrosis developed. Functional studies emphasize that SCYL1 deficiency is linked to impaired intracellular trafficking. CONCLUSION: SCYL1 deficiency can cause recurrent low-GGT cholestatic liver dysfunction in conjunction with a variable neurological phenotype. Like NBAS deficiency, it is a member of the emerging group of congenital disorders of intracellular trafficking causing hepatopathy. PMID- 29419821 TI - The Use of Individual Provider Performance Reports by US Hospitals. AB - Medicare reimbursement for hospitals is increasingly tied to performance. The use of individual provider performance reports offers the potential to improve clinical outcomes through social comparison, and isolated cases of clinical dashboard uses at specific institutions have been previously reported. However, little is known about overall trends in how hospitals use the electronic health record to track and provide feedback on provider performance. We used data from 2013 to 2015 from the American Hospital Association (AHA) Annual Survey Information Technology Supplement, which asked hospitals if they have used electronic data to create performance profiles. We linked these data to AHA Annual Survey responses for all general adult and pediatric hospitals. Multivariable logistic regression was used to model the odds of use as a function of hospital characteristics. In 2015, 65.8% of the 2334 respondents used performance profiles, whereas 59.3% of the 2077 respondents used them in 2013. Report use was associated with non-profit status (odds ratio [OR], 2.77; 95% confidence interval [CI], 1.94-3.95) compared to for-profit, large hospital size (OR, 2.37; 95% CI, 1.56-3.60) compared to small size, highest quartile of bed adjusted expenditures compared to bottom quartile (OR, 2.09; 95% CI, 1.55-2.82; P < .01), and participation in a health maintenance organization (OR, 1.50; 95% CI, 1.17-1.90; P < .01) or bundled payment program (OR, 1.61; 95% CI, 1.18- 2.19; P < .01). While a majority of hospitals now use such profiles, more than a third do not. The hospitals that do not use performance profiles may be less well positioned to adapt to value-based payment reforms. PMID- 29419820 TI - Correction: Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data. AB - In the published version of this article, the name of the 18th author was misspelled as Minjie Lou. The correct name is Minjie Luo. The authors regret the error. PMID- 29419822 TI - Immunotherapy-Induced Colitis: An Emerging Problem for the Hospitalist. AB - Since their introduction for melanoma treatment, the use of immune checkpoint inhibitors (ICIs) has rapidly expanded. Though their impact on survival is irrefutable, these medications have been associated with autoimmune-like adverse events related to their ability to induce the immune system. One of the most commonly affected organ systems is the gastrointestinal (GI) tract, in which manifestations range from mild diarrhea to severe colitis with intestinal perforation. Because of the increased use of ICIs, hospitalists are caring for an increasing number of patients experiencing their adverse events. We present a case-oriented review of the GI adverse events associated with the use of ICIs to familiarize the hospitalist with their mechanism of action and potential complications and to emphasize the importance of early diagnosis and treatment to decrease morbidity and mortality. PMID- 29419823 TI - Positive effect of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) on homogeneous photocatalytic reduction of CO2. AB - A significant decrease in the amount of the sacrificial electron donor triethanolamine (TEOA) required for the homogeneous photocatalytic reduction of CO2 using rhenium-based catalytic systems can be achieved by adding small quantities of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to the reaction mixture. The turnover numbers (TONs) and frequencies (TOFs) measured for the reactions described herein are even higher than those observed in reaction mixtures containing high concentrations of TEOA. Furthermore, replacing TEOA with DBU in the solutions of Re(i)/Ru(ii) mixed catalytic systems leads to a doubling of the values of TON and TOF. PMID- 29419825 TI - Synthesis and structure determination via ultra-fast electron diffraction of the new microporous zeolitic germanosilicate ITQ-62. AB - Here, we present the synthesis and structure determination of the new zeolite ITQ 62. Its structure was determined via ultra-fast electron diffraction tomography and refined using powder XRD data of the calcined material. This new zeolite contains a tridirectional channel system of highly distorted 8-rings, as well as a monodirectional 12-ring channel system. PMID- 29419824 TI - Massive quantum regions for simulations on bio-nanomaterials: synthetic ferritin nanocages. AB - QM/MM molecular dynamics simulations on the 4His-DeltaC* protein cage have been performed using multiple active zones (up to 86 quantum regions). The regulation and nanocage stability exerted by the divalent transition metal ions in the monomer-to-cage conversion have been understood by comparing high level quantum trajectories obtained using Cu2+ and Ni2+ coordination ions. PMID- 29419826 TI - How should multicomponent supramolecular gels be characterised? AB - Low molecular weight gels, or supramolecular gels, are formed when small molecules self-assemble into fibrous structures. Above a critical concentration, the entanglement and cross-linking of these structures leads to the formation of a self-supporting gel. There are many examples where a single component is used to form such gels. There is however an ever-increasing interest in using multiple components. Here, if each component is able to form a gel by itself, a range of fibre types are possible, formed by either random or specific associations between the low molecular weight gelators (LMWG). The properties of the networks will depend on how the LMWG assemble into the primary fibrous structures and then how these primary structures entangle. As such, to understand these gels, it is necessary to understand the networks across multiple length scales. Here, we discuss the current state of the art, the effectiveness of the different techniques that have been used, and hopefully provide the impetus for the field to move away from the cartoon-level discussion of assembly. PMID- 29419827 TI - Precursor non-stoichiometry to enable improved CH3NH3PbBr3 nanocrystal LED performance. AB - High photoluminescence quantum yields and narrow emission wavelengths, combined with low temperature solution processing, make CH3NH3PbBr3 nanocrystals (NCs) favorable candidates for light-emitting applications. Herein, we describe the synthesis of CH3NH3PbBr3 NC inks by a convenient room-temperature ligand assisted reprecipitation protocol. We further investigate the effect of modulation of the CH3NH3Br : PbBr2 ratio during NC synthesis on the optical properties, crystallinity, particle size distribution and film formation of the NC ink. Subsequently, we fabricate LEDs using these NCs as the emissive layer and the highest efficiency (1.75% external quantum efficiency) and brightness (>2700 cd m 2) is achieved for the 1.15 : 1 precursor ratio. It is inferred that the NC surface properties and film coverage are more crucial than the photoluminescence intensity to achieve high device efficiency. Moreover, by separating the NC synthesis and thin film formation processes, we can exert more control during device fabrication, which makes it very promising for scale-up applications. PMID- 29419828 TI - Rational design of double-shelled Fe-, N-, and S-tridoped hollow mesoporous carbon spheres as high-performance catalysts for organic reactions. AB - Herein, hollow large-pore mesoporous carbon spheres with double Fe-, N-, and S tridoped shells (DSHM-Fe/SNC) were fabricated via a rational self-sacrificing template route. Benefiting from the abundance of multi-heteroatom doping induced active sites, unique hierarchical structures to enhance active site exposure, and conductive networks to facilitate electron transfer, the as-prepared DSHM-Fe/SNC materials exhibit remarkable catalytic performance and excellent reusability toward reduction of p-nitrophenol. PMID- 29419829 TI - Ion hydration: linking self-diffusion and reorientational motion to water structure. AB - Ions affect the self-diffusion and relaxation of water. Such ion-induced changes of water dynamics have long been rationalized in terms of the change of the water structure around the ions. The aim of this paper is to establish a link between dynamics and the "water structure" on the basis of the extended jump (EJ) model for the reorientational motion of water, Eyring's transition state theory of the self-diffusion of water, and the statistical thermodynamic preferential solvation theory developed from the Kirkwood-Buff (KB) theory. Through the synthesis of the above three, we formulate a scheme to correlate the ion-induced water dynamics changes to the water structure. With this new formulation, it is shown that chaotropic or negatively hydrated ions preferentially bind the transition state of water motion thereby stabilizing the transition state, whereas the exclusion of kosmotropes or positively hydrated ions suppresses the formation of the transition state. The ion effects on water dynamics are thus analyzed in a unified manner in terms of KB integrals, which represent the (averaged) "structures" of water. PMID- 29419830 TI - Light-matter interaction in the strong coupling regime: configurations, conditions, and applications. AB - Resonance interaction between a molecular transition and a confined electromagnetic field can reach the coupling regime where coherent exchange of energy between light and matter becomes reversible. In this case, two new hybrid states separated in energy are formed instead of independent eigenstates, which is known as Rabi splitting. This modification of the energy spectra of the system offers new possibilities for controlled impact on various fundamental properties of coupled matter (such as the rate of chemical reactions and the conductivity of organic semiconductors). To date, the strong coupling regime has been demonstrated in many configurations under different ambient conditions. However, there is still no comprehensive approach to determining parameters for achieving the strong coupling regime for a wide range of practical applications. In this review, a detailed analysis of various systems and corresponding conditions for reaching strong coupling is carried out and their advantages and disadvantages, as well as the prospects for application, are considered. The review also summarizes recent experiments in which the strong coupling regime has led to new interesting results, such as the possibility of collective strong coupling between X-rays and matter excitation in a periodic array of Fe isotopes, which extends the applications of quantum optics; a strong amplification of the Raman scattering signal from a coupled system, which can be used in surface-enhanced and tip-enhanced Raman spectroscopy; and more efficient second-harmonic generation from the low polaritonic state, which is promising for nonlinear optics. The results reviewed demonstrate great potential for further practical applications of strong coupling in the fields of photonics (low-threshold lasers), quantum communications (switches), and biophysics (molecular fingerprinting). PMID- 29419831 TI - Electrochemically controlled winding and unwinding of substrate-supported carbon nanoscrolls. AB - Carbon nanoscrolls (CNSs) formed spontaneously on the basal plane of highly ordered pyrolytic graphite (HOPG) show winding and unwinding movements when potential steps from 0 V to -0.5 V, -0.6 V and -0.9 V are applied on HOPG immersed in an aqueous electrolyte solution (0.1 M H2SO4). Reversible changes in CNS radial dimensions exceeding 10 nm in the axial direction and 50 nm in the lateral direction are ascribed to variations in the surface tension and electric double-layer structure under applied potentials. Radial motion is observed exclusively on scrolled tube-shaped nanostructures, while other parts of the HOPG surface including planar areas, simple bended and lifted step edges, and kinks remain intact. The mechanism explaining the observed phenomenon is proposed and its significance for prospective applications in electrochemically controlled nanomechanical actuators is outlined. PMID- 29419832 TI - Decarbonylative thioetherification by nickel catalysis using air- and moisture stable nickel precatalysts. AB - A general, highly selective method for decarbonylative thioetherification of aryl thioesters by C-S cleavage is reported. These reactions are promoted by a commercially-available, user-friendly, inexpensive, air- and moisture-stable nickel precatalyst. The process occurs with broad functional group tolerance, including free anilines, cyanides, ketones, halides and aryl esters, to efficiently generate thioethers using ubiquitous carboxylic acids as ultimate cross-coupling precursors (cf. conventional aryl halides or pseudohalides). Selectivity studies and site-selective orthogonal cross coupling/thioetherification are described. This thioester activation/coupling has been highlighted in the expedient synthesis of biorelevant drug analogue. In light of the synthetic utility of thioethers and Ni(ii) precatalysts, we anticipate that this user-friendly method will be of broad interest. PMID- 29419833 TI - A simple "mix-and-detection" method for the sensitive detection of telomerase from cancer cells under absolutely isothermal conditions. AB - We develop a simple "mix-and-detection" method for the sensitive detection of telomerase from cancer cells under absolutely isothermal conditions. This method enables one-step and one-tube detection of telomerase with a detection limit of 3 cells, and it can be further applied for the screening of telomerase inhibitors and the discrimination of cancer cells from normal cells. PMID- 29419834 TI - A complete set of pnictocarbynes: [M([triple bond, length as m dash]CAPh2)(CO)2(Tp*)] (M = Mo, W; A = N, P, As, Sb, Bi; Tp* = hydrotris(dimethylpyrazolyl)-borate). AB - The first two complete series of pnictogen functionalised carbyne complexes, [M([triple bond, length as m-dash]CAPh2)(CO)2(Tp*)] (M = Mo, W; A = N, P, As, Sb, Bi; Tp* = hydrotris(3,5-dimethylpyrazol-1-yl)borate), have been prepared. The heavier analogues (A ? N) result from successive treatment of [M([triple bond, length as m-dash]CBr)(CO)2(Tp*)] with nBuLi and ClAPPh2 (A = P, Sb, Bi) or BrAsPh2 and include the first examples of arsino, stibino or bismuthino carbyne complexes. PMID- 29419836 TI - Nanoscale diffusive memristor crossbars as physical unclonable functions. AB - Physical unclonable functions have emerged as promising hardware security primitives for device authentication and key generation in the era of the Internet of Things. Herein, we report novel physical unclonable functions built upon the crossbars of nanoscale diffusive memristors that translate the stochastic distribution of Ag clusters in a SiO2 matrix into a random binary bitmap that serves as a device fingerprint. The random dispersion of Ag led to an uneven number of clusters at each cross-point, which in turn resulted in a stochastic ability to switch in the Ag:SiO2 diffusive memristors in an array. The randomness of the dispersion was a barrier to fingerprint cloning and the unique fingerprints of each device were persistent after fabrication. Using an optimized fabrication procedure, we maximized the randomness and achieved an inter-class Hamming distance of 50.68%. We also discovered that the bits were not flipping after over 104 s at 400 K, suggesting superior reliability of our physical unclonable functions. In addition, our diffusive memristor-based physical unclonable functions were easy to fabricate and did not require complicated post processing for digitization and thus, provide new opportunities in hardware security applications. PMID- 29419837 TI - Gold-catalyzed N,O-functionalization of 1,4-diyn-3-ols with N-hydroxyanilines to form highly functionalized pyrrole derivatives. AB - This work describes new N,O-functionalization of 1,4-diyn-3-ols with N hydroxyanilines to yield highly functionalized pyrrole derivatives. In a postulated mechanism, N-hydroxyaniline attacks the more electron-rich alkynes via regioselective N-attack to form unstable ketone-derived nitrones that react with their tethered alkynes via an intramolecular oxygen-transfer to form alpha-oxo gold carbenes. This new method is applicable to a short synthesis of a bioactive molecule, a PDE4 inhibitor. PMID- 29419839 TI - Tunable clustering of magnetic nanoparticles in microgels: enhanced magnetic relaxivity by modulation of network architecture. AB - In the present work we used microgels as colloidal containers for the loading of hydrophobic magnetic nanoparticles using the solvent exchange method. We varied systematically two parameters: (i) the crosslinking degree of microgels (1-4.5 mol% crosslinker) and (ii) loading of hydrophobic magnetite nanoparticles (d = 7 nm) in microgels (2-10 wt%). The experimental data show that the interplay between these two parameters provides efficient control over the clustering of magnetic nanoparticles in the microgel structure. Transverse magnetization relaxation measurements indicate that the formation of nanoparticle clusters in microgels induces non-linear enhancement of the relaxivity with the increase of nanoparticle loading in microgels. The results suggest that the modulation of the microgel network architecture can be efficiently applied to trigger self-assembly processes inside microgels and design hybrid colloids with unusual morphologies and properties. PMID- 29419840 TI - Chemoselective and stereospecific iodination of alkynes using sulfonium iodate(i) salt. AB - An efficient and highly chemoselective iodination of alkynes using a sulfonium iodate(i) electrophilc reagent under metal-free conditions has been realized. The reactivity of sulfonium iodate(i) salt could be significantly diverse in the presence of water as the solvent, enabling the (E)-1,2-diiodoalkenes stereospecifically. This stereodivergent approach is amenable to a wide range of alkyne substrates and demonstrates a diverse functional group tolerance resulting in synthetically valuable 1-iodoalkyne and (E)-vicinal-diiodoalkenes in good to excellent yields (up to 99%) with 100% selectivity under ambient conditions. PMID- 29419842 TI - Correction: New di-anchoring A-pi-D-pi-A configured organic chromophores for DSSC application: sensitization and co-sensitization studies. AB - Correction for 'New di-anchoring A-pi-D-pi-A configured organic chromophores for DSSC application: sensitization and co-sensitization studies' by Praveen Naik et al., Photochem. Photobiol. Sci., 2018, DOI: 10.1039/c7pp00351j. PMID- 29419843 TI - Driving water cavitation in a hydrogel cavity. AB - We study the dynamics of the dehydration process of a hydrogel with a cavity filled with water. We identify two transient phases: the first one dominated by an inflatable-balloon deformation mode, and the second by a suction effect, determining highly not homogeneous deformation modes of the hydrogel walls. This last phase triggers negative pressures into the cavity up to the typical values of water cavitation. An analysis of the factors allowing cavitation pressure to form inside the cavity is proposed, to allow for precise tuning of the key geometrical and material parameters. PMID- 29419846 TI - Tailoring the energy band in flexible photodetector based on transferred ITO/Si heterojunction via interface engineering. AB - Interface engineering is an important method to modulate electronic structures for improving the physical properties of semiconductors as well as designing novel devices. Recently, development of flexible electronic devices based on inorganic thin films on flexible substrates, which provides solutions to meet the emerging technological demands, may also expend the methodology of interface engineering. Herein, a semitransparent photodetector based on an indium-tin oxide (ITO)-on-silicon (Si) heterojunction was fabricated on a flexible substrate and investigated under mechanical bending strains. It is found that the barrier height of the heterojunction can be tailored continuously and reversibly from 0.23 eV to 0 eV, corresponding to the Schottky and Ohmic junctions respectively. Meanwhile, the turn-on voltage and the response time of the as-prepared photodetector can be obviously reduced under bending strain, which can be attributed to the modulation of the Si bandgap and hole mobility. Our experimental studies not only shed new light on the strain modulation mechanism of the heterojunction interface, but also pave a prominent way to integrated high performance flexible photodetectors. PMID- 29419847 TI - Wrinkling patterns in soft shells. AB - Curvature plays an important role in the morphological evolution of soft shells under stretch. Here, through a combination of experiment, theory and simulation, we investigate the behavior of a hemispherical soft shell subject to an increasing outward point force at its pole. In contrast to an inward point force inducing a polygonal pattern of buckling in the shell, we observe a four-stage morphological transition and symmetry breaking under an increasing outward point force. The shell undergoes axisymmetric deformation around its pole and then buckles into a non-axisymmetric shape with a number of shallow wrinkles emanating from the pole, followed by the emergence of crater-like deep crumples and ultimately a transformation into a wrinkled pseudocone. Our theoretical analysis and numerical simulations yield the critical conditions for the morphological transitions at each stage of deformation and reveal the underlying interplays between elastic bending and stretching energies and the curvature of the shell. PMID- 29419848 TI - Successive addition of two different Grignard reagents to nitriles: access to alpha,alpha-disubstituted propargylamine derivatives. AB - The successive addition of two different Grignard reagents to acyl cyanohydrins was performed with success by taking advantage of the low reactivity of alkynyl Grignard reagents. The experimental conditions were adjusted so that they were not reactive during the first addition step, but reactive only in the second one. The synthetic utility of the prepared compounds was validated by the preparation of chiral quaternary alpha-amino acids. PMID- 29419849 TI - BRAF V600 Mutation Profile of Metastatic Melanoma in the Thrace Region of Turkey. AB - OBJECTIVE: BRAF is the most common mutation in melanoma. The most common subtype is BRAF V600E, followed by V600K. Initially, the authors aimed to investigate whether clinicopathological features of melanoma are associated with BRAF mutations. We then aimed to present the relationships between the clinicopathological features and the mutated subtype (V600E vs V600K). MATERIAL AND METHOD: 61 patients with metastatic malignant melanoma (affecting the lymph node or other distant sites) were selected. Patient data regarding age at the time of diagnosis, sex, metastatic site (lymph node, distant metastasis or both) and primary tumour site were obtained from the hospital's database. Tissue samples containing at least 30% tumour cells were isolated from the specimens of 61 patients (24 samples from primary tumours and 37 from metastatic foci) for BRAF analysis. Comparisons between the BRAF V600 mutation and clinicopathological and histopathological features were performed. RESULTS: BRAF V600 mutation was detected in 34 (55.7%) patients. The subtype was BRAF V600E in 22 (64.7%) patients, BRAF V600K in 11(32.4%) patients and BRAF V600R in 1(2.9%) patient. The crucial results of the present study may be summarized as follows: i) BRAF V600 mutation was more common in older patients and tumors with BRAF V600 mutation revealed necrosis and LVI more commonly than wild-type tumors, ii) BRAF V600K mutation was more common in older patients and BRAF V600K mutated tumors exhibited ulceration more commonly than tumors with BRAF V600E mutation (close to significant). CONCLUSION: The BRAF V600 mutation may have interactions with prognostic clinicoptahological features of melanoma including necrosis and lymphovascular invasion. V600K mutation may be more common than expected and may have different associations with properties of the tumor such as tumor ulceration and patient age. Investigation of the mutated subtype of the BRAF gene may therefore reveal more detailed data about the management of melanoma and may also prevent missing of candidates for BRAF inhibitor therapies. PMID- 29419851 TI - [Identification of pathogenic mutations in two Chinese families affected with primary localized cutaneous amyloidosis]. AB - OBJECTIVE To identify potential mutations in two Chinese families affected with primary localized cutaneous amyloidosis. METHODS Peripheral blood samples of the family were collected with informed consent. Genomic DNA was extracted with a phenol chloroform method. All of the 17 exons and their flanking splicing sites of the OSMR gene were amplified with PCR and subjected to Sanger sequencing. Suspected mutations were verified with PCR - restriction fragment length polymorphism and high-resolution melting assays. RESULTS A missense mutation (c.1538G>A) was found in exon 10 of the OSMR gene in all of the six patients from family 1. A missense mutation (c.2081C>T) was found in exon 14 of the OSMR gene in all of the four patients from family 2. The same mutations were not found among the healthy controls. CONCLUSION Two missense mutations (c.1538G>A and c.2081C>T) were detected in the OSMR gene in two Chinese families affected with primary localized cutaneous amyloidosis. Our findings have further confirmed the pathogenicity of such mutations. PMID- 29419850 TI - [Discussion on the standard of clinical genetic testing report and the consensus of gene testing industry]. AB - The widespread application of next generation sequencing (NGS) in clinical settings has enabled testing, diagnosis, treatment and prevention of genetic diseases. However, many issues have arisen in the meanwhile. One of the most pressing issues is the lack of standards for reporting genetic test results across different service providers. The First Forum on Standards and Specifications for Clinical Genetic Testing was held to address the issue in Shenzhen, China, on October 28, 2017. Participants, including geneticists, clinicians, and representatives of genetic testing service providers, discussed problems of clinical genetic testing services across in China and shared opinions on principles, challenges, and standards for reporting clinical genetic test results. Here we summarize expert opinions presented at the seminar and report the consensus, which will serve as a basis for the development of standards and guidelines for reporting of clinical genetic testing results, in order to promote the standardization and regulation of genetic testing services in China. PMID- 29419852 TI - [Clinical features of patients with Becker muscular dystrophy and deletions of the rod domain of dystrophin gene]. AB - OBJECTIVE To explore the clinical features of patients carrying deletions of the rod domain of the dystrophin gene. METHODS Clinical data of 12 Chinese patients with Becker muscular dystrophy (BMD) and such deletions was reviewed. RESULTS Most patients complained of muscle weakness of lower limbs. Two patients had muscle cramps, one had increased creatine kinase (CK) level, and one had dilated cardiomyopathy. CONCLUSION Compared with DMD, the clinical features of BMD are much more variable, particularly for those carrying deletions of the rod domain of the dystrophin gene. Muscular weakness may not be the sole complaint of BMD. The diagnosis of BMD cannot be excluded by moderately elevated CK. For male patients with dilated cardiomyopathy, the possibility of BMD should be considered. PMID- 29419853 TI - [Genetic analysis and prenatal diagnosis for ten families affected with tuberous sclerosis complex]. AB - OBJECTIVE To provide prenatal diagnosis for families affected with tuberous sclerosis complex and explore the correlation between phenotype and genotype. METHODS For probands from 10 families, all exons and splicing regions of the TSC1 and TSC2 genes were analyzed with high throughput DNA sequencing. Suspected mutations were verified by Sanger sequencing. RESULTS All probands were found to have mutations, which included 1 case with TSC1 mutation and 9 cases with TSC2 mutations (missense mutations in 6, nonsense mutations in 2, and frameshifting mutation in 1 case). Prenatal diagnosis was provided for 9 cases, and 1 fetus was found to carry a mutation. Genetic analysis has identified a novel pathogenic mutation (TSC2 c.2415-2416 ins GT). CONCLUSION Identification of pathological mutations for tuberous sclerosis complex can facilitate genetic counseling and prenatal diagnosis for the affected families. PMID- 29419854 TI - [Analysis of 10 patients with duplications of 15q11q13 region and autism features]. AB - OBJECTIVE To analyze the clinical and genetic features of 10 unrelated patients with duplications of 15q11q13 region and autism features.METHODS Karyotyping,chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) were carried out for the patients and their parents.RESULTS Eight patients presented with a supernumerary marker chromosome (SMC) of unknown origin by G-banding analysis and triplication of the 15q11q13 region by high resolution CMA analysis. Two remaining patients had normal karyotypes but duplications of the 15q11q13 region. All duplications have encompassed the Prader Willi/Angelman syndrome critical region (PWACR). Similar gains in copy number were not detected among the parents of the patients,suggesting a de novo origin for them. Analysis of SNP-array data of the family trios using Chromosome Analysis Suite Software found that the copy number gains have originated from the mothers.The diagnosis of 15q11q13 duplication syndrome was ascertained. For patients with SMC detected by karyotyping analysis,a FISH assay using probes specific for the 15q11q13 region showed that such SMC also derived from chromosome 15q11q13 region and contained two copy numbers, which was consistent with the result of CMA.CONCLUSION Ten patients with autism and 15q11q13 duplications were identified with combined karyotyping, CMA and FISH analysis. A phenotype - genotype correlation was established. PMID- 29419855 TI - [Clinical report of testicular hypoplasia combined with 21-hydroxylase deficiency]. AB - OBJECTIVE To investigate the correlation of 21-hydroxylase deficiency (21-OHD) with male testicular dysplasia. METHODS Clinical data of 8 infertile males with congenital adrenal hyperplasia due to 21-OHD was retrospectively analyzed. In addition, potential mutations of the CYP21A2 gene was detected. RESULTS All patients were referred because of azoospermia or severe oligospermia and had small testis with averaged testicular volume of 6.1 mL. Three patients had testicular adrenal rest tumors. Endocrinologic examinations revealed low levels of leutinizing hormone and follicular stimulating hormone, normal or elevated testosterone, elevated progesterone, elevated or normal adrenocoticotropic hormone, and low or normal cortisol. All patients had adrenal cortical hyperplasia, 5 with adrenal adenoma, 1 case associated with bilateral adrenal myelolipoma. All patients were given glucocorticoid replacement therapy for 3 to 6 months, which successfully improved the seminal status of 6 patient and resulted pregnancies in 5 couples. Seven pathogenic mutations of the CYP21A2 gene among the 8 patients. CONCLUSION 21-OHD can cause testicular hypoplasia and spermatogenic failure. Glucocorticoids and operations can obtain good result and improve spermatogenesis. Our results have shown a good genotype/phenotype correlation in these cases. All patients have carried the p.Ile172Asn mutation, which is associated with simple virilizing form. PMID- 29419856 TI - [Analysis of SLC25A13 gene mutations in five infants with neonatal intrahepatic cholestasis caused by citrin deficiency]. AB - OBJECTIVE To identify potential mutations in five infants with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). METHODS The SLC25A13 gene was analyzed by next-generation sequencing. Suspected mutations were confirmed by PCR and Sanger sequencing in the probands and their parents. Impact of novel mutations was predicted with PolyPhen-2 software. RESULTS All neonates have harbored mutations of the SLC25A13 gene. Eight mutations were discovered, which included two novel mutations (c.1357A>G and c.1663dup23). All parents were found to be carriers of the mutations. CONCLUSION Mutations of the SLC25A13 gene probably underlie the NICCD among the five patients, among which 851del4 and 1638-1660dup were the most common ones. This has enriched the spectrum of SLC25A13 mutation in association with NICCD. PMID- 29419857 TI - [Detection of GCDH mutations in five Chinese patients with glutaric acidemia type I]. AB - OBJECTIVE To detect potential mutations of GCDH gene in five patients with glutaric acidemia type I (GA-I). METHODS Genomic DNA was extracted from peripheral blood samples from the patients. The 11 exons and their flanking sequences of the GCDH gene were amplified with PCR and subjected to direct sequencing. RESULTS Four mutations of the GCDH gene were identified among the patients, which included c.532G>A (p.G178R), c.533G>A (p.G178E), c.106_107delAC (p.Q37fs*5) and c.1244-2A>C. Among these, c.1244-2A>C was the most common, while c.106_107delAC was a novel mutation, which was predicted to be pathogenic by MutationTaster software. CONCLUSION The diagnosis of GA-I has been confirmed in all of the five patients. Identification of the novel GCDH mutations has enriched the mutational spectrum of the GCDH gene. PMID- 29419858 TI - [Origin and morphological features of small supernumerary marker chromosomes in Turner syndrome]. AB - OBJECTIVE To explore the origin and morphological features of small supernumerary marker chromosomes (sSMCs) in Turner syndrome. METHODS For 5 cases of Turner syndrome with a sSMC identified by conventional G-banding, dual-color fluorescence in situ hybridization (FISH) was applied to explore their origin and morphological features. RESULTS Among the 5 cases, 3 have derived from the X chromosome, which included 2 ring chromosomes and 1 centric minute. For the 2 sSMCs derived from the Y chromosome, 1 was ring or isodicentric chromosome, while the other was an isodicentric chromosome. CONCLUSION The sSMCs found in Turner syndrome have almost all derived from sex chromosomes. The majority of sSMCs derived from the X chromosome will form ring chromosomes, while a minority will form centric minute. While most sSMC derived from Y chromosome may exist as isodicentric chromosomes, and a small number may exist as rings. For Turner syndrome patients with sSMCs, dual-color FISH may be used to delineate their origins to facilitate genetic counseling and selection of clinical regime. PMID- 29419860 TI - [Performance of prenatal screening by non-invasive cell-free fetal DNA testing for women with various indications]. AB - OBJECTIVE To assess the performance of non-invasive prenatal testing (NIPT) based on massive parallel sequencing. METHODS A total of 10 275 maternal blood samples were collected. Fetal chromosomal aneuploides were subjected to low coverage whole genome sequencing. Patients with high risks received further prenatal diagnosis. The outcome of all patients were followed up. RESULTS High-throughput sequencing detected 72 pregnancies with fetal autosomal chromosomal aneuploidy, including 57 cases of trisomy 21, 14 cases of trisomy 18, and 1 case of trisomy 13. The positive predictive value for trisomies 21 and 18 were 98.25% and 91.67%, respectively. Comparing its performance in intermediate or high risk pregnancies, advanced maternal age pregnancies and volunteering to test pregnancies, the positive predictive value were 100%, 95%, 90% and 50%, respectively. The follow up result was only 1 case of 21 trisomy false negative with high risk. For the 56 cases of trisomy 21, the high risk group accounted for 55%, advanced maternal age accounted for 29%, the intermediate risk referred to 14%, the volunteering to test group accounted for 2%. CONCLUSION The performance of NIPT for trisomies 21, 18 and 13 was satisfactory. The method can be used for women with advanced gestational age. NIPT has offered an ideal secondary screening method for those with an intermediate or high risk, and can reduce the rate of birth defects. PMID- 29419859 TI - [Identification of 22q11.2 microdeletion among patients with congenital heart diseases using droplet digital PCR]. AB - OBJECTIVE To develop a new method for detecting 22q11.2 deletion syndrome (22q11.2 DS) in clinical settings. METHODS Specific primers and fluorescence probes were designed to target the TBX1 gene within the 22q11.2 deletion region and a reference gene RPP30. Multiplexed droplet digital PCR (ddPCR) was run to detect the 22q11.2 microdeletion by calculating the ratio of positive droplet number of TBX1/RPP30. RESULTS Three cases of 22q11.2 microdeletion previously confirmed by array comparative genome hybridization were successfully identified. Subsequently, the ddPCR detected two further cases of 22q11.2 microdeletion among 14 children with congenital heart diseases. CONCLUSION The ddPCR technique has provided a rapid and cost-effective method for detecting 22q11.2 microdeletion in clinical settings. PMID- 29419861 TI - [Data analysis of non-invasive prenatal testing based on special loci in cell free fetal DNA]. AB - OBJECTIVE To analyze the data of non-invasive prenatal testing based on specific loci of circulating cell-free fetal DNA (cffDNA). METHODS Selected loci of target chromosomes were analyzed by sequence capture and sequencing. Meanwhile, 600 loci were selected from other chromosomes for determining the concentration of cffDNA. RESULTS A total of 768 specific loci were captured on chromosomes 21 and 18, and used to determine whether the two were abnormal. When the minimum concentration of detected cffDNA was set at 3% and the threshold of Z score was set to [-6,6], the specificity of the analysis was 99.37% and the sensitivity was 100%. CONCLUSION A reliable, convenient and low-cost analytical method has been developed. The method requires less sequencing data for non-invasive prenatal testing, and can accurately detect abnormalities of fetal chromosomes 21 and 18, and simultaneously determine the concentration of cffDNA. PMID- 29419862 TI - [Application of BoBs technique for 690 cases of prenatal diagnosis]. AB - OBJECTIVE To assess the value of BAC-on-Beads(BoBs) technology combined with conventional chromosomal karyotyping for reducing birth defects. METHODS For 690 women with singleton pregnancy and indication for prenatal diagnosis, aneuploidies of chromosomes 13, 18, 21, X and Y, in addition with 9 microdeletions and microduplications, were detected with the BoBs assay. And the results were compared with that of conventional karyotyping of amniocytes. RESULTS Karyotyping analysis attained a positive rate of 6.08% (42/690), which included 36 aneuploidies and 6 structural aberrations. The BoBs assay attained a detection rate of 5.95% (41/689). In addition to all chromosomal aneuploidies detected by conventional karyotyping, the Bobs assay has detected 3 cases with Xp22 region microdeletions, 1 case with 22q11 segment duplication, and 1 case with 5p15 microduplication. No balanced translocation or chromosomal polymorphisms was detected. CONCLUSION BoBs technique combined with conventional karyotyping is suitable for rapid diagnosis of a large number of prenatal cases and increasing the detection rate for fetal chromosomal abnormalities. PMID- 29419863 TI - [Construction and validation of eukaryotic expression vectors for human ABO subgroup genes]. AB - OBJECTIVE To construct eukaryotic expression vectors for human ABO and subgroup genes A101, B101, CisAB01, Ael05, B(A)04 and Bw03, and validate their expression in vitro. METHODS Total RNA was isolated from individuals with the A101 and B101 subgroups. cDNA of A101 and B101 was synthesized by reverse transcription and amplified with specific primers. Subgroup genes CisAB01, Ael05, B(A)04 and Bw03 were then amplified with PCR for site-directed mutagenesis. Fragments of the ABO genes were directionally linked to pcDNA3.1 positive-eukaryotie expression vectors. After antibiotic screening, the sequences were analyzed. The vectors were transfected into Hela cells, and the expression of target proteins was detected by Western blotting and immunofluorescence assay. RESULTS Sanger sequencing has confirmed that pDNA3.1-A101, pDNA3.1-CisAB01, pDNA3.1-Ael05, pDNA3.1-B101, pDNA3.1- B(A)04, pDNA3.1-Bw03 positive-eukaryotic expression vector were successfully constructed. The results of Western blotting and immunofluorescence revealed clear presence of the expressed proteins. CONCLUSION Eukaryotic expression vectors for ABO subgroup genes were successfully constructed and worked well in Hela cells in vitro, which can facilitate further study of the ABO blood group proteins. PMID- 29419864 TI - [Analysis of a consanguineous pedigree affected with hereditary coagulation factor XII deficiency caused by homozygous Gly341Arg mutation]. AB - OBJECTIVE To analyze the laboratory phenotype and FXII gene mutation in a consanguineous Chinese pedigree affected with factor XII (FXII) deficiency. METHODS Activated partial thromboplastin time (APTT), FXII activity (FXII:C) and FXII antigen (FXII:Ag) of the proband and her family members (10 individuals from 3 generations) were determined. Sanger sequencing was used to detect potential mutation within the 14 exons, their flanking regions and 5',3'-untranslated regions of the FXII gene. Suspected mutations were verified by backward sequencing. Conservation of the amino acids were analyzed with ClustalX-2.1-win. Four online bioinformatics software (PolyPhen-2, PROVEAN, SIFT and MutationTaster) were used to assess the impact of the mutations on the protein function. RESULTS The APTT of the proband and her elder brother have prolonged to 61.6 s and 68.6 s,and their FXII:C and FXII:Ag have decreased to 12%, 10% and 11%, 10%, respectively. The APTT of the paternal grandmother, maternal grandmother, father, mother, elder paternal aunt and elder maternal aunt were all normal, but their FXII:C and FXII:Ag have reduced to half of the normal value. Gene sequencing found that the proband and her elder brother have both carried a homozygous missense c.1078G>A (p.Gly341Arg) mutation in exon 10 of the FXII gene, for which the paternal grandmother, maternal grandmother, father, mother, elder paternal aunt and elder maternal aunt were heterozygous. Bioinformatic analysis suggested that the Gly341 is highly conserved, while p.Gly341Arg is a harmful mutation which may cause disease by affecting the function of FXII protein. CONCLUSION Homozygous p.Gly341Arg mutation, caused by consanguineous marriage, probably underlies the congenital FXII deficiency in this pedigree. PMID- 29419865 TI - [Screening of genetic mutations in a Chinese pedigree affected with hypokalemic periodic paralysis]. AB - OBJECTIVE To screen for mutations in a Chinese pedigree affected with hypokalemic periodic paralysis. METHODS The proband and nine family members were enrolled for the analysis of CACNA1S and SCN4A gene mutations. Genomic DNA was extracted from peripheral blood samples. The coding regions of the two genes were amplified with PCR and subjected to Sanger sequencing. Potential impact of suspected mutations was predicted with Bioinformatics software. The mutations were also verified among 100 healthy controls. RESULTS The proband and 5 family members (including 5 males and 1 female) had presented with episodes of flaccid paralysis accompanied by low serum potassium. Genetic testing has identified a c.664C>T (p.Arg222Trp) mutation in the proband, which has been reported previously. The same mutation was identified in other 5 affected members from the family. No mutation of the CACNA1S gene was detected. CONCLUSION The c.664C>T mutation of the SCN4A gene probably underlies the hypokalemic periodic paralysis in this family. All patients from the family have shown a complete penetrance of the disease. PMID- 29419866 TI - [Analysis of POMT1 gene mutation in a pedigree affected with congenital muscular dystrophy]. AB - OBJECTIVE To analyze mutation of POMT1 gene in a Chinese family affected with congenital muscular dystrophy (CMD). METHODS Peripheral blood samples of the family including one affected and two unaffected individuals, in addition with chorionic villous sample from the fetus, were collected. PCR was used to amplify exons 19 and 20 of the POMT1 gene, and the products were sequenced directly. Based on the result of genetic testing, prenatal diagnosis of the fetus was attained. RESULTS The proband was found to carry a heterozygous missense mutation c.1939G>A (p.Ala647Thr) in exon 19 of the POMT1 gene inherited from the mother and a heterozygous frameshift mutation c.2141delG (p.Trp714Ter) in exon 20 inherited from the father. Prenatal diagnosis revealed that the fetus has carried the c.1939G>A (p.Ala647Thr) missense mutation. With the disease causing mutation, the fetus was predicted to have similar phenotype as its mother. CONCLUSION The compound heterozygous mutations of c.1939G>A (p.Ala647Thr) and c.2141delG (p.Trp714Ter) probably underlie the CMD in this family. Based on the result, prenatal diagnosis may be provided. PMID- 29419867 TI - [Analysis of SOX10 gene mutation in a family affected with Waardenburg syndrome type II]. AB - OBJECTIVE To detect potential mutation of SOX10 gene in a pedigree affected with Warrdenburg syndrome type II. METHODS Genomic DNA was extracted from peripheral blood samples of the proband and his family members. Exons and flanking sequences of MITF, PAX3, SOX10, SNAI2, END3 and ENDRB genes were analyzed by chip capturing and high throughput sequencing. Suspected mutations were verified with Sanger sequencing. RESULTS A c.127C>T (p.R43X) mutation of the SOX10 gene was detected in the proband, for which both parents showed a wild-type genotype. CONCLUSION The c.127C>T (p.R43X) mutation of SOX10 gene probably underlies the ocular symptoms and hearing loss of the proband. PMID- 29419868 TI - [Concurrent APC and MLH1mutations identified in a family affected with familial adenomatous polyposis]. AB - OBJECTIVE To report on concurrent mutations of APC and MLH1 genes identified in a family affected with familial adenomatous polyposis(FAP). METHODS The proband was diagnosed with FAP based on her clinical manifestation, family history and histopathology examination. She developed endometrial epithelial neoplasia(EIN) two years later. With peripheral blood samples collected from her and members of her family, genomic DNA was extracted, and mutations of the APC and MLH1 genes were analyzed by Sanger sequencing. RESULTS Two novel heterozygous mutations were identified respectively in the APC gene(c.637C>T, p.R213X) and the MLH1 gene(c.1153C>T, p.R385C) in the proband. The former has resulted in a truncated protein, while the latter has led to substitution of Arginine by Cystine. CONCLUSION The concurrent mutations of the APC and MLH1 genes probably underline the FAP and Lynch syndrome(LS) in this pedigree. As the first female identified with such mutations, the proband manifested later onset of symptoms with certain degree of variation. For patient with FAP, a detailed family history should be taken.Potential mutation of the APC gene should be screened.Non-intestinal manifestations should be searched. For those who have developed endometrial lesion such as EIN, mutation of the MMR gene (associated with LS) should also be screened. PMID- 29419869 TI - [Identification of a novel STK11 gene mutation in a family affected with hereditary Peutz-Jeghers syndrome]. AB - OBJECTIVE To explore the genetic basis for a family affected with Peutz-Jeghers syndrome (PJS). METHODS Genomic DNA was extracted from peripheral blood and oral swab samples from the patient and her relatives. Next-generation sequencing (NGS) was used to analyze 106 target genes by capturing the exons and adjacent intronic regions. Suspected pathogenic mutation was verified by NGS. RESULTS A missense STK11 mutation was detected in the proband, which was not reported previously. The mutation has caused substitution of Leucine by Proline. NGS has detected the same mutation in the mother but not among other relatives. CONCLUSION This hereditary case of PJS may be attributed to the missense mutation of the STK11 gene. PMID- 29419870 TI - [Identification of a novel EXT1 mutation in a pedigree affected with hereditary multiple exostosis]. AB - OBJECTIVE To detect potential mutations of the EXT1 and EXT2 genes in a pedigree affected with hereditary multiple exostosis (HME). METHODS For a four-generation family with 7 affected individuals from 17 family members,genomic DNA was extracted from peripheral venous blood samples. All exons of the EXT1 and EXT2 genes were screened for potential mutation by PCR and Sanger sequencing. RESULTS A novel heterozygous frameshift mutation c.1202delT (p.I401Tfs*2)was found in exon 4 of the EXT1 gene in the proband and the other 6 affected individuals. The same mutation was not detected among the healthy members from the family. The mutation has given rise a truncated EXT1 protein with loss of 345 amino acids. CONCLUSION A novel frameshift mutation of the EXT1 gene has been identified in a pedigree affected with HME, which has enriched the mutational spectrum of the EXT1 gene and may facilitate genetic counseling and prenatal diagnosis for the family. PMID- 29419871 TI - [Identification of de novo chromosomal structural abnormalities using whole genome sequencing]. AB - OBJECTIVE To assess the value of whole genome sequencing for the identification of de novo structural chromosomal abnormalities. METHODS Whole genome sequencing was utilized to analyze a boy with a peripheral blood karyotype of 46,XY,ins(3)(q21p13p21). The patient manifested with ocular abnormalities including blepharophimosis and ptosis. RESULTS Whole genome sequencing suggested a fragmentation of chromosome 3 (from position 55 473 257 to 78 341 929) has been inserted into between 136 876 730 to 138 643 831, and the breakpoints have occurred in the intergenic region. Meanwhile, there was a deletion between 138 643 831 and 138 694 476. This region contains FOXL2, a pathogenic gene associated with blepharophimosis-ptosis-epicanthus inversus syndrome. CONCLUSION De novo structural chromosomal abnormalities may be caused by novel breakpoints or microdeletion flanking the deletion region. To confirm its pathogenic nature, a mutation needs to be assessed at both genetic and genomic levels, for which whole genome sequencing is a good option. PMID- 29419872 TI - [Clinical and genetic analysis of a patient with cutis laxa]. AB - OBJECTIVE To identify potential mutation in a patient with cutis laxa through exome sequencing of genetic disease-related genes and explore its clinical and genetic features. METHODS Clinical data was collected for the proband and her parents. Exome sequencing was carried out on the proband. Suspected mutations were verified by Sanger sequencing. RESULTS Exome sequencing identified a compound heterozygous mutation of the ATP6V0A2 gene, c.187C>T (p.R63X) and c.1189G>C (p.A397P), in the proband. The mutations were respectively inherited from the father and mother. The patient was diagnosed with autosomal recessive cutis laxa type 2A (ARCL2A). CONCLUSION A case with ARCL2A was diagnosed. The novel mutation has expanded the spectrum of ATP6V0A2 mutations. Exome sequencing is a useful tool for the diagnosis of complex genetic diseases. PMID- 29419873 TI - [Genetic analysis of a case with atypical neonatal Cri-du-chat syndrome]. AB - OBJECTIVE To analyze the clinical features and genetic mutations in a neonate with atypical Cri-du-chat syndrome, whom only featured with weak cry but had no dysmorphic facial features and congenital heart disease. METHODS G-banding karyotyping was performed on the child and her parents. The result was validated by fluorescence in situ hybridization (FISH). Chromosome microarray (CMA) was used to further delineate the mutation. RESULTS G-banding analysis suggested that the child had a karyotype of 46,XX,del(5)(p14p15), while both of his parents had a normal karyotype. FISH confirmed the absence of D5S23 and D5S721 at 5p15.2. A 25.7 Mb deletion was detected in the 5p15.33p14.1 region by CMA. CONCLUSION The phenotype of Cri-du-chat syndrome can vary significantly among patients, particularly in neonates, and can be easily mis-diagnosed. Combined cytogenetic and molecular analysis can identify the missing fragments with greater precision. PMID- 29419874 TI - [Association of single nucleotide polymorphisms of CDH13 gene with metabolic syndrome among ethnic Han Chinese]. AB - OBJECTIVE To assess the association of single nucleotide polymorphisms (SNPs) of the T-cadherin (CDH13) gene with metabolic syndrome (MS) among ethnic Han Chinese.METHODS Genotypes of 6 SNPs(rs11646213, rs12596316, rs3865188, rs12444338, rs12051272, and rs7195409) of the CDH13 gene among 453 patients with MS and 526 controls were determined with a TaqMan method, and their association with MS was assessed. RESULTS For 5 SNPs (rs11646213, rs3865188, rs12444338, rs12051272, and rs7195409), no difference was found in allelic and genotypic frequencies of the CDH13 gene between the two groups. Comparing with rs12596316 (AA+GG) genotype, rs12596316 AG genotype has significantly increased the risk of MS(P = 0.01,OR = 1.38,95%CI: 1.07-1.78), though no association was found between particular alleles of the rs12596316 with MS.There was no difference in the frequencies of rs11646213-rs12596316-rs3865188-rs12444338-rs12051272 haplotype between the two groups(P > 0.05). CONCLUSION No association was found between the five SNPs (rs11646213, rs3865188, rs12444338, rs12051272 and rs7195409) of the CDH13 gene with the MS, while the rs12596316AG genotype of the CDH13 gene is associated with the susceptibility to MS among ethnic Han Chinese. PMID- 29419875 TI - [Association of polymorphisms of KIR2DL4 gene with leukemia among ethnic Hans from southern China]. AB - OBJECTIVE To assess the association of polymorphisms of KIR2DL4 gene with leukemia among ethnic Hans from southern China. METHODS A total of 590 leukemia patients were recruited, which included 283 cases of acute lymphoblastic leukemia (ALL), 277 cases of acute myeloid leukemia (AML), and 80 cases of chronic myeloid leukemia (CML). Meanwhile, 306 healthy controls were randomly selected from volunteer blood donors. Both groups were subjected to sequence-based typing of the entire coding sequence of the KIR2DL4 gene using an in-house assay. The genotype for each sample was determined with Assign 4.7 SBT software. The frequencies of each detected KIR2DL4 allele, the 9A type KIR2DL4 allele and 10A type KIR2DL4 allele of the ALL, AML and CML groups were compared with those of the control group. RESULTS Five KIR2DL4 alleles, namely KIR2DL4*001, *005, *006, *008 and *011, were detected in the ALL, AML and CML groups as well as the control group. A significant difference was detected in the frequencies of KIR2DL4*011 and 10A type KIR2DL4 allele between the ALL group and the control group (KIR2DL4*011: OR = 1.66, P = 0.01; 10A type KIR2DL4: OR = 0.42, P = 0.03), but was lost after P correction (Pc > = 0.05). No significant difference was detected in the frequencies of KIR2DL4 alleles, the 9A type KIR2DL4 and 10A type KIR2DL4 allele between the AML and CML patient groups compared with the control group (P > 0.05, Pc > 0.05). CONCLUSION The allelic diversity of the KIR2DL4 locus showed no significant association with leukemia among ethnic Hans from southern China. PMID- 29419877 TI - [Defect of thiamine transport and activation and related disease]. AB - Thiamine, also known as vitamin B1, is an important vitamin for the body. The activated form of thiamine pyrophosphate is involved in cell metabolism as an important co-enzyme. Defects of thiamine transport and activation may cause lack of thiamine and affection of cell metabolism, leading a variety of diseases. This review has summarized defects of thiamine transport and activation and related diseases. PMID- 29419876 TI - [Association of sodium ion transporter gene polymorphisms with essential hypertension among ethnic Koreans from Mudanjiang]. AB - OBJECTIVE To assess the association of SLC12A3 and SCNN1B gene polymorphisms (rs11643718 and rs12447134) with essential hypertension among ethnic Koreans from Mudanjiang, China. METHODS For 204 patients with essential hypertension and 186 healthy controls, the genotypes of rs11643718 and rs12447134 loci were determined with an improved multiplex ligase detection reaction (iMLDR) method. RESULTS Allelic and genotypic frequencies of rs11643718 of SLC12A3 gene are associated with the onset of disease hypertension (P <0.05) as well as systolic blood pressure (P < 0.01, under a recessive model). No association was found between rs12447134 of SCNN1B gene with the onset of disease (P > 0.05) but diastolic blood pressure (P < 0.05, under a recessive model). CONCLUSION The polymorphisms of rs11643718 locus is associated with the susceptibility for essential hypertension among ethnic Koreans from Mudanjiang area and can be used as a predictor for the disease. PMID- 29419878 TI - [Progress in genetic research on non-immune hydrops fetalis]. AB - Non-immune factors are the most common cause of hydrops fetalis, which may manifest as abnormal accumulation of fluid in the body cavities. Hydrops fetalis is a complex condition with a high mortality rate. The prognosis is depending on the underlying disease and is particularly poor in those with chromosomal aberrations or monogenic disorders. In this paper, advance in the research on non immune hydrops fetalis is reviewed. PMID- 29419880 TI - Inequalities in dental caries experience among 4-year-old New Zealand children. AB - OBJECTIVES: To investigate ethnic-specific deprivation gradients in early childhood dental caries experience considering different domains of deprivation. METHODS: We used cross-sectional near whole population-level data on 318 321 four year-olds attending the "B4 School check," a national health and development check in New Zealand, across 6 fiscal years (2010/2011 to 2015/2016). The "lift the lip" screening tool was used to estimate experience of any caries and severe caries. We investigated deprivation gradients using the Index of Multiple Deprivation (IMD), which measures seven domains of deprivation across 5958 geographical areas ("data zones"). Ethnicity was categorized into five groups: (i) Maori, (ii) Pacific, (iii) Asian, (iv) Middle Eastern, Latin American and African (MELAA) and (v) European & Other (combined). We used a random intercepts model to estimate mutually adjusted associations between deprivation, ethnicity, age, fiscal year, and evidence of any dental caries experience. RESULTS: Reports of any caries experience decreased from 15.8% (95% CI: 15.7; 15.9%) to 14.7% 95% CI: 14.4; 14.8%), while reports of severe caries experience increased from 3.0% (95% CI: 3.0; 3.1%) to 4.4% (95% CI: 4.3; 4.5%) from 2010/2011 to 2015/2016. This varied by ethnicity with larger increases in severe caries for Pacific children from 7.1% (95% CI: 6.8; 7.4%) to 14.1% (95% CI: 13.7; 14.5%). There were deprivation gradients in dental caries experience with considerable variation by ethnicity and by domain of deprivation. The association between deprivation and dental caries experience was weakest for Asian children and was most pronounced for Pacific and Maori children. CONCLUSION: Socioeconomic gradients in dental caries experience are evident by age 4 years, and these gradients vary by ethnicity and domain of deprivation. PMID- 29419879 TI - Fatigability and endurance performance in cancer survivors: Analyses from the Baltimore Longitudinal Study of Aging. AB - BACKGROUND: Fatigue is prevalent and distressing among cancer survivors, but its subjective nature makes it difficult to identify. Fatigability, defined as task specific fatigue, and endurance performance may be useful supplemental measures of functional status in cancer survivors. METHODS: Fatigability, endurance performance, and cancer history were assessed every 2 years in Baltimore Longitudinal Study of Aging participants between 2007 and 2015. Fatigability was defined according to the Borg rating of perceived exertion scale after a 5 minute, slow treadmill walk; and endurance performance was calculated according to the ability and time to complete a fast-paced, 400-meter walk. The association between cancer history, fatigability, and endurance performance was evaluated using longitudinal analyses adjusted for age, sex, body mass index, and comorbidities. RESULTS: Of 1665 participants, 334 (20%) reported a history of cancer. A combination of older age (>65 years) and a history of cancer was associated with 3.8 and 8.6 greater odds of high perceived fatigability and poor endurance, respectively (P < .01). Older adults with and without a history of cancer walked 42 and 23 seconds slower than younger adults without a history of cancer, respectively (P < .01). The median times to the development of high fatigability and poor endurance were shorter among those who had a history of cancer compared with those who had no history of cancer (P < .01). CONCLUSIONS: The current findings suggest that a history of cancer is associated with fatigability and poor endurance and that this effect is significantly greater in older adults. Evaluating the effects of cancer and age on fatigability may illuminate potential pathways and targets for future interventions. Cancer 2018;124:1279-87. (c) 2018 American Cancer Society. PMID- 29419881 TI - An adapted isolation procedure reveals Photobacterium spp. as common spoilers on modified atmosphere packaged meats. AB - : The genus Photobacterium comprises species of marine bacteria, commonly found in open-ocean and deep-sea environments. Some species (e.g. Photobacterium phosphoreum) are associated with fish spoilage. Recently, culture-independent studies have drawn attention to the presence of photobacteria on meat. This study employed a comparative isolation approach of Photobacterium spp. and aimed to develop an adapted isolation procedure for recovery from food samples, as demonstrated for different meats: Marine broth is used for resuspending and dilution of food samples, followed by aerobic cultivation on marine broth agar supplemented with meat extract and vancomycin at 15 degrees C for 72 h. Identification of spoilage-associated microbiota was carried out via Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry using a database supplemented with additional mass spectrometry profiles of Photobacterium spp. This study provides evidence for the common abundance of multiple Photobacterium species in relevant quantities on various modified atmosphere packaged meats. Photobacterium carnosum was predominant on beef and chicken, while Photobacterium iliopiscarium represented the major species on pork and Photobacterium phosphoreum on salmon, respectively. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates highly frequent isolation of multiple photobacteria (Photobacterium carnosum, Photobacterium phosphoreum, and Photobacterium iliopiscarium) from different modified-atmosphere packaged spoiled and unspoiled meats using an adapted isolation procedure. The abundance of photobacteria in high numbers provides evidence for the hitherto neglected importance and relevance of Photobacterium spp. to meat spoilage. PMID- 29419882 TI - Vertebral Fracture: Diagnostic Difficulties of a Major Medical Problem. PMID- 29419883 TI - Trauma rates and patterns in specific pathogen free (SPF) rhesus macaque (Macaca mulatta) groups. AB - There are some predictable patterns of trauma in captive rhesus macaque (Macaca mulatta) social groups. Several factors have been documented to contribute to these patterns, including group formation of unrelated animals, and the establishment of dominance ranks. Here, we report on how socially induced trauma in groups of rhesus monkeys is influenced by the breeding season, numbers of matrilines per group and matriline size. We analyzed 3 years of data collected from veterinary admittance logs for four groups in our specific pathogen free (SPF) breeding colony. Since the groups differed in time from formation, both the numbers of matrilines and the composition of those matrilines were different. Across the four groups, trauma rates were significantly higher during the fall breeding season than the spring and summer months when births occur. The group that was formed most recently, comprised of the greatest number of matrilines but fewest related animals, showed significantly higher rates of trauma than the older social groups. Further, the middle and lowest ranking families received signifincantly higher rates of trauma than the highest ranking families, suggesting a rank-related phenomenon. Additionally, there was a significant negative correlation between numbers of adult females in a matriline and rates of trauma observed in each matriline, but the numbers of adult females are significantly higher in the top ranked families compared to all of the other matrilines. These findings suggest that trauma rates increase during the breeding season and may be exacerbated in recently formed breeding groups that have smaller matrilines and reduced opportunities for social support to mitigate rank related aggression. Management practices should be devised to ensure adequate matrilineal size to decrease rates of trauma in captive rhesus macaque groups. PMID- 29419884 TI - Balancing tonic and phasic inhibition in hypothalamic corticotropin-releasing hormone neurons. AB - KEY POINTS: GABA transporter (GAT) blockade recruits extrasynaptic GABAA receptors (GABAA Rs) and amplifies constitutive presynaptic GABAB R activity. Extrasynaptic GABAA Rs contribute to a tonic current. Corticosteroids increase the tonic current mediated by extrasynaptic GABAA Rs. ABSTRACT: Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and circulating glucocorticoids (CORT) are important feedback controllers of CRH output. Surprisingly little is known about the direct effects of CORT on GABA synapses in PVN. Here we used whole-cell patch clamp recordings from CRH neurons in mouse hypothalamic brain slices to examine the effects of CORT on synaptic and extrasynaptic GABA signalling. We show that GABA transporters (GATs) limit constitutive activation of presynaptic GABAB receptors and ensure high release probability at GABA synapses. GATs in combination with GABAB receptors also curtail extrasynaptic GABAA R signalling. CORT has no effect on synaptic GABA signalling, but increases extrasynaptic GABA tone through upregulation of postsynaptic GABAA receptors. These data show that efficient GABA clearance and autoinhibition control the balance between synaptic (phasic) and extrasynaptic (tonic) inhibition in PVN CRH neurons. This balance is shifted towards increased extrasynaptic inhibition by CORT. PMID- 29419887 TI - Chiroptical and vibrational spectroscopic study of genuine and counterfeit medicines containing tadalafil. AB - The production and distribution of counterfeit pharmaceuticals present a serious problem worldwide. This is true especially in case of phosphodiesterase type 5 inhibitors for treating erectile dysfunction, where consumers often prefer buying them anonymously from unverified sources. In this study, genuine and counterfeit Cialis(r) 20 mg tablets were analyzed by electronic circular dichroism, vibrational circular dichroism, and infrared spectroscopy. The characteristic spectral patterns were identified by comparison with the spectra of tadalafil standard as an active pharmaceutical ingredient, and its presence was confirmed in all samples. The amount of tadalafil, however, was markedly lower in the case of counterfeit tablet as the observed band intensities were considerably lower. No other significant differences between the genuine and counterfeit tablets were revealed. Ab initio density functional theory calculations provided a detailed description of the stable conformers of tadalafil in a solution and enabled thorough interpretation of the experimental spectra. PMID- 29419886 TI - Morphological diversity and phylogeny of the diatom genus Entomoneis (Bacillariophyta) in marine plankton: six new species from the Adriatic Sea. AB - The diatom genus Entomoneis is known from the benthos and plankton of marine, brackish, and freshwaters. Entomoneis includes diatoms with a bilobate keel elevated above the valve surface, a sigmoid canal raphe, and numerous girdle bands. Owing mostly to the scarcity of molecular data for a diverse set of species, the phylogeny of Entomoneis has not been investigated in depth. The few previous studies that included Entomoneis were focused on broader questions and the available data were from a small number of either unidentified Entomoneis or well-known species (e.g., E. paludosa). Since the first description of new species combining both molecular and morphological characters (E. tenera), we have continued to cultivate and investigate Entomoneis in the plankton of the Adriatic Sea. Combined multigene phylogeny (SSU rDNA sequences, rbcL, and psbC genes) and morphological observations (LM, SEM and TEM) revealed six new Entomoneis species supported by phylogenetic and morphological data: E. pusilla, E. gracilis, E. vilicicii, E. infula, E. adriatica, and E. umbratica. The most important morphological features for species delineation were cell shape, the degree and mode of torsion, valve apices, the appearance and structure of the transition between keel and valve body, the ultrastructure and the shape of the girdle bands, and the arrangement and density of perforations along the valve and valvocopulae. Our results highlight the underappreciated diversity of Entomoneis and call for a more in-depth morphological and molecular investigation of this genus especially in planktonic habitats. PMID- 29419888 TI - Evaluation of T-lymphocyte subpopulations in actinic keratosis, in situ and invasive squamous cell carcinoma of the skin. AB - BACKGROUND: Tumor infiltrating lymphocytes (TILs) represent important regulators of carcinogenesis. Cutaneous invasive squamous cell carcinoma (inSCC) develops through precursor lesions, namely in situ squamous cell carcinoma (isSCC) and actinic keratosis (AK), representing a natural model of carcinogenesis. The study evaluates TIL subpopulations in inSCC and its precursors by comparing 2 semiquantitative scoring systems, and assesses the presence of regulatory T-cells (Tregs) in these lesions. METHODS: Paraffin sections from 33 cases of AK, 19 isSCCs and 34 inSCCs with adjacent precursor lesions or normal skin (NS) were immunostained for CD3, CD4, CD8 and Foxp3. TIL subgroups were evaluated by the semiquantitative Klintrup-Makinen (K-M) score, and by a more detailed modification of this system. Treg counts were assessed by image analysis quantification. RESULTS: An increase of all TIL subpolulations from precursor lesions toward inSCC was shown by both scoring systems. Treg counts progressively increased from NS to AK and isSCC, but decreased in inSCC. Tregs were more numerous in pT2 and around indolent inSCCs compared to T1 and aggressive subtypes. CONCLUSIONS: T-cells and cytotoxic T-cells progressively increase in cutaneous squamous cell carcinogenesis, while Treg counts diminish in inSCC. The K-M score is an appropriate, easily applicable TIL scoring system in cutaneous inSCC. PMID- 29419889 TI - Response to Dr Lamy and Dr Gonzalez-Rodriguez. PMID- 29419890 TI - Genetic and clinical findings in a Chinese cohort of patients with collagen VI related myopathies. AB - Collagen VI-related myopathy, caused by pathogenic variants in the genes encoding collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with 40 UCMD and 20 BM. Muscle with biopsies revealed dystrophic changes and showed completely deficiency of collagen VI or sarcolemma specific collagen VI deficiency. We identified 62 different pathogenic variants in these 60 patients, with 34 were first reported while 28 were previously known; 72 allelic pathogenic variants in COL6A1 (25/72, 34.7%), COL6A2 (33/72, 45.8%) and COL6A3 (14/72, 19.4%). We also found somatic mosaic variant in the parent of 1 proband by personal genome machine amplicon deep sequencing for mosaicism. Here we provide clinical, histological and genetic evidence of collagen VI-related myopathy in 60 Chinese patients. NGS is a valuable approach for diagnosis and accurate diagnosis provides useful information for genetic counseling of related families. PMID- 29419891 TI - Technical Note: Kinect V2 surface filtering during gantry motion for radiotherapy applications. AB - PURPOSE: In radiotherapy, the Kinect V2 camera, has recently received a lot of attention concerning many clinical applications including patient positioning, respiratory motion tracking, and collision detection during the radiotherapy delivery phase. However, issues associated with such applications are related to some materials and surfaces reflections generating an offset in depth measurements especially during gantry motion. This phenomenon appears in particular when the collimator surface is observed by the camera; resulting in erroneous depth measurements, not only in Kinect surfaces itself, but also as a large peak when extracting a 1D respiratory signal from these data. METHODS: In this paper, we proposed filtering techniques to reduce the noise effect in the Kinect-based 1D respiratory signal, using a trend removal filter, and in associated 2D surfaces, using a temporal median filter. Filtering process was validated using a phantom, in order to simulate a patient undergoing radiotherapy treatment while having the ground truth. RESULTS: Our results indicate a better correlation between the reference respiratory signal and its corresponding filtered signal (Correlation coefficient of 0.76) than that of the nonfiltered signal (Correlation coefficient of 0.13). Furthermore, surface filtering results show a decrease in the mean square distance error (85%) between the reference and the measured point clouds. CONCLUSION: This work shows a significant noise compensation and surface restitution after surface filtering and therefore a potential use of the Kinect V2 camera for different radiotherapy-based applications, such as respiratory tracking and collision detection. PMID- 29419892 TI - Autosomal recessive hyper-IgE syndrome in two brothers of a Chinese family with a novel mutation in DOCK8 gene. PMID- 29419893 TI - Cover Image, Volume 233, Number 5, May 2018. PMID- 29419894 TI - Cancer in the older adult: Implications for therapy and future research. PMID- 29419896 TI - Comparison of effectiveness and safety of excimer lamp vs topical calcipotriol clobetasol propionate combination in the treatment of palmoplantar psoriasis. AB - BACKGROUND: Very few studies have assessed the efficacy of excimer in the treatment of palmoplantar psoriasis (PPP), and none has compared the excimer with calcipotriol-clobetasol propionate combination. PURPOSE: To compare the effectiveness and safety of excimer lamp vs topical ointment containing calcipotriol (0.005% w/w) and clobetasol propionate (0.05% w/w) combination in PPP. METHODS: This right-left randomization trial included 36 patients with PPP, who received treatment with excimer lamp (twice weekly) on one side and calcipotriol-clobetasol combination (once daily) on another side for 12 weeks, followed by 8 weeks of follow-up. Recruitment and response assessment was done by 2 experienced dermatologists (SD and TN) using modified palmoplantar pustular psoriasis area and severity index score (mPPPASI, originally devised for palmoplantar pustulosis, suitably modified to assess response in PPP). Primary outcome measure was percentage improvement in mPPPASI at 12 weeks, which was classified as minimal (<=25%), mild (>25%-50%), moderate (>50%-75%), and marked (>75%). Secondary outcome measures were the proportion of patients achieving >75% reduction in mPPPASI and the time taken to achieve it. RESULTS: Of 36 recruited patients, 33 completed treatment and 21 adhered to 8-weeks follow-up. The mean mPPPASI on the excimer-treated sides reduced significantly from 7.75 +/- 4.62 to 4.01 +/- 4.07 (P < .001) at 12th week (end of the treatment) and 2.66 +/- 3.97 at 20th week (at 8 weeks follow-up). The mean mPPPASI on the calcipotriol-clobetasol combination treated sides reduced significantly from 7.36 +/- 4.46 to 3.55 +/- 3.77 (P < .001) and 2.70 +/- 3.97 at 12th week and 20th week, respectively. The reduction was significant for both treatment and the difference between the two was not statistically significant. Minimal, mild, moderate, and marked improvement was seen in 5/33 (15.2%) and 1/33 (3.0%), 6/33 (18.2%) and 8/33 (24.2%), 12/33 (36.4%) and 13/33 (39.4%), and 8/33 (24.2%) and 8/33 (24.2%) sides in the excimer and calcipotriol-clobetasol combination, respectively. A total of 8 patients in each group achieved mPPPASI 75 at 12 weeks. The mPPPASI 75 was achieved at 2, 4, and 8 weeks in 1, 2, and 8 patients, respectively, using either modalities. The adverse effects (most commonly hyperpigmentation) were noted more frequently on the excimer-treated sides; however, they were well tolerated. CONCLUSION: Both excimer lamp and calcipotriol-clobetasol propionate combination are equally effective in the treatment of PPP. PMID- 29419895 TI - Pulmonary artery perfusion versus no perfusion during cardiopulmonary bypass for open heart surgery in adults. AB - BACKGROUND: Available evidence has been inconclusive on whether pulmonary artery perfusion during cardiopulmonary bypass (CPB) is associated with decreased or increased mortality, pulmonary events, and serious adverse events (SAEs) after open heart surgery. To our knowledge, no previous systematic reviews have included meta-analyses of these interventions. OBJECTIVES: To assess the benefits and harms of single-shot or continuous pulmonary artery perfusion with blood (oxygenated or deoxygenated) or a preservation solution compared with no perfusion during cardiopulmonary bypass (CPB) in terms of mortality, pulmonary events, serious adverse events (SAEs), and increased inflammatory markers for adult surgical patients. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, and advanced Google for relevant studies. We handsearched retrieved study reports and scanned citations of included studies and relevant reviews to ensure that no relevant trials were missed. We searched for ongoing trials and unpublished trials in the World Health Organization International Clinical Trials Registry Platform (ICTRP) and at clinicaltrials.gov (4 July 2017). We contacted medicinal firms producing preservation solutions to retrieve additional studies conducted to examine relevant interventions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared pulmonary artery perfusion versus no perfusion during CPB in adult patients (? 18 years). DATA COLLECTION AND ANALYSIS: Two independent review authors extracted data, conducted fixed effect and random-effects meta-analyses, and calculated risk ratios (RRs) or odds ratios (ORs) for dichotomous outcomes. For continuous data, we have presented mean differences (MDs) and 95% confidence intervals (CIs) as estimates of the intervention effect. To minimize the risk of systematic error, we assessed risk of bias of included trials. To reduce the risk of random errors caused by sparse data and repetitive updating of cumulative meta-analyses, we applied Trial Sequential Analyses (TSAs). We used GRADE principles to assess the quality of evidence. MAIN RESULTS: We included in this review four RCTs (210 participants) reporting relevant outcomes. Investigators randomly assigned participants to pulmonary artery perfusion with blood versus no perfusion during CPB. Only one trial included the pulmonary artery perfusion intervention with a preservation solution; therefore we did not perform meta-analysis. Likewise, only one trial reported patient-specific data for the outcome "pulmonary events"; therefore we have provided no results from meta-analysis. Instead, review authors added two explorative secondary outcomes for this version of the review: the ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2); and intubation time. Last, review authors found no comparable data for the secondary outcome inflammatory markers.The effect of pulmonary artery perfusion on all-cause mortality was uncertain (Peto OR 1.78, 95% CI 0.43 to 7.40; TSA adjusted CI 0.01 to 493; 4 studies, 210 participants; GRADE: very low quality). Sensitivity analysis of one trial with overall low risk of bias (except for blinding of personnel during the surgical procedure) yielded no evidence of a difference for mortality (Peto OR 1.65, 95% CI 0.27 to 10.15; 1 study, 60 participants). The TSA calculated required information size was not reached and the futility boundaries did not cross; thus this analysis cannot refute a 100% increase in mortality.The effect of pulmonary artery perfusion with blood on SAEs was likewise uncertain (RR 1.12, 95% CI 0.66 to 1.89; 3 studies, 180 participants; GRADE: very low quality). Data show an association between pulmonary artery perfusion with blood during CPB and a higher postoperative PaO2/FiO2 ratio (MD 27.80, 95% CI 5.67 to 49.93; 3 studies, 119 participants; TSA adjusted CI 5.67 to 49.93; GRADE: very low quality), although TSA could not confirm or refute a 10% increase in the PaO2/FiO2 ratio, as the required information size was not reached. AUTHORS' CONCLUSIONS: The effects of pulmonary artery perfusion with blood during cardiopulmonary bypass (CPB) are uncertain owing to the small numbers of participants included in meta-analyses. Risks of death and serious adverse events may be higher with pulmonary artery perfusion with blood during CPB, and robust evidence for any beneficial effects is lacking. Future randomized controlled trials (RCTs) should provide long-term follow-up and patient stratification by preoperative lung function and other documented risk factors for mortality. One study that is awaiting classification (epub abstract with preliminary results) may change the results of this review when full study details have been published. PMID- 29419898 TI - In Memoriam Priscilla Ann Campbell 1941-1998. PMID- 29419897 TI - Comparison of measured and predicted specific optical rotation in gas and solution phases: A test for the polarizable continuum model of solvation. AB - A comparative theoretical and experimental study of dispersive optical activity is presented for a set of small, rigid organic molecules in gas and solution phases. Target species were chosen to facilitate wavelength-resolved measurements of specific rotation in rarefied vapors and in organic solvents having different polarities, while avoiding complications due to conformational flexibility. Calculations were performed with two density functionals (B3LYP and CAM-B3LYP) and with the coupled-cluster singles and doubles (CCSD) ansatz, and solvent effects were included through use of the polarizable continuum model (PCM). Across the various theoretical methods surveyed, CCSD with the modified velocity gauge provided the best overall performance for both isolated and solvated conditions. Zero-point vibrational corrections to equilibrium calculations of chiroptical response tended to improve agreement with gas-phase experiments, but the quality of performance realized for solutions varied markedly. Direct comparison of measured and predicted specific-rotation suggests that PCM, in general, is not able to reproduce attendant solvent shifts (neither between gas and solution phases nor among solvents) and fares better in estimating actual medium-dependent values of this property (although the error is rather system dependent). Thus, more elaborate solvation models seem necessary for a proper theoretical description of solvation in dispersive optical activity. PMID- 29419899 TI - Editor's Comment. AB - When we undertook the editorship of this journal in July 1995, few of us realized how quickly online publishing was going to flourish. In only three years, a number of the scientific journals we read today are online with the full text of their articles. We therefore made arrangements with Cadmus Journal Services to publish an on-line version of JLB concurrent with the print version prepared by the Mack Printing Group. PMID- 29419900 TI - Th 1 and Th 2 cytokines cooperate to stimulate mannose-receptor-mediated phagocytosis. AB - The mannose receptor is a macrophage surface receptor that mediates both endocytosis and phagocytosis. Previous work has demonstrated that the prototypical Th 2 cytokine, interleukin-4 (IL-4), increases both cell-surface receptor expression and mannose receptor-mediated endocytosis, whereas the prototypical Th 1 cytokine, interferon-gamma (IFN-gamma), decreases both surface expression and endocytosis. In many aspects of the immune response, Th 1 and Th 2 cytokines oppose each others' actions. We demonstrate that IL-4 and IFN-gamma alone and together enhance mannose receptor-mediated phagocytosis, despite opposing effects on cell-surface mannose receptor expression and endocytosis. Thus these usually antagonistic cytokines cooperate in increasing mannose receptor phagocytic function. The cooperative effect of these cytokines is not observed for Fc receptor-mediated phagocytosis. The Th 2 cytokine IL-13 exerts similar effects to IL-4. Our results suggest that Th 1 and Th 2 cytokines may act in concert at sites of inflammation to enhance mannose receptor-mediated phagocytosis of microorganisms. J. Leukoc. Biol. 64: 108-113; 1998. PMID- 29419901 TI - Cytokeratin 19 expression is a risk factor for metastasis in cutaneous squamous cell carcinoma. PMID- 29419902 TI - Individualized Postnatal Growth Trajectories for Preterm Infants. AB - BACKGROUND: Growth of preterm infants is monitored using fetal charts despite individual trajectories being downshifted postnatally by adaptational processes. The study aims to compare different approaches to create individualized postnatal trajectories. METHODS: Three approaches to achieve growth similar to healthy term infants at 42+0/7 weeks postmenstrual age (PMA) on World Health Organization growth standards (WHOGS) (target weight) were tested by comparing trajectories obtained by: 1) following birth percentiles (Birth-Weight-Percentile Approach); 2) following percentiles achieved at day of life 21 (Postnatal-Percentile Approach); 3) using day-specific fetal median growth velocities starting at day of life 21 (Fetal-Median-Growth Approach [FMGA]). The primary outcome was delta weight (DeltaW), defined as difference between target weight (WHOGS) at 42+0/7 weeks and weight predicted by trajectories. The secondary outcome was DeltaW vs %fat mass in a cohort of 20 disease-free surviving very low-birth-weight infants. RESULTS: Birth-Weight-Percentile and Postnatal-Percentile Approach showed high DeltaW; FMGA alone reduced DeltaW. Introducing a factor to FMGA to reflect the transition to extrauterine conditions (Growth-Velocity Approach [GVA]) minimized DeltaW. GVA merged with target and best normalized for body composition related to DeltaW. CONCLUSIONS: GVA provides an evidence-based approach for individualized growth trajectories. GVA is based on physiologic data and that healthy preterm infants adjust their postnatal trajectory below their birth percentile. GVA may reflect a biologic principle because it matches consistently with WHOGS at 42+0/7 weeks for all preterm infants from 24 to 34 weeks. This concept could become a bedside tool to aid clinicians in monitoring growth, guiding nutrition, and minimizing chronic adult disease risks as a consequence of unguided, inappropriate growth. PMID- 29419904 TI - Predatory conferences: Caveat emptor! PMID- 29419903 TI - Synthesis of Functionalized Difluorocyclopropanes: Unique Building Blocks for Drug Discovery. AB - Difluorocyclopropane-containing building blocks for drug discovery were synthesized from the functionalized alkenes and TMSCF3 /NaI. Novel fluorinated acids, amines, amino acids, alcohols, ketones and sulfonyl chlorides were obtained. PMID- 29419905 TI - Once weekly targeted excimer light produced modest repigmentation of vitiligo over a 20-week period. PMID- 29419906 TI - Waiting times. PMID- 29419907 TI - Granulomatous tattoo reaction with associated uveitis successfully treated with methotrexate. PMID- 29419908 TI - Comments on a new classification, treatment algorithm and prognosis-estimating system for sigmoid volvulus: patient determination for elective surgery. PMID- 29419909 TI - Cardiovascular biomarkers in clinical studies of type 2 diabetes. AB - When planning cardiovascular (CV) studies in type 2 diabetes (T2D), selection of CV biomarkers is a complex issue. Because the pathophysiology of CV disease (CVD) in T2D is multifactorial, ideally, the selected CV biomarkers should cover all aspects of the known pathophysiology of the disease. This will allow the researcher to distinguish between effects on different aspects of the pathophysiology. To this end, we discuss a host of biomarkers grouped according to their role in the pathogenesis of CVD, namely: (1) cardiac damage biomarkers; (2) inflammatory biomarkers; and (3) novel biomarkers (oxidative stress and endothelial dysfunction biomarkers). Within each category we present the best currently validated biomarkers, with special focus on the population of interest (people with T2D). For each individual biomarker, we discuss the physiological role, validation in the general population and in people with T2D, analytical methodology, modifying factors, effects of glucose-lowering drugs, and interpretation. This approach will provide clinical researchers with the information necessary for planning, conducting and interpreting results from clinical trials. Furthermore, a systematic approach to selection of CV biomarkers in T2D research will improve the quality of future research. PMID- 29419911 TI - Normoglycemic glucagonoma syndrome associated with necrolytic migratory erythema. PMID- 29419910 TI - The giant mycoheterotrophic orchid Erythrorchis altissima is associated mainly with a divergent set of wood-decaying fungi. AB - The climbing orchid Erythrorchis altissima is the largest mycoheterotroph in the world. Although previous in vitro work suggests that E. altissima has a unique symbiosis with wood-decaying fungi, little is known about how this giant orchid meets its carbon and nutrient demands exclusively via mycorrhizal fungi. In this study, the mycorrhizal fungi of E. altissima were molecularly identified using root samples from 26 individuals. Furthermore, in vitro symbiotic germination with five fungi and stable isotope compositions in five E. altissima at one site were examined. In total, 37 fungal operational taxonomic units (OTUs) belonging to nine orders in Basidiomycota were identified from the orchid roots. Most of the fungal OTUs were wood-decaying fungi, but underground roots had ectomycorrhizal Russula. Two fungal isolates from mycorrhizal roots induced seed germination and subsequent seedling development in vitro. Measurement of carbon and nitrogen stable isotope abundances revealed that E. altissima is a full mycoheterotroph whose carbon originates mainly from wood-decaying fungi. All of the results show that E. altissima is associated with a wide range of wood- and soil-inhabiting fungi, the majority of which are wood-decaying taxa. This generalist association enables E. altissima to access a large carbon pool in woody debris and has been key to the evolution of such a large mycoheterotroph. PMID- 29419912 TI - Enantioselective Synthesis of the Spirotropanyl Oxindole Scaffold through Bimetallic Relay Catalysis. AB - Spirotropanyl oxindole alkaloids like alstonisine and chitosenine show a wide range of bioactivites. We report the first enantioselective synthesis of the spirotropanyl oxindole scaffold by means of a bimetallic relay catalysis strategy. A new class of E-oximino alpha-diazo ketones was developed for the intramolecular generation of transient azomethine ylides catalyzed by an achiral RhII complex and a subsequent intermolecular 1,3-dipolar cycloaddition catalyzed by a chiral N,N'-dioxide NdIII Lewis acid complex. The enantioselectively catalyzed transformation has broad scope and yields the desired spirotropanyl oxindole cycloadducts in high yields and with very high enantio- and diastereoselectivity. PMID- 29419913 TI - Variation in the diagnosis and clinical management of lentigo maligna across Europe: a survey study among European Association of Dermatologists and Venereologists members. AB - BACKGROUND: Lentigo maligna (LM), a form of melanoma in situ, is treated to prevent progression to lentigo maligna melanoma (LMM). Surgical treatment is the gold standard. However, treatment guidelines are based on expert opinion, and comparative studies are lacking. OBJECTIVE: The objective of this study was to assess the diagnostic methods and clinical management of LM patients among European dermatologists and residents. METHODS: A survey consisting of 29 questions about diagnostic methods and treatment options used for LM patients was sent to 3308 members of the European Association of Dermatologists and Venereologists (EADV). RESULTS: Most questions were multiple choice, and multiple answers could be ticked per question. A total of N = 415 (12.5%) completed surveys were included in the analyses. A combination of clinical diagnosis (65.7%), dermatoscopy (83.4%) and histopathology (88.2%) is used by most respondents to diagnose LM. Tissue for histopathological evaluation was collected most often using a single punch biopsy in 61.0%. The most common treatment for LM patients <60 years of age is surgery (97.6%). For LM patients >70 years of age, 66.8% of the respondents preferred surgical treatment. Non-surgical options such as radiotherapy (17.0%), topical imiquimod (30.6%), watchful waiting (19.6%) or cryotherapy (20.4%) were used in this elderly group. Subanalysis showed that respondents who take into account patient preference used topical imiquimod, radiotherapy and watchful waiting more often. CONCLUSION: In conclusion, the results of this survey show that there is a variance in the diagnostic methods and treatment modalities used for LM across Europe. Surgery remains the most utilized option. However, non-surgical options, such as topical imiquimod and radiotherapy, are most often used for elderly patients. We recommend that future studies focus on patient preference and compare surgical to non-surgical therapy. PMID- 29419914 TI - Early laser intervention to reduce scar formation - a systematic review. AB - The ability of laser treatment to affect wound healing and subsequently minimize scar formation has been investigated in recent years. However, no systematic review links these clinical trials. The aim of this study was to systematically review and evaluate clinical evidence for early laser intervention to reduce scar formation in studies where laser treatment was introduced less than 3 months after wounding. We searched PubMed using relevant keywords in June 2017. Titles, abstracts and articles were sorted according to inclusion and exclusion criteria. Methodological quality was evaluated according to Cochrane Collaborations risk-of bias assessment guideline by two independent authors. Twenty-five articles met the inclusion criteria. In total, 22 of 25 studies were controlled studies, and 17 of 25 studies compared laser treatment vs. untreated control scars. The following laser devices have been investigated: pulsed dye laser (PDL), potassium titanyl-phosphate (KTP) laser, fractional erbium:glass 1540 nm/1550 nm, fractional/full ablation erbium-doped yttrium aluminium garnet (Er:YAG) laser or fractional CO2 laser. Eighteen studies applied laser treatments 2-4 times with 2- to 8-week intervals, while seven studies applied only one laser treatment. Follow up time ranged from 1 to 12 months with 18 studies using a follow-up time <=3 months. In general, laser-treated wounds and scars showed benefit from laser intervention, though not always reaching significance. Significant scar improvement was found in three of four studies using laser treatment in inflammation phase, in six of 16 studies with laser initiated in the proliferation phase and in two of five studies in the remodelling phase. High risk of bias was found in randomization and allocation concealment, and low risk of bias with regard to blinding of outcome assessment and lost to follow-up. In conclusion, laser intervention when introduced in inflammation, proliferation or remodelling phase has the potential to reduce cutaneous scar formation. Further, high-quality studies are needed before standard protocols can be implemented in clinical practice. PMID- 29419915 TI - Skin manifestations in patients with hepatitis C virus-related chronic liver disease. PMID- 29419916 TI - Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand. AB - Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. While TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 activity (a disintegrin and metalloprotease thrombospondin, number 13). A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. While early confirmation of aHUS is often not possible, except in the minority of patients in whom autoantibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA. PMID- 29419917 TI - Long-term efficacy and safety of ertugliflozin monotherapy in patients with inadequately controlled T2DM despite diet and exercise: VERTIS MONO extension study. AB - AIM: This phase III, multicentre, randomized study (ClinicalTrials.gov; NCT01958671) evaluated the efficacy and safety of ertugliflozin monotherapy in adults with inadequately controlled type 2 diabetes (glycated haemoglobin [HbA1c], 7.0% to 10.5% [53-91 mmol/mol]) despite diet and exercise. MATERIALS AND METHODS: The 52-week study comprised a 26-week, double-blind, placebo-controlled period (Phase A) during which 461 participants received placebo, ertugliflozin 5 mg/d or ertugliflozin 15 mg/d. This was followed by a 26-week active-controlled period (Phase B) during which participants in the placebo group who had not received glycaemic rescue therapy had blinded metformin added. Results to Week 52 are reported. Because of the use of metformin in Phase B, no statistical comparisons of efficacy were made between the ertugliflozin and placebo/metformin groups at Week 52. RESULTS: The mean (standard error) change from baseline to Week 52 in HbA1c was -0.9% (0.1) and -1.0% (0.1) in the ertugliflozin 5 and 15 mg groups, respectively. The proportions of participants with HbA1c <7.0% at Week 52 were 25.6% and 28.5%, respectively. Ertugliflozin reduced fasting plasma glucose, body weight and systolic blood pressure (SBP). The incidence of genital mycotic infections (GMIs) in females was significantly higher in both ertugliflozin groups (5 mg, 26.9%; 15 mg, 29.0%) vs the placebo/metformin group (9.9%), and in males was significantly higher in the 15 mg group (7.8%) vs the placebo/metformin group (1.2%). Ertugliflozin was not associated with increased incidence of urinary tract infections, symptomatic hypoglycaemia or hypovolaemia adverse events compared with placebo/metformin. CONCLUSIONS: Ertugliflozin treatment over 52 weeks improved glycaemic control and reduced body weight and SBP, but increased GMIs. PMID- 29419918 TI - Isolation of vancomycin-resistant Enterococcus from apparently healthy human animal attendants, cattle and cattle wastes in Tanzania. AB - AIM: The study aimed to isolate and characterize Enterococcus species from apparently healthy waste attendants, cattle and cattle waste in Tanzania. Emphasis was given to antimicrobial resistance and in particular occurrence of vancomycin (VA)-resistant enterococci. METHODS AND RESULTS: Faecal samples were collected from healthy cattle, cattle waste attendants and cattle house wastes, and isolation of Enterococcus species was performed using Slanetz Bartley agar. Isolates were characterized with regard to species, antimicrobial susceptibility and presence of VA resistance genes. Enterococcus faecalis was the most prevalent species from all sources of isolation (43.5%), followed by Enterococcus faecium (38.4%). Isolates of E. faecium showed a higher number of phenotypic antimicrobial resistance than isolates of E. faecalis. Fifty-eight isolates, which showed resistance or intermediate resistance to VA by disc diffusion test, were analysed for VA-resistant Enterococcus (VRE) by PCR. The vanA gene was detected in 14 isolates of E. faecium and 12 isolates of E. faecalis, while vanB was detected in three isolates. No isolates were found to carry vanC1-gene. CONCLUSION: VRE was detected in both human and cattle samples, despite no known use of antimicrobial agents that can select for VRE in livestock in Tanzania. Enterococcus faecalis was the most commonly isolated species from cattle and humans. SIGNIFICANCE AND IMPACT OF THE STUDY: The study provides information on the prevalence of VRE in human and nonhuman samples in Tanzania calling for further studies on the origin of VRE in such isolates, since no selection mechanism in Tanzania are known. PMID- 29419919 TI - Beta cell function after intensive subcutaneous insulin therapy or intravenous insulin infusion at onset of type 1 diabetes in children without ketoacidosis. AB - BACKGROUND: Our aim was to see if IV insulin therapy at diagnosis preserves beta cell function better than multiple subcutaneous (SC) injections. METHODS: Fifty four children 9.9 +/- 3.5 years (range 2.8-14.9) without ketoacidosis were included in a 2 years, randomized multicenter study with insulin SC or 48 to 72 hours IV initially. Thirty-three (61%) were boys, 22 (41%) were pubertal. Forty eight subjects completed 12 months follow-up and 43 completed 24 months. At 1, 6, 12, and 24 months, hemoglobin A1c (HbA1c), C-peptide and insulin/kg/24 h were measured. At 24 months, a mixed-meal tolerance test (MMTT) was performed. RESULTS: HbA1c at diagnosis was 10.7%, (93 mmol/mol) for IV, 10.7%, (94 mmol/mol) for SC. During the first 2 full days of insulin therapy, mean plasma glucose was 8.2 mmol/L for IV, 9.5 for SC (P = .025). Mean insulin dose was 1.5 U/kg/d for IV vs 1.0 for SC (P = .001). Sixteen (7 in IV, 9 in SC group) started with insulin pumps during the follow-up. At 24 months, we saw no significant differences: HbA1c (7.5%, 58 mmol/mol, for IV, 7.2%, 55 mmol/mol, for SC; ns), insulin doses (0.79 vs 0.88 U/kg/d; ns), fasting C-peptide (0.08 vs 0.12 nmol/L; ns), maximal MMTT response (0.19 vs 0.25 nmol/L; ns) and AUC (18.26 vs 23.9 nmol/L*min; ns). Peak C-peptide >0.2 nmol/L in the combined IV and SC groups correlated significantly with HbA1c and C-peptide at onset in a multiple regression. CONCLUSION: Residual beta cell function at 2 years seems to be independent from initial insulin regimens but related to HbA1c and C-peptide at onset. PMID- 29419920 TI - The regular use of an emollient improves symptoms of atopic dermatitis in children: a randomized controlled study. AB - BACKGROUND: Emollients are considered as a first-line therapy for the treatment of atopic dermatitis (AD). However, evidence-based proof that the regular use of emollients reduces AD severity is lacking. OBJECTIVE: To assess whether the regular use of emollients results in a reduction in AD severity in children with AD. METHODS: In this multicentre randomized, parallel group, open-label study, children with mild-to-moderate AD were recruited during a flare. After flare resolution with a topical corticosteroid, patients were randomized to V0034CR emollient, reference emollient or no emollient (1:1:1 ratio), for 12 weeks. AD severity was assessed regularly by physicians [Scoring for Atopic Dermatitis (SCORAD) and subcomponents, IGA] and by parents (PO-SCORAD and POEM). RESULTS: A total of 335 patients were randomized to V0034CR (n = 111), reference emollient (n = 116) or no emollient (n = 108). After 12 weeks of treatment, SCORAD score was reduced by 5.28 points in the V0034CR group and by 3.36 points in the reference emollient group compared with the no emollient group (+4 points; P < 0.001 in both emollient groups vs. no emollient group). In a similar manner, PO SCORAD score was reduced by 4.88 and 2.67 points in the V0034CR and reference emollient groups, respectively, but increased by 2.90 points in the no emollient group (P < 0.001). Similar results were observed for POEM. A continuous decrease in all scores was observed over the 12-week treatment period. At the end of the study, the percentage of patients in complete remission (i.e. without a new flare over the treatment period) was higher in the V0034CR (59.5%) and reference emollient (44.3%) groups than in the no emollient group (29.8%; P < 0.001). CONCLUSION: These results demonstrate that the regular use of emollients in children with mild-to-moderate AD reduces the severity of symptoms and, therefore, support their use as a first-line treatment for these patients. PMID- 29419921 TI - The evolving contribution of non-communicable diseases to maternal mortality in Jamaica, 1998-2015: a population-based study. AB - OBJECTIVE: To describe trends in indirect cause-specific pregnancy-related mortality from 1998 to 2015. DESIGN: Secondary analysis of annual, national cross sectional database of maternal and late maternal deaths, identified through active surveillance of deaths among women aged 10-50 years. SETTING: Jamaica, a middle-income Caribbean country. POPULATION: Maternal and late maternal deaths. METHODS: Descriptive trend analyses of demographic and cause-specific maternal and pregnancy-related mortality ratios undertaken comparing the periods 1998 2003, 2004-2009 and 2010-2015. Multivariate logistic regression was used to confirm changes in risk of indirect death. MAIN OUTCOME MEASURES: Maternal, pregnancy-related, direct, indirect and cause-specific mortality ratios (deaths/100 000 live births). RESULTS: Maternal deaths from indirect conditions increased between the first two periods (P = 0.004) and stabilised in the third (P = 0.085). Associated with upward movement in cardiovascular deaths (P[trend] = 0.003), women under 25 years were at elevated risk (odds ratio 1.44, 95% CI 1.00 2.08; P = 0.052). Haematological/immunological conditions (69% sickle cell disease) ranked second but did not vary with time. Health service utilisation was similar across age, parity, health region and major cause categories (non communicable diseases, non-obstetric infections, direct), however women with indirect conditions spent more time in hospital (median 5 days versus 3 days) and more often died after the puerperium. CONCLUSIONS: Medical conditions, especially cardiovascular disease, are increasingly associated with maternal and late maternal mortality. Middle-income countries need to simultaneously improve management of indirect conditions, while redoubling efforts to reduce direct deaths. Postpuerperal medical services should be integrated into routine infant health services to improve continuity of care during this high-risk period. TWEETABLE ABSTRACT: Maternal survival (SDG 3.1) in LMICs requires better care for women with both non-communicable diseases and obstetric conditions. PMID- 29419922 TI - Transcriptome profiles of sunflower reveal the potential role of microsatellites in gene expression divergence. AB - The mechanisms by which natural populations generate adaptive genetic variation are not well understood. Some studies propose that microsatellites can function as drivers of adaptive variation. Here, we tested a potentially adaptive role for transcribed microsatellites with natural populations of the common sunflower (Helianthus annuus L.) by assessing the enrichment of microsatellites in genes that show expression divergence across latitudes. Seeds collected from six populations at two distinct latitudes in Kansas and Oklahoma were planted and grown in a common garden. Morphological measurements from the common garden demonstrated that phenotypic variation among populations is largely explained by underlying genetic variation. An RNA-Seq experiment was conducted with 96 of the individuals grown in the common garden and differentially expressed (DE) transcripts between the two latitudes were identified. A total number of 825 DE transcripts were identified. DE transcripts and nondifferentially expressed (NDE) transcripts were then scanned for microsatellites. The abundance of different motif lengths and types in both groups were estimated. Our results indicate that DE transcripts are significantly enriched with mononucleotide repeats and significantly depauperate in trinucleotide repeats. Further, the standardized mononucleotide repeat motif A and dinucleotide repeat motif AG were significantly enriched within DE transcripts while motif types, C, AT, ACC and AAC in DE transcripts, are significantly differentiated in microsatellite tract length between the two latitudes. The tract length differentiation at specific microsatellite motif types across latitudes and their enrichment within DE transcripts indicate a potential functional role for transcribed microsatellites in gene expression divergence in sunflower. PMID- 29419924 TI - The pursuit of happiness: The thin line between rights and duties. PMID- 29419925 TI - Pregnancy-Associated Stroke (2018/006). PMID- 29419926 TI - Neonatal Outcomes in the Birth Center Setting: A Systematic Review. AB - INTRODUCTION: This systematic review investigates the effect of the birth center setting on neonatal mortality in economically developed countries to aid women and clinicians in decision making. METHODS: We searched the Google Scholar, CINAHL, and PubMed databases using key terms birth/birthing center or out of hospital with perinatal/neonatal outcomes. Ancestry searches identified additional studies, and an alert was set for new publications. We included primary source studies in English, published after 1980, conducted in a developed country, and researching planned birth in centers with guidelines similar to American Association of Birth Centers standards. After initial review, we conducted a preliminary analysis, assessing which measures of neonatal health, morbidity, and mortality were included across studies. RESULTS: Neonatal mortality was selected as the sole summary measure as other measures were sporadically reported or inconsistently defined. Seventeen studies were included, representing at least 84,500 women admitted to a birth center in labor. There were substantial differences of study design, sampling techniques, and definitions of neonatal outcomes across studies, limiting conclusive statements of the effect of intrapartum care in a birth center. No reviewed study found a statistically increased rate of neonatal mortality in birth centers compared to low-risk women giving birth in hospitals, nor did data suggest a trend toward higher neonatal mortality in birth centers. As in all birth settings, nulliparous women, women aged greater than 35 years, and women with pregnancies of more than 42 weeks' gestation may have an increased risk of neonatal mortality. DISCUSSION: There are substantial flaws in the literature concerning the effect of birth center care on neonatal outcomes. More research is needed on subgroups at risk of poor outcomes in the birth center environment. To expedite research, consistent use of national and international definitions of perinatal and neonatal mortality within data registries and greater detail on adverse outcomes would be beneficial. PMID- 29419928 TI - Index of ACNM Documents and Publications, January 2018. PMID- 29419927 TI - Prevalence of Prolonged Latent Phase and Labor Outcomes: Review of Birth Records in a Swedish Population. AB - INTRODUCTION: The prevalence of a prolonged latent phase of labor has been described as ranging from 5% to 6.5% in previous research. The aim of this study was to describe the prevalence of the prolonged latent phase of 18 hours or more, based on women's report, in women intending vaginal birth and who had spontaneous onset of labor. An additional aim was to compare the incidence of obstetric interventions, and the labor and neonatal outcomes in women with and without a prolonged latent phase. METHODS: A descriptive and comparative study was performed in a mid-sized hospital in western Sweden. The sample consisted of 1343 birth records of women who intended vaginal births and who had spontaneous onset of labor at 37 or more weeks' gestation during a one-year period (2013-2014). Background characteristics, obstetric interventions, and labor and neonatal outcomes were compared between women with latent phases lasting less than 18 hours and 18 hours or more, based on women's self-report. Odds ratios with 95% confidence intervals were calculated for the different exposure variables. RESULTS: A prolonged latent phase lasting 18 hours or more occurred in 23% of all births analyzed (n = 1343). A prolonged latent phase was more common among nulliparous women (29.2%) but also common for multiparous women (17%). Nulliparous and multiparous women who experienced a prolonged latent phase were more often exposed to amniotomy during latent phase. For nulliparous women, the adjusted odds ratio (aOR) was 11.57 (95% confidence interval [CI], 5.25-25.51) and for multiparous women the aOR was 18.73 (95% CI, 9.06-38.69). Similarly, amniotomy during active phase was more common for both nulliparous and multiparous women who experienced a prolonged latent phase (aOR, 4.05; 95% CI, 2.53-6.47 and aOR, 3.93; 95% CI, 2.43-6.37, respectively). Women with latent phases of 18 hours or more, more often experienced augmentation of labor during all phases, especially during latent phase. For nulliparous women, the aOR was 10.13 (95% CI, 2.82-36.39) and for multiparous women, aOR was11.9 (95% CI, 3.69 38.71). A prolonged latent phase was associated with more instrumental vaginal births for multiparas (aOR, 2.58; 95% CI, 1.27-5.26) and emergency cesarean regardless of parity (nulliparous women: aOR, 3.21; 95% CI, 1.08-9.50 and multiparous women: aOR, 3.93; 95% CI, 1.67-9.26). DISCUSSION: Based on women's self-report, the prevalence of a prolonged latent phase in women at term who planned a vaginal birth and had spontaneous onset of labor was higher than previously reported. Women with a prolonged latent phase were more likely to receive obstetric interventions. Assisted vaginal birth was more common for nulliparous women with prolonged latent phase and emergency cesarean occurred more frequently for both nulliparous women and multiparous women with a prolonged latent phase. PMID- 29419929 TI - Identification of the novel allele, HLA-C*01:136 in a German cord blood donor originating from Azerbaijan. AB - HLA-C*01:136 identified by next generation sequencing and confirmed by Sanger sequencing. PMID- 29419930 TI - STAT1 is a sex-specific tumor suppressor in colitis-associated colorectal cancer. AB - The interferon-inducible transcription factor STAT1 is a tumor suppressor in various malignancies. We investigated sex-specific STAT1 functions in colitis and colitis-associated colorectal cancer (CRC) using mice with specific STAT1 deletion in intestinal epithelial cells (STAT1?IEC ). Male but not female STAT1?IEC mice were more resistant to DSS-induced colitis than sex-matched STAT1flox/flox controls and displayed reduced intraepithelial infiltration of CD8+ TCRalphabeta+ granzyme B+ T cells. Moreover, DSS treatment failed to induce expression of T-cell-attracting chemokines in intestinal epithelial cells of male but not of female STAT1?IEC mice. Application of the AOM-DSS protocol for induction of colitis-associated CRC resulted in increased intestinal tumor load in male but not in female STAT1?IEC mice. A sex-specific stratification of human CRC patients corroborated the data obtained in mice and revealed that reduced tumor cell-intrinsic nuclear STAT1 protein expression is a poor prognostic factor in men but not in women. These data demonstrate that epithelial STAT1 is a male specific tumor suppressor in CRC of mice and humans. PMID- 29419932 TI - Population dynamics of the diamondback moth, Plutella xylostella (L.), in northern China: the effects of migration, cropping patterns and climate. AB - BACKGROUND: The diamondback moth, Plutella xylostella (L.), is the most widely distributed pest of Brassica vegetables. Control of P. xylostella has relied on insecticides and it has developed resistance to most insecticides. Although research has clarified the resistance status of P. xylostella and the mechanisms of its resistance in northern China, little work has been conducted on long-term population dynamics in the key vegetable-growing areas of the region. RESULTS: We reviewed and summarized the history of P. xylostella field management practices in northern China (Haidian, Changping, Xuanhua and Zhangbei). Moths were caught in pheromone traps throughout the cropping season and P. xylostella phenology and the general trends in abundance were analysed using DYMEX modelling software. The initial input in the spring determined population size in all years. The seasonal phenology and variation in abundance in most years and sites were simulated, suggesting that the suitable climate creates the conditions for population outbreaks, and growers' actual management level (spraying and crop hygiene) influenced population abundance. CONCLUSION: Based on climate and using the timing of the initial peak in pheromone trap captures as a biofix, the timing of emergence of the next generation can be forecast, and more effective scouting and regional management strategies against this pest can be developed. (c) 2018 Society of Chemical Industry. PMID- 29419931 TI - Observations on the ex situ perfusion of livers for transplantation. AB - Normothermic ex situ liver perfusion might allow viability assessment of livers before transplantation. Perfusion characteristics were studied in 47 liver perfusions, of which 22 resulted in transplants. Hepatocellular damage was reflected in the perfusate transaminase concentrations, which correlated with posttransplant peak transaminase levels. Lactate clearance occurred within 3 hours in 46 of 47 perfusions, and glucose rose initially during perfusion in 44. Three livers required higher levels of bicarbonate support to maintain physiological pH, including one developing primary nonfunction. Bile production did not correlate with viability or cholangiopathy, but bile pH, measured in 16 of the 22 transplanted livers, identified three livers that developed cholangiopathy (peak pH < 7.4) from those that did not (pH > 7.5). In the 11 research livers where it could be studied, bile pH > 7.5 discriminated between the 6 livers exhibiting >50% circumferential stromal necrosis of septal bile ducts and 4 without necrosis; one liver with 25-50% necrosis had a maximum pH 7.46. Liver viability during normothermic perfusion can be assessed using a combination of transaminase release, glucose metabolism, lactate clearance, and maintenance of acid-base balance. Evaluation of bile pH may offer a valuable insight into bile duct integrity and risk of posttransplant ischemic cholangiopathy. PMID- 29419933 TI - A serious adverse event secondary to rapid intravenous levetiracetam injection in a dog. AB - OBJECTIVE: To describe a serious adverse event as a result of rapid intravenous injection of undiluted levetiracetam in a dog. CASE SUMMARY: An 8-year-old female spayed Chihuahua was evaluated for cluster seizures and tachypnea. The patient was administered an intravenous dose of undiluted levetiracetam (60 mg/kg) and immediately developed tachycardia, hyperglycemia, hypotension, and a dull mentation. The patient's blood pressure and mentation did not respond to intravenous fluid boluses but improved immediately after administration of epinephrine intravenously. The patient subsequently developed respiratory failure necessitating mechanical ventilation, prior to cardiac arrest. Necropsy examination noted a pulmonary inflammatory cell infiltrate, pulmonary edema, and interstitial pneumonia. NEW OR UNIQUE INFORMATION PROVIDED: This report documents a serious adverse event associated with intravenous levetiracetam administration to a dog. PMID- 29419934 TI - Evaluation of nafamostat mesilate as an alternative anticoagulant during intermittent hemodialysis in healthy Beagle dogs. AB - OBJECTIVE: To evaluate nafamostat mesilate (NM) as an alternative anticoagulant agent for intermittent hemodialysis (IHD). DESIGN: Prospective randomized study. SETTING: University teaching hospital. ANIMALS: Eighteen healthy Beagle dogs. INTERVENTIONS: In group 1 (n = 6), NM was administered at a dose of 0.5 mg/kg/h during IHD for 5 hours. In group 2 (n = 6), NM was administered at a low dose of 0.25 mg/kg/h during IHD. In group 3 (n = 6), which was the control group, unfractionated heparin (UFH) was administered during IHD. The evaluated parameters included: the amount of residual blood clots in the blood chamber and arterial side of the dialyzer; the levels of hemoglobin, hematocrit, and platelets; and the prothrombin time (PT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT). MEASUREMENTS AND MAIN RESULTS: Groups 1 and 2 successfully completed IHD without serious coagulation in the extracorporeal circulation. The residual blood clotting in the blood chamber and arterial side of the dialyzer did not significantly differ in groups 1 and 2 compared to group 3 (group 1 vs group 3, P = 1.000; and group 2 vs group 3, P = 1.000). No significant differences were observed between pre- and posttreatment PTs in groups 1 (P = 0.476) and 2 (P = 0.597), between pre- and posttreatment aPTTs in groups 1 (P = 0.983) and 2 (P = 0.977), and between pre- and posttreatment ACT in groups 1 (P = 0.282) and 2 (P = 0.401). In group 3, a significant elevation of ACT was observed at the posttest (P < 0.001). CONCLUSIONS: The results of this study in healthy Beagle dogs suggest that NM at 0.25 mg/kg/h may be a valid alternative to UFH for IHD. Further studies are needed in patients at high risk of bleeding. PMID- 29419935 TI - Treatment of acute kidney injury associated with cyclosporine overdose in a dog using hemodialysis and charcoal hemoperfusion. AB - OBJECTIVE: To describe the management of cyclosporine overdose using hemodialysis and hemoperfusion in a dog. CASE SUMMARY: A 6-year-old, spayed female Australian Shepherd was presented for treatment of cyclosporine overdose and acute kidney injury. Five days prior to presentation, the dog had been diagnosed by its referring veterinarian with immune-mediated thrombocytopenia. Treatment was initiated with prednisone, but since no response was noted, azathioprine (50 mg PO q 24 h) and cyclosporine (6 mg/kg IV q 24 h) were added. On day 4, an overdose of cyclosporine (33 mg/kg IV) was administered accidentally. Upon presentation, serum biochemistry panel revealed azotemia [creatinine, 521.6 MUmol/L (5.9 mg/dL); BUN, 59.3 mmol/L (166 mg/dL)], increased activities of liver enzymes, and hyperbilirubinemia. Due to the presumed diagnosis cyclosporine overdose and acute kidney injury, a combined hemodialysis and charcoal hemoperfusion treatment was planned. Hemosorba CH-350 charcoal hemoperfusion cartridge was placed in series upstream in the extracorporeal circuit from the hemodialyzer. A 3-hour treatment was performed and a total of 0.74 L/kg of blood was processed. Pretreatment blood cyclosporine concentration was 960 nmol/L (1154 ng/mL) and decreased to 440 nmol/L (529 ng/mL) posttreatment (54% fractional reduction, 18% per hour). Thirty one hours following treatment, blood cyclosporine concentration was 220 nmol/L (265 ng/mL; 1.5% decrease per hour). Twelve days following presentation to our hospital, the dog was euthanized due to lack of response to medical management. NEW OR UNIQUE INFORMATION PROVIDED: Combined hemodialysis and charcoal hemoperfusion treatment can significantly reduce blood cyclosporine concentrations following acute intoxication or overdosage, and should be considered as an option for decontamination in such cases. PMID- 29419936 TI - Pioneering women in mass spectrometry - an interview with Catherine E. Costello. PMID- 29419937 TI - Structure-property relationship study of the HPLC enantioselective retention of neuroprotective 7-[(1-alkylpiperidin-3-yl)methoxy]coumarin derivatives on an amylose-based chiral stationary phase. AB - The enantiomer separation of a number of racemic 7-[(1-alkylpiperidin-3 yl)methoxy]coumarin derivatives, some of which show outstanding in vitro multitarget neuroprotective activities, was successfully achieved on a polysaccharide-based chiral stationary phase, bearing amylose tris(3,5 dimethylphenylcarbamate) as a chiral selector, in normal polar mode (methanol and acetonitrile as the mobile phases). The majority of the screened selectands, especially those bearing 1-(3-X-benzyl)piperidin-3-yl moieties, showed baseline enantiomer separations, and compound 8 (X = NO2 ) was the best resolved (alpha = 2.01; RS = 4.27). Linear free energy relationships, usefully complemented by molecular docking calculations, have the key role in enantioselective retention of aromatic interactions between pi-donor moieties in the chiral selector and pi acceptor moieties in selectand, strengthened by hydrogen bond interaction between a hydrogen bond donor in the chiral selector and the hydrogen bond acceptor group(s) in the selectand. Statistically, reliable equations highlighted the importance of the substituent's size and substitution pattern (meta better than para) to affect the enantiorecognition of the title compounds. The chromatographic data support the scalability of the optimized experimental conditions for preparative purposes. PMID- 29419938 TI - Finely Controlled Stepwise Engineering of Pore Environments and Mechanistic Elucidation of Water-Stable, Flexible 2D Porous Coordination Polymers. AB - Two porous coordination polymers (PCPs) with different topologies (NTU-19: sql and NTU-20: dia) underwent finely controlled, stepwise crystal conversions to yield a common water-stable, flexible 2D framework (NTU-22: kgm). The crystal conversions occurred directly at higher temperature via the 3D intermediate (NTU 21: nbo), which could be observed at lower temperature. The successful isolation of the intermediate product of NTU-21, characterization with in situ PXRD and UV/Vis spectra were combined with DFT calculations to allow an understanding of the dynamic processes at the atomic level. Remarkably, breakthrough experiments demonstrate NTU-22 with integral structural properties allowed significant CO2 /CH4 mixture separation. PMID- 29419939 TI - Response to: Regarding "HIV protease inhibitors and mortality following kidney transplantation". PMID- 29419941 TI - Towards the full spectrum of genes for human skin colour. PMID- 29419940 TI - Development and evaluation of a holistic surgical head and neck cancer post treatment follow-up clinic using touchscreen technology-Feasibility study. AB - The efficacy of traditional follow-up care is being challenged, as cancer survivors' supportive and psychological needs are often neither identified, nor addressed. This study's aim was to develop a holistic surgical follow-up clinic for oral and oropharyngeal cancer patients were participants completed a disease specific health-related quality of life tool (UWQOLv4) and item prompt list (Patient Concern Inventory) on a touchscreen computer. Information generated was used to focus the consultation on patient's identified needs and concerns. By means of a prospective non-randomised, pre-test post-test design, this follow-up clinic was evaluated using the patient enablement instrument (PEI) and patient content checklist (PCC). Feasibility was explored from the patient perspective (satisfaction survey) and clinician perspective (qualitative interview). Forty four consecutive patients were recruited. Findings demonstrating five of the eight topics (overall QOL, emotions, head and neck symptoms, side-effects of treatment, chronic non-specific) on PCC were discussed more frequently, but changes were not statistically significant. The PEI highlighted a trend towards perceived improvement in four of the six items. Using touchscreen computers to aid communication during routine follow-up was reported as both feasible and beneficial by patients and clinicians. Providing a patient-focused follow-up consultation can facilitate the identification of unmet needs, permitting timely and appropriate intervention being initiated. PMID- 29419942 TI - Professional nursing values: A concept analysis. AB - AIM: The aim of this concept analysis is to clarify the meaning of professional nursing values. BACKGROUND: In a time of increasing ethical dilemmas, it is essential that nurses internalize professional values to develop and maintain a professional identity. However, nursing organizations and researchers provide different conceptions of professional nursing values, leading to a lack of clarity as to the meaning and attributes of this construct. DESIGN: Walker and Avant's (2011) method was used to guide an analysis of this concept. DATA SOURCE: Resources published from 1973 to 2016 were identified via electronic databases and hand-searching of reference lists. REVIEW METHODS: A review of the literature was completed and the data were analyzed to identify uses of the concept; the defining attributes of the concept; borderline, related, contrary, and illegitimate examples; antecedents and consequences; and empirical referents. RESULTS: Professional nursing values were defined as important professional nursing principles of human dignity, integrity, altruism, and justice that serve as a framework for standards, professional practice, and evaluation. CONCLUSIONS: Further research is needed in the development and testing of professional nursing values theory, and the reassessment of values instruments. Core professional values that are articulated may help unify the profession and demonstrate the value of nursing to the public. PMID- 29419943 TI - The role of social context in symptom appraisal and help-seeking among people with lung or colorectal symptoms: A qualitative interview study. AB - Prolonged diagnostic intervals are associated with poorer outcomes, and the patient interval appears to be a substantial contributor to the overall length of the diagnostic interval. This study sought to understand how the broader context of people's lives influenced symptom appraisal and help-seeking, comparing experiences by length of the patient interval. Patients referred with a suspicion of lung or colorectal cancer were invited to complete a questionnaire about their symptoms, with 26 respondents purposively sampled to take part in a semi structured interview about their patient intervals. Embodied experience, appraisal, help-seeking decision-making and consultation were identified as component stages of the patient interval, with the factors affecting movement between these stages located in one of four contextual domains: individual experience, interpersonal relationships, healthcare system interactions and social and temporal context. The length of the patient interval was related to the type of symptom(s) experienced, discussion of symptoms with others and the social responsibilities people held during symptomatic periods. A contextual model of the patient interval illustrates the stages and domains of this interval, as grounded in the data from this study. The model has potential application to future studies examining the patient interval for a range of symptoms. PMID- 29419944 TI - Incident learning in radiation oncology: A review. AB - Incident learning is a key component for maintaining safety and quality in healthcare. Its use is well established and supported by professional society recommendations, regulations and accreditation, and objective evidence. There is an active interest in incident learning systems (ILS) in radiation oncology, with over 40 publications since 2010. This article is intended as a comprehensive topic review of ILS in radiation oncology, including history and summary of existing literature, nomenclature and categorization schemas, operational aspects of ILS at the institutional level including event handling and root cause analysis, and national and international ILS for shared learning. Core principles of patient safety in the context of ILS are discussed, including the systems view of error, culture of safety, and contributing factors such as cognitive bias. Finally, the topics of medical error disclosure and second victim syndrome are discussed. In spite of the rapid progress and understanding of ILS, challenges remain in applying ILS to the radiation oncology context. This comprehensive review may serve as a springboard for further work. PMID- 29419945 TI - Shared mental models of cancer survivorship care. AB - Quality cancer survivorship care relies on care continuity within the healthcare team. The purpose of this study was to explore the perspectives of healthcare team members regarding cancer survivorship care using the framework of shared mental models. Semi-structured interviews of cancer survivors, primary support individuals, oncology providers, primary care providers and registered nurses were completed. Data were extrapolated to seven primary themes with associated secondary themes. Primary themes included survivor definition and identity, care setting, team member roles, care gaps, survivor needs, barriers to care and facilitators of care. Through these themes, participants emphasised the individuality of the survivorship experience, acknowledged care gaps and described ongoing needs of cancer survivors. Information provision and communication were noted as care facilitators. Through clarification of team member roles, healthcare providers will be equipped to promote cancer survivor transition by focusing on care continuity, communication and collaboration. PMID- 29419947 TI - Cotard Syndrome Resulting From Valacyclovir Toxicity. PMID- 29419946 TI - Photoacoustic microscopy for evaluating combretastatin A4 phosphate induced vascular disruption in orthotopic glioma. AB - The use of an optical resolution photoacoustic microscopy (OR-PAM) system to evaluate the vascular disruptive effect of combretastatin A4 Phosphate (CA4P) on a murine orthotopic glioma with intact skull is described here. Second generation optical-resolution photoacoustic microscopy scanner with a 532 nm pulsed diode pumped solid-state laser that specifically matches the absorption maximum of hemoglobin in tissues was used to image orthotopic glioma inoculated in mouse brain. Two-dimensional maps of brain vasculature with a lateral resolution of 5 MUm and a depth of 700 MUm at a field of view 5 * 4 mm were acquired on normal brain and glioma brain. Longitudinal imaging of the brain pre- and post administration of CA4P, a FDA approved drug for solid tumors, enabled the monitoring of hemodynamic changes in tumor vasculature revealing the well documented vascular shutdown and recovery associated with this drug. Our study marks the beginning of potential prospects of this technology as an imaging tool for preclinical and clinical study of pathologies characterized by changes in the vasculature. PMID- 29419948 TI - Treatment-Refractory Obsessive-Compulsive Disorder in Adults: A Cost Effectiveness Analysis of Treatment Strategies. AB - OBJECTIVE: This study sought to assess the cost-effectiveness of 7 treatment strategies for treatment-refractory obsessive-compulsive disorder (OCD) in adults. METHODS: A model was developed to evaluate treatment alternatives for adults (18-64 years old) that consisted of 2 parts: a decision analytic model and a Markov model. The decision analytic model stratified 7 outpatient treatment strategies, and the Markov model accumulated benefits and costs across the life expectancy of a simulated cohort of individuals. The model was parameterized with probabilistic and deterministic parameters from the literature and an outcomes database to perform a Monte Carlo simulation of a hypothetical cohort of 100,000 adults with OCD to estimate net health benefits (NHBs), costs, and incremental cost-effectiveness ratio (ICER) for each treatment strategy. OCD was considered treatment refractory in adults with an OCD diagnosis who failed first-line therapies. Encounters took place from 2012 to 2015, and the analyses were performed from November 2016 to February 2017. RESULTS: Partial hospitalization with step-down to intensive outpatient treatment was the most cost-effective of the 7 strategies, with an estimated ICER of $7,983 and mean (SD) NHB of 10.96 (0.53) quality-adjusted life-years (QALYs) remaining. This result was 2.2 QALYs greater than that of the trial-based antidepressant and cognitive-behavioral therapy (ADM + CBT) strategy. Three additional ADM + CBT strategies were estimated not to be statistically significantly different from each other. These 4 ADM + CBT strategies outperformed both pharmacotherapy-only strategies. CONCLUSIONS: Treatment strategies that include higher-intensity CBT, with effectiveness outcomes that approached efficacy estimates, were superior to real world CBT strategies. However, given the limited availability of high-quality CBT, especially through use of commercial insurance networks, specialized treatment programs offer greater effectiveness than real-world therapies in achieving wellness for this severe patient population. PMID- 29419949 TI - Depression With Mixed Features in Major Depressive Disorder: A New Diagnosis or There All Along? PMID- 29419951 TI - [Update in posterior urethral valves]. PMID- 29419950 TI - The Psychiatric Assessment and Brief Intervention Program: Partnering With Primary Care Providers. AB - Objective: To present the structure and outcomes to date for the Psychiatric Assessment and Brief Intervention (PABI), a pilot program developed at University of California, San Francisco, to improve access of primary care patients to mental health services. PABI offers diagnostic evaluations and brief (up to 3 months) evidence-based treatment, including pharmacologic management and psychotherapy, to medical patients 18 years of age and older. Core PABI features are ensuring prompt access, actively partnering with patients and referring providers, and coordinating seamless transitions of care. Methods: Demographic and clinical variables and outcome indicators were collected for all patients seen in PABI from October 2015 to June 2017. Descriptive statistics and mixed effects linear models were used to analyze the data. Results: During the study period, 139 patients (54% women, mean [SD] age of 48.2 [17.5] years) with a mean of 2 DSM-5 psychiatric diagnoses each (range, 1-5) were seen. Mean time to access was 8 days, with a mean length of stay in the program of 11 weeks. Compared to baseline, final behavioral health measure scores showed significant improvement: the mean Patient Health Questionnaire-9 score decreased by 5.9 points (95% CI, 4.6-7.2), and the mean 7-item Generalized Anxiety Disorder scale score was 4.4 points lower (95% CI, 3.2-5.6; both P values < .0001). Conclusions: This brief psychiatric treatment program provides prompt access to quality mental health care for patients with medical comorbidities. Results to date suggest that this program leads to significantly improved clinical outcomes. Further research is needed to determine its long-term sustainability and generalizability. PMID- 29419952 TI - [Long-term results of the early endoscopic treatment of acquired tracheal subglottic stenosis: 10 years of experience]. AB - INTRODUCTION: Acquired stenosis of the airway is a common complication after endotracheal intubation. Endoscopic dilation has been accepted as the treatment of choice in cases detected precociously. Our goal is to know the current status of the patients treated in our hospital with endoscopic dilation in the last 10 years. MATERIAL AND METHODS: Retrospective cohort study of patients with subglottic and tracheal acquired stenosis (STAS) early treated endoscopically with balloon dilation at our center in the last 10 years. Bronchoscopy control at 2 weeks, a month, 3 and 6 months post-dilation were performed and later on depending on the symptoms. RESULTS: 32 patient were treated in the period considered. The median age was 4.5 (3-120) months. There were necessary 2.5 (1-5) dilations per patient. All cases were extubated in the operating room or in the following 24 hours. There were no complications during the procedure. Follow-up time was 6 (1-10) years. Only 1 of the 32 patients have had recurrence of stenosis 2 years after, it was secondary to reintubations due to new surgical interventions; which it was dilated successfully. CONCLUSIONS: Early endoscopic dilation in the acquired airway stenosis is a safe and effective long-term procedure. The results support the use of this technique as a treatment of choice in these patients. PMID- 29419953 TI - [The role of fetal magnetic resonance imaging in the study of congenital diaphragmatic hernia]. AB - INTRODUCTION AND OBJECTIVES: Different echographic and fetal magnetic resonance (MRI) measurements have been described in the diagnosis of associated malformations and the prognosis of congenital diaphragmatic hernia (CDH). We have reviewed our experience searching for useful isolated or combined parameters and how MRI can complement ultrasound. MATERIAL AND METHODS: We evaluated 29 fetuses with CDH. We examined ultrasonography: Lung to Head (LHR o/e) and in MRI: ipsilateral lung volume (IPV) and total expressed as percentage of observed / expected lung volume (VPT o/e) and percentage of herniated liver (PHH). We studied: survival, ECMO and associated malformations. RESULTS: LHR o/e was the measure that best predicted survival (p< 0.05). VPT o/e did not predict survival or the need of ECMO (p> 0.05). PHH >=19% was related to the need of ECMO. IPV < 2 cc required ECMO more frequently (p< 0.018) and when it was 0 cc in all cases. No combination of MR measurements was superior to LHR o/e in prediction of survival. MRI complemented the ultrasound in 4 cases: diaphragmatic eventration diagnosed with HDC, right HDC with fluid in the sac that suggested thoracic cyst, differentiation between spleen and lung that measured together overestimated the LHR and/or suspicion of Cornelia de Lange due to facial malformations. CONCLUSIONS: Not a single or combined MRI measurement exceeds LHR o/e in survival prediction. MRI is related to prognosis and can be used to support ultrasound in making decisions. MRI occasionally provides complementary morphological information. PMID- 29419954 TI - [Analysis of the comorbidities and role of laparoscopy in recurrent abdominal pain]. AB - INTRODUCTION AND OBJECTIVES: Recurrent abdominal pain is defined as > 3 episodes of abdominal pain accompanied by affectation of the daily activity, during > 3 months. Our objective is to analyze the role of diagnostic and/or therapeutic laparoscopy. MATERIAL AND METHODS: A descriptive, retrospective study from 2004 to 2016. Patients: <14 years with DAR who underwent laparoscopy. Variables: age, sex, history, surgical findings, histology and follow-up. RESULTS: 55 patients. Mean age: 10.7 years. Female 63, 6%. Probability of allergic comorbidity: 27.27% [16.138-40.962] (CI 95%). Probability of subsequent psychological comorbidity: 12.72% [5.27 -24.48] (95% CI). Histological changes 31/55 (56.36%): lymphoid nodular hyperplasia 10/31, appendicular inflammation 7/31, fecalite 3/31, carcinoid tumor 1/31, appendicular fibrosis 3/31, Meckel diverticulum 1/31, association of several of the above 8/31. Macroscopic alterations 31/55 (56.36%): appendicular pathology 10/31, adhesions 5/31, lymph nodes 2/31, ileitis 2/31, tubal cysts 1/31, Meckel 1/31 diverticulum, several of the previous ones 10/31. Remission of symptoms: 30/55 (54.54%). In some cases, with partial improvement (4/55) or persistence of symptoms (21/55), organic and/ or psychological cause was demonstrated (16/25). CONCLUSIONS: Recurrent abdominal pain seems to have a significant association with an allergic or psychological history. Exploratory laparoscopy is a useful diagnostic and therapeutic technique. PMID- 29419956 TI - [Evaluation of redundancy of tests in acute appendicitis]. AB - AIM: Evaluation of the redundancy of abdominal ultrasound tests in the diagnosis of acute appendicitis in a third level hospital. MATERIAL AND METHODS: Retrospective study of patients treated for suspected acute appendicitis in 2011 at our center. The variables of the study were: age, origin of the patient, blood count, number of ultrasounds performed, surgery and final diagnosis based on surgical findings. We defined as redundant ultrasound the request for a new ultrasound in patients with a final diagnosis of appendicitis and previous positive ultrasound.nd total expressed as percentage of observed / expected lung volume (VPT o/e) and percentage of herniated liver (PHH). We studied: survival, ECMO and associated malformations. RESULTS: 340 patients with a mean age of 9.4 years (range 2-13) were analyzed, 278 of whom had appendicitis and 62 non specific abdominal pain. 246 were derived from other centers of which 217 (88%) provided an ultrasound. Of the 198 patients referred with positive ultrasound, 76 cases were repeated, of which 78.9% can be considered as redundant. From the total of patients with appendicitis, 29.6% were operated on with 2 or more ultrasounds. Leukocytosis was not found to influence ultrasound redundancy (15,600 vs 15,100, p > 0.05). CONCLUSION: The 78.9% of the duplicate ultrasounds do not fit the definition of rational use of a diagnostic test. The greater request for ultrasound is not attributable to differences on the blood test results, nevertheless the origin of the patient seems to influence in that request. PMID- 29419955 TI - [Predictive factors of gangrenous post-appendectomy intra-abdominal abscess. A case-control study]. AB - BACKGROUND: Acute appendicitis is the most frequent surgical urgency in children. Frequently, it can be complicated with an intraabdominal abscess that will require a longer and expensive treatment. Our aim is to know if it is possible to predict this complication before its beginning. MATERIAL AND METHODS: Retrospective case-control study with patients treated between 2011 and 2016, paired according to their own characteristics (age, sex and weight), clinical aspects (symptoms, time of their onset, physical examination) and type of appendicitis (gangrenous). The main variable was the appearance of an intraabdominal abscess in the postoperative period (cases). Univariate and multivariate analysis were performed, with a statistical significance level of p < 0.05. RESULTS: We included 54 cases and 108 controls. The occurrence of intraabdominal abscess was significantly associated with preoperative hyponatremia (p < 0.001), elevated CRP (p < 0.05), appendix perforation (p < 0.001) and wound infection (p < 0.001). The multivariate analysis dismissed the value of the CRP as an abscess predictor but showed association in the other three variables cited before. There was no association with the presence of generalized peritonitis at the intervention or the type of surgical approach. CONCLUSIONS: Appendix perforation, infection of the surgical wound and hyponatremia at diagnosis are predictive factors for the appearance of a postoperative intraabdominal abscess after acute gangrene appendicitis. We believe that early identification would favor the secondary prevention of this complication and the decrease of its morbidity. PMID- 29419957 TI - [Risk factors associated with the development of enterocolitis in Hirschsprung's disease]. AB - OBJECTIVES: Hirschsprung's-associated enterocolitis (HAEC) is a live-threatening complication that remains badly understood. Our objective is to identify the risk factors related to the development of HAEC in the cohort of patients with Hirschsprung's disease (HD) treated in our center. METHODS: We reviewed the patients treated for HD between 2000 and 2016. Ninety four patients were included, and the clinical details related to the disease were evaluated. Our primary outcome measure was the development of HAEC. Relative risks are presented with 95% confidence intervals. RESULTS: Twenty seven patients out of the ninety four (28.7%) suffered HAEC. None of them died from this complication. The extended aganglionosis, the need of a preoperative stoma, a transabdominal surgery and the diagnosis before the age of 7.2 months were related to a higher risk of suffering HAEC. CONCLUSIONS: HAEC remains a common complication in patients suffering from HD, especially those with complex forms. The identification of the risk factors could result in a better control of the HAEC, which lead to a faster diagnosis and treatment, reducing the morbi-mortality related to HAEC. PMID- 29419958 TI - [Total parathyroidectomy, autoimplant and cryopreservation for the treatment of hyperparathyroidism of renal origin in children and young adults]. AB - OBJECTIVES: To describe our initial experience in the treatment of hyperparathyroidism (HPP) of renal cause using total or subtotal parathyroidectomy, autoimplant and cryopreservation in pediatric patients. Secondary HPP is the increased function of the parathyroid hormone (PTH) due to an abnormal phosphocalcic metabolism in patients with chronic renal failure (CRF). This situation produces increased bone resorption resulting in osteodystrophy and endovascular calcifications. Surgical treatment is aimed to diminish the level of PTH in CRF patients, to avoid HPP complications. METHODS AND MATERIALS: Descriptive, monocentric and retrospective study of a case series of patients with secondary and tertiary hyperparathyroidism, who went through total or subtotal parathyroidectomy, autoimplant and cryopreservation between 2009 and 2016. We analyzed the following variables: age, calcemia, PTH, phosphatemia, alkaline phosphatase (ALP), follow-up and complications. The continuous variables are expressed in median and interquartile range or in mean and SD, according to their distribution. The categorical variables were expressed in percentages and frequencies (repeated sentence). RESULTS: Number of patients included: 13. Mean age of the patients was 16.7 years old. Preoperative median calcium dosage was 9.1 mg/dl (IQR: 8.9-9.5). Median PTH was 2,600 pg/ml (IQR: 1,400 pg/ml to 2,785 pg/ml). Intraoperatory dosage of PTH reported a median drop of 86.6% in the first 15 minutes (IQR: 80.5-95.9). After the first 48 hours, median calcemia was 9 mg/dl (IQR: 7.7-9.4) and median PTH was 40 pg/ml (IQR: 20 113). We did not identify intraoperatory complications. In the immediate post operatory stage, mean IV calcium therapy was 4 days (SD: 2.39). Median time of follow-up was 18 months (IQR 9-36). Two patients had hungry bone syndrome and one patient had a recurrence of the pathology as remote post operatory complications. After a year, median calcemia, was 9 mg/dl (IQR: 7.6-9.3) and median PTH was 50 pg/ml (IQR: 28.5-108). The decrease in PTH and ALP were statistically significant with p value < 0.05. CONCLUSION: In our study, total parathyroidectomy with auto implant is a safe and effective option for the treatment of secondary and tertiary hyperparathyroidism in pediatric patients. This could also prevent bone complications. PMID- 29419959 TI - [Nephroblastoma. Long-term experience in the multidisciplinary approach]. AB - OBJECTIVES: Main objective: to perform a descriptive study of patients with nephroblastoma, diagnostic tests, medical and surgical treatment. Secondary objective: to evaluate the rate of relapse and 5-year survival and risk factors for relapse and death. MATERIALS AND METHODS: Retrospective study of patients with nephroblastoma treated according to the protocol of the SIOP-2001. Demographic variables, comorbidities and associated syndromes were collected. Other data were tumor location, size, extent and stage. The relapse rate and the development of other secondary tumors as well as the long-term survival were also studied. RESULTS: We collected 33 patients with nephroblastoma. A biopsy was performed in 7 patients (21.2%). The Kaplan-Meir curve for event-free survival (tumor recurrence) was 84% with a 95% CI = [0.73-0.98] and the Kaplan-Meier overall survival curve was 0.93 95% CI [0.85-1]. Recurrence occurred in all patients before the first year. CONCLUSIONS: Nephroblastoma is a tumor with a favorable prognosis. The unfavorable histology as well as advanced stages are factors of a poor prognosis. The follow-up must be exhaustive during the first year after the diagnosis. PMID- 29419960 TI - [Fibrous hamartoma in childhood. A case description of large size and review of the literature]. AB - INTRODUCTION: Fibrous hamartoma of infancy is a rare soft tissue tumour that usually appears before 2 years of age, typically in the upper extremities of male infants. CASE REPORT: We report the case of a 2 year old boy with a large and rapidly growing tumour in the upper extremity. COMMENTS: We describe the case, its differential diagnosis and the immunhistological characteristics, and we discuss the non-aggressive surgical treatment, based on the benign behaviour of this tumour. PMID- 29419962 TI - Retraction: Rural-urban differentials in the rates and factors associated with post-neonatal mortality in Nigeria: Evidence from the 2013 national household survey, Emmanuel Olorunleke Adewuyi, Samuel John Adama, Kazeem Adefemi, Olufemi Abayomi Akintunde and Lydia Babatunde Bulndi. PMID- 29419961 TI - What the Data Say About HIM Professional Trends. PMID- 29419963 TI - [In process]. PMID- 29419964 TI - [In process]. PMID- 29419966 TI - [In process]. PMID- 29419965 TI - [In process]. PMID- 29419967 TI - [In process]. PMID- 29419968 TI - Family Trade: Multigenerational HIM Professionals Make the Industry a Tradition. PMID- 29419969 TI - [In process]. PMID- 29419970 TI - [In process]. PMID- 29419971 TI - [In process]. PMID- 29419972 TI - Hiring a WORKFORCE that works: Right out of the gate and down the road. PMID- 29419973 TI - The Quest for Managing Cyberthreats in Healthcare. PMID- 29419978 TI - In Data Analytics and Informatics, One is the Loneliest Number. PMID- 29419979 TI - [In process]. PMID- 29419980 TI - Standards, Information Governance, Informatics--Essential Components of HIM Workforce Education. PMID- 29419981 TI - [In process]. PMID- 29419982 TI - [In process]. PMID- 29419983 TI - [In process]. PMID- 29419984 TI - [In process]. PMID- 29419985 TI - [In process]. PMID- 29419986 TI - [In process]. PMID- 29419987 TI - [In process]. PMID- 29419988 TI - [In process]. PMID- 29419989 TI - Prevalence of babesiosis (Babesia bovis and Babesia bigemina) in cattle and water buffalo in Nueva Ecija, Philippines using Nested Polymerase Chain Reaction AB - The study was conducted to determine the prevalence of Babesia bovis and Babesia bigemina infection in blood samples of cattle and water buffaloes using nested polymerase chain reaction (nested-PCR). It also aimed to generate a spot map showing areas in Nueva Ecija, the Philippines where B. bovis and B. bigemina were detected. Whole blood samples of cattle (148) and water buffalo (65) were collected for DNA extraction and subsequent nested-PCR to detect B. bovis and B. bigemina. To further confirm and validate the nested-PCR results, three selected positive samples for each B. bovis and B. bigemina were sequenced and examined for homology analysis. The results showed that the prevalence of B. bovis, B. bigemina and mixed infection in cattle were 11.49% (17/148), 10.81% (16/148) and 5.41% (8/148), respectively. Homology analysis of nucleotide sequence of three selected DNA samples for each B. bovis showed two 99% and one 96% (partial sequence analysis) identities with B. bovis Thailand strain, while B. bigemina positive samples showed all 100% identities with B. bigemina Philippine strain. The result did not demonstrate in all water buffalo samples. These findings provide information about the prevalence of B. bovis and B. bigemina in cattle and water buffaloes in Nueva Ecija, which can be beneficial for strategic planning, disease management, and control and prevention. PMID- 29419990 TI - [In process]. PMID- 29419991 TI - [In process]. PMID- 29419993 TI - [In process]. PMID- 29419994 TI - [In process]. PMID- 29419992 TI - The first reported case of resistance of gastrointestinal nematodes to benzimidazole anthelmintic in goats in Poland AB - Fecal egg count reduction (FECR) test with albendazole and egg hatch test (EHT) with thiabendazole (TBZ) were performed in a dairy goat herd suspected of anthelmintic resistance to benzimidazoles. The herd had been regularly dewormed with fenbendazole for 5 previous years and despite that it remained infected with several species of gastrointestinal nematodes (Trichostrongylus colubriformis, Teladorsagia circumcincta, and Haemonchus contortus). Albendazole was administered per os at dose of 20 mg/kg to 10 goats (treated group), while 10 other goats remained untreated (control group). Fecal egg count (FEC) was determined using McMaster egg counting method before and 7 days after the treatment in the treated group, and once (at the latter moment) in the control group. EHT was performed on the pooled rectal sample collected from treated goats. EHT comprised the negative control and 7 consecutive concentrations of TBZ (0.05, 0.1, 0.2, 0.3, 0.5, 1.0, 2.0 MUg/ml) according to the standard procedure. Two hundredeggs/larvae were counted to determine percentage of unhatched eggs, which was adjusted by the natural mortality. TBZ dose effective in preventing hatching of 50% of eggs (ED50) was determined using the log-probit transformation. Median FEC (range) before the treatment was 1000 (250-3450) epg in the treated group and dropped to 150 (50-500) epg after the treatment (p=0.005). Median FEC (range) after the treatment was also significantly lower in the treated than in control group (p=0.009), where it was 725 (0-5050) epg. FECR between the treated and control group was 81%(95% CI: 49%, 93%). FECR in the treated group was 83% and 74% based on average and individual approach, respectively. ED50 value of TBZ was 0.78 MUg/ml. Only H. contortus persisted in the treated group after treatment. The results indicate resistance of H. contortus to a benzimidazole anthelmintic, which is the first such case reported in Polish goats. PMID- 29419995 TI - Detection of Plasmodium falciparum chloroquine resistance transporter (PfCRT) mutant gene amongst malaria-infected pregnant women in Calabar, Nigeria AB - Chemotherapy is the mainstay in malaria control and management. For some time, chloroquine (CQ) was a drug of choice for the treatment of malaria. It was effective against all forms of malaria, cheap and readily available. The increased resistance of malaria parasites to CQ led to widespread abandonment of the drug in African and Asian countries on the prompting of the World Health Organization. Currently, artemisinin-based combination therapy is the gold standard for the treatment of malaria. This study investigates the presence of the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT) mutant gene, a molecular marker responsible for CQ resistance in malaria parasites. A total of 369 pregnant women were microscopically screened for malaria infection using thin and thick blood films stained with Giemsa. Subsequently, malaria parasite DNA was extracted from the blood of malaria positive participants. The PfCRT gene was amplified using Polymerase Chain Reaction (PCR). A Restriction Fragment LengthPolymorphism analysis of the gene was performed to confirm mutant forms. The results showed that 251 (68.0%) of the participants had Plasmodium falciparum in their blood. Molecular examination revealed the presence of PfCRT mutant genes in 28% of the study population. Notwithstanding the decline in the prevalence of PfCRT T76 mutation since the antimalarial policy change in Nigeria, the 28% prevalence recorded in this study is considered high after ten years of the withdrawal of CQ in the treatment of uncomplicated malaria. PMID- 29419996 TI - [In process]. PMID- 29419997 TI - IG Case Study: Rady Children's Hospital--San Diego. Prioritizing Information Governance Initiatives Already Underway. PMID- 29419998 TI - [In process]. PMID- 29419999 TI - [In process]. PMID- 29420000 TI - [In process]. PMID- 29420001 TI - Evolving Roles in Clinical Documentation Improvement: Physician Practice Opportunities. PMID- 29420002 TI - [In process]. PMID- 29420003 TI - [In process]. PMID- 29420004 TI - Understanding Respiratory Diagnoses. PMID- 29420006 TI - Semper Hi-Tech. PMID- 29420005 TI - Building the Coding Career Ladder. PMID- 29420007 TI - Nanoceria-Supported Ruthenium(0) Nanoparticles: Highly Active and Stable Catalysts for Hydrogen Evolution from Water. AB - Ruthenium(0) nanoparticles supported on nanoceria (Ru0/CeO2) were prepared by reduction of Ru3+ ions on the surface of ceria using aqueous solution of NaBH4. The Ru0/CeO2 samples were characterized by advanced analytical tools and employed as electrocatalysts on the glassy carbon electrode (GCE) in hydrogen evolution from water. The GCE, modified by Ru0/CeO2 (1.86 wt % Ru), provides an incredible electrocatalytic activity with a high exchange current density of 0.67 mA.cm-2, low overpotential of 47 mV at j = 10 mA.cm-2, and small Tafel slope of 41 mV.dec 1. Moreover, this modified GCE provides an unprecedented long-term stability without changing the onset potential (33 mV) even after 10 000 scans in acidic water splitting at room temperature. The hydrogen gas, evolved during the water splitting using the Ru0/CeO2 (1.86 wt % Ru) electrocatalyst, was also collected. The amount of the evolved H2 gas matches well with the calculated value, which indicates the achievement of nearly 100% Faradaic efficiency. PMID- 29420008 TI - General Method for Generating Circular Gradients of Active Proteins on Nanofiber Scaffolds Sought for Wound Closure and Related Applications. AB - Scaffolds functionalized with circular gradients of active proteins are attractive for tissue regeneration because of their enhanced capability to accelerate cell migration and/or promote neurite extension in a radial fashion. Here, we report a general method for generating circular gradients of active proteins on scaffolds composed of radially aligned nanofibers. In a typical process, the scaffold, with its central portion raised using a copper wire to take a cone shape, was placed in a container (upright or up-side-down), followed by dropwise addition of bovine serum albumin (BSA) solution into the container. As such, a circular gradient of BSA was generated along each nanofiber. The bare regions uncovered by BSA were then filled with an active protein of interest. In demonstrating their potential applications, we used different model systems to examine the effects of two types of protein gradients. While the gradient of laminin and epidermal growth factor accelerated the migration of fibroblasts and keratinocytes, respectively, from the periphery toward the center of the scaffold, the gradient of nerve growth factor promoted the radial extension of neurites from the embryonic chick dorsal root ganglion. This method for generating circular gradients of active proteins can be readily extended to different types of scaffolds to suit wound closure and related applications that involve cell migration and/or neurite extension in a radial fashion. PMID- 29420009 TI - Surface-Segregation-Induced Nanopapillae on FDTS-Blended PDMS Film and Implications in Wettability, Adhesion, and Friction Behaviors. AB - Polymer composites have been extensively used to tune the surface property (e.g., wettability, friction, and adhesion) for its advantages of cost-effectiveness, high efficiency, and ease of fabrication. In this work, different amount of trichloro(1H,1H,2H,2H-perfluorooctyl)silane (FDTS) was added into poly(dimethylsiloxane) elastomer to prepare polymer composite films and were selected as a model to illustrate the effects of surface segregation on surface topology, wettability, friction, and adhesion. The results show that the added FDTS forms aggregations and increasing the content of FDTS leads to the difficulty of air bubble elimination, increase in viscosity, and drop in transparency. Driven by the differences of chemical potential, FDTS aggregations migrate to the air-polymer interface, resulting in surface enrichment and formation of nanopapillae (1-200 nm). This phenomenon becomes more significant with the increment in FDTS. The change in surface composition and structure generates profound effects on wettability, friction, and adhesion. The addition of FDTS makes the surface relatively oleophobic and further increasing the content of FDTS does not helpful in improving the oleophobicity due to the notable aggregation. Friction forces first grow with the increasing content of FDTS and then decline after the maximum point at 1.0 wt % of FDTS, which is attributed to the generated regular larger nanopappillae at high concentration. However, these larger nanopapillae lead to the increase in adhesion because more interactions are formed. The findings demonstrate the behaviors of FDTS in polymer composites and provide important guidance for controlling the formation of nanostructures via aggregation and phase segregation and exploring their implications on surface properties. PMID- 29420010 TI - Lanthanide-Directed Assembly of Interfacial Coordination Architectures-From Complex Networks to Functional Nanosystems. AB - Metallo-supramolecular engineering on surfaces provides a powerful strategy toward low-dimensional coordination architectures with prospects for several application fields. To date, most efforts have relied on transition metal centers, and only recently did we pioneer lanthanide-directed assembly. Coordination spheres and motifs with rare-earth elements generally display distinct properties and structural features. The size of the cations and shielding role of the 4f orbitals induces high coordination numbers, frequently entailing flexible coordination geometries. Following Pearson's hard and soft acid-base theory, lanthanide cations are hard Lewis acids and thus feature strong affinity for nitrile, terpyridine, and carboxylate donor moieties. The prevailing oxidation state is +3, although in certain compounds stable +2 or +4 cations occur. The chemistry of rare-earth elements is currently receiving widespread attention, as they are key ingredients for established and emerging 21st century science and technology with relevance for energy conversion, sensing, catalysis, magnetism, photonics, telecommunications, superconductivity, biomedicine, and quantum engineering. In this Account, we review recent advances toward the design of interfacial supramolecular nanoarchitectures incorporating lanthanide centers. We apply controlled ultrahigh vacuum conditions whereby atomistically clean substrates are prepared and exposed to ultrapure atomic and molecular beams of the chosen sublimable constituents. We focus on direct molecular-level investigations and in situ assembly operative close to equilibrium conditions. Our scanning probe microscopy techniques provide atomistic insights regarding the formation, stability, and manipulability of metal-organic compounds and networks. In order to gain deeper insights into the experimental findings, complementary computational analysis of bond characteristics, electronic properties, and coordination motifs has been performed for several case studies. Exemplary elements under consideration include cerium, gadolinium, dysprosium, and europium. By the use of ditopic molecular linkers equipped with carbonitrile moieties, adaptive coordination spheres are unveiled, yielding vertices with two- to sixfold symmetry. The respective coordination nodes underlie the expression of complex networks, such as semiregular Archimedean tessellations for cerium- or gadolinium-directed assemblies and random-tiling quasicrystalline characteristics for europium. Tunability via constituent stoichiometry regulation is revealed for bimolecular arrangements embedding europium centers, simultaneously connecting to carbonitrile and terypyridine ligands. Ditopic carboxylate linkers yield robust reticular networks based on a lateral coordination number of 8 for either gadolinium or dysprosium complexation, featuring a prevalent ionic nature of the coordination bond. Orthogonal insertion protocols give rise to d-f reticular architectures exploiting macrocyclic tetradentate cobalt complexation and peripheral carbonitrile-gadolinium coordination, respectively. Furthermore, lanthanides may afford metalation of adsorbed free-base tetrapyrrole species and can be engaged for interfacial synthesis of sandwich compounds, thus providing prospects for columnar design of coordination architectures. Finally, direct manipulation experiments achieved lateral displacement of single supramolecules and molecular rotation of sandwich or other molecular units. These findings evidence prospects for advancing molecular machinery components. The presented accomplishements herald further advancements in metallo-supramolecular design on surfaces, with versatile nanosystems and architectures emanating from the flexible coordination spheres. The embedding and systematic rationalization of lanthanide centers in tailored interfacial environments are keys to establishing relations between structure and physicochemical characteristics toward the generation of novel functionalities with technological significance. PMID- 29420011 TI - Liquid-Metal-Based Super-Stretchable and Structure-Designable Triboelectric Nanogenerator for Wearable Electronics. AB - The rapid advancement of intelligent wearable electronics imposes the emergent requirement for power sources that are deformable, compliant, and stretchable. Power sources with these characteristics are difficult and challenging to achieve. The use of liquid metals as electrodes may provide a viable strategy to produce such power sources. In this work, we propose a liquid-metal-based triboelectric nanogenerator (LM-TENG) by employing Galinstan as the electrode and silicone rubber as the triboelectric and encapsulation layer. The small Young's modulus of the liquid metal ensures the electrode remains continuously conductive under deformations, stretching to a strain as large as ~300%. The surface oxide layer of Galinstan effectively prevents the liquid Galinstan electrode from further oxidization and permeation into silicone rubber, yielding outstanding device stability. Operating in the single-electrode mode at 3 Hz, the LM-TENG with an area of 6 * 3 cm2 produces an open-circuit voltage of 354.5 V, transferred short-circuit charge of 123.2 nC, short-circuit current of 15.6 MUA, and average power density of 8.43 mW/m2, which represent outstanding performance values for TENGs. Further, the LM-TENG maintains stable performance under various deformations, such as stretching, folding, and twisting. LM-TENGs in different forms, such as bulk-shaped, bracelet-like, and textile-like, are all able to harvest mechanical energy from human walking, arm shaking, or hand patting to sustainably drive wearable electronic devices. PMID- 29420012 TI - Enhanced Immunotherapy Based on Photodynamic Therapy for Both Primary and Lung Metastasis Tumor Eradication. AB - Metastasis and recurrence are two unavoidable and intractable problems in cancer therapy, despite various robust therapeutic approaches. Currently, it seems that immunotherapy is an effective approach to solve these problems, but the high heterogeneity of tumor tissue, inefficient presentation of tumor antigen, and deficient targeting ability of therapy usually blunt the efficacy of immunotherapy and hinder its clinical application. Herein, an approach based on combining photodynamic and immunological therapy was designed and developed. We synthesized a chimeric peptide, PpIX-1MT, which integrates photosensitizer PpIX with immune checkpoint inhibitor 1MT via a caspase-responsive peptide sequence, Asp-Glu-Val-Asp (DEVD), to realize a cascaded synergistic effect. The PpIX-1MT peptide could form nanoparticles in PBS and accumulate in tumor areas via the enhanced penetration retention effect. Upon 630 nm light irradiation, the PpIX 1MT nanoparticles produced reactive oxygen species, induced apoptosis of cancer cells, and thus facilitated the expression of caspase-3 and the production of tumor antigens, which could trigger an intense immune response. The subsequently released 1MT upon caspase-3 cleavage could further strengthen the immune system and help to activate CD8+ T cells effectively. This cascaded synergistic effect could inhibit both primary and lung metastasis tumor effectively, which may provide the solution for solving tumor recurrence and metastasis clinically. PMID- 29420013 TI - Swelling and Free-Volume Characteristics of TEMPO-Oxidized Cellulose Nanofibril Films. AB - Cellulose nanofibrils (CNFs) are becoming increasingly ubiquitous in diverse technologies requiring sustainable nanoscale species to form or modify films. The objective of the present study is to investigate the swelling behavior and accompanying free volume of self-standing TEMPO-oxidized (TO) CNF films in the presence of water vapor. For this purpose, we have performed time-resolved swelling experiments on films, prepared according to different experimental protocols, at 90% relative humidity (RH) and ambient temperature. Corresponding free-volume characteristics are elucidated by positron annihilation lifetime spectroscopy (PALS) conducted at ambient temperature and several RH levels. Increasing the drying temperature of the films (from ambient to 50 degrees C) is observed to promote an increase in film density, which serves to reduce bulk swelling. These elevated drying temperatures likewise cause the free-volume pore size measured by PALS to decrease, while the corresponding total free-volume fraction remains nearly constant. Similarly, dispersion of TO-CNF into aqueous suspensions by ultrasonication prior to film formation increases both the total free-volume fraction and pore size but reduces the size of individual nanofibrils with little net change in bulk swelling. The swelling and concurrent free-volume measurements reported here generally reveal an increase in the free volume of TO CNF films with increasing RH. PMID- 29420014 TI - Ultrafast Ligand Self-Exchanging Gadolinium Complexes in Ionic Liquids for NMR Field Probes. AB - Concurrent magnetic field monitoring in MRI with an array of NMR field probes allows for reducing image imperfections. High 19F concentrations together with short relaxation times are basic probe properties. We present the NMR properties of [Gd(NTf2)4]- dissolved in an ionic liquid consisting of an imidazolium cation and the [NTf2]- anion. These solutions achieve fluorine concentrations as high as 26 M and rapid relaxation times in the sub-ms time range. The second order self exchange rate of coordinated [NTf2]- with [NTf2]- as determined with [Y(NTf2)4]- is 4.5 * 105.M-1.s-1. X-ray structure analyses confirm the coordination number of eight around Gd3+ and Y3+. These ionic-liquid solutions are thus excellent candidates for dynamically probing the NMR fields in MRI. PMID- 29420015 TI - Robust Ionic Current Sensor for Bacterial Cell Size Detection. AB - Ionic current sensing methods are useful tools for detecting sub- to several micron scale particles such as bacteria. However, conventional commercially available ionic current sensing devices are not suitable for on-site measurement use because of inherent limitations on their robustness. Here, we proposed a portable robust ionic current sensor (Robust-ICS) using a bridge circuit that offers a high signal-to-noise (S/N) ratio by suppressing background current. Because the Robust-ICS can tolerate increased noise in current sensing, a simple, lightweight electromagnetic shield can be used and measurements under large electromagnetic noise conditions can be made. The weight of the device was lowered below 4 kg and outdoor particle detection measurements were completed successfully. Accuracy of size detection of Staphylococcus aureus ( S. aureus) was equivalent to that obtained by SEM imaging. PMID- 29420016 TI - On the Magnetic Coupling and Spin Crossover Behavior in Complexes Containing the Head-to-Tail [FeII2(MU-SCN)2] Bridging Unit: A Magnetostructural Experimental and Theoretical Study. AB - A new dinuclear complex [{Fe(tpc-OBn)(NCS)(MU-NCS)}2] (1) based on the tripodal tpc-OBn ligand (tpc-OBn = tris(2-pyridyl)benzyloxymethane), containing bridging MU-kappaN:kappaS-SCN and terminal kappaN-SCN thiocyanate ligands, has been prepared and characterized by single crystal X-ray diffraction, magnetic studies, and DFT theoretical calculations. This complex represents the first example of dinuclear FeII complex with double MU-kappaN:kappaS-SCN bridges in a head-to-tail configuration that exhibits ferromagnetic coupling between metal ions (JFeFe = +1.08 cm-1). Experimental and theoretical magnetostructural studies on this kind of infrequent FeII dinuclear complex containing a centrosymmetrically [Fe2(MU SCN)2] bridging fragment show that the magnitude and sign of the magnetic coupling parameter, JFeFe, depend to a large extent on the Fe-N-C (alpha) angle, so that JFeFe decreases linearly when alpha decreases. The calculated crossover point below which the magnetic interactions change from ferromagnetic to antiferromagnetic is found at 162.3 degrees . In addition, experimental results obtained in this work and those reported in the literature suggest that large Ntripodal-FeII distances and bent N-bound terminal kappaN-SCN ligands favor the high spin state of the FeII ions, while short Ntripodal-FeII distances and almost linear Fe-N-C angles favor a stronger ligand field, which enables the FeII ions to show spin crossover (SCO) behavior. PMID- 29420017 TI - Polystyrene Nanoplastics-Enhanced Contaminant Transport: Role of Irreversible Adsorption in Glassy Polymeric Domain. AB - Nanoplastics (NPs) are becoming an emerging pollutant of global concern. A potential risk is that NPs may serve as carriers to increase the spreading of coexisting contaminants. In this study, we examined the effects of polystyrene nanoplastics (PSNPs, 100 nm), used as a model NP, on the transport of five organic contaminants of different polarity in saturated soil. The presence of low concentrations of PSNPs significantly enhanced the transport of nonpolar (pyrene) and weakly polar (2,2',4,4'-tetrabromodiphenyl ether) compounds, but had essentially no effects on the transport of three polar compounds (bisphenol A, bisphenol F, and 4-nonylphenol). The strikingly different effects of NPs on the transport of nonpolar/weakly polar versus polar contaminants could not be explained with different adsorption affinities, but was consistent with the polarity-dependent extents of desorption hysteresis. Notably, desorption hysteresis was only observed for nonpolar/weakly polar contaminants, likely because nonpolar compounds tended to adsorb in the inner matrices of glassy polymeric structure of polystyrene (resulting in physical entrapment of adsorbates), whereas polar compounds favored surface adsorption. This hypothesis was verified with supplemental adsorption and desorption experiments of pyrene and 4-nonylphenol using a dense, glassy polystyrene polymer and a flexible, rubbery polyethylene polymer. Overall, the findings of this study underscore the potentially significant environmental implication of NPs as contaminant carriers. PMID- 29420018 TI - Post-Treatment-Free Solution-Processed Reduced Phosphomolybdic Acid Containing Molybdenum Oxide Units for Efficient Hole-Injection Layers in Organic Light Emitting Devices. AB - We report the development of solution-processed reduced phosphomolybdic acid (rPMA) containing molybdenum oxide units for post-treatment-free hole-injection layers (HILs) in organic light-emitting devices (OLEDs). The physical and chemical properties of rPMA, including its structure, solubility in several solvents, film surface roughness, work function, and valence states, were investigated. The formation of gap states just below the Fermi level of rPMA was observed. Without any post-treatment after the formation of rPMA films, OLEDs employing rPMA as an HIL exhibited a very low driving voltage and a high luminous efficiency. The low driving voltage was attributed to the energy level alignment between the gap states formed by reduction and the HOMO level of the hole transport layer material N,N'-bis(1-naphthyl)-N,N'-diphenyl-(1,1'-biphenyl)-4,4' diamine. PMID- 29420019 TI - Environment of the Eu3+ Ion within Nanocrystalline Eu-Doped BaAl2O4: Correlation of X-ray Diffraction, Mossbauer Spectroscopy, X-ray Absorption Spectroscopy, and Photoluminescence Investigations. AB - Powder samples of pure BaAl2O4 and doped with 4.9 atom % Eu in relation to Ba were prepared by a hydrothermal route. The samples were characterized by X-ray diffraction, 151Eu Mossbauer spectroscopy, synchrotron-based X-ray absorption spectroscopy at the Ba L3- and Eu L3-edges, and photoluminescence measurements. Diffraction lines were broadened, indicating that the samples were nanocrystallline. The samples possessed a hexagonal crystal structure, space group P63. 151Eu Mossbauer spectroscopy revealed the presence of Eu in the 3+ oxidation state. The same information on the Eu oxidation state was also obtained by the Eu L3-edge X-ray absorption near-edge structure of the doped sample. Extended X-ray absorption fine structure showed an Eu3+ ion substituted for Ba2+ on the Ba2 site in the BaAl2O4 host structure, with charge compensation by an interstitial O in the vicinity of the Ba2 site. That was confirmed by a Rietveld structure refinement for the Eu-doped BaAl2O4 sample. Analysis of the diffraction line broadening for the prepared samples was performed simultaneously with the structure refinement. Both the dopant Eu3+ and the interstitial O acted as defects in the host BaAl2O4 lattice, which increased the lattice strain from 0.02% for pure BaAl2O4 to 0.17% for the Eu-doped sample. Crystallite sizes in the samples increased with Eu doping from 32 nm for pure BaAl2O4 to 36 nm for Eu doped BaAl2O4. This could likely be related to the increase in the diffusion rate of the cations in the sample when a part of the Ba2+ cation content was exchanged with smaller Eu3+ cations. The Eu-doped BaAl2O4 sample exhibited red photoluminescence under excitation with lambdaexc = 308 nm. The observed emission spectrum indicated that Eu3+ ions occupied the Ba site with lower symmetry in the doped sample. PMID- 29420020 TI - Calcium-Induced Molecular Rearrangement of Peptide Folds Enables Biomineralization of Vaterite Calcium Carbonate. AB - Proteins can control mineralization of CaCO3 by selectively triggering the growth of calcite, aragonite or vaterite phases. The templating of CaCO3 by proteins must occur predominantly at the protein/CaCO3 interface, yet molecular-level insights into the interface during active mineralization have been lacking. Here, we investigate the role of peptide folding and structural flexibility on the mineralization of CaCO3. We study two amphiphilic peptides based on glutamic acid and leucine with beta-sheet and alpha-helical structures. Though both sequences lead to vaterite structures, the beta-sheets yield free-standing vaterite nanosheet with superior stability and purity. Surface-spectroscopy and molecular dynamics simulations reveal that reciprocal structuring of calcium ions and peptides lead to the effective synthesis of vaterite by mimicry of the (001) crystal plane. PMID- 29420022 TI - Transcriptomics-Related Mechanisms of Supplementing Laying Broiler Breeder Hens with Dietary Daidzein to Improve the Immune Function and Growth Performance of Offspring. AB - Daidzein (DA) is an isoflavone that is primarily extracted from soy plants. This study evaluated the effects of supplementing laying broiler breeder hens with dietary DA on the immune function and growth performance of their offspring and the underlying mechanism. A total of 720 breeders were divided into three treatment groups that were fed either a control diet (CON), a DA-low-supplemented diet (DLS, CON+20 mg/kg DA), or a DA-high-supplemented diet (DHS, CON+100 mg/kg DA) for 8 weeks, and eggs were collected for hatching during the final week. The broiler offspring received a basal diet for 42 days, and blood, livers, and immune organs were collected at 21 and 42 days of age. DLS treatment promoted embryonic development and increased growth hormone levels, body weight, feed intake, and carcass traits on days 21 and 42 of broilers. Additionally, the IgA and IgG concentrations, antibody titers, and antioxidant capacity of broilers were increased at 21 days of age, and B lymphocyte differentiation was increased at 42 days. Besides, DLS treatment upregulated the expression of genes related to embryonic and muscle development in offspring and regulated mitogen-activated protein kinase (MAPK), transforming growth factor beta (TGF-beta), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), and Toll-like receptor signaling. DHS treatment decreased the percentage of abdominal fat in the broilers at 42 days, but it did not significantly affect embryonic development, growth performance, or IgA and IgG concentrations. In summary, providing dietary DA supplementation at 20 mg/kg to broiler breeders can improve their immune function and growth performance. PMID- 29420021 TI - Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells. AB - Chemical tools and methods that report on G protein-coupled receptor (GPCR) expression levels and receptor occupancy by small molecules are highly desirable. We report the development of LEI121 as a photoreactive probe to study the type 2 cannabinoid receptor (CB2R), a promising GPCR to treat tissue injury and inflammatory diseases. LEI121 is the first CB2R-selective bifunctional probe that covalently captures CB2R upon photoactivation. An incorporated alkyne serves as ligation handle for the introduction of reporter groups. LEI121 enables target engagement studies and visualization of endogenously expressed CB2R in HL-60 as well as primary human immune cells using flow cytometry. Our findings show that strategically functionalized probes allow monitoring of endogenous GPCR expression and engagement in human cells using tandem photoclick chemistry and hold promise as biomarkers in translational drug discovery. PMID- 29420023 TI - Palladium/PC-Phos-Catalyzed Enantioselective Arylation of General Sulfenate Anions: Scope and Synthetic Applications. AB - Herein we reported an efficient palladium-catalyzed enantioselective arylation of both alkyl and aryl sulfenate anions to deliver various chiral sulfoxides in good yields (up to 98%) with excellent enantioselectivities (up to 99% ee) by the use of our developed chiral O,P-ligands (PC-Phos). PC-Phos are easily prepared in short steps from inexpensive commercially available starting materials. The single-crystal structure of the PC4/PdCl2 showed that a rarely observed 11 membered ring was formed via the O,P-coordination with the palladium(II) center. The salient features of this method include general substrate scope, ease of scale-up, applicable to the late-stage modification of bioactive compounds, and the synthesis of a marketed medicine Sulindac. PMID- 29420024 TI - Hydrophosphorylation of Alkynes Catalyzed by Palladium: Generality and Mechanism. AB - We carried out a comprehensive study on the generality, scope, limitations, and mechanism of the palladium-catalyzed hydrophosphorylation of alkynes with P(O)-H compounds (i.e., H-phosphonates, H-phosphinates, secondary phosphine oxides, and hypophosphinic acid). For H-phosphonates, Pd/dppp was the best catalyst. Both aromatic and aliphatic alkynes, with a variety of functional groups, were applicable to produce the Markovnikov adducts in high yields with high regioselectivity. Aromatic alkynes showed higher reactivity than aliphatic alkynes. Terminal alkynes reacted faster than internal alkynes. Sterically crowded H-phosphonates disfavored the addition. For H-phosphinates and secondary phosphine oxides, Pd/dppe/Ph2P(O)OH was the catalyst of choice, which led to highly regioselective formation of the Markovnikov adducts. By using Pd(PPh3)4 as the catalyst, hypophosphinic acid added to terminal alkynes to give the corresponding Markovnikov adducts. Phosphinic acids, phosphonic acid, and its monoester were not applicable to this palladium-catalyzed hydrophosphorylation. Mechanistic studies showed that, with a terminal alkyne, (RO)2P(O)H reacted, like a Bronsted acid, to selectively generate the alpha-alkenylpalladium intermediate via hydropalladation. On the other hand, Ph(RO)P(O)H and Ph2P(O)H gave a mixture of alpha- and beta-alkenylpalladium complexes. In the presence of Ph2P(O)OH, hydropalladation with this acid took place first to selectively generate the alpha-alkenylpalladium intermediate. A subsequent ligand exchange with a P(O)H compound gave the phosphorylpalladium intermediate which produced the Markovnikov adduct via reductive elimination. Related intermediates in the catalytic cycle were isolated and characterized. PMID- 29420025 TI - TCMAnalyzer: A Chemo- and Bioinformatics Web Service for Analyzing Traditional Chinese Medicine. AB - Traditional Chinese medicine (TCM) has been widely used and proven effective in long term clinical practice. However, the molecular mechanism of action for many TCMs remains unclear due to the complexity of many ingredients and their interactions with biological receptors. This is one of the major roadblocks in TCM modernization. In order to solve this problem, we have developed TCMAnalyzer, which is a free web-based toolkit allowing a user to (1) identify the potential compounds that are responsible for the bioactivities for a TCM herb through scaffold-activity relation searches using structural search techniques, (2) investigate the molecular mechanism of action for a TCM herb at the systemic level, and (3) explore the potentially targeted bioactive herbs. The toolkit can result in TCM networks that demonstrate the relations among natural product molecules (small molecular ligands), putative protein targets, pathways, and diseases. These networks are graphically depicted to reveal the mechanism of actions for a TCM herb or to identify new molecular scaffolds for new chemotherapies. TCMAnalyzer is freely available at http://www.rcdd.org.cn/tcmanalyzer . PMID- 29420026 TI - A2TiO5 (A = Dy, Gd, Er, Yb) at High Pressure. AB - The structural evolution of lanthanide A2TiO5 (A = Dy, Gd, Yb, Er) at high pressure is investigated using synchrotron X-ray diffraction. The effects of A site cation size and of the initial structure are systematically examined by varying the composition of the isostructural lanthanide titanates and the structure of dysprosium titanate polymorphs (orthorhombic, hexagonal, and cubic), respectively. All samples undergo irreversible high-pressure phase transformations, but with different onset pressures depending on the initial structure. While each individual phase exhibits different phase transformation histories, all samples commonly experience a sluggish transformation to a defect cotunnite-like (Pnma) phase for a certain pressure range. Orthorhombic Dy2TiO5 and Gd2TiO5 form P21am at pressures below 9 GPa and Pnma above 13 GPa. Pyrochlore type Dy2TiO5 and Er2TiO5 as well as defect-fluorite-type Yb2TiO5 form Pnma at ~21 GPa, followed by Im3m. Hexagonal Dy2TiO5 forms Pnma directly, although a small amount of remnants of hexagonal Dy2TiO5 is observed even at the highest pressure (~55 GPa) reached, indicating kinetic limitations in the hexagonal Dy2TiO5 phase transformations at high pressure. Decompression of these materials leads to different metastable phases. Most interestingly, a high-pressure cubic X-type phase (Im3m) is confirmed using high-resolution transmission electron microscopy on recovered pyrochlore-type Er2TiO5. The kinetic constraints on this metastable phase yield a mixture of both the X-type phase and amorphous domains upon pressure release. This is the first observation of an X-type phase for an A2BO5 composition at high pressure. PMID- 29420027 TI - UV and IR Photochemistries of Malonaldehyde Trapped in Cryogenic Matrices. AB - UV and IR photochemistries of malonaldehyde, the simplest molecule exhibiting an intramolecular proton exchange, have been studied in four cryogenic matrices at 4.3 K, N2, Ne, Ar, and Xe. Samples have been irradiated using a UV and IR OPO type tunable laser, and with a broad band UV mercury lamp. UV and IR spectra have been recorded and compared with theoretical calculations carried out at the SAC CI/6-31++G(d,p) (UV transitions) and B3LYP/6-311++G(2d,2p) (IR spectra) levels of theory. After deposition, the intramolecularly H-bonded form is found exclusively, while several open forms are formed upon UV irradiation. These open forms show ability to interconvert upon UV irradiation too. Some of them are also able to isomerize upon selective IR irradiations. The whole set of results allowed us to identify seven isomers among the eight postulated. The photodynamics of the electronic relaxation of malonaldehyde have also been investigated. By following the decay or rise of suited specific vibrational bands in the IR spectra, and by comparing the results with an earlier study of the homologous acetylacetone, we deduced that the electronic relaxation of malonaldehyde proceeds through singlet states, most probably through a 3-fold conical intersection, as postulated from theoretical calculations. In contrast with acetylacetone, malonaldehyde does not show fragmentation after UV excitation. PMID- 29420028 TI - Multimetallic Ni- and Pd-Catalyzed Cross-Electrophile Coupling To Form Highly Substituted 1,3-Dienes. AB - The synthesis of highly substituted 1,3-dienes from the coupling of vinyl bromides with vinyl triflates is reported for the first time. The coupling is catalyzed by a combination of (5,5'-bis(trifluoromethyl)-2,2'-bipyridine)NiBr2 and (1,3-bis(diphenylphosphino)propane)PdCl2 in the presence of a zinc reductant. This method affords tetra- and penta-substituted 1,3-dienes that would otherwise be difficult to access and tolerates electron-rich and -poor substituents, heterocycles, an aryl bromide, and a pinacol boronate ester. Mechanistically, the reaction appears to proceed by an unusual zinc-mediated transfer of a vinyl group between the nickel and palladium centers. PMID- 29420029 TI - Comparative Investigation of the Thermoresponsive Behavior of Two Diblock Copolymers Comprising PNIPAM and PMDEGA Blocks. AB - The thermoresponsive behavior of two diblock copolymers PS- b-PNIPAM and PS- b PMDEGA, which both comprise a hydrophobic polystyrene (PS) block but different thermoresponsive blocks, also differing in length, poly( N-isopropylacrylamide) (PNIPAM) and poly(methoxy diethylene glycol acrylate) (PMDEGA), respectively, was comparatively investigated in a wide temperature range. Concentrated aqueous solutions containing 25 wt % polymer were studied by small-angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), and broadband dielectric spectroscopy (BDS). DSC measurements show that, during the demixing phase transition, the hydration number per oligo(ethylene glycol) side chain in the PS- b-PMDEGA solution decreases rather gradually, even up to 20 degrees C above the onset of the transition, i.e., the cloud point (CP). In contrast, the PS- b PNIPAM solution exhibits an abrupt, stepwise dehydration behavior at its CP, indicated by the sharp, narrow endothermic peak. BDS measurements suggest that the organization of the expelled water during the phase transition and the subsequent evolution of the micellar aggregates are different for the two copolymers. In the PS- b-PMDEGA solution, the long-range charge transport process changes significantly at its CP and strong interfacial polarization processes appear, probably due to charge accumulation at the interfaces between the micellar aggregates and the aqueous medium. On the contrary, in the PS- b-PNIPAM solution, the phase transition has only a marginal effect on the long-range conduction process and is accompanied by a reduction in the high-frequency (1 MHz) dielectric permittivity, epsilon'. The latter effect is attributed to the reduced polarization strength of local chain modes due to an enhancement of intra and interchain hydrogen bonds (HBs) in the polymer-rich phase during the water detaching process. Surprisingly, our BDS measurements indicate that prior to both the demixing and remixing processes the local chain mobility increases temporally. Our dielectric studies suggest that for PS- b-PNIPAM the water detaching process initiates a few degrees below CP and that the local chain mobility and intra- and/or interchain HBs of the PNIPAM blocks may control its thermoresponsive behavior. Dielectric "jump" experiments show that the kinetics of micellar aggregation in the PS- b-PMDEGA solution is slower than that in the PS- b-PNIPAM solution and is independent of the target temperature within the two phase region. From the experimental point of view, it is shown that the dielectric susceptibility, especially, the dielectric permittivity, epsilon', is a well-suited probe for monitoring both the reversible changes in the molecular dipolar bond polarizability and the long-range interfacial polarization at the phase transition. PMID- 29420030 TI - Quantitative Analysis of Solid-State Homonuclear Correlation Spectra of Antiparallel beta-Sheet Alanine Tetramers. AB - Poly-l-alanine (PLA) sequences are a key element in the structure of the crystalline domains of spider dragline silks, wild silkworm silks, antifreeze proteins, and amyloids. To date, no atomic-level structures of antiparallel (AP) PLA longer than Ala4 have been reported using the single-crystal X-ray diffraction analysis. In this work, dipolar-assisted rotational resonance solid state NMR spectra were observed to determine the effective internuclear distances of 13C uniformly labeled alanine tetramer with antiparallel (AP) beta-sheet structure whose atomic coordinates are determined from the X-ray crystallographic analysis. Initial build-up rates, R j, k, were obtained from the build-up curves of the cross peaks by considering the internuclear distances arising in the master equation. Subsequently, experimentally obtained effective internuclear distances, reffj, k(obs), were compared with the calculated reffj, k(calc) values obtained from the X-ray crystallographic data. Fairly good correlation between reffj, k(obs) and reffj, k(calc) was obtained in the range of 1.0-6.0 A, with the standard deviation of 0.244 A, without considering the zero-quantum line-shape functions. It was further noted that the internuclear distances of intermolecular contributions provide details relating to the molecular packing in solid-state samples. Thus, the present data agree well with AP-beta-sheet packing but do not agree with P-beta-sheet packing. PMID- 29420031 TI - Source-Free Exchange-Correlation Magnetic Fields in Density Functional Theory. AB - Spin-dependent exchange-correlation energy functionals in use today depend on the charge density and the magnetization density: Exc[rho, m]. However, it is also correct to define the functional in terms of the curl of m for physical external fields: Exc[rho,? * m]. The exchange-correlation magnetic field, Bxc, then becomes source-free. We study this variation of the theory by uniquely removing the source term from local and generalized gradient approximations to the functional. By doing so, the total Kohn-Sham moments are improved for a wide range of materials for both functionals. Significantly, the moments for the pnictides are now in good agreement with experiment. This source-free method is simple to implement in all existing density functional theory codes. PMID- 29420032 TI - Solvent-Assisted Desorption of 2,5-Lutidine from Polyurethane Films. AB - A fundamental understanding of chemical interactions and transport mechanisms that result from introducing multiple chemical species into a polymer plays a key role in the development and optimization of membranes, coatings, and decontamination formulations. In this study, we explore the solvent-assisted desorption of a penetrant (2,5-lutidine) in polyurethane with aprotic (acetonitrile) and protic (methanol) solvents. Chemical interactions between solvent, penetrant, and polymer functional groups are characterized via time resolved Fourier transform infrared spectroscopy (FTIR) during single and multicomponent exposures. For both solvents, an increase in the extraction rate of the penetrant is observed when the solvent is applied during desorption. Inspection of the FTIR spectra reveals two potential mechanisms that facilitate the enhanced desorption rate: (1) penetrant/solvent competition for hydrogen donor groups on the polymer backbone and (2) disruption of the self-interaction (cohesive forces) between neighboring polymer chains. Finally, the aprotic solvent is found to generate an order of magnitude greater desorption rate of the penetrant, which is attributed to a greater disruption of the self-interaction during penetrant desorption compared to the protic solvent and the inability of an aprotic solvent to form larger and potentially slower penetrant-solvent complexes. PMID- 29420033 TI - Hyper Open-Shell Excited Spin States of Transition-Metal Compounds: FeF2, FeF2...Ethane, and FeF2...Ethylene. AB - Spin-state energetics are important for understanding properties that involve more than one spin state, for example, catalysis occurring on two or more potential energy surfaces corresponding to different electronic spins. Very often, multiple-spin processes involve transition-metal compounds, and therefore, it is important to understand the electronic structure and energetics of such compounds in different spin states. In this work, we benchmark relative spin state energies of FeF2 with respect to the quintet ground spin state using both single-configurational and multiconfigurational methods, and we examine how they are affected by the binding of ethane and ethylene to the iron center. We also benchmark the binding energies of the complexes. The single-configurational methods used in this work are the Hartree-Fock method, 32 exchange-correlation functionals, and the CCSD(T) coupled-cluster method in both restricted and unrestricted formalisms. The multiconfigurational methods that have been used are CASSCF, CASPT2, CASPT3, MRCI, MRCI+Q, and MR-ACPF. The spin-state splitting energies depend on the functional chosen, and of the 32 exchange-correlation functionals investigated here, we find that for the septet and spin-projected triplet states of FeF2 the M06 functional is the best when compared to our best estimates from multireference calculations. If all nine excitation energies are considered, where there are three excited spin states (singlet, triplet, and septet) for each of the three systems (FeF2, FeF2...ethane, and FeF2...ethylene), the three best-performing functionals are HLE16, SOGGA11-X, and M06-2X. We find that the binding of ethane perturbs the relative spin-state energy of FeF2 by only a small amount, but the stronger binding of ethylene has a larger effect. For the spin-state splitting energies of FeF2 using single-reference CCSD(T), we find that the predicted results depend very strongly on precisely how the calculations are done, in particular, on the spin-restricted or spin-unrestricted character of the SCF reference state, which can differ even by around 50 kcal/mol for the SCF reference state and the subsequent CCSD(T) calculations. Upon analyzing the wave functions of both the spin-restricted or spin-unrestricted formalisms, we find that the lowest-energy singlet and triplet states of the complexes, just like FeF2 in isolation, can have more unpaired electrons than they are usually assumed to have, i.e., they can be hyper open-shell electronic configurations, and this can significantly lower the energy. PMID- 29420035 TI - Photochemistry of the Simplest Criegee Intermediate, CH2OO: Photoisomerization Channel toward Dioxirane Revealed by CASPT2 Calculations and Trajectory Surface Hopping Dynamics. AB - The photochemistry of Criegee intermediates plays a significant role in atmospheric chemistry, but it is relatively less explored compared with their thermal reactions. Using multireference CASPT2 electronic structure calculations and CASSCF trajectory surface-hopping molecular dynamics, we have revealed a dark state-involved A1A -> X1A photoisomerization channel of the simple Criegee intermediate (CH2OO) that leads to a cyclic dioxirane. The excited molecules on the A1A state, which can have either originated from the B1A state via B1A -> A1A internal conversion or formed by state-selective electronic excitation, is driven by the out-of-plane motion toward a perpendicular A/X1A minimal-energy crossing point (MECI) then radiationless decay to the ground state with an average time constant of ~138 fs, finally forming dioxirane at ~254 fs. The dynamics starting from the A1A state show that the quantum yield of photoisomerization from the simple Criegee intermediate to dioxirane is 38%. The finding of the A1A -> X1A photoisomerization channel is expected to broaden the reactivity profile and deepen the understanding of the photochemistry of Criegee intermediates. PMID- 29420034 TI - Functionalized Nitronyl Nitroxide Biradicals for the Construction of 3d-4f Heterometallic Compounds. AB - Functionalized nitronyl nitroxide biradical ligands incorporating pyridine groups hold CoII and LnIII ions together, creating biradical-based 3d-4f tetranuclear complexes [Ln2Co2(hfac)10(NITPhPybis)2] [LnIII = Gd (1), Tb (2), Dy (3), and Ho (4); NITPhPybis = 5-(4-pyridyl)-1,3-bis(1'-oxyl-3'-oxido-4',4',5',5'-tetramethyl 4,5-hydro-1 H-imidazol-2-yl)benzene; hfac = hexafluoroacetylacetonate]. These complexes have a centrosymmetric cyclic molecular structure in which two biradicals perform as tetradentate ligands to bind two CoII and two LnIII ions, resulting in a rare octaspin system. Direct-current (dc) magnetic susceptibility studies reveal that the strong antiferromagnetic CoII-NO magnetic exchange dominates the present magnetic system, while magnetic coupling of Gd-ON is ferromagnetic. Analysis of the magnetic data of the Gd complex allows us to determine the magnetic parameters through the appropriate magnetic model. Alternating-current (ac) magnetic susceptibility investigations indicate that 2 displays frequency-dependent out-of-phase signals under a zero dc field, while ac magnetic susceptibilities of 3 show field-induced frequency dependence, which is a typical feature of slow relaxation of the magnetization. Complexes 1-4 represent the first nitronyl nitroxide biradical-based 3d-4f compounds. PMID- 29420036 TI - Light-Induced Electron Spin-Polarized (ESP) EPR Signal of the P800+ Menaquinone- Radical Pair State in Oriented Membranes of Heliobacterium modesticaldum: Role/Location of Menaquinone in the Homodimeric Type I Reaction Center. AB - Function/location of menaquinone (MQ) was studied in the photosynthetic reaction center of Heliobacterium (Hbt.) modesticaldum (hRC), which is one of the most primitive homodimeric type I RCs. The spin-polarized electron paramagnetic resonance signals of light-induced radical pair species, which are made of oxidized electron donor bacteriochlorophyll g (P800+) and reduced menaquinone (MQ ) or iron-sulfur cluster (FX-), were measured in the oriented membranes of Hbt. modesticaldum at cryogenic temperature. The spectral shape of transient electron spin-polarized signal of P800+FX- radical pair state varied little with respect to the direction of the external magnetic field. It suggested a dominant contribution of the spin evolution on the precursor primary radical pair P800+A0- state with the larger isotropic magnetic exchange interaction J than the anisotropic dipole interaction D. The pure P800+MQ- signal was simulated by subtracting the effects of spin evolution during the electron-transfer process. It was concluded that the J value of the P800+MQ- radical pair is negative with an amplitude almost comparable to | D|. It is in contrast to a positive and small J value of the P700+PhyQ- state in photosystem I (PS I). The results indicate similar but somewhat different locations/binding sites of quinones between hRC and PS I. PMID- 29420037 TI - Large Davydov Splitting and Strong Fluorescence Suppression: An Investigation of Exciton Delocalization in DNA-Templated Holliday Junction Dye Aggregates. AB - Exciton delocalization in dye aggregate systems is a phenomenon that is revealed by spectral features, such as Davydov splitting, J- and H-aggregate behavior, and fluorescence suppression. Using DNA as an architectural template to assemble dye aggregates enables specific control of the aggregate size and dye type, proximal and precise positioning of the dyes within the aggregates, and a method for constructing large, modular two- and three-dimensional arrays. Here, we report on dye aggregates, organized via an immobile Holliday junction DNA template, that exhibit large Davydov splitting of the absorbance spectrum (125 nm, 397.5 meV), J and H-aggregate behavior, and near-complete suppression of the fluorescence emission (~97.6% suppression). Because of the unique optical properties of the aggregates, we have demonstrated that our dye aggregate system is a viable candidate as a sensitive absorbance and fluorescence optical reporter. DNA templated aggregates exhibiting exciton delocalization may find application in optical detection and imaging, light-harvesting, photovoltaics, optical information processing, and quantum computing. PMID- 29420038 TI - The Speed of Publication. PMID- 29420039 TI - Synthesis of Chiral Pyrazolone and Spiropyrazolone Derivatives through Squaramide Catalyzed Reaction of Pyrazolin-5-ones with o-Quinone Methides. AB - A bifunctional squaramide-catalyzed reaction of pyrazolin-5-ones with o-quinone methides in situ generated from 2-(1-tosylalkyl)phenols has been successfully developed, providing a facile access to chiral pyrazolones with high enantioselectivities. In addition, the chiral spiropyrazolones with adjacent tertiary and quaternary stereogenic centers can also be obtained through cascade chlorination/cyclization of the chiral pyrazolones. PMID- 29420041 TI - Synthesis of Thieno[3,2-b]indoles via Halogen Dance and Ligand-Controlled One-Pot Sequential Coupling Reaction. AB - A two-pot synthesis of thieno[3,2-b]indole from 2,5-dibromothiophene is described. A halogen dance of 2,5-dibromothiophene was performed with LDA, and subsequent Negishi coupling was performed with 2-iodoaniline derivatives to provide the corresponding coupling products. The resulting two bromo groups have different reactivities, which were utilized for the one-pot Suzuki-Miyaura coupling/intramolecular Buchwald-Hartwig amination to produce thieno[3,2-b]indole via an assisted tandem catalysis that involved in situ ligand exchange. PMID- 29420042 TI - Iron-Catalyzed Radical Cycloaddition of 2H-Azirines and Enamides for the Synthesis of Pyrroles. AB - A novel and efficient Fe-catalyzed radical cycloaddition of 2H-azirines and enamides for the synthesis of substituted pyrroles has been developed. The radical cycloaddition reaction proceeded through a conceptually new Fe(II) catalyzed homolytic cleavage of C-N bond of 2H-azirines sequential radical cyclization with enamides. The reaction used readily available starting materials, tolerated various functional groups, and afforded valuable triaryl substituted pyrroles in good to high yields under mild reaction conditions. PMID- 29420043 TI - Chemical Events in Oligo(3-methoxythiophene) Coating Solutions and Their Effect on the Goldlike Coating Film Properties. AB - Metal-free, metal-like lustrous films may find applications in a variety of fields, and a study of the factors affecting their stability is highly desirable. In particular, chemical events occurring in the coating solutions might affect the supramolecular organization of the films and therefore the metal-like luster. Herein, the chemical events occurring in acetonitrile and nitromethane coating solutions of oligo(3-methoxythiophene) and their effect on the optical properties of the films were investigated by X-ray diffraction, UV-vis absorption, and viscosity measurements. In acetonitrile, the oligomers underwent gradual dedoping with time, but only small changes in viscosity were observed. The solution was applied to a glass plate to yield a dark brown film, which turned into a goldlike lustrous film by rubbing. In nitromethane, the supramolecular structure of the oligomers changed with time from the nonaggregated state to pi-dimers and then to pi-stacks, and the viscosity increased. The properties of the goldlike films prepared from this solution were greatly affected by this chemical event. Remarkably, the pi-dimer solution provided the film with the highest specular reflectance, yellowness, greenness, brightness, and crystallinity. PMID- 29420040 TI - Integrity of Glycosylation Processing of a Glycan-Depleted Trimeric HIV-1 Immunogen Targeting Key B-Cell Lineages. AB - Broadly neutralizing antibodies (bNAbs) that target the trimeric HIV-1 envelope glycoprotein spike (Env) are tools that can guide the design of recombinant Env proteins intended to engage the predicted human germline precursors of bNAbs (gl bNAbs). The protein components of gl-bNAb epitopes are often masked by glycans, while mature bNAbs can evolve to accommodate or bypass these shielding glycans. The design of germline-targeting Env immunogens therefore includes the targeted deletion of specific glycan sites. However, the processing of glycans on Env trimers can be influenced by the density with which they are packed together, a highly relevant point given the essential contributions under-processed glycans make to multiple bNAb epitopes. We sought to determine the impact of the removal of 15 potential N-glycan sites (5 per protomer) from the germline-targeting soluble trimer, BG505 SOSIP.v4.1-GT1, using quantitative, site-specific N-glycan mass spectrometry analysis. We find that, compared with SOSIP.664, there was little overall change in the glycan profile but only subtle increases in the extent of processing at sites immediately adjacent to where glycans had been deleted. We conclude that multiple glycans can be deleted from BG505 SOSIP trimers without perturbing the overall integrity of the glycan shield. PMID- 29420044 TI - Diels-Alder Reaction of Isobenzofurans/Cyclopentadienones with Tetrathiafulvalene: Preparation of Naphthalene, Fluoranthene, and Fluorenone Derivatives. AB - Diels-Alder reaction of 1,3-diarylbenzo[c]furan/cyclopentadienone with TTF followed by triflic acid mediated cleavage of the resulting adducts led to the formation of the respective 1,4-diaryl substituted naphthalenes, fluoranthenes, and fluorenones. The photophysical properties of representative diaryl substituted hydrocarbons are also reported. PMID- 29420045 TI - Thiocarbamate-Directed Tandem Olefination-Intramolecular Sulfuration of Two Ortho C-H Bonds: Application to Synthesis of a COX-2 Inhibitor. AB - A palladium-catalyzed dual ortho C-H bond activation of aryl thiocarbamates is developed. This tandem reaction initiates by thiocarbamate-directed ortho C-H palladation, which leads to favorable olefin insertion rather than reductive elimination. The oxidative Heck reaction followed by another C-H activation and sulfuration affords the dual-functionalized products. This reaction provides a concise route to the S,O,C multisubstituted benzene skeleton which could be successfully applied for the synthesis of a COX-2 inhibitor. PMID- 29420046 TI - Multifunctionalization of Unactivated Cyclic Ketones via Synergistic Catalysis of Copper and Diarylamine: Access to Cyclic alpha-Enaminone. AB - A multifunctionalization of unactivated cyclic ketones via synergistic catalysis of copper and diarylamine for the direct synthesis of cyclic alpha-enaminone is reported for the first time. This reaction goes through oxidative alpha amination, followed by a desaturation, and features mild reaction conditions, a broad substrate scope, and great functional group tolerance. PMID- 29420047 TI - Synthetic Approach to Benzocyclobutenones Using Visible Light and a Phosphonate Auxiliary. AB - Reported herein is a two-step procedure to synthesize benzocyclobutenones from (o alkylbenzoyl)phosphonates. It consists of a visible-light-driven cyclization reaction forming phosphonate-substituted benzocyclobutenols and subsequent elimination reaction of the H-phosphonate, which assumes a key role as the recyclable auxiliary. A wide variety of functionalized benzocyclobutenones, which include those difficult to synthesize by conventional methods, are efficiently synthesized. PMID- 29420048 TI - Carbohydrate Microarrays Containing Glycosylated Fluorescent Probes for Assessment of Glycosidase Activities. AB - Carbohydrate microarrays, containing glycosylated fluorescent probes, have been constructed using N-hydroxysuccinimide (NHS) ester-conjugated BSA modified surfaces. When the carbohydrate moieties were cleaved from the fluorescent probes in the conjugates by glycosidases, the fluorescence signals of the probes were enhanced. In this study, we have applied these microarrays to profile glycosidase activities and have employed them to determine IC50 values of glycosidase inhibitors. PMID- 29420049 TI - Steric Stabilization of gamma-Fe2O3 Superparamagnetic Nanoparticles in a Hydrophobic Ionic Liquid and the Magnetorheological Behavior of the Ferrofluid. AB - Hydrophobic ionic liquid ferrofluids (ILFFs) are studied for use in electrospray thrusters for microsatellite propulsion under nonatmospheric and in high temperature environments. We synthesized a hydrophobic ILFF by dispersing sterically stabilized gamma-Fe2O3 nanoparticles (NPs) in the ionic liquid 1-ethyl 3-methylimidazolium bis(trifluoromethylsulfonyl)imide. A diblock copolymer, C4 RAFT-AA10-DEAm60, was synthesized to facilitate multipoint bidentate anchoring to the NP through the acrylic acid block. The DEAm60 layer was incorporated to generate steric repulsion between particles to protect against the aggregation of magnetized particles arising from dipole-dipole attraction. The effect of shearing and variation in the magnetic field strength on the steric repulsion was examined using the DLVO theory. The effect of varying the magnetic field strength and particle concentration on the viscoelastic properties of the ferrofluid was evaluated using rheometry. The viscosity of the ferrofluid increased with the magnetic field strength, indicating that the magnetized particles assembled into a structure. The level of straining required to break down the structure formed by the magnetized particles increased with the magnetic field strength and particle concentration. The absence of particle interlocking during shearing was indicated by the smooth viscosity versus shear rate traces. The DLVO analysis showed that increasing the magnetic attraction between the particles causes the DEAm60 brush layers on the particles to overlap more, resulting in an increase in the steric repulsion. As overlapping increases, osmotic repulsion is caused before progressing to a strong elastic repulsion. The effect of the polymer solubility and particle interaction due to hydrodynamic forces on the steric repulsion was also analyzed. PMID- 29420050 TI - Happier Healers: Randomized Controlled Trial of Mobile Mindfulness for Stress Management. AB - PURPOSE: Medical students have higher rates of depression and psychologic distress than the general population, which may negatively impact academic performance and professional conduct. This study assessed whether 10-20 min of daily mindfulness meditation for 30 days, using a mobile phone application, could decrease perceived stress and improve well-being for medical students. METHODS: Eighty-eight medical students were stratified by class year and randomized to either intervention or control groups to use the mobile application Headspace, an audio-guided mindfulness meditation program, for 30 days. All participants completed the Perceived Stress Scale (PSS), Five-Facet Mindfulness Questionnaire (FFMQ), and General Well-Being Schedule (GWBS) at baseline (T1), 30 days (T2), and 60 days (T3). Repeated measures analysis of variance (rANOVA) was conducted for intervention versus control groups across T1, T2, and T3 to examine differences in stress, mindfulness, and well-being. RESULTS: There was a significant interaction between time and treatment group for perceived stress and well-being. Perceived stress significantly decreased for the intervention group from T1 to T3 (F[2,142] = 3.98, p < 0.05). General well-being significantly increased for the intervention group compared to the control group from T1 to T2, and the increase was sustained through T3 (F[2,144] = 3.36, p < 0.05). CONCLUSIONS: These results highlight that a mobile audio-guided mindfulness meditation program is an effective means to decrease perceived stress in medical students, which may have implications on patient care. Integrating mindfulness training into medical school curricula for management of school- and work-related stress may lead to fewer negative physician outcomes (e.g., burnout, anxiety, and depression) and improved physician and patient outcomes. This has implications for a broad group of therapists and healthcare providers, ultimately improving quality of healing and patient care. PMID- 29420051 TI - Loss of CDKN2B Promotes Fibrosis via Increased Fibroblast Differentiation Rather Than Proliferation. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by excessive scarring and fibroblast activation. We previously showed that fibroblasts from patients with IPF are hypermethylated at the CDKN2B gene locus, resulting in decreased CDKN2B expression. Here, we examine how diminished CDKN2B expression in normal and IPF fibroblasts affect fibroblast function, and how loss of CDKN2B contributes to IPF pathogenesis. We first confirmed that protein expression of CDKN2B was diminished in IPF lungs in situ. Loss of CDKN2B was especially notable in regions of increased myofibroblasts and fibroblastic foci. The degree of CDKN2B hypermethylation was particularly elevated in patients with radiographic honeycombing, a marker of more advanced fibrosis, and increased DNA methylation correlated with decreased expression. Although CDKN2B is traditionally considered a cell cycle inhibitor, loss of CDKN2B did not result in an increase in fibroblast proliferation, but instead was associated with an increase in myofibroblast differentiation. An increase in myofibroblast differentiation was not observed when CDKN2A was silenced. Loss of CDKN2B was associated with an increase in the transcription factors serum response factor and myocardin-related transcription factor A, and overexpression of CDKN2B in IPF fibroblasts inhibited myofibroblast differentiation. Finally, decreased CDKN2B expression was noted in fibroblasts from a murine model of fibrosis, and Cdkn2b-/ mice developed greater histologic fibrosis after bleomycin injury. These findings identify a novel function for CDKN2B that differs from its conventional designation as a cell cycle inhibitor and demonstrate the importance of this protein in pulmonary fibrosis. PMID- 29420052 TI - Generic Respiratory Symptoms and Branded Lung Diseases. Same Difference? PMID- 29420053 TI - Comparison of blood lipid-lowering effects of olive oil and other plant oils: A systematic review and meta-analysis of 27 randomized placebo-controlled clinical trials. AB - OBJECTIVE: We aim to report a systematic review and meta-analysis of randomized controlled trials (RCTs) on effects of olive oil consumption compared with other plant oils on blood lipids. METHODS: PubMed, web of science, Scopus, ProQuest, and Embase were systematically searched until September 2017, with no age, language and design restrictions. Weighed mean difference (WMD) and 95% confidence interval (CI) were expressed as effect size. Sensitivity analyses and pre specified subgroup was conducted to evaluate potential heterogeneity. Meta regression analyses were performed to investigate association between blood lipid lowering effects of olive oil and duration of treatment. RESULTS: Twenty-seven trials, comprising 1089 participants met the eligibility criteria. Results of this study showed that compared to other plant oils, high-density lipoprotein level increased significantly more for OO (1.37 mg/dl: 95% CI: 0.4, 2.36). Also OO consumption reduced total cholesterol (TC) (6.27 mg/dl, 95% CI: 2.8, 10.6), Low-density lipoprotein (LDL-c) (4.2 mg/dl, 95% CI: 1.4, 7.01), and triglyceride (TG) (4.31 mg/dl, 95% CI: 0.5, 8.12) significantly less than other plant oils. There were no significant effects on Apo lipoprotein A1 and Apo lipoprotein B. CONCLUSION: This meta-analysis suggested that OO consumption decreased serum TC, LDL-c, and TG less but increased HDL-c more than other plant oils. PMID- 29420054 TI - Telephone based weight loss intervention: Relevance for developing countries. AB - Obesity is a major public health challenge not only for developed but developing countries as well. The World Health Organization recommends the immediate use of effective, efficient and widely accessible weight loss interventions. Telephone based weight loss intervention could provide a cheaper and wider reach of obese participants. Previous systematic reviews on telephone based weight loss interventions either excluded studies that had obese participants with co morbidities or were silent on their inclusion. Obese/overweight individuals with co-morbidities constitute an important population in any weight loss intervention study due to the strong association of obesity with major chronic health conditions. This paper, reviews the efficacy of telephone based weight loss intervention solely in overweight/obese individuals with obesity related diseases and discusses its relevance for developing countries. PMID- 29420055 TI - Functional Results of Open Brostrom Ankle Ligament Repair Augmented With a Suture Tape. AB - BACKGROUND: The Brostrom procedure is the most commonly used lateral ligament repair for chronic instability, but there is concern about the strength of the repair and the risk of reinjury. Currently, the InternalBraceTM ligament augmentation repair is an accepted augmentation method for management of a Brostrom procedure. Our hypothesis was that augmentation of the Brostrom repair with an InternalBraceTM would allow accelerated rehabilitation and return to activity and would aid in stability of the repair without a tendency to stretch. METHODS: Eighty-one patients with lateral ankle instability procedures repaired with a Brostrom and InternalBraceTM augmentation were evaluated at a one-time postoperative visit between 6 and 24 months. Outcomes included demographics, surgical time, the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle Hindfoot score, Veterans Rand 12-Item Health Survey (VR-12), Foot and Ankle Ability Measure (FAAM), Visual Analog Scale (VAS), satisfaction, and objective clinical measurements. Eighty-one patients were analyzed including 30 males and 51 females. Median age was 34 years (range, 18-62 years) with a median return for follow-up of 11.5 months (range, 6-27 months). RESULTS: Average postoperative VAS and satisfaction were 0.8 +/- 1.4 and 9.1 +/- 1.6, respectively. Mean return to sport (n = 68) was 84.1 days. Average AOFAS Ankle-Hindfoot score was 94.3. A score of 90 or higher on the FAAM Sports subscale was seen in 79.0% of the subjects. The single-leg hop test (Limb Symmetry Index %) showed that 86.4% of patients returned to normal or near normal function. The tape measure method and ankle dorsiflexion comparisons showed a significant difference: 9.2 +/- 3.3 cm (operative side) and 10.4 +/- 3.7 cm (contralateral side) ( P = .034). Ankle plantar flexion comparison (goniometer) was 48.5 +/- 11.5 degrees (operative side) and 49.7 +/- 11.9 degrees (contralateral side), showing no difference ( P = .506). CONCLUSION: These results suggest that InternalBraceTM augmentation of a Brostrom procedure is a safe and efficacious procedure that produces favorable outcomes in patients in terms of preventing recurrent instability in the ankle in the short term. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29420056 TI - In-Game Health Communication: Delivering Low-Fear Health Messages in a Low-Fear Videogame. AB - OBJECTIVE: Prior research has demonstrated that psychological immersion (or "transportation") into virtual gaming worlds can heighten influence from health promotion messages embedded in the backgrounds of gaming scenes. However, research to date has only studied the effectiveness of embedding graphic, fear based messages in the background of violent, first-person videogames. This study sought to examine whether transportation into a nonviolent videogame can heighten persuasion from low-fear, nongraphic health messages. METHODS: Willingness to drive under the influence of alcohol (DUI) was measured in an undergraduate sample (MAGE = 19) at the start of the semester, and n = 220 returned 0-3 months later to play a car-racing videogame. All were randomly assigned to play either a version of the game containing background billboards that delivered simple, text based anti-DUI messages or consumer advertising. Self-reported levels of transportation were assessed, as well as postgame willingness to DUI. RESULTS: Exposure to anti-DUI messages from within the game predicted lower postgame willingness to DUI. Moreover, replicating prior research, the effect of message exposure was largest among those who reported higher levels of pregame willingness to DUI, and higher levels of in-game transportation. CONCLUSION: This study replicates prior research by suggesting that immersive videogames that promote transportation can be used to effectively deliver health communications. Results also expand prior research by providing the first evidence that such effects can generalize when health messaging orients around nongraphic, lower fear messages embedded within immersive but lower fear videogames. PMID- 29420057 TI - Chemical compounds and mechanisms involved in the formation and stabilization of foam in sparkling wines. AB - The visual properties of sparkling wine including foam and bubbles are an indicator of sparkling wine quality. Foam properties, particularly foam height (FH) and foam stability (TS), are significantly influenced by the chemical composition of the wine. This review investigates our current knowledge of specific chemical compounds and, the mechanisms by which they influence the foam properties of sparkling wines. Grape and yeast proteins, amino acids, polysaccharides, phenolic compounds, organic acids, fatty acids, ethanol and sugar are examined with respect to their contribution to foam characteristics in sparkling wines made with the Traditional, Transfer, and Charmat and carbonation methods. Contradictory results have been identified that appear to be due to the analytical methods used to measure and quantify compounds and foam. Biopolymer complexes are discussed and absent knowledge with regards to thaumatin-like proteins (TLPs), polysaccharides, amino acids, oak-derived phenolic compounds and organic acids are identified. Future research is also likely to concentrate on visual analysis of sparkling wines by in-depth imaging analysis and specific sensory analysis techniques. PMID- 29420058 TI - Athletic Training Student Core Competency Implementation During Patient Encounters. AB - CONTEXT: Health care research evidence suggests that early patient encounters (PEs), as well as the purposeful implementation of professional core competencies (CCs), for athletic training students (ATSs) may be beneficial to their ability to provide care. However, no investigators have related facets of the clinical education experience with CC implementation as a form of summative assessment of the clinical experience. OBJECTIVE: To determine the relationship between the frequency and length of PEs, as well as the student's role and clinical site during PEs, and the students' perceived CC implementation during these encounters. DESIGN: Cross-sectional study. SETTING: Professional athletic training program, National Collegiate Athletic Association Division I institution. PATIENTS OR OTHER PARTICIPANTS: We purposefully recruited 1 athletic training program that used E*Value software; 40 participants (31 females, 9 males) enrolled in the professional phase (12 first year, 14 second year, 14 third year) participated. INTERVENTION(S): Participants viewed a 20 minute recorded CC educational module followed by educational handouts, which were also posted online for reference throughout the semester. The E*Value software was used to track PEs, including the type of encounter (ie, actual patient, practice encounter, didactic practice scenario), the type of site where the encounter occurred (university, high school), and the participant's role (observed, assisted, performed), as well as responses to an added block of questions indicating which, if any, of the CCs were implemented during the PE. MAIN OUTCOME MEASURE(S): Variables per patient were PE length (minutes), participant role, site at which the encounter occurred, and whether any of the 6 CCs were implemented ( yes/ no). Variables per participant were average encounter length (minutes), encounter frequency, modal role, clinical site assignment, and the number of times each CC was implemented. Separate 1-way analyses of variance were used to examine the relationships between role or clinical site and implementation of total number of CCs. Multiple linear regressions were used to determine how the average length and frequency of PEs were related to the average and total number of implemented CCs. Binary logistic regression models indicated how the length of each encounter, role of the participant, and type of clinical site related to the implementation of each CC. RESULTS: The roles of participants during PEs were related to their ability to implement the total number of CCs ( F = 103.48, P < .001). Those who observed were likely to implement fewer total CCs than those who assisted (M diff = -0.29, P < .001); those who assisted were likely to implement more total CCs than those who performed (M diff = 0.32, P < .001). Frequency of encounters was the only significant variable in the model examining all independent variables with CC implementation ( b4,32 = 3.34, t = 9.46, P < .001). CONCLUSIONS: The role of the student, namely assisting during PEs, and the volume of PEs should be considered priorities for students to promote greater CC implementation. PMID- 29420059 TI - Airway Management in Athletes Wearing Lacrosse Equipment. AB - CONTEXT: Patient ventilation volume and rate have been found to be compromised due to the inability to seal a pocket mask over the chinstrap of football helmets. The effects of supraglottic airway devices such as the King LT and of lacrosse helmets on these measures have not been studied. OBJECTIVE: To assess the effects of different airway management devices and helmet conditions on producing quality ventilations while performing cardiopulmonary resuscitation on simulation manikins. DESIGN: Crossover study. SETTING: Simulation laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-six athletic trainers (12 men, 24 women) completed this study. INTERVENTION(S): Airway-management device (pocket mask, oral pharyngeal airway, King LT airway [KA]) and helmet condition (no helmet, Cascade helmet, Schutt helmet, Warrior helmet) served as the independent variables. Participant pairs performed 2 minutes of 2-rescuer cardiopulmonary resuscitation under 12 trial conditions. MAIN OUTCOME MEASURE(S): Ventilation volume (mL), ventilation rate (ventilations/min), rating of perceived difficulty (RPD), and percentage of quality ventilations were the dependent variables. RESULTS: A significant interaction was found between type of airway-management device and helmet condition on ventilation volume and rate ( F12,408 = 2.902, P < .0001). In addition, a significant interaction was noted between airway management device and helmet condition on RPD scores ( F6,204 = 3.366, P = .003). The no-helmet condition produced a higher percentage of quality ventilations compared with the helmet conditions ( P <= .003). Also, the percentage of quality ventilations differed, and the KA outperformed each of the other devices ( P <= .029). CONCLUSIONS: The helmet chinstrap inhibited quality ventilation (rate and volume) in airway procedures that required the mask to be sealed on the face. However, the KA allowed quality ventilation in patients wearing a helmet with the chinstrap fastened. If a KA is not available, the helmet may need to be removed to provide quality ventilations. PMID- 29420061 TI - Fish consumption and cardiovascular disease related biomarkers: A review of clinical trials. AB - The purpose of this review is to collect and compare fish intervention studies. Prospective studies have outlined the beneficial effect of frequent fish consumption on cardiovascular incidents that is attributed to n-3 fatty acids incorporated in fish, mainly eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids. This outcome triggered clinical trials to examine the effect of either fish intake or consumption of n-3 fatty acids via capsules on biomarkers related to cardiovascular disease (CVD). The absence of a recent review focusing on clinical trials regarding fish intake and not n-3 fatty acids supplements rendered necessary the composition of this article. In total, 28 studies on healthy volunteers were found to meet the inclusion criteria. With EPA and DHA intake varying between 0.03 to 5 g per day, biomarkers, such as triglycerides, high-density lipoprotein and platelet aggregation, tended to ameliorate when daily intake exceeded 1 g per day, while the most common inflammatory marker, C reactive protein, was not affected. In all, fish consumption gives promising results; yet fish micronutrients, total diet fat, as well as other dietary habits may also affect biomarkers. Therefore, all these factors should be considered in future clinical trials in order for one to draw more reliable conclusions. PMID- 29420062 TI - Epidemiology of vitamin D insufficiency and deficiency in a population in a sunny country: Geospatial meta-analysis in Brazil. AB - Studies conducted among populations of tropical countries have reported high prevalences of vitamin D deficiency and insufficiency. Information resulting from meta-analyses on the spatial distribution of vitamin D deficiency and insufficiency in tropical countries is still rare. The aim of this review was investigated the prevalence of vitamin D deficiency and insufficiency among the Brazilian population. Observational studies were searched in eight electronically databases. Additionally, theses and dissertations and abstracts were screened. Details on study design, methods, population, mean and data on serum concentrations of vitamin D in different age groups in Brazil were extracted. Data were pooled using a random-effects model and choropleth maps were created based on the geopolitical regions of the country. 72 published paper met the inclusion criteria. The mean vitamin D concentration among the Brazilian population between 2000 and 2017 of 67.65 nmol/L (95% CI: 65.91, 69.38 nmol/L).The prevalences of vitamin D deficiency and insufficiency were 28.16% (95% CI: 23.90, 32.40) and 45.26% (95% CI: 35.82, 54.71), respectively, for the Brazilian population. The highest prevalence of deficiency were observed in the southern and southeastern regions and the highest occurrence of vitamin D insufficiency was among the populations of the southeastern and northeastern regions. Finally, there are high prevalence of inadequate vitamin D concentrations among the population, regardless of age group in Brazil. The development of vitamin D food fortification policies in needs to be cautious and carefully planned. PMID- 29420060 TI - Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis. AB - RATIONALE: Platelets may interact with the immune system in tuberculosis (TB) to regulate human inflammatory responses that lead to morbidity and spread of infection. OBJECTIVES: To identify a functional role of platelets in the innate inflammatory and matrix-degrading response in TB. METHODS: Markers of platelet activation were examined in plasma from 50 patients with TB before treatment and 50 control subjects. Twenty-five patients were followed longitudinally. Platelet monocyte interactions were studied in a coculture model infected with live, virulent Mycobacterium tuberculosis (M.tb) and dissected using qRT-PCR, Luminex multiplex arrays, matrix degradation assays, and colony counts. Immunohistochemistry detected CD41 (cluster of differentiation 41) expression in a pulmonary TB murine model, and secreted platelet factors were measured in BAL fluid from 15 patients with TB and matched control subjects. MEASUREMENTS AND MAIN RESULTS: Five of six platelet-associated mediators were upregulated in plasma of patients with TB compared with control subjects, with concentrations returning to baseline by Day 60 of treatment. Gene expression of the monocyte collagenase MMP-1 (matrix metalloproteinase-1) was upregulated by platelets in M.tb infection. Platelets also enhanced M.tb-induced MMP-1 and -10 secretion, which drove type I collagen degradation. Platelets increased monocyte IL-1 and IL 10 and decreased IL-12 and MDC (monocyte-derived chemokine; also known as CCL-22) secretion, as consistent with an M2 monocyte phenotype. Monocyte killing of intracellular M.tb was decreased. In the lung, platelets were detected in a TB mouse model, and secreted platelet mediators were upregulated in human BAL fluid and correlated with MMP and IL-1beta concentrations. CONCLUSIONS: Platelets drive a proinflammatory, tissue-degrading phenotype in TB. PMID- 29420063 TI - Distribution of Enterotoxin- and Epsilon-Positive Clostridium perfringens Spores in U.S. Retail Spices. AB - The role of spices as vehicles of foodborne illness prompted an examination of bacterial spores in these products. Here, we report on the levels and characteristics of spores of Clostridium perfringens associated with 247 U.S. retail spices. Forty-three confirmed isolates from 17% of samples were obtained, present at levels ranging from 3.6 to 2,400/g. Twenty-seven (63%) of C. perfringens isolates were positive for the enterotoxin gene ( cpe). Seven random spice isolates produced enterotoxin at levels of between 4 and 16 ng/mL, compared with three outbreak (control) strains that each produced enterotoxin levels of >1,024 ng/mL. D95 degrees C levels (1.0 to 3.3 min) of spores of four randomly selected spice isolates suggests a plasmid-localized cpe, while one had D95 degrees C (>45 min) consistent with chromosomally located cpe. Five of the 43 isolates possessed the epsilon toxin gene ( etx, as well as cpe). Foods could easily become contaminated with spores of cpe-positive C. perfringens by the addition of spices. Because of its spore-forming ability, its rapid generation times at elevated temperatures, improper heating, cooling, and holding conditions could lead to elevated levels of C. perfringens in foods, a requirement for its implication in foodborne outbreaks. PMID- 29420064 TI - Carbon dots: Principles and their applications in food quality and safety detection. AB - In the past ten years, as a novel and prospective nanomaterials, carbon dots have acquired tremendous attention for their unique optical and physicochemical properties, high compatibility and low cost, as well as great potential in sensing area. This review aims to present the current detecting principles based on carbon dots and other nano biological technologies, involving fluorescence quenching and recovery mechanisms. The synthetic and modificatory approaches in making carbon dots including top-down and bottom-up methods, as well as surface passivation and heteroatom doping ways are introduced. Their applications in food area, concerning detection of nutrients, restricted or banned substances as well as foodborne pathogenic bacteria and the toxins secreted are discussed. Finally, the difficulties to be overcome or problems to be solved are presented, and other novel techniques to combine with carbon dots to obtain more stable and specific nanosensors in various fields are proposed. Although carbon dots based sensors have shown the potential in sensing aspect of food area, as food samples are complex in compositions that may cause interferences, more novel techniques are needed to combine with carbon dots to develop sensitive and specific sensing probes. PMID- 29420065 TI - Role for Cela1 in Postnatal Lung Remodeling and Alpha-1 Antitrypsin-Deficient Emphysema. AB - Alpha-1 antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplant. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro. We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and to detect any effects it may have in the context of AAT deficiency. The lungs of Cela1-/- mice had aberrant lung elastin structure and higher elastance as assessed with the flexiVent system. On the basis of in situ zymography with ex vivo lung stretch, Cela1 was solely responsible for stretch-inducible lung elastase activity. By mass spectrometry, Cela1 degraded mature elastin similarly to pancreatic elastase. Cela1 promoter and protein sequences were phylogenetically distinct in the placental mammal lineage, suggesting an adaptive role for lung-expressed Cela1 in this clade. A 6-week antisense oligonucleotide mouse model of AAT deficiency resulted in emphysema with increased Cela1 mRNA and reduction of approximately 70 kD Cela1, consistent with covalent binding of Cela1 by AAT. Cela1-/- mice were completely protected against emphysema in this model. Cela1 was increased in human AAT-deficient emphysema. Cela1 is important in physiologic and pathologic stretch-dependent remodeling processes in the postnatal lung. AAT is an important regulator of this process. Our findings provide proof of concept for the development of anti-Cela1 therapies to prevent and/or treat AAT-deficient emphysema. PMID- 29420066 TI - CC chemokine receptor 2 promotes recruitment of myeloid cells associated with insulin resistance in nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a common disease, closely associated with obesity and insulin resistance. We investigated the presence of a subset of myeloid cells associated with metabolic disturbance in the liver of patients with NAFLD and a murine model of obesity-induced liver disease. Gene and protein expression in liver and serum was investigated with RT-PCR or ELISA and correlated to clinical disease. Liver-infiltrating immune cells were isolated from normal or diseased human liver for flow cytometric analysis. In animal experiments, mice were fed a high-fat diet (60% of calories from fat) for 16 wk, or high-fat diet with 30% fructose for 32 wk to induce steatohepatitis and fibrosis. A small molecule inhibitor of CC chemokine receptor 2 (CCR2), CCX872, was administered to some mice. A subset of CD11c+CD206+ immune cells was enriched in human liver tissue, and greater infiltration was observed in NAFLD. The presence of CD11c+CD206+ myeloid cells correlated with systemic insulin resistance. CD11c+CD206+ cells expressed high levels of CCR2, and liver CC chemokine ligand 2 (CCL2) expression was increased in nonalcoholic steatohepatitis and correlated with disease activity. In mice, CCR2 inhibition reduced infiltration of liver CD11b+CD11c+F4/80+ monocytes, which are functional homologs of human CD11c+CD206+ cells, and improved liver injury and glycemic control. A role for CCR2/CCL2 in human NAFLD has long been postulated. These data confirm a role for this chemokine/receptor axis, through mediating adipose and hepatic infiltration of myeloid cells. Inhibition of CCR2 improved hepatic inflammation and fibrosis in murine models of NAFLD. These data confirm the rationale for targeting CCR2 to treat NAFLD. NEW & NOTEWORTHY These data show for the first time that CD11c+CD206+ myeloid cells, previously associated with human adipose tissue inflammation, infiltrate into liver tissue in nonalcoholic fatty liver disease. These cells express CCR2. Inhibition of CCR2 in mice inhibits hepatic inflammation caused by a murine homolog of these myeloid cells and improves experimental liver disease. PMID- 29420070 TI - Are You Listening, Facebook? On Cybersecurity and Virtual Worlds. PMID- 29420072 TI - Dispelling the Pseudopsychology of Cybercrime. PMID- 29420067 TI - Organic solute transporter OSTalpha/beta is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury. AB - The heteromeric steroid transporter organic solute transporter alpha/beta (OSTalpha/beta, SLC51A/B) was discovered over a decade ago, but its physiological significance in the liver remains uncertain. A major challenge has been the lack of suitable models expressing OSTalpha/beta. Based on observations first reported here that hepatic OSTalpha/beta is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OSTalpha/beta function and interaction with drugs and bile acids. OSTalpha/beta expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OSTalpha/beta-mediated transport in the established in vitro model. The effect of bile acids and drugs, including those associated with cholestatic drug-induced liver injury, on OSTalpha/beta-mediated transport was evaluated. Expression of OSTalpha/beta was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OSTalpha/beta was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OSTalpha/beta-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OSTalpha/beta inhibitors: a biomarker for cholestasis, glycochenodeoxycholic acid; the major metabolite of troglitazone, troglitazone sulfate; and a macrocyclic antibiotic, fidaxomicin. Additionally, some drugs (e.g., digoxin) consistently stimulated taurocholate uptake in OSTalpha/beta-overexpressing cells. Our findings demonstrate that OSTalpha/beta is an important transporter in liver disease and imply a role for this transporter in bile acid-bile acid and drug-bile acid interactions, as well as cholestatic drug-induced liver injury. NEW & NOTEWORTHY The organic solute transporter OSTalpha/beta is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OSTalpha/beta substrates exhibit rapid, linear, and concentration-driven transport in an OSTalpha/beta overexpressing cell line. Drugs associated with hepatotoxicity modulate OSTalpha/beta-mediated taurocholate transport. These data suggest that hepatic OSTalpha/beta plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition. PMID- 29420068 TI - VIP is involved in peripheral CRF-induced stimulation of propulsive colonic motor function and diarrhea in male rats. AB - We investigated whether vasoactive intestinal peptide (VIP) and/or prostaglandins contribute to peripheral corticotropin-releasing factor (CRF)-induced CRF1 receptor-mediated stimulation of colonic motor function and diarrhea in rats. The VIP antagonist, [4Cl-D-Phe6, Leu17]VIP injected intraperitoneally completely prevented CRF (10 ug/kg ip)-induced fecal output and diarrhea occurring within the first hour after injection, whereas pretreatment with the prostaglandins synthesis inhibitor, indomethacin, had no effect. In submucosal plexus neurons, CRF induced significant c-Fos expression most prominently in the terminal ileum compared with duodenum and jejunum, whereas no c-Fos was observed in the proximal colon. c-Fos expression in ileal submucosa was colocalized in 93.4% of VIP positive neurons and 31.1% of non-VIP-labeled neurons. CRF1 receptor immunoreactivity was found on the VIP neurons. In myenteric neurons, CRF induced only a few c-Fos-positive neurons in the ileum and a robust expression in the proximal colon (17.5 +/- 2.4 vs. 0.4 +/- 0.3 cells/ganglion in vehicle). The VIP antagonist prevented intraperitoneal CRF-induced c-Fos induction in the ileal submucosal plexus and proximal colon myenteric plexus. At 60 min after injection, CRF decreased VIP levels in the terminal ileum compared with saline (0.8 +/- 0.3 vs. 2.5 +/- 0.7 ng/g), whereas VIP mRNA level detected by qPCR was not changed. These data indicate that intraperitoneal CRF activates intestinal submucosal VIP neurons most prominently in the ileum and myenteric neurons in the colon. It also implicates VIP signaling as part of underlying mechanisms driving the acute colonic secretomotor response to a peripheral injection of CRF, whereas prostaglandins do not play a role. NEW & NOTEWORTHY Corticotropin-releasing factor (CRF) in the gut plays a physiological role in the stimulation of lower gut secretomotor function induced by stress. We showed that vasoactive intestinal peptide (VIP)-immunoreactive neurons in the ileal submucosal plexus expressed CRF1 receptor and were prominently activated by CRF, unlike colonic submucosal neurons. VIP antagonist abrogated CRF-induced ileal submucosal and colonic myenteric activation along with functional responses (defecation and diarrhea). These data point to VIP signaling in ileum and colon as downstream effectors of CRF. PMID- 29420074 TI - Extracellular acidosis suppresses calcification of vascular smooth muscle cells by inhibiting calcium influx via L-type calcium channels. AB - Vascular calcification such as arteriosclerosis, which is characterized by a calcification of the tunica media, is a severe complication of chronic kidney disease (CKD), contributing to the high prevalence of cardiovascular morbidity and mortality in patients with CKD. An essential step during the development of arteriosclerosis is the transdifferentiation/calcification of vascular smooth muscle cells (VSMCs), resembling osteogenesis. Metabolic acidosis, a common clinical manifestation in CKD, is known to decrease vascular calcification. To understand the underlying regulatory mechanisms of acidosis, we investigated whether the acidosis-decreased VSMC calcification involves altered signaling of the LTCC/Ca2+/Runx2 pathway. Vascular calcifications, calcium content, runt related transcription factor 2 (Runx2), alkaline phosphatase (ALP), L-type calcium channel (LTCC) beta3 subunits, and calcium influx were measured in vivo or in vitro. Calcified nodules and calcium content increased either in aorta sections of vascular calcified rats or in VSMCs induced by beta-GP. The expression of Runx2 and ALP activity markedly rose, accompanied by the increasing expression of LTCC beta3 subunits and calcium influx. However, acidosis supplementation successfully attenuated VC and VSMC calcification and inhibited Runx2, ALP, LTCC beta3 subunits, and calcium influx. In conclusion, acidosis significantly attenuated vascular calcification in association with downregulation of the LTCC/Ca2+/Runx2 pathway. PMID- 29420073 TI - Open-label pilot study of injectable naltrexone for cannabis dependence. AB - BACKGROUND: There are no FDA-approved pharmacotherapies for cannabis use disorders (CUD), despite the evaluation of numerous medications. Notably, chronic dosing of oral naltrexone decreases self-administration of cannabis in human laboratory studies. OBJECTIVES: To test the feasibility of long-acting injectable naltrexone for the treatment of CUD, while obtaining preliminary safety and efficacy data. METHODS: Twelve adult participants (seven male) meeting DSM-IV-TR criteria for cannabis dependence enrolled into an 8-week, open-label pilot study conducted at an academic treatment research clinic. They received 380 mg intramuscular injections of long-acting naltrexone on study day 1 and at the start of study week 5. Outcome measures included percentages of study completers and participants who received the second injection, frequency of adverse events (AEs), and cannabis consumption measured by average daily grams, dollars, and using days per week as measured by timeline follow-back and urine oral delta-9 tetrahydrocannabinol (THC) concentrations. RESULTS: Of the 12 participants enrolled in the study, 9 completed the study and 6 received the second injection. There were no severe AEs but an unexpected AE led to the addition of supportive medications to the protocol. Number of cannabis use days per week significantly decreased over the course of the study (p = .001). Creatinine-corrected urine THC concentrations and average daily cannabis use per study week in grams and in dollars did not decrease over the course of the study. CONCLUSIONS: Long-acting injectable naltrexone is a feasible intervention for CUD worthy of further study in a placebo-controlled, double-blinded randomized clinical trial. PMID- 29420075 TI - Effect of statin therapy on pulse wave velocity: A meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVE: Arterial stiffness (AS) is an independent cardiovascular risk factor. A number of studies have reported a beneficial role of statins on AS albeit with controversial results, in addition to their effects on lipid profile. Therefore, we carried out a meta-analysis of the available randomized controlled trials assessing the effects of statin therapy on AS, in the attempt to reach more definitive conclusions. METHODS: A systematic search of the on-line databases available up to March 2017 was conducted, including intervention studies reporting AS expressed by carotid-femoral pulse wave velocity (PWV), as difference between the effects of treatment with or without statins. For each study, mean difference (MD) and 95% confidence intervals (CI) were pooled using a random effect model. RESULTS: Eleven studies met the pre defined inclusion criteria, for a total of 573 participants and 2-144 weeks' intervention time. In the pooled analysis, statin therapy was associated with a 6.8% (95% C.I.: -11.7 to -1.8) reduction in PWV. There was significant heterogeneity among studies (I2 = 96%); none of the study characteristics seems to have influenced the effect of statin use on PWV. CONCLUSIONS: The results of this meta-analysis suggest that statin therapy reduces AS. This effect appears to be at least in part independent of the changes in blood pressure and lipid profile. PMID- 29420076 TI - Circadian and short-term blood pressure abnormalities after liver transplantation. AB - Liver transplantation remains the only therapeutic method in end-stage liver disease. Cardiovascular system diseases, including arterial hypertension, are considered one of the main risk factors increasing mortality in this population. The aim of the study was the evaluation of circadian blood pressure patterns in liver transplant recipients. In a group of 107 liver transplant recipients, a 24 hour ambulatory blood pressure monitoring (ABPM) was performed. The ABPM revealed arterial hypertension in 88.79% and unsatisfactory blood pressure (BP) control in 71.03% of the study participants. The abnormal circadian BP pattern was observed in 90.65% of liver recipients. The subgroup of patients with preserved BP circadian rhythm was characterized by higher standard deviation (SD) and coefficient of variation (CV) values for 24-hour systolic, diastolic and mean arterial blood pressure (SBP, DBP, and MAP). There were no such differences for other short-term blood pressure variability (ST BPV) parameters: SD and CV of day time and night-time SBP, DBP and MAP values. Arterial hypertension and circadian BP abnormalities are present in a majority of liver transplant recipients. BP circadian rhythm is not associated with ST BPV parameters assessed separately during awake and sleep period which suggests that both groups of parameters could reflect different cardiovascular phenomena after liver transplantation. PMID- 29420077 TI - Tiotropium added to low- to medium-dose inhaled corticosteroids (ICS) versus low- to medium-dose ICS alone for adults with mild to moderate uncontrolled persistent asthma: A systematic review and meta-analysis. AB - OBJECTIVE: To assess the efficacy and safety profile of tiotropium when added to low- to medium-dose inhaled corticosteroid (ICS) regimen versus low- to medium dose ICS alone for adults with mild to moderate uncontrolled persistent asthma. DATA SOURCES: The online databases Pubmed, Embase and the Cochrane Library were searched for relevant data published up to November 14, 2017; we also conducted a supplementary search using clinicaltrials.gov. STUDY SELECTIONS: Only randomized control trials were included in this review. RESULTS: Four studies met our inclusion criteria for this review. In our review, two crossover studies were rated as "high risk" in the domain of "other bias" because a washout was not performed between each intervention. Lung function was significantly improved in the patient group receiving low- to medium-dose ICS with tiotropium. Results were consistent between each of three subgroups (tiotropium dry powder inhaler 18 MUg or Respimat Soft Mist inhaler 5 ug, Respimat Soft Mist inhaler 2.5 MUg, and Respimat Soft Mist inhaler 1.25 MUg). Although no significant difference in Asthma Control Questionnaire (ACQ) score was found between the two treatment groups, substantial heterogeneity was observed. The incidence of serious adverse events between the two treatment groups was not statistically significant. CONCLUSIONS: Tiotropium as a once daily add-on to low- to medium-dose ICS may be efficacious and well-tolerated treatment in adults with moderate uncontrolled asthma. However, as only a few studies were identified, more studies of better design and long-term trial duration are required in the future. PMID- 29420078 TI - Poor sleep is responsible for the impaired nocturnal blood pressure dipping in elderly hypertensive: A cross-sectional study of elderly. AB - OBJECTIVE: This study was aimed to assess whether sleep disorder was associated with an increased risk of less nocturnal blood pressure (BP) dipping in elderly patients with hypertension. METHODS: Cases were 1006 patients, aged >60 years, who were admitted to hospital with diagnosed hypertension during 2016-2017, and were divided into three groups with the systolic nocturnal BP dipping of 10%, and 0% as the cut-off value. The patients' sleep was evaluated by Pittsburgh sleep quality index (PSQI). RESULTS: Compared to non-dipper BP rhythm patients (n = 382) and dipper BP rhythm patients (n = 132), reverse dipper patients (n = 492) exhibited higher PSQI score and had higher scores on six components with the exception of use sleep drug (p < 0.05). Multivariate logistic regression indicated that poor sleep, which was defined as high score of PSQI or its seven components, was associated with prevalence of reverse dipper in elderly hypertensive (odds ratio (OR) = 1.17, (95% confidence interval (CI), 1.13-1.21, p < 0.05) after adjusting for risk factors of hypertension. Multiple linear regression analysis showed that there was a significant negative correlation between PSQI score (include its seven components) and nocturnal BP dipping value after adjusting for risk factors of hypertension (beta = -0.584, p < 0.001). CONCLUSIONS: In elderly patients with hypertension, poor sleep quality individuals were more prone to reverse dipper BP rhythm. Even adjusting for the effect of known risk factors of hypertension, poor sleep may contribute to attenuated BP dipping in elderly hypertensive. PMID- 29420079 TI - Increased masked hypertension prevalence in patients with obesity. AB - OBJECTIVES: Masked hypertension is associated with an increased risk for cardiovascular conditions. The aim of the study was to evaluate the relationship obesity parameters, including body weight, waist circumference, and body mass index. METHODS: The study group consisted of 251 consecutive outpatient subjects without overt hypertension. Subjects were classified according to BMI. After a complete medical history and laboratory examination, patients' height, weight, waist circumference heart rate, and office blood pressure were recorded. All subjects underwent ambulatory blood pressure monitoring. Masked hypertension is defined as normal office blood pressure measurement and high ambulatory blood pressure level. RESULTS: Baseline characteristics in patients and controls were similar. Prevalence of Masked hypertension was significantly higher in patients with obesity than controls (30.9% vs 5.7%, p < 0.001). Body mass index (33.2 +/- 4.3 vs 25.1 +/- 2.7 p < 0.001), waist circumference (98.5 +/- 11.7 vs 86.8 +/- 8.8, p < 0.001), and weight (86.5 +/- 11.8 vs. 69 +/- 9.1, p < 0.001) in patients with obesity were significantly higher than in patients with normal weight. Office Systolic BP (121.8 +/- 4.4 vs 120.5 +/- 4.78, p = 0.035), ambulatory daytime systolic BP (128.8 +/- 8.9 vs 124.5 +/- 7.4, p < 0.001), ambulatory daytime diastolic BP (73.9 +/- 9.5 vs 71.5 +/- 7.0, p = 0.019), ambulatory night time systolic BP in patients with obesity was significantly higher than in patients with normal weight. CONCLUSION: This study demonstrated that masked hypertension prevalence is higher in patients with obesity than control patients. It can be suggested that predefining obesity might be helpful in early detection of masked hypertension. PMID- 29420080 TI - Calcium ion cyclotron resonance in dissipative water structures. AB - Weak magnetic and electromagnetic fields affect physiological processes in animals, plants, and microorganisms. Ion cyclotron resonance (ICR) is discussed as one of the sensitive mechanisms, which enable perception of the geomagnetic field and its orientation. Numerous biological effects are observed involving several small ions, showing windows of predicted frequencies and intensities. The pioneering work of Guiliano Preparata and Emilio Del Giudice using quantum electrodynamics showed that spontaneously originating coherent regions in water facilitate ICR effects at incoherent water phase boundaries. Here we examine the ICR response of the calcium ion (Ca2+), crucial for many life processes. We use an aqueous solution containing the biologically ubiquitous membrane lipid L-alpha phosphatidylcholine that serves as a biomimetic proxy for dynamic light scattering (DLS) and nonlinear dielectric spectroscopy (NLDS) measurements. One notable result is that this system approaches a new equilibrium upon addition of calcium by means of the oscillatory Belousov-Zhabotinsky chemical reaction, oscillations are significantly reduced under Ca2+ ICR application. Secondly an "oscillator" of calcium ions appears to be able to itself couple coherently and predictably to large-scale coherent regions in water. This system appears able to regulate ion fluxes in response to very weak environmental electromagnetic fields. PMID- 29420081 TI - Depressive symptoms in the trajectory of craving during smoking cessation treatment: A latent growth curve model. AB - BACKGROUND: Depressive symptoms and craving are related to smoking maintenance; however, little is known about the association between trajectories of depressive symptoms and smoking craving after quitting. OBJECTIVES: We examined if depressive symptom change relates to change in craving following smoking cessation treatment. METHODS: Participants were 362 (64.1% female; 35.9% male) adult treatment seeking smokers who quit smoking after treatment. Depressive symptoms and craving trajectories were evaluated during smoking cessation treatment until 6 months follow-up. A latent growth curve model was used to study the correlation between trajectories. RESULTS: Depressive symptoms and smoking craving reduced significantly after quitting. Change in depressive symptoms was significantly related to change in craving symptoms over time. CONCLUSIONS: Quitting smoking was related to a reduction in depressive symptoms and craving. Clinically, the reduction of depressive symptoms is associated with reduce craving. The data suggest depression plays an important role in craving change following treatment. PMID- 29420082 TI - Invited Brief Commentary: Sentinel Lymph Node Status is a Main Prognostic Parameter Needful for the Correct Staging of Patients with Melanoma Thicker than 4 mm: Single Institutional Experience and Literature Meta-analysis. PMID- 29420083 TI - An investigation of neuroinjury biomarkers after sport-related concussion: from the subacute phase to clinical recovery. AB - OBJECTIVES: To characterise a panel of neuroinjury-related blood biomarkers after sport-related concussion (SRC). We hypothesised significant differences in biomarker profiles between athletes with SRC and healthy controls at both subacute and medical clearance time points. METHODS: Thirty-eight interuniversity athletes were recruited over two athletic seasons (n = 19 SRC; n = 19 healthy matched-control). High-sensitivity immunoassay was used to evaluate 11 blood analytes at both the subacute phase after SRC and at medical clearance. RESULTS: Univariate analysis identified elevated circulating peroxiredoxin-6 (PRDX-6) in athletes with SRC compared to healthy controls at the subacute time point. Multivariate analyses yielded similar results in the subacute phase, but identified both PRDX-6 and T-tau as significant contributors to class separation between athletes with SRC and controls at medical clearance. CONCLUSIONS: Our results are consistent with the increasing recognition that physiological recovery after SRC extends beyond clinical recovery. Blood biomarkers appear to be useful in elucidating the biology of brain restitution after SRC. However, their implementation requires mindfulness of factors such as academic stress, exercise, and injury heterogeneity. PMID- 29420084 TI - Meeting Report EuroG20 Meeting on Cancer-Associated Thrombosis (CAT) Bergamo, Italy 7 April 2016. AB - The EuroG20 meeting on cancer-associated thrombosis (CAT) convened in Bergamo, Italy on 7 April 2016 to discuss a selection of controversial topics in CAT management. This satellite meeting besides ICTHIC in Bergamo has the objective to propose an European Guidance on CAT in various complex situations where evidence based guidelines are lacking, driven by eminence-based thoughts of 20 experts and key opinion leaders in thrombosis from EU area and 8 experts from the rest of the world. PMID- 29420085 TI - Reactive Oxygen Species Play a Biphasic Role in Brain Ischemia. AB - OBJECTIVE: Reactive oxygen species (ROS) are the essential mechanism involving in the ischemic process. Due to their complex characteristics, the precise effects of ROS on post-ischemic neurons remain uncertain. This study aimed to investigate the potential role of ROS in brain ischemia. METHODS: Dynamic ROS levels in the perifocal cortex were evaluated after right middle cerebral artery occlusion (MCAO) of SD rats. Furthermore the role of ROS was assessed following delayed treatment with the ROS scavenger dimethylthiourea (DMTU) after brain ischemia. RESULTS: ROS levels markedly increased at 1 hr after reperfusion and then gradually decreased as the post-reperfusion time interval increased. ROS levels reached their lowest point at 3 days after reperfusion before increasing and showing a second peak at 7 days after reperfusion. ROS levels negatively correlated with neurological function scores. Delayed DMTU treatment after stroke worsened neurological outcomes, decreased microvessel density and inhibited stress-activated protein kinase activation. CONCLUSION: ROS may play a biphasic role in cerebral ischemia. Namely, ROS may induce damage during the injury phase of brain ischemia and participate in improving neurological function during the recovery phase. PMID- 29420086 TI - A review of obesity and asthma across the life span. AB - OBJECTIVE: This literature review aims to compare obese-asthmatic adults and children, and to characterize differences and similarities between the two subgroups from epidemiological, demographical, phenotypical, and physiological perspectives. METHODS: Literature search was conducted using Pubmed database with "obesity," "asthma," "epidemiology," "cluster analysis," "demography," "mechanics," and ''FeNO'' as search terms. METHODS: Articles investigating epidemiological, demographic, phenotypical variation, and mechanical aspects of breathing specifically in obese asthmatics were identified. The studies were then divided according to age: children (<18 years of age) and adults (>18 years of age). RESULTS: Increase in asthma incidence and prevalence is observed in both obese-asthmatic children and adults. Asthma prevalence is greater in adult females regardless of ethnic background, and in men of African American and Hispanic ethnicities. Degree of weight gain and early onset of menarche appears to directly affect asthma severity in adolescent girls and females. Airway hyperresponsiveness and fractional exhaled nitric oxide do not have any positive correlation with high BMI in obese-asthmatic children and adults. Obesity also alters lung mechanics in asthmatics, but the impact is different for children and adults likely due to differential effect of obesity on central and peripheral airway. CONCLUSION: Existing literature suggests both similarities and differences in obese-asthmatic children and adults. The most pertinent differences are related to gender, ethnicity, and lung functions. PMID- 29420087 TI - Prevalence and features of asthma-chronic obstructive pulmonary disease overlap in Northern Italy general population. AB - OBJECTIVE: There is controversy about the diagnostic criteria, prevalence, symptoms, and spirometry characteristics of asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO). Recent data indicate that the fixed method for diagnosing airway obstruction (AO) may overestimate ACO prevalence in the elderly, and a variable method may be more accurate. We aimed at estimating ACO prevalence in a general population sample and comparing patient and clinical features in subjects with ACO, COPD, and asthma. METHODS: We analyzed data from a cross-sectional study estimating COPD prevalence in randomly selected adults aged 20-79 years in Verona, Italy, and estimated prevalence and analyzed characteristics of asthma, COPD, and ACO. ACO was defined as AO (Forced Expiratory Volume in one second-FEV1/ Forced Vital Capacity-FVC < Lower Limit of Normal-LLN), highly positive bronchodilator test (>=15% increase in FEV1 and FVC >=400 mL), and personal self-reported history of physician diagnosed asthma and atopy. RESULTS: One thousand two hundred and thirty-six patients were included; 207 (16.7%) had asthma, COPD, or ACO (mean ages: 61.2, 59.7, and 57.2 years, respectively). The 3 groups had similar clinical and demographic variables; however, spirometry revealed differences between ACO and COPD patients, particularly post-bronchodilator FEV1 reversibility, which was detected in ACO and asthma patients but not in those with COPD. CONCLUSION: ACO prevalence in Northern Italy was estimated at 2.1%, in the range of values reported by previous studies. Marked differences between ACO and COPD revealed by spirometry may have important clinical implications in terms of treatment for patients with ACO. PMID- 29420088 TI - Urinary angiotensinogen level is correlated with blood pressure level and proteinuria in patients with masked hypertension. AB - Urinary angiotensinogen (UAGT) level is an index of the intrarenal-renin angiotensin system status and is significantly correlated with blood pressure (BP) and proteinuria in patients with hypertension (HT). We aimed to investigate the possible relationship between UAGT levels and albuminuria in masked hypertensives. A total of 96 nondiabetic treated hypertensive patients were included in this study. The patients were divided into two groups: masked hypertensives (office BP <140/90 mmHg and ambulatory BP >=130/80 mmHg) and controlled hypertensives (office BP <140/90 mmHg and ambulatory BP <130/80). The mean UAGT/UCre level and urinary albumin-creatinine ratio (UACR) of masked hypertensives were higher than those of controlled hypertensives (7.76 MUg/g vs 4.02 MUg/g, p < 0.001 and 174.21 mg/g vs 77.74 mg/g, p < 0.001, respectively). A significant positive correlation was found between UAGT/UCre levels and ambulatory systolic BP and diastolic BP levels in patients with masked HT, but this was not found with office SBP or DBP levels. Importantly, UAGT/UCre levels showed a significant positive correlation with UACR in both groups, but correlation of the UAGT levels with UACR was more pronounced in masked hypertensives (r = 0.854, p < 0.001 vsr = 0.512, p < 0.01). As a result, UAGT level was increased in patients with masked HT, which was associated with an elevation in albuminuria. Overproduction of the UAGT may play a pivotal role in development of proteinuria. PMID- 29420089 TI - Characterization of vascular dysregulation in meriones shawi after high-calorie diet feeding. AB - The present study was initiated to characterize vascular dysregulations (contraction and relaxation) associated with metabolic defects in Merions shawi, a rodent from the gerbillidae family, submitted to 12 weeks high-calorie diet. This diet induces a type 2 diabetes/metabolic syndrome phenotype with hypertension. In diabetic meriones, body weight increase was associated with hyperglycemia, increased insulinemia, and insulin resistance. Compared to lean meriones, diabetic meriones showed decreased aorta contraction to noradrenaline, which was normalized after NOS inhibition. Endothelium-dependent relaxation to carbachol was enhanced, while relaxing effects of the NO donor SNAP and of diazoxide were unchanged. Insulin-evoked relaxation was depressed in aorta from diabetic meriones, and L-arginine relaxed contracted arteries from diabetic meriones, but not from lean meriones. Urine NOX level and iNOS mRNA muscle expression were significantly higher in diabetic meriones compared to lean animals. These data strongly suggest that iNOS may have a pathogenic role in vascular dysfunction observed in diet-induced diabetic meriones. PMID- 29420091 TI - Concordance among children, caregivers, and clinicians on barriers to controller medication use. AB - OBJECTIVE: While much research has addressed asthma medication adherence, few have combined quantitative and qualitative data, and none has addressed the triad of child, caregiver, and clinician simultaneously. This study assessed, with mixed methods, barriers to medication adherence within this triad. METHODS: We conducted interviews with publicly-insured children with asthma, their caregivers, and their primary-care clinicians. Children (7-17 years) had been prescribed daily inhaled corticosteroids and visited the ED for asthma (past year). Participants answered open-ended and survey questions, rating suggested barriers to medication use (never vs. ever a barrier). McNemar's tests compared report of barriers by each group (children, caregivers, clinicians), and assessed concordance within triads. RESULTS: Fifty child-caregiver dyads participated (34 clinicians). Children (40% female; median age 10 years) had mostly non-Hispanic black (90%) caregivers with less than or equal to high-school education (68%). For barriers, children and clinicians were more likely than caregivers to report medications running out. Clinicians were also more likely to cite controllers being a "pain to take" (vs. children) and forgetfulness (vs. caregivers) (all p < .05). There was a lack of within-triad concordance regarding barriers to adherence, especially regarding medication running out, worrying about taking a daily medication, and medication being a pain to take. Qualitative data revealed themes of competing priorities, home routines, and division of responsibility as prominent contributors to medication adherence. CONCLUSIONS: There was significant disagreement among children, caregivers, and clinicians regarding barriers to daily use of asthma medications. To tailor asthma management conversations, clinicians should understand family-specific barriers and child caregiver disagreements. PMID- 29420090 TI - LXRalpha is expressed at higher levels in healthy people compared to atherosclerosis patients and its over-expression polarizes macrophages towards an anti-inflammatory MPhi2 phenotype. AB - OBJECTIVES: (1) To investigate the expression patterns of MPhi1 and MPhi2 phenotype markers of peripheral blood monocyte (PBMC)-derived macrophages in atherosclerosis patients and healthy controls, as well as the expression correlation among these genes. (2) To elucidate whether a high level of liver X receptor alpha (LXRalpha) expression is associated with anti-inflammatory MPhi2 type polarization. DESIGN: Peripheral blood monocytes (PBMCs) were obtained from 28 patients with carotid artery plaques and 10 normal persons, who did not have carotid artery plaques. M1 and M2 phenotype markers were analyzed after cellular differentiation into macrophages. Human macrophages derived from healthy donors were transfected with plasmid DNA encoding LXRalpha and control null-plasmids. Gene expression levels were quantified after further differentiation. RESULTS: Three genes (LXRalpha, CD68, and CD36) were expressed at a significantly lower rate in the atherosclerotic group than normal patients. There were correlations between the expression of LXRalpha, CD68, and peroxisome proliferator-activated receptor (PPARgamma), and between CD163, CD36 and scavenger receptor class A (SRA1). Macrophages over-expressing LXRalpha exhibited enhanced expression level of MPhi2-type genes and decreased expression level of MPhi1-type genes. CONCLUSIONS: PBMCs from healthy persons were predisposed to the MPhi2 differentiation phenotype, which exhibits elevated cholesterol uptake and anti inflammatory properties. LXRalpha over-expression polarizes macrophages towards the anti-inflammatory MPhi2 phenotype. PMID- 29420093 TI - The effects of fasting on heart rate variability in hypertensive patients. AB - Heart rate variability (HRV) is an independent indicator of increased mortality in patients with myocardial infarction and congestive heart failure. The effects of fasting on the HRV are not known in hypertensive patients. Therefore, studying the effects of Ramadan fasting on hypertensive patients' HRV seems reasonable to address. We conducted a prospective study including 20 hypertensive patients with sinus rhythm. HRV was determined twice by ambulatory 24-hour Holter recordings at fasting during and after Ramadan. Subjects mean age was 55 +/- 11.8 years. Sex ratio was 1.5. When two groups compared, statistically significant differences were found in terms of SDNN (113 +/- 71 vs 140 +/- 38, p = 0.001), SDANN (109.7 +/- 45 vs 134.8 +/- 48.3, p = 0.008), T power (2368.7 +/- 121.3 vs 3660.5 +/- 170.9, p = 0.03) and LF (552.2 +/- 31.3 vs 903.7 +/- 48.9, p < 0.0001) values. HRV parameters were found to be decreased in Ramadan. Thus, Ramadan fasting enhances the activity of the sympathetic system in hypertensive patients. PMID- 29420092 TI - An assessment of platelet parameters in different ethnic groups with hypertension subtypes and associated risk factors in Xinjiang, China. AB - The goal of this study was to investigate platelet parameters in populations with hypertension subtypes among the Han, Uygur, and Kazakh ethnic groups and their associated risk factors in Xinjiang, northwestern China. In total, 9816 adult participants were recruited from a multiethnic, cross-sectional cardiovascular risk survey. Our results indicated that the platelet counts in Han, Uygur, and Kazakh participants with isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic diastolic hypertension (SDH) varied significantly (P < 0.001). Additionally, the mean platelet volume (MPV) in Han, Uygur, and Kazakh participants with ISH was significantly different (P < 0.05). Furthermore, the individual platelet parameters had different associated risk factors. For example, the risk factors for platelet counts were Uygur ethnicity, Kazakh ethnicity, drinking, ISH, diabetes, and high triglycerides (TGs). The risk factors for MPV were Uygur ethnicity, smoking, overweight, obesity, ISH, IDH, diabetes, and high TGs. Gender was a risk factor for abnormal plateletcrit (PCT) values. Only a low high-density lipoprotein cholesterol level was found to be a risk factor for platelet distribution width (PDW). We suggest that more attention should be paid to platelet parameters and the associated risk factors to reinforce the effect of antiplatelet therapy and to provide a clinical basis for preventing the occurrence of thrombosis complications and cerebro- and cardiovascular diseases effectively. PMID- 29420094 TI - The Clinical Spectrum of Multiple Endocrine Neoplasia Type 2A with Cutaneous Lichen Amyloidosis in Ethnic Han Chinese. AB - This study systematically reviewed previous literatures and analyzed the genotype phenotype relationship between the multiple endocrine neoplasia type 2A (MEN 2A) cutaneous lichen amyloidosis (CLA) and RET/OSMR/IL31RA mutations. RET/OSMR/IL31RA screening was performed on 8 RET-carriers from 3 independent Chinese MEN 2A families. Besides, 51 MEN 2A-CLA patients in 116 RET carriers from literatures were clustered and analyzed. Our results indicated that almost all MEN 2A-CLA patients exhibited CLA which was located in the scapular region and carried RET mutation at codon 634. Meanwhile, we firstly described MEN 2A-CLA here in Chinese Han patient with RET p.C634F mutation. PMID- 29420095 TI - Flexibility and strength training in asthma: A pilot study. AB - OBJECTIVE: Although less is known about musculoskeletal factors that may contribute to asthma symptoms, body-based treatments addressing movement restrictions of the chest and shoulders may be a useful adjunct to asthma pharmacotherapy. In this pilot study, we compared asthma symptoms, pulmonary function tests, and medication use before and after a course of resistance flexibility and strength training (RFST) treatments in human subjects with asthma. METHODS: Patients with asthma (n = 10; mean age 23 years) completed questionnaires (Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Test (ACT)), spirometry, chest wall excursion, and shoulder range of motion (ROM) before and after a series of four RFST treatments over 47 +/- 21 days. Each treatment consisted of a one-hour session involving eccentric stretching of the arm, shoulder, and chest while lying in a supine position. RESULTS: Significant clinical improvement was observed for mean ACQ scores from pre- to post-treatment (mean decrease 0.73, 95% CI 0.26-1.09, Cohen d = 2.25, p =.0014). No significant improvement was observed in the ACT, AQLQ, or spirometry, although inhaler use decreased for half of the subjects and did not change for the remaining subjects (i.e. none increased). Chest wall excursion and all ROM tests trended toward improvement, but was only statistically significant (p <.05) for the arm raise in the frontal plane. CONCLUSION: RFST may be a beneficial, nonpharmacological method to decrease asthma symptoms. Future studies should be conducted involving a larger sample size, longer intervention time, control group, and blood collection to test inflammatory mediators. PMID- 29420096 TI - Gamma globulin replacement therapy in uncontrolled, severe asthma associated with humoral immunodeficiency: A series of five case reports. AB - We report on five adult cases of the rare association of asthma with humoral immunodeficiency (huID). All patients had uncontrolled asthma related to recurrent respiratory infections. Asthma was diagnosed according to the Global Initiative for Asthma (GINA) guidelines, and bronchiectasis was ruled out by a CT chest scan. Two men (aged 28 and 60) presented with pollen allergies, chronic rhinosinusitis, and IgG deficiency (7.8 and 7.6 g/L, respectively). Both patients underwent surgery for nasal polyposis but relapsed with acute sinusitis and severe asthma exacerbations requiring treatment with oral corticosteroids and antibiotics. The immunoglobulin replacement therapy (IRT) partially relieved the asthma by reducing the number of exacerbations. A 55-year-old woman presented with nonallergic, corticosteroid-dependent asthma (20 mg/day prednisone) and IgG deficiency (5.72 g/L). IRT improved asthma control (fall in the Asthma Control Questionnaire (ACQ)-7 score from 3.5 to 1.7) and enabled withdrawal of the corticosteroids. In a 47-year-old woman with an IgG2 subclass deficiency (1.9 g/L) and asthma, IRT increased the degree of asthma control (fall in the ACQ-7 score from 2.8 to 1.1). A 75-year-old woman presented with corticosteroid dependent asthma (40 mg/day prednisone), IgM and IgG deficiencies (0.28 g/L and 5.36 g/L, respectively), and recurrent respiratory, skin and urinary infections. Again, IRT improved asthma control (fall in the ACQ-7 score from 2.5 to 1.2), reduced the number of hospitalizations for asthma exacerbations, and enabled a 10 mg reduction in the daily dose of prednisone. These observations suggest that IRT may improve disease control in some patients with asthma and associated huID. PMID- 29420097 TI - Hemostatic Comparison of a Polysaccharide Powder and a Gelatin Powder. AB - : Purpose/Aim: Powdered hemostats have been widely adopted for their ease-of-use; however, their efficacy has been limited resulting in applications restricted to low-level bleeds. This study investigates the use of bovine-derived gelatin particles (BGP) as a standalone hemostatic powder and compare BGP to commercially available microporous polysaccharide hemospheres (MPH). MATERIALS AND METHODS: The powders were investigated for their hemostatic efficacy in a heparinized pre clinical bleeding model limited to grade 1 and 2 bleeds on a validated intraoperative bleeding scale, which represents the accepted, clinical use of hemostatic powders. RESULTS: At 10 minutes, the hemostatic success of lesions treated with BGP were 78% while MPH were 22%. The odds ratio for hemostatic success of BGP relative to MPH was 15.18 (95% CI: 7.37, 31.27). The 95% lower limit of the odds ratio was greater than 1. This indicates that BGP are superior to MPH (p < 0.001). The median time to hemostasis for BGP was 1.6 minutes and MPH was 14.5 minutes. The ratio for time to hemostasis of MPH relative to BGP was 9.23 (95% CI: 6.99, 12.19). This indicates that BGP achieve significantly faster time to hemostasis (p < 0.001). CONCLUSIONS: Characterization of tissue explant ultrastructure, particle size, and swelling revealed differences in the materials. BGP, in addition to absorbing fluid and concentrating clotting factors and platelets, integrate into the clot and stabilize the fibrin matrix. BGP have advantages over MPH in terms of speed and efficacy. BGP are a favorable biomaterial for further research that greatly improve the limited efficacy of powdered hemostats. PMID- 29420098 TI - Smad6 Methylation Represses NFkappaB Activation and Periodontal Inflammation. AB - The balance between pro- and anti-inflammatory signals maintains tissue homeostasis and defines the outcome of chronic inflammatory diseases such as periodontitis, a condition that afflicts the tooth-supporting tissues and exerts an impact on systemic health. The induction of tissue inflammation relies heavily on Toll-like receptor (TLR) signaling, which drives a proinflammatory pathway through recruiting myeloid differentiation primary response gene 88 (MyD88) and activating nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB). TLR-induced production of proinflammatory cytokines and chemokines is reined in by anti-inflammatory cytokines, including the transforming growth factor beta (TGFbeta) family of cytokines. Although Smad6 is a key mediator of TGFbeta-induced anti-inflammatory signaling, the exact mechanism by which TGFbeta regulates TLR proinflammatory signaling in the periodontal tissue has not been addressed to date. In this study, we demonstrate for the first time that the ability of TGFbeta to inhibit TLR-NFkappaB signaling is mediated by protein arginine methyltransferase 1 (PRMT1)-induced Smad6 methylation. Upon methylation, Smad6 recruited MyD88 and promoted MyD88 degradation, thereby inhibiting NFkappaB activation. Most important, Smad6 is expressed and methylated in the gingival epithelium, and PRMT1-Smad6 signaling promotes tissue homeostasis by limiting inflammation. Consistent with this, disturbance of Smad6 methylation exacerbates inflammation and bone loss in experimental periodontitis. The dissected mechanism is therapeutically important, as it highlights the manipulation of PRMT1-Smad6 signaling as a novel promising strategy to modulate the host immune response in periodontitis. PMID- 29420099 TI - Ocular Complications in Influenza Virus Infection. AB - PURPOSE: To describe a case series of ocular complications associated with upper respiratory tract infections. METHODS: Four patients aged 21-61 years (three females, one male) had confirmed ocular complications connected with a general upper respiratory tract infection with myalgia and fever. Ophthalmological examination, including a visual acuity test, a slit-lamp exam, intraocular pressure measurements, fluorescein and indocyanine green angiography, optical coherence tomography (OCT), and diagnostic tests for influenza were performed in the patients (RT-PCR, HAI). RESULTS: Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) was diagnosed in three patients and serous macular detachment (SME) in one. Influenza virus infection was confirmed by molecular biological methods (RT-PCR) or the hemagglutination inhibition test (HAI) in two patients. All patients were treated with systemic prednisone. CONCLUSION: A coincidence between APMPPE and SME epitheliopathy and influenza virus infection was observed in different months of a given epidemic season. PMID- 29420100 TI - Innovative Clinical Training Site for Psychiatric Mental Health Nurse Practitioner Students: Elementary School-Based Group Therapy (Manuscript ID UMHN 2017-0143). AB - The aim of this clinical training site innovation is to develop accessible pediatric mental health clinical training sites for psychiatric mental health nurse practitioner (PMHNP) students. Mental health services in school settings provide treatment in the child's community and create opportunities for innovation and collaboration with teachers, school counselors, and school psychologists. School settings provide opportunities for early recognition of anxiety symptoms and accessible treatment that can help close the gap in clinical training sites for this population. Mild and moderate symptoms of anxiety often go untreated and may affect academic performance negatively. Cognitive behavioral play therapy is an effective treatment modality provided by PMHNP students and supports the roles of school personnel. PMID- 29420102 TI - Family appraisal of paediatric acquired brain injury: a social work clinical intervention trial. AB - OBJECTIVE: To compare the efficacy of a new intervention 'Family Forward' with 'Usual Care' social work practice in optimising family appraisal of a child's acquired brain injury to ensure better adaptation during the inpatient rehabilitation phase of care and early transition home. RESEARCH DESIGN: Single site, prospective, sequential comparison group design. METHODS AND PROCEDURES: Families were recruited on admission to an inpatient rehabilitation service based at a tertiary paediatric hospital. The 'Usual Care' group (n = 22; 29 parents) recruitment, intervention and data collection were completed first (Phase 1), followed by the 'Family Forward' group (n = 25; 43 parents) (Phase 2). Parents/caregivers completed measures: (Impact of Event Scale- Revised: IES-R; Parents Experience of Childhood Illness and Brief Illness Perception Questionnaire: Brief IPQ) at the time of their child's inpatient rehabilitation admission, inpatient rehabilitation discharge, and 6 weeks post-discharge. MAIN OUTCOMES AND RESULTS: There were more children with traumatic brain injuries in the Family Forward group (n = 13) than Usual Care (n = 6) and the Family Forward group had a longer hospital admission (days, M = 56.4, SD = 46.1 vs. M = 37.5, SD = 16.4, p = 0.019). No significant group differences were found for family appraisal outcomes at any of the three time-points. Both groups reported reductions in trauma and grief responses, emotional experiences and perceptions of their child's injury at post-intervention and follow-up. Both groups continued to have depleted emotional resources (PECI scale) at 6 weeks post-discharge. CONCLUSIONS: The study contributes important insights into family appraisal experience in the early stages following paediatric acquired brain injury. In this context, 'Family Forward' needs to incorporate interventions that support and promote ongoing family appraisal as issues related to their child's injury arise over time. Future research is needed to focus on whether the Family Forward approach does sustain family system adaptation (a key aim informing the design of the intervention) over the longer term. PMID- 29420101 TI - Leveraging Genomics for Head and Neck Cancer Treatment. AB - The genomic landscape of head and neck squamous cell carcinoma (HNSCC) has been recently elucidated. Key epigenetic and genetic characteristics of this cancer have been reported and substantiated in multiple data sets, including those distinctive to the growing subset of human papilloma virus (HPV)-associated tumors. This increased understanding of the molecular underpinnings of HNSCC has not resulted in new approaches to treatment. Three Food and Drug Administration approved molecular targeting agents are currently available to treat recurrent/metastatic disease, but these have exhibited efficacy only in subsets of HNSCC patients, and thus surgery, chemotherapy, and/or radiation remain as standard approaches. The lack of predictive biomarkers to any therapy represents an obstacle to achieving the promise of precision medicine. This review aims to familiarize the reader with current insights into the HNSCC genomic landscape, discuss the currently approved and promising molecular targeting agents under exploration in laboratories and clinics, and consider precision medicine approaches to HNSCC. PMID- 29420103 TI - Conjunctival Flap with Biodegradable Collagen Matrix Implantation for the Treatment of Scleromalacia after Periocular Surgery. AB - PURPOSE: To report a new surgical procedure using biodegradable collagen matrix (Ologen) implantation with conjunctival flap for reconstruction of scleromalacia after periocular surgery. METHODS: A total of 26 areas of 25 eyes in 25 patients were included. We divided all eyes according to the preoperative extent of calcified plaque or scleral defect as follows: small, large, and large and severe. Morphologic outcomes were graded from 0 to 7, with higher scores indicating worse cosmetic outcomes. RESULTS: Mean follow-up period was 8.3 +/- 5.6 months. No eyes showed recurrence or specific complications related to Ologen such as implant extrusion or allergic reaction. Minor complications such as flap vessel engorgement and flap hypertrophy were easily treated. Mean morphologic outcome scores were 1.8, 2.4, and 5.3 in groups 1, 2, and 3, respectively. DISCUSSION: The combined surgery may be an effective and safe procedure for the treatment of scleromalacia after periocular surgeries. PMID- 29420104 TI - Tocilizumab as first treatment option in optic neuropathy secondary to Graves' orbitopathy. AB - Dysthyroid optic neuropathy (DON) is one of the complications that can affect Graves' orbitopathy (GO) patients. Its prevalence is estimated at less than 5%. It is usually treated with intravenous steroids, radiotherapy or orbital decompression. Tocilizumab has been proposed as a treatment option in cases of GO refractory to steroid treatment, with good clinical results. Our aim is to report the case of a patient with optic neuropathy secondary to GO treated with tocilizumab as primary treatment option. PMID- 29420105 TI - A Wnt-Responsive PDL Population Effectuates Extraction Socket Healing. AB - Stem cells residing in the periodontal ligament (PDL) support the homeostasis of the periodontium, but their in vivo identity, source(s), and function(s) remain poorly understood. Here, using a lineage-tracing mouse strain, we identified a quiescent Wnt-responsive population in the PDL that became activated in response to tooth extraction. The Wnt-responsive population expanded by proliferation, then migrated from the PDL remnants that remained attached to bundle bone, into the socket. Once there, the Wnt-responsive progeny upregulated osteogenic protein expression, differentiated into osteoblasts, and generated the new bone that healed the socket. Using a liposomal WNT3A protein therapeutic, we showed that a single application at the time of extraction was sufficient to accelerate extraction socket healing 2-fold. Collectively, these data identify a new stem cell population in the intact periodontium that is directly responsible for alveolar bone healing after tooth removal. PMID- 29420107 TI - Development of a Rapid Fluorescence-Based High-Throughput Screening Assay to Identify Novel Kynurenine 3-Monooxygenase Inhibitor Scaffolds. AB - Kynurenine 3-monooxygenase (KMO) is a well-validated therapeutic target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Huntington's disease (HD). This work reports a facile fluorescence-based KMO assay optimized for high-throughput screening (HTS) that achieves a throughput approximately 20-fold higher than the fastest KMO assay currently reported. The screen was run with excellent performance (average Z' value of 0.80) from 110,000 compounds across 341 plates and exceeded all statistical parameters used to describe a robust HTS assay. A subset of molecules was selected for validation by ultra-high-performance liquid chromatography, resulting in the confirmation of a novel hit with an IC50 comparable to that of the well-described KMO inhibitor Ro 61-8048. A medicinal chemistry program is currently underway to further develop our novel KMO inhibitor scaffolds. PMID- 29420106 TI - Syncytial variant of nodular sclerosing Hodgkin lymphoma in children: A prognostic factor? AB - Nodular sclerosing Hodgkin lymphoma (HL) has an excellent prognosis in children. The syncytial variant (SV) of HL in adults represents a clinic pathologic entity with a worse outcome. We report the clinical features and the course of the disease of three children with refractory HL. The three patients with SV were analyzed in a retrospective multi-institutional study conducted in Israel in 51 children diagnosed with refractory or recurrent HL between 1997 and 2014. All the three children developed multiple recurrences soon after diagnosis. All three received at least three different chemotherapy combinations with autologous bone marrow transplantation for two patients, allogenic bone marrow transplantation in one, and immunotherapy in one. One patient died of disease, one is in complete response of the disease but developed a second metastatic malignancy, and one is alive without disease. This retrospective study shows that SV histology may be a prognostic factor for poor outcome in children diagnosed with HL. PMID- 29420108 TI - Asthma diagnosis among children along an urban-rural gradient. AB - OBJECTIVE: Studies have reported lower asthma prevalence in rural compared to urban areas. While environmental factors have mostly been implicated for these differences, the lower asthma prevalence could also be linked to asthma under diagnosis in rural children. We investigate if rural children experience under diagnosis of asthma more compared to urban children. METHODS: In 2013, we conducted a cross-sectional survey of schoolchildren across an urban-rural gradient in Saskatchewan, Canada. The participants formed sampling frame for future studies. In 2015, we approached those who gave consent in 2013 for further testing, repeated the survey, and conducted clinical testing. Based on survey responses, children were classified into "no asthma," "at-risk-for-asthma," and "diagnosed asthma." We then classified asthma status as either "no asthma" or "probable asthma" based on a validated asthma algorithm. RESULTS: The study population of 335 schoolchildren (aged 7-17 years) comprised of 73.4% from large urban, 13.7% from small urban, and 12.8% from rural areas. Proportion with report of physician-diagnosed asthma was 28.5% (Large urban), 34.8% (Small urban), and 20.9% (Rural). Mean percent predicted FEV1 and FEF25%-75% were lower in rural compared to small urban and large urban children (p < 0.05). Among those not classified as with "diagnosed asthma" by the survey, the algorithm further identified presence of asthma in 5.5% large urban, 8.1% small urban, and 18.8% rural children (p = 0.03). CONCLUSION: The study revealed evidence of asthma underdiagnosis in rural areas and further supports the use of objective measures in addition to symptoms history when investigating asthma across urban-rural gradients. PMID- 29420110 TI - Educational and home-environment asthma interventions for children in urban, low income, minority families. AB - OBJECTIVE: This review examined the impact of environmental change and educational interventions targeting young children from minority groups living in urban environments and who were from low-income families. DATA SOURCES: A scoping methodology was used to find research across six databases, including CINAHL, ERIC, PsycINFO, PubMed, MEDLINE, and EMBASE. STUDY SELECTION: 299 studies were identified. Duplicates were removed leaving 159 studies. After reviewing for inclusion and exclusion criteria, 23 manuscripts were identified for this study: 11 featured home-environment change interventions and 12 emphasized education of children. RESULTS: Studies were reviewed to determine key interventions and outcomes for children. Both environmental interventions and educational programs had positive outcomes. Interventions did not always impact health outcomes, such as emergency department visits. CONCLUSIONS: Results indicated many of the environmental change and education interventions improved asthma management and some symptoms. A multipronged approach may be a good method for targeting both education and change in the home and school environment to promote the well-being of young children in urban areas. New research with careful documentation of information about study participants, dose of intervention (i.e., number and duration of sessions, booster sessions) and specific intervention components also will provide guidance for future research. PMID- 29420109 TI - Vasodilation and Antihypertensive Activities of Swietenia macrophylla (Mahogany) Seed Extract. AB - The seeds of Swietenia macrophylla King (SM) (Meliaceae) are used as a folk medicine for the treatment of hypertension in Malaysia. However, the antihypertensive and vasorelaxant effects of SM seeds are still not widely studied. Thus, this study was designed to investigate the in vivo antihypertensive effects and in vitro mechanism of vasorelaxation of a 50% ethanolic SM seed extract (SM50) and the fingerprint of SM50 was developed through tri-step Fourier transform infrared (FTIR) spectroscopy. The vasorelaxant activity and the underlying mechanisms of SM50 were evaluated on thoracic aortic rings isolated from Sprague-Dawley rats in the presence of antagonists. The pharmacological effect of SM50 was investigated by oral administration of spontaneously hypertensive rats (SHRs) with three different doses of SM50 (1000, 500, and 250 mg/kg/day) for 4 weeks and their systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were measured weekly using tail-cuff method. The tri-step FTIR macro-fingerprint of SM50 showed that SM50 contains stachyose, flavonoids, limonoids, and ester, which may contribute to its vasorelaxant effect. The results showed that the vasorelaxant activity of SM50 was mostly attributed to channel-linked receptors pathways through the blockage of voltage-operated calcium channels (VOCC). SM50 also acts as both potassium channels opener and inositol triphosphate receptor (IP3R) inhibitor, followed by beta2-adrenergic pathway, and ultimately mediated through the nitric oxide/soluble guanylyl cyclase/cyclic 3',5'-guanosine monophosphate (NO/sGC/cGMP) signaling pathways. The treatment of SM50 also significantly decreased the SBP and DBP in SHRs. In conclusion, the antihypertensive mechanism of SM50 was mediated by VOCC, K+ channels, IP3R, G-protein-coupled beta2-adrenergic receptor, and followed by NO/sGC/cGMP signaling mechanism pathways in descending order. The data suggested that SM50 has the potential to be used as a herbal medicament to treat hypertension. PMID- 29420111 TI - Increased Aqueous Humor CD4+/CD8+ Lymphocyte Ratio in Sarcoid Uveitis. AB - PURPOSE: To determine aqueous humor CD4+/CD8+ T-lymphocyte ratio changes in sarcoid and non-sarcoid uveitis with anterior chamber involvement. METHODS: The case-control study includes 61 patients with either anterior uveitis, intermediate uveitis with anterior spill, or panuveitis. A total of 21 of them were categorized as sarcoid uveitis and 40 as non-sarcoid uveitis according to diagnostic criteria. CD4+/CD8+ ratio in the aqueous humor was determined using flow cytometry. RESULTS: Significantly higher CD4+/CD8+ ratio in the aqueous humor was observed in patients with sarcoid uveitis (6.3 +/- 1.4; mean +/- SEM) compared to non-sarcoid uveitis (1.6 +/- 0.1; mean +/- SEM). Whole blood CD4+/CD8+ ratio was not elevated in subjects with sarcoid and non-sarcoid uveitis. Aqueous humor CD4+/CD8+ ratio >3.5 was observed to be associated with sarcoid uveitis (OR 38, 95% CI 7.0-205.2). CONCLUSION: Increased aqueous humor CD4+/CD8+ ratio in sarcoid uveitis. Immunophenotyping of localized lymphocytosis in aqueous humor could be utilized as an additional confirmatory marker for ocular sarcoidosis. PMID- 29420112 TI - Low-dose bevacizumab as an effective pre-treatment for peri-tumoral brain edema prior to CyberKnife radiosurgery: A case report. AB - A 75-y-old Chinese female patient diagnosed with lung adenocarcinoma with brain metastasis suffered severe nausea and vomiting, and these symptoms were contraindications for CyberKnife treatment. Neither mannitol, nor dexamethasone, relieved the symptoms. However, after the patient received a single dose of bevacizumab (200 mg, 2.9 mg/kg), the patient's symptoms were significantly relieved. The patient subsequently completed a successful CyberKnife treatment. In addition, the patient received an oral treatment of gefitinib. At 15 months post treatment, the patient's brain tumor was controlled. Thus, administration of bevacizumab at a low dose (2.9 mg/kg) may significantly alleviate peri-tumoral brain edema and its symptoms, thereby facilitating radiosurgery treatment. PMID- 29420113 TI - Risk Factors for Development of Rhegmatogenous Retinal Detachment in Patients with Uveitis. AB - PURPOSE: To describe risk factors for development of rhegmatogenous retinal detachment (RRD) in patients with uveitis. METHODS: We performed a retrospective review of 411 consecutive human immunodeficiency virus-negative patients with uveitis (571 affected eyes) and report on prevalence, risk factors and visual outcomes of patients with RRD. RESULTS: Prevalence of RRD was 7% of all patients with uveitis. Multivariate analysis revealed that posterior uveitis and panuveitis were associated with RRD (P = 0.001). Strong association between RRD development and infectious uveitis was also observed (P = 0.009). Acute retinal necrosis (ARN) was firmly associated with RRD development (P = 0.016). Although anatomical success was obtained, functional outcome was poor. Poor visual outcomes at 6-month and 1-year follow-up were associated with initial VA < counting fingers (P = 0.05, P = 0.044). CONCLUSIONS: Prevalence of RRD in uveitis was 7% and development of RRD was encountered in posterior and panuveitis. Infectious uveitis (specifically ARN) formed a high risk for RRD. PMID- 29420114 TI - Role of CT Chest and Cytology in Differentiating Tuberculosis from Presumed Sarcoidosis in Uveitis. AB - PURPOSE: To report the role of CT chest and cytology in suspected tubercular and sarcoid uveitis. METHODS: This is a retrospective, interventional case series of 376 uveitis patients with suspected ocular tuberculosis (TB)/sarcoidosis seen between January 2010 and April 2015 at the Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh. All underwent CT chest, and had following inclusion criteria: (1) Presence of active granulomatous anterior/intermediate/posterior uveitis or panuveitis; (2) a documented tuberculin skin test/QuantiFERON-TB Gold test; (3) all other causes of infectious/non-infectious uveitis ruled out. A total of 206 patients had abnormal CT chest, of which 147 patients with minimum four months follow up were studied. Based on CT findings and amenability of involved lymph nodes, conventional transbronchial needle aspiration (TBNA)/endobronchial ultrasoundguided TBNA (EBUS TBNA) or fine needle aspiration cytology (FNAC) of peripheral nodes was performed by an interventional pulmonologist. All smears were subjected to cytopathological examination, and Ziehl-Neelsen staining for acid-fast bacilli (AFB). The detection of the underlying etiology (TB or sarcoidosis) was the main outcome measure. RESULTS: CT chest demonstrated mediastinal/hilar lymph nodes in 123/147 (83.7%) patients. Twenty four (16.2%) patients with parenchymal involvement were diagnosed TB (n = 20) or sarcoidosis (n = 4). Sixty nine patients with subcentimetric lymph nodes that were not amenable to biopsy were diagnosed clinico-radiologically as TB (42) and sarcoidosis (27). Fifty-four patients underwent biopsy from various sites that diagnosed TB and sarcoidosis in 21 (38.2%) patients each. Five TBLB/EBUS TBNA smears and seven FNAC smears demonstrated AFB. CONCLUSIONS: In systemically asymptomatic individuals presenting with uveitis, CT chest helped to establish the diagnosis of TB/sarcoidosis in 71.43% cases (105 out of 147) using only the clinico radiological criteria, while a confirmed diagnosis of TB/sarcoidosis was possible only in 42 cases (28.57%) by EBUS/TBNA guided cytological examination. PMID- 29420116 TI - Antibody persistence after pneumococcal conjugate vaccination in patients with chronic lymphocytic leukemia. AB - Patients with chronic lymphocytic leukemia (CLL) are at a high risk for infections caused by Streptococcus pneumoniae. A pneumococcal conjugate vaccine (PCV) can induce a significant antibody response for some CLL patients. In this study we investigated antibody persistence after PCV7 in patients with CLL. The study material comprised 24 patients with CLL and 8 immunocompetent controls. The median antibody concentrations five years after PCV7 were lower for six pneumococcal serotypes in patients with CLL compared to controls, but the difference was not statistically significant. Depending on the serotype, the percentage of the CLL patients with antibody levels suggested to provide protection against invasive pneumococcal disease (IPD) varied from 29 to 71% five years after vaccination. This data suggests that PCV could result in antibody persistence at least five years in CLL patients. PMID- 29420115 TI - Regulation of Th17 cells by P. UF1 against systemic Listeria monocytogenes infection. AB - Regulation of Th17 and Th1 cell responses against intracellular pathogens, including Listeria monocytogenes (L. m), is critical to limit inflammation induced tissue damage. We recently demonstrated the ability of P. UF1 bacterium derived from the intestinal bacterial commensals of preterm infants fed human breast milk to significantly mitigate pathogen-induced inflammation limiting colonic tissue damage. Here we further elucidated the potential of P. UF1 to also regulate innate and T cells, particularly Th17 and Th1 cells, against systemic L. m infection. Data demonstrate that P. UF1 not only robustly regulated protective Th17 and Th1 cells, but also sustained regulatory T cells (Treg cells) resulting in accelerated L. m clearance. Together, regulation of pathogenic inflammation by a novel probiotic bacterium such as P. UF1 may illuminate a new strategy to specifically control Th17-Th1 cells via IL-10+ Treg cells to limit systemic tissue damage induced by intracellular pathogens, including L. m. PMID- 29420117 TI - Inhibition of IL-10 and TGF-beta receptors on dendritic cells enhances activation of effector T-cells to kill cholangiocarcinoma cells. AB - Tumor escapes host immune responses by producing immunosuppressive cytokines, such as IL-10 and TGF-beta, secreted into the tumor microenvironment. These cytokines play important roles in the suppression of dendritic cell (DC) function, leading to decreased immune responses of the effector CD4+ and CD8+ T cells. To improve DC functions and enhance cytolytic activity of activated effector T-cells, we suppressed the effect of these cytokines on DCs by using specific neutralizing antibodies that inhibit IL-10 and TGF-beta receptors. Monocyte-derived DCs generated in vitro showed up-regulation of MHC (HLA-DR) and co-stimulatory molecules (CD40 and CD86). The IL-10 and TGF-beta receptors were expressed and localized on cell membrane of DCs, as shown by Western blot analysis and immunofluorescence staining, whereas the IL-10 and TGF-beta ligands were detected in the culture supernatants of DCs and cholangiocarcinoma (CCA) cell line, respectively. Inhibition of the IL-10 and TGF-beta receptors on DCs by specific neutralizing antibodies significantly increased level of IFN-gamma and enhanced cytolytic activity of the DC-activated effector T-cells against CCA cell line. These results indicate that the IL-10 and TGF-beta receptors are the targets for inhibition to increase DC functions and enhance cytolytic activity of the DC-activated effector T-cells against CCA cells. Thus, inhibition of the IL 10 and TGF-beta receptors on DCs is crucial in the preparation of DC-activated effector T cells for adoptive T-cell therapy. PMID- 29420118 TI - Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial. AB - Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose. PMID- 29420119 TI - Cross-protection induced by VA-MENGOC-BC(r) vaccine. AB - I would like to comment on the article "Commentary: Impact of meningococcal group B OMV vaccines, beyond their brief", DOI: 10.1080/21645515.2017.1381810. The author states that meningococcal group B OMVs vaccines -such as VA-MENGOC-BC(r)- may induce moderate protection against Neisseria gonorrhoeae. I agree. However, the author states that "there was no evidence of effectiveness in the younger children." The effectiveness of VA-MENGOC-BC(r) in heterologous contexts has been higher than 80% in individuals older than 4 years old, but the effectiveness in younger children should not be undervalued; it has usually been higher than 60%, and results markedly higher when evaluated based on mortality rates. There is strong evidence that VA-MENGOC-BC(r) may induce cross-protection against heterologous N. meningitidis strains and N. gonorrhoeae. PMID- 29420120 TI - Seroprevalence of antibodies to measles and rubella eight months after a vaccination campaign in the southeast of Iran. AB - Eight months after the mass immunization campaign of November 2015 against measles and rubella in the southeast of Iran, in order to evaluate the sero immunity level of the people living in the mentioned region, a serosurvey study was performed. Using a multi-stage probability proportional to size cluster sampling, the sera of 1,056 participants, ranging from 15 months to 20 years old, were tested for measles and rubella IgG antibodies in the National Reference Laboratory at Tehran University of Medical Sciences, Tehran, Iran. The seroprevalence rates of antibodies against measles and rubella in the age groups below 16 years were respectively 98.4 and 93.2%. In the age group of 16 to 20 years, who was not the target of the mass immunization campaign, the said rates were respectively 91.7% and 87.4%. The herd immunity of the age groups below 16 years, who were the target of the campaign, is favourably high and reassuring both for measles and for rubella. Campaigns of supplementary vaccination play a substantial role for filling the gaps in the herd immunity. PMID- 29420121 TI - Reduction by enhanced coagulation of dissolved organic nitrogen as a precursor of N-nitrosodimethylamine. AB - Raw water from the Banglen (BL) water treatment plant (WTP) and Bangkhen (BK) WTP in central Thailand and Hatyai (HY) WTP in southern Thailand was investigated for dissolved organic nitrogen (DON) reduction. The DON(mg N/L) and the dissolved organic carbon (DOC)/DON ratio were 0.34 and 21, 0.24 and 18, and 1.12 and 3 for the raw waters from BL, BK, and HY WTPs, respectively. Polyaluminum chloride (PACl) dosages of 150, 80, and 40 mg/L at pH 7 were the optimal coagulation conditions for the raw waters from BL, BK, and HY WTPs, respectively, and could reduce DON by 50%, 42%, and 42%, respectively. PACl and powder activated carbon (PAC, both in mg/L) at 150 and 20, 80 and 20, and 40 and 60 could reduce DON in the raw waters from BL, BK, and HY WTPs by 71%, 67%, and 29%, respectively. DOC/DON values of water treated with PACl were similar to those of raw water. DOC/DON values of water treated with PACl and PAC were lower than those of raw water. N-nitrosodimethylamine (NDMA) formation potentials of raw water, water treated with PACl, or both PACl and PAC, and organic fractions of BL, BK, and HY WTPs were below the detection limits of 542 and 237 ng/L, respectively. Reductions in fluorescence intensities of tryptophan-like substances at peaks 240/350 and 280/350 (nmEx/nmEm) were moderately (correlation coefficient, R = 0.85 and 0.86) and fairly (R = 0.59, 0.67, and 0.75) correlated with DON reduction. PMID- 29420123 TI - Talimogene laherparepvec: First in class oncolytic virotherapy. AB - Oncolytic viruses represent a novel drug class in which native or modified viruses mediate tumor regression through selective replication within and lysis of tumor cells as well as induction of systemic antitumor immunity capable of eradicating tumor at distant, uninjected sites. Talimogene laherparepvec (TVEC) is a type I herpes simplex virus genetically modified to preferentially replicate in tumor cells, enhance antigen loading of MHC class I molecules and express granulocyte-macrophage colony-stimulating factor to increase tumor-antigen presentation by dendritic cells. It is presently the only oncolytic virus approved by the FDA with an indication for advanced melanoma based upon improved durable response rate in a randomized, phase III trial. Clinical trials are underway in melanoma investigating TVEC as neoadjuvant monotherapy and in combination with checkpoint inhibitors for unresectable disease as well as in an array of other malignancies. It is appropriate to review TVEC's biology mechanism of action, clinical indication and future directions as a prototype of the burgeoning class of oncolytic viruses. PMID- 29420122 TI - Bridging the gap: Super-resolution microscopy of epithelial cell junctions. AB - Cell junctions are critical for cell adhesion and communication in epithelial tissues. It is evident that the cellular distribution, size, and architecture of cell junctions play a vital role in regulating function. These details of junction architecture have been challenging to elucidate in part due to the complexity and size of cell junctions. A major challenge in understanding these features is attaining high resolution spatial information with molecular specificity. Fluorescence microscopy allows localization of specific proteins to junctions, but with a resolution on the same scale as junction size, rendering internal protein organization unobtainable. Super-resolution microscopy provides a bridge between fluorescence microscopy and nanoscale approaches, utilizing fluorescent tags to reveal protein organization below the resolution limit. Here we provide a brief introduction to super-resolution microscopy and discuss novel findings into the organization, structure and function of epithelial cell junctions. PMID- 29420125 TI - Deep ECGNet: An Optimal Deep Learning Framework for Monitoring Mental Stress Using Ultra Short-Term ECG Signals. AB - BACKGROUND: Stress recognition using electrocardiogram (ECG) signals requires the intractable long-term heart rate variability (HRV) parameter extraction process. This study proposes a novel deep learning framework to recognize the stressful states, the Deep ECGNet, using ultra short-term raw ECG signals without any feature engineering methods. METHODS: The Deep ECGNet was developed through various experiments and analysis of ECG waveforms. We proposed the optimal recurrent and convolutional neural networks architecture, and also the optimal convolution filter length (related to the P, Q, R, S, and T wave durations of ECG) and pooling length (related to the heart beat period) based on the optimization experiments and analysis on the waveform characteristics of ECG signals. The experiments were also conducted with conventional methods using HRV parameters and frequency features as a benchmark test. The data used in this study were obtained from Kwangwoon University in Korea (13 subjects, Case 1) and KU Leuven University in Belgium (9 subjects, Case 2). Experiments were designed according to various experimental protocols to elicit stressful conditions. RESULTS: The proposed framework to recognize stress conditions, the Deep ECGNet, outperformed the conventional approaches with the highest accuracy of 87.39% for Case 1 and 73.96% for Case 2, respectively, that is, 16.22% and 10.98% improvements compared with those of the conventional HRV method. CONCLUSIONS: We proposed an optimal deep learning architecture and its parameters for stress recognition, and the theoretical consideration on how to design the deep learning structure based on the periodic patterns of the raw ECG data. Experimental results in this study have proved that the proposed deep learning model, the Deep ECGNet, is an optimal structure to recognize the stress conditions using ultra short-term ECG data. PMID- 29420126 TI - Low-Dose Radiation Promotes Dendritic Cell Migration and IL-12 Production via the ATM/NF-KappaB Pathway. AB - For dendritic cells (DCs) to initiate an immune response, their ability to migrate and to produce interleukin-12 (IL-12) is crucial. It has been previously shown that low-dose radiation (LDR) promoted IL-12 production by DCs, resulting in increased DC activity that contributed to LDR hormesis in the immune system. However, the molecular mechanism of LDR-induced IL-12 production, as well as the effect of LDR on DC migration capacity require further elucidation. Using the JAWSII immortalized mouse dendritic cell line, we showed that in vitro X-ray irradiation (0.2 Gy) of DCs significantly increased DC migration and IL-12 production, and upregulated CCR7. The neutralizing antibody against CCR7 has been shown to abolish LDR-enhanced DC migration, demonstrating that CCR7 mediates LDR promoting DC migration. We identified nuclear factor kappaB (NF-kappaB) as the central signaling pathway that mediated LDR-enhanced expression of IL-12 and CCR7 based on findings that 0.2 Gy X-ray irradiation activated NF-kappaB, showing increased nuclear p65 translocation and NF-kappaB DNA-binding activity, while an NF-kappaB inhibitor blocked LDR-enhanced expression of IL-12 and CCR7, as well as DC migration. Finally, we demonstrated that 0.2 Gy X-ray irradiation promoted ATM phosphorylation and reactive oxygen species generation; however, only the ATM inhibitor abolished the LDR-induced NF-kappaB-mediated expression of IL-12 and CCR7. Altogether, our data show that exposure to LDR resulted in a hormetic effect on DCs regarding CCR7-mediated migration and IL-12 production by activating the ATM/NF-kappaB pathway. PMID- 29420127 TI - Two-stage approach based on zone and dose findings for two-agent combination Phase I/II trials. AB - In Phase I/II trials for a combination therapy of two agents, we ideally want to explore as many dose combinations as possible with limited sample size in Phase I and to reduce the number of untried dose combinations before moving to Phase II. Efficient collection of toxicity data in Phase I would eventually improve the accuracy of optimal dose combination identification in Phase II. In this paper, we develop a novel dose-finding method based on efficacy and toxicity outcomes for two-agent combination Phase I/II trials. We propose a "zone-finding stage" that determines the most admissible toxicity zone on the dose combination matrix and subsequently select the dose combination allocated to the next patient from that zone in Phase I. Upon completion of this zone-finding stage, we allocate the next patient to the dose combination determined by adaptive randomization of the admissible toxicity and efficacy dose combinations in Phase II. Simulation studies demonstrated the utility of the proposed zone-finding stage and proved that the operating characteristic of the proposed method was no worse than the existing method. The sensitivity of the proposed method, as well as the operating characteristic of this method when the efficacy outcome is delayed, was also examined. PMID- 29420124 TI - Embryonic skin development and repair. AB - Fetal cutaneous wounds have the unique ability to completely regenerate wounded skin and heal without scarring. However, adult cutaneous wounds heal via a fibroproliferative response which results in the formation of a scar. Understanding the mechanism(s) of scarless wound healing leads to enormous clinical potential in facilitating an environment conducive to scarless healing in adult cutaneous wounds. This article reviews the embryonic development of the skin and outlines the structural and functional differences in adult and fetal wound healing phenotypes. A review of current developments made towards applying this clinical knowledge to promote scarless healing in adult wounds is addressed. PMID- 29420129 TI - Combined Application of Glutamate Transporter Inhibitors and Hypothermia Discriminates Principal Constituent Processes Involved in Glutamate Homo- and Heteroexchange in Brain Nerve Terminals. AB - Deep and profound hypothermia is successfully practiced in the prevention of ischemic stroke consequences and aortic arch cardiac surgery accompanied by reduction of cerebral circulation. Hypothermia is a current neuroprotection standard in hypoxic/ischemic encephalopathy. Drug-hypothermia administration is proposed as a new approach in pharmacotherapy for neonatal seizures. Also, hypothermia is useful as neuroprotective approach in long-term interplanetary space missions. We recently revealed gradual dynamics of hypothermia-induced decrease in transporter-mediated release and uptake of L-[14C]glutamate in presynaptic rat brain nerve terminals (synaptosomes), thereby confirming potent unspecific neuroprotective effect of hypothermia. Glutamate homo- and heteroexchange are significant mechanisms involved in the maintenance of the extracellular glutamate level in nerve terminals. We have analyzed whether glutamate homo- and heteroexchange in nerve terminals is temperature sensitive. In this study we showed that synaptosomal glutamate-induced L-[14C]glutamate release (homoexchange) and D-aspartate- and DL-threo-beta-hydroxyaspartate induced L-[14C]glutamate release (heteroexchange) gradually decreased from deep (27 degrees C) to profound (17 degrees C) hypothermia with dynamics similar to that of glutamate transporter reversal. Interestingly, ambient L-[14C]glutamate concentration in the nerve terminal preparations remained unaltered during hypothermia administration. Therefore, we demonstrated that glutamate homo- and heteroexchange decreased from deep to profound hypothermia thereby preventing further elevation of extracellular glutamate. Hypothermia uncovered the principal processes contributing to glutamate homo- and heteroexchange in nerve terminals and the maintenance of definite ambient glutamate concentration. Additionally, we showed that glutamate transporter reversal can be nonpathological and occurs under physiological conditions at least as a part of homo- and heteroexchange mechanisms. PMID- 29420128 TI - Effects of porcine acellular dermal matrix treatment on wound healing and scar formation: Role of Jag1 expression in epidermal stem cells. AB - Skin wound healing involves Notch/Jagged1 signaling. However, little is known how Jag1 expression level in epidermal stem cells (ESCs) contributes to wound healing and scar formation. We applied multiple cellular and molecular techniques to examine how Jag1 expression in ESCs modulates ESCs differentiation to myofibroblasts (MFB) in vitro, interpret how Jag1 expression in ESCs is involved in wound healing and scar formation in mice, and evaluate the effects of porcine acellular dermal matrix (ADM) treatment on wound healing and scar formation. We found that Jag1, Notch1 and Hes1 expression was up-regulated in the wound tissue during the period of wound healing. Furthermore, Jag1 expression level in the ESCs was positively associated with the level of differentiation to MFB. ESC specific knockout of Jag1 delayed wound healing and promoted scar formation in vivo. In addition, we reported that porcine ADM treatment after skin incision could accelerate wound closure and reduce scar formation in vivo. This effect was associated with decreased expression of MFB markers, including alpha-SMA Col-1 and Col-III in wound tissues. Finally, we confirmed that porcine ADM treatment could increase Jag1, Notch1 and Hesl expression in wound tissues. Taken together, our results suggested that ESC-specific Jag1 expression levels are critical for wound healing and scar formation, and porcine ADM treatment would be beneficial in promoting wound healing and preventing scar formation by enhancing Notch/Jagged1 signaling pathway in ESCs. PMID- 29420130 TI - Ectoparasitism by Chigger Mite Larvae (Acari: Trombiculidae) in a Wintering Population of Catharus ustulatus (Turdidae) in Southeastern Peru. AB - We document chigger mite (Acari: Trombiculidae) ectoparasitic infestation (prevalence and intensity) on a population of Catharus ustulatus (Turdidae) wintering at a site (PAD A) in southeastern Peru undergoing development for natural gas exploration. We compare prevalence (i.e., the proportion of individuals infested by chigger mites) and intensity (i.e., the average number of larvae and larvae clusters in infested individuals) at forest edge (<100 m) and interior (>100 m) from PAD A because variations in biotic (e.g., vegetation cover) and abiotic (e.g., relative humidity and temperature) factors are expected to influence chigger mite abundance. Chigger mite prevalence was 100%; all C. ustulatus captured were infested regardless of distance. The range of variation in larvae (2-72 larvae/individual) and cluster intensity (1-4 clusters/individual) did not differ between edge and interior ( P > 0.05), despite differences in herbaceous vegetation cover (UM-W = 180, n = 30, 31; P < 0.01). Ectoparasitic prevalence and intensity in long-distance migratory birds might add risks to an already hazardous journey; because ectoparasitic variation and other selective pressures experienced by individuals at each locality not only may be a cause of within-site mortality, but, by affecting the physical condition of birds, may be carried over to subsequent sites and affect reproductive success and survival. Documenting ectoparasitism at any phase of the life cycle of migrants could improve understanding of population declines of migratory birds. PMID- 29420132 TI - Tumour-associated and non-tumour-associated microbiota: Addendum. AB - In a recent study1 we reported that tissue-associated microbial Co-abundance Groups (CAGs) were differentially associated with colorectal cancer (CRC). Two of the CAGs, which we named Pathogen CAG and Prevotella CAG, were correlated with a gene expression signature indicative of a TH17 response. A TH17 response has been associated with decreased survival in patients with CRC2, and members of the Pathogen CAG such as Fusobacterium nucleatum, Escherichia coli and Bacteroides fragilis have been repeatedly reported to be associated with CRC-development. Thus we hypothesized that the abundance of these CAGs may be associated with poor survival. In this Addendum we extend our analysis of the at-surgery microbiota to microbiota profiles obtained after surgery for CRC which we analyzed in the context of survival data for patients with CRC. Surprisingly we found that high tissue-associated abundance of the previously defined Prevotella- and Pathogen CAGs at surgery was associated with longer survival. Furthermore, we detected an association of the Bacteroidetes CAG in pre-surgery faecal microbiota with stability of the microbiota after surgery. PMID- 29420131 TI - T-cell receptor excision circle levels and safety of paediatric immunization: A population-based self-controlled case series analysis. AB - T-cell receptor excision circle levels are a surrogate marker of T-cell production and immune system function. We sought to determine whether non pathological levels of infant T-cell receptor excision circles were associated with adverse events following immunization. A self-controlled case series design was applied on a sample of 231,693 children who completed newborn screening for severe combined immunodeficiency in Ontario, Canada between August 2013 and December 2015. Exposures included routinely administered pediatric vaccines up to 15 months of age. Main outcomes were combined health services utilization for recognized adverse events following immunization. 1,406,981 vaccination events were included in the final dataset. 103,007 children received the Pneu-C-13 or Men-C-C vaccine and 97,998 received the MMR vaccine at 12 months of age. 67,725 children received the varicella immunization at 15 months. Our analysis identified no association between newborn T-cell receptor excision circle levels and subsequent health services utilization events following DTa-IPV-Hib, Pneu-C 13, and Men-C-C vaccinations at 2-month (RI 0.94[95%CI 0.87-1.02]), 4-month (RI 0.82[95%CI 0.75-0.9]), 6-month (RI 0.63[95%CI 0.57-0.7]) and 12-month (RI 0.49[95%CI 0.44-0.55]). We also found no trends in health services utilization following MMR (RI 1.43[95%1.34-1.52]) or varicella (RI 1.14[95%CI 1.05-1.23]) vaccination. Our findings provide further support for the safety of pediatric vaccinations. PMID- 29420133 TI - Distribution of Antimicrobial Resistance Genes and Class 1 Integron Gene Cassette Arrays in Motile Aeromonas spp. Isolated from Goldfish (Carassius auratus). AB - Aeromonas spp. are opportunistic pathogens related to multiple infectious diseases in ornamental fishes. In the present study, the antimicrobial susceptibility, resistance genes, and integrons of 65 goldfish-borne Aeromonas spp. were evaluated. The isolates were identified as A. hydrophila (n = 30), A. veronii (n = 32), and A. punctata (n = 3) by gyrB sequencing. The antimicrobial susceptibility testing of the isolates designated that most of the isolates were resistant to amoxicillin (100.00%), nalidixic acid (100.00%), ampicillin (98.46%), tetracycline (92.31%), rifampicin (86.15%), and cephalothin (61.54%) and each of the isolates showed multiple antimicrobial resistance phenotype (resistant to >=3 classes of antimicrobials). PCR amplification of antimicrobial resistance genes revealed that the plasmid-mediated quinolone resistance gene, qnrS, was the most prevalent (73.85%) among the isolates. The other antimicrobial resistance genes were detected in the following proportions: qnrB (26.15%), aac(6')-Ib-cr (4.60%), tetA (16.92%), tetE (21.54%), aac(6')-Ib (29.23%), and aphAI-IAB (7.69%). The IntI gene was found in 64.62% isolates, and four class 1 integron gene cassette profiles (incomplete dfrA1, catB3-aadA1, dfrA1-orfC, and qacE2-orfD) were identified. These data suggest that goldfish-borne Aeromonas spp. serve as a reservoir of antimicrobial resistance genes and class 1 integrons. PMID- 29420134 TI - Comparison of immunogenicity between hepatitis B vaccines with different dosages and schedules among healthy young adults in China: A 2-year follow-up study. AB - Immunogenicity of hepatitis B vaccine between 20 MUg with 3-dose schedule and 60 MUg with 2-dose regimens was compared 2 years after primary immunization. A total of 353 healthy adults aged 18-25 years were enrolled in the study and randomly assigned (1: 1: 1) into 3 vaccine groups: A (20 MUg, 0-1-6 month), B (60 MUg, 0-1 month) and C (60 MUg, 0-2 month). Serum samples were collected at 1 month after a series vaccination and 12 months, 24 months after the first-dose. The GMC level of anti-HBs antibody was measured using Chemiluminescent Microparticle ImmunoAssay (CMIA). There were 59, 45 and 55 vaccinees available to follow-up with 2 year later in vaccine groups A, B and C, respectively. No significant differences existed in sex ratio, age and body mass index (BMI) among vaccinees at month 24 and the corresponding participants at baseline in each group (P > 0.05). The seroprotection rates in group A, B and C were 98.31%, 88.37% and 85.19%, respectively (P = 0.014), reflecting the fact that the rate of group A was significantly higher than that in group C (P = 0.026). Also, the GMC level of anti-HBs antibody in group A was significantly higher than those of other two groups (427.46 mIU/ml vs. 89.74 mIU/ml, 89.80 mIU/ml, respectively; all P < 0.01). This data suggested that the standard 20 MUg (0-1-6 month) regimen of hepatitis B vaccine should be recommended as a priority on the premise of complete compliance in adults. PMID- 29420136 TI - Preparation, Purification, and Identification of a Monoclonal Antibody Against the C-Terminal Domain of Semaphorin3F. AB - Class three semaphorins were originally identified as mediators of axon guidance, which repelled axons and collapsed growth cones. As a member of class three semaphorins, semaphorin3F (Sema3F) has been found to have similar effects on tumor cells and endothelial cells and also is implicated in the signaling of tumor metastasis by forming a complex with neuropilins and plexins. In this study, our laboratory produced a monoclonal antibody against the C-terminal domain of Sema3F (Sema3Fc mAb) using the hybridoma method, expecting to explore the potential role of the antibody and its application in the detection of Sema3F. The capture enzyme-linked immunosorbent assay (ELISA) method indicated that mAb belonged to the IgM subclass and purified Sema3Fc mAb had a titer of 5.12 * 105 against Sema3Fc by indirect ELISA. In addition, results showed that the Sema3Fc mAb could be applied in such experiments as Western blotting, flow cytometry, immunofluorescence, and immunocytochemical staining. It indicates the Sema3Fc mAb is available in the detection of Sema3F with specificity and will help further study the role and mechanism of Sema3F among tumor cells. PMID- 29420135 TI - Impaired Sleep Mediates the Negative Effects of Training Load on Subjective Well Being in Female Youth Athletes. AB - BACKGROUND: Although increased training load (TL) and impaired sleep are associated with decreases in subjective well-being in adult athletes, these relationships among female youth athletes are unclear. It is unknown whether the effects of sleep and TL on well-being are independent or whether alterations in sleep mediate the effects of TL on subjective well-being. HYPOTHESIS: Sleep and TL exert independent effects on subjective well-being among youth athletes, although alterations in sleep mediate a significant portion of the effect of TL on well-being in female youth athletes. STUDY DESIGN: Prospective cohort study. LEVEL OF EVIDENCE: Level 4. METHODS: A total of 65 female soccer athletes (age range, 13-18 years) were monitored for 1 year. Daily TL was determined by session rating of perceived exertion and converted to z-scores. Every morning, participants recorded sleep duration in hours and rated stress, mood, fatigue, and soreness on a scale from -3 to +3 (worst to best). Linear mixed-effects models and mediation analysis were used to evaluate the independent effects of TL and sleep on well-being. RESULTS: Average sleep duration was 7.9 +/- 1.4 hours during the study period. In the multivariable model, TL and sleep duration were independently associated with fatigue (TL: beta = -0.19, P < 0.001; sleep: beta = 0.15, P < 0.001), mood (TL: beta = -0.030, P = 0.014; sleep: beta = 0.13, P < 0.001), stress (TL: beta = -0.055, P = 0.001; sleep: beta = 0.13, P < 0.001), and soreness (TL: beta = -0.31, P < 0.001; sleep: beta = 0.022, P = 0.042). Sleep duration mediated a significant portion of the effect of TL on mood (26.8%, P < 0.001), fatigue (12.6%, P < 0.001), and stress (24.5%, P < 0.001). CONCLUSION: Among female youth athletes, decreased sleep duration and increased TL are independently associated with impairments of subjective well-being. In addition, decreased sleep mediates a significant portion of the negative effect of increases in TL on subjective well-being. CLINICAL RELEVANCE: Monitoring and promoting sleep among female adolescent athletes may significantly improve subjective well-being, particularly during periods of increased TL. PMID- 29420137 TI - In Situ Localization of Ribosomal Sites in Peckoltia and Ancistomus (Loricariidae: Hypostominae) from the Amazon Basin. AB - Loricariidae is a diverse group of fish from the neotropical region, occupying a wide variety of freshwater environments. Cytogenetic data have brought important insights into Loricariidae diversity because they help validate undescribed species as well as our understanding of inter- and intraspecific diversity. However, conventional cytogenetic approaches are limited in their ability to detect variability in some lineages, as seen in the Peckoltia clade, owing to their apparent conserved karyotype. Thus, the aim of this work was to map 5S and 18S ribosomal (rDNA) sites in five species of Peckoltia and one species of Ancistomus from the Amazon basin, and discusses the mechanisms of organization and diversification of these clusters. The species analyzed were found to have 2n = 52 and share KF = 38 m-sm +14st-a chromosomes, except Peckoltia vittata with KF = 34 m-sm +18st-a. Extensive variations in the number and location of 5S and 18S rDNA sites were observed among species. These data indicate that inversions are not the most important events in karyotype evolution in this group, and should prove useful in identifying the species studied here. In addition to inversions, transpositions are important evolutionary events that are involved at least in rDNA clusters spreading in Peckoltia and probably in other species of Hypostominae. PMID- 29420138 TI - A Mixed-Methods Study on the Barriers and Facilitators of Telemedicine for Newborn Resuscitation. AB - BACKGROUND: Teleneonatology may improve the quality of high-risk newborn resuscitations performed by general providers in community settings. Variables that affect teleneonatology utilization have not been identified. INTRODUCTION: The objective of our mixed-methods study was to understand the barriers and facilitators experienced by local care providers who receive teleneonatology services. MATERIALS AND METHODS: In October 2015, an electronic survey was sent to 349 teleneonatology participants at 6 community hospitals to assess user satisfaction, technology usability and acceptability, and impact on patient care. From December 2015 to June 2016, 49 participants were involved in focus groups and individual interviews to better understand barriers and facilitators of teleneonatology implementation. Qualitative data were analyzed using a thematic approach. RESULTS: Survey response rate was 31.8% (N = 111). Of 93 survey respondents, 88 (94.6%) agreed that teleneonatology was needed at their hospitals, and of 52 participants, 50 (96.2%) believed that teleneonatology consults were helpful. We identified multiple facilitators and barriers to program implementation in education and training, process and work flow, communication, and technology. DISCUSSION: Local care teams believed that teleneonatology was valuable for connection to a remote neonatologist. Successful program implementation may be facilitated by communicating the value of teleneonatology, engaging local stakeholders in program training and education, maintaining supportive professional relationships, and designing simple, highly reliable clinical work flows. CONCLUSIONS: Teleneonatology is viewed as an innovative, valuable service by local care teams. The identified barriers and facilitators to program use should be considered when implementing a teleneonatology program. PMID- 29420140 TI - Participatory approaches to workplace safety management: bridging the gap between behavioral safety and participatory ergonomics. AB - Many researchers and practitioners argue the importance of end-user involvement in workplace safety management, but the research literature and practices remain fractured across orientations. The primary aim of this article is to bridge the gap between two major participatory safety management approaches: behavioral safety and participatory ergonomics. First, an overview and brief history of participative management is presented to provide context for its application to workplace safety. Next, behavioral safety and participatory ergonomics are separately examined in terms of their origins and core elements. Finally, based on this examination, unifying elements between behavioral safety and participatory ergonomics will be presented to provide a comprehensive account of participatory safety management. PMID- 29420139 TI - An inexpensive sensor for noise. AB - Noise is a pervasive workplace hazard that varies spatially and temporally. The cost of direct-reading instruments for noise hampers their use in a network. The objectives for this work were to: (1) develop an inexpensive noise sensor (<$100) that measures A-weighted sound pressure levels within +/-2 dBA of a Type 2 sound level meter (SLM; ~$1,800); and (2) evaluate 50 noise sensors for use in an inexpensive sensor network. The inexpensive noise sensor consists of an electret condenser microphone, an amplifier circuit, and a microcontroller with a small form factor (28 mm by 47 mm by 9 mm) than can be operated as a stand-alone unit. Laboratory tests were conducted to evaluate 50 of the new sensors at 5 sound levels: (1) ambient sound in a quiet office; (2) 3 pink noise test signals from 65-85 dBA in 10 dBA increments; and (3) 94 dBA using a SLM calibrator. Ninety four percent of the noise sensors (n = 46) were within +/-2 dBA of the SLM for sound levels from 65-94 dBA. As sound level increased, bias decreased, ranging from 18.3% in the quiet office to 0.48% at 94 dBA. Overall bias of the sensors was 0.83% across the 75 dBA to 94 dBA range. These sensors are available for a variety of uses and can be customized for many applications, including incorporation into a stationary sensor network for continuous monitoring of noise in manufacturing environments. PMID- 29420141 TI - Residential inter-zonal ventilation rates for exposure modeling. AB - Residential inter-zonal (e.g., between rooms) ventilation is comprised of fresh air infiltration in and exfiltration out of the whole house plus the "fresh" air that is entering (and exiting) the room of interest from other rooms or areas within the house. Clearly, the inter-zone ventilation rate in any room of interest will be greater than the infiltration/exfiltration ventilation rate of outdoor air for the whole house. The purpose of this study is to determine how much greater the inter-zonal ventilation rate is in typical U.S. residences compared to the whole house ventilation rate from outdoor air. The data for this statistical analysis came from HouseDB, a 1995 EPA database of residential ventilation rates. Analytical results indicate that a lognormal distribution provides the best fit to the data. Lognormal probability distribution functions (PDFs) are provided for various inter-zonal ventilation rates for comparison to the PDF for the whole house ventilation rates. All ventilation rates are expressed as air change rates per hour (ACH). These PDFs can be used as inputs to exposure models. This analysis suggests that if one were performing a deterministic analysis for unknown housing stocks in the U.S., a default mean and median ACH values of 0.4/hr and 0.3/hr, respectively, for whole house ventilation would be appropriate; and 0.7/hr and 0.6/hr, respectively, for inter-zonal ventilation. PMID- 29420142 TI - The Surprise Question and Identification of Palliative Care Needs among Hospitalized Patients with Advanced Hematologic or Solid Malignancies. AB - BACKGROUND: Little is known about quality of life (QOL), depression, and end-of life (EOL) outcomes among hospitalized patients with advanced cancer. OBJECTIVE: To assess whether the surprise question identifies inpatients with advanced cancer likely to have unmet palliative care needs. DESIGN: Prospective cohort study and long-term follow-up. SETTING/SUBJECTS: From 2008 to 2010, we enrolled 150 inpatients at Duke University with stage III/IV solid tumors or lymphoma/acute leukemia and whose physician would not be surprised if they died in less than one year. MEASUREMENTS: We assessed QOL (FACT-G), mood (brief CES D), and EOL outcomes. RESULTS: Mean FACT-G score was quite low (66.9; SD 11). Forty-five patients (30%) had a brief CES-D score of >=4 indicating a high likelihood of depression. In multivariate analyses, better QOL was associated with less depression (OR 0.91, p < 0.0001), controlling for tumor type, education, and spiritual well-being. Physicians correctly estimated death within one year in 101 (69%) cases, yet only 37 patients (25%) used hospice, and 4 (2.7%) received a palliative care consult; 89 (60.5%) had a do-not-resuscitate order, and 63 (43%) died in the hospital. CONCLUSIONS: The surprise question identifies inpatients with advanced solid or hematologic cancers having poor QOL and frequent depressive symptoms. Although physicians expected death within a year, EOL quality outcomes were poor. Hospitalized patients with advanced cancer may benefit from palliative care interventions to improve mood, QOL, and EOL care, and the surprise question is a practical method to identify those with unmet needs. PMID- 29420143 TI - Complications of Intravitreous Injections in Patients with Diabetes. AB - Intravitreous injections are presently the second most frequently performed ophthalmic procedure and the most common vitreoretinal procedure. In diabetic patients, intravitreous injections are frequently performed for the treatment of center-involved diabetic macular edema, proliferative diabetic retinopathy, or other co-existing retinal vascular disease. Diabetic patients may be at higher risk of adverse events compared to non-diabetic individuals, given frequent systemic comorbidities, such as cardiovascular and renal disease and increased susceptibility to infection. This review highlights the potential complications and safety considerations in intravitreous injections in patients with diabetes. PMID- 29420144 TI - Complications of Optic Nerve Sheath Fenestration as a Treatment for Idiopathic Intracranial Hypertension. AB - There are a number of surgical options for treatment of idiopathic intracranial hypertension (IIH) when it is refractory to medical treatment and weight loss. Optic nerve sheath fenestration (ONSF) is one of these options. Use of this procedure varies among centers due to experience with the procedure and concern for associated complications that can result in severe loss of vision. This review summarizes the literature concerning post-surgical complications of ONSF for IIH. PMID- 29420145 TI - Body map of regional vs. whole body sweating rate and sweat electrolyte concentrations in men and women during moderate exercise-heat stress. AB - This study determined the relations between regional (REG) and whole body (WB) sweating rate (RSR and WBSR, respectively) as well as REG and WB sweat Na+ concentration ([Na+]) during exercise. Twenty-six recreational athletes (17 men, 9 women) cycled for 90 min while WB sweat [Na+] was measured using the washdown technique. RSR and REG sweat [Na+] were measured from nine regions using absorbent patches. RSR and REG sweat [Na+] from all regions were significantly ( P < 0.05) correlated with WBSR ( r = 0.58-0.83) and WB sweat [Na+] ( r = 0.74 0.88), respectively. However, the slope and y-intercept of the regression lines for most models were significantly different than 1 and 0, respectively. The coefficients of determination ( r2) were 0.44-0.69 for RSR predicting WBSR [best predictors: dorsal forearm ( r2 = 0.62) and triceps ( r2 = 0.69)] and 0.55-0.77 for REG predicting WB sweat [Na+] [best predictors: ventral forearm ( r2 = 0.73) and thigh ( r2 = 0.77)]. There was a significant ( P < 0.05) effect of day-to-day variability on the regression model predicting WBSR from RSR at most regions but no effect on predictions of WB sweat [Na+] from REG. Results suggest that REG cannot be used as a direct surrogate for WB sweating responses. Nonetheless, the use of regression equations to predict WB sweat [Na+] from REG can provide an estimation of WB sweat [Na+] with an acceptable level of accuracy, especially using the forearm or thigh. However, the best practice for measuring WBSR remains conventional WB mass balance calculations since prediction of WBSR from RSR using absorbent patches does not meet the accuracy or reliability required to inform fluid intake recommendations. NEW & NOTEWORTHY This study developed a body map of regional sweating rate and regional (REG) sweat electrolyte concentrations and determined the effect of within-subject (bilateral and day-to-day) and between subject (sex) factors on the relations between REG and the whole body (WB). Regression equations can be used to predict WB sweat Na+ concentration from REG, especially using the forearm or thigh. However, prediction of WB sweating rate from REG sweating rate using absorbent patches does not reach the accuracy or reliability required to inform fluid intake recommendations. PMID- 29420146 TI - Methylene blue counteracts cyanide cardiotoxicity: cellular mechanisms. AB - In adult left ventricular mouse myocytes, exposure to sodium cyanide (NaCN) in the presence of glucose dose-dependently reduced contraction amplitude, with ~80% of maximal inhibitory effect attained at 100 uM. NaCN (100 uM) exposure for 10 min significantly decreased contraction and intracellular Ca2+ concentration ([Ca2+]i) transient amplitudes, systolic but not diastolic [Ca2+]i, and maximal L type Ca2+ current ( ICa) amplitude, indicating acute alteration of [Ca2+]i homeostasis largely accounted for the observed excitation-contraction abnormalities. In addition, NaCN depolarized resting membrane potential ( Em), reduced action potential (AP) amplitude, prolonged AP duration at 50% (APD50) and 90% repolarization (APD90), and suppressed depolarization-activated K+ currents but had no effect on Na+-Ca2+ exchange current ( INaCa). NaCN did not affect cellular adenosine triphosphate levels but depolarized mitochondrial membrane potential (DeltaPsim) and increased superoxide (O2.-) levels. Methylene blue (MB; 20 ug/ml) added 3 min after NaCN restored contraction and [Ca2+]i transient amplitudes, systolic [Ca2+]i, Em, AP amplitude, APD50, APD90, ICa, depolarization activated K+ currents, DeltaPsim, and O2.- levels toward normal. We conclude that MB reversed NaCN-induced cardiotoxicity by preserving intracellular Ca2+ homeostasis and excitation-contraction coupling ( ICa), minimizing risks of arrhythmias ( Em, AP configuration, and depolarization-activated K+ currents), and reducing O2.- levels. NEW & NOTEWORTHY Cyanide poisoning due to industrial exposure, smoke inhalation, and bioterrorism manifests as cardiogenic shock and requires rapidly effective antidote. In the early stage of cyanide exposure, adenosine triphosphate levels are normal but myocyte contractility is reduced, largely due to alterations in Ca2+ homeostasis because of changes in oxidation reduction environment of ion channels. Methylene blue, a drug approved by the U.S. Food and Drug Administration, ameliorates cyanide toxicity by normalizing oxidation-reduction state and Ca2+ channel function. PMID- 29420148 TI - Vo2peak is an acceptable estimate of cardiorespiratory fitness but not Vo2max. PMID- 29420149 TI - Muscle glycogen depletion does not alter segmental extracellular and intracellular water distribution measured using bioimpedance spectroscopy. AB - Although each gram of glycogen is well known to bind 2.7-4.0 g of water, no studies have been conducted on the effect of muscle glycogen depletion on body water distribution. We investigated changes in extracellular and intracellular water (ECW and ICW) distribution in each body segment in muscle glycogen depletion and glycogen-recovery condition using segmental bioimpedance spectroscopy technique (BIS). Twelve male subjects consumed 7.0 g/kg body mass of indigestible (glycogen-depleted group) or digestible (glycogen-recovered group) carbohydrate for 24 h after a glycogen-depletion cycling exercise. Muscle glycogen content using 13C-magnetic resonance spectroscopy, blood hydration status, body composition, and ECW and ICW content of the arm, trunk, and leg using BIS were measured. Muscle glycogen content at the thigh muscles decreased immediately after exercise (glycogen-depleted group, 71.6 +/- 12.1 to 25.5 +/- 10.1 mmol/kg wet wt; glycogen-recovered group, 76.2 +/- 16.4 to 28.1 +/- 16.8 mmol/kg wet wt) and recovered in the glycogen-recovered group (72.7 +/- 21.2 mmol/kg wet wt) but not in the glycogen-depleted group (33.2 +/- 12.6 mmol/kg wet wt) 24 h postexercise. Fat-free mass decreased in the glycogen-depleted group ( P < 0.05) but not in the glycogen-recovered group 24 h postexercise. However, no changes were observed in ECW and ICW content at the leg in both groups. Our results suggested that glycogen depletion per se does not alter body water distribution as estimated via BIS. This information is valuable in assessing body composition using BIS in athletes who show variable glycogen status during training and recovery. NEW & NOTEWORTHY Segmental bioimpedance spectroscopy analysis reveals the effect of muscle glycogen depletion on body segmental water distribution in controlled conditions. Despite the significant difference in the muscle glycogen levels at the leg, no difference was observed in body resistance and the corresponding water content of the extracellular and intracellular compartments. PMID- 29420147 TI - Exercise intolerance in Type 2 diabetes: is there a cardiovascular contribution? AB - Physical activity is critically important for Type 2 diabetes management, yet adherence levels are poor. This might be partly due to disproportionate exercise intolerance. Submaximal exercise tolerance is highly sensitive to muscle oxygenation; impairments in exercising muscle oxygen delivery may contribute to exercise intolerance in Type 2 diabetes since there is considerable evidence for the existence of both cardiac and peripheral vascular dysfunction. While uncompromised cardiac output during submaximal exercise is consistently observed in Type 2 diabetes, it remains to be determined whether an elevated cardiac sympathetic afferent reflex could sympathetically restrain exercising muscle blood flow. Furthermore, while deficits in endothelial function are common in Type 2 diabetes and are often cited as impairing exercising muscle oxygen delivery, no direct evidence in exercise exists, and there are several other vasoregulatory mechanisms whose dysfunction could contribute. Finally, while there are findings of impaired oxygen delivery, conflicting evidence also exists. A definitive conclusion that Type 2 diabetes compromises exercising muscle oxygen delivery remains premature. We review these potentially dysfunctional mechanisms in terms of how they could impair oxygen delivery in exercise, evaluate the current literature on whether an oxygen delivery deficit is actually manifest, and correspondingly identify key directions for future research. PMID- 29420150 TI - Adaptations in muscle oxidative capacity, fiber size, and oxygen supply capacity after repeated-sprint training in hypoxia combined with chronic hypoxic exposure. AB - In this study, we investigate adaptations in muscle oxidative capacity, fiber size and oxygen supply capacity in team-sport athletes after six repeated-sprint sessions in normobaric hypoxia or normoxia combined with 14 days of chronic normobaric hypoxic exposure. Lowland elite field hockey players resided at simulated altitude (>=14 h/day at 2,800-3,000 m) and performed regular training plus six repeated-sprint sessions in normobaric hypoxia (3,000 m; LHTLH; n = 6) or normoxia (0 m; LHTL; n = 6) or lived at sea level with regular training only (LLTL; n = 6). Muscle biopsies were obtained from the m. vastus lateralis before (pre), immediately after (post-1), and 3 wk after the intervention (post-2). Changes over time between groups were compared, including likelihood of the effect size (ES). Succinate dehydrogenase activity in LHTLH largely increased from pre to post-1 (~35%), likely more than LHTL and LLTL (ESs = large-very large), and remained elevated in LHTLH at post-2 (~12%) vs. LHTL (ESs = moderate large). Fiber cross-sectional area remained fairly similar in LHTLH from pre to post-1 and post-2 but was increased at post-1 and post-2 in LHTL and LLTL (ES = moderate-large). A unique observation was that LHTLH and LHTL, but not LLTL, improved their combination of fiber size and oxidative capacity. Small-to moderate differences in oxygen supply capacity (i.e., myoglobin and capillarization) were observed between groups. In conclusion, elite team-sport athletes substantially increased their skeletal muscle oxidative capacity, while maintaining fiber size, after only 14 days of chronic hypoxic residence combined with six repeated-sprint training sessions in hypoxia. NEW & NOTEWORTHY Our novel findings show that elite team-sport athletes were able to substantially increase the skeletal muscle oxidative capacity in type I and II fibers (+37 and +32%, respectively), while maintaining fiber size after only 14 days of chronic hypoxic residence combined with six repeated-sprint sessions in hypoxia. This increase in oxidative capacity was superior to groups performing chronic hypoxic residence with repeated sprints in normoxia and residence at sea level with regular training only. PMID- 29420151 TI - Altered Achilles tendon function during walking in people with diabetic neuropathy: implications for metabolic energy saving. AB - The Achilles tendon (AT) has the capacity to store and release elastic energy during walking, contributing to metabolic energy savings. In diabetes patients, it is hypothesized that a stiffer Achilles tendon may reduce the capacity for energy saving through this mechanism, thereby contributing to an increased metabolic cost of walking (CoW). The aim of this study was to investigate the effects of diabetes and diabetic peripheral neuropathy (DPN) on the Achilles tendon and plantarflexor muscle-tendon unit behavior during walking. Twenty-three nondiabetic controls (Ctrl); 20 diabetic patients without peripheral neuropathy (DM), and 13 patients with moderate/severe DPN underwent gait analysis using a motion analysis system, force plates, and ultrasound measurements of the gastrocnemius muscle, using a muscle model to determine Achilles tendon and muscle-tendon length changes. During walking, the DM and particularly the DPN group displayed significantly less Achilles tendon elongation (Ctrl: 1.81; DM: 1.66; and DPN: 1.54 cm), higher tendon stiffness (Ctrl: 210; DM: 231; and DPN: 240 N/mm), and higher tendon hysteresis (Ctrl: 18; DM: 21; and DPN: 24%) compared with controls. The muscle fascicles of the gastrocnemius underwent very small length changes in all groups during walking (~0.43 cm), with the smallest length changes in the DPN group. Achilles tendon forces were significantly lower in the diabetes groups compared with controls (Ctrl: 2666; DM: 2609; and DPN: 2150 N). The results strongly point toward the reduced energy saving capacity of the Achilles tendon during walking in diabetes patients as an important factor contributing to the increased metabolic CoW in these patients. NEW & NOTEWORTHY From measurements taken during walking we observed that the Achilles tendon in people with diabetes and particularly people with diabetic peripheral neuropathy was stiffer, was less elongated, and was subject to lower forces compared with controls without diabetes. These altered properties of the Achilles tendon in people with diabetes reduce the tendon's energy saving capacity and contribute toward the higher metabolic energy cost of walking in these patients. PMID- 29420152 TI - Ischemic conditioning increases strength and volitional activation of paretic muscle in chronic stroke: a pilot study. AB - Ischemic conditioning (IC) on the arm or leg has emerged as an intervention to improve strength and performance in healthy populations, but the effects on neurological populations are unknown. The purpose of this study was to quantify the effects of a single session of IC on knee extensor strength and muscle activation in chronic stroke survivors. Maximal knee extensor torque measurements and surface EMG were quantified in 10 chronic stroke survivors (>1 yr poststroke) with hemiparesis before and after a single session of IC or sham on the paretic leg. IC consisted of 5 min of compression with a proximal thigh cuff (inflation pressure = 225 mmHg for IC or 25 mmHg for sham) followed by 5 min of rest. This was repeated five times. Maximal knee extensor strength, EMG magnitude, and motor unit firing behavior were measured before and immediately after IC or sham. IC increased paretic leg strength by 10.6 +/- 8.5 Nm, whereas no difference was observed in the sham group (change in sham = 1.3 +/- 2.9 Nm, P = 0.001 IC vs. sham). IC-induced increases in strength were accompanied by a 31 +/- 15% increase in the magnitude of muscle EMG during maximal contractions and a 5% decrease in motor unit recruitment thresholds during submaximal contractions. Individuals who had the most asymmetry in strength between their paretic and nonparetic legs had the largest increases in strength ( r2 = 0.54). This study provides evidence that a single session of IC can increase strength through improved muscle activation in chronic stroke survivors. NEW & NOTEWORTHY Present rehabilitation strategies for chronic stroke survivors do not optimally activate paretic muscle, and this limits potential strength gains. Ischemic conditioning of a limb has emerged as an effective strategy to improve muscle performance in healthy individuals but has never been tested in neurological populations. In this study, we show that ischemic conditioning on the paretic leg of chronic stroke survivors can increase leg strength and muscle activation while reducing motor unit recruitment thresholds. PMID- 29420153 TI - Individualized estimation of human core body temperature using noninvasive measurements. AB - A rising core body temperature (Tc) during strenuous physical activity is a leading indicator of heat-injury risk. Hence, a system that can estimate Tc in real time and provide early warning of an impending temperature rise may enable proactive interventions to reduce the risk of heat injuries. However, real-time field assessment of Tc requires impractical invasive technologies. To address this problem, we developed a mathematical model that describes the relationships between Tc and noninvasive measurements of an individual's physical activity, heart rate, and skin temperature, and two environmental variables (ambient temperature and relative humidity). A Kalman filter adapts the model parameters to each individual and provides real-time personalized Tc estimates. Using data from three distinct studies, comprising 166 subjects who performed treadmill and cycle ergometer tasks under different experimental conditions, we assessed model performance via the root mean squared error (RMSE). The individualized model yielded an overall average RMSE of 0.33 (SD = 0.18) degrees C, allowing us to reach the same conclusions in each study as those obtained using the Tc measurements. Furthermore, for 22 unique subjects whose Tc exceeded 38.5 degrees C, a potential lower Tc limit of clinical relevance, the average RMSE decreased to 0.25 (SD = 0.20) degrees C. Importantly, these results remained robust in the presence of simulated real-world operational conditions, yielding no more than 16% worse RMSEs when measurements were missing (40%) or laden with added noise. Hence, the individualized model provides a practical means to develop an early warning system for reducing heat-injury risk. NEW & NOTEWORTHY A model that uses an individual's noninvasive measurements and environmental variables can continually "learn" the individual's heat-stress response by automatically adapting the model parameters on the fly to provide real-time individualized core body temperature estimates. This individualized model can replace impractical invasive sensors, serving as a practical and effective surrogate for core temperature monitoring. PMID- 29420154 TI - Hip position and sex differences in motor unit firing patterns of the vastus medialis and vastus medialis oblique in healthy individuals. AB - Weakness of the vastus medialis oblique (VMO) has been proposed to explain the high prevalence of knee pain in female subjects. Clinicians commonly use exercises in an attempt to preferentially activate the VMO. Recently, our group found evidence to support clinical theory that the VMO is neurologically distinct from the vastus medialis (VM). However, the ability to voluntarily activate these muscle subsections is still disputed. The aim of this study was to determine if VM and VMO activation varies between sexes and if control of the two muscles is different between rehabilitation exercises. Thirteen men and 13 women performed isometric straight leg raises in two hip positions, neutral hip rotation and 30 degrees lateral hip rotation. Bipolar intramuscular fine-wire electrodes were inserted into the VM and VMO to obtain motor unit recruitment thresholds and initial firing rates at recruitment. Linear mixed models and Tukey post hoc tests were used to assess significant differences in 654 motor units. Women demonstrated faster motor unit firing rate at recruitment, 1.18 +/- 0.56 Hz higher than men. Motor units fired 0.47 +/- 0.19 Hz faster during neutral hip rotation compared with lateral hip rotation. The VMO motor units were recruited 2.92 +/- 1.28% earlier than the VM. All motor units were recruited 3.74 +/- 1.27% earlier during neutral hip rotation than lateral hip rotation. Thus the VM and the VMO can be activated differentially, and their motor unit recruitment properties are affected by sex and hip position. NEW & NOTEWORTHY This is the first study to reveal differential activation of the vastus medialis oblique from the vastus medialis in clinical exercise protocols. Our research group used fine wire electrodes to examine EMG signals of the vastus medialis oblique and vastus medialis to avoid possible cross talk. We also consider the effect of sex on motor unit firing patterns because of higher prevalence of knee pain in women, and yet few studies evaluating the sex differences in neuromuscular control. PMID- 29420155 TI - Surface electromyographic amplitude does not identify differences in neural drive to synergistic muscles. AB - Surface electromyographic (EMG) signal amplitude is typically used to compare the neural drive to muscles. We experimentally investigated this association by studying the motor unit (MU) behavior and action potentials in the vastus medialis (VM) and vastus lateralis (VL) muscles. Eighteen participants performed isometric knee extensions at four target torques [10, 30, 50, and 70% of the maximum torque (MVC)] while high-density EMG signals were recorded from the VM and VL. The absolute EMG amplitude was greater for VM than VL ( P < 0.001), whereas the EMG amplitude normalized with respect to MVC was greater for VL than VM ( P < 0.04). Because differences in EMG amplitude can be due to both differences in the neural drive and in the size of the MU action potentials, we indirectly inferred the neural drives received by the two muscles by estimating the synaptic inputs received by the corresponding motor neuron pools. For this purpose, we analyzed the increase in discharge rate from recruitment to target torque for motor units matched by recruitment threshold in the two muscles. This analysis indicated that the two muscles received similar levels of neural drive. Nonetheless, the size of the MU action potentials was greater for VM than VL ( P < 0.001), and this difference explained most of the differences in EMG amplitude between the two muscles (~63% of explained variance). These results indicate that EMG amplitude, even following normalization, does not reflect the neural drive to synergistic muscles. Moreover, absolute EMG amplitude is mainly explained by the size of MU action potentials. NEW & NOTEWORTHY Electromyographic (EMG) amplitude is widely used to compare indirectly the strength of neural drive received by synergistic muscles. However, there are no studies validating this approach with motor unit data. Here, we compared between-muscles differences in surface EMG amplitude and motor unit behavior. The results clarify the limitations of surface EMG to interpret differences in neural drive between muscles. PMID- 29420157 TI - Dynamic cerebral autoregulation during cognitive task: effect of hypoxia. AB - Changes in cerebral blood flow (CBF) subsequent to alterations in the partial pressures of oxygen and carbon dioxide can modify dynamic cerebral autoregulation (CA). While cognitive activity increases CBF, the extent to which it impacts CA remains to be established. In the present study we determined whether dynamic CA would decrease during a cognitive task and whether hypoxia would further compound impairment. Fourteen young healthy subjects performed a simple Go/No-go task during normoxia and hypoxia (inspired O2 fraction = 12%), and the corresponding relationship between mean arterial pressure (MAP) and mean middle cerebral artery blood velocity (MCA Vmean) was examined. Dynamic CA and steady-state changes in MCA V in relation to changes in arterial pressure were evaluated with transfer function analysis. While MCA Vmean increased during the cognitive activity ( P < 0.001), hypoxia did not cause any additional changes ( P = 0.804 vs. normoxia). Cognitive performance was also unaffected by hypoxia (reaction time, P = 0.712; error, P = 0.653). A decrease in the very low- and low-frequency phase shift (VLF and LF; P = 0.021 and P = 0.01) and an increase in LF gain were observed ( P = 0.037) during cognitive activity, implying impaired dynamic CA. While hypoxia also increased VLF gain ( P < 0.001), it failed to cause any additional modifications in dynamic CA. Collectively, our findings suggest that dynamic CA is impaired during cognitive activity independent of altered systemic O2 availability, although we acknowledge the interpretive complications associated with additional competing, albeit undefined, inputs that could potentially distort the MAP-MCA Vmean relationship. NEW & NOTEWORTHY During normoxia, cognitive activity while increasing cerebral perfusion was shown to attenuate dynamic cerebral autoregulation (CA) yet failed to alter reaction time, thereby questioning its functional significance. No further changes were observed during hypoxia, suggesting that impaired dynamic CA occurs independently of altered systemic O2 availability. However, impaired dynamic CA may reflect a technical artifact, given the confounding influence of additional inputs that could potentially distort the mean arterial pressure-mean middle cerebral artery blood velocity relationship. PMID- 29420156 TI - Spatial persistence of reduced specific ventilation following methacholine challenge in the healthy human lung. AB - Specific ventilation imaging was used to identify regions of the healthy lung (6 supine subjects, ages 21-41 yr, 3 men) that experienced a fall in specific ventilation following inhalation of methacholine. This test was repeated 1 wk later and 3 mo later to test for spatial recurrence. Our data showed that 53% confidence interval (CI; 46%, 59%) of volume elements that constricted during one methacholine challenge did so again in another and that this quantity did not vary with time; 46% CI (28%, 64%) recurred 1 wk later, and 56% CI (51%, 61%) recurred 3 mo later. Previous constriction was a strong predictor for future constriction. Volume elements that constricted during one challenge were 7.7 CI (5.2, 10.2) times more likely than nonconstricted elements to constrict in a second challenge, regardless of whether the second episode was 1 wk [7.7 CI (2.9, 12.4)] or 3 mo [7.7 CI (4.6, 10.8)] later. Furthermore, posterior lung elements were more likely to constrict following methacholine than anterior lung elements (volume fraction 0.43 +/- 0.22 posterior vs. 0.10 +/- 0.03 anterior; P = 0.005), and basal elements that constricted were more likely than their apical counterparts to do so persistently through all three trials (volume fraction 0.14 +/- 0.04 basal vs. 0.04 +/- 0.04 apical; P = 0.003). Taken together, this evidence suggests a physiological predisposition toward constriction in some lung elements, especially those located in the posterior and basal lung when the subject is supine. NEW & NOTEWORTHY The spatial pattern of bronchoconstriction following methacholine is persistent over time in healthy individuals, in whom chronic inflammation and airway remodeling are assumed to be absent. This suggests that regional lung inflation and airway structure may play dominant roles in determining the spatial pattern of methacholine bronchoconstriction. PMID- 29420158 TI - Intermittent PTH 1-34 administration improves the marrow microenvironment and endothelium-dependent vasodilation in bone arteries of aged rats. AB - Inflammation coincides with diminished marrow function, vasodilation of blood vessels, and bone mass. Intermittent parathyroid hormone (PTH) administration independently improves marrow and vascular function, potentially impacting bone accrual. Currently, the influence of marrow and intermittent PTH administration on aged bone blood vessels has not been examined. Vasodilation of the femoral principal nutrient artery (PNA) was assessed in the presence and absence of marrow. Furthermore, we determined the influence of PTH 1-34 on 1) endothelium dependent vasodilation and signaling pathways [i.e., nitric oxide (NO) and prostacyclin (PGI2)], 2) endothelium-independent vasodilation, 3) cytokine production by marrow cells, and 4) bone microarchitecture and bone static and dynamic properties. Young (4-6 mo) and old (22-24 mo) male Fischer-344 rats were treated with PTH 1-34 or a vehicle for 2 wk. In the absence and presence of marrow, femoral PNAs were given cumulative doses of acetylcholine, with and without the NO and PGI2 blockers, and diethylamine NONOate. Marrow-derived cytokines and bone parameters in the distal femur were assessed. Exposure to marrow diminished endothelium-dependent vasodilation in young rats. Reduced bone volume and NO-mediated vasodilation occurred with old age and were partially reversed with PTH. Additionally, PTH treatment in old rats restored endothelium dependent vasodilation in the presence of marrow and augmented IL-10, an anti inflammatory cytokine. Endothelium-independent vasodilation was unaltered, and PTH treatment reduced osteoid surfaces in old rats. In conclusion, the marrow microenvironment reduced vascular function in young rats, and PTH treatment improved the marrow microenvironment and vasodilation with age. NEW & NOTEWORTHY This study investigated the influence of the marrow microenvironment on bone vascular function in young and old rats. An inflamed marrow microenvironment may reduce vasodilator capacity of bone blood vessels, diminishing delivery of blood flow to the skeleton. In young rats, the presence of the marrow reduced vasodilation in the femoral principal nutrient artery (PNA). However, intermittent parathyroid hormone administration (i.e., a treatment for osteoporosis) improved the marrow microenvironment and vasodilator capacity in old PNAs. PMID- 29420159 TI - Identifying the mechanical and neural properties of the sternocleidomastoid muscles. AB - Neck muscles are preferentially activated in specific force directions, but the constraints that the central nervous system considers when programming these preferred directions of muscle activity are unknown. The current study used ultrasound shear wave elastography (SWE) to investigate whether the material properties of the sternocleidomastoid (SCM) muscles exhibit preferred directions similar to their preferred direction of muscle activity during an isometric task. Twenty-four healthy participants matched isometric forces in 16 axial directions. All force targets were scaled to 20% of a maximum voluntary contraction. Muscle activity was recorded with surface electromyography (EMG) from six muscles (the bilateral SCMs, upper trapezius, and splenius capitis muscles), and shear wave velocities (SWVs) were recorded with SWE from both SCM muscles. We observed statistically significant differences between the preferred directions of muscle activity and SWVs for both the left SCM ( P = 0.002) and the right SCM ( P < 0.001), with the SWE data exhibiting a more lateral preferred direction. Significant differences in the spatial focus ( P < 0.001) were also observed, with the dispersion of SWV data covering a greater angular range than the EMG data during isometric tasks. The preferred directions of muscle activity and material properties for the SCM muscles were closer than previous comparisons of muscle activity and moment arms, suggesting muscle mechanics could play a more important role than anatomy in how the central nervous system spatially tunes muscle activation. NEW & NOTEWORTHY Our study used a novel combination of surface electromyography and ultrasound shear wave elastography to investigate the neuromuscular control of the neck. Our work highlights differences in how the activation and material properties of the sternocleidomastoid muscles are modulated as the central nervous system stabilizes the neck during isometric force production. These findings provide normative data for future studies to investigate pathologic changes to both the activation and material properties of the sternocleidomastoid muscles. PMID- 29420160 TI - Mito-Tempo prevents nicotine-induced exacerbation of ischemic brain damage. AB - Nicotine may contribute to the pathogenesis of cerebrovascular disease via the generation of reactive oxygen species (ROS). Overproduction of ROS leads to brain damage by intensifying postischemic inflammation. Our goal was to determine the effect of Mito-Tempo, a mitochondria-targeted antioxidant, on ischemic brain damage and postischemic inflammation during chronic exposure to nicotine. Male Sprague-Dawley rats were divided into four groups: control, nicotine, Mito-Tempo treated control, and Mito-Tempo-treated nicotine. Nicotine (2 mg.kg-1.day-1) was administered via an osmotic minipump for 4 wk. Mito-Tempo (0.7 mg.kg-1.day-1 ip) was given for 7 days before cerebral ischemia. Transient focal cerebral ischemia was induced by occlusion of the middle cerebral artery for 2 h. Brain damage and inflammation were evaluated after 24 h of reperfusion by measuring infarct volume, expression of adhesion molecules, activity of matrix metalloproteinase, brain edema, microglial activation, and neutrophil infiltration. Nicotine exacerbated infarct volume and worsened neurological deficits. Nicotine did not alter baseline ICAM-1 expression, matrix metallopeptidase-2 activity, microglia activation, or neutrophil infiltration but increased these parameters after cerebral ischemia. Mito-Tempo did not have an effect in control rats but prevented the chronic nicotine-induced augmentation of ischemic brain damage and postischemic inflammation. We suggest that nicotine increases brain damage following cerebral ischemia via an increase in mitochondrial oxidative stress, which, in turn, contributes to postischemic inflammation. NEW & NOTEWORTHY Our findings have important implications for the understanding of mechanisms contributing to increased susceptibility of the brain to damage in smokers and users of nicotine-containing tobacco products. PMID- 29420161 TI - Economic evaluation of pneumococcal vaccines for adults aged over 50 years in Belgium. AB - Streptococcus pneumoniae causes a high disease burden including pneumonia, meningitis and septicemia. Both a polysaccharide vaccine targeting 23 serotypes (PPV23) and a 13-valent conjugate vaccine (PCV13) are indicated for persons aged over 50 years. We developed and parameterized a static multi-cohort model to estimate the incremental cost-effectiveness and budget-impact of these vaccines at different uptake levels. Using three different vaccine efficacy scenarios regarding non-invasive pneumococcal pneumonia and extensive uni- and multivariate sensitivity analyses, we found a strong preference for PPV23 over PCV13 in all age groups at willingness to pay levels below ?300 000 per quality adjusted life year (QALY). PPV23 vaccination would cost on average about ?83 000, ?60 000 and ?52 000 per QALY gained in 50-64, 65-74 and 75-84 year olds, whereas for PCV13 this is about ?171 000, ?201 000 and ?338 000, respectively. Strategies combining PPV23 and PCV13 vaccines were most effective but generally less cost-effective. When assuming a combination of increased duration of PCV13 protection, increased disease burden preventable by PCV13 and a 75% reduction of the PCV13 price, PCV13 could become more attractive in <75 year olds, but would remain less attractive than PPV23 from age 75 years onwards. These observations are independent of the assumption that PPV23 has 0% efficacy against non-invasive pneumococcal pneumonia. Pneumococcal vaccination would be most cost-effective in Belgium, when achieving high uptake with PPV23 in 75-84 year olds, as well as by negotiating a lower market-conform PPV23 price to improve uptake and cost-effectiveness. PMID- 29420162 TI - Human Vaccines & Immunotherapeutics: News. PMID- 29420163 TI - Letter from the Editor. PMID- 29420167 TI - Artificial Intelligence Reconsidered. PMID- 29420166 TI - Curcumin-mediated regulation of intestinal barrier function: The mechanism underlying its beneficial effects. AB - Curcumin has anti-inflammatory, anti-oxidant and anti-proliferative properties established largely by in vitro studies. Accordingly, oral administration of curcumin beneficially modulates many diseases including diabetes, fatty-liver disease, atherosclerosis, arthritis, cancer and neurological disorders such as depression, Alzheimer's or Parkinson's disease. However, limited bioavailability and inability to detect curcumin in circulation or target tissues has hindered the validation of a causal role. We established curcumin-mediated decrease in the release of gut bacteria-derived lipopolysaccharide (LPS) into circulation by maintaining the integrity of the intestinal barrier function as the mechanism underlying the attenuation of metabolic diseases (diabetes, atherosclerosis, kidney disease) by curcumin supplementation precluding the need for curcumin absorption. In view of the causative role of circulating LPS and resulting chronic inflammation in the development of diseases listed above, this review summarizes the mechanism by which curcumin affects the several layers of the intestinal barrier and, despite negligible absorption, can beneficially modulate these diseases. PMID- 29420165 TI - Relationship between G proteins coupled receptors and tight junctions. AB - Tight junctions (TJs) are sites of cell-cell adhesion, constituted by a cytoplasmic plaque of molecules linked to integral proteins that form a network of strands around epithelial and endothelial cells at the uppermost portion of the lateral membrane. TJs maintain plasma membrane polarity and form channels and barriers that regulate the transit of ions and molecules through the paracellular pathway. This structure that regulates traffic between the external milieu and the organism is affected in numerous pathological conditions and constitutes an important target for therapeutic intervention. Here, we describe how a wide array of G protein-coupled receptors that are activated by diverse stimuli including light, ions, hormones, peptides, lipids, nucleotides and proteases, signal through heterotrimeric G proteins, arrestins and kinases to regulate TJs present in the blood-brain barrier, the blood-retinal barrier, renal tubular cells, keratinocytes, lung and colon, and the slit diaphragm of the glomerulus. PMID- 29420168 TI - Obstetric Outcomes and Delivery-Related Health Care Utilization and Costs Among Pregnant Women With Multiple Chronic Conditions. AB - Our objective was to measure obstetric outcomes and delivery-related health care utilization and costs among pregnant women with multiple chronic conditions. We used 2013-2014 data from the National Inpatient Sample to measure obstetric outcomes and delivery-related health care utilization and costs among women with no chronic conditions, 1 chronic condition, and multiple chronic conditions. Women with multiple chronic conditions were at significantly higher risk than women with 1 chronic condition or no chronic conditions across all outcomes measured. High-value strategies are needed to improve birth outcomes among vulnerable mothers and their infants. PMID- 29420169 TI - Trends in Hookah Use Among New York City Middle and High School Students, 2008 2014. AB - We examined trends in hookah use among New York City middle and high school students. We calculated prevalences, linear trends, and odds ratios of ever and current hookah use, by selected demographic variables, using 2008 through 2014 data from the New York State Youth Tobacco Survey. The prevalence of ever hookah use increased overall from 2008 through 2014 (8.9% to 13.0%, P = .01); current use was stable during this period but increased across many demographic characteristics. Our results indicate a need for efforts to educate populations with increasing prevalence of hookah use as well as policies that regulate use to reduce and denormalize hookah smoking. PMID- 29420170 TI - Jak-Stat pathway induces Drosophila follicle elongation by a gradient of apical contractility. AB - Tissue elongation and its control by spatiotemporal signals is a major developmental question. Currently, it is thought that Drosophila ovarian follicular epithelium elongation requires the planar polarization of the basal domain cytoskeleton and of the extra-cellular matrix, associated with a dynamic process of rotation around the anteroposterior axis. Here we show, by careful kinetic analysis of fat2 mutants, that neither basal planar polarization nor rotation is required during a first phase of follicle elongation. Conversely, a JAK-STAT signaling gradient from each follicle pole orients early elongation. JAK STAT controls apical pulsatile contractions, and Myosin II activity inhibition affects both pulses and early elongation. Early elongation is associated with apical constriction at the poles and with oriented cell rearrangements, but without any visible planar cell polarization of the apical domain. Thus, a morphogen gradient can trigger tissue elongation through a control of cell pulsing and without a planar cell polarity requirement. PMID- 29420171 TI - AP2sigma Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity. AB - Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic signaling via multiple G-protein pathways remain unknown. Here, we investigated the effects of disease-causing mutations of the adaptor protein-2sigma subunit (AP2sigma) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2sigma mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2sigma mutations reduced CaSR signaling via Galphaq/11 and Galphai/o pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling, which was predominantly mediated by Galphaq/11. Thus, compartmental bias for CaSR-mediated Galphaq/11 endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling. PMID- 29420172 TI - ICAMs Are Not Obligatory for Functional Immune Synapses between Naive CD4 T Cells and Lymph Node DCs. AB - Protective immune responses depend on the formation of immune synapses between T cells and antigen-presenting cells (APCs). The two main LFA-1 ligands, ICAM-1 and ICAM-2, are co-expressed on many cell types, including APCs and blood vessels. Although these molecules were suggested to be key players in immune synapses studied in vitro, their contribution to helper T cell priming in vivo is unclear. Here, we used transgenic mice and intravital imaging to examine the role of dendritic cell (DC) ICAM-1 and ICAM-2 in naive CD4 T cell priming and differentiation in skin-draining lymph nodes. Surprisingly, ICAM deficiency on endogenous CD40-stimulated lymph node DCs did not impair their ability to arrest and prime CD4 lymphocyte activation and differentiation into Th1 and Tfh effectors. Thus, functional T cell receptor (TCR)-specific helper T cell synapses with antigen-presenting DCs and subsequent proliferation and early differentiation into T effectors do not require LFA-1-mediated T cell adhesiveness to DC ICAMs. PMID- 29420164 TI - Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. AB - BACKGROUND: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS: Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .). PMID- 29420174 TI - Nascent Induced Pluripotent Stem Cells Efficiently Generate Entirely iPSC-Derived Mice while Expressing Differentiation-Associated Genes. AB - The ability of induced pluripotent stem cells (iPSCs) to differentiate into all adult cell types makes them attractive for research and regenerative medicine; however, it remains unknown when and how this capacity is established. We characterized the acquisition of developmental pluripotency in a suitable reprogramming system to show that iPSCs prior to passaging become capable of generating all tissues upon injection into preimplantation embryos. The developmental potential of nascent iPSCs is comparable to or even surpasses that of established pluripotent cells. Further functional assays and genome-wide molecular analyses suggest that cells acquiring developmental pluripotency exhibit a unique combination of properties that distinguish them from canonical naive and primed pluripotency states. These include reduced clonal self-renewal potential and the elevated expression of differentiation-associated transcriptional regulators. Our observations close a gap in the understanding of induced pluripotency and provide an improved roadmap of cellular reprogramming with ramifications for the use of iPSCs. PMID- 29420173 TI - Asymmetric PI3K Activity in Lymphocytes Organized by a PI3K-Mediated Polarity Pathway. AB - Unequal transmission of nutritive signaling during cell division establishes fate disparity between sibling lymphocytes, but how asymmetric signaling becomes organized is not understood. We show that receptor-associated class I phosphatidylinositol 3-kinase (PI3K) signaling activity, indexed by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) staining, is spatially restricted to the microtubule-organizing center and subsequently to one pole of the mitotic spindle in activated T and B lymphocytes. Asymmetric PI3K activity co localizes with polarization of antigen receptor components implicated in class I PI3K signaling and with facultative glucose transporters whose trafficking is PI3K dependent and whose abundance marks cells destined for differentiation. Perturbation of class I PI3K activity disrupts asymmetry of upstream antigen receptors and downstream glucose transporter traffic. The roles of PI3K signaling in nutrient utilization, proliferation, and gene expression may have converged with the conserved role of PI3K signaling in cellular symmetry breaking to form a logic for regenerative lymphocyte divisions. PMID- 29420179 TI - JARID2 and AEBP2 Mimic Histone Tails to Promote PRC2 Activity. AB - Structures of PRC2 with its cofactors suggest context-dependent activation affected by cofactor binding. PMID- 29420180 TI - CD10+GPR77+ Cancer-Associated Fibroblasts Promote Chemoresistance. AB - CD10 and GPR77 define a cancer-associated fibroblast (CAF) subset that sustains cancer stemness. PMID- 29420178 TI - Methodological quality and synthesis of case series and case reports. AB - Case reports and case series are uncontrolled study designs known for increased risk of bias but have profoundly influenced the medical literature and continue to advance our knowledge. In this guide, we present a framework for appraisal, synthesis and application of evidence derived from case reports and case series. We propose a tool to evaluate the methodological quality of case reports and case series based on the domains of selection, ascertainment, causality and reporting and provide signalling questions to aid evidence-based practitioners and systematic reviewers in their assessment. We suggest using evidence derived from case reports and case series to inform decision-making when no other higher level of evidence is available. PMID- 29420175 TI - CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function. AB - Various kinases, including a cyclin-dependent kinase (CDK) family member, regulate the growth and functions of primary cilia, which perform essential roles in signaling and development. Neurological disorders linked to CDK-Like (CDKL) proteins suggest that these underexplored kinases may have similar functions. Here, we present the crystal structures of human CDKL1, CDKL2, CDKL3, and CDKL5, revealing their evolutionary divergence from CDK and mitogen-activated protein kinases (MAPKs), including an unusual ?J helix important for CDKL2 and CDKL3 activity. C. elegans CDKL-1, most closely related to CDKL1-4 and localized to neuronal cilia transition zones, modulates cilium length; this depends on its kinase activity and ?J helix-containing C terminus. Human CDKL5, linked to Rett syndrome, also localizes to cilia, and it impairs ciliogenesis when overexpressed. CDKL5 patient mutations modeled in CDKL-1 cause localization and/or cilium length defects. Together, our studies establish a disease model system suggesting cilium length defects as a pathomechanism for neurological disorders, including epilepsy. PMID- 29420182 TI - KRASG12D Gene Dosage Drives Pancreatic Tumor Evolution and Progression. AB - Allelic imbalance with increased KrasG12D gene dosage drives key PDAC characteristics. PMID- 29420181 TI - Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. AB - Nivolumab plus ipilimumab achieves higher response rates than previously reported for nivolumab alone. PMID- 29420183 TI - Moving Evolution Education Forward: A Systematic Analysis of Literature to Identify Gaps in Collective Knowledge for Teaching. AB - Evolution is a unifying theory in biology and is challenging for undergraduates to learn. An instructor's ability to help students learn is influenced by pedagogical content knowledge (PCK), which is topic-specific knowledge of teaching and learning. Instructors need PCK for every topic they teach, which is a tremendous body of knowledge to develop alone. However, investigations of undergraduate thinking and learning have produced collective PCK that is available in peer-reviewed literature. Currently, it is unclear whether the collective PCK available adequately addresses the topics in evolution that college instructors teach. We systematically examined existing literature to determine what collective PCK for teaching evolution is available and what is missing. We conducted an exhaustive literature search and analyzed 316 relevant papers to determine: the evolutionary topics addressed; whether the focus was student thinking, assessment, instructional strategies, or goals; and the type of work (e.g., empirical, literature review). We compared the collective PCK available in the literature with the topics taught in a sample of 32 undergraduate evolution courses around the country. On the basis of our findings, we propose priorities for the evolution education research community and propose that PCK is a useful lens for guiding future research on teaching and learning biology. PMID- 29420184 TI - Teacher Knowledge for Active-Learning Instruction: Expert-Novice Comparison Reveals Differences. AB - Active-learning strategies can improve science, technology, engineering, and mathematics (STEM) undergraduates' abilities to learn fundamental concepts and skills. However, the results instructors achieve vary substantially. One explanation for this is that instructors commonly implement active learning differently than intended. An important factor affecting how instructors implement active learning is knowledge of teaching and learning. We aimed to discover knowledge that is important to effective active learning in large undergraduate courses. We developed a lesson-analysis instrument to elicit teacher knowledge, drawing on the theoretical construct of teacher noticing. We compared the knowledge used by expert (n = 14) and novice (n = 29) active learning instructors as they analyzed lessons. Experts and novices differed in what they noticed, with experts more commonly considering how instructors hold students accountable, topic-specific student difficulties, whether the instructor elicited and responded to student thinking, and opportunities students had to generate their own ideas and work. Experts were also better able to support their lesson analyses with reasoning. This work provides foundational knowledge for the future design of preparation and support for instructors adopting active learning. Improving teacher knowledge will improve the implementation of active learning, which will be necessary to widely realize the potential benefits of active learning in undergraduate STEM. PMID- 29420185 TI - Landscape of antimicrobial stewardship programs in Ontario: a survey of hospitals. AB - BACKGROUND: Antimicrobial resistance is an important public health issue globally and in Canada. To understand the current state of antimicrobial stewardship programs in Ontario health care facilities, Public Health Ontario conducted a voluntary survey of hospitals in the province. METHODS: The Ontario Antimicrobial Stewardship Program Landscape Survey was distributed online to hospitals, targeting front-line antimicrobial stewardship clinicians. The survey was open for 5 weeks in fall 2016. We used email and telephone reminders to encourage response. We performed descriptive and inferential statistical analyses at an aggregate level and by hospital type. Mental health and ambulatory sites were excluded. RESULTS: The response rate was 74.0% (97/131 organizations). Of the 97, 90 (93%) reported having a formal antimicrobial stewardship program or were in the process of implementing a formal program. Just over half (50 [56%]) identified appropriate antibiotic use as part of the organization's quality improvement plan, strategic goal or priority. Half (45 [50%]) of programs did not have designated resources; those that did are underresourced with respect to physician and pharmacist staffing. The scope of implementation of program strategies was variable. Fifty hospitals (56%) reported tracking antimicrobial expenditures, 47 (52%) reported tracking defined daily dose, and 35 (39%) reported tracking days of therapy. INTERPRETATION: Most Ontario hospitals have a formal antimicrobial stewardship program, but there are opportunities for improvement. Future efforts should increase the priority of and improve resource allocation for antimicrobial stewardship programs so that programs can continue to grow in scope and impact. PMID- 29420186 TI - Campaigners win right to challenge NHS England over accountable care organisations. PMID- 29420187 TI - Clinical care and complicity with torture. PMID- 29420188 TI - Human 3beta-hydroxysteroid dehydrogenase deficiency associated with normal spermatic numeration despite a severe enzyme deficit. AB - Human 3 beta-hydroxysteroid dehydrogenase deficiency (3b-HSD) is a very rare form of congenital adrenal hyperplasia resulting from HSD3B2 gene mutations. The estimated prevalence is less than 1/1,000,000 at birth. It leads to steroidogenesis impairment in both adrenals and gonads. Few data are available concerning adult testicular function in such patients. We had the opportunity to study gonadal axis and testicular function in a 46,XY adult patient, carrying a HSD3B2 mutation. He presented at birth a neonatal salt-wasting syndrome. He had a micropenis, a perineal hypospadias and two intrascrotal testes. HSD3B2 gene sequencing revealed a 687del27 homozygous mutation. The patient achieved normal puberty at the age of 15 years. Transition from the paediatric department occurred at the age of 19 years. His hormonal profile under hydrocortisone and fludrocortisone treatments revealed normal serum levels of 17OH-pregnenolone, as well as SDHEA, ACTH, total testosterone, inhibin B and AMH. Pelvic ultrasound identified two scrotal testes of 21 mL each, without any testicular adrenal rest tumours. His adult spermatic characteristics were normal, according to WHO 2010 criteria, with a sperm concentration of 57.6 million/mL (N > 15), 21% of typical forms (N > 4%). Sperm vitality was subnormal (41%; N > 58%). This patient, in contrast to previous reports, presents subnormal sperm parameters and therefore potential male fertility in a 24-years-old patient with severe 3b-HSD deficiency. This case should improve counselling about fertility of male patients carrying HSD3B2 mutation. PMID- 29420189 TI - Randomized Comparisons of Double-Dose Clopidogrel or Adjunctive Cilostazol Versus Standard Dual Antiplatelet in Patients With High Posttreatment Platelet Reactivity: Results of the CREATIVE Trial. AB - BACKGROUND: Patients undergoing percutaneous coronary intervention react differently to antiplatelet drugs. Those with low responsiveness to clopidogrel have a higher risk of cardiac ischemic events. The goal of this study is to conduct a head-to-head comparison of the safety and effectiveness of intensified antiplatelet therapies (either double-dose clopidogrel [DOUBLE] or adjunctive cilostazol [TRIPLE]) and conventional strategy (STANDARD) in patients after percutaneous coronary intervention. METHODS: In this single-center, randomized, controlled trial, we used thromboelastography, a platelet function test, to select 1078 patients undergoing percutaneous coronary intervention at high thrombotic risk and compared the intensified antiplatelet therapies with standard antiplatelet therapy. The primary outcome was the incidence of major adverse cardiac and cerebrovascular events at 18 months after percutaneous coronary intervention, defined as a composite of all-cause death, myocardial infarction, target vessel revascularization, or stroke. Bleeding Academic Research Consortium defined bleeding complications (types 1, 2, 3, or 5) were the safety end points. RESULTS: The primary end point occurred in 52 patients (14.4%) in the STANDARD group, 38 patients (10.6%) in the DOUBLE group, and 30 patients (8.5%) in the TRIPLE group (hazard ratio, 0.720; 95% confidence interval, 0.474-1.094, DOUBLE versus STANDARD; hazard ratio, 0.550; 95% confidence interval, 0.349-0.866, TRIPLE versus STANDARD). No significant difference in the rates of major bleeding (Bleeding Academic Research Consortium grade>=3) was found in the DOUBLE group (3.34% versus 1.93% in STANDARD, P=0.133) and the TRIPLE group (2.53% versus 1.93% in STANDARD, P=0.240). The rate of Bleeding Academic Research Consortium defined minor bleeding increased in the DOUBLE group (27.4% versus 20.3% in STANDARD, P=0.031), but not in the TRIPLE group (23.6% versus 20.3% in STANDARD, P=0.146). CONCLUSIONS: In patients with low responsiveness to clopidogrel, as measured by thromboelastography, the intensified antiplatelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding. Decreased trend of negative outcomes could be observed in patients with double dosage of clopidogrel, but the difference was not significant. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01779401. PMID- 29420190 TI - Genome-Wide Association and Genomic Selection for Resistance to Amoebic Gill Disease in Atlantic Salmon. AB - Amoebic gill disease (AGD) is one of the largest threats to salmon aquaculture, causing serious economic and animal welfare burden. Treatments can be expensive and environmentally damaging, hence the need for alternative strategies. Breeding for disease resistance can contribute to prevention and control of AGD, providing long-term cumulative benefits in selected stocks. The use of genomic selection can expedite selection for disease resistance due to improved accuracy compared to pedigree-based approaches. The aim of this work was to quantify and characterize genetic variation in AGD resistance in salmon, the genetic architecture of the trait, and the potential of genomic selection to contribute to disease control. An AGD challenge was performed in ~1,500 Atlantic salmon, using gill damage and amoebic load as indicator traits for host resistance. Both traits are heritable (h2 ~0.25-0.30) and show high positive correlation, indicating they may be good measurements of host resistance to AGD. While the genetic architecture of resistance appeared to be largely polygenic in nature, two regions on chromosome 18 showed suggestive association with both AGD resistance traits. Using a cross-validation approach, genomic prediction accuracy was up to 18% higher than that obtained using pedigree, and a reduction in marker density to ~2,000 SNPs was sufficient to obtain accuracies similar to those obtained using the whole dataset. This study indicates that resistance to AGD is a suitable trait for genomic selection, and the addition of this trait to Atlantic salmon breeding programs can lead to more resistant stocks. PMID- 29420191 TI - The Molecular and Genetic Characterization of Second Chromosome Balancers in Drosophila melanogaster. AB - Balancer chromosomes are multiply inverted and rearranged chromosomes used in Drosophila melanogaster for many tasks, such as maintaining mutant alleles in stock and complex stock construction. Balancers were created before molecular characterization of their breakpoints was possible, so the precise locations of many of these breakpoints are unknown. Here, we report or confirm the positions of the 14 euchromatic breakpoints on the 2nd chromosome balancers SM1, SM5, CyO, and SM6a This total includes three breakpoints involved in a complex rearrangement on SM5 that is associated with the duplication of two genomic regions. Unbiased sequencing of several balancers allowed us to identify stocks with incorrectly identified balancers as well as single and double crossover events that had occurred between 2nd chromosome balancers and their homologs. The confirmed crossover events that we recovered were at least 2 Mb from the closest inversion breakpoint, consistent with observations from other balancer chromosomes. Balancer chromosomes differ from one another both by large tracts of sequence diversity generated by recombination and by small differences, such as single nucleotide polymorphisms (SNPs). Therefore, we also report loss-of function mutations carried by these chromosomes and unique SNP and InDel polymorphisms present on only single balancers. These findings provide valuable information about the structure of commonly used 2nd chromosome balancers and extend recent work examining the structure of X and 3rd chromosome balancers. Finally, these observations provide new insights into how the sequences of individual balancers have diverged over time. PMID- 29420193 TI - Clinicoserological factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease. AB - PURPOSE: To investigate the factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease (ROD). METHODS: Twenty-eight patients with biopsy-proven IgG4-ROD treated between March 2010 and January 2017 were included in this retrospective study. Clinical features, serum IgG4 levels, systemic involvement, treatments and treatment outcome, factors associated with response to treatment and recurrence were assessed. RESULT: Thirteen men and 15 women (mean age 50.8 years) were evaluated over mean follow up period of 27.3 months. Elevated serum IgG4 levels (>1.35 g/L) and systemic disease were noted in 9 (32%) and 18 patients (64%), respectively. The lacrimal gland was involved in all patients, and 22 patients (78.6%) had bilateral involvement. Most patients (82%) responded well to systemic steroids, but 12 (43%) relapsed after the initial steroid treatment, requiring additional therapies to achieve remission. Complete response to initial steroid treatment was associated with elevated serum IgG4 levels before treatment (P=0.001) and bilateral orbital involvement (P=0.050). Recurrence was associated with elevated serum IgG4 levels before treatment (P=0.007), lower dose (P=0.057) and shorter duration of initial steroids (P=0.042). Patients with recurrence eventually required significantly more steroids than those without recurrence (P=0.011). CONCLUSIONS: Patients with IgG4-ROD responded well to systemic steroid treatment, but recurrence was common, particularly among those with elevated serum IgG4 levels and shorter duration of initial steroid treatment. Low-dose maintenance treatment with systemic steroids should be considered to avoid recurrence in patients with elevated serum IgG4 levels. PMID- 29420194 TI - Effect of manual eyelid manipulation on intraocular pressure measurement by rebound tonometry. AB - BACKGROUND/AIMS: To investigate the effect of eyelid manipulation on the measurement of intraocular pressure (IOP) using two different tonometries (rebound tonometry (RT) vs Goldmann applanation tonometry (GAT)). METHODS: 103 patients with primary open-angle glaucoma were prospectively enrolled. For all of the patients, IOP measurements were performed in three different ways: (1) RT with lid manipulation (LM), (2) RT without LM and (3) GAT. The order of the three measurements was randomly selected. Additionally, the palpebral fissure height (PFH; elliptical space between upper and lower eyelids) was measured. RESULTS: The mean value of IOP measured by GAT was 13.97+/-2.80 mm Hg, which was not significantly different from that by RT without LM (13.75+/-2.44 mm Hg; P=0.096), but which was significantly lower than that by RT with LM (15.21+/-2.91 mm Hg; P<0.001). On a Bland-Altman plot, RT with LM was overestimated relative to GAT (mean: -1.5) and RT without LM (mean: -1.2). Among the high IOPs (>20 mm Hg), interestingly, those measured by RT without LM were significantly lower than those measured by GAT (P<0.001). In the subgroup analysis of PFH, the smaller the PFH, the more exaggerated the IOP difference between GAT (P=0.014) and RT with LM (P<0.001). CONCLUSION: RT-measured IOP was significantly exaggerated when manipulation was applied to the eyelid. This overall trend was more pronounced when PFH was small. GAT-measured IOP, meanwhile, showed a good correlation with IOP measured using RT without LM. PMID- 29420192 TI - Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins. AB - Autophagy is a conserved eukaryotic process with metabolic, immune, and general homeostatic functions in mammalian cells. Mammalian autophagosomes fuse with lysosomes in a SNARE-driven process that includes syntaxin 17 (Stx17). How Stx17 translocates to autophagosomes is unknown. In this study, we show that the mechanism of Stx17 recruitment to autophagosomes in human cells entails the small guanosine triphosphatase IRGM. Stx17 directly interacts with IRGM, and efficient Stx17 recruitment to autophagosomes requires IRGM. Both IRGM and Stx17 directly interact with mammalian Atg8 proteins, thus being guided to autophagosomes. We also show that Stx17 is significant in defense against infectious agents and that Stx17-IRGM interaction is targeted by an HIV virulence factor Nef. PMID- 29420195 TI - Progressive change in peripapillary atrophy in myopic glaucomatous eyes. AB - AIM: To evaluate the progressive change in peripapillary atrophy (PPA) according to its shape and to explore the relationship between PPA progression and glaucoma worsening in myopic eyes. METHODS: A total of 159 eyes of 159 patients with myopic (axial length (AXL) >24 mm) glaucoma (mean follow-up 4.4 years, 35 eyes with minimal PPA, 40 concentric-type PPA eyes (>270 degrees around the optic disc) and 84 eccentric-type PPA eyes (<270 degrees )) were included. Sequential stereoscopic colour optic disc photographs were evaluated to qualitatively determine PPA progression. Factors associated with PPA progression were explored by Cox proportional hazard modelling in each PPA group. RESULTS: Patients with concentric PPA were older than patients with eccentric PPA (54.1+/-11.7 vs 44.1+/ 11.7 years; P<0.001), and AXL was longer in the eccentric group than in the other groups (25.54+/-1.68 vs 25.28+/-1.53 vs 26.41+/-1.29 mm; P<0.001). Twenty-six eyes (65%) in the concentric group and 36 eyes (42.9%) in the eccentric group showed PPA progression. Older age (hazard ratio (HR) 1.059, P=0.008), worse baseline visual field mean deviation (HR 0.857, P=0.009) and greater baseline PPA area (HR 1.000, P=0.012) were associated with PPA progression in the concentric type. Glaucoma progression (HR 3.690, P=0.002) and longer AXL (HR 1.521, P=0.002) were associated with PPA progression in the eccentric type. CONCLUSIONS: Relationship between glaucoma worsening and PPA progression was strongest in myopic glaucomatous eyes with eccentric type PPA. PMID- 29420196 TI - Enhanced patient research participation: a Photovoice study in Blantyre Malawi. AB - OBJECTIVES: Patient involvement in palliative care research is a desirable if challenging goal. Photovoice is an action research method in which affected communities gather photographs to document and discuss their communities' strengths and concerns. Engagement with policymakers is a separately stated goal. Photovoice is increasingly used in health-related research but has not been widely described in the palliative care literature. We report on experiences and lessons learnt using Photovoice in Blantyre, Malawi to encourage its wider use in research and practice. METHODS: Thirteen co-researchers (six patients and seven household carers, mean age 47 years) receiving community-based palliative care, attended nine half-day group sessions over a 4-month period. Co-researchers produced, selected and analysed photographs. On completion of data collection, they conducted an advocacy event, including a photographic exhibition, to which media representatives and community leaders were invited. RESULTS: Procedures to ensure safety of co-researchers and to obtain consent of individuals identified in the photographs were developed during the planning phase. Co-researchers engaged with the Photovoice process with enthusiasm, although frailty and physical disability (poor sight) limited participation for some older adults. Inclusion of palliative care staff within the research team helped to facilitate open dialogue and clinical review where appropriate. CONCLUSIONS: In this Photovoice study, patients and family members receiving palliative care engaged in an exploration of household well-being using photography, participatory analysis and an advocacy event. With appropriate planning, Photovoice can be adapted to a range of settings to enhance patient participation. PMID- 29420198 TI - US public health chief resigns over tobacco investments. PMID- 29420197 TI - Muscle metastases: rare problem with unusual solution. AB - Skeletal muscle is an unusual site for metastasis from malignancy. We report a patient who presented with calf metastases from a squamous cell carcinoma of lung. Attempts were made to control his pain conservatively for almost 2 years before he was referred for a below-knee amputation. He did well following this and was able to stop the majority of his analgesic drugs. PMID- 29420199 TI - Bisphosphonates reduce the risk of knee replacement: we need more analyses! PMID- 29420200 TI - Lupus Low Disease Activity State (LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: post-hoc analysis of the Phase IIb MUSE trial of anifrolumab. AB - OBJECTIVES: In a post-hoc analysis, we aimed to validate the Lupus Low Disease Activity State (LLDAS) definition as an endpoint in an systemic lupus erythematosus (SLE) Phase IIb randomised controlled trial (RCT) (MUSE [NCT01438489]) and then utilize LLDAS to discriminate between anifrolumab and placebo. METHODS: Patients received intravenous placebo (n=102) or anifrolumab (300 mg, n=99; 1,000 mg, n=104) Q4W plus standard of care for 48 weeks. LLDAS attainment (SLE Disease Activity Index 2000 <=4 without major organ activity, no new disease activity, Physician's Global Assessment <=1, prednisolone <=7.5 mg/d and standard immunosuppressant dosage tolerance) was assessed. Associations with endpoints and LLDAS attainment differences between treatments were explored. RESULTS: LLDAS attainment at Week 52 was associated with SLE Responder Index 4 (SRI[4]) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) (74/85[87%] and 62/84[74%] were also SRI[4] and BICLA responders, respectively; both nominal p<0.001). Only 74/159 (47%) of SRI(4) and 62/121 (51%) of BICLA responders reached LLDAS.Anifrolumab-treated patients achieved earlier LLDAS, and more spent at least half their observed time in LLDAS (OR vs. placebo; 300 mg: 3.04, 95% CI 1.34 to 6.92, nominal p=0.008; 1,000 mg: 2.17, 95% CI 0.93 to 5.03, nominal p=0.072) vs placebo-treated patients. At Week 52, 17/102 (17%), 39/99 (39%) and 29/104 (28%) of patients on placebo, anifrolumab 300 and 1,000 mg, respectively, attained LLDAS (OR vs. placebo; 300 mg: 3.41, 95% CI 1.73 to 6.76, p<0.001; 1,000 mg: 2.03, 95% CI 1.01 to 4.07, nominal p=0.046). CONCLUSIONS: LLDAS attainment represents a clinically meaningful SLE outcome measure, and anifrolumab is associated with more patients who met LLDAS criteria versus placebo. These data support LLDAS as an SLE RCT endpoint. TRIAL REGISTRATION NUMBER: NCT1438489; Post-results. PMID- 29420201 TI - Response to: 'Seeing the glass either half full or half empty: response to the correspondence 'Switching from the bio-originators to biosimilar: is it premature to recommend this procedure?'' by Scherlinger and Schaeverbeke. PMID- 29420203 TI - Meet the First Authors. PMID- 29420202 TI - Response to: 'Is the PET/CT first choice for differential diagnosis of FUO/IUO?' by Armagan et al. PMID- 29420204 TI - Boosting Endothelial Autophagy by MicroRNA Delivery Quenches Vascular Inflammation. PMID- 29420206 TI - Julia Liu: Breaking Through the Ties That Bind. PMID- 29420205 TI - Peering Into the Future of CAD Genomics. PMID- 29420207 TI - Circulation Research 2017 Best Manuscript Award Winners. PMID- 29420208 TI - RNA Editing: Unexplored Opportunities in the Cardiovascular System. PMID- 29420209 TI - It's in the Field of View! Coronary Artery Analysis on Chest Computed Tomographic Angiography. PMID- 29420210 TI - New Insights Into the Role of mTOR Signaling in the Cardiovascular System. AB - The mTOR (mechanistic target of rapamycin) is a master regulator of several crucial cellular processes, including protein synthesis, cellular growth, proliferation, autophagy, lysosomal function, and cell metabolism. mTOR interacts with specific adaptor proteins to form 2 multiprotein complexes, called mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2). In the cardiovascular system, the mTOR pathway regulates both physiological and pathological processes in the heart. It is needed for embryonic cardiovascular development and for maintaining cardiac homeostasis in postnatal life. Studies involving mTOR loss-of-function models revealed that mTORC1 activation is indispensable for the development of adaptive cardiac hypertrophy in response to mechanical overload. mTORC2 is also required for normal cardiac physiology and ensures cardiomyocyte survival in response to pressure overload. However, partial genetic or pharmacological inhibition of mTORC1 reduces cardiac remodeling and heart failure in response to pressure overload and chronic myocardial infarction. In addition, mTORC1 blockade reduces cardiac derangements induced by genetic and metabolic disorders and has been reported to extend life span in mice. These studies suggest that pharmacological targeting of mTOR may represent a therapeutic strategy to confer cardioprotection, although clinical evidence in support of this notion is still scarce. This review summarizes and discusses the new evidence on the pathophysiological role of mTOR signaling in the cardiovascular system. PMID- 29420213 TI - Letter by Zhao and Schooling Regarding Article, "Thyroid Function and the Risk of Atherosclerotic Cardiovascular Morbidity and Mortality: The Rotterdam Study". PMID- 29420214 TI - Response by Bano et al to Letter Regarding Article, "Thyroid Function and the Risk of Atherosclerotic Cardiovascular Morbidity and Mortality: The Rotterdam Study". PMID- 29420211 TI - Translational Implications of Platelets as Vascular First Responders. AB - Platelets play a vital role in normal hemostasis to stem blood loss at sites of vascular injury by tethering and adhering to sites of injury, recruiting other platelets and blood cells to the developing clot, releasing vasoactive small molecules and proteins, and assembling and activating plasma coagulation proteins in a tightly regulated temporal and spatial manner. In synchrony with specific end products of coagulation, primarily cross-linked fibrin, a stable thrombus quickly forms. Far beyond physiological hemostasis and pathological thrombosis, emerging evidence supports platelets playing a pivotal role in vascular homeostasis, inflammation, cellular repair, regeneration, and wide range of autocrine and paracrine functions. In essence, platelets play both structural and functional roles as reporters, messengers, and active transporters surveying the vasculature for cues of environmental or developmental stimuli and participating as first responders.1 In this review, we will provide a contemporary perspective of platelet physiology, including fundamental, translational, and clinical constructs that apply directly to human health and disease. PMID- 29420212 TI - Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease. AB - Increasing evidence shows that conventional cardiovascular risk factors are incompletely predictive of cardiovascular disease, particularly in elderly individuals, suggesting that there may still be unidentified causal risk factors. Although the accumulation of somatic DNA mutations is a hallmark of aging, its relevance in cardiovascular disease or other age-related conditions has been, with the exception of cancer, largely unexplored. Here, we review recent clinical and preclinical studies that have identified acquired mutations in hematopoietic stem cells and subsequent clonal hematopoiesis as a new cardiovascular risk factor and a potential major driver of atherosclerosis. Understanding the mechanisms underlying the connection between somatic mutation-driven clonal hematopoiesis and cardiovascular disease will be highly relevant in the context of personalized medicine, as it may provide key information for the design of diagnostic, preventive, or therapeutic strategies tailored to the effects of specific somatic mutations. PMID- 29420215 TI - Correction to: Shine on, Young Physician-Scientist. PMID- 29420217 TI - Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms. PMID- 29420216 TI - Myocardial Scar Delineation Using Diffusion Tensor Magnetic Resonance Tractography. AB - BACKGROUND: Late gadolinium enhancement (LGE) is the current standard for myocardial scar delineation. In this study, we introduce the tractographic propagation angle (PA), a metric of myofiber curvature (degrees/unit distance) derived from diffusion tensor imaging (DTI), and compare its use to LGE and invasive scar assessment by endocardial voltage mapping. METHODS AND RESULTS: DTI was performed on 7 healthy human volunteers, 5 patients with myocardial infarction, 6 normal mice, and 7 mice with myocardial infarction. LGE to delineate the infarct and border zones was performed with a 2-dimensional inversion recovery gradient-echo sequence. Ex vivo DTI was performed on 5 normal human and 5 normal sheep hearts. Endocardial electroanatomic mapping and subsequent ex vivo DTI was performed on 5 infarcted sheep hearts. PA in the normal human hearts varied smoothly and was generally <4. The mean PA in the infarct zone was significantly elevated (10.34+/-1.02 versus 4.05+/-0.45, P<0.05). Regions with a PA <=4 consistently had a bipolar voltage >=1.5 mV, whereas those with PA values between 4 and 10 had voltages between 0.5 and 1.5 mV. A PA threshold >4 was the most accurate DTI-derived measure of infarct size and demonstrated the greatest correlation with LGE (r=0.95). CONCLUSIONS: We found a strong correlation between infarct size by PA and LGE in both mice and humans. There was also an inverse relationship between PA values and endocardial voltage. The use of PA may enable myocardial scar delineation and characterization of arrhythmogenic substrate without the need for exogenous contrast agents. PMID- 29420218 TI - Neighborhood Socioeconomic Status and Outcomes Following the Norwood Procedure: An Analysis of the Pediatric Heart Network Single Ventricle Reconstruction Trial Public Data Set. AB - BACKGROUND: Children with single ventricle heart disease require frequent interventions and follow-up. Low socioeconomic status (SES) may limit access to high-quality care and place these children at risk for poor long-term outcomes. METHODS AND RESULTS: Data from the SVR (Pediatric Heart Network Single Ventricle Reconstruction Trial Public Use) data set were used to examine the relationship of US neighborhood SES with 30-day and 1-year mortality or cardiac transplantation and length of stay among neonates undergoing the Norwood procedure (n=525). Crude rates of death or transplantation at 1 year after Norwood were highest for patients living in neighborhoods with low SES (lowest tertile 37.0% versus middle tertile 31.0% versus highest tertile 23.6%, P=0.024). After adjustment for patient demographics, birth characteristics, and anatomy, patients in the highest SES tertile had significantly lower risk of death or transplant than patients in the lowest SES tertile (hazard ratio 0.62, 95% confidence interval, 0.40, 0.96). When SES was examined continuously, the hazard of 1-year death or transplant decreased steadily with increasing neighborhood SES. Hazard ratios for 30-day transplant-free survival and 1-year transplant-free survival were similar in magnitude. There were no significant differences in length of stay following the Norwood procedure by SES. CONCLUSIONS: Low neighborhood SES is associated with worse 1-year transplant-free survival after the Norwood procedure, suggesting that socioeconomic and environmental factors may be important determinants of outcome in critical congenital heart disease. Future studies should investigate aspects of SES and environment amenable to intervention. CLINICAL TRIAL REGISTRATION: URL:http://www.clinicaltrials.gov> http://www.clinicaltrials.gov. Unique identifier: NCT00115934. PMID- 29420219 TI - Neopterin Counters Vascular Inflammation and Atherosclerosis. AB - BACKGROUND: Neopterin, a metabolite of GTP, is produced by activated macrophages and is abundantly expressed within atherosclerotic lesions in human aorta and carotid and coronary arteries. We aimed to clarify the influence of neopterin on both vascular inflammation and atherosclerosis, as neither effect had been fully assessed. METHODS AND RESULTS: We investigated neopterin expression in coronary artery lesions and plasma from patients with coronary artery disease. We assessed the atheroprotective effects of neopterin in vitro using human aortic endothelial cells, human monocyte-derived macrophages, and human aortic smooth muscle cells. In vivo experiments included a study of aortic lesions in apolipoprotein E deficient mice. Neopterin expression in coronary artery lesions and plasma was markedly increased in patients with versus without coronary artery disease. In human aortic endothelial cells, neopterin reduced proliferation and TNF-alpha (tumor necrosis factor alpha)-induced upregulation of MCP-1 (monocyte chemotactic protein 1), ICAM-1 (intercellular adhesion molecule 1), and VCAM-1 (vascular cell adhesion molecule 1). Neopterin attenuated TNF-alpha-induced monocyte adhesion to human aortic endothelial cells and the inflammatory macrophage phenotype via NF kappaB (nuclear factor-kappaB) downregulation. Neopterin suppressed oxidized low density lipoprotein-induced foam cell formation associated with CD36 downregulation and upregulation of ATP-binding cassette transporters A1 and G1 in human monocyte-derived macrophages. In human aortic smooth muscle cells, neopterin suppressed angiotensin II-induced migration and proliferation via c Src/Raf-1/ERK1/2 downregulation without inducing apoptosis. Exogenous neopterin administration and endogenous neopterin attenuation with its neutralizing antibody for 4 weeks retarded and promoted, respectively, the development of aortic atherosclerotic lesions in apolipoprotein E-deficient mice. CONCLUSIONS: Our results indicate that neopterin prevents both vascular inflammation and atherosclerosis and may be induced to counteract the progression of atherosclerotic lesions. Consequently, neopterin could be of use as a novel therapeutic target for atherosclerotic cardiovascular diseases. PMID- 29420220 TI - BQ323636.1, a Novel Splice Variant to NCOR2, as a Predictor for Tamoxifen Resistant Breast Cancer. AB - Purpose: Adjuvant tamoxifen treatment revolutionized the management of estrogen receptor (ER)-positive breast cancers to prevent cancer recurrence; however, drug resistance compromises its clinical efficacy. The mechanisms underlying tamoxifen resistance are not fully understood, and no robust biomarker is available to reliably predict those who will be resistant. Here, we study BQ323636.1, a novel splice variant of the NCOR2 gene, and evaluate its efficacy in predicting tamoxifen resistance in patients with breast cancer.Experimental Design: A monoclonal anti-BQ323636.1 antibody that specifically recognizes the unique epitope of this splice variant was generated for in vitro mechanistic studies and for in vivo analysis by immunohistochemistry on tissue microarrays of two independent cohorts of 358 patients with more than 10 years clinical follow-up data, who had ER-positive primary breast cancer and received adjuvant tamoxifen treatment. An orthotopic mouse model was also used.Results: Overexpression of BQ323636.1 conferred resistance to tamoxifen in both in vitro and in an orthotopic mouse model. Mechanistically, coimmunoprecipitation showed BQ323636.1 could bind to NCOR2 and inhibit the formation of corepressor complex for the suppression of ER signaling. Nuclear BQ3232636.1 overexpression in patients samples was significantly associated with tamoxifen resistance (P = 1.79 * 10-6, sensitivity 52.9%, specificity 72.0%). In tamoxifen-treated patients, nuclear BQ323636.1 overexpression was significantly correlated with cancer metastasis and disease relapse. Nuclear BQ323636.1 was also significantly associated with poorer overall survival (P = 1.13 * 10-4) and disease-specific survival (P = 4.02 * 10 5).Conclusions: These findings demonstrate that BQ323636.1 can be a reliable biomarker to predict tamoxifen resistance in patients with ER-positive breast cancer. Clin Cancer Res; 24(15); 3681-91. (c)2018 AACRSee related commentary by Jordan, p. 3480. PMID- 29420221 TI - Adjuvant Transarterial Chemoembolization for HBV-Related Hepatocellular Carcinoma After Resection: A Randomized Controlled Study. AB - Purpose: The survival of patients with hepatocellular carcinoma (HCC) recurrence after curative resection is usually poor. We sought to evaluate the safety and efficacy of adjuvant transarterial chemoembolization (TACE) in HBV-related HCC patients with an intermediate (a single tumor larger than 5 cm without microvascular invasion) or high risk (a single tumor with microvascular invasion, or two or three tumors) of recurrence.Experimental Design: In this randomized phase 3 trial, 280 eligible patients were assigned to adjuvant TACE (n = 140) or no adjuvant treatment (control; n = 140) groups. The primary endpoint was recurrence-free survival (RFS); secondary endpoints included overall survival (OS) and safety. Multivariable Cox-proportional hazards model was used to determine the independent impact of TACE on patients' outcomes.Results: Patients who received adjuvant TACE had a significantly longer RFS than those in the control group [56.0% vs. 42.1%, P = 0.01; HR, 0.68; 95% confidence interval (CI), 0.49-0.93]. Patients in the adjuvant TACE group had 7.8% higher 3-year OS rate than the control group (85.2% vs. 77.4%; P = 0.04; HR, 0.59; 95% CI, 0.36-0.97). The impact of adjuvant TACE on RFS and OS remained significant after controlling for other known prognostic factors (HR, 0.67; P = 0.01 for RFS; and HR, 0.59; P = 0.04 for OS). There was no grade 3 or 4 toxicity after adjuvant TACE.Conclusions: For patients with HBV-related HCC who had an intermediate or high risk of recurrence after curative hepatectomy, our study showed adjuvant TACE significantly reduced tumor recurrence, improved RFS and OS, and the procedure was well tolerated. Clin Cancer Res; 24(9); 2074-81. (c)2018 AACR. PMID- 29420222 TI - Human Papillomavirus DNA Methylation as a Biomarker for Cervical Precancer: Consistency across 12 Genotypes and Potential Impact on Management of HPV Positive Women. AB - Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated.Experimental Design: In this nested case-control study, we tested up to 30 cases of precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi type methylation assay with current triage strategies.Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives.Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. Clin Cancer Res; 24(9); 2194-202. (c)2018 AACR. PMID- 29420223 TI - Oxidative Phosphorylation as an Emerging Target in Cancer Therapy. AB - Cancer cells have upregulated glycolysis compared with normal cells, which has led many to the assumption that oxidative phosphorylation (OXPHOS) is downregulated in all cancers. However, recent studies have shown that OXPHOS can be also upregulated in certain cancers, including leukemias, lymphomas, pancreatic ductal adenocarcinoma, high OXPHOS subtype melanoma, and endometrial carcinoma, and that this can occur even in the face of active glycolysis. OXPHOS inhibitors could therefore be used to target cancer subtypes in which OXPHOS is upregulated and to alleviate therapeutically adverse tumor hypoxia. Several drugs including metformin, atovaquone, and arsenic trioxide are used clinically for non oncologic indications, but emerging data demonstrate their potential use as OXPHOS inhibitors. We highlight novel applications of OXPHOS inhibitors with a suitable therapeutic index to target cancer cell metabolism. Clin Cancer Res; 24(11); 2482-90. (c)2018 AACR. PMID- 29420225 TI - Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis. AB - OBJECTIVES: Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. Diverse aetiological agents and wide heterogeneity in individual tumours impede effective and personalised treatment. Tonicity responsive enhancer-binding protein (TonEBP) is a transcriptional cofactor for the expression of proinflammatory genes. Although inflammation is intimately associated with the pathogenesis of HCC, the role of TonEBP is unknown. We aimed to identify function of TonEBP in HCC. DESIGN: Tumours with surrounding hepatic tissues were obtained from 296 patients with HCC who received completion resection. TonEBP expression was analysed by quantitative reverse transcription quantitative real-time PCR (RT-PCR) and immunohfistochemical analyses of tissue microarrays. Mice with TonEBP haplodeficiency, and hepatocyte-specific and myeloid-specific TonEBP deletion were used along with HCC and hepatocyte cell lines. RESULTS: TonEBP expression is higher in tumours than in adjacent non tumour tissues in 92.6% of patients with HCC regardless of aetiology associated. The TonEBP expression in tumours and adjacent non-tumour tissues predicts recurrence, metastasis and death in multivariate analyses. TonEBP drives the expression of cyclo-oxygenase-2 (COX-2) by stimulating the promoter. In mouse models of HCC, three common sites of TonEBP action in response to diverse aetiological agents leading to tumourigenesis and tumour growth were found: cell injury and inflammation, induction by oxidative stress and stimulation of the COX 2 promoter. CONCLUSIONS: TonEBP is a key component of the common pathway in tumourigenesis and tumour progression of HCC in response to diverse aetiological insults. TonEBP is involved in multiple steps along the pathway, rendering it an attractive therapeutic target as well as a prognostic biomarker. PMID- 29420224 TI - Precision Oncology Decision Support: Current Approaches and Strategies for the Future. AB - With the increasing availability of genomics, routine analysis of advanced cancers is now feasible. Treatment selection is frequently guided by the molecular characteristics of a patient's tumor, and an increasing number of trials are genomically selected. Furthermore, multiple studies have demonstrated the benefit of therapies that are chosen based upon the molecular profile of a tumor. However, the rapid evolution of genomic testing platforms and emergence of new technologies make interpreting molecular testing reports more challenging. More sophisticated precision oncology decision support services are essential. This review outlines existing tools available for health care providers and precision oncology teams and highlights strategies for optimizing decision support. Specific attention is given to the assays currently available for molecular testing, as well as considerations for interpreting alteration information. This article also discusses strategies for identifying and matching patients to clinical trials, current challenges, and proposals for future development of precision oncology decision support. Clin Cancer Res; 24(12); 2719 31. (c)2018 AACR. PMID- 29420227 TI - Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn's disease : a randomised controlled trial. AB - OBJECTIVE: Crohn's disease (CD) pathogenesis associated with dysbiosis and presence of pathobionts in the lumen, intracellular compartments and epithelial biofilms. Azithromycin is active in all three compartments. Our goal was to evaluate if azithromycin-based therapy can improve response and induce remission compared with metronidazole alone in paediatric CD. DESIGN: This blinded randomised controlled trial allocated children 5-18 years with 1012.5 or remission using intention to treat analysis. RESULTS: 73 patients (mean age 13.8+/-3.1 years) were enrolled, 35 to group 1 and 38 to group 2. Response and remission rates at week 8 were identical 23/35 (66%) in group 1 and 17/38 (45%) and 15/38 (39%) in group 2 (P=0.07 and P=0.025, respectively). The needed to treat for remission was 3.7. Faecal calprotectin declined significantly in group 1 (P=0.003) but not in group 2 (p=0.33), and was lower at week 8 (P=0.052). Additional therapy was required in 6/35(17%) from group 1 versus 16/38(42%) in group 2 (P=0.027) by week 8. Among 12 failures in group 2, open-label azithromycin led to remission in 10/12 (83%). CONCLUSIONS: The combination of azithromycin and metronidazole failed to improve response but was superior for induction of remission and reduction in calprotectin. TRIAL REGISTRATION NUMBER: NCT01596894. PMID- 29420226 TI - Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study. AB - OBJECTIVE: For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. DESIGN: We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4-10 weeks after surgery. Somatic mutations in individual patient's tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. RESULTS: We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). CONCLUSION: Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy. PMID- 29420228 TI - Backlog of missing GP letters is worse than feared. PMID- 29420229 TI - Sociodemographic differences in symptom severity and duration among women referred to secondary care for menorrhagia in England and Wales: a cohort study from the National Heavy Menstrual Bleeding Audit. AB - OBJECTIVE: To examine symptom severity and duration at time of referral to secondary care for heavy menstrual bleeding (HMB) by socioeconomic deprivation, age and ethnicity DESIGN: Cohort analysis of data from the National HMB Audit linked to Hospital Episode Statistics data. SETTING: English and Welsh National Health Services (secondary care): February 2011 to January 2012. PARTICIPANTS: 15 325 women aged 18-60 years in England and Wales who had a new referral for HMB to a gynaecology outpatient department METHODS: Multivariable linear regression to calculate adjusted differences in mean symptom severity and quality of life scores at first outpatient visit. Multivariable logistic regression to calculate adjusted ORs. Adjustment for body mass index, parity and comorbidities. PRIMARY OUTCOME MEASURES: Mean symptom severity score (0=best, 100=worst), mean condition specific quality of life score (0=worst, 100=best) and symptom duration (>=1 year). RESULTS: Women were on average 42 years old and 12% reported minority ethnic backgrounds. Mean symptom severity and condition-specific quality of life scores were 61.8 and 34.7. Almost three-quarters of women (74%) reported having had symptoms for >=1 year. Women from more deprived areas had more severe symptoms at their first outpatient visit (difference -6.1; 95% CI-7.2 to -4.9, between least and most deprived quintiles) and worse condition-specific quality of life (difference 6.3; 95% CI 5.1 to 7.5). Symptom severity declined with age while quality of life improved. CONCLUSIONS: Women living in more deprived areas reported more severe HMB symptoms and poorer quality of life at the start of treatment in secondary care. Providers should examine referral practices to explore if these differences reflect women's health-seeking behaviour or how providers decide whether or not to refer. PMID- 29420230 TI - Detailed systematic analysis of recruitment strategies in randomised controlled trials in patients with an unscheduled admission to hospital. AB - OBJECTIVES: To examine the design and findings of recruitment studies in randomised controlled trials (RCTs) involving patients with an unscheduled hospital admission (UHA), to consider how to optimise recruitment in future RCTs of this nature. DESIGN: Studies within the ORRCA database (Online Resource for Recruitment Research in Clinical TriAls; www.orrca.org.uk) that reported on recruitment to RCTs involving UHAs in patients >18 years were included. Extracted data included trial clinical details, and the rationale and main findings of the recruitment study. RESULTS: Of 3114 articles populating ORRCA, 39 recruitment studies were eligible, focusing on 68 real and 13 hypothetical host RCTs. Four studies were prospectively planned investigations of recruitment interventions, one of which was a nested RCT. Most recruitment papers were reports of recruitment experiences from one or more 'real' RCTs (n=24) or studies using hypothetical RCTs (n=11). Rationales for conducting recruitment studies included limited time for informed consent (IC) and patients being too unwell to provide IC. Methods to optimise recruitment included providing patients with trial information in the prehospital setting, technology to allow recruiters to cover multiple sites, screening logs to uncover recruitment barriers, and verbal rather than written information and consent. CONCLUSION: There is a paucity of high quality research into recruitment in RCTs involving UHAs with only one nested randomised study evaluating a recruitment intervention. Among the remaining studies, methods to optimise recruitment focused on how to improve information provision in the prehospital setting and use of screening logs. Future research in this setting should focus on the prospective evaluation of the well-developed interventions to optimise recruitment. PMID- 29420231 TI - Perceptions, experiences and expectations of physicians regarding the role of pharmacists in low-income and middle-income countries: the case of Tehran hospital settings. AB - OBJECTIVE: Pharmacists play a pivotal role in the health continuum, and the perceptions and expectations of physicians towards pharmacists have been reported as a key factor in the interprofessional relationship. This study aimed to elicit the perceptions and expectations of physicians towards the role of pharmacists in hospitals to clarify the level of interaction between physicians and pharmacists in hospital settings. DESIGN: A cross-sectional survey using a self-administered questionnaire was conducted to collect data in 2016. METHODS: A cross-sectional study was carried out at 20 large government hospitals in Tehran Province. Data was collected using a questionnaire consisting of four sections. It includes a section on demographic profile and three sections to measure the perceptions of physicians towards pharmacists, the expectations of physicians and their experiences with pharmacists, respectively. RESULTS: More than two-thirds of physicians (67.2%) agreed that pharmacists were a reliable source of general drug information. The majority of physicians (90.6%) expected pharmacists to advise their patients about the dose and administration of their medications. Almost half of the physicians (51.6%) agreed that they were usually informed by pharmacists regarding potential problems in their prescriptions. Both senior and junior residents had the view that pharmacists would inform them if any potential problems with their prescriptions were discovered (P=0.04). CONCLUSION: This study demonstrated that physicians had positive view on pharmacists' clinically defined roles and also accepted pharmacists as a valuable source of general drug information. However, the perceptions and expectations of physicians towards pharmacists did not match their real experience. Therefore, improving the awareness of physicians about the benefits of interprofessional collaboration with pharmacists seems to be a key step towards the implementation of pharmaceutical care practices in Iran. PMID- 29420232 TI - Better outcome from arthroscopic partial meniscectomy than skin incisions only? A sham-controlled randomised trial in patients aged 35-55 years with knee pain and an MRI-verified meniscal tear. AB - OBJECTIVE: Compare arthroscopic partial meniscectomy to a true sham intervention. METHODS: Sham-controlled superiority trial performed in three county hospitals in Denmark comparing arthroscopic partial meniscectomy to skin incisions only in patients aged 35-55 years with persistent knee pain and an MRI-confirmed medial meniscus lesion. A computer-generated table of random numbers generated two comparison groups. Participants and outcome assessors were blinded to group allocation. Exclusions were locking knees, high-energy trauma or severe osteoarthritis. Outcomes were collected at baseline, 3 and 24 months. We hypothesised no difference between groups. The primary outcome was the between group difference in change from baseline to 2 years in the mean score across all five normalised Knee injury and Osteoarthritis Outcome Score (KOOS) subscales (KOOS5). RESULTS: Forty-four patients (of the estimated 72) underwent randomisation; 22 in each group. Sixteen participants (36%) were non-blinded and eight participants (36%) from the sham group crossed over to the surgery group prior to the 2-year follow-up. At 2 years, both groups reported clinically relevant improvements (surgery 21.8, skin incisions only 13.6), the mean difference between groups was 8.2 in favour of surgery, which is slightly less than the cut-off of 10 prespecified to represent a clinically relevant difference; judged by the 95% CI (-3.4 to 19.8), a possibility of clinically relevant difference could not be excluded. In total, nine participants experienced 11 adverse events; six in the surgery group and three in the skin incisions-only group. CONCLUSION: We found greater improvement from arthroscopic partial meniscectomy compared with skin incisions only at 2 years, with the statistical uncertainty of the between-group difference including what could be considered clinically relevant. Because of the study being underpowered, nearly half in the sham group being non-blinded and one-third crossing over to surgery, the results cannot be generalised to the greater patient population. TRIAL REGISTRATION NUMBER: NCT01264991. PMID- 29420233 TI - Using confirmatory factor analysis to explore associated factors of intimate partner violence in a sample of Chinese rural women: a cross-sectional study. AB - OBJECTIVES: To estimate the prevalence of intimate partner violence (IPV) among a sample of rural Chinese women and to explore associated factors. DESIGN: Cross sectional study. SETTING: Rural areas of Guangyuan City, Sichuan, China. PARTICIPANTS: We recruited 1501 women, aged 16 years and older, who had been living locally for at least 2 years and reported being married or in a relationship during the past 12 months. They were among a sample of 1898 potential participants from our larger parent study on the prevalence of depressive-distress symptoms. METHODS: Participants completed demographic and social economic measures, the Short Form of the Revised Conflict Tactics Scale and the Duke Social Support Index. We applied chi2 test, analysis of variance and confirmatory factor analysis for analysis. RESULTS: The overall prevalence of IPV in the past 12 months was 29.05%; the prevalence of physical, psychological and sexual violence was 7.66%, 26.58% and 3.20%, respectively. The overall prevalence was highest among women aged 16-29 years, and was more common among those without a high school diploma and who saw their family's financial status as very poor or stagnant. Women who were not victims of IPV had higher levels of social support. Confirmatory factor analysis showed that the total effects of social support on physical, psychological and sexual violence were -0.12, -0.35 and -0.12, respectively. The indirect effects of objective economic status on physical, psychological and sexual violence were -0.047, -0.014 and -0.047, respectively, but the total effect was not significant. The indirect effect of education on psychological violence was -0.056. CONCLUSION: IPV is common in rural Guangyuan. Our data are comparable with the findings from north-west of China. Social support is an important protective factor. Future work is needed to develop, test and later disseminate potential IPV interventions, with a focus on building actual and perceived supportive social networks. PMID- 29420234 TI - 'Care Under Pressure': a realist review of interventions to tackle doctors' mental ill-health and its impacts on the clinical workforce and patient care. AB - INTRODUCTION: Mental ill-health is prevalent across all groups of health professionals and this is of great concern in many countries. In the UK, the mental health of the National Health Service (NHS) workforce is a major healthcare issue, leading to presenteeism, absenteeism and loss of staff from the workforce. Most interventions targeting doctors aim to increase their 'productivity' and 'resilience', placing responsibility for good mental health with doctors themselves and neglecting the organisational and structural contexts that may have a detrimental effect on doctors' well-being. There is a need for approaches that are sensitive to the contextual complexities of mental ill-health in doctors, and that do not treat doctors as a uniform body, but allow distinctions to account for particular characteristics, such as specialty, career stage and different working environments. METHODS AND ANALYSIS: Our project aims to understand how, why and in what contexts support interventions can be designed to minimise the incidence of doctors' mental ill-health. We will conduct a realist review-a form of theory-driven interpretative systematic review-of interventions, drawing on diverse literature sources. The review will iteratively progress through five steps: (1) locate existing theories; (2) search for evidence; (3) select articles; (4) extract and organise data and (5) synthesise evidence and draw conclusions. The analysis will summarise how, why and in what circumstances doctors' mental ill-health is likely to develop and what can remediate the situation. Throughout the project, we will also engage iteratively with diverse stakeholders in order to produce actionable theory. ETHICS AND DISSEMINATION: Ethical approval is not required for our review. Our dissemination strategy will be participatory. Tailored outputs will be targeted to: policy makers; NHS employers and healthcare leaders; team leaders; support organisations; doctors experiencing mental ill-health, their families and colleagues. PROSPERO REGISTRATION NUMBER: CRD42017069870. PMID- 29420236 TI - Risk factors, diagnosis and non-surgical treatment for meniscal tears: evidence and recommendations: a statement paper commissioned by the Danish Society of Sports Physical Therapy (DSSF). AB - This statement aimed at summarising and appraising the available evidence for risk factors, diagnostic tools and non-surgical treatments for patients with meniscal tears. We systematically searched electronic databases using a pragmatic search strategy approach. Included studies were synthesised quantitatively or qualitatively, as appropriate. Strength of evidence was determined according to the Grading of Recommendations Assessment Development and Evaluation framework. Low-quality evidence suggested that overweight (degenerative tears, k=3), male sex (k=4), contact and pivoting sports (k=2), and frequent occupational kneeling/squatting (k=3) were risk factors for meniscal tears. There was low to moderate quality evidence for low to high positive and negative predictive values, depending on the underlying prevalence of meniscal tears for four common diagnostic tests (k=15, n=2474). Seven trials investigated exercise versus surgery (k=2) or the effect of surgery in addition to exercise (k=5) for degenerative meniscal tears. There was moderate level of evidence for exercise improving self-reported pain (Effect Size (ES)-0.51, 95% CI -1.16 to 0.13) and function (ES -0.06, 95% CI -0.23 to 0.11) to the same extent as surgery, and improving muscle strength to a greater extent than surgery (ES -0.45, 95% CI 0.62 to -0.29). High-quality evidence showed no clinically relevant effect of surgery in addition to exercise on pain (ES 0.18, 95% 0.05 to 0.32) and function (ES, 0.13 95% CI -0.03 to 0.28) for patients with degenerative meniscal tears. No randomised trials comparing non-surgical treatments with surgery in patients younger than 40 years of age or patients with traumatic meniscal tears were identified. Diagnosis of meniscal tears is challenging as all clinical diagnostic tests have high risk of misclassification. Exercise therapy should be recommended as the treatment of choice for middle-aged and older patients with degenerative meniscal lesions. Evidence on the best treatment for young patients and patients with traumatic meniscal tears is lacking. PMID- 29420237 TI - Better than what? Comparisons in low back pain clinical trials. PMID- 29420235 TI - Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance. AB - Caseinolytic peptidase P (ClpP) is a mammalian quality control protease that is proposed to play an important role in the initiation of the mitochondrial unfolded protein response (UPRmt), a retrograde signaling response that helps to maintain mitochondrial protein homeostasis. Mitochondrial dysfunction is associated with the development of metabolic disorders, and to understand the effect of a defective UPRmt on metabolism, ClpP knockout (ClpP-/-) mice were analyzed. ClpP-/- mice fed ad libitum have reduced adiposity and paradoxically improved insulin sensitivity. Absence of ClpP increased whole-body energy expenditure and markers of mitochondrial biogenesis are selectively up-regulated in the white adipose tissue (WAT) of ClpP-/- mice. When challenged with a metabolic stress such as high-fat diet, despite similar caloric intake, ClpP-/- mice are protected from diet-induced obesity, glucose intolerance, insulin resistance, and hepatic steatosis. Our results show that absence of ClpP triggers compensatory responses in mice and suggest that ClpP might be dispensable for mammalian UPRmt initiation. Thus, we made an unexpected finding that deficiency of ClpP in mice is metabolically beneficial. PMID- 29420238 TI - Poverty and reductions in fitness levels in children and adolescents in upper middle-income countries. PMID- 29420239 TI - Depression and anxiety symptoms in 17 teams of female football players including 10 German first league teams. AB - BACKGROUND: Information on the prevalence of mental health problems of elite athletes is inconclusive, most probably due to methodological limitations, such as low response rates, heterogeneous samples. AIMS: To evaluate the prevalence and risk factors of depression and anxiety symptoms in high-level female football players. METHODS: Female football players of 10 German first league (Bundesliga) and 7 lower league teams were asked to answer a questionnaire on players' characteristics, the Center of Epidemiologic Studies Depression Scale (CES-D) and the Generalised Anxiety Disorder (GAD-7) scale. RESULTS: A total of 290 players (184 first and 106 lower league players) took part in the study. The CES-D score indicated mild to moderate symptoms of depression in 48 (16.6%) and severe symptoms in 41 (14.1%) players. The GAD-7 score indicated an at least moderate generalised anxiety disorder in 24 (8.3%) players. The prevalence of depression symptoms and generalised anxiety disorders was similar to the female general population of similar age. However, significantly more second league players reported symptoms of depression than first league players, and thus the prevalence of depression symptoms in second league players was higher than in the general population. Only a third of the 45 (15.7%) players who stated that they currently wanted or needed psychotherapeutic support received it. CONCLUSION: The prevalence of depression and generalised anxiety symptoms in elite football players is influenced by personal and sport-specific variables. It is important to raise awareness of athletes' mental health problems in coaches and team physicians, to reduce stigma and to provide low-threshold treatment. PMID- 29420240 TI - Is it time to give population health surveillance a late fitness test? PMID- 29420241 TI - Sports medicine highlights from other journals. PMID- 29420242 TI - Peripheral T-cell lymphoma mimicking classic Hodgkin's lymphoma in a patient presenting with fevers of unknown origin. AB - A 52-year-old man presented to our hospital for further workup of fever of unknown origin after an extensive workup at an outside hospital had failed to reveal a diagnosis. At the outside hospital, he underwent excisional biopsy of the left supraclavicular lymph node, which showed non-necrotising granulomatous changes, and a bone marrow biopsy which showed a normocellular marrow. He was discharged without a diagnosis with recommendations to present to a tertiary hospital. During his admission, his hospital course was complicated by new direct hyperbilirubinaemia and eosinophilia, prompting liver and skin biopsies which showed CD30+ and CD3+ cells. He subsequently underwent left axillary lymph node biopsy, which was reported as 'classic Hodgkin's lymphoma'. With worsening lab values and T cells noted on liver and skin biopsies, excisional lymph node biopsy was sent to the National Institute of Health, where it was confirmed patient had peripheral T cell lymphoma. PMID- 29420243 TI - Mycobacterium shimoidei: an uncommon non-tuberculous infection in a UK patient. AB - We present the case of a 69-year-old man with significant respiratory comorbidities who presented with slow growing pulmonary nodules which cavitated. Subsequent sputum sampling grew Mycobacterium shimoidei, a non-tuberculous mycobacterium species and an uncommon cause of infection in the UK. We describe the diagnostic process and subsequent treatment regimen. PMID- 29420244 TI - Chronic lymphocytic leukaemia with necrotic herpetic adenitis: an elusive clinical condition. AB - Herpes simplex virus (HSV) adenitis is a rare but important cause of morbidity in immunocompromised patients. Chronic lymphocytic leukaemia (CLL)/Small lymphocytic lymphoma (SLL) is an indolent disease which impairs the cellular and humoral immunity, predisposing patients to a myriad of infections. Clinically, herpetic adenitis can mimic large cell (Richter's) transformation in patients with CLL. To date, less than 30 cases of HSV adenitis have been reported in the literature. We report a case of a patient with CLL with no prior history of HSV infection, who presented with rapidly enlarging lymph nodes after initial response to idelalisib raising the suspicion of Richter's transformation. However, excisional biopsy of a lymph node revealed HSV adenitis along with CLL, which was confirmed by immunohistochemical staining. PMID- 29420245 TI - Imported gnathostomiasis manifesting as cutaneous larva migrans and Loffler's syndrome. AB - Here, we report an unusual case of invasive gnathostomiasis in a returning traveller, with a shifting pattern of relapsing cutaneous disease. The previously fit and well 32-year-old man first presented with serpiginous, pruriginous erythematous tracks characteristic of cutaneous larva migrans shortly after returning from South-East Asia. He was systemically well with no other symptoms. After ivermectin therapy, he re-presented with respiratory symptoms, peripheral eosinophilia and transient pulmonary infiltrates; the classic triad of Loffler's syndrome associated with invasive helminth infection. Gnathostoma spinigerum immunoblot was positive. After a second round of ivermectin therapy his respiratory symptoms resolved, but the patient's cutaneous disease relapsed repeatedly over months, with migratory erythematous swellings appearing and settling after a few days. He was treated with a 21-day course of albendazole and is lesion free at 40 weeks post initial presentation. PMID- 29420246 TI - ARDS complicating pustular psoriasis: treatment with low-dose corticosteroids, vitamin C and thiamine. AB - We report the case of a 45-year-old Caucasian woman with a history of psoriasis, admitted to our Medical intensive care unit following the acute onset of diffuse rash and progressive dyspnoea and hypoxaemia requiring escalating respiratory support (continuous positive airway pressure of 10 cm H2O). Her chest X-ray was consistent with findings of non-cardiogenic pulmonary oedema. Echocardiogram was normal. Dermatology considered her skin lesions to be consistent with psoriasis vulgaris with pustular flare. In the absence of an identifiable cause for her respiratory failure, she was diagnosed with acute respiratory distress syndrome due to her psoriatic flare. Treatment with cyclosporine was initiated together with low-dose systemic corticosteroids, intravenous vitamin C and thiamine. The patient made a dramatic recovery being weaned to nasal cannulae within 24 hours after the initiation of this treatment protocol and was discharged home a few days later. PMID- 29420247 TI - Macrophages and cytotoxic T cells infiltrate the destructed mitral tissue in Kawasaki disease. AB - Kawasaki disease (KD) is an acute febrile systemic vasculitic syndrome especially affecting medium-sized arteries, including the coronary artery. Inflammation may involve all organs, and valvulitis is one of the cardiovascular complications that occurs in the acute phase of KD. However, details regarding the mechanism are unclear. An infant developed KD and severe mitral regurgitation with deformity and prolapse of the mitral tissue and underwent mitral valvotomy 1 year later. Histopathological study was conducted, and infiltrating cells consisted of mainly macrophages and cytotoxic T cells were found in resected mitral valve tissue. In addition, inflammation remained a long time after KD had developed. PMID- 29420248 TI - Acute pancreatitis due to a Bochdalek hernia in an adult patient. PMID- 29420250 TI - Role for MRP in the regulation of the epithelial cell cytoskeleton. PMID- 29420251 TI - Corrigendum. PMID- 29420252 TI - Role of osteopontin in decidualization and pregnancy success. AB - OPN is essential for blastocyst implantation and placentation. Previous study found that miR181a was increased while miR181b was downregulated in endometrium during decidualization. However, the information regarding their effects on decidualization in human endometrium is still limited. Here, we report a novel role of OPN and miR181b in uterine decidualization and pregnancy success in humans. The expression of OPN was high in endometrium in secretory phase and in vitro decidualized hESC, whereas miR181b expression was low in identical conditions. Further analysis confirmed that OPN expression was upregulated by cAMP and C/EBPbeta signal pathway, while downregulated by miR181b. Increased OPN expression could promote the expression of decidualization-related and angiogenesis-related genes. Conversely, the processes of decidualization and angiogenesis in hESC were compromised by inhibiting OPN expression in vitro OPN expression was repressed in implantation failure group when compared with successful pregnancy group in IVF/ICSI-ET cycles. These findings add a new line of evidence supporting the fact that OPN is involved in decidualization and pregnancy success. PMID- 29420253 TI - The C-X-C signalling system in the rodent vs primate testis: impact on germ cell niche interaction. AB - In zebrafish, action of the chemokine Cxcl12 is mediated through its G-protein coupled seven-transmembrane domain receptor Cxcr4 and the atypical receptor Cxcr7. Employing this animal model, it was revealed that this Cxcl12 signalling system plays a crucial role for directed migration of primordial germ cells (PGC) during early testicular development. Importantly, subsequent studies indicated that this regulatory mechanism is evolutionarily conserved also in mice. What is more, the functional role of the CXCL12 system does not seem to be limited to early phases of testicular development. Data from mouse studies rather demonstrate that CXCL12 and its receptors are also involved in the homing process of gonocytes into their niches at the basal membrane of the seminiferous tubules. Intriguingly, even the spermatogonial stem cells (SSCs) present in the adult mouse testis appear to maintain the ability to migrate towards a CXCL12 gradient as demonstrated by functional in vitro migration assays and in vivo germ cell transplantation assays. These findings not only indicate a role of the CXCL12 system throughout male germ cell development in mice but also suggest that this system may be evolutionarily conserved. In this review, we take into account the available literature focusing on the localization patterns of the CXCL12 system not only in rodents but also in primates, including the human. Based on these data, we discuss whether the CXCL12 system is also conserved between rodents and primates and discuss the known and potential functional consequences. PMID- 29420249 TI - Recent insights into the cellular and molecular determinants of aging. AB - Aging is the gradual decline of physiological functions and organismal fitness, which leads to age-dependent fitness loss, diseases and eventually mortality. Understanding the cause of aging constitutes one of most intriguing areas of research in biology. On both the cellular and molecular levels, it has been hypothesized that there are aging determinants to control the onset and progression of aging, including the loss of beneficial components and accumulation of detrimental factors. This Review highlights the recent advance in identifying various factors that affect the aging process, focusing on how these determinants affect the lifespan and fitness of a cell or organism. With more and more aging determinants revealed, further understanding about their functions and interconnections could enable the development of specific intervention to extend healthy lifespan and reduce the risk of age-related diseases. PMID- 29420255 TI - Development and Translational Application of a Minimal Physiologically Based Pharmacokinetic Model for a Monoclonal Antibody against Interleukin 23 (IL-23) in IL-23-Induced Psoriasis-Like Mice. AB - The interleukin (IL)-23/Th17/IL-17 immune pathway has been identified to play an important role in the pathogenesis of psoriasis. Many therapeutic proteins targeting IL-23 or IL-17 are currently under development for the treatment of psoriasis. In the present study, a mechanistic pharmacokinetics (PK)/pharmacodynamics (PD) study was conducted to assess the target-binding and disposition kinetics of a monoclonal antibody (mAb), CNTO 3723, and its soluble target, mouse IL-23, in an IL-23-induced psoriasis-like mouse model. A minimal physiologically based pharmacokinetic model with target-mediated drug disposition features was developed to quantitatively assess the kinetics and interrelationship between CNTO 3723 and exogenously administered, recombinant mouse IL-23 in both serum and lesional skin site. Furthermore, translational applications of the developed model were evaluated with incorporation of human PK for ustekinumab, an anti-human IL-23/IL-12 mAb developed for treatment of psoriasis, and human disease pathophysiology information in psoriatic patients. The results agreed well with the observed clinical data for ustekinumab. Our work provides an example on how mechanism-based PK/PD modeling can be applied during early drug discovery and how preclinical data can be used for human efficacious dose projection and guide decision making during early clinical development of therapeutic proteins. PMID- 29420254 TI - Methionine sulfoxide reductase B3 requires resolving cysteine residues for full activity and can act as a stereospecific methionine oxidase. AB - The oxidation of methionine residues in proteins occurs during oxidative stress and can lead to an alteration in protein function. The enzyme methionine sulfoxide reductase (Msr) reverses this modification. Here, we characterise the mammalian enzyme Msr B3. There are two splice variants of this enzyme that differ only in their N-terminal signal sequence, which directs the protein to either the endoplasmic reticulum (ER) or mitochondria. We demonstrate here that the enzyme can complement a bacterial strain, which is dependent on methionine sulfoxide reduction for growth, that the purified recombinant protein is enzymatically active showing stereospecificity towards R-methionine sulfoxide, and identify the active site and two resolving cysteine residues. The enzyme is efficiently recycled by thioredoxin only in the presence of both resolving cysteine residues. These results show that for this isoform of Msrs, the reduction cycle most likely proceeds through a three-step process. This involves an initial sulfenylation of the active site thiol followed by the formation of an intrachain disulfide with a resolving thiol group and completed by the reduction of this disulfide by a thioredoxin-like protein to regenerate the active site thiol. Interestingly, the enzyme can also act as an oxidase catalysing the stereospecific formation of R methionine sulfoxide. This result has important implications for the role of this enzyme in the reversible modification of ER and mitochondrial proteins. PMID- 29420256 TI - Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP. AB - Lower plasma nicotinamide phosphoribosyltransferase (NAMPT) levels are associated with improved response to methotrexate (MTX) in patients with juvenile idiopathic arthritis. Cell-based studies confirmed that reduced cellular NAMPT activity potentiates the pharmacologic activity of MTX; however, the mechanism of this interaction has yet to be defined. Therefore, in this study, we investigate the mechanism of enhanced pharmacologic activity of MTX in NAMPT-deficient A549 cells. Small interfering RNA-based silencing of NAMPT expression resulted in a greater than 3-fold increase in sensitivity to MTX (P < 0.005) that was completely reversed by supplementation with folinic acid. Despite a 68% reduction in cellular NAD levels in NAMPT-deficient cells, no change in expression or activity of dihydrofolate reductase was observed and uptake of MTX was not significantly altered. MTX did not potentiate the depletion of cellular NAD levels, but NAMPT-deficient cells had significant elevations in levels of intermediates of de novo purine biosynthesis and were 4-fold more sensitive to depletion of ATP by MTX (P < 0.005). Supplementation with hypoxanthine and thymidine completely reversed the antiproliferative activity of MTX in NAMPT deficient cells and corresponded to repletion of the cellular ATP pool without any effect on NAD levels. Together, these findings demonstrate that increased MTX activity with decreased NAMPT expression is dependent on the antifolate activity of MTX and is driven by enhanced sensitivity to the ATP-depleting effects of MTX. For the first time, these findings provide mechanistic details to explain the increase in pharmacological activity of MTX under conditions of reduced NAMPT activity. PMID- 29420257 TI - Psychological resilience and post-traumatic growth in disaster-exposed organisations: overview of the literature. AB - As disasters become increasingly prevalent, and reported on, a wealth of literature on post-disaster mental health has been published. Most published evidence focuses on symptoms of mental health problems (such as post-traumatic stress disorder, depression and anxiety) and psychosocial factors increasing the risk of such symptoms. However, a recent shift in the literature has moved to exploring resilience and the absence of adverse lasting mental health effects following a disaster. This paper undertakes a qualitative review of the literature to explore factors affecting psychological resilience, as well as the potential positive impact of experiencing a disaster (post-traumatic growth) by examining the literature on employees in disaster-exposed organisations. We identify several protective factors: training, experience, and perceived (personal) competence; social support; and effective coping strategies. Post traumatic growth frequently appeared to occur at both personal and professional levels for those rescue staff after a disaster, giving employees a greater appreciation of life and their relationships, enhancing their self-esteem and providing a sense of accomplishment and better understanding of their work. Implications, in terms of how to build a resilient workforce, are discussed. PMID- 29420259 TI - Oklahoma's induced seismicity strongly linked to wastewater injection depth. AB - The sharp rise in Oklahoma seismicity since 2009 is due to wastewater injection. The role of injection depth is an open, complex issue, yet critical for hazard assessment and regulation. We developed an advanced Bayesian network to model joint conditional dependencies between spatial, operational, and seismicity parameters. We found that injection depth relative to crystalline basement most strongly correlates with seismic moment release. The joint effects of depth and volume are critical, as injection rate becomes more influential near the basement interface. Restricting injection depths to 200 to 500 meters above basement could reduce annual seismic moment release by a factor of 1.4 to 2.8. Our approach enables identification of subregions where targeted regulation may mitigate effects of induced earthquakes, aiding operators and regulators in wastewater disposal regions. PMID- 29420258 TI - Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells. AB - Alveoli, the lung's respiratory units, are tiny sacs where oxygen enters the bloodstream. They are lined by flat alveolar type 1 (AT1) cells, which mediate gas exchange, and AT2 cells, which secrete surfactant. Rare AT2s also function as alveolar stem cells. We show that AT2 lung stem cells display active Wnt signaling, and many of them are near single, Wnt-expressing fibroblasts. Blocking Wnt secretion depletes these stem cells. Daughter cells leaving the Wnt niche transdifferentiate into AT1s: Maintaining Wnt signaling prevents transdifferentiation, whereas abrogating Wnt signaling promotes it. Injury induces AT2 autocrine Wnts, recruiting "bulk" AT2s as progenitors. Thus, individual AT2 stem cells reside in single-cell fibroblast niches providing juxtacrine Wnts that maintain them, whereas injury induces autocrine Wnts that transiently expand the progenitor pool. This simple niche maintains the gas exchange surface and is coopted in cancer. PMID- 29420260 TI - Topological insulator laser: Theory. AB - Topological insulators are phases of matter characterized by topological edge states that propagate in a unidirectional manner that is robust to imperfections and disorder. These attributes make topological insulator systems ideal candidates for enabling applications in quantum computation and spintronics. We propose a concept that exploits topological effects in a unique way: the topological insulator laser. These are lasers whose lasing mode exhibits topologically protected transport without magnetic fields. The underlying topological properties lead to a highly efficient laser, robust to defects and disorder, with single-mode lasing even at very high gain values. The topological insulator laser alters current understanding of the interplay between disorder and lasing, and at the same time opens exciting possibilities in topological physics, such as topologically protected transport in systems with gain. On the technological side, the topological insulator laser provides a route to arrays of semiconductor lasers that operate as one single-mode high-power laser coupled efficiently into an output port. PMID- 29420263 TI - Topological insulator laser: Experiments. AB - Physical systems exhibiting topological invariants are naturally endowed with robustness against perturbations, as manifested in topological insulators materials exhibiting robust electron transport, immune from scattering by defects and disorder. Recent years have witnessed intense efforts toward exploiting these phenomena in photonics. Here we demonstrate a nonmagnetic topological insulator laser system exhibiting topologically protected transport in the cavity. Its topological properties give rise to single-mode lasing, robustness against defects, and considerably higher slope efficiencies compared to the topologically trivial counterparts. We further exploit the properties of active topological platforms by assembling the system from S-chiral microresonators, enforcing predetermined unidirectional lasing without magnetic fields. This work paves the way toward active topological devices with exciting properties and functionalities. PMID- 29420262 TI - C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions. AB - Polymorphisms in C1orf106 are associated with increased risk of inflammatory bowel disease (IBD). However, the function of C1orf106 and the consequences of disease-associated polymorphisms are unknown. Here we demonstrate that C1orf106 regulates adherens junction stability by regulating the degradation of cytohesin 1, a guanine nucleotide exchange factor that controls activation of ARF6. By limiting cytohesin-1-dependent ARF6 activation, C1orf106 stabilizes adherens junctions. Consistent with this model, C1orf106-/- mice exhibit defects in the intestinal epithelial cell barrier, a phenotype observed in IBD patients that confers increased susceptibility to intestinal pathogens. Furthermore, the IBD risk variant increases C1orf106 ubiquitination and turnover with consequent functional impairments. These findings delineate a mechanism by which a genetic polymorphism fine-tunes intestinal epithelial barrier integrity and elucidate a fundamental mechanism of cellular junctional control. PMID- 29420265 TI - Climate, ecosystems, and planetary futures: The challenge to predict life in Earth system models. AB - Many global change stresses on terrestrial and marine ecosystems affect not only ecosystem services that are essential to humankind, but also the trajectory of future climate by altering energy and mass exchanges with the atmosphere. Earth system models, which simulate terrestrial and marine ecosystems and biogeochemical cycles, offer a common framework for ecological research related to climate processes; analyses of vulnerability, impacts, and adaptation; and climate change mitigation. They provide an opportunity to move beyond physical descriptors of atmospheric and oceanic states to societally relevant quantities such as wildfire risk, habitat loss, water availability, and crop, fishery, and timber yields. To achieve this, the science of climate prediction must be extended to a more multifaceted Earth system prediction that includes the biosphere and its resources. PMID- 29420266 TI - Our science, our society. PMID- 29420267 TI - News at a glance. PMID- 29420261 TI - Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. AB - Neuronal synapse formation and remodeling are essential to central nervous system (CNS) development and are dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this affects CNS synapses is largely unknown. Here, we show that the interleukin-1 family cytokine interleukin-33 (IL-33) is produced by developing astrocytes and is developmentally required for normal synapse numbers and neural circuit function in the spinal cord and thalamus. We find that IL-33 signals primarily to microglia under physiologic conditions, that it promotes microglial synapse engulfment, and that it can drive microglial-dependent synapse depletion in vivo. These data reveal a cytokine-mediated mechanism required to maintain synapse homeostasis during CNS development. PMID- 29420268 TI - India plans to land near moon's south pole. PMID- 29420269 TI - Judge orders unmasking of anonymous peer reviewers. PMID- 29420270 TI - NASA seeks to revive lost probe that traced solar storms. PMID- 29420271 TI - Forever young? Naked mole rats may know the secret. PMID- 29420272 TI - Accelerator boom hones China's engineering expertise. PMID- 29420273 TI - Dams nudge Amazon's ecosystems off-kilter. PMID- 29420274 TI - Human nature, observed. PMID- 29420275 TI - Out of balance in the Arctic. PMID- 29420276 TI - Enhancing responses to cancer immunotherapy. PMID- 29420277 TI - Stealth reactions driving carbon fixation. PMID- 29420278 TI - Lighting up superconducting stripes. PMID- 29420279 TI - Galaxy motions cause trouble for cosmology. PMID- 29420280 TI - Tracing single-cell histories. PMID- 29420281 TI - Scientifically assess impacts of sustainable investments. PMID- 29420282 TI - Malaria in Venezuela requires response. PMID- 29420283 TI - Integrated approach to malaria control. PMID- 29420284 TI - Response: Integrated approach to malaria control. PMID- 29420285 TI - A whirling plane of satellite galaxies around Centaurus A challenges cold dark matter cosmology. AB - The Milky Way and Andromeda galaxies are each surrounded by a thin plane of satellite dwarf galaxies that may be corotating. Cosmological simulations predict that most satellite galaxy systems are close to isotropic with random motions, so those two well-studied systems are often interpreted as rare statistical outliers. We test this assumption using the kinematics of satellite galaxies around the Centaurus A galaxy. Our statistical analysis reveals evidence for corotation in a narrow plane: Of the 16 Centaurus A satellites with kinematic data, 14 follow a coherent velocity pattern aligned with the long axis of their spatial distribution. In standard cosmological simulations, <0.5% of Centaurus A like systems show such behavior. Corotating satellite systems may be common in the universe, challenging small-scale structure formation in the prevailing cosmological paradigm. PMID- 29420286 TI - A primordial and reversible TCA cycle in a facultatively chemolithoautotrophic thermophile. AB - Inorganic carbon fixation is essential to sustain life on Earth, and the reductive tricarboxylic acid (rTCA) cycle is one of the most ancient carbon fixation metabolisms. A combination of genomic, enzymatic, and metabolomic analyses of a deeply branching chemolithotrophic Thermosulfidibacter takaii ABI70S6T revealed a previously unknown reversible TCA cycle whose direction was controlled by the available carbon source(s). Under a chemolithoautotrophic condition, a rTCA cycle occurred with the reverse reaction of citrate synthase (CS) and not with the adenosine 5'-triphosphate-dependent citrate cleavage reactions that had been regarded as essential for the conventional rTCA cycle. Phylometabolic evaluation suggests that the TCA cycle with reversible CS may represent an ancestral mode of the rTCA cycle and raises the possibility of a facultatively chemolithomixotrophic origin of life. PMID- 29420287 TI - Reversibility of citrate synthase allows autotrophic growth of a thermophilic bacterium. AB - Biological inorganic carbon fixation proceeds through a number of fundamentally different autotrophic pathways that are defined by specific key enzymatic reactions. Detection of the enzymatic genes in (meta)genomes is widely used to estimate the contribution of individual organisms or communities to primary production. Here we show that the sulfur-reducing anaerobic deltaproteobacterium Desulfurella acetivorans is capable of both acetate oxidation and autotrophic carbon fixation, with the tricarboxylic acid cycle operating either in the oxidative or reductive direction, respectively. Under autotrophic conditions, the enzyme citrate synthase cleaves citrate adenosine triphosphate independently into acetyl coenzyme A and oxaloacetate, a reaction that has been regarded as impossible under physiological conditions. Because this overlooked, energetically efficient carbon fixation pathway lacks key enzymes, it may function unnoticed in many organisms, making bioinformatical predictions difficult, if not impossible. PMID- 29420288 TI - High-energy, high-fat lifestyle challenges an Arctic apex predator, the polar bear. AB - Regional declines in polar bear (Ursus maritimus) populations have been attributed to changing sea ice conditions, but with limited information on the causative mechanisms. By simultaneously measuring field metabolic rates, daily activity patterns, body condition, and foraging success of polar bears moving on the spring sea ice, we found that high metabolic rates (1.6 times greater than previously assumed) coupled with low intake of fat-rich marine mammal prey resulted in an energy deficit for more than half of the bears examined. Activity and movement on the sea ice strongly influenced metabolic demands. Consequently, increases in mobility resulting from ongoing and forecasted declines in and fragmentation of sea ice are likely to increase energy demands and may be an important factor explaining observed declines in body condition and survival. PMID- 29420289 TI - Polarity compensation mechanisms on the perovskite surface KTaO3(001). AB - The stacking of alternating charged planes in ionic crystals creates a diverging electrostatic energy-a "polar catastrophe"-that must be compensated at the surface. We used scanning probe microscopies and density functional theory to study compensation mechanisms at the perovskite potassium tantalate (KTaO3) (001) surface as increasing degrees of freedom were enabled. The as-cleaved surface in vacuum is frozen in place but immediately responds with an insulator-to-metal transition and possibly ferroelectric lattice distortions. Annealing in vacuum allows the formation of isolated oxygen vacancies, followed by a complete rearrangement of the top layers into an ordered pattern of KO and TaO2 stripes. The optimal solution is found after exposure to water vapor through the formation of a hydroxylated overlayer with ideal geometry and charge. PMID- 29420290 TI - Probing optically silent superfluid stripes in cuprates. AB - Unconventional superconductivity in the cuprates coexists with other types of electronic order. However, some of these orders are invisible to most experimental probes because of their symmetry. For example, the possible existence of superfluid stripes is not easily validated with linear optics, because the stripe alignment causes interlayer superconducting tunneling to vanish on average. Here we show that this frustration is removed in the nonlinear optical response. A giant terahertz third harmonic, characteristic of nonlinear Josephson tunneling, is observed in La1.885Ba0.115CuO4 above the transition temperature Tc = 13 kelvin and up to the charge-ordering temperature Tco = 55 kelvin. We model these results by hypothesizing the presence of a pair density wave condensate, in which nonlinear mixing of optically silent tunneling modes drives large dipole-carrying supercurrents. PMID- 29420291 TI - Observation of chiral phonons. AB - Chirality reveals symmetry breaking of the fundamental interaction of elementary particles. In condensed matter, for example, the chirality of electrons governs many unconventional transport phenomena such as the quantum Hall effect. Here we show that phonons can exhibit intrinsic chirality in monolayer tungsten diselenide. The broken inversion symmetry of the lattice lifts the degeneracy of clockwise and counterclockwise phonon modes at the corners of the Brillouin zone. We identified the phonons by the intervalley transfer of holes through hole phonon interactions during the indirect infrared absorption, and we confirmed their chirality by the infrared circular dichroism arising from pseudoangular momentum conservation. The chiral phonons are important for electron-phonon coupling in solids, phonon-driven topological states, and energy-efficient information processing. PMID- 29420292 TI - The piRNA targeting rules and the resistance to piRNA silencing in endogenous genes. AB - Piwi-interacting RNAs (piRNAs) silence transposons to safeguard genome integrity in animals. However, the functions of the many piRNAs that do not map to transposons remain unknown. Here, we show that piRNA targeting in Caenorhabditis elegans can tolerate a few mismatches but prefer perfect pairing at the seed region. The broad targeting capacity of piRNAs underlies the germline silencing of transgenes in C. elegans Transgenes engineered to avoid piRNA recognition are stably expressed. Many endogenous germline-expressed genes also contain predicted piRNA targeting sites, and periodic An/Tn clusters (PATCs) are an intrinsic signal that provides resistance to piRNA silencing. Together, our study revealed the piRNA targeting rules and highlights a distinct strategy that C. elegans uses to distinguish endogenous from foreign nucleic acids. PMID- 29420294 TI - In praise of slow. PMID- 29420296 TI - Refining Radiation for the Next Century. PMID- 29420293 TI - Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. AB - Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis Genes for colibactin (clbB) and Bacteroides fragilis toxin (bft), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with E. coli (expressing colibactin), and enterotoxigenic B. fragilis showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria. PMID- 29420297 TI - The protein kinase D1-mediated classical protein secretory pathway regulates the Ras oncogene-induced senescence response. AB - Senescent cells develop a senescence-associated secretory phenotype (SASP). The factors secreted by cells with a SASP have multiple biological functions that are mediated in an autocrine or paracrine manner. However, the status of the protein kinase D1 (PKD1; also known as PRKD1)-mediated classical protein secretory pathway, from the trans-Golgi network (TGN) to the cell surface, during cellular senescence and its role in the cellular senescence response remain unknown. Here, we show that the activities or quantities of critical components of this pathway, including PKD1, ADP-ribosylation factor 1 (ARF1) and phosphatidylinositol 4 kinase IIIbeta (PI4KIIIbeta), at the TGN are increased in senescent cells. Blocking of this pathway decreases IL-6 and IL-8 (hereafter IL-6/IL-8) secretion and results in IL-6/IL-8 accumulation in SASP-competent senescent cells. Inhibition of this pathway reduces IL-6/IL-8 secretion during Ras oncogene induced senescence (OIS), retards Ras OIS and alleviates its associated ER stress and autophagy. Finally, targeting of this pathway triggers cell death in SASP factor-producing senescent cells due to the intracellular accumulation of massive amounts of IL-6/IL-8. Taken together, our results unveil the hyperactive state of the protein secretory pathway in SASP-competent senescent cells and its critical functions in mediating SASP factor secretion and the Ras OIS process, as well as in determining the fate of senescent cells. PMID- 29420299 TI - Phosphorylation of ARHGAP19 by CDK1 and ROCK regulates its subcellular localization and function during mitosis. AB - ARHGAP19 is a hematopoietic-specific Rho GTPase-activating protein (RhoGAP) that acts through the RhoA/ROCK pathway to critically regulate cell elongation and cytokinesis during lymphocyte mitosis. We report here that, during mitosis progression, ARHGAP19 is sequentially phosphorylated by the RhoA-activated kinases ROCK1 and ROCK2 (hereafter ROCK) on serine residue 422, and by CDK1 on threonine residues 404 and 476. The phosphorylation of ARHGAP19 by ROCK occurs before mitosis onset and generates a binding site for 14-3-3 family proteins. ARHGAP19 is then phosphorylated by CDK1 in prometaphase. The docking of 14-3-3 proteins to phosphorylated S422 protects ARHGAP19 from dephosphorylation of the threonine sites and prevents ARHGAP19 from relocating to the plasma membrane during prophase and metaphase, thus allowing RhoA to become activated. Disruption of these phosphorylation sites results in premature localization of ARHGAP19 at the cell membrane and in its enrichment to the equatorial cortex in anaphase leading to cytokinesis failure and cell multinucleation. PMID- 29420298 TI - The importance of membrane microdomains for bile salt-dependent biliary lipid secretion. AB - Alternative models explaining the biliary lipid secretion at the canalicular membrane of hepatocytes exist: successive lipid extraction by preformed bile salt micelles, or budding of membrane fragments with formation of mixed micelles. To test the feasibility of the latter mechanism, we developed a mathematical model that describes the formation of lipid microdomains in the canalicular membrane. Bile salt monomers intercalate into the external hemileaflet of the canalicular membrane, to form a rim to liquid disordered domain patches that then pinch off to form nanometer-scale mixed micelles. Model simulations perfectly recapitulate the measured dependence of bile salt-dependent biliary lipid extraction rates upon modulation of the membrane cholesterol (lack or overexpression of the cholesterol transporter Abcg5-Abcg8) and phosphatidylcholine (lack of Mdr2, also known as Abcb4) content. The model reveals a strong dependence of the biliary secretion rate on the protein density of the membrane. Taken together, the proposed model is consistent with crucial experimental findings in the field and provides a consistent explanation of the central molecular processes involved in bile formation. PMID- 29420300 TI - Sexual dimorphism in the width of the mouse synaptonemal complex. AB - Sexual dimorphism has been used to describe morphological differences between the sexes, but can be extended to any biologically related process that varies between males and females. The synaptonemal complex (SC) is a tripartite structure that connects homologous chromosomes in meiosis. Here, aided by super resolution microscopy techniques, we show that the SC is subject to sexual dimorphism, in mouse germ cells. We have identified a significantly narrower SC in oocytes and have established that this difference does not arise from a different organization of the lateral elements nor from a different isoform of transverse filament protein SYCP1. Instead, we provide evidence for the existence of a narrower central element and a different integration site for the C-termini of SYCP1, in females. In addition to these female-specific features, we speculate that post-translation modifications affecting the SYCP1 coiled-coil region could render a more compact conformation, thus contributing to the narrower SC observed in females. PMID- 29420301 TI - Numerical investigation of complete mandibular dentures stabilized by conventional or mini implants in patient individual models. AB - Poor stability of a complete denture is a common problem due to bone atrophy of the edentulous ridge. The aim of the present study was to analyze denture stability after receiving implants and to study the biomechanical properties of denture implants and the bone bed using conventional or mini implants. Five models based on computed tomography (CT) data of edentulous patients were created. The overdentures' connection to the implants was assured by means of ball head abutments and rubber rings. In three models, the denture was supported by two to four conventional implants and in two models, the overdenture was supported by three to five mini implants. The dentures were loaded according to the individual biting forces which was clinically measured by means of pressure sheets. After implantation, the biting forces and displacements of overdentures increased in comparison to complete dentures. Displacements and stresses were higher with mini implants than with conventional ones. Stress in the implants was markedly below the yield stress of titanium grade 5 (880 MPa). An increase in the stress in the bone around the implants was noticed as compared to the situation with complete dentures which was below the physiological range of bone loading (<4 MPa). PMID- 29420302 TI - OR.NET - secure dynamic networks in the operating room and clinic. PMID- 29420303 TI - Prognostic value of HE4 in patients with ovarian cancer. AB - Background There is no consensus in the medical community about the prognostic role of preoperative serum levels of human epididymis protein 4 (HE4) in ovarian cancer (OC). The purpose of this meta-analysis was to establish whether preoperative serum levels of HE4 are associated with OC prognosis. Content Eligible studies were searched for in PubMed, ClinicalTrials.gov, CNKI and Wanfang Med Online. We performed a meta-analysis of 1315 OC cases from 14 published articles. Summary Our meta-analysis demonstrated that high HE4 was associated with poor overall survival (OS) (random effects model, hazard ratio [HR]=1.91, 95% confidence interval [CI]=1.40-2.614, p<0.0001; I2=52%, p=0.04) and; progression-free survival (PFS) (random effects model, HR=1.38, 95% CI=1.13 1.69, p=0.002; I2=85%, p<0.00001). However, subgroup analysis showed that high HE4 was not associated with poor OS (fixed effects model, HR=1.86, 95% CI=0.89 3.89, p=0.1; I2=34%, p=0.22) or PFS (random effects model, HR=1.34, 95% CI=0.95 1.88, p=0.1; I2=69%, p=0.007) for studies including only Asian populations. Outlook In conclusion, this meta-analysis shows that high HE4 was associated with poor OC OS and PFS overall. However, the association of high HE4 with poor OS and PFS was not observed for Asians. Large-scale, multi-center investigations should be performed. PMID- 29420304 TI - Accurate determination of the CYP2D6 (*1/*4)xN genotype by quantitative PCR. AB - BACKGROUND: CYP2D6 is responsible for the metabolism of approximately 25% of all drugs. The expression of cytochrome P450 2D6 (CYP2D6) is influenced by a combination of factors including polymorphisms in the CYP2D6 gene. Analysis of the CYP2D6 genotype is used to personalize the medication to a patient's metabolism. Although many genotypes can be determined using standard genotype analysis, in some cases, an incomplete analysis is performed. The CYP2D6 genotype *1/*4 often occurs in combination with a multiplication of the CYP2D6 gene, and is reported as (*1/*4)xN. Accurate determination of the multiplied gene is essential to provide a phenotype prediction for these patients. Duplication of the *1 gene leads to an extensive metabolizer genotype whereas multiplication of the *4 gene would not lead to extra functional enzyme and therefore provides an intermediate metabolizer phenotype. METHODS: Here, a technique is described in which the copy numbers of both the *4 and *1 genes are determined using quantitative PCR techniques. RESULTS AND CONCLUSIONS: This technique provides a method to predict the patient's CYP2D6 phenotype, and is therefore an important step toward personalized medicine. PMID- 29420305 TI - Effect of SLCO1B1 gene polymorphisms and vitamin D on statin-induced myopathy. AB - Background Statin therapy used to lower cholesterol levels results in a substantial reduction in cardiovascular complications. Previous observations in different ethnic populations showed that rs2306283A>G, p.Asn130Asp and rs4149056T>C, p.Val174Ala in solute carrier organic anion transporter 1B1 (SLCO1B1) gene encoding the organic transporter protein may be responsible for statin uptake, thus explaining the majority of statin-associated symptoms. In addition to the genetic component, vitamin D (vit D) deficiency is common in Saudi Arabia and worldwide and may cause muscle dysfunction and ache. The aim of the present study was first to reveal an effect of vit D, rs2306283A>G, and rs4149056T>C and related haplotypes on statin-associated myopathy (SAM) and then to investigate a possible interaction between low vit D levels and the above mentioned variants. Methods The genomic DNA obtained from 50 individuals diagnosed with hypercholesterolemia was genotyped using light SNiP hybridization probes. Results Low vit D levels were associated with SAM (OR=3.6, p=0.03); however, CK levels, rs2306283A>G, and rs4149056T>C did not show any association. Interestingly, rs4149056T>C was interacting with vit D to influence SAM (p=0.02). Haplotype analysis showed that SLCO1B1 *1B and *15 were more prevalent in individuals with SAM (p=0.05). When stratified according to vit D levels, rs2306283A allele showed an increase in individuals having SAM along with low vit D (p=0.03). Conclusions Although preliminary, our results show an involvement of vit D and rs4149056T>C of SLCO1B1 in SAM. PMID- 29420307 TI - The roles of special proresolving mediators in pain relief. AB - The resolution of acute inflammation, once thought to be a passive process, is now recognized as an active one. The productions of endogenous special proresolving mediators (SPMs) are involved in this process. SPMs, including lipoxins, resolvins, protectins, and maresins, are endogenous lipid mediators generated from omega-6 arachidonic acid or omega-3 poly-unsaturated fatty acids during the resolution phase of acute inflammation. They have potent anti inflammatory and proresolving actions in various inflammatory disorders. Due to the potent proresolving and anti-inflammatory effects, SPMs are also used for pain relief. This review focuses on the mechanisms by which SPMs act on their respective G-protein-coupled receptors in immune cells and nerve cells to normalize pain via regulating inflammatory mediators, transient receptor potential ion channels, and central sensitization. SPMs may offer novel therapeutic approaches for preventing and treating pain conditions associated with inflammation. PMID- 29420306 TI - Dose-dependent effects of vitamin 1,25(OH)2D3 on oxidative stress and apoptosis. AB - Background The purpose of this study is to examine the dose-dependent effects of vitamin 1,25(OH)2D3 on apoptosis and oxidative stress. Methods In this study, 50 male Balb/c mice were used as control and experiment groups. The mice were divided into 5 groups each consisting of 10 mice. Calcitriol was intraperitoneally administered as low dose, medium dose, medium-high dose and high dose vitamin D groups (at 0.5, 1, 5 and 10 MUg/kg, respectively), for three times a week during 14 days. At the end of the study, annexin V was measured by enzyme-linked immunosorbent assay method, and total antioxidant capacity and total oxidant status values were measured by colorimetric method in serum. Hematoxylin eosin staining was performed in liver tissues and periodic acid schiff staining was performed in kidney tissues. Results While comparing the results of medium-high dose (5 MUg/kg) and high dose (10 MUg/kg) vitamin D administration to that of the control group, it was observed that serum antioxidant status and annexin V levels decreased and glomerular mesenchial matrix ratio increased in kidney (p<0.05). In addition to these findings, in the group receiving high dose vitamin D (10 MUg/kg), it was observed that the damage to the liver increased together with the the oxidative stress index values (p<0.05). Conclusions As a result, this study was the first in the literature to report that use of high-dose vitamin D (10 MUg/kg) results in oxidant effect, rather than being an antioxidant, and causes severe histopathological toxicity in the liver and kidney. PMID- 29420308 TI - Additive varying-coefficient model for nonlinear gene-environment interactions. AB - Gene-environment (G*E) interaction plays a pivotal role in understanding the genetic basis of complex disease. When environmental factors are measured continuously, one can assess the genetic sensitivity over different environmental conditions on a disease trait. Motivated by the increasing awareness of gene set based association analysis over single variant based approaches, we proposed an additive varying-coefficient model to jointly model variants in a genetic system. The model allows us to examine how variants in a gene set are moderated by an environment factor to affect a disease phenotype. We approached the problem from a variable selection perspective. In particular, we select variants with varying, constant and zero coefficients, which correspond to cases of G*E interaction, no G*E interaction and no genetic effect, respectively. The procedure was implemented through a two-stage iterative estimation algorithm via the smoothly clipped absolute deviation penalty function. Under certain regularity conditions, we established the consistency property in variable selection as well as effect separation of the two stage iterative estimators, and showed the optimal convergence rates of the estimates for varying effects. In addition, we showed that the estimate of non-zero constant coefficients enjoy the oracle property. The utility of our procedure was demonstrated through simulation studies and real data analysis. PMID- 29420309 TI - A versatile three-dimensional foam fabrication strategy for soft and hard tissue engineering. AB - The fabrication strategies of three-dimensional porous biomaterials have been extensively studied and well established in the past few decades, yet the biocompatibility and versatility of porous architecture preparation is still lacking. Herewith, we present a novel and green 3D porous foam fabrication technique for both soft and hard engineering. By utilizing the gelatinization and retrogradation properties of starches, stabilized porous constructs made of various building blocks, from living cells to ceramic particles, were created for the first time. In soft tissue engineering applications, 3D cultured tissue foam (CTF) with controlled cell release properties was developed, and foams constituting osteoblasts, fibroblasts and vascular endothelial cells all exhibited high mechanical stability and preservation of cell viability or functions. More importantly, the CTF achieved sustained self-release of cells controlled by serum concentration (containing amylase) and the released cells also maintained high viability and functions. In the context of hard tissue engineering applications, ceramic/bioglass (BG) foam scaffolds were developed by a similar starch-assisted foaming strategy where the resultant bone scaffolds of hydroxyapatite (HA)/BG and Si3N4/BG possessed >70% porosity with interconnected macropores (sizes 200 ~ 400 MUm), fine pores (sizes 1 ~ 10 MUm) and superior mechanical properties despite the high porosity. Additionally, in vitro and in vivo evaluations of the biological properties revealed that porous HA/BG foam exhibits the desired biocompatibility and osteogenesis. The in vivo study indicated new bone ingrowth after 1 week and significant increases in new bone volume after 2 weeks. In conclusion, the presented foaming strategy provides opportunities for biofabricating CTF with different cells for different target soft tissues and preparing porous ceramic/BG foams with different material components and high strengths, showing great versatility in soft and hard tissue engineering. PMID- 29420310 TI - Generation of genipin cross-linked fibrin-agarose hydrogel tissue-like models for tissue engineering applications. AB - The generation of biomimetic and biocompatible artificial tissues is the basic research objective for tissue engineering (TE). In this sense, the biofabrication of scaffolds that resemble the tissues' extracellular matrix is an essential aim in this field. Uncompressed and nanostructured fibrin-agarose hydrogels (FAH and NFAH, respectively) have emerged as promising scaffolds in TE, but their structure and biomechanical properties must be improved in order to broaden their TE applications. Here, we generated and characterized novel membrane-like models with increased structural and biomechanical properties based on the chemical cross-linking of FAH and NFAH with genipin (GP at 0.1%, 0.25%, 0.5% and 0.75%). Furthermore, the scaffolds were subjected to rheological (G, G', G" modulus), ultrastructural and ex vivo biocompatibility analyses. Results showed that all GP concentrations increased the stiffness (G) and especially the elasticity (G') of FAH and NFAH. Ultrastructural analyses demonstrated that GP and nanostructuration of FAH allowed us to control the porosity of FAH. In addition, biological studies revealed that higher concentration of GP (0.75%) started to compromise the cell function and viability. Finally, this study demonstrated the possibility to generate natural and biocompatible FAH and NFAH with improved structural and biomechanical properties by using 0.1%-0.5% of GP. However, further in vivo studies are needed in order to demonstrate the biocompatibility, biodegradability and regeneration capability of these cross-linked scaffolds. PMID- 29420311 TI - In2Ga2ZnO7 oxide semiconductor based charge trap device for NAND flash memory. AB - The programming characteristics of charge trap flash memory device adopting amorphous In2Ga2ZnO7 (a-IGZO) oxide semiconductors as channel layer were evaluated. Metal-organic chemical vapor deposition (MOCVD) and RF-sputtering processes were used to grow a 45 nm thick a-IGZO layer on a 20 nm thick SiO2 (blocking oxide)/p++-Si (control gate) substrate, where 3 nm thick atomic layer deposited Al2O3 (tunneling oxide) and 5 nm thick low-pressure CVD Si3N4 (charge trap) layers were intervened between the a-IGZO and substrate. Despite the identical stoichiometry and other physicochemical properties of the MOCVD and sputtered a-IGZO, a much faster programming speed of MOCVD a-IGZO was observed. A comparable amount of oxygen vacancies was found in both MOCVD and sputtered a IGZO, confirmed by x-ray photoelectron spectroscopy and bias-illumination instability test measurements. Ultraviolet photoelectron spectroscopy analysis revealed a higher Fermi level (E F) of the MOCVD a-IGZO (~0.3 eV) film than that of the sputtered a-IGZO, which could be ascribed to the higher hydrogen concentration in the MOCVD a-IGZO film. Since the programming in a flash memory device is governed by the tunneling of electrons from the channel to charge trapping layer, the faster programming performance could be the result of a higher E F of MOCVD a-IGZO. PMID- 29420312 TI - Three-dimensional cross-linking composite of graphene, carbon nanotubes and Si nanoparticles for lithium ion battery anode. AB - Various graphene-based Si nanocomposites have been reported to improve the performance of active materials in Li-ion batteries. However, these candidates still yield severe capacity fading due to the electrical disconnection and fractures caused by the huge volume changes over extended cycles. Therefore, we have designed a novel three-dimensional cross-linked graphene and single-wall carbon nanotube structure to encapsulate the Si nanoparticles. The synthesized three-dimensional structure is attributed to the excellent self-assembly of carbon nanotubes with graphene oxide as well as a thermal treatment process at 900 degrees C. This special structure provides sufficient void spaces for the volume expansion of Si nanoparticles and channels for the diffusion of ions and electrons. In addition, the cross-linking of the graphene and single-wall carbon nanotubes also strengthens the stability of the structure. As a result, the volume expansion of the Si nanoparticles is restrained. The specific capacity remains at 1450 mAh g-1 after 100 cycles at 200 mA g-1. This well-defined three dimensional structure facilitates superior capacity and cycling stability in comparison with bare Si and a mechanically mixed composite electrode of graphene, single-wall carbon nanotubes and silicon nanoparticles. PMID- 29420314 TI - Femoral Artery Bypass Graft Pseudoaneurysm Rupture in a Transfemoral Amputee. AB - The case of a patient with an actively bleeding pseudoaneurysm associated with remnants of a polytetrafluoroethylene femoral bypass graft in his transfemoral residual limb is described. Initial graft placement was due to peripheral arterial disease. During subsequent transfemoral amputation, remnants of the nonpatent graft were retained in the residuum. After 4 yrs of lower limb prosthesis use, a proximal anastomosis pseudoaneurysm developed (with avulsion of graft remnants). The patient presented to clinic with a 5-day history of increased left groin fullness and largely nonradiating pain (rated 10/10). He was diagnosed with a pseudoaneurysm (1.9 cm) originating from the left common femoral artery and an associated hematoma (8 cm) on computed tomography; this required emergent reoperation. This case highlights the importance surrounding the decision to leave or explant neovascularization materials, which may carry significant risk for infection or physical disruption complications in residual limbs. PMID- 29420316 TI - Relative Survival Instead of Overall Survival Should Be Used as Outcome When Analyzing the Effect of Age After Treatment of Hepatocellular Carcinoma. PMID- 29420315 TI - Prolonged Catheter Use and Infection in Regional Anesthesia: A Retrospective Registry Analysis. AB - BACKGROUND: Prolonged catheter use is controversial because of the risk of catheter-related infection, but the extent to which the risk increases over time remains unknown. We thus assessed the time-dependence of catheter-related infection risk up to 15 days. METHODS: Our analysis was based on the German Network for Regional Anesthesia, which includes 25 centers. We considered 44,555 patients who had surgery between 2007 and 2014 and had continuous regional anesthesia as well as complete covariable details. Cox regression analysis was performed and adjusted for confounding covariables to examine the relationship between catheter duration and probability of infection-free catheter use. RESULTS: After adjustment for confounding factors, the probability of infection free catheter use decreases with each day of peripheral and epidural catheter use. In peripheral catheters, it was 99% at day 4 of catheter duration, 96% at day 7, and 73% at day 15. In epidural catheters, it was 99% at day 4 of catheter duration, 95% at day 7, and 73% at day 15. Only 31 patients (0.07%) had severe infections that prompted surgical intervention. Among these were five catheters that initially had only mild or moderate signs of infection and were left in situ; all progressed to severe infections. CONCLUSIONS: Infection risk in catheter use increases over time, especially after four days. Infected catheters should be removed as soon as practical. VISUAL ABSTRACT: An online visual overview is available for this article at http://links.lww.com/ALN/B683. PMID- 29420317 TI - Reply to "Relative Survival Instead of Overall Survival Should be Used as Outcome When Analyzing the Effect of Age After Treatment of Hepatocellular Carcinoma". PMID- 29420318 TI - Disparities in Rates of Surgical Intervention Among Racial and Ethnic Minorities in Medicare Accountable Care Organizations. AB - OBJECTIVE: To assess the effect of Accountable Care Organizations (ACOs) on the use of surgical services among racial and ethnic minorities. BACKGROUND: Health reform efforts were expected to reduce healthcare disparities. The impact of ACOs on existing disparities in access to surgical care remains unknown. METHODS: We used national Medicare data (2009-2014) to compare rates of surgery among white, African American, Hispanic, and Asian Medicare beneficiaries for coronary artery bypass grafting, colectomy, total hip arthroplasty, hip fracture repair, and lumbar spine surgery. We performed a pre-post difference in differences analysis between African American, Hispanic, and Asian patients receiving surgical care in ACO and non-ACO organizations before and after the implementation of ACOs. The time period 2009 to 2011 was considered the pre-ACO period, and 2012 to 2014 the post-ACO period. RESULTS: Rates of surgical intervention in the ACO cohort were significantly lower (P < 0.001) as compared to non-ACOs for whites, African Americans, Hispanics, and Asians in both the pre- and post-ACO periods. There was no significant difference in the adjusted change in the rate of surgical interventions among minority patients as compared to whites in ACOs and non-ACOs between 2009 to 2011 and 2012 to 2014. The odds of receiving surgical intervention were lowest for minority patients in ACOs during the post-ACO period (P < 0.001). CONCLUSIONS: We found persistent differences in the use of surgery among racial and ethnic minorities between the time periods 2009 to 2011 and 2012 to 2014. These disparities were not impacted by the formation of ACOs. Programs that specifically incentivize ACOs to improve surgical access for minorities may be necessary. PMID- 29420319 TI - Rivaroxaban for Left Ventricular Thrombus. PMID- 29420320 TI - High-intensity handgrip training lowers blood pressure and increases heart rate complexity among postmenopausal women: a pilot study. AB - OBJECTIVE: Handgrip exercise is an emerging strategy for resting blood pressure (BP) reduction requiring minimal time and exercise effort. However, the research literature is currently limited to handgrip protocol designs predominantly prescribing sustained grip contractions, with little assessment of alternative options. Furthermore, our understanding of the utility of handgrip exercise would be strengthened by an evaluation of the physiological mechanisms driving BP reductions and an assessment of the interindividual response variability. As such, this research was designed to perform an initial evaluation of the pragmatic effectiveness of a novel at-home, high-intensity, unilateral (nondominant) handgrip exercise training program in reducing resting BP, while simultaneously exploring mediators of BP change including a neurocardiac index of autonomic nervous control [heart rate (HR) variability], measures of arterial stiffness (radial augmentation index and carotid-radial pulse wave velocity), and cardiovascular reactivity to psychophysiological stressors. METHODS: Postmenopausal women were recruited to complete 8 weeks of handgrip exercise training. Aforementioned measures of resting BP and mediators of BP change were acquired at the midway point and end of training. RESULTS: All participants (n=17) completed training with high self-reported adherence (96.9%) and improvement in grip strength (2.7+/-2.4kg, P<0.05). Handgrip training reduced resting systolic BP (-5.1+/-7.7 mmHg, P<0.05) and improved HR complexity (sample entropy: 0.24+/-0.31, P<0.05), without significant changes to resting diastolic BP, HR, or arterial stiffness (all P>0.05). CONCLUSION: This pilot study successfully shows the potential utility of high-intensity intermittent handgrip exercise for improvements in cardiovascular health among postmenopausal women, with additional research required to further explore the underlying physiological mechanisms driving such improvements. PMID- 29420321 TI - Texture Analysis and Machine Learning for Detecting Myocardial Infarction in Noncontrast Low-Dose Computed Tomography: Unveiling the Invisible. AB - OBJECTIVES: The aim of this study was to test whether texture analysis and machine learning enable the detection of myocardial infarction (MI) on non contrast-enhanced low radiation dose cardiac computed tomography (CCT) images. MATERIALS AND METHODS: In this institutional review board-approved retrospective study, we included non-contrast-enhanced electrocardiography-gated low radiation dose CCT image data (effective dose, 0.5 mSv) acquired for the purpose of calcium scoring of 27 patients with acute MI (9 female patients; mean age, 60 +/- 12 years), 30 patients with chronic MI (8 female patients; mean age, 68 +/- 13 years), and in 30 subjects (9 female patients; mean age, 44 +/- 6 years) without cardiac abnormality, hereafter termed controls. Texture analysis of the left ventricle was performed using free-hand regions of interest, and texture features were classified twice (Model I: controls versus acute MI versus chronic MI; Model II: controls versus acute and chronic MI). For both classifications, 6 commonly used machine learning classifiers were used: decision tree C4.5 (J48), k-nearest neighbors, locally weighted learning, RandomForest, sequential minimal optimization, and an artificial neural network employing deep learning. In addition, 2 blinded, independent readers visually assessed noncontrast CCT images for the presence or absence of MI. RESULTS: In Model I, best classification results were obtained using the k-nearest neighbors classifier (sensitivity, 69%; specificity, 85%; false-positive rate, 0.15). In Model II, the best classification results were found with the locally weighted learning classification (sensitivity, 86%; specificity, 81%; false-positive rate, 0.19) with an area under the curve from receiver operating characteristics analysis of 0.78. In comparison, both readers were not able to identify MI in any of the noncontrast, low radiation dose CCT images. CONCLUSIONS: This study indicates the ability of texture analysis and machine learning in detecting MI on noncontrast low radiation dose CCT images being not visible for the radiologists' eye. PMID- 29420322 TI - Improved Detection of Foreign Bodies on Radiographs Using X-ray Dark-Field and Phase-Contrast Imaging. AB - PURPOSE: The aim of this study was to investigate whether the detection of foreign bodies can be improved using dark-field and phase-contrast radiography compared with conventional (transmission) radiographs. MATERIALS AND METHODS: Experiments were performed using ex vivo pig paws, which were prepared with differently sized foreign bodies of metal, wood, and glass (n = 10 each). Paws without foreign bodies served as controls (n = 30). All images were acquired using an experimental grating-based large object radiography system. Five blinded readers (second- to fourth-year radiology residents) were asked to assess the presence or absence of any foreign body. Sensitivity and specificity for the detection of metal, wood, glass, and any foreign body were calculated and compared using McNemar test and generalized linear mixed models. RESULTS: Sensitivity for the detection of metal foreign bodies was 100% for all readers and image combinations. The sensitivity for the detection of wooden foreign bodies increased from 2% for transmission images to 78% when dark-field images were added (P < 0.0001). For glass foreign bodies, sensitivity increased from 84% for transmission images to 96% when adding phase-contrast images (P = 0.041). Sensitivity for the detection of any foreign body was 91% when transmission, dark field, and phase-contrast images were viewed simultaneously, compared with 62% for transmission images alone (P < 0.0001). Specificity was 99% to 100% across all readers and radiography modalities. CONCLUSIONS: Adding dark-field images substantially improves the detection of wooden foreign bodies compared with the analysis of conventional (transmission) radiographs alone. Detection of glass foreign bodies was moderately improved when adding phase-contrast images. PMID- 29420323 TI - Management of Carpal Tunnel Syndrome. AB - The American Academy of Orthopaedic Surgeons (AAOS) has developed Appropriate Use Criteria (AUC) for Management of Carpal Tunnel Syndrome. Evidence-based information, in conjunction with the clinical expertise of physicians, was used to develop the criteria to improve patient care and obtain best outcomes while considering the subtleties and distinctions necessary in making clinical decisions. To provide the evidence foundation for this AUC, the AAOS Evidence Based Medicine Unit provided the writing panel and voting panel with the 2016 AAOS Clinical Practice Guideline titled Management of Carpal Tunnel Syndrome Evidence-Based Clinical Practice Guideline. The Management of Carpal Tunnel Syndrome AUC clinical patient scenarios were derived from indications typical of patients with suspected carpal tunnel syndrome in clinical practice, as well as from current evidence-based clinical practice guidelines and supporting literature to identify the appropriateness of treatments. The 135 patient scenarios and 6 treatments were developed by the writing panel, a group of clinicians who are specialists in this AUC topic. Next, a separate, multidisciplinary, voting panel (made up of specialists and nonspecialists) rated the appropriateness of treatment of each patient scenario using a 9-point scale to designate a treatment as Appropriate (median rating, 7 to 9), May Be Appropriate (median rating, 4 to 6), or Rarely Appropriate (median rating, 1 to 3). PMID- 29420324 TI - Conjunctival Autograft Combined With Either Preoperative Mitomycin C Injection or Intraoperative Local Mitomycin C Over the Medial Rectus Muscle Tendon in Primary Pterygium Surgery. AB - PURPOSE: To evaluate and compare the recurrence rate and complications of conjunctival autograft (CAG) combined with preoperative mitomycin C (MMC) injection versus CAG with intraoperative local MMC over the medial rectus muscle tendon in primary pterygium. STUDY DESIGN: Randomized prospective study. METHODS: This study included 108 eyes of 108 patients with primary fleshy or growing pterygium. All patients were from rural areas and less than 50 years old. Fifty three patients were treated with injection of 0.1 mL of 0.15 mg/mL MMC into the body of pterygium followed 1 day later by pterygium excision and CAG (group I), and 55 patients were treated with pterygium excision and local application of 0.2 mg/mL MMC for 2 min over the medial rectus tendon followed by CAG (group II). The minimum follow-up period was 18 months. RESULTS: Two patients from group I and one patient from group II did not complete the follow-up period and were excluded. There were no statistically significant differences between the two groups regarding age, sex, laterality, or follow-up period. Recurrence occurred in 2 eyes in group I (3.92%) and 1 eye in group II (1.85%); (P=0.52). All recurrences occurred in male patients of less than 30 years of age. No significant complications were encountered in both groups. CONCLUSIONS: Both preoperative MMC injection followed 1 day later by pterygium excision with CAG, and pterygium excision and intraoperative local application of MMC on the medial rectus tendon are successful in treating primary pterygium with low recurrence rate and few complications. PMID- 29420325 TI - Variation of Coma Aberration With Prismatic Soft Contact Lenses. AB - PURPOSE: To analyze the variation in vertical coma and the rest of ocular aberrations before and after fitting prismatic soft contact lenses (PSCL). METHODS: Thirty-seven eyes of 20 healthy subjects (24.30+/-2.03 years) were evaluated to analyze the variation in ocular wavefront aberrations before and after fitting PSCL of different base-down prism values (1.0, 1.5, and 2.0 prism diopters [PD]), designed to study its influence in the compensation of vertical coma aberration. A Hartmann-Shack sensor with a wavelength of 780 nm was used, considering a pupil size of 3 mm. In addition, the influence of PSCL in visual function under photopic conditions in terms of high-contrast visual acuity and contrast sensitivity was evaluated. RESULTS: There was statistically significant differences (P<0.05) in ocular aberrations from first to seventh order after fitting PSCL, but only the differences in vertical tilt, horizontal tilt, defocus, vertical astigmatism, and vertical coma were clinically relevant (Strehl ratio <0.8). The mean of vertical coma (MUm) was 0.022+/-0.030 for control, 0.045+/-0.064 for 1.0 PD (P=0.645), 0.048+/-0.053 for 1.5 PD (P=0.037), and 0.074+/-0.047 for 2.0 PD (P<0.001). The changes in visual function under photopic conditions were not clinically relevant. CONCLUSIONS: PSCL induce a magnitude of vertical coma aberration directly proportional to prism value without affecting the rest of ocular high-order aberrations. PMID- 29420326 TI - Corneal Biomechanical Properties in Obstructive Sleep Apnea Syndrome. AB - OBJECTIVES: To investigate the corneal biomechanical properties and anterior segment parameters in patients with obstructive sleep apnea syndrome (OSAS). METHODS: Fifty-four eyes of 54 patients with OSAS and 20 eyes of 20 healthy subjects were included. Patients with mild and moderate OSAS (Respiratory Disturbance Index [RDI] <30) enrolled in group 1, those with severe OSAS (RDI>=30) in group 2 and controls in group 3. Corneal biomechanical properties including corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann correlated intraocular pressure (IOPg), and corneal-compensated intraocular pressure (IOPcc) were measured with ocular response analyzer. Maximum (Kmax), minimum (Kmin), and mean simulated (SimKm) keratometry values, corneal astigmatism (CA), and central corneal thickness (CCT) were evaluated with Pentacam Scheimpflug imaging. RESULTS: The mean CH and CRF were significantly lower in group 2. The mean CH was 10.9+/-1.4 mm Hg in group 1, 10.1+/-1.1 mm Hg in group 2, and 12.1+/-1.2 mm Hg in group 3 (P<0.001). The mean CRF was 11.1+/ 1.8 mm Hg in group 1, 9.9+/-1.1 mm Hg in group 2, and 12.2+/-1.2 mm Hg in group 3 (P<0.001). The CH and CRF values were similar between the groups 1 and 3 (P=0.867 and P=0.743). Corneal-compensated intraocular pressure, IOPg, Kmax, Kmin, SimKm, CA, and CCT values were not statistically different among the three groups. CONCLUSIONS: Patients with severe OSAS had lower CH and CRF values. The lower CH and CRF values in the severe group were possibly related to changes of the structural properties in the cornea. PMID- 29420327 TI - Defining the Key Parts of a Procedure: Implications for Overlapping Surgery. AB - INTRODUCTION: The American College of Surgeons' Statements on Principles requires attending surgeons to be present for the "key parts" of surgical procedures, but the term is not defined. The research question addressed in this study is whether a functional definition of the critical or key steps of common orthopaedic surgical procedures can be reliably constructed. We used the examples of hip and knee arthroplasty because these procedures are highly structured and divisible into distinct subroutines. METHODS: We surveyed 100 experienced orthopaedic surgeons regarding whether particular steps in knee and hip arthroplasty procedures were considered "key." The patterns of individual surgeons' responses were compared among surgeons for overall reliability. The steps frequently cited as key were also identified. RESULTS: The agreement rates among surgeons for the definitions of the key parts of hip and knee arthroplasty were 3.2% and 8.6%, respectively. For both procedures, five steps were identified as key by >90% of the respondents. DISCUSSION: The agreement rate on what constitutes the key parts of hip and knee arthroplasty was poor, despite the fact that these are highly structured procedures. Accordingly, defining the key parts for a given procedure must rely on either the operating surgeon's discretion or a consensus definition. Imposing a single surgeon's standard on others is not the optimal approach because such a standard is likely to be idiosyncratic. CONCLUSION: A consensus standard articulated by the orthopaedic surgery community may be the best means for identifying the key parts of orthopaedic surgical operations. The data presented here suggest a foundation upon which a consensus definition for the key parts of arthroplasty procedures may be built. PMID- 29420328 TI - Tacrolimus Optic Neuropathy. AB - BACKGROUND: Tacrolimus (FK506, Prograf) is a potent immunosuppressant, which inhibits cytokine synthesis and blocks T-cell development. Optic neuropathy from tacrolimus toxicity is very uncommon but, when present, can result in severe vision loss. METHODS: Case series and review of the literature. RESULTS: We present 3 patients with tacrolimus optic neuropathy after bone marrow transplantation complicated by graft-vs-host disease and demonstrate the differing clinical and radiologic presentation of this presumed toxic optic neuropathy. CONCLUSIONS: Tacrolimus optic neuropathy can manifest in a multitude of clinical presentations and can have devastating visual consequences. PMID- 29420329 TI - The Prevalence of Multiple-Choice Testing in Registered Nurse Licensure Qualifying Nursing Education Programs in New York State. AB - AIM: The aim of this study was to describe nurse educators' use of multiple choice questions (MCQs) in testing in registered nurse licensure-qualifying nursing education programs in New York State. METHOD: This study was a descriptive correlational analysis of data obtained from surveying 1,559 nurse educators; 297 educators from 61 institutions responded (response rate [RR] = 19 percent), yielding a final cohort of 200. RESULTS: MCQs were reported to comprise a mean of 81 percent of questions on a typical test. Baccalaureate program respondents were equally likely to use MCQs as associate degree program respondents (p > .05) but were more likely to report using other methods of assessing student achievement to construct course grades (p < .01). Both groups reported little use of alternate format-type questions. CONCLUSION: Respondent educators reported substantial reliance upon the use of MCQs, corroborating the limited data quantifying the prevalence of use of MCQ tests in licensure qualifying nursing education programs. PMID- 29420330 TI - Promoting Interprofessional Collaborative Practice Through Simulation. AB - A 12-week program was developed to educate nursing, medicine, and physician assistant faculty on the principles and best practices of simulation. The goal was to facilitate team building and collaborative practice through the implementation of an interprofessional (IP) simulation experience for students. Workshops focused on IP communication involving seminar-based instruction, discussion, and the progressive development of an IP simulation based on a National League for Nursing Advancing Care Excellence for Seniors scenario. During the final session, students participated in the simulation while faculty evaluated and revised the scenario to best meet the needs of students from the three disciplines. PMID- 29420331 TI - Framework for Considering Productive Aging and Work. AB - OBJECTIVES: The U.S. population is experiencing a demographic transition resulting in an aging workforce. The objective of this article is to elucidate and expand an approach to keep that workforce safe, healthy, and productive. METHODS: This article elucidates the framework for the National Center for Productive Aging at Work of the National Institute for Occupational Safety and Health. Subject matter experts used a snowball method to review published literature to substantiate elements in the framework. RESULTS: Evidence-based literature supports a productive aging framework for the workforce involving the following elements: 1) life span perspective; 2) comprehensive and integrated approaches to occupational safety and health; 3) emphasis on positive outcomes for both workers and organizations; and 4) supportive work culture for multigenerational issues. CONCLUSION: The productive aging framework provides a foundational and comprehensive approach for addressing the aging workforce. PMID- 29420332 TI - The Association Between Time Taken to Report, Lodge, and Start Wage Replacement and Return-to-Work Outcomes. AB - OBJECTIVE: The aim of the study was to determine if prolonged times taken to notify, file, adjudicate, and start wage replacement for workers' compensation claims are associated with poorer return-to-work (RTW) outcomes. METHODS: Using 71,607 claims lodged 2007 to 2012, logistic regression determined associations between time to claim filing, adjudication, and payment and (1) socio demographic/economic, occupational, and injury-related factors; and (2) 52 weeks of wage replacement (WR). RESULTS: Prolonged times for all processing steps were associated with increased odds of reaching 52 weeks of WR. Prolonged times in more than one step increased the odds of a long-term claim. Being female was the only variable consistently associated with each prolonged processing time. CONCLUSIONS: The predictive ability of prolonged times in claim lodgement and processing and compensation payments demonstrate that shorter claims management and adjudication times could improve RTW outcomes. PMID- 29420333 TI - Prevalence of Therapeutic Drug Monitoring for Lithium and the Impact of Regulatory Warnings: Analysis Using Japanese Claims Database. AB - BACKGROUND: Therapeutic drug monitoring (TDM) for lithium is recommended in guidelines; however, the prevalence of TDM for lithium is seldom reported. We have therefore investigated the prevalence of TDM for lithium and evaluated the impact of the regulatory warnings requiring routine TDM for lithium. METHODS: Monthly claims data covering around 1.7 million persons aged 20-74 years old during the period January 1, 2005, and March 31, 2015, were evaluated. All patients who had at least one prescription for lithium were selected and included to calculate the annual prevalence of TDM for lithium. Also we assessed whether the 2 regulatory warnings requiring routine TDM for lithium and issued in April 2012 and September 2012 had an impact on TDM for lithium, using segmented regression analysis. RESULTS: Between 2005 and 2014, 136,956 prescriptions of lithium were issued to 5823 patients, and the annual prevalence of TDM for lithium was 14.9% (95% confidence interval, 14.7%-15.1%). The analysis revealed that the mean prevalence increased abruptly by 6.9% (P = 0.001) after the regulatory warning in April 2012, whereas that the warning in September 2012 decreased by 1.2% (P = 0.47). There was no significant change in trends of period prevalence after the warning in April 2012 (April 2012-August 2012) compared with prevalence before the warning (April 2010-March 2012). Similarly, no significant change was observed in the trends before (April 2012-August 2012) and after (September 2012-March 2014) the subsequent warning in September 2012. CONCLUSIONS: Results showed that the prevalence of TDM for lithium was low, although TDM for lithium was strongly recommended by the guidelines. Regulatory warnings requiring compliance with the measurement of blood levels during treatment with lithium, issued twice during the five-month period, were associated with an increase in the prevalence of TDM for lithium. However, the impact of the second warning was not remarkable compared with the first warning. PMID- 29420334 TI - Immunogenicity moderation effect of interleukin-24 on myelogenous leukemia cells. AB - Previous studies have shown that interleukin-24 (IL-24) has tumor-suppressing activity by multiple pathways. However, the immunogenicity moderation effect of IL-24 on malignant cells has not been explored extensively. In this study, we investigated the role of IL-24 in immunogenicity modulation of the myelogenous leukemia cells. Data show that myelogenous leukemia cells express low levels of immunogenicity molecules. Treatment with IL-24 could enhance leukemia cell immunogenicity, predominantly regulate leukemia cells to produce immune associated cytokines, and improve the cytotoxic sensitivity of these cells to immune effector cells. IL-24 expression could retard transplanted leukemia cell tumor growth in vivo in athymic nude mice. Moreover, IL-24 had marked effects on downregulating the expression of angiogenesis-related proteins vascular endothelial growth factor, cluster of differentiation (CD) 31, CD34, collagen IV and metastasis-related factors CD147, membrane type-1 matrix metalloproteinase (MMP), and MMP-2 and MMP-9 in transplanted tumors. These findings indicated novel functions of this antitumor gene and characterized IL-24 as a promising agent for further clinical trial for hematologic malignancy immunotherapy. PMID- 29420335 TI - Any place left for induction chemotherapy for locally advanced head and neck squamous cell carcinoma? AB - The issue of induction chemotherapy (ICT) interest in locoregionally advanced squamous cell cancer of the head and neck is a real epic that has been carried out over four phase III studies: PARADIGM, DECIDE, NCT01086826 and lastly the conclusive GORTEC 2007-02. With no significant benefit in overall survival of ICT, followed by concurrent chemoradiation over the standard chemoradiotherapy alone, in three of these studies, and a significant number of treatment-related deaths with the standard regimen docetaxel, cisplatin, and fluorouracil, ICT is no longer a hot topic. However, this strategy might still be useful in the aim of limiting the metastatic extension affecting up to 30% of patients: ICT is systematically associated with a reduced metastatic relapse even though the survival effect is never statistically significant when compared directly with concomitant radiochemotherapy. This review summarizes the major studies with their limits and discusses how the ICT could improve the patients' prognosis in the future. PMID- 29420336 TI - Lenalidomide at the dose of 25 mg every other day in patients affected by multiple myeloma and renal failure: a real-life experience. AB - Renal impairment (RI) is a relevant complication of patients affected by multiple myeloma (MM); it can be present in up to 30-35% of newly diagnosed MM and is linked to a poor outcome. However, early recognition and early treatment with novel agents can overcome the negative impact of RI and even reverse kidney damage in most cases. Lenalidomide, available as an oral compound, is an immunomodulatory drug with both antiproliferative and immunomodulatory activity that is largely used in the management of MM. Dose reduction is mandatory in RI; however, there is no theoretical assumption against the possibility that protracting the time of full standard doses can be equally effective and tolerated by patients requiring reduced doses. In this report, we describe our retrospective experience, in 18 patients, with the administration of lenalidomide 25 mg every other day for patients with MM and RI. The overall response ratio was 66.5%. More than half (61.1%) of the patients had a renal response. The median progression-free survival was 8 months (range: 3-18 months). No serious adverse event occurred during treatment, and it was never necessary to disrupt or delay treatment for toxicity. These preliminary observations point to a significant therapeutic effect of lenalidomide, at the dose of 25 mg every other day for 21 days, with logistic and economic advantages. However, these results should be validated by controlled studies involving larger numbers of patients. PMID- 29420338 TI - Curcumin reverses irinotecan resistance in colon cancer cell by regulation of epithelial-mesenchymal transition. AB - The objective of this study was to investigate the effect and the mechanism by which curcumin reverses irinotecan-induced chemotherapy resistance in colon cancer. Construction of irinotecan-resistant colon cancer model LoVo/CPT-11R cells was performed by increasing drug concentration. The Cell Counting Kit-8 assay was used to detect inhibition of proliferation; cell morphology was observed by an optical microscope. Quantitative RT-PCR and western blotting were performed to detect molecular marker expressions during epithelial-mesenchymal transition (EMT); drug-resistant cells were treated with curcumin at different concentrations and Cell Counting Kit-8 was reperformed to detect cell proliferation after treatments. Drug-resistant cells were then divided into four groups: control group, irinotecan group, curcumin group, and irinotecan+curcumin group; quantitative RT-PCR and western blotting were performed to detect molecular marker expressions during epithelial-mesenchymal transition. Flow cytometry was used to detect cell apoptosis after grouping, and apoptosis-related protein was detected by western blotting. LoVo/CPT-11R cells could survive in culture medium containing irinotecan at 60 MUg/ml and the drug-resistance index was 5.69; the drug-resistant cells had a larger volume than normal cells and were poorly connected to each other. E-cadherin expression was downregulated, whereas vimentin and N-cadherin expressions were upregulated. After curcumin treatment, drug-resistant cell proliferation was significantly inhibited; in the curcumin+irinotecan treatment group, E-cadherin expression was upregulated, whereas vimentin and N-cadherin expressions were downregulated. Curcumin could significantly increase cell apoptosis. EMT is involved in the development of irinotecan resistance and curcumin can reverse this drug resistance through reversion of the EMT process. PMID- 29420339 TI - Probable drug-drug interaction between erlotinib and amiodarone causes severe neurotoxicity in a patient with advanced lung cancer. AB - Drug-drug interactions (DDIs) are of great concern in the treatment of cancer, especially when target therapies, such as tyrosine kinase inhibitors, are being used. Here, we report a case of probable DDI between erlotinib and amiodarone leading to severe neurotoxicity. Amiodarone inhibits P-glycoprotein (P-gp), for which erlotinib is a substrate. P-gp is an important drug transporter that is involved in limiting the blood-brain barrier penetration of erlotinib. Clinicians should be aware of emerging data characterizing the effect of the P-gp transport system on drug exposure and its potential for DDI. PMID- 29420337 TI - Anticancer effect of (S)-crizotinib on osteosarcoma cells by targeting MTH1 and activating reactive oxygen species. AB - MTH1 has become a new rising star in the field of 'cancer phenotypic lethality' and can be targeted in many kinds of tumors. This study aimed to explore the anticancer effect of MTH1-targeted drug (S)-crizotinib on osteosarcoma (OS) cells. We detected MTH1 expression in OS tissues and cells using immunohistochemistry and western blot. The effects of MTH1 on OS cell viability were explored using the siRNA technique and CCK8. The anticancer effects of the MTH1-targeted drug (S)-crizotinib on OS cells were explored by in-vitro assays. The intracellular 8-oxo-dGTP level and oxygen reactive species (ROS) of OS cells were detected by Cy3-conjugated avidin staining and dichlorofluorescein diacetate staining, respectively. The expression of MTH1 was significantly higher in OS tissues and cell lines than that in the corresponding adjacent tissues and osteoblastic cell line. The proliferation of OS cells was significantly inhibited through knockdown of MTH1 by siRNA technology. (S)-Crizotinib could inhibit the proliferation of OS cells with an increase in the apoptosis levels and causing G0/G1 arrest by targeting MTH1 and activating ROS. In addition, (S)-crizotinib could inhibit the migration of OS cells. (S)-Crizotinib could suppress the proliferation and migration, cause G0/G1 arrest, and increase the apoptosis level of OS cells by targeting MTH1 and activating ROS. This study will provide a promising therapeutic target and the theoretical basis for the clinical application of (S)-crizotinib in OS. PMID- 29420340 TI - Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung. AB - The standard-of-care for advanced small cell lung cancer (SCLC) is chemotherapy with cisplatin+etoposide (C+E). Most patients have chemosensitive disease at the outset, but disease frequently relapses and limits survival. Efforts to improve therapeutic outcomes in SCLC and other neuroendocrine cancers have focused on epigenetic agents, including the histone deacetylase inhibitor belinostat. The primary objective was to determine the maximum tolerated dose of the combination of belinostat (B) with C+E. Belinostat was administered as a 48-h continuous intravenous infusion on days 1-2; cisplatin was administered as a 1-h intravenous infusion on day 2; and etoposide was administered as a 1-h intravenous infusion on days 2, 3, and 4. Twenty-eight patients were recruited in this single-center study. The maximum tolerated dose was belinostat 500 mg/m/24 h, cisplatin 60 mg/m, and etoposide 80 mg/m. The combination was safe, although some patients were more susceptible to adverse events. Hematologic toxicities were most commonly observed. Objective responses were observed in 11 (39%) of 28 patients and seven (47%) of 15 patients with neuroendocrine tumors (including SCLC). Patients carrying more than three copies of variant UGT1A1 (*28 and *60) had higher serum levels of belinostat because of slower clearance. DNA damage peaked at 36 h after the initiation of belinostat, as did global lysine acetylation, but returned to baseline 12 h after the end of infusion. The combination of B+C+E is safe and active in SCLC and other neuroendocrine cancers. Future phase II studies should consider genotyping patients for UGT1A1*28 and UGT1A1*60 and to identify patients at an increased risk of adverse events. PMID- 29420341 TI - Is Overall Mortality the Right Composite Endpoint in Clinical Trials of Acute Respiratory Distress Syndrome? AB - OBJECTIVES: Overall mortality in patients with acute respiratory distress syndrome is a composite endpoint because it includes death from multiple causes. In most acute respiratory distress syndrome trials, it is unknown whether reported deaths are due to acute respiratory distress syndrome or the underlying disease, unrelated to the specific intervention tested. We investigated the causes of death after contracting acute respiratory distress syndrome in a large cohort. DESIGN: A secondary analysis from three prospective, multicenter, observational studies. SETTING: A network of multidisciplinary ICUs. PATIENTS: We studied 778 patients with moderate-to-severe acute respiratory distress syndrome treated with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We examined death in the ICU from individual causes. Overall ICU mortality was 38.8% (95% CI, 35.4-42.3). Causes of acute respiratory distress syndrome modified the risk of death. Twenty-three percent of deaths occurred from refractory hypoxemia due to nonresolving acute respiratory distress syndrome. Most patients died from causes unrelated to acute respiratory distress syndrome: 48.7% of nonsurvivors died from multisystem organ failure, and cancer or brain injury was involved in 37.1% of deaths. When quantifying the true burden of acute respiratory distress syndrome outcome, we identified 506 patients (65.0%) with one or more exclusion criteria for enrollment into current interventional trials. Overall ICU mortality of the "trial cohort" (21.3%) was markedly lower than the parent cohort (relative risk, 0.55; 95% CI, 0.43-0.70; p < 0.000001). CONCLUSIONS: Most deaths in acute respiratory distress syndrome patients are not directly related to lung damage but to extrapulmonary multisystem organ failure. It would be challenging to prove that specific lung-directed therapies have an effect on overall survival. PMID- 29420343 TI - Being a Team Physician. PMID- 29420344 TI - Pay Attention to the Pes Anserine in Knee Osteoarthritis. PMID- 29420346 TI - Pediatric Inactivity Triad: A Risky PIT. PMID- 29420345 TI - Implications of a Third Gender for Elite Sports. PMID- 29420348 TI - Core Muscle Injuries in Athletes. AB - Lower abdominal and groin injuries are among the most common causes of pain and lost playing time in sports. Perhaps the most important obstacle in understanding these injuries is the lack of consensus on nomenclature. There have been numerous advances in recent years in the understanding, prevention, diagnosis, and treatment of these injuries. The purpose of this review is to provide a general perspective on the current understanding of these injuries and a summary of recent advances. PMID- 29420347 TI - Venous Thromboembolic Event After Elective Anterior Cruciate Ligament Reconstruction: A Case Report. PMID- 29420349 TI - Thyroid Disorders in Athletes. AB - When athletic performance begins to deteriorate, it is important to identify possible underlying etiologies to explain such a phenomenon. Causes include inadequate nutrition, improper training habits, infection, and hematologic or endocrine diseases. In athletes, a thorough investigation of potentially reversible underlying medical conditions may be warranted when there are noted disruptions in training, competition, and recovery. Thyroid disorders should be considered in athletes in whom such a condition is suspected. The clinical picture may not be entirely clear, as athletes may have serum laboratory values that do not accurately correlate with the presenting signs and symptoms, as one might expect. That picture is even further muddled in individuals undergoing significant physiologic stress, and in whom anabolic agents or exogenous thyroid hormone are used. Because there are currently no consensus guidelines on the matter, return to play issues must be addressed when implementing treatment strategies and monitoring serial laboratory values on a case-by-case basis. PMID- 29420350 TI - Energy Drinks: A Contemporary Issues Paper. AB - Since their introduction in 1987, energy drinks have become increasingly popular and the energy drink market has grown at record pace into a multibillion-dollar global industry. Young people, students, office workers, athletes, weekend warriors, and service members frequently consume energy drinks. Both health care providers and consumers must recognize the difference between energy drinks, traditional beverages (e.g., coffee, tea, soft drinks/sodas, juices, or flavored water), and sports drinks. The research about energy drinks safety and efficacy is often contradictory, given the disparate protocols and types of products consumed: this makes it difficult to draw firm conclusions. Also, much of the available literature is industry-sponsored. After reports of adverse events associated with energy drink consumption, concerns including trouble sleeping, anxiety, cardiovascular events, seizures, and even death, have been raised about their safety. This article will focus on energy drinks, their ingredients, side effects associated with their consumption, and suggested recommendations, which call for education, regulatory actions, changes in marketing, and additional research. PMID- 29420351 TI - Sacroiliac Joint Dysfunction in the Athlete: Diagnosis and Management. PMID- 29420352 TI - Response to Letter to the Editor: Sacroiliac Joint Dysfunction in the Athlete: Diagnosis and Management. PMID- 29420354 TI - The Rise and Fall of Transcranial Doppler Ultrasonography for the Diagnosis of Vasospasm in Aneurysmal Subarachnoid Hemorrhage. PMID- 29420355 TI - Inotropic Effects of Nicorandil on Cardiac Contractility Assessed by Left Ventricular Pressure-Volume Relationship Analyses in Anesthetized Monkeys. AB - Nicorandil is a representative antianginal drug that has dual properties of a nitrate and adenosine triphosphate-sensitive potassium (KATP) channel agonist; however, its effects on integrated cardiac function have not been fully understood. This study was conducted to clarify the functional, hemodynamic, and electrophysiological effects of nicorandil using ventricular pressure-volume loop analysis in isoflurane-anesthetized monkeys. Nicorandil was given intravenously at therapeutic doses of 0.2 and 2 mg/kg over 10 minutes to cynomolgus monkeys (n = 5) with a pause of 10 minutes between the 2 doses. Nicorandil at 0.2 mg/kg caused decreases in systemic blood pressure and left ventricular end-diastolic pressure by its vasodilating action. Nicorandil at 2 mg/kg also exhibited positive inotropic action demonstrated by increased slopes of preload recruitable stroke work relationship, which is a load-independent inotropic parameter. In load-dependent inotropic parameters, positive inotropy of nicorandil was also indicated by the shortened QA interval and increased contractility index; however, significant changes were not observed in the maximal upstroke velocity of left ventricular pressure. Moreover, reflex tachycardia accompanied by shortening of QT/QTc intervals was observed. Overall, the isoflurane-anesthetized monkey model with pressure-volume loop analysis revealed cardiac variables of nicorandil, including a positive inotropy contributable to cardiac performance in addition to its vasodilatory effect. These findings provide useful information when considering the prescription of nicorandil in patients. PMID- 29420353 TI - Clusterin in Neuroendocrine Epithelial Neoplasms: Absence of Expression in a Well differentiated Tumor Suggests a Jejunoileal Origin. AB - Clusterin, a widely expressed, tissue-specific glycoprotein, is a diagnostic marker of several tumor types, including anaplastic large cell lymphoma, follicular dendritic cell sarcoma, and tenosynovial giant cell tumor. A recent study has suggested it is highly expressed by well-differentiated neuroendocrine tumors (NET) arising at most anatomic sites, with the exception of jejunoileal tumors, and that it is similarly not expressed by poorly differentiated neuroendocrine carcinomas (NEC). We sought to validate this result in a large cohort of NETs and NECs. Clusterin immunohistochemistry was performed on tissue microarrays of 255 NETs [45 lung, 4 stomach, 8 duodenum, 75 pancreas (62 primary, 13 metastatic), 107 jejunoileum (69 primary, 38 metastatic), 16 appendix] and 88 NECs (43 visceral, 45 Merkel cell). Extent (%) and intensity (0, 1+, 2+, 3+) of staining were assessed and an H-score (extent x intensity) calculated. An average H-score >5 was considered positive. Clusterin expression was noted in 82.4% of 148 nonjejunoileal NETs (average H-score 183) and only 8.4% of 107 jejunoileal NETs (average H-score, 31), as well as 19.3% of NECs (average H-score, 36). Clusterin is frequently, strongly expressed by NETs of diverse anatomic sites, with the exception of jejunoileal tumors, in which it is only rarely, weakly expressed. It is occasionally, weakly expressed by NECs. Most metastatic NETs of occult origin arise in the pancreas or the jejunoileum. For cases in which an initial site of origin immunopanel (eg, islet 1, PAX6, CDX2) is ambiguous, addition of clusterin may be diagnostically useful, with absence of expression suggesting a jejunoileal origin. PMID- 29420356 TI - Dose-Effect of Irbesartan on Cyclooxygenase-2 and Matrix Metalloproteinase-9 Expression in Rabbit Atherosclerosis. AB - Irbesartan has previously shown antiatherosclerotic effects on human carotid atherosclerotic plaques. Our study aimed to assess the dose-effect of irbesartan on cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) in rabbit atherosclerotic aorta. New Zealand rabbits were randomly divided into 6 groups: normal control (NC), high cholesterol (HC), low-dose (10 mg.kg.day), medium-dose (20 mg.kg.d), and high-dose (30 mg.kg.d) irbesartan and celecoxib (20 mg.kg.d). Except for the NCs, rabbits were fed a HC diet for 14 weeks to induce atherosclerosis. Aortic atherosclerotic lesions and messenger RNA and protein expression of COX-2, MMP-9, and nuclear factor-kappaB (NF-kappaB) were subsequently measured. The surface area of aortic atherosclerotic lesions was visibly larger in the HC group than in NCs (P < 0.01), but showed considerable reduction with medium- and high-dosage irbesartan and celecoxib treatments (P < 0.01). In medium- and high-dosage irbesartan and celecoxib groups, COX-2 and MMP 9 expression and NF-kappaB activity were significantly lower than in the high cholesterol group (P < 0.01). No significant differences in treatment effects were observed between the high-dosage irbesartan and celecoxib groups (P > 0.05). Our results indicate that medium and high doses of irbesartan and celecoxib have antiatherosclerotic effects in aortic plaques via inhibition of COX-2 and MMP-9 by suppressing NF-kappaB activation. High-dose irbesartan has effects similar to celecoxib. PMID- 29420358 TI - Cardiomyopathy Secondary to Long-Term Treatment With Lithium: A Case Report and Literature Review. PMID- 29420357 TI - Acetyl Cholinesterase Inhibitors and Cell-Derived Peripheral Inflammatory Cytokines in Early Stages of Alzheimer's Disease. AB - BACKGROUND: Clinical and preclinical studies firmly support the involvement of the inflammation in the pathogenesis of Alzheimer's disease (AD). Despite acetylcholinesterase inhibitors (AChEI) being widely used in AD patients, there is no conclusive evidence about their impact on the inflammatory response. METHODS: This study investigates peripheral proinflammatory cytokines (interferon gamma [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], and interleukins 1beta [IL-1beta] and 6 [IL-6]) by firstly comparing peripheral blood mononuclear cell (PBMC)-derived secretion in drug-naive and AChEI-treated AD patients versus healthy controls. A subset of those drug-naive AD patients, who were prescribed the AChEI donepezil, was followed-up for 6 months to investigate if donepezil suppresses proinflammatory cell-derived cytokine secretion. RESULTS: Patients with AD showed higher levels of PBMC-derived proinflammatory cytokines (IFN gamma, TNF-alpha, IL-1beta, and IL-6) in comparison with healthy controls. On reexamination, previously drug-naive AD patients who received donepezil treatment for 6 months displayed a decrease in cell-derived IFN-gamma, TNF-alpha, IL-1beta, and IL-6. CONCLUSIONS: Proinflammatory PBMC-derived cytokines were increased in patients with AD in comparison with healthy controls and donepezil-reduced proinflammatory cytokines when examining drug-naive AD patients before and after AChEI treatment. PMID- 29420359 TI - Crohn's Disease: A Critical Approach to Publication Procedures and Citation Behavior of the Global Research Network. AB - BACKGROUND AND GOALS: Crohn's disease (CD) is an inflammatory bowel disease, which can lead to abdominal pain, weight loss, fatigue, severe diarrhea, and malnutrition. Despite enormous efforts and progress in diagnosis and therapy, there are still many aspects of uncertainty leading to an increasing scientific interest in this topic. As it is challenging to survey all articles regarding CD and to measure their scientific importance, this study uses reliable scientometric tools to evaluate the global research output on CD related to quantitative and qualitative aspects and in chronological and geographical context. STUDY: We conducted a scientometric analysis to assess all global research activity on CD from 1900 until 2013. We analyzed the research output of countries, individual institutions, journals, authors and their collaborative networks and depicted our findings by density-equalizing map projections. RESULTS: The worldwide research architecture indicated that the United States, the United Kingdom, Germany, and France play leading role regarding scientific activity, h-indices, multilateral and bilateral cooperations. There is a dramatic increase of collaborative publications since the 1990s, which underlines recent studies pronouncing that the scientific progress will be mainly depending on international cooperations. CONCLUSIONS: We conclude that the field of CD is constantly progressing, in which the influence of international cooperations on the scientific productivity is of major and growing importance. North American and Western European nations constitute the scientific leaders in the field of CD whereas developing or underdeveloped countries did not exhibit considerable research productivity. PMID- 29420361 TI - Primary Ovarian Carcinoid: Extensive Clinical Experience With an Underrecognized Uncommon Entity. AB - PURPOSE: Primary ovarian neuroendocrine tumors (NETs) develop in pure form or in association with other tumors, mainly teratomas. The available data regarding this rare condition are limited. Much of the literature focuses on single case reports, previously dismissed as a totally benign disorder, and thus long-term considerations and evidence-based management guidelines are lacking. The objective of the current study was to describe the clinical and pathologic characteristics and the effect of various therapeutic modalities on patient morbidity and mortality from 2 major centers. A secondary objective was to highlight that carcinoid syndrome may be manifest in the absence of metastatic disease. METHODS: The authors retrospectively studied a cohort of 34 consecutive patients with primary ovarian NETs who attended either the Oxford University Hospitals or Beatson Oncology Centre, Glasgow, between 1984 and 2014, and had their ovarian carcinoid data (eg, tumor growth, chemotherapy regimen) and mortality outcomes assessed. RESULTS: All patients were women, with an average age of 53 years (range, 23-87 years) at diagnosis. Of the 34 patients, 8 patients (23.5%) presented with carcinoid symptoms. Carcinoid heart disease was evident in 2 of the 34 patients (6%). All patients had a primary ovarian carcinoid tumor on histopathology, and 2 patients had bilateral ovarian carcinoids. Teratoma associations could be assessed in 29 tumors, with 20 (69%) of 29 showing a pathological association. The mean tumor size was 48 mm (range, 4-120 mm; SD, 40 mm). The mean follow-up was 4.5 years, ranging up to 17 years. The disease has been quiescent with no evidence of relapse in 22 of 34 patients; in 12 of 34 patients, it was metastatic. There were 5 patients who received treatment with somatostatin analogs or chemotherapy, whereas 8 patients (23.5%) died of disease. Metastatic disease was found up to 11 years from initial diagnosis. CONCLUSIONS: Primary ovarian NET is rare and likely underrepresented in the literature. It can no longer be simply dismissed as a generally benign entity and may present with both the carcinoid syndrome and carcinoid heart disease. It requires careful evaluation and long-term review. PMID- 29420360 TI - Effectiveness of a single session of dual-transcranial direct current stimulation in combination with upper limb robotic-assisted rehabilitation in chronic stroke patients: a randomized, double-blind, cross-over study. AB - The impact of transcranial direct current stimulation (tDCS) is controversial in the neurorehabilitation literature. It has been suggested that tDCS should be combined with other therapy to improve their efficacy. To assess the effectiveness of a single session of upper limb robotic-assisted therapy (RAT) combined with real or sham-tDCS in chronic stroke patients. Twenty-one hemiparetic chronic stroke patients were included in a randomized, controlled, cross-over double-blind study. Each patient underwent two sessions 7 days apart in a randomized order: (a) 20 min of real dual-tDCS associated with RAT (REAL+RAT) and (b) 20 min of sham dual-tDCS associated with RAT (SHAM+RAT). Patient dexterity (Box and Block and Purdue Pegboard tests) and upper limb kinematics were evaluated before and just after each intervention. The assistance provided by the robot during the intervention was also recorded. Gross manual dexterity (1.8+/-0.7 blocks, P=0.008) and straightness of movement (0.01+/-0.03, P<0.05) improved slightly after REAL+RAT compared with before the intervention. There was no improvement after SHAM+RAT. The post-hoc analyses did not indicate any difference between interventions: REAL+RAT and SHAM+RAT (P>0.05). The assistance provided by the robot was similar during both interventions (P>0.05). The results showed a slight improvement in hand dexterity and arm movement after the REAL+RAT tDCS intervention. The observed effect after a single session was small and not clinically relevant. Repetitive sessions could increase the benefits of this combined approach. PMID- 29420362 TI - Malignant Endometrial Polyps in Uterine Serous Carcinoma: The Prognostic Value of Polyp Size and Lymphovascular Invasion. AB - OBJECTIVES: Uterine serous carcinoma (USC) involving an endometrial polyp and concurrent extrauterine disease is associated with poor prognosis. We examined the clinicopathological profiles of patients with stage 1A USC with and without polyp involvement and the role of polyp size and lymphovascular invasion (LVI) as prognostic indicators for extrauterine disease in patients with early USC. METHODS/MATERIALS: From 2002 to 2014, 242 patients with pure USC were identified. Fisher exact test was used for categorical variables. The student t test was used for means. Logistic regression was used to compute the odds ratio for continuous and categorical variables. RESULTS: Among stage 1A patients, the odds ratio of developing extrauterine disease for every 1 cm increase in polyp size is 1.368 (95% confidence interval, 1.034-1.810). Polyp size is only significantly associated with advanced stage disease for patients with myometrial invasion. A higher percent of LVI was found in stage 4 patients (31%). There is no survival or recurrence difference for stage 1 patients regardless of treatment or observation. CONCLUSIONS: Polyp size does not predict extrauterine disease for USC patients with disease in polyp only or disease in polyp and endometrium. Further study is needed to investigate whether presence of LVI is a prognostic factor. PMID- 29420363 TI - A Novel Method to Facilitate Uterine Delivery at Robotic Hysterectomy. AB - Minimally invasive platforms have afforded women undergoing hysterectomy the advantages of improved postoperative pain control, reduced complication rates, and shorter inpatient recovery time. In patients where malignancy has been confirmed or suspected, the necessity for uterine delivery per vagina is imperative to maintain these advantages without compromising oncological outcome.A previously unreported technique of enlarging the apical circumference of the vagina during robotic hysterectomy facilitates intact uterine passage after extended reflection of the bladder and/or rectum. Significant increases in vault circumference can be gained through even small midline incisions of the vaginal wall, with an additional 5-cm incision almost doubling the apical aperture in certain cases.We present our series of 21 cases that support this safe, reliable, and simple method for intact uterine delivery during robotic hysterectomy in minimally invasive gynecological oncology practice. PMID- 29420364 TI - Assessing Patient-reported Quality of Life Outcomes in Vulva Cancer Patients: A Systematic Literature Review. AB - OBJECTIVES: Vulva cancer (VC) treatment carries a high risk of severe late effects that may have a negative impact on quality of life (QoL). Patient reported outcome measures (PROMs) are increasingly used when evaluating disease- and treatment-specific effects. However, the adequacy of measures used to assess sequelae and QoL in VC remains unclear. The aims of the present study were to evaluate disease- and treatment-related effects as measured by PROMs in VC patients and to identify available VC-specific PROMs. METHODS/MATERIALS: A systematic literature search from 1990 to 2016 was performed. The inclusion criterion was report of disease- and treatment-related effects in VC patients using PROMs in the assessment. Methodological and reporting quality was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement. This systematic review was performed as part of phase 1 of the development of a European Organisation for Research and Treatment of Cancer QoL questionnaire for VC patients. RESULTS: The search revealed 2299 relevant hits, with 11 articles extracted including a total of 535 women with VC; no randomized controlled trials were identified. The selected studies exhibited great heterogeneity in terms of PROMs use. Twenty-one different instruments assessed QoL. Most of the questionnaires were generic. Different issues (sexuality, lymphedema, body image, urinary and bowel function, vulva-specific symptoms) were reported as potentially important, but the results were not systematically collected. Only one VC-specific questionnaire was identified but did not allow for assessment and reporting on a scale level. CONCLUSIONS: Vulva cancer treatment is associated with considerable morbidity deteriorating QoL. To date, there is no validated PROM available that provides adequate coverage of VC related issues. The study confirms the need for a VC-specific QoL instrument with sensitive scales that allows for broad cross-cultural application for use in clinical trials. PMID- 29420365 TI - Nicotinamide N-methyltransferase: potential involvement in cutaneous malignant melanoma. AB - Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyzes the N methylation of nicotinamide and pyridine compounds, participating in xenobiotic and drug metabolism. Data on literature have evidenced a possible role of NNMT in many solid cancers, but no data are currently available in cutaneous melanoma. Recent important advances have been achieved in the treatment of advanced melanoma with targeted therapy and immunotherapy. However, the identification of biomarkers that can be used for the detection of early stage disease as well as for monitoring the therapeutic response during treatment is of utmost importance. The aim of this study was to study the possible role of NNMT in melanoma. In the present study, we carried out immunohistochemical analyses to evaluate the expression of the enzyme NNMT in 34 melanomas and 34 nevi. Moreover, we explored the relationship between NNMT levels and the prognostic parameters of patients with melanoma. The results obtained showed significantly (P<0.0001) higher NNMT expression in melanoma compared with that detected in nevi. In addition, a significant (P<0.05) inverse relationship was found between enzyme levels and Breslow thickness, Clark level, the presence/number of mitoses, and ulceration. Taken together, these data seem to suggest that NNMT could represent a molecular biomarker for melanoma, thus highlighting its potential for both diagnosis and prognosis of this neoplasm. PMID- 29420366 TI - Short article: Endoscopic ultrasound-guided fine-needle aspiration of portal vein thrombosis in patients with chronic liver disease and suspicion of hepatocellular carcinoma. AB - BACKGROUND: Differentiation between benign and malignant portal vein thrombosis (PVT) in the setting of a hepatocellular carcinoma (HCC) is of paramount importance. Histological analysis is usually not carried out because of potential severe side effects of the percutaneous approach. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) may be safer and may guide the clinical management of patients with HCC. OBJECTIVE: To describe the feasibility of the EUS-FNA in a series of patients with HCC and PVT. MATERIALS AND METHODS: A chart review of patients with PVT was performed from 2014 to 2016 in three tertiary care hospitals of Spain. Patients with chronic liver disease and PVT with a suspicion of HCC referred for EUS-FNA were included. The impact of the EUS-FNA was assessed by comparing staging following the Barcelona Clinic Liver Cancer algorithm (BCLC) before and after EUS-FNA. RESULTS: Of 104 patients with PVT and chronic liver disease, 23 were considered candidates for EUS-FNA. Eight patients were referred for EUS-FNA. The technique was feasible in seven patients and FNA was positive in six patients. No side effects were reported. EUS-FNA upstaged six out of seven (85.7%) patients: one patient BCLC stage B, two patients BCLC stage A, and three patients in whom the HCC was not diagnosed before EUS-FNA of the PVT. A benign PVT was found in the explant of the only patient with a negative PVT. CONCLUSION: EUS-FNA is a valuable technique in selected patients with chronic liver disease with PVT. It is feasible, safe, and may alter the clinical management in these patients. PMID- 29420367 TI - Early Response Assessed by Contrast-Enhanced Ultrasound in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy. AB - The study was aimed to investigate the role of contrast-enhanced ultrasound (CEUS) in evaluating the response of patients with breast cancer after receiving neoadjuvant chemotherapy (NAC). A systematic search was conducted in PubMed, Spring, Wanfang, and CNKI databases from 1923 to December 2016. Based on fixed effect model or randomized effects model, standardized mean difference (SMD) with its 95% confidence interval (95% CI) was calculated in accordance with heterogeneity analysis. Cochran Q and I tests were used to measure heterogeneity. Sensitivity analysis was performed to evaluate the strength of the meta-analysis. In total, 8 studies were enrolled in the meta-analysis. Tumor size of breast cancer was obviously decreased when evaluated by CEUS (SMD, 0.96; 95% CI, 0.76 1.15) after NAC. After aggregating the data by the fixed effect model, the CEUS time-intensity curve showed a great reduction in the area under the curve of patients receiving NAC (SMD, 0.38; 95% CI, 0.08-0.69). Based on CEUS, tumor size and area under the CEUS time-intensity curve were both reduced. We suggest that the CEUS is a promising tool for evaluating the response of breast cancer after NAC. PMID- 29420368 TI - Myofibroblastoma of the Breast: Ultrasonography, Mammography, and Magnetic Resonance Imaging Features With Pathologic Correlation. AB - Myofibroblastoma (MFB) of the breast is an uncommon benign stromal tumor. Herein, we present histopathologically proven MFB that hyperechoic well-defined breast mass in the ultrasonography and circumscribed high-density mass in mammography. Additionally, internal septations and hyperintense appearance on magnetic resonance imaging are very valuable findings in the differential diagnosis of MFB. PMID- 29420369 TI - Efficacy and Toxicity of Fifth-line Nivolumab in a 15-Year-Old Girl With Metastatic Juvenile Renal Cell Carcinoma. PMID- 29420370 TI - Hepatoblastoma in a Child With Early-onset Cirrhosis. AB - Hepatoblastoma is the most common hepatic malignancy of childhood with known genetic predispositions and perinatal risk factors, with rare case reports occurring in the setting of cirrhosis. This case describes a young patient with cirrhosis attributed to early-onset hereditary hemochromatosis who was diagnosed with hepatoblastoma with uncommon histologic findings, evidence of chemotherapy resistance who ultimately succumbed to her disease. It is important to consider diagnoses beyond hepatocellular carcinoma in this scenario and consider early biopsy. With atypical histology, the tumor may respond poorly to conventional treatment and aggressive surgery or intensive therapy should be contemplated. PMID- 29420371 TI - High-dose Chemotherapy is Efficacious and Well Tolerated in a Toddler With Aicardi Syndrome and Malignant Sacrococcygeal Teratoma. AB - Aicardi syndrome (AS) is a rare neurodevelopmental disorder, predominantly seen in female individuals, which appears to have an increased risk of both benign and malignant neoplasia. We report the case of a child with AS who presented with metastatic malignant sacrococcygeal tumor (with yolk sac elements) which recurred and then was treated with 3 cycles of high-dose chemotherapy with autologous stem cell rescue. The patient tolerated therapy with acceptable toxicity and remains in clinical remission 3 months after the completion of therapy. Her neurological status remains similar to that before diagnosis with the exception of chemotherapy induced hearing loss. This is the first description a sacrococcygeal teratoma in a patient with Aicardi, as well as the first use of intensified consolidation chemotherapy in a patient with Aicardi, which was well tolerated and resulted in remission. The use of chemotherapy should be considered for all patients with AS and malignancy. PMID- 29420373 TI - The Zinc and Copper Levels in Thalassemia Major Patients, Receiving Iron Chelation Therapy. AB - Essential trace elements deficiency including zinc and copper are frequently reported in the literature, but the results are controversial. The aim of this study was to evaluate zinc and copper levels in thalassemia major (TM) patients who were on regular transfusion and iron chelation therapy. In a case-control cross-sectional study 43 TM patients and 43 age-matched and sex-matched healthy controls were examined. Patients were selected by convenience sampling method from TM patients who were registered in Thalassemia Clinic during 6 months. Serum zinc and copper levels were evaluated in all subjects. Zinc and copper dietary intake were also assessed. The median zinc level in the participants was significantly lower than the control group (35 [6.3 to 298] vs. 173 [3.1 to 584] MUg/dL; P<0.05), but the mean copper level was significantly higher in the patients in comparison with the control group (260+/-118 vs. 201+/-69 MUg/dL; P<0.05). In contrast, the mean zinc and copper dietary intake in the patient's group were significantly lower than the control group. The mean serum zinc and copper levels in the patient's group were not different according to iron chelation therapy type. Also, zinc and copper levels in the patient's group were not statistically significant based on ferritin level, age, and duration of therapy. Essential trace elements level change and deficiency might occur in TM patients. Hence, routine assessment of these elements is recommended for better management. PMID- 29420372 TI - Mutation Screening of the Kruppel-like Factor 1 Gene in Individuals With Increased Fetal Hemoglobin Referred for Hemoglobinopathy Investigation in South of Iran. AB - BACKGROUND: Any mutation in the Kruppel-like factor 1 (KLF1) gene may interfere with its proper related function in the erythropoiesis process and lead to alterations in proper activation of its downstream protein through globin switching, which results in an increase in fetal hemoglobin (HbF). This study aimed to investigate whether KLF1 mutation can associate with high level of HbF in individuals with increased fetal hemoglobin referred for screening of hemoglobinopathies in south of Iran. MATERIALS AND METHODS: The human KLF1 gene was amplified via the polymerase chain reaction procedure, and sequencing was used to determine any mutation in these patients. Moreover, XmnI polymorphisms in the position of -158 of gamma-globin gene promoter were analyzed in all patients by polymerase chain reaction restriction fragment length polymorphism. RESULT: Analysis of sequencing revealed a missense mutation in the KLF1 gene, p.Ser102Pro (c.304T>C), which was detectable in 10 of 23 cases with elevated HbF level. This mutation was only detected in individuals who had a HbF level between 3.1% and 25.6%. Statistical analysis showed that the frequency of C allele is significantly correlated with a high level of HbF (P<0.05). The allele frequency of positive result of XmnI polymorphism in individuals with increased HbF level was also significant, which showed an association with increased HbF level (P<0.05). CONCLUSIONS: To the best of our knowledge, this is the first report of p.Ser102Pro (c.304T>C) in the KLF1 gene in beta-thalassemia patients with increased level of fetal hemoglobin. According to statistical results of p.Ser102Pro mutation and XmnI polymorphism, it has been strongly suggested that both polymorphisms have an association with increased HbF samples. These nucleotide changes alone may not be the only elements raising the level of HbF, and other regulatory and modifying factors also play a role in HbF production. PMID- 29420374 TI - Clinical Outcomes of Digital Three-Dimensional Hydroxyapatite in Repairing Calvarial Defects. AB - PURPOSE: The objective of this article is to present the long-term outcomes of digital three-dimensional (3D) hydroxyapatite (HA) implants used for calvarial defects. Porous HA provide good results and have many characteristics, making it suitable for calvarial defect reconstruction. However, using HA may be associated with potentially serious complications, including infection and exposure. The authors used digital 3D HA for cranioplasty for many years and accumulated considerable experience from using it. The authors found that digital 3D HA is an effective method for cranioplasty, showing low complication rate. METHODS: A total of 57 patients underwent calvarial defect reconstruction with 3D HA from June 2009 to August 2016. The follow-up period was 1 to 5 years. RESULTS: Most patients (91.2%) were greatly satisfied with the esthetic outcomes of the surgery. The highest rate of complication was seroma (8.8%). Two patients developed postoperative infections (3.5%). One patient with infections was successfully treated with antibiotic therapy. Another patient was required to undergo an extensive surgical debridement followed by delayed autogenous bone reconstruction. One patient suffered from implant exposure. No hematoma, unexpected fractures, asymmetry, and contour or implant abnormalities occurred. CONCLUSIONS: The digital 3D HA implant was highly biocompatible and durable for the reconstruction of calvarial defects. With appropriate treatment, the proposed method was able to achieve a functional and cosmetic reconstruction with lesser complications. PMID- 29420375 TI - The Effect of Upper Aging Blepharoplasty on Upper and Lower Eyelid Position. AB - PURPOSE: Change in eyelid position after upper blepharoplasty is an important factor that can affect postoperative patient satisfaction. However, no one has investigated eyelid changes during follow-up for upper eyelid surgery. Thus, the purpose of this study was to investigate position changes in the upper and lower eyelids during the follow-up period after upper blepharoplasty in Korean. METHODS: The authors retrospectively reviewed the clinical records of patients who underwent upper blepharoplasty for uncomplicated upper eyelid dermatochalasis. Digital photographs were taken preoperatively, immediately after surgery, and at 1 week postoperative, 1 month postoperative, and 3 months postoperative. Our main-effect variables were marginal reflex distance (MRD) 1 and 2 and palpebral fissure height (PFH), which were measured from digital photographs using ImageJ software. RESULTS: We enrolled 180 eyes from 90 patients (M: 35 and F: 55) with a mean age of 63.8 +/- 10.3 years. The eyelid measurements (MRD1, MRD2, PFH) taken preoperatively, immediately after surgery, and 1 week, 1 month, and 3 months postoperative were, respectively: MRD1 (mm): 2.56 +/- 1.08, 1.91 +/- 0.86, 2.21 +/- 1.02, 2.66 +/- 1.01, 2.75 +/- 0.99; MRD2 (mm): 4.91 +/- 0.93, 4.62 +/- 0.87, 4.68 +/- 0.90, 4.87 +/- 0.86, 4.91 +/- 0.83; and PFH (mm): 7.48 +/- 1.64, 6.53 +/- 1.46, 6.89 +/- 1.53, 7.52 +/- 1.51, 7.65 +/- 1.49. All postoperative measurements for MRD1 and PFH were significantly different from the preoperative measurement, except for measurements taken 1 month postoperative. MRD2 measurements differed significantly from the preoperative measurements immediately after surgery and 1 week postoperative. Among age, preoperative PFH, and amount of skin-muscle resection, only preoperative PFH significantly affected PFH changes immediately after surgery and at 3 months postoperative (OR 0.636, 95% CI 0.478-0.847, OR 0.506, 95% CI 0.386-0.663). CONCLUSION: All eyelid measurements (MRD1, MRD2, and PFH) decreased 1 week postoperatively from values immediately after surgery, but MRD1 and PFH increased slightly 3 months postoperative. We note that postoperative changes in PFH may be large in patients with large PFH before blepharoplasty. It should also be noted that reverse ptosis of the lower eyelid occurs immediately after upper eyelid surgery. PMID- 29420376 TI - A Minimally Invasive Endoscopic Approach to Midcheek Mass: Showcase for Technical Description. AB - BACKGROUND: Surgical approaches to the midcheek area are challenging. This area is included between the lower eyelid above, and the upper lip below. The peculiar anatomical location makes it really important for attractiveness, thus the need to obtain a correct balance between the operation's safety and minimally invasive aspect. To the authors' knowledge, this is the first showcase and technical description of a novel minimally invasive endoscopic approach for midcheek mass removal. METHODS: Making 3 incisions in concealed area an endoscopically aided facial dissection was performed to remove a solitary venus malformation of the left midcheek region. RESULTS: After the surgical procedure was performed, no hematoma, no edema, or facial nerve paralysis were observed. To date, during the follow-up period, no recurrence of the lesion has been observed, and the quality of life of the patient was good with a minimally scar outcome. Magnetic resonance imaging, performed 2 weeks postoperatively, demonstrated a complete removal of the mass CONCLUSION:: The authors' finding experience suggests that the minimally invasive approach provides an excellent surgical window that achieves greater exposure for the dissection of the midcheek area. Further clinical applications are required to assess advantages and/or limitations of this procedure. PMID- 29420377 TI - Modified Lengthening Temporalis Myoplasty Involving an Extended Lazy-S Incision to Avoid Facial Scar Formation. AB - BACKGROUND: Lengthening temporalis myoplasty is a faster and less invasive alternative to free muscle transfer for smile reconstruction. However, it requires a nasolabial fold incision, which leaves a midfacial scar. Based on esthetic considerations, a modified approach, involving an extended lazy-S (parotidectomy) incision instead of a nasolabial fold incision, was developed. METHODS: A cadaveric study involving 10 hemifaces was conducted. From February 2013 to March 2016, the modified lengthening temporalis myoplasty procedure was employed in 10 patients. The results were graded from 1 (poor) to 5 (excellent) according to the Terzis grading system. The excursion of the oral commissure was also measured. RESULTS: The extended lazy-S incision provides easy and safe access to the coronoid process and good visibility. The patients' mean age was 56.5 years, and the mean duration of the postoperative follow-up period was 22.2 months. The patients' underlying conditions included acoustic neuroma (n = 2), Bell palsy (n = 3), congenital conditions (n = 2), brain infarction (n = 1), Ramsay Hunt syndrome (n = 1), and malignant parotid lymphoma (n = 1). One patient suffered a surgical site infection, which was successfully treated with irrigation. All the patients achieved improvements in smile symmetry: 2, 5, and 3 patients obtained excellent, good, and moderate results, respectively. The excursion of the oral commissure ranged from 5 to 10 mm. CONCLUSION: The modified lengthening temporalis myoplasty procedure provides satisfactory functional outcomes without causing significant complications. It does not leave a facial scar and is a preferable option, especially for young and female patients, and patients who have undergone ablative surgery involving the parotid region. PMID- 29420378 TI - Purely Spinal Epidural Capillary Hemangiomas. AB - Capillary hemangiomas (CAs) are benign endothelial cell neoplasms that are often encountered superficially in the soft tissues of the head and neck region. Most of the reported purely spinal epidural hemangiomas have been of cavernous type, and the occurrence of purely spinal epidural CA is exceedingly rare, and there are only 12 reported cases of spinal epidural CAs in the English literature. Herein, the authors report the 13th case of purely spinal epidural CAs, and the clinical characteristics, histopathological features, and treatment were also investigated. PMID- 29420379 TI - Review of "Are We Ready for Our Close-Up? Why and How We Must Embrace Video in the OR" by Langerman A, Grantcharov TP in Ann Surg 266: 934-936, 2017. PMID- 29420380 TI - Review of "Beyond Infrastructure: Understanding Why Patients Decline Surgery in the Developing World" by Lerman BJ, Alsan M, Chia NJ, Brown JA, Wren SM in Ann Surg 266:975-980, 2017. PMID- 29420381 TI - Surgical Treatment of Osteoma in the Basilar Region of the Mandible. AB - Osteoma is an uncommon benign osteogenic tumor characterized by the proliferation of compact and cancellous bone. The objective of this study was to report a case of osteoma in the basilar region of the mandible. The patient reported no pain, but the affected area was tender to touch and there was esthetic concern because of the apparent swelling. The mass measured approximately 5 cm in diameter and extended to the lingual area of the mandible. A vestibular approach was used for surgical treatment. After infiltration of a local anesthetic and vasoconstrictor, to expose the mandibular ramus, an incision was made with an electric scalpel along the external oblique ridge through the mucosa, submucosa and muscle, fascia and periosteum until the lower second molar, 3 to 5 mm inferior to the mucogingival junction. A mucoperiosteal flap was raised until the base of the mandible to access the tumor. Osteotomy was performed and the tumor was removed. The patient shows no recurrence of the tumor after 1 year and 6 months of follow up. Periodical clinical and radiographic follow-up are satisfactory since recurrence is rare. PMID- 29420382 TI - An Unusual Presentation of Conjunctival Dermolipoma With a Skin Tag. AB - Dermolipoma is considered the second most common benign conjunctival tumor in children after nevus. Usually, dermolipoma located just deep in the superotemporal bulbar and forniceal conjunctiva. The authors describe an uncommon presentation of dermolipoma that arise in the conjunctiva as well as in the skin of the lateral canthus. A 5-month-old baby with lateral limbal lesion involving the conjunctiva and the skin underwent excision biopsy. The pathological examination found a dermolipoma in the conjunctiva as well as in the dermis. The outcomes of the excision were satisfactorily functional and cosmetic.This is only the second case of dermolipoma in the dermis in normal baby that described those far in the literature. This case should raise the awareness that dermolipoma should be considered in differential diagnosis of lesions of the lateral cantus and the periocular skins near it. PMID- 29420383 TI - Primitive Squamous Cell Carcinoma of Pterygopalatine Fossa. AB - Primitive tumors of pterygopalatine fossa (PPF) are often benign tumors or extension of a malignant sinonasal tract. Primitive tumors may rarely occur in PPF.The authors present a 71-year-old woman with a 6-month history of left cranial nerve palsy. Magnetic resonance imaging and positron emission tomography computed tomography showed an enhancing isolated lesion at the PPF. A transmaxillary biopsy was performed, leading to diagnosis of primitive squamous cell carcinoma. The patient underwent radiotherapy treatment.Primitive tumors of PPF are rare and diagnosis may be difficult. Endoscopic access for diagnosis can be performed. Squamous cell carcinoma occurring in PPF is associated with poor prognosis. PMID- 29420384 TI - A Rare Cause of Objective Tinnitus: Jugular Diverticulum. AB - The jugular bulb is a venous structure linking the sigmoid sinus with the internal jugular vein. Jugular diverticulum is a rare condition characterized by extraluminal outpouching from the jugular bulb. As the patients may be totally asymptomatic, but sensorineural symptoms such as sensorineural hearing loss, tinnitus and vertigo can also occur. Diagnosis of these patients can be made by some radiologic methods such as high-resolution computerized tomography, magnetic resonance imaging, or a novel radiologic technique flat panel computed tomography. In this paper we report a 22-year-old female patient with jugular diverticulum presenting with tinnitus complaint. PMID- 29420385 TI - Orthognathic Surgery and Implant-Supported Bridge in a Class III Patient Injured in a Motor Vehicle Accident. AB - Occlusal and esthetic rehabilitation of jaw deformities in patients with partially edentulous maxilla are challenging procedures. This article describes a patient involving a skeletal Class III, 36-year-old male patient with a single bilateral anterior partially edentulous maxilla resulting from injuries sustained in a motor vehicle accident; his anterior teeth had been lost for more than 10 years. His lip protruded from the lateral view due to the proclined upper incisors and mandibular protrusion.Because of the facial deformity and inadequate prosthesis of the maxilla, the prosthesis had dropped out repeatedly. Bone deficiency was prominent in the area of the anterior maxillary region and required augmentation for implant restoration.Consultation among the prosthodontist, orthodontist, and patient led to a decision to perform an orthognathic surgery and bone graft before implant treatment. After orthodontic treatment combined with orthognathic surgery, 3 dental implants were placed with simultaneous iliac bone graft for prosthetic rehabilitation. The treatment restored the maxillary dental arch, which supported the upper lip with appropriate occlusion, both esthetically and functionally. After a 2-year clinical follow-up, the orthoprosthesis of the maxilla remained stable, and the patient was satisfied with the outcome of treatment. The combination of orthodontic, surgical, and dental implant treatment could be an option for skeletal Class III patients with bone-deficient, edentulous jaws. PMID- 29420386 TI - Neurofibroma of the Nasal Ala: Pediatric Nasal Reconstruction. AB - Benign tumors of the nasal cavity originating from a peripheral nerve sheath are rare. The authors present a case of a 3-month-old boy with a mass in the left nasal vestibule. The surgical resection was complicated by full-thickness necrosis of more than 50% of the nasal ala. The tumor was diagnosed histopathologically as a neurofibroma with glial heterotopia. The details of the nasal reconstruction with a paramedian forehead flap in 3 stages and postoperative results are provided with satisfactory cosmetic and functional results. PMID- 29420387 TI - High-Grade Conventional Osteosarcoma of the Mandible Associated With P53 Germline Mutation. AB - High-grade conventional osteosarcoma of the mandible is a rare entity that can manifest as a rapidly growing mass. The authors report the case of a young adult patient with right mandible pain and swelling and a history of humeral osteosarcoma treated over 1 decade earlier. Computed tomography and magnetic resonance imaging showed a mass arising from the right mandible that progressed despite induction chemotherapy and the patient underwent surgery. Histopathology revealed the presence of malignant osteoblasts and osteoid, which led to the diagnosis of high-grade conventional osteosarcoma. There were also regional lymph node metastases. Genetic testing revealed a p53 germline mutation. The presence of mandibular osteosarcoma in a young patient should raise the suspicion of an underlying p53 germline mutation. Ultimately, the recurrent tumor regressed with Etoposide and Ifosfamide. PMID- 29420388 TI - Monitoring the Prescribed and Experienced Heart Rate Derived Training Loads in Elite Field Hockey Players. AB - This study examined the congruence between the prescribed and experienced heart rate derived training loads over a five week periodized mesocycle. Twenty-four elite female field hockey players training as part of a national team were monitored prior to an (FIH) Hockey World League tournament. Three on-field training sessions per week were prospectively designed focusing on technical, tactical, and physiologically-oriented hockey drills. A training load value, modelling the periodized weekly loading scheme, was prescribed for each training session and was calculated using normative training load responses from performing on-field hockey drills. Magnitude based inferences focusing on the effect size (ES) and a Pearson Correlation Coefficient (r) were utilized to examine the degree of difference and the strength of correlation between the prescribed and experienced training loads. A significant correlation was observed between the experienced and prescribed training loads over the five-week mesocycle [r = 0.92, 90% CL (0.84:0.96)]. The percentage difference and the effect size between the achieved and prescribed training loads were as follows, Week1 demonstrated a 2.0% difference [ES = 0.10, 90% CL (-0.22:0.41)], Week 2 a 5.4% difference [ES = -0.41, 90% CL (-0.75:-0.07)], Week3 a -1.5% difference [ES = -0.09, 90% CL (-0.37:0.20)], Week4 a 7.1% difference [ES = 0.46, 90% CL (0.14:0.78)] and Week5 a 3.5% difference [ES = 0.18, 90% CL (-0.17:0.53)]. This investigation demonstrates the efficacy for coaches to prospectively design on field training sessions utilizing normative training load data to enhance the congruence between the prescribed and experienced training loads over a periodized mesocycle. PMID- 29420389 TI - Variability and Reliability of Punching Impact Kinetics in Untrained Participants and Experienced Boxers. AB - Lenetsky, S, Brughelli, M, Nates, RJ, Cross, MR, and Lormier, AV. Variability and reliability of punching impact kinetics in untrained participants and experienced boxers. J Strength Cond Res 32(7): 1838-1842, 2017-Striking impact kinetics are central to performance in combat sports. Despite a multitude of assessment, few in the literature have explored the variability and reliability of punching force assessment. Consequently, this study assessed the variability and reliability of measured punching impact kinetics in untrained and experienced boxers using a recently developed and validated method of striking dynamometry. Intrasession (both cohorts) and intersession (untrained only) measures of impulse, peak, and mean force were determined across 4 punch types (jabs, crosses, lead, and rear hand hooks) using coefficient of variation (CV), intraclass correlation coefficients (ICCs), and typical error of measurement (TEM). Moderate (ICC <0.67 or CV >10%) to small (ICC >0.67 and CV <10%) variability was found for intrasession results of both groups, the majority having small variability. Intersession findings of the untrained cohort had a similar spread of variability, but with the majority exhibiting moderate variability. All variables except for mean force of the cross in the experienced boxer cohort were found to exhibit a "moderated" magnitude of reliability determined by standardized TEM scores (TEM = 0.60-1.19) during intrasession testing. All variables had moderate reliability during intersession. This method was found to have acceptable variability and reliability when monitoring punching impact kinetics. PMID- 29420391 TI - Clinical Management of Endometriosis. AB - Endometriosis is a common and challenging condition of reproductive-aged women that carries a high individual and societal cost. The many molecular dissimilarities between endometriosis lesions and eutopic endometrium create difficulties in the development of new drug therapies and treatments. Surgery remains the gold standard for definitive diagnosis, but it must be weighed against the risks of surgical morbidity and potential decreases in ovarian reserve, especially in the case of endometriomas. Safe and effective surgical techniques are discussed within this article for various presentations of endometriosis. Medical therapy is suppressive rather than curative, and regimens that are long-term and affordable with minimal side effects are recommended. Recurrences are common and often rapid when medical therapy is discontinued. Endometriosis in the setting of infertility is reviewed and appropriate management is discussed, including when and whether surgery is warranted in this at-risk population. In patients with chronic pain, central sensitization and myofascial pain are integral components of a multidisciplinary approach. Endometriosis is associated with an increased risk of epithelial ovarian cancer; however, the risk is low and currently no preventive screening is recommended. Hormone therapy for symptomatic women with postsurgical menopause should not be delayed as a result of concerns for malignancy or recurrence of endometriosis. PMID- 29420390 TI - Specific Adaptations in Performance and Muscle Architecture After Weighted Jump Squat vs. Body Mass Squat Jump Training in Recreational Soccer Players. AB - Coratella, G, Beato, M, Milanese, C, Longo, S, Limonta, E, Rampichini, S, Ce, E, Bisconti, AV, Schena, F, and Esposito, F. Specific adaptations in performance and muscle architecture after weighted jump-squat vs. body mass squat jump training in recreational soccer players. J Strength Cond Res 32(4): 921-929, 2018-The aim of the present study was to compare the effects of weighted jump-squat training (WJST) vs. body mass squat jump training (BMSJT) on quadriceps' muscle architecture, lower-limb lean-mass (LM) and muscle strength, performance in change of direction (COD), and sprint and jump in recreational soccer players. Forty-eight healthy soccer players participated in an offseason randomized controlled trial. Before and after an 8-week training intervention, vastus lateralis pennation angle, fascicle length, muscle thickness, LM, squat 1RM, quadriceps and hamstrings isokinetic peak torque, agility T-test, 10-and 30-m sprints, and squat-jump (SJ) were measured. Although similar increases were observed in muscle thickness, fascicle length increased more in WJST (Effect size [ES] = 1.18, 0.82-1.54) than in BMSJT (ES = 0.54, 0.40-0.68), and pennation angle increased only in BMSJT (ES = 1.03, 0.78-1.29). Greater increases in LM were observed in WJST (ES = 0.44, 0.29-0.59) than in BMSJT (ES = 0.21, 0.07-0.37). The agility T-test (ES = 2.95, 2.72-3.18), 10-m (ES = 0.52, 0.22-0.82), and 30-m sprints (ES = 0.52, 0.23-0.81) improved only in WJST, whereas SJ improved in BMSJT (ES = 0.89, 0.43-1.35) more than in WJST (ES = 0.30, 0.03-0.58). Similar increases in squat 1RM and peak torque occurred in both groups. The greater inertia accumulated within the landing phase in WJST vs. BMSJT has increased the eccentric workload, leading to specific eccentric-like adaptations in muscle architecture. The selective improvements in COD in WJST may be related to the increased braking ability generated by the enhanced eccentric workload. PMID- 29420392 TI - Health and Well-Being for All: Delivering on the Promise for Those We Serve. PMID- 29420393 TI - Implementing Innovations in Global Women's, Children's, and Adolescents' Health: Realizing the Potential for Implementation Science. AB - The launch of the United Nations Sustainable Development Goals and the new Secretary General's Global Strategy for Women's, Children's, and Adolescents' Health are a window of opportunity for improving the health and well-being of women, children, and adolescents in the United States and around the world. Realizing the full potential of this historic moment will require that we improve our ability to successfully implement life-saving and life-enhancing innovations, particularly in low-resource settings. Implementation science, a new and rapidly evolving field that addresses the "how-to" component of providing sustainable quality services at scale, can make an important contribution on this front. A synthesis of the implementation science evidence indicates that three interrelated factors are required for successful, sustainable outcomes at scale: 1) effective innovations, 2) effective implementation, and 3) enabling contexts. Implementation science addresses the interaction among these factors to help make innovations more usable, to build ongoing capacity to assure the effective implementation of these innovations, and to ensure enabling contexts to sustain their full and effective use in practice. Improving access to quality services will require transforming health care systems and, therefore, much of the focus of implementation science in global health is on improving the ability of health systems to serve as enabling contexts. The field of implementation science is inherently interdisciplinary and academe will need to respond by facilitating collaboration among scientists from relevant disciplines, including evaluation, improvement, and systems sciences. Platforms and programs to facilitate collaborations among researchers, practitioners, policymakers, and funders are likewise essential. PMID- 29420394 TI - Second-Stage Duration and Outcomes Among Women Who Labored After a Prior Cesarean Delivery. AB - OBJECTIVE: To characterize probabilities of vaginal delivery based on second stage duration along with maternal and neonatal risks for women undergoing labor after cesarean delivery. METHODS: This unplanned secondary analysis of the Maternal-Fetal Medicine Units Cesarean Registry, a prospective observational cohort, assessed outcomes in women with a prior uterine scar and included women with a previous cesarean delivery without prior vaginal delivery who reached the second stage of labor. The primary outcome was mode of delivery by second-stage duration. Secondary outcomes included assessment of individual adverse maternal (chorioamnionitis, atony, endometritis, hysterectomy, uterine rupture or dehiscence, and red cell transfusion) and neonatal (cord pH less than 7.10, Apgar score less than 6 at 5 minutes, neonatal intensive care unit admission, and ventilatory support) outcomes. RESULTS: Of 4,579 women with a previous cesarean delivery who reached the second stage of labor, 4,147 (90.6%) delivered vaginally. As second stage increased, successful vaginal delivery rates decreased: 97.3% at less than 1 hour (95% CI 96.6-97.9%), 91.5% at 1 to less than 2 hours (95% CI 89.8-93.1%), 78.5% at 2 to less than 3 hours (95% CI 74.5-82.1%), 62.3% at 3 to less than 4 hours (95% CI 55.2-69.1%), and 45.6% at 4 hours or greater (95% CI 37.7-53.7%). Risk of all adverse maternal outcomes increased with the length of the second stage. Specifically, risk of uterine rupture or dehiscence increased with second-stage length from less than 1 hour (0.7%), 1 to less than 2 hours (1.4%), 2 to less than 3 hours (1.5%), to 3 hours or greater (3.1%) (P<.001 for differential risk across the second stage). Risk of neonatal outcomes did not differ significantly by second-stage length. CONCLUSION: Although many women with a longer second stage (greater than 3 hours) will achieve successful vaginal delivery, these patients may be at increased risk for adverse maternal outcomes and should have close observation of fetal heart rate monitoring, maternal vital signs, and symptoms suggestive of uterine rupture or dehiscence. PMID- 29420395 TI - Ulipristal Acetate for Treatment of Symptomatic Uterine Leiomyomas: A Randomized Controlled Trial. AB - OBJECTIVE: To assess efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas. METHODS: This phase 3, double-blind, placebo-controlled study enrolled premenopausal women (aged 18-50 years) with abnormal uterine bleeding, one or more discrete leiomyomas, and uterine size 20 weeks of gestation or less. Patients were randomized 1:1:1 to 5 mg ulipristal, 10 mg ulipristal, or placebo once daily for 12 weeks followed by 12-week drug-free follow-up. Coprimary endpoints were rate of and time to amenorrhea, defined as no bleeding for the last 35 consecutive days of treatment. Secondary endpoints included rates of amenorrhea from day 11 and change from baseline to endpoint in the Revised Activities subscale of the Uterine Fibroid Symptom and Quality of Life questionnaire, which includes questions pertaining to physical and social activities. Safety assessments included adverse event monitoring and endometrial biopsies. A sample size of 150 was planned to compare separately each dose of ulipristal with placebo. RESULTS: From March 2014 to March 2016, 157 patients were randomized. Demographics were similar across treatment groups. Amenorrhea was achieved by 25 of 53 (47.2% [97.5% CI 31.6-63.2]) and 28 of 48 (58.3% [97.5% CI 41.2-74.1]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 1 of 56 (1.8% [97.5% CI 0.0-10.9]) placebo-treated patients (both P<.001). Time to amenorrhea was shorter for both ulipristal doses compared with placebo (P<.001), and both doses of ulipristal resulted in improved quality of life compared with placebo (P<.001). Common adverse events (5% or greater in either ulipristal group during treatment) were hypertension, elevated blood creatinine phosphokinase, and hot flushes. Serious adverse events occurred in four patients, but none was considered related to treatment. Endometrial biopsies were benign. CONCLUSION: Ulipristal at 5 mg and 10 mg were well tolerated and superior to placebo in rate of and time to amenorrhea in women with symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov number, NCT02147197. PMID- 29420396 TI - Use of Antihypertensive Medications During Delivery Hospitalizations Complicated by Preeclampsia. AB - OBJECTIVE: To evaluate temporal trends in use of antihypertensive medications during delivery hospitalizations complicated by preeclampsia and risk of maternal stroke over the same time period. METHODS: The Perspective database was used to perform a retrospective cohort study evaluating antihypertensive drugs dispensed during delivery hospitalizations complicated by preeclampsia from 2006 to the first quarter of 2015. Medications evaluated included nifedipine, hydralazine, and oral and intravenous labetalol. Adjusted models for receipt of antihypertensive agents accounting for demographic and hospital factors were created. Hospital-level rates of antihypertensive administration for women with severe preeclampsia were analyzed. Risk of stroke during delivery hospitalization was evaluated. RESULTS: A total of 239,454 patients with preeclampsia were included in the analysis including 126,595 women with mild, 31,628 with superimposed, and 81,231 with severe preeclampsia. Overall, 105,409 women received a hypertensive agent. From 2006 to 2014, for all patients with preeclampsia, receipt of oral labetalol increased from 20.3% to 31.4%, intravenous labetalol from 13.3% to 21.4%, hydralazine from 12.8% to 16.9%, nifedipine from 15.0% to 18.2%, and more than one medication from 16.5% to 25.8%. The proportion of patients with preeclampsia receiving any antihypertensive medication rose from 37.8% in 2006 to 49.4% in 2015. In adjusted models, temporal trends retained significance. Rates of antihypertensive administration for severe preeclampsia varied significantly by hospital. For severe preeclampsia, the risk for stroke decreased from 13.5 per 10,000 deliveries in 2006-2008 (n=27) to 9.7 in 2009-2011 (n=25) to 6.0 in 2012-2014 (n=20) (P=.02). CONCLUSION: Use of multiple antihypertensive agents to treat preeclamptic women increased over the study period for women with mild, superimposed, and severe preeclampsia. There was substantial hospital variation in use of antihypertensive agents. This trend was associated with decreased risk of maternal stroke. PMID- 29420397 TI - Exercise-Induced Abdominal Wall Muscle Injury Resulting in Rhabdomyolysis and Mimicking an Acute Abdomen. AB - BACKGROUND: Rhabdomyolysis is characterized by muscle necrosis and release of intracellular constituents, causing muscle pain, weakness, and myoglobinuria. This can be attributed to muscle injury after strenuous exercise. If the abdominal wall is involved, clinical presentation may resemble an acute abdomen. CASE: A 27-year-old woman, gravida 4 para 2, presented with swelling and pain of the mons pubis and abdominal pain after intense powerlifting 2 days prior. A computed tomography scan was performed, revealing abdominal wall inflammation. Although myoglobinuria was absent, there was high suspicion for rhabdomyolysis, which was confirmed by an elevated creatine kinase level. The patient improved after receiving intravenous fluids and abstaining from physical activity. CONCLUSION: Abdominal wall muscle injury resulting in rhabdomyolysis can imitate an acute abdomen in a healthy woman presenting with abdominal pain and swelling. PMID- 29420398 TI - Sliding Sign for Intra-abdominal Adhesion Prediction Before Repeat Cesarean Delivery. AB - BACKGROUND: The sliding sign (the relative motion between the abdominal and uterine wall as assessed by ultrasonography) may help identify severe intra abdominal adhesions before repeat cesarean delivery. METHODS: We conducted a prospective observational study of scheduled repeat cesarean deliveries. Using transabdominal ultrasonography, while the parturient breathed deeply, the ultrasonographer recorded a video clip in a sagittal plane lateral to the umbilicus. These clips were assessed for the presence (sliding-positive) or absence (sliding-negative) of relative movement between the maternal abdominal and uterine wall. Surgeons blinded to ultrasonography results graded the severity of intraperitoneal adhesions intraoperatively. Study outcomes were the accuracy of the preoperative sliding sign for prediction of severe adhesions and its association with surgical times and bleeding. EXPERIENCE: We recruited 370 women. A negative sliding sign was associated with severe adhesions (sensitivity 56%, 95% CI 35-76; specificity 95%, 95% CI 93-97). A similar accuracy (sensitivity 64%, 95% CI 43-82; specificity 94%, 95% CI 92-97) was achieved by combining the sliding sign with a history of adhesions in the previous surgery. In multivariable models, a negative sliding sign was significantly correlated with a longer interval from skin incision to delivery and increased risk for bleeding. CONCLUSION: A negative sliding sign predicts severe intra-abdominal adhesions encountered during repeat cesarean delivery, longer time to delivery, and a higher chance of bleeding. PMID- 29420399 TI - Appendiceal Endometriosis and Ectopic Pregnancy Occurring Simultaneously. AB - BACKGROUND: In the setting of a known ectopic pregnancy, severe abdominal pain with clinical concern for rupture is an indication for emergency surgery. In rare cases, appendiceal pathology may occur simultaneously. CASE: A woman with a known ectopic pregnancy presented to the emergency department with a clinical picture consistent with its rupture. At the time of surgery, an appendectomy also was performed owing to concern for concurrent appendicitis; histopathologic examination revealed appendiceal endometriosis. CONCLUSION: During surgical management of ectopic pregnancy, it is important to undertake a thorough examination of the pelvis, because patients may present with multiple concurrent pathologies. In the setting of an emergency operation, when the diagnosis seems clear, this survey should not be forgotten. PMID- 29420400 TI - Customized Pessary Fabrication Using Three-Dimensional Printing Technology. AB - BACKGROUND: Pessaries are a treatment option for pelvic organ prolapse, stress urinary incontinence (SUI), and cervical incompetence. An effective pessary is comfortable, corrects the presenting problem, does not cause adverse effects, and is easy to remove. Discomfort and poor fit limit the usefulness of pessaries for many women. Each patient presents with unique anatomy and thus the effectiveness of commercially available pessaries may be limited by lack of customization. METHOD: A patient presenting with SUI and failed commercial pessary fittings desired nonsurgical treatment. Using a mold fabricated with a three-dimensional printer and polylactic acid filament, a medical-grade silicone pessary was custom made for the patient. EXPERIENCE: The silicone pessary was placed vaginally in the patient for a period of 48 hours. The patient did not report any discomfort or bladder leakage. In addition, the pessary did not dislodge with coughing, sneezing, or straining. After removal, a speculum examination showed normal epithelium. CONCLUSION: We report the successful insertion of a customized three dimensional-printed pessary in a patient with SUI. Three-dimensional-printed pessaries are feasible and their utility may extend to the patient with anatomy incompatible with commercially available pessaries. PMID- 29420401 TI - Cancer Risk After Midurethral Sling Surgery Using Polypropylene Mesh. AB - OBJECTIVE: To assess whether there is any association between the implantation of synthetic polypropylene mesh slings for the treatment of stress urinary incontinence (SUI) and risk of cancer. METHODS: We performed a nationwide cohort study based on the general female population in Sweden. All women entered the observational period as unexposed on January 1, 1997, and contributed person-time as unexposed unless they underwent a midurethral sling procedure for SUI, after which they contributed person-time as exposed until first occurrence of any cancer, death, emigration, or end of the observational period (December 31, 2009). Occurrence of primary cancer was ascertained from the Cancer Register. Hazard ratios (HRs) with 95% CIs were calculated by Cox proportional hazards regression. RESULTS: The final study population included 5,385,186 women, including 20,905 exposed, encompassing a total of 44,012,936 person-years at risk. Other than an inverse association with rectal cancer (HR 0.5, 95% CI 0.3 0.8), there were no significant differences in risk between exposed and unexposed women for pelvic organ cancers including ovarian (HR 0.8, 95% CI 0.5-1.2), endometrial (HR 1.1, 95% CI 0.8-1.4), cervical (HR 0.4, 95% CI 0.2-1.0), bladder, and urethra (HR 0.7, 95% CI 0.4-1.2). No significant association was observed between exposed women and primary cancer in any organ system when compared with unexposed women. The relative risk for cancer after exposure showed little variation over time except for an inverse overall correlation within the first 4 years of surgery (HR 0.7, 95% CI 0.7-0.8). The incidence rates per 100,000 person years (95% CIs) for exposed vs unexposed women were 20.5 (14.3-29.5) vs 21.0 (20.6-21.5) for rectal cancer, 25.5 (18.4-35.3) vs 19.8 (19.4-20.2) for ovarian cancer, 65.0 (53.0-79.8) vs 33.1 (32.6-33.7) for endometrial cancer, 5.7 (2.8 11.3) vs 11.9 (11.6-12.2) for cervical cancer, and 19.1 (13.1-27.8) vs 13.3 (13.0 13.7) for bladder and urethra cancer. CONCLUSION: Our results suggest that midurethral polypropylene sling surgery for SUI is not associated with an increased cancer risk later in life. PMID- 29420402 TI - Twenty-Week Abortion Bans on Pregnancies With a Congenital Diaphragmatic Hernia: A Cost-Effectiveness Analysis. AB - OBJECTIVE: To estimate the effect of 20-week abortion bans on maternal and consequent neonatal health outcomes and costs in the setting of fetal congenital diaphragmatic hernia. METHODS: A decision-analytic model was built using TreeAge software to evaluate the effect of a 20-week ban on abortion in a theoretical cohort of 921 women diagnosed with fetal congenital diaphragmatic hernia. Probabilities, utilities, and costs were derived from the literature. The cohort size was based on the annual rate of prenatal diagnoses of congenital diaphragmatic hernia and live births among the 20 states with bans. The threshold for cost-effectiveness was set at $100,000 per quality-adjusted life-year. Analysis was completed from the maternal perspective. Clinical outcomes included mode of delivery, maternal death, intrauterine fetal death, neonatal death, neurodevelopmental disability, and use of extracorporeal membrane oxygenation. One-way sensitivity analysis was used on all variables and Monte Carlo simulation was performed. RESULTS: A policy restricting termination was associated with higher costs, at an additional $158,419,623, with decreased quality of life and 674 fewer quality-adjusted life-years. With 20-week bans in place, 60 women would travel out of state to obtain abortions. There would be 158 more live births affected by congenital diaphragmatic hernia. Of these births, 45 neonates would die before 28 days after birth and an additional 37 would have long-term neurodevelopmental disability. CONCLUSION: In this model, bans that limit abortions beyond 20 weeks of gestation were associated with worse health outcomes and increased costs for women with pregnancies complicated by congenital diaphragmatic hernia. The restriction of health care access should be considered in terms of the long-term outcomes and economic effect on individuals and society. PMID- 29420403 TI - Use of Long-Acting Reversible Contraception by Obstetrics and Gynecology Residents: An Examination of Access for All Women. AB - Although long-acting reversible contraception (LARC) use is increasing in the general female population, only 12% of all women who use contraception and 4.8% of nulliparous women in the United States use either the intrauterine device (IUD) or contraceptive implant. In several studies, however, female physicians prefer LARC for contraception. In 2016, an anonymous electronic survey was administered to all U.S. obstetrics and gynecology residents before the start of the annual in-training examination administered by the Council on Resident Education in Obstetrics and Gynecology. The survey included questions about LARC, including personal use. Fifty percent of female residents or the female partners of male residents used IUDs for contraception, 31.3% used combined oral contraceptives, and 3% used a contraceptive implant. Among nulliparous residents, 37.7% used IUDs. This rate of IUD use was five times the rate reported by the general female population and eight times the nulliparous rate in the United States. Obstetrics and gynecology residents understand the benefits of LARC, but have minimal barriers to access. When barriers and cost are removed and the full range of contraceptive options is offered, the majority of contracepting women and adolescents choose LARC. With the high rates of unintended pregnancy and maternal morbidity and mortality in the United States-especially among poor and minority women-all women, regardless of income, race-ethnicity, and career, should have awareness of and access to these effective contraceptive methods. PMID- 29420404 TI - Association Between Labor and Delivery Unit Census and Delays in Patient Management: Findings From a Computer Simulation Module. AB - OBJECTIVE: To demonstrate the association between increases in labor and delivery unit census and delays in patient care decisions using a computer simulation module. METHODS: This was an observational cohort study of labor and delivery unit nurse managers. We developed a computer module that simulates the physical layout and clinical activity of the labor and delivery unit at our tertiary care academic medical center, in which players act as clinical managers in dynamically allocating nursing staff and beds as patients arrive, progress in labor, and undergo procedures. We exposed nurse managers to variation in patient census and measured the delays in resource decisions over the course of a simulated shift. We used mixed logistic and linear regression models to analyze the associations between patient census and delays in patient care. RESULTS: Thirteen nurse managers participated in the study and completed 17 12-hour shifts, or 204 simulated hours of decision-making. All participants reported the simulation module reflected their real-life experiences at least somewhat well. We observed 1.47-increased odds (95% CI 1.18-1.82) of recommending a patient ambulate in early labor for every additional patient on the labor and delivery unit. For every additional patient on the labor and delivery unit, there was a 15.9-minute delay between delivery and transfer to the postpartum unit (95% CI 2.4-29.3). For every additional patient in the waiting room, we observed a 33.3-minute delay in the time patients spent in the waiting room (95% CI 23.2-43.5) and a 14.3-minute delay in moving a patient in need of a cesarean delivery to the operating room (95% CI 2.8-25.8). CONCLUSION: Increasing labor and delivery unit census is associated with patient care delays in a computer simulation. Computer simulation is a feasible and valid method of demonstrating the sensitivity of care decisions to shifts in patient volume. PMID- 29420406 TI - Risk of Adverse Pregnancy Outcomes at Advanced Maternal Age. AB - OBJECTIVE: To study the possible associations between advanced maternal age and risk of selected adverse pregnancy outcomes. METHODS: The study used a nationwide cohort of 369,516 singleton pregnancies in Denmark followed from 11-14 weeks of gestation to delivery or termination of pregnancy. Pregnant women aged 35 years or older were divided into two advanced maternal age groups, 35-39 years and 40 years or older, and compared with pregnant women aged 20-34 years. Adverse pregnancy outcomes were chromosomal abnormalities, congenital malformations, miscarriage, stillbirth, and birth before 34 weeks of gestation. Multivariable logistic regression analyses were performed to investigate associations between advanced maternal age and adverse pregnancy outcomes. Furthermore, a risk prediction model for a composite adverse pregnancy outcome was made with prespecified predicting factors. RESULTS: Among the pregnant women aged 40 years or older, 10.82% experienced one or more of the selected adverse pregnancy outcomes compared with 5.46% of pregnant women aged 20-34 years (odds ratio [OR] 2.02, 99.8% CI 1.78-2.29). When pregnant women 40 years or older were compared with women aged 20-34 years, they had a higher risk of chromosomal abnormalities (3.83% vs 0.56%, OR 7.44 [CI 5.93-9.34]), miscarriage (1.68% vs 0.42%, OR 3.10 [CI 2.19-4.38]), and birth before 34 weeks of gestation (2.01% vs 1.21%, OR 1.66 [CI 1.23-2.24]), but no increased risk of congenital malformations and stillbirth. The risk prediction chart showed that advanced maternal age, use of assisted reproductive technology, nulliparous pregnancy, smoking during pregnancy, and obesity increased the absolute predictive risk of an adverse pregnancy outcome. CONCLUSION: Women older than 40 years have a higher risk of chromosomal abnormalities, miscarriage, and birth before 34 weeks of gestation than younger women and should be monitored accordingly. No increased risk was observed for stillbirth and other congenital malformations. Several factors increase the risk of adverse pregnancy outcomes, but advanced maternal age drives a high proportion of the total risk score. PMID- 29420405 TI - Rate of Pelvic Organ Prolapse Surgery Among Privately Insured Women in the United States, 2010-2013. AB - OBJECTIVE: To analyze utilization of, and payments for, pelvic organ prolapse procedures after the 2011 U.S. Food and Drug Administration (FDA) communication regarding transvaginal mesh. METHODS: This is a retrospective cohort study examining private claims from three insurance providers for inpatient and outpatient prolapse procedures from 2010 to 2013 in the Health Care Cost Institute. Primary outcomes were the change in utilization of prolapse procedures, with and without mesh, before and after the July 2011 FDA communication. Secondary outcomes were the changes in payments and reimbursements for these procedures. Utilization rates and payments were compared using generalized linear models and interrupted time-series analysis. RESULTS: Utilization of prolapse procedures decreased from 12.3 to 9.7 per 10,000 woman years (P=.027) with a decrease of 30.7% (3.9 in 2010 to 2.7 in 2013, P=.05) in number of mesh procedures and 16.6% (8.4 in 2010 to 7.0 in 2013, P=.011) for nonmesh procedures. Quarterly utilization of mesh procedures was increasing before the FDA communication and then significantly declined after its release (slope=0.024 vs -0.025, P=.002). Nonmesh procedures, however, were already slightly decreasing before July 2011 and continued to decline at a more rapid pace after that time, although not significantly (slope=-0.004 vs -0.022, P=.47). Inpatient utilization decreased 52.2% (P=.002), whereas outpatient utilization increased 18.5% (P=.132). Payments for individual inpatient procedures, with and without mesh, increased by 12.0% ($8,315 in 2010 to $9,315 in 2013, P=.001) and 15.6% ($7,826 in 2010 to $9,048 in 2013, P=.005), respectively, whereas those for outpatient procedures increased by 41% ($4,961 in 2010 to $6,981 in 2013, P=.006) and 30% ($3,955 in 2010 to $5,149 in 2013, P=.004), respectively. CONCLUSION: Use of prolapse surgery declined during the study period. After the 2011 FDA communication regarding transvaginal mesh, there was a significant decrease in the utilization of procedures with mesh but not for those without mesh. A shift toward outpatient surgeries was observed, and payments for both individual inpatient and outpatient cases increased. PMID- 29420407 TI - Maternal Malignancy Evaluation After Discordant Cell-Free DNA Results. AB - Cell-free DNA screening for fetal aneuploidy is a commonly used testing strategy in pregnancies at high risk for fetal aneuploidy. The use of cell-free DNA screening is expanding to the low-risk population, because the detection rate for trisomy 21 surpasses that of traditional screening modalities. Although the sensitivity and specificity of cell-free DNA are superior to traditional screening, false-positive results do occur and may indicate an adverse maternal health condition, including maternal mosaicism or, rarely, malignancy. The risk of maternal cancer is significantly elevated when more than one aneuploidy is detected that is discordant from fetal karyotype. Given this risk as well as the rising incidence of cancer in pregnancy, patient counseling and malignancy evaluation should be considered in women when more than one aneuploidy is detected. We reviewed the published literature and developed an algorithm to evaluate women when these results are identified. PMID- 29420408 TI - Catholic Health Care and Women's Health. AB - Catholic health care facilities account for approximately one sixth of the U.S. health care market, have recently demonstrated successful growth, and serve as the only local hospital in certain remote locations. The Ethical and Religious Directives for Catholic Health Care Services is a set of guidelines created and revised by church leaders that applies the church's teaching, particularly as it relates to concern for human dignity, to modern-day medical practice; all Catholic health care facilities and providers within these facilities are required to abide. Strict interpretation of these directives limits family planning and most infertility services. Many women, however, do not anticipate differences to reproductive health care based on Catholic affiliation, and recent patient reports and legal enactments have highlighted the tension that arises when women are unable to receive medically indicated family planning services. In this article, I demonstrate that reproductive health care services are not consistently prohibited and that clinics often do not inform patients when scheduling appointments when restrictions exist. I highlight ethical concerns about patient autonomy as it relates to modern-day practice and recommend solutions including greater transparency and efforts to improve uniformity of practice at Catholic health care facilities. PMID- 29420409 TI - Surgical Outcomes After Apical Repair for Vault Compared With Uterovaginal Prolapse. AB - OBJECTIVE: To retrospectively compare surgical success and complications between vaginal vault prolapse compared with uterovaginal prolapse in women who underwent apical prolapse repair for stage II-IV prolapse. METHODS: Women in one of three Pelvic Floor Disorders Network prolapse surgical trials were included. Absence of bothersome bulge symptoms, no prolapse beyond the hymen, and no subsequent prolapse treatment defined success and was our primary outcome. Secondary outcomes included comparison of quality-of-life measures, anatomic changes, and adverse events. Pelvic organ prolapse quantification (POP-Q) and quality-of-life measures were administered at baseline and 1-2 years postoperatively. Comparisons were controlled for study site, age, body mass index, baseline POP-Q, apical and anterior or posterior repair performed, and prior prolapse repair. Outcomes measured at multiple time points were analyzed using longitudinal models to assess whether differences existed across study follow-up. RESULTS: Four hundred twenty-one women underwent vault prolapse, and 601 underwent uterovaginal prolapse apical repair. The vault prolapse group was older, more likely to be white, and to have prior urinary incontinence or prolapse repair, stage IV prolapse, and more prolapse bother on a validated scale (all P<=.034). The vault prolapse group was more likely to undergo sacrocolpopexy (228/421 [54%] vs 93/601 [15%]); the uterovaginal prolapse group was more likely to undergo vaginal repair (508/601 [85%] vs 193/421 [46%] P<.001). There were no differences in success (odds ratio [OR] 0.76 for vault prolapse vs uterovaginal prolapse, 95% CI 0.51 1.15, P=.20), changes in Pelvic Organ Prolapse Distress Inventory scores (-79.4 vs -79.8, P=.89), postoperative POP-Q point C measurements (-7.0 vs -7.1 cm, P=.41), or serious adverse events (86/421 [20%] vs 90/601 [15%], P=.86) between groups. Among women who underwent a vaginal approach for repair of vault prolapse (n=193) or uterovaginal prolapse (n=508), there were no differences in success rates (OR 0.67, 95% CI 0.43-1.04, P=.09) at 1-2 years postoperatively. CONCLUSION: Surgical success of stage II-IV vault prolapse and uterovaginal prolapse apical repair was similar whether performed vaginally or abdominally at 1-2 years postoperatively. PMID- 29420410 TI - Fetal Survival in Second-Trimester Termination of Pregnancy Without Feticide. AB - OBJECTIVE: To evaluate the rate of live birth and the duration of survival after termination of pregnancy without feticide. METHODS: We conducted a retrospective analysis of 241 terminations of pregnancy without feticide for fetal anomalies or genetic abnormalities between 20 0/7 and 24 0/7 weeks of gestation at a single tertiary care referral center in Europe between February 2003 and May 2017. A multivariate binary regression model was used to evaluate factors associated with live birth. RESULTS: Pregnancies were terminated at a mean gestational age of 22.1+/-1.1 completed weeks of gestation. Median birth weight was 440 g (range 141 1,890 g). Live birth occurred in 122 cases (50.6%, 95% CI 44.4-56.8); median survival time was 32 minutes (range 1-267 minutes). Factors associated with live birth were gestational age at labor induction (odds ratio 1.41, 95% CI 1.01-2.01; P=.049) and fetal anomalies (P=.046). CONCLUSION: After termination of pregnancy without feticide between 20 0/7 and 24 0/7 weeks of gestation, the live birth rate was 50.6% (95% CI 44.4-56.8). A lower gestational age at labor induction and the presence of skeletal, cerebral, renal, or multiple fetal anomalies increased the chance of stillbirth. PMID- 29420411 TI - Maternal and Perinatal Outcomes After Laparoscopic Sleeve Gastrectomy. AB - OBJECTIVE: To examine associations of laparoscopic sleeve gastrectomy with maternal and perinatal outcomes. METHODS: We conducted a retrospective case control study of deliveries that occurred from 2006 to 2016 at two university hospitals. The study group comprised all women who had undergone laparoscopic sleeve gastrectomy and who delivered during the study period. If a woman had more than one pregnancy during the study period, data from only her first pregnancy were used. A control group was established by matching preoperative body mass index (BMI), age, parity, delivery history, and delivery year. RESULTS: Data from 238 women were analyzed, 119 post-laparoscopic sleeve gastrectomy and 119 matched control parturients. Among the post-laparoscopic sleeve gastrectomy patients, the median preoperative BMI was 41.7 (interquartile range 39.9-44.4) and the median postoperative BMI was 28.9 (26.6-32.0). Compared with the control group, the study group had lower rates of gestational diabetes mellitus (3.4% vs 17.6%, P=.001), large-for-gestational-age neonates (1.7% vs 19.3%, P=.001), and birth weight greater than 4,000 g (0.8% vs 7.6%, P=.02) but higher proportions of small for-gestational-age (SGA) neonates (14.3% vs 4.2%, P=.01) and low-birth-weight neonates (12.6% vs 4.2%, P=.03). Rates of gestational hypertensive disorders and prematurity were comparable between the groups. For the study group, hemoglobin levels were lower in early pregnancy (median 12.6 vs 13.2 g/dL, P=.001) and after delivery (10.5 vs 10.8 g/dL, P=.002), and a higher proportion of patients were treated with intravenous iron supplementation during pregnancy (14.3% vs 0.8%, P=.001). Cesarean delivery rates during labor were lower in the study group (10.1% vs 20.2%, P=.04). CONCLUSION: Laparoscopic sleeve gastrectomy was associated with reduced rates of gestational diabetes mellitus, excessive fetal growth, and cesarean delivery and an increased rate of SGA and low-birth-weight neonates. PMID- 29420412 TI - Suture Compared With Staple Closure of Skin Incision for High-Order Cesarean Deliveries. AB - OBJECTIVE: To compare wound complication rates in tertiary or higher-order cesarean delivery based on wound closure technique. METHODS: We performed a retrospective cohort study of all tertiary or higher-order cesarean deliveries performed by one group practice in a large academic medical center from 2005 to 2017. We excluded patients with a vertical skin incision. Although the study was not randomized, wound closure type was relatively uniform in this practice and based on time period: before 2011, the preferred closure was staple closure; after 2011, subcuticular suture closure was preferred. All patients received preoperative antibiotics and closure of subcutaneous tissue 2 cm deep or greater. The primary outcome was a wound complication, defined as a wound infection requiring antibiotics or a wound separation requiring wound packing or reclosure any time up to 6 weeks after delivery. Regression analysis was used to control for any significant differences at baseline between the groups. RESULTS: There were 551 patients with tertiary or higher-order cesarean delivery, 192 (34.8%) of whom had staple closure and 359 (65.2%) of whom had suture closure. Suture closure was associated with a significantly lower rate of wound complication (4.7% [17/359, 95% CI 3.0%-7.5%] vs 11.5% [22/192, 95% CI 7.7%-16.7%], P=.003). On regression analysis controlling for the number of prior cesarean deliveries and the participation of a resident in the closure, suture closure remained independently associated with a lower risk of a wound complication (adjusted odds ratio 0.44, 95% CI 0.23-0.86). CONCLUSION: For women undergoing their third or higher-order cesarean delivery, suture closure is associated with a lower rate of wound complications. PMID- 29420413 TI - Preventing Mitochondrial Disease: A Path Forward. AB - In a possible first, the heritable transmission of a fatal mitochondrial DNA disease (Leigh syndrome) may have been prevented by replacing the mutation bearing mitochondria of oocytes with donated mutation-free counterparts. The procedure, carried out by a U.S.-led team, took place in Mexico in circumvention of a statutory U.S. moratorium on mitochondrial replacement. This development calls into question the regulatory utility of a national moratorium in a globalized world wherein cross-border care is increasingly prevalent. This development also calls to account the moral defensibility of a moratorium that acquiesces in the birth of gravely ill children whose afflictions could have been prevented. In this Current Commentary, we outline a potential path forward by analyzing the dual imprint of the moratorium, examining its legislative shortcomings, exploring its motivational roots, considering its national effect, and proposing its unlinking from the related yet distinct ban on editing the genome of the human embryo. PMID- 29420414 TI - The Comprehensive Addiction and Recovery Act: Opioid Use Disorder and Midwifery Practice. AB - The federal response to the opioid use disorder crisis has included a mobilization of resources to encourage office-based pharmacotherapy with buprenorphine, an effort culminating in the 2016 Comprehensive Addiction and Recovery Act, signed into law as Public Law 114-198. The Comprehensive Addiction and Recovery Act was designed to increase access to treatment with special emphasis on services for pregnant women and follow-up for infants affected by prenatal substance exposure. In this effort, the Comprehensive Addiction and Recovery Act laudably expands eligibility for obtaining a waiver to prescribe buprenorphine to nurse practitioners and physician assistants. However, certified nurse-midwives and certified midwives, who care for a significant proportion of pregnant and postpartum women and attend a significant proportion of births in the United States, were not included in the Comprehensive Addiction and Recovery Act legislation. In this commentary, we argue that an "all-hands" approach to providing office-based medication-assisted treatment for opioid use disorder is essential to improving access to treatment. Introduced in the House of Representatives in September 2017, the Addiction Treatment Access Improvement Act (H.R. 3692) would allow midwives to apply for the federal waiver to prescribe buprenorphine and is supported by the American College of Obstetricians and Gynecologists and the American College of Nurse-Midwives. We support this change and encourage the U.S. Congress to act quickly to allow midwives to prescribe medication-assisted treatment for pregnant women with opioid use disorder. PMID- 29420415 TI - Delayed Presentation of Cecal Perforation With Tension-Free Vaginal Tape. AB - BACKGROUND: Tension-free vaginal tape (TVT) is a popular operative treatment for stress urinary incontinence (SUI). It has a low risk of adverse events, and injuries, particularly to the bowel, are rare. Case reports that have previously discussed these injuries and subsequent removal of TVT have not provided additional insight into management of SUI after these injuries occur. CASE: A postmenopausal woman with persistent SUI presented more than 1 year after TVT placement with bowel perforation incidentally discovered on routine screening colonoscopy. She underwent removal of the TVT and subsequent placement of a fascial sling with postoperative resolution of SUI. CONCLUSION: This case provides additional evidence for bowel injury as a postoperative TVT complication and describes an approach to complicated TVT and persistent SUI. PMID- 29420416 TI - What Is New in Cannabis Use in Pregnancy?: Best Articles From the Past Year. AB - This month we focus on current research in cannabis use in pregnancy. Dr. Metz discusses four recent publications, which are concluded with a "bottom line" that is a take-home message. A complete reference for each can be found in on this page along with direct links to abstracts. PMID- 29420417 TI - Connect the Dots-March 2018. PMID- 29420418 TI - Pain Management in Patients Undergoing Radical Pelvic Exenteration Surgery: Opioid Stewardship and the Development of Evidence-Based Alternatives. PMID- 29420419 TI - Facilitating Transitions From Pediatric to Adult Surgical Care. PMID- 29420420 TI - Extended-Duration Venous Thromboembolism Prophylaxis Following Colorectal Surgery: Ready for Prime Time? PMID- 29420421 TI - Chemotherapy: A Senior Surgeon's Personal Challenge. PMID- 29420422 TI - Health Care in Tanzania. PMID- 29420423 TI - The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Hemorrhoids. PMID- 29420424 TI - Anal Fissure. PMID- 29420425 TI - Expert Commentary on Anal Fissure. PMID- 29420426 TI - A Population-Based Study of Complications After Colorectal Surgery in Patients Who Have Received Bevacizumab. AB - BACKGROUND: Patients receiving Bevacizumab, a vascular endothelial growth factor inhibitor used to treat metastatic colorectal cancer, may be at greater risk of complications after colorectal surgery because of impaired healing. OBJECTIVE: The purpose of this study was to describe population-based rates of complications of colorectal surgery after Bevacizumab treatment and evaluate the relationship between time since last treatment and risk of complications. DESIGN: This was a population-based retrospective cohort study using administrative and cancer registry data. SETTINGS: The study was conducted in Ontario, Canada. PATIENTS: Patients with metastatic colorectal cancer receiving Bevacizumab between January 2008 and December 2011 were followed for a year after treatment or until death. MAIN OUTCOME MEASURES: Administrative data were used to identify patients who underwent colorectal surgery after initiation of Bevacizumab and to determine whether they experienced a complicated postoperative course. The relationship between time since last Bevacizumab treatment (<=28 d, 29 d to 3 mo, and >3 mo) and risk of postoperative complications was evaluated using logistic regression. RESULTS: Of the 2759 patients who received Bevacizumab for the treatment of metastatic colorectal cancer, 265 underwent a colorectal procedure after exposure. The majority had a bowel resection or repair with no stoma (47.5%) and had emergency surgery (61.1%). Overall, 96 (36.2%) had a complicated postoperative course, including 20.4% readmission, 12.5% wound complications, and 7.9% mortality rate within 30 days of surgery. Adjusted multivariate analysis showed no difference in the likelihood of a complicated postoperative course among patients undergoing surgery within 28 days of receiving their last Bevacizumab dose compared with 29 days to 3 months (OR = 1.23 (95% CI, 0.53 2.84), or 3 to 12 months (OR = 0.98 (95% CI, 0.46-2.09) after receiving Bevacizumab. LIMITATIONS: Reliance on administrative data to measure complications limited the scope of this study. CONCLUSIONS: Patients with metastatic colorectal cancer requiring colorectal surgery after exposure to Bevacizumab experience substantial morbidity and mortality. The risk of complications is not detectably associated with time since exposure. See Video Abstract at http://links.lww.com/DCR/A474. PMID- 29420427 TI - The Price We Pay for Radical Curative Pelvic Exenterations: Prevalence and Management of Pain. AB - BACKGROUND: Pelvic exenterations are extensive surgical procedures for locally advanced or recurrent malignancies of the pelvis. However, this is often at the cost of significant morbidity due to perioperative pain, which has been poorly studied. OBJECTIVE: This study aims to review perioperative pain management in patients undergoing pelvic exenteration. DESIGN: This is a retrospective review of patients undergoing pelvic exenteration between January 2013 and December 2014. Data were gathered from medical records and a prospectively maintained database. SETTING: This study was conducted at a single quaternary referral center for pelvic exenteration. PATIENTS: Consecutive patients underwent pelvic exenteration at a single center. INTERVENTIONS: Pelvic exenteration was performed in consecutive patients. MAIN OUTCOMES MEASURES: Primary outcomes were the prevalence of preoperative pain, preoperative opiate use (type, dosage), and postoperative pain (verbal numerical rating scale). Secondary outcomes included the number of pain consultations and correlations between preoperative opiate use, length of stay, and extent of resection (en bloc sacrectomy and nerve excision). RESULTS: Ninety-nine patients underwent pelvic exenteration. Sixty-one patients (61.6%) underwent major nerve resection and/or sacrectomy. Thirty patients (30%) required opiates preoperatively, with a mean daily morphine equivalent of 72.9 mg (SD 65.0 mg). Patients on preoperative opiates were more likely to have worse pain postoperatively and to require higher opiate doses and more pain consultations (9.3 vs 4.8; p < 0.001). Major nerve excision and sacrectomy were not associated with worse postoperative pain. By discharge, 60% still required opiate analgesia. LIMITATIONS: Retrospective study design, the subjective nature of pain assessment because of a lack of valid methods to objectively quantify pain, and the lack of long-term follow-up were limitations of this study. CONCLUSIONS: Perioperative pain is a significant issue among patients undergoing pelvic exenteration. One in three patients require high-dose opiates preoperatively that is associated with worse pain outcomes. Potential areas to improve pain outcomes in these complex patients could include increased use of regional anesthesia, antineuropathic agents, and opiate-sparing techniques. See Video Abstract at http://links.lww.com/DCR/A572. PMID- 29420428 TI - Prior Surgical Score: An Analysis of the Prognostic Significance of an Initial Nondefinitive Surgical Intervention in Patients With Peritoneal Carcinomatosis of a Colorectal Origin Undergoing Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy. AB - BACKGROUND: The prior surgical score estimates the extent of previous surgical intervention by quantitating surgical dissection within 9 abdominopelvic regions. OBJECTIVE: Our aim was to analyze the prognostic significance of the prior surgical score in our cohort of patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis of a colorectal origin. DESIGN: This was a retrospective analysis of a prospectively maintained database for all patients treated for peritoneal carcinomatosis of a colorectal origin. SETTINGS: The prospectively maintained surgical oncology tumor database was analyzed for the study period 1989-2014. PATIENTS: A total of 407 patients diagnosed with peritoneal carcinomatosis of a colorectal origin and treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy were included in this analysis. MAIN OUTCOME MEASURES: The prognostic significance and clinicopathologic factors associated with an initial nondefinitive surgical intervention in patients with peritoneal carcinomatosis of a colorectal origin undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy was evaluated. RESULTS: There were 210 men (51.6%) and 197 women (48.4%) in the study. Mean age at presentation was 53.7 years (range, 19.0-87.0 y). Data on prior surgical score for 69 patients were missing, leaving us with a study cohort of 338 patients. Grouped by prior surgical score, 46 (13.6%) had a prior surgical score of 0 versus 25 (7.4%), 122 (36.1%), and 145 (42.9%) who had a prior surgical score of 1, 2, or 3. Overall survival was 53.0%. Three- and 5-year survival rates were 75% and 75% for group prior surgical score 0 versus 26% and 13%, 39% and 37%, and 21% and 16% for group prior surgical scores 1, 2, and 3. Median survival time for the various prior surgical score groups were 180.0, 30.4, 30.5, and 21.3 months for prior surgical scores 0, 1, 2, and 3 (p = 0.000). A total of 87.2% of the prior surgical score 0 group had a completeness of cytoreduction score of 0/1 (no residual disease/tumor <0.25 cm) versus 68.0%, 68.1%, and 48.6% for prior surgical scores of 1, 2, or 3 (p = 0.000). Significant independent predictors of a shorter survival in multivariate analysis included a high cytoreduction score status (p < 0.000) and a high prior surgical score (p = 0.05). LIMITATIONS: This study was limited by its retrospective, population-based design. CONCLUSIONS: The extent of a previous nondefinitive surgical intervention contributes to the poor prognosis associated with peritoneal carcinomatosis of a colorectal origin. Independent predictors for an improved overall survival include completeness of cytoreduction and low prior surgical score. See Video Abstract at http://links.lww.com/DCR/A573. PMID- 29420429 TI - Elevated Venous Thromboembolism Risk Following Colectomy for IBD Is Equal to Those for Colorectal Cancer for Ninety Days After Surgery. AB - BACKGROUND: The risk of postoperative venous thromboembolism is high in patients with colon cancer and IBD. Although The American Society of Colon and Rectal Surgeons suggests posthospital prophylaxis after surgery in patients with colon cancer, there are no such recommendations for patients with IBD. OBJECTIVE: This study aims to analyze the incidence and risk factors for postoperative venous thromboembolism. DESIGN: This was a retrospective review using the Explorys platform. SETTINGS: Aggregated electronic medical records from 26 major health care systems across the United States from 1999 to 2017 were used for this study. PATIENTS: Patients who underwent colon surgery were included. MAIN OUTCOME MEASURES: Patients were followed up to 90 days postoperatively for deep vein thrombosis and pulmonary embolism. RESULTS: A total of 75,620 patients underwent colon resections, including 32,020 patients with colon cancer, 9850 patients with IBD, and 33,750 patients with diverticulitis. The 30-day incidence of venous thromboembolism was higher in patients with cancer and IBD than in patients with diverticulitis (2.9%, 3.1%, and 2.4%, p < 0.001 for both comparisons). The 30-day incidence of venous thromboembolism in patients with ulcerative colitis is greater than in patients with Crohn's disease (4.1% vs 2.1%, p < 0.001). The cumulative incidence of venous thromboembolism increased from 1.2% at 7 days after surgery to 4.3% at 90 days after surgery in patients with cancer, and from 1.3% to 4.3% in patients with IBD. In multivariable analysis, increase in the risk of venous thromboembolism was associated with cancer diagnosis, IBD diagnosis, age >=60, smoking, and obesity. LIMITATIONS: This study was limited by its retrospective nature and by the use of the aggregated electronic database, which is based on charted codes and contains only limited collateral clinical data. CONCLUSIONS: Because of the elevated and sustained risk of postoperative thromboembolism, patients with IBD, especially ulcerative colitis, might benefit from extended thromboembolism prophylaxis similar to that of patients with colon cancer. See Video Abstract at http://links.lww.com/DCR/A544. PMID- 29420430 TI - Risk of Recurrent Disease and Surgery Following an Admission for Acute Diverticulitis. AB - BACKGROUND: Diverticular disease accounts for significant morbidity and mortality and may take the form of recurrent episodes of acute diverticulitis. The role of elective surgery is not clearly defined. OBJECTIVE: This study aimed to define the rate of hospital admission for recurrent acute diverticulitis and risk factors associated with recurrence and surgery. DESIGN: This is a retrospective population-based cohort study. SETTINGS: National Health Service hospital admissions for acute diverticulitis in England between April 2006 and March 2011 were reviewed. PATIENTS: Hospital Episode Statistics data identified adult patients with the first episode of acute diverticulitis (index admission), and then identified recurrent admissions and elective or emergency surgery for acute diverticulitis during a minimum follow-up period of 4 years. Exclusion criteria included previous diagnoses of acute diverticulitis, colorectal cancer, or GI bleeding, and prior colectomy or surgery or death during the index admission. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: The primary outcomes measured were recurrent admissions for acute diverticulitis and patients requiring either elective or emergency surgery during the study period. RESULTS: Some 65,162 patients were identified with the first episode of acute diverticulitis. The rate of hospital admission for recurrent acute diverticulitis was 11.2%. A logistic regression model examined factors associated with recurrent acute diverticulitis and surgery: patient age, female sex, smoking, obesity, comorbidity score >20, dyslipidemia, and complicated acute diverticulitis increased the risk of recurrent acute diverticulitis. There was an inverse relationship between patient age and recurrence. Similar factors were associated with elective and emergency surgery. LIMITATIONS: The cases of acute diverticulitis required inpatient management and the use of Hospital Episode Statistics, relying on the accuracy of diagnostic coding. CONCLUSIONS: This is the largest study assessing the rates of hospital admission for recurrent acute diverticulitis. Knowledge of the rate and risk factors for recurrent acute diverticulitis is required to aid discussion and decision making with patients regarding the need and timing of elective surgery. Some factors associated with recurrence are modifiable; therefore, weight reduction and smoking cessation can be championed. See Video Abstract at http://links.lww.com/DCR/A449. PMID- 29420431 TI - Challenges in Transition of Care for Patients With Anorectal Malformations: A Systematic Review and Recommendations for Comprehensive Care. AB - BACKGROUND: Anorectal malformations are one of the most common congenital intestinal anomalies affecting newborns. Despite advances in neonatal care and surgical techniques, many patients with a history of anorectal malformations are affected by long-term challenges involving bowel and bladder dysfunction, sexual dysfunction, and psychosocial issues. These outcomes or challenges are additionally exacerbated by the lack of a structured transition of care from the pediatric to the adult setting. OBJECTIVE: The purpose of this review is to describe the long-term outcomes affecting patients with a history of anorectal malformations, review the current literature on transition of care, and make recommendations for developing a standardized program for transitioning care for a select group of colorectal surgical patients. DATA SOURCES: An extensive PubMed review of articles in English was performed to evaluate current best practices for chronic illnesses of childhood with residual symptoms or need for medical care into adulthood. STUDY SELECTION: Meta-Analysis of Observational Studies in Epidemiology group guidelines were followed. MAIN OUTCOME MEASURES: The primary outcome for this review was the existence of transitional services for patients with a history of anorectal malformations and evaluations of long-term outcomes affecting patients with a history of anorectal malformations. RESULTS: Systematic review revealed improved results in transition programs as determined by patient follow-up, medication adherence, and patient and family satisfaction through the use of multidisciplinary teams. Standardized tools for assessing all aspects of patient outcomes and quality of life are essential for describing the burden of disease affecting a transitioning population. LIMITATIONS: This is a retrospective review of the current status of a complex and rapidly evolving field of delivery of care. More work is needed to apply uniform approaches and assess the impact, patient outcomes, and quality of life. CONCLUSIONS: Patients who undergo childhood procedures for anorectal malformations often experience chronic symptoms related to the bowel, bladder, and reproductive organs, as well as psychosocial disturbances. This population will benefit from appropriate engagement in transitional care plans. See Video Abstract at http://links.lww.com/DCR/A543. PMID- 29420432 TI - Distinguishing Anal Squamous Cell Carcinoma and Rectal Squamous Cell Carcinoma in Secondary Data Sets. PMID- 29420433 TI - The Authors Reply. PMID- 29420434 TI - Quality of Life in Patients With Rectal Cancer After Chemoradiation: Watch-and Wait Policy Versus Standard Resection-Are We Comparing Apples to Oranges? PMID- 29420435 TI - The Authors Reply. PMID- 29420437 TI - Objectively Differentiating Movement Patterns between Elite and Novice Athletes. AB - INTRODUCTION: Movement screens are frequently used to identify abnormal movement patterns that may increase risk of injury or hinder performance. Abnormal patterns are often detected visually based on the observations of a coach or clinician. Quantitative or data-driven methods can increase objectivity, remove issues related to interrater reliability and offer the potential to detect new and important features that may not be observable by the human eye. Applying principal component analysis (PCA) to whole-body motion data may provide an objective data-driven method to identify unique and statistically important movement patterns, an important first step to objectively characterize optimal patterns or identify abnormalities. Therefore, the primary purpose of this study was to determine if PCA could detect meaningful differences in athletes' movement patterns when performing a non-sport-specific movement screen. As a proof of concept, athlete skill level was selected a priori as a factor likely to affect movement performance. METHODS: Motion capture data from 542 athletes performing seven dynamic screening movements (i.e., bird-dog, drop-jump, T-balance, step down, L-hop, hop-down, and lunge) were analyzed. A PCA-based pattern recognition technique and a linear discriminant analysis with cross-validation were used to determine if skill level could be predicted objectively using whole-body motion data. RESULTS: Depending on the movement, the validated linear discriminant analysis models accurately classified 70.66% to 82.91% of athletes as either elite or novice. CONCLUSIONS: We have provided proof that an objective data driven method can detect meaningful movement pattern differences during a movement screening battery based on a binary classifier (i.e., skill level in this case). Improving this method can enhance screening, assessment, and rehabilitation in sport, ergonomics, and medicine. PMID- 29420438 TI - Retinal Nerve Fiber Layer Thickness in Various Retinal Diseases. AB - SIGNIFICANCE: Peripapillary retinal nerve fiber layer (RNFL) thickness measurements may be influenced by the range and severity of lesions that are observed distinctively in each retinal disease. PURPOSE: We investigated the effects of various macular (central serous chorioretinopathy, macular hole, epiretinal membrane, wet age-related macular degeneration) and retinal vascular (branch retinal vein occlusion, central retinal vein occlusion, diabetic macular edema) diseases on peripapillary RNFL thickness measurements using spectral domain optical coherence tomography. METHODS: Six hundred thirty-one eyes from 464 patients with various retinal diseases and 167 controls of similar age were included in this retrospective study. Using spectral-domain optical coherence tomography, we measured the thickness of the macula and the RNFL in both various retinal disease eyes and normal control eyes. Four sectorial and average RNFL thicknesses were compared between each disease and age-matched control eyes. The macular thicknesses were also compared. RESULTS: In the macular disease group, superior (P = .033) and temporal (P = .024) quadrant RNFL thicknesses of central serous chorioretinopathy and temporal (P < .001) quadrant RNFL thicknesses of epiretinal membrane were greater than the age-matched control eyes. No RNFL measurements in macular hole or wet age-related macular degeneration differed significantly from the controls. In the retinal vascular disease group, all sectorial and average RNFL thicknesses of diabetic macular edema and central retinal vein occlusion were greater than those of the controls (all P < .05). In branch retinal vein occlusion, superior (P = .012) and temporal (P < .001) quadrant RNFL thicknesses were greater than those of the controls. CONCLUSIONS: Peripapillary RNFL thickness measurements may be influenced by the range and severity of lesions that are observed distinctively in each retinal disease. It also appeared that macular disease had a local effect on RNFL thickness, whereas retinal vascular disease had a diffuse effect on RNFL thickness. PMID- 29420440 TI - Rapid Increases in Syphilis in Reproductive-Aged Women in Japan: A Warning for Other Countries? PMID- 29420439 TI - Rapid Increase in Reports of Syphilis Associated With Men Who Have Sex With Women and Women Who Have Sex With Men, Japan, 2012 to 2016. AB - BACKGROUND: In Japan, syphilis reports have recently increased rapidly. However, unlike other developed countries where men who have sex with men (MSM) were associated with the rise, the increase in Japan has been attributed more to men who have sex with women (MSW) and women who have sex with men (WSM). We report on this increase based on surveillance data. METHODS: Syphilis is a notifiable disease requiring all laboratory-confirmed cases to be reported; stage and sex of the sex partner(s) suspected as the infection source are also reported. Focusing on primary and secondary (P&S) cases, we describe the temporal, demographic, and geographic distributions of reported cases in 2012 through 2016. RESULTS: A total of 7040 (64.0%) of 10,997 cases were P&S; the annual rate of increase was greatest for P&S and the proportion of P&S increased over time. Among P&S cases (1609 MSM, 2768 MSW, and 1323 WSM), MSW and WSM each surpassed MSM cases in 2016. Men were older with a wider age distribution (median, 37 years; interquartile range, 28-46 years) relative to women (median, 26 years; interquartile range, 21 34 years). Among women, 20- to 24-year-olds consistently had the highest reporting rate, reaching 9.0 per 100,000 in 2016. Congenital syphilis reports increased from 0.4 in 2012 to 1.4 per 100,000 live births in 2016. Although Tokyo prefecture had the highest reporting rate (3.98 per 100,000 person-years), the proportionate contribution from Tokyo decreased in 2016. CONCLUSIONS: Reports on P&S syphilis increased yearly among MSW and WSM. Young women seem to be at particular risk, and with increased reports of congenital syphilis, syphilis prevention and control is currently a public health priority in Japan. PMID- 29420441 TI - Neurosyphilis: Knowledge Gaps and Controversies. AB - After reaching a nadir at the turn of the century, syphilis rates in the United States have increased since 2000. Treponema pallidum may disseminate to the central nervous system within hours to days after inoculation. In this review, we focus on knowledge gaps and areas of controversy in neurosyphilis epidemiology, diagnosis, and management. Modern estimates of the prevalence of neurosyphilis are hindered by the lack of consistent reporting data and are based on relatively small retrospective cohort studies. The various diagnostic modalities for neurosyphilis have significant limitations. Although several novel biomarkers for neurosyphilis have been evaluated, none to date have found a place in clinical practice. The role of a cerebrospinal fluid examination in patients without neurological symptoms continues to be an area of controversy, whereas the data for the use of antibiotic regimens other than intravenous aqueous or intramuscular procaine penicillin for the treatment of neurosyphilis are limited. As syphilis incidence continues to increase unabated in many countries around the world, it is critical to address these gaps of knowledge. PMID- 29420442 TI - Differences in Partner Services Outcomes for Men Who Have Sex With Men Diagnosed With Primary and Secondary Syphilis by HIV Serostatus. AB - BACKGROUND: Differences in partner services outcomes in men who have sex with men (MSM) by HIV serostatus have not been explored as a potential driver of differential early syphilis (ES) burden in this population. METHODS: We compared partner services outcomes (number of partners named, notified, tested, diagnosed, and treated) between HIV-positive and HIV-negative MSM initiated for ES partner services in Texas from 2013 to 2016 using logistic regression and Wilcoxon-Mann Whitney tests. Logistic regression was used to assess the relationship between HIV serostatus and having a no-partner-initiated (NPI) partner services interview controlling for demographic characteristics, prior partner services interactions, and geosocial phone application use. RESULTS: A total of 4161 HIV-positive MSM and 5254 HIV-negative MSM were initiated for ES partner services. HIV-positive MSM named fewer partners than did HIV-negative MSM (mean, 1.2 vs. 1.9; P < 0.001) and had lower indices of partners notified, tested, diagnosed, and treated. HIV seropositivity was significantly associated with NPI. However, this association was not significant when limited to MSM with previous partner services interviews (adjusted risk ratio [aRR] 1.06; P = 0.38); in this subset of MSM, using geosocial phone application was negatively associated with having an NPI interview (aRR, 0.90), and having 1 (aRR, 1.33) or more than 1 previous NPI interview (aRR, 1.57) was associated with an NPI interview during the study period. CONCLUSIONS: Suboptimal outcomes for syphilis partner service may result in missed opportunities for testing and treatment of sexual contacts, which could allow for propagation of syphilis. Implementation of innovative protocols is needed to ensure that partner services continue to be an effective and acceptable method of syphilis disease intervention in MSM. PMID- 29420443 TI - Factors Associated With Syphilis Testing and a History of Syphilis Infection Among a Sample of Transgender Women in Jamaica. AB - BACKGROUND: Globally, social inequalities contribute to elevated sexually transmitted infections (STIs) rates among transgender women. High syphilis prevalence has been documented among transgender women in Latin America. Little is known, however, of syphilis testing uptake among transgender women in Jamaica, where homosexuality is criminalized. The study objective was to understand factors associated with opting-in for syphilis testing and a syphilis infection history among transgender women in Jamaica. METHODS: We conducted a cross sectional tablet-based survey of 137 transgender women between March and November 2015 in Jamaica. Bivariate analyses were used to assess differences across sociodemographic, intrapersonal, interpersonal, and structural factors based on syphilis infection history. We conducted univariable and multivariable logistic regression to determine the odds ratio for opting-in for syphilis testing for all factors associated with testing uptake at a P value of less than 0.05 in bivariate analyses, controlling for sociodemographic characteristics. RESULTS: Among 137 participants, 83 (60.6%) opted in for syphilis screening and 8 (9.6%) had positive rapid test results. One quarter of participants (n = 26; 25.2%) reported being HIV positive. Opting-in for syphilis testing was associated with the following: 1 health (HIV-positive serostatus: adjusted odds ratio [AOR], 4.33; 95% confidence interval [CI], 1.31-14.26), 1 intrapersonal (perceived STI risk: AOR, 1.58; 95% CI, 1.04-2.40), 1 interpersonal (childhood sexual abuse: AOR, 2.80; 95% CI, 1.03-7.62), and 1 structural (incarceration: AOR, 0.27; 95% CI, 0.11-0.71) factor. CONCLUSIONS: This study identified factors (HIV-positive serostatus, perceived STI risk, childhood sexual abuse, no incarceration history) associated with syphilis testing uptake among transgender women. Findings can inform multilevel STI testing, prevention, and care strategies tailored for transgender women in Jamaica. PMID- 29420444 TI - An Application of Syndemic Theory to Identify Drivers of the Syphilis Epidemic Among Gay, Bisexual, and Other Men Who Have Sex With Men. AB - BACKGROUND: We applied syndemic theory to explore the degree to which syndemic conditions explain the syphilis epidemic affecting Canadian gay and bisexual men who have sex with men (GBMSM). METHODS: Data from a national survey comprising 7872 GBMSM were analyzed using multivariable logistic regression to measure associations between recent syphilis diagnosis (RSD; in previous 12 months) and the following variables: (1) sociodemographic information (sexuality, HIV status, age, income, ethnicity, relationship status), (2) antigay stigma (bullying, physical violence, sexual violence, career discrimination, health care discrimination), (3) syndemic conditions (suicidality, intimate partner violence, depression, illicit substance use, binge drinking), (4) sexual behaviors, (5) health care discrimination, and (6) the cumulative count of antigay experiences and syndemic conditions. RESULTS: Three percent (n = 235) of GBMSM surveyed reported an RSD. Men were more likely to report an RSD if they were HIV positive (adjusted odds ratio [AOR], 6.27; 95% confidence interval [CI], 4.66-8.43). Recent syphilis diagnosis was also positively associated with career discrimination, health care discrimination, substance use, and intimate partner violence. Furthermore, prevalence of RSD increased with each additional form of stigma or syndemic condition. The odds of reporting RSD was 5.2 (95% CI, 1.0 25.9) times higher for men who reported experiencing all 4 forms of antigay stigma compared with those who reported no stigma, after adjusting for sociodemographics. Similarly, the adjusted odds of reporting RSD was 12.2 (95% CI, 2.0%-74.8%) times higher for GBMSM experiencing 5 syndemic conditions compared with those reporting no syndemic conditions. CONCLUSIONS: Evidence from this large cross-sectional study suggests that the Canadian syphilis epidemic among GBMSM is being driven by a syndemic constituted by multiple social and psychological conditions. Interventions addressing specific psychosocial health outcomes that increase the risk for syphilis should be developed and integrated within targeted sexual health services and syphilis prevention initiatives. PMID- 29420445 TI - Frequency of Nucleic Acid Amplification Test Positivity Among Men Who Have Sex With Men Returning for a Test-of-Cure Visit 7 to 30 Days After Treatment of Laboratory-Confirmed Neisseria gonorrhoeae Infection at 2 Public Sexual Health Clinics, New York City, 2013 to 2016. AB - BACKGROUND: The Centers for Disease Control and Prevention 2015 Sexually Transmitted Disease Treatment Guidelines recommend that clinicians consider cephalosporin treatment failure in patients who deny interval sexual exposure and are nucleic acid amplification test (NAAT) positive for Neisseria gonorrhoeae (NG) at least 7 days after adequate treatment. We evaluate the real-world implications of the interval the Centers for Disease Control and Prevention recommends for a NAAT test-of-cure (TOC), by ascertaining the frequency of NG NAAT positivity at different anatomic sites among men who have sex with men (MSM) at TOC 7 to 30 days after treatment. METHODS: We analyzed data from the medical records of MSM with laboratory-confirmed NG who were presumptively treated for NG during the period from June 2013 to April 2016 and returned for a TOC visit within 30 days. Data examined included symptoms, site of NG specimen collection, treatment regimen, follow-up testing, and intervening sexual activity. RESULTS: There were 1027 NG-positive specimens obtained from 763 MSM patients at 889 presumptive treatment visits. Of these, 44% (337/763) MSM returned for 1 or more TOC visits, and 413 specimens were collected a median of 10 days after presumptive treatment. Three percent (14/413) of specimens collected were NG NAAT positive at TOC a median of 13 days after treatment: 5% (12/256) of urethral specimens, 1% (1/147) of anorectal specimens (P = 0.037, urethral vs. anorectal), and 10% (1/10) of oropharyngeal specimens (P = 0.40, urethral vs. oropharyngeal). CONCLUSIONS: A small percent of patients were NG NAAT positive at TOC. Compared with anorectal specimens, urethral specimens were more frequently still positive at TOC. A large proportion of MSM will return for a TOC visit as part of standard clinical care. PMID- 29420446 TI - Investigating the Geographic Distribution of Shigellosis Among Men and Women in Massachusetts: Possible Implications for Men Who Have Sex With Men. AB - Shigellosis has emerged as a nontraditional sexually transmitted infection with high rates among men who have sex with men. Although anecdotal evidence has surfaced regarding shigellosis clustering among men who have sex with men in Massachusetts, little scientific research documents these occurrences. We present the first spatial distribution of shigellosis across Massachusetts. PMID- 29420447 TI - Age-Specific Pattern of Anogenital Wart in Men Who Have Sex With Men. AB - We examined the proportion of anogenital warts in men who have sex with men attending a sexual health center. Anal warts were most common in younger men who have sex with men (5.8% for age <21 years) and became less common with age (2.8% in age >50 years), but penile warts occurred at approximately the same proportion (~1.5%) over all age groups. PMID- 29420448 TI - The Interaction of Sexual Validation, Criminal Justice Involvement, and Sexually Transmitted Infection Risk Among Adolescent and Young Adult Males. AB - BACKGROUND: Young men who have been involved with the criminal justice system are more likely to have concurrent sexual partners, a key driver of sexually transmitted infections. The value men place on having sexual relationships to validate themselves may play an important role in understanding this association. METHODS: Data were from a household survey. Young men (N = 132), aged 16 to 24 years, self-reported whether they ever spent time in jail or juvenile detention and if they had sexual partnerships that overlapped in time. A novel scale, "Validation through Sex and Sexual Relationships" (VTSSR) assessed the importance young men place on sex and sexual relationships (alpha = 0.91). Weighted logistic regression accounted for the sampling design. RESULTS: The mean (SD) VTSSR score was 23.7 (8.8) with no differences by race. Both criminal justice involvement (CJI) (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.12-12.1) and sexual validation (OR, 1.10; 95% CI, 1.04-1.16) were associated with an increased odds of concurrency; however, CJI did not remain associated with concurrency in the fully adjusted model. There was effect modification, CJI was associated with concurrency among those who scored high on sexual validation (OR, 9.18; 95% CI, 1.73-48.6]; however, there was no association among those who scored low on sexual validation. Racial differences were observed between CJI and concurrency, but not between sexual validation and concurrency. CONCLUSIONS: Sexual validation may be an important driver of concurrency for men who have been involved with the criminal justice system. Study findings have important implications on how sexual validation may explain racial differences in rates of concurrency. PMID- 29420449 TI - Rising Chlamydia and Gonorrhoea Incidence and Associated Risk Factors Among Female Sex Workers in Australia: A Retrospective Cohort Study. AB - BACKGROUND: Female sex workers in Australia have achieved some of the lowest documented prevalences of human immunodeficiency virus (HIV) and other sexually transmissible infections globally but rates overall are increasing in Australia and warrant closer investigation. METHODS: We constructed a retrospective cohort using repeat testing data extracted from a network of 42 sexual health clinics. Poisson and Cox regression were used to determined trends in incidence and risk factors for HIV, chlamydia, gonorrhoea, and infectious syphilis among female sex workers. RESULTS: From 2009 to 2015, 18,475 women reporting sex work attended a participating service. The overall incidence of urogenital chlamydia was 7.7/100 person years (PY), declining by 38% from 2009 to 2013 before increasing by 43% to 2015 (P < 0.001); anorectal chlamydia incidence was 0.6/100 PY, and pharyngeal was 1.9/100 PY, which increased significantly during the study period (P < 0.001, both). For gonorrhoea, the urogenital incidence was 1.4/100 PY, anorectal incidence was 0.3/100 PY, P < 0.001), and 3.6/100 PY for pharyngeal; urogenital incidence doubled during the study period, anorectal increased fivefold, and pharyngeal more than tripled (P < 0.001, all). Incidence of infectious syphilis was 0.4/100 PY, which remained stable from 2009 to 2015 (P = 0.09). There were seven incident infections of HIV among female sex workers (0.1/100 PY). Inconsistent condom use with private partners, higher number of private partner numbers, recent injecting drug use, younger age, and country of birth variously predicted sexually transmissible infections among female sex workers. CONCLUSIONS: Although infectious syphilis and HIV remain uncommon in female sex workers attending Australian sexual health clinics, the increasing incidence of gonorrhoea across anatomical sites and increasing chlamydia after a period of decline demands enhanced health promotion initiatives. PMID- 29420450 TI - A Pilot Study to Increase the Efficiency of HIV Outreach Testing Through the Use of Timely and Geolocated HIV Viral Load Surveillance Data. AB - BACKGROUND: Eliminating HIV transmission in a population necessitates identifying population reservoirs of HIV infection and subgroups most likely to transmit. HIV viral load is the single most important predictor of HIV transmission. The objective of this analysis was to evaluate whether a public health practice pilot project based on community viral load resulted in increases in the proportion of time spent testing in high viral load areas (process measure) and 3 outcome measures-the number and percent of overall HIV diagnoses, new diagnoses, and high viral load positives-in one mid-Atlantic US city with a severe HIV epidemic. METHODS: The evaluation was conducted during three, 3-month periods for 3 years and included the use of community viral load, global positioning system tracking data, and statistical testing to evaluate the effectiveness of the pilot project. RESULTS: The proportion of time spent outreach testing in high viral load areas (69%-84%, P < 0.001) and the overall number and percent of HIV positives ((60 (3%) to 127 (6%), P < 0.001) significantly increased for 3 years. The number and percent of new diagnoses (3 (0.1%) to 6 (0.2%)) and high viral load positives (5 (0.2%) to 9 (0.4%)) increased, but the numbers were too small for statistical testing. DISCUSSION: These results suggest that using community viral load to increase the efficiency of HIV outreach testing is feasible and may be effective in identifying more HIV positives. The pilot project provides a model for other public health practice demonstration projects. PMID- 29420451 TI - How Good Is Your Rule of Thumb? Validating Male-to-Female Case Ratio as a Proxy for Men Who Have Sex With Men Involvement in N. gonorrhoeae Incidence at the County Level. AB - BACKGROUND: Lacking information on men who have sex with men (MSM) for most reported cases, sexually transmitted disease (STD) programs in the United States have used crude measures such as male-to-female case ratios (MFCR) as a rule of thumb to gauge MSM involvement at the local level, primarily with respect to syphilis cases in the past. Suitability of this measure for gonorrhea incidence has not previously been investigated. METHODS: A random sample of gonorrhea cases reported from January 2010 through June 2013 were interviewed in selected counties participating in the STD Surveillance Network to obtain gender of sex partners and history of transactional sex. Weighted estimates of proportion of cases among MSM and proportion reporting transactional sex were developed; correlation between MFCR and proportion MSM was assessed. RESULTS: Male-to-female case ratio ranged from 0.66 to 8.7, and the proportion of cases occurring among MSM varied from 2.5% to 62.3%. The MFCR was strongly correlated with proportion of cases among MSM after controlling for transactional sex (Pearson partial r = 0.754, P < 0.0001). CONCLUSIONS: Male-to-female case ratio for gonorrhea at the county level is a reliable proxy measure indicating MSM involvement in gonorrhea case incidence and should be used by STD programs to tailor their programmatic mix to include MSM-specific interventions. PMID- 29420452 TI - Preparing for the Chlamydia and Gonorrhea Self-Test. AB - New technology may soon allow individuals to test themselves for chlamydia and gonorrhea. These new self-tests might help increase screening, but they will also bring new issues for treatment, prevention, and surveillance. Providers will need to decide how to respond to patients who present after a positive screening test and how to approach partner testing and treatment. Research will be needed to identify approaches to increase screening using these tests. Laboratory-based surveillance will not capture infections if testing does not involve a laboratory, so new surveillance techniques will be needed. Self-tests are new tools that will soon be available. We should be prepared to use them. PMID- 29420453 TI - Buschke-Lowenstein Tumors in a 12-Year-Old Girl. PMID- 29420455 TI - Assessing the quality of care for haemophilia at the Yaounde' reference treatment Centre of Cameroon: Erratum. PMID- 29420454 TI - Systemic lupus erythematosus: disease activity may influence the release of endothelial microparticles? AB - : To evaluate blood-borne endothelial microparticles (EMPs) in women with SLE and correlated these to disease activity as defined by the SLEDAI-2K score. The study takes cross-sectional design. A total of 90 age-matched women were recruited including: G1 (healthy volunteers, n = 30), G2 (women with SLE and low disease activity (SLEDAI-2K score <=4; n = 30) and G3 (women with SLE and moderate/high disease activity (SLEDAI-2K score >4; n = 30). Blood was collected in 3.2% sodium citrate. Subsequently, the microparticles were purified by ultracentrifugation and labeled with anti-CD51/61 and anti-Annexin-V antibodies. Quantification and phenotyping were performed using flow cytometry. The number of EMPs was significantly higher in SLE patients compared with controls (P = 0.0178). When SLE patients were stratified according to disease activity, the number of EMPs was significantly increased in women with moderate-to-high disease activity compared with controls (P = 0.0074). We observed a correlation between the number of EMPs and age (r = -0.34; P = 0.0123) and between the number of EMPs and SLEDAI 2K score (r = 0.30; P = 0.04). Our results suggest that the SLE causes increased EMPs release, especially in patients with SLEDAI-2K score greater than 4. Although measurement of the EMPs could be useful in distinguishing patients with SLE from health controls, they have limited value in differentiating between SLE subtypes. PMID- 29420456 TI - Examining the Relationship of an All-Cause Harm Patient Safety Measure and Critical Performance Measures at the Frontline of Care. AB - BACKGROUND: In 2015, the Institute of Medicine Vital Signs report called for a new patient safety composite measure to lessen the reporting burden of patient harm. Before this report, two patient safety organizations had developed an electronic all-cause harm measurement system leveraging data from the electronic health record, which identified and grouped harms into five broad categories and consolidated them into one all-cause harm outcome measure. OBJECTIVES: The objective of this study was to examine the relationship between this all-cause harm patient safety measure and the following three performance measures important to overall hospital safety performance: safety culture, employee engagement, and patient experience. METHODS: We studied the relationship between all-cause harm and three performance measures on eight inpatient care units at one hospital for 7 months. RESULTS: The findings demonstrated strong correlations between an all-cause harm measure and patient safety culture, employee engagement, and patient experience at the hospital unit level. Four safety culture domains showed significant negative correlations with all-cause harm at a P value of 0.05 or less. Six employee engagement domains were significantly negatively correlated with all-cause harm at a P value of 0.01 or less, and six of the ten patient experience measures were significantly correlated with all cause harm at a P value of 0.05 or less. CONCLUSIONS: The results show that there is a strong relationship between all-cause harm and these performance measures indicating that when there is a positive patient safety culture, a more engaged employee, and a more satisfying patient experience, there may be less all-cause harm.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29420457 TI - Ultrasonography in the Diagnosis of Temporomandibular Disorders: A Meta-Analysis. AB - BACKGROUND The increased prevalence of temporomandibular disorders (TMDs) requires searching for new, easily accessible diagnostic methods. In addition to routine clinical examination, various methods of imaging temporomandibular joints are available, such as magnetic resonance imaging, computed tomography scans, or scintigraphy. Ultrasound imaging, due to short examination time, low cost, and non-invasiveness, should be recommended as a routine diagnostic procedure. The aim of the study was to investigate whether ultrasound imaging can be used in the diagnosis of temporomandibular joint disorders. MATERIAL AND METHODS Publications during the period 2006 to March 2017 from the US National Library of Medicine database were selected for analysis by entering the terms "ultrasonography", "ultrasound", "USG", "temporomandibular joint", "TMJ", "temporomandibular disorders", and "TMD". Papers were chosen if they met the required criteria relating to the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of this diagnostic technique with regard to imaging articular disc displacement, joint effusion, and condylar abnormalities. RESULTS The search yielded 1883 publications, of which 8 were selected that met the criteria for inclusion in the analysis. For articular disc displacement examinations, the following results were obtained: sensitivity 75.6%; specificity 69.1%; accuracy 76.1%; positive predictive value 72.2%; negative predictive value 65.6%. When the examinations of joint effusion and condylar abnormalities were included, the results were respectively 66.9%; 70.8%; 69.9%; 75.8%; and 62.4%. CONCLUSIONS The use of ultrasonography in the diagnosis of temporomandibular disorders requires standardizing the method as well as further research to confirm its effectiveness. PMID- 29420458 TI - Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger - United States, 2018. AB - In October 2017, the Advisory Committee on Immunization Practices (ACIP) approved the Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger - United States, 2018. The 2018 child and adolescent immunization schedule summarizes ACIP recommendations, including several changes from the 2017 immunization schedules, in three figures and footnotes to the figures. These documents can be found on the CDC immunization schedule website (https://www.cdc.gov/vaccines/schedules/index.html). These immunization schedules are approved by ACIP (https://www.cdc.gov/vaccines/acip/index.html), the American Academy of Pediatrics (https://www.aap.org), the American Academy of Family Physicians (https://www.aafp.org), and the American College of Obstetricians and Gynecologists (https://www.acog.org). Health care providers are advised to use the figures and the footnotes together. The full ACIP recommendations for each vaccine, including contraindications and precautions, can be found at https://www.cdc.gov/vaccines/hcp/acip-recs/index.html. Providers should be aware that changes in recommendations for specific vaccines can occur between annual updates to the childhood/adolescent immunization schedules. If errors or omissions are discovered within the child and adolescent schedule, CDC posts revised versions on the CDC immunization schedule website. PMID- 29420459 TI - Vital Signs: Asthma in Children - United States, 2001-2016. AB - BACKGROUND: Asthma is the most common chronic lung disease of childhood, affecting approximately 6 million children in the United States. Although asthma cannot be cured, most of the time, asthma symptoms can be controlled by avoiding or reducing exposure to asthma triggers (allergens and irritants) and by following recommendations for asthma education and appropriate medical care. METHODS: CDC analyzed asthma data from the 2001-2016 National Health Interview Survey for children aged 0-17 years to examine trends and demographic differences in health outcomes and health care use. RESULTS: Asthma was more prevalent among boys (9.2%) than among girls (7.4%), children aged >=5 years (approximately 10%) than children aged <5 years (3.8%), non-Hispanic black (black) children (15.7%) and children of Puerto Rican descent (12.9%) than among non-Hispanic white (white) children (7.1%), and children living in low income families (10.5%) than among those living in families with income >=250% of the Federal Poverty Level (FPL) (approximately 7%). Asthma prevalence among children increased from 8.7% in 2001 to 9.4% in 2010, and then decreased to 8.3% in 2016. Although not all changes were statistically significant, a similar pattern was observed among subdemographic groups studied, with the exception of Mexican/Mexican-American children, among whom asthma prevalence increased from 5.1% in 2001 to 6.5% in 2016. Among children with asthma, the percentage who had an asthma attack in the past 12 months declined significantly from 2001 to 2016. Whereas asthma prevalence was lower among children aged 0-4 years than among older children, the prevalence of asthma attacks (62.4%), emergency department or urgent care center (ED/UC) visits (31.1%), and hospitalization (10.4%) were higher among children with asthma aged 0-4 years than among those aged 12-17 years (44.8%, 9.6%, and 2.8%, respectively). During 2013, children with asthma aged 5-17 years missed 13.8 million days of school per year (2.6 days per child). Compared with 2003, in 2013, the prevalence of adverse health outcomes and health care use were significantly lower and the prevalence of having an action plan to manage asthma was higher. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Asthma remains an important public health and medical problem. The health of children with asthma can be improved by promoting asthma control strategies, including asthma trigger reduction, appropriate guidelines-based medical management, and asthma education for children, parents, and others involved in asthma care. PMID- 29420461 TI - QuickStats: Percentage* of All Emergency Department (ED) Visits? Made by Patients with Asthma,S by Sex and Age Group - National Hospital Ambulatory Medical Care Survey, United States 2014-2015. AB - During 2014-2015, patients who had asthma documented in the medical record accounted for 9.5% of all ED visits in the United States, with the highest percentage for children aged 5-17 years (13.6%), compared with 6.6% for children aged 0-4 years, 9.9% for adults aged 18-64 years, and 6.5% for those aged >=65 years. Among those aged 0-4 years, boys were more likely than girls to have a visit with asthma recorded, but for the older age groups, 18-64 and >=65, women with asthma documented were more likely than men to have an ED visit. The difference by sex for those aged 5-17 years was not statistically significant. PMID- 29420460 TI - Outbreak of Fluoroquinolone-Resistant Campylobacter jejuni Infections Associated with Raw Milk Consumption from a Herdshare Dairy - Colorado, 2016. AB - In August 2016, a local public health agency (LPHA) notified the Colorado Department of Public Health and Environment (CDPHE) of two culture-confirmed cases of Campylobacter infection among persons who consumed raw (unpasteurized) milk from the same herdshare dairy. In Colorado, the sale of raw milk is illegal; however, herdshare programs, in which a member can purchase a share of a herd of cows or goats, are legal and are not regulated by state or local authorities. In coordination with LPHAs, CDPHE conducted an outbreak investigation that identified 12 confirmed and five probable cases of Campylobacter jejuni infection. Pulsed-field gel electrophoresis (PFGE) patterns for the 10 cases with available isolates were identical using the enzyme Sma. In addition, two milk samples (one from the dairy and one obtained from an ill shareholder) also tested positive for the outbreak strain. Five C. jejuni isolates sent to CDC for antimicrobial susceptibility testing were resistant to ciprofloxacin, tetracycline, and nalidixic acid (1). Although shareholders were notified of the outbreak and cautioned against drinking the milk on multiple occasions, milk distribution was not discontinued. Although its distribution is legal through herdshare programs, drinking raw milk is inherently risky (2). The role of public health in implementing control measures associated with a product that is known to be unsafe remains undefined. PMID- 29420462 TI - Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older - United States, 2018. AB - In October 2017, the Advisory Committee on Immunization Practices (ACIP) voted to approve the Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States, 2018. The 2018 adult immunization schedule summarizes ACIP recommendations in two figures and a table of contraindications and precautions for vaccines recommended for adults, and is intended is to assist health care providers in implementing the current ACIP recommendations for vaccinating adults. The schedule can be found at https://www.cdc.gov/vaccines/schedules.* The full ACIP recommendations for each vaccine are available at https://www.cdc.gov/vaccines/hcp/acip-recs/index.html. The 2018 adult immunization schedule has also been approved by the American College of Physicians (https://www.acponline.org), the American Academy of Family Physicians (https://www.aafp.org), the American College of Obstetricians and Gynecologists (https://www.acog.org), and the American College of Nurse-Midwives (http://www.midwife.org). The ACIP-recommended use of each vaccine is developed after an in-depth review of vaccine-related data, including data on disease epidemiology, vaccine efficacy and effectiveness, vaccine safety, feasibility of program implementation, and economic aspects of immunization policy (1). PMID- 29420463 TI - Nonfatal Assaults Among Persons Aged 10-24 Years - United States, 2001-2015. AB - In 2015, persons aged 10-24 years who were treated for nonfatal assault injuries in emergency departments (EDs) in the United States accounted for 32% of the approximately 1.5 million patients of all ages that EDs treated for nonfatal assault injuries (1). CDC analyzed data from the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP) to examine 2001-2015 trends in nonfatal assault injuries among youths treated in EDs, by sex and age group, and to assess current rates by sex, age group, mechanism of injury, and disposition (1). Rates for 2001-2015 were significantly higher among males than among females and among young adults aged 20-24 years than among youths aged 10-14 and 15-19 years. During 2011-2015, rates declined for all groups. The 2015 rate among persons aged 10-24 years was 753.2 per 100,000 population, the lowest in the 15 year study period. Despite encouraging trends, the assault rate among young persons remains high. Rates in 2015 were higher among males, persons aged 20-24 years, and those who incurred intentional strike or hit injuries. Nearly one in 10 patients were admitted to the hospital, transferred to another hospital, or held for observation. Youth violence prevention strategies, including primary prevention approaches that build individual skills, strengthen family relationships, or connect young persons treated in EDs to immediate and ongoing support, can be implemented to decrease injuries and fatalities (2). PMID- 29420464 TI - Potential Confounding of Diagnosis of Rabies in Patients with Recent Receipt of Intravenous Immune Globulin. AB - Rabies is an acute encephalitis that is nearly always fatal. It is caused by infection with viruses of the genus Lyssavirus, the most common of which is Rabies lyssavirus. The Council of State and Territorial Epidemiologists (CSTE) defines a confirmed human rabies case as an illness compatible with rabies that meets at least one of five different laboratory criteria.* Four of these criteria do not depend on the patient's rabies vaccination status; however, the remaining criterion, "identification of Lyssavirus-specific antibody (i.e. by indirect fluorescent antibody...test or complete [Rabies lyssavirus] neutralization at 1:5 dilution) in the serum," is only considered diagnostic in unvaccinated patients. Lyssavirus-specific antibodies include Rabies lyssavirus-specific binding immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies and Rabies lyssavirus neutralizing antibodies (RLNAs). This report describes six patients who were tested for rabies by CDC and who met CSTE criteria for confirmed human rabies because they had illnesses compatible with rabies, had not been vaccinated for rabies, and were found to have serum RLNAs (with complete Rabies lyssavirus neutralization at a serum dilution of 1:5). An additional four patients are described who were tested for rabies by CDC who were found to have serum RLNAs (with incomplete Rabies lyssavirus neutralization at a serum dilution of 1:5) despite having not been vaccinated for rabies. None of these 10 patients received a rabies diagnosis; rather, they were considered to have been passively immunized against rabies through recent receipt of intravenous immune globulin (IVIG). Serum RLNA test results should be interpreted with caution in patients who have not been vaccinated against rabies but who have recently received IVIG. PMID- 29420465 TI - Notes from the Field: Assessment of Rabies Exposure Risk Among Residents of a University Sorority House - Indiana, February 2017. PMID- 29420466 TI - Processing bulk natural wood into a high-performance structural material. AB - Synthetic structural materials with exceptional mechanical performance suffer from either large weight and adverse environmental impact (for example, steels and alloys) or complex manufacturing processes and thus high cost (for example, polymer-based and biomimetic composites). Natural wood is a low-cost and abundant material and has been used for millennia as a structural material for building and furniture construction. However, the mechanical performance of natural wood (its strength and toughness) is unsatisfactory for many advanced engineering structures and applications. Pre-treatment with steam, heat, ammonia or cold rolling followed by densification has led to the enhanced mechanical performance of natural wood. However, the existing methods result in incomplete densification and lack dimensional stability, particularly in response to humid environments, and wood treated in these ways can expand and weaken. Here we report a simple and effective strategy to transform bulk natural wood directly into a high performance structural material with a more than tenfold increase in strength, toughness and ballistic resistance and with greater dimensional stability. Our two-step process involves the partial removal of lignin and hemicellulose from the natural wood via a boiling process in an aqueous mixture of NaOH and Na2SO3 followed by hot-pressing, leading to the total collapse of cell walls and the complete densification of the natural wood with highly aligned cellulose nanofibres. This strategy is shown to be universally effective for various species of wood. Our processed wood has a specific strength higher than that of most structural metals and alloys, making it a low-cost, high-performance, lightweight alternative. PMID- 29420468 TI - Contesting early archaeology in California. PMID- 29420467 TI - HER kinase inhibition in patients with HER2- and HER3-mutant cancers. AB - Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology. PMID- 29420469 TI - Dopamine neuron activity before action initiation gates and invigorates future movements. AB - Deciding when and whether to move is critical for survival. Loss of dopamine neurons (DANs) of the substantia nigra pars compacta (SNc) in patients with Parkinson's disease causes deficits in movement initiation and slowness of movement. The role of DANs in self-paced movement has mostly been attributed to their tonic activity, whereas phasic changes in DAN activity have been linked to reward prediction. This model has recently been challenged by studies showing transient changes in DAN activity before or during self-paced movement initiation. Nevertheless, the necessity of this activity for spontaneous movement initiation has not been demonstrated, nor has its relation to initiation versus ongoing movement been described. Here we show that a large proportion of SNc DANs, which did not overlap with reward-responsive DANs, transiently increased their activity before self-paced movement initiation in mice. This activity was not action-specific, and was related to the vigour of future movements. Inhibition of DANs when mice were immobile reduced the probability and vigour of future movements. Conversely, brief activation of DANs when mice were immobile increased the probability and vigour of future movements. Manipulations of dopamine activity after movement initiation did not affect ongoing movements. Similar findings were observed for the initiation and execution of learned action sequences. These findings causally implicate DAN activity before movement initiation in the probability and vigour of future movements. PMID- 29420471 TI - Experimental observation of Bethe strings. AB - Almost a century ago, string states-complex bound states of magnetic excitations were predicted to exist in one-dimensional quantum magnets. However, despite many theoretical studies, the experimental realization and identification of string states in a condensed-matter system have yet to be achieved. Here we use high resolution terahertz spectroscopy to resolve string states in the antiferromagnetic Heisenberg-Ising chain SrCo2V2O8 in strong longitudinal magnetic fields. In the field-induced quantum-critical regime, we identify strings and fractional magnetic excitations that are accurately described by the Bethe ansatz. Close to quantum criticality, the string excitations govern the quantum spin dynamics, whereas the fractional excitations, which are dominant at low energies, reflect the antiferromagnetic quantum fluctuations. Today, Bethe's result is important not only in the field of quantum magnetism but also more broadly, including in the study of cold atoms and in string theory; hence, we anticipate that our work will shed light on the study of complex many-body systems in general. PMID- 29420470 TI - Cryo-EM shows how dynactin recruits two dyneins for faster movement. AB - Dynein and its cofactor dynactin form a highly processive microtubule motor in the presence of an activating adaptor, such as BICD2. Different adaptors link dynein and dynactin to distinct cargoes. Here we use electron microscopy and single-molecule studies to show that adaptors can recruit a second dynein to dynactin. Whereas BICD2 is biased towards recruiting a single dynein, the adaptors BICDR1 and HOOK3 predominantly recruit two dyneins. We find that the shift towards a double dynein complex increases both the force and speed of the microtubule motor. Our 3.5 A resolution cryo-electron microscopy reconstruction of a dynein tail-dynactin-BICDR1 complex reveals how dynactin can act as a scaffold to coordinate two dyneins side-by-side. Our work provides a structural basis for understanding how diverse adaptors recruit different numbers of dyneins and regulate the motile properties of the dynein-dynactin transport machine. PMID- 29420473 TI - Magnetic cage and rope as the key for solar eruptions. AB - Solar flares are spectacular coronal events that release large amounts of energy. They are classified as either eruptive or confined, depending on whether they are associated with a coronal mass ejection. Two types of model have been developed to identify the mechanism that triggers confined flares, although it has hitherto not been possible to decide between them because the magnetic field at the origin of the flares could not be determined with the required accuracy. In the first type of model, the triggering is related to the topological complexity of the flaring structure, which implies the presence of magnetically singular surfaces. This picture is observationally supported by the fact that radiative emission occurs near these features in many flaring regions. The second type of model attributes a key role to the formation of a twisted flux rope, which becomes unstable. Its plausibility is supported by simulations, by interpretations of some observations and by laboratory experiments. Here we report modelling of a confined event that uses the measured photospheric magnetic field as input. We first use a static model to compute the slowly evolving magnetic state of the corona before the eruption, and then use a dynamical model to determine the evolution during the eruption itself. We find that a magnetic flux rope must be present throughout the entire event to match the field measurements. This rope evolves slowly before saturating and suddenly erupting. Its energy is insufficient to break through the overlying field, whose lines form a confining cage, but its twist is large enough to trigger a kink instability, leading to the confined flare, as previously suggested. Topology is not the main cause of the flare, but it traces out the locations of the X-ray emission. We show that a weaker magnetic cage would have produced a more energetic eruption with a coronal mass ejection, associated with a predicted energy upper bound for a given region. PMID- 29420472 TI - High performance plasma amyloid-beta biomarkers for Alzheimer's disease. AB - To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-beta deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-beta positron emission tomography (PET) imaging or measurement of amyloid-beta in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-beta markers. Here we demonstrate the measurement of high-performance plasma amyloid-beta biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-beta precursor protein (APP)669-711/amyloid-beta (Abeta)1-42 and Abeta1-40/Abeta1-42 ratios, and their composites, to predict individual brain amyloid-beta-positive or -negative status was determined by amyloid-beta-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-beta burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-beta-PET burden and levels of Abeta1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-beta burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening. PMID- 29420475 TI - Holen et al. reply. PMID- 29420474 TI - Enhancer redundancy provides phenotypic robustness in mammalian development. AB - Distant-acting tissue-specific enhancers, which regulate gene expression, vastly outnumber protein-coding genes in mammalian genomes, but the functional importance of this regulatory complexity remains unclear. Here we show that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. We used genome editing to create 23 mouse deletion lines and inter crosses, including both single and combinatorial enhancer deletions at seven distinct loci required for limb development. Unexpectedly, none of the ten deletions of individual enhancers caused noticeable changes in limb morphology. By contrast, the removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genome-wide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of three representative developmental structures (limb, brain and heart) uncovered more than one thousand cases in which five or more enhancers with redundant activity patterns were found near the same gene. Together, our data indicate that enhancer redundancy is a remarkably widespread feature of mammalian genomes that provides an effective regulatory buffer to prevent deleterious phenotypic consequences upon the loss of individual enhancers. PMID- 29420476 TI - Evolutionary history of the angiosperm flora of China. AB - High species diversity may result from recent rapid speciation in a 'cradle' and/or the gradual accumulation and preservation of species over time in a 'museum'. China harbours nearly 10% of angiosperm species worldwide and has long been considered as both a museum, owing to the presence of many species with hypothesized ancient origins, and a cradle, as many lineages have originated as recent topographic changes and climatic shifts-such as the formation of the Qinghai-Tibetan Plateau and the development of the monsoon-provided new habitats that promoted remarkable radiation. However, no detailed phylogenetic study has addressed when and how the major components of the Chinese angiosperm flora assembled to form the present-day vegetation. Here we investigate the spatio temporal divergence patterns of the Chinese flora using a dated phylogeny of 92% of the angiosperm genera for the region, a nearly complete species-level tree comprising 26,978 species and detailed spatial distribution data. We found that 66% of the angiosperm genera in China did not originate until early in the Miocene epoch (23 million years ago (Mya)). The flora of eastern China bears a signature of older divergence (mean divergence times of 22.04-25.39 Mya), phylogenetic overdispersion (spatial co-occurrence of distant relatives) and higher phylogenetic diversity. In western China, the flora shows more recent divergence (mean divergence times of 15.29-18.86 Mya), pronounced phylogenetic clustering (co-occurrence of close relatives) and lower phylogenetic diversity. Analyses of species-level phylogenetic diversity using simulated branch lengths yielded results similar to genus-level patterns. Our analyses indicate that eastern China represents a floristic museum, and western China an evolutionary cradle, for herbaceous genera; eastern China has served as both a museum and a cradle for woody genera. These results identify areas of high species richness and phylogenetic diversity, and provide a foundation on which to build conservation efforts in China. PMID- 29420477 TI - Limited emission reductions from fuel subsidy removal except in energy-exporting regions. AB - Hopes are high that removing fossil fuel subsidies could help to mitigate climate change by discouraging inefficient energy consumption and levelling the playing field for renewable energy. In September 2016, the G20 countries re-affirmed their 2009 commitment (at the G20 Leaders' Summit) to phase out fossil fuel subsidies and many national governments are using today's low oil prices as an opportunity to do so. In practical terms, this means abandoning policies that decrease the price of fossil fuels and electricity generated from fossil fuels to below normal market prices. However, whether the removal of subsidies, even if implemented worldwide, would have a large impact on climate change mitigation has not been systematically explored. Here we show that removing fossil fuel subsidies would have an unexpectedly small impact on global energy demand and carbon dioxide emissions and would not increase renewable energy use by 2030. Subsidy removal would reduce the carbon price necessary to stabilize greenhouse gas concentration at 550 parts per million by only 2-12 per cent under low oil prices. Removing subsidies in most regions would deliver smaller emission reductions than the Paris Agreement (2015) climate pledges and in some regions global subsidy removal may actually lead to an increase in emissions, owing to either coal replacing subsidized oil and natural gas or natural-gas use shifting from subsidizing, energy-exporting regions to non-subsidizing, importing regions. Our results show that subsidy removal would result in the largest CO2 emission reductions in high-income oil- and gas-exporting regions, where the reductions would exceed the climate pledges of these regions and where subsidy removal would affect fewer people living below the poverty line than in lower-income regions. PMID- 29420479 TI - Isomer depletion as experimental evidence of nuclear excitation by electron capture. AB - The atomic nucleus and its electrons are often thought of as independent systems that are held together in the atom by their mutual attraction. Their interaction, however, leads to other important effects, such as providing an additional decay mode for excited nuclear states, whereby the nucleus releases energy by ejecting an atomic electron instead of by emitting a gamma-ray. This 'internal conversion' has been known for about a hundred years and can be used to study nuclei and their interaction with their electrons. In the inverse process-nuclear excitation by electron capture (NEEC)-a free electron is captured into an atomic vacancy and can excite the nucleus to a higher-energy state, provided that the kinetic energy of the free electron plus the magnitude of its binding energy once captured matches the nuclear energy difference between the two states. NEEC was predicted in 1976 and has not hitherto been observed. Here we report evidence of NEEC in molybdenum-93 and determine the probability and cross-section for the process in a beam-based experimental scenario. Our results provide a standard for the assessment of theoretical models relevant to NEEC, which predict cross-sections that span many orders of magnitude. The greatest practical effect of the NEEC process may be on the survival of nuclei in stellar environments, in which it could excite isomers (that is, long-lived nuclear states) to shorter-lived states. Such excitations may reduce the abundance of the isotope after its production. This is an example of 'isomer depletion', which has been investigated previously through other reactions, but is used here to obtain evidence for NEEC. PMID- 29420478 TI - Dynamic basis for dG*dT misincorporation via tautomerization and ionization. AB - Tautomeric and anionic Watson-Crick-like mismatches have important roles in replication and translation errors through mechanisms that are not fully understood. Here, using NMR relaxation dispersion, we resolve a sequence dependent kinetic network connecting G*T/U wobbles with three distinct Watson Crick mismatches: two rapidly exchanging tautomeric species (Genol*T/UG*Tenol/Uenol; population less than 0.4%) and one anionic species (G*T /U-; population around 0.001% at neutral pH). The sequence-dependent tautomerization or ionization step was inserted into a minimal kinetic mechanism for correct incorporation during replication after the initial binding of the nucleotide, leading to accurate predictions of the probability of dG*dT misincorporation across different polymerases and pH conditions and for a chemically modified nucleotide, and providing mechanisms for sequence-dependent misincorporation. Our results indicate that the energetic penalty for tautomerization and/or ionization accounts for an approximately 10-2 to 10-3-fold discrimination against misincorporation, which proceeds primarily via tautomeric dGenol*dT and dG*dTenol, with contributions from anionic dG*dT- dominant at pH 8.4 and above or for some mutagenic nucleotides. PMID- 29420480 TI - Dynamics and number of trans-SNARE complexes determine nascent fusion pore properties. AB - The fusion pore is the first crucial intermediate formed during exocytosis, yet little is known about the mechanisms that determine the size and kinetic properties of these transient structures. Here, we reduced the number of available SNAREs (proteins that mediate vesicle fusion) in neurons and observed changes in transmitter release that are suggestive of alterations in fusion pores. To investigate these changes, we employed reconstituted fusion assays using nanodiscs to trap pores in their initial open state. Optical measurements revealed that increasing the number of SNARE complexes enhanced the rate of release from single pores and enabled the escape of larger cargoes. To determine whether this effect was due to changes in nascent pore size or to changes in stability, we developed an approach that uses nanodiscs and planar lipid bilayer electrophysiology to afford microsecond resolution at the single event level. Both pore size and stability were affected by SNARE copy number. Increasing the number of vesicle (v)-SNAREs per nanodisc from three to five caused a twofold increase in pore size and decreased the rate of pore closure by more than three orders of magnitude. Moreover, pairing of v-SNAREs and target (t)-SNAREs to form trans-SNARE complexes was highly dynamic: flickering nascent pores closed upon addition of a v-SNARE fragment, revealing that the fully assembled, stable SNARE complex does not form at this stage of exocytosis. Finally, a deletion at the base of the SNARE complex, which mimics the action of botulinum neurotoxin A, markedly reduced fusion pore stability. In summary, trans-SNARE complexes are dynamic, and the number of SNAREs recruited to drive fusion determines fundamental properties of individual pores. PMID- 29420482 TI - Saving lives and property with accurate flood forecasts. PMID- 29420481 TI - Many mutations in one clinical-trial basket. PMID- 29420484 TI - Existing rules cover gene-drive applications. PMID- 29420483 TI - Geneticists unravel secrets of super-invasive crayfish. PMID- 29420485 TI - Truck tracks, wolf lawsuit and a fertility first. PMID- 29420486 TI - Quest for publication metrics undermines regional research. PMID- 29420488 TI - The science that's never been cited. PMID- 29420487 TI - Kid co-authors in South Korea spur government probe. PMID- 29420489 TI - Bulgaria in the cold as European Union freezes its innovation funding. PMID- 29420490 TI - Fossil-fuel subsidies assessed. PMID- 29420491 TI - Maths classification is getting a revision. PMID- 29420492 TI - Protect the neglected half of our blue planet. PMID- 29420494 TI - Don't belittle junior researchers in meetings. PMID- 29420495 TI - Solitons divide and conquer. PMID- 29420496 TI - Big data needs a hardware revolution. PMID- 29420498 TI - UN agency targets black-carbon pollution from ships. PMID- 29420500 TI - A chirp, a roar and a whisper. PMID- 29420502 TI - Smoking gun for a rare mutation mechanism. PMID- 29420501 TI - How decolonization could reshape South African science. PMID- 29420503 TI - Evolutionary race as predators hunt prey. PMID- 29420504 TI - How going green can raise cash for your lab. PMID- 29420505 TI - Let's move beyond the rhetoric: it's time to change how we judge research. PMID- 29420506 TI - Strategy for making safer opioids bolstered. PMID- 29420507 TI - Wood made denser and stronger. PMID- 29420508 TI - Restore justice in Turkey. PMID- 29420509 TI - Debate blooms over anatomy of the world's first flower. PMID- 29420511 TI - Baleen whale species on brink of extinction for first time in 300 years. PMID- 29420512 TI - Bitcoin's alarming carbon footprint. PMID- 29420513 TI - Epidemics which never came: yellow fever (1883) and bubonic plague (1902-1903) in Baja California AB - This paper seeks to clarify the epidemic panorama that was generated in Baja California in the late nineteenth and early twentieth 20th century's, specifically that occurred in 1883 and 1902, years in which it is claimed occurred epidemics of yellow fever and bubonic plague respectively. However, as demonstrated in our study they never occurred due to social-demographic conditions in the area. PMID- 29420514 TI - Mortality of young people with cancer: clinical-epidemiological characteristics of death and emerging ethical aspects AB - Objective: To describe the epidemiological, clinical, and ethical aspects of the mortality of young people with cancer in Mexico. Methods: 63 medical records from 14 to 18-year-old patients, with cancer, who died between 2011 and 2014, were reviewed to obtain epidemiological and clinical characteristics of their death. The study sites were three tertiary referral hospitals in Mexico City. Results: Of 40 young people in terminal phase, 16 (40%) continued to receive curative treatment; of the 51 whose place of death was known, 45 (88%) died in hospital. Of the 41 who died within 30 days of their last hospitalization, deaths were due to complications (51%), progression of the disease (41%), and deaths of those in palliative care (7%). Conclusions: Oncological practice rests on what is known as a biomedical model. The results of this study suggest the urgent need for, and support the implementation of, true palliative-care services. More importantly, these findings underscore the necessity of putting the ethics of clinical practice into action, such that best practice in medicine is reinforced. PMID- 29420515 TI - Preprints in biomedicine: alternative or complement to the traditional model of publication? AB - The peer-review system has allowed the quality control of the manuscripts submitted for publication to scientific journals for over three centuries. However, due to its relative slowness and other drawbacks, some researchers, mainly in the areas of Physics and Mathematics, started some decades ago to propagate, by electronic means, manuscripts not yet submitted to a journal for formal publication. The dissemination of this practice led to the establishment of permanent repositories like ArXiv, to which preprints can be sent to be published whitou charge, allowing also the search and download of the works they containwith no payment required from the reader. In biomedical sciences, the adoption of the system has been slower than in the exact sciences and previous attempts like e-biomed, Netprints, and Nature Precedings did not prosper. A new generation of repositories like bioRXiv, inspired by ArXiv, seems to enjoy an increasing acceptance among biomedical researchers. Here, we discuss the potential role of this emerging system to establish discovery priority in biomedicine and to improve manuscripts before they are submitted to scientific journals besides other applications which could be implemented in the extent that the model becomes more popular. PMID- 29420516 TI - Effects of a minor surgery on health related quality of life in children from different perspectives AB - Objective: To compare the health related quality of life (HRQoL) perceptions in parents and physician regarding the patient undergoing ambulatory surgery, and to analyse the evolution of HRQoL before and after the ambulatory surgery. Method: 36 patients underwent ambulatory surgical interventions taken part in this study. The questionnaires EQ-5D-Y were administered to the patients and questionnaires EQ-5D-Y proxy to parents and physicians. Variable TTO was used. Results: Statistical differences were found at baseline between answers of patients and physicians (p < 0.05). However, after surgery, answers of patients and proxies were similar. Conclusions: Paediatric patients undergone to a minor surgery improve HRQoL after the operation and this improvement goes on a month after the surgery. PMID- 29420517 TI - Frequency of subgroups of the antigen "a" among volunteer donors AB - Introduction: The presence of weak variants of blood type A represents a challenge in the practice of immunohematology fordiscrepancies in the time of the classification. It is common in blood banks to perform a forward and reverse typing for thepurpose of confirming the blood type, but not all the people with a subgroup A2 have developed anti-A1 antibodies. Objective: We present a descriptive, observational and transversal study that establishes the proportion of subgroups of A antigen with the analysis of manual tube technique and monoclonal antibodies like anti-A, anti-A1 (Dolichus biflorus lectins extract) and anti-H. Methods: The analysis involved a total of 818 samples of voluntary blood donor, selected by random sampling, which were initially classified as 737 of Type A, and 81 as Type AB, with a confidence level of 95% (alpha error of 5% and 3% of precision). Results: The present study evaluated the existence of the subgroups A1, A2, A1B, A2B, A intermediate and A intB. Conclusions: It is recommended the identification of subgroups in different types of blood in the laboratory and blood banks. PMID- 29420518 TI - Gabapentine 300 mg vs. 450 mg as anesthetic premedication for reactive hypertension, anxiety and analgesia AB - Objective: Observe the behavior of gabapentin to reduce reactive hypertension secondary to anxiety and pain in patientsundergoing ophthalmic surgery as well as opioid consumption between groups. Method: Clinical randomized double blind controlled trial that analyzed 125 patients divided into three groups: Group A, gabapentin 300 mg; Group B, gabapentin 450 mg; and Group C, amaranth dragees as a control 2 h before the surgical procedure. Chi-squared test was used in sociodemographic variables and one-way ANOVA for continuous numeric variables. It was considered as significant a p < 0.05 for a study of two tails with a power of 80% beta. Results: Anxiety and analgesia intraoperative and postoperative had significant differences between groups. Lower consumption of opioid was found in the groups that used gabapentin. Conclusions: Gabapentin orally 300 or 450 mg h prior to surgery reduces pain, anxiety and postoperative opioid consumption in patients undergoing ophthalmic surgery. PMID- 29420519 TI - Dermatologists happiness and satisfaction AB - Objective: To assess the level of happiness and satisfaction in the life and medical practice of dermatologists in Mexico. Method: A descriptive study (online survey) was conducted focused on practicing dermatologists in our country. Questions included demographic characteristics, the Pemberton happiness index (with local validation) and questions that assessed the degree of personal satisfaction. Descriptive statistics were used to obtain the central tendency and dispersion. Measures of central tendency and dispersion were performed; to compare categorical variables, contingency tables for chi-square test were used and when comparing quantitative variables with normal distribution, Student's t t test was used. Results: 219 surveys were included, 72.6% female and 27.4% male, with an average age of 45.6 and an average of 16 years of medical practice. Most of them (64.8%) graduate from Mexico City; 93% were very satisfied with the specialty and 98.6% of them would choose the same once again, the most important reason is to encompass medical and surgical areas. The level of happiness by using the Pemberton scale was "high" (mode: 9.11; standard deviation: 1.73). Conclusions: This first study in Latin America on this subject in dermatologists showed high levels of satisfaction and happiness in both professional and personal areas. PMID- 29420520 TI - Frecuency of antigens and alloantibodies of Diego system in blood AB - Introduction: The Diego blood group is an irregular blood system which has been involved in cases of hemolytic disease of the newborn and post transfusion reactions, in this system have been identified 22 erythrocyte antigens, among which the pair Dia/Dib is the most important because those have the most immunogenic potential. Objective: This research aims to determine the frequency of antigen Dia and their respective alloantibody in the Ecuadorian population. Methods: It was performed a simple random sampling in the donor population, being later tested tube agglutination by the presence or absence of the antigen and its alloantibody Dia applying gel agglutination technique. Results: It was observed an antigen prevalence of 25% against a 6.09%of percentage alloimmunization due to Dia antigen, without significant differences between men and women and these being independent of the age and origin of the donor, showing that there are some Diego positive cases in Ecuadorian population as probably cases of transfusional alloinmunization or due to fetal-maternal alloinmunization. Conclusions and Recommendations: The frequency distribution of antigens and alloantibodies from the Diego blood group is almost uniform in the population, due presumably to the high incidence of miscegenation in our country. Therefore it becomes vitally important the implementation of this blood system inside the protocols of irregular antibodies identification in Ecuadorian blood banks. PMID- 29420521 TI - Strawberry polyphenols decrease oxidative stress in chronic diseases AB - Consumption of hypercaloric diets leads to increase of free fatty acids (FFA), pro-inflammatory cytokines and production of oxygen and nitrogen reactive species. These alterations induce oxidative and nitrosative stress causing dysfunction of tissues and consequently the development of chronic diseases. Therefore, it is important to decrease oxidative stress and thus preventing the development of these diseases. Strawberry has a lot of Vitamin C and polyphenols, compounds with excellent antioxidant properties, which may be an option for reducing oxidative stress and therefore to prevent the development of some diseases. Studies conducted in vitro in animal models and clinical studies support that this fruit can be a good alternative to reduce oxidative stress and thus reducing and/or preventing the development of diseases in humans. PMID- 29420522 TI - Association of risk factors with primary open angle glaucoma in adults over the age of 40 AB - Objective: To determine the association of systemic diseases, as well as smoking and alcohol with primary open-angle glaucoma (POAG) in adults over 40 years age. Method: A revision of the records of patients older than 40 years aged who had been diagnosed with glaucoma, which were selected at the outpatient care dept. Information was obtained through the automated hospital information system, which included socio-demographic and clinical variables. Data base was created and was processed by SPSS V20 program. Results: 1,020 patient, 548 (53.7%) with a diagnosis of POAG, mean age of patients 73.2 +/- 11.16 years, of which 193 (35.2%) were male and 355 (64.8%) female. A significant relationship was found between POAG and increasing age (p = 0.000), diabetes mellitus (p = 0.056) and hypertension (p = 0.098). While no relationship was found between POAG and cancer, smoking and alcohol intake was found. Conclusions: These results display the need of carrying out more specific studies of causal type to establish best possible partnerships and thus carry out prevention programs for early diagnosis. PMID- 29420523 TI - From Romanticism and fiction to reality: Dippel, Galvani, Aldini and "the Modern Prometheus". Brief history of nervous impulse AB - Mary Wollstonecraft Godwin, better known as Mary Shelley, and her romantic vision of the world gave life to an endless progeny of literacy stories; also originated the myth of the mortal creator who generate life from science. Unexpectedly the history has been considered as a myth, due to acts grounded in facts of certain "truthful;" such were galvanism and the study of the electrical potential in living beings by the two Italian physicians: Luigi Galvani and Giovanni Aldini. Also, is possible to proclaim direct influence on the work by the European folklore surrounding the theologian, alchemist Johann Konrad Dippel and physician who habited the Frankenstein's Castle from his birth, and further developing the "life elixir." The similarities between the novel and the life of the three historical figures suggests that Mary Shelley, belonging to a socially graceful and educated class, was aware of the scientific dispute over the understanding of electricity. Shelley's creative world, full of gothic and romantic hues, shows direct influence of alchemy speaking of the "spark of life" as well as works published by Galvani and Aldini. PMID- 29420524 TI - Analysis of cutaneous pigmentation in a sample AB - Background: The blend of hemoglobin, carotenes, and melanin defines the skin color. Constitutive pigmentation is genetically determined, facultative color is induced when skin is exposed to environment. The objective was to quantify both pigmentations in a sample of Mexican population and to analyze its relationship with sex, age, and phototype. Methods: We evaluated 259 individuals during the winter. Skin colorimetry was obtained by diffuse reflectance spectrometry, using the International Commission of Illumination coordenates. L*a*b* parameters were measured and the individual typological angle (ITA) was estimated from forehead, thorax, neck, forearms, and buttocks areas. Results: Facultative pigmentation differed from constitutive in L*, a*, and ITA degrees values. In men, L* and ITA degrees parameters were lower. Constitutive pigmentation was similar between sexes. Phototypes III, IV, and V showed differences in L*, b*, and ITA degrees . Facultative values such as L*, a*, ATI degrees , and the constitutive a* reduce as age increases. Conclusions: The cutaneous tones of a sample of population were quantified recognizing their values for white, light brown, and dark brown skin. A reference frame for research related to cutaneous pigmentationin Mexico is presented. PMID- 29420525 TI - History of Medicine is a science PMID- 29420526 TI - Typhus, yellow fever and Medicine in Mexico during the French intervention AB - French intervention in Mexico (1861-1867) is particularly full of episodes of patriotic heroism in terms of military, politic and, even, religious affairs, however this history is also rich in episodes related to diseases and the evolution of Mexican scientific medicine practice, epidemics such as typhus (nowadays knows as rickettsiosis), yellow fever, or cholera. Principally, this context outlined the Mexican history and influenced the course of the nation. The epidemics served as fertile land for the development of medicine science leading by prominent physicians, particularly by doctor Miguel Francisco Jimenez. PMID- 29420527 TI - Etiology of cutaneous vasculitis: utility of a systemic approach AB - : Cutaneous vasculities (CV) represents a diagnostic challenge, occurs as primary cutaneous disorder or as a manifestation ofother entities. Objective: To search the cause of CV. Methods: Patients with CV were prospectively evaluated. In all patients, skin biopsies were drawn, and direct immunofluorescence was done in most of the patients. American College of Rheumatology (ACR) and Chapel Hill Consensus Conference Criteria (CHCC) were used for classification. Results: 32 patients were studied. There was female predominance (71.8%). Children presented drug-associated CV or Schonlein-Henoch purpura (SHP). Adults presented more frequently SHP, systemic lupus erythematosus or paraneoplastic vasculitis, other diagnosis as polyarteritis nodosa, microscopic polyangiitis, thrombotic vasculitis (post-puerperal), antiphospholipid syndrome, Churg-Strauss syndrome, and drug-associated CV were presented. Using the ACR and CHCC criteria, 50% of cases were classified. Discussion: In our institution, during this work the etiologic diagnostic of CV increased more than twice. However, in the case of HSV or LA and SHP none of the proposed criteria had high specificity; other parameters were used to discern between both. Six patients remained as not classified. In our view, cryoglobulins and hepatitis serology do not seem useful unless patient's history supports they need to be done. Unclassified patients were followed-up closely for 2 years. PMID- 29420528 TI - Assessment of the methodological and ethical quality of clinical trials published in family medicine journals AB - Objective: To evaluate some methodological and ethical quality variables of clinical trials (CTs) published in 10 family medicinejournals. Methods: Quality descriptive study of 10 family medicine journals including CTs in humans published since 2010 to 2013. We obtained 141 CT and 2447 were excluded. Results: CTs parallels controlled in 92.9% (95% confidence interval [95% CI]: 92.0-93.9). Masked randomization in 72.3% (95% CI: 71.7-73.1), decentralized in 51.8% (95% CI: 51.4-52.4) and using as control an active treatment in 82.2% (95% CI: 81.5 83.1). Wrote informed consent in 48.9% (95% CI: 48.5-49.5) and it was not withdrawn in 56.0% of cases (95% CI: 55.5-56.7). Approval by clinical research ethics committee (CREC) in 134, and there was no conflict of interest in 117 CTs. Average kappa was 0.96 (95% CI: 0.93-0.99). Conclusions: We observe an increase in some quality variables like masked randomization (19.6%) and approval by CREC (75%) post CONSORT, in CTs published in 10 family medicine journals (2010-2013). PMID- 29420529 TI - Vbeta T cell receptor (TCR) genes in circulating cells of patients with systemic lupus erythematosus and their healthy relatives AB - Objective: We investigated the proportion of Vbeta T cell receptor (TCR) gene expression in peripheral CD3+ lymphocytes in familial and non-familial systemic lupus erythematosus (SLE) patients. Method: The Vbeta TCR repertoire was studied in 14 families in which several members had SLE. The Vbeta TCR usage in SLE patients (n = 27) was compared with that in healthy members of these multiplex families (n = 47), in 37 sporadic SLE patients who had no relatives with SLE, and in 15 healthy unrelated controls. Vbeta TCR repertoire expression was studied by multiparameter flow cytometry with the use of an array of 24 different Vbeta TCR gene family-specific monoclonal antibodies. Results: We found the same Vbeta TCR expression profile in the comparisons between sporadic SLE and familial SLE cases and healthy relatives, which included increased expression of Vbeta 5.2, Vbeta 11 and Vbeta 16, and lower expression of Vbeta 3, Vbeta 4, Vbeta 7.1 and Vbeta 17. Interestingly, solely Vbeta 17 was differentially expressed among sporadic and familial SLE. Also, increased expression of Vbeta 9 was the hallmark among familial SLE (casesand h ealthy relatives) in comparison to controls. Conclusion: These results highlight the notion that the final profile of the Vbeta TCR repertoire seen in familial and non-familial SLE seems to arise from the interaction of genetic, environmental, and immunoregulatory factors. Furthermore, it may contribute to the immunologic abnormalities affecting relatives of SLE patients. PMID- 29420530 TI - Complications associated to percutaneous catheter in preterm and term born children AB - Objective: Identify percutaneous catheter-related complications in preterm and term newborns. Methods: Comparative cross-section. Were included newborns whit percutaneous catheter insertion, blood culture results and distal catheter segment. Were formed two groups: Preterm and term. Results: Were analyzed the data of preterm (n = 50) and term (n = 50) newborn, the gestational age was 30 +/ 3 and 40 +/- 2 (p = 0.01). The frecuency in preterm and term newborn was respectively, sepsis catheter 36 and 18% (p = 0.02; OR: 2.56; 95% CI: 1.02-7.17), infected catheter 50 and 22% (p = 0.01; OR: 5.92; 95% CI: 1.66-23.12), colonized catheter of 24 and 14% (p = 0.01; OR: 3.58; 95% CI: 1.32-9.90), local infection 14 and 8% (p = 0.03; OR: 1.87; 95% CI: 1.45-8.29), infiltration 18 and 4% (p = 0.02; OR: 5.27; 95% CI: 1.17-59), accidental removal 6 and 22% (p = 0.02; OR: 0.23; 95% CI: 0.05-0.87) and catheter rupture 10 and 28% (p = 0.02; OR: 0.29; 95% CI: 0.08-0.98). Conclusions: We found a higher association of infections and infiltrations by percutaneous catheter in preterm and term prevailed in accidental removal and catheter rupture. PMID- 29420531 TI - Differential roles of the Drosophila EMT-inducing transcription factors Snail and Serpent in driving primary tumour growth. AB - Several transcription factors have been identified that activate an epithelial-to mesenchymal transition (EMT), which endows cells with the capacity to break through basement membranes and migrate away from their site of origin. A key program in development, in recent years it has been shown to be a crucial driver of tumour invasion and metastasis. However, several of these EMT-inducing transcription factors are often expressed long before the initiation of the invasion-metastasis cascade as well as in non-invasive tumours. Increasing evidence suggests that they may promote primary tumour growth, but their precise role in this process remains to be elucidated. To investigate this issue we have focused our studies on two Drosophila transcription factors, the classic EMT inducer Snail and the Drosophila orthologue of hGATAs4/6, Serpent, which drives an alternative mechanism of EMT; both Snail and GATA are specifically expressed in a number of human cancers, particularly at the invasive front and in metastasis. Thus, we recreated conditions of Snail and of Serpent high expression in the fly imaginal wing disc and analysed their effect. While either Snail or Serpent induced a profound loss of epithelial polarity and tissue organisation, Serpent but not Snail also induced an increase in the size of wing discs. Furthermore, the Serpent-induced tumour-like tissues were able to grow extensively when transplanted into the abdomen of adult hosts. We found the differences between Snail and Serpent to correlate with the genetic program they elicit; while activation of either results in an increase in the expression of Yorki target genes, Serpent additionally activates the Ras signalling pathway. These results provide insight into how transcription factors that induce EMT can also promote primary tumour growth, and how in some cases such as GATA factors a 'multi hit' effect may be achieved through the aberrant activation of just a single gene. PMID- 29420532 TI - The feasibility of equilibria in large ecosystems: A primary but neglected concept in the complexity-stability debate. AB - The consensus that complexity begets stability in ecosystems was challenged in the seventies, a result recently extended to ecologically-inspired networks. The approaches assume the existence of a feasible equilibrium, i.e. with positive abundances. However, this key assumption has not been tested. We provide analytical results complemented by simulations which show that equilibrium feasibility vanishes in species rich systems. This result leaves us in the uncomfortable situation in which the existence of a feasible equilibrium assumed in local stability criteria is far from granted. We extend our analyses by changing interaction structure and intensity, and find that feasibility and stability is warranted irrespective of species richness with weak interactions. Interestingly, we find that the dynamical behaviour of ecologically inspired architectures is very different and richer than that of unstructured systems. Our results suggest that a general understanding of ecosystem dynamics requires focusing on the interplay between interaction strength and network architecture. PMID- 29420533 TI - Drosophila Gr64e mediates fatty acid sensing via the phospholipase C pathway. AB - Animals use taste to sample and ingest essential nutrients for survival. Free fatty acids (FAs) are energy-rich nutrients that contribute to various cellular functions. Recent evidence suggests FAs are detected through the gustatory system to promote feeding. In Drosophila, phospholipase C (PLC) signaling in sweet sensing cells is required for FA detection but other signaling molecules are unknown. Here, we show Gr64e is required for the behavioral and electrophysiological responses to FAs. GR64e and TRPA1 are interchangeable when they act downstream of PLC: TRPA1 can substitute for GR64e in FA but not glycerol sensing, and GR64e can substitute for TRPA1 in aristolochic acid but not N methylmaleimide sensing. In contrast to its role in FA sensing, GR64e functions as a ligand-gated ion channel for glycerol detection. Our results identify a novel FA transduction molecule and reveal that Drosophila Grs can act via distinct molecular mechanisms depending on context. PMID- 29420534 TI - Strategies to improve treatment coverage in community-based public health programs: A systematic review of the literature. AB - BACKGROUND: Community-based public health campaigns, such as those used in mass deworming, vitamin A supplementation and child immunization programs, provide key healthcare interventions to targeted populations at scale. However, these programs often fall short of established coverage targets. The purpose of this systematic review was to evaluate the impact of strategies used to increase treatment coverage in community-based public health campaigns. METHODOLOGY/ PRINCIPAL FINDINGS: We systematically searched CAB Direct, Embase, and PubMed archives for studies utilizing specific interventions to increase coverage of community-based distribution of drugs, vaccines, or other public health services. We identified 5,637 articles, from which 79 full texts were evaluated according to pre-defined inclusion and exclusion criteria. Twenty-eight articles met inclusion criteria and data were abstracted regarding strategy-specific changes in coverage from these sources. Strategies used to increase coverage included community-directed treatment (n = 6, pooled percent change in coverage: +26.2%), distributor incentives (n = 2, +25.3%), distribution along kinship networks (n = 1, +24.5%), intensified information, education, and communication activities (n = 8, +21.6%), fixed-point delivery (n = 1, +21.4%), door-to-door delivery (n = 1, +14.0%), integrated service distribution (n = 9, +12.7%), conversion from school- to community-based delivery (n = 3, +11.9%), and management by a non-governmental organization (n = 1, +5.8%). CONCLUSIONS/SIGNIFICANCE: Strategies that target improving community member ownership of distribution appear to have a large impact on increasing treatment coverage. However, all strategies used to increase coverage successfully did so. These results may be useful to National Ministries, programs, and implementing partners in optimizing treatment coverage in community based public health programs. PMID- 29420535 TI - Sociodemographic, obstetric characteristics, antenatal morbidities, and perinatal depressive symptoms: A three-wave prospective study. AB - OBJECTIVES: This study aimed (1) to investigate the pattern of perinatal depressive symptoms, and (2) to determine the relationships between sociodemographic characteristics, obstetric factors, antenatal morbidities, postnatal conditions, and perinatal depressive symptoms using a structural equation model (SEM). METHOD: A three-wave prospective longitudinal design was used for 361 women in their second trimester, third trimester, and at six weeks postpartum. The Edinburgh Postnatal Depression Scale (EPDS) was used to assess the depressive symptoms. RESULTS: The intensity of depressive symptoms was the highest in the second trimester among the three waves. The SEM showed that unmarried status, unplanned pregnancy, gestational diabetes, and headache were significantly associated with EPDS in the first and second waves. The EPDS in the first wave was able to predict the EPDS in the second and third waves. The SEM has satisfactorily fit with the data (chi-square/degree of freedom = 1.42, incremental fit index = 0.91, Tucker-Lewis index = 0.90, comparative fit index = 0.91, and root mean square error of approximation = 0.03). CONCLUSION: The findings highlight the significance of monitoring depressive symptoms in the second trimester. Findings from this study could be useful in the design of effective intervention among women with unmarried status, unplanned pregnancy, gestational diabetes, and headache in order to reduce risk of perinatal depressive symptoms. PMID- 29420536 TI - Randomized trial of one-hour sodium bicarbonate vs standard periprocedural saline hydration in chronic kidney disease patients undergoing cardiovascular contrast procedures. AB - BACKGROUND: Guidelines advise periprocedural saline hydration for prevention of contrast induced-acute kidney injury (CI-AKI). We analysed whether 1-hour sodium bicarbonate hydration administered solely prior to intra-arterial contrast exposure is non-inferior to standard periprocedural saline hydration in chronic kidney disease (CKD) patients undergoing elective cardiovascular diagnostic or interventional contrast procedures. METHODS: We performed an open-label multicentre non-inferiority trial between 2011-2014. Patients were randomized to 1 hour pre-procedure sodium bicarbonate hydration (250 ml 1.4%, N = 168) or 4-12 hours saline hydration (1000 ml 0.9%, N = 165) prior to and following contrast administration (2000 ml of saline total). Primary outcome was the relative serum creatinine increase (%) 48-96 hours post contrast exposure. Secondary outcomes were: incidence of CI-AKI (serum creatinine increase>25% or >44MUmol/L), recovery of renal function, the need for dialysis, and hospital costs within two months follow-up. RESULTS: Mean relative creatinine increase was 3.1% (95%CI 0.9 to 5.2%) in the bicarbonate and 1.1% (95%CI -1.2 to 3.5%) in the saline arm, mean difference 1.9% (95%CI -1.2 to 5.1%, p-non-inferiority <0.001). CI-AKI occurred in 11 (6.7%) patients randomized to sodium bicarbonate and 12 (7.5%) to saline (p = 0.79). Renal function did not fully recover in 40.0% and 44.4% of CI-AKI patients, respectively (p = 0.84). No patient required dialysis. Mean costs for preventive hydration and clinical preparation for the contrast procedure were $1158 for sodium bicarbonate vs. $1561 for saline (p < 0.001). CONCLUSION: Short hydration with sodium bicarbonate prior to elective cardiovascular diagnostic or therapeutic contrast procedures is non-inferior to standard periprocedural saline hydration in CKD patients with respect to renal safety and results in considerable healthcare savings. TRIAL REGISTRATION: Netherlands Trial Register (http://www.trialregister.nl/trialreg/index.asp), Nr NTR2699. PMID- 29420537 TI - Paediatric schistosomiasis: What we know and what we need to know. AB - Schistosomiasis affects over 200 million people worldwide, most of whom are children. Research and control strategies directed at preschool-aged children (PSAC), i.e., <=5 years old, have lagged behind those in older children and adults. With the recent WHO revision of the schistosomiasis treatment guidelines to include PSAC, and the recognition of gaps in our current knowledge on the disease and its treatment in this age group, there is now a concerted effort to address these shortcomings. Global and national schistosome control strategies are yet to include PSAC in treatment schedules. Maximum impact of schistosome treatment programmes will be realised through effective treatment of PSAC. In this review, we (i) discuss the current knowledge on the dynamics and consequences of paediatric schistosomiasis and (ii) identify knowledge and policy gaps relevant to these areas and to the successful control of schistosome infection and disease in this age group. Herein, we highlight risk factors, immune mechanisms, pathology, and optimal timing for screening, diagnosis, and treatment of paediatric schistosomiasis. We also discuss the tools required for treating schistosomiasis in PSAC and strategies for accessing them for treatment. PMID- 29420538 TI - Th-POK regulates mammary gland lactation through mTOR-SREBP pathway. AB - The Th-inducing POK (Th-POK, also known as ZBTB7B or cKrox) transcription factor is a key regulator of lineage commitment of immature T cell precursors. It is yet unclear the physiological functions of Th-POK besides helper T cell differentiation. Here we show that Th-POK is restrictedly expressed in the luminal epithelial cells in the mammary glands that is upregulated at late pregnancy and lactation. Lineage restrictedly expressed Th-POK exerts distinct biological functions in the mammary epithelial cells and T cells in a tissue specific manner. Th-POK is not required for mammary epithelial cell fate determination. Mammary gland morphogenesis in puberty and alveologenesis in pregnancy are phenotypically normal in the Th-POK-deficient mice. However, Th-POK deficient mice are defective in triggering the onset of lactation upon parturition with large cellular lipid droplets retained within alveolar epithelial cells. As a result, Th-POK knockout mice are unable to efficiently secret milk lipid and to nurse the offspring. Such defect is mainly attributed to the malfunctioned mammary epithelial cells, but not the tissue microenvironment in the Th-POK deficient mice. Th-POK directly regulates expression of insulin receptor substrate-1 (IRS-1) and insulin-induced Akt-mTOR-SREBP signaling. Th-POK deficiency compromises IRS-1 expression and Akt-mTOR-SREBP signaling in the lactating mammary glands. Conversely, insulin induces Th-POK expression. Thus, Th POK functions as an important feed-forward regulator of insulin signaling in mammary gland lactation. PMID- 29420540 TI - Perceived class climate and school-aged children's life satisfaction: The role of the learning environment in classrooms. AB - The aim of this study is to examine the impact of class-level class climate on school-aged children's life satisfaction. Data was derived from the German National Educational Panel Study (NEPS) using sixth grade school-aged children (n = 4,764, 483 classes). Class climate includes indicators of teachers' care and monitoring, demands, interaction, autonomy, as well as school-aged children's attitudes towards schoolwork at the class- and individual-level. Results showed that individual perceived class climate in terms of teachers' care and monitoring and autonomy was positively related to life satisfaction, whereas school-related demands were related to lower life satisfaction. Besides teachers' care and monitoring at class-level, indicators of class climate were not associated with school-aged children's life satisfaction, while the individual perceived class climate is more important for life satisfaction. PMID- 29420539 TI - Characteristics of inflammatory reactions during development of liver abscess in hamsters inoculated with Entamoeba nuttalli. AB - BACKGROUND: Entamoeba nuttalli is an intestinal protozoan with pathogenic potential that can cause amebic liver abscess. It is highly prevalent in wild and captive macaques. Recently, cysts were detected in a caretaker of nonhuman primates in a zoo, indicating that E. nuttalli may be a zoonotic pathogen. Therefore, it is important to evaluate the pathogenicity of E. nuttalli in detail and in comparison with that of E. histolytica. METHODOLOGY/PRINCIPAL FINDINGS: Trophozoites of E. nuttalli GY4 and E. histolytica SAW755 strains were inoculated into liver of hamsters. Expression levels of proinflammatory factors of hamsters and virulence factors from E. histolytica and E. nuttalli were compared between the two parasites. Inoculations with trophozoites of E. nuttalli resulted in an average necrotic area of 24% in liver tissue in 7 days, whereas this area produced by E. histolytica was nearly 50%. Along with the mild liver tissue damage induced by E. nuttalli, expression levels of proinflammatory factors (TNF alpha, IL-6 and IL-1beta) and amebic virulence protein genes (lectins, cysteine proteases and amoeba pores) in local tissues were lower with E. nuttalli in comparison with E. histolytica. In addition, M2 type macrophages were increased in E. nuttalli-induced amebic liver abscesses in the late stage of disease progression and lysate of E. nuttalli trophozoites induced higher arginase expression than E. histolytica in vitro. CONCLUSIONS/SIGNIFICANCE: The results show that differential secretion of amebic virulence proteins during E. nuttalli infection triggered lower levels of secretion of various cytokines and had an impact on polarization of macrophages towards a M1/M2 balance. However, regardless of the degree of macrophage polarization, there is unambiguous evidence of an intense acute inflammatory reaction in liver of hamsters after infection by both Entamoeba species. PMID- 29420541 TI - Genetic compensation triggered by actin mutation prevents the muscle damage caused by loss of actin protein. AB - The lack of a mutant phenotype in homozygous mutant individuals' due to compensatory gene expression triggered upstream of protein function has been identified as genetic compensation. Whilst this intriguing process has been recognized in zebrafish, the presence of homozygous loss of function mutations in healthy human individuals suggests that compensation may not be restricted to this model. Loss of skeletal alpha-actin results in nemaline myopathy and we have previously shown that the pathological symptoms of the disease and reduction in muscle performance are recapitulated in a zebrafish antisense morpholino knockdown model. Here we reveal that a genetic actc1b mutant exhibits mild muscle defects and is unaffected by injection of the actc1b targeting morpholino. We further show that the milder phenotype results from a compensatory transcriptional upregulation of an actin paralogue providing a novel approach to be explored for the treatment of actin myopathy. Our findings provide further evidence that genetic compensation may influence the penetrance of disease causing mutations. PMID- 29420542 TI - Host preferences support the prominent role of Hyalomma ticks in the ecology of Crimean-Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne zoonotic agent that is maintained in nature in an enzootic vertebrate-tick-vertebrate cycle. Hyalomma genus ticks have been implicated as the main CCHFV vector and are key in maintaining silent endemic foci. However, what contributes to their central role in CCHFV ecology is unclear. To assess the significance of host preferences of ticks in CCHFV ecology, we performed comparative analyses of hosts exploited by 133 species of ticks; these species represent 5 genera with reported geographical distribution over the range of CCHFV. We found that the composition of vertebrate hosts on which Hyalomma spp. feed is different than for other tick genera. Immatures of the genus Hyalomma feed preferentially on species of the orders Rodentia, Lagomorpha, and the class Aves, while adults concentrate mainly on the family Bovidae. With the exception of Aves, these hosts include the majority of the vertebrates consistently reported to be viremic upon CCHFV infection. While other tick genera also feed on these hosts, Hyalomma spp. almost completely concentrate their populations on them. Hyalomma spp. feed on less phylogenetically diverse hosts than any other tick genus, implying that this network of hosts has a low resilience. Indeed, removing the most prominent hosts quickly collapsed the network of parasitic interactions. These results support the intermittent activity of CCHFV foci: likely, populations of infected Hyalomma spp. ticks exceed the threshold of contact with humans only when these critical hosts reach adequate population density, accounting for the sporadic occurence of clinical tick-transmitted cases. Our data describe the association of vertebrate host preferences with the role of Hyalomma spp. ticks in maintaining endemic CCHFV foci, and highlight the importance of host-tick dynamics in pathogen ecology. PMID- 29420543 TI - Does the chronic care model meet the emerging needs of people living with multimorbidity? A systematic review and thematic synthesis. AB - BACKGROUND: The Chronic Care Model (CCM) emerged in the 1990s as an approach to re-organize primary care and implement critical elements that enable it to proactively attend to patients with chronic conditions. The chronic care landscape has evolved further, as most patients now present with multiple chronic conditions and increasing psychosocial complexity. These patients face accumulating and overwhelming complexity resulting from the sum of uncoordinated responses to each of their problems. Minimally Disruptive Medicine (MDM) was proposed to respond to this challenge, aiming at improving outcomes that matter to patients with the smallest burden of treatment. We sought to critically appraise the extent to which MDM constructs (e.g., reducing patient work, improving patients' capacity) have been adopted within CCM implementations. METHODS: We conducted a systematic review and qualitative thematic synthesis of reports of CCM implementations published from 2011-2016. RESULTS: CCM implementations were mostly aligned with the healthcare system's goals, condition specific, and targeted disease-specific outcomes or healthcare utilization. No CCM implementation addressed patient work. Few reduced treatment workload without adding additional tasks. Implementations supported patient capacity by offering information, but rarely offered practical resources (e.g., financial assistance, transportation), helped patients reframe their biography with chronic illness, or assisted them in engaging with a supportive social network. Few implementations aimed at improving functional status or quality of life, and only one-third of studies were targeted for patients of low socioeconomic status. CONCLUSION: MDM provides a lens to operationalize how to care for patients with multiple chronic conditions, but its constructs remain mostly absent from how implementations of the CCM are currently reported. Improvements to the primary care of patients with multimorbidity may benefit from the application of MDM, and the current CCM implementations that do apply MDM constructs should be considered exemplars for future implementation work. PMID- 29420544 TI - Carotenoid coloration and health status of urban Eurasian kestrels (Falco tinnunculus). AB - As the world experiences rapid urban expansion, natural landscapes are being transformed into cities at an alarming rate. Consequently, urbanization is identified as one of the biggest environmental challenges of our time, yet we lack a clear understanding of how urbanization affects free-living organisms. Urbanization leads to habitat fragmentation and increased impervious surfaces affecting for example availability and quality of food. Urbanization is also associated with increased pollution levels that can affect organisms directly, via ecophysiological constraints and indirectly by disrupting trophic interactions in multi-species networks. Birds are highly mobile, while an individual is not necessarily exposed to urban stressors around the clock, but nestlings of altricial birds are. Such a city-dwelling species with a long nestling phase is the Eurasian kestrel (Falco tinnunculus) in Vienna, Austria, which forage on a diverse diet differing in composition from rural habitats. Furthermore, prey items vary in nutritional value and contents of micronutrients like carotenoids, which might impact the nestlings' health. Carotenoids are pigments that are incorporated into integument tissues but also have antioxidant and immunostimulatory capacity, resulting in a trade-off between these functions. In nestlings these pigments function in parent-offspring communication or sibling competition by advertising an individual's physical or physiological condition. Anthropogenic disturbance and pollutants could have disruptive effects on the coloration of these traits. In this study, we measured carotenoid based coloration and other indicators of individual health (body condition and susceptibility to the ectoparasite Carnus hemapterus) of 154 nestling kestrels (n = 91 nests) along an urban gradient from 2010 to 2015. We found skin yellowness of nestlings from nest-sites in the city-center to be least pronounced. This result might indicate that inner-city nestlings are strongly affected by urban stressors and depleted their stores of dietary carotenoids for health-related functions rather than coloration. In addition, skin yellowness intensified with age and was stronger pronounced in earlier nests. Since the immune system of nestlings is still developing, younger chicks might need more antioxidants to combat environmental stress. Additionally, parasite infection intensity was highest in nestlings with less intense skin yellowness (paler or less yellow pigmented integuments) and in earlier nests of the season. In combination with results from previous studies, our findings provide further support for the low quality of the inner-city habitat, both in terms of productivity and individual health. PMID- 29420545 TI - Association of gene polymorphism of SDF1(CXCR12) with susceptibility to HIV-1 infection and AIDS disease progression: A meta-analysis. AB - OBJECTIVES: Genetic polymorphism of viral receptors is relevant to risks of HIV-1 infection, while it is still under debated whether the polymorphism of SDF1, a unique ligand for HIV-1 coreceptor CXCR4, is associated with HIV susceptibility and AIDS disease progression. Therefore, we provided an updated quantitative assessment by meta-analysis from 16 case-control and 7 cohort studies. METHODS: Articles reporting the relationship between SDF1 polymorphism and HIV susceptibility or AIDS progression were retrieved from PubMed, Embase and Ovid electronic databases up to Apr 2017. Data were pooled by odds ratios (ORs) for HIV-1 infection with 95% confidence intervals (CIs) and summary relative hazards (RHs) for AIDS progression with 95% CIs using 1987 Center for Disease Control (CDC) case definition of AIDS (CDC87) and 1993 Center for Disease Control (CDC) case definition of AIDS (CDC93) and death as endpoints. RESULTS: As a result, 16 studies regarding susceptibility to HIV-1 infection with 2803 HIV-infected patients and 3697 healthy individuals and 7 studies regarding disease progression with 4239 subjects were included in the meta-analysis. For risks of infection, no evidences indicated SDF1 polymorphism was associated with the risk of HIV-1 infection in all genetic models (recessive model: OR = 0.94, 95% Cl: 0.75-1.17; homozygous model: OR = 0.89, 95% Cl: 0.70-1.15; heterozygous model: OR = 1.06, 95% Cl: 0.83-1.35; allele model: OR = 0.95, 95% Cl: 0.79-1.13), Furthermore, we failed to find an delayed AIDS progression except in some specific cohorts including MACS cohorts (RH = 0.38, 95% Cl: 0.17-0.59 for time to AIDS; RH = 0.27, 95% Cl: 0.07-0.46 for time to death at the study entry). CONCLUSIONS: Overall, no significant association was found between SDF1 polymorphism and HIV susceptibility. A protective effect of SDF1 on AIDS progression and death was seen especially in two studies based on the same cohorts. In conclusion, SDF1 polymorphism exerts a moderate protective effect against AIDS disease deterioration in some specific populations. PMID- 29420546 TI - Microbubbles combined with ultrasound therapy in ischemic stroke: A systematic review of in-vivo preclinical studies. AB - BACKGROUND: Microbubbles (MBs) combined with ultrasound sonothrombolysis (STL) appears to be an alternative therapeutic strategy for acute ischemic stroke (IS), but clinical results remain controversial. OBJECTIVE: The aim of this systematic review is to identify the parameters tested; to assess evidence on the safety and efficacy on preclinical data on STL; and to assess the validity and publication bias. METHODS: Pubmed(r) and Web of ScienceTM databases were systematically searched from January 1995 to April 2017 in French and English. We included studies evaluating STL on animal stroke model. This systematic review was conducted in accordance with the PRISMA guidelines. Data were extracted following a pre-defined schedule by two of the authors. The CAMARADES criteria were used for quality assessment. A narrative synthesis was conducted. RESULTS: Sixteen studies met the inclusion criteria. The result showed that ultrasound parameters and types of MBs were heterogeneous among studies. Numerous positive outcomes on efficacy were found, but only four studies demonstrated superiority of STL versus recombinant tissue-type plasminogen activator on clinical criteria. Data available on safety are limited. LIMITATIONS: Quality assessment of the studies reviewed revealed a number of biases. CONCLUSION: Further in vivo studies are needed to demonstrate a better efficacy and safety of STL compared to currently approved therapeutic options. SYSTEMATIC REVIEW REGISTRATION: http://syrf.org.uk/protocols/. PMID- 29420548 TI - Large-scale climatic phenomena drive fluctuations in macroinvertebrate assemblages in lowland tropical streams, Costa Rica: The importance of ENSO events in determining long-term (15y) patterns. AB - Understanding how environmental variables influence the distribution and density of organisms over relatively long temporal scales is a central question in ecology given increased climatic variability (e.g., precipitation, ENSO events). The primary goal of our study was to evaluate long-term (15y time span) patterns of climate, as well as environmental parameters in two Neotropical streams in lowland Costa Rica, to assess potential effects on aquatic macroinvertebrates. We also examined the relative effects of an 8y whole-stream P-enrichment experiment on macroinvertebrate assemblages against the backdrop of this long-term study. Climate, environmental variables and macroinvertebrate samples were measured monthly for 7y and then quarterly for an additional 8y in each stream. Temporal patterns in climatic and environmental variables showed high variability over time, without clear inter-annual or intra-annual patterns. Macroinvertebrate richness and abundance decreased with increasing discharge and was positively related to the number of days since the last high discharge event. Findings show that fluctuations in stream physicochemistry and macroinvertebrate assemblage structure are ultimately the result of large-scale climatic phenomena, such as ENSO events, while the 8y P-enrichment did not appear to affect macroinvertebrates. Our study demonstrates that Neotropical lowland streams are highly dynamic and not as stable as is commonly presumed, with high intra- and inter-annual variability in environmental parameters that change the structure and composition of freshwater macroinvertebrate assemblages. PMID- 29420547 TI - Coronary artery calcium before and after hospitalization with pneumonia: The MESA study. AB - BACKGROUND: Epidemiological analyses demonstrate that pneumonia survivors have a higher risk of myocardial infarction than people with similar load of risk factors for atherosclerotic cardiovascular disease (ASCVD) but without pneumonia. This may be due to a higher baseline burden of ASCVD in patients with pneumonia that is not captured by the accounting of known ASCVD risk factors in epidemiological analyses or to unfavorable accelerating effects of pneumonia on atherosclerosis. METHODS: We analyzed data from the Multi-Ethnic Study of Atherosclerosis. We identified 54 participants that were hospitalized for pneumonia during study follow-up and that also had assessment of coronary artery calcium (CAC, an objective marker of coronary atherosclerotic burden) before and after this hospitalization. We matched them to 54 participants who were not hospitalized for pneumonia but that had CAC assessments at the same study visits as the pneumonia cases. We compared baseline CAC scores and their progression between groups. RESULTS: Baseline CAC scores were similar in both groups (median [IQR]; 6.3 [0-356.8] in pneumonia participants vs. 10.8 [0-178.3] in controls; p = 0.25). After a median of 4.8 years, the direction and magnitude of CAC score change, and the slope of CAC score progression between groups was also similar (median change [IQR], 21.8 [0 to 287.29] in participants with pneumonia versus 15.8 [0 to 140.94] in controls, p = 0.28; difference in slope, 7.7, 95% CI -9.0 to 24.6, p = 0.18). However, among participants with high baseline ASCVD risk (i.e. ACC/AHA 10-year risk estimate >=7.5%), participants with pneumonia showed a larger increase in CAC scores (median change [IQR]; 159.10 [38.55-407.34] versus 48.72 [0.97-246.99] in controls; p = 0.02) and a trend towards a steeper slope of CAC score progression (difference in slope, 19.7, 95% CI -6.6 to 45.6, p = 0.07). CONCLUSION: Pneumonia may accelerate the progression of atherosclerosis in people with high baseline ASCVD risk. PMID- 29420549 TI - Contexts of vulnerability and the acceptability of new biomedical HIV prevention technologies among key populations in South Africa: A qualitative study. AB - BACKGROUND: New biomedical prevention technologies (NPTs) may contribute to substantially reducing incident HIV infections globally. We explored acceptability and preferences for NPTs among key and other vulnerable populations in two South African townships. METHODS: We conducted six focus groups and 12 in depth interviews with adolescents, and adult heterosexual men, women, and men who have sex with men (MSM) (n = 48), and eight in-depth interviews with key informant healthcare workers. The interview guide described pre-exposure prophylaxis (PrEP), vaginal rings, rectal microbicides and HIV vaccines, and explored acceptability and product preferences. Focus groups and in-depth interviews (45-80 minutes) were conducted in Xhosa, audiotaped, and transcribed and translated into English. Data were coded and reviewed using framework analysis with NVivo software. RESULTS: Overall, initial enthusiasm and willingness to use NPTs evolved into concerns about how particular NPTs might affect or require alterations in one's everyday lifestyle and practices. Different product preferences and motivations emerged by population based on similarity to existing practices and contexts of vulnerability. Adult women and female adolescents preferred a vaginal ring and HIV vaccine, motivated by longer duration of protection to mitigate feared repercussions from male partners, including threats to their marriage and safety, and a context of ubiquitous rape. Male adolescents preferred an HIV vaccine, seen as protection in serodiscordant relationships and convenient in obviating the HIV stigma and cost involved in buying condoms. Adult men preferred PrEP, given familiarity with oral medications and mistrust of injections, seen as enabling serodiscordant couples to have a child. MSM preferred a rectal microbicide given familiarity with gel-based lubricants, with concerns about duration of protection in the context of unplanned consensual sex and rape. CONCLUSIONS: Biomedical interventions to prevent HIV transmission, rather than obviating social-structural factors that produce vulnerability, may be limited by these same factors. Implementation of NPTs should engage local communities to understand real-world constraints and strategise to deliver effective, multi-level combination prevention. PMID- 29420550 TI - Spectrum of interstitial lung diseases at a tertiary center in a developing country: A study of 803 subjects. AB - BACKGROUND: The spectrum of interstitial lung diseases (ILDs) have mainly been reported from the developed countries; data from developing countries is sparse and conflicting. The aim of this study is to describe the distribution of various ILDs from a developing country. METHODS: This is an analysis of prospectively collected clinical, radiological and histological data of consecutive subjects (age >12 years) with ILDs from a single tertiary care medical center. The diagnosis of the specific subtype of ILD was made according to standard criteria for various ILDs. RESULTS: A total of 803 subjects (mean age, 50.6 years; 50.2% women) were enrolled between March 2015 to February 2017 of which 566 (70.5%) were diagnosed during the study period (incident cases). Sarcoidosis (42.2%), idiopathic pulmonary fibrosis (IPF, 21.2%), connective tissue disease (CTD) related ILDs (12.7%), hypersensitivity pneumonitis (10.7%), and non-IPF idiopathic interstitial pneumonias (9.2%) were the most common ILDs. The spectrum of ILDs was not significantly different (p = 0.87) between incident and prevalent cases. A histopathological specimen was obtained in 49.9% of the subjects yielding a histologically confirmed diagnosis in 40.6%. A diagnostic procedure was not performed in 402 subjects; the most common reasons were presence of definite usual interstitial pneumonia pattern on high resolution computed tomography and patients' unwillingness to undergo the procedure. CONCLUSION: Sarcoidosis, IPF and CTD-ILDs were the most common ILDs seen at a tertiary center in northern India similar to the spectrum reported from developed countries. More studies are required from developing countries to ascertain the spectrum of ILDs in different geographic locales. PMID- 29420551 TI - Survival factors of hospitalized out-of-hospital cardiac arrest patients in Taiwan: A retrospective study. AB - The chain of survival has been shown to improve the chances of survival for victims of cardiac arrest. Post-cardiac arrest care has been demonstrated to significantly impact the survival of out-of-hospital cardiac arrest (OHCA). How post-cardiac arrest care influences the survival of OHCA patients has been a main concern in recent years. The objective of this study was to assess the survival outcome of hospitalized OHCA patients and determine the factors associated with improved survival in terms of survival to discharge. We conducted a retrospective observational study by analyzing records from the National Health Insurance Research Database of Taiwan from 2007 to 2013. We collected cases with an International Classification of Disease Clinical Modification, 9th revision primary diagnosis codes of 427.41 (ventricular fibrillation, VF) or 427.5 (cardiac arrest) and excluded patients less than 18 years old, as well as cases with an unknown outcome or a combination of traumatic comorbidities. We then calculated the proportion of survival to discharge among hospitalized OHCA patients. Factors associated with the dependent variable were examined by logistic regression. Statistical analysis was conducted using SPSS 22 (IBM, Armonk, NY). Of the 11,000 cases, 2,499 patients (22.7%) survived to hospital discharge. The mean age of subjects who survived to hospital discharge and those who did not was 66.7+/-16.7 and 71.7+/-15.2 years, respectively. After adjusting for covariates, neurological failure, cardiac comorbidities, hospital level, intensive care unit beds, transfer to another hospital, and length of hospital stay were independent predictors of improved survival. Cardiac rhythm on admission was a strong factor associated with survival to discharge (VF vs. non VF: adjusted odds ratio: 3.51; 95% confidence interval: 3.06-4.01). In conclusion, cardiac comorbidities, hospital volume, cardiac rhythm on admission, transfer to another hospital and length of hospital stay had a significant positive association with survival to discharge in hospitalized OHCA patients in Taiwan. PMID- 29420552 TI - Human Borrelia miyamotoi infection in California: Serodiagnosis is complicated by multiple endemic Borrelia species. AB - To determine whether human Borrelia miyamotoi infection occurs in the far-western United States, we tested archived sera from northwestern California residents for antibodies to this emerging relapsing fever spirochete. These residents frequently were exposed to I. pacificus ticks in a region where B. miyamotoi tick infection has been reported. We used a two-step B. miyamotoi rGlpQ assay and a B. miyamotoi whole-cell lysate (WCL) assay to detect B. miyamotoi antibody. We also employed Borrelia hermsii and Borrelia burgdorferi WCL assays to examine if these Borrelia induce cross reacting antibody to B. miyamotoi. Sera were collected from 101 residents in each of two consecutive years. The sera of 12 and 14 residents in years one and two, respectively, were B. miyamotoi rGlpQ seroreactive. Sufficient sera were available to test 15 of the 26 seropositive samples using B. miyamotoi and B. hermsii WCL assays. Two residents in year one and seven residents in year two were seroreactive to both Borrelia antigens. Although discernible differences in seroreactivity were evident between the B. miyamotoi and B. hermsii WCL assays, infection with one or the other could not be determined with certainty. Sera from two Borrelia burgdorferi /B. miyamotoi seropositive subjects reacted strongly against B. miyamotoi and B. hermsii WCL antigens. Ecological, epidemiological, and clinical data implicated B. miyamotoi as the probable cause of infection among those whose sera reacted against both antigens. Our findings suggest that human B. miyamotoi infection occurs in northern California and that B. hermsii and B. burgdorferi infections produce antibodies that cross-react with B. miyamotoi antigens. Health care professionals in the far-western United States should be aware that B. miyamotoi disease may occur throughout the geographic distribution of I. pacificus and that improved relapsing fever group spirochete antibody assays are urgently needed. PMID- 29420553 TI - A new data assimilation method for high-dimensional models. AB - In the variational data assimilation (VarDA), the typical way for gradient computation is using the adjoint method. However, the adjoint method has many problems, such as low accuracy, difficult implementation and considerable complexity, for high-dimensional models. To overcome these shortcomings, a new data assimilation method based on dual number automatic differentiation (AD) is proposed. The important advantages of the method lies in that the coding of the tangent-linear/adjoint model is no longer necessary and that the value of the cost function and its corresponding gradient vector can be obtained simultaneously through only one forward computation in dual number space. The numerical simulations for data assimilation are implemented for a typical nonlinear advection equation and a parabolic equation. The results demonstrate that the new method can reconstruct the initial conditions of the high dimensional nonlinear dynamical system conveniently and accurately. Additionally, the estimated initial values can converge to the true values quickly, even if noise is present in the observations. PMID- 29420554 TI - Medium Chain Triglycerides enhances exercise endurance through the increased mitochondrial biogenesis and metabolism. AB - Medium Chain Triglycerides (MCT) is a dietary supplement and usually used along with medications for treating food absorption disorders including diarrhea, steatorrhea and liver disease. It has been shown that MCT plays a role in lowering weight, and decreasing metabolic syndrome, abdominal obesity and inflammation. However, it is still unknown whether MCT enhances exercise endurance. Here, we demonstrated that MCT containing diet improves high temperature induced exercise performance impairment. We found that MCT up regulates the expression and protein levels of genes involved in mitochondrial biogenesis and metabolism. Further investigation demonstrated that the increased mitochondrial biogenesis and metabolism is mediated through the activation of Akt and AMPK signaling pathways and inhibition of TGF-beta signaling pathway. Collectively, our findings indicate a beneficial effect of dietary MCT in exercise performance through the increase of mitochondrial biogenesis and metabolism. PMID- 29420555 TI - Validity and reliability of an accelerometer-based player tracking device. AB - This study aimed to determine the intra- and inter-device accuracy and reliability of wearable athletic tracking devices, under controlled laboratory conditions. A total of nineteen portable accelerometers (Catapult OptimEye S5) were mounted to an aluminum bracket, bolted directly to an Unholtz Dickie 20K electrodynamic shaker table, and subjected to a series of oscillations in each of three orthogonal directions (front-back, side to side, and up-down), at four levels of peak acceleration (0.1g, 0.5g, 1.0g, and 3.0g), each repeated five times resulting in a total of 60 tests per unit, for a total of 1140 records. Data from each accelerometer was recorded at a sampling frequency of 100Hz. Peak accelerations recorded by the devices, Catapult PlayerLoadTM, and calculated player load (using Catapult's Cartesian formula) were used for the analysis. The devices demonstrated excellent intradevice reliability and mixed interdevice reliability. Differences were found between devices for mean peak accelerations and PlayerLoadTM for each direction and level of acceleration. Interdevice effect sizes ranged from a mean of 0.54 (95% CI: 0.34-0.74) (small) to 1.20 (95% CI: 1.08-1.30) (large) and ICCs ranged from 0.77 (95% CI: 0.62-0.89) (very large) to 1.0 (95% CI: 0.99-1.0) (nearly perfect) depending upon the magnitude and direction of the applied motion. When compared to the player load determined using the Cartesian formula, the Catapult reported PlayerLoadTM was consistently lower by approximately 15%. These results emphasize the need for industry wide standards in reporting validity, reliability and the magnitude of measurement errors. It is recommended that device reliability and accuracy are periodically quantified. PMID- 29420556 TI - Interactions between youth and mental health professionals: The Youth Aware of Mental health (YAM) program experience. AB - THE YOUTH AWARE OF MENTAL HEALTH (YAM) EXPERIENCE: Youth stand at the core of much mental health promotion, yet little is written about their experiences of such efforts. We aimed to take this on by interviewing youth after they participated in Youth Aware of Mental Health (YAM), a universal mental health promotion program. YAM has a non-anticipatory methodology that provides youth with a safe space for reflection, role-play, and discussion. Addressing everyday mental health, YAM invites the experiences and issues relevant to the youth present to influence the program in a slightly different direction every time. The YAM instructor guides the participants but does not present the youth with given formulas on how to solve their problems. Like any mental health promotion, YAM appeals to some more than others in its intended audience and individuals engage with the program in many different ways. We set out to learn more about these experiences. CONVERSATIONS ABOUT MENTAL HEALTH: Thirty-two semi-structured interviews were conducted with 15-17 year olds in Estonia, Italy, Romania and Spain. In these interviews, the researchers made an effort to discuss mental health in terms relevant to youth. Still, wide-ranging levels of motivation, ease with engaging in dialogue with mental health professionals, and comfort with the format and content of YAM were detected. The youth were clustered in five different groups relating to their positioning vis-a-vis the researcher during the interview. The following evocative labels were used: "interested", "foot in the door", "respect for authority", "careful", and "not my topic". Corresponding labels were devised for their YAM experience: "engaged", "initially hesitant", "cautious", "eager to please", or "disengaged". We also observed that the researchers brought their own expectations and employed a variety of approaches that led to anticipating answers, stating the obvious, or getting along better with some of the youth. These modes of interaction were categorized under: "favoritism", "familiarity", "frustration", "out of sync", and "insecurity". Similar power dynamics likely transpire in other encounters between youth and researchers, including interventions such as YAM. YOUTH AND MENTAL HEALTH PROFESSIONALS: NOTICING THE DYNAMICS AT PLAY: As mental health professionals, we need to be aware of the professional habits and biases that sometimes obstruct us in understanding the experiences of youth. By initiating dialogue and listening closely to youth we can find a way to those experiences. Qualitative research can help bring the underlying interplay between mental health professionals and youth to the surface while also orienting the conversation towards topics that matter to youth. Some youth are more interested or feel more at ease in speaking openly with mental health professionals, while others find such exchanges less appealing or almost intolerable. Future mental health promotion initiatives would benefit from involving youth in the design of interventions to create an inclusive atmosphere and engage with topics that appeal to youth with diverse experiences of mental health. PMID- 29420557 TI - Capillary networks and follicular marginal zones in human spleens. Three dimensional models based on immunostained serial sections. AB - We have reconstructed small parts of capillary networks in the human splenic white pulp using serial sections immunostained for CD34 alone or for CD34 and CD271. The three-dimensional (3D) models show three types of interconnected networks: a network with very few long capillaries inside the white pulp originating from central arteries, a denser network surrounding follicles plus periarterial T-cell regions and a network in the red pulp. Capillaries of the perifollicular network and the red pulp network have open ends. Perifollicular capillaries form an arrangement similar to a basketball net located in the outer marginal zone. The marginal zone is defined by MAdCAM-1+ marginal reticular stromal cells. Perifollicular capillaries are connected to red pulp capillaries surrounded by CD271+ stromal capillary sheath cells. The scarcity of capillaries inside the splenic white pulp is astonishing, as non-polarised germinal centres with proliferating B-cells occur in adult human spleens. We suggest that specialized stromal marginal reticular cells form a barrier inside the splenic marginal zone, which together with the scarcity of capillaries guarantees the maintenance of gradients necessary for positioning of migratory B- and T lymphocytes in the human splenic white pulp. PMID- 29420558 TI - Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative. AB - The current model of binding of the antitumor antibiotic olivomycin A (1) to GC rich DNA regions presumes that coordination of the magnesium divalent cation with drug dimers is necessary for binding of 1 into the minor groove of the DNA duplex. Previously we have synthesized the derivatives of 1 termed 'short acid' (2) and its N,N-dimethylaminoethylamide (3). The latter compound demonstrated an improved tolerance in vivo compared to 1 and good therapeutic potency in animal models. We herein report that compound 3 is able to form stable complexes with DNA in the absence of Mg2+, in striking contrast to 1 whose binding to the DNA absolutely requires Mg2+. The mode of binding of 3 to DNA is similar in the presence or absence of Mg2+ as determined by circular dichroism. The affinity to DNA of 3 in Mg2+-free solution was similar to that of 1 or 3 in the presence of Mg2+ at low ionic strength. Non-electrostatic contributions to total free energy of binding of 1 and 3 to DNA were comparable for Mg2+-free complexes. Our data strongly suggest that electrostatic interaction of the positively charged 3 can compensate for the absence of divalent ions in complexes with DNA. This new property of the olivomycin A derivative expands the mechanistic knowledge of the modes of interaction with DNA of small molecular weight drug candidates. PMID- 29420559 TI - Effects of different radio-opacifying agents on physicochemical and biological properties of a novel root-end filling material. AB - BACKGROUND/PURPOSE: Radio-opacity is an essential attribute of ideal root-end filling materials because it is important for clinicians to observe root canal filling and to facilitate the follow-up instructions. The novel root-end filling material (NRFM) has good cytocompatibility and physicochemical properties but low intrinsic radio-opacity value. To improve its radio-opacity value, three novel radio-opaque root-end filling materials (NRRFMs) were developed by adding barium sulphate (NRFM-Ba), bismuth trioxide (NRFM-Bi) and zirconium dioxide (NRFM-Zr) to NRFM, respectively. The purpose of this study was to identify the suitable radio opacifier for NRFM through evaluating their physicochemical and biological properties, in comparison with NRFM and glass ionomer cement (GIC). METHODS: NRRFMs were characterized using X-ray diffraction (XRD) and Fourier transform infrared spectrophotometry (FTIR). Physicochemical properties including setting time, compressive strength, porosity, pH variation, solubility, washout resistance, contact angle and radiopacity were investigated. Cytocompatibility of both freshly mixed and set NRRFMs was investigated by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Alkaline phosphatase (ALP) activity assay and alizarin red staining were used to investigate the osteogenic differentiation potential of NRFM-Zr. Data were analyzed using two-way ANOVA (pH variation, solubility and ALP activity) and one-way ANOVA (for the other variables). RESULTS: (1) NRRFMs were primarily composed of hydroxyapatite, calcium carboxylate salt and the corresponding radio-opacity agents (barium sulphate, bismuth trioxide or zirconium dioxide). (2) Besides similar physicochemical properties in terms of setting time, pH variation, solubility, washout resistance and contact angle to NRFM, NRFM-Bi and NRFM-Zr exhibited lower porosity and greater compressive strength after being set for 7 days and their radio-opacity were greater than the 3 mm aluminium thickness specified in ISO 6876 (2001). (3) MTT assay revealed that freshly mixed and set NRFM-Zr presented better cell viability than NRFM-Ba and NRFM-Bi at 24 hours and 48 hours (P<0.05). (4) NRFM-Zr significantly enhanced ALP activity and calcium formation of human osteoblast-like Saos-2 cells when compared with negative group and GIC (P<0.05). CONCLUSION: NRFM-Zr presents desirable physicochemical and biological properties, thus zirconium dioxide may be a suitable radio-opacifier for NRFM. PMID- 29420560 TI - Effect of fruiting body bacteria on the growth of Tricholoma matsutake and its related molds. AB - Tricholoma matsutake (pine mushroom, PM) is a prized mushroom in Asia due to its unique flavor and pine aroma. The fruiting body of PM forms only in its natural habitat (pine forest), and little is known regarding the natural conditions required for successful generation of the fruiting bodies in this species. Recent studies suggest that microbial interactions may be associated with the growth of PM; however, there have been few studies of the bacterial effects on PM growth. In this study, we surveyed which bacteria can directly and indirectly promote the growth of PM by using co-cultures with PM and molds associated with the fruiting body. Among 16 bacterial species isolated from the fruiting body, some species significantly influenced the mycelial growth of PM and molds. Most bacteria negatively affected PM growth and exhibited various enzyme activities, which suggests that they use the fruiting body as nutrient source. However, growth promoting bacteria belonging to the Dietzia, Ewingella, Pseudomonas, Paenibacillus, and Rodococcus were also found. In addition, many bacteria suppressed molds, which suggests an indirect positive effect on PM as a biocontrol agent. Our results provide important insights toward a better understanding of the microbial interactions in the fruiting body of PM, and indicate that growth-promoting bacteria may be an important component in successful cultivation of PM. PMID- 29420561 TI - Implication of KRT16, FAM129A and HKDC1 genes as ATF4 regulated components of the integrated stress response. AB - The ATF4 transcription factor is a key regulator of the adaptive integrated stress response (ISR) induced by various stresses and pathologies. Identification of novel transcription targets of ATF4 during ISR would contribute to the understanding of adaptive networks and help to identify novel therapeutic targets. We were previously searching for genes that display an inverse regulation mode by the transcription factors ATF4 and p53 in response to mitochondrial respiration chain complex III inhibition. Among the selected candidates the human genes for cytokeratine 16 (KRT16), anti-apoptotic protein Niban (FAM129A) and hexokinase HKDC1 have been found highly responsive to ATF4 overexpression. Here we explored potential roles of the induction of KRT16, FAM129A and HKDC1 genes in ISR. As verified by RT-qPCR, a dysfunction of mitochondrial respiration chain and ER stress resulted in a partially ATF4 dependent stimulation of KRT16, FAM129A and HKDC1 expression in the HCT116 colon carcinoma cell line. ISRIB, a specific inhibitor of ISR, was able to downregulate the ER stress-induced levels of KRT16, FAM129A and HKDC1 transcripts. An inhibition of ATF4 by RNAi attenuated the induction of KRT16, FAM129A and HKDC1 mRNAs in response to ER stress or to a dysfunctional mitochondrial respiration. The similar induction of the three genes was observed in another tumor-derived cervical carcinoma cell line HeLa. However, in HaCaT and HEK293T cells that display transformed phenotypes, but do not originate from patient-derived tumors, the ER stress-inducing treatments resulted in an upregulation of FAM129A and HKDC1, but not KRT16 transcripts, By a luciferase reporter approach we identified a highly active ATF4-responsive element within the upstream region of the KRT16 gene. The results suggest a conditional regulation of KRT16 gene by ATF4 that may be inhibited in normal cells, but engaged during cancer progression. Potential roles of KRT16, FAM129A and HKDC1 genes upregulation in adaptive stress responses and pathologies are discussed. PMID- 29420562 TI - Induction of apoptosis by pinostrobin in human cervical cancer cells: Possible mechanism of action. AB - Pinostrobin (PN) is a naturally occurring dietary bioflavonoid, found in various medicinal herbs/plants. Though anti-cancer potential of many such similar constituents has been demonstrated, critical biochemical targets and exact mechanism for their apoptosis-inducing actions have not been fully elucidated. The present study was aimed to investigate if PN induced apoptosis in cervical cancer cells (HeLa) of human origin. It is demonstrated that PN at increasing dose effectivity reduced the cell viability as well as GSH and NO2- levels. Condensed nuclei with fragmented chromatin and changes in mitochondrial matrix morphology clearly indicated the role of mitochondria in PN induced apoptosis. A marked reduction in mitochondrial membrane potential and increased ROS production after PN treatment showed involvement of free radicals, which in turn further augment ROS levels. PN treatment resulted in DNA damage, which could have been triggered by an increase in ROS levels. Decrease in apoptotic cells in the presence of caspase 3 inhibitor in PN-treated cells suggested that PN induced apoptosis via caspase dependent pathways. Additionally, a significant increase in the expression of proteins of extrinsic (TRAIL R1/DR4, TRAIL R2/DR5, TNF RI/TNFRSF1A, FADD, Fas/TNFRSF6) and intrinsic pathway (Bad, Bax, HTRA2/Omi, SMAC/Diablo, cytochrome C, Pro-Caspase-3, Cleaved Caspase-3) was observed in the cells exposed to PN. Taken together, these observations suggest that PN efficiently induces apoptosis through ROS mediated extrinsic and intrinsic dependent signaling pathways, as well as ROS mediated mitochondrial damage in HeLa cells. PMID- 29420563 TI - Towards a novel model for studying the nutritional stage dynamics of the Colombian population by age and socioeconomic status. AB - Low-and middle-income countries (LMICs) are experiencing a nutritional transition in which the burden of obesity tends to shift towards the lower-socioeconomic status (SES) group. We propose a system dynamics (SD) model for assessing the nutritional stage dynamics of the Colombian urban population by age and SES projected to 2030. This SD model captures the ageing population according to body mass index (BMI) categories and SES. In this model, the transference rates (TRs) between BMI categories by age and SES are estimated using a heuristic based on data obtained from national surveys. The simulation results show that the Colombian population, particularly those aged 20 to 39 years with a lower SES, is moving towards the overweight and obese categories. The TRs for overweight and obese categories in the lower SES group (the mean TR from not overweight to overweight = 0.0215 (per year) and mean TR from overweight to obese = 0.0098 (per year)) are increasing more rapidly than the those in the middle (the mean TR from not overweight to overweight = 0.0162 (per year) and mean TR from overweight to obese = 0.0065 (per year)) and higher SES groups (the mean TR from not overweight to overweight = 0.0166 and mean TR from overweight to obese = 0.0054 (per year)). Additionally, from 2005 to 2010, individuals aged 20 to 39 years had the highest TRs towards the overweight and obese categories (from 0.026 to 0.036 per year and from 0.0064 to 0.012 per year, respectively). The TRs also indicated that children aged 0 to 14 years are moving from the obese to overweight and from the overweight to not overweight categories. These TRs show that the Colombian population is experiencing an SES-related nutritional transition that is affecting the lower SES population. The proposed model could be implemented to assess the nutritional transitions experienced in other LMICs. PMID- 29420564 TI - Using best-worst scaling choice experiments to elicit the most important domains of health for health-related quality of life in Singapore. AB - Health-related quality of life (HRQOL) instruments are sometimes used without explicit understanding of which HRQOL domains are important to a given population. In this study, we sought to elicit an importance hierarchy among 27 HRQOL domains (derived from the general population) via a best-worst scaling survey of the population in Singapore, and to determine whether these domains were consistently valued across gender, age, ethnicity, and presence of chronic illnesses. We conducted a community-based study that sampled participants with quotas for gender, ethnicity, age, presence of chronic illness, and interview language. For the best-worst scaling exercise, we constructed comparison sets according to a balanced incomplete block design resulting in 13 sets of questions, each with nine choice tasks. Each task involved three HRQOL domains from which participants identified the most and least important domain. We performed a standard analysis of best-worst object scaling design (Case 1) using simple summary statistics; 603 residents participated in the survey. The three most important domains of health were: "the ability to take care of self without help from others" (best-worst score (BWS): 636), "healing and resistance to illness" (BWS: 461), and "having good relationships with family, friends, and others" (BWS: 373). The 10 top-ranked domains included physical, mental, and social health. The three least important domains were: "having a satisfying sex life" (BWS: -803), "having normal physical appearance" (BWS: -461), and "interacting with others (talking, shared activities, etc.)" (BWS: -444). Generally, top-ranked domains were consistently valued across gender, age, ethnicity, and presence of chronic illness. We conclude that the 10 top-ranked domains reflect physical, mental, and social dimensions of well-being suggesting that the sampled population's views on health are consistent with the World Health Organization's definition of health, "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity". PMID- 29420565 TI - Catecholamines alter the intrinsic variability of cortical population activity and perception. AB - The ascending modulatory systems of the brain stem are powerful regulators of global brain state. Disturbances of these systems are implicated in several major neuropsychiatric disorders. Yet, how these systems interact with specific neural computations in the cerebral cortex to shape perception, cognition, and behavior remains poorly understood. Here, we probed into the effect of two such systems, the catecholaminergic (dopaminergic and noradrenergic) and cholinergic systems, on an important aspect of cortical computation: its intrinsic variability. To this end, we combined placebo-controlled pharmacological intervention in humans, recordings of cortical population activity using magnetoencephalography (MEG), and psychophysical measurements of the perception of ambiguous visual input. A low-dose catecholaminergic, but not cholinergic, manipulation altered the rate of spontaneous perceptual fluctuations as well as the temporal structure of "scale free" population activity of large swaths of the visual and parietal cortices. Computational analyses indicate that both effects were consistent with an increase in excitatory relative to inhibitory activity in the cortical areas underlying visual perceptual inference. We propose that catecholamines regulate the variability of perception and cognition through dynamically changing the cortical excitation-inhibition ratio. The combined readout of fluctuations in perception and cortical activity we established here may prove useful as an efficient and easily accessible marker of altered cortical computation in neuropsychiatric disorders. PMID- 29420566 TI - A novel monoclonal antibody targeting carboxymethyllysine, an advanced glycation end product in atherosclerosis and pancreatic cancer. AB - Advanced glycation end products are formed by non-enzymatic reactions between proteins and carbohydrates, causing irreversible lysine and arginine alterations that severely affect protein structure and function. The resulting modifications induce inflammation by binding to scavenger receptors. An increase in advanced glycation end products is observed in a number of diseases e.g. atherosclerosis and cancer. Since advanced glycation end products also are present in healthy individuals, their detection and quantification are of great importance for usage as potential biomarkers. Current methods for advanced glycation end product detection are though limited and solely measure total glycation. This study describes a new epitope-mapped single chain variable fragment, D1-B2, against carboxymethyllysine, produced from a phage library that was constructed from mouse immunizations. The phage library was selected against advanced glycation end product targets using a phage display platform. Characterization of its binding pattern was performed using large synthetic glycated peptide and protein libraries displayed on microarray slides. D1-B2 showed a preference for an aspartic acid, three positions N-terminally from a carboxymethyllysine residue and also bound to a broad collection of glycated proteins. Positive immunohistochemical staining of mouse atherosclerotic plaques and of a tissue microarray of human pancreatic tumors confirmed the usability of the new scFv for advanced glycation end product detection in tissues. This study demonstrates a promising methodology for high-throughput generation of epitope-mapped monoclonal antibodies against AGE. PMID- 29420568 TI - An expert botanical feature extraction technique based on phenetic features for identifying plant species. AB - In this paper, we present a new method to recognise the leaf type and identify plant species using phenetic parts of the leaf; lobes, apex and base detection. Most of the research in this area focuses on the popular features such as the shape, colour, vein, and texture, which consumes large amounts of computational processing and are not efficient, especially in the Acer database with a high complexity structure of the leaves. This paper is focused on phenetic parts of the leaf which increases accuracy. Detecting the local maxima and local minima are done based on Centroid Contour Distance for Every Boundary Point, using north and south region to recognise the apex and base. Digital morphology is used to measure the leaf shape and the leaf margin. Centroid Contour Gradient is presented to extract the curvature of leaf apex and base. We analyse 32 leaf images of tropical plants and evaluated with two different datasets, Flavia, and Acer. The best accuracy obtained is 94.76% and 82.6% respectively. Experimental results show the effectiveness of the proposed technique without considering the commonly used features with high computational cost. PMID- 29420567 TI - Outcome and clinical course of EHEC O104 infection in hospitalized patients: A prospective single center study. AB - OBJECTIVES: Shiga-toxin producing O157:H7 Entero Haemorrhagic E. coli [STEC/EHEC] are the most common cause of Haemolytic Uraemic Syndrome [HUS] related to infectious haemorrhagic colitis. Nearly all recommendations on long term treatment of EHEC infections refer to this strain. The 2011 outbreak in Northern Europe was the first of this dimension to be caused by the serotype O104:H4. We report on the 3.5 year follow up of 61 patients diagnosed with symptomatic EHEC O104:H4 infection in spring 2011. METHODS: Patients with EHEC O104 infection were followed in a monocentric, prospective observational study at four time points: 4, 12, 24 and 36 months. These data include the patients' histories, clinical findings, and complications. RESULTS: Sixty-one patients suffering from EHEC O104:H4 associated enterocolitis participated in the study at the time of hospital discharge. The mean age of patients was 43 +/- 2 years, 37 females and 24 males. 48 patients participated in follow up 1 [FU 1], 34 patients in follow up 2 [FU 2], 23 patients in follow up 3 [FU 3] and 18 patients in follow up 4 [FU 4]. Out of 61 patients discharged from the hospital and included in the study, 54 [84%] were examined at least at one additional follow up. Serum creatinine decreased significantly between discharge and FU 1 from 1.3 +/- 0.1 mg/dl to 0.7 +/- 0.1 mg/dl [p = 0.0045]. From FU 1 until FU 4, no further change in creatinine levels could be observed. The patients need of antihypertensive medications decreased significantly [p = 0.0005] between discharge and FU 1 after four months. From FU 1 until FU 3, 24 months later, no further significant change in antihypertensive treatment was observed. CONCLUSIONS: Our findings suggest that patients free of pathological findings at time of discharge do not need a specific follow up. Patients with persistent health problems at hospital discharge should be clinically monitored over four months to evaluate chronic organ damage. Progressive or new emerging renal damage could not be observed over time in any patient. PMID- 29420569 TI - Hydrodynamic characteristics of knotted and knotless purse seine netting panels as determined in a flume tank. AB - Nylon (PA) netting is widely used in purse seines and other fishing gears due to its high strength and good sinking performance. However, hydrodynamic properties of nylon netting of different characteristics are poorly understood. This study investigated hydrodynamic characteristics of nylon netting of different knot types and solidity ratios under different attack angles and flow velocities. It was found that the hydrodynamic coefficient of netting panels was related to Reynolds number, solidity ratio, attack angle, knot type and twine construction. The solidity ratio was found to positively correlate with drag coefficient when the netting was normal to the flow (CD90), but not the case when the netting was parallel to the flow (CD0). For netting panels inclined to the flow, the inclined drag coefficient had a negative relationship with the solidity ratio for attack angles between 0 degrees and 50 degrees , but a positive relationship for attack angles between 50 degrees and 90 degrees . The lift coefficient increased with the attack angle, reaching the culminating point at an attack angle of 50 degrees , before subsequent decline. We found that the drag generated by knot accounted for 15-25% of total drag, and the knotted netting with higher solidity ratio exhibited a greater CD0, but it was not the case for the knotless netting. Compared to knotless polyethylene (PE) netting, the drag coefficients of knotless PA netting were dominant at higher Reynolds number (Re>2200). PMID- 29420570 TI - QT-interval evaluation in primary percutaneous coronary intervention of ST segment elevation myocardial infarction for prediction of myocardial salvage index. AB - Assessing the efficacy of revascularization therapy in patients with ST-segment elevation myocardial infarction (STEMI) is extremely important in order to guide subsequent management and assess prognosis. We aimed to determine the relationship between corrected QT-interval (QTc) changes on standard sequential ECG and myocardial salvage index in anterior STEMI patients after successful primary percutaneous coronary intervention. Fifty anterior STEMI patients treated by primary percutaneous coronary intervention underwent quantitative ECG analysis and cardiac magnetic resonance. For each patient the difference (DeltaQTc) between the QTc of ischemic myocardium (maximum QTc in anterior leads) versus remote myocardium (minimum QTc in inferior leads) during the first six days after STEMI was measured. The QTc in anterior leads was significantly longer than QTc in inferior leads (p<0.0001). At multivariate analysis, DeltaQTC and peak troponin I were the only independent predictors for late gadolium enhancement while DeltaQTc and left ventricular ejection fraction were independent predictors of myocardial salvage index <60%. The receiver operative curve of DeltaQTc showed an area under the curve of 0.77 to predict a myocardial salvage index <0.6. In conclusion, in a subset of patients with a first occurrence of early revascularized anterior STEMI, DeltaQTc is inversely correlated with CMR-derived myocardial salvage index and may represent a useful parameter for assessing efficacy of reperfusion therapy. PMID- 29420572 TI - Frequencies of chromosomal inversions in Drosophila melanogaster in Fukushima after the nuclear power plant accident. AB - In order to investigate genetic impact of a large amount of radionuclides released by the Fukushima Dai-ichi Nuclear Power Plant accident in 2011, we surveyed 2,304 haploid genomes of Drosophila melanogaster collected in three localities in Fukushima in 2012 and 2013 for chromosomal inversions. No unique inversion was found in 298 genomes in 2012 and only two in 2,006 genomes in 2013. The observed frequencies were even lower than the long-term average frequency of unique inversions in Japan. The common cosmopolitan inversions were also examined in Fukushima, Kyoto, and Iriomote (Okinawa) in 2012. Among three samples in Fukushima, the flies in Iizaka, where environmental radiation level was the highest, showed the lowest frequency of In(2L)t, but the highest frequency of In(3R)P, contrary to the expectation of decreasing of their frequencies in higher polluted areas. These results suggest that, at this level of genetic analysis, Fukushima populations of D. melanogaster would not have been negatively impacted following the release of radionuclides. Transposable P-element mobility was not likely to induce DNA damage solely or synergistically with radioactivity, because their transposition activity was totally repressed in the Fukushima strains. However, it should be noted that, because of limitations in access to the exclusion zone, we could only sample the populations in areas of relatively low radioactive contamination (0.39-0.63 MUSv/h). Therefore, the present study is likely to be underpowered to detect any effects that might be expected in heavily contaminated areas. PMID- 29420571 TI - The bacterial community associated with the sheep gastrointestinal nematode parasite Haemonchus contortus. AB - Culture-independent methods were used to study the microbiota of adult worms, third-stage larvae and eggs, both in faeces and laid in vitro, of Haemonchus contortus, a nematode parasite of the abomasa of ruminants which is a major cause of production losses and ill-health. Bacteria were identified in eggs, the female reproductive tract and the gut of adult and third-stage larvae (L3). PCR amplification of 16S rRNA sequences, denaturing gradient gel electrophoresis (DGGE) and clone libraries were used to compare the composition of the microbial communities of the different life-cycle stages of the parasites, as well as parasites and their natural environments. The microbiomes of adult worms and L3 were different from those in the abomasum or faeces respectively. The H. contortus microbiota was mainly comprised of members of the phyla Proteobacteria, Firmicutes and Bacteroidetes. Bacteria were localised in the gut, inside eggs and within the uterus of adult female worms using the universal FISH Eub338 probe, which targets most bacteria, and were also seen in these tissues by light and transmission electron microscopy. Streptococcus/Lactococcus sp. were identified within the distal uterus with the probe Strc493. Sequences from the genera Weissella and Leuconostoc were found in all life-cycle stages, except eggs collected from faeces, in which most sequences belonged to Clostridium sp. Bacteria affiliated with Weissella/Leuconostoc were identified in both PCR-DGGE short sequences and clone libraries of nearly full length 16S rRNA bacterial sequences in all life-cycle stages and subsequently visualised in eggs by fluorescent in situ hybridisation (FISH) with group-specific probes. This strongly suggests they are vertically transmitted endosymbionts. As this study was carried out on a parasite strain which has been maintained in the laboratory, other field isolates will need to be examined to establish whether these bacteria are more widely dispersed and have potential as targets to control H. contortus infections. PMID- 29420573 TI - Prevalence of diagnosed temporomandibular disorders: A cross-sectional study in Brazilian adolescents. AB - BACKGROUND: The prevalence of signs and symptoms of temporomandibular disorders (TMD) increases during adolescence and adulthood. Few studies have examined TMD prevalence in Brazilian adolescents. AIM: To investigate the prevalence of TMD in Brazilian adolescents. METHODS: A representative population-based sample of 934 adolescents (10-14-years-old) was examined. TMD screening was performed using a questionnaire by the American Academy of Orofacial Pain. TMD diagnoses used research diagnostic criteria for temporomandibular disorders (RDC/TMD-Axis-I). Examinations were performed by a single calibrated examiner (kappa > 0.80). RESULTS: The prevalence of TMD symptoms was 34.9%; the most frequently reported symptoms were headache and neck ache (20.9%), followed by joint sounds (18.5%). Myofascial pain was the most prevalent type (10.3%), followed by disc displacement with reduction (8.0%) and arthralgia (3.5%). There was a significant association between sex and TMD symptoms; prevalence was significantly higher in girls (RP = 1.37; 95% CI = 1.14-1.65; p = 0.001). Myofascial pain of TMD and displacement with reduction were more prevalent in girls (RP = 1.76; p = 0.007 and RP = 2.06; p = 0.004, respectively). CONCLUSION: TMD symptoms were present in 34.9% of adolescents, with myofascial pain being the most prevalent type (10.3%). TMD was significantly more common in girls. Routine pediatric dental care should include a TMD screening. PMID- 29420574 TI - Evolution of technology convergence networks in Korea: Characteristics of temporal changes in R&D according to institution type. AB - This study investigates the temporal changes in development of technology convergence networks by institution type, i.e., public research institute (PRI), university and industry. Using the co-classification of technological domains of patents, we identified technology convergence of Korean patents, which were filed at Korea Intellectual Properties Office (KIPO) from 1997 to 2011. We conducted a network analysis at the technology level to search for the key technology fields and frequent instances of technology convergence. The results show that technology convergence networks have grown significantly in the recent period regardless of the institution type. While industries started to conspicuously engage in technology convergence in the late 1990s, universities or PRIs did not do so until the mid-2000s. This discrepancy in the phase of technology convergence is attributed to the temporal difference in R&D stage (e.g., basic research and commercial product development). Our findings imply that corporal and governmental R&D management decision on promising technology fields will be more effective if the decision makers carefully consider the type of R&D entity in analyzing technological landscapes. PMID- 29420576 TI - Relative age effect in elite soccer: More early-born players, but no better valued, and no paragon clubs or countries. AB - The paper analyses two datasets of elite soccer players (top 1000 professionals and UEFA Under-19 Youth League). In both, we find a Relative Age Effect (RAE) for frequency, but not for value. That is, while there are more players born at the start of the competition year, their transfer values are no higher, nor are they given more game time. We use Poisson regression to derive a transparent index of the discrimination present in RAE. Also, because Poisson is valid for small frequency counts, it supports analysis at the disaggregated levels of country and club. From this, we conclude there are no paragon clubs or countries immune to RAE; that is clubs and countries do not differ systematically in the RAE they experience; also, that Poisson regression is a powerful and flexible method of analysing RAE data. PMID- 29420575 TI - Glycoproteins in circulating immune complexes are biomarkers of patients with Indian PKDL: A study from endemic districts of West Bengal, India. AB - BACKGROUND: Post Kala Azar Dermal Leishmaniasis (PKDL) occurs as dermal consequence of previous Visceral Leishmaniasis (VL) infection and serves as an important reservoir for transmission of VL. Diagnosis of PKDL is often challenging for its symptomatic resemblance to other co-endemic diseases like Leprosy or Vitiligo. Parasitological examination by slit-skin smear and culture are the standard methods but lack high sensitivity. Thus, for efficient control of VL, reliable diagnostic and prognostic assay of PKDL are required. OBJECTIVE: Previously, glycoproteins (9-OAcSA) have been reported as promising biomarkers of Indian VL patients. However, till date, the status of glycans in Indian PKDL patients remains unexplored. Accordingly, in this study, the glyco-profile of PKDL Circulating Immune Complexes (CICs) as compared to other cross diseases like Vitiligo and Leprosyhas been investigated. Further, a novel Glyco CIC assay has been developed for efficient Indian PKDL patient diagnosis. METHODS/PRINCIPAL FINDING: In the present study, 90 PKDL patients were enrolled from 3 VL endemic districts of West Bengal during 2015-16. Glycosylation profile of isolated CICs from sera of PKDL patients were initially analyzed through gradient SDS gel electrophoresis followed by PAS silver double staining, which revealed the presence of several glycan rich PKDL specific proteins of varying molecular weights. To further characterize the glyco-profile of acid dissociated affinity purified immuno-reactive antigens present in the CICs, glycosylation was demonstrated in these purified CIC antigens by DIG glycan differentiation kit with or without glycosidase as well as neuraminidase treatment. Diagnostic evaluation of the newly developed colorimetric Glyco CIC assay through Receiver Operating Characteristic (ROC) curve analysis revealed excellent (0.99) AUC value as compared to other conventional serodiagnostic assays like PEG CIC, Parasite ELISA (IgG and IgM). Additionally, longitudinal monitoring of 18 PKDL patients further revealed its good prognostic utility. CONCLUSION: These results highlight the glycosylation status of CICs among Indian PKDL patients present in all the studied endemic districts of West Bengal. These PKDL biomarkers were completely absent in cross diseases like Vitiligo and Leprosy. Further, the newly developed Glyco CIC assay had an improved sensitivity of 95.6%, specificity of 99.3%, NPV of 97.1% and PPV of 98.9%. PMID- 29420578 TI - Evolutionary Wavelet Neural Network ensembles for breast cancer and Parkinson's disease prediction. AB - Wavelet Neural Networks are a combination of neural networks and wavelets and have been mostly used in the area of time-series prediction and control. Recently, Evolutionary Wavelet Neural Networks have been employed to develop cancer prediction models. The present study proposes to use ensembles of Evolutionary Wavelet Neural Networks. The search for a high quality ensemble is directed by a fitness function that incorporates the accuracy of the classifiers both independently and as part of the ensemble itself. The ensemble approach is tested on three publicly available biomedical benchmark datasets, one on Breast Cancer and two on Parkinson's disease, using a 10-fold cross-validation strategy. Our experimental results show that, for the first dataset, the performance was similar to previous studies reported in literature. On the second dataset, the Evolutionary Wavelet Neural Network ensembles performed better than all previous methods. The third dataset is relatively new and this study is the first to report benchmark results. PMID- 29420577 TI - Differing HIV vulnerability among female sex workers in a high HIV burden Indian state. AB - INTRODUCTION: The HIV sentinel surveillance [HSS] conducted in 2010-11 among female sex workers [FSW] in the state of Maharashtra, India provided an opportunity to assess characteristics of different types of FSWs and their HIV risk. It is important for India's National AIDS Control Program, to understand the differences in vulnerability among these FSW, in order to define more specific and effective risk reduction intervention strategies. Therefore, we analyzed data from HSS with the objective of understanding the HIV vulnerability among different types of FSW in Maharashtra. MATERIAL AND METHODS: Cross sectional data collected as a part of HSS among FSWs in year 2010-11 from 21 sentinel sites in the state of Maharashtra were analyzed to understand the vulnerability and characteristics of different types of female sex workers based on their place of solicitation using multinomial logistic regression. RESULTS: While the HIV prevalence was 6.6% among all FSWs, it was 9.9% among brothel based [BB], 9% among street based [SB] and 3.1% and 3.7% among home based [HB], and bar based [Bar-B] sex workers respectively. SB FSWs were least likely to be located in HIV low burden districts [ANC] [ARRR: 0.61[95% CI: 0.49, 0.77]], but were 6 times more likely to be recently [<1 year] involved in sex work [ARRR: 6.15 [95% CI: 3.15, 12.0]]. The number of clients of SB FSWs in the preceding week were lower than 11% [ARRR: 0.89 [95%CI: 0.87, 0.90]] as compared to the BB FSWs denoting lesser client load. The duration since last paid sex was shorter [ARRR: 0.94[95%CI: 0.91, 0.96]] as compared to the BB FSWs. CONCLUSION: Street based FSWs have emerged as one of the most vulnerable types of FSW with a high HIV prevalence similar to BB FSWs. Our study reveals that they have more frequent sex acts despite lower client loads, and are more likely to be located in districts highly affected by HIV (ANC prevalence >1%). We identify them as a group to be focused on for prevention interventions and it is likely that they would be easily amenable to novel interventions due to their higher literacy rate as compared to other typologies. PMID- 29420579 TI - Characterization of indole-3-pyruvic acid pathway-mediated biosynthesis of auxin in Neurospora crassa. AB - Plants, bacteria and some fungi are known to produce indole-3-acetic acid (IAA) by employing various pathways. Among these pathways, the indole-3-pyruvic acid (IPA) pathway is the best studied in green plants and plant-associated beneficial microbes. While IAA production circuitry in plants has been studied for decades, little is known regarding the IAA biosynthesis pathway in fungal species. Here, we present the first data for IAA-producing genes and the associated biosynthesis pathway in a non-pathogenic fungus, Neurospora crassa. For this purpose, we used a computational approach to determine the genes and outlined the IAA production circuitry in N. crassa. We then validated these data with experimental evidence. Here, we describe the homologous genes that are present in the IPA pathway of IAA production in N. crassa. High-performance liquid chromatography and thin-layer chromatography unambiguously identified IAA, indole-3-lactic acid (ILA) and tryptophol (TOL) from cultures supplemented with tryptophan. Deletion of the gene (cfp) that encodes the enzyme indole-3-pyruvate decarboxylase, which converts IPA to indole-3-acetaldehyde (IAAld), results in an accumulation of higher levels of ILA in the N. crassa culture medium. A double knock-out strain (Deltacbs 3;Deltaahd-2) for the enzyme IAAld dehydrogenase, which converts IAAld to IAA, shows a many fold decrease in IAA production compared with the wild type strain. The Deltacbs-3;Deltaahd-2 strain also displays slower conidiation and produces many fewer conidiospores than the wild type strain. PMID- 29420580 TI - How many strides are required for a reliable estimation of temporal gait parameters? Implementation of a new algorithm on the phase coordination index. AB - BACKGROUND: The Phase coordination index (PCI), a temporal gait measure that quantifies consistency and accuracy in generating the anti-phased left-right stepping pattern, assesses bilateral coordination of gait in various cohorts (e.g., Parkinson's disease, post stroke). As PCI is based on mean values calculated across a series of gait cycles, individuals are required to perform lengthy walking trials, prolonging gait assessments which cause discomfort to some of them. This study introduces an algorithm to identify the required number of strides to obtain a reliable, characteristic PCI value. METHODS: Simulated data sets, as well as physiological data (obtained from healthy elderly and young persons, from over ground and treadmill trials) were used in this research. A series of N-1 PCI values was calculated for i = 2,3,4...N gait cycles for each participant. There is a value i = k, representing certain number of cycles, for which no significant change in PCI occurs as additional cycles are added, termed point of stabilization (POS). The algorithm presented here uses a 2-stage iterative process to determine POS. Stage 1 searches for the gross location of the interval of PCI values containing the POS. In stage 2, the algorithm performs a high-resolution recursive, iterative process within this interval to find the exact point. The criterion for defining stability within a window of PCI values is a coefficient of variation (CV) of <= 5%. RESULTS: Our recursive, iterative algorithm indicates that ~23 strides on average should be captured to attain a characteristic PCI. CONCLUSIONS: Gait trials with at least 23 strides on average should suffice to obtain a reliable estimation of PCI in healthy young adults. While this methodology may be considered generic, future studies should obtain POS values based on additional cohorts (e.g., disabled participants, fixed walking speeds). PMID- 29420581 TI - Towards the identification of a gene for prostrate tillers in barley (Hordeum vulgare L.). AB - Tiller angle, an important agronomic trait, contributes to crop production and plays a vital role in breeding for plant architecture. A barley line V-V-HD, which has prostrate tillers during vegetative growth and erect tillers after booting, is considered the ideal type for repressing weed growth and increasing leaf area during early growth. Genetic analysis identified that the prostrate trait in V-V-HD is controlled by a single gene. A double haploid population with 208 lines from V-V-HD * Buloke was used to map the prostrate growth gene. Ninety six SNP markers were used for primary mapping, and subsequently, SSR and InDel markers were used for fine mapping. The gene was fine-mapped to a 3.53 Mb region on chromosome 3HL between the markers InDelz3028 and InDelz3032 with 52 candidate genes located in this region. Gene annotation analysis of the 52 genes within the target region indicated that a gene involved in zinc-ion binding (gene ID HORVU3Hr1G090910) is likely to be the candidate gene for prostrate growth in V-V HD, and is linked to the denso/sdw gene. Association analysis showed that prostrate plants were shorter, flowered later. PMID- 29420582 TI - Ethyl pyruvate ameliorates hepatic injury following blunt chest trauma and hemorrhagic shock by reducing local inflammation, NF-kappaB activation and HMGB1 release. AB - BACKGROUND: The treatment of patients with multiple trauma including blunt chest/thoracic trauma (TxT) and hemorrhagic shock (H) is still challenging. Numerous studies show detrimental consequences of TxT and HS resulting in strong inflammatory changes, organ injury and mortality. Additionally, the reperfusion (R) phase plays a key role in triggering inflammation and worsening outcome. Ethyl pyruvate (EP), a stable lipophilic ester, has anti-inflammatory properties. Here, the influence of EP on the inflammatory reaction and liver injury in a double hit model of TxT and H/R in rats was explored. METHODS: Female Lewis rats were subjected to TxT followed by hemorrhage/H (60 min, 35+/-3 mm Hg) and resuscitation/R (TxT+H/R). Reperfusion was performed by either Ringer's lactated solution (RL) alone or RL supplemented with EP (50 mg/kg). Sham animals underwent all surgical procedures without TxT+H/R. After 2h, blood and liver tissue were collected for analyses, and survival was assessed after 24h. RESULTS: Resuscitation with EP significantly improved haemoglobin levels and base excess recovery compared with controls after TxT+H/R, respectively (p<0.05). TxT+H/R induced significant increase in alanine aminotransferase levels and liver injury were attenuated by EP compared with controls (p<0.05). Local inflammation as shown by increased gene expression of IL-6 and ICAM-1, enhanced ICAM-1 and HMGB1 protein expression and infiltration of the liver with neutrophils were also significantly attenuated by EP compared with controls after TxT+H/R (p<0.05). EP significantly reduced TxT+H/R-induced p65 activation in liver tissue. Survival rates improved by EP from 50% to 70% after TxT+H/R. CONCLUSIONS: These data support the concept that the pronounced local pro-inflammatory response in the liver after blunt chest trauma and hemorrhagic shock is associated with NF kappaB. In particular, the beneficial anti-inflammatory effects of ethyl pyruvate seem to be regulated by the HMGB1/NF-kappaB axis in the liver, thereby, restraining inflammatory responses and liver injury after double hit trauma in the rat. PMID- 29420583 TI - Controlled hypothermia may improve surfactant function in asphyxiated neonates with or without meconium aspiration syndrome. AB - BACKGROUND: Whole-body hypothermia (WBH) is used to improve neurological outcomes in perinatal asphyxia. Recent studies suggested a beneficial effect of hypothermia for some types of acute respiratory failure. However, no data are available about the biophysical function of human surfactant during WBH. We investigated whether WBH improves surfactant biophysical properties in asphyxiated neonates with or without meconium aspiration syndrome (MAS). METHODS: Non-bronchoscopic bronchoalveolar lavage (BAL) has been collected from 10 asphyxiated neonates (2 with MAS, 8 with no lung disease (NLD)) at different time points (pre-WBH, 24h, 48h, 72h of WBH and post-WBH). Surfactant was extracted and tested by captive bubble surfactometry (CBS) in triplicate, at 37 degrees C and 33.5 degrees C, through initial adsorption and dynamic compression-expansion cycling. Phosphatidylcholine and cholesterol were assayed using enzymatic methods. Clinical data were recorded in real-time. RESULTS: Minimum surface tension under dynamic testing was significantly improved as assessed at 33.5 degrees C compared with its behavior at 37 degrees C in NLD neonates: the difference was evident after at least 72h of WBH and remained significant at 6h after rewarming (72h: p = 0.009; rewarming: p = 0.040). Similar results were obtained in MAS patients whose surfactant activity improved already at 48h of hypothermia. Total cholesterol showed a trend to increase at the first 24-48h of hypothermia in NLD patients. Conversely, hypothermia seemed to reduce the excess of exogenous cholesterol in MAS surfactant. CONCLUSIONS: Surfactant biophysical properties may improve after 48-72h of WBH in asphyxiated neonates and the improvement is maintained shortly after rewarming. Due to study limitations, further studies are warranted to better clarify the effects of hypothermia on surfactant activity. PMID- 29420584 TI - A novel stock forecasting model based on High-order-fuzzy-fluctuation Trends and Back Propagation Neural Network. AB - In this paper, we propose a hybrid method to forecast the stock prices called High-order-fuzzy-fluctuation-Trends-based Back Propagation(HTBP)Neural Network model. First, we compare each value of the historical training data with the previous day's value to obtain a fluctuation trend time series (FTTS). On this basis, the FTTS blur into fuzzy time series (FFTS) based on the fluctuation of the increasing, equality, decreasing amplitude and direction. Since the relationship between FFTS and future wave trends is nonlinear, the HTBP neural network algorithm is used to find the mapping rules in the form of self-learning. Finally, the results of the algorithm output are used to predict future fluctuations. The proposed model provides some innovative features:(1)It combines fuzzy set theory and neural network algorithm to avoid overfitting problems existed in traditional models. (2)BP neural network algorithm can intelligently explore the internal rules of the actual existence of sequential data, without the need to analyze the influence factors of specific rules and the path of action. (3)The hybrid modal can reasonably remove noises from the internal rules by proper fuzzy treatment. This paper takes the TAIEX data set of Taiwan stock exchange as an example, and compares and analyzes the prediction performance of the model. The experimental results show that this method can predict the stock market in a very simple way. At the same time, we use this method to predict the Shanghai stock exchange composite index, and further verify the effectiveness and universality of the method. PMID- 29420585 TI - Distribution of triclosan-resistant genes in major pathogenic microorganisms revealed by metagenome and genome-wide analysis. AB - The substantial use of triclosan (TCS) has been aimed to kill pathogenic bacteria, but TCS resistance seems to be prevalent in microbial species and limited knowledge exists about TCS resistance determinants in a majority of pathogenic bacteria. We aimed to evaluate the distribution of TCS resistance determinants in major pathogenic bacteria (N = 231) and to assess the enrichment of potentially pathogenic genera in TCS contaminated environments. A TCS resistant gene (TRG) database was constructed and experimentally validated to predict TCS resistance in major pathogenic bacteria. Genome-wide in silico analysis was performed to define the distribution of TCS-resistant determinants in major pathogens. Microbiome analysis of TCS contaminated soil samples was also performed to investigate the abundance of TCS-resistant pathogens. We experimentally confirmed that TCS resistance could be accurately predicted using genome-wide in silico analysis against TRG database. Predicted TCS resistant phenotypes were observed in all of the tested bacterial strains (N = 17), and heterologous expression of selected TCS resistant genes from those strains conferred expected levels of TCS resistance in an alternative host Escherichia coli. Moreover, genome-wide analysis revealed that potential TCS resistance determinants were abundant among the majority of human-associated pathogens (79%) and soil-borne plant pathogenic bacteria (98%). These included a variety of enoyl acyl carrier protein reductase (ENRs) homologues, AcrB efflux pumps, and ENR substitutions. FabI ENR, which is the only known effective target for TCS, was either co-localized with other TCS resistance determinants or had TCS resistance associated substitutions. Furthermore, microbiome analysis revealed that pathogenic genera with intrinsic TCS-resistant determinants exist in TCS contaminated environments. We conclude that TCS may not be as effective against the majority of bacterial pathogens as previously presumed. Further, the excessive use of this biocide in natural environments may selectively enrich for not only TCS-resistant bacterial pathogens, but possibly for additional resistance to multiple antibiotics. PMID- 29420587 TI - Seasonal and annual variability of coastal sulphur plumes in the northern Benguela upwelling system. AB - We investigated the seasonal and annual variability of surface sulphur plumes in the northern Benguela upwelling system off Namibia because of their significant impacts on the marine ecosystem, fishing industry, aquaculture farming and tourism due to their toxic properties. We identified the sulphur plumes in ocean colour satellite data of the medium resolution imaging spectrometer (MERIS) for the 2002-2012 time period using the differences in the spectral properties of Namibian Benguela optical water types. The sulphur events have a strong seasonal cycle with pronounced main and off-seasons forced by local and remote-driven processes. The main peak season is in late austral summer and early austral autumn at the beginning of the annual upwelling cycle caused by increasing equatorwards alongshore winds. The sulphur plume activity is high between February and April during the seasonal oxygen minimum associated with the seasonal reduction of cross-shore ventilation of the bottom waters, the seasonal southernmost position of the Angola Benguela Frontal Zone, the seasonal maximum of water mass fractions of South Atlantic and Angola Gyre Central Waters as well as the seasonal arrival of the downwelling coastal trapped waves. The off-season is in austral spring and early austral summer during increased upwelling intensity and enhanced oxygen supply. The annual variability of sulphur events is characterized by very high activities in years 2004, 2005 and 2010 interrupted by periods of lower activity in years 2002 to 2003, 2006 to 2009 and 2011 to 2012. This result can be explained by the relative contributions or adding effects of local and remote-driven forces (from the equatorial area). The probability for the occurrence of sulphur plumes is enhanced in years with a lower annual mean of upwelling intensity, decreased oxygen supply associated with decreased lateral ventilation of bottom waters, more southern position of the Angola Benguela Frontal Zone, increased mass fraction of South Atlantic Central Water and stronger downwelling coastal trapped waves. Understanding of the variability and forcing processes of the toxic sulphur events will help in the future to monitor and forecast them as well as to manage their social and economic consequences in the northern Benguela upwelling system off Namibia. PMID- 29420586 TI - Prediction of loss to follow-up in long-term supportive periodontal therapy in patients with chronic periodontitis. AB - AIM: This study examined the predictors of loss to follow-up in long-term supportive periodontal therapy in patients with chronic periodontitis. METHODS: A total of 280 patients with moderate to severe chronic periodontitis in a tertiary care hospital in China were investigated and followed over the course of study. Questionnaires on clinical and demographic characteristics, self-efficacy for oral self-care and dental fear at baseline were completed. Participants were followed to determine whether they could adhere to long-term supportive periodontal therapy. Binary logistic regression analysis was used to examine the association between clinical and demographic characteristics, self-efficacy for oral self-care, dental fear and loss to follow-up in long-term supportive periodontal therapy. RESULTS: The loss to follow-up in long-term supportive periodontal therapy was significantly associated with age [adjusted OR = 1.042, 95% confidence interval (CI): 1.012-1.074, p = 0.006], severe periodontitis [adjusted OR = 4.892, 95%CI: 2.280-10.499, p<0.001], periodontal surgery [adjusted OR = 11.334, 95% CI: 2.235-57.472, p = 0.003], and middle and low scoring of self-efficacy scale for self-care groups. The adjusted ORs of loss to follow-up for the middle- (54-59) and low-scoring groups (15-53) were 71.899 (95%CI: 23.926-216.062, p<0.001) and 4.800 (95% CI: 2.263-10.182, p<0.001), respectively, compared with the high-scoring SESS group (60-75). CONCLUSION: Age, severity of periodontitis, periodontal surgery and the level of self-efficacy for self-care may be effective predictors of loss to follow-up in long-term supportive periodontal therapy in patients with chronic periodontitis. PMID- 29420588 TI - A closed-loop multi-level model of glucose homeostasis. AB - BACKGROUND: The pathophysiologic processes underlying the regulation of glucose homeostasis are considerably complex at both cellular and systemic level. A comprehensive and structured specification for the several layers of abstraction of glucose metabolism is often elusive, an issue currently solvable with the hierarchical description provided by multi-level models. In this study we propose a multi-level closed-loop model of whole-body glucose homeostasis, coupled with the molecular specifications of the insulin signaling cascade in adipocytes, under the experimental conditions of normal glucose regulation and type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: The ordinary differential equations of the model, describing the dynamics of glucose and key regulatory hormones and their reciprocal interactions among gut, liver, muscle and adipose tissue, were designed for being embedded in a modular, hierarchical structure. The closed-loop model structure allowed self-sustained simulations to represent an ideal in silico subject that adjusts its own metabolism to the fasting and feeding states, depending on the hormonal context and invariant to circadian fluctuations. The cellular level of the model provided a seamless dynamic description of the molecular mechanisms downstream the insulin receptor in the adipocytes by accounting for variations in the surrounding metabolic context. CONCLUSIONS/SIGNIFICANCE: The combination of a multi-level and closed-loop modeling approach provided a fair dynamic description of the core determinants of glucose homeostasis at both cellular and systemic scales. This model architecture is intrinsically open to incorporate supplementary layers of specifications describing further individual components influencing glucose metabolism. PMID- 29420589 TI - Comparison of switching bipolar ablation with multiple cooled wet electrodes and switching monopolar ablation with separable clustered electrode in treatment of small hepatocellular carcinoma: A randomized controlled trial. AB - OBJECTIVE: A randomized controlled trial was conducted to prospectively compare the therapeutic effectiveness of switching bipolar (SB) radiofrequency ablation (RFA) using cooled-wet electrodes and switching monopolar (SM) RFA using separable clustered (SC) electrodes in patients with hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: This prospective study was approved by our Institutional Review Board. Between April 2014 and January 2015, sixty-nine patients with 74 HCCs were randomly treated with RFA using either internally cooled-wet (ICW) electrodes in SB mode (SB-RFA, n = 36) or SC electrodes in SM mode (SM-RFA, n = 38). Technical parameters including the number of ablations, ablation time, volume, energy delivery, and complications were evaluated. Thereafter, 1-year and 2-year local tumor progression (LTP) free survival rates were compared between the two groups using the Kaplan-Meier method. RESULTS: In the SB-RFA group, less number of ablations were required (1.72+/-0.70 vs. 2.31+/ 1.37, P = 0.039), the ablation time was shorter (10.9+/-3.9 vs.14.3+/-5.0 min, p = 0.004), and energy delivery was smaller (13.1+/-6.3 vs.23.4+/-12.8 kcal, p<0.001) compared to SM-RFA. Ablation volume was not significantly different between SB-RFA and SM-RFA groups (61.8+/-24.3 vs.54.9+/-23.7 cm3, p = 0.229). Technical failure occurred in one patient in the SM-RFA group, and major complications occurred in one patient in each group. The 1-year and 2-year LTP free survival rates were 93.9% and 84.3% in the SB-RFA group and 94.4% and 88.4% in the SM-RFA group (p = 0.687). CONCLUSION: Both SB-RFA using ICW electrodes and SM-RFA using SC electrodes provided comparable LTP free survival rates although SB-RFA required less ablations and shorter ablation time. PMID- 29420590 TI - Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls. AB - OBJECTIVE: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC). METHOD: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis. RESULTS: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP 10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL 12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab. CONCLUSION: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL 23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS. PMID- 29420591 TI - Country of infection among HIV-infected patients born abroad living in French Guiana. AB - BACKGROUND: Over 75% of patients in the HIV cohort in French Guiana are of foreign origin. Our objective was to estimate what proportion of the migrant population of HIV-infected patients in Cayenne had been infected in French Guiana. METHODS: We included patients of known foreign origin who were followed in Cayenne, for whom the year of arrival in French Guiana was known and the initial CD4 count at the time of diagnosis was available. The time between seroconversion and time at diagnosis was estimated using the formula [square root (CD4 at seroconversion)-square root(CD4 at HIV diagnosis)] / slope of CD4 decline.CD4 counts at the time of infection and the slope were computed in an age and ethnicity-dependent variable. RESULTS: The median estimated time between infection and diagnosis was 4.5 years (IQR = 0.2-9.2). Overall, using a median estimate of CD4 count at the time of infection, it was estimated that 53.2% (95% CI = 48.3-58%) of HIV infected foreign patients had acquired HIV after having arrived in French Guiana. Patients having arrived in French Guiana before and during the 1990s and those receiving their HIV diagnosis before 2010 were more likely to have been infected in French Guiana. CONCLUSIONS: Contrary to widespread belief suggesting that most migrants are already HIV-infected when they arrive in French Guiana, a large proportion of foreign HIV patients seem acquire the virus in French Guiana.There is still much to do in terms of primary prevention and testing among migrants. PMID- 29420592 TI - Effects of fin fold mesenchyme ablation on fin development in zebrafish. AB - The evolution of the tetrapod limb involved an expansion and elaboration of the endoskeletal elements, while the fish fin rays were lost. Loss of fin-specific genes, and regulatory changes in key appendicular patterning genes have been identified as mechanisms of limb evolution, however their contributions to cellular organization and tissue differences between fins and limbs remains poorly understood. During early larval fin development, hoxa13a/hoxd13a expressing fin fold mesenchyme migrate through the median and pectoral fin along actinotrichia fibrils, non-calcified skeletal elements crucial for supporting the fin fold. Fin fold mesenchyme migration defects have previously been proposed as a mechanism of fin dermal bone loss during tetrapod evolution as it has been shown they contribute directly to the fin ray osteoblast population. Using the nitroreductase/metronidazole system, we genetically ablated a subset of hoxa13a/hoxd13a-expressing fin fold mesenchyme to assess its contributions to fin development. Following the ablation of fin fold mesenchyme in larvae, the actinotrichia are unable to remain rigid and the median and pectoral fin folds collapse, resulting in a reduced fin fold size. The remaining cells following ablation are unable to migrate and show decreased actinodin1 mesenchymal reporter activity. Actinodin proteins are crucial structural component of the actinotrichia. Additionally, we show a decrease in hoxa13a, hoxd13a, fgf10a and altered shha, and ptch2 expression during larval fin development. A continuous treatment of metronidazole leads to fin ray defects at 30dpf. Fewer rays are present compared to stage-matched control larvae, and these rays are shorter and less defined. These results suggest the targeted hoxa13a/hoxd13a-expressing mesenchyme contribute to their own successful migration through their contributions to actinotrichia. Furthermore, due to their fate as fin ray osteoblasts, we propose their initial ablation, and subsequent disorganization produces truncated fin dermal bone elements during late larval stages. PMID- 29420593 TI - Preconception paternal bisphenol A exposure induces sex-specific anxiety and depression behaviors in adult rats. AB - Bisphenol A (BPA), an environmental endocrine-disrupting compound, has drawn a great attention for its adverse effect on behavioral development. Maternal exposure to this compound has been reported to induce anxiety and depression in offspring, but the effect of its paternal exposure is rarely discussed. This study investigated whether preconception paternal BPA exposure can affect the emotions of male rats and their offspring. Eighteen adult male rats (F0) received either a vehicle or 50 MUg/kg/day BPA diet for 21 weeks and were then mated with non-exposed females to produce offspring (F1). The affective behaviors of F0 and F1 rats were evaluated in the open-field test, the elevated-plus maze and the forced swimming test, and their serum corticosterone were then examined. BPA exposure induced increased anxiety behaviors along with increased serum corticosterone in F0 rats. This paternal exposure also led to increased anxiety behaviors in F1 females and aggravated depression behaviors in both sexes of F1 rats. Furthermore, only F1 females exhibited increased serum corticosterone. Overall, these data indicate that preconception paternal exposure to a low dose of BPA may induce transgenerational sex-specific impairments in the affection of adult rats. PMID- 29420594 TI - Effects of metabolic syndrome on bone mineral density, histomorphometry and remodelling markers in male rats. AB - This study aimed to evaluate the effects of metabolic syndrome (MetS) induced by high-carbohydrate high-fat (HCHF) diet on bone mineral density (BMD), histomorphometry and remodelling markers in male rats. Twelve male Wistar rats aged 12 weeks old were randomized into two groups. The normal group was given standard rat chow while the HCHF group was given HCHF diet to induce MetS. Abdominal circumference, blood glucose, blood pressure, and lipid profile were measured for the confirmation of MetS. Bone mineral density, histomorphometry and remodelling markers were evaluated for the confirmation of bone loss. The HCHF diet caused central obesity, hyperglycaemia, hypertension, and dyslipidaemia in male rats. No significant difference was observed in whole body bone mineral content and BMD between the normal and HCHF rats (p>0.05). For bone histomorphometric parameters, HCHF diet-fed animals had significantly lower osteoblast surface, osteoid surface, osteoid volume, and significantly higher eroded surface; resulting in a reduction in trabecular bone volume (p<0.05). Feeding on HCHF diet caused a significantly higher CTX-1 level (p<0.05), but did not cause any significant change in osteocalcin level compared to normal rats (p>0.05). In conclusion, HCHF diet-induced MetS causes imbalance in bone remodelling, leading to the deterioration of trabecular bone structure. PMID- 29420595 TI - Combination therapy for cancer with oncolytic virus and checkpoint inhibitor: A mathematical model. AB - Oncolytic virus (OV) is a replication competent virus that selectively invades cancer cells; as these cells die under the viral burden, the released virus particles proceed to infect other cancer cells. Oncolytic viruses are designed to also be able to stimulate the anticancer immune response. Thus, one may represent an OV by two parameters: its replication potential and its immunogenicity. In this paper we consider a combination therapy with OV and a checkpoint inhibitor, anti-PD-1. We evaluate the efficacy of the combination therapy in terms of the tumor volume at some later time, for example, 6 months from initial treatment. Since T cells kill not only virus-free cancer cells but also virus-infected cancer cells, the following question arises: Does increasing the amount of the checkpoint inhibitor always improve the efficacy? We address this question, by a mathematical model consisting of a system of partial differential equations. We use the model to construct, by simulations, an efficacy map in terms of the doses of the checkpoint inhibitor and the OV injection. We show that there are regions in the map where an increase in the checkpoint inhibitor actually decreases the efficacy of the treatment. We also construct efficacy maps with checkpoint inhibitor vs. the replication potential of the virus that show the same antagonism, namely, an increase in the checkpoint inhibitor may actually decrease the efficacy. These results have implications for clinical trials. PMID- 29420596 TI - Flexible endoscopy for pediatric tracheobronchial metallic stent placement, maintenance and long-term outcomes. AB - OBJECTIVES: To assess the placement, surveillance management and long-term outcomes of the tracheobronchial (TB) balloon expandable metallic stent (BEMS) managed by therapeutic flexible endoscopy (TFE). METHODS: This is a retrospective review and analysis of all computerized medical records and related flexible endoscopy videos of pediatric patients who received TB BEMS during 20 years period, from January 1997 to December 2016. TFE techniques with forceps debridement, balloon dilatation and laser ablation were used to implant stents, perform regular surveillance, maintain their functions, and expand the diameters of BEMS. Short-length (30cm-36cm) endoscopes of OD 3.2mm to 5.0mm coupled with the noninvasive ventilation, without ventilation bag, mask or airway tube, supported the whole procedures. RESULTS: 146 BEMS were implanted in 87 consecutive children, including 84 tracheal, 15 carinal and 47 bronchial stents. At the time of placement, the mean age was 35.6 +/- 54.6 month-old (range 0.3 228) and the mean body weight was 13.9 +/- 10.6 kg (range 2.2-60). Surveillance period was 9.4 +/- 6.7 years (range, 0.3-18.0). Satisfactory clinical improvements were noted immediately in all but two patients. Seventy-two (82.8%) patients were still alive with stable respiratory status, except two patients necessitating TFE management every two months. Fifty-one stents, including 35 tracheal and 16 bronchial ones, were successfully retrieved mainly with rigid endoscopy. Implanted stents could be significantly (< .001) further expanded for growing TB lumens. The final stent diameters were positively correlated to the implanted duration. Altogether, 33 stents expired (15 patients), 51 were retrieved (40 patients), and 62 remained and functioning well (38 patients), with their mean duration of 7.4 +/- 9.5, 34.9 +/- 36.3 and 82.3 +/- 62.5 months, respectively. CONCLUSION: In pediatric patients, TFE with short-length scopes coupled with this NIV support has provided a safe, feasible and effective modality in placing and subsequently managing TB BEMS with acceptable long-term outcomes. PMID- 29420597 TI - Geographical and environmental determinants of the genetic structure of wild barley in southeastern Anatolia. AB - Despite the global value of barley, compared to its wild progenitor, genetic variation in this crop has been drastically reduced due to the process of domestication, selection and improvement. In the medium term, this will negatively impact both the vulnerability and yield stability of barley against biotic and abiotic stresses under climate change. Returning to the crop wild relatives (CWR) as sources of new and beneficial alleles is a clear option for enhancing the resilience of diversity and adaptation to climate change. Southeastern Anatolia constitutes an important part of the natural distribution of wild barley in the Fertile Crescent where important crops were initially domesticated. In this study, we investigated genetic diversity in a comprehensive collection of 281 geo-referenced wild barley individuals from 92 collection sites with sample sizes ranging from 1 to 9 individuals per site, collected from southeastern Anatolia and 131 domesticated genotypes from 49 different countries using 40 EST-SSR markers. A total of 375 alleles were detected across entire collection, of which 283 were carried by domesticated genotypes and 316 alleles were present in the wild gene pool. The number of unique alleles in the wild and in the domesticated gene pool was 92 and 59, respectively. The population structure at K = 3 suggested two groups of wild barley namely G1-W consisting wild barley genotypes from the western part and G1-E comprising those mostly from the eastern part of the study area, with a sharp separation from the domesticated gene pool. The geographic and climatic factors jointly showed significant effects on the distribution of wild barley. Using a Latent Factor Mixed Model, we identified four candidate loci potentially involved in adaptation of wild barley to three environmental factors: temperature seasonality, mean temperature of driest quarter, and precipitation of coldest quarter. These loci are probably the targets of genomic regions, with potential roles against abiotic stresses. PMID- 29420598 TI - Antenatal care service quality increases the odds of utilizing institutional delivery in Bahir Dar city administration, North Western Ethiopia: A prospective follow up study. AB - BACKGROUND: In Ethiopia, more than 62% of pregnant women attend antenatal care at least once, yet only about one in four women give birth at health facility. This gap has fueled the need to investigate on the quality of ANC services at public health facilities and its link with the use of institutional delivery. OBJECTIVE: To assess the linkage between ANC quality and the use of institutional delivery among pregnant women attending ANC at public health facilities of BDR City Administration. METHODS: A facility based prospective follow up study was conducted. and nine hundred seventy pregnant women with gestational age <= 16 weeks who came for their first ANC visit were enrolled.Women were followed from their first ANC visit until delivery. Longitudinal data was collected during consultation with ANC providers using structured observation checklist. ANC service was considered as acceptable quality if women received >=75th percentile of the essential ANC services. Generalized Estimating Equation (GEE) was carried out to control cluster effect among women who received ANC in the same facility. RESULTS: Among 823 pregnant women who completed follow up, only about one third (27.6%) received acceptable quality of ANC services. In one health facility syphilis test was not done at all for the last two years. The odds of giving birth at health institution among pregnant women who received acceptable ANC quality service was about 3.38 times higher than among pregnant women who received unacceptable ANC quality service (AOR = 3.38, 95% CI: 1.67, 6.83). CONCLUSION AND RECOMMENDATION: In this study the quality of ANC service provision in public health facilities was compromised/low. Provision of quality ANC service had a great role in promoting institutional delivery. Therefore the local authorities at each level of health sector or the nongovernmental organizations working to improve maternal health need to provide training on focused antenatal care protocol for ANC providers. PMID- 29420599 TI - Comorbidity, disability, and healthcare expenditure of ankylosing spondylitis in Korea: A population-based study. AB - BACKGROUND: Ankylosing spondylitis (AS) is an inflammatory rheumatic disease typically diagnosed in young age and follows a chronic progressive course. Its impact on the patient is life-long and the burden that AS exerts on society is increasing cumulatively every year. We aimed to quantify the burden of AS and to identify the factors associated with comorbidity, disability, and healthcare expenditure in Korean AS patients. METHODS: We conducted a nationwide, population based study using health insurance data (2003-2013). The analysis included individuals with incident AS (1,111 patients) and controls (5,555 patients) matched by age, sex, income, and geographic region. The incidence rates of extra articular manifestations (EAMs), comorbidities, mortality, and disability (type and severity) were compared between AS patients and controls. Annual health expenditure per patient was also analyzed. Associations were expressed as odds ratios (ORs) with 95% confidence intervals (95%CIs). RESULTS: During the follow up, 28% of AS patients experienced at least one EAM. AS diagnosis was significantly associated with Charlson comorbidity index >=3 (OR 2.18, 95% CI 1.91-2.48). Disability rate was higher in AS patients than in controls regardless of cause and severity (OR 2.94, 95% CI 2.48-3.48), but crude incidence rate ratios for mortality were not significantly higher. On multivariate analysis, male sex (OR 3.18, 95% CI 2.13-4.75), presence of an EAM (OR 1.63, 95% CI 1.15 2.32), and older age at diagnosis (OR 1.27, 95% CI 1.20-1.35) were evidently associated with increased disability in AS. Presence of an EAM was also associated with increased AS-unrelated expenditures in biologic-naive patients (median, 1112 vs. 877 USD per person, P < 0.05). CONCLUSIONS: In patients with AS, demographic factors and systemic manifestations including EAMs and other comorbidities were associated with increased disability and healthcare expenditures. PMID- 29420600 TI - Effects of precipitation changes on switchgrass photosynthesis, growth, and biomass: A mesocosm experiment. AB - Climate changes, including chronic changes in precipitation amounts, will influence plant physiology and growth. However, such precipitation effects on switchgrass, a major bioenergy crop, have not been well investigated. We conducted a two-year precipitation simulation experiment using large pots (95 L) in an environmentally controlled greenhouse in Nashville, TN. Five precipitation treatments (ambient precipitation, and -50%, -33%, +33%, and +50% of ambient) were applied in a randomized complete block design with lowland "Alamo" switchgrass plants one year after they were established from tillers. The growing season progression of leaf physiology, tiller number, height, and aboveground biomass were determined each growing season. Precipitation treatments significantly affected leaf physiology, growth, and aboveground biomass. The photosynthetic rates in the wet (+50% and +33%) treatments were significantly enhanced by 15.9% and 8.1%, respectively, than the ambient treatment. Both leaf biomass and plant height were largely increased, resulting in dramatically increases in aboveground biomass by 56.5% and 49.6% in the +50% and +33% treatments, respectively. Compared to the ambient treatment, the drought (-33% and -50%) treatments did not influence leaf physiology, but the -50% treatment significantly reduced leaf biomass by 37.8%, plant height by 16.3%, and aboveground biomass by 38.9%. This study demonstrated that while switchgrass in general is a drought tolerant grass, severe drought significantly reduces Alamo's growth and biomass, and that high precipitation stimulates its photosynthesis and growth. PMID- 29420601 TI - Taenia solium, Taenia saginata, Taenia asiatica, their hybrids and other helminthic infections occurring in a neglected tropical diseases' highly endemic area in Lao PDR. AB - Most part of Southeast Asia is considered endemic for human-infecting Taenia tapeworms; Taenia solium, T. saginata, and T. asiatica. However, until now there was no report of the occurrence of human cases of T. asiatica in Lao PDR. This study, conducted in Savannakhet Province, Lao PDR, microscopically examined a total of 470 fecal samples by Kato Katz method and found 86% of people harboring at least one helminth. Hookworms were detected in 56% of the samples besides Opisthorchis like eggs (42%), Trichuris trichiura (27%), Ascaris spp. (14%), and Taenia spp. (4%) eggs. Serology for cysticercosis showed 6.8% positives with results varying from 3% to 14.3% in Ethnic School students and Kalouk Kao village respectively. Species-specific PCR targeting mitochondrial DNA (mtDNA) of 28 tapeworms, recovered from 16 patients, revealed T. solium (n = 2), T. saginata (n = 21), and T. asiatica (n = 5). Two patients were confirmed to be coinfected with T. saginata and T. asiatica, indicating the endemicity of the 3 human Taenia in Lao PDR. However, nucleotide sequencing of a nuclear DNA gene, DNA polymerase delta (pold) revealed that all the tapeworms identified as T. asiatica using mtDNA had T. saginata type allele at pold locus, demonstrating that they are not "pure T. asiatica" but the hybrid descendants between the two species, confirming the wide distribution of hybrids of T. saginata/ T. asiatica in Southeast Asia. The high prevalence of several helminthic NTDs in east Savannakhet area even with conventional control measures indicates the importance to establish wide and multifaceted health programs to sustainably improve the quality of life of the populations living in these communities. PMID- 29420603 TI - Impact of underlying heart disease per se on the utility of preoperative NT proBNP in adult cardiac surgery. AB - OBJECTIVE: The primary aim was to investigate the role of underlying heart disease on preoperative NT-proBNP levels in patients admitted for adult cardiac surgery, after adjusting for the known confounders age, gender, obesity and renal function. The second aim was to investigate the predictive value of preoperative NT-proBNP with regard to severe postoperative heart failure (SPHF) and postoperative mortality. METHODS: A retrospective cohort study based on preoperative NT-proBNP measurements in an unselected cohort including all patients undergoing first time surgery for coronary artery disease (CAD; n = 2226), aortic stenosis (AS; n = 406) or mitral regurgitation (MR; n = 346) from April 2010 to August 2016 in the southeast region of Sweden (n = 2978). Concomitant procedures were not included, with the exception of Maze or tricuspid valve procedures. RESULTS: Preoperative NT-proBNP was 1.67 times (p<0.0001) and 1.41 times (p<0.0001) higher in patients with AS or MR respectively, than in patients with CAD after adjusting for confounders. NT-proBNP demonstrated significant discrimination with regard to SPHF in CAD (AUC = 0.79, 95%CI 0.73 0.85, p<0.0001), MR (AUC = 0.80, 95%CI 0.72-0.87, p<0.0001) and AS (AUC = 0.66, 95%CI 0.51-0.81, p = 0.047). In CAD patients NT-proBNP demonstrated significant discrimination with regard to postoperative 30-day or in-hospital mortality (AUC = 0.78; 95%CI 0.71-0.85, p<0.0001). The number of deaths was too few in the AS and MR group to permit analysis. Elevated NT-proBNP emerged as an independent risk factor for SPHF, and postoperative mortality in CAD. CONCLUSIONS: Patients with AS or MR have higher preoperative NT-proBNP than CAD patients even after adjusting for confounders. The predictive value of NT-proBNP with regard to SPHF was confirmed in CAD and MR patients but was less convincing in AS patients. PMID- 29420602 TI - Extended diversity analysis of cultivated grapevine Vitis vinifera with 10K genome-wide SNPs. AB - Grapevine is a very important crop species that is mainly cultivated worldwide for fruits, wine and juice. Identification of the genetic bases of performance traits through association mapping studies requires a precise knowledge of the available diversity and how this diversity is structured and varies across the whole genome. An 18k SNP genotyping array was evaluated on a panel of Vitis vinifera cultivars and we obtained a data set with no missing values for a total of 10207 SNPs and 783 different genotypes. The average inter-SNP spacing was ~47 kbp, the mean minor allele frequency (MAF) was 0.23 and the genetic diversity in the sample was high (He = 0.32). Fourteen SNPs, chosen from those with the highest MAF values, were sufficient to identify each genotype in the sample. Parentage analysis revealed 118 full parentages and 490 parent-offspring duos, thus confirming the close pedigree relationships within the cultivated grapevine. Structure analyses also confirmed the main divisions due to an eastern-western gradient and human usage (table vs. wine). Using a multivariate approach, we refined the structure and identified a total of eight clusters. Both the genetic diversity (He, 0.26-0.32) and linkage disequilibrium (LD, 28.8-58.2 kbp) varied between clusters. Despite the short span LD, we also identified some non recombining haplotype blocks that may complicate association mapping. Finally, we performed a genome-wide association study that confirmed previous works and also identified new regions for important performance traits such as acidity. Taken together, all the results contribute to a better knowledge of the genetics of the cultivated grapevine. PMID- 29420605 TI - The fate and effect of monensin during anaerobic digestion of dairy manure under mesophilic conditions. AB - There is growing concern about residual antibiotics and feed additives in the manure of treated animals because of the effects of these residues in the environment. Monensin is the most widely used ionophore coccidiostat in the U.S. The objective of this study was to determine the fate and effect of monensin during the anaerobic digestion of dairy manure. Duplicate plug flow field-scale digesters were operated using non-amended dairy manure and dairy manure amended with monensin to 1 and 10 mg/L for 56 days at 30 degrees C at an organic loading rate of 1.4 kg VS/m3-d and 17-day hydraulic retention time. Results showed that monensin was reduced approximately 70% during anaerobic digestion. Methane production from digesters using manure amended with 1 mg/L monensin was comparable to that from digesters operated without added monensin. However, digesters using manure amended with 10 mg/L monensin yielded 75% less methane than digesters using manure without added monensin. These results suggest that anaerobic digestion is an effective treatment for reducing, but not eliminating, monensin in dairy manure. Monensin did not reduce methane production at concentrations expected in dairy manure at recommended dosage rates. PMID- 29420604 TI - Opioid utilization among pediatric patients treated for newly diagnosed acute myeloid leukemia. AB - PURPOSE: A cohort of pediatric patients with AML treated at hospitals contributing to the Pediatric Health Information System was used to evaluate differences in opioid utilization by sex, age, race, and insurance. METHODS: Billing data were used to compute the prevalence of opioid exposure and to quantify rates of utilization among those exposed to opioids as days of use per 1000 inpatient days. Multivariable regressions were used to compare opioid prevalence, and rates of utilization among those exposed. RESULTS: On average across courses, 95.2% of patients were exposed to analgesics, 84.7% were exposed to non-opioid analgesics and 77.7% were exposed to opioids. The proportion of opioid-exposed patients increased with age, but did not differ by gender, race, or insurance status. Analyses limited to patients exposed to opioids revealed modest differences in days of opioid use among female patients (adjusted rate ratio (aRR) = 1.19, 95% CI: 1.11, 1.28), patients <1 year (aRR = 1.37, 95% CI: 1.21, 1.55) or >=10 years of age (aRR = 1.63, 95% CI: 1.46, 1.82), whereas Asian patients received fewer days of opioids compared with white patients (aRR = 0.76, 95% CI: 0.61, 0.95). There was moderate hospital-level variability in both the prevalence of opioid utilization overall and preference for specific opioid medications. There was greater inconsistency in practice concerning choices for supplemental and alternative opioids than in first-line opioid utilization. CONCLUSION: Additional work is needed to discern whether observed differences in opioid utilization by age and race reflect a difference in treatment or a difference in the experience of pain. Future studies should also explore the factors which guide decisions on opioid selections in an attempt to explain the variability across institutions. PMID- 29420606 TI - Multifunctional nanoparticles for real-time evaluation of toxicity during fetal development. AB - Increasing production of nanomaterials in industrial quantities has led to public health concerns regarding exposure, particularly among pregnant women and developing fetuses. Information regarding the barrier capacity of the placenta for various nanomaterials is limited due to challenges working with ex vivo human placentas or in vivo animal models. To facilitate real-time in vivo imaging of placental transport, we have developed a novel, multifunctional nanoparticle, based on a core of mesoporous silica nanoparticles (MSN), and functionalized for magnetic resonance imaging (MRI), ultrasound, and fluorescent microscopy. Our MSN particles were tested as a tracking method for harmful and toxic nanomaterials. In gravid mice, intravenous injections of MSN were administered in the maternal circulation in early gestation (day 9) and late gestation (day 14). MRI and ultrasound were used to track the MSN following the injections. Changes in contrast relative to control mice indicated that MSN were observed in the embryos of mice following early gestation injections, while MSN were excluded from the embryo by the placenta following late gestation injections. The timing of transplacental barrier porosity is consistent with the notion that in mice there is a progressive increasing segregation by the placenta in later gestation. In addition, built-in physico-chemical properties of our MSN may present options for the therapeutic treatment of embryonic exposure. For example, if preventive measures such as detoxification of harmful compounds are implemented, the particle size and exposure timing can be tailored to selectively distribute to the maternal side of the trophoblast or delivered to the fetus. PMID- 29420607 TI - Chronic pain patients can be classified into four groups: Clustering-based discriminant analysis of psychometric data from 4665 patients referred to a multidisciplinary pain centre (a SQRP study). AB - OBJECTIVE: To subgroup chronic pain patients using psychometric data and regress the variables most responsible for subgroup discrimination. DESIGN: Cross sectional, registry-based study. SETTING AND SUBJECTS: Chronic pain patients assessed at a multidisciplinary pain centre between 2008 and 2015. METHODS: Data from the Swedish quality registry for pain rehabilitation (SQRP) were retrieved and analysed by principal component analysis, hierarchical clustering analysis, and partial least squares-discriminant analysis. RESULTS: Four subgroups were identified. Group 1 was characterized by low "psychological strain", the best relative situation concerning pain characteristics (intensity and spreading), the lowest frequency of fibromyalgia, as well as by a slightly older age. Group 2 was characterized by high "psychological strain" and by the most negative situation with respect to pain characteristics (intensity and spreading). Group 3 was characterized by high "social distress", the longest pain durations, and a statistically higher frequency of females. The frequency of three neuropathic pain conditions was generally lower in this group. Group 4 was characterized by high psychological strain, low "social distress", and high pain intensity. CONCLUSIONS: The identification of these four clusters of chronic pain patients could be useful for the development of personalized rehabilitation programs. For example, the identification of a subgroup characterized mainly by high perceived "social distress" raises the question of how to best design interventions for such patients. Differentiating between clinically important subgroups and comparing how these subgroups respond to interventions is arguably an important area for further research. PMID- 29420608 TI - alphaEbeta7, alpha4beta7 and alpha4beta1 integrin contributions to T cell distribution in blood, cervix and rectal tissues: Potential implications for HIV transmission. AB - Cell surface expression of alpha4beta7, alpha4beta1 and alphaEbeta7 integrins play a key role in T cell distribution. Understanding the contribution of integrins to the density and ratios of CD4+: CD4negT cell at the portals of entry for HIV is of fundamental importance for the advance of more effective HIV prevention strategies. We therefore set out to characterize and compare the expression of alpha4beta7, alpha4beta1 and alphaEbeta7 integrins on systemic, cervical and rectal CD4+ and CD4negT cells isolated from a cohort of healthy Kenyan women at low risk for sexually transmitted infections (STI) (n = 45). Here we show that blood and cervix were enriched in alpha4+beta1+CD4+T cells and alpha4+beta7hiCD4+T cells, whereas the rectum had an equal frequency of alpha4+beta7hiCD4+T cells and alphaE+beta7hiCD4+T cells. Most cervical and rectal alphaE+beta7hiCD4+T cells expressed CCR5 as well as CD69. Interestingly, alphaEbeta7 was the predominant integrin expressed by CD4negT cells in both mucosal sites, outnumbering alphaE+beta7hiCD4+T cells approximately 2-fold in the cervix and 7-fold in the rectum. The majority of alphaE+beta7hiCD4negT cells expressed CD69 at the mucosa. Taken together, our results show unique tissue specific patterns of integrin expression. These results can help in guiding vaccine design and also the use of therapeutically targeting integrin adhesion as a means to preventing HIV. PMID- 29420609 TI - Construction and analysis for differentially expressed long non-coding RNAs and MicroRNAs mediated competing endogenous RNA network in colon cancer. AB - Long non-coding RNA (lncRNA) has been confirmed to act as a key regulatory molecule in different types of cancers and play a significant role in tumors initiation and progression. LncRNA can be as acompeting endogenous RNA(ceRNA) to regulate the expression of targeted genes by sponging miRNA. In the present study, we explore the functional roles and regulatory mechanisms of lncRNAs as ceRNAs in colon cancer and their potential implications for prognosis.The lncRNAs, miRNAs and mRNAs expression profiles of 341 colon cancer tissues and 27 non-tumor colon tissues were downloaded from The Cancer Genome Atlas (TCGA) database. Differential expression of RNAs was identified using the "DESeq" bioconductor package in R. PPI network of differentially expressed genes was constructed using the STRING database. Survival analysis was estimated based on Kaplan-Meier curve analysis. We used KOBAS 3.0 to analyze the KEGG pathway of DEGs. The dysregulated lncRNA-associated ceRNA network was constructed in colon cancer based on bioinformatics generated from miRanda, PicTar, TargetScan, miRDB and miRcode. A total of 791 DElncRNAs and 200 DEmiRNAs were identified in colon cancer compared with matched normal tissues with thresholds of |log2foldChange (FC)| >3.0and adjusted P value<0.05.Twenty DElncRNAs were identified, may be related to tumorigenesis and/or progression of colon cancer. Nine out of 20 dysregulated lncRNA were found to be significantly associated with overall survival (P value<0.05). Finally, we successfully constructed colon cancer associated ceRNA network, including 9 colon cancer-specific lncRNAs, 13 miRNAS and 70 mRNAs. In conclusion, our study will contribute to improve the understanding of ceRNA network regulatory mechanisms in colon cancer. These identified novel lncRNAs can be as candidate prognostic biomarkers or potential therapeutic targets. PMID- 29420610 TI - Estimation of actomyosin active force maintained by tropomyosin and troponin complex under vertical forces in the in vitro motility assay system. AB - The interaction between actin filaments and myosin molecular motors is a power source of a variety of cellular functions including cell division, cell motility, and muscular contraction. In vitro motility assay examines actin filaments interacting with myosin molecules that are adhered to a substrate (e.g., glass surface). This assay has been the standard method of studying the molecular mechanisms of contraction under an optical microscope. While the force generation has been measured through an optically trapped bead to which an actin filament is attached, a force vector vertical to the glass surface has been largely ignored with the in vitro motility assay. The vertical vector is created by the gap (distance) between the trapped bead and the glass surface. In this report, we propose a method to estimate the angle between the actin filament and the glass surface by optically determining the gap size. This determination requires a motorized stage in a standard epi-fluorescence microscope equipped with optical tweezers. This facile method is applied to force measurements using both pure actin filaments, and thin filaments reconstituted from actin, tropomyosin and troponin. We find that the angle-corrected force per unit filament length in the active condition (pCa = 5.0) decreases as the angle between the filament and the glass surface increases; i.e. as the force in the vertical direction increases. At the same time, we demonstrate that the force on reconstituted thin filaments is approximately 1.5 times larger than that on pure actin filaments. The range of angles we tested was between 11 degrees and 36 degrees with the estimated measurement error less than 6 degrees . These results suggest the ability of cytoplasmic tropomyosin isoforms maintaining actomyosin active force to stabilize cytoskeletal architecture. PMID- 29420611 TI - Inductions of granulosa cell luteinization and cumulus expansion are dependent on the fibronectin-integrin pathway during ovulation process in mice. AB - It has been known that EGF-like factor secreted from LH-stimulated granuloma cells acts on granulosa cells and cumulus cells to induce ovulation process. Granulosa cells are changed the morphology with differentiating cell functions to produce progesterone. Cumulus cells are detached to make a space between the cells to accumulate hyaluronan rich matrix. LH also changes extracellular matrix (ECM) components including fibronectin in the follicular walls and granulosa cell layers. EGF like factor and fibronectin synergistically play important roles in numerous cell functions, especially cancer cell migration, estimating that fibronectin would impact on granulosa cells and cumulus cells. To clear this hypothesis, the localizations of fibronectin and its receptor integrin were observed by immunofluorescence technique. The functions were monitored by the detection of downstream signaling pathway, focal adhesion kinase (FAK). The pharmacological approach in both in vivo and in vitro were used for analyzing the physiological roles of FAK during ovulation process. The immunofluorescence staining revealed that fibronectin and integrin were observed in granulosa cells, cumulus cells and the space between cumulus cells and oocyte at 4 and 8 h after hCG injection. Concomitantly with the changes of fibronectin-integrin localization, FAK was phosphorylated in periovulatory follicles. The injection of FAK inhibitor suppressed not only ovulation but also luteinization of granulosa cells and cumulus expansion. In cultured-granulosa cells, fibronectin-integrin synergistically activated FAK with amphiregulin (AREG). Such cooperative stimulations induced a morphological change in granulosa cells, which resulted in the maximum level of progesterone production via the induction of Hsd3b. When cumulus-oocyte complexes (COCs) were cultured with AREG in the presence of serum, the maximum level of cumulus expansion was observed. The AREG-induced cumulus expansion was also suppressed by FAK inhibitor. Thus, it is concluded that fibronectin and AREG synergistically activate FAK not only in granulosa cells and cumulus cells to induce successful ovulation process. PMID- 29420612 TI - Correlates of sexual initiation among European adolescents. AB - BACKGROUND: Sexuality is a physiological component of adolescent development, though early initiation is associated with reproductive health risk. This study aimed at identifying correlates and predictors of sexual initiation in a large multinational cohort of European adolescents. METHODS: A questionnaire addressing socio-demographics, behaviours, mental health and sexual activity, was delivered to 11,110 adolescents recruited from 168 randomly selected schools in 10 European countries between 2009 and 2011. A follow-up questionnaire was delivered after 12 months. The longitudinal association of baseline risk behaviors, psychological attributes and contextual vulnerabilities, with sexual initiation during follow up was evaluated through simple and multivariable age/sex stratified logistic regression. Multinomial logistic regression measured the association between predictors and sexual initiation with or without coexisting reproductive risk factors, such as multiple partners or infrequent condom use. RESULTS: Baseline sexual experience was reported by 19.2% of 10,757 respondents (median age 15; IQR 14-15; females 59.6%). This was significantly more frequent among pupils older than 15 (41%) and males (20.8%). Of 7,111 pupils without previous experience who were available at follow-up (response rate 81.8%), 17% reported sexual initiation, without differences between females and males. Baseline smoking (age/sex adjusted odds ratio [aOR] 3.63), alcohol use (aOR 2.95), illegal drugs use (aOR 2.72), and poor sleep (aOR 1.71) predicted sexual initiation. Stratified analyses showed a particularly strong association in case of younger and female pupils, and, among girls, when initiation was reported together with multiple partners and/or infrequent condom use. Externalizing (i.e. conduct and hyperactivity) symptoms independently predicted sexual initiation. Internalizing difficulties (i.e. emotional and peer problems) were negatively associated with early and risky sexual initiation among boys. Significant predictors included also being bullied, fighting, truancy, and low parental involvement. CONCLUSIONS: Adolescent sexual behaviours are related to non-sexual risk behaviours, psychological difficulties and contextual vulnerabilities. While gateway effects explain some associations, a comprehensive model is needed to understand adolescent sexual behaviours, their physical, mental, and social health outcomes, and their potential positive effects on wellbeing. Tailored interventions may need to consider younger girls as a particularly vulnerable group in view of a strong association between non-sexual and sexual behaviors. PMID- 29420614 TI - Correction: TWEAK Regulates Muscle Functions in a Mouse Model of RNA Toxicity. AB - [This corrects the article DOI: 10.1371/journal.pone.0150192.]. PMID- 29420613 TI - Patient-reported adherence to statin therapy, barriers to adherence, and perceptions of cardiovascular risk. AB - BACKGROUND: Patient reports of their adherence behaviors, concerns about statins, and perceptions of atherosclerotic cardiovascular disease (ASCVD) risk could inform approaches for improving adherence to statin therapy. We examined these factors and their associations with adherence. METHODS: We conducted telephone interviews among a stratified random sample of adults receiving statins within an integrated delivery system (N = 730, 81% response rate) in 2010. We sampled equal numbers of individuals in three clinical risk categories: those with 1) coronary artery disease; 2) diabetes or other ASCVD diagnosis; and 3) no diabetes or ASCVD diagnoses. We assessed 15 potential concerns about and barriers to taking statins, and perceived risk of having a heart attack in the next 10 years (0-10 scale). We calculated the proportion of days covered (PDC) by statins in the last 12 months using dispensing data and used multivariate logistic regression to examine the characteristics associated with non-adherence (PDC<80%). Analyses were weighted for sampling proportions. RESULTS: Sixty-one percent of patients with PDC<50% reported not filling a new prescription, splitting or skipping statins, or stopping refilling statins in the last 12 months vs. 15% of those with PDC>=80% (p<0.05). The most commonly reported concerns about statins were preferring to lower cholesterol with lifestyle changes (66%), disliking medications in general (59%), and liver or kidney problems (31%); having trouble remembering to take statins (9%) was the most common reason for taking less than prescribed. In multivariate analyses, clinical risk categories were not significantly associated with odds of non-adherence; however, those with higher perceived risk of heart attack were less likely to be non-adherent. CONCLUSIONS: Patient-reported medication-taking behaviors were correlated with statin PDC and those with lower perceived cardiovascular risk were less likely to be adherent. These findings highlight the importance of eliciting from and educating patients on their adherence behaviors and ASCVD risks. PMID- 29420615 TI - Correction: Socio-behavioral risk factors among older adults living with HIV in Thailand. AB - [This corrects the article DOI: 10.1371/journal.pone.0188088.]. PMID- 29420616 TI - Lactobacillus plantarum lipoteichoic acid inhibits biofilm formation of Streptococcus mutans. AB - Dental caries is a biofilm-dependent oral disease and Streptococcus mutans is the known primary etiologic agent of dental caries that initiates biofilm formation on tooth surfaces. Although some Lactobacillus strains inhibit biofilm formation of oral pathogenic bacteria, the molecular mechanisms by which lactobacilli inhibit bacterial biofilm formation are not clearly understood. In this study, we demonstrated that Lactobacillus plantarum lipoteichoic acid (Lp.LTA) inhibited the biofilm formation of S. mutans on polystyrene plates, hydroxyapatite discs, and dentin slices without affecting the bacterial growth. Lp.LTA interferes with sucrose decomposition of S. mutans required for the production of exopolysaccharide, which is a main component of biofilm. Lp.LTA also attenuated the biding of fluorescein isothiocyanate-conjugated dextran to S. mutans, which is known to have a high affinity to exopolysaccharide on S. mutans. Dealanylated Lp.LTA did not inhibit biofilm formation of S. mutans implying that D-alanine moieties in the Lp.LTA structure were crucial for inhibition. Collectively, these results suggest that Lp.LTA attenuates S. mutans biofilm formation and could be used to develop effective anticaries agents. PMID- 29420617 TI - Virologists-Heroes need weapons. PMID- 29420618 TI - Recombinant expression, purification and biochemical characterization of kievitone hydratase from Nectria haematococca. AB - Kievitone hydratase catalyzes the addition of water to the double bond of the prenyl moiety of plant isoflavonoid kievitone and, thereby, forms the tertiary alcohol hydroxy-kievitone. In nature, this conversion is associated with a defense mechanism of fungal pathogens against phytoalexins generated by host plants after infection. As of today, a gene sequence coding for kievitone hydratase activity has only been identified and characterized in Fusarium solani f. sp. phaseoli. Here, we report on the identification of a putative kievitone hydratase sequence in Nectria haematococca (NhKHS), the teleomorph state of F. solani, based on in silico sequence analyses. After heterologous expression of the enzyme in the methylotrophic yeast Pichia pastoris, we have confirmed its kievitone hydration activity and have assessed its biochemical properties and substrate specificity. Purified recombinant NhKHS is obviously a homodimeric glycoprotein. Due to its good activity for the readily available chalcone derivative xanthohumol (XN), this compound was selected as a model substrate for biochemical studies. The optimal pH and temperature for hydratase activity were 6.0 and 35 degrees C, respectively, and apparent Vmax and Km values for hydration of XN were 7.16 MUmol min-1 mg-1 and 0.98 +/- 0.13 mM, respectively. Due to its catalytic properties and apparent substrate promiscuity, NhKHS is a promising enzyme for the biocatalytic production of tertiary alcohols. PMID- 29420619 TI - A national survey of lung cancer specialists' views on low-dose CT screening for lung cancer in Korea. AB - Lung cancer specialists play an important role in designing and implementing lung cancer screening. We aimed to describe their 1) attitudes toward low-dose lung computed tomography (LDCT) screening, 2) current practices and experiences of LDCT screening and 3) attitudes and opinions towards national lung cancer screening program (NLCSP). We conducted a national web-based survey of pulmonologists, thoracic surgeons, medical oncologists, and radiological oncologists who are members of Korean Association for Lung Cancer (N = 183). Almost all respondents agreed that LDCT screening increases early detection (100%), improves survival (95.1%), and gives a good smoking cessation counseling opportunity (88.6%). Most were concerned about its high false positive results (79.8%) and the subsequent negative effects. Less than half were concerned about radiation hazard (37.2%). Overall, most (89.1%) believed that the benefits outweigh the risks and harms. Most (79.2%) stated that they proactively recommend LDCT screening to those who are eligible for the current guidelines, but the screening propensity varied considerably. The majority (77.6%) agreed with the idea of NLCSP and its beneficial effect, but had concerns about the quality control of CT devices (74.9%), quality assurance of radiologic interpretation (63.3%), poor access to LDCT (56.3%), and difficulties in selecting eligible population using self-report history (66.7%). Most (79.2%) thought that program need to be funded by a specialized fund rather than by the National Health Insurance. The opinions on the level of copayment for screening varied. Our findings would be an important source for health policy decision when considering for NLCSP in Korea. PMID- 29420620 TI - Validity and reliability of GPS and LPS for measuring distances covered and sprint mechanical properties in team sports. AB - This study aimed to investigate the validity and reliability of global (GPS) and local (LPS) positioning systems for measuring distances covered and sprint mechanical properties in team sports. Here, we evaluated two recently released 18 Hz GPS and 20 Hz LPS technologies together with one established 10 Hz GPS technology. Six male athletes (age: 27+/-2 years; VO2max: 48.8+/-4.7 ml/min/kg) performed outdoors on 10 trials of a team sport-specific circuit that was equipped with double-light timing gates. The circuit included various walking, jogging, and sprinting sections that were performed either in straight-lines or with changes of direction. During the circuit, athletes wore two devices of each positioning system. From the reported and filtered velocity data, the distances covered and sprint mechanical properties (i.e., the theoretical maximal horizontal velocity, force, and power output) were computed. The sprint mechanical properties were modeled via an inverse dynamic approach applied to the center of mass. The validity was determined by comparing the measured and criterion data via the typical error of estimate (TEE), whereas the reliability was examined by comparing the two devices of each technology (i.e., the between device reliability) via the coefficient of variation (CV). Outliers due to measurement errors were statistically identified and excluded from validity and reliability analyses. The 18 Hz GPS showed better validity and reliability for determining the distances covered (TEE: 1.6-8.0%; CV: 1.1-5.1%) and sprint mechanical properties (TEE: 4.5-14.3%; CV: 3.1-7.5%) than the 10 Hz GPS (TEE: 3.0 12.9%; CV: 2.5-13.0% and TEE: 4.1-23.1%; CV: 3.3-20.0%). However, the 20 Hz LPS demonstrated superior validity and reliability overall (TEE: 1.0-6.0%; CV: 0.7 5.0% and TEE: 2.1-9.2%; CV: 1.6-7.3%). For the 10 Hz GPS, 18 Hz GPS, and 20 Hz LPS, the relative loss of data sets due to measurement errors was 10.0%, 20.0%, and 15.8%, respectively. This study shows that 18 Hz GPS has enhanced validity and reliability for determining movement patterns in team sports compared to 10 Hz GPS, whereas 20 Hz LPS had superior validity and reliability overall. However, compared to 10 Hz GPS, 18 Hz GPS and 20 Hz LPS technologies had more outliers due to measurement errors, which limits their practical applications at this time. PMID- 29420621 TI - Animal TSEs and public health: What remains of past lessons? PMID- 29420622 TI - Study of retina and choroid biological parameters of rhesus monkeys eyes on scleral collagen cross-linking by riboflavin and ultraviolet A. AB - To evaluate ocular fundus biological changes after scleral collagen cross-linking (CXL) with riboflavin/ ultraviolet A (UVA) on rhesus monkeys in vivo by analyzing retina and choroid biological parameters. Six 3-year-old male rhesus monkeys (12 eyes) were observed in this study, with scleral CXL procedures applied on superior temporal equatorial sclera on random eyes of all rhesus. Optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) examination were performed before and 1 week, 1 month, 3 months and 6 months after CXL. The thickness of retina and choroid and the flow density of retinal superficial vascular networks were analyzed respectively in different regions after CXL. As for retina thickness and flow density of retinal superficial vascular networks, no statistical difference was noted between CXL eyes and control eyes at 1 day, 1week, 1 month, 3 months and 6 months (P>0.05). Among choroid parameters, the choroidal thickness in 1500MUm temporal to the fovea center of CXL eyes revealed a significant reduction in 1 week postoperatively (P<0.05), but it subsequently increased from 1 month postoperatively, and no statistical difference was found between two groups in the following periods (P>0.05). The choroidal thickness nearby crosslinked region may change temporarily following scleral CXL, and it might recover gradually after 1 month postoperatively. The vascular flow density and thickness of retina were not affected by scleral CXL. Further study should be performed to evaluate the potential adverse effects at the direct vicinity of the application site and the long-term effect of scleral CXL in clinical application. PMID- 29420623 TI - Correction: Evidence of molting and the function of "rock-nosing" behavior in bowhead whales in the eastern Canadian Arctic. AB - [This corrects the article DOI: 10.1371/journal.pone.0186156.]. PMID- 29420624 TI - The influence of a semi-arid sub-catchment on suspended sediments in the Mara River, Kenya. AB - The Mara River Basin in East Africa is a trans-boundary basin of international significance experiencing excessive levels of sediment loads. Sediment levels in this river are extremely high (turbidities as high as 6,000 NTU) and appear to be increasing over time. Large wildlife populations, unregulated livestock grazing, and agricultural land conversion are all potential factors increasing sediment loads in the semi-arid portion of the basin. The basin is well-known for its annual wildebeest (Connochaetes taurinus) migration of approximately 1.3 million individuals, but it also has a growing population of hippopotami (Hippopotamus amphibius), which reside within the river and may contribute to the flux of suspended sediments. We used in situ pressure transducers and turbidity sensors to quantify the sediment flux at two sites for the Mara River and investigate the origin of riverine suspended sediment. We found that the combined Middle Mara Talek catchment, a relatively flat but semi-arid region with large populations of wildlife and domestic cattle, is responsible for 2/3 of the sediment flux. The sediment yield from the combined Middle Mara-Talek catchment is approximately the same as the headwaters, despite receiving less rainfall. There was high monthly variability in suspended sediment fluxes. Although hippopotamus pools are not a major source of suspended sediments under baseflow, they do contribute to short term variability in suspended sediments. This research identified sources of suspended sediments in the Mara River and important regions of the catchment to target for conservation, and suggests hippopotami may influence riverine sediment dynamics. PMID- 29420625 TI - Effects of ocean acidification and hydrodynamic conditions on carbon metabolism and dissolved organic carbon (DOC) fluxes in seagrass populations. AB - Global change has been acknowledged as one of the main threats to the biosphere and its provision of ecosystem services, especially in marine ecosystems. Seagrasses play a critical ecological role in coastal ecosystems, but their responses to ocean acidification (OA) and climate change are not well understood. There have been previous studies focused on the effects of OA, but the outcome of interactions with co-factors predicted to alter during climate change still needs to be addressed. For example, the impact of higher CO2 and different hydrodynamic regimes on seagrass performance remains unknown. We studied the effects of OA under different current velocities on productivity of the seagrass Zostera noltei, using changes in dissolved oxygen as a proxy for the seagrass carbon metabolism, and release of dissolved organic carbon (DOC) in a four-week experiment using an open-water outdoor mesocosm. Under current pH conditions, increasing current velocity had a positive effect on productivity, but this depended on shoot density. However, this positive effect of current velocity disappeared under OA conditions. OA conditions led to a significant increase in gross production rate and respiration, suggesting that Z. noltei is carbon limited under the current inorganic carbon concentration of seawater. In addition, an increase in non-structural carbohydrates was found, which may lead to better growing conditions and higher resilience in seagrasses subjected to environmental stress. Regarding DOC flux, a direct and positive relationship was found between current velocity and DOC release, both under current pH and OA conditions. We conclude that OA and high current velocity may lead to favourable growth scenarios for Z. noltei populations, increasing their productivity, non structural carbohydrate concentrations and DOC release. Our results add new dimensions to predictions on how seagrass ecosystems will respond to climate change, with important implications for the resilience and conservation of these threatened ecosystems. PMID- 29420627 TI - Correction: Auditory and cognitive performance in elderly musicians and nonmusicians. AB - [This corrects the article DOI: 10.1371/journal.pone.0187881.]. PMID- 29420626 TI - Integrated micro/messenger RNA regulatory networks in essential thrombocytosis. AB - Essential thrombocytosis (ET) is a chronic myeloproliferative disorder with an unregulated surplus of platelets. Complications of ET include stroke, heart attack, and formation of blood clots. Although platelet-enhancing mutations have been identified in ET cohorts, genetic networks causally implicated in thrombotic risk remain unestablished. In this study, we aim to identify novel ET-related miRNA-mRNA regulatory networks through comparisons of transcriptomes between healthy controls and ET patients. Four network discovery algorithms have been employed, including (a) Pearson correlation network, (b) sparse supervised canonical correlation analysis (sSCCA), (c) sparse partial correlation network analysis (SPACE), and, (d) (sparse) Bayesian network analysis-all through a combined data-driven and knowledge-based analysis. The result predicts a close relationship between an 8-miRNA set (miR-9, miR-490-5p, miR-490-3p, miR-182, miR 34a, miR-196b, miR-34b*, miR-181a-2*) and a 9-mRNA set (CAV2, LAPTM4B, TIMP1, PKIG, WASF1, MMP1, ERVH-4, NME4, HSD17B12). The majority of the identified variables have been linked to hematologic functions by a number of studies. Furthermore, it is observed that the selected mRNAs are highly relevant to ET disease, and provide an initial framework for dissecting both platelet-enhancing and functional consequences of dysregulated platelet production. PMID- 29420628 TI - Correction: DeltaNp63alpha-Mediated Induction of Epidermal Growth Factor Receptor Promotes Pancreatic Cancer Cell Growth and Chemoresistance. AB - [This corrects the article DOI: 10.1371/journal.pone.0026815.]. PMID- 29420629 TI - Correction: Quantitative in vivo mapping of myocardial mitochondrial membrane potential. AB - [This corrects the article DOI: 10.1371/journal.pone.0190968.]. PMID- 29420630 TI - Correction: Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases. AB - [This corrects the article DOI: 10.1371/journal.pone.0177829.]. PMID- 29420631 TI - An alternatively spliced form affecting the Marked Box domain of Drosophila E2F1 is required for proper cell cycle regulation. AB - Across metazoans, cell cycle progression is regulated by E2F family transcription factors that can function as either transcriptional activators or repressors. For decades, the Drosophila E2F family has been viewed as a streamlined RB/E2F network, consisting of one activator (dE2F1) and one repressor (dE2F2). Here, we report that an uncharacterized isoform of dE2F1, hereon called dE2F1b, plays an important function during development and is functionally distinct from the widely-studied dE2F1 isoform, dE2F1a. dE2F1b contains an additional exon that inserts 16 amino acids to the evolutionarily conserved Marked Box domain. Analysis of de2f1b-specific mutants generated via CRISPR/Cas9 indicates that dE2F1b is a critical regulator of the cell cycle during development. This is particularly evident in endocycling salivary glands in which a tight control of dE2F1 activity is required. Interestingly, close examination of mitotic tissues such as eye and wing imaginal discs suggests that dE2F1b plays a repressive function as cells exit from the cell cycle. We also provide evidence demonstrating that dE2F1b differentially interacts with RBF1 and alters the recruitment of RBF1 and dE2F1 to promoters. Collectively, our data suggest that dE2F1b is a novel member of the E2F family, revealing a previously unappreciated complexity in the Drosophila RB/E2F network. PMID- 29420633 TI - Correction: Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. AB - [This corrects the article DOI: 10.1371/journal.pone.0186802.]. PMID- 29420632 TI - Implication of SPARC in the modulation of the extracellular matrix and mitochondrial function in muscle cells. AB - Secreted protein, acidic and rich in cysteine (SPARC) is differentially associated with cell proliferation and extracellular matrix (ECM) assembly. We show here the effect of exogenous SPARC inhibition/induction on ECM and mitochondrial proteins expression and on the differentiation of C2C12 cells. The cells were cultured in growth medium (GM) supplemented with different experimental conditions. The differentiation of myoblasts was studied for 5 days, the expressions of ECM and mitochondrial proteins were measured and the formation of the myotubes was quantified after exogenous induction/inhibition of SPARC. The results indicate that the addition of recombinant SPARC protein (rSPARC) in cell culture medium increased the differentiation of C2C12 myoblasts and myogenin expression during the myotube formation. However, the treatment with antibody specific for SPARC (anti-SPARC) prevented the differentiation and decreased myogenin expression. The induction of SPARC in the proliferating and differentiating C2C12 cells increased collagen 1a1 protein expression, whereas the inhibition decreased it. The effects on fibronectin protein expression were opposite. Furthermore, the addition of rSPARC in C2C12 myoblast increased the expression of mitochondrial proteins, ubiquinol-cytochrome c reductase core protein II (UQCRC2) and succinate dehydrogenase iron-sulfur subunit (SDHB), whereas the anti-SPARC decreased them. During the differentiation, only the anti SPARC had the effects on mitochondrial proteins, NADH dehydrogenase ubiquinone 1 beta subcomplex subunit 8 (NADHB8), SDHB and cytochrome c oxidase 1 (MTCO1). Thus, SPARC plays a crucial role in the proliferation and differentiation of C2C12 and may be involved in the link between the ECM remodeling and mitochondrial function. PMID- 29420634 TI - Ligand binding modulates the structural dynamics and activity of urokinase-type plasminogen activator: A possible mechanism of plasminogen activation. AB - The catalytic activity of trypsin-like serine proteases is in many cases regulated by conformational changes initiated by binding of physiological modulators to exosites located distantly from the active site. A trypsin-like serine protease of particular interest is urokinase-type plasminogen activator (uPA), which is involved in extracellular tissue remodeling processes. Herein, we used hydrogen/deuterium exchange mass spectrometry (HDXMS) to study regulation of activity in the catalytic domain of the murine version of uPA (muPA) by two muPA specific monoclonal antibodies. Using a truncated muPA variant (muPA16-243), containing the catalytic domain only, we show that the two monoclonal antibodies, despite binding to an overlapping epitope in the 37s and 70s loops of muPA16-243, stabilize distinct muPA16-243 conformations. Whereas the inhibitory antibody, mU1 was found to increase the conformational flexibility of muPA16-243, the stimulatory antibody, mU3, decreased muPA16-243 conformational flexibility. Furthermore, the HDXMS data unveil the existence of a pathway connecting the 70s loop to the active site region. Using alanine scanning mutagenesis, we further identify the 70s loop as an important exosite for the activation of the physiological uPA substrate plasminogen. Thus, the data presented here reveal important information about dynamics in uPA by demonstrating how various ligands can modulate uPA activity by mediating long-range conformational changes. Moreover, the results provide a possible mechanism of plasminogen activation. PMID- 29420635 TI - Correction: Pockets as structural descriptors of EGFR kinase conformations. AB - [This corrects the article DOI: 10.1371/journal.pone.0189147.]. PMID- 29420636 TI - Prediction models for patients with esophageal or gastric cancer: A systematic review and meta-analysis. AB - BACKGROUND: Clinical prediction models are increasingly used to predict outcomes such as survival in cancer patients. The aim of this study was threefold. First, to perform a systematic review to identify available clinical prediction models for patients with esophageal and/or gastric cancer. Second, to evaluate sources of bias in the included studies. Third, to investigate the predictive performance of the prediction models using meta-analysis. METHODS: MEDLINE, EMBASE, PsycINFO, CINAHL, and The Cochrane Library were searched for publications from the year 2000 onwards. Studies describing models predicting survival, adverse events and/or health-related quality of life (HRQoL) for esophageal or gastric cancer patients were included. Potential sources of bias were assessed and a meta analysis, pooled per prediction model, was performed on the discriminative abilities (c-indices). RESULTS: A total of 61 studies were included (45 development and 16 validation studies), describing 47 prediction models. Most models predicted survival after a curative resection. Nearly 75% of the studies exhibited bias in at least 3 areas and model calibration was rarely reported. The meta-analysis showed that the averaged c-index of the models is fair (0.75) and ranges from 0.65 to 0.85. CONCLUSION: Most available prediction models only focus on survival after a curative resection, which is only relevant to a limited patient population. Few models predicted adverse events after resection, and none focused on patient's HRQoL, despite its relevance. Generally, the quality of reporting is poor and external model validation is limited. We conclude that there is a need for prediction models that better meet patients' information needs, and provide information on both the benefits and harms of the various treatment options in terms of survival, adverse events and HRQoL. PMID- 29420637 TI - Isolation and characterization of mesenchymal stem cells from human fetus heart. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are promising cells for cardiovascular regenerative medicine. However, their potential may be limited, because of their restricted cardiovascular differentiation potential and decline in their number and functional characteristics with increasing donor age. We have previously shown that rat fetus heart harbors primitive MSCs and administration of these cells improved left ventricular (LV) function after ischemia/reperfusion injury in rats. To evaluate their potential as a new cell type for clinical cardiovascular cell therapy, we have undertaken this study on the isolation and characterization of human fetal cardiac MSCs (hfC-MSCs). METHODS: MSCs were isolated from the heart of five 14-16-week-old aborted human fetuses and studied for their growth characteristics, karyotypic stability and senescence over successive passages, expression of mesenchymal and embryonal markers by flow cytometry and immunocytochemistry, constitutive expression of cardiovascular genes by RT-PCR, differentiation into cells of the cardiovascular lineage and their immunomodulatory properties. RESULTS: The hfC-MSCs grew as adherent monolayer with spindle shaped morphology and exhibited rapid proliferation with an average population doubling time of 34 hours and expansion to up to more than 80 population doublings with maintenance of a normal karyotype and without senescence. Immunophenotyping showed that they had similar phenotype as human bone marrow mesenchymal stem cells (hBM-MSCs) expressing CD73, CD90, CD105 and lacking expression of CD31, CD34, CD45, HLA-DR. However, hfC-MSCs expressed significantly higher levels of CD117 and SSEA-4 compared to hBM-MSCs. In addition, hfC-MSCs expressed the embryonal markers Oct-4, Nanog and Sox-2 as compared to hBM-MSCs. Further, hfC-MSCs had significantly higher expression of the cardiovascular genes viz. ISL-1, flk-1, GATA-4, NKX2.5 and MDR-1 as compared to hBM-MSCs, and could be differentiated into major cardiovascular cells (cardiomyocytes, endothelial cells, smooth muscle cells). Interestingly, hfC-MSCs markedly reduced T-lymphocyte proliferation with an increased secretion of TGF beta and IL-10. CONCLUSIONS: Our results show that human fetus heart is a novel source of primitive MSCs with cardiovascular commitment which may have a potential therapeutic application in cardiovascular regenerative medicine. PMID- 29420638 TI - A desirability-based multi objective approach for the virtual screening discovery of broad-spectrum anti-gastric cancer agents. AB - Gastric cancer is the third leading cause of cancer-related mortality worldwide and despite advances in prevention, diagnosis and therapy, it is still regarded as a global health concern. The efficacy of the therapies for gastric cancer is limited by a poor response to currently available therapeutic regimens. One of the reasons that may explain these poor clinical outcomes is the highly heterogeneous nature of this disease. In this sense, it is essential to discover new molecular agents capable of targeting various gastric cancer subtypes simultaneously. Here, we present a multi-objective approach for the ligand-based virtual screening discovery of chemical compounds simultaneously active against the gastric cancer cell lines AGS, NCI-N87 and SNU-1. The proposed approach relays in a novel methodology based on the development of ensemble models for the bioactivity prediction against each individual gastric cancer cell line. The methodology includes the aggregation of one ensemble per cell line using a desirability-based algorithm into virtual screening protocols. Our research leads to the proposal of a multi-targeted virtual screening protocol able to achieve high enrichment of known chemicals with anti-gastric cancer activity. Specifically, our results indicate that, using the proposed protocol, it is possible to retrieve almost 20 more times multi-targeted compounds in the first 1% of the ranked list than what is expected from a uniform distribution of the active ones in the virtual screening database. More importantly, the proposed protocol attains an outstanding initial enrichment of known multi-targeted anti gastric cancer agents. PMID- 29420639 TI - Cognitive dysfunction in naturally occurring canine idiopathic epilepsy. AB - Globally, epilepsy is a common serious brain disorder. In addition to seizure activity, epilepsy is associated with cognitive impairments including static cognitive impairments present at onset, progressive seizure-induced impairments and co-morbid dementia. Epilepsy occurs naturally in domestic dogs but its impact on canine cognition has yet to be studied, despite canine cognitive dysfunction (CCD) recognised as a spontaneous model of dementia. Here we use data from a psychometrically validated tool, the canine cognitive dysfunction rating (CCDR) scale, to compare cognitive dysfunction in dogs diagnosed with idiopathic epilepsy (IE) with controls while accounting for age. An online cross-sectional study resulted in a sample of 4051 dogs, of which n = 286 had been diagnosed with IE. Four factors were significantly associated with a diagnosis of CCD (above the diagnostic cut-off of CCDR >=50): (i) epilepsy diagnosis: dogs with epilepsy were at higher risk; (ii) age: older dogs were at higher risk; (iii) weight: lighter dogs (kg) were at higher risk; (iv) training history: dogs with more exposure to training activities were at lower risk. Impairments in memory were most common in dogs with IE, but progression of impairments was not observed compared to controls. A significant interaction between epilepsy and age was identified, with IE dogs exhibiting a higher risk of CCD at a young age, while control dogs followed the expected pattern of low-risk throughout middle age, with risk increasing exponentially in geriatric years. Within the IE sub-population, dogs with a history of cluster seizures and high seizure frequency had higher CCDR scores. The age of onset, nature and progression of cognitive impairment in the current IE dogs appear divergent from those classically seen in CCD. Longitudinal monitoring of cognitive function from seizure onset is required to further characterise these impairments. PMID- 29420640 TI - Disparities in availability of essential medicines to treat non-communicable diseases in Uganda: A Poisson analysis using the Service Availability and Readiness Assessment. AB - OBJECTIVE: Although the WHO-developed Service Availability and Readiness Assessment (SARA) tool is a comprehensive and widely applied survey of health facility preparedness, SARA data have not previously been used to model predictors of readiness. We sought to demonstrate that SARA data can be used to model availability of essential medicines for treating non-communicable diseases (EM-NCD). METHODS: We fit a Poisson regression model using 2013 SARA data from 196 Ugandan health facilities. The outcome was total number of different EM-NCD available. Basic amenities, equipment, region, health facility type, managing authority, NCD diagnostic capacity, and range of HIV services were tested as predictor variables. FINDINGS: In multivariate models, we found significant associations between EM-NCD availability and region, managing authority, facility type, and range of HIV services. For-profit facilities' EM-NCD counts were 98% higher than public facilities (p < .001). General hospitals and referral health centers had 98% (p = .004) and 105% (p = .002) higher counts compared to primary health centers. Facilities in the North and East had significantly lower counts than those in the capital region (p = 0.015; p = 0.003). Offering HIV care was associated with 35% lower EM-NCD counts (p = 0.006). Offering HIV counseling and testing was associated with 57% higher counts (p = 0.048). CONCLUSION: We identified multiple within-country disparities in availability of EM-NCD in Uganda. Our findings can be used to identify gaps and guide distribution of limited resources. While the primary purpose of SARA is to assess and monitor health services readiness, we show that it can also be an important resource for answering complex research and policy questions requiring multivariate analysis. PMID- 29420641 TI - When are pathogen genome sequences informative of transmission events? AB - Recent years have seen the development of numerous methodologies for reconstructing transmission trees in infectious disease outbreaks from densely sampled whole genome sequence data. However, a fundamental and as of yet poorly addressed limitation of such approaches is the requirement for genetic diversity to arise on epidemiological timescales. Specifically, the position of infected individuals in a transmission tree can only be resolved by genetic data if mutations have accumulated between the sampled pathogen genomes. To quantify and compare the useful genetic diversity expected from genetic data in different pathogen outbreaks, we introduce here the concept of 'transmission divergence', defined as the number of mutations separating whole genome sequences sampled from transmission pairs. Using parameter values obtained by literature review, we simulate outbreak scenarios alongside sequence evolution using two models described in the literature to describe transmission divergence of ten major outbreak-causing pathogens. We find that while mean values vary significantly between the pathogens considered, their transmission divergence is generally very low, with many outbreaks characterised by large numbers of genetically identical transmission pairs. We describe the impact of transmission divergence on our ability to reconstruct outbreaks using two outbreak reconstruction tools, the R packages outbreaker and phybreak, and demonstrate that, in agreement with previous observations, genetic sequence data of rapidly evolving pathogens such as RNA viruses can provide valuable information on individual transmission events. Conversely, sequence data of pathogens with lower mean transmission divergence, including Streptococcus pneumoniae, Shigella sonnei and Clostridium difficile, provide little to no information about individual transmission events. Our results highlight the informational limitations of genetic sequence data in certain outbreak scenarios, and demonstrate the need to expand the toolkit of outbreak reconstruction tools to integrate other types of epidemiological data. PMID- 29420642 TI - Evaluation of inner retinal layers as biomarkers in mild cognitive impairment to moderate Alzheimer's disease. AB - Inner retina in Alzheimer's Disease (AD) may experience neuroinflammation resulting in atrophy. The objective of our study was to determine whether retinal GCIPL (ganglion cell-inner plexiform layer) or nerve fiber layer (NFL) thickness may serve as noninvasive biomarkers to diagnose AD. This cross-sectional case control study enrolled 15 mild cognitive impairment (MCI) patients, 15 mild moderate AD patients, and 18 cognitively normal adults. NFL and GCIPL thicknesses on optical coherence tomography (OCT) were measured using Duke Optical Coherence Tomography Retinal Analysis Program (DOCTRAP) and Spectralis software. We demonstrated that regional thicknesses of NFL or GCIPL on macular or nerve OCTs did not differ between groups. However, a multi-variate regression analysis identified macular areas with a significant thickening or thinning in NFL and GCIPL in MCI and AD patients. Our primary findings controvert previous reports of thinner NFL in moderate-to-severe AD. The areas of thickening of GCIPL and NFL in the macula adjacent to areas of thinning, as revealed by a more complex statistical model, suggest that NFL and GCIPL may undergo dynamic changes during AD progression. PMID- 29420644 TI - Inference of financial networks using the normalised mutual information rate. AB - In this paper, we study data from financial markets, using the normalised Mutual Information Rate. We show how to use it to infer the underlying network structure of interrelations in the foreign currency exchange rates and stock indices of 15 currency areas. We first present the mathematical method and discuss its computational aspects, and apply it to artificial data from chaotic dynamics and to correlated normal-variates data. We then apply the method to infer the structure of the financial system from the time-series of currency exchange rates and stock indices. In particular, we study and reveal the interrelations among the various foreign currency exchange rates and stock indices in two separate networks, of which we also study their structural properties. Our results show that both inferred networks are small-world networks, sharing similar properties and having differences in terms of assortativity. Importantly, our work shows that global economies tend to connect with other economies world-wide, rather than creating small groups of local economies. Finally, the consistent interrelations depicted among the 15 currency areas are further supported by a discussion from the viewpoint of economics. PMID- 29420643 TI - Immunophenotypic characterization of human T cells after in vitro exposure to different silicone breast implant surfaces. AB - The most common complication of silicone breast implants is capsular contracture (massive scar formation around the implant). We postulate that capsular contracture is always a sequel to inflammatory processes, with both innate and adaptive immune mechanisms participating. In general, fibroblasts and macrophages have been used as cell types to evaluate in vitro the biocompatibility of breast implant surfaces. Moreover, also T cells have been found at the implant site at the initial stage of fibrous capsule formation. However, only few studies have addressed the influence of surfaces with different textures on T-cell responses. The aim of the present study was to investigate the immune response of human peripheral blood mononuclear cells (PBMC) to commercially available silicone breast implants in vitro. PBMC from healthy female blood donors were cultured on each silicone surface for 4 days. Proliferation and phenotype of cultured cells were assessed by flow cytometry. Cytokine levels were determined by multiplex and real-time assay. We found that silicone surfaces do not induce T-cell proliferation, nor do they extensively alter the proportion of T cell subsets (CD4, CD8, naive, effector memory). Interestingly, cytokine profiling identified matrix specific differences, especially for IL-6 and TNF-alpha on certain surface topographies that could lead to increased fibrosis. PMID- 29420645 TI - The role of global economic policy uncertainty in long-run volatilities and correlations of U.S. industry-level stock returns and crude oil. AB - We investigate how Global Economic Policy Uncertainty (GEPU) drives the long-run components of volatilities and correlations in crude oil and U.S. industry-level stock markets. Using the modified generalized autoregressive conditional heteroskedasticity mixed data sampling (GARCH-MIDAS) and dynamic conditional correlation mixed data sampling (DCC-MIDAS) specifications, we find that GEPU is positively related to the long-run volatility of Financials and Consumer Discretionary industries; however, it is negatively related to Information Technology, Materials, Telecommunication Services and Energy. Unlike the mixed role of GEPU in the long-run volatilities, the long-run correlations are all positively related to GEPU across the industries. Additionally, the rankings of the correlations of Energy and Materials are time-invariant and classified as high, with the little exception of the latter. The Consumer Staples industry is time-invariant in the low-ranking group. Our results are helpful to policy makers and investors with long-term concerns. PMID- 29420647 TI - Authors and editors assort on gender and geography in high-rank ecological publications. AB - Peer-reviewed publication volume and caliber are widely-recognized proxies for academic merit, and a strong publication record is essential for academic success and advancement. However, recent work suggests that publication productivity for particular author groups may also be determined in part by implicit biases lurking in the publication pipeline. Here, we explore patterns of gender, geography, and institutional rank among authors, editorial board members, and handling editors in high-impact ecological publications during 2015 and 2016. A higher proportion of lead authors had female first names (33.9%) than editorial board members (28.9%), and the proportion of female first names among handling editors was even lower (21.1%). Female editors disproportionately edited publications with female lead authors (40.3% of publications with female lead authors were handled by female editors, though female editors handled only 34.4% of all studied publications). Additionally, ecological authors and editors were overwhelmingly from countries in the G8, and high-ranking academic institutions accounted for a large portion of both the published work, and its editorship. Editors and lead authors with female names were typically affiliated with higher ranking institutions than their male peers. This description of author and editor features provides a baseline for benchmarking future trends in the ecological publishing culture. PMID- 29420646 TI - Employment status and mortality in the context of high and low regional unemployment levels in Belgium (2001-2011): A test of the social norm hypothesis across educational levels. AB - Because of compositional effects (more highly educated unemployed) and differences in the vulnerability towards the health consequences of unemployment (i.e. disappointment paradox hypothesis and/or status inconsistency for highly educated unemployed), it is argued that indicators of educational attainment need to be included when investigating the social norm of unemployment. Data from the 2001 census linked to register data from 2001-2011 are used, selecting all Belgian employed and unemployed between 30 and 59-year-old at time of the census. Poisson multilevel modelling was used to account for clustering of respondents within sub-districts. For individuals with low education levels, the relative difference in mortality rate ratios between the unemployed and employed is smallest in those regions where aggregate unemployment levels are high. For highly educated, this social norm effect was not found. This study suggest that the social norm effect is stronger for workers with low education levels, while highly educated workers suffer from disappointment and status inconsistency. PMID- 29420648 TI - Selection of surgical treatment approaches for cervicothoracic spinal tuberculosis: A 10-year case review. AB - BACKGROUND: Cervicothoracic spinal tuberculosis is a rare disease. Due to its difficult and challenging surgical exposure, its surgical treatment approach remains inconclusive. Long-term follow-up studies to address this puzzling issue are rarely seen in the literature. The purpose of this study was to explore the selection of surgical treatment approaches for cervicothoracic spinal tuberculosis through a 10-year case review. METHODS: From January 2003 to January 2013, 45 patients suffering from cervicothoracic spinal tuberculosis were treated surgically. According to the relation between the tuberculosis lesion segments and the suprasternal notch on sagittal MRI, 19 patients were treated with a single-stage anterior debridement, fusion and instrumentation approach, and the other 26 patients were treated with a single-stage anterior debridement and fusion, posterior fusion and instrumentation approach. The clinical efficacy was evaluated using statistical analysis based on the Cobb angle of kyphosis, the Neck Disability Index (NDI) and the Japanese Orthopedic Association (JOA) scoring system. The neurofunctional recovery was assessed by the American Spinal Injury Association (ASIA) system. RESULTS: All patients were followed up for 6.6 years on average (range 3-13 years). No instrumentation loosening, migration or breakage was observed during the follow-up. The kyphosis angle and NDI and JOA scores were significantly changed from preoperative values of 34.7+/-6.8 degrees , 39.6+/-4.6 and 10.7+/-2.8 to postoperative values of 10.2+/-2.4 degrees , 11.4+/-3.6 and 17.6+/-2.4, respectively (p<0.05). Aside from one recurrent patient, bone fusion was achieved in the other 44 patients within 6 to 9 months (mean 7.2 months). No severe postoperative complications occurred, and patients' neurologic function was improved in various degrees. CONCLUSIONS: In the surgical treatment of cervicothoracic spinal tuberculosis, single-stage cervical anterior approach with or without partial manubriotomy is capable of complete debridement for tuberculosis lesions. The manner of fixation should be selected based on the anatomical relation of the suprasternal notch and the diseased segments as revealed on sagittal MRI images. PMID- 29420649 TI - Income, occupation and education: Are they related to smoking behaviors in China? AB - BACKGROUND: The association between socioeconomic status (SES) and smoking behaviors may differ across countries. This study aimed to estimate the association between socioeconomic status (income, occupation and education) and multiple measures of smoking behaviors among the Chinese elderly population. METHODS: Using data from the China Health and Retirement Longitudinal Study in 2013, we examined the relationship between socioeconomic status and smoking behaviors through multivariate regression analysis. Sample selection models were applied to correct for sample selection bias. Smoking behaviors were measured by four indicators: smoking status, cigarette consumption, health risks related to smoking, and smoking dependence. Analyses were stratified by gender and urban rural residence. RESULTS: Among Chinese people aged 45 years or older, smokers accounted for 40% of the population in 2013, smoking 19 cigarettes per day. It was also found that 79% of smokers were at an increased health risk. Overall, although the influence of income on smoking behaviors was small and even insignificant, occupation and education levels were significantly associated with smoking behaviors. Managers or professionals were more likely to smoke, however there was no significant relationship with smoking dependence. Individuals with higher educational attainment were less likely to be associated with smoking behaviors. In addition, gender and urban-rural differences existed in the relationship between SES and smoking behaviors. CONCLUSIONS: Smoking disparities among diverse levels of socioeconomic status existed but varied greatly by SES indicators and population characteristics. Tobacco control policies in China should be increasingly focused on populations with low socioeconomic status in order to break the link between socioeconomic disadvantage and smoking behaviors. Further actions should mitigate inequalities in education, improve the social culture of cigarette use, and tailor interventions based on characteristics of the population. PMID- 29420650 TI - Context-dependent concurrent adaptation to static and moving targets. AB - Is the neural control of movements towards moving targets independent to that of static targets? In the following experiments, we used a visuomotor rotation adaptation paradigm to examine the extent to which adapting arm movements to static targets generalize to that of moving targets (i.e. pursuit or tracking). In the first and second experiments, we showed that adaptation to perturbed tracking movements generalizes to reaching movements; reach aftereffects following perturbed tracking were about half the size (~9 degrees ) of those produced following reach training (~ 19 degrees ). Given these findings, in the final experiment we associated opposing perturbations (-30 degrees and +30 degrees ) with either reaching or tracking movements and presented them within the same experimental block to determine whether these contexts allow for dual adaptation. We found that the group that experienced opposing perturbations was able to reduce both reaching and tracking errors, as well as produce reach aftereffects following dual training of ~7 degrees , which were substantially smaller than those produced when reach training was not concurrent with tracking training. This reduction in reach aftereffects is consistent with the extent of the interference from tracking training as measured by the reach aftereffects produced when only that condition was performed. These results suggest partial, but not complete, overlap in the learning processes involved in the acquisition of tracking and reaching movements. PMID- 29420651 TI - Plasma membrane aquaporins mediates vesicle stability in broccoli. AB - The use of in vitro membrane vesicles is attractive because of possible applications in therapies. Here we aimed to compare the stability and functionality of plasma membrane vesicles extracted from control and salt-treated broccoli. The impact of the amount of aquaporins was related to plasma membrane osmotic water permeability and the stability of protein secondary structure. Here, we describe for first time an increase in plant aquaporins acetylation under high salinity. Higher osmotic water permeability in NaCl vesicles has been related to higher acetylation, upregulation of aquaporins, and a more stable environment to thermal denaturation. Based on our findings, we propose that aquaporins play an important role in vesicle stability. PMID- 29420652 TI - Long-term clinical, immunological and virological outcomes of patients on antiretroviral therapy in southern Myanmar. AB - OBJECTIVE: To study the long-term clinical, immunological and virological outcomes among people living with HIV on antiretroviral therapy (ART) in Myanmar. METHODS: A retrospective analysis of people on ART for >9 years followed by a cross-sectional survey among the patients in this group who remained on ART at the time of the survey. Routinely collected medical data established the baseline clinical and demographic characteristics for adult patients initiating ART between 2004 and 2006. Patients remaining on ART between March-August 2015 were invited to participate in a survey assessing clinical, virological, immunological, and biochemical characteristics. RESULTS: Of 615 patients included in the retrospective analysis, 35 (6%) were lost-to-follow-up, 9 (1%) were transferred, 153 died (25%) and 418 (68%) remained active in care. Among deaths, 48 (31.4%) occurred within 3 months of ART initiation, and 81 (52.9%) within 12 months, 90.1% (n = 73) of which were initially classified as stage 3/4. Of 385 patients included in the survey, 30 (7.7%) were on second-line ART regimen; 373 (96.8%) had suppressed viral load (<250 copies/ml). The mean CD4 count was 548 cells/ mm3 (SD 234.1) after >=9 years on treatment regardless of the CD4 group at initiation. Tuberculosis while on ART was diagnosed in 187 (48.5%); 29 (7.6%) had evidence of hepatitis B and 53 (13.9%) of hepatitis C infection. CONCLUSIONS: Appropriate immunological and virological outcomes were seen among patients on ART for >=9 years. However, for the complete initiating cohort, high mortality was observed, especially in the first year on ART. Concerning co-infections, tuberculosis and viral hepatitis were common among this population. Our results demonstrate that good long-term outcomes are possible even for patients with advanced AIDS at ART initiation. PMID- 29420653 TI - Estimating the mutational load for cardiovascular diseases in Pakistani population. AB - The deleterious genetic variants contributing to certain diseases may differ in terms of number and allele frequency from population to population depending on their evolutionary background. Here, we prioritize the deleterious variants from Pakistani population in manually curated gene list already reported to be associated with common, Mendelian, and congenital cardiovascular diseases (CVDs) using the genome/exome sequencing data of Pakistani individuals publically available in 1000 Genomes Project (PJL), and Exome Aggregation Consortium (ExAC) South Asia. By applying a set of tools such as Combined Annotation Dependent Depletion (CADD), ANNOVAR, and Variant Effect Predictor (VEP), we highlighted 561 potentially detrimental variants from PJL data, and 7374 variants from ExAC South Asian data. Likewise, filtration from ClinVar for CVDs revealed 03 pathogenic and 02 likely pathogenic variants from PJL and 112 pathogenic and 42 likely pathogenic variants from ExAC South Asians. The comparison of derived allele frequencies (DAF) revealed many of these prioritized variants having two fold and higher DAF in Pakistani individuals than in other populations. The highest number of deleterious variants contributing to common CVDs in descending order includes hypertension, atherosclerosis, heart failure, aneurysm, and coronary heart disease, and for Mendelian and congenital CVDs cardiomyopathies, cardiac arrhythmias, and atrioventricular septal defects. PMID- 29420654 TI - World wide spatial capital. AB - In its most basic form, the spatial capital of a neighborhood entails that most aspects of daily life are located close at hand. Urban planning researchers have widely recognized its importance, not least because it can be transformed in other forms of capital such as economical capital (e.g., house prices, retail sales) and social capital (e.g., neighborhood cohesion). Researchers have already studied spatial capital from official city data. Their work led to important planning decisions, yet it also relied on data that is costly to create and update, and produced metrics that are difficult to compare across cities. By contrast, we propose to measure spatial capital in cheap and standardized ways around the world. Hence the name of our project "World Wide Spatial Capital". Our measures are cheap as they rely on the most basic information about a city that is currently available on the Web (i.e., which amenities are available and where). They are also standardized because they can be applied in any city in the five continents (as opposed to previous metrics that were mainly applied in USA and UK). We show that, upon these metrics, one could produce insights at the core of the urban planning discipline: which areas would benefit the most from urban interventions; how to inform planning depending on whether a city's activity is mono- or poly-centric; how different cities fare against each other; and how spatial capital correlates with other urban characteristics such as mobility patterns and road network structure. PMID- 29420655 TI - Context or composition: How does neighbourhood deprivation impact upon adolescent smoking behaviour? AB - Neighbourhood effects studies have demonstrated an association between area deprivation and smoking behaviour whereby people living in deprived neighbourhoods are more likely to smoke than those in non-deprived neighbourhoods. This evidence though is based largely upon data that ignores long term exposures to neighbourhood contexts and is confounded by neighbourhood selection bias. In this study, we investigate the temporal ordering of exposure to neighbourhood deprivation throughout childhood and whether associations between neighbourhood deprivation and cigarette smoking are due to compositional or contextual neighbourhood effects. Data come from a UK cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). We use longitudinal measures of neighbourhood deprivation and self-reported smoking behaviour for 2744 children to examine the influence of neighbourhood deprivation on smoking status and smoking heaviness at age 17. Our results demonstrate that children who are born into and grow up in deprived neighbourhoods are up to twice as likely to be smokers at age 17 than those in non-deprived neighbourhoods. These associations are largely due to family socioeconomic position and the intergenerational transmission of smoking behaviour from parents to children; compositional rather than direct contextual 'neighbourhood effects'. Our findings highlight the importance of considering longitudinal exposure to neighbourhood deprivation over cross sectional exposure. In conclusion, we find that it is the family rather than the neighbourhood into which a child is born that determines their smoking behaviour. PMID- 29420656 TI - Technical adequacy of bisulfite sequencing and pyrosequencing for detection of mitochondrial DNA methylation: Sources and avoidance of false-positive detection. AB - The existence of cytosine methylation in mammalian mitochondrial DNA (mtDNA) is a controversial subject. Because detection of DNA methylation depends on resistance of 5'-modified cytosines to bisulfite-catalyzed conversion to uracil, examined parameters that affect technical adequacy of mtDNA methylation analysis. Negative control amplicons (NCAs) devoid of cytosine methylation were amplified to cover the entire human or mouse mtDNA by long-range PCR. When the pyrosequencing template amplicons were gel-purified after bisulfite conversion, bisulfite pyrosequencing of NCAs did not detect significant levels of bisulfite-resistant cytosines (brCs) at ND1 (7 CpG sites) or CYTB (8 CpG sites) genes (CI95 = 0% 0.94%); without gel-purification, significant false-positive brCs were detected from NCAs (CI95 = 4.2%-6.8%). Bisulfite pyrosequencing of highly purified, linearized mtDNA isolated from human iPS cells or mouse liver detected significant brCs (~30%) in human ND1 gene when the sequencing primer was not selective in bisulfite-converted and unconverted templates. However, repeated experiments using a sequencing primer selective in bisulfite-converted templates almost completely (< 0.8%) suppressed brC detection, supporting the false positive nature of brCs detected using the non-selective primer. Bisulfite-seq deep sequencing of linearized, gel-purified human mtDNA detected 9.4%-14.8% brCs for 9 CpG sites in ND1 gene. However, because all these brCs were associated with adjacent non-CpG brCs showing the same degrees of bisulfite resistance, DNA methylation in this mtDNA-encoded gene was not confirmed. Without linearization, data generated by bisulfite pyrosequencing or deep sequencing of purified mtDNA templates did not pass the quality control criteria. Shotgun bisulfite sequencing of human mtDNA detected extremely low levels of CpG methylation (<0.65%) over non CpG methylation (<0.55%). Taken together, our study demonstrates that adequacy of mtDNA methylation analysis using methods dependent on bisulfite conversion needs to be established for each experiment, taking effects of incomplete bisulfite conversion and template impurity or topology into consideration. PMID- 29420657 TI - Ecological traps in shallow coastal waters-Potential effect of heat-waves in tropical and temperate organisms. AB - Mortality of fish has been reported in tide pools during warm days. That means that tide pools are potential ecological traps for coastal organisms, which happen when environmental changes cause maladaptive habitat selection. Heat-waves are predicted to increase in intensity, duration and frequency, making it relevant to investigate the role of tide pools as traps for coastal organisms. However, heat waves can also lead to acclimatization. If organisms undergo acclimatization prior to being trapped in tide pools, their survival chances may increase. Common tide pool species (46 species in total) were collected at a tropical and a temperate area and their upper thermal limits estimated. They were maintained for 10 days at their mean summer sea surface temperature +3 degrees C, mimicking a heat-wave. Their upper thermal limits were estimated again, after this acclimation period, to calculate each species' acclimation response. The upper thermal limits of the organisms were compared to the temperatures attained by tide pool waters to investigate if 1) tide pools could be considered ecological traps and 2) if the increase in upper thermal limits elicited by the acclimation period could make the organisms less vulnerable to this threat. Tropical tide pools were found to be ecological traps for an important number of common coastal species, given that they can attain temperatures higher than the upper thermal limits of most of those species. Tide pools are not ecological traps in temperate zones. Tropical species have higher thermal limits than temperate species, but lower acclimation response, that does not allow them to survive the maximum habitat temperature of tropical tide pools. This way, tropical coastal organisms seem to be, not only more vulnerable to climate warming per se, but also to an increase in the ecological trap effect of tide pools. PMID- 29420659 TI - Correction: Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias. AB - [This corrects the article DOI: 10.1371/journal.pone.0187503.]. PMID- 29420658 TI - Comparing residential contamination in a Houston environmental justice neighborhood before and after Hurricane Harvey. AB - INTRODUCTION: Polycyclic aromatic hydrocarbons (PAHs) are complex environmental toxicants. Exposure to them has been linked to adverse health outcomes including cancer, as well as diseases of the skin, liver, and immune system. Based on an ongoing community engagement partnership with stakeholder groups and residents, we conducted a small longitudinal study to assess domestic exposure to PAHs among residents of Manchester, an environmental justice neighborhood located in the East End of Houston, TX. METHODS: In December, 2016, we used fiber wipes to collect samples of household dust from 25 homes in Manchester. Following Hurricane Harvey, in September 2017, we revisited 24 of the 25 homes to collect soil samples from the front yards of the same homes. Wipes and soil were analyzed for the presence of PAHs using gas chromatography-mass spectrometry (GC-MS) methods. Principal component analysis plots, heatmaps, and PAH ratios were used to compare pre- and post-Hurricane Harvey samples. RESULTS: While direct comparison is not possible, we present three methods for comparing PAHs found in pre-hurricane fiber wipes and post-hurricane soil samples. The methods demonstrate that the PAHs found before and after Hurricane Harvey are likely from similar sources and that those sources are most likely to be associated with combustion. We also found evidence of redistribution of PAHs due to extreme flooding associated with Hurricane Harvey. DISCUSSION: Residents of the Manchester neighborhood of Houston, TX, are exposed to a range of PAHs in household dust and outdoor soil. While it was not possible to compare directly, we were able to use several methods to assess detected concentrations, changes in site-specific PAH allocations, and PAH origination. Additional research is needed to identify specific sources of domestic PAH exposure in these communities and continued work involving community members and policy makers should aim to develop interventions to reduce domestic exposure to and prevent negative health outcomes from PAHs. PMID- 29420660 TI - Contextual and individual factors associated with dental services utilisation by Brazilian adults: A multilevel analysis. AB - BACKGROUND: Inequalities in the utilisation of dental services in Brazil are remarkable. The aim of this study was to evaluate the association of contextual and individual factors with the utilisation of dental services by Brazilian adults using the Andersen's behavioural model. METHODS: Individual-level data from 27,017 adults residents in the State capitals who were interviewed in the 2013 Brazilian National Health Survey were pooled with contextual city-level data. The outcomes were non-utilisation of dental services and last dental visit over 12 months ago. Individual predisposing variables were age, sex, race/skin colour, schooling and social network. Individual enabling variables included income, health insurance and registration in primary health care. Individual need variables were self-perceived dental health and self-reported missing teeth. Multilevel logistic regression models were performed to estimate odds ratio (OR) and 95% confidence intervals (95% CIs) of the association of contextual and individual predisposing, enabling and need-related variables with dental services outcomes. RESULTS: Predisposing (OR = 0.89; 95% CI 0.81-0.97) and enabling (OR = 0.90; 95% CI 0.85-0.96) contextual factors were associated with non-utilisation of dental services. Individual predisposing (sex, race/skin colour, schooling), enabling (income, health insurance) and need (self-perceived oral health, missing teeth) were associated with non-utilisation of dental services and last dental visit over 12 months ago. The latter was also associated with other individual predisposing (age, social network) and need (eating difficulties due to oral problems) characteristics. CONCLUSIONS: Individual and contextual determinants influenced dental services utilisation in Brazilian adults. These factors should be on the policy agenda and considered in the organisation of health services aiming to reduce oral health inequalities related to access and utilisation of dental services. PMID- 29420661 TI - Comparative analysis of genetic diversity and differentiation of cauliflower (Brassica oleracea var. botrytis) accessions from two ex situ genebanks. AB - Cauliflower (Brassica oleracea var. botrytis) is an important vegetable crop for human nutrition. We characterized 192 cauliflower accessions from the USDA and IPK genebanks with genotyping by sequencing (GBS). They originated from 26 different countries and represent about 44% of all cauliflower accessions in both genebanks. The analysis of genetic diversity revealed that accessions formed two major groups that represented the two genebanks and were not related to the country of origin. This differentiation was robust with respect to the analysis methods that included principal component analysis, ADMIXTURE and neighbor joining trees. Genetic diversity was higher in the USDA collection and significant phenotypic differences between the two genebanks were found in three out of six traits investigated. GBS data have a high proportion of missing data, but we observed that the exclusion of single nucleotide polymorphisms (SNPs) with missing data or the imputation of missing SNP alleles produced very similar results. The results indicate that the composition and type of accessions have a strong effect on the structure of genetic diversity of ex situ collections, although regeneration procedures and local adaptation to regeneration conditions may also contribute to a divergence. Fst-based outlier tests of genetic differentiation identified only a small proportion (<1%) of SNPs that are highly differentiated between the two genebanks, which indicates that selection during seed regeneration is not a major cause of differentiation between genebanks. Seed regeneration procedures of both genebanks do not result in different levels of genetic drift and loss of genetic variation. We therefore conclude that the composition and type of accessions mainly influence the level of genetic diversity and explain the strong genetic differentiation between the two ex situ collections. In summary, GBS is a useful method for characterizing genetic diversity in cauliflower genebank material and our results suggest that it may be useful to incorporate routine genotyping into accession management and seed regeneration to monitor the diversity present in ex situ collections and to reduce the loss of genetic diversity during seed regeneration. PMID- 29420663 TI - Research matters: How a brother with Down syndrome inspired a PhD in tuberculosis and an ardor for science communication. PMID- 29420662 TI - Generation of high-affinity, internalizing anti-FGFR2 single-chain variable antibody fragment fused with Fc for targeting gastrointestinal cancers. AB - Fibroblast growth factor receptors (FGFRs) are promising targets for antibody based cancer therapies, as their substantial overexpression has been found in various tumor cells. Aberrant activation of FGF receptor 2 (FGFR2) signaling through overexpression of FGFR2 and/or its ligands, mutations, or receptor amplification has been reported in multiple cancer types, including gastric, colorectal, endometrial, ovarian, breast and lung cancer. In this paper, we describe application of the phage display technology to produce a panel of high affinity single chain variable antibody fragments (scFvs) against the extracellular ligand-binding domain of FGFR2 (ECD_FGFR2). The binders were selected from the human single chain variable fragment scFv phage display libraries Tomlinson I + J and showed high specificity and binding affinity towards human FGFR2 with nanomolar KD values. To improve the affinity of the best binder selected, scFvF7, we reformatted it to a bivalent diabody format, or fused it with the Fc region (scFvF7-Fc). The scFvF7-Fc antibody construct presented the highest affinity for FGFR2, with a KD of 0.76 nM, and was selectively internalized into cancer cells overexpressing FGFR2, Snu-16 and NCI-H716. Finally, we prepared a conjugate of scFvF7-Fc with the cytotoxic drug monomethyl auristatin E (MMAE) and evaluated its cytotoxicity. The conjugate delivered MMAE selectively to FGFR2-positive tumor cells. These results indicate that scFvF7-Fc vcMMAE is a highly potent molecule for the treatment of cancers with FGFR2 overexpression. PMID- 29420664 TI - The first dipeptidyl peptidase III from a thermophile: Structural basis for thermal stability and reduced activity. AB - Dipeptidyl peptidase III (DPP III) isolated from the thermophilic bacteria Caldithrix abyssi (Ca) is a two-domain zinc exopeptidase, a member of the M49 family. Like other DPPs III, it cleaves dipeptides from the N-terminus of its substrates but differently from human, yeast and Bacteroides thetaiotaomicron (mesophile) orthologs, it has the pentapeptide zinc binding motif (HEISH) in the active site instead of the hexapeptide (HEXXGH). The aim of our study was to investigate structure, dynamics and activity of CaDPP III, as well as to find possible differences with already characterized DPPs III from mesophiles, especially B. thetaiotaomicron. The enzyme structure was determined by X-ray diffraction, while stability and flexibility were investigated using MD simulations. Using molecular modeling approach we determined the way of ligands binding into the enzyme active site and identified the possible reasons for the decreased substrate specificity compared to other DPPs III. The obtained results gave us possible explanation for higher stability, as well as higher temperature optimum of CaDPP III. The structural features explaining its altered substrate specificity are also given. The possible structural and catalytic significance of the HEISH motive, unique to CaDPP III, was studied computationally, comparing the results of long MD simulations of the wild type enzyme with those obtained for the HEISGH mutant. This study presents the first structural and biochemical characterization of DPP III from a thermophile. PMID- 29420666 TI - Correction: Sensitivity of self-reported opioid use in case-control studies: Healthy individuals versus hospitalized patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0183017.]. PMID- 29420665 TI - Electroretinographic evidence suggesting that the type 2 diabetic retinopathy of the sand rat Psammomys obesus is comparable to that of humans. AB - PURPOSE: Type 2 diabetic retinopathy is the main cause of acquired blindness in adults. The aim of this work was to examine the retinal function of the sand rat Psammomys obesus as an animal model of diet-induced type 2 diabetes when subjected to a hypercaloric regimen. MATERIALS AND METHODS: Hyperglycemia was induced in Psammomys obesus by high caloric diet (4 kcal/g). The visual function of control (n = 7) and diabetic (n = 7) adult rodents were followed up during 28 consecutive weeks with full-field electroretinogram(ERG) recordings evoked to flashes of white light according to the standard protocol of the International Society for Clinical Electrophysiology of Vision protocol (ISCEV). RESULTS: Twenty-eight weeks following the induction of diabetes, results revealed significantly reduced and delayed photopic and scotopic ERG responses in diabetic rats compared to control rats. More specifically, we noted a significant decrease in the amplitude of the dark-adapted 0.01ERG (62%), a- and b-wave amplitudes of the dark-adapted 3.0 ERG (33.6%, 55.1%) and the four major oscillatory potentials components (OP1-OP4) (39.0%, 75.2%, 54.8% and 53.7% respectively). In photopic conditions, diabetic rats showed a significant decrease in a- and b-wave (30.4%, 43.4%), photopic negative response (55.3%), 30 Hz flicker (63.7%), OP1-OP4(51.6%, 61.8%, 68.3% and 47.5% respectively) and S-cone (34.7%). Significantly delayed implicit times were observed for all ERG components in the diabetic animals. Results obtained are comparable to those characterizing the retinal function of patients affected with advanced stage of diabetic retinopathy. CONCLUSION: Psammomys obesus is a useful translational model to study the pathophysiology of diabetic retinopathy in order to explore new therapeutic avenues in human patients. PMID- 29420668 TI - The analysis of the oral DNA virome reveals which viruses are widespread and rare among healthy young adults in Valencia (Spain). AB - We have analysed oral wash samples from 72 healthy young adults in Valencia (Spain) for a metagenomic analysis through the construction of shotgun libraries and high-throughput-sequencing. The oral viral communities have been taxonomically characterised as well as and the gene content from the latter. The majority of viruses are found in few individuals, with single occurrences being the most widespread ones, whereas universally distributed viruses, while present, are relatively rare, with bacteriophages from families Siphoviridae and Myoviridae, and Streptococcus phages, as well as the eukaryotic viral family Herpesviridae amongst the most widespread viruses. No significant differences were found between females and males for either viruses and bacteria in abundance and alpha and beta diversity. The virome show similarities with other oral viromes previously reported for healthy individuals, suggesting the existence of a universal core of oral viruses, at least in the Western society, regardless of the geographical location. PMID- 29420667 TI - A comparison of RSV and influenza in vitro kinetic parameters reveals differences in infecting time. AB - Influenza and respiratory syncytial virus (RSV) cause acute infections of the respiratory tract. Since the viruses both cause illnesses with similar symptoms, researchers often try to apply knowledge gleaned from study of one virus to the other virus. This can be an effective and efficient strategy for understanding viral dynamics or developing treatment strategies, but only if we have a full understanding of the similarities and differences between the two viruses. This study used mathematical modeling to quantitatively compare the viral kinetics of in vitro RSV and influenza virus infections. Specifically, we determined the viral kinetics parameters for RSV A2 and three strains of influenza virus, A/WSN/33 (H1N1), A/Puerto Rico/8/1934 (H1N1), and pandemic H1N1 influenza virus. We found that RSV viral titer increases at a slower rate and reaches its peak value later than influenza virus. Our analysis indicated that the slower increase of RSV viral titer is caused by slower spreading of the virus from one cell to another. These results provide estimates of dynamical differences between influenza virus and RSV and help provide insight into the virus-host interactions that cause observed differences in the time courses of the two illnesses in patients. PMID- 29420669 TI - Insights into the reproduction of some Antarctic dendroceratid, poecilosclerid, and haplosclerid demosponges. AB - Sponges are a dominant element of the Antarctic benthic communities, posing both high species richness and large population densities. Despite their importance in Antarctic ecosystems, very little is known about their reproductive patterns and strategies. In our study, we surveyed the tissue of six different species for reproductive elements, namely, Dendrilla antarctica Topsent, 1905 (order Dendroceratida), Phorbas areolatus (Thiele, 1905), Kirkpatrickia variolosa (Kirkpatrick, 1907), and Isodictya kerguelenensis (Ridley & Dendy, 1886) (order Poecilosclerida), and Hemigellius pilosus (Kirkpatrick, 1907) and Haliclona penicillata (Topsent, 1908) (Haplosclerida). Samples of these six species containing various reproductive elements were collected in Deception Island and were processed for both light and transmission electron microscopy (TEM). Even though we were not able to monitor the entire reproductive cycle, due to time and meteorological conditions, we report important aspects of the reproduction of these species. This includes oocyte and embryo morphology and cell ultrastructure, follicular structures and nurse cell activity, as well as vitellogenesis. All species were brooding their embryos within their mesohyl. Both oocytes and embryos were registered in the majority of the studied species, and a single sperm cell being carried to an egg for fertilization was observed in H. penicillata. While the reproductive periods of all species coincided temporally, some of them seemed to rely on a single spawning event, this being suggested by the synchronic oogenesis and embryogenesis occurrence of D. antarctica, P. areolatus and I. kerguelenensis. In contrast, K. variolosa had an asynchronous embryo development, which suggests several larval release events. Our results suggest that differences in the reproductive strategies and morphological traits might succeed in the coexistence of these species at the same habitat avoiding the direct competition between them. PMID- 29420671 TI - Correction: A Likelihood Approach to Estimate the Number of Co-Infections. AB - [This corrects the article DOI: 10.1371/journal.pone.0097899.]. PMID- 29420670 TI - Influence of humic acid and dihydroxy benzoic acid on the agglomeration, adsorption, sedimentation and dissolution of copper, manganese, aluminum and silica nanoparticles - A tentative exposure scenario. AB - This work focuses on kinetic aspects of stability, mobility, and dissolution of bare Cu, Al and Mn, and SiO2 NPs in synthetic freshwater (FW) with and without the presence of natural organic matter (NOM). This includes elucidation of particle and surface interactions, metal dissolution kinetics, and speciation predictions of released metals in solution. Dihydroxy benzoic acid (DHBA) and humic acid adsorbed rapidly on all metal NPs (<1 min) via multiple surface coordinations, followed in general by rapid agglomeration and concomitant sedimentation for a large fraction of the particles. In contrast, NOM did not induce agglomeration of the SiO2 NPs during the test duration (21 days). DHBA in concentrations of 0.1 and 1 mM was unable to stabilize the metal NPs for time periods longer than 6 h, whereas humic acid, at certain concentrations (20 mg/L) was more efficient (>24 h). The presence of NOM increased the amount of released metals into solution, in particular for Al and Cu, whereas the effect for Mn was minor. At least 10% of the particle mass was dissolved within 24 h and remained in solution for the metal NPs in the presence of NOM. Speciation modeling revealed that released Al and Cu predominantly formed complexes with NOM, whereas less complexation was seen for Mn. The results imply that potentially dispersed NPs of Cu, Al and Mn readily dissolve or sediment close to the source in freshwater of low salinity, whereas SiO2 NPs are more stable and therefore more mobile in solution. PMID- 29420672 TI - In Vivo Effect of Titanium Implants with Porous Zinc-Containing Coatings Prepared by Plasma Electrolytic Oxidation Method on Osseointegration in Rabbits. AB - PURPOSE: The aim of this study was to confirm the in vivo effect of surface modified titanium (Ti) implants with zinc (Zn) prepared by a plasma electrolytic oxidation (PEO) method on the process of osseointegration. MATERIALS AND METHODS: Forty-five New Zealand white rabbits were used. Implants were divided into three groups due to different surface treatments (the PEO-Zn group, the PEO-calcium phosphorus [Ca/P] group, and the sandblasted [control] group) and were randomly inserted into rabbits' mandibles. The implant surface morphology and chemical state of the relevant elements were observed. The maximum push-out force, the bone-to-implant contact (BIC), and the mineral apposition ratio (MAR) were detected at 4, 8, and 12 weeks after implantation. RESULTS: A two-layer structure, with a dense inner layer and a porous outer layer, was found in the PEO samples. In the PEO-Zn group, CaHPO4.2H2O (dicalcium phosphate dihydrate) was the main calcium compound, and ZnO was identified as the predominant form of Zn. More bone deposition was found on the top of the PEO-Zn implant, which was also confirmed by scanning electron microscope (SEM) afterward, and the shear strength reached a maximum value of 1.57 +/- 0.26 MPa at 12 weeks compared with the sandblasted group and the PEO-Ca/P group. The BIC values and the MARs of the PEO Zn group were significantly higher than the control group, especially at the early weeks (P < .05), and first reached maximum values of 73.91% +/- 9.01% and 4.89 +/- 0.60 MUm/d at 12 weeks, respectively. CONCLUSION: Implants with Zn coating by the PEO method could accelerate bone formation and bone remodeling, shorten the osseointegration period, and enhance bone-implant bonding force. PMID- 29420673 TI - Influence of Different Screw Torque Levels on the Biomechanical Behavior of Tapered Prosthetic Abutments. AB - PURPOSE: To study the force used for tightening tapered one-piece prosthetic abutments and their influence on the removal torque value and stress level of the prosthetic abutment after cyclic loading. MATERIALS AND METHODS: Fourteen implants and prosthetic abutments were divided into two groups (n = 7): G1, 20 Ncm; and G2, 32 Ncm (manufacturer recommended). A 20-mm T-shaped horizontal bar was adapted to the abutments. A 12-Hz cyclic loading was applied to the specimens in an electrodynamic testing system with the maximum number of cycles set to 106. Specimens were inclined by 15 degrees from the vertical axis, and a 5-mm off center vertical load was applied to generate a combination of bending and torquing moments on the tapered connections. Progressive loads (from 164.85 to 362.85 N) were applied when the previous sample survived 106 cycles. The paired t test compared the screw removal torque with the initial tightening torque for each group (alpha = .05). A finite element analysis (FEA) of the mechanical testing analyzed the regions of stress concentration. RESULTS: No specimens failed after 106 cyclic loadings. The mean screw removal torque for both groups was similar to the initial abutment torque value applied for each group (G1, 20.36 +/- 8.73 Ncm; and G2, 35.61 +/- 6.99 Ncm) (P > .05). FEA showed similar stress behavior for both groups in the study despite the different simulated screw preloads (G1: 200 N; G2: 320 N). The coronal region of the implant body presented the highest strain values in both groups. CONCLUSION: Tightening tapered one-piece prosthetic abutments at 20 and 32 Ncm maintains a stable connection after cyclic loading. The stresses generated by the different tightening forces during cyclic loading are highest at the coronal level of the connection. PMID- 29420675 TI - GCPred: a web tool for guanylyl cyclase functional centre prediction from amino acid sequence. AB - Summary: GCPred is a webserver for the prediction of guanylyl cyclase (GC) functional centres from amino acid sequence. GCs are enzymes that generate the signalling molecule cyclic guanosine 3', 5'-monophosphate from guanosine-5' triphosphate. A novel class of GC centres (GCCs) has been identified in complex plant proteins. Using currently available experimental data, GCPred is created to automate and facilitate the identification of similar GCCs. The server features GCC values that consider in its calculation, the physicochemical properties of amino acids constituting the GCC and the conserved amino acids within the centre. From user input amino acid sequence, the server returns a table of GCC values and graphs depicting deviations from mean values. The utility of this server is demonstrated using plant proteins and the human interleukin-1 receptor-associated kinase family of proteins as example. Availability and implementation: The GCPred server is available at http://gcpred.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29420674 TI - Histomorphometric Study of New Bone Formation Comparing Defect Healing with Three Bone Grafting Materials: The Effect of Osteoporosis on Graft Consolidation. AB - PURPOSE: Bone grafting materials are frequently utilized in oral surgery and periodontology to fill bone defects and augment lost or missing bone. The purpose of this study was to compare new bone formation in bone defects created in both normal and osteoporotic animals loaded with three types of bone grafts from different origins. MATERIALS AND METHODS: Forty-eight female Wistar rats were equally divided into control normal and ovariectomized animals. Bilateral 2.5-mm femur defects were created and filled with an equal weight of (1) natural bone mineral (NBM, BioOss) of bovine origin, (2) demineralized freeze-dried bone allograft (DFDBA, LifeNet), or (3) biphasic calcium phosphate (BCP, Vivoss). Following 3 and 6 weeks of healing, hematoxylin and eosin and TRAP staining was performed to determine new bone formation, material degradation, and osteoclast activity. RESULTS: All bone substitutes demonstrated osteoconductive potential at 3 and 6 weeks with higher osteoclast numbers observed in all ovariectomized animals. NBM displayed continual new bone formation with little to no sign of particle degradation, even in osteoporotic animals. DFDBA particles showed similar levels of new bone formation but rapid particle degradation rates with lower levels of mineralized tissue. BCP bone grafts demonstrated significantly higher new bone formation when compared with both NBM and DFDBA particles; however, the material was associated with higher osteoclast activity and particle degradation. Interestingly, in osteoporotic animals, BCP displayed synergistically and markedly more rapid rates of particle degradation. CONCLUSION: Recent modifications to synthetically fabricated materials were shown to be equally or more osteopromotive than NBM and DFDBA. However, the current BCP utilized demonstrated much faster resorption properties in osteoporotic animals associated with a decrease in total bone volume when compared with the slowly/nonresorbing NBM. The results from this study point to the clinical relevance of minimizing fast-resorbing bone grafting materials in osteoporotic phenotypes due to the higher osteoclastic activity and greater material resorption. PMID- 29420676 TI - Principal metabolic flux mode analysis. AB - Motivation: In the analysis of metabolism, two distinct and complementary approaches are frequently used: Principal component analysis (PCA) and stoichiometric flux analysis. PCA is able to capture the main modes of variability in a set of experiments and does not make many prior assumptions about the data, but does not inherently take into account the flux mode structure of metabolism. Stoichiometric flux analysis methods, such as Flux Balance Analysis (FBA) and Elementary Mode Analysis, on the other hand, are able to capture the metabolic flux modes, however, they are primarily designed for the analysis of single samples at a time, and not best suited for exploratory analysis on a large sets of samples. Results: We propose a new methodology for the analysis of metabolism, called Principal Metabolic Flux Mode Analysis (PMFA), which marries the PCA and stoichiometric flux analysis approaches in an elegant regularized optimization framework. In short, the method incorporates a variance maximization objective form PCA coupled with a stoichiometric regularizer, which penalizes projections that are far from any flux modes of the network. For interpretability, we also introduce a sparse variant of PMFA that favours flux modes that contain a small number of reactions. Our experiments demonstrate the versatility and capabilities of our methodology. The proposed method can be applied to genome-scale metabolic network in efficient way as PMFA does not enumerate elementary modes. In addition, the method is more robust on out-of steady steady-state experimental data than competing flux mode analysis approaches. Availability and implementation: Matlab software for PMFA and SPMFA and dataset used for experiments are available in https://github.com/aalto-ics kepaco/PMFA. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29420678 TI - Cerebral pneumography and the 20th century localization of brain tumours. PMID- 29420677 TI - The Economics of Healthcare Shape the Practice of Neuropsychology in the Era of Integrated Healthcare. AB - The healthcare system in the United States is in the midst of a major transformation that has affected all healthcare specialties, including clinical psychology/neuropsychology. If this shift in the economics of healthcare reimbursement continues, it promises to impact clinical practice patterns for neuropsychologists far into the next decade. PMID- 29420679 TI - TWO AUTHORS REPLY. PMID- 29420680 TI - The Prolonged Masking of Temporal Acoustic Inputs with Noise Drives Plasticity in the Adult Rat Auditory Cortex. AB - The prolonged masking of auditory inputs with white noise has been shown to reopen the critical period for spectral tuning in the adult rat auditory cortex. Here, we argue that the masking of salient temporal inputs in particular is responsible for changes in neuronal activity that lead to this experience dependent plasticity. We tested this hypothesis by passively exposing adult rats to 2 weeks of amplitude-modulated (AM) white noise with different modulation depths from 0% (no modulation) to 100% (strong modulation). All exposed rats displayed evidence of cortical plasticity as measured by receptive field bandwidths, tonotopic gradients, and synchronization during spontaneous activity. However, this plasticity was fundamentally different in nature for rats exposed to unmodulated noise, as a second passive exposure to pure tones elicited tonotopic reorganization in rats exposed to 0% AM noise only. Detection of c-FOS expression in excitatory and inhibitory cells through post-mortem immunohistochemistry also revealed different patterns of cellular activation depending on modulation depth. Together, these results indicate that the absence of temporal modulation promotes noise-induced plasticity in the adult auditory cortex and suggest an important and continuous role for temporally salient inputs in the maintenance of mature auditory circuits. PMID- 29420681 TI - Years of life lost due to influenza-attributable mortality in older adults in the Netherlands: a competing risks approach. AB - We estimated the influenza mortality burden in adults 60 years of age and older in the Netherlands in terms of years of life lost, taking into account competing mortality risks. Weekly laboratory surveillance data for influenza and other respiratory pathogens and weekly extreme temperature served as covariates in Poisson regression models fitted to weekly age-group specific mortality data for the period 1999/2000 through 2012/13. Burden for age-groups 60-64 through 85-89 years was computed as years of life lost before age 90 (YLL90) using restricted mean lifetimes survival analysis and accounting for competing risks. Influenza attributable mortality burden was greatest for persons aged 80-84 years, at 914 YLL90 per 100,000 persons (95% uncertainty interval:867, 963), followed by 85-89 years (787 YLL90/100,000; 95% uncertainty interval:741, 834). Ignoring competing mortality risks in the computation of influenza-attributable YLL90 would lead to substantial over-estimation of burden, from 3.5% for 60-64 years to 82% for persons aged 80-89 years at death. Failure to account for competing mortality risks has implications for accuracy of disease burden estimates, especially among persons aged 80 years and older. As the mortality burden borne by the elderly is notably high, prevention initiatives may benefit from being redesigned to more effectively prevent infection in the oldest age-groups. PMID- 29420682 TI - GCevobase: an evolution-based database for GC content in eukaryotic genomes. AB - Summary: How to comprehend the underlying mechanism behind the origin and evolution of genome composition such as GC content has been regarded as a long standing crucial question, highlighting its biological significance and functional relevance. To varying extents, several systematically identified patterns of GC content variations are shown to be linked to a set of genomic features in the events of replication, transcription, translation and recombination, with strong contrasts between diverse phylogenetic or taxonomical groups. In this situation, we develop a repository-GCevobase-which houses compositional and size related data presented in various forms from 1118 genomes including 5 major clades of eukaryotic species such as vertebrates, invertebrates, plants, fungi and protists. It analyzes the cautiously selected sequences with clearly-defined bases and structures them under the taxonomical classification system (kingdom, phylum, class, order and family) at the genome and gene scales. It uses the diversified and intelligible graphs to show the statistical measurements of GC content in the sequence, at the three codon positions and at 4-fold degenerate sites and CDS length and their genome-wide correlations and display the evolutionary pathways of GC content by taking into account between-species orthologs and within-species paralogs for each annotated gene. In addition, a lot of internal and external links have been created, making it an effective communication between the data from individual genomes and the raw data are downloadable. Availability and implementation: https://github.com/NextGenBioinformatics/GCevobase. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29420683 TI - An Unusual Delayed Type Reaction Following Periorbital Filler Injection With Hyaluronic Acid. AB - Level of Evidence 5: PMID- 29420684 TI - Open-source chemogenomic data-driven algorithms for predicting drug-target interactions. AB - While novel technologies such as high-throughput screening have advanced together with significant investment by pharmaceutical companies during the past decades, the success rate for drug development has not yet been improved prompting researchers looking for new strategies of drug discovery. Drug repositioning is a potential approach to solve this dilemma. However, experimental identification and validation of potential drug targets encoded by the human genome is both costly and time-consuming. Therefore, effective computational approaches have been proposed to facilitate drug repositioning, which have proved to be successful in drug discovery. Doubtlessly, the availability of open-accessible data from basic chemical biology research and the success of human genome sequencing are crucial to develop effective in silico drug repositioning methods allowing the identification of potential targets for existing drugs. In this work, we review several chemogenomic data-driven computational algorithms with source codes publicly accessible for predicting drug-target interactions (DTIs). We organize these algorithms by model properties and model evolutionary relationships. We re-implemented five representative algorithms in R programming language, and compared these algorithms by means of mean percentile ranking, a new recall-based evaluation metric in the DTI prediction research field. We anticipate that this review will be objective and helpful to researchers who would like to further improve existing algorithms or need to choose appropriate algorithms to infer potential DTIs in the projects. The source codes for DTI predictions are available at: https://github.com/minghao2016/chemogenomicAlg4DTIpred. PMID- 29420685 TI - Gender Differences in Symptom Reporting on Baseline Sport Concussion Testing Across the Youth Age Span. AB - Background: Little is known regarding gender differences in concussion symptom reporting developmentally across the age span, specifically in pre-adolescent athletes. The present study asks: Do boys and girls differ in symptom reporting across the pre-adolescent to post-adolescent age span? Method: This retrospective study utilized baseline assessments from 11,695 10-22 year-old athletes assigned to 3 independent groups: Pre-adolescent 10-12 year olds (n = 1,367; 12%), Adolescent 13-17 year olds (n = 2,974; 25%), and Late Adolescent 18-22 year olds (n = 7,354; 63%). Males represented 60% of the sample. Baseline ImPACT composite scores and Post-Concussion Symptom Scale scores (Total, Physical, Cognitive, Emotional, Sleep) were analyzed for the effects of age and gender. Results: Statistically significant main effects were found for age and gender on all ImPACT composites, Total Symptoms, and Symptom factors. Significant interaction effects were noted between age and gender for all ImPACT composites, Total Symptoms, and Symptom factors. Total Symptoms and all Symptom factors were highest in adolescents (ages 13-17) for males and females. In the 10-12 age group, females displayed lower Total Symptoms, Physical, and Sleep factors than males. Conclusion: The notion of females being more likely than males to report symptoms does not appear to apply across the developmental age span, particularly prior to adolescence. Females show greater emotional endorsement across the youth age span (10-22 years). Adolescence (13-17 years) appears to be a time of increased symptomatology that may lessen after the age of 18. PMID- 29420686 TI - Marginal false discovery rates for penalized regression models. AB - Penalized regression methods are an attractive tool for high-dimensional data analysis, but their widespread adoption has been hampered by the difficulty of applying inferential tools. In particular, the question "How reliable is the selection of those features?" has proved difficult to address. In part, this difficulty arises from defining false discoveries in the classical, fully conditional sense, which is possible in low dimensions but does not scale well to high-dimensional settings. Here, we consider the analysis of marginal false discovery rates (mFDRs) for penalized regression methods. Restricting attention to the mFDR permits straightforward estimation of the number of selections that would likely have occurred by chance alone, and therefore provides a useful summary of selection reliability. Theoretical analysis and simulation studies demonstrate that this approach is quite accurate when the correlation among predictors is mild, and only slightly conservative when the correlation is stronger. Finally, the practical utility of the proposed method and its considerable advantages over other approaches are illustrated using gene expression data from The Cancer Genome Atlas and genome-wide association study data from the Myocardial Applied Genomics Network. PMID- 29420687 TI - Intermittent mTOR Inhibition Reverses Kidney Aging in Old Rats. PMID- 29420688 TI - Incidence and Clinical Profile of Norovirus Disease in Guatemala, 2008-2013. AB - Background: Acute gastroenteritis (AGE) is a leading infectious cause of morbidity worldwide, particularly among children in developing countries. With the decline of rotavirus disease rates following introduction of rotavirus vaccines, the relative importance of norovirus will likely increase. Our objectives in this study were to determine the incidence and clinical profile of norovirus disease in Guatemala. Methods: We analyzed data from a population-based surveillance study conducted in Guatemala from 2008 through 2013. Demographic information, clinical data, and stool samples were collected from patients who presented with AGE (>=3 liquid stools within 24 hours that initiated 7 days before presentation). Estimated incidence of hospitalized, outpatient, and total community norovirus disease was calculated using surveillance data and household surveys of healthcare use. Results: We included 999 AGE hospitalizations and 3189 AGE outpatient visits at facilities, of which 164 (16%) and 370 (12%), respectively, were positive for norovirus. Severity of norovirus was milder than of rotavirus. Community incidence of norovirus ranged from 2068 to 4954 per 100000 person-years (py) in children aged<5 years. Children aged <5 years also had higher incidence of norovirus-associated hospitalization (51-105 per 100000 py) compared with patients aged >=5 years (0-1.6 per 100000 py and 49-80 per 100000 py, respectively). Conclusions: This study highlights the burden of norovirus disease in Guatemala, especially among young children. These data can help prioritize development of control strategies, including the potential use of vaccines, and provide a baseline to evaluate the impact of such interventions. PMID- 29420689 TI - PDK1 Deficit Impairs the Development of the Dentate Gyrus in Mice. AB - 3-Phosphoinositide-dependent protein kinase-1 (PDK1) is crucial for the development of the dentate gyrus (DG), the first gateway receiving afferent inputs from the entorhinal cortex. However, the role of PDK1 in DG development is unclear. In the present study, by crossing Pdk1fl/fl mice with the Emx1-cre line, we identified that the ablation of PDK1 disrupted the development of DG via decreasing the proliferation, and increasing the differentiation of dentate neural progenitor cells, downregulating AKT activity and upregulating GSK3beta signaling. Moreover, PDK1 deletion disrupted the distribution of Reelin+ cells and decreased the level of Reelin mRNA which may contribute to the defective migration of progenitor cells and the disrupted radial glial scaffolds. Furthermore, the inhibition of GSK3beta activity partially restored the decreased proliferation of primary neural stem cells in vitro. Taken together, our data indicated that the ablation of PDK1 affected the proliferation and differentiation of dentate neural progenitor cells in mice. PMID- 29420690 TI - omicsPrint: detection of data linkage errors in multiple omics studies. AB - Summary: OmicsPrint is a versatile method for the detection of data linkage errors in multiple omics studies encompassing genetic, transcriptome and/or methylome data. OmicsPrint evaluates data linkage within and between omics data types using genotype calls from SNP arrays, DNA- or RNA-sequencing data and includes an algorithm to infer genotypes from Illumina DNA methylation array data. The method uses classification to verify assumed relationships and detect any data linkage errors, e.g. arising from sample mix-ups and mislabeling. Graphical and text output is provided to inspect and resolve putative data linkage errors. If sufficient genotype calls are available, first degree family relations also are revealed which can be used to check parent-offspring relations or zygosity in twin studies. Availability and implementation: omicsPrint is available from BioConductor; http://bioconductor.org/packages/omicsPrint. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29420691 TI - RE: "VITAMIN D AND FRACTURE RISK IN EARLY CHILDHOOD: A CASE-CONTROL STUDY". PMID- 29420692 TI - Neural Representations of the Full Spatial Field in Auditory Cortex of Awake Marmoset (Callithrix jacchus). AB - Unlike visual signals, sound can reach the ears from any direction, and the ability to localize sounds from all directions is essential for survival in a natural environment. Previous studies have largely focused on the space in front of a subject that is also covered by vision and were often limited to measuring spatial tuning along the horizontal (azimuth) plane. As a result, we know relatively little about how the auditory cortex responds to sounds coming from spatial locations outside the frontal space where visual information is unavailable. By mapping single-neuron responses to the full spatial field in awake marmoset (Callithrix jacchus), an arboreal animal for which spatial processing is vital in its natural habitat, we show that spatial receptive fields in several auditory areas cover all spatial locations. Several complementary measures of spatial tuning showed that neurons were tuned to both frontal space and rear space (outside the coverage of vision), as well as the space above and below the horizontal plane. Together, these findings provide valuable new insights into the representation of all spatial locations by primate auditory cortex. PMID- 29420693 TI - FWER and FDR control when testing multiple mediators. AB - Motivation: The biological pathways linking exposures and disease risk are often poorly understood. To gain insight into these pathways, studies may try to identify biomarkers that mediate the exposure/disease relationship. Such studies often simultaneously test hundreds or thousands of biomarkers. Results: We consider a set of m biomarkers and a corresponding set of null hypotheses, where the jth null hypothesis states that biomarker j does not mediate the exposure/disease relationship. We propose a Multiple Comparison Procedure (MCP) that rejects a set of null hypotheses or, equivalently, identifies a set of mediators, while asymptotically controlling the Family-Wise Error Rate (FWER) or False Discovery Rate (FDR). We use simulations to show that, compared to currently available methods, our proposed method has higher statistical power to detect true mediators. We then apply our method to a breast cancer study and identify nine metabolites that may mediate the known relationship between an increased BMI and an increased risk of breast cancer. Availability and implementation: R package MultiMed on https://github.com/SiminaB/MultiMed. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29420694 TI - L1000FWD: fireworks visualization of drug-induced transcriptomic signatures. AB - Motivation: As part of the NIH Library of Integrated Network-based Cellular Signatures program, hundreds of thousands of transcriptomic signatures were generated with the L1000 technology, profiling the response of human cell lines to over 20 000 small molecule compounds. This effort is a promising approach toward revealing the mechanisms-of-action (MOA) for marketed drugs and other less studied potential therapeutic compounds. Results: L1000 fireworks display (L1000FWD) is a web application that provides interactive visualization of over 16 000 drug and small-molecule induced gene expression signatures. L1000FWD enables coloring of signatures by different attributes such as cell type, time point, concentration, as well as drug attributes such as MOA and clinical phase. Signature similarity search is implemented to enable the search for mimicking or opposing signatures given as input of up and down gene sets. Each point on the L1000FWD interactive map is linked to a signature landing page, which provides multifaceted knowledge from various sources about the signature and the drug. Notably such information includes most frequent diagnoses, co-prescribed drugs and age distribution of prescriptions as extracted from the Mount Sinai Health System electronic medical records. Overall, L1000FWD serves as a platform for identifying functions for novel small molecules using unsupervised clustering, as well as for exploring drug MOA. Availability and implementation: L1000FWD is freely accessible at: http://amp.pharm.mssm.edu/L1000FWD. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29420696 TI - Sensitivity Analyses for Misclassification of Cause of Death in the Parametric G Formula. AB - Cause-specific mortality is an important outcome in studies of interventions to improve survival, yet causes of death can be misclassified. Here, we present an approach to perform sensitivity analyses for misclassification of cause of death in the parametric g-formula. The g-formula is useful method to estimate effects of interventions in epidemiologic research because it appropriately accounts for time-varying confounding affected by prior treatment and can estimate risk under dynamic treatment plans. We illustrate our approach using an example comparing acquired immune deficiency syndrome (AIDS)-related mortality under immediate and delayed treatment strategies in a cohort of therapy-naive adults entering care for human immunodeficiency virus in the United States. In the standard g-formula approach, 10-year risk of AIDS-related mortality under delayed treatment was 1.73 (95% CI: 1.17, 2.54) times the risk under immediate treatment. In a sensitivity analysis assuming that AIDS-related death was measured with sensitivity of 95% and specificity of 90%, the 10-year risk ratio comparing AIDS-related mortality between treatment plans was 1.89 (95% CI: 1.13, 3.14). When sensitivity and specificity are unknown, this approach can be used to estimate the effects of dynamic treatment plans under a range of plausible values of sensitivity and specificity of the recorded event type. PMID- 29420695 TI - Daily and Nondaily Oral Preexposure Prophylaxis in Men and Transgender Women Who Have Sex With Men: The Human Immunodeficiency Virus Prevention Trials Network 067/ADAPT Study. AB - Background: Nondaily dosing of oral preexposure prophylaxis (PrEP) may provide equivalent coverage of sex events compared with daily dosing. Methods: At-risk men and transgender women who have sex with men were randomly assigned to 1 of 3 dosing regimens: 1 tablet daily, 1 tablet twice weekly with a postsex dose (time driven), or 1 tablet before and after sex (event-driven), and were followed for coverage of sex events with pre- and postsex dosing measured by weekly self report, drug concentrations, and electronic drug monitoring. Results: From July 2012 to May 2014, 357 participants were randomized. In Bangkok, the coverage of sex events was 85% for the daily arm compared with 84% for the time-driven arm (P = .79) and 74% for the event-driven arm (P = .02). In Harlem, coverage was 66%, 47% (P = .01), and 52% (P = .01) for these groups. In Bangkok, PrEP medication concentrations in blood were consistent with use of >=2 tablets per week in >95% of visits when sex was reported in the prior week, while in Harlem, such medication concentrations occurred in 48.5% in the daily arm, 30.9% in the time driven arm, and 16.7% in the event-driven arm (P < .0001). Creatinine elevations were more common in the daily arm (P = .050), although they were not dose limiting. Conclusions: Daily dosing recommendations increased coverage and protective drug concentrations in the Harlem cohort, while daily and nondaily regimens led to comparably favorable outcomes in Bangkok, where participants had higher levels of education and employment. Clinical Trials Registration: NCT01327651. PMID- 29420697 TI - Environmental Influences on Infant Cortical Thickness and Surface Area. AB - Cortical thickness (CT) and surface area (SA) vary widely between individuals and are associated with intellectual ability and risk for various psychiatric and neurodevelopmental conditions. Factors influencing this variability remain poorly understood, but the radial unit hypothesis, as well as the more recent supragranular cortex expansion hypothesis, suggests that prenatal and perinatal influences may be particularly important. In this report, we examine the impact of 17 major demographic and obstetric history variables on interindividual variation in CT and SA in a unique sample of 805 neonates who received MRI scans of the brain around 2 weeks of age. Birth weight, postnatal age at MRI, gestational age at birth, and sex emerged as important predictors of SA. Postnatal age at MRI, paternal education, and maternal ethnicity emerged as important predictors of CT. These findings suggest that individual variation in infant CT and SA is explained by different sets of environmental factors with neonatal SA more strongly influenced by sex and obstetric history and CT more strongly influenced by socioeconomic and ethnic disparities. Findings raise the possibility that interventions aimed at reducing disparities and improving obstetric outcomes may alter prenatal/perinatal cortical development. PMID- 29420698 TI - Qualitative Evaluation of the Immediate Copy of the Rey-Osterrieth Complex Figure: Comparison Between Vascular and Degenerative MCI Patients. AB - Objective: The immediate copy of the Rey-Osterrieth Complex Figure (ROCF) is considered a visuo-spatial test. However, reproducing this complex structure possibly involves also executive functions, such as planning and organizational strategies. In a previous study, we found a high rate of impaired performances in this test in a sample of subcortical vascular mild cognitive impairment patients. Executive functions contribution in the immediate copy of the ROCF can be assessed with the Boston Qualitative Scoring System (BQSS). We aimed at examining whether BQSS executive scores of ROCF immediate copy: (1) differ between vascular (v-MCI) and degenerative MCI (d-MCI) patients; (2) can at least partly explain the high rate of abnormal ROCF immediate copy performances in v-MCI patients. Method: Thirty d-MCI patients (age 75.2 +/- 4.4) and 27 v-MCI (age 73.2 +/- 6.9) were enrolled. The performances of patients were scored using the BQSS executive scores (Fragmentation, Planning, Organization, Perseveration) during the accomplishment of ROCF immediate copy. Results: Comparing d-MCI and v-MCI performances, d-MCI patients scored worse on ROCF delayed recall (9.9 +/- 4.7 vs. 13.4 +/- 5.9, p = .020) and MMSE (23.9 +/- 2.6 vs. 27.8 +/- 2.3, p = .001) while v-MCI patients had more frequently impaired performances in ROCF immediate copy (40% vs. 81%, p = .001) and showed worse scores on Fragmentation (2.4 +/- 0.9 vs. 1.8 +/- 1.3, p = .035), Planning (2.4 +/- 0.8 vs. 1.8 +/- 1, p = .039), Organization (4.8 +/- 1.3 vs. 3.6 +/- 2.1, p = .017), and Perseveration (3.5 +/- 0.8 vs. 2.9 +/- 1.2, p = .048). Conclusions: The performance of v-MCI patients in ROCF immediate copy seemed to be more affected by executive dysfunction than the performance obtained by d-MCI. When analyzing ROCF performances, a qualitative approach allows to evaluate patients' strategies during the reproduction, and thus to discriminate between executive and visuo-constructional abilities. PMID- 29420699 TI - O-GlcNAcPRED-II: an integrated classification algorithm for identifying O GlcNAcylation sites based on fuzzy undersampling and a K-means PCA oversampling technique. AB - Motivation: Protein O-GlcNAcylation (O-GlcNAc) is an important post-translational modification of serine (S)/threonine (T) residues that involves multiple molecular and cellular processes. Recent studies have suggested that abnormal O G1cNAcylation causes many diseases, such as cancer and various neurodegenerative diseases. With the available protein O-G1cNAcylation sites experimentally verified, it is highly desired to develop automated methods to rapidly and effectively identify O-GlcNAcylation sites. Although some computational methods have been proposed, their performance has been unsatisfactory, particularly in terms of prediction sensitivity. Results: In this study, we developed an ensemble model O-GlcNAcPRED-II to identify potential O-GlcNAcylation sites. A K-means principal component analysis oversampling technique (KPCA) and fuzzy undersampling method (FUS) were first proposed and incorporated to reduce the proportion of the original positive and negative training samples. Then, rotation forest, a type of classifier-integrated system, was adopted to divide the eight types of feature space into several subsets using four sub-classifiers: random forest, k-nearest neighbour, naive Bayesian and support vector machine. We observed that O-GlcNAcPRED-II achieved a sensitivity of 81.05%, specificity of 95.91%, accuracy of 91.43% and Matthew's correlation coefficient of 0.7928 for five-fold cross-validation run 10 times. Additionally, the results obtained by O GlcNAcPRED-II on two independent datasets also indicated that the proposed predictor outperformed five published prediction tools. Availability and implementation: http://121.42.167.206/OGlcPred/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29420700 TI - The Role of Sex, Gender, Health Factors, and Job Context in Workplace Accommodation Use Among Men and Women with Arthritis. AB - Background: With the aging of populations in many countries, workers are expected to remain employed longer but may struggle with the onset of common, chronic conditions like arthritis. To date, few studies have examined workplace policies and practices that could help accommodate individuals with arthritis, and fewer still have used a sex and gender-based approach to explore similarities and differences between women and men. Objectives: This study compared the health and work contexts of workers aged >=50 years to better understand similarities and differences between women and men in accommodation availability, need, use, and unmet needs. Methods: A cross-sectional survey of men and women with osteoarthritis (OA), inflammatory arthritis (IA), or both OA and IA was administered online or by telephone and assessed demographics (e.g. age, education), health (e.g. pain, fatigue, workplace activity limitations), work context factors (e.g. job sector, full/part-time work, job control), and workplace accommodations (e.g. health benefits, flexible hours, special equipment/adaptations, modified duties). Sex and gender-based analyses examined similarities and differences between men and women and included descriptive statistics, multivariable multinomial analyses, and nested regression analyses. Results: There was a 58.9% response rate and final sample of 463 participants (women, n = 266; men, n = 197; OA = 59.0%; IA/both IA and OA = 23.7%; unsure = 17.3%). Women and men were significantly different in a number of health (e.g. fatigue, health variability, workplace activity limitations) and work context factors (e.g. job sector, part-time work, job stress). However, in other respects, they were similar (e.g. pain, job involving physical demands, size of organization, shift work, union membership, job control). There were no differences between men and women in the availability or use of workplace accommodations. However, women reported significantly more accommodation needs and had greater unmet needs. Multivariable multinomial analyses found male/female as a binary variable did not explain differences in accommodation need, use, and unmet need. Nested analyses highlighted that differences in health variables explained male/female differences in accommodation need, while work context differences explained male/female differences in whether needs were met. Conclusions: The findings highlight that women and men draw on a range of existing accommodation policies and practices to help manage their arthritis and that most have their accommodation needs met. Decomposing the context within which men and women with arthritis work suggests that women may face health and work context challenges that differ from men and that are related to greater accommodation needs and unmet need. This highlights potential vulnerabilities in the work of women that need to be addressed. PMID- 29420701 TI - Cerebellar Functional Connectivity in Term- and Very Preterm-Born Infants. AB - Cortical resting state networks have been consistently identified in infants using resting state-functional connectivity magnetic resonance imaging (rs-fMRI). Comparable studies in adults have demonstrated cerebellar components of well established cerebral networks. However, there has been limited investigation of early cerebellar functional connectivity. We acquired non-sedated rs-fMRI data in the first week of life in 57 healthy, term-born infants and at term-equivalent postmenstrual age in 20 very preterm infants (mean birth gestational age 27 +/- 2 weeks) without significant cerebral or cerebellar injury. Seed correlation analyses were performed using regions of interests spanning the cortical and subcortical gray matter and cerebellum. Parallel analyses were performed using rs fMRI data acquired in 100 healthy adults. Our results demonstrate that cortico cerebellar functional connectivity is well-established by term. Intra- and cortico-cerebellar functional connectivity were largely similar in infants and adults. However, infants showed more functional connectivity structure within the cerebellum, including stronger homotopic correlations and more robust anterior posterior anticorrelations. Prematurity was associated with reduced correlation magnitudes, but no alterations in intra- and cortico-cerebellar functional connectivity topography. These results add to the growing evidence that the cerebellum plays an important role in shaping early brain development during infancy. PMID- 29420702 TI - Rab23 Regulates Radial Migration of Projection Neurons via N-cadherin. AB - Radial migration of cortical projection neurons is a prerequisite for shaping a distinct multilayered cerebral cortex during mammalian corticogenesis. Members of Rab GTPases family were reported to regulate radial migration. Here, in vivo conditional knockout or in utero knockdown (KD) of Rab23 in mice neocortex causes aberrant polarity and halted migration of cortical projection neurons. Further investigation of the underlying mechanism reveals down-regulation of N-cadherin in the Rab23-deficient neurons, which is a cell adhesion protein previously known to modulate radial migration. (Shikanai M, Nakajima K, Kawauchi T. 2011. N cadherin regulates radial glial fiber-dependent migration of cortical locomoting neurons. Commun Integr Biol. 4:326-330.) Interestingly, pharmacological inhibition of extracellular signal-regulated kinases (ERK1/2) also decreases the expression of N-cadherin, implicating an upstream effect of ERK1/2 on N-cadherin and also suggesting a link between Rab23 and ERK1/2. Further biochemical studies show that silencing of Rab23 impedes activation of ERK1/2 via perturbed platelet derived growth factor-alpha (PDGFRalpha) signaling. Restoration of the expression of Rab23 or N-cadherin in Rab23-KD neurons could reverse neuron migration defects, indicating that Rab23 modulates migration through N-cadherin. These studies suggest that cortical neuron migration is mediated by a molecular hierarchy downstream of Rab23 via N-cadherin. PMID- 29420703 TI - Inhibition of SREBP With Fatostatin Does Not Attenuate Early Diabetic Nephropathy in Male Mice. AB - Sterol regulatory element binding protein (SREBP) is an important potential mediator of kidney fibrosis and is known to be upregulated in diabetic nephropathy. We evaluated the effectiveness of SREBP inhibition as treatment of diabetic nephropathy. Type 1 diabetes was induced in uninephrectomized male CD1 mice with streptozotocin. The mice were treated with the SREBP inhibitor fatostatin for 12 weeks. At the endpoint, kidney function and pathologic findings were assessed. Fatostatin inhibited the increase of both isoforms of SREBP (types 1 and 2) in diabetic kidneys. Treatment attenuated basement membrane thickening but did not improve hyperfiltration, albuminuria, or kidney fibrosis in diabetic mice. The treatment of nondiabetic mice with fatostatin led to hyperfiltration and increased the glomerular volume to levels seen in diabetic mice. This was associated with increased renal inflammation and a trend toward increased renal fibrosis. Both in vivo and in cultured renal proximal tubular epithelial cells, fatostatin increased the expression of the proinflammatory cytokine monocyte chemoattractant protein-1. Thus, SREBP inhibition with fatostatin not only is ineffective in preventing diabetic nephropathy but also leads to kidney injury in nondiabetic mice. Further research on the efficacy of other SREBP inhibitors and the specific roles of SREBP-1 and SREBP-2 in the treatment and pathogenesis of diabetic nephropathy is needed. PMID- 29420704 TI - Pacemaker implantation rate after transcatheter aortic valve implantation with early and new-generation devices: a systematic review. AB - Aims: The incidence of new-onset conduction abnormalities requiring permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) with new-generation prostheses remains debated. This systematic review analyses the incidence of PPI after TAVI with new-generation devices and evaluates the electrical, anatomical, and procedural factors associated with PPI. In addition, the incidence of PPI after TAVI with early generation prostheses was reviewed for comparison. Methods and results: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist, this systematic review screened original articles published between October 2010 and October 2017, reporting on the incidence of PPI after implantation of early and new-generation TAVI prostheses. Of the 1406 original articles identified in the first search for new generation TAVI devices, 348 articles were examined for full text, and finally, 40 studies (n = 17 139) were included. The incidence of a PPI after the use of a new-generation TAVI prosthesis ranged between 2.3% and 36.1%. For balloon expandable prostheses, the PPI rate remained low when using an early generation SAPIEN device (ranging between 2.3% and 28.2%), and with the new-generation SAPIEN 3 device, the PPI rate was between 4.0% and 24.0%. For self-expandable prostheses, the PPI rates were higher with the early generation CoreValve device (16.3-37.7%), and despite a reduction in PPI rates with the new Evolut R, the rates remained relatively higher (14.7-26.7%). When dividing the studies according to the highest (>26.0%) and the lowest (<12.1%) quintile of PPI rate, patients within the highest quintile were more frequently women when compared with the lowest quintile group (50.9% vs. 46.3%, P < 0.001). Pre-existent conduction abnormalities (electrical factor), calcification of the left ventricular outflow tract (anatomical factor), and balloon valvuloplasty and depth of implantation (procedural factors) were associated with increased risk of PPI. Conclusion: The rate of PPI after TAVI with new-generation devices is highly variable. Specific recommendations for implantation of each prosthesis, taking into consideration the presence of pre-existent conduction abnormalities and anatomical factors, may be needed to reduce the risk of PPI. PMID- 29420706 TI - Risk of cancer and repeated urgent referral after negative investigation for cancer. AB - Introduction: Many countries have implemented cancer patient pathways (CPPs) for organ-specific cancers. However, due to high symptom diversity, it can be difficult for the General Practitioner (GP) to decide on the appropriate CPP. Objective: The aim of this study was to estimate the proportion of patients who were referred to a second CPP, were diagnosed with cancer or died within 6 months after receiving a negative result from clinical investigation through an initial CPP. Methods: We conducted a historical cohort study using routinely collected data with 6 months of follow-up. Data were collected from Danish registries. Results: We included 109998 study subjects: 0.6% received a cancer diagnosis, 2.3% died and 6.1% were referred to a second CPP within 6 months. A total of 48.9% of the re-referrals after a first CPP in the gastrointestinal (GI) area were also referred to a second CPP in the GI area. Re-referral to a second CPP corresponded to a positive predictive value (PPV) of 4.4% to be diagnosed with cancer. Conclusion: A total of 6% of patients who received a negative result after investigation in an organ-specific CPP were re-referred within 6 months to a new organ-specific CPP; many of these were in the same anatomical area as the first CPP. The PPV of 4.4% to be diagnosed with cancer indicates that some cancers may be missed in the diagnostic investigation through the first CPP. This calls for reconsideration of how CPPs may best support the primary cancer diagnosis. PMID- 29420707 TI - Association of left ventricular late gadolinium enhancement with left atrial low voltage areas in patients with atrial fibrillation. AB - Aims: Presence of late gadolinium enhancement (LGE) is related to adverse cardiovascular outcome. Many patients suffering from atrial fibrillation (AF) undergo cardiovascular magnetic resonance (CMR) imaging prior to ablation. Since quantification of atrial fibrosis still lacks reproducibility, we sought to investigate risk factors for the presence of left ventricular (LV)-LGE and a possible correlation between ventricular fibrosis as defined by positive LGE and pathological atrial voltage maps evaluated by 3D mapping systems. Methods and results: Between May 2015 and January 2017, 241 patients with AF (73% persistent AF, 71% male, mean age 62.8 +/- 10.1 years, Redo procedure in 24%, AF history 4.5 +/- 5.2 years) underwent CMR including LV LGE prior to pulmonary vein (PV) isolation at Heart Center Leipzig. Depending on CMR results, two groups were separated: 'LV-LGE negative' (Group A, n = 197, 82%) and 'LV-LGE positive' (Group B, n = 44, 18%). To identify low voltage areas (LVA), a 3D electro-anatomic map was created during PV isolation. Multivariate analysis revealed male gender [odds ratio (OR) 7.6, 95% confidence interval (95% CI) 2.4-23.9, P = 0.001] and an increased CHA2DS2VASc Score (OR 1.6, 95% CI 1.2-2.2, P = 0.004) as significantly associated with LV-LGE. Impaired left ventricular ejection fraction, LV dilatation, larger LA size and, enlarged septum diameter occurred significantly more often in the 'LGE positive' group. Low voltage areas were detected in 83 patients overall (34%): Group A: n = 64/197 (33%), Group B: n = 19/44 (43%) (P = 0.177). Conclusion: Male gender and high CHA2DS2VASc Score are significantly associated with presence of LV-LGE, but LV-LGE is not associated with left atrial LVA. PMID- 29420705 TI - Differential Expression of microRNAs in Peripheral Blood Mononuclear Cells Identifies Autophagy and TGF-Beta-Related Signatures Aberrantly Expressed in Inflammatory Bowel Disease. AB - Background and Aims: MicroRNAs [miRNAs] have emerged as important regulators in inflammatory bowel disease [IBD]. This study investigated differential expression of miRNAs across clinical phenotypes in a well-characterized cohort of IBD patients and healthy controls [HCs]. Methods: A cohort of Crohn's disease [CD] and ulcerative colitis [UC] patients and HCs was prospectively accrued. Total RNA was extracted from peripheral blood mononuclear cells for all subjects. miRNA expression was measured using NanoString technologies. The subjects were stratified according to disease activity and location. Statistical significance was assessed per miRNA across outcomes and corrected for multiple testing. miRNA regulation of transcription of important results was confirmed in vitro by a dual luciferase reporter assay and autophagy function was evaluated using immunofluorescence imaging of LC3 puncta in HeLa cells. Results: In total, 120 subjects were enrolled. Seventy-four miRNAs were differentially expressed across CD, UC and HCs. Comparing quiescent CD [CDq] with HCs we found ten miRNAs upregulated in CDq. When comparing colonic CD [CCD] to UC, seven miRNAs were upregulated in CCD. The most differentially expressed miRNA in CCD vs UC was miR 874-3p, and we showed its possible utility as a biomarker of differential diagnosis. We showed miR-874-3p targets ATG16L1 and reduces its expression in vitro. An miR-874-3p mimic dysregulates autophagy by a reduction of LC3 in vitro. Conclusions: We identified unique miRNA signatures expressed in distinct IBD phenotypes. These associations highlight pathways dysregulated by aberrant miRNA expression, revealing possible mechanisms underlying the pathophysiology of IBD, but also suggest a cluster of miRNAs as readily accessible biomarkers to aid in differential diagnosis. PMID- 29420708 TI - Sex Differences in Maturation of Human Embryonic Stem Cell-Derived beta Cells in Mice. AB - Pancreatic progenitors derived from human embryonic stem cells (hESCs) are now in clinical trials for insulin replacement in patients with type 1 diabetes. Animal studies indicate that pancreatic progenitor cells can mature into a mixed population of endocrine cells, including glucose-responsive beta cells several months after implantion. However, it remains unclear how conditions in the recipient may influence the maturation and ultimately the function of these hESC derived cells. Here, we investigated the effects of (1) pregnancy on the maturation of human stage 4 (S4) pancreatic progenitor cells and (2) the impact of host sex on both S4 cells and more mature stage 7 (S7) pancreatic endocrine cells implanted under the kidney capsule of immunodeficient SCID-beige mice. Pregnancy led to increased proliferation of endogenous pancreatic beta cells, but did not appear to affect proliferation or maturation of S4 cells at midgestation. Interestingly, S4 and S7 cells both acquired glucose-stimulated C-peptide secretion in females before males. Moreover, S4 cells lowered fasting blood glucose levels in females sooner than in males, whereas the responses with S7 cells were similar. These data indicate that the host sex may impact the maturation of hESC-derived cells in vivo and that this effect can be minimized by more advanced differentiation of the cells before implantation. PMID- 29420709 TI - Rapid deployment aortic valve replacement in a minimal access setting: intermediate clinical and echocardiographic outcomes. AB - OBJECTIVES: Transcatheter procedures have overtaken conventional operations in Germany. Considering that this is a highly competitive field, a rate of 25% for minimal access aortic valve replacement seems to be disappointingly low. One way to promote minimal access techniques is through the systematic use of rapid deployment valves. METHODS: A total of 143 patients underwent rapid deployment aortic valve replacement via upper right hemisternotomy between March 2012 and September 2015. All patients were followed up annually. Echocardiographic assessment of the valve was performed after 12 months. The cumulative follow-up time was 275.2 patient-years. The median follow-up time was 1.9 years. RESULTS: The mean age was 76.4 +/- 6.2 years, and the mean logistic EuroSCORE was 11.0 +/- 4.3%. Early all-cause mortality was 2.8% (n = 4). Actuarial survival after 1 year was 91.6 +/- 2.4%, and after 3 years, it was 84.4 +/- 3.6%. Mean transprosthetic gradient after 12 months was 10.3 +/- 3.8 mmHg. New onset of higher grade paravalvular leakage did not occur during the follow-up period. Perioperatively, higher grade paravalvular leakage (aortic insufficiency >1+) occurred in 2 cases (1.4%) . CONCLUSIONS: Rapid deployment aortic valve replacement can be performed safely in a minimal access setting with low complication rates and good haemodynamic results. Therefore, rapid deployment valves are a relevant option in minimal access surgery. PMID- 29420710 TI - Accuracy and reproducibility of aortic annular measurements obtained from echocardiographic 3D manual and semi-automated software analyses in patients referred for transcatheter aortic valve implantation: implication for prosthesis size selection. AB - Aims: A 3D transoesophageal echocardiography (3D-TOE) reconstruction tool has recently been introduced. The system automatically configures a geometric model of the aortic root and performs quantitative analysis of these structures. We compared the measurements of the aortic annulus (AA) obtained by semi-automated 3D-TOE quantitative software and manual analysis vs. multislice computed tomography (MSCT) ones. Methods and results: One hundred and seventy-five patients (mean age 81.3 +/- 6.3 years, 77 men) who underwent both MSCT and 3D-TOE for annulus assessment before transcatheter aortic valve implantation were analysed. Hypothetical prosthetic valve sizing was evaluated using the 3D manual, semi-automated measurements using manufacturer-recommended CT-based sizing algorithm as gold standard. Good correlation between 3D-TOE methods vs. MSCT measurements was found, but the semi-automated analysis demonstrated slightly better correlations for AA major diameter (r = 0.89), perimeter (r = 0.89), and area (r = 0.85) (all P < 0.0001) than manual one. Both 3D methods underestimated the MSCT measurements, but semi-automated measurements showed narrower limits of agreement and lesser bias than manual measurements for most of AA parameters. On average, 3D-TOE semi-automated major diameter, area, and perimeter underestimated the respective MSCT measurements by 7.4%, 3.5%, and 4.4%, respectively, whereas minor diameter was overestimated by 0.3%. Moderate agreement for valve sizing for both 3D-TOE techniques was found: Kappa agreement 0.5 for both semi-automated and manual analysis. Interobserver and intraobserver agreements for the AA measurements were excellent for both techniques (intraclass correlation coefficients for all parameters >0.80). Conclusion: The 3D-TOE semi-automated analysis of AA is feasible and reliable and can be used in clinical practice as an alternative to MSCT for AA assessment. PMID- 29420711 TI - Fibrogenesis resulting from cyclic bleeding: the Holy Grail of the natural history of ectopic endometrium. PMID- 29420712 TI - The role of the general practitioner in return to work after cancer-a systematic review. AB - Background: The number of cancer patients and survivors of working age is increasing. General Practitioners (GPs) may have a significant role in psychosocial cancer care, including work-related concerns. Therefore, we performed a systematic literature review to identify the role of the GP in work related concerns and integration/reintegration into work of cancer patients and/or survivors. Methods: We searched PubMed, Embase, Cinahl, PsycINFO and Cochrane Library, irrespective of study design. We found 4863 articles and, after removing duplicates, we screened 3388 articles by title and abstract and reviewed 66 of these in full text. The Critical Appraisal Skills Programme tool was used to assess the methodological quality of included articles. We used narrative synthesis to describe the role of the GP. Results: We included four qualitative studies from three countries. Two of these studies focused on the health care professionals' perspectives and two studies focused on patients' perspectives regarding the role of the GP. Lack of communication between health care professionals, lack of knowledge about work-related concerns and limited resources were recurring themes in these papers. Fully establishing the role of the GP is difficult given the small number of studies on work-related concerns in cancer patients in primary care. Conclusion: There is little evidence regarding the role of the general practitioner in cancer care and work guidance. Therefore, further research should focus on the role that is desired for GPs and on interventions to study the feasibility of GP involvement in the return to work of cancer patients and/or survivors. PMID- 29420713 TI - Symptoms in primary care with time to diagnosis of brain tumours. AB - Background: Brain tumours often present with varied, non-specific features with other diagnoses usually being more likely. Objective: To examine how different symptoms and patient demographics predict variations in time to brain tumour diagnosis. Methods: We conducted a secondary analysis of brain tumour cases from National Audit of Cancer Diagnosis in Primary Care. We grouped neurological symptoms into six domains (headache, behavioural/cognitive change, focal neurology, 'fits, faints or falls', non-specific neurological, and other/non specific) and calculated times for patient presentation, GP referral, specialist consultation and total pathway interval. We calculated odds ratios (ORs) for symptom domains comparing the slowest to other quartiles. Results: Data were available for 226 cases. Median (interquartile range) time for the total pathway interval was 24 days (7-65 days). The most common presentation was focal neurology (33.2%) followed by 'fits, faints or falls' and headache (both 20.8%). Headache only (OR = 4.11, 95% CI = 1.10, 15.5) and memory complaints (OR = 4.82, 95% CI = 1.15, 20.1) were associated with slower total pathway compared to 'fits, faints or falls'. GPs were more likely to consider that there had been avoidable delays in referring patients with headache only (OR = 4.17, 95% CI = 1.14, 15.3). Conclusion: Patients presenting to primary care with headache only or with memory complaints remain problematic with potentially avoidable delays in referral leading to a longer patient pathway. This may or may not impact on the efficacy and morbidity of therapies. Additional aids are required to help doctors differentiate when to refer headaches and memory complaints urgently for a specialist opinion. PMID- 29420715 TI - Modulation of Nuclear Receptor Function by Chromatin Modifying Factor TIP60. AB - Nuclear receptors (NRs) are transcription factors that bind to specific DNA sequences known as hormone response elements located upstream of their target genes. Transcriptional activity of NRs can be modulated by binding of the compatible ligand and transient interaction with cellular coregulators, functioning either as coactivators or as corepressors. Many coactivator proteins possess intrinsic histone acetyltransferase (HAT) activity that catalyzes the acetylation of specific lysine residues in histone tails and loosens the histone DNA interaction, thereby facilitating access of transcriptional factors to the regulatory sequences of the DNA. Tat interactive protein 60 (TIP60), a member of the Mof-Ybf2-Sas2-TIP60 family of HAT protein, is a multifunctional coregulator that controls a number of physiological processes including apoptosis, DNA damage repair, and transcriptional regulation. Over the last two decades or so, TIP60 has been extensively studied for its role as NR coregulator, controlling various aspect of steroid receptor functions. The aim of this review is to summarize the findings on the role of TIP60 as a coregulator for different classes of NRs and its overall functional implications. We also discuss the latest studies linking TIP60 to NR-associated metabolic disorders and cancers for its potential use as a therapeutic drug target in future. PMID- 29420714 TI - The DNA Methylation Landscape of Stickleback Reveals Patterns of Sex Chromosome Evolution and Effects of Environmental Salinity. AB - Epigenetic mechanisms such as DNA methylation are a key component of dosage compensation on sex chromosomes and have been proposed as an important source of phenotypic variation influencing plasticity and adaptive evolutionary processes, yet little is known about the role of DNA methylation in an ecological or evolutionary context in vertebrates. The threespine stickleback (Gasterosteus aculeatus) is an ecological and evolutionary model system that has been used to study mechanisms involved in the evolution of adaptive phenotypes in novel environments as well as the evolution heteromorphic sex chromosomes and dosage compensation in vertebrates. Using whole genome bisulfite sequencing, we compared genome-wide DNA methylation patterns between threespine stickleback males and females and between stickleback reared at different environmental salinities. Apparent hypermethylation of the younger evolutionary stratum of the stickleback X chromosome in females relative to males suggests a potential role of DNA methylation in the evolution of heteromorphic sex chromosomes. We also demonstrate that rearing salinity has genome-wide effects on DNA methylation levels, which has the potential to lead to the accumulation of epigenetic variation between natural populations in different environments. PMID- 29420716 TI - Racial/Ethnic Disparities in the Lifetime Risk of Chlamydia trachomatis Diagnosis and Adverse Reproductive Health Outcomes Among Women in King County, Washington. AB - Background: Chlamydia trachomatis is the most common reportable infection in the United States and can cause pelvic inflammatory disease (PID) and tubal factor infertility (TFI). Methods: We created life tables to estimate the "lifetime" risk of chlamydia diagnosis among women aged 15-34 years in King County, Washington, between 1992 and 2014. We estimated the lifetime risk of chlamydia associated PID and TFI incorporating published estimates of the risk of sequelae. Results: There were 51464 first chlamydia diagnoses in 1992-2014. For women born between 1980 and 1984, the lifetime risk of chlamydia diagnosis was 19.8% overall and 14.0% for non-Hispanic white, 64.9% for non-Hispanic black, and 32.6% for Hispanic women. The cumulative risk of chlamydia by age 24 increased overall from 13.9% to 17.3% among women born between 1975 and 1994 but declined among non Hispanic black women, among whom risk by age 24 declined from 57.3% among women born between 1980 and 1984 to 38.6% among women born between 1990 and 1994. The lifetime risk of chlamydia-associated PID among women born between 1980 and 1984 ranged from 0.33% to 1.14%. Among non-Hispanic white, non-Hispanic black, and Hispanic women, the lifetime risk of chlamydia-associated TFI was 0.04%, 0.20%, and 0.10%, respectively. Conclusions: Over 60% of non-Hispanic black women had at least 1 chlamydia diagnosis by age 34 in the birth cohorts most affected, a risk almost 5 times that in non-Hispanic whites. An estimated 1 in 500 non-Hispanic black women develops chlamydia-associated TFI. More effective control measures are needed. PMID- 29420717 TI - Surgical outcomes of aortic repair via transapical cannulation and the adventitial inversion technique for acute Type A aortic dissection. AB - OBJECTIVES: To evaluate the surgical outcomes of aortic repair via transapical cannulation and the adventitial inversion technique for acute Type A aortic dissection. METHODS: Between 2008 and 2015, a total of 300 patients with acute Type A aortic dissection underwent emergency surgery, consisting of 271 hemiarch repairs and 29 total aortic arch replacements, using transapical cannulation and the adventitial inversion technique at a distal anastomosis. The mean follow-up periods were 31.7 +/- 25.2 months. Overall, 18% (54/300) of the patients were octogenarians, and 21.7% (65/300) had cardiac tamponade; 25% (75/300) had preoperative malperfusion. RESULTS: The in-hospital and 30-day mortality rates were 8.3% (25/300) and 6.7% (20/300), respectively. The 30-day mortality rate was 2.7% (6/225) among patients without preoperative malperfusion and 18.7% (14/75) among patients with malperfusion (P < 0.0001), 7.4% (4/54) among octogenarians and 6.5% (16/246) among patients aged less than 80 years (P = 0.81), and 6.3% (17/271) among patients treated with hemiarch repair and 10.3% (3/29) among patients treated with total aortic arch replacement (P = 0.403). Preoperative malperfusion was an independent predictor of perioperative mortality in a multivariable analysis. During the follow-up period, distal reintervention was performed in 11% (33/300) of the patients. The rates of freedom from reintervention at 1, 3 and 5 years were 95.9%, 88.9% and 80.0%, respectively. The overall survival rates at 1, 3 and 5 years were 88.7%, 86.7% and 82.0%, respectively. The in-hospital mortality rate for elective reintervention was 3.0% (1/33). CONCLUSIONS: Aortic repair via transapical cannulation and the adventitial inversion technique for acute Type A aortic dissection provides good early and mid-term results. The safety of elective distal reintervention can be guaranteed. To obtain better operative outcomes, effective treatment for cases with malperfusion is mandatory. PMID- 29420718 TI - Predictors of right ventricular failure after implantation of left ventricular assist devices. PMID- 29420720 TI - Whale tail left atrial appendage anatomy: implications for percutaneous closure devices. PMID- 29420721 TI - Acute and long-term efficacy and safety with a single cryoballoon application as compared with the standard dual application strategy: a prospective randomized study using the second-generation cryoballoon for pulmonary vein isolation in patients with symptomatic atrial fibrillation. AB - Aims: A single cryoballoon (CB) application per vein for pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF) could save time and was therefore compared to the standard approach of two consecutive CB applications for acute and long-term efficacy and safety. Methods and results: Patients with symptomatic AF were randomized to a single CB application per vein guided by an Achieve(r) catheter (Single cryo-arm) or to two CB applications using a standard guidewire (Routine cryo-arm). The primary endpoint was the rate of acute complete PVI. Secondary endpoints were freedom from AF evaluated by electrocardiogram and 7 days Holter at 6 and 12 months, symptoms by Symptom Severity Questionnaires and EHRA score and quality of life (QoL) by EQ5D-5L at 12 months. Among 140 patients included, PVI was achieved in 271 (100%) veins in the Single cryo-arm and in 269/271 (99.3%) veins in the Routine cryo-arm, P = 0.25. The procedure time was shorter in the Single cryo-arm, mean +/- standard deviation 99.4 +/- 33.3 min vs. 118.4 +/- 34.3 min, P = 0.0015. Freedom from AF after one procedure at 12 months did not differ; 73.9.0% (Single cryo) vs. 71.4% (Routine), P = 0.74. Symptoms and QoL did also not differ between the two groups. There was a lower complication rate in the Single cryo-group, 2.9% vs. 12.9%, P = 0.03. Conclusion: A single CB application shortens the procedure time without affecting acute or long-term efficacy, as compared to the routine two-application strategy, which with the lower complication rates has important implications when defining standards for PVI. PMID- 29420719 TI - Microbial Dark Matter Investigations: How Microbial Studies Transform Biological Knowledge and Empirically Sketch a Logic of Scientific Discovery. AB - Microbes are the oldest and most widespread, phylogenetically and metabolically diverse life forms on Earth. However, they have been discovered only 334 years ago, and their diversity started to become seriously investigated even later. For these reasons, microbial studies that unveil novel microbial lineages and processes affecting or involving microbes deeply (and repeatedly) transform knowledge in biology. Considering the quantitative prevalence of taxonomically and functionally unassigned sequences in environmental genomics data sets, and that of uncultured microbes on the planet, we propose that unraveling the microbial dark matter should be identified as a central priority for biologists. Based on former empirical findings of microbial studies, we sketch a logic of discovery with the potential to further highlight the microbial unknowns. PMID- 29420722 TI - Craniofacial morphology and growth in young patients with congenital or childhood onset myotonic dystrophy. AB - Background/objectives: This study investigated the craniofacial morphology of young individuals with congenital or childhood onset myotonic dystrophy type 1 (DM1) compared to healthy subjects. The study also followed growth changes in their facial morphology over a 5-year period. Materials/methods: Lateral cephalograms of the 26 subjects (young patients with DM1 from west and south Sweden) were taken at baseline and after a 5-year period. These radiographs were compared with normal standards based on healthy individuals from the Michigan Growth Study, according to their age and sex, using paired t-tests (P < 0.05). Results: On examination of initial radiographic measurements, patients with DM1 showed, in the sagittal plane, larger ANB and smaller SNPg angles. Analysis of the vertical plane showed the mandibular plane angle (ML-NSL) and the intermaxillary angle (ML-NL) to be larger. During the 5-year follow-up period, the intermaxillary angle (ML-NL) remained the same in the group with DM1 whereas this angle decreased in healthy individuals. Limitations: For ethical reasons, historical cephalometric norms were used to compare the growth and the craniofacial morphology of patients with DM1. Conclusions/implications: Young patients with DM1 had already from the beginning a more retrognathic profile and hyperdivergent skeletal aberration with a steep mandibular plane and large intermaxillary angle when compared with healthy individuals. The intermaxillary angle did not decrease during the observation period, contrary to what was observed in healthy individuals. PMID- 29420723 TI - Lithotripsy-assisted transfemoral aortic valve implantation. PMID- 29420724 TI - Clinical pharmacists working within family practice: what is the evidence? PMID- 29420725 TI - Guidelines for the Standardization of Genital Photography. AB - Plastic surgery relies on photography for both clinical practice and research. The Photographic Standards in Plastic Surgery laid the foundation for standardized photography in plastic surgery. Despite these advancements, the current literature lacks guidelines for genital photography, thus resulting in a discordance of documentation. The authors propose photographic standards for the male and female genitalia to establish homogeneity in which information can be accurately exchanged. All medical photographs include a sky-blue background, proper lighting, removal of distractors, consistent camera framing, and standard camera angles. We propose the following guidelines to standardize genital photography. In the anterior upright position, feet are shoulder-width apart, and arms are placed posteriorly. The frame is bounded superiorly by the xiphoid umbilicus midpoint and inferiorly by the patella. For circumferential documentation, frontal 180 degree capture via 45 degree intervals is often sufficient. Images in standard lithotomy position should be captured at both parallel and 45 degrees above the horizontal. Images of the phallus should include both the flaccid and erect states. Despite the increasing incidence of genital procedures, there lacks a standardized methodology in which to document the genitalia, resulting in a substantial heterogeneity in the current literature. Our standardized techniques for genital photography set forth to establish a uniform language that promotes more effective communication with both the patient as well as with colleagues. The proposed photography guidelines provide optimal visualization and standard documentation of the genitalia, allowing for accurate education, meaningful collaborations, and advancement in genital surgery. PMID- 29420726 TI - Identification and validation of appropriate reference genes for qRT-PCR analysis in Corynebacterium glutamicum. AB - Real-time quantitative PCR (qRT-PCR) is a fast and efficient technology for detecting gene expression levels in the study of the Corynebacterium glutamicum protein expression system, but it requires normalization to ensure the reliability of the results obtained. We selected 13 genes from the commonly used housekeeping genes and from transcriptome data as candidate reference genes. The Ct values of the 13 genes were obtained by qRT-PCR at different fermentation stages and under three stress conditions (temperature, acid and salt). The expression stability of the reference genes was evaluated by geNorm and NormFinder software. For the study of different growth stages, the most appropriate reference genes are Ncgl2772 and leua, which encode acetyl-CoA carboxylase beta subunit and 2-isopropylmalate synthase, separately. For the study of different stress factors, the optimal minimum number of reference genes is 3, with Ncgl2772, gyrb encoding DNA gyrase B and siga encoding RNA polymerase sigma factor A as the most suitable combination. Additionally, clpx and clpc, encoding ClpX and ClpC protease subunits, were used to validate the candidate reference genes. The identification of new reference genes makes qRT-PCR more convenient, and using these genes for normalization can improve the accuracy and reliability of the measurements of target gene expression levels obtained by qRT PCR for C. glutamicum. PMID- 29420727 TI - Sudden death in Ebstein's anomaly: are we killing our patients with surgery? PMID- 29420728 TI - Unusual coarctation repair with double lumen distal arch. PMID- 29420729 TI - Combination Treatment With Exogenous GDNF and Fetal Spinal Cord Cells Results in Better Motoneuron Survival and Functional Recovery After Avulsion Injury With Delayed Root Reimplantation. AB - When spinal roots are torn off from the spinal cord, both the peripheral and central nervous system get damaged. As the motoneurons lose their axons, they start to die rapidly, whereas target muscles atrophy due to the denervation. In this kind of complicated injury, different processes need to be targeted in the search for the best treatment strategy. In this study, we tested glial cell derived neurotrophic factor (GDNF) treatment and fetal lumbar cell transplantation for their effectiveness to prevent motoneuron death and muscle atrophy after the spinal root avulsion and delayed reimplantation. Application of exogenous GDNF to injured spinal cord greatly prevented the motoneuron death and enhanced the regeneration and axonal sprouting, whereas no effect was seen on the functional recovery. In contrast, cell transplantation into the distal nerve did not affect the host motoneurons but instead mitigated the muscle atrophy. The combination of GDNF and cell graft reunited the positive effects resulting in better functional recovery and could therefore be considered as a promising strategy for nerve and spinal cord injuries that involve the avulsion of spinal roots. PMID- 29420731 TI - Reply to Gokalp et al. PMID- 29420730 TI - Clinical differences between men and women undergoing surgery for acute Type A aortic dissection. AB - OBJECTIVES: The differences in clinical features, surgical outcome and long-term prognosis between men and women who undergo surgery for Type A aortic dissection are not well known. METHODS: From January 2004 to December 2016, 303 patients, consisting of 147 women and 156 men, underwent surgery for acute Type A aortic dissection at our institution. We compared clinical outcomes between the 2 cohorts. RESULTS: Women were older than men (72.6 vs 63.0; P < 0.001). Operative mortality was similar between the groups (8.2% vs 8.9%; P = 0.80). The duration of intensive care unit stay (54 vs 64 h median; P = 0.03) and mechanical ventilator support (34 vs 43 h; P = 0.02) was significantly shorter in women. Multivariate logistic regression analysis revealed that preoperative cardiopulmonary resuscitation, cardiac tamponade, chronic obstructive pulmonary disease, haemodialysis and longer cardiopulmonary bypass time were independent risk factors for early death. Among the hospital survivors, the actuarial survival rate was 59.0% in women and 65.7% in men at 10 years (P = 0.81). During the follow-up period, there were 9 female and 27 male patients who underwent reoperation related to the aortic dissection. The rate of 10-year actuarial freedom from reoperation was 80.7% in women and 53.1% in men (log-rank P = 0.018). CONCLUSIONS: No differences were observed in both early and long-term mortality between women and men. Male patients had a significantly higher rate of reoperation. CLINICAL REGISTRATION NUMBER: UMIN000029179. PMID- 29420732 TI - Comparison of Techniques for Sampling Adult Necrophilous Insects From Pig Carcasses. AB - Studies of the pre-colonization interval and mechanisms driving necrophilous insect ecological succession depend on effective sampling of adult insects and knowledge of their diel and successional activity patterns. The number of insects trapped, their diversity, and diel periodicity were compared with four sampling methods on neonate pigs. Sampling method, time of day and decomposition age of the pigs significantly affected the number of insects sampled from pigs. We also found significant interactions of sampling method and decomposition day, time of sampling and decomposition day. No single method was superior to the other methods during all three decomposition days. Sampling times after noon yielded the largest samples during the first 2 d of decomposition. On day 3 of decomposition however, all sampling times were equally effective. Therefore, to maximize insect collections from neonate pigs, the method used to sample must vary by decomposition day. The suction trap collected the most species-rich samples, but sticky trap samples were the most diverse, when both species richness and evenness were factored into a Shannon diversity index. Repeated sampling during the noon to 18:00 hours period was most effective to obtain the maximum diversity of trapped insects. The integration of multiple sampling techniques would most effectively sample the necrophilous insect community. However, because all four tested methods were deficient at sampling beetle species, future work should focus on optimizing the most promising methods, alone or in combinations, and incorporate hand-collections of beetles. PMID- 29420733 TI - Reproductive Behaviors of Anoplophora glabripennis (Coleoptera: Cerambycidae) in the Laboratory. AB - The reproductive behaviors of individual pairs of Anoplophora glabripennis (Motschulsky) (Coleoptera: Cerambycidae)-all combinations of three populations and three different ages-were observed in glass jars in the laboratory on Acer saccharum Marshall (Sapindales: Sapindaceae) host material. The virgin female occasionally made first contact, but mounting did not occur until the male antennated or palpated the female. If the female was receptive (older females initially less receptive than younger ones), the male mated with her immediately after mounting and initiated a prolonged pair-bond. When the female was not receptive, some males abandoned the attempt while most performed a short antennal wagging behavior. During the pair-bond, the male continuously grasped the female's elytral margins with his prothoracic tarsi or both pro- and mesothoracic tarsi. The male copulated in a series of three to four bouts (averaging three to five copulations each) during which the female chewed oviposition sites or walked on the host. Between bouts, the female oviposited and fertile eggs were deposited as soon as 43 min after the first copulation. Females became unreceptive again after copulation and the duration of the pair-bond depended on the male's ability to remain mounted. Some population differences were seen which may be climatic adaptations. A single pair-bond was sufficient for the female to achieve ~60% fertility for her lifetime, but female fecundity declined with age at mating. Under eradication conditions, mates will become more difficult to find and females that find mates will likely produce fewer progeny because they will be older at the time of mating. PMID- 29420734 TI - Convergent pathways of the hyperferritinemic syndromes. AB - Hyperferritinemia and pronounced hemophagocytosis help distinguish a subset of patients with a particularly inflammatory and deadly systemic inflammatory response syndrome. Two clinically similar disorders typify these hyperferritinemic syndromes: hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). HLH is canonically associated with a complete disturbance of perforin/granzyme-mediated cytotoxicity, whereas MAS occurs in the context of the related rheumatic diseases systemic juvenile idiopathic arthritis and adult-onset Still's disease, with associated IL-1 family cytokine activation. In practice, however, there are accumulating lines of evidence for innate immune dysregulation in HLH as well as partial impairments of cytotoxicity in MAS, and these mechanisms likely represent only a fraction of the host and environmental factors driving hyperferritinemic inflammation. Herein, we present new findings that highlight the pathogenic differences between HLH and MAS, two conditions that present with life-threatening hyperinflammation, hyperferritinemia and hemophagocytosis. PMID- 29420735 TI - 12-Oxo-Phytodienoic Acid Enhances Wheat Resistance to Hessian Fly (Diptera: Cecidomyiidae) Under Heat Stress. AB - 12-Oxo-phytodienoic acid (OPDA) plays unique roles in plant defenses against biotic and abiotic stresses. In the current study, we infested two resistant wheat (Triticum aestivum L.) cultivars, 'Molly' and 'Iris', with an avirulent Hessian fly population and determined the impact of exogenous OPDA application on wheat resistance to the insect under heat stress. We observed that Molly and Iris treated with OPDA solution prior to the heat treatment exhibited significantly enhanced insect resistance. We also measured OPDA concentrations at Hessian fly feeding sites in Molly infested with Hessian flies. We found that exogenous application of OPDA resulted in increased abundance of endogenous OPDA in Molly seedlings and that OPDA abundance in plants treated with the combination of heat and OPDA was similar to that of plants in the incompatible interaction. Our results suggest that high abundance of endogenous OPDA may be necessary for wheat under heat stress to resist to Hessian fly infestation. PMID- 29420736 TI - Loss of Motor Neurons Innervating Cervical Muscles in Patients With Multiple System Atrophy and Dropped Head. AB - We investigated whether loss of motor neurons innervating the neck muscles contributes to dropped head (DH) in multiple system atrophy (MSA). From 75 patients with autopsy-proven MSA, we retrieved 3 who had DH (MSA-DH), and examined the 4th cervical cord segments. Neurons of the medial and lateral nuclear groups (MNG and LNG) innervate the neck and shoulder muscles, respectively. We measured the area of individual neurons in the MNG and LNG, and created an area-frequency histogram. Neurons were classified as large or small based on their area, and their total numbers in the MNG and LNG were counted. In the MNG, the numbers of both total neurons and large neurons were significantly lower in MSA patients than in the controls (214.2 +/- 91.4 vs 521.3 +/- 74.8, p = 0.0030, and 26.2 +/- 9.1 vs 88.0 +/- 34.6, p = 0.020, respectively), and were significantly lower in MSA-DH than in MSA-nonDH (139.7 +/- 7.6 vs 288.7 +/- 74.6, p = 0.048, and 18.0 +/- 4.1 vs 34.3 +/- 4.1, p = 0.016, respectively). There were no differences in the LNG neuron counts between the MSA-DH and MSA-nonDH groups. Loss of cervical motor neurons may be responsible for DH in MSA. PMID- 29420737 TI - Efficient delivery of large DNA from Escherichia coli to Synechococcus elongatus PCC7942 by broad-host-range conjugal plasmid pUB307. AB - Synechococcus elongatus PCC7942, a cyanobacterium that uses light and carbon dioxide to grow, has a high ability to incorporate DNA by transformation. To assess the effective delivery of large DNA in plasmid form, we cloned the endogenous plasmid pANL (46.4 kbp) into a BAC vector of Escherichia coli. The plasmid p38ANL (54.3 kbp) replaced the native plasmid. To assess the delivery of larger DNA into PCC7942, p38ANL was fused to the broad-host-range conjugal transfer plasmid pUB307IP (53.5 kbp). The resulting plasmid pUB307IP501 (107.9 kbp) was transmitted from E. coli to PCC7942 by simple mixing of donor and recipient cultures. PCC7942 transcipients possessed only pUB307IP501, replacing the preexisting pANL. In contrast, the pUB307IP501 plasmid was unable to transform PCC7942, indicating that natural transformation of DNA may be restricted by size limitations. The ability to deliver large DNA by conjugation may lead to genetic engineering in PCC7942. PMID- 29420738 TI - Transcription-Associated Mutation Promotes RNA Complexity in Highly Expressed Genes-A Major New Source of Selectable Variation. AB - Alternatively spliced transcript isoforms are thought to play a critical role for functional diversity. However, the mechanism generating the enormous diversity of spliced transcript isoforms remains unknown, and its biological significance remains unclear. We analyzed transcriptomes in saker falcons, chickens, and mice to show that alternative splicing occurs more frequently, yielding more isoforms, in highly expressed genes. We focused on hemoglobin in the falcon, the most abundantly expressed genes in blood, finding that alternative splicing produces 10-fold more isoforms than expected from the number of splice junctions in the genome. These isoforms were produced mainly by alternative use of de novo splice sites generated by transcription-associated mutation (TAM), not by the RNA editing mechanism normally invoked. We found that high expression of globin genes increases mutation frequencies during transcription, especially on nontranscribed DNA strands. After DNA replication, transcribed strands inherit these somatic mutations, creating de novo splice sites, and generating multiple distinct isoforms in the cell clone. Bisulfate sequencing revealed that DNA methylation may counteract this process by suppressing TAM, suggesting DNA methylation can spatially regulate RNA complexity. RNA profiling showed that falcons living on the high Qinghai-Tibetan Plateau possess greater global gene expression levels and higher diversity of mean to high abundance isoforms (reads per kilobases per million mapped reads >=18) than their low-altitude counterparts, and we speculate that this may enhance their oxygen transport capacity under low-oxygen environments. Thus, TAM-induced RNA diversity may be physiologically significant, providing an alternative strategy in lifestyle evolution. PMID- 29420739 TI - Importance of risk comparison for individual and societal decision-making after the Fukushima disaster. AB - Risk comparison is essential for effective societal and individual decision making. After the Fukushima disaster, studies compared radiation and other disaster-related risks to determine the effective prioritizing of measures for response. Evaluating the value of risk comparison information can enable effective risk communication. In this review, the value of risk comparison after the Fukushima disaster for societal and individual decision-making is discussed while clarifying the concept of radiation risk assessment at low doses. The objectives of radiation risk assessment are explained within a regulatory science framework, including the historical adoption of the linear non-threshold theory. An example of risk comparison (i.e. radiation risk versus evacuation-related risk in nursing homes) is used to discuss the prioritization of pre-disaster measures. The effective communication of risk information by authorities is discussed with respect to group-based and face-to-face approaches. Furthermore, future perspectives regarding radiation risk comparisons are discussed. PMID- 29420740 TI - Effect of high night temperature on storage lipids and transcriptome changes in developing seeds of oilseed rape. AB - Global warming causes a faster increase of night temperature than of day temperature in tropical and subtropical zones. Little is known about the effect of high night temperature on storage lipids and transcriptome changes in oilseed rape. This study compared the total fatty acids and fatty acid compositions in seeds of two oilseed rape cultivars between high and low night temperatures. Their transcriptome profiles were also analyzed. High night temperature significantly affected the total fatty acids and fatty acid compositions in seeds of both low and high oil content cultivars, namely Jiuer-13 and Zheyou-50, thereby resulting in 18.9% and 13.7% total fatty acid reductions, respectively. In particular, high night temperature decreased the relative proportions of C18:0 and C18:1 but increased the proportions of C18:2 and C18:3 in both cultivars. In depth analysis of transcriptome profiles revealed that high night temperature up regulated gibberellin signaling during the night-time. This up-regulation was associated with the active expression of genes involved in fatty acid catabolism, such as those in beta-oxidation and glyoxylate metabolism pathways. Although the effect of temperature on plant lipids has been previously examined, the present study is the first to focus on night temperature and its effect on the fatty acid composition in seeds. PMID- 29420741 TI - Use of text-mining methods to improve efficiency in the calculation of drug exposure to support pharmacoepidemiology studies. AB - Background: Efficient generation of structured dose instructions that enable researchers to calculate drug exposure is central to pharmacoepidemiology studies. Our aim was to design and test an algorithm to codify dose instructions, applied to the NHS Scotland Prescribing Information System (PIS) that records about 100 million prescriptions per annum. Methods: A natural language processing (NLP) algorithm was developed that enabled free-text dose instructions to be represented by three attributes - quantity, frequency and qualifier - specified by three, three and two variables, respectively. A sample of 15 593 distinct dose instructions was used to test, validate and refine the algorithm. The final algorithm used a zero-assumption approach and was then applied to the full dataset. Results: The initial algorithm generated structured output for 13 152 (84.34%) of the 15 593 sample dose instructions, and reviewers identified 767 (5.83%) incorrect translations, giving an accuracy of 94.17%. Following subsequent refinement of the algorithm rules, application to the full dataset of 458 227 687 prescriptions (99.67% had dose instructions represented by 4 964 083 distinct instructions) generated a structured output for 92.3% of dose instruction texts. This varied by therapeutic area (from 86.7% for the central nervous system to 96.8% for the cardiovascular system). Conclusions: We created an NLP algorithm, operational at scale, to produce structured output that gives data users maximum flexibility to formulate, test and apply their own assumptions according to the medicines under investigation. Text mining approaches can provide a solution to the safe and efficient management and provisioning of large volumes of data generated through our health systems. PMID- 29420743 TI - Meropenem potentiation of aminoglycoside activity against Pseudomonas aeruginosa: involvement of the MexXY-OprM multidrug efflux system. AB - Objectives: To assess the ability of meropenem to potentiate aminoglycoside (AG) activity against laboratory and AG-resistant cystic fibrosis (CF) isolates of Pseudomonas aeruginosa and to elucidate its mechanism of action. Methods: AG resistance gene deletions were engineered into P. aeruginosa laboratory and CF isolates using standard gene replacement technology. Susceptibility to AGs +/- meropenem (at 1/2 MIC) was assessed using a serial 2-fold dilution assay. mexXY expression and MexXY-OprM efflux activity were quantified using quantitative PCR and an ethidium bromide accumulation assay, respectively. Results: A screen for agents that rendered WT P. aeruginosa susceptible to a sub-MIC concentration of the AG paromomycin identified the carbapenem meropenem, which potentiated several additional AGs. Meropenem potentiation of AG activity was largely lost in a mutant lacking the MexXY-OprM multidrug efflux system, an indication that it was targeting this efflux system in enhancing P. aeruginosa susceptibility to AGs. Meropenem failed to block AG induction of mexXY expression or MexXY-OprM efflux activity, suggesting that it may be interfering with some MexXY-dependent process linked to AG susceptibility. Meropenem potentiated AG activity versus AG resistant CF isolates, enhancing susceptibility to at least one AG in all isolates and susceptibility to all tested AGs in 50% of the isolates. Notably, meropenem potentiation of AG activity was linked to MexXY in some but not all CF isolates in which this was examined. Conclusions: Meropenem potentiates AG activity against laboratory and CF strains of P. aeruginosa, both dependent on and independent of MexXY, highlighting the complexity of AG resistance in this organism. PMID- 29420742 TI - Population-level Outcomes and Cost-Effectiveness of Expanding the Recommendation for Age-based Hepatitis C Testing in the United States. AB - Background: The US Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force recommend one-time hepatitis C virus (HCV) testing for persons born 1945-1965 and targeted testing for high-risk persons. This strategy targets HCV testing to a prevalent population at high risk for HCV morbidity and mortality, but does not include younger populations with high incidence. To address this gap and improve access to HCV testing, age-based strategies should be considered. Methods: We used a simulation of HCV to estimate the effectiveness and cost-effectiveness of HCV testing strategies: 1) standard of care (SOC) - recommendation for one-time testing for all persons born 1945 1965, 2) recommendation for one-time testing for adults >=40 years (>=40 strategy), 3) >=30 years (>=30 strategy), and 4) >=18 years (>=18 strategy). All strategies assumed targeted testing of high-risk persons. Inputs were derived from national databases, observational cohorts and clinical trials. Outcomes included quality-adjusted life expectancy, costs, and cost-effectiveness. Results: Expanded age-based testing strategies increased US population lifetime case identification and cure rates. Greatest increases were observed in the >=18 strategy. Compared to the SOC, this strategy resulted in an estimated 256,000 additional infected persons identified and 280,000 additional cures at the lowest cost per QALY gained (ICER = $28,000/QALY). Conclusions: In addition to risk based testing, one-time HCV testing of persons 18 and older appears to be cost effective, leads to improved clinical outcomes and identifies more persons with HCV than the current birth cohort recommendations. These findings could be considered for future recommendation revisions. PMID- 29420744 TI - Risk factors for metastasis to No.14v lymph node and prognostic value of 14v status for gastric cancer patients after surgery. AB - Background: D2 procedure has been accepted as the standard lymphadenectomy for advanced GC, while the role of No.14v lymph node (14v) dissection for distal GC is still controversial. Methods: A total of 284 GC patients receiving D2 plus 14v dissection in our center were enrolled. Patients were categorized into two groups based on 14v status: positive group (PG) and negative group (NG). Clinicopathological factors correlated with 14v metastasis and prognostic variables were respectively analyzed. Results: Thirty-five patients (12.3%) had 14v metastasis. Metastasis to No.4d and No.6 lymph node were independent variables affecting 14v metastasis. Patients with positive 14v had a significant lower 3-year overall survival (OS) rate than those without (3-year OS: 42.9% vs. 70.3%, P < 0.001). Multivariable analysis demonstrated that 14v status was an independent prognostic factor for III stage GC (hazard ratio 1.462, 95% confident interval: 1.182-2.309, P = 0.027). The prognosis of 14v positive patients correlated with tumor size and No.6 lymph node status in univariate analysis. Conclusion: GC patients with No.4d and No.6 lymph node metastasis were more likely to have positive 14v. Status of 14v was an independent prognostic factor for III stage GC. Patients with 14v metastasis usually had a poorer prognosis, while survival in such patients after curative surgery was similar to that of patients staged IIIc without 14v metastasis. PMID- 29420745 TI - Biceps Tenodesis and Intra-articular Decompression for Treatment of Superior Labral Tear from Anterior to Posterior and Associated Paralabral Cyst in Active Duty Military. AB - Background: To examine the outcomes of combined biceps tenodesis and indirect, intra-articular arthroscopic paralabral cyst decompression for the treatment of active duty military patients with superior labral from anterior to posterior tears and associated paralabral cysts. Methods: Retrospective chart review of all active duty patients at our institution from 2011 to 2014 with superior labral from anterior to posterior tears and associated paralabral cysts at the spinoglenoid notch treated with biceps tenodesis and indirect arthroscopic cyst decompression. Patient charts were examined for pre- and post-operative parameters including strength, range of motion, visual analog scale pain score, American Shoulder and Elbow Surgeon Score, and Single Assessment Numeric Evaluation Score. Results: Seven patients met study criteria. All patients presented with chronic shoulder pain and decreased external rotation strength, and three patients had clinically apparent muscular atrophy. Pre- and post operative assessment showed external rotation strength increased from a median of 4 (range 4-4) to 5 (range 4-5; p-value = 0.014), Single Assessment Numeric Evaluation increased from a median of 50 (range 0-70) to 75 (range 30-95; p-value = 0.031), American Shoulder and Elbow Surgeon increased from a median of 46.0 (range 32.0-58.0) to 66.5 (range 58.0-98.0; p-value = 0.068), and visual analog scale pain score decreased from a median of 3 (range 1-8) to 0 (range 0-5; p value = 0.017). Median follow-up was 66 wk (range 36-138 wk). The change was statistically significant (p <0.05) for external rotation strength, Single Assessment Numeric Evaluation, and VAS reduction. Post-operatively, all patients returned to full duty at a median of 20 wk (range 12-36 wk). Conclusion: The use of biceps tenodesis in conjunction with indirect, intra-articular arthroscopic paralabral cyst decompression is an effective technique in an active patient population with superior labral from anterior to posterior tear with associated paralabral cyst. PMID- 29420746 TI - Probiotic treatment during neonatal age provides optimal protection against experimental asthma through the modulation of microbiota and T cells. AB - The incidence of allergic diseases, which increased to epidemic proportions in developed countries over the last few decades, has been correlated with altered gut microbiota colonization. Although probiotics may play a critical role in the restoration of gut homeostasis, their efficiency in the control of allergy is controversial. Here, we aimed to investigate the effects of probiotic treatment initiated at neonatal or adult ages on the suppression of experimental ovalbumin (OVA)-induced asthma. Neonatal or adult mice were orally treated with probiotic bacteria and subjected to OVA-induced allergy. Asthma-like symptoms, microbiota composition and frequencies of the total CD4+ T lymphocytes and CD4+Foxp3+ regulatory T (Treg) cells were evaluated in both groups. Probiotic administration to neonates, but not to adults, was necessary and sufficient for the absolute prevention of experimental allergen-induced sensitization. The neonatally acquired tolerance, transferrable to probiotic-untreated adult recipients by splenic cells from tolerant donors, was associated with modulation of gut bacterial composition, augmented levels of cecum butyrate and selective accumulation of Treg cells in the airways. Our findings reveal that a cross-talk between a healthy microbiota and qualitative features inherent to neonatal T cells, especially in the Treg cell subset, might support the beneficial effect of perinatal exposure to probiotic bacteria on the development of long-term tolerance to allergens. PMID- 29420747 TI - Description of Larval Instars To Fill a Gap in Forensic Entomology: The Larvae of Paralucilia pseudolyrcea (Diptera: Calliphoridae). AB - A fundamental assumption of forensic entomology for estimating the postmortem interval is that insect species are accurately identified, which depends on diagnostic morphological characters. Larvae of the blow fly Paralucilia pseudolyrcea (Mello, 1969) (Diptera: Calliphoridae) were sampled from four corpses in the state of Parana, Brazil, but despite the forensic importance of this species, morphological data for the identification of its larval instars are lacking, limiting its usefulness in such cases. Thus, the main goal of this study was to describe the larval instars of P. pseudolyrcea. The material was obtained from a colony established by larvae collected from a corpse of a murder case. Overall, the distribution of spines is a key character for identifying this species in the first, second and third instars. Other characteristics, such as the presence of an accessory oral sclerite, the small cirri, the number of lobes of the anterior spiracle and the morphology of posterior spiracles, separates P. pseudolyrcea from other necrophagous blow flies. The detailed morphological description provided here facilitates the identification of larval instars of P. pseudolyrcea and their differentiation from those of other calliphorid species. PMID- 29420748 TI - The present state of radiation exposure from pediatric CT examinations in Japan what do we have to do? AB - The use of computed tomography (CT) has increased dramatically over the past several decades and has resulted in a concurrent increase in medical exposure to ionizing radiation. Several recent studies have examined the link between medical radiation and the risk of cancer, especially in children. The cancer risk associated medical exposure has not been definitively confirmed. However, we have to reduce unwarranted medical radiation exposure in pediatric patients. Justification and optimization are of great importance in order to minimize these risks, and the standardization of CT usage is essential. However, in Japan no clinical guidelines for the use of CT have been commonly agreed upon, especially in children. Furthermore, the CT-associated radiation exposure in Japan varies widely among the different facilities. Further studies based on a nationwide survey in Japan will be required in order to establish simple and useful clinical guidelines. PMID- 29420749 TI - Prospective randomized investigation implementing immunonutritional therapy using a nutritional supplement with a high blend ratio of omega-3 fatty acids during the perioperative period for head and neck carcinomas. AB - Objectives: The purpose of this study is to evaluate whether a nutritional supplement with a high blend ratio of omega-3 fatty acids can minimize weight loss and attenuate increases in inflammatory marker levels during the perioperative period in patients undergoing surgery for head and neck carcinoma. Methods: Patients with >=5% weight loss within 6 months were considered as targets for aggressive nutritional intervention. Among these patients, those with head and neck squamous cell carcinoma, who underwent major invasive surgery with free flap reconstruction were included in the present study. The patients were randomized into two groups: the 'nutritional supplementation group' and the 'non intervention group'. The nutritional supplementation group received two packs of Prosure(r) (an eicosapentaenoic acid [EPA]-enriched oral nutritional supplement) per day for 28 days during the perioperative period. Results: Compliance with the Prosure(r) dosage was very good at 6277/6720 ml (average) before surgery (93%) and 5229/6720 ml after surgery (78%), and a significant increase in EPA concentration was shown in the group that received Prosure(r) (P < 0.0001: Welch's t-test). However, 28 days of nutritional supplementation did not lead to further weight change or changes in the inflammatory marker levels of patients were already showing cachexia (based on weight loss). Interestingly, no further change in the mean weight was noted in these patients. The incidence of postoperative complications did not differ between the two groups. Conclusion: In this trial, immunonutritional therapy using a nutritional supplement with a high blend ratio of omega-3 fatty acids from 2 weeks before surgery until 2 weeks after surgery was not effective for maintaining the nutritional status of head and neck carcinoma patients. PMID- 29420751 TI - Enhanced Multi-Service Markets: An Evolution in Military Health System Governance. AB - Background: The evolution of governance models for the Military Health System's (MHS) large hospitals, called medical treatment facilities (MTFs), has culminated with the effort to implement Enhanced Multi-Service Markets (eMSM). The term eMSM refers to two separate concepts. First, MSM refers to those geographic areas, that is, markets, which have the following characteristics: they have MTFs that are operated by two or more Department of Defense (DoD) Services, that is, Army, Navy, or Air Force; there is a large beneficiary population; there is a substantial amount of direct care (i.e., beneficiaries are treated at MTFs instead of TRICARE's purchased care from civilian providers); and there is a substantial readiness and training platform. Second, the term "enhanced" refers to an increase in management authority over clinical and business operations, readiness, and MTF workload. Methods: A retrospective review was conducted to study the evolution of military and civilian health care delivery models for the purpose of understanding how governance models have changed since the 1980s to design and manage MTFs with overlapping catchments areas. Primary and secondary data sources were analyzed through a comprehensive literature review. Findings: Since the 1980s, the MHS governance models have evolved from testing various managed care models to a regionally focused TRICARE model and culminating with an overlapping catchment area model entitled eMSMs. The eMSM model partially fulfills the original vision because the eMSM leaders have limited budgetary and resource allocation authority. Discussion: The various models sought to improve governance of overlapping catchment areas with the intent to enhance medical readiness, community health, and individual health care while reducing costs. However, the success of the current model, that is, eMSMs, cannot be fully assessed because the eMSM model was not fully implemented as originally envisioned. Instead, the current eMSM model partially implements the eMSM model. As a result, the current eMSMs operate solely through cooperation and collaboration, without directive authority. Nevertheless, there have been some market-specific initiatives. Further analysis is necessary in the event that eMSM market managers are granted governance authority. This authority would include the ability to allocate the overall market's budget, determine common clinical and business functions, optimize the readiness of both the medical and the operational forces assigned to the market, and reallocate resources to optimize MTF workload. The results of this analysis may determine whether the fully implemented eMSMs optimize patient-centric initiatives as well as improve the market's efficiency and effectiveness. PMID- 29420750 TI - Self-Face Recognition Begins to Share Active Region in Right Inferior Parietal Lobule with Proprioceptive Illusion During Adolescence. AB - We recently reported that right-side dominance of the inferior parietal lobule (IPL) in self-body recognition (proprioceptive illusion) task emerges during adolescence in typical human development. Here, we extend this finding by demonstrating that functional lateralization to the right IPL also develops during adolescence in another self-body (specifically a self-face) recognition task. We collected functional magnetic resonance imaging (fMRI) data from 60 right-handed healthy children (8-11 years), adolescents (12-15 years), and adults (18-23 years; 20 per group) while they judged whether a presented face was their own (Self) or that of somebody else (Other). We also analyzed fMRI data collected while they performed proprioceptive illusion task. All participants performed self-face recognition with high accuracy. Among brain regions where self-face related activity (Self vs. Other) developed, only right IPL activity developed predominantly for self-face processing, with no substantial involvement in other face processing. Adult-like right-dominant use of IPL emerged during adolescence, but was not yet present in childhood. Adult-like common activation between the tasks also emerged during adolescence. Adolescents showing stronger right lateralized IPL activity during illusion also showed this during self-face recognition. Our results suggest the importance of the right IPL in neuronal processing of information associated with one's own body in typically developing humans. PMID- 29420752 TI - The significance of human spermatozoa vacuoles can be elucidated by a novel procedure of array comparative genomic hybridization. AB - STUDY QUESTION: Is there an association between spermatozoon genomic stability and vacuolar morphology and location? SUMMARY ANSWER: The genomic stability of spermatozoa is associated with specific characteristics of vacuolar morphology (depth) and location (cellular compartment, i.e. nucleus and equatorial region). WHAT IS KNOWN ALREADY: Genetic anomalies in sperm are correlated with semen abnormalities, yet the advantage of morphologically based selection of spermatozoa for IVF according to current criteria is controversial. Selection criteria based on the number of vacuoles and their size have been proposed and are widely applied. Nevertheless, it has not improved the ICSI success rates, suggesting the currently used vacuole criteria are incomplete. STUDY DESIGN, SIZE, DURATION: Normal sperm according to Motile Sperm Organelle Morphology Examination criteria (MSOME) and common vacuole grading were evaluated. An additional evaluation of sperm vacuole morphology according to novel vacuole criteria (i.e. location and depth) was conducted. An assessment to align these specific vacuolar morphology features with genomic stability was conducted among spermatozoa from infertile patients and healthy fertile donors aged 24-38 between June 2015 and July 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Single spermatozoa (n = 53) from 16 infertile patients and 14 fertile donors were morphologically and genetically evaluated. Each spermatozoon was examined morphologically, by ultra-magnification *6300, and genetically by a novel comparative genomic hybridization protocol, without the use of reference DNA, to assess chromosomal instability as evident by copy number variations (CNV). MAIN RESULTS AND THE ROLE OF CHANCE: We established an association between genomic stability and vacuolar morphology as a base for a new classification according to novel vacuolar criteria, specifically depth and location. Genomic instability was found to be related to these two main features of vacuoles and, surprisingly not to the number and size of vacuoles as in the previously proposed classifications. High CNV spermatozoa were characterized by vacuoles located in the nucleus and/or equatorial segment or by deep vacuoles, while, low CNV spermatozoa were characterized by a complete lack of vacuoles or non-deep vacuoles not located in the nucleus/equatorial segment. A putative threshold of ~265 CNV was deduced to distinguish between genetically stable and unstable spermatozoa, and 94% of the tested spermatozoa segregated accordingly. LIMITATIONS REASONS FOR CAUTION: A relatively small sample of spermatozoa were examined-53 in total. However, the association between vacuoles location and morphology and genomic stability was significant. This is the first study evaluating spermatozoon genomic stability with respect to vacuole morphology according to novel vacuole criteria (i.e. location and depth) and further investigation is warranted to verify the value of these criteria in larger sample size clinical studies. WIDER IMPLICATIONS OF THE FINDINGS: Our results, which are based on spermatozoon vacuoles morphological classification and genomic parameters, indicate an association between vacuoles morphology and location and genomic stability. The data presented herein suggest the existence of subpopulations of spermatozoa potentially appropriate for IVF ICSI, as they appear normal according to the current MSOME and vacuoles classification, however they are almost certainly genetically damaged. As current criteria have yet to achieve an unequivocal evaluation of the implantation potential of a given spermatozoon, we propose novel criteria, based on specific vacuolar morphological traits; depth and location, as these were found aligned with genomic findings. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. The authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A. PMID- 29420753 TI - CORRIGENDUM FOR "Sex-Dimorphic Effects of Prenatal Treatment With Dexamethasone". PMID- 29420754 TI - Thyroid-Specific PPARgamma Deletion Is Benign in the Mouse. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is widely expressed at low levels and regulates many physiological processes. In mice and humans, there is evidence that PPARgamma can function as a tumor suppressor. A PAX8 PPARgamma fusion protein (PPFP) is oncogenic in a subset of thyroid cancers, suggesting that inhibition of endogenous PPARgamma function by the fusion protein could contribute to thyroid oncogenesis. However, the function of PPARgamma within thyrocytes has never been directly tested. Therefore, we have created a thyroid-specific genetic knockout of murine Pparg and have studied thyroid biology in these mice. Thyroid size and histology, the expression of thyroid specific genes, and serum T4 levels all are unaffected by loss of thyroidal PPARgamma expression. PPFP thyroid cancers have increased activation of AKT, and mice with thyroid-specific expression of PPFP combined with thyroid-specific loss of PTEN (a negative regulator of AKT) develop thyroid cancer. Therefore we created mice with combined thyroid-specific deletions of Pparg and Pten to test if there is oncogenic synergy between these deletions. Pten deletion alone results in benign thyroid hyperplasia, and this is unchanged when combined with deletion of Pparg. We conclude that, at least in the contexts studied, thyrocyte PPARgamma does not play a significant role in the development or function of the thyroid and does not function as a tumor suppressor. PMID- 29420755 TI - Non-linear association between long-term outcome and preoperative neutrophil-to lymphocyte ratio in patients undergoing curative resection for gastric cancer: a retrospective analysis of 1335 cases in a tetrachotomous manner. AB - Objective: Although the prognostic utility of the pretreatment neutrophil-to lymphocyte ratio (NLR) has been widely reported for gastric cancer and several other malignancies, the optimal patient stratification methodologies for such analyses have yet to be established. We aimed to examine the predictive value of preoperative NLR in patients with operable gastric cancer, and to elucidate whether or not the relationship between long-term outcome and pretreatment NLR is monotonically linear. Methods: Preoperative data from 1335 patients who underwent curative surgery for gastric cancer were retrospectively evaluated. Patients were divided into four groups (Q1-Q4) according to preoperative NLR (1.59, 2.11 and 2.96). Survival time was calculated applying the Cox proportional hazard model to both univariate and multivariate estimates. Results: On univariate Cox regression analysis, preoperative NLR was significantly associated with overall survival (OS) and relapse-free survival (RFS). On subsequent multivariate analysis, preoperative NLR, as a tetrachotomous variable, was independently associated with OS and RFS (P = 0.028, 0.023, respectively). When comparing Q1 with Q3 or Q4 in multivariate analysis, there were no significant prognostic differences in OS (P = 0.23, 0.37, respectively) and RFS (P = 0.26, 0.46, respectively). The Q2 group showed significantly longer RFS than the Q1 group (hazard ratio 0.69, 95% confidence interval 0.48-0.99, P = 0.048). Conclusions: Although preoperative NLR was significantly associated with long-term outcome in gastric cancer patients, the association was not linear. PMID- 29420757 TI - Characteristics and Health Needs of Veterans with Other-than-Honorable Discharges: Expanding Eligibility in the Veterans Health Administration. AB - Background: There has been nearly no research on the health of veterans with Other-than-Honorable (OTH) discharges because they have traditionally not been eligible for health care through the Department of Veterans Affairs (VA). However, the Secretary of the VA has recently expanded eligibility provisions to provide access to some VA health care services to veterans with OTH discharges to help address any urgent mental health care needs. It is unknown if veterans with OTH discharges have worse mental health and potentially greater mental health care needs than other veterans. Methods: Using data from the 2001 National Survey of Veterans, this study examined the characteristics and health status of veterans with OTH discharges compared with veterans with honorable or general discharges. Physical and mental health was assessed with the 12-item Short Form health survey. Findings: Bivariate comparisons revealed that veterans with OTH discharges were younger, reported lower income, were more likely to lack health insurance, and reported more mental health problems than other veterans. After controlling for other factors, veterans with OTH discharges were still younger and reported more mental health problems than other veterans. Post hoc analyses revealed veterans with OTH discharges were significantly more likely to report having accomplished less because of emotional problems, performed activities less carefully because of emotional problems, felt less calm and peaceful, and felt more downhearted and blue in the previous 4 wk than other veterans. Discussion: These findings suggest that veterans with OTH discharges have substantial mental health care needs and may benefit from the VA's recent provision granting them increased access to VA care but some may need more comprehensive mental health care services. PMID- 29420756 TI - Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials. AB - Objectives: Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual acting antimalarials. Methods: We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile. Results: We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at <100 nM (8 were IMPs and 4 were 2-APs) and were also active against early stage gametocytes and asexual parasites, with >1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes. Conclusions: This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies. PMID- 29420758 TI - Moulds associated with contaminated ocular and injectable drugs: FDA recalls, epidemiology considerations, drug shortages, and aseptic processing. AB - Recent (2012) grave but rare outbreaks of fungal meningitis and endophthalmitis associated with drugs contaminated with select environmental moulds (Exserohilum and Fusarium, respectively) have exacerbated mycology concerns for formulation, good laboratory practices (GLP), and use of the final drug product. Intensified investigations (2013-2015) by the Food and Drug Administration (FDA) that included added responsibilities for specialty compounding laboratories have prompted at least nine voluntary mould-related drug recalls during 2014-2015. Both primary manufactures (five recalls, two companies) and secondary-processing compound laboratories (at least eight recalls, six companies) and near 0.8 million units were involved. These constituted minor fractions of recalled drug products in an estimated 2500 recalls among other causes during this time period. Recalls of similar drugs in 2016 were indirectly related to fungi. None of the mould-related- drug-recall episodes during 2014-2016 have been identified with fungal disease outbreaks. The recalls included drugs in short supply worldwide such as injectable sodium chloride- and related saline solutions as well as ocular formulations. Insufficient environmental monitoring and GLP compliance, particularly for aseptic processing of non-preserved formulations, appeared to be underlying factors in the fungal contaminations. Observations of mould growth in drugs during their processing should be accurately recorded and investigated; cryptic listings under "particulate" designations should be avoided. Confirmed identifications for chronic contaminants are recommended. Heat-tolerant moulds with resistant morphotypes are prime concerns. PMID- 29420759 TI - Non-modifiable Risk Factors Associated with Sternoclavicular Joint Dislocations in the U.S. Military. AB - INTRODUCTION: Sternoclavicular joint (SCJ) dislocations, although uncommon, are observed in patients with ligamentous laxity as well as those who experience traumatic injuries. The incidence and epidemiology of this costly and debilitating injury to our relatively young and active military population have not previously been reported. The purpose of this study is to consider and quantify the non-modifiable risk factors associated with this injury. METHODS: Using Defense Medical Epidemiological Database, first-time occurrences, from 2006 to 2015 for the ICD-9-CM code 839.61 (closed dislocation of the SCJ), were obtained and further categorized by gender, race, age, rank, and branch of service. Race was classified based on self-reporting of patients into White, Black, or other categories. Age was divided into the categories of less than 20 yr, 20-24 yr, 25-29 yr, 30-34 yr, 35-39 yr, and greater than 40 yr. Rank was categorized as junior enlisted (E-1 to E-4), senior enlisted (E-5 to E-9), junior officer (O-1 to O-3), and senior officer (O-4 to O-10). Branch of service includes Army, Navy, Air Force, and Marines. Multivariate data analysis was performed to obtain rate per 1,000 person-years as well as adjusted rate (adjusted for age group, gender, race, rank, and service) to isolate risk factors. RESULTS: Between 2006 and 2015, 427 cases of closed SCJ dislocations occurred among an at-risk population of 13,772,342 person-years for an unadjusted incidence rate (IR) of 0.031 per 1,000 person-years. The annual unadjusted IR ranged from 0.017 in 2006 to 0.059 in 2014 with the greatest increase occurring between 2006 and 2007 representing 61% increase in the rate of injuries. Males were almost twice as likely to sustain these injuries compared with females (adjusted rate ratio 1.73; 95% confidence interval [CI] 1.23, 2.43). Age was not found to be a risk factor for the development of these injuries with IRs for each age group overlapping with 95% CI for all other age groups. Similarly, the other category for race was also not found to be a statistically significant risk factor. Junior Officers (adjusted rate 0.017; 95% CI 0.011, 0.025) were found least likely to suffer from these injuries with Junior Enlisted (0.034; 95% CI 0.030, 0.040) and Senior Enlisted (0.032; 95% CI 0.028, 0.037) most at risk. Being in the Navy (0.019; 95% CI 0.015, 0.025) was found to be most protective compared with Air Force (0.032; 95% CI 0.026, 0.039), Army (0.036; 95% CI 0.031, 0.041), and Marines (0.036; 95% CI 0.028, 0.045). DISCUSSION and CONCLUSION: Annual unadjusted IR of SCJ dislocations readily increased from 2006 to 2014. Statistically significant risk factors, for suffering a closed SCJ dislocation, identified by our study, were male sex, enlisted rank, and branch of service other than Navy. Age and race were not found to have a statistically significant risk. These results can shed light on non-modifiable risk factors for dislocations of the SCJ and can be used in other studies to aid in reducing injury burden on the U.S. Military. PMID- 29420760 TI - Nail Raman spectroscopy: A promising method for the diagnosis of onychomycosis. An ex vivo pilot study. AB - Trichophyton rubrum and Candida species comprise the majority of onychomycosis pathogens. The aim of this study was to evaluate Raman spectroscopy for the differentiation between healthy and either T. rubrum or Candida infected nails. Raman measurements were performed on clippings (N = 52) infected either by T. rubrum (N = 12) or Candida species (N = 14; C. parapsilosis (sensu lato): N = 11, C. glabrata: N = 1, C. albicans: N = 2) with healthy nails (N = 26) used as controls. Systematic spectral differences were observed in the 500-520 cm-1 band region, attributable to a diverting imprint of the disulfide stretching of cystine and cysteine residues among samples. Particularly, Candida infected nails demonstrated a shoulder at 519 cm-1, corresponding to the signal of the less stable gauche-gauche-trans conformation of the disulfide bond. Two additional bands at 619 and 648 cm-1, corresponding to the C-S stretching vibration, were more evident in the T. rubrum infected nails. Finally, a Raman band at 1550 cm-1, attributable to amide II and tryptophan (Trp) content, was undetectable in Candida infected nails. Using principal component analysis (PCA), efficient differentiation of healthy, T. rubrum and Candida species infected nails was achieved. Soft independent modeling of class analogy (SIMCA) and partial least squares-discriminant analysis (PLS-DA) were further applied to generate diagnostic algorithms for the classification of Raman spectra. Both techniques succeeded in modeling clinical nail samples in three groups according to their mycological categories. Raman spectroscopy is a promising method for the differentiation of healthy vs. diseased nails, including efficient differentiation between onychomycosis caused by T. rubrum and Candida species. PMID- 29420761 TI - Chinese Military Evaluation of a Portable Near-Infrared Detector of Traumatic Intracranial Hematomas. AB - Introduction: Secondary brain injury is the main cause of mortality from traumatic brain injury (TBI). One hallmark of TBI is intracranial hemorrhage, which occurs in 40-50% of severe TBI cases. Early identification of intracranial hematomas in TBI patients allows early surgical evacuation and can reduce the case fatality rate of TBI. As pre-hospital care is the weakest part of Chinese emergency care, there is an urgent need for a capability to detect brain hematomas early. In China, in addition to preventing injuries and diseases in military staff and in enhancing the military armed forces during war, military medicine participates in actions such as emergency public health crises, natural disasters, emerging conflicts, and anti-terrorist campaigns during peacetime. The purpose of this observational study is to evaluate in the Chinese military general hospital the performance of a near-infrared (NIR)-based portable device, developed for US Military, in the detection of traumatic intracranial hematomas. The endpoint of the study was a description of the test characteristics (sensitivity, specificity, and positive and negative predictive values [NPV]) of the portable NIR-based device in identification of hematomas within its detection limits (volume >3.5 mL and depth <2.5 cm) compared with computed tomography (CT) scans as the gold standard. Materials and Methods: The Infrascanner Model 2000 NIR device (InfraScan, Inc., Philadelphia, PA, USA) was used for hematoma detection in patients sustaining TBI. Data were collected in the People's Liberation Army General Hospital in Beijing using the NIR device at the time of CT scans, which were performed to evaluate suspected TBI. One hundred and twenty seven patients were screened, and 102 patients were included in the per protocol population. Of the 102 patients, 24 were determined by CT scan to have intracranial hemorrhage. The CT scans were read by an independent neuroradiologist who was blinded to the NIR measurements. Results: The NIR device demonstrated sensitivity of 100% (95% confidence intervals [CI] 82.8-100%) and specificity of 93.6% (95%CI 85-97.6%) in detecting intracranial hematomas larger than 3.5 mL in volume and that were less than 2.5 cm from the surface of the brain. Blood contained within scalp hematomas was found to be a major cause of false-positive results with this technology. Conclusion: The study showed that the Infrascanner is a suitable portable device in Chinese population for detecting preoperative intracranial hematomas in remote locations, emergency rooms, and intensive care units. It could aid military medics, physicians, and hospital staff, permitting better triage decisions, earlier treatment, and reducing secondary brain injury caused by acute and delayed hematomas. PMID- 29420762 TI - Military Internal Medicine Resident Decision to Apply to Fellowship and Extend Military Commitment. AB - Introduction: Nationally, the number of internal medicine physicians practicing in primary care has decreased amidst increasing interest in hospitalist medicine. Current priorities in the Military Health System include access to primary care and retention of trained personnel. Recently, we have conducted a study of military internal medicine residents' decision to enter infectious disease. As part of our larger effort, we saw an opportunity to characterize factors impacting decision making of internal medicine residents' desire to apply for subspecialty training and to extend active duty service obligations. Materials and Methods: Questions were developed after discussion with various military graduate medical education and internal medicine leaders, underwent external review, and were added to a larger question set. The survey link was distributed electronically to all U.S. military affiliated residencies' graduating internal medicine residents in December 2016-January 2017. Data were analyzed by decision to apply to fellowship and decision to extend military obligation using Fisher's exact test or Pearon's chi-square test. Results: Sixty-eight residents from 10 of 11 military residency programs responded, for a response rate of 51%. The majority (62%) applied to fellowship to start after residency completion. Reasons cited for applying to fellowship included wanting to become a specialist as soon as possible (74%), wishing to avoid being a general internist (57%), and because they are unable to practice as a hospitalist in the military (52%). Fellowship applicants were more likely to plan to extend their military obligation than non applicants, as did those with longer duration of military commitments. No other factors, including Uniformed Services University attendance or participation in undergraduate military experiences, were found to impact plan to extend active duty service commitment. Conclusion: The majority of graduating internal medicine residents apply for fellowship and report a desire to avoid being a general internist. Prospective fellows anticipate extending their active duty commitment, as do those with longer commitments. PMID- 29420763 TI - Analysis of the in vitro activity of human neutrophils against Aspergillus fumigatus in presence of antifungal and immunosuppressive agents. AB - Neutrophils are essential in the first line defense against moulds. This in vitro study assessed different neutrophil effector mechanisms in the presence of clinically relevant antifungal and immunosuppressive agents. Therapeutic concentrations of liposomal amphotericin B led to reduced IL-8 and oxidative burst response to the synthetic stimulus PMA, whereas no major alterations of oxidative burst, phagocytosis, or cytokine response to germinated stages of Aspergillus fumigatus and no supra-additive effects of antifungal and immunosuppressive drugs were observed. Conventional and liposomal amphotericin B as well as voriconazole, however, led to reduced neutrophil extracellular trap formation in response to A. fumigatus germ tubes. PMID- 29420764 TI - Cancer incidence rates in the world from the Cancer Incidence in Five Continents XI. PMID- 29420765 TI - Promises and challenges of immuno-oncology from a clinical perspective. PMID- 29420766 TI - Military Medic Performance with Employment of a Commercial Intraosseous Infusion Device: A Randomized, Crossover Study. AB - Background: Obtaining intraosseous (IO) access remains an invaluable skill in the management and resuscitation of patients on the battlefield. The U.S. Army Combat Medic is currently trained to utilize a sternal IO device (FAST1(r) Intraosseous Infusion System); however, the Arrow(r) EZ-IO(r) Intraosseous Vascular Access System offers unique benefits including ease of use, reload ability, and placement location versatility. Studies have demonstrated high success rates in the operational settings using the EZ-IO(r) System; however, no prospective studies have been conducted to assess the performance of U.S. Army's conventional Combat Medics using the EZ-IO(r) System. We hypothesized that EZ-IO(r) System naive medics would have a statistically significant success rate advantage utilizing the proximal tibia approach versus proximal humerus approach. Methods: A total of 77 U.S. Army Medics (Military Occupational Specialty [MOS] 68 W) volunteer participants were recruited to participate in this randomized, crossover study. Participants received a standardized audio-visual-enhanced lecture on EZ-IO(r) System use without hands-on training and then randomized into two study groups according to which anatomical approach they would attempt first. Results were analyzed to determine participants' first-attempt mean success rates, mean required time to properly place the needle into simulated humeral head and proximal tibial bone models, and mean survey results measuring the participant's subjective assessment of the two approaches to include, along with training and testing experience. The data of those not naive to the employment of the EZ-IO(r) System were excluded. Results: The primary outcome measurement of overall mean participant success rate with attempted insertions into proximal tibial and humeral head bone models was 88% and 86%, respectively, demonstrating no statistically significant difference by approach, with no significant learning or design confounding effects (p > 0.05). Secondary outcomes of mean procedural time and subjective comfort and skill benefit were reported. Successful procedure times between the two anatomical approaches demonstrated a statistically significant mean time advantage of 17.1 s (p < 0.05) in proximal tibia IO placement. Overall participant mean subjective comfort level utilizing the EZ IO(r) System (0- to 10-point scale with a 0 being not comfortable and a 10 being very comfortable) was 8.2, with no statistically significant difference in comfort discovered when comparing the two approaches. Participants reported a mean subjective score (0-10 scale with a 0 providing no benefit and a 10 providing extreme benefit) of 9.3 when asked how beneficial their newly learned IO system skill was to their overall medical skillset. Conclusions: The overall first-attempt success rates of U.S. Army Combat Medics employing the EZ-IO(r) System are similar to the success rates of FAST1(r) device employment and similar to the success of other provider cohorts using the EZ-IO(r) device. Coupled with perceived benefit of adding the EZ-IO(r) System to their combat medic skillset, these data warrant further study and consideration for the incorporation of commercial IO systems into U.S. Army Combat Medic initial, sustainment, and pre combat training and standard issue equipment. PMID- 29420768 TI - Which cell defines endometriosis? PMID- 29420767 TI - Evaluation of trypan blue stain in the TC20 automated cell counter as a point-of care for the enumeration of viable cryptococcal cells in cerebrospinal fluid. AB - Cerebrospinal fluid (CSF) culture can determine a quantitative viability of Cryptococcus yeasts; however, culture has a long turnaround-time. The TC20 automated cell counter (Bio-Rad) is a benchtop instrument used to count cells in 30 seconds. In vitro studies suggest trypan blue staining can distinguish between viable and dead cryptococcal yeasts. We hypothesized that trypan blue staining with automated cell counting may provide rapid quantification of viable CSF Cryptococcus yeasts. In sum, 96 HIV-infected participants with cryptococcal meningitis were enrolled and provided 194 CSF specimens in Kampala, Uganda. Cryptococcosis was diagnosed by CSF cryptococcal antigen (CRAG). CSF was stained with trypan blue and quantified yeasts with the TC20 cell counter. We compared the log10 transformed cell counter readings with gating of 4-10 MUm versus log10 quantitative Cryptococcus cultures/ml. TC20 showed more positive results (95.4%) overall than culture (78.4%) with reference to CSF CRAG. TC20 had higher readings compared to culture in most cases with only a 25% level of agreement between the two methods. TC20 had a poor correlation to culture throughout the 14 days of antifungal therapy. The median of log10 transformed counts were 5.22 (IQR = 4.79 5.44) for the TC20 and 3.99 (IQR = 2.59-5.14) for culture. Overall, a linear regression showed no significant relationship between the TC20 and culture (r = 0.0025; P = .92). TC20 automated cell counting with trypan blue staining was poorly predictive of the quantitative CSF culture and could not be used as a substitute for quantitative culture. PMID- 29420769 TI - Lonafarnib synergizes with azoles against Aspergillus spp. and Exophiala spp. AB - Farnesylation, which is catalyzed by farnesyltransferase, promotes membrane association of the modified protein and protein-protein interactions, and plays an important role in a number of physiological processes of pathogenic fungi, including stress response, environmental adaption and virulence. Lonafarnib is an orally bioavailable nonpeptide tricyclic farnesyltransferase inhibitor with excellent pharmacokinetic and safety profile. In the present study, we investigated the in vitro activities of lonafarnib alone or combined with azoles, including itraconazole, voriconazole, and posaconazole, against 22 strains of Aspergillus spp. and 18 strains of Exophiala dermatitidis via broth microdilution checkerboard technique. Lonafarnib alone was inactive against all isolates tested. However, synergistic effects between lonafarnib and itraconazole were observed in 86% Aspergillus strains and 94% E. dermatitidis strains. In addition, lonafarnib/posaconazole combination also exhibited synergism against 59% of Aspergillus strains and 100% E. dermatitidis strains. However, synergistic effects of lonafarnib/voriconazole were only observed in 32% Aspergillus strains and 28% E. dermatitidis strains. The effective working ranges of lonafarnib were 2-4 MUg/ml and 1-4 MUg/ml against Aspergillus isolates and E. dermatitidis isolates, respectively. No antagonism was observed in all combinations. This study demonstrated that lonafarnib could enhance the in vitro antifungal activity of itraconazole, posaconazole and voriconazole against Aspergillus spp. and E. dermatitidis, suggesting that azoles, especially itraconazole and posaconazole, combined with farnesyltransferase inhibitor might provide a potential strategy to the management of Aspergillus and Exophiala infections. However, further studies are warranted to elucidate the underlying mechanism and to investigate the potential of reliable and safe application in clinical practice. PMID- 29420770 TI - Rationale for Utilization of Obesity Pharmacotherapy in the Active Duty Population. PMID- 29420771 TI - Genitourinary Injuries Among Female U.S. Service Members During Operation Iraqi Freedom and Operation Enduring Freedom: Findings from the Trauma Outcomes and Urogenital Health (TOUGH) Project. AB - Introduction: Until recently, female U.S. service members (SMs) have not been permitted to serve in direct combat roles. However, during Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF), a large number of female SMs have been wounded while serving in combat support roles. This included an unprecedented number of women with genitourinary (GU) injuries. No previous studies have reported either the incidence or clinical picture of these injuries. The objective of this study is to describe the epidemiology of GU injuries among female U.S. SMs during OIF/OEF and understand the potential for increased female GU injuries in future conflicts and the long-term sequelae from these injury patterns. Materials and Methods: The Department of Defense Trauma Registry was reviewed to identify all U.S. SMs diagnosed with GU injury from 2001 to 2013. The Department of Defense Trauma Registry includes data for wounded SMs treated at any U.S. combat support hospital, the in-theater equivalent of a civilian trauma center. Female SMs with ICD-9-CM diagnosis codes and/or Abbreviated Injury Scale codes for GU injury were included. Data on all females with GU injury were reviewed, including battle injury (BI) and non-BI. Basic demographic and injury characteristics were reported. Results: Among the 1,463 U.S. SMs diagnosed with GU injury while deployed to OIF/OEF, 20 (1.4%) were female (median age: 25 yr; interquartile range 21-27 yr). Of these, nine were BI (45%) and 11 were non-BI (55%). The distribution of injury location was as follows: renal injuries (n = 12), vulvar injuries (n = 3), vaginal injuries (n = 3), perineal injury (n = 1), and bladder injury (n = 1). Median Injury Severity Score was in the severe range of 21 (interquartile range 6-32), and four women (20%) died of their wounds. Important associated injuries included colorectal (n = 5) and lower extremity amputation(s) (n = 2). The most common mechanism of injury among the nine women with GU BI was improvised explosive device blast (n = 6), followed by other explosions (n = 2) and gunshot wound (n = 1). Mechanisms of GU non-BI varied, including gunshot wound (n = 2), fall (n = 2), fire/flame (n = 1), knife wound (n = 1), unintentional machine injury (n = 1), motor vehicle accident (n = 1), sports injury (n = 1), fight (n = 1), and pedestrian injury (n = 1). Conclusion: Female GU injuries comprise a small portion of all GU injuries sustained during OIF/OEF with the most predominant being renal injury. Now that the ground combat exclusion policy has been lifted, these data can be used as a model for the expected injury patterns in future female combatants. Long-term applications for these data include research and development for personal protective equipment and development of a multidisciplinary approach to long-term comprehensive care following GU trauma. PMID- 29420772 TI - Purchased Behavioral Health Care Received by Military Health System Beneficiaries in Civilian Medical Facilities, 2000-2014. AB - Introduction: Behavioral health conditions are a significant concern for the U.S. military and the Military Health System (MHS) because of decreased military readiness and increased health care utilization. Although MHS beneficiaries receive direct care in military treatment facilities, a disproportionate majority of behavioral health treatment is purchased care received in civilian facilities. Yet, limited evidence exists about purchased behavioral health care received by MHS beneficiaries. This longitudinal study (1) estimated the prevalence of purchased behavioral health care and (2) identified patient and visit characteristics predicting receipt of purchased behavioral health care in acute care facilities from 2000 to 2014. Materials and Methods: Medical claims with Major Diagnostic Code 19 (mental disorders/diseases) or 20 (alcohol/drug disorders) as primary diagnoses and TRICARE as the primary/secondary payer were analyzed for MHS beneficiaries (n = 17,943) receiving behavioral health care in civilian acute care facilities from January 1, 2000, to December 31, 2014. The primary dependent variable, receipt of purchased behavioral health care, was modeled for select mental health and substance use disorders from 2000 to 2014 using generalized estimating equations. Patient characteristics included time, age, sex, and race/ethnicity. Visit types included inpatient hospitalization and emergency department (ED). Time was measured in days and visits were assumed to be correlated over time. Behavioral health care was described by both frequency of patients and visit type. The University of South Carolina Institutional Review Board approved this study. Results: From 2000 to 2014, purchased care visits increased significantly for post-traumatic stress disorder, adjustment, anxiety, mood, bipolar, tobacco use, opioid/combination opioid dependence, nondependent cocaine abuse, psychosocial problems, and suicidal ideation among MHS beneficiaries. The majority of care was received for mental health disorders (78.8%) and care was most often received in EDs (56%). Most commonly treated diagnoses included mood, tobacco use, and alcohol use disorders. ED visits were associated with being treated for anxiety (excluding post-traumatic stress disorder; Adjusted odds ratio [AOR]: 9.14 [95% confidence interval (CI): 8.26, 10.12]), alcohol use disorders (AOR = 1.67 [95% CI: 1.53, 1.83]), tobacco use (AOR = 1.16 [95% CI: 1.06, 1.26]), nondependent cocaine abuse (AOR = 5.47 [95% CI: 3.28, 9.12]), nondependent mixed/unspecified drug abuse (AOR = 7.30 [95% CI: 5.11, 10.44]), and psychosis (AOR = 1.38 [95% CI: 1.20, 1.58]). Compared with adults age 60 yr and older, adolescents (ages 12-17 yr), and adults under age 60 yr were more likely to be treated for suicidal ideation, adjustment, mood, bipolar, post-traumatic stress disorder, nondependent cocaine, and mixed/unspecified drug abuse. Adults under age 60 yr also had increased odds of being treated for tobacco use disorders, alcohol use disorders, and opioid/combination opioid dependence compared with adults age 60 yr and older. Conclusions: Over the past 15 yr, purchased behavioral health care received by MHS beneficiaries in acute care facilities increased significantly. MHS beneficiaries received the majority of purchased behavioral health care for mental health disorders and were treated most often in the ED. Receiving behavioral health care in civilian EDs raises questions about access to outpatient behavioral health care and patient-centered care coordination between civilian and military facilities. Given the influx of new Veterans Health Administration users from the MHS, findings have implications for military, veteran, and civilian facilities providing behavioral health care to military and veteran populations. PMID- 29420773 TI - Trends in Surgical Management of Anterior Shoulder Instability: Increased Utilization of Bone Augmentation Techniques?. AB - Purpose: The purpose of this study is to evaluate the trends in surgical management for anterior shoulder instability in the U.S. Military. Methods: A retrospective analysis of military service members undergoing arthroscopic or open shoulder stabilization from 2012 to 2015 within the U.S. Military Health System was conducted. Demographic and surgical variables were extracted from the medical record. Chi-square and linear regression analysis were performed to identify temporal trends by surgical procedures and concomitant surgery. Associations between demographic variables and surgical procedure were evaluated using logistic regression analysis with odds ratios and 95% confidence intervals. Results: Eight thousand five hundred and eighty nine surgeries were performed for anterior shoulder instability. The arthroscopic Bankart procedure remained the dominant surgical procedure over time (n = 8177, 95.2%), whereas the open Bankart procedure (n = 172, 2.0%) demonstrated a diminishing trend, which was significant on univariate analysis (p = 0.0009), but not statistically significant on linear regression (p = 0.12). Additionally, there was a significant trend toward increased utilization of the Latarjet procedure over the period studied (n = 33, 1.7% - n = 81, 3.56%) (p = 0.009). During the same time period, concomitant superior labrum anterior/posterior repairs decreased (n = 980, 11.4%; p = 0.0045), whereas rates of biceps tenodesis (n = 741, 8.6%; p = 0.05) increased significantly. When analyzing patient age as a continuous variable, increasing age was associated with a significantly higher likelihood of arthroscopic treatment (odds ratio 1.02, 95% confidence interval 1.00-1.03, p = 0.05). Conclusion: The rate of performing an arthroscopic Bankart repair has remained relatively stable as the dominant surgical procedure for shoulder instability in the military patient population. There was a significant trend of increased use of the Latarjet procedure, which likely reflects the recognition of bone loss through use of preoperative advanced imaging and computed tomography with three dimensional reconstructions. Additionally, there was a significant decrease in adjacent superior labrum anterior/posterior repairs over the study period, followed by a corresponding rise in biceps tenodesis. Level of evidence: level IV. PMID- 29420774 TI - High variability within Candida albicans transcription factor RLM1: Isolates from vulvovaginal infections show a clear bias toward high molecular weight alleles. AB - Previous studies have correlated the severity of recurrent vulvovaginal Candida infections (VVC) and balanitis in patients from China with the presence of some dominant genotypes at the ORF RLM1. Here we tested VVC vs non-VVC isolates from Portugal, Brazil and Greece and, although the same genotypes were identified in VVC isolates, they were present in only five out of 150 strains. However, this analysis showed that VVC isolates presented a higher percentage of genotypes with similar high molecular weight alleles, in comparison with strains isolated from other biological sources. PMID- 29420775 TI - Algorithm for Management of the Refractive Aerosinusitis Patient. AB - Introduction: For some career military aviators, their ability to continue on flight status is limited by the pressure and pain of aerosinusitis, which is present only while in the flying environment. Failure to treat their disease process can mean the end of their flying careers and the loss of valuable assets trained with taxpayer dollars. Because some medications commonly used in treatment of sinus diseases are not allowed in aviation, this presents a unique problem for their medical management. Surgical treatment must be aimed at treating to symptom relief and not solely disease mitigation. One alternative is operating "beyond the scope of disease" present during a one-atmosphere clinic visit. Materials and Methods: A case series of nine career aviators with aerosinusitis treated at one academic military Otolaryngology department in a tertiary care facility. Results from a treatment algorithm that balances symptomatology and staged surgical intervention are reviewed. The primary endpoint was return to flight duty. Results: For patients treated according to this algorithm, the mean time to return to flight duty was 3.8 mo, requiring an average of 1.2 surgeries. To date, 100% of career aviators have returned to flight duty using this method. Conclusion: Refractory aerosinusitis represents a potentially career-ending medical condition for the aviator and lost training costs to the taxpayers. Using the treatment algorithm presented, 100% of aviators were able to return to flight duty; a savings of millions of dollars for taxpayers. Future work will focus on modifications to the surgical techniques to reduce the extent of surgery while maintaining satisfactory results. Additional study should be undertaken to assess generalizability of these results in the broader aviation community. PMID- 29420777 TI - Management of Acute Upper Gastrointestinal Disease While at Sea. AB - Management of complex acute surgical pathology in austere environments necessitates rapid evaluation and resource appropriate management to avoid time associated morbidity and potentially mortality. Obstructive upper gastrointestinal (UGI) pathologies can be particularly challenging and associated with significant morbidity. Herein, we present six patients with UGI obstructions encountered over the course of an 8-mo deployment onboard a US Navy Aircraft Carrier. Each patient presented to our medical department with signs and symptoms of obstructive UGI pathology including one gastric volvulus requiring operative management at sea, one with a new diagnosis of achalasia requiring transportation and continental United States outpatient evaluation, and four patients with food impaction requiring urgent endoscopic management. Although UGI pathology is seldom encountered at sea, definitive surgical interventions, including prompt evaluation and management of these acute pathologies, can be performed in an austere environment. We wish to call attention to these potential encounters in order that underway deployed medical units and supporting resources ashore are prepared and equipped to intervene on acute UGI obstructive pathology. PMID- 29420776 TI - Cladogenesis and Genomic Streamlining in Extracellular Endosymbionts of Tropical Stink bugs. AB - Phytophagous stink bugs are globally-distributed and many harbor vertically inherited bacterial symbionts that are extracellular, yet little is known about how the symbiont's genomes have evolved under this transmission strategy. Genome reduction is common in insect intracellular symbionts but limited genome sampling of the extracellular symbionts of distantly-related stink bugs has precluded inferring patterns of extracellular symbiont genome evolution. To address this knowledge gap, we completely sequenced the genomes of the uncultivable bacterial symbionts of four neotropical stink bugs of the Edessa genus. Phylogenetic and comparative analyses indicated that the symbionts form a clade within the Pantoea genus and their genomes are highly-reduced (~0.8 Mb). Furthermore, genome synteny analysis and a jackknife approach for phylogenetic reconstruction, which corrected for long branch attraction artifacts, indicated that the Edessa symbionts were the result of a single symbiotic event that was distinct from the symbiosis event giving rise to Candidatus "Pantoea carbekii", the extracellular symbiont of the invasive pentatomid stink bug, Halyomorpha halys. Metabolic functions inferred from the Edessa symbiont genomes suggests a shift in genomic composition characteristic of its lifestyle in that they retained many host supportive functions while undergoing dramatic gene loss and establishing a stable relationship with their host insects. Given the undersampled nature of extracellular insect symbionts, this study is the first comparative analysis of these symbiont genomes from four distinct Edessa stink bug species. Finally, we propose the candidate name 'Candidatus Pantoea edessiphila' for the species of these symbionts with strain designations according to their host species. PMID- 29420778 TI - Deletion of Aspergillus nidulans GDP-mannose transporters affects hyphal morphometry, cell wall architecture, spore surface character, cell adhesion, and biofilm formation. AB - Systemic human fungal infections are increasingly common. Aspergillus species cause most of the airborne fungal infections. Life-threatening invasive aspergillosis was formerly found only in immune-suppressed patients, but recently some strains of A. fumigatus have become primary pathogens. Many fungal cell wall components are absent from mammalian systems, so they are potential drug targets. Cell-wall-targeting drugs such as echinocandins are used clinically, although echinocandin-resistant strains were discovered shortly after their introduction. Currently there are no fully effective anti-fungal drugs. Fungal cell wall glycoconjugates modulate human immune responses, as well as fungal cell adhesion, biofilm formation, and drug resistance. Guanosine diphosphate (GDP) mannose transporters (GMTs) transfer GDP-mannose from the cytosol to the Golgi lumen prior to mannosylation. Aspergillus nidulans GMTs are encoded by gmtA and gmtB. Here we elucidate the roles of A. nidulans GMTs. Strains engineered to lack either or both GMTs were assessed for hyphal and colonial morphology, cell wall ultrastructure, antifungal susceptibility, spore hydrophobicity, adherence and biofilm formation. The gmt-deleted strains had smaller colonies with reduced sporulation and with thicker hyphal walls. The gmtA deficient spores had reduced hydrophobicity and were less adherent and less able to form biofilms in vitro. Thus, gmtA not only participates in maintaining the cell wall integrity but also plays an important role in biofilm establishment and adherence of A. nidulans. These findings suggested that GMTs have roles in A. nidulans growth and cell-cell interaction and could be a potential target for new antifungals that target virulence determinants. PMID- 29420779 TI - The mitochondrial ABC transporter Atm1 plays a role in iron metabolism and virulence in the human fungal pathogen Cryptococcus neoformans. AB - Iron-sulfur clusters (ISC) are indispensable cofactors for essential enzymes in various cellular processes. In the model yeast Saccharomyces cerevisiae, the precursor of ISCs is exported from mitochondria via a mitochondrial ABC transporter Atm1 and used for cytosolic and nuclear ISC protein assembly. Although iron homeostasis has been implicated in the virulence of the human fungal pathogen Cryptococcus neoformans, the key components of the ISC biosynthesis pathway need to be fully elucidated. In the current study, a homolog of S. cerevisiae Atm1 was identified in C. neoformans, and its function was characterized. We constructed C. neoformans mutants lacking ATM1 and found that deletion of ATM1 affected mitochondrial functions. Furthermore, we observed diminished activity of the cytosolic ISC-containing protein Leu1 and the heme containing protein catalase in the atm1 mutant. These results suggested that Atm1 is required for the biosynthesis of ISCs in the cytoplasm as well as heme metabolism in C. neoformans. In addition, the atm1 mutants were avirulent in a murine model of cryptococcosis. Overall, our results demonstrated that Atm1 plays a critical role in iron metabolism and virulence for C. neoformans. PMID- 29420780 TI - Changes in Physical Performance During 21 d of Military Field Training in Warfighters. AB - Introduction: Few studies have reported the amount of physical activity (PA) and its associations to physical performance of warfighters during military field training (MFT). The purpose of this study was to investigate changes in neuromuscular performance and PA among male Finnish Army conscripts during a 21-d MFT and to evaluate their recovery during 4 d after MFT. Methods: Body composition and physical performance were measured four times during the study (before MFT (PRE), after 12 d (MID), post training (POST) and after 4 d of recovery (RECO)). PA was measured throughout MFT in a group of healthy young male conscripts (n=49) by using a tri-axial accelerometer. The study was approved by the Finnish Defence Forces and was granted ethics approval by the Ethics Committee of the University of Jyvaskyla. Results: Body mass declined significantly from 73.5 +/- 8.7 to 71.6 +/- 8.2 kg, but it recovered close to the PRE values (73.0 +/- 8.3 kg). The same trend was also found in skeletal muscle mass and fat mass. The change in body mass and in skeletal muscle mass correlated negatively with the change in vigorous physical activity (r = -0.374, p = 0.016, and r = -0.337, p = 0.031, respectively). Muscular endurance decreased significantly (p < 0.001) in sit-ups from the PRE (46 +/- 9 reps/min) values compared with MID (40 +/- 8 reps/min), POST (42 +/- 8 reps/min), and RECO (34 +/- 11 reps/min) values. Also in push-ups, the declines in the POST (34 +/- 10 reps/min) and RECO (34 +/- 13 reps/min) values (p < 0.001) from the PRE (40 +/- 13 reps/min) and MID (39 +/- 12 reps/min) values were observed. There was a significant decrease in a standing long jump in all measurement points MID (220 +/- 20 cm), POST (216 +/- 20 cm), and RECO (213 +/- 20 cm) as compared with the PRE values (229 +/- 23 cm, p < 0.001). There was no change in 3.2 km loaded march time between the PRE (23:57 +/- 4:12 min:s) and POST (23:44 +/- 5:02 min:s) measurement time points. In PA, the total number of steps per day was significantly (p < 0.001) greater during ST (13,722 +/- 2,379 steps) and MFT (13,937 +/- 2,276 steps) than during garrison days (9,550 +/- 2,569 steps). In POST, there was significantly (p < 0.001) more light (1.5-3.0 metabolic equivalent) (2:34:38 +/- 0:22:53 h:min:s in ST and 3:03:27 +/- 0:23:24 h:min:s in MFT) and moderate (3.0-6.0 metabolic equivalent) (2:12:15 +/- 0:23:14 h:min:s in ST and 2:47:59 +/- 0:27:23 h:min:s in MFT) PA than in the PRE measurements. Conclusion: This study demonstrated slight decrements in warfighter physical performance during the 21-d MFT. The conscripts were overloaded during MFT, but 4 d of recovery seemed not to be enough to obtain the PRE measurement values in physical performance. This study also showed changes in the muscular endurance levels and PA during the 21-d MFT. It is important for warfighters to have a good physical fitness level PRE training or combat. As the prolonged MFT may have adverse effects in warfighters muscular endurance and PA levels, it is important to have sufficient recovery time after long MFT to regain combat readiness. PMID- 29420781 TI - Corrigendum: Fine tuning chloroplast movements through physical interactions between phototropins. PMID- 29420782 TI - Protein profile of Brazilian Pythium insidiosum isolates. AB - Pythium insidiosum is an important aquatic Oomycota that causes pythiosis in mammals, especially horses, dogs, and humans; these inhabit marshy environments in tropical and subtropical areas. The aim of this study was to determine the protein profile, as well as identify likely immunodominant proteins, of Brazilian P. insidiosum isolates from southern Brazil, an important equine pythiosis endemic area. P. insidiosum isolates (horses, n = 20 and dogs, n = 02) were analyzed by SDS-PAGE and Western blot techniques. Horse, cattle, dog, and rabbit sera of both diseased and healthy animals were used to identify P. insidiosum proteins. SDS-PAGE protein profile detected antigens of molecular weights ranging from 100 to 20 KDa. Dog isolates revealed a protein profile similar to that of horse isolates. Anti-P. insidiosum antibodies in the sera of the four species could recognize proteins of different molecular weights (~74 KDa to ~24 KDa), and proteins ~50-55 KDa and ~34 KDa were shown to be immunodominant. Furthermore, ~74 KDa, ~60 KDa, ~30 KDa and ~24 KDa proteins were poorly recognized by host species antibodies. The Brazilian P. insidiosum isolates analyzed showed a similar protein profile; however, further studies are essential for the identification and characterization of proteins expressed by P. insidiosum, and an evaluation of the immunological profile of hosts susceptible to this Oomycota is necessary. PMID- 29420783 TI - Papillary muscle head repositioning for commissural prolapse in degenerative mitral valve disease. AB - OBJECTIVES: Surgical correction of commissural mitral valve prolapse can be challenging. Several surgical techniques, including commissural closure, leaflet resection with sliding plasty and chordal replacement, remain commonly in use. Conversely, papillary muscle head repositioning remains uncommonly utilized for the treatment of commissural prolapse. METHODS: Between January 2003 and December 2015, 518 patients underwent primary mitral valve repair for severe degenerative mitral valve regurgitation at our institution. Among them, 116 patients had non isolated commissural prolapse (14 anterolateral, 82 posteromedial and 20 bicommissural prolapse). Eighty-eight patients underwent papillary muscle head repositioning and presented the study cohort. RESULTS: The mean patient age was 62.8 +/- 12.5 years, and 32 (36%) patients were women. Postoperative echocardiography showed no residual mitral regurgitation in all but 1 (1%) patient in whom Grade 2+ regurgitation was seen. The freedom from late reintervention rates at 5 and 10 years were 96.1% [95% confidence interval (CI) 91.8-100%] and 92.7% (95% CI 86.4-99.0%), respectively. Upon reoperation, no recurrent commissural prolapse was observed. Echocardiographic follow-up demonstrated excellent valve repair durability. The freedom from Grade >=2+ mitral regurgitation rates at 5 and 10 years were 92.6% (95% CI 86.3-98.9%) and 86.1% (95% CI 76.7-95.5%), respectively. CONCLUSIONS: Papillary muscle head repositioning for the treatment of commissural mitral valve prolapse is a reproducible and reliable technique that provides excellent long-term results. PMID- 29420784 TI - Letter: Coiling of a Carotidocavernous Fistula via the Foramen Ovale: 2 Dimensional Operative Video. PMID- 29420785 TI - Interaction of receptor type of protein tyrosine phosphatase sigma (RPTPsigma) with a glycosaminoglycan library. AB - Receptor type of protein tyrosine phosphatase sigma (RPTPsigma) functions as a glycosaminoglycan (GAG) receptor of neuronal cells in both the central and peripheral nervous systems. Both chondroitin sulphate (CS) and heparan sulphate (HS) are important constituents of GAG ligands for RPTPsigma, although they have opposite effects on neuronal cells. CS inhibits neurite outgrowth and neural regeneration through RPTPsigma, whereas HS enhances them. We prepared recombinant RPTPsigma N-terminal fragment containing the GAG binding site and various types of biotin-conjugated GAG (CS and HS) with chemical modification and chemo enzymatic synthesis. Then interaction of the RPTPsigma N-terminal fragment was analysed using GAG-biotin immobilized on streptavidin sensor chips by surface plasmon resonance. Interaction of RPTPsigma with the CS library was highly correlated to the degree of disulphated disaccharide E unit, which had two sulphate groups at C-4 and C-6 positions of the N-acetylgalactosamine residue (CSE). The optimum molecular mass of CSE was suggested to be approximately 10 kDa. Heparin showed higher affinity to RPTPsigma than the CS library. Our GAG library will not only contribute to the fields of carbohydrate science and cell biology, but also provide medical application to regulate neural regeneration. PMID- 29420786 TI - One-Day Behavioral Intervention for Distressed Veterans with Migraine: Results of a Multimethod Pilot Study. AB - Introduction: Migraine, a chronic neurological disorder characterized by episodic severe headache pain and functional impairment, affects approximately 12% of the general US population. Veterans returning from Iraq or Afghanistan have two to four times the incidence of migraine of the general population. Veterans with migraines are more than twice as likely to have comorbid psychiatric conditions as veterans without migraines, with depression and post-traumatic stress disorder being most prevalent. This psychiatric-migraine comorbidity is of major public health significance, as it leads to decreased quality of life, poorer response to migraine and mental health treatment, and overall worse prognosis. Unfortunately, acceptable and effective treatments for these comorbid problems have rarely been investigated. The aims of this study are to examine the acceptability, feasibility, and preliminary efficacy of a 1-d acceptance and commitment therapy (ACT) plus Migraine Education workshop. Method: Twenty-five veterans with migraines and co-occurring depression and/or anxiety completed the 1-d ACT plus Migraine Education workshop. Veterans completed assessments of depressive and anxiety symptoms, general functioning, headache-related disability, and ACT specific skills at baseline and 3 mo after the workshop. Changes from baseline to 3-mo follow-up on the self-report and clinician-rated measures were assessed using the paired t-test and Wilcoxon signed-rank test. Veterans also completed semistructured qualitative interviews documenting their experiences with the workshop 2 wk and 3 mo following the intervention. Qualitative data were analyzed via directed content analysis. Individual codes were aggregated into larger themes agreed upon by consensus. Results: At 3-mo follow-up, veterans significantly improved in depressive and anxiety symptoms, general functioning, and headache-related disability compared with baseline. Additionally, veterans significantly improved in pain acceptance and engagement in valued life areas. In interviews, veterans indicated that the migraine education helped them feel more knowledgeable about their condition, and this empowered them to better manage their headaches, including talking to their physician about medication adjustments. The ACT component led to greater awareness of the role stress plays in exacerbating pain and ways to manage this stress, including greater acceptance and greater engagement in valued life activities. For some, however, the role of stress in exacerbating migraines needed to be highlighted more. Veterans appreciated being in a group with other veterans with similar health difficulties and wanted this to be incorporated into ongoing care at the Veterans Affairs medical center. The patient education manuals were useful to the veterans, with some referring to them during the months following the workshop. Conclusion: Findings of this small trial have important implications pending replication in a more rigorously designed large-scale study. A 1-d ACT plus Migraine Education workshop is an acceptable and feasible treatment approach for veterans with migraines and significant distress. Significantly reduced distress and disability, as well as improved coping skills, suggest that veterans were activated to engage more fully in their lives and clinical care. The availability of an effective transdiagnostic intervention that can be completed in 1 d is particularly valuable for veterans who have multiple comorbid conditions and who encounter practical barriers to engaging in the usual prescribed weekly therapy treatments. PMID- 29420787 TI - Military Health System Transformation Implications on Health Information Technology Modernization. AB - With the recent passage of the National Defense Authorization Act for Fiscal Year 2017, Congress has triggered groundbreaking Military Health System organizational restructuring with the Defense Health Agency assuming responsibility for managing all hospitals and clinics owned by the Army, Navy, and Air Force. This is a major shift toward a modern value-based managed care system, which will require much greater military-civilian health care delivery integration to be in place by October 2018. Just before the National Defense Authorization Act for Fiscal Year 2017 passage, the Department of Defense had already begun a seismic shift and awarded a contract for the new Military Health System-wide electronic health record system. In this perspective, we discuss the implications of the intersection of two large-scope and large-scale initiatives, health system transformation, and information technology modernization, being rolled out in the largest and most complex federal agency and potential risk mitigating steps. The Military Health System will require an expanded unified clinical leadership to spearhead short-term transformation; furthermore, developing, organizing, and growing a cadre of informatics expertise to expand the use and diffusion of novel solutions such as health information exchanges, data analytics, and others to transcend organizational barriers are still needed to achieve the long-term aim of health system reform as envisioned by the National Defense Authorization Act for Fiscal Year 2017. PMID- 29420788 TI - Phage display peptide libraries: deviations from randomness and correctives. AB - Peptide-expressing phage display libraries are widely used for the interrogation of antibodies. Affinity selected peptides are then analyzed to discover epitope mimetics, or are subjected to computational algorithms for epitope prediction. A critical assumption for these applications is the random representation of amino acids in the initial naive peptide library. In a previous study, we implemented next generation sequencing to evaluate a naive library and discovered severe deviations from randomness in UAG codon over-representation as well as in high G phosphoramidite abundance causing amino acid distribution biases. In this study, we demonstrate that the UAG over-representation can be attributed to the burden imposed on the phage upon the assembly of the recombinant Protein 8 subunits. This was corrected by constructing the libraries using supE44-containing bacteria which suppress the UAG driven abortive termination. We also demonstrate that the overabundance of G stems from variant synthesis-efficiency and can be corrected using compensating oligonucleotide-mixtures calibrated by mass spectroscopy. Construction of libraries implementing these correctives results in markedly improved libraries that display random distribution of amino acids, thus ensuring that enriched peptides obtained in biopanning represent a genuine selection event, a fundamental assumption for phage display applications. PMID- 29420789 TI - THE RESPONSE OF THE PHE NEUTRON PERSONAL DOSEMETER IN TERMS OF THE PROPOSED ICRU PERSONAL DOSE EQUIVALENT. AB - The ICRU is considering amending the definition of the operational quantity for personnel monitoring. The present work investigates the impact of the proposed change on the PHE neutron personal dosemeter, which utilizes electrochemically etched PADC and is currently optimized in terms of Hp(10). The energy-dependent dose response characteristics of the dosemeter, and its performance in realistic workplace neutron fields, are calculated and compared for both the current and proposed dose quantities, for both frontal and rotationally isotropic fields. Adoption of the proposed quantity would make the dosemeter more sensitive to normally incident neutrons, but it would require some modification to ensure that it is able to meet the recommendations of the current ISO standard at all energies and its directional dependence of response would be poorer. The implications of this are discussed. PMID- 29420791 TI - Substance Use and Psychological Distress Before and After the Military to Civilian Transition. AB - Background: Those currently serving in the military constitute a vulnerable population given their high-risk status for substance use, and population data suggest that veterans continue to engage in significant substance use long after their military service ends. Recent research suggests that the separation transition from active duty to civilian life may be critical in terms of the future functioning of the veteran. Methods: We sought to explore substance use prevalence, as well as potential emotional distress among veterans by retrospectively assessing substance use during active duty and following separation to examine possible changes in use over this period. This study assessed substance use and emotional distress in veterans (N = 80; 90% male) across the military to civilian transition. Findings: Repeated measures tests indicated that endorsement of alcohol use, cigarette use, and prescription drug misuse was similar during active duty and post-separation, and marijuana and hard drug use endorsement increased significantly in the 6-mo period post-separation. Further, comorbid use of different substances was common. Active duty levels of anxiety/depression and aggressive feelings were maintained from active duty to post-separation, and feeling alone and military-based trauma symptoms increased significantly. Finally, participants indicated that only a minority of the veterans they knew were doing emotionally well or did not have alcohol/substance use issues. Discussion: These findings indicate a clear need for substance use and psychological intervention availability before and after transition to enable veterans to transition to civilian life effectively. Based on the many issues at work during the transition process, programs may do well to focus more specifically on identification of problems and raising awareness, rather than awaiting more severe issues in the future. Validation of the difficulties of the separation transition, veterans' feelings of isolation, and the importance of veteran community support may help newly transitioning veterans find advocates who may help them navigate existing assistance programs. PMID- 29420792 TI - Assessment of Neurological Toxicity of Hydroxyethyl Starch 130/0.4 Injected in the Intrathecal Space in Rats. AB - Objective: Epidural blood patch is the procedure of choice to relieve postdural puncture headache. Hydroxyethyl-starch (HES) has been proposed as a patch in some circumstances such as in the case of hematological disease due to the theoretical risk of neoplastic seeding to the central nervous system. Acute neurological HES toxicity has been excluded by a previous animal study, but the long-term neurological toxicity has not been evaluated. Methods: Rats were randomly assigned to one of three groups: no intrathecal injection, 20 MUL of intrathecal saline, or a 20-MUL intrathecal HES (6% hydroxyethyl starch 130/0.4) administered via a cervical puncture. Clinical daily rat activity was measured before and after dural puncture by actinometry. The rats were killed at day 28, and the spinal cord was surgically removed and stained with hematoxylin-phloxine-saffron for gross and microscopic examination. Results: Eleven rats underwent dural puncture without injection, 11 were injected with normal saline, and 12 received intrathecal HES. No clinical or actimetric changes (total distance traveled, number of direction changes, and number of rearings) were observed up to one month after injection. Nonspecific histopathological changes were equally observed in all groups. Conclusions: The results of the current study indicate that intrathecal injection of HES in rats does not induce any clinical or histopathological evidence of long-term neuronal toxicity. Further safety studies in animals are warranted before HES might be considered a safe alternative to the classic epidural blood patch. PMID- 29420793 TI - Injuries Sustained During Modern Army Combatives Tournaments. AB - Introduction: Injuries sustained during Modern Army Combatives (MAC) tournaments can result in variable recovery time for involved competitors and unpredictable loss of readiness for military units. A paucity of MAC data is available to guide military medical providers and unit commanders on expected injuries or loss of readiness. Literature reviewing mixed martial arts competitions offers some insight but demonstrates variation in fight outcomes resulting in injuries ranging from 8.5% to 70% and it is difficult to effectively extrapolate such data to predict MAC tournament injuries. Materials and Methods: This study retrospectively reviews pre- and post-competition medical records from two MAC tournaments held at Fort Hood in 2014 and 2015 to provide descriptive clinical information on injury patterns to practitioners and military commanders. Results: Records from a total of 195 competitors with a mean age of 24.4 yr were analyzed with a total of 67 injuries, 29 of which resulted in duty limitations (14.8% of participants). Competitors participating in less-restrictive mixed martial arts style fighting (Advanced MAC) were 4.3 times more likely to sustain an injury than those limited to upper body grappling events (95% confidence interval 2.30 8.16). Military Acute Concussion Evaluations were reliably recorded both pre- and post-competition in 44% of total participants with no significant statistical difference between pre- and post-tournament evaluations. Duty profile limitations of injured competitors averaged 1 mo in duration. Conclusions: MAC tournaments result in injury rates comparable with other combative sports and military training courses. PMID- 29420790 TI - Structurally distinct Mre11 domains mediate MRX functions in resection, end tethering and DNA damage resistance. AB - Sae2 cooperates with the Mre11-Rad50-Xrs2 (MRX) complex to initiate resection of DNA double-strand breaks (DSBs) and to maintain the DSB ends in close proximity to allow their repair. How these diverse MRX-Sae2 functions contribute to DNA damage resistance is not known. Here, we describe mre11 alleles that suppress the hypersensitivity of sae2Delta cells to genotoxic agents. By assessing the impact of these mutations at the cellular and structural levels, we found that all the mre11 alleles that restore sae2Delta resistance to both camptothecin and phleomycin affect the Mre11 N-terminus and suppress the resection defect of sae2Delta cells by lowering MRX and Tel1 association to DSBs. As a consequence, the diminished Tel1 persistence potentiates Sgs1-Dna2 resection activity by decreasing Rad9 association to DSBs. By contrast, the mre11 mutations restoring sae2Delta resistance only to phleomycin are located in Mre11 C-terminus and bypass Sae2 function in end-tethering but not in DSB resection, possibly by destabilizing the Mre11-Rad50 open conformation. These findings unmask the existence of structurally distinct Mre11 domains that support resistance to genotoxic agents by mediating different processes. PMID- 29420794 TI - Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis. AB - Itraconazole (ITC) is the drug of choice for treating paracoccidioidomycosis (PCM); nonetheless, patients with the chronic form of this mycosis develop fibrosis, a residual pulmonary abnormality, even after treatment. Recently, we observed that the depletion of neutrophils with a specific monoclonal antibody (mAb-anti-Ly6G) during the chronic stages of PCM was associated with a decrease in the fungal burden, the inflammatory response and a reduction of fibrosis. Herein, we aimed to evaluate the effect of ITC in combination with the mAb-anti Ly6G in an experimental model of pulmonary PCM. BALB/c male mice were challenged with Paracoccidioides brasiliensis yeasts and treated with the mAb-anti-Ly6G and/or ITC at 4th week post-infection (p.i.) and then sacrificed at 12th week p.i. to assess neutrophil subpopulations, fungal load, collagen, expression of fibrosis- and pro-inflammatory-related genes and histopathology. We observed that combination of ITC/mAb-anti-Ly6G favored the control of infection and diminished the inflammatory response. Of note, such therapeutic strategy reduced the expression of IL-1beta, IL-6, IL-17, IL-10, TNF-alpha, TGF-beta1, TGF-beta3, GATA 3, RORc, Ahr, MMP-1alpha, MMP-8 MMP-15, TIMP-1, and TIMP-2 genes in an additive manner compared to those mice treated with the mAb or ITC alone. Interestingly, ITC induced an increase of type-II neutrophils even in those mice treated with the mAb-anti-Ly6G. These results indicate that combination ITC/mAb-anti-Ly6G reduced the infection and pulmonary fibrosis through down-regulation of inflammatory and pro-fibrotic genes. Additionally, we confirmed the immunomodulatory properties of this antifungal in vivo. This work emphasizes the importance of exploring new potential combination treatments to treat fungal infections. PMID- 29420795 TI - The Burden of Opioid-Induced Constipation in Younger Patients with Chronic Noncancer Pain. AB - Objective: The purpose of this analysis was to evaluate the experience of opioid induced constipation in younger patients and identify differences in the experience of opioid-induced constipation and its symptoms between younger patients (<50 years) and older patients (50-64 years). Design: Post hoc analysis of data from a 24-week prospective, multinational, longitudinal observational cohort study (NCT01928953). Setting: Outpatient clinics in the United States, Canada, Germany, and United Kingdom. Subjects: Two age-based subgroups of adult patients with chronic noncancer pain receiving four or more weeks of daily opioid therapy and experiencing opioid-induced constipation within the previous two weeks. Methods: The number of spontaneous bowel movements, frequency of constipation symptoms, amount of bother associated with symptoms, Patient Assessment of Constipation-Symptoms questionnaire, and health-related quality of life and function outcomes. Results: Overall, 419 patients were included in this analysis (younger patients, N = 184; older patients, N = 235). Among younger and older patients, respectively, constipation occurred within the first week after initiating opioid therapy for 32.8% and 35.9%. At baseline, the mean numbers of spontaneous bowel movements/week were 1.3 and 1.5, and moderate opioid-induced constipation-related interference with pain management was reported by 46.6% and 44.5%. Younger patients generally reported that opioid-induced constipation symptoms were more bothersome than did older patients. The impact of opioid induced constipation on health-related quality of life, work productivity, and day-to-day activities was comparable. Conclusions: In these patients receiving opioid therapy for chronic noncancer pain, the burden of opioid-induced constipation was comparable or greater for patients aged <50 years compared with that for patients aged 50-64 years. PMID- 29420796 TI - Demographic changes threaten the social integration of aging adults in rural regions. AB - Objectives: Contextual influences of the living environment on the social integration of adults has been primarily studied cross-sectionally. Here, we argue that context (i.e., urban vs. rural environment) as well as changes in context (i.e., population decline) are potentially important for the development of social integration across middle adulthood and late life. Method: We used a large scale longitudinal data set representative of the late middle-aged and older German population (N = 4790; aged 40 to 85 years) that assessed participants every 6 years across three waves. To examine our assumptions, we implemented multilevel latent growth curve models. Results: We found that declines in network size were more pronounced in rural than in urban areas. Moreover, age-related declines in network size, social engagement, and social support were particularly pronounced in rural districts that demonstrated above average population decline. Discussion: Our results imply that ongoing demographic changes, particularly in rural areas, may introduce additional barriers for maintaining social integration into late life. PMID- 29420797 TI - Octopus-toolkit: a workflow to automate mining of public epigenomic and transcriptomic next-generation sequencing data. AB - Octopus-toolkit is a stand-alone application for retrieving and processing large sets of next-generation sequencing (NGS) data with a single step. Octopus-toolkit is an automated set-up-and-analysis pipeline utilizing the Aspera, SRA Toolkit, FastQC, Trimmomatic, HISAT2, STAR, Samtools, and HOMER applications. All the applications are installed on the user's computer when the program starts. Upon the installation, it can automatically retrieve original files of various epigenomic and transcriptomic data sets, including ChIP-seq, ATAC-seq, DNase-seq, MeDIP-seq, MNase-seq and RNA-seq, from the gene expression omnibus data repository. The downloaded files can then be sequentially processed to generate BAM and BigWig files, which are used for advanced analyses and visualization. Currently, it can process NGS data from popular model genomes such as, human (Homo sapiens), mouse (Mus musculus), dog (Canis lupus familiaris), plant (Arabidopsis thaliana), zebrafish (Danio rerio), fruit fly (Drosophila melanogaster), worm (Caenorhabditis elegans), and budding yeast (Saccharomyces cerevisiae) genomes. With the processed files from Octopus-toolkit, the meta analysis of various data sets, motif searches for DNA-binding proteins, and the identification of differentially expressed genes and/or protein-binding sites can be easily conducted with few commands by users. Overall, Octopus-toolkit facilitates the systematic and integrative analysis of available epigenomic and transcriptomic NGS big data. PMID- 29420798 TI - Vacuolar Phosphate Transporter 1 (VPT1) Affects Arsenate Tolerance by Regulating Phosphate Homeostasis in Arabidopsis. AB - Arsenate [As(V)] is toxic to nearly all organisms. Soil-borne As(V) enters plant cells mainly through the plasma membrane-localized phosphate (Pi) transporter PHT1 family proteins due to its chemical similarity to Pi. We report here that VPT1, a major vacuolar phosphate transporter which contributes to vacuolar Pi sequestration, is associated with As(V) tolerance in Arabidopsis. vpt1 mutants displayed enhanced tolerance to As(V) toxicity, whereas plants overexpressing VPT1 were more sensitive to As(V) as compared with the wild-type plants. Measurements of arsenic content indicated that vpt1 mutants accumulated less arsenic and, in contrast, up-regulating VPT1 expression contributed to higher levels of arsenic accumulation in plants. To examine further how VPT1 may modulate arsenic contents in plants, we surveyed the expression patterns of all the PHT1 family members that play roles in As(V) uptake, and found that many of the PHT1 genes were down-regulated in the vpt1 mutant as compared with the wild type under Pi-sufficient conditions, but not when Pi levels were low in the medium. Interestingly, As(V) sensitivity assays indicated that As(V) resistance in vpt1 mutants was prominent only under Pi-sufficient but not under Pi-deficient conditions. These results suggest that under Pi-sufficient conditions, loss of VPT1 leads to elevated levels of Pi in the cytosol, which in turn suppressed the expression of PHT1-type transporters and reduced accumulation of arsenic. PMID- 29420799 TI - New insights into the key role of interleukin 6 in vascular calcification of chronic kidney disease. PMID- 29420800 TI - Yesterday and Today: The Impact of Research Conducted at Camp Detrick on Botulinum Toxin. AB - Introduction: This review summarizes the research conducted on botulinum toxin (BoTx) from 1943 to 1956 by a small group of Camp Detrick investigators and their staff. A systematic, cross-disciplinary approach was used to develop effective vaccines against this biological warfare threat agent. In response to the potential need for medical countermeasures against BoTx during World War II, the refinement of isolation and purification techniques for BoTx successfully led to the large-scale production of botulinum toxoid vaccines. In addition, the work at Camp Detrick provided the foundation for the subsequent use of BoTx as a tool for studying the trophic regulation of skeletal muscle within motor neuron terminals and, more recently, for elucidation of the intricate details of neurotransmitter release at the molecular level. Indirectly, Camp Detrick investigators also played a significant role in studies that culminated in the use of BoTx as a pharmaceutical product that has been approved by the U.S. Food and Drug Administration for treating movement disorders, autonomic dysfunctions, and other conditions. Methods: Online literature searches were performed with Google, Google Scholar, PubMed, the bibliography from the Camp Detrick technical library, and at the Defense Technical Information Center. Reference lists in some of the primary research publications and reviews also provided source material. Search terms included botulinum, botulinus, and Camp Detrick. References related to the subsequent impacts of the Camp Detrick results were selected and cited from reviews and primary references in the more recent literature. Notes on toxin nomenclature and potential sources of error in this study are presented. Results: The literature searches returned 27 citations of Camp Detrick authors, 24 of which were articles in peer-reviewed journals. The publications by these investigators included several disciplines such as biochemistry, immunology, pharmacology, physiology, and toxicology. A fundamental finding was the identification of critical nutritional components for improved growth of Clostridium botulinum and the increased production of BoTx serotype A. The purification processes that were developed at Camp Detrick allowed for the production of crystalline material to be scaled up for the manufacture of toxoid vaccine. Based on the research by Camp Detrick scientists, a toxoid supply of over 1 million units was available to vaccinate ~300,000 troops before the large scale operations of D-Day. Conclusions: BoTx research during the period 1943 to 1956 resulted in refinements in the techniques for isolating and purifying the crystalline BoTx type A. These results led to the development and manufacture of a toxoid vaccine that was available in a sufficient quantity to protect ~300,000 warfighters in a large-scale military operation. One of the most important long term consequences derived from the knowledge gained by the efforts at Camp Detrick was the development in the 1980s of safe and effective therapeutic uses for BoTx type A, the most lethal biological substance known. PMID- 29420801 TI - In vitro effects of promethazine on cell morphology and structure and mitochondrial activity of azole-resistant Candida tropicalis. AB - The aim of this study was to evaluate the effect of promethazine on the antifungal minimum inhibitory concentrations against planktonic cells and mature biofilms of Candida tropicalis, as well as investigate its potential mechanisms of cell damage against this yeast species. Three C. tropicalis isolates (two azole-resistant and one azole-susceptible) were evaluated for their planktonic and biofilm susceptibility to promethazine alone and in combination with itraconazole, fluconazole, voriconazole, amphotericin B, and caspofungin. The antifungal activity of promethazine against C. tropicalis was investigated by performing time-kill curve assays and assessing rhodamine 6G efflux, cell size/granularity, membrane integrity, and mitochondrial transmembrane potential, through flow cytometry. Promethazine showed antifungal activity against planktonic cells and biofilms at concentrations of 64 and 128 MUg/ml, respectively. The addition of two subinhibitory concentrations of promethazine reduced the antifungal MICs for all tested azole drugs against planktonic growth, reversing the resistance phenotype to all azoles. Promethazine decreased the efflux of rhodamine 6G in an azole-resistant strain. Moreover, promethazine decreased cell size/granularity and caused membrane damage, and mitochondrial membrane depolarization. In conclusion, promethazine presented synergy with azole antifungals against resistant C. tropicalis and exhibited in vitro cytotoxicity against C. tropicalis, altering cell size/granularity, membrane integrity, and mitochondrial function, demonstrating potential mechanisms of cell damage against this yeast species. PMID- 29420802 TI - MALDI-TOF MS analysis of bovine and zoonotic Trichophyton verrucosum isolates reveals a distinct peak and cluster formation of a subgroup with Trichophyton benhamiae. AB - The zoophilic dermatophyte Trichophyton verrucosum is the most important causative agent of bovine dermatophytosis. Additionally, it causes profound and poorly healing skin infections in humans indicating the high zoonotic potential. The objective of this study was to establish differentiation of T. verrucosum from other dermatophytes by mass spectrometry and to identify distinct features of the mass spectra. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was successful for identification of this pathogen only after extension of the database of the manufacturer with spectra from T. verrucosum strains, which were identified as such by sequencing of the internal transcribed spacer (ITS) region. MALDI-TOF MS analysis was conducted with 46 field isolates from cattle, two live vaccine strains, and 10 isolates from humans identified as T. verrucosum by sequence analysis of the ITS region. The results suggest a very good agreement of both methods. Comparison with the mass spectra of 68 strains of other keratinophilic fungi revealed that most T. verrucosum wild-type isolates showed a characteristic peak at 7950-7954 m/z, which was missing in the spectra of other keratinophilic fungi and the live vaccine strains. The spectra of T. verrucosum were most similar to the spectra of T. benhamiae, an emerging zoophilic dermatophyte. In summary, MALDI-TOF MS is a powerful and reliable tool to identify T. verrucosum. PMID- 29420803 TI - Species of Aspergillus section Aspergillus from clinical samples in the United States. AB - The diversity of Aspergillus species in clinical samples is continuously increasing. Species under the former name Eurotium, currently accommodated in section Aspergillus of the genus Aspergillus, are xerophilic fungi widely found in the human environment and able to grow on substrates with low water activity. However, their prevalence in the clinical setting is poorly known. We have studied the presence of these species in a set of clinical samples from the United States using a multilocus sequence analysis based on the internal transcribed spacer (ITS) region of the rRNA, and fragments of the genes beta tubulin (BenA), calmodulin (CaM), and polymerase II second largest subunit (RPB2). A total of 25 isolates were studied and identified as follows: A. montevidensis (44%), A. chevalieri (36%), A. pseudoglaucus (8%), and A. costiformis (4%). A new species Aspergillus microperforatus is also proposed, which represented 8% of the isolates studied and is characterized by uniseriate conidial heads, subglobose to pyriform vesicles, rough conidia, globose to subglobose cleistothecia, and lenticular and smooth ascospores. The in vitro antifungal activity of eight clinically available antifungals was also determined against these isolates, with the echinocandins and posaconazole having the most potent activity. PMID- 29420804 TI - In Reply: Coiling of a Carotidocavernous Fistula via the Foramen Ovale: 2 Dimensional Operative Video. PMID- 29420805 TI - Localization and Elimination of Attentional Dysfunction in Schizophrenia During Visual Search. AB - Theories of the locus of visual selective attention dysfunction in schizophrenia propose that the deficits arise from either an inability to maintain working memory representations that guide attention, or difficulty focusing lower-level visual attention mechanisms. However, these theoretical accounts neglect the role of long-term memory representations in controlling attention. Here, we show that the control of visual attention is impaired in people with schizophrenia, and that this impairment is driven by an inability to shift top-down attentional control from working memory to long-term memory across practice. Next, we provide converging evidence for the source of attentional impairments in long-term memory by showing that noninvasive electrical stimulation of medial frontal cortex normalizes long-term memory related neural signatures and patients' behavior. Our findings suggest that long-term memory structures may be a source of impaired attentional selection in schizophrenia when visual attention is taxed during the processing of multi-object arrays. PMID- 29420806 TI - A History of Shoulder Instability in the Military: Where We Have Been and What We Have Learned. AB - Introduction: Shoulder instability is one of the most common pathologies seen by the orthopedic sports medicine surgeon. With a uniquely young, high-demand patient population in the U.S. Military, the incidence of shoulder instability is remarkably more common than the civilian population. As such, military orthopedic surgeons and sports medicine and shoulder specialists have developed a unique understanding and experience of shoulder instability. The historical advances of shoulder instability in the military have been instrumental in understanding the epidemiology, evaluation, pathology, treatment of first-time shoulder subluxations and dislocations, operative and non-operative treatment options, arthroscopic and open stabilization methods, management of the in-season athlete, treatment of combined and circumferential labral pathology, and associated pathology. Methods: The purpose of this article is to chronicle the experience of military orthopedic surgeons in treating shoulder instability. We discuss how this unique experience has led to a better understanding of the epidemiology and pathology of this condition and how we have adapted our clinical practice to improve patient outcomes. Results: The historical contribution of U.S. Military orthopedics to the understanding of shoulder instability has been monumental. This article reviews the evolution of shoulder instability treatment and the understanding as it has evolved in the U.S. Military. It further elaborates on our understanding of the epidemiology of shoulder instability in the U.S. Military, with attention given to our incidence of 1.69 per 1000 person-years, approximately 20 times higher incidence than the general population. We discuss known risk factors for dislocation that contribute to this incidence, which are specific to military service. We address pathologic changes seen following a first-time instability event, including an analysis of labral injury and the role of these pathologic changes in recurrent instability. We also review our results from arthroscopic evaluation of first-time dislocations and compare the pathologic changes with those following a first-time subluxation. Evaluation of treatment outcomes is discussed, comparing operative and non-operative results as well as open and arthroscopic stabilization in the U.S. Military population and contact/collision athletes. Finally, we address how these results drive our current treatment algorithm. Discussion and Conclusion: The physical demands of military service result in a high rate of shoulder instability relative to the general population. For years military orthopedic surgeons have sought to better understand this pathology and learn how to optimally manage it so as to reduce this heavy burden of disease. This article discusses our experience with treating shoulder instability, provides an overview of the lessons learned, and provides a historical perspective for the evolution of shoulder instability understanding in the U.S. Military. PMID- 29420807 TI - Transoceanic Dispersal and Plate Tectonics Shaped Global Cockroach Distributions: Evidence from Mitochondrial Phylogenomics. AB - Following the acceptance of plate tectonics theory in the latter half of the 20th century, vicariance became the dominant explanation for the distributions of many plant and animal groups. In recent years, however, molecular-clock analyses have challenged a number of well-accepted hypotheses of vicariance. As a widespread group of insects with a fossil record dating back 300 My, cockroaches provide an ideal model for testing hypotheses of vicariance through plate tectonics versus transoceanic dispersal. However, their evolutionary history remains poorly understood, in part due to unresolved relationships among the nine recognized families. Here, we present a phylogenetic estimate of all extant cockroach families, as well as a timescale for their evolution, based on the complete mitochondrial genomes of 119 cockroach species. Divergence dating analyses indicated that the last common ancestor of all extant cockroaches appeared ~235 Ma, ~95 My prior to the appearance of fossils that can be assigned to extant families, and before the breakup of Pangaea began. We reconstructed the geographic ranges of ancestral cockroaches and found tentative support for vicariance through plate tectonics within and between several major lineages. We also found evidence of transoceanic dispersal in lineages found across the Australian, Indo-Malayan, African, and Madagascan regions. Our analyses provide evidence that both vicariance and dispersal have played important roles in shaping the distribution and diversity of these insects. PMID- 29420809 TI - Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells. AB - Analyzing mixture toxicity requires an in-depth understanding of the mechanisms of action of its individual components. Substances with the same target organ, same toxic effect and same mode of action (MoA) are believed to cause additive effects, whereas substances with different MoAs are assumed to act independently. Here, we tested 2 triazole fungicides, propiconazole, and tebuconazole (Te), for individual and combined effects on liver toxicity-related endpoints. Both triazoles are proposed to belong to the same cumulative assessment group and are therefore thought to display similar and additive behavior. Our data show that Te is an antagonist of the constitutive androstane receptor (CAR) in rats and humans, while propiconazole is an agonist of this receptor. Both substances activate the pregnane X-receptor (PXR) and further induce mRNA expression of CYP3A4. CYP3A4 enzyme activity, however, is inhibited by propiconazole. For common targets of PXR and CAR, the activation of PXR by Te overrides CAR inhibition. In summary, propiconazole and Te affect different hepatotoxicity relevant cellular targets and, depending on the individual endpoint analyzed, act via similar or dissimilar mechanisms. The use of molecular data based on research in human cell systems extends the picture to refine cumulative assessment group grouping and substantially contributes to the understanding of mixture effects of chemicals in biological systems. PMID- 29420808 TI - JC polyoma viruria associates with protection from chronic kidney disease independently from apolipoprotein L1 genotype in African Americans. AB - Background: Viral infections can trigger chronic kidney disease (CKD) and the urine virome may inform risk. The Natural History of APOL1-Associated Nephropathy Study (NHAANS) reported that urine JC polyomavirus (JCPyV) associated with a lower risk of APOL1-associated nephropathy in African Americans. Herein, association was assessed between urine JCPyV with CKD in African Americans independent from the APOL1 genotype. Methods: Quantitative polymerase chain reaction was performed for urinary detection of JCPyV and BK polyoma virus (BKPyV) in 200 newly recruited nondiabetic African Americans. A combined analysis was performed in these individuals plus 300 NHAANS participants. Results: In the 200 new participants, urine JCPyV was present in 8.8% of CKD cases and 45.8% of nonnephropathy controls (P = 3.0 * 10-8). In those with APOL1 renal-risk genotypes, JCPyV was detected in 5.1% of cases and 40.0% of controls (P = 0.0002). In those lacking APOL1 renal-risk genotypes, JCPyV was detected in 12.2% of cases and 48.8% of controls (P = 8.5 * 10-5). BKPyV was detected in 1.3% of cases and 0.8% of controls (P = 0.77). In a combined analysis with 300 NHAANS participants (n = 500), individuals with urine JCPyV had a 63% lower risk of CKD compared with those without urine JCPyV (odds ratio 0.37; P = 4.6 * 10-6). RNA fluorescence in situ hybridization confirmed the presence of JCPyV genomic DNA and JCPyV messenger RNA (mRNA) in nondiseased kidney. Conclusions: Inverse relationships exist between JCPyV viruria and non-diabetic CKD. Future studies should determine whether renal inflammation associated with CKD is less permissive for JCPyV reactivation/replication or whether JCPyV is a marker of reduced host immune responsiveness that diminishes immune pathologic contributions to CKD. PMID- 29420810 TI - Arabidopsis thaliana Trihelix Transcription Factor AST1 Mediates Salt and Osmotic Stress Tolerance by Binding to a Novel AGAG-Box and Some GT Motifs. AB - Trihelix transcription factors are characterized by containing a conserved trihelix (helix-loop-helix-loop-helix) domain that binds to GT elements required for light response, and they play roles in light stress and in abiotic stress responses. However, only a few of them have been functionally characterized. In the present study, we characterized the function of AST1 (Arabidopsis SIP1 clade Trihelix1) in response to salt and osmotic stress. AST1 shows transcriptional activation activity, and its expression is induced by osmotic and salt stress. A conserved sequence highly present in the promoters of genes regulated by AST1 was identified, which was bound by AST1, and termed the AGAG-box with the sequence [A/G][G/A][A/T]GAGAG. Additionally, AST1 also binds to some GT motifs including the sequence of GGTAATT, TACAGT, GGTAAAT and GGTAAA, but failed in binding to the sequence of GTTAC and GGTTAA. Chromatin immunoprecipitation combined with quantitative real-time reverse transcription-PCR analysis suggested that AST1 binds to the AGAG-box and/or some GT motifs to regulate the expression of stress tolerance genes, resulting in reduced reactive oxygen species, Na+ accumulation, stomatal apertures, lipid peroxidation, cell death and water loss rate, and increased proline content and reactive oxygen species scavenging capability. These physiological changes affected by AST1 finally improve salt and osmotic tolerance. PMID- 29420811 TI - Genetic and Molecular Mechanisms of Quantitative Trait Loci Controlling Maize Inflorescence Architecture. AB - The establishment of inflorescence architecture is critical for the reproduction of flowering plant species. The maize plant generates two types of inflorescences, the tassel and the ear, and their architectures have a large effect on grain yield and yield-related traits that are genetically controlled by quantitative trait loci (QTLs). Since ear and tassel architecture are deeply affected by the activity of inflorescence meristems, key QTLs and genes regulating meristematic activity have important impacts on inflorescence development and show great potential for optimizing grain yield. Isolation of yield trait-related QTLs is challenging, but these QTLs have direct application in maize breeding. Additionally, characterization and functional dissection of QTLs can provide genetic and molecular knowledge of quantitative variation in inflorescence architecture. In this review, we summarize currently identified QTLs responsible for the establishment of ear and tassel architecture and discuss the potential genetic control of four ear-related and four tassel-related traits. In recent years, several inflorescence architecture-related QTLs have been characterized at the gene level. We review the mechanisms of these characterized QTLs. PMID- 29420812 TI - Expeditionary Force Health Protection for Global Health Engagement: Lessons Learned from Continuing Promise 2017. AB - Background: Global health engagement (GHE) is an important priority for the Military Health Service as such activities strengthen the health capabilities of partner nations and improve interoperability. By their very nature, GHE activities are predominantly conducted in low-resource areas with limited infrastructure and substantial humanitarian need. The Department of Defense is evaluating leaner, flexible force packages to accomplish GHE missions and better prepare uniformed medical providers to provide care in austere environments. Methods: Observations made during the execution of Continuing Promise 2017, a recurring civil-military humanitarian operation conducted in Central and South America, are offered herein. Descriptions of relevant force health protection (FHP) threats experienced by mission personnel and mitigation measures successfully employed to prevent illness are provided. Relevant Department of Defense instructions are reviewed and risk mitigation strategies are compared with published standards and expert recommendations. Findings: In addition to well-described sanitation, hygiene, and infectious disease challenges that traditionally accompany military field activities, providing health care services to host nation populations in low-resource settings generates unique FHP vulnerabilities. Public health expertise leveraged throughout the planning and execution of GHE activities is instrumental for successfully identifying and mitigating the numerous FHP risks present. Discussion: Experiences from Continuing Promise 2017 demonstrate the expeditionary public health practitioner's role as a force multiplier has never been more relevant. A variety of public health countermeasures are available to successfully mitigate FHP threats experienced during GHE events. The public health lessons learned from Continuing Promise 2017 assist mission planners, commanders, and health care providers ensure that GHE participants remain healthy enough to accomplish the mission and meet America's commitments to partner nations. PMID- 29420813 TI - Sport Psychology for the Soldier Athlete: A Paradigm Shift. AB - Background: Competitive athletes train body and mind in preparation for competition with mental fortitude often providing the "winning edge." Similarly, the current-day warfighter faces significant physical and psychological challenges and must be prepared to respond to life-threatening danger with mental and physical agility. Sport Psychology for the Soldier Athlete recognizes the soldier as an elite athlete and provides training required to perform at the highest caliber. Through this curriculum, mental skills coaching in goal setting, imagery, positive self-talk, and heart rate control is integrated into routine physical fitness training. These skills commonly used by professional and Olympic athletes for optimal performance provide soldiers with the ability to manage every day military stressors. Sport Psychology for the Soldier Athlete supports GEN Milley's top priority of readiness and decreases the cost of Army Physical Fitness Test (APFT) failures. Procedures: Soldiers from a large military treatment facility participated in a 6-wk sport psychology mental skills training program led by an Army occupational therapist. The training that was integrated into regularly scheduled physical training consisted of 10 min of physical readiness training, 10 min of mental skills coaching followed by push-up, sit-up, and running drills focusing on the mental skills learned. Semi-annual APFT scores following the sport psychology training were compared with the five previous semi APFT scores for the same company using analysis of variance. Findings: Results comparing company APFT scores to the previous five semi-annual tests showed statistical significance of 0.001 with the intervention group achieving an average 13- to 14-point improvement. Post-training survey showed 91% of participants recognizing the benefit of these "life skills" in other Army tasks such as weapons qualification, combat medic tasks, and career planning. Soldiers acknowledged this curriculum as quality hands-on training with the suggestion for further development. Discussion: A proactive approach to incorporating mental skills training into the military culture, Sport Psychology for the Soldier Athlete, is in direct alignment with The Army Human Dimension Strategy of developing mental and physical proficiency. This paradigm shift is both timely and necessary for answering readiness and resilience needs of U.S troops and provides additional tools for attaining optimal physical and mental endurance. PMID- 29420815 TI - Limonene inhibits Candida albicans growth by inducing apoptosis. AB - Anti-Candida potential of limonene was evaluated against planktonic growth, biofilm (adhesion, development and maturation) and morphogenesis of Candida albicans in this study. Limonene is a major constituent of citrus oil and most frequently used terpene in food and beverage industry due to its pleasant fragrance, nontoxic, and is generally recognized as safe (GRAS) flavoring agent as well as treatment option in many gastrointestinal diseases.Limonene exhibited excellent anti-Candida activity and was equally effective against planktonic growth of C. albicans isolates differentially susceptible to FLC (N = 35). Limonene inhibited morphogenesis significantly at low concentration. However, it showed stage dependent activity against biofilm formation, that is, it was more effective against adhesion followed by development and maturation. Limonene also exhibited excellent synergy with FLC against planktonic and biofilm growth. SWATH MS analysis led to identification of limonene responsive proteins that provided molecular insight of its anti-Candida activity. Proteomic analysis revealed upregulation of proteins involved in cell wall glucan synthesis (Kre6); oxidative stress (Rhr2, Adh7 and Ebp1); DNA damage stress (Mbf1 and Npl3); nucleolar stress (Rpl11, Rpl7, Rpl29, Rpl15) and down regulation of cytoskeleton organization (Crn1, Pin3, Cct8, Rbl2), and so forth, in response to limonene. Limonene mediated down regulation of Tps3 indicates activation of caspase (CaMca1) and induction of apoptosis in C. albicans. These results suggest that limonene inhibits C. albicans growth by cell wall/membrane damage induced oxidative stress that leads to DNA damage resulting into modulation of cell cycle and induction of apoptosis through nucleolar stress and metacaspase dependent pathway. PMID- 29420814 TI - Missed cleavage opportunities by FEN1 lead to Okazaki fragment maturation via the long-flap pathway. AB - RNA-DNA hybrid primers synthesized by low fidelity DNA polymerase alpha to initiate eukaryotic lagging strand synthesis must be removed efficiently during Okazaki fragment (OF) maturation to complete DNA replication. In this process, each OF primer is displaced and the resulting 5'-single-stranded flap is cleaved by structure-specific 5'-nucleases, mainly Flap Endonuclease 1 (FEN1), to generate a ligatable nick. At least two models have been proposed to describe primer removal, namely short- and long-flap pathways that involve FEN1 or FEN1 along with Replication Protein A (RPA) and Dna2 helicase/nuclease, respectively. We addressed the question of pathway choice by studying the kinetic mechanism of FEN1 action on short- and long-flap DNA substrates. Using single molecule FRET and rapid quench-flow bulk cleavage assays, we showed that unlike short-flap substrates, which are bound, bent and cleaved within the first encounter between FEN1 and DNA, long-flap substrates can escape cleavage even after DNA binding and bending. Notably, FEN1 can access both substrates in the presence of RPA, but bending and cleavage of long-flap DNA is specifically inhibited. We propose that FEN1 attempts to process both short and long flaps, but occasional missed cleavage of the latter allows RPA binding and triggers the long-flap OF maturation pathway. PMID- 29420816 TI - A small, portable RNA device for the control of exon skipping in mammalian cells. AB - Splicing is an essential and highly regulated process in mammalian cells. We developed a synthetic riboswitch that efficiently controls alternative splicing of a cassette exon in response to the small molecule ligand tetracycline. The riboswitch was designed to control the accessibility of the 3' splice site by placing the latter inside the closing stem of a conformationally controlled tetracycline aptamer. In the presence of tetracycline, the cassette exon is skipped, whereas it is included in the ligand's absence. The design allows for an easy, context-independent integration of the regulatory device into any gene of interest. Portability of the device was shown through its functionality in four different systems: a synthetic minigene, a reporter gene and two endogenous genes. Furthermore, riboswitch functionality to control cellular signaling cascades was demonstrated by using it to specifically induce cell death through the conditionally controlled expression of CD20, which is a target in cancer therapy. PMID- 29420817 TI - Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease. AB - Background: Metabolism of glutamine by glutaminase 1 (GLS1) plays a key role in tumor cell proliferation via the generation of ATP and intermediates required for macromolecular synthesis. We hypothesized that glutamine metabolism also plays a role in proliferation of autosomal-dominant polycystic kidney disease (ADPKD) cells and that inhibiting GLS1 could slow cyst growth in animal models of ADPKD. Methods: Primary normal human kidney and ADPKD human cyst-lining epithelial cells were cultured in the presence or absence of two pharmacologic inhibitors of GLS1, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) and CB 839, and the effect on proliferation, cyst growth in collagen and activation of downstream signaling pathways were assessed. We then determined if inhibiting GLS1 in vivo with CB-839 in the Aqp2-Cre; Pkd1fl/fl and Pkhd1-Cre; Pkd1fl/fl mouse models of ADPKD slowed cyst growth. Results: We found that an isoform of GLS1 (GLS1-GAC) is upregulated in cyst-lining epithelia in human ADPKD kidneys and in mouse models of ADPKD. Both BPTES and CB-839 blocked forskolin-induced cyst formation in vitro. Inhibiting GLS1 in vivo with CB-839 led to variable outcomes in two mouse models of ADPKD. CB-839 slowed cyst growth in Aqp2-Cre; Pkd1fl/fl mice, but not in Pkhd1-Cre; Pkd1fl/fl mice. While CB-839 inhibited mammalian target of rapamycin (mTOR) and MEK activation in Aqp2-Cre; Pkd1fl/fl, it did not in Pkhd1-Cre; Pkd1fl/fl mice. Conclusion: These findings provide support that alteration in glutamine metabolism may play a role in cyst growth. However, testing in other models of PKD and identification of the compensatory metabolic changes that bypass GLS1 inhibition will be critical to validate GLS1 as a drug target either alone or when combined with inhibitors of other metabolic pathways. PMID- 29420818 TI - Multi-locus sequence typing provides epidemiological insights for diseased sharks infected with fungi belonging to the Fusarium solani species complex. AB - Fusarium spp. are saprobic moulds that are responsible for severe opportunistic infections in humans and animals. However, we need epidemiological tools to reliably trace the circulation of such fungal strains within medical or veterinary facilities, to recognize environmental contaminations that might lead to infection and to improve our understanding of factors responsible for the onset of outbreaks. In this study, we used molecular genotyping to investigate clustered cases of Fusarium solani species complex (FSSC) infection that occurred in eight Sphyrnidae sharks under managed care at a public aquarium. Genetic relationships between fungal strains were determined by multi-locus sequence typing (MLST) analysis based on DNA sequencing at five loci, followed by comparison with sequences of 50 epidemiologically unrelated FSSC strains. Our genotyping approach revealed that F. keratoplasticum and F. solani haplotype 9x were most commonly isolated. In one case, the infection proved to be with another Hypocrealian rare opportunistic pathogen Metarhizium robertsii. Twice, sharks proved to be infected with FSSC strains with the same MLST sequence type, supporting the hypothesis the hypothesis that common environmental populations of fungi existed for these sharks and would suggest the longtime persistence of the two clonal strains within the environment, perhaps in holding pools and life support systems of the aquarium. This study highlights how molecular tools like MLST can be used to investigate outbreaks of microbiological disease. This work reinforces the need for regular controls of water quality to reduce microbiological contamination due to waterborne microorganisms. PMID- 29420819 TI - Evaluation of the hepatobiliary system in patients with paracoccidioidomycosis treated with cotrimoxazole or itraconazole. AB - A prospective study was performed in 200 paracoccidioidomycosis (PCM) patients, 51 presenting the acute/subacute form (AF) and 149 the chronic form (CF), submitted to the evaluation of the hepatobiliary system at admission and during the follow-up treatment with cotrimoxazole (CMX) or itraconazole (ITC). This study aimed to better evaluate the involvement of the hepatobiliary system in PCM and the effect of these antifungal compounds on this system. Serum levels of direct bilirubin (DB), total bilirubin (TB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) were evaluated. At admission, all the variables showed changes with elevated values ranging from 6.2% for TB to 32.6% for GGT. After treatment, the incidence of elevated serum levels ranged from 3.6% for DB to 27.5% for ALT. The course of the alterations during the treatment showed regression to normal values in CMX-treated patients and persistence in ITC-treated patients but without the need to discontinue the therapy. Our findings contribute to the knowledge of the hepatobiliary involvement by Paracoccidioides sp. and to a safe follow-up of PCM patients under treatment. PMID- 29420820 TI - Breakthrough candidemia after the introduction of broad spectrum antifungal agents: A 5-year retrospective study. AB - Candidemia is the main invasive fungal disease among hospitalized patients. Several breakthrough candidemia (BrC) cases have been reported, but few studies evaluate the epidemiology, risk factors, molecular characterization, antifungal susceptibility profile and outcome of those patients, especially in developing countries and including patients using broad spectrum antifungals. We conducted a retrospective study from 2011 to 2016, including patients aged 12 years or older with candidemia. Epidemiological characteristics and risk factors for candidemia were evaluated and compared with patients with BrC using univariate and multivariate analysis. Sequential Candida isolates from BrC were identified by internal transcribed spacer sequencing, genotyped with amplified fragment length polymorphism fingerprinting (AFLP), and tested for antifungal susceptibility. From 148 candidemia episodes, 27 breakthrough episodes (18%) were identified, with neutropenia and mucositis being independent risk factors for BrC. Candida non-albicans was more frequent in the BrC group (P < .001). AFLP showed high correlation with conventional methods of identification among breakthrough isolates and a high genetic similarity among isolates from the same patient was observed. C. albicans was the most susceptible species with low MIC values for all antifungal agents tested. In contrast, we found isolates of C. glabrata, C. parapsilosis and C. tropicalis resistant to triazoles and echinocandins. In conclusion, BrC occurred mainly in severely immunosuppressed patients, with neutropenia and mucositis. Mortality did not differ between the groups. Candida non-albicans species were more recovered from BrC, with C. albicans being the most susceptible to antifungals. PMID- 29420821 TI - Unstructured 5'-tails act through ribosome standby to override inhibitory structure at ribosome binding sites. AB - Initiation is the rate-limiting step in translation. It is well-known that stable structure at a ribosome binding site (RBS) impedes initiation. The ribosome standby model of de Smit and van Duin, based on studies of the MS2 phage coat cistron, proposed how high translation rates can be reconciled with stable, inhibitory structures at an RBS. Here, we revisited the coat protein system and assessed the translation efficiency from its sequestered RBS by introducing standby mutations. Further experiments with gfp reporter constructs assessed the effects of 5'-tails-as standby sites-with respect to length and sequence contributions. In particular, combining in vivo and in vitro assays, we can show that tails of CA-dinucleotide repeats-and to a lesser extent, AU-repeats dramatically increase translation rates. Tails of increasing length reach maximal rate-enhancing effects at 16-18 nucleotides. These standby tails are single stranded and do not exert their effect by structure changes in the neighboring RBS stem-loop. In vitro translation and toeprinting assays furthermore demonstrate that standby effects are exerted at the level of translation initiation. Finally, as expected, destabilizing mutations within the coat RBS indicate an interplay with the effects of standby tails. PMID- 29420822 TI - Bifactor Modeling of the Positive and Negative Syndrome Scale: Generalized Psychosis Spans Schizoaffective, Bipolar, and Schizophrenia Diagnoses. AB - Objective: Common genetic variation spans schizophrenia, schizoaffective and bipolar disorders, but historically, these syndromes have been distinguished categorically. A symptom dimension shared across these syndromes, if such a general factor exists, might provide a clearer target for understanding and treating mental illnesses that share core biological bases. Method: We tested the hypothesis that a bifactor model of the Positive and Negative Syndrome Scale (PANSS), containing 1 general factor and 5 specific factors (positive, negative, disorganized, excited, anxiety), explains the cross-diagnostic structure of symptoms better than the traditional 5-factor model, and examined the extent to which a general factor reflects the overall severity of symptoms spanning diagnoses in 5094 total patients with a diagnosis of schizophrenia, schizoaffective, and bipolar disorder. Results: The bifactor model provided superior fit across diagnoses, and was closer to the "true" model, compared to the traditional 5-factor model (Vuong test; P < .001). The general factor included high loadings on 28 of the 30 PANSS items, omitting symptoms associated with the excitement and anxiety/depression domains. The general factor had highest total loadings on symptoms that are often associated with the positive and disorganization syndromes, but there were also substantial loadings on the negative syndrome thus leading to the interpretation of this factor as reflecting generalized psychosis. Conclusions: A bifactor model derived from the PANSS can provide a stronger framework for measuring cross-diagnostic psychopathology than a 5-factor model, and includes a generalized psychosis dimension shared at least across schizophrenia, schizoaffective, and bipolar disorder. PMID- 29420823 TI - Characterization of Nannizziopsis guarroi with genomic and proteomic analysis in three lizard species. AB - Fungal infections in captive as well as in free-living reptiles caused by emerging obligate pathogenic fungi appear with increasing frequency and give occasion to establish new and fast methods for routine diagnostics. The so-called yellow fungus disease is one of the most important and common fungal dermatomycoses in central bearded dragons (Pogona vitticeps) and green iguanas (Iguana iguana) and is caused by Nannizziopsis guarroi. The aim of this study was to prove reliability in identification of N. guarroi with Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) in comparison to molecular biological analysis of ribosomal DNA genes. In seven lizards from three different species, including central bearded dragons, green iguanas, and a European green lizard (Lacerta viridis), dermatomycoses caused by N. guarroi were diagnosed by isolation of the fungal pathogen as well as histopathological confirmation of the granulomatous inflammatory reaction in deep skin biopsies. With this survey, we proved that MALDI-TOF MS is a diagnostic tool for accurate identification of N. guarroi. Besides small subunit 18S rDNA (SSU) and internal transcribed spacer (ITS)1-5.8S rDNA, a large fragment of the large subunit of the 28S rDNA (LSU), including the domain (D)1 and D2 have been sequenced, for phylogenetical analysis. Large fragment of the LSU from N. guarroi has been sequenced for the first time. Yellow fungus disease in a European lizard species is described for the first time to our knowledge as well, which could be of importance for free-ranging populations of European lizards. PMID- 29420824 TI - Differentiating true and false schematic memories in older adults. AB - Objective: While schemas aid memory for schematically related information, the gist induced by the schema can also lead to high rates of false memories, especially in older adults. The neural mechanisms that support and differentiate true and false memories in aging are not well understood. The current study sought to clarify this, using a novel scene paradigm to investigate the role of schemas on true and false memories in older adults. Methods: Healthy older adults encoded schematic scenes (e.g., bathroom). At retrieval, participants were tested on their memory for both schematic and non-schematic targets and lures while fMRI data was collected. Results: Results indicate that true memories were supported by the typical retrieval network, and activity in this network was greater for true than false memories. Schema specific retrieval was supported by mPFC, extending this common finding to aging. While no region differentiated false memories compared to correct rejections, results showed that individual differences in false memory rates were associated with variability in neural activity. Discussion: The findings underscore the importance of elucidating the neural basis of cognition within older adults, as well as the specific contribution of individual differences to the neural basis of memory errors in aging. PMID- 29420825 TI - Placental Findings in Singleton Stillbirths: A Case-control Study. AB - Aims: This prospective observational study compared placental lesions of stillbirth cases and live birth controls, and aimed to determine the cause of stillbirth. Methods: The study enrolled 85 stillbirths and 85 live births at the time of delivery. Results: There was significantly increased incidence of placental abruption (p = 0.005) and gestational diabetes (p = 0.032) in mothers with stillbirths. Histopathological examination of placenta was significantly abnormal in stillbirths compared with live births (p = 0.004). Delayed villous maturation was significantly more in stillbirths (38.82 vs. 16.47%; p = 0.002). Acute (30.59 vs. 16.47%; p = 0.04) and chronic diffuse villitis (16.47 vs. 4.7%; p = 0.02), chorionic plate acute vasculitis (28.235 vs. 14.11%; p = 0.04) were significantly more in stillbirths. Foetal vascular thrombi in the chorionic plate (30.58 vs. 14.12%; p = 0.02) and avascular villi (24.7 vs. 8.23%; p = 0.006) were significantly more in stillbirths. Conclusion: These abnormal placental patterns could provide information about the etiopathogenisis in stillbirths of unknown aetiology. PMID- 29420826 TI - Transcriptional profile of the human skin pathogenic fungus Mucor irregularis in response to low oxygen. AB - Mucormycosis is one of the most invasive mycosis and has caused global concern in public health. Cutaneous mucormycosis caused by Mucor irregularis (formerly Rhizomucor variabilis) is an emerging disease in China. To survive in the human body, M. irregularis must overcome the hypoxic (low oxygen) host microenvironment. However, the exact molecular mechanism of its pathogenicity and adaptation to low oxygen stress environment is relatively unexplored. In this study, we used Illumina HiSeq technology (RNA-Seq) to determine and compare the transcriptome profile of M. irregularis CBS103.93 under normal growth condition and hypoxic stress. Our analyses demonstrated a series of genes involved in TCA, glyoxylate cycle, pentose phosphate pathway, and GABA shunt were down-regulated under hypoxic condition, while certain genes in the lipid/fatty acid metabolism and endocytosis were up-regulated, indicating that lipid metabolism was more active under hypoxia. Comparing the data with other important human pathogenic fungi such as Aspergillus spp., we found that the gene expression pattern and metabolism in responses to hypoxia in M. irregularis were unique and different. We proposed that these metabolic changes can represent a species-specific hypoxic adaptation in M. irregularis, and we hypothesized that M. irregularis could use the intra-lipid pool and lipid secreted in the infection region, as an extracellular nutrient source to support its hypoxic growth. Characterizing the significant differential gene expression in this species could be beneficial to uncover their role in hypoxia adaptation and fungalpathogenesis and further facilitate the development of novel targets in disease diagnosis and treatment against mucormycosis. PMID- 29420828 TI - Time to rethink sleep quality: PSQI scores reflect sleep quality on workdays. AB - The Pittsburgh Sleep Quality Index (PSQI) is the most common measure of sleep quality. Its questions refer to "usual" sleep habits during the last month. Considering how different sleep-wake behavior can be between workdays and work free days, we hypothesized that sleep quality should show similar differences. We investigated these potential differences in a cross-sectional online study using the original and two adapted versions of the PSQI that replaced "usual" by explicitly referring to sleep on workdays or work-free days. Additionally, we investigated how these scores relate to chronotype and social jetlag assessed by the Munich ChronoType Questionnaire. Participants were recruited online, they had to be older than 18 years, following regular weekly work schedules, and they should not be shift workers. Repeated-measures analysis of variance was used to compare the three different versions of the PSQI (usual, work, and work-free). To find out whether PSQI score differences could be predicted by chronotype and/or social jetlag a mediation analysis was carried out. Workday PSQI scores were similar to the original "usual" scores, two points higher than the PSQI score on work-free days and above the cutoff designating poor sleep quality. PSQI components and time variables also differed between workdays and work-free days. Chronotype correlated with the difference between PSQI scores on workdays and on work-free days, an association mediated by social jetlag. Our results suggest that the original PSQI predominantly reports sleep quality on workdays and that work schedules may affect sleep quality. The mediation of social jetlag on the association of chronotype and PSQI score differences could mean that not chronotype per se, but rather the collision of an individuals' chronotype with fixed work schedules explains the differences between sleep on workdays and work free days. Understanding how sleep quality differs between workdays and work-free days, how this difference can adequately be assessed through directing participants to focus on their sleep specifically on workdays vs. work-free days, and how circadian factors modulate this difference, is crucial to improve sleep quality. PMID- 29420827 TI - Effects of lower versus higher phosphate diets on fibroblast growth factor-23 levels in patients with chronic kidney disease: a systematic review and meta analysis. AB - Background: Elevated fibroblast growth factor-23 (FGF23) levels increase the risk of cardiovascular diseases in patients with chronic kidney disease (CKD). We aimed to compare the effects of different dietary interventions, lower versus higher phosphate levels, on FGF23 in patients with CKD. Methods: We conducted electronic literature searches of Medline, PubMed, Embase and the Cochrane Library for publications up to 29 October 2016 for randomized clinical trials that compared lower versus higher phosphate dietary interventions in adults with CKD. The primary outcome was the difference in change-from-baseline FGF23 levels between intervention groups. Considering the difference in measurement units between intact FGF23 and C-terminal FGF23 assays, the treatment effect was analysed as the standardized mean difference (SMD) with the 95% confidence interval (CI). Results: We identified five trials enrolling a total of 94 normophosphataemic patients with Stage 3B CKD. The study duration ranged from 1 to 12 weeks. Compared with higher phosphate diets, lower phosphate diets tended to reduce FGF23 levels (SMD -0.74, 95% CI -1.54 to 0.07, P = 0.07). Subgroup analyses showed a trend (P for interaction = 0.09) towards a better FGF23 lowering effect by lower phosphate diets in studies using the intact FGF23 assay (SMD -1.14, 95% CI -2.24 to -0.04) than those using the C-terminal FGF23 assay (SMD -0.05, 95% CI -0.67 to 0.57). Conclusions: Short-term dietary phosphate restriction tends to reduce FGF23 levels in patients with moderately decreased kidney function, and the FGF23-lowering effects tend to be more prominent when measured with the intact FGF23 assay. PMID- 29420829 TI - An interview with Dr Janice Bahr. PMID- 29420831 TI - Mouse knockout models reveal largely dispensable but context-dependent functions of lncRNAs during development. PMID- 29420830 TI - Acellular therapeutic approach for heart failure: in vitro production of extracellular vesicles from human cardiovascular progenitors. AB - Aims: We have shown that extracellular vesicles (EVs) secreted by embryonic stem cell-derived cardiovascular progenitor cells (Pg) recapitulate the therapeutic effects of their parent cells in a mouse model of chronic heart failure (CHF). Our objectives are to investigate whether EV released by more readily available cell sources are therapeutic, whether their effectiveness is influenced by the differentiation state of the secreting cell, and through which mechanisms they act. Methods and results: The total EV secreted by human induced pluripotent stem cell-derived cardiovascular progenitors (iPSC-Pg) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) were isolated by ultracentrifugation and characterized by Nanoparticle Tracking Analysis, western blot, and cryo electron microscopy. In vitro bioactivity assays were used to evaluate their cellular effects. Cell and EV microRNA (miRNA) content were assessed by miRNA array. Myocardial infarction was induced in 199 nude mice. Three weeks later, mice with left ventricular ejection fraction (LVEF) <= 45% received transcutaneous echo-guided injections of iPSC-CM (1.4 * 106, n = 19), iPSC-Pg (1.4 * 106, n = 17), total EV secreted by 1.4 * 106 iPSC-Pg (n = 19), or phosphate-buffered saline (control, n = 17) into the peri-infarct myocardium. Seven weeks later, hearts were evaluated by echocardiography, histology, and gene expression profiling, blinded to treatment group. In vitro, EV were internalized by target cells, increased cell survival, cell proliferation, and endothelial cell migration in a dose-dependent manner and stimulated tube formation. Extracellular vesicles were rich in miRNAs and most of the 16 highly abundant, evolutionarily conserved miRNAs are associated with tissue-repair pathways. In vivo, EV outperformed cell injections, significantly improving cardiac function through decreased left ventricular volumes (left ventricular end systolic volume: -11%, P < 0.001; left ventricular end diastolic volume: -4%, P = 0.002), and increased LVEF (+14%, P < 0.0001) relative to baseline values. Gene profiling revealed that EV-treated hearts were enriched for tissue reparative pathways. Conclusion: Extracellular vesicles secreted by iPSC-Pg are effective in the treatment of CHF, possibly, in part, through their specific miRNA signature and the associated stimulation of distinct cardioprotective pathways. The processing and regulatory advantages of EV could make them effective substitutes for cell transplantation. PMID- 29420832 TI - Afghanistan and Iraq War Veterans: Mental Health Diagnoses are Associated with Respiratory Disease Diagnoses. AB - Introduction: Many veterans of the wars in Afghanistan and Iraq have concomitant respiratory conditions and mental health conditions. We wanted to evaluate the association of mental health diagnoses with respiratory disease diagnoses among post-deployment veterans. Methods: We conducted a retrospective cohort study of all Afghanistan and Iraq War veterans who were discharged from the military or otherwise became eligible to receive Veterans Health Administration services. The primary exposure was receipt of a mental health diagnosis and the primary outcome was receipt of a respiratory diagnosis as recorded in the electronic health record. We used multivariable adjusted logistic regression to measure the associations of mental health diagnoses with respiratory diagnoses and conducted several analyses exploring the timing of the diagnoses. Results: Among 182,338 post-deployment veterans, 14% were diagnosed with a respiratory condition, 77% of whom had a concomitant mental health diagnosis. The incidence rates were 5,363/100,000 person-years (p-y), 587/100,000 p-y, 1,450/100,000 p-y, and 233/100,000 p-y for any respiratory disease diagnosis, bronchitis, asthma, and chronic obstructive lung disease diagnoses, respectively, after the date of first Veterans Health Administration utilization. Any mental health diagnosis was associated with increased odds for any respiratory diagnosis (adjusted odds ratio 1.41, 95% confidence interval 1.37-1.46). The association of mental health diagnoses and subsequent respiratory disease diagnoses was stronger and more consistent than the converse. Conclusion: Many Afghanistan and Iraq War veterans are diagnosed with both respiratory and mental illnesses. Comprehensive plans that include care coordination with mental health professionals and treatments for mental illnesses may be important for many veterans with respiratory diseases. PMID- 29420833 TI - Health Care Provider Intervention and Utilization of Cessation Assistance in 12 Low- and Middle-Income Countries. AB - Background and Aim: There is a need to improve utilization of cessation assistance in low- and middle-income countries (LMICs), and tobacco cessation research has been identified as priority in LMICs. This study evaluates the relationship between health care provider intervention and cessation assistance utilization in LMICs. Methods: Data from 13 967 participants (aged >=15 years, 90.3% males) of the Global Adults Tobacco Survey conducted in 12 LMICs (74.3% 97.3% response rates) were analyzed with utilization of counseling/cessation clinic, WHO-recommended medications, and quitline as outcome variables. Health care provider intervention ("no intervention," only "tobacco screening," "quit advice") was the exposure variable. Weighted multiple logistic regression models were used to examine the relationship between each outcome variable and the exposure variable, adjusting for other covariates. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are reported. Results: Approximately 52%, 8%, and 40% of participants received no intervention, only tobacco screening, and advice to quit, respectively. Overall, 0.4%, 1.9%, 3.0%, and 4.5% used quitline, WHO-recommended medications, counseling/cessation clinic, and any cessation assistance, respectively. Compared with no intervention, quit advice was associated with increased utilization of quitline (OR = 2.24, 95% CI = 1.2 to 4.4), WHO-recommended medications (OR = 1.67, 95% CI = 1.2 to 2.3), counseling/cessation clinic (OR = 4.41, 95% CI = 3.2 to 6.1), and any assistance (any of the three types) (OR = 2.80, 95% CI = 2.2 to 3.6). Conclusion: The findings of this study suggest that the incorporation of quit advice by health care providers in tobacco control programs and health care systems in LMICs could potentially improve utilization of cessation assistance to improve smoking cessation in LMICs. Implications: This first study of association between health care provider intervention and the utilization of cessation assistance in LMICs reports that there was a missed opportunity to provide quit advice to about 60% of smokers who visited a health care provider in the past year. The odds of utilization of counseling/cessation clinic, WHO-recommended medications, and quitline were significantly increased in participants who were advised to quit smoking. The results suggest that effective integration and implementation of advice to quit in tobacco control programs and the national health care systems may increase the use of cessation assistance to quit smoking. PMID- 29420834 TI - Echocardiographic 3D-guided 2D planimetry in quantifying left-sided valvular heart disease. AB - Echocardiographic 3D-guided 2D planimetry can improve the accuracy of valvular disease assessment. Acquisition of 3D pyramidal dataset allows subsequent multiplanar reconstruction with accurate orthogonal plane alignment to obtain the correct borders of an anatomic orifice or flow area. Studies examining the 3D guided 2D planimetry approach in left-sided valvular heart disease were identified and reviewed. The strongest evidence exists for estimating mitral valve area in patients with rheumatic mitral valve stenosis and vena contracta area in patients with mitral regurgitation (both primary and secondary). 3D guided approach showed excellent feasibility and reproducibility in most studies, as well as time efficiency and good correlation with reference and comparator methods. Therefore, 3D-guided 2D planimetry can be used as an important clinical tool in quantifying left-sided valvular heart disease, especially mitral valve disorders. PMID- 29420835 TI - Validity of self-reported tooth counts and masticatory status study of a Japanese adult population. AB - Self-reported measures of oral health are often used to assess oral health in populations or groups, but their validity or reliability needs repeated confirmation. The objective of this cross-sectional study was to evaluate the validity of self-reported tooth counts and masticatory status, using data obtained from a sample of Japanese adults. A total of 2356 adults aged 40 to 75 years participated in a questionnaire survey and a clinical oral examination from 2013 through 2016. Self-reported measures were compared with clinically measured values. For tooth counts, mean clinical and self-reported tooth counts in all participants were 23.68 and 23.78 teeth, and no significant difference was detected. Spearman's, Pearson's and intra-class correlation coefficients between clinical and self-reported tooth counts were 0.771, 0.845 and 0.843, respectively. According to the Bland-Altman analysis, the mean difference between clinical and self-reported tooth counts was -0.098 (95% CI: -0.242, 0.047). The upper limit of agreement was 6.919 (95% CI: 6.669, 7.169), and the lower limit of agreement was -7.115 (95% CI: -7.365, -6.865). No significant fixed or proportional bias was observed. For masticatory status, the crude or age- and gender-adjusted mean numbers of total teeth, posterior teeth and 3 kinds of functional tooth units significantly decreased with the deterioration of masticatory status. This study indicated that self-reports were within an acceptable range of clinical measures. Therefore, self-reports were considered valid alternatives to clinical measures to estimate tooth counts and masticatory status in a current Japanese adult population. PMID- 29420836 TI - Morphology of early intrauterine deaths with full trisomy 15. AB - OBJECTIVE: The morphologic features of embryos with full trisomy 15 are described. METHOD: A total of 1195 pregnancy losses were examined embryoscopically and cytogenetically. RESULTS: Of 1173 successfully karyotyped specimens, full trisomy 15 was diagnosed cytogenetically in 59 cases (5%). All 59 trisomy 15 embryos were diagnosed cytogenetically in the group of 962 embryonic miscarriages (6%). Trisomy 15 was not registered in 171 anembryonic or yolk sac miscarriages, and no case of full trisomy 15 was observed in 62 fetal miscarriages. Fifty-eight embryos with full trisomy 15 showed structural defects on embryoscopic examination. The most common defects were craniofacial anomalies (n = 73), retarded development of the limbs (n = 39), and abnormally short umbilical cords closely attaching the embryo to the chorionic plate (n = 27). Seven embryos were classified as growth disorganized. Limb reduction defects with a prevalence of 5.6/10 000 births, all affecting upper limb development (10 terminal transverse limb reduction defects and 3 embryos with split hand), were registered in 13 (22%) trisomy 15 embryos. CONCLUSION: Limb reduction defects and craniofacial abnormalities are a typical feature of trisomy 15. Gene dosage imbalances related to trisomy 15 might be the main molecular mechanism underlying the developmental defects observed in the present study and require further investigation. PMID- 29420837 TI - Carcinosarcoma mimicking a feline injection-site sarcoma in a cat. AB - A 15-year-old spayed female domestic short-haired cat with cutaneous/subcutaneous well-circumscribed, alopecic mass approximately 25 * 30 mm in diameter, localized to the left shoulder region was brought to the veterinary surgery department. Despite the suggestive location and macroscopic appearance, feline injection-site sarcoma was not suspected based on the cytologic examination of fine-needle aspirates. The tumor was surgically resected, and tissue sections were evaluated microscopically. The tumor was found to be nonencapsulated with a distinct border between the neoplastic parenchyma and surrounding connective tissue. The neoplastic tissue consisted of 2 cell populations: elongated to spindle-shaped cells arranged in bands and cords and malignant epithelial-like cells. Both populations showed microscopic features of malignancy. Multinucleate giant cells with irregular cytoplasm were scattered among the neoplastic cells. The spindle shaped cells strongly expressed vimentin but did not express alpha-smooth muscle actin (alpha-SMA) or cytokeratin. Desmin was strongly expressed in about 0-5% of cells. Epithelial-like cells expressed cytokeratin, but not vimentin, desmin, or alpha-SMA. Multinucleate giant cells expressed vimentin, but did not alpha-SMA, desmin, or cytokeratin. Based on microscopic observations and IHC results, the final diagnosis was carcinosarcoma with histologic features compatible with feline injection-site sarcoma, but without the clinical aggressiveness of this tumor. PMID- 29420838 TI - Study Design Parameters Affecting Exposure Response Analysis of QT Data: Results From Simulation Studies. AB - The operating characteristics of dose-escalating studies in terms of false negative predictions of the QT effect and the power to exclude clinically relevant QT effects are not quantitatively established. One thousand single ascending-dose (SAD) studies with 7 dose groups with 6/2 subjects on active drug/placebo were generated through simulation for each of 32 scenarios with (1) 8 different QT effects of the study drug and (2) achieved plasma concentration 2- or 4-fold above therapeutic levels. For each subject, drug-free QT data from a thorough QT study were subsampled to capture the circadian profile, on which a drug effect was added. The percentage of false-negative studies was between 4% and 9% when the drug's QT effect was set to 10 milliseconds. If a somewhat lower effect of 6.7 milliseconds was set at therapeutic concentrations, the fraction of negative studies was higher, 40% to 60% when the variability of the QT data was well controlled. When the QT effect was set to 5 milliseconds at therapeutic plasma concentrations, the power of SAD studies to exclude 10 milliseconds QT effect was generally above 70% (74% to 94%) with well-controlled QT variability, whereas the power was reduced to 36% to 69% if supratherapeutic plasma concentrations were not achieved. The rate of false-negative studies was acceptably low in placebo-controlled SAD studies. With a drug with no or a small QT effect, supratherapeutic plasma concentrations, and well-controlled variability of QT data, the power of SAD studies to exclude a relevant effect was above 70%. PMID- 29420839 TI - Underwater endoscopic mucosal resection of a duodenal adenoma with biopsy scars. PMID- 29420841 TI - Daphnia magna microRNAs respond to nutritional stress and ageing but are not transgenerational. AB - Maternal effects, where the performance of offspring is determined by the condition of their mother, are widespread and may in some cases be adaptive. The crustacean Daphnia magna shows strong maternal effects: offspring size at birth and other proxies for fitness are altered when their mothers are older or when mothers have experienced dietary restriction. The mechanisms for this transgenerational transmission of maternal experience are unknown, but could include changes in epigenetic patterning. MicroRNAs (miRNAs) are regulators of gene expression that have been shown to play roles in intergenerational information transfer, and here, we test whether miRNAs are involved in D. magna maternal effects. We found that miRNAs were differentially expressed in mothers of different ages or nutritional state. We then examined miRNA expression in their eggs, their adult daughters and great granddaughters, which did not experience any treatments. The maternal (treatment) generation exhibited differential expression of miRNAs, as did their eggs, but this was reduced in adult daughters and lost by great granddaughters. Thus, miRNAs are a component of maternal provisioning, but do not appear to be the cause of transgenerational responses under these experimental conditions. MicroRNAs may act in tandem with egg provisioning (e.g., with carbohydrates or fats), and possibly other small RNAs or epigenetic modifications. PMID- 29420842 TI - Acute myocardial infarction complicated with ventricular septal rupture and intracranial hemorrhage. AB - Ventricular septal rupture (VSR) is a rare but fatal complication of acute myocardial infarction (AMI) with an associated mortality that ranges from 41% to 80%. The treatment consists of supplemental oxygenation, afterload reduction, intraaortic balloon pump, and surgical repair. In selected patients, extracorporeal membrane oxygenation (ECMO) and/or percutaneous closure of the defect can be considered if anatomically appropriate. Echocardiography evaluates the morphology and location of the defect, anatomical concerns for percutaneous closure, and accompanying pathologies. We present a 48-year-old man with inferior myocardial infarction and basal VSR who was not a candidate for percutaneous closure. Surgery was planned, but he died from extensive subarachnoid and intracranial hemorrhage. PMID- 29420840 TI - Stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy. AB - OBJECTIVE: To evaluate the outcomes 1 year and longer following stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy in a large series of patients treated over a 5-year period since introduction of this novel technique. METHODS: Surgical outcomes of a consecutive series of 58 patients with mesial temporal lobe epilepsy who underwent the surgery at our institution with at least 12 months of follow-up were retrospectively evaluated. A subgroup analysis was performed comparing patients with and without mesial temporal sclerosis. RESULTS: One year following stereotactic laser amygdalohippocampotomy, 53.4% (95% confidence interval [CI] = 40.8-65.7%) of all patients were free of disabling seizures (Engel I). Three of 9 patients became seizure-free following repeat ablation. Subgroup analysis showed that 60.5% (95% CI = 45.6-73.7%) of patients with mesial temporal sclerosis were free of disabling seizures as compared to 33.3% (95% CI = 15.0-58.5%) of patients without mesial temporal sclerosis. Quality of Life in Epilepsy-31 scores significantly improved at the group level, few procedure-related complications were observed, and verbal memory outcome was better than historical open resection data. INTERPRETATION: In an unselected consecutive series of patients, stereotactic laser amygdalohippocampotomy yielded seizure-free rates for patients with mesial temporal lobe epilepsy lower than, but comparable to, the outcomes typically associated with open temporal lobe surgery. Analogous to results from open surgery, patients without mesial temporal sclerosis fared less well. This novel procedure is an effective minimally invasive alternative to resective surgery. In the minority of patients not free of disabling seizures, laser ablation presents no barrier to additional open surgery. Ann Neurol 2018;83:575-587. PMID- 29420843 TI - Conserving and managing the subnivium. AB - In regions where snowfall historically has been a defining seasonal characteristic of the landscape, warming winters have reduced the depth, duration, and extent of snowpack. However, most management and conservation has focused on how aboveground wildlife will be affected by altered snow conditions, even though the majority of species that persist through the winter do so under the snowpack in a thermally stable refugium: the subnivium. Shortened winters, forest management practices, and winter recreation can alter subnivium conditions by increasing snow compaction and compromising thermal stability at the soil-snow interface. To help slow the loss of the subnivium in the face of rapidly changing winter conditions, we suggest managers adopt regional conservation plans for identifying threatened snow-covered environments; measure and predict the effects land cover and habitat management has on local subnivium conditions; and control the timing and distribution of activities that disturb and compact snow cover (e.g., silvicultural practices, snow recreation, and road and trail maintenance). As a case study, we developed a spatially explicit model of subnivium presence in a working landscape of the Chequamegon National Forest, Wisconsin. We identified landscapes where winter recreation and management practices could threaten potentially important areas for subnivium persistence. Similar modeling approaches could inform management decisions related to subnivium conservation. Current climate projections predict that snow seasons will change rapidly in many regions, and as result, we advocate for the immediate recognition, conservation, and management of the subnivium and its dependent species. PMID- 29420844 TI - Absorption Characteristics and Quantum Yields of Singlet Oxygen Generation of Thioguanosine Derivatives. AB - 6-Thioguanine (1a) is considered to be photochemotherapeutic due to its specific characteristics of photosensitivity to UVA light and singlet molecular oxygen generation. To extend its phototherapeutic ability, two related thioguanines, 8 thioguanine (2a) and 6,8-dithioguanine (3a), have been designed and explored. Since the solubility of these thioguanines in dehydrated organic solvents is too poor to study, their triacetyl-protected ribonucleosides, that is, 2',3',5'-tri-O acetyl-6-thioguanosine (1c), 2',3',5'-tri-O-acetyl-8-thioguanosine (2c) and 2',3',5'-tri-O-acetyl-6,8-dithioguanosine (3c) were prepared and investigated. The absorption maxima of 1c, 2c and 3c in acetonitrile were found at longer wavelengths than that of unthiolated guanosine (4c). Especially, 3c has the longest wavelength for absorption maximum and the highest value in terms of molar absorption coefficient among all thionucleobases and thionucleosides reported. These absorption properties were also well reproduced by quantum chemical calculations. Quantum yields of singlet oxygen generation of 2c and 3c were determined by near-infrared emission measurements to be as large as that of 1c. These results suggest that the newly synthesized thioguanosines, in particular 3c, can be further developed as a potential photosensitive agent for light induced therapies. PMID- 29420845 TI - Conscious control of breathing: A key to prevention of sudden unexpected death in epilepsy? PMID- 29420846 TI - Screening of illegally adulterated 1,4-dihydropyridine calcium antagonists in traditional Chinese medicines by a high-performance liquid chromatography electrospray ionization in-source collision-induced dissociation triple quadrupole mass spectrometric method. PMID- 29420847 TI - Is Antimicrobial Photodynamic Therapy Effective for Microbial Load Reduction in Peri-implantitis Treatment? A Systematic Review and Meta-Analysis. AB - The systematic review and meta-analysis were undertaken to evaluate the effectiveness of antimicrobial photodynamic therapy (aPDT) in the microbiological alteration beneficial to peri-implantitis treatment. This study is registered with PROSPERO, number CRD42017064215. Bibliographic databases including Cochrane Library, Web of Science, Scopus and PubMed were searched from inception to 8 January 2017. The search strategy was assembled from the following MeSH Terms: "Photochemotherapy," "Dental Implants" and "Peri-Implantitis." Unspecific free text words and related terms were also included. The Cochrane Collaboration's tool was used to evaluate the risk of bias of included studies. The random-effect model was chosen, and heterogeneity was evaluated using the I2 test. Three studies met the inclusion criteria. Meta-analysis demonstrated an association between aPDT and reduction in viable bacteria counts for: Aggregatibacter actinomycetemcomitans (OR = 1.31; confidence interval = 1.13, 1.49; P < 0.00001), Porphyromonas gingivalis (OR = 4.08; confidence interval = 3.22, 4.94; P < 0.00001) and Prevotella intermedia (OR = 1.66; confidence interval = 1.06, 2.26; P < 0.00001). A aPDT appears to be effective in bacterial load reduction in peri implantitis and has a positive potential as an alternative therapy for peri implantitis. PMID- 29420848 TI - Why do children with severe bronchopulmonary dysplasia not attend neonatal follow up care? Parental views of barriers. AB - AIM: To assess in children with severe bronchopulmonary dysplasia at a corrected age of 18-36 months: (i) Neonatal follow-up clinic attendance rates; (ii) Parent identified reasons for difficulty attending neonatal follow-up. METHODS: Mixed methods study utilising semi-structured phone interviews with parents of infants eligible for follow-up with severe bronchopulmonary dysplasia (defined as gestational age <32 weeks and requiring >=30% FiO2 and/or >2 L nasal cannula at 36 weeks post-menstrual age) at 18-36 months corrected age. Questions addressed barriers to neonatal follow-up attendance. Enrolment continued to saturation (no new themes emerging). RESULTS: A total of 58 infants (69% male) were enrolled. Infants were 26 +/- 2.1 weeks gestational age and birth weight 794 +/- 262 g. At 28 +/- 5.8 months corrected age, 26% had never attended neonatal follow-up clinic, 16% stopped attending before discharge, 5% were discharged, and 53% were still followed. Longer travel distance from home to follow-up clinic was associated with poorer attendance. Parent-generated items related to neonatal follow-up barriers were coded into four themes: Logistics, Time, Perceptions and Emotional Stress. CONCLUSION: Despite high risk of developmental delay in infants with severe bronchopulmonary dysplasia, neonatal follow-up rates are suboptimal. Careful review of parent-identified barriers could be utilised to develop targeted strategies to improve neonatal follow-up attendance in this high-risk population. PMID- 29420849 TI - Expression of microRNA-155 in inflammatory cells modulates liver injury. AB - : MicroRNA 155 (miR-155) is involved in immune and inflammatory diseases and is associated with liver fibrosis and steatohepatitis. However, the mechanisms involved in miR-155 regulation of liver injury are largely unknown. The role of miR-155 in acute liver injury was assessed in wild-type (WT), miR-155-/- , and miR-155-/- mice transplanted with WT bone marrow. Additionally, miR-155 expression was evaluated in liver tissue and peripheral blood mononuclear cells of patients with autoimmune hepatitis. Concanavalin A, but not acetaminophen, treatment increased the expression of miR-155 in liver tissue of WT mice. Concanavalin A induced increases in cell death, liver aminotransferases, and expression of proinflammatory cytokines (chemokine [C-X-C motif] ligands 1, 5, 9, 10, and 11; chemokine [C-C motif] ligands 2 and 20; and intercellular cell adhesion molecule 1) in miR-155-/- compared to WT mice. Importantly, these animals showed a significant decrease in cluster of differentiation 4 positive/chemokine (C-X-C motif) receptor 3-positive and forkhead box p3-positive cell recruitment but no changes in other inflammatory cell populations. Mechanistically, miR-155-deficient regulatory T cells showed increased SH2 domain containing inositol 5-phosphatase 1 expression, a known target of miR-155. Inhibition of SH2 domain-containing inositol 5-phosphatase 1 in miR-155-/- mice restored forkhead box p3 recruitment and reduced liver cytokine expression. Transplantation of bone marrow from WT animals into miR-155-/- mice partially reversed the effect of concanavalin A on miR-155-/- mice as assessed by proinflammatory cytokines and cell death protein expression. Patients with autoimmune hepatitis showed a marked increase in miR-155 expression in the liver but reduced expression of miR-155 in peripheral blood mononuclear cells. CONCLUSION: miR-155 expression is altered in both liver tissue and circulating inflammatory cells during liver injury, thus regulating inflammatory cell recruitment and liver damage; these results suggest that maintaining miR-155 expression in inflammatory cells might be a potential strategy to modulate liver injury. (Hepatology 2018). PMID- 29420850 TI - Chitotriosidase inhibits allergic asthmatic airways via regulation of TGF-beta expression and Foxp3+ Treg cells. AB - BACKGROUND: Chitotriosidase (chitinase 1, Chit1), a major true chitinase in humans, is induced in childhood asthma and has been implicated in the pathogenesis of a variety of inflammatory and tissue remodeling responses. However, the role and the mechanisms that underlie these contributions to the diseases have not been defined. We hypothesized that Chit1 plays a significant role in the pathogenesis of allergic asthma. METHODS: Wild-type and Chit1 deficient mice and cells in culture were used to define the roles of Chit1 in models of allergic adaptive Th2 inflammation. In addition, the levels of sputum Chit1 were evaluated in pediatric asthma patients and compared to control. RESULTS: The levels of sputum Chit1 were significantly increased in the patients with childhood asthma. Mice with Chit1 null mutation demonstrated enhanced allergic Th2 inflammatory and cytokine and IgE responses to OVA or house dust mite allergen sensitization and challenge. However, the expression levels of TGF beta1 were significantly decreased with a diminished number of Foxp3+ regulatory T cells (Treg) in the lungs of Chit1-/- mice compared to WT controls. In vitro, the absence of Chit1 significantly reduced TGF-beta-stimulated conversion of CD4+ CD25- naive T cells to CD4+ Foxp3+ Treg cells, suggesting Chit1 is required for optimal effect of TGF-beta1 in Treg cell differentiation. CONCLUSION: Chit1 plays a protective role in the pathogenesis of allergic inflammation and asthmatic airway responses via regulation of TGF-beta expression and Foxp3+ Treg cells. PMID- 29420851 TI - Analysis of the reliability of the Italian version of the Oral Behaviours Checklist and the relationship between oral behaviours and trait anxiety in healthy individuals. AB - BACKGROUND: The Oral Behaviours Checklist (OBC) is a valid 21-item instrument quantifying the self-reported frequency of oral behaviours. An Italian version (OBC-It) has been released recently. Anxiety and oral behaviours are known to be associated in individuals with oro-facial pain due to temporomandibular disorders (TMD). However, information about this relationship in pain-free individuals is still limited. OBJECTIVES: The aim of this study was to test the reliability of the OBC-It and its reduced version (OBC-It 6), focusing on tooth clenching related wake-time oral behaviours, and the effect of patient instructions on reliability. A second aim was to test the association between trait anxiety and oral behaviours in pain-free individuals. METHODS: Two hundred and eighty-two TMD free students, divided into 2 groups (Group A, n = 139, mean age +/- SD = 22.6 +/ 5.4 years; Group B, n = 143, 23.7 +/- 4.2 years), filled in the State-Trait Anxiety Inventory and the OBC-It. Group B received instructions about the OBC-It, while Group A did not. After 2 weeks, both groups filled in the OBC-It again. However, Group B was further divided into 2 subgroups, B1 and B2 . The first received the same instructions again, while B2 did not. RESULTS: The test-retest reliability of the OBC-It (A: ICC = .87; B1 : ICC = .94; B2 : ICC = .95) and OBC It 6 (A: ICC = .85; B1 : ICC = .89; B2 : ICC = .93) was excellent in all groups. Trait anxiety was weakly associated with OBC-It only in women (R2 = .043, P = .021). CONCLUSIONS: The OBC-It is a reliable tool but further subjects' instructions might be needed. Trait anxiety has a limited effect on oral behaviours in TMD-free subjects. PMID- 29420852 TI - Seascape genomics reveals adaptive divergence in a connected and commercially important mollusc, the greenlip abalone (Haliotis laevigata), along a longitudinal environmental gradient. AB - Populations of broadcast spawning marine organisms often have large sizes and are exposed to reduced genetic drift. Under such scenarios, strong selection associated with spatial environmental heterogeneity is expected to drive localized adaptive divergence, even in the face of connectivity. We tested this hypothesis using a seascape genomics approach in the commercially important greenlip abalone (Haliotis laevigata). We assessed how its population structure has been influenced by environmental heterogeneity along a zonal coastal boundary in southern Australia linked by strong oceanographic connectivity. Our data sets include 9,109 filtered SNPs for 371 abalones from 13 localities and environmental mapping across ~800 km. Genotype-environment association analyses and outlier tests defined 8,786 putatively neutral and 323 candidate adaptive loci. From a neutral perspective, the species is better represented by a metapopulation with very low differentiation (global FST = 0.0081) and weak isolation by distance following a stepping-stone model. For the candidate adaptive loci, however, model based and model-free approaches indicated five divergent population clusters. After controlling for spatial distance, the distribution of putatively adaptive variation was strongly correlated to selection linked to minimum sea surface temperature and oxygen concentration. Around 80 candidates were annotated to genes with functions related to high temperature and/or low oxygen tolerance, including genes that influence the resilience of abalone species found in other biogeographic regions. Our study includes a documented example about the uptake of genomic information in fisheries management and supports the hypothesis of adaptive divergence due to coastal environmental heterogeneity in a connected metapopulation of a broadcast spawner. PMID- 29420853 TI - Updates on resources, software tools, and databases for plant proteomics in 2016 2017. AB - Proteomics data processing, annotation, and analysis can often lead to major hurdles in large-scale high-throughput bottom-up proteomics experiments. Given the recent rise in protein-based big datasets being generated, efforts in in silico tool development occurrences have had an unprecedented increase; so much so, that it has become increasingly difficult to keep track of all the advances in a particular academic year. However, these tools benefit the plant proteomics community in circumventing critical issues in data analysis and visualization, as these continually developing open-source and community-developed tools hold potential in future research efforts. This review will aim to introduce and summarize more than 50 software tools, databases, and resources developed and published during 2016-2017 under the following categories: tools for data pre processing and analysis, statistical analysis tools, peptide identification tools, databases and spectral libraries, and data visualization and interpretation tools. Intended for a well-informed proteomics community, finally, efforts in data archiving and validation datasets for the community will be discussed as well. Additionally, the author delineates the current and most commonly used proteomics tools in order to introduce novice readers to this omics discovery platform. PMID- 29420854 TI - Transgastric endoscopic submucosal dissection of esophageal cancer with cervical stricture. PMID- 29420855 TI - A laser desorption ionization/matrix-assisted laser desorption ionization target system applicable for three distinct types of instruments (LinTOF/curved field RTOF, LinTOF/RTOF and QqRTOF) with different performance characteristics from three vendors. AB - RATIONALE: We have developed a target system which enables the use of only one target (i.e. target preparation set) for three different laser desorption ionization (LDI)/matrix-assisted laser desorption ionization (MALDI) mass spectrometric instruments. The focus was on analysing small biomolecules with LDI for future use of the system for the study of meteorite samples (carbonaceous chondrites) using devices with different mass spectrometric performance characteristics. METHODS: Three compounds were selected due to their potential presence in meteoritic chondrites: tryptophan, 2-deoxy-d-ribose and triphenylene. They were prepared (with and without MALDI matrix, i.e. MALDI and LDI) and analysed with three different mass spectrometers (LinTOF/curved field RTOF, LinTOF/RTOF and QqRTOF). The ion sources of two of the instruments were run at high vacuum, and one at intermediate pressure. Two devices used a laser wavelength of 355 nm and one a wavelength of 337 nm. RESULTS: The developed target system operated smoothly with all devices. Tryptophan, 2-deoxy-d-ribose and triphenylene showed similar desorption/ionization behaviour for all instruments using the LDI mode. Interestingly, protonated tryptophan could be observed only with the LinTOF/curved field RTOF device in LDI and MALDI mode, while sodiated molecules were observed with all three instruments (in both ion modes). Deprotonated tryptophan was almost completely obscured by matrix ions in the MALDI mode whereas LDI yielded abundant deprotonated molecules. CONCLUSIONS: The presented target system allowed successful analyses of the three compounds using instruments from different vendors with only one preparation showing different analyser performance characteristics. The elemental composition with the QqRTOF analyser and the high-energy 20 keV collision-induced dissociation fragmentation will be important in identifying unknown compounds in chondrites. PMID- 29420856 TI - Antimicrobial Photodynamic Therapy as a Co-adjuvant in Endodontic Treatment of Deciduous Teeth: Case Series. AB - To assure the success of endodontic treatment, the root canal must be completely decontaminated. Thus, some methods have been researched in an attempt to effectively eliminate microorganisms from the interior of the root canal system. Among them is conventional endodontic therapy in conjunction with photodynamic therapy (PDT). Five anterior deciduous teeth were treated endodontically with the conventional technique and PDT. For PDT, 0.005% methylene blue was used as a photosensitizer and a 660 nm laser. After the conventional endodontic therapy, the photosensitizer was applied inside the root canal, 3 min of pre-irradiation time, and then, the laser was applied for 40s with an energy of 4J. Afterward, the canal was irrigated with saline solution and the sealing material of the root canal was placed. The microbiological analysis of the samples was collected before and after the treatments were performed. Observing the results obtained in this case series, which showed a bacterial reduction from 37.57% to 100%, and the clear difficulty in the success of endodontic treatment of deciduous teeth, antimicrobial photodynamic therapy can be considered an alternative of easy application that does not generate microbial resistance, to act as a support in the decontamination of the root canals. PMID- 29420857 TI - Nature-oriented daycare diversifies skin microbiota in children-No robust association with allergies. PMID- 29420858 TI - Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice. AB - : Liver sinusoidal endothelial cells (LSECs) critically regulate liver homeostasis and diseases through angiocrine factors. Notch is critical in endothelial cells (ECs). In the current study, Notch signaling was activated by inducible EC-specific expression of the Notch intracellular domain (NIC). We found that endothelial Notch activation damaged liver homeostasis. Notch activation resulted in decreased fenestration and increased basement membrane, and a gene expression profile with decreased LSEC-associated genes and increased continuous EC-associated genes, suggesting LSEC dedifferentiation. Consistently, endothelial Notch activation enhanced hepatic fibrosis (HF) induced by CCl4 . Notch activation attenuated endothelial nitric oxide synthase (eNOS)/soluble guanylate cyclase (sGC) signaling, and activation of sGC by 3-(5'-hydroxymethyl 2'-furyl)-1-benzylindazole (YC-1) reversed the dedifferentiation phenotype. In addition, Notch activation subverted the hepatocyte-supporting angiocrine profile of LSECs by down-regulating critical hepatocyte mitogens, including Wnt2a, Wnt9b, and hepatocyte growth factor (HGF). This led to compromised hepatocyte proliferation under both quiescent and regenerating conditions. Whereas expression of Wnt2a and Wnt9b was dependent on eNOS-sGC signaling, HGF expression was not rescued by the sGC activator, suggesting heterogeneous mechanisms of LSECs to maintain hepatocyte homeostasis. CONCLUSION: Endothelial Notch activation results in LSEC dedifferentiation and accelerated liver fibrogenesis through eNOS-sGC signaling, and alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration (LR). (Hepatology 2018). PMID- 29420860 TI - Flickers of speciation: Sympatric colour morphs of the arc-eye hawkfish, Paracirrhites arcatus, reveal key elements of divergence with gene flow. AB - One of the primary challenges of evolutionary research is to identify ecological factors that favour reproductive isolation. Therefore, studying partially isolated taxa has the potential to provide novel insight into the mechanisms of evolutionary divergence. Our study utilizes an adaptive colour polymorphism in the arc-eye hawkfish (Paracirrhites arcatus) to explore the evolution of reproductive barriers in the absence of geographic isolation. Dark and light morphs are ecologically partitioned into basaltic and coral microhabitats a few metres apart. To test whether ecological barriers have reduced gene flow among dark and light phenotypes, we evaluated genetic variation at 30 microsatellite loci and a nuclear exon (Mc1r) associated with melanistic coloration. We report low, but significant microsatellite differentiation among colour morphs and stronger divergence in the coding region of Mc1r indicating signatures of selection. Critically, we observed greater genetic divergence between colour morphs on the same reefs than that between the same morphs in different geographic locations. We hypothesize that adaptation to the contrasting microhabitats is overriding gene flow and is responsible for the partial reproductive isolation observed between sympatric colour morphs. Combined with complementary studies of hawkfish ecology and behaviour, these genetic results indicate an ecological barrier to gene flow initiated by habitat selection and enhanced by assortative mating. Hence, the arc-eye hawkfish fulfil theoretical expectations for the earliest phase of speciation with gene flow. PMID- 29420859 TI - Amygdala-stimulation-induced apnea is attention and nasal-breathing dependent. AB - OBJECTIVE: Evidence suggests that disordered breathing is critically involved in Sudden Unexpected Death in Epilepsy (SUDEP). To that end, evaluating structures that are activated by seizures and can activate brain regions that produce cardiorespiratory changes can further our understanding of the pathophysiology of SUDEP. Past preclinical studies have shown that electrical stimulation of the human amygdala induces apnea, suggesting a role for the amygdala in controlling respiration. In this study, we aimed to both confirm these findings in a larger group of patients with intractable temporal lobe epilepsy (TLE) and also further explore the anatomical and cognitive properties of this effect. METHODS: Seven surgical TLE patients had depth electrodes implanted in the amygdala that were used to deliver electrical stimulation during functional mapping preceding resection. Real-time respiratory monitoring was performed in each patient to confirm apnea. RESULTS: Our data confirm that amygdala stimulation reliably induces apnea (occurring in all 7 patients) and further suggest that apnea can be overcome by instructing the patient to inhale, and can be prevented entirely by breathing through the mouth before electrical stimulation. Finally, stimulation induced apnea occurred only when stimulating the medial-most amygdalar contacts located in the central nucleus. INTERPRETATION: These findings confirm a functional connection between the amygdala and respiratory control in humans. Moreover, they suggest specific amygdalar nuclei may be critical in mediating this effect and that attentional state is critical to apnea mediated by amygdala activation-perhaps alluding to future development of strategies for the prevention of SUDEP. Ann Neurol 2018;83:460-471. PMID- 29420861 TI - Do subjects with minimal motor features have prodromal Parkinson disease? AB - OBJECTIVE: Understanding the pathological changes underlying mild motor features of the eldery and defining a patient population with prodromal Parkinson disease (PD) are of great clinical importance. It remains unclear, however, how to accurately and specifically diagnose prodromal PD. We examined whether older adults with minimal parkinsonian motor features have nigrostriatal degeneration and alpha-synuclein pathology consistent with prodromal PD. METHODS: Brain sections were obtained from older adults with a clinical diagnosis of PD (n = 21) and without a clinical diagnosis of PD (n = 27) who underwent motor examination proximate to death. Cases without PD were further dichotomized into no motor deficit (n = 9) or minimal motor features (n = 18) groups using a modified Unified Parkinson's Disease Rating Scale. We performed quantitative unbiased stereological analyses of dopaminergic neurons/terminals and alpha-synuclein accumulation in the nigrostriatal system. RESULTS: In all subjects with minimal motor features, there were significant reductions in dopaminergic neurons and terminals in the substantia nigra and putamen that were intermediate between subjects with no motor deficit and PD. Phosphorylated alpha-synuclein inclusions were observed in the substantia nigra that were of similar density to what was seen in PD. Furthermore, there was greater Lewy neuritic pathology in the putamen relative to PD patients. Lastly, neurons with alpha-synuclein inclusions displayed reductions in tyrosine hydroxylase expression that were comparable in subjects with both minimal motor features and PD. INTERPRETATION: Minimal motor features in older adults may represent prodromal PD and identify at-risk individuals for testing putative neuroprotective interventions that could slow or prevent PD progression. Ann Neurol 2018;83:562-574. PMID- 29420862 TI - Palladium-Catalyzed Reductive Insertion of Alcohols into Aryl Ether Bonds. AB - Palladium on carbon catalyzes C-O bond cleavage of aryl ethers (diphenyl ether and cyclohexyl phenyl ether) by alcohols (R-OH) in H2 . The aromatic C-O bond is cleaved by reductive solvolysis, which is initiated by Pd-catalyzed partial hydrogenation of one phenyl ring to form an enol ether. The enol ether reacts rapidly with alcohols to form a ketal, which generates 1-cyclohexenyl-O-R by eliminating phenol or an alkanol. Subsequent hydrogenation leads to cyclohexyl-O R. PMID- 29420863 TI - Functional biogeography and host specificity of bacterial communities associated with the Marine Green Alga Ulva spp. AB - Bacterial communities play an essential role for the function of marine macroalgae. Recent work has shown that bacterial communities associated with individual macroalgae possess on a local scale a functional core that is likely derived from diverse members of functional guilds. It is not known whether such functional cores also exist across large spatial scales or between closely related host species. To address this, we studied here the bacterial communities on three species of the green macroalgal genus Ulva from different geographic locations. While the taxonomic composition was too variable to describe a community core, we identified genes that were enriched across all Ulva samples as compared to the communities of the surrounding seawater. Of these core functions, 70% were consistently found and independent of the Ulva species and biogeography, while the remaining functions (~30%) are possibly involved in local or host specific adaptations. For each host individual, the core functions are provided by bacteria with distinct phylogenetic origin and these bacteria could constitute a global guild of Ulva-associated bacteria. Together, our results demonstrate the presence of a stable core set of functional genes in the bacterial communities associated with closely related host species and across large biogeographies. PMID- 29420864 TI - Preparation of Tetradentate Copper Chelators as Potential Anti-Alzheimer Agents. AB - The uncontrolled redox activity of metal ions, especially copper, in the brains of patients with Alzheimer's disease (AD) should be considered the origin of intense oxidative damage to neurons in the AD brain. To obtain low-molecular weight copper chelators that act as tetradentate ligands, we designed new compounds based on an 8-aminoquinoline motif with a lateral chain attached at the 2-position of the aromatic ring. Some of these new ligands, termed TDMQ for TetraDentate MonoQuinolines, are specific for copper chelation. Full characterization of these ligands is reported, as well as their affinities for CuII , and their capacities to inhibit oxidative stress induced by copper amyloids activated by a reductant. Such metal ligands can be considered as potential anti-AD agents, as they should be able to regulate the homeostasis of copper in brain tissue. PMID- 29420865 TI - A novel approach to wildlife transcriptomics provides evidence of disease mediated differential expression and changes to the microbiome of amphibian populations. AB - Ranaviruses are responsible for a lethal, emerging infectious disease in amphibians and threaten their populations throughout the world. Despite this, little is known about how amphibian populations respond to ranaviral infection. In the United Kingdom, ranaviruses impact the common frog (Rana temporaria). Extensive public engagement in the study of ranaviruses in the UK has led to the formation of a unique system of field sites containing frog populations of known ranaviral disease history. Within this unique natural field system, we used RNA sequencing (RNA-Seq) to compare the gene expression profiles of R. temporaria populations with a history of ranaviral disease and those without. We have applied a RNA read-filtering protocol that incorporates Bloom filters, previously used in clinical settings, to limit the potential for contamination that comes with the use of RNA-Seq in nonlaboratory systems. We have identified a suite of 407 transcripts that are differentially expressed between populations of different ranaviral disease history. This suite contains genes with functions related to immunity, development, protein transport and olfactory reception among others. A large proportion of potential noncoding RNA transcripts present in our differentially expressed set provide first evidence of a possible role for long noncoding RNA (lncRNA) in amphibian response to viruses. Our read-filtering approach also removed significantly more bacterial reads from libraries generated from positive disease history populations. Subsequent analysis revealed these bacterial read sets to represent distinct communities of bacterial species, which is suggestive of an interaction between ranavirus and the host microbiome in the wild. PMID- 29420866 TI - A Miniaturized Escherichia coli Green Light Sensor with High Dynamic Range. AB - Genetically engineered photoreceptors enable unrivaled control over gene expression. Previously, we ported the Synechocystis PCC 6803 CcaSR two-component system, which is activated by green light and deactivated by red, into Escherichia coli, resulting in a sensor with a sixfold dynamic range. Later, we optimized pathway protein expression levels and the output promoter sequence to decrease transcriptional leakiness and to increase the dynamic range to approximately 120-fold. These CcaSR v 1.0 and v 2.0 systems have been used for precise quantitative, temporal, and spatial control of gene expression for a variety of applications. Recently, other workers deleted two PAS domains of unknown function from the CcaS sensor histidine kinase in a system similar to CcaSR v 1.0. Here we apply these deletions to CcaSR v 2.0, resulting in a v 3.0 light sensor with an output four times less leaky and a dynamic range of nearly 600-fold. We demonstrate that the PAS domain deletions have no deleterious effect on CcaSR green light sensitivity or response dynamics. CcaSR v 3.0 is the best performing engineered bacterial green light sensor available, and should have broad applications in fundamental and synthetic biology studies. PMID- 29420867 TI - Applying network theory to animal movements to identify properties of landscape space use. AB - Network (graph) theory is a popular analytical framework to characterize the structure and dynamics among discrete objects and is particularly effective at identifying critical hubs and patterns of connectivity. The identification of such attributes is a fundamental objective of animal movement research, yet network theory has rarely been applied directly to animal relocation data. We develop an approach that allows the analysis of movement data using network theory by defining occupied pixels as nodes and connection among these pixels as edges. We first quantify node-level (local) metrics and graph-level (system) metrics on simulated movement trajectories to assess the ability of these metrics to pull out known properties in movement paths. We then apply our framework to empirical data from African elephants (Loxodonta africana), giant Galapagos tortoises (Chelonoidis spp.), and mule deer (Odocoileous hemionus). Our results indicate that certain node-level metrics, namely degree, weight, and betweenness, perform well in capturing local patterns of space use, such as the definition of core areas and paths used for inter-patch movement. These metrics were generally applicable across data sets, indicating their robustness to assumptions structuring analysis or strategies of movement. Other metrics capture local patterns effectively, but were sensitive to specified graph properties, indicating case specific applications. Our analysis indicates that graph-level metrics are unlikely to outperform other approaches for the categorization of general movement strategies (central place foraging, migration, nomadism). By identifying critical nodes, our approach provides a robust quantitative framework to identify local properties of space use that can be used to evaluate the effect of the loss of specific nodes on range wide connectivity. Our network approach is intuitive, and can be implemented across imperfectly sampled or large-scale data sets efficiently, providing a framework for conservationists to analyze movement data. Functions created for the analyses are available within the R package moveNT. PMID- 29420868 TI - Pharmacokinetics and Safety of Risperidone Subcutaneous Implants in Stable Patients With Schizophrenia. AB - A subcutaneous risperidone implant (RI) formulation was developed to improve medication adherence in schizophrenia. Two phase 1 studies were conducted to evaluate the pharmacokinetics of RI in adult patients with schizophrenia. In study 1, all subjects were stable on 4 mg oral risperidone; subsequently, the first subject received 375 mg RI for 1 month, and the remaining subjects received 375 mg RI for 3 months. In study 2, all subjects were stable on oral risperidone 4 mg, 6 mg, or 8 mg and subsequently received RI 480 mg, 720 mg, or 960 mg, respectively, for 6 months. Blood samples were collected at prespecified time points. Various pharmacokinetic parameters were determined in both studies. In both studies risperidone total active moiety plasma concentrations following RI increased slowly, reached therapeutic levels within approximately 2 days, and remained relatively stable. In study 1, the average concentration for RI was 81.3% of the oral trough concentration and 27.5% of the oral peak concentration. In study 2, the steady-state concentration for RI was comparable to the oral trough concentration of the corresponding dose. Patient disease status remained stable with no major safety issues. RI may represent an alternative formulation for schizophrenia treatment with a lower peak-to-trough plasma drug ratio than oral risperidone. PMID- 29420869 TI - Vulnerability of the Great Barrier Reef to climate change and local pressures. AB - Australia's Great Barrier Reef (GBR) is under pressure from a suite of stressors including cyclones, crown-of-thorns starfish (COTS), nutrients from river run-off and warming events that drive mass coral bleaching. Two key questions are: how vulnerable will the GBR be to future environmental scenarios, and to what extent can local management actions lower vulnerability in the face of climate change? To address these questions, we use a simple empirical and mechanistic coral model to explore six scenarios that represent plausible combinations of climate change projections (from four Representative Concentration Pathways, RCPs), cyclones and local stressors. Projections (2017-2050) indicate significant potential for coral recovery in the near-term, relative to current state, followed by climate-driven decline. Under a scenario of unmitigated emissions (RCP8.5) and business-as-usual management of local stressors, mean coral cover on the GBR is predicted to recover over the next decade and then rapidly decline to only 3% by year 2050. In contrast, a scenario of strong carbon mitigation (RCP2.6) and improved water quality, predicts significant coral recovery over the next two decades, followed by a relatively modest climate-driven decline that sustained coral cover above 26% by 2050. In an analysis of the impacts of cumulative stressors on coral cover relative to potential coral cover in the absence of such impacts, we found that GBR-wide reef performance will decline 27%-74% depending on the scenario. Up to 66% of performance loss is attributable to local stressors. The potential for management to reduce vulnerability, measured here as the mean number of years coral cover can be kept above 30%, is spatially variable. Management strategies that alleviate cumulative impacts have the potential to reduce the vulnerability of some midshelf reefs in the central GBR by 83%, but only if combined with strong mitigation of carbon emissions. PMID- 29420870 TI - Application of sunflower stalk-carbon nitride nanosheets as a green sorbent in the solid-phase extraction of polycyclic aromatic hydrocarbons followed by high performance liquid chromatography. AB - A green biocomposite of sunflower stalks and graphitic carbon nitride nanosheets has been applied as a solid-phase extraction adsorbent for sample preparation of five polycyclic aromatic hydrocarbons in different solutions using high performance liquid chromatography with ultraviolet detection. Before the modification, sunflower stalks exhibited relatively low adsorption to the polycyclic aromatic hydrocarbons extraction. The modified sunflower stalks showed increased adsorption to the analytes extraction due to the increase in surface and existence of a pi-pi interaction between the analytes and graphitic carbon nitride nanosheets on the surface. Under the optimal conditions, the limits of detection and quantification for five polycyclic aromatic hydrocarbons compounds could reach 0.4-32 and 1.2-95 ng/L, respectively. The method accuracy was evaluated using recovery measurements in spiked real samples and good recoveries from 71 to 115% with relative standard deviations of <10% have been achieved. The developed method was successfully applied for polycyclic aromatic hydrocarbons determination in various samples-well water, tap water, soil, vegetable, and barbequed meat (kebab)-with analytes contents ranging from 0.065 to 13.3 MUg/L. The prepared green composite as a new sorbent has some advantages including ease of preparation, low cost, and good reusability. PMID- 29420871 TI - The in vitro activity of selected mouthrinses on standard strains of fungi AB - An oral cavity hygiene plays a key role in prophylactic and therapeutic measures to prevent pathological changes caused by different viruses, bacteria, fungi and protozoa. It is important to maintain proper oral hygiene and assist the removal of potent pathogens; use of the mouthrinses can be one of method providing to these goal. The purpose of this study was to investigate the effects of selected mouthrinses on the standard strains of Candida presented in the oral cavity. Eight reference strains of fungi were investigated: C. albicans (CBS 2312), C. albicans (L 45), C. albicans (ATCC 24433), C. dubliniensis (CBS 7987), C. glabrata (CBS 862), C. krusei (CBS 573), C. parapsilosis (CBS 10947) and C. tropicalis (CBS 2424). Thirteen mouthrinses were used in the study, including pure chlorhexidine (CHX), and 12 commercially available varieties: Azulan, Colgate Plax Complete Care Sensitive, Corsodyl 0,2%, Curasept ADS 205, Dentosept, Dentosept A, Eludril Classic, Listerine Total care, Octenidol, Oral-B Pro-Expert Clinic Line, Sylveco and Tinctura salviae. The present study used a qualitative diffusion in agar gel-well plate method to evaluated the antifungal properties of mouthrinses. Among the 12 commercially available mouthrinses examined in the study, the following were not found to show antifungal activity: Azulan, Dentosept, Eludril Classic, Listerine Total care, Tinctura salviae. The largest inhibition zones were produced by Dentosept, Chlorhexidine and Colgate. The smallestinhibition zones were produced by Octenidol and Curasept. With regard to mouthwash type, statistically significant differences in growth inhibition zone diameter were found between the following pairs of fungi: C. albicans and C. krusei for Colgate without dilution and with 1:2 dilution; C. albicans and C. glabrata for Corsodryl without dilution and with 1:2 dilution; C. albicans and C. dubliniensis for Dentosept A without dilution; C. glabrata and C. parapsilosis with 1:2 dilution; C. dubliniensis and C. tropicalis for Sylveco without dilution, 1:2 dilution and 1:4 dilution; C. dubliniensis and C. parapsilosis for Sylveco without dilution, 1:2 dilution and 1:4 dilution. The lowest MIC values calculated from the Iinear regression equation, indicating the strongest potential activity, were obtained for Dentosept A, followed by chlorhexidine; the lowest activity, was calculated for Curasept and for Octenidol. Some of the tested mouthrinses have antimycotic properties at commercially available concentrations. In spite of the fact that chlorhexidine is thought to be the gold standard for mouthrinse use, Dentosept has stronger antimycotic activity and acts on a wider spectrum of fungi species. Chlorhexidine and Colgate do not appear to act against C. tropicalis, neither does Curaspet against C.dubliniensis; therefore, the determination of the fungus species is necessary. PMID- 29420872 TI - In vivo confocal microscopy and in vitro culture techniques as tools for evaluation of severe Acanthamoeba keratitis incidents AB - Amphizoic amoebae belonging to the genus Acanthamoeba are known as etiological agents of sight-threatening Acanthamoeba keratitis. The leading risk factor for the development of this serious human disease is contact lens wearing which popularity increases worldwide, also in Poland. The disease with active epithelial inflammations, corneal ulcers, including loss of the visual acuity is a serious medical problem as an emerging threat for the public health related to improper contact lens hygiene. The treatment of the amoebic keratitis is difficult, often unsuccessful due to delayed proper diagnosis. The clinical picture of the disease, often with severe course is nonspecific, similar to that occurring in viral, fungal or bacterial keratitis, thus clinical symptoms alone are not sufficient to identify the causative agent of the amoebic infection. Early diagnosis is decisive for the suitable therapeutic management and the treatment efficacy. In our studies, several complicated, difficult to treat Acanthamoeba keratitis incidences pertaining Polish patients using contact lenses have been retrospectively analyzed in terms of the usefulness of non-invasive methods of in vivo confocal microscopy and in vitro culture techniques applied for diagnosis. Hyper-reflective double-walled spherical Acanthamoeba cysts, with a more reflective outer wall were detected in the epithelium and anterior layers of the corneal stroma. In vivo confocal microscopy, if available, may be a valuable, sensitive tool for diagnosis in late identified severe infections mainly with strong viability strains, however confoscan may offer limited value at lowintensity amoebic infections. The microscopic visualization of amoebae in slides prepared directly from corneal scraping and laboratory examinations of specimens from in vitro cultivated corneal isolates allow to confirm or verify results of in vivo examinations, furthermore to identify directly the pathogens and to clarify previous misdiagnoses. PMID- 29420873 TI - Pathomorphology of the brain in the acute form of African swine fever AB - The brains of 10 infected pigs were examined for histopathology and presence of African swine fever virus (ASFV) DNA ASFV infection induces inflamed meninges, cerebral edema and vascular thrombosis, as well as subdural hematomas. Slight tension in the dura mater, flattening of the gyri and narrowing of the sulci were also observed at four days post infection (dpi). Enlarged perivascular spaces were detected for most vessels of the brain after three to four dpi. Considerable lymphocytic infiltration of the brain tissue was observed at the terminal stage of disease. ASFV was present in all investigated areas of brain beginning from three to four dpi. The isolated virus do not differ from the used in present study Georgia 2007 strain. PMID- 29420874 TI - Occurrence of ticks (Parasitiformes, Ixodida, Amblyommidae) on the skin of African buffalo Syncerus caffer (Sparrman, 1779) (Mammalia, Artiodactyla) originating from an area of the Republic of South Africa AB - Most ticks of the genus Amblyomma and Rhipicephalus are typical ectoparasites of bovine. However, information about survival in different environmental conditions or coexistence of different species is lacking. Amblyomma hebraeum Koch, 1844, Rhipicephalus appendiculatus Neumann, 1901 and R. maculatus Neumann, 1901 were found in the skin (fixed in the salt) of an African buffalo Syncerus caffer (Sparrman, 1779), brought to Poland from the Republic of South Africa. Most of the ticks were still alive during their collection. PMID- 29420876 TI - Lord Ernest Jackson Lawson Soulsby (1926-2017) - pro memoria PMID- 29420875 TI - An uncommon manifestation of a common disease AB - Neurocysticercosis is the common parasitic disease of the central nervous system. One of the uncommon manifestations and a rare complication is its disseminated form. Human cysticercosis is caused by the spreading of the embryo of Taenia solium in the intestine via the hepatoportal system to different tissues and internal organs of the body. The organs most commonly affected are the subcutaneous tissue, skeletal muscles, lungs, brain, eyes, liver, and occasionally the heart, thyroid, and pancreas. We report a case of a 62 year old male, who has been presented, with seizures and subcutaneous nodules on both extremities. After investigation he was diagnosed as a case of disseminated cysticercosis involving brain, subcutaneous tissue, liver, muscles and pericardial fat. PMID- 29420877 TI - Functional Dual-Color Indicator To Achieve in Situ Visualization of Intracellular Glycosylation. AB - A functional dual-color indicator is designed for in situ visualization of intracellular glycosylation. Using O-GlcNAcylation as model, the indicator is constructed on a poly-GlcNAc-coated gold nanoparticle (AuNP) by assembling dye labeled lectin (FSWGA) and then another dye-labeled GlcNAc (FGlcNAc) through the two opposite subunits of FSWGA. These dyes possess negligible overlapping emission and can be quenched by AuNP. In the presence of intracellular dissociated GlcNAc residue and O-GlcNAcylated proteins, the assembled FGlcNAc and the conjugate of FSWGA with FGlcNAc are released from AuNP through the dynamic competitive conjugation, which lights up the fluorescence of two dyes, respectively, and provides a simple technique for simultaneously monitoring the level of O-GlcNAcylated proteins and the total amount of GlcNAc groups in living cells. The practicality of the protocol for visually monitoring the biological pathway between intracellular O-GlcNAcylation and cell surface differentiation related proteins demonstrates a convenient and powerful tool for research of glycosylation equilibrium and related biological processes. PMID- 29420878 TI - Can Two-Dimensional IR-ECD Mass Spectrometry Improve Peptide de Novo Sequencing? AB - Two-dimensional mass spectrometry (2D MS) correlates precursor and fragment ions without ion isolation in a Fourier transform ion cyclotron resonance mass spectrometer (FTICR MS) for tandem mass spectrometry. Infrared activated electron capture dissociation (IR-ECD), using a hollow cathode configuration, generally yields more information for peptide sequencing in tandem mass spectrometry than ECD (electron capture dissociation) alone. The effects of the fragmentation zone on the 2D mass spectrum are investigated as well as the structural information that can be derived from it. The enhanced structural information gathered from the 2D mass spectrum is discussed in terms of how de novo peptide sequencing can be performed with increased confidence. 2D IR-ECD MS is shown to sequence peptides, to distinguish between leucine and isoleucine residues through the production of w ions as well as between C-terminal ( b/ c) and N-terminal ( y/ z) fragments through the use of higher harmonics, and to assign and locate peptide modifications. PMID- 29420879 TI - From Noncovalent Chalcogen-Chalcogen Interactions to Supramolecular Aggregates: Experiments and Calculations. AB - This review considers noncovalent bonds between divalent chalcogen centers. In the first part we present X-ray data taken from the solid state structures of dimethyl- and diphenyl-dichalcogenides as well as oligoalkynes kept by alkyl sulfur, -selenium, and -tellurium groups. Furthermore, we analyzed the solid state structures of medium sized (12-24 ring size) selenium coronands and medium to large rings with alkyne and alkene units between two chalcogen centers. The crystal structures of the cyclic structures revealed columnar stacks with close contacts between neighboring rings via noncovalent interactions between the chalcogen centers. To get larger space within the cavities, rings with diyne units between the chalcogen centers were used. These molecules showed channel like structures in the solid state. The flexibility of the rings permits inclusion of guest molecules such as five-membered heterocycles and aromatic six membered rings. In the second part we discuss the results of quantum chemical calculations. To treat properly the noncovalent bonding between chalcogens, we use diffuse augmented split valence basis sets in combination with electron correlation methods. Our model substances were 16 dimers consisting of two Me-X Me (X = O, S, Se, Te) pairs and dimers of Me-X-Me/Me-X-CN (X = O, S, Se, Te) pairs. The calculations show the anticipated increase of the interaction energy from (Me-O-Me)2 (-2.15 kcal/mol) to (Me-O-Me/Me-Te-CN) (-6.59 kcal/mol). An analysis by the NBO method reveals that in the case of the chalcogen centers O and S the hydrogen bridges between the molecules dominate. However, in the case of Se and Te the major bonding between the pairs originates from dispersion forces between the chalcogen centers. It varies between -1.7 and -4.0 kcal/mol. PMID- 29420880 TI - Multifunctional Polymeric Micelles with Amplified Fenton Reaction for Tumor Ablation. AB - Relative to normal cells, tumor cells lack adequate capability of reactive oxygen scavenging. Thus, tumor cells can be selectively killed by increasing the concentration of reactive oxygen species in tumor tissue. In this report, we construct an integrated multifunctional polymeric nanoparticle which can selectively improve hydrogen peroxide (H2O2) levels in tumor tissue and convert them into more active hydroxyl radicals by Fenton reaction. First, the diblock copolymers containing polyethylene glycol (PEG) and poly(glutamic acid) modified by beta-cyclodextrin (beta-CD) were synthesized. The block copolymer, ferrocenecarboxylic acid hexadecyl ester (DFc), and ascorbyl palmitate (PA) were coassembled in aqueous solution to obtain stable core-shell micelles through the inclusion complexation between beta-CD moieties in the block copolymer and ferrocene (Fc) groups from DFc. After intravenous injection, the particles achieved significant accumulation in tumor tissue where ascorbic acid at the pharmacological concentration promotes the production of H2O2, and subsequently Fenton reaction was catalyzed by Fc groups to produce hydroxyl radicals to efficiently kill cancer cells and suppress tumor growth. The micellar systems possess great potentials toward cancer therapy through synergistic H2O2 production and conversion into hydroxyl radicals specifically in tumor tissue. PMID- 29420881 TI - Calcium-MicroRNA Complex-Functionalized Nanotubular Implant Surface for Highly Efficient Transfection and Enhanced Osteogenesis of Mesenchymal Stem Cells. AB - Controlling mesenchymal stem cell (MSC) differentiation by RNA interference (RNAi) is a promising approach for next-generation regenerative medicine. However, efficient delivery of RNAi therapeutics is still a limiting factor. In this study, we have developed a simple, biocompatible, and highly effective delivery method of small RNA therapeutics into human MSCs (hMSCs) from an implant surface by calcium ions. First, we demonstrated that simple Ca/siRNA targeting green fluorescent protein (GFP) nanocomplexes were able to efficiently silence GFP in GFP-expressing hMSCs with adequate Ca2+ concentration (>5 mM). In addition, a single transfection could obtain a long-lasting silencing effect for more than 2 weeks. All three of the main endocytosis pathways (clathrin- and caveolin-mediated endocytosis and macropinocytosis) were involved in the internalization of the Ca/siRNA complexes by MSCs, and macropinocytosis plays the most dominant role. Furthermore, the Ca/siRNA complexes could be efficiently loaded onto the titanium implant surface when pretreated with anodization to create a nanotube (NT) layer. Because of the hydrophilic property of the NT surface, the Ca/siRNA was quickly loaded (less than 4 h) with high efficiency (nearly 100%), forming an even amorphous coating. The Ca/siRNA-coated NT surface showed an initial burst release of 80% of the siRNA complexes over 2 h, which is adequate to achieve robust gene silencing of attached hMSCs. To demonstrate the therapeutic potential of our Ca/siRNA coating technology, Ca/antimiR-138 complexes were loaded on to the NT surface, which strongly enhanced the osteogenic differentiation of hMSCs. In conclusion, our findings suggest that Ca2+ is an effective and biocompatible carrier to deliver small RNA therapeutics into hMSCs, both in solution and from functionalized surfaces, which provides a novel approach to control the MSC differentiation and tissue regeneration. PMID- 29420882 TI - Multiplex Immuno-MALDI-TOF MS for Targeted Quantification of Protein Biomarkers and Their Proteoforms Related to Inflammation and Renal Dysfunction. AB - Circulating proteins are widely used as biomarkers in clinical applications for the diagnosis, prediction, and treatment of numerous diseases. Immunoassays are the most common technologies for quantification of protein biomarkers and exist in various formats. Traditional immunoassays offer sensitive and fast analyses but cannot differentiate between proteoforms. Protein microheterogeneity, mainly due to post-translational modification, has been recognized as a fingerprint for different pathologies, and knowledge about proteoforms is an important step toward personalized medicine. Mass spectrometry (MS) has emerged to be a powerful technique for the characterization and quantification of proteoforms. We have established a novel four-plex immunoassay based on Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight (MALDI-TOF) MS for the targeted quantification of the inflammatory markers C-reactive protein (CRP), serum amyloid A (SAA), and calprotectin (S100A8/9) and the kidney function marker cystatin C (CysC). Antibodies were covalently bound to superparamagnetic beads, which delivered robust and fast sample processing. Polyhistidine-tagged recombinant target proteins were used as internal standards for quantification. Our method identified a number of proteoforms for SAA ( n = 11), S100A8/9 ( n = 4) and CysC ( n = 4). The assay was characterized by low limits of detection (0.01-0.06 MUg/mL) and low coefficients of variation (3.8-9.4%). Method validation demonstrated good between-assay agreement with immuno-turbidimetry ( R2 = 0.963 for CRP), ELISA ( R2 = 0.958 for SAA; R2 = 0.913 for S100A8/9), and nephelometry ( R2 = 0.963 for CysC). The low sample consumption of 20 MUL and the high sample throughput of 384 samples per day make this targeted immuno-MALDI approach suited for assessment of inflammatory and renal status in large cohort studies based on precious biobanks samples. PMID- 29420883 TI - Characterization of Mechanisms of Glutathione Conjugation with Halobenzoquinones in Solution and HepG2 Cells. AB - Halobenzoquinones (HBQs) are a class of emerging disinfection byproducts. Chronic exposure to chlorinated drinking water is potentially associated with an increased risk of human bladder cancer. HBQ-induced cytotoxicity involves depletion of cellular glutathione (GSH), but the underlying mechanism remains unclear. Here we used ultrahigh performance liquid chromatography-high resolution mass spectrometry and electron paramagnetic resonance spectroscopy to study interactions between HBQs and GSH and found that HBQs can directly react with GSH, forming various glutathionyl conjugates (HBQ-SG) in both aqueous solution and HepG2 cells. We found that the formation of HBQ-SG varies with the initial molar ratio of GSH to HBQ in reaction mixtures. Higher molar ratios of GSH to HBQ facilitate the conjugation of more GSH molecules to an HBQ molecule. We deduced the reaction mechanism between GSH and HBQs, which involves redox cycling-induced formation of halosemiquinone (HSQ) free radicals and glutathione disulfide, Michael addition, as well as nucleophilic substitution. The proposed reaction rates are in the following order: formation of HSQ radicals > substitution of bromine by GSH > Michael addition of GSH on the benzoquinone ring > substitution of chlorine by GSH > substitution of the methyl group by GSH. The conjugates identified in HBQ-treated HepG2 cells were the same as those found in aqueous solution containing a 5:1 ratio of GSH:HBQs. PMID- 29420884 TI - A Sensitive "Turn-On" Fluorescent Sensor for Melamine Based on FRET Effect between Polydopamine-Glutathione Nanoparticles and Ag Nanoparticles. AB - In this work, Ag nanoparticles (AgNPs) were synthesized quickly by a one-step method utilizing polydopamine-glutathione nanoparticles (PDA-GNPs) as a reducing agent. The PDA-GNPs and the generated AgNPs acted as the energy donor and acceptor, respectively. Accordingly, the fluorescence of PDA-GNPs was quenched on the basis of fluorescence resonance energy transfer (FRET). In the presence of melamine, the preferential combination of Ag(I) and melamine to form Ag(I) melamine complex prevents Ag(I) from forming AgNPs, together with fluorescence enhancement compared with the absence of melamine. Under the optimal conditions including the concentration of AgNO3, reaction time, reaction temperature, and pH, the fluorescence enhancement efficiency has a linear response to the concentration of melamine from 0.1 to 40 MUM with a detection limit of 23 nM for melamine. The proposed method is simple, time-saving, and low-cost, which was further applied to detect melamine in real milk products with satisfactory results. PMID- 29420885 TI - Equilibrium Relationship between SVOCs in PVC Products and the Air in Contact with the Product. AB - Phthalates and phthalate alternatives are semivolatile organic compounds (SVOCs) present in many PVC products as plasticizers to enhance product performance. Knowledge of the mass-transfer parameters, including the equilibrium concentration in the air in contact with the product surface ( y0), will greatly improve the ability to estimate the emission rate of SVOCs from these products and to assess human exposure. The objective of this study was to measure y0 for different PVC products and to evaluate its relationship with the material-phase concentrations ( C0). Also, C0 and y0 data from other sources were included, resulting in a substantially larger data set ( Ntotal = 34, T = 25 degrees C) than found in previous studies. The results show that the material/gas equilibrium relationship does not follow Raoult's law and that therefore the assumption of an ideal solution is invalid. Instead, Henry's law applies, and the Henry's law constant for all target SVOCs consists of the respective pure liquid vapor pressure and an activity coefficient gamma, which accounts for the nonideal nature of the solution. For individual SVOCs, a simple partitioning relationship exists, but Henry's law is more generally applicable and will be of greater value in rapid exposure assessment procedures. PMID- 29420886 TI - Benchmark Study Based on 2P2IDB to Gain Insights into the Discovery of Small Molecule PPI Inhibitors. AB - Protein-protein interactions (PPIs) have been regarded as novel and highly promising drug targets in drug discovery. Numerous new experimental techniques and computational approaches have been developed to assist the design of PPI modulators during the past two decades. However, identification and optimization of small-molecule inhibitors targeting PPIs is still a particularly challenging task due to the "undruggable" profiles of PPI interfaces. Nowadays, in silico screening, especially docking-based virtual screening, has emerged as an effective method to complement experimental high-throughput screening in identifying novel and potent small-molecule PPI inhibitors. Here, on the basis of the 2P2IDB database, we explored the structural features of the known small molecule PPI inhibitors and analyzed the characteristics of the PPI binding pockets. More importantly, we evaluated the sampling power and screening power of six popular docking programs for PPI targets. Our results indicate that the chlorinated conjugate group and amidelike linkage are two types of privileged fragments of PPI inhibitors; the average druggability of the binding sites of the PPI targets in 2P2IDB is slightly worse than that of traditional ones; both academic and commercial docking programs exhibit an acceptable accuracy on pose prediction for PPI inhibitors, but their screening powers for identifying PPI inhibitors are still not satisfactory. It is expected that our work can provide valuable guidance on the construction of PPI-focused library, the determination of druggable PPI binding pocket, and the selection of docking program for the screening of small-molecule PPI inhibitors. PMID- 29420887 TI - Glutathione S-Transferase pi-Activatable O2-(Sulfonylethyl Derived) Diazeniumdiolates Potently Suppress Melanoma in Vitro and in Vivo. AB - A group of glutathione S-transferase pi (GSTpi) activatable O2-(sulfonylethyl derived) diazeniumdiolates 5-12 were designed and synthesized. These compounds could be activated by GSTpi to initiate the beta-elimination reaction, liberating an active vinyl sulfone-based GSH derivative and a diazeniumdiolate anion which subsequently releases NO in situ. The most active compound 6 released relatively high levels of NO and inhibited proliferation of melanoma B16 cells, superior to a diazeniumdiolate-based anticancer agent JS-K (1). Importantly, 6 had 8-fold less inhibitory activity against normal epithelial JB6 Cl 30-7b cells. The inhibitory activity of 6 could be diminished by an NO scavenger or GSTpi inhibitor. Furthermore, 6 induced nitration of mitochondrial tyrosine in B16 cells and inoculated B16 tumors in mice, which might be responsible for oxidation of protein leading to tumor suppression. Finally, 6 significantly retarded the B16 cells growth in a mouse xenograft model. These findings suggest that 6 may have a potential to treat melanoma. PMID- 29420888 TI - Theory of Anisotropic Circular Dichroism of Excitonically Coupled Systems: Application to the Baseplate of Green Sulfur Bacteria. AB - A simple exciton theory for the description of anisotropic circular dichroism (ACD) spectra of multichromophoric systems is presented that is expected to be of general use for the analysis of structure-function relationships of molecular aggregates such as photosynthetic light-harvesting antennae. The theory is applied to the baseplate of green sulfur bacteria. It is demonstrated that only the combined analysis of ACD and circular dichroism (CD) spectra for the present baseplate bacteriochlorophyll (BChl) a dimer allows for an unambiguous determination of the parameters of the exciton Hamiltonian from experimental data. The analysis of experimental absorption and linear dichroism spectra suggests that either the NMR structure has to be refined or in addition to the dimers seen in the NMR structure and in the CD and ACD spectra, BChl a monomers are present in the baseplate carotenosome sample. A refined dimer structure is presented, explaining all four optical spectra. PMID- 29420890 TI - Immunoblotting Quantification Approach for Identifying Potential Hypoallergenic Citrus Cultivars. AB - The inherent allergens of citrus fruits, such as Cit s 1, Cit s 2, Cit s 3 can cause allergic reactions. A better understanding of the genetic factors (cultivar to cultivar) affecting the allergenic potential of citrus fruits would be beneficial for further identification of hypoallergenic genotypes. In the present study, an immunoblotting quantification approach was adopted to assess the potential allergenicity of 21 citrus cultivars, including nine subgroups (tangerine, satsuma, orange, pummelo, grapefruit, lemon, kumquat, tangor, and tangelo). To prepare highly sensitive and specific rabbit polyclonal antibodies, antigenicity of purified rCit s 1.01, rCit s 2.01, and rCit s 3.01 peptides were enhanced with high epitope density in a single protein molecule. The data integration of three citrus allergen quantifications demonstrated that the four pummelo cultivars (Kao Phuang Pummelo, Wanbai Pummelo, Shatian Pummelo, and Guanxi Pummelo) were potential hypoallergenic, compared with other 8 subgroups. Moreover, the immunological analyses with sera of allergic subjects revealed that Shatian Pummelo and Guanxi Pummelo showed the lowest immunoreactivity in 8 representative citrus cultivars. These potential hypoallergenic genotypes are of great significance to not only allergic consumers but also citrus breeders in the genetic improvement of hypoallergenic citrus as breeding resources. PMID- 29420892 TI - Probing Ionic Liquid Electrolyte Structure via the Glassy State by Dynamic Nuclear Polarization NMR Spectroscopy. AB - Dynamic nuclear polarization (DNP)-enhanced solid-state NMR spectroscopy has been used to study an ionic liquid salt solution (N-methyl-N-propyl-pyrrolidinium bis(fluorosulfonyl)imide, C3mpyrFSI, containing 1.0 m lithium bis(fluorosulfonyl)imide, 6LiFSI) in its glassy state at a temperature of 92 K. The incorporation of a biradical to enable DNP signal enhancement allowed the proximities of the lithium to the individual carbon sites on the pyrrolidinium cation to be probed using a 13C-6Li REDOR pulse sequence. Distributions in Li-C distances were extracted and converted into a 3D map of the locations of the Li+ relative to the C3mpyr that shows remarkably good agreement with a liquid-phase molecular dynamics simulation. PMID- 29420891 TI - Design, Synthesis, and Evaluation of Orally Bioavailable Quinoline-Indole Derivatives as Innovative Multitarget-Directed Ligands: Promotion of Cell Proliferation in the Adult Murine Hippocampus for the Treatment of Alzheimer's Disease. AB - A novel series of quinoline-indole derivatives were synthesized and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease (AD). Biological evaluation revealed that the derivatives had multifunctional profiles including antioxidant effects, blood-brain barrier (BBB) penetration, biometal chelation, Abeta aggregation modulation, neurotrophic and neuroprotective properties. Moreover, several representative target derivatives demonstrated hippocampal cell proliferation in living adult mice by intracerebroventricular (icv) injection or oral administration. Further drug-like property analysis demonstrated that the optimized compound, 8d (WI-1758), had liver microsomal metabolic stability, was well tolerated (>2000 mg/kg), and had a rational pharmacokinetic profile, as well as an oral bioavailability of 14.1% and a positive log BB (-0.19) to cross the BBB in vivo. Pharmacodynamics studies demonstrated that chronic oral administration of 8d.HCl substantially ameliorated the cognitive and spatial memory deficits in APP/PS1 AD mice and noticeably reduced overall cerebral beta-amyloid deposits. PMID- 29420893 TI - Direct Calorimetric Observation of the Rigid Amorphous Fraction in a Semiconducting Polymer. AB - The performance of polymeric semiconductors is profoundly affected by the thermodynamic state of its crystalline and amorphous fractions and how they affect the optoelectronic properties. While intense research has been conducted on the crystalline features, fundamental understanding of the amorphous fraction(s) is still lacking. Here, we employ fast scanning calorimetry to provide insights on the glass transition of the archetypal conjugated polymer poly(3-hexylthiophene) (P3HT). According to the conceptual definition of the glass transition temperature (Tg), that is, the temperature marking the crossover from the melt in metastable equilibrium to the nonequilibrium glass, an enthalpy relaxation should be observed by calorimetry when the glass is aged below Tg. Thus, we are able to identify the enthalpy relaxations of mobile and rigid amorphous fractions (MAF and RAF, respectively) of P3HT and to determine their respective Tg. Our work moreover highlights that the RAF should be included in structural models when establishing structure/property interrelationships of polymer semiconductors. PMID- 29420894 TI - Revealing Catalytically Relevant Surface Species by Kinetic Isotope Effect Spectroscopy: H-Bonding to Ester Carbonyl of trans-Ethyl Pyruvate Controls Enantioselectivity on a Cinchona-Modified Pt Catalyst. AB - Monitoring active surface species on an operating technical catalyst is a challenging task due to the presence of multiple different adsorption sites and the abundance of bulk species. In this work, kinetic isotope effect (KIE) spectroscopy is introduced to capture the signals of catalytically relevant hydrogenation species from the IR spectroscopic detection in attenuated total reflection mode. The catalytic interface formed between a cinchona-modified Pt/Al2O3 catalyst and the solvent toluene is sensitively probed directly at the rate limiting step(s) during the asymmetric hydrogenation of ethyl pyruvate by measuring the effects of substituting H2 by D2 kinetically and spectroscopically in the same operando experiment. The application of KIE spectroscopy provides unprecedented molecular level insight into the structure of the diastereomeric intermediate surface complex and the phenomenon rate enhancement, which revolutionizes our understanding of chirally modified metal catalysts. PMID- 29420889 TI - Hydrodynamics in Cell Studies. AB - Hydrodynamic phenomena are ubiquitous in living organisms and can be used to manipulate cells or emulate physiological microenvironments experienced in vivo. Hydrodynamic effects influence multiple cellular properties and processes, including cell morphology, intracellular processes, cell-cell signaling cascades and reaction kinetics, and play an important role at the single-cell, multicellular, and organ level. Selected hydrodynamic effects can also be leveraged to control mechanical stresses, analyte transport, as well as local temperature within cellular microenvironments. With a better understanding of fluid mechanics at the micrometer-length scale and the advent of microfluidic technologies, a new generation of experimental tools that provide control over cellular microenvironments and emulate physiological conditions with exquisite accuracy is now emerging. Accordingly, we believe that it is timely to assess the concepts underlying hydrodynamic control of cellular microenvironments and their applications and provide some perspective on the future of such tools in in vitro cell-culture models. Generally, we describe the interplay between living cells, hydrodynamic stressors, and fluid flow-induced effects imposed on the cells. This interplay results in a broad range of chemical, biological, and physical phenomena in and around cells. More specifically, we describe and formulate the underlying physics of hydrodynamic phenomena affecting both adhered and suspended cells. Moreover, we provide an overview of representative studies that leverage hydrodynamic effects in the context of single-cell studies within microfluidic systems. PMID- 29420895 TI - Dopant-Dependent Electronic Structures Observed for M2Au36(SC6H13)24 Clusters (M = Pt, Pd). AB - Heteroatom doping is a powerful means to tune the optical and electronic properties of gold clusters at the atomic level. We herein report that doping a Au38 cluster with Pt and Pd atoms leads to core-doped [Pt2Au36(SC6H13)24]2- and [Pd2Au36(SC6H13)24]0, respectively. Voltammetric investigations show that these clusters exhibit drastically different electronic structures; whereas the HOMO LUMO gap of [Pt2Au36(SC6H13)24]2- is found to be 0.95 V, that of [Pd2Au36(SC6H13)24]0 is drastically decreased to 0.26 V, suggesting Jahn-Teller distortion of the 12-electron cluster. Density functional investigations confirm that the HOMO-LUMO gap of the Pd-doped cluster is indeed reduced. Analysis of the optimized geometry for the 12-electron [Pd2Au36(SC6H13)24]0 reveals that the rod like M2Au21 core becomes more flattened upon Pd-doping. Reversible geometrical interconversion between [Pt2Au36(SC6H13)24]0 and [Pt2Au36(SC6H13)24]2- is clearly demonstrated by manipulating the oxidation state of the cluster. PMID- 29420896 TI - Cyclophosphazene-Based Hybrid Nanoporous Materials as Superior Metal-Free Adsorbents for Gas Sorption Applications. AB - Cyclophosphazene-based inorganic-organic hybrid nanoporous materials (CHNMs) have been synthesized by a facile solvothermal method. The condensation of pyrrole with the reaction product of phosphonitrilic chloride trimer and 4 hydroxybenzaldehyde resulted in the formation of high-surface-area CHNMs. The maximum specific surface area (SABET) of 1328 m2 g-1 with hierarchical pore structures having micropores centered at 1.18 nm and mesopores in the range of 2.6-3.6 nm was estimated from the N2 sorption analysis. Observation of high SABET could be attributed to the synergy effect exerted by the cyclophosphazene moiety owing to its three-dimensional paddle wheel structure. The metal-free adsorbent exhibited a high and reversible CO2 uptake of 22.8 wt % at 273 K and 1 bar. The performance is on the higher side among the reported metal-free inorganic-organic hybrid nanoporous adsorbents. Moreover, the high H2 uptake of 2.02 wt % at 77 K and 1 bar is an added advantage. The superior performance of the adsorbents for the gas sorption applications could be attributed to the combined effect of high SABET and hierarchical pore structure, which has made CHNMs good candidates for energy and environmental applications. PMID- 29420897 TI - Temperature-Dependent Hydrophobic Crossover Length Scale and Water Tetrahedral Order. AB - Experimental Raman multivariate curve resolution and molecular dynamics simulations are performed to demonstrate that the vibrational frequency and tetrahedrality of water molecules in the hydration-shells of short-chain alcohols differ from those of pure water and undergo a crossover above 100 degrees C (at 30 MPa) to a structure that is less tetrahedral than pure water. Our results demonstrate that the associated crossover length scale decreases with increasing temperature, suggesting that there is a fundamental connection between the spectroscopically observed crossover and that predicted to take place around idealized purely repulsive solutes dissolved in water, although the water structure changes in the hydration-shells of alcohols are far smaller than those associated with an idealized "dewetting" transition. PMID- 29420898 TI - Organocatalyzed, Visible-Light Photoredox-Mediated, One-Pot Minisci Reaction Using Carboxylic Acids via N-(Acyloxy)phthalimides. AB - An improved, one-pot Minisci reaction has been developed using visible light, an organic photocatalyst, and carboxylic acids as radical precursors via the intermediacy of in situ-generated N-(acyloxy)phthalimides. The conditions employed are mild, demonstrate a high degree of functional group tolerance, and do not require a large excess of the carboxylic acid reactant. As a result, this reaction can be applied to drug-like scaffolds and molecules with sensitive functional groups, enabling late-stage functionalization, which is of high interest to medicinal chemistry. PMID- 29420899 TI - Importance of Net Hydrophobicity in the Cellular Uptake of All-Hydrocarbon Stapled Peptides. AB - All-hydrocarbon stapled peptides make up a promising class of protein-protein interaction regulators; their potential therapeutic benefit arises because they have a high binding affinity and specificity for intracellular molecules. The cell permeation efficacy of these peptides is a critical determinant of their bioactivity. However, the factors that determine their cellular uptake remain an active area of research. In this study, we evaluated the effect of stapled (or cross-linked) formation on the cellular uptake of six known all-hydrocarbon stapled peptides. We found that the rate of cellular uptake of unstapled peptides (i.e., those bearing olefinic non-natural amino acids that are not subjected to olefin metathesis) was higher than that for the corresponding stapled peptides. Additionally, the insertion of these olefinic non-natural amino acids into peptide sequences significantly increased their rate of cellular uptake. According to the high-performance liquid chromatography retention times, the overall hydrophobicity of unstapled peptides was greater than that of stapled peptides, followed by that of the original peptides without olefinic non-natural amino acids. There was not a close correlation between helical content and the rate of cellular uptake of these peptides. Therefore, the increase in overall hydrophobicity resulting from the introduction of non-natural amino acids, rather than the structural stabilization resulting from staple formation, is the key driver promoting cellular uptake. Macropinocytosis, a form of fluid-phase endocytosis, was involved in the cellular uptake of all six peptides. PMID- 29420900 TI - Highly Asymmetric Chiral Domain-Wall Velocities in Y-Shaped Junctions. AB - Recent developments in spin-orbit torques allow for highly efficient current driven domain wall (DW) motion in nanowires with perpendicular magnetic anisotropy. Here, we show that chiral DWs can be driven into nonequilibrium states that can persist over tens of nanoseconds in Y-shaped magnetic nanowire junctions that have an input and two symmetric outputs. A single DW that is injected into the input splits and travels at very different velocities in the two output branches until it reaches its steady-state velocity. We find that this is due to the disparity between the fast temporal evolution of the spin current derived spin-orbit torque and a much-slower temporal evolution of the DMI-derived torque. Changing the DW polarity inverts the velocity asymmetry in the two output branches, a property that we use to demonstrate the sorting of domains. PMID- 29420902 TI - Robust Nanowrapping of Reduced Graphene Oxide by Metal-Organic Network Films between Fe Ions and Tetra(Catechol-Substituted) Porphyrin. AB - We found the utilization of porphyrin-based metal-organic network films composed of tetra(catechol-substituted)porphyrin (cPor) and Fe ions for robust wrapping materials of graphene oxide (GO), which can keep the dispersion state under the chemical reduction of GO to reduced graphene oxide (rGO) in water. The tetra(catechol-substituted)porphyrin (cPor) was designed for soft-wrapping methods because the aromatic porphyrin moieties can be strongly adsorbed onto the surface of GO or rGO via both pi-pi interactions and the catechol-Fe coordination network formation. The GO sheets covered with the cPor-Fe films were reduced chemically in water under retention of the wrapped nanostructure of the cPor Fe/GO sheets. The obtained rGO composites after chemical reduction are characterized by using UV-vis absorption, Raman, and X-ray photoelectron spectroscopy (XPS) spectra, as well as thermogravimetric analysis and energy dispersive X-ray spectroscopy (EDX). XPS and EDX spectra showed the presence of Fe species, which originates from the coordinated Fe-catechol nodes in the wrapped cPor-Fe films. The wrapped rGO sheets could be easily handled in water because of their high solubility therein and exhibits electric conductivity. In dynamic light scattering analysis, the average diameter of rGO composites before and after reduction changed slightly from 419 +/- 309 to 663 +/- 697 nm, indicating that the chemical reduction is not significantly influenced by the size of the rGO composite or the solubility. It is expected that the soft wrapping cPor-Fe/rGO should employ the applications to prepare functional materials such as modified electrodes, catalysts, energy-storage materials, and electronic devices. PMID- 29420901 TI - Enhancing Efficacy and Stability of an Antiheroin Vaccine: Examination of Antinociception, Opioid Binding Profile, and Lethality. AB - In recent years, drug conjugate vaccines have shown promise as therapeutics for substance use disorder. As a means to improve the efficacy of a heroin conjugate vaccine, we systematically explored 20 vaccine formulations with varying combinations of carrier proteins and adjuvants. In regard to adjuvants, we explored a Toll-like receptor 9 (TLR9) agonist and a TLR3 agonist in the presence of alum. The TLR9 agonist was cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826), while the TLR3 agonist was virus-derived genomic doubled-stranded RNA (dsRNA). The vaccine formulations containing TLR3 or TLR9 agonist alone elicited strong antiheroin antibody titers and blockade of heroin-induced antinociception when formulated with alum; however, a combination of TLR3 and TLR9 adjuvants did not result in improved efficacy. Investigation of month-long stability of the two lead formulations revealed that the TLR9 but not the TLR3 formulation was stable when stored as a lyophilized solid or as a liquid over 30 days. Furthermore, mice immunized with the TLR9 + alum heroin vaccine gained significant protection from lethal heroin doses, suggesting that this vaccine formulation is suitable for mitigating the harmful effects of heroin, even following month-long storage at room temperature. PMID- 29420903 TI - Photothermal Circular Dichroism Induced by Plasmon Resonances in Chiral Metamaterial Absorbers and Bolometers. AB - Chiral photochemistry remains a challenge because of the very small asymmetry in the chiro-optical absorption of molecular species. However, we think that the rapidly developing fields of plasmonic chirality and plasmon-induced circular dichroism demonstrate very strong chiro-optical effects and have the potential to facilitate the development of chiral photochemistry and other related applications such as chiral separation and sensing. In this study, we propose a new type of chiral spectroscopy-photothermal circular dichroism. It is already known that the planar plasmonic superabsorbers can be designed to exhibit giant circular dichroism signals in the reflection. Therefore, upon illumination with chiral light, such planar metastructures should be able to generate a prominent asymmetry in their local temperatures. Indeed, we demonstrate this chiral photothermal effect using a chiral plasmonic absorber. Calculated temperature maps show very strong photothermal circular dichroism. One of the structures computed in this Letter could serve as a chiral bolometer sensitive to circularly polarized light. Overall, this chiro-optical effect in plasmonic metamaterials is much greater than the equivalent effect in any chiral molecular system or plasmonic bioassembly. Potential applications of this effect are in polarization sensitive surface photochemistry and chiral bolometers. PMID- 29420905 TI - Sex-related differences in fuel utilization and hormonal response to exercise: implications for individuals with type 1 diabetes. AB - Sex-related differences in metabolic and neuroendocrine response to exercise in individuals without diabetes have been well established. Men and women differ in fuel selection during exercise, in which women rely to a greater extent on fat oxidation, whereas males rely mostly on carbohydrate oxidation for energy production. The difference in fuel selection appears to be mediated by sex related differences in hormonal (including catecholamines, growth hormone, and estrogen) response to different types and intensities of exercise. In general, men exhibit an amplified counter-regulatory response to exercise, with elevated levels of catecholamines compared with women. However, women exhibit greater sensitivity to the lipolytic action of the catecholamines and deplete less of their glycogen stores than men during exercise, which suggests that women may experience a greater defense in blood glucose control after exercise than men. Conversely, little is known about sex-related differences in response to exercise in individuals with type 1 diabetes (T1D). A single study investigating sex related differences in response to moderate aerobic exercise in individuals with T1D found sex-related differences in catecholamine response and fuel selection, but changes in blood glucose were not measured. To our knowledge, there are no studies investigating sex-related differences in blood glucose responses to different types and intensities of exercise in individuals with T1D. This review summarizes sex-related differences in exercise responses that could potentially impact blood glucose levels during exercise in individuals with T1D and highlights the need for further research. PMID- 29420904 TI - Unstable Inflation Causing Injury. Insight from Prone Position and Paired Computed Tomography Scans. AB - RATIONALE: It remains unclear how prone positioning improves survival in acute respiratory distress syndrome. Using serial computed tomography (CT), we previously reported that "unstable" inflation (i.e., partial aeration with large tidal density swings, indicating increased local strain) is associated with injury progression. OBJECTIVES: We prospectively tested whether prone position contains the early propagation of experimental lung injury by stabilizing inflation. METHODS: Injury was induced by tracheal hydrochloric acid in rats; after randomization to supine or prone position, injurious ventilation was commenced using high tidal volume and low positive end-expiratory pressure. Paired end-inspiratory (EI) and end-expiratory (EE) CT scans were acquired at baseline and hourly up to 3 hours. Each sequential pair (EI, EE) of CT images was superimposed in parametric response maps to analyze inflation. Unstable inflation was then measured in each voxel in both dependent and nondependent lung. In addition, five pigs were imaged (EI and EE) prone versus supine, before and (1 hour) after hydrochloric acid aspiration. MEASUREMENTS AND MAIN RESULTS: In rats, prone position limited lung injury propagation and increased survival (11/12 vs. 7/12 supine; P = 0.01). EI-EE densities, respiratory mechanics, and blood gases deteriorated more in supine versus prone rats. At baseline, more voxels with unstable inflation occurred in dependent versus nondependent regions when supine (41 +/- 6% vs. 18 +/- 7%; P < 0.01) but not when prone. In supine pigs, unstable inflation predominated in dorsal regions and was attenuated by prone positioning. CONCLUSIONS: Prone position limits the radiologic progression of early lung injury. Minimizing unstable inflation in this setting may alleviate the burden of acute respiratory distress syndrome. PMID- 29420907 TI - The Phase Diagram of a Self-Absorbed Life: Carl Djerassi in Retrospect-From the Pill to the Pen. PMID- 29420906 TI - Development of an InDel polymorphism database for jute via comparative transcriptome analysis. AB - Jute (Corchorus spp.) is one of the most commercially important bast fiber crops in the world. However, molecular markers and high-density genetic maps are still lacking on jute compared with other crops. Insertion/deletion (InDel) markers, one of the most abundant sources of DNA/RNA variations in plant genomes, can easily be distinguished among different accessions using high-throughput sequencing. Using three transcriptome datasets, we identified and developed InDel markers. Altogether, 51 172 InDel sites in 18 800 unigenes were discovered, and the number of InDel loci per unigene varied from 1 to 31. Further, we found 94 InDel types, varying from 1 to 159 bp; the most common were single-nucleotide (23 028), binucleotide (9824), and trinucleotide (9182). In total, 49 563 InDels in 18 445 transcripts were discovered in the comparison between TC and YG, followed by 48 934 InDels in 18 408 transcripts between NY and YG, and 3570 InDels in 2701 unigenes between NY and TC. Additionally, there were 1273 InDel sites in 1129 unigenes with polymorphisms between any two of the three accessions. Twenty-nine (58%) primer pairs represented polymorphisms when compared to the jute accessions, and PIC varied from 0.340 to 0.680, with an average of 0.491. PMID- 29420915 TI - SGE1 is involved in conidiation and pathogenicity of Fusarium oxysporum f.sp. cubense. AB - The ascomycete fungus Fusarium oxysporum f.sp. cubense race 4 (Foc TR4) causes vascular wilt diseases in banana (Musa spp.). In the present study, the role of SGE1 in regulating growth, conidiation, and pathogenicity of Foc TR4 was investigated. Deletion of SGE1 did not influence vegetative growth but impaired the conidiation of Foc TR4. Besides, the SGE1 deletion mutant basically lost pathogenicity on banana plantlets. Observation under the microscope indicated that the penetration and colonization processes were severely impaired in the SGE1 deletion mutant. Proteomics analysis suggested that SGE1 regulated the production of a series of proteins of Foc TR4. Taken together, our results suggest that SGE1 plays an important role in regulating conidiation and pathogenicity in fungal pathogen Foc TR4. PMID- 29420916 TI - Rutin attenuates cerebral ischemia-reperfusion injury in ovariectomized rats via estrogen-receptor-mediated BDNF-TrkB and NGF-TrkA signaling. AB - Rutin, a flavonoid glycoside, has been reported to exert neuroprotective effects. Loss of endogenous estrogen and dysregulation of the estrogen receptor (ER) signaling pathway are associated with the increased risk of stroke in women after menopause. This study was performed to investigate whether rutin could protect against cerebral ischemia by modulating the ER pathway. Ovariectomized (OVX) rats were given intraperitoneal injections of vehicle (dimethyl sulfoxide), rutin (100 mg/kg body mass) or 17beta-estradiol (100 MUg/kg body mass) for 5 consecutive days. Then, the rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h followed by a 24 h reperfusion to establish the cerebral ischemia reperfusion (I/R) injury. We found that rutin improved the sensorimotor performance and recognition memory of rats subjected to I/R, decreased the infarct size, and attenuated neuron loss. Rutin treatment also increased the levels of ERalpha, ERbeta, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), tropomyosin receptor kinase A (TrkA), TrkB, and phospho-cAMP responsive element binding protein (p-CREB) in rat hippocampus and cerebral cortex. The protective effects of rutin were comparable to that of 17beta estradiol, and were partially blocked by ICI182780, an ER antagonist. The above results suggest that rutin preconditioning ameliorates cerebral I/R injury in OVX rats through ER-mediated BDNF-TrkB and NGF-TrkA signaling. PMID- 29420917 TI - Predictive Factors of Hamstring Tendon Regeneration and Functional Recovery After Harvesting: A Prospective Follow-up Study. AB - BACKGROUND: Semitendinosus and gracilis tendons may regenerate after harvesting for ligament reconstruction procedures. However, predictive factors of tendon regeneration and the extent of functional recovery remain unclear. PURPOSE: To identify predictive factors for hamstring tendon regeneration and to examine the morbidity of nonregenerated hamstring tendons. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Of the 154 patients who were included in a prospective follow-up study, 79 underwent reconstruction of the anterior cruciate ligament entailing the hamstring tendons and met the following inclusion criteria: (1) anterior cruciate ligament rupture diagnosed by physical examination and magnetic resonance imaging (MRI), (2) MRI within 6 months after trauma, (3) age between 18 and 45 years, and (4) 2-year follow-up MRI data available. Hamstring tendon regeneration was assessed as complete if a tendon-like structure could be visualized at the level of the joint line or more cranially. Patient characteristics-such as age, sex, body mass index, alcohol/nicotine use, activity level (Tegner scores), and functional instability (1-legged hop test)-were evaluated preoperatively and at 2 years to determine predictive factors for tendon regeneration or examine functional recovery of hamstring tendon regeneration. RESULTS: At 2 years' follow-up, 67.1% of the patients showed regeneration of semitendinosus tendons, 81.0% of gracilis tendons, and 59.5% of both tendons. The likelihood of semitendinosus tendon regeneration significantly decreased with aging (odds ratio [OR], 0.92 change per year of age; 95% CI, 0.84 0.99; P = .03) and smoking (OR, 0.20; 95% CI, 0.05-0.77; P = .02). No predictive factor was found for gracilis tendon regeneration. Regeneration of the semitendinosus and gracilis tendons was negatively related with smoking (OR, 0.22; 95% CI, 0.06-0.79; P = .02). Patients without regeneration showed similar postoperative visual analog scale scores during physical activity, similar Tegner scores, and a significant decrease of the upper leg circumference, as compared with their preoperative results. Regardless of the regeneration status, 1-legged hop test results significantly increased at 2-year follow-up. CONCLUSION: Hamstring tendon regeneration occurs less frequently in older patients and in smokers. However, absence of regenerated tendons does not seem to cause a loss of function. PMID- 29420921 TI - Summa cum Laude: Richard Dawkin's Brief Candle in the Dark. PMID- 29420922 TI - Mortality and Cause of Death in Younger Homeless Veterans. AB - OBJECTIVES: Increased mortality has been documented in older homeless veterans. This retrospective study examined mortality and cause of death in a cohort of young and middle-aged homeless veterans. METHODS: We examined US Department of Veterans Affairs records on homelessness and health care for 2000-2003 and identified 23 898 homeless living veterans and 65 198 non-homeless living veterans aged 30-54. We used National Death Index records to determine survival status. We compared survival rates and causes of death for the 2 groups during a 10-year follow-up period. RESULTS: A greater percentage of homeless veterans (3905/23 898, 16.3%) than non-homeless veterans (4143/65 198, 6.1%) died during the follow-up period, with a hazard ratio for risk of death of 2.9. The mean age at death (52.3 years) for homeless veterans was approximately 1 year younger than that of non-homeless veterans (53.2 years). Most deaths among homeless veterans (3431/3905, 87.9%) and non-homeless veterans (3725/4143, 89.9%) were attributed to 7 cause-of-death categories in the International Classification of Diseases, 10th Revision (cardiovascular system; neoplasm; external cause; digestive system; respiratory system; infectious disease; and endocrine, nutritional, and metabolic diseases). Death by violence was rare but was associated with a significantly higher risk among homeless veterans than among non-homeless veterans (suicide hazard ratio = 2.7; homicide hazard ratio = 7.6). CONCLUSIONS: Younger and middle aged homeless veterans had higher mortality rates than those of their non homeless veteran peers. Our results indicate that homelessness substantially increases mortality risk in veterans throughout the adult age range. Health assessment would be valuable for assessing the mortality risk among homeless veterans regardless of age. PMID- 29420923 TI - High Level of Identity of Calreticulin Gene Sequences of Ixodes persulcatus and Ixodes pavlovskyi Ticks. AB - In southern regions of Western Siberia, Ixodes persulcatus ticks co-exist with Ixodes pavlovskyi. Both tick species have similar morphology, and natural hybridization of I. persulcatus and I. pavlovskyi ticks has been observed. To investigate the role of I. pavlovskyi ticks and I. persulcatus/ I. pavlovskyi hybrids as vectors, correct identification of tick species is necessary. The nuclear crt gene might be useful in distinguishing I. persulcatus from I. pavlovskyi ticks. Genetic variability in this gene has been studied and substantial differences between crt gene sequences of I. persulcatus and I. pavlovskyi ticks has been demonstrated. In this study, maximum-likelihood analysis showed that sequences of I. persulcatus and I. pavlovskyi ticks were identical or highly homologous among themselves. These results were confirmed by a Bayesian phylogeny. We conclude that crt gene sequences of I. persulcatus and I. pavlovskyi cannot be used for distinguishing these tick species and that the conflicting results of prior studies reflect samples from incorrectly identified ticks rather than real genetic differences between I. persulcatus and I. pavlovskyi. PMID- 29420924 TI - Modernizing Centers for Disease Control and Prevention Informatics Using Surveillance Data Platform Shared Services. PMID- 29420926 TI - Process redesign of a surgical pathway improves access to cataract surgery for Aboriginal and Torres Strait Islander people in South East Queensland. AB - The Institute for Urban Indigenous Health (IUIH) aimed to improve access to cataract surgery in urban South East Queensland (SEQ) for Indigenous Australians, without compromising clinical visual outcomes. The Penchansky and Levesque concept of access as the 'fit' between the patient's needs and the ability of the system to meet those needs was used to inform the redesign of the mainstream cataract surgical pathway. The IUIH staff and community stakeholders mapped the traditional external cataract surgical pathway and then innovatively redesigned it to reduce the number of patients being removed by the system at key transition points. The integration of eye health within the primary health care (PHC) clinic has improved the continuity and coordination of care along the surgical pathway, and ensured the sustainability of collaborative partnerships with key external organisations. Audit data demonstrated a significant increase in utilisation of cataract surgical services after the process redesign. Previous studies have found that PHC models involving integration, coordination and continuity of care enhance patient health outcomes; however, the IUIH surgical model extends this to tertiary care. There is scope to apply this model to other surgical pathways and communities who experience access inequity. PMID- 29420925 TI - Pre-exercise beta-hydroxy-beta-methylbutyrate free-acid supplementation improves work capacity recovery: a randomized, double-blinded, placebo-controlled study. AB - The purpose of this study was to investigate the effects of a single-dose of beta hydroxy-beta-methylbutyrate free acid (HMB-FA) supplementation on muscle recovery after a high-intensity exercise bout. Twenty-three trained young males were randomly assigned to receive either a single-dose supplementation of 3 g of HMB FA (n = 12; age, 22.8 +/- 3.0 years) or placebo (PLA; n = 11; age, 22.9 +/- 3.1 years). A muscle damage protocol was applied 60 min after supplementation, and consisted of 7 sets of 20 drop jumps from a 60-cm box with 2-min rest intervals between sets. Muscle swelling, countermovement jump (CMJ), maximal voluntary isometric torque (MVIT), and work capacity (WC) were measured before, immediately after, and 24, 48, and 72 h after the exercise protocol. Muscle swelling, CMJ, and MVIT changed similarly in both groups after the exercise protocol (p < 0.001), but returned to pre-exercise levels after 24 h in both groups. WC decreased similarly in both groups after the exercise protocol (p < 0.01). For HMB-FA, WC returned to pre-exercise level 24 h after exercise protocol. However, for PLA, WC did not return to pre-exercise level even 72 h after the exercise protocol. In summary, a single-dose of HMB-FA supplementation improved WC recovery after a high-intensity exercise bout. However, HMB-FA did not affect the time-course of muscle swelling, MVIT, and CMJ recovery. PMID- 29420927 TI - Wimpy Nerves: piRNA Pathway Curbs Axon Regrowth after Injury. AB - While PIWI-interacting RNAs (piRNAs) are primarily recognized as guardians of genome integrity, new functions of these small non-coding RNAs are emerging. In this issue, Kim et al. (2018) describe a piRNA-based mechanism that limits axon regeneration in C. elegans. PMID- 29420928 TI - On the Path from Proteomics to Function: GABAAR Trafficking Takes a Turn. AB - There are significant challenges in identifying receptor-specific functional interactors in vivo. In this issue of Neuron, Ge et al. (2018) identify a novel GABAA receptor (GABAAR)-interacting protein, Clptm1, that regulates forward trafficking of GABAARs and inhibitory transmission. PMID- 29420929 TI - When Acetylcholine Unlocks Feedback Inhibition in Cortex. AB - Acetylcholine promotes cognitive function through the regulation of cortical circuits. In this issue of Neuron, Urban-Ciecko et al. (2018) demonstrate how this neuromodulator can rapidly boost synapses from pyramidal to somatostatin neurons, unlocking a new computational ability in the cortical microcircuitry. PMID- 29420930 TI - Better than Optimal. AB - Using a novel visual-tactile paradigm in rats, Nikbakht et al. (2018) describe multisensory behavior that outperformed predictions of optimal cue combination (indicating cross-modal synergy) and exposed encoding in PPC neurons (of stimulus and choice signals) that was independent of stimulus modality. PMID- 29420933 TI - Precisely Timed Nicotinic Activation Drives SST Inhibition in Neocortical Circuits. AB - Sleep, waking, locomotion, and attention are associated with cell-type-specific changes in neocortical activity. The effect of brain state on circuit output requires understanding of how neuromodulators influence specific neuronal classes and their synapses, with normal patterns of neuromodulator release from endogenous sources. We investigated the state-dependent modulation of a ubiquitous feedforward inhibitory motif in mouse sensory cortex, local pyramidal (Pyr) inputs onto somatostatin (SST)-expressing interneurons. Paired whole-cell recordings in acute brain slices and in vivo showed that Pyr-to-SST synapses are remarkably weak, with failure rates approaching 80%. Pharmacological screening revealed that cholinergic agonists uniquely enhance synaptic efficacy. Brief, optogenetically gated acetylcholine release dramatically enhanced Pyr-to-SST input, via nicotinic receptors and presynaptic PKA signaling. Importantly, endogenous acetylcholine release preferentially activated nicotinic, not muscarinic, receptors, thus differentiating drug effects from endogenous neurotransmission. Brain state- and synapse-specific unmasking of synapses may be a powerful way to functionally rewire cortical circuits dependent on behavioral demands. PMID- 29420931 TI - SPARK: A US Cohort of 50,000 Families to Accelerate Autism Research. AB - The Simons Foundation Autism Research Initiative (SFARI) has launched SPARKForAutism.org, a dynamic platform that is engaging thousands of individuals with autism spectrum disorder (ASD) and connecting them to researchers. By making all data accessible, SPARK seeks to increase our understanding of ASD and accelerate new supports and treatments for ASD. PMID- 29420932 TI - Dopamine's Effects on Corticostriatal Synapses during Reward-Based Behaviors. AB - Many learned responses depend on the coordinated activation and inhibition of synaptic pathways in the striatum. Local dopamine neurotransmission acts in concert with a variety of neurotransmitters to regulate cortical, thalamic, and limbic excitatory inputs to drive the direct and indirect striatal spiny projection neuron outputs that determine the activity, sequence, and timing of learned behaviors. We review recent advances in the characterization of stereotyped neuronal and operant responses that predict and then obtain rewards. These depend on the local release of dopamine at discrete times during behavioral sequences, which, acting with glutamate, provides a presynaptic filter to select which excitatory synapses are inhibited and which signals pass to indirect pathway circuits. This is followed by dopamine-dependent activation of specific direct pathway circuits to procure a reward. These steps may provide a means by which higher organisms learn behaviors in response to feedback from the environment. PMID- 29420934 TI - Vigilance-Associated Gamma Oscillations Coordinate the Ensemble Activity of Basolateral Amygdala Neurons. AB - Principal basolateral amygdala (BL) neurons profoundly influence motivated behaviors, yet few of them are activated by emotionally valenced stimuli. Here, we show that a likely explanation for this paradox is the synchronizing influence of the high-gamma rhythm. High-gamma (75-95 Hz) entrained BL firing more strongly than all other rhythms. It was most pronounced during states of increased vigilance, when rats were apprehensive. Relative to behavioral states, high-gamma produced minor changes in firing rates yet dramatic increases in synchrony. Moreover, connected pairs of cells showed similarly high levels of entrainment and synchronization. Unexpectedly, prefrontal- and accumbens-projecting cells, respectively, showed high and low entrainment by high-gamma, indicating that this rhythm differentially synchronizes the activity of BL neurons projecting to specific sites. Overall, our findings suggest that individual BL neurons encode information not only by changing their firing rates, but also by synchronizing their collective activity, amplifying their impact on target structures. PMID- 29420936 TI - Bassoon Controls Presynaptic Autophagy through Atg5. PMID- 29420937 TI - Development and Refinement of Functional Properties of Adult-Born Neurons. PMID- 29420935 TI - The Mouse Cortical Connectome, Characterized by an Ultra-Dense Cortical Graph, Maintains Specificity by Distinct Connectivity Profiles. AB - The inter-areal wiring pattern of the mouse cerebral cortex was analyzed in relation to a refined parcellation of cortical areas. Twenty-seven retrograde tracer injections were made in 19 areas of a 47-area parcellation of the mouse neocortex. Flat mounts of the cortex and multiple histological markers enabled detailed counts of labeled neurons in individual areas. The observed log-normal distribution of connection weights to each cortical area spans 5 orders of magnitude and reveals a distinct connectivity profile for each area, analogous to that observed in macaques. The cortical network has a density of 97%, considerably higher than the 66% density reported in macaques. A weighted graph analysis reveals a similar global efficiency but weaker spatial clustering compared with that reported in macaques. The consistency, precision of the connectivity profile, density, and weighted graph analysis of the present data differ significantly from those obtained in earlier studies in the mouse. PMID- 29420938 TI - Quantitative and rapid detection of C-reactive protein using quantum dot-based lateral flow test strip. AB - A novel QD-based immunoassay on a paper-based lateral flow system has been developed to quantitatively detect C-reactive protein (CRP). Different standard CRP antigens from 1 to 200 MUg mL-1 were diluted 200-fold and only 60 MUL diluted sample were needed to load onto the sample pad. The QD fluorescence signals on the test line and the control line were able to be observed within 3 min after the initiation of assay, and the limit of detection was as sensitive as 0.30 ng mL-1 by measuring the fluorescence intensity immediately afterwards with fluorescence immunoassay analyzer. The linearity on the detection of QD fluorescence signals has been established well in the range of 0.5 ng mL-1 and 1 MUg mL-1 for CRP. The precision of the assay has been confirmed for low coefficient of variation (CV), satisfying less than 15% (intra-assay and inter assay), and the accuracy of assay meets the requirements with the mean recovery of the control was 102.63%. These results indicated that such newly developed platform was reliable with high sensitivity, rapidness, and could cover a broad range of target concentrations. Furthermore, a total of 135 human serum clinical samples with inflammation or infection with the concentration of CRP from 0.2 to 200 MUg mL-1 has been used to check the performance of this QD-based LFIA, it correlated very well with Roche Tina-quant CRP (Latex) (r = 0.966, n = 135). PMID- 29420939 TI - "Turn-off" fluorescent sensor based on double quantum dots coupled with chemometrics for highly sensitive and specific recognition of 53 famous green teas. AB - Fluorescent "turn-off" sensors based on double quantum dots (QDs) has attracted increasing attention in the detection of many materials due to their properties such as more useful information, higher fluorescence efficiency and stability compared with the fluorescent "turn-off" sensors based on single QDs. In this work, highly sensitive and specific method for recognition of 53 different famous green teas was developed based on the fluorescent "turn-off" model with water soluble ZnCdSe-CdTe double QDs. The fluorescence of the two QDs can be quenched by different teas with varying degrees, which results in the differences in positions and intensities of two peaks. By the combination of classic partial least square discriminant analysis (PLSDA), all the green teas can be discriminated with high sensitivity, specificity and a satisfactory recognition rate of 100% for training set and 100% for prediction set, respectively. The fluorescent "turn-off" sensors based on the single QDs (either ZnCdSe QDs or CdTe QDs) coupled with PLSDA were also employed to recognize the 53 famous green teas with unsatisfactory results. Therefore, the fluorescent "turn-off" sensors based on the double QDs is more appropriate for the large-class-number classification (LCNC) of green teas. Herein, we have demonstrated, for the first time, that so many kinds of famous green teas can be discriminated by the "turn-off" model of double QDs combined with chemometrics, which has largely extended the capability of traditional fluorescence and chemometrics, as well as exhibits great potential to perform LCNC in other practical applications. PMID- 29420941 TI - Voltammetric determination of tartaric acid in wines by electrocatalytic oxidation on a cobalt(II)-phthalocyanine-modified electrode associated with multiway calibration. AB - The electrocatalytic oxidation of tartaric acid on a carbon paste electrode modified with cobalt (II)-phthalocyanine was demonstrated and applied to the development of a highly sensitive, simple, fast and inexpensive voltammetric sensor to determine tartaric acid. The electrochemical behavior of the modified electrode was investigated by cyclic and square wave voltammetry, and the effect of experimental variables, such as dispersion and loading of cobalt (II) phthalocyanine, together with optimum conditions for sensing the analyte by square wave voltammetry were assessed. In addition, the absence of a significant memory effect combined with the ease of electrode preparation led to the development of a sensitive and direct method to determine tartaric acid in wines. Interferences from other low molecular weight organic acids commonly present in wines were circumvented by using a multiway calibration technique, successfully obtaining the second order advantage by modeling voltammetric data with unfolded partial least square with residual bilinearization (U-PLS/RBL). A linear response range between 10 and 100 MUmol L-1 (r = 0.9991), a relative prediction error of 4.55% and a recovery range from 96.41 to 102.43% were obtained. The proposed method is non-laborious, since it does not use sample pretreatment such as filtration, extraction, pre-concentration or cleanup procedures. PMID- 29420940 TI - Triethylamine-assisted Mg(OH)2 coprecipitation/preconcentration for determination of trace metals and rare earth elements in seawater by inductively coupled plasma mass spectrometry (ICP-MS). AB - In this paper, we report an improved magnesium hydroxide, Mg(OH)2, coprecipitation method for the determination of 16 trace elements (Al, V, Cr, Mn, Mn, Fe, Co, Ni, Cu, Zn, Ga, As, Se, Sb, Sn and Pb) and 18 rare earth elements (REEs), including Sc, Y, U and Th in seawater and estuarine water samples. The procedure involves coprecipitation of the trace elements and REEs on Mg(OH)2 upon addition of a small volume of triethylamine (TEA) followed by analysis of the dissolved pellet solutions by inductively coupled plasma mass spectrometry (ICP MS). Three-step sequential coprecipitation was carried out on 10 mL aliquots of seawater to eliminate the matrix ions and to preconcentrate the analytes of interest into a 1 mL final volume. Spike recoveries varied from 85% (Th) to 105% (Y). Calcium (Ca), sodium (Na) and potassium (K) matrices were virtually eliminated from the analysis solutions. Collision reaction interface (CRI) technology utilizing H2 and He gases was employed to determine its effectiveness in removing the spectral interferences originating from the residual Mg matrix, TEA and plasma gases. H2 was more effective than He in reducing spectral interferences from TEA and plasma gases. Limits of detection (LODs) ranged from 0.01 ng L-1 (Ho) to 72 ng L-1 (Al). The method was validated by using certified seawater (CASS-4) and estuarine water (SLEW-3) reference materials. Precision for five (n = 5) replicate measurements were between 1.2% (Pr) and 18% (Lu). Fe, Pb, Sn, and Zn impurities in TEA were significant in comparison to the levels in CASS 4 and SLEW-3, while relatively high background signals impacted determinations of low levels of Sc and Th. The effects of these hurdles on precision and accuracy were alleviated by measuring these elements in spiked CASS-4 and SLEW-3. PMID- 29420942 TI - Synthesis of gold-palladium nanowaxberries/dodecylamine-functionalized graphene quantum dots-graphene micro-aerogel for voltammetric determination of peanut allergen Ara h 1. AB - The paper reports synthesis of gold-palladium nanowaxberries(AuPd NWs)/dodecylamine-functionalized graphene quantum dots(D-GQDs)-graphene micro aerogel(GMA). D-GQDs was used as a solid particle surfactant for stabilizing Pickering emulsion of toluene-in-graphene oxide aqueous dispersion. Graphene oxide sheets in the aqueous phase are reduced by hydrazine hydrate, diffused into the toluene droplet and self-assembled into graphene oxide micro-gels. Followed by freeze-drying, thermal annealing and hybridized with AuPd NWs. The as-prepared AuPd NWs/D-GQDs-GMA shows an unique three-dimensional structure with the size of microns. The small size and strong polarity make it can be directly dispersed in ethanol to form stable dispersion for sensor preparation. The hybrid of GMA, D GQDs and AuPd NWs greatly improves the electron transfer, electroactive surface area and ion diffusion. The architecture of conductor/semiconductor/conductor achieves to a significant amplification of detection signal. The DNA biosensor based on the AuPd NWs/D-GQDs-GMA exhibits ultrasensitive differential pulse voltammetric (DPV) response towards peanut allergen Ara h 1. The DPV signal linearly increases with increasing DNA concentration in the range of 1.0 * 10-22 1.0 * 10-17 M with the detection limit of 4.7 * 10-23 M (S/N = 3). The analytical method was successfully applied to voltammetric determination of peanut allergen Ara h 1 in peanut milk beverage. PMID- 29420943 TI - A novel aptamer-based online magnetic solid phase extraction method for the selective determination of 8-hydroxy-2'-deoxyguanosine in human urine. AB - In this work, an innovative magnetic aptamer adsorbent (Fe3O4-aptamer MNPs) was synthesized for the selective extraction of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Amino-functionalized-Fe3O4 was crosslinked with 8-OHdG aptamer by glutaraldehyde and fixed into a steel stainless tube as the sorbent of magnetic solid phase extraction (MSPE). After selective extraction by the aptamer adsorbent, the adsorbed 8-OHdG was desorbed dynamically and online analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS). The synthesized sorbent presented outstanding features, including specific selectivity, high enrichment capacity, stability and biocompatibility. Moreover, this proposed MSPE-HPLC-MS can achieve adsorption and desorption operation integration, greatly simplify the analysis process and reduce human errors. When compared with offline MSPE, a sensitivity enhancement of 800 times was obtained for the online method. Some experimental parameters such as the amount of the sorbent, sample flow rate and sample volume, were optimized systematically. Under the optimal conditions, low limit of detection (0.01 ng mL-1, S/N = 3), limit of quantity (0.03 ng mL-1, S/N = 10) and wide linear range with a satisfactory correlation coefficient (R2 >= 0.9992) were obtained. And the recoveries of 8-OHdG in the urine samples varied from 82% to 116%. All these results revealed that the method is simple, rapid, selective, sensitive and automated, and it could be expected to become a potential approach for the selective determination of trace 8-OHdG in complex urinary samples. PMID- 29420944 TI - Highly selective determination of ultratrace inorganic arsenic species using novel functionalized miniaturized membranes. AB - A simple method for highly selective determination of trace and ultratrace arsenic ions, i.e. arsenite and arsenate, was developed. The method is based on new miniaturized membranes, 5 mm diameter and 4.4 mg weight, which are prepared by synthesis of amorphous silica coating on cellulose fibers followed by the modification with (3-mercaptopropyl)-trimethoxysilane. The batch adsorption experiments show that membranes have high selectivity toward arsenite in the presence of heavy metals and anions that usually exist in natural water. Arsenite can be quantitatively adsorbed at pH 1 from 50 mL sample within 60 min using the miniaturized membrane with maximum adsorption capacity of 60 mg g-1. The excellent adsorptive properties of membranes open the path to simple and selective determination of trace and ultratrace arsenite in water. Moreover, the membranes can be applied in the arsenic speciation due to their selectivity toward arsenite in the presence of arsenate. After adsorption, the arsenite retained onto the membrane is directly measured by energy-dispersive X-ray fluorescence spectrometry, avoiding elution step usually required in other spectroscopy techniques. The method is characterized by excellent enrichment factor of 972, detection limit of 0.045 ng mL-1 and can be successfully applied in analysis of high salinity water, which is difficult to analyze by other spectroscopy techniques. The proposed method is a solvent-free approach based on the use of miniaturized membranes as sorbent followed by the direct measurement using a low-power X-ray spectrometer without either elution step or gas consumption during measurement. It can be considered as environmentally friendly and meets the standards of green analytical chemistry principles. PMID- 29420945 TI - Improved approach for routine monitoring of 129I activity and 129I/127I atom ratio in environmental samples using TMAH extraction and ICP-MS/MS. AB - To reconstruct 131I deposition and identify the source of radioiodine due to the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, 129I activity and 129I/127I atom ratio should be obtained by preparing and analyzing large numbers of samples economically. In this study, great efforts were made to realize mild TMAH (tetramethyl ammonium hydroxide) extraction of environmental samples at 90 degrees C to obtain solutions suitable for the following triple-quadrupole inductively coupled plasma-mass spectrometry (ICP-QQQ) MS/MS mode analysis. After releasing iodine from organic matter in the TMAH extraction solution via K2S2O8 oxidation, organic matter was removed effectively by solvent extraction and back extraction to avoid a serious matrix effect during ICP-QQQ analysis. At the same time, interfering elements, especially, Mo, Cd, and In were also removed effectively, to avoid their undesirable interferences during mass spectrometric analysis. In addition, 0.01% (NH4)2SO3 was selected to introduce I- into ICP-QQQ to ensure there was no memory effect and a stable signal was gotten. Subsequently, ICP-QQQ MS/MS mode was applied to further eliminate polyatomic interferences (127I(H2 and D)+, 97MoO2+, 113InO+, and 113CdO+) and isobaric interference from 129Xe+. Finally, the developed method was successfully applied to measure 129I/127I atom ratios ((2.61-27.0) * 10-7) and 129I activities (3.51 11.4 mBq kg-1) in soil samples. The developed method allows a greater number of ordinary laboratories to participate in the field of radioiodine analysis. PMID- 29420946 TI - High-pressure photon ionization time-of-flight mass spectrometry combined with dynamic purge-injection for rapid analysis of volatile metabolites in urine. AB - Small molecule metabolites are widely used as biomarkers in the research field of metabolomics for disease diagnosis and exposure assessment. As a readily available biofluid containing plenty of volatile organic metabolites (VOMs), urine is ideal for non-invasive metabolomic analysis; however, there is still lack of rapid analysis method for VOMs in urine. Here we report a kind of rapid method for urine analysis by employing high-pressure photon ionization time-of flight mass spectrometry (HPPI-TOFMS) combined with dynamic purge-injection. Various types of metabolites, such as ketones, alcohols, acids, sulfides, pyrroles and amines were detected directly by simple acidification or alkalization of urines. It is noteworthy that nitrogen-containing compounds, especially polar amines, could be ultrasensitively measured without any derivatization. The analytical capability of the direct HPPI-MS technique was demonstrated by analyzing five valuable metabolites, i.e., toluene, 2,5 dimethylpyrrole, trimethlyamine, styrene, and p-xylene, which exhibited relatively low limits of detection, wide linear range and satisfactory repeatability. Being highly sensitive and humidity-friendly, the whole analytical procedure is easily operated in less than 6 min. Interestingly, a new biomarker 2,5-dimethylpyrrole was exclusively found in the smoker's urine sample besides toluene. The work presents a novel tool for rapid nontarget disease biomarkers screening or target monitoring of specific compounds through the investigation of volatile metabolites in urine. PMID- 29420947 TI - Investigation of hydride generation from arsenosugars - Is it feasible for speciation analysis? AB - Hydride generation (HG) from arsenosugars (dimethylarsinoylribosides) in batch and flow injection modes was studied. Its efficiency was found higher in H2SO4 medium than in HCl and higher in the batch mode than in the flow injection mode. To increase the efficiency in the flow injection mode a new generator with two inlets of NaBH4 solution was designed. This modified generator was interfaced between a HPLC column and an atomic fluorescence detector. The arsenosugars studied yielded HG efficiencies in the range 13-30% most probably due to a complicated mechanism of HG. While the mechanism included a formation of two structures of the analyte-borane-complexes, only one of them can lead to a formation of volatile arsanes (dimethylarsane, methylarsane, and arsane were identified). PMID- 29420948 TI - Double labelling of intracellular mitochondria and nucleolus using thiophene pyridium salt with high quantum yield as biosensor and its application in stimulated emission depletion nanoscopy. AB - Probe for dual-site target distinct subcellular compartments from cytosol and nucleus is an attractive approach, however, which was scarcely reported. Herein, a series of small-molecular thiophene pyridium salt derivatives (MitoNuc1-4) possessing water-soluble, high quantum yield and two-photon activity were rationally designed, and their structures were crystallographic confirmed. Systematic photophysical and biological imaging property investigations were carried out for them. It was found that MitoNuc1-4 exhibit two-photon absorption properties in the near infrared region, and MitoNuc1 has membrane permeability and cationic nature, rendering it to be double labelling of mitochondria and nucleolus in living cells with superb photo-stability and non-invasiveness. It also demonstrated that MitoNuc1 in living cells can monitor mitochondrial division in real time and revealed nucleolar ultrastructure under stimulated emission depletion nanoscopy. PMID- 29420949 TI - Nickel-mediated allosteric manipulation of G-quadruplex DNAzyme for highly selective detection of histidine. AB - Since abnormal metabolism of histidine (His) is defined as an indicator of several diseases, detection of His in biological fluids becomes increasingly urgent to us. However, due to similar structures and properties of different amino acids, selective quantification of His is difficulty, and typically needs the participation of special reagents. In this work, we report for the first time that nickel ions (Ni2+) can induce the allostery of G-quadruplex, and is thus able to manipulate the activity of G-quadruplex DNAzyme. Experimental results indicate the interaction between Ni2+ and guanine is critical to the allostery. In comparison with Ni2+-guanine interaction, Ni2+-His interaction exhibits higher affinity. Therefore, a colorimetric His biosensor is fabricated, and His can be facilely discriminated by naked eyes. Relying on the high activity of DNAzyme, His in a range of 50 nM-400 MUM is determined with this method, and low detection limit (36 nM) is obtained. More importantly, His can be directly distinguished in the absence of other toxic reagents. In addition, the amount of His in serum is also measured, suggesting the applicability of this biosensor in real sample detection. Overall, this work provides an alternative way to design G-quadruplex DNAzyme-based analytical approaches. PMID- 29420950 TI - Amplified fluorescence detection of serum prostate specific antigen based on metal-dependent DNAzyme assistant nanomachine. AB - An amplified fluorescence biosensing strategy for serum prostate specific antigen (PSA) was developed on the basis of DNAzyme. In presence of cofactor Zn2+, Zn2+ dependent DNAzyme could cleave the hairpin substrate probes which were dispersed in solution and generate remarkable fluorescent signal. Taking advantage of the magnetic beads as a carrier, one target protein could bring plentiful hairpin substrate probes on to the electrode through a sandwich structure (Ab1/PSA/biotin Ab2). Moreover, during the cleavage process of as formed DNAzyme, DNAzyme did not be destroyed and could further react with other hairpin probes, then generated continuous fluorescent signal. Benefited by this amplified strategy, the limit of detection (LOD) was low to 0.05 ng mL-1, which was much lower than our previous reports. This method could be applied to detect different protein biomarkers in serum without corresponding aptamers by changing the corresponding antibodies and thus showed a remarkable prospect in clinical application. PMID- 29420951 TI - Fluorouracil Filtering Surgery Study One-Year Follow-up. AB - Two hundred thirteen patients participated in the Fluorouracil Filtering Surgery Study, a randomized clinical trial, to determine the efficacy and safety of subconjunctivally injected 5-fluorouracil after filtering surgery in eyes with poor prognoses. Twenty-eight (27%) of the 105 eyes in the 5-fluorouracil group and 54 (50%) of the 108 eyes in the standard group were classified as failures, defined by reoperation for control of intraocular pressure during the first year or an intraocular pressure greater than 21 mm Hg at the one-year visit (P = .0007, Mantel-Haenszel chi-square). Corneal epithelial toxicity and transient visual acuity loss were more common in the 5-fluorouracil group (P < .001, chi square); however, the visual acuities and the mean visual field sensitivities were not significantly different at one year. We recommend the use of subconjunctivally injected 5-fluorouracil after trabeculectomy in eyes with uncontrolled glaucoma and poor prognoses, specifically after previous cataract extraction or unsuccessful filtering surgery. PMID- 29420952 TI - Micromanaging Memory. PMID- 29420953 TI - Peripheral Activity and Central Substrates of BACE1: Therapeutic Implications for Alzheimer's Disease. PMID- 29420954 TI - Compliance With Guideline-Directed Medical Therapy in Contemporary Coronary Revascularization Trials. AB - BACKGROUND: Despite the well-established benefits of secondary cardiovascular prevention, the importance of concurrent medical therapy in clinical trials of coronary revascularization is often overlooked. OBJECTIVES: The goal of this study was to assess compliance with guideline-directed medical therapy (GDMT) in clinical trials and its potential impact on the comparison between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). METHODS: The Cochrane Central Register of Controlled Trials and MEDLINE were searched from 2005 to August 2017. Clinical trial registries and reference lists of relevant studies were also searched. Randomized controlled trials comparing PCI with drug eluting stents versus CABG and reporting medical therapy after revascularization were included. The study outcome was compliance with GDMT, defined as the following: 1) any antiplatelet agent plus beta-blocker plus statin (GDMT1); and 2) any antiplatelet agent plus beta-blocker plus statin plus angiotensin converting enzyme inhibitor/angiotensin receptor blocker (GDMT2). Data collection and analysis were performed according to the methodological recommendations of The Cochrane Collaboration. RESULTS: From a total of 439 references, 5 trials were included based on our inclusion and exclusion criteria. Overall, compliance with GDMT1 was low and decreased over time from 67% at 1 year to 53% at 5 years. Compliance with GDMT2 was even lower and decreased from 40% at 1 year to 38% at 5 years. Compliance with both GDMT1 and GDMT2 was higher in PCI than in CABG at all time points. Meta-regression suggested an association between lower use of GDMT1 and adverse clinical outcomes in PCI versus CABG at 5 years. CONCLUSIONS: Compliance with GDMT in contemporary clinical trials remains suboptimal and is significantly lower after CABG than after PCI, which may influence the comparison of clinical trial endpoints between those study groups. PMID- 29420955 TI - Suboptimal Medical Therapy After Coronary Revascularization: A Missed Opportunity. PMID- 29420956 TI - Performance of Coronary Risk Scores Among Patients With Chest Pain in the Emergency Department. AB - BACKGROUND: Both the modified History, Electrocardiogram, Age, Risk factors and Troponin (HEART) score and the Emergency Department Assessment of Chest pain Score (EDACS) can identify patients with possible acute coronary syndrome (ACS) at low risk (<1%) for major adverse cardiac events (MACE). OBJECTIVES: The authors sought to assess the comparative accuracy of the EDACS (original and simplified) and modified HEART risk scores when using cardiac troponin I (cTnI) cutoffs below the 99th percentile, and obtain precise MACE risk estimates. METHODS: The authors conducted a retrospective study of adult emergency department (ED) patients evaluated for possible ACS in an integrated health care system between 2013 and 2015. Negative predictive values for MACE (composite of myocardial infarction, cardiogenic shock, cardiac arrest, and all-cause mortality) were determined at 60 days. Reclassification analyses were used to assess the comparative accuracy of risk scores and lower cTnI cutoffs. RESULTS: A total of 118,822 patients with possible ACS were included. The 3 risk scores' accuracies were optimized using the lower limit of cTnI quantitation (<0.02 ng/ml) to define low risk for 60-day MACE, with reclassification yields ranging between 3.4% and 3.9%, while maintaining similar negative predictive values (range 99.49% to 99.55%; p = 0.27). The original EDACS identified the largest proportion of patients as low risk (60.6%; p < 0.0001). CONCLUSIONS: Among ED patients with possible ACS, the modified HEART score, original EDACS, and simplified EDACS all predicted a low risk of 60-day MACE with improved accuracy using a cTnI cutoff below the 99th percentile. The original EDACS identified the most low-risk patients, and thus may be the preferred risk score. PMID- 29420957 TI - Evaluating Chest Pain in the Emergency Department: Searching for the Optimal Gatekeeper. PMID- 29420959 TI - Cardiovascular Risk Beyond Low-Density Lipoprotein Cholesterol. PMID- 29420958 TI - Lipids, Lipoproteins, and Metabolites and Risk of Myocardial Infarction and Stroke. AB - BACKGROUND: Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes. OBJECTIVES: This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH). METHODS: In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a 1-SD higher metabolic marker. RESULTS: Very low-, intermediate-, and low-density lipoprotein particles were positively associated with MI and IS. High-density lipoprotein (HDL) particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles were associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (OR: 0.79 and 0.88, respectively), whereas cholesterol in small HDL was not (OR: 0.99 and 1.06, respectively). Triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose, and docosahexaenoic acid were associated with all 3 diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH. CONCLUSIONS: Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with MI. Glycoprotein acetyls and several non-lipid-related metabolites associated with all 3 diseases. PMID- 29420960 TI - Long-Term Sirolimus for Primary Immunosuppression in Heart Transplant Recipients. AB - BACKGROUND: Small studies have reported superiority of sirolimus (SRL) over calcineurin inhibitor (CNI) in mitigating cardiac allograft vasculopathy (CAV) after heart transplantation (HT). However, data on the long-term effect on CAV progression and clinical outcomes are lacking. OBJECTIVES: The aim of this study was to test the long-term safety and efficacy of conversion from CNI to SRL as maintenance therapy on CAV progression and outcomes after HT. METHODS: A cohort of 402 patients who underwent HT and were either treated with CNI alone (n = 134) or converted from CNI to SRL (n = 268) as primary immunosuppression was analyzed. CAV progression was assessed using serial coronary intravascular ultrasound during treatment with CNI (n = 99) and after conversion to SRL (n = 235) in patients who underwent at least 2 intravascular ultrasound studies. RESULTS: The progression in plaque volume (2.8 +/- 2.3 mm3/mm vs. 0.46 +/- 1.8 mm3/mm; p < 0.0001) and plaque index (plaque volume-to-vessel volume ratio) (12.2 +/- 9.6% vs. 1.1 +/- 7.9%; p < 0.0001) were significantly attenuated when treated with SRL compared with CNI. Over a mean follow-up period of 8.9 years from time of HT, all cause mortality occurred in 25.6% of the patients and was lower during treatment with SRL compared with CNI (adjusted hazard ratio: 0.47; 95% confidence interval: 0.31 to 0.70; p = 0.0002), and CAV-related events were also less frequent during treatment with SRL (adjusted hazard ratio: 0.35; 95% confidence interval: 0.21 to 0.59; p < 0.0001). Further analyses suggested more attenuation of CAV and more favorable clinical outcomes with earlier conversion to SRL (<=2 years) compared with late conversion (>2 years) after HT. CONCLUSIONS: Early conversion to SRL is associated with attenuated CAV progression and with lower long-term mortality and fewer CAV-related events compared with continued CNI use. PMID- 29420961 TI - The Return of the mTOR Inhibitors: Getting it Right in Patients After Cardiac Transplantation. PMID- 29420962 TI - Activation of Serine One-Carbon Metabolism by Calcineurin Abeta1 Reduces Myocardial Hypertrophy and Improves Ventricular Function. AB - BACKGROUND: In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria. OBJECTIVES: The authors aimed to determine the role of the calcineurin splicing variant CnAbeta1 in the context of cardiac hypertrophy and its mechanism of action. METHODS: Transgenic mice overexpressing CnAbeta1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnAbeta1 (CnAbeta1Deltai12 mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses. RESULTS: In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnAbeta1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAbeta1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnAbeta1. CnAbeta1Deltai12 mice show increased cardiac hypertrophy and declined contractility. CONCLUSIONS: The metabolic reprogramming induced by CnAbeta1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approaches. PMID- 29420963 TI - A Surprising Noncanonical Role for Calcineurin in Pressure-Induced Cardiac Hypertrophy. PMID- 29420964 TI - Metabolic Surgery: Weight Loss, Diabetes, and Beyond. AB - The alarming rise in the worldwide prevalence of obesity is paralleled by an increasing burden of type 2 diabetes mellitus. Metabolic surgery is the most effective means of obtaining substantial and durable weight loss in individuals with obesity. Randomized trials have recently shown the superiority of surgery over medical treatment alone in achieving improved glycemic control, as well as a reduction in cardiovascular risk factors. The mechanisms seem to extend beyond the magnitude of weight loss alone and include improvements in incretin profiles, insulin secretion, and insulin sensitivity. Moreover, observational data suggest that the reduction in cardiovascular risk factors translates to better patient outcomes. This review describes commonly used metabolic surgical procedures and their current indications and summarizes the evidence related to weight loss and glycemic outcomes. It further examines their potential effects on cardiovascular outcomes and mortality and discusses future perspectives. PMID- 29420965 TI - Environmental Noise and the Cardiovascular System. AB - Noise has been found associated with annoyance, stress, sleep disturbance, and impaired cognitive performance. Furthermore, epidemiological studies have found that environmental noise is associated with an increased incidence of arterial hypertension, myocardial infarction, heart failure, and stroke. Observational and translational studies indicate that especially nighttime noise increases levels of stress hormones and vascular oxidative stress, which may lead to endothelial dysfunction and arterial hypertension. Novel experimental studies found aircraft noise to be associated with oxidative stress-induced vascular damage, mediated by activation of the NADPH oxidase, uncoupling of endothelial nitric oxide synthase, and vascular infiltration with inflammatory cells. Transcriptome analysis of aortic tissues from animals exposed to aircraft noise revealed changes in the expression of genes responsible for the regulation of vascular function, vascular remodeling, and cell death. This review focuses on the mechanisms and the epidemiology of noise-induced cardiovascular diseases and provides novel insight into the mechanisms underlying noise-induced vascular damage. PMID- 29420966 TI - Tele-Cardiology in the Syrian War. PMID- 29420967 TI - Increasing Pulmonary Arterial Pressure at Low Level of Exercise in Asymptomatic, Organic Mitral Regurgitation. PMID- 29420968 TI - Impact of Sleep Duration and Race on Recurrent Cardiovascular Events Following Acute Coronary Syndrome. PMID- 29420970 TI - LDL-Cholesterol and Atherosclerotic Cardiovascular Disease: Innocent Bystander or Essential Ingredient. PMID- 29420969 TI - Left Ventricle Replacement Fibrosis Detected by CMR Associated With Cardiovascular Events in Systemic Sclerosis Patients. PMID- 29420971 TI - Reply: LDL-Cholesterol and Atherosclerotic Cardiovascular Disease: Innocent Bystander or Essential Ingredient? PMID- 29420972 TI - Is Skipping Breakfast a Marker for Current Smoking? PMID- 29420973 TI - Breakfast Skipping, Atherosclerosis Disease, and Free Fatty Acids. PMID- 29420974 TI - Reply: Skipping Breakfast Is a Marker of Unhealthy Lifestyle. PMID- 29420975 TI - Prostate Cancer and the Evolving Role of Biomarkers in Screening and Diagnosis. AB - The diagnosis and management of prostate cancer have substantially changed over the last 3 decades. Serum prostate-specific antigen (PSA) was adopted for screening in the 1990s after it was found to be a sensitive indicator of disease. Because of a lack of specificity for significant disease, indiscriminate PSA testing led to overdiagnosis and overtreatment. Several biomarkers have been developed that are superior to PSA in stratifying a man's risk for harboring potentially lethal prostate cancer. PMID- 29420976 TI - MR Imaging of Prostate Zonal Anatomy. AB - McNeal first described the zonal anatomy of the prostate about 40 years ago, outlining 4 zones of the prostate and defining their relation to the urethra and the ejaculatory ducts. The zonal anatomy remains the accepted model for describing the prostate and the zones are well-depicted on MR imaging, including the central zone, which until recently was grouped with the transition zone in the radiology literature. An accurate understanding of the zonal anatomy and periprostatic anatomy is key for accurate interpretation of the prostate MR imaging. PMID- 29420977 TI - Technique of Multiparametric MR Imaging of the Prostate. AB - Multiparametric MR imaging provides detailed anatomic assessment of the prostate as well as information that allows the detection and characterization of prostate cancer. To obtain high-quality MR imaging of the prostate, radiologists must understand sequence optimization to overcome commonly encountered technical challenges. This review discusses the techniques that are used in state-of-the art MR imaging of the prostate, including imaging protocols, hardware considerations, and important aspects of patient preparation, with an emphasis on the recommendations provided in the prostate imaging-reporting and data system version 2 guidelines. PMID- 29420978 TI - Multiparametric MR imaging of the Prostate: Interpretation Including Prostate Imaging Reporting and Data System Version 2. AB - mp-MRI of the prostate is a complex study that combines anatomic and functional imaging. The complexity of this technique, along with an increasing demand, has brought new challenges to imaging interpretation. The Prostate Imaging Reporting and Data System provides radiologists with guidelines to standardize interpretation. This article discusses the interpretation of the pulse sequences recommended in the Prostate Imaging Reporting and Data System version 2 guidelines, reviews advanced quantitative imaging tools, and discusses future directions. PMID- 29420979 TI - Multiparametric Prostate MR Imaging: Impact on Clinical Staging and Decision Making. AB - Meaningful changes to the approach of prostate cancer staging and management have been made over the past decade with increasing demand for high-quality multiparametric MR imaging (mpMRI) of the prostate. This article focuses on the evolving paradigm of prostate cancer staging, with emphasis on the role of mpMRI on staging and its integration into clinical decision making. Current prostate cancer staging systems are defined and mpMRI's role in the detection of non-organ confined disease and how it has an impact on the selection of appropriate next steps are discussed. Several imaging pitfalls, limitations, and future directions of mpMRI also are discussed. PMID- 29420980 TI - MR Imaging for Prostate Cancer Screening and Active Surveillance. AB - The current prostate cancer management paradigm has been criticized in recent years for contributing to the overdiagnosis and overtreatment of the disease. Active surveillance is an avenue by which to reduce overtreatment, but patient selection and monitoring remain a challenge. The use of prostate MR imaging has been growing in recent years and has been incorporated into prostate cancer screening and patient selection and monitoring for active surveillance. This review article discusses the current evidence for the use of MR imaging in each of those settings. PMID- 29420982 TI - Multiparametric MR imaging of the Prostate: Pitfalls in Interpretation. AB - Multiparametric MR imaging is widely embraced for the diagnosis, staging, and surveillance of prostate cancer. However, normal anatomic structures and many benign entities have overlapping imaging features with prostate cancer. Although some of these entities require biopsy and histopathologic diagnosis, some have characteristic imaging features that are suggestive of their diagnosis. Knowledge of these pitfalls is important in establishing a correct diagnosis and avoiding unnecessary biopsies, as these entities are encountered routinely in clinical practice. PMID- 29420983 TI - MR Imaging-Targeted Prostate Biopsies. AB - Conventional ultrasound-guided prostate biopsies have multiple limitations leading to underdetection of clinically significant prostate cancer (PCa) and overdetection of clinically insignificant PCa. Multiparametric MR imaging of the prostate offers better localization of prostatic tumors in comparison with ultrasound imaging and can help address these limitations. MR imaging-identified lesions can be targeted for biopsy directly in-gantry or indirectly using a fusion of MR imaging and ultrasound imaging. The fusion may be performed by the operator visually or using a software fusion device. In this article, we review the various techniques for MR imaging-targeted prostate biopsies and their clinical impact for PCa diagnosis. PMID- 29420981 TI - Prostate MR Imaging for Posttreatment Evaluation and Recurrence. AB - Prostate multiparametric MR imaging (mpMRI) plays an important role in local evaluation after treatment of prostate cancer. After radical prostatectomy, radiation therapy, and focal therapy, mpMRI can be used to visualize normal post treatment changes and to diagnose locally recurrent disease. An understanding of the various treatments and expected changes is essential for complete and accurate post-treatment mpMRI interpretation. PMID- 29420984 TI - MR Imaging-Guided Focal Treatment of Prostate Cancer: An Update. AB - Focal treatment of prostate cancer has evolved from a concept to a practice in the recent few years and is projected to fill an existing need, bridging the gap between conservative and radical traditional treatment options. With its low morbidity and rapid recovery time compared with whole-gland treatment alternatives, focal therapy is poised to gain more acceptance among patients and health care providers. As our experience with focal treatment matures and evidence continues to accrue, the landscape of this practice might look quite different in the future. PMID- 29420985 TI - Role of Prostate MR Imaging in Radiation Oncology. AB - The use of prostate MR imaging in radiotherapy continues to evolve. This article describes its current application in the selection of treatment regimens, integration in treatment planning or simulation, and assessment of response. An expert consensus statement from the annual MR in RT symposium is presented, as a list of 21 key quality indicators for the practice of MR imaging simulation in prostate cancer. Although imaging requirements generally follow PIRADSv2 guidelines, additional requirements specific to radiotherapy planning are described. MR imaging-only workflows and MR imaging-guided treatment systems are expected to replace conventional computed tomography-based practice, further adding specific requirements for MR imaging in radiotherapy. PMID- 29420987 TI - Prostate MR Imaging. PMID- 29420988 TI - Introduction to the Special Issue. PMID- 29420989 TI - Supplemental protein from dairy products increases body weight and vitamin D improves physical performance in older adults: a systematic review and meta analysis. AB - The purpose of these systematic review and meta-analysis was to assess the effectiveness of dairy components on nutritional status and physical fitness in older adults, as evidence for efficacy of the supplementation of these components is inconclusive. Scopus and MEDLINE were searched. Main inclusion criteria for articles were as follows: double-blind, randomized, placebo-controlled trials including participants aged >=55 years who received dairy components or a placebo. Outcome measures were nutrient status (body weight and body mass index) and physical fitness (body composition, muscle strength, and physical performance). Thirty-six trials with 4947participants were included. Most trials investigated protein and vitamin D supplementation and showed no effect on the outcomes. Meta-analysis on the effect of protein on body weight showed a significant increase in mean difference of 1.13 kg (95% confidence interval, 0.59 1.67). This effect increased by selecting trials with study a duration of 6 months in which less nourished and physically fit participants were included. Trials where the participants were (pre-)frail, inactive older adults or when supplementing >=20 g of protein per day tended to increase lean body mass. Only small significant effects of vitamin D supplementation on Timed Up and Go (mean difference -0.75 seconds; 95% confidence interval -1.44 to -0.07) were determined. This effect increased when vitamin D doses ranged between 400 and 1000 IU. Additional large randomized controlled trials of >=6 months are needed regarding the effect of dairy components containing an adequate amount of vitamin D (400-1000 IU) and/or protein (>=20 g) on nutritional status and physical fitness in malnourished or frail older adults. PMID- 29420986 TI - Future Perspectives and Challenges of Prostate MR Imaging. AB - MR imaging is an important part of prostate cancer diagnosis. Variations in quality and skill in general practice mean results are not as impressive as they were in academic centers. This observation provides an impetus to improve the method. Improved quality assurance will likely result in better outcomes. Improved characterization of clinically significant prostate cancer may assist in making MR imaging more useful. Improved methods of registering MR imaging with transrectal ultrasound imaging and robotic arms controlling the biopsy can reduce the impact of inexperienced operators and make the entire system of MR imaging guided biopsies more robust. PMID- 29420990 TI - Potential roles of vitamin E in age-related changes in skeletal muscle health. AB - Skeletal muscle disorders including sarcopenia are prevalent during the complex biological process of aging. Loss of muscle mass and strength commonly seen in sarcopenia is induced by impaired neuromuscular innervation, transition of skeletal muscle fiber type, and reduced muscle regenerative capacity, all attributable to chronic inflammation, oxidative stress, and mitochondrial dysfunction. Current literature suggests that vitamin E molecules (alpha-, beta-, gamma-, delta-tocopherols and the corresponding tocotrienols) with their antioxidant and anti-inflammatory capabilities may mitigate age-associated skeletal dysfunction and enhance muscle regeneration, thus attenuating sarcopenia. Preclinical and human experimental studies show that vitamin E benefits myoblast proliferation, differentiation, survival, membrane repair, mitochondrial efficiency, muscle mass, muscle contractile properties, and exercise capacity. Limited number of human cross-sectional observational studies reveal positive associations between serum tocopherol level and muscle strength. Several factors, including difficulties in validating vitamin E intake and deficiency, variations in muscle-protective activity and metabolism of diverse forms of vitamin E, and lack of understanding of the mechanisms of action, preclude randomized clinical trials of vitamin E in people with sarcopenia. Future research should consider long-term clinical trials of with adequate sample size, advanced imaging technology and omics approaches to investigate underlying mechanisms and assess clinically meaningful parameters such as muscle strength, physical performance, and muscle mass in sarcopenia prevention and/or treatment. PMID- 29420991 TI - A low-glycemic index and -glycemic load diet is associated with not only higher intakes of micronutrients but also higher intakes of saturated fat and sodium in Japanese children and adolescents: the National Health and Nutrition Survey. AB - We investigated the hypothesis that the dietary glycemic index (GI) and glycemic load (GL) of Japanese children is associated with both favorable and unfavorable aspects of dietary intake. This cross-sectional study was based on 1-day weighed dietary record data from 3866 children in the 2012 National Health and Nutrition Survey, Japan. The GI of foods was assigned based on a stepwise published strategy using values from common GI databases. Mean dietary GI and GL were, respectively, 63.4 and 108.2 for children aged 1-6 years, 64.7 and 166.5 for those aged 7-14 years, and 66.3 and 196.0 for those aged 15-19 years. Irrespective of age, the top contributor to dietary GL was white rice (GI 76; 48% 60%). White rice not only was positively associated with dietary GI but also contributed most (28%-35%) to interindividual variation in dietary GI. For dietary GL, ~90% of the variation was explained by carbohydrate-rich foods (mainly white rice; 43%-70%), all of which were positive predictors. At the nutrient level, only carbohydrate intake was positively associated with dietary GI and GL, whereas intakes of all other nutrients including saturated fat and sodium showed inverse associations (with some exceptions). In conclusion, dietary GI and GL of Japanese children were primarily determined by the high-GI food white rice and were thus relatively high compared with those observed in Western countries. A low-GI and -GL diet was associated with both favorable (higher intakes of micronutrients) and unfavorable (higher intakes of saturated fat and sodium) aspects of dietary patterns. PMID- 29420992 TI - Food acceptability affects ghrelin and insulin levels in healthy male subjects. A pilot study. AB - The obesity prevalence worldwide is reaching epidemic proportions, which makes the understanding of the mechanisms that regulate appetite of paramount importance. This study assessed whether the hedonic characteristics of a food item (high acceptability [HA] vs modified low acceptability [LA]) have a significant effect on postprandial ghrelin and insulin levels and appetite scores of isoenergetic meals in normal-weight men. We hypothesize that food acceptability would significantly impact appetite scores and affect the studied postprandial hormones. Eleven healthy men with normal body mass index (19-25 kg/m2) were recruited for a randomized, crossover design. Subjects were randomly assigned to 1 of 2 meals: vanilla custard with acesulfame-K (LA, excessively sweet) or without it (HA). One week later, subjects were crossed over to ingest the other meal. Blood samples were withdrawn before meal (time 0) and after 15, 30, 60, 120, 180, and 240 minutes and were analyzed for ghrelin, insulin, and glucose. Appetite scores were also recorded at the above time points, and acceptability was measured. Ghrelin levels were significantly higher (P<.05) for LA meal at 180 and 240 minutes than the HA meal. Insulin levels were significantly higher (P<.05) for HA meal at 15 and 30 minutes than the LA meal. Appetite scores varied from baseline levels for both meals but not between meals at different time points. The results suggest that the hedonic properties of a meal could affect food intake and appetite through stimulation or inhibition of appetite hormones, suggesting the need to assess the acceptability of foods in formulating weight-reducing diets. PMID- 29420993 TI - Glucagon-like peptide-2 improves intestinal immune function and diminishes bacterial translocation in a mouse model of parenteral nutrition. AB - Parenteral nutrition (PN) is associated with increased infectious risks due to impaired intestinal immunity. Although glucagon-like peptide-2 (GLP-2) enhances the gut barrier function, it is uncertain whether it improves mucosal immunologic barrier function. We hypothesized that injecting the PN mouse model with GLP-2 improved innate and acquired immunity, and prevented bacterial translocation. Forty-eight hours after venous cannulation, male Institute of Cancer Research mice were randomly divided into 3 groups based on their diet: chow with saline (n = 10), PN (n = 9), or PN + GLP-2 (30 MUg bid per mouse, n = 10) provided for 5 days. Compared with chow, PN reduced interleukin (IL)-4 and IL-13 levels (P < .05, respectively), whereas, compared with PN alone, GLP-2 injection increased IL 4 and IL-13 levels (P < .05, respectively). Compared with chow, PN considerably suppressed, whereas GLP-2 improved, secretory phospholipase A2 and cryptdin-4 expression. PN, compared with chow, considerably decreased lysozyme and polymeric immunoglobulin receptor levels, whereas, compared with PN, GLP-2 significantly increased these protein levels (P < .01, respectively). In tissue and luminal samples, compared with chow, PN reduced secretory immunoglobulin A levels (P < .05), whereas, compared with PN alone, GLP-2 increased secretory immunoglobulin A levels (P < .05). Functionally, more bacterial translocation was observed in the PN group compared with the chow group (P < .001), and GLP-2 injection decreased bacterial translocation to chow levels (P < .05). In summary, GLP-2 treatment may improve intestinal innate and acquired immunity, and prevent bacterial translocation in mice on total parenteral nutrition. PMID- 29420994 TI - l-Theanine and caffeine improve target-specific attention to visual stimuli by decreasing mind wandering: a human functional magnetic resonance imaging study. AB - Oral intake of l-theanine and caffeine supplements is known to be associated with faster stimulus discrimination, possibly via improving attention to stimuli. We hypothesized that l-theanine and caffeine may be bringing about this beneficial effect by increasing attention-related neural resource allocation to target stimuli and decreasing deviation of neural resources to distractors. We used functional magnetic resonance imaging (fMRI) to test this hypothesis. Solutions of 200mg of l-theanine, 160mg of caffeine, their combination, or the vehicle (distilled water; placebo) were administered in a randomized 4-way crossover design to 9 healthy adult men. Sixty minutes after administration, a 20-minute fMRI scan was performed while the subjects performed a visual color stimulus discrimination task. l-Theanine and l-theanine-caffeine combination resulted in faster responses to targets compared with placebo (?=27.8milliseconds, P=.018 and ?=26.7milliseconds, P=.037, respectively). l-Theanine was associated with decreased fMRI responses to distractor stimuli in brain regions that regulate visual attention, suggesting that l-theanine may be decreasing neural resource allocation to process distractors, thus allowing to attend to targets more efficiently. l-Theanine-caffeine combination was associated with decreased fMRI responses to target stimuli as compared with distractors in several brain regions that typically show increased activation during mind wandering. Factorial analysis suggested that l-theanine and caffeine seem to have a synergistic action in decreasing mind wandering. Therefore, our hypothesis is that l-theanine and caffeine may be decreasing deviation of attention to distractors (including mind wandering); thus, enhancing attention to target stimuli was confirmed. PMID- 29420995 TI - Cysteine ameliorates allergic inflammatory reactions by suppressing thymic stromal lymphopoietin production in activated human mast cells. AB - Thymic stromal lymphopoietin (TSLP) derived by mast cells is recognized as a critical factor in many allergic inflammatory disorders. Cysteine is a well-known amino acid which exhibits anti-inflammatory activities. However, the effect and mechanism of cysteine on TSLP production have not been investigated. Thus, we hypothesized that cysteine may regulate TSLP production from mast cells. To test this hypothesis, the anti-inflammatory effects and signaling pathways of cysteine were investigated in phorbol 12-myristate 13-acetate 4 and calcium ionophore A23187 (PMACI)-stimulated human mast cell line HMC-1. Cysteine dramatically attenuated the levels of TSLP of both mRNA and protein without cytotoxicity. Moreover, cysteine suppressed caspase-1 activation and nuclear factor-kappaB translocation. The phosphorylation of p38 and c-Jun N-terminal kinase was downregulated in all cases in PMACI-stimulated HMC-1 cells treated with cysteine. In addition, cysteine decreased PMACI-induced proinflammatory cytokines in terms of both protein and mRNA levels. In conclusion, cysteine regulates TSLP production by blocking caspase-1, nuclear factor-kappaB, p38, and c-Jun N terminal kinase-dependent pathways in activated HMC-1 cells, suggesting its potential as a regulator of allergic inflammatory diseases. PMID- 29420996 TI - Walnut extract modulates activation of microglia through alteration in intracellular calcium concentration. AB - Diets supplemented with walnuts have shown to protect brain against oxidative and inflammatory cytotoxicity and promote protective cellular and cognitive function. The current study was undertaken to test the hypothesize that whole walnut extract (WNE) inhibits lipopolysaccharide (LPS)-induced microglial activation by regulating calmodulin (CaM) expression through [Ca2+]i. To test this hypothesis, we used an in vitro model the highly aggressively proliferating immortalized cells, a rat microglial cell line, treated with various concentrations of WNEs. Treatment with WNE (1.5%, 3%, or 6%) induced a slow rise in intracellular calcium in a concentration- and time-dependent manner, and this rise became exaggerated when cells were depolarized with potassium chloride (100 mmol/L). Cells treated with WNE (1%, 3%, or 6%) upregulated CaM protein levels, with 1 hour posttreatment being the peak time, regardless of WNE concentration. Interestingly, this WNE-induced upregulation of CaM was blocked by pretreatment with thapsigargin. Additionally, treatment with WNE (1%, 3%, or 6%) 1 hour prior to LPS treatment was found to be effective in preventing LPS-induced upregulation of inducible nitric oxide synthase expression, upregulation of ionized Ca2+ binding adaptor-1, and downregulation of CaM. These findings suggest that bioactive compounds in walnut are capable of modulating microglial activation through regulation of intracellular calcium and CaM expression. Nutritional interventions using walnuts may be effective in the amelioration of chronic inflammation and neurodegeneration. PMID- 29420997 TI - l-Carnosine supplementation attenuated fasting glucose, triglycerides, advanced glycation end products, and tumor necrosis factor-alpha levels in patients with type 2 diabetes: a double-blind placebo-controlled randomized clinical trial. AB - Considering the pathologic importance of metabolic disturbances, advanced glycation end products (AGEs), and chronic inflammation in diabetes mellitus and ameliorating potentials of l-carnosine in hampering these detritions and because these effects have not been investigated in patients with type 2 diabetes (T2D) so far, we conducted the current study. We hypothesized that l-carnosine would improve glycemic control, lipid profile, AGE, soluble receptor of AGEs (sRAGE), and inflammatory markers. In a randomized, double-blind, placebo-controlled clinical trial, 54 patients with T2D were recruited and assigned into either intervention group (n=27, receiving 2 capsules of l-carnosine 500 mg each) or control group (n=27). Blood samples and dietary intakes information were collected at baseline and after 12 weeks of intervention. l-Carnosine supplementation resulted in significant decrease in fat mass and an increase in fat-free mass in the intervention group compared with the placebo group (1.5% and 1.7%, respectively) (P<.05). A significant reduction in fasting blood glucose (13.1 mg/dL); glycated hemoglobin (.6%); and serum levels of triglycerides (29.8 mg/dL), carboxymethyl lysine (91.8 ng/mL), and tumor necrosis factor-alpha was detected in the l-carnosine group compared with the placebo group (P<.05). In the l-carnosine group, a significant reduction in serum pentosidine levels (2.8 ng/mL) was observed compared with those at baseline (P<.05). No significant differences were observed in dietary intake, body mass index, systolic and diastolic blood pressure, fasting insulin levels, homeostasis model assessment of insulin resistance and secretion, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, sRAGE, interleukin (IL)-6, and IL-1beta levels between the groups after adjusting for baseline values and covariates (P>.05). Collectively, l-carnosine lowered fasting glucose, serum levels of triglycerides, AGEs, and tumor necrosis factor-alpha without changing sRAGE, IL-6, and IL-1beta levels in T2D patients. PMID- 29420998 TI - Comments on "Predictors of Change in Physical Function in Older Adults in Response to Long-Term, Structured Physical Activity: The LIFE Study". PMID- 29421000 TI - The Authors Respond. PMID- 29420999 TI - Comparative Efficacy of Intra-Articular Steroid Injection and Distension in Patients With Frozen Shoulder: A Systematic Review and Network Meta-Analysis. PMID- 29421001 TI - Thrombus aspiration and prehospital ticagrelor administration in ST-elevation myocardial infarction: Findings from the ATLANTIC trial. AB - BACKGROUND: The potential interactions between prehospital (pre-H) ticagrelor administration and thrombus aspiration (TA) in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) have never been studied. Therefore, we evaluated the potential benefit of TA and pre-H ticagrelor treatment in patients enrolled in the ATLANTIC trial (NCT01347580). METHODS: This analysis included 1,630 patients who underwent primary PCI. Multivariate analysis was used to explore the potential association of TA and pre-H treatment to clinical outcomes. Potential interactions between TA and pre-H ticagrelor were also explored. RESULTS: A total of 941 (57.7%) patients underwent TA. In adjusted multivariate logistic model, pre-H ticagrelor treatment was significantly associated with less frequent new MI or definite stent *thrombosis (ST) (odds ratio [OR] 0.43, 95% CI 0.20-0.92, P=.031), or definite ST (OR 0.26, 95% CI 0.07-0.91, P=.036) at 30 days. Patients treated with TA had higher frequency of Thrombolysis in Myocardial Infarction (TIMI) flow 0-1 compared with no-TA group (80.7% vs 51.9%, P<.0001). TA when also adjusted for TIMI flow 0-1 showed significant association only for higher bailout use of glycoprotein IIb/IIIa inhibitors (OR 1.72, 95% CI 1.18-2.50, P=.004) and more frequent 30-day TIMI major bleeding (OR 2.92, 95% CI 1.10-7.76, P=.032). No significant interactions between TA and pre-H ticagrelor were present for the explored end points. CONCLUSIONS: TA when left to physicians' discretion was used in high-risk patients, was associated with bailout use of glycoprotein IIb/IIIa inhibitors and TIMI major bleeding, and had no impact on 30-day clinical outcomes. Conversely, pre-H ticagrelor treatment predicted lower 30-day rates of ST or new MI without interaction with TA. PMID- 29421002 TI - Evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST-AF PCI trial. AB - BACKGROUND: The optimal antithrombotic treatment after percutaneous coronary intervention (PCI) with stenting in patients with atrial fibrillation (AF) is unknown. In the ENGAGE AF-TIMI 48 trial, edoxaban was noninferior to a vitamin K antagonist (VKA) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF. The effects of edoxaban in combination with single- or dual-antiplatelet therapy in the setting of PCI are unexplored. DESIGN: The ENTRUST-AF PCI trial is a multinational, multicenter, randomized, open-label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF. Patients are randomized between 4 hours and 5 days after successful PCI to either an edoxaban-based strategy (experimental arm; 60 mg [or 30 mg according to dose reduction criteria] once daily plus a P2Y12 antagonist [default clopidogrel, 75 mg once daily] for 12 months) or a VKA-based strategy (control arm; VKA plus a P2Y12 antagonist [as above] plus acetylsalicylic acid [100 mg once daily] for 30 days to 12 months). The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis-defined major or clinically relevant nonmajor bleeding. The main efficacy end point is the composite of cardiovascular death, stroke, systemic embolic events, spontaneous myocardial infarction, and definite stent thrombosis. SUMMARY: The ENTRUST-AF PCI trial tests the hypothesis that an edoxaban-based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual-antiplatelet therapy in patients with AF in need of oral anticoagulation. The relative risk of ischemic events between groups will be compared. PMID- 29421003 TI - Determinants of radiation dose during right transradial access: Insights from the RAD-MATRIX study. AB - BACKGROUND: The RAD-MATRIX trial reported a large operator radiation exposure variability in right radial percutaneous coronary procedures. The reasons of these differences are not well understood. Our aim was to appraise the determinants of operator radiation exposure during coronary right transradial procedures. METHODS: Patient arrangement during transradial intervention was investigated across operators involved in the RAD-MATRIX trial. Operator radiation exposure was analyzed according to the position of the patient right arm (close or far from the body) and in relation to the size of the upper leaded glass. RESULTS: Among the 14 operators who agreed to participate, there was a greater than 10-fold difference in radiation dose at thorax level (from 21.5 to 267 MUSv) that persisted after normalization by dose-area product (from 0.35 to 3.5 MUSv/Gy*cm2). Among the operators who positioned the instrumented right arm far from the body (110.4 MUSv, interquartile range 71.5-146.5 MUSv), thorax dose was greater than that in those who placed the instrumented arm close to the right leg (46.1 MUSv, 31.3-56.8 MUSv, P = .02). This difference persisted after normalization by dose-area product (P = .028). The use of a smaller full glass shield was also associated with a higher radiation exposure compared with a larger composite shield (147.5 and 60 MUSv, respectively, P = .016). CONCLUSIONS: In the context of the biggest radiation study conducted in patients undergoing transradial catheterization, the instrumented right arm arrangement close to the leg and greater upper leaded shield dimensions were associated with a lower operator radiation exposure. Our findings emphasize the importance of implementing simple preventive measures to mitigate the extra risks of radiation exposure with right radial as compared with femoral access. PMID- 29421004 TI - Variation in practice patterns in device closure of atrial septal defects and patent ductus arteriosus: An analysis of data from the IMproving Pediatric and Adult Congenital Treatment (IMPACT) registry. AB - : Practice variation is a potentially important measure of healthcare quality. The IMPACT registry provides a representative national sample with which to study practice variation in trans-catheter interventions for congenital heart disease. METHODS: We studied cases for closure of atrial septal defect (ASD) and patent ductus arteriosus (PDA) in IMPACT between January 1, 2011, and September 30, 2015, using hierarchical multivariate models studying (1) the distribution of indications for closure and (2) in patients whose indication for closure was left (LVVO) or right ventricular volume overload (RVVO), the factors influencing probability of closure of a small defect (either in size or in terms of the magnitude of shunt). RESULTS: Over the study period, 5233 PDA and 4459 ASD cases were performed at 77 hospitals. The indications for ASD closure were RVVO in 84% and stroke prevention in 13%. Indications for PDA closure were LVVO in 57%, endocarditis prevention in 36%, and pulmonary hypertension in 7%. There was statistically significant variability in indications between hospitals for PDA and ASD procedures (median rate ratio (MRR): 1.3 and 1.1; both P<.001). The proportion of cases for volume overload with a Qp:Qs <1.5:1 decreased with increasing PDA and ASD procedural volume (P=.04 and 0.05). For ASD, the proportion was higher at hospitals with a larger proportion of adult cases (P=.0007). There was significant variation in practice in the risk of closing PDA <2 mm for LVVO (MRR: 1.4, P<.001). CONCLUSION: There is measurable variation in transcatheter closure of PDA and ASD. Further research is necessary to study whether this affects outcomes or resource utilization. PMID- 29421005 TI - Systematic review and meta-analysis of endovascular and surgical revascularization for patients with chronic lower extremity venous insufficiency and varicose veins. AB - BACKGROUND: Chronic lower extremity venous disease (LECVD) is twice as prevalent as coronary heart disease, and invasive therapies to treat LECVD accounted for an estimated $290 million in Medicare expenditures in 2015. Despite increasing use of these invasive therapies, their comparative effectiveness is unknown. METHODS: We conducted a systematic review and meta-analysis of treatments for patients (symptomatic and asymptomatic) with lower extremity varicosities and/or lower extremity chronic venous insufficiency/incompetence/reflux. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for relevant English language studies published from January 2000 to July 2016. We included comparative randomized controlled trials (RCTs) with >20 patients and observational studies with >500 patients. Short-, intermediate-, and long-term outcomes of placebo, mechanical compression therapy, and invasive therapies (surgical and endovascular) were included. Quality ratings and evidence grading was performed. Random-effects models were used to compute summary estimates of effects. RESULTS: We identified a total of 57 studies representing 105,878 enrolled patients, including 53 RCTs comprised of 10,034 patients. Among the RCTs, 16 were good quality, 28 were fair quality, and 9 were poor quality. Allocation concealment, double blinding, and reporting bias were inadequately addressed in 25 of 53 (47%), 46 of 53 (87%), and 15 of 53 (28.3%), respectively. Heterogeneity in therapies, populations, and/or outcomes prohibited meta-analysis of comparisons between different endovascular therapies and between endovascular intervention and placebo/compression. Meta-analysis evaluating venous stripping plus ligation (high ligation/stripping) compared with radiofrequency ablation revealed no difference in short-term bleeding (odds ratio [OR]=0.30, 95% CI -0.16 to 5.38, P=.43) or reflux recurrence at 1-2 years (OR=0.76, 95% CI 0.37-1.55, P=.44). Meta-analysis evaluating high ligation/stripping versus endovascular laser ablation revealed no difference in long-term symptom score (OR 0.02, 95% CI -0.19 to 0.23, P=.84) or quality of life at 2 years (OR 0.06, 95% CI -0.12 to 0.25, P=.50). CONCLUSIONS: The paucity of high-quality comparative effectiveness and safety data in LECVD is concerning given the overall rise in endovascular procedures. More high-quality studies are needed to determine comparative effectiveness and guide policy and practice. PMID- 29421006 TI - Mechanism for temporal changes in exercise capacity after Fontan palliation: Role of Doppler echocardiography. AB - BACKGROUND: The objective was to better understand Doppler hemodynamics and exercise capacity in patients with Fontan palliation by delineating the hemodynamic mechanism for temporal changes in their peak oxygen consumption (Vo2). METHODS: We performed a retrospective review of adult Fontan patients with systemic left ventricle (LV) who underwent serial transthoracic echocardiograms (TTE) and cardiopulmonary exercise tests (CPET) at Mayo Clinic in 2000-2015. TTE and CPET data were used (1) to determine agreement between Vo2 and Doppler derived LV function indices (eg, stroke volume index [SVI] and cardiac index [CI]) and (2) to determine agreement between temporal changes in peak Vo2 and LV function indices. RESULTS: Seventy-five patients (44 men; 59%) underwent 191 pairs of TTE and CPET. At baseline, mean age was 24+/-3 years, peak Vo2 was 22.9+/-4.1 mL/kg/min (63+/-11 percent predicted), SVI was 43+/-15 mL/m2, and CI was 2.9+/-0.9 L/min/m2. Peak Vo2 correlated with SVI (r=0.30, P<.001) and with CI (r=0.45, P<.001) in the 153 pairs of TTE and CPET in patients without cirrhosis. Temporal changes in percent predicted peak Vo2 correlated with changes in SVI (r=0.48, P=.005) and CI (r=0.49, P=.004) among the 33 patients without interventions during the study. In the 19 patients with Fontan conversion, percent predicted peak Vo2 and chronotropic index improved. CONCLUSIONS: Overall, there was a temporal decline in peak Vo2 that correlated with decline in Doppler SVI. In the patients who had Fontan conversion operation, there was a temporal improvement in peak Vo2 that correlated with improvement in chronotropic index. PMID- 29421007 TI - Arrival and survival of the fittest. PMID- 29421008 TI - Cardiorespiratory fitness versus physical activity as predictors of all-cause mortality in men. AB - BACKGROUND: Although both cardiorespiratory fitness (CRF) and physical activity (PA) are associated with mortality, whether they are associated with all-cause mortality independent of each other is unclear. METHODS: CRF was assessed by a maximal exercise test and PA was measured by self-report in 8,171 male veterans. The predictive power of CRF and PA, along with clinical variables, was assessed for all-cause mortality during a mean (+/-SD) follow-up 8.7 (4.4) years during which there were 1,349 deaths. RESULTS: CRF was associated with mortality after adjusting for clinical variables and remained a strong predictor of mortality after further adjusting for PA (hazard ratio 0.85, 95% CI 0.83-0.87). PA was a significant predictor of mortality after controlling for clinical variables; however, the association was eliminated after further adjusting for CRF (hazard ratio 0.98, 95% CI 0.88-1.10). In CRF-stratified analysis, being active (>=150 min/wk) was not associated with mortality within the unfit or fit categories (P>.4). However, in PA-stratified analysis, subjects categorized as fit (>=7 metabolic equivalents [METS]) had a lower risk of mortality regardless of PA status (P<.001). CONCLUSIONS: In adult men, PA was associated with mortality independent of established risk factors, but not CRF. Conversely, CRF remained a strong predictor of mortality independent of PA status and established risk factors. PMID- 29421009 TI - How well does early-career investigators' cardiovascular outcomes research training align with funded outcomes research? AB - BACKGROUND: Outcomes research training programs should prepare trainees to successfully compete for research funding. We examined how early-career investigators' prior and desired training aligns with recently funded cardiovascular (CV) outcomes research. METHODS: We (1) reviewed literature to identify 13 core competency areas in CV outcomes research; (2) surveyed early career investigators to understand their prior and desired training in each competency area; (3) examined recently funded grants commonly pursued by early career outcomes researchers to ascertain available funding in competency areas; and (4) analyzed alignment between investigator training and funded research in each competency area. We evaluated 185 survey responses from early-career investigators (response rate 28%) and 521 funded grants from 2010 to 2014. RESULTS: Respondents' prior training aligned with funded grants in the areas of clinical epidemiology, observational research, randomized controlled trials, and implementation/dissemination research. Funding in community-engaged research and health informatics was more common than prior training in these areas. Respondents' prior training in biostatistics and systematic review was more common than funded grants focusing on these specific areas. Respondents' desired training aligned similarly with funded grants, with some exceptions; for example, desired training in health economics/cost-effectiveness research was more common than funded grants in these areas. Restricting to CV grants (n=132) and National Heart, Lung, and Blood Institute-funded grants (n=170) produced similar results. CONCLUSIONS: Identifying mismatch between funded grants in outcomes research and early-career investigators' prior/desired training may help efforts to harmonize investigator interests, training, and funding. Our findings suggest a need for further consideration of how to best prepare early-career investigators for funding success. PMID- 29421010 TI - Training cardiovascular outcomes researchers: A survey of mentees and mentors to identify critical training gaps and needs. AB - BACKGROUND: Many young investigators are interested in cardiovascular (CV) outcomes research; however, the current training experience of early investigators across the United States is uncertain. METHODS: From April to November 2014, we surveyed mentees and mentors of early-stage CV outcomes investigators across the United States. We contacted successful grantees of government agencies, members of professional organizations, and trainees in CV outcomes training programs. RESULTS: A total of 185 (of 662) mentees and 76 (of 541) mentors completed the survey. Mentees were equally split by sex; most had completed training >3 years before completing the survey and were clinicians. Mentors were more likely women, mostly >=20 years posttraining, and at an associate/full professor rank. Mentors reported devoting more time currently to clinical work than when they were early in their career and mentoring 2-4 people simultaneously. More than 80% of mentees started training to become academicians and completed training with the same goal. More than 70% of mentees desired at least 50% research time in future jobs. More than 80% of mentors believed that future investigators would need more than 50% time dedicated to research. Most mentees (80%) were satisfied with their relationship with their mentor and reported having had opportunities to develop independently. Mentors more frequently than mentees reported that funding cutbacks had negatively affected mentees' ability to succeed (84% vs 58%). Across funding mechanisms, mentees were more optimistic than mentors about securing funding. Both mentees and mentors reported greatest preparedness for job/career satisfaction (79% for both) and publications (84% vs 92%) and least preparedness for future financial stability (48% vs 46%) and work-life balance (47% vs 42%). CONCLUSIONS: Survey findings may stimulate future discourse and research on how best to attract, train, and retain young investigators in CV outcomes research. Insights may help improve existing training programs and inform the design of new ones. PMID- 29421011 TI - Effect of adding GLP-1RA on mortality, cardiovascular events, and metabolic outcomes among insulin-treated patients with type 2 diabetes: A large retrospective UK cohort study. AB - BACKGROUND: Combining a GLP-1 receptor agonist (GLP-1RA) with insulin is often an effective treatment strategy for overweight patients with type 2 diabetes (T2D), but little is known about the longer-term effects on cardiovascular and mortality outcomes in routine clinical practice in the United Kingdom. We therefore compared the times to a major nonfatal cardiovascular (CV) event and all-cause mortality among overweight patients with T2D treated with insulin alone versus insulin+GLP-1RA in a large UK database. METHODS: A retrospective cohort study was conducted in 18,227 patients with insulin-treated T2D from UK General Practices using The Health Improvement Network database. The 5-year risk of mortality and a 3-point composite of all-cause mortality and nonfatal CV outcomes (myocardial infarction or stroke) was compared between a propensity score-matched cohort of those on insulin alone (n=1,793) and insulin+GLP-1RA (n=1,793), irrespective of other diabetes therapies, providing a total of 12,682 person-years of follow-up. Cox proportional hazard models were used to estimate the hazard ratios of the outcomes. RESULTS: Hemoglobin A1c reduction was similar between both groups ( 0.42 vs -0.33%, P=.089 at 12 months). Overall, 3-point composite events of all cause mortality and CV events (major adverse cardiovascular even) were 98 versus 55 for the insulin alone versus insulin+GLP-1RA groups, respectively (14.7 vs 9.2 per 1,000 person-years; adjusted hazard ratio [aHR]: 0.64; 95% CI: 0.42-0.98; P=.038). Corresponding composite nonfatal CV events were 33 versus 28 (6.0 vs 5.6 per 1,000 person-years; aHR: 0.76; 95% CI: 0.41-1.42; P=.393), whereas all-cause mortality events were 49 versus 13 (6.9 vs 2.0 per 1,000 person-years; aHR: 0.35; 95% CI: 0.17-0.73; P=.005). CONCLUSION: Based on a large UK cohort in routine clinical practice, adding a GLP-1RA to insulin therapy is associated with a reduction in risk of composite CV events and all-cause mortality but a nonsignificant higher risk of hospitalization for heart failure in overweight patients with T2D. PMID- 29421012 TI - Clinical features and outcomes of patients with type 2 myocardial infarction: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial. AB - BACKGROUND: Type 2 myocardial infarction (MI) is characterized by an imbalance between myocardial blood supply and demand, leading to myocardial ischemia without coronary plaque rupture, but its diagnosis is challenging. METHODS: In the TRACER trial, patients with non-ST-segment elevation acute coronary syndromes were included. We aimed to describe provoking factors, cardiac biomarker profiles, treatment patterns, and clinical outcomes of patients with type 2 MIs. MI events during trial follow-up were adjudicated by an independent clinical events classification committee (CEC) and were classified according to the Third Universal Definition of MI. Using available source documents retrieved as part of the CEC process, we performed a retrospective chart abstraction to collect details on the type 2 MIs. Cox regression models were used to explore the association between MI type (type 1 or type 2) and cardiovascular death. RESULTS: Overall, 10.3% (n=1327) of TRACER participants had a total of 1579 adjudicated MIs during a median follow-up of 502 days (25th and 75th percentiles [IQR] 349 667). Of all MIs, 5.2% (n=82) were CEC-adjudicated type 2 MIs, occurring in 76 patients. The incidence of type 2 MI was higher in the first month following randomization, after which the distribution became more scattered. The most frequent potential provoking factors for type 2 MIs were tachyarrhythmias (38.2%), anemia/bleeding (21.1%), hypotension/shock (14.5%), and hypertensive emergencies (11.8%). Overall, 36.3% had a troponin increase >10* the upper limit of normal. Coronary angiography was performed in 22.4% (n=17) of patients during hospitalizations due to type 2 MIs. The hazard of cardiovascular death was numerically higher following type 2 MI (vs. no MI, adj. HR 11.82, 95% CI 5.71 24.46; P<.0001) than that of type 1 MI (vs. no MI, adj. HR 8.90, 95% CI 6.93 11.43; P<.0001). CONCLUSIONS: Type 2 MIs were more prevalent in the first month after ACS, were characterized by the presence of triggers and infrequent use of an invasive strategy, and were associated with a high risk of death. Further efforts are needed to better define the role and implications of type 2 MI in both clinical practice and research. PMID- 29421014 TI - Use of echocardiography in outpatients with chest pain and normal resting electrocardiograms referred to Mayo Clinic Rochester. AB - OBJECTIVES: To determine how often unnecessary resting echocardiograms that are "not recommended" by clinical practice guidelines are performed in patients with stable chest pain and normal resting electrocardiograms (ECGs). BACKGROUND: There are scant data to indicate how often Class III recommendations are ignored in clinical practice. PATIENTS AND METHODS: We searched electronically all medical records of referral outpatients seen at Mayo Clinic Rochester from January 1, 2010, through December 31, 2013, to identify patients with stable chest pain and known or suspected coronary artery disease who underwent resting echocardiography and had normal resting ECGs and no other indication for echocardiography. RESULTS: Of the 15,529 referral outpatients who were evaluated at Mayo Clinic Rochester with chest pain, 3976 (25.6%) had resting echocardiograms. Eight hundred seventy of these 3976 patients (21.9%) had normal resting ECGs. Six hundred nineteen of these 870 patients (71.1%) had other indications for echocardiography. The remaining 251 patients (6.3% of all echocardiograms and 1.6% of all patients) had normal resting ECGs and no other indication for echocardiography. Two hundred thirty-nine of these 251 patients (95.2%) had normal echocardiograms. Of the 12 abnormal echocardiograms, only 4 led to any change in clinical management. Sixty-one of these 251 echocardiograms (24.3%) were "preordered" before the provider (physicians, nurses, physician assistants) visit. CONCLUSION: Echocardiograms were performed in 1 in 4 referral outpatients with chest pain seen at Mayo Clinic Rochester. However, only 1 in 16 of these echocardiograms was performed in violation of the class III recommendation in the American College of Cardiology Foundation/American Heart Association guidelines for the management of stable angina. These unnecessary echocardiograms were almost always normal, and had little impact on clinical management. The rate of unnecessary echocardiograms could be decreased by eliminating preordering. PMID- 29421013 TI - Toward personalized risk assessment in patients with chronic heart failure: Detailed temporal patterns of NT-proBNP, troponin T, and CRP in the Bio-SHiFT study. PMID- 29421015 TI - Duration of ischemia and treatment effects of pre- versus in-hospital ticagrelor in patients with ST-segment elevation myocardial infarction: Insights from the ATLANTIC study. AB - BACKGROUND: Among patients with STEMI in the ATLANTIC study, pre-hospital administration of ticagrelor improved post-PCI ST-segment resolution and 30-day stent thrombosis. We investigated whether this clinical benefit with pre-hospital ticagrelor differs by ischemic duration. METHODS: In a post hoc analysis we compared absence of ST-segment resolution post-PCI and stent thrombosis at 30 days between randomized treatment groups (pre- versus in-hospital ticagrelor) stratified by symptom onset to first medical contact (FMC) duration [<=1 hour (n = 773), >1 to <=3 hours (n = 772), and >3 hours (n = 311)], examining the interaction between randomized treatment strategy and duration of symptom onset to FMC for each outcome. RESULTS: Patients presenting later after symptom onset were older, more likely to be female, and have higher baseline risk. Patients with symptom onset to FMC >3 hours had the greatest improvement in post-PCI ST segment elevation resolution with pre- versus in-hospital ticagrelor (absolute risk difference: <=1 hour, 2.9% vs. >1 to <=3 hours, 3.6% vs. >3 hours, 12.2%; adjusted p for interaction = 0.13), while patients with shorter duration of ischemia had greater improvement in stent thrombosis at 30 days with pre- versus in-hospital ticagrelor (absolute risk difference: <=1 hour, 1.3% vs. >1 hour to <=3 hours, 0.7% vs. >3 hours, 0.4%; adjusted p for interaction = 0.55). Symptom onset to active ticagrelor administration was independently associated with stent thrombosis at 30 days (adjusted OR 1.89 per 100 minute delay, 95%CI 1.20-2.97, P < .01), but not post-PCI ST-segment resolution (P = .41). CONCLUSIONS: The effect of pre-hospital ticagrelor to reduce stent thrombosis was most evident when given early within 3 hours after symptom onset, with delay in ticagrelor administration after symptom onset associated with higher rate of stent thrombosis. These findings re-emphasize the need for early ticagrelor administration in primary PCI treated STEMI patients. PMID- 29421016 TI - Rationale and design of the DEAR-OLD trial: Randomized evaluation of routinely Deferred versus EARly invasive strategy in elderly patients of 75 years or OLDer with non-ST-elevation myocardial infarction. AB - BACKGROUND: Comparing with conservative strategy, early invasive approach has been shown to be beneficial for initially stabilized patients with non-ST elevation myocardial infarction (NSTEMI). However, concerns of increased risk of bleeding and other complications associated with early revascularization in patients aged >=75 years persist. A routinely deferred invasive strategy aiming to facilitate revascularization after stabilizing the culprit lesion predominates across China. AIM: The aim was to compare efficacy and safety of deferred invasive strategy versus guideline-recommended early invasive strategy in initially stabilized Chinese patients aged >=75 years with NSTEMI. METHODS: Twenty qualified centers from 10 different provinces throughout mainland China will contribute to the study. Eligible patients will be central randomized to a routine deferred invasive approach or an early invasive approach (coronary angiography >72 hours or <24 hours of admission and appropriate revascularization). Patients meeting the inclusion criteria but not randomized for any reason will be registered. The primary end point of the present study is a composite of all-cause mortality, nonlethal (re) MI, ischemic stroke, and urgent revascularization at 1 year. Noninferiority design is used, and the inferiority margin was set to be 5%. The goal is to enroll 696 patients with expected primary end point rates of 30%, 2-tailed alpha of .05, power of 80%, and dropout rate of 5%. CONCLUSIONS: The DEAR-OLD trial is a prospective, nationwide, multicenter, noninferiority-designed, open-label randomized clinical trial evaluating efficacy and safety of routinely deferred invasive strategy compared with early invasive strategy in Chinese elderly patients with NSTEMI. PMID- 29421017 TI - Temporal trends in patient referral for Transcatheter aortic valve replacement and reasons for exclusion at a high-volume Center in the United States. AB - BACKGROUND: Clinical indications for transcatheter aortic valve replacement (TAVR) and elements of the implantation procedure, including delivery system miniaturization and novel access options, have evolved over time. The reasons patients are excluded from TAVR also have changed. The impact of these changes on patient referral for and exclusion from TAVR is unknown. METHODS: We retrospectively analyzed patients referred to our center for TAVR from January 2010 to August 2016 to evaluate reasons for patient exclusion. Patients were divided into three groups based on initial screening date for trends in demographics and exclusion: Group 1, 2010-2012; Group 2, 2012-2014; Group 3, 2014 to August 1, 2016. Annual trends for patient exclusion from TAVR were assessed. RESULTS: One thousand nine hundred fifty-three patients were referred and underwent screening for TAVR. The rates at which patients were referred for TAVR were 23.8, 25.9, and 24.5 per month in groups 1, 2, and 3, respectively. Rate of patient exclusion from TAVR decreased from 68% in Group 1 to 38% in Group 3 (P < .001). The largest percentage of patients (29.4%) were initially excluded from TAVR for cardiac reasons, but this trend has decreased over time. Twenty-five percent are excluded for lack of procedural indication. Exclusion from TAVR for vascular access reasons decreased from 7.9% in 2010 to 1.0% in 2016 (P = .017). CONCLUSIONS: Referral numbers have been robust since TAVR became available. The percentage of patients excluded from TAVR has decreased over time. Patients are most commonly excluded from TAVR for concomitant coronary artery disease (CAD), asymptomatic severe AS, moderate AS, or non-cardiac critical illness. Patients with CAD and those with asymptomatic severe AS or moderate AS should be a focus for continued research in TAVR. PMID- 29421018 TI - Biomarkers in stable coronary artery disease. AB - Coronary artery disease (CAD) remains a significant cause of morbidity and mortality around the world. Patients with stable CAD can have an unpredictable clinical trajectory; thus, additional tools to prognosticate risk in this cohort are warranted. In recent years, a wide range of biomarkers has been recognized for their diagnostic capabilities in patients with stable CAD, identifying those with obstructive disease who may require more intensive preventive therapies or even consideration of percutaneous coronary intervention in some circumstances. In addition, a multiple-biomarker approach may identify stable CAD patients at highest risk for future major adverse cardiac events. Thus, randomized controlled trials to assess biomarker-guided preventive therapy in this cohort appear warranted. PMID- 29421020 TI - Effects of hyperoxia on myocardial injury following cardioversion-A randomized clinical trial. AB - : Oxygen has long been assumed beneficial for all ill and injured patients. However, hyperoxia may be harmful and aggravate myocardial injury such as that caused by myocardial infarction. We aimed to investigate if hyperoxia increases myocardial injury following direct current cardioversion compared with room air. METHODS: Patients undergoing elective biphasic cardioversion for atrial fibrillation or atrial flutter were randomized to receive room air or oxygen (10 15 L/min) during the procedure. The primary endpoint was the difference in high sensitive Troponin I (hs-cTnI) and -T (hs-cTnT) measured 2 hours before and 4 hours after cardioversion. Secondary endpoints were differences in Copeptin and NT-pro-BNP. RESULTS: A total of 65 patients were randomized to high-flow oxygen (male: 71%, mean age 66.9 years) and 59 patients to room air (male: 80%, mean age 65.5 years). There was no difference in hs-cTnI between patients treated with oxygen compared to patients treated with room air (P=.09) and no significant difference for hs-cTnT, ratio 1.08 (95% CI: 0.99-1.18) (P=.09). Median hs-cTnI difference before and after cardioversion was 0.1 (interquartile range (IQR): 0.5 to 0.5) ng/L for the high-flow oxygen group and -0.3 (IQR: -1.1 to 0.4) ng/L for the room air group. There was no difference in Copeptin between patients treated with oxygen compared to room air (ratio 1.06 (95% CI: 0.89-1.27) (P=.51) or NT-pro-BNP (difference-6.0 ng/L (95% CI: -78.5 to 66.6) P=.87). CONCLUSION: Direct current cardioversion of atrial fibrillation/flutter with and without high flow oxygen supplement was not associated with myocardial injury evaluated by high sensitive myocardial biomarkers. PMID- 29421019 TI - Access to routine care and risks for 30-day readmission in patients with cardiovascular disease. AB - BACKGROUND: Studies have shown that access to routine medical care is associated with the prevention, diagnosis, and treatment of chronic diseases. However, studies have not examined whether patient-reported difficulties in access to care are associated with rehospitalization in patients with cardiovascular disease. METHODS: Electronic medical records and a standardized survey were used to examine cardiovascular patients admitted to a large medical center from January 1, 2015 through January 10, 2017 (n=520). All-cause readmission within 30 days of discharge was the primary outcome for analysis. Logistic regression models were used to examine the association between access to care and 30-day readmission while adjusting for patient demographics, socioeconomic status, healthcare utilization, and health status. RESULTS: Nearly 1-in-6 patients (15.7%) reported difficulty in accessing routine medical care; and those who were younger, male, non-white, uninsured, with heart failure, and had low social support were significantly more likely to report difficulty. Patients who reported difficulty in accessing care had significantly higher rates of 30-day readmission than patients who did not report difficulty (33.3% vs. 17.9%; P=.001); and the risks remained largely unchanged after accounting for nearly two dozen covariates (unadjusted odds ratio [OR]=2.29; 95% CI, 1.46-3.60 vs. adjusted OR=2.17; 95% CI, 1.29-3.66). Risks for readmission were especially high for patients who reported issues with transportation (OR=3.24; 95% CI, 1.28-8.16) and scheduling appointments (OR=3.56; 95% CI, 1.43-8.84), but not for other reasons (OR=1.47; 95% CI, 0.61-3.54). CONCLUSIONS: Cardiovascular patients who reported difficulty in accessing routine care had substantial risks of readmission within 30 days after discharge. These findings have important implications for identifying high risk patients and developing interventions to improve access to routine medical care. PMID- 29421021 TI - Confusion regarding the meaning of the term left ventricular filling pressure given the nonequivalence of left ventricular end-diastolic pressure and mean left atrial pressure. PMID- 29421022 TI - Foreword. PMID- 29421024 TI - Management of surgical challenges in actively treated cancer patients. PMID- 29421025 TI - Profiling of modified nucleosides from ribonucleic acid digestion by supercritical fluid chromatography coupled to high resolution mass spectrometry. AB - A method based on supercritical fluid chromatography coupled to high resolution mass spectrometry for the profiling of canonical and modified nucleosides was optimized, and compared to classical reverse-phase liquid chromatography in terms of separation, number of detected modified nucleosides and sensitivity. Limits of detection and quantification were measured using statistical method and quantifications of twelve nucleosides of a tRNA digest from E. coli are in good agreement with previously reported data. Results highlight the complementarity of both separation techniques to cover the largest view of nucleoside modifications for forthcoming epigenetic studies. PMID- 29421026 TI - Analysis of four sulfonylurea herbicides in cereals using modified Quick, Easy, Cheap, Effective, Rugged, and Safe sample preparation method coupled with liquid chromatography-tandem mass spectrometry. AB - A modified Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) sample preparation method, coupled with liquid chromatography-electrospray ionization tandem mass spectrometry, has been developed for the simultaneous analysis of four commonly used sulfonylurea herbicides, ethoxysulfuron, halosulfuron-methyl, mesosulfuron-methyl and orthosulfamuron, in rice, maize, wheat and soybean. Adsorption of the analytes onto the primary-secondary amine used in the clean-up step was avoided by using 1% formic acid in acetonitrile as the extraction solvent to maintain the acidic herbicides in a non-ionized state. Trueness studies were carried out at three levels (2.5, 25 and 250 MUg/kg for ethoxysulfuron and 5, 50 and 500 MUg/kg for the other three analytes). Promising trueness (70.2%-119.8%) was achieved for all herbicides in all matrices after clean-up, with relative standard deviations (RSDr) < 18.6%. Satisfactory matrix effects (-19.7% to 14.8%) were also obtained. Good linearity of the calibration curves was achieved, with determination coefficients (r) >= 0.9956, when the concentration of ethoxysulfuron was in the range 0.5-50 MUg/L and that of the other three analytes was in the range 1.0-500 MUg/L. The RSDwR for within laboratory reproducibility was 5.7%. The validated method was successfully used to analyze real samples. PMID- 29421027 TI - Enteric Immunity: Happy Gut, Healthy Animal. AB - In this article, key concepts important for enteric immunity are discussed. The gastrointestinal tract is the largest immune organ of the body. The mucosal barrier, the tight junctions and the "kill zone," along with the gut mucosa and maintaining an "anti-inflammatory" state are essential for "good gut health." The microbiome, the microorganisms in the gastrointestinal tract, which has more cells then the entire animal's body, is essential for immune development, immune response, and maximizing ruminant productivity. Direct-fed microbials aid in both microbiome stability "homeostasis" and immune function. PMID- 29421028 TI - Clostridial Abomasitis and Enteritis in Ruminants. AB - Clostridial abomasitis and enteritis are important alimentary diseases observed in all domestic ruminant species. These diseases most commonly result from overgrowth of Clostridium perfringens types A, B, C, D, and E with the associated release of bacterial exotoxins that result in necrosis of the abomasal or intestinal mucosa. Clostridium difficile may also be associated with enteritis in calves but is much less common than disease caused by C perfringens. This article reviews the causes, pathophysiology, clinical signs, diagnosis, treatment, and prevention of clostridial gastrointestinal diseases in ruminants. Particular emphasis is given to describing the various forms of disease and treatment of individual cases. PMID- 29421029 TI - Gastrointestinal Nematodes, Diagnosis and Control. AB - Disease caused by nematodes in the gastrointestinal tract of cattle is primarily economic and the effect of treatment is cattle grow larger faster because of increased feed intake. The disease, control measures, and drugs used must be focused on different ages and environments. Different drugs should be used against the parasites most likely affected by the specific drug and administered how and when it will accomplish the best sustainable control. Management needs to ensure that at-risk animals are exposed to sufficient worms to stimulate their immunologic response but not overwhelm it. PMID- 29421030 TI - 2017: The Year of Psychopathology. PMID- 29421031 TI - An enzymatic alternative for the synthesis of nucleoside 5'-monophosphates. AB - A new procedure was carried out for the synthesis of nucleoside 5' monophosphates, involving the use of two enzymes. The first step applied phospholipase D from Streptomyces netropsis and phosphatidylcholine as phosphatidyl donor, to give 5'-(3-sn-phosphatidyl) nucleosides (C, U, A, I). These were selectively hydrolysed in the second step by the action of phospholipase C from Bacillus cereus to produce the respective 5'-nucleotides. Application of this methodology on a preparative scale conducted to 5'-adenosine monophosphate in 63% overall yield from adenosine. The regioselectivity of these enzymes avoids protection steps, the overall synthesis is performed under mild reaction conditions and product isolation is easily achieved. PMID- 29421032 TI - Producing functional recombinant human keratinocyte growth factor in Pichia pastoris and investigating its protective role against irradiation. AB - Keratinocyte Growth Factor (KGF) is a paracrine-acting, epithelial mitogen that plays a prominent role in the regeneration of damaged epithelial tissues. In spite of different attempts to produce recombinant human KGF in many organisms, including bacteria, mammalian cells, plant cells and insect cells; production of recombinant form suffers from lower yields and recovery relative to other recombinant proteins of similar size and properties. Due to many advantages of Pichia pastoris expression systems for producing industrial enzymes and pharmaceutical proteins, in this study P. pastoris was chosen as a host for KGF expression. For preparing human KGF coding sequence, MCF-7 cell line was treated with 1,25-Dihydroxy vitamin D3 for inducing the expression of KGF. The coding sequence of 23N-terminal truncated KGF form was amplified using RT-PCR technique and then cloned into the yeast expression vector in frame with the yeast alpha factor secretion signal. The recombinant plasmid was integrated into Pichia pastoris strain X-33 genome. Western blotting and Mass Spectrometry demonstrated that recombinant human KGF (rhKGF) was correctly expressed after methanol induction and secreted into the media. The recombinant protein was purified from the media by heparin affinity chromatography. MTT assay showed that the purified rhKGF had a proliferative effect on NIH3T3 and A549 cell lines. In addition, protective effect of recombinant KGF was assessed in A549 cell line after irradiation. The results showed that the recombinant protein was biologically active. Finally, the effect of recombinant KGF was investigated on proliferation of MCF-7 cell line and its response to radiation. The results showed that pre treatment of KGF have a protective effect on MCF-7 cell line after irradiation. PMID- 29421033 TI - Biodegradation of fibrillated oil palm trunk fiber by a novel thermophilic, anaerobic, xylanolytic bacterium Caldicoprobacter sp. CL-2 isolated from compost. AB - Oil palm trunk (OPT) is one of the most promising lignocellulosic bioresources. To develop effective biodegradation, thermophilic, anaerobic microorganisms were screened from bovine manure compost using fibrillated OPT (f-OPT) pretreated by wet disk milling as the substrate. One thermophilic, anaerobic bacterium, strain CL-2, whose 16S rDNA gene has 98.6% sequence identity with that of Caldicoprobacter faecale DSM 20678T, exhibited high degradation activity (32.7% reduction in total dry solids of f-OPT). Strain CL-2 did not use cellulose as a carbon source, but used hemicelluloses such as xylan, arabinoxylan, starch and pectin at 70 degrees C. Phylogenetic and morphologic analyses and the polysaccharide use suggest that CL-2 may be classified as a novel species of Caldicoprobacter, named Caldicoprobacter sp. CL-2. To characterize enzymatic activities of CL-2, extracellular enzymes were prepared from culture broth using beechwood xylan as the carbon source. The extracellular enzymes showed high xylanase activity, but low cellulase activity, suggesting that f-OPT degradation may depend on xylanase activity. To understand the xylanase system of CL-2, a major xylanase was cloned and characterized. The xylanase (CalXyn11A) had a modular structure consisting of a glycoside hydrolase (GH) family-11 domain and a family 36 carbohydrate-binding module. CalXyn11A did not show f-OPT degradation activity, but a strong synergistic effect was observed when CalXyn11A was added to the extracellular enzyme preparation. These results indicate that, rather than working alone, CalXyn11A has an important role in enhancing total lignocellulose degradation activity by cooperation with other GHs. PMID- 29421034 TI - Stereoselective hydroxylation of isophorone by variants of the cytochromes P450 CYP102A1 and CYP101A1. AB - The stereoselective oxidation of hydrocarbons is an area of research where enzyme biocatalysis can make a substantial impact. The cyclic ketone isophorone was stereoselectively hydroxylated (>=95%) by wild-type CYP102A1 to form (R)-4 hydroxyisophorone, an important chiral synthon and flavour and fragrance compound. CYP102A1 variants were also selective for 4-hydroxyisophorone formation and the product formation rate increased over the wild-type enzyme by up to 285 fold, with the best mutants being R47L/Y51F/I401P and A74G/F87V/L188Q. The latter variant, which contained mutations in the distal substrate binding pocket, was marginally less selective. Combining perfluorodecanoic acid decoy molecules with the rate accelerating variant R47L/Y51F/I401P engendered further improvement with the purified enzymes. However when the decoy molecules were used with A74G/F87V/L188Q the amount of product generated by the enzyme was reduced. Addition of decoy molecules to whole-cell turnovers did not improve the productivity of these CYP102A1 systems. WT CYP101A1 formed significant levels of 7-hydroxyisophorone as a minor product alongside 4-hydroxyisophorone. However the F87W/Y96F/L244A/V247L CYP101A1 mutant was >=98% selective for (R)-4 hydroxyisophorone. A comparison of the two enzyme systems using whole-cell oxidation reactions showed that the best CYP101A1 variant was able to generate more product. We also characterised that the further oxidation metabolite 4 ketoisophorone was produced and then subsequently reduced to levodione by an endogenous Escherichia coli ene reductase. PMID- 29421035 TI - Improvement in thermostability of xylanase from Geobacillus thermodenitrificans C5 by site directed mutagenesis. AB - Enzymes activity and stability at extreme temperature can be intensified by regularly applying protein engineering. In the present study, two amino acids were perceived to mark the temperature dependability of xylanase from Geobacillus thermodenitrificans C5. Six mutants of G. thermodenitrificans C5 were built through site-directed mutagenesis by interchanging the residue with proline and glutamic acid (R81P, H82E, W185P, D186E, double mutant W185P/D186E and triple mutant H82E/W185P/D186E). Both mutant and wild type enzymes were quantified in host E. coli BL21. In comparison to wild type, the temperature was enhanced by 4 degrees C, 5 degrees C and 11 degrees C in H82E, W185P/D186E and H82E/W185P/D186E mutant models, respectively. The mutant H82E and the combined substitutions (H82E/W185P/D186E) showed the most pronounced shifts in their half lives for thermal inactivation. Half-life was increased 13 times at 60 degrees C, 15 times at 65 degrees C, 9 times at 70 degrees C and 5 times at 75 degrees C by H82E/W185P/D186E mutant. Mutations in xylanase enzyme causes rigidification of essential chain and filling of groove that leads to stabilization of mutants and finally resulted into enhancement in their thermostability. PMID- 29421037 TI - Essential role of amino acid position 71 in substrate preference by meso diaminopimelate dehydrogenase from Symbiobacterium thermophilum IAM14863. AB - meso--Diaminopimelate dehydrogenase (meso-DAPDH) catalyzes the reversible oxidative deamination of the d-configuration of meso-2,6-diaminopimelate (meso DAP) and is thought to have substrate specificity toward meso-DAP. The discovery of the meso-DAPDH from Symbiobacterium thermophilum IAM14863 (StDAPDH) revealed meso-DAPDH members with broad substrate specificity. In order to elucidate the substrate-preference mechanism of StDAPDH, it is necessary to identify the key residues related to this mechanism. Our previous work suggested that the non active-site R71 of StDAPDH was related to substrate preference. Here, we report the key roles of the non-active site on the catalysis of StDAPDH. In order to explore the mechanism through which non-active-site R71 only affected the amination activity of StDAPDH, we performed molecular dynamic simulations and investigated the functional role of R71 in the type II meso-DAPDH StDAPDH. Site directed mutagenesis with the allelic site A69 of CgDAPDH as a target proved that when replaced by Arg at position 71 of StDAPDH, the CgA69R mutant showed higher catalytic efficiencies toward a series of 2-keto acids, ranging from 1.2- to 1.5 fold. These findings provide some guidelines for improving our understanding of the broad substrate specificity of StDAPDH. PMID- 29421036 TI - Enzymatically and chemically oxidized lignin nanoparticles for biomaterial applications. AB - Cross-linked and decolorized lignin nanoparticles (LNPs) were prepared enzymatically and chemically from softwood Kraft lignin. Colloidal lignin particles (CLPs, ca. 200 nm) in a non-malodorous aqueous dispersion could be dried and redispersed in tetrahydrofuran (THF) or in water retaining their stability i.e. spherical shape and size. Two fungal laccases, Trametes hirsuta (ThL) and Melanocarpus albomyces (MaL) were used in the cross-linking reactions. Reactivity of ThL and MaL on LignoboostTM lignin and LNPs was confirmed by high performance size exclusion chromatography (HPSEC) and oxygen consumption measurements with simultaneous detection of red-brown color due to the formation of quinones. Zeta potential measurements verified oxidation of LNPs via formation of surface-oriented carboxylic acid groups. Dynamic light scattering (DLS) revealed minor changes in the particle size distributions of LNPs after laccase catalyzed radicalization, indicating preferably covalent intraparticular cross linking over polymerization. Changes in the surface morphology of laccase treated LNPs were imaged by atomic force (AFM) and transmission emission (TEM) microscopy. Furthermore, decolorization of LNPs without degradation was obtained using ultrasonication with H2O2 in alkaline reaction conditions. The research results have high impact for the utilization of Kraft lignin as nanosized colloidal particles in advanced bionanomaterial applications in medicine, foods and cosmetics including different sectors from chemical industry. PMID- 29421038 TI - Microbial production of uracil by an isolated Methylobacterium sp. WJ4 using methanol. AB - In this study, we report the production of uracil from methanol by an isolated methylotrophic bacterium, Methylobacterium sp. WJ4. The use of methanol as alternative carbon feedstock is attractive option in biotechnology. As a feedstock of biotechnological processes, methanol has distinct advantages over methane. This is not only due to physical and chemical considerations, but also to the properties of the pertinent organisms. Besides, with a wide array of biological activities and synthetic accessibility, uracil is considered as privileged structures in drug discovery. Uracil analogues have been applied to treatments of patients with cancer or viral infections. In this respect, it is meaningful to produce uracil using methanol. The effect of process parameters and methanol concentration for uracil production were investigated and optimized. Uracil production was remarkably increased to 5.76mgg cell dry weight-1 in optimized condition. The results were significant for further understanding of methylotrophic bacteria on uracil production. PMID- 29421039 TI - Aspergillus niger whole-cell catalyzed synthesis of caffeic acid phenethyl ester in ionic liquids. AB - Synthesis of caffeic acid ester essentially requires an efficient esterification process to produce various kinds of medicinally important ester derivatives. In the present study, a comprehensive and comparative analysis of whole-cell catalyzed caffeic acid esters production in ionic liquids (ILs) media was performed. Olive oil induced mycelial mass of halotolerant Aspergillus niger (A.niger) EXF 4321 was freeze dried and used as a catalyst. To ensure maximum solubilization of caffeic acid for highest substrate loading several ILs were screened and 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([Emim][Tf2N]) was found to have the maximum solubility and favoured for enzymatic activity of freeze dried mycelia. The whole-cell catalyzed synthesis of caffeic acid phenethyl ester (CAPE) conditions were optimized and bioconversion up to 84% was achieved at a substrate molar ratio of 1:20 (caffeic acid:2-phenyl ethanol), 30 degrees C for 12h. Results obtained during this study were encouraging and helpful to design a bioreactor system to produce caffeic acid derived esters. PMID- 29421040 TI - A thermophilic enzymatic cocktail for galactomannans degradation. AB - The full utilization of hemicellulose sugars (pentose and exose) present in lignocellulosic material, is required for an efficient bio-based fuels and chemicals production. Two recombinant thermophilic enzymes, an endo-1,4-beta mannanase from Dictyoglomus turgidum (DturCelB) and an alpha-galactosidase from Thermus thermophilus (TtGalA), were assayed at 80 degrees C, to assess their heterosynergystic association on galactomannans degradation, particularly abundant in hemicellulose. The enzymes were tested under various combinations simultaneously and sequentially, in order to estimate the optimal conditions for the release of reducing sugars. The results showed that the most efficient degree of synergy was obtained in simultaneous assay with a protein ratio of 25% of DturCelB and 75% of TtGalA, using Locust bean gum as substrate. On the other hand, the mechanism of action was demonstrated through the sequential assays, i.e. when TtGalA acting as first to enhance the subsequent hydrolysis performed by DturCelB. The synergistic association between the thermophilic enzymes herein described has an high potential application to pre-hydrolyse the lignocellulosic biomasses right after the pretreatment, prior to the conventional saccharification step. PMID- 29421041 TI - Characterization of a topologically unique oxygenase from Sphingobium sp. PNB capable of catalyzing a broad spectrum of aromatics. AB - A Rieske non-heme iron ring-hydroxylating oxygenase (RHO) from Sphingobium sp. PNB involved in the initial oxidation of a wide range of low and high molecular weight polycyclic aromatic hydrocarbons (PAHs) was investigated. The RHO was shown to comprise of the gene products of distantly located ahdA1f-ahdA2f, ahdA3 and ahdA4 genes, which encoded the oxygenase alpha- and beta-subunits, ferredoxin and reductase, respectively. In silico structural analysis of AhdA1f revealed a very large substrate-binding pocket, satisfying the spatial requirements to accommodate high molecular weight substrates. In addition, an atypical substrate access channel was noticed from the topology analysis of the oxygenase. Guided by molecular docking studies, dioxygenation of several PAHs as well as alkyl- and aryl benzenes was examined with the recombinant AhdA1fA2f expressed in Escherichia coli. Chromatographic and mass spectrometric analyses confirmed that AhdA1fA2f displays broad substrate specificity towards a wide range of aromatic hydrocarbons including potential xenobiotics, demonstrating metabolic robustness of strain PNB. PMID- 29421042 TI - Biosynthesis of gold and selenium nanoparticles by purified protein from Acinetobacter sp. SW 30. AB - Synthesis of nanoparticles is an enzymatic reduction process in microorganisms. In the present study, a protein, lignin peroxidase has been purified by DEAE Cellulose anion exchange chromatography and Biogel P-150 gel filtration chromatography from the cell suspension of Acinetobacter sp. SW30 responsible for the synthesis of gold nanoparticles (AuNP) and selenium nanoparticles (SeNP). The purified fraction has a specific activity of 29.4U/mg/min with 959 fold purification. Native and SDS PAGE confirmed that purified lignin peroxidase is monomeric enzyme with 97.4KDa molecular weight. The enzyme synthesized spherical crystalline AuNP (10+/-2nm) and amorphous SeNP (100+/-10nm). It has maximum activity at pH 2 and temperature 40 degrees C, with 1.0mMKm value, when n propanol was used as a substrate. Activity was completely inhibited by sodium thiosulphate and zinc sulphate. This is the first report on association of lignin peroxidase in the synthesis of AuNP and SeNP from Acinetobacter sp. SW30. PMID- 29421043 TI - Influence of support materials on continuous hydrogen production in anaerobic packed-bed reactor with immobilized hydrogen producing bacteria at acidic conditions. AB - This study assesses the impact of different support materials (Mutag BioChipTM, expanded clay and activated carbon) on microbial hydrogen production in an anaerobic packed-bed reactor (APBR) treating synthetic waste water containing glucose as the main carbon source at low pH value. The APBRs were inoculated with acid pretreated anaerobic sludge and operated at pH value of 4+/-0.2 and hydraulic retention time (HRT) of 3h. The maximum hydrogen yield of 1.80mol H2/mol glucose was achieved for the APBR packed with Mutag BioChipTM (R1), followed by expanded clay (R2, 1.74mol H2/mol glucose) and activated carbon (R3, 1.46mol H2/mol glucose). It was observed that the investigated support materials influenced the immobilization of hydrogen producing bacteria and consequently hydrogen production performance as well as composition of soluble metabolites. The main metabolic products were acetic acid and butyric acid accompanied with a smaller content of ethanol. The data indicated that in reactors with higher hydrogen yield (R1 and R2), acetate/butyrate (HAc/HBu) ratios were 1.7 and 1.6, respectively, while in the reactor with the lowest hydrogen yield (R3) the obtained HAc/HBu ratio was 4.8. Finally, stable hydrogen and organic acids production throughout the steady-state operation period at low pH values was achieved in all reactors. PMID- 29421044 TI - Eco-friendly polyvinyl alcohol/carboxymethyl cellulose hydrogels reinforced with graphene oxide and bentonite for enhanced adsorption of methylene blue. AB - Eco-friendly polyvinyl alcohol/carboxymethyl cellulose (isolated from pineapple peel) hydrogels reinforced with graphene oxide and bentonite were prepared as efficient adsorbents for methylene blue (MB). The structure and morphology of the prepared hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), X-ray diffraction (XRD), thermogravimetry (TG) and differential scanning calorimetry (DSC). Introducing graphene oxide and bentonite into the hydrogels evidently enhanced the thermal stability, swelling ability and MB adsorption capacity. The effects of initial concentration of MB, pH, contact time and temperature on MB adsorption capacity of the prepared hydrogels were investigated. Adsorption kinetics and equilibrium adsorption isotherm fitted pseudo-second-order kinetic model and Langmuir isotherm model well, respectively. After introducing graphene oxide and bentonite into the hydrogels, the maximum adsorption capacity calculated from the Langmuir isotherm model reached 172.14 mg/g at 30 degrees C, obviously higher than the hydrogels prepared without these additions (83.33 mg/g). Furthermore, all the prepared hydrogels also displayed good reusability for the efficient removal of MB. Consequently, the prepared hydrogels could be served as eco-friendly, stable, efficient and reusable adsorbents for anionic dyes in wastewater treatment. PMID- 29421045 TI - On the effects of hydroxyl substitution degree and molecular weight on mechanical and water barrier properties of hydroxypropyl methylcellulose films. AB - In line with the increasing demand for sustainable packaging materials, this contribution aimed to investigate the film-forming properties of hydroxypropyl methylcellulose (HPMC) to correlate its chemical structure with film properties. The roles played by substitution degree (SD) and molecular weight (Mw) on the mechanical and water barrier properties of HPMC films were elucidated. Rheological, thermal, and structural experiments supported such correlations. SD was shown to markedly affect film affinity and barrier to moisture, glass transition, resistance, and extensibility, as hydroxyl substitution lessens the occurrence of polar groups. Mw affected mostly the rheological and mechanical properties of HPMC-based materials. Methocel(r) E4 M led to films featuring the greatest tensile strength (ca., 67 MPa), stiffness (ca., 1.8 GPa), and extensibility (ca., 17%) and the lowest permeability to water vapor (ca., 0.9 g mm kPa-1 h-1 m-2). These properties, which arise from its longer and less polar chains, are desirable for food packaging materials. PMID- 29421046 TI - Interactions between microfibrillar cellulose and carboxymethyl cellulose in an aqueous suspension. AB - New microstructures with interesting, unique and stable textures, particularly relevant to food systems were created by redispersing Microfibrillar cellulose (MFC). This paper reports the interactions between microfibrillar cellulose and carboxymethyl cellulose (CMC) in redispersed aqueous suspensions, by using rheological measurements on variable ratios of MFC/CMC and correlating these with apparent water mobility as determined by time domain NMR. MFC is a network of cellulose fibrils produced by subjecting pure cellulose pulp to high-pressure mechanical homogenisation. A charged polymer such as CMC reduces the aggregation of microfibrillar/fibre bundles upon drying. Small amplitude oscillatory rheological analysis showed viscoelastic gel-like behaviour of suspensions which was independent of the CMC content in the MFC suspension. A viscous synergistic effect was observed when CMC was added to MFC before drying, leading to improved redispersibility of the suspension. Novel measurements using NMR relaxation suggested that the aggregated microfibrillar/fibre bundles normally dominate the relaxation times (T2). The dense microfibrillar network plays an important role in generating stable rheological properties and controlling the mobility of the polymer and hence the apparent mobility of the water in the suspensions. PMID- 29421047 TI - A molecular dynamics study of cellulose inclusion complexes in NaOH/urea aqueous solution. AB - We investigated the dissolution state of cellulose in NaOH/urea aqueous solution using molecular dynamics simulations. All the components, including cellulose, NaOH, urea and H2O were combined into one simulation. A clear and detailed description for the formation of cellulose inclusion complexes has been stated. The simulation results showed that the cellulose inclusion complexes exhibited anisotropic properties. In this system, the sodium ions and hydroxide ions located at the regions of hydroxyl and hydroxymethyl groups in cellulose molecules. However, the urea molecules occupied the faces of the hydrophobic pyranose rings. The hydrogen-bonding configuration and lifetime of hydrogen bonds in cellulose inclusion complexes were also systematically characterized. The spatial structure of inclusion complexes, the hydrogen-bonding interaction between cellulose and solvent molecules, the diffusive property of solvent molecules and the distribution of water-water angles in cellulose inclusion complexes were discussed in details. The NaOH, urea and H2O molecules surrounding the cellulose chain within radial distance 0.35 nm have smaller diffusion coefficients than those in bulk state. The water-water angles provide a quantitative estimate of hydrophobic effect of cellulose. PMID- 29421048 TI - Physicochemical characterization of polysaccharides from Chlorella pyrenoidosa and its anti-ageing effects in Drosophila melanogaster. AB - The physicochemical characteristics and in vitro antioxidant and in vivo anti ageing activities of partial purified Chlorella pyrenoidosa polysaccharides (PCPPs) were investigated. The building blocks of PCPPs were mainly composed of D glucose, D-galactose and D-mannose. The average molecular weight of PCPPs was 9,950 Da. In vitro antioxidant activity assays showed that PCPPs could effectively scavenge hydroxyl, 1,1-diphenyl-2-picrylhydrazyl, and superoxide radicals, with stronger effect on hydroxyl radicals. Furthermore, the mean lifespan of the male and female Drosophila melanogaster was extended by 11.5% and 10.6%, respectively. This was accompanied by an increase in the total activity of the endogenous antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and catalase in young or old D. melanogaster administered with PCPPs. Moreover, a gender-dependent difference was observed both in lifespan and antioxidant enzyme activities in D. melanogaster. The results indicated that C. pyrenoidosa polysaccharides are potential natural antioxidants in extending lifespan. PMID- 29421049 TI - Optimized extraction of pectin-like polysaccharide from Suaeda fruticosa leaves: Characterization, antioxidant, anti-inflammatory and analgesic activities. AB - Box-Behnken design (BBD) was performed via ultrasound-assisted system to optimize extraction yield and total antioxidant ability of polysaccharides from Suaeda fruticosa. Three independent variables were studied: temperature, time and pH with optimal settings 90 degrees C, 37 min and 2.9, respectively. Under these settings, isolation yield and total antioxidant activity were 34.0% and 31.8 mg ascorbic acid equivalent/g material, respectively. Furthermore, preliminary structure study was carried out using UV-vis analysis, Fourier transform infrared spectroscopy (FT-IR) and Nuclear magnetic resonance (1D (1H, 13C NMR) and 2D (1H, 1H COSY, 1H/13C HSQC)) methods Size exclusion chromatography (SEC) determination revealed that polysaccharide extracted had an average molecular weight of 240 kDa. Chemical composition analyses showed that extracted polysaccharide was a pectin-like polysaccharide with uronic acid content (47.5%) and neutral monosaccharides (52.5%) constituted mainly of arabinose, mannose, galactose, rhamnose, glucose and xylose in the molar percentage of 48.63%, 5.85%, 29.42%, 7.96%, 6.54% and 1.60%, respectively. This sugar composition was typical of that of a galactoarabinan. Importantly, the optimum polysaccharide possesses significant potentials in antioxidant activity effect. Moreover, pharmacological investigation of extracted polysaccharide revealed a good anti-inflammatory effect and interesting peripheral as well as central antinociceptive activities. PMID- 29421050 TI - Homogeneous synthesis and characterization of chitosan ethers prepared in aqueous alkali/urea solutions. AB - The etherification of chitosan dissolved in aqueous LiOH/KOH/urea solutions was conducted for the first time. The structure and solution properties of the chitosan ethers were characterized using FT-IR, NMR, SEC-LLS, elemental analysis, and zeta-potential measurement. Chitosan ethers with different degrees of substitution (DSs) were obtained by adjusting the molar ratio of the etherifying agent to N-acetylglucosamine unit (AGU) of chitosan. The total DS for methyl chitosan (MCh) increased from 1.17 to 2.25, and trimethyl chitosan (TMCh) was obtained with DSN-trimethyl as high as 0.48. The total DS for carboxymethyl chitosan (CMCh) was in the range 0.75-1.45. Both N-substitution and O substitution were observed, and the OH groups at C-6 displayed relative higher reactivity than the OH groups at C-3. In comparison with the traditional methods and solvents, aqueous alkali/urea solutions proved to be a stable and more homogeneous medium for preparing chitosan ethers with higher DS through a one step reaction. PMID- 29421051 TI - Diurnal changes of glycogen molecular structure in healthy and diabetic mice. AB - Glycogen is a complex branched glucose polymer functioning as a blood-sugar reservoir in animals. Liver glycogen beta particles can bind together to form alpha particles, which have a slower enzymatic degradation to glucose. The linkage between beta particles in alpha particles in diabetic liver breaks (is fragile) in dimethyl sulfoxide (DMSO), a H-bond disruptor, consistent with blood sugar homeostasis loss in diabetes. We examined diurnal changes in the molecular structure of healthy and diabetic mouse-liver glycogen. Healthy mouse glycogen was fragile to DMSO during glycogen synthesis but not degradation; diabetic glycogen was always fragile. Two alternative mechanisms for this are suggested: healthy glycogen is fragile when formed and becomes stable during subsequent degradation, a process damaged in diabetes; alternatively, there are two types of glycogen: one compact but fragile and the other loose but non-fragile. This suggests potential types of diabetes drug targets through modifying the activities of glycogen synthesis enzymes. PMID- 29421052 TI - Maltose formation in wheat dough depending on mechanical starch modification and dough hydration. AB - This study investigates the maltose formation during grinding of flour and dough processing (kneading, fermentation) attributed to mechanical flour or rather mechanical starch modification (MSM) and dough hydration. A strong rise of maltose formation up to 334% was observed during kneading due to improved accessibility of mechanical modified starch to amylolytic enzymes, whereas during proofing only a minor rise was detectable. The maltose release was more pronounced with high MSM and low dough hydration. Low dough hydration levels of 158 g water 100 g-1 flour instead of 178 g water 100 g-1 flour also intensified the maltose utilization by yeast (+37% with MSM of 4.78 g 100 g-1 flour; +27% with MSM of 7.46 g 100 g-1 flour), whereas increased maltose concentrations were not utilized by yeast during a fermentation cycle of 60 min. Consequently, high maltose concentrations based on MSM should have no relevant effect on the gas production during 60 min fermentation. However, the gas production by yeast might be prolonged due to enhanced substrate availability and thus could be relevant for elongated proofing methods. PMID- 29421053 TI - Therapeutic roles of polysaccharides from Dendrobium Officinaleon colitis and its underlying mechanisms. AB - Polysaccharide, as a promising candidate to meet the medication requirement of ulcerative colitis (UC), is increasingly attracting extensive interest. Dendrobium officinale has been widely used to treat gastrointestinal sickness in the clinical treatment of Traditional Chinese Medicine. However, it remains largely unknown whether polysaccharides (DOPS) from Dendrobium officinale can treat UC. The purpose of this paper is to confirm therapeutic action of DOPS to UC and explored its underlying mechanisms. We noted that DOPS could dramatically improve clinical signs and symptoms, decrease mortality, alleviate colonic pathological damage, and reestablish the balance of pro- and anti-inflammatory cytokines in DSS-induced acute UC mice. Moreover, DOPS treatment could also markedly suppress the activation of NLRP3 inflammasome and beta-arrestin1 in vivo and in vitro. This study showed that DOPS possesses appreciable therapeutic effect to treat experimental acute UC mice. Its mechanism could be related to inhibition of NLRP3 inflammasome and beta-arrestin1 signaling pathways. PMID- 29421054 TI - Design and development of guar gum based novel, superabsorbent and moisture retaining hydrogels for agricultural applications. AB - The novel hydrogels were synthesized by grafting guar gum with acrylic acid and cross-linking with ethylene glycol di methacrylic acid (EGDMA). The synthesis of hydrogel was confirmed by characterization through 13C NMR, FTIR spectroscopy, SEM micrography, thermo-gravimetric analysis and water absorption studies under different solutions. Synthesized hydrogel (GG-AA-EGDMA) was confirmed to be biodegradable with half-life period of 77 days through soil burial biodegradation studies. The effects of hydrogel treatment on soil were evaluated by studying various physico-chemical properties of soil like bulk density, porosity, water absorption and retention capacity etc. The hydrogel which could absorb up to 800 ml water per gram, after addition to soil, improved its porosity, moisture absorption and retention capacity significantly. Water holding capacity of water increased up to 54% of its original and porosity also increased up to 9% of its original. The synthesized hydrogel revealed tremendous potential as soil conditioning material for agricultural applications. PMID- 29421055 TI - Isomalto/malto-polysaccharide structure in relation to the structural properties of starch substrates. AB - Isomalto/malto-polysaccharides (IMMPs) are soluble dietary fibres produced by the enzymatic modification of starch with 4,6-alpha-glucanotransferase (GTFB). The structure, size, and linkage distribution of these IMMPs has remained largely unknown, since most structural information has been based on indirect measurements such as total alpha-(1->6) content, iodine staining and GTFB hydrolytic activity. This study provides a deeper understanding of IMMP structure in relation to its respective starch substrate, by combining preparative fractionation with linkage compositition analysis. IMMPs were produced from a variety of amylose-rich and amylose-free starches. The extent of modification was investigated per IMMP molecular weight (Mw)-fraction, distinguishing between linear alpha-(1->6) linkages introduced by GTFB and starch's native alpha-(1 >4,6) branching points. It emerged that the amount of alpha-(1->6) linkages was consistently higher in IMMP low Mw-fractions and that GTFB activity was limited by native alpha-(1->4,6) linkages. The presence of amylose turned out to be a prerequisite for the incorporation of linear alpha-(1->6) linkages in amylopectin. PMID- 29421056 TI - Taste masking and rheology improvement of drug complexed with beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin by hot-melt extrusion. AB - This study aimed to mask fluconazole (FLU) taste and improve its rheological properties by an efficient process of cyclodextrin complexation. For this, hot melt extrusion (HME) was used to obtain extrudates composed of FLU, hydroxypropylcellulose, and one of two different cyclodextrins (beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin) maintaining the drug:cyclodextrin molar ratio at 1:0.3 or 1:0.2, respectively. Samples were characterized by physicochemical tests, palatability using e-tongue and antifungal assays. Drug stability was preserved after HME, according to spectroscopy test (correlation coefficient >0.9) and HPLC-assay (100-107%). Flowability was improved in HME systems with compressibility of <12%. Similarly, floodability exhibited significant enhancement (dispersibility <10%). Whereas extrudates of FLU containing only the polymeric matrix led to a slow drug dissolution efficiency (18.6%) and a partial drug taste masking; extrudates containing cyclodextrin accelerated FLU dissolution (dissolution efficiency approx. 30%) and provided a complete drug taste masking. Moreover, HME process could produce drug complexes with high complexation efficiency and preserve its antifungal activity. PMID- 29421057 TI - Structural characterization of bioactive heteropolysaccharides from the medicinal fungus Inonotus obliquus (Chaga). AB - The aim of this paper was to perform a comprehensive characterization of polysaccharides isolated from the interior (IOI) and exterior (IOE) parts of the fungus Inonotus obliquus. Pre-extraction with DCM and MeOH, followed by water and alkali extraction and ethanol precipitation gave two water extracts and two alkali extracts. Neutral and acidic polysaccharide fractions were obtained after anion-exchange chromatography of the water extracts. The neutral polysaccharides (60-73 kDa) were heterogeneous and branched and consisted of a (1 -> 3)-linked beta-Glc backbone with (1 -> 6)-linked kinks in the chain at approximately every fifth residue, with branches of (1 -> 6)-linked beta-Glc in addition to substantial amounts of (1 -> 6)-linked alpha-Gal with 3-O-methylation at about every third Gal residue. The acidic polysaccharide fractions (10-31 kDa) showed similar structural motifs as the neutral fractions differing mainly by the presence of (1 -> 4)-linked alpha-GalA and alpha-GlcA. beta-Xyl, alpha-Man and alpha-Rha were also present in varying amounts in all fractions. No major structural differences between the IOI and IOE fractions were observed. An alkaline polysaccharide fraction (>450 kDa) was obtained from the IOI alkali extract, and consisted mainly of (1 -> 3)- and (1 -> 6)-linked beta-Glc and (1 -> 4)-linked beta-Xyl. Several of the fractions showed in vitro immunomodulatory effect by increasing NO production in the murine macrophage and dendritic cell lines J774.A1 and D2SC/1. Most fractions managed to increase NO production only at the highest concentration tested (100 MUg/ml), while the neutral fraction IOE WN activated potent NO production at 10 MUg/ml and was considered the most promising immunomodulating fraction in this study. PMID- 29421058 TI - Structural comparison, antioxidant and anti-inflammatory properties of fucosylated chondroitin sulfate of three edible sea cucumbers. AB - Three fucosylated chondroitin sulfate (fCS) were obtained from edible sea cucumbers Apostichopus japonicus, Stichopus chloronotus and Acaudina molpadioidea collected from China. fCS from Stichopus chloronotus was firstly reported. The detailed structures of fCSs, particularly the fucose branches, were investigated and compared. 1H and 13C NMR of the polysaccharide identified three sulfation patterns of fucose branches: 4-O-, 2,4-di-O, and 3,4-di-O-sulfation variously existed in different fCSs. The backbone structure was confirmed by the monosaccharide composition and two-dimensional NMR. Antioxidant properties of fCSs were evaluated by the scavenging abilities on 1,1-diphenyl-2-picrylhydrazyl, nitric oxide radicals and inhibition of lipid peroxidation. The results showed that their activities could be affected by the sulfation patterns of the fucose branches, and O-4 sulfation is particularly important for its activities. The anti-inflammatory assays of fCS-Am showed significant reduction of the carrageenan induced edema in a dose depended manner, which could be used as a potential antiallergic agent. PMID- 29421059 TI - Combination of carbon nanotube and cyclodextrin nanosponge chemistry to develop a heterogeneous Pd-based catalyst for ligand and copper free C-C coupling reactions. AB - Carbon nanotubes and cyclodextrin nanosponge were hybridized and used as a support for embedding Pd(0) nanoparticles and developing a novel and heterogeneous catalyst, Pd@CDNS-CNT, for promoting ligand and copper-free Sonogashira and Heck coupling reactions in aqueous media and mild reaction condition. Cyclodextrin nanosponge could contribute to catalysis through encapsulating the reagents and transferring them in the vicinity of Pd nanoparticles. The results established that the catalytic activity of Pd@CDNS-CNT was superior to those of Pd@CNT, Pd@CDNS and Pd@CNT + CDNS, indicating the synergism between the components of the hybrid system. Notably, various aryl halides including aryl iodide, bromide and chloride were useful substrates for the coupling reactions and affording the corresponding products in high to excellent yields in short reaction times. Moreover, the catalyst was recyclable up to six reaction runs with negligible Pd leaching. PMID- 29421060 TI - Alginate-polymethacrylate hybrid hydrogels for potential osteochondral tissue regeneration. AB - Porous scaffolds based on alginate-polymethacrylate hybrid hydrogels intended for bone and cartilage regeneration were prepared through controlled calcium ions diffusion from an agar mould. The double interconnected network of such materials combines into a single porous structure maintained by both noncovalent crosslinks (calcium ions for alginate) and covalent crosslinks (polymethacrylate crosslinked by the addition of mixtures of mono and bifunctional monomers). The alginate component ensures the appropriate micro-environment to mimic the extra-cellular matrix, whereas the polymethacrylate improves the mechanical performances of the hybrid hydrogels, helping to overcome the mechanical limitations of the alginate component. Morphological characterization and porosity analysis of the hybrid scaffolds were assessed by scanning electron microscopy and micro-computed tomography. Relative concentration and distribution of calcium ions were evaluated by atomic absorption and dispersive X-ray analysis, respectively. Uniaxial compressive mechanical tests were conducted to evaluate the compressive elastic modulus of the hybrid hydrogels that was correlated with their swelling ratio and crosslinking degree. As was envisaged a much higher modulus (about seven times) was obtained for the hybrid Alg/HE hydrogel than with alginate alone. PMID- 29421061 TI - Physicochemical and immunological characterization of chitosan-coated bacteriophage nanoparticles for in vivo mycotoxin modeling. AB - To propose a novel modeling of aflatoxin immunization and surrogate toxin conjugate from AFB1 vaccines, an immunogen based on the mimotope, (i.e. a peptide displayed phage that mimics aflatoxins epitope without toxin hazards) was designed. The recombinant phage 3P30 was identified by phage display technology and exhibited the ability to bind, dose dependent, specifically to its cognate target - anti-AFB1 antibody. In immunization assay, the phage-displayed mimotope and its peptide chemically synthesized were able to induce specific anti-AFB1 antibodies, indicating the proof of concept for aflatoxin mimicry. Furthermore, the phage 3P30 was homogeneously coated with chitosan, which also provided a tridimensional matrix network for mucosal delivery. After intranasal immunization, chitosan coated phages improved specific immunogenicity compared to the free antigen. It can be concluded that affinity-selected phage may contribute to the rational design of epitope-based vaccines in a prospectus for the control of aflatoxins and possibly other mycotoxins, and that chitosan coating improved the vectorization of the vaccine by the mucosal route. PMID- 29421062 TI - Synthesis and evaluation of thermo-rheological behaviour and ionotropic crosslinking of new gellan gum-alkyl derivatives. AB - This paper reports the synthesis and the physicochemical characterization of two series of gellan gum (GG) derivatives functionalized with alkyl chains with different number of carbon, from 8 to 18. In particular, low molecular weight gellan gum samples with 52.6 or 96.7 kDa, respectively, were functionalized with octylamine (C8), dodecylamine (C12) and octadecylamine (C18) by using bis(4 nitrophenyl) carbonate (4-NPBC) as a coupling agent. Thermo-rheological and ionotropic crosslinking properties of these gellan gum-alkyl derivatives were evaluated and related to the degree of derivatization in alkyl chains. Results suggested as length and degree of derivatization differently influenced coil-to helix gelation mechanism of GG derivatives, ionotropic crosslinking, and strength of crosslinked hydrogels obtained in CaCl2 0.102 M and NaCl 0.15 M. Statement of hypothesis: The insertion of alkyl chains on the gellan gum backbone interferes with coil-to-helix transition mechanism and allows the production of hydrophobically assembled hydrogels. PMID- 29421063 TI - Targeted delivery of SNX-2112 by polysaccharide-modified graphene oxide nanocomposites for treatment of lung cancer. AB - Graphene oxide (GO) is a promising material for biomedical applications, particularly in drug delivery, due to its exceptional chemical and physical properties. In this work, an innovative GO-based carrier was developed by modifying GO with chitosan (CHI) to improve the biocompatibility, and followed by the conjugation of hyaluronic acid (HA), the target ligand for CD44, to realize the specific recognition of tumor cells and improve the efficiency of anti-tumor drug delivery. The resulting product GO-CHI-HA was loaded with an anti-cancer drug SNX-2112, which is the Hsp90 inhibitor. The total release amount and release rate of SNX-2112 were significantly higher in acidic condition than in physiological condition. GO-CHI-HA with a low concentration had little impact on the lysis of red blood cells (RBCs) and blood coagulation and showed low toxicity in A549 cells and NHBE cells. The GO-CHI-HA/SNX-2112 proved to be effective in inhibiting and killing A549 cells while having lower cytotoxicity against normal human bronchial epithelial cells (NHBE cells). Furthermore, in vivo toxicity of the materials towards vital organs in SD rats were also studied through histological examinations and blood property analyses, the results of which showed that although inflammatory response was developed in the short-term, GO CHI-HA/SNX-2112 caused no severe long-term injury. Therefore, this drug delivery system showed great potential as an effective and safe drug delivery system with little adverse side effects for cancer therapy. PMID- 29421064 TI - Chinese quince seed gum and poly (N,N-diethylacryl amide-co-methacrylic acid) based pH-sensitive hydrogel for use in drug delivery. AB - In this investigation, a variety of innovative pH-sensitive polymers consisting of Chinese quince seed gum (CQSG) and poly (N,N-diethylacryl amide-co-methacrylic acid) were synthesized via free radical polymerization for controlled drug delivery. The resultant hydrogel polymers were characterized by scanning electron microscopy and X-ray diffraction, analyzed by Fourier-transform infrared spectroscopy, and confirmed with thermogravimetry. Results suggested the hydrogel polymers were composed of CQSG chains physically entangled in poly (N,N diethylacryl amide-co-methacrylic acid) networks. Swelling properties of these hydrogels were strongly affected by the contents of CQSG and crosslinkers. The drug delivery applications of the hydrogels were evaluated using bovine serum albumin (BSA) as a model drug in vitro release. It was determined that BSA release from the hydrogels was pH-sensitive under simulated gastrointestinal conditions. All of these attributes imply that the new proposed CQSG/poly (N,N diethylacryl amide-co-methacrylic acid) hydrogel polymers can be used as a good medium for oral delivery of proteinaceous drugs. PMID- 29421066 TI - Complications in Surgery for Brachial Plexus Birth Injury: Avoidance and Treatment. AB - Brachial plexus birth injuries are rare, with treatment and follow-up often required from infancy until skeletal maturity. We review complications that may occur related to primary nerve surgery or secondary musculoskeletal procedures, and discuss how these may be avoided. PMID- 29421065 TI - Capsaicin-sensitive cutaneous primary afferents convey electrically induced itch in humans. AB - Specially designed transcutaneous electrical stimulation paradigms can be used to provoke experimental itch. However, it is unclear which primary afferent fibers are activated and whether they represent pathophysiologically relevant, C-fiber mediated itch. Since low-threshold mechano-receptors have recently been implicated in pruriception we aimed to characterize the peripheral primary afferent subpopulation conveying electrically evoked itch in humans (50Hz stimulation, 100MUs square pulses, stimulus-response function to graded stimulus intensity). In 10 healthy male volunteers a placebo-controlled, 24-h 8% topical capsaicin-induced defunctionalization of capsaicin-sensitive (transient receptor potential V1-positive, 'TRPV1'+) cutaneous fibers was performed. Histaminergic itch (1% solution introduced by a prick test lancet) was provoked as a positive control condition. Capsaicin pretreatment induced profound loss of warmth and heat pain sensitivity (pain threshold and supra-threshold ratings) as assessed by quantitative sensory testing, indicative of efficient TRPV1-fiber defunctionalization (all outcomes: P<0.0001). The topical capsaicin robustly, and with similar efficaciousness, inhibited itch intensity evoked by electrical stimulation and histamine (-89+/-4.1% and -78+/-4.9%, respectively, both: P<0.0001 compared to the placebo patch area). The predominant primary afferent substrate for electrically evoked itch in humans, using the presently applied stimulation paradigm, is concluded to be capsaicin-sensitive polymodal C-fibers. PMID- 29421067 TI - Patient Safety Movement: History and Future Directions. AB - Despite progress within the past 15 years, improving patient safety in health care remains an important public health issue. The history of safety policies, research, and development has revealed that this issue is more complex than initially perceived and is pertinent to all health care settings. Solutions, therefore, must be approached at the systems level and supplemented with a change in safety culture, especially in higher risk fields such as surgery. To do so, health care agents at all levels have started to prioritize the improvement of nontechnical skills such as teamwork, communication, and accountability, as reflected by the development of various checklists and safety campaigns. This progress may be sustained by adopting teamwork training programs that have proven successful in other high-risk industries, such as crew resource management in aviation. These techniques can be readily implemented among surgical teams; however, successful application depends heavily on the strong leadership and vigilance of individual surgeons. PMID- 29421068 TI - Lean and Green Hand Surgery. AB - Health care in the United States is both expensive and wasteful. The cost of health care in the United States continues to increase every year. Health care spending for 2016 is estimated at $3.35 trillion. Per capita spending ($10,345 per person) is more than twice the average of other developed countries. The United States also leads the world in solid waste production (624,700 metric tons of waste in 2011). The health care industry is second only to the food industry in annual waste production. Each year, health care facilities in the United States produce 4 billion pounds of waste (660 tons per day), with as much as 70%, or around 2.8 billion pounds, produced directly by operating rooms. Waste disposal also accounts for up to 20% of a hospital's annual environmental services budget. Since 1992, waste production by hospitals has increased annually by a rate of at least 15%, due in part to the increased usage of disposables. Reduction in operating room waste would decrease both health care costs and potential environmental hazards. In 2015, the American Association for Hand Surgery along with the American Society for Surgery of the Hand, American Society for Peripheral Nerve Surgery, and the American Society of Reconstructive Microsurgery began the "Lean and Green" surgery project to reduce the amount of waste generated by hand surgery. We recently began our own "Lean and Green" project in our institution. Using "minor field sterility" surgical principles and Wide Awake Local Anesthesia No Tourniquet (WALANT), both surgical costs and surgical waste were decreased while maintaining patient safety and satisfaction. As the current reimbursement model changes from quantity to quality, "Lean and Green" surgery will play a role in the future health care system. PMID- 29421069 TI - Technique of Dynamic Flexor Digitorum Superficialis Transfer to Lateral Bands for Proximal Interphalangeal Joint Deformity Correction in Severe Dupuytren Disease. AB - Pseudo-boutonniere deformity is an uncommon complication from long-standing proximal interphalangeal (PIP) joint contracture in Dupuytren disease. Prolonged flexion contracture of the PIP joint can lead to central slip attenuation and resultant imbalances in the extensor mechanism. We present a technique of flexor digitorum superficialis (FDS) tendon transfer to the lateral bands to correct pseudo-boutonniere deformity at the time of palmar fasciectomy for the treatment of Dupuytren disease. The FDS tendon is transferred from volar to dorsal through the lumbrical canal and sutured into the dorsally mobilized lateral bands. This technique presents an approach to the repair of pseudo-boutonniere deformity in Dupuytren disease. PMID- 29421070 TI - Chimeric Free Vascularized Metatarsophalangeal Joint With Toe Fillet Flap: A Technique for Reconstruction of the Posttraumatic Metacarpophalangeal Joint With Concomitant Soft Tissue Defect. AB - For painful, dysfunctional, posttraumatic metacarpophalangeal (MCP) joints, the free vascularized toe joint transfer may represent a good solution. Successful reconstruction is potentially limited, however, by 2 features of the traditional vascularized metatarsophalangeal (MTP) transfer: inadequate arc of flexion and insufficient soft tissue coverage. The solution to both of these dilemmas lies in the manner of utilizing the donor site. Because of its innate hyperextensibility, rotating the MTP 180 degrees volar to dorsal provides the greatest arc of flexion in the reconstructed MCP. Excellent soft tissue coverage can be provided by elevating the skin paddle of the transferred second toe as a chimeric fillet flap, based on the tibial plantar digital artery. PMID- 29421075 TI - Comparing methods suitable for monitoring marine mammals in low visibility conditions during seismic surveys. AB - Loud sound emitted during offshore industrial activities can impact marine mammals. Regulations typically prescribe marine mammal monitoring before and/or during these activities to implement mitigation measures that minimise potential acoustic impacts. Using seismic surveys under low visibility conditions as a case study, we review which monitoring methods are suitable and compare their relative strengths and weaknesses. Passive acoustic monitoring has been implemented as either a complementary or alternative method to visual monitoring in low visibility conditions. Other methods such as RADAR, active sonar and thermal infrared have also been tested, but are rarely recommended by regulatory bodies. The efficiency of the monitoring method(s) will depend on the animal behaviour and environmental conditions, however, using a combination of complementary systems generally improves the overall detection performance. We recommend that the performance of monitoring systems, over a range of conditions, is explored in a modelling framework for a variety of species. PMID- 29421076 TI - Global change impacts on large-scale biogeographic patterns of marine organisms on Atlantic oceanic islands. AB - Past climate changes provide important clues for advancement of studies on current global change biology. We have tested large-scale biogeographic patterns through four marine groups from twelve Atlantic Ocean archipelagos and searched for patterns between species richness/endemism and littoral area, age, isolation, latitude and mean annual sea-surface temperatures. Species richness is strongly correlated with littoral area. Two reinforcing effects take place during glacial episodes: i) species richness is expected to decrease (in comparison with interglacial periods) due to the local disappearance of sandy/muddy-associated species; ii) because littoral area is minimal during glacial episodes, area per se induces a decrease on species richness (by extirpation/extinction of marine species) as well as affecting speciation rates. Maximum speciation rates are expected to occur during the interglacial periods, whereas immigration rates are expected to be higher at the LGM. Finally, sea-level changes are a paramount factor influencing marine biodiversity of animals and plants living on oceanic islands. PMID- 29421077 TI - Tape seagrass (Enhalus acoroides) as a bioindicator of trace metal contamination in Merambong shoal, Johor Strait, Malaysia. AB - Revealing the potential of seagrass as a bioindicator for metal pollution is important for assessing marine ecosystem health. Trace metal (111Cd, 63Cu, 60Ni, 208Pb, 66Zn) concentrations in the various parts (root, rhizome, and blade) of tape seagrass (Enhalus acoroides) collected from Merambong shoal of Sungai Pulai estuary, Johor Strait, Malaysia were acid-extracted using a microwave digester and analysed via inductively coupled plasma-mass spectrometry (ICP-MS). The ranges of trace metal concentrations (in MUgg-1 dry weight) were as follows: Cd (0.05-0.81), Cu (1.62-27.85), Ni (1.89-9.35), Pb (0.69-4.16), and Zn (3.44 35.98). The translocation factor revealed that E. acoroides is a hyperaccumulator plant, as its blades can accumulate high concentrations of Cd, Cu, Ni, and Zn, but not Pb. The plant limits Pb mobility to minimize Pb's toxic impact. Thus, E. acoroides is a potential bioindicator of metal pollution by Cd, Cu, Ni, and Zn in estuarine environments. PMID- 29421078 TI - Settling fluxes and ecotoxicological risk assessment of fine sedimentary metals in Tema Harbour (Ghana). AB - Sediment traps were deployed in the Tema Harbour to estimate the settling fluxes of silt-clay particles and associated metals (Fe, Mn, Pb, Cr, Cu, Zn, Ni, Hg, Sn and As) and characterise their potential ecotoxicological risks. The mean daily settling fluxes of the silt-clay particles and associated metals ranged from 42.7 to 85.0gm-2d-1 and 1.3*10-2 to 49.4mgm-2d-1, respectively, and were characterised by large fluctuations at each station. The silt-clay and metal fluxes strongly correlated, indicating the important role of the silt-clay particles in metal transport and distribution in the harbour. Geochemical indices indicated anthropogenic influences on the harbour as the Pb, Cr, Zn, Hg, Sn and As content in the settling silt-clay particles exceeded their average crustal concentrations. Sediment quality guidelines indicated these metals pose appreciable ecotoxicological risks, particularly As. Increasing temporal trends in As necessitates increased pollution control efforts at the harbour. PMID- 29421079 TI - Ongoing biodegradation of Deepwater Horizon oil in beach sands: Insights from tracing petroleum carbon into microbial biomass. AB - Heavily weathered petroleum residues from the Deepwater Horizon (DwH) disaster continue to be found on beaches along the Gulf of Mexico as oiled-sand patties. Here, we demonstrate the ongoing biodegradation of weathered Macondo Well (MW) oil residues by tracing oil-derived carbon into active microbial biomass using natural abundance radiocarbon (14C). Oiled-sand patties and non-oiled sand were collected from previously studied beaches in Mississippi, Alabama, and Florida. Phospholipid fatty acid (PLFA) analyses illustrated that microbial communities present in oiled-sand patties were distinct from non-oiled sand. Depleted 14C measurements of PLFA revealed that microbes on oiled-sand patties were assimilating MW oil residues five years post-spill. In contrast, microbes in non oiled sand assimilated recently photosynthesized carbon. These results demonstrate ongoing biodegradation of weathered oil in sand patties and the utility of 14C PLFA analysis to track the biodegradation of MW oil residues long after other indicators of biodegradation are no longer detectable. PMID- 29421080 TI - Efficacy of seawater for washing oiled birds during an oil spill response. AB - Aquatic pollution events can be detrimental to the survival of wildlife, particularly birds. To decontaminate affected birds, large quantities of fresh water are required. A recent study using seabird feathers, demonstrated that seawater wash/rinse can effectively remove oil from feathers. However to determine whether seawater was effective for live birds, we used 36 mallard ducks to replicate the oiled feather wash/rinse study. We investigated the time and volume of water used, bird water-proofing scores after daily swims and a barbule amalgamation index (BAI), for feathers collected at stages throughout the process. Results indicate that for oiled mallard ducks, the use of seawater for decontamination wash/rinse was effective. Seawater wash however, took longer and used a greater quantity of water. Time to birds being waterproof, was not significantly different between groups. The use of seawater has worldwide application for oiled wildlife response activities particularly in areas where freshwater supplies are limited. PMID- 29421081 TI - Bacterial community structure in response to environmental impacts in the intertidal sediments along the Yangtze Estuary, China. AB - This study was designed to investigate the characteristics of bacterial communities in intertidal sediments along the Yangtze Estuary and their responses to environmental factors. The results showed that bacterial abundance was significantly correlated with salinity, SO42- and total organic carbon, while bacterial diversity was significantly correlated with SO42- and total nitrogen. At different taxonomic levels, both the dominant taxa and their abundances varied among the eight samples, with Proteobacteria being the most dominant phylum in general. Cluster analysis revealed that the bacterial community structure was influenced by river runoff and sewerage discharge. Moreover, SO42-, salinity and total phosphorus were the vital environmental factors that influenced the bacterial community structure. Quantitative PCR and sequencing of sulphate reducing bacteria indicated that the sulphate reduction process occurs frequently in intertidal sediments. These findings are important to understand the microbial ecology and biogeochemical cycles in estuarine environments. PMID- 29421082 TI - Inactivation of Scrippsiella trochoidea cysts by different physical and chemical methods: Application to the treatment of ballast water. AB - Effects of heating, ultraviolet (UV), ultrasound (US), hydrogen peroxide (H2O2) and freshwater, and the combined treatments on inactivation of cysts of Scrippsiella trochoidea and cysts in sediment suspension were studied. Heating was the most efficient way to inactivate cyst germination, and cysts were completely inactivated at 38 degrees C for 5h. UV, US, and freshwater efficiently inhibited but could not completely inactivate cyst germination. Effects of heating, UV, and US on cyst germination decreased for cysts in sediment, and germination rates increased by 6.7-48% compared to the same treatment for cysts without sediment. H2O2 significantly inhibited cyst germination, but complete inactivation occurred at high concentration for long duration (100mg/L, 6d). The combined treatments were more effective, especially the combinations of heating and UV. The results suggested that heating might be a feasible way for ballast water treatment especially after combined with filtration and UV. PMID- 29421083 TI - Identifying oil/marine snow associations in mesocosm simulations of the Deepwater Horizon oil spill event using solid-state 13C NMR spectroscopy. AB - The Deepwater Horizon oil spill stimulated the release of marine snow made up of dead/living plankton/bacteria and their exopolymeric polysaccharide substances (EPS), termed marine oil snow (MOS), promoting rapid removal of oil from the water column into sediments near the well site. Mesocosm simulations showed that Macondo surrogate oil readily associates with the marine snow. Quantitative solid state 13C NMR readily distinguishes this oil from naturally formed marine snow and reveals that adding the dispersant Corexit enhances the amount of oil associated with the MOS, thus contributing to rapid removal from the water column. Solvent extraction of MOS removes the oil-derived compounds for analysis by one and two-dimensional GC/MS and evaluation of potential transformations they undergo when associated with the EPS. The results reveal that the oil associated with EPS is subjected to rapid transformation, in a matter of days, presumably by bacteria and fungi associated with EPS. PMID- 29421085 TI - Distribution correlations of cadmium to calcium, phosphorus, sodium and chloridion in mangrove Aegiceras corniculatum root tissues. AB - Nutriment distributions might influence Cd distribution and Cd tolerance in mangrove plant roots. To demonstrate this, Aegiceras corniculatum was stressed by Cd, and the distributions of Cd, Ca, P, Na and Cl in plant roots were detected with the aid of SEM-EDX. It was found that endodermis, pith and xylem were the predominant tissues for retardation and regional enrichment of Cd. Na and Cl distributions suggest a critical role of salt resistance tissues on Cd tolerance in roots. P participated in Cd retardation and regional enrichment of endodermis and xylem. P, Na, Cl and Ca distribution had a high correlation to that of Cd in roots. The synergetic accumulation between Ca and Cd could be a crucial mechanism for Cd tolerance in A. corniculatum roots. In conclusion, the research of Cd and nutriment distributions in A. corniculatum roots deepens the understanding on Cd tolerance in mangrove plants. PMID- 29421084 TI - Mercury content of blue crabs (Callinectes sapidus) from southern New England coastal habitats: Contamination in an emergent fishery and risks to human consumers. AB - Total mercury (Hg; ppm dry weight) was measured in blue crabs, Callinectes sapidus, collected from Narraganset Bay and adjacent coastal lagoons and tidal rivers (Rhode Island/Massachusetts, USA) from May to August 2006-2016. For juvenile crabs (21-79mm carapace width, CW), total Hg was significantly greater in chelae muscle tissue (mean+/-1 SD=0.32+/-0.21ppm; n=65) relative to whole bodies (0.21+/-0.16ppm; n=19), and irrespective of tissue-type, crab Hg was positively related to CW indicating bioaccumulation of the toxicant. Across a broader range of crab sizes (43-185mm CW; n=465), muscle Hg concentrations were significantly higher in crabs from the Taunton River relative to other locations (0.71+/-0.35ppm and 0.20+/-0.10ppm, respectively). Spatial variations in crab Hg dynamics were attributed to habitat-specific Hg burdens of their prey, including bivalves, gastropods, polychaetes, and shrimp. Prey Hg, in turn, was directly related to localized sediment Hg and methylmercury conditions. Biota-sediment accumulation factors for crabs and prey were negatively correlated with sediment organic content, verifying that organically-enriched substrates reduce Hg bioavailability. From a human health perspective, frequent consumption of crabs from the Taunton River may pose a human health risk (23% of legal-size crabs exceeded US EPA threshold level); thus justifying spatially-explicit Hg advisories for this species. PMID- 29421086 TI - Modeling for the allocation of oil spill recovery capacity considering environmental and economic factors. AB - This study presents a regional oil spill risk assessment and capacities for marine oil spill response in Korea. The risk assessment of oil spill is carried out using both causal factors and environmental/economic factors. The weight of each parameter is calculated using the Analytic Hierarchy Process (AHP). Final regional risk degrees of oil spill are estimated by combining the degree and weight of each existing parameter. From these estimated risk levels, oil recovery capacities were determined with reference to the recovery target of 7500kl specified in existing standards. The estimates were deemed feasible, and provided a more balanced distribution of resources than existing capacities set according to current standards. PMID- 29421087 TI - Holocene ecosystem shifts and human-induced loss of Arca and Ostrea shell beds in the north-eastern Adriatic Sea. AB - The molluscan assemblages in a sediment core from the north-eastern Adriatic show significant compositional changes over the past 10,000yrs related to (1) natural deepening driven by the post-glacial sea-level rise, (2) increasing abundance of skeletal sand and gravel, and (3) anthropogenic impacts. The transgressive phase (10,000-6000 BP) is characterized by strongly time-averaged communities dominated by infaunal bivalves. During the early highstand (6000-4000 BP), the abundance of epifaunal filter feeders and grazers increases, and gastropods become more important. Epifaunal dominance culminates during the late highstand (4000-2000 BP) with the development of extensive shell beds formed by large-sized Arca noae and Ostrea sp. bivalves. This community persists until the early 20th century, when it falls victim to multiple anthropogenic impacts, mainly bottom trawling, and is substituted by an infauna-dominated community indicative of instability, disturbance and organic enrichment. The re-establishment of this unique shell-bed ecosystem can be a goal for restoration efforts. PMID- 29421088 TI - Anticyclonic eddies increase accumulation of microplastic in the North Atlantic subtropical gyre. AB - There are fundamental gaps in our understanding of the fates of microplastics in the ocean, which must be overcome if the severity of this pollution is to be fully assessed. The predominant pattern is high accumulation of microplastic in subtropical gyres. Using in situ measurements from the 7th Continent expedition in the North Atlantic subtropical gyre, data from satellite observations and models, we show how microplastic concentrations were up to 9.4 times higher in an anticyclonic eddy explored, compared to the cyclonic eddy. Although our sample size is small, this is the first suggestive evidence that mesoscale eddies might trap, concentrate and potentially transport microplastics. As eddies are known to congregate nutrients and organisms, this phenomenon should be considered with regards to the potential impact of plastic pollution on the ecosystem in the open ocean. PMID- 29421089 TI - Anthropogenic and natural variability in the composition of sedimentary organic matter of the urbanised coastal zone of Montevideo (Rio de la Plata). AB - This study is aimed to identify the different sources of sedimentary organic matter (SOM) within Montevideo coastal zone (MCZ). To this end delta13C, delta15N and C/N ratio were analysed in surface sediments and a sediment core. Sediment core analysis showed that until ~1950CE SOM was mainly marine, observing a shift towards lower delta13C in recent sediments, evidencing an estuarine composition. This trend was associated to the climatic variability, which exerted a major influence on the SOM composition, leading to an increased input of terrigenous material and associated anthropogenic contaminants. Surface sediments collected during different El Nino South Oscillation (ENSO) phases did not show inter annual variability in SOM composition, which was mainly marine in both eastern and western region of MCZ and estuarine in Montevideo Bay. This spatial pattern provides new insights on the dynamics and factors affecting organic matter sources available for primary consumers along the study region. PMID- 29421090 TI - Polychlorinated biphenyls (PCBs) in recreational marina sediments of San Diego Bay, southern California. AB - Polychlorinated biphenyl (PCB) concentrations were determined in surface sediments from three recreational marinas in San Diego Bay, California. Total PCB concentrations ranged from 23 to 153, 31-294, and 151-1387ngg-1 for Shelter Island Yacht Basin (SIYB), Harbor Island West (HW) and Harbor Island East (HE), respectively. PCB concentrations were significantly higher in HE and PCB group composition differed relative to HW and SIYB, which were not significantly different from each other in concentration or group composition. In marina sediments there was a predominance (82-85%) of heavier molecular weight PCBs with homologous groups (6CL-7CL) comprising 59% of the total. In HE 75% of the sites exceeded the effect range median (ERM), and toxicity equivalence (TEQ dioxin-like PCBs) values were higher relative to those of HW and SIYB, suggesting a potential ecotoxicological risk. PMID- 29421091 TI - Trajectory prediction of oil spill with Pisces 2 around Bay of Izmir, Turkey. AB - The purpose of this study is to determine the risky areas by simulating trajectory of ship based oil spill in Bay of Izmir. To get well informed about fate, this study makes the best possible use one trajectory model. PISCES 2 (Potential Incident Simulation, Control and. Evaluation System), has been conducted for simulation of main weathering processes of oil spill. Hence in order to identify the risky areas, two scenarios have been developed depending on the type and amount of pollutants. In this study it is concluded that Yenikale, Inciralti and Guzelbahce will be at risk of contamination in case of accidental oil spill at Yenikale Entrance. Finally, the PISCES 2 software provided highly reliable solutions in evaporation rate and dispersion rate calculations when compared to approaches accepted in the literature. However in the surface area calculations, there is a serious difference between the size of the area calculated by the software and the size of the area proposed by oil spill science. PMID- 29421092 TI - Mangrove clearing impacts on macrofaunal assemblages and benthic food webs in a tropical estuary. AB - Despite over 21,000ha of mangrove forests being removed per year in Brazil, ecological changes following mangrove deforestation have been overlooked. Here we evaluated changes in benthic macrofaunal assemblages and food-webs at a mangrove removal and natural sites in a tropical estuary in Eastern Brazil. The impacted site had coarser sediment particle sizes suggesting significant changes in sedimentation processes after forest clearing. Spatial differences in macrofaunal abundance, biomass and diversity were not directly associated with the removal of mangrove forests, supporting recolonization of impacted areas by estuarine fauna. However, benthic assemblage composition, infaunal delta13C signatures and food web diversity markedly differed at the impacted site being strongly related to sedimentary changes. The loss of infaunal trophic diversity that followed mangrove removal suggests that large-scale forest clearing may impact estuarine food webs, with potential consequences to nearby coastal ecosystems given the high clearing rate of mangrove forests in Brazil. PMID- 29421093 TI - Quality assessment of pollution indicators in marine water at critical locations of the Gulf of Mannar Biosphere Reserve, Tuticorin. AB - The present study focused on the shoreline environment of urban and industrial areas, and the aim of this study was to assess the coastal water quality in the Gulf of Mannar Biosphere Reserve. Water samples were collected from five different coastal sites during the premonsoon and monsoon seasons. The samples were analyzed following the standard methods. The results showed that the levels of microbiological indicators in the samples highly exceeded the regional and national standard seawater permissible limits, and environmental parameters such as the total suspended solid and dissolved oxygen were affected significantly (p<0.05). To identify frequent pollution indicators, their levels should be estimated to determine possible pollution in coastal ecosystems due to human interventions. PMID- 29421094 TI - Impact of two plastic-derived chemicals, the Bisphenol A and the di-2-ethylhexyl phthalate, exposure on the marine toxic dinoflagellate Alexandrium pacificum. AB - The effects of two plastic-derived chemicals: Bisphenol A (BPA) and di-2 ethylhexyl phthalate (DEHP) were assessed on abundance and physiological responses of the marine toxic dinoflagellate Alexandrim pacificum. During 7days experiment, A. pacificum was exposed to different levels of BPA and DEHP (separately and in mixture). The responses were evaluated and compared with controls. Results showed that A. pacificum was highly sensitive to this contaminants comparing to other phytoplankton species. BPA and DEHP caused the decrease of the biomass (1.2 to 50 times lower relative to the controls), as well as the perturbation of the photosystem and the photosynthetic activity. Nevertheless, our results show a recovery of contaminated cells activity depending on exposure time and BPA and DEHP contamination. This could be related to an adaptation to induced stress or a degradation of BPA and DEHP in the medium. PMID- 29421095 TI - Methylmercury in tissues of Atlantic sturgeon (Acipenser oxyrhynchus) from the Saint John River, New Brunswick, Canada. AB - Environmental contamination by mercury is a concern in marine food webs, and especially for large fish. We examined methylmercury (MeHg) levels in blood, muscle and liver of 35 individual Atlantic sturgeon (Acipenser oxyrhynchus), a commercially harvested, anadromous fish eastern Canada. Females had higher blood and liver MeHg levels than males, and in some tissues there was a suggestion of higher mercury in longer fish. Collectively, sturgeon MeHg levels were far below Canadian and international guidelines for safe consumption of fish meat. PMID- 29421096 TI - Concept for a hyperspectral remote sensing algorithm for floating marine macro plastics. AB - There is growing global concern over the chemical, biological and ecological impact of plastics in the ocean. Remote sensing has the potential to provide long term, global monitoring but for marine plastics it is still in its early stages. Some progress has been made in hyperspectral remote sensing of marine macroplastics in the visible (VIS) to short wave infrared (SWIR) spectrum. We present a reflectance model of sunlight interacting with a sea surface littered with macro plastics, based on geometrical optics and the spectral signatures of plastic and seawater. This is a first step towards the development of a remote sensing algorithm for marine plastic using light reflectance measurements in air. Our model takes the colour, transparency, reflectivity and shape of plastic litter into account. This concept model can aid the design of laboratory, field and Earth observation measurements in the VIS-SWIR spectrum and explain the results. PMID- 29421097 TI - Microplastic in beach sediments of the Isle of Rugen (Baltic Sea) - Implementing a novel glass elutriation column. AB - To extent the understanding on microplastics in the marine environment we performed a case study at four beaches on the Isle of Rugen considering abundance and spatial distribution of microplastics in beach sediments. For the analysis, density separation via a glass elutriation column was implemented. In advance, efficiencies were tested for two polymers, being not buoyant in water. Recovery rates of 80% for PET and 72% for PVC particles in sandy samples were achieved. A median abundance of 88.10 (Q1=55.01/Q3=114.72) microplastic particles per kg dry sediment or 2862.56 (Q1=1787.34/Q3=3727.28) particles per m2 was found at the beaches on Rugen. Fibers were more abundant than fragments at all beaches. In this study, no statistically significant differences but only tendencies were determined between the beaches with different exposition and anthropogenic activity as well as for distribution patterns which showed that microplastic fragments accumulate in topographic depressions, similar to macrolitter items. PMID- 29421098 TI - Carbon accumulation and storage capacity in mangrove sediments three decades after deforestation within a eutrophic bay. AB - A dated sediment core from an eutrophic mangrove area presented non-significant differences in carbon accumulation rates before (55.7+/-10.2gm-2yr-1) and after three decades of deforestation (59.7+/-7.2gm-2yr-1). Although eutrophication effects appear to compensate the loss of mangrove organic matter input, the results in this work show a threefold lower carbon accumulation than the global averages estimated for mangrove sediments. The effects of increasing eutrophication and enhanced sediment dry bulk density observed after deforestation (~30% higher) did not result in higher carbon stocks. Moreover, the lower TOC:OP (<400) and C:N (~20) molar ratios, as well as increased nutrient accumulation, reflect the dominance of phytoplankton-derived organic matter after deforestation, resulting in less-efficient sedimentary carbon sinks. These results indicate that the organic material deposited from eutrophication may not compensate mangrove deforestation losses on carbon accumulation in mangrove ecosystems. PMID- 29421099 TI - Metals and As content in sediments and Manila clam Ruditapes philippinarum in the Tagus estuary (Portugal): Impacts and risk for human consumption. AB - The Manila clam is emerging as a relevant species for the Portuguese market. The present work was conducted in the Tagus estuary to evaluate 1) the metals and As content in the sediments of the Tagus estuary, especially on those areas subjected to Manila clam harvesting 2) the metals and As content in clams, and the risk associated with their consumption 3) the physiological and biochemical responses of the clam to metals and As contamination, and its possible role as a pollution bioindicator in the estuarine environment. The most contaminated sediments were identified nearby industrial areas, nevertheless clams collected in low contaminated areas showed high metals and As concentrations. The condition index, glycogen content, membrane oxidative damage, biotransformation enzymes and metallothioneins showed consistent responses to metals and As content in clams. Results emphasize the need for the development of a management plan for the species exploitation in the Tagus estuary. PMID- 29421101 TI - Tracing the source of marine debris on the beaches of northern New South Wales, Australia: The Bottles on Beaches program. AB - Identifying the source of marine plastic pollution accumulating on ocean beaches is often difficult as unidentifiable fragments of plastic usually predominate. In this study, we surveyed plastic bottles as a relatively identifiable subset of plastics on 30km of beach along a 200-km section of the north coast of New South Wales, Australia. Source and product type (contents) were determined using barcodes, inscriptions/embossing, or bottle shape and characteristics. Country of origin and product type could be determined for two-thirds of the 694 bottles found. Just over half (51%) of these were of domestic origin with the remainder dominated by bottles from China (24%) and south-east Asian countries (21%). As most of the foreign bottles lacked marine growth, and are unavailable for purchase in the region, passing ships are hypothesised as the primary source. PMID- 29421100 TI - Assessment of metal contamination in estuarine surface sediments from Dongying City, China: Use of a modified ecological risk index. AB - Surface sediments and clam Meretrix meretrix were collected from a northern estuarine region in Dongying City, China. Sediments were analysed for heavy metals (Hg, As, Cd, Cr, Cu, Pb, and Zn) and the clams were tested for metallothioneins (MTs) and lysosomal membrane stability (LMS). The heavy metal total concentrations decreased in the order of Cr>Zn>Cu>Pb>As>Cd>Hg. The results of Bureau Communautaire de Reference (BCR) sequential extraction of heavy metals showed that the geochemical speciation of all heavy metals was dominated by residual fraction. According to the responses of biomarkers in M. meretrix, the modified potential ecological risk index (PERI-B) can more accurately reflect heavy metals pollution. PERI-B showed all sediment samples have low or moderate risk, except at site S10 (considerable risk), and the main contribution of ecological risk heavy metals were Cd and Hg. PMID- 29421102 TI - Biogeographic vulnerability to ocean acidification and warming in a marine bivalve. AB - Anthropogenic CO2 emissions are rapidly changing seawater temperature, pH and carbonate chemistry. This study compares the embryonic development under high pCO2 conditions across the south-north distribution range of the marine clam Limecola balthica in NW Europe. The combined effects of elevated temperature and reduced pH on hatching success and size varied strongly between the three studied populations, with the Gulf of Finland population appearing most endangered under the conditions predicted to occur by 2100. These results demonstrate that the assessment of marine faunal population persistence to future climatic conditions needs to consider the interactive effects of co-occurring physico-chemical alterations in seawater within the local context that determines population fitness, adaptation potential and the system resilience to environmental change. PMID- 29421103 TI - Growth, condition and metal concentration in juveniles of two Diplodus species in ports. AB - High abundances of juvenile fish in certain ports suggest they might provide alternative nursery habitats for several species. To further investigate this possibility, post-settlement growth, metal uptake and body condition were estimated in 127 juveniles of two seabream species, collected in 2014-15, inside and outside the highly polluted ports of the Bay of Toulon. This showed that differences in local pollution levels (here in Hg, Cu, Pb and Zn) are not consistently mirrored within fish flesh. Muscle metal concentrations, below sanitary thresholds for both species, were higher in ports for Cu, Pb and V only. Otherwise, fish muscle composition principally differed by species or by year. Juvenile growth and condition were equivalent at all sites. Higher prey abundance in certain ports might therefore compensate the deleterious effects of pollution, resulting in similar sizes and body conditions for departing juvenile fish than in nearby natural habitats. PMID- 29421104 TI - Desorption modeling of hydrophobic organic chemicals from plastic sheets using experimentally determined diffusion coefficients in plastics. AB - To evaluate rate of migration from plastic debris, desorption of model hydrophobic organic chemicals (HOCs) from polyethylene (PE)/polypropylene (PP) films to water was measured using PE/PP films homogeneously loaded with the HOCs. The HOCs fractions remaining in the PE/PP films were compared with those predicted using a model characterized by the mass transfer Biot number. The experimental data agreed with the model simulation, indicating that HOCs desorption from plastic particles can generally be described by the model. For hexachlorocyclohexanes with lower plastic-water partition coefficients, desorption was dominated by diffusion in the plastic film, whereas desorption of chlorinated benzenes with higher partition coefficients was determined by diffusion in the aqueous boundary layer. Evaluation of the fraction of HOCs remaining in plastic films with respect to film thickness and desorption time showed that the partition coefficient between plastic and water is the most important parameter influencing the desorption half-life. PMID- 29421105 TI - Are acid volatile sulfides (AVS) important trace metals sinks in semi-arid mangroves? AB - Acid-volatile sulfides (AVS) formation and its role on trace metals bioavailability were studied in semi-arid mangroves. The semi-arid climatic conditions at the studied sites, marked by low rainfall and high evapotranspiration rates, clearly limited the AVS formation (AVS contents varied from 0.10 to 2.34MUmolg-1) by favoring oxic conditions (Eh>+350mV). The AVS contents were strongly correlated with reactive iron and organic carbon (r=0.84; r=0.83 respectively), evidencing their dominant role for AVS formation under semi arid conditions. On the other hand, the recorded SigmaSEM/AVS values remained >1 evidencing a little control of AVS over the bioavailability of trace metals and, thus, its minor role as a sink for toxic metals. PMID- 29421106 TI - Bioaccumulation of heavy metals in oyster (Saccostrea cucullata) from Chabahar bay coast in Oman Sea: Regional, seasonal and size-dependent variations. AB - The concentration of heavy metals was determined in tissues of oyster, Saccostrea cuccullata, phytoplanktons and water samples from intertidal regions of the Chabahar bay, Oman sea. Oysters were collected from 5 stations and during spring, summer and autumn seasons. The heavy metals content in oysters, planktons and water samples showed variations depending on season, sampling station and size of the oysters. The heavy metals in water, plankton and tissue of oyster were higher in summer and the lowest metal contents were observed in autumn. The oyster tissue samples of size-class had lowest concentrations of Co, Pb, Ar and Cu. The maximum tissue levels of Ar, Cu, Ni and Zn were observed in oysters of size-class II while the values of Cd, Co and Pb had maximum levels in those of size-class III. The minimum levels of Cd and also Ni and Zn were found respectively in tissue of the oysters of size-class II and size-class III. There were significant differences in heavy metal content of oyster tissue, planktons and water samples between sampling stations. In all sampling stations and during all sampling seasons, the concentrations of heavy metals (except Cu) were almost higher in soft tissues than in hard tissues of oysters especially in oysters of size-class II and III. Seasonal analysis of tissue heavy metal content of oysters showed no significant differences between sampling stations. PMID- 29421107 TI - Micro-plastic ingestion by waterbirds from contaminated wetlands in South Africa. AB - Despite a large literature on the impacts of micro-plastic pollution in marine ecosystems, very little research has focused on these pollutants in freshwater ecosystems. Recently, however, a few studies have demonstrated that micro-plastic pollutants are ingested by freshwater taxa, including birds. To explore this potential environmental threat in African freshwater systems we quantified micro plastic pollutants in the faeces and feather brushings of seven southern African duck species. We analysed 283 faecal samples and 408 feather brushings, and found that 5% of faecal samples and 10% of feather samples contained micro-plastic fibres. The presence and abundance of micro-fibres differed between sampling sites, with significantly higher amounts recorded for the site that received effluent from a sewage treatment facility. Additionally, micro-fibre presence differed across duck species, indicating that foraging behaviour affects plastic ingestion. Our study confirms that African freshwater ecosystems and the biodiversity they support are under threat from micro-plastic contamination. PMID- 29421108 TI - Identification of the earlier human-induced sedimentation change in Daya Bay, northern South China Sea using 210Pb and 137Cs. AB - Over the past 30years, the rapid development of the Chinese economy resulted in environmental problems, especially in coastal areas. To discern the effects of anthropogenic activities, 210Pb and 137Cs were examined in the sediment from Daya Bay, northern South China Sea. The specific activity of 137Cs showed a clear maximum, corresponding to 1963. 210Pb specific activity varied from 25.1 to 78.5Bq kg-1. 210Pb distribution showed a hiatus at 18-19cm with 5-6cm of older sediment (>150years), indicating direct land-originating material over a short timescale rather than natural processes. This event was attributed to the human induced redistribution of sediment during reclamation. Based on the 137Cs-labeled 1963 and 210Pb-chronologies, this event was confined to late 1977, earlier than the generally recognized significant anthropogenic activities. Thus, information archived in the sediment or in records prior to the 1970s would be better environmental background in Daya Bay. PMID- 29421109 TI - Drowning in debris: Solutions for a global pervasive marine pollution problem. PMID- 29421110 TI - Marine snow increases the adverse effects of oil on benthic invertebrates. AB - After the Deepwater Horizon oil spill, a MOSSFA (Marine Oil Snow Sedimentation and Flocculent Accumulation) event took place, transporting an estimated 14% of total released oil to the sediment, and smothering parts of the benthic ecosystem. This microcosm study describes the effects of oiled artificial marine snow on benthic macroinvertebrates. Corophium volutator survival was reduced by 80% in oil-contaminated snow. Hydrobia ulvae survival was reduced by 40% in oil contaminated snow, possibly due to consumption of oiled snow. Macoma balthica was sensitive to marine snow, addition of oil slightly decreased survival. This study reveals trait-dependent sensitivity to oil with or without marine snow. The main drivers for organismal response to marine snow and oil are motility, sensitivity to hypoxia and oil toxicity, and feeding habits. Adverse effects of MOSSFA events on benthos will have consequence for the benthic-pelagic habitat and food chain, and should receive more attention in oil spill management. PMID- 29421111 TI - Ecological risk assessment to marine organisms induced by heavy metals in China's coastal waters. AB - China's coastal environment has been heavily affected by the loading of terrestrial pollutants in recent decades, and quantitative risk assessment is urgently needed to assess the ecological risks of China's coastal environment. We assessed the ecological risks induced by five heavy metals (including Cu, Zn, Pb, Hg and As) in China's coastal waters for three groups of marine organisms (including crustacean, fish and mollusc) based on data obtained from a nationwide unified coastal environment monitoring program consisting of 301 sampling sites. The results show that higher heavy metal concentrations occurred more frequently in the Bohai Sea and in the estuaries of major sea-going rivers. The ecological risks decreased in the following order: Bohai Sea>Yellow Sea>South China Sea>East China Sea. There was generally low ecological risk, but certain hotspots existed near Tianjin and Jinzhou, which had relatively high ecological risks caused by Cu and Zn. PMID- 29421113 TI - Abnormalities in bivalve larvae from the Puck Bay (Gulf of Gdansk, southern Baltic Sea) as an indicator of environmental pollution. AB - This study described the occurrence of abnormalities in bivalve larvae from the Puck Bay. Analyses of plankton samples collected in 2012-2013 showed that larval Mytilus trossulus, Mya arenaria, and Cerastoderma glaucum exhibited abnormalities that could indicate adverse environmental impacts. The deformities were mainly in shells, but missing soft tissue fragments and protruding vela were also noted. In addition to larval studies, we analyzed benthic postlarvae of Mytilus trossulus. Interestingly, grooves and notches at different locations of the prodissoconch, dissoconch, and shell margin were observed. Some of these deformations were reminiscent of the indentations found on the shell edge of larvae. Comparing the proportion of abnormal postlarvae to larvae with shell abnormalities suggested that the survival of larvae with shell abnormalities was low. Overall, our results suggested that the ratio of abnormal bivalve larvae could be used as an indicator of the biological effects of hazardous substances in the pelagic environment. PMID- 29421112 TI - Hexabromocyclododecanes (HBCDs) in fish: Evidence of recent HBCD input into the coastal environment. AB - Hexabromocyclododecanes (HBCDs) are flame retardants and emerging persistent organic pollutants. In the present study, alpha-, beta-, and gamma-HBCDs were measured in several fish species from rivers and an electronic waste (e-waste) recycling site in Pearl River Delta, South China. The concentrations of HBCDs were 12.8 to 640, 5.90 to 115, and 34.3 to 518ng/g lipid weight (lw) in mud carp (Cirrhinus molitorella), tilapia (Tilapia nilotica), and plecostomus (Hypostomus plecostomus), respectively. Plecostomus showed the highest HBCD concentrations among three fish species. The contributions of alpha-HBCD to total HBCDs were 78% to 97%, 93% to 99%, and 87% to 98% in carp, tilapia, and plecostomus, respectively. Fish samples from a harbor and the e-waste site exhibited the highest HBCD concentrations among all samples. The HBCD concentrations were not significantly correlated with the gross domestic product or population data. e Waste recycling activities, harbor construction, and shipment might be recent HBCD sources. PMID- 29421114 TI - Long-term evaluation of water quality parameters of the Karoun River using a regression approach and the adaptive neuro-fuzzy inference system. AB - This paper investigates chemical water quality parameters of the Karoun, the greatest and the most important river of Iran, during a 48-year period, from 1968 to 2015. Water discharge (Q) fluctuates between 191.1m3s-1 and 1758.7m3s-1, with a decreasing trend over the 48-year period. Except pH, other water quality parameters increased, significantly, so that the rate of increase for EC and TDS was 25.71MUScm-1y-1 and 16.66mgl-1y-1, respectively. Moreover, SO4-2, HCO3-, Cl-, Ca+2, Mg+2 and Na+ have increased by 0.116, 0.012, 0.151, 0.066, 0.052 and 0.168meql-1y-1, respectively. Result indicated that water discharge can be a satisfactory predictor of chemical water quality parameters in this river. It was finally concluded when water discharge of the river decreases to less than ~500m3s-1, the vales of water salinity (EC and TDS) and soluble salts will increase, severely. PMID- 29421115 TI - A baseline study on the concentration of trace elements in the surface sediments off Southwest coast of Tamil Nadu, India. AB - Forty two surface sediment samples were collected in order to document baseline elemental concentration along the Southwest coast of Tamil Nadu, India. The elements detected were Manganese (Mn), Zinc (Zn), Iron (Fe), Copper (Cu), Nickel (Ni) and Lead (Pb). The concentration of Fe and Mn was primarily controlled by the riverine input. The source of Pb and Zn is attributed to leaded petrol and anti-biofouling paints. The calculated index (EF, Igeo and CF) suggests that the sediments of the study area are significantly enriched with all elements except Pb. The contamination factor showed the order of Mn>Zn>Fe>Cu>Ni>Pb. The sediment pollution index (SPI) revealed that the sediments belonged to low polluted to dangerous category. The correlation matrix and dendrogram showed that the elemental distribution was chiefly controlled by riverine input as well as anthropogenic activity in the coast. PMID- 29421116 TI - Organochlorine pesticides in surface waters from Reloncavi Fjord and the inner sea of Chiloe (~39.5 degrees S - 43 degrees S), Chilean Patagonia. AB - Surface water samples from the environmental continuum spanning rivers (Petrohue, Cochamo, Puelo), fjord (Reloncavi), and the inner sea of Chiloe in Chilean Patagonia were analyzed to estimate concentration and distribution of dissolved Organochlorine pesticides (OCPs). High concentrations of HCHs, DDTs and endosulfan found in surface waters from rivers suggest that rivers are the major source of dissolved OCPs to coastal marine ecosystems. We interpret variations in the distribution and concentration as an apparent oscillation between rain and snow-scavenging processes that might determine the type of OCPs that can be preferentially deposited on mountains, glaciers, rivers, estuaries, and finally transferred to the marine realm. Predominance of alpha-HCH, gamma-HCH, p,p'-DDE and alpha-endosulfan compounds suggest that the main deposition mechanism of OCPs to the Chilean Patagonia is rain scavenging. Snow and rain can be additional sources of OCPs that must be considered for future studies in fjord systems in Chilean Patagonia. PMID- 29421117 TI - Recovery of the New Zealand muricid dogwhelk Haustrum scobina from TBT-induced imposex. AB - Levels of imposex in the muricid dogwhelk Haustrum scobina (Quoy & Gaimard, 1833) were assessed in two major New Zealand ports between 2015 and 2017, 12+years after the banning of TBT-based antifouling paints. In the 1990s imposex was common adjacent to port facilities and marinas in Waitemata and Tauranga Harbours, and several populations were found to be largely sterile and in decline. By 2015-17 imposex was largely absent from Tauranga Harbour and considerably reduced in Waitemata Harbour. In Waitemata Harbour imposex remained in areas adjacent to hull cleaning facilities and marinas, but at low levels and frequencies. These data highlight the success of the 2003 banning of TBT-based antifouling paints in reducing levels of imposex in New Zealand ports. However, these reductions in antifouling chemicals and subsequent population recoveries may have had unforseen effects within these harbours including changes in community structure and the arrival of non-indigenous species. PMID- 29421118 TI - Optimization of disinfection by-product analysis methods for IMO G9 approval. AB - This study assessed the methods for analyzing disinfection by-products (DBPs) to determine which were most suitable for ballast water in an approval test according to the Procedure for Approval of Ballast Water Management Systems that make use of Active Substances (G9). The existing analysis methods are optimized for drinking water. Therefore, it is necessary to assess the characteristics of ballast water, which has high levels of total residual oxidants (TROs) and salinity, prior to applying the existing methods. Sample preservation, pre treatment and instrumental analysis methods were summarized based on certified test methods and the G9 final approval reports. Following the assessment, applicable methods were selected in consideration of the matrix effect arising from the high levels of TROs and salinity. The applicability was assessed using seawater and brackish water. The results are expected to be applied to the G9 test as well as in investigations of DBPs in ballast water. PMID- 29421119 TI - Plastic ingestion in aquatic-associated bird species in southern Portugal. AB - Excessive use of plastics in daily life and the inappropriate disposal of plastic products are severely affecting wildlife species in both coastal and aquatic environments. Birds are top-predators, exposed to all threats affecting their environments, making them ideal sentinel organisms for monitoring ecosystems change. We set a baseline assessment of the prevalence of marine plastic litter affecting multi-species populations of aquatic birds in southern Portugal. By examining 160 stomach contents from 8 species of aquatic birds, we show that 22.5% were affected by plastic debris. Plastic was found in Ciconia ciconia, Larus fuscus and L. michahellis. Ciconia ciconia ingested the highest amount (number of items and total mass) of plastic debris. Polydimethylsiloxane (PDMS, silicones) was the most abundant polymer and was recorded only in C. ciconia. Plastic ingestion baseline data are of crucial importance to evaluate changes through time and among regions and to define management and conservation strategies. PMID- 29421120 TI - Effects of meteorological factors on the temporal distribution of red tides in Tolo Harbour, Hong Kong. AB - Red tides represent a major environmental issue in coastal waters globally. However, few studies have examined the relationship between red tides and meteorological factors. Thus, we used a 32-year time-series of frequent red tide events in Tolo Harbour and Channel, to study their relationship with meteorological factors. Most red tides are dominated by dinoflagellates in March, while most diatom red tides in May. Dinoflagellate and diatom red tides respond differently to different meteorological factors. Warming air temperatures in spring favor the generation of dinoflagellate red tides, while precipitation hinders them. The optimum temperature range is approximately 17-23 degrees C and 26-29 degrees C for dinoflagellate and diatom red tides, respectively. Moderate northeasterly winds promote the formation of dinoflagellate red tides. Dinoflagellate red tides are not hindered by cloudy weather and occur in sunlight of varying brightness, whereas diatoms red tides require a certain amount of bright sunlight. PMID- 29421121 TI - Decarbonizing the international shipping industry: Solutions and policy recommendations. AB - Ship-source greenhouse gas (GHG) emissions could increase by up to 250% by 2050 from their 2012 levels, owing to increasing global freight volumes. Binding international legal agreements to regulate GHGs, however, are lacking as technical solutions remain expensive, and crucial industrial support is absent. In 2003, the International Maritime Organization adopted Resolution A.963 (23) to regulate shipping CO2 emissions via technical, operational, and market-based routes. However, progress has been slow and uncertain; there is no concrete emission reduction target or definitive action plan. Yet, a full-fledged roadmap may not even emerge until 2023. In this policy analysis, we revisit the progress of technical, operational, and market-based routes and the associated controversies. We argue that 1) a performance-based index, though good intentioned, has loopholes affecting meaningful CO2 emission reductions driven by technical advancements; 2) using slow steaming to cut energy consumption stands out among all operational solutions thanks to its immediate and obvious results, but with the already slow speed in practice, this single source has limited emission reduction potential; 3) without a technology-savvy shipping industry, a market-based approach is essentially needed to address the environmental impact. To give shipping a 50:50 chance for contributing fairly and proportionately to keep global warming below 2 degrees C, deep emission reductions should occur soon. PMID- 29421123 TI - Life on Earth is better than ever! PMID- 29421122 TI - A relative contribution of carbon from green tide algae Cladophora glomerata and Ulva intestinalis in the coastal food webs in the Neva Estuary (Baltic Sea). AB - We analyzed stable isotope composition of carbon and nitrogen of suspended organic matter (seston) and tissues of macroalgae, macroinvertebrates and fish from the coastal area of the highly eutrophic Neva Estuary to test a hypothesis that organic carbon of macroalgae Cladophora glomerata and Ulva intestinalis produced during green tides may be among primary sources supporting coastal food webs. The Stable Isotope Bayesian mixing model (SIAR) showed that consumers poorly use organic carbon produced by macroalgae. According to the results of SIAR modeling, benthic macroinvertebrates and fish mostly rely on pelagic derived carbon as a basal resource for their production. Only some species of macroinvertebrates consumed macroalgae. Fish used this resource directly consuming zooplankton or indirectly via benthic macroinvertebrates. This was consistent with the results of the gut content analysis, which revealed a high proportion of zooplankton in the guts of non-predatory fish. PMID- 29421124 TI - Unraveling the performance of the benthic index AMBI in a subtropical bay: The effects of data transformations and exclusion of low-reliability sites. AB - We investigated the relationship between the AMBI index and different contamination proxies in an urbanized bay in South America (SE Brazil), and the effect of (a) abundance data transformation and (b) exclusion of low-reliability sites (high SD; low N) on the index' performance. Poor ecological quality and opportunistic species were related to an increase in contaminants concentrations and mud content. Good ecological status and sensitive species (EG I) were mainly related to increased hydrodynamics. Data transformation caused minimal changes to the overall relationships, but exclusion of low-reliability sites improved the relationship between ecological groups and contamination proxies. Our results show that AMBI is robust in detecting effects of different contaminants in the area and reinforce the importance of the index as a tool for coastal management, but local joint efforts are needed to improve and adjust local species classification in ecological groups to improve the index' performance. PMID- 29421125 TI - The need for a formalised system of Quality Control for environmental policy science. AB - Research science used to inform public policy decisions, herein defined as "Policy-Science", is rarely subjected to rigorous checking, testing and replication. Studies of biomedical and other sciences indicate that a considerable fraction of published peer-reviewed scientific literature, perhaps half, has significant flaws. To demonstrate the potential failings of the present approaches to scientific Quality Control (QC), we describe examples of science associated with perceived threats to the Great Barrier Reef (GBR), Australia. There appears a serious risk of efforts to improve the health of the GBR being directed inefficiently and/or away from the more serious threats. We suggest the need for a new organisation to undertake quality reviews and audits of important scientific results that underpin government spending decisions on the environment. Logically, such a body could also examine policy science in other key areas where governments rely heavily upon scientific results, such as education, health and criminology. PMID- 29421126 TI - Extended imposex monitoring in N Atlantic Spain confirms punctual attainment of European environmental objectives for TBT. AB - Legislation in the European Union (EU) aimed at reaching by 2015 a Good Ecological Status in regard to tributyltin (TBT, the biocide used in traditional antifouling paints). With a view to check such an achievement in N Atlantic Spain, baseline monitoring of gastropod imposex (the recommended assessment tool) was extended up to that date. In Galicia (the Western part of the study area) the use of the rock snail Nucella lapillus since 1996 had shown this environmental objective to be met as soon as 2009, but new surveys reveal no further improvement thereafter. As for the Eastern Cantabrian coast, imposex levels in the mud snail Nassarius reticulatus progressively declined from 2006 to 2015, when records finally complied with expectations. Both data sets are confronted and discussed in relation to the diverse environmental factors that may be determining the distribution of gastropods in these regions. PMID- 29421127 TI - Dioxin-like compounds bioavailability and genotoxicity assessment in the Gulf of Follonica, Tuscany (Northern Tyrrhenian Sea). AB - The Gulf of Follonica (Italy) is impacted by the chemical pollution from ancient mining activity and present industrial processes. This study was aimed to determine the bioavailability of dioxin-like compounds (DLCs) in coastal marine environment and to assess the genotoxic potential of waste waters entering the sea from an industrial canal. Moderately high levels of DCLs compounds (? PCDDs + PCDFs 2.18-29.00 pg/g dry wt) were detected in Mytilus galloprovincialis transplanted near the waste waters canal and their corresponding Toxic Equivalents (TEQs) calculated. In situ exposed mussels did not show any genotoxic effect (by Comet and Micronucleus assay). Otherwise, laboratory exposure to canal waters exhibited a reduced genomic template stability (by RAPD-PCR assay) but not DNA or chromosomal damage. Our data reveal the need to focus on the levels and distribution of DLCs in edible species from the study area considering their potential transfer to humans through the consumption of sea food. PMID- 29421128 TI - Assessment of organotins and imposex in two estuaries of the northeastern Brazilian coast. AB - Butyltin compounds (BTs) were used worldwide, especially because of their properties as biocides. Due to its high toxicity, the use of tributyltin (TBT) in antifouling paints has been prohibited in most countries. The occurrence and impact of BTs were assessed in surface sediments and in Stramonita rustica populations of two tropical estuaries that host major ports in northeastern Brazil. SigmaBT concentrations ranged from Authigenic P>Organic P>Fe-P>Loosely P. Bioavailable phosphorus concentration was between 153ppm and 240ppm and consisted 37.21+/-3% of total phosphorus. Based on molar ratio of TOC/OP, organic matter obtained from the studied stations suggested a terrestrial origin. PMID- 29421133 TI - Spatio-temporal variation of anthropogenic marine debris on Chilean beaches. AB - We examined the hypothesis that in an emerging economy such as Chile the abundances of Anthropogenic Marine Debris (AMD) on beaches are increasing over time. The citizen science program Cientificos de la Basura ("Litter Scientists") conducted three national surveys (2008, 2012 and 2016) to determine AMD composition, abundance, spatial patterns and temporal trends. AMD was found on all beaches along the entire Chilean coast. Highest percentages of AMD in all surveys were plastics and cigarette butts, which can be attributed to local sources (i.e. beach users). The Antofagasta region in northern Chile had the highest abundance of AMD compared with all other zones. Higher abundances of AMD were found at the upper stations from almost all zones. No significant tendency of increasing or decreasing AMD densities was observed during the 8years covered by our study, which suggests that economic development alone cannot explain temporal trends in AMD densities. PMID- 29421134 TI - Baseline concentrations and distributions of Polycyclic Aromatic Hydrocarbons in surface sediments from the Qatar marine environment. AB - Coastal sediments in marine waters of Qatar have the potential of being contaminated by Polycyclic Aromatic Hydrocarbons (PAHs) due to extensive petroleum exploration and transportation activities within Qatar's Marine Exclusive Economic Zone. In this study, the concentration and distribution of sixteen PAHs classed as USEPA priority pollutants were measured in sediments from the eastern Qatari coast. PAHs were recovered from sediments via accelerated solvent extraction and then analyzed using Gas Chromatography-Mass Spectrometry. Total concentrations of the PAHs were in the range of 3.15-14.35MUg/kg, and the spatial distribution of PAHs is evaluated in the context of sediment total organic content, depth and the grain size together with and the proximity of petroleum exploration and transportation activities. The data show that the concentrations of PAHs within the study area were in the low-range, suggesting a low risk to marine organisms and limited transfer of PAHs into the food web. PMID- 29421135 TI - Assessing impacts of simulated oil spills on the Northeast Arctic cod fishery. AB - We simulate oil spills of 1500 and 4500m3/day lasting 14, 45, and 90days in the spawning grounds of the commercial fish species, Northeast Arctic cod. Modeling the life history of individual fish eggs and larvae, we predict deviations from the historical pattern of recruitment to the adult population due to toxic oil exposures. Reductions in survival for pelagic stages of cod were 0-10%, up to a maximum of 43%. These reductions resulted in a decrease in adult cod biomass of <3% for most scenarios, up to a maximum of 12%. In all simulations, the adult population remained at full reproductive potential with a sufficient number of juveniles surviving to replenish the population. The diverse age distribution helps protect the adult cod population from reductions in a single year's recruitment after a major oil spill. These results provide insights to assist in managing oil spill impacts on fisheries. PMID- 29421136 TI - Heavy metal levels of ballast waters in commercial ships entering Bushehr port along the Persian Gulf. AB - In this study we report the concentration levels of heavy metals (including Pb, Cd, Hg, Cr, Ni, Fe, Mn, Cu) in ballast water of commercial ships, entering Bushehr port for the first time in the region of the Persian Gulf. The concentration levels of Cu and Fe in all samples of the ballast water were higher compared with the coastal waters of Bushehr port. In the case of Cd, 76.47% of samples had higher concentration level compared with the coastal waters of Bushehr port. Results showed that in a long term the ballast water has the potential to change the chemical quality in marine environments and also may affect the human health and marine ecosystem where ships discharge their ballast water. Therefore, permanent monitoring as well as treatment of ballast water before discharging is crucial to keep the marine environment health. PMID- 29421137 TI - Mercury concentrations in three ray species from the Pacific coast of Baja California Sur, Mexico: Variations by tissue type, sex and length. AB - Total mercury concentrations ([THg]) were determined in muscle and liver of the bat ray (Myliobatis californica), shovelnose guitarfish (Pseudobatos productus) and banded guitarfish (Zapteryx exasperata). Generalized linear models (GLM) were used to determine the effects of size and sex in [THg] and showed that both are determinants of [THg] in these species. The [THg] in both tissues significantly increased with length especially in sexually mature organisms with a steeper slope for mature male than mature female. This may relate to elasmobranchs sexual dimorphism driven variation in growth rates. Median muscle [THg] was significantly greater than liver in each ray species but there were some individuals with higher liver [THg] than muscle. There were individuals with muscle [THg] higher than the advisory thresholds of 0.2 and 0.5mgkg-1ww (2.4 and 11% of the bat ray; 2.1 and 10% of the shovelnose guitarfish; 12.6 and 45% of the banded guitarfish, respectively). PMID- 29421138 TI - Exogenous phosphorus enhances cadmium tolerance by affecting cell wall polysaccharides in two mangrove seedlings Avicennia marina (Forsk.) Vierh and Kandelia obovata (S., L.) Yong differing in cadmium accumulation. AB - Phosphorous (P) is an essential element that mediates various stresses in plants. In this study, the effects of P on polysaccharides in the root cell walls of two hydroponically cultivated mangrove seedlings (A. marina and K. obovata) that differ in Cd accumulation ability were examined in the context of Cd stress. The results showed that A. marina exhibited a higher degree of tolerance to Cd than K. obovata. In both mangrove seedlings, pectin and hemicellulose 1 increased significantly with increasing P levels, the effects of which were greater in A. marina under Cd stress. In addition, cell wall pectin methylesterase (PME) activity was markedly increased in the presence of Cd and P compared with Cd alone. These effects were more pronounced in A. marina than in K. obovata. Taken together, the results of this study provide further insight into the mechanisms of P-mediated alleviation of Cd stress in mangrove seedlings. PMID- 29421139 TI - High zinc exposure leads to reduced dimethylsulfoniopropionate (DMSP) levels in both the host and endosymbionts of the reef-building coral Acropora aspera. AB - Dimethylsulfoniopropionate (DMSP) is a biogenic compound that could be involved in metal detoxification in both the host and endosymbionts of symbiotic corals. Acropora aspera, a common reef-building coral of the Great Barrier Reef, was exposed to zinc doses from 10 to 1000MUg/L over 96h, with zinc being a low-toxic trace metal commonly used in the shipping industry. Over time, significantly lower DMSP concentrations relative to the control were found in both the host and symbionts in the highest zinc treatment where zinc uptake by both partners of the symbiosis was the highest. This clearly indicates that DMSP was consumed or stopped being produced under high and extended zinc exposure. This drop in DMSP was first observed in the host tissue, suggesting that the coral host was the first to respond to metal contamination. Such decrease in DMSP concentrations could influence the long-term health of corals under zinc exposure. PMID- 29421140 TI - [Quality care indicators in primary health care from the perspective of respiratory health: current and future changes]. PMID- 29421141 TI - [Vitamin D deficiency in childhood: an opportunity for prevention]. AB - The prevalence of vitamin D deficiency in the pediatric population has increased in recent years and continues to be underdiagnosed and undertreated. According to data from the "ENSANUT 2006" (National Health and Nutrition Survey), the prevalence of vitamin D deficiency in Mexico was 16% in children aged 2-12 years. Vitamin D plays a critical role in the formation and bone homeostasis and consequently on growth. Its deficiency is clearly associated with diseases such as rickets and osteomalacia, and it has been linked to other diseases such as obesity, metabolic syndrome, diabetes, cancer, respiratory infections and immune system disease. Specific risk groups have been described in the medical literature for vitamin D deficiency in which supplementation may offer a benefit. Currently, there is still controversy in defining the serum levels of proficiency and dose supplementation. In Mexico, the daily suggested intake of vitamin D is 5.6MUg (224 IU), which is significantly lower than the recommendations in the U.S. and Europe (i.e., between 400 and 1000 IU/day). An increase in vitamin D deficiency has been reported in recent years. There is no consensus regarding the sufficiency levels of vitamin D. Cut-off values vary from 20 to 30ng/ml. Therefore, the objective of this review was to provide an overview of the problem in the pediatric population and to describe the groups at risk, as well as to analyze the current recommendations for vitamin D supplementation. Vitamin D deficiency was considered rare in Mexico according to the National Institute of Medical Science and Nutrition Salvador Zubiran. Lack of evidence did not help to establish the international recommended daily intake. Currently, vitamin D deficiency must be recognized as a health problem, worthy of attention and action. We suggest that prospective studies are carried out in our country where the relationship between serum vitamin D deficiency and poor bone mineralization will be established. PMID- 29421143 TI - [Adiponectin levels in breast milk of overweight/obese and normal weight mothers in the metropolitan area of Monterrey, Mexico]. AB - BACKGROUND: Given the current epidemic of childhood obesity, it has become increasingly important to understand the risks and protective factors associated with this disease. Breastfeeding has been identified as a protective factor; however, the mechanism responsible has not been elucidated. One of the current theories analyzes the role of hormones in breast milk, with special emphasis on adiponectin. This study aims to compare adiponectin levels in breast milk of mothers with normal weight with those in breast milk of overweight/obese mothers as well as to correlate these levels with the infant's weight gain. METHODS: Forty samples of breast milk were analyzed for adiponectin levels using ELISA, 20 from mothers with normal weight and 20 from overweight/obese mothers. RESULTS: Adiponectin levels were lower in breast milk obtained from overweight/obese mothers than in breast milk from mothers with normal weight (p <0.05). When comparing infant weight gain, those fed with breast milk containing higher concentrations of adiponectin had a lower weight gain than those fed with breast milk containing low levels of the hormone (p <0.05). CONCLUSIONS: There is a strong negative correlation between mothers' BMI and adiponectin levels in breast milk. Mothers with a higher BMI had lower adiponectin levels in their breast milk. There is also a negative relationship between adiponectin levels in breast milk and weight gain of breastfed infants. Infants breast fed with adiponectin rich breast milk had a lower weight gain. PMID- 29421142 TI - Quality of care for children with upper respiratory infections at Mexican family medicine clinics. AB - BACKGROUND: Upper respiratory infections are the principal cause of morbidity in children <5 years of age. The objectives of this study were (i) to develop quality-of-care indicators for evaluation of care for children with upper respiratory infections (URI) at the primary care level using data from the electronic health records and (ii) to evaluate the quality of URI care offered to children <5 years of age at family medicine clinics (FMCs). METHODS: Development of indicators following the RAND-UCLA method was used. A cross-sectional analysis of quality of care provided for children with URI in four FMCs in Mexico City where 10,677 children <5 years of age with URI participated. The source of information was data from 2009 electronic health records. Quality of care was evaluated using six indicators developed in the first stage of this study. RESULTS: The quality of care evaluation identified that only 15% of children had registries of intentional search of respiratory distress signs and 27% received information on warning signs. More than 61% of children diagnosed with uncomplicated and nonstreptococcal URI received antibiotic prescription during the first visit. In the case of children diagnosed with streptococcal pharyngitis or tonsillitis, 57.5% received the appropriate antibiotic. On average, the percentage of recommended care received was 47.2%. CONCLUSIONS: It is reasonable to promote the use of electronic health records to routinely evaluate the quality of URI care. It is necessary to consider quality flaws that were found in order to endorse strategies aimed at strengthening the technical capacity of health personnel to exercise evidence-based clinical practice. PMID- 29421144 TI - [Epidemiologic profile of children with burns from the Civil Hospital of Guadalajara "Dr. Juan I. Menchaca", 2009-2011]. AB - BACKGROUND: Burns are a public health problem, ranking among the 20 principal causes of morbidity in Mexico. Children are a more vulnerable group to suffer from these injuries. For that reason, we analyzed cases in order to gain a better comprehension and to propose preventive measures for this problem. The aim of the study was to determine the epidemiological profile of those injuries to allow us to plan and implement actions for burn prevention. METHODS: We conducted a cross sectional study that included demographic characteristics of the child, the parents and the burn injuries from children treated at this Burn Unit. Statistical analysis was done to calculate amounts, proportions and 95% confidence intervals. RESULTS: The epidemiological profile of the injuries included males (63.4%) <5 years of age (65.2%) with educational level according to their age (56.2%). Parents of the included children were <35 years old with basic educational level. Burns were caused by hot water (56.2%) and occurred between noon and midnight (73.0%). The majority of the burns were shallow and deep second-degree or minor (69.2%) and affected <20% of body surface area (74.5%). CONCLUSIONS: This epidemiological profile paved the way for preventive actions beginning with scientific research to guide the actions in a progressive direction along with the cooperative actions of public and private institutions in the development of programs and strategies. The end result would be the establishment of a public policy for accidental injuries. PMID- 29421145 TI - [Prevalence of kidney disease in asymptomatic children with family history of renal replacement therapy]. AB - BACKGROUND: Having a first- or second-degree relative with chronic kidney disease (CKD) has been reported as a risk factor for CKD development. The aim of the study was to determine the prevalence of CKD in children with a first- or second degree relative undergoing renal replacement therapy (hemodialysis or renal transplant). METHODS: A screening study was performed in asymptomatic children with a family history of CKD in a first- or second-degree relative undergoing renal replacement therapy. Informed consent was obtained in all cases. A clinical examination was performed. Blood and urine samples were obtained for serum creatinine, serum electrolytes, urinalysis, and microalbumin/creatinine ratio. RESULTS: There were 45 subjects included with a median age of 9.6 years; 24 (53%) were male. Urinary abnormality/CKD was observed in 11 subjects (24.4%). The most common urinary abnormalities were hematuria (6/11) and microalbuminuria (4/11). Stage 2 CKD was found in seven subjects and four subjects with stage 1 CKD. CONCLUSIONS: The study of families of patients undergoing renal replacement therapy is useful to identify children in early stages of kidney disease. PMID- 29421146 TI - [Congenital central alveolar hypoventilation syndrome]. AB - BACKGROUND: Congenital central alveolar hypoventilation syndrome (CCAHS) is a rare sleep-related breathing disorder. Although increasingly frequently diagnosed in sleep clinics and pediatric pulmonology services, its epidemiology is not known. There are about 300 reported cases reported in the literature with an incidence of 1 case per 200,000 live births. CCAHS is characterized by alveolar hypoventilation that occurs or worsens during sleep and is secondary to a reduction/absence of the ventilatory response to hypercapnia and/or hypoxemia. In 90% of the cases it is due to a PARM-type mutation of the PHOX2B gene. Treatment includes mechanical ventilation and diaphragmatic pacemaker. If therapy is not initiated promptly the patient can evolve to chronic respiratory failure, pulmonary hypertension, cor pulmonale and death. CASE REPORTS: In this paper we present three cases of CCAHS diagnosed, treated and followed up at the Sleep Disorders Clinic of the National Institute of Respiratory Diseases in Mexico. CONCLUSIONS: Early diagnosis is important to initiate ventilatory support so as to prevent any complications and to reduce mortality. PMID- 29421147 TI - [Association of benzocaine and paracetamol with neonatal-acquired methemoglobinemia]. AB - BACKGROUND: Drug-induced acquired methemoglobinemia in the newborn is a rare event; however, when it develops, early diagnosis and proper treatment become paramount because it can evolve rapidly into a particularly serious disease causing permanent brain damage or death. CASE REPORT: We report a unique case of severe methemoglobinemia that developed in a newborn associated with a minimal application of a benzocaine healing cream to an anal surgical wound while on acetaminophen. In addition to benzocaine as the primary cause in this case, we raise the possibility that acetaminophen-a mild oxidant-increased the susceptibility of the patient to benzocaine, leading to severe clinical methemoglobinemia based on the known immaturity of the enzymatic systems involved in caines and acetaminophen clearance in the newborn. Treatment of methemoglobinemia is reviewed. CONCLUSIONS: Methemoglobinemia is a serious condition that can be easily induced by the use of oxidant medications in the newborn like local anesthetics. The possibility of unexpected drug to drug interactions, particularly between commonly used medications such as acetaminophen with other methemoglobin-causing agents, must always be kept in mind. Because of the possible deleterious consequences, mandatory labelling of caine-containing local anesthetic creams, gels and sprays with a warning for the likelihood of causing severe methemoglobinemia in children is recommended. Also, prohibiting their use in the newborn becomes mandatory. PMID- 29421148 TI - [Cockayne syndrome]. PMID- 29421149 TI - [Informed consent and parental refusal for medical treatment in childhood. The threshold of medical and social tolerance. Part II]. AB - Medical care in pediatric patients is conditional to parental consent. Parents decide the time and type of treatment they want their children to receive when they are ill. The physician should request parental consent before carrying out the most appropriate therapy. When parents refuse the treatment offered, the physician should seek alternative therapies that may be better accepted by parents and find the most beneficial treatment for children and their families. If physicians and parents are unable to agree on the best therapeutic methods, then the physician becomes involved in an ethical conflict related to the best interests of the child and parental choices. From the above posture, the following questions arise: What should the physician do when faced with this situation? Should the physician use legal measures to force parents to accept treatment? Under what conditions is it justified to force parents and when should the decision be tolerated? What is the role of the Hospital Bioethics Committee concerning this issue? This second part focuses on proposing four practical criteria to be used by the physician and Hospital Bioethics Committee when all alternative therapies and conciliatory options have been exhausted with parents and they continue to refuse treatment. The physician then has to make a decision because the child is placed at risk of harm. This decision focuses on whether there is danger to the minor arising from the decisions of parents and if such harm is avoidable. PMID- 29421150 TI - [Prevalence of congenital inherited multifactorial malformations according to birth and fetal death certificates. Mexico, 2008-2012]. PMID- 29421151 TI - Fractional excretion as a new marker of tubular damage in children with chronic kidney disease. AB - OBJECTIVES: Vitamin D-binding protein (VDBP), retinol-binding protein (RBP)4, and heat shock proteins (hsp) are markers of tubular function and apoptosis, accompanying chronic kidney disease (CKD) from its earliest stages. Fractional excretion of proteins with urine is a marker of tubular damage. The aim of study was to assess the usefulness of fractional excretion (FE) of VDBP, RBP4, HSF1 and Hsp27 as markers of tubular damage in the course of CKD. METHODS: The study group consisted of 70 children with CKD stages 1-5, treated conservatively, and 12 age matched controls with normal kidney function. The serum and urine concentrations of VDBP, RBP4, HSF1 and Hsp27 were assessed by ELISA. The fractional excretion of analyzed parameters was calculated according to the formula: ([parameter urine concentration] * [creatinine serum concentration]) / ([parameter serum concentration] * [creatinine urine concentration])*100%. RESULTS: The FE values of all parameters exceeded 1% in CKD stage 2. However, the values of FE have raised significantly versus control group no sooner than CKD stage 2 (RBP4 and HSF1), stage 3 (VDBP) or stage 4 (Hsp27). CONCLUSION: Fractional excretion of RBP4 and HSF1 with urine may become a valuable marker, assessing the damage of tubular cells in children with CKD. PMID- 29421152 TI - Smac mimetic induces an early wave of gene expression via NF-kappaB and AP-1 and a second wave via TNFR1 signaling. AB - Smac (second mitochondria-derived activator of caspases) mimetics are considered as promising cancer therapeutics, but little is yet known about how they alter gene expression. In this study, we used an unbiased genome-wide expression array to investigate gene regulation induced by the Smac mimetic BV6 in breast cancer cell lines. Here, we discover that tumor necrosis factor (TNF)alpha/TNF receptor 1 (TNFR1) auto-/paracrine signaling regulates Smac mimetic-stimulated changes in gene expression in a time-dependent manner. TNFR1-independent and -dependent genes account for two subsequent waves of BV6-induced gene expression. While the first wave mostly comprises TNFR1-independent genes and involves nuclear factor kappa B (NF-kappaB) and activator protein (AP)-1 transcription factors, the second wave largely depends on TNFR1 signaling. Interestingly, disrupting auto /paracrine TNFalpha/TNFR1 signaling by knockdown of TNFR1 strongly attenuates the BV6-induced second wave of gene expression and upregulation of many pathways, including NF-kappaB, apoptosis and immune signaling, while activation of mitogen activated protein kinase (MAPK) signaling occurs also in TNFR1 knockdown cells. Thus, BV6 alters gene expression in a time- as well as TNFR1-dependent manner. PMID- 29421153 TI - Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI. AB - Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xenografts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin beta1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer. PMID- 29421154 TI - Development of calcium bodies in Hylonsicus riparius (Crustacea: Isopoda). AB - Calcium bodies are internal epithelial sacs found in terrestrial isopods of the family Trichoniscidae that contain a mineralized extracellular matrix that is deposited and resorbed in relation to the molt cycle. Calcium bodies in several trichoniscids are filled with bacteria, the function of which is currently unknown. The woodlouse Hyloniscus riparius differs from other trichoniscids in that it possesses two different pairs of calcium bodies, the posterior pair being filled with bacteria and the anterior pair being devoid of bacteria. We explored the development of these organs and bacterial colonization of their lumen during the postmarsupial development with the use of optical clearing and whole-body confocal imaging of larval and juvenile stages. Our results show that calcium bodies are formed as invaginations of the epidermis in the region of intersegmental membranes during the postmarsupial development. The anterior pair of calcium bodies is generated during the first postmarsupial manca stage, whereas the posterior calcium bodies first appear in juveniles and are immediately colonized by bacteria, likely through a connection between the calcium body lumen and the body surface. Mineral is deposited in calcium bodies as soon as they are present. PMID- 29421155 TI - Constant morphological patterns in the hemolymph vascular system of crayfish (Crustacea, Decapoda). AB - We present a study of the hemolymph vascular system of the marbled crayfish, Procambarus fallax f. virginalis, the only crayfish species known to be parthenogenetic. To identify potential evolutionary patterns, we compared data from a total of 48 specimens of P. fallax with 22 specimens of Orconectes limosus. Visualizations (2D and 3D) were carried out using a combination of classical and modern morphological techniques. Our data were compared to the existing literature. Like all Decapoda, both P. fallax and O. limosus have a hemolymph vascular system, consisting of a globular heart with seven off branching arteries. We were able to visualize in detail the heart of crayfish for the first time, i.e., the myocard with its clusters of muscles running through the lumen of the heart, the valves and flaps of ostia and arteries. Furthermore, the branching patterns of the seven artery systems were analyzed. Anatomical structures identified to be consistent in all specimens of both species were combined as ground pattern of hemolymph vascular system features for Astacida. PMID- 29421157 TI - Double Major Duodenal Papillae: A Rare Congenital Anomaly of Hepatic and Pancreatic Drainage System. PMID- 29421159 TI - The effects of chronic stress on the human brain: From neurotoxicity, to vulnerability, to opportunity. AB - For the last five decades, science has managed to delineate the mechanisms by which stress hormones can impact on the human brain. Receptors for glucocorticoids are found in the hippocampus, amygdala and frontal cortex, three brain regions involved in memory processing and emotional regulation. Studies have shown that chronic exposure to stress is associated with reduced volume of the hippocampus and that chronic stress can modulate volumes of both the amygdala and frontal cortex, suggesting neurotoxic effects of stress hormones on the brain. Yet, other studies report that exposure to early adversity and/or familial/social stressors can increase vulnerability to stress in adulthood. Models have been recently developed to describe the roles that neurotoxic and vulnerability effects can have on the developing brain. These models suggest that developing early stress interventions could potentially counteract the effects of chronic stress on the brain and results going along with this hypothesis are summarized. PMID- 29421160 TI - Functional elucidation of LvToll 3 receptor from P. vannamei through RNA interference and its potential role in the shrimp antiviral response. AB - There is a continuing debate on whether an antiviral immunity similar to vertebrate interferon response exists in invertebrates. Recent advances in penaeid immunology identified several new members of the Toll receptor family and one of these is LvToll3 (Litopenaeus vannamei Toll3). It is hypothesized in this study that LvToll3 responds to pathogen associated molecular patterns (PAMPs) such as dsRNA, which then activates certain antiviral pathways in penaeids. RNA interference (RNAi) was used to determine differences in the expression levels of specific genes putatively involved in the antiviral response through qPCR. Results showed that LvToll3 upregulation could be elicited through the introduction of double stranded RNA (dsRNA) regardless of sequence relative to initial levels in the 3rd hour. Furthermore, statistically intriguing trend in the overall expression of Vago 4/5 and Interferon regulatory factor (IRF) suggests that both these genes are affected by the expression of LvToll3. Dicer showed no statistical difference between the experimentally treated (LvToll3 dsRNA), positive control (GFP-dsRNA), and control (PBS) samples corroborating the assertion that dicer is part of another antiviral mechanism that acts in concert with Toll system. These findings suggests that LvToll3 plays a critical role in penaeid antiviral immunity when molecular patterns associated with viruses are detected. PMID- 29421158 TI - Behavioral and structural adaptations to stress. AB - Unpredictable aversive experiences, or stressors, lead to changes in depression- and anxiety-related behavior and to changes in hippocampal structure including decreases in adult neurogenesis, granule cell and pyramidal cell dendritic morphology, and volume. Here we review the relationship between these behavioral and structural changes and discuss the possibility that these changes may be largely adaptive. Specifically, we suggest that new neurons in the dentate gyrus enhance behavioral adaptability to changes in the environment, biasing behavior in novel situations based on previous experience with stress. Conversely, atrophy like changes in the hippocampus and decreased adult neurogenesis following chronic stress may serve to limit stress responses and stabilize behavior during chronic stress. PMID- 29421161 TI - Therapies for gestational diabetes and their implications for maternal and offspring health: Evidence from human and animal studies. AB - Obesity prior to and during pregnancy is associated with an increased risk of complications during pregnancy. One of the most common complications of pregnancy is gestational diabetes mellitus (GDM), a condition characterized by hyperglycemia and insulin resistance that is diagnosed in the third trimester of pregnancy. GDM predisposes both mothers and their children to increased obesity and cardiometabolic disorders, namely type 2 diabetes and cardiovascular disease. Current treatments include lifestyle changes and insulin injections, but oral anti-diabetic drugs such as metformin and glyburide are increasingly prescribed as they do not require injections. However, the long-term implications of therapies for diabetes during pregnancy on mothers and their offspring are not fully understood. In this review, we describe current treatments for GDM, including the first line lifestyle interventions such as exercise as well as insulin, glyburides and metformin. We also review selected natural health products that are sometimes used by individuals during pregnancy that could also be an effective therapeutic in pregnancies characterized by obesity or GDM. We focus on both the short- and long-term effects of treatments on the health of mothers and their offspring. We review the current literature from clinical research and animal studies. PMID- 29421162 TI - The tip link protein Cadherin-23: From Hearing Loss to Cancer. AB - Cadherin-23 is an atypical member of the cadherin superfamily, with a distinctly long extracellular domain. It has been known to be a part of the tip links of the inner ear mechanosensory hair cells. Several studies have been carried out to understand the role of Cadherin-23 in the hearing mechanism and defects in the CDH23 have been associated with hearing impairment resulting from defective or absence of tip links. Recent studies have highlighted the role of Cadherin-23 in several pathological conditions, including cancer, suggesting the presence of several unknown functions. Initially, it was proposed that Cadherin-23 represents a yet unspecified subtype of Cadherins; however, no other proteins with similar characteristics have been identified, till date. It has a unique cytoplasmic domain that does not bear a beta-catenin binding region, but has been demonstrated to mediate cell-cell adhesions. Several protein interacting partners have been identified for Cadherin-23 and the roles of their interactions in various cellular mechanisms are yet to be explored. This review summarizes the characteristics of Cadherin-23 and its roles in several pathologies including cancer. PMID- 29421163 TI - Rasch Analysis of the Edmonton Symptom Assessment System. AB - CONTEXT: The Edmonton Symptom Assessment System (ESAS) is a widely used multisymptom assessment tool in cancer and palliative care settings, but its psychometric properties have not been widely tested using modern psychometric methods such as Rasch analysis. OBJECTIVES: To apply Rasch analysis to the ESAS in a community palliative care setting and determine its suitability for assessing symptom burden in this group. METHODS: ESAS data collected from 229 patients enrolled in a community hospice service were evaluated using a partial credit Rasch model with RUMM2030 software (RUMM Laboratory Pty, Ltd., Duncraig, WA). Where disordered thresholds were discovered, item rescoring was undertaken. Rasch model fit and differential item functioning were evaluated after each iterative phase. RESULTS: Uniform rescoring was necessary for all 12 items to display ordered thresholds. The best model fit was achieved after item rescoring and combining three pairs of locally dependent items into three superitems (chi2 = 29.56 [27]; P = 0.33) that permitted ordinal-to-interval conversion. CONCLUSION: The ESAS satisfied unidimensional Rasch model expectations in a 12 item format after minor modifications. This included uniform rescoring of the disordered response categories and creating superitems to improve model fit and clinical utility. The accuracy of the ESAS scores can be improved by using ordinal-to-interval conversion tables published in the article. PMID- 29421164 TI - The Long-Term Impact of Neurofeedback on Symptom Burden and Interference in Patients With Chronic Chemotherapy-Induced Neuropathy: Analysis of a Randomized Controlled Trial. AB - CONTEXT: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment and may adversely affect quality of life (QOL) for years. OBJECTIVES: We explored the long-term effects of electroencephalographic neurofeedback (NFB) as a treatment for CIPN and other aspects of QOL. METHODS: Seventy-one cancer survivors (mean age 62.5; 87% females) with CIPN were randomized to NFB or to a waitlist control (WLC) group. The NFB group underwent 20 sessions of NFB where rewards were given for voluntary changes in electroencephalography. Measurements of pain, cancer-related symptoms, QOL, sleep, and fatigue were obtained at baseline, end of treatment, and one and four months later. RESULTS: Seventy one participants enrolled in the study. At the end of treatment, 30 in the NFB group and 32 in the WLC group completed assessments; at four months, 23 in the NFB group and 28 in the WLC completed assessments. Linear mixed model analysis revealed significant group * time interaction for pain severity. A general linear model determined that the NFB group had greater improvements in worst pain (primary outcome) and other symptoms such as numbness, cancer-related symptom severity, symptom interference, physical functioning, general health, and fatigue compared with the WLC group at the end of treatment and four months (all P < 0.05). Effect sizes were moderate or large for most measures. CONCLUSION: NFB appears to result in long-term reduction in multiple CIPN symptoms and improved postchemotherapy QOL and fatigue. PMID- 29421165 TI - A Pragmatic Evaluation of Symptom Distress After Group Meditation for Cancer Patients and Caregivers: A Preliminary Report. AB - CONTEXT: Complementary health approaches such as meditation may help improve cancer patient and caregiver symptoms, yet little research has examined the clinical application of these programs. OBJECTIVES: We explored the effects of a meditation group class, offered as part of an integrative medicine clinic at a comprehensive cancer center, on patient and caregiver self-reported symptoms. METHODS: Participants (patients and caregivers) of any three meditation group classes offered-Power of Breath (PB), Sacred Sounds (SS), and Movement & Breath (MB)-were asked to complete the Edmonton Symptom Assessment Scale (ESAS; scale 0 10, 10 most severe) before and after participation. ESAS individual items and subscales were analyzed; distress subscales included global (global distress score 0-90), physical (physical distress score 0-60), and psychological (psychological distress score, 0-20). Data were analyzed examining premeditation/postmeditation scores using paired t-tests and between types of meditation using analyses of variance. RESULTS: One hundred forty-two unique participants (76 patients and 66 caregivers) attended one or more meditation groups (mean 1.84) from May to December 2015 (265 total attendance: PB n = 92; SS n = 87; MB n = 86). For all participants, we observed clinically significant reduction/improvement in global distress scores (-5.17, SD 8; P < 0.0001) and in individual symptoms (ESAS decrease >= 1; means) of well-being (-1.36 SD 1.7; P < 0.0001), fatigue (-1.34 SD 1.9; P < 0.0001), anxiety (-1.26 SD 1.6; P < 0.001), and shortness of breath (-1.2 SD 2; P = 0.001). Comparing class length (60 vs. 90 minutes), class content (PB vs. SS vs. MB), and participants (caregivers vs. patients), there were no statistically significant differences in symptom score reduction. CONCLUSION: A single meditation group class offered as part of clinical care resulted in relief of multiple self-reported symptoms in both patients and caregivers. PMID- 29421166 TI - Defining the Scope of Prognosis: Primary Care Clinicians' Perspectives on Predicting the Future Health of Older Adults. AB - CONTEXT: Studies examining the attitudes of clinicians toward prognostication for older adults have focused on life expectancy prediction. Little is known about whether clinicians approach prognostication in other ways. OBJECTIVES: To describe how clinicians approach prognostication for older adults, defined broadly as making projections about patients' future health. METHODS: In five focus groups, 30 primary care clinicians from community-based, academic affiliated, and Veterans Affairs primary care practices were given open-ended questions about how they make projections about their patients' future health and how this informs the approach to care. Content analysis was used to organize responses into themes. RESULTS: Clinicians spoke about future health in terms of a variety of health outcomes in addition to life expectancy, including independence in activities and decision making, quality of life, avoiding hospitalization, and symptom burden. They described approaches in predicting these health outcomes, including making observations about the overall trajectory of patients to predict health outcomes and recognizing increased risk for adverse health outcomes. Clinicians expressed reservations about using estimates of mortality risk and life expectancy to think about and communicate patients' future health. They discussed ways in which future research might help them in thinking about and discussing patients' future health to guide care decisions, including identifying when and whether interventions might impact future health. CONCLUSION: The perspectives of primary care clinicians in this study confirm that prognostic considerations can go beyond precise estimates of mortality risk and life expectancy to include a number of outcomes and approaches to predicting those outcomes. PMID- 29421167 TI - Prenatal Material Hardship and the Internal Locus of Control Over the Prevention of Child Obesity: Progress Report. PMID- 29421169 TI - Long-term nitrogen dioxide exposure assessment using back-extrapolation of satellite-based land-use regression models for Australia. AB - Assessing historical exposure to air pollution in epidemiological studies is often problematic because of limited spatial and temporal measurement coverage. Several methods for modelling historical exposures have been described, including land-use regression (LUR). Satellite-based LUR is a recent technique that seeks to improve predictive ability and spatial coverage of traditional LUR models by using satellite observations of pollutants as inputs to LUR. Few studies have explored its validity for assessing historical exposures, reflecting the absence of historical observations from popular satellite platforms like Aura (launched mid-2004). We investigated whether contemporary satellite-based LUR models for Australia, developed longitudinally for 2006-2011, could capture nitrogen dioxide (NO2) concentrations during 1990-2005 at 89 sites around the country. We assessed three methods to back-extrapolate year-2006 NO2 predictions: (1) 'do nothing' (i.e., use the year-2006 estimates directly, for prior years); (2) change the independent variable 'year' in our LUR models to match the years of interest (i.e., assume a linear trend prior to year-2006, following national average patterns in 2006-2011), and; (3) adjust year-2006 predictions using selected historical measurements. We evaluated prediction error and bias, and the correlation and absolute agreement of measurements and predictions using R2 and mean-square error R2 (MSE-R2), respectively. We found that changing the year variable led to best performance; predictions captured between 41% (1991; MSE-R2 = 31%) and 80% (2003; MSE-R2 = 78%) of spatial variability in NO2 in a given year, and 76% (MSE-R2 = 72%) averaged over 1990-2005. We conclude that simple methods for back-extrapolating prior to year-2006 yield valid historical NO2 estimates for Australia during 1990-2005. These results suggest that for the time scales considered here, satellite-based LUR has a potential role to play in long term exposure assessment, even in the absence of historical predictor data. PMID- 29421170 TI - Plant bioactives and redox signaling: (-)-Epicatechin as a paradigm. AB - Polyphenols are bioactives claimed to be responsible for some of the health benefits provided by fruit and vegetables. It is currently accepted that the bioactivities of polyphenols can be mostly ascribed to their interactions with proteins and lipids. Such interactions can affect cell oxidant production and cell signaling, and explain in part the ability of polyphenols to promote health. EC can modulate redox sensitive signaling by: i) defining the extent of oxidant levels that can modify cell signaling, function, and fate, e.g. regulating enzymes that generate superoxide, hydrogen peroxide and nitric oxide; or ii) regulating the activation of transcription factors sensible to oxidants. The latter includes the regulation of the nuclear factor E2-related factor 2 (Nfr2) pathway, which in turn can promote the synthesis of antioxidant defenses, and of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway, which mediates the expression of oxidants generating enzymes, as well as proteins not involved in redox reactions. In summary, a significant amount of data vindicates the participation of EC in redox regulated signaling pathways. Progress in the understanding of the molecular mechanisms involved in EC biological actions will help to define recommendations in terms of which fruit and vegetables are healthier and the amounts necessary to provide health effects. PMID- 29421168 TI - Associations of urinary phthalate metabolites and lipid peroxidation with sperm mitochondrial DNA copy number and deletions. AB - BACKGROUND: Phthalates, a chemical class of plasticizers, are ubiquitous environmental contaminants that have been associated with oxidative stress. Mitochondria DNA copy number (mtDNAcn) and DNA deletions (mtDNAdel) are emerging biomarkers for cellular oxidative stress and environment exposures. OBJECTIVES: To examine associations of urinary phthalate metabolite and isoprostane concentrations on sperm mtDNAcn and mtDNAdel in male partners undergoing assisted reproductive technologies (ART). METHODS: Ninety-nine sperm samples were collected from male partners undergoing ART at Baystate Medical Center in Springfield, MA as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Seventeen urinary phthalate metabolite concentrations were analyzed by the Centers for Disease Control using tandem mass spectrometry. Urinary 15-F2t-isoprostane concentrations, a biomarker of lipid peroxidation, were measured using a competitive enzyme-linked immunosorbent assay. A triplex qPCR method was used to determine the relative quantification of mtDNAcn and mtDNAdel. RESULTS: Sperm mtDNAcn and mtDNAdel were positively correlated (Spearman rho = 0.31; p = .002). Adjusting for age, BMI, current smoking, race, and measurement batch, urinary monocarboxy-isononyl phthalate (MCNP) concentrations were positively associated with mtDNAcn (beta = 1.63, 95% CI: 0.14, 3.11). Other urinary phthalate metabolite and isoprostane concentrations were not associated with sperm mtDNAcn or mtDNAdel. CONCLUSIONS: Among this cohort of male ART participants, those with higher MCNP had higher mtDNAcn; other phthalate metabolites and isoprostane were not associated with mtDNAcn and mtDNAdel. Given our relatively small sample size, our results should be interpreted with caution. Future research is needed to replicate the findings in larger studies and among sperm samples obtained from the general population. PMID- 29421171 TI - New therapy from old drugs: synergistic bactericidal activity of sulfadiazine with colistin against colistin-resistant bacteria, including plasmid-mediated colistin-resistant mcr-1 isolates. AB - The recent emergence of colistin (COL) resistance, particularly mcr-1 plasmid mediated COL resistance in Gram-negative bacteria, has led to renewed interest in antibiotic combinations to overcome clinical therapeutic impasses. The aim of this study was to evaluate the potential of the synergistic and bactericidal activity of COL in combination with sulphonamide compounds, including sulfadiazine (SDI), sulfamethoxazole (SMX) and trimethoprim/sulfamethoxazole (SXT), as well as trimethoprim (TMP) against clinical COL-resistant bacterial strains, including strains with the plasmid-encoded mcr-1 gene. A collection of 55 COL-resistant and -susceptible strains from different origins (Laos, Thailand and France) was used in this study. Several in vitro methods were used to determine the potential of the synergistic activity of these combinations, including Etest on agar pre-treated plates, the Etest cross method and the chequerboard assay. A time-kill assay was performed to evaluate the potential bactericidal activity of combinations in addition to synergistic activity. Significant synergistic activity was observed with all combinations tested. The combination of COL + SDI presented the highest synergistic effect against the various species of COL-resistant strains (92.7%). For the other combinations, a synergistic effect was also observed but with lower frequency for COL + SMX (33.3%), COL + TMP (47.3%) and COL + SXT (31.5%). Synergy was observed independently of the COL resistance mechanism. These in vitro results suggest that the combination of COL + SDI would appear to be justifiable in patients with multidrug-resistant bacterial infections that cannot be treated with COL monotherapy. PMID- 29421172 TI - The efficacy of greater occipital nerve block for the treatment of migraine: A systematic review and meta-analysis. AB - Greater occipital nerve (GON) block has some potential in treating migraine. We conduct a systematic review and meta-analysis to investigate the impact of GON block on pain management of migraine. We have systematically searched randomized controlled trials (RCTs) assessing the efficacy of GON block versus placebo for migraine in various databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases. The primary outcome is pain intensity. Meta analysis is performed using the random-effect model. Seven RCTs are included in the meta-analysis. Compared with control intervention in migraine patients, GON block intervention can significantly reduce pain intensity (Mean difference = 1.24; 95% CI = -1.98 to -0.49; P = 0.001) and analgesic medication consumption (Mean difference = -1.10; 95% CI = -2.07 to -0.14; P = 0.02), but has no remarkable impact on head duration (Mean difference = -6.96; 95% CI = -14.09 to 0.18; P = 0.0.06) and adverse events (RR = 0.93; 95% CI = 0.52 to 1.65; P = 0.80). GON block intervention is able to significantly reduce pain intensity and analgesic medication consumption in migraine patients. PMID- 29421173 TI - Effects of chlorpromazine on sleep quality, clinical and emotional measures among patients with schizophrenia. AB - OBJECTIVES: The present study was aimed to examine the effects of chlorpromazine on sleep quality, clinical and emotional measures in people suffering from schizophrenia. PATIENTS AND METHODS: Twenty-five patients with schizophrenia or schizoaffective disorder were enrolled in this study. Our study included a one week running-in no-treatment period and two-month experimental period. Patients received chlorpromazine during the experimental period. The baseline and treatment outcome were recorded. The objective and subjective sleep were respectively measured by a wrist actigraph and two sleep questionnaires (Mini Sleep Questionnaire (MSQ) and Pittsburgh Sleep Quality Index Hebrew Translation (PSQI-H)). Besides, Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale (PANSS) were performed to assess the clinical psychopathology levels, and while Calgary Depression Scale for schizophrenia (CDSS) and Hamilton Anxiety Rating Scale (HAS) had been carried out to examine the emotional changes. RESULTS: There was a significant effect of chlorpromazine treatment on four objective sleep variables: longest wake episode, sleep onset latency, sleep percentage, and mean activity level (all P < 0.05). However, no significant differences were found in the subjective sleep measures. Likewise, psychopathology levels and emotional measures (depression level and anxiety level) were statistically improved by chlorpromazine treatment compared to the baseline (P < 0.05 or P < 0.01). CONCLUSION: Our results demonstrate that chlorpromazine could improve the insomnia and psychopathology symptoms of patients with schizophrenia. PMID- 29421174 TI - [Salmonella enterica: an ally in the therapy of cancer]. AB - Salmonella enterica, a species of facultative anaerobic bacteria, has demonstrated success as a live-attenuated bacterial vector for vaccination. S. enterica has also demonstrated promise as a therapeutic agent against cancer. Pre clinical and clinical trials have shown that S. enterica is localized in both solid and semi-solid tumors as well as in metastatic tumors. Moreover, S. enterica reduces resistance to treatment with other agents. In this review we present the novel therapeutic anti-cancer approaches that use S. enterica both for its ability as a delivery system for heterologous moieties against cancer and for its direct anti-cancer properties. PMID- 29421175 TI - ? PMID- 29421176 TI - ADIPOQ and ADIPOR2 gene polymorphisms: association with overweight/obesity in Mexican children. AB - BACKGROUND: ENSANUT 2012 showed a combined prevalence of overweight and obesity of 34.4% in Mexican children. Single nucleotide polymorphisms (SNPs) of the ADIPOQ and ADIPOR2 genes have been reported in many populations, but their association with obesity has not been confirmed in other studies. Our aim was to determine the association of SNPs from ADIPOQ and ADIPOR2 genes with obesity in Mexican children. METHODS: A total of 2,634 children from 6 to 12 years old were enrolled in the study from four IMSS Units in Mexico City. We selected 1,469 unrelated children (745 normal weight and 724 overweight/obese). Phenotype characterization included anthropometric measurements, blood pressure, biochemical parameters, insulin concentrations and presence of acanthosis nigricans (AN). Analysis of the SNPs rs182052, rs266729, rs2241766, rs822393 of ADIPOQ and rs11061971 of ADIPOR2 was carried out in the DNA samples. RESULTS: The study showed significant differences (p <0.05) between groups in waist circumference, blood pressure, presence of AN, insulin concentrations, HOMA-IR, fasting glucose and lipid parameters, being higher in obese children. No associations in ADIPOQ variants with the presence of overweight/obesity were found. The presence of the variant rs11061971 of ADIPOR2 in children had a significant association with protection of overweight/obesity (OR 0.79, 95% CI 0.68-0.93, p = 0.003). Also, the log-additive model confirmed the association by codominant and dominant models (p <0.05). CONCLUSIONS: The presence of rs11061971 of ADIPOR2 variant confers protection against obesity and could be used as a marker in Mexican children. PMID- 29421177 TI - [Congenital tuberculosis: a challenge to overcome]. PMID- 29421178 TI - [Prediction instrument for obesity in adolescents at the Policlinico Universitario "Manuel Gonzalez Diaz", 2013-2014]. AB - BACKGROUND: Obesity is one of the principal non declarable diseases affecting children and adolescents. METHODS: With the objective of developing a predictive instrument to identify high-risk adolescents with obesity, a cohort prospective study was carried out at the Policlinic "Manuel Gonzalez Diaz", Bahia Honda City from 2013-2014. It was developed in three stages. In the first stage, 1800 adolescents from 10-19 years of age were included. The prevalence was identified and the most relevant characteristics of obesity were described (defined as body mass index >97th percentile according to age and sex). In the second stage we identified the possibility of the diagnosis of factors that increase the probability of obesity. The third stage elaborated and validated an obesity predictor instrument from the results of the initial stages. RESULTS: To apply the instrument to sample A for internal elaboration and validation, sensitivity was 77.78% and specificity was 86.11%. Area under the curve (AUC) receiver operating characteristic (ROC) was 0.86, whereas for sample B the sensitivity was 79.63% and specificity was 92.13%. Positive predictive value (PPV) was 83.5% and negative predictive value (NPV) was 90.05%. CONCLUSIONS: The instrument allows predicting the risk for developing obesity in adolescents with acceptable sensitivity and high specificity. Its routine application will be interesting in pediatric health consultations. PMID- 29421179 TI - [Utility of a physiologic stability index based on Transport Risk Index of Physiologic Stability (TRIPS) for the evaluation of infants transferred to a specialized hospital]. AB - BACKGROUND: Neonatal mortality is a public health priority. We review the physiological instability of the newborn after a transfer, which contributes to increased neonatal mortality. The objective of this work was to determine whether the Transport Risk Index of Physiologic Stability (TRIPS) in newborns transferred to the Neonatal Intensive Care Unit of a secondary hospital serves as a predictor of early neonatal mortality. METHODS: We use the TRIPS to predict neonatal death in the first 7 days after patients' admission. RESULTS: Neonatal mortality at 7 days after admission is related to the TRIPS rating. The score of the survivors and neonatal deaths show a significant difference (p: 0.009). For a score of 16, a sensitivity of 62% and a specificity of 84%; area under the curve of 0.757 was determined. CONCLUSIONS: Physiological index weighting using TRIPS is a good predictor of neonatal mortality. It is important to establish measures to improve physiological stability of the newborn before, during and after the transfer in order to reduce neonatal mortality. PMID- 29421180 TI - [Genetic and neuroendocrine aspects in autism spectrum disorder]. AB - The autism spectrum disorder (ASD) was described in 1943 and is defined as a developmental disorder that affects social interaction and communication. It is usually identified in early stages of development from 18 months of age. Currently, autism is considered a neurological disorder with a spectrum covering cases of different degrees, which is associated with genetic factors, not genetic and environmental. Among the genetic factors, various syndromes have been described that are associated with this disorder. Also, the neurobiology of autism has been studied at the genetic, neurophysiological, neurochemical and neuropathological levels. Neuroimaging techniques have shown multiple structural abnormalities in these patients. There have also been changes in the serotonergic, GABAergic, catecholaminergic and cholinergic systems related to this disorder. This paper presents an update of the information presented in the genetic and neuroendocrine aspects of autism spectrum disorder. PMID- 29421181 TI - [Childhood obesity: a risk factor for development of flatfoot]. AB - BACKGROUND: In Mexico, the prevalence of overweight and obesity is 34.4% in school-age children (ENSANUT 2012), which may induce a vicious cycle of flatfoot plantalgia-sedentarism-obesity, although the presence and degree of flatfoot in school-age children with obesity has not yet been described in a Mexican population. The objective of the study was to determine the prevalence of flatfoot and its association with obesity in school-age children living in Tampico. METHODS: An analytical and cross-sectional study with 1128 students, 48.8% male and 51.2% female, 9- to 11-years of age. Anthropometric measurements (weight and height) were performed. Body mass index (BMI) was calculated and obesity was considered a BMI percentile >95. Plantar footprint was photographed via a podoscope using Denis classification to diagnose flatfoot grades. RESULTS: The prevalence of overweight/obesity was 49.1% and of flatfoot was 12.1% (male: 8.1%, female: 4%, p = 0.28). The association between obesity and flatfoot was significant (p <0.001) and there was a 2.5 times higher risk of overweight-obese children compared to those of normal weight. CONCLUSIONS: There is an association between obesity and flatfoot. We suggest implementing secondary prevention measures in this population. PMID- 29421182 TI - [Perinatal tuberculosis]. AB - BACKGROUND: Perinatal tuberculosis is acquired during birth or during the early neonatal period. Although its incidence is unknown, a search was conducted in Medline and 28 cases were found of perinatal tuberculosis reported from 1983 to 2011. Diagnosis of this disease is important due to having nonspecific symptoms that are mistaken for other infectious diseases. The disease has a high mortality rate (60%); therefore, it requires prompt diagnostic suspicion by the medical staff to prevent a fatal outcome. CASE REPORT: We describe the case of a 3-month old male whose 29-year-old mother died of septic shock at 15 days of delivery. The infant's condition began within 30 days of age with cough and difficulty breathing with a diagnosis of multiple foci pneumonia. The infant presented respiratory impairment, meriting change of antibiotics twice, without improvement. The autopsy report of the mother revealed peritoneal tuberculosis. PCR was carried out using tracheal aspirate and pleural fluid of the patient, which were positive for Mycobacterium tuberculosis. Perinatal diagnosis of tuberculosis was established. No hepatic granuloma was found. CONCLUSIONS: Perinatal infection should be suspected in children with sepsis and/or pneumonia unresponsive to antibiotics. In this care, the history of tuberculosis in the mother should have oriented the diagnosis. PMID- 29421183 TI - [Pulmonary aplasia: report of two cases]. AB - BACKGROUND: Pulmonary aplasia is a rare disorder of lung development characterized by the presence of a rudimentary main bronchus in the absence of lung and pulmonary artery. It is generally associated with other congenital defects and must be suspected in the presence of a total radiopaque hemithorax. CASE REPORTS: We describe two cases of pulmonary aplasia diagnosed in the Hospital Infantil de Mexico "Federico Gomez" in the last 5 years. The first case was a female who presented respiratory distress from birth with a radiopaque left hemithorax in which the diagnosis of pulmonary aplasia was completed with bronchoscopy and lung scan. Her evolution has been insidious, characterized by chronic respiratory symptoms, oxygen dependence and pneumonias. The second case is a 5 year old female, who remained asymptomatic untill the age of two years when she was hospitalized for gastroeteritis. She underwet chest X-rays with findings suspicious of right diaphragmatic hernia. She was then transferred to our hospital. She underwent surgery at which time diaphragmatic eventration and no ipsilateral lung were found. The diagnosis was completed with a blind bottom main right bronchus in bronchoscopy. CONCLUSIONS: Pulmonary aplasia is an uncommon pathology. Due to great variability in clinical presentation, there must be a high index of suspicion in the presence of a fully radiopaque hemithorax. Among the diagnostic methods, X-rays, tomography and lung scan are useful. Bronchoscopy is required for diagnostic confirmation. Surgical removal of the stump and translocation of the diaphragm have been proposed as surgical options. PMID- 29421184 TI - [Miliary tuberculosis: the reemergence of diseases and lack of clinical suspicion]. PMID- 29421185 TI - [Mortality in children under 15 years of age due to non-transmissible diseases. Mexico, 2000-2014]. PMID- 29421186 TI - Gray matter deficits and altered resting-state connectivity in the superior temporal gyrus among individuals with problematic hypersexual behavior. AB - Neuroimaging studies on the characteristics of hypersexual disorder have been accumulating, yet alternations in brain structures and functional connectivity in individuals with problematic hypersexual behavior (PHB) has only recently been studied. This study aimed to investigate gray matter deficits and resting-state abnormalities in individuals with PHB using voxel-based morphometry and resting state connectivity analysis. Seventeen individuals with PHB and 19 age-matched healthy controls participated in this study. Gray matter volume of the brain and resting-state connectivity were measured using 3T magnetic resonance imaging. Compared to healthy subjects, individuals with PHB had significant reductions in gray matter volume in the left superior temporal gyrus (STG) and right middle temporal gyrus. Individuals with PHB also exhibited a decrease in resting-state functional connectivity between the left STG and left precuneus and between the left STG and right caudate. The gray matter volume of the left STG and its resting-state functional connectivity with the right caudate both showed significant negative correlations with the severity of PHB. The findings suggest that structural deficits and resting-state functional impairments in the left STG might be linked to PHB and provide new insights into the underlying neural mechanisms of PHB. PMID- 29421187 TI - Activation of the subthalamic nucleus suppressed by high frequency stimulation: A c-Fos immunohistochemical study. AB - Deep brain stimulation applied at high frequency (HFS) to the subthalamic nucleus (STN) is used to ameliorate the symptoms of Parkinson's disease. The mechanism by which this is achieved remains controversial. In particular, it is uncertain whether HFS has a suppressive or excitatory action locally within the STN. Brief exposure of rats to ether anesthesia evokes pathological burst firing and associated expression of the immediate early gene c-Fos in STN neurons. We used this ether model of STN activation to test the effect of a range of HFS parameters on c-Fos expression evoked by the anesthetic. The elevated baseline of c-Fos expression afforded the possibility of detecting further excitatory, or suppressive effects of STN HFS. Four HFS protocols were examined; 130, 200 and 260 Hz with 60 us, and 130 Hz with 90 us pulse width (HFS intensity:150-300 uA). All HFS protocols were applied for 20 min while the animals were exposed to ether. Ether-evoked expression of c-Fos immunoreactivity was suppressed by HFS at 200 and 260 Hz with a pulse width of 60 us, and by 130 Hz when the pulse width was increased to 90 us. HFS at 130 Hz with the 60 us pulse width had no significant effect and HFS alone caused negligible c-Fos expression in the STN. These findings suggest that HFS of the STN causes significant suppression of evoked neuronal activity. It remains to be determined whether this locally suppressive property of HFS is associated with the efficacy of STN deep brain stimulation to relieve the symptoms of Parkinson's disease. PMID- 29421188 TI - Mismatch negativity and psychophysical detection of rising and falling intensity sounds. AB - Human subjects demonstrate a perceptual priority for rising level sounds compared with falling level sounds. The aim of the present study was to investigate whether or not the perceptual preference for rising intensity can be found in the preattentive processing indexed by mismatch negativity (MMN). Reversed oddball stimulation was used to produce MMNs and to test the behavioral discrimination of rising, falling and constant level sounds. Three types of stimuli served as standards or deviants in different blocks: constant level sounds and two kinds of rising/falling sounds with gradual or stepwise change of intensity. The MMN amplitudes were calculated by subtracting ERPs to identical stimuli presented as standard in one block and deviant in another block. Both rising and falling level deviants elicited MMNs which peaked after 250 ms and did not overlap with N1 waves. MMN was elicited by level changes even when the deviants were not discriminated behaviorally. Most importantly, we found dissociation between earlier and later stages of auditory processing: the MMN responses to the level changes were mostly affected by the direction of deviance (increment or decrement) in the sequence, whereas behavioral performance depended on the direction of the level change within the stimuli (rising or falling). PMID- 29421189 TI - UTX - moonlighting in the cytoplasm? AB - The X-linked histone demethylase UTX has a pivotal role in cellular and developmental processes including embryogenesis, hematopoiesis and cancer. UTX removes di- and trimethyl groups on histone H3 lysine 27, thereby regulating gene expression. But there is growing evidence that UTX displays biological functions independent of its histone demethylase activity. To elucidate these novel functions, it is of great interest to define subcellular localizations of UTX. Here we show for the first time that native UTX is primarily localized in the cytoplasm whereas ectopic GFP and Flag-tagged UTX display nuclear and cytoplasmic localization. While its epigenetic function is exerted in the nucleus, its cytoplasmic localization points to a novel function. PMID- 29421190 TI - Identification of a high affinity binding site for abscisic acid on human lanthionine synthetase component C-like protein 2. AB - Lanthionine synthetase component C-like protein 2 (LANCL2) has been identified as the mammalian receptor mediating the functional effects of the universal stress hormone abscisic acid (ABA) in mammals. ABA stimulates insulin independent glucose uptake in myocytes and adipocytes via LANCL2 binding in vitro, improves glucose tolerance in vivo and induces brown fat activity in vitro and in vivo. The emerging role of the ABA/LANCL2 system in glucose and lipid metabolism makes it an attractive target for pharmacological interventions in diabetes mellitus and the metabolic syndrome. The aim of this study was to investigate the presence of ABA binding site(s) on LANCL2 and identify the amino acid residues involved in ABA binding. Equilibrium binding assays ([3H]-ABA saturation binding and surface plasmon resonance analysis) suggested multiple ABA-binding sites, prompting us to perform a computational study that indicated one putative high-affinity and two low-affinity binding sites. Site-directed mutagenesis (single mutant R118I, triple mutants R118I/R22I/K362I and R118I/S41A/E46I) and equilibrium binding experiments on the mutated LANCL2 proteins identified a high-affinity ABA-binding site involving R118, with a KD of 2.6 nM +/- 1.2 nM, as determined by surface plasmon resonance. Scatchard plot analysis of binding curves from both types of equilibrium binding assays revealed a Hill coefficient >1, suggesting cooperativity of ABA binding to LANCL2. Identification of the high-affinity ABA binding site is expected to allow the design of ABA agonists/antagonists, which will help to understand the role of the ABA/LANCL2 system in human physiology and disease. PMID- 29421191 TI - [Central venous-catheter related bacteremia: incidence and risk factors in a hospital in western Mexico]. AB - BACKGROUND: Central venous catheters (CVC) are needed for monitoring and treatment of critically ill patients; however, their use increases the risk of bacteremia. The aim of the study was to quantify the incidence of central venous catheter-related bacteremia (CVCRB) and to identify factors associated with this infection. METHODS: A prospective cohort study was conducted in a concentration hospital of western Mexico. The association of CVCRB and study variables was investigated using multivariate Cox regression analysis. RESULTS: Two hundred four patients with CVC were studied. The average age was 4.6 years; 66.2% were male. Insertion sites of the catheters were subclavian vein 72.5% (n = 148), jugular vein 20.1% (n = 41) and femoral vein 7.4% (n = 15). CVCRB incidence was 6.5 events/1,000 catheter days; microorganisms identified were gram-positive cocci 37.5% (n = 6), gram-negative bacilli 37.5% (n = 6) and Candida albicans 25% (n = 4). It was observed that the increase in catheter manipulations per day was associated with bacteremia (HR 1.14, 95% CI 1.06 - 1.23), whereas the use of intravenous antibiotics showed a protective effect (HR 0.84, 95% CI 0.76-0.92). CONCLUSIONS: In addition to strategies of maximum caution when placing or manipulating the catheter, we recommend decreasing, as much as possible, disconnects between the CVC and infusion line. Antibiotics showed a protective effect, but the outcome is uncertain and promotion of antimicrobial resistance should be considered. PMID- 29421192 TI - [Multiple hereditary osteochondromatosis in a family]. AB - BACKGROUND: Multiple hereditary osteochondromatosis is characterized by the growing of benign cartilaginous tumors in form of exostosis, predominately in the metaphysis of long bones. It is described with a prevalence of 1/50,000 individuals. CASE REPORTS: This article presents the clinical information and its autosomal dominant inheritance pattern where exotoxin genes (EXT gene family) were affected in a three-member family with multiple hereditary osteochondromatosis. The three patients showed altered arcs of movement of wrists, shoulders and ankles. Clinical diagnosis was confirmed with radiology and malignancy was ruled out in all patients. CONCLUSIONS: This disease requires frequent medical evaluation, surgical bone correction when the normal function is involved, surveillance for malignant transformation, and genetic counseling. PMID- 29421193 TI - [Sarcoidosis in childhood. A rare systemic disease]. AB - BACKGROUND: Sarcoidosis is a systemic disease of unknown etiology that rarely occurs in children. It usually affects the lungs, however, it may involve various organs. It occasionally affects the general condition, and causes fever, hepatomegaly and splenomegaly. CASE REPORT: We report the case of a twelve-year old adolescent with late-onset childhood sarcoidosis which diagnosis was confirmed by lymph node histopathological study. The patient presented general condition, hypercalcemia, erythema nodosum, severe lung disorders, lymphadenopathy, hepatomegaly and testicular mass. He received treatment with steroids, with excellent clinical response. CONCLUSIONS: We highlight the importance of considering the diagnosis of sarcoidosis in patients with hepatomegaly, lymphadenopathy, diffuse lung damage, erythema nodosum, testicular mass and hypercalcemia, as well as the need for a multidisciplinary approach to assess multiple organ involvement and the early beginning of steroid treatment in order to prevent the progression of the disease. PMID- 29421194 TI - [Infant with progressive jaundice, cirrhosis and proximal tubulopathy]. PMID- 29421195 TI - [To live well: health care or life project? Part I]. AB - To live well is a universal human aspiration as well as the ultimate goal of the services that take care of people's health. In this paper, two different ideas are discussed about how to achieve it: health care and life project. Part I begins with a detailed account of human degradation and the social inequities responsible for the unprecedented social and cultural breakdown of the actual society. Under this interpretative framework, the medicalization of human life as result of the alienating consumerism is analyzed as well as the excesses it entails from both health care institutions and health services users. By exploring the reasons of medicalization, it becomes clear that its influence in our actual lifestyles has driven us to be obsessed with being healthy and horrified of diseases; this works as a very effective mean of social control from the powers that maintain and deepen inequality. As such, the first to benefit from it is the health industry. This constant concern for health takes us away from our goal of living well since it causes anxiety, insecurity and disquietude. In conclusion, different considerations about the inconveniences of devoting all our energies towards health care are offered and it is suggested that instead we all have the responsibility of creating a more hospitable and inclusive world. PMID- 29421196 TI - [Overweight and obesity: are they an irremediable situation?] PMID- 29421197 TI - Chikungunya fever: current status in Mexico. AB - Chikungunya fever is a tropical vector-borne disease that has been spreading rapidly around the world during the last 10 years, and which has been usually misdiagnosed as dengue. Nowadays, this disease is increasing in Mexico, mainly in the southern and central zones of the country, being significantly more common in women, children and young adults (28% in<20 years of age). The classical presentation includes fever, arthralgia, polyarthritis, back-pain, and skin rashes. Although symptoms and treatment are similar to those for dengue, there are key clinical features to differentiate these two diseases. PMID- 29421198 TI - [Effect of an intervention based on child-care centers to reduce risk behaviors for obesity in preschool children]. AB - BACKGROUND: Preschool age is a critical stage for health promotion and prevention of obesity, which is an emerging public health problem in children. The aim of this study was to design and evaluate the effect of a multifaceted intervention based on child-care centers to reduce risk behaviors for obesity among preschool children. METHODS: A 12-month cluster-randomized community trial was conducted in 16 Mexican Institute of Social Security child-care centers in Mexico City. Children between 2 and 4 years of age enrolled in the selected child-care centers participated in the study. Intervention comprised 12 weekly curriculum sessions for the children, and six family workshops. Changes in children's dietary and physical activity, food availability at home, and maternal feeding styles were determined after 6 and 12 months. Changes within groups among stages, and between groups by stage were analyzed through chi2 test. RESULTS: The intervention showed decrease of home availability for some non-recommended foods and increase in physical activity in the intervention group compared to the usual care group. CONCLUSIONS: Improvement in physical activity can be effective in the long term; innovative strategies aimed to modify family dietary risk behaviors are required. PMID- 29421199 TI - Lexical tonal discrimination in Zapotec children. A study of the theta rhythm. AB - BACKGROUND: Zapotec is a language used mainly in the state of Oaxaca in Mexico of tonal characteristic; homophone words with difference in fundamental frequency with different meanings. Our objective was to analyze changes in the electroencephalographic (EEG) theta rhythm during word discrimination of lexical tonal bi-syllabic homophone word samples of Zapotec. METHODS: We employed electroencephalography analysis during lexical tonal discrimination in 12 healthy subjects 9-16 years of age. RESULTS: We observed an increase in theta relative power between lexical discrimination and at rest eyes-open state in right temporal site. We also observed several significant intra- and inter-hemispheric correlations in several scalp sites, mainly in left fronto-temporal and right temporal areas when subjects were performing lexical discrimination. CONCLUSIONS: Our data suggest more engagement of neural networks of the right hemisphere are involved in Zapotec language discrimination. PMID- 29421200 TI - [Curriculum analysis and comparison between strategies or programs for early child development in Mexico]. AB - BACKGROUND: Most of the strategies or programs that support early child development in Mexico are independent efforts that vary in scale, services offered and means of providing them. For the evaluation of the quality of these programs, an important aspect is the curriculum content. The aim of this study was to analyze and compare the curriculum content of the different strategies or programs focused on the promotion and intervention of early child development, which are offered by the Federal Government in Health and Education sectors in Mexico. METHODS: We conducted a review of the curriculum content of the strategies and programs. The qualitative phase consisted of a comparative analysis where 75 indicators proposed by the Inter-American Development Bank were identified. The quantitative phase consisted of a descriptive analysis of the indicators. Finally, the analyses were compared to establish the performance of each one. RESULTS: Six strategies or programs were identified. In the analysis of the presence of indicators, the Oportunidades de Aprendizaje (Learning Opportunities, LO) strategy showed a larger number of indicators. In the amplitude analysis, both PEI-CONAFE and LO were the best balanced. Finally, in depth analysis of the indicators LO and Skills for life were the best balanced while PEI-CONAFE was the best balanced in the social-emotional area, CeNSIA program for language and LO for cognitive development area. CONCLUSIONS: LO strategy showed the closest level of contents established by the Inter-American Development Bank. PMID- 29421201 TI - [Atypical and incomplete Kawasaki disease in pediatric age]. PMID- 29421202 TI - [Respiratory monitoring of pediatric patients in the Intensive Care Unit]. AB - Respiratory monitoring plays an important role in the care of children with acute respiratory failure. Therefore, its proper use and correct interpretation (recognizing which signals and variables should be prioritized) should help to a better understanding of the pathophysiology of the disease and the effects of therapeutic interventions. In addition, ventilated patient monitoring, among other determinations, allows to evaluate various parameters of respiratory mechanics, know the status of the different components of the respiratory system and guide the adjustments of ventilatory therapy. In this update, the usefulness of several techniques of respiratory monitoring including conventional respiratory monitoring and more recent methods are described. Moreover, basic concepts of mechanical ventilation, their interpretation and how the appropriate analysis of the information obtained can cause an impact on the clinical management of the patient are defined. PMID- 29421203 TI - [Kawasaki disease at a pediatric hospital in Mexico]. AB - BACKGROUND: Kawasaki disease (KD) is one of the most common systemic vasculitis in children under 5 years of age. The epidemiology of the disease is not well established in Mexico. The objective of this study was to describe the epidemiology, clinical features and treatment of patients with KD at the Hospital Infantil de Mexico Federico Gomez (HIMFG). METHODS: We conducted a retrospective, descriptive and analytical study of patients diagnosed from January 2004 to December 2014 with KD in the HIMFG. RESULTS: We analyzed 204 cases from which 55% were male, with a median age of 32.5 months (6-120) and a rate of hospitalization of 96%. Twenty percent of patients presented incomplete KD. No differences in the somatometric measurements or vitals were reported. The most frequent symptoms were fever, conjunctivitis (89%), oral changes (84%), pharyngitis (88%) and strawberry tongue (83%). We found higher acute phase reactants in the classic presentation. Echocardiographic alterations in 60 patients (29%), of which 12% were ectasia and 11% reported coronary aneurysms. On the other hand, 169 (83%) patients received intravenous immunoglobulin (IVIG), 18 (9%) presented resistance to IVIG, 6 (3%) required corticosteroids, and 2 (1%) infliximab; all received acetylsalicylic acid. CONCLUSIONS: There were no important differences between classic and incomplete presentations. The incidence of cardiac alterations is less than previously reported in Mexico, but similar to that of other countries. PMID- 29421205 TI - [Concordance of glomerular filtration rate with creatinine clearance in 24-hour urine and Schwartz and Schwartz updated]. AB - BACKGROUND: Reference methods for the quantification of the glomerular filtration rate (GFR) are difficult to use in clinical practice; formulas for evaluating GFR based on serum creatinine (SCr) and/or creatinine clearance are used. The aim of this study was to quantify the correlation and concordance of GFR with creatinine clearance in 24-hour urine (GFR24) and Schwartz and Schwartz updated formulas. METHODS: Cross-sectional study involving healthy pediatric patients and with chronic kidney disease (CKD) from 5 to 16.9 years. Linear correlation between GFR 24 and two formulas was evaluated with the Pearson correlation coefficient (r) and intraclass correlation coefficient (ICC). RESULTS: We studied 134 patients, of which 59.7% were male. Mean age was 10.8 years. The average GFR24 was 140.34ml/min/1.73m2; 34.3% (n=46) had GFR <90ml/min/1.73m2. Moderate linear correlation between GFR24 and Schwartz (r= 0.63) and Schwartz updated (r= 0.65) formulas was observed. There was good concordance between the GFR24 and Schwartz (ICC= 0.77) and updated Schwartz (ICC= 0.77) formulas. Schwartz classical formula in patients with GFR24 >= 90ml/min/1.73m2 estimated higher values, while Schwartz updated underestimated values. CONCLUSIONS: There is moderate correlation and good concordance between the GFR24 and Schwartz and Schwartz updated formulas. The concordance was better in patients with obesity and lower in women, patients with hyperfiltration and normal weight. PMID- 29421206 TI - [Retroperitoneal malignant peripheral nerve sheath tumor a preschool child]. AB - BACKGROUND: Malignant tumors of peripheral nerve sheath (MPNSTs for its acronym in English) are aggressive sarcomas that occur generally in adulthood and are located mainly on the trunk and lower limbs, with a high association with neurofibromatosis type 1 (NF1). CASE REPORT: A 34-months-old female infant without NF1 with a palpable abdominal mass is described. The mass corresponded to a retroperitoneal MPNST. The diagnostic approach and management are presented, highlighting the complications and sequelae that occurred during evolution. CONCLUSIONS: MPNSTs are important despite their low incidence because of their aggressiveness, and should be considered upon the detection of a mass located at paravertebral level or limbs, especially in patients with NF1. The cornerstone of the treatment lies in a complete surgical resection due to the high rate of recurrence, with limited therapeutic response to radiotherapy and chemotherapy. This case presents the clinical manifestations and complications that can be expected with these tumors and their harmful behaviour. The absence of NF1 does not exclude the diagnosis. PMID- 29421204 TI - [Pediatric patients with type 1-diabetes: growth and growth failure associated factors]. AB - BACKGROUND: Type 1 diabetes (T1D) usually occurs in the pediatric age and affects the growth of children. The aim of this work was to describe growth and growth failure associated factors in a population of children with T1D in a tertiary level pediatric hospital. METHODS: A case-control nested in a cohort study was conducted. We included patients with TD1 under 16 years of age with a minimum follow-up of 12 months. Data as age at T1D diagnosis, anthropometry, glycosylated hemoglobin (HbA1c), as well as the pubertal development (Tanner stage) were collected at the time of diagnosis and during 4 years of follow-up. At the end of the follow-up, patients with growth failure and without it were compared, matched by sex, age at TD1 diagnosis. Univariate and multivariate analyses were performed. RESULTS: On the first year of follow-up, 95 patients were gathered, 88 patients were still followed by the second year, 56 patients were kept for the third year, and 46 patients were still followed-up by the fourth year. Median age was 9.5 years and 50% were preadolescents. During their evolution, 50% had growth failure. According to the multivariate analysis, the factor associated with growth failure was the HbA1c in the first year post-diagnosis (OR 4.08; 95% CI 1.34-12.42). CONCLUSIONS: In the first year post-diagnosis of children with T1D, HbA1c was associated with growth failure. PMID- 29421207 TI - [An atypical presentation of Infantile Alexander disease lacking macrocephaly]. AB - BACKGROUND: Alexander disease is a rare form of leukodystrophy that involves mainly astrocytes; it is inherited in an autosomal recessive manner and occurs by mutations in the GFAP gene, located on chromosome 17q21. It can occur at any age and its infantile form is characterized by macrocephaly, seizures, severe motor and cognitive delay, and progressive spasticity or ataxia. CASE REPORT: An 8 month-old female was evaluated with a history of neurodevelopmental delay and unprovoked focal motor seizures. Physical examination showed normal head circumference, increased motor responses to tactile and noise stimuli, pyramidal signs and no visceromegalies. Widespread hypodense white matter was found on magnetic resonance and lumbar puncture showed hyperproteinorrachia. Krabbe disease was ruled out by enzymatic assay and gene sequencing of GALC. In the reassessment of the case, abnormalities in neuroimaging lead to suspicion of Alexander disease, and GFAP gene sequencing reported a pathogenic mutation in exon 4 c.716G>A, which caused a change of arginine to histidine at position 239 of the protein (p.Arg239His). CONCLUSIONS: The radiographic signs observed in the resonance were decisive for the diagnosis, later confirmed by molecular study. It is important to consider that certain mutations are not associated with macrocephaly, which may cause delay in diagnosis. PMID- 29421208 TI - [Extraskeletal Ewing sarcoma in a 16-year-old female adolescent]. PMID- 29421209 TI - [Congenital macroglossia: clinical features and therapeutic strategies in paediatric patients]. AB - Congenital macroglossia is a condition that consists in an enlarged tongue that in resting position protrudes beyond the alveolar ridge. It has been classified in two categories: true macroglossia, which occurs in congenital or acquired forms, and relative macroglossia. As this alteration may be due to different causes, its incidence is not known. It is more frequently associated to Beckwith Wiedemann syndrome, to mucopolysaccharidosis diseases and to Pompe's disease, and it has been less frequently associated to lymphangioma, hemangioma or isolated muscular hypertrophy. Macroglossia is characterized by an enlarged and thick tongue that may have fissures and ulcers, may cause language alterations, difficulties for feeding and swallowing, sialorrhea and recurrent infections of the upper airway or even its obstruction. Its clinical evaluation must include a complete clinical chart with careful physical exploration and a pedigree of that may identify the presence or absence of a hereditary associated syndrome. Macroglossia management is complex. More than twenty different surgical options to reduce the tongue size have been proposed, however, so far there is not a general agreement in this respect. The objective of this work is to review clinical and surgical aspects related to macroglossia from the point of view of non-surgical pediatricians and genetists, addressed to the different medical specialists, including the maxillofacial surgeons involved in the management of these patients. PMID- 29421210 TI - [Oliver Sacks: the genious as neurologist, writer and patient]. PMID- 29421211 TI - EvoStruct-Sub: An accurate Gram-positive protein subcellular localization predictor using evolutionary and structural features. AB - Determining subcellular localization of proteins is considered as an important step towards understanding their functions. Previous studies have mainly focused solely on Gene Ontology (GO) as the main feature to tackle this problem. However, it was shown that features extracted based on GO is hard to be used for new proteins with unknown GO. At the same time, evolutionary information extracted from Position Specific Scoring Matrix (PSSM) have been shown as another effective features to tackle this problem. Despite tremendous advancement using these sources for feature extraction, this problem still remains unsolved. In this study we propose EvoStruct-Sub which employs predicted structural information in conjunction with evolutionary information extracted directly from the protein sequence to tackle this problem. To do this we use several different feature extraction method that have been shown promising in subcellular localization as well as similar studies to extract effective local and global discriminatory information. We then use Support Vector Machine (SVM) as our classification technique to build EvoStruct-Sub. As a result, we are able to enhance Gram positive subcellular localization prediction accuracies by up to 5.6% better than previous studies including the studies that used GO for feature extraction. PMID- 29421212 TI - Understanding the Venus flytrap through mathematical modelling. AB - Among carnivorous plants, the Venus flytrap is of particular interest for the rapid movement of its snap-traps and hypothesised prey selection, where small prey are allowed to escape from the traps. In this paper, we provide the first mathematical cost-benefit model for carnivory in the Venus flytrap. Specifically, we analyse the dynamics of prey capture; the costs and benefits of capturing and digesting its prey; and optimisation of trap size and prey selection. We fit the model to available data, making predictions regarding trap behaviour. In particular, we predict that non-prey sources, such as raindrops or wind, cause a large proportion of trap closures; only few trap closures result in a meal; most of the captured prey are allowed to escape; the closure mechanism of a trap is triggered about once every two days; and a trap has to wait more than a month for a meal. We also find that prey capture of traps of the Venus flytrap follows the Beddington-DeAngelis functional response. These predictions indicate that the Venus flytrap is highly selective in its prey capture. PMID- 29421213 TI - Editorial. PMID- 29421214 TI - Solubility Determination of Active Pharmaceutical Ingredients Which Have Been Recently Added to the List of Essential Medicines in the Context of the Biopharmaceutics Classification System-Biowaiver. AB - Since the publication of Lindenberg et al., which classified orally administered active pharmaceutical ingredients (APIs) on the 2004 Essential Medicines List (EML) of the World Health Organization according to the Biopharmaceutics Classification System (BCS), various APIs have been added to the EML. In this work, BCS classifications for 16 of the orally administered APIs which were added to the EML after 2004 were determined. To establish a reliable solubility classification for all these compounds, a miniaturized shake-flask method was introduced. This method enables a fast, economical determination of the BCS solubility class while reliably discriminating between "highly soluble" and "not highly soluble" compounds. Nine of the 16 APIs investigated were classified as "highly soluble" compounds, making them potential candidates for an approval of multisource drug products via the BCS-based biowaiver procedure. The choice of dose definition (which currently varies among the guidances pertaining to BCS based bioequivalence published by various regulatory authorities) had no effect on the solubility classification of any of the 16 substances evaluated. BCS classification of the compounds was then completed using permeability data obtained from the literature. As several APIs decomposed at one or more pH values, a decision tree for determining their solubility was established. PMID- 29421215 TI - Sweeping of Adsorbed Therapeutic Protein on Prefillable Syringes Promotes Micron Aggregate Generation. AB - This study evaluated how differences in the surface properties of prefillable syringe barrels and in-solution sampling methods affect micron aggregates and protein adsorption levels. Three syringe types (glass barrel with silicone oil coating [GLS/SO+], glass barrel without silicone oil coating [GLS/SO-], and cyclo olefin polymer [COP] barrel syringes) were tested with 3 therapeutic proteins (adalimumab, etanercept, and infliximab) using 2 sampling methods (aspiration or ejection). After quiescent incubation, solutions sampled by aspiration exhibited no significant change in micron aggregate concentration in any syringes, whereas those sampled by ejection exhibited increased micron aggregates in both GLS syringe types. Micron aggregate concentration in ejected solutions generally increased with increasing density of adsorbed proteins. Notably, COP syringes contained the lowest micron aggregate concentrations, which were independent of the sampling method. Correspondingly, the adsorbed protein density on COP syringes was the lowest at 1-2 mg/m2, which was much less compared with that on GLS syringes and was calculated to be equivalent to only 1-2 protein layers, as visually confirmed by high-speed atomic force microscopy. These data indicate that low-adsorption prefillable syringes should be used for therapeutic proteins because protein aggregate concentration in the ejected solution is elevated by increased protein adsorption to the syringe surface. PMID- 29421216 TI - The Preparation and Physicochemical Characterization of Aluminum Hydroxide/TLR7a, a Novel Vaccine Adjuvant Comprising a Small Molecule Adsorbed to Aluminum Hydroxide. AB - Adjuvants are necessary to enable vaccine development against a significant number of challenging pathogens for which effective vaccines are not available. We engineered a novel small-molecule immune potentiator, a benzonaphthyridine agonist targeting toll-like receptor 7 (TLR7), as a vaccine adjuvant. TLR7 agonist (TLR7a) was engineered to be adsorbed onto aluminum hydroxide (AlOH), and the resulting AlOH/TLR7a was evaluated as a vaccine adjuvant. AlOH/TLR7a exploits the flexibility of AlOH formulations, has an application in many vaccine candidates, and induced good efficacy and safety profiles against all tested antigens (bacterial- and viral-derived protein antigens, toxoids, glycoconjugates, and so forth) in many animal models, including nonhuman primates. In this article, we describe the outcome of the physicochemical characterization of AlOH/TLR7a. Reverse-phase ultra performance liquid chromatography, confocal microscopy, flow cytometry, zeta potential, and phosphophilicity assays were used as tools to demonstrate the association of TLR7a to AlOH and to characterize this novel formulation. Raman spectroscopy, nuclear magnetic resonance, and mass spectroscopy were also used to investigate the interaction between TLR7a and AlOH (data not shown). This pivotal work paved the way for AlOH/TLR7a to progress into the clinic for evaluation as an adjuvant platform for vaccines against challenging preventable diseases. PMID- 29421217 TI - D-Optimal Design in the Development of Rheologically Improved In Situ Forming Ophthalmic Gel. AB - In situ forming ophthalmic gels need to be fine tuned considering all the biopharmaceutical challenges of the front of the eye in order to increase drug residence time at the application site resulting in its improved bioavailability and efficacy. The aim of this study was to develop in situ forming ophthalmic poloxamer P407/poloxamer P188/chitosan gel fine tuned in terms of polymer content, temperature of gelation, and viscosity. Minimizing the total polymer content while retaining the advantageous rheological properties has been achieved by means of D-optimal statistical design. The optimal in situ forming gel was selected based on minimal polymer content (P407, P188, and chitosan concentration of 14.2%, 1.7%, and 0.25% w/w, respectively), favorable rheological characteristics, and in vitro resistance to tear dilution. The optimal in situ forming gel was proved to be robust against entrapment of active pharmaceutical ingredients making it a suitable platform for ophthalmic delivery of active pharmaceutical ingredients with diverse physicochemical properties. PMID- 29421218 TI - The Safety and Tolerability of Topically Delivered Kynurenic Acid in Humans. A Phase 1 Randomized Double-Blind Clinical Trial. AB - Scarring is a consequence of biological tissue repair following trauma. Currently, there are no generally agreed ways to prevent scarring. Recently, kynurenic acid has shown to be a potent modulator of extracellular matrix deposition and remodeling. Kynurenic acid can reduce matrix deposition and other fundamental characteristics of fibrosis in vitro and in vivo. Specifically, kynurenic acid has shown to increase matrix metalloproteinase-1 activity and subsequently reduce collagen deposition in a rabbit ear scar model. In the present study kynurenic acid cream in different concentrations was topically applied on healthy skin on volunteers to assess skin reactions and skin sensitivity in both acute and chronic application settings. Skin reactions were assessed, and concentrations for kynurenic acid were assessed both form serum and urine. Results showed to acute or delayed skin reactions. Kynurenic acid was not detectable in blood at any time point, and only trace elements of kynurenic acid were found in urine. This study supports safety and tolerability of topically administered FS2 when using a liposomal, compounding base carrier. PMID- 29421220 TI - Structure Determination and Characterization of a Family of Primary Alcohol Solvates. AB - We report the preparation and structural characterization of a family of primary alcohol solvates of a small-molecule hydrochloride salt. The structures of the solvates are probed by powder and single crystal X-ray diffraction, and the compounds were additionally characterized by polarized light microscopy, thermogravimetric analysis, and dynamic scanning calorimetry. A comparison of the lattices of each compound is also provided. The results demonstrate the existence of a common solvating channel and highlight the importance of understanding the form landscape early in the development process. PMID- 29421219 TI - Development of Stabilizing Formulations of a Trivalent Inactivated Poliovirus Vaccine in a Dried State for Delivery in the NanopatchTM Microprojection Array. AB - The worldwide switch to inactivated polio vaccines (IPVs) is a key component of the overall strategy to achieve and maintain global polio eradication. To this end, new IPV vaccine delivery systems may enhance patient convenience and compliance. In this work, we examine NanopatchTM (a solid, polymer microprojection array) which offers potential advantages over standard needle/syringe administration including intradermal delivery and reduced antigen doses. Using trivalent IPV (tIPV) and a purpose-built evaporative dry-down system, candidate tIPV formulations were developed to stabilize tIPV during the drying process and on storage. Identifying conditions to minimize tIPV potency losses during rehydration and potency testing was a critical first step. Various classes and types of pharmaceutical excipients (~50 total) were then evaluated to mitigate potency losses (measured through D-antigen ELISAs for IPV1, IPV2, and IPV3) during drying and storage. Various concentrations and combinations of stabilizing additives were optimized in terms of tIPV potency retention, and 2 candidate tIPV formulations containing cyclodextrin and a reducing agent (e.g., glutathione), maintained >=80% D-antigen potency during drying and subsequent storage for 4 weeks at 4 degrees C, and >=60% potency for 3 weeks at room temperature with the majority of losses occurring within the first day of storage. PMID- 29421221 TI - Folate-Conjugated Superoxide Dismutase Adsorbed Over Antioxidant Mimicking Nanomatrix Frameworks for Treatment of Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease occurring in larger population, characterized by synovial inflammation followed by destruction of joint. Major concerned factor for cause of RA has been related to oxidative stress due to environmental toxicity and immune imbalance. Reactive oxygen species generated from macrophages communes series of oxidation at cellular and genetic level and leads to generation of inflammatory cytokines for provoking inflammation in RA. Superoxide dismutase and catalase are supposed to be potential antioxidant enzymes to scavange free radicals. However, many clinical studies report reduced potency of enzyme due to lack of its targeting efficacy. Therefore, the aim of the work involves development of nanomatrix mimicking as catalase over which folate-linked superoxide dismutase was adsorbed for a macrophage targeting. The developed formulation was optimized, characterized for morphological studies, enzyme loading efficiency, protein activity, and in vitro drug release. Quantification of interleukin 6 was performed by indirect enzyme linked immunosborent assay over macrophage cell lines to determine in vitro treatment efficacy. It is concluded that the prepared system can act as enzyme reservoir to deliver acid labile enzymes in controlled form to efficiently treat RA. PMID- 29421222 TI - Shy herbivores forage more efficiently than bold ones regardless of information processing overload. AB - The neural constraint hypothesis is central to understanding decision-making by foraging herbivorous insects which make decisions less efficiently when they face multiple choices for numerous resource types and/or at high densities instead of a fewer choices. Previous studies have also shown the relationship between personality type and decision-making style. How personality types correlate with foraging efficiency among herbivores is however, largely untested. To answer this question, we used a widespread, polyphagous, floriphilic katydid, Phaneroptera brevis (Orthoptera: Tettigoniidae) and two naturalised, Asteraceae, food plants, Bidens pilosa and Sphagneticola trilobata, as model systems. After we determined each katydid's exploration and boldness levels, we examined its foraging efficiency across different combinations of floral resource choice and density. We showed: (1) For the first time within the Tettigonioidea lineage that this katydid exhibits different personality types in exploration and boldness. (2) Contrary to our prediction, we did not find any support for the neural constraint hypothesis because more floral resource choice at a high density did not reduce foraging efficiency. (3) Surprisingly, bold katydids tend to be less efficient foragers than shy ones. Our findings have enhanced understanding of herbivore behavioural ecology and knowledge to better deal with potential pest herbivores. PMID- 29421223 TI - State-dependent cognition and its relevance to cultural evolution. AB - Individuals cope with their worlds by using information. In humans in particular, an important potential source of information is cultural tradition. Evolutionary models have examined when it is advantageous to use cultural information, and psychological studies have examined the cognitive biases and priorities that may transform cultural traditions over time. However, these studies have not generally incorporated the idea that individuals vary in state. I argue that variation in state is likely to influence the relative payoffs of using cultural information versus gathering personal information; and also that people in different states will have different cognitive biases and priorities, leading them to transform cultural information in different ways. I explore hunger as one example of state variable likely to have consequences for cultural evolution. Variation in state has the potential to explain why cultural traditions and dynamics are so variable between individuals and populations. It offers evolutionarily-grounded links between the ecology in which individuals live, individual-level cognitive processes, and patterns of culture. However, incorporating heterogeneity of state also makes the modelling of cultural evolution more complex, particularly if the distribution of states is itself influenced by the distribution of cultural beliefs and practices. PMID- 29421224 TI - Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: Correlations between clinical, phenotypic, genotypic characteristics and mortality in a tertiary teaching hospital in Malaysia. AB - Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious infection that can result in significant morbidity and mortality. A retrospective cohort study was conducted to determine the predictors of mortality in patient with MRSA bacteremia correlating with clinical, phenotypic and genotypic characteristics of the relevant strains. Most of the bacteremia cases were healthcare-associated (P < 0.0001). Older age (P < 0.0001) and comorbidities (diabetes mellitus, hypertension and chronic kidney disease) were identified as the risk factors for MRSA bacteremia. All the strains were sensitive to vancomycin. Most MRSA strains causing bacteremia belonged to SCCmec type III ST239 and exhibited pulsotype H. According to the multivariate analysis, age >= 60 years old (P = 0.022), female gender (P = 0.0003), pneumonia (P = 0.011) as source of infection as well as high APACHE II, Charlson comorbidity Index and Pitt's bacteremia scores were significantly associated with patient's mortality. There were emergence of MRSA clones such as SCCmec type I-ST152, SCCmec type V ST45 and SCCmec type V-ST951 that was discovered for the first time in Malaysia. To our knowledge, this is the first study correlating the clinical, phenotypic and genotypic characteristics of patients with MRSA bacteremia as well as determining the risk factors for mortality in Malaysian hospital. PMID- 29421225 TI - Molecular survey on the occurrence of arthropod-borne pathogens in wild brown hares (Lepus europaeus) from Central Italy. AB - Data about the spreading of arthropod-borne pathogens among hare populations are very scant, so the aim of the present preliminary study was to investigate, through molecular analysis, the occurrence of Anaplasma phagocytophilum, Bartonella sp., Borrelia burgdorferi sensu lato, Coxiella burnetii, Francisella tularensis, Leishmania spp. and piroplasms DNA in blood of 51 wild hares (Lepus europaeus) living in protected areas in Tuscany. All hares resulted negative for A. phagocytophilum, Bartonella sp., B. burgdorferi s.l., C. burnetii and F. tularensis. Five animals (9.8%) were positive for Leishmania and one hare (1.9%) tested positive for piroplasms. Sequencing of this sample showed a piroplasm similar to one Babesia isolate from the same animal species in Turkey. Therefore, to the best of our knowledge, this is the first molecular report of piroplasms occurring in wild hares from Italy, and the second worldwide. The examined hares appeared to be in good health status, corroborating the hypothesis of a chronic carrier state of some vector borne agents for this animal species. PMID- 29421226 TI - Chronic active EBV infection: the experience of the Samsung Medical Center in South Korea. AB - BACKGROUND: Chronic active EBV infection (CAEBV) of T-cell or NK-cell type is an EBV+ polyclonal, oligoclonal or often monoclonal lymphoproliferative disorder (LPD) recognized as representing the spectrum of EBV-associated T-cell and NK cell LPD with different clinical presentations; one systemic and two cutaneous disorders including hydroa vacciniforme-like T-cell LPD and mosquito bite hypersensitivity. The systemic form of the disease is characterized by fever, persistent hepatitis, hepatosplenomegaly and lymphadenopathy, which shows varying degrees of clinical severity depending on the immune response of the host and the EBV viral load. CASE REPORTS: We described the clinicopathological findings of two children with CAEBV with a brief review of the literature. CONCLUSIONS: Recognition of the disease is important for adequate management of the patient. EBV analysis should be included in the principal diagnostic tests for febrile children. PMID- 29421227 TI - Primary immunodeficiencies and B-cell lymphomas. AB - INTRODUCTION: In primary immunodeficiencies there is a failure in the anti-tumor defense. Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies characterized by an alteration in the differentiation of B lymphocytes (BL). Epstein-Barr virus (EBV) is an ubiquitous virus that selectively infects the BL. In patients with immunodeficiency, uncontrolled proliferation of infected BL and the action of viral proteins promote the development of lymphomas. CLINICAL CASES: At the University Hospital Sant Joan de Deu, Barcelona, 28 patients were diagnosed with CVID from 2000 to 2013. This paper describes four patients who developed non-Hodgkin's lymphoma (NHL). The lymphoma was associated with EBV in two of the cases. Patients were<18 years old, diagnosed with lymphoma between 4 and 13 years old. Two patients were treated with rituximab as monotherapy and achieved complete remission. Two patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and radiotherapy or rituximab and achieved complete remission. CONCLUSIONS: Early detection of EBV infections and NHL in all patients diagnosed with CVID is recommended, regardless of age at diagnosis. PMID- 29421228 TI - Viral etiology in pediatric hematological neoplasms. PMID- 29421229 TI - Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: response to HLH 04 treatment protocol. AB - INTRODUCTION: Hemophagocytic syndrome, macrophage activation syndrome, reactive histiocytosis or hemophagocytic lymphohistiocytosis (HLH) represent a group of diseases whose common thread is reactive or neoplastic mononuclear phagocytic system cells and dendritic cell proliferation. CLINICAL CASE: We present a case of an HLH probably associated with Epstein-Barr virus (EBV) in a 4-year-old male patient treated with HLH-04 protocol. Viral etiology in HLH is well accepted. In this case, clinical picture of HLH was assumed secondary to EBV infection because IgM serology at the time of clinical presentation was the only positive factor in the viral panel. CONCLUSIONS: Diagnosis of HLH is the critical first step to successful treatment. The earlier it is identified, the less the tissue damage and reduced risk of multiple organ failure, which favors treatment response. PMID- 29421230 TI - Recent advances in the risk factors, diagnosis and management of Epstein-Barr virus post-transplant lymphoproliferative disease. AB - Fifty years after the first reports of Epstein-Barr virus (EBV)-associated endemic Burkitt's lymphoma, EBV has emerged as the third most prevalent oncogenic virus worldwide. EBV infection is associated with various malignancies including Hodgkin and non-Hodgkin lymphoma, NK/T-cell lymphoma and nasopharyngeal carcinoma. Despite the highly specific immunologic control in the immunocompetent host, EBV can cause severe complications in the immunocompromised host (namely, post-transplant lymphoproliferative disease). This is particularly a problem in patients with delayed immune reconstitution post-hematopoietic stem cell transplant or solid organ transplant. Despite advances in diagnostic techniques and treatment algorithms allowing earlier identification and treatment of patients at highest risk, mortality rates remain as high as 90% if not treated early. The cornerstones of treatment include reduction in immunosuppression and in vivo B cell depletion with an anti-CD20 monoclonal antibody. However, these treatment modalities are not always feasible due to graft rejection, emergence of graft vs. host disease, and toxicity. Newer treatment modalities include the use of adoptive T cell therapy, which has shown promising results in various EBV related malignancies. In this article we will review recent advances in risk factors, diagnosis and management of EBV-associated malignancies, particularly post-transplant lymphoproliferative disease. We will also discuss new and innovative treatment options including adoptive T cell therapy as well as management of special situations such as chronic active EBV and EBV-associated hemophagocytic lymphohistiocytosis. PMID- 29421232 TI - Epstein-Barr virus infection of infants: implications of early age of infection on viral control and risk for Burkitt lymphoma. AB - Since its first description by Denis Burkitt, endemic Burkitt's lymphoma (BL), the most common childhood cancer in sub-Saharan Africa, has led scientists to search for clues to the origins of this malignancy. The discovery of Epstein-Barr virus (EBV) in BL cells over 50 years ago led to extensive sero-epidemiology studies and revealed that rather than being a virus restricted to areas where BL is endemic, EBV is ubiquitous in the world's population with an estimated greater than 90% of adults worldwide infected. A second pathogen, Plasmodium falciparum (P. falciparum) malaria is also linked to BL. In this review, we will discuss recent studies that indicate a role for P. falciparum malaria in dysregulating EBV infection, and increasing the risk for BL in children living where P. falciparum malaria transmission is high. PMID- 29421231 TI - Correlation between viral load of cytomegalovirus and tacrolimus and sirolimus levels in transplanted pediatric patients. AB - INTRODUCTION: Survival of transplant patients and grafts depends largely on the use of immunosuppressive drugs. However, a balance remains to be established among immunosuppression, transplant rejection and cytomegalovirus (CMV) infection, which results in a high rate of morbidity and mortality. The aim of this study was to define a better strategy for monitoring transplanted patients based on the analysis of the blood concentration of sirolimus and tacrolimus and the burden of CMV. METHODS: Fifty five post-transplant (kidney and liver) pediatric patients, nine treated with sirolimus and 46 treated with tacrolimus, were included. A total of 541 measurements were obtained. In each measurement the concentration of immunosuppressant in whole blood and CMV viral load in plasma and whole blood was quantified by real-time PCR. Pearson correlation coefficient (r) was estimated. RESULTS: Values of r <=0.0747 were found for the relationship between dose and concentration of immunosuppressant; r = 0.9406 for the relationship between viral load in whole blood and plasma, and r <=0.4616 for the relationship between concentration of immunosuppressant and viral load. CONCLUSIONS: These data support that the doses of immunosuppressive drugs do not correlate with the levels of the same in whole blood. Therefore, systemic levels of immunosuppressant should be constantly monitored together with CMV load. Meanwhile, a high correlation between viral load measured in whole blood and plasma was found. PMID- 29421233 TI - Epidemiology of Epstein-Barr virus-associated pediatric lymphomas from Argentina. AB - More than 90% of the population is infected by Epstein-Barr virus (EBV), which has sophisticatedly evolved to survive silently in B cells for the life of infected individuals. However, if the virus-host balance is disturbed, latent EBV infection could be associated with several lymphomas. The age at primary infection varies substantially worldwide, and exposure to EBV is likely to be due to socioeconomic factors. In Argentina, EBV infection is mostly subclinical and 90% of patients are seropositive by the age of 3 years; therefore, its epidemiological characteristics resemble those of an underdeveloped or developing population. EBV-positive Hodgkin lymphoma (HL) in young adults from developed populations has been attributed to delayed primary EBV infection as suggested by the association with recent mononucleosis development. EBV-associated Burkitt lymphoma and Hodgkin lymphoma in children from Argentina display frequencies similar to those observed in developed countries, whereas EBV presence in pediatric diffuse large B-cell lymphoma is slightly increased compared to those populations. However, EBV presence is statistically associated particularly with patients < 10 years of age in all three entities. Therefore, a relationship between low age of EBV seroconversion and B-cell lymphoma development risk could be suggested in children from Argentina. PMID- 29421234 TI - Molecular epidemiology of acute leukemia in children: causal model, interaction of three factors-susceptibility, environmental exposure and vulnerability period. AB - Acute leukemias have a huge morphological, cytogenetic and molecular heterogeneity and genetic polymorphisms associated with susceptibility. Every leukemia presents causal factors associated with the development of the disease. Particularly, when three factors are present, they result in the development of acute leukemia. These phenomena are susceptibility, environmental exposure and a period that, for this model, has been called the period of vulnerability. This framework shows how the concepts of molecular epidemiology have established a reference from which it is more feasible to identify the environmental factors associated with the development of leukemia in children. Subsequently, the arguments show that only susceptible children are likely to develop leukemia once exposed to an environmental factor. For additional exposure, if the child is not susceptible to leukemia, the disease does not develop. In addition, this exposure should occur during a time window when hematopoietic cells and their environment are more vulnerable to such interaction, causing the development of leukemia. This model seeks to predict the time when the leukemia develops and attempts to give a context in which the causality of childhood leukemia should be studied. This information can influence and reduce the risk of a child developing leukemia. PMID- 29421235 TI - Analysis of rat cardiac myocytes and fibroblasts identifies combinatorial enhancer organization and transcription factor families. AB - Cardiac fibroblasts play key roles in both health and disease. Their regulatory elements, transcription factors (TFs), and mechanisms of expression control have not been fully elucidated. We used a differential open chromatin approach, coupled with active enhancer mark, transcriptomic, and computational TFs binding analysis to map cell-type-specific active enhancers in cardiac fibroblasts and cardiomyocytes, and outline the TFs families that control them. This approach was validated by its ability to uncover the known cardiomyocyte TF biology in an unbiased manner, and was then applied to cardiac fibroblasts. We identified Tead, Sox9, Smad, Tcf, Meis, Rbpj, and Runx1 as the main cardiac fibroblasts TF families. Our analysis shows that in both cell types, distal enhancers, containing concentrated combinatorial clusters of multiple tissue expressed TFs recognition motifs, are combinatorically clustered around tissue specific genes. This model for tissue specific gene expression in the heart supports the general "billboard" model for enhancer organization. PMID- 29421236 TI - MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload. AB - Heart failure remains a major public-health problem with an increase in the number of patients worsening from this disease. Despite current medical therapy, the condition still has a poor prognosis. Heart failure is complex but mitochondrial dysfunction seems to be an important target to improve cardiac function directly. Our goal was to analyze the effects of MitoQ (100 uM in drinking water) on the development and progression of heart failure induced by pressure overload after 14 weeks. The main findings are that pressure overload induced heart failure in rats decreased cardiac function in vivo that was not altered by MitoQ. However, we observed a reduction in right ventricular hypertrophy and lung congestion in heart failure animals treated with MitoQ. Heart failure also decreased total mitochondrial protein content, mitochondrial membrane potential in the intermyofibrillar mitochondria. MitoQ restored membrane potential in IFM but did not restore mitochondrial protein content. These alterations are associated with the impairment of basal and stimulated mitochondrial respiration in IFM and SSM induced by heart failure. Moreover, MitoQ restored mitochondrial respiration in heart failure induced by pressure overload. We also detected higher levels of hydrogen peroxide production in heart failure and MitoQ restored the increase in ROS production. MitoQ was also able to improve mitochondrial calcium retention capacity, mainly in the SSM whereas in the IFM we observed a small alteration. In summary, MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload, by decreasing hydrogen peroxide formation, improving mitochondrial respiration and improving mPTP opening. PMID- 29421237 TI - Silencing of long isoforms of nuclear factor erythroid 2 like 1 primes macrophages towards M1 polarization. AB - Macrophages are a major component of the immune system and play an important role in regulating the magnitude, duration, and quality of the inflammatory response. Dissecting the functions of transcription factors regulating macrophage activation is important for understanding the inflammatory responses. Nuclear factor erythroid 2 like 1 (NFE2L1, also known as Nrf1) is a CNC-bZIP protein, which has multiple isoforms. While the exact physiological functions of various isoforms of NFE2L1 are still under investigation, accumulating evidence indicate that long isoforms of NFE2L1 (NFE2L1(L)) are important regulators in the antioxidant response, proteasome homeostasis and inflammation. In this study, we found that NFE2L1(L) was upregulated in response to LPS stimulation in RAW264.7 macrophages. Stable knockdown of Nfe2l1(L) (Nfe2l1(L)-KD) in RAW264.7 cells resulted in increased expression of multiple genes indicative of M1 polarization, including Il6, Il1beta, Cox2, and Ccl2, under both resting and LPS-challenged conditions. In addition, lentiviral shRNA-mediated silencing of NFE2L1(L) in human monocytic SC and THP1 cells also significantly increased mRNA expression of IL6, IL1beta, and TNFalpha. Furthermore, transient silence of NFE2L1(L) in primary human monocytes isolated from peripheral blood by nucleofection with small interfering RNA resulted in increased expression of IL6 and TNFalpha. Analysis of the key transcription factors involved in M1 polarization revealed that Nfe2l1(L)-KD RAW264.7 cells have increased mRNA and protein expression and phosphorylation of STAT1 and STAT3 under both resting and M1 polarized conditions. Activation of the NFkappaB, ERK1/2 and p38 pathways in response to LPS was not affected by the reduction of NFE2L1(L). Moreover, Nfe2l1(L)-KD cells were found to have elevated levels of intracellular ROS, but macrophage M1 polarization induced by Nfe2l1(L) silence was independent of ROS accumulation. Collectively, our results show that knockdown of Nfe2l1(L) leads macrophages to M1 polarization by disinhibition of STAT1/3, and not through the NFkappaB, ERK1/2 and/or p38 signaling pathways. These findings indicate that NFE2L1(L) functions as a negative regulator of M1 polarization and pro-inflammatory response in macrophages. PMID- 29421238 TI - Extracellular redox state shift: A novel approach to target prostate cancer invasion. AB - AIM: Extracellular superoxide dismutase (ECSOD) and the cysteine/glutamate transporter (Cys)/(xCT) are tumor microenvironment (TME) redox state homeostasis regulators. Altered expression of ECSOD and xCT can lead to imbalance of the TME redox state and likely have a profound effect on cancer invasion. In the present study, we investigated whether ECSOD and xCT could be therapeutic targets for prostate cancer (PCa) invasion. RESULTS: Immunohistochemistry of tumor microarray PCa tissues (N = 165) with high Gleason scores indicated that xCT protein expression is significantly increased while ECSOD protein expression is significantly decreased. Metastatic PCa indicated ECSOD protein expression is significantly decreased in epithelial area whereas xCT protein expression is significantly increased in stromal area. Furthermore, inhibition of extracellular O2*- by overexpression of ECSOD or alteration of the extracellular Cys/CySS ratio by knockdown of xCT protein inhibited PCa cell invasion. Simultaneous overexpression of ECSOD and knockdown xCT inhibited PCa cell invasion more than overexpression of ECSOD or knockdown of xCT alone. In the co-culturing system, simultaneous overexpression of ECSOD and knockdown of xCT in prostate stromal WPMY-1 cells inhibited PCa cell invasiveness more than overexpression of ECSOD alone. The decrease in PCa invasion correlated with increased of extracellular H2O2 levels. Notably, overexpression of catalase in TME reversed the inhibitory effect of ECSOD on cancer cell invasion. CONCLUSION: Impaired ECSOD activity and an upregulated of xCT protein expression may be clinical features of an aggressive PCa, particularly metastatic cancers and/or those with a high Gleason score. Therefore, shifting the extracellular redox state toward an oxidizing status by targeted modulation of ECSOD and xCT, in both cancer and stromal cells, may provide a greater strategy for potential therapeutic interventions of aggressive PCa. PMID- 29421239 TI - New neolignans from Selaginella picta and their protective effect on HT-22 cells. AB - Three new compounds, pictalignans A (1), B (2), C (3), along with three known analogues, syringaresinol (4), 3,3',5-trimethoxy-4',7-epoxy-8,5'-neoligan-4',9,9' triol (5), 4,9-dihydroxy-4',7-epoxy-8',9'-dinor-8,5'-neolignan-7'-oic acid (6) were isolated from the 75% aqueous ethanol extract of Selaginella picta. Their structures were established by physicochemical properties and spectroscopic methods, and absolute configurations of new compounds were elucidated by experimental and calculated ECD spectra. Compounds 1-3 are neolignans with additional one or two C6-C3 structural units attached to hydroxypropyl group, which are extremely rare in nature. All new compounds exhibited moderate protective effect against the injury of HT-22 cells induced by L-Glutamate in vitro, and compound 1 showed better protective effect than positive drug with the concentrations of 10 MUM to 15 MUM. PMID- 29421240 TI - Stilbenes with anti-inflammatory and cytotoxic activity from the rhizomes of Bletilla ochracea Schltr. AB - Four new dihydrophenanthrenofuran, bleochranols A-D (1-4), along with 21 known compounds including phenanthrenes (5-14) and bibenzyls (15-25) were isolated and elucidated from the rhizomes of Bletilla ochracea. Combination of 1D/2D NMR techniques and the Electronic Circular Dichroism (ECD) spectroscopy based on the empirical helicity rules, chemical structure of those isolates were determined. All the compounds were evaluated for cytotoxicity against HL-60, SMMC-7721, A 549, MCF-7 and SW480 human cancer cell lines by MTS assay and anti-inflammatory activity by nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages. Among the 25 tested compounds, bleochranol A (1) showed remarkable cytotoxic activity against HL-60, A-549, and MCF-7 with IC50 values of 0.24 +/- 0.03, 3.51 +/- 0.09 and 3.30 +/- 0.99 MUM respectively. The anti-inflammatory assay showed that compound 12 exhibited most potential activity against NO production in RAW 264.7 macrophages with IC50 2.86 +/- 0.17 MUM. The results indicated that the main chemical constituents of B. ochracea were phenanthrene and bibenzyl and similar to that of B. striata. PMID- 29421241 TI - FT-NIR characterization with chemometric analyses to differentiate goldenseal from common adulterants. AB - Goldenseal (Hydrastis canadensis L.) has been a popular herb since the 1970s, with a US market share of over $32 million in 2014. Wild goldenseal has been listed in the Convention on International Trade in Endangered Species for decades. Limits in supply and greed for profit have led to adulteration with similar but more accessible and inexpensive plant materials. Fourier transform near-infrared spectroscopy (FT-NIR) coupled with three different chemometric models, partial least squares (PLS) regression, soft independent modeling of class analogy (SIMCA), and moving window principal component analysis (MW-PCA) provide fast, simple, nondestructive approaches to differentiating pure goldenseal from 4 common pure adulterants (yellow dock, yellow root, coptis, Oregon grape). All three models successfully differentiated authentic goldenseal from adulterants. The models were t-tested for detection of goldenseal intentionally mixed with individual adulterants at 2% to 95% theoretical levels made computationally. The PLS model was unable to detect adulterants mixed with goldenseal at any level. The SIMCA model was the best for detection of yellow root and Oregon grape adulteration in goldenseal, as low as 10%. The MW-PCA model proved best for detection of yellow dock at >= 15% and coptis adulteration >=5% in goldenseal. This study demonstrates that NIR spectroscopy coupled with chemometric analyses is a good tool for industry and investigators to implement for rapid detection of goldenseal adulteration in the marketplace, but also indicates that the specific approach to chemometric analysis must be evaluated and selected on a case-by-case basis in order to achieve useful sensitivity and specificity. PMID- 29421242 TI - Flavonoids from Mirabilis himalaica. AB - Six previously undescribed flavonoids, 2S-5-methoxy-6-methyl-7,2' dihydroxyflavanone, 5,7,2'-trihydroxy-6-methylflavone, 5,7,6'-trihydroxy-6 methylcoumaronochromone, 2,4',6'-trihydroxy-2'-methoxy-3'-methylchalcone, 6R,11 dimethoxy-9-hydroxyrotenoid, and 6R,11-dimethoxy-9-hydroxy-10-methylrotenoid, along with eight known flavonoids, including 2S-5-methoxy-6-methyl-7,4' dihydroxyflavanone, not previously reported as a natural product, and seven rotenoids, boeravinone A, B, D, P, F, coccineone B, and mirabijalone E, were isolated from the ethyl acetate soluble fraction of Mirabilis himalaica roots. Their structures were established by the extensive spectroscopic analysis, including HRESIMS, UV, NMR and ECD. All compounds were evaluated for their cytotoxic activities against three human cancer cell lines: A375 (melanoma), A549 (lung), and PLC (hepatoma). PMID- 29421244 TI - Involvement of NO/NMDA-R pathway in the behavioral despair induced by amphetamine withdrawal. AB - Abrupt discontinuation of chronic amphetamine consumption leads to withdrawal symptoms including depression, anhedonia, dysphoria, fatigue, and anxiety. These irritating symptoms may result in continuing to take the drug or can lead to suicidal behavior. Past studies have shown the involvement of various biologic systems in depression induced following amphetamine withdrawal (AW). However, there is no evidence about the relation between nitric oxide (NO) with NMDA receptors on depression following AW. In this study, we examined the involvement of the NO/NMDA pathways on depressive-like behaviors after 24 h withdrawal following 5 continuous days of amphetamine administration in male NMRI mice. Behavioral tasks used for depression assessment included the forced swimming test (FST), the Splash test and the open field test (OFT). In order to evaluate the role of NO/NMDA pathways animals treated with MK-801 (NMDA-R antagonist), Aminoguanidine (AG), a selective iNOS inhibitor, Nomega-Nitro-l-arginine (L-NNA), a non-selective NOS inhibitor and 7-Nitro indazole (7-NI), a selective nNOS inhibitor. We also measured the level of nitrite in the hippocampus. Our data showed that AW induced the depressive-like effect in the FST and the Splash test. We showed that administration of AG, L-NNA, and MK-801 mitigated AW induced depression, however, 7-NI was failed to decrease depressive-like behaviors. Also, the antidepressant-like effect of co-injection of sub-effective doses of MK-801 with AG suggested that inducible nitric oxide synthase (iNOS) is associated with NMDA-R in AW induced depression. In conclusion, both NO and NMDA-R pathways are involved and related to each other in depression induced following AW. PMID- 29421243 TI - Three new alkaloids from Xylopia vielana and their antiinflammatory activities. AB - Three new aporphine alkaloids, xylopialoids A-C (1-3), along with three known aporphine alkioids (4-6) and three other known compounds (7-9) were isolated from the roots of Xylopia vielana. Among these three new aporphine alkaloids, xylopialoid C (3) showed a special carbamido group directly connected to the nitrogen. The chemical structures of these nine compounds were determined by a combination of 1D and 2D NMR, MS, CD spectrum and Cu Kalpha X-ray crystallographic analyses. All these six alkaloids were firstly tested for the inhibitory activities against the production of NO in RAW264.7 cells stimulated by lipopolysaccharide (LPS). Among these compounds, 4 showed a potential inhibitory activity against the production of nitric oxide with IC50 value of 1.39 MUM. PMID- 29421245 TI - Effect of glucagon-like peptide-1 analogue; Exendin-4, on cognitive functions in type 2 diabetes mellitus; possible modulation of brain derived neurotrophic factor and brain Visfatin. AB - BACKGROUND: Brain derived neurotrophic factor (BDNF) is one of the most essential neurotrophic factors in the brain. BDNF is involved in learning, memory and locomotion suggesting it as a target in type 2 diabetes mellitus (T2DM) associated cognitive changes. Visfatin; an adipokine discovered to be expressed in the brain; was found to have multiple effects including its participation in keeping energy supply to the cell and is consequentially involved in cell survival. Its role in cognitive functions in T2DM was not studied before. Recent studies point to the possible neuro-protective mechanisms of glucagon-like peptide 1 analogue: Exendin-4 (Ex-4) in many cognitive disorders, but whether BDNF or Visfatin are involved or not in its neuro-protective mechanisms; is still unknown. AIMS: to study the changes in cognitive functions in T2DM, either not treated or treated with Glucagon-like peptide 1 (GLP-1) analogue: Ex-4, and to identify the possible underlying mechanisms of these changes and whether BDNF and brain Visfatin are involved. METHODS: A total of 36 adult male wistar albino rats were divided into 4 groups; Control, Exendin-4 control, Diabetic and Exendin-4 treated groups. At the end of the study, Y-maze and open field tests were done the day before scarification to assess spatial working memory and locomotion, respectively. Fasting glucose and insulin, lipid profile and tumor necrosis factor- alpha (TNF-alpha) were measured in the serum. Homeostasis model assessment insulin resistance was calculated. In the brain tissue, malondialdehyde (MDA) level, gene expression and protein levels of BDNF and Visfatin, area of degenerated neurons, area of glial cells and area % of synaptophysin immunoexpression were assessed. RESULTS: Compared with the control, the untreated diabetic rats showed insulin resistance, dyslipidemia and elevation of serum TNF-alpha. The brain tissue showed down-regulation of BDNF gene expression and reduction of its protein level, up-regulation of Visfatin gene expression and elevation of its protein level, increase in MDA, area of degenerated neurons and area of glial cells and reduction in area % of synaptophysin immunoexpression. These changes were paralleled with significant deterioration in spatial working memory and locomotion. Treatment of diabetic rats with Ex-4 reversed all these changes. CONCLUSION: T2DM has a negative impact on cognitive functions through different pathological and subcellular mechanisms. The current study provides evidence for involvement of BDNF and brain Visfatin in T2DM- associated cognitive dysfunction. BDNF and brain Visfatin were also found to contribute to the neuro-protective effect of Ex-4 via modulation of inflammation, oxidative stress, neuro-degeneration and synaptic function. PMID- 29421246 TI - Repeated restraint stress reduces the acquisition and relapse of methamphetamine conditioned place preference but not behavioral sensitization. AB - The studies for the effects of stress on drug addiction were mostly obtained using sequential exposure to stress and drugs. However, few studies have been conducted on the effects of simultaneous exposure to stress and methamphetamine (METH) on METH-induced reward effects and behavioral sensitization. Thus, we examined the effects of simultaneous exposure to restraint stress and METH on METH-induced addictive behaviors using conditioned place preference (CPP) in mice. During the conditioning period, the mice were exposed to 2 h restraint stress before administration of METH or saline for 4 days. To investigate the effect of restraint stress on drug relapse, the mice were exposed to 2 h of restraint stress for 4 days during the late period of withdrawal. The results showed that the acquisition of METH CPP was impaired by simultaneous exposure to restraint stress and METH administration and the impairment of METH CPP was retained until METH-induced reinstatement. Additionally, based on locomotor activity data measured during METH reinstatement, simultaneous stress exposure during the conditioning phase increased METH-induced locomotor sensitization. We also found that the magnitude of METH-primed relapse was reduced in mice exposed to restraint stress during the late period of withdrawal. Taken together, these findings suggest that simultaneous exposure to restraint stress and METH can reduce the acquisition and relapse of METH-induced addictive behaviors but not behavioral sensitization. PMID- 29421247 TI - "It Encourages Them to Complain": A Qualitative Study of the Unintended Consequences of Assessing Patient-Reported Pain. AB - : The "Pain as the 5th Vital Sign" initiative intended to address undertreatment of pain by encouraging routine pain assessment and management. In the Veterans Health Administration, routine pain screening has been practiced in primary care for more than a decade, but has not improved the quality of pain management measured using several process indicators, and some have expressed concerns of potentially fostering undesirable use of prescription opioids. We sought to evaluate the consequences of routine pain screening on clinical practice. We conducted 9 interdisciplinary focus groups with 60 primary care providers and staff from 5 outpatient Veterans Health Administration clinics. We identified 5 themes reflecting 1 intended and 4 unintended consequences of routine pain screening: it 1) facilitates identification of patients with pain who might otherwise be overlooked, 2) may need to be targeted toward specific patients and contexts rather than universally applied, 3) often shifts visit focus away from more emergent concerns, 4) may encourage "false positives" and prompt providers to intervene when treatment is not a priority, and 5) engenders a "pain problem" and hinders patients from considering alternative strategies. These findings suggest changes to support patient-centered pain assessment and improve targeted screening and interventions for population pain management. PERSPECTIVE: This article describes some of the potential unintended consequences of implementing routine pain screening in primary care. This information may help clinicians be more strategic in their consideration and use of pain screening among their patients. PMID- 29421248 TI - Visuospatial Aptitude Testing Differentially Predicts Simulated Surgical Skill. AB - OBJECTIVE: To determine whether visuospatial perception (VSP) testing is correlated to simulated or intraoperative surgical performance as rated by the American College of Graduate Medical Education (ACGME) milestones. DESIGN: (Canadian Task Force classification II-2). SETTING: Two academic training institutions. PARTICIPANTS: Forty-one residents, including 19 from Brigham and Women's Hospital and 22 from the Mayo Clinic, from 3 different specialties: obstetrics and gynecology, general surgery, and urology. INTERVENTION: Participants underwent 3 different tests: visuospatial perception testing (VSP), Fundamentals of Laparoscopic Surgery (FLS) peg transfer, and da Vinci robotic simulation peg transfer. Surgical grading from the ACGME milestones tool was obtained for each participant. Demographic and background information was also collected, including specialty, year of training, previous experience with simulated skills, and surgical interest. Standard statistical analyses were performed using Student's t test, and correlations were determined using adjusted linear regression models. MEASUREMENTS AND MAIN RESULTS: In univariate analysis, Brigham and Women's Hospital and Mayo Clinic training programs differed in times and overall scores for both the FLS peg transfer and da Vinci robotic simulation peg transfer tests (p < .05 for all). In addition, type of residency training affected time and overall score on the robotic peg transfer test. Familiarity with tasks correlated with higher score and faster task completion (p = .05 for all except VSP score). There were no differences in VSP scores by program, specialty, or year of training. In adjusted linear regression modeling, VSP testing was correlated only to robotic peg transfer skills (average time, p = .006; overall score, p = .001). Milestones did not correlate to either VSP or surgical simulation testing. CONCLUSION: VSP score was correlated with robotic simulation skills, but not with FLS skills or ACGME milestones. This suggests that the ability of VSP score to predict competence differs between tasks. Therefore, further investigation of aptitude testing is needed, especially before its integration as an entry examination into a surgical subspecialty. PMID- 29421249 TI - What is the Best Surgeon's Knot? Evaluation of the Security of the Different Laparoscopic Knot Combinations. AB - STUDY OBJECTIVE: To investigate the security of various knot combinations in laparoscopic surgery. DESIGN: Prospective nonrandomized trial (Canadian Task Force classification II). SETTING: Storz Training Centre, Sao Paulo, Brazil. INTERVENTION: Different knot combinations (n = 2000) were performed in a laparoscopic trainer. Dry or wet 2.0 polyglycolic acid or dry 2-0 poliglecaprone 25 was used. The tails were cut at 10 mm, and the loops were tested in a dynamometer. The primary endpoints were the forces at which the knot combination opened or at which the suture broke. Resulting tail lengths were measured. MEASUREMENTS AND MAIN RESULTS: Surprisingly, the combination of a 2-throw half knot (H2) and a symmetric 1-throw half knot (H1s) (a surgical flat knot) opened at <1 Newton (N) in 2.5% of tests and at <10 N in 5% of tests. This occasional opening at low forces persisted after 1 or 2 additional H1s knots. A sequence of an H2 or a 3-throw half knot (H3) followed by a H2, either symmetric or asymmetric (H2H2 or H3H2), resulted in 100% secure knots that never opened at forces below 30 N. Other safe combinations were H2H1s followed by 2 blocking half hitches, and a sequence of 5 half hitches with 3 blocking sequences. CONCLUSION: A traditional surgical knot (H2H1s) occasionally opens with little force and thus is potentially dangerous. Safe knots are H2H2 and H3H2 combinations, a sequence of 5 half hitches with 3 blocking sequences, and H2H1s together with 2 blocking half hitches. PMID- 29421250 TI - [Benefits of newborn feeding with the initiation formula: On-demand vs. gastric capacity]. PMID- 29421251 TI - [Dengue in Mexico: Increase in the juvenile population during the last decade]. AB - Dengue is one of the principal vector-transmitted diseases leading to important public health problems in Mexico and Latin America. On the American continent this disease has been reported mostly in adults, which contrasts with Asian countries where pediatric dengue is more prominent. During the last decade a shift towards pediatric dengue has been reported in various countries of the American continent. This review, elaborated from data published by the Mexican Ministry of Health, focuses on dengue in Mexico during the last three decades, showing that during the last decade dengue fever and dengue hemorrhagic fever has begun to shift towards a juvenile and pediatric population. PMID- 29421252 TI - How much does your baby cry? Expectations, patterns and perceptions of infant crying in Mexico. AB - BACKGROUND: A limited number of studies have examined infant crying patterns in less affluent societies, but none of them have been longitudinal in nature. The aim of this study was to describe reported infant crying patterns in a cohort of Mexican infants and examine how these are associated with crying-related maternal expectations, general perceptions and help-seeking behavior. METHODS: Observational cohort study, 204 primiparous mothers and their infants, recruited at birth and visited in their homes at nine different time points from 1 to 24 weeks of infant age. RESULTS: Mothers reported that their infants cried less than infants in other more affluent societies, although not less frequently. A previously reported evening clustering of crying was present, with a subtle 24-h crying peak emerging around 2 to 4 weeks. Having an expectation of an infant who will be difficult to soothe and/or an increased report of crying frequency were associated with perceptions of maternal anguish, which was associated with maternal concern and help-seeking behaviors related to crying. CONCLUSIONS: Similarities and differences were found in the crying patterns reported by mothers of Mexican infants and others previously studied. Expectations and reports of crying behavior were associated with maternal perceptions, which may have a role in reducing crying-related anguish and demand on health services. PMID- 29421253 TI - [On demand infant formula vs. gastric capacity during the neonatal transition period]. AB - BACKGROUND: Newborn formula feeding can be given ad libitum (AL) or as calculated gastric capacity (CGC). The objective of the study was to determine if the technique used to offer the newborn formula (AL vs. CGC) modifies volume intake, tolerance and risk for hypoglycemia. METHODS: The study design was an open, nonrandomized clinical trial. Patients were healthy term newborns. All newborns were followed for 24h. We determined the total volume ingested (ml/kg), oral tolerance (vomiting, regurgitation, abdominal circumference), impact on weight and hypoglycemic events. RESULTS: One hundred fifty four infants were included (CGC=90 and AL=64). The AL group consumed slightly more formula (8ml/kg, 95% CI 5 11) with greater variation between intakes. There was no difference in the percentage of weight loss (2.1% vs. 2%, P=0.78). AL group also showed more vomiting (17.2% vs. 6.7%, P=0.02) and increased abdominal distension (43.8% vs. 22.2%, P=0.007). Only one newborn in the CGC group had hypoglycemia (P=1.00). CONCLUSIONS: CGC feedings allows constant intake with less risk for intolerance without increasing the possibility of hypoglycemia or weight loss. PMID- 29421254 TI - [Clinical profile of a cohort of Silver-Russell syndrome patients followed at the Hospital Infantil de Mexico Federico Gomez from 1998 to 2012]. AB - BACKGROUND: Patients with Silver-Russell syndrome suffer from severe intrauterine and postnatal growth retardation, relative macrocephaly and body asymmetry, among other characteristics. It is caused by several genetic and epigenetic mechanisms in 11p15.5 in 40% of the cases and maternal uniparental disomy of chromosome 7 in 10%. METHODS: Twenty patients with a diagnosis of Silver-Russell syndrome who were seen at the HIMFG from 1998 to 2012, were evaluated according to international clinical criteria confirming the diagnosis in nine of the subjects. RESULTS: All patients showed intrauterine and postnatal growth retardation and short stature, both considered as major criteria of Silver-Russell syndrome. Relative macrocephaly was present in 78% of the patients and asymmetry in 33%. Other characteristics such as renal tubular acidosis were present > 50% of the cases. CONCLUSIONS: The clinical diagnosis of Silver-Russell syndrome is complex. Short stature is the main reason for seeking medical attention and is helpful in the identification of a differential diagnosis. This situation underlines the importance of growth and development evaluation of all patients and particularly in those with short stature to identify those cases that may require molecular studies, with implications in management, prognosis and genetic counseling. PMID- 29421255 TI - [Use of the evidence-based guidelines for management of bronchiolitis]. AB - INTRODUCTION: The aim of this study was to analyze the medical care of children<5 years of age with acute bronchiolitis in relation to the most relevant practices of evidence-based guidelines for bronchiolitis. METHODS: We reviewed the charts of 197 hospitalized infants with acute bronchiolitis during 2012 to 2013 to analyse whether the guideline recommendations were used according to: American Academic of Pediatritians (AAP), Scotish Intercollegiate Guidelines Network (SIGN), Sector Salud Mexico (SS), and Guia Practica Clinica Bronquiolitis, Espana (GPCBA). RESULTS: We evaluated 197 patients attended by 49 pediatricians. Of the recommended actions, in 110 patients (55.8%) aspirate secretions were indicated, 105 patients (53%) received supplemental oxygen and 63 patients (31.9%) used inhaled hypertonic solution. Non-recommended actions were carried out in 166 patients (84%) who received inhaled bronchodilators, 143 patients (72%) who inhaled steroids, 110 patients (55.8%) who were prescribed antibiotics, 76 patients (38%) who had nebulization and 52 patients (26.3%) were administered systemic steroids. Physicians with<10 years of expertise prescribed more systemic steroids. CONCLUSIONS: Despite the dissemination of good clinical practice guidelines for the management of acute bronchiolitis, its adoption has not been totally completed. PMID- 29421256 TI - [Airway obstruction due to cystic hygroma in a newborn]. AB - BACKGROUND: Cystic hygroma is a diffuse dilatation of the lymphatic system, which can be prenatally diagnosed by ultrasound. The incidence is 1/6,000 live births and 1/750 spontaneous abortions. This malformation can occur at the cervical level located in the inferior lateral part of the neck where it appears with large single or multilocular cavities. It is generally caused by a lack of connection with jugular lymphatic channels or with the venous drainage system lymph sacs. CASE REPORT: In order to emphasize these diseases and non-surgical treatment options, we present a patient with a cervical cystic hygroma that compromises the airway and digestive tract due to tumor extension and treatment with pure ethanol with clinical improvement. CONCLUSIONS: Depending on the characteristics of the lesion, treatment options are surgery, pharmacological or mixed. When the extension involves vital organs, the best option is to reduce the size of the lesion and the compromise of the adjacent organ. This is done by sclerotherapy and, if necessary, surgery. PMID- 29421257 TI - [Eleven-year-old male patient with jaundice, drowsiness and vomiting]. PMID- 29421258 TI - [Adverse effects of marijuana in children: Could its knowledge limit the legalization of drugs in Mexico?] AB - A reflection on whether to expose, determine and clarify the effects of marijuana on pregnant adolescents and their fetus is a determining factor to consider more judiciously the tendency to legalize marijuana in Mexico. We emphasize alterations in the central nervous system, immune system and some genetic aspects of the fetus and its potential expressions at different stages of a child's life. Should pediatricians and parents allow, in addition to the difficulties that their patients and children face today, the risk that is the affordability of marijuana? That is the challenge to overcome. PMID- 29421259 TI - [Scientific reductionism and social control of mind. Part I]. AB - The first part of this essay starts from the conventional premise of reductionism, which states 'the whole is nothing more than the sum of its parts'. According to scientific reductionism (SR), knowledge of the complex can only be achieved through simpler components, which means complex systems are explained by reduction to its most basic parts. Three kinds of SR are defined: ontological, theoretical and methodological. SR origins dwell within the efforts made by early humans to understand natural phenomena and its importance to survival. According to E. Morin, the reason behind SR being the favorite approach in science comes from the dysjunction, reduction, simplification and exclusion paradigm. The holistic approach as opposed to SR studies vital phenomena from the idea of complexity. From this perspective, not only does SR have almost no relevance in the solution of humanity's greatest problems like society inequality, human dignity and environmental degradation, it also contributes to maintain the statu quo. PMID- 29421264 TI - Global collective motions in the mammalian and bacterial respiratory complex I. AB - The respiratory complex I is an enzyme responsible for the conversion of chemical energy into an electrochemical proton motive force across the membrane. Despite extensive studies, the mechanism by which the activity of this enormous, ca. 1 MDa, redox-coupled proton pump is regulated still remains unclear. Recent structural studies (Zhu et al., Nature 2016; Fiedorczuk et al., Nature 2016) resolved complex I in different conformations connected to the active-to-deactive (A/D) transition that regulate complex I activity in several species. Based on anisotropic network models (ANM) and principal component analysis (PCA), we identify here transitions between experimentally resolved structures of the mammalian complex I as low-frequency collective motions of the enzyme, highlighting similarities and differences between the bacterial and mammalian enzymes. Despite the reduced complexity of the smaller bacterial enzyme, our results suggest that the global dynamics of complex I is overall conserved. We further probe how the supernumerary subunits could be involved in the modulation of the A/D-transition, and show that in particular the 42 kDa and B13 subunits affect the global motions of the mammalian enzyme. PMID- 29421265 TI - The tail of the ventral tegmental area in behavioral processes and in the effect of psychostimulants and drugs of abuse. AB - The tail of the ventral tegmental area (tVTA) is a recently identified structure that exerts a major inhibitory drive onto midbrain dopamine (DA) neurons. Also referred to as the rostromedial tegmental nucleus (RMTg), the tVTA is a cluster of gamma-aminobutyric acid (GABA)ergic neurons that starts within the posterior end of the VTA, where it is restricted dorsolateral to the caudal part of the interpeduncular nucleus, and extends into the pons. First identified in the rat, the tVTA has been described in many species, including mice and monkeys, as a region exhibiting similar anatomical and behavioral properties; it receives strong excitatory inputs from the lateral habenula (LHb), conveys negative reward related information, and inhibits midbrain DA neuron activity. As an important inhibitory afferent to midbrain DA neurons, the tVTA is also implicated in drug abuse and in the complex interplay between reward and aversion processes. The overarching goal of this review is to provide the current state of knowledge on the anatomy and connectivity of the tVTA and to discuss recent evidence implicating this structure in reward-related processes and in the effect of psychostimulants and drugs of abuse. PMID- 29421266 TI - Neural correlates of working memory in first episode and recurrent depression: An fMRI study. AB - BACKGROUND: Patients suffering from major depressive disorder (MDD) show deficits in working memory (WM) performance accompanied by bilateral fronto-parietal BOLD signal changes. It is unclear whether patients with a first depressive episode (FDE) exhibit the same signal changes as patients with recurrent depressive episodes (RDE). METHODS: We investigated seventy-four MDD inpatients (48 RDE, 26 FDE) and 74 healthy control (HC) subjects performing an n-back WM task (0-back, 2 back, 3-back condition) in a 3T-fMRI. RESULTS: FMRI analyses revealed deviating BOLD signal in MDD in the thalamus (0-back vs. 2-back), the angular gyrus (0-back vs. 3-back), and the superior frontal gyrus (2-back vs. 3-back). Further effects were observed between RDE vs. FDE. Thus, RDE displayed differing neural activation in the middle frontal gyrus (2-back vs. 3-back), the inferior frontal gyrus, and the precentral gyrus (0-back vs. 2-back). In addition, both HC and FDE indicated a linear activation trend depending on task complexity. CONCLUSIONS: Although we failed to find behavioral differences between the groups, results suggest differing BOLD signal in fronto-parietal brain regions in MDD vs. HC, and in RDE vs. FDE. Moreover, both HC and FDE show similar trends in activation shapes. This indicates a link between levels of complexity-dependent activation in fronto-parietal brain regions and the stage of MDD. We therefore assume that load-dependent BOLD signal during WM is impaired in MDD, and that it is particularly affected in RDE. We also suspect neurobiological compensatory mechanisms of the reported brain regions in (working) memory functioning. PMID- 29421267 TI - Pre-articulatory electrical activity associated with correct naming in individuals with aphasia. AB - Picture naming is a language task that involves multiple neural networks and is used to probe aphasia-induced language deficits. The pattern of neural activation seen in healthy individuals during picture naming is disrupted in individuals with aphasia, but the time-course of the disruption remains unclear. Specifically, it remains unclear which anatomical and temporal aspects of neural processing are necessary for correct naming. Here, we tested two individuals with stroke induced aphasia, and compared the differences in the event-related potentials (ERPs) and current sources when they made correct vs. erroneous responses during picture naming. The pre-articulatory ERP activity was significantly different between the two responses. Current source analysis revealed that the ability to recruit left temporal and frontal areas within a 300 550 ms time window after stimulus onset contributed to correct responses. These results suggest that targeted neuromodulation in these areas could lead to better treatment outcomes in patients with aphasia. PMID- 29421268 TI - High prevalence of pineal cysts in adults who stutter. PMID- 29421270 TI - Atypical temporal activation pattern and central-right brain compensation during semantic judgment task in children with early left brain damage. AB - In this study we investigated the event-related potentials (ERPs) during the semantic judgment task (deciding if the two Chinese characters were semantically related or unrelated) to identify the timing of neural activation in children with early left brain damage (ELBD). The results demonstrated that compared with the controls, children with ELBD had (1) competitive accuracy and reaction time in the semantic judgment task, (2) weak operation of the N400, (3) stronger, earlier and later compensational positivities (referred to the enhanced P200, P250, and P600 amplitudes) in the central and right region of the brain to successfully engage in semantic judgment. Our preliminary findings indicate that temporally postlesional reorganization is in accordance with the proposed right hemispheric organization of speech after early left-sided brain lesion. During semantic processing, the orthography has a greater effect on the children with ELBD, and a later semantic reanalysis (P600) is required due to the less efficient N400 at the former stage for semantic integration. PMID- 29421269 TI - Context-dependent lexical ambiguity resolution: MEG evidence for the time-course of activity in left inferior frontal gyrus and posterior middle temporal gyrus. AB - An MEG study investigated the role of context in semantic interpretation by examining the comprehension of ambiguous words in contexts leading to different interpretations. We compared high-ambiguity words in minimally different contexts (to bowl, the bowl) to low-ambiguity counterparts (the tray, to flog). Whole brain beamforming revealed the engagement of left inferior frontal gyrus (LIFG) and posterior middle temporal gyrus (LPMTG). Points of interest analyses showed that both these sites showed a stronger response to verb-contexts by 200 ms post stimulus and displayed overlapping ambiguity effects that were sustained from 300 ms onwards. The effect of context was stronger for high-ambiguity words than for low-ambiguity words at several different time points, including within the first 100 ms post-stimulus. Unlike LIFG, LPMTG also showed stronger responses to verb than noun contexts in low-ambiguity trials. We argue that different functional roles previously attributed to LIFG and LPMTG are in fact played out at different periods during processing. PMID- 29421271 TI - Event-related desynchronization of mu and beta oscillations during the processing of novel tool names. AB - According to the embodied cognition framework, the formation of conceptual representations integrates the type of experience during learning. In this electroencephalographic study, we applied a linguistic variant of a training paradigm, in which participants learned to associate novel names to novel tools while either manipulating or visually exploring them. The analysis focused on event-related desynchronization (ERD) of oscillations in the mu and beta frequency range, which reflects activation of sensorimotor brain areas. After three training sessions, processing names of manipulated tools elicited a stronger ERD of the beta (18-25 Hz, 140-260 ms) and the lower mu rhythm (8-10 Hz, 320-440 ms) than processing names of visually explored tools, reflecting a possible reactivation of experiential sensorimotor information. Given the unexpected result that familiarized pseudo-words elicited an ERD comparable to names of manipulated tools, our findings could reflect a suppression of sensorimotor activity during the processing of objects with exclusively visual features. PMID- 29421272 TI - Native language status of the listener modulates the neural integration of speech and iconic gestures in clear and adverse listening conditions. AB - Native listeners neurally integrate iconic gestures with speech, which can enhance degraded speech comprehension. However, it is unknown how non-native listeners neurally integrate speech and gestures, as they might process visual semantic context differently than natives. We recorded EEG while native and highly-proficient non-native listeners watched videos of an actress uttering an action verb in clear or degraded speech, accompanied by a matching ('to drive'+driving gesture) or mismatching gesture ('to drink'+mixing gesture). Degraded speech elicited an enhanced N400 amplitude compared to clear speech in both groups, revealing an increase in neural resources needed to resolve the spoken input. A larger N400 effect was found in clear speech for non-natives compared to natives, but in degraded speech only for natives. Non-native listeners might thus process gesture more strongly than natives when speech is clear, but need more auditory cues to facilitate access to gestural semantic information when speech is degraded. PMID- 29421273 TI - Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion. PMID- 29421275 TI - Reprograming immunity to food allergens. PMID- 29421276 TI - SCCA2 is a reliable biomarker for evaluating pediatric atopic dermatitis. PMID- 29421274 TI - Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation. AB - BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, infections, and susceptibility to autoimmunity and malignancies. Thrombocytopenia is a constant finding, but its pathogenesis remains elusive. OBJECTIVE: To dissect the basis of the WAS platelet defect, we used a novel conditional mouse model (CoWas) lacking Wiskott-Aldrich syndrome protein (WASp) only in the megakaryocytic lineage in the presence of a normal immunologic environment, and in parallel we analyzed samples obtained from patients with WAS. METHODS: Phenotypic and functional characterization of megakaryocytes and platelets in mutant CoWas mice and patients with WAS with and without autoantibodies was performed. Platelet antigen expression was examined through a protein expression profile and cluster proteomic interaction network. Platelet immunogenicity was tested by using ELISAs and B-cell and platelet cocultures. RESULTS: CoWas mice showed increased megakaryocyte numbers and normal thrombopoiesis in vitro, but WASp-deficient platelets had short lifespan and high expression of activation markers. Proteomic analysis identified signatures compatible with defects in cytoskeletal reorganization and metabolism yet surprisingly increased antigen-processing capabilities. In addition, WASp deficient platelets expressed high levels of surface and soluble CD40 ligand and were capable of inducing B-cell activation in vitro. WASp-deficient platelets were highly immunostimulatory in mice and triggered the generation of antibodies specific for WASp-deficient platelets, even in the context of a normal immune system. Patients with WAS also showed platelet hyperactivation and increased plasma soluble CD40 ligand levels correlating with the presence of autoantibodies. CONCLUSION: Overall, these findings suggest that intrinsic defects in WASp-deficient platelets decrease their lifespan and dysregulate immune responses, corroborating the role of platelets as modulators of inflammation and immunity. PMID- 29421277 TI - Epidermal lipid composition, barrier integrity, and eczematous inflammation are associated with skin microbiome configuration. AB - BACKGROUND: Genomic approaches have revealed characteristic site specificities of skin bacterial community structures. In addition, in children with atopic dermatitis (AD), characteristic shifts were described at creases and, in particular, during flares, which have been postulated to mirror disturbed skin barrier function, cutaneous inflammation, or both. OBJECTIVE: We sought to comprehensively analyze microbial configurations in patients with AD across body sites and to explore the effect of distinct abnormalities of epidermal barrier function. METHODS: The skin microbiome was determined by using bacterial 16S rRNA sequencing at 4 nonlesional body sites, as well as acute and chronic lesions of 10 patients with AD and 10 healthy control subjects matched for age, sex, and filaggrin (FLG) mutation status. Nonlesional sampling sites were characterized for skin physiology parameters, including chromatography-based lipid profiling. RESULTS: Epidermal lipid composition, in particular levels of long-chain unsaturated free fatty acids, strongly correlated with bacterial composition, in particular Propionibacteria and Corynebacteria abundance. AD displayed a distinct community structure, with increased abundance and altered composition of staphylococcal species across body sites, the strongest loss of diversity and increase in Staphylococcus aureus seen on chronic lesions, and a progressive shift from nonlesional skin to acute and chronic lesions. FLG-deficient skin showed a distinct microbiome composition resembling in part the AD-related pattern. CONCLUSION: Epidermal barrier integrity and function affect the skin microbiome composition. AD shows an altered microbial configuration across diverse body sites, which is most pronounced at sites of predilection and AD. Eczematous affection appears to be a more important determinant than body site. PMID- 29421278 TI - Perspectives in cancer: molecular findings, computational-designed drugs, and patient care. PMID- 29421279 TI - Why computational methods for the study of biological macromolecules and their effectors? PMID- 29421280 TI - Is there something else besides the proapoptotic AVPI-segment in the Smac/DIABLO protein? AB - In mammals, apoptosis is the main mechanism to eliminate unwanted cells, securing tissue homeostasis and consequently maintaining the health in the organism. Classically, apoptosis culminates with the activation of caspases, which are enzymes that display cysteine protease activity to degrade specific substrates implied in essential cellular processes. This process is highly regulated. A key regulation mechanism is mediated by the Inhibitor of Apoptosis Proteins (IAPs) family members, which inhibit the activated forms of caspases through physical interaction with them. Smac/DIABLO, a mitochondrial protein that is translocated to the cytoplasm in apoptotic conditions, derepresses the IAP-mediated caspase inhibition through physical interaction with IAPs. The first four amino acids (AVPI) of Smac/DIABLO mediate the interaction with IAPs and subsequent apoptosis induction. This interaction has lead to the creation of small molecules mimicking the AVPI segment for potential anticancer therapy. Nevertheless, several studies have pointed out the existence of AVPI-independent functions of Smac/DIABLO. The aim of this review was to provide a landscape of these underestimated AVPI independent biological functions that have been observed using different approaches, such as the study of endogenous splice variant isoforms and truncated and mutated artificial proteins. PMID- 29421281 TI - Antibody-mediated targeting of the transferrin receptor in cancer cells. AB - Iron is essential for cell growth and is imported into cells in part through the action of transferrin (Tf), a protein that binds its receptor (TfR1 or CD71) on the surface of a cell, and then releases iron into endosomes. TfR1 is a single pass type-II transmembrane protein expressed at basal levels in most tissues. High expression of TfR1 is typically associated with rapidly proliferating cells, including various types of cancer. TfR1 is targeted by experimental therapeutics for several reasons: its cell surface accessibility, constitutive endocytosis into cells, essential role in cell growth and proliferation, and its overexpression by cancer cells. Among the therapeutic agents used to target TfR1, antibodies stand out due to their remarkable specificity and affinity. Clinical trials are being conducted to evaluate the safety and efficacy of agents targeting TfR1 in cancer patients with promising results. These observations suggest that therapies targeting TfR1 as direct therapeutics or delivery conduits remain an attractive alternative for the treatment of cancers that overexpress the receptor. PMID- 29421282 TI - Participation of mesenchymal stem cells in the regulation of immune response and cancer development. AB - The relevance of the microenvironment in the initiation, promotion, and progression of cancer has been postulated. Mesenchymal stem cells (MSCs) have been identified as important components of the tumor stroma, which are capable of affecting the development of cancer through various mechanisms. In particular, MSCs immunosuppressive properties play an important role. It has been shown that bone marrow-derived and other healthy tissues-derived MSCs are capable of regulating the immune response by affecting the activation, maturation, proliferation, differentiation, and effector function of cells of the immune system, such as neutrophils, macrophages, dendritic cells, natural killer cells (NK) and T-lymphocytes. Similar mechanisms have been identified in MSCs associated with different types of tumors, where they generate an immunosuppressive microenvironment by decreasing the cytotoxic activity of T lymphocytes and NK cells, skew macrophage differentiation towards an M2 phenotype, and decrease the secretion of Th1-type cytokines. Also, the cytokines, chemokines, and factors secreted by the transformed cells or other cells from the tumor stroma are capable of modulating the functions of MSCs. PMID- 29421283 TI - Bactofection of sequences encoding a Bax protein peptide chemosensitizes prostate cancer tumor cells. AB - BACKGROUND: Tumor cell resistance to chemotherapy agents is one of the main problems in the eradication of different neoplasias. One of the mechanisms of this process is the overexpression of anti-apoptotic proteins such as Bcl-2 and Bcl-XL; blocking the activity of these proteins may contribute to the sensitization of tumor cells and allow the adequate effects of chemotherapeutic drugs. METHODS AND RESULTS: This study adressed the transfection of prostate cancer cells (PC3) with a plasmid encoding a recombinant protein with an antagonist peptide from the BH3 region of the Bax protein fused to the GFP reporter protein (BaxGFP). This protein induced apoptosis of these tumor cells; further, selective transport of this plasmid to the tumor cell with Salmonella enterica serovar Typhimurium (strain SL3261), a live-attenuated bacterial vector, can induce sensitization of the tumor cell to the action of drugs such as cisplatin, through a process known as bactofection. CONCLUSIONS: These results suggest that Salmonella enterica can be used as a carrier vector of nucleotide sequences encoding heterologous molecules used in antitumor therapy. PMID- 29421284 TI - Evaluation of the TRPM2 channel as a biomarker in breast cancer using public databases analysis. AB - BACKGROUND: Breast cancer is one of the most common malignancies affecting women. Recent investigations have revealed a major role of ion channels in cancer. The transient receptor potential melastatin-2 (TRPM2) is a plasma membrane and lysosomal channel with important roles in cell migration and cell death in immune cells and tumor cells. METHODS: In this study, we investigated the prognostic value of TRPM2 channel in breast cancer, analyzing public databases compiled in OncomineTM (Thermo Fisher, Ann Arbor, MI) and online Kaplan-Meier Plotter platforms. RESULTS: The results revealed that TRPM2 mRNA overexpression is significant in situ and invasive breast carcinoma compared to normal breast tissue. Furthermore, multi-gene validation using OncomineTM showed that this channel is coexpressed with proteins related to cellular migration, transformation, and apoptosis. On the other hand, Kaplan-Meier analysis exhibited that low expression of TRPM2 could be used to predict poor outcome in ER- and HER2+ breast carcinoma patients. CONCLUSIONS: TRPM2 is a promising biomarker for aggressiveness of breast cancer, and a potential target for the development of new therapies. PMID- 29421285 TI - Alveolar rhabdomyosarcoma: origin and prognostic implications of molecular findings. AB - We present the case of a 2-year-old male patient with a facial tumor partially treated with chemotherapy before his admission to our institution. The tumor involved from the frontal region to the maxillary floor, the orbit, and the maxillary and sphenoid sinuses. The histopathological diagnosis revealed a stage IV alveolar rhabdomyosarcoma with infiltration to bone marrow and cerebrospinal fluid. He was managed with four cycles of adriamycin, actinomycin, cyclophosphamide and vincristine; cisplatin and irinotecan were added to the last cycle. The tumor had a 50% size reduction, but the patient died after a neutropenia and fever episode. The aggressive behavior of alveolar rhabdomyosarcoma has been associated with the expression of oncogenic fusion proteins resulting from chromosomal translocations, particularly t(2;13) (q35;q14) PAX3/FOXO1, and t(1;13) (p36;q14) PAX7/FOXO1 which were present in this patient. PMID- 29421286 TI - Application of computational methods for anticancer drug discovery, design, and optimization. AB - Developing a novel drug is a complex, risky, expensive and time-consuming venture. It is estimated that the conventional drug discovery process ending with a new medicine ready for the market can take up to 15 years and more than a billion USD. Fortunately, this scenario has recently changed with the arrival of new approaches. Many novel technologies and methodologies have been developed to increase the efficiency of the drug discovery process, and computational methodologies have become a crucial component of many drug discovery programs. From hit identification to lead optimization, techniques such as ligand- or structure-based virtual screening are widely used in many discovery efforts. It is the case for designing potential anticancer drugs and drug candidates, where these computational approaches have had a major impact over the years and have provided fruitful insights into the field of cancer. In this paper, we review the concept of rational design presenting some of the most representative examples of molecules identified by means of it. Key principles are illustrated through case studies including specifically successful achievements in the field of anticancer drug design to demonstrate that research advances, with the aid of in silico drug design, have the potential to create novel anticancer drugs. PMID- 29421287 TI - New perspectives on the computational characterization of the kinetics of binding unbinding in drug design: implications for novel therapies. AB - The efficiency and the propensity of a drug to be bound to its target protein have been inseparable concepts for decades now. The correlation between the pharmacological activity and the binding affinity has been the first rule to design and optimize a new drug rationally. However, this argument does not prove to be infallible when the results of in vivo assays have to be confronted. Only recently, we understand that other magnitudes as the kinetic rates of binding and unbinding, or the mean residence time of the complex drug-protein, are equally relevant to draw a more accurate model of the mechanism of action of a drug. It is in this scenario where new computational techniques to simulate the all-atom dynamics of the biomolecular system find its valuable place on the challenge of designing new molecules for more effective and less toxic therapies. PMID- 29421288 TI - Allergies: diseases closely related to cancer. AB - Allergies are hypersensitivity reactions that occur through specific type Th2 immunological mechanisms characterized by different soluble mediators, as well as specific cells of the immune system. In recent decades, evidence has emerged relating this disease with cancer development. However, most of the results of epidemiology studies have been controversial and contradictory. There are mainly two trends. While the first indicates that allergies can reduce the risk of cancer, the other indicates that they may increase this risk. The first trend can be explained by the immunosurveillance hypothesis, which states that the increased immune surveillance after the immune hyper-responsiveness can inhibit or exert a protective effect against the development of cancer. Similarly, the prophylaxis hypothesis suggests that the physical effects of allergy symptoms can prevent cancer by removing potential carcinogens. In contrast, the opposing hypothesis propose that there is a deviation of the immune response toward Th2, which favors the development of cancer, or that the process of chronic inflammation favors the generation of mutations, and therefore the development of cancer. With the purpose of understanding more about these two hypotheses, the main soluble and cellular factors of allergic diseases that could be playing a key role in the development or inhibition of cancer were considered in this review. PMID- 29421289 TI - Role of diets rich in omega-3 and omega-6 in the development of cancer. AB - Over the past decade, some studies have addressed the therapeutic effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) and the opposite effects of omega-6 (omega-6) PUFAs on several diseases, including cardiovascular disorders, diabetes, neurodegenerative diseases, and cancer. Research demonstrates the safety of these naturally occurring ingredients. Of particular interest, several studies have shown that omega-3 PUFAs possess a therapeutic role against certain types of cancer. It is also known that omega-3 PUFAs can improve the efficacy and tolerability of chemotherapy. Previous reports have indicated that suppression of nuclear factor-kappaB, activation of AMPK/SIRT1, modulation of cyclooxygenase (COX) activity, and up-regulation of novel anti-inflammatory lipid mediators such as protectins, maresins, and resolvins, are the main mechanisms of the antineoplastic effect of omega-3 PUFAs. In contrast, several studies have demonstrated that omega-6 PUFAs induce progression in certain types of cancer. In this review, we discuss epidemiological and experimental studies addressing the relationship between the development of some types of cancer, including colon and colorectal carcinoma, breast cancer, prostate cancer, lung cancer and neuroblastoma, and the ingestion to omega-3 and omega-6 (PUFAs). We also discuss the clinical data, addressing the therapeutic role of omega-3 PUFA against different types of cancer. PMID- 29421290 TI - Instruments to measure the quality of life in patients with oral mucositis undergoing oncological treatment: a systematic review of the literature. AB - BACKGROUND: Oral mucositis (OM) is an inflammatory reaction of the oropharyngeal mucosa to cumulative chemotherapy (CT) and radiation therapy (RT), affecting one or more parts of the digestive tract along with the quality of life (QoL) of the patient. The goal of this study was to identify valid and reliable tools to evaluate QoL related to OM. METHODS: A systematic review of the literature was conducted up to May 2016. Articles were selected by peers using the PubMed database through a search following the inclusion and exclusion criteria and STAndards for the Reporting of Diagnostic accuracy studies (STARD) checklist with a cut-off point >= 70%. RESULTS: We identified four relevant articles that described instruments to assess the QoL related to OM in patients undergoing cancer treatment. CONCLUSIONS: The evaluation of the QoL in patients with OM is a difficult scenario because of its multiple variables. The knowledge of this relationship is limited because general instruments of oral health or cancer therapy are commonly used for evaluation. However, valid instruments are already available for estimating the impact of OM on the QoL from the patient's perspective. PMID- 29421291 TI - Medical interventions for cancer treatment-induced symptoms in children: an overview. AB - BACKGROUND: Childhood cancer accounts for 0.5 to 4.6% of the total number of cases in any population. According to the treatment, some side effects are present. Most adverse reactions can cause severe consequences for the survival of the patient. The more effective interventions for the management and the prevention of treatment-induced symptoms (TIS) in children with cancer are necessary to know. The objective of this review was to identify and describe available scientific evidence on the efficacy and safety of interventions used for the management and prevention of TIS in children with cancer. METHODS: We conducted a systematic review of the literature on studies that evaluated or described the effectiveness of interventions used for the management and prevention of TIS in children with cancer in some of the major electronic databases. Results were qualitative synthesized and presented as evidence tables. RESULTS: We identified eight systematic reviews. The revisions included experimental studies. All participants, including children and adults, were patients diagnosed with some cancer about to receive or that received treatment. CONCLUSIONS: The results showed only a reduced number of clinical trials that have evaluated the interventions for the management of TIS in children with cancer. In addition, the available evidence was limited and of poor quality. It is necessary to conduct more clinical trials with good methodological quality and high statistical power. PMID- 29421292 TI - A Modified Post-Transplant Cyclophosphamide Regimen, for Unmanipulated Haploidentical Marrow Transplantation, in Acute Myeloid Leukemia: A Multicenter Study. AB - We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50 mg/kg on days +3 and +5. The median age was 51 (range, 17-74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% for <60 or >=60 years of age) and 26% for advanced patients (17% versus 41% for <60 or >=60 years of age). In a multivariate analysis, active disease at transplant was the only negative predictor of survival, TRM and relapse. The original PT-CY regimen can be modified with CsA on day 0, still providing protection against GVHD, low toxicity, and encouraging low relapse incidence in AML patients, also over 60 years of age. PMID- 29421293 TI - Chronic Ocular Sequelae of Stevens-Johnson Syndrome in Children: Long-term Impact of Appropriate Therapy on Natural History of Disease. AB - PURPOSE: To describe the long-term ocular and visual morbidity in children with chronic sequelae of Stevens-Johnson syndrome (SJS) and visual outcomes of various management strategies. DESIGN: Retrospective comparative case series. METHODS: This study included 568 eyes of 284 children with SJS who presented between 1990 and 2015. Affected eyes received either conservative therapy (n = 440) or definitive management (n = 128), including lid margin mucous membrane grafting (MMG), prosthetic replacement of the ocular surface ecosystem (PROSE) contact lenses, allogeneic limbal transplantation, or keratoprosthesis using an algorithmic approach based on the severity of dryness and cause and extent of corneal damage. The primary outcome measure was best-corrected visual acuity (BCVA). RESULTS: Two thirds of patients presented more than a year after acute SJS, 99% without prior amniotic membrane grafting, with low vision or blindness in 60% of eyes. Children 8 years or younger in age had significantly worse ocular and visual morbidity (P <= .037). At 5 years of follow-up, definitive therapy significantly altered the natural history of the disease by improving BCVA and preventing the development or progression of keratopathy, as compared to conservative therapy (P <= .002). In eyes with lid-related keratopathy, MMG was significantly more effective than PROSE, although both were significantly better than conservative therapy and the combination of MMG followed by PROSE provided the best results (P < .0001). CONCLUSION: Children receiving suboptimal care during acute SJS presented later with severe ocular and visual morbidity. Timely therapy, particularly with PROSE and MMG in eyes with lid-related keratopathy, changed the natural course and helped in preserving and improving vision. PMID- 29421294 TI - Jalili Syndrome: Cross-sectional and Longitudinal Features of Seven Patients With Cone-Rod Dystrophy and Amelogenesis Imperfecta. AB - PURPOSE: To characterize a series of 7 patients with cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI) owing to confirmed mutations in CNNM4, first described as "Jalili Syndrome." DESIGN: Retrospective observational case series. METHODS: Seven patients from 6 families with Jalili Syndrome were identified at 3 tertiary referral centers. We systematically reviewed their available medical records, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging (FAF), color fundus photography, and electrophysiological assessments. RESULTS: The mean age at presentation was 6.7 years (range 3-16 years), with 6 male and 1 female patient. CNNM4 mutations were identified in all patients. The mean Snellen best-corrected visual acuity (BCVA) at presentation was 20/246 (range 20/98 to 20/399) in the right eye and 20/252 (range 20/98 to 20/480) in the left. Nystagmus was observed in all 7 patients, and photophobia was present in 6. Funduscopic findings at presentation were variable, ranging from only mild disc pallor to retinal vascular attenuation and macular atrophy. Multimodal imaging demonstrated disease progression in all 7 patients over time. Electroretinography uniformly revealed progressive cone-rod dysfunction. CONCLUSIONS: Jalili Syndrome is a rare CORD associated with AI. We have further characterized its ocular phenotype, including describing SD-OCT, FAF, and electrophysiological features; and report several novel disease-causing sequence variants. Moreover, this study presents novel longitudinal data demonstrating structural and functional progression over time, allowing better informed advice on prognosis. PMID- 29421295 TI - Association Between Optic Nerve Head Deformation and Retinal Microvasculature in High Myopia. AB - PURPOSE: To evaluate the retinal microvasculature of peripapillary and macular regions in highly myopic eyes and investigate the association between the vascular parameters and optic nerve head (ONH) deformation. DESIGN: Cross sectional study. METHODS: Seventy-one subjects with highly myopic eyes and 26 subjects with emmetropic eyes were included. Horizontal B-scan images of the ONH were obtained using optical coherence tomography (OCT) and horizontal tilt angles were measured. Integrated automated algorithms in the Avanti OCT angiography were used to quantify the peripapillary vessel density and area of the foveal avascular zone (FAZ) at the level of superficial and deep vascular networks. Association between horizontal disc tilt and the vascular parameters was evaluated. RESULTS: The mean axial length and horizontal tilt angle were 26.73 +/ 0.63 mm and 9.77 +/- 3.00 degrees in the highly myopic group and 23.46 +/- 0.55 mm and 5.95 +/- 3.48 degrees in the emmetropic group, respectively. Highly myopic eyes exhibited significantly lower average peripapillary vessel density (P = .010) and larger superficial and deep FAZs (P = .001 and P < .001, respectively) compared with emmetropic eyes. Linear regression analyses showed that horizontal tilt angle significantly correlated the average peripapillary vessel density (P = .037) and the areas of superficial (P < .001) and deep (P < .001) FAZs. CONCLUSIONS: The retinal microvasculature was significantly different in highly myopic eyes according to the degree of horizontal optic disc tilt. In addition to peripapillary vessel density, FAZ can be affected by the degree of optic disc tilt. PMID- 29421296 TI - Probing links between action perception and action production in Parkinson's disease using Fitts' law. AB - Information on how the subcortical brain encodes information required to execute actions or to evaluate others' actions remains scanty. To clarify this link, Fitts'-law tasks for perception and execution were tested in patients with Parkinson's disease (PD). For the perception task, participants were shown apparent motion displays of a person moving their arm between two identical targets and reported whether they judged that the person could realistically move at the perceived speed without missing the targets. For the motor task, participants were required to touch the two targets as quickly and accurately as possible, similarly to the person observed in the perception task. In both tasks, the PD group exhibited, or imputed to others, significantly slower performances than those of the control group. However, in both groups, the relationships of perception and execution with task difficulty were exactly those predicted by Fitts' law. This suggests that despite dysfunction of the subcortical region, motor simulation abilities reflected mechanisms of compensation in the PD group. Moreover, we found that patients with PD had difficulty in switching their strategy for estimating others' actions when asked to do so. PMID- 29421297 TI - Reply by the Authors. PMID- 29421298 TI - Re: Serra-Aracil et al.: The Place of Transanal Endoscopic Surgery in the Treatment of Rectourethral Fistula (Urology 2018;111:139-144). PMID- 29421299 TI - Impact of Statin Intake on Kidney Stone Formation. AB - OBJECTIVES: To determine whether statin intake affects nephrolithiasis risk, and whether higher lipid levels correlate with stone risk. Dyslipidemia is a known independent risk factor for urolithiasis, and emerging evidence suggests common biological pathways. Previous work has suggested that statins protect against new stone formation, but these findings have not been verified by other investigators. METHODS: We queried our Institution's Electronic Data Warehouse for all patients who were newly diagnosed with hyperlipidemia between 2009 and 2011, and had never taken a statin drug. These patients' clinical outcomes were followed until 2015, to assess whether they had been newly prescribed statins and whether they had developed symptomatic urolithiasis. Patient demographics, stone risk factors, prescription data, and serum lipid values were collected. RESULTS: 101,259 patients met inclusion criteria, 47.8% of whom received a statin prescription during the study period. Patients prescribed statins were significantly older, had a greater likelihood of osteoporosis, hemiplegia, immobility, and more likely to take a thiazide diuretic. Patients without a history of urolithiasis who were started on statin therapy were significantly less likely to develop new stones than patients not taking statins. This protective effect was even greater in patients with a history of stone disease. Lipid parameters (LDL, TG, cholesterol) were lower in the statin-treated group, suggesting overall compliance with these medications. CONCLUSIONS: Our data confirms previous work that statins protect against urinary stone formation, however the underlying mechanism seems to be distinct from statins' lipid lowering effect. PMID- 29421300 TI - Development and Validity of a Silicone Renal Tumor Model for Robotic Partial Nephrectomy Training. AB - OBJECTIVE: To provide a training tool to address the technical challenges of robot-assisted laparoscopic partial nephrectomy, we created silicone renal tumor models using 3-dimensional printed molds of a patient's kidney with a mass. In this study, we assessed the face, content, and construct validity of these models. MATERIALS AND METHODS: Surgeons of different training levels completed 4 simulations on silicone renal tumor models. Participants were surveyed on the usefulness and realism of the model as a training tool. Performance was measured using operation-specific metrics, self-reported operative demands (NASA Task Load Index [NASA TLX]), and blinded expert assessment (Global Evaluative Assessment of Robotic Surgeons [GEARS]). RESULTS: Twenty-four participants included attending urologists, endourology fellows, urology residents, and medical students. Post training surveys of expert participants yielded mean results of 79.2 on the realism of the model's overall feel and 90.2 on the model's overall usefulness for training. Renal artery clamp times and GEARS scores were significantly better in surgeons further in training (P <=.005 and P <=.025). Renal artery clamp times, preserved renal parenchyma, positive margins, NASA TLX, and GEARS scores were all found to improve across trials (P <.001, P = .025, P = .024, P <=.020, and P <=.006, respectively). CONCLUSION: Face, content, and construct validity were demonstrated in the use of a silicone renal tumor model in a cohort of surgeons of different training levels. Expert participants deemed the model useful and realistic. Surgeons of higher training levels performed better than less experienced surgeons in various study metrics, and improvements within individuals were observed over sequential trials. Future studies should aim to assess model predictive validity, namely, the association between model performance improvements and improvements in live surgery. PMID- 29421302 TI - Recent advances in reconstructing microbial secondary metabolites biosynthesis in Aspergillus spp. AB - High throughput genome sequencing has revealed a multitude of potential secondary metabolites biosynthetic pathways that remain cryptic. Pathway reconstruction coupled with genetic engineering via heterologous expression enables discovery of novel compounds, elucidation of biosynthetic pathways, and optimization of product yields. Apart from Escherichia coli and yeast, fungi, especially Aspergillus spp., are well known and efficient heterologous hosts. This review summarizes recent advances in heterologous expression of microbial secondary metabolite biosynthesis in Aspergillus spp. We also discuss the technological challenges and successes in regard to heterologous host selection and DNA assembly behind the reconstruction of microbial secondary metabolite biosynthesis. PMID- 29421303 TI - Ultrafast glucose-responsive, high loading capacity erythrocyte to self-regulate the release of insulin. AB - : Insulin (INS) delivery system that can mimic normal insulin secretion to maintain the blood glucose level (BGL) in the normal range is an ideal treatment for diabetes. However, most of the existing closed-loop INS delivery systems respond slowly to the changes in BGL, resulting in a time lag between the abnormal BGL and the release of INS, which is not suitable for practical application. In this study, glucose oxidase (GOx)-modified erythrocytes are used as INS carriers (GOx-INS-ER) that can rapidly self-regulate the release of INS upon the changes in BGL. In this system, glucose can be broken down into gluconic acid and hydrogen peroxide by GOx-INS-ER, and the latter will rupture the erythrocyte membrane to release INS within minutes. A pulsatile release of INS can be achieved upon the changes in the glucose concentration. This GOx-INS-ER enables diabetic rats to overcome hyperglycemia within 1 h, and a single injection of this GOx-INS-ER into the STZ-induced diabetic rats can maintain the BGL in the normal range up to 9 days. STATEMENT OF SIGNIFICANCE: Diabetes mellitus has been a major public health threatener with global prevalence. Although, glucose-responsive carriers that can release insulin (INS) in a closed loop have been explored greatly in recent years, their sluggish glucose responsive property and low INS-loading content greatly restrict their practical application [ACS Nano, 2013, 7, 4194]. In this work, we reported INS-loaded erythrocytes featuring ultrafast glucose-responsive property and high INS loading content, which could release INS in a closed loop. These GOX-INS-ERs could respond to the changes in glucose level within several minutes and self-regulate the release of INS for a long time. Single injection of GOX-INS-ER can overcome hyperglycemia in diabetic mice within 1 h and maintain the baseline level of glucose up to 9 days. We think our method may provide a robust way to potentiate diabetes treatment. PMID- 29421301 TI - Computational prediction of drug solubility in water-based systems: Qualitative and quantitative approaches used in the current drug discovery and development setting. AB - In this review we will discuss recent advances in computational prediction of solubility in water-based solvents. Our focus is set on recent advances in predictions of biorelevant solubility in media mimicking the human intestinal fluids and on new methods to predict the thermodynamic cycle rather than prediction of solubility in pure water through quantitative structure property relationships (QSPR). While the literature is rich in QSPR models for both solubility and melting point, a physicochemical property strongly linked to the solubility, recent advances in the modelling of these properties make use of theory and computational simulations to better predict these properties or processes involved therein (e.g. solid state crystal lattice packing, dissociation of molecules from the lattice and solvation). This review serves to provide an update on these new approaches and how they can be used to more accurately predict solubility, and also importantly, inform us on molecular interactions and processes occurring during drug dissolution and solubilisation. PMID- 29421304 TI - Beta-defensins - Underestimated peptides in influenza combat. AB - Defensins are a family of host defense peptides present in vertebrates, invertebrates and plants. They display broad antimicrobial activity and immunomodulatory functions. Herein, the natural anti-influenzal role of beta defensins, as well as their potential usage as anti-influenza vaccine adjuvants and therapeutic agents, is reviewed. This article summarizes previously published information on beta-defensin modes of action, expression changes after influenza infection and vaccination, biotechnological usage and possible boosting of their production by dietary supplementation. PMID- 29421305 TI - Molecular characterization of complete genome of a canine distemper virus associated with fatal infection in dogs in Gabon, Central Africa. AB - Canine distemper (CD) is the most deadly disease in dogs with mortality rates reaching 50%. The pathological agent, the CD virus (CDV), generally causes a severe systemic disease, although the nervous form can coexist with the acute catarrhal form in the same individual. In this study, we describe an outbreak of 18 cases of CD that occurred in 2015 in a German Shepherd dog population in northwestern Gabon. In addition, we determined the sequence of the CDV genotype associated with this fatal distemper infection in Gabon and compared it with other published CDV sequences. The CDV was detected using RT-PCR on cDNA from RNA of harvested brains and other organs. The identification was confirmed by sequencing amplicons. Moreover, we obtained the whole genome sequence using high throughput sequencing. Phylogenetic analysis revealed that Gabonese CDV strain clustered with European strains belonging to the Europe genotype. This study provided the first molecular detection of the CDV strain associated with this fatal distemper infection in Central Africa region. PMID- 29421306 TI - Prenatal cold stress: Effect on maternal hippocampus and offspring behavior in rats. AB - In mammals, environmental factors including cold stress exert dramatic effects on adult health during late gestation, the cold stress response refers to an organism's response to cold. Indeed, cells and organs, including the hippocampus, are coordinated to respond to prevent hypothermia. The hippocampus act as an important brain structure that regulates the activity of the hypothalamic pituitary-adrenal (HPA) axis, and suppress the stress reaction through feedback regulation of the HPA axis. To evaluate the response of the hippocampus during prenatal cold stress, we established a prenatal cold stress rat model. The molecular and signaling pathways responsible for the hippocampus cold exposure response were investigated. We assessed the glucocorticoid receptor, mineralocorticoid receptor, brain-derived neurotrophic factor (BDNF), RNA-binding motif protein 3 (RBM3), heat shock protein 70, protein expression, and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and nuclear factor-kappa B pathways. Male and female offspring behavior were evaluated. Cold stress reduced the BDNF level in the maternal hippocampus in contrast to the increase in RBM3. BDNF has been shown to induce and RBM3 inhibits ERK phosphorylation. We measured p-ERK1/2 and showed low-level phosphorylation in the hippocampus after cold stress. Furthermore, we demonstrated that cold stress enhanced phosphorylation of P65 on Ser536, and led to apoptosis of the hippocampus in a caspase 3-independent manner. Behavioral tests were performed on pubescent male and female offspring, both of which showed evidence of reduced anxiety-like behavior. In summary, a more thorough understanding of these mechanisms may lead to maternal intervention that can reverse the damage of prenatal stressors or prevent the damage altogether and improve the physical quality of neonatal rats. PMID- 29421307 TI - Long noncoding RNA complementarity and target transcripts abundance. AB - Eukaryotic mRNA metabolism regulates its stability, localization, and translation using complementarity with counter-part RNAs. To modulate their stability, small and long noncoding RNAs can establish complementarity with their target mRNAs. Although complementarity of small interfering RNAs and microRNAs with target mRNAs has been studied thoroughly, partial complementarity of long noncoding RNAs (lncRNAs) with their target mRNAs has not been investigated clearly. To address that research gap, our lab investigated whether the sequence complementarity of two lncRNAs, lincRNA-p21 and OIP5-AS1, influenced the quantity of target RNA expression. We predicted a positive correlation between lncRNA complementarity and target mRNA quantity. We confirmed this prediction using RNA affinity pull down, microarray, and RNA-sequencing analysis. In addition, we utilized the information from this analysis to compare the quantity of target mRNAs when two lncRNAs, lincRNA-p21 and OIP5-AS1, are depleted by siRNAs. We observed that human and mouse lincRNA-p21 regulated target mRNA abundance in complementarity dependent and independent manners. In contrast, affinity pull down of OIP5-AS1 revealed that changes in OIP5-AS1 expression influenced the amount of some OIP5 AS1 target mRNAs and miRNAs, as we predicted from our sequence complementarity assay. Altogether, the current study demonstrates that partial complementarity of lncRNAs and mRNAs (even miRNAs) assist in determining target RNA expression and quantity. PMID- 29421308 TI - HMGB1-mediated DNA bending: Distinct roles in increasing p53 binding to DNA and the transactivation of p53-responsive gene promoters. AB - HMGB1 is a chromatin-associated protein that has been implicated in many important biological processes such as transcription, recombination, DNA repair, and genome stability. These functions include the enhancement of binding of a number of transcription factors, including the tumor suppressor protein p53, to their specific DNA-binding sites. HMGB1 is composed of two highly conserved HMG boxes, linked to an intrinsically disordered acidic C-terminal tail. Previous reports have suggested that the ability of HMGB1 to bend DNA may explain the in vitro HMGB1-mediated increase in sequence-specific DNA binding by p53. The aim of this study was to reinvestigate the importance of HMGB1-induced DNA bending in relationship to the ability of the protein to promote the specific binding of p53 to short DNA duplexes in vitro, and to transactivate two major p53-regulated human genes: Mdm2 and p21/WAF1. Using a number of HMGB1 mutants, we report that the HMGB1-mediated increase in sequence-specific p53 binding to DNA duplexes in vitro depends very little on HMGB1-mediated DNA bending. The presence of the acidic C-terminal tail of HMGB1 and/or the oxidation of the protein can reduce the HMGB1-mediated p53 binding. Interestingly, the induction of transactivation of p53-responsive gene promoters by HMGB1 requires both the ability of the protein to bend DNA and the acidic C-terminal tail, and is promoter-specific. We propose that the efficient transactivation of p53-responsive gene promoters by HMGB1 depends on complex events, rather than solely on the promotion of p53 binding to its DNA cognate sites. PMID- 29421309 TI - Female offspring birth weight is associated with Body Mass Index, waist circumference and metabolic syndrome in Latin American women at 10-years postpartum. AB - AIMS: We aimed to assess whether female offspring birth weight (BW) is associated with anthropometric and metabolic outcomes in Chilean mothers at 10-years postpartum. METHODS: We assessed data from 396 Chilean mother-daughter pairs participating in the longitudinal Chilean Growth and Obesity Cohort (GOCS) and Determinants of Breast Cancer Risk (DERCAM) studies. Multivariate linear and logistic regression models were performed to associate female offspring BW with maternal Body Mass Index (BMI), waist circumference, type 2 diabetes mellitus, metabolic syndrome and its components at 10-years postpartum. RESULTS: At 10 years postpartum, 69% of mothers were overweight, 65% had central adiposity and 26% had metabolic syndrome. Adjusted linear regression models showed associations between female offspring BW and (1) maternal BMI (%Delta GM = 4.46; 95% CI 0.25 8.85); and (2) waist circumference (%Delta GM = 3.25; 95% CI 0-6.60). Adjusted logistic regression models showed associations between female offspring BW and (1) maternal metabolic syndrome (OR = 3.48; 95% CI 1.50-8.11); (2) central adiposity (OR = 2.37; 95% CI 1.08-5.22); and (3) hypertriglyceridemia (OR = 3.19; 95% CI 1.40-7.23). CONCLUSIONS: Female offspring BW was associated with maternal anthropometric and metabolic outcomes at 10-years postpartum. Our findings add to the emerging evidence that offspring BW might be a potential indicator for future maternal anthropometric and metabolic risks. PMID- 29421310 TI - Mortality trends and cause of death in patients with new-onset type 2 diabetes and controls: A 24-year follow-up prospective cohort study. AB - AIMS: Our aim was to assess causes of death and temporal changes in excess mortality among patients with new-onset type 2 diabetes in Skaraborg, Sweden. METHODS: Patients from the Skaraborg Diabetes Register with prospectively registered new-onset type 2 diabetes 1991-2004 were included. Five individual controls matched for sex, age, geographical area and calendar year of study entry were selected using population records. Causes of deaths until 31 December 2014 were retrieved from the Cause of Death Register. Adjusted excess mortality among patients and temporal changes of excess mortality were calculated using Poisson models. Cumulative incidences of cause-specific mortality were calculated by competing risk regression. RESULTS: During 24 years of follow-up 4364 deaths occurred among 7461 patients in 90,529 person-years (48.2/1000 person-years, 95% CI 46.8-49.7), and 18,541 deaths in 479,428 person-years among 37,271 controls (38.7/1000 person-years, 38.1-39.2). The overall adjusted mortality hazard ratio was 1.47 (p < .0001) among patients diagnosed at study start 1991 and decreased by 2% (p < .0001) per increase in calendar year of diagnosis until 2004. Excess mortality was mainly attributed to endocrine and cardiovascular cause of death with crude subdistributional hazard ratios of 5.06 (p < .001) and 1.22 (p < .001). CONCLUSIONS: Excess mortality for patients with new-onset type 2 diabetes was mainly attributed to deaths related to diabetes and the cardiovascular system, and decreased with increasing year of diagnosis 1991-2004. Possible explanations could be temporal trends of earlier diagnosis due to lowered diagnostic thresholds and intensified diagnostic activities, as well as improved treatment. PMID- 29421311 TI - Cross-pathway control gene CPC1/GCN4 coordinates with histone acetyltransferase GCN5 to regulate catalase-3 expression under oxidative stress in Neurospora crassa. AB - Catalase is an important enzyme found in nearly all aerobic organisms and plays an essential role in protecting cells from oxidative damage by catalyzing the degradation of hydrogen peroxide into water and oxygen. In filamentous fungus Neurospora crassa, the expression levels of catalases are rigorously regulated by morphogenetic transition during growth and development in cells. Our study revealed that catalase-3 transcription is positively regulated by histone acetyltransferase GCN5 and the cross-pathway control gene cpc-1, as the cat-3 expression level is significantly decreased in gcn5KO and cpc-1 (j-5) mutants. Moreover, gcn5KO and cpc-1 (j-5) mutants could not respond to H2O2 treatment due to the inadequate cat-3 transcription, while wild-type strains showed high expression levels of catalase upon H2O2 treatment. The global H3 acetylation and the acetylation of H3 at cat-3 locus dramatically decreased in gcn5KO under normal or oxidative stress conditions. Meanwhile, the expression of CAT-3 is reduced in gcn5E146Q, the catalytically dead mutant, suggesting that the catalytic activity of GCN5 functions in regulation of cat-3 transcription. In addition, GCN5 cannot acetylate histone H3 efficiently at cat-3 locus in cpc-1 (j 5) mutant strains under normal or oxidative stress conditions. Furthermore, ChIP assays data revealed that the CPC1/GCN4 can directly target the cat-3 promoter region, which may recruit GCN5 to modify the histone acetylation of this region. These results disclosed a distinctive function of CPC1/GCN4 in the regulatory pathway of cat-3 transcription, which is mediated by GCN5-dependent acetylation. PMID- 29421312 TI - DiscoVista: Interpretable visualizations of gene tree discordance. AB - Phylogenomics has ushered in an age of discordance. Analyses often reveal abundant discordances among phylogenies of different parts of genomes, as well as incongruences between species trees obtained using different methods or data partitions. Researchers are often left trying to make sense of such incongruences. Interpretive ways of measuring and visualizing discordance are needed, both among alternative species trees and gene trees, especially for specific focal branches of a tree. Here, we introduce DiscoVista, a publicly available tool that creates a suite of simple but interpretable visualizations. DiscoVista helps quantify the amount of discordance and some of its potential causes. PMID- 29421313 TI - Biologics in allergic and immunologic diseases: Promises and challenges in the era of personalized medicine. PMID- 29421314 TI - Baseline asthma burden, comorbidities, and biomarkers in omalizumab-treated patients in PROSPERO. PMID- 29421315 TI - Urinary exoglycosidases, reference values in healthy children. AB - PURPOSE: The purpose of the study was to determine the effect of age on lysosomal exoglycosidase activities: alpha-fucosidase, beta-galactosidase, beta glucuronidase and alpha-mannosidase in healthy children and adolescents. MATERIAL AND METHODS: Urine samples were collected from 203 healthy children and adolescents (girls = 99, boys = 104), aged six months to 17.9 years. The activities of alpha-fucosidase, beta-galactosidase, beta-glucuronidase and alpha mannosidase were determined by colorimetric method and expressed in pKat/MUg of creatine (pKat/MUg Cr.). RESULTS: Urinary alpha-fucosidase, beta-galactosidase, beta-glucuronidase and alpha-mannosidase activities (pKat/MUg Cr.) were the highest in children below 3 years of age in comparison to the remaining age groups. There was a statistically significant negative correlation between urinary alpha-fucosidase, beta-galactosidase, beta-glucuronidase and alpha mannosidase (pKat/MUg Cr.) and age (r = -0.36; r = -0.36; r = -0.35; r = -0.35; at p < 0.0001, respectively). In addition, we constructed the reference values for urinary activity of alpha-fucosidase, beta-galactosidase, beta-glucuronidase and alpha-mannosidase (pKat/MUg Cr.) in percentiles according to age in 3-year intervals. CONCLUSIONS: Our study is the first to show reference values for urinary alpha-fucosidase, beta-galactosidase, beta-glucuronidase and alpha mannosidase in children and adolescents. PMID- 29421316 TI - In vitro activity of novel anti-MRSA cephalosporins and comparator antimicrobial agents against staphylococci involved in prosthetic joint infections. AB - OBJECTIVES: Ceftaroline and ceftobiprole are new parenteral cephalosporins with potent activity against methicillin-resistant (MR) staphylococci, which are the leading cause of prosthetic joint infections (PJIs). The aim of this study was to determine and compare the in vitro activities of both molecules against staphylococcal isolates recovered from clinically documented PJIs. METHODS: A collection of 200 non-duplicate clinical isolates [100 Staphylococcus aureus and 100 coagulase-negative staphylococci (CoNS), including 19 and 27 MR isolates, respectively] was studied. Minimum inhibitory concentrations (MICs) of oxacillin, ceftaroline, ceftobiprole, vancomycin, teicoplanin, clindamycin, levofloxacin, linezolid and daptomycin were determined by the broth microdilution method. Bactericidal activity (at 4* MIC) of ceftaroline, ceftobiprole, vancomycin, teicoplanin, linezolid and daptomycin was assessed by time-kill assay. RESULTS: Among the S. aureus isolates, 100% were susceptible to ceftaroline (MIC50/90, 0.25/0.5MUg/mL) and 98% were susceptible to ceftobiprole (MIC50/90, 0.5/1MUg/mL), regardless of their methicillin resistance. The two ceftobiprole-non-susceptible strains (including one MRSA) showed MICs at 4mg/L. Against CoNS isolates, ceftaroline and ceftobiprole exhibited in vitro potency with MIC50/90 values at 0.06/0.25MUg/mL and 0.25/1MUg/mL, respectively. At 4* MIC, ceftaroline and ceftobiprole showed rapid and marked bactericidal activity against both S. aureus and CoNS (after 24/12h and 12/6h of incubation, respectively), whilst none of the other molecules tested had a bactericidal effect by 24h. CONCLUSIONS: This study showed that ceftaroline and ceftobiprole have excellent in vitro activity against clinical isolates of staphylococci involved in PJIs. These molecules may therefore represent promising alternatives for the treatment of such infections. PMID- 29421317 TI - Genotypic detection of fluoroquinolone resistance in drug-resistant Mycobacterium tuberculosis at a tertiary care centre in south Coastal Karnataka, India. AB - OBJECTIVES: This study aimed to characterise mutations associated with fluoroquinolone resistance in drug-resistant Mycobacterium tuberculosis clinical isolates at a tertiary care centre in south Coastal Karnataka, India. METHODS: DNA from 50 M. tuberculosis clinical isolates was extracted and the gyrA and gyrB genes were amplified. Purified amplicons of gyrA and gyrB were sequenced and extended-sequencing PCR products were analysed. Analysis of mutations in gyrA and gyrB was done using the MUBII-TB-DB database. Statistical analysis was performed using SPSS v.22 and data were compared by chi2 test. A P-value of <0.05 was considered statistically significant. RESULTS: Mutations conferring resistance to fluoroquinolones were observed in 9 isolates (18%). The gyrA A281G (D94G) mutation was observed in 3 isolates (6%), whereas mutations G280T (D94Y) and A281C (D94A) were each observed in 1 isolate (2%). Mutation G1498A (D500N) in gyrB alone was observed in 2 isolates (4%). Two isolates (4%) had mutations both in gyrA and gyrB; gyrA mutation T271C (S91P) was observed in one isolate, whereas the other isolate had gyrA C269G (A90G), but both isolates had a common G1498A (D500N) gyrB mutation. G284C mutation conferring S95T polymorphism (not associated with fluoroquinolone resistance) was observed in 39/50 isolates (78%). CONCLUSION: gyrA mutations at codons 94, 91 and 90 and gyrB mutation G1498A (D500N) were the most common mutations associated with fluoroquinolone resistance in clinical isolates in this study. Future studies including a larger number of samples are desirable to fully explore the true extent of fluoroquinolone resistance and mutations associated with them. PMID- 29421318 TI - Antimicrobial resistance, biofilm-forming ability and virulence potential of Pseudomonas aeruginosa isolated from burn patients in northern Iran. AB - OBJECTIVES: Pseudomonas aeruginosa is a frequent cause of infectious diseases, such as burn and wound infections, making it one of the most menacing opportunistic pathogens. The aim of this study was to investigate the antimicrobial resistance, biofilm-forming ability, and frequency of genes involved in biofilm formation and virulence of P. aeruginosa isolated from burn infections in Iran. METHODS: Resistance of 90 P. aeruginosa isolates to 12 antimicrobial agents as well as production of extended-spectrum beta-lactamase (ESBL) and metallo-beta-lactamase (MBL) enzymes were assessed phenotypically according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Biofilm-forming capacity was assayed in a microtitre plate. The frequency of biofilm- and virulence-associated genes was investigated by PCR. Mutations in gyrA and parC in ciprofloxacin-resistant isolates were also determined by PCR. RESULTS: In phenotypic assays, 72.2% (65/90) of P. aeruginosa isolates were multidrug-resistant (MDR), 55.5% (50/90) and 35.6% (32/90) were positive for ESBL and MBL production, respectively, and 67.8% (61/90) were positive for biofilm formation. Biofilm- and virulence-associated genes were identified in >50% of the P. aeruginosa isolates, with toxA and lasB being the most frequent. All of the virulence genes were more common in biofilm-forming and MDR phenotypes. Two point mutations in gyrA and one in parC in high-level ciprofloxacin-resistant isolates were identified. CONCLUSIONS: The results of this study indicate that there is a high frequency of multidrug resistance and a high percentage of virulence associated genes present in clinical P. aeruginosa isolates in Iran. PMID- 29421319 TI - Antimicrobial stigmatization: Public health concerns about conventional pig farming and pig farmers' experiences with stigmatization. AB - According to the World Health Organization, antimicrobial resistance is one of the most severe threats to public health. Since the 1950's contemporary farming of pigs has been heavily dependent on the use of antibiotics. Recently, concerned experts of public health have become more outspoken, often, criticizing pig farmers for social irresponsibility and gambling with public health. Danish pig farmers are internationally renewed for their relatively low use of antibiotics. Nevertheless, the public criticism aimed at farmers is relatively strong in Denmark. Based on qualitative interviews with 30 pig farmers and 21 public health experts, this article sets out how pig farmers, according to public health experts, threaten public health and how pig farmers, according to the farmers, experience and internalize stigmatization related to their lives as farmers. By focusing on Danish pig farmers' experiencing public condemnation from scientific experts as well as in their local communities, this article proceeds along the line of existing research on health-related stigmatization. PMID- 29421320 TI - Retinoic acid receptor beta, a potential therapeutic target in the inhibition of adenovirus replication. AB - Human adenoviruses (HAdVs) usually cause mild respiratory infections, but they can also lead to fatal outcomes for immunosuppressive patients. Unfortunately, there has been no specific anti-HAdV drug approved for medical use. A better understanding of the nature of virus-host interactions during infection is beneficial to the discovery of potential antiviral targets and new antiviral drugs. In this study, a time-course transcriptome analysis of HAdV-infected human lung epithelial cells (A549 cells) was performed to investigate virus-host interactions, and several key host molecules involved in the HAdV infection process were identified. The RARbeta (retinoic acid receptor beta) molecule, one of the upstream regulatory factors of differentially expressed genes (DEGs), played important roles in HAdV replication. The results of reverse transcription polymerase chain reaction (RT-PCR) and Western blotting showed that RARbeta mRNA and protein were downregulated by HAdV infection in the A549 cells. The knockdown of RARbeta by RARbeta siRNA increased the HAdV production and the overexpression of RARbeta decreased the HAdV production. Furthermore, FDA-approved Tazarotene, which is an RAR selective agonist with relatively more selectivity for RARbeta, was found to inhibit HAdV replication in vitro. Taken together, our study presents a key host molecule in adenovirus infection, which could be developed as a potential host target to an anti-adenovirus drug. In addition, this study provides evidence for the re-exploitation of an FDA-approved small molecule for therapeutic applications in adenovirus replication. PMID- 29421321 TI - 2017 international meeting of the Global Virus Network. AB - The Global Virus Network (GVN) was established in 2011 to strengthen research and responses to emerging viral causes of human disease and to prepare against new viral pandemics. There are now 40 GVN Centers of Excellence and 6 Affiliate laboratories in 24 countries. The 2017 meeting was held from September 25-27 in Melbourne, Australia, and was hosted by the Peter Doherty Institute for Infection and Immunity and the Institut Pasteur. This report highlights the recent accomplishments of GVN researchers in several important areas of medical virology, including the recent Zika epidemic, infections by human papillomavirus, influenza, HIV, hepatitis C, HTLV-1, and chikungunya viruses, and new and emerging viruses in the Australasia region. Plans for the 2018 meeting also are noted. PMID- 29421322 TI - Differences in steady-state glutamate levels and variability between 'non-task active' conditions: Evidence from 1H fMRS of the prefrontal cortex. AB - Proton functional magnetic resonance spectroscopy (1H fMRS) is a noninvasive neuroimaging technique capable of detecting dynamic changes in glutamate related to task-related demands at a temporal resolution under 1 min. Several recent 1H fMRS studies demonstrated elevated steady-state levels of glutamate of 2% or greater during different 'task-active' conditions, relative to a 'non-task active' control condition. However, the 'control' condition from these studies does vary with respect to the degree of constraining behavior, which may lead to different glutamate levels or variability between 'control' conditions. The purpose of this 1H fMRS study was to compare the steady-state levels and variability of glutamate in the left dorsolateral prefrontal cortex (dlPFC) of 16 healthy adults across four different putative 'non-task-active' conditions: relaxed with eyes closed, passive visual fixation crosshair, visual flashing checkerboard, and finger tapping. Results showed significantly lower glutamate levels during the passive visual fixation crosshair than the visual flashing checkerboard and the finger tapping conditions. Moreover, glutamate was significantly less variable during the passive visual fixation crosshair and the visual flashing checkerboard than the relaxed eyes closed condition. Of the four conditions, the passive visual fixation crosshair condition demonstrated the lowest and least variable glutamate levels potentially reflecting the least dlPFC engagement, but greatest behavioral constraint. These results emphasize the importance of selecting a proper 'control' condition to reflect accurately a 'non task-active' steady-state level of glutamate with minimal variability during 1H MRS investigations. PMID- 29421323 TI - Somatosensory BOLD fMRI reveals close link between salient blood pressure changes and the murine neuromatrix. AB - The neuromatrix, or "pain matrix", is a network of cortical brain areas which is activated by noxious as well as salient somatosensory stimulation. This has been studied in mice and humans using blood oxygenation level-dependent (BOLD) fMRI. Here we demonstrate that BOLD effects observed in the murine neuromatrix in response to salient somatosensory stimuli are prone to reflect mean arterial blood pressure (MABP) changes, rather than neural activity. We show that a standard electrostimulus typically used in murine somatosensory fMRI can induce substantial elevations in MABP. Equivalent drug-induced MABP changes - without somatosensory stimulation - evoked BOLD patterns in the neuromatrix strikingly similar to those evoked by electrostimulation. This constitutes a serious caveat for murine fMRI. The regional specificity of these BOLD patterns can be attributed to the co-localization of the neuromatrix with large draining veins. Based on these findings we propose a cardiovascular support mechanism whereby abrupt elevations in MABP provide additional energy supply to the neuromatrix and other essential brain areas in fight-or-flight situations. PMID- 29421324 TI - Effects of propofol anesthesia on the processing of noxious stimuli in the spinal cord and the brain. AB - Drug-induced unconsciousness is an essential component of general anesthesia, commonly attributed to attenuation of higher-order processing of external stimuli and a resulting loss of information integration capabilities of the brain. In this study, we investigated how the hypnotic drug propofol at doses comparable to those in clinical practice influences the processing of somatosensory stimuli in the spinal cord and in primary and higher-order cortices. Using nociceptive reflexes, somatosensory evoked potentials and functional magnet resonance imaging (fMRI), we found that propofol abolishes the processing of innocuous and moderate noxious stimuli at low to medium concentration levels, but that intense noxious stimuli evoked spinal and cerebral responses even during deep propofol anesthesia that caused profound electroencephalogram (EEG) burst suppression. While nociceptive reflexes and somatosensory potentials were affected only in a minor way by further increasing doses of propofol after the loss of consciousness, fMRI showed that increasing propofol concentration abolished processing of intense noxious stimuli in the insula and secondary somatosensory cortex and vastly increased processing in the frontal cortex. As the fMRI functional connectivity showed congruent changes with increasing doses of propofol - namely the temporal brain areas decreasing their connectivity with the bilateral pre-/postcentral gyri and the supplementary motor area, while connectivity of the latter with frontal areas is increased - we conclude that the changes in processing of noxious stimuli during propofol anesthesia might be related to changes in functional connectivity. PMID- 29421325 TI - Localizing bicoherence from EEG and MEG. AB - We propose a new method for the localization of nonlinear cross-frequency coupling in EEG and MEG data analysis, based on the estimation of bicoherences at the source level. While for the analysis of rhythmic brain activity, source directions are commonly chosen to maximize power, we suggest to maximize bicoherence instead. The resulting nonlinear cost function can be minimized effectively using a gradient approach. We argue, that bicoherence is also a generally useful tool to analyze phase-amplitude coupling (PAC), by deriving formal relations between PAC and bispectra. This is illustrated in simulated and empirical LFP data. The localization method is applied to EEG resting state data, where the most prominent bicoherence signatures originate from the occipital alpha rhythm and the mu rhythm. While the latter is hardly visible using power analysis, we observe clear bicoherence peaks in the high alpha range of sensorymotor areas. We additionally apply our method to resting-state data of subjects with schizophrenia and healthy controls and observe significant bicoherence differences in motor areas which could not be found from analyzing power differences. PMID- 29421326 TI - Kv3 K+ currents contribute to spike-timing in dorsal cochlear nucleus principal cells. AB - Exposure to loud sound increases burst-firing of dorsal cochlear nucleus (DCN) fusiform cells in the auditory brainstem, which has been suggested to be an electrophysiological correlate of tinnitus. The altered activity of DCN fusiform cells may be due to down-regulation of high voltage-activated (Kv3-like) K+ currents. Whole cell current-clamp recordings were obtained from DCN fusiform cells in brain slices from P15-P18 CBA mice. We first studied whether acoustic over-exposure (performed at P15) or pharmacological inhibition of K+ currents with tetraethylamonium (TEA) affect fusiform cell action potential characteristics, firing frequency and spike-timing relative to evoking current stimuli. We then tested whether AUT1, a modulator of Kv3 K+ currents reverses the effects of sound exposure or TEA. Both loud sound exposure and TEA decreased the amplitude of action potential after-hyperpolarization, reduced the maximum firing frequency, and disrupted spike-timing. These treatments also increased post synaptic voltage fluctuations at baseline. AUT1 applied in the presence of TEA or following acoustic over-exposure, did not affect the firing frequency, but enhanced action potential after-hyperpolarization, prevented the increased voltage fluctuations and restored spike-timing. Furthermore AUT1 prevented the occurrence of bursts. Our study shows that the effect on spike-timing is significantly correlated with the amplitude of the action potential after hyperpolarization and the voltage fluctuations at baseline. In conclusion, modulation of putative Kv3 K+ currents may restore regular spike-timing of DCN fusiform cell firing following noise exposure, and could provide a means to restore deficits in temporal encoding observed during noise-induced tinnitus. PMID- 29421327 TI - Nrf2 protects human lens epithelial cells against H2O2-induced oxidative and ER stress: The ATF4 may be involved. AB - Our previous study has shown heme oxygenase-1 (HO-1) protects human lens epithelial cells (LECs) against H2O2-induced oxidative stress and apoptosis. Nrf2, the major regulator of HO-1, is triggered during the mutual induction of oxidative stress and ER stress. In response to ER stress, unfolded protein response (UPR) serves as a program of transcriptional and translational regulation mechanism with PERK involved. Both Nrf2 and ATF4 are activated as the downstream effect of PERK signaling coordinating the convergence of dual stresses. However, the ways in which Nrf2 interacting with ATF4 regulates deteriorated redox state have not yet been fully explored. Here, the transfected LECs with Nrf2 overexpression illustrated enhanced resistance in morphology and viability upon H2O2 treatment condition. Intracellular ROS accumulation arouses ER stress, initiating PERK dependent UPR and inducing the downstream signal Nrf2 and ATF4 auto-phosphorylation. Further, converging at target promoters, ATF4 facilitates Nrf2 with the expression of ARE-dependent phase II antioxidant and detoxification enzymes. According to either Nrf2 or ATF4 gene modification, our data suggests a novel interaction between Nrf2 and ATF4 under oxidative and ER stress, thus drives specific enzymatic and non-enzymatic reactions of antioxidant mechanisms maintaining redox homeostasis. Therapies that restoring Nrf2 or ATF4 expression might help to postpone LECs aging and age-related cataract formation. PMID- 29421328 TI - The effect of a single anti-Vascular Endothelial Growth Factor injection on neonatal growth and organ development: In-vivo study. AB - Retinopathy of prematurity (ROP) is one of the leading causes of blindness in preterm Infants. Anti-vascular endothelial growth factor (VEGF) is emerging as a promising treatment, but there is insufficient evidence on their safety. We investigate the effect of systemic anti-VEGF in rat pups with equivalent maturity to a 32 week neonate. A single dose of either anti-VEGF antibody (n = 7) or saline (control group; n = 6) was administered to newborn rats intra-peritoneally on the first day of life. 14 days' post treatment, the serum concentration of anti-VEGF was measured and the brain, lung, heart, kidney and liver were harvested and weighed. The heart was processed to measure the Fulton index (a surrogate for pulmonary hypertension). All other organs were processed for mRNA expression of VEGF and VEGF-receptors (R1&R2). No group differences in body and organ weights were noted. The anti-VEGF was still detected in serum 14 days post Injection and resulted in increase in lung (p < 0.002) and kidney (p < 0.01) VEGF mRNA expressions and the lung (p < 0.02) VEGF-R1 and kidney (P < 0.001) VEGF-R2 mRNA expressions. The treated pups exhibited increased total heart weight (p < 0.01) and Fulton Index (p < 0.05). No changes were seen in the liver and brain. Anti-VEGF antibody did not affect mortality, total body and organ weights, but was associated with pulmonary hypertension. Expression of lung and kidney VEGF and its receptors was increased, whilst the brain and liver did not show changes. Dosing experiments can now be targeted to assess safety threshold and at anti VEGF dose used in human ROP treatment. PMID- 29421329 TI - Corrigendum to "Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data" [Exp. Eye Res. 137C (2015) 111-124]. PMID- 29421330 TI - Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse. AB - The present study was designed to identify genomic loci modulating the susceptibility of retinal ganglion cells (RGC) to elevated intraocular pressure (IOP) in the BXD recombinant inbred mouse strain set. IOP was elevated by injecting magnetic microspheres into the anterior chamber and blocking the trabecular meshwork using a handheld magnet to impede drainage. The IOP was then measured over the next 21 days. Only animals with IOP greater than 25 mmHg for two consecutive days or an IOP above 30 mmHg on a single day after microsphere injection were used in this study. On day 21, mice were sacrificed and the optic nerve was processed for histology. Axons were counted for both the injected and the control eye in 49 BXD strains, totaling 181 normal counts and 191 counts associated with elevated IOP. The axon loss for each strain was calculated and the data were entered into genenetwork.org. The average number of normal axons in the optic nerve across all strains was 54,788 +/- 16% (SD), which dropped to 49,545 +/- 20% in animals with artificially elevated IOP. Interval mapping demonstrated a relatively similar genome-wide map for both conditions with a suggestive Quantitative Trait Locus (QTL) on proximal Chromosome 3. When the relative axon loss was used to generate a genome-wide interval map, we identified one significant QTL (p < 0.05) on Chromosome 18 between 53.6 and 57 Mb. Within this region, the best candidate gene for modulating axon loss was Aldh7a1. Immunohistochemistry demonstrated ALDH7A1 expression in mouse RGCs. ALDH7A1 variants were not significantly associated with glaucoma in the NEIGHBORHOOD GWAS dataset, but this enzyme was identified as part of the butanoate pathway previously associated with glaucoma risk. Our results suggest that genomic background influences susceptibility to RGC degeneration and death in an inducible glaucoma model. PMID- 29421331 TI - Genotoxicity of aflatoxins and their precursors in human cells. AB - Aflatoxins are found as food contaminant and some of them demonstrate a carcinogenic effect. The aflatoxins biosynthetic pathway involves 15 successive steps. The aim of this study was to compare the toxicity of aflatoxins and their precursors in three human cell lines. We tested the four aflatoxins and two of their metabolites; three early metabolic precursors and two late biosynthetic precursors. Cyclopiazonic acid, synthesized in parallel with aflatoxins, was also tested. The cytotoxicity and the genotoxicity was evaluated with the gammaH2AX assay in three human cell lines with different bioactivation capacities. Our results indicated that the most genotoxic chemicals in the three cell lines were in decreasing order sterigmatocystin (ST), aflatoxin B1 (AFB1), aflatoxicol (AFL), aflatoxin G1 (AFG1) and versicolorin A (VERA). Aflatoxin M1 (AFM1) demonstrated genotoxic property in only one cell line. The other tested compounds did not demonstrate any genotoxic activity. Overall, our results suggested different genotoxic mechanisms of action for the tested compounds, involving specific bioactivation pathways. Moreover, some metabolic precursors of aflatoxins demonstrated genotoxic potential equivalent or greater to AFB1. This should be taking into account for the development of new strategies intended to reduce the aflatoxins exposure and for human risk assessment. PMID- 29421332 TI - In vitro permeation of palladium powders through intact and damaged human skin. AB - The use of palladium (Pd) has grown in the last decades, commonly used in automotive catalytic converters, jewellery and dental restorations sectors. Both general and working population can be exposed to this metal, which may act as skin sensitizer. This study investigated in vitro palladium powders permeation through excised intact and damaged human skin using the Franz diffusion cell method and the effect of rapid skin decontamination using sodium laureth sulphate. 1 mL of a 10 min sonicated suspension made of 2.5 g of Pd powder in 50 mL synthetic sweat at pH 4.5 and room temperature was applied to the outer surface of the skin membranes for 24 h. Pd permeation, assessed by ICP-MS, was higher when damaged skin was used (p = 0.03). Final flux permeation values and lag times were 0.02 +/- 0.01 MUg cm-2 h-1 and 6.00 +/- 3.95 h for intact, and 0.10 +/- 0.02 MUg cm-2 h-1 and 2.05 +/- 1.49 h for damaged skin samples, respectively. Damaged skin protocol enhances Pd skin penetration inside dermal layer (p = 0.04), thus making the metal available for systemic uptake. Pd penetration (p = 0.02) and permeation (p = 0.012) through intact skin decreased significantly when a cleaning procedure was applied. This study demonstrates that after skin exposure to Pd powders a small permeation of the metal happen both through intact and damaged skin and that an early decontamination with a common cleanser can significantly decrease the final amount of metal available forsystemic uptake. PMID- 29421333 TI - The urinary metabolites of DINCH(r) have an impact on the activities of the human nuclear receptors ERalpha, ERbeta, AR, PPARalpha and PPARgamma. AB - DINCH(r) (di-isononyl cyclohexane-1,2-dicarboxylate) is a non-phthalate plasticizer that has been developed to replace phthalate plasticizers such as DEHP (di-2-ethylhexyl phthalate) or DINP (di-isononyl phthalate). DINCH(r) is metabolized to its corresponding monoester and subsequently to oxidized monoester derivatives. These are conjugated to glucuronic acid and subject to urinary excretion. In contrast to DINCH(r), there are almost no toxicological data available regarding its primary and secondary metabolites. The present study aimed at the characterization of potential endocrine properties of DINCH(r) and five DINCH(r) metabolites by using reporter gene assays to monitor the activity of the human nuclear receptors ERalpha, ERbeta, AR, PPARalpha and PPARgamma in vitro. DINCH(r) itself did not have any effect on the activity of these receptors whereas DINCH(r) metabolites were shown to activate all these receptors. In the case of AR, DINCH(r) metabolites predominantly enhanced dihydrotestosterone stimulated AR activity. In the H295R steroidogenesis assay, neither DINCH(r) nor any of its metabolites affected estradiol or testosterone synthesis. In conclusion, primary and secondary DINCH(r) metabolites exert different effects at the molecular level compared to DINCH(r) itself. All these in vitro effects of DINCH(r) metabolites, however, were only observed at high concentrations such as 10 MUM or above which is about three orders of magnitude above reported DINCH(r) metabolite concentrations in human urine. Thus, the in vitro data do not support the notion that DINCH(r) or any of the investigated metabolites may exert considerable endocrine effects in vivo at relevant human exposure levels. PMID- 29421334 TI - Impact of cadmium exposure on swine enterocytes. AB - We tested cadmium (Cd2+) effects on porcine IPEC-J2 cells, which represent an in vitro model of the interaction between intestinal cells and both infectious and non-infectious stressors. Accordingly, we investigated the effects of low (2 MUM) to moderate (20 MUM) concentrations of Cd2+, in terms of pro-inflammatory gene expression and protein release, as well as of infectivity in a Salmonella typhimurium penetration model. Our data showed a significant (P < .001) increase of intracellular Cd2+ after 3, 6 and 24 h of exposure with respect to levels at 1 h. These data showed the ability of IPEC-J2 to absorb Cd2+ as a function of both time and concentration. Also, the absorption of this heavy metal was related to a significant modulation of important pro-inflammatory messengers. In particular, down-regulation of IL-8 was associated with a significant decrease of Salmonella typhimurium ability to penetrate into IPEC-J2 cells, in agreement with a previous study in which an anti-IL 8 antibody could significantly inhibit Salmonella penetration into the same cells (Razzuoli et al., 2017). This finding demonstrates the ability of Cd2+ to affect the outcome of an important host pathogen relationship. In conclusion, our study highlighted the ability of an environmental pollutant like Cd2+ to modulate innate immune responses in terms of chemokine release and gene expression, and susceptibility to microbial infections. PMID- 29421335 TI - NLRP3 inflammasome activation in the thymus of MPTP-induced Parkinsonian mouse model. AB - Ample evidence shows that Parkinson's disease (PD) is more than simply a central nervous system (CNS) disorder: the immune system appears to participate in PD pathogenesis. Extracellular misfolded alpha-synuclein (alpha-syn) may trigger an inflammatory response in the brain. Abnormal immune responses are involved in the development of PD, but little is known about the relationship between the thymus malfunction and the pathogenesis of PD. The present study investigated 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced impairment in thymus and explored possible mechanisms involved in PD pathogenesis. After subcutaneous injection of MPTP (25 mg/kg) every 4 days for 40-days, immune responses became unbalanced, with increased IL-1beta concentrations. On histopathology, mice treated with MPTP displayed pathological involution and damaged ultrastructure of the thymus. Both the PD-related oligomeric alpha-synuclein and oxidative stress related nitrated-alpha-synuclein (Tyr125, Tyr133) in mice treated with MPTP were elevated. Correspondingly, oxidative stress damage was detected in the form of increased 8-hydroxyguanosine staining. Moreover, MPTP significantly increased expression of caspase-8, NF-kappaB, NLPR3, and caspase-1 in the thymus. These results suggested that MPTP was toxic to mouse thymus via a mechanism involving the NF-kappaB and NLRP3 inflammasome pathway. These results suggested that environmental factors may lead to pathological changes in the thymus that are similar to those in the central nervous system. A disordered thymus might take part in the development of PD, and its enhanced immune response might promote the degenerative changes in the brain. PMID- 29421336 TI - Do scores on the Food Craving Inventory and Three-Factor Eating Questionnaire correlate with expected brain regions of interest in people with obesity? AB - OBJECTIVE: To examine whether subscales of Food Craving Inventory (FCI) and Three factor Eating Questionnaire (TFEQ) correlate with brain functional magnetic resonance imaging food-cue reactivity (fMRI-FCR) in the brain. METHODS: Thirty two male and female adults with obesity (19-60years; 30-39.9kg/m2) participated in a 3-week dietary intervention (1120kcal/day from either 1) total meal replacement shakes, 2) portion-controlled typical food. FCI, TFEQ and fMRI-FCR were measured pre- and post-intervention. Correlations between pre-intervention fMRI-FCR and standardized pre-intervention FCI and TFEQ subscales; and also post- versus pre-intervention change in fMRI-FCR (DeltafMRI-FCR) and standardized changes in FCI and TFEQ subscales were examined at the whole brain level using tools in FMRIB Software Library. RESULTS: Twenty-eight subjects completed the intervention. Pre-intervention high-fat food cravings (P=0.041) and fast-food cravings (P=0.017) were negatively correlated with fMRI-FCR of several brain regions that regulate executive control over ingestion (i.e. bilateral lateral frontal pole, dorsolateral prefrontal cortex and dorsal anterior cingulate cortex). Post- vs. pre-intervention change in sweet (P=0.012) and fast food cravings (P=0.004) were negatively correlated with DeltafMRI-FCR of bilateral lateral frontal pole, dorsolateral prefrontal cortex, inferior frontal gyrus (pars opercularis) and dorsal anterior cingulate cortex (i.e. brain regions that regulate executive control over ingestion). Negative correlations were also observed between the changes in sweet and fast food cravings and DeltafMRI-FCR of brain regions that regulate food reward (i.e. bilateral mid-anterior insula, right nucleus accumbens), motor readiness to ingest (i.e. bilateral precentral gyrus), internally focused attention (i.e. bilateral precuneus and posterior cingulate cortex) and visual object recognition (i.e. occipital pole, lateral occipital cortex and middle and inferior temporal cortices). Changes in cravings for starchy food (P=0.032) and overall food cravings (P=0.027) were also negatively correlated with DeltafMRI-FCR of brain regions involved in regulating internally focused attention and visual object recognition. CONCLUSIONS: In individuals with obesity, decreased food cravings seem to be reflective of increased fMRI-FCR of brain regions that regulate executive control over ingestion. Taken together, constructs measured by FCI seem to be reflective of neurophysiological processes underlying ingestive behavior and the changes in neurophysiological processes occurring during calorie restriction. CLINICAL TRIALS REGISTRY NUMBER: NCT02637271; the protocol is available at https://clinicaltrials.gov/ct2/show/NCT02637271. PMID- 29421337 TI - Role of D1- and D2-like dopaminergic receptors in the nucleus accumbens in modulation of formalin-induced orofacial pain: Involvement of lateral hypothalamus. AB - The role of dopaminergic system in modulation of formalin-induced orofacial nociception has been established. The present study aims to investigate the role of dopaminergic receptors in the nucleus accumbens (NAc) in modulation of nociceptive responses induced by formalin injection in the orofacial region. One hundred and six male Wistar rats were unilaterally implanted with two cannulae into the lateral hypothalamus (LH) and NAc. Intra-LH microinjection of carbachol, a cholinergic receptor agonist, was done 5min after intra-accumbal administration of different doses of SCH23390 (D1-like receptor antagonist) or sulpiride (D2 like receptor antagonist). After 5min, 50MUl of 1% formalin was subcutaneously injected into the upper lip for inducing the orofacial pain. Carbachol alone dose dependently reduced both phases of the formalin-induced orofacial pain. Intra accumbal administration of SCH23390 (0.25, 1 and 4MUg/0.5MUl saline) or sulpiride (0.25, 1 and 4MUg/0.5MUl DMSO) before LH stimulation by carbachol (250nM/0.5MUl saline) antagonized the antinociceptive responses during both phases of orofacial formalin test. The effects of D1- and D2-like receptor antagonism on the LH stimulation-induced antinociception were almost similar during the early phase. However, compared to D1-like receptor antagonism, D2-like receptor antagonism was a little more effective but not significant, at blocking the LH stimulation induced antinociception during the late phase of formalin test. The findings revealed that there is a direct or indirect neural pathway from the LH to the NAc which is at least partially contributed to the modulation of formalin-induced orofacial nociception through recruitment of both dopaminergic receptors in this region. PMID- 29421338 TI - Increasing flavor variety with herbs and spices improves relative vegetable intake in children who are propylthiouracil (PROP) tasters relative to nontasters. AB - American children do not meet the recommended daily servings of vegetables, and previous research suggests children who can taste the bitterness of 6-n propylthiouracil (PROP) are more likely to have low vegetable intake. This study tested the hypothesis that adding multiple herb and spice blends to vegetables to increase flavor variety within a meal would increase vegetable intake in 3-5year old children. Children attended two laboratory visits and consumed two test meals of common foods: macaroni and cheese, applesauce, carrots, milk, and water. On one visit, the meal included three servings of carrots with different herb and spice blends (Variety condition). On the other visit, all three servings of carrots were seasoned with the same herb and spice blend (No Variety condition). Overall, children consumed similar amounts of carrots by condition (36.5+/-40.5g versus 35.9+/-43.8g at the Variety and No Variety conditions, respectively); however, this relationship was moderated by PROP status. Children who tasted PROP as bitter (tasters) consumed a greater proportion of carrots during the Variety condition relative to nontasters (p=0.03). These findings suggest that children who taste PROP as bitter may be more receptive than nontasters to manipulations that increase flavor-variety of vegetables using herbs and spices. PMID- 29421339 TI - Genomic Analyses Yield Markers for Identifying Agronomically Important Genes in Potato. AB - Wild potato species have substantial phenotypic and physiological diversity. Here, we report a comprehensive assessment of wild and cultivated potato species based on genomic analyses of 201 accessions of Solanum section Petota. We sequenced the genomes of these 201 accessions and identified 6 487 006 high quality single nucleotide polymorphisms (SNPs) from 167 accessions in clade 4 of Solanum section Petota, including 146 wild and 21 cultivated diploid potato accessions with a broad geographic distribution. Genome-wide genetic variation analysis showed that the diversity of wild potatoes is higher than that of cultivated potatoes, and much higher genetic diversity in the agronomically important disease resistance genes was observed in wild potatoes. Furthermore, by exploiting information about known quantitative trait loci (QTL), we identified 609 genes under selection, including those correlated with the loss of bitterness in tubers and those involved in tuberization, two major domesticated traits of potato. Phylogenetic analyses revealed a north-south division of all species in clade 4, not just those in the S. brevicaule complex, and further supported S. candolleanum as the progenitor of cultivated potato and the monophyletic origin of cultivated potato in southern Peru. In addition, we analyzed the genome of S. candolleanum and identified 529 genes lost in cultivated potato. Collectively, the molecular markers generated in this study provide a valuable resource for the identification of agronomically important genes useful for potato breeding. PMID- 29421340 TI - 'VIOLET': a fluorescence-based simulation exercise for training healthcare workers in the use of personal protective equipment. AB - BACKGROUND: Healthcare workers caring for patients with high-consequence infectious diseases (HCIDs) require protection from pathogen exposure, for example by wearing personal protective equipment (PPE). Protection is acquired through the inherent safety of the PPE components, but also their safe and correct use, supported by adequate training and user familiarity. However, the evidence base for HCID PPE ensembles and any associated training is lacking, with subsequent variation between healthcare providers. AIM: To develop an evidence based assessment and training tool for evaluating PPE ensembles and doffing protocols, in the assessment of patients with suspected HCIDs. METHODS: VIOLET (Visualising Infection with Optimised Light for Education and Training) comprises a healthcare mannequin adapted to deliver simulated bodily fluids containing UV fluorescent tracers. On demand and remotely operated, the mannequin projectile vomits (blue), coughs (red), has diarrhoea (yellow) and is covered in sweat (orange). Wearing PPE, healthcare staff participate in an HCID risk assessment and examination of the 'patient', thereby becoming exposed to these bodily fluids. Contamination of PPE is visualized and body-mapped under UV light before and after removal. Observational findings and participant feedback, around its use as a training exercise, is also recorded. FINDINGS: Significant contamination from different exposure events was seen, enabling evaluation of PPE and doffing procedures used. Observational data and participant feedback demonstrated its strengths and success as a training technique. CONCLUSION: Simulation exercises using VIOLET provide evidence-based assessment of PPE ensembles, and are a valuable resource for training of healthcare staff in wearing and safe doffing of PPE. PMID- 29421341 TI - Inguinal Hyperhidrosis: Case Report of an Uncommon Cause of Vaginitis. AB - BACKGROUND: Hyperhidrosis (excessive sweating) affects 1%-3% of the population. Primary focal hyperhidrosis most commonly affects the axilla, palms, and soles. There are few case reports of hyperhidrosis of the genital region, typically described as inguinal hyperhidrosis or Hexsel's hyperhidrosis. CASE: A 17-year old girl presented with 3 years of copious, clear "vaginal" discharge causing significant emotional distress. After extensive gynecologic and urologic workup was negative, further review of her history was notable for excessive axillary sweating. Inguinal hyperhidrosis was suspected and she was treated with topical aluminum chloride hexahydrate with complete resolution of her symptoms. SUMMARY AND CONCLUSIONS: Inguinal hyperhidrosis, compared with other sites, is not widely described in the literature. Awareness of inguinal hyperhidrosis is important because it causes significant social embarrassment but is a treatable condition. PMID- 29421342 TI - More than Grapes and Bleeding: An Updated Look at Pelvic Rhabdomyosarcoma in Young Women. AB - STUDY OBJECTIVE: To review our local experience with urogenital rhabdomyosarcoma (RMS) to determine the most common clinical presentation(s). DESIGN: Retrospective case series of all female patients with urogenital RMS who presented to a tertiary pediatric hospital between 1996 and 2016. All institutional electronic pathology reports were screened for RMS and those that were pelvic in origin and occurred in female patients were included for further analysis. Seventeen cases of urogenital RMS in female patients were identified and reviewed. SETTING: This study was conducted at The Royal Children's Hospital in Melbourne, Australia. This is a tertiary referral center for the state of Victoria and surrounding areas, which services more than 1.5 million pediatric patients. PARTICIPANTS: Female pediatric patients (ages 0-18 years) who presented to The Royal Children's Hospital with eventual pathologic tissue diagnosis of urogenital RMS. MAIN OUTCOME MEASURES: The cases were reviewed for clinical presentation, duration of symptoms before initial presentation, time to tissue diagnosis, and outcomes of treatment. RESULTS: Of the 17 cases reviewed, 5 (29%) presented with perineal mass, 4 (24%) presented with each of abdominal mass and grape-like lesions/hemorrhagic mass at the introitus, 3 (18%) with nonspecific symptoms only, and 1 (6%) with vulvar inflammation. CONCLUSION: The clinical presentation of urogenital RMS in women is heterogeneous, and the classically described presentation of grape-like lesions at the introitus and vaginal bleeding represents only a small proportion of clinical presentations. Awareness of other presentations, which appear to be more common than previously recognized, needs to be increased to ensure timely diagnosis and treatment. PMID- 29421343 TI - Applications of virtual reality in individuals with alcohol misuse: A systematic review. AB - BACKGROUND: Alcohol use and misuse have been intensively studied, due to their negative consequences in the general population. Evidence-based literature emphasizes that alcohol craving plays a crucial role in the development and maintenance of alcohol-drinking patterns. Many individuals develop Alcohol Use Disorders (AUD); significantly, after treatment many also experience relapses, in which alcohol craving has been repeatedly implicated. Cue-exposure therapy (CET) has been widely used in the treatment of alcohol misuse, but the results are inconsistent. Virtual reality (VR) can add effectiveness to cue-exposure techniques by providing multiple variables and inputs that enable personalized alcohol use assessment and treatment. The aim of this review was to examine the applications of virtual reality in individuals who misuse alcohol. METHOD: We conducted an exhaustive literature search of the Web of Science, Scopus, Embase, Google Scholar, and PsycInfo databases, using as search items terms such as "alcohol" and its derivates, and virtual reality. RESULTS: We identified 13 studies on alcohol craving that implemented virtual reality as an assessment or treatment tool. CONCLUSIONS: The studies that incorporate VR present clear limitations. First, no clinical trials were conducted to explore the efficacy of the VR as a treatment tool; nor were there any studies of the generalization of craving responses in the real world, or of the long-term effects of VR treatment. Despite these limitations, the studies included showed consistent results as regards eliciting and reducing alcohol craving. We suggest that VR shows promise as a tool for the assessment and treatment of craving among individuals with alcohol misuse. Further studies implementing VR in the field of alcohol consumption are now required. PMID- 29421344 TI - Does consistent motivation to stop smoking improve the explanation of recent quit attempts beyond current motivation? A cross-sectional study. AB - AIMS: In seeking to provide more accurate models of population quit attempt rates, this study assessed whether a single self-report measure of consistent motivation to stop smoking adds useful explanatory power over and above an established measure of current motivation to stop. METHOD: Data from 16,657 current smokers in England were collected between October 2012 and June 2017 using cross-sectional household surveys. Smokers were asked whether they had made a serious quit attempt in the past year and they answered two questions on motivation to stop (current motivation and consistent motivation to stop smoking). Having made at least one quit attempt in the past year was regressed in logistic models onto current motivation to stop and consistent motivation to stop individually and then together, with both models adjusting for sociodemographic variables and a measure of nicotine dependence. RESULTS: The addition of consistent motivation to stop smoking added substantially to the fit of the model over and above the established measure of current motivation to quit (chi2(1, N = 16,657) = 901.7, p < 0.001) with an adjusted odds ratio of 4.1 (95% CI = 3.7-4.5, p < 0.001). CONCLUSION: Consistent motivation to stop smoking substantially improves the modelling of recent smoking cessation attempts over and above current motivation to stop. The consistency of smokers' motivation to quit may be a useful explanatory and target variable in future intervention studies. PMID- 29421345 TI - Chronic cannabis use and attentional bias: Extended attentional capture to cannabis cues. AB - INTRODUCTION: A significant proportion of chronic cannabis users experience occupational, social, and psychological problems thought to reflect, in part, cannabis-related cognitive and emotional attentional biases. The emotional attentional blink (EAB) is a unique test of attentional bias that assesses automatic responses, cue-detection failures, and rapid and temporally extended biases. Using the EAB, we tested users' and non-users' attentional biases and how cannabis exposure correlates with these attentional biases. METHODS: Forty-eight regular cannabis users and 51 non-users completed demographic, psychological, and cannabis-use reports and two EAB target-detection experiments. Each experiment comprised 160 trials. Each trial included a rapid serial visual presentation of images with one of four types of distractor images (cannabis, generically positive, neutral, or scrambled) preceding the target image. Distractor images were presented 200ms (Lag 2) or 800ms (Lag 8) before the target in Experiment 1 and 200ms (Lag 2) or 500ms (Lag 5) before the target in Experiment 2. RESULTS: Chronic cannabis users exhibited exaggerated, immediate attentional bias (Lag 2) and exaggerated, extended attentional bias (Lag 5) compared to non-users. The intensity of cannabis-use (grams per week) correlated with more errors at the extended attentional bias durations (Lags 5 and 8). CONCLUSIONS: Our results represent novel evidence of automatic attentional capture consistent with an exaggerated "wanting" motive in models of addiction. Our unique evidence of temporally extended attentional biases is consistent with attentional disengagement deficits associated with chronic cannabis use. PMID- 29421346 TI - Very light smoking and alternative tobacco use among college students. AB - INTRODUCTION: Concurrent use of cigarettes with alternative tobacco products (ATPs), even among very light smokers, may be harmful. This study examined current use of e-cigarettes, cigars, and hookah, and susceptibility to future use of these products in a sample of college student cigarette smokers. METHODS: Participants were 1161 18-29 year old (M age = 21.15; SD = 2.72; 52.7% female; 41.2% non-Hispanic white) current, or past 30-day cigarette smokers, drawn from a larger study. Current smokers were categorized as very light smokers [<=5 cigarettes per day (cpd)] and heavier smokers (>5 cpd). RESULTS: 88.6% of all participating college student smokers were very light smokers and 67.7% used at least one ATP concurrently. The prevalence of current use in this sample was 42.9% for e-cigarettes, 36.4% for hookah, and 25.9% for cigars. Compared to heavier smokers, very light smokers were more likely to be younger, racial/ethnic minorities, and four-year versus two-year college students. Multilevel logistic regression models showed that after controlling for socio-demographic characteristics and substance use, being a very light smoker, compared with a heavier smoker, was negatively associated with concurrent e-cigarette use, but positively associated with concurrent cigar use, and not associated with concurrent hookah use. Moreover, compared to heavier smokers, very light smokers reported being more susceptible to future cigar and hookah use, but not e cigarette use. CONCLUSIONS: Concurrent use of cigarettes with ATPs is popular among all college student smokers, but very light smokers are more likely than heavier smokers to use combustible ATPs. Smoking intervention programs and campus policies should caution smokers, especially very light smokers, against ATP use. PMID- 29421348 TI - Diffusion-weighted MRI measures suggest increased white-matter integrity in Internet gaming disorder: Evidence from the comparison with recreational Internet game users. AB - Several studies have suggested that Internet gaming disorder (IGD) is related to altered brain white matter integrity. However, seeming inconsistencies exist and may reflect comparison groups not matched well for certain gaming characteristics. In order to address this possible concern, we recruited in the present study individuals with recreational Internet game use (RGU) comprised of individuals who spend similar amounts of time as IGD subjects playing online games without developing IGD. Diffusion tensor imaging data were collected from 42 IGD and 44 RGU subjects. Whole-brain comparisons showed that IGD subjects demonstrated increased fractional anisotropy (FA) in the bilateral anterior thalamic radiation, anterior limb of the internal capsule, bilateral corticospinal tract, bilateral inferior fronto-occipital fasciculus, corpus callosum, and bilateral inferior longitudinal fasciculus. In addition, Internet addiction severity was positively correlated with FA values. Taken together, we conclude that IGD is associated with measures of increased white-matter integrity in tracts linking reward circuitry and sensory and motor control systems. PMID- 29421349 TI - The association between bouts of moderate to vigorous physical activity and patterns of sedentary behavior with frailty. AB - OBJECTIVES: To determine if bouts of moderate-vigorous physical activity (MVPA) and patterns of sedentary behavior are associated with frailty. METHOD: Accelerometry from community-dwelling adults >=50 years old (n = 2317) enrolled in the 2003-04 and 2005-06 National Health and Nutrition Examination Survey were used. Bouted (>=10 min) and sporadic (<10 min) durations of MVPA were analyzed based on meeting 0%, 1-49%, 50-99%, and >=100% of physical activity guidelines (150 min/week of MVPA). Prolonged sedentary behavior were bouts lasting >=30 min. Breaks from sedentary behavior were defined as any >=1 min interruption in sedentary behavior. Average intensity (counts/min) and duration (minutes) during breaks were also analyzed. Frailty was measured with a 46-item frailty index. RESULTS: Multivariable linear regression models adjusting for age, sex, education, ethnicity, income, marital status, smoking, alcohol consumption, body mass index, total sedentary time and accelerometer wear time indicated that meeting any percentage of the activity guidelines with bouted and sporadic MVPA was associated with reduced frailty. This relationship peaked at meeting 50-99% of guidelines and was associated with a 1.5 and 2.0 point reduction in the frailty index for bouted and sporadic MVPA, respectively. Two additional prolonged sedentary behavior bouts/day were associated with an additional frailty index deficit while every additional 100 cpm in average break intensity and every 2 min in average break duration were associated with one less deficit. Total sedentary breaks were not associated with frailty. CONCLUSION: These population level data give justification for determining if interventions which target short bouts of MVPA and interrupting prolonged, uninterrupted time spent in sedentary behaviors can treat or prevent frailty worsening. PMID- 29421347 TI - The emerging marijuana retail environment: Key lessons learned from tobacco and alcohol retail research. AB - The emerging retail market for recreational marijuana use warrants research and surveillance as such markets are established in more US states. This research can be informed by the existing literature regarding tobacco and alcohol, which highlights the impact of spatial access to tobacco and alcohol retailers and exposure to tobacco and alcohol marketing on smoking and drinking among youth and young adults. Prior research indicates that tobacco and alcohol retailers, as well as medical marijuana dispensaries, are disproportionately located in neighborhoods characterized by socioeconomic disadvantage and by higher proportions of racial/ethnic minorities and young adults. Moreover, retail marketing or point-of-sale practices may differentially target subpopulations and differ by neighborhood demography and local policy. This literature and the methods employed for studying the tobacco and alcohol market could inform research on the retail environment for marijuana, as current gaps exist. In particular, much of the existing literature involves cross-sectional research designs; longitudinal studies are needed. Moreover, standardized measures are needed for systematic monitoring of industry marketing practices and to conduct research examining neighborhood differences in exposure to retail marketing for marijuana and its contribution to use modality and frequency, alone and in combination with nicotine and alcohol. The use of standardized measures for tobacco and alcohol marketing have been critical to develop an evidence base from cross-sectional and longitudinal studies that document the impact of retail marketing on substance use by adolescents and adults. Similar research is needed to establish an evidence base to inform federal, state, and local regulations of marijuana. PMID- 29421350 TI - Long-term evaluation of osteoarthritis sheep knee, treated with TGF-beta3 and BMP 6 induced multipotent stem cells. AB - BACKGROUND: Hyaline articular cartilage, which protects the bones of diarthrodial joints from forces associated with load bearing, frictions, and impacts has very limited capacities for self-repair. Over the years, the trend of treatments has shifted to regenerations and researchers have been on the quest for a lasting regeneration. We evaluated the treatment of osteoarthritis by chondrogenically induced ADSCs and BMSCs for a long time functional recovery. METHODS: Osteoarthritis was induced at the right knee of sheep by complete resection of ACL and medial meniscus. Stem cells from sheep were induced to chondrogenic lineage. Test sheep received 5 mls single doses of 2 * 107 autologous PKH26 labelled ADSCs or BMSCs, while controls received basal medium. Functional recovery of the knees was evaluated via electromyography. RESULTS: Induced ADSCs had 625, 255, 393, 908, 409, 157 and 1062 folds increases of collagen I, collagen II, aggrecan, SOX9, cartilage oligomeric protein, chondroadherin and fibromodullin compare to uninduced cells, while BMSCs had 702, 657, 321, 276, 337, 233 and 1163 respectively; p = .001. Immunocytochemistry was positive for these chondrogenic markers. 12 months post-treatment, controls scored 4 in most regions using ICRS, while the treated had 8; P = .001. Regenerated cartilages were positive to PKH26 and demonstrated the presence of condensing cartilages on haematoxylin and eosin; and Safranin O. OA degenerations caused significant amplitude shift from right to left hind limb. After treatments, controls persisted with significant decreases; while treated samples regained balance. CONCLUSIONS: Both ADSCs and BMSCs had increased chondrogenic gene expressions using TGF-beta3 and BMP-6. The treated knees had improved cartilage scores; PKH26 can provide elongated tracking, while EMG results revealed improved joint recoveries. These could be suitable therapies for osteoarthritis. PMID- 29421351 TI - Age-related remodelling of the myotendinous junction in the mouse soleus muscle. AB - The age-related loss of muscle mass and function predominantly affect muscles of the lower limbs and have largely been associated with decline in muscle fibre size and number, although the exact mechanisms underlying these losses are poorly understood. In addition, consistent reports that the loss of muscle strength exceeds that which can be explained by declines in muscle mass has widened the search for causes of sarcopenia to include supporting tissues such as the extracellular matrix and tendons. Although the changes to both muscle and tendon with age are well characterised, little work has focused on the interface between these two tissues, the myotendinous junction (MTJ). Given the crucial role for this structure in force transfer between muscle and tendon, we asked whether the myotendinous junction underwent structural changes with age in lower limb muscle. We used whole muscle to assess gross muscle and tendon morphology, and immunohistochemistry to determine fibre and MTJ profile number in young (6 months), middle aged (18 months) and elderly (24 months) C57BL/6 female mice. MTJ length was quantified using serial cross sections of the soleus muscle. We found an apparent 3.5-fold increase in MTJ profiles per cross section with no increase in fibre number in old mice, and found this to be a result of a doubling in length of the MTJ region with age. This coincided with an increase in proximal tendon length (31%), as well as an increase in collagen deposition between 6 and 24-months of age consistent with an expansion of the fibre termination area. These findings uncover a previously undescribed effect of ageing on the MTJ and open up new lines of investigation into the role of this structure in the age related loss of muscle function. PMID- 29421352 TI - Combined effects of antimony and sodium diethyldithiocarbamate on soil microbial activity and speciation change of heavy metals. Implications for contaminated lands hazardous material pollution in nonferrous metal mining areas. AB - The combined effects of antimony (Sb) and sodium diethyldithiocarbamate (DDTC), a common organic flotation reagent, on soil microbial activity and speciation changes of heavy metals were investigated for the first time. The results showed that the exchangeable fraction of Sb was transformed to a stable residual fraction during the incubation period, and the addition of DDTC promoted the transformation compared with single Sb pollution, probably because DDTC can react with heavy metals to form a complex. In addition, the presence of DDTC and Sb inhibited the soil microbial activity to varying degrees. The growth rate constant k of different interaction systems was in the following order on the 28th day: control group >= single DDTC pollution > combined pollution > single Sb pollution. A correlation analysis showed that the concentration of exchangeable Sb was the primary factor that affected the toxic reaction under combined pollution conditions, and it significantly affected the characteristics of the soil microorganisms. All the observations provide useful information for a better understanding of the toxic effects and potential risks of combined Sb and DDTC pollution in antimony mining areas. PMID- 29421353 TI - Enhanced bioelectroremediation of a complexly contaminated river sediment through stimulating electroactive degraders with methanol supply. AB - Bioelectroremediation is an efficient, sustainable, and environment-friendly remediation technology for the complexly contaminated sediments. Although various recalcitrant pollutants could be degraded in the electrode district, the degradation efficiency was generally confined by the low total organic carbon (TOC) content in the sediment. How to enhance the electroactive degraders' activity and efficiency remain poorly understood. Here we investigated the bioeletroremediation of a complexly contaminated river sediment with low TOC in a cylindric sediment microbial fuel cell stimulated by methanol. After 200 days treatment, the degradation efficiencies of total petroleum hydrocarbons (TPH), polycyclic aromatic hydrocarbons (PAH), and cycloalkenes (CYE) in the electrode district with methanol stimulation were 1.45-4.38 times higher compared with those in the non-electrode district without methanol stimulation. The overall electrode district communities were significantly positively correlated with the variables of the enhanced TPH, PAH, CYE and TOC degradation efficiencies (p < .01). The joint electrical and exogenous methanol stimulation selectively enriched electroactive degraders (Geobacter and Desulfobulbus) in the anode biofilms, and their proportion was markedly positively correlated with the characteristic and total pollutants degradation efficiencies (p < .001). This study offers a new insight into the response of key electroactive degraders to the joint stimulation process. PMID- 29421354 TI - Risk management of ochratoxigenic fungi and ochratoxin A in maize grains by bioactive EVOH films containing individual components of some essential oils. AB - Aspergillus steynii and Aspergillus tubingensis are possibly the main ochratoxin A (OTA) producing species in Aspergillus section Circumdati and section Nigri, respectively. OTA is a potent nephrotoxic, teratogenic, embryotoxic, genotoxic, neurotoxic, carcinogenic and immunosuppressive compound being cereals the first source of OTA in the diet. In this study bioactive ethylene-vinyl alcohol copolymer (EVOH) films containing cinnamaldehyde (CINHO), linalool (LIN), isoeugenol (IEG) or citral (CIT) which are major components of some plant essential oils (EOs) were produced and tested against A. steynii and A. tubingensis growth and OTA production in partly milled maize grains. Due to the favourable safety profile, these bioactive compounds are considered in the category "GRAS". The study was carried out under different water activity (0.96 and 0.99 aw), and temperature (24 and 32 degrees C) conditions. ANOVA showed that class of film, fungal species, aw and temperature and their interactions significantly affected growth rates (GR), ED50 and ED90 and the doses for total fungal growth inhibition and OTA production. The most effective EVOH films against both species were those containing CINHO. ED50, ED90 and doses for total growth and OTA inhibition were 165-405, 297-614, 333-666 MUg of EVOH-CINHO/plate (25 g of maize grains), respectively, depending on environmental conditions. The least efficient were EVOH-LIN films. ED50, ED90 and doses for total growth and OTA inhibition were 2800->3330, >3330 and >3330 MUg of EVOH-LIN/plate (25 g of maize grains), respectively. The effectiveness of the bioactive films increased with increasing doses. Overall, A. tubingensis was less sensitive to treatments than A. steynii. Depending on the species, aw and temperature affected GR and OTA production in a different way. In A. steynii cultures, optimal growth occurred at 0.96 aw and 32 degrees C while optimal OTA production happened at 0.99 aw and 32 degrees C. In A. tubingensis cultures optimal growth happened at 0.99 aw and 32 degrees C, although the best conditions for OTA production were 0.99 aw and 24 degrees C. Thus, these species can be very competitive in warm climates and storage conditions. The EVOH-CINHO films followed by EVOH-IEG and EVOH-CIT films, designed in this study and applied in vapour phase, can be potent antifungal agents against A. steynii and A. tubingensis and strong inhibitors of OTA biosynthesis in maize grains at very low doses. This is the first study on the impact that interacting environmental conditions and bioactive films containing individual components of EOs have on the growth of these ochratoxigenic fungi and on OTA production in maize grains. PMID- 29421355 TI - Outgraded produce variably retains surface inoculated Escherichia coli through washing. AB - The use of secondary quality produce has gained attention as a solution to food waste in both the U.S. and Europe. The purpose of this study was to evaluate the impact of using secondary quality or outgraded produce on the retention of surface inoculated E. coli following a rinse treatment on four model fresh produce systems (apple, tomato, carrot, lettuce). A three-strain cocktail of rifampicin-resistant generic E. coli, with a concentration of 9.0 log CFU/mL, was spot-inoculated on the intact surfaces of U.S. No.1 grade produce items and damaged or decayed areas of outgraded produce items. Generally, outgraded produce of all four kinds retained higher levels of inoculated E. coli following two postharvest treatments, chlorinated (150 ppm) or water only. However, physical damage, those defects which compromised the integrity of the produce surface, lead to significantly greater E. coli levels following rinsing than did physiological defects. Compared to U.S. No.1 quality apples, outgraded apples retained 4.3 +/- 1.4 log CFU/g more E. coli following water only treatment, and 3.6 +/- 1.7 log CFU/g more following chlorine treatment. Outgraded tomatoes retained significantly more (3.5 +/- 1.1 log CFU/g) inoculated E. coli following water only rinse and 3.0 +/- 1.4 log CFU/g more inoculated E. coli following chlorine treatment than U.S. No.1 quality tomatoes did under the same treatment conditions. Outgraded carrots retained 1 +/- 1.1 log more CFU/g inoculated E. coli following water only treatment and 0.5 +/- 0.8 log more CFU/g inoculated E. coli following chlorine treatment, compared to U.S. No.1 carrots. Outgraded lettuce leaves retained 1.6 +/- 0.5 log CFU/g more inoculated E. coli following water only treatment and 4.1 +/- 0.4 log CFU/g more inoculated E. coli following chlorine treatment than did U.S. No.1 quality lettuce leaves under the same treatment conditions. Treating with 150 ppm chlorine was not sufficient to eliminate the increased microbial retention associated with secondary quality or outgraded produce, and the efficacy of disinfection was greatly affected by type of defect. Apples with physical damage retained significantly higher E. coli loads than did those with physiological defects, an additional 2.6 log CFU/g under chlorine treatment and 0.8 log CFU/g more under was water only treatment. Tomatoes with physical damage had a 1.3-log CFU/g and 0.6-log CFU/g average increase of retained E. coli counts compared to those with physiological defects following a chlorine and water only treatment, respectively. Although a chlorine dip provided only a modest reduction in pathogens, generally, outgraded produce with physiological defects may present less food safety risks if introduced into the fresh market than does produce with physical damage due to their enhanced retention of bacterial cells. Therefore, as industry considers how to minimize its food waste problem, preferentially directing physically damaged produce away from the fresh market will help to minimize risk while maximizing food resources. PMID- 29421356 TI - The impact of dairy cows' bedding material and its microbial content on the quality and safety of milk - A cross sectional study of UK farms. AB - The introduction of bedding dairy cows on recycled manure solids (RMS) in the UK led to concern by competent authorities that there could be an increased, unacceptable risk to animal and human health. A cross-sectional study was designed to evaluate the microbial content of different bedding materials, when used by dairy cows, and its impact on the microbial content of milk. Data were collected from farms bedding lactating cows on sand (n=41), sawdust (n=44) and RMS (n=40). The mean duration of RMS use prior to sampling was 13months. Total bacterial count, and counts of Streptococcus/Enterococcus spp., Staphylococcus spp., Bacillus cereus, thermophilic, thermoduric and psychrotrophic bacteria were determined in used bedding and milk. Samples were evaluated for the presence/absence of Listeria monocytogenes, Salmonella spp. and Yersinia enterocolitica. Data on milking practices were collected to investigate their potential to reduce microbial transfer from bedding to milk. There were substantial differences in bacterial counts both within and between bedding materials. However, there were no significant differences between bedding groups in counts in milk for any of the organisms studied, and no significant correlations between bacterial load in used bedding and milk. Fore-milking was associated with a reduced total bacterial count in milk. Dipping teats with disinfectant and drying, prior to milking, was associated with lower numbers of Streptococcus/Enterococcus spp. in milk. Disinfecting clusters between milking different cows was associated with a reduction in thermophilic and psychrotrophic counts in milk. This study did not provide evidence that use of RMS bedding increased the risk of presence of Y. enterocolitica, Salmonella spp. or L. monocytogenes in milk. However, the strength of this conclusion should be tempered by the relatively small number of farms on which Y. enterocolitica and Salmonella spp. were isolated. It is concluded that, despite the higher bacterial load of RMS, its use as bedding for lactating dairy cows need not be associated with a higher bacterial load in milk than the use of sand or sawdust. However, this finding must be interpreted in the light of the relatively recent introduction of RMS as a bedding material on the farms studied. Teat preparation provides a control point for the potential transfer of microorganisms from bedding to milk. The detection of zoonotic pathogens in a small proportion of milk samples, independent of bedding type, indicates that pasteurisation of milk prior to human consumption remains an important control measure. PMID- 29421357 TI - Characterisation of ail-positive Yersinia enterocolitica of different biotypes using HRMA. AB - Yersiniosis is one of the four most frequent foodborne zoonotic diseases in Europe, and Yersinia enterocolitica is the primary agent in human infections. The ail gene is an important chromosomal virulence marker of Y. enterocolitica which encodes Ail, a 17-kDa outer membrane protein that promotes attachment and invasion. In the present study, ail-positive Y. enterocolitica strains of different biotypes were examined using high resolution melting analysis (HRMA) and DNA sequencing. Genotype data relating to Y. enterocolitica strains isolated from different sources and belonging to different biotypes were compared. Applied method allowed efficient distinguishing of three genotypes and phylogenetic groups: 1A - included non-pathogenic Y. enterocolitica strains; 1B - consisted of highly pathogenic Y. enterocolitica strains and 2/4 - involved weakly pathogenic Y. enterocolitica strains. Amplicon genotyping based on HRMA supports rapid identification of ail SNPs correlated with biotype of examined Y. enterocolitica strains. PMID- 29421358 TI - Ability of Shiga toxigenic Escherichia coli to survive within dry-surface biofilms and transfer to fresh lettuce. AB - Biofilms are known to play important roles in bacterial survival and persistence in food-processing environments. This study aimed to determine the ability of the top 7 STEC serotypes to form biofilms on polystyrene (POL) and stainless steel (SS) plates and to quantify their survival and transfer from dry-surface biofilms to lettuce pieces. The ability of 14 STEC strains to form biofilms on these two materials at different exposure times and temperatures was assessed using crystal violet, Congo red and SEM. At 10 degrees C all serotypes were weak biofilm producers on both surfaces. In contrast, serotypes O45-040, O45-445, O103-102, O103-670 and O157-R508 were strong biofilm producers at 25 degrees C. Strains O103-102, O103-670, O111-CFS, O111-053 and O157:H7-R508 were expressers of curli. Under scanning electron microscopy, strains O103-670, O111-CFS, O157-R508, and O121-083 formed more discernible multilayer, mature biofilms on SS coupons. Regardless of the surface (POL/SS), all STEC strains were able to transfer viable cells onto fresh lettuce within a short contact time (2 min) to varying degrees (up to 6.35 log cfu/g). On POL, viable cell of almost all serotypes exhibited decreased detachment (p = 0.001) over 6 days; while after 30 days on SS, serotypes O45-040, O103-102, O103-670, O111-053, O111-CFS, O121-083, O145-231 O157:H7-R508 and O157:H7-122 were transferred to lettuce. After enrichment, all 14 STEC strains were recovered from dry-surface biofilms on POL and SS plates after 30 days. Results demonstrated that the top 7 STEC remained viable within dry-surface biofilms for at least 30 days, transferring to lettuce within 2 min of exposure and acting as a source of adulteration. PMID- 29421359 TI - Emergence of plasmid-mediated colistin-resistance in CMY-2-producing Escherichia coli of lineage ST2197 in a Tunisian poultry farm. AB - Our study aimed to investigate colistin resistance and the mechanisms involved in a collection of 35 extended-spectrum beta-lactamase (ESBL) and 13 CMY-2-producing E. coli strains which were previously recovered from chicken gut microbiota in Tunisia, as well as to determine the genetic location of mcr genes. Forty-eight ESBL and CMY-2-producing E. coli strains were obtained from 137 fecal samples of healthy chickens during 2013. These strains were tested for colistin resistance by the broth microdilution method, and screened for mcr-1 and mcr-2 genes by PCR. Two of these strains were colistin-resistant (MIC = 8 mg/L). Both harbored the mcr-1 gene, were CMY-2 producers, and were additionally resistant to tetracycline, ciprofloxacin, chloramphenicol, gentamicin, tobramycin and trimethoprim-sulfamethoxazole. They shared phylogroup A, the same pulsed-field gel electrophoresis (PFGE)-pattern, and were typed as ST2197. In both strains, ISApl1 and pap2 were detected upstream and downstream of mcr-1 gene, respectively. The analysis of the two mcr-1-positive strains and their transconjugants by PCR-based replicon typing and S1-PFGE, demonstrated that mcr-1 gene is linked to an IncP plasmid (~242 kb), and blaCMY-2 to an IncI1 plasmid (97 kb). The occurrence of E. coli harboring mcr-1 gene among intestinal microbiota in poultry and its location on a conjugative plasmid could represent a risk for public health. The evolution of this type of resistant microorganisms should be evaluated in the future. PMID- 29421360 TI - Discrimination of infectious and heat-treated norovirus by combining platinum compounds and real-time RT-PCR. AB - Human noroviruses (NoV) are major agents of foodborne outbreaks. Because of the lack of a standardized cell culture method, real-time reverse transcriptase PCR is now commonly used for the detection of NoV in foodstuffs and environmental samples. However, this approach detects the viral nucleic acids of both infectious and non-infectious viruses and needs to be optimized to predict infectivity for public health risk assessment. The aim of this study was to develop a viability PCR method to discriminate between native and heat-treated virus, for both NoV and its surrogate, murine norovirus (MNV). To this end, screening of viability markers (monoazide dyes, platinum and palladium compounds) was performed on viral RNA, native virus or heat-treated virus, and incubation conditions were optimized with PtCl4, the most efficient viability marker. Multiple MNV molecular models were designed: no impact of amplicon length was observed on inactivated MNV genomic titer; but the 5'NTR, ORF1 and 3'UTR regions resulted in higher reductions than central genomic regions. The optimal viability PCR conditions developed (incubation with 2.5 mM PtCl4 in PBS for 10 min at 5 degrees C) were finally applied to MNV by performing heat inactivation studies and to native and heat-treated NoV clinical strains. The viability PCR discriminated efficiently between native and heat-inactivated MNV at 72 degrees C and 80 degrees C, and efficiently reduced the genomic titer of heat-treated NoV strains. This viability PCR method could be useful to study heat inactivation kinetics of NoV and MNV. It could also be evaluated for the identification of infectious enteric viruses in foodstuffs and environmental samples. PMID- 29421361 TI - Quantification of the Campylobacter contamination on broiler carcasses during the slaughter of Campylobacter positive flocks in semi-industrialized slaughterhouses. AB - Campylobacter contamination of broiler carcasses has been little studied in semi industrialized slaughterhouses in developing countries, where several steps are carried out manually or with limited technology. In this study, we performed quantification of the Campylobacter contamination on carcasses at four steps in the slaughter process in three Ecuadorian slaughterhouses. Therefore, 15 Campylobacter positive batches were sampled in three commercial slaughterhouses. For every batch, caecal content and five samples of breast skin were taken and examined for Campylobacter counts at the following steps: after plucking, after evisceration, after final washing and after water chilling. Slaughterhouse C was the only slaughterhouse in which Campylobacter counts increased significantly after evisceration. No significant differences were found between counts after evisceration and after final washing (P > 0.05). In all slaughterhouses, a significant reduction of Campylobacter counts (0.11 to 2.55 log10 CFU/g) was found after the chilling step. The presence of chlorine in the chilling water was associated with the highest reduction in Campylobacter counts on the carcasses. A high variability of Campylobacter counts was found within and between batches slaughtered in the same slaughterhouse. Campylobacter counts in caecal content samples were not correlated with counts on carcasses after plucking nor after evisceration. PMID- 29421362 TI - Increased exposure to extended-spectrum beta-lactamase-producing multidrug resistant Enterobacteriaceae through the consumption of chicken and sushi products. AB - The aim of this study was to determine the occurrence and patterns of resistance of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae in food products purchased in Navarra, northern Spain. A total of 174 samples of fish and chicken were analyzed from September 2015 to September 2016, including raw and ready-to-eat products: trout (n = 25), salmon (n = 28), panga (n = 13), chicken nuggets and chicken scalopes (n = 32), sushi (n = 31) and sliced cooked poultry (n = 45). Cefpodoxime-resistant strains were isolated on ChromID ESBL agar and further phenotypic (antimicrobial study on MicroScan(c) NM37 panel) and genotypic characterization (multiplex PCR, sequencing and multi-locus sequence typing, MLST) was performed to confirm and characterize ESBL producers. Raw chicken and sushi have been determined as the most risky products regarding transmission of ESBL-producing Enterobacteriaceae (occurrence 53.1% and 19.4%, respectively), while sliced cooked poultry products appear to be a safe product in this aspect. With regard to raw fish, prevalence in salmon was lower (3.6%) than in trout and panga (16.0%). Ninety-eight per cent of ESBL isolates (n = 50) show multidrug resistant profiles, highlighting the high resistances against quinolones and tetracyclines observed in chicken isolates, as well as against ertapenem and chloramphenicol in sushi strains. Predominant beta-lactamase type was SHV-12 (50.1%), followed by TEM-type (24.5%) and CTX-M (20.8%). In addition, CTX-M type was only detected in chicken products. The phylogenetic study showed the prevalence of groups A (35%), F (25%) and B1 (15%), usually related to nonvirulent strains. MLST E. coli isolates (n = 20) were grouped into 5 clonal complexes (CC) and 15 sequence types (ST), showing high clonal diversity. ST117 was the prevalent sequence type, while the human pathogen ST131 was not detected in this study. The high prevalence of ESBL-producing multidrug-resistant Enterobacteriaceae detected in products of widespread consumption such as chicken and sushi, increases the concern regarding human exposure to superbugs and encourages the need to improve surveillance of this public health issue. PMID- 29421363 TI - Alternative patulin pathway unproven. PMID- 29421364 TI - Identifying possible non-thermal effects of radio frequency energy on inactivating food microorganisms. AB - Radio frequency (RF) heating has been successfully used for inactivating microorganisms in agricultural and food products. Athermal (non-thermal) effects of RF energy on microorganisms have been frequently proposed in the literature, resulting in difficulties for developing effective thermal treatment protocols. The purpose of this study was to identify if the athermal inactivation of microorganisms existed during RF treatments. Escherichia coli and Staphylococcus aureus in apple juice and mashed potato were exposed to both RF and conventional thermal energies to compare their inactivation populations. A thermal death time (TDT) heating block system was used as conventional thermal energy source to simulate the same heating treatment conditions, involving heating temperature, heating rate and uniformity, of a RF treatment at a frequency of 27.12 MHz. Results showed that a similar and uniform temperature distribution in tested samples was achieved in both heating systems, so that the central sample temperature could be used as representative one for evaluating thermal inactivation of microorganisms. The survival patterns of two target microorganisms in two food samples were similar both for RF and heating block treatments since their absolute difference of survival populations was <1 log CFU/ml. The statistical analysis indicated no significant difference (P > 0.05) in inactivating bacteria between the RF and the heating block treatments at each set of temperatures. The solid temperature and microbial inactivation data demonstrated that only thermal effect of RF energy at 27.12 MHz was observed on inactivating microorganisms in foods. PMID- 29421365 TI - Inhibition of quorum sensing-controlled virulence factors and biofilm formation in Pseudomonas fluorescens by cinnamaldehyde. AB - Pseudomonas fluorescens, an important food spoiling bacteria, uses quorum sensing to control biofilm formation and motility. To date, only a few compounds targeting the LuxR-based quorum sensing system of P. fluorescens have been identified. In the present study, the quorum sensing inhibitory effect of cinnamaldehyde at sublethal concentrations was investigated in terms of inhibition of the extracellular protease, biofilm formation, and swimming and swarming motility. The total volatile basic nitrogen value was also measured to evaluate the effect of cinnamaldehyde on quality preservation of turbot fillets stored at 4 +/- 1 degrees C for 15 days. The results showed that cinnamaldehyde significantly inhibited quorum sensing-dependent factors in P. fluorescens and extended the storage life of turbot. Unexpectedly, cinnamaldehyde did not interfere with production of AHLs (N-acylhomoserine lactones) by P. fluorescens, as shown by measurement of AHL production using GC-MS. Molecular docking analysis revealed that cinnamaldehyde can interact with the LuxR-type protein of P. fluorescens, which could constitute the molecular basis of the quorum sensing inhibition observed. These findings strongly suggest that cinnamaldehyde is a quorum sensing inhibitor with great potential for the preservation of aquatic products to guarantee food safety. PMID- 29421366 TI - Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat. AB - The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF 1), but also glutamatergic transmission, including receptors such as the N-methyl d-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients. PMID- 29421367 TI - Mothers, fathers, sons, and daughters: Are there sex differences in the organization of secure base behavior during early childhood. AB - Recent empirical studies reporting sex differences in attachment relationships have prompted investigators to consider why and under what conditions such results might be observed. This study was designed to explore possibilities of identifying sex differences in the organization of attachment-relevant behavior during early childhood. Observations of 119 children (59 boys) with their mothers and (separately) with their fathers were completed and children were described using the AQS. Results indicated that girls and boys did not differ with respect to global attachment security but at more specific level analyses revealed differences between parents that reflected differences in the behaviors of girls vs. boys with mothers and fathers. Our findings contradict arguments from evolutionary psychologists claiming that sex differences in attachment organization arise during middle childhood. By adopting an attachment measure sensitive to the possibility of behavioral sex differences our data suggest that such differences may be detectable earlier in development. Moreover, these differences are subtle and nuanced and do not suggest large sex differences in attachment security per se. PMID- 29421368 TI - Construct validation of the hybrid model of posttraumatic stress disorder: Distinctiveness of the new symptom clusters. AB - Despite the factor analytic support for the seven-factor hybrid model (Armour et al., 2015) of posttraumatic stress disorder (PTSD), little research has examined the degree to which newly established symptom clusters (i.e., negative affect, anhedonia, dysphoric arousal, anxious arousal, externalizing behavior) functionally and meaningfully differ in their associations with other clinical phenomena. The aim of the current study was to examine the degree to which newly established PTSD symptom clusters differentially relate to co-occurring psychopathology and related clinical phenomena through Wald testing using latent variable modeling. Participants were 535 trauma-exposed undergraduates who completed the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5; Weathers et al., 2013) and Personality Assessment Inventory (PAI; Morey, 1991). As expected and in line with results from previous studies, significant heterogeneity emerged for dysphoric arousal, anxious arousal, and externalizing behavior. However, there was less evidence for the distinctiveness of negative affect and anhedonia. Results indicate that only some of the newly established symptom clusters significantly differ in their associations with related clinical phenomena and that the hybrid model might not provide a meaningful framework for understanding which PTSD symptoms relate to associated features. Limitations include a non-clinical sample and reliance on retrospective self-report assessment measures. PMID- 29421369 TI - Who benefits most from therapist-assisted internet-delivered cognitive behaviour therapy in clinical practice? Predictors of symptom change and dropout. AB - Internet-delivered cognitive behavioral therapy (ICBT) is effective for treating anxiety and depression, but not for all patients. Predictors of dropout and outcomes from ICBT remain unclear and the literature could benefit from study of response to ICBT among larger community samples using advanced statistical techniques. In this study, we sought to identify predictors of dropout and symptom change in a large community sample (n = 1201) who received therapist assisted transdiagnostic ICBT targeting anxiety and/or depression. Logistic regression was used to assess dropout, and showed that those who fully completed ICBT lessons (n = 880) were older and endorsed lower psychological distress at intake than those who only partially completed ICBT lessons (n = 321). During the course of therapy, patients responded to the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 at six time points. Autoregressive latent trajectory models were fitted to this data to assess the ability of demographic variables, program engagement, psychological and medical service usage, and psychological distress to explain individual variance in initial symptom levels and symptom change over time. Higher symptom scores at pre-treatment were predictive of greater symptom improvement. Symptom improvement was greater in those who were off work on disability and those without higher post-secondary education. Clinical implications are discussed. PMID- 29421370 TI - Resolving the vulnerability paradox in the cross-national prevalence of posttraumatic stress disorder. AB - Socioeconomically disadvantaged individuals are at heightened risk for developing posttraumatic stress disorder (PTSD) following exposure to trauma. Yet a study of cross-national lifetime prevalence rates of PTSD revealed that countries scoring high on an index reflecting cultural and socioeconomic disadvantage exhibited lower rates of PTSD in response to trauma, evincing what the authors called "a vulnerability paradox in the cross-national prevalence of post-traumatic stress disorder" Duckers, Alisic, & Brewin (2016a, p. 300). Drawing on classic studies in sociology and political science concerning the ecological fallacy, the author suggests ways to resolve the striking paradox discovered by Duckers et al. PMID- 29421371 TI - Changing disgust through imagery rescripting and cognitive reappraisal in contamination-based obsessive-compulsive disorder. AB - Contamination-related obsessive-compulsive disorder (C-OCD) is characterized by strongly experienced disgust and fear, in response to potentially contaminating stimuli. Both emotions differ in their susceptibility for change by habituation and extinction, which are important processes for the success of exposure therapy. Even though the response rates for exposure therapy for C-OCD are very good, it seems promising to test additional therapeutic techniques which target disgust more directly. Therefore, imagery rescripting and cognitive reappraisal were evaluated for their potential to change levels of disgust (within-subject), in the two-session laboratory study with 30 participants, with diagnosed C-OCD, and 30 matched, healthy controls (between-subject), presented. The results show that both emotion-regulation strategies reduced disgust better than a non intervention control task (counting fishes), across all the participants. Therefore, both strategies seem to be applicable and effective for reducing disgust, in the short term, in participants with diagnosed C-OCD. The implications of these findings for the experimental approach and for the clinical treatment of C-OCD, are discussed. PMID- 29421372 TI - ICD-11 complex PTSD among Israeli male perpetrators of intimate partner violence: Construct validity and risk factors. AB - The International Classification of Diseases 11th Version (ICD-11) will include Complex Posttraumatic Stress Disorder (CPTSD) as a unique diagnostic entity comprising core PTSD and DSO (disturbances in self-organization) symptoms. The current study had three aims: (1) assessing the validity of CPTSD in a unique population of male perpetrators of intimate partner violence; (2) examining whether exposure to different types of traumatic events would be associated with the two proposed CPTSD factors, namely PTSD or DSO; and (3) assessing the differential association of various sociodemographic and symptom characteristics with each factor. Participants were 234 males drawn randomly from a sample of 2600 men receiving treatment at 66 domestic violence centers in Israel. Data were collected using the International Trauma Questionnaire (ITQ) - Hebrew version. Confirmatory factor analysis supported the factorial validity of ICD-11 CPTSD. Cumulative lifetime trauma and physical childhood neglect were associated with PTSD and DSO, while cumulative childhood violence exposure was associated only with DSO. Anxiety was associated only with DSO; depression more strongly with DSO than PTSD. Religious level contributed only to PTSD; compulsory military service only to DSO. The study supports the distinction between PTSD and DSO in the CPTSD construct and introduces the role of cultural variables. PMID- 29421373 TI - High risk, high reward: Daily perceptions of social challenge and performance in social anxiety disorder. AB - Individuals with Social Anxiety Disorder (SAD) have difficulty engaging in social situations because their actions are predicated on minimizing the subjectively biased high potential for rejection. That is, individuals with SAD frequently perceive social situations as challenging, and their performance as subpar. Yet when individuals perceive themselves as succeeding in challenging situations, they typically report these situations as enjoyable and rewarding. This subjective experience of succeeding in a challenging situation has been studied as flow (Csikszentmihalyi, 1975; 2000). Thirty-three adults with SAD and 34 matched healthy controls completed a baseline assessment, along with daily and experience sampling entries for 14 days. Results were analyzed using three-level generalized linear mixed effects models, with observations nested within days, nested within participants. Although individuals with and without SAD experienced the same frequency of flow in daily life, social situations led to proportionally more flow in participants with SAD than healthy controls. Both results were unexpected, and reasons for them are explored at length. Several experiential variables (positive emotions during and importance ascribed to the event) predicted the probability of flow during each situation. These results offer intervention-relevant suggestions for how individuals may benefit from seeking out challenging situations that offer maximal rewards. PMID- 29421374 TI - [Early child development in Mexico: advances and challenges]. PMID- 29421375 TI - [Evaluation of early childhood development: benefits for the future of children and countries]. PMID- 29421376 TI - [Comparative analysis of child development screening tools designed and validated in Mexico]. AB - BACKGROUND: In recent years a number of child development screening tools have been developed in Mexico; however, their properties have not been compared. The objective of this review was to compare the report quality and risk bias of the screening tools developed and validated in Mexico in their published versions. METHODS: A search was conducted in databases, gray literature and cross references. The resultant tests were compared and analyzed using STARD, QUADAS and QUADAS-2 criteria. RESULTS: "Valoracion Neuroconductual del Desarrollo del Lactante" (VANEDELA), "Evaluacion del Desarrollo Infantil or EDI" (CDE in English), "Prueba de Tamiz del Neurodesarrollo infantil" (PTNI), "Cartillas de Vigilancia para identificar alteraciones en el Desarrollo del Lactante" (CVDL) and "Indicadores de riesgo del Perfil de Conductas de Desarrollo" (INDIPCD-R) were included for the comparison. No test fulfilled all STARD items. The most complete in their methodological description were VANEDELA and EDI. The areas lacking more data on the reports were recruiting and patient selection (VANEDELA, PTNI, CVDL, INDIPCD-R). In QUADAS evaluation, all had some risk bias, but some serious concerns of risk bias were raised by patient sampling and by the choice of gold standard in two tests (PTNI, INDIPCD-R). CONCLUSIONS: Child development screening tests created and validated in Mexico have variable report quality and risk bias. The test with the best validation report quality is VANEDELA and the one with the lowest risk of bias is EDI. PMID- 29421377 TI - [Impact of a training model for the Child Development Evaluation Test in primary care]. AB - BACKGROUND: The Child Development Evaluation (CDE) Test is a screening tool designed and validated in Mexico for the early detection of child developmental problems. For professionals who will be administering the test in primary care facilities, previous acquisition of knowledge about the test is required in order to generate reliable results. The aim of this work was to evaluate the impact of a training model for primary care workers from different professions through the comparison of knowledge acquired during the training course. METHODS: The study design was a before/after type considering the participation in a training course for the CDE test as the intervention. The course took place in six different Mexican states from October to December 2013. The same questions were used before and after. RESULTS: There were 394 participants included. Distribution according to professional profile was as follows: general physicians 73.4%, nursing 7.7%, psychology 7.1%, nutrition 6.1% and other professions 5.6%. The questions with the lowest correct answer rates were associated with the scoring of the CDE test. In the initial evaluation, 64.9% obtained a grade lower than 20 compared with 1.8% in the final evaluation. In the initial evaluation only 1.8% passed compared with 75.15% in the final evaluation. CONCLUSIONS: The proposed model allows the participants to acquire general knowledge about the CDE Test. To improve the general results in future training courses, it is required to reinforce during training the scoring and interpretation of the test together with the previous lecture of the material by the participants. PMID- 29421378 TI - [Design of a supervision model for administration of the Child Development Evaluation Test at primary care facilities in Mexico]. AB - BACKGROUND: The Child Development Evaluation (CDE) test designed and validated in Mexico has been used as a screening tool for developmental problems in primary care facilities across Mexico. Heterogeneous results were found among those states where these were applied, despite using the same standardized training model for application. The objective was to evaluate a supervision model for quality of application of the CDE test at primary care facilities. METHODS: A study was carried out in primary care facilities from three Mexican states to evaluate concordance of the results between supervisor and primary care personnel who administered the test using two different methods: direct observation (shadow study) or reapplication of the CDE test (consistency study). RESULTS: There were 380 shadow studies applied to 51 psychologists. General concordance of the shadow study was 86.1% according to the supervisor: green 94.5%, yellow 73.2% and red 80.0%. There were 302 re-test evaluations with a concordance of 88.1% (n=266): green 96.8%, yellow 71.7% and red 81.8%. There were no differences between CDE test subgroups by age. CONCLUSIONS: Both shadow and re-test study were adequate for the evaluation of the quality of the administration of the CDE Test and may be useful as a model of supervision in primary care facilities. The decision of which test to use relies on the availability of supervisors. PMID- 29421379 TI - [Diagnostic evaluation of the developmental level in children identified at risk of delay through the Child Development Evaluation Test]. AB - BACKGROUND: The Child Development Evaluation (or CDE Test) was developed in Mexico as a screening tool for child developmental problems. It yields three possible results: normal, slow development or risk of delay. The modified version was elaborated using the information obtained during the validation study but its properties according to the base population are not known. The objective of this work was to establish diagnostic confirmation of developmental delay in children 16- to 59-months of age previously identified as having risk of delay through the CDE Test in primary care facilities. METHODS: A population-based cross-sectional study was conducted in one Mexican state. CDE test was administered to 11,455 children 16- to 59-months of age from December/2013 to March/2014. The eligible population represented the 6.2% of the children (n=714) who were identified at risk of delay through the CDE Test. For inclusion in the study, a block randomization stratified by sex and age group was performed. Each participant included in the study had a diagnostic evaluation using the Battelle Development Inventory, 2nd edition. RESULTS: From the 355 participants included with risk of delay, 65.9% were male and 80.2% were from rural areas; 6.5% were false positives (Total Development Quotient ?90) and 6.8% did not have any domain with delay (Domain Developmental Quotient <80). The proportion of delay for each domain was as follows: communication 82.5%; cognitive 80.8%; social-personal 33.8%; motor 55.5%; and adaptive 41.7%. There were significant differences in the percentages of delay both by age and by domain/subdomain evaluated. CONCLUSIONS: In 93.2% of the participants, developmental delay was corroborated in at least one domain evaluated. PMID- 29421380 TI - [Population-based study of child developmental screening in Mexican PROSPERA beneficiaries younger than 5 years old]. AB - BACKGROUND: Evaluacion del Desarrollo Infantil or Child Development Evaluation (CDE) test, a screening tool designed and validated in Mexico, classifies child development as normal (green) or abnormal (developmental lag or yellow and risk of delay or red). Population-based results of child development level with this tool are not known. The objective of this work was to evaluate the developmental level of children aged 1-59 months living in poverty (PROSPERA program beneficiaries) through application of the CDE test. METHODS: CDE tests were applied by specifically trained and standardized personnel to children <5 years old who attended primary care facilities for a scheduled appointment for nutrition, growth and development evaluation from November 2013 to May 2014. RESULTS: There were 5,527 children aged 1-59 months who were evaluated; 83.8% (n=4,632) were classified with normal development (green) and 16.2% (n=895) as abnormal: 11.9% (n=655) as yellow and 4.3% (n=240) as red. The proportion of abnormal results was 9.9% in children <1 year of age compared with 20.8% at 4 years old. The most affected areas according to age were language at 2 years (9.35%) and knowledge at 4 years old (11.1%). Gross motor and social areas were more affected in children from rural areas; fine motor skills, language and knowledge were more affected in males. CONCLUSIONS: The proportion of children with abnormal results is similar to other population-based studies. The highest rate in older children reinforces the need for an early-based intervention. The different pattern of areas affected between urban and rural areas suggests the need for a differentiated intervention. PMID- 29421381 TI - [Steps to transform a necessity into a validated and useful screening tool for early detection of developmental problems in Mexican children]. AB - A screening test is an instrument whose primary function is to identify individuals with a probable disease among an apparently healthy population, establishing risk or suspicion of a disease. Caution must be taken when using a screening tool in order to avoid unrealistic measurements, delaying an intervention for those who may benefit from it. Before introducing a screening test into clinical practice, it is necessary to certify the presence of some characteristics making its worth useful. This "certification" process is called validation. The main objective of this paper is to describe the different steps that must be taken, from the identification of a need for early detection through the generation of a validated and reliable screening tool using, as an example, the process for the modified version of the Child Development Evaluation Test (CDE or Prueba EDI) in Mexico. PMID- 29421382 TI - [Health Social Protection System for early detection and care of child developmental problems in Mexico]. PMID- 29421384 TI - [Child abuse: its knowledge, attention and diffusion in three pediatric hospitals in Mexico]. AB - Child abuse (CA) was observed in Mexico since the early 60's through isolated publications from clinical cases and where manifestations of physical injury or sexual abuse predominated. Since the 90's, the Clinic for Integral Care of the Abused Child was established at the National Institute of Pediatrics (CAINM-INP, for its Spanish acronym), which actions were addressed to the care, teaching and research on this topic. This approach was replicated in two hospital centers in the country: the Clinic for Integral Care of the Abused Children at Children's Specialty Care Hospital of Chihuahua and the Pediatric Service of the General Hospital of Mexicali. The main objective of this work was to present to the medical community, paramedics, and other professionals who interact with the pediatric population and society, the efforts that have been made in Mexico to address this legal, medical, and social pathology in a logical manner, and always aimed at protecting victims and their families. PMID- 29421383 TI - Latrunculin B and substratum stiffness regulate corneal fibroblast to myofibroblast transformation. AB - The transformation of keratocytes and fibroblasts to myofibroblasts is important to corneal wound healing as well as formation of stromal haze. The purpose of this study was to determine the effect of latrunculin B, an actin cytoskeleton disruptor in conjunction with a fundamental biophysical cue, substrate stiffness, on myofibroblast transformation in vitro and in vivo. Rabbit corneal fibroblasts were cultured on substrates of differing compliance (1.5, 22, and 71 kPa) and tissue culture plastic (TCP; > 1 GPa) in media containing 0 or 10 ng/ml TGFbeta1 for 72 h. Cells were treated with 0.4 MUM Lat-B or DMSO for 30 min every 24 h for 72 h. RNA was collected from cells and expression of alpha-smooth muscle actin (alpha-SMA), keratocan, and ALDH1A1 determined using qPCR; immunocytochemistry was used to assess alpha-SMA protein expression. A rabbit phototherapeutic keratectomy (PTK) model was used to assess the impact of 0.1% Lat-B (n = 3) or 25% DMSO (vehicle control, n = 3) on corneal wound healing by assessment of epithelial wound size with fluorescein stain and semi-quantitative stromal haze scoring by an observer masked to treatment group as well as Fourier-domain optical coherence tomography (FD-OCT) at set time points. Statistical analysis was completed using one-way or two-way analysis of variance. Treatment with Lat-B versus DMSO resulted in significantly less alphaSMA mRNA (P <= 0.007) for RCF cells grown on 22 and 71 kPa substrates as well as TCP without or with TGFbeta1, and significantly decreased alpha-SMA protein expression in RCFs cultured on the intermediate (22 kPa) stiffness in the absence (P = 0.028) or presence (P = 0.018) of TGFbeta1. Treatment with Lat-B versus DMSO but did not significantly alter expression of keratocan or ALDH1A1 mRNA in RCFs (P > 0.05) in the absence or presence of TGFbeta1, but RCFs grown on stiff hydrogels (71 kPa) had significantly more keratocan mRNA expression versus the 22 kPa hydrogel or TCP (P < 0.001) without TGFbeta1. Administration of topical Lat-B BID was well tolerated by rabbits post-PTK but did not significantly alter epithelial wound closure, stromal haze score, stromal haze thickness as measured by FD-OCT in comparison to DMSO-treated rabbits. When corneal stromal cells are cultured on substrates possessing biologically relevant substratum stiffnesses, Lat-B modulates mRNA and protein expression of alpha-SMA and thus modulates myofibroblast transformation. At a dose and dose-frequency that reduced IOP in human glaucoma patients, Lat-B treatment did not substantially impact corneal epithelial or stromal wound healing in a rabbit PTK model. While a significant impact on wound healing was observed at the concentration and dose frequency reported here was not found, encouraging in vitro data support further investigations of topically applied Lat B to determine if this compound can reduce stromal fibrosis. PMID- 29421385 TI - Risk factors evaluation for urolithiasis among children. AB - BACKGROUND: The prevalence of pediatric urolithiasis varies from 0.01-0.03%. Urolithiasis may be caused by anatomical, metabolic and environmental factors. Recurrence varies between 16 to 67%, and it is frequently associated with metabolic abnormalities. The objective of the present work was the identification of risk factors that promote urolithiasis in a child population. METHODS: This study included 162 children with urolithiasis and normal renal function (mean age 7.5 years). Risk factors were investigated in two stages. In the first stage, 24 hour urine, and blood samples were analyzed to assess metabolic parameters and urinary tract infection. During the second stage, the effect of calcium restriction and a calcium load on renal Ca excretion were evaluated. Data were statistically analyzed. RESULTS: Urolithiasis was observed in 0.02% of children, 50% of them with family history of urinary stones. There were multiple risk factors for urolithiasis including hypocitraturia (70%), hypomagnesuria (42%), hypercalciuria (37%; in 11/102 was by intestinal hyperabsorption, in 13/102 was unclassified. Ca resorption or renal Ca leak were not detected). We also detected alkaline urine (21%), systemic metabolic acidosis (20%), urinary infections (16%), nephrocalcinosis with urolithiasis (11%), oliguria (8%), urinary tract anomalies, hyperuricosemia and hypermagnesemia (7% each one), hypercalcemia (6%), hyperoxaluria (2%) and hypercystinuria (0.61%). CONCLUSIONS: Hypocitraturia and hypomagnesuria were the most frequent risk factors associated with urolithiasis, followed by hypercalciuria. High PTH values were excluded. Children presented two or more risk factors for urolithiasis. PMID- 29421386 TI - [Clinical profile of dengue and predictive severity variables among children at a secondary care hospital of Chilpancingo, Guerrero, Mexico: case series]. AB - BACKGROUND: Dengue continues to increase globally. Currently, the highest incidence of first infection occurs in paediatric population, where severe dengue fever is potentially lethal. This study characterizes the clinical profile of paediatric patients with dengue fever in the South of Mexico. METHODS: We undertook a series case study of 133 paediatric inpatients who presented clinical diagnosis of non-severe dengue and severe dengue fever. We described univariate analysis as means or percentages, using 0.05 as significance level. We estimated the prediction of severe dengue considering clinical signs and symptoms only using GLMM (Generalised Linear Mixed Models). RESULTS: 58% (77/133) patients had severe dengue. There were significant differences among the dengue groups, in the following signs and symptoms: Fever, abdominal pain, epistaxis and platelet count. Children older than four years old had a higher proportion of severe dengue (p<0.05). GLMM identified a group of four clinical signs and symptoms (fever >=39 degrees C, myalgia, arthralgia and abdominal pain) as predictors of severe dengue. CONCLUSIONS: The results of this exploratory study suggest changes in the frequency of clinical signs and symptoms among paediatric inpatients. Paediatric patients with a presumptive diagnosis of dengue, showing fever of >=39 degrees C, myalgia, arthralgia and abdominal pain should be considered as potential cases of severe dengue. PMID- 29421387 TI - [Fitness indicators in Mexican schoolchildren with overweight and obesity]. AB - BACKGROUND: The components of physical fitness are important as indicators of health in school children. The main objective of this study was to analyze the differences in the components of fitness among school children overweight /obese and normal. METHODS: 491 schoolchildren participated, from the city of Chihuahua, Mexico. Components of physical condition, anthropometric variables and blood pressure were measured. Descriptive statistics, analysis of variance and frequency measurements were performed, including only the students who performed all the tests. RESULTS: 45% (n = 205) of the sample were girls and 55% (n = 251) were boys. The mean age in girls was 8.8 +/- 1.8 years, and in boys 8.9 +/- 1.9 years. 39% of schoolchildren were overweight or obese. Waist circumference shows 15.6% of school children with a percentile >=90, and regarding blood pressure about 13.1% of the children are classified with some form of hypertension. Schoolchildren with normal weight show greater flexibility (0.007) *, more repetitions in the arm flexions (0,000)* and abdominal pushups (0,000)*, and less time in the speed test (0.008)* when compared to schoolchildren with obesity. CONCLUSIONS: In the present study, we observed that schoolchildren with overweight and obesity have a significantly lower performance in physical tests. So, the different aspects of physical condition evaluated can serve as immediate indicators of potential health risks for overweight children. PMID- 29421388 TI - [Acute colonic pseudo-obstruction (Ogilvie syndrome) post-renal transplant]. AB - BACKGROUND: Acute colonic pseudo-obstruction, also known as Ogilvie syndrome, is a rare gastrointestinal syndrome in children. It is characterized by a marked dilatation of the colon evidenced by imaging and absence of mechanical obstruction. Patients typically present with abdominal pain and distended, tympanic abdomen, with peristalsis present, accompanied by nausea and vomiting. Up to 40% of patients can pass gas and/or have bowel movements. We decide to report this case because this syndrome is very rare in pediatric patients, and no cases have been reported in a post-renal transplant pediatric patient. CASE REPORT: 13 year old male patient with past medical history of psychomotor retardation due to perinatal asphyxia and chronic renal failure secondary to bilateral renal hypoplasia. Treated with peritoneal dialysis for one year until kidney transplant was performed. Currently under immunosuppressive regime. He began his condition with mild abdominal pain accompanied by semi-liquid stools, and progressive distention up to 78cm of abdominal circumference in 72hours, so image studies were performed. Managed with prokinetic drugs without any improvement. Two exploratory laparotomies observed flanges, without evidence of any mechanical obstruction. An abdominal magnetic resonance was performed, where important intestinal dilatation was observed with no evidence of mechanical obstruction. Ogilvie Syndrome was diagnosed, so management with neostigmine was established, which led to symptom resolution. CONCLUSIONS: This case is reported because this syndrome is very rare in children, there is little clinical suspicion and lack of management guides for diagnosis and treatment in patients of this age. PMID- 29421389 TI - [Spondylocostal dysostosis and acute cholangitis in pediatrics emergency room]. AB - BACKGROUND: Congenital malformations of the chest wall comprise a heterogeneous group of diseases denominated spondylocostal dysostosis. They have in common developmental abnormalities in the morphology of the structures of the chest and vertebrae with a broad characterization: from mild deformity without functional consequences to life-threatening injuries. We present the case of a girl with spondylocostal dysostosis and acute cholangitis. CLINICAL CASE: A 13-month-old girl with severe malnutrition, history of hydrocephalus and myelomeningocele at birth was admitted in the emergency pediatric room with fever and progressive respiratory distress. Clinical assessment revealed ribs and vertebral malformations and acute cholangitis. CONCLUSIONS: Complex rib abnormalities consist in deformities of the chest wall, which do not have a specific pattern and are extremely rare. When they are associated with myelomeningocele and hydrocephalus they may be considered as autosomal recessive inheritance spondylocostal dysostosis. The diagnosis is established by clinical assessment and X-rays. Spondylocostal dysostosis identification and complications related to their genetic and molecular causes are still a challenge for clinical pediatricians and the multidisciplinary medical team who treats these patients throughout lifetime. PMID- 29421390 TI - [Gastric adenocarcinoma with signet-ring cell and neuroendocrine differentiation. A rare cancer in adolescents]. PMID- 29421391 TI - [Midface alterations in childhood as pathogenesis of obstructive sleep apnea syndrome]. AB - The onset of nasal breathing sets a genetically determined impulse to aerate the face cavities or paranasal sinuses, which in turn initiate its growth creating the useful trafficable space for air during the development of the midface. Considering the evidence that the upper airway obstruction has a primary role in the pathogenesis of respiratory sleep disorders, any condition that causes a permanent difficulty to the nasal airflow during breathing will cause hypo development of the required amplitude in this airway, reducing the growth stimulation of the sinus cavities and altering the development of the midface as a whole. PMID- 29421392 TI - [To live well: health care or life project? Part II]. AB - On the basis that life project as the driving force behind the life experience, the quest for human dignity is the way for true progress and the improvement of human condition. It's pointed out the need to be aware of the meaning of life understanding the motives behind our will to live that is the antecedent of life project. The proposed life project is a cognitive adventure, capable of transcending consumerism, individualism and passivity, toward the creation of a more inclusive world where the improvement spiritual, intellectual and moral can be viable. Said life project entails: a) A primary need: to link oneself with like-minded people that synergize against the prevailing order b) A core: The everlasting struggle for sublimated dignity c) A desideratum: The well-being of the majority d) An unavoidable purpose: The creation of a suitable world build on different ethical, political, lawful, cognitive and ecological foundations. In conclusion, this paper analyzes the influence of projects with an alternate proposal to the endeavors centered in healthcare that favor individualism, passivity and the current status quo. The best example of said alternate proposals is the commonly called "good death". PMID- 29421393 TI - [Comparative analysis of child development screening tools designed and validated in Mexico]. PMID- 29421394 TI - [Answer to letter to the editor: Comparative analysis of child development screening tools designed and validated in Mexico]. PMID- 29421395 TI - Controlled release and antioxidant activity of chitosan or its glucosamine water soluble derivative microcapsules loaded with quercetin. PMID- 29421396 TI - Comparing the toxic potency in vivo of long-chain perfluoroalkyl acids and fluorinated alternatives. AB - Since 2000, long-chain perfluoroalkyl acids (PFAAs) and their respective precursors have been replaced by numerous fluorinated alternatives. The main rationale for this industrial transition was that these alternatives were considered less bioaccumulative and toxic than their predecessors. In this study, we evaluated to what extent differences in toxicological effect thresholds for PFAAs and fluorinated alternatives, expressed as administered dose, were confounded by differences in their distribution and elimination kinetics. A dynamic one-compartment toxicokinetic (TK) model for male rats was constructed and evaluated using test data from toxicity studies for perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorobutane sulfonic acid (PFBS), perfluorooctanoic acid (PFOA), perfluoroctanesulfonic acid (PFOS) and ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (GenX). Dose-response curves of liver enlargement from sub-chronic oral toxicity studies in male rats were converted to internal dose in serum and in liver to examine the toxicity ranking of PFAAs and fluorinated alternatives. Converting administered doses into equivalent serum and liver concentrations reduced the variability in the dose response curves for PFBA, PFHxA, PFOA and GenX. The toxicity ranking using modeled serum (GenX > PFOA > PFHxA > PFBA) and liver (GenX > PFOA ~ PFHxA ~ PFBA) concentrations indicated that some fluorinated alternatives have similar or higher toxic potency than their predecessors when correcting for differences in toxicokinetics. For PFOS and perfluorobutane sulfonic acid (PFBS) the conversion from administered dose to serum concentration equivalents did not change the toxicity ranking. In conclusion, hazard assessment based on internal exposure allows evaluation of toxic potency and bioaccumulation potential independent of kinetics and should be considered when comparing fluorinated alternatives with their predecessors. PMID- 29421398 TI - Integrating travel behavior with land use regression to estimate dynamic air pollution exposure in Hong Kong. AB - BACKGROUND: Epidemiological studies typically use subjects' residential address to estimate individuals' air pollution exposure. However, in reality this exposure is rarely static as people move from home to work/study locations and commute during the day. Integrating mobility and time-activity data may reduce errors and biases, thereby improving estimates of health risks. OBJECTIVES: To incorporate land use regression with movement and building infiltration data to estimate time-weighted air pollution exposures stratified by age, sex, and employment status for population subgroups in Hong Kong. METHODS: A large population-representative survey (N = 89,385) was used to characterize travel behavior, and derive time-activity pattern for each subject. Infiltration factors calculated from indoor/outdoor monitoring campaigns were used to estimate micro environmental concentrations. We evaluated dynamic and static (residential location-only) exposures in a staged modeling approach to quantify effects of each component. RESULTS: Higher levels of exposures were found for working adults and students due to increased mobility. Compared to subjects aged 65 or older, exposures to PM2.5, BC, and NO2 were 13%, 39% and 14% higher, respectively for subjects aged below 18, and 3%, 18% and 11% higher, respectively for working adults. Exposures of females were approximately 4% lower than those of males. Dynamic exposures were around 20% lower than ambient exposures at residential addresses. CONCLUSIONS: The incorporation of infiltration and mobility increased heterogeneity in population exposure and allowed identification of highly exposed groups. The use of ambient concentrations may lead to exposure misclassification which introduces bias, resulting in lower effect estimates than 'true' exposures. PMID- 29421397 TI - Local- and regional-scale air pollution modelling (PM10) and exposure assessment for pregnancy trimesters, infancy, and childhood to age 15 years: Avon Longitudinal Study of Parents And Children (ALSPAC). AB - We established air pollution modelling to study particle (PM10) exposures during pregnancy and infancy (1990-1993) through childhood and adolescence up to age ~15 years (1991-2008) for the Avon Longitudinal Study of Parents And Children (ALSPAC) birth cohort. For pregnancy trimesters and infancy (birth to 6 months; 7 to 12 months) we used local (ADMS-Urban) and regional/long-range (NAME-III) air pollution models, with a model constant for local, non-anthropogenic sources. For longer exposure periods (annually and the average of birth to age ~8 and to age ~15 years to coincide with relevant follow-up clinics) we assessed spatial contrasts in local sources of PM10 with a yearly-varying concentration for all background sources. We modelled PM10 (MUg/m3) for 36,986 address locations over 19 years and then accounted for changes in address in calculating exposures for different periods: trimesters/infancy (n = 11,929); each year of life to age ~15 (n = 10,383). Intra-subject exposure contrasts were largest between pregnancy trimesters (5th to 95th centile: 24.4-37.3 MUg/m3) and mostly related to temporal variability in regional/long-range PM10. PM10 exposures fell on average by 11.6 MUg/m3 from first year of life (mean concentration = 31.2 MUg/m3) to age ~15 (mean = 19.6 MUg/m3), and 5.4 MUg/m3 between follow-up clinics (age ~8 to age ~15). Spatial contrasts in 8-year average PM10 exposures (5th to 95th centile) were relatively low: 25.4-30.0 MUg/m3 to age ~8 years and 20.7-23.9 MUg/m3 from age ~8 to age ~15 years. The contribution of local sources to total PM10 was 18.5%-19.5% during pregnancy and infancy, and 14.4%-17.0% for periods leading up to follow-up clinics. Main roads within the study area contributed on average ~3.0% to total PM10 exposures in all periods; 9.5% of address locations were within 50 m of a main road. Exposure estimates will be used in a number of planned epidemiological studies. PMID- 29421399 TI - High plasma organochlorine pesticide levels are related to increased biological age as calculated by DNA methylation analysis. AB - BACKGROUND: Organochlorine pesticides (OCPs) have been shown in the experimental setting to alter DNA methylation. Since DNA methylation changes during the life span, formulas have been presented to calculate "DNA methylation age" as a measure of biological age. OBJECTIVES: We aimed to investigate if circulating levels of three OCPs were related to increased DNA methylation age METHODS: 71CpG DNA methylation age (Hannum formula) was calculated based on data from the Illumina 450 k Bead Methylation chip in 1000 subjects in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years at the examination). The difference between DNA methylation age and chronological age was calculated (DiffAge). 2,2-bis (4-chlorophenyl)-1,1-dichloroethene (p,p' DDE), hexachlorobenzene (HCB), and transnonachlor (TNC) levels were measured in plasma by high-resolution gas chromatography coupled mass spectrometry (HRGC HRMS). RESULTS: Increased p,p'-DDE and TNC, but not HCB, levels were related to increased DiffAge both in sex and BMI-adjusted models, as well as in multiple adjusted models (sex, education level, exercise habits, smoking, energy and alcohol consumption and BMI) (p = 0.0051 and p = 0.011, respectively). No significant interactions between the OCPs and sex or BMI regarding DiffAge were found. CONCLUSION: In this cross-sectional study, increased levels of two out of three OCPs were related to increased DNA methylation age, further suggesting negative health effects in humans of these widespread environmental contaminants. PMID- 29421400 TI - Exploring links between greenspace and sudden unexpected death: A spatial analysis. AB - Greenspace has been increasingly recognized as having numerous health benefits. However, its effects are unknown concerning sudden unexpected death (SUD), commonly referred to as sudden cardiac death, which constitutes a large proportion of mortality in the United States. Because greenspace can promote physical activity, reduce stress and buffer air pollutants, it may have beneficial effects for people at risk of SUD, such as those with heart disease, hypertension, and diabetes mellitus. Using several spatial techniques, this study explored the relationship between SUD and greenspace. We adjudicated 396 SUD cases that occurred from March 2013 to February 2015 among reports from emergency medical services (EMS) that attended out-of-hospital deaths in Wake County (central North Carolina, USA). We measured multiple greenspace metrics in each census tract, including the percentages of forest, grassland, average tree canopy, tree canopy diversity, near-road tree canopy and greenway density. The associations between SUD incidence and these greenspace metrics were examined using Poisson regression (non-spatial) and Bayesian spatial models. The results from both models indicated that SUD incidence was inversely associated with both greenway density (adjusted risk ratio [RR] = 0.82, 95% credible/ confidence interval [CI]: 0.69-0.97) and the percentage of forest (adjusted RR = 0.90, 95% CI: 0.81-0.99). These results suggest that increases in greenway density by 1 km/km2 and in forest by 10% were associated with a decrease in SUD risk of 18% and 10%, respectively. The inverse relationship was not observed between SUD incidence and other metrics, including grassland, average tree canopy, near-road tree canopy and tree canopy diversity. This study implies that greenspace, specifically greenways and forest, may have beneficial effects for people at risk of SUD. Further studies are needed to investigate potential causal relationships between greenspace and SUD, and potential mechanisms such as promoting physical activity and reducing stress. PMID- 29421401 TI - Association between prenatal exposure to multiple insecticides and child body weight and body composition in the VHEMBE South African birth cohort. AB - BACKGROUND: Pregnant women may be co-exposed to multiple insecticides in regions where both pyrethroids and dichlorodiphenyltrichloroethane (DDT) are used for indoor residual spraying (IRS) for malaria control. Despite the potential for adverse effects on offspring, there are few studies in areas where IRS is currently used and little is known about the effects of pyrethroids on children's health. METHODS: We investigated the relationship between concentrations of four urinary pyrethroid metabolites in urine and organochlorine pesticide concentrations in maternal blood collected near delivery on body weight and body composition among children <=2 years old participating in the prospective South Africa VHEMBE birth cohort (N = 708). We used measurements of length/height and weight collected at 1 and 2 years of age to calculate body mass index (BMI)-for age, weight-for-age, and weight-for-height z-scores based on World Health Organization standards. We fit separate single-pollutant mixed effects models for each exposure of interest and also stratified by sex. We also fit all analyte concentrations jointly by using a Bayesian kernel machine regression (BKMR) statistical method to assess variable importance of each analyte and to explore the potential for joint effects of the multiple exposures. RESULTS: Single pollutant linear mixed effects models showed that, among girls only, p,p'-DDT was associated with higher BMI-for-age (adjusted [a]beta = 0.22 [95% CI: 0.10, 0.35]; sex interaction p-value = 0.001), weight-for-height (abeta = 0.22 [95% CI: 0.09, 0.34]; sex interaction p-value = 0.002), and weight-for-age (abeta = 0.17 [95% CI: 0.05, 0.29], sex interaction p-value = 0.01). Although single-pollutant models suggested that p,p'-DDT and dichlorodiphenyldichloroethylene (p,p'-DDE) were also associated with these outcomes in girls, p,p'-DDE was no longer associated in multi-pollutant models with BKMR. The pyrethroid metabolites cis (2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylicacid (cis-DBCA) and trans 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (trans-DCCA) were inversely related to BMI-for-age and weight-for-height overall; however, results suggested that weight-for-age and weight-for-height associations for trans-DCCA (sex interaction p-valueweight-for-age = 0.02; p-valueweight-for-height = 0.13) and cis-DCCA (sex interaction p-valueweight-for-age = 0.02; p-valueweight-for height = 0.08) were strongest and most consistent in boys relative to girls. BKMR also revealed joint effects from the chemical mixture. For instance, with increased concentrations of p,p'-DDE, the negative exposure-response relationship for cis-DBCA on BMI-for-age became steeper. CONCLUSIONS: Our single-pollutant and multi-pollutant model results show that maternal serum p,p'-DDT concentration was consistently and positively associated with body composition and body weight in young girls and that maternal urinary pyrethroid metabolite concentrations (particularly cis-DBCA and trans-DCCA) were negatively associated with body weight and body composition in young boys. Joint effects of the insecticide exposure mixture were also apparent, underscoring the importance of using advanced statistical methods to examine the health effects of chemical mixtures. PMID- 29421403 TI - Plasma levels of polychlorinated biphenyls and risk of cutaneous malignant melanoma: A hospital-based case-control study. AB - Polychlorinated biphenyls (PCB) have been classified by the International Agency for Research on Cancer (IARC) in Group 1 as carcinogenic to human, based on sufficient evidence in humans of an increased risk of cutaneous malignant melanoma (CMM), however few studies have been done in the general population. This study examined the relationship between PCB plasma levels and risk of CMM adjusting for sun sensitivity and sun exposure in a province of Northern Italy (Brescia), where a chemical factory produced PCBs from 1938 to 1984 causing human contamination. A case-control study of 205 CMM patients and 205 control subjects was conducted. Cases and controls were assayed for plasma levels of 33 PCB congeners. No associations was found between risk of CMM and plasma levels of total PCB (OR = 0.81; 95% CI: 0.34-1.96 for highest vs lowest quartile) or specific congeners. The study confirmed the association with light skin colour (OR = 3.00; 95% CI: 1.91-4.73), cumulative lifetime UV exposure (OR = 2.56; 95% CI: 1.35-4.85) and high level of education (OR = 1.45; 95% CI: 1.03-2.05). This case-control study does not support the hypothesis of an association between current plasma levels of PCBs and CMM development in the general population. PMID- 29421402 TI - Serum homocysteine, arsenic methylation, and arsenic-induced skin lesion incidence in Bangladesh: A one-carbon metabolism candidate gene study. AB - BACKGROUND: Inorganic arsenic (As) is methylated via one carbon metabolism (OCM) to mono- and dimethylated arsenicals (MMA and DMA), facilitating urinary excretion. Hyperhomocysteinemia (HHcys), a marker of impaired OCM, is a risk factor for As-induced skin lesions, but the influences of single nucleotide polymorphisms (SNPs) in OCM genes on Hcys, As metabolism and skin lesion risk is unclear. OBJECTIVES: To (i) explore genetic sources of Hcys and the causal role of HHcys in As-induced skin lesion development using OCM genetic proxies for HHcys and (ii) identify OCM SNPs associated with urinary As metabolite proportions and/or skin lesion incidence. METHODS: We conducted a case-control study nested in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh which 876 incident skin lesion cases were matched to controls on sex, age, and follow-up time. We measured serum Hcys, urinary As metabolites, and 26 SNPs in 13 OCM genes. RESULTS: Serum Hcys and urinary %DMA were independently associated with increased and decreased odds of skin lesions, respectively. The T allele of MTHFR 677 C ? T (rs1801133) was associated with HHcys, higher %MMA, and lower %DMA, but not with skin lesions. Interactions between SNPs and water As on skin lesion risk were suggestive for three variants: the G allele of MTRR rs1801394 and T allele of FOLR1 rs1540087 were associated with lower odds of skin lesions with lower As (<=50 MUg/L), and the T allele of TYMS rs1001761 was associated with higher odds of skin lesions with higher As. CONCLUSIONS: While HHcys and decreased %DMA were associated with increased risk for skin lesions, and MTHFR 677 C ? T was a strong predictor of HHcys, MTHFR 677 C ? T was not associated with skin lesion risk. Future studies should explore (i) non-OCM and non-genetic determinants of Hcys and (ii) if genetic findings are replicated in other As-exposed populations, mechanisms by which OCM SNPs may influence the dose dependent effects of As on skin lesion risk. PMID- 29421404 TI - The human circulating miRNome reflects multiple organ disease risks in association with short-term exposure to traffic-related air pollution. AB - Traffic-related air pollution is a complex mixture of particulate matter (PM) and gaseous pollutants, such as nitrogen dioxide (NO2). PM exposure contributes to the pathogenesis of many diseases including several types of cancer, as well as pulmonary, cardiovascular and neurodegenerative diseases. Also exposure to NO2 has been related to increased cardiovascular mortality. In search of an early diagnostic biomarker for improved air pollution-associated health risk assessment, recent human studies have shown that certain circulating miRNAs are altered upon exposure to traffic-related air pollutants. Here, we present for the first time a global analysis of the circulating miRNA genome in an experimental cross-over study of a human population exposed to traffic-related air pollution. By utilizing next-generation sequencing technology and detailed real-time exposure measurements we identified 54 circulating miRNAs to be dose- and pollutant species-dependently associated with PM10, PM2.5, black carbon, ultrafine particles and NO2 already after 2 h of exposure. Bioinformatics analysis suggests that these circulating miRNAs actually reflect the adverse consequences of traffic pollution-induced toxicity in target tissues including the lung, heart, kidney and brain. This study shows the strong potential of circulating miRNAs as novel biomarkers for environmental health risk assessment. PMID- 29421405 TI - Pregnancy urinary bisphenol-A concentrations and glucose levels across BMI categories. AB - BACKGROUND: Pregnancy exposure to bisphenol-A (BPA) may be associated with gestational diabetes (GDM), but evidence from human studies is limited. Moreover, adiposity is associated with both higher BPA concentrations and GDM risk, and may act as a confounder or an effect modifier of the association. METHODS: We included 350 term births from the Lifecodes pregnancy cohort (Boston, MA), who had 1st and 2nd trimester measures of urinary BPA concentrations available. BPA measures were SG-adjusted and categorized into quartiles (Q). Multivariable adjusted linear regressions were used to determine the association between BPA, at both 1st and 2nd trimester, and glucose, in the overall population and by categories of 1st trimester BMI. RESULTS: No clear associations were seen between BPA and glucose levels in the overall population. From stratified analyses there was suggestive evidence of effect modification by maternal 1st trimester BMI, with significant associations observed among obese/overweight participants (1st trimester BPA concentrations for Q3 vs Q1: adj.beta = 14.1 mg/dL; 95% CI: 1.5, 26.6) (2nd trimester BPA concentrations for Q2 vs Q1: adj. beta = 16.9 mg/dL; 95% CI: 2.6, 31.2). CONCLUSION: No associations were found between BPA and glucose levels in the overall population. However, moderately high BPA concentrations were associated with increased glucose levels among overweight/obese women-a subgroup at high-risk of elevated glucose levels in pregnancy. PMID- 29421406 TI - Impacts of air pollution wave on years of life lost: A crucial way to communicate the health risks of air pollution to the public. AB - Limited studies have explored the impacts of exposure to sustained high levels of air pollution (air pollution wave) on mortality. Given that the frequency, intensity and duration of air pollution wave has been increasing in highly polluted regions recently, understanding the impacts of air pollution wave is crucial. In this study, air pollution wave was defined as 2 or more consecutive days with air pollution index (API) > 100. The impacts of air pollution wave on years of life lost (YLL) due to non-accidental, cardiovascular and respiratory deaths were evaluated by considering both consecutive days with high levels of air pollution and daily air pollution levels in Tianjin, China, from 2006 to 2011. The results showed the durational effect of consecutive days with high levels of air pollution was substantial in addition to the effect of daily air pollution. For instance, the durational effect was related to an increase in YLL of 116.6 (95% CI: 4.8, 228.5) years from non-accidental deaths when the air pollution wave was sustained for 4 days, while the corresponding daily air pollution's effect was 121.2 (95% CI: 55.2, 187.1) years. A better interpretation of the health risks of air pollution wave is crucial for air pollution control policy making and public health interventions. PMID- 29421407 TI - Biomonitoring PFAAs in blood and semen samples: Investigation of a potential link between PFAAs exposure and semen mobility in China. AB - Perfluoroalkyl acids (PFAAs) have been suspected to act as endocrine disruptors and adversely affect human reproductive health. We aimed to investigate the association between PFAAs in blood and semen, explore a potential link between PFAAs exposure and semen quality in the population of the Pearl River Delta (PRD) region in China, one of the "world factories". The monitoring results demonstrated that the population (103 male participants) from the PRD region in this study had higher PFAAs levels in blood and semen than some other areas in China. PFOS was found at the highest mean concentrations of 118.16 ng/mL in blood and 5.31 ng/mL in semen among the nine PFAAs. Significant associations were found between concentrations of several analytes in blood and semen, including Sigma9 PFAAs (r = 0.475, P < .01), PFOA (r = 0.215, P = .029), PFHS (r = 0.458, P < .01) and PFOS (r = 0.981, P < .01). BMI was the most important factor to PFAAs, but there was no significant difference in PFAAs concentrations in blood and semen collected from participants with different smoking and drinking habits, education background and occupations. Negative correlations were significantly observed between sperm motility and PFBA, PFPeA, PFHxA, PFBS, PFOA, PFHS, PFOS and Sigma9PFAAs in semen. Therefore, exposure to PFAAs may result in a decline in semen mobility in participants from the PRD region. PMID- 29421408 TI - Exposure to organophosphate flame retardants in spray polyurethane foam applicators: Role of dermal exposure. AB - BACKGROUND: Spray polyurethane foam (SPF) is a highly effective thermal insulation material that has seen considerable market growth in the past decade. Organophosphate flame retardants (PFRs) are added to SPF formulations to meet fire code requirements. A common flame retardant used in SPF formulations is tris 1-chloro 2-propyl phosphate (TCIPP), a suspected endocrine disruptor. Exposure monitoring efforts during SPF applications have focused primarily on the isocyanate component, a potent respiratory and dermal sensitizer. However, to our knowledge, there is no monitoring data for TCIPP. OBJECTIVE: To characterize occupational exposures to TCIPP and other flame retardants during SPF insulation. METHODS: Workers at four SPF insulation sites and one foam removal site (total n = 14) were recruited as part of this pilot study. Personal inhalation exposure to TCIPP was monitored with a CIP-10MI inhalable sampler and potential dermal exposure was assessed through the use of a glove dosimeter. Biomarkers of TCIPP and three other PFRs were measured in urine collected from workers pre-and post shift. Linear mixed effect models were used to analyze associations of urinary biomarkers with inhalation and dermal exposures and paired t-tests were used to examine the difference on the means of urinary biomarkers pre-and post-shift. Chemical analysis of all species was performed with liquid chromatography electrospray ionization tandem mass spectrometry. RESULTS: Geometric mean (GM) concentrations of TCIPP in personal air monitors and glove dosimeters collected from SPF applicators, 294.7 MUg/m3 and 18.8 mg/pair respectively. Overall, GM concentrations of the two TCIPP urinary biomarkers BCIPP and BCIPHIPP and (6.2 and 88.8 MUg/mL) were 26-35 times higher than reported in the general population. Post-shift levels of TCIPP biomarkers were higher than pre-shift even though workers at insulation sites wore supplied air respirators, gloves and coveralls. The urinary biomarkers for the other PFRs were not elevated post shift. Concentrations of TCIPP on glove dosimeters were positively associated with post shift urinary TCIPP biomarkers (p < 0.05) whereas concentrations in personal air samples were not. CONCLUSIONS: High levels of urinary biomarkers for TCIPP among SPF applicators, including post-shift, points to absorption of TCIPP during the work shift, in spite of the use of best industry exposure control practices. Dermal exposure appears to be an important, if not the primary exposure pathway for TCIPP, although inhalation or incidental ingestion of foam particles post-SPF application cannot be ruled out in this pilot study. PMID- 29421409 TI - Prenatal exposure to glycol ethers and sex steroid hormones at birth. AB - BACKGROUND: Glycol ethers (GEs) are oxygenated solvents widely found in occupational and consumer water-based products. Some of them are well-known reproductive and developmental toxicants. OBJECTIVES: To study the variations in circulating sex steroid hormones, measured in cord blood, according to biomarkers of prenatal GE exposure. METHODS: The study population comes from the PELAGIE mother-child cohort, which enrolled pregnant women from Brittany (France, 2002 2006). Maternal urine samples were collected from a random subcohort (n = 338) before 19 weeks' gestation, from which we measured 8 alkoxycarboxylic metabolites of GEs. We subsequently measured 13 sex steroid hormones and sex hormone-binding globulin (SHBG) in cord blood samples. Linear regressions adjusted for potential confounders were used, and nonlinear dose-response associations were investigated. RESULTS: The detection rates of GE metabolites ranged from 4% to 98%; only the 5 most detected (>20%) metabolites were investigated further. Phenoxyacetic acid (detection rate > 95%) was associated with lower levels of SHBG and various steroids (17-alpha-hydroxy-Pregnenolone, delta-5-androstenediol, and dehydroepiandrosterone) among boys and higher SHBG and 16-alpha-hydroxy dehydroepiandrosterone levels among girls. The two other highly detected metabolites, methoxyetoxyacetic acid and butoxyacetic acid, were associated with variations in estradiol. Butoxyacetic acid was associated with higher delta-5 androstenediol levels while detectable levels of methoxyacetic acid were associated with lower levels of this hormone. CONCLUSION: Our study suggests that prenatal exposure to GE may affect endocrine response patterns, estimated by determining blood levels of sex steroid hormones in newborns. These results raise questions about the potential role of these changes in the pathways between prenatal GE exposure and previously reported adverse developmental outcomes, including impaired neurocognitive performance. PMID- 29421410 TI - A review on airborne microorganisms in particulate matters: Composition, characteristics and influence factors. AB - Airborne microorganisms (AM), vital components of particulate matters (PM), are widespread in the atmosphere. Since some AM have pathogenicity, they can lead to a wide range of diseases in human and other organisms, meanwhile, some AM act as cloud condensation nuclei and ice nuclei which let them can affect the climate. The inherent characteristics of AM play critical roles in many aspects which, in turn, can decide microbial traits. The uncertain factors bring various influences on AM, which make it difficult to elaborate effect trends as whole. Because of the potential roles of AM in environment and potent effects of factors on AM, detailed knowledge of them is of primary significance. This review highlights the issues of composition and characteristics of AM with size-distribution, species diversity, variation and so on, and summarizes the main factors which affect airborne microbial features. This general information is a knowledge base for further thorough researches of AM and relevant aspects. Besides, current knowledge gaps and new perspectives are offered to roundly understand the impacts and application of AM in nature and human health. PMID- 29421411 TI - Excretion of Di-2-ethylhexyl phthalate (DEHP) metabolites in urine is related to body mass index because of higher energy intake in the overweight and obese. AB - A higher body mass index (BMI) has been positively associated with the rate of excretion of di-2-ethylhexyl phthalate (DEHP) metabolites in urine in data from the National Health and Nutrition Examination Survey (NHANES), suggesting an association between DEHP exposure and BMI. The association, however, may be due to the association between body mass maintenance and higher energy intake, with higher energy intake being accompanied by a higher intake of DEHP. To examine this hypothesis, we ran a Monte Carlo simulation with a DEHP physiologically based pharmacokinetic (PBPK) model for adult humans. A realistic exposure sub model was used, which included the relation of body weight to energy intake and of energy intake to DEHP intake. The model simulation output, when compared with urinary metabolite data from NHANES, supported good model validity. The distribution of BMI in the simulated population closely resembled that in the NHANES population. This indicated that the simulated subjects and DEHP exposure model were closely aligned with the NHANES population of interest. In the simulated population, the ordinary least squares regression coefficient for log(BMI) as a function of log(DEHP nmol/min) was 0.048 (SE 0.001), as compared with the reported value of 0.019 (SE 0.005). In other words, given our model structure, the higher energy intake in the overweight and obese, and the concomitant higher DEHP exposure, describes the reported relationship between BMI and DEHP. PMID- 29421412 TI - Right Subclavian Artery Aneurysms with Fibromuscular Dysplasia. AB - Subclavian artery aneurysms (SAAs) are rare and even more uncommon in patients with fibromuscular dysplasia (FMD). A 20-year-old man with a past medical history of moyamoya disease presented with an abnormal mass shadow in the apex of the right lung on chest X-ray. Based on computed tomography imaging, a diagnosis of right SAA was established, and an excision of the aneurysm was performed. Because the left vertebral artery is dominant, the proximal and distal right subclavian artery and right vertebral artery were clamped. Then, the aneurysm was excised, and resection anastomosis was performed. Histological findings revealed FMD. The postsurgical course has been uneventful after 2 years. Among treatment modalities, open surgery would be the first choice for SAAs with FMD, despite the current era of endovascular surgeries. PMID- 29421413 TI - Vertebral Osteophyte as Possible Etiology of Aortoenteric Fistula. AB - Aortoenteric fistula (AEF) and aortoenteric erosion (AEE) are deadly and difficult to diagnose. We present here a case report of a patient with a delayed diagnosis of AEF whose preoperative imaging revealed a large vertebral osteophyte which likely directed the aortic impulse into the duodenum. We believe this is the first report documenting an anatomical explanation for AEF/AEE and conclude that the presence of vertebral osteophytes should be considered a risk factor when assessing preoperative likelihood of AEF/AEE. PMID- 29421414 TI - How to Treat a Patient with Thromboangiitis Obliterans: A Systematic Review. AB - To date, there is still no treatment protocol for patients with thromboangiitis obliterans (TAO) who are also afflicted with critical limb ischemia (CLI). Smoking cessation on its own cannot be considered a treatment for the purposes of salvaging a limb of a TAO patient with CLI. The aim of this review was to evaluate different studies of various treatment protocols for avoiding amputation in TAO patients. A systematic search for relevant studies dating from 1990 to the end of 2016 was performed on the PubMed, SCOPUS, and Science Direct databases. Only 24 studies fulfilled the inclusion criteria, of which only one was a randomized controlled trial (RCT). The remaining studies were quasi-experimental with various treatments and follow-up durations. Therefore, meta-analysis was not performed. Judging from the major amputation rates after the suggested treatments were performed, no treatment was particularly effective. This review demonstrated that more standard RCTs are needed to resolve this treatment issue involved in TAO. In addition, because health insurance coverage for TAO patients differs by country, regional cost-benefit and cost-efficacy studies of the suggested treatments for TAO are highly recommended. PMID- 29421415 TI - Clinical Outcomes of Total Endovascular Aneurysm Repair for Aortic Aneurysms Involving the Proximal Anastomotic Aneurysm following Initial Open Repair for Infrarenal Abdominal Aortic Aneurysm. AB - BACKGROUND: To evaluate initial and midterm clinical outcomes of aortic aneurysms involving the proximal anastomotic aneurysm (AAPAAs) following initial open repair for infrarenal abdominal aortic aneurysm. METHODS: Between July 2006 and August 2015, 24 patients underwent elective endovascular repair for the treatment of AAPAAs at our institution. AAPAA classification has been categorized as 3 types. Type I AAPAA is the most extensive, extending from the descending aorta to the prior proximal anastomosis as similar to Crawford type II or III thoracoabdominal aortic aneurysm. Type II AAPAA is limited to the aortic aneurysm below the diaphragm including the abdominal visceral arteries. Finally, similar to pararenal abdominal aortic aneurysm, type III AAPAA involves the renal origins, but does not extend to the celiac and superior mesenteric arteries. Total endovascular aneurysm repair (t-EVAR) consisted of fenestrated EVAR (f EVAR), multibranched EVAR (t-Branch), and snorkel EVAR (s-EVAR) were performed for patients with high-risk open surgical repair. We retrospectively analyzed 24 cases, which were categorized with 3 types of AAPAA. RESULTS: F-EVAR, t-Branch, and s-EVAR for AAPAAs were performed in 15 patients (62.5%), 5 patients (20.8%), and 4 patients (16.7%), respectively. Type I and type II AAPAA were identified in 13 patients (54.2%) and 7 patients (29.2%), and type III AAPAA was identified in 4 patients (16.7%). Technical success was 95.8%, and clinical success was 79.2% with t-EVAR. Spinal cord ischemia was identified in 2 patients (8.3%) of type I AAPAA, the 30-day mortality rate was 4.2% (n = 1, type I AAPAA). Type II and III endoleaks occurred in 1 (4.2%, type III AAPAA) and 3 patients (12.5%, each case of type I, II, and III AAPAA), respectively. There was no open conversion or aneurysm rupture in the late follow-up period. The estimated overall survival rates of t-EVAR after 1 and 3 years were 95.6% and 76.2%, respectively. Rates of freedom from aneurysm-related death and secondary intervention of t-EVAR at 3 years were 90.1% and 89.7%, respectively. Finally, rates of target vessel patency at 1 and 3 years were 95.3% and 88.8%, respectively. CONCLUSIONS: Our initial to midterm results of t-EVAR for the treatment of AAPAA were generally good with low rates of perioperative mortality and aneurysm-related death. However, more attentions should be paid for the treatment of type I AAPAA with high incidence of major adverse events. PMID- 29421416 TI - Primary Stenting of Right-Sided Subclavian Artery Stenosis Presenting as Subclavian Steal Syndrome: Report of 3 Cases and Literature Review. AB - BACKGROUND: Right-sided subclavian artery stenosis (SAS) is a rare cerebrovascular disease involving the upper extremities. Considering an endovascular approach for its management requires increased endovascular and catheterization skills when compared with the left side, due to the close approximation of the right subclavian artery origin, vertebral, and common carotid arteries. METHODS: Three patients suffering from proximal right-sided SAS were treated in our center through primary stenting. Percutaneous transfemoral and transbrachial approaches were used for vascular access, whereas in 2 cases an additional carotid protection device was deployed intraoperatively. RESULTS: Technical success was met in all 3 cases, with no intraoperative or postoperative complications being observed. All patients resumed ambulation and were uneventfully discharged the next day with dual antiplatelet medication. No recurrent stenosis was reported in duplex ultrasound scan during 6-month follow up, with all patients reporting resolution of their symptoms. DISCUSSION: Subclavian artery stenosis is an uncommon vascular disease, showing a 4-fold left, rather than right-sided predisposition. Although a low-grade stenosis is usually asymptomatic and may remain unobserved, a severe stenosis may cause retrograde blood flow in the ipsilateral vertebral artery, leading to a medical condition with various clinical symptoms, known as subclavian steal syndrome. A number of open surgical techniques exist for management of subclavian artery stenosis, although a paradigm shift in the 21st century has led to the introduction of minimally invasive techniques for its treatment, with available modalities including angioplasty, stenting, and the kissing stent technique. PMID- 29421417 TI - Positional Changes of an Endurant Endograft Leading to Simultaneous Ipsilateral Iliac Limb Obstruction and Contralateral Type IIIa Endoleak. AB - We report the case of a 79-year-old man who was admitted to our department with acute limb ischemia due to the occlusion of the left iliac limb of an Endurant endograft. The admission computed tomography angiography revealed also a type IIIa endoleak due to modular disconnection of the iliac extensions from the right iliac limb of the endograft main body. Interestingly, during the 4-year post endovascular aneurysm repair period, an increased kinking of the right limb has been observed leading to an almost cross-limb configuration of the limbs at the time of complications. To our knowledge, this is the first case in the literature of the simultaneous presence of limb thrombosis and late type IIIa endoleak with this particular device. The ischemia was treated with a femoro-femoral cross-over bypass, and the endoleak was corrected with the position of 2 Endurant iliac limb extensions bridging the dislocated endograft pieces. PMID- 29421419 TI - Contemporary Results of Endovascular Repair of Isolated Abdominal Aortic Dissection with Unibody Bifurcated Stent Grafts. AB - OBJECTIVES: To report the midterm safety and efficacy of the AegisTM-B (Microport, Shanghai, China) unibody bifurcated stent graft for endovascular treatment of isolated abdominal aortic dissection (IAAD). BACKGROUND: Isolated abdominal aorta dissection (IAAD) is a rare event. Endovascular stent grafts seem to offer an efficient therapeutic approach to treat IAAD. However, the relatively small diameter of the infrarenal aorta and aortic bifurcation remains the main anatomical limitation to endovascular repair. METHODS: Between 2008 and 2015, we retrospectively evaluated 32 IAAD patients (21 men; mean age 58 +/- 18 years), who underwent endovascular repair using AegisTM-B unibody bifurcated stent graft. Narrow proximal landing zone and narrow distal aorta was present in 11 (34.4%) patients and 10 (31.3%) patients, respectively. In the follow-up period, aortic remodeling was observed with computed tomography angiography. RESULTS: All patients were treated by endovascular means, with a primary technical success rate of 100%. During a mean follow-up period of 30.71 +/- 16.36 months (range, 8 56 months), no death, rupture, stent fracture, material failure, or device migration was observed. Complete false lumen thrombosis was observed in all patients at 1 year, and all patients were free from false lumen growth in the follow-up. CONCLUSIONS: Endovascular treatment of IAAD using the AegisTM-B system appears to be safe and effective. Results from this study suggest this algorithm can provide stable, secure fixation for IAAD patients with narrow proximal landing zone, and distal aorta. PMID- 29421418 TI - Fewer Complications in the Obese Following Lower Extremity Endovascular Interventions. AB - BACKGROUND: The prevalence of obesity is increasing in the United States; however, its impact on adverse outcomes in patients with peripheral vascular disease is not well studied. Obesity is associated with higher rates of complications following open bypass surgery, but limited data are available on its effect on endovascular intervention. This study aimed to identify whether obese patients suffer the same complications when undergoing lower extremity endovascular interventions. METHODS: All patients who underwent femoropopliteal or tibial endovascular interventions between 2011 and 2013 were identified in the Targeted Vascular Module of the National Surgical Quality Improvement Program. Patients were stratified into 5 groups based on their body mass index (BMI): underweight (<18.6), normal weight (18.6-24.9), overweight (25-29.9), obese (30 34.9), and morbidly obese (>=35). Those patients without a documented BMI or a defined target lesion were excluded. Baseline demographics, patient characteristics, operative details, and outcomes were compared using univariate analysis between the BMI groups. Multivariable logistic regression was used to account for patient demographics and operative details. RESULTS: 3,246 patients underwent endovascular interventions (78% femoropopliteal and 22% tibial). Of these, 137 (4%) were underweight, 881 (27%) were normal weight, 1,193 (37%) were overweight, 647 (20%) were obese, and 388 (12%) were morbidly obese. There were no differences in 30-day mortality; however, surgical site infection (SSI) was higher in the morbidly obese (5% vs. normal weight: 2%, P = 0.02), whereas untreated patency loss was lower (morbidly obese: 0.5%, obese: 1%, normal weight: 2%, P = 0.02). Other important 30-day outcomes, including bleeding and amputation, were similar across the BMI groups. Following multivariate analysis, SSI remained more common in the morbidly obese (odds ratio [OR]: 2.6, 95% confidence interval [CI]: 1.4-5.0), whereas untreated patency loss remained lower in both overweight and morbidly obese patients (overweight: OR 0.5, 95% CI: 0.2 0.9 and morbidly obese: OR: 0.2, 95% CI: 0.05-0.85). Length of stay >1 day was significantly lower in the overweight, obese, and morbidly obese (OR 0.7, 95% CI: 0.6-0.8; OR 0.6, 95% CI: 0.5-0.7; and OR 0.7, 95% CI: 0.5-0.9, respectively). CONCLUSIONS: Few major complications occur in the obese in the first 30 days following endovascular interventions, and obesity is not an independent predictor of 30-day mortality. Rates of postoperative SSIs are low overall, although they are highest in morbidly obese patients (5%, compared to 2% in normal weight patients). Given this knowledge, endovascular interventions are a prudent treatment option for this patient population. PMID- 29421420 TI - Continuous Blood Glucose Monitoring May Detect Carotid Occlusion Intolerance during Carotid Artery Stenting. AB - BACKGROUND: The frequency of the occurrence of adverse events associated with carotid artery stenting (CAS) is usually low, but serious adverse events such as cerebral hyperperfusion syndrome (CHS) may occur. Real-time monitoring is ideal for the early detection of adverse events during the surgical procedure. This study aimed to evaluate continuous blood glucose (BG) monitoring for the detection of adverse events during CAS. METHODS: Forty patients undergoing scheduled CAS were prospectively enrolled. An artificial pancreas was used for continuous BG monitoring (once per minute), using venous blood extracted at a rate of 2 mL/hr during CAS. The primary endpoint was a correlation between BG change and adverse events. RESULTS: CAS was discontinued in 1 patient, and BG was not measured in 5 patients (12.5%) because of the inability to extract blood. Among 34 evaluable patients, no patient developed CHS, but 3 patients (9%) experienced carotid occlusion intolerance. During CAS, BG was significantly higher in patients with carotid occlusion intolerance (median: 5 mg/dL) than in patients without carotid occlusion intolerance (median: 0 mg/dL) (P = 0.0221). A cutoff BG value >=4 mg/dL during CAS showed 50% sensitivity and 100% specificity for the detection of carotid occlusion intolerance. There was no significant correlation between BG change and other adverse events. CONCLUSIONS: BG elevation may help detect carotid occlusion intolerance although it is still unknown whether BG monitoring can detect CHS. Further studies should validate that a cutoff BG elevation value of >=4 mg/dL during CAS indicates carotid occlusion intolerance. PMID- 29421421 TI - Laparoscopic Resection of a Middle Colic Artery Aneurysm. AB - We report herein the successful laparoscopic resection of an asymptomatic 3-cm middle colic artery aneurysm in a young woman. Endovascular treatment represents nowadays the first-line option facing visceral artery aneurysm, but in this case, embolization was excluded because of hostile anatomy. Advantages of laparoscopic approach were the safe resection of the aneurysm with immediate evaluation of the bowel tolerance and the possibility of a histological examination of the arterial wall, without the disadvantages of laparotomy. PMID- 29421422 TI - Influence of Body Weight on Surgical Treatment for Neurogenic Thoracic Outlet Syndrome. AB - BACKGROUND: Body weight affects outcomes of surgical treatment for various conditions, but its effects on the treatment of neurogenic thoracic outlet syndrome (NTOS) are unknown. The purpose of this study was to evaluate the influence of body weight on technical and functional outcomes of surgical treatment for NTOS. METHODS: A retrospective review of prospectively collected data was conducted for 265 patients who underwent supraclavicular decompression for NTOS between January 1, 2014 and March 31, 2016. Patients were grouped according to 6 standard body mass index (BMI) categories. The influence of BMI on measures of surgical outcome was analyzed using Pearson correlation statistics, analysis of variance (ANOVA), and multivariate logistic regression. RESULTS: Mean patient age was 33.3 +/- 0.7 years (range, 12-70), and 208 (78%) patients were women. Mean BMI was 27.2 +/- 0.4 (range 16.8-49.9), with 7 underweight (3%), 95 normal (36%), 84 overweight (32%), 47 obese-I (18%), 15 obese-II (6%), and 17 obese-III (6%). There was a slight but significant association between BMI and age (Pearson P < 0.0001, r = 0.264; ANOVA P = 0.0002), but no correlations between BMI and other preoperative variables. There were no differences between BMI groups for intraoperative, immediate postoperative, or 3-month outcomes. Multivariate logistic regression demonstrated that BMI had no significant effect on functional outcome as measured by the extent of improvement in Disability of the Arm, Shoulder, and Hand score at 3 months (P = 0.429). CONCLUSIONS: There was no substantive influence of BMI on preoperative characteristics or intraoperative, postoperative, or 3-month outcomes for patients with NTOS, and no indication of an "obesity paradox" for this condition. Supraclavicular decompression for NTOS achieves similar outcomes across the BMI spectrum. PMID- 29421423 TI - Rupture of an Abdominal Aortic Aneurysm in a Young Man with Marfan Syndrome. AB - Abdominal aortic aneurysms (AAAs) are very rare in Marfan syndrome. We present a case with a young nonsmoking and normotensive male with Marfan syndrome, who developed an infrarenal AAA that presented with rupture to the retroperitoneal cavity causing life-threatening bleeding shock. The patient had acute aortic surgery and survived. Five months before this incident, the patient had uneventful elective aortic root replacement (ad modum David) due to an enlarged aortic root. At that time, his abdominal aorta was assessed with a routine ultrasound scan that showed a normal-sized abdominal aorta. This documents that the aneurysm had evolved very rapidly despite young age and absence of risk factors. PMID- 29421425 TI - A Custom-Made Treovance(r) Abdominal Aortic Aneurysm Endograft to Correct Late Failure of Trombone Technique with a Tube Endograft. AB - BACKGROUND: Unfavorable anatomy is one of the major limitations of endovascular aortic aneurysm repair (EVAR) with specifically adverse proximal neck morphology excluding many patients from receiving the standard endograft devices. Thoracic tube endografts have been used to overcome the issue of wide infrarenal necks, either as a sole device (single tubes or double tubes using the trombone technique) or as the proximal part of a bifurcated device fixed to the aortic bifurcation or infrarenally oriented. However, custom-made large proximal diameter bifurcated endograft designs have never been used. METHODS: We present the case of a 56-year-old man with Marfan syndrome, suffering abdominal aortic aneurysm (AAA) enlargement from a type Ib endoleak after previous EVAR with 2 Endofit tube endografts (trombone technique). He was considered unfit for open surgery while possible alternatives such as fenestrated endovascular AAA repair and chimney technique were excluded. RESULTS: The patient was treated with a custom-made 44-mm proximal diameter, bifurcated Bolton Medical Treovance device with technical and clinical success. No immediate or perioperative complications were noted. Follow-up after 6 months showed graft patency and no endoleak of any type. CONCLUSIONS: This alternative technique for hostile proximal neck management is promising and needs long-term follow-up; an issue which is discussed within the broader context of custom-made device regulations. PMID- 29421424 TI - Renal Fenestration Closure Technique in Fenestrated Endovascular Repair for Pararenal Aortic Aneurysm. AB - PURPOSE: To describe an endovascular technique to close a renal artery fenestration during fenestrated endograft implant for a pararenal abdominal aortic aneurysm (p-AAA) without interfering with other visceral vessels. REPORT: A 76-year-old man with p-AAA underwent repair by a 4 fenestrations custom-made endograft. At the intraprocedural angiography, the right renal artery was occluded. To avoid a high-flow endoleak from fenestration, we performed the following technique: a 9F-steerable sheath was used to advance a 7F sheath through the fenestration into aneurism. A balloon-expandable covered stent was deployed across the fenestration and then occluded by 2 vascular plugs. At the completion angiography, there was no endoleak from the right renal fenestration, and at 6-month period, p-AAA remained completely excluded. CONCLUSIONS: The present technique can be a safe and effective therapeutic option to propose in cases of impossible target visceral vessels cannulation during p-AAA repair using a custom-made device to avoid the aneurysmal sac perfusion. PMID- 29421426 TI - Surgical Treatment of Cephalic Arch Problems in Arteriovenous Fistulas: A Center Experience. AB - BACKGROUND: Cephalic arch problems, mainly stenosis, are a common cause of arteriovenous fistulas (AVFs) failure, and the most effective treatment is yet to be clearly defined. Restenosis usually occurs soon, and multiple interventions become necessary to maintain patency and functionality. The authors present the experience of their center with cephalic vein transposition in a group of patients with different problems involving the cephalic arch. METHODS: After consultation of the medical records, an observational retrospective analysis was performed to evaluate the outcomes of surgical treatment in cephalic arch problems of AVFs treated at the author's center between January 2013 and December 2015. The considered outcomes were endovascular intervention rate, thrombosis rate, and primary and secondary patencies. RESULTS: Seven patients were treated by venovenostomy with transposition of the cephalic arch and anastomosis to the axillary vein. The average patient age was 72 years (59-81), and most patients were female (71%) and diabetic (71%). All accesses were brachiocephalic AVFs with a mean duration of 4 years (1-7). The underlying problems were intrinsic cephalic arch stenosis (n = 5), entrapment of the cephalic vein (n = 1), and clinically significant vein tortuosity at the cephalic arch (n = 1). These last 2 problems conducted to a surgical approach as first-line therapy instead of endovascular intervention, the initial treatment in the other 5 cases (all with high-pressure balloons, with cutting balloon in one case). Previous thrombotic episodes were reported in 57% of the patients. The mean access flow before surgical intervention was 425 mL/min (350-1,500). No complications related with the surgical procedure were reported. One patient underwent surgical thrombectomy after AVF thrombosis, followed by transposition of the vein. In another case, a simultaneous flow reduction was performed. Most of the patients on dialysis (5/6) used the AVF after surgery. After a mean follow-up period of 9 months (1-22), surgical treatment was associated with a reduction in endovascular intervention rate (1.9 interventions per patient-year presurgery versus 0.4 postsurgery; P < 0.05) and thrombosis rate (0.93 thrombotic episodes per patient-year presurgery versus 0.17 postsurgery; P < 0.05). The problems leading to endovascular reintervention were as follows: new venous anastomosis stenosis (57%), axillary vein stenosis (29%), and swing-point stenosis (14%). Primary and secondary patencies at 6 months were 57% and 71%, respectively. CONCLUSIONS: In this group of patients with cephalic arch problems and multiple previous procedures, surgical treatment was associated with a reduction in endovascular intervention and thrombosis rate but did not avoid reintervention. Facing the complexity and multiplicity of the cephalic arch complications, treatment should be individually decided. PMID- 29421427 TI - Left Brachiocephalic Venous Aneurysm: A Rare Clinical Finding. AB - Brachiocephalic venous aneurysm is an extremely rare condition, with <20 cases reported in the literature. We present a case of a 72-year-old man who was referred to our department owing to a large aneurysm of the left brachiocephalic vein that was incidentally discovered on computed tomography. Further workup confirmed an isolated saccular aneurysm of the left brachiocephalic vein. The patient underwent aneurysmectomy via sternotomy with no requirement for a vascular graft or cardiopulmonary bypass. The postoperative course and follow-up were uneventful. PMID- 29421428 TI - Cryopreserved Homografts in Infected Infrainguinal Fields Are Associated with Frequent Reinterventions and Poor Amputation-Free Survival. AB - BACKGROUND: Single-length saphenous vein continues to be the conduit of choice in infected-field critical limb ischemia. However, half of these individuals have inadequate vein secondary to previous use or chronic venous disease. We reviewed our outcomes of infected-field infrainguinal bypasses performed with cryopreserved homografts (CHs), a widely accepted alternative to autogenous vein in this setting. METHODS: This is a retrospective, institutional descriptive analysis of infected-field infrainguinal revascularizations between 2012 and 2015. RESULTS: Twenty-four operations were performed in the same number of patients for limb ischemia with signs of active infection. The mean age of the cohort examined was 62.5 +/- 14.4 (standard deviation) years. Mean Society of Vascular Surgery risk score was 3.9 with a baseline Rutherford's chronic ischemia score of 4.3 at presentation. Emergent procedures constituted 29% of cases, and the remainder cases were urgent procedures. The CH bypass captured was a reoperative procedure in all but one of the patients. Culture positivity was present in 75% of cases with Staphylococcus aureus (29%), the most commonly isolated organism. Thirty-day mortality and major adverse cardiovascular events were both 4%. Amputation-free survival (AFS) was 75% at 30 days. Similarly, 30 day reintervention was 38% with debridement (43%) and bleeding (29%), the most common indications. Average duration of follow-up was 27.9 +/- 20.4 months (range: 0.5-60.4). Mean length of stay was 14.8 days. Reinfection requiring an additional procedure or antibiotic regimen separate from the index antibiotic course was 13%. Primary patency and AFS at 1 year was 50% and 58%, respectively. Primary patency and AFS at 2 years was 38% and 52%, respectively. Limb salvage at 1 and 2 years was 70% and 65%, respectively. Fifteen patients (63%) required reintervention during the follow-up period with 40% of those subjects undergoing multiple procedures. CONCLUSIONS: CHs remain a marginal salvage conduit in the setting of infection and no autogenous choices. Therefore, clinicians should individualize usage of this high-cost product in highly selected patients only. PMID- 29421429 TI - True Aneurysm of the Anterior Tibial Artery. AB - Most anterior tibial aneurysm cases described in the literature are pseudoaneurysms resulting from trauma. Since 1967, only 8 cases published on true anterior tibial artery aneurysms were atraumatic. Recent experience with an atraumatic aneurysm of the anterior tibial artery prompted a literature review regarding their incidence, and accordingly, we feel the need exists for greater recognition and understanding of this entity. PMID- 29421430 TI - It Pays to Prepare: Human Motor Preparation Depends on the Relative Value of Potential Response Options. AB - Alternative motor responses can be prepared in parallel. Here, we used electroencephalography (EEG) to test whether the parallel preparation of alternative response options is modulated by their relative value. Participants performed a choice response task with three potential actions: isometric contraction of the left, the right, or both wrists. An imperative stimulus (IS) appeared after a warning cue, such that the initiation time of a required action was predictable, but the specific action was not. To encourage advanced preparation, the target was presented 200 ms prior to the IS, and only correct responses initiated within +/-100 ms of the IS were rewarded. At baseline, all targets were equally rewarded and probable. Then, responses with one hand were made more valuable, either by increasing the probability that the left or right target would be required (Exp. 1; n = 31) or by increasing the reward magnitude of one target (Exp. 2, n = 36). We measured reaction times, movement vigor, and an EEG correlate of action preparation (value-based lateralized readiness potential) prior to target presentation. Participants responded earlier to more frequent and more highly rewarded targets, and movements to highly rewarded targets were more vigorous. The EEG was more negative over the hemisphere contralateral to the more repeated/rewarded hand, implying an increased neural preparation of more valuable actions. Thus, changing the value of alternative response options can lead to greater preparation of actions associated with more valuable outcomes. This preparation asymmetry likely contributes to behavioral biases that are typically observed toward repeated or rewarded targets. PMID- 29421431 TI - Introducing Autoimmunity at the Synapse by a Novel Animal Model of Experimental Autoimmune Myasthenia Gravis. AB - The neuromuscular junction (NMJ) is a peripheral synapse between motor neurons and skeletal muscle fibers that controls muscle contraction. The NMJ is the target of various disorders including myasthenia gravis (MG), an autoimmune disease in which auto-antibodies (auto-Abs) attack the synapse, and thus cause muscle weakness in patients. There are multiple auto-Abs in the MG patient sera, but not all the Abs are proven to be pathogenic, which increases the difficulties in clinical diagnoses and treatments. To establish the causative roles of auto Abs in MG pathogenesis, the experimental autoimmune MG (EAMG) induced by the active immunization of auto-antigens (auto-Ags) or the passive transfer of auto Abs is required. These models simulate many features of the human disease. To date, there are three kinds of EAMG models reported, of which AChR-EAMG and MuSK EAMG are well characterized, while the recent LRP4-EAMG is much less studied. Here, we report a current summary of LRP4-EAMG and its pathogenic mechanisms. The features of LRP4-EAMG are more similar to those of AChR-EAMG, indicating a similar clinical treatment for LRP4- and AChR-positive MG patients, compared to MuSK-positive MG patients. PMID- 29421433 TI - The Neurotoxin DSP-4 Induces Hyperalgesia in Rats that is Accompanied by Spinal Oxidative Stress and Cytokine Production. AB - Central neuropathic pain (CNP) a significant problem for many people, is not well understood and difficult to manage. Dysfunction of the central noradrenergic system originating in the locus coeruleus (LC) may be a causative factor in the development of CNP. The LC is the major noradrenergic nucleus of the brain and plays a significant role in central modulation of nociceptive neurotransmission. Here, we examined CNS pathophysiological changes induced by intraperitoneal administration of the neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine hydrochloride). Administration of DSP-4 decreased levels of norepinephrine in spinal tissue and cerebrospinal fluid (CSF) and led to the development of thermal and mechanical hyperalgesia over 21 days, that was reversible with morphine. Hyperalgesia was accompanied by significant increases in noradrenochrome (oxidized norepinephrine) and expression of 4-hydroxynonenal in CSF and spinal cord tissue respectively at day 21, indicative of oxidative stress. In addition, spinal levels of pro-inflammatory cytokines (interleukins 6 and 17A, tumor necrosis factor-alpha), as well as the anti-inflammatory cytokine interleukin10 were also significantly elevated at day 21, indicating that an inflammatory response occurred. The inflammatory effect of DSP-4 presented in this study that includes oxidative stress may be particularly useful in elucidating mechanisms of CNP in inflammatory disease states. PMID- 29421432 TI - DC-Evoked Modulation of Excitability of Myelinated Nerve Fibers and Their Terminal Branches; Differences in Sustained Effects of DC. AB - Direct current (DC) evokes long-lasting changes in neuronal networks both presynaptically and postsynaptically and different mechanisms were proposed to be involved in them. Different mechanisms were also suggested to account for the different dynamics of presynaptic DC actions on myelinated nerve fibers stimulated before they entered the spinal gray matter and on their terminal branches. The aim of the present study was to examine whether these different dynamics might be related to differences in the involvement of K+ channels. To this end, we compared effects of the K+ channel blocker 4-amino-pyridine (4-AP) on DC-evoked changes in the excitability of afferent fibers stimulated within the dorsal columns (epidurally) and within their projection areas in the dorsal horn and motor nuclei (intraspinally). 4-AP was applied systemically in deeply anesthetized rats. DC-evoked increases in the excitability of epidurally stimulated afferent nerve fibers, and increases in field potentials evoked by these fibers, were not affected by 4-AP. In contrast, sustained decreases rather than increases in the excitability of intraspinally stimulated terminal nerve branches were evoked by local application of DC in conjunction with 4-AP. The study leads to the conclusion that 4-AP-sensitive K+ channels contribute to the sustained DC-evoked post-polarization increases in the excitability at the level of terminal branches of nerve fibers but not of the nodes of Ranvier nor within the juxta-paranodal regions where other mechanisms would be involved in inducing the sustained DC-evoked changes. PMID- 29421434 TI - Differential Spinal and Supraspinal Activation of Glia in a Rat Model of Morphine Tolerance. AB - Development of tolerance is a well known pharmacological characteristic of opioids and a major clinical problem. In addition to the known neuronal mechanisms of opioid tolerance, activation of glia has emerged as a potentially significant new mechanism. We studied activation of microglia and astrocytes in morphine tolerance and opioid-induced hyperalgesia in rats using immunohistochemistry, flow cytometry and RNA sequencing in spinal- and supraspinal regions. Chronic morphine treatment that induced tolerance and hyperalgesia also increased immunoreactivity of spinal microglia in the dorsal and ventral horns. Flow cytometry demonstrated that morphine treatment increased the proportion of M2-polarized spinal microglia, but failed to impact the number or the proportion of M1-polarized microglia. In the transcriptome of microglial cells isolated from the spinal cord (SC), morphine treatment increased transcripts related to cell activation and defense response. In the studied brain regions, no activation of microglia or astrocytes was detected by immunohistochemistry, except for a decrease in the number of microglial cells in the substantia nigra. In flow cytometry, morphine caused a decrease in the number of microglial cells in the medulla, but otherwise no change was detected for the count or the proportion of M1- and M2-polarized microglia in the medulla or sensory cortex. No evidence for the activation of glia in the brain was seen. Our results suggest that glial activation associated with opioid tolerance and opioid induced hyperalgesia occurs mainly at the spinal level. The transcriptome data suggest that the microglial activation pattern after chronic morphine treatment has similarities with that of neuropathic pain. PMID- 29421435 TI - Long Non-coding RNA BC168687 is Involved in TRPV1-mediated Diabetic Neuropathic Pain in Rats. AB - Long noncoding RNAs (lncRNAs) participate in a diverse range of molecular and biological processes, and dysregulation of lncRNAs has been observed in the pathogenesis of various human diseases. We observed alterations in mechanical withdrawal thresholds (MWT) and thermal withdrawal latencies (TWL) in streptozotocin (STZ)-induced diabetic rats treated with small interfering RNA (siRNA) of lncRNA BC168687. We detected expression of transient receptor potential vanilloid type 1 (TRPV1) in rat dorsal root ganglia (DRG) by a series of molecular experiments. We determined relative levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in rat serum by enzyme-linked immunosorbent assay (ELISA). In addition, we examined extracellular regulated protein kinases (ERK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways by Western blot (WB). We showed that the MWT and TWL of diabetic rats increased significantly compared with control. Expression of TRPV1 receptors in DRG substantially decreased. Relative levels of TNF-alpha and IL-1beta in the serum of lncRNA BC168687 siRNA-treated rats were reduced. Phosphorylation (p)-ERK and p-p38 signaling pathways in DRG were also decreased. Taken together, we concluded lncRNA BC168687 siRNA may alleviate TRPV1-mediated diabetic neuropathic pain. PMID- 29421436 TI - Dopamine, Noradrenaline and Serotonin Receptor Densities in the Striatum of Hemiparkinsonian Rats following Botulinum Neurotoxin-A Injection. AB - Parkinson's disease (PD) is characterized by a degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that causes a dopamine (DA) deficit in the caudate-putamen (CPu) accompanied by compensatory changes in other neurotransmitter systems. These changes result in severe motor and non-motor symptoms. To disclose the role of various receptor binding sites for DA, noradrenaline, and serotonin in the hemiparkinsonian (hemi-PD) rat model induced by unilateral 6-hydroxydopamine (6-OHDA) injection, the densities of D1, D2/D3, alpha1, alpha2, and 5HT2A receptors were longitudinally visualized and measured in the CPu of hemi-PD rats by quantitative in vitro receptor autoradiography. We found a moderate increase in D1 receptor density 3 weeks post lesion that decreased during longer survival times, a significant increase of D2/D3 receptor density, and 50% reduction in 5HT2A receptor density. alpha1 receptor density remained unaltered in hemi-PD and alpha2 receptors demonstrated a slight right left difference increasing with post lesion survival. In a second step, the possible role of receptors on the known reduction of apomorphine-induced rotations in hemi-PD rats by intrastriatally injected Botulinum neurotoxin-A (BoNT-A) was analyzed by measuring the receptor densities after BoNT-A injection. The application of this neurotoxin reduced D2/D3 receptor density, whereas the other receptors mainly remained unaltered. Our results provide novel data for an understanding of the postlesional plasticity of dopaminergic, noradrenergic and serotonergic receptors in the hemi-PD rat model. The results further suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing the interhemispheric imbalance in D2/D3 receptor density. PMID- 29421437 TI - Effects of acupuncture on the levels of serum estradiol and pituitary estrogen receptor beta in a rat model of induced super ovulation. AB - AIMS: Acupuncture is frequently recommended as a complementary therapy for infertility. However, whether acupuncture can prevent early ovarian hyperstimulation syndrome has not been examined and its potential mechanisms are not well understood. MAIN METHODS: Forty rats were randomized into four groups: Control, Ovarian Stimulation Model, Acupuncture, and Human Chorionic Gonadotropin (HCG). Serum estradiol, progesterone, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels were measured by enzyme-linked immunosorbent assay. Pituitary ER mRNA and ERbeta expression were detected by real-time PCR and western blotting respectively. The pathology of rat ovaries were observed by light microscopy. KEY FINDINGS: We observed significantly lower estradiol levels in the Acupuncture group than in the Model group and increased LH levels in the HCG group than in Model and Acupuncture groups. Testosterone and FSH levels were significantly lower in the Acupuncture group than in the HCG group. Western blotting showed significantly lower pituitary ERbeta expression in the Model group than in the Control group and higher expression in the Acupuncture group than in the Model group. Real-time PCR showed lower pituitary ER mRNA expression in the Acupuncture group than in the Model group. Hematoxylin and eosin staining showed a lower proportion of atretic follicles in Acupuncture and HCG groups than in Model and Control groups. Instead, Acupuncture and HCG groups showed growing and mature follicles. SIGNIFICANCE: Our results demonstrate a relationship between acupuncture and the hypothalamic-pituitary-gonadal axis, and the potential mechanism underlying the preventative effects of acupuncture on the incidence of early ovarian hyperstimulation syndrome. PMID- 29421438 TI - In vitro study of FUZ as a novel potential therapeutic target in non-small-cell lung cancer. AB - FUZ is regarded as a planar cell polarity effector that controls multiple cellular processes during vertebrate development. However, the role of FUZ in tumor biology remains poorly studied. Our purpose of this study is to discover the physiological effects and mechanism of FUZ in non-small-cell lung cancer (NSCLC) in vitro. With the help of bioinformatics analysis, we noticed that the expression level of FUZ negatively correlates with prognosis of NSCLC patients. Exogenous FUZ expression markedly promoted cell proliferation of NSCLC cells. The phosphorylation of Erk1/2, STAT3 and related signaling molecules were induced activated after FUZ over-expression. FUZ also plays an important role in cell motility by regulating cell signaling pathways and inducing epithelial to mesenchymal transition (EMT). FUZ promotes EMT along with the up-regulation of N cadherin, vimentin, Zeb1, Twist1 and decreased level of E-cadherin. Furthermore, we also carried out FUZ directed siRNA treatments to prove the above observations. Knockdown of FUZ resulted in delayed cell growth as well as impaired cell migration and reversed EMT phonotype. Importantly, we reported for the first time that FUZ is a BNIP3-interacting protein. Loss of FUZ resulted in decreased BNIP3 protein level, but no influence on BNIP3 mRNA level, suggesting weakened stability of BNIP3 protein. Overall, our results in vitro show that FUZ is responsible for NSCLC progression and metastasis, suggesting that FUZ can be a potential therapeutic target for NSCLC. PMID- 29421439 TI - LncRNA FAL1 promotes cell proliferation and migration by acting as a CeRNA of miR 1236 in hepatocellular carcinoma cells. AB - BACKGROUND: Long non-coding RNAs (LncRNAs) have been demonstrated to play crucial role in tumor growth and metastasis for hepatocellular carcinoma (HCC). LncRNA FAL1 has been indicated to promote the progression of various cancers. However, the role of lncRNA FAL1 in HCC was poorly understood. METHODS: The expression levels of lncRNA FAL1 in HCC tissues and cells were determined by RT-qPCR. The roles of lncRNA FAL1 on HCC cells were investigated by MTT, colony formation, transwell, RT-qPCR, and Western blotting. The miRNA binding sites of lncRNA FAL1 was predicted using RegRNA 2.0 and miR-1236 was validated to target lncRNA FAL1 by luciferase reporter assays and RT-qPCR. Finally, the expression levels of lncRNA FAL1 in serum exosome of HCC patients was also investigated and the role of exosome-mediated lncRNA FAL1 was further investigated by co-culturing with HCC cells. RESULTS: This study first showed that lncRNA FAL1 was up-regulated in HCC tissues and functioned as an oncogene in HCC. LncRNA FAL1 could accelerate cell proliferation and metastasis as a ceRNA mechanism by competitively binding to miR 1236. Moreover, lncRNA FAL1 was also up-regulated in serum exosome of HCC patients and could transfer lncRNA FAL1 to HCC cells to increase their abilities of cell proliferation and migration. CONCLUSIONS: Taken together, this study indicated that lncRNA FAL1 functions as an oncogenic in HCC and may be a novel diagnostic biomarker or a novel target for the treatment of HCC in future. PMID- 29421440 TI - Evaluation of interferon-gamma release assays in extrasanguinous body fluids for diagnosing tuberculosis: A systematic review and meta-analysis. AB - AIMS: In this study, we conducted a meta-analysis to systematically compare the diagnostic accuracy of IGRAs performed for extrasanguinous body fluids with that performed for blood in the diagnosis of TB. MAIN METHODS: Multiple English and Chinese databases were searched up to November 2017. Studies that complied with the guidelines for the Quality Assessment of Diagnostic Accuracy Studies and used QuantiFERON-TB Gold In-Tube and/or T-SPOT.TB (ELISPOT) assays on both blood and extrasanguinous body fluids were included. Statistical analysis was performed using Stata 12.0 software. Since publication bias is a concern in the meta analysis of diagnostic studies, we tested for this using Begg's funnel plots. KEY FINDING: Among the 1332 articles searched from the databases, 24 articles met the inclusion criteria, which included 1040 samples in the patient group and 1044 samples in the control group. For extrasanguinous body fluids, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) area under the curve (AUC) were 87% (95% CI: 0.81-0.91), 89% (95% CI: 0.84-0.93), 8.22 (95% CI 5.38-12.56), 0.15 (95% CI: 0.10-0.21), 44.92 (95% CI: 25.61-78.81), and 0.94 (95% CI: 0.92-0.96), respectively. For peripheral blood, these values were 83% (95% CI: 0.79-0.87), 74% (95% CI: 0.68 0.79), 3.17 (95% CI 2.63-3.84), 0.23 (95% CI: 0.19-0.29), 12.99 (95% CI: 10.19 16.57), and 0.86 (95% CI: 0.82-0.89), respectively. SIGNIFICANCE: IGRAs performed on extrasanguinous body fluids exhibited a better diagnostic accuracy compared with IGRAs performed on peripheral blood for diagnosing TB. PMID- 29421441 TI - Simultaneous determination of Vitamin A, 25-hydroxyl vitamin D3 alpha-tocopherol in small biological fluids by liquid chromatography-tandem mass spectrometry. AB - A sensitive method for the simultaneous analysis of vitamin A (VA), 25-hydroxyl vitamin D3 (25-OH VD3) and alpha-tocopherol (VE) in children plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated. Sample preparation chose the solid phase extraction. 100 MUL of plasma was mixed with 300 MUL ethanol contained 4 MUL isotope-labelled analytes. After a series operation, the supernatant was applied to the solid phase extraction (SPE) plate (HLB MUElution plate). The eluate was evaporated, and reconstituted in 100 MUL methanol. And then, 6 MUL reconstituted sample was injected into LC-MS/MS. Quantitative analysis was carried out by multiple reaction monitoring (MRM) with a positive mode electrospray (ESi + ). Separations of VA, 25-OH VD3 and VE were performed on an Acquity UPLC reversed-phase Phenyl-Hexyl analytical column (CSH, 2.1 * 50 mm, 1.7 MUm). Gradient elution was used at a flow rate of 0.4 mL/min with a mobile phase consisting of 0.1% formic acid solution and 0.1% formic acid, 5 mM ammonium formate in acetonitrile. The total time of analysis was 10 min. The method had a limit of quantification (LOQ) of 10.03, 1.20, and 0.04 ng/mL for VA, 25-OH VD3 and VE in methanol, respectively. The linear calibration curves were fitted over the range of 0.14-14.32 MUg/mL, 1.80-180.29 ng/mL, and 6.03-602.99 ng/mL for VA, 25-OH VD3 and VE in methanol. The correlation coefficients were greater than 0.998 for all analytes. The recoveries for all analytes were between 80 and 120% with the inter- and intra-day precisions (presented as relative standard deviation, RSD%) less than 10.0%. Analysis of VA, 25-OH VD3 and VE in recurrent respiratory tract infection children plasma and anemic infants' fingertip blood was then carried out using this method and statistical analysis of the data with statistic package for social science 20.0 (SPSS 20.0). Using this method, multiple fat-soluble vitamins could be detected at the same time. Solid phase extraction was used to simplify sample pretreatment. MUElution plate used here could reduce the sample volume, only 100 MUL sample was used in this method, and 6 MUL reconstituted sample was injected into LC-MS/MS. This makes the method appropriate for larger sample pretreatment, and suitable for children, especially infants and newborns' sample detection, in whom the circulation blood was low. PMID- 29421442 TI - RAGE may act as a tumour suppressor to regulate lung cancer development. AB - Although the correlation of the RAGE rs2070600 polymorphism and cancer risk has been confirmed, detailed studies with functional and experimental evaluations are lacking. In this study, we first aimed to examine whether this polymorphism is associated with cancer risk based on the latest published data, and consistent with previous meta-analyses, a significant association between the rs2070600 polymorphism and cancer risk was observed (A versus G: OR = 1.25; 95% CI = 1.12 1.40). In additional stratified analyses based on cancer type, rs2070600 was significantly associated with an increased risk of lung cancer (A versus G: OR = 1.20; 95% CI = 1.09-1.33). Moreover, TCGA database showed that the expression level of RAGE was significantly lower in lung cancer tumour tissues than in adjacent non-tumour tissues, which was validated in the GEO database. Additionally, eQTL analysis indicated that the rs2070600 polymorphism may modify the expression level of RAGE in lung squamous cell carcinoma tissues (P = 0.09). Finally, we performed functional experiments in lung cancer cells and preliminarily demonstrated that RAGE may act as a tumour suppressor in lung cancer development. These findings provide evidence that the variant A allele of rs2070600 may decrease the expression of the tumour suppressor gene RAGE, thereby increasing lung cancer risk. PMID- 29421443 TI - Epigenetic editing: How cutting-edge targeted epigenetic modification might provide novel avenues for autoimmune disease therapy. AB - Autoimmune diseases are enigmatic and complex, and most been associated with epigenetic changes. Epigenetics describes changes in gene expression related to environmental influences mediated by a variety of effectors that alter the three dimensional structure of chromatin and facilitate transcription factor or repressor binding. Recent years have witnessed a dramatic change and acceleration in epigenetic editing approaches, spurred on by the discovery and later development of the CRISPR/Cas9 system as a highly modular and efficient site specific DNA binding domain. The purpose of this article is to offer a review of epigenetic editing approaches to date, with a focus on alterations of DNA methylation, and to describe a few prominent published examples of epigenetic editing. We will also offer as an example work done by our laboratory demonstrating epigenetic editing of the FOXP3 gene in human T cells. Finally, we discuss briefly the future of epigenetic editing in autoimmune disease. PMID- 29421444 TI - Alternative NAD(P)H dehydrogenase and alternative oxidase: Proposed physiological roles in animals. AB - The electron transport systems in mitochondria of many organisms contain alternative respiratory enzymes distinct from those of the canonical respiratory system depicted in textbooks. Two of these enzymes, the alternative NADH dehydrogenase and the alternative oxidase, were of interest to a limited circle of researchers until they were envisioned as gene therapy tools for mitochondrial disease treatment. Recently, these enzymes were discovered in several animals. Here, we analyse the functioning of alternative NADH dehydrogenases and oxidases in different organisms. We propose that both enzymes ensure bioenergetic and metabolic flexibility during environmental transitions or other conditions which may compromise the operation of the canonical respiratory system. PMID- 29421445 TI - Relationships between allostatic load, unhealthy behaviors, and depressive disorder in U.S. adults, 2005-2012 NHANES. AB - Unhealthy behaviors may modify relationships between chronic stress and depression among diverse older adults. We analyzed nationally representative cross-sectional data from participants aged 40-79 years of the 2005-2012 National Health and Nutrition Examination Survey. Unhealthy behaviors included current smoking, excessive/binge drinking, insufficient physical activity, and fair/poor diet. Allostatic load was defined by 10 biomarkers indicating the cumulative physiologic burden of stress. Depressive disorder was assessed using the Patient Health Questionnaire. Multivariable logistic regression examined whether current smoking, excessive/binge drinking, insufficient physical activitiy, and fair/poor diet modified relationships between allostatic load and depressive disorder. Mean age of 12,272 participants was 55.6 years (standard error = 0.19), 51.9% were women, and most had at least a high school education (81.8%). Latinos (11.3%) and African Americans (10.4%) were more likely than Whites (7.1%; p < 0.001) to meet depressive disorder criteria. Allostatic load was not associated independently with depressive disorder in any racial/ethnic group and this lack of a relationship did not differ by the extent of unhealthy behaviors. Although Latinos and African Americans report higher levels of depression than Whites, physiological markers of stress do not appear to explain these differences. PMID- 29421446 TI - Transnasal Transsphenoidal Elevation of Optic Chiasm in Secondary Empty Sella Syndrome Following Prolactinoma Treatment. AB - BACKGROUND: Prolactinomas are typically treated nonsurgically with a dopamine agonist. Once the tumor shrinks, adjacent eloquent structures, such as the optic apparatus, can become skeletonized and herniate into the dilated parasellar space. CASE DESCRIPTION: A 48-year-old man with a prolactin-secreting macroadenoma treated with cabergoline presented with progressive bitemporal hemianopsia. Magnetic resonance imaging showed no recurrence of disease and a stretched optic chiasm herniating into an empty sella. Elevation of the optic chiasm via a transnasal transsphenoidal approach with ALLODERM graft and septal cartilage strut was performed. The patient was discharged home the next day with significant improvement in vision; magnetic resonance imaging showed interval elevation of the optic chiasm. CONCLUSIONS: We review secondary empty sella syndrome and discuss surgical strategies for optic chiasmapexy. PMID- 29421447 TI - Prognostic Significance of Magnetic Resonance Imaging in Patients with Severe Nonpenetrating Traumatic Brain Injury Requiring Decompressive Craniectomy. AB - BACKGROUND: Diffuse axonal injury (DAI) detected on magnetic resonance imaging (MRI) may be useful to predict outcome after traumatic brain injury (TBI). METHODS: This study compared the ability of the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) prognostic model with DAI on MRI to predict the 18-month neurologic outcome in 56 patients who had required decompressive craniectomy after TBI. RESULTS: Of the 56 patients included in the study (19 scans occurred within 14 days; median time for all patients 24 days, interquartile range 14-42), 18 (32%) had evidence of DAI on the MRI scans. The presence of DAI on the MRI diffusion-weighted (DW) T2*-weighted gradient echo and susceptibility-weighted (SWI) sequences was associated with an increased risk of unfavorable outcome at 18 months compared with patients without DAI (44% vs. 17%, difference = 27%, 95% confidence interval 2.4-46.7%; P = 0.032), particularly when the brainstem was involved. However, neither the grading (I to IV) nor the number of brain regions with DAI was as good as the IMPACT model in discriminating between patients with unfavorable and favorable outcomes (area under the receiver operating characteristic curve: 0.625 and 0.621 vs. 0.918, respectively; P < 0.001 for both comparisons). After adjustment for the IMPACT prognostic risks, DAI in different brain regions and the grading of DAI were also not independently associated with unfavorable outcome. CONCLUSIONS: The prognostic significance of DAI on MRI may, in part, be captured by the IMPACT prognostic model. More research is needed before MRI should be routinely used to prognosticate the outcomes in patients with TBI requiring decompressive craniectomy. PMID- 29421448 TI - A Potential New Risk Factor for Stroke: Streptococcus Mutans With Collagen Binding Protein. AB - BACKGROUND: Among human oral bacteria, particular kinds of Streptococcus mutans (SM) known as dental caries pathogens contain a collagen-binding protein, Cnm, and show platelet aggregation inhibition and matrix metalloproteinase-9 activation. We have previously reported that these strains may be a risk factor for intracerebral hemorrhage. As a major sample-providing hospital, we report the clinical details, including intracranial aneurysms and ischemic stroke. METHODS: After the study received approval from the Ethical Committee, 429 samples of whole saliva were obtained from patients who were admitted to or visited our hospital between February 16, 2010, and February 28, 2011. The study cohort comprised 48 patients with cardioembolic stroke (CES), 151 with non-CES infarct, 54 with intracerebral hemorrhage (ICH), 43 with ruptured intracranial aneurysm (RIA), and 97 with unruptured intracranial aneurysm (UIA). Cultured SM was identified as Cnm-positive when the corresponding gene was positive. The results were compared with those from 79 healthy volunteers. Relationships between Cnm positive SM and known risk factors, including hypertension, diabetes, hyperlipidemia, smoking, and alcohol consumption, were analyzed. RESULTS: A statistically significant high Cnm-positive rate was observed in patients with CES, non-CES infarct, ICH, and RIA (P = 0.002, 0.039, 0.013, and 0.009, respectively). There were no relationships between Cnm-positive SM and known risk factors. CONCLUSIONS: Specific types of oral SM can be a risk factor for cardioembolic infarct, intracerebral hemorrhage, and intracranial aneurysm rupture. Further study is needed. PMID- 29421449 TI - Potential Uses of Isolated Toxin Peptides in Neuropathic Pain Relief: A Literature Review. AB - Neuropathic pain is a subset of chronic pain that is caused by neurons that are damaged or firing aberrantly in the peripheral or central nervous systems. The treatment guidelines for neuropathic pain include antidepressants, calcium channel alpha2 delta ligands, topical therapy, and opioids as a second-line option. Pharmacotherapy has not been effective in the treatment of neuropathic pain except in the treatment of trigeminal neuralgia with carbamazepine. The inability to properly treat neuropathic pain causes frustration in both the patients and their treating physicians. Venoms, which are classically believed to be causes of pain and death, have peptide components that have been implicated in pain relief. Although some venoms are efficacious and have shown benefits in patients, their side-effect profile precludes their more widespread use. This review identifies and explores the use of venoms in neuropathic pain relief. This treatment can open doors to potential therapeutic targets. We believe that further research into the mechanisms of action of these receptors as well as their functions in nature will provide alternative therapies as well as a window into how they affect neuropathic pain. PMID- 29421450 TI - Case of Spinal Osteoblastoma in Elderly: Is It Really a Young Patient's Disease? AB - BACKGROUND: Osteoblastoma is a benign bone-forming tumor, sometimes locally invasive, that may involve any bone. The highest incidence is between 20 and 30 years of age, and there are no cases described in the elderly. METHODS: We report a case of an elderly patient with a lesion in the lumbar spine in which osteoblastoma diagnosis was made. CONCLUSIONS: Osteoblastoma is a rare tumor older than 50 years of age, but it should be considered in the differential diagnosis of bone lesions of the spine in adulthood and in the elderly, to avoid a delay in the treatment. PMID- 29421451 TI - Intracranial Hypertension and Cerebral Autoregulation: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To present a systematic review and meta-analysis to establish the relation between cerebral autoregulation (CA) and intracranial hypertension. METHODS: An electronic search using the term "Cerebral autoregulation and intracranial hypertension" was designed to identify studies that analyzed cerebral blood flow autoregulation in patients undergoing intracranial pressure (ICP) monitoring. The data were used in meta-analyses and sensitivity analyses. RESULTS: A static CA technique was applied in 10 studies (26.3%), a dynamic technique was applied in 25 studies (65.8%), and both techniques were used in 3 studies (7.9%). Static CA studies using the cerebral blood flow technique revealed impaired CA in patients with an ICP >=20 (standardized mean difference [SMD] 5.44%, 95% confidence interval [CI] 0.25-10.65, P = 0.04); static CA studies with transcranial Doppler revealed a tendency toward impaired CA in patients with ICP >=20 (SMD -7.83%, 95% CI -17.52 to 1.85, P = 0.11). Moving correlation studies reported impaired CA in patients with ICP >=20 (SMD 0.06, 95% CI 0.07-0.14, P < 0.00001). A comparison of CA values and mean ICP revealed a correlation between greater ICP and impaired CA (SMD 5.47, 95% CI 1.39-10.1, P = 0.01). Patients with ICP >=20 had an elevated risk of impaired CA (OR 2.27, 95% CI 1.20-4.31, P = 0.01). CONCLUSIONS: A clear tendency toward CA impairment was observed in patients with increased ICP. PMID- 29421452 TI - Marriage and Partnership Integrity After Aneurysmal Subarachnoid Hemorrhage: Small Alterations in Neurologic Status Matter Most. AB - OBJECTIVE: Common sequelae of subarachnoid hemorrhage (SAH) include somatic and/or cognitive impairment. This can cause emotional stress, social tensions, and difficulties in relationships. To test our hypothesis that more severe somatic and cognitive impairments increased the likelihood of disruption of a relationship after SAH, we assessed the integrity of marriage or partnership status in a well-evaluated subset of SAH patients. METHODS: Our sample comprised 50 SAH patients who were discharged to a neurologic, in-house rehabilitation center between 2005 and 2010. Deficits on admission to the rehabilitation center were divided into 18 categories and grouped into minor and major somatic deficits, as well as cognitive deficits. Clinical outcome scores, marital/partnership status, and duration of partnership before ictus were recorded. A follow-up questionnaire after 4.3 (2012) and 8.8 (2017) years was used to assess changes in marital/partnership status. Possible predictor parameters were estimated and included in a stepdown regression analysis. RESULTS: In 2012, after a mean follow-up of 4.3 years, 8 of the 50 SAH patients were divorced or separated, whereas after 8.8 years only 1 additional relationship had ended. In our regression model analysis, a "short duration of relationship" before SAH and the presence of a "few minor somatic deficits" were associated with a higher likelihood of divorce or separation in the near future and remained unchanged at long-term follow-up. CONCLUSION: Contrary to our hypothesis, neither the presence of severe somatic or cognitive deficits nor clinical evaluation scores reliably predicted divorce or separation after SAH. PMID- 29421453 TI - Adrenal Axis Insufficiency After Endoscopic Transsphenoidal Resection of Pituitary Adenomas. AB - INTRODUCTION: Hormonal insufficiency of 1 or more pituitary axes can appear after pituitary surgery. Adrenal axis impairment after surgery can lead to serious consequences if not identified and treated. OBJECTIVE: Assess early and late postoperative adrenal insufficiency (AI) and identify the risk factors predicting their occurrence after endoscopic transsphenoidal resection of pituitary adenomas. METHOD: Retrospective review identified 176 pituitary adenomas resected using an endoscopic transsphenoidal approach. Patients taking steroids preoperatively, Cushing disease patients, and patients with incomplete records were excluded. Sixty-nine patients were excluded according to our exclusion criteria. RESULTS: The study group thus included 107 patients (total of 111 operations). The median age was 50 years (range, 18-89 years). The median duration of follow-up was 30 months (range, 6-74 months). Eighty-three patients (74.7%) had macroadenomas, and 89 (59.3%) had nonfunctional adenomas. Of the 111 procedures, 61 patients (55%) had early AI. Of the 61 patients, 48 patients (79%) were not taking steroids in long-term follow-up, and only 13 (21%) required long term replacement. Sixteen of the patients undergoing 111 procedures (14.4%) had AI on long-term follow-up. Of those 16 patients, 13 were already taking steroids and 3 had new diagnoses of AI. Age, male gender, and cerebrospinal fluid (CSF) leaks were associated with persistent postoperative AI (P = 0.018, P = 0.001, P = 0.007, respectively). CONCLUSION: Hypothalamic pituitary adrenal axis insufficiency is common after endoscopic transsphenoidal surgery. Male gender, age greater than 50 years, visual impairment, and intraoperative CSF leak were correlated with late postoperative AI. More than two thirds of patients in whom early AI developed did not require steroids in the long term. PMID- 29421454 TI - Morphometric Analysis of the Uncinate Process as a Landmark for Anterior Controllable Antedisplacement and Fusion Surgery: A Study of Radiologic Anatomy. AB - OBJECTIVE: This study used the uncinate process (UP) base as the landmark to measure the various distances of the interested anatomic structures to improve the practicality of anterior controllable antedisplacement and fusion (ACAF) for ossification of the posterior longitudinal ligament (OPLL). METHODS: Computed tomographic (CT) scan data of 20 OPLL patients were studied. We investigated the base distance of the UP, transverse foramen (TF) to UP base, pedicle to UP base, posterior to anterior UP, maximal width of OPLL, and width of the vertebrae-OPLL complex (VOC). RESULTS: Base distance of the UP shows an increasing trend from C3 to C7. The average base distance of the UP ranges from 14.6 mm at C3 to 22.7 mm at C7. The TF to UP distance ranges from 4.6 to 7.2 mm. The pedicle to UP distance is significantly shorter than upper levels at C7 and C6. The posterior to anterior UP ranges from -3.7 to -5.7 mm with an increasing trend from C3 to C7. The maximal width of OPLL is 13.2 mm on average. The mean width of the VOC in the ACAF cases is 16.8 mm on average. CONCLUSIONS: The results show that the UP can serve as a landmark for the location of longitudinal osteotomies in ACAF. However, preoperative measurement of CT images should be conducted for an individual dependent surgical planning of ACAF. PMID- 29421455 TI - Relaxing Sphenoidal Slit Incision to Extend the Anterior and Posterior Reach of Pedicled Nasoseptal Flaps During Endoscopic Skull Base Reconstruction of Transcribriform Defects: Technical Note and Results in 20 Patients. AB - BACKGROUND: Reconstruction of large anterior skull base (ASB) defects after an endoscopic endonasal transcribriform approach (EEA-TC) remains a challenge despite the advent of the vascularized pedicled nasoseptal flap (PNSF). OBJECTIVE: We describe a relaxing PNSF slit incision that extends the anterior and posterior reach of the PNSF to maximize tensionless flap coverage of transcribriform ASB defects. METHODS: A retrospective chart review was conducted on 20 consecutive patients who underwent endoscopic endonasal transcribriform approach and subsequent PNSF reconstruction with a relaxing slit incision. At the time of endoscopic ASB reconstruction, the PNSF is rotated into position so that the anterior margin of the flap is situated at the posterior table of the frontal sinus. A relaxing slit incision is made across the sphenoidal segment of the PNSF, which is the segment of flap that bridges across the sphenoid sinus once the flap is rotated into position. The anterior reach of the flap is increased to adequately cover the posterior table of the frontal sinus, and the redundant sphenoidal flap is rotated posteriorly to make contact to the bony planum sphenoidale. RESULTS: No patients developed postoperative cerebrospinal fluid leaks (0%). The ASB repair was monitored via postoperative outpatient nasal endoscopy at various time points, which demonstrated excellent mucosalization of the ASB with a mean follow-up of 19.2 months (range: 4.1-36.2 months). CONCLUSIONS: Our simple relaxing slit incision in the sphenoidal portion of the PNSF allows for maximal tensionless coverage of extensive transcribriform defects by increasing the anterior and posterior reach of the flap. PMID- 29421456 TI - Development of a risk assessment tool for osteoporotic fracture prevention: A claims data approach. AB - BACKGROUND: In aging societies osteoporotic fractures are a major health problem with high economic costs. Targeting prevention at individuals at high risk is important to reduce the future burden of fractures. Available risk assessment tools (e.g., FRAX(r), QFracture, the algorithm provided by the German Osteology Society (DVO-Tool)) rely on self-reported patient information to predict fracture risk. Time and resource constraints, limited access to clinical data, and (un)willingness to participate may hamper the use of these tools. To overcome such obstacles, the aim is to develop a fracture risk assessment tool based on claims data that may be directly used on an institutional level. METHODS: Administrative claims data of an elderly (>=65years) population (N=298,530) for the period from 2006 through 2014 was used. Major osteoporotic fractures (MOF) were identified based on hospital diagnoses. We applied Cox proportional hazard regression to determine the association of individual risk factors and fracture risk. Hazard ratios were used to construct a risk score. The discriminative ability of the score was evaluated using C-statistics. RESULTS: We identified 7864 MOF during follow-up. The median time to first fracture during follow-up was 371.5days. Individuals with a MOF during follow-up had a higher mean and median risk score (mean: 4.53; median: 4) than individuals without MOF (mean: 3.07; median: 3). Adding drug-related risk factors slightly improved discrimination compared to a simple model with age, gender, and prior fracture. CONCLUSION: We developed a fracture risk score model based on in-hospital treated subjects to predict MOF that can be used on an institutional level. The score included age, sex and prior fracture as risk factors. Adding other risk factors involved very small improvement in discrimination. PMID- 29421457 TI - Political economy of hope as a cultural facet of biomedicalization: A qualitative examination of constraints to hospice utilization among U.S. end-stage cancer patients. AB - A growing body of social science literature is devoted to describing processes of biomedicalization. The issue of biomedicalization is especially relevant for individuals suffering from end-stage cancer and hoping that aggressive end-of life interventions, which are riddled with uncertainty around quantity or quality of life, will produce a 'cure'. To examine hospice underutilization among end stage cancer patients, we apply the anthropological concept 'political economy of hope,' which describes how personal and collective 'hope' is associated with the political and economic structures that produce biomedicalization processes. Previous studies have examined hospice underutilization among end-stage cancer patients and have identified barriers stemming from patient and physician characteristics or health insurance reimbursement policies. Yet, these studies do not provide an organized synthesis of how barriers articulate, how they are part of the longitudinal decision-making process, or describe the sociocultural context surrounding hospice care enrollment decisions. This paper focuses on US specific mechanisms and is based on qualitative, in-depth, interviews with physicians at an academic hospital (N = 24). We find that hospice underutilization results from a web of interconnected constraints surrounding end stage cancer patients. Our research reveals how hospice care contradicts the political and economic structures associated with end-stage cancer care and illustrates how end-stage cancer patients are transformed into a form of biovalue, a fundamental commodity sustaining the political economy of hope. PMID- 29421458 TI - A systematic review of the methodological and practical challenges of undertaking randomised-controlled trials with cognitive disability populations. AB - Approximately 10% of the world's population have a cognitive disability. Cognitive disabilities can have a profound impact on a person's social, cognitive or mental functioning, requiring high levels of costly health and social support. Therefore, it is imperative that interventions and services received are based upon a sound evidence-base. For many interventions for this population, this evidence-base does not yet exist and there is a need for more Randomised Controlled Trials (RCTs). The process of conducting RCTs with disabled populations is fraught with methodological challenges. We need a better understanding of these methodological barriers if the evidence-bases are to be developed. The purpose of this study was to explore the methodological and practical barriers to conducting trials with adults with cognitive disabilities. As a case example, the literature regarding RCTs for people with intellectual disabilities (ID) was used to highlight these pertinent issues. A systematic literature review was conducted of RCTs with adults with ID, published from 2000 to 2017. A total of 53 papers met the inclusion criteria and were reviewed. Some of the barriers reported were specific to the RCT methodology and others specific to people with disabilities. Notable barriers included; difficulties recruiting; obtaining consent; resistance to the use of control groups; engaging with carers, staff and stakeholders; the need to adapt interventions and resources to be disability-accessible; and staff turnover. Conducting RCTs with people with cognitive disabilities can be challenging, however with reasonable adjustments, many of these barriers can be overcome. Researchers are not maximising the sharing of their experience-base. As a result, the development of evidence-bases remains slow and the health inequities of people with disabilities will continue to grow. The importance of the MRC guidelines on process evaluations, together with implications for the dissemination of 'evidence-base' and 'experience-base' are discussed. PMID- 29421459 TI - "Nothing is going to change three months from now": A mixed methods characterization of food bank use in Greater Vancouver. AB - North American food bank use has risen dramatically since the 1980s, and over 850,000 Canadians were estimated to have visited a food bank monthly in 2015. Food banks serve multiple roles in communities, ranging from 'emergency responses' to individualized and short-term experiences of hunger, to 'chronic' supports as part of long-term subsistence strategies. This study used a mixed methods design to examine the spectrum of food bank user experiences in a large urban context, as part of a community-based project aiming to envision a redesign of the food bank to contribute to broader community food security outcomes. Survey (n = 77) and focus group (n = 27) results suggested that participants widely viewed food banks as a long-term food-access strategy. Inadequate financial resources, steep increases in housing and food costs, and long-term health challenges emerged as the most prominent factors influencing food bank use. Participants commonly reported unmet food needs despite food bank use, limited agency over factors influencing access to sufficient food, and anticipated requiring food bank services in future. These findings contest global constructions of food banks as "emergency" food providers and support growing evidence that food banks are an insufficient response to chronic poverty, lack of affordable housing and insufficient social assistance rates underlying experiences of food insecurity. Participants envisioned changes to the food bank system to increase community food security including improved food quality and quantity (short-term), changes to service delivery and increased connections with health services (capacity building), and a greater role in poverty reduction advocacy (system redesign). PMID- 29421460 TI - Media coverage of the Zika crisis in Brazil: The construction of a 'war' frame that masked social and gender inequalities. AB - Between 2015 and 2016, Zika became an epidemic of global concern and the focus of intense media coverage. Using a hybrid model of frame and social representations theory, we examine how the Zika outbreak was reported in two major newspapers in Brazil: O Globo and Folha de Sao Paulo. The analysis of 186 articles published between December 2015 and May 2016 reveals a dominant 'war' frame supported by two sub-frames: one focused on eradicating the vector (mosquito) and another on controlling microcephaly, placing the burden of prevention on women. Scientific uncertainties about the virus and its relationship to microcephaly coupled with political uncertainties in Brazil increased the power of the war frame. This frame gave prominence and legitimacy to certain representations of disease management during the crisis, masking social and gender inequalities. We show how the cartography of the disease overlaps with that of poverty and regional inequality in Brazil to argue that addressing socio-economic aspects is essential, but normally neglected, in media communications during disease outbreaks like Zika. PMID- 29421461 TI - Assessing the feasibility of community health insurance in Uganda: A mixed methods exploratory analysis. AB - Community health insurance (CHI) aims to provide financial protection and facilitate health care access among poor rural populations. Given common operational challenges that hamper the full development of the scheme, there is need to undertake systematic feasibility studies. These are scarce in the literature and usually they do not provide a comprehensive analysis of the local context. The present research intends to adopt a mixed-methods approach to assess ex-ante the feasibility of CHI. In particular, eight preconditions are proposed to inform the viability of introducing the micro insurance. A case study located in rural northern Uganda is presented to test the effectiveness of the mixed methods procedure for the feasibility purpose. A household survey covering 180 households, 8 structured focus group discussions, and 40 key informant interviews were performed between October and December 2016 in order to provide a complete and integrated analysis of the feasibility preconditions. Through the data collected at the household level, the population health seeking behaviours and the potential insurance design were examined; econometric analyses were carried out to investigate the perception of health as a priority need and the willingness to pay for the scheme. The latter component, in particular, was analysed through a contingent valuation method. The results validated the relevant feasibility preconditions. Econometric estimates demonstrated that awareness of catastrophic health expenditures and the distance to the hospital play a critical influence on household priorities and willingness to pay. Willingness is also significantly affected by socio-economic status and basic knowledge of insurance principles. Overall, the mixed-methods investigation showed that a comprehensive feasibility analysis can shape a viable CHI model to be implemented in the local context. PMID- 29421463 TI - Unintended consequences of the 'bushmeat ban' in West Africa during the 2013-2016 Ebola virus disease epidemic. AB - Following the 2013-2016 outbreak of Ebola virus disease (EVD) in West Africa, governments across the region imposed a ban on the hunting and consumption of meat from wild animals. This injunction was accompanied by public health messages emphasising the infectious potential of wild meat, or 'bushmeat.' Using qualitative methods, we examine the local reception and impact of these interventions. Fieldwork was focused in 9 villages in the Eastern and Southern provinces of Sierra Leone between August and December 2015. We conducted 47 semi structured interviews, coordinated 12 informal group discussions, and conducted direct observations throughout. We also draw from research undertaken in Sierra Leone immediately before the outbreak, and from our participation in the EVD response in Guinea and Sierra Leone. Our findings underscore the social and political reverberations of hunting proscriptions. Messaging that unilaterally stressed the health risk posed by wild meat contradicted the experiences of target publics, who consume wild meat without incident. This epistemic dissonance radically undercut the effectiveness of the ban, which merely served to proliferate informal networks of wild animal trade and sale-rendering the development of acceptable, evidence-based surveillance and mitigation strategies for zoonotic spillovers almost impossible. Further, the criminalisation of wild meat consumption fuelled fears and rumours within communities under considerable strain from the health, social, and economic effects of the epidemic, entrenching distrust towards outbreak responders and exacerbating pre-existing tensions within villages. These unintended consequences are instructive for public health emergency response and preparedness. While wild meat is a risk for zoonotic infection, mitigating those risks entails interventions that fully take into account the local significances of hunting-including a communicative engagement that is designed, validated, and continually refined before emergency situations. Ultimately, our research questions the value of legal sanctions as a means of behavioural change in an emergency context. PMID- 29421464 TI - Gender inequality, economic growth, and the intergenerational transmission of adverse health consequences at birth. AB - We estimate a gender differential in the intergenerational transmission of adverse birth outcomes. We link Taiwan birth certificates from 1978 to 2006 to create a sample of children born in the period 1999-2006 that includes information about their parents and their maternal grandmothers. We use maternal sibling fixed effects to control for unobserved family-linked factors that may be correlated with birth outcomes across generations, and define adverse birth outcomes as small for gestational age. We find that when a mother is in the 5th percentile of birth weight for her gestational age, then her female children are 49-53% more likely to experience the same adverse birth outcome compared to other female children, while her male children are 27-32% more likely to experience this relative to other male children. We then investigate whether long-run improvements in local socio-economic conditions experienced by the child's family, as measured by intergenerational changes in town-level maternal education, affect the gender differential. We find no evidence that intergenerational improvements in socioeconomic conditions reduce the gender differential. PMID- 29421462 TI - Low perceived control over health is associated with lower treatment uptake in a high mortality population of Bolivian forager-farmers. AB - Indigenous people worldwide suffer from higher rates of morbidity and mortality than neighboring populations. In addition to having limited access to public health infrastructure, indigenous people may also have priorities and health perceptions that deter them from seeking adequate modern healthcare. Here we propose that living in a harsh and unpredictable environment reduces motivation to pursue deliberate, costly action to improve health outcomes. We assess whether variation in Health Locus of Control (HLC), a psychological construct designed to capture self-efficacy with respect to health, explains variation in treatment uptake behavior among Tsimane Amerindians (N = 690; age range: 40-89 years; 55.8% female; data collection: 2008-2012), a high mortality and morbidity indigenous population in the Bolivian Amazon, Beni Department. Comparisons with two industrialized populations in Japan (Miyagi prefecture; e0 = 76.6 years) and the United Kingdom (Caerphilly county borough; e0 = 81.2 years) confirm that Tsimane (e0 = 54.1 years) have a more externalized HLC. Multilevel level models were used to investigate whether HLC predicts treatment uptake, and mediates the relationship between modernization and treatment uptake. External HLC scores were predictive of treatment outcomes: Powerful others scores were positively associated with probability of receiving modern treatment (adjusted odds ratio [OR] = 1.33), while Chance scores were negatively associated with probability of receiving modern treatment (adjusted OR = 0.76). We found no effects, however, of Internal HLC or educational capital on treatment uptake. Overall, our findings indicate that health-related decision-making is influenced more by a psychological orientation affecting self-efficacy, shaped in part by perceptions of environmental unpredictability and harshness, than by limited knowledge, education or other indicators of modernization. PMID- 29421465 TI - Rethinking health sector procurement as developmental linkages in East Africa. AB - Health care forms a large economic sector in all countries, and procurement of medicines and other essential commodities necessarily creates economic linkages between a country's health sector and local and international industrial development. These procurement processes may be positive or negative in their effects on populations' access to appropriate treatment and on local industrial development, yet procurement in low and middle income countries (LMICs) remains under-studied: generally analysed, when addressed at all, as a public sector technical and organisational challenge rather than a social and economic element of health system governance shaping its links to the wider economy. This article uses fieldwork in Tanzania and Kenya in 2012-15 to analyse procurement of essential medicines and supplies as a governance process for the health system and its industrial links, drawing on aspects of global value chain theory. We describe procurement work processes as experienced by front line staff in public, faith-based and private sectors, linking these experiences to wholesale funding sources and purchasing practices, and examining their implications for medicines access and for local industrial development within these East African countries. We show that in a context of poor access to reliable medicines, extensive reliance on private medicines purchase, and increasing globalisation of procurement systems, domestic linkages between health and industrial sectors have been weakened, especially in Tanzania. We argue in consequence for a more developmental perspective on health sector procurement design, including closer policy attention to strengthening vertical and horizontal relational working within local health-industry value chains, in the interests of both wider access to treatment and improved industrial development in Africa. PMID- 29421466 TI - Getting pain on the table in primary care physical exams. AB - Using conversation analysis and a dataset of 171 video recordings of US primary care encounters (2003-2005), this paper examines patients' unsolicited pain informings - e.g. "that hurts" - during the physical examination phase of acute care visits. I argue that when patients experience pain in a physical exam but have not been asked a question like "does that hurt?", they face an interactional dilemma. Having presented their health problem to a doctor, they have tacitly set in motion epistemic and interactional asymmetries through which the doctor investigates the problem on their behalf. In this context, volunteering unsolicited pain information could facilitate progress towards an accurate diagnosis, but it could also be heard as independently asserting the relevance of pain to what the doctor is doing, thereby departing from the previously established asymmetries. I show that patients manage this dilemma by using turn design practices to implicitly account for unsolicited pain informings as motivated by a virtual solicitation and/or a sudden pain sensation. With these practices, patients manage to share potentially relevant pain information without accountably being heard to assert its relevance to the doctor's diagnostic inquiry. This achievement demonstrates how asymmetries in doctor-patient communication are a joint accomplishment of both doctors and patients, and are incarnate in the details of everyday clinical interactions. PMID- 29421467 TI - Trajectories of women's abortion-related care: A conceptual framework. AB - We present a new conceptual framework for studying trajectories to obtaining abortion-related care. It assembles for the first time all of the known factors influencing a trajectory and encourages readers to consider the ways these macro- and micro-level factors operate in multiple and sometimes conflicting ways. Based on presentation to and feedback from abortion experts (researchers, providers, funders, policymakers and advisors, advocates) (n = 325) between 03/06/2014 and 22/08/2015, and a systematic mapping of peer-reviewed literature (n = 424) published between 01/01/2011 and 30/10/2017, our framework synthesises the factors shaping abortion trajectories, grouped into three domains: abortion specific experiences, individual contexts, and (inter)national and sub-national contexts. Our framework includes time-dependent processes involved in an individual trajectory, starting with timing of pregnancy awareness. This framework can be used to guide testable hypotheses about enabling and inhibiting influences on care-seeking behaviour and consideration about how abortion trajectories might be influenced by policy or practice. Research based on understanding of trajectories has the potential to improve women's experiences and outcomes of abortion-related care. PMID- 29421468 TI - Differentiating the effect of social enterprise activities on health. AB - An emerging stream of literature has focused on the ways in which social enterprises might act on the social determinants of health. However, this previous work has not taken a sufficiently broad account of the wide range of stakeholders involved in social enterprises and has also tended to reduce and simplify a complex and heterogeneous set of organisations to a relatively homogenous social enterprise concept. In an attempt to address these gaps, we conducted an empirical investigation between August 2014 and October 2015 consisting of qualitative case studies involving in-depth semi-structured interviews and a focus group with a wide variety of stakeholders from three social enterprises in different regions of Scotland. We found that different forms of social enterprise impact on different dimensions of health in different ways, including through: engendering a feeling of ownership and control; improving environmental conditions (both physical and social); and providing or facilitating meaningful employment. In conclusion, we highlight areas for future research. PMID- 29421469 TI - Negotiating relevance in pre-operative assessments. AB - Preoperative assessments provide an essential clinical risk assessment aimed at identifying patient risks and requirements prior to surgery. As such they require effective and sensitive information-gathering skills. In addition to physical examination, the preoperative assessment includes a series of routine questions assessing a patient's fitness for surgery. These questions are typically designed to elicit minimal, 'no problem' responses, but patients sometimes produce expanded responses that extend beyond the projected information. Our analysis reveals that troubles-telling is often invoked by both nurses and patients as an effective, patient-centred resource for negotiating the medical relevance of patients' concerns in these contexts. PMID- 29421470 TI - Health disparities, politics, and the maintenance of the status quo: A new theory of inequality. AB - Individuals participate in politics to influence the politicians that prescribe the policies and programs that distribute the public goods and services that shape the social determinants of health. But the opportunity to participate in politics is conditional on survival, and in the U.S., the haves enjoy a significant survival advantage over the have-nots. This process can be detected looking at the relationship between age and participation: It is inflated by the fact that, as time progresses, a higher proportion of low-SES, low-level participation individuals die and are therefore excluded from the available pool of participants faster than high-SES, high-level participation individuals. We analyze this mechanism applying propensity scores matching and multivariate regressions on data from MIDUS I (Midlife in the United States: A National Study of Health and Well-being) and its 10-year mortality follow-up. Results show that health differences between 10-year survivors and non-survivors explain 56% of their differences in socio-political participation. Survivors participate at higher levels than non-survivors across all age groups and SES levels; without detrimental differences in health, individuals would participate 28% more as they age. The same disadvantaged individuals whose increased participation would pressure for redistributive policies are those who die off from the available pool of participants at much higher rates than socioeconomically advantaged individuals. The proposed conceptual model helps to explain how, through the early disappearance of the poor, continuing socio-political participation of high SES survivors helps to perpetuate inequality in the status quo. PMID- 29421471 TI - Gender matters in cardiac rehabilitation and diabetes: Using Bourdieu's concepts. AB - BACKGROUND: Habitual practices are challenged by chronic illness. Cardiac rehabilitation (CR) involves changes to habits of diet, activity and tobacco use, and although it is effective for people with diabetes and cardiovascular disease (CVD), some participants are reportedly less likely to complete programs and adopt new health related practices. Within the first three months of enrolling in CR, attrition rates are highest for women and for people with diabetes. Previous studies and reviews indicate that altering habits is very difficult, and the social significance of such change requires further study. PURPOSE: The purpose of the study was to use Bourdieu's concepts of habitus, capital and field to analyse the complexities of adopting new health practices within the first three months after enrolling in a CR program. We were particularly interested in gender issues. METHODS: Thirty-two men and women with diabetes and CVD were each interviewed twice within the first three months of their enrolment in one of three CR programs in Toronto, Canada. RESULTS: Attention to CR goals was not always the primary consideration for study participants. Instead, a central concern was to restore social dignity within other fields of activity, including family, friendships, and employment. Thus, study participants evolved improvised tactical approaches that combined both physical and social rehabilitation. These improvised tactics were socially embedded and blended new cultural capital with existing (often gendered) cultural capital and included: concealment, mobilizing cooperation, re-positioning, and push-back. CONCLUSIONS: Our findings suggest that success in CR requires certain baseline levels of capital - including embodied, often gendered, cultural capital - and that efforts to follow CR recommendations may alter social positioning. PMID- 29421472 TI - Health care input constraints and cost effectiveness analysis decision rules. AB - Results of cost effectiveness analyses (CEA) studies are most useful for decision makers if they face only one constraint: the health care budget. However, in practice, decision makers wishing to use the results of CEA studies may face multiple resource constraints relating to, for instance, constraints in health care inputs such as a shortage of skilled labour. The presence of multiple resource constraints influences the decision rules of CEA and limits the usefulness of traditional CEA studies for decision makers. The goal of this paper is to illustrate how results of CEA can be interpreted and used in case a decision maker faces a health care input constraint. We set up a theoretical model describing the optimal allocation of the health care budget in the presence of a health care input constraint. Insights derived from that model were used to analyse a stylized example based on a decision about a surgical robot as well as a published cost effectiveness study on eye care services in Zambia. Our theoretical model shows that applying default decision rules in the presence of a health care input constraint leads to suboptimal decisions but that there are ways of preserving the traditional decision rules of CEA by reweighing different cost categories. The examples illustrate how such adjustments can be made, and makes clear that optimal decisions depend crucially on such adjustments. We conclude that it is possible to use the results of cost effectiveness studies in the presence of health care input constraints if results are properly adjusted. PMID- 29421473 TI - Representing autism: Challenges of collective representation in German and Israeli associations for and of autistic people. AB - The important work done by various associations of and for people with disabilities is legitimated by their claim for collective representation. However, there is little empirical research that examines the organizational basis for such claims. We focus on patient/disability advocacy associations that illustrate a split of representation between organizations of and for autism. Drawing on documentary analysis and semi-structured interviews conducted in 2015 2017 with members and office-holders of autism associations in Germany and Israel, we highlight several common gaps and their relations to the organizational characteristics of the associations: Representing only part of the autism spectrum, and lack of efficient procedures for including the variety of members. We conclude by discussing the language and epistemology of "high functioning"/"Aspies" vs. "low-functioning"/"Kanners" as politically and culturally embedded, highlighting the significance and difficulties of dialogue amidst autism-related epistemic communities. PMID- 29421475 TI - Safety, trust, and disclosure: A qualitative examination of violence against refugee adolescents in Kiziba Camp, Rwanda. AB - Refugee adolescents face increased vulnerability to child protection risks including abuse, neglect, violence, and exploitation. The aim of this qualitative study was to examine the nature of violence against adolescents in Kiziba Camp, Rwanda, using an ecological framework to analyze the factors that influence protection risks and abuse disclosure across multiple system levels. In order to understand these issues more comprehensively, a transgenerational inquiry sought perceptions from both adolescents and their caregivers. In April 2016, as part of a larger, comprehensive study on adolescent protection, 19 focus group discussions were conducted with a total of 70 adolescents and 68 caregivers from the Democratic Republic of Congo. A qualitative content analysis identified three salient themes. First, structural protection risks exist for adolescents in Kiziba Camp, with economic insecurity and resource constraints resulting in specific risks such as overcrowded housing and adolescents traveling for firewood collection. Second, intergenerational conflict between caregivers and adolescents was perceived to negatively influence abuse disclosure. Lastly, protection mechanisms and reporting pathways were underutilized as caregivers and adolescents expressed concern over the shame, embarrassment, and social rejection that characterized formal disclosure in Kiziba, often rooted in restrictive and inequitable gender norms. These findings suggest that efforts at child protection should be multi-faceted and address structural aspects of risk; household levels of communication and trust; and societal norms that deter abuse reporting. The study also underscores the need for further research on risk and protective factors in camp settings to better tailor interventions aiming to reduce violence against children. PMID- 29421474 TI - Improving recruitment to clinical trials during pregnancy: A mixed methods investigation. AB - OBJECTIVE: To identify reasons underlying women's refusal to participate in a pregnancy trial and to identify ways of increasing recruitment. DESIGN: Mixed methods study using a questionnaire and qualitative interviews. SAMPLE: A questionnaire asking them to indicate reasons for their decision was completed by 296 pregnant women who declined to participate in one of two trials of nutritional supplementation in a large teaching hospital in southern England. Qualitative interview data were collected from two samples of pregnant women: 1) 30 women who declined to participate in a trial but completed the questionnaire; and 2) 44 women who participated in a trial. RESULTS: Questionnaire data from pregnant women who declined to participate suggested the major barriers to participation were study requirements, including taking study medication, having a bone scan or blood tests, or being too busy. Thematic analysis of interview data identified differences in self-efficacy and levels of trust in medical research between participants and decliners. Participants believed that the research would cause no harm, while decliners felt they or their unborn child would be at risk. When faced with potential obstacles, participants found ways around them while decliners felt they were insurmountable. CONCLUSIONS: Recruitment methods for pregnancy trials should focus on building women's trust in the trial, and on enhancing women's self-efficacy so they feel able to meet trial requirements. Suggestions for building trust include investing time in open, honest discussion of the risks and benefits of participation, improving visibility of the research team, testimonials from previous participants and advertising study safety and ethical conduct. Self-efficacy can be enhanced by training research staff in empowering styles of communication enabling women to feel heard and supported to problem-solve. These strategies could be implemented relatively easily into pregnancy trial protocols, and their effectiveness tested through their impact on recruitment rates. PMID- 29421476 TI - Understanding the micro and macro politics of health: Inequalities, intersectionality & institutions - A research agenda. AB - This essay brings together intersectionality and institutional approaches to health inequalities, suggesting an integrative analytical framework that accounts for the complexity of the intertwined influence of both individual social positioning and institutional stratification on health. This essay therefore advances the emerging scholarship on the relevance of intersectionality to health inequalities research. We argue that intersectionality provides a strong analytical tool for an integrated understanding of health inequalities beyond the purely socioeconomic by addressing the multiple layers of privilege and disadvantage, including race, migration and ethnicity, gender and sexuality. We further demonstrate how integrating intersectionality with institutional approaches allows for the study of institutions as heterogeneous entities that impact on the production of social privilege and disadvantage beyond just socioeconomic (re)distribution. This leads to an understanding of the interaction of the macro and the micro facets of the politics of health. Finally, we set out a research agenda considering the interplay/intersections between individuals and institutions and involving a series of methodological implications for research - arguing that quantitative designs can incorporate an intersectional institutional approach. PMID- 29421477 TI - Returns home by children and changes in parents' well-being in Europe. AB - Co-resident adult children may be a source of emotional and instrumental support for older parents, but also a source of conflict and stress. Results from previous research are far from conclusive and indicate that intergenerational co residence may have both negative and positive effects on parents' depressive symptoms and physical health. We analyse longitudinal data from four waves of the Survey of Health, Ageing and Retirement in Europe (2007-2015) to examine whether returns to the parental home by adult children are associated with changes in the quality of life of parents aged 50-75. Results from fixed effects linear regression models show that returns to the parental home by adult children were associated with decreases in parents' quality of life and that this largely reflected declines associated with the return of a child to an 'empty nest' where no other children were still co-resident. In line with previous research which has indicated differing effects of co-residence on parents' depressive symptoms by cultural tradition, this effect was largely driven by decreases in parents' quality of life in a grouping of Nordic/social-democratic. There were no associations between changes in parental quality of life and the returning child's characteristics, although unemployment of a child was negatively, and new partnership of a child, positively associated with changes in parental quality of life. PMID- 29421478 TI - Feed addition of curcumin to laying hens showed anticoccidial effect, and improved egg quality and animal health. AB - The aim of this study was to evaluate whether the addition of curcumin in the diet of commercial laying hens could have an anticoccidial action and improve egg quality. For this, 60 laying hens were divided into three groups: T0 (the control group); T30 and T50 (30 and 50 mg/kg of curcumin in the feed, respectively). Eggs recently laid were collected on days 14 and 21 of the experiment, and stored for 21 days. It was observed increased specific gravity and yolk index in stored eggs of the groups T30 and T50 compared to T0. The yolk color reduced in the eggs stored from groups T30 and T50 compared to T0. Moreover, TBARS levels were lower in fresh and stored eggs from groups T30 and T50. It was observed increased TAC levels in fresh eggs from groups T30 and T50 and in stored eggs from the group T50. The presence of curcumin was not detected by HPLC in the yolk and albumen. Seric levels of albumin and uric acid did not differ between groups, while seric levels of total proteins increased on day 21 on groups T30 and T50. Finally, it was observed a significant reduction on the number of oocysts in fecal samples on days 14 and 21 of T30 and T50 compared to T0. Based on these evidences, it is possible to conclude that the addition of curcumin in the diet of laying hens has an anticoccidial effect and improves egg quality. PMID- 29421479 TI - Viral load, tissue distribution and histopathological lesions in goats naturally and experimentally infected with the Small Ruminant Lentivirus Genotype E (subtype E1 Roccaverano strain). AB - Small Ruminant Lentivirus (SRLV) subtype E1, also known as Roccaverano strain, is considered a low pathogenic virus on the basis of natural genetic deletions, in vitro properties and on-farm observations. In order to gain more knowledge on this atypical lentivirus we investigated the in vivo tropism of Roccaverano strain in both, experimentally and naturally infected goats. Antibody responses were monitored as well as tissue distribution and viral load, evaluated by real time PCR on single spliced (gag/env) and multiple spliced (rev) RNA targets respectively, that were compared to histopathological lesions. Lymph nodes, spleen, alveolar macrophages and mammary gland turned out to be the main tissue reservoirs of genotype E1-provirus. Moreover, mammary gland and/or mammary lymph nodes acted as active replication sites in dairy goats, supporting the lactogenic transmission of this virus. Notably, a direct association between viral load and concomitant infection or inflammatory processes was evident within organs such as spleen, lung and testis. Our results validate the low pathogenicity designation of SRLV genotype E1 in vivo, and confirm the monocyte-macrophage cell lineage as the main virus reservoir of this genotype. Accordingly, SRLV genotype E displays a tropism towards all tissues characterized by an abundant presence of these cells, either for their own anatomical structure or for an occasional infectious/inflammatory status. PMID- 29421480 TI - Advanced nutritional and stem cells approaches to prevent equine metabolic syndrome. AB - Horses metabolic disorders have become an important problem of modern veterinary medicine. Pathological obesity, insulin resistance and predisposition toward laminitis are associated with Equine Metabolic Syndrome (EMS). Based on pathogenesis of EMS, dietary and cell therapy management may significantly reduce development of this disorder. Special attention has been paid to the diet supplementation with highly bioavailable minerals and mesenchymal stem cells (MSC) which increase insulin sensitivity. In nutrition, there is a great interests in natural algae enriched via biosorption process with micro- and macroelements. In the case of cellular therapy, metabolic condition of engrafted cells may be crucial for the effectiveness of the therapy. Although, recent studies indicated on MSC deterioration in EMS individuals. Here, we described the combined nutritional and stem cells therapy for the EMS treatment. Moreover, we specified in details how EMS affects the adipose-derived stem cells (ASC) population. Presented here, combined kind of therapy- an innovative and cutting edge approach of metabolic disorders treatment may become a new gold standard in personalized veterinary medicine. PMID- 29421481 TI - The different effects of linseed and fish oil supplemented diets on insulin sensitivity of rabbit does during pregnancy. AB - This study investigates the effects of linseed (rich in alpha-linolenic acid (ALA)) and fish oil (rich in eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)) supplementation on the insulin resistance of pregnant rabbits. Two months before insemination, the rabbits (15 animals/group) were fed different diets: commercial standard (group C), supplemented with 10% extruded linseed (group L), and 3% fish oil (group FO). The L group does showed both the highest feed intake before AI (P < 0.01) and the highest body weight (BW) throughout pregnancy (P < 0.001). The L does yielded less milk than the C does (P < 0.001); however, no differences were observed in either weight or size of litter at weaning. Regardless of diet, insulin concentrations and HOMA-IR values were higher during the first half of pregnancy (P < 0.001). Nevertheless, the L does showed higher mean insulin concentrations than FO rabbits (P < 0.01) and the lowest glucose clearance (P < 0.01) during pregnancy. On the other hand, pregnant FO rabbits showed the lowest glucose concentrations (P < 0.05) and the lowest Homeostasis model assessment values for insulin resistance (HOMA-IR, P < 0.05) as well as a faster restoration of baseline glucose levels following glucose load (P < 0.001). Before and during pregnancy, the BW of the rabbits was positively related to fasting sample- and tolerance test-derived indices of insulin resistance (P < 0.05) suggesting that a high pre-pregnancy BW predisposes to gestational insulin resistance. Linseed supplementation increased BW and predisposed to insulin resistance during pregnancy; whereas, fish oil improved insulin sensitivity without significant changes in BW. PMID- 29421482 TI - Minimum alveolar concentration: Key concepts and a review of its pharmacological reduction in dogs. Part 2. AB - OBJECTIVE: To outline the major components of the minimum alveolar concentration (MAC) and review the literature regarding pharmacological manipulation of the MAC of halothane, isoflurane, sevoflurane, enflurane, and desflurane in dogs. The pharmacological agents included are alpha-2 agonists, benzodiazepines, propofol, opioids, lidocaine, acepromazine, non-steroidal anti-inflammatory agents (NSAIDs), maropitant, and NMDA antagonists. Part 2 of this review will focus on the effect of opioids, lidocaine, NSAIDs, maropitant, acepromazine, and NMDA antagonists on MAC. DATABASES USED: PubMed, Google Scholar, CAB Abstracts. Search terms used: minimum alveolar concentration, MAC, dog, canine, inhaled anesthetic potency, isoflurane, sevoflurane, desflurane, enflurane, and halothane. CONCLUSIONS: Opioids, lidocaine, NSAIDs, maropitant, acepromazine, and NMDA antagonists have been shown to reduce the MAC of inhaled anesthetics in dogs and allow for clinically important decreases in inhalant anesthetic use. Thus, the use of these agents potentially decrease the adverse cardiovascular and pulmonary effects associated with the use of high concentrations of inhaled anesthetics. PMID- 29421483 TI - Effect of suckler cow vaccination against glycoprotein E (gE)-negative bovine herpesvirus type 1 (BoHV-1) on passive immunity and physiological response to subsequent bovine respiratory disease vaccination of their progeny. AB - The study objectives were: 1) to characterise the development of immunocompetence in beef suckler calves from birth to three months of age, and 2) to trace glycoprotein E (gE)-negative bovine herpesvirus type 1 (BoHV-1) antibodies from dam to calf and subsequent vaccination against pneumonia. Thirty multiparous beef suckler, spring-calving cows, consisting of two genotypes were involved; Limousin*Friesian (LF) and Charolais*Limousin (CL). Cows were immunised against the inactivated antigen strain of BoHV-1 (gE- (IBR marker vaccine) at day -84 and received a booster at day -56 relative to the expected calving date (d 0). Calves were immunised at 14 and 42days of age against PI-3 virus, BRSV and Mannheimia (Pasteurella) haemolytica serotype A1 using a commercial vaccine administered subcutaneously. Additionally, calves were immunised against BoHV-1 at 42days of age, using 1 dose of a live commercial vaccine administered intranasally. Blood samples were collected from all calves (n=30) via jugular venipuncture at birth, prior to colostrum feeding (0h), at 12h (h), 24h, 72h and 168h after the initial feeding of colostrum, and at d 7, 14, 28, 42, 56 and 84 post birth. The mean ratio of gE negative antibodies circulating in the blood of LF and CL dams pre partum scored negative to gE ab (S/N>=0.70). Antibody levels of BoHV-1 (wild type (wt)) peaked at 12h post-birth in calves and declined thereafter, as the maternal antibodies decayed. There was no difference in BoHV-1 and BRSV antibody levels in calves post vaccination. PMID- 29421484 TI - Winter honey bee colony losses, Varroa destructor control strategies, and the role of weather conditions: Results from a survey among beekeepers. AB - Sets of treatments that were applied against varroa mites in the Luxembourgish beekeeper community were surveyed annually with a questionnaire between the winters 2010/11 and 2014/15. The average temperature and the precipitation sum of the month, when the respective varroa control method was applied were considered as co-variables when evaluating the efficacy of varroa control regimes. Success or failure of control regimes was evaluated based on the percentage of colonies lost per apiary in the winter following the treatment(s). Neither a positive nor a negative effect of formic acid (concentration 60%, w/v) on the colony losses could be found, irrespective of the weather conditions around the time of application. The higher concentration of 85% formic acid was linked with reduced colony losses when applications were done in August. Colony losses were reduced when Thymovar was applied in July or August, but applications in September were associated with increased losses compared with apiaries not treated with Thymovar during the same period. Apilife application in July as well as Apivar applications between July and September were associated with reduced colony losses. The removal of the drone brood and trickled oxalic acid application had beneficial effects when being done in April and December, respectively. Relatively warm (3.0+/-1.3 degrees C) and wet (507.0+/-38.6mm/2months) conditions during the winter months December and January and relatively cool (17.2+/-1.4 degrees C average monthly temperature) and wet (110.8+/-55.5mm/month) conditions in July were associated with elevated honey bee colony losses. PMID- 29421485 TI - The expression of major histocompatibility complex class I in endometrial epithelial cells from dairy cow under a simulating hypoxic environment. AB - During the first trimester of pregnancy in dairy cows, the fetus is mainly recognized by the expression of major histocompatibility complex class I (MHC-I) in the maternal immune system. Before the embryo begins to implant in the maternal uterus, it requires a long time to remodel and develop vessels in the placenta. During this stage, the embryos are exposed to a hypoxic environment. However, the expression of bovine MHC-I has not been determined in hypoxic bovine endometrial epithelial cells (bEECs). Hypoxia-inducible factor-1alpha (HIF 1alpha) is a marker for hypoxic conditions in cells. In the present study, we used cobalt chloride (CoCl2) to establish a hypoxic cell model and then determined the expression of the classical gene BoLA-A and the non-classical gene MICB. qRT-PCR and western blot assays were applied to determine the expression of HIF-1alpha. qRT-PCR was performed to detect the levels of BoLA-A and MICB mRNAs. The results showed that HIF-1alpha expression was increased in the hypoxic cell model. The expression of BoLA-A was increased, but MICB levels were decreased in bEECs. Our study provides a basis for exploring the cattle intrauterine environment during pregnancy. PMID- 29421486 TI - Activation of mast cells in skin abscess induced by Staphylococcus aureus (S. aureus) infection in mice. AB - The skin abscess is a common inflammatory disease that occurs following the ubiquitous S. aureus infection. In our study, a skin abscess murine model was established and the dynamics of mast cells chemotaxing was evaluated. In the S. aureus-infected mice, severe infiltration of inflammatory cells in the dermis were observed, and mast cells were markedly accumulated in the skins. Besides, tryptase, the marker for mast cells activation, has a positive correlation with mast cell activity. The mast cells identified in the tissues were likely to be activated since they were associated with cell degranulation and the presence of tryptase. Our results suggested that mast cells and its mediator tryptase contribute to the inflammation of skin abscess induced by S. aureus infection. PMID- 29421487 TI - Differentially expressed genes in response to cyadox in swine liver analyzed by DDRT-PCR. AB - Cyadox is a good antimicrobial growth-promoter of quinoxalines. However, the molecular mechanism of action remains unclear. A growth performance study and mRNA differential display reverse transcription polymerase chain reaction (DDRT PCR) in combination with Northern dot-blot and reverse Northern dot-blot analysis were conducted to determine the differentially expressed genes in liver tissues of piglets after treatment with cyadox. Transcription levels of the differentially expressed genes were quantificated by realtime RT-PCR in porcine primary hepotocytes. Cyadox could significantly promote body weight of piglets via feed with average daily gain (ADG) improved by 24.7% and 64.8% in 100 and 500mg/kg group, compared with control. A total of eight differentially expressed genes were found, of which the expression levels of five genes had positive correlation with cyadox dose. One gene expression had a negative correlation with cyadox dose and it was a new gene. The other two genes were up-regulated by cyadox, but the expression quantity was invariably when the cyadox doses were increased. Among the up-regulated genes, one was transcriptional regulating factor, two were growth-related factors, one was involved in immune defense and immune-regulation and three might be involved in the maintenance of normal development. In primary cultured pig hepatocytes, cyadox treatment evoked a significant time-dependent effect of eight genes expression. The results suggest, at the transcriptional level in vitro and in vivo, that growth factor and metabolism may be associated with cyadox growth-promoting activity, whereas immune defense and immune-regulation could play major roles in prophylaxis of cyadox in piglets. PMID- 29421488 TI - Comparison of the pharmacodynamics of protamine zinc insulin and insulin degludec and validation of the continuous glucose monitoring system iPro2 in healthy cats. AB - With the aim to improve current therapeutic and monitoring options for diabetic cats, the present study compared pharmacodynamic parameters of protamine zinc insulin (PZI) and insulin degludec and validated the continuous glucose monitoring system (CGMS) iPro2 with Sof-sensor and Enlite-sensor focusing on the low glycemic range. Three doses (0.1, 0.2 and 0.3IU/kg) of the two insulin preparations and the CGMS iPro2 with two different sensors were tested in six healthy cats. After each insulin administration, onset of action, time to glucose nadir and duration of action were calculated by measuring glucose concentrations with a portable blood glucose meter (PBGM). After sensor placement, paired PBGM and sensor glucose measurements were done and analytical and clinical accuracy were calculated according to the ISO 15197:2013 criteria. Onset of action, time to glucose nadir and glucose nadir were similar for both insulin formulations. Duration of action of insulin degludec was significantly longer than those of PZI at 0.1IU/kg (P=0.043) and 0.2IU/kg (P=0.043). Overall, 166/191 (87%) Sof-sensor measurements and 106/121 (88%) Enlite-sensor measurements met ISO criteria for analytical accuracy, and all sensor measurements fulfilled ISO criteria for clinical accuracy. Insulin degludec was well tolerated in healthy cats and showed longer duration of action than PZI. Further studies on the use of insulin degludec in diabetic cats might be recommended. Both sensors had good clinical accuracy, when used with the CGMS iPro2, but the analytical accuracy was below the minimum set by ISO 15197:2013. PMID- 29421489 TI - Stress level effects on sport performance during trotting races in Spanish Trotter Horses. AB - The stress level is suggested to have a negative effect on horses during equestrian competitions, specifically in trotter racing. The main objectives of this study were to measure stress levels in Spanish Trotter Horse races with a reliable non-invasive method, and determining the threshold level of stress that leads to the best performance results and also shows when the stress perceived by the horse becomes distress. One hundred and thirty individuals were evaluated, measuring their performance (based on racing time per kilometre (TPK)) and their stress (based on eye temperature, assessed with infrared thermography, and heart rate) in different competitions. Eye temperature and heart rate measurements were collected 2h before the race and immediately following the race, and the increases of eye temperature (?ET) and heart rate were estimated. ?ET and eye temperature before the race showed significant differences related to the performance level after a GLM analysis. The segmented regression analysis indicated that when the animal was more stressed before the race than just after finishing it (?ET<0), it showed the poorest competition results, and from the breakpoint (reached at ?ET=-0.97%), horse's performance started to improve. When comparing eye temperature variables and TPK with a response surface plot, TPK was optimum (77.27s) when the eye temperature before the race and ?ET reached values of 37.61 degrees C and 7.57%, respectively. Therefore, the stress levels of the horse before the race influence its competition results, and ?ET during competitions reaching a threshold point is related to an improvement in performance results. PMID- 29421490 TI - Decline of antibody response in indirect ELISA tests during the periparturient period caused diagnostic gaps in Coxiella burnetii and BVDV serology in pluriparous cows within a Holstein dairy herd. AB - In cattle, indirect enzyme-linked immunosorbent assay (ELISA) tests are commonly used in serological routine diagnostics. In a longitudinal study design, changes in relative optical density (OD) from drying-off until week 11 after calving were analyzed in blood and milk samples from pluriparous dairy cows (n=21) using a commercial indirect anti-C. burnetii ELISA test. In a second part of this study, changes over time were evaluated in blood and milk samples of 11 of these cows in an indirect ELISA detecting anti-Bovine viral diarrhea virus (BVDV) antibodies. Regarding the cows which were still in the herd at the time of calving, blood serological qualitative changes from positive to negative or indeterminate were demonstrated in 7/20 cows (35%) for the anti-C. burnetii indirect ELISA and in 2/10 cows (20%) for the anti-BVDV indirect ELISA, respectively, during the period from 14days ante partum to calving. Relative OD in the anti-C. burnetii and the anti-BVDV indirect ELISA tests followed basically similar courses over time. In blood serum, relative OD initially increased after drying-off, before a drop around calving was observed. After the colostrum period, relative OD in blood serum showed an increase until week 11 of lactation. In colostrum samples, relative OD levels were higher than in milk samples obtained one day before drying-off. After parturition, relative OD in milk decreased until week 6 of lactation in the anti-C. burnetii indirect ELISA and until week 11 in the anti BVDV indirect ELISA, respectively. In conclusion, blood serological investigations in periparturient dairy cows using indirect ELISA kits should be avoided. PMID- 29421491 TI - Development of a finite element model of the ligamentous cervical vertebral column of a Great Dane. AB - Cervical spondylomyelopathy (CSM), also known as wobbler syndrome, affects mainly large and giant-breed dogs, causing compression of the cervical spinal cord and/or nerve roots. Structural and dynamic components seem to play a role in the development of CSM; however, pathogenesis is not yet fully understood. Finite element models have been used for years in human medicine to study the dynamic behavior of structures, but it has been mostly overlooked in veterinary studies. To our knowledge, no specific ligamentous spine models have been developed to investigate naturally occurring canine myelopathies and possible surgical treatments. The goal of this study was to develop a finite element model (FEM) of the C2-C7 segment of the ligamentous cervical vertebral column of a neurologically normal Great Dane without imaging changes. The FEM of the intact C2-C7 cervical vertebral column had a total of 188,906 elements (175,715 tetra elements and 12,740 hexa elements). The range of motion (in degrees) for the FEM subjected to a moment of 2Nm was approximately 27.94 in flexion, 25.86 in extension, 24.14 in left lateral bending, 25.27 in right lateral bending, 17.44 in left axial rotation, and 16.72 in right axial rotation. We constructed a ligamentous FEM of the C2-C7 vertebral column of a Great Dane dog, which can serve as a platform to be modified and adapted for studies related to biomechanics of the cervical vertebral column and to further improve studies on osseous-associated cervical spondylomyelopathy. PMID- 29421492 TI - Poly(2-acrylamido-2-methylpropane sulfonic acid) grafted magnetic chitosan microspheres: Preparation, characterization and dye adsorption. AB - A novel chitosan-based magnetic adsorbent [poly(2-acrylamido-2-methylpropane sulfonic acid) grafted magnetic chitosan microspheres, PMCMs] was successfully fabricated via free radical polymerization for effectively removing the cationic dye methylene blue (MB). The effects of initial solution pH (1.0-10.0), temperature (30-50 degrees C), contact time (0-660min) and initial concentration (50-1600mg/L) were studied. The results indicated that the adsorption capacity increased with the increasing of initial solution pH and temperature. The adsorption kinetic and adsorption equilibrium data fitted closely to the pseudo second-order kinetic model and Langmuir isotherm model respectively, confirming monolayer adsorption. The maximum adsorption capacity of PMCMs for MB at initial solution 9.0 were 1000, 1250 and 1428mg/g at 30, 40 and 50 degrees C, respectively. Furthermore, the magnetic microspheres could be easily separated using a magnet and effectively regenerated after finishing the treatment process. Therefore, PMCMs are promising candidates for the removal of dye from wastewater. PMID- 29421493 TI - Preferential hepatic uptake of paclitaxel-loaded poly-(d-l-lactide-co-glycolide) nanoparticles - A possibility for hepatic drug targeting: Pharmacokinetics and biodistribution. AB - Liver cancer is a leading cause of death related to cancer worldwide. Poly(d-l lactide-co-glycolide) (PLGA) nanoparticles provide prolonged blood residence time and sustained drug release, desirable for cancer treatment. To achieve this, we have developed paclitaxel-loaded PLGA nanoparticles by emulsification solvent evaporation method and evaluated by in vitro and in vivo studies. The results obtained from in vitro study showed that drug loading efficiency was 84.25% with an initial burst release followed by sustained drug release. Cellular uptake and in vitro cytotoxicity of the formulated nanoparticles using HepG2, Huh-7 cancer cells and Chang liver cells were also investigated. The formulated nanoparticles showed more cytotoxic effect at lower concentration and were internalized well by HepG2 cells compared to free-drug and marketed formulation. Prolonged half-life and higher plasma and liver drug concentrations of the formulated nanoparticles were observed as compared to free drug and marketed formulation in rats. Thus, paclitaxel-loaded polymeric nanoparticle has shown its potential for the treatment of liver cancer. PMID- 29421494 TI - Dissolution behavior of silk fibroin in a low concentration CaCl2-methanol solvent: From morphology to nanostructure. AB - Regenerated Silk biomaterials are usually pre-formed from silk fibroin solutions. However, the dissolution of silk fibroin in proper solvents by a simple and low cost way is still a challenge. Here, we employed a CaCl2-methanol solvent system with a very low CaCl2 concentration of 6wt% to dissolve silk fibroin. During the dissolution process, the evaporation of methanol cause the changing of solvation sheath of ions in the solvent. The remaining solvent with the incomplete solvation sheath is absorbed by the silk fiber and interacts with fibroin chains to complete the solvation sheath, which accounts for the dissolution of silk fibroin. Silk fibroin dissolution stops as all the solvation sheaths are complete. The final CaCl2 concentration is ca. 26% and silk fibroin is completely dissolved with a yield of about 90%. Silk fibroin is dissolved into multi-scale nanofibrils solution which is potential for producing regenerated silk fibroin materials for functional applications. PMID- 29421495 TI - The prevalence of HLA alleles in a lupus nephritis population. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a severe autoimmune disease that involves multiple organ systems. Lupus nephritis (LN) is a complication of SLE and is associated with poor survival and high morbidity. Many genomic studies have been performed worldwide, and several histocompatibility leukocyte antigen (HLA) loci are linked to lupus susceptibility. OBJECTIVE: The present study evaluated the association of HLA alleles in a lupus patient population, LN group and control group. The second objective evaluated whether HLA allele match or mismatch influenced kidney graft survival in a kidney transplanted lupus population. METHODS: This study was a retrospective study of 2 major groups: general lupus patients (GSLE - n = 108) and a control group (GControl - n = 216). Both groups were also divided into subgroups. RESULTS: The control group was divided into two subgroups: a healthy control group (HeCTRL) and transplant control group (TxCTRL). The GSLE group was composed of transplanted lupus patients (TxSLE) and non-transplanted lupus patients (nTxSLE). Comparison of the demographics between groups did not reveal differences between ethnicity and gender. A difference in the prevalence of three alleles, B*08, DRB1*08 and DRB1*15, was observed. These alleles were more prevalent in the lupus subgroups compared to the control groups. Five-year survival was not different between patients carrying the allele DRB1*15 in either group (overall p = 0.075; TxSLE p = 0.419; TxCTRL = 0.309). The presence of the match with this allele in the receptor was evaluated and did not demonstrate any difference in graft survival in both groups (p = 0.146) or when analyzed separately in each group (TxCTRL p = 0.739; TxSLE = 0.297). CONCLUSION: This study demonstrated that the presence of HLA-DRB1*15 was a strong factor that predisposed patients to the development of SLE and LN, but did not influence kidney graft survival. PMID- 29421496 TI - [Head injury in children: The clinical paradigm]. PMID- 29421497 TI - [Complex of amniotic deformities, adhesions, mutilations: Endless debate]. AB - Amniotic deformities, adhesions, mutilations (ADAM) complex is a broad heterogeneous spectrum of congenital anomalies. ADAM complex is characterized by constriction rings, amputation of fingers or limbs and the presence of the amniotic band. However, it may also involve craniofacial disruptions, body wall defects and internal organ abnormalities. The aim of this review is to present the results found in regard to ADAM complex from its historical background, clinical manifestations, epidemiology, etc. In particular, our attention was focused on demonstrating the varying etiopathogenesis theories of ADAM complex and their contradictions. The study was conducted using the databases of PubMed, EBSCO host, Ovid, SpringerLink, Scopus, nature.com, JAMA and ScienceDirect with the following keywords for the search: "amniotic band syndrome", "amniotic band sequence", "Streeter dysplasia", "ADAM complex". In this study we used 22 full text articles. Patients with ADAM complex require a complete pre- and postnatal evaluation to integrate the diagnosis and to decide on timely treatment. It is important for clinicians and surgeons to possess knowledge of this entity. Further research is necessary to establish a nosological basis. PMID- 29421498 TI - [Clinical decision to perform cranial computed tomography in children with non severe head injury]. AB - BACKGROUND: The main goal of this article was to evaluate if the decision to perform cranial computed tomography (CT) in children with minor head injury is determined by the presence or absence of the physician during assessment in the emergency room. METHODS: Clinical files of 92 patients from 8 months to 4 years of age were selected. Those children were evaluated at the emergency department of the Spanish Hospital of Mexico due to non-severe traumatic brain injury. Glasgow Coma Scale (GCS) score was determined in all patients. Groups of patients were compared: 1) patients having CT, 2) patients with a physician who attended the initial assessment, 3) patients whose attending physician did not arrive to assess the patient and 4) patients assessed by the emergency room staff. RESULTS: 38% of patients with non-severe brain injury underwent CT, 8.6% had a brain injury visible on the CT. Moderate intensity impacts were greater in patients with CT. Regarding the ECG, it was found that most children scored 15 points (p=0.03). In patients without a physician, a greater trend was demonstrated for performing CT. CONCLUSIONS: Patients with minor head injury but without neurological signs should undergo a detailed clinical evaluation in order to avoid unwarranted CT. PMID- 29421499 TI - [Parasitological transition: Experience in a third-level pediatric hospital (1990 2010)]. AB - BACKGROUND: In recent years, the main reason for parasitological diagnosis was suspicion of a parasitic etiology. Currently, diagnosis and consultation are associated with co-morbidity with a hemato-oncological, autoimmune, immunodeficiency or post-transplant condition. METHODS: Results collected from the Parasitology Laboratory of the Hospital Infantil de Mexico Federico Gomez from January 1990 to December 2010 were analyzed to determine the frequency and distribution of parasites and commensals per year and decade. RESULTS: There were 211,600 samples analyzed with a statistical media of 10,100 and a standard deviation of 3,500 samples. Percentage of observations for parasitic structures as well as commensals was 37.73% according to Pearson Chi square with a significant difference among percentages between decades (p<0.0001). CONCLUSIONS: Behavioral tendency of intestinal parasitosis during the last two decades shows a change in frequency and genera from the agents that were reported at this pediatric health care level. The processing of epidemiologic information is important in order to determine the response of the parasitosis and its variations over time. PMID- 29421500 TI - [Social determinants of infant mortality in socioeconomic deprived rural areas in Mexico]. AB - BACKGROUND: The aim of this study was to identify determinants of infant mortality in rural areas in Mexico and recommend strategies for its decrease. METHODS: A study was conducted in a sample of 16 municipalities among those with the lowest index of human development. Infant deaths were identified through official data, records and through interviews with civil authorities, health workers and community leaders. Mothers of children who died were also interviewed. RESULTS: In most cases, deaths were related with intermediate social determinants (living conditions and health services converged). The most important critical factors were the prevention programs and delays in receiving healthcare. Deficiencies in intersectorial policies to guarantee effective access to health services were found. CONCLUSIONS: To decrease infant mortality in rural areas of Mexico, geographic access has to be improved as well as investment in resources and training health personnel in intercultural competence and primary health care skills. PMID- 29421501 TI - [Long term follow up of a patient with type I vitamin D-dependent rickets]. AB - BACKGROUND: Vitamin D dependent rickets type I is a rare hereditary disease due to a mutation in CYP27B1 encoding the 1alpha-hydroxylase gene. Clinically, the condition is characterized by hypocalcemic rickets in early infancy due to a deficit in the production of the vitamin D active metabolite 1,25-dihydroxy vitamin D3. CASE REPORT: We report the case of a patient diagnosed at 11 months with follow-up until 9 years of age. CONCLUSIONS: The pathophysiology of the disease and the relevance of early diagnosis and management are discussed. PMID- 29421502 TI - [Retinitis pigmentosa in an adolescent]. AB - BACKGROUND: Retinitis pigmentosa is the most common chronic and inherited condition of retinal dystrophy. The progressive involvement of retinal photoreceptors and other layers characterize this condition. This situation results in optic disc pallor and retinal pigment deposition vascular attenuation. CASE REPORT: We present the case of a 15-year-old male with a history of 6 months evolution characterized by night blindness and bilateral impairment of superior temporal vision. CONCLUSIONS: This type of dystrophy is a genetic and progressive eye condition that begins during adolescence and produces visual impairment. PMID- 29421503 TI - [Type I congenital lung malformation]. PMID- 29421504 TI - [Informed consent and parental refusal to medical treatment in childhood. The threshold of medical and social tolerance. Part I]. AB - Informed consent is a right of all individuals and no one can force anyone to receive treatment against their wishes. The right to accept or refuse treatment persists in individuals who are incompetent from a legal point of view; this is exercised on their behalf by a third party. Children are considered incompetent to make medical decisions about their own health and their parents or legal guardians are empowered to make those decisions. However, parental authority is not absolute and there are situations where their decisions are not the best, sometimes leading to jeopardizing the well-being and even the lives of their children, forcing the state to intervene on behalf of the best interests of the child. This is the reason why it is necessary to ask the following questions: is it really the child's best interest that moves us to legally intervene when a parent refuses to accept the proposed medical treatment or is the damage done to make this decision? What kind of parental decisions are those that should not be tolerated? After a review of the theme, we conclude that if the decision of the parents regarding a medical decision is considered to be made with maleficence that is harmful to the child, it is justified that the State intervenes. Finally, we exposed four criteria that can be used in making decisions in complex cases where parents refuse treatment for their children. PMID- 29421505 TI - [Gonzalo Gutierrez Trujillo: Mexican, Pediatrician, Writer]. PMID- 29421506 TI - Jatrophane diterpenoids with multidrug-resistance modulating activity from the latex of Euphorbia nicaeensis. AB - Seven previously undescribed jatrophane diterpenoids, nicaeenin A-G, with eight known jatrophane diterpenoids, namely euphodendrophanes A-C, F, N, O, Q, S, were isolated from latex of Euphorbia nicaeensis collected in Serbia. The chemical structures of the compounds were determined by spectroscopic analysis including 1D and 2D NMR and HRESIMS experiments. All but one of the previously undescribed jatrophanes, showed significant potential to inhibit P-glycoprotein (P-gp) activity in two MDR cancer cells (NCI-H460/R and DLD1-TxR). The most powerful were nicaeenin F and nicaeenin G. Moreover nicaeenin G significantly stronger sensitized NCI-H460/R cells to DOX than Dex-VER. PMID- 29421507 TI - Changes in isovitexin-O-glycosylation during the development of young barley plants. AB - Phenylpropanoids are a class of plant natural products that have many biological functions, including stress defence. In barley, phenylpropanoids have been described as having protective properties against excess UV-B radiation and have been linked to resistance to pathogens. Although the phenylpropanoid composition of barley has recently been addressed in more detail, the biosynthesis and regulation of this pathway have not been fully established. Barley introgression lines, such as the S42IL-population offer a set of genetically diverse plants that enable the correlation of metabolic data to distinct genetic regions on the barley genome and, subsequently, identification of relevant genes. The phenylpropanoid profiles of the first and third leaf of barley seedlings in Scarlett and four members of the S42IL-population were obtained by LC-MS. Comparison of the leaf profiles revealed a change in the glycosylation pattern of the flavone-6-C-glucoside isovitexin in the elite cultivar Scarlett. The change was characterized by the stepwise decrease in isovitexin-7-O-glucoside (saponarin) and an increase in isovitexin-2"-O-beta-D-glucoside content. The lines S42IL-101-, -177 and -178 were completely devoid of isovitexin-2"-O-beta-D glucoside. Parallel glucosyltransferase assays were consistent with the observed metabolic patterns. The genetic region responsible for this metabolic effect was located on chromosome 1H between 0.21 and 15.08 cM, encompassing 505 gene candidates in the genome of the sequenced cultivar Morex. Only one of these genes displayed sequence similarity with glucosyltransferases of plant secondary metabolism that possessed the characteristic PSPG motif. PMID- 29421508 TI - Triterpenoids from the leaves of Ilex chinensis. AB - Eleven previously undescribed compounds including two triterpenes, ilexchinenin A and ilexchinenin B, and nine triterpenoid saponins, ilexchinenosides A-I, along with twelve known triterpenoids were isolated from the leaves of Ilex chinensis Sims (Aquifoliaceae). Their structures were elucidated by spectroscopic analysis and comparison with known compounds. Furthermore, eight compounds exhibited significant inhibitory effects on NO production of lipopolysaccharide (LPS) induced murine macrophages, while nine compounds exhibited potent hepatoprotective activity against N-acetyl-p-aminophenol (APAP)-induced HepG2 cell damage in in vitro assays. PMID- 29421509 TI - Morning glory resin glycosides as alpha-glucosidase inhibitors: In vitro and in silico analysis. AB - Twenty-seven individual resin glycosides from the morning glory family (Convolvulaceae) were evaluated for their alpha-glucosidase inhibitory potential. Four of these compounds displayed an inhibitory activity comparable to acarbose, which was used as a positive control. Molecular modeling studies performed by docking analysis were accomplished to predict that the active compounds and acarbose bind to the alpha-1,4-glucosidase enzyme catalytic site of MAL12 from the yeast Saccharomyces cerevisiae through stable hydrogen bonds primarily with the amino acid residues HIS279 and GLN322. Docking studies with the human maltase glucoamylase (MGAM) also identified binding modes for resin glycosides inside the catalytic site in the proximity of TYR1251. These results postulate that resin glycosides may be a source of phytotherapeutic agents with antihyperglycemic properties for the prophylaxis and treatment of non-insulin-dependent type 2 diabetes mellitus. PMID- 29421510 TI - Relationship between chemotypic and genetic diversity of natural populations of Artemisia herba-alba Asso growing wild in Tunisia. AB - A total of 80 individuals collected from eight populations growing wild in different geographic zones were considered to assess the intraspecific variability of essential oil composition, genetic diversity and population structure of Artemisia herba-alba. The essential oil composition varied significantly between populations. Essential oil profiles were classified into four chemotypes (trans-sabinyl acetate, alpha-thujone/trans-sabinyl acetate, camphor and alpha-thujone/camphor/beta-thujone). Despite significant correlation between the amount of some essential oil compounds and a set of climatic data, the global chemical divergence among populations was not related to their bioclimatic and geographic appurtenances. A high level of genetic diversity within populations was revealed either with RAPD and ISSR markers (Na = 1.67, PPL = 66.5%, H = 0.26, I = 0.38 and Na = 1.7, PPL = 69.8%, H = 0.26, I = 0.38, respectively). The level of genetic diversity varied across populations and chemotypes. Populations from the alpha-thujone/trans-sabinyl acetate chemotype exhibited the highest genetic diversity as revealed by the RAPD markers. However, populations from alpha-thujone/camphor/beta-thujone chemotype showed the important genetic variation determined by ISSR markers. A significant genetic differentiation among populations and among chemotypes was detected. The combined analysis showed a significant correlation (r = 0.484, p = .032) between the chemical and molecular markers. The PCA, performed on percentages of major oil compounds and the frequencies of polymorphic RAPD and ISSR bands, divided populations according to their chemotypic classification. Taking into consideration the current situation of A. herba-alba populations and their endangered habitats, these results are of value in order to ensure the in-situ and ex-situ conservation of this medicinal species. PMID- 29421511 TI - Specialized metabolites from Ageratina adenophora and their inhibitory activities against pathogenic fungi. AB - The Asteraceae plant Ageratina adenophora (also called Eupatorium adenophorum) has became the most destructive invasive species in China, especially the southwestern region, and is gravely threatening the native biodiversity. Its high reproductive capacity is partly due to the developed root system. From the roots of A. adenophora, ten compounds including three previously undescribed benzofuran derivatives (7-hydroxy-dehydrotremetone, 7,10,11-trihydroxy dehydrotremetone, 10 oxo-7-hydroxy-nordehydrotremetone), a previously undescribed chromene derivative (5-beta-glucosyl-7-demethoxy-encecalin) and a previously undescribed monoterpene glucoside (8-hydroxy-8-beta-glucosyl-2-carene) were isolated and identified. The previously undescribed structures were established by spectroscopic studies including 1D and 2D-NMR and HR-MS analyses. Antifungal activity of six compounds against one strain of pathogenic fungus of A. adenophora, Alternaria alternata, and other four strains of agricultural pathogenic fungi, Colletotrichum gloeosporioides, C. musae, Rhizoctonia solani and Fusarium oxysporum f. sp. niveum were investigated. The most abundant compound we isolated from A. adenophora roots was 7-hydroxy-dehydrotremetone, which showed significant broad spectral inhibitory activity against the growth of all tested fungal strains, with diameter of inhibitory zones ranging from 13.90 +/- 1.05 mm to 17.28 +/- 0.46 mm at 50 MUg/disk (nystatin: 24.76 +/- 1.19 mm to 36.64 +/- 0.85 mm). Encecalin also showed weak inhibitory activity against F. oxysporum f. sp. niveum, while other compounds were not active. Our results suggested that 7 hydroxy-dehydrotremetone might function as a constitutive defense compound in the roots of A. adenophora against pathogenic fungi. PMID- 29421512 TI - CRISPR/Cas9-mediated efficient targeted mutagenesis of RAS in Salvia miltiorrhiza. AB - The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR-associated) system is a powerful genome editing tool that has been used in many species. In this study, we focused on the phenolic acid metabolic pathway in the traditional Chinese medicinal herb Salvia miltiorrhiza, using the CRISPR/Cas9 system to edit the rosmarinic acid synthase gene (SmRAS) in the water soluble phenolic acid biosynthetic pathway. The single guide RNA (sgRNA) was designed to precisely edit the most important SmRAS gene, which was selected from 11 family members through a bioinformatics analysis. The sequencing results showed that the genomes of 50% of the transgenic regenerated hairy roots had been successfully edited. Five biallelic mutants, two heterozygous mutants and one homozygous mutant were obtained from 16 independent transgenic hairy root lines when the sgRNA was driven by the Arabidopsis U6 promoter, while no mutants were obtained from 13 independent transgenic hairy root lines when the sgRNA was driven by the rice U3 promoter. Subsequently, expression and metabolomics analysis showed that the contents of phenolic acids, including rosmarinic acid (RA) and lithospermic acid B, and the RAS expression level were decreased in the successfully edited hairy root lines, particularly in the homozygous mutants. In addition, the level of the RA precursor 3,4-dihydroxyphenyllactic acid clearly increased. These results indicated that the CRISPR/Cas9 system can be utilized to identify important genes in a gene family with the assistance of bioinformatics analysis and that this new technology is an efficient and specific tool for genome editing in S. miltiorrhiza. This new system presents a promising potential method to regulate plant metabolic networks and improve the quality of traditional Chinese medicinal herbs. PMID- 29421513 TI - Dihydro-beta-agarofurans from the roots of the Australian endemic rainforest tree Maytenus bilocularis act as leucine transport inhibitors. AB - Phytochemical studies of the roots of the Australian plant, Maytenus bilocularis, resulted in the identification of six previously undescribed dihydro-beta agarofuran sesquiterpenoids, bilocularins D-I, along with three known natural products, namely 1alpha,2alpha,6beta,15-tetraacetoxy-9beta-benzoyloxydihydro-beta agarofuran, pristimerin, and celastrol. The structures of all compounds were characterized via analysis of 1D/2D NMR and MS data. The absolute configuration of bilocularin D was defined by X-ray crystallography analysis. Bilocularins D and G, 1alpha,2alpha,6beta,15-tetraacetoxy-9beta-benzoyloxydihydro-beta agarofuran, and celastrol inhibited leucine transport in the human prostate cancer cell line LNCaP with IC50 values ranging from 2.5-27.9 MUM, which were more potent than the L-type amino acid transporter (LAT) family inhibitor 2 aminobicyclo[2,2,1]-heptane-2-carboxylic acid (BCH). Bilocularins D-F are the first examples of dihydro-beta-agarofurans bearing a hydroxyacetate group. PMID- 29421514 TI - Gallocatechin biosynthesis via a flavonoid 3',5'-hydroxylase is a defense response in Norway spruce against infection by the bark beetle-associated sap staining fungus Endoconidiophora polonica. AB - One of the best-studied defense responses to fungal infection in Norway spruce (Picea abies) is the biosynthesis of flavan-3-ols, which accumulate as monomers or polymers known as proanthocyanidins. The individual flavan-3-ol units consist of compounds with a 3',4'-dihydroxylated B ring [2,3-(trans)-(+)-catechin or 2,3 (cis)-(-)-epicatechin] and compounds with a 3',4',5'-trihydroxylated B ring [2,3 (trans)-(+)-gallocatechin or 2,3-(cis)-(-)-epigallocatechin]. While much is known about the biosynthesis and biological activity of catechin in Norway spruce, there is little comparable information about gallocatechin or epigallocatechin. We found that there was a significant increase in the gallocatechin content of Norway spruce bark and wood after inoculation with the bark beetle-associated sap staining fungus Endoconidiophora polonica. Gallocatechins increased proportionally more than catechins as both monomers and units of polymers. A flavonoid 3',5'-hydroxylase gene identified in Norway spruce was shown by heterologous expression in Nicotiana benthamiana to be involved in the conversion of 2,3 (trans)-(+)-catechin to 2,3 (trans)-(+)-gallocatechin. The formation of the trihydroxylated B ring in Norway spruce occurs at the level of flavan-3-ols, rather than at the level of dihydroflavonols as in many angiosperms. The transcript abundance of the flavonoid 3',5'-hydroxylase gene also increased significantly during fungal infection underlining its importance in gallocatechin biosynthesis. Comparisons of the effect of 2,3 (trans)-(+)-catechin and 2,3 (trans)-(+)-gallocatechin on fungal growth revealed that 2,3 (trans)-(+)-catechin is a stronger inhibitor of fungal growth, while 2,3 (trans)-(+)-gallocatechin is a stronger inhibitor of melanin biosynthesis. PMID- 29421515 TI - Anti-inflammatory steroidal glycosides from the berries of Solanum nigrum L. (European black nightshade). AB - Seven previously undescribed steroidal glycosides, along with three known congeners were isolated from the unripe berries of Solanum nigrum L. (Solanaceae). Their structures were elucidated on basis of 1D and 2D NMR, HR-ESI MS spectroscopic data and GC analysis after acid hydrolysis. The potential inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide in RAW 264.7 cell line and the anti-proliferative activities against five cancer cell lines (HL-60, U-937, Jurkat, K562 and HepG2) were evaluated. Seven compounds exhibited inhibition activities on NO production with IC50 values ranging from 11.33 to 49.35 MUM. Structure-activity relationships of the isolated compounds were also discussed. PMID- 29421516 TI - Bioactive halogenated dihydroisocoumarins produced by the endophytic fungus Lachnum palmae isolated from Przewalskia tangutica. AB - Guided by the UPLC-ESIMS profile, seven previously undescribed halogenated dihydroisocoumarins, palmaerones A-G, along with eleven known dihydroisocoumarins, were isolated from Lachnum palmae, an endophytic fungus from Przewalskia tangutica by exposure to a histone deacetylase inhibitor SAHA. Structures of the isolates were elucidated by analysis of their NMR, MS and optical rotation values. The antimicrobial, anti-inflammatory and cytotoxic activities of palmaerones A-G were evaluated. Palmaerones A-G showed antimicrobial activities against the strains (C. neoformans, Penicillium sp., C. albicans, B. subtilis and S. aureus), and palmaerone E exhibited potential antimicrobial activities against all the test strains with the MIC value in the range of 10-55 MUg/mL. Palmaerones A and E exhibited moderate inhibitory effects on NO production in LPS-induced RAW 264.7 cells, with the IC50 values of 26.3 and 38.7 MUM, respectively and no obvious toxicities were observed at 50 MUM. Palmaerone E showed weak cytotoxicity against HepG2 with the IC50 value of 42.8 MUM. This work provides an effective strategy for expanding natural product resource. PMID- 29421517 TI - Morusin induces paraptosis-like cell death through mitochondrial calcium overload and dysfunction in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological cancers. Morusin, a prenylated flavonoid extracted from the root bark of Morus australis, has been reported to exhibit anti-tumor activity against various human cancers except EOC. In the present study, we explored the potential anti-cancer activity of morusin against EOC in vitro and in vivo and possible underlying mechanisms for the first time. We first found that morusin effectively inhibited EOC cell proliferation and survival in vitro and suppressed tumor growth in vivo. Then we observed that treatment of EOC cells with morusin resulted in paraptosis-like cell death, a novel mode of non-apoptotic programmed cell death that is characterized by extensive cytoplasmic vacuolation due to dilation of the endoplasmic reticulum (ER) and mitochondria and lack of apoptotic hallmarks. In addition, we discovered that morusin induced obvious increase in mitochondrial Ca2+ levels, accumulation of ER stress markers, generation of reactive oxygen species (ROS), and loss of mitochondrial membrane potential (Deltapsim) in EOC cells. Furthermore, pretreatment with 4, 4' diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS), a chemical inhibitor of voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane, effectively inhibited mitochondrial Ca2+ influx, cytoplasmic vacuolation and cell death induced by morusin in EOC cells. Moreover, DIDS pretreatment also suppressed morusin-induced accumulation of ER stress markers, ROS production and depletion of Deltapsim. Consistently, tumor xenograft assays showed that co treatment with DIDS partially reversed the inhibitory effects of morusin on tumor growth in vivo and inhibited the increased levels of ER stress markers induced by morusin in tumor tissues. Collectively, our results suggest that VDAC-mediated Ca2+ influx into mitochondria and subsequent mitochondrial Ca2+ overload contribute to mitochondrial swelling and dysfunction, leading to morusin-induced paraptosis-like cell death in EOC. This study may provide alternative therapeutic strategies for EOC exhibiting resistance to apoptosis. PMID- 29421519 TI - Improvement of antihyperglycemic activity of nano-thymoquinone in rat model of type-2 diabetes. AB - Thymoquinone is a bioactive constituent of Nigella sativa seeds. It has been reported to possess antihyperglycemic effect in rats. However, the effect of nanoformulation (NF) of thymoquinone has not been reported in literature. So, the present study was designed with the aim to investigate the effect of nanoformulation of thymoquinone in streptozotocin-nicotinamide induced type-2 diabetic rats and compare its effect with pure bioactive compound as well as metformin, a standard antidiabetic drug. It is the first study reporting the use of thymoquinone NF against diabetes. Polymeric nanocapsules (NCs) of thymoquinone and metformin were prepared by nanoprecipitation method using gum rosin, a biocompatible polymer. Box-Behnken statistical analysis tool was used for the optimization of polymer and other excipients. The NCs were then characterized with respect to particle size, stability, morphology, and in vitro drug dissolution profiles. Furthermore, thymoquinone (20, 40 & 80 mg/kg), metformin (150 mg/kg) and their nanoformulations (20, 40 & 80 mg/kg for thymoquinone and 80 mg/kg for metformin) per se were administered for 21 successive days to type-2 diabetic rats. Body weight and blood glucose levels were measured every week for 3 weeks. Serum lipid profile and glycosylated hemoglobin were estimated on 22nd day. The nanocapsules were stable, spherical in shape and size was less than 100 nm. Thymoquinone-and metformin-loaded NCs showed sustained release profile as compared to their pure forms. Oral administration of thymoquinone, metformin and their nanoformulations significantly decreased blood glucose level and glycated haemoglobin; and improved the lipid profile of diabetic rats as compared to diabetic control rats. Thymoquinone-loaded NCs (containing 10, 20 and 40 mg of thymoquinone) produced dose-dependent antihyperglycemic effect and this effect was comparable to thymoquinone and metformin. In conclusion, thymoquinone nanocapsules (actually containing half of the doses of thymoquinone) produced better antihyperglycemic effect in type-2 diabetic rats as compared to thymoquinone alone. PMID- 29421518 TI - miR-7-5p overexpression suppresses cell proliferation and promotes apoptosis through inhibiting the ability of DNA damage repair of PARP-1 and BRCA1 in TK6 cells exposed to hydroquinone. AB - Hydroquinone (HQ), one of the major metabolic products of benzene, is a carcinogen, which induces apoptosis and inhibit proliferation in lymphoma cells. microRNA-7-5p (miR-7-5p), a tumor suppressor, participates in various biological processes including cell proliferation and apoptosis regulation by repressing expression of specific oncogenic target genes. To explore whether miR-7-5p is involved in HQ-induced cell proliferation and apoptosis, we assessed the effect of miR-7-5p overexpression on induction of apoptosis analyzed by FACSCalibur flow cytometer in transfection of TK6 cells with miR-7-5p mimic (TK6- miR-7-5p). We observed an increased apoptosis by 25.43% and decreased proliferation by 28.30% in TK6-miR-7-5p cells compared to those negative control cells (TK6-shNC) in response to HQ treatment. Furthermore, HQ might active the apoptotic pathway via partly downregulation the expression of BRCA1 and PARP-1, followed by p53 activation, in TK6-miR-7-5p cells. In contrast, attenuated p53 and BRCA1 expression was observed in shPARP-1 cells than in NC cells after HQ treatment. Therefore, we conclude that HQ may activate apoptotic signals via inhibiting the tumor suppressive effects of miR-7-5p, which may be mediated partly by upregulating the expression of PARP-1 and BRCA1 in control cells. The increase of miR-7-5p expression further intensified downregulation of PARP-1 and BRCA1 in TK6 miR-7-5p cells, resulting in an increase of apoptosis and proliferation inhibited. PMID- 29421520 TI - Mesenchymal stem cell (MSC)-mediated survival of insulin producing pancreatic beta-cells during cellular stress involves signalling via Akt and ERK1/2. AB - Mesenchymal stem cells (MSC) are of interest for cell therapy since their secreted factors mediate immunomodulation and support tissue regeneration. This study investigated the direct humoral interactions between MSC and pancreatic beta-cells using human telomerase-immortalized MSC (hMSC-TERT) and rat insulinoma derived INS-1E beta-cells. hMSC-TERT supported survival of cocultured INS-1E beta cells during cellular stress by alloxan (ALX) and streptozotocin (STZ), but not in response to IL-1beta. Accordingly, hMSC-TERT had no effect on inflammatory cytokine-related signalling via NF-kB and p-JNK but maintained p-Akt and upregulated p-ERK1/2. Inhibition of either p-Akt or p-ERK1/2 did not abolish protection by hMSC-TERT but activated the respective non-inhibited pathway. This suggests that one pathway compensates for the other. Main results were confirmed in mouse islets except hMSC-TERT-mediated upregulation of p-ERK1/2. Therefore, MSC promote beta-cell survival by preservation of p-Akt signalling and further involve p-ERK1/2 activation in certain conditions such as loss of p-Akt or insulinoma background. PMID- 29421521 TI - Disodium cromoglycate may act as a novel adjuvant for UV-attenuated Toxoplasma gondii vaccine in mouse model. AB - We have proven the beneficial effects during acute Toxoplasma gondii infection when mast cells were inhibited by disodium cromoglycate (DSCG). Here we investigated the adjuvant effect of DSCG on the protective efficacy of UV attenuated T. gondii (UV-Tg) vaccine. Mice were infected with 102Tg alone or infected with 102Tg plus DSCG (Tg + DSCG), immunized with 105 UV-Tg and challenged with 102Tg (UV-Tg + Tg) or immunized with 105 UV-Tg plus DSCG and challenged with 102Tg (UV-Tg + DSCG + Tg). Compared to Tg group, Tg + DSCG, UV-Tg + Tg, and UV-Tg + DSCG + Tg showed significantly prolonged survival times, decreased parasite burdens, reduced liver histopathologies, and increased levels of Th1 and Th2 cytokines and IL-17 in the livers and spleens by using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Compared to UV-Tg + Tg, UV-Tg + DSCG + Tg had significantly longer survival time, lower tissue parasite burden and histopathological score, and higher levels of Th1 and Th2 cytokines and IL-17 in the livers or spleens. Our data suggest that DSCG may play an adjuvant role in the immunization induced by UV-attenuated T. gondii in mice, by promoting cellular immune response against T. gondii challenge. PMID- 29421522 TI - Prostaglandin-endoperoxide synthase 2 (cyclooxygenase-2), a complex target for colorectal cancer prevention and therapy. AB - A plentiful literature has linked colorectal cancer (CRC) to inflammation and prostaglandin-endoperoxide synthase (PTGS)2 expression. Accordingly, several nonsteroidal antiinflammatory drugs (NSAIDs) have been tested often successfully in CRC chemoprevention despite their different ability to specifically target PTGS2 and the low or null expression of PTGS2 in early colon adenomas. Some observational studies showed an increased survival for patients with CRC assuming NSAIDs after diagnosis, but no clinical trial has yet demonstrated the efficacy of NSAIDs against established CRC, where PTGS2 is expressed at high levels. The major limits for the application of NSAIDs, or specific PTGS2 inhibitors, as adjuvant drugs in CRC are (1) a frequent confusion about the physiological role of PTGS1 and PTGS2, reflecting in CRC pathology and therapy; (2) the presence of unavoidable side effects linked to the intrinsic function of these enzymes; (3) the need of established criteria and markers for patient selection; and (4) the evaluation of the immunomodulatory potential of PTGS2 inhibitors as possible adjuvants for immunotherapy. This review has been written to rediscover the multifaceted potential of PTGS2 targeting, hoping it could act as a starting point for a new and more aware application of NSAIDs against CRC. PMID- 29421523 TI - Maraviroc improves hepatic triglyceride content but not inflammation in a murine nonalcoholic fatty liver disease model induced by a chronic exposure to high-fat diet. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. Its severity ranges from simple steatosis to cirrhosis. C-C chemokine ligand type 5 or RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted) plays an important role in the progression of hepatic inflammation and fibrosis. Our objective was to examine the preventive and therapeutic effects of maraviroc (MVC), a C-C chemokine receptor 5 antagonist, on liver pathology in an NAFLD mouse model. A total of 60 male C57BL/6 mice were randomly assigned to 1 of 4 groups: (1) high-fat diet (HFD) group or control group, (2) preventive group (HFD group plus MVC in drinking water since the beginning of the study), (3) early-therapeutic group (HFD group plus MVC in drinking starting at week 24 of the study), and (4) late therapeutic group (HFD group plus MVC in drinking water starting at week 36 of the study). All mice were sacrificed at week 48. The hepatic triglyceride concentration in the HFD group was significantly higher than that in the groups treated with MVC at any time. Gene expression associated with lipogenesis (diacylglycerol acyltransferase 2 and proliferator-activated receptor-gamma), insulin resistance (insulin receptor substrate-2), and beta-oxidation (carnitine palmitoyltransferase 1A and acyl-CoA oxidase) was significantly reduced in all the groups treated with MVC. In summary, the beneficial effect of MVC on hepatic steatosis is maintained throughout the study. PMID- 29421525 TI - Impact of calcium-sensitive dyes on the beating properties and pharmacological responses of human iPS-derived cardiomyocytes using the calcium transient assay. AB - INTRODUCTION: Calcium-based screening of hiPS-CMs is a useful preclinical safety evaluation platform with the ability to generate robust signals that facilitates high-throughput screening and data analysis. However, due to the potential inherent toxicities, it is important to understand potential effects of different calcium-sensitive dyes on the hiPS-CMs model. METHODS: We compared three calcium sensitive fluorescence dyes (Cal520, ACTOne and Calcium 5) for their impact on the variability, the beating properties and the pharmacological responses of hiPS CMs using the Hamamatsu FDSS/MUCell imaging platform. Direct effects of three dyes on the electrophysiological properties of hiPS-CMs were evaluated with the multi-electrode array (MEA) Axion Maestro platform. RESULTS: We propose a specific experimental protocol for each dye which gives the most optimal assay conditions to minimize variability and possible adverse effects. We showed that Cal520 had the smallest effect on hiPS-CMs together with the longest-lasting stable amplitude signal (up to 4 h). Although all dyes had a (minor) acute effect on hiPS-CMs, in the form of reduced beat rate and prolonged field potential duration, the selection of the dye did not influence the pharmacological response of four cardioactive drugs (dofetilide, moxifloxacin, nimodipine and isoprenaline). DISCUSSION: In conclusion, we have documented that different calcium sensitive dyes have only minor direct (acute) effects on hiPS-CMs with Cal520 showing the least effects and the longest lasting signal amplitude. Importantly, drug-induced pharmacological responses in hiPS-CMs were comparable between the three dyes. These findings should help further improve the robustness of the hiPS-CMs-based calcium transient assay as a predictive, preclinical cardiac safety evaluation tool. PMID- 29421526 TI - [The real health impact of a newborn from a pregnancy with hypertensive disorder]. PMID- 29421524 TI - Nontypeable Haemophilus influenzae DNA stimulates type I interferon expression via STING signaling pathway. AB - : Nontypeable Haemophilus influenzae (NTHI) is one of the leading causes of acute exacerbations of COPD (AECOPD). Although the immunoregulation function of NTHI outer member protein and endotoxin were confirmed, the role of NTHI DNA in activating immune responses remains to be elucidated. In this study, we found expression of IFN-beta and IFN stimulated gene CXCL10 in host cells was forcefully elevated after treating with NTHI and NTHI DNA. Interestingly, we tested increased level of STING in NTHI infected mice lung. Meanwhile, STING expression in lung of mimic COPD murine model was higher than healthy mice after NTHI infection. Importantly, knockout of STING or overexpression of STING, TBK1 and IRF3 respectively impaired or enhanced IFN-beta and CXCL10 expression during treating with NTHI and NTHI DNA. NTHI and NTHI DNA-induced I-IFN response appeared to be mediated by cGAS. Collectively, we suggested that NTHI DNA as a PAMP triggered I-IFN response, which was STING/TBK1/IRF3 dependent. SUMMARY: NTHI is the leading cause of acute exacerbations of COPD (AECOPD). Since AECOPD is an immune event, it is meaningful to elucidate the mechanism under NTHI induced immune response. It has been revealed that lipooligosaccharides and protein of NTHI could induce host immune response, but the function of NTHI nuclide acid during infection is unclear. In this research, we demonstrate NTHI DNA is a trigger for I-IFN expression, and the STING/TBK1/IRF3 pathway plays an integral role in sensing NTHI DNA to induce I-IFN expression. Moreover, by long-term intrabronchial infection of LPS, we constructed a mimic COPD murine model, in which the STING expression in lung tissues were higher than healthy mice after NTHI infection, which led us to surmise that NTHI cause AECOPD by inducing I-IFN production via STING signal pathway. PMID- 29421527 TI - Retinoblastoma in Mexico: part I. A review of general knowledge of the disease, diagnosis, and management. AB - This is the first of a two-part review that aims to report the current knowledge of retinoblastoma (Rb) and its implications in Mexico (including the authors' experience at the leading Rb centers), identify the gaps in practice, and propose solutions to improve diagnosis, treatment, and patient uptake. In this first part, general knowledge of Rb diagnosis and management is summarized with a focus on the latest advances in chemotherapy. A general review of peer-reviewed literature of Rb was conducted on PubMed. Key findings were summarized. Provided there is early detection and referral of patients followed by appropriate conservative management, Rb is curable. In developed countries, the primary treatment outcome is ocular salvage with sight preservation. Advanced chemotherapeutic options such as intra-arterial and intravitreal chemotherapy can now save even the most advanced tumors. Advances in Rb therapy are generally limited to developed countries. The implications in Mexico, of the findings from this review will be discussed in Part 2, which will be a comprehensive situational analysis of the state of Rb programming in Mexico, including a review of current demographic data available from hospitals that have Rb programs or treat Rb. PMID- 29421528 TI - [Microbiology of bronchoalveolar lavage in infants with bacterial community acquired pneumonia with poor outcome]. AB - BACKGROUND: Community-acquired pneumonia (CAP) is one of the most common infectious causes of morbidity and mortality in children <5 years of age. The aim of the study was to clarify the bacterial etiologic diagnosis in infants with CAP. METHODS: A prospective, cross-sectional and descriptive study in patients 6 months to 2 years 11 months of age with CAP with poor outcome was conducted. Patients were admitted to the Pediatric Pneumology Service and underwent bronchoscopy with bronchoalveolar lavage (BAL), taking appropriate measures during the procedure to limit the risk of contamination. RESULTS: Aerobic bacteria isolated were Moraxella sp. 23%, Streptococcus mitis 23%, Streptococcus pneumoniae 18%, Haemophilus influenzae 12%, Streptococcus oralis 12%, and Streptococcus salivarius 12%. CONCLUSIONS: In contrast to other reports, we found Moraxella sp. to be a major bacterial pathogen, possibly because of improved detection with bronchoscopy plus BAL. PMID- 29421529 TI - [Diabetic ketoacidosis in children: hospital experience. A 15-year retrospective study]. AB - BACKGROUND: Diabetic ketoacidosis (DKA) is one of the major complications of diabetes mellitus (DM). The objective of this report was to highlight the clinical and laboratory importance in the treatment of patients with DKA during a 15-year period treated at the Hospital Infantil del Estado de Sonora (HIES). METHODS: We retrospectively reviewed 140 patients with episodes of DKA to report clinical and laboratory features, mortality, and treatment with HIES protocol. RESULTS: Mortality was 0%. Using descriptive statistics we observed minimal complications without neurologic sequelae in three patients with cerebral edema. CONCLUSIONS: The HIES protocol is a practical and effective electrolyte and acid base treatment for DKA. PMID- 29421530 TI - [Newborn of mother with HELLP syndrome: characteristics and role of prematurity, low birth-weight and leukopenia in evolution]. AB - BACKGROUND: HELLP syndrome is a serious hypertensive disorder of pregnancy with important neonatal problems in the newborn. The objective of this work was to determine the characteristics of these infants and its neonatal evolution. METHODS: A retrospective observational study of all newborns of mothers with HELLP syndrome born in a university hospital between January 1, 2008 and December 31, 2013 was carried out. Thirty-three infants from 28 pregnancies (five twin gestations) were studied. A descriptive and comparative analysis between groups and a multivariate analysis of factors associated with mortality in the series took place. RESULTS: Of 33 newborns studied (2.2 newborns/1,000 infants total), two were stillbirths (6.1% of the total) and four died after birth (12.9% of live neonates) with overall perinatal mortality of 18.2%. Pregnancies in 28 infants ended before 37 weeks (84.8%) and 11 pregnancies ended before week 32 (33.3%). Seven infants weighed<1500g (four weighed <1000g). Of the 31 live births, 13 infants were in a <10th percentile weight for gestational age (41.9%), 20 needed neonatal resuscitation (64.5%) and 14 had leukopenia at birth (45.2%). In the final logistic regression, neonatal mortality was associated with extreme prematurity regardless of underweight, leukopenia and/or need for neonatal resuscitation. CONCLUSIONS: Children of mothers with HELLP syndrome have a high mortality associated with extreme prematurity, independent of the presence of leukopenia, low weight for gestational age and need for neonatal resuscitation. PMID- 29421531 TI - [Incontinentia pigmenti with defect in cellular immunity]. AB - BACKGROUND: Incontinentia pigmenti is a rare, X-linked genetic disease and affects all ectoderm-derived tissues such as skin, appendages, eyes, teeth and central nervous system as well as disorders of varying degree of cellular immunity characterized by decreasing melanin in the epidermis and increase in the dermis. When the condition occurs in males, it is lethal. CASE REPORT: We present the case of a 2-month-old infant with severe incontinentia pigmenti confirmed by histological examination of skin biopsy. The condition evolved with severe neurological disorders and seizures along with severe cellular immune deficiency, which affected the development of severe infections and caused the death of the patient. CONCLUSIONS: The importance of early clinical diagnosis is highlighted along with the importance of multidisciplinary management of neurological disorders and infectious complications. PMID- 29421532 TI - Perinatal factors and type 1 diabetes-associated dysbiosis in Mexican infants. AB - BACKGROUND: Type 1 diabetes (T1D) is currently an autoimmune disease occurring more frequently and early in life. T1D development requires genetic predisposition and environmental factors, which influence the gut microbiota in early infancy and could increase the risk for T1D-associated autoimmunity. In Mexico there are no published microbiota studies in children <6 years old with T1D. CASE REPORTS: We report two contrasting Mexican T1D cases of children <6 years of age and a third case of a healthy child prior to autoimmunity and T1D onset. Perinatal factors, feeding regimes in the first year of life and gut microbiota composition are discussed and related to the T1D onset. The three cases show a particular microbiota profile with decreased bacterial diversity as compared with healthy children, which could be related to environmental factors prior to the development of T1D and disease control. CONCLUSIONS: T1D infant cases presented a decreased bacterial diversity, which appeared before autoimmunity and T1D onset. Glycemic control could tend to correct the gut dysbiosis in T1D children. Prospective studies are needed to follow-up healthy children at high genetic risk to assess factors related to the microbiota structure. PMID- 29421533 TI - [Late prematurity with gastroschisis and severe hypoalbuminemia]. PMID- 29421534 TI - [Clinical research design and causality: does oral rotavirus vaccine cause intussusception?] AB - Design of clinical research whose purpose is to answer questions about causality can be classified in relation to four axes: the number of study groups, the implementation of an experimental maneuver, cause-effect directionality and source from which the data are collected. The basic designs used in epidemiology are the clinical trial, the cohort study, the case-control study and the cross sectional survey. This text aims to facilitate the identification and understanding of each of these designs through examples related to the association between rotavirus vaccination and intussusception. PMID- 29421535 TI - [Parental decisions that do not risk children's lives but place them at significant harm: foregoing vaccination]. AB - The decisions of parents to forego vaccines "mandatory" for their children generate in physician and pediatricians some dilemmas and issues such as what to do when parents do not authorize administration of vaccines to their children? Do parents place their children at risk severe enough to notify governmental child protection services and treat this as parental negligence? What to do in the situation where the parental decision to forego immunization of their children affects others? The best interests of the child include ensuring the child's benefit over any other situation. Related to this, parents against vaccines have arguments to justify their position that physicians cannot force parents to immunize their children. By the same principle, physicians must ensure the welfare of children and remain alert, respecting that parental decisions do not exceed the threshold of "no harm to the child" and only if the parental decision in regard to foregoing vaccination places the child at risk of serious harm is government intervention justified. This resource should be left as the last resort because most conflicts must be resolved within the relationship of the physicians with the parents. PMID- 29421536 TI - SIRT3 inhibits prostate cancer metastasis through regulation of FOXO3A by suppressing Wnt/beta-catenin pathway. AB - SIRT3, a mitochondrial NAD+-dependent deacetylase, has been reported to restrain prostate cancer growth both in vitro and in vivo, however, its role in metastatic prostate cancer has not been revealed. In this study, we reported that SIRT3 inhibited the epithelial-mesenchymal transition (EMT) and migration of prostatic cancer cells in vitro and their metastasis in vivo. Consistently, based on analyses of tissue microarray and microarray datasets, lower SIRT3 expression level was correlated with higher prostate cancer Gleason scores, and SIRT3 expression were significantly decreased in metastatic tissues compared with prostate tumor tissues. Mechanistically, SIRT3 promoted FOXO3A expression by attenuating Wnt/beta-catenin pathway, thereby inhibiting EMT and migration of prostate cancer cells. Indeed, SIRT3's inhibitory effect on EMT and migration of prostate cancer cells can be rescued after applying Wnt/beta-catenin pathway activator LiCl, or boosted by wnt inhibitor XAV939. Together, this study revealed a novel mechanism for prostate cancer metastasis that involves SIRT3/ Wnt/beta catenin/ FOXO3A signaling to modulate EMT and cell migration. PMID- 29421537 TI - Neuronal activity in the sagittalis nucleus of the hypothalamus after ovarian steroid hormone manipulation and sexual behavior in female rat. AB - During extended observation of estrogen receptor (ER) alpha-immunoreactive neurons in the hypothalamus, we previously identified a novel nucleus, the Sagittalis Nucleus of the Hypothalamus (SGN), in the interstitial area between the arcuate nucleus and the ventromedial hypothalamic nucleus. The SGN exhibits sexual dimorphism in its volume and cell count, and estrous cycle related variations in ERalpha-immunoreactivity. These characteristics of the SGN implicate the nucleus in sex-biased brain functions and behaviors. In this study, we examined involvement of the SGN in sexual arousal in female rats. Immunohistochemical staining of c-Fos, a marker of neuronal activity was performed after administration of an estrus-inducing dose of estrogen and progesterone in ovariectomized female rats. Analysis of microscopic images showed a significant increase in the number of c-Fos-expressing neurons in the SGN following hormonal manipulation. Moreover, neuronal activity in the region exhibited a further increase after each animal was coupled with a male and allowed to mate. These results suggest that the SGN plays an important role in sexual activity in female rat. PMID- 29421538 TI - Sleep deprivation precipitates the development of amphetamine-induced conditioned place preference in rats. AB - Sleep deprivation (SD) and amphetamine use are commonly associated conditions. SD shares similar neurobiological effects with psychostimulants, playing an important role in drug addiction, especially through conditioning manipulations. The aim of the present study was to investigate the effects of SD on the development of amphetamine-induced conditioned place preference (CPP) in a protocol with a reduced number of conditioning sessions. Male adult Wistar rats were submitted to 4 conditioning sessions (2 sessions/day) in the CPP apparatus, half with saline (non-drug-paired compartment) and half with 2 mg/kg amphetamine (drug-paired compartment) after control (home-cage maintained) or SD (6 h gentle handling method) conditions. Control animals did not express a preference for the amphetamine-paired compartment, showing that 2 conditioning sessions with the drug were not sufficient to establish CPP. On the other hand, animals submitted to SD during the conditioning sessions expressed a preference for the amphetamine paired compartment, which was maintained across the entire test session. SD precipitated the development of CPP to amphetamine, showing that lack of sleep can contribute to the establishment of a conditioning between the drug effect and environmental cues. PMID- 29421539 TI - Salvianolic acid B promotes neural differentiation of induced pluripotent stem cells via PI3K/AKT/GSK3beta/beta-catenin pathway. AB - Salvianolic acid B (Sal B), a water-soluble component mainly extracted from the traditional Chinese medicine Salvia miltiorrhiza, has potential anti inflammatory, anti-oxidative and anti-apoptotic actions to protect neural cells. Here, we explore the effects and mechanisms of Sal B on the promotion of differentiation of induced pluripotent stem cells (iPSCs) into neural stem cells (NSCs), then further into neurons. During the processes of neural differentiation of iPSCs, Sal B or a phosphatidylinositide 3 kinase (PI3K) inhibitor (LY294002) were added to the medium. Sal B substantially improved proliferation of iPSC derived NSCs and neurons. Furthermore, Sal B significantly stimulated PI3K/AKT/GSK3 beta/beta-catenin pathway. However, LY294002 attenuated the Sal B induced increase. Therefore, these outcomes suggest that Sal B markedly enhances neural differentiation of iPSCs via the PI3K/AKT/GSK3beta/beta-catenin pathway. PMID- 29421540 TI - Why do so many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? AB - The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35 functionally diverse spinocerebellar ataxia genes have been identified. The main question that remains yet unsolved is why do some many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? To address this question it is important to identify intrinsic pathways important for Purkinje Cell function and survival. In this review, we discuss the current consensus on shared mechanisms underlying the pervasive Purkinje Cell loss in spinocerebellar ataxia. Additionally, using recently published cell type specific expression data, we identified several Purkinje Cell-specific genes and discuss how the corresponding pathways might underlie the vulnerability of Purkinje Cells in response to the diverse genetic insults causing spinocerebellar ataxia. PMID- 29421542 TI - Leptin levels and its correlation with crack-cocaine use severity: A preliminary study. AB - BACKGROUND: Crack-cocaine is an important public health problem in Brazil and worldwide. It is a potent form of cocaine which results in rapid and damaging stimulating effects on the central nervous system through inhibition of the dopamine transporter. Some studies have suggested that both food and drugs - including crack, can act on the same brain reward mechanisms, altering the dopamine pathways that modulate behavioral responses. Our hypothesis was that leptin, a well-known peptide that modulates energy metabolism and appetite, can be used as a biomarker for drug use. METHODS: Anthropometric data, drug use profiles, and leptin serum levels were evaluated in a cross-sectional study of 40 crack-cocaine users. RESULTS: Leptin showed an inverse correlation with the severity of crack use, and this correlation remained when corrected by body mass index (BMI) and body composition by bioimpedance (BIA). The majority of subjects were eutrophic or overweight/obese considering BMI and BIA, and these variables were not significantly associated with the severity of crack use, but positively correlated with leptin levels. CONCLUSIONS: Our preliminary findings suggest that leptin could be involved in drug use severity, perhaps through pathways similar to those whereby it modulates food intake. Considering the anthropometric parameters, these findings provide additional evidence that low weight is not predominant in crack users. PMID- 29421543 TI - Sigma 1 receptor mediated HMGB1 expression in spinal cord is involved in the development of diabetic neuropathic pain. AB - No study has been conducted to examine the interactions of sigma-1 receptor (Sigma-1R) and high mobility group box 1 protein (HMGB1) in the development of diabetic peripheral neuropathy. Thus, we examined the effects of streptozotocin (STZ) treatment on expression of HMGB1 in subcellular levels in the dorsal root ganglion (DRG) in both wild-type and Sigma-1R-/- mice and evaluated the effects of repeated intrathecal administrations of selective Sigma-1R antagonists BD1047, agonist PRE-084, or HMGB1 inhibitor glycyrrhizin on peripheral neuropathy in wild type mice. We found that STZ-induced tactile allodynia and thermal hyperalgesia was associated with increased total HMGB1 expression in DRG. STZ treatment promoted the distribution of HMGB1 into cytoplasm. Furthermore, STZ induced modest peripheral neuropathy and did not alter HMGB1 levels in DRG or the distribution of either cytoplasmic or nuclear HMGB1 in Sigma-1R-/- mice compared to sham control mice. Additionally, repeated stimulation of Sigma-1R in the spinal cord induced tactile allodynia and thermal hyperalgesia at 1 week. This phenomenon was associated with increased cytoplasmic HMGB1 translocation and HMGB1 expression in DRG. Finally, we found that repeated blockade of either Sigma 1R or HMGB1 in the spinal cord after STZ treatment prevent the development of tactile allodynia and thermal hyperalgesia at 1 week. These effects were associated with decreased cytoplasmic HMGB1 translocation and HMGB1 expression in DRG. Taken together, our results suggest that Sigma-1R-mediated enhancement of HMGB1 expression in the DRG is critical for the development of peripheral neuropathy in type 1 diabetes. PMID- 29421541 TI - Ion channel dysfunction in cerebellar ataxia. AB - Cerebellar ataxias constitute a heterogeneous group of disorders that result in impaired speech, uncoordinated limb movements, and impaired balance, often ultimately resulting in wheelchair confinement. Motor dysfunction in ataxia can be attributed to dysfunction and degeneration of neurons in the cerebellum and its associated pathways. Recent work has suggested the importance of cerebellar neuronal dysfunction resulting from mutations in specific ion-channels that regulate membrane excitability in the pathogenesis of cerebellar ataxia in humans. Importantly, even in ataxias not directly due to ion-channel mutations, transcriptional changes resulting in ion-channel dysfunction are tied to motor dysfunction and degeneration in models of disease. In this review, we describe the role that ion-channel dysfunction plays in a variety of cerebellar ataxias, and postulate that a potential therapeutic strategy that targets specific ion channels exists for cerebellar ataxia. PMID- 29421544 TI - Deregulation of synaptic plasticity in autism. AB - A puzzling observation in the study of autism spectrum disorder (ASD) in mouse models has been the deregulation of long-term synaptic depression (LTD), a form of experience-dependent synaptic plasticity, across brain areas and across syndromic and non-syndromic forms of autism. This review attempts to approach this phenomenon from a largely, but not exclusively, cerebellar perspective. Three potential consequences of LTD deregulation are discussed that are relevant for ASD phenotypes: resulting impairment of proper developmental synaptic pruning, impairment of motor coordination and motor learning, and impairment of the processing of sensory input. PMID- 29421545 TI - Travel medicine related to the El Camino pilgrimage. PMID- 29421546 TI - One-pot synthesis of albumin-gadolinium stabilized polypyrrole nanotheranostic agent for magnetic resonance imaging guided photothermal therapy. AB - Theranostic agents with perfect properties are needed urgently for the development of imaging guided photothermal therapy (PTT). In this work, Gd integrated polypyrrole nanotheranostic agent (PPy@BSA-Gd) was successfully built through selecting bovine serum albumin (BSA) as both stabilizers for polymerization and biomimetic mineralization in "one pot". The obtained PPy@BSA Gd possessed high stability and excellent photothermal property. Besides, relevant cellular assays indicated that PPy@BSA-Gd had fantastic cytocompatibility which could be further internalized by cancer cells. Due to their high longitudinal relaxivity value (r1 = 10.203 mM-1 s-1), PPy@BSA-Gd could serve as considerable probe for T1-weighted magnetic resonance imaging (MRI). After tail vein injection of PPy@BSA-Gd, the MR signal of tumor section exhibited a time-dependent increase, indicating effective tumor accumulation of PPy@BSA-Gd. Notably, when exposed to 808 nm laser, the tumor growth of PPy@BSA-Gd treated mice could be inhibited by photothermal ablation successfully. All the results demonstrated the well-designed PPy@BSA-Gd have the potential for tumor diagnose and photothermal therapy. PMID- 29421547 TI - Lower fluidity of supported lipid bilayers promotes neuronal differentiation of neural stem cells by enhancing focal adhesion formation. AB - Extensive studies have been performed to understand how the mechanical properties of a stem cell's microenvironment influence its behaviors. Supported lipid bilayers (SLBs), a well-known biomimetic platform, have been used to mimic the dynamic characteristics of the extracellular matrix (ECM) because of their fluidity. However, the effect of the fluidity of SLBs on stem cell fate is unknown. We constructed SLBs with different fluidities to explore the influence of fluidity on the differentiation of neural stem cells (NSCs). The results showed that the behavior of NSCs was highly dependent on the fluidity of SLBs. Low fluidity resulted in enhanced focal adhesion formation, a dense network of stress fibers, stretched and elongated cellular morphology and increased neuronal differentiation, while high fluidity led to less focal adhesion formation, immature stress fibers, round cellular morphology and more astrocyte differentiation. Mechanistic studies revealed that low fluidity may have enhanced focal adhesion formation, which activated FAK-MEK/ERK signaling pathways and ultimately promoted neuronal differentiation of NSCs. This work provides a strategy for manipulating the dynamic matrix surface for the development of culture substrates and tissue-engineered scaffolds, which may aid the understanding of how the dynamic ECM influences stem cell behaviors as well as improve the efficacy of stem cell applications. PMID- 29421548 TI - Bacteria-responsive intelligent wound dressing: Simultaneous In situ detection and inhibition of bacterial infection for accelerated wound healing. AB - The evolved resistance of antibiotics exhibited by some dreaded clinical pathogens and formation of biofilms has caused life-threatening problems for patients with burns and other wounds. Here, in order to avoid antibiotic overuse, and thus decreasing the occurrence of antimicrobial-resistant bacteria, a theranostic wound dressing, composed of biocompatible UV-photocrosslinkable methacrylated gelatin (GelMA) encapsulating both antimicrobial and fluorescent vesicles, has been developed. The system can respond to the microbiological environment of the wound via a simple color change and antimicrobials release only when require and this is in essence passive as they do not respond to their local environments and benign bacteria, and only operates when pathogenic bacteria exist. Both in Vitro and in Vivo study demonstrated that the proposed wound dressing was able to kill/inhibit the growth of methicillin-resistant S. aureus and P. aeruginosa, whilst providing a visual warning of infection, due to vesicle bilayer membrane lysed by toxins secreted by the two strains of pathogens but not by a non-pathogenic Escherichia coli species. The strategy of microbiologically responsive wound dressing proposed here could also be used as a general methodology for the design and fabrication of bacterial responsive functional biomaterials that offer opportunities to combat drug-resistant bacterial infections. PMID- 29421549 TI - Unique electrophysiological and impedance signatures between encapsulation types: An analysis of biological Utah array failure and benefit of a biomimetic coating in a rat model. AB - Intracortical microelectrode arrays, especially the Utah array, remain the most common choice for obtaining high dimensional recordings of spiking neural activity for brain computer interface and basic neuroscience research. Despite the widespread use and established design, mechanical, material and biological challenges persist that contribute to a steady decline in recording performance (as evidenced by both diminished signal amplitude and recorded cell population over time) or outright array failure. Device implantation injury causes acute cell death and activation of inflammatory microglia and astrocytes that leads to a chronic neurodegeneration and inflammatory glial aggregation around the electrode shanks and often times fibrous tissue growth above the pia along the bed of the array within the meninges. This multifaceted deleterious cascade can result in substantial variability in performance even under the same experimental conditions. We track both impedance signatures and electrophysiological performance of 4 * 4 floating microelectrode Utah arrays implanted in the primary monocular visual cortex (V1m) of Long-Evans rats over a 12-week period. We employ a repeatable visual stimulation method to compare signal-to-noise ratio as well as single- and multi-unit yield from weekly recordings. To explain signal variability with biological response, we compare arrays categorized as either Type 1, partial fibrous encapsulation, or Type 2, complete fibrous encapsulation and demonstrate performance and impedance signatures unique to encapsulation type. We additionally assess benefits of a biomolecule coating intended to minimize distance to recordable units and observe a temporary improvement on multi-unit recording yield and single-unit amplitude. PMID- 29421550 TI - Reversible opening of the blood-brain barrier by claudin-5-binding variants of Clostridium perfringens enterotoxin's claudin-binding domain. AB - The blood-brain barrier (BBB) prevents entry of neurotoxic substances but also that of drugs into the brain. Here, the paracellular barrier is formed by tight junctions (TJs) with claudin-5 (Cldn5) being the main sealing constituent. Transient BBB opening by targeting Cldn5 could improve paracellular drug delivery. The non-toxic C-terminal domain of Clostridium perfringens enterotoxin (cCPE) binds to a subset of claudins, e.g., Cldn3, -4. Structure-based mutagenesis was used to generate Cldn5-binding variants (cCPE-Y306W/S313H and cCPE-N218Q/Y306W/S313H). These cCPE-variants were tested for transient TJ opening using multiple in vitro BBB models: Primary porcine brain endothelial cells, coculture of primary rat brain endothelial cells with astrocytes and mouse cerebEND cells. cCPE-Y306W/S313H and cCPE-N218Q/Y306W/S313H but neither cCPE-wt nor cCPE-Y306A/L315A (not binding to claudins) decreased transendothelial electrical resistance in a concentration-dependent and reversible manner. Furthermore, permeability of carboxyfluorescein (with size of CNS drugs) was increased. cCPE-Y306W/S313H but neither cCPE-wt nor cCPE-Y306A/L315A bound to Cldn5-expressing brain endothelial cells. However, freeze-fracture EM showed that cCPE-Y306W/S313H did not cause drastic TJ breakdown. In sum, Cldn5-binding cCPE variants enabled mild and transient opening of brain endothelial TJs. Using reliable in vitro BBB models, the results demonstrate that cCPE-based biologics designed to bind Cldn5 improve paracellular drug delivery across the BBB. PMID- 29421551 TI - Suppress orthotopic colon cancer and its metastasis through exact targeting and highly selective drug release by a smart nanomicelle. AB - The treatment of metastatic cancer is a huge challenge at the moment. Highly precise targeting delivery and drug release in tumor have always been our pursuit in cancer therapy, especially to advance cancer with metastasis, for increasing the efficacy and biosafety. We established a smart nanosized micelle, formed by tocopherol succinate (TOS) conjugated hyaluronic acid (HA) using a disulfide bond linker. The micelle (HA-SS-TOS, HSST) can highly specifically bind with CD44 receptor over-expressed tumor, and response selectively to high GSH level in the cells, inducing disulfide bond breakage and the release of the payload (paclitaxel, PTX). To predict the antitumor efficacy of the micelles more clinically, we established an orthotopic colon cancer model with high metastasis rate, which could be visualized by the luciferase bioluminescence. Our data confirmed CD44 high expression in the colon cancer cells. Highly matching between the micellar fluorescence and bioluminescence of cancer cells in intestines demonstrated an exact recognition of our micelles to orthotopic colon tumor and its metastatic cells, attributing to the mediation of CD44 receptors. Furthermore, the fluorescence of the released Nile Red from the micelles was found only in the tumor and its metastatic cells, and almost completely overlapped with the bioluminescence of the cancer cells, indicating a highly selective drug release. Our micelles presented an excellent therapeutic effect against metastatic colon cancer, and induced significantly prolonged survival time for the mice, which might become a promising nanomedicine platform for the future clinical application against advanced cancers with high CD44 receptor expression. PMID- 29421552 TI - Nanofibrous peptide hydrogel elicits angiogenesis and neurogenesis without drugs, proteins, or cells. AB - The design of materials for regenerative medicine has focused on delivery of small molecule drugs, proteins, and cells to help accelerate healing. Additionally, biomaterials have been designed with covalently attached mimics of growth factors, cytokines, or key extracellular matrix components allowing the biomaterial itself to drive biological response. While the approach may vary, the goal of biomaterial design has often centered on promoting either cellular infiltration, degradation, vascularization, or innervation of the scaffold. Numerous successful studies have utilized this complex, multicomponent approach; however, we demonstrate here that a simple nanofibrous peptide hydrogel unexpectedly and innately promotes all of these regenerative responses when subcutaneously implanted into the dorsal tissue of healthy rats. Despite containing no small molecule drugs, cells, proteins or protein mimics, the innate response to this material results in rapid cellular infiltration, production of a wide range of cytokines and growth factors by the infiltrating cells, and remodeling of the synthetic material to a natural collagen-containing ECM. During the remodeling process, a strong angiogenic response and an unprecedented degree of innervation is observed. Collectively, this simple peptide-based material provides an ideal foundational system for a variety of bioregenerative approaches. PMID- 29421553 TI - Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis. AB - Glioblastoma (GBM) is the most lethal primary adult brain tumor and its pathology is hallmarked by distorted neovascularization, diffuse tumor-associated macrophage infiltration, and potent immunosuppression. Reconstituting organotypic tumor angiogenesis models with biomimetic cell heterogeneity and interactions, pro-/anti-inflammatory milieu and extracellular matrix (ECM) mechanics is critical for preclinical anti-angiogenic therapeutic screening. However, current in vitro systems do not accurately mirror in vivo human brain tumor microenvironment. Here, we engineered a three-dimensional (3D), microfluidic angiogenesis model with controllable and biomimetic immunosuppressive conditions, immune-vascular and cell-matrix interactions. We demonstrate in vitro, GL261 and CT-2A GBM-like tumors steer macrophage polarization towards a M2-like phenotype for fostering an immunosuppressive and proangiogenic niche, which is consistent with human brain tumors. We distinguished that GBM and M2-like immunosuppressive macrophages promote angiogenesis, while M1-like pro-inflammatory macrophages suppress angiogenesis, which we coin "inflammation-driven angiogenesis." We observed soluble immunosuppressive cytokines, predominantly TGF-beta1, and surface integrin (alphavbeta3) endothelial-macrophage interactions are required in inflammation-driven angiogenesis. We demonstrated tuning cell-adhesion receptors using an integrin (alphavbeta3)-specific collagen hydrogel regulated inflammation-driven angiogenesis through Src-PI3K-YAP signaling, highlighting the importance of altered cell-ECM interactions in inflammation. To validate the preclinical applications of our 3D organoid model and mechanistic findings of inflammation-driven angiogenesis, we screened a novel dual integrin (alphavbeta3) and cytokine receptor (TGFbeta-R1) blockade that suppresses GBM tumor neovascularization by simultaneously targeting macrophage-associated immunosuppression, endothelial-macrophage interactions, and altered ECM. Hence, we provide an interactive and controllable GBM tumor microenvironment and highlight the importance of macrophage-associated immunosuppression in GBM angiogenesis, paving a new direction of screening novel anti-angiogenic therapies. PMID- 29421554 TI - Improved magnetic regulation of delivery profiles from ferrogels. AB - While providing the ability to magnetically enhance delivery rates, ferrogels have not been able to produce the various types of regulated delivery profiles likely needed to direct complex biological processes. For example, magnetically triggered release after prolonged periods of payload retention have not been demonstrated and little has been accomplished towards remotely controlling release rate through alterations in the magnetic signal. Also, strategies do not exist for magnetically coordinating multi-drug sequences. The purpose of this study was to develop these capabilities through improved ferrogel design and investigating how alterations in the magnetic signal impact release characteristics. Results show that delivery rate can be remotely regulated using the frequency of magnetic stimulation. When using an optimized biphasic ferrogel design, stimulation at optimized frequencies enabled magnetically triggered deliveries after a delay of 5 days that were 690- to 1950-fold higher than unstimulated baseline values. Also, a sequence of two payloads was produced by allowing one payload to initially diffuse out of the ferrogel, followed by magnetically triggered release of a different payload on day 5. Finally, it was demonstrated that two payloads could be sequentially triggered for release by first stimulating at a frequency tuned to preferentially release one payload (after 24 h), followed by stimulation at a different frequency tuned to preferentially release the other payload (After 4 days). The strategies developed here may expand the utility of ferrogels in clinical scenarios where the timing and sequence of biological events can be tuned to optimize therapeutic outcome. PMID- 29421555 TI - Synthetic design of growth factor sequestering extracellular matrix mimetic hydrogel for promoting in vivo bone formation. AB - Synthetic scaffolds that possess an intrinsic capability to protect and sequester sensitive growth factors is a primary requisite for developing successful tissue engineering strategies. Growth factors such as recombinant human bone morphogenetic protein-2 (rhBMP-2) is highly susceptible to premature degradation and to provide a meaningful clinical outcome require high doses that can cause serious side effects. We discovered a unique strategy to stabilize and sequester rhBMP-2 by enhancing its molecular interactions with hyaluronic acid (HA), an extracellular matrix (ECM) component. We found that by tuning the initial protonation state of carboxylic acid residues of HA in a covalently crosslinked hydrogel modulate BMP-2 release at physiological pH by minimizing the electrostatic repulsion and maximizing the Van der Waals interactions. At neutral pH, BMP-2 release is primarily governed by Fickian diffusion, whereas at acidic pH both diffusion and electrostatic interactions between HA and BMP-2 become important as confirmed by molecular dynamics simulations. Our results were also validated in an in vivo rat ectopic model with rhBMP-2 loaded hydrogels, which demonstrated superior bone formation with acidic hydrogel as compared to the neutral counterpart. We believe this study provides new insight on growth factor stabilization and highlights the therapeutic potential of engineered matrices for rhBMP-2 delivery and may help to curtail the adverse side effects associated with the high dose of the growth factor. PMID- 29421556 TI - Self-indicating, fully active pharmaceutical ingredients nanoparticles (FAPIN) for multimodal imaging guided trimodality cancer therapy. AB - Conventional drug delivery systems contain substantial amounts of excipients such as polymers and lipids, typically with low drug loading capacity and lack of intrinsic traceability and multifunctionality. Here, we report fully active pharmaceutical ingredient nanoparticles (FAPIN) which were self-assembled by minimal materials, but seamlessly orchestrated versatile theranostic functionalities including: i) self-delivery: no additional carriers were required, all components in the formulation are active pharmaceutical ingredients; ii) self-indicating: no additional imaging tags were needed. The nanoparticle itself was composed of 100% imaging agents, so that the stability, drug release, subcellular dispositions, biodistribution and therapeutic efficacy of FAPINs can be readily visualized by ample imaging capacities, including energy transfer relay dominated, dual-color fluorogenic property, near-infrared fluorescence imaging and magnetic resonance imaging; and iii) highly effective trimodality cancer therapy, encompassing photodynamic-, photothermal- and chemo therapies. FAPINs were fabricated with very simple material (a photosensitizer drug conjugate), unusually achieved ~10 times better in vitro antitumor activity than their free counterparts, and were remarkably efficacious in patient-derived xenograft (PDX) glioblastoma multiforme animal models. Only two doses of FAPINs enabled complete ablation of highly-malignant PDX tumors in 50% of the mice. PMID- 29421557 TI - Harnessing macrophage-mediated degradation of gelatin microspheres for spatiotemporal control of BMP2 release. AB - Biomaterials-based approaches to harnessing the immune and inflammatory responses to potentiate wound healing hold important promise. Bone fracture healing is characterized by an acute inflammatory phase, followed by a transition to a regenerative and repair phase. In this study, we developed genipin-crosslinked gelatin microspheres designed to be preferentially degraded by inflammatory (M1) macrophages. Highly crosslinked (>90%) microspheres allowed efficient incorporation of bioactive bone morphogenetic protein 2 (BMP2), a potent stimulator of osteogenesis in progenitor cells, via electrostatic interactions. Release of BMP2 was directly correlated with degradation of the gelatin matrix. Exposure of microspheres to polarized murine macrophages showed that degradation was significantly higher in the presence of M1 macrophages, relative to alternatively activated (M2) macrophages and unpolarized controls. Microsphere degradation in the presence of non-inflammatory cells resulted in very low degradation rates. The expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) by macrophages were consistent with the observed phenotype-dependent degradation rates. Indirect co-culture of BMP2-loaded microspheres and macrophages with isolated adipose-derived mesenchymal stem cells (MSC) showed that M1 macrophages produced the strongest osteogenic response, comparable to direct supplementation of the culture medium with BMP2. Controlled release systems that are synchronized with the inflammatory response have the potential to provide better spatiotemporal control of growth factor delivery and therefore may improve the outcomes of recalcitrant wounds. PMID- 29421558 TI - Lysosomal deposition of copper oxide nanoparticles triggers HUVEC cells death. AB - The increasing use of copper oxide nanoparticles (CuONPs) has led to major concerns regarding both the predominant physicochemical properties and the potential toxic effects on the environment and human health. The objective of this study is to explore the possible mechanisms underlying the toxicity of CuONPs in vascular endothelial cells. We found that CuONPs induced the cell death in human umbilical vein endothelial cells (HUVECs) through a caspase-independent pathway. Our results also demonstrated that CuONPs were prevalently deposited within lysosomes. The lysosomal deposition of CuONPs led to lysosomal dysfunction, resulting in the impairment of autophagic flux and the accumulation of undegraded autophagosomes. Nevertheless, blockage of the lysosomal deposition of CuONPs could significantly attenuate HUVEC cell death. Interestingly, we found that the inhibition of lysosomal deposition of CuONPs reduced the release of Cu ions, which has been considered as the crucial factor for the toxicity of CuONPs. In summary, our results indicate that the lysosomal deposition of CuONPs (along with the enhanced release of Cu ions form CuONPs) triggers CuONPs-induced HUVEC cell death. Our findings provide an insight into the mechanism of toxicity to the cardiovascular system induced by toxic metal oxide nanoparticles exposure. PMID- 29421559 TI - Enrichment of high-functioning human iPS cell-derived hepatocyte-like cells for pharmaceutical research. AB - Human iPS cell-derived hepatocyte-like cells are expected to be utilized in pharmaceutical research. However, the purity of high-functioning hepatocyte-like cells is not high enough. In particular, the purity of cytochrome P450 3A4 (CYP3A4), which is a representative hepatic drug-metabolizing enzyme, positive cells is still quite low (approximately 20%). To address this problem, we established the CYP3A4-NeoR-EGFP transgenic reporter human iPS cell line (CYP3A4 NeoR-EGFP iPS cells) by using genome editing technology. The CYP3A4-NeoR-EGFP iPS cells were differentiated into hepatocyte-like cells, and then the hepatocyte like cells were treated with neomycin to concentrate the hepatocyte-like cells which strongly express CYP3A4. After the neomycin treatment, the percentage of CYP3A4-positive cells was higher than 80%. The gene expression levels of various drug-metabolizing enzymes, transporters, and hepatic transcription factors were significantly enhanced by neomycin treatment. In addition, the CYP1A2, 2C19, 2D6, and 3A4 activities and biliary excretion capacities were significantly increased by neomycin treatment. We also confirmed that the detection sensitivity of drug inducing hepatotoxicity was enhanced by neomycin treatment. We succeeded in obtaining human iPS cell-derived hepatocyte-like cells that highly express CYP3A4 at high purity. We believe that our high-purity and high-functioning hepatocyte like cells could be used to evaluate the risk of drug candidates. PMID- 29421561 TI - Inhibition of tumor-promoting stroma to enforce subsequently targeting AT1R on tumor cells by pathological inspired micelles. AB - Cancer associated fibroblasts (CAFs) are the most abundant, genetically stable stroma cells and localize near blood vessels within "finger-like" collagen-rich stroma, which lead to restrained drug transport in dense stroma instead of tumor cells inside tumor mass, especially for targeting micelles. Meanwhile, the bioactive cytokines secreted by stroma cells result in microenvironment mediated drug resistance (TMDR). Hence, a biologically inspired Telmisartan (Tel) grafting glycolipid micelles (Tel-CSOSA) are constructed, which can sequentially target angiotensin II type I receptor (AT1R) overexpressed on both CAFs and tumor cells. More Tel-CSOSA are demonstrated to specifically accumulate in tumor site compared to CSOSA. In addition, the retention of Tel-CSOSA is primarily prolonged around tumor vessel in virtue of CAFs targeting and the stroma barrier. In contrast, the elimination of "finger-like" ECM resulting from CAFs apoptosis by Tel-CSOSA/DOX contributes to a more uniform and deeper penetration post-administration, which can enforce subsequently tumor cells targeting. Meanwhile, cytokines are decreased along with CAFs apoptosis so that tumor cells are more vulnerable to chemotherapeutics. Collectively, this strategy of sequentially targeting CAFs and tumor cells could synergistically increase antitumor therapy with reversed TMDR. PMID- 29421560 TI - Dual non-viral gene delivery from microparticles within 3D high-density stem cell constructs for enhanced bone tissue engineering. AB - High-density mesenchymal stem cell (MSC) aggregates can be guided to form bone like tissue via endochondral ossification in vitro when culture media is supplemented with proteins, such as growth factors (GFs), to first guide the formation of a cartilage template, followed by culture with hypertrophic factors. Recent reports have recapitulated these results through the controlled spatiotemporal delivery of chondrogenic transforming growth factor-beta1 (TGF beta1) and chondrogenic and osteogenic bone morphogenetic protein-2 (BMP-2) from microparticles embedded within human MSC aggregates to avoid diffusion limitations and the lengthy, costly in vitro culture necessary with repeat exogenous supplementation. However, since GFs have limited stability, localized gene delivery is a promising alternative to the use of proteins. Here, mineral coated hydroxyapatite microparticles (MCM) capable of localized delivery of Lipofectamine-plasmid DNA (pDNA) nanocomplexes encoding for TGF-beta1 (pTGF beta1) and BMP-2 (pBMP-2) were incorporated, alone or in combination, within MSC aggregates from three healthy porcine donors to induce sustained production of these transgenes. Three donor populations were investigated in this work due to the noted MSC donor-to-donor variability in differentiation capacity documented in the literature. Delivery of pBMP-2 within Donor 1 aggregates promoted chondrogenesis at week 2, followed by an enhanced osteogenic phenotype at week 4. Donor 2 and 3 aggregates did not promote robust glycosaminoglycan (GAG) production at week 2, but by week 4, Donor 2 aggregates with pTGF-beta1/pBMP-2 and Donor 3 aggregates with both unloaded MCM and pBMP-2 enhanced osteogenesis compared to controls. These results demonstrate the ability to promote osteogenesis in stem cell aggregates through controlled, non-viral gene delivery within the cell masses. These findings also indicate the need to screen donor MSC regenerative potential in response to gene transfer prior to clinical application. Taken together, this work demonstrates a promising gene therapy approach to control stem cell fate in biomimetic 3D condensations for treatment of bone defects. PMID- 29421562 TI - Exogenous ROS-induced cell sheet transfer based on hematoporphyrin-polyketone film via a one-step process. AB - To date, most of invasive cell sheet harvesting methods have used culture surface property variations, such as wettability, pH, electricity, and magnetism, to induce cell detachment. These methods that rely on surface property changes are effective when cell detachment prior to application is necessary, but of limited use when used for cell sheet transfer to target regions. The study reports a new reactive oxygen species (ROS)-induced strategy based on hematoporphyrin incorporated polyketone film (Hp-PK film) to transfer cell sheets directly to target areas without an intermediate harvesting process. After green LED (510 nm) irradiation, production of exogenous ROS from the Hp-PK films induces cell sheet detachment and transfer. The study suggests that ROS-induced cell detachment property of the Hp-PK film is closely related to conformational changes of extracellular matrix (ECM) proteins. Also, this strategy with the Hp-PK film can be applied by regulating production rate of exogenous ROS in various types of cells, including fibroblasts, mesenchymal stem cells and keratinocytes. In conclusion, ROS-induced method using the Hp-PK film can be used for one-step cell sheet transplantation and has potential in biomedical applications. PMID- 29421563 TI - Lipophilic indocarbocyanine conjugates for efficient incorporation of enzymes, antibodies and small molecules into biological membranes. AB - Decoration of cell membranes with biomolecules, targeting ligands and imaging agents is an emerging strategy to improve functionality of cell-based therapies. Compared to covalent chemistry or genetic expression on the cell surface, lipid painting (i.e., incorporation of lipid-conjugated molecules into the cell bilayer) is a fast, non-damaging and less expensive approach. Previous studies demonstrated excellent incorporation and retention of distearyl indocarbocyanine dye DiI in membranes of cells in vitro and in vivo. In order to exploit the membrane stability of DiI, we synthesized an amino-DiI derivative, to which we subsequently conjugated an antibody (cetuximab), an enzyme (superoxide dismutase), and a small molecule (DyLight 800). Red blood cells have long been used as drug delivery vehicles so they were utilized as a model to study the incorporation of DiI conjugates in the plasma membrane. All the DiI constructs demonstrated fast and efficient ex vivo incorporation in the membrane of mouse RBCs, resulting in millions of exogenous molecules per RBC. Following an intravenous injection into mice, the molecules were detected on circulating RBCs for several days. DiI anchored molecules showed longer residence time in blood and significantly higher area under the curve (AUC) compared to free non conjugated molecules. Thus, cetuximab, SOD and DyLight painted on RBC showed 5.5 fold, 6.5-fold and 78-fold increase in the AUC, respectively, compared to the non modified molecules. Lipophilic indocarbocyanine anchors are a promising technology for incorporation of biomolecules and small molecules into biological membranes for in vivo applications. PMID- 29421565 TI - A self-delivery membrane system for enhanced anti-tumor therapy. AB - Nowadays, cell membrane targeting therapy has drawn much attention for its high anti-tumor effect by avoiding the cellular barriers. In this study, therapeutic agent conjugated chimeric peptide (Cp) was anchored in cracked cancer cell membranes (CCCM) to construct a self-delivery membrane system (M-Cp), which could relize precise cell membrane targeting therapy. It was found that compared with Cp, M-Cp could target to the cancer cell membrane with longer retention time, which is very crucial for in vivo applications. And the superior cell membrane targeting ability was attributed to the specific proteins (focal adhesion proteins, focal adhesion kinase, RHO family proteins, and integrin) on the CCCM surface. Importantly, the M-Cp could promote tumor-specific immune response, which further enhanced anti-tumor effect when combined with therapeutic agents in M-Cp. What's more, this self-delivery membrane system could be used as a template for cell membrane targeting therapy by changing the therapeutic agents as well as the CCCM, and this strategy would open a new window for various cell membrane targeting therapy. PMID- 29421564 TI - High-density lipoprotein-mimicking nanodiscs carrying peptide for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia. AB - Therapeutic strategies using endogenous stem cell mobilizer can provide effective cell-free therapy for addressing various ischemic diseases. In particular, substance P (SP) exhibited therapeutic regeneration by facilitating mobilization of endogenous stem cells from bone marrow to the injured sites. However, its therapeutic effect has been limited due to short half-life and rapid degradation of administered SP peptides in vivo. Here we sought to develop high-density lipoprotein (HDL)-mimicking nanodiscs conjugated with SP (HDL-SP) in order to increase the in vivo half-life, bone marrow targeting, and therapeutic efficacy of SP for the treatment of diabetic peripheral ischemia. Conjugation of SP onto HDL nanodisc led to remarkable ~3215- and ~1060-fold increase in the ex vivo and in vivo half-lives of SP, respectively. Accordingly, HDL-SP nanodiscs improved retention of SP in bone marrow after systemic administration, leading to efficient mobilization of stem cells from bone marrow into blood circulation and reduction of systemic inflammation. Consequently, nanodisc based SP peptide delivery promoted blood vessel formation, blood perfusion recovery and markedly improved limb salvage in diabetic hindlimb ischemia model relative to administration of free SP without nanodisc modification. Therefore, HDL-SP nanodisc can provide a novel strategy for the treatment of diabetic ischemia and HDL nanodisc modification could be potentially useful for the extension of plasma circulation of other labile peptides. PMID- 29421566 TI - Protecting neurons from cerebral ischemia/reperfusion injury via nanoparticle mediated delivery of an siRNA to inhibit microglial neurotoxicity. AB - Complement component C3 (C3) plays a central role in microglial neurotoxicity following cerebral ischemia/reperfusion (I/R) injury. In this study, we focused on the role of nanoparticles loaded with C3 siRNA (NPsiC3) in inhibiting microglial neurotoxicity after brain (I/R) injury. NPsiC3 inhibited the hypoxia/re-oxygenation-induced increase in C3 expression in microglia in vitro. Importantly, treatment with NPsiC3 decreased C3b deposition on neurons and reduced microglia-mediated neuronal damage under hypoxia/re-oxygen conditions. Nanoparticles could effectively deliver C3-siRNA from the blood into ischemic penumbra across the blood-brain barrier (BBB) and significantly decrease C3 expression in microglia and ischemic brain tissue, while reducing the number of infiltrating inflammatory cells and the concentration of pro-inflammatory factors in the penumbra. Furthermore, NPsiC3 also prevented neuronal apoptosis, reduced the volume of the ischemic zone, and substantially improved functional recovery after I/R injury. Therefore, the NPsiC3-induced inhibition of microglial neurotoxicity represents a novel therapeutic strategy for treating brain I/R injury. PMID- 29421567 TI - Targeting polyamine transport in Trypanosoma cruzi. AB - Polyamines play critical roles as regulators of cell growth and differentiation. In contrast with other protozoa, the human parasite Trypanosoma cruzi, the etiological agent of Chagas disease, is auxotrophic for polyamines. Therefore, their intracellular availability depends exclusively on polyamine transport and inhibition of these uptake processes can alter the viability of the parasite. The polyamine analogues used in this work were successfully tested as antiproliferative agents in cancer cells, bacteria, fungi and also showed a potent antiplasmodial effect. We evaluated the activity of these compounds on polyamine transport in T. cruzi and assessed the effects on parasite viability. Three polyamine derivatives, AMXT1501, Ant4 and Ant44, inhibited the putrescine transport in epimastigotes (the insect stage of T. cruzi) with calculated IC50 values of 2.43, 5.02 and 3.98 MUM, respectively. In addition, only Ant4 and Ant44 inhibited spermidine transport with IC50 of 8.78 MUM and 13.34 MUM, respectively. The Ant4 analogue showed a high trypanocidal effect on trypomastigotes (the bloodstream stage of T. cruzi) with an IC50 of 460 nM, (SI = 12.7) while in epimastigotes the IC50 was significantly higher (16.97 MUM). In addition, we studied the effect of the combination of benznidazole, a drug used in treating Chagas disease, with Ant4 on the viability of epimastigotes. The combined treatment produced a significant increase on the inhibition of parasites growth compared with individual treatments. In summary, these results suggest that Ant4, a putrescine conjugate, is a promising compound for the treatment of Chagas disease because it showed a potent trypanocidal effect via its inhibition of polyamine import. PMID- 29421568 TI - Novel dissymmetric 3,5-bis(arylidene)-4-piperidones as potential antitumor agents with biological evaluation in vitro and in vivo. AB - Thirty-five novel dissymmetric 3,5-bis(arylidene)-4-piperidone derivatives (BAPs, 6a-h, 7a-h, 8a-g, 9a-g, 10a-e) were synthesized and evaluated the cytotoxicity. BAPs 6d, 7h, 8g, 9g demonstrated the most potentially inhibitory activities against HepG2 and THP-1 but lower cytotoxicity toward LO2. In vitro, 6d, 7h, 8g, 9g can effectively up-regulate BAX expression, down-regulate Bcl-2 expression in HepG2 cell. They could reasonably bind to the active site of Bcl-2 protein proved by molecular docking modes. The most active BAP 6d induced HepG2 cells apoptosis in a dose-dependent manner by flow cytometrey. The cellular uptake of HepG2 cells showed 6d mainly accumulated into the nuclei by confocal laser scanning microscopy (CLSM). In vivo, 6d suppressed the growth of HepG2 xenografts in nude mice and relatively nontoxic to mice. These results suggest that 6d could be therapeutically beneficial as potential therapeutic agent for the early clinical treatment of liver cancers. PMID- 29421569 TI - Design, synthesis and biological evaluation of hybrid nitroxide-based non steroidal anti-inflammatory drugs. AB - Dual-acting hybrid anti-oxidant/anti-inflammatory agents were developed employing the principle of pharmacophore hybridization. Hybrid agents were synthesized by combining stable anti-oxidant nitroxides with conventional non-steroidal anti inflammatory drugs (NSAIDs). Several of the hybrid nitroxide-NSAID conjugates displayed promising anti-oxidant and anti-inflammatory effects on two Non-Small Cell Lung Cancer (NSCLC) cells (A549 and NCI-H1299) and in ameliorating oxidative stress induced in 661 W retinal cells. One ester-linked nitroxide-aspirin analogue (27) delivered better anti-inflammatory effects (cyclooxygenase inhibition) than the parent compound (aspirin), and also showed similar reactive oxygen scavenging activity to the anti-oxidant, Tempol. In addition, a nitroxide linked to the anti-inflammatory drug indomethacin (39) significantly ameliorated the effects of oxidative stress on 661 W retinal neurons at efficacies greater or equal to the anti-oxidant Lutein. Other examples of the hybrid conjugates displayed promising anti-cancer activity, as demonstrated by their inhibitory effects on the proliferation of A549 NSCLC cells. PMID- 29421570 TI - Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates. AB - A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AbetaO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AbetaO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi target drug prototype candidate for AD treatment. PMID- 29421571 TI - Synthesis of novel Chlorin e6-curcumin conjugates as photosensitizers for photodynamic therapy against pancreatic carcinoma. AB - Curcumin (cur) has been comprehensively studied for its various biological properties, more precisely for its antitumor potential and it has shown the promising results as well. On the other hand, Chlorin e6 (Ce6) has mostly been used as a photosensitizer in photodynamic therapy (PDT) against a variety of carcinomas. In the present study, we have synthesized a series of Chlorin e6 curcumin (Ce6-cur) conjugates and investigated their photosensitizing potential against pancreatic cancer cell lines. All the synthesized compounds were characterized by UV, 1H NMR, 13C NMR and LC-MS. These Ce6-cur conjugates showed better physicochemical properties and higher singlet oxygen generation capability. The cellular uptake was studied in AsPC-1 cells using fluorescence activated cell sorting (FACS). Compound 17 was rapidly internalized within 30 min and sustained for 24 h. Compound 17 showed excellent PDT efficacy with IC50 of 40, 35 and 41 nM against AsPC-1, MIA PaCa-2 and PANC-1 respectively with exceptional dark/phototoxicity ratio in the range of 2371-7500. Moreover, the treatment of compound 17 upregulated the expression of BAX, Cytochrome-C and cleaved caspase 9 while downregulating the Bcl-2 expression an anti-apoptotic protein marker. These results demonstrate outstanding capability of compound 17 as a potent photosensitizer which could improve the PDT efficacy in pancreatic cancer patients. PMID- 29421572 TI - Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents. AB - A series of 1,4-substituted arylalkyl piperazine derivatives were synthesized and studied with the aim to obtain potent P-gp-dependent multidrug-resistant (MDR) reversers. The new compounds were designed on the basis of the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity. All new compounds were active in the pirarubicin uptake assay on the doxorubicin-resistant erythroleukemia K562 cells (K562/DOX). In particular, compounds bearing methoxy aromatic moieties showed fairly high reversal activities. The most potent compounds, 8, 9, 10 and 13, were further studied by evaluating their doxorubicin cytotoxicity enhancement (reversal fold, RF) and the inhibition of P-gp-mediated rhodamine-123 (Rhd 123) efflux on the K562/DOX cell line. The results of all pharmacological assays indicated that the combination of a basic piperazine scaffold with arylalkyl residues allowed us to obtain very interesting P-gp modulating compounds. Two long-lasting P-gp pump modulators (9 and 10) were identified; they were able to inhibit remarkably the P gp substrate rhodamine-123 efflux on the resistant K562/DOX cell line after 60 min. Overall compound 9 appeared the most promising compound being a potent and long-lasting P-gp-dependent MDR modulator. PMID- 29421573 TI - 6,7-Dimorpholinoalkoxy quinazoline derivatives as potent EGFR inhibitors with enhanced antiproliferative activities against tumor cells. AB - A series of novel 6,7-dimorpholinoalkoxy quinazoline derivatives was designed, synthesized and evaluated as potent EGFR inhibitors. Most of synthesized derivatives exhibited moderate to excellent antiproliferative activities against five human tumor cell lines. Compound 8d displayed the most remarkable inhibitory activities against tumor cells expressing wild type (A431, A549 and SW480 cells) or mutant (HCC827 and NCI-H1975 cells) epidermal growth factor receptor (EGFR) (with IC50 values in the range of 0.37-4.87 MUM), as well as more potent inhibitory effects against recombinant EGFR tyrosine kinase (EGFR-TK, wt or T790M) (with the IC50 values of 7.0 and 9.3 nM, respectively). Molecular docking showed that 8d can form four hydrogen bonds with EGFR, and two of them were located in the Asp855-Phe856-Gly857 (DFG) motif of EGFR. Meanwhile, 8d can significantly block EGF-induced EGFR activation and the phosphorylation of its downstream proteins such as Akt and Erk1/2 in human NSCLC cells. Also, 8d mediated cell apoptosis and the prolongation of cell cycle progression in G0/G1 phase in A549 cells. The work would have remarkable implications for further design and development of more potent EGFR tyrosine kinase inhibitors (TKIs). PMID- 29421574 TI - Erratum. PMID- 29421575 TI - Targeting cancer stem cells in the clinic: Current status and perspectives. AB - Resistance to chemotherapy and cancer relapse are major clinical challenges attributed to a sub population of cancer stem cells (CSCs). The concept of CSCs has been the subject of intense research by the oncology community since evidence for their existence was first published over twenty years ago. Emerging data indicates that they are also able to evade novel therapies such as targeted agents, immunotherapies and anti-angiogenics. The inability to appropriately identify and isolate CSCs is a major hindrance to the field and novel technologies are now being utilized. Agents that target CSC-associated cell surface receptors and signaling pathways have generated promising pre-clinical results and are now entering clinical trial. Here we discuss and evaluate current therapeutic strategies to target CSCs. PMID- 29421576 TI - MiR-93-5p targeting PTEN regulates the NMDA-induced autophagy of retinal ganglion cells via AKT/mTOR pathway in glaucoma. AB - BACKGROUND: Glaucoma is hallmarked with the death of retinal neurons in the ganglion cell layer, which results in irreversible vision loss. The abnormal levels of miRNA have been associated with glaucoma. Our study purposed to explore the underlying molecule mechanism of miR-93-5p in NMDA-induced glaucoma. METHODS: The Sprague-Dawley (SD) rats were used for the establishment of glaucoma model with the injection of NMDA. Vision behavior test were performed on the glaucoma rats. MiR-93-5p expression was determined by real-time PCR. The levels of autophagy-related protein and PTEN were assessed by Western blot assays. TUNEL assay and flow cytometry were performed to analyze cell apoptosis in vivo and in vitro, respectively. And cell viability was examined by CKK-8 assay. The relationship between miR-93-5p and PTEN was confirmed by Dual-Luciferase reporter gene system. RESULTS: NMDA-induced glaucoma rats exhibited less time in the dark box, suggesting the recession of their vision. Moreover, the retinal ganglion cell (RGC) viability was reduced not only in the glaucoma rat models but also in the glaucoma RGC models. The autophagy-related protein was obviously increased in the NMDA-treated rats or RGCs. PTEN regulated the autophagy of RGCs through AKT/mTOR pathway in NMDA-treated RGCs. MiR-93-5p could target regulate PTEN negatively, and exhibit the similar effect of 3-MA on the survival of RGCs. CONCLUSION: Up-regulation of miR-93-5p binding with PTEN suppressed the autophagy of RGCs through AKT/mTOR pathway in NMDA-induced glaucoma. PMID- 29421577 TI - MicroRNA-204 protects H9C2 cells against hypoxia/reoxygenation-induced injury through regulating SIRT1-mediated autophagy. AB - Ischemia/reperfusion (I/R) injury is a main cause of acute myocardial infarction, and the pathogenesis of I/R injury is still not definitely confirmed. In the present study, we aimed to explore the roles of miR-204 in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury in vitro. The H9C2 cells were subjected to hypoxia for 12 h followed by reoxygenation for another 24 h, and we found that miR-204 was significantly down-regulated after H/R treatment. Transfection of miR 204 mimics attenuated the H/R-induced impaired cell viability and increased apoptosis rates. Furthermore, SIRT1 was identified as a direct target of miR-204, and its expression is negatively regulated by miR-204. Forced expression of SIRT1 could partly rescue the effects of miR-204 on H/R-induced apoptosis and autophagy. Taken together, our study first revealed that overexpression of miR 204 has a protective effect against myocardial I/R injury. PMID- 29421578 TI - Long non-coding RNA ENST01108 promotes carcinogenesis of glioma by acting as a molecular sponge to modulate miR-489. AB - Gliomas are the most common primary malignant tumor in the adult central nervous system with poor prognosis. Exploring novel biomarkers and elucidating underlying molecular mechanisms to provide effective therapeutic methods is in an urgent need. Long noncoding RNAs (lncRNAs) is involved in various human diseases including cancer. However, studies on lncRNAs and gliomas are limited. In this study, we explored the expression patterns of lncRNAs in 4 pairs of glioma samples and adjacent normal tissues via microarray and chose the most up regulated lncRNA ENST01108 (ENST01108) to further verify its oncogenic role in glioma. Clinical data suggest that ENST01108 is closely associated with the malignant status in glioma. In vitro experiment demonstrated that overexpression of ENST01108 promoted glioma cell proliferation, migration, invasion, EMT process and survival, while knockdown of ENST01108 has an opposite effect, indicating that ENST01108 serves as an oncogenic property in glioma carcinogenesis. Further, we identified miR-489 as a direct target of ENST01108 and ENST01108 negatively regulate miR-489 by act as a sponge. SIK1 is verified as the direct target of miR 489 and it is negatively regulated by miR-489. ENST01108 also positively regulate SIKI and it promotes SIKI expression by suppressing miR-489. Taken together, the reciprocal repression of ENST011081 and miR-489 may be served as potential targets for cancer therapeutics in glioma. PMID- 29421579 TI - Polyphenol-enriched extract of Rosa rugosa Thunb regulates lipid metabolism in diabetic rats by activation of AMPK pathway. AB - This study was designed to investigate the mechanism of polyphenol-enriched extract of Rosa rugosa Thunb (RPE) in the control of dyslipidemia in diabetic rats. RPE was tested at three dosages (37.5 mg/kg, 75 mg/kg and 150 mg/kg) in the rat dyslipidemia model established with high fat diet feeding in combination with STZ injection (30 mg/kg). The RPE effect was evaluated after 4 weeks of treatment. In the RPE-treated rats, hepatic total cholesterol (TC) and triglyceride (TG) were significantly reduced, lipoprotein lipase (LPL) and liver lipase (HL) were significantly increased. The levels of alanine transaminase (ALT) and aspartate transaminase (AST) were decreased in the serum. Those effects of RPE were observed primarily at the mediate and high dosages. Expression of FGF21 was increased in the liver tissue and hepatic cell line 1c1c7 by RPE. The signals of p-AMPK, p-ACC, ACC, p-SIRT, and PGC-1alpha were significantly induced in the liver by RPE. The results suggest that RPE may improve hepatic steatosis and liver function by induction of AMPK signaling activity in the control of dyslipidemia. PMID- 29421580 TI - Ghrelin attenuates ultraviolet B radiation-induced impairment in capacities of epidermal stem cells. AB - Persistent exposure to solar ultraviolet radiation (UVR) causes continuous damages to skin, including progressive impairment of epidermal stem cells (ESCs) capacities. Ghrelin is the only known endogenous orexigenic hormone, which has displayed its various pharmacological functions. In the current study, we found that the specific receptor of ghrelin, growth hormone secretagogue receptor (GHS R), is expressed in ESCs. Interestingly, GHS-R expression is significantly upregulated in response to ultraviolet B (UVB) radiation. We also found that ghrelin treatment prevented UVB radiation-induced reduction in cell viability and the release of lactate dehydrogenase (LDH). Additionally, ghrelin reduced UVB radiation-induced generation of reactive oxygen species (ROS) and restored the intracellular level of reduced glutathione (GSH). UVB radiation significantly suppressed the expressions of integrin beta1 and Krt19, the two major ESC markers, which were restored by ghrelin. Notably, knockdown of GHS-R abolished the effects of ghrelin on the expressions of integrin beta1 and Krt19, suggesting the involvement of GHS-R. Also, we found that ghrelin treatment inhibited UVB radiation- induced reduction of Wnt1, Wnt3a, Myc, and cyclin D1 at both the mRNA levels and the protein levels. Taken together, our findings identify a novel function of ghrelin on maintaining the capacities of ESCs against UVB radiation. PMID- 29421581 TI - Therapeutic efficacy of osthole against dinitrobenzene sulphonic acid induced colitis in rats. AB - Several mediators were associated with the pathogenesis of inflammatory bowel disease such as oxidative stress through the production of reactive oxygen metabolites, neutrophils infiltration and release of pro-inflammatory cytokines. This study was designed to investigate the therapeutic efficacy of osthole against dinitrobenzene sulfonic acid (DNBS) induced-colitis in rats through its anti-oxidant and anti-inflammatory properties. Colitis was induced in rats by single intracolonic instillation of (250 MUl DNBS-25 mg/rat). Then 4 days later, rats were received oral administration of either (osthole 50 mg/kg), (sulfasalazine 500 mg/kg) or both in combination for 7 consecutive days. Body weight, some hematological parameters, colonic malondialdehyde (MDA) and myeloperoxidase activity (MPO), antioxidant parameters, colon injury and mucosa architectures were assessed. T helper (Th1)-related cytokines [Tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (INF-gamma)], Th2-relarted cytokines (interleukin-4 [IL-4 and IL-10], and Th-17 related cytokines [IL-17] were determined by ELISA. Osthole significantly improved the loss in body weight. That was accompanied with a remarkable amelioration of the disruption of the colonic architecture as well as a significant improvement in the antioxidant defense system. A reduction in MPO and MDA was observed in flamed colon. Treatment with either osthole or combination therapy showed suppressive activities on pro-inflammatory Th2-related cytokines and upregulation of anti inflammatory Th2-related cytokines The results of this study suggest that osthole exert beneficial therapeutic effect in experimental colitis and improved the efficacy of the synthetized drugs such as sulfasalazine. Therefore, osthole may have a valuable sound in the treatment of inflammatory bowel disease. PMID- 29421582 TI - Ginseng phytochemicals as therapeutics in oncology: Recent perspectives. AB - During the last few decades, cancer has mushroomed as a major health issue; and almost all drugs used for its therapy are very toxic with lethal side effects. Complementary and alternative medicines gain popularity among health professionals in recent era owing to its preventive mechanism against side effect chemotherapeutic drugs. Efforts are focused by scientists to isolate compounds from medicinal plant that have chemotherapeutic attributes; and ability to neutralize the side effects of chemotherapy. Ginseng is an oriental medicinal recipe from Araliceae family and Panax species. The chemotherapeutic effect of ginsenoside is resultant of its appetites, anti-proliferative, anti-angiogenic, anti-inflammatory and anti-oxidant properties. The anticancer effect of ginseng is proven in various types of cancer, including; breast, lung, liver, colon and skin cancer. It increases the mitochondrial accumulation of apoptosis protein and downregulate the expression of anti-apoptotic protein. It also aids in the reduction of alopecia, fatigue and nausea, the known side effects of chemotherapeutic drugs. The aim of the present review is to provide the brief review of the recent researches related to mechanism of action of ginseng in different types of cancer as complementary and alternative medicine on different body organs. PMID- 29421583 TI - Icariside II attenuates myocardial fibrosis by inhibiting nuclear factor-kappaB and the TGF-beta1/Smad2 signalling pathway in spontaneously hypertensive rats. AB - Studies have demonstrated that icariin plays important roles in preventing hypertension and improving myocardial hypertrophy, inflammatory and infiltration. Icariside (ICS II) is the main metabolite of icariin, which has anti-inflammatory and anti-oxidant activities and protects against ischaemic brain injury. Whether ICS II improves myocardial fibrosis in spontaneously hypertensive rats (SHRs) and the related mechanism remain unknown. Some studies have suggested that TGF-beta and the nuclear factor kappaB signalling pathway play a key role in the progression of myocardial fibrosis. Therefore, in the current study, we aimed to evaluate the effects of ICS II on induced myocardial fibrosis in SHRs and explore the mechanism underlying this activity. The SHRs were treated with ICS II (4, 8, and 16 mg/kg) via daily gavage for 12 weeks. Left ventricular function was detected using the Vevo2100 system, and the collagen area was measured by Masson staining. The results indicated that ICS II markedly improved left ventricular function and decreased the left ventricular myocardial collagen area compared with the SHR group. To further investigate the mechanism underlying this activity, we measured the protein expression of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta1 (TGF beta1), Smad2, inhibitory kappaB (IkappaB), and nuclear factor kappaB (NF-kappaB) p65 by Western blot. The results showed that ICS II inhibited NF-kappaB p65 expression and the TGF-beta1/Smad2 signalling pathways. In conclusion, the present results suggest that ICS II suppresses myocardial fibrosis in SHRs, and this effect might be at least partially mediated through suppression of NF-kB signalling and the TGF-beta1/Smad2 signalling pathway. PMID- 29421584 TI - Effective long-term solution to therapeutic remission in Inflammatory Bowel Disease: Role of Azathioprine. AB - Azathioprine (AZA) is a well-known immunosuppressant used for many years for its ability to ensure long term disease remission in inflammatory bowel diseases (IBD) at an affordable cost to the public. However, the side effect profile has raised many concerns with numerous investigations into the risk, cause and prevention of these effects. Much of the side effect profile of AZA can be linked to a single nucleotide polymorphism (SNP) in the thiopurine methyltransferase (TPMT) gene which ensures the breakdown and efficacy of AZA. Mutated TPMT alleles result in low or deficient TPMT levels which directly correlate to cytotoxity. This is a review of the role of AZA in the treatment of IBD. Knowing a patient's TPMT status allows the prescribing doctor to make an informed decision about dosage and be more alert to the signs of cytotoxicity. It is essential to include "early warning" SNP testing into common practice to ensure therapeutic efficacy. PMID- 29421585 TI - Immune function against bacteria of chitin deacetylase 1 (EcCDA1) from Exopalaemon carinicauda. AB - Chitin deacetylase (CDA, EC 3.5.1.41), belonging to a family of extracellular chitin-modifying enzymes, can catalyze the deacetylation of chitin. In this study, the full-length cDNA sequence encoding chitin deacetylase 1 (EcCDA1) was obtained fromExopalaemon carinicauda. The complete nucleotide sequence of EcCDA1 contained a 1611 bp open reading frame (ORF) encoding EcCDA1 precursor of 536 amino acids. The domain architecture of the deduced EcCDA1 protein contained a signal peptide, a chitin-binding peritrophin-A domain (ChtBD2), a low-density lipoprotein receptor class A domain (LDLa) and a Polysacc_deac_1 domain. EcCDA1 mRNA was predominantly expressed in the gills. The expression of EcCDA1 in the prawns challenged with Vibrio parahaemolyticus and Aeromonas hydrophila changed in a time-dependent manner. The expression of EcCDA1 in the prawns challenged with V. parahaemolyticus was up-regulated at 12 h (p < 0.05), and significantly up-regulated at 24 h and 48 h (p < 0.01), and then returned to the control levels at 96 h post-challenge (p > 0.05). At the same time, the expression in Aeromonas challenged group was significantly up-regulated at 12, 24 and 48 h (p < 0.01) and returned to the control levels at 120 h post-challenge (p > 0.05). Then, EcCDA1 was recombinantly expressed in Pichia pastoris and the purified recombinant EcCDA1 could not inhibit the growth of V. parahaemolyticus or A. hydrophila, which indicated that the CDA1 may play its biological activity in immune defense by deacetylation from chitin. PMID- 29421586 TI - Immunological response of the Sub-Antarctic Notothenioid fish Eleginops maclovinus injected with two strains of Piscirickettsia salmonis. AB - Eleginops maclovinus is an endemic fish to Chile that lives in proximity to salmonid culture centers, feeding off of uneaten pellet and salmonid feces. Occurring in the natural environment, this interaction between native and farmed fish could result in the horizontal transmission of pathogens affecting the aquaculture industry. The aim of this study was to evaluate the innate and adaptive immune responses of E. maclovinus challenged with P. salmonis. Treatment injections (in duplicate) were as follows: control (100 MUL of culture medium), wild type LF-89 strain (100 MUL, 1 * 108 live bacteria), and antibiotic resistant strain Austral-005 (100 MUL, 1 * 108 live bacteria). The fish were sampled at various time-points during the 35-day experimental period. The gene expression of TLRs (1, 5, and 8), NLRCs (3 and 5), C3, IL-1beta, MHCII, and IgMs were significantly modulated during the experimental period in both the spleen and gut (excepting TLR1 and TLR8 spleen expressions), with tissue-specific expression profiles and punctual differences between the injected strains. Anti-P. salmonis antibodies increased in E. maclovinus serum from day 14-28 for the LF-89 strain and from day 14-35 for the Austral-005 strain. These results suggest temporal activation of the innate and adaptive immune responses in E. maclovinus tissues when injected by distinct P. salmonis strains. The Austral-005 strain did not always cause the greatest increases/decreases in the number of transcripts, so the magnitude of the observed immune response (mRNA) may not be related to antibiotic resistance. This is the first immunological study to relate a pathogen widely studied in salmonids with a native fish. PMID- 29421587 TI - Mucus glycosylation, immunity and bacterial microbiota associated to the skin of experimentally ulcered gilthead seabream (Sparus aurata). AB - Interest in fish skin immunity and its associated microbiota has greatly increased among immunologists. The objective of this study is to know if skin ulcers may be associated with changes in the mucus composition and microbial diversity. The abundance of terminal carbohydrates, several enzymes (protease, antiprotease, peroxidase, lysozyme) and total immunoglobulin M levels were evaluated in skin mucus of experimentally ulcered gilthead seabream (Sparus aurata L.). Furthermore, the composition of the microbiota of ulcered and non ulcered skin has been determined using Illumina Miseq technology. Significant decreases of terminal abundance of alpha-D-mannose, alpha-D-glucose and N-acetyl galactosamine in skin mucus of ulcered fish, compared to control fish were detected. The levels of IgM and all the tested enzymes in mucus were decreased in ulcered fish (compared to control fish) although the observed decreases were only statistically significant for proteases and antiproteases. Concomitantly, the analysis of the composition of the skin microbiota showed clear differences between ulcered and non-ulcered areas. The genus taxonomic analysis showed that Staphylococcus and Lactobacillus were more abundant in non-ulcered skin whereas in ulcered area were Streptococcus and Granulicatella. Important decreases of the number of sequences related to Alteromonas, Thalassabius and Winogradskyella were detected in ulcered skin whilst slight increases of sequences related to Flavobacterium, Chryseobacterium and Tenacibaculum genera were observed. Overall these results demonstrated that the presence of skin ulcers provide microenvironments that perturb both the mucus composition and microbial biodiversity of this important external surface which seem to be more vulnerable to diseases. PMID- 29421589 TI - A modified ketogenic gluten-free diet with MCT improves behavior in children with autism spectrum disorder. PMID- 29421588 TI - Homeostatic and non-homeostatic controls of feeding behavior: Distinct vs. common neural systems. AB - Understanding the neurobiological controls of feeding behavior is critical in light of the growing obesity pandemic, a phenomenon largely based on excessive caloric consumption. Feeding behavior and its underlying biological substrates are frequently divided in the literature into two separate categories: [1] homeostatic processes involving energy intake based on caloric and other metabolic deficits, and [2] non-homeostatic processes that involve feeding driven by environmental and cognitive factors. The present review summarizes both historic and recent research examining the homeostatic regulation of feeding with specific emphasis on hypothalamic and hindbrain circuitry that monitor and regulate various metabolic signals. Regarding non-homeostatic controls, we highlight higher-order brain structures that integrate feeding-relevant external, interoceptive, and cognitive factors, including sensory cortical processing, learned associations in the hippocampus, and reward-based processing in the nucleus accumbens and interconnected mesolimbic circuitry. Finally, the current review focuses on recent evidence that challenges the traditional view that distinct neural systems regulate homeostatic vs. non-homeostatic controls of feeding behavior. Specifically, we highlight several feeding-related endocrine systems that act on both lower- and higher-order substrates, present evidence for the modulation of learned and cognitive feeding-relevant behaviors by lower-order brain regions, and highlight data showing that apparent homeostatic-based feeding behavior is modulated by higher-order brain regions. Our concluding perspective is that the classic dissociation between homeostatic and non-homeostatic constructs in relation to feeding behavior is limited with regards to understanding the complex integrated neurobiological systems that control energy balance. PMID- 29421590 TI - Snacking: A cause for concern. AB - Snacking, like any dietary behavior, can be practiced in a manner that is healthful or not. The case presented in this critical review of the literature is that snacking is problematic, primarily due to its contribution to positive energy balance and promotion of overweight/obesity. There is strong evidence that snacking is associated with greater energy intake. How this translates to body weight is less clear, largely due to limitations of experimental measurement tools and research designs. Correction for these shortcomings reveals evidence implicating snacking in the high prevalence of overweight/obesity supported by multiple plausible mechanisms. Given the popularity of snacking and its potential to positively contribute to diet quality, it is recommended that efforts be made to better understand and harness snacking to a better purpose. PMID- 29421591 TI - Voluntary exercise increases resilience to social defeat stress in Syrian hamsters. AB - Exposure to social stressors can cause profound changes in an individual's well being and can be an underlying factor in the etiology of a variety of psychopathologies, such as post-traumatic stress disorder (PTSD). In Syrian hamsters, a single social defeat experience results in behavioral changes collectively known as conditioned defeat (CD), and includes an abolishment of territorial aggression and the emergence of high levels of defensive behaviors. In contrast, voluntary exercise has been shown to promote stress resilience and can also have anxiolytic-like effects. Although several studies have investigated the resilience-inducing effects of voluntary exercise after exposure to physical stressors, such as restraint and electric shock, few studies have examined whether exercise can impart resilience in response to ethologically-based stressors, such as social defeat. In Experiment 1, we tested the hypothesis that voluntary exercise can have anxiolytic-like effects in socially defeated hamsters. In the elevated plus maze, the exercise group exhibited a significant reduction in risk assessment, a commonly used index of anxiety, compared to the no-exercise group. In the open-field test, animals in the exercise group exhibited a significant reduction in locomotor behavior and rearing, also an indication of an anxiolytic-like effect of exercise. In Experiment 2, we examined whether exercise can reverse the defeat-induced potentiation of defensive behaviors using the CD model. Socially defeated hamsters in the exercise group exhibited significantly lower levels of defensive/submissive behaviors compared to the no-exercise group upon exposure to the resident aggressor. Taken together, these results are among the first to suggest that voluntary exercise may promote resilience to social defeat stress in Syrian hamsters. PMID- 29421592 TI - Anti-nociceptive effect of methanol extract of leaves of Senna singueana in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Senna singueana (Del.) Lock (Fabaceae) is a shrub or tree found in Ethiopia and other African countries. It has been traditionally used for different conditions including treatment of pain conditions in humans and animals. Although various reports are available in the literature claiming different activities of the plant, scientific studies supporting analgesic potential of S. singueana are lacking and the present study aimed to investigate the antinociceptive effect of methanol extract of leaves of S. singueana in mice. MATERIALS AND METHODS: Anti-nociceptive activity of S. singueana (200 mg/kg and 400 mg/kg, p.o) was investigated using acetic acid-induced writhing, formalin induced paw licking, and hot plate tests. Acute oral toxicity was determined using a slightly modified guideline (423) of the Organization for Economic Cooperation and Development. RESULTS: S. singueana extract increased the percentage of inhibition of writhing response and licking response (neurogenic and inflammatory phase) in acetic acid-induced writhing and formalin-induced paw licking tests, respectively. It also significantly (p <= 0.05) increased the percentage of mean maximal effect (%MPE) compared to control group in the hot plate test. In all models, the combination of S. singueana with either diclofenac or morphine produced statistically significant increase (p <= 0.05) in the percentage of inhibition of writhing, paw licking, and %MPE compared to single treatment groups. It was also found that the 400 mg/kg extract produced higher antinociceptive effects (p <= 0.05) compared to the 200 mg/kg. CONCLUSION: S. singueana leaves may have analgesic effect that is mediated through both peripheral and central mechanisms and could be used as adjuvant treatment to the modern analgesics. PMID- 29421593 TI - Protective effects of a traditional Chinese herbal formula Jiang-Xian HuGan on Concanavalin A-induced mouse hepatitis via NF-kappaB and Nrf2 signaling pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jiang-Xian HuGan (JXHG) formulated by five natural products including Freshwater clam (Corbicula fluminea), Curcuma longa L., Ligustrum lucidum, Eclipta prostrata (L.) L. and Paeonia lactiflora Pall., has exhibited a great hepatoprotective effect. AIM OF THIS STUDY: We investigated the effect of JXHG on concanavalin A (ConA)-induced acute live injury in mice, and to elucidate its underlying molecular mechanisms. MATERIALS AND METHODS: Jiangkanling Capsule (900 mg/kg), low-dose JXHG (LJXHG, 700 mg/kg), high-dose JXHG (HJXHG, 1400 mg/kg) were administered to mice by oral gavage daily for 20 days prior to a single intravenous injection of ConA (20 mg/kg). Liver injury was evaluated by measuring the serum levels of enzymes and cytokines as well as liver histological analysis. We also measured the hepatic expression of cytokines at mRNA levels and the proteins related to NF-kappaB and Nuclear factor (erythroid derived 2)-like 2 (Nrf2) signaling pathways. RESULT: Our results showed that JXHG pretreatment significantly alleviated ConA-induced live injury as evidenced by decreased serum levels of glutamic-pyruvic transaminase (ALT) and glutamic oxalacetic transaminase (AST), and reduced hepatocyte apoptosis and mortality. Furthermore, JXHG was able to significantly reduce the serum levels of proinflammatory cytokines, down-regulate the mRNA expression of interleukin-6 (IL 6) and interferon-gamma (IFN-gamma), and up-regulate IL-10 as well as superoxide dimutase-1 (SOD1), glutathione reductase (GSR) and Glutathione peroxidase 2 (GPX2) mRNA in the liver tissues after Con A injection. In addition, JXHG pretreatment dramatically suppressed the phosphorylation of NF-kappaB p65 (p65), increased Nrf2 expression, and decreased the expression ratio of cleaved caspase 3/caspase-3 in liver tissues. CONCLUSION: These results suggest that JXHG protects against ConA-induced acute live injury through inhibiting NF-kappaB mediated inflammatory pathway and promoting Nrf2 mediated anti-oxidative stress signaling pathway. PMID- 29421594 TI - DNA damaging potential of Ganoderma lucidum extracts. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (Lingzhi or Reishi) is a medicinal mushroom historically used in Asian countries to treat a wide variety of diseases and prolong life. In the last years, G. lucidum has been internationally recognized as an effective adjuvant in cancer treatment. Among active components, the most recent research indicates that polysaccharides modulate the immune response favoring the recovery from toxicity of chemo and radiotherapy while triterpenes are cytotoxic to tumoral cells mainly by altering gene expression. Beyond this body of evidence on the efficacy of G. lucidum in cancer treatment, it is not yet understood whether these extracts exert the same mechanisms of action than current antitumoral drugs. AIM OF THE STUDY: In this study, we tested the DNA damaging potential of G. lucidum extracts by the beta galactosidase biochemical prophage induction assay (BIA) using doxorubicin, a DNA intercalating agent, as a positive control. This assay was traditionally used to screen microbial metabolites towards antitumoral agents. Here, we used this bacterial assay for the first time to assess DNA damage of herbal drugs. RESULTS: After a bioguided assay, only a purified fraction of G. lucidum containing a mixture of C16 and C18:1 fatty acids exerted weak activity which could not be attributed to direct interaction with DNA. At the same concentrations, the induction observed for doxorubicin was clearly contrasting. CONCLUSIONS: The micro BIA assay could be successfully used to demonstrate differences in cellular effects between G. lucidum extracts and doxorubicin. These results showed that G. lucidum extracts display weak DNA damaging potential. Since DNA injury promotes aging and cancer, our results substantiate the traditional use of this mushroom to prolong life. PMID- 29421596 TI - Initial Medical Treatment of Acute Pancreatitis: American Gastroenterological Association Institute Technical Review. PMID- 29421595 TI - Improvement of Cisplatin-induced renal dysfunction by Schisandra chinensis stems via anti-inflammation and anti-apoptosis effects. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis (Turcz.) Baill is a frequently used traditional Chinese medicine, and modern pharmacological research has proven that S. chinensis has antioxidant, anti-hepatotoxity, anti inflammatory, and anti-nephrotoxic effects. Cisplatin is widely used as antineoplastic drug at present, but the clinical application is limited owing to its nephrotoxicity. AIM OF THE STUDY: To demonstrate the renoprotective activity of the extract of the stems of S. chinensis (SCE) in mice established by cisplatin-triggering acute kidney injury (AKI). The possible molecular mechanism of nephroprotection exhibited by SCE was evaluated for the first time. MATERIALS AND METHODS: Mice in SCE groups were pre-treated with SCE for 10 consecutive days, and on 7th day 1 h after final administration, following intraperitoneal injection of cisplatin with 20 mg/kg was treated to cisplatin group and SCE groups. On the 10th day, renal function, histopathological change, and oxidative stress markers were investigated. RESULTS: Renal oxidative stress level characterized by elevated heme oxygenase 1 (HO-1), cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) expression was obviously reduced by SCE pre treatment. In addition, SCE was found to suppress inflammatory response through the reduction of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-kappaB) p65 activation. SCE treatment also inhibited activation of apoptotic pathways through down-regulating Bax, cleaved caspase-3, 8, 9 and up-regulating Bcl-2 expression levels. CONCLUSION: These findings illustrated that SCE possessed powerful protective effect on AKI caused by cisplatin via amelioration of oxidative stress, inflammation and apoptosis. PMID- 29421601 TI - Novel contiguous gene deletion in peruvian girl with Trichothiodystrophy type 4 and glutaric aciduria type 3. AB - Trichothiodystrophy type 4 is a rare autosomal recessive and ectodermal disorder, characterized by dry, brittle, sparse and sulfur-deficient hair and other features like intellectual disability, ichthyotic skin and short stature, caused by a homozygous mutation in MPLKIP gene. Glutaric aciduria type 3 is caused by a homozygous mutation in SUGCT gene with no distinctive phenotype. Both genes are localized on chromosome 7 (7p14). We report an 8-year-old female with short stature, microcephaly, development delay, intellectual disability and hair characterized for dark, short, coarse, sparse and brittle associated to classical trichorrhexis microscopy pattern. Chromosome microarray analysis showed a 125 kb homozygous pathogenic deletion, which includes genes MPLKIP and SUGCT, not described before. This is the first case described in Peru of a novel contiguous gene deletion of Trichothiodystrophy type 4 and Glutaric aciduria type 3 performed by chromosome microarray analysis, highlighting the contribution and importance of molecular technologies on diagnosis of rare genetic conditions. PMID- 29421602 TI - Report of two unrelated families with Jalili syndrome and a novel nonsense heterozygous mutation in CNNM4 gene. AB - Jalili syndrome (JS) is an autosomal recessive disease characterized by a combination of cone-rode retinal dytrophy (CRD) and amelogenesis imperfect (AI). Mutations in cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) gene cause JS. Here we described 2 families (3 members) affected by JS. In the first family, JS was caused by the homozygous p.Leu324Pro (c.971T > C) missense mutation and the affected patient developed both CRD and AI. In the second family, a specific combination of a compound heterozygous mutation was found - the p.Leu324Pro (c.971T > C) missense transition and the novel p.Tyr581* (c.1743C > G) nonsense mutation. The proband showed CRD and AI, but her father just developed eye alterations. Together, these findings suggest that the p.Leu324Pro mutation in homozygosis induces a complete phenotype with both CRD and AI, but in heterozygosis and in composition with the novel p.Tyr581* nonsense mutation in CNNM4 promotes variable clinical expressivity, particularly with lack of dental phenotypes. These different phenotypes could be explained by deletions affecting the proband's homologous allele, epistasia or interactions with environmental factors leading to residual activity of protein. PMID- 29421603 TI - Associations of neighborhood-level racial residential segregation with adverse pregnancy outcomes. AB - BACKGROUND: Previous analyses utilizing birth certificate data have shown environmental factors such as racial residential segregation may contribute to disparities in adverse pregnancy outcomes. However, birth certificate data are ill equipped to reliably differentiate among small for gestational age, spontaneous preterm birth, and medically indicated preterm birth. OBJECTIVE: We sought to utilize data from electronic medical records to determine whether residential segregation among Black women is associated with an increased risk of adverse pregnancy outcomes. STUDY DESIGN: The study population was composed of 4770 non-Hispanic Black women who delivered during the years 2009 through 2013 at a single urban medical center. Addresses were geocoded at the level of census tract, and this tract was used to determine the degree of residential segregation for an individual's neighborhood. Residential segregation was measured using the Gi* statistic, a z-score that measures the extent to which the neighborhood racial composition deviates from the composition of the larger surrounding area. The Gi* statistic z-scores were categorized as follows: low (z < 0), medium (z = 0-1.96), and high (z > 1.96). Adverse pregnancy outcomes included overall preterm birth, spontaneous preterm birth, medically indicated preterm birth, and small for gestational age. Hierarchical logistic regression models accounting for clustering by census tract and repeated births among mothers were used to estimate odds ratios of adverse pregnancy outcomes associated with segregation. RESULTS: In high segregation areas, the prevalence of overall preterm birth was significantly higher than that in low segregation areas (15.5% vs 10.7%, respectively; P < .001). Likewise, the prevalence of spontaneous preterm birth and medically indicated preterm birth were higher in high (9.5% and 6.0%) vs low (6.2% and 4.6%) segregation neighborhoods (P < .001 and P = .046, respectively). The associations of high segregation with overall preterm birth (odds ratio, 1.31; 95% confidence interval, 1.02-1.69) and spontaneous preterm birth (odds ratio, 1.37; 95% confidence interval, 1.02-1.85) remained significant with adjustment for neighborhood poverty, insurance status, parity, and maternal medical conditions. CONCLUSION: Among non-Hispanic Black women in an urban area, high levels of segregation were independently associated with the higher odds of spontaneous preterm birth. These findings highlight one aspect of social determinants (ie, segregation) through which adverse pregnancy outcomes may be influenced and points to a potential target for intervention. PMID- 29421604 TI - Neonatal morbidity associated with vaginal delivery of noncephalic second twins. AB - BACKGROUND: Management of noncephalic second twin delivery rests on the results of population-based retrospective studies of twin births that have shown higher neonatal mortality and morbidity for second twins with noncephalic, compared with cephalic, presentations after vaginal delivery of the first twin. Because these studies are flawed by data of questionable validity, do not report the obstetrical practices at delivery, and do not allow collection of potential confounding variables, we performed a national prospective study specially designed to evaluate the management of twins' delivery. OBJECTIVE: We sought to assess neonatal mortality and morbidity according to second twin presentation after vaginal birth of the first twin. STUDY DESIGN: The Jumeaux Mode d'Accouchement study was a nationwide prospective population-based cohort study of twin deliveries performed in 176 maternity units in France from February 2014 through March 2015. The primary outcome was a composite of intrapartum mortality and neonatal mortality and morbidity. Neonatal outcomes of second twins born >=32 weeks of gestation after vaginal delivery of the first cephalic or breech twin were compared according to the noncephalic or cephalic second twin presentation. Multivariable logistic regression models controlled for potential confounders. Subgroup analyses were conducted according to the breech or transverse presentation of the noncephalic second twin, and gestational age at delivery, before or after 37 weeks of gestation. RESULTS: Among 3903 second twins enrolled in the study, 2384 (61.1%) were in cephalic and 1519 (38.9%) in noncephalic presentations, of whom 999 (25.6%) were in breech and 520 (13.3%) in transverse presentation. Composite neonatal mortality and morbidity did not differ between the noncephalic and cephalic group (47/1519 [3.1%] vs 59/2384 [2.5%]; adjusted odds ratio, 1.23; 95% confidence interval, 0.81-1.85). No significant difference between groups was shown for the primary outcome in subgroup analyses according to type of noncephalic second twin presentation or gestational age at delivery. Cesarean delivery rates for the second twin were lower in the breech than in the cephalic group (14/999 [1.4%] vs 75/2384 [3.1%], P = .003) and lower in the cephalic than in the transverse group (75/2384 [3.1%] vs 35/520 [6.7%], P < .001). CONCLUSION: Noncephalic and cephalic second twin presentations after vaginal delivery of the first twin >=32 weeks of gestation are associated with similar low composite neonatal mortality and morbidity. Vaginal delivery of noncephalic second twin is a reasonable option. PMID- 29421605 TI - Impaired insulin signaling and spatial learning in middle-aged rats: The role of PTP1B. AB - The insulin and Brain-Derived Neurotrophic Factor (BDNF) signaling in the hippocampus promotes synaptic plasticity and memory formation. On the other hand, aging is related to the cognitive decline and is the main risk factor for Alzheimer's Disease (AD). The Protein-Tyrosine Phosphatase 1B (PTP1B) is related to several deleterious processes in neurons and emerges as a promising target for new therapies. In this context, our study aims to investigate the age-related changes in PTP1B content, insulin signaling, beta-amyloid content, and Tau phosphorylation in the hippocampus of middle-aged rats. Young (3 months) and middle-aged (17 months) Wistar rats were submitted to Morris-water maze (MWM) test, insulin tolerance test, and molecular analysis in the hippocampus. Aging resulted in increased body weight, and insulin resistance and decreases learning process in MWM. Interestingly, the middle-aged rats have higher levels of PTP-1B, lower phosphorylation of IRS-1, Akt, GSK3beta, mTOR, and TrkB. Also, the aging process increased Tau phosphorylation and beta-amyloid content in the hippocampus region. In summary, this study provides new evidence that aging-related PTP1B increasing, contributing to insulin resistance and the onset of the AD. PMID- 29421606 TI - Longitudinal associations between serum 25-hydroxyvitamin D, physical activity, knee pain and dysfunction and physiological falls risk in community-dwelling older adults. AB - AIMS: To describe the longitudinal associations between physiological falls risk, and between-person and within-person effects of 25-hydroxyvitamin D (25OHD), physical activity (PA), knee pain and dysfunction in community-dwelling older people. METHODS: Data for 1053 participants (51% women; mean age 63 +/- 7.4 years) studied at baseline, 2.5, 5, and 10 years were analysed. Falls risk (Z score) was measured using the Physiological Profile Assessment. Knee pain and dysfunction were assessed using the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC). Moderate-to-vigorous PA (MVPA) was measured using accelerometer. Linear mixed-effect regression models, with adjustment for confounders, were used to estimate the association between physiological falls risk and between-person and within-person effects of PA, 25OHD and WOMAC score. RESULTS: Between-person effects showed that 10-year average physiological falls risk was lower in participants who had a higher 10-year average 25OHD (beta = 0.005 per nmol/l, 95% CI: -0.008, -0.002), log-MVPA (beta = -0.16 per minute, 95% CI: -0.22, -0.10) and lower mean WOMAC score (beta = 0.005 per-unit score, 95% CI: 0.003, 0.01). Within-person effects showed that a higher physiological falls risk at any time-point was associated with higher than average WOMAC score (beta = 0.002 per-unit score, 95% CI: 0.0003, 0.004) and lower than average log-MVPA (beta = -0.15 per minute, 95% CI: -0.24, -0.06), but not 25OHD, at the same time point. CONCLUSION: Having higher WOMAC global score above an individual's average increases the risk of falling, whereas, increasing one's own MVPA level further reduces their risk of falling. The presence of between-person but not within person associations for 25OHD suggests the former may be confounded by other factors. PMID- 29421607 TI - Differences in muscle adaptation to a 12-week mixed power training in elderly men, depending on usual protein intake. AB - INTRODUCTION: Normal aging is often associated with a decline of muscle mass (MM), strength (MS) and quality (MQ: MS/MM), leading to functional incapacities. This aging-related deterioration of muscles may involve a decreased protein intake. Mixed power training has been recently shown to induce positive effects on MM, MS and MQ. However, to our knowledge, no study has examined if muscle adaptations following mixed power training could be influenced by the daily amount of protein ingested in elderly men. METHODS: Twenty-one men completed the intervention and were divided into 2 groups based on their usual protein intake: PROT 1.1- (<1.1 g.kg-1.d-1 [n = 10; 73 +/- 3 years]) and PROT 1.2+ (>1.2 g.kg-1.d 1 [n = 11; 73 +/- 3 years]). Body composition (DXA: lean and fat masses), MS (1 maximal repetition on leg-press and handgrip strength), MQ (MS/body mass and MS/lower limb lean mass), functional capacities (Short Physical Performance Battery/Senior Fitness Test), dietary intake (3-day food record) and energy expenditure (accelerometer; 7 days) were measured. Mixed power training intervention consisted in power and functional exercises (12 weeks; 3 times/week; 1 h/session). RESULTS: Lower limb MS increase in the PROT 1.2+ group was greater from that of the PROT 1.1- group when normalized to lower limbs lean mass (p = 0.036). In addition, a trend for greater gain in lower limb MS normalized to body mass (p = 0.053) was observed in the PROT 1.2+. CONCLUSION: To optimize mixed power training effects on muscle function, healthy older men should ingest daily at least 1.2 g.kg-1.d-1 of protein. These beneficial effects of a higher usual protein intake were observed especially for MQ, which is one of the best predictors of functional capacities in older adults. PMID- 29421608 TI - Defining drug and target protein distributions after stent-based drug release: Durable versus deployable coatings. AB - BACKGROUND: Innovations in drug eluting stent designs make it increasingly important to develop models for differentiating performance through spatial definition of drug, receptor binding and cell state. METHODS: Two designs of sirolimus analog eluting stents were implanted into porcine coronary arteries for 28, 60 or 90 days (n = 9/time point), durable coating (Xience) and deployable absorbable coating (MiStent). Explanted arteries were evaluated for drug content (n = 3/time point) by LC-MS/MS and for drug and target protein (mTOR) distributions by immunofluorescence (IF, n = 6/time point). A computational model was developed to predict drug release and arterial distribution maps. RESULTS: Both stents released the majority of drug load by 28 days, with different tissue retention efficiencies (91.4 +/- 4.9% MiStent versus 21.5 +/- 1.9% Xience, P < 0.001). Computational modeling of MiStent coating deployment and microcrystal dissolution recapitulated in vivo drug release and net tissue content and predicted that >98.5% of deployed drug remains crystalline through 90 days. Immunofluorescence and computational modeling showed peristrut drug localization for both stents, with similar peaks, but high interstrut levels only at sites of coating deployment from the absorbable coating. Co-localization of mTOR-IF with drug-IF for both devices showed persistent drug effects, though with differential drug-receptor pharmacokinetics. CONCLUSIONS: Immunofluorescence and computational modeling provide insights into drug distribution and binding status that can help differentiate drug delivery technologies. Herein we found that tissue deployment of slow dissolving crystalline drug particles results in temporally and spatially more uniform drug delivery to interstrut zones that might otherwise be under dosed without excess peristrut drug. PMID- 29421609 TI - Colorectal cancer lung metastasis treatment with polymer-drug nanoparticles. AB - Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States; the predominant cause for mortality is metastasis to distant organs (e.g., lung). A major problem limiting the success of chemotherapy in metastatic CRC is the inability to target tumor tissues selectively and avoid severe side effects to normal tissues and organs. Here, we demonstrate polymeric nanoparticles (PNPs) entrapping chemotherapeutic agents provide a new therapeutic option for treating CRC that has metastasized to the lung. PNPs assembled from FDA approved biocompatible block copolymer accumulated predominantly in lung tissue. PNPs showed negligible accumulation in liver, spleen and kidneys, which was confirmed by fluorescent nanoparticle imaging and analysis of PI3K inhibition in the organs. PNPs entrapping PI3K inhibitors (i.e., wortmannin and PX866) suppressed CRC lung metastasis growth, and SN-38-loaded PNPs completely eliminated CRC lung metastasis. Our results demonstrate that polymer-drug nanoparticles offer a new approach to reduce toxicity of cancer therapy and has the potential to improve outcomes for patients with lung metastasis. PMID- 29421610 TI - Lipase catalysed biodiesel synthesis with integrated glycerol separation in continuously operated microchips connected in series. AB - Although the application of microreactors in different processes has been extensively explored in recent decades, microreactors continue to be underexplored in the context of the enzyme-catalysed process for biodiesel production. Due to their numerous advantages, microreactors could become the next step in the development of a biodiesel production process characterised by sustainability, cost-effectiveness and energy efficiency. In this investigation, biodiesel production was catalysed by lipase from Thermomyces lanuginosus (Lipolase L100). Edible sunflower oil was used as a model substrate in order to investigate the process. After optimal process conditions had been determined, waste-cooking oil was used for biodiesel production to make the production process more sustainable. Three different substrate-feeding strategies were investigated and finally an optimal strategy was proposed. In all the investigated systems, fatty acids methyl esters (FAME) content was higher than 95% and obtained in a significantly shorter time (less than 2 h) compared to the batch process in which biodiesel production was catalysed by lipase (C = 95%, t = 96 h). After the optimal biodiesel production system had been proposed, an integrated system with two microchips connected in series was developed. The first microchip was used for biodiesel production and the second for simultaneous purification i.e. glycerol separation. Finally, purified biodiesel was produced with glycerol content below the detection limit. PMID- 29421611 TI - GPR30 activation improves memory and facilitates DHPG-induced LTD in the hippocampal CA3 of middle-aged mice. AB - Reduced estrogen levels and decreased expression of related receptors are typical cerebral features of aging. The G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) is considered a novel therapeutic target for neurodegenerative diseases. In this study, we demonstrated that hippocampal GPR30 expression was reduced in middle-aged mice compared with young adult mice. GPR30 agonist G1 improved both fear and spatial memory in both male and female middle aged mice, but not in young adult mice, which were blocked by the GPR30 antagonist G15. Interestingly, a group I metabotropic glutamate receptor (mGluR) agonist, 3,5-dihydroxyphenylglycine (DHPG)-induced long-term depression (LTD) in mossy fiber-cornu ammonis 3 (MF-CA3) synapses but not Schaffer collateral-CA1 (SC CA1) synapses was facilitated in brain slices from G1-treated middle-aged mice. Long-term potentiation (LTP) in SC-CA1 synapses was not affected in slices from G1-treated mice. The effects of GPR30 activation on memory and DHPG-LTD in MF-CA3 synapses were further confirmed by viral expression of GPR30 in the CA3. The regulation of hippocampal synaptic plasticity by G1 treatment might be related to brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling, as G15 also blocked G1-induced activation of the BDNF-TrkB pathway. Moreover, we found that DHPG triggered GluA internalization in slices from G1 treated mice but not control mice. Pharmacological experiments showed that G1 mediated facilitation of DHPG-induced LTD in MF-CA3 synapses was dependent on protein kinase B (Akt), mammalian target of rapamycin (mTor), and TrkB signaling. In conclusion, our results indicate that GPR30 activation improves memory in middle-aged mice, likely through facilitating synaptic plasticity in the CA3. This study provides novel evidence that GPR30 activation can improve memory in middle-aged animals. PMID- 29421612 TI - Revisiting metaplasticity: The roles of calcineurin and histone deacetylation in unlearning odor preference memory in rat pups. AB - Previous work has shown that 24 h duration odor preference learning, induced by one-trial training, generates a down-regulation of the GluN1 receptor in anterior piriform cortex at 3 h, and results in metaplastic unlearning if a second training trial is given at 3 h. The GluN1 receptor upregulates at 24 h so 24 h spaced training is highly effective in extending memory duration. The present study replicates the piriform cortex unlearning result in the olfactory bulb circuit and further studies the relationship between the initial training strength and its associated metaplastic effect. Intrabulbar infusions that block calcineurin or inhibit histone deacetylation normally produce extended days-long memory. If given during training, they are not associated with GluN1 downregulation at 3 h and do not recruit an unlearning process at that time. The two memory strengthening protocols do not appear to interact, but are also not synergistic. These outcomes argue that it is critical to understand the metaplastic effects of training in order to optimize training protocols in the service of either memory strengthening or of memory weakening. PMID- 29421613 TI - Does the Medical Insurance Siglo XXI have the potential to reduce neonatal and under-5 mortality rate in Mexico? PMID- 29421615 TI - An approximation to data on mortality and out-of-pocket expenses for medical attention of infants <2 years old affiliated with the Medical Insurance Siglo XXI. AB - BACKGROUND: Medical Insurance Siglo XXI (MISXXI) in Mexico provides funds for the medical and preventive care of children from households lacking any health insurance, thus seeking to reduce impoverishing due to health problems. This paper analyzes mortality of children <2 years of age affiliated with this program and out-of-pocket expenses attributable to this event. METHODS: An in-home survey addressed to determine the health conditions of children affiliated with MISXXI was carried out in all Mexican states. If the infant had died, information was collected with emphasis on diagnosis (death certificate), medical attention and out-of-pocket expenses. Diagnoses were classified in agreement with ICD-10. RESULTS: Of 9181 children, 74 died by the time during which the survey was gathered; 51% of children died before 28 days. Deaths were attributable to short gestation, low birth weight, asphyxia, or sepsis. In newborns who died before 7 days of age, 95.7% received medical care; however, among those who died between 7 and 28 days, only 58% received medical care. During the neonatal period, medical care was predominantly given in the Ministry of Health facilities. During the post-neonatal period, almost all children received medical care, predominantly in private facilities, a reason for households incurring in out-of-pocket expenditures. CONCLUSIONS: Mortality of infants who are beneficiaries of MISXXI mainly occurs during the neonatal period; however, households incurred in out-of pocket expenditures, especially in the post-neonatal period. It seems convenient to boost the access of users to benefits provided by this medical insurance. PMID- 29421614 TI - [Malignant neoplasms in the neonate]. AB - Cancer in children has characteristics that differentiate it from other types reported in later ages. Overall survival at 3 years is up to 70% depending on the tumor studied. Major organs and systems affected are the hematopoietic system, central nervous system and sympathetic and mesenchymal tissues. The increased incidence of neonatal tumors observed in this and other studies is based on the increasing number of solid tumors (teratomas and neuroblastomas) because cases of central nervous system tumors and leukemias have remained constant. Ultrasonography is the first line of approach and can detect up to 70% of fetal anomalies. The physiology of the newborn causes the necessary multidisciplinary treatment in neoplastic disease to be modified substantially in this age group to avoid toxicity and sequelae. The most common treatment is surgery. Achieving timely diagnostic treatment options are effective in improving the survival of these patients. PMID- 29421616 TI - [Reliability for detection of developmental problems using the semaphore from the Child Development Evaluation test: Is a yellow result different from a red result?] AB - BACKGROUND: The Child Development Evaluation (CDE) is a screening tool designed and validated in Mexico for detecting developmental problems. The result is expressed through a semaphore. In the CDE test, both yellow and red results are considered positive, although a different intervention is proposed for each. The aim of this work was to evaluate the reliability of the CDE test to discriminate between children with yellow/red result based on the developmental domain quotient (DDQ) obtained through the Battelle Development Inventory, 2nd edition (in Spanish) (BDI-2). METHODS: The information was obtained for the study from the validation. Children with a normal (green) result in the CDE were excluded. Two different cut-off points of the DDQ were used (BDI-2): <90 to include low average, and developmental delay was considered with a cut-off<80 per domain. Results were analyzed based on the correlation of the CDE test and each domain from the BDI-2 and by subgroups of age. RESULTS: With a cut-off DDQ<90, 86.8% of tests with yellow result (CDE) indicated at least one domain affected and 50% 3 or more compared with 93.8% and 78.8% for red result, respectively. There were differences in every domain (P<0.001) for the percent of children with DDQ<80 between yellow and red result (CDE): cognitive 36.1% vs. 61.9%; communication: 27.8% vs. 50.4%, motor: 18.1% vs. 39.9%; personal-social: 20.1% vs. 28.9%; and adaptive: 6.9% vs. 20.4%. CONCLUSIONS: The semaphore result yellow/red allows identifying different magnitudes of delay in developmental domains or subdomains, supporting the recommendation of different interventions for each one. PMID- 29421617 TI - Mexican registry of pediatric cardiac surgery. First report. AB - BACKGROUND: Currently, there is a spreading worldwide tendency to characterize health issues and to propose alternative solutions via the creation of computerized databases. The aim of this study was to present the results in a computerized database of pediatric cardiac surgeries developed under the auspices of the Mexican Association of Specialists in Congenital Heart Diseases (Asociacion Mexicana de Especialistas en Cardiopatias Congenitas A.C) and coordinated by the collegiate group of Pediatric Cardiology and Surgery as petitioned by the National Institutes of Health and High Specialty Hospitals Coordinating Commission. METHODS: We analyzed all cases registered in the database during a 1-year observation period (August 1, 2011 to July 31, 2012) by all major Health Ministry-dependent institutes and hospitals offering surgical services related to pediatric cardiopathies to the non-insured population. RESULTS: Seven institutions participated voluntarily in completing the database. During the analyzed period, 943 surgeries in 880 patients with 7% reoperations (n=63) were registered. Thirty-eight percent of the surgeries were performed in children <1 year of age. The five most common cardiopathies were patent ductus arteriosus (n=96), ventricular septal defect (n=86), tetralogy of Fallot (n=72), atrial septal defect (n=68), and aortic coarctation (n=54). Ninety percent of surgeries were elective and extracorporeal circulation was used in 62% of surgeries. Global mortality rate was 7.5% with the following distribution in the RACHS-1 score categories: 1 (n=4, 2%), 2 (n=19, 6%), 3 (n=22, 8%), 4 (n=12, 19%), 5 (n=1, 25%), 6 (n=6, 44%), and non-classifiable (n=2, 9%). CONCLUSIONS: This analysis provides a representative view of the surgical practices in cardiovascular diseases in the pediatric population at the national non-insured population level. However, incorporating other health institutions to the national registry database will render a more accurate panorama of the national reality in surgical practices in the population <18 years of age. PMID- 29421618 TI - [Prevalence of Down syndrome using certificates of live births and fetal deaths in Mexico 2008-2011]. AB - BACKGROUND: Down syndrome (DS) or trisomy 21 is the most common genetic cause of mental retardation with the clinical presentation of a series of well-defined characteristics. Advanced maternal age has been associated with DS. METHODS: The databases of all the certificates of live births and fetal deaths in Mexico were combined. Codes based on the International Classification of Diseases 10th Revision (ICD-10) in Chapter XVII "Congenital malformations, deformations and chromosomal abnormalities" were selected. RESULTS: A database of 8,250,375 births during the period 2008-2011 was constructed: 99.2% were live births with 0.8% of fetal deaths and 3,076 cases diagnosed with DS. CONCLUSIONS: The importance of this report is to initiate an epidemiological surveillance of newborn cases of DS nationwide and by state using census information systems available in the country since 2008. An increased risk has been observed for having a child with DS since the mother is >= 35 years, as has been reported in other studies. PMID- 29421619 TI - [Nutcracker syndrome: Cause of non-glomerular hematuria and massive proteinuria]. AB - BACKGROUND: Nutcracker syndrome caused by compression of the left renal vein between the aorta and superior mesenteric artery is a non-glomerular cause of left renal bleeding and left varicocele. It has also been recognized to be an important cause of orthostatic proteinuria. CASE REPORT: A 17-year-old male was evaluated due to recurrent macroscopic hematuria. Physical examination showed left varicocele. Body mass index 16.3 kg/m2. Urinalysis demonstrated hematuria and massive proteinuria. Renal biopsy showed mild mesangial glomerular proliferation. Cystoscopy showed hematuria originating from the left ureter. Doppler ultrasonography and contrast-enhanced computed angiotomography revealed a peak velocity of the left renal vein of 20cm/s, ratio of peak velocity of aortomesenteric and hilar portions of left renal vein of 7.7 and enlargement of the left renal vein in the hilar portion. With a diagnosis of nutcracker syndrome, the patient received conservative treatment. During follow-up, progressive remission of the recurrent episodes of hematuria and proteinuria was observed. The patient had no clinical symptoms or abnormal urinalysis. At 13 months of follow-up the body mass index was 19 kg/m2. CONCLUSIONS: This case shows the relationship between the increase in body mass index and remission of nutcracker syndrome, manifested as left varicocele, hematuria and massive proteinuria. All symptoms disappeared with the increase of body mass index, probably due to increase in retroperitoneal fat with improvement of the aortomesenteric angle of the left renal vein. PMID- 29421620 TI - [Laparoscopic cholecystectomy in a patient with ventriculoperitoneal shunt system]. AB - BACKGROUND: Pediatric patients with hydrocephalus and ventriculoperitoneal (VP) shunt systems are not exempt from suffering from gastrointestinal diseases. Today, with technological advances it would be controversial to not offer the benefits of minimally invasive surgery. To date, no studies have been carried out comparing different techniques to assess the best way to prevent intracranial hypertension. However, there are increasing reports of safe surgery in children with VP shunt operated by laparoscopy. CASE REPORT: We present the case of a 14 year-old male who presented for laparoscopic cholecystectomy with a VP shunt system. The patient had clinical data of cholecystitis; therefore, it was decided to perform laparoscopic cholecystectomy. The patient experienced a satisfactory evolution with hospital discharge at 72h postoperatively. CONCLUSIONS: Currently, it is common that children with hydrocephalus and VP systems may require some type of laparoscopic surgery. This surgery is safe for various procedures including gallbladder and ovarian pathology. Satisfactory results will help the surgeon make a better surgical decision in this type of pediatric patient. PMID- 29421621 TI - [Congenital hepatic fibrosis: Complications and management]. PMID- 29421622 TI - [Treatment of idiopathic nephrotic syndrome in children]. AB - The annual incidence of the nephrotic syndrome has been estimated to be 1-3 per 100,000 children<16 year of age. In children, the most common cause of nephrotic syndrome is idiopathic nephrotic syndrome (INS). INS is defined by the presence of proteinuria and hypoalbuminemia and by definition is a primary disease. Renal biopsy study shows non-specific histological abnormalities of the kidney including minimal changes, focal and segmental glomerular sclerosis, and diffuse mesangial proliferation. Steroid therapy is applied in all cases of INS. Renal biopsy is usually not indicated before starting corticosteroid therapy. The majority of patients (80-90%) are steroid-responsive. Children with INS who do not achieve a complete remission with corticosteroid therapy commonly present focal and segmental glomerular sclerosis and require treatment with calcineurin inhibitors (cyclosporine or tacrolimus), mycophenolate mofetil or rituximab, plus renin-angiotensin system blockade. In this article we review the recent accepted recommendations for the treatment of children with INS. PMID- 29421623 TI - [Scientific reductionism and social control of mind. Part II]. AB - In the second part of this essay, the progressive subordination of scientific endeavor and knowledge of business and profit is pointed out. For instance, the way facts are prioritized over concepts and ideas in scientific knowledge can translate into technological innovation, central to enterprise competitiveness and key to social mechanisms of control (military, cybernetic, ideological). Overcoming the scientific reductionism approach indicates recognizing the need to define progress in another way, one that infuses scientific knowledge with real liberating and inquisitive power. Power is essential in the search for a more collaborative, inclusive and pluralistic society where respect for human dignity and care for the ecosystem that we live in are prioritized. PMID- 29421624 TI - Comprehensive overview of murine epididymal mononuclear phagocytes and lymphocytes: Unexpected populations arise. AB - Despite increasing evidence that epididymal immune disorders can lead to infertility, the cells and mechanisms underlying epididymal immunity remain poorly understood. In this study, we propose a rather exhaustive overview of innate and adaptive immune cells present in the murine caput and cauda epididymis. Using flow cytometry and a wide set of markers, we screened the broadest panel of immune cells ever, in this organ. For the first time, we unequivocally quantified the innate populations of monocytes, macrophages, and dendritic cells subtypes. We also revealed the presence of B cells, gamma delta T cells, and double negative T cells in the murine epididymis. They were localized by immunofluorescence stainings, and appeared to be all present in the interstitium and epithelium along the organ, but with respective preferential regional distribution. Altogether, these findings provide new insights on the actors and potential mechanisms involved in the immune responses against genital tract ascending pathogens and in the setting and maintenance of tolerance toward the sperm cells. PMID- 29421625 TI - Microglia, the missing link in maternal immune activation and fetal neurodevelopment; and a possible link in preeclampsia and disturbed neurodevelopment? AB - Disturbances in fetal neurodevelopment have extensively been related to neurodevelopmental disorders in early and later life. Fetal neurodevelopment is dependent on adequate functioning of the fetal immune system. During pregnancy, the maternal immune system is challenged to both tolerate the semi-allogenic fetus and to protect the mother and fetus from microbes. The fetal immune system is influenced by maternal immune disturbances; therefore, perturbations in maternal immunity likely do not only alter pregnancy outcome but also alter fetal neurodevelopment. A possible common pathway could be modulating the functioning of tissue macrophages in the placenta and brain. Maternal immune tolerance towards the fetus involves several complex adaptations. In this active maternal immune state, the fetus develops its own immunity. As cytokines and other players of the immune system -which can pass the placenta- are involved in neurodevelopment, disruptions in immune balance influence fetal neurodevelopment. Several studies reported an association between maternal immune activation, complications of pregnancy as preeclampsia, and altered neonatal neurodevelopment. A possible pathway involves dysfunctioning of microglia cells, the immune cells of the brain. Functionality of microglia cells during normal pregnancy is, however, poorly understood. The recent outbreak of ZIKA virus (ZKV), but also the literature on virus infections in general and its consequences on microglial cell function and fetal neurodevelopment show the devastating effects a virus infection during pregnancy can have. PMID- 29421626 TI - Molecular simulation aspects of amyloid peptides at membrane interface. AB - The interactions of amyloid peptides with cell membranes play an important role in maintaining the integrity and functionality of cell membrane. A thorough molecular-level understanding of the structure, dynamics, and interactions between amyloid peptides and cell membranes is critical to amyloid aggregation and toxicity mechanisms for the bench-to-bedside applications. Here we review the most recent computational studies of amyloid peptides at model cell membranes. Different mechanisms of action of amyloid peptides on/in cell membranes, targeted by different computational techniques at different lengthscales and timescales, are rationally discussed. Finally, we have proposed some new insights into the remaining challenges and perspectives for future studies to improve our understanding of the activity of amyloid peptides associated with protein misfolding diseases. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. PMID- 29421627 TI - [Antibiotic resistance in urinary infection: the never-ending story]. PMID- 29421628 TI - [Nephrogenic diabetes insipidus]. AB - The anti-diuretic hormone arginine-vasopressin (AVP) is released from the pituitary and regulates water reabsorption in the principal cells of the kidney collecting duct. Binding of AVP to the arginine-vasopressin receptor type-2 in the basolateral membrane leads to translocation of aquaporin-2 water channels to the apical membrane of the principal cells of the collecting duct, inducing water permeability of the membrane. This results in water reabsorption in the collecting duct of the nephron following an osmotic gradient. Nephrogenic diabetes insipidus is caused by partial or complete renal resistance to the effects of AVP. Congenital nephrogenic diabetes insipidus is a disorder associated with mutations in either the AVPR2 or AQP2 gene, causing the inability of patients to concentrate their urine. Acquired nephrogenic diabetes insipidus can be caused by electrolyte imbalances (e.g., hypercalcemia, hypokalemia), renal/extra-renal diseases and drugs (e.g., lithium toxicity). This article reviews the causes, clinical manifestations, diagnosis and treatment of patients with nephrogenic diabetes insipidus. Based on more in-depth mechanistic understanding, new therapeutic strategies are current being explored. PMID- 29421629 TI - [Antimicrobial susceptibility of uropathogens from uncomplicated urinary tract infection in a pediatric hospital]. AB - BACKGROUND: Urinary tract infection in children is well recognized as a cause of acute morbidity and chronic medical conditions. As a result, appropriate use of antimicrobial agents, however, increases antibiotic resistance and complicates its treatment due to increased patient morbidity, costs, rates of hospitalization, and use of broader-spectrum antibiotics. The goal of this study was to determine antibiotic susceptibility to commonly used agents for urinary tract infection against recent urinary isolates. METHODS: A total of 457 consecutive children attending the emergency room at the Hospital Infantil de Mexico Federico Gomez with symptoms of uncomplicated lower urinary tract infection were eligible for inclusion. Patients who had had symptoms for>=7 days and those who had had previous episodes of urinary tract infection, received antibiotics or other complicated factors were excluded. Midstream and catheter urine specimens were collected. All isolates were identified and the in vitro activities of antimicrobials were determined. RESULTS: The most frequently isolated urinary pathogens were as follows: Escherichia coli (E. coli) (312, 68.3%), Enterococcus spp. (42, 11%), Klebsiella pneumoniae (K. pneumoniae) (40, 8.7%), Pseudomonas aeruginosa (P. aeruginosa) (34, 7.5%), Proteus mirabilis (P. mirabilis) (21, 4.5%), Enterobacter cloacae (8, 1.7%). The resistance to trimetoprim/sulfametoxazol (%) was 73.7, 62.2, 100, 52, and 50, respectively, for E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis and Enterobacter spp., 92.5 for Enterococcus faecalis (E. faecalis) and 49.9 for Enterococcus faecium (E. faecium). Ampicillin was 86.3, 45, 100, 47.9, and 66.6% for the same strains, ciprofloxacin 33.8, 9, 18.8, 0, 0%, nitrofurantoin 4.4, 13, 97.7, 70, 0%; to E. faecalis 0% and 16.7% to E. faecium. CONCLUSIONS: Frequently prescribed empirical agents for uncomplicated urinary tract infection demonstrate lowered in vitro susceptibilities when tested against recent clinical isolates. PMID- 29421630 TI - [Evaluation of the quality of care of transient tachypnea in newborns affiliated with the Medical Insurance Siglo XXI program]. AB - BACKGROUND: Evaluation of the quality of care of the newborn with complications is an indispensable element for the improvement of strategies directed to reduce newborn mortality rates. The aim of this work was to evaluate the quality of technical and interpersonal care in the management of transient tachypnea of the newborn (TTN) of patients affiliated with the program "Medical Insurance Siglo XXI". METHODS: A cross-sectional study was conducted in 61 hospitals affiliated with the Health Ministry with at least two cases of TTN during the first semester of 2011. Variables such as mother's health, pregnancy, birth and birth complication characteristics were analyzed. Also, newborn interventions and health conditions upon discharge were included. To measure the quality of care according to prevention, diagnosis and treatment, quality indicators were defined and validated. RESULTS: We analyzed 256 case files with a diagnosis of TTN; 8.9% of the mothers presented risk factors (asthma, diabetes) and 53.5% had complications during pregnancy. There were 60% of cases with TTN born by cesarean delivery; one third of these children had low birth weight and 14% were transferred to another hospital. As for the quality indicators in the area of prevention, more than 90% of risk factors (smoking, asthma, cesarean delivery) were identified. Diagnostic indicators showed that 86-98% of respiratory distress symptoms were sought. Indicators of treatment achieved satisfactory figures for monitoring and support measures. CONCLUSIONS: Prevention, diagnosis and treatment indicators made it possible to consider that most TTN cases received appropriate treatment. It is advisable to develop effective strategies to prevent TTN, such as increasing efforts to reduce the increasing rates of cesarean deliveries. PMID- 29421631 TI - [Mean age of dental eruption in a school-age population analyzed by 2 methods]. AB - BACKGROUND: Because dental eruption is the result of a series of physiological events, it is important to acknowledge precisely the mean age of exfoliation and eruption of each dental organ. This is useful to establish diagnostic, preventive and treatment criteria. The aim of this study was to compare the cross-sectional and cohort methods toward estimating the average age of dental eruption. METHODS: The study sample was comprised of 524 school-age children from the State of Mexico (273 females and 251 males). Only permanent teeth were surveyed: the first upper molar and central and lateral incisors and the first lower molar. The cohort was observed during a 3-year period until the tooth budded. Dental mirror, tongue depressor and day light were used. Cross-sectional method consisted of permanent teeth observed after the first year. RESULTS: In both methods, teeth budded first in females. The average ages of dental eruption according to both methods did not show statistical difference in 88% of the teeth. CONCLUSIONS: Measurement of the age of dental eruption through cross-sectional method provides reliable data in relation to the cohort method. PMID- 29421632 TI - [Food preferences and nutritional status in school-age children living in Mexico City]. AB - BACKGROUND: Childhood is a basic period for the development of habits and their continuation during the course of life. The objective of this study was to identify food preferences and their variations according to the nutritional status in school-age children living in Mexico City. METHODS: A cross-sectional study was carried out including 1465 school-age children attending eight public elementary schools in Mexico City. Children were asked to complete a questionnaire regarding their preferences to 70 selected different foods. Anthropometric measurements were also carried out. Parents of the children provided sociodemographic information. For each food, the preference was evaluated using a Likert scale. Frequencies were calculated for the total sample and for different nutritional status levels. RESULTS: Median age of children was 9 years old. Forty-eight percent of the children were overweight or obese. The most preferred foods were fruits, pizzas, flavored milk, and French fries. The least preferred foods were vegetables, whole-grain cereals, fish, meat, and panela cheese. Plain water (72%) and sugar-sweetened beverages (71%) had a high level of preference. There was no preference variation according to nutritional status. CONCLUSIONS: Food preference patterns of school-age children are a risk for unhealthy food consumption as well as for the increase in obesity prevalence in this population. Interventions focused on the promotion of a healthy food environment are necessary, aimed at improving food preferences from early childhood. PMID- 29421633 TI - [Scimitar syndrome: a case series]. AB - BACKGROUND: Scimitar syndrome is a rare and complex congenital anomaly of the lung with multiple variables and is named for its resemblance to the classical radiological crooked sword. Its defining feature is the anomalous pulmonary drainage. It is associated with various cardiothoracic malformations and a wide spectrum of clinical manifestations. CASE SERIES: Nine patients diagnosed with scimitar syndrome found in the database of Hospital Infantil de Mexico between 2009 and 2013 were reviewed. Demographic records, clinical status and hemodynamic parameters reported were collected. CONCLUSIONS: This case series called attention to certain differences between our group of patients and those reported in the international literature. Patients were predominantly female and were diagnosed between 1 and 20 months of life. All were asymptomatic at the time of the study. Half of the patients had a history of respiratory disease and all patients had with pulmonary hypertension. Surgical management was required in on third of the patient group. PMID- 29421634 TI - [Congenital toxoplasmosis]. AB - BACKGROUND: Toxoplasmosis, caused by Toxoplasma gondii, is transmitted to humans in several ways, such as transplacental spread. It is estimated that this parasite infects a third of the world population and it is associated with congenital infection and fetal loss. Only 10 to 20% of the cases are symptomatic. CASE REPORT: We present the case of a pre-term newborn that had been referred to a tertiary care center. During the in-hospital period, diagnosis of congenital toxoplasmosis with many systemic manifestations was performed. CONCLUSIONS: Most cases of congenital toxoplasmosis are asymptomatic. Diagnosis tests and a complete physical examination should be performed on all newborns with suspicion of infection to detect all possible manifestations as in the case reported. PMID- 29421635 TI - [Kwashiorkor type malnutrition]. PMID- 29421636 TI - [Microtia-atresia: clinical, genetic and genomic aspects]. AB - Mexico has a prevalence of microtia of 7.37/10,000 (newborns), 3 times higher than the prevalence reported in other populations (USA 2-3/10,000). Microtia is defined as a congenital malformation of the external ear characterized by a small auricular lobe with an abnormal shape. It is more often unilateral and on the right side. Males are more frequently affected than females. It can occur as an isolated defect or can be associated with other abnormalities such as stenosis of the external auditory canal. In three of the main pediatric hospitals in Mexico, microtia is among the most important causes of attendance in the Genetics Department. Microtia-atresia must be considered as a major malformation with important repercussions in hearing function requiring multidisciplinary medical care in order to limit the disability associated and to provide genetic counseling. Its etiology is complex. Only in a minor number of cases it has been possible to identify a main genetic component (as in monogenic presentations) or a main environmental cause (as in fetal alcohol syndrome or pregestational diabetes). In most cases this malformation is multifactorial. Due to the relevance that the frequency of microtia atresia has in different health services in Mexico, it is important that all medical professionals are aware of its clinical, molecular and inherited characteristics. PMID- 29421637 TI - [Conceptual proposal for an operational model of integrated care in public health services for children]. PMID- 29421638 TI - Women's experiences of childbirth in Middle Eastern countries: A narrative review. PMID- 29421639 TI - Preparing midwifery students for practice: The value of elective placements in enhancing midwifery practice. AB - An elective placement where students are facilitated to access different models of midwifery care was included in the 18 month Higher Diploma Midwifery programme in 2008 in a university in Ireland. All students since then have had the opportunity to experience this placement which is advocated by the regulatory board for Nursing and Midwifery in Ireland (NMBI). This paper details the integration of an elective placement referred to as an 'observation week' into the 18 month midwifery programme. It includes a description of the organisation of the observation week, a summary of services accessed by midwifery students, student evaluation of their experience and mechanisms for feedback of these experiences to our partners in clinical practice. The benefits and the challenges of the observation week are considered with reference to the published literature. PMID- 29421640 TI - Sustaining a newly implemented competence-based midwifery programme in Lesotho: Emerging issues. AB - The need to develop midwives who improve maternal and neonatal outcomes underpins decisions to adopt competence-based education models in low- and middle-income countries. Competence-based education means a shift in the training of midwives to include student self-directed performance-oriented training. Sustaining the implementation of a curricular innovation, such as a competence-based curriculum, requires new skills and resources by countries adopting such innovation. The skills and resources needed to sustain such a curricular innovation are influenced by issues that arise during implementation of the curricular innovation. Through structured interviews with stakeholders in midwifery education and document analysis in a small sub-Saharan African country, we reveal emerging issues that threaten the sustainability of a newly implemented competence-based midwifery curriculum. In this article, we argue that monitoring and supporting the implementation of a curricular innovation, is essential in enhancing midwifery education institutions ability to sustain curricular innovation. Regulation through professional bodies and councils enhance institutional, programmatic and classroom accountability. PMID- 29421641 TI - Improving the quality and content of midwives' discussions with low-risk women about their options for place of birth: Co-production and evaluation of an intervention package. AB - OBJECTIVE: Women's planned place of birth is gaining increasing importance in the UK, however evidence suggests that there is variation in the content of community midwives' discussions with low risk women about their place of birth options. The objective of this study was to develop an intervention to improve the quality and content of place of birth discussions between midwives and low-risk women and to evaluate this intervention in practice. DESIGN: The study design comprised of three stages: (1) The first stage included focus groups with midwives to explore the barriers to carrying out place of birth discussions with women. (2) In the second stage, COM-B theory provided a structure for co-produced intervention development with midwives and women representatives; priority areas for change were agreed and the components of an intervention package to standardise the quality of these discussions were decided. (3) The third stage of the study adopted a mixed methods approach including questionnaires, focus groups and interviews with midwives to evaluate the implementation of the co-produced package in practice. SETTING: A maternity NHS Trust in the West Midlands, UK. PARTICIPANTS: A total of 38 midwives took part in the first stage of the study. Intervention design (stage 2) included 58 midwives, and the evaluation (stage 3) involved 66 midwives. Four women were involved in the intervention design stage of the study in a Patient and Public Involvement role (not formally consented as participants). FINDINGS: In the first study stage participants agreed that pragmatic, standardised information on the safety, intervention and transfer rates for each birth setting (obstetric unit, midwifery-led unit, home) was required. In the second stage of the study, co-production between researchers, women and midwives resulted in an intervention package designed to support the implementation of these changes and included an update session for midwives, a script, a leaflet, and ongoing support through a named lead midwife and regular team meetings. Evaluation of this package in practice revealed that midwives' knowledge and confidence regarding place of birth substantially improved after the initial update session and was sustained three months post-implementation. Midwives viewed the resources as useful in prompting discussions and aiding communication about place of birth options. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Co-production enabled development of a pragmatic intervention to improve the quality of midwives' place of birth discussions with low-risk women, supported by COM-B theory. These findings highlight the importance of co production in intervention development and suggest that the place of birth package could be used to improve place of birth discussions to facilitate informed choice at other Trusts across the UK. PMID- 29421642 TI - Women's motivation, perception and experience of complementary and alternative medicine in pregnancy: A meta-synthesis. AB - BACKGROUND: complementary and Alternative Medicine use during pregnancy is popular in many countries, including Australia. There is currently little evidence to support this practice, which raises the question of women's motivation for use of these therapies and the experiences they encounter. OBJECTIVE: this study aims to explore the perceptions, motivations and experiences of pregnant women with regard to their use of Complementary and Alternative Medicine during pregnancy. METHODS: a systemic review and meta synthesis of the available research was conducted. Five databases were explored - CINAHL Plus, Medline, PubMed, AMED and Web of Science using the search terms complementary and alternative medicine; pregnancy; and pregnant. Articles included in this meta-synthesis were screened using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses tool. FINDINGS: ten initial themes were drawn from the six studies. These ten themes were summarised by three cluster themes. The results suggest that women are using Complementary and Alternative Medicine in their pregnancy as a means of supporting their sense of self determination, to pursue a natural and safe childbirth, and because they experience a close affiliation with the philosophical underpinnings of Complementary and Alternative Medicine as an alternative to the biomedical model. CONCLUSION: these findings are important to practitioners, policy makers, governing bodies and researchers, providing insight into the motivations for Complementary and Alternative Medicine use by women in pregnancy. PMID- 29421643 TI - Association between maternal death and cesarean section in Latin America: A systematic literature review. AB - BACKGROUND: it is critically important to explore a possible relationship between cesarean section and maternal mortality in Latin America, where the highest cesarean section rates in the world are found. Our aim was to conduct a systematic literature review on the relationship between maternal death and caesarean section in Latin America. METHODS: we undertook a systematic review through six electronic databases. Studies that reported any association analysis between maternal mortality and the mode of delivery in Latin America were included. Papers that fulfilled the inclusion criteria were then read fully, and a quality assessment was conducted with the PROMPT tool. RESULTS: seven articles were identified for final analysis, all of which were observational studies. Most of the studies were retrospective (6) and one was prospective. Of the retrospective studies, 3 were case control and 3 were cross-sectional. Most of the publications on this topic suggest that there may be an increased risk of maternal mortality with cesarean section compared with vaginal birth (odds ratio ranging from 1.6 to 7.08). However, it is evident that there is a lack of studies with this subject, especially those that take into account the differences in risk between women delivered by cesarean section or by vaginal birth. CONCLUSIONS: most of the articles showed that there may be an increased risk of maternal mortality with cesarean section compared with vaginal birth. However, it is clear that there is a limited number of studies published on this issue. Additional studies with a better methodological design should be conducted. PMID- 29421644 TI - Experiences of the graduates of the first baccalaureate midwifery programme in Pakistan: A descriptive exploratory study. AB - BACKGROUND: in 2012 the Aga Khan University in Karachi, Pakistan opened the country's first bachelor's degree program in midwifery for women who held diplomas in nursing and midwifery. The principal aims were to prepare midwives who would be competent to provide full-scope practice. For quality assurance, the programme was continuously monitored and assessed. As part of this ongoing evaluation process we sought in-depth feedback from the first graduates about their student experiences. OBJECTIVE: this study aimed to explore the experiences of the first graduates of a Bachelor of Science in Midwifery (BScM) program to deepen our understanding of their views of the program's strengths and difficulties and to obtain their suggestions for change. DESIGN AND METHODS: This qualitative descriptive exploratory study used universal sampling to collect data from all 21 of the first graduates of the BScM Program. Data collection involved focus group discussions using a semi structured interview guide and content analysis. The study was approved by Institutional Ethics Review Committee. FINDINGS: three main themes emerged from the data: (1) Competence acquisition, (2) Attitude transformation, and (3) Strengths and limitations of the program. CONCLUSIONS: the study findings highlighted that the degree program in midwifery had a positive impact on graduates' perceptions of their knowledge, skills, attitudes and ability to implement evidence-based midwifery practice. The graduates regarded the university's environment, teaching-learning strategies, preceptorship model, self-directed learning and exposure to diverse clinical settings as major facilitators in achieving competence. PMID- 29421645 TI - Feeding of tobacco blend or nicotine induced weight loss associated with decreased adipocyte size and increased physical activity in male mice. AB - Although epidemiological data and results from rodent studies support an inverse relationship between nicotine consumption and body weight, the molecular mechanisms are poorly understood. CD-1 mice were fed a basal diet or a basal diet containing low or high dose smokeless tobacco blend or high dose nicotine tartrate for 14 weeks. High dose tobacco blend and nicotine tartrate diets vs. basal diet reduced mouse body weight (16.3% and 19.7%, respectively), epididymal (67.6% and 72.5%, respectively) and brown adipose weight (42% and 38%, respectively), epididymal adipocyte size (46.4% and 41.4%, respectively), and brown adipose tissue lipid droplet abundance, with no elevation of adipose tissue inflammation. High dose tobacco blend and nicotine diets also increased mouse physical activity and decreased respiratory exchange ratio, suggesting that high dose nicotine intake induces adipose tissue triglyceride lipolysis to provide fatty acids as an energy source. Both low and high dose tobacco blend and nicotine diet feeding vs. basal diet increased plasma insulin levels (2.9, 3.6 and 4.3-fold, respectively) and improved blood glucose disposal without affecting insulin sensitivity. Feeding of the high dose tobacco blend or nicotine feeding in mice induces body weight loss likely by increasing physical activity and stimulating adipose tissue triglyceride lipolysis. PMID- 29421646 TI - Protective effects of dietary luteolin against mercuric chloride-induced lung injury in mice: Involvement of AKT/Nrf2 and NF-kappaB pathways. AB - Food-derived compound luteolin possesses multiple pharmacological activities. Accordingly, we focused on exploring the protective effects of luteolin (100 mg/kg) against mercuric chloride (HgCl2) (5 mg/kg) stimulated lung injury and the molecular mechanisms of lung protection effects in mouse. The influence of luteolin on histologic changes, oxidative stress, proinflammatory cytokine production, neutrophil activation, and apoptosis were assayed in HgCl2-induced lung injury. Luteolin administration attenuated pulmonary histologic conditions and apoptotic change. The protective effects of luteolin might be attributed to the reduction of myeloperoxidase, inflammatory cytokines, malondialdehyde, and the increase of superoxide dismutase and glutathione. Luteolin promoted protein kinase B (AKT) phosphorylation and translocation of nuclear factor erythroid 2 related factor 2 (Nrf2) into nucleus, and inhibited activation of nuclear factor kappa B (NF-kappaB) in HgCl2-induced lung injury. Taken together, dietary luteolin may be an effective candidate for treatment of HgCl2-induced lung injury by preventing NF-kappaB activation and activating AKT/Nrf2 pathway. PMID- 29421647 TI - Characterisation of the borgwaldt LM4E system for in vitro exposures to undiluted aerosols from next generation tobacco and nicotine products (NGPs). AB - Traditional in vitro exposure to combustible tobacco products utilise exposure systems that include the use of smoking machines to generate, dilute and deliver smoke to in vitro cell cultures. With reported lower emissions from next generation tobacco and nicotine products (NGPs), including e-cigarettes and tobacco heating products (THPs), diluting the aerosol is potentially not required. Herein we present a simplified exposure scenario to undiluted NGP aerosols, using a new puffing system called the LM4E. Nicotine delivery from an e cigarette was used as a dosimetry marker, and was measured at source across 4 LM4E ports and in the exposure chamber. Cell viability studies, using Neutral Red Uptake (NRU) assay, were performed using H292 human lung epithelial cells, testing undiluted aerosols from an e-cigarette and a THP. E-cigarette mean nicotine generated at source was measured at 0.084 +/- 0.005 mg/puff with no significant differences in delivery across the 4 different ports, p = 0.268 (n = 10/port). Mean nicotine delivery from the e-cigarette to the in vitro exposure chamber (measured up to 100 puffs) was 0.046 +/- 0.006 mg/puff, p = 0.061. Aerosol penetration within the LM4E was 55% from source to chamber. H292 cells were exposed to undiluted e-cigarette aerosol for 2 h (240 puffs) or undiluted THP aerosol for 1 h (120 puffs). There were positive correlations between puff number and nicotine in the exposed culture media, R2 = 0.764 for the e-cigarette and R2 = 0.970 for the THP. NRU determined cell viability for e-cigarettes after 2 h' exposure resulted in 21.5 +/- 17.0% cell survival, however for the THP, full cytotoxicity was reached after 1-h exposure. PMID- 29421648 TI - Curcumin ameliorates cadmium-induced nephrotoxicity in Sprague-Dawley rats. AB - Chronic exposure to cadmium (Cd) causes remarkable damage to the kidneys, a target organ of accumulated Cd after oral administration. The aim of the present study was to investigate the protective effect of curcumin against Cd-induced nephrotoxicity. Sprague-Dawley male rats were divided into the following four treatment groups: control, curcumin (50 mg/kg, oral), CdCl2, (25 mg/kg, oral), and pre-treatment with curcumin (50 mg/kg) 1 h prior to the administration of CdCl2 (25 mg/kg, oral) for 7 days. At 24 h after the final treatment, the animals were killed, and the biomarkers associated with nephrotoxicity were measured. Our data indicated that blood urea nitrogen (BUN) and serum creatinine (sCr) levels were significantly reduced by curcumin pre-treatment in CdCl2-treated animals. Histopathological studies showed hydropic swelling and hypertrophy of the proximal tubular cells in the renal cortex after Cd treatment. Pretreatment with curcumin ameliorated the histological alterations induced by Cd. The urinary excretion of kidney injury molecule-1 (Kim-1), osteopontin (OPN), tissue inhibitor of metalloproteinases 1 (TIMP-1), neutrophil gelatinase-associated lipocalin (NGAL), and netrin-1 significantly reduced by curcumin treatment compared to that in the CdCl2-treated group. The administration of curcumin provided a significant protective effect against Cd-induced nephrotoxicity. PMID- 29421649 TI - Polyamide magnetic palygorskite for the simultaneous removal of Hg(II) and methyl mercury; with factorial design analysis. AB - A novel efficient adsorbent was prepared by the modification of magnetic palygorskite (MPG) by polyamide via the interfacial polymerization of trimesoyl chloride with m-phenylenediamine. The prepared magnetic palygorskite modified with polyamide (MPGP) material was appraised for its removal of the Hg(II) and CH3Hg species from aqueous solutions. The developed adsorbent was characterized using spectroscopic techniques. The adsorption ability of the MPGP sorbent was systematically investigated by using the batch method. Factorial design analysis was applied to study the effect of different batch parameters on the adsorption yield of both mercury species. These factors include mercury concentration, initial pH, sorbent amount and contact time. The equilibrium data coincided with the Langmuir adsorption isotherm indicating the maximum adsorption capacity of the MPGP was determined as 211.93 mg/g for Hg(II) and 159.73 mg/g for CH3Hg. The kinetic mechanism of the adsorption of both mercury species was well defined by the pseudo-second-order while the adsorption processes demonstrated spontaneity and an exothermic character at the studied temperatures. The cycling adsorption/desorption tests made by using a 1 mol/L HCl solution demonstrated that the MPGP had good reusable performance up to seven cycles. Based on the results it can be suggested that the synthesized MPGP sorbent can be handled for the elimination of Hg(II) and CH3Hg from wastewater effluents. PMID- 29421650 TI - First report of an unusual novel double mutation affecting the transcription repression domain of MeCP2 and causing a severe phenotype of Rett syndrome: Molecular analyses and computational investigation. AB - Rett syndrome is an X-linked neurodevelopmental disorder that develops a profound intellectual and motor disability and affects 1 from 10 000 to 15 000 live female births. This disease is characterized by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress which is caused by mutations occurred in the X-linked MECP2 gene, encoding the methyl-CpG binding protein 2. This research study reports a molecular analysis via an exhaustive gene sequencing which reveals an unusual novel double mutation (c.695 G > T; c.880C > T) located in a highly conserved region in MECP2 gene affecting the transcription repression domain (TRD) of MeCP2 protein and leading for the first time to a severe phenotype of Rett syndrome. Moreover, a computational investigation of MECP2 mutations demonstrates that the novel mutation c.695 G > T is highly deleterious which affects the MeCP2 protein showing also an adverse impact on MECP2 gene expression and resulting in an affected folding and decreased stability of MECP2 structures. Thus, the altered TRD domain engenders a disrupted process of MECP2 functions. Therefore, this is the first study which highlights a novel double mutation among the transcription repression domain (TRD) of MeCP2 protein in Rett patient with a severe clinical phenotype in North Africa region. PMID- 29421651 TI - An update on oxysterol biochemistry: New discoveries in lipidomics. AB - Oxysterols are oxidised derivatives of cholesterol or its precursors post lanosterol. They are intermediates in the biosynthesis of bile acids, steroid hormones and 1,25-dihydroxyvitamin D3. Although often considered as metabolic intermediates there is a growing body of evidence that many oxysterols are bioactive and their absence or excess may be part of the cause of a disease phenotype. Using global lipidomics approaches oxysterols are underrepresented encouraging the development of targeted approaches. In this article, we discuss recent discoveries important in oxysterol biochemistry and some of the targeted lipidomic approaches used to make these discoveries. PMID- 29421652 TI - Functional and structural characterization of a beta-glucosidase involved in saponin metabolism from intestinal bacteria. AB - Saponins are natural glycosides widely used in medicine and the food industry. Although saponin metabolism in human is dependent on intestinal microbes, few involving bacteria enzymes have been identified. We cloned BlBG3, a GH3 beta glucosidase from Bifidobacterium longum, from human stool. We found that BlBG3 catalyzes the hydrolysis of glycoside furostanol and ginsenoside Rb1 at higher efficiency than other microbial beta-glucosidases. Structural analysis of BlBG3 in complex with d-glucose revealed its three unique loops, which form a deep pocket and participate in substrate binding. To understand how substrate is bound to the pocket, molecular docking was performed and the binding interactions of protobioside with BlBG3 were revealed. Mutational study suggested that R484 and H642 are critical for enzymatic activity. Our study presents the first structural and functional analysis of a saponin-processing enzyme from human microbiota. PMID- 29421653 TI - Modulation of hyaluronan polymer size regulates proliferation of perimysial fibroblasts in thyroid eye disease. AB - In active thyroid eye disease (TED), the extraocular muscles feature excessive hyaluronan (HA) accumulation and increased fibroblast proliferation. To investigate the effects of HA on proliferation, we cultured perimysial fibroblasts from extraocular muscles of active TED patients, and adopted IGF-1 and PH20 as modulators for HA concentration and HA polymer size. Based on the results, IGF-1 increased HA concentration, promoted high molecular weight HA (HMW HA) proportion and stimulated fibroblast proliferation. Hyaluronidase PH20 decreased HA concentration, but caused HMW-HA accumulation and exaggerating proliferation as well. Combined treatment with both reagents resulted in retention of low molecular weight HA (LMW-HA), and suppressed fibroblast proliferation. Pearson correlation demonstrated no significance between HA concentration and proliferation. Mitogenic investigation unveiled the stimulatory effects of HMW-HA via membrane depolarization and inhibitive effects of LMW-HA via membrane hyperpolarization. Our findings offer insights into the essential role of HA molecular weight during TED pathogenesis. PMID- 29421654 TI - Extracellular acidification by lactic acid suppresses glucose deprivation-induced cell death and autophagy in B16 melanoma cells. AB - In solid tumors, cancer cells survive and proliferate under conditions of microenvironment stress such as poor nutrients and hypoxia due to inadequate vascularization. These stress conditions in turn activate autophagy, which is important for cancer cell survival. However, autophagy has a contrary effect of inducing cell death in cancer cells cultured in vitro under conditions of glucose deprivation. In this study, we hypothesized that supplementation of lactic acid serves as a means of cell survival under glucose-deprived conditions. At neutral pH, cell death of B16 murine melanoma cells by autophagy under glucose-deprived conditions was observed. However, supplementation of lactic acid suppressed cell death and autophagy in B16 melanoma cells when cultured in glucose-deprived conditions. Sodium lactate, which does not change extracellular pH, did not inhibit cell death, while HCl-adjusted acidic pH suppressed cell death under glucose-deprived conditions. These results suggested that an acidic pH is crucial for cell survival under glucose-deprived conditions. PMID- 29421655 TI - Adamts18 deficiency increases arterial thrombus formation associated with vascular defects in mice. AB - ADAMTS18 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) that are known for their crucial role in development, angiogenesis, inflammation and coagulation. It was previously reported that ADAMTS18 cleaved by thrombin induced platelet fragmentation, through which thrombus were dissolved. However, it remains unclear whether this represents a dominant physiologic mechanism controlling thrombus growth in vivo. Here, we used an established Adamts18 knockout (KO) mouse model to determine its function in thrombus formation. ADAMTS18 deficiency accelerated FeCl3-induced carotid artery thrombosis and aggravated postischemic cerebral infarction in mice. However, this accelerated thrombus phenotype in Adamts18 KO mice was not due to the lack of ADAMTS18-mediated-platelet fragmentation. Moreover, Adamts18 deficiency exerted little effects on mouse platelet functions. The underlying molecular mechanisms could be attributed in part to the abnormal vascular remodeling, including deficiency of carotid body (glomus) and aberrant carotid basal lamina. These results indicate a novel function of ADAMTS18 in vascular remodeling and associated thrombus formation. PMID- 29421656 TI - Inhibition of 5-lipoxygenase represses neutrophils activation and activates apoptosis in pancreatic tissues during acute necrotizing pancreatitis. AB - Pancreatic glandular necrosis is rapid inflammation of the pancreas and contributes to severe acute pancreatitis in humans. The pathogenesis of pancreatic tissue inflammation during acute pancreatitis is still largely unknown. Recent studies suggest that 5-lipoxygenase (5-LOX) is an essential mediator in modulating cell death pathways in human diseases. In this study, we aimed to evaluate the effects of a 5-LOX inhibitor, zileuton, on tissue apoptosis and neutrophils activation in pancreatic tissues during acute necrotizing pancreatitis (ANP) in a rat model. In this present study, both mRNA and protein levels of 5-LOX are upregulated during ANP and zileuton treatment is shown to repress ANP-induced upregulation of 5-LOX levels. In addition, zileuton treatment is found to repress blood biomarkers of neutrophils activation such as soluble intercellular adhesive molecular 1 (ICAM-1), soluble E-selectin (E-selectin), soluble P-selectin (P-selectin), leukotriene B4 (LTB4), and myeloperoxidase (MPO). Also, zileuton treatment attenuates pancreatic tissue pathology, upregulates caspase-3, downregulates B-cell lymphoma 2 (Bcl-2), and activates tissue apoptosis evaluated by TUNEL staining. Our results show that 5-LOX plays an important role in activating apoptosis and repressing neutrophils activation during ANP. The current study suggests that 5-LOX can be used as a potential target for the treatment of ANP. PMID- 29421657 TI - Rabbit models provide insights into bone formation related biological process in atherosclerotic vascular calcification. AB - Featured as ectopic mineralization along blood vessels, vascular calcification is a major risk factor for a number of prevalent diseases including atherosclerosis. As recent studies identify vascular calcification as a tightly regulated process recapitulating embryonic bone formation, in this study, RNA-seq data generated from rabbit models with inherited or induced hyperlipidemia and atherosclerosis were used, to investigate bone formation related signals and biological processes in atherosclerotic vascular calcification. Evident activation of bone formation was found, together with presence and functioning of bone resorption cell osteoclasts, which were found to possibly also promote bone formation in this disease. Resistance of bone formation and calcification were also found, through down-regulation of pro-ossification regulators and up-regulation of protective inhibitors and Wnt antagonists. Levels of activation and resistance of bone formation differed between the two disease models, suggesting different underlying mechanisms and corresponding treatments. In addition, loss-of-function of protective inhibitors KL and SOST, and possibly crucial role of GPNMB were also highlighted for treatment or further study. PMID- 29421658 TI - Polyene phosphatidylcholine overcomes oxaliplatin resistance in human gastric cancer BGC823 cells. AB - Intrinsic or acquired resistance to oxaliplatin (L-OHP) is a major reason of treatment failure in gastric cancer and limits therapeutic success. Here we generated an oxaliplatin resistant gastric cancer cell line, BGC823/L-OHP, to investigate the effect of a hepatoprotective compound, polyene phosphatidylcholine (PPC), on conquest of oxaliplatin resistance. BGC823/L-OHP cells showed less sensitive to L-OHP directed growth inhibition than the parental BGC823 cells. PPC treatment significantly increased anti-proliferative activity of L-OHP on resistant cells and promoted L-OHP triggered apoptosis, indicating that drug resistance was overcome. Mechanistically, L-OHP incubation stimulated upregulation of an ABC family protein, ABCF2, and the expression was inhibited by PPC. Moreover, expression levels of the stemness factor Nanog and its regulator TLR4 were notably enhanced in BGC823/L-OHP cells and reduced by PPC treatment. To conclude, PPC can overcome oxaliplatin resistance in gastric cancer cells via promoting apoptosis, inhibiting ABCF2, as well via reducing cancer stem cell-like features. The combination therapeutic strategy could serve to increase oxaliplatin effectiveness in the clinic. PMID- 29421659 TI - RIP2 enhances cell survival by activation of NF-KB in triple negative breast cancer cells. AB - Receptor-interacting protein 2 (RIP2) is an essential mediator of inflammation and innate immunity, but little is known about its role outside the immune system. Recently, RIP2 has been linked to chemoresistance of triple negative breast cancer (TNBC), the most aggressive breast cancer subtype for which there is an urgent need for targeted therapies. In this study we show that high expression of RIP2 in breast tumors correlates with a worse prognosis and a higher risk of recurrence. We also demonstrate that RIP2 confers TNBC cell resistance against paclitaxel and ceramide-induced apoptosis. Overexpression of RIP2 lead to NF-kappaB activation, which contributed to higher expression of pro survival proteins and cell survival. Conversely, RIP2 knockdown inhibited NF kappaB signaling, reduced levels of anti-apoptotic proteins and sensitized cells to drug treatment. Together, these data show that RIP2 promotes survival of breast cancer cells through NF-kappaB activation and that targeting RIP2 may be therapeutically beneficial for treatment of TNBC. PMID- 29421660 TI - Liver-specific deletion of TSHR inhibits hepatic lipid accumulation in mice. AB - The effect of thyroid-stimulating hormone receptor (TSHR) on hepatic lipid accumulation in vivo is not fully understood. Further, while TSHR in the thyroid has been studied extensively, whether and how the absence of TSHR in the liver affects systemic energy metabolism has not yet been reported. To examine these effects, we generated hepatic TSHR conditional knockout (LT-KO) mice using Cre/LoxP recombination technology. The liver-specific TSHR-knockout (LT-KO) mice exhibited not only lower hepatic triglyceride and cholesterol contents due to modified synthesis and catabolism of lipids in the liver, but also decreased serum lipids, especially serum LDL-C levels. Abnormalities of TSHR in the thyroid affect whole-body energy balance; however, measurements taken in metabolic chambers showed that the hepatic TSHR conditional deletion had no impact on systemic energy metabolism. Unlike its critical role in maintaining the normal growth and function of the thyroid gland, our results demonstrated that hepatic TSHR is involved in liver lipid metabolism and has little effect on energy metabolism. PMID- 29421661 TI - Caspase independent cleavages of TDP-43 generates 35kD fragment that cause apoptosis of breast cancer cells. AB - Transactive response DNA-binding protein 43kD (TDP-43) is a major component of tau-negative and ubiquitin-positive inclusions that characterize ALS (amyotrophic lateral sclerosis) and FTLD (frontotemporal lobar degeneration). Due to its central role in neurodegenerative disease pathogenesis, most research recently has focused on its role associated with neurodegeneration disease, research on neuron and glial cell showed that pathological TDP-43 is associated with cell apoptosis which lead to loss of functional neurons and glial cells. However, little is known about its role on cancer cells, here we report a 35kD fragment of TDP-43 also plays a key role in apoptosis of breast cancer cells, and may be served as a potential therapeutic target to cure cancer. PMID- 29421662 TI - Deficiency of alpha Calcitonin-gene-related peptide impairs peri-implant angiogenesis and osseointegration via suppressive vasodilative activity. AB - Blood supply is essential for the bone healing process to obtain successful osseointegration. alpha Calcitonin gene-related peptide (alphaCGRP) is osteoanabolic and is the most potent microvascular vasodilator currently known with validated angiogenic effect in vitro. We previously demonstrated that lentiviral alphaCGRP overexpression vector system could express the gene effectively to enhance titanium implant osseointegration. In this study, we investigated the effect of alphaCGRP on peri-implant angiogenesis during healing process in vivo. Based on investigation of blood vessel alteration in the peri implant region of wild-type mice, we found a reduced angiogenesis alongside a decline in bone-implant contact percentage and bone mass in alphaCGRP -/- mice. Overexpression of alphaCGRP could partly rescue the impairment. Alterations were also detected in three-dimensional vascular structural parameters and expression of bone and vessel related genes. The results showed alphaCGRP increased vascular volume fraction and mean vessel size, as well as spatially relocated vessels approximate to the region of bone formation. And angiogenic and osteogenic genes were significantly upregulated in the transfection and alphaCGRP+/+ group. These results suggested that alphaCGRP played a synergic role in angiogenesis and osseointegration, partly as a consequence of its vasodilative activity. PMID- 29421663 TI - Hsa_circ_0001649: A circular RNA and potential novel biomarker for colorectal cancer. AB - The circRNAs are differentially expressed in a wide range of cancers in regulating their initiation and progression, and could be used to make a diagnosis for some diseases like tumor as a new biomarker. However, the correlation and the mechanism of action between circRNAs and colorectal cancer (CRC) are still unclear. In this study, by using qRT-PCRs, we detected the expression level of hsa_circ_0001649 in tissue and serum samples from CRC patients, and the cultured cell has been detected. We found that the hsa_circ_0001649 in CRC is significantly lower than the expression level of correspondent nontumorous tissues (n = 64, P < 0.01). We also tested the HCT116 cell lines, and the similar result is observed (n = 15, P < 0.01). Moreover, we detected the serum samples obtained before and after surgery, showing significantly the expression level of hsa_circ_0001649 in the same patient is up regulated after surgery (n = 18, P < 0.01). Besides, we analyzed the correlation between clinicopathological date and the expression level of hsa_circ_0001649, we found that hsa_circ_0001649 expression level is closely associated with pathological differentiation (P = 0.037), and the result also illustrated that the expression level of hsa_circ_0001649 is no direct correlation with age, gender, TMN stage, lymphatic metastasis, CEA, CA19-9, and CA-724 levels. The area under the receiver operating characteristic (ROC) curve was 0.857. In conclusion, this study showed that the expression level of hsa_circ_0001649 was down regulated in CRC and could use it as a new biomarker for specific and sensitive inspection of CRC. PMID- 29421664 TI - Epidemiology and outcome of paediatric out-of-hospital cardiac arrests: A paediatric sub-study of the Pan-Asian resuscitation outcomes study (PAROS). AB - BACKGROUND: The Pan Asian Resuscitation Outcomes Study (PAROS) is a retrospective study of out- of-hospital cardiac arrest(OHCA), collaborating with EMS agencies and academic centers in Japan, South Korea, Malaysia, Singapore, Taiwan, Thailand and UAE-Dubai. The objectives of this study is to describe the characteristics and outcomes, and to find factors associated with survival after paediatric OHCA. METHODS: We studied all children less than 17 years of age with OHCA conveyed by EMS and non-EMS transports from January 2009 to December 2012. We did univariate and multivariate logistic regression analyses to assess the factors associated with survival-to-discharge outcomes. RESULTS: A total of 974 children with OHCA were included. Bystander cardiopulmonary resuscitation rates ranged from 53.5% (Korea), 35.6% (Singapore) to 11.8% (UAE). Overall, 8.6% (range 0%-9.7%) of the children survived to discharge from hospital. Adolescents (13-17 years) had the highest survival rate of 13.8%. 3.7% of the children survived with good neurological outcomes of CPC 1 or 2. The independent pre-hospital factors associated with survival to discharge were witnessed arrest and initial shockable rhythm. In the sub-group analysis, pre-hospital advanced airway [odds ratio (OR) = 3.35, 95% confidence interval (CI) = 1.23-9.13] was positively associated with survival-to-discharge outcomes in children less than 13 years-old. Among adolescents, bystander CPR (OR = 2.74, 95%CI = 1.03-7.3) and initial shockable rhythm (OR = 20.51, 95%CI = 2.15-195.7) were positive factors. CONCLUSION: The wide variation in the survival outcomes amongst the seven countries in our study may be due to the differences in the delivery of pre-hospital interventions and bystander CPR rates. PMID- 29421665 TI - Inhaled hexadecyl-treprostinil provides pulmonary vasodilator activity at significantly lower plasma concentrations than infused treprostinil. AB - INS1009 is a long acting pulmonary vasodilator prodrug of treprostinil (TRE) that is formulated in a lipid nanoparticle for inhaled delivery by nebulization. This study examined the ability of INS1009 to inhibit vasoconstriction in the pulmonary vasculature of rats and dogs and the extent to which local activity within the lung contributes to its activity. Rats received a single dose of INS1009 by nose-only inhalation or were given a continuous intravenous (i.v.) infusion of TRE, followed by an i.v. challenge of the thromboxane mimetic pulmonary vasoconstrictor U46619 and the increase in pulmonary arterial pressure (PAP) was measured. In beagle dogs, INS1009 was given by inhalation via face mask and TRE was given by continuous i.v. infusion; vasoconstriction was then induced by inhaled hypoxia with reduction of FIO2 to 0.10. Changes in the dog's right ventricular pulse pressure (RVPP) were measured using implanted telemetry probes. Blood samples were collected in rats and dogs immediately after the challenge to measure the plasma TRE concentration. Exposure of rats to inhaled INS1009 (0.5, 3.0 and 20.9 MUg/kg) inhibited the U46619-induced increase in PAP at all doses up to 6 h with statistically significant inhibition up to 24 h with the pooled dose response data. The concentration of TRE in the plasma at which PAP was reduced by 50% was approximately 60-fold lower for INS1009 (EC50 = 0.08 ng/mL) as compared to i.v. TRE (EC50 = 4.9 ng/mL). In dogs, INS1009 (2.7-80.9 MUg/kg) inhibited the hypoxia-induced increase in RVPP at all doses up to 6 h with activity once again observed with the pooled dose-response of 10 MUg/kg and higher at 24 h. The concentration of TRE in the plasma at which RVPP was reduced by 50% was approximately 550-fold lower for INS1009 (EC50 = 0.0075 ng/mL) as compared to i.v. TRE (EC50 = 4.1 ng/mL). These studies, in two species and by two different pulmonary vasoconstrictor challenges, demonstrate that inhaled INS1009 not only has long-acting vasodilatory effects but also that the local activity within the lung contributes to this response. Therefore, INS1009 may offer the opportunity to effect pulmonary vasodilation for long periods but with substantially lower systemic exposure than infused TRE. PMID- 29421666 TI - Compatibility of medication with PRISCUS criteria and identification of drug interactions in a large cohort of patients with COPD. AB - Patients with COPD are often of advanced age and have a high number of medications due to their lung disease and comorbidities. Thus they are at risk for unwanted effects from drugs, either due to age or due to interactions between drugs. These issues are not clarified. We therefore assessed the number of medications and potential adverse effects in a large cohort of patients with COPD. The analysis was performed in 2741 patients of the German COPD cohort COSYCONET, using baseline data (visit 1) and follow-up data after about 1.5 years (visit 3). Spirometric GOLD grades 1-4 were found in 8/35/32/9% of patients and GOLD groups ABCD in 7/25/4/48% of patients, while the remaining patients (n = 450, 16.4%) could not be classified according to GOLD criteria. The compatibility of medication with age was evaluated via the PRISCUS list, drug interactions via the AiD clinic system, whereby only drug combinations occurring in at least 10 patients were considered (nine unwanted interactions, one wanted interaction). The median numbers of medications were 5 or more in all patient categories, among them 3 or more non-respiratory medications. In the total population there were 153 patients (10.2%) aged >=65 years who had any medication of the PRISCUS list with intermediate or low risk. Serious adverse combinations of drugs according to AiD occurred in 114 patients (4.2%), while the number of unwanted but only potentially clinically relevant combinations was 175 (6.4%). The number of wanted combinations was 219 (8.0%). These numbers did not markedly change when restricting the analysis to patients of GOLD grades 1-4. Moreover, the results were similar for visit 1 and visit 3. We conclude that in a large cohort of COPD patients about 10% of patients aged at least 65 years had medications that could interfere with their age and that the proportions of patients with either unwanted or wanted drug interactions were both in the range of 8-10%. These results suggest that problems arising from the high number of medications were not very frequent in the COPD cohort analysed. PMID- 29421667 TI - Socioeconomic factors associated with full childhood vaccination in Bangladesh, 2014. AB - OBJECTIVES: Childhood vaccination in Bangladesh has improved, but there is room for improvement. This study estimated full immunization coverage in Bangladeshi children and characterized risk factors for incomplete immunization. METHODS: Using the 2014 Bangladesh Demographic and Health Survey (DHS), full vaccination of children aged 12 to 24 months was examined; this was defined as the receipt of one dose of bacillus Calmette-Guerin (BCG), three doses of pentavalent vaccine, three doses of oral polio vaccine (OPV), and one dose of measles-containing vaccine (MCV). Associations between full vaccination and selected risk factors were assessed by logistic regression. RESULTS: Overall, 83% of children were fully vaccinated. BCG had the highest completion (97%), followed by OPV (92%), pentavalent vaccine (91%), and MCV (85%). Full vaccination coverage ranged from 64.4% in Sylhet to 90.0% in Rangpur and was lowest among non-locals of all regions (78.4%). Children who were in the lowest wealth quintile, who had mothers without antenatal care visits, or who had mothers without autonomy in healthcare decision-making were less likely to be fully vaccinated. CONCLUSIONS: Overall, full vaccination of children is high, but varies by vaccine type. Disparities still exist by wealth and by region. Maternal access to care and autonomy in healthcare decision-making are associated with higher vaccination coverage. PMID- 29421669 TI - The effects of polymer concentration, shear rate and temperature on the gelation time of aqueous Silica-Poly(ethylene-oxide) "Shake-gels". AB - HYPOTHESIS: Aqueous mixtures of silica and Poly(ethylene-oxide) (PEO) are known as "Shake-gels" due to the formation of reversible gels when subject to an applied force, such as shaking. This shear-thickening effect can be observed using a rheometer, via distinct and abrupt increases in the viscosity of the material. Preliminary experiments qualitatively showed that the time elapsed before this occurs, termed the gelation time, varied depending on the conditions used. This paper reports on a systematic study into the effects of polymer concentration, shear rate and temperature on the gelation time, to quantify any relationships that exist between the variables and develop understanding of the gelation mechanism and kinetics. EXPERIMENTS: Different constant shear rates were applied to samples at various polymer concentrations and temperatures using a rheometer with concentric cylinder geometry. FINDINGS: The gelation time varied significantly from several seconds to an hour or more and was exponentially accelerated by shear rate. A peak in gelation time occurred at medium polymer concentrations of 0.35-0.40% (25% silica) and at a temperature about 20 degrees C. Higher temperatures also exponentially accelerated the gelation time as kinetic effects dominated the thermodynamic and structural resistances to gel formation. PMID- 29421668 TI - First report of sporadic cases of Candida auris in Colombia. AB - BACKGROUND: Candida auris is a recently reported Candida species that is phenotypically similar to Candida haemulonii and related to hospital outbreaks. This organism can be misidentified as Candida haemulonii, Candida famata, Candida catenulata, or Rhodotorula glutinis by phenotypic approaches. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and DNA sequence analysis using internal transcribed spacer rDNA bar-coding provide an accurate identification. CASE REPORTS: Three cases of C. auris infection in patients with risk factors for fungal infection (one admitted to the intensive care unit, one with lymphoma, and one with HIV; all three with previous antibiotic use) are reported; these infections were not epidemiologically related. Yeast isolates were recovered from blood, ocular secretion, and bronchoalveolar lavage and were misidentified as C. catenulata and Candida albicans by the phenotypic MicroScan method. The isolates were confirmed to be C. auris by means of MALDI-TOF MS and DNA sequence analysis. Antifungal susceptibility testing was performed on these C. auris isolates, which exhibited high minimum inhibitory concentrations to triazoles and amphotericin B. One patient survived and the other two died. Only one of these deaths was related to fungemia. CONCLUSIONS: C. auris is an emerging and opportunistic multidrug resistant human pathogen. It is necessary to strengthen measures to achieve an accurate and quick identification and also to avoid its dissemination. This will require improvements in health and infection control measures, as well as the promotion of antifungal stewardship in healthcare facilities. PMID- 29421670 TI - Improvement of zinc substitution in the reactivity of magnetite coupled with aqueous Fe(II) towards nitrobenzene reduction. AB - The reduction of nitrobenzene (NB) by Zn-substituted magnetite coupled with aqueous Fe(II) was studied. A series of Zn-substituted magnetites (Fe3-xZnxO4, x = 0, 0.25, 0.49, 0.74, and 0.99) were synthesized by a coprecipitation method followed by systematic analysis of the variation in structure and physicochemical properties of magnetite using XRD, TEM, TG, BET and XAFS. All of the samples had a spinel structure by Zn substitution. Zn2+ primarily occupied the tetrahedral sites, but a portion of them moved to the octahedral sites at higher Zn level. Zn substitution increased the BET specific surface area and surface hydroxyl amount. The electron balance indicated that the NB reduction was primarily through the heterogeneous reaction by Fe3-xZnxO4 and adsorbed Fe(II), where NB in aqueous solution was reduced by structural Fe2+ in magnetite recharged by adsorbed Fe(II). Various factors, such as aqueous Fe(II) concentration, magnetite stoichiometry and Zn level, were investigated to illustrate their effects on the reduction processes. Both the rate constant kobs and electron transfer amount illustrated that Zn substitution generally improved the reduction activity of the Fe3-xZnxO4/Fe(II) system, while overdose of Zn retarded the process. This issue was attributed to the variation in electron conductivity of Fe3-xZnxO4 and Zn2+ occupancy. PMID- 29421671 TI - Self-assembled gelatin-iota-carrageenan encapsulation structures for intestinal targeted release applications. AB - In this work, natural biopolymeric encapsulation structures were developed through the self-assembly of gelatin and iota-carrageenan in aqueous solutions. The interactions of this binary system and of a ternary system containing a polyphenol-rich extract were deeply explored for the development of intestinal delivery systems. The processing of the structures (extrusion vs. freeze-drying) greatly influenced release properties, explained by the specific interactions between gelatin and polyphenols, thus allowing for tuning the processing conditions depending on the desired target application. Release was further controlled by incorporating a divalent salt, giving raise to extract-loaded iota carrageenan/gelatin capsules with adequate release profiles for intestinal targeted delivery. These results demonstrate the potential of exploiting biopolymer interactions for designing bioactive delivery systems using environmentally friendly processes which do not involve the use of toxic or harsh solvents or cross-linkers. PMID- 29421672 TI - Magnetic cobaltic nanoparticle-anchored carbon nanocomposite derived from cobalt dipicolinic acid coordination polymer: An enhanced catalyst for environmental oxidative and reductive reactions. AB - Direct carbonization of cobalt complexes represents as a convenient approach to prepare magnetic carbon/cobalt nanocomposites (MCCNs) as heterogeneous environmental catalysts. However, most of MCCNs derived from consist of sheet like carbon matrices with very sparse cobaltic nanoparticles (NPs), making them exhibit relatively low catalytic activities, porosity and magnetism. In this study, dipicolinic acid (DPA) is selected to prepare a 3-dimensional cobalt coordination polymer (CoDPA). MCCN derived from CoDPA can consist of a porous carbon matrix embedded with highly-dense Co0 and Co3O4 NPs. This magnetic Co0/Co3O4 NP-anchored carbon composite (MCNC) appears as a promising heterogeneous catalyst for oxidative and reductive environmental catalytic reactions. As peroxymonosulfate (PMS) activation is selected as a model catalytic oxidative reaction, MCNC exhibits a much higher catalytic activity than Co3O4, a benchmark catalyst for PMS activation. The reductive catalytic activity of MCNC is demonstrated through 4-nitrophenol (4-NP) reduction in the presence of NaBH4. MCNC could rapidly react with NaBH4 to generate H2 for hydrogenation of 4-NP to 4 aminophenol (4-AP). In comparison with other precious metallic catalysts, MCNC also shows a relatively high catalytic activity. These results indicate that MCNC is a conveniently prepared and highly effective and stable carbon-supported cobaltic heterogeneous catalyst for versatile environmental catalytic applications. PMID- 29421673 TI - N-doped carbon coated anatase TiO2 nanoparticles as superior Na-ion battery anodes. AB - N-doped carbon coated TiO2 nanoparticles (TiO2@NC) were synthesized through a simple two-step route, in which dopamine was simultaneously utilized as both nitrogen and carbon sources. With TiO2@NC applied in the Na-ion battery (SIB) anodes, the continuous and uniform N-doped carbon layer can not only enhance the electrical conductivity of TiO2 and facilitate the surface pseudocapacitive process, but also serve as a buffer layer to accommodate the volume expansion during the sodiation-desodiation processes. The as-prepared TiO2@NC exhibits excellent electrochemical performance when utilized as the SIB anodes, which delivers a remarkably high reversible capacity of 250.2 mAh g-1 at a rate of 0.25C (84 mA g-1) after 200 cycles and still retains 122.1 mAh g-1 at 10C (3.35 A g-1) even after 3000 cycles accompanied with a 95.3% retention of the maximum capacity, outperforming most of the reported TiO2/C-based composites as SIB anodes. To our best knowledge, the preparation of TiO2@NC with dopamine as both nitrogen and carbon sources and its application in the SIB anodes are reported for the first time. PMID- 29421674 TI - Highly selective oxidation of styrene to benzaldehyde over a tailor-made cobalt oxide encapsulated zeolite catalyst. AB - A tailor-made catalyst with cobalt oxide particles encapsulated into ZSM-5 zeolites (Co3O4@HZSM-5) was prepared via a hydrothermal method with the conventional impregnated Co3O4/SiO2 catalyst as the precursor and Si source. Various characterization results show that the Co3O4@HZSM-5 catalyst has well organized structure with Co3O4 particles compatibly encapsulated in the zeolite crystals. The Co3O4@HZSM-5 catalyst was employed as an efficient catalyst for the selective oxidation of styrene to benzaldehyde with hydrogen peroxide as a green and economic oxidant. The effect of various reaction conditions including reaction time, reaction temperature, different kinds of solvents, styrene/H2O2 molar ratio and catalyst dosage on the catalytic performance were systematically investigated. Under the optimized reaction condition, the yield of benzaldehyde can achieve 78.9% with 96.8% styrene conversion and 81.5% benzaldehyde selectivity. Such an excellent catalytic performance can be attributed to the synergistic effect between the confined reaction environment and the proper acidic property. In addition, the reaction mechanism with Co3O4@HZSM-5 as the catalyst for the selective oxidation of styrene to benzaldehyde was reasonably proposed. PMID- 29421675 TI - Surface and anti-fouling properties of a polyampholyte hydrogel grafted onto a polyethersulfone membrane. AB - Zwitterion polymers have anti-fouling properties; therefore, grafting new zwitterions to surfaces, particularly as hydrogels, is one of the leading research directions for preventing fouling. Specifically, polyampholytes, polymers of random mixed charged subunits with a net-electric charge, offer a synthetically easy alternative for studying new zwitterions with a broad spectrum of charged moieties. Here, a novel polyampholyte hydrogel was grafted onto the surface of polyethersulfone membrane by copolymerizing a mixture of vinylsulfonic acid (VSA) and [2-(methacryloyloxy)ethyl]trimethylammonium chloride (METMAC) as the negatively and positively charged monomers, respectively, using various monomer ratios in the polymerization solution, and with N,N' methylenebisacrylamide as the crosslinker. The physicochemical, morphological and anti-fouling properties of the modified membranes were systematically investigated. Hydrophilic hydrogels were successfully grafted using monomers at different molar ratios. A thin-film zwitterion hydrogel (~90 nm) was achieved at a 3:1 [VSA:METMAC] molar ratio in the polymerization solution. Among all examined membranes, the zwitterion polyampholyte-modified membrane demonstrated the lowest adsorption of proteins, humic acid, and sodium alginate. It also had low fouling and high flux recovery following filtration with a protein or with an extracellular polymeric substance solution. These findings suggest that this polyampholyte hydrogel is applicable as a low fouling surface coating. PMID- 29421676 TI - Dynamic forces between emulsified water drops coated with Poly-Glycerol-Poly Ricinoleate (PGPR) in canola oil. AB - The dynamic collision of emulsified water drops in the presence of non-ionic surfactants plays a crucial role in many practical applications. Interaction force between water drops coated with non-ionic food grade surfactants is expected to exhibit rich dynamic behavior that is not yet explored. The collision forces between immobilized water drops in canola oil in the presence of a well known food grade surfactant polyglycerol polyricinoleate (PGPR) are measured at concentrations well below typically used to form stable emulsions. An extension or kink, attributed to a short-range attractive interaction due to PGPR bridging between the drops, was observed in the retract portion of the force curves at higher applied forces or slower collision velocities. The Stokes-Reynolds-Young Laplace (SRYL) model was used to calculate theoretical force curves. For higher collisions velocities, the agreement between the calculated and experiment data was acceptable, but the SRYL model failed to describe the extension or kink feature observed at slower velocities below. Both the AFM data and the comparison to the model calculation indicated the presence of a short-range attractive force, not of a hydrodynamic origin, attributed to the bridging and extension of PGPR molecules on the surface of water drops below saturation of the interface. PMID- 29421677 TI - Graphene oxide/chitosan sponge as a novel filtering material for the removal of dye from water. AB - Although graphene oxide (GO)-based materials are attractive media for water treatment, their separation from water for reuse remains a challenge. This study investigated the self-assembly of GO sheets in the presence of chitosan (CS), a natural polyaminosaccharide, into sponges. We found that about 93% of added CS could be combined with GO, regardless of the CS concentration. There exists an upper critical gelation limit, below which hydrogel forms and above which precipitation takes place. Results indicate that upon freeze-drying, a stable GO/CS sponge was generated only at a CS content of >=9%. Sponges with CS content between 9% and 41% had good filtering performance. The sponges were characterized with XRD, SEM and FTIR measurements and the interaction between GO and CS was analyzed. The GO/CS sponge with CS content of 9% had adsorption capacity of 275.5 mg/g for methylene blue (MB), a model dye molecule. Both electrostatic attraction and hydrophobic interactions are responsible for MB adsorption by GO/CS sponges. The GO/CS sponge could be regenerated for repeated use using 0.5 M NaOH solution as desorption reagent. Our fixed-bed column studies illustrate that the GO/CS sponge performed well as a filtering material for removing MB from water. PMID- 29421678 TI - Enhanced generation of hydroxyl radicals on well-crystallized molybdenum trioxide/nano-graphite anode with sesame cake-like structure for degradation of bio-refractory antibiotic. AB - Anodic electro-catalysis oxidation is a highly effective way to solve the pollution problem of antibiotics in wastewater and receiving water bodies. In this study, for the first time, molybdenum trioxide/Nano-graphite (MoO3/Nano-G) composites are synthesized as anodic catalysts by a surfactant-assisted solvothermal method followed by low-temperature calcination. The effects of the proportion of MoO3 to Nano-G (10, 30 and 50%) on the properties of composites are investigated through structural characterizations and electrochemical measurements. Results indicate that MoO3(30)/Nano-G electrode displays the electro-catalysis degradation efficiency of 99.9% towards ceftazidime, which is much higher than those of Nano-G (46.7%) and dimensionally stable anode (69.2%). The degradation mechanism for ceftazidime is studied by investigating the yields and kinds of active species. Results show that all of the OH, O2- and H2O2 are responsible for the electro-catalytic degradation process, and the produced OH radicals are the major active species for ceftazidime degradation. The synergistic effects between MoO3 and Nano-G greatly contribute to the activation of H2O molecules to produce OH, meanwhile the special sesame cake-like structure facilitates to the exposure of contaminants to OH on active sites to enhance the degradation efficiency. These results suggest that MoO3/Nano-G electrodes can be considered as the promising catalysts for treating bio-refractory organic wastewater. PMID- 29421679 TI - Reinforced carbon fiber laminates with oriented carbon nanotube epoxy nanocomposites: Magnetic field assisted alignment and cryogenic temperature mechanical properties. AB - The epoxy nanocomposites with ordered multi-walled carbon nanotubes (MWCNTs) were used to influence the micro-cracks resistance of carbon fiber reinforced epoxy (CF/EP) laminate at 77 K, Oxidized MWCNTs functionalized with Fe3O4 (Fe3O4/O MWCNTs) with good magnetic properties were prepared by co-precipitation method and used to modify epoxy (EP) for cryogenic applications. Fe3O4/O-MWCNTs reinforced carbon fiber epoxy composites were also prepared through vacuum assisted resin transfer molding (VARTM). The ordered Fe3O4/O-MWCNTs were observed to have effectively improved the mechanical properties of epoxy (EP) matrix at 77 K and reduce the coefficient of thermal expansion (CTE) of EP matrix. The ordered Fe3O4/O-MWCNTs also obviously improved the micro-cracks resistance of CF/EP composites at 77 K. Compared to neat EP, the CTE of ordered Fe3O4/O-MWCNTs modified CF/EP composites was decreased 37.6%. Compared to CF/EP composites, the micro-cracks density of ordered Fe3O4/O-MWCNTs modified CF/EP composites at 77 K was decreased 37.2%. PMID- 29421680 TI - Inhibitory effect of konjac glucomanan on pitting corrosion of AA5052 aluminium alloy in NaCl solution. AB - A natural carbohydrate polymer, konjac glucomanan, has been extracted from commercial product and studied as a green corrosion inhibitor for AA5052 aluminium alloy in 3.5 wt% NaCl solution by high-performance gel permeation chromatography (GPC), thermo gravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectra, electrochemical measurement and surface characterization techniques. The results of GPC measurements suggest the weight average molecular weight and the number-average molecular weight of KGM with 98.2% purity are 1.61 * 105 g/mol and 1.54 * 105 g/mol, respectively. Potentiodynamic polarization curves show konjac glucomanan behaves as a mixed type inhibitor with dominant anodic effect and that its maximum efficiency at 200 ppm is 94%. Electrochemical impedance spectroscopy (EIS) studies reveal the resistance of oxide film is approximately two orders of magnitude greater than the resistance of adsorbed inhibitor layer and that they both increase with KGM concentration. Moreover, in-situ electrochemical noise (EN) detection demonstrates that the growth and propagation stages of the pitting corrosion germinating on metal surface are blocked by polysaccharide additive, which is confirmed by the surface analysis of aluminium alloy using scanning electron microscope (SEM), energy dispersive spectroscopy (EDS) and Raman spectroscopy. At last, it is found that the addition of KGM makes it harder for water droplet containing NaCl to wet the metallic substrate. PMID- 29421681 TI - Synthesis of highly porous inorganic adsorbents derived from metal-organic frameworks and their application in efficient elimination of mercury(II). AB - Innovative solid-phase adsorbent is needed urgently for highly efficient extraction of mercury (Hg(II)) from aqueous solution. Herein, highly porous inorganic materials, including ZrOx, ZrOxyPhos and ZrSulf, were obtained from topotactic transformations of metal-organic frameworks (MOFs) via a facile ligand extraction process, which preserved the original MOF morphology and introduced useful functionalities. ZrOx and ZrOxyPhos exhibited high adsorption efficiency for Hg(II). And ZrSulf showed fastest adsorption kinetics (1.1 * 10-2 g/(mg min)) and highest adsorption capacity (824 mg/g) among the obtained three inorganic materials due to the presence of accessible sulfur-based functionality, which surpassed most of other benchmark porous adsorbents. Moreover, ZrSulf showed good regeneration ability and excellent selectivity for Hg(II) in the presence of other coexisting metal ions, such as Cd(II), Ni(II), Co(II), Mn(II) and Zn(II), and other inorganic cations, such as K+ and Na+. The excellent adsorption performance of ZrSulf towards Hg(II) can be traceable to the covalent bond formation with sulfur-based functionality combined with ion exchange with Na. Given its low-cost and easy preparation nature, ZrSulf could be potentially valuable candidates for the elimination of Hg(II) from aqueous media. Changing the MOF templates and using different digest solutions will introduce different metal and structural possibilities, which demonstrates the potential of such ligand extraction method for synthesizing porous inorganic adsorbents for heavy metal ion decontamination. PMID- 29421682 TI - Free-standing and flexible organic cathode based on aromatic carbonyl compound/carbon nanotube composite for lithium and sodium organic batteries. AB - Free-standing and flexible organic cathode based on aromatic carbonyl compound/carbon nanotubes (CNTs) has been successfully synthesized by a simple vacuum filtration strategy. The obtained flexible and free-standing film could be directly used as the binder-, additive- and current collector-free cathode for lithium ion batteries (LIBs) and sodium ion batteries (SIBs). Benefitting from the synergistic effect provided by the aromatic carbonyl compound and CNTs, the flexible organic cathode shows excellent lithium and sodium storage properties, including high reversible capacity (~150 mAh g-1 at 50 mA g-1 for LIBs and 57.8 mAh g-1 at 25 mA g-1 for SIBs), excellent cycling stability (over 500 cycles for LIBs and 300 cycles for SIBs) and good rate capability (48 mAh g-1 even at 2000 mA g-1 for LIBs and 48 mAh g-1 even at 1000 mA g-1 for SIBs). In view of the simple preparation process and excellent performance, the proposed strategy might open new avenues for the design of high-performance flexible organic electrode for the application in energy storage and conversion. PMID- 29421683 TI - CuS/RGO hybrid photocatalyst for full solar spectrum photoreduction from UV/Vis to near-infrared light. AB - To make full use of the solar energy, it remains a great challenge for semiconductor photocatalysts to harvest the full solar light spectrum from ultraviolet (UV) to visible even the near infrared (NIR) wavelength. Here we show firstly the CuS/RGO (reduced graphene oxide) hybrid photocatalyst synthesized via a microwave assisted method with full solar light (UV-Vis-NIR) active for efficient Cr(VI) reduction. The CuS/RGO displays high absorption and catalytic activity in the UV, visible and even the NIR light regions. As co-catalyst, RGO can separate and inhibit the recombination of charge carriers, consequently improving the catalytic activity. Only 1wt% RGO emersions can reduce 90% of Cr(VI) under the radiation of light over the full spectrum. Findings may provide a new strategy and substance to expand the utilization range of solar light from UV to visible even the NIR energy. PMID- 29421684 TI - Porous microcapsules with tunable pore sizes provide easily controllable release and bioactivity. AB - In this paper, porous microcapsules with tunable pore sizes were prepared using interfacial polymerization by employing a temperature-responsive cross-linking agent above its so-called cloud point temperature (Tscp). The influences of porosity on the surface morphology, release profile and biological activity of the microcapsules were investigated. The results showed that both pore size and pore density could be controlled by regulating either the amount of cross-linking agent or the ratio of core material to shell material. Furthermore, the porosity of the microcapsules determined their release properties and further regulated the bioactivity of the microcapsules. In addition, the mechanism of pore formation was confirmed by investigating the morphology of microcapsules below the Tscp. The microencapsulation methodology described here is convenient and versatile, which can be easily extended to encapsulate a broad range of lipophilic core materials. PMID- 29421685 TI - Surface sodium lignosulphonate-immobilized sawdust particle as an efficient adsorbent for capturing Hg2+ from aqueous solution. AB - In this work, the soluble sodium lignosulphonate (LSNa) molecules were successfully grafted onto the surface of pine sawdust (PSD) particles to obtain an efficient adsorbent (PSD-LS) for removing Hg2+ from wastewater. In advance, the surface of sawdust particles were carboxymethylated by chloroacetic acid, the LSNa would be anchored on the surface by a heterogeneous esterification reaction occurred between the hydroxyl of LSNa and carboxyl on PSD surface. The resultant product (PSD-LS) exhibited a good adsorption performance for Hg2+ with adsorption capacity up to 164.77 mg/g and it was characterized by scanning electron microscope (SEM), energy dispersive X-ray diffraction (EDX), Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). The effects of pH, contact time, adsorption temperature and initial concentration on the adsorption of Hg2+ were investigated. Results showed that the pseudo-second-order kinetics and Langmuir isotherm model could describe the adsorption process better. In addition, the composite adsorbent has outstanding reusability with high and stable desorption rates under several continuous cycle. These findings suggested that PSD-LS was a potential adsorbent to remove hazardous metal ions from wastewater. PMID- 29421686 TI - Fabrication of anti-fouling, anti-bacterial and non-clotting PVDF membranes through one step "outside-in" interface segregation strategy. AB - Herein we provide an "outside-in" interface segregation strategy to modify polyvinylidene fluoride (PVDF) membranes with anti-fouling, anti-bacterial and non-clotting performances for the first time. The coagulation bath composed of DMAc, water and synthesized copolymer was used to solidify and modify membrane during phase inversion process. The functional polymer e.g. poly(vinylpyrrolidone vinyltriethoxysilane) (PVP-VTES), poly(dimethylamino ethyl methacrylate vinyltriethoxysilane) (PDMAEMA-VTES), poly(acrylic acid-sodium p-styrene sulfonate-vinyltriethoxysilane) (PAA-SSNa-VTES) was segregated into membrane interface from outside coagulation bath. Further hydro-thermal reaction was implemented to crosslink the functional copolymer on membrane surface. The surface chemistry (ATR-FTIR, XPS) and physical properties (SEM, contact angle, flux) confirmed surface segregation of corresponding copolymer. The membranes showed excellent anti-fouling (BSA adsorption ~19.1 MUg/cm2), anti-bacterial (E. coli inhibition) and non-clotting (extended APTT, PT, TT and reduced FIB) performances respectively, which is clinically significant to hemocompatible membranes. The non-clotting membrane showed unprecedented prolonged activated partial thromboplastin time (APTT ~ 53 s when sample area is minimized to 1/32 cm2). The thermodynamic segregation of the copolymer driven by surface tension and membrane gelation kinetics was investigated to understand the "outside-in" interface segregation route during phase inversion. Overall, the membrane fabrication and modification can be finished simultaneously in ~2 min, demonstrating its potential in a continuous large scale production. PMID- 29421687 TI - Baseline Blood Pressure, the 2017 ACC/AHA High Blood Pressure Guidelines, and Long-Term Cardiovascular Risk in SPRINT. AB - BACKGROUND: The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines include lower thresholds to define hypertension than previous guidelines. Little is known about the impact of these guideline changes in patients with or at high risk for cardiovascular disease. METHODS: In this exploratory analysis using baseline blood pressure assessments in Systolic Blood Pressure Intervention Trial (SPRINT), we evaluated the prevalence and associated cardiovascular prognosis of patients newly reclassified with hypertension based on the 2017 ACC/AHA (systolic blood pressure >=130 mm Hg or diastolic blood pressure >=80 mm Hg) compared with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) guidelines (systolic blood pressure >=140 mm Hg or diastolic blood pressure >=90 mm Hg). The primary endpoint was the composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or cardiovascular death. RESULTS: In 4683 patients assigned to the standard treatment arm of SPRINT, 2328 (49.7%) met hypertension thresholds by JNC 7 guidelines, and another 1424 (30.4%) were newly reclassified as having hypertension based on the 2017 ACC/AHA guidelines. Over 3.3-year median follow up, 319 patients experienced the primary endpoint (87 of whom were newly reclassified with hypertension based on the revised guidelines). Patients with hypertension based on prior guidelines compared with those newly identified with hypertension based on the new guidelines had similar risk of the primary endpoint (2.3 [95% confidence interval {CI}, 2.0-2.7] vs 2.0 [95% CI, 1.6-2.4] events per 100 patient-years; adjusted HR, 1.10 [95% CI, 0.84-1.44]; P = .48). CONCLUSIONS: The 2017 ACC/AHA high blood pressure guidelines are expected to significantly increase the prevalence of patients with hypertension (perhaps to a greater extent in higher-risk patient cohorts compared with the general population) and identify greater numbers of patients who will ultimately experience adverse cardiovascular events. PMID- 29421688 TI - First Portrait of a Syphilitic Patient: Ulrich von Hutten. PMID- 29421690 TI - Social Determinants of Treatment Response. AB - Socioeconomic status is consistently linked to population health and specifically to the finding that there is decreasing health associated with decreasing social position. Despite the substantial literature, an analogous literature that is focused on clinical practice, and especially consideration of the individual, is almost nonexistent. Even in the absence of these data, physicians routinely incorporate patient life experience (biography) into their estimation of a patient's clinical trajectory (prognosis) and when making therapeutic decisions. Some advances have occurred that strengthen the evidence base, such as the US Food and Drug Administration decision to show all results from randomized controlled trials on newly approved drugs by age, sex, and race. In this article we review the current status of research on the impact of social determinants of treatment response and illustrate the important role of the therapeutic context in both research and practice. Examples are provided in which a patient's "biography" alters treatment response in subgroups of the population studied. We also provide examples in which multi-omic data and biographical information in a single individual can illuminate the clinical expression of disease. Finally, we suggest a research agenda that would better support physicians who use social and behavioral features as important elements in their decision making in clinical care. PMID- 29421689 TI - Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension. AB - BACKGROUND: Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction. METHODS: Using an adjusted model for age, sex, pulmonary vascular resistance, and medication use, associations of fasting blood glucose, glycated hemoglobin, and the presence of diabetes mellitus were evaluated with markers of disease severity in 162 patients with pulmonary arterial hypertension. RESULTS: A surrogate measure of increased pulmonary artery stiffness, elevated pulmonary arterial elastance (P = .012), along with reduced log(pulmonary artery capacitance) (P = .006) were significantly associated with the presence of diabetes mellitus in patients with pulmonary arterial hypertension in a fully adjusted model. Similar associations between pulmonary arterial elastance and capacitance were noted with both fasting blood glucose and glycated hemoglobin. Furthermore, right ventricular wall thickness on echocardiography was greater in pulmonary arterial hypertension patients with diabetes, supporting the link between right ventricular remodeling and diabetes. CONCLUSION: Cumulatively, these data demonstrate that an increase in right ventricular afterload, beyond pulmonary vascular resistance alone, may influence right ventricular remodeling and provide a mechanistic link between the susceptibility to right ventricular dysfunction in patients with both diabetes mellitus and pulmonary arterial hypertension. PMID- 29421691 TI - The development of an IgG avidity Western blot with potential to differentiate patients with active Lyme borreliosis from those with past infection. AB - OBJECTIVES: Current serological methods cannot distinguish active from past infection with Borrelia burgdorferi sensu lato. The aim of this study was to develop an IgG avidity Western blot and assess its potential to differentiate patients with early and late Lyme borreliosis (LB) i.e. active disease, from those infected in the past. METHODS: An IgG avidity Western blot was developed. Penalized linear discriminant analysis (PLDA) was employed to compare the Western blot/avidity Western blot profiles of an evaluation panel consisting of 75 sera from patients with early (n = 26) and late (n = 24) LB and past infection (n = 25). The PLDA models produced were used to predict infection stage for 20 well characterised sera from the Centers for Disease Control and Prevention (CDC) Lyme disease serum repository and 112 routine seropositive sera (disease stage unknown), to validate and assess the usefulness of the avidity Western blot/avidity Western blot and PLDA approach. RESULTS: PLDA correctly classified 40/51 (78%) of patients when early LB and past infection groups in the evaluation panel were compared. Likewise, when late LB and past infection groups were compared, 34/49 (69%) were correct. The resultant PLDA models correctly predicted infection stage for 18/20 (90%) of the CDC sera, validating the use of the avidity Western blot/avidity Western blot and PLDA approach. When tested with the routine sera, 21/29 (72%) tested with the early LB vs. past infection model were correct but only 32/83 (39%) with the late LB vs. past infection model. Past infection was predicted for 40/112 (35%) of the routine sera, 80% of which correlated with the clinical picture. CONCLUSION: The Western blot/avidity Western blot with PLDA approach shows exciting potential for being able to predict disease stage in some patients with LB, which could improve patient management. PMID- 29421692 TI - Evaluating the Impact of Breast Density on Preoperative MRI in Invasive Lobular Carcinoma. AB - BACKGROUND: The focus of this study was to assess the accuracy of breast MRI in predicting pathologic tumor size in invasive lobular carcinoma (ILC) and to evaluate the incidence and factors associated with the detection of additional MRI lesions in ILC patients. STUDY DESIGN: We retrospectively reviewed data from patients with stage I to III ILC diagnosed between 2010 and 2016 at our institution. Univariable and multivariable logistic regression were used to determine factors associated with detection of additional suspicious lesions on MRI. RESULTS: The cohort included 99 women with ILC who underwent preoperative MRI, with a median age of 61 years (range 35 to 80 years). The sensitivity of MRI for detecting invasive lobular carcinoma was 99%, higher than that of mammography (68%) and ultrasound (92%). Mammography and ultrasound had a tendency to underestimate ILC, and MRI estimates of final tumor size were concordant in the majority (58.6%) of cases, with a median discordance of -2 mm. Magnetic resonance imaging detected additional ipsilateral malignancy in 23.2%, occult contralateral disease in 3.0%, and altered surgical management in 29.3% of ILC cases. In multivariable analyses, factors significantly associated with additional suspicious findings on MRI included higher breast density (odds ratio 3.19; 95% CI 1.01 to 10.0) and lymph node-positive disease (odds ratio 4.02; 95% CI 0.96 to 16.9). CONCLUSIONS: Preoperative MRI is a useful adjunct to conventional breast imaging in ILC, particularly in women with dense breast tissue. PMID- 29421693 TI - Enhanced Recovery after Colorectal Surgery: Can We Afford Not to Use It? AB - BACKGROUND: Enhanced recovery pathways (ERPs) aim to reduce length of stay without adversely affecting short-term outcomes. High pharmaceutical costs associated with ERP regimens, however, remain a significant barrier to widespread implementation. We hypothesized that ERP would reduce hospital costs after elective colorectal resections, despite the use of more expensive pharmaceutical agents. STUDY DESIGN: An ERP was implemented in January 2016 at our institution. We collected data on consecutive colorectal resections for 1 year before adoption of ERP (traditional, n = 160) and compared them with consecutive resections after universal adoption of ERP (n = 146). Short-term surgical outcomes, total direct costs, and direct hospital pharmacy costs were compared between patients who received the ERP and those who did not. RESULTS: After implementation of the ERP, median length of stay decreased from 5.0 to 3.0 days (p < 0.01). There were no differences in 30-day complications (8.1% vs 8.9%) or hospital readmission (11.9% vs 11.0%). The ERP patients required significantly less narcotics during their index hospitalization (211.7 vs 720.2 morphine equivalence units; p < 0.01) and tolerated a regular diet 1 day sooner (p < 0.01). Despite a higher daily pharmacy cost ($477 per day vs $318 per day in the traditional cohort), the total direct pharmacy cost for the hospitalization was reduced in ERP patients ($1,534 vs $1,859; p = 0.016). Total direct cost was also lower in ERP patients ($9,791 vs $11,508; p = 0.004). CONCLUSIONS: Implementation of an ERP for patients undergoing elective colorectal resection substantially reduced length of stay, total hospital cost, and direct pharmacy cost without increasing complications or readmission rates. Enhanced recovery pathway after colorectal resection has both clinical and financial benefits. Widespread implementation has the potential for a dramatic impact on healthcare costs. PMID- 29421694 TI - Resuscitative Endovascular Balloon Occlusion of the Aorta and Resuscitative Thoracotomy in Select Patients with Hemorrhagic Shock: Early Results from the American Association for the Surgery of Trauma's Aortic Occlusion in Resuscitation for Trauma and Acute Care Surgery Registry. AB - BACKGROUND: Aortic occlusion is a potentially valuable tool for early resuscitation in patients nearing extremis or in arrest from severe hemorrhage. STUDY DESIGN: The American Association for the Surgery of Trauma's Aortic Occlusion in Resuscitation for Trauma and Acute Care Surgery registry identified trauma patients without penetrating thoracic injury undergoing aortic occlusion at the level of the descending thoracic aorta (resuscitative thoracotomy [RT] or zone 1 resuscitative endovascular balloon occlusion of the aorta [REBOA]) in the emergency department (ED). Survival outcomes relative to the timing of CPR need and admission hemodynamic status were examined. RESULTS: Two hundred and eighty five patients were included: 81.8% were males, with injury due to penetrating mechanisms in 41.4%; median age was 35.0 years (interquartile range 29 years) and median Injury Severity Score was 34.0 (interquartile range 18). Resuscitative thoracotomy was used in 71%, and zone 1 REBOA in 29%. Overall survival beyond the ED was 50% (RT 44%, REBOA 63%; p = 0.004) and survival to discharge was 5% (RT 2.5%, REBOA 9.6%; p = 0.023). Discharge Glasgow Coma Scale score was 15 in 85% of survivors. Prehospital CPR was required in 60% of patients with a survival beyond the ED of 37% and survival to discharge of 3% (all p > 0.05). Patients who did not require any CPR before had a survival beyond the ED of 70% (RT 48%, REBOA 93%; p < 0.001) and survival to discharge of 13% (RT 3.4%, REBOA 22.2%, p = 0.048). If aortic occlusion patients did not require CPR but presented with hypotension (systolic blood pressure <90 mmHg; 9% [65% RT; 35% REBOA]), they achieved survival beyond the ED in 65% (p = 0.009) and survival to discharge of 15% (RT 0%, REBOA 44%; p = 0.008). CONCLUSIONS: Overall, REBOA can confer a survival benefit over RT, particularly in patients not requiring CPR. Considerable additional study is required to definitively recommend REBOA for specific subsets of injured patients. PMID- 29421696 TI - Purification and characterization of beta-galactosidase from probiotic Pediococcus acidilactici and its use in milk lactose hydrolysis and galactooligosaccharide synthesis. AB - beta-galactosidase is a commercially important enzyme that was purified from probiotic Pediococcus acidilactici. The enzyme was extracted from cells using sonication and subsequently purified using ammonium sulphate fractionation and successive chromatographies on Sephadex G-100 and Q-Sepharose. The enzyme was purified 3.06-fold up to electrophoretic homogeneity with specific activity of 0.883 U/mg and yield of 28.26%. Molecular mass of beta-galactosidase as estimated by SDS-PAGE and MALDI-TOF was 39.07 kDa. The enzyme is a heterodimer with subunit mass of 15.55 and 19.58 kDa. The purified enzyme was optimally active at pH 6.0 and stable in a pH range of 5.8-7.0 with more than 97% activity. Purified beta galactosidase was optimally active at 50 degrees C. Kinetic parameters Km and Vmax for purified enzyme were 400 uM and 1.22 * 10-1 U respectively. Its inactivation by PMSF confirmed the presence of serine at the active site. The metal ions had different effects on enzyme. Ca2+, Mg2+ and Mn2+ slightly activated the enzyme whereas NH4+, Co2+ and Fe3+ slightly decreased the enzyme activity. Thermodynamic parameters were calculated that suggested that beta galactosidase is less stable at higher temperature (60 degrees C). Purified enzyme effectively hydrolysed milk lactose with lactose hydrolysing rate of 0.047 min-1 and t1/2 of 14.74 min. This is better than other studied beta galactosidases. Both sonicated Pediococcus acidilactici cells and purified beta galactosidase synthesized galactooligosaccharides (GOSs) as studied by TLC at 30% and 50% of lactose concentration at 47.5 degrees C. These findings indicate the use of beta-galactosidase from probiotic bacteria for producing delactosed milk for lactose intolerant population and prebiotic synthesis. pH and temperature optima and its activation by Ca2+ shows that it is suitable for milk processing. PMID- 29421695 TI - NO inhibitors function as potential anti-neuroinflammatory agents for AD from the flowers of Inula japonica. AB - The extensive pathology studies revealed that Alzheimer's disease (AD) is closely related to neuroinflammation and anti-neuroinflammatory agents may be potentially useful for the treatment of AD. Inula japonica is a member of the Asteraceae plant family and its flowers have been used as a healthy tea and a traditional Chinese medicine. Our continuous search for new nitric oxide (NO) inhibitory substances as anti-neuroinflammatory agents for AD resulted in the isolation of two new sesquiterpenes and ten known terpenes from the flowers of I. japonica. Their structures were established on the basis of extensive analysis of NMR and MS spectroscopic data, as well as calculated and experimental electronic circular dichroism (ECD) spectra. Among these isolates, compound 1 is a new sesquiterpene with a rare tricyclic fused skeleton, and 2 processes a 1,10-seco-eudesmane skeleton. The anti-neuroinflammatory effects were examined by inhibiting NO release in LPS-induced murine microglial BV-2 cells. The possible mechanism of NO inhibition was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the iNOS protein. The present study disclosed that the flowers of I. japonica as a healthy tea are potentially useful for AD and related neuroinflammatory diseases. PMID- 29421697 TI - A new entry into the portfolio of alpha-glucosidase inhibitors as potent therapeutics for type 2 diabetes: Design, bioevaluation and one-pot multi component synthesis of diamine-bridged coumarinyl oxadiazole conjugates. AB - Diabetes mellitus (DM), a chronic multifarious metabolic disorder resulting from impaired glucose homeostasis has become one of the most challenging diseases with severe life threat to public health. The inhibition of alpha-glucosidase, a key carbohydrate hydrolyzing enzyme, could serve as one of the effective methodology in both preventing and treating diabetes through controlling the postprandial glucose levels and suppressing postprandial hyperglycemia. In this context, three series of diamine-bridged bis-coumarinyl oxadiazole conjugates were designed and synthesized by one-pot multi-component methodology. The synthesized conjugates (4a-j, 5a-j, 6a-j) were evaluated as potential inhibitors of glucosidases. Compound 6f containing 4,4'-oxydianiline linker was identified as the lead and selective inhibitor of alpha-glucosidase enzyme with an IC50 value of 0.07 +/- 0.001 MUM (acarbose: IC50 = 38.2 +/- 0.12 MUM). This inhibition efficacy was ~545 fold higher compared to the standard drug. Compound 6f was also emerged as the lead molecule against intestinal maltase-glucoamylase with good inhibition strength (IC50 = 0.04 +/- 0.02 MUM) compared to acarbose (IC50 = 0.06 +/- 0.01 MUM). Against beta-glucosidase enzyme, compound 6 g was noted as the lead inhibitor with IC50 value of 0.08 +/- 0.002 MUM. Michaelis-Menten kinetic experiments were performed to explore the mechanism of inhibition. Molecular docking studies of the synthesized library of hybrid structures against glucosidase enzyme were performed to describe ligand-protein interactions at molecular level that provided an insight into the biological properties of the analyzed compounds. The results suggested that the inhibitors could be stabilized in the active site through the formation of multiple interactions with catalytic residues in a cooperative fashion. In addition, strong binding interactions of the compounds with the amino acid residues were effective for the successful identification of alpha-glucosidase inhibitors. PMID- 29421698 TI - Design, synthesis, characterization, antimicrobial evaluation and molecular modeling studies of some dehydroacetic acid-chalcone-1,2,3-triazole hybrids. AB - A series of new dehydroacetic acid chalcone-1,2,3-triazole hybrids as potential antimicrobial agents was designed, synthesized and characterized by FTIR, NMR and HRMS spectral techniques. All the synthesized compounds were screened in vitro against four bacterial strains (Staphylococcus epidermidis, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) and two fungal strains (Aspergillus niger and Candida albicans). The antimicrobial results indicated that some of the compounds showed remarkable activities comparable to the standard drugs. Most of the compounds exhibited better efficacy compared to the DHA, which is itself an antimicrobial agent. The synergistic effect in biological activity was observed when DHA, chalcone and 1,2,3-triazole are conjugated. The molecular modeling studies of compound 5j into E. coli topoisomerase II DNA gyrase B were also performed. PMID- 29421699 TI - Synthesis and biological evaluation of novel N,N'-diaryl cyanoguanidines acting as potent and selective carbonic anhydrase II inhibitors. AB - A series of novel N,N''-diaryl cyanoguanidines were synthesized by reacting diphenyl N-cyanocarbonimidate with sulfanilamide followed by treatment of the obtained cyano-O-phenylisourea with substituted aromatic amines. The newly prepared N,N''-diaryl cyanoguanidines showed a very interesting inhibition profile against four selected human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, hCA I and hCA II (cytosolic), hCA IV (membrane-bound), and hCA IX (transmembrane). All these compounds showed a potent inhibition against isoform hCA II,with inhibition constants in the low nanomolar range, as well as a high selectivity for hCA II over hCA I, IV and IX. Since hCA II is an important drug target for antiglaucoma agents, these isoform-selective inhibitors may be considered of interest for further medicinal/pharmacologic studies. PMID- 29421700 TI - Synthesis, biological evaluation and molecular modeling studies of phenyl /benzhydrylpiperazine derivatives as potential MAO inhibitors. AB - Monoamine oxidase inhibitors (MAOIs) are potential drug candidates for the treatment of various neurological disorders like Parkinson's disease, Alzheimer's disease and depression. In the present study, two series of 4-substituted phenylpiperazine and 1-benzhydrylpiperazine (1-21) derivatives were synthesized and screened for their MAO-A and MAO-B inhibitory activity using Amplex Red assay. Most of the synthesized compounds were found selective for MAO-B isoform except compounds 3, 7, 8, 9 and 13 (MAO-A selective) while compound 11 was non selective. In the current series, compound 12 showed most potent MAO-B inhibitor activity with IC50 value of 80 nM and compound 7 was found to be most potent MAO A inhibitor with IC50 value of 120 nM and both the compounds were found reversible inhibitors. Compound 8 was found most selective MAO-A inhibitor while compound 20 was found most selective inhibitor for MAO-B isoform. In the cytotoxicity evaluation, all the compounds were found non-toxic to SH-SY5Y and IMR-32 cells at 25 uM concentration. In the ROS studies, compound 8 (MAO-A inhibitor) reduced the ROS level by 51.2% while compound 13 reduced the ROS level by 61.81%. In the molecular dynamic simulation studies for 30 ns, compound 12 was found quite stable in the active cavity of MAO-B. Thus, it can be concluded that phenyl- and 1-benzhydrylpiperazine derivatives are promising MAO inhibitors and can act as a lead to design potent, and selective MAO inhibitors for the treatment of various neurological disorders. PMID- 29421701 TI - Ionic liquid-enabled synthesis, cholinesterase inhibitory activity, and molecular docking study of highly functionalized tetrasubstituted pyrrolidines. AB - A small library of novel spiropyrrolidine heterocyclic hybrids has been prepared regioselectively in 1-butyl-3-methylimidazoliumbromide ([bmim]Br) with good to excellent yields using a [3+2] cycloaddition reaction. These synthesized compounds were evaluated as potential agents for treating Alzheimer's disease. Compound 4b showed the most potent activity, with an IC50 of 7.9 +/- 0.25 uM against acetylcholinesterase (AChE). The inhibition mechanisms for the most active compounds on AChE and butyrylcholinesterase (BChE) receptors were elucidated using molecular docking simulations. PMID- 29421702 TI - Exploiting the biological efficacy of benzimidazole based Schiff base complexes with l-Histidine as a co-ligand: Combined molecular docking, DNA interaction, antimicrobial and cytotoxic studies. AB - Four new metal complexes were synthesized and screened for their cytotoxic activity after sufficient assertion from the preliminary DNA binding studies. The metal complexes could bind to CT-DNA through intercalation binding mode. This has also been confirmed by the molecular docking studies. The DNA cleavage efficiencies of these complexes with pBR322 DNA were investigated by gel electrophoresis. The complexes were found to promote the cleavage of pBR322 DNA from the supercoiled form I to the open circular form II in the presence of an oxidizing agent (H2O2). The in vitro chemosensitivity of the studied complexes exhibits significant cytotoxic effects, compared to those reported for cisplatin. These findings represent a prompting to search for the probable interaction of these complexes with other cellular elements of fundamental consequence in cell proliferation. The in vitro anticancer activities indicate that the Cu(II) complex is active against the selected human tumor cell lines, and the order of in vitro anticancer activities is consistent with the DNA-binding affinities. Towards noncancerous cell line, Cu(II) complex exhibits very low toxicity. On the other hand all the complexes have been found to exhibit cytotoxic effects against cancerous cell lines with potency more than that of the widely used drug cisplatin and hence they have the potential to act as promising anticancer agents. Captivatingly, they are non-toxic to normal cell lymphocytes revealing that they are selective in killing only the cancer cells. PMID- 29421703 TI - Design, synthesis and in vitro alpha-glucosidase inhibition of novel dihydropyrano[3,2-c]quinoline derivatives as potential anti-diabetic agents. AB - A novel series of dihydropyrano[3,2-c]quinoline derivatives 6a-q were synthesized and evaluated for their in vitro alpha-glucosidase inhibitory activities. All newly synthesized compounds displayed potent alpha-glucosidase inhibitory activity in the range of 10.3 +/- 0.3 uM-172.5 +/- 0.8 uM against the yeast alpha glucosidase enzyme when compared to the standard drug acarbose (IC50 = 750.0 +/- 1.5 uM). Among these compounds, compounds 6e and 6d displayed the most potent alpha-glucosidase inhibitory activity (IC50 = 10.3 +/- 0.3 and 15.7 +/- 0.5 uM, respectively). The kinetic analysis of the most potent compounds 6e and 6d revealed that compound 6e inhibited alpha-glucosidase in an uncompetitive manner (Ki = 11 uM) while compound 6d was a non-competitive inhibitor (Ki = 28 uM) of the enzyme. Then, the cytotoxicity of the most potent compounds (i.e., compounds 6a, 6d, 6e, 6 g, 6j, and 6l) were evaluated for toxicity using the breast cancer cell lines MDA-MB231, MCF-7, and T-47D by using a MTT assay, and no toxicity was observed. PMID- 29421704 TI - A simple, cheap but reliable method for evaluation of zinc chelating properties. AB - BACKGROUND: Zinc is an essential trace element. Both its lack and excess are associated with pathological states. The former is more common and can ensue from the excessive treatment with clinically used iron/copper chelators. AIM AND METHOD: The aim of this work was to prepare a reliable, rapid and cheap method for the screening of zinc chelation. Spectrophotometric assessment using a known zinc indicator dithizone was selected. RESULTS: Initial screening performed by comparison of spectra of dithizone and its complex with zinc suggested 530 and 570 nm as suitable wavelengths for determination of zinc at pH 4.5 while 540 and 590 nm for pH 5.5-7.5. Additional research showed the lower wavelengths to be more suitable. The sensitivity of the method was always bellow 1 MUM with good linearity relationship between absorbance and zinc concentration. The method suitability was confirmed by use of two known zinc chelators, ethylenediaminetetraacetic acid (EDTA) and N,N,N',N'-tetrakis(2-pyridylmethyl) 1,2-ethylenediamine (TPEN). CONCLUSION: This method represents a sufficiently precise method for zinc chelation screening usable at pathophysiologically relevant pH conditions. Such method can be employed for both screening of novel zinc chelators and for testing affinity of other metal chelators for zinc. PMID- 29421705 TI - Discovery of thiazolin-4-one-based aromatic sulfamates as a new class of carbonic anhydrase isoforms I, II, IV, and IX inhibitors. AB - Herein we report the synthesis of a new series of aromatic sulfamates investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IV, and IX. The reported derivatives, obtained by a sulfamoylation reaction of the corresponding phenolic precursors, bear arylthiazolin-4-one moieties as spacers between the benzenesulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Thiazolin-4-ones are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. Phenolic precursors, also evaluated for CA inhibition, did not exhibit noteworthy efficacy in inhibiting the screened hCAs, whereas low nanomolar inhibitors were evidenced within the sulfamates subset mainly against hCA II (KIs in the range of 28.7-84.3 nM) and IX (KIs in the range of 17.6-73.3 nM). The variety of substituents appended at the outer aromatic portion almost generally reduced the inhibitory efficacy against isoforms II and IV, increasing instead that against the tumor-associated isoform IX. PMID- 29421706 TI - Synthesis and properties of the para-trimethylammonium analogues of green fluorescence protein (GFP) chromophore: The mimic of protonated GFP chromophore. AB - At low pH, protons from the external, bulk solution can protonate the phenoxide group of the p-HBDI chromophore in wild-type green fluorescent protein (wtGFP) and its mutants, and likely continue to tentatively protonate the phenol hydroxyl group of the same chromophores. Because the protonated GFP chromophore is a transient, we prepare the stable p-trimethylammonium analogues (2a and 2b) of the GFP chromophore to mimic it and explore their properties. What we found is that the p-trimethylammonium analogues of the GFP chromophore have the highly electrophilic amidine carbon, blue-shifted electronic absorption, smaller molar absorptivity, smaller fluorescent quantum yield, and faster E-Z thermoisomerization rate. The amidine carbon of the p-trimethylammonium analogue (2b) of the GFP chromophore is the only site that is attacked by very weak nucleophile of water, resulting in ring-opening of the imidazolinone moiety. The half-life of its decay rate in D2O is around 33 days. Actually, acid-catalyzed hydrolysis of p-HBDI also results in ring-opening of the imidazolinone moiety. The ratio of the acid-catalyzed hydrolysis rate constants [kobs(p-HBDI)/kobs(1b)] between p-HBDI and 1b (p-dimethylammonium analogue of the GFP chromophore) is dramatically increased from 0.30 at pH = 2 to 0.63 at pH = 0. This is the evidence that more and more phenol hydroxyl groups of p-HBDI are tentatively protonated in a low-pH aqueous solution and that accelerates hydrolysis of p-HBDI in the way similar to the quaternary ammonium derivatives 2a and 2b in water. With this view point, 2a and 2b still can partially mimic the cationic p-HBDI with the protonated phenol hydroxyl group. Implication of the experiment is that the amidine carbon of the chromophore in wtGFP and its mutants at very low pH should be highly electrophilic. Whether ring-opening of the imidazolinone moiety of the GFP chromophore would occur or not depends on if water molecules can reach the amidine carbon of the chromophore inside wtGFP and its mutants. PMID- 29421707 TI - Design and synthesis of novel coumarin-pyridinium hybrids: In vitro cholinesterase inhibitory activity. AB - A novel series of coumarin-pyridinium hybrids were synthesized and evaluated as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Ellman's method. Among synthesized compounds, 1-(3-fluorobenzyl)-4-((2-oxo-2H chromene-3-carboxamido)methyl)pyridinium bromide (7l) was found to be the most active compound toward AChE (IC50 = 10.14 uM), 1-(3-chlorobenzyl)-3-((2-oxo-2H chromene-3-carboxamido)methyl)pyridinium bromide (7g) and 1-(2,3-dichlorobenzyl) 3-((2-oxo-2H-chromene-3-carboxamido)methyl)pyridinium chloride (7h) depicted the best BChE inhibitory activity (IC50s = 0.32 and 0.43 uM, respectively). Although most compounds showed moderate to good anti-AChE activity, their anti-BChE activity was more significant and compound 7g was found as the most selective BChE with SI of 101.18. Also, kinetic study of the compounds 7g and 7l displayed a mixed type inhibition for both AChE and BChE. Furthermore, they were evaluated against beta-secretase; however, they showed low inhibitory activity. PMID- 29421708 TI - Characterization and structure-activity relationship studies of flavonoids as inhibitors against human carboxylesterase 2. AB - Human carboxylesterases (hCEs) are key enzymes from the serine hydrolase superfamily. Among all identified hCEs, human carboxylesterase 2 (hCE2) plays crucial roles in the metabolic activation of ester drugs including irinotecan and flutamide. Selective and potent hCE2 inhibitors could be used to alleviate the toxicity induced by hCE2-substrate drugs. In this study, more than fifty flavonoids were collected to assay their inhibitory effects against hCE2 using a fluorescence-based method. The results demonstrated that C3 and C6 hydroxy groups were essential for hCE2 inhibition, while O-glycosylation or C-glycosylation would lead to the loss of hCE2 inhibition. Among all tested flavonoids, 5,6 dihydroxyflavone displayed the most potent inhibitory effect against hCE2 with the IC50 value of 3.50 MUM. The inhibition mechanism of 5,6-dihydroxyflavone was further investigated by both experimental and docking simulations. All these findings are very helpful for the medicinal chemists to design and develop more potent and highly selective flavonoid-type hCE2 inhibitors. PMID- 29421709 TI - Engineering of Talaromyces thermophilus lipase by altering its crevice-like binding site for highly efficient biocatalytic synthesis of chiral intermediate of Pregablin. AB - The scissile fatty acid binding site of lipases is divided into different sub groups and plays an important role in the catalytic properties of the enzymes. In this study, the Talaromyces thermophilus lipase was engineered by altering its crevice-like binding site for efficient synthesis of chiral intermediate of Pregablin through kinetic resolution of 2-carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester (CNDE). The substitution of residues located at the crevice-like binding site with phenylalanine (Phe) resulted in significantly increased hydrolysis activity. The variant L206F/P207F/L259F exhibited a 37.23-fold and 47.02-fold improvement in the specific activity and turnover number (kcat) toward CNDE, respectively. Simultaneously, the optimum temperature and substrate preference were both altered in the variants. The study herein successfully engineered the TTL with improved catalytic properties for efficient biosynthesis of Pregablin intermediate. The investigation of structure-functional relationship provided important guidance for further modification of lipases with crevice-like binding site domain. PMID- 29421710 TI - Novel pyrimidine-pyridine hybrids: Synthesis, cyclooxygenase inhibition, anti inflammatory activity and ulcerogenic liability. AB - Some derivatives containing pyrido[2,3-d:6,5d']dipyrimidine-4,5-diones (9a-f), tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles (11a-c) and 6-(4-acetylphenyl) 2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrimido[4,5-d]pyrimidin-4-one (12) were synthesized from 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (8). The anti inflammatory effect of these candidates was determined and the ulcer indices were calculated for active compounds. 7-Amino-5-(3,4,5-trimethoxyphenyl)-4-oxo-2 thioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile (11c) exhibited better edema inhibition than celecoxib. Moreover, compounds 9b, 9d and 11c revealed better COX-2 inhibitory activity in a range (IC50 = 0.25-0.89 uM) than celecoxib (IC50 = 1.11 uM). Regarding ulcerogenic liability, all of the compounds under the study were less ulcerogenic than indomethacin. Molecular docking studies had been carried on active candidates 9d and 11c to explore action mode of these candidates as leads for discovering other anti-inflammatory agents. PMID- 29421711 TI - Silibinin phosphodiester glyco-conjugates: Synthesis, redox behaviour and biological investigations. AB - New silibinin phosphodiester glyco-conjugates were synthesized by efficient phosphoramidite chemistry and were fully characterized by 2D-NMR. A wide-ranging study focused on the determination of their pKa and E degrees values as well as on their radical scavenging activities by different assays (DPPH, ABTS+ and HRSA) was conducted. The new glyco-conjugates are more water-soluble than silibinin, and their radical scavenging activities are higher than those of silibinin. The conjugation therefore improves both the water solubilities and antioxidant activities of the flavonolignan moieties. The serum stability was evaluated under physiological conditions, and the glyco-conjugates degraded with half-lives of 40 70 h, making them useful in pro-drug approaches. We started by treating androgen dependent prostate cancer (PCa) LNCaP cells and then expanded our studies to androgen-independent PCa PC3 and DU145 cells. In most cases, the new derivatives significantly reduced both total and live cell numbers, albeit at different levels. Anti-HIV activities were evaluated and the glucosamine-phosphate silibinin derivative showed higher activity (IC50 = 73 MUM) than silibinin. PMID- 29421712 TI - Neuroprotection by new ligustrazine-cinnamon acid derivatives on CoCl2-induced apoptosis in differentiated PC12 cells. AB - A new series of ligustrazine-cinnamon acid derivatives had been designed and synthesized as potential neuro-protective agents. Among the derivatives, 3a exhibited the promising neuroprotective activity (EC50 = 3.68 MUM). Moreover, with the deep research of the drug pathway, it (the further mechanism researches) suggested compound 3a could inhibit the apoptosis of injured PC12 cells via blocking the mitochondria apoptosis pathway including up-regulation the ratio of Bcl-2/Bax, down-regulation the expression of cytochrome-c (Cyt-c) and inhibition of the activity of caspase-9 and -3. In addition, the structure-activity relationships (SARs) of novel compounds were also discussed. PMID- 29421713 TI - Discovery of thinopyrimidine-triazole conjugates as c-Met targeting and apoptosis inducing agents. AB - Five series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing triazole (21-26, 27-34, 35-41, 42-47 and 48-54) were designed and synthesized. And all the target compounds were evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds (43, 49 and 52) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Moreover, SARs and docking studies indicated that thieno[3,2 d]pyrimidine bearing triazole moiety was privileged structure for the activity. Especially, the Cl atom on the 4-C position of aryl group showed the best activity. The most promising compound 49 showed 3.7-5.4-fold more activity than the lead drug Foretinib against A549, HepG2 and MCF-7 cell lines, with the IC50 values of 0.9 +/- 0.1 uM, 0.5 +/- 0.1 uM and 1.1 +/- 0.2 uM, respectively. And The experiments of enzyme-based showed that 49 inhibitor the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM). What's more, According to the result of AO single staining and Annexin V/PI staining, it's claimed that the 49 could induce late apoptosis of HepG2 cells and by a concentration-dependent manner. PMID- 29421714 TI - Synthesis, biological evaluation and computational studies of novel iminothiazolidinone benzenesulfonamides as potent carbonic anhydrase II and IX inhibitors. AB - A series of iminothiazolidinone-sulfonamide hybrids (2a-k) was synthesized by heterocyclization of sulfanilamide thioureas with methyl bromoacetate and characterized by spectroscopic techniques, mass and elemental analysis. The synthesized derivatives were screened against four relevant human (h) isoforms of carbonic anydrases (CAs, EC 4.2.1.1) I, II, IV and IX. These enzymes are involved in a variety of diseases, including glaucoma, retinitis pigmentosa, epilepsy, arthritis, and tumors. Derivatives 2a-2k exhibited the best inhibitory activity against the cytosolyc hCA II (KIs are reaching the sub-nanomolar range, 0.41-37.8 nM) and against the tumor-associated isoform hCA IX (KIs are spanning between 24.3 and 368.3 nM). The binding mode of the reported iminothiazolidinone benzenesulfonamides within hCA II and IX catalytic clefts was investigated by docking studies. PMID- 29421715 TI - Carbazole alkaloids with antiangiogenic activities from Clausena sanki. AB - Two new carbazole alkaloids 1 and 2, and eleven known congeners 3-13 were isolated and identified from Clausena sanki for the first time. Their structures were elucidated on the basis of extensive UV, IR, MS, NMR spectroscopic data and comparison with literatures. The compounds 1-13 were evaluated by MTT assay to determine whether they decreased VEGF-mediated cell proliferation in HUVECs with Axitinib as positive control. Among them, compounds 1, 2, 6, 8, and 13 (MUM) exhibited moderate antiangiogenic activities, which inhibited VEGF-induced HUVEC proliferation in vitro with IC50 values of 12.1 (C.I. 8.2-15.2), 58.1 (C.I. 56.3 63.4), 13.7 (C.I. 9.2-15.4), 16.0 (C.I. 9.5-16.4), and 63.2 (C.I. 57.8-65.7) MUM, respectively. Moreover, the antiangiogenic activities of compounds 1-13 were evidenced in vivo in the zebrafish embryo model. As a result, compounds 1, 2, 6, 8, and 13 showed effectively suppress angiogenesis. These research results may guide the search for new natural products with antiangiogenic attributes. PMID- 29421716 TI - Synthesis of benzimidazole-linked-1,3,4-oxadiazole carboxamides as GSK-3beta inhibitors with in vivo antidepressant activity. AB - Recent findings of potential implications of glycogen synthase kinase-3beta (GSK 3beta) dysfunction in psychiatric disorders like depression, have increased focus for development of GSK-3beta inhibitors with possible anti-depressant activity. Keeping this in view, we synthesized a series of benzimidazole-linked-1,3,4 oxadiazole carboxamides and evaluated them for in vitro GSK-3beta inhibition. Active compounds were investigated for in vivo antidepressant activity in Wistar rats. Docking studies of active compounds have also been performed. Among nineteen compounds synthesized, compounds 7a, 7r, 7j, and 7d exhibited significant potency against GSK-3beta in sub-micromolar range with IC50 values of 0.13 MUM, 0.14 MUM, 0.20 MUM, 0.22 MUM respectively and significantly reduced immobility time (antidepressant-like activity) in rats compared to control group. Docking study showed key interactions of these compounds with GSK-3beta. These compounds may thus serve as valuable candidates for subsequent development of effective drugs against depression and related disorders. PMID- 29421717 TI - Palladium nanoparticles and rGO co-modified BiVO4 with greatly improved visible light-induced photocatalytic activity. AB - A ternary composite, Pd-rGO-BiVO4, was fabricated with reduced graphene oxide (rGO) and palladium nanoparticles decorated on the surface of BiVO4. As-prepared samples were tested for the photocatalytic degradation of phenol under visible light irradiation. Enhancement was observed for the ternary structure, merits of which may be as follows: 1) rGO wrapped BiVO4 facilitated the photogenerated electrons transfer, 2) palladium nanoparticles served as electron acceptors, 3) palladium nanoparticles on the surface were capable of absorbing visible light photons. The uptake of photogenerated charge carriers would improve their separation and more oxidative species may be produced that can participate in the degradation of organics. Due to the SPR effect of palladium nanoparticles on the surface, the harvesting capacity of the photocatalyst to absorb visible light photons was increased, and thus its photocatalytic activity was improved. It should be noted that phenol was more easily adsorbed by rGO due to the pi-pi interaction between rGO and phenol, which also contributed to the enhancement in the photocatalytic activity. This work provides new evidence to confirm the advances of ternary structures applied in the photocatalytic removal of phenolic compounds in water under visible light irradiation. PMID- 29421718 TI - Ranking and similarity of conventional, microwave and ultrasound element sequential extraction methods. AB - This study aims to compare three extraction techniques of four sequential element extraction steps from soil and sediment samples that were taken from the location of the Pancevo petrochemical industry (Serbia). Elements were extracted using three different techniques: conventional, microwave and ultrasound extraction. A novel procedure - sum of the ranking differences (SRD) - was able to rank the techniques and elements, to see whether this method is a suitable tool to reveal the similarities and dissimilarities in element extraction techniques, provided that a proper ranking reference is available. The concentrations of the following elements Al, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, Si, Sn, Sr, V and Zn were determined through ICP OES. The different efficiencies and recovery values of element concentrations using each of the three extraction techniques were examined by the CRM BCR-701. By using SRD, we obtained a better separation between the different extraction techniques and steps when we rank their differences among the samples while lower separation was obtained according to analysed elements. Appling this method for ordering the elements could be useful for three purposes: (i) to find possible associations among the elements; (ii) to find possible elements that have outlier concentrations or (iii) detect differences in geochemical origin or behaviour of elements. Cross-validation of the SRD values in combination with cluster and principal component analysis revealed the same groups of extraction steps and techniques. PMID- 29421719 TI - Zearalenone induced embryo and neurotoxicity in zebrafish model (Danio rerio): Role of oxidative stress revealed by a multi biomarker study. AB - In the present study, we evaluated the zearalenone induced adverse effects in zebrafish embryos using various endpoints like embryo toxicity, heart rate, oxidative stress indicators (reactive oxygen species (ROS), lipid peroxidation (LPO), Nitric oxide (NO)), antioxidant responses (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase enzyme (GST) and reduced glutathione (GSH), metabolic biomarkers (lactate dehydrogenase (LDH) and Nitric oxide (NO)), neurotoxicity (acetylcholinesterase (AChE)), genotoxicity (comet assay and acridine orange staining (AO)) and histological analysis. In this study, four concentrations 350, 550, 750 and 950 MUg/L of ZEA were chosen based on LC10 and LC50 values of the previous report. The results shows that ZEA induces developmental defects like pericardial edema, hyperemia, yolk sac edema, spine curvature and reduction in heart rate from above 550 MUg/L exposure and the severity was increased with concentration and time dependent manner. Significant induction in oxidative stress indices (ROS, LPO and NO), reduction in antioxidant defence system (SOD, CAT, GPx, GST and GSH) and changes in metabolic biomarkers (LDH and AP) were observed at higher ZEA exposed concentration. Neurotoxic effects of ZEA were observed with significant inhibition of AChE activity at higher exposure groups (750 and 950 MUg/L). Moreover, we also noticed DNA damage, apoptosis and histological changes in the higher ZEA treatments at 96 h post fertilization (hpf) embryos. Hence, in the present study we concluded that oxidative stress is the main culprit in ZEA induced developmental, genotoxicity and neurotoxicity in zebrafish embryos. PMID- 29421720 TI - QSAR prediction of additive and non-additive mixture toxicities of antibiotics and pesticide. AB - Antibiotics and pesticides may exist as a mixture in real environment. The combined effect of mixture can either be additive or non-additive (synergism and antagonism). However, no effective predictive approach exists on predicting the synergistic and antagonistic toxicities of mixtures. In this study, we developed a quantitative structure-activity relationship (QSAR) model for the toxicities (half effect concentration, EC50) of 45 binary and multi-component mixtures composed of two antibiotics and four pesticides. The acute toxicities of single compound and mixtures toward Aliivibrio fischeri were tested. A genetic algorithm was used to obtain the optimized model with three theoretical descriptors. Various internal and external validation techniques indicated that the coefficient of determination of 0.9366 and root mean square error of 0.1345 for the QSAR model predicted that 45 mixture toxicities presented additive, synergistic, and antagonistic effects. Compared with the traditional concentration additive and independent action models, the QSAR model exhibited an advantage in predicting mixture toxicity. Thus, the presented approach may be able to fill the gaps in predicting non-additive toxicities of binary and multi component mixtures. PMID- 29421721 TI - Photoinduced reduction of high concentration Hg(II) to Hg2Cl2 from acid wastewater with the presence of fulvic acid under anaerobic conditions. AB - In order to recover mercury from high concentration Hg(II) acid wastewater, UV irradiation was used to reduce Hg(II) to Hg2Cl2 with the presence of fulvic acid and chloride ion. When simulated wastewater with Hg(II) concentration of 1000 mg L-1 was treated, > 90% of Hg(II) removal efficiency was achieved under the condition of extra Cl- dosage of 5 g L-1, FA dosage of 2 g L-1, pH of 3.0 and 120 min of UV irradiation. Kinetics study showed that the photoreduction process could be well described by pseudo-first order kinetic mode, and the Hg(II) reduction rate was tested to be 0.0422 min-1. Characterization results indicated that FA-Hg(II) complexes were firstly formed and then broken down into smaller molecules after the UV treatment, in which process highly reductive species (i.e. COO, COOH) were produced. These reductive species mediated the reduction of Hg(II). With the presence of Cl-, Hg2Cl2 was practically the only detected Hg based product in the photoreduction process. This technique was also employed to treat CODCr analysis wastewater (initial Hg(II) concentration > 1000 mg L-1). With 90 min of reaction, most of the Hg(II) was removed from the system leaving less than 30% that could be further treated by chemical participation or adsorption method. PMID- 29421722 TI - Efficacy of cheap amendments for stabilizing trace elements in contaminated paddy fields. AB - In situ stabilization of trace elements by adding cheap amendments is an emerging technology for large-scale soil remediation. Various amendments have been examined well in the literature, but related have focused predominantly on short term laboratory scale incubation or pot experiments. This study applied dolomitic lime at 40 ton ha-1, oyster shell (OS) at 80 ton ha-1, and sugarcane bagasse compost (SC) at 60 ton ha-1 to a paddy field in Taiwan for two rice (Oryza sativa L.) cropping seasons. The aims of study were to gain an understanding of the bioavailable concentrations of Cr, Ni, Cu, and Zn in the amended soil and the metal uptake of rice for practical amendment use in field-scale remediation of contaminated soils. The treatments of lime and OS significantly (p < 0.05) decreased the 0.1 N HCl-extractable metals in the soil. The increase in soil pH was the key factor in decreasing the bioavailable pool of metals in the soil by using lime and OS. The concentrations of Cu, Zn, and Ni in the brown rice were substantially reduced only through the addition of OS, and thus OS met the requirement of being a cheap, locally available, and environmentally compatible amendment for field-scale soil remediation. The translocation of Cr in rice plants is heavily restricted, and thus no significant differences in Cr uptake by rice grain were observed between the different amendment treatments. However, SC is not recommended as an immobilization agent because it caused a pH decrease in the amended soil. PMID- 29421723 TI - Humic like substances for the treatment of scarcely soluble pollutants by mild photo-Fenton process. AB - Humic-like substances (HLS) extracted from urban wastes have been tested as auxiliaries for the photo-Fenton removal of thiabendazole (TBZ) under simulated sunlight. Experimental design methodology based on Doehlert matrices was employed to check the effects of hydrogen peroxide concentration, HLS amount as well as TBZ loading; this last parameter was studied in the range 25-100 mg/L, to include values below and above the limit of solubility at pH = 5. Very satisfactory results were reached when TBZ was above solubility if HLS and H2O2 amounts were high. This could be attributed to an interaction of HLS-TBZ that enhances the solubility of the pollutant. Additional evidence supporting the latter interaction was obtained by fluorescence measurements (excitation emission matrices) and parallel factor analysis (PARAFAC). PMID- 29421724 TI - Simultaneous determination of iodinated haloacetic acids and aromatic iodinated disinfection byproducts in waters with a new SPE-HPLC-MS/MS method. AB - Iodinated disinfection byproducts (DBPs) are an emerging category of halogenated DBPs in concern due to their high toxicity. Among them, polar iodinated DBPs, mainly including iodinated haloacetic acids (HAAs) and aromatic iodinated DBPs, were reported to be especially toxic. Thus, simultaneous determination of these polar iodinated DBPs in disinfected waters is of great significance for DBP studies. In this study, it was found that traditional liquid-liquid extraction, which was adopted for the determination of polar iodinated DBPs, was actually not suitable for the determination of monoiodoacetic acid (MIAA) and diiodoacetic acid (DIAA) due to the low recoveries, and thus a new SPE-HPLC-MS/MS method was developed for the simultaneous determination of iodinated HAAs and aromatic iodinated DBPs. The parameters for SPE pretreatment were optimized, including SPE cartridge, eluent volume, formic acid content in eluent, and sample pH before SPE. The new method was demonstrated to be sensitive and accurate with detection limits of 0.15, 0.04, 0.03, 0.02, 0.06, and 0.06 ng/L, quantitation limits of 0.48, 0.13, 0.10, 0.06, 0.19, and 0.19 ng/L, and precision of 8.3%, 6.0%, 12.3%, 8.8%, 11.4%, and 15.6% for MIAA, DIAA, 3,5-diiodo-4-hydroxybenzaldehyde, 3,5 diiodosalicylic acid, 2,6-diiodo-4-nitrophenol and 2,4,6-triiodophenol, respectively. The recoveries of these six polar iodinated DBPs were all in the range of 70-110%. The new method was applied to the determination of iodinated HAAs and aromatic iodinated DBPs in nine tap water samples, and they were detected with concentrations ranging from 0.03 to 3.97 ng/L, among which MIAA was detected in all the samples with the highest concentrations. PMID- 29421725 TI - Do recommended doses of glyphosate-based herbicides affect soil invertebrates? Field and laboratory screening tests to risk assessment. AB - Despite glyphosate-based herbicides are widely used in agriculture, forestry and gardens, little is known about its effects on non-target organisms. The present work evaluated the ecotoxicity of four formulated products (Roundup(r) Original, Trop(r), Zapp(r) Qi 620 and Crucial(r)) on soil invertebrates. Screening ecotoxicity tests were carried out with soil and oat straw collected in a field experiment, besides laboratory-spiked soils. Screening tests included avoidance behaviour of earthworms (Eisenia andrei), collembolans (Folsomia candida) and isopods (Porcellio dilatatus) in single and multispecies tests; reproduction of collembolans (F. candida), and bait lamina in field. Non-avoidance behaviour was observed in standard tests (earthworms) in soil, neither in multispecies tests (earthworm + isopods) using oat straw, while for collembolans it occurred for the product Zapp(r) Qi 620 even at the recommended dose. Reproduction of F. candida was not impaired even at high doses in laboratory-spiked soils. Feeding activity on bait lamina test was impaired in treatment corresponding to the red label product, Crucial(r). Results showed the relevance of bait lamina test on screening the impact of herbicides in the field. The findings highlight the importance of considering different formulations for the same active ingredient in risk assessment of pesticides. PMID- 29421726 TI - Optimal groundwater security management policies by control of inexact health risks under dual uncertainty in slope factors. AB - Groundwater remediation is a complicated system with time-consuming and costly challenges, which should be carefully controlled by appropriate groundwater management. This study develops an integrated optimization method for groundwater remediation management regarding cost, contamination distribution and health risk under multiple uncertainties. The integration of health risk into groundwater remediation optimization management is capable of not only adequately considering the influence of health risk on optimal remediation strategies, but also simultaneously completing remediation optimization design and risk assessment. A fuzzy chance-constrained programming approach is presented to handle multiple uncertain properties in the process of health risk assessment. The capabilities and effectiveness of the developed method are illustrated through an application of a naphthalene contaminated case in Anhui, China. Results indicate that (a) the pump-and-treat remediation system leads to a low naphthalene contamination but high remediation cost for a short-time remediation, and natural attenuation significantly affects naphthalene removal from groundwater for a long-time remediation; (b) the weighting coefficients have significant influences on the remediation cost and the performances both for naphthalene concentrations and health risks; (c) an increased level of slope factor (sf) for naphthalene corresponds to more optimal strategies characterized by higher environmental benefits and lower economic sacrifice. The developed method could be simultaneously beneficial for public health and environmental protection. Decision makers could obtain the most appropriate remediation strategies according to their specific requirements with high flexibility of economic, environmental, and risk concerns. PMID- 29421727 TI - Abatement of the antibiotic levofloxacin in a solar photoelectro-Fenton flow plant: Modeling the dissolved organic carbon concentration-time relationship. AB - The degradation of solutions of the antibiotic levofloxacin (LVN) in sulfate medium at pH 3.0 has been investigated at pre-pilot scale by solar photoelectro Fenton (SPEF) process. The flow plant included an FM01-LC filter-press cell equipped with a Ti|Pt anode and a three-dimensional-like air-diffusion cathode, connected to a compound parabolic collector as photoreactor and a continuous stirred tank under recirculation batch mode. The effect of volumetric flow rate on H2O2 electrogeneration from O2 reduction was assessed. Then, the influence of initial LVN concentration and Fe2+ concentration as catalyst on dissolved organic carbon (DOC) removal was thoroughly investigated. LVN was gradually mineralized by SPEF process, with faster DOC abatement at 0.50 mM Fe2+, yielding 100% after 360 min at applied cathodic potential of -0.30 V|SHE. The high mineralization current efficiency (MCE) and low specific energy consumption (ECDOC) revealed the extraordinary role of homogeneous hydroxyl radicals and natural UV light, which allowed the degradation of the antibiotic and its by-products with MCE values greater than 100%. Five cyclic by-products, N,N-diethylformamide and three short chain linear carboxylic acids were detected by GC-MS and HPLC analyses. A parametric model to simulate the DOC decay versus electrolysis time was implemented for the SPEF pre-pilot flow plant, showing good agreement with experimental data. PMID- 29421728 TI - Environmental scenarii for the degradation of oxo-polymers. AB - The fate of oxo-polymers in nature is strongly dependent on environmental conditions, mainly on the intensity and duration of sunshine, which vary with the season and the climate. In this work, we report the effect of different scenarii on the production and the molecular composition of oligomers released from oxo biodegradable HDPE films. Under our experimental conditions, the duration of accelerated weathering corresponded to a period of 3 months to 3 years of exposure to outside conditions under temperate climate. In addition, the oligomers were extracted in three different solvents: i) water to mimics the natural environment; ii) acetone and chloroform to identify oligomers trapped in the polymer matrix. The combination of high-resolution mass spectrometry and 1H NMR spectroscopy gives an extensive picture of the relative concentrations and the structural compositions of the extracted oligomers in the different tested conditions. In particular, the masses, the number of oxygen and carbon atoms could be determined for up to 2283 molecules. Globally the concentration and the size of oligomers increased with the duration of extraction, the level of aging of the polymer and the use of non-polar solvents. Surprisingly, the presence of highly oxidized molecules in acetone and chloroform extract, suggested an important swelling of HPDE films in these solvents and a better diffusion of these oligomers in the matrix. In nature, the biodegradability of oligomers could result from processes occurring both at the molecular (oxidation) and the macromolecular (diffusion and release) levels. PMID- 29421729 TI - Two combined mechanisms responsible to hexavalent chromium removal on active anaerobic granular consortium. AB - Hexavalent chromium (Cr VI) from industrial wastewaters represents a highly toxic source at low concentrations. Biological treatments with anaerobic granular biomass are a promising alternative for the Cr VI bioremediation. This study evaluated the Cr VI removal in a range of 5-500 mg/L, using an active anaerobic granular consortium. Two removal mechanisms were differentiated from the assays: 1) biological reduction of 70 mg/L to Cr III at a concentration of 250 mg Cr VI/L and 2) physical bioadsorption of 297 mg of Cr VI/L or 31.39 mg of Cr VI/gbiomass at concentration of 500 mg Cr VI /L. The half-maximal inhibitory concentration (IC50) values for the rate and production of methane were 1.4 and 253 mg/L, respectively. In addition, Cr VI is a biostimulant that increase the methane production, in a range from 5 to 100 mg/L, of the anaerobic consortium. This work demonstrates the potential application of the anaerobic granular consortium in metal bioremediation. PMID- 29421730 TI - Removal of herbicides in a biopurification system is not negatively affected by oxytetracycline or fungally pretreated oxytetracycline. AB - The disposal of agricultural antibiotic-containing wastewater in biopurification systems (BPS) employed in the treatment of pesticides, may negatively affect the removal capacity of these devices. This work aimed to employ a fungal pretreatment of oxytetracycline (OTC)-rich wastewater, before its disposal in a BPS used for the treatment of two pesticides. The fungal treatment at reactor scale (stirred tank reactor, 3L) with biomass of Trametes versicolor efficiently removed 100 mg L-1 OTC in only 60 h. However, ecotoxicity tests on seed germination with Lactuca sativa revealed that antibiotic elimination did not correlate with a decrease in toxicity. After the pretreatment, treated OTC was discarded in biomixtures used for the elimination of the herbicides ametryn and terbutryn. The co-application of treated or untreated OTC did not inhibit the removal of the herbicides; moreover, in both cases their removal seemed to be slightly enhanced in the presence of OTC or its residues, with respect to antibiotic-free biomixtures. Estimated half-lives ranged from 28.4 to 34.8 d for ametryn, and 34.0-51.0 d for terbutryn. In addition, the biomixture was also able to remove OTC in the presence of the herbicides, with an estimated half-life of 38 d. Remarkably, the toxicity of the wastewater containing OTC or treated OTC was mostly eliminated after its disposal in the biomixture. Overall results suggest that, given the high efficiency of the biomixture, the fungal pretreatment of OTC-containing wastewater is not mandatory before its disposal in the BPS. PMID- 29421731 TI - Nanostructured Co3O4 grown on nickel foam: An efficient and readily recyclable 3D catalyst for heterogeneous peroxymonosulfate activation. AB - Cobalt-based heterogeneous catalyst has been recognized as one of most efficient activators for peroxymonosulfate (PMS) decomposition, but usually suffers from the poor stability and difficulty to recover and reuse. Here easily recyclable cobalt oxide (Co3O4) nanowires and nanoflowers grown on nickel foam (NF) are fabricated by a hydrothermal and calcination method. The prepared 3D Co3O4/NF catalyst is characterized and applied as a heterogeneous catalyst for PMS activation to generate sulfate radicals for decomposition of Acid Orange 7 (AO7). The results show that the AO7 degradation rate increases with cobalt loading and PMS dosage, but decreases with the increase of solution pH. The Co3O4/NF catalyst using 2 mM Co(NO3)2.6H2O as cobalt source exhibits highest activity, and almost complete decolorization could be achieved within 30 min. The diverse effects of coexisting anions (SO42-, HCO3-, NO3- and Cl-) on AO7 degradation are observed and explained. After 10 consecutive runs, excellent catalytic reactivity of the catalyst remains while the level of leached cobalt during the catalyst usage is much lower than the maximum allowable concentration in drinking and natural water. More importantly, the macroscopic Co3O4/NF catalyst shows advantage of easy recycling after application compared to traditional catalysts. It is believed that the as-prepared Co3O4/NF is promising to be an effective and green heterogeneous catalyst for PMS activation to degrade organic pollutants for environmental application. PMID- 29421732 TI - Electrochemical degradation of industrial textile dye disperse yellow 3: Role of electrocatalytic material and experimental conditions on the catalytic production of oxidants and oxidation pathway. AB - This study aimed to verify the efficiency of the electrochemical oxidation process for removal the industrial textile Disperse Yellow 3 (DY3) dye in aqueous solutions using different electrocatalytic materials: boron-doped diamond (BDD), Ti/Ru0.3Ti0.7O2 and Ti/Pt anodes. The results were obtained by applying different current densities (40 and 60 mA cm-2) at 40 degrees C using different supporting electrolytes (Na2SO4 50 mM and NaCl 50 mM) under values of pH about 2.3, 7.0 and 10.0. Results obtained shown that the process was faster at the beginning of the process for all electrocatalytic materials, using Na2SO4 as electrolyte, being more efficient for BDD anode reaching more than 90% of TOC and color decay independently of the current density and pH and supporting electrolyte; while up to 50% of color and TOC was eliminated, using the other anodic materials in sulfate. In NaCl medium a complete mineralization was achieved at Ti/Ru0.3Ti0.7O2 at short electrolysis time, followed by BDD and Ti/Pt. The corresponding kinetic analysis confirms these results. Trends of active chlorine species synthesized at Ti/Ru0.3Ti0.7O2, BDD and Ti/Pt anodes, at different pH conditions, demonstrated that, the concentration of active chlorine species depends on the pH conditions and electrode material. Finally, a cost comparison for each electrocatalytic material under different experimental conditions was realized exhibiting the lowest energy consumption and electrolysis time in NaCl medium. Based on the results obtained, the electrochemical elimination of dye and the profile of the carboxylic by-products formed depend on the nature of material, pH and supporting electrolyte. PMID- 29421733 TI - Effects of dispersible MoS2 nanosheets and Nano-silver coexistence on the metabolome of yeast. AB - As a new rising star in the post-graphene two-dimensional materials (2DMs), molybdenum disulfide (MoS2) attracts increasing attentions and is widely applied. However, the chemical and toxicological interaction between MoS2 and other co contaminants is still poorly understood. Nano-silver (N-Ag) is the most commonly used nanomaterial in commercial products and distributed widely in the environment. Herein, we investigated the effects of chitosan functionalized MoS2 (CS-MoS2) nanosheets, a water-dispersible form of MoS2, on the microbial toxicity of N-Ag. We found that the incorporation of CS-MoS2 nanosheets attenuated the oxidative stress induced by N-Ag on yeast cells, while caused more membrane stress. In addition, the inhibition of N-Ag on the metabolic activities of yeast cells could be attenuated by CS-MoS2 nanosheets as well. The coexistence of N-Ag and CS-MoS2 nanosheets mainly perturbed the amino acid-related metabolic pathways in yeast cells, and phosphoric acid was a potential nanotoxicity biomarker. We further found that CS-MoS2 nanosheets dramatically absorbed the Ag ion released from N-Ag, which might be responsible for its attenuation effect on the microbial toxicity of N-Ag. Our findings provide more new insights for the ecotoxicity evaluation of MoS2 and other 2DMs. PMID- 29421734 TI - Transport of low molecular weight organic compounds in compacted illite and kaolinite. AB - 14C-containing dissolved organic compounds may significantly contribute to the calculated annual overall dose emanated from a deep geological repository for radioactive waste. To date, there is a general lack of knowledge concerning the transport behaviour of low molecular weight organic compounds in the geosphere. The present work is aiming at a generic approach to measure weak adsorption of such compounds onto selected clay minerals. Percolation experiments were employed to sensitively measure the retardation of low molecular weight carboxylates and alcohols in compacted illite and kaolinite as a function of the ionic strength. Detection limits of ~10-5 m3 kg-1 for the involved sorption distribution coefficients were attained thereby. The adsorption of alcohols on clays was near the detection limit and assumed to occur predominately via H-bonding. The adsorption of organic anions was influenced by several factors such as molecular structure, type of clay surfaces and the chemical composition of the aqueous phase. It was found that the relative position of neighbouring hydroxyl groups strongly influenced the retardation behaviour. Alpha-hydroxylated carboxylates, such as lactate, were found to be most retarded. Ligand exchange at the edge aluminol sites is the most probable explanation for the uptake of the negatively charged organic test compounds by the clay surface. The breakthrough behaviour of organic anions was additionally impacted by anion exclusion in illite. The demonstrated weak retardation of the test compounds can be robustly introduced in transport models, leading thus to a much lower contribution of 14C to the expected long-term overall dose. PMID- 29421735 TI - Long-term exposure of Mytilus galloprovincialis to diclofenac, Ibuprofen and Ketoprofen: Insights into bioavailability, biomarkers and transcriptomic changes. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) represent a growing concern for marine ecosystems due to their ubiquitous occurrence and documented adverse effects on non-target organisms. Despite the remarkable efforts to elucidate bioaccumulation and ecotoxicological potential under short-term conditions, limited and fragmentary information is available for chronic exposures. In this study bioavailability, molecular and cellular effects of diclofenac (DIC), ibuprofen (IBU) and ketoprofen (KET) were investigated in mussels Mytilus galloprovincialis exposed to the realistic environmental concentration of 2.5 MUg/L for up to 60 days. Results indicated a significant accumulation of DIC and IBU but without a clear time-dependent trend; on the other hand, KET concentrations were always below the detection limit. Analyses of a large panel of molecular, biochemical and cellular biomarkers highlighted that all investigated NSAIDs caused alterations of immunological parameters, genotoxic effects, modulation of lipid metabolism and changes in cellular turn-over. This study provided the evidence of long-term ecotoxicological potential of NSAIDs, further unraveling the possible hazard for wild marine organisms. PMID- 29421736 TI - Associations between DDT and egg parameters of the House Sparrow Passer domesticus from the Thohoyandou area of South Africa. AB - This study investigated whether the pesticide DDT (Dichlorodiphenyltrichloroethane) and its metabolites, DDE (Dichlorodiphenyldichloroethylene) and DDD (Dichlorobischlorophenylethane) were associated with adverse effects on multiple endpoints of the eggs of House Sparrows from the Thohoyandou area in South Africa, where DDT is used for malaria control. Eggshell thickness, pore numbers, pore shapes, and volume densities of the pores were measured to test possible adverse effects. Analysis was done using a scanning electron microscope and the concentrations of the pesticides were determined with the aid of gas chromatography-mass spectrometry. The highest concentrations recorded was p,p'-DDE at 0.84 MUg/g wm (wet mass) in the eggs collected from Mangondi (a site last sprayed five years before sampling). Overall, the concentrations of total DDT recorded in this study were lower than reported by most other studies conducted in the same area. The association between DDT concentrations and House Sparrows eggshells were noticeable in the eggshell thicknesses, with significant differences between the eggs collected from Muledane (a site last sprayed 30 years before sampling) and Makula (a site sprayed both years of sampling) (P < 0.0022). Limited differences were found between the pore numbers and pore density of eggshells from the various sites. It may be that the limited effect on the pore numbers and volume densities of the pores are associated with low concentrations of DDT in the House Sparrow eggs. PMID- 29421737 TI - Chemometric study on the electrochemical incineration of diethylenetriaminepentaacetic acid using boron-doped diamond anode. AB - The electrochemical incineration of diethylenetriaminepentaacetic acid (DTPA) with boron-doped diamond (BDD) anode had been initially performed under galvanostatic conditions. The main and interaction effects of four operating parameters (flow rate, applied current density, sulfate concentration and initial DTPA concentration) on mineralization performance were investigated. Under similar experimental conditions, Doehlert matrix (DM) and central composite rotatable design (CCRD) were used as statistical multivariate methods in the optimization of the anodic oxidation processes. A comparison between DM model and CCRD model revealed that the former was more accurate, possibly due to its higher operating level numbers employed (7 levels for two variables). Despite this, these two models resulted in quite similar optimum operating conditions. The maximum TOC removal percentages at 180 min were 76.2% and 73.8% for case of DM and CCRD, respectively. In addition, with the aid of quantum chemistry calculation and LC/MS analysis, a plausible degradation sequence of DTPA on BDD anode was also proposed. PMID- 29421738 TI - Associations between PBDEs exposure from house dust and human semen quality at an e-waste areas in South China-A pilot study. AB - Previous studies have confirmed that house dust is one of the main sources of polybrominated diphenyl ethers (PBDEs) exposure, and also indicated that PBDEs might affect human semen quality. The aim of this study was to explore the association between PBDEs concentration in house dust and the semen quality of male resident. Results showed that the semen qualities of the residents living around the e-waste dismantling workshops for a long time (3-17years) at the e waste areas in South China significantly decreased, and the DNA damage of sperms were aggravated. The adjusted correlation analysed by multiple linear regression model showed that the sperm concentration and count both had negative correlation with BDE47 level in semen (beta = -0.295, 95%CI: -0.553~-0.036; beta = -0.400, 95%CI: -0.708~-0.092, respectively). In addition, the sperm progressive motility [(A+B)%] and sperm viability both had negative correlation with BDE100 level in dust (beta = -0.360, 95%CI: -0.680~-0.040; beta = -0.114, 95% CI: -0.203~-0.025, respectively). And there were significant linear positive correlation between PBDE congener (e.g. BDE28, 47, 153) concentrations in dust and in paired semen samples (rs = 0.367-0.547, p < 0.05). This study suggested that exposure to PBDEs from house dust might have adverse effects on human semen quality. But the results need to be confirmed in further studies with a large-scale sampling, and find out more direct and convincing evidence. PMID- 29421739 TI - An improved method for determining dermal exposure to polycyclic aromatic hydrocarbons. AB - Many workers are occupationally exposed to polycyclic aromatic hydrocarbons (PAHs), which may cause various health problems, and some PAHs are known or suspected carcinogens. PAH exposure is primarily monitored by air sampling, but contamination may also occur through dermal exposure. PAHs adsorbed to the skin can be sampled by tape-stripping, but subsequent extraction of sampling tapes in organic solvent also releases diverse co-eluting substances that are difficult to remove before analysis of the PAHs by gas chromatography/mass spectrometry (GC/MS). The objective of this study was to optimise a procedure for analytical clean-up after extraction of 32 PAHs from tape-strips, by dialysis in organic solvent using semipermeable membranes. With triplicate subsamples, the developed method yields acceptable precision and repeatability for both the 32 PAHs, across the concentration range 10-160 ng per sample, and for a certified reference material (urban dust). The optimized clean-up procedure and GC/MS methodology was used to assess PAHs on skin from the lower part of the ventral side of the wrist and just below the collar bone of three firefighters and seven controls (office workers). Several gaseous and particle-bound PAHs were detected in all samples, including controls. Thus, the optimized procedure using semipermeable membranes for clean-up of tape-strip extracts can be used to assess the dermal exposure of both occupational and general populations to multiple PAHs. The results also show that both gaseous and particle-bound PAHs, including alkylated species, may be present on skin. PMID- 29421740 TI - Occurrence and speciation of arsenic and mercury in estuarine sediments affected by mining activities (Asturias, northern Spain). AB - Sediments contaminated by Hg and As from two historical mining areas have been deposited in the Nalon estuary (Asturias, northern Spain) since 1850. Total mercury (Hgtotal) concentrations in the sediments range from 0.20 MUg g-1 to 1.33 MUg g-1, most of it in the form of sulphides. Concentrations of methylmercury (303.20-865.40 pg g-1) are up to two orders of magnitude lower than the concentration of Hgtotal. Total As concentration (Astotal) is enriched compared to the background level for the area. The relative abundance of As(V) on As(III) in the sediments ranges from 97.6% to 100%, whereas inorganic Hg accounts for more than 99% of the total Hg. The occurrence of the most toxic species, inorganic As(III) and organic methylmercury, seem to be related to redox conditions together with the amounts of sulphur which act as natural barriers which inhibit the biological and chemical speciation processes. Despite the high amounts of Hg and As present in the sediments, their transference to the water column appear to be limited thus converting sediments in an effective sink of both elements. Special attention should be paid to potential variations of the environmental conditions which might increase the element mobility and exchange between sediments and the water column. PMID- 29421741 TI - Removal of metal(oid)s from contaminated water using iron-coated peat sorbent. AB - This study aimed at combining iron and peat to produce a sorbent suitable for a simultaneous removal of cations and anions from a solution. Peat powder, an industrial residue, was coated with iron by immersing peat into iron salt solutions. The adsorption efficiency of the newly produced sorbent towards As, Cr, Cu and Zn was tested by means of batch adsorption experiments at a constant pH value of 5. Coating of Fe on peat significantly increased the adsorption of As (from <5% to 80%) and Cr (from <3% to 25%) in comparison to uncoated peat. Removal of cations on coated peat slightly decreased (by 10-15%), yet remained within acceptable range. Electron Microscopy combined with X-Ray Energy Dispersive Spectroscopy revealed that iron coating on the peat was rather homogenous and As and Cr were abundantly adsorbed on the surface. By contrast, Cu and Zn displayed a sparing distribution on the surface of the iron coated peat. These results indicate that iron-peat simultaneously target sufficient amounts of both cations and anions and can be used for a one-step treatment of contaminated groundwater. PMID- 29421742 TI - A titration method for determining individual oxidant concentration in the dual sodium persulfate and hydrogen peroxide oxidation system. AB - The use of a dual oxidation system, which combines sodium persulfate (Na2S2O8, SPS) and hydrogen peroxide (H2O2, HP) is increasing as an in-situ chemical oxidation (ISCO) process for soil and groundwater remediation. An analytical method was assessed in this study for determining individual oxidant concentration in order to understand the interactions, and variations in the concentrations, of SPS and HP in aqueous systems containing both SPS and HP. The iodometric titration method was demonstrated to be capable of measuring total oxidant (SPS + HP) concentration; while the ceric sulfate titration method can be used specifically for measuring HP in the dual oxidation system without interfering with the iodometric titration. Therefore, SPS concentration can be deduced by subtraction of the HP concentration from the total oxidant concentration. Direct iodometric titration for determination of total oxidant at concentration above 20 mM exhibited <8% concentration. Based on the results of indirect determination of SPS in the dual oxidation system, an approximate 10% concentration variation was expected. This research may serve as a reference for measuring oxidant variations in this ISCO dual oxidant application. PMID- 29421743 TI - Antifouling enhancement of polyimide membrane by grafting DEDA-PS zwitterions. AB - In order to improve the water flux and antifouling property of polyimide (PI) membrane, zwitterions are grafted on PI membrane surface via a two-step modification route by reactions with N,N-diethylethylenediamine (DEDA) and 1,3 propane sultone (PS) sequentially. The reaction mechanism and physicochemical properties of membranes are confirmed via various characterization techniques. The anti-biofouling performance of the zwitterion-grafted PI membranes is evaluated by bacterial suspension immersion tests in Escherichia coli (E. coli) and staphylococcus aureus (S. aureus) solutions. The antifouling property is assessed via the filtration test using the bovine serum albumin (BSA) and dodecyl trimethyl ammonium bromide (DTAB) aqueous feed solutions. The effect of the reaction time with DEDA in the zwitterion-grafted process on the antifouling property is further investigated systematically. The results show that both the anti-biofouling and antifouling performances of zwitterion-grafted PI membranes are significantly improved. PMID- 29421744 TI - Simultaneous determination of eighteen nitro-polyaromatic hydrocarbons in PM2.5 by atmospheric pressure gas chromatography-tandem mass spectrometry. AB - A new atmospheric pressure gas chromatography-tandem mass spectrometry (APGC MS/MS) was developed to simultaneously separate, identify and quantify 18 nitro polyaromatic hydrocarbons (NPAHs) in air fine particulate matter (PM2.5). Compared with traditional negative chemical ionization (NCI) or electron impact ionization (EI)-MS/MS methods, APGC-MS/MS equipped with an atmospheric pressure chemical ionization (APCI) source provided better sensitivity and selectivity for NPAHs analysis in PM2.5.18 NPAHs were completely separated, and satisfactory linear response (R2 > 0.99), low instrumental detection limits (0.20-2.18 pg mL 1) and method detection limits (0.001-0.015 pg m-3) were achieved. Due to the reliable performance of the instrument, only minimal sample pretreatment is needed. It ensured the satisfactory method recovery (70%-120%) and qualified repeatability (RSD: 1.1%-17.2%), which met the requirement of trace analysis of NAPHs in the real environmental PM2.5. Using the developed method, the actual PM2.5 samples collected from Taiyuan, China in both summer and winter were analyzed, and 17 NPAHs but 2-nitrofluorene were detected and quantified. According to the obtained NAPH concentration results, the generation mechanism of NPAHs in PM2.5 and the effects on NPAHs formation caused by some ambient air pollutants were preliminarily discussed: secondary photochemical reaction might be the dominant source of NPAHs in PM2.5 collected from Taiyuan in both summer and winter; ambient air pollutants (NO2, SO2, CO) had more contribution on the NPAHs secondary formation of PM2.5 in winter. PMID- 29421745 TI - Enhanced generation of perfluoroalkyl carboxylic acids (PFCAs) from fluorotelomer alcohols (FTOHs) via ammonia-oxidation process. AB - With the phase-out of persistent, bioaccumalative, and toxic perfluoroalkyl carboxylic acids (PFCAs), it is needed to explore the potential release of PFCAs from precursors being emitted into the environment. Biotransformation of fluorotelomer alcohols (FTOHs) via biological processes in wastewater treatment plants (WWTPs) leads to discharge of PFCAs into receiving waters. However, the commonly existed microbial activity that can impact on FTOHs biodegradation in WWTPs remains unclear. The objective of present research was to explore the relationship between ammonia-oxidation process and the enhanced PFCAs generation from FTOHs biodegradation under aerobic activated sludge. The obtained results indicate that the cometabolism process performed by nitrifying microorganisms (NMs) was responsible for enhanced PFCAs generation. Among NMs, the ammonia oxidation bacteria that can express non-specific enzyme of ammonia monooxygenases resulted in the enhanced PFCAs generation from FTOHs. Meanwhile, the different addition amount of ammonia contributed to different defluorination efficiency of FTOHs. The present study further correlated the enhanced PFCAs generation from FTOHs biodegradation with ammonia-oxidation process, which can provide practical information on effective management of PFCAs generation in WWTPs. PMID- 29421746 TI - Polychlorinated biphenyl concentrations in pooled serum from people in different age groups from five Chinese cities. AB - Polychlorinated biphenyl (PCB) concentrations in human serum samples pooled by donor age and sex (>=60, 50-59, 40-49, 30-39, and 20-29 years old) were determined. The pooled samples were supplied by hospitals in five Chinese cities, which were Yitong (Jilin Province), Weifang (Shandong Province), Ganzi (Sichuan Province), Huaihua (Hunan Province), and Lingshui (Hainan Province). The total PCB concentrations were relatively low compared with concentrations that have been found in other parts of the world. Pentachlorobiphenyls were the dominant PCBs. The total PCB concentrations and the concentrations of most of the pentachlorobiphenyl congeners were slightly higher in the samples from younger donors than in the samples from older donors. The results indicated there is a new source of PCBs in China. Heptachlorobiphenyls in Lingshui may have been transported from Vietnam. Statistical analysis showed that young and old people had been exposed to different sources of PCBs. PCB 126 contributed more than the other dioxin-like PCBs to the total toxic equivalents when the samples were examined as a whole or by city, and the total toxic equivalents were higher in younger people than in older people for the whole sample set and for the Yitong samples. PMID- 29421747 TI - Degradation of di (2-ethylhexyl) phthalate in sediment by a surfactant-enhanced Fenton-like process. AB - This is the premier study reporting the remediation of di (2-ethylhexyl) phthalate (DEHP) contaminated sediment by a surfactant-enhanced Fenton-like system. Three widely used non-ionic surfactants were tested, and the order for desorption and solubilization of DEHP was determined as Tween 80 > Triton X-100 > Brij 35. The degradation of DEHP was studied at a near natural pH of 6.0 by two Fenton treatments: (i) Fe3+/H2O2 and (ii) Fe3+/PCA/H2O2. Results show that the addition of PCA can significantly enhance DEHP removal from 48.9% to 92.5%. This is consistent with observation that PCA maintained at a relative high level of iron ions, which can catalyze H2O2 to generate the reactive hydroxyl radicals (OH). Most of the added Tween 80 and a portion of OM were co-oxidized together with DEHP due to the non-selective nature of OH, which leaded to an increase in DOC content and decreases in sediment pH and total N content. The results provide an efficient and eco-friendly technique for the remediation of DEHP contaminated sediment, and also give insight to its environmental implications. PMID- 29421748 TI - Impact of a commercial glyphosate formulation on adsorption of Cd(II) and Pb(II) ions on paddy soil. AB - Use of glyphosate as a weedicide on rice cultivation has been a controversial issue in Sri Lanka, due to the hypothesis that the metal complexes of commercial glyphosate is one of the causative factors of Chronic Kidney Disease of unknown aetiology (CKDu) prevalent in some parts of Sri Lanka. The effect of commercial glyphosate on the adsorption and desorption of Cd(II) and Pb(II) ions on selective paddy soil studied using batch experiments, over a wide concentration range, indicates that the Langmuir adsorption isotherm model is obeyed at low initial metal ion concentrations while the Freundlich adsorption isotherm model obeys at high metal ion concentrations in the presence and absence of glyphosate. For all cases, adsorption of both Cd(II) and Pb(II) ions obeys pseudo second order kinetics, suggesting that initial adsorption is a chemisorption process. In the presence of glyphosate formulation, the extent of adsorption of Cd(II) and Pb(II) ions on soil is decreased, while their desorption is increased at high concentrations of glyphosate. Low concentrations of glyphosate formulation do not significantly affect the desorption of metal ions from soil. Reduction of adsorption leads to enhance the concentration of Cd(II) and Pb(II) ions in the aqueous phase when in contact with soil. PMID- 29421750 TI - Functionalized biochar derived from heavy metal rich feedstock: Phosphate recovery and reusing the exhausted biochar as an enriched soil amendment. AB - This paper provides a circular win-win approach for recycling rhizofiltration biomass into multifunctional engineered biochar for various environmental applications (e.g. phosphate recovery) with a potential reuse of the exhausted biochar as an enriched soil amendment. Functionalized biochars were derived from the disposals of water hyacinth (Eichhornia crassipes) plants grown in synthetic contaminated water spiked with either Fe2+ (Fe-B), Mn2+ (Mn-B), Zn2+ (Zn-B) or Cu2+ (Cu-B) comparing with the original drainage water as a control treatment (O B). The in-situ functionalization of biochar via the inherently heavy metal-rich feedstock produced homogenous organo-mineral complexes on biochar matrix without environmental hazards (e.g. volatilization or chemical sludge formation) associated with other post-synthetic functionalization methods. Physicochemical analyses (SEM-EDS, XRD, FTIR, BET and zeta potential (zeta)) confirmed the functionalization of Fe-B, Zn-B and Cu-B due to organo-mineral complexes formation, maximizing specific surface area, lowering the electronegativity, originating positively charged functional groups, and thus improving the anion exchange capacity (AEC) comparing with O-B. In contrary, physicochemical characteristics of Mn-B was in similarity with those of O-B. Phosphate recovery by the functionalized biochar was much greater than that of the unfunctionalized forms (O-B and Mn-B). Precipitation was the dominant chemisorption mechanisms for phosphate sorption onto biochar compared to other mechanisms (ion exchange, electrostatic attraction and complexation with active functional groups). The exhausted biochar showed an ameliorating effect on the low water and nutrient supply potentials of sandy soil, and thus improved fresh biomass yield and nutritional status of maize seedlings with some restrictions on its high micronutrient content. PMID- 29421749 TI - Increased coiling frequency linked to apoptosis in the brain and altered thyroid signaling in zebrafish embryos (Danio rerio) exposed to the PBDE metabolite 6-OH BDE-47. AB - Polybrominated diphenyl ethers (PBDEs) are a group of brominated flame retardants that are ubiquitously detected in the environment and associated with adverse health outcomes. 6-OH-BDE-47 is a metabolite of the flame retardant, 2,2',4,4' Tetrabromodiphenyl ether (BDE-47), and there is increasing concern regarding its developmental neurotoxicity and endocrine disrupting properties. In this study, we report that early life exposure in zebrafish (Danio rerio) embryos to 6-OH-BDE 47 (50 and 100 nM) resulted in higher coiling frequency and significantly increased apoptotic cells in the brain. These effects were partially rescued by overexpression of thyroid hormone receptor beta (THRbeta) mRNA. Moreover, exposure to 100 nM 6-OH-BDE-47 significantly reduced the number of hypothalamic 5 hydroxytryptamine (5-HT, serotonin)-immunoreactive (5-HT-ir) neurons and the mRNA expression of tryptophan hydroxylase 2 (TPH2). These results indicate that 6-OH BDE-47 affected thyroid hormone regulation through THRbeta and negatively impacted the nervous system, in turn, affecting coiling behavior. Correlations of these endpoints suggest that coiling frequency could be used as an indicator of neurotoxicity in embryos. PMID- 29421751 TI - Veterinary drug, 17beta-trenbolone promotes the proliferation of human prostate cancer cell line through the Akt/AR signaling pathway. AB - Trenbolone acetate (TBA) is a synthetic anabolic steroidal growth factor that is used for rapid muscle development in cattle. The absorbed TBA is hydrolyzed to the active form, 17beta-trenbolone (17 TB; 17beta-hydroxy-estra-4,9,11-trien-3 one) in meat and milk products, which can cause adverse health effects in humans. Similar to 5alpha-dihydrotestosterone (DHT), 17 TB was reported to exhibit endocrine disrupting effects on animals and humans due to its androgenic effect via binding to the androgen receptor. The purpose of this study is to investigate the molecular mechanism of cell proliferation in prostate cancer (PCa) cells treated with 17 TB. We found that 17 TB induces AR-dependent cell proliferation in the human prostate cancer cell line, 22Rv1 in a concentration dependent manner. Treatment with 17 TB increased the expression of cell cycle regulatory proteins, cyclin D2/CDK-4 and cyclin E/CDK-2, whereas the expression of p27 was down-regulated. Furthermore, phosphorylation of Rb and activation of E2F were also induced, which suggests the activation of cyclin D2/CDK-4 and cyclin E/CDK-2 in the cells. When 22Rv1 cells were exposed to 30 pM of 17 TB, which is the effective concentration (EC50) value required to observe proliferative effects on 22Rv1 cells, the expression levels of the phosphorylated forms of Akt and GSK3beta were increased. This study demonstrates that 17 TB induces AR-dependent proliferation through the modulation of cell cycle-related proteins in the Akt signaling pathway. The present study provides an effective methodology for identifying cell proliferation signaling of veterinary drugs that exert AR agonistic effects. PMID- 29421752 TI - The content of trace element iron is a key factor for competition between anaerobic ammonium oxidation and methane-dependent denitrification processes. AB - Coupling of anaerobic ammonium oxidation (Anammox) with denitrifying anaerobic methane oxidation (DAMO) is a sustainable pathway for nitrogen removal and reducing methane emissions from wastewater treatment processes. However, studies on the competitive relation between Anammox bacteria and DAMO bacteria are limited. Here, we investigated the effects of variations in the contents of trace element iron on Anammox and DAMO microorganisms. The short-term results indicated that optimal concentrations of iron, which obviously stimulated the activity of Amammox bacteria, DAMO bacteria and DAMO archaea, were 80, 20, and 80 MUM, respectively. The activity of Amammox bacteria increased more significant than DAMO bacteria with increasing contents of trace element iron. After long-term incubation with high content of trace element iron of 160 MUM in the medium, Candidatus Brocadia (Amammox bacteria) outcompeted Candidatus Methylomirabilis oxyfera (DAMO bacteria), and ANME-2d (DAMO archaea) remarkably increased in number and dominated the co-culture systems (64.5%). Meanwhile, with further addition of iron, the removal rate of ammonium and nitrate increased by 13.6 and 9.2 times, respectively, when compared with that noted in the control. As far as we know, this study is the first to explore the important role of trace element iron contents in the competition between Anammox bacteria and DAMO bacteria and further enrichment of DAMO archaea by regulating the contents of trace element iron. PMID- 29421753 TI - Occurrence of illicit drugs in two wastewater treatment plants in the South of Italy. AB - In this study the occurrence and the behavior of illicit drugs and their metabolites have been investigated for two wastewater treatment plants (WWTPs) (namely, WWTP-1 and WWTP-2) located in Sicily (island of Italy). Samples were analyzed for methamphetamine, cocaine (COC), 3,4-methylenedioxymethamphetamine (MDMA), methadone (METH), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), 3,4-methylenedioxy amphetamine (MDA); 3,4-methylenedioxy ethylamphetamine (MDEA), 11-nor-9-carboxy-Delta9-tetrahydrocannabinol (THC-COOH) and Benzoylecgonine (BEG). The BEG, COC, MOR and THC-COOH were found at the highest concentration in both WWTPs. The Wastewater-based epidemiology calculation for BEG, COC, cannabinoids and THC-COOH was performed. On average, for both plants, population consumes 1.6 and 23.4 dose 1000 inh-1 day-1 of cocaine and cannabis, respectively. For WWTP-1 negative removals of illicit drugs were observed. For WWTP-2 the following average removal efficiencies were obtained: BEG (77.85%), COC (92.34%), CODEINE (64.75%), MOR (90.16%) and THC-COOH (68.64%). PMID- 29421754 TI - Altitudinal and spatial variations of polycyclic aromatic hydrocarbons in Nepal: Implications on source apportionment and risk assessment. AB - Although several global/regional studies have detailed the high level of polycyclic aromatic hydrocarbons in urban areas worldwide, unfortunately, Nepal has never been part of any global/regional regular monitoring plan. Despite few sporadic studies exist, the systematic monitoring and integrated concentration of PAHs in urban region of Nepal are lacking. In this study, the concentrations, sources, and health risk assessment of 16 PAHs in air (n = 34) were investigated in suspected source areas/more densely populated regions of Nepal. Four potential source areas in Nepal were focused as it was conjectured that urban centers in plain areas (Birgunj and Biratnagar) would possibly be more influenced by PAHs as a result of intense biomass/crop residue burning than those in hilly areas (Kathmandu and Pokhara). The overall concentrations of ?16PAHs ranged from 4.3 to 131 ng/m3 (median 33.3 ng/m3). ?16PAH concentrations in plain areas were two folds higher than those in hilly areas. PHE was the most abundant followed by FLUA, PYR, and NAP, which accounted for 36%, 15%, 12%, and 9% of ?16PAHs, respectively. Principal component analysis confirmed that PAHs in highly urbanized areas (Kathmandu and Pokhara) were related to diesel exhausts and coal combustion, while PAHs in less urbanized regions (Birgunj and Biratnagar) originated from biomass and domestic wood combustions. Furthermore, in the urban areas of Nepal, vehicular emission could also influence atmospheric PAHs. The lifetime cancer risk per million populations due to PAH exposures was estimated to be higher for plain areas than that for hilly areas, suggesting a relatively greater risk of cancer in people living in plain areas. PMID- 29421755 TI - Validation of the BCR sequential extraction procedure for natural radionuclides. AB - Determining the availability of natural radionuclides in environmental conditions is increasingly important in order to evaluate their toxicity. A validated procedure is necessary to ensure the comparability and accuracy of the results obtained by different laboratories. For that, an optimised BCR sequential extraction procedure has been applied to the certified reference material (CRM), coded as BCR-701, and their resulting liquid and solid fractions were subjected to an exhaustive chemical and radioactivity characterisation. In this sense, several material characterisation techniques were used for chemical, mineralogical, and radioactive characterisation, in order to gain basic information about the obtained fractions. In accordance with the results of this work, the BCR sequential extraction procedure has been validated for the most significant alpha-emitter natural radionuclides (210Po, 234U, 238U, 230Th, 232Th, and 226Ra). It has been demonstrated that their mobility is related to the speciation under environmental conditions and the type of radionuclide; we have even found differences between radionuclides of the same element, such as the cases of the pairs 234U238U and 230Th232Th, for the BCR-701. In addition, we found that radium was mainly bound to the reducible fraction (Fe and Mn oxyhydroxides), uranium to the oxidizable fraction (organic matter and sulphides), and that the polonium and thorium isotopes had a high affinity with the particulate phase (non-mobile fraction). PMID- 29421756 TI - Carbon and nitrogen mineralization and enzyme activities in soil aggregate-size classes: Effects of biochar, oyster shells, and polymers. AB - Biochar (BC) and polymers are cost-effective additives for soil quality improvement and long-term sustainability. The additional use of the oyster shells (OS) powder in BC- or polymer-treated soils is recommended as a nutrient source, to enhance aggregation and to increase enzyme activities. The effects of soil treatments (i.e., BC (5 Mg ha-1) and polymers (biopolymer at 0.4 Mg ha-1 or polyacrylamide at 0.4 Mg ha-1) with or without the OS (1%)) on the short-term changes were evaluated based on a 30-day incubation experiment with respect to several variables (e.g., CO2 release, NH4+ and NO3- concentrations, aggregate size classes, and enzyme activities in an agricultural Luvisol). The BC and BP with the addition of OS increased the portion of microaggregates (<0.25 mm) relative to the control soil without any additions, while PAM alone increased the portion of large macroaggregates (1-2 mm). Concentrations of NO3- also increased in soils treated with OS, OS + BC, and OS + BP as result of the increased chitinase and leucine aminopeptidase activities. The BC and BP when treated with the additional OS had significant short-term impacts on N mineralization without affecting C mineralization in soil. Consequently, the combination of BC or BP with OS was seen to accelerate N turnover without affecting C turnover (and related C losses) from soil. As such, the addition of these additives contributed considerably to the improvement of soil fertility and C sequestration. PMID- 29421757 TI - Rare earth elements profile in a cultivated and non-cultivated soil determined by laser ablation-inductively coupled plasma mass spectrometry. AB - Rare earth elements (REEs) have several applications but the effects on environment are not well known. Therefore, the aim of this work is to establish a method for direct solid sample analysis by laser ablation-inductively coupled plasma mass spectrometry (LA-ICP-MS) to evaluate the concentration and distribution of REEs in cultivated and non-cultivated soil. Samples were collected in two areas to 40 cm of depth. The LA-ICP-MS method is easy to be implemented and the sample treatment is very fast comprising only its drying, grounding and pressing as a pellet. The accuracy of the method was evaluated by using a certified reference material (BCR 667 - Estuarine Sediment, Institute for Reference Materials and Measurements (IRMM)) where good agreement with the certified values was obtained. Analyte recovery at two levels of concentration (2.5 and 15.0 MUg g-1) was also performed and recoveries in the range of 85%-120% were achieved, values that are acceptable for LA-ICP-MS analysis. In general, the concentration of the REEs is higher in the cultivated soil and increased from the surface to deeper layers, which can be a consequence of fertilizer application. PMID- 29421758 TI - Combining spectroscopic techniques and chemometrics for the interpretation of lichen biomonitoring of air pollution. AB - A screening evaluation of lichen thalli, based on spectroscopic techniques coupled with chemometrics, is proposed as fast, simple and "green" method for the biomonitoring of air pollution. For two consecutive years, lichen thalli of Pseudevernia furfuracea were exposed for three months in selected sites of Liguria (NW-Italy) according to different levels and types of air pollution. At the end of the exposure period, transplanted thalli were analyzed by a set of monitoring techniques, including Front-Face Fluorescence Spectroscopy (FFFS), Near Infrared Spectroscopy (NIRS) and Plant Efficiency Analyser (PEA). Data were compared with values of air pollutants recorded during the exposure period by the Regional Agency for Environmental Protection, in order to relate lichen physiological indicators with the effects of atmospheric concentrations. A chemometric evaluation of the analytical signals, including principal component analysis (PCA) and quadratic discriminant analysis (QDA), was performed; the mean prediction rate of the discriminant models calculated on the FFFS emission spectra ranged from 70 to 75% on the external test sets. Front-face fluorescence spectroscopy proved to be a promising technique for the determination of level and type of pollutants in lichen thalli. PMID- 29421759 TI - Arsenic-induced nutrient uptake in As-hyperaccumulator Pteris vittata and their potential role to enhance plant growth. AB - It is known that arsenic (As) promotes growth of As-hyperaccumulator Pteris vittata (PV), however, the associated mechanisms are unclear. Here we examined As induced nutrient uptake in P. vittata and their potential role to enhance plant growth in sterile agar by excluding microbial effects. As-hyperaccumulator P. multifida (PM) and non-hyperaccumulator P. ensiformis (PE) belonging to the Pteris genus were used as comparisons. The results showed that, after 40 d of growth, As induced biomass increase in hyperaccumulators PV and PM by 5.2-9.4 fold whereas it caused 63% decline in PE. The data suggested that As played a beneficial role in promoting hyperaccumulator growth. In addition, hyperaccumulators PV and PM accumulated 7.5-13, 1.4-3.6, and 1.8-4.4 fold more As, Fe, and P than the non-hyperaccumulator PE. In addition, nutrient contents such as K and Zn were also increased while Ca, Mg, and Mn decreased or unaffected under As treatment. This study demonstrated that As promoted growth in hyperaccumulators and enhanced Fe, P, K, and Zn uptake. Different plant growth responses to As among hyperaccumulators PV and PM and non-hyperaccumulator PE may help to better understand why hyperaccumulators grow better under As-stress. PMID- 29421760 TI - Effect of organic loading rate on the removal of DMF, MC and IPA by a pilot-scale AnMBR for treating chemical synthesis-based antibiotic solvent wastewater. AB - This study focuses on the effects of organic loading rate (OLR) on the removal of N,N-Dimethylformamide(DMF), m-Cresol (MC) and isopropyl alcohol (IPA) by a pilot scale anaerobic membrane bioreactor (AnMBR) for treating chemical synthesis-based antibiotic solvent wastewater at period of improved influent COD concentration with decreased HRT. The whole process was divided into five stages in terms of the variation of OLR ranging from 3.9 to 12.7 kg COD/(m3.d). During 249 days of operating time, the average DMF, MC, IPA removal efficiency were 96.9%,98.2% and 96.4%, respectively. Cake layer was accumulated on the membrane surface acted as a dynamic secondary biofilm which lead to the increase of physical removal rate. In addition, mathematical statistical models was built on the linear regression techniques for exploring the inner relationship between EPS and the performance of the AnMBR. PMID- 29421761 TI - Kinetics and equilibrium adsorption study of selenium oxyanions onto Al/Si and Fe/Si coprecipitates. AB - Inappropriate treatments for the effluents from semiconductor plants might cause the releases and wide distributions of selenium (Se) into the ecosystems. In this study, Al/Si and Fe/Si coprecipitates were selected as model adsorbents as they often formed during the wastewater coagulation process, and the removal efficiency of selenite (SeO3) and selenate (SeO4) onto the coprecipitates were systematically examined. The removal efficiency of SeO3 and SeO4 was highly related to surface properties of Al/Si and Fe/Si coprecipitates. The surface attached Al shell of Al/Si coprecipitates shielded a portion of negative charges from the core SiO2, resulting in a higher point of zero charge than that of Fe/Si coprecipitates. Thus, adsorption of SeO3/SeO4 was favorable on the Al/Si coprecipitates. Adsorptions of both SeO3 and SeO4 on Al/Si coprecipitates were exothermic reactions. On Fe/Si coprecipitates, while SeO3 adsorption also showed the exothermic behavior, SeO4 adsorption occurred as an endothermic reaction. The kinetic adsorption data of SeO3/SeO4 on Al/Si and Fe/Si coprecipitates were described well by the pseudo-second-order kinetic model. SeO4 and SeO3 adsorption on Fe/Si or Al/Si were greatly inhibited by the strong PO4 ligand, whereas the weak ligand such as SO4 only significantly affected SeO4 adsorption. The weakest complex between SeO4 and Al was implied by the essentially SeO4 desorption as SeO4/PO4 molar ratios decreased from 0.5 to 0.2. These results were further confirmed by the less SeO4 desorption (41%) from Fe/Si coprecipitates than that from Al/Si coprecipitates (78%) while PO4 was added sequentially. PMID- 29421762 TI - Removal of haloacetamides and their precursors at water purification plants applying ozone/biological activated carbon treatment. AB - Haloacetamides (HAcAms) are nitrogenous disinfection byproducts in drinking water. The profiles of six HAcAms and their formation potentials (FPs) upon chlorination at water purification plant 1 (WPP-1) in September 2016 and at WPP-2 in September 2016 and January 2017 were investigated. HAcAms were removed effectively when they were formed via intermediate chlorination during water purification processes. Removal of total HAcAm-FPs ranged from 50% to 75%. Coagulation/flocculation/sand filtration showed the highest removal of total HAcAm-FPs. As for individual HAcAms, while chlorinated acetamide-FPs were removed, brominated acetamide-FPs, particularly 2,2-dibromoacetamide, remained. The bromine incorporation factors increased during all water purification processes except ozonation and the ozone/hydrogen peroxide process for diHAcAms (2,2-dichloroacetamide, 2-bromo-2-chloroacetamide, and 2,2-dibromoacetamide). The trends in relationships between DOM indices (fractions of dissolved organic matter, ultraviolet absorbance at 260 nm, and fluorescence intensities representing humic-like and tryptophan-like compounds) and total HAcAm-FPs during ozonation and ozone/hydrogen peroxide process were different from those during other processes. PMID- 29421763 TI - Cd sequestration by bacteria-aluminum hydroxide composites. AB - Microbe-associated aluminum (Al) hydroxides occur naturally in aquatic and geologic environments and they might play a crucial role in the sequestration of trace metals because these composite solids comprise both reactive mineral and organic surface, but how they do it still remains unknown. Here we replicate Al hydroxide organo-mineral composite formation in soil and sediments by synthesising composites using Pseudomonas putida cells, during coprecipitation with Al hydroxide. Morphological and ATR-FTIR analysis show closely attached nano sized Al hydroxides on the bacterial surface. For composites dominated by either bacteria or Al hydroxide, an enhanced metal adsorption is observed on the composites than on pure Al hydroxide at pH < 6. Cd uptake by the mainly Al mineral composite is approximately additive, i.e., the sum of the end-member metal adsorptivities, whereas that on the mainly bacteria composite is non additive. This non-additive sorption is not only due to the blockage of surface reactive sorption sites, but more importantly the changes of surface charge when bacteria and Al mineral are interacted. EXAFS results show that Cd is predominately sorbed as a bidentate corner-sharing complex on the amorphous Al hydroxide surface and a carboxyl-binding on the bacterial surface. This study has important implications for understanding both Al and trace metal cycling in microbe-rich geologic environments. PMID- 29421764 TI - Degradation of polycyclic aromatic hydrocarbons in soil mesocosms by microbial/plant bioaugmentation: Performance and mechanism. AB - In order to study the degradation of polycyclic aromatic hydrocarbons (PAHs) in an aged and highly contaminated soil, four bioremediation strategies (indigenous microorganisms, microbial bioaugmentation with a PAH-degrading and bioemulsifier producing strain, Rhodococcus ruber Em1, plant bioaugmentation with Orychophragmus violaceus and their combination) were compared and the enhanced degradation mechanism was investigated in soil mesocosms. Degradation rates over a period of 175 days showed that Em1 combined with Orychophragmus violaceus promoted a significant enhancement of PAHs degradation. In inoculated microcosms with Rhodococcus ruberEm1, mineralization reached a lower level in the absence than in the presence of plants. Elimination of PAHs was significantly enhanced (increased by 54.45%) in the bioaugmented mesocosms. Quantitative PCR indicated that copy numbers of linA and RHD-like gene (encoding PAH-ring hydroxylating dioxygenase) in the mesocosm with plant were three and five times higher than those in the mesocosm without plant, respectively. Transcript copy numbers of RHD like gene and 16S rRNA gene of strain Em1 in mesocosm with plant were two and four times higher than those in the mesocosm without plant, respectively. Taken together, the results of this study show that plants or Rhodococcus ruber Em1 enhance total PAHs removal, moreover their effects are necessarily cumulative by combined strains and plants. PMID- 29421765 TI - Degradation of tetrabromobisphenol A by ferrate(VI) oxidation: Performance, inorganic and organic products, pathway and toxicity control. AB - This study systematically investigated the degradation of tetrabromobisphenol A (TBBPA) by ferrate (VI) oxidation. The reaction kinetics between ferrate (VI) with TBBPA were studied under pseudo-first-order conditions in the pH range 5.5 10.5. Then, a series of batch experiments were carried out to investigate other factors, including the ferrate (VI) dosage, temperature and interfering ions. Additionally, the generation of inorganic products (bromide ion and bromate) was evaluated. The organic intermediates were identified, and possible pathways were proposed. In addition, the toxicity variation was analyzed with marine luminous bacteria (V. fischeri). Degradation of TBBPA by ferrate (VI) oxidation was confirmed to be an effective and environmentally friendly technique. The reaction was fitted with a second-order rate model. With a ferrate (VI) dosage of 25.25 MUmol/L, TBBPA concentration of 1.84 MUmol/L, an initial pH of 7.0, and a temperature of 25 degrees C, a 99.06% TBBPA removal was achieved within 30 min. The evaluation of inorganic products showed that the capacity of ferrate (VI) oxidation to yield bromide ions was relatively strong and could prevent the formation of bromate compared to photocatalytic and mechanochemical techniques. Eleven intermediates were identified, and the proposed degradation pathway indicated that TBBPA might undergo debromination, beta scission, substitution, deprotonation and oxidation. The results of toxicity testing showed that ferrate (VI) could effectively control the toxicity of the treated samples, although the toxicity increased in the initial reaction stage due to the accumulation and destruction of more toxic intermediates. PMID- 29421766 TI - A common surfactant used in food packaging found to be toxic for reproduction in mammals. AB - : Migration from a multilayer plastic material intended for food contact showed that 2,4,7,9-tetramethyl-5-decyne-4,7-diol mixture (surfynol), used as a surfactant in the adhesive employed to build the multilayer, was transferred to water and other food simulants in contact with the plastic. When these multilayer plastics were used for containing seminal doses for artificial insemination, it was found that fertility was seriously damaged in terms of motility, acrosome integrity, mitochondrial activity and penetration capacity in the cells, thus affecting male fertility. Quantitative proteomic analysis of exposed germinal cells demonstrated the inhibition of key proteins involved in the fertilization capacity by affecting the cytoskeleton, sperm motility, the energy machinery and sperm defense mechanisms against oxidation, therefore confirming the surfactant induced male infertility. These results open up new and interesting perspectives for the study of reprotoxicity caused by different chemicals common in our daily lives. SIGNIFICANCE: This paper demonstrates the toxicity for reproduction of a common surfactant used in food packaging and the scientific reasons why the sperm loses reproductive capacity in presence of this chemical. So, the surfactant affects the male fertility. The surfactant is present in many adhesives used either for building multilayer materials or to glue paper and plastic in food packaging. This is the first time that reprotoxicity is demonstrated for this compound. According to the theoretical approach Threshold of Toxicological Concern (TTC) the compound is highly toxic but experimental data did not exist so far. The study described in this paper and the results obtained open a door to further research in which male infertility caused by chemicals could be demonstrated. PMID- 29421767 TI - Exploring the usefulness of the complex in vitro intestinal epithelial model Caco 2/HT29/Raji-B in nanotoxicology. AB - The use of in vitro barrier models is gaining relevance as an alternative to animal studies in risk assessment, pharmacokinetic, and toxicological studies in general. These models permit an easier evaluation of the underlying mechanisms taking place at the molecular and cellular levels on the barrier site. Here, we report several methodological modifications of the three-dimensional in vitro intestinal epithelial model Caco-2/HT29/Raji-B for its successful application in the Nanotoxicology field. In addition, new insights in the study of specific molecular markers and new confocal microscope approaches have also been incorporated. Due to the multiple variables and parameters playing a part when the model's complexity is increased, we have monitored the barrier's formation and cell differentiation over time. Finally, the practical usability of the proposed model was tested by evaluating the action of the food additives titanium dioxide and silica dioxide nanoparticles (TiO2NPs and SiO2NPs). The NPs associated effects were evaluated by confocal microscopy. We have demonstrated the essential role of the mucus layer in the decrease of cellular uptake, avoiding potential NPs-cell nuclei interactions. PMID- 29421768 TI - Developmental neurotoxicity in the progeny after maternal gavage with chlorpyrifos. AB - Today, developmental intellectual disorders affect one out of six children in industrialised countries. Intensively used in agriculture, the neurotoxicant pesticide chlorpyrifos (CPF) is known for its environmental persistence and bioaccumulation. Its role has not yet been established in the aetiology of intellectual impairments. Here we assessed whether maternal ingestion of low CPF dose in rats could impair the cerebral function of their progeny. Rat dams received daily CPF exposures (1 mg/kg, per os) during gestation and lactation. Behaviours relevant to mental retardation were measured in the surface righting, negative geotaxis and grip strength at post-natal days (PND) 3 and 7. Open field tests were performed at PND 16, 18 and 20. Fear conditioning was assessed at PND 34. Startle inhibition was tested at PND 31 and 60. According to the results, the progeny of CPF-treated dams showed slower negative geotaxis as neonates, lower novelty exploration as juveniles and faster startle reflex as adolescents and adults. This data suggests that developmental CPF relevant to human exposure may impair novelty-related activity and sensori-motor functions, thus adaptability to the environment. This data supports the hypothesis that CPF may contribute to behavioural disorders including acquisition retardation and consequences as an adult. PMID- 29421770 TI - Cystitis Cystica Glandularis: Radiological Imitator of Urothelial Carcinoma. PMID- 29421769 TI - Hepatitis B Virus Infection in Iranian Hemodialysis Patients: a Systematic Review and Meta-Analysis. AB - INTRODUCTION: Hepatitis B virus (HBV) infection in hemodialysis patients and its associated adverse health consequences are a worldwide health priority. This systematic review aimed to provide evidence on HBV infection in Iranian hemodialysis patients. MATERIALS AND METHODS: Through a comprehensive systematic review of literature, which led to meta-analysis of findings, we estimated the pooled prevalence of HBV infection in Iranian hemodialysis patients. The main international electronic data sources were MEDLINE, Institute of Scientific Information, and Scopus. We also search several Persian-language databases. All cross-sectional and analytical studies conducted in Iran concerning HBV infection were included irrespective of date and language. RESULTS: Of 602 publications retrieved from literature search, 66 met the inclusion criteria, and 36 were eligible for including in the study. The prevalence rate varied from zero to 9.75% across different provinces. The national prevalence of HBV was reported between 2.1% and 18.2%. Significant heterogeneity was found between reported prevalence rates (I2 = 83.5%, P < .001), as a result of which, we used random effect analysis. Results of meta-analysis showed that the estimated pooled prevalence was 4% (95% confidence interval, 3.3% to 4.7%). CONCLUSIONS: To our knowledge, this was the first comprehensive systematic review of HBV infection in the hemodialysis patients of Iran. Results could be useful for informed health policy making and planning further studies in this field. PMID- 29421771 TI - Serum Beta-Trace Protein for Assessment of Kidney Function in Neonates. AB - INTRODUCTION: Compared to the conventional methods, serum beta-trace protein (BTP) has been shown to be more helpful for estimating glomerular filtration rate; however, its value is remained unclear in neonates. The present study aimed to investigate the range of serum BTP level in healthy term neonates and its value to estimate glomerular filtration rate. MATERIALS AND METHODS: This cross sectional study was conducted on 50 healthy term neonates without underlying cardiovascular or kidney disorders who were admitted to Ali Asghar hospital in 2013. Serum BTP was measured using an automated nephelometric immunoassay. Glomerular filtration rate was assessed using the Schwartz equation based on serum creatinine level. RESULTS: The mean age of the neonates was 6.2 +/- 3.6 days (range, 2 to 17 days), their mean gestational age was 38.02 +/- 0.20 weeks, and their mean height was 49.8 +/- 1.7 cm. The mean serum BTP level was 0.41 +/- 0.11 mg/L (range, 0.19 mg/L to 0.92 mg/L). The mean serum creatinine level was 0.49 +/- 0.16 mg/dL (range, 0.3 mg/dL to 1.0 mg/dL). The mean estimated GFR was 48.90 +/- 15.88 mL/min. A positive correlation was observed between the reciprocal concentrations of BTP and GFR (r = 0.383, P = .006). Furthermore, the reciprocal concentrations of BTP was associated with the reciprocal concentrations of serum creatinine level (r = 0.365, P = .009). CONCLUSIONS: Measurement of serum BTP can be a reliable tool for detecting kidney function in neonates. Further studies are warranted to design a suitable formula for GFR estimation based on serum BTP in neonates. PMID- 29421772 TI - Effects of Coenzyme Q10 Supplementation on Gene Expressions Related to Insulin, Lipid, and Inflammation Pathways in Patients With Diabetic Nephropathy. AB - INTRODUCTION: Data on the effects of coenzyme Q10 (CQ10) on gene expression related to insulin, lipid, and inflammation in patients with diabetic nephropathy (DN) are scarce. This study aimed to determine the effects of CQ10 supplementation on gene expression related to insulin, lipid, and inflammation pathways in patients with DN. MATERIALS AND METHODS: Forty patients with DN, aged 40 to 85 years old, were randomly assigned into 2 groups to receive either 100 mg/d of CQ10 supplements (n = 20) or placebo (n = 20), for 12 weeks. Gene expression related to signaling pathway of insulin, lipid, and inflammation were determined in blood samples using a reverse transcriptase polymerase chain reaction method. RESULTS: Quantitative results of reverse transcriptase polymerase chain reaction demonstrated that compared with the placebo, CQ10 administration upregulated gene expression of peroxisome proliferator-activated receptor-gamma (P = .02) in peripheral blood mononuclear cells of the patients with DN. In addition, compared with the placebo, CQ10 supplementation downregulated gene expression of interleukin-1 (P = .003) and tumor necrosis factor-alpha (P = .02). No significant effects were observed on gene expression of oxidized low-density lipoprotein, lipoprotein(a), glucose transporter-1, transforming growth factor-beta in the CQ10 group. CONCLUSIONS: Overall, CQ10 supplementation for 12 weeks in DN patients significantly improved gene expression of peroxisome proliferator-activated receptor-gamma, interleukin-1, and tumor necrosis factor-alpha. PMID- 29421773 TI - Study of Urine Composition of Patients With Recurrent Nephrolithiasis in Lorestan, Iran. AB - INTRODUCTION: Nephrolithiasis is one of the most common urinary tract diseases. After the first episode of urinary calculus, the risk of recurrence is nearly 40% to 50% at 5 years. Nephrolithiasis is a systemic disease that is associated with some metabolic disorders. This study aimed to provide a picture of the frequency of metabolic abnormalities in patients with nephrolithiasis from west part of Iran. MATERIALS AND METHODS: Patients with recurrent urinary tract calculi referred to the Nephrology-Urology Clinics in Khorramabad city were recruited. After collection of demographic data of all the patients, 24-hour urine and blood samples were taken to measure biochemical factors. RESULTS: Of the 232 participants, 125 were males and 107 were females. Hyperoxaluria was seen in 93 (40.1%) of the participants, hypercalciuria in 55 (23.7%), hypocitraturia in 58 (25%), and hyperuricosuria in 33 (14.9%). Hyperoxaluria in the males was significantly more frequent than in the female patients. There were no significant differences between the two groups in other urinary metabolic disorders. CONCLUSIONS: Patients with nephrolithiasis from Lorestan province may have metabolic characteristics varying from those of regions; ethnicity may be a possible reason. Variation of dietary regimens, such as the amount of meat or vegetable in the diet that can change oxalate, calcium, or citrate of urine, might have influenced the results. Time of sampling is another factor. Population specific studies are helpful to health care providers for preventive planning for nephrolithiasis. PMID- 29421774 TI - Efficacy and Safety of Rituximab in Children With Steroid- and Cyclosporine resistant and Steroid- and Cyclosporine-dependent Nephrotic Syndrome. AB - INTRODUCTION: There is evidence of the effectiveness of rituximab in treatment of nephrotic syndrome in children. The present study aimed to assess safety and the therapeutic effectiveness of rituximab in steroid- and cyclosporine-resistant pediatric nephrotic syndrome. MATERIALS AND METHODS: Forty-three children with steroid- and cyclosporine-resistant or steroid- and cyclosporine-dependent noncongenital nephrotic syndrome were included in the study to receive intravenous rituximab, 375 mg/m2/wk, for 4 weeks. The children were followed up for 2 years. Effectiveness was defined as remission of proteinuria in response to rituximab. Side effects of rituximab were monitored. RESULTS: Overall, 23 (57.1%) of the children had steroid- and cyclosporine-resistant nephrotic syndrome, of whom 8 (34.8%) revealed complete response and 3 (13%) revealed partial response. Seven children (16.7%) had late-resistant nephrotic syndrome, of whom 6 (85.7%) revealed complete response and none revealed partial response. Ten children (26.2%) had steroid- and cyclosporine-dependence all of whom revealed complete response to rituximab. Complete response rate was significantly higher in those with drug-dependent pattern than the other groups (P = .002). There was no association between response to rituximab and pathological basis of disease. Side effects were found in 4 patients as leukopenia in 2, alopecia in 1, and eosinophilia in 1. CONCLUSIONS: Rituximab is effective for children with nephrotic syndrome with high efficacy and well tolerability, especially in those with steroid- and cyclosporine-dependent nephrotic syndrome. PMID- 29421775 TI - Increased Urine Interleukin-17 and Interleukin-22 Levels in Patients With Candidal Urinary Tract Infection. AB - INTRODUCTION: Candiduria is common in the hospitalized patients. This study aimed to quantify interleukin (IL)-17 and IL-22 levels in urine of candiduric patients. MATERIALS AND METHODS: A case-control study was conducted on inpatients at Hashemi Nejad Kidney Center. Thirty-four patients were identified with Candida species in their urine samples (> 103 colony-forming units per milliliter and presence of Candida species only). Urine samples with concomitant infections were excluded. Thirty-four patients with negative direct examination and culture were included as the control patients. Interleulin-17 and IL-22 levels were measured in the lyophilized and nonlyophilized urine. The relevant cytokine titers of the two groups were compared, and the association of cytokine elevation and candiduria was investigated. RESULTS: The majority of the candiduric patients were from the intensive care and urology units of women. Only 4 patients (11.7%) manifested fever and dysuria. Massive leukocyturia was observed in 4 patients. Candida glabrata was the most commonly isolated species (44%). Levels of the urine IL-17 and IL-22 were significantly elevated in the candiduric patients, when compared to the noncandiduric controls. While an increased IL-17 level was significantly associated with candiduria (odds ratio, 1.09; 95% confidence interval, 1.003 to 1.17; P = .04), an increased IL-22 level was not. The results showed that lyophilized urine samples maximized the detection power of urinary cytokines. CONCLUSIONS: Our results indicated that direct examination, fungal urine culture, and investigation of urine IL-17 and IL-22 levels are useful tools for diagnosis of Candida urinary tract infection. PMID- 29421776 TI - Association Between Matrix Metalloproteinase-3 Activity and Glomerular Filtration Rate and Albuminuria Status in Patients With Type 2 Diabetes Mellitus. AB - INTRODUCTION: Diabetic nephropathy is pictured as matrix accumulation and thickening of glomerular basal membrane. Matrix metalloproteinases (MMPs) are major proteases involved in extracellular matrix degradation. Moreover, plasminogen activator inhibitor-1 (PAI-1) primarily regulates plasmin dependent proteolysis. It plays a role in renal fibrosis causing extracellular matrix accumulation through inhibition of plasmin-dependent extracellular matrix degradation. This study investigated PAI-1 serum level and MMP-3 activity and their correlation with glomerular filtration rate in patients with diabetes mellitus. MATERIALS AND METHODS: In a case-control design, serum PAI-1 concentrations and MMP-3 activity were measured in 80 patients with normoalbuminuria, microalbuminuria, and macroalbuminuria. Receiver operating characteristics curve analysis was used to assess the diagnostic accuracy of MMP 3 activity in discriminating albuminuria. RESULTS: In the patients with microalbuminuria, serum PAI-1 levels were higher compared with macroalbuminuric patients (P < .001). The patients with macroalbuminuria exhibited a significantly lower MMP-3 activity than the patients with microalbuminuria and normoalbuminuria (P < .001). No significant correlation was found between serum MMP-3 activity and serum PAI-1 levels in those with normoalbuminuria, microalbuminuria, and macroalbuminuria. The MMP-3 activity had a strong positive correlation with estimated glomerular filtration (r = 0.853, P < .001). CONCLUSIONS: We found that there was a positive correlation between glomerular filtration rate and MMP-3 activity in diabetic patients. This concludes that MMP-3 may have a role in the pathogenesis of diabetic nephropathy progressions towards macroalbuminuria, and therefore, MMP-3 activity may be used in evaluating albuminuria status. PMID- 29421777 TI - Effect of Hemodialysis on Global and Regional Cardiac Function in Children With End-stage Renal Disease. AB - INTRODUCTION: Changes in cardiac structure and function are common among patients with end-stage renal disease. The aim of this study was to evaluate the effect of hemodialysis on global and segmental cardiac function in children with end-stage renal disease. MATERIALS AND METHODS: Fifty-two children with ESRD who were on long-term hemodialysis at Nemazee Hospital, Shiraz, were enrolled. They underwent echocardiography (M-mode, 2-dimensional, Doppler, and speckle echocardiography) 30 minutes prior to and after hemodialysis, and the values were compared. RESULTS: The mean age of the patients was 13.00 +/- 3.53 years. There was a significant reduction in left ventricular systolic and diastolic dimensions and volume (P < .001) and the E:A ratio after dialysis (P = .03). Global and longitudinal strain and strain rate showed no significant changes before and after hemodialysis. CONCLUSIONS: Hemodialysis with volume reduction decreases left ventricular volume but not regional strain and strain rate significantly in children. This study showed preload independency of speckle echocardiography in children. PMID- 29421778 TI - Prevalence of Sarcopenia and Dynapenia and Their Determinants in Iranian Peritoneal Dialysis Patients. AB - INTRODUCTION: Uremic sarcopenia and dynapenia are prevalent in chronic kidney disease patients, including dialysis patients. The present study was designed to determine the prevalence of sarcopenia and dynapenia and their determinants in peritoneal dialysis (PD) patients in Tehran, Iran. MATERIALS AND METHODS: All eligible PD patients at the peritoneal dialysis centers of Tehran were included in this cross-sectional study. Skeletal muscle mass and muscle strength were assessed using bioelectrical impedance analysis and hand grip strength, respectively. Physical performance was determined by a 4-m walk gait speed test. RESULTS: The prevalence rates of dynapenia and sarcopenia were 43.0% and 11.5% in the PD patients, respectively. There were significant associations between the prevalence of dynapenia and the age of patients (P = .03), physical activity level (P = .04), and the presence of diabetes mellitus (P = .005). In addition, a significant association was found between the prevalence of sarcopenia and sex (P = .009). CONCLUSIONS: This study indicates that uremic sarcopenia and dynapenia are prevalent in PD patients in Tehran, Iran. These conditions may contribute to physical disability, decreased the quality of life, increased morbidity, and a high mortality rate. Therefore, prevention and treatment of uremic sarcopenia and dynapenia are necessary for Iranian PD patients. PMID- 29421779 TI - Nephropathic Cystinosis Mimicking Bartter Syndrome: a Novel Mutation. AB - Cystinosis is a rare autosomal recessive disorder resulting from defective lysosomal transport of cystine due to mutations in the cystinosin lysosomal cystine transporter (CTNS) gene. The clinical phenotype of nephropathic cystinosis is characterized by renal tubular Fanconi syndrome and development of end-stage renal disease during the first decade. Although metabolic acidosis is the classically prominent finding of the disease, a few cases may present with hypokalemic metabolic alkalosis mimicking Bartter syndrome. Bartter-like presentation may lead to delay in diagnosis and initiation of specific treatment for cystinosis. We report a case of a 6-year-old girl initially presenting with the features of Bartter syndrome that was diagnosed 2 years later with nephropathic cystinosis and a novel CTNS mutation. PMID- 29421780 TI - Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice. AB - BACKGROUND/AIMS: The myocardial sarcoplasmic reticulum calcium ATPase (SERCA2a) is a pivotal pump responsible for calcium cycling in cardiomyocytes. The present study investigated the effect of luteolin (Lut) on restoring SERCA2a protein level and stability reduced by myocardial ischemia/reperfusion (I/R) injury. We verified a hypothesis that Lut protected against myocardial I/R injury by regulating SERCA2a SUMOylation. METHODS: The hemodynamic data, myocardial infarct size of intact hearts, apoptotic analysis, mitochondrial membrane potential (DeltaPsim), the level of SERCA2a SUMOylation, and the activity and expression of SERCA2a were examined in vivo and in vitro to clarify the cardioprotective effects of Lut after SUMO1 was knocked down or over-expressed. The putative SUMO conjugation sites in mouse SERCA2a were investigated as the possible regulatory mechanism of Lut. RESULTS: Initially, we found that Lut reversed the SUMOylation and stability of SERCA2a as well as the expression of SUMO1, which were reduced by I/R injury in vitro. Furthermore, Lut increased the expression and activity of SERCA2a partly through SUMO1, thus improving DeltaPsim and reducing apoptotic cells in vitro and promoting the recovery of heart function and reducing infarct size in vivo. We also demonstrated that SUMO acceptor sites in mouse SERCA2a involving lysine 585, 480 and 571. Among the three acceptor sites, Lut enhanced SERCA2a stability via lysine 585. CONCLUSIONS: Our results suggest that Lut regulates SERCA2a through SUMOylation at lysine 585 to attenuate myocardial I/R injury. PMID- 29421781 TI - The Myth of Blunted Gamers: No Evidence for Desensitization in Empathy for Pain after a Violent Video Game Intervention in a Longitudinal fMRI Study on Non Gamers. AB - BACKGROUND/AIMS: It is a common concern in the research field and the community that habitual violent video gaming reduces empathy for pain in its players. However, previous fMRI studies have only compared habitual game players against control participants cross-sectionally. However the observed pattern of results may be due to a priori differences in people who become gamers and who not. In order to derive the causal conclusion that violent video game play causes desensitisation, longitudinal studies are needed. METHODS: Therefore we conducted a longitudinal fMRI intervention study over 16 weeks. Participants were randomly assigned to 1) play a violent video game (Grand Theft Auto 5), 2) perform a social life simulation game (The Sims 3) 30 min/day for 8 weeks, 3) serve as passive control. To assess empathy processing, participants were exposed to painful and non-painful stimuli (e.g. someone cutting a cucumber with or without hurting herself) either as real photographs or video-game like depictions in a 3T MRI scanner before and after the training intervention as well as two months after training. RESULTS: We did not find any evidence for desensitization in the empathy network for pain in the violent video game group at any time point. CONCLUSIONS: The present results provide strong evidence against the frequently proclaimed negative effects of playing violent video games and will therefore help to communicate a more realistic scientific perspective of the effects of violent video gaming in real life. PMID- 29421782 TI - Retraction Statement. PMID- 29421786 TI - Speaker and Observer Perceptions of Physical Tension during Stuttering. AB - PURPOSE: Speech-language pathologists routinely assess physical tension during evaluation of those who stutter. If speakers experience tension that is not visible to clinicians, then judgments of severity may be inaccurate. This study addressed this potential discrepancy by comparing judgments of tension by people who stutter and expert clinicians to determine if clinicians could accurately identify the speakers' experience of physical tension. METHOD: Ten adults who stutter were audio-video recorded in two speaking samples. Two board-certified specialists in fluency evaluated the samples using the Stuttering Severity Instrument-4 and a checklist adapted for this study. Speakers rated their tension using the same forms, and then discussed their experiences in a qualitative interview so that themes related to physical tension could be identified. RESULTS: The degree of tension reported by speakers was higher than that observed by specialists. Tension in parts of the body that were less visible to the observer (chest, abdomen, throat) was reported more by speakers than by specialists. The thematic analysis revealed that speakers' experience of tension changes over time and that these changes may be related to speakers' acceptance of stuttering. CONCLUSION: The lack of agreement between speaker and specialist perceptions of tension suggests that using self-reports is a necessary component for supporting the accurate diagnosis of tension in stuttering. PMID- 29421784 TI - Complement Activation in Capillary Cerebral Amyloid Angiopathy. AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) is classified as type 1 with capillary amyloid beta (Abeta) or type 2 without capillary Abeta. While it is known that CAA activates complement, an inflammatory mediator, there is no information on the relationship between capillary Abeta and complement activation. METHODS: We evaluated 34 autopsy brains, including 22 with CAA and 12 with other neurodegenerative diseases. We assessed the vascular density of CAA by analyzing the expression of complement (C1q, C3d, C6, C5b-9), macrophage scavenger receptor (MSR), and apolipoprotein E (ApoE). RESULTS: Capillary immunostaining for C1q, C3d, MSR, and ApoE was identified almost exclusively in CAA-type1 brains. There was intense expression of C1q, C3d, MSR, and ApoE, as well as weaker expression of C5b-9 and C6 in the arteries/ arterioles of both CAA subtypes, but not in control brains. C5b-9 and C6 were preferentially expressed in arteries/arterioles with subcortical hemorrhage or cortical superficial siderosis. Triple immunofluorescence revealed that C1q, C3d, and ApoE were colocalized with Abeta in CAA brain capillaries. CONCLUSION: Complement, MSR, and ApoE were only coexpressed in the presence of Abeta accumulation in capillaries, suggesting a role for complement activation in the propagation of Abeta. Additionally, C5b-9 expression may be associated with hemorrhagic brain injury in CAA. PMID- 29421787 TI - A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect. AB - Many studies have shown that molecular karyotyping is an effective diagnostic tool in individuals with developmental delay/intellectual disability. We report on a de novo interstitial 1q22q23.1 microdeletion, 1.6 Mb in size, detected in a patient with short stature, microcephaly, hypoplastic corpus callosum, cleft palate, minor facial anomalies, congenital heart defect, camptodactyly of the 4 5th fingers, and intellectual disability. Chromosomal microarray analysis revealed a 1.6-Mb deletion in the 1q22q23.1 region, arr[GRCh37] 1q22q23.1(155630752_157193893)*1. Real-time PCR analysis confirmed its de novo origin. The deleted region encompasses 50 protein-coding genes, including the morbid genes APOA1BP, ARHGEF2, LAMTOR2, LMNA, NTRK1, PRCC, RIT1, SEMA4A, and YY1AP1. Although the unique phenotype observed in our patient can arise from the haploinsufficiency of the dosage-sensitive LMNA gene, the dosage imbalance of other genes implicated in the rearrangement could also contribute to the phenotype. Further studies are required for the delineation of the phenotype associated with this rare chromosomal alteration and elucidation of the critical genes for manifestation of the specific clinical features. PMID- 29421788 TI - Analysis of Hospital Charges of Inpatients with Acute Ischemic Stroke in Beijing, China, 2012-2015. AB - BACKGROUND: The study aimed to analyze the hospital charges of the inpatients with acute ischemic stroke in Beijing and determine the factors associated with hospital costs. METHODS: Medical records of hospitalized patients with a primary diagnosis of ischemic stroke according to International Classification of Diseases 10th Revision codes were collected from 121 hospitals in Beijing from March 1, 2012, to February 28, 2015. Distribution characteristics of hospital charges for different hospital levels (level 2 hospitals and level 3 hospitals) and types (Western medicine hospitals and Chinese medicine hospitals) were studied. Linear regression analysis was used to examine the association among hospital costs and factors that influenced total hospital charges. RESULTS: There were 158,781 admissions for ischemic stroke, 63.1% of the patients were male and their mean age was 67.7 +/- 12.4 years, the median length of hospital stay (LOHS) was 13.5 days (interquartile range 9.9-18.1 days). The median hospital charge was 2,112 (1,436-3,147) US dollars. Of these, 46.7% were for medicine, 21.1% for laboratory and examination, and 16.3% for therapy. LOHS, hospital level, and pulmonary infection were key determinants of the hospital charges. CONCLUSIONS: The proportion of medicine fees for the ischemic stroke inpatients showed a downward trend during the period from 2012 to 2015, but medicine fees still accounted for the largest percentage of hospital charges in China. LOHS emerged to be the main determinant of the cost. Decreasing medicine fees and LOHS might be strategies to decrease hospital charges and reduce economic burden of stroke in China. PMID- 29421789 TI - Mechanism of Action of STW 5 in Functional Dyspepsia and IBS: The Origin of Multi Target. AB - BACKGROUND: STW 5 is a complex herbal combination preparation composed of 9 different herbal extracts. As an herbal medicinal product, this preparation is indicated for treating functional dyspepsia (FD) and irritable bowel syndrome (IBS). Its efficacy and practical applicability was demonstrated in several clinical studies. SUMMARY: Each herbal constituent of STW 5 has distinct effects on the gastrointestinal tract, and each shows activity through different mechanisms of action: among others, the single extracts have effects on nerves, smooth muscles, epithelial, and inflammatory cells. For example, they have relaxing or tonicizing effects on gastrointestinal muscles, and they counteract inflammation through different physiological systems, contributing to the clinical efficacy through modulation of multiple therapeutic targets. Key Messages: STW 5 is a role model for the concept of multi-targeting in therapy. Especially in complex syndromes such as FD and IBS, simultaneous multi-targeting of different functional causes seems to be a more promising approach than the classical paradigm of one disease - one receptor - one effect. PMID- 29421791 TI - [33. Deutscher Krebskongress - Perspektiven verandern Krebs - Krebs verandert Perspektiven. Diagnose - Therapie - (Uber-)Leben. Berlin, 21.-24. Februar 2018: Abstracts]. PMID- 29421790 TI - Edgar Adrian (1889-1977) and Shell Shock Electrotherapy: A Forgotten History? AB - The English electrophysiologist Edgar Adrian (1889-1977) was the recipient of the Nobel Prize for physiology in 1932 for his research on the functions of neurons. During World War I, at Queen Square in London, he devised an intensive electrotherapeutic treatment for shell-shocked soldiers. The procedure, developed with Lewis Yealland (1884-1954), was similar to "torpillage," the faradic psychotherapy used in France. Adrian and Yealland considered that the pain accompanying the use of faradic current was necessary for both therapeutic and disciplinary reasons, especially because of the suspicion of malingering. According to Adrian, this controversial electric treatment was only able to remove motor or sensitive symptoms. After the war, he finally admitted that war hysteria was a complex and difficult phenomenon. PMID- 29421792 TI - Functional Dyspepsia and Irritable Bowel Syndrome: Beyond Rome IV. AB - BACKGROUND: The correct diagnosis of functional gastrointestinal disorders (FGIDs) is quite a challenge. The overlaps between syndromes can complicate the interpretation of clinical data. SUMMARY: The incidence of functional digestive disorders and irritable bowel syndrome are still underestimated with the currently applied diagnostic tools, and the management of the seemingly elusive disease is not satisfactory. For this reason, the "Rome" criteria were created to provide a better understanding and classification of FGIDs. Key Messages: Rome diagnostic criteria and recommendations should be used in the design and performance of clinical studies in the field of functional dyspepsia and irritable bowel syndrome. PMID- 29421793 TI - Phytotherapy in Functional Gastrointestinal Disorders. AB - BACKGROUND: Phytotherapy is an important therapeutic option in functional gastrointestinal diseases (FGID). It has a large tradition, with different approaches in different regions of the world, some of which have made their way into modern evidence-based medicine (EBM). SUMMARY: Taking into account the number of herbs in use, and also the cumulated scientific evidence on them, FGID are possibly the most important indication in phytotherapy. This does not only apply for European phytotherapy, but also for other regions, such as Asia. Within European phytotherapy, herbs active in FGID are usually classified according to their main active constituents and their activities. Typically, the herbs used in FGID are grouped into amara, aromatica, amara aromatica combining both properties, herbs stimulating gastric secretion, herbs containing spasmolytic and carminative essential oils or spasmolytic alkaloids, mucilaginosa soothing the mucosa, and flavonoid containing drugs with anti-inflammatory properties. In phytotherapy, different plants are frequently combined to maximize effectiveness and specificity of action. Very potent combination products can be developed when the mechanisms of action of the combination partners are complementary. This approach can be demonstrated by the example of STW 5. For this herbal combination product, therapeutic efficacy in FGID has been clinically proven according to the highest standards of EBM. This example also underlines that modern rational phytotherapy is definitely part of modern EBM. Key Messages: FGID is one of the most important indications in phytotherapy and rationally combined herbal preparations are established evidence-based therapeutic options. PMID- 29421794 TI - Does a Ureteral Obstruction Affect the Contralateral Kidney Morphology? A Stereological Analysis in a Rodent Model. AB - OBJECTIVE: To investigate, in a rodent model, the influence of an obstructed kidney/ureter on the contralateral organ morphology. METHODS: Thirty-six rats were randomly assigned into the following groups: untreated ureteral obstruction group (UO-U, n = 10), submitted to a ligature of the ureter at day 0; UO group (at day 0) followed by nephrectomy after 24 h (UO-N, n = 8); nephrectomy group (N, n = 9), submitted to nephrectomy at day 0; and sham group (S, n = 9), submitted to simulated surgery at day 0. All these procedures were performed on the left kidney/ureter. All animals were euthanized 30 days after surgery, and the right kidneys were collected for stereological analysis. Data were compared using a one-way analysis of variance with Bonferroni's post test, considering p < 0.05 as significant. RESULTS: The kidney volume, weight, and cortical volume were augmented in groups UO-N and N, compared to group S. Kidneys from the UO-U group showed only a moderate augmentation in kidney weight, with a reduction in the cortical-medullar ratio, compared to the kidneys in group S. No differences in the glomerular volumetric density, volume-weighted glomerular volume, and number of glomeruli were observed among the right kidneys of the studied groups. CONCLUSION: An obstructed kidney/ureter is more prejudicial to the contralateral kidney morphology than an absent kidney. PMID- 29421795 TI - Production and Molecular Cytogenetic Characterization of a Durum Wheat-Thinopyrum elongatum 7E Disomic Addition Line with Resistance to Fusarium Head Blight. AB - Wheatgrass, Thinopyrum elongatum (2n = 2x = 14, EE), is an important wild relative of wheat with many excellent traits, including resistance to Fusarium head blight (FHB), that can be used for durum wheat improvement. Through hybridization of the durum cultivar "Langdon" with the amphiploid 8801 (AABBEE), a disomic alien addition line (2n = 30) with a pair of Th. elongatum 7E chromosomes was obtained and confirmed using chromosome-specific molecular markers of Th. elongatum and genomic in situ hybridization (GISH). This line is meiotically and reproductively stable, generally forming 15 bivalents at meiosis including 14 pairs from Langdon and 1 from Th. elongatum with 2 chiasmata each as revealed by GISH analysis. At the adult growth stages under field conditions, this addition line shows high resistance to FHB, with less than 16% infection on visual observation in 2 years (2014 and 2015). This addition line is shorter in height and has narrower leaves and shorter spikes as compared to its parent Langdon. So the linkage group 7E might be a further source of wheat improvement by targeted introgression approaches. PMID- 29421796 TI - Variability in Predialysis Systolic Blood Pressure and Long-Term Outcomes in Hemodialysis Patients. AB - BACKGROUND/AIMS: While systolic blood pressure variability (SBPV) is an independent risk factor for mortality in the general population, its association with outcomes in hemodialysis patients has been less well-investigated. METHODS: In this retrospective study, we enrolled 99 eligible HD patients from 2006 to 2016. Predialysis blood pressure measurements obtained over 1-year period were used to determine each patient's BPV. The standard deviation (SD), the coefficient of variation (CV) and the variation independent of the mean (VIM) were used as metrics of BPV. RESULTS: During a median follow-up period of 68 months, 52 patients died, and cardiovascular disease (31.3%) was the primary cause of death in these patients. After adjusting for covariates, the hazard ratios (HRs) for all-cause and cardiovascular mortality were 1.80 (95% confidence interval (CI) 1.11-2.92) and 1.71 (95% CI 1.01-2.90), respectively, for a one percent increase in CV. Variability in the volume removed per session and predialysis serum albumin and calcium levels were identified as factors associated with BPV. CONCLUSION: In this study, we demonstrate that greater variability in predialysis SBP is associated with long-term mortality in hemodialysis patients. Controlling volume variation, avoiding hypoalbuminemia and reducing blood calcium levels might reduce SBP variability and thereby improve prognoses in these patients. PMID- 29421797 TI - Functional Gastrointestinal Disorders: Complex Treatments for Complex Pathophysiological Mechanisms. PMID- 29421798 TI - Management and Survival of Pleural Mesothelioma: A Record Linkage Study. AB - BACKGROUND: Pleural mesothelioma (PM) is a rare, highly lethal tumor. A definite consensus on its management has yet to be established. OBJECTIVES: To assess management, overall survival (OS), and their predictors in a cohort of patients from Lombardy, the largest Italian region (about 10 million inhabitants). METHODS: Through a record linkage between Lombardy health care administrative databases, we identified patients diagnosed with PM in 2006-2011 without history of cancer, evaluating their management. OS from PM diagnosis was estimated using the Kaplan-Meier method. Predictors of OS and of treatment were assessed using Cox regression models with time-dependent covariates when appropriate. RESULTS: Out of 1,326 patients, 754 (56.9%) received treatment for PM: 205 (15.5%) underwent surgery, and 696 (52.5%) used chemotherapy. Surgery was spread across several hospitals, and most patients diagnosed in nonspecialized centers (70%) underwent surgery in the same centers. Age at diagnosis was a strong inverse determinant of surgery. Determinants of receiving chemotherapy were younger age, a more recent first diagnosis, and first diagnosis in a specialized center. OS was 45.4% at 1 year, 24.8% at 2 years, and 9.6% at 5 years (median 11 months). OS decreased with age, and was higher for those who underwent surgery, but not for those treated with chemotherapy. CONCLUSIONS: Management of PM varied widely in clinical practice, and significant predictors of treatment were younger age and recent diagnosis, though a high proportion of patients were not treated. Patients were treated in various hospitals, indicating the importance of concentrating serious rare neoplasms in Comprehensive Cancer Centers (as recognized by the Italian Health Ministry). PMID- 29421799 TI - An International Genetic Survey of Breed-Specific Diseases in Working Dogs from the United States, Israel, and Poland. AB - Genetic diseases occur in breeds used for law enforcement. As important team members, dogs are expected to operate at peak performance for several years and are significant investments for both the initial purchase and extensive, specialized training. Previous studies have not focused on causes for retirement or euthanasia as genetic (inherited) versus acquired (environmental). We performed direct mutational analysis for breed-specific conditions on samples from 304 dogs including 267 law enforcement (122 US, 87 Israeli, and 58 Polish) and 37 search and rescue dogs. Genetic testing identified 29% (n = 89) of the dogs tested to be carriers of a genetic mutation and 6% (n = 19) to be at risk for a debilitating inherited condition that may eventually impair the dog's ability to work. At-risk dogs included Labrador Retrievers (n = 4) with exercise induced collapse, Bloodhounds (n = 2) with degenerative myelopathy (DM), and German Shepherd dogs with DM (n = 12) or leukocyte adhesion deficiency, type III (n = 1). A substantial number of working dogs were shown to be at risk for genetic conditions that may shorten the dog's career. The loss of dogs, due to early retirement or euthanasia, as a result of preventable genetic conditions has an emotional cost to handlers and financial cost to service organizations that can be avoided with genetic screening prior to breeding, buying, or training. PMID- 29421800 TI - Health-Related Quality of Life and Its Factors of Hemodialysis Patients in Suzhou, China. AB - BACKGROUND: To identify factors of health-related quality of life (HRQOL) of Chinese end-stage renal disease patients undergoing hemodialysis (HD). METHODS: In all, 315 HD patients were recruited from a tertiary hospital in Suzhou, China. Each patient completed the Kidney Disease Quality of Life Short Form. It generated 4 types of HRQOL scores: PCS score, MCS score, kidney disease component summary (KDCS) score, and SF-6D index score. Multiple linear regressions were conducted to identify the factors associated with each of the scores. RESULTS: Factors associated with poorer HRQOL were determined including: middle age and above (>=45 years), without partner, presence of complication, long dialysis vintage (>=4.5 years) with physical component summary; low education level, presence of comorbidity, long dialysis vintage, low hemoglobin level with mental component summary; without partner, presence of comorbidity, long dialysis vintage with KDCS; middle age and above, without partner, low education level; long dialysis vintage, more frequent dialysis (>=2 times/week) with SF-6D. CONCLUSION: The study evaluated the HRQOL of HD patients in mainland China. PMID- 29421802 TI - Postoperative Liver Failure Criteria for Predicting Mortality after Major Hepatectomy with Extrahepatic Bile Duct Resection. AB - BACKGROUND: Post-hepatectomy liver failure (PHLF) is a serious complication after major hepatectomy with extrahepatic bile duct resection (Hx with EBDR) that may cause severe morbidity and even death. The purpose of this study was to compare several criteria systems as predictors of PHLF-related mortality following Hx with EBDR for perihilar cholangiocarcinoma (PHCC). METHODS: The study cohort consisted of 222 patients who underwent Hx with EBDR for PHCC. We compared several criteria systems, including previously established criteria (the International Study Group of Liver Surgery (ISGLS) criterion; and the "50-50" criterion), and our institution's novel systems "Max T-Bili" defined as total bilirubin (T-Bili) >7.3 mg/dL during post-operative days (POD) 1-7, and the "3-4 50" criterion, defined as total bilirubin >4 mg/dL and prothrombin time <50% on POD #3. RESULTS: Thirteen patients (5.8%) died from PHLF-related causes. The 3-4 50 criterion showed high positive predictive values (39.1%), the 3-4-50, Max T Bili, and 50-50 criterion showed high accuracies (91.7, 86.9, and 90.5%, respectively) and varying sensitivities (69.2, 69.2, and 38.5% respectively). CONCLUSIONS: The 3-4-50, Max T-Bili, and 50-50 criterion were all useful for predicting PHLF-related mortality after Hx with EBDR for PHCC. PMID- 29421801 TI - The Contribution of Whole Blood Viscosity to the Process of Aortic Valve Sclerosis. AB - OBJECTIVE: We aimed to investigate whether increased whole blood viscosity (WBV) could be an important factor for the occurrence of aortic valve sclerosis (AVS). SUBJECTS AND METHODS: A total of 209 patients were enrolled in the study. WBV was calculated using the hematocrit and total plasma protein at a low shear rate (LSR) and a high shear rate (HSR). AVS was defined as irregular valve thickening and calcification (without evidence of outflow obstruction) documented by a peak transvalvular velocity < 2.5 m/s on echocardiographic examination. The patient group consisted of 109 patients with AVS (77 females, 32 males), and 100 subjects without AVS (65 females, 35 males) were assigned to the control group. RESULTS: In the AVS group, WBV values were significantly higher for HSR (17.4 +/- 0.5 vs. 17.1 +/- 0.7 208 s-1, p < 0.001) and LSR (65.9 +/- 12.5 vs. 59.7 +/- 16.7 0.5 s 1, p = 0.002). In multivariate logistic regression analysis, WBV at HSR and LSR were independent predictors of AVS (odds ratio, OR: 2.24, 95% confidence interval, CI: 1.38-3.64, p = 0.001; OR: 1.026, 95% CI: 1.006-1.046, p = 0.01, respectively). Receiver-operating characteristic (ROC) curve analysis indicated that a WBV cutoff value of 65.4 at LSR had a sensitivity of 46.8% and a specificity of 60.0% (area under the ROC curve, AUC: 0.615, 95% CI: 0.535-0.696, p = 0.004), and a WBV cutoff value of 17.1 at HSR had a sensitivity of 61.5% and specificity of 53% (AUC: 0.648, 95% CI: 0.571-0.725, p < 0.001) for the prediction of AVS. CONCLUSION: This study demonstrated that WBV was independently associated with AVS. WBV could be an indicator of inflammation and vessel remodeling without evidence of outflow obstruction. PMID- 29421803 TI - Portuguese Observational Study of Ischaemic Stroke in Patients Medicated with Non Vitamin K Antagonist Oral Anticoagulants. AB - INTRODUCTION: Clinical trials and subsequent meta-analyses showed advantages of non-vitamin K antagonists oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation. The impact of preadmission anticoagulation in acute ischaemic stroke (AIS) has not been established. OBJECTIVE: To compare functional outcome of patients with AIS with preadmission NOACs vs. VKAs. METHODS: A retrospective analysis was conducted on consecutive AIS patients under oral anticoagulation (VKAs or NOACs) admitted in 4 Portuguese hospitals within a period of 30 months. Two primary outcomes were defined and compared between VKA and NOAC groups: symptomatic intracerebral hemorrhage transformation (sICH) and modified Rankin Scale (mRS) at 3 months. RESULTS: Four hundred sixty-nine patients were included, of whom 332 (70.8%) were treated with VKA and 137 (29.2%) with NOAC. Patients' median age was 78.0 and 234 (49.9%) were male. NOAC-treated patients had a higher median CHA2DS2-VASc score than those under VKA (5.0 vs. 4.0, p = 0.023). The two primary outcomes showed no statistical differences between the VKAs' group and the NOACs' group (sICH: 5.4 vs. 5.4% [p = 0.911]; mRS at 3 months: 3.0 vs. 3.0 [p = 0.646], respectively). CONCLUSION: Preadmission anticoagulation with NOACs in AIS has a functional impact similar to that of VKAs. PMID- 29421804 TI - Retraction Statement. PMID- 29421805 TI - Association between Toll-Like Receptor 4 T399I Gene Polymorphism and the Susceptibility to Crohn's Disease: A Meta-Analysis of Case-Control Studies. AB - BACKGROUND/AIMS: This article was undertaken to investigate the association of toll-like receptor 4 (TLR4) polymorphism (Thr399Ile) and risk of Crohn's disease (CD) by performing a meta-analysis. METHODS: Articles were chosen based on PubMed, Embase, China National Knowledge Internet, and Chinese Wanfang databases (up to 12th October 2016). Specific inclusion criteria were used to evaluate articles. Meta-analysis was performed by using a random or fixed effect model. Fifteen eligible case-control studies were finally included into this meta analysis. We estimated the summary OR with its corresponding 95% CI to assess the association. RESULTS: Summary results of this meta-analysis showed a moderate association between the TLR4 T399I polymorphism and the risk of CD (allele model: OR 1.26, 95% CI 1.06-1.50, p = 0.009; heterozygote model: OR 1.36, 95% CI 1.11 1.66, p = 0.003; dominant model: OR 1.35, 95% CI 1.10-1.64, p = 0.004; homozygote model: OR 1.08, 95% CI 0.44-2.64, p = 0.866; recessive model: OR 0.97, 95% CI 0.40-2.35, p = 0.946). Stratified analysis on geographical area, ethnicity, and genotypic methods suggested that the polymorphism was associated with increased risk of CD in Asia and Asians, and "T" allele only moderately increased CD risk within polymerase chain reaction-restricted fragment length polymorphism. CONCLUSIONS: Our meta-analysis suggests that TLR4 T399I polymorphism is moderately associated with susceptibility to CD, and more studies are needed to confirm our conclusion. PMID- 29421806 TI - Taking Warfarin with Heparin Replacement and Direct Oral Anticoagulant Is a Risk Factor for Bleeding after Endoscopic Submucosal Dissection for Early Gastric Cancer. AB - BACKGROUND: Although bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) remains problematic, especially in patients taking anticoagulants, there are differing views on the ideal and optimal management for these patients. This study investigated the risk of bleeding after ESD in patients taking anticoagulants. METHODS: We enrolled 61 consecutive patients taking anticoagulants (anticoagulant group) and 968 patients taking no antithrombotic agents (non-antithrombotic group) treated with ESD for EGC between December 2010 and October 2016. We analyzed the risk factors for bleeding after ESD in relation to the various clinical factors. RESULTS: Incidences of bleeding after ESD were significantly higher (14%; 11/76) in the anticoagulant group compared to the non-antithrombotic group (3%; 40/1,167). Moreover, bleeding after ESD was significantly more common in patients in the warfarin monotherapy group (14%; 5/37) and in the direct oral anticoagulant (DOAC) monotherapy group (22%; 4/18), compared to the non-antithrombotic group. Multivariate analysis revealed that dialysis, the use of anticoagulants, and an operation time >=75 min were independent risk factors for bleeding after ESD. CONCLUSIONS: Our data suggest that patients who take warfarin and receive heparin bridging, and those who take DOAC medication, are prone to bleeding after ESD for EGC. PMID- 29421807 TI - The Clinical Management of Main Duct Intraductal Papillary Mucinous Neoplasm of the Pancreas. AB - BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas comprise a heterogeneous group of intraductal mucin-producing neoplasms representing a typical adenoma-to-carcinoma sequence. The involvement of the main pancreatic duct (MPD) is a feature of paramount importance, directly related to a more aggressive biology and a higher malignancy rate. METHOD: We review and discuss the clinical management of IPMNs with a MPD involvement, recalling the different consensus guidelines and addressing recent controversies in literature, presenting the current clinical practice in Verona Pancreas Institute. RESULTS: All the aspects of surgical management were discussed, from the indication for surgery to the intraoperative management and the follow-up strategies. CONCLUSION: The management of presumed IPMNs involving the MPD at our Institution is in line with the International Association of Pancreatology 2012 guidelines, revised in 2016. Surgical resection proposed should achieve the complete removal of the tumor with negative margins. Despite a good prognosis in terms of survival of overall resected main duct intraductal papillary mucinous neoplasms, follow-up should not be discontinued. PMID- 29421808 TI - Pathophysiology of Functional Gastrointestinal Disorders: A Holistic Overview. AB - Background and Summary: Traditionally, functional gastrointestinal disorders (FGID), including functional dyspepsia or irritable bowel syndrome (IBS), are defined by more or less specific symptoms and the absence of structural or biochemical abnormalities that cause these symptoms. This concept is now considered to be outdated; if appropriate tests are applied, structural or biochemical abnormalities that explain or cause the symptoms may be found in many patients. Another feature of FGID are the highly prevalent psychiatric comorbidities, such as depression and anxiety. It is implied that mood disorders "cause" gastrointestinal symptoms. In fact, epidemiological data now provide strong evidence that in subsets of cases, gastrointestinal (GI) symptoms arise first and mood disorders occur later, while in other patients the reverse appears to happen. Possible mechanisms for gut-brain dysfunction have been identified, with systemic minimal inflammation as a causal factor in at least some subjects. Other mechanisms that play a role in FGID include chronic infections, intestinal microbiota, low-grade mucosal inflammation including the increase of eosinophils, systemic immune activation, altered intestinal permeability, in diarrhea predominant IBS altered bile salt metabolism, abnormalities in the serotonin metabolism and genetic factors. All these factors might be modulated by environmental factors such as diet. Key Messages: While a number of factors can be linked to specific symptoms (e.g., pain or diarrhea), it is evident that the symptom-based categorization of patients will not allow targeted treatments that specifically address the underlying pathophysiology. PMID- 29421809 TI - A Potassium-Selective Current Affected by Micromolar Concentrations of Anion Transport Inhibitors. AB - BACKGROUND/AIMS: In the human genome, more than 400 genes encode ion channels, which are ubiquitously expressed and often coexist and participate in almost all physiological processes. Therefore, ion channel blockers represent fundamental tools in discriminating the contribution of individual channel types to a physiological phenomenon. However, unspecific effects of these compounds may represent a confounding factor. Three commonly used chloride channel inhibitors, i.e. 4,4'-diisothiocyano-2,2'-stilbene-disulfonic acid (DIDS), 5-nitro-2-[(3 phenylpropyl) amino]benzoic acid (NPPB) and the anti-inflammatory drug niflumic acid were tested to identify the lowest concentration effective on Cl- channels and ineffective on K+ channels. METHODS: The activity of the above mentioned compounds was tested by whole cell patch-clamp on the swelling-activated Cl- current ICl,swell and on the endogenous voltage-dependent, outwardly rectifying K+ selective current in human kidney cell lines (HEK 293/HEK 293 Phoenix). RESULTS: Micromolar (1-10 uM) concentrations of DIDS and NPPB could not discriminate between the Cl- and K+ selective currents. Specifically, 1 uM DIDS only affected the K+ current and 10 uM NPPB equally affected the Cl- and K+ currents. Only relatively high (0.1-1 mM) concentrations of DIDS and prolonged (5 minutes) exposure to 0.1-1 mM NPPB preferentially suppressed the Cl- current. Niflumic acid preferentially inhibited the Cl- current, but also significantly affected the K+ current. The endogenous voltage-dependent, outwardly rectifying K+ selective current in HEK 293/HEK 293 Phoenix cells was shown to arise from the Kv 3.1 channel, which is extensively expressed in brain and is involved in neurological diseases. CONCLUSION: The results of the present study underscore that sensitivity of a given physiological phenomenon to the Cl- channel inhibitors NPPB, DIDS and niflumic acid may actually arise from an inhibition of Cl- channels but can also result from an inhibition of voltage-dependent K+ channels, including the Kv 3.1 channel. The use of niflumic acid as anti inflammatory drug in patients with concomitant Kv 3.1 dysfunction may result contraindicated. PMID- 29421810 TI - Is There a Role for Double J Stent Culture in Contemporary Urology? AB - INTRODUCTION: To present the incidence of bacterial colonization on ureteral double J stents (DJS); isolate the uropathogens; define the rate of multi resistant bacteria strains (MRBS) and present their clinical importance. MATERIALS AND METHODS: The whole body of 105 DJSs was examined for the presence of uropathogens. RESULTS: The main etiology for stent placement was lithiasis (57.1%). The most frequently cultured microorganisms were staphylococcus (28.6%). Forty-four stents hosted MRBS. 25 (23.8%), 10 (9.5%) and 8 (7.6%) of the patients were affected by malignancy, diabetes mellitus and chronic renal failure respectively. Apart from the female gender, none of the examined factors (age, duration of stenting and chronic diseases) was correlated with the colonization or the presence of MRBS. Eleven of the 61 stented patients (18%) who were operated upon developed a febrile urinary tract infections (UTI). In 7 of them the stent hosted MRBS (63.6%). After taking into consideration the sensitivity report, we altered our initial empirical antibacterial prophylaxis to targeted antibacterial treatment in the patients with MRBS with rapid remission of their infection and no urosepsis event. CONCLUSION: The knowledge of bacteriologic flora of DJS can be very helpful in an evidence-based prophylactic and therapeutic practice. Stent examination could be recommended in high-risk cases of developing UTI and sepsis after a urologic operation. PMID- 29421811 TI - Swiprosin-1 Promotes Mitochondria-Dependent Apoptosis of Glomerular Podocytes via P38 MAPK Pathway in Early-Stage Diabetic Nephropathy. AB - BACKGROUND/AIMS: Podocyte injury, especially podocyte apoptosis, plays a major role in early-stage diabetic nephropathy (DN). Swiprosin-1, also known as EF hand domain containing 2 (EFhd2), is a Ca2+-binding protein in different cell types. However, the function of swiprosin-1 in podocytes remains unknown. METHODS: The expression and distribution of swiprosin-1 were investigated in the mouse renal glomerulus and conditionally immortalized mouse podocyte cell line MPC-5. The expression of swiprosin-1 was also detected in streptozotocin (STZ)-treated mice and MPC-5 cells treated with high glucose (HG). Nephrin and podocin were detected by immunohistochemistry and immunofluroscence. Collagen IV, transforming growth factor-beta (TGF-beta) and fibronectin mRNA expressions were assayed by real-time PCR. Apoptotic proteins and phosphorylation of p38 mitogen-activated protein kinase (MAPK) were detected by immunoblotting. RESULTS: Swiprosin-1 was found to be expressed in podocytes of the mouse glomerulus and MPC-5 cells. Swiprosin-1 expression was increased in STZ-treated mice and MPC-5 cells treated with HG. In Swiprosin-1-/- diabetic mice, kidney/ body weight, urinary albumin, podocyte foot process effacement and glomerular basement membrane thickening were attenuated; the downregulation of nephrin and podocin expression in the glomerulus was inhibited; and the upregulation of collagen IV, TGF-beta and fibronectin mRNA expression in the renal cortex was ameliorated as compared with those in diabetic swiprosin-1+/+ mice. In addition, the increased apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation in Swiprosin-1-/- diabetic mice were inhibited as compared with those in diabetic swiprosin-1+/+ mice. Knockdown of swiprosin-1 in MPC-5 cells reduced the apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation induced by HG. Targeted knockdown of p38 attenuated the increased apoptosis of MPC-5 cells over expressing swiprosin-1. CONCLUSION: Swiprosin-1 expression in podocytes of the mouse glomerulus played a critical role in early-stage DN. Swiprosin-1 deficiency in early DN attenuated mitochondria-dependent podocyte apoptosis induced by hyperglycemia or HG via p38 MAPK signaling pathway. PMID- 29421812 TI - Serum Soluble Interleukin 2 Receptor Level as a Marker of Acute Rejection in Pediatric Kidney Transplant Recipients. AB - BACKGROUND: Despite advances in immunosuppression, acute allograft rejection remains one of the key factors affecting patient and graft survival in pediatric kidney transplantation. The aim of the study is to evaluate the role of serum soluble IL2 receptor (sIL2R) level as a noninvasive assessment parameter of acute rejection (AR). METHOD: Serum sIL2R level was measured (using enzyme-linked immune-sorbent assay technique) in 60 pediatric kidney transplant recipients (30 recipients with AR and 30 transplant recipients with stable graft function). RESULTS: The mean values of sIL2R level in patients experiencing AR (14.8 +/- 6.54) ng/mL were significantly higher than that in patients with stable graft functions (6.44 +/-1.95) ng/mL (p = 0.0001). In addition; patients with AR proved by graft biopsy had their mean values of sIL2R level (16.19 +/- 7.48) ng/mL significantly higher than that of other recipients in the study population (p = 0.032). CONCLUSION: Serum sIL2R level may serve as a noninvasive diagnostic indicator in pediatric kidney transplant recipients experiencing AR. PMID- 29421813 TI - Repeatability and Reproducibility of Foveal Avascular Zone Area Measurement on Normal Eyes by Different Optical Coherence Tomography Angiography Instruments. AB - PURPOSE: To compare the foveal avascular zone (FAZ) area measurements produced by different optical coherence tomography angiography (OCTA). METHODS: Healthy enrolled volunteers underwent OCTA using 2 different devices: Spectralis HRA+OCTA (Heidelberg Engineering, Heidelberg, Germany) and RS-3000 Advance (Nidek, Gamagori, Japan). Two graders measured FAZ in both superficial (SCP) and deep (DCP) retinal capillary plexuses. The SCP and DCP en face images were visualized automatically segmenting 2 separate slabs defined by the arbitrary segmentation lines created by the software of each OCT device. One grader repeated each measure twice. RESULTS: Fifty-nine eyes were included. The mean FAZ was 0.33 +/- 0.09 mm2 at the SCP and 0.57 +/- 0.17 mm2 at the DCP measured with RS-3000 versus 0.30 +/- 0.08 and 0.35 +/- 0.08 mm2, respectively, measured with Spectralis. The measurements of the 2 devices were significantly different (p < 0.0001). The intraoperator agreement was excellent at the SCP (intraclass correlation coefficient, ICC: 0.97 with Spectralis and 0.96 with RS-3000). At the DCP, it was good with Spectralis and fair with RS-3000 (ICC: 0.85 and 0.64, respectively). The interoperator agreement was excellent for Spectralis and good for RS-3000 at the SCP (ICC: 0.97 and 0.93, respectively). It was good at the DCP with both devices (ICC: 0.74 with RS-3000 and 0.81 with Spectralis). CONCLUSIONS: FAZ measurements obtained with different OCTA devices differ. These findings should be considered in follow-up studies of patients with retinal vascular diseases. PMID- 29421814 TI - Herbal Preparation STW 5 for Functional Gastrointestinal Disorders: Clinical Experience in Everyday Practice. AB - BACKGROUND: The most common functional gastrointestinal disorders (FGID) are functional dyspepsia (FD) and irritable bowel syndrome (IBS), with a prevalence in the general population of 15-20% (FD) and 10% (IBS), respectively. The complexity of pathophysiologic mechanisms and limitations in therapeutic options make the management of FD and IBS patients a challenge in routine clinical practice. SUMMARY: Syndromes classified as FGID frequently overlap, and coexist with gastroesophageal reflux disease (GERD). Patients with overlapping symptoms are more likely to seek medical care. The challenge for routine clinical practice is to find the best approach for treatment of multiple symptoms. STW 5, a combination of 9 herbal extracts, was shown to have multi-target effects: it normalizes the disturbed gastrointestinal motility, alleviates hypersensitivity, inhibits inflammation, suppresses gastric hypersecretion, and modulates the microbiota. Controlled randomized studies proved STW 5 to be efficacious both in FD and IBS, with control over the full spectrum of upper and lower gastrointestinal symptoms. STW 5 reduced concomitant heartburn in FD patients. STW 5 was well tolerated in the examined populations, independent of concomitant diseases and concomitant medication. Key Messages: The clinical use of the herbal preparation STW 5 in FD and IBS is evidence-based. STW 5 is an example for the concept of multi-target therapy. It offers treatment opportunities in routine clinical practice with high prevalence of overlap of FGID and concomitant GERD. Considering that FD and IBS are typically chronic and recurrent conditions, the clinically observed good tolerability and safety of STW 5 is an advantage. PMID- 29421816 TI - B1a Lymphocytes (CD19+CD5+) Deficiency in Patients with Crohn's Disease and Its Relation with Disease Severity. AB - BACKGROUND/AIMS: B1a cells (CD19+CD5+) are considered elements of the innate immune system. The aim of this study was to evaluate the frequency of B1a cells in the peripheral blood of patients with Crohn's disease (CD) and its relation with disease severity. METHODS: In this prospective study, a total of 128 subjects (64 CD patients and 64 healthy controls) were studied. B1a cells in peripheral blood, CD Activity Index, and Simple Endoscopic Score of B1a cells were studied. RESULTS: A significant decrease of B1a cells in peripheral blood was observed in patients with CD versus controls (p = 0.002), especially in perforating or penetrating patterns (p = 0.017). A lower frequency of B1a cells is related to increased endoscopic severity (Spearman's Rho: -0.559, p = 0.004). The mean frequency of B1a cells in patients with pre- and post-study surgery was significantly lower than that in patients who did not undergo surgery (p = 0.050 and p = 0.026, respectively). CONCLUSIONS: The B1a cell count in peripheral blood is lower in CD patients. This decrease is directly related to the severity of the disease (penetrating or perforating, Simple Endoscopy Score and surgery complication). These results pointed to the fact that B1a cells play an important role in immune protection in CD. PMID- 29421817 TI - STW 5 (Iberogast) Therapy in Gastrointestinal Functional Disorders. AB - BACKGROUND: Functional gastrointestinal disorders (FGIDs) are very common and affect populations worldwide. A majority of patients are affected by a variety of heterogenous gastrointestinal symptoms (GIS) related to the upper and lower digestive system with frequent overlap and mostly of mild to moderate degree. The herbal medicinal preparation STW 5 is documented as an effective therapeutic option for treating FGID. Studies Conducted in Summary: STW 5 has been in use for more than 50 years in clinical practice and proven to be effective and safe in the management of FGID. The high efficacy of STW 5 on symptoms clustered in functional dyspepsia (FD) and irritable bowel syndrome (IBS) as well as on individual abdominal symptoms is demonstrated in 5 controlled, randomized double blind studies in FD and in one trial conducted in patients with IBS. In addition the beneficial therapeutic effect of STW 5 on FGD as well as safety issues have been reported in a series of non interventional studies conducted in several thousands of adult patients and including 980 children. An additional study has been performed addressing the question as to how quickly the therapeutic effect is obtained after STW 5 administration. Key Messages from These Studies: STW 5 is an effective phyto-medication for treating patients with FD and IBS. STW 5 acts beneficially on abdominal symptom clusters as well as on individual GIS in adults and children. The time to onset of action is rapid, well tolerated and safe. The repetitive use of STW 5 is an appropriate option in clinical practice for patients with FGID. PMID- 29421823 TI - [What do we know about osteitis pubis in athletes?] AB - BACKGROUND: Osteitis pubis is a common cause of chronic groin pain. Due to high clinical uncertainty and varying etiopathology, the diagnosis is often delayed. Especially athletes suffer from this disease, but patients with orthopaedic, traumatological, neurological, urological, gynaecological, and rheumatic complaints can also be affected. Osteitis pubis can be treated by conservative as well as surgical techniques. MATERIAL AND METHODS: Systematic literature research, descriptive presentation of the studies, and interpretation of evidence based medicine results. RESULTS: The scientific level of studies about osteitis pubis and the number of athletes included are low overall. A statistical comparison is methodically difficult due to the heterogeneity of publications. The leading clinical symptom of osteitis pubis is an aching symphysis pubica. Unfortunately, there are no characteristic clinical pathognomonic signs. The medical diagnosis is based on an exclusion of various differential diagnoses (e. g. sports hernia, femoroacetabular impingement, adductor lesion) and a comparison of medical history, clinical examination, and imaging methods. After a period of rest, osteitis pubis is quite often a self-limiting disease and will initially be treated conservatively. If this fails, surgical intervention has to be considered depending on concurrent pathologies. CONCLUSION: Specific guidelines for the diagnosis and treatment of osteitis pubis do not exist as yet. But there is consensus that a surgical intervention should only be performed if conservative treatment fails. The level of evidence for the studies is low. A meta-analytical evaluation based on the existing publications is not possible as yet. The number of recorded athletes in relation to the socio-economic consequences of the disease, especially in professional sport, is low. PMID- 29421824 TI - The Main Determinants of Serum Resistin Level in Type 2 Diabetic Patients are Renal Function and Inflammation not Presence of Microvascular Complication, Obesity and Insulin Resistance. AB - AIM: The association of increased resistin levels in chronic kidney disease with diabetic nephropathy has not yet been clarified. Our aim was to analyze the relationship between serum resistin levels and various diabetic microvascular complications in patients. METHODS: A total of 83 patients were enrolled in this cross-sectional study. The subjects were divided into 3 groups: 27 patients with type 2 diabetes mellitus (T2DM) having no diabetic retinopathy (DRP) or microalbuminuria and having normal renal function were included in Group-1, 28 patients with T2DM having DRP and normal renal function in Group-2, and 28 patients with T2DM with DRP and microalbuminuria and an estimated glomerular filtration rate (eGFR) of<60 ml/min/1.73 m2 in Group-3. Serum resistin levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: The mean age of the patients [46 female (55.4%)] was 54.8+/-9.1 years. The resistin level in Group-3 was significantly higher than in Group-1 and Group-2 (p<0.001).However the resistin level was not different between Group-1 (without microvascular complications) and Group-2 (with microvascular complications). The resistin level was found to be correlated negatively with eGFR (r=-0.459; p<0.001) and albumin (r=-0.402; p<0.001), and positively with high-sensitivity C-reactive protein (hs CRP) (r=0.366; p=0.001). In multivariate analysis, it was observed that eGFR and hs-CRP were independent determinants of plasma resistin level. CONCLUSION: The main determinants of resistin level in patients with T2DM are the level of renal function and inflammation rather than presence of microvascular complications, obesity and insulin resistance. PMID- 29421825 TI - Insulin-Leptin Axis, Cardiometabolic Risk and Oxidative Stress in Elderly with Metabolic Syndrome. AB - Insulin and leptin have an overlapping anorexigenic action as well as opposite effects on glucose and lipid metabolism. The study focuses on the biochemical and clinical relevance of new indices of insulin-leptin axis utilized in the study of the relationships between leptinemia, insulin sensitivity and oxidative stress, in elderly subjects with metabolic syndrome. We conducted clinical studies on elderly people with metabolic syndrome versus control subjects by creating new insulin-adipogenic indices, namely Insulin-to-Leptin Ratio (ILR) and Insulin Adipogenic Resistance index (IAR-index). Inflammation and oxidative stress biomarkers evaluated were the high-sensitivity C-reactive protein (hsCRP), the advanced oxidation protein products (AOPP), and the serum antioxidant capacity measured as ferric reducing antioxidant potential (FRAP). The metabolic syndrome group showed significantly (p<0.01) lower levels of ILR and not significant (p=0.09) higher values of IAR-index, as compared to the control group. In metabolic syndrome subjects, the IAR-index was significantly positively correlated with uric acid (r=0.313, p<0.05), FRAP (r=0.347, p<0.05) and AOPP (r=0.677, p<0.01), and negatively correlated with HDL-cholesterol (r=- 0.340, p<0.05) as well as with the ratio FRAP/uric acid (r=- 0.315, p<0.05). ILR and IAR index reflected the biological state of adipose and pancreatic beta-cells and seem to depict the adipo-insular axis status related to metabolic and oxidative stress better than individual markers. Therefore, ILR and IAR-index could represent integrated high-potential biomarkers for disease and patient stratification. PMID- 29421826 TI - Association of Low Urine pH with Insulin Resistance in Non-Diabetic Japanese Subjects. AB - BACKGROUND: Epidemiology studies have revealed that patients with obesity, hyperglycemia, or hypertension are associated with a decreased urine pH. These metabolic disorders are related to insulin resistance; however, the association between urine pH and insulin resistance remains unclear. METHODS: To evaluate this association while controlling for covariates, the present study was conducted in 1084 non-diabetic Japanese subjects undergoing health examination. Fasting urine pH was analyzed using an automated urine dipstick analyzer. The subjects were divided into five groups according to urine pH: those with pH <5.5, 5.5, 6.0, 6.5, and >6.5. Insulin resistance was determined using the homeostatic model assessment of insulin resistance (HOMA-IR) and divided into three categories: lower, middle, and higher tertiles of HOMA-IR. Analysis of covariance and multivariate logistic regression analysis were used to control confounding factors including serum uric acid. RESULTS: Analysis of covariance showed an increase in the mean HOMA-IR from 1.26, 1.46, 1.69, and 1.75 to 1.89 with a decrease in urine pH (p<0.001). Subjects with urine pH <=5.5 had a significantly higher HOMA-IR than those with urine pH>6.5. Furthermore, multivariate logistic regression analysis showed that urine pH had an inverse and independent association with HOMA-IR. In subjects with urine pH 5.5 and <5.5, adjusted odds ratio (95% confidence interval) for the incidence of higher tertile of HOMA-IR was 1.34 (1.04-1.73) and 1.52 (1.09-2.13), respectively (reference, subjects with a urine pH>6.5). CONCLUSION: Insulin resistance is independently associated with a lower urine pH, possibly via lower formation of ammonium in the kidneys. PMID- 29421827 TI - Combining Various Methods to Assess Insulin Sensitivity in Nonobese Rat after Sleeve Gastrectomy. AB - BACKGROUND: Sleeve gastrectomy (SG) procedure has been proved to improve insulin sensitivity and sustain anti-diabetic effects. Our aim is to co-use several methods to measure insulin sensitivity and investigate the effect of SG on hepatic and peripheral insulin sensitivity at early and long-term stages of postoperation. METHODS: Thirty 11-week-old male Goto-Kakizaki rats were divided into SG, sham-operated SG (SOSG), and control groups. They were observed before operation and for 36 weeks of postoperation. Insulin tolerance test (ITT) and homeostasis model of assessment for insulin resistance index(HOMA-IR)were used to measure insulin resistance before operations and at 2 and 36 weeks of postoperation; Pyruvate challenge test (PCT) was administrated to assess the gluconeogenesis capability in order to reflect hepatic insulin sensitivity before operation and at 2 and 36 weeks of postoperation; Hyperinsulinemic euglycemic clamps (HIEC) was conducted before operation and at 2 and 36 weeks of postoperation to calculate the endogenous hepatic glucose production (HGP) at the basal and steady-state for evaluation of hepatic insulin sensitivity, and calculate the exogenous glucose infusion rate (GIR) at the steady-state for evaluation of peripheral insulin sensitivity. RESULTS: The data showed that compared with rats in the sham and control groups, rats in SG group had 1) significantly lower AUCITT, HOMA-IR and AUC PCT values at 2 and 36 weeks of postoperation, 2) lower basal state HGP, but not steady-state GIR at 2 weeks of postoperation, and 3) significantly different basal and steady-state HGP and steady-state GIR at 36 weeks of postoperation. In addition, the basal and steady state HGP and the steady-state GIR were significantly different between rats in SG group at 2 and 36 weeks of postoperation. CONCLUSIONS: This study explored insulin sensitivity of rats after SG by jointly using a variety of techniques. The results showed that SG time-dependently improved the hepatic and peripheral insulin sensitivity. PMID- 29421828 TI - Serum CTRP3 Level is Associated with Osteoporosis in Postmenopausal Women. AB - BACKGROUND: As a novel adipokine, CTRP3 involves in various functions of energy metabolism. Recent advance reveals a complex interaction between bone and adipose tissue via the secretion of adipokines. AIMS: A hospital-based case-control study was conducted to investigate the role of serum CTRP3 in osteoporosis among postmenopausal women. METHODS: Serum levels of CTRP3 and osteocalcin were measured. Bone mineral density (BMD) was obtained on femoral neck and lumbar spines by dual energy X-ray absorptiometry. RESULTS: Serum CTRP3 level was lower in subjects with osteoporosis (76.7+/-22.1 ng/ml) than it in controls (89.4+/ 22.5 ng/ml) (P<0.001). Meanwhile, the frequency of osteoporosis presented a significant decrease (66.4%, 53.9% and 35.9%, P<0.001), in the tertiles of serum CTRP3. Furthermore, serum CTRP3 witnessed an association with a lower risk of osteoporosis (adjusted odds ratio=0.973, 95% confidence interval [0.963-0.983], P<0.001). Lastly, serum CTRP3 level was positively correlated with femoral BMD (r=0.403, P<0.001), lumbar BMD (r=0.368, P<0.001), and HDL-C (r=0.118, P=0.022), among all participants after adjustment. Meanwhile, CTRP3 presented negative correlations with HOMA-IR (r=-0.136, P=0.008) and insulin (r=-0.192, P <0.001). CONCLUSIONS: It shows that a decreased serum level of CTRP3 was independently associated with osteoporosis. PMID- 29421829 TI - Impact of Depression and Psychosocial Treatment on Heart Rate Variability in Patients with Type 2 Diabetes Mellitus: An Exploratory Analysis Based on the HEIDIS Trial. AB - OBJECTIVES: To explore the impact of depression on heart rate (HR) and heart rate variability (HRV) as a marker of autonomic nervous system (ANS) impairment in depressed and non-depressed patients with advanced type 2 diabetes mellitus (T2DM) and to explore possible effects of an acceptance- and mindfulness-based group intervention (MBSR) on HR and HRV. METHODS: Alongside a prospective clinical trial, we collected demographic, psychosocial and clinical data from 113 chronic T2DM patients in a standardized setting. At baseline and after one year, depressive mood was assessed with the Patient Health Questionnaire (PHQ-9), and autonomic function was determined by measuring HR and HRV markers. A subsample was randomly assigned to take part in eight MBSR sessions. RESULTS: Of the 113 T2DM patients (77.9% men; mean age=58.8+/-7.0 years; diabetes duration 11.5+/-7.0 years), 33 showed clinically relevant depressive symptoms at baseline. In cross sectional analysis, we found no association between depression and HR/HRV (all comparisons p>0.05). In prospective regression analysis depression did not predict follow-up scores of HRV. The patients who participated in the MBSR intervention showed a tendency toward improved parasympathetic control (RMSSD, CV, E-I-Ratio) with small-to-moderate effect sizes (d<=0.38). CONCLUSIONS: Depression was not directly associated with cardiac autonomic control in this sample, but MBSR training may have positively influenced HR and HRV. In advanced diabetes, somatic and behavioral parameters seem to be more predictive than depression for the course of autonomic functioning, but the pathways remain unclear. PMID- 29421830 TI - Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism - What We Know in Mammals and What We Can Learn From Yeast. AB - Levels of reactive metabolites such as reactive carbonyl and oxygen species are increased in patients with diabetes mellitus. The most important reactive dicarbonyl species, methylglyoxal (MG), formed as by-product during glucose metabolism, is more and more recognized as a trigger for the development and progression of diabetic complications. Although it is clear that MG provokes toxic effects, it is currently not well understood what cellular changes MG induces on a molecular level that may lead to pathophysiological conditions found in long-term diabetic complications. Here we review the current knowledge about the molecular effects that MG can induce in a cell. Within the mammalian system, we will focus mostly on the metabolic effects MG exerts when applied systemically to rodents or when applied in vitro to pancreatic beta-cells and adipocytes. Due to the common limitations associated with complex model organisms, we then summarize how yeast as a very simple model organism can help to gain valuable comprehensive information on general defence pathways cells exert in response to MG stress. Pioneering studies in additional rather simple eukaryotic model organisms suggest that many cellular reactions in response to MG are highly conserved throughout evolution. PMID- 29421831 TI - Amplitude-Integrated EEG and Cerebral Near-Infrared Spectroscopy in Cooled, Asphyxiated Infants. AB - OBJECTIVE: To assess the predictive value of amplitude-integrated electroencephalography EEG (aEEG) and near-infrared spectroscopy (NIRS) during therapeutic hypothermia. PATIENTS AND METHODS: We studied 39 cooled, asphyxiated infants. We assessed aEEG and calculated mean regional cerebral oxygen saturation (rcSO2) during and after treatment. At 30 months, we performed a neurological examination and administered the Bayley Scales of Infant and Toddler Development, 3rd edition. We calculated the odds ratios (ORs) of abnormal aEEG and rcSO2 for severely abnormal outcome. RESULTS: At 6 and 12 hours, severely abnormal aEEGs predicted severely abnormal outcomes (OR, 7.7 [95% confidence interval, CI, 1.39 42.6] and 24.4 [95% CI 4.2-143] respectively), as did epileptic activity (OR 28.9, 4.6-183). During the first 48 hours, rcSO2 was not associated with outcome, but at 72 hours after birth and after rewarming it was, with ORs for severely abnormal outcomes of 12.8 (1.31-124) and 21.6 (1.05-189), respectively. In multivariate analyses, aEEG and rcSO2 remained independently predictive in the model at 48 hours and significantly from 72 hours after birth onward. CONCLUSION: aEEG was a strong predictor of adverse outcome. After 48 hours of cooling, a higher rcSO2 was associated with a severely abnormal outcome, adding to the predictive value of aEEG in cooled, asphyxiated infants. PMID- 29421832 TI - Heparin-Induced Thrombocytopenia during Obstetric Hospital Admissions. AB - INTRODUCTION: The rate of heparin-induced thrombocytopenia (HIT) on a population basis is unknown. The objective of this study was to characterize the risk for HIT during antepartum, delivery, and postpartum hospitalizations in the United States. MATERIALS AND METHODS: A large administrative database was used to determine the risk of HIT in hospitalized obstetric patients who received unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Patients were presumed to have HIT if they were exposed to UFH or LMWH, received a diagnosis of HIT, and were administered a medication for the treatment of HIT including bivalirudin, argatroban, fondaparinux, or lepirudin. We queried severe complications of HIT including arterial thrombosis, limb amputation, heart failure, and death. RESULTS: We identified 66,468 antepartum hospitalizations, 66,741 delivery hospitalizations, and 16,325 postpartum readmissions where women received pharmacologic prophylaxis. Of these, 10 antepartum admissions, 1 delivery admission, and 14 postpartum readmissions involved a diagnosis of HIT with treatment of bivalirudin, argatroban, fondaparinux, or lepirudin. There were no deaths and no diagnoses of arterial thrombosis, limb amputation, heart failure, and death. CONCLUSION: Risk for HIT among hospitalized obstetric patients is low. In this cohort, no cases of death or severe complications were noted in relation to the diagnosis. PMID- 29421833 TI - Choice of Trial of Labor after Cesarean and Association with Likelihood of Success. AB - OBJECTIVE: To investigate whether the predicted chance of success is associated with the choice to undergo trial of labor after cesarean (TOLAC). STUDY DESIGN: Retrospective cohort study of women with a single prior nonelective cesarean delivering a term singleton in 2012 at a tertiary care hospital. A vaginal birth after cesarean (VBAC) score (likelihood of success) was estimated for each patient. The primary outcome was percentage of women choosing TOLAC among women with favorable (> 70% likelihood) and unfavorable VBAC scores. Other factors such as desired sterilization, provider type, and spontaneous labor were included in the analysis. RESULTS: In 2012, 434 women were eligible: 73 with VBAC score >70%, and 361 with score <=70%. Of those with score >70%, 63% chose TOLAC, compared with 21% with score <=70% (p < 0.01). In a multivariable analysis, spontaneous labor onset was highly associated with choosing TOLAC: adjusted odds ratio 26.7 (95% confidence interval 13.86-51.29). The choice of TOLAC was also positively associated with resident provider and desired fertility. CONCLUSION: Almost four in ten women with a history of nonelective primary cesarean and a very high predicted likelihood of VBAC choose elective repeat cesarean. Spontaneous labor was strongly associated with the choice to undergo TOLAC. PMID- 29421834 TI - Endoscopic clipping prior to n-butyl-2-cyanoacrylate injection for gastric varices with a large gastrorenal shunt. PMID- 29421835 TI - Successful closure of esophagomediastinal fistula with endoclips and an endoloop after endoscopic submucosal dissection. PMID- 29421836 TI - Drugs in Pregnancy and Lactation - Medications Used in Swiss Obstetrics. AB - BACKGROUND: In order to improve the safety for drugs in pregnancy and lactation, data on the clinical practice must be collected and validated. METHODS: Data on the medications routinely used were requested from the university hospitals for obstetrics and the non-university perinatal centres in Switzerland and recommendations and guidelines of scientific societies for the various fields of application were sought. RESULTS: Part I: For during pregnancy and the peripartal period respectively, 69 and 21 different active constituents of medications were identified from at least 4 centres. For during pregnancy, the active constituents used in most of the centres are nifedipine, iron i. v. and oral, labetalol and magnesium sulphate, amoxicillin with clavulanic acid, paracetamol, dalteparine, metoclopramide as well as atosiban and hexoprenaline; for during the peripartal period betamethasone, misoprostol, oxytocin, clindamycin as well as fibrinogen, sulprostone and tranexamic acid were most frequently cited. Recommendations of various scientific societies were found primarily for pregnancy-specific fields of application. CONCLUSION: The same active constituents of medications are consistently used in Swiss perinatal centres for the main indications in pregnant women. Despite the existing experience and available evidence, they are mainly used off-label. Official authorisations for frequently or consistently used active ingredients should be granted. PMID- 29421837 TI - All-Inside Single-Bundle Reconstruction of the Anterior Cruciate Ligament with the Anterior Half of the Peroneus Longus Tendon Compared to the Semitendinosus Tendon: A Two-Year Follow-Up Study. AB - The anterior half of the peroneus longus tendon (AHPLT) has been reported to be acceptable for ligament reconstruction with respect to strength and safety. However, there is little information regarding the clinical outcomes after using the AHPLT compared with other autograft tendons. A prospective randomized controlled study was performed to compare the results of 62 cases of all-inside anatomical single-bundle anterior cruciate ligament (ACL) reconstruction using the AHPLT and 62 cases using semitendinosus graft with an average of 30.0 +/- 3.6 months' follow-up. Tunnel placements of enrolled cases were measured on three dimensional (3D) computed tomography (CT) and X-ray imaging. Knee stability was assessed using the anterior drawer test, pivot shift test, and KT-1000. The International Knee Documentation Committee (IKDC) 2000 subjective score was used to evaluate functional outcomes. The American Orthopedic Foot and Ankle Score (AOFAS) and the assessment of eversion muscle strength were performed to evaluate the function of the ankle donor site. Tunnel positions, which were confirmed with 3D CT, were in the anatomical positions. At the final follow-up, there were no significant differences between the semitendinosus group and the AHPLT group in the IKDC score (90.4 +/- 7.1 vs. 89.3. +/- 8.4), KT 1000 measurements (1.71 +/- 0.57 vs. 1.85 +/- 0.77), pivot shift test, and Visual Analogue Scale (VAS) (0.15 +/- 0.36 vs. 0.10 +/- 0.30). No obvious ankle site complications were found at 24 months. The average AOFAS score of the AHPLT group was comparable to that of the semitendinosus tendon group (99.1 +/- 1.40 vs. 99.5 +/- 1.21). There was no significant difference in clinical outcomes or knee stability between the semitendinosus group and the AHPLT group at the 2-year follow-up. An AHPLT autograft may be a good alternative for all-inside ACL reconstruction with respect to its strength, safety, and donor site morbidity. PMID- 29421838 TI - Knee Pain and the Use of Various Types of Footwear-A Review. AB - Knee pain is a highly prevalent condition in the United States with multiple etiologies, with two of the most common sources being osteoarthritis (OA) and patellofemoral pain (PFP). These conditions can lead to reduced physical function and a poor quality of life. Various modalities have been used to decrease the amount of knee pain that individuals' experience; however, they are not always successful and can be expensive. Several studies have reported on specialized footwear for symptomatic alleviation of conditions that affect the knee, this is because it has been theorized that certain footwear can alter the forces placed by muscles on lower-extremity joints, and can potentially alleviate pain by reducing the load placed on the joint. Therefore, the purpose of this study was to review the current literature on the use of various types of footwear used in patients who suffer from knee pain. Specifically, we evaluated: (1) knee OA and (2) PFP and the effect that different footwear has on patients' symptoms. Multiple different types of footwear and orthosis were utilized to treat patients with chronic knee pain. However, the results from reported outcomes by different studies are conflicting, which warrant further studies. Nevertheless, there are enough positive results to view this as a potential major modality to utilize for the treatment of knee OA. PMID- 29421839 TI - Variability in the Clock Face View Description of Femoral Tunnel Placement in ACL Reconstruction Using MRI-Based Bony Models. AB - Though controversial, the "clock face view" of the intercondylar notch remains a way some surgeons communicate regarding placement of the femoral tunnel in anterior cruciate ligament reconstruction. The purpose of this study was to quantify the differences in angle measurement between several previous descriptions of the clock face view by using a new reference standard. Three Tesla magnetic resonance imaging (MRI) was used to scan 10 human knees to create three-dimensional MRI-based bony models which were used for measurements. A standardized clock face view was developed with the knee flexed to 90 degrees using the junction of the cartilage and cortex of the medial and lateral surfaces of medial and lateral femoral condyles as the 3 o'clock and 9 o'clock, respectively, with the 12 o'clock established as the midpoint of the roof of the intercondylar notch. With the knee viewed at 90 degrees of flexion, an "idealized" femoral tunnel position was plotted on the medial wall of the lateral femoral condyle at 30 degrees (corresponding to the 10 o'clock or 2 o'clock position). The clock faces as described by Edwards et al, Heming et al, and Mochizuki et al were each then overlaid on this same model and the difference in measurement calculated. The average angles measured when the previously described clock faces were projected onto the idealized clock face view comparing a mark made at 30 degrees were 47.7 degrees , 7.2 degrees , and 49.8 degrees for the methods described by Edwards et al, Heming et al, and Mochizuki et al, respectively (all p < 0.001). Significant variation exists between angle measurements in simulated femoral tunnel placement based on the varying descriptions of the intercondylar clock face. PMID- 29421840 TI - [Fertility Preservation in Prepubertal und Pubertal Children and Adolescents]. AB - BACKGROUND: Due to rising survival rates in cancer and autoimmune diseases fertility preservation before gonadotoxic therapies has become increasingly important. Although fertility can be significantly affected by gonadotoxic therapies, the possibility of fertility preservation during childhood has not been sufficiently considered so far. METHODS: Selective literature research with presentation of fertility preservation methods, their indications, implementations, risks and efficacy. RESULTS: Measures are indicated in all girls and boys at high risk of gonadal damage. The complexity of the techniques requires special expertise in the counseling and implementation, which is offered to girls in counselling Germany especially in the centers of FertiPROTEKT (www.fertiprotekt.com). In girls, mainly cryopreservation of ovary tissue is considered. In postpubertal girls cryopreservation of oocytes is also possible. In postpubertal boys sperm can be preserved. Freezing of testicular tissue is still experimental in prepubertal boys. Success rates are still difficult to quantify; birth rates of about 50% are discussed. All procedures are not covered by health insurance. CONCLUSION: In children and adolescents, measures of fertility preservation should be considered in cases of highly gonadotoxic therapies, and appropriate advice should be given by specialists. PMID- 29421841 TI - [Endonasal endoscopic surgery of choanal atresia - long term results]. AB - INTRODUCTION: Choanal atresia is a rare abnormality. As neonates depend on transnasal respiration, bilateral choanal atresia causes an acute emergency. Transnasal endoscopic resection of congenital choanal atresia is a well established therapy. However, the surgical technique has not yet been standardized. METHODS: A retrospective chart review was performed with a follow up examination between 9 to 87 months after surgery. 11 patients (7 with unilateral atresia, 4 with bilateral atresia) were included. The choana was opened and enlarged endoscopically by resection of the posterior septal wall and bony reduction up to skull base and nasal floor. Intraoperative handling, intra- and postoperative complications, restenosis and adequate respiratory function were assessed. RESULTS: No intraoperative complications could be observed. Three premature babies underwent surgical intervention within their first postnatal week with an average weight of 2540 g. 2/11 patients suffered from a minor episode of epistaxis as a postoperative complication. Long-term success without restenosis was 73 % (for unilateral atresia) and 100 % for bilateral (atresia). CONCLUSIONS: Choosing an endonasal endoscopic approach to resect choanal atresia via resection of the posterior septal wall and circular bony reduction is a successful therapy with low morbidity. PMID- 29421842 TI - Early psychological impact of Paris terrorist attacks on healthcare emergency staff: A cross-sectional study. AB - BACKGROUND: The terrorist attacks in Paris and Saint Denis on November 13, 2015 were an unprecedented traumatic event in France. It was an especially distressing ordeal for the healthcare personnel involved in the care of the victims. The aim of this study was to estimate the effect of direct participation in the rescue on posttraumatic stress disorder (PTSD) symptoms among these workers. METHODS: Less than a month later, 613 healthcare providers (professionals and paraprofessionals) from three hospitals in the Paris suburbs were asked to complete an anonymous questionnaire. A multivariable Poisson model estimated the effect of participating onsite in the rescue (exposure variable) on the number of PTSD symptoms measured by the Trauma Screening Questionnaire (TSQ; outcome variable), adjusted for covariates. RESULTS: Two hundred thirty-three providers completed the assessment (38% response rate), 130 participated directly in the rescue (56%). Participation was associated with a higher number of symptoms of PTSD (RR = 1.34, P = .002) than for nonparticipants. Female gender (RR = 1.39, P < .001) and basic (vs. advanced or intermediate) life-saving training (RR = 1.42, P = .004) were also associated with more PTSD symptoms. Participants in the rescue were at 2.76 times more risk of a probable PTSD diagnosis (OR = 2.76, P = .037), defined as reporting at least six PTSD symptoms. Sensitivity analyses using propensity score matching supported the robustness of our findings. CONCLUSIONS: Healthcare providers directly involved in the rescue of the victims of the Paris and Saint Denis attacks reported a significantly higher psychological impact, defined by PTSD symptoms, than those not directly involved. PMID- 29421843 TI - Physical interactions among flavonoid enzymes in snapdragon and torenia reveal the diversity in the flavonoid metabolon organization of different plant species. AB - Flavonoid metabolons (weakly-bound multi-enzyme complexes of flavonoid enzymes) are believed to occur in diverse plant species. However, how flavonoid enzymes are organized to form a metabolon is unknown for most plant species. We analyzed the physical interaction partnerships of the flavonoid enzymes from two lamiales plants (snapdragon and torenia) that produce flavones and anthocyanins. In snapdragon, protein-protein interaction assays using yeast and plant systems revealed the following binary interactions: flavone synthase II (FNSII)/chalcone synthase (CHS); FNSII/chalcone isomerase (CHI); FNSII/dihydroflavonol 4-reductase (DFR); CHS/CHI; CHI/DFR; and flavonoid 3'-hydroxylase/CHI. These results along with the subcellular localizations and membrane associations of snapdragon flavonoid enzymes suggested that FNSII serves as a component of the flavonoid metabolon tethered to the endoplasmic reticulum (ER). The observed interaction partnerships and temporal gene expression patterns of flavonoid enzymes in red snapdragon petal cells suggested the flower stage-dependent formation of the flavonoid metabolon, which accounted for the sequential flavone and anthocyanin accumulation patterns therein. We also identified interactions between FNSII and other flavonoid enzymes in torenia, in which the co-suppression of FNSII expression was previously reported to diminish petal anthocyanin contents. The observed physical interactions among flavonoid enzymes of these plant species provided further evidence supporting the long-suspected organization of flavonoid metabolons as enzyme complexes tethered to the ER via cytochrome P450, and illustrated how flavonoid metabolons mediate flower coloration. Moreover, the observed interaction partnerships were distinct from those previously identified in other plant species (Arabidopsis thaliana and soybean), suggesting that the organization of flavonoid metabolons may differ among plant species. PMID- 29421844 TI - High Surface Area SnO2 -Ta2 O5 Composite for Visible Light-driven Photocatalytic Degradation of an Organic Dye. AB - SnO2 -Ta2 O5 nanocomposite was synthesized by a facile coprecipitation method and further calcined to obtain crystalline powder. Phase formation, morphology, bandgap and photocatalytic properties were analyzed using powder X-ray diffraction, scanning electron microscopy, UV-Vis diffused reflectance spectroscopy, BET surface area and Raman spectroscopy, respectively. Effect of calcination temperature on the crystallinity of the composite was studied. The as prepared samples of SnO2 , Ta2 O5 and SnO2 -10wt%Ta2 O5 composite as well as the calcined composite sample were tested for photocatalytic activity for methylene blue dye degradation under visible light. Photocatalytic studies reveal that the as-prepared SnO2 -10wt%Ta2 O5 composite showed the best photocatalytic activity for the degradation of methylene blue (MB) by harvesting visible-light radiation efficiently. Further mineralization of methylene blue, estimated by COD analysis, is found to have degraded with an efficiency of 91.6%. The study demonstrates that heterostructure of SnO2 -Ta2 O5 nanocomposite could be applied in photocatalytic purification of organic pollutants. PMID- 29421845 TI - Effects of Repeated UVA Irradiation on Human Skin Fibroblasts Embedded in 3D Tense Collagen Matrix. AB - Skin photoaging is caused by cumulative UVA exposure that leads to dermal matrix alterations associated with impaired fibroblast functions. In this study, we evaluated the effects of repeated UVA irradiation on mechanically stressed fibroblasts which were embedded in 3D tense collagen matrix. By comparison to 2D monolayer culture, we investigated the expressions of alpha-smooth muscle actin (alpha-SMA) cytoskeleton and alpha2 subunit of integrin receptors, as well as the collagen metabolism, focusing to MMP-1 and collagen type-I expressions. We found that UVA exposure reduces collagen levels in both culture conditions. However, concerning integrin alpha2 and alpha-SMA expression, UVA irradiation had no effect on 2D culture, whereas in tense 3D culture, it had an inhibitory effect. In UVA-irradiated 3D culture, fibroblasts acquired elongated shape and lost their dynamic interaction with collagen fibers through a decrease in integrin alpha2 and alpha-SMA. Fibroblast responses to UVA irradiation were different in 2D versus 3D environment, highlighting the importance of collagen environment in the regulation of mechanical activities. The behavior of fibroblast upon mechanical stimulation closely mimics stressed extracellular environment. The model of UVA irradiated fibroblasts cultured in tense 3D collagen gel illustrated the in vivo situation of both mechanically stressed and photoaged human skin. PMID- 29421847 TI - Seascape models reveal places to focus coastal fisheries management. AB - To design effective marine reserves and support fisheries, more information on fishing patterns and impacts for targeted species is needed, as well as better understanding of their key habitats. However, fishing impacts vary geographically and are difficult to disentangle from other factors that influence targeted fish distributions. We developed a set of fishing effort and habitat layers at high resolution and employed machine learning techniques to create regional-scale seascape models and predictive maps of biomass and body length of targeted reef fishes for the main Hawaiian Islands. Spatial patterns of fishing effort were shown to be highly variable and seascape models indicated a low threshold beyond which targeted fish assemblages were severely impacted. Topographic complexity, exposure, depth, and wave power were identified as key habitat variables that influenced targeted fish distributions and defined productive habitats for reef fisheries. High targeted reef fish biomass and body length were found in areas not easily accessed by humans, while model predictions when fishing effort was set to zero showed these high values to be more widely dispersed among suitable habitats. By comparing current targeted fish distributions with those predicted when fishing effort was removed, areas with high recovery potential on each island were revealed, with average biomass recovery of 517% and mean body length increases of 59% on Oahu, the most heavily fished island. Spatial protection of these areas would aid recovery of nearshore coral reef fisheries. PMID- 29421846 TI - Survey highlights important discrepancies between definitions of paediatric abnormal growth taught to medical students in 23 European countries. AB - AIM: This study compared the definitions of abnormal growth that are taught across Europe to explain previously reported variations in growth-monitoring practices. METHODS: We developed two online surveys in 2016 to obtain the definitions of abnormal growth in European countries and approached the national chairs of the European Confederation of Primary Care Paediatricians in 18 countries and the International Federation of Medical Students' Associations in 33 countries. RESULTS: We obtained definitions from 10 of 18 paediatricians and 18 of 33 students, covering 23 of the 33 European countries surveyed. Abnormal faltering growth was always defined, either by a single parameter (24%) or combined parameters (76%). Four static parameters were used: standardised height (100%), standardised weight (60%), standardised body mass index (12%) and distance to target height (20%). Two dynamic parameters were used: growth deflection (28%) and growth velocity (32%). The thresholds used to define abnormal faltering growth varied slightly in some cases and widely in others. Abnormal accelerated growth appeared in 52% of the definitions, with important variations in parameters and thresholds. CONCLUSION: There were important between country discrepancies in the definitions of paediatric abnormal growth that were taught in 23 European countries. Standardisation is vital. PMID- 29421848 TI - Characterization, conservation and loss of dignity at the end-of- life in the emergency department. A qualitative protocol. AB - AIMS: To explore and understand the experiences of terminally ill patients and their relatives regarding dignity during end-of-life care in the emergency department. BACKGROUND: The respect given to the concept of dignity is significantly modifying the clinical relationship and the care framework involving the end-of-life patient in palliative care units, critical care units, hospices and their own homes. This situation is applicable to in-hospital emergency departments, where there is a lack of research which takes the experiences of end-of-life patients and their relatives into account. DESIGN: A phenomenological qualitative study. METHODS: The protocol was approved in December 2016 and will be carried out from December 2016-December 2020. The Gadamer's philosophical underpinnings will be used in the design and development of the study. The data collection will include participant observation techniques in the emergency department, in-depth interviews with terminally ill patients and focus groups with their relatives. For the data analysis, the field notes and verbatim transcriptions will be read and codified using ATLAS.ti software to search for emerging themes. DISCUSSION: Emerging themes that contribute to comprehending the phenomenon of dignity in end-of-life care in the emergency department are expected to be found. This study's results could have important implications in the implementation of new interventions in emergency departments. These interventions would be focused on improving: the social acceptance of death, environmental conditions, promotion of autonomy and accompaniment and assumption (takeover) of dignified actions and attitudes (respect for human rights). PMID- 29421849 TI - A validated liquid chromatography/tandem mass spectrometry method for the analysis of efavirenz in 0.2 mg hair samples from human immunodeficiency virus infected patients. AB - RATIONALE: Drug levels in hair provide a longer window of detection, compared to plasma drug levels, and therefore hair analysis has the advantage of assessing adherence over a longer period of time. No methods for the analysis of antiretroviral drugs in hair currently exist in South Africa, and worldwide there is only one validated method for the determination of efavirenz in hair that has been published. METHODS: Efavirenz was extracted from 0.2 mg of hair through a simultaneous pulverization and extraction step. Separation was achieved on an Agilent Poroshell C18 column using an isocratic elution with a total run time of 3 min. A triple quadrupole mass spectrometer set to electrospray ionization in positive multiple reaction monitoring mode was used for detection. The method was validated over the concentration range 0.625-40 ng/mg. RESULTS: Using ten times less hair than in a previously published method, the lower limit of quantitation was validated at 0.625 ng/mg. The interday and intraday assay precision, expressed as the percentage coefficient of variation (CV), for spiked calibration standards and quality control samples was lower than 7% and accuracy ranged from 97 to 110%. For quality controls prepared from authentic hair the CV was less than 12%. The extraction efficiency for authentic quality control samples was determined to be 83% after repeated extractions of the same samples. CONCLUSIONS: This paper reports the first quantitative method for the determination of efavirenz in hair to be developed in South Africa. The validated method allowed for the successful monitoring of efavirenz in hair collected from HIV-infected patients as part of a clinical study. PMID- 29421850 TI - A study on the information-motivation-behavioural skills model among Chinese adults with peritoneal dialysis. AB - AIM AND OBJECTIVE: To examine whether the information-motivation-behavioural skills model could predict self-care behaviour among Chinese peritoneal dialysis patients. BACKGROUND: Peritoneal dialysis is a treatment performed by patients or their caregivers in their own home. It is important to implement theory-based projects to increase the self-care of patients with peritoneal dialysis. The information-motivation-behavioural model has been verified in diverse populations as a comprehensive, effective model to guide the design, implementation and evaluation of self-care programmes. DESIGN: A cross-sectional, observational study. METHODS: A total of 201 adults with peritoneal dialysis were recruited at a 3A grade hospital in China. Participant data were collected on demographics, self-care information (knowledge), social support (social motivation), self-care attitude (personal motivation), self-efficacy (behaviour skills) and self-care behaviour. We also collected data on whether the recruited patients had peritoneal dialysis-associated peritonitis from electronic medical records. Measured variable path analysis was performed using mplus 7.4 to identify the information-motivation-behavioural model. RESULTS: Self-efficacy, information and social motivation predict peritoneal dialysis self-care behaviour directly. Information and personal support affect self-care behaviour through self efficacy, whereas peritoneal dialysis self-care behaviour has a direct effect on the prevention of peritoneal dialysis-associated peritonitis. CONCLUSIONS: The information-motivation-behavioural model is an appropriate and applicable model to explain and predict the self-care behaviour of Chinese peritoneal dialysis patients. Poor self-care behaviour among peritoneal dialysis patients results in peritoneal dialysis-associated peritonitis. RELEVANCE TO CLINICAL PRACTICE: The findings suggest that self-care education programmes for peritoneal dialysis patients should include strategies based on the information-motivation behavioural model to enhance knowledge, motivation and behaviour skills to change or maintain self-care behaviour. PMID- 29421851 TI - Respiratory characteristics of individuals with non-specific low back pain: A cross-sectional study. AB - Non-specific low back pain (NS-LBP) is known to cause respiratory dysfunction. In this study, we investigated alterations in breathing, respiratory strength and endurance, core stability, diaphragm mobility, and chest expansion among patients with NS-LBP and healthy individuals. The specific aim of the study was to correlate between respiratory function and other variables among NS-LBP patients. Thirty four patients with NS-LBP were matched with 34 healthy participants before undergoing total faulty breathing scale, spirometer, respiratory pressure meter, chest expansion, ultrasound, and pressure biofeedback measurements. There were signs of faulty breathing in the NS-LBP patients when compared to the healthy participants. Diaphragmatic mobility and respiratory muscle endurance were lower in the NS-LBP group. Chest expansion exhibited a significant decrease at the level of the fourth intercostal space in the NS-LBP group, but respiratory muscle strength and core stability were not significant between the two groups. Positive correlations were found to be fairly significant regarding respiratory muscle strength. The findings of this study indicated altered respiratory characteristics in the NS-LBP patients, and suggested that they would improve through respiratory exercises. PMID- 29421853 TI - Antiphotoaging Effect of Prunus yeonesis Blossom Extract via Inhibition of MAPK/AP-1 and Regulation of the TGF-betaI/Smad and Nrf2/ARE Signaling Pathways. AB - Cherry blossoms have attracted attention as an ingredient with potential for use in skincare products. However, no skin photoaging-related research has been performed with this plant. In this study, cherry blossom extract (CBE) at 1, 10 and 100 MUg mL-1 was investigated for its skin antiphotoaging effects in UVB irradiated normal human dermal fibroblasts (NHDF) cells in vitro. Our results showed that CBE markedly increased type-I procollagen during UVB exposure via two pathways. Firstly, transcription activator protein-1 expression and MAP kinases were downregulated, consequently reducing the production of matrix metalloproteinase (MMP)-1 and MMP-3. Secondly, transforming growth factor TGF betaI secretion was upregulated by Smads. Application of CBE facilitated the nuclear translocation of Nrf2 against reactive oxygen species (ROS)-induced damage, which is essential for the coordinated induction of cytoprotective enzymes. Together, our findings suggest that CBE may be a promising ingredient for skin aging therapy and provide a novel approach for alleviating cutaneous aging. PMID- 29421852 TI - Shifts in diversification rates and host jump frequencies shaped the diversity of host range among Sclerotiniaceae fungal plant pathogens. AB - The range of hosts that a parasite can infect in nature is a trait determined by its own evolutionary history and that of its potential hosts. However, knowledge on host range diversity and evolution at the family level is often lacking. Here, we investigate host range variation and diversification trends within the Sclerotiniaceae, a family of Ascomycete fungi. Using a phylogenetic framework, we associate diversification rates, the frequency of host jump events and host range variation during the evolution of this family. Variations in diversification rate during the evolution of the Sclerotiniaceae define three major macro-evolutionary regimes with contrasted proportions of species infecting a broad range of hosts. Host-parasite cophylogenetic analyses pointed towards parasite radiation on distant hosts long after host speciation (host jump or duplication events) as the dominant mode of association with plants in the Sclerotiniaceae. The intermediate macro-evolutionary regime showed a low diversification rate, high frequency of duplication events and the highest proportion of broad host range species. Our findings suggest that the emergence of broad host range fungal pathogens results largely from host jumps, as previously reported for oomycete parasites, probably combined with low speciation rates. These results have important implications for our understanding of fungal parasites evolution and are of particular relevance for the durable management of disease epidemics. PMID- 29421854 TI - Allopolyploidization in Cucumis contributes to delayed leaf maturation with repression of redundant homoeologous genes. AB - The important role of polyploidy in plant evolution is widely recognized. However, many questions remain to be explored to address how polyploidy affects the phenotype of the plant. To shed light on the phenotypic and molecular impacts of allopolyploidy, we investigated the leaf development of a synthesized allotetraploid (Cucumis * hytivus), with an emphasis on chlorophyll development. Delayed leaf maturation was identified in C. * hytivus, based on delayed leaf expansion, initial chlorophyll deficiency in the leaves and disordered sink source transition. Anatomical observations also revealed disturbed chloroplast development in C. *hytivus. The determination of chlorophyll biosynthesis intermediates suggested that the chlorophyll biosynthesis pathway of C. * hytivus is blocked at the site at which uroporphyrinogen III is catalysed to coproporphyrinogen III. Three chlorophyll biosynthesis-related genes, HEMA1, HEME2 and POR, were significantly repressed in C. * hytivus. Sequence alignment showed both synonymous and non-synonymous substitutions in the HEMA1, HEME2 and POR genes of the parents. Cloning of the chlorophyll biosynthetic genes suggested the retention of homoeologs. In addition, a chimeric clone of the HEMA1 gene that consisted of homologous genes from the parents was identified in C. * hytivus. Overall, our results showed that allopolyploidization in Cucumis has resulted in disturbed chloroplast development and reduced chlorophyll biosynthesis caused by the repressed expression of duplicated homologous genes, which further led to delayed leaf maturation in the allotetraploid, C. * hytivus. The preferential retention/loss of certain types of genes and non-reciprocal homoeologous recombination were also supported in the present study, which provides new insights into the impact of allopolyploidy. PMID- 29421855 TI - Leucocyte- and platelet-rich fibrin block for bone augmentation procedure: A proof-of-concept study. AB - AIM: The objective of this proof-of-concept study was to investigate the effects of a new guided bone regeneration technique with a tissue engineering approach. MATERIALS AND METHODS: This single cohort observational study evaluated the outcome of the leucocyte- and platelet-rich fibrin (L-PRF) Block for horizontal bone augmentation in the maxilla. The L-PRF Block is prepared by mixing a particulated biomaterial with chopped L-PRF membranes at a 50:50 ratio and adding liquid fibrinogen to glue all together. Horizontal augmentation was assessed linearly and volumetrically immediately after surgery and 5-8 months later by matching consecutive cone beam computed tomography (CBCTs). RESULTS: Ten patients (mean age of 50.7 years [+/-17.2]) representing 15 sites with horizontal alveolar deficiencies were included. Superimposition of pre-operative and posthealing CBCT scans showed an average linear horizontal bone gain of 4.6 mm (+/-2.3), 5.3 mm (+/-1.2) and 4.4 mm (+/-2.3), measured at 2, 6 and 10 mm from the alveolar crest, respectively. The volumetric gain was 1.05 cm3 (+/-0.7) on average. The resorption rate after 5-8 months was 15.6% (+/-6.7) on average. CONCLUSIONS: L PRF Block may be a suitable technique to augment deficient alveolar ridges. PMID- 29421857 TI - Validation of Questionnaire and Diary Measures of Time Outdoors Against an Objective Measure of Personal Ultraviolet Radiation Exposure. AB - Self-reported sun exposure is commonly measured using questionnaires or diaries, but there are limited data on their validity, particularly for population subgroups. This research aimed to compare self-reported sun exposure, measured as (1) habitual time outdoors over the past month on weekends and weekdays and (2) a 4-day diary measure, against objective measurement of personal ultraviolet radiation using polysulfone film dosimeters. From November 2015 to January 2016, 94 people (22-69 years and living in New South Wales, Australia) completed a questionnaire, 4-day diary and 4-day dosimeter measures of overall, weekday and weekend sun exposure. Spearman correlations and Bland-Altman plots were used to measure agreement. The overall weekly correlation was 0.57 (95% confidence interval [CI] 0.44, 0.68) between standard erythemal doses (SEDs) measured by dosimeter and time spent outdoors measured by questionnaire, 0.74 (95% CI 0.66 0.81) between dosimeter and diary, and 0.59 (95% CI 0.48-0.68) between questionnaire and diary measures. Validity was lower for younger people and weekend sun exposure. There was strong correlation between dosimeter and sun diary measures and moderate correlation between dosimeter and questionnaire measures. Daily measurement over a longer period may be required to accurately capture weeklong sun exposure in all population subgroups. PMID- 29421856 TI - Relationship of toothbrushing to metabolic syndrome in middle-aged adults. AB - AIM: To examine the effect of toothbrushing on the development of metabolic syndrome (MetS), including assessment of periodontal status, in middle-aged adults. METHODS: This 5-year follow-up retrospective study was performed in 3,722 participants (2,897 males and 825 females) aged 35-64 years who underwent both medical check-ups and dental examinations. Metabolic components included obesity, elevated triglycerides, blood pressure, fasting glucose and reduced high-density lipoprotein. Toothbrushing frequency was assessed using a questionnaire. Periodontal disease was defined as having at least one site with a pocket depth of >=4 mm. Logistic regression analysis was performed to evaluate the relationship between toothbrushing frequency at the baseline examination and the development of MetS (>=3 components). RESULTS: During follow-up, 11.1% of participants developed MetS. After adjusting for potential confounders including periodontal disease, participants with more frequent daily toothbrushing tended to have significantly lower odds of developing MetS (p for trend = .01). The risk of development of MetS was significantly lower in participants brushing teeth >=3 times/day than in those brushing teeth <=1 time/day (odds ratio = 0.64, 95% confidence interval = 0.45-0.92). CONCLUSIONS: Frequent daily toothbrushing was associated with lower risk of development of MetS. PMID- 29421858 TI - Staying well with bipolar disorder: A qualitative analysis of five-year follow-up interviews with young people. AB - : WHAT IS ALREADY KNOWN ABOUT THE TOPIC?: Bipolar disorder is a long-term condition which causes ongoing disruptions to the individual's life. Current evidence suggests that a combination of medication in combination with psychotherapy is more effective than medication alone. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: There are few published reports of the effects of interventions (pharmacological or psychotherapeutic) for treatment in bipolar disorder. While both psychotherapies provided a framework for understanding bipolar disorder each had specific strategies that participants identified as effective. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Because bipolar disorder is a long-term condition, its treatment needs to incorporate psychotherapeutic approaches that address the unique nature of its impact on each individual and provide individualized strategies for managing the disorder. Both Interpersonal and Social Rhythm Therapy and Specialist Supportive Care provide strategies that promote personal recovery. ABSTRACT: Introduction The primary outcomes from this study of psychotherapy for young people with bipolar disorder identified that most participants had continued to remain well. Given that up to 80% of people relapse within 2 years, it was important to establish how these participants described the process of staying well. Aim To examine how participants in a psychotherapy for young people with bipolar disorder study at 5-year follow-up described their experiences of the intervention and its impact on living with the disorder. Methods This qualitative study was conducted 5 years after participants had completed a psychotherapy intervention in a randomized controlled trial for young people with bipolar disorder. Thirty people were recruited into this qualitative study and interviewed regarding their experiences. The data were analysed using an inductive thematic analysis. Findings Three themes were identified from the data: self-awareness in the context of bipolar disorder; understanding my bipolar disorder; and learning to stay well with bipolar disorder. Conclusions Mental health nurses can promote the factors that participants found helpful in learning to stay well self-awareness, understanding the unique characteristics of their disorder, learning to take care of the self and stabilization of social rhythms. PMID- 29421859 TI - Review shows that maternal obesity induces serious adverse neonatal effects and is associated with childhood obesity in their offspring. AB - AIM: Obesity at the start of pregnancy has been rising worldwide, increasing the risk of maternal complications. We reviewed the independent effects of maternal obesity during pregnancy on neonatal adverse outcomes and the risk of childhood obesity and adverse cardio-metabolic profiles. METHODS: We searched MEDLINE for papers published in English between December 2007 and November 2017, focusing primarily on human studies published in the last five years. However, we also chose to highlight examples derived from model animals that could bring mechanistic insight and preventive and therapeutic avenues. RESULTS: Our review showed that maternal obesity had independent effects on neonatal adverse outcomes such as macrosomia, perinatal mortality and birth defects. Maternal obesity alone increased the risks for adverse neonatal outcomes, including macrosomia, perinatal mortality, induced preterm birth and birth defects. In association with excess gestational weight gain, mainly early in pregnancy, increased the risks of childhood obesity, higher fat mass and, to a smaller extent, adverse cardio metabolic profiles. Animal models highlighted sexually dimorphic responses to maternal obesity. CONCLUSION: Maternal obesity induced serious adverse neonatal effects and was associated with childhood obesity in their offspring. The peri conceptional period is critical for metabolic programming, and obese women need close monitoring from conception. PMID- 29421860 TI - Face transplantation-current status and future developments. AB - More than thirty-five facial allograft transplantations (FAT) have been reported worldwide since the pioneering case performed in France in the year 2005. FAT has received tremendous interest by the medical field and the general public while gaining strong support from multiple disciplines as a solution for reconstructing complex facial defects not amenable/responsive to conventional methods. FAT has expanded the frontiers of reconstructive microsurgery, immunology and transplantation, and established its place in the cross section of multiple disciplines. The procedure introduces complex scientific, ethical, and societal issues. Patients and physicians are called to deal with a variety of-sometimes everlasting-challenges, such as immunosuppression management and psychosocial hurdles. This review reflects on the surgical and scientific advancements in FAT and milestones reached in the last 12 years. It aims to encourage active discussion regarding the current practices and techniques used in FAT and suggest future directions that may allow transitioning into the next phase of FAT, which we describe as safe, reliable, and accessible standard operation for selected patients. PMID- 29421861 TI - Simvastatin protects against acetaminophen-induced liver injury in mice. AB - The present study aimed to investigate the effect of simvastatin on acetaminophen (APAP) hepatotoxicity in a mouse model. Male C57BL/6 mice were allocated into the following groups: control, APAP, APAP+SIM10, APAP+SIM20, APAP+SIM100 and APAP+SIM200 groups. The mice in the APAP group were treated with saline intraperitoneally (i.p.) 72 h before and 24 h or 72 h after APAP challenge (i.p., 400 mg/kg of APAP). The simvastatin-treated groups were treated with different doses of simvastatin i.p. (10, 20, 100 and 200 mg/kg/day) as in the APAP group. After 24 h or 72 h of APAP challenge, blood and liver samples were collected to detect hepatic injury and liver regeneration. The results showed that low doses of simvastatin (10 and 20 mg/kg) could significantly reverse the histological change and decrease hepatic injury. Simvastatin also reduced the serum cytokine levels and transcriptional levels of tumor necrosis factor-alpha and interleukin 6 in the liver. The malonyldialdehyde and myeloperoxidase levels significantly decreased in the simvastatin treatment groups compared with the APAP group. Simvastatin restored the decrease in superoxide dismutase, catalase, glutathione and glutathione peroxidase activities induced by APAP hepatotoxicity. In addition, simvastatin inhibited hepatic C/EBP-homologous protein expression and hepatocyte apoptosis. However, simvastatin had no effect on liver regeneration after APAP hepatotoxicity. Moreover, high doses could aggravate APAP-induced liver injury. In conclusion, low doses of simvastatin had a significant therapeutic effect in APAP-induced liver injury by inhibiting oxidative stress, inflammation and apoptosis. However, high doses of simvastatin had adverse hepatotoxicity. PMID- 29421862 TI - Corrigendum to 'Metapristone suppresses non-small cell lung cancer proliferation and metastasis via modulating RAS/RAF/MEK/MAPK signaling pathway' [Biomed. Pharmacother. 90 (2017) 437-445]. PMID- 29421863 TI - Retraction notice to "Protection of rats spinal cord ischemia-reperfusion injury by inhibition of MiR-497 on inflammation and apoptosis: Possible role in pediatrics" [Biomed. Pharmacother. 81 (2016) 337-344]. PMID- 29421864 TI - Registry-based stroke research in Taiwan: past and future. AB - Stroke registries are observational databases focusing on the clinical information and outcomes of stroke patients. They play an important role in the cycle of quality improvement. Registry data are collected from real-world experiences of stroke care and are suitable for measuring quality of care. By exposing inadequacies in performance measures of stroke care, research from stroke registries has changed how we manage stroke patients in Taiwan. With the success of various quality improvement campaigns, mortality from stroke and recurrence of stroke have decreased in the past decade. After the implementation of a nationwide stroke registry, researchers have been creatively expanding how they use and collect registry data for research. Through the use of the nationwide stroke registry as a common data model, researchers from many hospitals have built their own stroke registries with extended data elements to meet the needs of research. In collaboration with information technology professionals, stroke registry systems have changed from web-based, manual submission systems to automated fill-in systems in some hospitals. Furthermore, record linkage between stroke registries and administrative claims databases or other existing databases has widened the utility of registry data in research. Using stroke registry data as the reference standard, researchers have validated several algorithms for ascertaining the diagnosis of stroke and its risk factors from claims data, and have also developed a claims-based index to estimate stroke severity. By making better use of registry data, we believe that we will provide better care to patients with stroke. PMID- 29421865 TI - In Vitro Efficacy of Free and Nanoparticle Formulations of Gallium(III) meso Tetraphenylporphyrine against Mycobacterium avium and Mycobacterium abscessus and Gallium Biodistribution in Mice. AB - The nontuberculous mycobacterial (NTM) pathogens, M. avium complex (MAC) and M. abscessus, can result in severe pulmonary infections. Current antibiotics confront significant challenges for treatment of these NTM infections due to emerging multidrug-resistance. Thus, development of new antibiotics targeted against these agents is needed. We examined the inhibitory activities of Ga(NO3)3, GaCl3, gallium meso-tetraphenylporphyrine (GaTP), and gallium nanoparticles (GaNP) against intra- and extracellular M. avium and M. abscessus. GaTP, an analogue of natural heme, inhibited growth of both M. avium and M. abscessus with MICs in Fe-free 7H9 media of 0.5 and 2 MUg/mL, respectively. GaTP was more active than Ga(NO3)3 and GaCl3. Ga(NO3)3 and GaCl3 were not as active in Fe-rich media compared to Fe-free media. However, GaTP was much less impacted by exogenous Fe, with MICs against M. avium and M. abscessus of 2 and 4 MUg/mL, respectively, in 7H9 OADC media (Fe rich). Confocal microscopy showed that GaNP penetrates the M. avium cell wall. As assessed by determining colony forming units, GaNP inhibited the growth of NTM growing in THP-1 macrophages up to 15 days after drug-loading of the cells, confirming a prolonged growth inhibitory activity of the GaNP. Biodistribution studies of GaNP conducted in mice showed that intraperitoneal injection is more effective than intramuscular injection in delivering Ga(III) into lung tissue. GaTP exhibits potential as a lead compound for development of anti-NTM agents that target heme-bound iron uptake mechanisms by mycobacteria and inhibit growth by disrupting mycobacterial iron acquisition/utilization. PMID- 29421867 TI - Design Strategy for Improving Optical and Electrical Properties and Stability of Lead-Halide Semiconductors. AB - Broad absorption, long-lived photogenerated carriers, high conductance, and high stability are all required for a light absorber toward its real application on solar cells. Inorganic-organic hybrid lead-halide materials have shown tremendous potential for applications in solar cells. This work offers a new design strategy to improve the absorption range, conductance, photoconductance, and stability of these materials. We synthesized a new photochromic lead-chloride semiconductor by incorporating a photoactive viologen zwitterion into a lead-chloride system in the coordinating mode. This semiconductor has a novel inorganic-organic hybrid structure, where 1-D semiconducting inorganic lead-chloride nanoribbons covalently bond to 1-D semiconducting organic pi-aggregates. It shows high stability against light, heat, and moisture. After photoinduced electron transfer (PIET), it yields a long-lived charge-separated state with a broad absorption band covering the 200-900 nm region while increasing its conductance and photoconductance. This work is the first to modify the photoconductance of semiconductors by PIET. The observed increasing times of conductivity reached 3 orders of magnitude, which represents a record for photoswitchable semiconductors. The increasing photocurrent comes mainly from the semiconducting organic pi-aggregates, which indicates a chance to improve the photocurrent by modifying the organic component. These findings contribute to the exploration of light absorbers for solar cells. PMID- 29421866 TI - Molecular Docking-Based Design and Development of a Highly Selective Probe Substrate for UDP-glucuronosyltransferase 1A10. AB - Intestinal and hepatic glucuronidation by the UDP-glucuronosyltransferases (UGTs) greatly affect the bioavailability of phenolic compounds. UGT1A10 catalyzes glucuronidation reactions in the intestine, but not in the liver. Here, our aim was to develop selective, fluorescent substrates to easily elucidate UGT1A10 function. To this end, homology models were constructed and used to design new substrates, and subsequently, six novel C3-substituted (4-fluorophenyl, 4 hydroxyphenyl, 4-methoxyphenyl, 4-(dimethylamino)phenyl, 4-methylphenyl, or triazole) 7-hydroxycoumarin derivatives were synthesized from inexpensive starting materials. All tested compounds could be glucuronidated to nonfluorescent glucuronides by UGT1A10, four of them highly selectively by this enzyme. A new UGT1A10 mutant, 1A10-H210M, was prepared on the basis of the newly constructed model. Glucuronidation kinetics of the new compounds, in both wild type and mutant UGT1A10 enzymes, revealed variable effects of the mutation. All six new C3-substituted 7-hydroxycoumarins were glucuronidated faster by human intestine than by liver microsomes, supporting the results obtained with recombinant UGTs. The most selective 4-(dimethylamino)phenyl and triazole C3 substituted 7-hydroxycoumarins could be very useful substrates in studying the function and expression of the human UGT1A10. PMID- 29421868 TI - Domino Aryne Annulation via a Nucleophilic-Ene Process. AB - 1,2-Benzdiyne equivalents possess the unique property that they can react with two arynophiles through iteratively generated 1,2- and 2,3-aryne intermediates. Upon rational modification on the second leaving group of these aryne precursors, a domino aryne annulation approach was developed through a nucleophilic-ene reaction sequence. Various benzo-fused N-heterocyclic frameworks were achievable under transition metal-free conditions with a broad substrate scope. PMID- 29421869 TI - Enantioselective 1,2-Difunctionalization of 1,3-Butadiene by Sequential Alkylation and Carbonyl Allylation. AB - A highly enantioselective three-component coupling of 1,3-butadiene with a variety of fluorinated or nonfluorinated alkyl halides and aldehydes has been achieved relying on a Cr/Co bimetallic catalysis system. The strategy established here facilitates straightforward introduction of the privileged fluoro functionalities into homoallylic alcohols from bulk feedstock materials in a highly anti-diastereo and enantioselective manner. PMID- 29421870 TI - Chiral Organic Cages with a Triple-Stranded Helical Structure Derived from Helicene. AB - We report the use of helicene with an intrinsic helical molecular structure to prepare covalent organic cages via imine condensation. The organic cages revealed a [3+2]-type architecture containing a triple-stranded helical structure with three helicene units arranged in a propeller-like fashion with the framework integrally twisted. Such structural chirality was retained upon dissolution in organic solvents, as indicated by a strong diastereotopy effect in proton NMR and unique Cotton effects in circular dichroism spectra. Further study on chiral adsorption showed that the chiral organic cages possess considerable enantioselectivity toward a series of aromatic racemates. PMID- 29421871 TI - Charge-Transfer within Zr-Based Metal-Organic Framework: The Role of Polar Node. AB - Metal-organic frameworks (MOFs) are emerging materials for electro- and photo chemical applications, where an understanding of the underlying charge-transfer (CT) process will facilitate designing new materials. However, the involvement of counterions in traditional electrochemical experiments complicates the probe on the role of various components during a CT event. A CT reaction between photoexcited MOF linker and a node-anchored ferrocene, within mesoporous framework NU-1000, was spectroscopically probed without the involvement of electrolyte based counterions. Dielectric dependent CT kinetics indicate that the process involves a high reorganization energy that is required to polarize the node bound hydroxyl/aqua ligands. The findings have clear implication on the design of MOF-based electrocatalysis and photoelectrochemical devices. PMID- 29421872 TI - Perspective of Advanced Glycation End Products on Human Health. AB - In the last 20 years, the effects of advanced glycation end products (AGEs) on health have received increasing attention. High AGE levels in the body correlate with the progression of many diseases, such as diabetes, cardiovascular disease, and some cancers. However, whether AGEs are a cause of these diseases or represent accompanying symptoms of these diseases still needs to be elucidated by more comprehensive research. Recently, many researchers have begun to investigate the effects of AGE intake-induced variations of gut microbiota on disease progression, which will further explain the impact of AGEs on health and open a new chapter in AGE research. PMID- 29421873 TI - Phosphorus Speciation and Solubility in Aeolian Dust Deposited in the Interior American West. AB - Aeolian dust is a significant source of phosphorus (P) to alpine oligotrophic lakes, but P speciation in dust and source sediments and its release kinetics to lake water remain unknown. Phosphorus K-edge XANES spectroscopy shows that calcium-bound P (Ca-P) is dominant in 10 of 12 dust samples (41-74%) deposited on snow in the central Rocky Mountains and all 42 source sediment samples (the fine fraction) (68-80%), with a lower proportion in dust probably because acidic snowmelt dissolves some Ca-P in dust before collection. Iron-bound P (Fe-P, ~54%) dominates in the remaining two dust samples. Chemical extractions (SEDEX) on these samples provide inaccurate results because of unselective extraction of targeted species and artifacts introduced by the extractions. Dust releases increasingly more P in synthetic lake water within 6-72 h thanks to dissolution of Ca-P, but dust release of P declines afterward due to back adsorption of P onto Fe oxides present in the dust. The back sorption is stronger for the dust with a lower degree of P saturation determined by oxalate extraction. This work suggests that P speciation, poorly crystalline minerals in the dust, and lake acidification all affect the availability and fate of dust-borne P in lakes. PMID- 29421874 TI - The Different Faces of 4'-Pyrimidinyl-Functionalized 4,2':6',4''-Terpyridines: Metal-Organic Assemblies from Solution and on Au(111) and Cu(111) Surface Platforms. AB - A comparative investigation of crystal growth from solution and on-surface assembly in vacuo between copper and three 4'-(2-R-pyrimidin-5-yl)-4,2':6',4'' terpyridines, with R = H (1), Me (2), or Et (3), is presented. In solution, ligand 3 combines with copper(II) acetate or copper(I) triflate in MeOH solution to give [Cu2(OAc)4(3)]n or {[Cu(3)(OMe)(MeOH)][CF3SO3].MeOH}n. In [Cu2(OAc)4(3)]n, paddle-wheel {Cu2(MU-OAc)4} nodes direct the assembly of one dimensional (1D) zigzag chains which pack into two-dimensional (2D) sheets. In {[Cu(3)(OMe)(MeOH)][CF3SO3].MeOH}n, the solvent is a ligand and also generates {Cu2(MU-OMe)2} units which function as planar 4-connecting nodes to generate a 2D (4,4) net with ligand 3. On Au(111) or Cu(111) surfaces in vacuo, no additional solvent or anions are involved in the assembly. The different substituents in 1, 2, or 3 allow precise molecular resolution imaging in scanning tunneling microscopy. On Au(111), 1 and 2 assemble into close-packed assemblies, while 3 forms a regular porous network. The deposition of Cu adatoms results in reorganization leading to ladder-shaped surface metal-organic motifs. These on surface coordination assemblies are independent of the 4'-substituent in the 4,2':6',4''-tpy and are reproduced on Cu(111) where Cu adatoms are available during the deposition and relaxation process at room temperature. Upon annealing at elevated temperatures, the original surface assemblies of 1 and 3 are modified and a transition from ladders into rhomboid structures is observed; for 2, a further quasi-hexagonal nanoporous network is observed. PMID- 29421876 TI - Development of a Knudsen-type matrix coater for sample preparation for mass spectrometry imaging. AB - The use of time-of-flight secondary ion mass spectrometry (SIMS) is of increasing interest for biological and medical applications due to its ability to provide chemical information on a submicrometer scale. However, the detection of larger biomolecules such as phospholipids and peptides is often inhibited by high fragmentation rates and low ionization efficiencies. One way to increase the secondary ion molecular yield is to chemically modify the surface using the matrix-enhanced SIMS approach, where an organic matrix is placed upon the surface. In this study, a Knudsen cell type matrix coater was developed in order to produce well-defined thicknesses of a matrix on a sample in order to study the effect of these matrix layers on the secondary ions. Using this technique, an order of magnitude enhancement of the useful ion yield for lipids was observed and clear enhancement of image contrast for lipids in brain tissue was demonstrated. The study shows that the layer thickness has a great influence on the emission of secondary ions, and therefore, its precise control is important for optimal yield enhancement. PMID- 29421875 TI - Development of a UiO-Type Thin Film Electrocatalysis Platform with Redox-Active Linkers. AB - Metal-organic frameworks (MOFs) as electrocatalysis scaffolds are appealing due to the large concentration of catalytic units that can be assembled in three dimensions. To harness the full potential of these materials, charge transport to the redox catalysts within the MOF has to be ensured. Herein, we report the first electroactive MOF with the UiO/PIZOF topology (Zr(dcphOH-NDI)), i.e., one of the most widely used MOFs for catalyst incorporation, by using redox-active naphthalene diimide-based linkers (dcphOH-NDI). Hydroxyl groups were included on the dcphOH-NDI linker to facilitate proton transport through the material. Potentiometric titrations of Zr(dcphOH-NDI) show the proton-responsive behavior via the -OH groups on the linkers and the bridging Zr-MU3-OH of the secondary building units with pKa values of 6.10 and 3.45, respectively. When grown directly onto transparent conductive fluorine-doped tin oxide (FTO), 1 MUm thin films of Zr(dcphOH-NDI)@FTO could be achieved. Zr(dcphOH-NDI)@FTO displays reversible electrochromic behavior as a result of the sequential one-electron reductions of the redox-active NDI linkers. Importantly, 97% of the NDI sites are electrochemically active at applied potentials. Charge propagation through the thin film proceeds through a linker-to-linker hopping mechanism that is charge balanced by electrolyte transport, giving rise to cyclic voltammograms of the thin films that show characteristics of a diffusion-controlled process. The equivalent diffusion coefficient, De, that contains contributions from both phenomena was measured directly by UV/vis spectroelectrochemistry. Using KPF6 as electrolyte, De was determined to be De(KPF6) = (5.4 +/- 1.1) * 10-11 cm2 s-1, while an increase in countercation size to n-Bu4N+ led to a significant decrease of De by about 1 order of magnitude (De(n-Bu4NPF6) = (4.0 +/- 2.5) * 10-12 cm2 s 1). PMID- 29421877 TI - Nanometer-scale molecular organization in lipid membranes studied by time-of flight secondary ion mass spectrometry. AB - The organization of lipid membranes plays an important role in a wide range of biological processes at different length scales. Herein, the authors present a procedure based on time-of-flight secondary ion mass spectrometry (ToF-SIMS) to characterize the nanometer-scale ordering of lipids in lipid membrane structures on surfaces. While ToF-SIMS is a powerful tool for label-free analysis of lipid containing samples, its limited spatial resolution prevents in-depth knowledge of how lipid properties affect the molecular assembly of the membrane. The authors overcome this limitation by measuring the formation of lipid dimers, originating in the same nanometer-sized primary ion impact areas. The lipid dimers reflect the local lipid environment and thus allow us to characterize the membrane miscibility on the nanometer level. Using this technique, the authors show that the chemical properties of the constituting lipids are critical for the structure and organization of the membrane on both the nanometer and micrometer length scales. Our results show that even at lipid surface compositions favoring two phase systems, lipids are still extracted from solid, gel phase, domains into the surrounding fluid supported lipid bilayer surrounding the gel phase domains. The technique offers a means to obtain detailed knowledge of the chemical composition and organization of lipid membranes with potential application in systems where labeling is not possible, such as cell-derived supported lipid bilayers. PMID- 29421878 TI - Construction of a coarse-grain quasi-classical trajectory method. II. Comparison against the direct molecular simulation method. AB - This work presents the analysis of non-equilibrium energy transfer and dissociation of nitrogen molecules (N2(Sigmag+1)) using two different approaches: the direct molecular simulation (DMS) method and the coarse-grain quasi-classical trajectory (CG-QCT) method. The two methods are used to study thermochemical relaxation in a zero-dimensional isochoric and isothermal reactor in which the nitrogen molecules are heated to several thousand degrees Kelvin, forcing the system into strong non-equilibrium. The analysis considers thermochemical relaxation for temperatures ranging from 10 000 to 25 000 K. Both methods make use of the same potential energy surface for the N2(Sigmag+1)-N2(Sigmag+1) system taken from the NASA Ames quantum chemistry database. Within the CG-QCT method, the rovibrational energy levels of the electronic ground state of the nitrogen molecule are lumped into a reduced number of bins. Two different grouping strategies are used: the more conventional vibrational-based grouping, widely used in the literature, and energy-based grouping. The analysis of both the internal state populations and concentration profiles show excellent agreement between the energy-based grouping and the DMS solutions. During the energy transfer process, discrepancies arise between the energy-based grouping and DMS solution due to the increased importance of mode separation for low energy states. By contrast, the vibrational grouping, traditionally considered state-of the-art, captures well the behavior of the energy relaxation but fails to consistently predict the dissociation process. The deficiency of the vibrational grouping model is due to the assumption of strict mode separation and equilibrium of rotational energy states. These assumptions result in errors predicting the energy contribution to dissociation from the rotational and vibrational modes, with rotational energy actually contributing 30%-40% of the energy required to dissociate a molecule. This work confirms the findings discussed in Paper I [R. L. Macdonald et al., J. Chem. Phys. 148, 054309 (2018)], which underlines the importance of rotational energy to the dissociation process, and demonstrates that an accurate non-equilibrium chemistry model must accurately predict the deviation of rovibrational distribution from equilibrium. PMID- 29421879 TI - Accurate image-charge method by the use of the residue theorem for core-shell dielectric sphere. AB - An accurate image-charge method (ICM) is developed for ionic interactions outside a core-shell structured dielectric sphere. Core-shell particles have wide applications for which the theoretical investigation requires efficient methods for the Green's function used to calculate pairwise interactions of ions. The ICM is based on an inverse Mellin transform from the coefficients of spherical harmonic series of the Green's function such that the polarization charge due to dielectric boundaries is represented by a series of image point charges and an image line charge. The residue theorem is used to accurately calculate the density of the line charge. Numerical results show that the ICM is promising in fast evaluation of the Green's function, and thus it is useful for theoretical investigations of core-shell particles. This routine can also be applicable for solving other problems with spherical dielectric interfaces such as multilayered media and Debye-Huckel equations. PMID- 29421880 TI - Sparsity of the wavefunction from the generalized Pauli exclusion principle. AB - Electron occupations that arise from pure quantum states are restricted by a stringent set of conditions that are said to generalize the Pauli exclusion principle. These generalized Pauli constraints (GPCs) define the boundary of the set of one-electron reduced density matrices (1-RDMs) that are derivable from at least one N-electron wavefunction. In this paper, we investigate the sparsity of the Slater-determinant representation of the wavefunction that is a necessary, albeit not sufficient, condition for its 1-RDM to lie on the boundary of the set of pure N-representable 1-RDMs or in other words saturate one of the GPCs. The sparse wavefunction, we show, is exact not only for 3 electrons in 6 orbitals but also for 3 electrons in 8 orbitals. For larger numbers of electrons and/or orbitals in the lowest spin state, the exact wavefunction does not generally saturate one of the GPCs, and hence, the sparse representation is typically an approximation. Because the sparsity of the wavefunction is a necessary but not sufficient condition for saturation of one of the GPCs, optimization of the sparse wavefunction Ansatz to minimize the ground-state energy does not necessarily produce a wavefunction whose 1-RDM exactly saturates one of the GPCs. While the sparse Ansatz can be employed with arbitrary orbitals or optimized orbitals, in this paper, we explore the Ansatz with the natural orbitals from full configuration interaction, which yields an upper bound to the ground-state energy that equals the exact energy for a given basis set if the full configuration-interaction wavefunction saturates the Ansatz's GPC. With calculations on the boron isoelectronic sequence, the dinitrogen cation N2+, hydrogen chains, and cyclic conjugated pi systems, we examine the quality of the sparse wavefunction Ansatz from the amount of correlation energy recovered. PMID- 29421881 TI - Insight into ethylene interactions with molybdenum suboxide cluster anions from photoelectron spectra of chemifragments. AB - Recent studies on reactions between MoxOy- cluster anions and H2O/C2H4 mixtures revealed a complex web of addition, hydrogen evolution, and chemifragmentation reactions, with chemifragments unambiguously connected to cluster reactions with C2H4. To gain insight into the molecular-scale interactions along the chemifragmentation pathways, the anion photoelectron (PE) spectra of MoC2H2-, MoC4H4-, MoOC2H2-, and MoO2C2H2- formed directly in MoxOy- + C2H4 (x > 1; y >= x) reactions, along with supporting CCSD(T) and density functional theory calculations, are presented and analyzed. The complexes have spectra that are all consistent with eta2-acetylene complexes, though for all but MoC4H4-, the possibility that vinylidene complexes are also present cannot be definitively ruled out. Structures that are consistent with the PE spectrum of MoC2H2- differ from the lowest energy structure, suggesting that the fragment formation is under kinetic control. The PE spectrum of MoO2C2H2- additionally exhibits evidence that photodissociation to MoO2- + C2H2 may be occurring. The results suggest that oxidative dehydrogenation of ethylene is initiated by Lewis acid/base interactions between the Mo centers in larger clusters and the pi orbitals in ethylene. PMID- 29421882 TI - Water adsorbate phases on ZnO and impact of vapor pressure on the equilibrium shape of nanoparticles. AB - ZnO nanoparticles are used as catalysts and have potential applications in gas sensing and solar energy conversion. A fundamental understanding of the exposed crystal facets, their surface chemistry, and stability as a function of environmental conditions is essential for rational design and improvement of synthesis and properties. We study the stability of water adsorbate phases on the non-polar low-index (101-0) and (112-0) surfaces from low coverage to multilayers using ab initio thermodynamics. We show that phonon contributions and the entropies due to a 2D lattice gas at low coverage and multiple adsorbate configurations at higher coverage have an important impact on the stability range of water adsorbate phases in the (T,p) phase diagram. Based on this insight, we compute and analyze the possible growth mode of water films for pressures ranging from UHV via ambient conditions to high pressures and the impact of water adsorption on the equilibrium shape of nanoparticles in a humid environment. A 2D variant of the Wulff construction shows that the (101-0) and (112-0) surfaces coexist on 12-faceted prismatic ZnO nanoparticles in dry conditions, while in humid environment, the (101-0) surface is selectively stabilized by water adsorption resulting in hexagonal prisms. PMID- 29421883 TI - Electronic and spectroscopic characterizations of SNP isomers. AB - High-level ab initio electronic structure calculations were performed to characterize SNP isomers. In addition to the known linear SNP, cyc-PSN, and linear SPN isomers, we identified a fourth isomer, linear PSN, which is located ~2.4 eV above the linear SNP isomer. The low-lying singlet and triplet electronic states of the linear SNP and SPN isomers were investigated using a multi reference configuration interaction method and large basis set. Several bound electronic states were identified. However, their upper rovibrational levels were predicted to pre-dissociate, leading to S + PN, P + NS products, and multi-step pathways were discovered. For the ground states, a set of spectroscopic parameters were derived using standard and explicitly correlated coupled-cluster methods in conjunction with augmented correlation-consistent basis sets extrapolated to the complete basis set limit. We also considered scalar and core valence effects. For linear isomers, the rovibrational spectra were deduced after generation of their 3D-potential energy surfaces along the stretching and bending coordinates and variational treatments of the nuclear motions. PMID- 29421884 TI - Multiscale weighted colored graphs for protein flexibility and rigidity analysis. AB - Protein structural fluctuation, measured by Debye-Waller factors or B-factors, is known to correlate to protein flexibility and function. A variety of methods has been developed for protein Debye-Waller factor prediction and related applications to domain separation, docking pose ranking, entropy calculation, hinge detection, stability analysis, etc. Nevertheless, none of the current methodologies are able to deliver an accuracy of 0.7 in terms of the Pearson correlation coefficients averaged over a large set of proteins. In this work, we introduce a paradigm-shifting geometric graph model, multiscale weighted colored graph (MWCG), to provide a new generation of computational algorithms to significantly change the current status of protein structural fluctuation analysis. Our MWCG model divides a protein graph into multiple subgraphs based on interaction types between graph nodes and represents the protein rigidity by generalized centralities of subgraphs. MWCGs not only predict the B-factors of protein residues but also accurately analyze the flexibility of all atoms in a protein. The MWCG model is validated over a number of protein test sets and compared with many standard methods. An extensive numerical study indicates that the proposed MWCG offers an accuracy of over 0.8 and thus provides perhaps the first reliable method for estimating protein flexibility and B-factors. It also simultaneously predicts all-atom flexibility in a molecule. PMID- 29421885 TI - A real-time extension of density matrix embedding theory for non-equilibrium electron dynamics. AB - We introduce real-time density matrix embedding theory (DMET), a dynamical quantum embedding theory for computing non-equilibrium electron dynamics in strongly correlated systems. As in the previously developed static DMET, real time DMET partitions the system into an impurity corresponding to the region of interest coupled to the surrounding environment, which is efficiently represented by a quantum bath of the same size as the impurity. In this work, we focus on a simplified single-impurity time-dependent formulation as a first step toward a multi-impurity theory. The equations of motion of the coupled impurity and bath embedding problem are derived using the time-dependent variational principle. The accuracy of real-time DMET is compared to that of time-dependent complete active space self-consistent field (TD-CASSCF) theory and time-dependent Hartree-Fock (TDHF) theory for a variety of quantum quenches in the single impurity Anderson model (SIAM), in which the Hamiltonian is suddenly changed (quenched) to induce a non-equilibrium state. Real-time DMET shows a marked improvement over the mean field TDHF, converging to the exact answer even in the non-trivial Kondo regime of the SIAM. However, as expected from analogous behavior in static DMET, the constrained structure of the real-time DMET wavefunction leads to a slower convergence with respect to active space size, in the single-impurity formulation, relative to TD-CASSCF. Our initial results suggest that real-time DMET provides a promising framework to simulate non-equilibrium electron dynamics in which strong electron correlation plays an important role, and lays the groundwork for future multi-impurity formulations. PMID- 29421886 TI - Photophysics of phenol and pentafluorophenol: The role of nonadiabaticity in the optical transition to the lowest bright 1pipi* state. AB - We report multimode vibronic coupling of the energetically low-lying electronic states of phenol and pentafluorophenol in this article. First principles nuclear dynamics calculations are carried out to elucidate the optical absorption spectrum of both of the molecules. This is motivated by the recent experimental measurements [S. Karmakar et al., J. Chem. Phys. 142, 184303 (2015)] on these systems. Diabatic vibronic coupling models are developed with the aid of adiabatic electronic energies calculated ab initio by the equation of motion coupled cluster quantum chemistry method. A nuclear dynamics study on the constructed electronic states is carried out by both the time-independent and time-dependent quantum mechanical methods. It is found that the nature of low energy pisigma* transition changes, and in pentafluorophenol the energy of the first two 1pisigma* states, is lowered by about half an eV (vertically, relative to those in phenol), and they become energetically close to the optically bright first excited 1pipi* (S1) state. This results in strong vibronic coupling and multiple multi-state conical intersections among the pipi* and pisigma* electronic states of pentafluorophenol. The impact of associated nonadiabatic effects on the vibronic structure and dynamics of the 1pipi* state is examined at length. The structured vibronic band of phenol becomes structureless in pentafluorophenol. The theoretical results are found to be in good accord with the experimental finding at both high energy resolution and low energy resolution. PMID- 29421887 TI - Poisson-Fermi modeling of ion activities in aqueous single and mixed electrolyte solutions at variable temperature. AB - The combinatorial explosion of empirical parameters in tens of thousands presents a tremendous challenge for extended Debye-Huckel models to calculate activity coefficients of aqueous mixtures of the most important salts in chemistry. The explosion of parameters originates from the phenomenological extension of the Debye-Huckel theory that does not take steric and correlation effects of ions and water into account. By contrast, the Poisson-Fermi theory developed in recent years treats ions and water molecules as nonuniform hard spheres of any size with interstitial voids and includes ion-water and ion-ion correlations. We present a Poisson-Fermi model and numerical methods for calculating the individual or mean activity coefficient of electrolyte solutions with any arbitrary number of ionic species in a large range of salt concentrations and temperatures. For each activity-concentration curve, we show that the Poisson-Fermi model requires only three unchanging parameters at most to well fit the corresponding experimental data. The three parameters are associated with the Born radius of the solvation energy of an ion in electrolyte solution that changes with salt concentrations in a highly nonlinear manner. PMID- 29421888 TI - Water entrapment and structure ordering as protection mechanisms for protein structural preservation. AB - In this paper, molecular dynamics is used to further gain insight into the mechanisms by which typical pharmaceutical excipients preserve the protein structure. More specifically, the water entrapment scenario will be analyzed, which states that excipients form a cage around the protein, entrapping and slowing water molecules. Human growth hormone will be used as a model protein, but the results obtained are generally applicable. We will show that water entrapment, as well as the other mechanisms of protein stabilization in the dried state proposed so far, may be related to the formation of a dense hydrogen bonding network between excipient molecules. We will also present a simple phenomenological model capable of explaining the behavior and stabilizing effect provided by typical cryo- and lyo-protectants. This model uses, as input data, molecular properties which can be easily evaluated. We will finally show that the model predictions compare fairly well with experimental data. PMID- 29421889 TI - Communication: Time-dependent optimized coupled-cluster method for multielectron dynamics. AB - Time-dependent coupled-cluster method with time-varying orbital functions, called time-dependent optimized coupled-cluster (TD-OCC) method, is formulated for multielectron dynamics in an intense laser field. We have successfully derived the equations of motion for CC amplitudes and orthonormal orbital functions based on the real action functional, and implemented the method including double excitations (TD-OCCD) and double and triple excitations (TD-OCCDT) within the optimized active orbitals. The present method is size extensive and gauge invariant, a polynomial cost-scaling alternative to the time-dependent multiconfiguration self-consistent-field method. The first application of the TD OCC method of intense-laser driven correlated electron dynamics in Ar atom is reported. PMID- 29421890 TI - Refined analysis of the X 2A2<-X 1A1 photoelectron spectrum of furan. AB - The X 2A2<-X 1A1 photoelectron spectrum of furan has been studied by a time independent eigenstate-free Raman wave function approach based on multi dimensional potential energy surfaces obtained from explicitly correlated distinguishable clusters calculations. Individual vibronic transitions with the most significant Franck-Condon factors were determined by our recently developed residual-based algorithm for the calculation of eigenpairs in conjunction with the formalism of contracted invariant Krylov subspaces. The account of anharmonic and temperature effects allowed us to explain most bands in an experimental high resolution zero kinetic energy photoelectron spectrum. This led to the reassignment of many spectral features, as well as a refined interpretation of the intensity mechanism for the corresponding transitions. PMID- 29421891 TI - Similarity-transformed equation-of-motion vibrational coupled-cluster theory. AB - A similarity-transformed equation-of-motion vibrational coupled-cluster (STEOM XVCC) method is introduced as a one-mode theory with an effective vibrational Hamiltonian, which is similarity transformed twice so that its lower-order operators are dressed with higher-order anharmonic effects. The first transformation uses an exponential excitation operator, defining the equation-of motion vibrational coupled-cluster (EOM-XVCC) method, and the second uses an exponential excitation-deexcitation operator. From diagonalization of this doubly similarity-transformed Hamiltonian in the small one-mode excitation space, the method simultaneously computes accurate anharmonic vibrational frequencies of all fundamentals, which have unique significance in vibrational analyses. We establish a diagrammatic method of deriving the working equations of STEOM-XVCC and prove their connectedness and thus size-consistency as well as the exact equality of its frequencies with the corresponding roots of EOM-XVCC. We furthermore elucidate the similarities and differences between electronic and vibrational STEOM methods and between STEOM-XVCC and vibrational many-body Green's function theory based on the Dyson equation, which is also an anharmonic one-mode theory. The latter comparison inspires three approximate STEOM-XVCC methods utilizing the common approximations made in the Dyson equation: the diagonal approximation, a perturbative expansion of the Dyson self-energy, and the frequency-independent approximation. The STEOM-XVCC method including up to the simultaneous four-mode excitation operator in a quartic force field and its three approximate variants are formulated and implemented in computer codes with the aid of computer algebra, and they are applied to small test cases with varied degrees of anharmonicity. PMID- 29421892 TI - Communication: Renormalization method for infinite lattice sums revisited: Lattice sums with Bloch phase factors. AB - An infinite lattice summation scheme based on the idea of renormalization is generalized to enable the evaluation of infinite lattice sums with Bloch phase factors which can occur when treating long-range interactions in infinite periodic systems. The scheme is fast, with easily adjustable accuracy and is not limited to any choice of special points in the Brillouin zone. Illustrative calculation for a first few contributions for a simple cubic lattice is presented. PMID- 29421893 TI - Inclusion of orbital relaxation and correlation through the unitary group adapted open shell coupled cluster theory using non-relativistic and scalar relativistic Hamiltonians to study the core ionization potential of molecules containing light to medium-heavy elements. AB - The orbital relaxation attendant on ionization is particularly important for the core electron ionization potential (core IP) of molecules. The Unitary Group Adapted State Universal Coupled Cluster (UGA-SUMRCC) theory, recently formulated and implemented by Sen et al. [J. Chem. Phys. 137, 074104 (2012)], is very effective in capturing orbital relaxation accompanying ionization or excitation of both the core and the valence electrons [S. Sen et al., Mol. Phys. 111, 2625 (2013); A. Shee et al., J. Chem. Theory Comput. 9, 2573 (2013)] while preserving the spin-symmetry of the target states and using the neutral closed-shell spatial orbitals of the ground state. Our Ansatz invokes a normal-ordered exponential representation of spin-free cluster-operators. The orbital relaxation induced by a specific set of cluster operators in our Ansatz is good enough to eliminate the need for different sets of orbitals for the ground and the core-ionized states. We call the single configuration state function (CSF) limit of this theory the Unitary Group Adapted Open-Shell Coupled Cluster (UGA-OSCC) theory. The aim of this paper is to comprehensively explore the efficacy of our Ansatz to describe orbital relaxation, using both theoretical analysis and numerical performance. Whenever warranted, we also make appropriate comparisons with other coupled cluster theories. A physically motivated truncation of the chains of spin-free T operators is also made possible by the normal-ordering, and the operational resemblance to single reference coupled-cluster theory allows easy implementation. Our test case is the prediction of the 1s core IP of molecules containing a single light- to medium-heavy nucleus and thus, in addition to demonstrating the orbital relaxation, we have addressed the scalar relativistic effects on the accuracy of the IPs by using a hierarchy of spin-free Hamiltonians in conjunction with our theory. Additionally, the contribution of the spin-free component of the two-electron Gaunt term, not usually taken into consideration, has been estimated at the Self-Consistent Field (DeltaSCF) level and is found to become increasingly important and eventually quite prominent for molecules with third period atoms and below. The accuracies of the IPs computed using UGA-OSCC are found to be of the same order as the Coupled Cluster Singles Doubles (DeltaCCSD) values while being free from spin contamination. Since the UGA-OSCC uses a common set of orbitals for the ground state and the ion, it obviates the need of two N5 AO to MO transformation in contrast to the DeltaCCSD method. PMID- 29421894 TI - Markov modeling of peptide folding in the presence of protein crowders. AB - We use Markov state models (MSMs) to analyze the dynamics of a beta-hairpin forming peptide in Monte Carlo (MC) simulations with interacting protein crowders, for two different types of crowder proteins [bovine pancreatic trypsin inhibitor (BPTI) and GB1]. In these systems, at the temperature used, the peptide can be folded or unfolded and bound or unbound to crowder molecules. Four or five major free-energy minima can be identified. To estimate the dominant MC relaxation times of the peptide, we build MSMs using a range of different time resolutions or lag times. We show that stable relaxation-time estimates can be obtained from the MSM eigenfunctions through fits to autocorrelation data. The eigenfunctions remain sufficiently accurate to permit stable relaxation-time estimation down to small lag times, at which point simple estimates based on the corresponding eigenvalues have large systematic uncertainties. The presence of the crowders has a stabilizing effect on the peptide, especially with BPTI crowders, which can be attributed to a reduced unfolding rate ku, while the folding rate kf is left largely unchanged. PMID- 29421895 TI - Expedite random structure searching using objects from Wyckoff positions. AB - Random structure searching has been proved to be a powerful approach to search and find the global minimum and the metastable structures. A true random sampling is in principle needed yet it would be highly time-consuming and/or practically impossible to find the global minimum for the complicated systems in their high dimensional configuration space. Thus the implementations of reasonable constraints, such as adopting system symmetries to reduce the independent dimension in structural space and/or imposing chemical information to reach and relax into low-energy regions, are the most essential issues in the approach. In this paper, we propose the concept of "object" which is either an atom or composed of a set of atoms (such as molecules or carbonates) carrying a symmetry defined by one of the Wyckoff positions of space group and through this process it allows the searching of global minimum for a complicated system to be confined in a greatly reduced structural space and becomes accessible in practice. We examined several representative materials, including Cd3As2 crystal, solid methanol, high-pressure carbonates (FeCO3), and Si(111)-7 * 7 reconstructed surface, to demonstrate the power and the advantages of using "object" concept in random structure searching. PMID- 29421896 TI - Extension of Kirkwood-Buff theory to the canonical ensemble. AB - Kirkwood-Buff (KB) integrals are notoriously difficult to converge from a canonical simulation because they require estimating the grand-canonical radial distribution. The same essential difficulty is encountered when attempting to estimate the direct correlation function of Ornstein-Zernike theory by inverting the pair correlation functions. We present a new theory that applies to the entire, finite, simulation volume, so that no cutoff issues arise at all. The theory gives the direct correlation function for closed systems, while smoothness of the direct correlation function in reciprocal space allows calculating canonical KB integrals via a well-posed extrapolation to the origin. The present analysis method represents an improvement over previous work because it makes use of the entire simulation volume and its convergence can be accelerated using known properties of the direct correlation function. Using known interaction energy functions can make this extrapolation near perfect accuracy in the low density case. Because finite size effects are stronger in the canonical than in the grand-canonical ensemble, we state ensemble correction formulas for the chemical potential and the KB coefficients. The new theory is illustrated with both analytical and simulation results on the 1D Ising model and a supercritical Lennard-Jones fluid. For the latter, the finite-size corrections are shown to be small. PMID- 29421897 TI - Lamb dip CRDS of highly saturated transitions of water near 1.4 MUm. AB - Doppler-free saturated-absorption Lamb dips were measured at sub-Pa pressures on rovibrational lines of H216O near 7180 cm-1, using optical feedback frequency stabilized cavity ring-down spectroscopy. The saturation of the considered lines is so high that at the early stage of the ring down, the cavity loss rate remains unaffected by the absorption. By referencing the laser source to an optical frequency comb, transition frequencies are determined down to 100 Hz precision and kHz accuracy. The developed setup allows resolving highly K-type blended doublets separated by about 10 MHz (to be compared to a HWHM Doppler width on the order of 300 MHz). A comparison with the most recent spectroscopic databases is discussed. The determined K-type splittings are found to be very well predicted by the most recent variational calculations. PMID- 29421898 TI - Construction of a coarse-grain quasi-classical trajectory method. I. Theory and application to N2-N2 system. AB - This work aims to construct a reduced order model for energy transfer and dissociation in non-equilibrium nitrogen mixtures. The objective is twofold: to present the Coarse-Grain Quasi-Classical Trajectory (CG-QCT) method, a novel framework for constructing a reduced order model for diatom-diatom systems; and to analyze the physics of non-equilibrium relaxation of the nitrogen molecules undergoing dissociation in an ideal chemical reactor. The CG-QCT method couples the construction of the reduced order model under the coarse-grain model framework with the quasi-classical trajectory calculations to directly construct the reduced model without the need for computing the individual rovibrational specific kinetic data. In the coarse-grain model, the energy states are lumped together into groups containing states with similar properties, and the distribution of states within each of these groups is prescribed by a Boltzmann distribution at the local translational temperature. The required grouped kinetic properties are obtained directly by the QCT calculations. Two grouping strategies are considered: energy-based grouping, in which states of similar internal energy are lumped together, and vibrational grouping, in which states with the same vibrational quantum number are grouped together. A zero-dimensional chemical reactor simulation, in which the molecules are instantaneously heated, forcing the system into strong non-equilibrium, is used to study the differences between the two grouping strategies. The comparison of the numerical results against available experimental data demonstrates that the energy-based grouping is more suitable to capture dissociation, while the energy transfer process is better described with a vibrational grouping scheme. The dissociation process is found to be strongly dependent on the behavior of the high energy states, which contribute up to 50% of the dissociating molecules. Furthermore, up to 40% of the energy required to dissociate the molecules comes from the rotational mode, underscoring the importance of accounting for this mode when constructing non equilibrium kinetic models. In contrast, the relaxation process is governed primarily by low energy states, which exhibit significantly slower transitions in the vibrational binning model due to the prevalence of mode separation in these states. PMID- 29421899 TI - Nucleation of the lamellar phase from the disordered phase of the renormalized Landau-Brazovskii model. AB - Using the zero-temperature string method, we investigate nucleation of a stable lamellar phase from a metastable disordered phase of the renormalized Landau Brazovskii model at parameters explicitly connected to those of an experimentally accessible diblock copolymer melt. We find anisotropic critical nuclei in qualitative agreement with previous experimental and analytic predictions; we also find good quantitative agreement with the predictions of a single-mode analysis. We conduct a thorough search for critical nuclei containing various predicted and experimentally observed defect structures. The predictions of the renormalized model are assessed by simulating the bare Landau-Brazovskii model with fluctuations. We find that the renormalized model makes reasonable predictions for several important quantities, including the order-disorder transition (ODT). However, the critical nucleus size depends sharply on proximity to the ODT, so even small errors in the ODT predicted by the renormalized model lead to large errors in the predicted critical nucleus size. We conclude that the renormalized model is a poor tool to study nucleation in the fluctuating Landau Brazovskii model, and recommend that future studies work with the fluctuating bare model directly, using well-chosen collective variables to investigate kinetic pathways in the disorder -> lamellar transition. PMID- 29421900 TI - Dynamics of the OH stretching mode in crystalline Ba(ClO4)2.3H2O. AB - The vibrational dynamics of the OH stretching mode in Ba(ClO4)2 trihydrate are investigated by means of femtosecond infrared spectroscopy. The sample offers plane cyclic water trimers in the solid phase that feature virtually no hydrogen bond interaction between the water molecules. Selective excitation of the symmetric and asymmetric stretching leads to fast population redistribution, while simultaneous excitation yields quantum beats, which are monitored via a combination tone that dominates the overtone spectrum. The combination of steady state and time-resolved spectroscopy with quantum chemical simulations and general theoretical considerations gives indication of various aspects of symmetry breakage. The system shows a joint population lifetime of 8 ps and a long-lived coherence between symmetric and asymmetric stretching, which decays with a time constant of 0.6 ps. PMID- 29421901 TI - Effect of pore geometry on the compressibility of a confined simple fluid. AB - Fluids confined in nanopores exhibit properties different from the properties of the same fluids in bulk; among these properties is the isothermal compressibility or elastic modulus. The modulus of a fluid in nanopores can be extracted from ultrasonic experiments or calculated from molecular simulations. Using Monte Carlo simulations in the grand canonical ensemble, we calculated the modulus for liquid argon at its normal boiling point (87.3 K) adsorbed in model silica pores of two different morphologies and various sizes. For spherical pores, for all the pore sizes (diameters) exceeding 2 nm, we obtained a logarithmic dependence of fluid modulus on the vapor pressure. Calculation of the modulus at saturation showed that the modulus of the fluid in spherical pores is a linear function of the reciprocal pore size. The calculation of the modulus of the fluid in cylindrical pores appeared too scattered to make quantitative conclusions. We performed additional simulations at higher temperature (119.6 K), at which Monte Carlo insertions and removals become more efficient. The results of the simulations at higher temperature confirmed both regularities for cylindrical pores and showed quantitative difference between the fluid moduli in pores of different geometries. Both of the observed regularities for the modulus stem from the Tait-Murnaghan equation applied to the confined fluid. Our results, along with the development of the effective medium theories for nanoporous media, set the groundwork for analysis of the experimentally measured elastic properties of fluid-saturated nanoporous materials. PMID- 29421902 TI - Publisher's Note: "Diffusion-influenced reaction rates for active 'sphere-prolate spheroid' pairs and Janus dimers" [J. Chem. Phys. 148, 024107 (2018)]. PMID- 29421903 TI - Contrasting two different interpretations of the dynamics in binary glass forming mixtures. AB - In a series of papers on binary glass-forming mixtures of tripropyl phosphate (TPP) with polystyrene (PS), Kahlau et al. [J. Chem. Phys. 140, 044509 (2014)] and Bock et al. [J. Chem. Phys. 139, 064508 (2013); J. Chem. Phys. 140, 094505 (2014); and J. Non-Cryst. Solids 407, 88-97 (2015)] presented the data on the dynamics of the two components studied over the entire composition range by several experimental methods. From these sets of data, obtained by multiple experimental techniques on mixtures with a large difference DeltaTg ~ 200 K between the glass transition temperatures of two starting glass formers, they obtained two alpha-relaxations, alpha1 and alpha2. The temperature dependence of the slower alpha1 is Vogel-Fulcher like, but the faster alpha2 is Arrhenius. We have re-examined their data and show that their alpha2-relaxation is the Johari Goldstein (JG) beta-relaxation with Arrhenius T-dependence admixed with a true alpha2-relaxation having a stronger temperature dependence. In support of our interpretation of their data, we made dielectric measurements at elevated pressures P to show that the ratio of the alpha1 and alpha2 relaxation times, taualpha1(T,P)/taualpha2(T,P), is invariant to variations of T and P, while taualpha1(T,P) is kept constant. This property proves unequivocally that the alpha2-relaxation is the JG beta-relaxation, the precursor of the alpha1 relaxation. Subsequently, the true but unresolved alpha2-relaxation is recovered, and its relaxation times with much stronger temperature dependence are deduced, as expected for the alpha-relaxation of the TPP component. The results are fully compatible with those found in another binary mixture of methyltetrahydrofuran with tristyrene and PS with DeltaTg ~ 283 K, even larger than DeltaTg ~ 200 K of the mixture of TPP with PS, and in several polymer blends. The contrast between the two very different interpretations brought out in this paper is deemed beneficial for further progress in this research area. PMID- 29421904 TI - Theory of activated glassy dynamics in randomly pinned fluids. AB - We generalize the force-level, microscopic, Nonlinear Langevin Equation (NLE) theory and its elastically collective generalization [elastically collective nonlinear Langevin equation (ECNLE) theory] of activated dynamics in bulk spherical particle liquids to address the influence of random particle pinning on structural relaxation. The simplest neutral confinement model is analyzed for hard spheres where there is no change of the equilibrium pair structure upon particle pinning. As the pinned fraction grows, cage scale dynamical constraints are intensified in a manner that increases with density. This results in the mobile particles becoming more transiently localized, with increases of the jump distance, cage scale barrier, and NLE theory mean hopping time; subtle changes of the dynamic shear modulus are predicted. The results are contrasted with recent simulations. Similarities in relaxation behavior are identified in the dynamic precursor regime, including a roughly exponential, or weakly supra-exponential, growth of the alpha time with pinning fraction and a reduction of dynamic fragility. However, the increase of the alpha time with pinning predicted by the local NLE theory is too small and severely so at very high volume fractions. The strong deviations are argued to be due to the longer range collective elasticity aspect of the problem which is expected to be modified by random pinning in a complex manner. A qualitative physical scenario is offered for how the three distinct aspects that quantify the elastic barrier may change with pinning. ECNLE theory calculations of the alpha time are then presented based on the simplest effective-medium-like treatment for how random pinning modifies the elastic barrier. The results appear to be consistent with most, but not all, trends seen in recent simulations. Key open problems are discussed with regard to both theory and simulation. PMID- 29421905 TI - Feed-forward coherent link from a comb to a diode laser: Application to widely tunable cavity ring-down spectroscopy. AB - We apply a feed-forward frequency control scheme to establish a phase-coherent link from an optical frequency comb to a distributed feedback (DFB) diode laser: This allows us to exploit the full laser tuning range (up to 1 THz) with the linewidth and frequency accuracy of the comb modes. The approach relies on the combination of an RF single-sideband modulator (SSM) and of an electro-optical SSM, providing a correction bandwidth in excess of 10 MHz and a comb-referenced RF-driven agile tuning over several GHz. As a demonstration, we obtain a 0.3 THz cavity ring-down scan of the low-pressure methane absorption spectrum. The spectral resolution is 100 kHz, limited by the self-referenced comb, starting from a DFB diode linewidth of 3 MHz. To illustrate the spectral resolution, we obtain saturation dips for the 2nu3 R(6) methane multiplet at MUbar pressure. Repeated measurements of the Lamb-dip positions provide a statistical uncertainty in the kHz range. PMID- 29421906 TI - Renner-Teller effects in the photoelectron spectra of CNC, CCN, and HCCN. AB - The line intensity of photoelectron spectra when either the neutral or cationic species display a Renner-Teller coupling is derived and applied to the modeling of the photoelectron spectra of CNC, CCN, and HCCN. The rovibronic energy levels of these three radicals and of their cations are investigated starting from ab initio results. A model treating simultaneously the bending mode and the overall rotation is developed to deal with the quasilinearity problem in CNC+, CCN+, and HCCN and accounts for the large amplitude nature of their bending mode. This model is extended to treat the Renner-Teller coupling in CNC, CCN, and HCCN+. Based on the derived photoelectron line intensity, the photoelectron spectra of all three molecules are calculated and compared to the experimental ones. PMID- 29421907 TI - Curvature and bottlenecks control molecular transport in inverse bicontinuous cubic phases. AB - We perform a simulation study of the diffusion of small solutes in the confined domains imposed by inverse bicontinuous cubic phases for the primitive, diamond, and gyroid symmetries common to many lipid/water mesophase systems employed in experiments. For large diffusing domains, the long-time diffusion coefficient shows universal features when the size of the confining domain is renormalized by the Gaussian curvature of the triply periodic minimal surface. When bottlenecks are widely present, they become the most relevant factor for transport, regardless of the connectivity of the cubic phase. PMID- 29421908 TI - Glass-like stress relaxation of a permanent gelatin network as a signature of pretransitional helix-coil fluctuations. AB - The stress response of permanently crosslinked gelatin gels was recently observed to display glass-like features, namely, a stretched-exponential behavior terminated by an exponential decay, the characteristic time scales of which increase dramatically with decreasing temperature. This phenomenon is studied here using a model of flexible polymer gel network where relaxation proceeds via elementary monomer exchanges between helix and coil segments. The relaxation dynamics of a full network simulation is found to be nearly identical to that of a model of independent strands, which shows that for flexible polymer gels in the range of elastic moduli of interest, both strand contour length disorder and elastic couplings are irrelevant. We thus focus on the independent strand model and find it not only to explain the observed functional form of the stress relaxation curves but also to yield predictions that match very satisfactorily the experimental measurements of final relaxation time and total stress drop. The system under study thus constitutes a rare case where the origin of glass-like behavior can be unambiguously identified, namely, as the signature of the enhancement of helix content fluctuations when approaching from above the mean field helix-coil transition of strands. PMID- 29421909 TI - Computational investigation of non-covalent interactions in 1-butyl 3 methylimidazolium/bis(trifluoromethylsulfonyl)imide [bmim][Tf2N] in EMD and NEMD. AB - Non-covalent interactions (NCIs) play a crucial role in the behavior and properties of ionic liquids (ILs). These interactions are particularly important for non-equilibrium properties such as the change in viscosity due to shearing forces (shear viscosity). Therefore, a detailed understanding of these interactions can improve our understanding of these important classes of liquids. Here, we have employed quantum mechanical energy decomposition analysis (EDA) and NCI analysis to investigate a series of representative 1-butyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide ([bmim][Tf2N]) ion pairs extracted from classical equilibrium and non-equilibrium molecular dynamics simulations. EDA based on symmetry-adapted perturbation theory (SAPT) for the complete monomers, as well as fragment SAPT (FSAPT), for the functional fragments has been carried out. In general, the electrostatic component comprises ~80% of the intermolecular interaction, and significant contributions from other components (induction and dispersion) are also observed, especially for interactions involving bifurcated hydrogen bonds. The FSAPT analysis suggests that caution is warranted when employing simplified assumptions for non-bonded interactions, e.g., focusing only on hydrogen bonds between functional fragments, since this view may not provide a complete picture of the complicated interactions between the ions. In non-equilibrium molecular dynamics, the total interaction energies of some fragments have a significant qualitative change as the shear rate increases. Our results indicate that the inter-fragment interactions play a fundamental role in the viscous behavior of ILs, suggesting that the exclusive use of geometric criteria to analyze inter-molecular interactions in these systems is not sufficient to investigate shear-thinning effects. PMID- 29421910 TI - Effect of humidity on the absorption continua of CO2 and N2 near 4 MUm: Calculations, comparisons with measurements, and consequences for atmospheric spectra. AB - We present a theoretical study of the effects of collisions with water vapor molecules on the absorption, around 4 MUm, in both the high frequency wing of the CO2 nu3 band and the collision-induced fundamental band of N2. Calculations are made for the very first time, showing that predictions based on classical molecular dynamics simulations enable, without adjustment of any parameter, very satisfactory agreement with the few available experimental determinations. This opens the route for a future study in which accurate temperature-dependent (semi empirical) models will be built and checked through comparisons between computed and measured atmospheric spectra. This is of interest since, as demonstrated by simulations, neglecting the humidity of air can lead to significant modifications of the atmospheric transmission (and thus also emission) between 2000 and 2800 cm 1. PMID- 29421911 TI - Intrathoracic leak after an Ivor Lewis procedure for an esophageal neoplasm treated with a stent. AB - A 75-year-old male who underwent an Ivor Lewis esophagectomy due to a distal adenocarcinoma had a leak at the gastroplasty on the 5th day after surgery, which required two surgeries and a primary suture. He was transferred to our hospital due to a poor outcome and endoscopy revealed a 2.5cm gap perianastomotically on the gastroplasty wall, for which a stent was placed. Due to hemodynamic impairment, a thoracotomy procedure was performed, which revealed stent protrusion into the cavity. The patient underwent an esophagogastric anastomosis resection, cervical esophagostomy and gastrostomy. Sepsis was resolved postoperatively and the patient had a protracted stay in the PACU due to poor respiratory dynamics following a prolonged intubation. PMID- 29421913 TI - Gastrointestinal stromal tumors: 16 years' experience within a university hospital. AB - AIM: the aim was to convey our 16-year experience regarding gastrointestinal stromal tumors within in a high volume university hospital. Factors that may impact on patient survival were evaluated. MATERIAL AND METHODS: all patients diagnosed with gastrointestinal stromal tumors in our clinic over a 16-year period were retrospectively evaluated. All patients included in the study had their tumors surgically resected. Survival analyses were performed using the Kaplan-Meier method. Survival time comparisons between groups were performed using the log-rank test. The effect of continuous variables on survival times were evaluated via a Cox-regression analysis with a backward conditional method. RESULTS: one hundred and thirty-five patients (76 males and 59 females) were included into the study and the mean age was 62.8 +/- 13.3 years. Overall survival time was 121.3 +/- 7.0 months and the 5-year survival rate was 66.6 +/- 4.2%. Patients with colorectal tumors had significantly lower survival times than patients with tumors located in the stomach (p = 0.001) and small intestine (p = 0.033). Patients with moderate risk scores had a significantly longer survival compared to patients with high risk scores (p = 0.003) and patients with tumor recurrence had a significantly shorter survival (p < 0.001). There was no significant relationship between survival and factors such as gender and tumor size (p > 0.05). However, age, Ki-67 and the mitotic index were poor prognostic factors and C-kit was considered as a good prognostic factor. CONCLUSION: some of the findings in this study are consistent with published data. However, our data significantly differs from previous studies such as the common finding of the effect of gender and tumor size on survival. PMID- 29421912 TI - Clinical guidelines for endoscopic mucosal resection of non-pedunculated colorectal lesions. AB - This document summarizes the contents of the Clinical Guidelines for the Endoscopic Mucosal Resection of Non-Pedunculated Colorectal Lesions that was developed by the working group of the Spanish Society of Digestive Endoscopy (GSEED of Endoscopic Resection). This document presents recommendations for the endoscopic management of superficial colorectal neoplastic lesions. PMID- 29421915 TI - Esophageal motor disorders are frequent during pre and post lung transplantation. Can they influence lung rejection? AB - BACKGROUND: lung transplantation (LTx) is a viable option for most patients with end-stage lung diseases. Esophageal motor disorders (EMD) are frequent in candidates for LTx, but there is very little data about changes in esophageal motility post-LTx. AIM: the aim of our study was to assess esophageal motor disorders by high resolution manometry (HRM) both pre-LTx and six months post-LTx in patients with and without organ rejection. STUDY: HRM (Manoscan(r)) was performed in 57 patients both pre-LTx and six months post-LTx. HRM plots were analyzed according to the Chicago classification 3.0. RESULTS: EMD were found in 33.3% and in 49.1% of patients pre-LTx and post-LTx, respectively, and abnormal peristalsis was more frequently found post-LTx (p = 0.018). Hypercontractile esophagus was frequently found post-LTx (1.8% and 19.3% pre-LTx and post-LTx, respectively). Esophagogastric junction (EGJ) morphology changed significantly pre-LTx and post-LTx; type I (normal) was more frequent post-LTx (63-2% and 82.5% respectively, p = 0.007). EMD were more frequent post-LTx in both the non rejection and rejection group, although particularly in the rejection group (43.2% and 69.2% respectively, p = 0.09). EMD such as distal spasm, hypercontractile esophagus and EGJ outflow obstruction were also observed more frequently post-LTx in the rejection group. CONCLUSION: significant changes in esophageal motility were observed pre-LTx and particularly post-LTx; hypercontractile esophagus was a frequent EMD found post-LTx. EMD were more frequent in the group of patients that experienced organ rejection compared to the non-rejection group. EMD leading to an impaired esophageal clearance should be considered as an additional factor that contributes to LTx failure. PMID- 29421914 TI - The safety of deep sedation with propofol controlled by the endoscopist in endoscopic retrograde cholangiopancreatography (ERCP): a prospective study in a tertiary hospital. AB - INTRODUCTION: propofol administered by an endoscopist with a trained nurse has evolved as an alternative to anesthesia monitoring and is increasingly common in the routine clinical practice, even in advanced endoscopy. OBJECTIVE: to evaluate the safety of deep sedation with endoscopist-controlled propofol in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). MATERIAL AND METHODS: this was a prospective study in patients undergoing ERCP under deep sedation with propofol. Different patient-related variables were included and the initial and final data on oxygen saturation (SatO2), blood pressure (BP) and heart rate (HR) were recorded in order to determine the presence of adverse events due to sedation (hypoxemia, hypotension, or bradycardia). RESULTS: a total of 661 patients underwent ERCP under sedation with propofol over a 24-month period. The rate of recorded adverse events was 9.7%. The most frequent adverse event was hypoxemia (5.7%), followed by bradycardia (2.4%) and hypotension (1.6%). According to the univariate analysis, the occurrence of adverse events due to sedation (AES) was associated with an ASA score >= III (p = 0.026), older patients (p = 0.009), higher body mass index (BMI) (p = 0.002) and a longer exploration time (p = 0.034). The induction dose of propofol was also associated with a greater likelihood of adverse events (p = 0.045) but not the total dose of propofol administered (p = 0.153). According to the multivariate logistic regression analysis, age, body mass index (BMI) and the duration of the exploration were independent predictors of SAE (p < 0.05). CONCLUSION: deep sedation with propofol controlled by trained endoscopy staff is a safe method in complex endoscopic procedures such as ERCP. PMID- 29421916 TI - A prospective, controlled assessment of the technical characteristics of a novel forward-viewing echoendoscope. AB - INTRODUCTION: endoscopic ultrasound (EUS) is a highly useful technique for the diagnosis and management of different gastrointestinal (GI) tract conditions. OBJECTIVE: to prospectively assess the clinical usefulness of a novel forward viewing echoendoscope (FV-CLA). METHODS: this was a cross-sectional observational study. All patients that underwent EUS over a two-month period were considered for the study. All mediastinal, perigastric and periduodenal stations were consistently assessed with a rating from 0 to 10 points with regard to the ease to obtain ultrasonographic sections and the quality of ultrasound images. The identified lesions were punctured when clinically indicated. RESULTS: a total of 45 patients were included. EUS was completed in 100% of patients, with two minor complications recorded. Echoendoscope maneuverability was graded as "A" (9-10 points), overall plane visibility was graded as "B" (7-8 points) and only stations 4L and 5 visualization were graded as "D" (< 7 points). Visualization of the pancreas and the rest of the EUS stations were rated as excellent or very good. The feasibility to perform EUS-FNA, even from the second portion of the duodenum, was graded excellent or very good. CONCLUSION: the FV-CLA allows a complete, high-quality examination of the upper GI tract, including EUS-FNA punctures. Some mediastinal stations are hardly accessible with this new device. A formal validation of the FV-CLA for EUS-guided therapy would be of interest. PMID- 29421917 TI - A Dieulafoy's lesion in a duodenal diverticulum. An infrequent cause of UGIB. AB - We present the case of an 82-year-old man with a history of heart failure, mitral regurgitation, type 2 DM, hypertension, dilated cardiomyopathy and a paroxysmal atrial flutter. The patient was under treatment with Sintrom. The patient presented to the emergency department due to melenic depositions of a one day evolution and dietary vomiting. There was no rectal bleeding and the patient was admitted three months previously due to self-limited melena with a normal gastroscopy. Anemia of 8 g and an overdose of Sintrom was diagnosed. A gastroscopy was performed and a large duodenal diverticulum with a fresh clot was found that was washed. A Dieulafoy lesion was subsequently found underneath with jet bleeding, which was sclerotic with adrenaline and a hemoclip. There was a favorable evolution after correcting the coagulopathy. PMID- 29421918 TI - Author's reply: Cystic pancreatic neuroendocrine tumors. A diagnostic challenge. AB - We are grateful for the helpful comments of Varas et al. with regard to the phenotype of cystic pancreatic neuroendocrine tumors (CPNT) reported in a recent meta-analysis of 436 patients. Varas et al. highlight the lower incidence of CPNT diagnosed incidentally in 135 patients (44.6%) in comparison with a recent series of 49 patients with an incidental tumor diagnosis of 56.5%. PMID- 29421919 TI - Late migration of a metal stent after EUS-drainage of a pancreatic pseudocyst abscess. AB - Endoscopic ultrasound (EUS)-guided drainage of pancreatic collections has replaced surgery as the first line of treatment due its accuracy and safety profile. A higher success rate and fewer adverse events has been observed using fully covered metal stent for the drainage. However, complications of EUS-guided drainage can appear. We present a case of late migration of the stent. PMID- 29421920 TI - Legacy Beliefs Across Generations: Comparing Views of Older Parents and Their Adult Children. AB - This mixed-methods study examined legacy beliefs (i.e., anticipated remembrances and linkages to the self after death) as understood in 14 older parent and adult child pairs. This work validates and expands on a 2005 typology of legacy beliefs from gerontologists, Elizabeth Hunter and Graham Rowles. A structured interview was administered separately to parents and children, coded for legacy examples (i.e., those unique to the parent, overlapping, unique to the child), and analyzed with respect to expectations of similarity reported by each participant. Most predicted moderate to high overlap in mutual understanding of parent legacy. This was not the case, as there were far more unique legacy examples given than shared. Pairs agreed least with respect to material legacies, with half showing no agreement. All reported finding the structured discussion of legacy to be beneficial, with some indicating an intention to continue these discussions further. This work may constitute a new approach to intervention. PMID- 29421921 TI - Robot-Assisted Radical Prostatectomy: A Step-by-Step Guide. AB - Radical prostatectomy remains an important means to treat prostate cancer. A major limiting factor to radical prostatectomy is short- and long-term complications, especially incontinence and sexual dysfunction. With the advent of robotic radical prostatectomy, the ability to easily evaluate technical issues with video has been realized. In this article, we present a step-by-step examination of our procedure and our results over the past 5 years. PMID- 29421922 TI - Pediatric Ureteroscopy. AB - In recent years, the incidence of nephrolithiasis in the pediatric population appears to be increasing. 1 This has placed a new emphasis on surgical management of stones in children. In the past, extracorporeal shockwave lithotripsy was the preferred management technique for stones in children. 2 More recently, though, advances in endoscopy have allowed ureteroscopy to be adapted to the pediatric population and this approach has become more frequently utilized not just for lower ureteral calculi but also for proximal ureteral and renal stones. PMID- 29421923 TI - Colletotrichine B, a new sesquiterpenoid from Colletotrichum gloeosporioides GT 7, a fungal endophyte of Uncaria rhynchophylla. AB - One new compound, colletotrichine B (1), was produced by the fungal Colletotrichum gloeosporioides GT-7. The structure of 1 was elucidated on the basis of spectroscopic analysis and X-ray crystallographic analysis. Monoamine oxidase (MAO), acetylcholinesterase (AChE) and phosphoinositide 3-kinase (PI3Kalpha) inhibitory activity of 1 was also evaluated. Compound 1 showed only AChE inhibiting activity with IC50 value of 38.0 +/- 2.67 MUg/mL. PMID- 29421924 TI - A 13-Year-Old Presenting With Recurrent Angioma Serpiginosum. AB - BACKGROUND: Angioma serpiginosum (AS) is a rare vascular abnormality consisting of proliferation and dilation of superficial blood vessels in the skin. AS typically presents in the first 2 decades of life and remains stable with time. CASE SUMMARY: We report the case of a 13-year-old female with an acquired, recurrent erythematous lesion with serpiginous borders on her left upper arm. Over several years, the lesion reappeared then disappeared 12 to 15 times. At one point, she developed a tender red nodule within the lesion; consequently, a biopsy was taken, revealing dilated telangiectatic vessels in the dermal papillae with mild, focal extravasation of erythrocytes. CONCLUSION: This case demonstrates a lesion with suggestive clinical and histological features of AS. However, this may be the first case of recurrent AS with a symptomatic episode. This case may contribute to the expanding clinical spectrum of this interesting disease entity. PMID- 29421925 TI - Pediatric Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Halted by Etanercept. AB - We report a case of an 11-year-old female with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) overlap, most likely triggered by sulfamethoxazole-trimethoprim, who was treated with the combination of methylprednisolone, cyclosporine, and etanercept. Her condition stabilized and her skin involvement did not progress after the addition of etanercept. To our knowledge, this is the first report of etanercept for pediatric SJS/TEN. PMID- 29421926 TI - Hydration requirements with emetogenic chemotherapy: granisetron extended-release subcutaneous versus palonosetron. AB - AIM: This retrospective analysis evaluated chemotherapy-induced nausea and vomiting (CINV)-related hydration needs with palonosetron or granisetron extended release subcutaneous (GERSC), approved in 2016 for CINV prevention. MATERIALS & METHODS: At a community practice, CINV-related hydration per chemotherapy cycle was determined following highly (HEC) or moderately emetogenic chemotherapy (MEC) and a guideline-recommended antiemetic regimen: NK-1 receptor antagonist, dexamethasone and either palonosetron only, GERSC only, or palonosetron switched to GERSC. RESULTS: Palonosetron-only patients (n = 93) had a significantly higher mean (standard deviation) hydration rate (0.9 [1.1]) than GERSC-only patients (n = 91; 0.3 [0.6]; p < 0.0001). Switched patients' (n = 48) hydration rates were significantly higher in the HEC subgroup with palonosetron (0.7 [1.2]) versus GERSC (0.5 [1.0]; p = 0.028). CONCLUSION: GERSC in a three-drug antiemetic regimen may reduce hydration needs following HEC or MEC. [Formula: see text]. PMID- 29421927 TI - Twin gestation in a Swyer syndrome patient with superimposed pre-eclampsia. PMID- 29421928 TI - A case of partial hydatidiform molar pregnancy with a placental diploid-triploid mosaicism associated with a euploid viable foetus complicated with severe pre eclampsia. PMID- 29421929 TI - Drug evaluation studies in neonates: how to overcome the current limitations. AB - INTRODUCTION: Regulatory initiatives have stimulated drug research in infants, but the potential impact of drugs to improve health outcome in neonates remains underexplored. Areas covered: In this review, we focus on current limitations in drug evaluation studies and how to overcome these. The low volume of studies has additional weaknesses such as single center studies, non-commercial sponsorship, overrepresentation of high postulated risk reductions, and underrepresentation of therapeutic exploratory studies. Master protocols and selection criteria for neonatal centers to participate in studies are useful to improve logistics related to performance. Limitations also relate to inaccurate assessment of drug effects (efficacy/safety). This is because of poor symptom recognition, case definitions, and suboptimal data on adverse drug reactions (ADRs) epidemiology. To overcome these limitations, it is necessary to develop core outcome sets, reference values, and specific ADR tools. The limitations identified and approaches suggested to improve drug evaluation are illustrated using neonatal abstinence syndrome as an example. Expert commentary: We anticipate to see an evolving neonatal clinical pharmacology discipline driven by neonatal pathophysiology and knowledge. Multidisciplinary collaborative efforts between health care providers, academia, pharmaceutical industry, advocacy groups and regulatory agencies are crucial to improve the impact of drug evaluation studies in neonates. PMID- 29421930 TI - Research and development of anti-Alzheimer's disease drugs: an update from the perspective of technology flows. AB - INTRODUCTION: Today, over 20 million people suffer from Alzheimer's disease (AD) worldwide. AD has become a critical issue to human health, especially in aging societies, and therefore it is a research hotspot in the global scientific community. The technology flow method differs from traditional reviews generating an informative overview of the research and development (R&D) landscape in a specific technological area. We need such an updated method to get a general overview of the R&D of anti-AD drugs in light of the dramatic developments in this area in recent years. Areas covered: This study collects patent data from the Integrity database. A total of 399 patents with 821 internal citation pairs in the US from 1978 to 2017 were analyzed. Patent citation network analysis was used to visualize the technology relationship. Expert opinion: For better production of anti-AD drugs, governments should emphasize the multi-target drug design, provide policy support for private companies, and encourage multilateral cooperation. The beta-amyloid peptide (Abeta) theory leaves much to be desired; neurotransmitter and tau protein hypotheses are worth further examination. The use of old drugs for new indications is promising, as are traditional herbal medicines. PMID- 29421931 TI - Haematocolpos caused by a large vulvar dermoid cyst complicating type Ib female circumcision. PMID- 29421933 TI - Predictors for choledocholitiasis in patients undergoing endoscopic ultrasound. AB - AIM: Biliary lithiasis is common in most western countries. Symptomatic patients will also have choledocholithiasis in 10% of the cases. For patients with intermediate probability of CBD stones, the recommended imaging studies are endoscopic ultrasound (EUS) or MRCP. This study aims to identify early factors that can be used as predictors for the presence of CBD stones, and by that to find which patient should undergo ERCP without an early EUS. METHODS: This is a retrospective cohort study including all patients who underwent EUS for suspected choledocholithiasis at the Soroka University Medical Center (SUMC) in the years 2009-2014. Data collection was performed by manual surveillance of patients' computerized files and data gathering after approval by the Soroka Institutional Review Board Results: One hundred seventy-five (175) patients were included in the study. The average age was 57, and 111 patients were women (64.2%). Sixty-two patients (35%) had common bile duct stones by EUS and underwent an ERCP. Eighty two percent of those 62 patients were found to have CBD stones at ERCP. Patients found positive for CBD stones by EUS were older than those who were negative (52 vs. 71 respectively, p < .001). These patients were also found to have a higher prevalence of ischemic heart disease and congestive heart failure. Common bile duct dilatation >=8mm and gallstones presence in abdominal ultrasonography were more common in patients found positive for CBD stones by EUS than in those who were found negative (45% vs. 24% p < .05, and 81% vs. 66% p < .05, respectively). Alkaline phosphatase (ALP) serum levels higher than 300 IU/L were found to be the only independent predictor for the existence of CBD stones (OR = 2.98, p = .001(. When ALP serum levels lower than 150 IU/L or GGT lower than 150 IU/L were measured, the probability of having CBD stones was low (NPV of 90% and 87%, respectively). CONCLUSIONS: ALP serum levels higher than 300 IU/L are an independent predictor for the presence of CBD stones. EUS is an excellent screening tool for choledocholithiasis before performing ERCP. In most patients who undergo an early EUS, a subsequent diagnostic ERCP will not be needed. PMID- 29421934 TI - Questioning diagnoses in clinical practice: a thematic analysis of clinical psychologists' accounts of working beyond diagnosis in the United Kingdom. AB - BACKGROUND: The British Psychological Society proposes that clinical psychologists are well placed to move beyond psychiatric diagnoses and develop alternative practices. AIMS: This study sought to explore what the application of these guiding principles looks like in clinical practice, the challenges faced and possible routes forward. METHODS: A purpose-designed survey was completed by 305 respondents and a thematic analysis completed. RESULTS: Thematic analysis was used to identify five superordinate themes relating to individuals, relational, others, structures and society, comprising of a total of 21 group themes. The presented group themes highlight an array of approaches to practicing beyond diagnosis and factors that help and hinder such action; from scaffolding change, becoming leaders, relating to the multi-disciplinary team, restructuring services and the processes of change. A key concept was "playing the diagnostic game". CONCLUSIONS: "Playing the diagnostic game" enables psychologists to manage an array of tensions and anxieties: conflicts between belief and practice, relationships with colleagues, and dilemmas of position and power. It also potentially limits a concerted questioning of diagnosis and consideration of alternatives. An alternative conceptual framework for non-diagnostic practice is needed to aid the collective efforts of clinical psychologists developing their practice beyond diagnosis, some of which have been highlighted in this study. Until then, ways of mitigating the perceived threats to questioning diagnosis need further exploration, theorising and backing. PMID- 29421932 TI - The 70-kDa heat shock protein (Hsp70) as a therapeutic target for stroke. AB - INTRODUCTION: The 70-kDa heat shock protein (Hsp70) is a cytosolic chaperone which facilitates protein folding, degradation, complex assembly, and translocation. Following stroke, these functions have the potential to lead to cytoprotection, and this has been demonstrated using genetic mutant models, direct gene transfer or the induction of Hsp70 via heat stress, approaches which limit its translational utility. Recently, the investigation of Hsp70-inducing pharmacological compounds, which, through their ability to inhibit Hsp90, has obvious clinical implications in terms of potential therapies to mitigate cell death and inflammation, and lead to neuroprotection from brain injury. Areas covered: In this review, we will focus on the role of Hsp70 in cell death and inflammation, and the current literature surrounding the pharmacological induction in acute ischemic stroke models with comments on potential applications at the clinical level. Expert opinion: Such neuroprotectants could be used to synergistically improve neurological outcome or to extend the time window of existing interventions, thus increasing the numbers of stroke victims eligible for treatment. PMID- 29421935 TI - The effect of catalase C262T gene polymorphism in susceptibility to ovarian cancer in Kermanshah province, Western Iran. AB - Ovarian cancer has a heterogeneous biology and behaviour. Oxidative stress can initiate chronic inflammation, which can sequentially facilitate chronic diseases, including cancer. Oxidative stress may arise when there is extra reactive oxygen species (ROS) production and/or inadequate defence mechanisms. There are some antioxidant defences that can fight against oxidative damage, including catalase (CAT) enzyme. We sought to evaluate the association of CAT C262T gene polymorphism with increased risk of ovarian cancer. A total of 74 paraffin-embedded ovarian cancer blocks were taken from the archive of Imam-Reza Hospital, Kermanshah University of Medical Sciences, between 2010 and 2014. Also, 153 blood samples were harvested from healthy volunteers. For genotyping of CAT C262T, we designed allele-specific polymerase chain reaction (AS-PCR). 'T' allele of CAT C262T showed a protective effect against the risk of ovarian cancer [OR = 0.4 (95% CI 0.25-0.6), p value <.001]. Calculating adjusted odds ratio showed the distribution of alleles and genotypes was not affected by age. The present study reported a significant association between the distribution of CAT C262T gene polymorphism and ovarian cancer for the first time in a sample of the Iranian population. Impact Statement What is already known on this subject: Ovarian cancer has a heterogeneous biology and behaviour at the clinical, cellular and molecular aspects. Ovulation releases follicular fluid containing reactive oxygen species which is related to changes in the microenvironment, such as inflammation, that could be a factor in early ovarian carcinogenesis. There are some antioxidant defences that can protect cells against oxidative damage, including catalase (CAT). Different studies investigated the relationships between CAT C262T polymorphism and several diseases. Belotte et al. ( 2015 ), for the first time, indicated no significant association between CAT C262T and the risk of ovarian cancer, while they showed this SNP is associated with poor survival and therefore may serve as a prognostic factor for ovarian cancer. What the results of this study add: In the present study, 'T' allele of CAT C262T showed a protective effect against the risk of ovarian cancer. Calculating adjusted odds ratio showed that the distribution of alleles and genotypes is not affected by age. What the implications are of these findings for clinical practice and/or further research: Pair-wise genetic analyses using SNPSTATS software showed that this genotyping was more compatible with recessive models, i.e. two copies of the associated variant are required to increase the risk of ovarian cancer. Further research about other antioxidant genes in a larger population is needed to predict the risk of ovarian cancer and survival rate of patients. PMID- 29421937 TI - Engaging Caregivers During Hospitalizations to Improve Hospital Transitions: The CARE Act. PMID- 29421938 TI - Uncertainty of Parents With Children Undergoing Herniorrhaphy. AB - This study reports the association between parental uncertainty and characteristics of 123 parent-child dyads prior to the child's herniorrhaphy. A cross-sectional study design and Mishel's Parents' Perception of Uncertainty Scale (PPUS) were used. Parent participants were married (98%), had a university degree (45%), identified with a religion (77%), and worked (69%). More boys (76%) than girls (23%) underwent herniorrhaphy (average age = 2.26 years); 60% were the first-born child and 25% were premature. More children presented with unilateral (63.4%; right = 44.7%, left = 18.7%) than bilateral (36.6%) hernias and most were primary (98%). Overall uncertainty was perceived as moderate and ambiguity had the highest score. Religion, birth order (first child), and hernia site (bilateral) explained 20.6% of total variance of uncertainty. Providing information about postoperative symptom and pain management is important for all parents, particularly for parents identified with a religion and whose first-born child had bilateral hernias. PMID- 29421939 TI - Social Support for Female Sexual Dysfunction in Fibromyalgia. AB - The aim of this study is to describe and understand experiences related to social support for women with fibromyalgia who suffer from sexual dysfunction. An interpretive qualitative research methodology based on Gadamer's philosophical hermeneutics was used. Data collection included a focus group and in-depth interviews with 13 women who averaged 44.8 years of age and 14.3 years since being diagnosed with fibromyalgia. Data were analyzed using Fleming's method and two themes were identified: "searching for understanding in socio-family support" and "lack of formal support regarding fibromyalgia patient's sexuality." The partner constitutes the main support for women with fibromyalgia. Although they can find understanding and social support in patient associations, they lack formal support from health care professionals. Women demand trusted and expert professionals, like sexologists and nurses, to carry out a multidisciplinary approach to tackle sexual dysfunction associated with fibromyalgia. PMID- 29421936 TI - Cardiorenal Safety of OTC Analgesics. AB - Over-the-counter analgesics are used globally for the relief of acute pain. Although effective, these agents can be associated with adverse effects that may limit their use in some people. In the early 2000s, observations from clinical trials of prescription-strength and supratherapeutic doses of nonselective and cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) raised safety concerns regarding the risk of cardiovascular adverse effects with the use of these medications. Subsequently, the US Food and Drug Administration mandated additional study of the cardiovascular safety of NSAIDs for a more comprehensive understanding of their risk. As these data were being collected, and based on a comprehensive review of prescription data and the recommendations of the US Food and Drug Administration Advisory Committee, the warning labels of over-the counter NSAIDs were updated to emphasize the potential cardiovascular risks of these agents. The recently reported "Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen" (PRECISION) trial, in which participants with osteoarthritis or rheumatoid arthritis and underlying cardiovascular risk factors were treated with prescription-strength celecoxib, ibuprofen, or naproxen, revealed similar rates of cardiovascular events (death from cardiovascular causes including hemorrhagic death, nonfatal myocardial infarction, or nonfatal stroke) among the 3 treatment groups. Although informative, the cardiovascular safety findings derived from PRECISION cannot be extrapolated to the safety of the over-the-counter pain relievers ibuprofen and naproxen, given that the doses used were higher (mean [standard deviation]: ibuprofen, 2045 [246] mg; naproxen, 852 [103] mg) and the durations of use longer (~20 months) than recommended with over-the-counter use of NSAIDs, which for ibuprofen is up to 10 days. This review discusses the cardiorenal safety of the most commonly used over-the-counter analgesics, ibuprofen, naproxen, and acetaminophen. Available data suggest that there is little cardiovascular risk when over-the-counter formulations of these agents are used as directed in their labels. PMID- 29421940 TI - Andrographolide engineered gold nanoparticle to overcome drug resistant visceral leishmaniasis. AB - Visceral leishmaniasis (VL) is World Health Organization designated most serious leishmaniasis with an annual mortality rate of 50,000. Even after country specific eradication programs, the disease continues to multiply with added complexities like resistance development, drug hypersensitivity and associated infections. Newer therapeutic interventions are urgently warranted to control the spread. Present study aims to arrive at terpenoid andrographolide engineered gold nanoparticle (AGAunps) facile synthesis and its efficacy evaluations against wild and drug resistant VL strains for the first time. Molecular bio-organic conjugation of AGAunp was confirmed in FT-IR and EDAX studies. Nano-gold plasmon response was recorded at 543 nm and the average size in TEM was 14 nm. SAED pattern and XRD observations proved fcc crystalline structure of nano-gold. AGAunp recorded spherical geometry in AFM and TEM. PDI value of 0.137 revealed the monodisperse nature of the nano-scale population. AGAunp exhibited strong antileishmanicidal effect both against wild type (IC50 19 +/- 1.7 uM) and sodium stibogluconate (IC50 55 +/- 7.3 uM)/paromomycin (IC50 41 +/- 6 uM) resistant strains. Complete macrophage uptake AGAunp's occured within two hours exposure. AGAunp macrophage cytotoxicity was significantly lower as compared to Amphotericin-B. Low toxic Andrographolide engineered gold nanoparticle emerged as promising alternatives in the control of wild and drug resistant VL. PMID- 29421941 TI - Zinc-dependent and independent actions of hydroxyhydroquinone on rat thymic lymphocytes. AB - Coffee contains hydroxyhydroquinone (HHQ). HHQ is one of the by-products released during bean roasting. Therefore, it is important to elucidate the bioactivity of HHQ to predict its beneficial or adverse effects on humans. We studied zinc dependent and independent actions of commercially procured synthetic HHQ in rat thymocytes using flow cytometric techniques with propidium iodide, FluoZin-3-AM, 5-chloromethylfluorescein diacetate, and annexin V-FITC. HHQ at 1050 uM elevated intracellular Zn2+ levels by releasing intracellular Zn2+. HHQ at 10 uM increased cellular thiol content in a zinc-dependent manner. However, HHQ at 30-50 uM reduced cellular thiol content. Although the latter actions of HHQ (30-50 uM) were suggested to increase cell vulnerability to oxidative stress, HHQ at 0.3-100 uM significantly protected cells against oxidative stress induced by H2O2. The process of cell death induced by H2O2 was delayed by HHQ, although both H2O2 and HHQ increased the population of annexin V-positive living cells. However, HHQ at 10-30 uM promoted cell death induced by A23187, a calcium ionophore. HHQ at 10-30 uM exerted contrasting effects on cell death caused by oxidative stress and Ca2+ overload. Because HHQ is considered to possess diverse cellular actions, coffee with reduced amount of HHQ may be preferable to avoid potential adverse effects. PMID- 29421942 TI - Autonomous motivation and quality of life as predictors of physical activity in patients with schizophrenia. AB - AIM: Being physically active is a complex behaviour in patients with schizophrenia. Several factors were identified as barriers to achieving active behaviours in this population. Therefore, the purpose of this study was to investigate among a number of barriers what predicts the most on physical activity (PA) in patients with schizophrenia. METHODS: A total of 114 patients (28?) with schizophrenia were included. Body mass index (BMI) was calculated. Autonomous and controlled motivation (Behavioural Regulation in Exercise Questionnaire - 3), self-esteem (Rosenberg Self-esteem scale), quality of life (World Health Organization Quality of Life Scale - Brief version) and functional exercise capacity (6-minute walk test - 6MWT) were evaluated. Multiple Regression Analysis was applied to assess the effect of these variables on Total PA per week (International Physical Activity Questionnaire - short version). RESULTS: Autonomous motivation and domains of quality of life were positively correlated with Total PA per week. Stepwise multiple regression analyses showed that of all the candidate factors to predict PA, autonomous motivation and global domain of quality of life were found as significant predictors. CONCLUSION: Our findings help to understand the importance of autonomous motivation and quality of life for PA in patients with schizophrenia. Knowledge about these predictors may provide guidance to improve PA behaviour in this population. PMID- 29421943 TI - Re-education begins at home: an overview of the discovery of in vivo-active small molecule modulators of endogenous stem cells. AB - INTRODUCTION: Degenerative diseases, such as Alzheimer's disease, heart disease and arthritis cause great suffering and are major socioeconomic burdens. An attractive treatment approach is stem cell transplantation to regenerate damaged or destroyed tissues. However, this can be problematic. For example, donor cells may not functionally integrate into the host tissue. An alternative methodology is to deliver bioactive agents, such as small molecules, directly into the diseased tissue to enhance the regenerative potential of endogenous stem cells. Areas covered: In this review, the authors discuss the necessity of developing these small molecules to treat degenerative diseases and survey progress in their application as therapeutics. They describe both the successes and caveats of developing small molecules that target endogenous stem cells to induce tissue regeneration. This article is based on literature searches which encompass databases for biomedical research and clinical trials. These small molecules are also categorized per their target disease and mechanism of action. Expert opinion: The development of small molecules targeting endogenous stem cells is a high-profile research area. Some compounds have made the successful transition to the clinic. Novel approaches, such as modulating the stem cell niche or targeted delivery to disease sites, should increase the likelihood of future successes in this field. PMID- 29421944 TI - Metabolomic evaluation of Euphorbia pekinensis induced nephrotoxicity in rats. AB - CONTEXT: Euphorbia pekinensis Rupr. (Euphorbiaceae) has long been used in the Orient, while its clinical use was limited due to its nephrotoxic effect. OBJECTIVE: The possible mechanism of nephrotoxicity of Euphorbia pekinensis (EPR) and its related constituents were investigated. MATERIALS AND METHODS: Petroleum ether (PE), acetic ether (AE) and n-butanol (BUT) extracted sections of EPR were separately given to Wistar rats by gavage at the dose of 3 g/kg/day for 10 weeks to determine the nephrotoxic section of EPR. Then, renal metabolic profiling of EPR after oral administration of nephrotoxic section was investigated and its related constituents were identified by LC/Q-TOF-MS method. RESULTS: The average values of creatinine (CREA) in PE, AE, BUT and control groups were 76.54 +/- 9.52, 54.12 +/- 10.34, 51.33 +/- 5.19 and 48.23 +/- 6.67 MUmol/L. The average values of blood urea nitrogen (BUN) in PE, AE, BUT and control groups were 15.25 +/- 3.37, 8.32 +/- 0.89, 9.22 +/- 1.78 and 8.47 +/- 1.33 mmol/L, respectively. Only kidney section of rats in PE group showed that glomeruli had cellular or fibrocellular crescents. Renal metabolic profiling showed disturbed metabolic pathways of purine, amino acid, phospholipids and sphingolipids in EPR nephrotoxicity. A total of 25 compounds [(-)-(1S)-15-hydroxy-18-carboxycembrene is a new compound] in PE section and 10 compounds in rat serum after administration of PE section were identified. CONCLUSIONS: This is the first time that the toxic compounds of PER and action mechanism of EPR nephrotoxicity were explored to provide a new reference for studying the toxic components of Traditional Chinese Medicine (TCM). PMID- 29421945 TI - Cytotoxicity of acetylcholinesterase reactivators evaluated in vitro and its relation to their structure. AB - The development of acetylcholinesterase reactivators, i.e., antidotes against organophosphorus poisoning, is an important goal of defense research. The aim of this study was to compare cytotoxicity and chemical structure of five currently available oximes (pralidoxime, trimedoxime, obidoxime, methoxime, and asoxime) together with four perspective oximes from K-series (K027, K074, K075, and K203). The cytotoxicity of tested substances was measured using two methods - colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay and impedance based real-time cytotoxicity assay - in three different cell lines (HepG2, ACHN, and NHLF). Toxicity was subsequently expressed as toxicological index IC50. The tested compounds showed different cytotoxicity ranging from 0.92 to 40.06 mM. In HepG2 cells, K027 was the least and asoxime was the most toxic reactivator. In ACHN and NHLF cell lines, trimedoxime was the compound with the lowest adverse effects, whereas the highest toxicity was found in methoxime treated cells. The results show that at least five structural features affect the reactivators' toxicity such as the number of oxime groups in the molecule, their position on pyridinium ring, the length of carbon linker, and the oxygen substitution or insertion of the double bond into the connection chain. Newly synthetized oximes with IC50 >= 1 mM evaluated in this three cell lines model might appear suitable for further testing. PMID- 29421946 TI - Methane emissions from landfill: influence of vegetation and weather conditions. AB - Vegetation plays an important role in CH4 transport and oxidation in landfill cover soil. This study investigated CH4 emission fluxes in two landfills with different surface coverage conditions and it found that the CH4 emission fluxes presented spatial and temporal disparities. A significant discrepancy in CH4 emission flux between day and night in areas covered with Kochia sieversiana indicated that enhanced diffusion induced by rising temperature was the main mechanism for CH4 transport during daytime. A significant increase of CH4 emission flux after the K. sieversiana and Suaeda glauca plants were cut indicated that these plants provide greater contributions to CH4 oxidation than to CH4 transport. Diel CH4 emission flux was found closely correlated with the climatic conditions. Diffusion was determined as the main mechanism for CH4 transport at daytime in bare area, mediated by solar radiation and air temperature. Diffusion and plant-mediated transport by convection was established as the main transport mechanism in areas covered with K. sieversiana. Our results further the understanding of both the CH4 emission mechanism and the impact of vegetation on CH4 oxidation, transport, and emission, which will benefit the development of a reliable model for landfill CH4 emissions. PMID- 29421947 TI - Population genetic structure and molecular diversity of Leucinodes orbonalis based on mitochondrial COI gene sequences. AB - Leucinodes orbonalis is a destructive pest found throughout eggplant cultivating fields of Tamil Nadu, India. The genetic diversity and its population structure were investigated in this pest using mitochondrial cytochrome c oxidase subunit I (COI) gene sequences from 20 populations of L. orbonalis collected from various agro-climatic conditions. The study indicated almost no genetic diversity among various populations. The COI nucleotide sequence based haplotype analysis also revealed no significant genetic variation among various populations. However, haplotype network analysis with three clades was nearly matching with the structure of phylogenetic analysis that showed geographical separations induced distribution of some genetic variation. The PCA and nMDS Shephard's plot analyses were also illustrated that the populations sampled were nearly matched with phylogenetic tree and haplotype network. This study on phylogeographical structure using the mitochondrial COI sequence diversity of L. orbonalis therefore suggested presence of few genetically distinct populations due to some specific habitat requirements. PMID- 29421948 TI - What is the experience of being readmitted to hospital for people 65 years and over? A review of the literature. AB - AIM: To explore the experience of readmissions to hospital from the perspective of older adults. METHODS: A systematic review with an interpretative approach was conducted. CINAHL, Embase, and Medline were consulted in October 2016. RESULTS: Six studies with data collection between 2004 and 2013 fit the relevant criteria and included a total of 68 older adults. Two overarching themes were developed with relevant subthemes: Experience during initial hospital stay distinguished by exclusion (Feeling powerless; Feeling disregarded; Perception of readiness for discharge); Patients experience uncertainty following discharge (Perception that community-based services are not available or adequate; Perception that hospital is the only safe place; Difficulty in adapting to a "new normal"). CONCLUSIONS: A cycle of exclusion exists during the initial hospital stay and beyond. The experience of being readmitted to hospital is challenging, mostly perceived as negative, and, existential, emotional and psychological well-being is not satisfactorily addressed by healthcare professionals. PMID- 29421949 TI - Sperm toxicity testing: UK best practice guideline from the Association of Biomedical Andrologists. AB - In order to ensure the quality and integrity of diagnostic semen analysis results, materials used should be tested to ensure that they do not interfere with sperm function. As a toxicity test, complex sperm function testing may be considered controversial, since the fertilizing capacity of single sperm can never be assured. In preference, sperm motility offers a unique means of assessing the toxicity of reagents and materials before they are used in routine practice. Motility is the semen parameter most likely to be influenced by the external environment. Indeed, it is the main reason that laboratories insist on supplying their own approved specimen containers and ensuring that patients, as far as possible, adhere to strict conditions for sample collection and transport prior to testing. This differs to other indirect tests of toxicity such as the mouse embryo assay, whereby the rate of mouse pre-implantation embryo development to the blastocyst stage is compared. This guideline is aimed at health care scientists who deal with andrology in both general pathology and specialised fertility laboratories, and provides a model approach to sperm toxicity testing. For assisted reproduction clinics, the same methodology can be used to test any consumables that are used for sperm processing, and as an indirect guide for any consumables that come into direct contact with oocytes and pre-implantation embryos. PMID- 29421950 TI - Current and future challenges in pediatric severe asthma. PMID- 29421951 TI - Developmental toxicity of deltamethrin and 3-phenoxybenzoic acid in embryo-larval stages of zebrafish (Danio rerio). AB - Synthetic pyrethroids are the major insecticides used widely in agriculture and household pest control. Deltamethrin (DM), a widely used type II pyrethroid insecticide, is a relatively potent neurotoxicant. 3-Phenoxybenzoic acid (PBA) is the major metabolite formed due to metabolism of DM. In order to illustrate the toxic response of zebrafish embryos/larvae to DM and PBA the present research was carried out. For this 4hpf embryos were treated with two concentrations of DM (100 and 200 MUg/L) for 48 h and PBA (1000 and 2000 MUg/L) for 96 h or 99.9% ethanol (solvent control). Early life stage parameters were observed at specified time points. DM-treated embryo/larvae exhibited increased mortality, delay in hatching time, decrease in percentage of hatched embryos, increase of heartbeat rate and decrease in blood flow; lightening of body and eye pigmentation in a dose dependent manner. Pericardial and yolk sac edema along with were also caused by DM. Along with these crooked notochord, tail deformation was noticed in hatched and unhatched embryos. In case of PBA treated embryos and larvae, increased embryos/larvae length and yolk sac size were observed. Other abnormalities like edema (yolk sac and pericardial), decreased eye and body pigmentation were also observed but in some embryos only. These were not as severe as observed in parental compound indicating that DM is more toxic than its metabolite PBA. The data contributes to a better understanding of the potential consequences of fish exposed to DM and PBA. PMID- 29421952 TI - Covalent immobilization of phytase on the multi-walled carbon nanotubes via diimide-activated amidation: structural and stability study. AB - Phytase is the most widely used feed enzyme in the world. This enzyme inactivates under pelleting conditions such as temperatures above 80 degrees C. The present study reported covalent attachment of phytase onto functionalized multi-walled carbon nanotubes (F-MWNT). The optimum enzyme loading and immobilization efficiency were 110 ug/mg of functionalized multi-walled carbon nanotubes and 62%, respectively. Characterization, structural changes and immobilization of phytase were studied by scanning electron microscopy (SEM), circular dichroism (CD), zeta potential measurement and Fourier transform infrared (FTIR) spectroscopy. Immobilized phytase exhibited improved stability towards temperature than the free phytase. The free phytase retain 3% and 27% of relative activity at 90 and 80 degrees C, respectively after 2 min of incubations. While immobilized phytase retained about 33% and 51% at the same condition. Also the results showed that the presence of small quantities of NaCl (<1 M) in the reaction media increased enzyme activity of immobilized phytase up to 78% but free phytase activity was not significantly changed until 1 M NaCl which increased by 30%. Higher concentrations of 1 M NaCl drastically reduced both free and immobilized phytase activities. PMID- 29421953 TI - Using Community Engagement and Navigators to Increase Colon Cancer Screening and Patient Outcomes. AB - A theory-driven tailored intervention developed in partnership with the community used evidence-based practices to (a) increase knowledge about colon cancer and screening and (b) assist patients in completing screenings. During the 16 months of delivery screening, patient navigators integrated into gastroenterology clinics met all goals, which included (a) enrolling an ethnically diverse group of participants ( N = 415) through inreach (clinic-referred patients who did not schedule appointments) and community outreach, (b) facilitating screening completions for 217 of the 358 (61%) patients identified as needing screening, and (c) obtaining satisfaction ratings from 89% of participants. A random sample ( N = 214) of nonnavigated patients matched on gender and age revealed no differences between navigated and nonnavigated patients on polyps detected. Navigated males (but not females) were significantly less likely than nonnavigated males to have either poor or only fair bowel preparation quality (odds ratio = .418, p = .020, 95% confidence interval [.197, .885]). Low-quality bowel preparation can lead to incomplete readings of the colon or cancelling a colonoscopy. This intervention demonstrates that evidence-based patient navigator programs are effective in increasing screening among a hard-to-reach population and improving bowel preparation quality for males. PMID- 29421954 TI - Combinatorial peptide library screening for discovery of diverse alpha glucosidase inhibitors using molecular dynamics simulations and binary QSAR models. AB - Human alpha-glucosidase is an enzyme involved in the catalytic cleavage of the glucoside bond and involved in numerous functionalities of the organism, as well as in the insurgence of diabetes mellitus 2 and obesity. Thus, developing chemicals that inhibit this enzyme is a promising approach for the treatment of several pathologies. Small peptides such as di- and tri-peptides may be in natural organism as well as in the GI tract in high concentration, coming from the digestive process of meat, wheat and milk proteins. In this work, we reported the first tentative hierarchical structure-based virtual screening of peptides for human alpha-glucosidase. The goal of this work is to discover novel and diverse lead compounds that my act as inhibitors of alpha-glucosidase such as small peptides by performing a computer aided virtual screening and to find novel scaffolds for further development. Thus, in order to select novel candidates with original structure we performed molecular dynamics (MD) simulations among the 12 top-ranked peptides taking as comparison the MD simulations performed on crystallographic inhibitor acarbose. The compounds with the lower RMSD variability during the MD, were reserved for in vitro biological assay. The selected 4 promising structures were prepared on solid phase peptide synthesis and used for the inhibitory assay, among them compound 2 showed good inhibitory activity, which validated our method as an original strategy to discover novel peptide inhibitors. Moreover, pharmacokinetic profile predictions of these 4 peptides were also carried out with binary QSAR models using MetaCore/MetaDrug applications. PMID- 29421955 TI - Serum S100 calcium binding protein A4 (S100A4, metatasin) as a diagnostic and prognostic biomarker in epithelial ovarian cancer. PMID- 29421956 TI - Olive mill wastewater pretreatment by combination of filtration on olive stone filters and coagulation-flocculation. AB - In the present study a new combined process, comprising filtration of raw olive mill wastewater (OMWW) on two successive olive stone (OS) filters followed by a coagulation-flocculation, was developed in order to perform an efficient pretreatment of OMWW. The results show that the use of OS filter leads to a higher removal of total suspended solids (TSS) and fatty matter (FM) from the raw OMWW (about 82.5% and 73.8%, respectively) and a depletion of total phenolic compounds (TP) and chemical oxygen demand (COD) (11.3% and 23.2%, respectively). The coagulation-flocculation was then applied to improve the removal of TP and COD from the filtered OMWW. For this purpose, a full-factorial design was used to study the effect of different factors involved in coagulation-flocculation. The studied variables were: pH (5-8), coagulant type (ferric chloride; FC and aluminum sulfate; AS), coagulant concentration (250-1000 mg/L) and flocculant (Anionique polyelectrolyte Superfloc A120 PWG) concentration (1-5 mg/L). The results reveal that the use of 250 mg/L FC and 5 mg/L flocculant at an acid pH (around 5) allows for, respectively, a removal of TP and COD of about 10.8% and 31.3%. PMID- 29421957 TI - Neurologic Involvement in Primary Immunodeficiency Disorders. AB - The nervous system may be affected in primary immune deficiency (PID) syndromes through infectious, autoimmune, neoplastic mechanisms, or as a primary feature of the syndrome. However certain neurologic problems do not conform to these etiopathogenetic groups. We retrospectively examined PID patients seen in neurology consultation between 2014 and 2017 in order to determine the spectrum of nervous system involvement. Among patients with confirmed neurologic problems (n = 35), common manifestations were encephalopathy and global developmental/cognitive delay. In 13 (37%) instances, the neurologic signs had no apparent relation with a treatment-related, infectious, or vascular complication and were considered as primary findings: acquired microcephaly, central nervous system malformation, or peripheral neuropathy. The diagnosis of PID was made after, and based on, the neurologic manifestation in 6 of 35 (17%) patients. Neurologic presentation may constitute the initial manifestation in some types of primary immune deficiency. PMID- 29421958 TI - Treating childhood traumatic brain injury with autologous stem cell therapy. AB - INTRODUCTION: Neonatal traumatic brain injury (TBI) is a significant cause of developmental disorders. Autologous stem cell therapy may enhance neonatal brain plasticity towards repair of the injured neonatal brain. Areas covered: The endogenous neonatal anti-inflammatory response can be enhanced through the delivery of anti-inflammatory agents. Stem cell therapy stands as a robust approach for sequestering the inflammation-induced cell death in the injured brain. Here, we discuss the use of umbilical cord blood cells and bone marrow stromal cells for acute and chronic treatment of experimental neonatal TBI. Autologous stem cell transplantation may dampen neuroinflammation. Clinical translation of this stem cell therapy will require identifying the therapeutic window post-injury and harvesting ample supply of transplantable autologous stem cells. Stem cell banking of cryopreserved cells may allow readily available transplantable cells and circumvent the unpredictable nature of neonatal TBI. Harnessing the anti-inflammatory properties of stem cells is key in combating the progressive neurodegeneration after the initial injury. Expert opinion: Combination treatments, such as with hypothermia, may enhance the therapeutic effects of stem cells. Stem cell therapy has immense potential as a stand-alone or adjunctive therapy for treating neuroinflammation associated with neonatal TBI acutely and for preventing further progression of the injury. PMID- 29421960 TI - Letter to the Editor regarding the article 'Left atrial volume index in patients with heart failure and severely impaired left ventricular systolic function: the role of established echocardiographic parameters, circulating cystatin C and galectin-3' by Zivlas et al. (2017). PMID- 29421959 TI - Accelerated ambulation after vascular access closure device. AB - BACKGROUND: Patients who are candidates to receive an Angioseal(r) (St. Jude Medical) device for arteriotomy closure are allowed to ambulate 20 min after the deployment of the device. More frequently, however, patients are kept on bed rest for several hours following Angioseal(r) deployment. The purpose of this study was to prospectively assess patients when ambulating 20 min after Angioseal(r) deployment instead of prolonged best rest of 2-3 h. METHODS: Patients undergoing angiography from the common femoral artery approach were included in the study if they received a 6 Fr Angioseal(r) closure device. RESULTS: Twenty-nine patients were successfully enrolled in the study; 27 (93.1%) patients ambulated at 20 min, 1 (3.45%) patient ambulated at 28 min, and 1 (3.45%) patient ambulated at 27 min due to transport times. There were zero complications with regard to hemorrhage or other groin complications. There is a substantial time difference in ambulation times between the conventional and early ambulation groups. CONCLUSION: Our study demonstrates that it is probably safe to ambulate patients who undergo diagnostic cardiac catheterization as early as 20 min after deployment of the 6 Fr Angioseal(r) closure device. ClinicalTrials.gov identifier: NCT03142126. PMID- 29421961 TI - Enhancing the auto-flocculation of photosynthetic bacteria to realize biomass recovery in brewery wastewater treatment. AB - Photosynthetic bacteria (PSB) wastewater treatment technology can simultaneously realize wastewater purification and biomass production. The produced biomass contains high value-added products, which can be used in medical and agricultural industry. However, because of the small size and high electronegativity, PSB are hard to be collected from wastewater, which hampers the commercialization of PSB based industrial processes. Auto-flocculation is a low cost, energy saving, non toxic biomass collection method for microbiology. In this work, the influence factors with their optimal levels and mechanism for enhancing the auto flocculation of PSB were investigated in pure cultivation medium. Then PSB auto flocculation performance in real brewery wastewater was probed. Results showed that Na+ concentration, pH and light intensity were three crucial factors except the initial inoculum sizes and temperature. In the pure medium cultivation system, the optimal condition for PSB auto-flocculation was as follows: pH was 9.5, inoculum size was 420 mg l-1, Na+ concentration was 0.067 mol l-1, light intensity was 5000 lux, temperature was 30 degrees C. Under the optimal condition, the auto-flocculation ratio and biomass recovery reached 85.0% and 1488 mg l-1, which improved by 1.67-fold and 2.14-fold compared with the PSB enrichment cultivation conditions, respectively. Mechanism analysis showed that the protein/polysaccharides ratio and absolute Zeta potential value had a liner relationship. For the brewery wastewater treatment, under the above optimal condition, the chemical oxygen demand removal reached 94.3% with the auto flocculation ratio and biomass recovery of 89.6% and 1510 mg l-1, which increased 2.75-fold and 2.77-fold, respectively. PMID- 29421962 TI - Molecular dynamics simulation of metal free structure of Lmb, a laminin-binding adhesin of Streptococcus agalactiae: metal removal and its structural implications. AB - Metal-binding receptors are one of the extracellular components of ATP-binding cassette transporters that are essential for regulation of metal homeostasis in bacteria. Laminin-binding adhesin (Lmb) of Streptococcus agalactiae falls under this class of solute binding proteins. It binds to zinc with a high affinity. Crystal structure of Lmb solved previously by our group reveals that the zinc is tetrahedrally coordinated by three histidines and a glutamate at the interdomain cleft. Lmb contains a long disordered loop close to the metal-binding site whose precise function is unknown. Several experimental attempts to produce apo-Lmb failed and this prompted us to carry out in silico studies to analyse the structural importance of the metal in Lmb. Here, we present the results of the molecular dynamics (MD) simulation studies of native, apo-(metal removed) and the long loop truncated Lmb models along with a homologous protein, TroA from Treponema pallidum that was taken up for validating the MD results of Lmb. Absence of a metal results in significant structural changes in Lmb, particularly at the metal-binding pocket and with the long loop, although the overall fold is retained. This study thus revealed that the Lmb can exist in different conformational states with subtle differences in the overall fold based on the presence or absence of the metal. This could be functionally important for a putative metal uptake and release and also for the adhesive function of Lmb in recognizing laminin, which contains a high number of zinc finger motifs. PMID- 29421963 TI - Making Football Safer: Assessing the Current National Football League Policy on the Type of Helmets Allowed on the Playing Field. AB - In an effort to reduce concussions in football, a helmet safety-rating system was developed in 2011 that rated helmets based on their ability to reduce g-forces experienced by the head across a range of impact forces measured on the playing field. Although this was considered a major step in making the game safer, the National Football League (NFL) continues to allow players the right to choose what helmet to wear during play. This prompted us to ask: What helmets do NFL players wear and does this helmet policy make the game safer? Accordingly, we identified the helmets worn by nearly 1000 players on Week 13 of the 2015-2016 season and Week 1 of the 2016-2017 season. Using stop-motion footage, we found that players wore a wide range of helmets with varying safety ratings influenced in part by the player's position and age. Moreover, players wearing lower safety rated helmets were more likely to receive a concussion than those wearing higher safety-rated helmets. Interestingly, many players suffering a concussion in 2015 did not switch to a higher safety-rated helmet in 2016. Using a helmet-to-helmet impactor, we found that the g-forces experienced in the highest safety-rated helmets were roughly 30% less than that for the lowest safety-rated helmets. These results suggest that the current NFL helmet policy puts players at increased risk of receiving a concussion as many players are wearing low safety rated helmets, which transmits more energy to the brain than higher safety-rated helmets, following collision. Thus, to reduce concussions, the NFL should mandate that players only wear helmets that receive the highest safety rating. PMID- 29421964 TI - OMW spillage control tool based on tracking p-Coumaric acid degradation by HPLC. AB - Olive mill wastewater (OMW) is a major watercourse pollutant agent with a high concentration of phenolic compounds. It is estimated that 30 million OMW m3 are released into rivers every year. Protecting the health of these courses against the uncontrolled discharges implies establishing an adequate legislation, where spillage control tools play a fundamental role. In this paper, a new tool for OMW spillage control is discussed. It is based on the use of a RP-HPLC-UV protocol to track p-Coumaric acid (pCA), a characteristic OMW phenolic compound, and its derivative compounds through their chemical oxidation and biological anaerobic degradation. Laboratory assays and real-life experiences allowed to determine degradation routes and apparition times for every pCA derivative, making it possible to detect an OMW spill and assess its age. Moreover, this RP-HPLC-UV introduces solid advantages over previous detection procedures, namely, quicker response times and smaller costs than HPLC methods and superior specificity than colorimetric methods. Finally, this tool was put to test in an actual OMW polluted watercourse. In all scenarios, the tool demonstrated solid reliability. PMID- 29421965 TI - Total aflatoxins in complementary foods produced at community levels using locally available ingredients in Ethiopia. AB - This study was conducted to determine the occurrence and levels of total aflatoxins in complementary foods (CFs) and their ingredients. A total of 126 samples collected from 20 Districts from Amhara, Tigray, Oromia, and Southern Nations Nationalities and Peoples (SNNP) regions were analysed for levels of total aflatoxins using enzyme linked immunosorbent assay (ELISA). Aflatoxins were detected in 62 out of 66 pre-milling samples with mean range of 0.3-9.9 ug/kg. Aflatoxins were also detected in 19 out of 20 post-production CFs and in all of the one-month stored CFs at households and grain banks, with a mean range of 0.5 8.0, 3.6-11.3, and 0.2-12.4 ug/kg, respectively. Overall, 3 out of 126 samples exceeded the maximum limit (10 ug/kg). Although most aflatoxin levels were below the maximum limit and thus considered to be safe for consumption, more effort should be implemented to reduce contamination, as these CFs are intended for consumption by young children. PMID- 29421967 TI - Effects of Psychological Inoculation Versus Health Education on Physical Activity: Two Randomized Controlled Studies. AB - BACKGROUND: Effects of health education (HE) on physical activity (PA) are limited. Also, HE fails to address people's personal barriers and social pressures. In contrast, "psychological inoculation" (PI) targets both topics. This research examined the effects of PI versus HE on PA-related barriers and on self-reported PA in 2 studies. METHODS: Randomized controlled trials were employed. Study 1 (N = 20) took place in Britain, while study 2 (N = 40) in Belgium, with nonphysically active participants. PI exposed people to challenging sentences reflecting barriers concerning PA, which they had to refute. In study 1, PA barriers and self-reported PA levels were assessed before and a week after interventions. In study 2, the degree of refuting challenging sentences was estimated and the level of PA was assessed before and 2 months after interventions. RESULTS: In study 1, in the PI condition alone, PA barriers significantly decreased and self-reported PA increased. Change in barriers correlated with posttreatment PA. In study 2, PA increased only in the PI group. Level of rejecting challenging sentences predicted PA later. Most group differences remained when controlling for baseline measures. CONCLUSIONS: PI is more effective than HE for increasing PA, and reducing its barriers is essential for this. PMID- 29421966 TI - Developmental Trends and Determinants of Physical Activity From Adolescence to Adulthood Differ by Ethnicity/Race and Sex. AB - BACKGROUND: Interventions to raise population physical activity generally show modest effects; one possible reason is that trends and determinants of moderate to vigorous physical activity (MVPA) differ between population subgroups. This study examined differences in trends and determinants of reported MVPA by ethnicity/race and sex in a 15-year longitudinal study. METHODS: Participants (n = 2092) in the Project Eating and Activity in Teens and Young Adults study were surveyed on MVPA behavior and potential determinants from adolescence to young adulthood. Generalized estimating equations were used to model age trends in MVPA and associations with determinants. RESULTS: Mean MVPA declined by 2.1 hours per week over 15 years of follow-up from adolescence to young adulthood. Asian males reported the lowest levels of MVPA at each age. Nonwhite females reported less MVPA than white females at each age. The association of body mass index (BMI) with MVPA differed by sex and ethnicity/race. Asian males and females showed lower levels of MVPA at both low and high BMI. CONCLUSIONS: Interventions to increase MVPA may need to begin earlier among Asian men and nonwhite women than among other groups. Asian adolescents with lower BMI show lower MVPA and may benefit from additional intervention efforts compared with Asian adolescents with normal BMI. PMID- 29421968 TI - Multiple Short Bouts of Walking Activity Attenuate Glucose Response in Obese Women. AB - BACKGROUND: We sought to determine the effect of multiple walking breaks from sedentary behavior (SED) on glucose responses in sedentary obese women. MATERIALS AND METHODS: Ten women [aged = 36 (5) y, body mass index = 38.0 (1.6) kg/m2, body fat = 49.6 (1.4)%] completed 3 conditions (48-h "washout" in-between conditions) following a standardized meal in random order: 4-hour SED, 4-hour SED with 2 minutes of moderate-intensity walking every 30 minutes (SED + 2 min), and 4-hour SED with 5 minutes of moderate-intensity walking every 30 minutes (SED + 5 min). Measurements included continuous interstitial glucose concentration monitoring immediately before and during standardized conditions and accelerometry for physical activity patterns during and in-between the standardized conditions. Repeated-measures 1-way analyses of variance (alpha = .05) with Bonferroni correction for post hoc comparisons were performed. Effect sizes (d [95% confidence interval]) were calculated as mean difference from SED/pooled standard deviation. RESULTS: Sedentary time was similar in the 48 hours preceding each condition (P > .05). By design, sedentary time was different between conditions (P < .001). Compared with SED, 2-hour postprandial glucose positive incremental area under the curve was lower for SED + 5 minutes (P = .005; d = - 0.57 [-1.48, 0.40]), but not for SED + 2 minutes (P = .086; d = - 0.71 [-1.63, 0.27]). Four hour postprandial glucose area under the curve was similar between conditions (P > .05). CONCLUSION: In sedentary obese women, 5 minutes of moderate-intensity walking breaks from SED each 30 minutes attenuate 2-hour postprandial glucose excursions. PMID- 29421969 TI - Management and Outcome of Prosthetic Vascular Graft Infections: A Single Center Experience. AB - BACKGROUND: Prosthetic vascular graft infection (PVGI) remains a severe and challenging complication in vascular surgery with high morbidity and mortality rates. Incidence has been reported between 1% and 6%. The aim of this study was to report our experience in terms of general and surgical management as well as outcome, over 15 years. METHODS: A retrospective consecutive study was conducted of all patients treated in our department for PVGI between January 2000 and December 2015. We analyzed all data relative to primary operation, duration interval between initial surgery and infections signs, infection site, type of microorganism involved, and surgical treatment modality, as well as evaluation of short- and long-term results. RESULTS: Sixty-two patients were admitted for PVGI. Primary revascularization procedures consisted of a peripheral bypass in 42 (68%) patients and an aortic bypass in the remaining 20 (32%) patients. Median interval between primary procedure and reintervention was 3 months (interquartile range 17 [IQR 17]) in the peripheral group and 48 months (IQR 70.5) in the aortic group. Complete excision of the prosthetic graft was carried out in 85% of the cases. Thirty-day mortality was 0% and 9.5% in the aortic and peripheral group, respectively. The overall survival rate was 62.3% at 2-years, 46.4% in the aortic group, and 69.7% in the peripheral group. CONCLUSIONS: Prosthetic vascular graft infection needs a multidisciplinary management with appropriate antibiotherapy, radical removal of the infected graft, and in situ reconstruction. This strategy gives satisfactory results in terms of mortality, morbidity, patency rates, and infection control. PMID- 29421970 TI - Temporal Trends of Physical Activity and Sedentary Behavior Simultaneity in Brazilian Students. AB - OBJECTIVE: To evaluate trends in physical activity and sedentary behavior simultaneity among Brazilian students from 2009 to 2015 and its association with independent variables. METHODS: This study presents a panel of 3 cross-sectional studies carried out in 2009, 2012, and 2015 (Pesquisa Nacional de Saude do Escolar-PeNSE). The population was comprised of ninth-grade public and private schools students from Brazilian capitals. Physical activity and sedentary behavior variables were combined to create the outcome of simultaneity of these risk factors. RESULTS: A large proportion of students were simultaneously inactive and sedentary in the 3 surveys. However, it was possible to observe a downward trend (2009: 56.4%; 95% confidence interval, 55.7-57.1; 2012: 53.7%; 95% confidence interval, 53.0-54.4; 2015: 51.9%; 95% confidence interval, 51.2-52.7). In 2015, estimates of physical inactivity and sedentary behavior simultaneity were greater than 48% for 20 out of 27 of the Brazilian states. Significant declining trends were observed among mideast residents, females, nonwhite, and those attending private schools. Only around 5%-7% of the adolescents were both active and nonsedentary in the 3 surveys. CONCLUSION: Despite of a slight decreasing trend in the proportion of Brazilian students simultaneously inactive and sedentary throughout the period, the prevalence remained elevated across the surveys. PMID- 29421971 TI - Sideline Concussion Assessment: The King-Devick Test in Canadian Professional Football. AB - Sideline assessment tools are an important component of concussion evaluations. To date, there has been little data evaluating the clinical utility of these tests in professional football. The purpose of this study was to evaluate the clinical utility of the King-Devick (K-D) test in evaluating concussions in professional football players. Baseline data was collected over two consecutive seasons in the Canadian Football League as part of a comprehensive medical baseline evaluation. A pilot study with the K-D test began in 2015 with 306 participants and the next year (2016) there were 917 participants. In addition, a sample of 64 participants completed testing after physical exertion (practice or game). Participants with concussion demonstrated significantly higher (slower) results compared with baseline and the exercise group (F[2,211] = 5.94; p = 0.003). The data revealed a specificity of 84% and sensitivity of 62% for our sample. Reliability from season to season was good (intraclass correlation coefficient [ICC] 2,1 = 0.88; 95% confidence interval [CI]: 0.83, 0.91). On average, participants improved performances by a mean of 1.9 sec (range, -26.6 to 23.8) in subsequent years. High reliability was attained in the exercise group. (ICC2,1 = 0.93; 95% CI: 0.89, 0.96). The K-D test presents as a reliable measure although sensitivity and specificity data from our sample indicate it should be used in conjunction with other measures for diagnosing concussion. Further research is required to identify stability of results over multiple usages. PMID- 29421972 TI - Canine Bocavirus Type 2 Infection Associated With Intestinal Lesions. AB - Bocaviruses are small nonenveloped DNA viruses belonging to the Bocaparvovirus genus of the Parvoviridae family and have been linked to both respiratory and enteric disease in humans and animals. To date, 3 bocaviruses, canine bocaviruses 1 to 3 (CBoV-1-3), have been shown to affect dogs with different disease manifestations reported for infected animals. We used next-generation sequencing to identify a novel strain of canine CBoV-2 (CBoV TH-2016) in a litter of puppies that died in Thailand from acute dyspnea and hemoptysis, for which no causal pathogen could be identified in routine assays. Analysis of the complete coding sequences of CBoV TH-2016 showed that this virus was most closely related to a strain previously identified in South Korea (isolate 14D193), with evidence of genetic recombination in the VP2 gene with related strains from South Korea and Hong Kong. Use of quantitative polymerase chain reaction showed the presence of CBoV TH-2016 in several tissues, suggesting hematogenous virus spread, while only intestinal tissue was found to be positive by in situ hybridization and electron microscopy. Histologic small intestinal lesions associated with CBoV TH-2016 infection were eosinophilic intranuclear inclusion bodies within villous enterocytes without villous atrophy or fusion, similar to those previously considered pathognomonic for CBoV-1 infection. Therefore, this study provides novel insights in the pathogenicity of canine bocavirus infections and suggests that a novel recombinant CBoV-2 may result in atypical findings of CBoV infection. Although the specific cause of death of these puppies remained undetermined, a contributory role of enteric CBoV TH-2016 infection is possible. PMID- 29421974 TI - The Relationship Between the Stanford Leisure-Time Activity Categorical Item and the Godin Leisure-Time Exercise Questionnaire Among Rural Intervention Participants of Varying Health Literacy Status. AB - BACKGROUND: A pragmatic, self-reported physical activity measure is needed for individuals of varying health literacy status. METHODS: This study is a secondary analysis of a 6-month behavioral intervention for rural Appalachian adults developed using health literacy strategies. We examined the relationship and responsiveness of the Stanford Leisure-Time Activity Categorical Item (L-Cat) and adapted Godin Leisure-Time Exercise Questionnaire (GLTEQ) and determined if baseline health literacy status moderates intervention effects. RESULTS: Of 301 enrolled participants, 289 completed the L-Cat at baseline and 212 at 6 months. Approximately 33% were low health literate and 43% reported annual income of <=$14,999. There was high agreement (84.1%) between the L-Cat and adapted GLTEQ for classifying individuals as meeting physical activity recommendations with little differences by health literacy level (low literacy 80.4% and high literacy 85.9%). The primary source of incongruent classification was the adapted GLTEQ classified almost 20% of individuals as meeting recommendations, whereas the L Cat classified them as not meeting recommendations. There were differences in responsiveness between measures, but baseline health literacy status did not moderate change in any L-Cat or adapted GLTEQ measures. CONCLUSION: Implications and recommendations for using the L-Cat 2.3 and GLTEQ among individuals of varying health literacy status are discussed. PMID- 29421975 TI - Inducing System-1-type diagnostic reasoning in second-year medical students within 15 minutes. AB - PURPOSE: Diagnostic reasoning literature debates the significance of "dual process theory" and the importance of its constituent types of thinking: System 1and System-2. This experimental study aimed to determine whether novice medical students could be trained to utilize System-1 thinking when making diagnoses based on chest X-rays. METHOD: Second-year medical students were recruited and presented with a series of eight online chest X-rays cases. Participants were shown half of the cases repeatedly during a training phase and the other half only twice. During the final test phase, they were shown all eight cases, providing a diagnosis as a free text answer. Dependent variables were diagnostic accuracy and response time. RESULTS: Thirty-two students participated. During the test phase, students responses were significantly more accurate and faster for cases which had been seen repeatedly during the training phase (mean score = 3.56/4, mean time = 2.34 s) compared with cases which had been seen only twice (mean score = 1.59/4, mean time = 7.50 s). CONCLUSION: This study demonstrates that it is possible to induce in novice students the speed-to-diagnosis and diagnostic accuracy typical of System-1-type reasoning. The full experimental design and the chest X-rays used may provide new opportunities to explore some of the issues surrounding dual-process theory. PMID- 29421973 TI - Multimodal Characterization of the Late Effects of Traumatic Brain Injury: A Methodological Overview of the Late Effects of Traumatic Brain Injury Project. AB - Epidemiological studies suggest that a single moderate-to-severe traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease, including Alzheimer's disease (AD) and Parkinson's disease (PD). Histopathological studies describe complex neurodegenerative pathologies in individuals exposed to single moderate-to-severe TBI or repetitive mild TBI, including chronic traumatic encephalopathy (CTE). However, the clinicopathological links between TBI and post-traumatic neurodegenerative diseases such as AD, PD, and CTE remain poorly understood. Here, we describe the methodology of the Late Effects of TBI (LETBI) study, whose goals are to characterize chronic post-traumatic neuropathology and to identify in vivo biomarkers of post-traumatic neurodegeneration. LETBI participants undergo extensive clinical evaluation using National Institutes of Health TBI Common Data Elements, proteomic and genomic analysis, structural and functional magnetic resonance imaging (MRI), and prospective consent for brain donation. Selected brain specimens undergo ultra-high resolution ex vivo MRI and histopathological evaluation including whole-mount analysis. Co-registration of ex vivo and in vivo MRI data enables identification of ex vivo lesions that were present during life. In vivo signatures of postmortem pathology are then correlated with cognitive and behavioral data to characterize the clinical phenotype(s) associated with pathological brain lesions. We illustrate the study methods and demonstrate proof of concept for this approach by reporting results from the first LETBI participant, who despite the presence of multiple in vivo and ex vivo pathoanatomic lesions had normal cognition and was functionally independent until her mid-80s. The LETBI project represents a multidisciplinary effort to characterize post-traumatic neuropathology and identify in vivo signatures of postmortem pathology in a prospective study. PMID- 29421978 TI - Where do the immune checkpoint inhibitors stand in the management of triple negative breast cancer? PMID- 29421977 TI - Chronic Alterations in Systemic Immune Function after Traumatic Brain Injury. AB - There is a compelling link between severe brain trauma and immunosuppression in patients with traumatic brain injury (TBI). Although acute changes in the systemic immune compartment have been linked to outcome severity, the long-term consequences of TBI on systemic immune function are unknown. Here, adult male C57Bl/6 mice underwent moderate-level controlled cortical impact (CCI) or sham surgery, and systemic immune function was evaluated at 1, 3, 7, 14, and 60 days post-injury. Bone marrow, blood, thymus, and spleen were examined by flow cytometry to assess changes in immune composition, reactive oxygen species (ROS) production, phagocytic activity, and cytokine production. Bone marrow derived macrophages (BMDMs) from sham and 60-day CCI mice were cultured for immune challenge studies using lipopolysaccharide (LPS) and interleukin-4 (IL-4) models. Acutely, TBI caused robust bone marrow activation and neutrophilia. Neutrophils and monocytes exhibited impairments in respiratory burst, cytokine production, and phagocytosis; in contrast, ROS levels and pro-inflammatory cytokine production were chronically elevated at 60 days post-injury. Cultures of BMDMs from chronic CCI mice demonstrated defects in LPS- and IL-4-induced polarization when compared with stimulated BMDMs from sham mice. TBI also caused thymic involution, inverted CD4:CD8 ratios, chronic T lymphopenia, greater memory conversion, increased T cell activation, impaired interferon gamma induction, and chronically elevated Th1 cytokine and ROS production. Collectively, our in-depth phenotypic and functional analyses demonstrate that TBI induces widespread suppression of innate and adaptive immune responses after TBI. Moreover, at chronic time points, TBI mice exhibit hallmarks of accelerated immune aging, displaying chronic deficits in systemic immune function. PMID- 29421980 TI - CD19-specific chimeric antigen receptor-modified (CAR)-T cell therapy for the treatment of chronic lymphocytic leukemia in the ibrutinib era. PMID- 29421981 TI - Standing in the GAP : To formulate a novel radioimmunotherapy regime to improve the long-term outcome in breast cancer. AB - AIM: The new radioimmunotherapeutic regime GAP15R aims to stimulate glucocorticoid-induced TNF-related protein (G) to overcome Treg suppression; add IFN-alpha (A) to promote inflammatory milieu; block PD1 (P) to disinhibit T effector cytotoxicity; add IL-15 (15) to enhance danger signals & T-cell expansion; and apply radiation (R) at critical time point to sustain localized inflammation. Patients & methods/materials & methods: This was tested in a murine 4T1 metastatic breast carcinoma model given GAP15R with regular monitoring of tumor volume and complications. RESULTS: We had demonstrated long-term complete remission up to 50% of treated mice, which is not associated with major treatment related complication, in cases with specific tumor burden. CONCLUSION: GAP15R is efficacious with potential to be applicable to other tumors. PMID- 29421982 TI - Immune-based therapies for metastatic prostate cancer: an update. AB - Prostate cancer (PC) is a common malignancy among elderly males and is noncurable once it becomes metastatic. In recent years, a number of antigen-delivery systems have emerged as viable and promising immunotherapeutic agents against PC. The approval of sipuleucel-T by the US FDA for the treatment of males with asymptomatic or minimally symptomatic castrate resistant PC was a landmark in cancer immunotherapy, making this the first approved immunotherapeutic. A number of vaccines are under clinical investigation, each having its own set of advantages and disadvantages. Here, we discuss the basic technologies underlying these different delivery modes, we discuss the completed and current human clinical trials, as well as the use of vaccines in combination with immune checkpoint inhibitors. PMID- 29421979 TI - Radiation therapy and immunotherapy: what is the optimal timing or sequencing? AB - Radiotherapy is a component of the standard of care for many patients with locally advanced nonmetastatic tumors and increasingly those with oligometastatic tumors. Despite encouraging advances in local control and progression-free and overall survival outcomes, continued manifestation of tumor progression or recurrence leaves room for improvement in therapeutic efficacy. Novel combinations of radiation with immunotherapy have shown promise in improving outcomes and reducing recurrences by overcoming tumor immune tolerance and evasion mechanisms via boosting the immune system's ability to recognize and eradicate tumor cells. In this review, we discuss preclinical and early clinical evidence that radiotherapy and immunotherapy can improve treatment outcomes for locally advanced and metastatic tumors, elucidate underlying molecular mechanisms and address strategies to optimize timing and sequencing of combination therapy for maximal synergy. PMID- 29421983 TI - Emerging immune targets for the treatment of multiple myeloma. AB - We reviewed emerging immune strategies for multiple myeloma (MM) therapy excluding US FDA approved drugs. In relapsed refractory MM, isatuximab (anti CD38) monotherapy achieved overall response (OR) of 24%. Other monoclonal antibodies that have shown efficacy in combination therapy include siltuximab (OR: 66%), indatuximab (OR: 78%), isatuximab (OR: 64.5%), pembrolizumab (OR: 60%), bevacizumab (OR: 70%), dacetuzumab (OR: 39%) and lorvotuzumab (OR: 56.4%). No OR was observed with monotherapy using BI-505, siltuximab, bevacizumab, AVE 1642, figitumumab, atacicept, milatuzumab, dacetuzumab, lucatumumab, IPH2101, lorvotuzumab, BT062 and nivolumab. We included seven clinical trials on chimeric antigen receptor (CAR) T cells. CAR T-cell targets include BCMA, CD19, KLC and CD138. A recent experience of CAR T-cell (B-cell maturation antigen) therapy in advanced MM has shown global response of 100%. The future of monoclonal antibodies and adoptive T cells for MM treatment seems promising. PMID- 29421985 TI - Mometasone furoate inhibits growth of acute leukemia cells in childhood by regulating PI3K signaling pathway. AB - OBJECTIVES: Acute lymphoblastic leukemia (ALL) is the most common cancer before the age of 15 years, seriously endangering the health of children. The main treatment for Childhood ALL was pharmacotherapy. But these drugs have many side effects and some of them could develop drug resistance quickly. Mometasone furoate (MF) is an efficient glucocorticoid for topical treatment of inflammation on the skin, lung and nose. METHODS: In this study, we investigated whether the MF had effects on ALL cells proliferation and migration. RESULTS: The CCK-8 proliferation test showed that the cell viability was the lowest at 25 nM MF treatment and the increased OD value was time-dependent. In transwell assay, the number of CCRF-CEM cells was reduced in MF treated group. We found the expression of anti-apoptotic protein bcl-2 decreased the expression of pro-apoptotic protein caspase3 and bax increased in CCRF-CEM cell line treated with MF. The expression of p-AKT, p-mTOR, p70S6 K, vascular endothelial growth factor and CyclinD1 were decreased in MF treated group. CONCLUSION: This study reveals that MF can inhibit proliferation and invasion/migration and induce apoptosis in Childhood ALL cells, which may be regulated by Phosphatidylinositol 3-kinase signaling pathway. These results suggest MF may be a potential new drug target for clinical ALL treatment. PMID- 29421988 TI - High-Density Lipoprotein Cholesterol (HDL-C) Levels Independently Correlates With Cardiac Arrhythmias and Atrial Fibrillation. AB - OBJECTIVE: Acute coronary syndrome is frequently complicated by rhythm disturbances, yet any association between high-density lipoprotein (HDL) cholesterol levels and arrhythmias in the setting of non-ST-segment elevation myocardial infarction (non-STEMI) is uncertain. The goal of this study was to evaluate any association between HDL-cholesterol levels and arrhythmias in the setting of non-STEMI. METHODS: Retrospective data from Phoenix Veterans Affair Medical Center records were utilized for our study. A total of 6881 patients were found who presented during 2000 to 2003 with non-STEMI with available fasting lipid panels collected within the first 24 hours of admission. Patients were followed for the development of rhythm disturbances up to 6 years after initial presentation, with a mean follow up of 1269 days. RESULTS: We found that high triglycerides/HDL and low-density lipid/HDL ratios were predictive of arrhythmias. However, low HDL levels had strongest association with highest odds ratio (OR) for development of arrhythmias (for HDL <31 mg/dL, OR = 3.72, 95% confidence interval [CI] = 2.55-5.44, P < .05) in patients with diabetes and (for HDL < 31 mg/dL, OR = 3.69, 95% CI = 2.85-4.71, P < .05) in patients without diabetes. Using multivariate analysis adjusting for comorbidities, low HDL level remained independently associated with arrhythmias. CONCLUSIONS: Patients with low HDL levels during hospitalization with non-STEMI have a greater risk of developing cardiac rhythm disturbances independent of other risk factors. These data suggest a possible protective role of HDL in preventing arrhythmias in the setting of acute coronary syndrome. PMID- 29421989 TI - Using Facebook in a Healthy Lifestyle Intervention: Feasibility and Preliminary Efficacy. AB - The purpose of this pilot quasi-experimental study was to examine the feasibility and preliminary efficacy of using Facebook in a 10-week lifestyle intervention with Head Start caregiver-preschooler dyads to improve healthy behaviors and reduce body mass index. Sixty-nine dyads participated with 39 in the intervention group. Average preschooler attendance rate for the Head Start center-based program was 77%, and caregiver participation rate was 87%. About 94% of the caregivers were satisfied with the program, and 97% would recommend the program to others and/or participate again. The intervention decreased preschoolers' body mass index z score (Cohen's d = -.30) and screen time ( d = -.21), and increased their fruit and vegetable intake ( d = .40) and moderate-to-vigorous physical activity ( d = .42). The intervention increased caregivers' fruit and vegetable intake ( d = .40). The intervention is feasible, and preliminary efficacy is encouraging, but further investigation using a rigorous study design is warranted. PMID- 29421990 TI - Measurement of soluble CD59 in CSF in demyelinating disease: Evidence for an intrathecal source of soluble CD59. AB - BACKGROUND: CD59, a broadly expressed glycosylphosphatidylinositol-anchored protein, is the principal cell inhibitor of complement membrane attack on cells. In the demyelinating disorders, multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), elevated complement protein levels, including soluble CD59 (sCD59), were reported in cerebrospinal fluid (CSF). OBJECTIVES: We compared sCD59 levels in CSF and matched plasma in controls and patients with MS, NMOSD and clinically isolated syndrome (CIS) and investigated the source of CSF sCD59 and whether it was microparticle associated. METHODS: sCD59 was quantified using enzyme-linked immunosorbent assay (ELISA; Hycult; HK374-02). Patient and control CSF was subjected to western blotting to characterise anti-CD59-reactive materials. CD59 was localised by immunostaining and in situ hybridisation. RESULTS: CSF sCD59 levels were double those in plasma (CSF, 30.2 ng/mL; plasma, 16.3 ng/mL). Plasma but not CSF sCD59 levels differentiated MS from NMOSD, MS from CIS and NMOSD/CIS from controls. Elimination of microparticles confirmed that CSF sCD59 was not membrane anchored. CONCLUSION: CSF levels of sCD59 are not a biomarker of demyelinating diseases. High levels of sCD59 in CSF relative to plasma suggest an intrathecal source; CD59 expression in brain parenchyma was low, but expression was strong on choroid plexus (CP) epithelium, immediately adjacent the CSF, suggesting that this is the likely source. PMID- 29421991 TI - Association of Early-Onset Spasticity and Risk for Cognitive Impairment With Mutations at Amino Acid 499 in SPAST. AB - Hereditary spastic paraplegia is a phenotypically and genetically heterogeneous group of neurodegenerative disorders characterized by lower extremity weakness and spasticity. Spastic paraplegia 4 (SPG4), caused by heterozygous mutations in the gene SPAST, typically causes a late-onset, uncomplicated form of hereditary spastic paraplegia in affected individuals. Additional clinical features in SPG4 have been reported on occasion, but no genotype-phenotype correlation has been established. Through targeted clinical testing, we identified 2 unrelated female patients with the same de novo p.Arg499His mutation in SPAST. Both patients presented with early-onset spasticity resulting in delayed motor milestones, which led to a diagnosis of cerebral palsy in one child and tethered cord in the other. Review of the literature identified several patients with mutations at amino acid 499 and early-onset symptoms associated with a risk of cognitive impairment. Early and accurate diagnosis of children with early-onset spasticity is important for informed prognosis and genetic counselling. PMID- 29421984 TI - Current state and future prospects of immunotherapy for glioma. AB - There is a large unmet need for effective therapeutic approaches for glioma, the most malignant brain tumor. Clinical and preclinical studies have enormously expanded our knowledge about the molecular aspects of this deadly disease and its interaction with the host immune system. In this review we highlight the wide array of immunotherapeutic interventions that are currently being tested in glioma patients. Given the molecular heterogeneity, tumor immunoediting and the profound immunosuppression that characterize glioma, it has become clear that combinatorial approaches targeting multiple pathways tailored to the genetic signature of the tumor will be required in order to achieve optimal therapeutic efficacy. PMID- 29421992 TI - Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression. AB - The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors. PMID- 29421993 TI - Zinc supplementation does not influence serum levels of VEGF, BDNF, and NGF in diabetic retinopathy patients: a randomized controlled clinical trial. AB - OBJECTIVES: This study was aimed to evaluate the effects of zinc (Zn) supplementation on serum levels of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in patients with diabetic retinopathy (DR). METHODS: In this randomized clinical trial, 50 patients with DR were allocated into the Zn (n = 25) and placebo (n = 25) groups to receive 30 mg Zn gluconate or maltose dextrin per day, respectively, for three months. Metabolic parameters and blood pressure were measured. Serum levels of Zn were assessed by atomic absorption spectrophotometry and serum levels of VEGF, BDNF and NGF by ELISA. RESULTS: Forty-five patients completed the intervention. Levels of VEGF, BDNF and NGF were not affected by the Zn supplementation. Levels of VEGF correlated negatively with levels of Zn and positively with BDNF and NGF. There was also a positive correlation between BDNF and NGF. Serum levels of VEGF, BDNF and NGF were negatively correlated with serum levels of the diabetic parameters measured. CONCLUSIONS: Strong positive relationship between the growth factors and their inverse association with metabolic factors is possibly suggesting the contribution of these factors in the pathogenesis of DR through acting in a same biological pathway. PMID- 29421994 TI - Spatio-seasonal variation of airborne asbestos concentration in urban areas of Shiraz, Iran. AB - Background Asbestos fiber is mainly released from friction product in brakes and clutch linings and from reinforcing agent in the asbestos-cement industry. It leads to serious health problem such as mesothelioma and lung cancer. The objectives of this study were to monitor the levels of asbestos fibers in ambient air of Shiraz, Iran during 2014, and to draw its GIS distribution map for the city. Methods Samples were collected by mixed cellulose ester filters mounted on an open-faced filter holder using a SKC sampling pump. Fiber counting was conducted using both phase contrast microscopy (PCM) method to determine total fibers, and scanning electron microscopy (SEM) method to identify non-asbestos from asbestos fibers. Results The average concentrations of asbestos fibers in ambient air of the city were 1.11 +/- 0.25 PCM f/l and 12.21 +/- 2.52 SEM f/l. The highest concentration of asbestos fibers was measured in Valiasr square amounting 1.96 +/- 0.34 PCM f/l and 16.87 +/- 2.14 SEM f/l. Conclusions The average of asbestos fibers in all sampling points was higher than the WHO guideline (0.05 PCM f/l, 2.2 SEM f/l). This may be attributed to the frequently occurrence of heavy traffic, the existence of relevant industries in and around the city, and the topographic characteristics of the city. Thus, product substitution, traffic smoothing and industrial sites relocating are suggested to eliminate the asbestos fibers emission. PMID- 29421996 TI - Role of ABC transporters in veterinary medicine: pharmaco-toxicological implications. AB - Unlike physicians, veterinary practitioners must deal with a number of animal species with crucial differences in anatomy, physiology and metabolism. Accordingly, the pharmacokinetic behaviour, the clinical efficacy and the adverse or toxic effects of drugs may differ across domestic animals. Moreover, the use of drugs in food-producing species may impose a risk for humans due to the generation of chemical residues in edible products, a major concern for public health and consumer's safety. As is clearly known in human beings, the ATP binding cassette (ABC) of transport proteins may influence the bioavailability and elimination of numerous drugs and other xenobiotics in domestic animals as well. A number of drugs, currently available in the veterinary market, are substrates of one or more transporters. Therefore, significant drug-drug interactions among ABC substrates may have unpredictable pharmaco-toxicological consequences in different species of veterinary interest. In this context, different investigations revealed the major relevance of P-gp and other transport proteins, like breast cancer resistance protein (BCRP) and multidrug resistance associated proteins (MRPs), in both companion and livestock animals. Undoubtedly, the discovery of the ABC transporters and the deep understanding of their physiological role in the different species introduced a new paradigm into the veterinary pharmacology. This review focus on the expression and function of the major transport proteins expressed in species of veterinary interest, and their impact in drug disposition, efficacy and toxicity. PMID- 29421995 TI - New drugs, therapeutic strategies, and future direction for the treatment of Pulmonary Arterial Hypertension. AB - Despite recent advances in pulmonary arterial hypertension (PAH) treatment, this condition is still characterized by an extremely poor prognosis. In this review, we discuss the use of newly-approved drugs for PAH treatment with already known mechanisms of action (macitentan), innovative targets (riociguat and selexipag), and novel therapeutic approaches with initial up-front combination therapy. Secondly, we describe new potential signalling pathways and investigational drugs with promising role in the treatment of PAH. PMID- 29421997 TI - Recent Advances in Lanthanide Based Nano-architectures as Probes for Ultra High Field Magnetic Resonance Imaging. AB - Paramagnetic Lanthanide ions incorporated into nano- architectures are emerging as a versatile platform for magnetic resonance imaging (MRI) contrast agents due to their strong contrast enhancement effects combined with the platform capability to include multiple imaging modalities. This short review examines the application of lanthanide based nano-architectures (nanoparticles and nano- assemblies) in the development of multifunctional probes for single and multimodal imaging involving high field MRI as one imaging modality. PMID- 29421998 TI - The Role of Selenium in Oxidative Stress and in Nonthyroidal Illness Syndrome (NTIS): an overview. AB - Selenium is a trace element, nutritionally classified as essential micronutrient, involved in maintaining the correct function of several enzymes incorporating the selenocysteine residue, namely the selenoproteins. The human selenoproteome including 25 proteins is here extensively described. The most relevant selenoproteins, including glutathione peroxidases, thioredoxin reductases and iodothyronine deiodinases are required for the proper cellular redox homeostasis as well as for the correct thyroid function, thus preventing oxidative stress and related diseases. This review summarizes the main advances on oxidative stress with a focus on selenium metabolism and transport. Moreover, thyroid-related disorders are discussed, considering that the thyroid gland contains the highest selenium amount per gram of tissue, also for future possible therapeutic implication. PMID- 29421999 TI - DNA double strand break repair - related synthetic lethality. AB - Cancer is a heterogeneous disease with a high degree of diversity between and within tumors. Our limited knowledge of their biology results in ineffective treatment. However, personalized approach may represent a milestone in the field of anticancer therapy. It can increase specificity of treatment against tumor initiating cancer stem cells (CSCs) and cancer progenitor cells (CPCs) with minimal effect on normal cells and tissues. Cancerous cells carry multiple genetic and epigenetic aberrations which may disrupt pathways essential for cell survival. Discovery of synthetic lethality has led a new hope of creating effective, personalized anti-tumor treatment. Synthetic lethality occurs when simultaneous inactivation of two genes or their products causes cell death whereas individual inactivation of either gene is not lethal. The effectiveness of numerous anti-tumor therapies depend on induction of DNA damage therefore tumor cells expressing abnormalities in genes whose products are crucial for DNA repair pathways are promising targets for synthetic lethality. Here, we discuss mechanistic aspects of synthetic lethality in the context of deficiencies in DNA double strand break repair pathways. In addition, we review clinical trials utilizing synthetic lethality interactions and discuss the mechanisms of resistance. PMID- 29422001 TI - Numeric, Agent-based or System Dynamics Model? Which Modeling Approach is the Best for Vast Population Simulation? AB - BACKGROUND: Alzheimer's disease is one of the most common mental illnesses. It is posited that more than 25% of the population is affected by some mental disease during their lifetime. Treatment of each patient draws resources from the economy concerned. Therefore, it is important to quantify the potential economic impact. METHODS: Agent-based, system dynamics and numerical approaches to dynamic modeling of the population of the European Union and its patients with Alzheimer's disease are presented in this article. Simulations, their characteristics, and the results from different modeling tools are compared. RESULTS: The results of these approaches are compared with EU population growth predictions from the statistical office of the EU by Eurostat. The methodology of a creation of the models is described and all three modeling approaches are compared. The suitability of each modeling approach for the population modeling is discussed. CONCLUSION: In this case study, all three approaches gave us the results corresponding with the EU population prediction. Moreover, we were able to predict the number of patients with AD and, based on the modeling method, we were also able to monitor different characteristics of the population. PMID- 29422000 TI - Controlled SLN Delivery by Thermoresponsive In-situ Forming Erodible Gels; A Whole-body and Organ Imaging Study. AB - BACKGROUND: Nanoparticles (NPs) suffer from rapid clearance from body and require frequent dosing if long treatment is required. METHOD: In order to solve this problem for solid lipid nanoparticles (SLN) and prolong their action, SLNs were incorporated into thermo-responsive Poloxamer sol-gels and their fate was investigated invivo and in-vitro using a near infrared lipophilic fluorescent dye; dialkylcarbocyanin [1]. Leakage test, release of intact SLNs from sol-gel and SLN size and zeta potential were investigated. Biodistribution of DiR formulations (solution, free SLN and SLN-Gel) was investigated by whole-body and ex-vivo organ imaging after intraperitoneal injection in mice. SLN showed particle size of about 165 nm and a negative zeta potential of about -36 mV. RESULTS: Leakage studies indicated that fluorescent probe does not release from SLNs. Imaging results revealed a steady profile for SLN-Gel over time, while the fluorescence intensity of solution and free SLN showed a burst followed by rapid clearance. Results also showed that SLN release occurs after gel erosion and follows a zero order profile. CONCLUSION: Our results indicate that NP incorporated gel can be used to control the release of SLNs from application site and prolong their action in a sustained manner. PMID- 29422002 TI - Identification and Temporal Characterization of Features Associated with the Conversion from Mild Cognitive Impairment to Alzheimer's Disease. AB - BACKGROUND: Diagnosing Alzheimer's disease (AD) in its earliest stages is important for therapeutic and support planning. Similarly, being able to predict who will convert from mild cognitive impairment (MCI) to AD would have clinical implications. OBJECTIVES: The goals of this study were to identify features from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database associated with the conversion from MCI to AD, and to characterize the temporal evolution of that conversion. METHODS: We screened the publically available ADNI longitudinal database for subjects with MCI who have developed AD (cases: n=305), and subjects with MCI who have remained stable (controls: n=250). Analyses included 1,827 features from laboratory assays (n=12), quantitative MRI scans (n=1,423), PET studies (n=136), medical histories (n=72), and neuropsychological tests (n=184). Statistical longitudinal models identified features with significant differences in longitudinal behavior between cases and matched controls. A multiple comparison adjusted log-rank test identified the capacity of the significant predictive features to predict early conversion. RESULTS: 411 features (22.5%) were found to be statistically different between cases and controls at the time of AD diagnosis; 385 features were statistically different at least 6 months prior to diagnosis, and 28 features distinguished early from late conversion, 20 of which were obtained from neuropsychological tests. In addition, 69 features (3.7%) had statistically significant changes prior to AD diagnosis. CONCLUSION: Our results characterized features associated with disease progression from MCI to AD, and, in addition, the log-rank test identified features which are associated with the risk of early conversion. PMID- 29422003 TI - Role of Nut Consumption in the Management of Cognitive Decline - A Mini-Review. AB - BACKGROUND: Currently, there is a significant increase in the number of older generation groups, which may result in serious economic and social issues. Therefore, there is a need to prolong the active life of these older individuals, especially by focusing on modifying lifestyle factors such as healthy nutrition. In fact, recent research has shown that, for example, nuts are an important part of people's healthy diet because they have appeared to be neuroprotective compounds which might maintain or in some cases even improve people's cognitive functions. OBJECTIVE: The purpose of this review study is to explore the role of the nut nutrition in the maintenance and delay of cognitive decline among older individuals. RESULTS: The findings indicate that the nut consumption may contribute to the delay of cognitive decline in aging. However, this nut diet is just one component of the multi-nutrient dietary intervention for health aging. CONCLUSION: More longitudinal controlled randomized studies have to be performed in this field to prove the efficacy of the nut nutrition for the delay of cognitive decline. PMID- 29422004 TI - Vitamin D and Subjective Memory Complaint in Community-Dwelling Older Adults. AB - BACKGROUND: Older adults with hypovitaminosis D report more often subjective cognitive complaints, especially with regards to memory. This raises prospects that vitamin D may improve older adults' subjective experience of memory disorders. OBJECTIVE: To determine among older community-dwellers whether higher serum 25- hydroxyvitamin D (25OHD) concentrations were associated with fewer memory complaints, while considering different subtypes of memory complaints. METHOD: One hundred eighty Caucasian community-dwellers with memory complaint and no dementia (mean+/-standard deviation, 71.1+/-3.4years; 33.3%female) from the French 'EVATEM study' were included in this analysis. Subjective memory complaints regarding memory lapses, problems learning new information, problems finding words, problems calculating and problems concentrating were assessed using a standardized questionnaire. Participants were categorized according to the highest tertile of serum 25OHD (i.e., >=68nmol/L). Age, gender, body mass index, morbidities burden, use of vitamin D supplements, cognitive performance, mood, serum concentrations of calcium, parathyroid hormone and vitamin B12, creatinine clearance, and season of evaluation were used as potential confounders. RESULTS: Compared to participants with 25OHD<68nmol/L (n=121), those with 25OHD>=68nmol/L had less often problems learning new information (P=0.027). There were no between-group differences for the other memory complaints. The highest 25OHD tertile was cross-sectionally associated with fewer problems learning new information (odds ratio (OR)=0.48, P=0.029), even after adjustment for potential confounders (OR=0.32, P=0.039). CONCLUSION: Higher vitamin D status was associated with reduced problems memorizing new information in older community-dwellers. This novel finding provides a scientific base for vitamin D replacement trials attempting to improve older patients' subjective experience of cognitive decline. PMID- 29422005 TI - The Role of Point of Care Ultrasound in the Injured Paediatric Patient. AB - The focus of this review is to examine the current state of paediatric Point of Care Ultrasound (POCUS) in the injured patient. POCUS has become useful across various medical specialties owing to its ease of use, reproducibility and non ionizing qualities. Point of care ultrasound has advanced over the past years and has proven to be an extremely useful adjunct in the injured child. Discussion will center around the challenges on when and how to best utilize POCUS. This includes but is not limited to: detection of peritoneal free fluid, pneumothoraces, hemothoraces, pericardial effusions, a wide array of fractures, lung contusions and many other applications. Discussion will also be focused on the evolution of POCUS, as well as a discussion around the determination of training standards. PMID- 29422006 TI - Inhibition of Neurogenesis by Zika Virus Infection. AB - BACKGROUND & OBJECTIVE: The link between Zika Virus (ZIKV) epidemic and neurological disorder has raised an urgent global alarm. The current epidemic of ZIKV has triggered quick responses in the scientific world. The first case of ZIKV was reported in 2015 from Brazil and now has spread over 30 countries. Nearly four hundred cases of traveler associated ZIKV infection have also been reported in the United States. ZIKV is primarily transmitted by mosquito belonging to the genus Aedes that are widely distributed throughout the world. Additionally, the virus can also be transmitted from male to female by sexual contact. The epidemiological investigations during the current outbreak found a causal link between infection in pregnant women and the development of microcephaly (MCPH) in their unborn babies. This finding is a cause of grave concern since MCPH is a serious neural developmental disorder that can lead to significant post-natal developmental abnormalities and disabilities. Recently, published data indicates that ZIKV infection severely affects the growth of fetal neural progenitor cells and cerebral neurons resulting in malformation of cerebral cortex leading to MCPH. Recently, it has been reported that ZIKV infection deregulates the signaling pathway of neuronal cell and inhibits the neurogenesis. CONCLUSION: In this review, we discussed the information about cellular and molecular mechanisms of neurodegeneration of human neuronal cells and inhibition of neurogenesis. The provided information in this review will be very useful further not only in neuro-scientific research but also in the desig and development of management strategies for MCPH and other mosquito-borne diseases. PMID- 29422007 TI - K+ Channels of Muller Glial Cells in Retinal Disorders. AB - BACKGROUND & OBJECTIVE: Muller cell is the major type of glial cell in the vertebrate retina. Muller cells express various types of K+ channels, such as inwardly rectifying K+ (Kir) channels, big conductance Ca2+-activated K+ (BKCa) channels, delayed rectifier K+ channels (KDR), and transient A-type K+ channels. These K+ channels play important roles in maintaining physiological functions of Muller cells. Under some retinal pathological conditions, the changed expression and functions of K+ channels may contribute to retinal pathogenesis. CONCLUSION: In this article, we reviewed the physiological properties of K+ channels in retinal Muller cells and the functional changes of these channels in retinal disorders. PMID- 29422008 TI - Lysosomal Potassium Channels: Potential Roles in Lysosomal Function and Neurodegenerative Diseases. AB - BACKGROUND & OBJECTIVE: The lysosome is a membrane-enclosed organelle widely found in every eukaryotic cell. It has been deemed as the stomach of the cells. Recent studies revealed that it also functions as an intracellular calcium store and is a platform for nutrient-dependent signal transduction. Similar with the plasma membrane, the lysosome membrane is furnished with various proteins, including pumps, ion channels and transporters. So far, two types of lysosomal potassium channels have been identified: large-conductance and Ca2+-activated potassium channel (BK) and TMEM175. TMEM175 has been linked to several neurodegeneration diseases, such as the Alzheimer and Parkinson disease. Recent studies showed that TMEM175 is a lysosomal potassium channel with novel architecture and plays important roles in setting the lysosomal membrane potential and maintaining pH stability. TMEM175 deficiency leads to compromised lysosomal function, which might be responsible for the pathogenesis of related diseases. BK is a well-known potassium channel for its function on the plasma membrane. Studies from two independent groups revealed that functional BK channels are also expressed on the lysosomal plasma membrane. Dysfunction of BK causes impaired lysosomal calcium signaling and abnormal lipid accumulation, a featured phenotype of most lysosomal storage diseases (LSDs). Boosting BK activity could rescue the lipid accumulation in several LSD cell models. Overall, the lysosomal potassium channels are essential for the lysosome physiological function, including lysosomal calcium signaling and autophagy. The dysfunction of lysosomal potassium channels is related to some neurodegeneration disorders. CONCLUSION: Therefore, lysosomal potassium channels are suggested as potential targets for the intervention of lysosomal disorders. PMID- 29422009 TI - Oxidation of Potassium Channels in Neurodegenerative Diseases: A Mini-Review. AB - BACKGROUND & OBJECTIVE: Increased level of reactive oxygen species is a hallmark of common neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease. ROS can oxidize macromolecules including DNA, lipids and proteins and cause oxidative damage to the cell. Emerging evidence indicate that potassium channels in the central nervous system are no exceptions to these oxidative modifications. CONCLUSION: In this mini-review, we summarized recent reports on the oxidation of potassium channels in the CNS and the consequently resulted changes in cell functions and viability, with focus on its implications in neurodegenerative diseases. PMID- 29422010 TI - Berberine Encapsulated PLGA-PEG Nanoparticles Modulate PCSK-9 in HepG2 Cells. AB - BACKGROUND: The developments of new parenteral approaches to target PCSK-9 for the treatment of LDL-Cholesterol has yielded impressive results; and have shown significant decreases in the risk of mortality associated with hypercholesterolemia. However improved and convenient alternate approaches that exploit the beneficial drug target properties of PCSK-9 also need to be explored and developed. One such approach is the oral administration of Berberine using nanotechnology. METHODS: Nanoprecipitation encapsulation and physiochemical characterization of Berberine Chloride in PLGA-PEG-PLGA block copolymer has been developed and characterized in Hep-G2 cells using Berberine Chloride encapsulated nanoparticle (Bc-NP). Evaluation of PCSK-9, SREBP- 1, LDL-r, HNF-1alpha mRNAs and PCSK-9 protein expression was performed using quantitative real-time PCR (qPCR) and median fluorescence intensity (MFI) of flow cytometric studies respectively. Pearson's correlation analysis of PCSK-9 mRNA and protein levels in Berberine chloride delivery was performed. RESULTS: The PCSK-9 mRNA and protein expression shows a relationship to the release of Berberine from the encapsulating PLGA-PEG PLGA polymer in a time dependent manner. CONCLUSION: PCSK-9 modulation by oral administration of Berberine using nanotechnology approach can improve its pharmacokinetic profile. Further studies are needed to maximize its delivery efficiency. PMID- 29422012 TI - A clinical analysis of vitrectomy for severe vitreoretinopathy in patients with chronic renal. AB - BACKGROUND: The recent advancement in the management of chronic renal failure (CRF) has significantly increased the longevity of the patients, which increase the incidence of severe vitreoretinopathy. The vitrectomy is highly risky in this particular group of patients due to their systemic comorbidity. The timing surgical intervention is usually delayed because of the systemic conditions. This study is to evaluate the safety and effectiveness of 25-guage vitrectomy for severe vitreoretinopathy in the CRF patients. METHODS: In this retrospective study, 16 eyes of 16 CRF patients with severe vitreoretinopathy were undergone 25 guage vitrectomy in the department of Ophthalmology of the Second Hospital of Tianjin Medical University from February 2015 to April 2017. The visual outcome, complications and perioperative medical management were documented and analyzed. RESULTS: The best-corrected visual acuity(BCVA)of fourteen eyes were lower than 20/200 preoperatively. Surgery duration ranged from 28 to 72 min, with a mean of 48.4 +/- 13.6 min. During the surgery, 12 eyes were diagnosed with DR, while two them were complicated with tractional retinal detachment and one with branch retinal vein occlusion. Three eyes were diagnosed with branch retinal vein occlusion, and one eye was diagnosed with hypertensive retinopathy. Postoperative BCVA of six eyes >=20/40, seven eyes >=20/200, and three eyes < 20/200. BCVA of eight eyes improved more than three lines, three eyes improved two lines, and four eyes improved one line. BCVA decreased from hand movement to light perception in one patient who developed neovascular glaucoma two weeks after surgery. CONCLUSION: In chronic renal failure patients with severe vitreoretinopathy, the well-planned minimally invasive vitrectomy is effective and safe. Additionally, careful management of the perioperative systemic conditions is important to improve the visual acuity and quality of life as well. PMID- 29422011 TI - Comparison of the prevalence of respiratory viruses in patients with acute respiratory infections at different hospital settings in North China, 2012-2015. AB - BACKGROUND: Acute respiratory infections (ARIs) are a great public health challenge globally. The prevalence of respiratory viruses in patients with ARIs attending at different hospital settings is fully undetermined. METHODS: Laboratory-based surveillance for ARIs was conducted at inpatient and outpatient settings of 11 hospitals in North China. The first 2-5 patients with ARIs were recruited in each hospital weekly from 2012 through 2015. The presence of respiratory viruses was screened by PCR assays. The prevalence of respiratory viruses was determined and compared between patients at different hospital settings. RESULTS: A total of 3487 hospitalized cases and 6437 outpatients/Emergency Department (ED) patients were enrolled. The most commonly detected viruses in the hospitalized cases were respiratory syncytial virus (RSV, 33.3%) in children less than two years old, adenoviruses (13.0%) in patients 15 34 years old, and influenza viruses (IFVs, 9.6%) in patients >=65 years. IFVs were the most common virus in outpatient/ED patients across all age groups (22.7%). After controlling for the confounders caused by other viruses and covariates, adenoviruses (adjusted odds ratio [aOR]: 3.97, 99% confidence interval [99% CI]: 2.19-7.20) and RSV (aOR: 2.04, 99% CI: 1.34-3.11) were independently associated with increased hospitalization in children, as well as adenoviruses in adults (aOR: 2.14, 99% CI: 1.19-3.85). Additionally, co-infection of RSV with IFVs was associated with increased hospitalization in children (aOR: 12.20, 99% CI: 2.65-56.18). CONCLUSIONS: A substantial proportion of ARIs was associated with respiratory viruses in North China. RSV, adenoviruses, and co infection of RSV and IFVs were more frequent in hospitalized children (or adenoviruses in adults), which might predict the severity of ARIs. Attending clinicians should be more vigilant of these infections. PMID- 29422013 TI - First and second trimester urinary metabolic profiles and fetal growth restriction: an exploratory nested case-control study within the infant development and environment study. AB - BACKGROUND: Routine prenatal care fails to identify a large proportion of women at risk of fetal growth restriction (FGR). Metabolomics, the comprehensive analysis of low molecular weight molecules (metabolites) in biological samples, can provide new and earlier biomarkers of prenatal health. Recent research has suggested possible predictive first trimester urine metabolites correlating to fetal growth restriction in the third trimester. Our objective in this current study was to examine urinary metabolic profiles in the first and second trimester of pregnancy in relation to third trimester FGR in a US population from a large, multi-center cohort study of healthy pregnant women. METHODS: We conducted a nested case-control study within The Infant Development and the Environment Study (TIDES), a population-based multi-center pregnancy cohort study. We identified 53 cases of FGR based on the AUDIPOG [Neonatal growth - AUDIPOG [Internet]. [cited 29 Nov 2016]. Available from: http://www.audipog.net/courbes_morpho.php?langue=en ] formula for birthweight percentile considering maternal height, age, and prenatal weight, as well as infant sex, gestational age, and birth rank. Cases were matched to 106 controls based on study site, maternal age (+/- 2 years), parity, and infant sex. NMR spectroscopy was used to assess concentrations of four urinary metabolites that have been previously associated with FGR (tyrosine, acetate, formate, and trimethylamine) in first and second trimester urine samples. We fit multivariate conditional logistic regression models to estimate the odds of FGR in relation to urinary concentrations of these individual metabolites in the first and second trimesters. Exploratory analyses of custom binned spectroscopy results were run to consider other potentially related metabolites. RESULTS: We found no significant association between the relative concentrations of each of the four metabolites and odds of FGR. Exploratory analyses did not reveal any significant differences in urinary metabolic profiles. Compared with controls, cases delivered earlier (38.6 vs 39.8, p < 0.001), and had lower birthweights (2527 g vs 3471 g, p < 0.001). Maternal BMI was similar between cases and controls. CONCLUSIONS: First and second trimester concentrations of urinary metabolites (acetate, formate, trimethylamine and tyrosine) did not predict FGR. This inconsistency with previous studies highlights the need for more rigorous investigation and data collection in this area before metabolomics can be clinically applied to obstetrics. PMID- 29422014 TI - Development of a tailored strategy to improve postpartum hemorrhage guideline adherence. AB - BACKGROUND: Despite the introduction of evidence based guidelines and practical courses, the incidence of postpartum hemorrhage shows an increasing trend in developed countries. Substandard care is often found, which implies an inadequate implementation in high resource countries. We aimed to reduce the gap between evidence-based guidelines and clinical application, by developing a strategy, tailored to current barriers for implementation. METHODS: The development of the implementation strategy consisted of three phases, supervised by a multidisciplinary expert panel. In the first phase a framework of the strategy was created, based on barriers to optimal adherence identified among professionals and patients together with evidence on effectiveness of strategies found in literature. In the second phase, the tools within the framework were developed, leading to a first draft. In the third phase the strategy was evaluated among professionals and patients. The professionals were asked to give written feedback on tool contents, clinical usability and inconsistencies with current evidence care. Patients evaluated the tools on content and usability. Based on the feedback of both professionals and patients the tools were adjusted. RESULTS: We developed a tailored strategy to improve guideline adherence, covering the trajectory of the third trimester of pregnancy till the end of the delivery. The strategy, directed at professionals, comprehending three stop moments includes a risk assessment checklist, care bundle and time-out procedure. As patient empowerment tools, a patient passport and a website with patient information was developed. The evaluation among the expert panel showed all professionals to be satisfied with the content and usability and no discrepancies or inconsistencies with current evidence was found. Patients' evaluation revealed that the information they received through the tools was incomplete. The tools were adjusted accordingly to the missing information. CONCLUSION: A usable, tailored strategy to implement PPH guidelines and practical courses was developed. The next step is the evaluation of the strategy in a feasibility trial. TRIAL REGISTRATION: Clinical trial registration: The Fluxim study, registration number: NCT00928863 . PMID- 29422015 TI - Is RNASEL:p.Glu265* a modifier of early-onset breast cancer risk for carriers of high-risk mutations? AB - BACKGROUND: Breast cancer risk for BRCA1 and BRCA2 pathogenic mutation carriers is modified by risk factors that cluster in families, including genetic modifiers of risk. We considered genetic modifiers of risk for carriers of high-risk mutations in other breast cancer susceptibility genes. METHODS: In a family known to carry the high-risk mutation PALB2:c.3113G>A (p.Trp1038*), whole-exome sequencing was performed on germline DNA from four affected women, three of whom were mutation carriers. RESULTS: RNASEL:p.Glu265* was identified in one of the PALB2 carriers who had two primary invasive breast cancer diagnoses before 50 years. Gene-panel testing of BRCA1, BRCA2, PALB2 and RNASEL in the Australian Breast Cancer Family Registry identified five carriers of RNASEL:p.Glu265* in 591 early onset breast cancer cases. Three of the five women (60%) carrying RNASEL:p.Glu265* also carried a pathogenic mutation in a breast cancer susceptibility gene compared with 30 carriers of pathogenic mutations in the 586 non-carriers of RNASEL:p.Glu265* (5%) (p < 0.002). Taqman genotyping demonstrated that the allele frequency of RNASEL:p.Glu265* was similar in affected and unaffected Australian women, consistent with other populations. CONCLUSION: Our study suggests that RNASEL:p.Glu265* may be a genetic modifier of risk for early onset breast cancer predisposition in carriers of high-risk mutations. Much larger case-case and case-control studies are warranted to test the association observed in this report. PMID- 29422016 TI - Malignancy during pregnancy in Japan: an exceptional opportunity for early diagnosis. AB - BACKGROUND: Malignancy during pregnancy has become a significant cause of maternal death in developed countries, likely due to both an older pregnant population, and increases of cervical cancer in younger women. Our aim is to investigate the clinical aspects of malignancy during pregnancy in Japan and to use this information to identify opportunities for earlier detection and treatment. METHODS: We provided a questionnaire to 1508 secondary or tertiary care hospitals in Japan. We reviewed the clinical characteristics of cases with malignancy during pregnancy for the period of January to December, 2008. From the 760 institutions which responded, we obtained clinical information for 227 unique cases. The questionnaire provided clinical information, including disease site, pregnancy outcome and how the disease was detected. RESULTS: The most common type of malignancy was cervical cancer (n = 162, 71.4%) followed by ovarian (n = 16, 7.0%) and breast cancer (n = 15, 6.6%). Leukemia (n = 7, 3.1%), colon cancer (n = 5, 2.2%), gastric cancer (n = 5, 2.2%), malignant lymphoma (n = 4, 1.8%), thyroid cancer (n = 3, 1.3%), brain cancer (n = 3, 1.3%), endometrial cancer (n = 2, 0.9%), and head and neck cancer (n = 2, 0.9%) accounted for the remaining cases. Overall, gynecological malignancies accounted for 79.3% (95% confidence interval 74.0-84.6) of pregnancy associated malignancies diagnosed in the present study. The majority of cervical cancers, 149 (92.0%) of 162, were diagnosed by a Pap (Papanicolaou) smear during early gestation. Ten (62.5%) of the ovarian cancer cases were diagnosed by ultrasonography during a prenatal checkup or at the time of initial pregnancy diagnosis. Out of 14 breast cancers, only one (7.1%) was diagnosed by screening breast exam. CONCLUSIONS: From this study, we reaffirm the clear and significant benefits of prenatal checkups starting at an early gestational age for the detection of gynecological cancers during pregnancy. Conversely, breast cancer detection during pregnancy was poor, suggesting new strategies for early identification of this disease are required. PMID- 29422017 TI - Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM. AB - BACKGROUND: Tumour cells have a high demand for arginine. However, a subset of glioblastomas has a defect in the arginine biosynthetic pathway due to epigenetic silencing of the rate limiting enzyme argininosuccinate synthetase (ASS1). These tumours are auxotrophic for arginine and susceptible to the arginine degrading enzyme, pegylated arginine deiminase (ADI-PEG20). Moreover, ASS1 deficient GBM have a worse prognosis compared to ASS1 positive tumours. Since altered tumour metabolism is one of the hallmarks of cancer we were interested to determine if these two subtypes exhibited different metabolic profiles that could allow for their non-invasive detection as well as unveil additional novel therapeutic opportunities. METHODS: We looked for basal metabolic differences using one and two-dimensional gas chromatography-time-of-flight mass spectrometry (1D/2D GC TOFMS) followed by targeted analysis of 29 amino acids using liquid chromatography-time-of-flight mass spectrometry (LC-TOFMS). We also looked for differences upon arginine deprivation in a single ASS1 negative and positive cell line (SNB19 and U87 respectively). The acquired data was evaluated by chemometric based bioinformatic methods. RESULTS: Orthogonal partial least squares discriminant analysis (OPLS-DA) of both the 1D and 2D GC-TOFMS data revealed significant systematic difference in metabolites between the two subgroups with ASS1 positive cells generally exhibiting an overall elevation of identified metabolites, including those involved in the arginine biosynthetic pathway. Pathway and network analysis of the metabolite profile show that ASS1 negative cells have altered arginine and citrulline metabolism as well as altered amino acid metabolism. As expected, we observed significant metabolite perturbations in ASS negative cells in response to ADI-PEG20 treatment. CONCLUSIONS: This study has highlighted significant differences in the metabolome of ASS1 negative and positive GBM which warrants further study to determine their diagnostic and therapeutic potential for the treatment of this devastating disease. PMID- 29422018 TI - Assessing the performance of a Loop Mediated Isothermal Amplification (LAMP) assay for the detection and subtyping of high-risk suptypes of Human Papilloma Virus (HPV) for Oropharyngeal Squamous Cell Carcinoma (OPSCC) without DNA purification. AB - BACKGROUND: Oropharyngeal Squamous Cell Carcinoma (OPSCC) is increasing in incidence despite a decline in traditional risk factors. Human Papilloma Virus (HPV), specifically subtypes 16, 18, 31 and 35, has been implicated as the high risk etiologic agent. HPV positive cancers have a significantly better prognosis than HPV negative cancers of comparable stage, and may benefit from different treatment regimens. Currently, HPV related carcinogenesis is established indirectly through Immunohistochemistry (IHC) staining for p16, a tumour suppressor gene, or polymerase chain reaction (PCR) that directly tests for HPV DNA in biopsied tissue. Loop mediated isothermal amplification (LAMP) is more accurate than IHC, more rapid than PCR and is significantly less costly. In previous work we showed that a subtype specific HPV LAMP assay performed similar to PCR on purified DNA. In this study we examined the performance of this LAMP assay without DNA purification. METHODS: We used LAMP assays using established primers for HPV 16 and 18, and new primers for HPV 31 and 35. LAMP reaction conditions were tested on serial dilutions of plasmid HPV DNA to confirm minimum viral copy number detection thresholds. LAMP was then performed directly on different human cell line samples without DNA purification. RESULTS: Our LAMP assays could detect 105, 103, 104, and 105 copies of plasmid DNA for HPV 16, 18, 31, and 35, respectively. All primer sets were subtype specific, with no cross amplification. Our LAMP assays also reliably amplified subtype specific HPV DNA from samples without requiring DNA isolation and purification. CONCLUSIONS: The high risk OPSCC HPV subtype specific LAMP primer sets demonstrated, excellent clinically relevant, minimum copy number detection thresholds with an easy readout system. Amplification directly from samples without purification illustrated the robust nature of the assay, and the primers used. This lends further support HPV type specific LAMP assays, and these specific primer sets and assays can be further developed to test for HPV in OPSCC in resource and lab limited settings, or even bedside testing. PMID- 29422019 TI - Identification of two novel null variants in CLN8 by targeted next-generation sequencing: first report of a Chinese patient with neuronal ceroid lipofuscinosis due to CLN8 variants. AB - BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) are one of the most frequent childhood-onset neurodegenerative pathologies characterized by seizures, progressive cognitive decline, motor impairment and loss of vision. For the past two decades, more than 430 variants in 13 candidate genes have been identified in the affected patients. Most of the variants were almost exclusively reported in Western patients, and very little clinical and genetic information was available for Chinese patients. CASE PRESENTATION: We report a Chinese boy whose clinical phenotypes were suspected to be NCL, including intractable epilepsy, cognitive and motor decline and progressive vision loss. Using targeted next-generation sequencing, two novel null variants in CLN8 (c.298C > T, p.Gln100Ter; c.551G > A, p.Trp184Ter) were detected in this patient in trans model. These two variants were interpreted as pathogenic according to the variant guidelines of the American College of Medical Genetics and Genomics. CONCLUSIONS: This is the first case report of NCL due to CLN8 variants in China. Our findings expand the variant diversity of CLN8 and demonstrate the tremendous diagnosis value of targeted next generation sequencing for pediatric NCLs. PMID- 29422020 TI - Cognitive medicine - a new approach in health care science. AB - BACKGROUND: The challenges of today's society call for more knowledge about how to maintain all aspects of cognitive health, such as speed/attention, memory/learning, visuospatial ability, language, executive capacity and social cognition during the life course. MAIN TEXT: Medical advances have improved treatments of numerous diseases, but the cognitive implications have not been sufficiently addressed. Disability induced by cognitive dysfunction is also a major issue in groups of patients not suffering from Alzheimer's disease or related disorders. Recent studies indicate that several negative lifestyle factors can contribute to the development of cognitive impairment, but intervention and prevention strategies have not been implemented. Disability due to cognitive failure among the workforce has become a major challenge. Globally, the changing aging pyramid results in increased prevalence of cognitive disorders, and the diversity of cultures influences the expression, manifestation and consequences of cognitive dysfunction. CONCLUSIONS: Major tasks in the field of cognitive medicine are basic neuroscience research to uncover diverse disease mechanisms, determinations of the prevalence of cognitive dysfunction, health economical evaluations, and intervention studies. Raising awareness for cognitive medicine as a clinical topic would also highlight the importance of specialized health care units for an integrative approach to the treatment of cognitive dysfunctions. PMID- 29422021 TI - Value of information methods to design a clinical trial in a small population to optimise a health economic utility function. AB - BACKGROUND: Most confirmatory randomised controlled clinical trials (RCTs) are designed with specified power, usually 80% or 90%, for a hypothesis test conducted at a given significance level, usually 2.5% for a one-sided test. Approval of the experimental treatment by regulatory agencies is then based on the result of such a significance test with other information to balance the risk of adverse events against the benefit of the treatment to future patients. In the setting of a rare disease, recruiting sufficient patients to achieve conventional error rates for clinically reasonable effect sizes may be infeasible, suggesting that the decision-making process should reflect the size of the target population. METHODS: We considered the use of a decision-theoretic value of information (VOI) method to obtain the optimal sample size and significance level for confirmatory RCTs in a range of settings. We assume the decision maker represents society. For simplicity we assume the primary endpoint to be normally distributed with unknown mean following some normal prior distribution representing information on the anticipated effectiveness of the therapy available before the trial. The method is illustrated by an application in an RCT in haemophilia A. We explicitly specify the utility in terms of improvement in primary outcome and compare this with the costs of treating patients, both financial and in terms of potential harm, during the trial and in the future. RESULTS: The optimal sample size for the clinical trial decreases as the size of the population decreases. For non-zero cost of treating future patients, either monetary or in terms of potential harmful effects, stronger evidence is required for approval as the population size increases, though this is not the case if the costs of treating future patients are ignored. CONCLUSIONS: Decision-theoretic VOI methods offer a flexible approach with both type I error rate and power (or equivalently trial sample size) depending on the size of the future population for whom the treatment under investigation is intended. This might be particularly suitable for small populations when there is considerable information about the patient population. PMID- 29422022 TI - Health care and societal costs of the management of children and adolescents with attention-deficit/hyperactivity disorder in Spain: a descriptive analysis. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition in childhood (5.3% to 7.1% worldwide prevalence), with substantial overall financial burden to children/adolescents, their families, and society. The aims of this study were to describe the clinical characteristics of children and adolescents with ADHD in Spain, estimate the associated direct/indirect costs of the disorder, and assess whether the characteristics and financial costs differed between children/adolescents adequately responding to currently available pharmacotherapies compared with children/adolescents for whom pharmacotherapies failed. METHODS: This was a multicenter, cross-sectional, descriptive analysis conducted in 15 health units representative of the overall Spanish population. Data on demographic characteristics, socio-occupational status, social relationships, clinical variables of the disease, and pharmacological and non-pharmacological treatments received were collected in 321 children and adolescents with ADHD. Direct and indirect costs were estimated over one year from both a health care system and a societal perspective. RESULTS: The estimated average cost of ADHD per year per child/adolescent was ?5733 in 2012 prices; direct costs accounted for 60.2% of the total costs (?3450). Support from a psychologist/educational psychologist represented 45.2% of direct costs and 27.2% of total costs. Pharmacotherapy accounted for 25.8% of direct costs and 15.5% of total costs. Among indirect costs (?2283), 65.2% was due to caregiver expenses. The total annual costs were significantly higher for children/adolescents who responded poorly to pharmacological treatment (?7654 versus ?5517; P = 0.024), the difference being mainly due to significantly higher direct costs, particularly with larger expenses for non-pharmacological treatment (P = 0.012). CONCLUSIONS: ADHD has a significant personal, familial, and financial impact on the Spanish health system and society. Successful pharmacological intervention was associated with lower overall expenses in the management of the disorder. PMID- 29422023 TI - Trained lay health workers reduce common mental disorder symptoms of adults with suicidal ideation in Zimbabwe: a cohort study. AB - BACKGROUND: Suicidal ideation may lead to deliberate self-harm which increases the risk of death by suicide. Globally, the main cause of deliberate self-harm is depression. The aim of this study was to explore prevalence of, and risk factors for, suicidal ideation among men and women with common mental disorder (CMD) symptoms attending public clinics in Zimbabwe, and to determine whether problem solving therapy delivered by lay health workers can reduce common mental disorder symptoms among people with suicidal ideation, using secondary analysis of a randomised controlled trial. METHODS: At trial enrolment, the Shona Symptom Questionnaire (SSQ) was used to screen for CMD symptoms. In the intervention arm, participants received six problem-solving therapy sessions conducted by trained and supervised lay health workers, while those in the control arm received enhanced usual care. We used multivariate logistic regression to identify risk factors for suicidal ideation at enrolment, and cluster-level logistic regression to compare SSQ scores at endline (6 months follow-up) between trial arms, stratified by suicidal ideation at enrolment. RESULTS: There were 573 participants who screened positive for CMD symptoms and 75 (13.1%) reported suicidal ideation at baseline. At baseline, after adjusting for confounders, suicidal ideation was independently associated with being aged over 24, lack of household income (household income yes/no; adjusted odds ratio 0.52 (95% CI 0.29, 0.95); p = 0.03) and with having recently skipped a meal due to lack of food (adjusted odds ratio 3.06 (95% CI 1.81, 5.18); p < 0.001). Participants who reported suicidal ideation at enrolment experienced similar benefit to CMD symptoms from the Friendship Bench intervention (adjusted mean difference - 5.38, 95% CI -7.85, - 2.90; p < 0.001) compared to those who had common mental disorder symptoms but no suicidal ideation (adjusted mean difference - 4.86, 95% CI -5.68, - 4.04; p < 0.001). CONCLUSIONS: Problem-solving therapy delivered by trained and supervised lay health workers reduced common mental disorder symptoms among participants with suicidal thoughts who attended primary care facilities in Zimbabwe. TRIAL REGISTRATION: pactr.org ldentifier: PACTR201410000876178. PMID- 29422024 TI - Protein evolution depends on multiple distinct population size parameters. AB - That population size affects the fate of new mutations arising in genomes, modulating both how frequently they arise and how efficiently natural selection is able to filter them, is well established. It is therefore clear that these distinct roles for population size that characterize different processes should affect the evolution of proteins and need to be carefully defined. Empirical evidence is consistent with a role for demography in influencing protein evolution, supporting the idea that functional constraints alone do not determine the composition of coding sequences.Given that the relationship between population size, mutant fitness and fixation probability has been well characterized, estimating fitness from observed substitutions is well within reach with well-formulated models. Molecular evolution research has, therefore, increasingly begun to leverage concepts from population genetics to quantify the selective effects associated with different classes of mutation. However, in order for this type of analysis to provide meaningful information about the intra and inter-specific evolution of coding sequences, a clear definition of concepts of population size, what they influence, and how they are best parameterized is essential.Here, we present an overview of the many distinct concepts that "population size" and "effective population size" may refer to, what they represent for studying proteins, and how this knowledge can be harnessed to produce better specified models of protein evolution. PMID- 29422025 TI - Peak CK-MB has a strong association with chronic scar size and wall motion abnormalities after revascularized non-transmural myocardial infarction - a prospective CMR study. AB - BACKGROUND: Large myocardial infarction (MI) is associated with adverse left ventricular (LV) remodeling (LVR). We studied the nature of LVR, with specific attention to non-transmural MIs, and the association of peak CK-MB with recovery and chronic phase scar size and LVR. METHODS: Altogether 41 patients underwent prospectively repeated cardiovascular magnetic resonance at a median of 22 (interquartile range 9-29) days and 10 (8-16) months after the first revascularized MI. Transmural MI was defined as >=75% enhancement in at least one myocardial segment. RESULTS: Peak CK-MB was 86 (40-216) MUg/L in median, while recovery and chronic phase scar size were 13 (3-23) % and 8 (2-19) %. Altogether 33 patients (81%) had a non-transmural MI. Peak CK-MB had a strong correlation with recovery and chronic scar size (r >= 0.80 for all, r >= 0.74 for non transmural MIs; p < 0.001). Peak CK-MB, recovery scar size, and chronic scar size, were all strongly correlated with chronic wall motion abnormality index (WMAi) (r >= 0.75 for all, r >= 0.73 for non-transmural MIs; p < 0.001). There was proportional scar size and LV mass resorption of 26% (0-50%) and 6% (- 2-14%) in median. Young age (< 60 years, median) was associated with greater LV mass resorption (median 9%vs.1%, p = 0.007). CONCLUSIONS: Peak CK-MB has a strong association with chronic scar size and wall motion abnormalities after revascularized non-transmural MI. Considerable infarct resorption happens after the first-month recovery phase. LV mass resorption is related to age, being more common in younger patients. PMID- 29422026 TI - Evaluation of a population-level strategy to promote tobacco treatment use among insured smokers: a pragmatic, randomized trial. AB - BACKGROUND: Most smokers do not use evidence-based smoking cessation treatment. Increasing utilization of these services is an important public health goal. Health care systems and insurers are well positioned to support this goal within their patient populations. We tested whether a brief, mail-based intervention increased utilization of tobacco cessation services among insured smokers. METHODS: Adult smokers were identified via automated health plan data and randomized to one of five treatment arms (n = 4767). Randomization was stratified by gender, age, and type of health plan coverage. Three arms received a letter containing motivational content and treatment referral information. Motivational content emphasized either the financial, health, or values-based benefits of quitting. One arm received a referral letter with no motivational content, and one arm received no letter. Enrollment in the referred tobacco cessation program was monitored for 5 months. Treatment was available to all participants through their insurance. RESULTS: Across all four letter conditions, 0.8% of participants enrolled in tobacco treatment compared to 0.9% in the no letter reference group (p = .69). No single letter condition was superior to the others (p = .71), but treatment uptake was greater among participants who received their care and coverage from the health plan versus those with insurance coverage only (1.2% vs. 0.3%, p < .01). CONCLUSIONS: A one-time, mailed letter is not a cost-effective strategy for promoting use of covered smoking cessation treatment within large health plan populations, particularly when the message source is an insurance provider only and does not also provide clinical care. Health plans and insurers should consider alternative outreach efforts to promote treatment uptake among smokers. TRIAL REGISTRATIONS: TRN registered retrospectively with ISRCTN registry ( www.isrctn.com ). Registered on 11/01/2018. Registration number: ISRCTN32311137 . PMID- 29422027 TI - OVAS: an open-source variant analysis suite with inheritance modelling. AB - BACKGROUND: The advent of modern high-throughput genetics continually broadens the gap between the rising volume of sequencing data, and the tools required to process them. The need to pinpoint a small subset of functionally important variants has now shifted towards identifying the critical differences between normal variants and disease-causing ones. The ever-increasing reliance on cloud based services for sequence analysis and the non-transparent methods they utilize has prompted the need for more in-situ services that can provide a safer and more accessible environment to process patient data, especially in circumstances where continuous internet usage is limited. RESULTS: To address these issues, we herein propose our standalone Open-source Variant Analysis Sequencing (OVAS) pipeline; consisting of three key stages of processing that pertain to the separate modes of annotation, filtering, and interpretation. Core annotation performs variant mapping to gene-isoforms at the exon/intron level, append functional data pertaining the type of variant mutation, and determine hetero/homozygosity. An extensive inheritance-modelling module in conjunction with 11 other filtering components can be used in sequence ranging from single quality control to multi file penetrance model specifics such as X-linked recessive or mosaicism. Depending on the type of interpretation required, additional annotation is performed to identify organ specificity through gene expression and protein domains. In the course of this paper we analysed an autosomal recessive case study. OVAS made effective use of the filtering modules to recapitulate the results of the study by identifying the prescribed compound-heterozygous disease pattern from exome-capture sequence input samples. CONCLUSION: OVAS is an offline open-source modular-driven analysis environment designed to annotate and extract useful variants from Variant Call Format (VCF) files, and process them under an inheritance context through a top-down filtering schema of swappable modules, run entirely off a live bootable medium and accessed locally through a web-browser. PMID- 29422029 TI - Ultrasound-guided identification of the cricothyroid membrane in a patient with a difficult airway: a case report. AB - BACKGROUND: Surgical cricothyroidotomy is considered to be the last resort for management of the difficult airway. A major point for a successful surgical cricothyroidotomy is to identify the location of the cricothyroid membrane. CASE PRESENTATION: We encountered a patient with progressive respiratory distress who was anticipated to have a difficult airway due to a large neck abscess. We prepared for both awake intubation and surgical cricothyroidotomy. The cricothyroid membrane could not be identified by palpation, but was readily identified using ultrasound. CONCLUSION: Ultrasound-guided identification of the cricothyroid membrane may be useful in a patient with a difficult airway due to neck swelling. PMID- 29422028 TI - The curious case of peroxiredoxin-5: what its absence in aves can tell us and how it can be used. AB - BACKGROUND: Peroxiredoxins are ubiquitous thiol-dependent peroxidases that represent a major antioxidant defense in both prokaryotic cells and eukaryotic organisms. Among the six vertebrate peroxiredoxin isoforms, peroxiredoxin-5 (PRDX5) appears to be a particular peroxiredoxin, displaying a different catalytic mechanism, as well as a wider substrate specificity and subcellular distribution. In addition, several evolutionary peculiarities, such as loss of subcellular targeting in certain species, have been reported for this enzyme. RESULTS: Western blotting analyses of 2-cys PRDXs (PRDX1-5) failed to identify the PRDX5 isoform in chicken tissue homogenates. Thereafter, via in silico analysis of PRDX5 orthologs, we went on to show that the PRDX5 gene is conserved in all branches of the amniotes clade, with the exception of aves. Further investigation of bird genomic sequences and expressed tag sequences confirmed the disappearance of the gene, though TRMT112, a gene located closely to the 5' extremity of the PRDX5 gene, is conserved. Finally, using in ovo electroporation to overexpress the long and short forms of human PRDX5, we showed that, though the gene is lost in birds, subcellular targeting of human PRDX5 is conserved in the chick. CONCLUSIONS: Further adding to the distinctiveness of this enzyme, this study reports converging evidence supporting loss of PRDX5 in aves. In-depth analysis revealed that this absence is proper to birds as PRDX5 appears to be conserved in non-avian amniotes. Finally, taking advantage of the in ovo electroporation technique, we validate the subcellular targeting of human PRDX5 in the chick embryo and bring forward this gain-of-function model as a potent way to study PRDX5 functions in vivo. PMID- 29422030 TI - Prioritizing disease genes with an improved dual label propagation framework. AB - BACKGROUND: Prioritizing disease genes is trying to identify potential disease causing genes for a given phenotype, which can be applied to reveal the inherited basis of human diseases and facilitate drug development. Our motivation is inspired by label propagation algorithm and the false positive protein-protein interactions that exist in the dataset. To the best of our knowledge, the false positive protein-protein interactions have not been considered before in disease gene prioritization. Label propagation has been successfully applied to prioritize disease causing genes in previous network-based methods. These network based methods use basic label propagation, i.e. random walk, on networks to prioritize disease genes in different ways. However, all these methods can not deal with the situation in which plenty false positive protein-protein interactions exist in the dataset, because the PPI network is used as a fixed input in previous methods. This important characteristic of data source may cause a large deviation in results. RESULTS: A novel network-based framework IDLP is proposed to prioritize candidate disease genes. IDLP effectively propagates labels throughout the PPI network and the phenotype similarity network. It avoids the method falling when few disease genes are known. Meanwhile, IDLP models the bias caused by false positive protein interactions and other potential factors by treating the PPI network matrix and the phenotype similarity matrix as the matrices to be learnt. By amending the noises in training matrices, it improves the performance results significantly. We conduct extensive experiments over OMIM datasets, and IDLP has demonstrated its effectiveness compared with eight state of-the-art approaches. The robustness of IDLP is also validated by doing experiments with disturbed PPI network. Furthermore, We search the literatures to verify the predicted new genes got by IDLP are associated with the given diseases, the high prediction accuracy shows IDLP can be a powerful tool to help biologists discover new disease genes. CONCLUSIONS: IDLP model is an effective method for disease gene prioritization, particularly for querying phenotypes without known associated genes, which would be greatly helpful for identifying disease genes for less studied phenotypes. AVAILABILITY: https://github.com/nkiip/IDLP. PMID- 29422031 TI - Transcripts within rod photoreceptors of the Zebrafish retina. AB - BACKGROUND: The purpose of this study was to identify transcripts of retinal rod photoreceptors of the zebrafish. The zebrafish is an important animal model for vision science due to rapid and tractable development, persistent neurogenesis of rods throughout the lifespan, and capacity for functional retinal regeneration. RESULTS: Zebrafish rods, and non-rod retinal cells of the xops:eGFP transgenic line, were separated by cell dissociation and fluorescence-activated cell sorting (FACS), followed by RNA-seq. At a false discovery rate of < 0.01, 597 transcripts were upregulated ("enriched") in rods vs. other retinal cells, and 1032 were downregulated ("depleted"). Thirteen thousand three hundred twenty four total transcripts were detected in rods, including many not previously known to be expressed by rods. Forty five transcripts were validated by qPCR in FACS-sorted rods vs. other retinal cells. Transcripts enriched in rods from adult retinas were also enriched in rods from larval and juvenile retinas, and were also enriched in rods sorted from retinas subjected to a neurotoxic lesion and allowed to regenerate. Many transcripts enriched in rods were upregulated in retinas of wildtype retinas vs. those of a zebrafish model for rod degeneration. CONCLUSIONS: We report the generation and validation of an RNA-seq dataset describing the rod transcriptome of the zebrafish, which is now available as a resource for further studies of rod photoreceptor biology and comparative transcriptomics. PMID- 29422032 TI - Risk factors associated with cluster size of Mycobacterium tuberculosis (Mtb) of different RFLP lineages in Brazil. AB - BACKGROUND: Tuberculosis (TB) transmission is influenced by patient-related risk, environment and bacteriological factors. We determined the risk factors associated with cluster size of IS6110 RFLP based genotypes of Mycobacterium tuberculosis (Mtb) isolates from Vitoria, Espirito Santo, Brazil. METHODS: Cross sectional study of new TB cases identified in the metropolitan area of Vitoria, Brazil between 2000 and 2010. Mtb isolates were genotyped by the IS6110 RFLP, spoligotyping and RDRio. The isolates were classified according to genotype cluster sizes by three genotyping methods and associated patient epidemiologic characteristics. Regression Model was performed to identify factors associated with cluster size. RESULTS: Among 959 Mtb isolates, 461 (48%) cases had an isolate that belonged to an RFLP cluster, and six clusters with ten or more isolates were identified. Of the isolates spoligotyped, 448 (52%) were classified as LAM and 412 (48%) as non-LAM. Our regression model found that 6-9 isolates/RFLP cluster were more likely belong to the LAM family, having the RDRio genotype and to be smear-positive (adjusted OR = 1.17, 95% CI 1.08-1.26; adjusted OR = 1.25, 95% CI 1.14-1.37; crude OR = 2.68, 95% IC 1.13-6.34; respectively) and living in a Serra city neighborhood decrease the risk of being in the 6-9 isolates/RFLP cluster (adjusted OR = 0.29, 95% CI, 0.10-0.84), than in the others groups. Individuals aged 21 to 30, 31 to 40 and > 50 years were less likely of belonging the 2-5 isolates/RFLP cluster than unique patterns compared to individuals < 20 years of age (adjusted OR = 0.49, 95% CI 0.28-0.85, OR = 0.43 95% CI 0.24-0.77and OR = 0. 49, 95% CI 0.26-0.91), respectively. The extrapulmonary disease was less likely to occur in those infected with strains in the 2-5 isolates/cluster group (adjustment OR = 0.45, 95% CI 0.24-0.85) than unique patterns. CONCLUSIONS: We found that a large proportion of new TB infections in Vitoria is caused by prevalent Mtb genotypes belonging to the LAM family and RDRio genotypes. Such information demonstrates that some genotypes are more likely to cause recent transmission. Targeting interventions such as screening in specific areas and social risk groups, should be a priority for reducing transmission. PMID- 29422033 TI - A case report of Tubo-ovarian abscess caused by Burkholderia pseudomallei. AB - BACKGROUND: Melioidosis, the disease caused by Burkholderia pseudomallei is endemic in the Northeastern part of Thailand, South-East Asia, and Northern Australia. The pelvic involvement of disease is rare even in an endemic area. Therefore, we describe in this report the clinical presentation, management, and outcome of the patient with primary tubo-ovarian abscess due to melioidosis. CASE PRESENTATION: A 31-year-old Thai cassava farmer woman presented with fever and abdominal pain at left lower quadrant for one month. She also had pain, swelling, and redness of the genitalia without any ulcer. She had odorless whitish vaginal discharge. The pelvic examination revealed excitation pain on the left side of her cervix. Transvaginal ultrasonography revealed a large left tubo-ovarian abscess size 9.4 * 4.8 cm located at anterior of the uterus. Urgent exploratory laparotomy revealed left hydrosalpinx with a large amount of pus. The pus culture grew Burkholderia pseudomallei. The computer tomography of the abdomen revealed multiple hepatosplenic abscesses. The patient underwent left salpingo oophorectomy and pus drainage. The pathological examination of excised left adnexa revealed chronic and acute suppurative inflammation with necrotic tissue. She was given intravenous ceftazidime for one month, and her clinical symptom improved. She was diagnosed with type 2 diabetes mellitus at this visit and treated with insulin injection. She continued to take oral co-trimoxazole for 20 weeks. The final diagnosis was disseminated melioidosis with left tubo-ovarian abscess and hepatosplenic abscesses in a newly diagnosed morbidly obese diabetic patient. CONCLUSION: Burkholderia pseudomallei should be considered as the causative organism of gynecologic infection among patient with risk factor resided in an endemic area who do not respond to standard antibiotics. The pus culture from the site of infection is the only diagnostic method of pelvic melioidosis, appropriate antibiotics, and adequate surgical drainage were the components of the successful outcome. PMID- 29422034 TI - The role of psychological factors in predicting latrine ownership and consistent latrine use in rural Ethiopia: a cross-sectional study. AB - BACKGROUND: Inadequate sanitation is one of the leading causes of disease in poor and middle-income countries. OBJECTIVE: The objective of the study was to identify the psychological factors that predict latrine ownership and consistent latrine use in the rural Becho district of central Ethiopia. METHOD: A quantitative, cross-sectional, community based study was conducted. A total of 1047 heads of household were interviewed using a structured questionnaire. Ownership of latrine and consistent latrine use constituted the outcome variable of the study. Data were entered using Epi Info version 3.5.4 and were analyzed using SPSS version 20. RESULTS: Of the 1047 households, 73% owned a traditional pit latrine. Among the psychological factors, attitude (AOR 1.70; 95% CI 1.21 2.37) and injunctive norm (AOR 6.18; 95% CI 4.46-10.44) were positively and significantly associated with latrine ownership. Among the demographic factors, having a family size of more than six (AOR = 1.43; 95% CI 1.01-1.97, having a child attending school (AOR = 1.88; 95% CI 1.17-3.02), and having a high school education (AOR = 1.98; 95% CI 1.34-2.87) were significantly associated with latrine ownership. With respect to exposure to communication about sanitation (the cues to action), households that had a family member who took part in Community Led Total Sanitation and Hygiene (CLTSH) triggering were three times more likely to be latrine owners than those who did not participate in CLTSH triggering (95% CI 1.92-4.78.) Results from adjusted logistic regression analysis of potential predictors of consistent latrine use showed that having a positive attitude (AOR 7.00; 95% CI 4.55-10.55), owning of a latrine that had superstructure (AOR 2.3 95% CI 1.47-3.48), having a clean latrine (AOR 1.69 95% CI 1.00-3.00), and having a latrine with a protected door (AOR 1.94; 95% CI 1.10 3.48) were significantly associated with consistent latrine use. CONCLUSION: The study findings showed that attitude and injunctive norm are the psychological predictors of latrine ownership, and consistent latrine use was associated with attitude, cleanliness of the latrine, and its privacy. Hence, sanitation intervention needs to focus on changing societal norms, attitudes, and the promotion of latrine quality. PMID- 29422035 TI - Lineage-specific duplications of NBS-LRR genes occurring before the divergence of six Fragaria species. AB - BACKGROUND: Plant disease resistance (R) genes are evolving rapidly and play a critical role in the innate immune system of plants. The nucleotide binding sites leucine rich repeat (NBS-LRR) genes are one of the largest classes in plant R genes. Previous studies have focused on the NBS-LRR genes from one or several species of different genera, and the sequenced genomes of the genus Fragaria offer the opportunity to study the evolutionary processes of these R genes among the closely related species. RESULTS: In this study, 325, 155, 190, 187, and 133 NBS-LRRs were discovered from F. x ananassa, F. iinumae, F. nipponica, F. nubicola, and F. orientalis, respectively. Together with the 144 NBS-LRR genes from F. vesca, a total of 1134 NBS-LRRs containing 866 multi-genes comprised 184 gene families across the six Fragaria genomes. Extremely short branch lengths and shallow nodes were widely present in the phylogenetic tree constructed with all of the NBS-LRR genes of the six strawberry species. The identities of the orthologous genes were highly significantly greater than those of the paralogous genes, while the Ks ratios of the former were very significantly lower than those of the latter in all of the NBS-LRR gene families. In addition, the Ks and Ka/Ks values of the TIR-NBS-LRR genes (TNLs) were significantly greater than those of the non-TIR-NBS-LRR genes (non-TNLs). Furthermore, the expression patterns of the NBS-LRR genes revealed that the same gene expressed differently under different genetic backgrounds in response to pathogens. CONCLUSIONS: These results, combined with the shared hotspot regions of the duplicated NBS-LRRs on the chromosomes, indicated that the lineage-specific duplication of the NBS-LRR genes occurred before the divergence of the six Fragaria species. The Ks and Ka/Ks ratios suggested that the TNLs are more rapidly evolving and driven by stronger diversifying selective pressures than the non-TNLs. PMID- 29422036 TI - Attitude and subjective wellbeing of non-compliant mothers to childhood oral polio vaccine supplemental immunization in Northern Nigeria. AB - BACKGROUND: Attitude and subjective well-being are important factors in mothers accepting or rejecting Oral Polio Vaccine (OPV) supplemental immunization. The purpose of the study was to determine the role of mothers' attitude and subjective wellbeing on non-compliance to OPV supplemental immunization in Northern Nigeria. METHODS: The study utilized a cross-sectional design to assess attitude and subjective well-being of mothers using previously validated VACSATC (Vaccine Safety, Attitudes, Training and Communication-10 items) & SUBI (Subjective Well-being Inventory-40 items) measures. A total of 396 participants (equal number of non-compliant and compliant mothers) from 94 non-compliant settlements were interviewed, after informed consent. T-test was run to assess difference in mean scores between the non-compliant and compliant mothers on VACSATC and SUBI measures. RESULTS: The research showed a significant difference in mean scores between the non-compliant and compliant groups on VACSATC measure of mothers' attitude (M = 18.9 non-compliant, compared to 26.5 compliant; p < 0.05). On subjective well-being, the study showed there was no significant difference in the mean scores of the SUBI measure (M = 77.4 non-compliant, compared to 78.0 compliant; p > 0.05). CONCLUSION: The research has shown that negative attitude is more commonly present in non-compliant mothers and may be a factor in vaccine refusal in Northern Nigeria. PMID- 29422037 TI - Coping strategies of women with postpartum depression symptoms in rural Ethiopia: a cross-sectional community study. AB - BACKGROUND: Most women with postpartum depression (PPD) in low- and middle-income countries remain undiagnosed and untreated, despite evidence for adverse effects on the woman and her child. The aim of this study was to identify the coping strategies used by women with PPD symptoms in rural Ethiopia to inform the development of socio-culturally appropriate interventions. METHODS: A population based, cross-sectional study was conducted in a predominantly rural district in southern Ethiopia. All women with live infants between one and 12 months post partum (n = 3147) were screened for depression symptoms using the validated Patient Health Questionnaire, 9 item version (PHQ-9). Those scoring five or more, 'high PPD symptoms', (n = 385) were included in this study. The Brief Coping with Problems Experienced (COPE-28) scale was used to assess coping strategies. Construct validity of the brief COPE was evaluated using confirmatory factor analysis. RESULTS: Confirmatory factor analysis of the brief COPE scale supported the previously hypothesized three dimensions of coping (problem-focused, emotion focused, and dysfunctional). Emotion-focused coping was the most commonly employed coping strategy by women with PPD symptoms. Urban residence was associated positively with all three dimensions of coping. Women who had attended formal education and who attributed their symptoms to a physical cause were more likely to use both problem-focused and emotion-focused coping strategies. Women with better subjective wealth and those who perceived that their husband drank too much alcohol were more likely to use emotion-focused coping. Dysfunctional coping strategies were reported by women who had a poor relationship with their husbands. CONCLUSIONS: As in high-income countries, women with PPD symptoms were most likely to use emotion-focused and dysfunctional coping strategies. Poverty and the low level of awareness of depression as an illness may additionally impede problem-solving attempts to cope. Prospective studies are needed to understand the prognostic significance of coping styles in this setting and to inform psychosocial intervention development. PMID- 29422038 TI - Physical activity patterns across time-segmented youth sport flag football practice. AB - BACKGROUND: Youth sport (YS) reaches a large number of children world-wide and contributes substantially to children's daily physical activity (PA), yet less than half of YS time has been shown to be spent in moderate-to-vigorous physical activity (MVPA). Physical activity during practice is likely to vary depending on practice structure that changes across YS time, therefore the purpose of this study was 1) to describe the type and frequency of segments of time, defined by contextual characteristics of practice structure, during YS practices and 2) determine the influence of these segments on PA. METHODS: Research assistants video-recorded the full duration of 28 practices from 14 boys' flag football teams (2 practices/team) while children concurrently (N = 111, aged 5-11 years, mean 7.9 +/- 1.2 years) wore ActiGraph GT1M accelerometers to measure PA. Observers divided videos of each practice into continuous context time segments (N = 204; mean-segments-per-practice = 7.3, SD = 2.5) using start/stop points defined by change in context characteristics, and assigned a value for task (e.g., management, gameplay, etc.), member arrangement (e.g., small group, whole group, etc.), and setting demand (i.e., fosters participation, fosters exclusion). Segments were then paired with accelerometer data. Data were analyzed using a multilevel model with segment as unit of analysis. RESULTS: Whole practices averaged 34 +/- 2.4% of time spent in MVPA. Free-play (51.5 +/- 5.5%), gameplay (53.6 +/- 3.7%), and warm-up (53.9 +/- 3.6%) segments had greater percentage of time (%time) in MVPA compared to fitness (36.8 +/- 4.4%) segments (p <= .01). Greater %time was spent in MVPA during free-play segments compared to scrimmage (30.2 +/- 4.6%), strategy (30.6 +/- 3.2%), and sport-skill (31.6 +/- 3.1%) segments (p <= .01), and in segments that fostered participation (36.1 +/- 2.7%) than segments that fostered exclusion (29.1 +/- 3.0%; p <= .01). Significantly greater %time was spent in low-energy stationary behavior in fitness (15.7 +/- 3.4%) than gameplay (4.0 +/- 2.9%) segments (p <= .01), and in sport-skill (17.6 +/- 2.2%) than free-play (8.2 +/- 4.2%), gameplay, and warm-up (10.6 +/- 2.6%) segments (p < .05). CONCLUSIONS: The %time spent in low-energy stationary behavior and in MVPA differed by characteristics of task and setting demand of the segment. Restructuring the routine of YS practice to include segments conducive to MVPA could increase %time spent in MVPA during practice. As YS reaches a large number of children worldwide, increasing PA during YS has the potential to create a public health impact. PMID- 29422039 TI - Nerve ablation after bronchial thermoplasty and sustained improvement in severe asthma. AB - BACKGROUND: Bronchial thermoplasty (BT) is a non-pharmacological intervention for severe asthma whose mechanism of action is not completely explained by a reduction of airway smooth muscle (ASM). In this study we analyzed the effect of BT on nerve fibers and inflammatory components in the bronchial mucosa at 1 year. METHODS: Endobronchial biopsies were obtained from 12 subjects (mean age 47 +/- 11.3 years, 50% male) with severe asthma. Biopsies were performed at baseline (T0) and after 1 (T1), 2 (T2) and 12 (T12) months post-BT, and studied with immunocytochemistry and microscopy methods. Clinical data including Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) scores, exacerbations, hospitalizations, oral corticosteroids use were also collected at the same time points. RESULTS: A statistically significant reduction at T1, T2 and T12 of nerve fibers was observed in the submucosa and in ASM compared to T0. Among inflammatory cells, only CD68 showed significant changes at all time points. Improvement of all clinical outcomes was documented and persisted at the end of follow up. CONCLUSIONS: A reduction of nerve fibers in epithelium and in ASM occurs earlier and persists at one year after BT. We propose that nerve ablation may contribute to mediate the beneficial effects of BT in severe asthma. TRIAL REGISTRATION: Registered on April 2, 2013 at ClinicalTrials.gov Identifier: NCT01839591 . PMID- 29422040 TI - Combined diet and physical activity is better than diet or physical activity alone at improving health outcomes for patients in New Zealand's primary care intervention. AB - BACKGROUND: A dearth of knowledge exists regarding how multiple health behavior changes made within an exercise prescription programme can improve health parameters. This study aimed to analyse the impact of changing diet and increasing exercise on health improvements among exercise prescription patients. METHODS: In 2016, a representative sample of all enroled New Zealand exercise prescription programme (Green Prescription) patients were surveyed (N = 1488, 29% male, 46% >= 60 yr). Seven subsamples were created according to their associated health problems; metabolic (n = 1192), physiological (n = 627), psychological (n = 447), sleep problems (n = 253), breathing difficulties (n = 243), fall prevention (n = 104), and smoking (n = 67). After controlling for sex and age, multinomial regression analyses were executed. RESULTS: Overall, weight problems were most prevalent (n = 886, 60%), followed by high blood pressure/risk of stroke (n = 424, 29%), arthritis (n = 397, 27%), and back pain/problems (n = 382, 26%). Among patients who reported metabolic health problems, those who changed their diet were 7.2, 2.4 and 3.5 times more likely to lose weight, lower their blood pressure, and lower their cholesterol, respectively compared to the control group. Moreover, those who increased their physical activity levels were 5.2 times more likely to lose weight in comparison to controls. Patients who both increased physical activity and improved diet revealed higher odds of experiencing health improvements than those who only made one change. Most notably, the odds of losing weight were much higher for patients changing both behaviours (17.5) versus changing only physical activity (5.2) or only diet (7.2). CONCLUSIONS: Although it is not currently a programme objective, policy makers could include nutrition education within the Green Prescription initiative, particularly for the 55% of patients who changed their diet while in the programme. Physical activity prescription with a complimentary nutrition education component could benefit the largest group of patients who report metabolic health problems. PMID- 29422041 TI - Association between empirically derived dietary patterns with blood lipids, fasting blood glucose and blood pressure in adults - the India migration study. AB - BACKGROUND: Dietary patterns (DPs) in India are heterogenous. To date, data on association of indigenous DPs in India with risk factors of nutrition-related noncommunicable diseases (cardiovascular disease and diabetes), leading causes of premature death and disability, are limited. We aimed to evaluate the associations of empirically-derived DPs with blood lipids, fasting glucose and blood pressure levels in an adult Indian population recruited across four geographical regions of India. METHODS: We used cross-sectional data from the Indian Migration Study (2005-2007). Study participants included urban migrants, their rural siblings and urban residents and their urban siblings from Lucknow, Nagpur, Hyderabad and Bangalore (n = 7067, mean age 40.8 yrs). Information on diet (validated interviewer-administered, 184-item semi-quantitative food frequency questionnaire), tobacco consumption, alcohol intake, physical activity, medical history, as well as anthropometric measurements were collected. Fasting blood samples were collected for estimation of blood lipids and glucose. Principal component analysis (PCA) was used to identify major DPs based on eigenvalue> 1 and component interpretability. Robust standard error multivariable linear regression models were used to investigate the association of DPs (tertiles) with total cholesterol (TC), low density lipoprotein-cholesterol (LDL C), high density lipoprotein-cholesterol (HDL-C), triglycerides, fasting-blood glucose (FBG), systolic and diastolic blood pressure (SBP and DBP) levels. RESULTS: Three major DPs were identified: 'cereal-savoury' (cooked grains, rice/rice-based dishes, snacks, condiments, soups, nuts), 'fruit-vegetable-sweets snacks' (Western cereals, vegetables, fruit, fruit juices, cooked milk products, snacks, sugars, sweets) and 'animal food' (red meat, poultry, fish/seafood, eggs) patterns. High intake of the 'animal food' pattern was positively associated with levels of TC (beta = 0.10 mmol/L; 95% CI: 0.02, 0.17 mmol/L; p-trend = 0.013); LDL-C (beta = 0.07 mmol/L; 95% CI: 0.004, 0.14 mmol/L; p-trend = 0.041); HDL-C (beta = 0.02 mmol/L; 95% CI: 0.004, 0.04 mmol/L; p-trend = 0.016), FBG: (beta = 0.09 mmol/L; 95% CI: 0.01, 0.16 mmol/L; p-trend = 0.021) SBP (beta = 1.2 mm/Hg; 95% CI: 0.1, 2.3 mm/Hg; p-trend = 0.032); DBP: (beta = 0.9 mm/Hg; 95% CI: 0.2, 1.5 mm/Hg; p-trend = 0.013). The 'cereal-savoury' and 'fruit-vegetable-sweets snacks' patterns showed no association with any parameter except for a positive association with diastolic blood pressure for high intake of 'fruits-vegetables sweets-snacks' pattern. CONCLUSION: Our results indicate positive associations of the 'animal food' pattern with cardio-metabolic risk factors in India. Further longitudinal assessments of dietary patterns in India are required to validate the findings. PMID- 29422042 TI - Scoping out the literature on mobile needle and syringe programs-review of service delivery and client characteristics, operation, utilization, referrals, and impact. AB - BACKGROUND: Needle and syringe program (NSP) service delivery models encompass fixed sites, mobile services, vending machines, pharmacies, peer NSPs, street outreach, and inter-organizational agreements to add NSP services to other programs. For programs seeking to implement or improve mobile services, access to a synthesis of the evidence related to mobile services is beneficial, but lacking. METHODS: We used a scoping study method to search MEDLINE, PSYCHInfo, Embase, Scopus, and Sociological for relevant literature. We identified 39 relevant manuscripts published between 1975 and November 2017 after removing duplicates and non-relevant manuscripts from the 1313 identified by the search. RESULTS: Charting of the data showed that these publications reported findings related to the service delivery model characteristics, client characteristics, service utilization, specialized interventions offered on mobile NSPs, linking clients to other services, and impact on injection risk behaviors. Mobile NSPs are implemented in high-, medium-, and low-income countries; provide equipment distribution and many other harm reduction services; face limitations to service complement, confidentiality, and duration of interactions imposed by physical space; adapt to changes in locations and types of drug use; attract people who engage in high-risk/intensity injection behavior and who are often not reached by other service models; and may lead to reduced injection-related risks. DISCUSSION: It is not clear from the literature reviewed, what are, or if there are, a "core and essential" complement of services that mobile NSPs should offer. Decisions about service complement for mobile NSPs need to be made in relation to the context and also other available services. Reports of client visits to mobile NSP provide a picture of the volume and frequency of utilization but are difficult to compare given varied measures and reference periods. CONCLUSION: Mobile NSPs have an important role to play in improving HIV and HCV prevention efforts across the world. However, more work is needed to create clearer assessment metrics and to improve access to NSP services across the world. PMID- 29422043 TI - Respiratory health effects of exposure to low levels of airborne endotoxin - a systematic review. AB - BACKGROUND: Elevated endotoxin levels have been measured in ambient air around livestock farms, which is a cause of concern for neighbouring residents. There is clear evidence that occupational exposure to high concentrations of airborne endotoxin causes respiratory inflammation, respiratory symptoms and lung function decline. However, health effects of exposure to low levels of endotoxin are less well described. The aim of this systematic review is to summarize published associations between exposure to relatively low levels of airborne endotoxin and respiratory health endpoints. METHODS: Studies investigating respiratory effects of measured or modelled exposure to low levels of airborne endotoxin (average < 100 EU/m3) were eligible for inclusion. In total, 1362 articles were identified through a Pubmed database search, of which 31 articles were included in this review. Studies were included up to February 2017. Overview tables and forest plots were created, and study quality was assessed. RESULTS: Twenty-two included studies had a cross-sectional design, others were designed as longitudinal observational (n = 7) or experimental (n = 2) studies. Most studies (n = 23) were conducted in an occupational setting, some involved domestic or experimental exposure. Several studies reported statistically significant effects of exposure to low levels of endotoxin on respiratory symptoms and lung function. However, considerable heterogeneity existed in the outcomes of the included studies and no overall estimate could be provided by meta-analysis to quantify the possible relationship. Instead, a best evidence synthesis was performed among studies examining the exposure-response relationship between endotoxin and respiratory outcomes. Significant exposure-response relationships between endotoxin and symptoms and FEV1 were shown in several studies, with no conflicting findings in the studies included in the best evidence synthesis. Significantly different effects of endotoxin exposure were also seen in vulnerable subgroups (atopics and patients with broncho-obstructive disease) and smokers. CONCLUSIONS: Respiratory health effects of exposure to low levels of airborne endotoxin (< 100 EU/m3) seem plausible. Future studies are needed to investigate ambient exposure to endotoxin and potential respiratory health effects, especially in vulnerable subgroups of the population. PMID- 29422044 TI - Endothelial Cdc42 deficiency impairs endothelial regeneration and vascular repair after inflammatory vascular injury. AB - BACKGROUND: Endothelial cell (EC) regeneration is essential for inflammation resolution and vascular integrity recovery after inflammatory vascular injury. Cdc42 is a central regulator of cell survival and vessel formation in EC development. However, it is unknown that whether Cdc42 could be a regulating role of EC repair following the inflammatory injury in the lung. The study sought to test the hypothesis that Cdc42 is required for endothelial regeneration and vascular integrity recovery after LPS-induced inflammatory injury. METHODS AND RESULTS: The role of Cdc42 for the regulation of pulmonary vascular endothelial repair was tested in vitro and in vivo. In LPS-induced acute lung injury (ALI) mouse models, knockout of the Cdc42 gene in ECs increased inflammatory cell infiltration and pulmonary vascular leakage and inhibited vascular EC proliferation, which eventually resulted in more severe inflammatory lung injury. In addition, siRNA-mediated knockdown of Cdc42 protein on ECs disrupted cell proliferation and migration and tube formation, which are necessary processes for recovery after inflammatory vascular injury, resulting in inflammatory vascular injury recovery defects. CONCLUSION: We found that Cdc42 deficiency impairs EC function and regeneration, which are crucial in the post-inflammatory vascular injury repair process. These findings indicate that Cdc42 is a potential target for novel treatments designed to facilitate endothelial regeneration and vascular repair in inflammatory pulmonary vascular diseases, such as ALI/ARDS. PMID- 29422045 TI - Evaluating organizational change in health care: the patient-centered hospital model. AB - BACKGROUND: An increasing number of hospitals react to recent demographic, epidemiological and managerial challenges moving from a traditional organizational model to a Patient-Centered (PC) hospital model. Although the theoretical managerial literature on the PC hospital model is vast, quantitative evaluations of the performance of hospitals that moved from the traditional to the PC organizational structure is scarce. However, quantitative analysis of effects of managerial changes is important and can provide additional argument in support of innovation. METHODS: We take advantage of a quasi-experimental setting and of a unique administrative data set on the population of hospital discharge charts (HDCs) over a period of 9 years of Lombardy, the richest and one of the most populated region of Italy. During this period three important hospitals switched to the PC model in 2010, whereas all the others remained with the functional organizational model. This allowed us to develop a difference-in difference analysis of some selected measures of efficiency and effectiveness for PC hospitals focusing on the "between-variability" of the 25 major diagnostic categories (MDCs) in each hospital and estimating a difference-in-difference model. RESULTS: We contribute to the literature that addresses the evaluation of healthcare and hospital change by providing a quantitative estimation of efficiency and effectiveness changes following to the implementation of the PC hospital model. Results show that both efficiency and effectiveness have significantly increased in the average MDC of PC hospitals, thus confirming the need for policy makers to invest in new organizational models close to the principles of PC hospital structures. CONCLUSIONS: Although an organizational change towards the PC model can be a costly process, implying a rebalancing of responsibilities and power among hospital personnel (e.g. medical and nursing staff), our results suggest that changing towards a PC model can be worthwhile in terms of both efficacy and efficiency. This evidence can be used to inform and sustain hospital managers and policy makers in their hospital design efforts and to communicate the innovation advantages within the hospital organizations, among the personnel and in the public debate. PMID- 29422046 TI - Easy and fast method for expression and native extraction of Plasmodium vivax Duffy binding protein fragments. AB - BACKGROUND: The Plasmodium vivax Duffy binding protein (PvDBP) has been the most studied ligand binding human reticulocytes to date. This molecule has a cysteine rich domain in region II (RII) which has been used as control for evaluating the target cell binding activity of several parasite molecules. However, obtaining rPvDBP-RII in a soluble form using the Escherichia coli expression system usually requires laborious and time-consuming steps for recovering the molecule's structure and function, considering it is extracted from inclusion bodies. The present study describes an easy and fast method for expressing and obtaining several PvDBP fragments which should prove ideal for use in protein-cell interaction assays. RESULTS: Two PvDBP encoding regions (rii and riii/v) were cloned in pEXP5-CT vector and expressed in E. coli and extracted from the soluble fraction (rPvDBP-RIIS and rPvDBP-RIII/VS) using a simple freezing/thawing protocol. After the purification, dichroism analysis enabled verifying high rPvDBP-RIIS and rPvDBP-RIII/VS secondary structure alpha-helix content, which was lowered when molecules were extracted from inclusion bodies (rPvDBP-RIIIB and rPvDBP-RIII/VIB) using a denaturing step. Interestingly, rPvDBP-RIIS, but not rPvDBP-RIIIB, bound to human reticulocytes, while rPvDBP-RIII/VS and rPvDBP RIII/VIB bound to such cells in a similar way to negative control (cells incubated without recombinant proteins). CONCLUSIONS: This research has shown for the first time how rPvDBP-RII can be expressed and obtained in soluble form using the E. coli system and avoiding the denaturation and refolding steps commonly used. The results highlight the usefulness of the rPvDBP-RIII/VS fragment as a non-binding control for protein-cell target interaction assays. The soluble extraction protocol described is a good alternative to obtain fully functional P. vivax proteins in a fast and easy way, which will surely prove useful to laboratories working in studying this parasite's biology. PMID- 29422047 TI - Challenges in the use of the mental health information system in a resource limited setting: lessons from Ghana. AB - BACKGROUND: One of the most successful modes of record-keeping and data collection is the use of health management information systems, where patient information and management plans are uniformly entered into a database to streamline the information and for ease of further patient management. For mental healthcare, a Mental Health Information System (MHIS) has been found most successful since a properly established and operational MHIS is helpful for developing equitable and appropriate mental health care systems. Until 2010, the system of keeping patient records and information in the Accra Psychiatric Hospital of Ghana was old and outdated. In light of this and other factors, a complete reforming of the mental health information systems in three psychiatric hospitals in Ghana was undertaken in 2010. Four years after its implementation, we explored user experiences with the new system, and report here the challenges that were identified with use of the new MHIS. METHODS: Individual semi structured interviews were conducted with nine clinical and administrative staff of the Accra Psychiatric Hospital to examine their experiences with the new MHIS. Participants in the study were in three categories: clinical staff, administrator, and records clerk. Participants' knowledge of the system and its use, as well as the challenges they had experienced in its use were explored using an interpretative phenomenological approach. RESULTS: The data suggest that optimal use of the current MHIS had faced significant implementation challenges in a number of areas. Central challenges reported by users included increased workload, poor staff involvement and training, and absence of logistic support to keep the system running. CONCLUSIONS: Setting up a new system does not guarantee its success. As important as it is to have a mental health information system, its usefulness is largely dependent on proper implementation and maintenance. Further, the system can facilitate policy transformation only when the place of mental health in district, regional and national health discourse improves. PMID- 29422048 TI - Tools for surveillance of anti-malarial drug resistance: an assessment of the current landscape. AB - To limit the spread and impact of anti-malarial drug resistance and react accordingly, surveillance systems able to detect and track in real-time its emergence and spread need to be strengthened or in some places established. Currently, surveillance of anti-malarial drug resistance is done by any of three approaches: (1) in vivo studies to assess the efficacy of drugs in patients; (2) in vitro/ex vivo studies to evaluate parasite susceptibility to the drugs; and/or (3) molecular assays to detect validated gene mutations and/or gene copy number changes that are associated with drug resistance. These methods are complementary, as they evaluate different aspects of resistance; however, standardization of methods, especially for in vitro/ex vivo and molecular techniques, is lacking. The World Health Organization has developed a standard protocol for evaluating the efficacy of anti-malarial drugs, which is used by National Malaria Control Programmes to conduct their therapeutic efficacy studies. Regional networks, such as the East African Network for Monitoring Antimalarial Treatment and the Amazon Network for the Surveillance of Antimalarial Drug Resistance, have been set up to strengthen regional capacities for monitoring anti-malarial drug resistance. The Worldwide Antimalarial Resistance Network has been established to collate and provide global spatial and temporal trends information on the efficacy of anti-malarial drugs and resistance. While exchange of information across endemic countries is essential for monitoring anti-malarial resistance, sustainable funding for the surveillance and networking activities remains challenging. The technology landscape for molecular assays is progressing quite rapidly, and easy-to-use and affordable new techniques are becoming available. They also offer the advantage of high throughput analysis from a simple blood spots obtained from a finger prick. New technologies combined with the strengthening of national reference laboratories in malaria-endemic countries through standardized protocols and training plus the availability of a proficiency testing programme, would contribute to the improvement and sustainability of anti-malarial resistance surveillance networks worldwide. PMID- 29422049 TI - Results from the CLUES study: a cluster randomized trial for the evaluation of cardiovascular guideline implementation in primary care in Spain. AB - BACKGROUND: The implementation of evidence-based clinical practice guidelines (CPG) can improve patients care. To date, the impact of implementation strategies has not been evaluated in our context. This study is aimed to evaluate the effectiveness of a multifaceted tailored intervention targeting clinician education for the implementation of three cardiovascular risk-related CPGs (type 2 diabetes, hypertension and dyslipidemia) in primary care at the Basque Health Service compared with usual implementation. METHODS: We conducted a cluster randomized controlled trial in two urban districts with 43 primary care units (PCU). Data from all patients diagnosed with diabetes, hypertension and all those eligible for coronary risk (CR) assessment were included. In the control group, guidelines were introduced in the usual way (by email, intranet and clinical meetings). In the intervention group, the implementation also included a specific website and workshops. Primary endpoints were annual HbA1c testing (diabetes), annual general laboratory testing (hypertension) and annual CR assessment (dyslipidemia). Secondary endpoints were process, prescription and clinical endpoints related with guideline recommendations. Analysis was performed at a PCU level weighted by cluster size. RESULTS: Significant differences between groups were observed in primary outcomes in the dyslipidemia CPG: increased CR assessment for both women and men (weighted mean difference, WMD, 13.58 and 12.91%). No significant differences were observed in diabetes and hypertension CPGs primary outcomes. Regarding secondary endpoints, annual CR assessment was significantly higher in both diabetic and hypertensive patients in the intervention group (WMD 28.16 and 27.55%). Rates of CR assessment before starting new statin treatments also increased (WMD 23.09%), resulting in a lower rate of statin prescribing in low risk women. Diuretic prescribing was higher in the intervention group (WMD 20.59%). Clinical outcomes (HbA1c and blood pressure control) did not differ between groups. CONCLUSIONS: The multifaceted implementation proved to be effective to increase the CR assessment and to improve prescription, but ineffective to improve diabetes and hypertension related outcomes. In order to obtain real improvements when cardiovascular issues are tackled, perhaps other or additional interventions need to be implemented besides education of professionals. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN 88876909 (retrospectively registered on January 13, 2009). PMID- 29422050 TI - Improved fatty aldehyde and wax ester production by overexpression of fatty acyl CoA reductases. AB - BACKGROUND: Fatty aldehydes are industrially relevant compounds, which also represent a common metabolic intermediate in the microbial synthesis of various oleochemicals, including alkanes, fatty alcohols and wax esters. The key enzymes in biological fatty aldehyde production are the fatty acyl-CoA/ACP reductases (FARs) which reduce the activated acyl molecules to fatty aldehydes. Due to the disparity of FARs, identification and in vivo characterization of reductases with different properties are needed for the construction of tailored synthetic pathways for the production of various compounds. RESULTS: Fatty aldehyde production in Acinetobacter baylyi ADP1 was increased by the overexpression of three different FARs: a native A. baylyi FAR Acr1, a cyanobacterial Aar, and a putative, previously uncharacterized dehydrogenase (Ramo) from Nevskia ramosa. The fatty aldehyde production was followed in real-time inside the cells with a luminescence-based tool, and the highest aldehyde production was achieved with Aar. The fate of the overproduced fatty aldehydes was studied by measuring the production of wax esters by a native downstream pathway of A. baylyi, for which fatty aldehyde is a specific intermediate. The wax ester production was improved with the overexpression of Acr1 or Ramo compared to the wild type A. baylyi by more than two-fold, whereas the expression of Aar led to only subtle wax ester production. The overexpression of FARs did not affect the length of the acyl chains of the wax esters. CONCLUSIONS: The fatty aldehyde production, as well as the wax ester production of A. baylyi, was improved with the overexpression of a key enzyme in the pathway. The wax ester titer (0.45 g/l) achieved with the overexpression of Acr1 is the highest reported without hydrocarbon supplementation to the culture. The contrasting behavior of the different reductases highlight the significance of in vivo characterization of enzymes and emphasizes the possibilities provided by the diversity of FARs for pathway and product modulation. PMID- 29422052 TI - High willingness to use rapid fentanyl test strips among young adults who use drugs. AB - BACKGROUND: Synthetic opioid overdose mortality among young adults has risen more than 300% in the USA since 2013, primarily due to the contamination of heroin and other drugs with illicitly manufactured fentanyl. Rapid test strips, which can be used to detect the presence of fentanyl in drug samples (before use) or urine (after use), may help inform people about their exposure risk. The purpose of this study was to determine whether young adults who use drugs were willing to use rapid test strips as a harm reduction intervention to prevent overdose. We hypothesized that those who had ever overdosed would be more willing to use the test strips. METHODS: We recruited a convenience sample of young adults who use drugs in Rhode Island from May to September 2017. Eligible participants (aged 18 to 35 with past 30-day drug use) completed an interviewer-administered survey. The survey assessed participant's socio-demographic and behavioral characteristics, overdose risk, as well as suspected fentanyl exposure, and willingness to use take-home rapid test strips to detect fentanyl contamination in drugs or urine. Participants were then trained to use the test strips and were given ten to take home. RESULTS: Among 93 eligible participants, the mean age was 27 years (SD = 4.8), 56% (n = 52) of participants were male, and 56% (n = 52) were white. Over one third (n = 34, 37%) had a prior overdose. The vast majority (n = 86, 92%) of participants wanted to know if there was fentanyl in their drug supply prior to their use. Sixty-five (70%) participants reported concern that their drugs were contaminated with fentanyl. After the brief training, nearly all participants (n = 88, 95%) reported that they planned to use the test strips. CONCLUSIONS: More than 90% of participants reported willingness to use rapid test strips regardless of having ever overdosed, suggesting that rapid fentanyl testing is an acceptable harm reduction intervention among young people who use drugs in Rhode Island. Study follow-up is ongoing to determine whether, how, and under what circumstances participants used the rapid test strips and if a positive result contributed to changes in overdose risk behavior. PMID- 29422053 TI - Addressing female genital mutilation in Europe: a scoping review of approaches to participation, prevention, protection, and provision of services. AB - BACKGROUND: Public and policy attention to female genital mutilation (FGM) in diaspora communities has increased in Europe, but research remains limited and misinformation abounds. As a first step to addressing these issues, this study explored FGM prevention and response interventions in Europe, using a scoping literature review and key informant interviews. METHODS: A scoping study design was selected, using Arksey and O'Malley's six-stage scoping framework to review identified sources. Key informant interviews were used to inform and add depth to literature findings. Findings were summarised thematically, guided by the Scottish Government's '4Ps' framework for tackling violence against women (i.e. participation, prevention, protection, providing services). RESULTS: Seventy literature sources, of 1095 screened, plus 16 individual and 3 group interview sources were included. Several countries have developed promising interventions supporting FGM resistance and recovery. However, gaps remain including community participation, professional knowledge and linkages, and evaluation of approaches. CONCLUSIONS: This scoping review is an initial attempt to describe available primary evidence on European initiatives responding to FGM. Further research is required to determine whether interventions are effective, while policy and practice development must be shaped and driven by the experiences, needs, and views of affected communities. PMID- 29422054 TI - Differential flow improvements after valve replacements in bicuspid aortic valve disease: a cardiovascular magnetic resonance assessment. AB - BACKGROUND: Abnormal aortic flow patterns in bicuspid aortic valve disease (BAV) may be partly responsible for the associated aortic dilation. Aortic valve replacement (AVR) may normalize flow patterns and potentially slow the concomitant aortic dilation. We therefore sought to examine differences in flow patterns post AVR. METHODS: Ninety participants underwent 4D flow cardiovascular magnetic resonance: 30 BAV patients with prior AVR (11 mechanical, 10 bioprosthetic, 9 Ross procedure), 30 BAV patients with a native aortic valve and 30 healthy subjects. RESULTS: The majority of subjects with mechanical AVR or Ross showed normal flow pattern (73% and 67% respectively) with near normal rotational flow values (7.2 +/- 3.9 and 10.6 +/- 10.5 mm2/ms respectively vs 3.8 +/- 3.1 mm2/s for healthy subjects; both p > 0.05); and reduced in-plane wall shear stress (0.19 +/- 0.13 N/m2 for mechanical AVR vs. 0.40 +/- 0.28 N/m2 for native BAV, p < 0.05). In contrast, all subjects with a bioprosthetic AVR had abnormal flow patterns (mainly marked right-handed helical flow), with comparable rotational flow values to native BAV (20.7 +/- 8.8 mm2/ms and 26.6 +/- 16.6 mm2/ms respectively, p > 0.05), and a similar pattern for wall shear stress. Data before and after AVR (n = 16) supported these findings: mechanical AVR showed a significant reduction in rotational flow (30.4 +/- 16.3 -> 7.3 +/- 4.1 mm2/ms; p < 0.05) and in-plane wall shear stress (0.47 +/- 0.20 -> 0.20 +/- 0.13 N/m2; p < 0.05), whereas these parameters remained similar in the bioprosthetic AVR group. CONCLUSIONS: Abnormal flow patterns in BAV disease tend to normalize after mechanical AVR or Ross procedure, in contrast to the remnant abnormal flow pattern after bioprosthetic AVR. This may in part explain different aortic growth rates post AVR in BAV observed in the literature, but requires confirmation in a prospective study. PMID- 29422055 TI - Calcineurin A beta deficiency ameliorates HFD-induced hypothalamic astrocytosis in mice. AB - ?: Astrocytosis is a reactive process involving cellular, molecular, and functional changes to facilitate neuronal survival, myelin preservation, blood brain barrier function and protective glial scar formation upon brain insult. The overall pro- or anti-inflammatory impact of reactive astrocytes appears to be driven in a context- and disease-driven manner by modulation of astrocytic Ca2+ homeostasis and activation of Ca2+/calmodulin-activated serine/threonine phosphatase calcineurin. Here, we aimed to assess whether calcineurin is dispensable for astrocytosis in the hypothalamus driven by prolonged high fat diet (HFD) feeding. Global deletion of calcineurin A beta (gene name: Ppp3cb) led to a decrease of glial fibrillary acidic protein (GFAP)-positive cells in the ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), and arcuate nucleus (ARC) of mice exposed chronically to HFD. The concomitant decrease in Iba1-positive microglia in the VMH further suggests a modest impact of Ppp3cb deletion on microgliosis. Pharmacological inhibition of calcineurin activity by Fk506 had no impact on IBA1-positive microglia in hypothalami of mice acutely exposed to HFD for 1 week. However, Fk506-treated mice displayed a decrease in GFAP levels in the ARC. In vivo effects could not be replicated in cell culture, where calcineurin inhibition by Fk506 had no effect on astrocytic morphology, astrocytic cell death, GFAP, and vimentin protein levels or microglia numbers in primary hypothalamic astrocytes and microglia co-cultures. Further, adenoviral overexpression of calcineurin subunit Ppp3r1 in primary glia culture did not lead to an increase in GFAP fluorescence intensity. Overall, our results point to a prominent role of calcineurin in mediating hypothalamic astrocytosis as response to acute and chronic HFD exposure. Moreover, discrepant findings in vivo and in cell culture indicate the necessity of studying astrocytes in their "natural" environment, i.e., preserving an intact hypothalamic microenvironment with neurons and non-neuronal cells in close proximity. PMID- 29422056 TI - Turning the tables on cytomegalovirus: targeting viral Fc receptors by CARs containing mutated CH2-CH3 IgG spacer domains. AB - BACKGROUND: During infection with human cytomegalovirus (HCMV) several viral proteins occur on cell surfaces in high quantity. We thus pursue an HLA independent approach for immunotherapy of HCMV using chimeric antigen receptors (CARs) and bispecific BiTE(r) antibody constructs. In this context, HCMV-encoded proteins that mediate viral immune evasion and bind human IgG might represent particularly attractive target antigens. Unlike in observations of similar approaches for HIV and hepatitis B and C viruses, however, HCMV-infected cells develop a striking resistance to cytotoxic effector functions at later stages of the replication cycle. In our study we therefore wanted to test two hypotheses: (1) CAR T cells can efficiently inhibit HCMV replication independently from cytotoxic effector functions, and (2) HCMV can be targeted by CH2-CH3 IgG spacer domains that contain mutations previously reported to prevent exhaustion and to rescue CAR T cell function in vivo. METHODS: Replication of GFP-encoding recombinant HCMV in fibroblasts in the presence and absence of supernatants from T cell co-cultures plus/minus cytokine neutralizing antibodies was analyzed by flow cytometry. CARs with wild type and mutated CH2-CH3 domains were expressed in human T cells by mRNA electroporation, and the function of the CARs was assessed by quantifying T cell cytokine secretion. RESULTS: We confirm and extend previous evidence of antiviral cytokine effects and demonstrate that CAR T cells strongly block HCMV replication in fibroblasts mainly by combined secretion of IFN-gamma and TNF. Furthermore, we show that fibroblasts infected with HCMV strains AD169 and Towne starting from day 3 have a high capacity for binding of human IgG1 and also strongly activate T cells expressing a CAR with CH2-CH3 domain. Importantly, we further show that mutations in the CH2-CH3 domain of IgG1 and IgG4, which were previously reported to rescue CAR T cell function by abrogating interaction with endogenous Fc receptors (FcRs), still enable recognition of FcRs encoded by HCMV. CONCLUSIONS: Our findings identify HCMV-encoded FcRs as an attractive additional target for HCMV immunotherapy by CARs and possibly bispecific antibodies. The use of specifically mutated IgG domains that bind to HCMV-FcRs without recognizing endogenous FcRs may supersede screening for novel binders directed against individual HCMV-FcRs. PMID- 29422057 TI - Navigation delivery models and roles of navigators in primary care: a scoping literature review. AB - BACKGROUND: Systems navigation provided by individuals or teams is emerging as a strategy to reduce barriers to care. Complex clients with health and social support needs in primary care experience fragmentation and gaps in service delivery. There is great diversity in the design of navigation and a lack of consensus on navigation roles and models in primary care. METHODS: We conducted a scoping literature review following established methods to explore the existing evidence on system navigation in primary care. To be included, studies had to be published in English between 1990 and 2013, and include a navigator or navigation process in a primary care setting that involves the community- based social services beyond the health care system. RESULTS: We included 34 papers in our review, most of which were descriptive papers, and the majority originated in the US. Most of the studies involved studies of individual navigators (lay person or nurse) and were developed to meet the needs of specific patient populations. We make an important contribution to the literature by highlighting navigation models that address both health and social service navigation. The emergence and development of system navigation signals an important shift in the recognition that health care and social care are inextricably linked especially to address the social determinants of health. CONCLUSIONS: There is a high degree of variance in the literature, but descriptive studies can inform further innovation and development of navigation interventions in primary care. PMID- 29422058 TI - An evaluation of E. coli in urinary tract infection in emergency department at KAMC in Riyadh, Saudi Arabia: retrospective study. AB - BACKGROUND: Urinary tract infection (UTIS) is a common infectious disease in which level of antimicrobial resistance are alarming worldwide. Therefore, this study aims to describe the prevalence and the resistance pattern of the main bacteria responsible for UTIS Escherichia coli (E. coli). METHODS: Retrospective chart review for patients admitted to emergency department and diagnosed with UTIS at KAMC, in Riyadh, Saudi Arabia between January to March 2008 was performed. Antimicrobial susceptibility to ampicillin, augmentin (amoxicillin/clavulanate), cefazolin, co-trimoxazole (sulfamethoxazole/trimethoprim), ciprofloxacin, and nitrofurantoin, and cefpodoxime was determined for 101 E. coli urinary isolates. RESULTS: Escherichia coli was the most prevalent pathogen contributing to UTIS representing 93.55, 60.24, and 45.83% of all pathogen isolated from urine culture of pediatric, adult, and elderly, respectively. High rates of resistance to ampicillin (82.76, 58, and 63.64%) and co-trimoxazole (51.72, 42, and 59.09%), among E. coli isolated from pediatric, adult and elderly respectively. Nitrofurantoin was the most active agent, followed by ciprofloxacin, augmentin and cefazolin. 22.77% of E. coli isolates exhibited multiple drug resistance (MDR). Among 66 and 49 isolates resistant to ampicillin and co-trimoxazole, respectively, 34.84 and 42.85% were MDR. In contrast, all isolates resistant to augmentin and nitrofurantoin were MRD, while 72.7 and 82.4% of isolates resistant to ciprofloxacin and cefazolin were MDR. CONCLUSIONS: High resistance was observed to ampicillin and co-trimoxazole which commonly used as empirical treatments for UTIS, limiting their clinical use. This necessitates continuous surveillance for resistance pattern of uropathogens against antibiotics. PMID- 29422059 TI - Hyperammonemia alters membrane expression of GluA1 and GluA2 subunits of AMPA receptors in hippocampus by enhancing activation of the IL-1 receptor: underlying mechanisms. AB - BACKGROUND: Hyperammonemic rats reproduce the cognitive alterations of patients with hepatic encephalopathy, including altered spatial memory, attributed to altered membrane expression of AMPA receptor subunits in hippocampus. Neuroinflammation mediates these cognitive alterations. We hypothesized that hyperammonemia-induced increase in IL-1beta in hippocampus would be responsible for the altered GluA1 and GluA2 membrane expression. The aims of this work were to (1) assess if increased IL-1beta levels and activation of its receptor are responsible for the changes in GluA1 and/or GluA2 membrane expression in hyperammonemia and (2) identify the mechanisms by which activation of IL-1 receptor leads to altered membrane expression of GluA1 and GluA2. METHODS: We analyzed in hippocampal slices from control and hyperammonemic rat membrane expression of AMPA receptors using the BS3 cross-linker and phosphorylation of the GluA1 and GluA2 subunits using phosphor-specific antibodies. The IL-1 receptor was blocked with IL-Ra, and the signal transduction pathways involved in modulation of membrane expression of GluA1 and GluA2 were analyzed using inhibitors of key steps. RESULTS: Hyperammonemia reduces GluA1 and increases GluA2 membrane expression and reduces phosphorylation of GluA1 at Ser831 and of GluA2 at Ser880. Hyperammonemia increases IL-1beta, enhancing activation of IL-1 receptor. This leads to activation of Src. The changes in membrane expression of GluA1 and GluA2 are reversed by blocking the IL-1 receptor with IL-1Ra or by inhibiting Src with PP2. After Src activation, the pathways for GluA2 and GluA1 diverge. Src increases phosphorylation of GluN2B at Tyr14721 and membrane expression of GluN2B in hyperammonemic rats, leading to activation of MAP kinase p38, which binds to and reduces phosphorylation at Thr560 and activity of PKCzeta, resulting in reduced phosphorylation at Ser880 and enhanced membrane expression of GluA2. Increased Src activity in hyperammonemic rats also activates PKCdelta which enhances phosphorylation of GluN2B at Ser1303, reducing membrane expression of CaMKII and phosphorylation at Ser831 and membrane expression of GluA1. CONCLUSIONS: This work identifies two pathways by which neuroinflammation alters glutamatergic neurotransmission in hippocampus. The steps of the pathways identified could be targets to normalize neurotransmission in hyperammonemia and other pathologies associated with increased IL-1beta by acting, for example, on p38 or PKCdelta. IL-1beta alters membrane expression of GluA1 and GluA2 AMPA receptor subunits by two difrerent mechanisms in the hippocampus of hyperammonemic rats. PMID- 29422051 TI - A systematic literature review of reviews on techniques for physical activity measurement in adults: a DEDIPAC study. AB - The links between increased participation in Physical Activity (PA) and improvements in health are well established. As this body of evidence has grown, so too has the search for measures of PA with high levels of methodological effectiveness (i.e. validity, reliability and responsiveness to change). The aim of this "review of reviews" was to provide a comprehensive overview of the methodological effectiveness of currently employed measures of PA, to aid researchers in their selection of an appropriate tool. A total of 63 review articles were included in this review, and the original articles cited by these reviews were included in order to extract detailed information on methodological effectiveness.Self-report measures of PA have been most frequently examined for methodological effectiveness, with highly variable findings identified across a broad range of behaviours. The evidence-base for the methodological effectiveness of objective monitors, particularly accelerometers/activity monitors, is increasing, with lower levels of variability observed for validity and reliability when compared to subjective measures. Unfortunately, responsiveness to change across all measures and behaviours remains under-researched, with limited information available.Other criteria beyond methodological effectiveness often influence tool selection, including cost and feasibility. However, researchers must be aware of the methodological effectiveness of any measure selected for use when examining PA. Although no "perfect" tool for the examination of PA in adults exists, it is suggested that researchers aim to incorporate appropriate objective measures, specific to the behaviours of interests, when examining PA in free-living environments. PMID- 29422060 TI - Discovery and cellular stress pathway analysis of 1,4-naphthoquinone derivatives with novel, highly potent broad-spectrum anticancer activity. AB - BACKGROUND: Chemotherapy and targeted therapies have made important strides in cancer treatment yet they often fail and new therapies are still needed. Here, we employed a phenotypic screen to identify and analyze the mechanism of action of novel small molecules that interfere with critical pathways involved in tumor cell growth, using chemoresistant A375 melanoma cells as a model. METHODS: Cell culture studies were performed in ATCC-recommended media. Compounds, and compound libraries were obtained from Boston University or purchased commercially. Effects on A375 cell viability, proliferation and morphology were determined by Celigo Image Cytometer and viability staining. Anticancer activity of the lead compound was tested in a xenograft nude mouse model. Signaling and cell death pathways were analyzed by SDS-PAGE and immunoblotting, and/or fluorescence microscopy. RESULTS: After evaluating 4477 compounds, one hit compound CB533 was identified that caused significant reduction of A375 cell growth. CB533 is an unexplored 1,4 naphthoquinone (NQ) derivative which unlike 1,4-NQ, induced rapid cell death without generating reactive oxygen species (ROS). Structure-activity relationship analysis showed that a pyrrolidine in the 1,4-NQ nucleus in lead compound Pyr-1 yielded optimal activity. CB533 and Pyr-1 had growth-suppressing effects on a large variety of chemotherapy-resistant cancer cell lines in the nano to picomolar range. Pyr-1 also significantly reduced growth of MDA-MB-231 breast cancer cells in nude mice. Pyr-1 rapidly induced activation of major stress pathways and autophagy, which was efficiently blocked by ERK, and somewhat by PI3K inhibitors. CONCLUSION: CB533 and lead Pyr-1 represent novel broad-spectrum, anticancer compounds that are up to 1000-fold more potent than plumbagin, a natural 1,4-NQ with known anticancer activity. Since the growth suppression activities of CB533 and Pyr-1 are unaffected by the chemotherapy resistance of cancer cells, these compounds have promising therapeutic potential. The pyrrolidine in the 3 position of the 1,4-NQ nucleus of Pyr-1 is a critical component of the pharmacophore. Pyr-1-induced cellular stress was mediated by an ERK, and to a lesser extent by an AKT-dependent pathway without involving apoptosis. Our data suggest that Pyr-1 derives its greatly enhanced antitumor activity via mimicking ROS-induced stress signaling without generating ROS, and likely committing cells to autophagy. PMID- 29422061 TI - N-acetylcysteine exposure is associated with improved survival in anti-nuclear antibody seropositive patients with usual interstitial pneumonia. AB - BACKGROUND: Mortality is similarly high among individuals with usual interstitial pneumonia (UIP) due to idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF). Circulating anti-nuclear antibodies (ANA) are commonly found in this patient population, suggesting possible aberrant immune activation. Because an environment of oxidative stress can result from immunologic activation, we hypothesized that ANA positive patients with UIP would have improved outcome when exposed to the antioxidant N-acetylcysteine (NAC) compared to ANA negative patients. METHODS: A single center, retrospective cohort analysis was performed. Patients with UIP due to IPF and IPAF were stratified according to ANA status to and NAC exposure. Transplant-free survival (TFS) was assessed using the Kaplan-Meier estimator and multivariable Cox regression adjusted for diagnosis, gender/age/physiology score, immunosuppressant exposure and anti-fibrotic exposure. RESULTS: Of 293 individuals with UIP due to IPF (74%) or IPAF (26%), NAC exposure was documented in 58 (19.8%). Among NAC exposed individuals, 33 (56.9%) were ANA seropositive and 25 (43.1%) were seronegative. NAC exposure was associated with improved TFS survival among ANA seropositive individuals in unadjusted analysis (plogrank = 0.02) and after multi-variable adjustment (HR 0.51, 95% CI 0.30-0.87; p = 0.01). There was no association between NAC exposure and TFS in ANA seronegative individuals (HR 1.26, 95% CI 0.69-2.32; p = 0.45). Formal interaction testing confirmed NAC*ANA interaction (p = 0.04) and sensitivity analysis demonstrated an increasing effect size associated with NAC therapy as ANA titer increased. Among patients with available genetic data, a marginally higher proportion of ANA positive patients (p = 0.08) carried the rs3750920 (TOLLIP) genotype previously shown to predict favorable outcome in NAC exposed patients. CONCLUSION: NAC exposure is associated with improved transplant-free survival ANA positive patients with UIP. These findings support the prospective collection of ANA data in in future NAC clinical trials performed in patients with UIP. PMID- 29422062 TI - Sexual and reproductive health services (SRHS) for adolescents in Enugu state, Nigeria: a mixed methods approach. AB - BACKGROUND: Availability and accessibility of sexual and reproductive health services for adolescents are very crucial for prevention and control of sexual and reproductive health problems. These services also play vital roles in the promotion of adolescents' sexual and reproductive health generally. The main purpose of the study was to determine the availability and accessibility (geographical and financial) of sexual and reproductive health services (SRHS) among adolescents in Enugu State, Nigeria. METHODS: A mixed methods approach was adopted for the study. 192 health facilities were reached to check availability of SRH services. Randomly sampled 1447 adolescents (12-22 years) completed the questionnaire correctly. Twenty-seven interviews and 18 group discussions were conducted. Instruments for data collection consisted of a checklist, a questionnaire, a focus group discussion guide and an in-depth interview guide. All instruments were pre-tested. Quantitative data were analyzed using descriptive statistics and Chi-square tests. NVivo 11 Pro software was used to code and thematically analyze the qualitative data. RESULTS: A total of 1447 adolescents (between 12 and 22 years) completed the questionnaire correctly. Among these adolescents, males constituted 42.9% while females were 57.1%. The majority (86.7%) of the adolescents reported availability of safe motherhood services, and 67.5% reported availability of services for prevention and management of STIs and HIV and AIDS. The majority reported that these services were geographically accessible but few were financially accessible to adolescents. However, qualitative data revealed that available services were not specifically provided for adolescents but for general use. Age (p = <= .05), education (p = <= .05) and income (p = <= .05) were found to be significantly associated with access to SRHS. CONCLUSION: SRHS were generally physically available but not financially accessible to adolescents. Adolescents' clinics were not available and this could affect the access of SRHS by adolescents. Education and income were significantly associated with access to SRHS. PMID- 29422063 TI - ISRIA statement: ten-point guidelines for an effective process of research impact assessment. AB - As governments, funding agencies and research organisations worldwide seek to maximise both the financial and non-financial returns on investment in research, the way the research process is organised and funded is becoming increasingly under scrutiny. There are growing demands and aspirations to measure research impact (beyond academic publications), to understand how science works, and to optimise its societal and economic impact. In response, a multidisciplinary practice called research impact assessment is rapidly developing. Given that the practice is still in its formative stage, systematised recommendations or accepted standards for practitioners (such as funders and those responsible for managing research projects) across countries or disciplines to guide research impact assessment are not yet available.In this statement, we propose initial guidelines for a rigorous and effective process of research impact assessment applicable to all research disciplines and oriented towards practice. This statement systematises expert knowledge and practitioner experience from designing and delivering the International School on Research Impact Assessment (ISRIA). It brings together insights from over 450 experts and practitioners from 34 countries, who participated in the school during its 5-year run (from 2013 to 2017) and shares a set of core values from the school's learning programme. These insights are distilled into ten-point guidelines, which relate to (1) context, (2) purpose, (3) stakeholders' needs, (4) stakeholder engagement, (5) conceptual frameworks, (6) methods and data sources, (7) indicators and metrics, (8) ethics and conflicts of interest, (9) communication, and (10) community of practice.The guidelines can help practitioners improve and standardise the process of research impact assessment, but they are by no means exhaustive and require evaluation and continuous improvement. The prima facie effectiveness of the guidelines is based on the systematised expert and practitioner knowledge of the school's faculty and participants derived from their practical experience and research evidence. The current knowledge base has gaps in terms of the geographical and scientific discipline as well as stakeholder coverage and representation. The guidelines can be further strengthened through evaluation and continuous improvement by the global research impact assessment community. PMID- 29422064 TI - "Antimicrobial and antiproliferative activity of essential oil, aqueous and ethanolic extracts of Ocimum micranthum Willd leaves". AB - BACKGROUND: Ocimum micranthum Willd is a plant used in traditional medicine practiced in the region of the Yucatan peninsula. In particular, it is used for the treatment of cutaneous infections and wound healing, however there are currently no existing scientific studies that support these applications. The aim of the present study was to evaluate the antimicrobial and the in vitro proliferative activity (on healthy mammalian cell lines) of the essential oil and extracts (aqueous and ethanolic) of this plant. METHODS: The minimal inhibitory concentration (MIC) of essential oil and aqueous and ethanolic extracts of Ocimum micranthum leaves against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Candida albicans was determined using the microdilution technique. The in vitro proliferative activity of human fibroblast (hFB) and Chinese hamster ovary (CHO-K1) cells treated with these extracts was evaluated using the MTT test. The hFB cell line was also evaluated using Trypan Blue assay. RESULTS: Candida albicans was more susceptible to the ethanolic extract and the aqueous extract (MIC value of 5 MUL/mL and 80 MUL/mL respectively). In the case of Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa, the MIC of the aqueous and ethanolic extract was 125 MUL/mL. The aqueous extract showed a significant (p < 0.05) antiproliferative effect on hFB cells at a concentration of 4%, with cell proliferation percentage values of 73.56% and 20.59% by MTT method and Trypan Blue assay, respectively; the same effect was observed for the ethanolic extract at concentration from 0.06% to 0.25% using MTT method and at a concentration from 0.125% to 0.25% using Trypan Blue assay. In CHO-K1 cells an antiproliferative effect was observed at a concentration of 8% of aqueous extract and from 0.06% to 0.25% of ethanolic extract using the MTT method. CONCLUSION: These assays showed that low concentrations of essential oil and extracts of Ocimum micranthum leaves are sufficient to cause an antiproliferative effect on the hFB cell line but do not produce an antimicrobial effect against the microorganisms evaluated. More studies are necessary to improve understanding of the mechanism of action of the compounds implicated in the bioactivities shown by the crude extracts. PMID- 29422065 TI - Fresh insights into the pyrimidine metabolism in the trypanosomatids. AB - The trypanosomatid parasites continue their killing spree resulting in significant annual mortality due to the lack of effective treatments and the prominence of these diseases in poorer countries. These dimorphic parasites thrive unchecked in the host system, outsmarting the immune mechanisms. An understanding of biology of these parasitic forms will help in the management and elimination of these fatal diseases. Investigation of various metabolic pathways in these parasites has shed light in the understanding of the unique biology of the trypansomatids. An understanding of these pathways have helped in tracing the soft targets in the metabolic pathways, which could be used as effective drug targets which would further impact the therupeutic implications. Pyrimidine pathway is a vital metabolic pathway which yields in the formation of pyrimidines, which are then integrated in nucleic acids (DNA and RNA) in sugars (UDP sugars) and lipids (CDP lipids). A wealth of data and information has been generated in the past decades by in-depth analyses of pyrimidine pathway in the trypanosomatid parasites, which can aid in the identification of anomalies between the parasitic and host counterpart which could be further harnessed to develop therapeutic interventions for the treatment of parasitic diseases. This review presents an updated and comprehensive detailing of the pyrimidine metabolism in the trypansomatids, their uniqueness and their distinctions, and its possible outcomes that would aid in the eradication of these parasitic diseases. PMID- 29422067 TI - Predictors of hospital mortality in adult trauma patients receiving extracorporeal membrane oxygenation for advanced life support: a retrospective cohort study. AB - BACKGROUND: Using extracorporeal membrane oxygenation (ECMO) to provide advanced life support in adult trauma patients remains a controversial issue now. The study was aimed at identifying the independent predictors of hospital mortality in adult trauma patients receiving ECMO for advanced cardiopulmonary dysfunctions. METHODS: This retrospective study enrolled 36 adult trauma patients receiving ECMO due to advanced shock or respiratory failure in a level I trauma center between August 2006 and October 2014. Variables collected for analysis were demographics, serum biomarkers, characteristics of trauma, injury severity score (ISS), damage-control interventions, indications of ECMO, and associated complications. The outcomes were hospital mortality and hemorrhage on ECMO. The multivariate logistic regression method was used to identify the independent prognostic predictors for the outcomes. RESULTS: The medians of age and ISS were 36 (27-49) years and 29 (19-45). Twenty-three patients received damage-control interventions before ECMO. Among the 36 trauma patients, 14 received ECMO due to shock and 22 for respiratory failure. The complications of ECMO are major hemorrhages (n = 12), acute renal failure requiring hemodialysis (n = 10), and major brain events (n = 7). There were 15 patients died in hospital, and 9 of them were in the shock group. CONCLUSIONS: The severity of trauma and the type of cardiopulmonary dysfunction significantly affected the outcomes of ECMO used for sustaining patients with post-traumatic cardiopulmonary dysfunction. Hemorrhage on ECMO remained a concern while the device was required soon after trauma, although a heparin-minimized protocol was adopted. TRIAL REGISTRATION: This study reported a health care intervention on human participants and was retrospectively registered. The Chang Gung Medical Foundation Institutional Review Board approved the study (no. 201601610B0) on December 12, 2016. All of the data were extracted from December 14, 2016, to March 31, 2017. PMID- 29422066 TI - Genome-wide analyses reveal a role of Polycomb in promoting hypomethylation of DNA methylation valleys. AB - BACKGROUND: Previous studies showed that the majority of developmental genes are devoid of DNA methylation at promoters even when they are repressed. Such hypomethylated regions at developmental genes are unusually large and extend well beyond proximal promoters, forming DNA methylation valleys (DMVs) or DNA methylation canyons. However, it remains elusive how most developmental genes can evade DNA methylation regardless of their transcriptional states. RESULTS: We show that DMVs are hypomethylated in development and are highly conserved across vertebrates. Importantly, DMVs are hotspots of regulatory regions for key developmental genes and show low levels of deamination mutation rates. By analyzing a panel of DNA methylomes from mouse tissues, we identify a subset of DMVs that are dynamically methylated. These DMVs are strongly enriched for Polycomb-deposited H3K27me3 when the associated genes are silenced, and surprisingly show elevated DNA methylation upon gene activation. 4C-seq analyses indicates that Polycomb-bound DMVs form insulated and self-interacting chromatin domains. Further investigations show that DNA hypomethylation is better correlated with the binding of Polycomb than with H3K27me3. In support of a role of Polycomb in DMV hypomethylation, we observe aberrant methylation in DMVs in mouse embryonic stem cells deficient in the EED protein. Finally, we show that Polycomb regulates hypomethylation of DMVs likely through ten-eleven translocation (TET) proteins. CONCLUSIONS: We show that Polycomb promotes the hypomethylation of DMVs near key developmental genes. These data reveal a delicate interplay between histone modifiers and DNA methylation, which contributes to their division at distinct gene targets, allowing lineage specifying genes to largely maintain DNA methylation-free at regulatory elements. PMID- 29422068 TI - Early evaluation of radiation-induced parotid damage in patients with nasopharyngeal carcinoma by T2 mapping and mDIXON Quant imaging: initial findings. AB - BACKGROUND: Radiation-induced parotid damage is a common complication in patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy to head and neck region, which severely reduce the life quality of those patients. The aim of this study was to early evaluate the changes of irradiated parotid glands with T2 mapping and mDIXON Quant imaging. METHODS: Forty-one patients with NPC underwent conventional magnetic resonance imaging for nasopharynx and neck, and T2 mapping and mDIXON Quant imaging for bilateral parotid glands within 2 weeks before radiotherapy (pre-RT), 5 weeks after the beginning of radiotherapy (mid-RT), and 4 weeks after radiotherapy (post-RT). Parotid volume, T2 values, fat fraction (FF) values, and mean radiation dose were recorded and analyzed. RESULTS: From pre-RT to mid-RT, parotid volume decreased (atrophy rate, 27.0 +/- 11.5%), while parotid T2 and FF values increased (change rate, 6.0 +/- 6.2% for T2 value and 9.1 +/- 9.9% for FF value) significantly. From mid-RT to post-RT, parotid T2 value continuously increased (change rate, 4.6 +/- 7.7%), but parotid FF value decreased (change rate, - 9.9 +/- 18.2%) significantly. Change rate of parotid T2 value significantly correlated with parotid atrophy rate from pre-RT to post-RT (r = 0.313, P = 0.027). Multiple linear regression analysis showed that parotid T2 value (standardized coefficient [SC] = - 0.259, P = 0.001) and FF value (SC = 0.320, P = 0.014) negatively correlated with parotid volume, while parotid T2 value positively correlated with MR scan time point (SC = 0.476, P = 0.001) significantly. Parotid T2 and FF values showed excellent reproducibility (intraclass correlation coefficient, 0.935-0.992). CONCLUSIONS: T2 mapping and mDIXON Quant imaging is useful for noninvasive evaluation of radiation-induced parotid damage. PMID- 29422069 TI - IL-1 family cytokines and soluble receptors in systemic lupus erythematosus. AB - BACKGROUND: Dysregulated production of cytokines has a critical role in systemic lupus. The aim of this work is to identify, by a comprehensive analysis of IL-1 family cytokines and receptors in serum, correlation between cytokines/receptors' levels and the clinical and serological features of the disease. METHODS: A full clinical evaluation was performed in 74 patients with systemic lupus erythematosus (SLE). C3, C4, anti-dsDNA and anti-C1q antibodies were measured. Cytokines of the IL-1 family (IL-1alpha, IL-1beta, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, ST2/sIL-1R4) and antagonists (IL-1Ra, IL-18 binding protein (IL-18BP)) were measured in serum by multiarray ELISA. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Data were analysed by non-parametric tests and by multivariate analysis, using partial least squares (PLS) models. RESULTS: Total IL-18, IL-18BP, sIL-1R4 and IL-1Ra levels were higher in SLE vs. CONTROLS: Total and free IL-18 and sIL-1R4 were higher in patients with active vs. inactive disease and correlated with ECLAM, anti-C1q and anti-dsDNA antibodies. sIL-1R2 was higher in patients with inactive disease, was negatively correlated with ECLAM and anti-C1q antibodies and was positively correlated with C3 levels. PLS identified sIL-1R4, sIL-1R2 and anti dsDNA as variables distinguishing patients with active from those with inactive disease; sIL-1R4, IL-18BP and anti-dsDNA identified patients with active nephritis; sIL-1R4, C3, IL-18 and free IL-18 identified patients with haematological involvement. CONCLUSION: The data support the use of IL-18, sIL 1R2 and sIL-1R4 as biomarkers of disease activity and organ involvement, and suggest that failure in the inhibition of IL-1 activation may be a critical event in the active stages of SLE. PMID- 29422070 TI - Copeptin levels and commonly used laboratory parameters in hospitalised patients with severe hypernatraemia - the "Co-MED study". AB - BACKGROUND: Hypernatraemia is common in inpatients and is associated with substantial morbidity. Its differential diagnosis is challenging, and delayed treatment may have devastating consequences. The most important hormone for the regulation of water homeostasis is arginine vasopressin, and copeptin, the C terminal portion of the precursor peptide of arginine vasopressin, might be a reliable new parameter with which to assess the underlying cause of hypernatraemia. METHODS: In this prospective, multicentre, observational study conducted in two tertiary referral centres in Switzerland, 92 patients with severe hyperosmolar hypernatraemia (Na+ > 155 mmol/L) were included. After a standardised diagnostic evaluation, the underlying cause of hypernatraemia was identified and copeptin levels were measured. RESULTS: The most common aetiology of hypernatraemia was dehydration (DH) (n = 65 [71%]), followed by salt overload (SO) (n = 20 [22%]), central diabetes insipidus (CDI) (n = 5 [5%]) and nephrogenic diabetes insipidus (NDI) (n = 2 [2%]). Low urine osmolality was indicative for patients with CDI and NDI (P < 0.01). Patients with CDI had lower copeptin levels than patients with DH or SO (both P < 0.01) or those with NDI. Copeptin identified CDI with an AUC of 0.99 (95% CI 0.97-1.00), and a cut-off value <= 4.4pmol/L showed a sensitivity of 100% and a specificity of 99% to predict CDI. Similarly, urea values were lower in CDI than in DH or SO (P < 0.05 and P < 0.01, respectively) or NDI. The AUC for diagnosing CDI was 0.98 (95% CI 0.96-1.00), and a cut-off value < 5.05 mmol/L showed high specificity and sensitivity for the diagnosis of CDI (98% and 100%, respectively). Copeptin and urea could not differentiate hypernatraemia induced by DH from that induced by SO (P = 0.66 and P = 0.30, respectively). CONCLUSIONS: Copeptin and urea reliably identify patients with CDI and are therefore helpful tools for therapeutic management in patients with severe hypernatraemia. TRIALS REGISTRATION: ClinicalTrials.gov, NCT01456533 . Registered on 20 October 2011. PMID- 29422071 TI - Prevalence and outcome of patients with non-ST segment elevation myocardial infarction with occluded "culprit" artery - a systemic review and meta-analysis. AB - BACKGROUND: The aim was to determine the prevalence and impact of an occluded "culprit" artery (OCA) in patients with non-ST segment elevation myocardial infarction (NSTEMI). METHODS: We searched PubMed, EMBASE, and Web of Science, with no language restrictions, up to 1 Jul. 2016. Observational cohorts or clinical trials of adult NSTEMI were eligible for inclusion to determine the prevalence if the proportion of OCA on coronary angiography was reported. Studies were further eligible for inclusion to determine the outcome if the association between OCA and clinical endpoints was reported. RESULTS: Among the 60,898 patients with NSTEMI enrolled in 25 studies, 17,212 were found to have OCA. The average proportion of OCA in NSTEMI was 34% (95% CI 30-37%). Patients with OCA were more likely to have left circumflex artery as their culprit artery (odds ratio (OR) 1.65, 95% CI 1.15-2.37, p = 0.007), and this was associated with lower left ventricular ejection fraction (standard mean difference -0.29, 95% CI -0.34 to -0.34, p < 0.001), higher peak enzyme level (standard mean difference 0.43, 95% CI 0.27-0.58, p < 0.001), and higher risk for cardiogenic shock (OR 1.66, 95% CI 1.35-2.04, p < 0.001), compared with patients with a non-occlusive culprit artery. Death rate (OR 1.72, 95% CI 1.49-1.98, p < 0.001) and recurrent myocardial infarction (OR 1.7, 95% CI 1.06-2.75, p = 0.029) were also higher in patients with OCA, compared with patients with a non-occlusive culprit artery. CONCLUSIONS: Patients with OCA comprised a substantial portion of the NSTEMI population. These patients present with more severe symptoms and worse clinical outcome. Whether these patients should be treated with more aggressive strategy warrants further study. PMID- 29422072 TI - Proteomics analysis of faecal proteins in the tick Haemaphysalis flava. AB - BACKGROUND: Ticks and tick-borne diseases are of major public health concern. Currently, development of vaccines against ticks is considered crucial for their control. A critical step in this process is the screening of viable antigens. Faeces are byproducts of digestion and blood meal utilization, and partly reflect the vitality and vector potential of ticks. However, an integrated analysis of proteins in tick faeces is lacking. The present study explored the protein components in the faeces of the tick Haemaphysalis flava, by liquid chromatography-tandem mass spectrometry (LC/MS-MS) to identify potential protein antigens for vaccine development against ticks. METHODS: Faeces from adult H. flava engorged females were collected. Proteins were extracted from faeces, and the trypsin-digested peptides were analyzed by LC/MS-MS. High confidence proteins were identified based on unique peptides revealed by MS. Potential faecal protein genes, as well as their sources, were also characterized by searching previous transcriptome datasets from the salivary glands and midgut of H. flava. RESULTS: In total, 21 were recognized with confidence. Amongst these, 18 were of likely tick origin, while three proteins (serum albumin, haemoglobin alpha and beta subunits) were likely from hosts. Seventeen unigenes corresponding to these proteins were retrieved by searching our previous H. flava salivary glands and midgut transcriptomic datasets. Some proteins were reported to prevent blood clotting, play a role in immunity and antibiosis, and formation of musculature. The functions of the remaining proteins are unknown. CONCLUSIONS: Identifying antigens for tick vaccine development is feasible by analyzing the faecal proteome as well as the transcriptomes of salivary glands and midguts. The vast number of proteins detected in tick faeces highlights the complexity of blood digestion in ticks, a field that needs more investigation. PMID- 29422073 TI - Biomechanical effects of different vertebral heights after augmentation of osteoporotic vertebral compression fracture: a three-dimensional finite element analysis. AB - BACKGROUND: Clinical results have shown that different vertebral heights have been restored post-augmentation of osteoporotic vertebral compression fractures (OVCFs) and the treatment results are consistent. However, no significant results regarding biomechanical effects post-augmentation have been found with different types of vertebral deformity or vertebral heights by biomechanical analysis. Therefore, the present study aimed to investigate the biomechanical effects between different vertebral heights of OVCFs before and after augmentation using three-dimensional finite element analysis. METHODS: Four patients with OVCFs of T12 underwent computed tomography (CT) of the T11-L1 levels. The CT images were reconstructed as simulated three-dimensional finite-element models of the T11-L1 levels (before and after the T12 vertebra was augmented with cement). Four different kinds of vertebral height models included Genant semi-quantitative grades 0, 1, 2, and 3, which simulated unilateral augmentation. These models were assumed to represent vertical compression and flexion, left flexion, and right flexion loads, and the von Mises stresses of the T12 vertebral body were assessed under different vertebral heights before and after bone cement augmentation. RESULTS: Data showed that the von Mises stresses significantly increased under four loads of OVCFs of the T12 vertebral body before the operation from grade 0 to grade 3 vertebral heights. The maximum stress of grade 3 vertebral height pre augmentation was produced at approximately 200%, and at more than 200% for grade 0. The von Mises stresses were significantly different between different vertebral heights preoperatively. The von Mises stresses of the T12 vertebral body significantly decreased in four different loads and at different vertebral body heights (grades 0-3) after augmentation. There was no significant difference between the von Mises stresses of grade 0, 1, and 3 vertebral heights postoperatively. The von Mises stress significantly decreased between pre augmentation and post-augmentation in T12 OVCF models of grade 0-3 vertebral heights. CONCLUSION: Vertebral augmentation can sufficiently reduce von Mises stresses at different heights of OVCFs of the vertebral body, although this technique does not completely restore vertebral height to the anatomical criteria. PMID- 29422074 TI - Cardiac output monitoring: throw it out... or keep it? PMID- 29422075 TI - Arenavirus infection correlates with lower survival of its natural rodent host in a long-term capture-mark-recapture study. AB - BACKGROUND: Parasite evolution is hypothesized to select for levels of parasite virulence that maximise transmission success. When host population densities fluctuate, low levels of virulence with limited impact on the host are expected, as this should increase the likelihood of surviving periods of low host density. We examined the effects of Morogoro arenavirus on the survival and recapture probability of multimammate mice (Mastomys natalensis) using a seven-year capture mark-recapture time series. Mastomys natalensis is the natural host of Morogoro virus and is known for its strong seasonal density fluctuations. RESULTS: Antibody presence was negatively correlated with survival probability (effect size: 5-8% per month depending on season) but positively with recapture probability (effect size: 8%). CONCLUSIONS: The small negative correlation between host survival probability and antibody presence suggests that either the virus has a negative effect on host condition, or that hosts with lower survival probability are more likely to obtain Morogoro virus infection, for example due to particular behavioural or immunological traits. The latter hypothesis is supported by the positive correlation between antibody status and recapture probability which suggests that risky behaviour might increase the probability of becoming infected. PMID- 29422076 TI - Barriers and facilitators for the management of vertigo: a qualitative study with primary care providers. AB - BACKGROUND: Although the management of patients presenting with vertigo and dizziness in primary care has been reported to be inefficient, little is known about the primary care providers' (PCPs) perspectives, needs, and attitudes regarding vertigo management. The objective of this study was to understand which challenges and barriers PCPs see when diagnosing and treating patients presenting with vertigo or dizziness. Specifically, we wanted to identify facilitators and barriers of successful guideline implementation in order to inform the development of targeted interventions. METHODS: A theory-based interview structure was developed based on the implementation theory of capability, opportunity, and motivation for behaviour change (COM-B) using questions based on constructs from the Theoretical Domains Framework (TDF) and the Consolidated Framework for Implementation Research (CFIR). Transcripts of the semi-structured interviews were analysed using directed content analysis. The pathways through which guideline characteristics and supportive interventions affect the relationship between the PCPs' perceived capability, opportunity, and motivation as well as their practice of managing vertigo patients were graphically presented using the COM-B model structure. RESULTS: Twelve PCPs from Bavaria in Southern Germany participated in semi-structured interviews. Diagnostics posed the biggest challenge in vertigo management to the PCPs. Requirements for an acceptable guideline were stakeholder involvement in the development process, clarity of presentation, and high applicability. Guideline implementation might be effectively supported through educational meetings and sustained by organisational interventions. CONCLUSIONS: From the PCPs' perspective, both guideline characteristics and interventions supporting guideline implementation may help resolve challenges in vertigo management in primary care. These results should be used to guide future interventions in the primary care setting to ensure successful and targeted patient management. PMID- 29422078 TI - Long term clinical history of an Italian cohort of infantile onset Pompe disease treated with enzyme replacement therapy. AB - BACKGROUND: Enzyme replacement therapy (ERT) has deeply modified the clinical history of Infantile Onset Pompe Disease (IOPD). However, its long-term effectiveness is still not completely defined. Available data shows a close relationship between clinical outcome and patients' cross-reactive immunological status (CRIM), being CRIM-negative status a negative prognostic factor. At the same time limited data are available on the long-term treatment in CRIM-positive infants. METHODS: A retrospective multicentre observational study was designed to analyse the long-term effectiveness of ERT in IOPD. Thirteen Italian centres spread throughout the country were involved and a cohort of 28 patients (15 females, 13 males, born in the period: February 2002-January 2013) was enrolled. IOPD diagnosis was based on clinical symptoms, enzymatic and molecular analysis. All patients received ERT within the first year of life. Clinical, laboratory, and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 71 months (5 years 11 months). RESULTS: Median age at onset, diagnosis and start of ERT were 2, 3 and 4 months, respectively. CRIM status was available for 24/28 patients: 17/24 (71%) were CRIM-positive. Nineteen patients (67%) survived > 2 years: 4 were CRIM-negative, 14 CRIM-positive and one unknown. Six patients (5 CRIM-positive and one unknown) never needed ventilation support (21,4%) and seven (6 CRIM-positive and one unknown: 25%) developed independent ambulation although one subsequently lost this function. Brain imaging study was performed in 6 patients and showed peri-ventricular white matter abnormalities in all of them. Clinical follow-up confirmed the better prognosis for CRIM-positive patients, though a slow, progressive worsening of motor and/or respiratory functions was detected in 8 patients. CONCLUSIONS: These data are the result of the longest independent retrospective study on ERT in IOPD reported so far outside clinical trials. The data obtained confirmed the better outcome of the CRIM-positive patients but at the same time, showed the inability of the current therapeutic approach to reverse or stabilize the disease progression. The results also evidenced the involvement of central nervous system in Pompe disease. To better understand the disease clinical history and to improve treatment efficacy larger multicentre studies are needed as well as the development of new therapeutic approaches. PMID- 29422077 TI - Adiponectin aggravates bone erosion by promoting osteopontin production in synovial tissue of rheumatoid arthritis. AB - BACKGROUND: We have previously reported that adiponectin (AD), an adipokine that is secreted by adipocytes, correlates well with progressive bone erosion in rheumatoid arthritis (RA). The exact mechanism of AD in promoting joint destruction remains unclear. Osteopontin (OPN) is required for osteoclast recruitment. We hypothesized that AD exacerbates bone erosion by inducing OPN expression in synovial tissue. This study aimed to evaluate a novel role for AD in RA. METHODS: The serum levels of AD and OPN were determined in 38 patients with RA, 40 patients with osteoarthritis (OA), and 20 healthy controls using enzyme-linked immunosorbent assay (ELISA). AD and OPN production were measured by double immunofluorescence in RA and OA synovial tissue. Quantitative real-time PCR and immunofluorescence were used to evaluate the mRNA and protein expression levels of OPN in RA synovial fibroblasts (RASFs) and OA synovial fibroblasts after pre-incubation with AD, respectively. Migration of the RAW264.7 osteoclast precursor cell line was assessed using the Transwell migration assay and co culture system. Bone destruction and osteoclastogenesis were assessed by immunohistochemical staining, microcomputed tomography and tartrate-resistant acid phosphatase (TRAP) staining in AD-treated collagen-induced arthritis (CIA) mice with or without OPN silencing. The expression levels of OPN and integrin alphavbeta3 in the ankle joint tissues of the mice were examined by double immunofluorescence. RESULTS: Our results indicated that the AD and OPN expression levels increased noticeably and were associated with each other in the RA serum. The AD distribution was coincident with that of OPN in the RA synovial tissue. AD stimulation of RASFs increased OPN production in a dose-dependent manner. AD treated RASFs promoted RAW264.7 cell migration, and the effect was blocked with a specific antibody against OPN. Silencing of OPN using lentiviral-OPN short hairpin RNA reduced the number of TRAP-positive osteoclasts and the extent of bone erosion in the AD-treated CIA mice. When bound to integrin alphavbeta3, OPN functions as a mediator of AD and osteoclasts. CONCLUSIONS: Our study provides new evidence of AD involvement in bone erosion. AD induces the expression of OPN, which recruits osteoclasts and initiates bone erosion. These data highlight AD as a novel target for RA treatment. PMID- 29422079 TI - Characterization and expression analysis of a newly identified glutathione S transferase of the hard tick Haemaphysalis longicornis during blood-feeding. AB - BACKGROUND: Ticks are obligate hematophagous parasites important economically and to health. Ticks consume large amounts of blood for their survival and reproduction; however, large amounts of iron in blood could lead to oxidative stress. Ticks use several molecules such as glutathione S-transferases (GSTs), ferritins, and peroxiredoxins to cope with oxidative stress. This study aimed to identify and characterize the GSTs of the hard tick Haemaphysalis longicornis in order to determine if they have a role in coping with oxidative stress. METHODS: Genes encoding GSTs of H. longicornis were isolated from the midgut CDNA library. Genes have been cloned and recombinant GSTs have been expressed. The enzymatic activities, enzyme kinetic constants, and optimal pH of the recombinant GSTs toward 1-chloro-2,4-dinitrobenzene (CDNB) were determined. The gene transcription and protein expression profiles were determined in the whole ticks and internal organs, and developmental stages using real time RT-PCR and Western blotting during blood feeding. The localization of GST proteins in organs was also observed using immunofluorescent antibody test (IFAT). RESULTS: We have isolated two genes encoding GSTs (HlGST and HlGST2). The enzymatic activity toward CDNB is 9.75 +/- 3.04 units/mg protein for recombinant HlGST and 11.63 +/- 4.08 units/mg protein for recombinant HlGST2. Kinetic analysis of recombinant HlGST showed K m values of 0.82 +/- 0.14 mM and 0.64 +/- 0.32 mM for the function of CDNB and GSH, respectively. Meanwhile, recombinant HlGST2 has K m values of 0.61 +/- 0.20 mM and 0.53 +/- 0.02 mM for the function of CDNB and GSH, respectively. The optimum pH of recombinant HlGST and recombinant HlGST2 activity was 7.5-8.0. Transcription of both GSTs increases in different developmental stages and organs during blood-feeding. GST proteins are upregulated during blood-feeding but decreased upon engorgement in whole ticks and in some organs, such as the midgut and hemocytes. Interestingly, salivary glands, ovaries, and fat bodies showed decreasing protein expression during blood-feeding to engorgement. Varying localization of GSTs in the midgut, salivary glands, fat bodies, ovaries, and hemocytes was observed depending on the feeding state, especially in the midgut and salivary glands. CONCLUSIONS: In summary, a novel GST of H. longicornis has been identified. Characterization of the GSTs showed that GSTs have positive correlation with the degree and localization of oxidative stress during blood feeding. This could indicate their protective role during oxidative stress. PMID- 29422080 TI - Operationalizing a model to quantify implementation of a multi-component intervention in a stepped-wedge trial. AB - BACKGROUND: It is challenging to interpret the results of multifaceted interventions due to complex program theories that are difficult to measure in a quantifiable manner. The aims of this paper were, first, to develop a model for a comprehensive quantitative implementation evaluation and, second, to operationalize it in the process evaluation of the stepped-wedge cluster randomized controlled trial: "Prevention of low back pain and its consequences among nurses' aides in elderly care" to investigate if implementation differed across intervention components, steps, and settings (workplaces). METHODS: Operationalization of a quantifiable measure of implementation requires three steps: (1) development of a program logic and intervention protocol, (2) description of a complete and acceptable delivery of the intervention, and (3) description of what determines the receipt of the intervention. Program logic from a previously developed multifaceted stepped-wedge intervention was used. The optimal delivery of the intervention was defined as the deliverers' full understanding and following of the intervention protocol and that they performed their best and contributed to the participants' attention and motivation (fidelity). The optimal receipt of the intervention was defined as participants being fully present at all intervention activities (participation), being motivated and satisfied, and having a good social support (responsiveness). Measurements of the fidelity, participation, and responsiveness were obtained from logbooks and questionnaires. Fidelity was multiplied by participation to measure exposure of the intervention to the individual. The implementation was determined from optimal delivery and optimal receipt on a scale from 0 (no implementation) to 100 (full implementation) on individual and organizational level. RESULTS: Out of 753 sessions, 95% were delivered. The sessions were delivered with 91% success (fidelity) across the organization. Average participation, fidelity, exposure, and responsiveness were 50, 93, 48, and 89% across all participants. The implementation of the intervention was uniform across steps (p = 0.252) and workplaces (p = 0.125) but not for intervention components (p = 0.000). However, participation, fidelity, exposure, and responsiveness varied between workplaces. CONCLUSIONS: This study developed a quantifiable implementation evaluation measuring participation, fidelity, exposure, and responsiveness. The quantifiable implementation evaluation was suitable for comparing implementation across steps, components, and settings and can be applied in the analyses on the impact of implementation of complex interventions. PMID- 29422081 TI - Bluetongue disease in small ruminants in south western Ethiopia: cross-sectional sero-epidemiological study. AB - OBJECTIVE: The status of bluetongue disease, vectors for transmission of the disease and the serotypes involved are not clearly known in Ethiopia. This sero epidemiological study was conducted to determine the seroprevalence and associated risk factors of bluetongue in small ruminants of South Western Ethiopia. RESULT: 422 serum samples were screened for the presence of bluetongue virus (BTV) specific antibodies using competitive enzyme-linked immunosorbent assay (c-ELISA) and 30.6% (129/422) (confidence interval CI 26.2-35%) of the sheep and goat serum samples were found positive. Multivariate analysis of several risk factors like age, sex, altitude, body condition and species of animals were studied and it was observed that species of animals, age and altitude had significant influence (P < 0.05) on seropositivity to BTV. Goats showed more seropositivity to bluetongue as compared to sheep [AOR = 2.4, 95% CI (1.5-3.9), P = 0.001], adult animals were more seropositive [AOR = 3.1, 95% CI (1.9-5.1), P = 0.001] than other age groups and animals at the lowland [AOR = 3.1, 95% CI (1.5-6.4), P = 0.002] showed more seropositivity to bluetongue than midland and high land. Sex and body condition of the animals had no statistically significant (P > 0.05) effect on seropositivity to bluetongue. PMID- 29422083 TI - Seroprevalence of hepatitis B surface antigen (HBsAg) in Bo, Sierra Leone, 2012 2013. AB - OBJECTIVE: The aim of this study was to determine the prevalence of hepatitis B surface antigen (HBsAg) among febrile individuals tested at Mercy Hospital Research Laboratory (MHRL) in Bo, Sierra Leone. RESULTS: A total of 860 febrile individuals ages 5 years and older were tested by MHRL between July 2012 and June 2013 with a Standard Diagnostics Bioline HBsAg rapid diagnostic test. The overall HBsAg prevalence rate was 13.7%, including a rate of 15.5% among males and 12.6% among females. The HBsAg rate did not differ by child or adult age group (p > 0.5). The prevalence rate in Bo was similar to the 11-15% HBsAg prevalence rates reported in the past decade from other studies across West Africa. Scaling up the infant hepatitis B vaccination program in Sierra Leone will be important for reducing the future burden of disease and premature death attributable to chronic viral hepatitis B disease. PMID- 29422082 TI - CBX7 regulates stem cell-like properties of gastric cancer cells via p16 and AKT NF-kappaB-miR-21 pathways. AB - BACKGROUND: Chromobox protein homolog 7 (CBX7), a member of the polycomb group (PcG) family of proteins, is involved in the regulation of cell proliferation and cancer progression. PcG family members, such as BMI, Mel-18, and EZH2, are integral constituents of the polycomb repressive complexes (PRCs) and have been known to regulate cancer stem cell (CSC) phenotype. However, the role of other PRCs' constituents such as CBX7 in the regulation of CSC phenotype remains largely elusive. This study was to investigate the role of CBX7 in regulating stem cell-like properties of gastric cancer and the underlying mechanisms. METHODS: Firstly, the role of CBX7 in regulating stem cell-like properties of gastric cancer was investigated using sphere formation, Western blot, and xenograft tumor assays. Next, RNA interference and ectopic CBX7 expression were employed to determine the impact of CBX7 on the expression of CSC marker proteins and CSC characteristics. The expression of CBX7, its downstream targets, and stem cell markers were analyzed in gastric stem cell spheres, common cancer cells, and gastric cancer tissues. Finally, the pathways by which CBX7 regulates stem cell like properties of gastric cancer were explored. RESULTS: We found that CBX7, a constituent of the polycomb repressive complex 1 (PRC1), plays an important role in maintaining stem cell-like characteristics of gastric cancer cells via the activation of AKT pathway and the downregulation of p16. Spearman rank correlation analysis showed positive correlations among the expression of CBX7 and phospho-AKT (pAKT), stem cell markers OCT-4, and CD133 in gastric cancer tissues. In addition, CBX7 was found to upregulate microRNA-21 (miR-21) via the activation of AKT-NF-kappaB pathway, and miR-21 contributes to CBX7-mediated CSC characteristics. CONCLUSIONS: CBX7 positively regulates stem cell-like characteristics of gastric cancer cells by inhibiting p16 and activating AKT-NF kappaB-miR-21 pathway. PMID- 29422084 TI - Anti-CD11b antibody treatment suppresses the osteoclast generation, inflammatory cell infiltration, and autoantibody production in arthritis-prone FcgammaRIIB deficient mice. AB - BACKGROUND: Previously we established an arthritis-prone FcgammaRIIB-deficient mouse strain (designated KO1). Anti-mouse CD11b mAb (5C6) has been reported to inhibit the recruitment of peripheral CD11b+ myelomonocytic cells from the blood to the inflammatory site. These cells include neutrophils and monocytes, both of which play important roles in the development of arthritis. Here we treated KO1 mice with 5C6 mAb in order to study its effect on arthritis development. METHODS: To evaluate the disease-preventive effect of 5C6, 4-month-old preclinical KO1 mice were divided into three groups: the first treated with 5C6 for 6 months, the second treated with normal rat IgG for 6 months, as a control, and the third left untreated. Arthritis severity and immunological abnormalities were compared among the groups, along with transcriptional levels of several important arthritis related factors in ankle joints, spleen, and peripheral blood cells. RESULTS: The 5C6 treatment ameliorated arthritis in KO1 mice, showing decreases in inflammatory cell infiltration and osteoclast formation. Analysis of transcriptional levels in ankle joints revealed that compared with the two control groups, the 5C6-treated group showed downregulated expression of RANK, RANKL, MCP-1, RANTES, TNFalpha, and IL-6, and at the same time showed significantly up-regulated expression of the decoy receptor for RANKL, i.e. osteoprotegerin. In addition, the disease suppression was associated with the lower serum levels of autoantibodies, and the decreased frequencies of activated B cells and plasma cells. The expression levels of B cell activation/differentiation-related cytokines were suppressed in spleen and peripheral leukocytes of the 5C6-treated mice. Intriguingly, while untreated KO1 mice spontaneously developed marked monocytosis, the 5C6-treated mice showed the significantly down-regulated frequency of monocytes. CONCLUSIONS: The outcome of 5C6 treatment was complex, in which the 5C6-mediated disease-preventive effect is likely due on one hand to the decrease in the recruitment of inflammatory cells and osteoclast precursor monocytes from the periphery into the joints, and on the other hand to the suppression of B cell activation/maturation and of autoantibody production via the suppression of B cell stimulating cytokine production. The lower levels of these cytokines may be the secondary effect of the lower frequency of monocytes, since monocytes/macrophages are the major producers of these cytokines. PMID- 29422085 TI - Substitution of amino acid residue V1213 in the helicase domain of the genotype 3 hepatitis E virus reduces virus replication. AB - BACKGROUND: Genotype 3 hepatitis E virus (HEV) infection is generally associated with mild disease. However, recently eight genotype 3 HEV isolates were identified from patients with severe hepatitis. Importantly, three mutations (S605P, I978V and V1213A) in these genotype 3 isolates were found to be typical of genotype 4 HEV, which is sometime associated with more severe hepatitis. Therefore in this study we seek to determine if these unique mutations contribute to enhanced virus replication and thus potentially severe disease. METHODS: In the lack of an efficient cell culture system to study the effect of mutations on HEV replication, we developed a genotype 3 HEV replicon with Renilla luciferase (Rluc) as reporter and subsequently used it to construct numerous mutants, including swMu-1 (V1213A), swMu-2 (Q1246H), swMu-3 (V1213A and Q1246H), swMu-4 (S605P and I978V), and swMu-5 (V1213A, S605P and I978V). RNA transcripts from mutant replicons were transfected into Huh7 S10-3 liver cells to measure the effect of mutations on HEV replication efficiency. RESULTS: The results showed that the V1213A mutant had the highest reduction in HEV replication efficiency than other mutants. The V1213A and S605P + I978V mutations have a cumulative, if not synergistic, effect on HEV replication. The Q1246H mutant decreased HEV replication compared to the wild-type HEV Rluc replicon but replicated better than the V1213A mutant. The amino acid residue V1213 favors the replication of both genotypes 3 and 4 HEV strains, but not genotype 1 HEV. CONCLUSION: The results suggested that the V1213A mutation reduced HEV replication, but is likely not associated with the reported severe hepatitis caused by genotype 3 HEV isolates containing this mutation. PMID- 29422086 TI - Adipocytokines in obese Ghanaian subjects with or without type 2 diabetes. AB - OBJECTIVE: This study aimed to evaluate serum leptin and high sensitivity C reactive protein (hsCRP) concentrations in obese Ghanaians with or without type 2 diabetes and to find out the extent to which their levels are influenced by underlying disorders. RESULTS: Obese subjects with type 2 diabetes had lower leptin but higher hsCRP levels compared with obese non-diabetic controls. There were negative correlations within the control group for glucose vs % muscle mass (r = - 0.378, p = 0.016), leptin vs % muscle mass (r = - 0.555, p = 0.001) and within the obese diabetic group for leptin vs % muscle mass (r = - 0.602, p = 0.001). Obese persons without diabetes were about three times more likely to have higher leptin levels compared with their obese diabetic counterparts (Odds ratio = 3.315, p < 0.001). Obese females independently had a tenfold increase in leptin levels compared with obese males. PMID- 29422087 TI - Integrated vector control of Aedes aegypti mosquitoes around target houses. AB - BACKGROUND: The developing fetuses of pregnant women are at high risk of developing serious birth defects following Zika virus infections. We applied an Integrated Vector Control (IVC) approach using source reduction, larviciding, and mass trapping with non-insecticidal sticky traps to protect targeted houses by reducing the density of female Aedes aegypti mosquitoes. METHODS: We tested the hypothesis that Ae. aegypti density could be reduced to below three female mosquitoes/trap/week around a target house in the center of a circular area with a 150 m radius using IVC. Two non-adjacent areas within the same neighbourhood were selected and randomly designated as the treatment or control areas. Sentinel Autocidal Gravid Ovitraps (SAGO traps) were placed in each study area and were sampled weekly from May to November, during the 2016 Zika epidemic in Puerto Rico. The experimental design was longitudinal with pre-and post-IVC treatment observations between treatment and control areas, and a partial cross-over design, where IVC was applied to the original control area after 2 months to determine if Ae. aegypti density converged to levels observed in the treatment area. Pools of female Ae. aegypti mosquitoes were analyzed by RT-PCR to detect Zika, dengue and chikungunya virus RNA. RESULTS: Overall, pre-treatment mosquito densities in the inner (0-50 m; 15.6 mosquitoes/trap/week), intermediate (50-100 m; 18.1) and outer rings (100-150 m; 15.6) were reduced after treatment to 2.8, 4.1, and 4.3 in the inner, middle, and outer rings, respectively. Density at the target house in the treatment area changed from 27.7 mosquitoes/trap/week before IVC to 2.1 after IVC (92.4% reduction), whereas after treating the original control area (cross-over) density changed from 22.4 to 3.5 (84.3% reduction). Vector reductions were sustained in both areas after IVC. Zika virus was detected in Ae. aegypti, but the low incidence of the virus precluded assessing the impact of IVC on Zika transmission during the study. CONCLUSIONS: Applying IVC to circular areas that were surrounded by untreated areas significantly decreased the number of mosquitoes around target houses located in the center. Gravid Ae. aegypti females in the center of the 150 m areas fell below threshold levels that possibly protect against novel invading arboviruses, such as chikungunya and Zika. PMID- 29422088 TI - Associations of Bcl-2 rs956572 genotype groups in the structural covariance network in early-stage Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disease, and genetic differences may mediate neuronal degeneration. In humans, a single nucleotide polymorphism in the B-cell chronic lymphocytic leukemia/lymphoma-2 (Bcl-2) gene, rs956572, has been found to significantly modulate Bcl-2 protein expression in the brain. The Bcl-2 AA genotype has been associated with reduced Bcl-2 levels and lower gray matter volume in healthy populations. We hypothesized that different Bcl-2 genotype groups may modulate large-scale brain networks that determine neurobehavioral test scores. METHODS: Gray matter structural covariance networks (SCNs) were constructed in 104 patients with AD using T1-weighted magnetic resonance imaging with seed-based correlation analysis. The patients were stratified into two genotype groups on the basis of Bcl-2 expression (G carriers, n = 76; A homozygotes, n = 28). Four SCNs characteristic of AD were constructed from seeds in the default mode network, salience network, and executive control network, and cognitive test scores served as the major outcome factor. RESULTS: For the G carriers, influences of the SCNs were observed mostly in the default mode network, of which the peak clusters anchored by the posterior cingulate cortex seed determined the cognitive test scores. In contrast, genetic influences in the A homozygotes were found mainly in the executive control network, and both the dorsolateral prefrontal cortex seed and the interconnected peak clusters were correlated with the clinical scores. Despite a small number of cases, the A homozygotes showed greater covariance strength than the G carriers among all four SCNs. CONCLUSIONS: Our results suggest that the Bcl-2 rs956572 polymorphism is associated with different strengths of structural covariance in AD that determine clinical outcomes. The greater covariance strength in the four SCNs shown in the A homozygotes suggests that different Bcl-2 polymorphisms play different modulatory roles. PMID- 29422089 TI - Cement pulmonary embolism as a complication of percutaneous vertebroplasty in cancer patients. AB - BACKGROUND: Vertebroplasty is a minimally invasive procedure commonly performed for vertebral compression fractures secondary to osteoporosis or malignancy. Leakage of bone cement into the paravertebral venous system and cement pulmonary embolism (cPE) are well described, mostly in patients with osteoporosis. Little is known about the clinical sequelae and outcomes in cancer patients. In this study, we report our experience with cPE following vertebroplasty performed in cancer patients. METHODS: Records of all consecutive cancer patients who underwent vertebroplasty at our institution were retrospectively reviewed. The procedure was performed via percutaneous injection of barium-opacified polymethyl methacrylate cement. RESULTS: A total of 102 cancer patients with a median age of 53 (19-83) years were included. Seventy-eight (76.5%) patients had malignant vertebral fractures, and 24 (23.5%) patients had osteoporotic fractures. Cement PE was detected in 13 (12.7%) patients; 10 (76.9%) patients had malignant fractures, and the remaining three had osteoporotic fractures. Cement PE was mostly asymptomatic; however, 5 (38.5%) patients had respiratory symptoms that led to the diagnosis. Only the five symptomatic patients were anticoagulated. Cement PE was more common with multiple myeloma (MM); it occurred in 7 (18.9%) of the 37 patients with MM compared with only three (7.3%) of the 41 patients with other malignancies. No difference in incidence was observed between patients with osteoporotic or malignant vertebral fractures. CONCLUSIONS: Cement PE is a relatively common complication following vertebroplasty and is mostly asymptomatic. Multiple myeloma is associated with the highest risk. Large-scale prospective studies can help identify risk factors and clinical outcomes and could lead to better prevention and therapeutic strategies. PMID- 29422090 TI - Assessing refugee healthcare needs in Europe and implementing educational interventions in primary care: a focus on methods. AB - The current political crisis, conflicts and riots in many Middle Eastern and African countries have led to massive migration waves towards Europe. European countries, receiving these migratory waves as first port of entry (POE) over the past few years, were confronted with several challenges as a result of the sheer volume of newly arriving refugees. This humanitarian refugee crisis represents the biggest displacement crisis of a generation. Although the refugee crisis created significant challenges for all national healthcare systems across Europe, limited attention has been given to the role of primary health care (PHC) to facilitate an integrated delivery of care by enhancing care provision to refugees upon arrival, on transit or even for longer periods. Evidence-based interventions, encompassing elements of patient-centredness, shared decision making and compassionate care, could contribute to the assessment of refugee healthcare needs and to the development and the implementation of training programmes for rapid capacity-building for the needs of these vulnerable groups and in the context of integrated PHC care. This article reports on methods used for enhancing PHC for refugees through rapid capacity-building actions in the context of a structured European project under the auspices of the European Commission and funded under the 3rd Health Programme by the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA). The methods include the assessment of the health needs of all the people reaching Europe during the study period, and the identification, development, and testing of educational tools. The developed tools were evaluated following implementation in selected European primary care settings. PMID- 29422091 TI - Effects of a partially supervised conditioning programme in cystic fibrosis: an international multi-centre randomised controlled trial (ACTIVATE-CF): study protocol. AB - BACKGROUND: Physical activity (PA) and exercise have become an accepted and valued component of cystic fibrosis (CF) care. Regular PA and exercise can positively impact pulmonary function, improve physical fitness, and enhance health-related quality of life (HRQoL). However, motivating people to be more active is challenging. Supervised exercise programs are expensive and labour intensive, and adherence falls off significantly once supervision ends. Unsupervised or partially supervised programs are less costly and more flexible, but compliance can be more problematic. The primary objective of this study is to evaluate the effects of a partially supervised exercise intervention along with regular motivation on forced expiratory volume in 1 s (FEV1) at 6 months in a large international group of CF patients. Secondary endpoints include patient reported HRQoL, as well as levels of anxiety and depression, and control of blood sugar. METHODS/DESIGN: It is planned that a total of 292 patients with CF 12 years and older with a FEV1 >= 35% predicted shall be randomised. Following baseline assessments (2 visits) patients are randomised into an intervention and a control group. Thereafter, they will be seen every 3 months for assessments in their centre for one year (4 follow-up visits). Along with individual counselling to increase vigorous PA by at least 3 h per week on each clinic visit, the intervention group documents daily PA and inactivity time and receives a step counter to record their progress within a web-based diary. They also receive monthly phone calls from the study staff during the first 6 months of the study. After 6 months, they continue with the step counter and web-based programme for a further 6 months. The control group receives standard care and keeps their PA level constant during the study period. Thereafter, they receive the intervention as well. DISCUSSION: This is the first large, international multi-centre study to investigate the effects of a PA intervention in CF with motivational feedback on several health outcomes using modern technology. Should this relatively simple programme prove successful, it will be made available on a wider scale internationally. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01744561 ; Registration date: December 6, 2012. PMID- 29422092 TI - A rare presentation of pheochromocytoma in pregnancy: a case report. AB - BACKGROUND: Early diagnosis of pheochromocytoma and its proper management can lessen its mortality and morbidity. This case report describes a 24-year-old pregnant woman with an unusual presentation of pheochromocytoma. CASE PRESENTATION: An Iranian 24-year-old primigravid woman from Kordistan province was referred to our center with left flank pain at 37 weeks of gestation. She had a history of gestational diabetes mellitus since the 12th week of gestation which was managed by insulin administration. She also had a history of pulsatile bi temporal headache for 2 years prior to her referral to us. She underwent complete abdominal and pelvic ultrasound imaging for her flank pain. This examination revealed a heterogeneous mass of 119 * 87 * 79 mm above her left kidney, highly suspicious of being an adrenal-originating tumor. Subsequently, we consulted an endocrinologist. She underwent abdominopelvic magnetic resonance imaging and her 24-hour urine metanephrine, normetanephrine, and vanillylmandelic acid were assessed. Finally, the diagnosis of pheochromocytoma was confirmed. She underwent a cesarean section and adrenal mass excision at the 40th week of gestation. This timely diagnosis resulted in her proper management and good maternal and neonatal treatment outcomes. CONCLUSIONS: Our patient had pheochromocytoma during pregnancy. She had no complaints about hypertension before or during pregnancy until giving birth to her child; her only symptoms were a vague left flank pain, gestational diabetes, and headaches for the past 2 years. The unusual symptom of flank pain led to timely diagnosis and a good treatment outcome. PMID- 29422093 TI - Reduced coronary collateralization in type 2 diabetic patients with chronic total occlusion. AB - BACKGROUND: The extent of coronary collateral formation is a primary determinant of the severity of myocardial damage and mortality after coronary artery occlusion. Type 2 diabetes mellitus (T2DM) represents an important risk factor for impaired collateral vessel growth. However, the mechanism of reduced coronary collateralization in type 2 diabetic patients remains unclear. METHODS: With the reference to the recent researches, this review article describes the pathogenic effects of T2DM on collateral development and outlines possible clinical and biochemical markers associated with reduced coronary collateralization in type 2 diabetic patients with chronic total occlusion (CTO). RESULTS: Diffuse coronary atherosclerosis in T2DM reduces pressure gradient between collateral donor artery and collateral recipient one, limiting collateral vessel growth and function. An interaction between advanced glycation end-products and their receptor activates several intracellular signaling pathways, enhances oxidative stress and aggravates inflammatory process. Diabetic condition decreases pro-angiogenic factors especially vascular endothelial growth factor and other collateral vessel growth related parameters. Numerous clinical and biochemical factors that could possibly attenuate the development of coronary collaterals have been reported. Increased serum levels of glycated albumin, cystatin C, and adipokine C1q tumor necrosis factor related protein 1 were associated with poor coronary collateralization in type 2 diabetic patients with stable coronary artery disease and CTO. Diastolic blood pressure and stenosis severity of the predominant collateral donor artery also play a role in coronary collateral formation. CONCLUSIONS: T2DM impairs collateral vessel growth through multiple mechanisms involving arteriogenesis and angiogenesis, and coronary collateral formation in patients with T2DM and CTO is influenced by various clinical, biochemical and angiographic factors. This information provides insights into the understanding of coronary pathophysiology and searching for potential new therapeutic targets in T2DM. PMID- 29422094 TI - Patient's experiences with the care for juvenile idiopathic arthritis across Europe. AB - BACKGROUND: To assess the views of juvenile idiopathic arthritis (JIA) patients and their parents on the care and treatment they receive in referral pediatric rheumatology centers throughout Europe. METHODS: In a collaboration between physicians and patient associations, a questionnaire was developed, covering various domains of JIA care, including demographics, diagnosis, referrals to various health care professionals, access to pain and fatigue management and support groups, information they received about the disease and awareness of and participation in research. The questionnaire was translated and distributed by parent associations and pediatric rheumatologists in 25 countries, 22 of which were European. After completion the replies were entered on the PRINTO website. Replies could either be entered directly by parents on the website or on paper. In these cases, the replies were scanned and emailed by local hospital staff to Utrecht where they were entered by I.R. in the database. RESULTS: The survey was completed by 622 parents in 23 countries. The majority (66.7%) of patients were female, with median age 10-11 years at the completion of the questionnaire. Frequencies of self-reported JIA categories corresponded to literature. Some patients had never been referred to the ophthalmologist (22.8%) or physiotherapist (31.7%). Low rates of referral or access to fatigue (3.5%) or pain management teams (10.0%), age appropriate disease education (11.3%), special rehabilitation (13.7%) and support groups (20.1%) were observed. Many patients indicated they did not have contact details for urgent advice (35.9%) and did not receive information about immunizations (43.2%), research (55.6%) existence of transition of care clinics (89,2%) or financial support (89.7%). While on immunosuppressive drugs, about one half of patients did not receive information about immunizations, travelling, possible infections or how to deal with chickenpox or shingles. CONCLUSIONS: Low rates of referral to health care professionals may be due to children whose illness is well managed and who do not need additional support or information. Improvements are needed, especially in the areas of supportive care and information patients receive. It is also important to improve doctor patient communication between visits. Physicians can be instrumental in the setting up of support groups and increasing patients' awareness of existing support. Suggestions are given to convey crucial pieces of information structurally and repeatedly to ensure, among other things, compliance. PMID- 29422096 TI - Geographic variation in sexual behavior can explain geospatial heterogeneity in the severity of the HIV epidemic in Malawi. AB - BACKGROUND: In sub-Saharan Africa, where ~ 25 million individuals are infected with HIV and transmission is predominantly heterosexual, there is substantial geographic variation in the severity of epidemics. This variation has yet to be explained. Here, we propose that it is due to geographic variation in the size of the high-risk group (HRG): the group with a high number of sex partners. We test our hypothesis by conducting a geospatial analysis of data from Malawi, where ~ 13% of women and ~ 8% of men are infected with HIV. METHODS: We used georeferenced HIV testing and behavioral data from ~ 14,000 participants of a nationally representative population-level survey: the 2010 Malawi Demographic and Health Survey (MDHS). We constructed gender-stratified epidemic surface prevalence (ESP) maps by spatially smoothing and interpolating the HIV testing data. We used the behavioral data to construct gender-stratified risk maps that reveal geographic variation in the size of the HRG. We tested our hypothesis by fitting gender-stratified spatial error regression (SER) models to the MDHS data. RESULTS: The ESP maps show considerable geographic variation in prevalence: 1-29% (women), 1-20% (men). Risk maps reveal substantial geographic variation in the size of the HRG: 0-40% (women), 16-58% (men). Prevalence and the size of the HRG are highest in urban centers. However, the majority of HIV-infected individuals (~75% of women, ~ 80% of men) live in rural areas, as does most of the HRG (~ 80% of women, ~ 85% of men). We identify a significant (P < 0.001) geospatial relationship linking the size of the HRG with prevalence: the greater the size, the higher the prevalence. SER models show HIV prevalence in women is expected to exceed the national average in districts where > 20% of women are in the HRG. Most importantly, the SER models show that geographic variation in the size of the HRG can explain a substantial proportion (73% for women, 67% for men) of the geographic variation in epidemic severity. CONCLUSIONS: Taken together, our results provide substantial support for our hypothesis. They provide a potential mechanistic explanation for the geographic variation in the severity of the HIV epidemic in Malawi and, potentially, in other countries in sub-Saharan Africa. PMID- 29422095 TI - What do patients care most about in China's public hospitals? Interviews with patients in Jiangsu Province. AB - BACKGROUND: Evaluations on different aspects of the performance of public hospitals in China have been conducted, usually based on indicators developed by literature review and expert suggestions. The patient perspective was not always considered. This study aims to identify what patients care most about in China's public hospitals exclusively from a patient perspective. METHODS: A mix of stratified sampling and typical sampling was used to select 15 public hospitals in Jiangsu Province of China. In each sampled hospital, a convenient sample of six outpatients and six inpatients was selected to conduct face-to-face individual interviews. An interview guide consisting of six open-ended questions was designed. Donabedian's quality of care framework was applied to categorize themes and subthemes, which were generated from patients' interviews by using the conventional content analysis approach. Frequencies of themes and subthemes were counted. RESULTS: Nine key themes were identified regarding patients' concerns about hospital care, which were environment and facilities, professional competence, hospital reputation, and morals of medical staff in the "structure" category of Donabedian's framework, caring attitudes and emotional support, medical costs, communication and information, and efficiency and coordination of care in the "process" category, and health outcomes in the "outcome" category. CONCLUSIONS: This study has identified and prioritized the aspects that patients care most about in China's public hospitals in Jiangsu Province exclusively from a patient perspective. A measurement tool of patient-reported experiences in public hospitals could be built based on this study. Efforts should be made to represent the patient perspective to further improve the reform of public hospitals in China. PMID- 29422097 TI - Re-excision and survival following breast conserving surgery in early stage breast cancer patients: a population-based study. AB - BACKGROUND: Increasing population-based evidence suggests that patients who receive breast conserving surgery (BCS) plus radiotherapy have superior survival than those who receive mastectomy. It is unclear, however, how BCS followed by re excision is associated with all-cause and breast cancer-specific mortality, and whether the BCS survival advantage is maintained if re-excision is needed. The aim of this study was to investigate the clinical, patient, provider and geographic variation associated with receipt of re-excision surgery, and to examine the relationship between re-excision and all-cause and breast cancer specific mortality. METHODS: All women diagnosed with stage I-III breast cancer in Alberta, Canada from 2002 to 2009 were identified from the Alberta Cancer Registry, of which 11,626 were eligible for study inclusion. Type of first breast cancer surgery after diagnosis, subsequent re-excisions within 1 year, surgeon (anonymized), and hospital were obtained from provincial physician claims data. Multilevel logistic regression with surgeons and hospitals as crossed random effects was used to estimate the adjusted odds ratios of re-excision by the factors of interest. Poisson regression models were fitted to compare all-cause and breast cancer-specific mortality by surgical pattern. RESULTS: Re-excision surgery was received by 19% (N = 5659) of patients who initially received BCS. The adjusted odds of re-excision varied significantly by geography of surgery, and by individual surgeon among stage I and II patients beyond the variation explained by the factors investigated (Stage I OR standard deviation (SD) = 0.43; stage II OR SD = 0.39). Patients who were treated with BCS plus re-excision surgery with either mastectomy or further BCS had similar all-cause and breast cancer-specific mortality as those treated with BCS without re-excision. CONCLUSION: These results suggest that breast cancer patients who are treated with BCS plus re-excision surgery by either mastectomy or further BCS have similar survival as those treated with BCS without re-excision. The significant variation in the likelihood of re-excision by geography and by individual surgeon is concerning, especially given the costs to the patient associated with additional surgery and the financial costs to the health system. PMID- 29422098 TI - Screening of intact yeasts and cell extracts to reduce Scrapie prions during biotransformation of food waste. AB - Yeasts can be used to convert organic food wastes to protein-rich animal feed in order to recapture nutrients. However, the reuse of animal-derived waste poses a risk for the transmission of infectious prions that can cause neurodegeneration and fatality in humans and animals. The aim of this study was to investigate the ability of yeasts to reduce prion activity during the biotransformation of waste substrates-thereby becoming a biosafety hurdle in such a circular food system. During pre-screening, 30 yeast isolates were spiked with Classical Scrapie prions and incubated for 72 h in casein substrate, as a waste substitute. Based on reduced Scrapie seeding activity, waste biotransformation and protease activities, intact cells and cell extracts of 10 yeasts were further tested. Prion analysis showed that five yeast species reduced Scrapie seeding activity by approximately 1 log10 or 90%. Cryptococcus laurentii showed the most potential to reduce prion activity since both intact and extracted cells reduced Scrapie by 1 log10 and achieved the highest protease activity. These results show that select forms of yeast can act as a prion hurdle during the biotransformation of waste. However, the limited ability of yeasts to reduce prion activity warrants caution as a sole barrier to transmission as higher log reductions are needed before using waste-cultured yeast in circular food systems. PMID- 29422099 TI - Applying the results based management framework to the CERCA multi-component project in adolescent sexual and reproductive health: a retrospective analysis. AB - BACKGROUND: Adolescent sexual and reproductive health (SRH), problems such as unplanned pregnancies are complex and multifactorial, thus requiring multifaceted prevention interventions. Evaluating the impact of such interventions is important to ensure efficiency, effectiveness and accountability for project funders and community members. In this study, we propose Results Based Management (RBM) as a framework for project management, using the Community Embedded Reproductive Health Care for Adolescents (CERCA) as a case study for RBM. The CERCA Project (2010-2014) tested interventions to reduce adolescent pregnancy in three Latin American countries, Bolivia, Ecuador and Nicaragua. Activities were designed to increase adolescent SRH behaviors in four domains: communication with parents, partners and peers; access to SRH information; access to SRH services; and use of contraception. When the project ended, the outcome evaluation showed limited impact with concerns about accuracy of monitoring and attrition of participants. METHODS: We reviewed and analyzed a series of CERCA documents and related data sources. Key findings from these documents were organized within an RBM framework (planning, monitoring, and impact evaluation) to understand how CERCA methodology and performance might have reaped improved results. RESULTS: Strengths and weaknesses were identified in all three elements of the RBM framework. In Planning, the proposed Theory of Change (ToC) differed from that which was carried out in the intervention package. Each country implemented a different intervention package without articulated assumptions on how the activities of intervention would bring about change. In Monitoring, the project oversight was mainly based on administrative and financial requirements rather than monitoring fidelity and quality of intervention activities. In Impact Evaluation, the original CERCA evaluation assessed intervention effects among adolescents, without identifying success and failure factors related to the outcomes, the nature of the outcomes, or cost-effectiveness of interventions. CONCLUSIONS: This analysis showed that multi-country projects are complex, entail risks in execution and require robust project management. RBM can be a useful tool to ensure a systematic approach at different phases within a multi-country setting. PMID- 29422101 TI - Effect of spirometry on intra-thoracic pressures. AB - OBJECTIVE: Due to the high intra-thoracic pressures associated with forced vital capacity manoeuvres, spirometry is contraindicated for vulnerable patients. However, the typical pressure response to spirometry has not been reported. Eight healthy, recreationally-active men performed spirometry while oesophageal pressure was recorded using a latex balloon-tipped catheter. RESULTS: Peak oesophageal pressure during inspiration was - 47 +/- 9 cmH2O (37 +/- 10% of maximal inspiratory pressure), while peak oesophageal pressure during forced expiration was 102 +/- 34 cmH2O (75 +/- 17% of maximal expiratory pressure). The deleterious consequences of spirometry might be associated with intra-thoracic pressures that approach maximal values during forced expiration. PMID- 29422100 TI - The influence of norepinephrine and phenylephrine on cerebral perfusion and oxygenation during propofol-remifentanil and propofol-remifentanil dexmedetomidine anaesthesia in piglets. AB - BACKGROUND: Vasopressors are frequently used to increase blood pressure in order to ensure sufficient cerebral perfusion and oxygenation (CPO) during hypotensive periods in anaesthetized patients. Efficacy depends both on the vasopressor and anaesthetic protocol used. Propofol-remifentanil total intravenous anaesthesia (TIVA) is common in human anaesthesia, and dexmedetomidine is increasingly used as adjuvant to facilitate better haemodynamic stability and analgesia. Little is known of its interaction with vasopressors and subsequent effects on CPO. This study investigates the CPO response to infusions of norepinephrine and phenylephrine in piglets during propofol-remifentanil and propofol-remifentanil dexmedetomidine anaesthesia. Sixteen healthy female piglets (25-34 kg) were randomly allocated into a two-arm parallel group design with either normal blood pressure (NBP) or induced low blood pressure (LBP). Anaesthesia was induced with propofol without premedication and maintained with propofol-remifentanil TIVA, and finally supplemented with continuous infusion of dexmedetomidine. Norepinephrine and phenylephrine were infused in consecutive intervention periods before and after addition of dexmedetomidine. Cerebral perfusion measured by laser speckle contrast imaging was related to cerebral oxygenation as measured by an intracerebral Licox probe (partial pressure of oxygen) and transcranial near infrared spectroscopy technology (NIRS) (cerebral oxygen saturation). RESULTS: During propofol-remifentanil anaesthesia, increases in blood pressure by norepinephrine and phenylephrine did not change cerebral perfusion significantly, but cerebral partial pressure of oxygen (Licox) increased following vasopressors in both groups and increases following norepinephrine were significant (NBP: P = 0.04, LBP: P = 0.02). In contrast, cerebral oxygen saturation (NIRS) fell significantly in NBP following phenylephrine (P = 0.003), and following both norepinephrine (P = 0.02) and phenylephrine (P = 0.002) in LBP. Blood pressure increase by both norepinephrine and phenylephrine during propofol-remifentanil dexmedetomidine anaesthesia was not followed by significant changes in cerebral perfusion. Licox measures increased significantly following both vasopressors in both groups, whereas the decreases in NIRS measures were only significant in the NBP group. CONCLUSIONS: Cerebral partial pressure of oxygen measured by Licox increased significantly in concert with the vasopressor induced increases in blood pressure in healthy piglets with both normal and low blood pressure. Cerebral oxygenation assessed by intracerebral Licox and transcranial NIRS showed opposing results to vasopressor infusions. PMID- 29422102 TI - Low Dose Medicine: theoretical background and scientific evidence. PMID- 29422103 TI - Sow performance in multi-suckling pens with different management routines. AB - Production systems with group housing of sows during a part of the lactation are used in certified organic production and can increase the occurrence of lactational estrus thus making batch-wise breeding difficult. The aim of this study was to investigate the occurrence of lactational estrus and time at return to estrus after weaning by following the performance of the sow (change in body weight, back fat and litter size) in three different management routines. The sows and their litters were moved from individual to multi-suckling pen at one (W1; n = 14), two (W2; n = 13), or 3 weeks (W3; n = 16) post farrowing. All sows had a total lactation of 6 weeks. Ovulation was monitored by analysis of fecal progesterone metabolites. Only one sow (W3) ovulated during lactation. Sows in the W2 and W3 groups had a shorter weaning-to-standing estrus interval than W1 sows (2.6 +/- 0.3; 2.7 +/- 0.2 and 4.0 +/- 0.3 days respectively, P < 0.001). The W1-sows and piglets might have kept their nursing bond more intact all through the group housing since the piglets were completely dependent on the nursing at the time of their move to the group pen, thereby staying in lactational anestrus and retaining standard weaning-estrous interval. There was no difference in litter size at grouping or at weaning between management routines and parities. Third and later parity sows had significantly thicker back fat at farrowing and at weaning than 1st and 2nd parity sows (P < 0.05). In conclusion, the occurrence of lactational estrus can be low in a multi-suckling pen and the interval between farrowing and move to a multi-suckling pen can affect the weaning to estrus interval. The short weaning-to-standing estrus interval seen in W2 and W3 suggests that estrus detection should start immediately post weaning for sows kept in multi-suckling pens. PMID- 29422104 TI - Paradigm-shift: radiological changes in the asymptomatic iNPH-patient to be: an observational study. AB - BACKGROUND: Many radiological signs are known for the diagnosis of idiopathic normal pressure hydrocephalus (iNPH). However, there is little information about these signs in the pre-symptomatic phase. For pathophysiological investigative purposes we conducted a descriptive image analysis study on pre-symptomatic patients. METHODS: Patients that had contact with either the neurological or neurosurgical department of the university hospital Tuebingen from 2010 through 2016 with magnetic resonance images > 3 years before onset of symptoms, were included. The date of onset and severity of symptoms, date of first imaging and birth date were recorded. Evan's index (EI), width of the third ventricle (3VW), tight high convexity (THC), Sylvian fissure, extent of white matter hyperintensities and aqueductal flow were assessed in images before and around symptom onset. RESULTS: Ten patients were included. In all ten patients the first symptom was gait disturbance. Nine of ten pre-symptomatic images showed classic signs for iNPH. EI showed a significant increase between the pre-symptomatic and symptomatic phase. 3VW showed a trend for increase without significance. THC changed back and forth over time within some patients. CONCLUSIONS: In accordance with the scarce literature available, radiological changes are present at least 3 years before onset of iNPH-symptoms. EI seems to be a robust measure for pre symptomatic radiological changes. Extrapolating the data, the development of iNPH typical changes might be an insidious process and the development of THC might be a variable and non-linear process. Further studies with larger sample sizes are necessary to put these findings into the pathophysiological perspective for the development of iNPH. PMID- 29422105 TI - Normal radiological anatomy of thyroid cartilage in 600 Chinese individuals: implications for anterior cervical spine surgery. AB - BACKGROUND: Thyroid cartilage is an important barrier in anterior cervical approach surgery. The objective of this study is to establish normative values for thyroid cartilage at three planes and to determine their significance on preoperative positioning and intraoperative traction in surgery via the anterior cervical approach. METHODS: Neck CT scans were collected from 600 healthy adults who did not meet any of the exclusion criteria. Transverse diameters (D1, D2, and D3) of the superior border of the thyroid cartilage (SBTC), inferior border of the thyroid cartilage (IBTC), and the trachea transverse diameters of the inferior border of the cricoid cartilage (IBCC) were measured on a horizontal plane. RESULTS: All measured variables had intra-class correlation coefficients (ICCs) of >= 0.7. The differences in transverse diameters on the same plane between males and females were significantly different (all p < 0.001). The SBTC is most often at C4 in women (59.5%) and C4/5 in men (36.4%), the IBTC is most often at C5 in women (48.1%) and men (46.2%), and the IBCC is primarily located at C6 in women (45.2%) and C6 or C6/7 in men (34.4%) (all p < 0.001). CONCLUSION: We present normative values for thyroid cartilage at three planes of SBTC, IBTC, and IBCC in Chinese individuals. The individual and gender differences in the location of the thyroid cartilage and the size of the thyroid cartilage and the cricoid cartilage provide an anatomical basis to localize the skin incision, to predict the difficulty of intraoperative exposure and retractor pulling, and to identify that the thyroid cartilage protected the pharyngoesophageal wall. PMID- 29422106 TI - 1x8 Gy versus 5x4 Gy for metastatic epidural spinal cord compression: a matched pair study of three prognostic patient subgroups. AB - BACKGROUND: This study provides separate comparisons of 1 * 8 Gy to 5 * 4 Gy for metastatic epidural spinal cord compression (MESCC) in patients with poor, intermediate and favorable survival prognoses. METHODS: Patients receiving 1 * 8 Gy were matched to patients receiving 5 * 4 Gy for age, gender, performance status, tumor type, involved vertebrae, other bone metastases, visceral metastases, interval between tumor diagnosis and MESCC, ambulatory status and time developing motor deficits. From a study including patients with poor (N = 156) or intermediate (N = 86) survival prognoses, subgroup analyses were performed. Furthermore, 232 new patients with favorable prognoses matched the same way were included. RESULTS: In poor prognoses patients, 6-month survival rates were 10% after 1 * 8 Gy and 6% after 5 * 4 Gy (p = 0.38); in-field reRT rates in few patients alive at 6 months were 15 and 2% (p = 0.16). In intermediate prognoses patients, 6-month survival rates were 49% after 1 * 8 Gy and 58% after 5 * 4 Gy (p = 0.30). ReRT rates at 6 months were 23 and 13% (p = 0.25). In favorable prognoses patients, 6-month survival rates were 89% after 1 * 8 Gy and 91% after 5 * 4 Gy. ReRT rates at 6 months were 14 and 3% (p = 0.007). In no subgroup, RT regimen had a significant impact on motor function. CONCLUSIONS: Since in patients with poor prognoses, outcomes after 1 * 8 Gy and 5 * 4 Gy were not significantly different, 1 * 8 Gy may be an option. In patients with intermediate prognoses, a trend was found in favor of 5 * 4 Gy. In patients with favorable prognoses, need for in-field reRT was greater after 1 * 8 Gy. PMID- 29422108 TI - Endodontic management of mandibular canine with two roots and two canals: a rare case report. AB - BACKGROUND: In general, mandibular canines have a single root and a single canal. The occurrence of two roots and two canals is a rare entity ranging from 1 to 5%. The anatomy of root canal morphology plays a decisive role in determining the conditions under which endodontic treatment can be performed effectively. Successful endodontic treatment comprises proper diagnosis, meticulous cleaning and shaping followed by three dimensional obturation. Failure to do so may lead to postoperative diseases, pain and further complications. This paper reports successful management of a mandibular canine with two roots and two canals. CASE PRESENTATION: 45-year-old Nepalese women with a non-significant medical history presented with a chief complaint of pain in a lower left front tooth. The pain disturbed her sleep and lingered for several minutes even after removal of a thermal stimulus. Clinical examination and testing revealed generalized severe attrition with tenderness to percussion in the mandibular left canine. Electric pulp test for all the mandibular anteriors revealed almost no response in the mandibular left canine. Intraoral periapical radiographs in different angulations were taken which revealed two roots and two canals. A clinical diagnosis of chronic irreversible pulpitis with symptomatic apical periodontitis was made and root canal therapy was performed following the standard protocols. CONCLUSION: Although the prevalence of two roots and two canals in mandibular canine is very low, the clinician should always be mindful of variations in the number of roots and canals for proper management of such cases. PMID- 29422107 TI - Rapid and ultra-sensitive quantitation of disease-associated alpha-synuclein seeds in brain and cerebrospinal fluid by alphaSyn RT-QuIC. AB - The diagnosis and treatment of synucleinopathies such as Parkinson disease and dementia with Lewy bodies would be aided by the availability of assays for the pathogenic disease-associated forms of alpha-synuclein (alphaSynD) that are sufficiently sensitive, specific, and practical for analysis of accessible diagnostic specimens. Two recent alphaSynD seed amplification tests have provided the first prototypes for ultrasensitive and specific detection of alphaSynD in patients' cerebrospinal fluid. These prototypic assays require 5-13 days to perform. Here, we describe an improved alpha-synuclein real time quaking-induced conversion (alphaSyn RT-QuIC) assay that has similar sensitivity and specificity to the prior assays, but can be performed in 1-2 days with quantitation. Blinded analysis of cerebrospinal fluid from 29 synucleinopathy cases [12 Parkinson's and 17 dementia with Lewy bodies] and 31 non-synucleinopathy controls, including 16 Alzheimer's cases, yielded 93% diagnostic sensitivity and 100% specificity for this test so far. End-point dilution analyses allowed quantitation of relative amounts of alphaSynD seeding activity in cerebrospinal fluid samples, and detection in as little as 0.2 MUL. These results confirm that alphaSynD seeding activity is present in cerebrospinal fluid. We also demonstrate that it can be rapidly detected, and quantitated, even in early symptomatic stages of synucleinopathy. PMID- 29422109 TI - Lack of pathogenic potential of peripheral alpha-synuclein aggregates from Parkinson's disease patients. AB - In Parkinson's disease (PD) there is widespread accumulation in the brain of abnormal alpha-synuclein aggregates forming intraneuronal Lewy bodies (LB). It is now well established that LB-type alpha-synuclein aggregates also occur in the peripheral autonomic nervous system in PD, from where it has been speculated they may progressively spread to the central nervous system through synaptically connected brain networks and reach the substantia nigra to trigger herein dopaminergic dysfunction/degeneration and subsequent parkinsonism. Supporting a pathogenic role for alpha-synuclein aggregates we have previously shown that LB purified from postmortem PD brains promote alpha-synuclein pathology and dopaminergic neurodegeneration when intracerebrally inoculated into wild-type mice. However, the pathogenic capacity of PD-derived peripheral alpha-synuclein aggregates remains unknown. Here we addressed this question using purified LB type alpha-synuclein aggregates from postmortem PD stellate ganglia (SG), a paravertebral sympathetic ganglion that exhibits consistent and conspicuous Lewy pathology in all PD patients. In contrast to our previous findings using nigral LB extracts, intracerebral inoculation of SG-derived LB into mice did not trigger long-term nigrostriatal neurodegeneration nor alpha-synuclein pathology. The differential pathogenic capacities of central- and peripheral-derived alpha synuclein aggregates appear independent of the absolute amount and basic biochemical properties of alpha-synuclein within these aggregates and may rely instead on differences in alpha-synuclein conformation and/or yet unrecognized brain region-specific intrinsic factors. Our results argue against a putative pathogenic capacity of peripheral alpha-synuclein aggregates to promote alpha synuclein pathology in the brain, propagate between neuronal networks or induce neurodegeneration. PMID- 29422110 TI - Supporting shared hypothesis testing in the biomedical domain. AB - BACKGROUND: Pathogenesis of inflammatory diseases can be tracked by studying the causality relationships among the factors contributing to its development. We could, for instance, hypothesize on the connections of the pathogenesis outcomes to the observed conditions. And to prove such causal hypotheses we would need to have the full understanding of the causal relationships, and we would have to provide all the necessary evidences to support our claims. In practice, however, we might not possess all the background knowledge on the causality relationships, and we might be unable to collect all the evidence to prove our hypotheses. RESULTS: In this work we propose a methodology for the translation of biological knowledge on causality relationships of biological processes and their effects on conditions to a computational framework for hypothesis testing. The methodology consists of two main points: hypothesis graph construction from the formalization of the background knowledge on causality relationships, and confidence measurement in a causality hypothesis as a normalized weighted path computation in the hypothesis graph. In this framework, we can simulate collection of evidences and assess confidence in a causality hypothesis by measuring it proportionally to the amount of available knowledge and collected evidences. CONCLUSIONS: We evaluate our methodology on a hypothesis graph that represents both contributing factors which may cause cartilage degradation and the factors which might be caused by the cartilage degradation during osteoarthritis. Hypothesis graph construction has proven to be robust to the addition of potentially contradictory information on the simultaneously positive and negative effects. The obtained confidence measures for the specific causality hypotheses have been validated by our domain experts, and, correspond closely to their subjective assessments of confidences in investigated hypotheses. Overall, our methodology for a shared hypothesis testing framework exhibits important properties that researchers will find useful in literature review for their experimental studies, planning and prioritizing evidence collection acquisition procedures, and testing their hypotheses with different depths of knowledge on causal dependencies of biological processes and their effects on the observed conditions. PMID- 29422112 TI - miR-630 inhibits epithelial-to-mesenchymal transition (EMT) by regulating Wnt/betacatenin pathway in gastric cancer cells. AB - Despite availability of different treatments, worldwide gastric cancer remains the second causes of cancer-related deaths. This study was aimed to explore the role of miR-630 in gastric cancer by investigating the underlying mechanism of inhibiting epithelial-tomesenchymal transition (EMT) of SGC-7901 and BGC-823 cells through Wnt/beta-catenin pathway. Results showed that miR-630 was down regulated in several gastric cancer cell lines, including SGC-7901 and BGC-823. Transfection of miR-630 mimic showed significantly decrease of wound healing in scratch assay, in both two cell lines compared to scramble group. Also, transfection of miR-630 mimic inhibited cell viability, migration and invasion of gastric cancer cells. miR-630 mimic transfection suppressed EMT by activating Wnt/beta-catenin pathway. This was supported by the fact that miR-630-mediated suppression of EMT phenotype was reversed in presence of Wnt/beta-catenin inhibitor, ICG001. miR-630 plays a protective role against gastric cancer by suppressing EMT through activating Wnt/beta-catenin pathway. PMID- 29422111 TI - An unusual case of interrupted cervical aortic arch associated with long segment coarctation of the descending thoracic aorta. AB - Interrupted aortic arch is a rare congenital anomaly in newborns and infants and is commonly associated with other cardiovascular anomalies. Here, we report an unusual case of type A interrupted cervical aortic arch associated with long segment coarctation of the descending thoracic aorta. Patent ductus arteriosus reconstituted the descending thoracic aorta. Proximal segments of the left common carotid and left subclavian arteries were atretic. Echocardiography-gated multidetector CT angiography not only identified the type of aortic arch interruption in the neonate but also delineated the exact anatomical details. PMID- 29422113 TI - Puerarin Inhibits Proliferation and Induces Apoptosis by Upregulation of miR-16 in Bladder Cancer Cell Line T24. AB - Bladder cancer (BC) is a common disease of the urinary system. Puerarin is a flavonoid extracted from Pueraria lobata. However, the role of puerarin in BC remains unclear. Hence, this study aimed to investigate the effect of puerarin on BC cells. Cell viability, proliferation, and apoptosis were measured by CCK-8, BrdU assay, and flow cytometry analysis, respectively. The expressions of miR-16, apoptosis-related factors, and the main factors of the NF-kappaB pathway were analyzed by qRT-PCR and Western blot. In this study, we found that cell viability and proliferation were significantly reduced, cell apoptosis was enhanced, and the mRNA level of miR-16 was upregulated in puerarin-treated T24 cells. Further, silencing of miR-16 inhibited the decrease in cell viability and the increase in apoptosis. The expression of main factors involved in the NF-kappaB signaling pathway was downregulated in the puerarin group, while miR-16 silencing alleviated these downregulations. More importantly, puerarin deactivated the NF kappaB signaling pathway via upregulation of miR-16. Also, miR-16 downregulated COX-2 expression via deactivation of the NF-kappaB signaling pathway. This study demonstrated that puerarin could inhibit cell proliferation, promote cell apoptosis, and deactivate NF-kappaB signaling pathway via upregulation of miR-16 in T24 cells. PMID- 29422114 TI - Upregulated lncRNA CASC2 may inhibit malignant melanoma development through regulating miR-18a-5p/RUNX1. AB - This study aimed to investigate the effect and underlying mechanism of lncRNA CASC2 in malignant melanoma (MM). Expression of CASC2 in MM tissues and cells were detected. A375 cells were transfected with pc-CASC2, si-CASC2, miR-18a-5p inhibitor or corresponding controls, and then cell proliferation, migration and invasion were detected using MTT assay, colony formation assay, and Transwell analysis, respectively. The relationship of miR-18a-5p and CASC2 or RUNX1 was detected by luciferase reporter assay. Compared with normal skin tissues or cells, the levels of CASC2 and RUNX1 were significantly reduced, while miR-18a-5p level was obviously increased in MM tissues (all p < 0.01). Cell viability, colony number, migration and invasion were significantly decreased in cells with pc-CASC2 compared with cells with pcDNA3.1 (all p < 0.05), meanwhile, these effects were consistent with cells with miR-18a-5p inhibitor. Then, the luciferase reporter assay revealed that CASC2 acted as a molecular sponge for miR 18a-5p and RUNX1 was a target gene of miR-18a-5p. Moreover, CASC2 overexpression promoted the expression of RUNX1, while upregulated miR-18a-5p significantly reversed the effect of CASC2 on RUNX1 level (all p < 0.05). Upregulated CASC2 may inhibit cell proliferation, migration and invasion through regulating miR-18a-5p and its target gene RUNX1 in MM. PMID- 29422115 TI - Long non-coding RNA H19 promotes proliferation and invasion in human glioma cells by downregulating miR-152. AB - MiR-152 and lncRNA H19 have been frequently implicated in various cellular process including cell proliferation, invasion, angiogenesis and apoptosis. However, the interaction between miR-152 and H19 in glioma has never been reported. qRT PCR was used to examine the expression of miR 152 and H19 in human glioma cell lines and normal human astrocytes (NHAs) cells The interaction between miR 152 and lncRNA H19 were assessed by dual luciferase reporter assay. MTT assay and transwell invasion assay were used to determine the proliferation and invasion of U251 and U87 cells. Xenograft tumor experiment was performed to confirm the role of H19 in vivo. The results showed that H19 expression was upregulated and miR 152 expression was downregulated in human glioma cell lines. H19 downregulation or miR-152 upregulation suppressed glioma cell proliferation and invasion in vitro. Moreover, H19 and miR-152 directly regulated each other. Furthermore, decreased miR-152 expression alleviated si-H19-induced inhibitory effects on proliferation and invasion in glioma cells. As expected, H19 silencing hindered glioma growth in vivo. Taken together, H19 promoted glioma cell proliferation and invasion by negatively regulating miR-152 expression, providing evidence for the potential application of H19 as a biomarker and therapy target for glioma. PMID- 29422116 TI - MicroRNA-139-3p suppresses tumor growth and metastasis in hepatocellular carcinoma by repressing ANXA2R. AB - The direct roles of miR-139-3p on hepatocellular carcinoma (HCC) cell growth and metastasis remain poorly understood. We attempt to demonstrate the regulatory role of miR139-3p in hepatocellular carcinoma (HCC) progression and its mechanisms behind. Here, we show that miR-139-3p expression was significantly reduced in the HCC tissues compared to para-tumor tissues. Exogenous overexpression of miR-139-3p inhibited the migration and invasion of HCC cells, whereas down-regulation of miR-139-3p was able to induced HCC HepG2 and SNU-449 cell lines migration and invasion. In addition, miR-139-3p inhibited HCC growth and lung metastasis in vivo mouse model, which is mainly regulated by Annexin A2 Receptor (ANXA2R). Finally, we identified the expression of miR-139-3p was inversely correlated with ANXA2R expression in human HCC tissue. All these results demonstrated that miR-139-3p inhibited the metastasis process in HCC by down-regulating ANXA2R expression. PMID- 29422117 TI - WITHDRAWN: Inhibition of eukaryotic initiation factor 3B suppresses cells proliferation and promotes cells apoptosis in chronic myeloid leukemia. AB - Ahead of Print article withdrawn by publisher.. PMID- 29422118 TI - From fundamental science to product: a bottom-up approach to sunscreen development. AB - Despite the pivotal role of ultraviolet (UV) radiation in sustaining life on Earth, overexposure to this type of radiation can have catastrophic effects, such as skin cancer. Sunscreens, the most common form of artificial protection against such harmful effects, absorb UV radiation before it reaches vulnerable skin cells. Absorption of UV radiation prompts ultrafast molecular events in sunscreen molecules which, ideally, would allow for fast and safe dissipation of the excess energy. However, our knowledge of these mechanisms remains limited. In this article, we will review recent advances in the field of ultrafast photodynamics (light induced molecular processes occurring within femtoseconds, fs, 10-15 s to picoseconds, ps, 10-12 s) of sunscreens. We follow a bottom-up approach to common sunscreen active ingredients, analysing any emerging trends from the current literature on the subject. Moreover, we will identify the main questions that remain unanswered, pinpoint some of the main challenges and finally comment on the outlook of this exciting field of research. PMID- 29422119 TI - Darwin endures, despite disparagement. AB - Evolution lies at the heart of the life sciences, and Charles Darwin is a towering historical figure within evolutionary science. One testimony to his lasting influence is that declaring Darwin to have been wrong all along remains a provocative way to command attention. The present paper discusses various strands of 'Darwin was wrong' partisans and their divergent views and motives: some are looking to Darwin to justify or condemn the political ideologies that they support or reject; others are concerned with the corrupting influence that the bleak cosmic outlook of evolution is deemed to exert on the moral or religious rectitude of impressionable minds, or regard Darwinism as a direct assault on religion; philosophers question the very coherence of the entire enterprise; and certain biologists aspire to go down in history as even greater than Darwin. It is sobering to reflect that this diverse group is united only by their poor grasp of Darwin's theory of natural selection. PMID- 29422120 TI - Proper balance of solvent-solute and solute-solute interactions in the treatment of the diffusion of glucose using the Drude polarizable force field. AB - Motivated by underestimation of the diffusion constant of glucose in aqueous solution at high glucose concentrations we performed additional optimization of the Drude polarizable hexopyranose monosaccharide force field. This indicated aggregation of the glucose at higher concentrations, which is a concern for studies of complex glycan systems such as the HIV Envelope where high effective concentrations of sugars are present. High-level quantum mechanical calculations were undertaken on water monohydrate-glucose interactions, on water cluster glucose interactions and on glucose-glucose dimers in stacked (parallel) and perpendicular orientations. Optimization of the nonbond and dihedral parameters targeting these data yielded a revised model that showed improved agreement with experimental aqueous diffusion data. However, limitations in the diffusion constants were still present. These were due to the SWM4-NDP inherently overestimating the diffusion constant of water, a problem that was validated by calculation of the aqueous diffusion constants using the SWM6-NDP water model. In addition, results show the water diffusion constant to be significantly overestimated at high glucose concentrations though the glucose diffusion is in satisfactory agreement with experiment. These results indicate the subtle balance of water-sugar, water-water and sugar-sugar interactions that needs to be properly modeled to account for the full range of aqueous behavior of sugars in aqueous solution. PMID- 29422121 TI - L-Proline/CeCl3.7H2O-NaI mediated stereoselective synthesis of alpha-2-deoxy glycosides from glucal. AB - Glucal with different alcohols can be converted into the corresponding 2-deoxy glycosides without Ferrier rearrangement in high yield by treatment with eco friendly transition metal based catalysts [CuCl3.2H2O-NaI (A) or CeCl3.7H2O-NaI (B)] and chiral amine ligand L-proline at various reaction conditions which were optimized for stereoselectivity. The catalyst CeCl3.7H2O-NaI (B) and ligand L proline in toluene, was found to be much more efficient and high atom economic for the stereoselective glycosidation of propargyl alcohol with glucal, afforded exclusively alpha-2-deoxy propargyl glycoside in 98% optimized yield. The ligand L-proline was used for the first time in stereoselective glycosidation of alpha-2 deoxy glycosides involving glucal and alcohols. PMID- 29422122 TI - Pain-Related Disparities: Are They Something Nurses Should Care About? PMID- 29422123 TI - Neighborhood, Socioeconomic, and Racial Influence on Chronic Pain. AB - The purpose of this review is to highlight the neighborhood, socioeconomic, and racial influences on chronic pain. Negative influences on the experience of chronic pain are explored and defined as any adverse stressor common in low socioeconomic, urban neighborhoods that potentially contributes to health disparity in African Americans experiencing chronic pain. The multifactorial influences on chronic pain disparity in African Americans are explored and expounded upon in this review of existing evidence. Databases used for the search included CINAHL, PubMed, and PsycArticles. The experience of chronic pain is multifaceted, existing with multiple comorbidities and lasting consequences. To improve the burden of chronic pain requires a multifactorial assessment that considers neighborhood risk factors, emphasis on environmental stressors, limitations to support networks, barriers to physical activity, and access to primary care providers with whom communication is open and without bias. A comprehensive assessment of barriers will aid in the development of interventions that reach beyond the physical factors of chronic pain, also considering the psychosocial barriers to improving the burden of chronic pain in African Americans living in impoverished urban neighborhoods. PMID- 29422124 TI - Experiences of Urban African Americans with Cancer Pain. AB - The experience of cancer pain is poorly understood from the perspective of African Americans, who experience higher levels of pain, more pain-related distress, and poorer function than Caucasians. Decreased perceived control over pain may play a greater role for African American patients, affecting pain related distress and function. The purpose of this study was to add to the understanding of cancer pain and perceived control over pain in African Americans, from the patients' perspective. This qualitative inquiry was part of a larger mixed-methods study testing an intervention to improve pain, pain-related distress, and functional status through increasing perceived control over pain. Participants were recruited from the waiting room of an urban comprehensive cancer and interviewed in their homes. Interviews with 18 adult cancer patients who self-identified as African American and reported experiencing moderate to severe pain (>4 on a 0-10 scale) within the past two weeks were included. Qualitative interviews were audiotaped, transcribed, and analyzed using a constant comparative method. Two major themes emerged from this qualitative inquiry: struggles of the chronic pain experience and benefits of perceived control over pain. Each theme contained several categories. The study unveiled the participants account of both struggles of the chronic pain experience and barriers of perceived control that can be assessed for and targeted in nursing intervention. Benefits to having perceived control over pain were also illustrated in the participants' narratives. PMID- 29422125 TI - Pain, Racial Discrimination, and Depressive Symptoms among African American Women. AB - African American women with osteoarthritis (OA) are at high risk of experiencing pain. They report more pain than non-Hispanic White women and men of other racial/ethnic groups. This pain can limit independence and diminish their quality of life. Despite the detrimental effects that pain can have on older African American women with OA, there is a dearth of literature examining factors beyond the OA pathology that are associated with pain outcomes within this population. The purpose of this study was to examine the relationships between racial discrimination and depressive symptoms with pain intensity in African American women with OA. The sample comprised of 120 African American women, aged 50-80 years, with OA, from Texas and New Mexico. The women completed survey booklets to answer study questionnaires. We used multiple linear regression to test associations between racial discrimination, depressive symptoms, and pain intensity. We tested whether depressive symptoms mediated the relationship between racial discrimination and pain intensity by using bootstrapping. Results indicated that racial discrimination was significantly associated with pain intensity and that this relationship was mediated by depressive symptoms, even after controlling for body mass index, years of education, and length of time with OA. Both depressive symptoms and racial discrimination may be modifiable. If these modifiable factors are addressed in this population, there may be decreased pain in middle-aged and older African American women. PMID- 29422126 TI - Highly selective and sensitive fluorescence sensing of nanomolar Zn2+ ions in aqueous medium using Calix[4]arene passivated Carbon Quantum Dots based on fluorescence enhancement: Real-time monitoring and intracellular investigation. AB - Carbon Quantum Dots (CDs) owing to its unique photophysical properties have attracted immense consideration of the researchers in last decade to explore its applications in the fields of bio-imaging and sensing. In the present work, we have developed a novel CDs functionalized with Calix[4]arene derivative by hydrothermal route to detect biologically pertinent Zn2+ ions. Surface modification of CDs enhances fluorescence efficiency apart from introducing active surface sites broadening its sensor capabilities. The obtained surface functionalized CDs exhibits a strong blue fluorescence under UV light (365 nm) with a quantum yield (Phi) of 56% which is appreciably good. Zn2+ ions get apprehended in the cavity formed due to passivation by Calix[4]arene moeity on the exterior of CDs having profuse -NH2 groups. Addition of Zn2+ ions into the solution of CDs results in remarkable enhancement in the fluorescence intensity attributed to Photo-induced Electron Transfer (PET) "OFF" phenomenon. The CDs based nanosensor exhibited a wide linear response with a detection limit of 7.34 nM. Significantly, CDs were shown to display insignificant cytotoxicity, decent biocompatibility, and virtuous resistance to photo-bleaching, good stability over a wide range of pH, insignificant variation in the emission intensity in the presence of high concentration of salt and excellent bio-labeling ability when tested on E. coli cell lines. Additionally, the detection results of Zn2+ ions obtained in real samples were in complete agreement with that obtained by Atomic Absorption Spectroscopy (AAS), signifying the prospective application of the proposed probe as a selective and sensitive sensor for Zn2+ ions. The proposed sensor was also applied for fluorescence imaging of intracellular Zn2+ ions. PMID- 29422127 TI - Direct analysis of aluminum alloys by CSigma laser-induced breakdown spectroscopy. AB - We report the application of CSigma laser-induced breakdown spectroscopy (Csigma LIBS) to quantitative analysis of aluminum alloys without sample preparation. Csigma-LIBS simplifies strongly the conventional calibration procedure of LIBS, replacing it with a characterization stage performed from the spectrum of a single standard sample. The aim of this work has been to provide a complete evaluation of the use of Csigma-LIBS for direct analysis by obtaining its figures of merit, including precision and limits of detection. Ten elements (Si, Fe, Cu, Mn, Mg, Cr, Ni, Zn, Ti and Ca) are determined in a set of six certified samples with a wide range of concentrations, from percent down to MUg/g levels. The average precision is 8.0% for concentrations higher than 0.1 wt% and 13% for concentrations between 0.1 wt% and 0.01 wt%. The limits of detection are in the range 1.4-9.7 MUg/g. PMID- 29422128 TI - Robust boosting neural networks with random weights for multivariate calibration of complex samples. AB - Neural networks with random weights (NNRW) has been used for regression due to its excellent performance. However, NNRW is sensitive to outliers and unstable to some extent in dealing with the real-world complex samples. To overcome these drawbacks, a new method called robust boosting NNRW (RBNNRW) is proposed by integrating a robust version of boosting with NNRW. The method builds a large number of NNRW sub-models sequentially by robustly reweighted sampling from the original training set and then aggregates these predictions by weighted median. The performance of RBNNRW is tested with three spectral datasets of wheat, light gas oil and diesel fuel samples. As comparisons to RBNNRW, the conventional PLS, NNRW and boosting NNRW (BNNRW) have also been investigated. The results demonstrate that the introduction of robust boosting greatly enhances the stability and accuracy of NNRW. Moreover, RBNNRW is superior to BNNRW particularly when outliers exist. PMID- 29422129 TI - Nearest clusters based partial least squares discriminant analysis for the classification of spectral data. AB - Partial Least Squares Discriminant Analysis (PLS-DA) is one of the most effective multivariate analysis methods for spectral data analysis, which extracts latent variables and uses them to predict responses. In particular, it is an effective method for handling high-dimensional and collinear spectral data. However, PLS-DA does not explicitly address data multimodality, i.e., within-class multimodal distribution of data. In this paper, we present a novel method termed nearest clusters based PLS-DA (NCPLS-DA) for addressing the multimodality and nonlinearity issues explicitly and improving the performance of PLS-DA on spectral data classification. The new method applies hierarchical clustering to divide samples into clusters and calculates the corresponding centre of every cluster. For a given query point, only clusters whose centres are nearest to such a query point are used for PLS-DA. Such a method can provide a simple and effective tool for separating multimodal and nonlinear classes into clusters which are locally linear and unimodal. Experimental results on 17 datasets, including 12 UCI and 5 spectral datasets, show that NCPLS-DA can outperform 4 baseline methods, namely, PLS-DA, kernel PLS-DA, local PLS-DA and k-NN, achieving the highest classification accuracy most of the time. PMID- 29422130 TI - A novel DNA sensor based on C60NPs-PAMAM-PtPNPs to detect VKORC1 gene for guiding rational clinical therapy with warfarin. AB - Reports have indicated that warfarin is the most widely prescribed anticoagulant. However, traditionally prescribed doses for each patient may be too low or too high. The therapeutic effect is often hindered by a lack of evidence-based medical information. Herein, our aim is to provide this information. To accomplish this challenge, we report the development of a novel assay based on biotinylated tetrahedral DNA as a capture probe and fullerene (C60)-based nanomaterial as a redox probe using an ultrasensitivity assay with the Vitamin K epoxide reductase complex, subunit 1 (VKORC1). Platinum porous nanoparticles (PtPNPs) were modified on amino-terminated polyamidoamine (PAMAM)-functionalized C60 nanoparticles (C60NPs). The resultant C60NPs-PAMAM-PtPNPs were used as a redox probe. In this design, C60 exhibited excellent redox activity that was triggered by tetraoctylammonium bromide (TOAB). To improve the immobilization of the tetrahedral DNA capture probe, avidin was introduced during the fabrication of the biosensor because it can provide more active sites for the immobilization capture probe. The free-standing probe on top of the tetrahedral DNA served as a receptor to hybridize with target DNA directly. Different pulse voltammetry (DPV) was applied to record the electrochemical signals, which increased linearly with the target DNA. Under optimal conditions, the prepared biosensor showed a wide linear relationship, from 1 pM to 10 nM, with detection limits of 0.33 pM. This strategy demonstrates a new avenue for the determination of tumour-related mutated nucleotides in biosamples. PMID- 29422131 TI - In-syringe solid-phase extraction for on-site sampling of pyrethroids in environmental water samples. AB - On-site sampling is an analytical approach that can ensure the accuracy of monitoring data and enhance the effectiveness of environmental protection measures. In the present work, an in-syringe solid-phase extraction (SPE) device was designed for on-site sampling of trace contaminants in environmental water samples followed by gas chromatography-mass spectrometry (GC-MS) analysis. Template assisted freeze casting followed by hydrazine vapor reduction approach was used to synthesize a hierarchical porous graphene aerogel (HPGA), which was used as the sorbent in the in-syringe SPE device. Environmental degradable pyrethroids were selected as the model analytes. Owing to the large specific surface area and hydrophobicity of HPGA, the target molecules could be completely extracted during one aspirating/dispensing cycle. The analytes were stable on the sorbent for at least 72 h when the device was stored under airtight and light free conditions, and were not affected by the pH value of sample solution. All results demonstrated that the device could meet the requirements of on-site sampling. For practical application, the limits of detection were found to be in the range of 0.012-0.11 ng mL-1 under the optimized conditions, and satisfactory recoveries in the range of 65.7-105.9% were obtained for the analysis of real samples. The results of this study demonstrate the immense potential of HPGA for the enrichment of trace environmental pollutants, and meanwhile promote the application of the in-syringe SPE technique as a promising candidate for on-site sampling. PMID- 29422132 TI - Dried blood spots and parallel artificial liquid membrane extraction-A simple combination of microsampling and microextraction. AB - In this paper, parallel artificial liquid membrane extraction (PALME) was used for the first time to clean-up dried blood spots (DBS) prior to ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Fundamental studies exploring amongst others desorption from the DBS in alkaline or acidic aqueous conditions, total extraction time and absolute recoveries were executed. Desorption and PALME were performed using a set of two 96-well plates, one of them housing the sample and the other comprising the supported liquid membrane (SLM) and the acceptor solution. In one procedure, amitriptyline and quetiapine (basic model analytes) were desorbed from the DBS using 250 MUL of 10 mM sodium hydroxide solution (aqueous), and subsequently extracted through the SLM consisting of 4 MUL of 1% trioctylamine in dodecyl acetate, and further into an acceptor solution consisting of 50 MUL of 20 mM formic acid. In a second procedure, ketoprofen, fenoprofen, flurbiprofen, and ibuprofen (acidic model analytes) were desorbed from the DBS into 20 mM formic acid, extracted through an SLM with dihexyl ether, and further into an acceptor solution of 25 mM ammonia. Within 60 min of PALME, both basic and acidic model analytes were effectively desorbed from the DBS and extracted into the acceptor solution, which was injected directly into the analytical instrument. Recoveries between 63 and 85% for the six model analytes were obtained. PALME provided excellent clean-up from the DBS samples, and acceptor solutions were free from phospholipids. Linearity was obtained with r2 > 0.99 for five of the six analytes. Accuracy, precision and UHPLC-MS/MS matrix effects were in accordance with the European Medicines Agency (EMA) guideline. Based on these experiments, PALME shows great potential for future processing of DBS in a short and simple way, and with the presented setup, up to 96 DBS can be processed within a total extraction time of 60 min. PMID- 29422133 TI - Detection of catechol using an electrochemical biosensor based on engineered Escherichia coli cells that surface-display laccase. AB - In this study, we report an electrochemical microbial biosensor that was made by immobilizing a bacterial laccase on the surface of Escherichia coli cells followed by adsorption of modified live cells onto a glassy-carbon electrode. Expression and surface localization of laccase on target cells were confirmed by Western blotting, flow cytometry assays and immunofluorescence microscopy observation. Increased tandem-aligned anchors with three repeats of the N terminal domain of an ice nucleation protein were used to construct a highly active E. coli whole cell laccase-based catalytic system. When the proposed biosensor was used to detect catechol, the electrochemical response under optimized pH conditions was linear within a concentration range of 0.5 MUM-300.0 MUM catechol. Metal ions (Mn2+, Fe3+, Cu2+, Mg2+, Al3+ and Zn2+) at concentrations from 1 to 10 mg L-1, bovine serum albumin and glucose at concentrations from 0.1 to 10 g L-1, and ascorbic acid at concentrations from 0.01 to 0.1 g L-1 did not cause a noticeable interference effect. The detection limit of 0.1 MUM catechol was comparable to those of other biosensors based on purified chemically modified laccases. When used to detect catechol in real red wine and tea samples, the biosensor offered a considerable level of accuracy comparable to the HPLC method as well as high recovery rates (98.2%-103.8%) towards all of the tested samples. Moreover, the developed system also exhibited high stability and reproducibility. PMID- 29422134 TI - Ultrasensitive detection of EGFR gene based on surface plasmon resonance enhanced electrochemiluminescence of CuZnInS quantum dots. AB - In our work, a novel DNA electrochemiluminescence (ECL) sensor based on CuZnInS quantum dots (QDs) and gold-nanoparticles (Au NPs) is developed for highly sensitive detection of epidermal growth factor receptor (EGFR) Gene, which has a close relation with the lung cancer. The CuZnInS QDs work as a novel kind of ECL luminophore, whose defect state emission is suitable for ECL sensing. To enhance the sensitivity of the sensing system, Au NPs are utilized creatively to strengthen the ECL intensity of CuZnInS QDS according to the surface plasmon resonance (SPR) effect. An ultrasensitive and universal detecting platform is built based on the SPR effect between Au NPs and CuZnInS QDS. The effect of the capped stabilizer on the ECL signal of QDs is firstly investigated. Three different stabilizers are used to cap the CuZnInS QDs, including mercaptopropionic acid (MPA), l-glutathione (GSH) and cysteamine (CA). MPA capped CuZnInS QDs possess the strongest ECL intensity among the three kinds of the CuZnInS QDs. Under the optimum conditions, a good linear relationship between ECL intensity and the concentration of target DNA is obtained in the range from 0.05 nmol L-1 to 1 nmol L-1. The detection limit is 0.0043 nmol L-1. The proposed DNA sensor has been employed for the determination of target DNA EGFR in human serum samples with satisfactory results. PMID- 29422135 TI - Electrospin-coating of nitrocellulose membrane enhances sensitivity in nucleic acid-based lateral flow assay. AB - Point-of-care biosensors are important tools developed to aid medical diagnosis and testing, food safety and environmental monitoring. Paper-based biosensors, especially nucleic acid-based lateral flow assays (LFA), are affordable, simple to produce and easy to use in remote settings. However, the sensitivity of such assays to infectious diseases has always been a restrictive challenge. Here, we have successfully electrospun polycaprolactone (PCL) on nitrocellulose (NC) membrane to form a hydrophobic coating to reduce the flow rate and increase the interaction rate between the targets and gold nanoparticles-detecting probes conjugates, resulting in the binding of more complexes to the capture probes. With this approach, the sensitivity of the PCL electrospin-coated test strip has been increased by approximately ten-fold as compared to the unmodified test strip. As a proof of concept, this approach holds great potential for sensitive detection of targets at point-of-care testing. PMID- 29422137 TI - Treating resistant tumors using HER3-targeted nanobiologics. PMID- 29422136 TI - Detection of urinary spermine by using silver-gold/silver chloride nanozymes. AB - In this paper, we report a simple one-step synthesis method for silver-gold bimetallic nanoparticles deposition on silver chloride nanosheets to form Ag Au/AgCl nanohybrid with oxidase-like and peroxidase-like catalytic activity. We used these nanohybrid in the detection of spermine. First, 13 nm-sized Au NPs were synthesized by citrate reduction of HAuCl4 solution, and then, Ag+ ions were added to the solution without any purification. The added Ag+ reacted with the Cl ions in the dispersion, thus immediately forming AgCl nanosheets through a precipitation reaction, and the aurophilic interactions with the Au NPs resulted in the formation and in situ self-deposition of Ag-Au NPs on the AgCl nanosheets at room temperature. We investigated the enzyme-mimicking activity of the Ag Au/AgCl nanohybrid in detail via the O2- or H2O2-Amplex Red (AR) redox system. The Ag-Au/AgCl nanohybrid exhibited at least 150-fold higher catalytic activity than that of Ag-Au NPs or AgCl nanosheets, due to synergistic effect. Spermine inhibited the enzyme-mimic activity of the Ag-Au/AgCl nanohybrid, thereby allowing for the construction of a probe for detecting nanomolar concentrations of spermine in urine samples. This cost-effective sensing system was used to easily and rapidly detect the concentrations of spermine in complex urine samples. PMID- 29422138 TI - Roles of the anterior basolateral amygdalar nucleus during exposure to a live predator and to a predator-associated context. AB - The basolateral amygdala complex, which includes the lateral, basolateral and basomedial nuclei, has been implicated in innate and contextual fear responses to predator threats. In the basolateral complex, the lateral and posterior basomedial nuclei are able to process predator odor information, and they project to the predator-responsive hypothalamic circuit; lesions in these amygdalar sites reduce innate responses and practically abolish contextual fear responses to predatory threats. In contrast to the lateral and posterior basomedial nuclei, the basolateral nucleus does not receive direct information from predator olfactory cues and has no direct link to the predator-responsive hypothalamic circuit. No attempt has previously been made to determine the specific role of the basolateral nucleus in fear responses to predatory threats, and we currently addressed this question by making bilateral N-methyl-D-aspartate lesions in the anterior basolateral nucleus of the amygdala (BLAa), which is often regarded as being contiguous with the lateral amygdalar nucleus, and tested both innate and contextual fear in response to cat exposure. Accordingly, BLAa lesions decreased both innate and contextual fear responses to predator exposure. Considering the targets of the BLAa, the nucleus accumbens appears to be a potential candidate to influence innate defensive responses to predator threats. The present findings also suggest that the BLAa has a role in fear memory of predator threat. The BLAa is likely involved in memory consolidation, which could potentially engage BLAa projection targets, opening interesting possibilities in the investigation of how these targets could be involved in the consolidation of predator-related fear memory. PMID- 29422139 TI - The effectiveness of theory- and model-based lifestyle interventions on HbA1c among patients with type 2 diabetes: a systematic review and meta-analysis. AB - OBJECTIVES: The prevalence of type 2 diabetes is rising rapidly around the world. A number of systematic reviews have provided evidence for the effectiveness of lifestyle interventions on diabetic patients. The effectiveness of theory- and model-based education-lifestyle interventions for diabetic patients are unclear. The systematic review and meta-analysis aimed to evaluate and quantify the impact of theory-based lifestyle interventions on type 2 diabetes. STUDY DESIGN: A literature search of authentic electronic resources including PubMed, Scopus, and Cochrane collaboration was performed to identify published papers between January 2002 and July 2016. METHODS: The PICOs (participants, intervention, comparison, and outcomes) elements were used for the selection of studies to meet the inclusion and exclusion criteria. Mean differences and standard deviations of hemoglobin A1c (HbA1c [mmol/mol]) level in baseline and follow-up measures of studies in intervention and control groups were considered for data synthesis. A random-effects model was used for estimating pooled effect sizes. To investigate the source of heterogeneity, predefined subgroup analyses were performed using trial duration, baseline HbA1c (mmol/mol) level, and the age of participants. Meta-regression was performed to examine the contribution of trial duration, baseline HbA1c (mmol/mol) level, the age of participants, and mean differences of HbA1c (mmol/mol) level. The significant level was considered P < 0.05. RESULTS: Eighteen studies with 2384 participants met the inclusion criteria. The pooled main outcomes by random-effects model showed significant improvements in HbA1c (mmol/mol) -5.35% (95% confidence interval = -6.3, -4.40; P < 0.001) with the evidence of heterogeneity across studies. CONCLUSION: The findings of this meta analysis suggest that theory- and model-based lifestyle interventions have positive effects on HbA1c (mmol/mol) indices in patients with type 2 diabetes. Health education theories have been applied as a useful tool for lifestyle change among people with type 2 diabetes. PMID- 29422140 TI - Getting under the skin. PMID- 29422141 TI - Changes over time in caregiving demand and difficulty in spousal caregivers of coronary artery bypass graft surgery patients. AB - Patients who undergo coronary artery bypass graft (CABG) surgery are often dependent on spouses or family members for care during their recovery. The purpose of this study was to examine changes over time in spousal caregivers of coronary artery bypass graft (CABG) patients in caregiving demand and caregiving difficulty and to identify the key demands and difficulties at each time point. Spouses (n=34) of CABG patients comprised the sample. Caregiving demand and caregiving difficulty were measured using the Caregiving Burden Scale at three time points (baseline [early hospital discharge] and 3 and 6months later) and analyzed using repeated measures analysis of variance. Mean scores of each item were used to identify the top four caregiving demands and difficulties at each time point. There was a significant decrease over time in caregiving demands (F [1.696]=13.62, p<0.001) and caregiving difficulties (F [1.613]=4.52, p=0.02). The most demanding and/or difficult caregiving activities at all time points were providing social support, managing behavior problems, taking on additional household tasks, and monitoring symptoms. Early in recovery, providing transportation was a top ranked demand and difficulty. Later in recovery (3 and 6months), managing finances became a top ranked demand and difficulty. In conclusion, caregiving demands and difficulties declined significantly over six months for the caregivers in this study. These results indicate that caregiving demands and difficulties change over time and ongoing assessments of spouses and family members are needed to help them manage the caregiving situation. PMID- 29422142 TI - Medical and pharmacy students shadowing advanced practice nurses to develop interprofessional competencies. AB - AIM: This article describes a job-shadowing project that partnered second-year medical and third-year pharmacy students with an advanced practice nurse (APN) for a four-hour job- shadowing experience. BACKGROUND: In order to address the Interprofessional Education Collaborative (IPEC) Expert Panel core competencies of interprofessional communication, teamwork, and roles/responsibilities, this project implemented a job-shadowing experience to increase students' knowledge of APN roles and interprofessional collaborative team practices. METHODS: Forty volunteer medical and pharmacy students were paired together and completed the job-shadowing activity with an APN. Assessment of knowledge was measured by pre- and post-project surveys. RESULTS: Pre- and post-job-shadowing differences demonstrated statistical significance in the interprofessional domains of role awareness, collaboration and communication. These results suggest that an APN job shadowing experience is effective in developing medical and pharmacy students' competencies in interprofessional collaborative practice. CONCLUSION: Specific recommendations include creating enhanced job-shadowing experiences within the curriculums of medicine, pharmacy, and nursing students, and assessing for evidence of enhanced IPEC competencies as a result of these learning experiences. PMID- 29422143 TI - Using cognitive interviews to improve a Psychological-Social-Spiritual Healing instrument: Voices of aging African Americans with serious illness. AB - AIM: The purpose of this study was to contribute to content validity, by providing input into the linguistic and pragmatic validities, of a 53 item Psychological-Social-Spiritual Healing instrument. BACKGROUND: Discovery of cultural values and beliefs from African American elders' experiences of illness provides insight for development of more culturally sensitive instruments. METHODS: Through an exploratory descriptive design, this study used cognitive interviewing methods to examine linguistic and pragmatic validity of the Psychological-Social-Spiritual Healing instrument, from the perspectives of aging seriously ill AAs. Participants were recruited from urban Jackson, MS from community settings from October 2014 to January 2015. With a purposefully chosen sample of seriously ill African Americans elders (N=15), and using the method of cognitive interviewing, responses related to cultural relevance, clarity and meaning of the 53 items of the instrument were collected. This in-depth query of items was accomplished through the use of both verbal probing and think aloud methods of cognitive interviewing. RESULTS: Thirty-seven items were retained. Eight items were revised. Eight items were deleted. CONCLUSIONS: From the expert input of seriously ill African American elders, a systematic decision-making process of item retention, revision or deletion led to the development of a more culturally sensitive Psychological-Social-Spiritual Healing instrument. PMID- 29422144 TI - The relation between patient education, patient empowerment and patient satisfaction: A cross-sectional-comparison study. AB - PURPOSE: Patient empowerment is a paradigm of clinical practice. The goal of patient empowerment is to lead patients' health and wellbeing. The aim of this study is to evaluate the relation between patient education, patient empowerment and patient satisfaction based on multi-hospital cross-sectional study design in Taiwan. METHODS: In this cross-sectional survey, 609 inpatients in four teaching hospitals in northern Taiwan from August 2009 to July 2010 were recruited. Data were collected using Chinese version of the Patient Perceptions of Empowerment Scale (PPES), Sufficiency of Patient Education Questionnaire (SPEQ) and Patient Satisfaction Questionnaire (PSQ). The multiple linear regression model was used to assess the independent effects of relevant factors on patient empowerment after controlling for the covariates. RESULTS: The overall mean empowerment scores was 44.80+/-5.94. There was a significant difference between the total scores and four dimensions of patient empowerment at different hospitals (t=5.44, p<=0.01). Sufficient patient education (beta=0.568, 95%CI: 0.486-0.649) and patient satisfaction (beta=0.317, 95%CI: 0.259-0.375) could significantly predict patient empowerment based on the multiple linear regression analysis, with a total variance was 54.4%. CONCLUSIONS: In conclusion, both sufficient patient education and patient satisfaction were positively related to patient empowerment. Hospitals in Taiwan should try to improve their patients' active involvement toward empowerment. PMID- 29422145 TI - Measuring the psychometric properties of the Arabic version of the spirituality questionnaire among university students in South Jordan. AB - Spirituality has been recently recognized in many areas around the world as a factor influencing the general health and wellbeing on individuals. There is a scarcity addressing this issue in the Middle East, like many other regions. Perhaps one reason for this is related to the absence of instruments measuring spirituality. The goal of this study was to investigate the psychometric properties of the spiritual questionnaire in university students in South Jordan. Exploratory and confirmatory factor analyses were performed on data coming from a sample of university students (n=1269). The questionnaire demonstrated validity and reliability. While the confirmatory factor analysis resulted in 29-item model, the exploratory factor analysis resulted in a 21-item model. The main factors in the model were self-awareness, importance of spiritual belief, spiritual practices, and spiritual needs. Spirituality questionnaire demonstrated good validity and reliability levels when used to measure spirituality among university students in Jordan. The 21-item model requires further testing to ensure stability over use. It is crucial in the future to test the impact of spirituality on the general health and wellbeing of adult individuals using the spirituality questionnaire and other research instruments. PMID- 29422146 TI - Overfilled urine specimens for gonorrhea and chlamydia testing: Implications for practice. AB - In clinical practice, patients provide samples that violate specimen collection guidelines. As no research exists to guide clinical practice for such situations involving sexually transmitted infections (STIs), we reviewed our clinical data to determine how to proceed when patients provided urine specimen >30mL. We tracked the quantity of urine, test outcomes, and whether or not patients returned to provide subsequent samples when notified to do so. Over 6months, 33 patients provided overfilled samples; we submitted 70% (n=23/33). From the submitted specimens, 5 infections were identified from 4 patients: all were positive for chlamydia and 1 for gonorrhea and chlamydia. This yielded the following positivity rates: 17.4% for chlamydia (n=4/23), and 4.3% for gonorrhea (n=1/23). For the group, the positivity rate was 17.4% (4 of 23 patients with infections), or 21.7% (5 infections from 23 patients). Lastly, only 60% of the patients instructed to return to clinic for retesting did so. Due to the possibility of false negative results, the ability to detect infections in overfilled samples, and because patients may not return for retesting, we recommend submitting overfilled samples, while also notifying patients to return to retest. This approach could maximize diagnostic rates, at least within STI testing clinics. PMID- 29422147 TI - Alcohol and drug screening and brief intervention behaviors among advanced practice registered nurse (APRN) students in clinical settings. AB - Previous research on training health professionals to identify and address unhealthy alcohol and drug use in patients through screening, brief intervention, and referral to treatment (SBIRT) has found that training increases knowledge about substance use and increases students' confidence in addressing substance use in patients. To date, however, there is little information on how health professional students integrate SBIRT into individual practice. Within a U.S. SBIRT training consortium, advanced practice registered nurse (APRN) students were required to practice SBIRT in clinical settings and complete assessment logs for each patient screened. Logs documented results from single item alcohol & drug screening questions; AUDIT or DAST responses; brief intervention (BI)/referral to treatment (RT) steps completed and patients' responses. 113 APRN students completed logs on 538 patients (mean age 44; SD 15.0; 53.5% female). Positive single question alcohol screens were more frequent than positive single question drug screens (55.3% vs. 25.5%). More than one third (36%) of the logs included high-risk AUDIT/DAST scores. The most utilized BI components were discussions regarding consequences of use (76%) and safe levels of use (70%), while the most utilized RT steps included referral to a mutual help group (15%) or a specialty treatment program (8%). Positive screening rates found by APRN students were higher than reported rates in most clinical settings. The logs also demonstrated that APRN students employed many of the SBIRT skills they were taught while also helping identify underutilized SBIRT steps, which may be addressed specifically in future SBIRT trainings. PMID- 29422148 TI - The role of job satisfaction, work engagement, self-efficacy and agentic capacities on nurses' turnover intention and patient satisfaction. AB - BACKGROUND: Nurses' voluntary turnover is a worrying global phenomenon which affects service quality. Retaining nursing staff within a hospital is important to eliminate the negative influence of voluntary turnover on the quality of care and organisation costs. OBJECTIVES: This research helps explain nurses' voluntary turnover by analysing the role of self-efficacy, agentic capacities, job satisfaction, and work engagement on hospital turnover intention, and to study the relationships between these variables and patient satisfaction. SETTING AND PARTICIPANTS: This study gathered data from 194 nurses and 181 patients from 22 inpatient wards at two hospitals in southern Italy. RESULTS: Correlation analysis revealed that job satisfaction, work engagement, self-efficacy and agentic capacities were positively interrelated and negatively correlated with turnover intention. Path analysis showed that self-efficacy, some agentic capacities (anticipation and self-regulation), job satisfaction, and work engagement had direct or indirect effects on nurses' turnover intention, and that job satisfaction exerted a stronger effect on turnover intention. Also, patient satisfaction was positively correlated with nurses' job satisfaction, work engagement, self-efficacy, self-regulation and anticipation and negatively correlated with nurses' turnover intention. CONCLUSION: Results highlighted the importance of implementing actions (for example through feedforward methodology and the goal setting technique) to improve self-efficacy, self-regulation skill, work engagement and job satisfaction in order to reduce nurses' turnover intention and increase patient satisfaction with nursing care. PMID- 29422149 TI - Nurses and nursing assistants decision-making regarding use of safe patient handling and mobility technology: A qualitative study. AB - AIM: This study explored decision-making regarding use of safe patient handling and mobility (SPHM) technology among registered nurses (RN) and nursing assistants (NA). BACKGROUND: Lifting injuries are common among healthcare workers. Despite development of standards for SPHM, the introduction of regulation for monitoring access to SPHM technology, and implementation of education programs and process improvements, threat of injury remains a concern. Although access to SPHM equipment is associated with decreased workplace injuries, access alone does not guarantee use. Questions remain concerning how healthcare workers make decisions to use SPHM equipment, and how they weigh decisions against personal safety. METHODS: A qualitative descriptive study was conducted. Data collection consisted of four 60min focus groups. Two focus groups consisted of all RNs (n=14) and two consisted of all NAs (n=11). Each focus group was audiotaped and transcribed verbatim. Transcripts were coded, repeating concepts identified, and codes collapsed into themes and subthemes. RESULTS: Qualitative analysis revealed three major themes: barriers to use, perceived risk, and coordination of care. Barriers to use include subthemes of physical barriers, knowledge and skill, and unit culture. Perceived risk includes patient risk and perceived risk to self. Coordination of care includes patient factors and characteristics, assessment of patient needs and abilities, and interprofessional collaboration. CONCLUSIONS: These findings provide new knowledge about the complexity of decision making among care providers in the use of SPHM technology. Interprofessional team approaches to patient assessment and care are important components of confident decision making in use of SPHM technology. PMID- 29422150 TI - Traditional practices for maternal and newborn care among Turkish postpartum women. AB - AIM: Researchers used descriptive study design to examine the traditional practices of women in relation to maternal and newborn care in the postpartum period. METHODS: 523 postpartum women included who were between 15 and 49years of age, had at least one child, and had no medical complications that affect the mother-infant health. A questionnaire was used to collect data. Comparisons were made between the responses about the women's knowledge of traditional practices and other variables. RESULTS: We found that women widely used traditional practices such as putting Koran (Holy book for Muslims) and packing needle under the mother's pillow to prevent mother from "al basmasi", pouring lead in a cup over the head of the newborn to repel evil spirits, and covering the baby's face with a piece of yellow cloth to prevent neonatal jaundice. The rate of using postpartum traditional practices increased with age and number of pregnancies and decreased with education (p<0.05). CONCLUSION: Educational activities are recommended to increase awareness of harmful traditional practices in the field of reproductive health for nurses and midwives. Health professionals should pay special attention to less educated, older and primiparous women from rural areas enable them to reinforce positive cultural practices, and discourage them from using harmful ones by providing non-critical scientific explanations. PMID- 29422151 TI - Interdisciplinary Ugandan perspectives on computerized intervention implementation for child survivors of severe malaria: A qualitative analysis. AB - PURPOSE: Severe malaria (SM) is the leading cause of pediatric cognitive impairment in sub-Saharan Africa. Computerized Cognitive Rehabilitation Therapy (CCRT), a promising intervention for children suffering from SM related cognitive delay, targets areas impacted by the disease (memory, attention, and executive function), but has yet to be implemented for daily use. This paper explores the perspectives of Ugandan professionals regarding CCRT implementation in the academic setting of Uganda. METHODS: A qualitative descriptive approach was taken to conduct interviews with Ugandan professionals directly or indirectly aware of an ongoing CCRT intervention trial. Eight individuals were consented and interviewed. Responses were analyzed thematically. Question topics included knowledge of malaria and CCRT, perspectives on implementation feasibility, and experience engaging in a global collaborative research endeavor. RESULTS: Facilitators included perceived value and environment. Potential barriers were geography and resource availability. Perceived value is seen, expected, and/or hoped for outcomes by adults involved in the child's development. Environment speaks to the internal environment of the CCRT program as well as the external environment of the school setting. Geography presents as a barrier due to the difficulty of accessing CCRT in rural settings. Resource availability was a consistently identified barrier to implementation including aspects of technological, financial, and understanding deficits leading to difficulties in CCRT dissemination. CONCLUSION: Results demonstrate optimism and hope of Ugandan professionals for CCRT in children who have survived SM. Professionals identify and prioritize needs for implementation uniquely, pointing to the value in interdisciplinary collaboration to ensure effective implementation of CCRT. PMID- 29422152 TI - Effects of hazard perception training (HPT) on nursing students' risk sensitivity to patient safety and developing safety control confidence. AB - PURPOSE: This study identifies the effects of hazard perception training (HPT) on nursing students' risk sensitivities and safety control confidence. METHODS: The study uses a nonequivalent control group pre-and post-test design. The participants were 107 senior nursing students, 52 in the experimental group, and 55 in the control group. The experimental group was shown 5 hospital situation pictures to determine hazard sensitivity. Students' risk sensitivity scores and safety control confidence were measured pre-HPT and post-HPT. RESULTS: The experimental group showed significantly higher (on) total risk sensitivity score (t=12.47, p<0.001) and themes, such as fall down (t=19.33, p<0.001), preoperative time out (t=3.18, p<0.001), invasive treatment (t=12.40, p<0.001), and medication (t=10.98, p<0.001). However, the difference for telephone orders was insignificant between the experimental and control groups (t=-0.17, p=0.864). In addition, difference of mean scores for safety control confidence was insignificant between the experimental and the control groups (t=1.10, p=0.275). CONCLUSION: Nursing education should incorporate hazard perception training more often, and educators need to develop education programs to improve nursing students' safety control confidence. Further, a Hazard Perception Training (HPT) that incorporates various kinds of educational methods for students majoring in healthcare fields is needed. PMID- 29422153 TI - Pregnant women's knowledge and awareness of nutrition. AB - The purpose of this study was to investigate effectiveness of an educational intervention on pregnant women's nutritional knowledge. Despite national guidelines, women face personal and healthcare barriers to adequate nutrition education. This quasi-experimental study involved a convenience sample of pregnant women (n=27). The Nutrition Knowledge Questionnaire (NKQ) was utilized for pre and post-tests. Additionally, participants were asked open-ended questions. Data analysis was performed using paired t-tests, linear regression, and qualitative thematic analysis. The mean pre-test and post-test scores on the NKQ were 30.0 and 38.96 respectively, representing a statistically significant increase (p<=0.00). Six qualitative themes emerged including nutrition as "important" and "a real eye opener." This study validates the use of an educational intervention based on MyPlate guidelines to increase pregnant women's knowledge of nutrition. PMID- 29422154 TI - Audit for quality of care and fate of maternal critical cases at Women's Health Hospital. AB - : Maternal deaths remain high, numbers at the facility level are relatively low. AIM: To evaluate effect of management guidelines on occurrence of maternal near miss in Women's Health Hospital. DESIGN: A cross-sectional study. SETTING: ICU of Women's Health Hospital's at Assiut Main University Hospital and Al-fayoum University Hospital. SUBJECTS: Convenient sample of 93 maternal near-miss cases including (Pregnancy or postpartum complications). TOOL: audit the applied critical care for severe condition related to obstetric complications and consist of three parts: Patient's demographic data, Audit of critical care and "Maternal near-miss" Fate. Data collected during a period of 1/3/2015 to 30/8/2015 for management guidelines and maternal outcomes. RESULTS: A statistical significant differences between the medical management and occurrence of sever maternal complications such as (severe postpartum hemorrhage, severe pre-eclampsia, Sepsis or severe systemic infection, uterine hemorrhage, ruptured uterus) (P=0.000, P=0.031, P=0.036, P=0.052, P=0.012 respectively). CONCLUSIONS: The maternal management guidelines was a successful tool in recording the gap between the current received management and standards management guidelines in ICU. Also they measure the effect of current management in ICU on maternal mortality and morbidity. PMID- 29422155 TI - The effect of the emotional intelligence education programme on quality of life in haemodialysis patients. AB - AIM: This study investigated the effect of the emotional intelligence education programme on quality of life of haemodialysis patients. BACKGROUND: Nurses need knowledge development regarding the impact of educational strategies on patients' quality of life suffering from chronic diseases. METHODS: A pragmatic quasi randomized controlled trial was conducted with 47 haemodialysis patients attending a university hospital in an urban area of Iran. The patients were randomly assigned to intervention (n=23) and control (n=24) groups. A socio demographic questionnaire, the Cyberia-Shrink Emotional Intelligence Questionnaire, and the Kidney Disease Quality of Life-Short Form were used to gather data. The intervention group attended an educational programme on emotional intelligence that consisted of six-group discussion sessions. To ensure the continuity of learning and to measure the subsequent expected behavioural changes, the patients filled out the data collection tools six and 12weeks after the completion of the education programme. RESULTS: The mean score of quality of life in the intervention group was 39.94+/-15.88 in pre-test, 44.87+/-16.04 six weeks and 52.47+/-16.07 at the 12weeks after the intervention (p=0.032). CONCLUSION: The consideration of emotional intelligence educational strategies by nurses requires its incorporation into pre-qualifying nursing degrees and professional development programmes. Nurse managers need to lead nurses for applying emotional intelligence in daily practice with the aim of providing an holistic patient care. PMID- 29422156 TI - Expert consensus to weight an adherence score for audit and feedback of practices that prevent necrotizing enterocolitis in very low birth weight infants. AB - OBJECTIVE: Necrotizing enterocolitis (NEC) is a catastrophic abdominal complication threatening the life of premature infants, but adoption of prevention and early recognition practices differs as do NEC rates in Neonatal Intensive Care Units (NICUs). The purpose of this research was to validate and weight an evidence-based adherence score (aka NEC-Zero Adherence Score) to prevent and foster timely recognition of NEC. STUDY DESIGN: An electronic Delphi (e-Delphi) approach was used to identify consensus. NEC experts were recruited via the NEC Society and surveyed until consensus and stability criteria for the Delphi were met (>=70% consensus and mean responses changed <15% between rounds). RESULTS: Expert panelists (n=22) were experienced (M=17.6, SD 11years) and predominately physicians (68%) or neonatal nurse practitioners (18%). Consensus (>70% by item) supported a 10 point score. Points were distributed across 1) an exclusive human milk diet (5 points), 2) standardized feeding protocols (3 points), 3) antibiotic stewardship (1 point), and 4) a unit-specified approach to early recognition (1 point). Withholding feeding during transfusion was controversial (M=0.50, SD 0.73) and met consensus criteria to drop from the score. CONCLUSIONS: Holding feeding during transfusion was dropped from the score. Relationships between the score and unit NEC rates as well as its utility for use in audit and feedback should be studied in the future. PMID- 29422157 TI - The effects of an interprofessional patient-centered communication intervention for patients with communication disorders. AB - PURPOSE OF THE STUDY: This small scale study examined the influence of an interprofessional (IP) evidence based patient-centered communication intervention (PCCI), delivered by trained nurses in collaboration with Speech Language Pathologists, on patient outcomes in an active stroke rehabilitation setting. DESIGN AND METHODS: The setting constraints imposed the use of a single-group pretest and post-test design to determine the influence of the intervention on patient outcomes. Validated tools measured patient quality of life (QOL), depressive symptoms and satisfaction with care. RESULTS: Patients (n=34) showed improvement in all outcomes from pretest to post-test, including quality of life, geriatric depressive symptoms, and satisfaction with care. IMPLICATIONS: The findings indicate that a comprehensive person-centered communication intervention has the potential to enhance patient outcomes at discharge. Challenges to implementing and evaluating evidence-based interventions in practice are highlighted. PMID- 29422158 TI - Actual and perceived nursing workload and the complexity of patients with total hip arthroplasty. AB - BACKGROUND: Little is known about the relation between patient complexity and nursing care of total hip arthroplasty (THA) patients. To improve patient care and hospital logistics, the aim of this study is to gain insight into the relation between patient complexity and the nursing staff's actual and perceived workload at an orthopedic ward during admission for a THA. DESIGN: Prospective cohort study of 45 THA patients in the year 2014. Duration and type of nursing care activities were recorded during the first postoperative morning. A questionnaire was used to analyze the perceived workload of the nursing staff. Both actual and perceived workload were analyzed for their relation with patient complexity, expressed in the American Society of Anesthesiologists (ASA) score, Charlson comorbidity index (CCI), Katz Activities of Daily Life score (Katz-ADL) and Body Mass Index (BMI). RESULTS: No relation was found between actual workload and measures for patient complexity. The perceived workload of the nursing staff was related to two complexity measures: ASA (r=0.71; p<0.001) and CCI (r=0.65; p=0.002). CONCLUSION: Patient comorbidity is related to the perceived workload of the nursing staff during admission for a THA. Patient complexity is not related to actual workload. This study gives a first insight into the relation between patient comorbidity and nursing staff workload, to try to improve staffing numbers at the ward as well as patient care in the process. PMID- 29422159 TI - Factors influencing turnover intention among registered nurses in Samar Philippines. AB - OBJECTIVE: Despite the massive nurse migration and turnover of nurses in the Philippines, there remains a lack of studies describing factors influencing the migration of Filipino nurses. This study explored the effects of nurses' characteristics, work satisfaction, and work stress with the intent to leave an organization among registered nurses in the Philippines. METHODS: This study utilized a descriptive, cross-sectional approach. One hundred sixty six (166) nurses participated in the study during the months of September 2015 to December 2015. Three standardized instruments were used in the study: Job Satisfaction Index (JSI), Job Stress Scale (JSS), and Turnover Intention Inventory Scale (TIIS). Data were analyzed using descriptive and inferential statistical tools. RESULTS: Nurses' ages were found to significantly influence their turnover intentions. Job satisfaction (beta=-0.47, p=0.001) and job stress (beta=0.23, p=0.001) strongly predicted turnover intentions in the nurses. The mean values for the job satisfaction scale, job stress scale, and turnover intention inventory scale were 3.13 (SD=0.60), 2.74 (SD=0.71), and 2.43 (SD=0.67) respectively. CONCLUSIONS: Several predictors of turnover intentions were determined in this study through nurses' age, job satisfaction, and job stress as being the most influential factors. Efforts to increase nurses' job satisfaction and reduce job stress should be implemented to halt further loss of these skilled groups of healthcare professionals. PMID- 29422160 TI - Using a community advisory board to develop a serious game for older adults undergoing treatment for cancer. AB - INTRODUCTION: Older adults undergoing treatment for cancer are at risk for serious complications such as chemotherapy-induced nausea and vomiting (CINV). Older adults are often overwhelmed by information and under-manage cancer treatment-related side effects. New educational strategies such as serious gaming may help teach or reinforce key symptom self-management strategies. This paper describes how a community advisory board of older adults, their caregivers, and oncology nurses were consulted to develop a serious game for CINV. METHODS: A formative evaluation process using a community advisory board (CAB) and a series of three focus groups were used to develop this serious game about managing CINV at home. RESULTS: The formative evaluation process and involvement of the CAB allowed researchers to learn about the experience of having CINV from an older adult perspective. Common themes related to CINV onset, severity and self management formed the basis for the serious games' script and scenarios. Themes were validated and CAB members provided feedback on a game prototype. Feedback from CAB members indicated that the serious game was realistic and reflective of their CINV experience. CONCLUSION: Including older adults in the development of a serious game was instrumental in creating a relevant educational opportunity. Serious gaming should be considered as a way to add to the educational experiences of older adults as generic teaching methods may not address the needs of all age groups. Exploring for new ways to emphasize key points related to symptom management and prioritize learning may impact outcomes for older adults. PMID- 29422161 TI - Expectations and perceptions of clients concerning the quality of care provided at a Brazilian hospital facility. AB - PURPOSE: To identify the expectations and perceptions of clients concerning the quality of hospital care provided to them and their respective companions at a private Brazilian hospital using SERVQUAL. The SERVQUAL questionnaire can provide information concerning expectations and perceptions of clients. In addition, it is able to identify the participation of frontline employees and how they contribute to the organization's end product (service delivery). METHODS: In total, 172 inpatients for surgical reasons answered the SERVQUAL questionnaire. It consists of 23 pairs of statements, 22 of which are distributed into the dimensions of tangibles, reliability, responsiveness, assurance and empathy. Statement 23 refers to the overall quality of care. Exploratory analysis, internal consistency (Cronbach's alpha) and the kappa Coefficient were calculated using the Statistical Package for Social Sciences and SAS 9.2. Ethical approval was obtained from the Institutional Review Board at the Hospital das Clinicas at the University of Sao Paulo at Ribeirao Preto Medical School. RESULTS: Most participants had a bachelor's degree and were over than 60years old. Cronbach's alpha coefficients indicated good internal consistency (alpha=0.93) and high levels of agreement were observed (91.10%). CONCLUSION: The SERVQUAL questionnaire was sensitive to items in each dimension for which clients' perceptions surpassed their expectations. IMPLICATIONS FOR NURSING MANAGEMENT: The continuous quality assessment of health services is mandatory for nursing leadership. The nursing leadership can further explore the SERVQUAL with a view to better attending to the clients' expectations. PMID- 29422162 TI - Intimate partner and sexual violence screening practices of college health care providers. AB - BACKGROUND: Female college students experience higher rates of intimate partner violence (IPV) and sexual violence (SV) compared to men of all ages, older women and young women who are not attending college. Experts and medical organizations have issued recommendations that health care providers should routinely screen women for IPV and SV. However, most female college students report they are not being screened for IPV and SV at college health centers. AIM: This exploratory study sought to examine the IPV and SV screening practices of college health care providers and identify individual and organizational influences using a cross sectional, quantitative survey design. METHODS: Sixty-four health care providers (physicians, nurse practitioners and registered nurses) from five colleges and universities in the northeastern U.S. were invited to participate in an anonymous, web-based survey about their IPV/SV-related screening practices and beliefs, and organizational characteristics of their college health centers. RESULTS: Twenty-six health care providers completed surveys (56% response rate). The median reported IPV/SV screening rate was 15%. More IPV/SV screening was reported by nurse practitioners, providers at state colleges, and by those in health centers that prioritized IPV/SV screening and had greater organizational capacity for change. CONCLUSIONS: College health centers represent unique, yet often missed, opportunities to screen for IPV/SV in a high-risk population. Provider- and organization-level influences should be incorporated into future interventions to improve IPV/SV screening in college health centers. Future studies with larger numbers of colleges and providers are needed to better understand organizational influences and identify mediators and moderators of effects. PMID- 29422163 TI - The impact of complementary therapies on psychosocial factors in women undergoing in vitro fertilization (IVF): A systematic literature review. AB - AIM: This review evaluates the impact of complementary therapies on psychosocial factors in women undergoing IVF. BACKGROUND: According to the CDC, nearly 7% of married women in the United States face infertility. Approximately 1.5% of all infants born in the U.S. annually are conceived through assisted reproductive technologies (ART), such as IVF. Women undergoing ART report distress, anxiety, and depression related to their treatment. Stress has been cited as the top reason why women terminate treatment. Complementary therapies, such as mind-body techniques, have been associated with decreasing stress and anxiety. METHODS: CINAHL and PubMED databases were searched for studies 1) published from January 2010 to 2017, 2) written in English, 3) that examined the effect of an complementary therapy on the psychological well-being of women undergoing, or about to be undergoing a cycle of IVF. RESULTS: The search revealed 11 studies published between 2010 and 2015 from a variety of countries. The most common research design was a randomized controlled trial (n=7). The psychosocial factor most frequently measured was anxiety (n=8). The forms of complementary therapy varied, with the most common being Hatha yoga, cognitive behavioral interventions, and mind-body therapies (n=2 each). CONCLUSIONS: Utilizing complementary therapies appears to be a positive way to decrease women's anxiety, depression, distress, and stress, and to increase fertility quality of life. This review informs providers that incorporating complementary therapies into the plan of care can lead to improved psychosocial health outcomes for women undergoing IVF. PMID- 29422164 TI - Understanding how patients use visualization during ablation of atrial fibrillation in reducing their experience of pain, anxiety, consumption of pain medication and procedure length: Integrating quantitative and qualitative results. AB - BACKGROUND: Patients who undergo radiofrequency ablation of atrial fibrillation with a light conscious sedation often feel pain during the procedure which can be difficult to relieve with pharmacological pain treatment alone. In a quasi experimental study, it was found that visualization together with usual pain medication reduced the amount of analgesics used. In addition, patients spontaneously expressed pain significantly fewer times outside the scheduled measurements. No difference was found in the perception of pain intensity or anxiety and procedure length in the study. In a subsequent qualitative study with patients from the intervention group in the quantitative study, patients reported visualization as a positive experience which helped them manage pain and anxiety by supporting their individual strategies and without inconvenience. AIM: To examine patients' experiences with the effect of visualization during ablation of atrial fibrillation and its association with pain intensity, anxiety, pain medication and procedure length. METHODS: A mixed-method study with explanatory sequential design including a quasi-experimental study with a control and an intervention group and a qualitative interview study with semi-structured interviews. The results from the two studies in the mixed method study have been integrated by merging and constructing follow-up joint displays. RESULTS: Three themes were identified from the integration of the results from the quantitative and qualitative studies when analyzing and interpreting the results: "Zero pain is not always the goal"; "Not a real procedure time reduction but a sense of time shrinkage" and "Importance of the nurse's presence, visualization or not". CONCLUSION: Visualization can help patients to manage procedural pain when going through ablation of atrial fibrillation but the effect of an intervention such as visualization cannot be measured by pain intensity because the effect of visualization helps patients to cope with the pain and not to reduce the experience of pain intensity. It was shown that the patients had a feeling of reduced procedure time, although it was not reduced statistically significantly by using visualization. Finally, patients did not feel high anxiety during the procedure which was in line with very low values of anxiety measured in the quantitative study but at the same time the presence of the staff was of great importance to them in providing a feeling of security. A reduction of analgesics as found in the study is not only a matter of safety, it is also important in the patient's perception. PMID- 29422165 TI - Evaluating the effectiveness of pre-operative platelet inhibition testing to reduce costs and pre-operative length of stay. AB - This was a retrospective study to assess the effectiveness of Society of Thoracic Surgeons (STS) Guidelines in reducing resource utilization at Washington Adventist Hospital, Takoma Park, Maryland. Pre and post operative stay (days), platelets and other blood product use, along with hospital costs were compared in elective Cardiac Surgical patients receiving P2Y12 inhibitors in the year prior to and year following the implementation of the STS guidelines of preoperative monitoring of platelet inhibition with VerifyNow. Our results demonstrated a significant decrease in length of stay, and although there was no discernible impact on other blood product use, there was a meaningful reduction in platelet use following implementation of the VerifyNow PRUTest assay for routine use in directing the timing of cardiac surgical procedures in this patient population. PMID- 29422166 TI - Certified nursing assistants' perspectives of the CARES(r) activities of daily living dementia care program. AB - BACKGROUND: There has been a proliferation of online training programs for nursing home direct care staff related to dementia care, yet little is known about the effectiveness of the training. Some evidence exists that online training is effective in addressing problem behaviors of nursing home residents with dementia by enhancing self-efficacy, improving attitudes, and increasing knowledge of nursing home staff. STUDY AIM: The current study aim was to evaluate the implementation of an online training program consisting of ten, one-hour modules which applies the CARES(r) concepts and learning framework to activities of daily living (ADL) care for persons with dementia. METHODS: Responses from Likert-type items, and open-ended questions were analyzed in a sample of 48 certified nursing assistants (CNAs) from 10 nursing homes in six states (ME, MT, ND, WI, MN, MO) that were part of a National Institute of Aging funded intervention study (Grant #AG026210). RESULTS: The mixed-method study findings indicated that CNAs gained a better understanding, more knowledge, and more confidence in caring for persons with dementia. Recommendations were made regarding training length and technical issues, and some questioned the practicality of providing person-centered care when resident assignment was very high. CNAs expressed satisfaction with the online training, found it easy to use, and many said they would recommend the training. CARES(r) ADL Dementia Care online training appears to be a viable way of helping CNAs address the personal care needs of long-term care residents. Future CARES(r) ADL Dementia Care program research should include more racially diverse CNAs. PMID- 29422168 TI - Validation of the cardiac health behavior scale for Korean adults with cardiovascular risks or diseases. AB - AIM: The purpose of this study was to validate the Cardiac Health Behavior Scale for Korean adults (CHB-K) to determine its validity and reliability. BACKGROUND: Cardiovascular diseases (CVDs) are one of the most important chronic diseases due to their high prevalence and mortality rates. Patients with cardiovascular risks or diseases need to perform appropriate cardiac health behaviors that help to prevent the progression of the disease and improve their health status. METHODS: This secondary analysis obtained data from two clinical trials of cardiac rehabilitation. Data from 298 patients with cardiovascular risks or diseases were analyzed for validation. Data analyses included correlation coefficients, t tests, and exploratory and confirmatory factor analyses using SPSS (version WIN 22.0) and AMOS (version 20.0). The Self-Efficacy Scale was used to assess convergent validity, while reliability was assessed using Cronbach's alpha coefficients. RESULTS: Five main factors were verified: health responsibility, physical activity, diet habit (eating habit and food choice), stress management, and smoking cessation. A set of 21 items from the 25-item scale was verified after performing item analysis, factor analyses, and critical evaluation of the statistical results. The 21-item CHB-K (CHB-K21) exhibited acceptable validity, and the model of the CHB-K21 provided a good fit to the data. Most of the factors were found to be moderately correlated with SES scores (r=0.45-0.52, p<0.001). The CHB-K21 also demonstrated acceptable reliability (Cronbach's alpha=0.83). CONCLUSIONS: The CHB-K21 demonstrates strong validity and reliability. It can be used to assess cardiac health behaviors in Korean adults with cardiovascular risks or diseases. PMID- 29422167 TI - Identification of populations at risk: Stillbirth toolkit for health care providers. AB - BACKGROUND: Maternity care and women's health are measured, in part, by the stillbirth rate of a country. The purposes of this pilot project were to: a) establish a baseline of health care provider knowledge regarding stillbirth risk factors based on geographic distribution (urban/rural) and provider licensure (MD, APRN, PA, CNM) and b) evaluate the utility of a Stillbirth Risk Factor Toolkit and its effects on provider knowledge. METHODS: Evaluative research using a retrospective pre-posttest survey design was completed. The study setting included primary care clinics (urban [n=25] and rural [n=25]) in Nebraska. Health care providers from N=50 clinics were surveyed about their knowledge of stillbirth risk factors (modifiable and non-modifiable) before and after reading the Toolkit. RESULTS: Providers were least knowledgeable regarding the definition of stillbirth and the number of weeks' gestation that constitute a stillbirth. Overall, there was no significant difference in baseline knowledge between rural and urban providers. Nearly half (43.8%) found the Toolkit to be very helpful and applicable to their patient population, and 34.8% said they would be very likely to utilize it with their patients. There was a statistically significant increase in knowledge of stillbirth risk factors among all health care providers after reviewing the Toolkit (p<0.001). CONCLUSIONS: Health providers had varied baseline knowledge about stillbirth. The Toolkit improved provider knowledge, but further research is needed to assess its impact on clinical practice. PMID- 29422169 TI - "I do the best I can:" Personal care preferences of patients of size. AB - AIM: Obesity is a common co-morbidity of hospitalized patients, and nurses sometimes have great difficulty meeting the skin care needs of patients of size. The purpose of this qualitative study was to identify successful self-care strategies patients of size used to care for themselves at home, in order to replicate these successes in the hospital. BACKGROUND: When patients who are obese are hospitalized they are vulnerable to complications, including skin integrity problems. These can be made worse for the patient if s/he cannot engage in their usual self-care hygiene practices. By uncovering self-developed solutions to hygienic care at home, nurses could incorporate these into their individualized plan of care. METHODS: This qualitative descriptive study used an appreciative inquiry approach, to discover what works well, in order to replicate these actions. A skilled qualitative nurse researcher used a semi-structured interview process to uncover the personal care preferences of patients whose admission body mass index (BMI) was >50. A step-wise approach was used for data reduction, and triangulation of researchers added to the study's trustworthiness. RESULTS: Fourteen patients of size were interviewed. Nine categories emerged from the data, all of which fit under the overarching theme: "I do the best I can." Multiple ideas for quality care, delivered while preserving patient dignity, were identified. Implications for nursing practice are included. CONCLUSION: Patients of size have developed creative and useful approaches to managing skin health that could be used in the hospital when patients are unable to manage their self care alone. PMID- 29422171 TI - Strict versus liberal insulin therapy in the cardiac surgery patient: An evidence based practice development, implementation and evaluation project. AB - BACKGROUND: Hyperglycemia post-cardiac surgery is associated with poor clinical outcomes. Recent studies suggest maintaining liberal glycemic control (<180mg/dL) using a continuous insulin infusion (CII) versus strict control achieves optimal outcomes and prevents hypoglycemia. PURPOSE: To develop, implement and evaluate a nurse managed liberal CII protocol. METHODS: Retrospective review of 144 strict CII patient records and 147 liberal CII patient records. RESULTS: Mean blood glucose was 159.8mg/dL (liberal CII) compared to 143.3mg/dL (strict CII) (p<=0.001). No surgical site infections occurred in either group. Mean ICU length of stay was 4.5days (liberal) versus 4.4days (strict) (p=0.74). Two 30-day mortalities occurred for the liberal cohort compared to no deaths in the strict group (p=0.49). Hypoglycemia incidence within 24h after surgery was 0.1% (liberal) compared to 0.3% (strict) compared to (p=0.16). CONCLUSION: Use of a nurse managed liberal CII resulted in similar outcomes with fewer incidents of hypoglycemia. PMID- 29422170 TI - "Mobile technology to improve heart failure outcomes: A proof of concept paper". AB - BACKGROUND: Heart failure (HF) causes significant symptom burden and human suffering with considerable economic burden due to hospital readmissions. Targeted interventions to encourage and support self-management behavior is warranted. AIM: To test the proof of concept of a mobile application (HeartMapp) in improving self-care management of patients with heart failure. METHOD: An exploratory inquiry used a field study strategy with purposeful sampling and constant comparative analysis to test the proof of concept of HeartMapp using The Business Model Canvas framework. RESULTS: A total of 125 individuals, who were identified as potential candidates to use the HeartMapp completed the interview over a seven-week period in 2016. Constant comparative analysis indicated themes that Skilled Nursing Facilities had increased readmissions. Participants from Skilled Nursing Facilities reported concern on lack of staffing, star rating, and malpractice claims. Two types of patients were identified as early adapters of technology and those in denial. Health care facilities reported challenges on transitional care, nurses struggle with engagement of patients on self-care management. To avoid readmission penalty, hospitals task home care agencies to keep the patients home for 30-days. While home care agencies rely on remote telemonitoring reported that current telemonitoring devices are costly to maintain, thus exploring novel technology. CONCLUSION: The Business Model Canvas provided directions for future testing of HeartMapp for its usability as an adjunct device in home health setting to improve self-management and enhance communication with providers, and ultimately reduce readmissions. PMID- 29422172 TI - Are you also overwhelmed by the predators? PMID- 29422173 TI - School-related factors affecting smoking intention among Korean middle school students. AB - INTRODUCTION: This study examined school-related factors affecting smoking intention among Korean middle school students who were current non-smokers. METHODS: We used a descriptive, cross-sectional design based on the model explaining smoking initiation among Asian adolescents, to analyze data from 561 adolescents aged 14-16years in middle school. RESULTS: School-related cognitive and psychological engagement and close friends' smoking were significantly associated with smoking intention after controlling for covariates, such as personal and familial factors. Of the familial factors, mothers' previous or current smoking status were significantly associated with smoking intention. In addition, for personal factors, smoking experience was associated with smoking intention. The explanatory power of these variables in the predictive model was 36.0%. CONCLUSION: Health care providers in schools and communities should develop smoking prevention strategies reflecting school-related factors associated with smoking intention such as improving school engagement and providing healthy alternative methods for social interaction with peers rather than smoking. PMID- 29422174 TI - Efficacy of a care bundle to prevent multiple infections in the intensive care unit: A quasi-experimental pretest-posttest design study. AB - BACKGROUND: Healthcare-associated infections extend hospitalization time, increase treatment costs and increase morbidity-mortality rates. OBJECTIVES: To evaluate the efficacy of a care bundle aimed at preventing three most frequent intensive care unit-acquired infections. MATERIALS AND METHOD: This quasi experimental study occurred in an 18-bed tertiary care intensive care unit at a university hospital in Turkey. The sample consisted of 120 patients older than 18years and receiving invasive mechanical ventilation therapy, or had a central venous catheter or urinary catheter. The study comprised three stages. In stage one, the intensive care unit nurses were trained in infection measures, VAP, CA UTIs and CLABSIs sections of the care bundle. In stage two, the trained nurses applied the care bundle and received feedback on any problematic issues. In stage three, the nurses' compatibility and efficacy of the infection prevention care bundle on the infection rates of VAP, CA-UTIs and CLABSIs were evaluated over three 3-month periods. RESULTS: Over 1000 ventilation days, ventilator-associated pneumonia infection rates were 23.4, 12.6, and 11.5, during January-March, April June and July-September, respectively, with January-March and April-June showing a significant decrease (chi2=6.934, p=0.031). The central line-associated bloodstream infection rates were 8.9, 4.2, and 9.9 per 1000 catheter days, during January-March, April-June and July-September, respectively, but were not significantly different based on pair-wise comparisons (p>0.05). The catheter associated urinary tract infection rates were higher during July-September (6.7/1000 catheter days) compared to January-March (5.7/1000 catheter days) and April-June (10.4/1000 catheter days) but the differences were not significant (p>0.05). CONCLUSIONS: The infection rates decreased with increased compatibility of the care bundle prepared from evidence-based guidelines. PMID- 29422175 TI - "Not getting worse" a qualitative study of patients perceptions of treatment goals in patients with heart failure. AB - BACKGROUND: Knowledge of patient reported outcomes helps to provide personalized care on a patient level, optimize care on a population level, and identify the most appropriate patient reported outcomes for clinical trials. To be able to provide personalized care to patients with HF, it is important to know which treatment goals patients with HF consider the most important. This is particularly useful for interventions aimed at improving symptoms, functional status, or health-related quality of life. AIM: The aim of this study was (1) to explore which treatment goals patients with heart failure (HF) perceive as important for their treatment and (2) to identify which treatment goals take priority over other treatment goals. METHODS: The study had a qualitative design and included one focus group interview with 6 patients with HF. Data were analyzed using qualitative content analysis. RESULTS: The overall theme of this study was found to be 'Not getting worse'. This theme was composed of 4 categories that described how the patients perceived the goals of treatment: to decrease symptoms, to improve physical function, to prevent readmission, and to live a normal life. None of the participants mentioned improved survival or being cured of their HF as a treatment goal. CONCLUSION: 'Not getting worse' was perceived as the treatment goal that matters to patients with HF and is in line with currently used endpoints for the evaluation of a treatment in a clinical trial. More research is necessary to develop endpoints that are consistent with the perception of patients, useful for clinical practice, and measurable. PMID- 29422176 TI - Life with a urostomy: A phenomenological study. AB - AIM: To explore the experiences of self-care of patients with urostomy and to identify the influencing factors of self-care. BACKGROUND: The creation of a urostomy results in the loss of an important bodily function and an alteration of the body image and causes physical, psychological, and social changes in the lifestyle through the adjustment and management of the new condition. In literature, there are few studies that analyze the lifestyle of people with urostomy. METHODS: In this qualitative design, an interpretative phenomenological analysis was used. Eleven people living with urostomies took part in semi structured interviews consisting of open-ended questions about their self-care experience. Data were collected between March and September 2016. RESULTS: Six themes and twelve subthemes emerged from the data analysis. The themes were: Surgery impact, body image, daily and social-life activities, stoma and sexuality, managing stoma education, family and friends' support. CONCLUSIONS: This study highlights the impact a stoma has on people's lives. This impact should be absorbed with personalized education before the surgery with the eventual need of a continuous and planned educational course respecting the patients' needs. This study shows that a continuous and planned educational plan is crucial for patients living with urostomies. Therefore, nurses should provide patients an adequate support and a personalized education program to cope with ostomy. PMID- 29422177 TI - Effects of simulation-based educational program in improving the nurses' self efficacy in caring for patients' with COPD and CHF in a post-acute care (PACU) setting. AB - The 2014 national percentage for 30-day readmissions among Medicare recipients from Post-Acute Care Unit (PACU) showed: Heart Failure (HF) with major complications and co-morbidities, an average of 24.09%, and Chronic Obstructive Pulmonary Disease (COPD) with complications and co-morbidities 23.12%. The percentage of readmissions for New Jersey among PACU showed: HF with major complications and co-morbidities, an average of 24.40% and COPD 26.35% (Avalere Health, 2014). For this study site, the hospital readmission rate was not specifically broken down according to condition/diagnosis. Overall, the hospital readmission rate was approximately 20%. A few percent lower than the national and state average, but still a considerable number. This study is significant in finding out whether a simulation based educational program will increase the nurses' self-efficacy in caring for these patients. The positive outcome of this study can provide a template for training PACU nurses to aid in decreasing hospital readmissions in this vulnerable population. The simulation-based educational program was approximately 5h in length, and it was divided into two parts, a presentation on HF and COPD, and the actual simulation scenario, using a low-fidelity manikin (LFM). There were approximately 20 Registered nurses as participants but 4 did not complete the post-simulation self-efficacy scale, and the 16 were included in the actual study. This study was able to define the effects of simulation-based educational program on the RNs self-efficacy in caring for COPD and HF patients. The participants' demographic information, i.e. age, educational attainment, years of experience, and previous work experience, did not show any differences in how much the nurses' self-efficacy improved. The post-simulation self-efficacy score of the participants showed approximately 5% increase compared to the pre-simulation score. The outcome of the study concluded the simulation-based educational program as having a significant effect on the participants' self-efficacy post-simulation. PMID- 29422178 TI - Understanding the cervical screening behaviour of Chinese women: The role of health care system and health professions. AB - BACKGROUND: In China, cervical cancer cases are increasing, making an impact on the worldwide burden of cervical cancer. Despite the initiatives undertaken by the Chinese government, the current coverage of cervical screening in China remains suboptimal. There is an urgent need to identify the facilitators and barriers associated with the uptake of cervical cancer screening among the Chinese population. PURPOSE: The study aimed to explore the experiences and perceptions of cervical cancer screening of mainland Chinese women in relation to their screening behaviour, particularly in the aspects of health care system and health profession roles. METHODS: A qualitative research was conducted using semi structured interviews. A total of 27 Chinese women aged 25 to 50 (both screened and non-screened women) completed the interviews. The analysis of the interview data was undertaken inductively using latent content analysis. DISCUSSION AND CONCLUSION: Results showed that organised health examination programmes provide a good basis for integrating cervical screening into broader checks on the health of women, and utilising different networks of social support facilitate the utilisation of the screening service. However, education on cervical cancer and screening must be made more generally available. More importantly, there is a need for a more participatory and empowering exchange in the encounter between health professions and these women. Appropriate training program is strongly recommended for health professions about communicate skills with patients. Future work should focus on identifying strategies to overcome the barriers to cervical screening related to health care system and medical professions among this population. PMID- 29422179 TI - Depressive symptoms are associated with in-hospital complications following acute myocardial infarction. AB - AIM: To examine the effect of depressive symptoms on in-hospital complication rates after Acute Myocardial Infarction (AMI). BACKGROUND: Coronary Heart Disease (CHD) is the primary cause of death worldwide. AMI is the most common consequence of CHD. Depressive symptoms are an important risk factor for CHD and increased risk of AMI. Understanding the relationship between depressive symptoms and short term complications for patients with AMI is important for determining their needs, developing interventions, and evaluating the outcomes of interventions. METHODS: A prospective observational study was conducted with 175 patients who were admitted to the Intensive Care Units (ICUs) of four large hospitals in Jordan. During the interview, within 72h (mean, 38+/-16h) of admission to the hospital, participants completed the sociodemographic and clinical questionnaire and the Beck Depression Inventory Scale. RESULTS: The mean age was 66.9+/ 11.0years. The number of patients with mild, moderate, and severe depressive symptoms who developed complications was significantly higher than those with minimal depressive symptoms, p?0.001. Patients with mild, moderate, and severe depressive symptoms had longer lengths of stay in the ICU and in hospital than patients with minimal depressive symptoms. Patients with mild, moderate and severe depressive symptoms were at 1.22 times higher risk for developing complications than patients with minimal depressive symptoms. Moreover, previous AMI history increased the risk for developing complication by 150%. CONCLUSIONS: Depressive symptoms were an independent predictor of complications and increased length of stay after AMI. Interventions to control depressive symptoms early after AMI are necessary. PMID- 29422180 TI - Self-care among Filipinos in the United States who have hypertension. AB - BACKGROUND: Despite the strong literature on the influence of self-care on hypertension (HTN) diagnosis, there is a notable lack of studies that explore self-care among Filipino immigrants in the United States (US) who have HTN. AIM: To determine the levels of and relationships between and among acculturation, acculturative stress, HTN self-efficacy, patient activation, and HTN self-care among first generation Filipino immigrants in the US who have HTN. DESIGN: A cross-sectional correlational design was used to determine the relationships between and among acculturation, acculturative stress, HTN self-efficacy, patient activation, and HTN self-care using the Transactional Model of Stress and Coping. One hundred and sixty-three community-dwelling first-generation Filipino immigrants participated in the study. METHODS: Data on HTN self-care, acculturation, acculturative stress, HTN self-efficacy, and patient activation were collected. RESULTS: The study results revealed that HTN self-efficacy and patient activation significantly contributed to the regression model that accounted for 29.5% of the variance in HTN self-care for this sample. Further analysis revealed that patient activation had a mediating role between HTN self efficacy and HTN self-care. CONCLUSIONS: Findings from this study revealed that HTN self-efficacy and patient activation were associated with self-care behaviors associated with HTN management for this sample. CLINICAL RELEVANCE: Findings from this study highlight the importance of addressing HTN self-efficacy and patient activation in improving HTN self-care for this population. PMID- 29422181 TI - Playing music improves well-being of oncology nurses. AB - BACKGROUND: Nurses experience high levels of stress associated with the demands of their workplace. Anxiety and depression symptoms are common in this occupational group and the necessity of supportive actions is vital. This is especially true for nurses working in high intensity and demanding settings such as oncology units. AIM: This study examined the effects of a music intervention on anxiety, depression, and psychosomatic symptoms of oncology nurses. METHODS: Forty-eight oncology nurses, were randomized to either an intervention group (n = 22) attending four consecutive weekly 1-h music classes or a control group with no intervention (n = 26) who maintained their usual lifestyle habits, for one month. Intervention group played and improvised music using percussion instruments. Courses consisted of varied multitask exercises of progressive difficulty, sometimes involving team playing, or individual performances. Depression, anxiety, and physical symptoms were measured before and after the end of the intervention. Anxiety and depression were assessed with the Hospital Anxiety and Depression Scale. Psychosomatic symptoms were assessed with Pennebaker Inventory omicronf Limbic Languidness. RESULTS: Anxiety, depression and psychosomatic symptoms significantly reduced for the intervention group at the end of the study. No statistical significant change was observed for the control group in any of the three psychological indicators. CONCLUSION: The findings of our study highlight the fact that music can be a cost-effective resource in developing interventions to reduce stress and improve well-being. Playing music can be the next step for further investigation, since we already know that listening to music is beneficial. PMID- 29422182 TI - A critical enquiry into the psychometric properties of the professional quality of life scale (ProQol-5) instrument. AB - AIM: This study had conducted a comprehensive analysis of the psychometric properties of Proqol 5, professional quality of work instrument among nurses and palliative care-workers on the basis of three independent datasets. The goal is to see the general applicability of this instrument across multiple populations. BACKGROUND: Although the Proqol scale has been widely adopted, there are few attempts that have thoroughly analyzed this instrument across multiple datasets using multiple populations. METHODS: A questionnaire was developed and distributed to palliative care-workers in Canada and Nurses at two hospitals in Australia and Canada, this resulted in 273 datasets from the Australian and 303 datasets from the Canadian nurses and 503 datasets from the Canadian palliative care-workers. A comprehensive psychometric property analysis was conducted including inter-item correlations, tests of reliability, and both convergent and discriminant validity as well as construct validity analyses. In addition, to test for the reverse coding artifacts in the BO scale, exploratory factor analysis was adopted. RESULTS: The psychometric property analysis of Proqol 5 was satisfactory for the compassion satisfaction construct. However, there are concerns with respect to the burnout and secondary trauma stress scales and recommendations are made regarding the coding and specific items which should improve the reliability and validity of these scales. CONCLUSION: This research establishes the strengths and weaknesses of the Proqol instrument and demonstrates how it can be improved. Through specific recommendations, the academic community is invited to revise the burnout and secondary traumatic stress scales in an effort to improve Proqol 5 measures. PMID- 29422183 TI - Illness perception, risk perception and health promotion self-care behaviors among Chinese patient with type 2 diabetes: A cross-sectional survey. AB - AIM: To explore illness perception and perceived risk of developing diabetes complications in relation to health-promoting self-care behaviors among Chinese patients with type 2 diabetes. BACKGROUND: Illness and risk perceptions are important determinants of various health behaviors. However, few studies have simultaneously examined the impacts of these two constructs on self-care among diabetic patients. METHODS: Data were collected on participants' characteristics, illness perception, risk perception, and health-promoting self-care behaviors over 6months among 304 subjects from three general hospitals. RESULTS: Significant associations between illness perception and risk perception were observed. Illness perception and/or risk perception explained an independent, small but significant proportion of the variance in each health-promoting self care behavior. CONCLUSION: One's perceptions of illness and future risk might be influential in understanding health-promoting self-care among diabetic patients. It may be useful to improve self-management by tailoring intervention content to individuals' illness-related perceptions. PMID- 29422184 TI - Health-promoting lifestyles and their related influences among nursing assistants in nursing homes in China. AB - OBJECTIVE: The aims are to assess the health-promoting lifestyle status of nursing assistants in nursing homes in China and explore the roles of demographic, health conception, perceived health behavior self-efficacy, and job satisfaction in health-promoting lifestyles. METHOD: Using a cross-sectional descriptive design and convenience sampling, 285 nursing assistants from different nursing homes in Hangzhou were investigated using the Health-Promoting Lifestyle Profile II, Self-Rated Abilities for Health Practice Scale, Health Conception Scale, Minnesota Satisfaction Questionnaire, and a demographic questionnaire to measure their health-promoting lifestyle status. The collected data were analyzed using SPSS20.0. RESULTS: The total score of health-promoting lifestyles among investigated nursing assistants is 114 (13). Six dimensions are standardized, including interpersonal relations, health responsibility, stress management; nutrition, spiritual growth, and physical activity, listed in descending order of their values. The variables of gender, education, number of care recipients, and religion appear to significantly influence nursing assistants' health-promoting lifestyles (p<0.05). Perceived health behavior self efficacy, health conception, and job satisfaction are significantly positively correlated with health-promoting lifestyles (p<0.05). Multiple regression analysis revealed that the predictor variables, such as gender, religion, number of care recipients, and perceived health behavior self-efficacy, can explain 48.4% of the variance in health-promoting lifestyles. CONCLUSION: The level of health-promoting lifestyles is mediocre in nursing assistants in China, with the highest score in interpersonal relations and the lowest score in physical activity. The variables of gender, education, number of care recipients, religion, and perceived health behavior self-efficacy can serve as effective predictors of health-promoting lifestyles. PMID- 29422185 TI - Addressing youth drinking. PMID- 29422186 TI - Mindfulness training in higher education students. PMID- 29422187 TI - Characterisation of urban spaces from space: going beyond the urban versus rural dichotomy. PMID- 29422188 TI - Women living with HIV in the Middle East and north Africa. PMID- 29422190 TI - Mother-to-child transmission must remain on the agenda. PMID- 29422189 TI - A mindfulness-based intervention to increase resilience to stress in university students (the Mindful Student Study): a pragmatic randomised controlled trial. AB - BACKGROUND: The rising number of young people going to university has led to concerns about an increasing demand for student mental health services. We aimed to assess whether provision of mindfulness courses to university students would improve their resilience to stress. METHODS: We did this pragmatic randomised controlled trial at the University of Cambridge, UK. Students aged 18 years or older with no severe mental illness or crisis (self-assessed) were randomly assigned (1:1), via remote survey software using computer-generated random numbers, to receive either an 8 week mindfulness course adapted for university students (Mindfulness Skills for Students [MSS]) plus mental health support as usual, or mental health support as usual alone. Participants and the study management team were aware of group allocation, but allocation was concealed from the researchers, outcome assessors, and study statistician. The primary outcome was self-reported psychological distress during the examination period, as measured with the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE OM), with higher scores indicating more distress. The primary analysis was by intention to treat. This trial is registered with the Australia and New Zealand Clinical Trials Registry, number ACTRN12615001160527. FINDINGS: Between Sept 28, 2015, and Jan 15, 2016, we randomly assigned 616 students to the MSS group (n=309) or the support as usual group (n=307). 453 (74%) participants completed the CORE-OM during the examination period and 182 (59%) MSS participants completed at least half of the course. MSS reduced distress scores during the examination period compared with support as usual, with mean CORE-OM scores of 0.87 (SD 0.50) in 237 MSS participants versus 1.11 (0.57) in 216 support as usual participants (adjusted mean difference -0.14, 95% CI -0.22 to -0.06; p=0.001), showing a moderate effect size (beta -0.44, 95% CI -0.60 to -0.29; p<0.0001). 123 (57%) of 214 participants in the support as usual group had distress scores above an accepted clinical threshold compared with 88 (37%) of 235 participants in the MSS group. On average, six students (95% CI four to ten) needed to be offered the MSS course to prevent one from experiencing clinical levels of distress. No participants had adverse reactions related to self-harm, suicidality, or harm to others. INTERPRETATION: Our findings show that provision of mindfulness training could be an effective component of a wider student mental health strategy. Further comparative effectiveness research with inclusion of controls for non specific effects is needed to define a range of additional, effective interventions to increase resilience to stress in university students. FUNDING: University of Cambridge and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care East of England. PMID- 29422191 TI - Identifying HIV care continuum gaps with verbal autopsy. PMID- 29422192 TI - Biochars induced modification of dissolved organic matter (DOM) in soil and its impact on mobility and bioaccumulation of arsenic and cadmium. AB - Biochar application has attracted great attention due to its diverse uses and benefits in the fields of environmental management and agriculture. Biochar modifies the composition of dissolved organic matter (DOM) in soil, which directly or indirectly controls the mobility of metal contaminants and their bioaccumulation. In this study, ten different hydrothermal biochars pyrolysed from mushroom waste (MSBC), soybean straw (SBBC), sewage sludge (SSBC), peanut shells (PNBC) and rice straw (RSBC) at two pyrolysis temperatures (200 degrees C and 350 degrees C) were used to investigate DOM changes in soil solution and their effects on metal availability and bioaccumulation. Biochar induced modification of soil DOM which was characterized by spectroscopic analysis of water soluble organic carbon, specific absorbance (SUVA254), UV-vis absorption, spectral slope (SR) and the absorption coefficient. Regarding rice plant growth, the biochar effects on biomass were greatly varied. Biochars (except for RSBC and MSBC) prepared at high temperature significantly (P <= 0.05) suppressed the availability of As and Cd in soil and their subsequent bioaccumulation in rice plants. The highest reduction (88%) in bioaccumulated As was observed in rice grown on soil amended with SBBC prepared at 350 degrees C (the highest temperature for hydrothermal technique). The addition of biochars (except RSBC and MSBC) prepared at high temperature markedly (p < 0.05) decreased AsIII (30 92%), while the effects on dimethylarsenic acid (DMA) and arsenate (AsV) concentrations were not significant except for SSBC350 (prepared at 350 degrees C) treatment. These results highlight the potential of biochar-DOM interactions as an important mechanism for suppressing the mobility and bioaccumulation of As and Cd in biochar-amended paddy agricultural systems. PMID- 29422193 TI - Remediation of lead-contaminated sediment by biochar-supported nano-chlorapatite: Accompanied with the change of available phosphorus and organic matters. AB - Some rivers in China have been seriously contaminated due to the discharge of lead (Pb) smelting wastewater. In this study, biochar-supported nano-chlorapatite (BC-nClAP) was synthesized to immobilize Pb in contaminated sediment. The remediation effect of BC-nClAP on Pb-contaminated sediment was evaluated through batch experiments and the materials were characterized by x-ray diffraction, scanning electron microscope, Brunner-Emmet-Teller and electronic differential system. It was found that BC-nClAP can transform Pb effectively from labile fraction into stable fraction with a maximum transformation efficiency increasing to 94.1% after 30 days of treatment, and the stabilization efficiency of toxicity characteristic leaching procedure reached 100% only after 16 days of treatment. The content of available phosphorus (AP) in the sediments treated by BC-nClAP was much less than that treated by nClAP, which indicated a lower risk of eutrophication and suggested the dissolution-precipitation mechanism involved in Pb immobilization. BC-nClAP presented the best immobilization efficiency of Pb and the content of organic matters in BC-nClAP treated samples increased the most, thus the OM might play an important role during the Pb immobilization. PMID- 29422194 TI - Ultrahigh selective adsorption of zwitterionic PPCPs both in the absence and presence of humic acid: Performance and mechanism. AB - Since zwitterionic PPCPs could be combined with humic acid (HA) leading to certain contaminants residue in aqueous solution, adsorbents with much stronger binding with zwitterionic PPCPs were needed to avoid this phenomenon. Through comparison of serial magnetic carboxyl modified hypercrosslinked resins including MA10, MA30, MA40 and MA70, MA50 was found to exhibit ultrahigh selective adsorption of zwitterionic PPCPs including tetracycline and quinolone antibiotics due to the remarkable synergistic effects generated from cation exchange interaction and non-ion exchange interaction. To figure out the effect of HA, other five adsorbents including hypercrosslinked resin Q100, aminated hypercrosslinked resin GMA50, anion exchange resin MIEX, wood-based activated carbon F400D and coal-based activated carbon Norit were chosen as comparison to MA50 in adsorption performance of tetracycline (TC) and ciprofloxacin (CPX). It turned out that the percentage of CPX or TC combined with HA in aqueous solution varied greatly for studied adsorbents. There existed serious false-positive adsorption during the adsorption process by some commercial adsorbents such as MIEX and F400D, while MA50 exhibited relatively lower false-positive adsorption, ensuring the maximum safety of effluents. Breakthrough tests showed that MA50 had significant advantages in PPCPs removal at environment concentration, indicating its potential in application for real water. PMID- 29422195 TI - Practice-based interpretation of ultrasound studies leads the way to more effective clinical support and less pharmaceutical and surgical intervention for breastfeeding infants. AB - BACKGROUND: breastfeeding optimises health outcomes for both mothers and infants. Although most women want to breastfeed, they report commencing infant formula because of nipple pain, unsettled infant behaviour, and infant growth concerns. To date, existing approaches to fit and hold ('latch and positioning') have been demonstrated not to help breastfeeding outcomes, and women report widespread dissatisfaction with the quality of support and conflicting advice they receive. Breast and nipple pain, difficulty with latching and sucking, fussing at the breast, back-arching, marathon feeds, excessively frequent feeds, poor weight gain, breast refusal, and crying due to poor satiety often signal suboptimal positional instability and impaired milk transfer, but may be misdiagnosed as medical conditions. Over the past two decades, there has been an exponential increase in numbers of infants being treated with medications, laser or scissors frenotomy, and manual therapy for unsettled behaviour and breastfeeding difficulty. New approaches to clinical breastfeeding support are urgently required. METHOD AND RESULTS: we analyse the findings of a literature search of PubMed and MEDLINE databases for ultrasound studies measuring sucking in term and preterm infants. The findings demonstrate that the Stripping Action Model of infant suck during breastfeeding, and the resultant Structural Model of infant suck dysfunction, are inaccurate. Instead, ultrasound data demonstrates the critical role of intra-oral vacuum for milk transfer. We integrate these two dimensional ultrasound results with clinical experience of the third dimension, volume, to propose a Gestalt Model of the biomechanics of healthy infant suck during breastfeeding. The Gestalt Model hypothesises that optimal intra-oral vacuums and breast tissue volumes are achieved when mother-infant positional stability eliminates conflicting intra-oral vectors, resulting in pain-free, effective milk transfer. CONCLUSION: the Gestalt Model of the biomechanics of healthy infant suck during breastfeeding opens up the possibility of a new clinical method which may prevent unnecessary medical treatments for breastfeeding problems and related unsettled infant behaviour in early life. PMID- 29422201 TI - Fetal size standards to diagnose a small- or a large-for-gestational-age fetus. PMID- 29422202 TI - Fetal Growth: Evaluation and Management. PMID- 29422203 TI - Customized growth charts: rationale, validation and clinical benefits. AB - Appropriate standards for the assessment of fetal growth and birthweight are central to good clinical care, and have become even more important with increasing evidence that growth-related adverse outcomes are potentially avoidable. Standards need to be evidence based and validated against pregnancy outcome and able to demonstrate utility and effectiveness. A review of proposals by the Intergrowth consortium to adopt their single international standard finds little support for the claim that the cases that it identifies as small are due to malnutrition or stunting, and substantial evidence that there is normal physiologic variation between different countries and ethnic groups. It is possible that the one-size-fits-all standard ends up fitting no one and could be harmful if implemented. An alternative is the concept of country-specific charts that can improve the association between abnormal growth and adverse outcome. However, such standards ignore individual physiologic variation that affects fetal growth, which exists in any heterogeneous population and exceeds intercountry differences. It is therefore more logical to adjust for the characteristics of each mother, taking her ethnic origin and her height, weight, and parity into account, and to set a growth and birthweight standard for each pregnancy against which actual growth can be assessed. A customized standard better reflects adverse pregnancy outcome at both ends of the fetal size spectrum and has increased clinicians' confidence in growth assessment, while providing reassurance when abnormal size merely represents physiologic variation. Rollout in the United Kingdom has proceeded as part of the comprehensive Growth Assessment Protocol (GAP), and has resulted in a steady increase in antenatal detection of babies who are at risk because of fetal growth restriction. This in turn has been accompanied by a year-on-year drop in stillbirth rates to their lowest ever levels in England. A global version of customized growth charts with over 100 ethnic origin categories is being launched in 2018, and will provide an individualized, yet universally applicable, standard for fetal growth. PMID- 29422204 TI - The World Health Organization fetal growth charts: concept, findings, interpretation, and application. AB - Ultrasound biometry is an important clinical tool for the identification, monitoring, and management of fetal growth restriction and development of macrosomia. This is even truer in populations in which perinatal morbidity and mortality rates are high, which is a reason that much effort is put onto making the technique available everywhere, including low-income societies. Until recently, however, commonly used reference ranges were based on single populations largely from industrialized countries. Thus, the World Health Organization prioritized the establishment of fetal growth charts for international use. New fetal growth charts for common fetal measurements and estimated fetal weight were based on a longitudinal study of 1387 low-risk pregnant women from 10 countries (Argentina, Brazil, Democratic Republic of Congo, Denmark, Egypt, France, Germany, India, Norway, and Thailand) that provided 8203 sets of ultrasound measurements. The participants were characterized by median age 28 years, 58% nulliparous, normal body mass index, with no socioeconomic or nutritional constraints (median caloric intake, 1840 calories/day), and had the ability to attend the ultrasound sessions, thus essentially representing urban populations. Median gestational age at birth was 39 weeks, and birthweight was 3300 g, both with significant differences among countries. Quantile regression was used to establish the fetal growth charts, which also made it possible to demonstrate a number of features of fetal growth that previously were not well appreciated or unknown: (1) There was an asymmetric distribution of estimated fetal weight in the population. During early second trimester, the distribution was wider among fetuses <50th percentile compared with those above. The pattern was reversed in the third trimester, with a notably wider variation >50th percentile. (2) Although fetal sex, maternal factors (height, weight, age, and parity), and country had significant influence on fetal weight (1-4.5% each), their effect was graded across the percentiles. For example, the positive effect of maternal height on fetal weight was strongest on the lowest percentiles and smallest on the highest percentiles for estimated fetal weight. (3) When adjustment was made for maternal covariates, there was still a significant effect of country as covariate that indicated that ethnic, cultural, and geographic variation play a role. (4) Variation between populations was not restricted to fetal size because there were also differences in growth trajectories. (5) The wide physiologic ranges, as illustrated by the 5th-95th percentile for estimated fetal weight being 2205-3538 g at 37 weeks gestation, signify that human fetal growth under optimized maternal conditions is not uniform. Rather, it has a remarkable variation that largely is unexplained by commonly known factors. We suggest this variation could be part of our common biologic strategy that makes human evolution extremely successful. The World Health Organization fetal growth charts are intended to be used internationally based on low-risk pregnancies from populations in Africa, Asia, Europe, and South America. We consider it prudent to test and monitor whether the growth charts' performance meets the local needs, because refinements are possible by a change in cut-offs or customization for fetal sex, maternal factors, and populations. In the same line, the study finding of variations emphasizes the need for carefully adjusted growth charts that reflect optimal local growth when public health issues are addressed. PMID- 29422205 TI - The INTERGROWTH-21st fetal growth standards: toward the global integration of pregnancy and pediatric care. AB - The purpose of the INTERGROWTH-21st project was to develop international, prescriptive standards for fetal growth assessed by ultrasound and fundal height, preterm postnatal growth, newborn size and body composition, maternal weight gain, and infant development at the age of 2 years. Hence, we have produced, based on World Health Organization recommendations, the first comprehensive set of international standards of optimal fetal and newborn growth that perfectly match the existing World Health Organization child growth standards. Uniquely, the same population was followed up longitudinally from 9 weeks of fetal life to 2 years of age, with growth, health, and nutritional status assessment at 2 years supporting the appropriateness of the population for construction of growth standards. The resulting package of clinical tools allows, for the first time, growth and development to be monitored from early pregnancy to infancy. The INTERGROWTH-21st fetal growth standards, which are based on observing >4500 healthy pregnancies, nested in a study of >59,000 pregnancies from populations with low rates of adverse perinatal outcomes, show how fetuses should grow-rather than the more limited objective of past references, which describe how they have grown at specific times and locations. Our work has confirmed the fundamental biological principle that variation in human growth across different populations is mostly dependent on environmental, nutritional, and socioeconomic factors. We found that when mothers' nutritional and health needs are met and there are few environmental constraints on growth, <3.5% of the total variability of skeletal growth was due to differences between populations. We propose that not recognizing the concept of optimal growth could deprive the most vulnerable mothers and their babies of optimal care, because local growth charts normalize those at highest risk for growth restriction and overweight, and can be valuable for policymakers to ensure rigorous evaluation and effective resource allocation. We strongly encourage colleagues to join efforts to provide integrated, evidence based growth monitoring to pregnant women and their infants worldwide. Presently, there are 23.3 million infants born small for gestational age in low- to middle income countries according to the INTERGROWTH-21st newborn size standards. We suggest that misclassification of these infants by using local charts could affect the delivery of optimal health care. PMID- 29422206 TI - Individualized growth assessment: conceptual framework and practical implementation for the evaluation of fetal growth and neonatal growth outcome. AB - Fetal growth abnormalities can pose significant consequences on perinatal morbidity and mortality of nonanomalous fetuses. The most widely accepted definition of fetal growth restriction is an estimated fetal weight less than the 10th percentile for gestational age according to population-based criteria. However, these criteria do not account for the growth potential of an individual fetus, nor do they effectively separate constitutionally small fetuses from ones that are malnourished. Furthermore, conventional approaches typically evaluate estimated fetal weight at a single time point, rather than using serial scans, to evaluate growth. This article provides a conceptual framework for the individualized growth assessment of a fetus/neonate based on measuring second trimester growth velocity of fetal size parameters to estimate growth potential. These estimates specify size models that generate individualized third-trimester size trajectories and predict birth characteristics. Comparisons of measured and predicted values are used to separate normally growing fetuses from those with growth abnormalities. This can be accomplished with individual anatomical parameters or sets of parameters. A practical and freely available software (Individualized Growth Assessment Program) has been developed to allow implementation of this approach for clinical and research purposes. PMID- 29422209 TI - Fetal growth velocity and body proportion in the assessment of growth. AB - Fetal growth restriction implies failure of a fetus to meet its growth potential and is associated with increased perinatal mortality and morbidity. Therefore, antenatal detection of fetal growth restriction is of major importance in an attempt to deliver improved clinical outcomes. The most commonly used approach towards screening for fetal growth restriction is by means of sonographic fetal weight estimation, to detect fetuses small for gestational age, defined by an estimated fetal weight <10th percentile for gestational age. However, the predictive accuracy of this approach is limited both by suboptimal detection rate (as it may overlook non-small-for-gestational-age growth-restricted fetuses) and by a high false-positive rate (as most small-for-gestational-age fetuses are not growth restricted). Here, we review 2 strategies that may improve the diagnostic accuracy of sonographic fetal biometry for fetal growth restriction. The first strategy involves serial ultrasound evaluations of fetal biometry. The information obtained through these serial assessments can be interpreted using several different approaches including fetal growth velocity, conditional percentiles, projection-based methods, and individualized growth assessment that can be viewed as mathematical techniques to quantify any decrease in estimated fetal weight percentile, a phenomenon that many care providers assess and monitor routinely in a qualitative manner. This strategy appears promising in high-risk pregnancies where it seems to improve the detection of growth-restricted fetuses at increased risk of adverse perinatal outcomes and, at the same time, decrease the risk of falsely diagnosing healthy constitutionally small-for-gestational-age fetuses as growth restricted. Further studies are needed to determine the utility of this strategy in low-risk pregnancies as well as to optimize its performance by determining the optimal timing and interval between exams. The second strategy refers to the use of fetal body proportions to classify fetuses as either symmetric or asymmetric using 1 of several ratios; these include the head circumference to abdominal circumference ratio, transverse cerebellar diameter to abdominal circumference ratio, and femur length to abdominal circumference ratio. Although these ratios are associated with small for gestational age at birth and with adverse perinatal outcomes, their predictive accuracy is too low for clinical practice. Furthermore, these associations become questionable when other, potentially more specific measures such as umbilical artery Doppler are being used. Furthermore, these ratios are of limited use in determining the etiology underlying fetal smallness. It is possible that the use of the 2 gestational-age-independent ratios (transverse cerebellar diameter to abdominal circumference and femur length to abdominal circumference) may have a role in the detection of mild-moderate fetal growth restriction in pregnancies without adequate dating. In addition, despite their limited predictive accuracy, these ratios may become abnormal early in the course of fetal growth restriction and may therefore identify pregnancies that may benefit from closer monitoring of fetal growth. PMID- 29422208 TI - Customized vs INTERGROWTH-21st standards for the assessment of birthweight and stillbirth risk at term. AB - BACKGROUND: Fetal growth abnormalities are linked to stillbirth and other adverse pregnancy outcomes, and use of the correct birthweight standard is essential for accurate assessment of growth status and perinatal risk. OBJECTIVE: Two competing, conceptually opposite birthweight standards are currently being implemented internationally: customized gestation-related optimal weight (GROW) and INTERGROWTH-21st. We wanted to compare their performance when applied to a multiethnic international cohort, and evaluate their usefulness in the assessment of stillbirth risk at term. STUDY DESIGN: We analyzed routinely collected maternity data from 10 countries with a total of 1.25 million term pregnancies in their respective main ethnic groups. The 2 standards were applied to determine small for gestational age (SGA) and large for gestational age (LGA) rates, with associated relative risk and population-attributable risk of stillbirth. The customized standard (GROW) was based on the term optimal weight adjusted for maternal height, weight, parity, and ethnic origin, while INTERGROWTH-21st was a fixed standard derived from a multiethnic cohort of low-risk pregnancies. RESULTS: The customized standard showed an average SGA rate of 10.5% (range 10.1 12.7) and LGA rate of 9.5% (range 7.3-9.9) for the set of cohorts. In contrast, there was a wide variation in SGA and LGA rates with INTERGROWTH-21st, with an average SGA rate of 4.4% (range 3.1-16.8) and LGA rate of 20.6% (range 5.1-27.5). This variation in INTERGROWTH-21st SGA and LGA rates was correlated closely (R = +/-0.98) to the birthweights predicted for the 10 country cohorts by the customized method to derive term optimal weight, suggesting that they were mostly due to physiological variation in birthweight. Of the 10.5% of cases defined as SGA according to the customized standard, 4.3% were also SGA by INTERGROWTH-21st and had a relative risk of 3.5 (95% confidence interval, 3.1-4.1) for stillbirth. A further 6.3% (60% of the whole customized SGA) were not SGA by INTERGROWTH 21st, and had a relative risk of 1.9 (95% confidence interval, 3.1-4.1) for stillbirth. An additional 0.2% of cases were SGA by INTERGROWTH-21st only, and had no increased risk of stillbirth. At the other end, customized assessment classified 9.5% of births as large for gestational age, most of which (9.0%) were also LGA by the INTERGROWTH-21st standard. INTERGROWTH-21st identified a further 11.6% as LGA, which, however, had a reduced risk of stillbirth (relative risk, 0.6; 95% confidence interval, 0.5-0.7). CONCLUSION: Customized assessment resulted in increased identification of small for gestational age and stillbirth risk, while the wide variation in SGA rates using the INTERGROWTH-21st standard appeared to mostly reflect differences in physiological pregnancy characteristics in the 10 maternity populations. PMID- 29422207 TI - A new customized fetal growth standard for African American women: the PRB/NICHD Detroit study. AB - BACKGROUND: The assessment of fetal growth disorders requires a standard. Current nomograms for the assessment of fetal growth in African American women have been derived either from neonatal (rather than fetal) biometry data or have not been customized for maternal ethnicity, weight, height, and parity and fetal sex. OBJECTIVE: We sought to (1) develop a new customized fetal growth standard for African American mothers; and (2) compare such a standard to 3 existing standards for the classification of fetuses as small (SGA) or large (LGA) for gestational age. STUDY DESIGN: A retrospective cohort study included 4183 women (4001 African American and 182 Caucasian) from the Detroit metropolitan area who underwent ultrasound examinations between 14-40 weeks of gestation (the median number of scans per pregnancy was 5, interquartile range 3-7) and for whom relevant covariate data were available. Longitudinal quantile regression was used to build models defining the "normal" estimated fetal weight (EFW) centiles for gestational age in African American women, adjusted for maternal height, weight, and parity and fetal sex, and excluding pathologic factors with a significant effect on fetal weight. The resulting Perinatology Research Branch/Eunice Kennedy Shriver National Institute of Child Health and Human Development (hereinafter, PRB/NICHD) growth standard was compared to 3 other existing standards--the customized gestation-related optimal weight (GROW) standard; the Eunice Kennedy Shriver National Institute of Child Health and Human Development (hereinafter, NICHD) African American standard; and the multinational World Health Organization (WHO) standard--utilized to screen fetuses for SGA (<10th centile) or LGA (>90th centile) based on the last available ultrasound examination for each pregnancy. RESULTS: First, the mean birthweight at 40 weeks was 133 g higher for neonates born to Caucasian than to African American mothers and 150 g higher for male than female neonates; maternal weight, height, and parity had a positive effect on birthweight. Second, analysis of longitudinal EFW revealed the following features of fetal growth: (1) all weight centiles were about 2% higher for male than for female fetuses; (2) maternal height had a positive effect on EFW, with larger fetuses being affected more (2% increase in the 95th centile of weight for each 10-cm increase in height); and (3) maternal weight and parity had a positive effect on EFW that increased with gestation and varied among the weight centiles. Third, the screen-positive rate for SGA was 7.2% for the NICHD African American standard, 12.3% for the GROW standard, 13% for the WHO standard customized by fetal sex, and 14.4% for the PRB/NICHD customized standard. For all standards, the screen-positive rate for SGA was at least 2-fold higher among fetuses delivered preterm than at term. Fourth, the screen-positive rate for LGA was 8.7% for the GROW standard, 9.2% for the PRB/NICHD customized standard, 10.8% for the WHO standard customized by fetal sex, and 12.3% for the NICHD African American standard. Finally, the highest overall agreement among standards was between the GROW and PRB/NICHD customized standards (Cohen's interrater agreement, kappa = 0.85). CONCLUSION: We developed a novel customized PRB/NICHD fetal growth standard from fetal data in an African American population without assuming proportionality of the effects of covariates, and without assuming that these effects are equal on all centiles of weight; we also provide an easy-to-use centile calculator. This standard classified more fetuses as being at risk for SGA compared to existing standards, especially among fetuses delivered preterm, but classified about the same number of LGA. The comparison among the 4 growth standards also revealed that the most important factor determining agreement among standards is whether they account for the same factors known to affect fetal growth. PMID- 29422210 TI - Pathophysiology of placental-derived fetal growth restriction. AB - Placental-related fetal growth restriction arises primarily due to deficient remodeling of the uterine spiral arteries supplying the placenta during early pregnancy. The resultant malperfusion induces cell stress within the placental tissues, leading to selective suppression of protein synthesis and reduced cell proliferation. These effects are compounded in more severe cases by increased infarction and fibrin deposition. Consequently, there is a reduction in villous volume and surface area for maternal-fetal exchange. Extensive dysregulation of imprinted and nonimprinted gene expression occurs, affecting placental transport, endocrine, metabolic, and immune functions. Secondary changes involving dedifferentiation of smooth muscle cells surrounding the fetal arteries within placental stem villi correlate with absent or reversed end-diastolic umbilical artery blood flow, and with a reduction in birthweight. Many of the morphological changes, principally the intraplacental vascular lesions, can be imaged using ultrasound or magnetic resonance imaging scanning, enabling their development and progression to be followed in vivo. The changes are more severe in cases of growth restriction associated with preeclampsia compared to those with growth restriction alone, consistent with the greater degree of maternal vasculopathy reported in the former and more extensive macroscopic placental damage including infarcts, extensive fibrin deposition and microscopic villous developmental defects, atherosis of the spiral arteries, and noninfectious villitis. The higher level of stress may activate proinflammatory and apoptotic pathways within the syncytiotrophoblast, releasing factors that cause the maternal endothelial cell activation that distinguishes between the 2 conditions. Congenital anomalies of the umbilical cord and placental shape are the only placental-related conditions that are not associated with maldevelopment of the uteroplacental circulation, and their impact on fetal growth is limited. PMID- 29422211 TI - Outcome in early-onset fetal growth restriction is best combining computerized fetal heart rate analysis with ductus venosus Doppler: insights from the Trial of Umbilical and Fetal Flow in Europe. AB - BACKGROUND: Early-onset fetal growth restriction represents a particular dilemma in clinical management balancing the risk of iatrogenic prematurity with waiting for the fetus to gain more maturity, while being exposed to the risk of intrauterine death or the sequelae of acidosis. OBJECTIVE: The Trial of Umbilical and Fetal Flow in Europe was a European, multicenter, randomized trial aimed to determine according to which criteria delivery should be triggered in early fetal growth restriction. We present the key findings of the primary and secondary analyses. STUDY DESIGN: Women with fetal abdominal circumference <10th percentile and umbilical pulsatility index >95th percentile between 26-32 weeks were randomized to 1 of 3 monitoring and delivery protocols. These were: fetal heart rate variability based on computerized cardiotocography; and early or late ductus venosus Doppler changes. A safety net based on fetal heart rate abnormalities or umbilical Doppler changes mandated delivery irrespective of randomized group. The primary outcome was normal neurodevelopmental outcome at 2 years. RESULTS: Among 511 women randomized, 362/503 (72%) had associated hypertensive conditions. In all, 463/503 (92%) of fetuses survived and cerebral palsy occurred in 6/443 (1%) with known outcome. Among all women there was no difference in outcome based on randomized group; however, of survivors, significantly more fetuses randomized to the late ductus venosus group had a normal outcome (133/144; 95%) than those randomized to computerized cardiotocography alone (111/131; 85%). In 118/310 (38%) of babies delivered <32 weeks, the indication was safety-net criteria: 55/106 (52%) in late ductus venosus, 37/99 (37%) in early ductus venosus, and 26/105 (25%) in computerized cardiotocography groups. Higher middle cerebral artery impedance adjusted for gestation was associated with neonatal survival without severe morbidity (odds ratio, 1.24; 95% confidence interval, 1.02-1.52) and infant survival without neurodevelopmental impairment at 2 years (odds ratio, 1.33; 95% confidence interval, 1.03-1.72) although birthweight and gestational age were more important determinants. CONCLUSION: Perinatal and 2-year outcome was better than expected in all randomized groups. Among survivors, 2-year neurodevelopmental outcome was best in those randomized to delivery based on late ductus venosus changes. Given a high rate of delivery based on the safety-net criteria, deciding delivery based on late ductus venosus changes and abnormal computerized fetal heart rate variability seems prudent. There is no rationale for delivery based on cerebral Doppler changes alone. Of note, most women with early-onset fetal growth restriction develop hypertension. PMID- 29422212 TI - Diagnosis and surveillance of late-onset fetal growth restriction. AB - By consensus, late fetal growth restriction is that diagnosed >32 weeks. This condition is mildly associated with a higher risk of perinatal hypoxic events and suboptimal neurodevelopment. Histologically, it is characterized by the presence of uteroplacental vascular lesions (especially infarcts), although the incidence of such lesions is lower than in preterm fetal growth restriction. Screening procedures for fetal growth restriction need to identify small babies and then differentiate between those who are healthy and those who are pathologically small. First- or second-trimester screening strategies provide detection rates for late smallness for gestational age <50% for 10% of false positives. Compared to clinically indicated ultrasonography in the third trimester, universal screening triples the detection rate of late smallness for gestational age. As opposed to early third-trimester ultrasound, scanning late in pregnancy (around 37 weeks) increases the detection rate for birthweight <3rd centile. Contrary to early fetal growth restriction, umbilical artery Doppler velocimetry alone does not provide good differentiation between late smallness for gestational age and fetal growth restriction. A combination of biometric parameters (with severe smallness usually defined as estimated fetal weight or abdominal circumference <3rd centile) with Doppler criteria of placental insufficiency (either in the maternal [uterine Doppler] or fetal [cerebroplacental ratio] compartments) offers a classification tool that correlates with the risk for adverse perinatal outcome. There is no evidence that induction of late fetal growth restriction at term improves perinatal outcomes nor is it a cost-effective strategy, and it may increase neonatal admission when performed <38 weeks. PMID- 29422213 TI - Antenatal glucocorticoids, magnesium sulfate, and mode of birth in preterm fetal small for gestational age. AB - A diagnosis of fetal growth restriction and subsequent preterm birth is associated with increased risks of adverse perinatal and neurodevelopmental outcomes and potentially long-lasting effects to adulthood. Most such cases are associated with placental insufficiency and the fetal response to chronic intrauterine hypoxemia and nutrient deprivation leads to substantial physiological and metabolic adaptations. The management of such pregnancies, especially with respect to perinatal interventions and birth mode, remains an unresolved dilemma. The benefits from standard interventions for threatened preterm birth may not be necessarily translated to pregnancies with small-for gestational-age fetuses. Clinical trials or retrospective studies on outcomes following administration of antenatal glucocorticoids and magnesium sulfate for neuroprotection when preterm birth is imminent either have yielded conflicting results for small-for-gestational-age fetuses, or did not include this subgroup of patients. Experimental models highlight potential harmful effects of administration of antenatal glucocorticoids and magnesium sulfate in the pregnancies with fetal small for gestational age although clinical data do not substantiate these concerns. In addition, heterogeneity in definitions of fetal small for gestational age, variations in the inclusion criteria, and the glucocorticoid regime contribute to inconsistent results. In this review, we discuss the physiologic adaptions of the small-for-gestational-age fetus to its abnormal in utero environment in relation to antenatal glucocorticoids; the impact of antenatal glucocorticoids and intrapartum magnesium sulfate in pregnancies with fetal small for gestational age; the current literature on birth mode for pregnancies with fetal small for gestational age; and the knowledge gaps in the existing literature. PMID- 29422214 TI - Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy. AB - Small for gestational age is usually defined as an infant with a birthweight <10th centile for a population or customized standard. Fetal growth restriction refers to a fetus that has failed to reach its biological growth potential because of placental dysfunction. Small-for-gestational-age babies make up 28-45% of nonanomalous stillbirths, and have a higher chance of neurodevelopmental delay, childhood and adult obesity, and metabolic disease. The majority of small for-gestational-age babies are not recognized before birth. Improved identification, accompanied by surveillance and timely delivery, is associated with reduction in small-for-gestational-age stillbirths. Internationally and regionally, detection of small for gestational age and management of fetal growth problems vary considerably. The aim of this review is to: summarize areas of consensus and controversy between recently published national guidelines on small for gestational age or fetal growth restriction; highlight any recent evidence that should be incorporated into existing guidelines; and identify future research priorities in this field. A search of MEDLINE, Google, and the International Guideline Library identified 6 national guidelines on management of pregnancies complicated by fetal growth restriction/small for gestational age published from 2010 onwards. There is general consensus between guidelines (at least 4 of 6 guidelines in agreement) in early pregnancy risk selection, and use of low-dose aspirin for women with major risk factors for placental insufficiency. All highlight the importance of smoking cessation to prevent small for gestational age. While there is consensus in recommending fundal height measurement in the third trimester, 3 specify the use of a customized growth chart, while 2 recommend McDonald rule. Routine third-trimester scanning is not recommended for small-for-gestational-age screening, while women with major risk factors should have serial scanning in the third trimester. Umbilical artery Doppler studies in suspected small-for-gestational-age pregnancies are universally advised, however there is inconsistency in the recommended frequency for growth scans after diagnosis of small for gestational age/fetal growth restriction (2-4 weekly). In late-onset fetal growth restriction (>=32 weeks) general consensus is to use cerebral Doppler studies to influence surveillance and/or delivery timing. Fetal surveillance methods (most recommend cardiotocography) and recommended timing of delivery vary. There is universal agreement on the use of corticosteroids before birth at <34 weeks, and general consensus on the use of magnesium sulfate for neuroprotection in early-onset fetal growth restriction (<32 weeks). Most guidelines advise using cardiotocography surveillance to plan delivery in fetal growth restriction <32 weeks. The recommended gestation at delivery for fetal growth restriction with absent and reversed end-diastolic velocity varies from 32 to >=34 weeks and 30 to >=34 weeks, respectively. Overall, where there is high-quality evidence from randomized controlled trials and meta-analyses, eg, use of umbilical artery Doppler and corticosteroids for delivery <34 weeks, there is a high degree of consistency between national small-for-gestational-age guidelines. This review discusses areas where there is potential for convergence between small-for gestational-age guidelines based on existing randomized controlled trials of management of small-for-gestational-age pregnancies, and areas of controversy. Research priorities include assessing the utility of late third-trimester scanning to prevent major morbidity and mortality and to investigate the optimum timing of delivery in fetuses with late-onset fetal growth restriction and abnormal Doppler parameters. Prospective studies are needed to compare new international population ultrasound standards with those in current use. PMID- 29422215 TI - Long-term cardiovascular consequences of fetal growth restriction: biology, clinical implications, and opportunities for prevention of adult disease. AB - In the modern world, cardiovascular disease is a leading cause of death for both men and women. Epidemiologic studies consistently have suggested an association between low birthweight and/or fetal growth restriction and increased rate of cardiovascular mortality in adulthood. Furthermore, experimental and clinical studies have demonstrated that sustained nutrient and oxygen restriction that are associated with fetal growth restriction activate adaptive cardiovascular changes that might explain this association. Fetal growth restriction results in metabolic programming that may increase the risk of metabolic syndrome and, consequently, of cardiovascular morbidity in the adult. In addition, fetal growth restriction is strongly associated with fetal cardiac and arterial remodeling and a subclinical state of cardiovascular dysfunction. The cardiovascular effects ocurring in fetal life, includes cardiac morphology changes, subclinical myocardial dysfunction, arterial remodeling, and impaired endothelial function, persist into childhood and adolescence. Importantly, these changes have been described in all clinical presentations of fetal growth restriction, from severe early- to milder late-onset forms. In this review we summarize the current evidence on the cardiovascular effects of fetal growth restriction, from subcellular to organ structure and function as well as from fetal to early postnatal life. Future research needs to elucidate whether and how early life cardiovascular remodeling persists into adulthood and determines the increased cardiovascular mortality rate described in epidemiologic studies. PMID- 29422220 TI - Recurrent severe aortic stenosis after transfemoral transcatheter valve-in-valve in-valve replacement. PMID- 29422221 TI - Detecting the leakage source of a reservoir using isotopes. AB - A good monitoring method is vital for understanding the sources of a water reservoir leakage and planning for effective restoring. Here we present a combination of several tracers (222Rn, oxygen and hydrogen isotopes, anions and temperature) for identification of water leakage sources in the Pushihe pumped storage power station which is in the Liaoning province, China. The results show an average 222Rn activity of 6843 Bq/m3 in the leakage water, 3034 Bq/m3 in the reservoir water, and 41,759 Bq/m3 in the groundwater. Considering that 222Rn activity in surface water is typically less than 5000 Bq/m3, the low level average 222Rn activity in the leakage water suggests the reservoir water as the main source of water. Results of the oxygen and hydrogen isotopes show comparable ranges and values in the reservoir and the leakage water samples. However, important contribution of the groundwater (up to 36%) was present in some samples from the bottom and upper parts of the underground powerhouse, while the leakage water from some other parts indicate the reservoir water as the dominant source. The isotopic finding suggests that the reservoir water is the main source of the leakage water which is confirmed by the analysis of anions (nitrate, sulfate, and chloride) in the water samples. The combination of these tracer methods for studying dam water leakage improves the accuracy of identifying the source of leaks and provide a scientific reference for engineering solutions to ensure the dam safety. PMID- 29422222 TI - Rating teams' non-technical skills in the emergency department: A qualitative study of nurses' experience. AB - INTRODUCTION: Non-technical skills (NTS) teamwork training can enhance clinicians' understanding of roles and improve communication. We evaluated a quality improvement project rating teams' NTS performance to determine the value of formal rating and debriefing processes. METHODS: In two Australian emergency departments the NTS of resuscitation teams were rated by senior nurses and medical staff. Key measures were leadership, teamwork, and task management using a valid instrument: Team Emergency Assessment Measure (TEAMTM). Emergency nurses were asked to attend a focus group from which key themes around the quality improvement process were identified. RESULTS: Main themes were: 'Team composition' (allocation of resuscitation team roles), 'Resuscitation leadership' (including both nursing and medical leadership roles) and 'TEAMTM ratings promote reflective practice' (providing staff a platform to discuss team effectiveness). Objective ratings were seen as enabling staff to provide feedback to other team members. Reflection on practice and debriefing were thought to improve communication, help define roles and responsibilities, and clarify leadership roles. CONCLUSION: Use of a non-technical skills rating scheme such as TEAMTM after team-based clinical resuscitation events was seen by emergency department nurses as feasible and a useful process for examining and improving multi disciplinary practice, while improving team performance. PMID- 29422223 TI - Which are the colors of the dress? Review of an atypical optic illusion. AB - OBJECTIVE: In 2015 the picture of a dress went viral on social media. A significant proportion of the population saw it as golden and white (G&W), while another significant proportion saw it as blue and black (B&B). The aim of this article is to review the related literature. MATERIAL AND METHODS: Bibliographic search conducted in Pubmed and Google. The algorithm used was: (color OR colour) AND (dress OR #thedress). The search was limited to the years 2015-2017. No language restrictions were used. The references of the located articles were used to widen the search. RESULTS: The search algorithm retrieved 23 articles related to the topic. Most of the works have been published in journals in the field of perception. Most works address the topic from the point of view of chromatic constancy. Genetic factors seem to have a low weight in the way the dress is perceived. There are few studies on the potential influence of ocular factors. CONCLUSION: This illusion has gained little attention in ophthalmology journals. Although colour constancy is certainly involved, there is still no theory available to explain the dichotomous character of this optical illusion. PMID- 29422224 TI - Development of a novel anatomical thin titanium mesh plate with reduction guidance and fixation function for Asian zygomatic-orbitomaxillary complex fracture. AB - For this study we developed an anatomical thin titanium mesh (ATTM) plate for Asian zygomaticomaxillary complex (ZMC) fracture repair with reduction guidance and fixation function. The ATTM plate profile was designed as an L-shape to fix at the anterior maxilla and lateral buttress of the ZMC. Computer-aided stamping analysis was performed on four screw-hole patterns in the ATTM plate - a control without screw-holes, square screw-holes, double screw-holes, and large-diameter, double screw-holes - using upper/lower dies of averaged ZMC reconstruction models. A regular ATTM plate of 0.6 mm thickness was manufactured and pre-bent using a patient-matched stamping process to verify its feasibility on three ZMC fracture models with one, two, and three fracture segments. The stamping analysis found that the double screw-holes design resulted in the most favorable performance among all the designs because of maximum von Mises stress (408 MPa) under the ultimate tensile strength. Positioning practice showed that the stamped, pre-bent ATTM plate can be used as a reduction guide to provide precise ZMC segment fixation in a completely passive fashion while limiting redundant rotation/micromovement between the separate bones in all directions. This study concluded that the ATTM plate with double screw-hole pattern design, using a patient-matched, pre-bent technique, can fit the ATTM plate/ZMC interface well, decrease mobility of unstable fracture segments, and provide good original facial contour recovery, while improving reduction efficiency. PMID- 29422230 TI - Commercial Sexual Exploitation of Children: Health Care Use and Case Characteristics. AB - OBJECTIVE: The purpose of this study was to describe pediatric health care utilization, familial psychosocial factors, child sexual abuse case characteristics, and patient demographic characteristics of adolescents prior to or at the time of their most recent identification as a victim of commercialized sexual exploitation of children (CSEC). METHODS: A retrospective chart review was conducted for the above detailed information of all adolescents presenting to the Emergency Department (ED) or Child Advocacy Center (CAC) of a pediatric hospital with concerns of suspected CSEC. RESULTS: Sixty-three adolescents were referred to the ED or CAC for CSEC concerns in the eighteen-month period. Nearly all (52, 82.5%) adolescents identified as potential CSEC victims received care at the pediatric hospital within one year of the CSEC concern being identified. CONCLUSIONS: Pediatric health care providers, including pediatric nurse practitioners, need to be more skilled in the prevention and identification of CSEC. PMID- 29422231 TI - Health professional-patient communication practices in East Asia: An integrative review of an emerging field of research and practice in Hong Kong, South Korea, Japan, Taiwan, and Mainland China. AB - OBJECTIVE: To provide an integrative review of literature on health communication in East Asia and detail culturally-specific influences. METHODS: Using PRISMA model, search of PubMed, PsychInfo, Web of Knowledge, ERIC and CINAHL databases were conducted for studies between January 2000 and March 2017, using the terms 'clinician/health professional-patient', 'nurse/doctor-patient, 'communication' and 'Asia'. RESULTS: 38 studies were included: Mainland China, Hong Kong, Japan, South Korea, and Taiwan. The existing body of research on clinician patient communication in East Asia can be classified: 1) understanding the roles and expectations of the nurse, clinician, patient, and family in clinician-patient consultations: a) nurse-patient communication; b) doctor-patient communication; c) the role of family member; and 2) factors affecting quality of care: d) cultural attitudes towards death and terminal illnesses; e) communication preferences affecting trust, decision-making and patient satisfaction; f) the extent to which patient centred care is being implemented in practice; and g) communication practices in multilingual/multi-disciplinary environments. CONCLUSION: The review detailed the complexity and heterogeneity of clinician patient communication across East Asia. The studies reviewed indicate that research in East Asia is starting to move beyond a preference for Western-based communication practices. PRACTICE IMPLICATIONS: There is a need to consider local culture in understanding and interpreting medical encounters in East Asia. The paper highlights the need for a specific culturally-appropriate model of health communication in East Asia which may significantly improve relationships between clinicians and patients. PMID- 29422232 TI - Combinations of antioxidants and/or of epigenetic enzyme inhibitors allow for enhanced collection of mouse bone marrow hematopoietic stem cells in ambient air. AB - Hematopoietic cell transplantation (HCT) is a treatment for malignant and non malignant disorders. However, sometimes the numbers of donor hematopoietic stem cells (HSC) are limiting, which can compromise the success of HCT. We recently published that collection and processing of mouse bone marrow (BM) and human cord blood cells in a hypoxic atmosphere of 3% O2 or in ambient air (~21% O2) in the presence of cyclosporine A yields increased numbers of HSC. We now show that collection and processing of mouse BM cells in ambient air in the presence of specific combinations of anti-oxidants and/or inhibitors of epigenetic enzymes can also enhance the collection of HSC, information of potential relevance for enhanced efficacy of HCT. PMID- 29422233 TI - Nerve function varies with hemoglobin A1c in controls and type 2 diabetes. AB - AIMS: To determine the cross-sectional threshold at which hemoglobin A1c (HbA1c) is associated with polyneuropathy in healthy controls, and the values associated with the most pronounced decline in nerve function in patients with diabetes. METHODS: We used data from a cross-sectional cohort study of healthy controls and type 2 diabetes patients assessed between November 2010 and May 2013. Healthy controls and patients with diabetes were compared at different HbA1c ranges: <5.5%, 5.5-5.9%, and 6-6.4% for controls, and 6.5-7.4% and >7.5% for patients with diabetes. RESULTS: The total cohort included 53 controls and 164 patients with diabetes. Subclinical small nerve fiber impairments were observed in controls at HbA1c levels of 5.5-6%, compared with HbA1c <5.5%, for example: lower Laser Doppler flare imaging area of 2.8 +/- 1.4 versus 3.9 +/- 2 mm2. The most prominent decline in both small and large nerve fiber function was seen with less impaired glycemic control and shorter duration of diabetes, i.e. at HbA1c levels of 6.5-7.4%, compared with >7.5%. CONCLUSIONS: These findings underscore the importance of early treatment at the prediabetes and early diabetes stages to prevent nerve fiber decline that is likely irreversible. PMID- 29422234 TI - An overview of type 2 diabetes and importance of vitamin D3-vitamin D receptor interaction in pancreatic beta-cells. AB - One significant health issue that plagues contemporary society is that of Type 2 diabetes (T2D). This disease is characterised by higher-than-average blood glucose levels as a result of a combination of insulin resistance and insufficient insulin secretions from the beta-cells of pancreatic islets of Langerhans. Previous developmental research into the pancreas has identified how early precursor genes of pancreatic beta-cells, such as Cpal, Ngn3, NeuroD, Ptf1a, and cMyc, play an essential role in the differentiation of these cells. Furthermore, beta-cell molecular characterization has also revealed the specific role of beta-cell-markers, such as Glut2, MafA, Ins1, Ins2, and Pdx1 in insulin expression. The expression of these genes appears to be suppressed in the T2D beta-cells, along with the reappearance of the early endocrine marker genes. Glucose transporters transport glucose into beta-cells, thereby controlling insulin release during hyperglycaemia. This stimulates glycolysis through rises in intracellular calcium (a process enhanced by vitamin D) (Norman et al., 1980), activating 2 of 4 proteinases. The rise in calcium activates half of pancreatic beta-cell proinsulinases, thus releasing free insulin from granules. The synthesis of ATP from glucose by glycolysis, Krebs cycle and oxidative phosphorylation plays a role in insulin release. Some studies have found that the beta-cells contain high levels of the vitamin D receptor; however, the role that this plays in maintaining the maturity of the beta-cells remains unknown. Further research is required to develop a more in-depth understanding of the role VDR plays in beta-cell function and the processes by which the beta cell function is preserved. PMID- 29422235 TI - Oesophageal Dieulafoy's lesion: An unusual cause of upper gastrointestinal bleeding. PMID- 29422236 TI - The psychosocial impact of inflammatory bowel disease and its management. From the patients' perspective. PMID- 29422237 TI - New coeliac disease treatments and their complications. AB - The only accepted treatment for coeliac disease is strict adherence to a gluten free diet. This type of diet may give rise to reduced patient quality of life with economic and social repercussions. For this reason, dietary transgressions are common and may elicit intestinal damage. Several treatments aimed at different pathogenic targets of coeliac disease have been developed in recent years: modification of gluten to produce non-immunogenic gluten, endoluminal therapies to degrade gluten in the intestinal lumen, increased gluten tolerance, modulation of intestinal permeability and regulation of the adaptive immune response. This review evaluates these coeliac disease treatment lines that are being researched and the treatments that aim to control disease complications like refractory coeliac disease. PMID- 29422238 TI - Eosinophilic oesophagitis: Current evidence-based diagnosis and treatment. AB - Eosinophilic oesophagitis (EoE) is a disease caused by an immune response to food antigens in contact with the oesophageal mucosa. Its diagnosis is defined by the combination of oesophageal dysfunction symptoms and inflammation of the oesophageal mucosa predominantly by eosinophils. Its chronic course and frequent progression to subepithelial fibrosis and oesophageal strictures indicate the need for treatment. The information provided by recent clinical trials and systematic reviews has led to the development of new clinical guidelines, endorsed by several European scientific societies. This review includes the most relevant aspects of the new guidelines, updates the EoE concept and reports its epidemiology and risk factors, associated conditions and its natural history in children and adults. Diagnostic criteria are provided, and tests for EoE diagnosis and monitoring and therapeutic options are analysed based on the best scientific evidence and consensus opinion of experts. PMID- 29422239 TI - Disorders of puberty. AB - Over the past 20 years, a clear secular trend toward the earlier onset of puberty has been described. A better knowledge should help clinicians attempting to define both precocious and delayed puberty (PP and DP, respectively). The definition of PP for girls is the appearance of secondary sex characteristics development before the age of 8 years, while DP is based on the absence of thelarche at the age of 13 years. Regarding PP, one should clinically distinguish between true precocious puberty, i.e., complete or central PP, and incomplete PP, which refers to premature thelarche, premature pubarche, and isolated menarche. Evaluation of girls of PP requires careful examination of the clinical expression, a GnRH test, and imaging of the central neurosystem. GnRH analog is considered the gold standard treatment of central precocious puberty. Peripheral PP should be managed according to the underlying causes. DP is suspected in girls with no breast development by the age of 13 years, or absence of menarche at 15 years with secondary sex characteristics. The clinical examination along with endocrine, radiological, and genetic investigation should be able to identify girls with permanent hypogonadism as opposed to those with transitory hypogonadism, who undergo spontaneous but DP. Estrogen therapy should be discussed according to the causes of DP. In all cases, emotional and psychosocial disorders should be considered for these girls with disorders of puberty. PMID- 29422240 TI - Screen-detected gallstone disease and autoimmune diseases - A cohort study. AB - BACKGROUND: Gallstone disease is highly prevalent and is associated with systemic inflammation. AIMS: To determine whether screen-detected gallstones or cholecystectomy are associated with the occurrence of autoimmune and autoinflammatory diseases and the most common subgroups thereof. METHODS: A cohort study of three randomly selected general population samples from Copenhagen was performed. Participants (n = 5928) were examined in the period 1982-1992, underwent abdominal ultrasound examination to detect gallstone disease, and followed through national registers until December 2014 (median 24.7 years) for occurrence of immunological diseases. Multivariable Cox regression analyses were performed. RESULTS: Gallstone disease was identified in 10% (591/5928) of participants, of whom 6.8% had gallstones and 3.2% had cholecystectomy at baseline. Gallstone disease was associated with incidence of autoimmune diseases (12.9% versus 7.92%; hazard ratio 1.46; 95% confidence interval [CI], [1.11;1.91]), diabetes mellitus type 1 (5.95% versus 3.67%; 1.53; [1.02;2.30]), and autoimmune thyroid disease (3.70% versus 1.59%; 2.06; [1.26;3.38]). Rheumatoid arthritis, autoinflammatory diseases, or any subgroups thereof were not associated. CONCLUSIONS: In a large general population sample, screen-detected gallstone disease was associated with the development of autoimmune diseases during long-term follow-up. Future research efforts are needed to further explore common disease mechanisms. PMID- 29422241 TI - From a fatty liver to a sugary blood. PMID- 29422242 TI - Transjugular intrahepatic portosystemic shunt for hepatorenal syndrome: A systematic review and meta-analysis. AB - BACKGROUND: Hepatorenal syndrome is a severe complication of advanced liver diseases with a dismal prognosis. AIMS: This systematic review and meta-analysis aims to explore the efficacy and safety of transjugular intrahepatic portosystemic shunt for the treatment of hepatorenal syndrome. METHOD: Publications were searched via PubMed and EMBASE databases. The pooled proportion and mean difference were calculated by using a random-effect model. RESULTS: Nine publications were included, in which 128 patients with hepatorenal syndrome were treated with transjugular intrahepatic portosystemic shunt. The pooled short-term and 1-year survival rates were 72% and 47% in type 1 hepatorenal syndrome and 86% and 64% in type 2 hepatorenal syndrome. No lethal procedure-related complications were observed. The pooled rate of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt was 49%. The pooled rate of renal function improvement after transjugular intrahepatic portosystemic shunt was 93% in type 1 hepatorenal syndrome and 83% in any type of hepatorenal syndrome. After transjugular intrahepatic portosystemic shunt, serum creatinine, blood urea nitrogen, serum sodium, sodium excretion, and urine volume were significantly improved; by comparison, serum bilirubin slightly increased, but the difference was not statistically significant. CONCLUSION: Limited evidence suggested a potential survival benefit of transjugular intrahepatic portosystemic shunt in patients with hepatorenal syndrome but with a high incidence of hepatic encephalopathy. PMID- 29422243 TI - Natural orifice endoscopic biopsy access - A tunnel of opportunity to gastrointestinal stromal tumors. PMID- 29422244 TI - Silymarin prevents diabetes-induced hyperpermeability in human retinal endothelial cells. AB - INTRODUCTION: Vascular endothelial growth factor (VEGF) plays an essential role in development of diabetic macular edema (DME). While there is evidence suggesting that silymarin, a flavonoid extracted from Silybum marianum, could be useful for prevention and treatment of diabetic nephropathy, no studies have been conducted in diabetic retinopathy (DR). The aim of this study was to assess the effect of silymarin on disruption of inner blood retinal barrier (BRB), the primary cause of DME. MATERIALS AND METHODS: Human retinal endothelial cells (HRECs) were cultured under standard (5.5mM D-glucose) and diabetogenic conditions (25mM D-glucose and 25mM D-glucose + recombinant vascular endothelial growth factor [rVEGF, 25mg/mL]). To assess cell viability, three concentrations of silymarin were tested (2, 4 and 10MUg/mL). The effect of silymarin on HREC disruption was determined using a dextran (70kD) permeability asssay. RESULTS: No differences were found in the viability of HRECs treated with 2 or 4MUg/mL of silymarin as compared to untreated cells, but viability significantly decreased after using 10MUg/mL. The concentration of 4 MUg/mL was therefore selected. Silymarin (4MUg/mL) caused a significant decrease in VEGF-induced permeability in both media with 5.5nM (422+/-58 vs. 600+/-72 ng/mL/cm2; p<0.03) and 25nM of D glucose (354 +/- 28 vs. 567 +/- 102 ng/mL/cm2; p<0.04). DISCUSSION: Our results show that silymarin is effective for preventing hyperpermeability induced by diabetic conditions in HRECs. Further studies are needed to assess whether silymarin could be useful to treat DME. PMID- 29422245 TI - EDDS enhanced Shewanella putrefaciens CN32 and alpha-FeOOH reductive dechlorination of carbon tetrachloride. AB - S,S-ethylenediamine-N,N-disuccinic acid (EDDS) enhanced reductive dissolution of alpha-FeOOH by Shewanella putrefaciens CN32 (CN32), resulting in formation of surface-bound Fe(II) species (FeIIEDDS) to improve reductive dechlorination of carbon tetrachloride (CT). The pseudo-first-order rate constants for bio reduction extents of alpha-FeOOH by CN32 in the presence of 1.36 mM EDDS was 0.023 +/- 0.0003 d-1 which was higher than without EDDS. The enhancement mechanism of bio-reduction was attributed to the strong complexation ability of EDDS to formed FeIIIEDDS, which could be better utilized by CN32. The dechlorination kinetic of CT by FeIIEDDS (2.016 h-1) in the presence of 1.36 mM EDDS was 24 times faster than without EDDS. Chloroform were detected as main products for the degradation of CT. The chemical analyses and morphological observation showed that combination between EDDS and Fe2+ produced FeIIEDDS complex, which had a reductive potential of -0.375 V and significantly enhanced CT dechlorination. The results showed that EDDS played an important role in enhancing the bio-reduction of alpha-FeOOH to accelerate reductive dechlorination of CT. PMID- 29422246 TI - Effectiveness of the IMFeD tool for the Identification and Management of Feeding Difficulties in Taiwanese children. AB - BACKGROUND: The Identification and Management of Feeding Difficulties (IMFeDTM) tool was introduced in 2011 for management of children with feeding difficulties and has been used in various countries around the world. This study aimed to assess its acceptance and effectiveness in clinical practice in Taiwan. METHODS: This was a prospective, observational, multicenter study where subjects were followed over 3 months. Outpatients identified as picky eaters, having poor appetite, poor weight gain, or weight loss were enrolled. The acceptance and effectiveness of IMFeD tool were evaluated by caregivers and pediatricians. RESULTS: Among 423 children who completed the study (235 boys, 188 girls; 78.8% aged <5 years, 21.3% aged 6-10 years), the most common feeding difficulties were poor appetite in a fundamentally vigorous child (85.3%) and highly selective intake (70.2%). Mean percentiles for height and weight were 34.6 +/- 25.3 and 20.3 +/- 21.3 at enrolment, and increased by 5.4 and 5.9 (p < 0.0001) at the last visit, respectively. Most caregivers (86.5%) thought that the IMFeD tool helped them to understand and better identify picky eating behaviors. Pediatricians reported that the IMFeD tool was effective in 99.3% of patients for managing picky eaters in clinical practice. CONCLUSIONS: The IMFeD tool was effective in addressing differences in needs according to type of feeding difficulty by providing a systematic approach to manage feeding difficulty in Taiwanese children. It is applicable to the clinical practice and well-accepted by pediatricians and caregivers. PMID- 29422247 TI - [The place of cancer's cure in the personalized medicine and immunotherapy]. PMID- 29422248 TI - [Why proton therapy? And how?] AB - Proton therapy is a radiotherapy, based on the use of protons, charged subatomic particles that stop at a given depth depending on their initial energy (pristine Bragg peak), avoiding any output beam, unlike the photons used in most of the other modalities of radiotherapy. Proton therapy has been used for 60 years, but has only become ubiquitous in the last decade because of recent major advances in particle accelerator technology. This article reviews the history of clinical implementation of protons, the nature of the technological advances that now allows its expansion at a lower cost. It also addresses the technical and physical specificities of proton therapy and the clinical situations for which proton therapy may be relevant but requires evidence. Different proton therapy techniques are possible. These are explained in terms of their clinical potential by explaining the current terminology (such as cyclotrons, synchrotrons or synchrocyclotrons, using superconducting magnets, fixed line or arm rotary with passive diffusion delivery or active by scanning) in basic words. The requirements associated with proton therapy are increased due to the precision of the depth dose deposit. The learning curve of proton therapy requires that clinical indications be prioritized according to their associated uncertainties (such as range uncertainties and movement in lung tumors). Many clinical indications potentially fall under proton therapy ultimately. Clinical strategies are explained in a paralleled manuscript. PMID- 29422250 TI - High expression of MMP-9 is associated with better prognosis in extrahepatic bile duct cancer patients. AB - PURPOSE: To evaluate the prognostic value of matrix metalloproteinase-9 (MMP-9) in patients with extrahepatic bile duct (EHBD) cancer undergoing surgical resection and adjuvant radiotherapy. METHODS: Between January 2000 and August 2006, patients who underwent complete resection followed by adjuvant radiotherapy for EHBD cancer were enrolled in this study. The expression of MMP-9 was assessed with immunohistochemical staining. The prognostic values of the MMP-9 expression and other clinicopathologic factors were evaluated in univariate and multivariate analyses. RESULTS: Sixty-six patients were included in this study. All received radiotherapy with a median dose of 40 Gy (range, 40-56), and 61 patients received concomitant fluoropyrimidine chemotherapy. MMP-9 was highly expressed in 33 patients (50.0%). MMP-9 expression was significantly associated with locoregional recurrence-free survival (LRRFS) and overall survival (OS) but not with distant metastasis-free survival (DMFS). The 5-year LRRFS and OS rates were 50.8% versus 86.5% (p = .0281), and 23.3% versus 68.1% (p = .0087) in patients with low and high expression of MMP-9, respectively. Among the clinicopathologic factors, tumor location was associated with DMFS and OS (p = .0292 and .0003, respectively). Nodal stage and histologic differentiation showed significant association with DMFS (p = .0277 and .0060, respectively). Based on multivariate analysis for OS, tumor location was the only significant prognostic factor (p = .0021), while MMP-9 expression showed marginal significance (p = .0633). CONCLUSION: MMP-9 expression is a useful prognostic factor for predicting LRRFS and OS in patients with EHBD cancer after surgical resection and adjuvant radiotherapy. PMID- 29422249 TI - Validation of an assessment tool: Estimation of Postoperative Overall Survival for Gastric Cancer. AB - BACKGROUND: Benchmarking of long-term surgical outcomes has rarely been attempted. We previously devised a prediction model for assessing the outcome of late survival after surgery, termed the Estimation of Postoperative Overall Survival for Gastric Cancer (EPOS-GC). This study was undertaken to validate EPOS GC in an external data set. METHODS: A retrospective cohort study was conducted in 11 cancer care hospitals in Japan, analyzing a consecutive series of patients who underwent elective gastric cancer resection between April 2007 and March 2009. EPOS-GC consists of three tumor-related variables and three physiological variables. The primary endpoint was postoperative overall survival. The observed to-expected (O/E) ratio of 5-year survival rates was defined as a metric of quality of care. The sample size for O/E was determined as 42. RESULTS: We included 2045 patients for analysis. The median (95% confidence interval) follow up time was 5.1 (1.2-6.8) years for censored patients. Although EPOS-GC demonstrated a good discriminative power (Harrell's C-index, 95% confidence interval: 0.80, 0.79-0.83), the calibration plot revealed that EPOS-GC underestimated 5-year survival rates in the high-risk group. Therefore, we recalibrated the model with Cox's regression analysis. The recalibrated EPOS-GC showed a good calibration, preserving the high discriminative power (C-index, 95% confidence interval: 0.80, 0.78-0.82). The O/E among hospitals according to the recalibrated EPOS-GC ranged between 0.87 and 1.27. The O/E correlated with hospital volumes (Spearman's correlation = 0.76, n = 11, p = .006). CONCLUSION: EPOS-GC with recalibration can convey risk-adjusted quality assurance regarding late survival following gastric cancer resection. PMID- 29422251 TI - Systematic review of current prognostication systems for primary gastrointestinal stromal tumors. AB - BACKGROUND: The advent of tyrosine kinase inhibitors as adjuvant therapy has revolutionized the management of GIST and emphasized the need for accurate prognostication systems. Numerous prognostication systems have been proposed for GIST but at present it remains unknown which system is superior. The present systematic review aims to summarize current prognostication systems for primary treatment-naive GIST. METHODS: A literature review of the Pubmed and Embase databases was performed to identify all published articles in English, from the 1st January 2002 to 28th Feb 2017, reporting on clinical prognostication systems of GIST. RESULTS: Twenty-three articles on GIST prognostication systems were included. These systems were classified as categorical systems, which stratify patients into risk groups, or continuous systems, which provide an individualized form of risk assessment. There were 16 categorical systems in total. There were 4 modifications of the National Institute of Health (NIH) system, 2 modifications of Armed Forces Institute of Pathology (AFIP) criteria and 3 modifications of Joensuu (modified NIH) criteria. Of the 7 continuous systems, there were 3 prognostic nomograms, 3 mathematical models and 1 prognostic heat/contour maps. Tumor size, location and mitotic count remain the main variables used in these systems. CONCLUSION: Numerous prognostication systems have been proposed for the risk stratification of GISTs. The most widely used systems today are the NIH, Joensuu modified NIH, AFIP and the Memorial Sloan Kettering Cancer Center nomogram. More validation and comparison studies are required to determine the optimal prognostication system for GIST. PMID- 29422252 TI - Achieving high quality standards in laparoscopic colon resection for cancer: A Delphi consensus-based position paper. AB - AIM: To investigate the rate of laparoscopic colectomies for colon cancer using registries and population-based studies. To provide a position paper on mini invasive (MIS) colon cancer surgery based on the opinion of experts leader in this field. METHODS: A systematic review of the literature was conducted using PRISMA guidelines for the rate of laparoscopy in colon cancer. Moreover, Delphi methodology was used to reach consensus among 35 international experts in four study rounds. Consensus was defined as an agreement >=75.0%. Domains of interest included nosology, essential technical/oncological requirements, outcomes and MIS training. RESULTS: Forty-four studies from 42 articles were reviewed. Although it is still sub-optimal, the rate of MIS for colon cancer increased over the years and it is currently >50% in Korea, Netherlands, UK and Australia. The remaining European countries are un-investigated and presented lower rates with highest variations, ranging 7-35%. Using Delphi methodology, a laparoscopic colectomy was defined as a "colon resection performed using key-hole surgery independently from the type of anastomosis". The panel defined also the oncological requirements recognized essential for the procedure and agreed that when performed by experienced surgeons, it should be marked as best practice in guidelines, given the principles of oncologic surgery be respected (R0 procedure, vessel ligation and mesocolon integrity). CONCLUSION: The rate of MIS colectomies for cancer in Europe should be further investigated. A panel of leaders in this field defined laparoscopic colectomy as a best practice procedure when performed by an experienced surgeon respecting the standards of surgical oncology. PMID- 29422253 TI - Robotic versus laparoscopic radical hysterectomy in early cervical cancer: A case matched control study. AB - BACKGROUND: This study aims at evaluating the feasibility, surgical outcome and oncological results observed after robotic radical hysterectomy (RH) compared to laparoscopy for patients with early stage cervical cancer (ECC) patients. METHODS: Between January 2010 and October 2016, 210 patients underwent RH for treatment of ECC: 70 underwent robotic approach (Cases), and 140 underwent laparoscopic approach (Controls). RESULTS: There was no statistically significant difference between the two approaches with regard to clinical patient characteristics and in terms of extent of RH and rate of pelvic and aortic lymphadenectomy. Operative time was significantly longer in the robotic versus laparoscopic group (median = 243 min, range 90-612 versus median = 210 min, range 80-660; p value = 0.008). Conversion to laparotomy was necessary in 4 patients (1.9%) in the whole series. No difference was found in terms of intraoperative and postoperative complications between the two groups. Overall, during the observation period, 34 (16.2%) patients experienced any grade postoperative complications, and 21 (10.0%) had >G2 complications. The 3-yr DFS was 88.0% versus 84.0% in robotic and laparoscopic group, respectively (p value = 0.866). Central and/or lateral pelvic disease represented the most common site of relapse. The 3-yr OS was 90.8% in patients underwent robotic RH versus 94.0% in patients underwent laparoscopic RH (p value = 0.924). CONCLUSIONS: The present study shows the equivalence of robotic and laparoscopic approaches to radical surgery of ECC patients, in terms of perioperative and postoperative outcomes with equivalent survival figures, and thus the choice of approach can be tailored to the choice of patient and surgeon. PMID- 29422254 TI - The Assisi Think Tank Meeting and Survey of post MAstectomy Radiation Therapy after breast reconstruction: The ATTM-SMART report. AB - PURPOSE: To describe the current European practise on post-mastectomy radiation therapy (PMRT) in relation to breast reconstruction. METHODS: A 21-item questionnaire was distributed online via Survey Monkey. Items referred to 1. general topics (country, centre, years of experience in breast cancer); 2. clinical decision making; 3. RT techniques and dosimetry; 4. dose fractionation. RESULTS: 283 responses were received from 19 countries. Most responders worked in public health services and in academic institutions and had 5-20 years experience. Although many indicated they were consulted about the timing and type of breast reconstructive surgery, final decisions were most often made by surgeons. Immediate reconstruction with expander followed by RT and subsequently permanent reconstruction with prosthesis was recommended by 61.6% of responders. Most (48.4%) adviced a boost only when margins were close or involved with an another 17.7% recommending it in the presence of high-risk features (T3-T4, lympho-vascular involvement). Intensity modulated RT was rarely used by about two thirds of responders, except when with 3D technique the dose constraints were not achieved or when regional lymph nodes were included. Almost 60% of responders did not use bolus/tissue equivalent material (TEM). The main indication for bolus/TEM use was skin involvement. The majority of responders used 1.8-2 Gy per fraction. CONCLUSIONS: The present survey highlighted controversial areas in clinical practise, confirming the uncertainties about the scheduling of PMRT and breast reconstruction. PMID- 29422255 TI - Prevention of spontaneous preterm birth: universal cervical length assessment and vaginal progesterone in women with a short cervix: time for action! PMID- 29422256 TI - Professional responsibility of transparency of obstetricians practicing in religious hospitals. PMID- 29422257 TI - Giants in Obstetrics and Gynecology Series: A profile of John C. Hobbins, MD. PMID- 29422258 TI - Expression Analysis of miR-29b in Malignant and Benign Breast Tumors: A Promising Prognostic Biomarker for Invasive Ductal Carcinoma With a Possible Histotype Related Expression Status. AB - BACKGROUND: Aberrations in microRNA levels seem to provide valuable information regarding breast cancer prognosis and therapy. In this study, we sought to analyze miR-29b expression in breast tumors and thus explore its clinical value. MATERIALS AND METHODS: One hundred twenty-one malignant and 56 benign breast tissue specimens were collected and subjected to extraction of total RNA, which was polyadenylated and reverse transcribed to cDNA. Subsequently, a highly sensitive quantitative real-time polymerase chain reaction protocol was developed and miR-29b levels, estimated via the comparative CT method, were finally subjected to comprehensive statistical analysis. RESULTS: MiR-29b levels did not differ between the analyzed benign and malignant breast tissue specimens, but were found to be significantly (P = .010) decreased in invasive ductal adenocarcinomas compared with their lobular counterparts, albeit receiver operating characteristics curve analysis did not verify the latter correlation. Additionally, miR-29b expression was elevated in samples with positive estrogen receptor status (P = .021) in the overall population, whereas it was negatively correlated (P = .035) with primary tumor staging in the ductal subset and increased in poorly-differentiated tumors of lobular origin (P = .041). Furthermore, Kaplan-Meier and Cox regression analyses showed that patients with ductal carcinoma and elevated miR-29b levels had a significantly longer disease free survival (P = .010) and a lower risk to relapse (hazard ratio = 0.35, 95% confidence interval, 0.15-0.81; P = .014). CONCLUSION: Our results provide evidence that miR-29b levels constitute a promising biomarker of favorable prognosis for patients with invasive ductal breast carcinoma and imply that its expression status might be affected by the histological origin of breast malignancy. PMID- 29422259 TI - Initiation of Adjuvant Endocrine Therapy in Black and White Women With Breast Cancer. AB - BACKGROUND: Adjuvant endocrine therapy reduces risk of recurrence and mortality in women with hormone receptor-positive breast cancer, yet many women never initiate it. We examined the influence of race, sociocultural factors, and process-of-care factors on initiation of adjuvant endocrine therapy in a racially diverse sample. PATIENTS AND METHODS: Eligible women were originally recruited for the Narrowing the Gaps in Adjuvant Therapy Study (2006-2011). Sociocultural and process-of-care factors were collected via telephone surveys before adjuvant therapy. Clinical factors were abstracted from charts. Penalized LASSO (least absolute shrinkage and selection operator) logistic regression model was used to identify variables associated with initiation. RESULTS: Of the 270 women, 55.6% were black and the rest were white. Most women (74.8%) initiated therapy. A significant interaction (P = .008) was found between race and age. Black women aged <= 50 years had the lowest initiation (59.7%) compared to black women > 50 years (87.1%), white women <= 50 years (73.7%), or white women > 50 years (72.0%). Multivariate analysis found that younger black women exhibited a marginally higher risk of noninitiation compared to older black women. Additionally, ratings of financial access, presence of comorbidities, and levels of communication were all associated with endocrine therapy initiation. CONCLUSION: Black women <= 50 years of age and women with financial constraints may be important subgroups for interventions. Patient-provider communication appears to be an important leverage point to foster therapy uptake. PMID- 29422260 TI - Palliative care for drug-resistant tuberculosis: when new drugs are not enough. PMID- 29422261 TI - Risk of colorectal adenomas in patients with celiac disease: a systematic review and meta-analysis. AB - INTRODUCTION AND AIMS: Whether celiac disease increases the risk of presenting with colorectal adenoma or not, has not been extensively evaluated. This question becomes relevant when considering early screening methods in patients with the disease. The aim of our article was to determine the risk of colorectal adenomas in celiac disease patients. MATERIALS AND METHODS: A computer-assisted search of the MEDLINE-Pubmed, EMBASE, LILACS, Cochrane Library, and Google Scholar databases was carried out, encompassing the time frame of 1966 to December 2016. The search strategy consisted of the following MESH terms: 'celiac disease' OR 'celiac sprue' AND 'colorectal' OR 'colorectal neoplasia' OR 'colorectal adenoma'. A fixed-effect model was used for the analyses. The first analysis dealt with the prevalence of all presentations of colorectal adenoma in patients with celiac disease and the second was on the prevalence of advanced adenomas. The outcomes were described as odds ratios (OR) with their 95% confidence intervals. RESULTS: The search identified 480 bibliographic citations, 17 of which were chosen for evaluation. Fourteen of those studies were rejected, leaving a final total of three for the analysis. Those studies included 367 cases of celiac disease and 682 controls. No significant heterogeneity was observed (I2=26%). There was no increased prevalence of colorectal adenomas in the celiac disease patients, when compared with the controls (OR: 0.94 [0.65-1.38]), and no significant difference was observed when assessing the prevalence of advanced adenomas (OR: 0.97 [0.48-1.97]). CONCLUSION: Celiac disease was not associated with an increased risk of colorectal adenomas. However, due to the limited evidence available, more studies are necessary to determine whether there is an actual association. PMID- 29422262 TI - AMPK Wars: the VMH Strikes Back, Return of the PVH. AB - Hypothalamic AMP-activated protein kinase (AMPK) is an important modulator of whole-body energy homeostasis, particularly within the ventromedial nucleus, where it regulates energy expenditure, glucose, and lipid metabolism. A recent paper in Cell Reports has demonstrated that AMPK in the paraventricular nucleus of the hypothalamus modulates dietary preference for carbohydrate over fat. PMID- 29422263 TI - Aldehyde-Induced DNA and Protein Adducts as Biomarker Tools for Alcohol Use Disorder. AB - Alcohol use disorder (AUD) screening frequently involves questionnaires complemented by laboratory work to monitor alcohol use and/or evaluate AUD associated complications. Here we suggest that measuring aldehyde-induced DNA and protein adducts produced during alcohol metabolism may lead to earlier detection of AUD and AUD-associated complications compared with existing biomarkers. Use of aldehyde-induced adducts to monitor AUD may also be important when considering that approximately 540 million people bear a genetic variant of aldehyde dehydrogenase 2 (ALDH2) predisposing this population to aldehyde-induced toxicity with alcohol use. We posit that measuring aldehyde-induced adducts may provide a means to improve precision medicine approaches, taking into account lifestyle choices and genetics to evaluate AUD and AUD-associated complications. PMID- 29422264 TI - Perilipin 2 levels are increased in patients with in-stent neoatherosclerosis: A clue to mechanisms of accelerated plaque formation after drug-eluting stent implantation. AB - BACKGROUND: Perilipin 2 (PLIN2) is a protein that potentially facilitates atherogenesis in native coronary arteries or arteries with an implanted drug eluting stent (DES). The aim of the study was to determine PLIN2 protein levels in peripheral monocytes of enrolled subjects and compare them between patients with native coronary artery disease (CAD) and those with an in-stent restenosis (ISR) due to neoatherosclerosis occurring >1 year after DES implantation. METHODS: Forty-two patients were prospectively enrolled in the study in 3:1 fashion and underwent coronary catheterization. Both groups were angiographically matched for CAD burden with respect to the number of diseased vessels. Neoatherosclerosis was determined by intracoronary optical coherence tomography (OCT) among patients with ISR. RESULTS: Patients with ISR due to neoatherosclerosis had significantly higher PLIN2 protein levels in peripheral blood monocytes compared to patients with native CAD (342.47 +/- 75.63[SE] versus 119.51 +/- 20.95, p < 0.001). PLIN2 protein levels did not significantly differ between unstable and stable disease phenotype (125.59 +/- 131.02 vs. 146.14 +/- 111.87, p = 0.109). CONCLUSIONS: In this explorative study, PLIN2 protein levels are significantly increased in patients with neoatherosclerosis, irrespective of clinical presentation, implicating that it might play a pathogenetic role in accelerated atherosclerosis after DES implantation. Further larger clinical studies are warranted to confirm these initial findings. PMID- 29422265 TI - Quality of life after percutaneous closure of patent foramen ovale in patients after cryptogenic stroke compared to a normative sample. AB - AIMS: Despite the widespread use of percutaneous closure of patent foramen ovale (PFO) in patients after a cryptogenic stroke, little is known about its impact on health-related quality of life (HRQoL). The aim of this study was to assess HRQoL in these patients compared to PFO patients not considered candidates for percutaneous closure, and to a normal population. METHODS AND RESULTS: A total of 402 patients with cryptogenic stroke or transient ischaemic attack (TIA) who had been referred to our center for PFO closure were invited to a long-term clinical follow-up (mean follow-up 5.5 years; range 3-13 years). HRQoL was assessed using the SF-36 Health Survey and data were compared with an age- and gender-matched reference group from the Swedish SF-36 normative database. Fifteen patients had died and 43 did not answer the SF-36. Of the remaining 344 patients, 208 had undergone PFO closure, and 136 had not. The closure group and reference group reported similar HRQoL levels. However, the non-closure group showed significantly lower HRQoL in role limitation - physical, vitality, general health, mental health (p < 0.05) and social functioning (p = 0.05) than the reference group and also had significantly lower scores than the closure group, correcting for age differences, on physical functioning, role limitation - physical, vitality and general health (p < 0.05). CONCLUSIONS: Non-closure patients had lower HRQoL than their counterparts in the normal population and the closure group. Percutaneous PFO closure is associated with a favorable quality of life. PMID- 29422266 TI - Right ventricular systolic function in patients undergoing transcatheter aortic valve implantation: A systematic review and meta-analysis. AB - BACKGROUND: Right ventricular (RV) systolic dysfunction is associated with worse survival in patients undergoing surgical aortic valve replacement (SAVR), yet it is not included in traditional risk scores of transcatheter aortic valve implantation (TAVI) candidates. We aimed to evaluate the prognostic value of RV systolic function on clinical outcomes in patients undergoing TAVI at one year follow-up; and, echocardiographic changes of RV systolic function up to 12 months after TAVI and compared with SAVR when possible. METHODS AND RESULTS: This systematic review and meta-analysis is registered in PROSPERO (CRD42017065761). Studies investigating RV systolic function with echocardiography in TAVI cohorts were identified from Medline, Embase and Cochrane databases. We used random effects models to assess differences in primary outcomes. Twenty-one studies were identified, where RV systolic function and clinical outcomes were assessed in eight (4016 patients) and RV systolic function changes were evaluated in 14 (1709 patients). For the primary outcome of all-cause death at one year, RV systolic dysfunction was associated with a significant 78% relative risk increase (risk ratio[95% confidence interval (CI)]) = 1.78[1.37, 2.31], P < 0.01), albeit significant heterogeneity (I2 = 64%, P < 0.01). RV systolic function was unchanged after TAVI throughout follow-up as shown with tricuspid annular plane systolic excursion (TAPSE)(mean difference[95% CI]pre-discharge = 0.03 [ 0.92,0.99]mm,1-3 months = -0.09[-0.89,0.71]mm,6-12 months = 0.52 [-0.29,1.32] mm, all P = NS), while TAPSE was significantly reduced after SAVR (pre-discharge = 10.17[-13.11,-7.24]mm, P < 0.01;1-3 months = -7.3[-8.17,-6.44]mm, P < 0.01;6-12 months = -5.99[-7.95,-4.03]mm, P < 0.01). CONCLUSIONS: RV systolic dysfunction was associated with a significant increase in all-cause mortality at one year after TAVI. RV systolic function was unchanged after TAVI up to 12 months, whereas deteriorated significantly after SAVR. PMID- 29422267 TI - Impact of a negative D-dimer result on the initial assessment of acute aortic dissection. AB - BACKGROUND: D-dimer shows high sensitivity but low specificity for the diagnosis of acute aortic dissection (AAD). Previous reports indicated that negative D dimer patients have shorter dissection length. However, whether patients with negative D-dimer results have a good prognosis is unknown. This study aimed to elucidate the clinical characteristics and implications of a negative D-dimer result on AAD diagnosis. METHODS: The study group comprised 126 patients (71 males, 55 females; mean age, 69 +/- 11 years) with AAD admitted to our hospital between April 2009 and March 2015. Blood samples on presentation were used for D dimer measurement. Clinical characteristics and outcomes were assessed. RESULTS: Nine (7.1%) and 117 (92.9%) exhibited negative and positive D-dimer results, respectively. The negative group showed a significantly lower extension score and a higher platelet count than the positive group. Multivariate analysis demonstrated that platelet count (odds ratio, 1.31 (1.09-1.58), p = 0.003) and extension score (odds ratio, 0.56 (0.33-0.96), p = 0.03) were significantly related to a negative result. Notably, 44% of patients in the negative group had type A dissection and 33% underwent an emergency operation due to cardiac tamponade. CONCLUSION: We found that high platelet count and low extension score were independent factors related to a negative D-dimer result. Even if the length of the dissection is short, an emergency operation is necessary in some patients with a negative D-dimer result. Physicians should recognize that a negative D dimer result alone cannot exclude patients with fatal AAD conditions. PMID- 29422269 TI - Selection of the Best of 2017 in Catheter Ablation. PMID- 29422268 TI - Selection of the Best of 2017 on the Usefulness of Cardiac Stimulation in the Treatment of Vasovagal Syncope. PMID- 29422270 TI - Tissue macrophages as mediators of a healthy relationship with gut commensal microbiota. AB - Mammals and microorganisms have evolved a complex and tightly controlled mutual relationship. This interaction grants protection and energy source for the microorganisms, and on the other hand, provides several immunologic, metabolic and physiological advantages for the host. The gastrointestinal tract (GI) harbors the largest bacteria diversity within the body and complex mechanisms control microbiota community under homeostasis. However, once disrupted, microbiota imbalance can lead to overt growth of resident and invasive populations, with potential risk for lethal diseases. In these cases, bacteria might also escape from the intestines and reach different organs through the blood and lymphatic circulation. To control these unwanted conditions, all body tissues are populated with resident macrophages that have the ability to capture and eliminate pathogens, avoiding their dissemination. Here we discuss the different routes for bacterial translocation from the intestinal tract, and how macrophages act in the removal of these microorganisms to prevent systemic infections and restore the homeostasis. PMID- 29422271 TI - Bladder resident macrophages: Mucosal sentinels. AB - Macrophages are instrumental in the response to infectious and noninfectious diseases, however, their role in the bladder is poorly understood. Indeed, the bladder is a mucosal tissue frequently overlooked in research, despite the prevalence of illnesses such as urinary tract infection and bladder cancer. Notably, bladder tissue macrophages are among the most populous resident immune cells in this organ and recent studies support that resident macrophages and infiltrating monocytes play nonredundant roles in response to infection, immunotherapy, and inflammation. Advancing our understanding of macrophage behavior in the bladder is complicated by the difficulty in obtaining tissue resident cells. Surmounting this challenge, however, for a greater understanding of macrophage ontology, impact on innate and adaptive immunity, and regulation of homeostasis, will ultimately contribute to better therapies for common afflictions of the bladder. PMID- 29422272 TI - Comparative evaluation of different gradient diffusion tests for detection of azole resistance in Aspergillus fumigatus. AB - Gradient diffusion assays Etest and MIC Test Strip for itraconazole, posaconazole and voriconazole as well as isavuconazole (MIC Test Strip) were evaluated for Aspergillus fumigatus against EUCAST broth microdilution. Both assays demonstrated generally good performance; however, posaconazole MIC Test Strip showed low agreement with broth microdilution due to MIC overestimation. PMID- 29422273 TI - Automated broth-based systems versus the MYCOTB plate for antimicrobial susceptibility testing of the Mycobacterium tuberculosis complex: challenges in interpretation. AB - We examined categorical agreement between automated mycobacterial susceptibility testing methods (Mycobacterial Growth Indicator Tube [MGIT] 960 System and the VersaTREK Mycobacteria Detection and Susceptibility System) which are based on single critical concentration (CC) "breakpoints" and a commercial microbroth dilution method (Sensititre Mycobacterium tuberculosis MIC Plate [MYCOTB]) which provides an MIC value. Mycobacterium tuberculosis isolates (n=355) were tested against three first-line antimycobacterial agents (ethambutol [EMB], isoniazid [INH], rifampin [RIF]) using the MYCOTB plate and either the MGIT 960 (site 1, n=142) or VersaTREK (site 2, n=213) systems. Overall categorical agreement was 96.8%. When stratified by drug and CC-defined susceptible and resistant isolates, concordance ranged from 75% to 100%. Interpretation of MIC-based results versus established CC-based results was challenging for drugs whose CC was not represented by an exactly equivalent concentration in the manufacturer-defined dilutions on the MYCOTB plate (EMB, INH). We propose interpretations of MYCOTB plate MICs using the currently available plate configuration. PMID- 29422275 TI - [Optical coherence tomography and in vivo confocal microscopy in pre-descemet corneal dystrophy]. PMID- 29422274 TI - A nitrocefin disc supplemented with ertapenem for rapid screening of carbapenemase-producing Enterobacteriaceae. AB - Reliable, simple and rapid methods for laboratory detection of carbapenemases are important for an appropriate antibiotic administration. A nitrocefin disc containing ertapenem for rapid screening of carbapenemase production among Enterobacteriaceae is developed in the present study. A total of 87 molecularly confirmed Enterobacteriaceae including 31 carbapenemase producers and 56 non carbapenemase producers, were tested with nitrocefin discs supplemented with and without ertapenem (20 MUg/disc). Nitrocefin discs with ertapenem successfully discriminated all 31 carbapenemase and all non-carbapenemase producers within 30 minutes. The sensitivity and specificity of the method were 100%. The minimum inhibitory concentrations (MICs) of ertapenem against all carbapenemase-producing isolates ranged from 1 to >=256 MUg/mL. This simple test could help to minimize the treatment failure and control the dissemination of infections caused by carbapenemase-associated resistant bacteria. It is a promising approach that could be performed routinely in any laboratory. PMID- 29422276 TI - Insertion of the Impella via the axillary artery for high-risk percutaneous coronary intervention. AB - Hemodynamic support with the Impella device is an important tool during high risk percutaneous coronary intervention. This device is usually inserted via the femoral artery. However, some patients have severe peripheral artery disease precluding the use of the femoral artery for this purpose. The axillary artery is a viable alternative in these cases. We reviewed the two access techniques for inserting the Impella via the axillary artery and also described 6 cases of successful implantation. PMID- 29422277 TI - Revascularization of radiation-induced carotid artery stenosis with carotid endarterectomy vs. carotid artery stenting: A systematic review and meta analysis. AB - OBJECTIVE: The incidence of carotid artery stenosis after head and neck radiation is anticipated to rise due to the increasing survival of patients with head and neck malignancies. It remains unclear whether carotid artery stenting (CAS) or endarterectomy (CEA) is the best treatment strategy for radiation-induced carotid artery stenosis. MATERIALS & METHODS: This study was performed according to the PRISMA and MOOSE guidelines. Eligible studies were identified through a comprehensive search of PubMed, Scopus and Cochrane Central until July 20, 2017. A meta-analysis of random effects model was conducted. The I-square statistic was used to assess for heterogeneity. RESULTS: Five studies and 143 patients were included. Periprocedural stroke, myocardial infarction (MI) and death rates were similar between the two revascularization approaches. However, the risk for cranial nerve (CN) injury was higher in the CEA group (OR: 7.09; 95% CI: 1.17 42.88; I2 = 0%). CEA was associated with lower mortality rates after a mean follow-up of 50 months (OR: 0.29; 95% CI: 0.09-0.97; I2 = 0%). No difference was identified in long-term restenosis rates between CEA and CAS. CONCLUSIONS: Patients with radiation-induced carotid artery stenosis can safely undergo both CAS and CEA with similar risks of periprocedural stroke, MI and death. However, patients treated with CEA have a higher risk for periprocedural CN injuries and a lower risk for long-term mortality. PMID- 29422278 TI - Micropuncture Kits to Obtain Large-Bore Peripheral Venous Access. PMID- 29422279 TI - Comparison of In-hospital Outcomes Between Transcatheter and Surgical Aortic Valve Replacement in Patients with Aortic Valve Stenosis: A Retrospective Cohort Study Using Administrative Data. AB - OBJECTIVE: The number of surgeries for valvular heart disease performed in Japan has greatly increased over the past decade, and surgical aortic valve replacements (SAVR) constitute the vast majority of aortic valve replacement procedures. Although transcatheter aortic valve implantation (TAVI) was recently introduced, studies have yet to compare the clinical outcomes between TAVI and SAVR in the Japanese healthcare setting. This study aimed to compare in-hospital outcomes between TAVI and SAVR using a multicenter administrative database. DESIGN: Retrospective cohort study. SETTING: Acute care hospitals in Japan. PARTICIPANTS: A total of 16,775 patients diagnosed with aortic valve stenosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main study outcome measure was in-hospital mortality. Based on multiple logistic regression analysis using inverse probability of treatment weighting, the odds ratio of in-hospital mortality for TAVI (relative to SAVR) was calculated to be 0.36 (95% confidence intervals: 0.13-0.98; p = 0.04). In patients aged 80 years or older, the odds ratio was even lower at 0.34 (95% confidence intervals: 0.15-0.73; p < 0.01). In addition, the incidences of reoperations, hemorrhagic complications, cardiac tamponade, and postoperative infections were significantly higher in the SAVR patients. CONCLUSIONS: This large-scale multicenter comparative analysis of TAVI and SAVR in Japan indicated that TAVI produced better clinical outcomes in patients with aortic valve stenosis. The improved outcomes were particularly notable in patients aged 80 years or older. PMID- 29422281 TI - Anesthesia for Cardiac Ablation. AB - As the complexity and duration of cardiac ablation procedures increase, there is a growing demand for anesthesiologist involvement in the electrophysiology suites for sedation and anesthesia provision, hemodynamic and neuromonitoring, and procedural guidance through transesophageal echocardiography. To deliver high quality perioperative care, it is important that the anesthesiologist is intimately familiar with the evolving techniques and technologies, the anesthetic options and ventilation strategies, and the anticipated postprocedural complications. PMID- 29422280 TI - Impact of Intubation Time on Survival following Coronary Artery Bypass Grafting: Insights from the Surgical Treatment for Ischemic Heart Failure (STICH) Trial. AB - OBJECTIVE: The authors aimed to assess determinants of intubation time and evaluate its impact on 30-day and 1-year postoperative survival in Surgical Treatment for Ischemic Heart Failure (STICH) trial patients. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: A multivariable Cox proportional hazards model was used among the 1,446 surgical patients from the STICH trial who survived 36 hours after operation, in order to identify perioperative factors associated with 30-day and 1-year postoperative mortality. A multivariable logistic regression model was used to determine risk factors associated with intubation time. MEASUREMENTS AND MAIN RESULTS: At 36 hours post-operation, 1,298 (out of 1,446) were extubated and 148 (10.2%) still intubated. Median postoperative intubation time was 11.4 hours. Among patients surviving 36 hours, a multivariable model was developed to predict 30-day (c-index = 0.88) and 1-year (c-index = 0.78) mortality. Intubation time was the strongest independent predictor of 30-day (hazard ratio [HR] 5.50) and 1-year mortality (HR 3.69). Predictors of intubation time >36 hours included mitral valve procedure, New York Heart Association class, left ventricular systolic volume index, creatinine, previous coronary artery bypass grafting (CABG), and age. Results were similar in patients surviving 24 hours post-operation, where intubation time was also the strongest predictor of 30-day (HR 4.18, c-index 0.87) and 1-year (HR 2.81, c-index 0.78) mortality. CONCLUSIONS: Intubation time is the strongest predictor of 30-day and 1-year mortality among patients with ischemic heart failure undergoing CABG. Combining intubation time with other mortality risk factors may allow the identification of patients at the highest risk for whom the development of specific strategies may improve outcomes. PMID- 29422282 TI - A Unique Easily Preventable Complication of a Newer Pulmonary Artery Introducer Sheath-Eyes Can See What the Mind Knows! PMID- 29422283 TI - Minimally Invasive Determinations of Oxygen Delivery and Consumption in Cardiac Surgery: An Observational Study. AB - OBJECTIVE: Evaluate minimally invasive assessment of oxygen delivery (DO2) and oxygen consumption (VO2) and determine its level of agreement with the gold standard approach of those measurements in patients undergoing cardiac surgery. DESIGN: Observational study. SETTING: Single center, VU University Medical Center (Amsterdam, The Netherlands). PARTICIPANTS: The study comprised 29 adult patients. INTERVENTION: Parallel measurements of invasive and minimally invasive parameters required for the calculation of DO2 and VO2. MEASUREMENTS AND MAIN RESULTS: Measurements were performed after anesthesia induction (T1) and before sternal closure (T2) in adult cardiac surgery. The invasive approach included arterial and pulmonary artery catheter-derived blood sampling and cardiac output measurements. The minimally invasive approach included pulse oximetry, point-of care hemoglobin, Nexfin-based cardiac output, and central venous catheter-derived blood sampling. Level of agreement was determined using Bland-Altman analysis and percentage error. DO2 and VO2 levels were determined in patients 71 +/- 8 years old. DO2 measurements showed a level of agreement of -17 +/- 57 L/min/m2 and -18 +/- 72 L/min/m2 with percentage errors of 35% and 38% at T1 and T2, respectively. VO2 assessment showed a level of agreement of -5 +/- 18 L/min/m2 and -12 +/- 22 L/min/m2, with percentage errors of 47% at T1 and T2. The highest percentage errors were for cardiac output measurements, 33% and 28% at T1 and T2, respectively. CONCLUSION: Agreement between minimally invasive and invasive DO2 and VO2 determinations is, moderate and poor, respectively. These findings may be explained by the poor agreement between minimally invasive and invasive cardiac output measurements. PMID- 29422285 TI - Tom Bird: one of the world's first experts in neurogenetics. PMID- 29422284 TI - Is Long-Acting P2Y12 Receptor Antagonist Therapy Ideal in Patients With Recently Implanted Drug-Eluting Stents in Need of Mechanical Circulatory Support? PMID- 29422286 TI - Visit-to-visit lipid variability: Clinical significance, effects of lipid lowering treatment, and (pharmaco) genetics. AB - In recent years, visit-to-visit variability of serum lipids has been linked to both clinical outcomes and surrogate markers for vascular disease. In this article, we present an overview of the current evidence connecting this intraindividual variability to these outcome measures, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. In addition, we undertook an explorative genome-wide association analysis on visit-to-visit variability of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, examining additive effects in 2530 participants from the placebo arm of the PROspective Study of Pravastatin in the Elderly at Risk trial. While we identified suggestive associations (P < 1 * 10-6) at 3 different loci (KIAA0391, amiloride-sensitive cation channel 1 neuronal [ACCN1], and Dickkopf WNT signaling pathway inhibitor 3 [DKK3]), previously published data from the genome-wide association study literature did not suggest plausible mechanistic pathways. Given the large degree of both clinical and methodological heterogeneity in the literature, additional research is needed to harmonize visit-to-visit variability parameters across studies and to definitively assess the possible role of (pharmaco)genetic factors. PMID- 29422287 TI - Emphysema and Interstitial Pneumonia in Rheumatoid Arthritis. PMID- 29422288 TI - Systems Signatures Reveal Unique Remission-path of Type 2 Diabetes Following Roux en-Y Gastric Bypass Surgery. AB - Roux-en-Y Gastric bypass surgery (RYGB) is emerging as a powerful tool for treatment of obesity and may also cause remission of type 2 diabetes. However, the molecular mechanism of RYGB leading to diabetes remission independent of weight loss remains elusive. In this study, we profiled plasma metabolites and proteins of 10 normal glucose-tolerant obese (NO) and 9 diabetic obese (DO) patients before and 1-week, 3-months, 1-year after RYGB. 146 proteins and 128 metabolites from both NO and DO groups at all four stages were selected for further analysis. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the represented physiological states (called the edge-states that reflect the interactions among the bio-molecules), and the related molecular networks of NO and DO patients, respectively. The principal component analyses (PCA) revealed that the edge states of the post-RYGB NO subjects were significantly different from those of the post-RYGB DO patients. Particularly, the time-dependent changes of the molecular hub-networks differed between DO and NO groups after RYGB. In conclusion, by developing molecular network-based systems signatures, we for the first time reveal that RYGB generates a unique path for diabetes remission independent of weight loss. PMID- 29422290 TI - Genetic variability of carbapenemase KPC-producing Klebsiella pneumoniae isolated at different states in Venezuela. AB - INTRODUCTION: In Venezuela, there have been some reports of carbapenemase KPC producing Klebsiella pneumoniae. Nevertheless, since the first report in 2008, only a few studies have been done on their molecular epidemiology in this country. METHODS: The aims of this study were to detect extended-spectrum betalactamase (ESBL)-producing (blaTEM and blaCTM-M-1) and to determine the genetic relationship between 30 isolates of carbapenemase KPC-producing K. pneumoniae taken from patients at eleven health centers in different states of Venezuela from January 2008 to December 2012, using pulsed-field gel electrophoresis (PFGE). RESULTS: All isolates were identified as K. pneumoniae subsp. pneumoniae. Isolates showed the highest resistance to the ertapenem, 97%. The KPC gene was detected in all studied strains. Seventy three percent showed ESBL, having the blaTEM in 68% and blaTEM, CTX-M-1 in 27% of the strains. Eleven groups were found using the field-pulsed gel electrophoresis. CONCLUSION: High genetic diversity was found during 2008-2012 in K. pneumoniae isolated at different states in Venezuela, some of them circulating at eleven health centers. Results showed the importance of performing epidemiologic studies and the need to develop some activities to control this type of microorganisms. PMID- 29422289 TI - Prevalence and Effects of Emphysema in Never-Smokers with Rheumatoid Arthritis Interstitial Lung Disease. AB - AIMS: Autoimmune conditions such as rheumatoid arthritis-related interstitial lung disease (RA-ILD) have been linked to the existence of emphysema in never smokers. We aimed to quantify emphysema prevalence in RA-ILD never-smokers and investigate whether combined pulmonary fibrosis and emphysema (CPFE) results in a worsened prognosis independent of baseline disease extent. METHODS: RA-ILD patients presenting to the Royal Brompton Hospital (n=90) and Asan Medical Center (n=155) had CT's evaluated for a definite usual interstitial pneumonia (UIP) pattern, and visual extents of emphysema and ILD. RESULTS: Emphysema, identified in 31/116 (27%) RA-ILD never-smokers, was associated with obstructive functional indices and conformed to a CPFE phenotype: disproportionate reduction in gas transfer (DLco), relative preservation of lung volumes. Using multivariate logistic regression, adjusted for patient age, gender and ILD extent, emphysema presence independently associated with a CT-UIP pattern in never-smokers (0.009) and smokers (0.02). On multivariate Cox analysis, following adjustment for patient age, gender, DLco, and a CT-UIP pattern, emphysema presence (representing the CPFE phenotype) independently associated with mortality in never-smokers (p=0.04) and smokers (p<0.05). CONCLUSION: 27% of RA-ILD never-smokers demonstrate emphysema on CT. Emphysema presence in never-smokers independently associates with a definite CT-UIP pattern and a worsened outcome following adjustment for baseline disease severity. PMID- 29422291 TI - A case-control study on the clinical impact of ventilator associated tracheobronchitis in adult patients who did not develop ventilator associated pneumonia. AB - OBJECTIVES: The main objective was to determine whether ventilator-associated tracheobronchitis (VAT) is related to increased length of ICU stay. Secondary endpoints included prolongation of hospital stay, as well as, ICU and hospital mortality. DESIGN: A retrospective matched case-control study. Each case was matched with a control for duration of ventilation (+/- 2 days until development of ventilator-associated tracheobronchitis), disease severity (Acute Physiology and Chronic Health Evaluation II) at admission +/- 3, diagnostic category and age +/-10 years. PATIENTS: Critically ill adults admitted to a polyvalent 30-beds ICU with the diagnosis of VAT in the period 2013-2016. MAIN RESULTS: We identified 76 cases of VAT admitted to our ICU during the study period. No adequate controls were found for 3 patients with VAT. There were no significant differences in demographic characteristics, reasons for admission and comorbidities. Patients with VAT had a longer ICU length of stay, median 22 days (14-35), compared to controls, median 15 days (8-27), p=.02. Ventilator days were also significantly increased in VAT patients, median 18 (9-28) versus 9 days (5-16), p=.03. There was no significant difference in total hospital length of stay 40 (28-61) vs. 35days (23-54), p=.32; ICU mortality (20.5 vs. 31.5% p=.13) and hospital mortality (30.1 vs. 43.8% p=.09). We performed a subanalysis of patients with microbiologically proven VAT receiving adequate antimicrobial treatment and did not observe significant differences between cases and the corresponding controls. CONCLUSIONS: VAT is associated with increased length of intensive care unit stay and longer duration of mechanical ventilation. This effect disappears when patients receive appropriate empirical treatment. PMID- 29422292 TI - Autoinflammatory keratinization diseases: An emerging concept encompassing various inflammatory keratinization disorders of the skin. AB - Classifying inflammatory skin diseases is challenging, especially for the expanding group of disorders triggered by genetic factors resulting in hyperactivated innate immunity that result in overlapping patterns of dermal and epidermal inflammation with hyperkeratosis. For such conditions, the umbrella term "autoinflammatory keratinization diseases" (AIKD) has been proposed. AIKD encompasses diseases with mixed pathomechanisms of autoinflammation and autoimmunity, and includes IL-36 receptor antagonist (IL-36Ra)-related pustulosis, CARD14-mediated pustular psoriasis, pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Mechanistically, the entities include generalized pustular psoriasis (GPP) without psoriasis vulgaris, impetigo herpetiformis and acrodermatitis continua, which are IL-36Ra-related pustuloses caused by loss-of-function mutations in IL36RN; GPP with psoriasis vulgaris and palmoplantar pustular psoriasis which are CARD14-mediated pustular psoriasiform dermatoses with gain-of-function variants of CARD14; PRP type V which is caused by gain-of-function mutations in CARD14; and, familial KLC in which mutations in NLRP1, an inflammasome sensor protein predominantly expressed in skin, have been identified. It is likely that further inflammatory keratinization disorders will also fall within the concept of AIKD, as elucidation of novel pathogenic mechanisms of inflammatory keratinization diseases emerges. A better understanding of the pathophysiology of AIKD is likely to lead to innovative, targeted therapies that benefit patients. PMID- 29422293 TI - Improving socket design to prevent difficult removal of locking screws. AB - INTRODUCTION: Reports of driver slippage leading to difficult locking screw removals have increased since the adoption of titanium for screw fabrication; the use of titanium is known to cause cross-threading and cold welding. Such problems occur most frequently in screws with hex sockets, and may cause serious surgical complications. This study aimed to improve screw socket design to prevent slippage and difficult screw removal. MATERIALS AND METHODS: Three types of small sockets (hex, Torx, and cruciate) and six types of large sockets (hex, Torx, Octatorx, Torx+ I, Torx+ II, and Torx+ III) with screw head diameters of 5.5 mm were manufactured from titanium, and corresponding screwdrivers were manufactured from stainless steel. The screw heads and drivers were mounted on a material testing machine, and torsional tests were conducted to simulate screw usage in clinical settings at two insertion depths: 1 and 2 mm. Ten specimens were tested from each design, and the maximum torque and failure patterns were recorded and compared. RESULTS: For small sockets in 2 mm conditions, the hex with the largest driver core had the highest torque, followed by Torx and cruciate. In these tests, the drivers were twisted off in all specimens. However, under the 1 mm condition, the hex slipped and the torque decreased markedly. Overall, torque was higher for large sockets than for small sockets. The Octatorx, with a large core and simultaneous deformation of the driver and socket lobes, had the highest torque at almost twice that of the small hex. The hex had the lowest torque, a result of slippage in both the 1 and 2 mm conditions. Torx plus designs, with more designed degrees of freedom, were able to maintain a higher driving angle and larger core for higher torque. CONCLUSIONS: The hex design showed slipping tendencies with a marked decrease in torque, especially under conditions with inadequate driver engagement. Large sockets allowed for substantial increases in torque. The Torx, Octatorx, and Torx plus designs displayed better performance than the hexes. Improvements to the socket design could effectively prevent slippage and solve difficult screw removal problems. PMID- 29422294 TI - Home, No Follow-Up: Are we ignoring the significance of unplanned clinic attendances, re-admission and mortality in the first 12 months post-operatively in over 65 year olds' hip fractures treated with DHS fixation? AB - INTRODUCTION: 80,000 hip fractures are admitted to UK hospitals annually (Royal College of Physicians, 2016). Little is known about 12-month post-operative re admission, unplanned clinic attendance and mortality. We aimed to determine if there is a role for routine follow-up for certain strata of our hip fracture population treated by Dynamic Hip Screw (DHS) Fixation based on unplanned attendance to clinics and whether it is possible to stratify risk of re admission, re-operation and mortality within the first 12 months post operatively. METHODS: A prospectively collated single centre database of patients >65 years old undergoing DHS fixation for traumatic hip fractures between August 2007 and February 2011 was retrospectively analysed. Pre-operative data regarding patient demographics, mobility, residence and co-morbidities were collected. Post operative (1, 4, 12 months) place of residence, mobility status, unplanned attendance to an orthopaedic clinic with symptoms relating to the respective limb, re-admission to hospital and mortality was collated. Regression analysis was performed (SPSS, IBM Corporation, version 24). P < 0.05 was considered significant. RESULTS: 648 consecutive patients were identified. Increasing age (p = 0.006) and presence of pressure sores during initial admission (p = 0.0019) increased the frequency of unplanned clinic attendance. No significant predictors of re-admission to hospital were found. Overall mortality was related to increasing age (p = 0.042), male gender (p = 0.004) and ASA grade (p = 0.009). CONCLUSION: There is no current vogue to follow-up such patients in this post operative period. We have identified variables that should be sought prior to discharge in this population. 22% of our population had at least one unplanned clinic attendance with a cost implication of approximately L50,132 (L151 per appointment) over the study period and potentially over L1.6 million pounds annually in the U.K. IMPLICATIONS: Formal follow-up/rehabilitation programs could be offered for those at risk of unplanned clinic attendance. Post-operative orthogeriatric and/or general practitioner follow-up may reduce 12-month mortality in those at risk but validated scoring and risk stratification systems are required to fully justify this. PMID- 29422295 TI - Relationship between systolic blood pressure on arrival at Emergency Department and mortality after an episode of acute heart failure. PMID- 29422296 TI - Improvement of bilateral lower-limb muscle oxygenation by low-density lipoprotein apheresis in a patient with peripheral artery disease undergoing hemodialysis. PMID- 29422297 TI - [Development of the facial feminization surgery patient's satisfaction questionnaire (QESFF1): Qualitative phase]. AB - OBJECTIVE: Facial feminization surgery is becoming a more frequently requested procedure in transsexual male to female patients transformation. A global way of reporting outcomes data and showing the beneficial impact of this specific procedure is necessary. The objective of this study is to develop a reliable and valid tool to report patients' outcomes after facial feminization surgery. METHODS: A systematic literature review, input from experts working with transsexual patients and patient interviews were used to develop the conceptual framework of the questionnaire. It includes the outcomes deemed important to facial feminization surgery and it was used to construct items of the questionnaire. RESULTS: There is no specific tool for measuring patients outcomes after facial feminization surgery. Ten experts and 18 patients participated to this study. The conceptual framework includes the following themes: satisfaction with facial feminine appearance; adverse effects; quality of life. The questionnaire includes fourteen separate Likert scales, with preoperative and postoperative versions. The reliability of the questionnaire is excellent with a medium Alpha score of 0.85. Facial feminization surgery is associated with high patient satisfaction in this sample (83.7+/-7.41). CONCLUSION: QESFF1 is a reliable questionnaire and its development follows the steps recommended by the patient-reported outcomes process. A large sample pilot test is needed to demonstrate its validity. The QESFF1 can provide physicians with the necessary tools to measure the impact of facial feminization surgery on male to female transsexual patients and also has the potential to support clinical trials. PMID- 29422299 TI - A randomized controlled trial examining a cognitive behavioral therapy intervention enhanced with cognitive remediation to improve work and neurocognition outcomes among persons with schizophrenia spectrum disorders. AB - This single blind, three-armed randomized controlled trial compared cognitive behavioral therapy (CBT) enhanced with cognitive remediation (CBT+CR) to CBT alone and an active control condition on work and neurocognition outcomes for persons with schizophrenia spectrum disorders. Seventy-five adult outpatients with schizophrenia or schizoaffective disorder were randomized to three study conditions (N=25 per group). The CBT intervention was the Indianapolis Vocational Intervention program (IVIP), consisting of weekly group and individual sessions focused on work-related content. Participants in the CBT+CR group received IVIP and Posit Science computer-based cognitive training. The active control group consisted of weekly vocational support groups and individual vocational support sessions. All participants were placed into a noncompetitive work assignment and were followed for 26weeks. Data collection included hours worked, weekly work performance ratings, and neurocognition assessed at baseline and 6months. Neurocognition was also assessed at 12months. Data were analyzed using multilevel linear models to account for nested, repeated measures data. Results indicate that participants in the CBT+CR condition worked significantly more hours and had a more positive trajectory of improving global work performance and work quality across the study compared with the CBT alone and vocational support condition. Compared to the other conditions, CBT+CR also had a significant increase in overall neurocognition that continued to the 12month follow-up, particularly in the domains of verbal learning and social cognition. In conclusion, CBT+CR may be an effective intervention to improve work functioning and neurocognition in persons with schizophrenia. PMID- 29422298 TI - Amino acid profiles of young adults differ by sex, body mass index and insulin resistance. AB - BACKGROUND AND AIMS: An increase in plasma branched-chain amino acids is associated with a higher risk of developing type 2 diabetes and cardiovascular diseases. However, little is known about the basal plasma amino acid concentrations in young adults. Our aim was to determine the plasma amino acid profiles of young adults and to evaluate how these profiles were modified by sex, body mass index (BMI) and insulin resistance (IR). METHODS AND RESULTS: We performed a transversal study with 608 Mexican young adults aged 19.9 +/- 2.4 years who were applicants to the Universidad Autonoma de San Luis Potosi. The subjects underwent a physical examination and provided a clinical history and a blood sample for biochemical, hormonal and amino acid analyses. The women had higher levels of arginine, aspartate and serine and lower levels of alpha aminoadipic acid, cysteine, isoleucine, leucine, methionine, proline, tryptophan, tyrosine, urea and valine than the men. The obese subjects had higher levels of alanine, aspartate, cysteine, ornithine, phenylalanine, proline and tyrosine and lower levels of glycine, ornithine and serine than the normal weight subjects. Subjects with IR (defined as HOMA > 2.5) had higher levels of arginine, alanine, aspartate, isoleucine, leucine, phenylalanine, proline, tyrosine, taurine and valine than the subjects without IR. Furthermore, we identified two main groups in the subjects with obesity and/or IR; one group was composed of amino acids that positively correlated with the clinical, biochemical and hormonal parameters, whereas the second group exhibited negative correlations. CONCLUSION: This study demonstrates that young adults with obesity or IR have altered amino acid profiles characterized by an increase in alanine, aspartate, proline and tyrosine and a decrease in glycine. PMID- 29422300 TI - Conversion to laparoscopic sleeve gastrectomy after failure of laparoscopic gastric band: A systematic review of the literature and cost considerations. AB - No universal consensus has been achieved as to whether the laparoscopic adjustable gastric band to laparoscopic sleeve gastrectomy conversion should be performed in one or two steps. To determine the differences in operative outcomes and cost, a systematic, comprehensive review of the literature was conducted using the PubMed database from the National Institutes of Health. Nine studies were included with 809 patients. Weighted averages were calculated to compare operative outcomes, and cost analyses were conducted with these averages. Results indicate a longer operative time for the one-step approach than the two-step approach, but studies included in the meta-analysis found no statistical difference between the two. The two-step approach was found to have a longer length of hospital stay, but this finding refuted included studies that indicate no significant difference. Complication rates were higher for the one-step approach than the two-step approach, and costs associated with complications average $806 more for one-step patients than two-step patients. This suggests that the two-step approach could prove better for patient safety and cost outcomes, but both approaches are comparable in operating time and length of stay. PMID- 29422301 TI - [False hypoxia in a newborn due to a haemoglobin F polymorphism]. PMID- 29422302 TI - [Bilateral pseudoangiomatous stromal hyperplasia of the breast]. PMID- 29422303 TI - [Cannabinoid hyperemesis syndrome]. PMID- 29422304 TI - [What the red stain of the tattoo hides]. PMID- 29422306 TI - Early removal of sequestrum in patients affected by medication-related osteonecrosis of the jaw. PMID- 29422305 TI - Seasonal biomass and alginate stock assessment of three abundant genera of brown macroalgae using multispectral high resolution satellite remote sensing: A case study at Ekas Bay (Lombok, Indonesia). AB - The potential of Indonesian bays as alginate producers was assessed by determining the stock of wild brown algae and exploring their biomass as alginophytes at the scale of entire bay, using a combination of field observations, remote sensing high resolution data and GIS tools. Ekas Bay in Lombok Island presented a stock of brown macroalgae which varied with season and species: for Padina the biomass reached 97.85+/-12.63 and 79.54+/-2.53tons in May/June and November respectively; for Sargassaceae species, it reached 669.70+/ 109.64 and 147.70+/-77.97tons in May/June and November respectively. The best alginate yields occurred during the May/June period: Padina could produce 9.10+/ 0.06tons DW of alginates. Interestingly, Sargassum/Turbinaria together allow 207.61+/-0.42tons DW of alginates. This study suggests that wild Sargassaceae represent an interesting stock in terms of biomass, alginate yield and M/G ratio. PMID- 29422307 TI - Percutaneous treatment of orofacial vascular malformations. AB - The aim of this study was to evaluate the efficacy of fluoroscopy-guided percutaneous injection of bleomycin as the primary treatment for low-flow vascular malformations. A total of 34 patients (mean (range) age 24 (8-51) years) with orofacial vascular lesions were treated in the Department of Interventional Radiology and Maxillofacial Surgery. There were 20 low-flow venous malformations, 11 lymphatic malformations, and three of mixed type. All patients were treated by fluoroscopy-guided percutaneous injection of a mixture of bleomycin (mean (range) 15 (5-15)mg) and a radio-opaque agent (Ultravist(r) (iopromide), Bayer)/session. The number of sessions ranged from one to six. The clinical response was complete in 21 patients, obvious in nine, and of clinical benefit in four. Patients were reviewed within the first week, third week, and at three-month periods until 24 months. There were no serious complications such as pulmonary fibrosis. Fluoroscopy-guided intralesional injection of bleomycin should be considered as the first-line treatment for lymphatic malformations because it is effective and reliable with few complications. PMID- 29422308 TI - Effect of bilayer charge on lipoprotein lipid exchange. AB - Lipoproteins play a key role in the onset and development of atherosclerosis, the formation of lipid plaques at blood vessel walls. The plaque formation, as well as subsequent calcification, involves not only endothelial cells but also connective tissue, and is closely related to a wide range of cardiovascular syndromes, that together constitute the number one cause of death in the Western World. High (HDL) and low (LDL) density lipoproteins are of particular interest in relation to atherosclerosis, due to their protective and harmful effects, respectively. In an effort to elucidate the molecular mechanisms underlying this, and to identify factors determining lipid deposition and exchange at lipid membranes, we here employ neutron reflection (NR) and quartz crystal microbalance with dissipation (QCM-D) to study the effect of membrane charge on lipoprotein deposition and lipid exchange. Dimyristoylphosphatidylcholine (DMPC) bilayers containing varying amounts of negatively charged dimyristoylphosphatidylserine (DMPS) were used to vary membrane charge. It was found that the amount of hydrogenous material deposited from either HDL or LDL to the bilayer depends only weakly on membrane charge density. In contrast, increasing membrane charge resulted in an increase in the amount of lipids removed from the supported lipid bilayer, an effect particularly pronounced for LDL. The latter effects are in line with previously reported observations on atherosclerotic plaque prone regions of long-term hyperlipidaemia and type 2 diabetic patients, and may also provide some molecular clues into the relation between oxidative stress and atherosclerosis. PMID- 29422309 TI - Diagnostic Utility of Cytokeratin-5 for the Identification of Proliferative Inflammatory Atrophy in the Canine Prostate. AB - Proliferative inflammatory atrophy (PIA), which is comprised of highly proliferative but atrophic prostate epithelial cells in association with chronic inflammation, is considered a risk lesion for prostate cancer in men, while its role in canine prostate carcinogenesis is still unknown. We evaluated the value of immunohistochemical labelling for the basal cell marker cytokeratin-5 (CK5) in identifying PIA lesions in 87 samples of formalin-fixed and paraffin wax-embedded canine prostate. Canine PIA showed cytological features identical to the human counterpart and in most cases was associated with chronic lymphoplasmacytic inflammation. PIA lesions were identified in a higher number of CK5-labelled slides (43 out of 87) compared with slides stained by haematoxylin and eosin (HE) (24 out of 87). This lesion was frequently present in normal, hyperplastic and neoplastic canine prostates, although it was underestimated on evaluation of HE stained slides. Therefore, CK5 can be considered a useful basal cell marker with high sensitivity and specificity for PIA. PMID- 29422310 TI - Multifocal Spinal Cord Nephroblastoma in a Dog. AB - A 1-year-old male American pit bull terrier was presented with a history of proprioceptive deficits and mild lameness of the right hindlimb, which progressed after 5 months to paraparesis, culminating in tetraparesis after 2 weeks. Necropsy findings were limited to the spinal cord and consisted of multiple, intradural, extramedullary, slightly red masses which produced segmental areas of medullary swelling located in the cervical intumescence, thoracolumbar column, sacral segment and cauda equina. Histological evaluation revealed a tumour, composed of epithelial, stromal and blastemal cells, with structures resembling tubules, acini and embryonic glomeruli. Immunohistochemical labelling for vimentin, cytokeratin and S100 was positive for the stromal, epithelial and blastemal cells, respectively. A final diagnosis of multifocal spinal cord nephroblastoma was established. This is the first report of such a tumour showing concomitant involvement of the cervicothoracic, thoracolumbar, sacral and cauda equina areas of the spinal cord. PMID- 29422311 TI - Merkel Cell Carcinoma in a Steer. AB - Merkel cell carcinoma is a rare and aggressive cutaneous neuroendocrine tumour reported only in man, dogs and cats. A 20-month-old Japanese black fattening steer was presented with necrotic protruding skin masses over the left thoracic area and a 20 * 25 cm subcutaneous mass in the left abdominal area. Microscopical evaluation of the masses revealed cords of small to medium-sized round tumour cells with marked anisocytosis and anisokaryosis and clear and vacuolated cytoplasm, which were separated by a delicate fibrovascular stroma and arranged in a trabecular and nested pattern. Necropsy examination revealed multiple solid white nodular masses in the lungs. Immunohistochemistry (IHC) for cytokeratin (CK) 20 and CKAE1/3 revealed focal perinuclear labelling of tumour cells. IHC for the neuroendocrine markers chromogranin A and neuron specific enolase, the neuroepithelial stem cell marker nestin and the hormonal markers adrenocorticotropic hormone and calcitonin revealed diffuse cytoplasmic labelling of all tumour cells. Ultrastructurally, the tumour cells contained few neurosecretory granules and abundant glycogen pools. The tumours were diagnosed as Merkel cell carcinoma with pulmonary metastases and this case represents the first such diagnosis in cattle. PMID- 29422312 TI - Altered Expression of Anti-Mullerian Hormone during the Early Stage of Bovine Persistent Ovarian Follicles. AB - Anti-Mullerian hormone (AMH) is a homodimeric glycoprotein expressed exclusively in the gonads. This hormone is an important regulator of the early growth of follicles through inhibitory effects on the recruitment of primordial follicles into the pool of growing follicles and on granulosa cell proliferation. Cystic ovarian disease (COD) is an important disorder affecting the fertility of dairy cattle. In the present study, we evaluated the expression of AMH in granulosa cells and AMH secretion into follicular fluid in pre-ovulatory follicles from control cows, animals with spontaneously arising COD and during the development of the disease, at 5, 10 and 15 days of follicular persistence. To this end, after an oestrous synchronization protocol, low doses of progesterone was administered for 5, 10 and 15 days after the expected day of ovulation (day 0 of follicular persistence) in treated cows (groups P5, P10 and P15, respectively), using an intravaginal progesterone-releasing device. Results showed a decrease in the expression of AMH in granulosa cells throughout folliculogenesis (P <0.05) and in the spontaneously arising follicular cysts and persistent follicles related to the control group (P <0.05). There was also a higher concentration of AMH in the follicular fluid of persistent follicles at 10 and 15 days of follicular persistence (P <0.05). Together, these results may indicate an alteration in AMH expression and secretion, which occurs early in folliculogenesis and incipiently during the development of COD, and which could contribute to the recurrence of this disease in cattle. PMID- 29422313 TI - Prognostic Value of Occult Isolated Tumour Cells within Regional Lymph Nodes of Dogs with Malignant Mammary Tumours. AB - Canine mammary tumours (CMTs) are the most common type of neoplasm in bitches. As in women, the presence of metastasis in regional lymph nodes is an important prognostic factor in bitches with mammary carcinomas, but the clinical significance of occult isolated tumour cells (ITCs) within lymph nodes is still undefined in this species. The effectiveness of immunohistochemistry (IHC) in identifying occult ITCs and micrometastasis (MIC) was compared with that of the conventional haematoxylin and eosin staining technique. The relationship between tumour size, histological type, histological grade and the presence of metastasis was evaluated. The overall survival (OS) of female dogs with occult mammary carcinomas and ITCs within lymph nodes was analysed. Fragments of mammary carcinoma and regional lymph nodes of 59 female dogs were also evaluated. Histological sections of mammary carcinoma and lymph node samples were studied for tumour diagnosis and lymph node samples were tested by IHC using a pan cytokeratin antibody. It was found that 35.2% of occult ITCs and 2.8% of hidden MIC were detected when IHC was used. There was a good correlation between the size of the tumour and metastasis to the lymph nodes (P = 0.77). ITCs were observed more frequently in the medullary region (60.7%) and metastases in the cortical region (44.4%). There was no significant difference in the OS between female dogs with occult ITCs and lymph nodes without ITCs. IHC can detect occult tumour cells in lymph nodes that are negative by histopathological examination. Female dogs with nodal ITCs do not have lower survival. PMID- 29422314 TI - Dental Pathology of the Grey Fox (Urocyon cinereoargenteus). AB - Museum specimens from 637 grey foxes (Urocyon cinereoargenteus) were examined macroscopically according to predefined criteria. Of the 637 specimens, 569 were included for further examination. The study population included more males (n = 261, 45.9%) than females (n = 196, 34.4%) and animals of unknown sex (n = 112, 19.7%). Additionally, 481 (84.5%) adults, 67 (11.8%) young adults and 21 (3.7%) individuals of unknown age comprised the study population, with juveniles and neonates excluded. The number of teeth present for examination was 23,066 (96.5%) with 624 (2.6%) absent artefactually, 15 (0.06%) absent congenitally and 193 (0.8%) lost ante mortem through acquired tooth loss. No persistent deciduous teeth or temporomandibular joint osteoarthritis were found in any of the specimens. Ten supernumerary teeth from nine (1.6%) specimens were encountered. Teeth with extra roots were found in 61 individuals (10.7%), with 0.4% of all teeth affected. Of the alveoli examined, 1,529 (6.4%) displayed bony changes suggestive of periodontitis, with 276 (48.7%) of individuals affected. Significantly more adults were affected by bony changes associated with stage 3 periodontitis than young adults. All specimens displaying stage 4 periodontitis were adults. Fractures affected 446 (78.4%) of the specimens examined and 3,554 (15.4%) of teeth present. Almost half (n = 10,856, 47.1%) of the teeth available for examination and most specimens (n = 487, 85.6%) displayed some degree of attrition or abrasion. Two individuals (0.4%) exhibited periapical lesions. Traumatic skull injuries affected 56 (9.8%) specimens. Characterizing the dental pathology in the grey fox provides key insight into the ecology of the species and factors contributing to fitness. PMID- 29422315 TI - Loss of Endothelial Barrier Antigen Immunoreactivity in Rat Retinal Microvessels is Correlated with Clostridium perfringens Type D Epsilon Toxin-induced Damage to the Blood-Retinal Barrier. AB - Clostridium perfringens type D epsilon toxin (ETX) is a potent neurotoxin producing a severe, and often fatal, neurological disorder in ruminant livestock. Microvascular damage appears to be the fundamental action of ETX in the brain and, recently, similar vascular injury, with subsequent severe vasogenic oedema, has been reported in the retina of rats given ETX. Endothelial barrier antigen (EBA) is a useful marker of an intact blood-brain barrier in rats and it has been shown that loss of EBA immunoreactivity is correlated with ETX-induced cerebral microvascular damage in this species. This paper reports, for the first time, that loss of EBA immunoexpression also occurs in rat retinal microvessels exposed to ETX, the marked reduction in EBA immunopositivity acting as a useful marker for blood-retinal barrier breakdown produced by this neurotoxin. PMID- 29422316 TI - Histological and Immunological Description of the Leishmanin Skin Test in Ibizan Hounds. AB - The leishmanin skin test (LST), a delayed-type hypersensitivity (DTH) reaction to Leishmania infantum, can specifically identify dogs that have made a cell mediated immune response to L. infantum infection. The Ibizan hound appears to be more resistant to L. infantum infection than other breeds of dog. The aim of this study was to describe the histological and immunohistochemical changes induced by the LST in Ibizan hounds living in an area highly endemic for leishmaniosis. The majority of dogs were apparently healthy, lacked serum antibody to L. infantum and blood parasitaemia, but had marked specific interferon gamma production after in-vitro blood stimulation with L. infantum. Leishmanin (3 * 108 killed promastigotes of L. infantum/ml) was injected intradermally and biopsy samples were obtained from a positive reaction at 72 h from nine Ibizan hounds. A moderate to intense, perivascular to interstitial dermatitis and panniculitis characterized the inflammatory response at the injection site. In addition, three samples had diffuse inflammation in the deep dermis and panniculus. Oedema and necrosis were present in the deep dermis and panniculus. Congestion and haemorrhage were observed in five biopsies. T lymphocytes (CD3+) and large mononuclear cells (lysozyme-) were the most prevalent cells. CD3+ cells were significantly more numerous than CD20+ B cells and lysozyme+ cells. B cells were sparsely distributed, especially in the deep dermis and panniculus. Rare neutrophils and macrophages (lysozyme+) were observed with few eosinophils. Toll like receptor (TLR)-2 protein was expressed in large mononuclear cells mainly located in the superficial dermis. Leishmania immunohistochemistry was negative and quantitative polymerase chain reaction was positive in all cases. The intradermal injection of killed L. infantum promastigotes in Ibizan hounds causes similar histological and immunohistochemical findings to those described for human subjects and are indicative of a DTH response. Moreover, TLR2 protein is expressed in inflammatory cells similar to findings in clinically affected skin biopsy samples. PMID- 29422317 TI - Laryngeal Granuloma due to Leishmania spp. Infection in a Dog. AB - A French bulldog with a previous history of leishmaniosis was presented due to respiratory distress associated with a laryngeal mass. The mass was excised and cytological and histopathological examination revealed pyogranulomatous inflammation with Leishmania spp. amastigotes. After surgery, the respiratory condition resolved; however, 3 months later the dog developed clinicopathological signs of leishmaniosis, which improved with systemic treatment. This case shows an atypical presentation of leishmaniosis with a focal tumour-like mass in the vocal folds as the only clinical sign. PMID- 29422318 TI - Assessment of Lymphoid Molecular Clonality in Canine Thymoma. AB - The aim of this study was to document the molecular clonality of lymphoid cells in canine thymoma using polymerase chain reaction for antigen receptor rearrangement (PARR). Fifteen formalin-fixed and paraffin wax-embedded samples of canine thymoma were analyzed for T- and B-cell receptor clonality. Two of these 15 cases were excluded from the study due to insufficient DNA concentration. Twelve of the 13 remaining samples (92.3%) showed a polyclonal lymphoid component and in one case the lymphoid component was monoclonal (T-cell clonality). PARR could therefore be a useful tool for differentiating canine thymoma from canine mediastinal lymphoma. PMID- 29422319 TI - Atypical Cowpox Virus Infection in a Series of Cats. AB - Within 4 weeks, five cats with skin lesions affecting the hindlimbs and mainly consisting of oedema, hyperaemia and plaque-like alterations were presented to the same veterinary clinic. The cats were suffering from lameness, trauma, renal insufficiency or complicated tail amputation. Although the lesions seemed unusual for a poxvirus infection, microscopical examination of biopsy samples or specimens taken during necropsy examination revealed ballooning degeneration of keratinocytes with eosinophilic, cytoplasmic inclusion bodies indicative of an orthopoxvirus infection. Cowpox virus infection was verified using immunohistochemistry and virus isolation. Molecular analysis revealed identical haemagglutinin gene sequences in four cases and spatiotemporal circumstances in some cases pointed to hospital-acquired transmission. Unusual manifestations of feline cowpox may have an unexpected risk for human infection. PMID- 29422320 TI - Oral, Maxillofacial and Dental Diseases in Captive Cheetahs (Acinonyx jubatus). AB - Descriptions of several oral, maxillofacial and dental conditions/diseases exist for a variety of captive large felids, but little is reported on the pathology of free roaming large felids. Apart from focal palatine erosions (FPEs) as initially described by Fitch and Fagan (1982) and some reference to absent incisor teeth, few data exist on diseases affecting the oral, maxillofacial and dental structures of cheetahs (Acinonyx jubatus), regardless of their captivity status. This study reports 18 different conditions affecting the teeth, bone and oral cavity soft tissue of cheetahs, based on initial assessment of 256 animals over 11 years (2002-2012) in South Africa and Namibia. This report excludes oral tumours or FPEs, but includes several acquired and developmental conditions never described before. PMID- 29422322 TI - [Exceptional etiology of acute renal: Burkitt's lymphoma]. AB - INTRODUCTION: Burkitt's lymphoma (BL) is an exceptional cause of acute renal failure (ARF). The origin of the tumor clone may be lymphoid follicles secondary to renal Epstein-Barr virus (EBV) infection. With the presentation of this clinical case, the pathogenesis, diagnostic criteria and evolution of this extremely rare affection will be discussed. OBSERVATION: A 4-year-old patient with a recent history of acute osteomyelitis of the right thigh presented an ARF without indications of post-infectious glomerulonephritis. Ultrasound showed enlarged kidneys without dilation of the excretory cavities. Diffuse interstitial infiltration of atypical lymphoid cells of medium size were noted upon renal biopsy. The tumor cells expressed antibodies against CD20, CD10, Bcl6, and Ki67 but not against Bcl2 or CD3. The search for an EBV infection was positive. A few days after diagnosis, the evolution was spontaneously fatal. DISCUSSION/CONCLUSION: BL of the kidney is a rare condition that accounts for less than 1 % of kidney tumors, associated almost invariably with EBV infection. The diagnosis is confirmed histologically by renal biopsy and the criteria of Malbrain affirms the primitive character of the lymphoma. BL of the kidney is a diagnostic and therapeutic emergency and may be fatal. PMID- 29422321 TI - Broad variability in pharmacokinetics of GH following rhGH injections in children. AB - OBJECTIVE: Daily subcutaneous self-injection of GH is used worldwide to treat short stature in childhood; longitudinal data on the impact of this regimen on GH uptake are lacking. DESIGN: Children with/without GH-deficiency participating in clinical trials were followed prospectively (<=8 times). Blood was sampled pre-GH injection (dose GH33/GH67 MUg/kg) and either every 30 min thereafter for 24 h (Experimental-setting; 59 GH-curves/15 children); or every 2 h thereafter for 16 h (Clinical-setting; 429 GH-curves/117 children). Pharmacokinetics were estimated by time Tmax (h) of maximal GH-concentration (Cmax, mU/L) and area under the curve for 16 h (AUC, mU/L * h). RESULTS: In the Clinical-setting, median Cmax was 71 mU/L and AUC was 534 mU/L * h, with coefficients of variation for intra individual variation of 39% and 36%, respectively, and inter-individual variation of 44% and 42%, respectively. 43% of Cmax and AUC variability was explained by GH dose and proxies for injection depth (baseline GH-level, GHpeakwidth, BMISDS). In the Experimental- versus Clinical-setting, 85% and 40% of GH-curves, respectively, reached zero-levels within 24 h. A longer duration was found following a more superficial GH-injection. Spontaneous GH-peaks were identified already 6 h after the GH-injection in about half of the curves of both GHD and non-GHD patients. CONCLUSION: Very broad intra-individual and inter-individual variability was found. A high GH-peak will optimize growth effects; the highest Cmax was found after a deep injection of GH at the higher dose and concentration. In as many as 60% of the children, GH remained detectable in serum after 24 h; a constant GH-level will promote IGF-I and metabolic effects. PMID- 29422325 TI - Polymerization efficiency affects interfacial fracture toughness of adhesives. AB - OBJECTIVE: To evaluate the effect of the kind and concentration of photo initiator on the degree of conversion (DC) of adhesives on dentin/glass substrates and their mini-interfacial fracture toughness (mini-iFT) to dentin. METHODS: We tested the adhesive Clearfil S3 Bond Plus and 4 derived experimental 'LUB' ('Leuven Univesity Bond') adhesives (all from Kuraray Noritake), namely 'LUB-CQ/amine_high', 'LUB-CQ/amine_low', 'LUB-TPO_high', and 'LUB-TPO_low', respectively containing 2.0wt% camphorquinone (CQ) and 2.0wt% EDMAB (amine), 0.35wt% CQ and 0.35wt% amine, 2.0wt% TPO, and 0.35wt% TPO. For DC, each adhesive was applied onto glass or dentin prior to being cured (Bluephase 20i; Ivoclar Vivadent: "high mode") for 10s. DC was measured at 5min, 10min, 1h, 24h and 1 week using micro-Raman spectroscopy (SENTERRA; BrukerOptik). For mini-iFT, each adhesive was bonded to 320-grit SiC-paper ground dentin and covered with composite (Z100; 3M ESPE). The restored teeth were cut in sticks (1.5*2.0*16mm), after which a single-gradient notch was prepared at the adhesive-dentin interface using a 150-MUm diamond blade. The micro-specimens were loaded until failure in a 4-point bending test and the mini-iFT in term of KQvM was calculated. RESULTS: DC was higher on dentin than on glass. All adhesives were adequately polymerized at 1 week, except for LUB-TPO_low. DC at 5min was significantly higher for LUB TPO_high than for both CQ/amine-based adhesives. The highest and most reliable mini-iFT was measured for LUB-CQ/amine_high, despite its 5-min DC was relatively low. No correlation between DC and mini-iFT was found. SIGNIFICANCE: Curing of TPO-based adhesives is faster, but the dark cure of the CQ/amine-containing adhesives is more efficient. The differences in curing profiles do affect the mechanical properties of the resultant interfaces at dentin. PMID- 29422324 TI - Abatacept in patients with rheumatoid arthritis and interstitial lung disease: A national multicenter study of 63 patients. AB - OBJECTIVE: Interstitial lung disease (ILD) is one of the most serious complications of rheumatoid arthritis (RA). In the present study, we aimed to assess the efficacy of abatacept (ABA) in patients with ILD associated to RA. METHODS: National multicenter, non-controlled, open-label registry study of RA patients with ILD treated with ABA. RESULTS: 63 patients (36 women) with RA associated ILD undergoing ABA therapy were studied. The mean +/- standard deviation age at the time of the study was 63.2 +/- 9.8 years. The median duration of RA and ILD from diagnosis were 6.8 and 1 year, respectively. RA was seropositive in 55 patients (87.3%). In 15 (23.8%) of 63 patients the development of ILD was closely related to the administration of synthetic or biologic disease modifying anti-rheumatic drugs. After a follow-up of 9.4 +/- 3.2 months, two thirds of patients remained stable whereas one-quarter experienced improvement in the Modified Medical Research Council scale. At that time forced vital capacity remained stable in almost two-thirds of patents and improved in one out of five patients assessed. Also, diffusing capacity of the lung for carbon monoxide remained stable in almost two-thirds and showed improvement in a quarter of the patients assessed. At 12 months, 50% of the 22 patients in whom chest HRCT scan was performed due persistence of respiratory symptoms showed stabilization, 8 (36.4%) improvement and 3 worsening of the HRCT scan pattern. Eleven of 63 patients had to discontinue ABA, mainly due to adverse events. CONCLUSION: ABA appears to be an effective in RA-associated ILD. PMID- 29422326 TI - Ion-releasing dental restorative composites containing functionalized brushite nanoparticles for improved mechanical strength. AB - OBJECTIVES: This study describes the synthesis of brushite nanoparticles (CaHPO4.2H2O) functionalized with triethylene glycol dimethacrylate (TEGDMA) and their application in dental restorative composites with remineralizing capabilities. METHODS: Nanoparticles were synthesized, with TEGDMA being added to one of the precursor solutions at three different molar ratios (0:1, 0.5:1 and 1:1, in relation to the ammonium phosphate precursor). Then, they were added (10 vol%) to a photocurable dimethacrylate matrix containing 50 vol% of reinforcing glass particles. The resulting composites were tested for degree of conversion, biaxial flexural strength and elastic modulus (after 24h and 28days in water), and ion release (over a 28-day period). Commercial composites (one microhybrid and one microfilled) were tested as controls. RESULTS: The final TEGDMA content in the functionalizing layer was modulated by the molar ratio added to the precursor solution. Functionalization reduced nanoparticle size, but did not reduce agglomeration. Improved mechanical properties were found for the composite containing nanoparticles with higher TEGDMA level in comparison to the composite containing non-functionalized nanoparticles or those with a low TEGDMA level. All brushite composites presented statistically significant reductions in strength after 28 days in water, but only the material with high-TEGDMA nanoparticles retained strength similar to the microhybrid commercial control. Overall, ion release was not affected by functionalization and presented steady levels for 28 days. SIGNIFICANCE: Though agglomeration was not reduced by functionalization, the improvement in the matrix-nanoparticle interface allowed for a stronger material, without compromising its remineralizing potential. PMID- 29422328 TI - Impact of Acoustic Radiation Force Excitation Geometry on Shear Wave Dispersion and Attenuation Estimates. AB - Shear wave elasticity imaging (SWEI) characterizes the mechanical properties of human tissues to differentiate healthy from diseased tissue. Commercial scanners tend to reconstruct shear wave speeds for a region of interest using time-of flight methods reporting a single shear wave speed (or elastic modulus) to the end user under the assumptions that tissue is elastic and shear wave speeds are not dependent on the frequency content of the shear waves. Human tissues, however, are known to be viscoelastic, resulting in dispersion and attenuation. Shear wave spectroscopy and spectral methods have been previously reported in the literature to quantify shear wave dispersion and attenuation, commonly making an assumption that the acoustic radiation force excitation acts as a cylindrical source with a known geometric shear wave amplitude decay. This work quantifies the bias in shear dispersion and attenuation estimates associated with making this cylindrical wave assumption when applied to shear wave sources with finite depth extents, as commonly occurs with realistic focal geometries, in elastic and viscoelastic media. Bias is quantified using analytically derived shear wave data and shear wave data generated using finite-element method models. Shear wave dispersion and attenuation bias (up to 15% for dispersion and 41% for attenuation) is greater for more tightly focused acoustic radiation force sources with smaller depths of field relative to their lateral extent (height-to-width ratios <16). Dispersion and attenuation errors associated with assuming a cylindrical geometric shear wave decay in SWEI can be appreciable and should be considered when analyzing the viscoelastic properties of tissues with acoustic radiation force source distributions with limited depths of field. PMID- 29422327 TI - Evaluation of biofilm formation on novel copper-catalyzed azide-alkyne cycloaddition (CuAAC)-based resins for dental restoratives. AB - OBJECTIVE: For the past several decades, the resins used in dental restorations have been plagued with numerous problems, including their implication in biofilm formation and secondary caries. The need for alternative resins is critical, and evaluation of biofilm formation on these resins is essential. The aim of this study was to evaluate in vitro biofilm formation on the surface of novel copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)-based resins and composites. METHODS: CuAAC-based resins/composites made from varying azide monomers and different copper concentrations were compared with BisGMA-TEGDMA resins/composites that served as the control. Biofilms were formed using a mono species model containing a luciferase-expressing strain of Streptococcus mutans. Luciferase activity was measured and the number of viable bacteria was enumerated on biofilms associated with each resin and composite. RESULTS: A significant reduction (p<0.05) in luciferase activity, and the number of viable bacteria recovered from biofilms on CuAAC-based resins and composites was observed in comparison to biofilms associated with the BisGMA-TEGDMA controls. SIGNIFICANCE: CuAAC-based resins do still allow for the formation of biofilms; however, the statistically significant reduction of growth that was associated with the CuAAC resin may enhance the longevity of restorations that incorporate CuAAC-based materials. PMID- 29422329 TI - Radiographic Cobb Angle: A Feature of Congenital Lumbar Spine Stenosis. AB - PURPOSE: A low cost, reproducible radiographic method of diagnosing congenital lumbar spinal stenosis (CLSS) is lacking. We hypothesized that the Cobb angle for lumbar lordosis would be smaller in patients with CLSS, based on observations in our spine clinic patient population. Here, we compared lumbar lordosis Cobb angles with the radiographic ratio method in patients with normal spine imaging, degenerative spinal stenosis, and with CLSS. MATERIALS AND METHODS: Orthopedic surgeons categorized patients with low back pain as "Normal," "Degenerative spinal stenosis," and "CLSS" based on clinical presentation and findings on lumbar magnetic resonance imaging. We included 30 patients from each cohort who had undergone lateral lumbar spine radiographs and lumbar magnetic resonance imaging. For each lateral radiograph, 2 measurement methods were used (1) 4-line lumbosacral Cobb angle between L2-S1 and (2) the ratio of the anteroposterior vertebral body diameter and spinal canal anteroposterior diameter at the L3 level. We performed logistic regression analyses of CLSS prediction by Cobb angle vs the ratio method in all three cohorts. Covariates included age, gender, and body mass index. RESULTS: The radiographic Cobb angles were smaller in CLSS patients when compared to the degenerative disease and normal cohorts: a smaller radiographic Cobb angle showed higher odds ratio (OR) of predicting CLSS diagnosis compared to the radiographic ratio when compared with degenerative disease (OR = 0.28; 95% CI: 0.11-0.78, P = 0.01) and when compared with the normal cohort (OR = 0.46; 95% CI: 0.24-0.92, P = 0.03). Radiographic ratio measurements showed no difference between the three cohorts (P = 0.12). CLSS was associated with male gender (P = 0.04), younger age (P = 0.01), and higher body mass index (P = 0.01). CONCLUSION: The radiographic Cobb angle method for lumbar lordosis may be useful for raising the possibility of CLSS as the diagnosis. PMID- 29422330 TI - Enhancement of cell growth and phycocyanin production in Arthrospira (Spirulina) platensis by metabolic stress and nitrate fed-batch. AB - Arthrospira (Spirulina) platensis is known to have high-quality proteins content and phycocyanin as one of the major pigment constituents of the cells, and the most challenging problem associated with phycocyanin production in Arthrospira is to optimize its intracellular accumulation. The present study evaluated the metabolic stress conditions (by nutrient enrichment) of Arthrospira platensis FACHB-314 for boosting biomass growth and high content phycocyanin accumulation. Experimental results showed that 5 mM sodium glutamate and 7.5 mM succinic acid could enhance biomass yield as well as phycocyanin accumulation compared with that of the control groups. The present study demonstrates that the biomass growth and phycocyanin accumulation were significantly enhanced in fed-batch cultivation of Arthrospira platensis by applying the substrates as metabolic stress agents combined with nitrate feeding strategy. cobA/hemD, hemG and ho genes presented the over-expression level with adding sodium glutamate and succinic acid in cultures, respectively, compared to the control groups. PMID- 29422331 TI - Evaluation of astatine-211-labeled octreotide as a potential radiotherapeutic agent for NSCLC treatment. AB - Octreotide is a somatostatin (SST) analogue currently used in the treatment of neuroendocrine tumors (NETs) with high binding affinity for the somatostatin receptor-2 (SSTR2) that is also overexpressed in non-small cell lung cancer cell (NSCLC). Alpha-particle-emitting astatine-211 (211At) is a promising radionuclide with appropriate physical and chemical properties for use in targeted anticancer therapies. To obtain an additional pharmacological agent for the treatment of NSCLC, we present the first investigation of the possible use of 211At-labeled octreotide as a potential alpha-radionuclide therapeutic agent for NSCLC treatment. 211At-SPC-octreotide exhibited observable higher uptake in lung, spleen, stomach and intestines than in other tissues. Through histological examination, 211At-SPC-octreotide demonstrated much more lethal effect than control groups (PBS, octreotide and free 211At). These promising preclinical results suggested that 211At labeled octreotide deserved to be further developed as a new anticancer agent for NSCLC. PMID- 29422332 TI - Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGFbetaRI). AB - The TGFbeta-TGFbetaR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFbetaR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFbetaRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFbeta-stimulated phospho-SMAD was observed in primary human T cells. PMID- 29422333 TI - Stress-induced crystal transition of poly(butylene succinate) studied by terahertz and low-frequency Raman spectroscopy and quantum chemical calculation. AB - We measured terahertz (THz) and low-frequency Raman spectra of Poly (butylene succinate) (PBS) which shows the crystal transition from alpha to beta by stretching. For the assignment of the absorption peaks in the low-frequency region, we performed quantum chemical calculations with Cartesian-coordinate tensor transfer (CCT) method. Four major peaks appeared in the THz spectra of PBS at around 58, 76, 90, and 100cm-1, and in the low-frequency Raman spectra a peak was observed at 88cm-1. The THz peak at 100cm-1 and the Raman peak at 88cm-1 show a shift to a lower wavenumber region with increasing temperature. The quantum chemical calculation of beta crystal form reveals the new peak appears above 100cm-1. It was found that two kinds of peaks overlapped at around 100cm-1 in the THz spectra of PBS. One of them can be assigned to a weak hydrogen bond between the C=O and CH2 groups in the intermolecular chains, which is perpendicular to the molecular chain of the alpha crystal form. Another one showed a parallel polarization which can be assigned to the intramolecular interaction between O (ether) and H-C groups in the beta crystal form. The position of the peak at around 100cm-1 in the perpendicular polarization changed to a lower wavenumber region with stretching, because of the weakening of the intermolecular hydrogen bonding by increasing the interatomic distances. On the other hand, that of the parallel polarization shifts to a higher wavenumber region because of the shortening of the interatomic distance from alpha to beta crystal form (the strength of the intramolecular hydrogen bonding became stronger) by stretching. PMID- 29422334 TI - One lung ventilation in a cat via tracheostomy for tracheal mass resection. PMID- 29422335 TI - Comparison of three continuous positive airway pressure (CPAP) interfaces in healthy Beagle dogs during medetomidine-propofol constant rate infusions. AB - OBJECTIVE: To compare the efficacy of three continuous positive airway pressure (CPAP) interfaces in dogs on gas exchange, lung volumes, amount of leak during CPAP and rebreathing in case of equipment failure or disconnection. STUDY DESIGN: Randomized, prospective, crossover, experimental trial. ANIMALS: Ten purpose-bred Beagle dogs. METHODS: Dogs were in dorsal recumbency during medetomidine-propofol constant rate infusions, breathing room air. Three interfaces were tested in each dog in a consecutive random order: custom-made mask (M), conical face mask (FM) and helmet (H). End-expiratory lung impedance (EELI) measured by electrical impedance tomography was assessed with no interface (baseline), with the interface only (No-CPAP for 3 minutes) and at 15 minutes of 7 cmH2O CPAP (CPAP delivery). PaO2 was assessed at No-CPAP and CPAP-delivery, partial pressure of inspired carbon dioxide (PICO2; rebreathing assessment) at No-CPAP and the interface leak (DeltaPleak) at CPAP-delivery. Mixed-effects linear regression models were used for statistical analysis (p<0.05). RESULTS: During CPAP delivery, all interfaces increased EELI by 7% (p<0.001). Higher DeltaPleak was observed with M and H (9 cmH2O) in comparison with FM (1 cmH2O) (p<0.001). At No CPAP, less rebreathing occurred with M (0.5 kPa, 4 mmHg) than with FM (1.8 kPa, 14 mmHg) and with H (1.4 kPa, 11 mmHg), but also lower PaO2 was measured with M (9.3 kPa, 70 mmHg) than with H (11.9 kPa, 90 mmHg) and FM (10.8 kPa, 81 mmHg). CONCLUSIONS AND CLINICAL RELEVANCE: All three interfaces can be used to provide adequate CPAP in dogs. The leak during CPAP-delivery and the risk of rebreathing and hypoxaemia, when CPAP is not maintained, can be significant. Therefore, animals should always be supervised during administration of CPAP with any of the three interfaces. The performance of the custom-made M was not superior to the other interfaces. PMID- 29422337 TI - Depressed and non-depressed mothers' touching during social interactions with their infants. AB - Touch is a critical channel of communication used by mothers to communicate and interact with their infants and to contribute to their infants' socio-emotional development. The present study examined maternal touching in 41 mothers with and without depressive symptomatology. Mothers and their 4-month-old infants participated in the Still-Face (maternal emotional unavailability) and Separation (maternal physical unavailability) procedures. Maternal touching behaviours were video-recorded and coded using the Caregiver Infant Touch Scale (CITS). Results indicated that mothers with higher levels of depressive symptoms engaged in less touching following the perturbation period in the Still-Face procedure, whereas mothers with lower levels of depressive symptoms maintained stable levels of touching across both interaction periods. Mothers with higher levels of depressive symptoms displayed less playful/stimulating types of touching. Taken together, these results underscore the importance of touch and suggest key differences in touching behaviour between dyads with maternal depressive symptomatology and those without. PMID- 29422336 TI - Assessment of macrofilaricidal activity of leaf extracts of Terminalia sp. against bovine filarial parasite Setaria cervi. AB - Antifilarial potential of three medicinal plants namely, Terminalia bellerica, Terminalia chebula and Terminalia catappa was explored using Setaria cervi, a bovine filarial parasite at concentrations of 2.5, 5 and 10mg/ml. Amongst all the extracts, methanol extract of T. bellerica showed highest macrofilaricidal activity i.e. 84.63+/-1.11 at 10mg/ml in MTT reduction assay with IC50 value of 2.7mg/ml. which was better than the standard DEC i.e. 79.22+/-3.1% at 10mg/ml with IC50 value 2.84mg/ml. Other plant extracts showed mild in vitro macrofilaricidal activity. T. bellerica methanol extract exhibited significant GST activity of 18.86+/-0.21 and 12.83+/-0.03MUM/ml/min at 5 and 10mg/ml with percentage inhibition value of 73.96% and 82.29% respectively. DEC showed GST activity value of 40.03+/-4.14 and 21.48+/-6.44MUM/ml/min with percentage inhibition value of 21.76% and 58.01% at 5 and 10mg/ml respectively. Thus, methanol extract of leaves of T. bellerica exhibited highly significant antifilarial potential and needs detailed analysis. PMID- 29422339 TI - Pulmonary Venous Occlusion as a Complication of Ablation Therapy for Atrial Fibrillation. PMID- 29422338 TI - Linear alpha-(1 -> 6)-d-glucan from Bifidobacterium bifidum BIM V-733D is low molecular mass biopolymer with unique immunochemical properties. AB - Role of microorganisms in induction of/protection from autoimmune diseases is proven though molecular mechanisms and bacterial/viral/yeast biopolymers responsible for these effects are in the research stage. Autoantobodies (AAbs) to thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg) as well as AAbs to transglutaminase 2 (anti-TG2) and antibodies to gliadins (anti-gliadins) are serological markers of autoimmune thyroid disease and celiac disease, respectively, and players in pathogenesis of these autoimmune diseases. In current study, biopolymer of Bifidobacterium bifidum BIM V-733D that interacts selectively with anti-gliadins (Bb-Ganti-gliadins) was isolated by affinity chromatography with anti-gliadins, purified by size exclusion chromatography on TSK 40 gel and identified by NMR as linear alpha-(1 -> 6)-d-glucan with molecular mass about 5000 Da. It was proven that compounds Bb-Ganti-gliadins and Bb-Ganti TPO/Bb-Ganti-Tg isolated early from the same strain [Kiseleva, E. P. et al., Benef Microbes.2013, 4, 375 -391] are the same substance designated GBb. Its unique immunochemical property is the ability to interact selectively with anti TPO, anti-Tg, anti-TG2 and anti-gliadins in presence of no less than 10-fold excess of total immunoglobulins of class G (tIgG), as it was proven by ELISA. Synthesis of GBb-bovine serum albumin (GBb-BSA) conjugate is an example of increasing the reliability and reproducibility of ELISA results by mediated immobilization of a polysaccharide covalently attached to a well-adsorbed protein. Taking into account that there are population of bispecific anti gliadins (anti-gliadins and anti-TG2 simultaneously) we regard our data as first argument in favor of hypothesis that GBb differentiates between human AAbs per se and other human Ig (e.g. antibodies to antigens of infectious agents) due to its binding with a yet unidentified site which is present in the molecules of all AAbs (independently on their specificity) and absent in other human Igs. PMID- 29422340 TI - Diagnosing Sleep Apnea-Hypopnea Syndrome in Children: Past, Present, and Future. PMID- 29422341 TI - Non-Invasive Mechanical Ventilation in Pneumonia Patients Without Chronic Obstructive Pulmonary Disease. PMID- 29422342 TI - Augmentation Therapy Nowadays: Con. PMID- 29422343 TI - Lung Cancer Unrelated to Smoking. PMID- 29422344 TI - Treatment of Obstructive Sleep Apnea Syndrome in Children: More Options, More Confusion. PMID- 29422345 TI - An analysis of the association between statin use and risk of endometrial and ovarian cancers in the Women's Health Initiative. AB - BACKGROUND: Statins have anti proliferative activity in vitro against endometrial and ovarian cancer and can affect levels of reproductive hormones. We analyzed data from the Women's Health Initiative (WHI) to assess whether statins are associated with risk of endometrial and ovarian cancer. METHODS: The WHI study included 161,808 postmenopausal women in which incident cases of endometrial (n = 1377) and ovarian cancer (n = 763) were identified over an average of 10.8 (SD + 3.3) years. Information on statin use and risk factors was collected at baseline and follow-up. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of statin use and risk of endometrial and ovarian cancer. All statistical tests were two sided. RESULTS: Statins were used at baseline by 7.5% women and by up to 25% at year nine. The multivariable adjusted HR for risk of endometrial cancer for baseline statin use was 0.74, 95% C.I. 0.59-0.94 and for ovarian cancer was 1.15, 95% C.I. 0.89-1.50. In time-dependent models, statins were not associated with endometrial cancer (HR 0.91, 95% C.I. 0.76-1.08) however there was an increased risk of ovarian cancer (HR 1.30, 95% CI 1.04-1.62), largely attributed to the effect of the hydrophilic statin, pravastatin (1.89, 95% CI 1.24-2.88). CONCLUSIONS: There was a reduction in risk of endometrial cancer among statin users at baseline but not in time-dependent models. Pravastatin use was associated with an increased risk of ovarian cancer. Analyses of larger numbers of cases are needed to evaluate these findings. PMID- 29422346 TI - Bone loss in women with BRCA1 and BRCA2 mutations. AB - OBJECTIVE: Estimate the prevalence and identify risk factors for bone loss in women with BRCA mutations. METHODS: Women, age 40 and older, with BRCA mutations identified from the Breast Cancer Surveillance database at Kaiser Permanente Northern California were invited to participate and undergo a dual-energy x-ray absorptiometry scan to assess for bone loss (osteopenia or osteoporosis). Multivariable logistic regression analysis was performed to assess clinical factors associated with bone loss. RESULTS: Of the 238 women in the final cohort, 20 women had intact ovaries (median age 54.5years) and 218 had undergone risk reducing salpingo-oophorectomy (RRSO) (median age 57). The prevalence of bone loss was 55% in the no RRSO group and 72.5% in the RRSO group (P=0.10). In multivariable analysis, only higher body mass index (OR 0.6 per 5kg/m2, 95% CI: 0.4-0.7) and nonwhite race compared to white (OR 0.5, 95% CI: 0.2-0.9) were protective for bone loss while older age (OR 1.5 per 10years, 95% CI: 1.1-2.1) and selective estrogen receptor modulator use (3.1, 95% CI: 1.2-10.1) were associated with increased odds of bone loss. Among women with RRSO, bone loss was more frequent in women who had postmenopausal (n=106) compared to women who had premenopausal RRSO (n=112), (82.1% and 63.4% respectively, P=0.002). In multivariable analysis, only BMI was protective of bone loss (OR 0.5, 95%, CI: 0.4-0.7) but neither age nor menopausal status at RRSO were associated with bone loss. CONCLUSION: Bone loss is common in women with BRCA mutations who undergo RRSO. PMID- 29422347 TI - Why a Planetary Boundary, If It Is Not Planetary, and the Boundary Is Undefined? A Reply to Rockstrom et al. PMID- 29422349 TI - Planetary Boundaries: Separating Fact from Fiction. A Response to Montoya et al. PMID- 29422348 TI - Microplastics: No Small Problem for Filter-Feeding Megafauna. AB - Microplastic pollution can impact filter-feeding marine megafauna, namely mobulid rays, filter-feeding sharks, and baleen whales. Emerging research on these flagship species highlights potential exposure to microplastic contamination and plastic-associated toxins. Research and its wide communication are needed to understand the magnitude of the issue and improve marine stewardship. PMID- 29422350 TI - The Ideal Total Hip Replacement Bearing Surface in the Young Patient: A Prospective Randomized Trial Comparing Alumina Ceramic-On-Ceramic With Ceramic-On Conventional Polyethylene: 15-Year Follow-Up. AB - BACKGROUND: The optimum bearing surface for total hip arthroplasty remains debatable. We have previously published our outcome at 10 years and this represents the 15-year follow-up. METHODS: A total of 58 hips (in 57 patients with a mean age of 42 years) were randomized to receive either ceramic-on-ceramic (CoC) or ceramic-on-polyethylene (CoP) total hip arthroplasty. We prospectively followed for survivorship, functional outcomes (using the Harris Hip Score and the St Michael's Hip Score [SMH]), and radiological outcomes. RESULTS: At a minimum of 15 years, 3 patients had died, but not been revised. Seven were lost to follow-up. Five cases from the CoP group were revised (4 for polyethylene wear and osteolysis). Four from the CoC were revised; one each for head fracture, instability, infection, and trunnionosis. Both groups showed statistically significant improvements in Harris Hip Score scores and SMH functional scores, with no difference between the 2 bearings. For the CoP group, there was an improvement from 15.6 to 21.5 in the SMH and from 48.8 to 88.7 (P > .05); and for CoC, this improvement was 15.8 to 23.5 and 50.3 to 94.6 (P > .05), respectively. Mean wear rate of the polyethylene was 0.092 mm/y and for the CoC was 0.018 mm/y. Two patients in the CoC group had evidence of acetabular osteolysis vs 3 in the CoP. Six patients had femoral osteolysis in the CoC group and 12 in the CoP group. CONCLUSION: Survivorship and function of the 2 bearing groups remains comparable; while the polyethylene wear and osteolysis may represent issues in the future. PMID- 29422351 TI - Comparison of the identification results of Candida species obtained by BD PhoenixTM and Maldi-TOF (Bruker Microflex LT Biotyper 3.1). AB - In patients with invasive fungal infections, the accurate and rapid identification of the genus Candida is of utmost importance since antimycotic sensitivity is closely related to the species. The aim of the present study was to compare the identification results of species of the genus Candida obtained by BD PhoenixTM (Becton Dickinson [BD]) and Maldi-TOF MS (Bruker Microflex LT Biotyper 3.1). A total of 192 isolates from the strain collection belonging to the Mycology Network of the Autonomous City of Buenos Aires, Argentina, were analyzed. The observed concordance was 95%. Only 10 strains (5%) were not correctly identified by the BD PhoenixTM system. The average identification time with the Yeast ID panels was 8h 22min. The BD PhoenixTM system proved to be a simple, reliable and effective method for identifying the main species of the genus Candida. PMID- 29422352 TI - Clinical Frailty as an Outcome Predictor After Transcatheter Aortic Valve Implantation. AB - Society of Thoracic Surgeons (STS) score and frailty index are calculated routinely as part of transcatheter aortic valve implantation (TAVI) assessment to determine procedure risk. We aim to evaluate the incremental improvement of STS risk score using frailty status in predicting short- and long-term outcome after TAVI. Study population included 544 consecutive TAVI patients who completed full frailty assessment and STS score calculation before the procedure. Frailty is defined by the presence of any 3 of the following 5 criteria: algorithm-defined grip strength and 15-foot walking tests, body mass index < 20 kg/m2, Katz activity of daily living <= 4/6, serum albumin < 3.5 g/dl. Multivariable logistic analysis of 30-day and 1-year mortality was performed using a logistic regression model that comprised the STS risk score model as a single variable. Based on frailty definition, 242 patients were frail and 302 patients were not. STS score was higher in the frail group than in the nonfrail group. Compared with STS risk score alone, frailty status was a significant predictor of 1-year mortality after TAVI procedure (odds ratio 1.0, 95% confidence interval [CI] 1.0 to 1.1, p = 0.029 vs 2.75, 95% CI 1.55 to 4.87, p <0.001, respectively). Although the c statistic of the 1-year STS risk prediction model only changed from 0.62 to 0.66 (p = 0.08), the net reclassification improvement increased significantly to 52.8% after adding frailty to the prediction model (95% CI 0.28 to 0.77, p <0.0001). Frailty status is associated with higher mortality in TAVI cohort and incrementally improves the well-validated STS risk prediction model. Frailty assessment should continue to be part of the preprocedural assessment to further improve patient outcomes after TAVI. PMID- 29422353 TI - Editorial: peptide receptor radionuclide therapy as neoadjuvant therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms. PMID- 29422354 TI - Re: Diagnostic performance of contrast-enhanced CT-scan in sinusoidal obstruction syndrome induced by chemotherapy of colorectal liver metastases: Radio pathological correlation. PMID- 29422355 TI - Infantile Tremor Syndrome: Response to B12 Therapy. PMID- 29422356 TI - Will 68Ga PSMA-radioligands be the only choice for nuclear medicine in prostate cancer in the near future? A clinical update. AB - Prostate Cancer (PCa) represents the most common malignant tumor in men but according to the European Association of Urology (EAU) guidelines, a mass screening for PCa diagnosis should not be performed due to over-diagnosis and over-treatment related problems. An early clinical diagnosis is possible, mainly based on digital rectal examination and Prostatic Specific Agent (PSA) testing. However, the only mandatory test to define the presence of PCa is ultrasound guided-biopsy, obtained on multiple samples, which has also a high prognostic value. In this context, diagnostic imaging plays an important role as confirmed by EAU that in a 2016 update of their guidelines on PCa stated the importance of Positron Emission Tomography (PET) with 11C- or 18F-choline combined with computed tomography (CT) to identify local relapse, lymph node involvement and metastatic spread at all stages. Consequently, in 2017, the European Association of Nuclear Medicine (EANM) together with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) published new guidelines for 68Ga-Prostate Specific Membrane Antigen (PSMA) PET/CT to help physicians in the recommendation, execution and interpretation of PET/CT scans in patients with PCa. Thus, the aim of this 'evidence paper' is to define the current diagnostic algorithm in PCa in order to increase the general level of confidence in approaching such a crucial topic. PMID- 29422357 TI - Outpatient Holmium laser fulguration: A safe procedure for treatment of recurrence of nonmuscle invasive bladder cancer. AB - BACKGROUND AND OBJECTIVE: Nonmuscle invasive bladder cancer has a high recurrence rate and a low progression rate. The aim of this study was to assess the effectiveness, safety and feasibility of Holmium laser fulguration in an outpatient regimen for selected tumours. MATERIAL AND METHOD: A prospective, longitudinal cohort study was conducted between January 2009 and December 2016. Seventy-nine Holmium laser fulguration procedures with subsequent instillation of mitomycin C were performed in an outpatient regimen on 59 patients with a history of low-risk bladder cancer and recurrence of small papillary tumours. We performed a descriptive data analysis and analysed the relapse-free time using Kaplan-Meier curves. RESULTS: All procedures were completed in one day, and only one patient required subsequent hospitalisation due to haematuria. Some 87.2% of the patients presented pain with a visual analogue score <=3. Recurrence occurred after 49.4% of the procedures (27.3% at 12 months). The median follow-up time was 17 months (range, 2-65). The onset of recurrence was significantly earlier after the second fulguration than after the first (median, 10 months vs. 56 months). CONCLUSIONS: Holmium laser fulguration and subsequent mitomycin C instillation in an outpatient regimen is a safe and feasible alternative to transurethral resection of bladder tumours in selected patients. Transurethral resection of the bladder tumour is recommended for patients with recurrence after fulguration, given the possibly higher risk of progression in these patients. PMID- 29422358 TI - Metformin in women at high risk of gestational diabetes mellitus. PMID- 29422359 TI - Association of type 2 diabetes mellitus with self-reported knee pain and clinical knee osteoarthritis: The Maastricht Study. PMID- 29422360 TI - EpApp: Development and evaluation of a smartphone/tablet app for adolescents with epilepsy. AB - The study aimed to comprehensively evaluate a mobile application (EpApp), designed with stakeholder input, to educate and facilitate management of adolescents with epilepsy. A prospective cohort of adolescents with epilepsy (13 19 years) and their parent/carer participated between June 2015 and December 2016. Primary outcome measure was knowledge acquisition. Secondary outcomes were psychosocial variables (attitude towards illness and seizure self-efficacy) and clinical parameters (medication adherence, seizure burden). Functionality, design, content and app utility were appraised via survey and open-ended questions. 51 adolescents completed baseline surveys (mean age 14.49 years), 36 follow-up surveys. Both self and general epilepsy knowledge increased following intervention (p <= 0.005). Significantly fewer medication reminders were required during intervention (M = 2.93, p = .002) and follow-up (M = 3.54, p = .030) compared to baseline (M = 6.64). Measures of app design, content, functionality and utility were very favourable. There was no significant improvement in seizure burden, or psychosocial parameters. Educational page-visits reflected interests and concerns. This study demonstrates that EpApp increases knowledge and is engaging. The app is available free, internationally via Android/Apple platforms. PMID- 29422361 TI - Primary diffuse leptomeningeal melanomatosis: Description and recommendations. AB - Primary melanocytic disease of the central nervous system is a rarely encountered condition currently without consensus on treatment and lacking major guidelines for management. Understanding the nature of the disease and differentiating primary melanocytic disease from the much more commonly encountered secondary (metastatic) melanoma is important in identifying the condition and pursuing appropriate treatment. PMID- 29422362 TI - Multiple cranial neuropathies as a presentation of spontaneous internal carotid artery dissection: A case report and literature review. AB - Cervical artery dissection is an underrecognized cause of lower cranial neuropathies and diagnosis can remain elusive if not properly investigated. We present a case of an internal carotid artery dissection that was initially missed in a 48-year-old man who presented with subacute-onset of dysarthria, dysphagia, and unilateral tongue weakness. Knowledge of the most common presenting symptoms, relevant neuroanatomy, and neuroimaging techniques is essential to avoid misdiagnosis. Pseudoaneurysm formation from subadventitial carotid artery dissection may result in compressive neuropathies of cranial nerves IX, X, XI, and XII without associated cerebral ischemia. The absence of intraluminal narrowing on CT or MR angiography should not dissuade the clinician; T1-weighted axial cervical MRI with fat-saturation provides the highest sensitivity and specificity to identify these lesions. PMID- 29422363 TI - Histopathology of 3 Tesla MRI-negative extratemporal focal epilepsies. AB - BACKGROUND: Information about the histopathology in 3 Tesla MRI negative extratemporal epilepsies is relatively limited. Most common histopathological findings in earlier (mixed 1.5 or 3 Tesla) MRI-negative series are focal cortical dysplasia (FCD), gliosis or normal findings. These series mostly use the older Palmini criteria for classification and grading. We focus on histopathology of only 3 Tesla MRI-negative extratemporal epilepsies according to the current ILAE criteria and investigate potential correlation to seizure outcome 1 year postoperatively. MATERIALS AND METHODS: Sixteen substrates of 3 Tesla MRI negative extratemporal epilepsies were examined in two steps. Standard stains and immunohistochemical reactions and Palmini criteria were used prospectively during the initial examination. Retrospectively, all specimens were re-examined and re evaluated. Phospho-6 and calretinin stains and ILAE criteria were used during the review examination. RESULTS: Initial examination revealed 5 FCDs Palmini 1b, two 1a, five 2a and 4 cases of gliosis. The review examination according to ILAE criteria revealed 6 FCDs type IIa, 2 FCDs Ib and 7 mild malformations of cortical development (mMCD) type II. None of our cases was labelled as isolated gliosis after the review examination. The incidence of FCD, after the review examination per ILAE criteria, was reduced to 56%; versus 75% per Palmini. CONCLUSIONS: In "true" 3 Tesla MRI-negative extratemporal epilepsies, incidence of FCD may be lower than in earlier MRI-negative series that included weaker MRI-field. Furthermore, consistent review examination may confirm the diagnosis of mMCD type II as substrate in cases diagnosed as "gliosis" or "normal" in the past. PMID- 29422364 TI - Glioblastoma arising within sites of encephalomalacia from cerebrovascular insult: two cases and a review of the literature. AB - Glioblastoma is the most common primary parenchymal brain malignancy, with median survival of less than one year. While there are likely multiple predisposing genetic and environmental factors in glioblastoma formation, chronic inflammation resulting from non-traumatic vascular brain injury is one proposed risk factor for oncogenesis. Here, we report two instances of glioblastoma arising within areas of encephalomalacia caused by remote vascular insults (one following aneurysmal subarachnoid hemorrhage and one following ischemic infarction), review the literature associating glioblastoma with prior brain injury, and discuss potential mechanisms for malignant transformation in injured brain tissue. PMID- 29422365 TI - In-hospital medical complications after non-operative and operative treatment of thoracolumbar fractures in patients over 75 years of age. AB - Management of spine fractures among the elderly is complicated by preexisting comorbidities and increased risk of osseous nonunion. Whether operative treatment is superior for the management of thoracolumbar fractures in the aged is unknown. The purpose of this study was to investigate the rates of in-hospital medical complications after non-operative and operative treatment of thoracolumbar fractures in elderly patients. The Nationwide Inpatient Sample database from 2002 to 2011 was used to identify patients over 75 years of age with a principal discharge diagnosis of thoracolumbar fracture without spinal cord injury. Three treatment groups were compared: non-operative treatment, operative treatment, and minimally-invasive vertebroplasty/kyphoplasty (VP/KP). A total of 59,565 patients were identified; 46,962 treated non-operatively, 1,487 treated operatively, and 11,116 treated with VP/KP. Operative patients had the longest length of hospital stay (P < 0.001) and the highest injury severity scores (P < 0.001). The percentage of patients who developed at least one complication was highest in the operative group (16.3%), versus 8.7% in the non-operative and 8.1% in the VP/KP group (P < 0.001). Even after controlling for potential confounders such as injury severity score, surgical patients had significantly higher odds of complication occurrence (P < 0.001). Adjusted charges were highest for operative patients ($123,777 +/- 135,997 vs. $27,116 +/- 32,694 [non-operative] and $42,326 +/- 31,984 [VP/KP]). Operative treatment for elderly patients has higher complication rates that need to be considered during preoperative patient counseling. Future research is necessary to elucidate the comparative rates of long-term complications and functional status outcomes for thoracolumbar fracture treatment among elderly patients. PMID- 29422366 TI - Ossified extradural en-plaque meningioma of the cervical spine. AB - A 57-year-old woman sustained gradually progressive sensorimotor disturbance in the left upper extremity for one year. Neurological examination found a diminished sensation below the left C7 dermatome and reduced strength in the left interosseous muscles. Computed tomography of the cervical spine revealed a high density mass at C7, in the left dorsal part of the spinal canal. Magnetic resonance imaging found an enhancing, en-plaque tumor at C6-T1, involving a non enhancing part, and considerable compression of the spinal cord. The patient underwent tumor resection through hemilaminectomy of C5-C7. The tumor was located epidurally, highly fibrous including bony-hard parts, and severely adhered to the dura mater that necessitated drilling for debulking. A subtotal resection was achieved and histological diagnosis was a fibrous meningioma with metaplastic ossification. Ossification may be a pathognomonic appearance of spinal extradural meningiomas that makes resection maneuvers difficult. PMID- 29422367 TI - CSF Tau supplements 14-3-3 protein detection for sporadic Creutzfeldt-Jakob disease diagnosis while transitioning to next generation diagnostics. AB - The pre-mortem clinical diagnosis of Creutzfeldt-Jakob disease (CJD) is supported by biomarkers, especially cerebrospinal fluid (CSF) 14-3-3 and total tau (Tau) protein levels. These CSF biomarkers have proven the most useful prior to transitioning to powerful next generation diagnostics employing protein amplification techniques such as the real time quaking-induced conversion (RT QuIC) assay. To enhance national diagnostic capacity while transitioning to RT QuIC assays an optimized CSF Tau cutoff was determined and shown to usefully supplement 14-3-3 protein detection. PMID- 29422368 TI - Long-term outcomes of Low-profile Visualized Intraluminal Support device usage in stent-assisted coiling of intracranial aneurysm. AB - Stent-assisted coil embolization technique have broadened indications for endovascular therapy of aneurysms. The Low-profile Visualized Intraluminal Support device (LVIS) is a self-expanding, nitinol single-braid and closed-cell device introduced fairly recently. We aim to evaluate long-term outcome of LVIS device in stent-assisted coiling of intracranial aneurysms. Between October 2012 and February 2013, a total of 55 patients with unruptured wide-necked intracranial aneurysms underwent coil embolization procedures involving LVIS devices. Clinical and anatomic parameters assessed included extent of aneurysmal occlusion, stent deployment status, and delayed complications. Anatomic outcomes were evaluated via DSA, MRA, and plain radiography (PR). Three patients were lost to follow-up after 6 months, but in 37 of 52 qualifying patients (mean follow-up, 27.1 months; range, 12-36 months) post-coiling recanalization was evaluable by DSA or MRA. Only one patient (2.7%) experienced minor recanalization, all others (97.3%) showing complete occlusion. Coil configurations were consistently stable by PR in 15 other patients (mean follow-up, 34.1 months; range, 30-39 months). No migration or altered expansion of stents was evident in 30 patients with available DSA and/or PR images. Three patients (5.8%) suffered delayed cerebral ischemia without neurologic sequelae, all as transient ischemic attacks and all related to withdrawal or change of anti-platelet medications. LVIS device usage in stent-assisted coil embolization of intracranial aneurysms provides excellent long-term results in terms of safety, efficacy and durability. PMID- 29422370 TI - You Can Trust a Crystal Ball About as Far as You Can Throw It. PMID- 29422369 TI - The National Vaccine Advisory Committee at 30: Impact and opportunity. AB - Thirty years after passage of legislation that created the National Vaccine Advisory Committee (NVAC) "to achieve optimal prevention of human infectious diseases through immunization and to achieve optimal prevention against adverse reactions to vaccines," this review reflects NVAC's role and impact on the U.S. vaccine and immunization enterprise as an external advisor to the Department of Health and Human Services. We reviewed the history of NVAC in the context of the principles of its establishment, with a focus on its reports and recommendations. We performed a systematic literature review to identify NVAC reports published in widely-accessible public health journals, and we reviewed the available archives to identify other reports and resolutions approved by the committee not published in journals. We characterized key issues considered by NVAC according to the five goals of the 2010 National Vaccine Plan. The predominance of NVAC activities to date related to the implementation of immunization across the lifespan and the many aspects of the system needed to foster the goal of full immunization. Reflecting on the impacts of NVAC to date, this review identified 30 NVAC approved reports published in journals, 22 stand-alone resolutions, and 26 unique unpublished reports. The development of new and improved vaccines continues to represent a significant priority for NVAC, and we identified several challenges related to future vaccine innovation. Given the many factors that impact on policy changes in the vaccine and immunization enterprise, we encountered challenges associated with demonstrating attribution of specific policy changes to NVAC recommendations. Although difficult to quantify, this review suggests that NVAC played an important role in the improvements in the U.S. immunization enterprise over the past 30 years and that NVAC can and will continue to play an important role supporting U.S. immunization going forward. PMID- 29422371 TI - Comparing the Exposure-Response Relationships of Physiological and Traditional Vocal Warm-ups on Aerodynamic and Acoustic Parameters in Untrained Singers. AB - OBJECTIVES: The aim of this study was to quantify the effects of traditional and physiological warm-up exercises and to determine the optimal duration of these methods using acoustic and aerodynamic metrics. METHODS: Twenty-six subjects were recruited to participate in both straw phonation exercises (physiological vocal warm-up) and traditional singing exercises (traditional vocal warm-up) for 20 minutes each, 24 hours apart. Phonation threshold pressure (PTP), fundamental frequency, jitter, shimmer, and noise-to-harmonics ratio were measured before the intervention (m0), as well as after 5 minutes (m5), 10 minutes (m10), 15 minutes (m15), and 20 minutes (m20) of intervention. RESULTS: PTP decreased significantly after straw phonation and reached a minimum value at 10 minutes (P < 0.001) and remained stable in traditional singing exercises. There were significant differences in fundamental frequency and shimmer from m0 to m15 and m20 in the traditional singing group (P = 0.001, P = 0.001, P = 0.001, and P = 0.002, respectively). No significant changes in acoustic parameters were observed after straw phonation. CONCLUSIONS: Both straw phonation exercises and traditional singing exercises are effective for voice warm-up. Straw phonation improves the subjects' fatigue resistance and vocal economy, resulting in a reduced PTP, whereas traditional singing exercises focus on technical singing skills, leading to an improvement of acoustic variables. PMID- 29422372 TI - Promoting health-enhancing physical activity in Europe: Current state of surveillance, policy development and implementation. AB - This study aims to present information on the surveillance, policy developments, and implementation of physical activity policies in the 28 European Union (EU) countries. Data was collected on the implementation of the EU Recommendation on health-enhancing physical activity (HEPA) across sectors. In line with the monitoring framework proposed in the Recommendation, a questionnaire was designed to capture information on 23 physical activity indicators. Of the 27 EU countries that responded to the survey, 22 have implemented actions on more than 10 indicators, four countries have implemented more than 20 indicators, and one country has fully addressed and implemented all of the 23 indicators of the monitoring framework. The data collected under this HEPA monitoring framework provided, for the first time, an overview of the implementation of HEPA-related policies and actions at the national level throughout the EU. Areas that need more investment are the "Senior Citizens" sector followed by the "Work Environment", and the "Environment, Urban Planning, and Public Safety" sectors. This information also enabled comparison of the state of play of HEPA policy implementation between EU Member States and facilitated the exchange of good practices. PMID- 29422373 TI - International Commission for Mountain Emergency Medicine Consensus Guidelines for On-Site Management and Transport of Patients in Canyoning Incidents. AB - Canyoning is a recreational activity that has increased in popularity in the last decade in Europe and North America, resulting in up to 40% of the total search and rescue costs in some geographic locations. The International Commission for Mountain Emergency Medicine convened an expert panel to develop recommendations for on-site management and transport of patients in canyoning incidents. The goal of the current review is to provide guidance to healthcare providers and canyoning rescue professionals about best practices for rescue and medical treatment through the evaluation of the existing best evidence, focusing on the unique combination of remoteness, water exposure, limited on-site patient management options, and technically challenging terrain. Recommendations are graded on the basis of quality of supporting evidence according to the classification scheme of the American College of Chest Physicians. PMID- 29422374 TI - Impact of revascularization procedures on Doppler parameters in patients with atherosclerotic renal artery stenosis. PMID- 29422375 TI - The Internal Medicine and Assessment of Gender Differences in Europe (IMAGINE): The new European Federation of Internal Medicine initiative on sex and gender medicine. PMID- 29422376 TI - Impaired renal function is associated with adverse outcomes in patients with chest pain discharged from internal medicine wards. AB - BACKGROUND: Assessment of chest pain is one of the most common reasons for hospital admissions in internal medicine wards. However, little is known regarding predictors for poor prognosis in patients discharged from internal medicine wards after acute coronary syndrome (ACS) rule-out. OBJECTIVE: To assess the association of kidney function with mortality and hospital admissions due to ACS in patients with chest pain who were discharged from internal medicine wards following ACS rule-out. METHODS: Included were patients admitted to an internal medicine ward who were subsequently discharged following an ACSrule-out during 2010-2016. The primary endpoint was the composite of all-cause mortality and hospital admission due to ACS at 30-days following hospital discharge. RESULTS: Included in the study were12,337 patients who were divided into 3 groups according to renal function. Considering patients with an eGFR >= 60 ml/min/1.73m2 as the reference group yielded adjusted hazard ratios for the composite of 30-day all-cause mortality and hospital admission for ACS that increased with reduced eGFR (HR = 2, 95%CI = 1.3-3.3, HR = 4.8, 95%CI = 3-7.6, for patients with eGFR of 45 to 59.9 or <45 ml/min/1.73m2, respectively, p < 0.001). Similarly, reduced renal function was associated with increased 1-year all-cause mortality (HR = 1.6, 95%CI = 1.2-2.2, HR = 4.5, 95%CI = 3.4-5.9, for patients with eGFR of 45-59.9 or <45 ml/min/1.73m2, respectively, p < 0.001). CONCLUSION: We found an independent graded association between lower eGFR and the risk of death and ACS among patients with chest pain who were discharged from internal medicine wards following an ACS rule-out. The eGFR may be combined in the risk stratification of patients with chest pain. PMID- 29422377 TI - Icon immunoconjugate treatment results in regression of red lesions in a non human primate (Papio anubis) model of endometriosis. AB - Endometriosis is a common condition in reproductive-aged women characterized by ectopic endometrial lesions of varied appearance, including red, white, blue, black or powder burn coloration, which contribute to chronic pain and infertility. The immunoconjugate molecule (Icon) targets Tissue Factor, a transmembrane receptor for Factor VII/VIIa that is aberrantly expressed in the endothelium supporting ectopic endometrial tissue. Icon has been shown to cause regression of endometriosis in a murine model of disease but prior to this study had not been tested in non-human primates. This study evaluated Icon as a novel treatment for endometriosis in non-human primates (Papio anubis) using an adenoviral vector (AdIcon) delivery system. Female baboons (n = 15) underwent surgical induction of endometriosis. After laparoscopic confirmation of endometriosis lesions 6-weeks post-surgery, the treatment group (n = 7) received weekly intraperitoneal injections of viral particles carrying the sequence for Icon, resulting in expression of the protein, while the control group (n = 8) received no treatment. Icon preferentially reduced the number and volume of red vascularized lesions. Icon may present a novel treatment for endometriosis by degrading red vascularized lesions, likely by targeting tissue factor aberrantly expressed in the lesion vasculature. PMID- 29422379 TI - Relation among Psychopathological Symptoms, Neuropsychological Domains, and Functional Disability in Subacute Poststroke Rehabilitation. AB - BACKGROUND: Neuropsychiatric disorders are commonly observed in patients following a stroke. Among 30%-60% of poststroke patients suffer from depression and anxiety (18%-25%). Some authors suggest an association between psychological symptoms and lesions in specific brain areas. In particular, lesions in left frontal cortex and left basal ganglia are frequently associated with poststroke depression and with comorbidity of anxiety and depression, whereas isolated anxiety symptoms are frequently observed after right hemispheric lesions. METHODS: We investigated the relationship between depressive symptoms and anxiety in patients with subacute stroke and lesion side, motor disability, and cognitive impairment. We enrolled 100 patients undergoing a rehabilitative program within 1 3 months after a first-onset stroke. RESULTS: Our patients presented mild to moderate depressive and anxious symptoms after stroke. In the comparison between patients with right and left lesions, during subacute poststroke phase, we did not find a specific link between existence of psychiatric symptoms and lesion side. However, in left lesion, depression correlated with age and alteration in delayed memory and attention, whereas memory deficit influenced anxiety symptoms. On the contrary, in right lesion, depressive symptoms were associated with attention ability, whereas anxiety was related to memory and attention. Depression and anxiety were not related to degree of neurological and functional deficits. CONCLUSIONS: The comorbidity between stroke and psychopathological disorders has been recognized as syndrome and should be diagnosed early and treated in order to improve the quality of life of patients and caregivers, and to improve rehabilitative process. PMID- 29422378 TI - The Basilar Artery on Computed Tomography Angiography Score for Acute Basilar Artery Occlusion Treated with Mechanical Thrombectomy. AB - BACKGROUND: Recently, the Basilar Artery on Computed Tomography Angiography (BATMAN) score predicts clinical outcome of acute basilar artery occlusion (BAO), yet there is no extensive external validation. The purpose of this study was to validate the prognostic value of BATMAN scoring system for the prediction of clinical outcome in patients with acute BAO treated with endovascular mechanical thrombectomy by using cerebral digital subtraction angiography (DSA). METHODS: We analyzed the clinical and angiographic data of consecutive patients with acute BAO from March 2012 to November 2016. The BATMAN scoring system was used to assess the collateral status and thrombus burden. Thrombolysis in Cerebral Infarction (TICI) score 2b-3 was defined as successful recanalization. Receiver operating characteristic (ROC) curve was used to determine the area under the curve (AUC) and the optimum cutoff value. Multivariate regression analysis was used to identify the predictor of clinical outcome. RESULTS: This study included 63 patients with acute BAO who underwent mechanical thrombectomy. Of these patients, 90.5% (57/63) achieved successful recanalization (TICI, 2b-3) and 34.9% (22/63) had a favorable outcome (modified Rankin Scale score 0-2). ROC analysis indicated that the AUC of the BATMAN score was .722 (95% confidence interval [CI], .594-.827), and the optimal cutoff value was 3 (sensitivity = 72.73, specificity = 63.41). In multivariate logistic regression analysis, the BATMAN score higher than 3 was associated with favorable outcome (odds ratio, 5.214; 95% CI, 1.47-18.483; P = .011). CONCLUSIONS: The BATMAN score on DSA seems to predict the functional outcome in patients of acute BAO treated with mechanical thrombectomy. PMID- 29422380 TI - Improvement in Door-to-Needle Time in Patients with Acute Ischemic Stroke via a Simple Stroke Activation Protocol. AB - BACKGROUND: In acute ischemic stroke (AIS), treatment with intravenous tissue type plasminogen activator (IV-tPA) is time-sensitive. All stroke centers make continual efforts to reduce door-to-needle time (DNT) with varying success. We present the impact of modifications to our stroke activation protocol on DNT. METHODS: We included 404 consecutive patients with AIS receiving IV-tPA between January 2014 and December 2016. First changes in stroke activation protocol were made in March 2015 in the form of prenotification by paramedics, direct transfer from ambulance to computed tomography (CT) scanner, and rapid en route neurological assessment by an emergency physician and neurologist. In March 2016, a second amendment was made where a stroke nurse accompanied the patient to expedite various steps in the treatment pathway, including endovascular treatment in eligible cases. RESULTS: Both protocol amendments resulted in improvement in DNT and door-to-CT time from 84 +/- 47 minutes before intervention to 69 +/- 33 minutes after protocol amendment 1 to 59 +/- 37 minutes after protocol amendment 2. In particular, the second amendment (144 patients) showed significant shortening of DNT compared with the 137 patients before (59 +/- 37 minutes versus 69 +/- 33 minutes, P = .020), with a higher percentage achieving the target of 60 minutes (68.1% versus 48.2%, P < .001). This finding was attributed to a reduction in both door-to-CT time and CT-to-needle time. This improvement remained consistent over subsequent months. CONCLUSIONS: The application of a simple systems-based, multidisciplinary stroke activation protocol may help in significant reduction in DNT. Encouraging increased patient ownership by stroke nurses appeared to be a promising approach for timely administration of definitive acute therapies. PMID- 29422381 TI - Spinal Cord Infarction Presenting as a Hemicord Syndrome: Report of 2 Cases. AB - Infarction of the spinal cord is a rare entity in clinical practice. Limited literature exists on spinal cord stroke treatment, and the management is often symptomatic. The anterior spinal cord syndrome is the most common phenomenology, but here we present 2 nontraumatic spinal hemicord infarctions in elderly patients and discuss the clinical and radiological characteristics. PMID- 29422382 TI - The activity of organic anion transporter-3: Role of dexamethasone. AB - Human organic anion transporter-3 (hOAT3) is richly expressed in the kidney, where it plays critical roles in the secretion, from the blood to urine, of clinically important drugs, such as anti-viral therapeutics, anti-cancer drugs, antibiotics, antihypertensives, and anti-inflammatories. In the current study, we examined the role of dexamethasone in hOAT3 transport activity in the kidney HEK293 cells. Cis-inhibition study showed that dexamethasone exhibited a concentration-dependent inhibition of hOAT3-mediated uptake of estrone sulfate, a prototypical substrate for the transporter, with IC50 value of 49.91 MUM. Dixon plot analysis revealed that inhibition by dexamethasone was competitive with a Ki = 47.08 MUM. In contrast to the cis-inhibition effect of dexamethasone, prolonged incubation (6 h) of hOAT3-expressing cells with dexamethasone resulted in an upregulation of hOAT3 expression and transport activity, kinetically revealed as an increase in the maximum transport velocity Vmax without meaningful alteration in substrate-binding affinity Km. Such upregulation was abrogated by GSK650394, a specific inhibitor for serum- and glucocorticoid-inducible kinases (sgk). Dexamethasone also enhanced sgk1 phosphorylation. Our study demonstrated that dexamethasone exhibits dual effects on hOAT3: it is a competitive inhibitor for hOAT3-mediated transport, and interestingly, when entering the cells, it stimulates hOAT3 expression and transport activity through sgk1. PMID- 29422383 TI - Inadequate sleep and muscle strength: Implications for resistance training. AB - OBJECTIVES: Inadequate sleep (e.g., an insufficient duration of sleep per night) can reduce physical performance and has been linked to adverse metabolic health outcomes. Resistance exercise is an effective means to maintain and improve physical capacity and metabolic health, however, the outcomes for populations who may perform resistance exercise during periods of inadequate sleep are unknown. The primary aim of this systematic review was to evaluate the effect of sleep deprivation (i.e. no sleep) and sleep restriction (i.e. a reduced sleep duration) on resistance exercise performance. A secondary aim was to explore the effects on hormonal indicators or markers of muscle protein metabolism. METHODS: A systematic search of five electronic databases was conducted with terms related to three combined concepts: inadequate sleep; resistance exercise; performance and physiological outcomes. Study quality and biases were assessed using the Effective Public Health Practice Project quality assessment tool. RESULTS: Seventeen studies met the inclusion criteria and were rated as 'moderate' or 'weak' for global quality. Sleep deprivation had little effect on muscle strength during resistance exercise. In contrast, consecutive nights of sleep restriction could reduce the force output of multi-joint, but not single-joint movements. Results were conflicting regarding hormonal responses to resistance training. CONCLUSION: Inadequate sleep impairs maximal muscle strength in compound movements when performed without specific interventions designed to increase motivation. Strategies to assist groups facing inadequate sleep to effectively perform resistance training may include supplementing their motivation by training in groups or ingesting caffeine; or training prior to prolonged periods of wakefulness. PMID- 29422385 TI - Drugs that reduce transmission of falciparum malaria. PMID- 29422384 TI - Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial. AB - BACKGROUND: Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants. METHODS: This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5-50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0.25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023. FINDINGS: Between June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; -10.2%, IQR -143.9 to 56.6; p<0.0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin piperaquine alone (n=12; -6.0%, IQR -126.1 to 86.9; p<0.0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild). INTERPRETATION: Adding a single dose of 0.25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly efficacious for preventing P falciparum transmission. Both primaquine and methylene blue were well tolerated. FUNDING: Bill & Melinda Gates Foundation, European Research Council. PMID- 29422386 TI - Multilayer global longitudinal strain in patients with cancer: A comparison of two vendors. AB - BACKGROUND: Global longitudinal strain (GLS) has several sources of variation. Strain multilayer tracking is a new tool that has not yet been validated in clinical practice. AIM: The purpose of this study was to investigate intervendor variability when measuring multilayer strain in patients receiving chemotherapy for cancer. METHODS: Patients receiving chemotherapy for cancer, who were referred for echocardiography, were included prospectively. First, the same operator performed two-dimensional echocardiography on each patient using the Vivid E9TM (General Electric, Fairfield, CT, USA) and the ACUSON SC2000TM (Siemens, Munich, Germany) ultrasound systems. Second, we assessed myocardial deformation by using their respective speckle-tracking software. Third, we compared absolute values of GLS for the two vendors in each apical view (four-, three- and two-chamber) and for each layer (endocardial, mid-myocardial and epicardial). RESULTS: Eighty patients with cancer were included prospectively between February and June 2015. For a given vendor, GLS values decreased from the endocardial layer to the epicardial layer. For a given view, GLS values obtained with the ACUSON SC2000 platform were systematically lower than those obtained with the Vivid E9 platform (P<0.0001). We observed a significant difference between the two platforms, irrespective of the layer, interlayer gradient or chamber view considered (P<0.0001). CONCLUSIONS: There was poor agreement for layer-specific strain evaluation between the Vivid E9 and ACUSON SC2000 platforms, using their dedicated software for strain multilayer assessment. These results suggest that, in clinical practice, the same system and software from the same vendor should be used for longitudinal follow-up. PMID- 29422387 TI - Discovery of novel potent HCV NS5B polymerase non-nucleoside inhibitors bearing a fused benzofuran scaffold. AB - This letter describes the discovery of a fused benzofuran scaffold viable for preparing a series of novel potent HCV NS5B polymerase non-nucleoside inhibitors. Designed on the basis of the functionalized benzofuran derivative nesbuvir (HCV 796), these compounds presumably bind similarly to the allosteric binding site in the "palm" domain of HCV NS5B protein. SAR of each potential hydrogen-bonding interaction site of this novel scaffold is discussed along with some preliminary genotypic profile and PK data of several advanced compounds. PMID- 29422388 TI - Acetazolamide-based [18F]-PET tracer: In vivo validation of carbonic anhydrase IX as a sole target for imaging of CA-IX expressing hypoxic solid tumors. AB - Carbonic anhydrase IX is overexpressed in many solid tumors including hypoxic tumors and is a potential target for cancer therapy and diagnosis. Reported imaging agents targeting CA-IX are successful mostly in clear cell renal carcinoma as SKRC-52 and no candidate was approved yet in clinical trials for imaging of CA-IX. To validate CA-IX as a valid target for imaging of hypoxic tumor, we designed and synthesized novel [18F]-PET tracer (1) based on acetazolamide which is one of the well-known CA-IX inhibitors and performed imaging study in CA-IX expressing hypoxic tumor model as 4T1 and HT-29 in vivo models other than SKRC-52. [18F]-acetazolamide (1) was found to be insufficient for the specific accumulation in CA-IX expressing tumor. This study might be useful to understand in vivo behavior of acetazolamide PET tracer and can contribute to the development of successful PET imaging agents targeting CA-IX in future. Additional study is needed to understand the mechanism of poor targeting of CA-IX, as if CA-IX is not reliable as a sole target for imaging of CA-IX expressing hypoxic solid tumors. PMID- 29422389 TI - Bacicyclin, a new antibacterial cyclic hexapeptide from Bacillus sp. strain BC028 isolated from Mytilus edulis. AB - A new cyclic hexapeptide, cyclo-(Gly-Leu-Val-IIe-Ala-Phe), named bacicyclin (1), was isolated from a marine Bacillus sp. strain associated with Mytilus edulis. The sequences of the amino acid building blocks of the cyclic peptide and its structure were determined by 1D- and 2D-NMR techniques. Marfey's analysis showed that the amino acid building blocks had L-configuration in all cases except for alanine and phenylalanine, which had D-configuration. Bacicyclin (1) exhibited antibacterial activity against the clinically relevant strains Enterococcus faecalis and Staphylococcus aureus with minimal inhibitory concentration values of 8 and 12 uM, respectively. These results demonstrate the potential of marine bacteria as a promising source for the discovery of new antibiotics. PMID- 29422391 TI - Stress shielding of the humerus in press-fit anatomic shoulder arthroplasty: review and recommendations for evaluation. AB - Uncemented press-fit humeral stems were developed with the goal of decreasing operative time, preserving bone stock, and easing revision. In recent years, short stems and stemless humeral implants have also become available. These press fit humeral implants have varying designs that can lead to changes in stress distribution in the proximal humerus. Such stress shielding manifests as bony adaptations and may affect long-term functional outcome and the ability to perform revision. However, current studies of humeral fixation during total shoulder arthroplasty are complicated because a variety of classification systems have been used to report findings. The purpose of this report is to review the current literature on press-fit fixation of the humeral component during total shoulder arthroplasty and propose minimum requirements for radiographic descriptions of stress shielding. PMID- 29422390 TI - Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on alpha1D/1A-adrenoreceptor subtypes. AB - alpha1-Adrenoceptor (alpha1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent alpha1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline induced contractile response of isolated rat prostatic vas deferens (alpha1A), spleen (alpha1B) and thoracic aorta (alpha1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable alpha1D/1A subtype selectivity, especially improved alpha1A subtype selectivity, and the ratios pA2 (alpha1D)/pA2 (alpha1B) and pA2 (alpha1A)/pA2 (alpha1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12. PMID- 29422392 TI - The immune imbalance in the second hit of pancreatitis is independent of IL-17A. AB - BACKGROUND: Severe acute pancreatitis (SAP) is characterised by two distinct clinical phases. Organ dysfunction and death is initially as a result of a systemic inflammatory response syndrome (SIRS). Systemic sepsis from infected pancreatic necrosis characterises the second phase, the so called 'second hit' of acute pancreatitis (AP). An immune imbalance during the second hit is postulated to contribute to the formation of the septic complications that occur in these patients. The pro-inflammatory T-helper (Th) 17 pathway has been shown to be an initiator of early SIRS in AP, however to date its role has not been established in the second hit in AP. METHODS: Thirty-six patients with mild (n = 16), moderate (n = 10) and severe (n = 10) acute pancreatitis were enrolled. Peripheral blood samples were drawn on days 7, 9, 11 and 13 of illness for analysis of routine clinical markers as well as cytokine analysis. Flow cytometry and a IL-17A ELISA was performed to determine cytokine concentrations. RESULTS: There were no significant differences between days 7, 9, 11 and 13 for either the mild/moderate or SAP groups for IL-17A (CBA assay or ELISA), IFN-gamma, TNF alpha, IL-2 or IL-4. For each of the study days, the mean IL-6 and IL-10 concentrations were significantly higher in the SAP group compared to the mild/moderate group. WCC, CRP and PCT were all significantly higher in severe acute pancreatitis over the study days. CONCLUSIONS: An immune imbalance exists in patients with SAP, however secreted IL-17A is not responsible for the second hit in AP. PMID- 29422394 TI - International Epilepsy Day: Celebrating a global day for epilepsy. PMID- 29422393 TI - A de novo GABRA2 missense mutation in severe early-onset epileptic encephalopathy with a choreiform movement disorder. AB - BACKGROUND: Early-onset epileptic encephalopathy (EOEE) is a severe convulsive disorder with a poor developmental prognosis. Although it has been associated with mutations in a number of genes, the fact that there is a large proportion of patients who remain undiagnosed suggests that there are many more still-unknown genetic causes of EOEE. Achieving a genetic diagnosis is important for understanding the biological basis of the disease, with its implications for treatment and family planning. METHODS: Whole-exome sequencing was performed in a family of Ashkenazi Jewish origin in which a male infant was diagnosed with EOEE. There was no family history of a similar neurologic disease. The patient had extreme hypotonia, neonatal hypothermia, choreiform movements, and vision impairment in addition to the convulsive disorder. RESULTS: A de novo heterozygous missense mutation, c.1003A > C, p.Asn335His, was identified in a conserved domain of GABRA2. GABRA2 encodes the alpha2 subunit of the GABAA receptor. CONCLUSIONS: In the context of previous reports of an association of de novo mutations in genes encoding different subunits of the GABAA receptor (GABRB1, GABRA1, GABRG2, GABRB3) with autosomal dominant epileptic disorders, we conclude that a de novo mutation in GABRA2 is likely to cause autosomal dominant EOEE accompanied by a movement disorder and vision impairment. PMID- 29422395 TI - Diurnal occurrence of complex febrile seizure and their severity in pediatric patients needing hospitalization. AB - Several studies describing the diurnal occurrence of febrile seizures have reported greater seizure frequency early or late in the evening relative to midnight or early morning. However, no articles have reported on the diurnal occurrence of complex febrile seizure. Moreover, no studies have addressed the relationship between seizure severity and diurnal occurrence. We retrospectively evaluated complex febrile seizures in 462 children needing hospitalization, and investigated the relationship between severity and diurnal occurrence according to four categorized time periods (morning, afternoon, evening, and night). Our study showed that complex febrile seizures occurred most often in the evening, peaking around 18:00 (18:00-18:59), and least often at night (02:00-02:59). In addition, the frequency with which patients developed status epilepticus or needed anticonvulsant treatments was also lower during the night. However, the seizure duration and the proportion of the patients who needed anticonvulsant treatment were the same among the four time periods. Furthermore, we compared three subclasses (repeated episodes of convulsions, focal seizures, and prolonged seizures (?15min)), two of the complex features (focal seizures and prolonged seizures), and all complex features among the four time periods. However, they were the same among the four time periods. Taken together, our data indicate that although the severity of seizures was stable over a 24-hour period, the occurrence of seizures in our cohort of pediatric patients with complex febrile seizures requiring hospitalization was highest in the evening and lowest at night. PMID- 29422396 TI - Cognitive impairment in early onset epilepsy is associated with reduced left thalamic volume. AB - OBJECTIVE: The objective of this study was to investigate whether reduction of thalamic volumes in children with early onset epilepsy (CWEOE) is associated with cognitive impairment. METHODS: This is a nested case-control study including a prospectively recruited cohort of 76 children with newly-diagnosed early onset epilepsy (onset <5years age) and 14 healthy controls presenting to hospitals within NHS Lothian and Fife. Quantitative volumetric analysis of subcortical structures was performed using volumetric T1-weighted magnetic resonance imaging (MRI) and correlated with the results of formal neurocognitive and clinical assessment. False discovery rate was used to correct for multiple comparisons as appropriate with q<0.05 used to define statistical significance. RESULTS: Age, gender, and intracranial volume (ICV)-adjusted left thalamic volumes were significantly reduced in CWEOE with cognitive impairment compared to CWEOE without impairment (5295mm3 vs 6418mm3, q=0.008) or healthy controls (5295mm3 vs 6410mm3, q<0.001). The differences in left thalamic volume remained if gray matter or cortical/cerebellar volumes were used as covariates rather than ICV (q<0.05). The degree of volume reduction correlated with the severity of cognitive impairment (q=0.048). SIGNIFICANCE: Reduced left thalamic volume may be a biomarker for cognitive impairment in CWEOE and could help inform the need for further formal cognitive evaluations and interventions. PMID- 29422397 TI - In reply to "re: Antibiotic prophylaxis in breast reduction surgery: A systematic review and meta-analysis". PMID- 29422398 TI - Upgrading the BREAST-Q questionnaire with donor site evaluation after PAP flap breast reconstruction. PMID- 29422399 TI - Quality of life improvement after chest wall masculinization in female-to-male transgender patients: A prospective study using the BREAST-Q and Body Uneasiness Test. AB - BACKGROUND: Chest reconstruction in many female-to-male (FTM) transgender individuals is an essential element of treatment for their gender dysphoria. In existing literature, there are very few longitudinal studies utilizing validated survey tools to evaluate patient reported outcomes surrounding this surgery. The purpose of our study is to prospectively evaluate patient reported satisfaction, improvement in body image, and quality of life following FTM chest wall reconstruction. METHODS: Our study was a prospective analysis of FTM patients who underwent chest reconstruction by a single surgeon (C.A.) between April 2015 and June 2016. The patients were surveyed preoperatively and 6 months after surgery utilizing the BREAST-Q breast reduction/mastectomy questionnaire and the Body Uneasiness Test (BUT-A). Analysis was performed on their self-reported demographic information, survey results, and chart review data. RESULTS: Of 87 eligible patients, 42 completed all surveys and could be linked to their chart data. From the BREAST-Q surveys, significant improvements were observed in the domains of breast satisfaction, psychosocial well-being, sexual satisfaction, and physical well-being. From the BUT-A surveys, we observed significant improvement in body image, avoidance, compulsive self-monitoring, and depersonalization. Groups with mental health conditions had poorer initial BUT-A scores and greater degree of improvement after surgery. CONCLUSIONS: As the prevalence of gender affirming surgery increases and as health policies are being developed in this area, the need for evidence-based studies surrounding specific interventions is essential. This study demonstrates significant improvement in a number of quality of life measurements in FTM patients after undergoing chest masculinization surgery. PMID- 29422400 TI - Predictors of arthrocentesis outcome on joint effusion in patients with disk displacement without reduction. AB - OBJECTIVES: The aim of this study was to investigate the preoperative variables in patients with articular disk displacement without reduction that may influence the results of arthrocentesis on joint effusion (JE). STUDY DESIGN: The records of 203 patients with clinical signs and symptoms of unilateral painful disk displacement without reduction and JE, confirmed by magnetic resonance imaging (MRI), and treated with arthrocentesis were selected. The following preoperative data were recorded: sex; age; joint side; pain duration; pain intensity, measurement with the visual analogue scale; and maximum interincisal distance (MID). All patients underwent a second MRI examination 3 to 4 months postoperatively to assess JE. The sample was then divided into 2 groups: group 1 (n = 160) comprised patients with no signs of JE; and group 2 (n = 43) comprised patients still showing signs of JE. Univariate and multivariate analyses were used to compare the groups. RESULTS: Among the studied variables, pain duration (P = .0175), pain intensity (P < .0001), and MID (P = .0085) were shown to affect arthrocentesis outcomes. The longer the pain duration (odds ratio [OR] = 0.930), the more intense was the pain (OR = 0.346), and the smaller the MID (OR = 0.562), the less were the chances of arthrocentesis completely eliminating JE. CONCLUSIONS: Pain duration, pain intensity, and MID can be used as predictors for the effect of arthrocentesis on JE outcomes and considered during treatment planning. PMID- 29422401 TI - Reply from Authors re: Thomas B.L. Lam, Sam McClinton. Between a Rock and a Hard Place: The Uncertainties in Managing Renal Stones. Eur Urol 2015;67:138-9. PMID- 29422402 TI - Reply from Authors re: Andrea Gallina, Alessandro Nini, Francesco Montorsi, Alberto Briganti. Metabolic Syndrome as a Marker for Prostate Cancer: Still a Work in Progress. Eur Urol 2015;67:71-2. PMID- 29422403 TI - Medical Officers in Sierra Leone: Surgical Training Opportunities, Challenges and Aspirations. AB - BACKGROUND: The critical shortage of human resources for healthcare falls most heavily on sub-Saharan nations such as Sierra Leone, where such workforce deficits have grave impacts on its burden of surgical disease. An important aspect in retention and development of the workforce is training. This study focuses on postgraduate surgical training (formal and short course) and perceptions of opportunities, challenges and aspirations, in a country where more than half of surgical procedures are performed by medical officers. METHODS: The study presents findings from 12 in-depth semi-structured interviews conducted with medical officers by the primary investigator in Sierra Leone between April and June 2017. Each interview was transcribed alongside an introspective reflexive journal to acknowledge and account for researcher biases. RESULTS: Two interviewees had accessed postgraduate surgical training and 10 (83%) had accessed short course surgically relevant training. The number of short courses accessed grew higher the more recently the medical officers had graduated. Supervision, short length and international standards were the most appreciated aspects of short training courses. Some medical officers perceived the formal postgraduate surgical training programme to be ill-equipped, doubting its credibility. This demotivated some from applying. CONCLUSIONS: Training is an essential aspect of developing an adequate surgical workforce. Faith must be restored in the capabilities of Sierra Leone's Ministry of Health and Sanitation to provide adequate and sustainable training. This study advocates for the use of short courses to restore this faith and the expansion of postgraduate surgical training to the districts through developing a regional teaching complex to provide short courses and eventually formal postgraduate training in the future. PMID- 29422404 TI - New Challenges for a Core Procedure: Development of a Faculty Workshop for Skills Maintenance for Abdominal Hysterectomy. AB - OBJECTIVE: To describe the development of a low-cost educational module for OB/GYN faculty skills maintenance for total abdominal hysterectomy (TAH), a low frequency core procedure in obstetrics and gynecology. DESIGN: After review of existing educational tools and utilization of a modified Delphi method to establish consensus regarding key procedural components for skills maintenance, a 2-hour workshop was developed to review knowledge and participate in a simulation focused on the critical steps in performing TAH. An expert in TAH delivered a lecture highlighting important surgical considerations. Participants then rotated through simulation stations for critical steps in TAH: dissecting the bladder, identifying the ureter, and closing the cuff. Knowledge gains were assessed with a written pre- and posttest. Consecutive focus groups were conducted with participants on effectiveness of the workshop, and suggestions for improvement. Ideas identified in the first focus group were incorporated into the second workshop. SETTING: Massachusetts General Hospital, an academic tertiary care facility with a single Obstetrics and Gynecology faculty group, located in Boston, Massachusetts. PARTICIPANTS: Eligible participants were recruited via email from full time specialists in General Obstetrics and Gynecology at Massachusetts General Hospital. Of the 25 eligible gynecology faculty subjects, 22 participated (88%). RESULTS: On pre or post-test comparison, 70% of participants scored higher on the posttest, demonstrating an increase in knowledge of critical TAH surgical steps. Focus group analyses identified the need for increased review and training demonstrations of TAH, and recommended continued offering of the workshop. CONCLUSIONS: Based on focus group responses and pre or posttest comparisons, the workshop was deemed feasible and enhanced short-term learning. Future directions include utilizing more challenging anatomic models and simulation scenarios and optimizing integration of expert demonstration and individualized coaching, as well as identifying regionally tailored surgical workshop programming. PMID- 29422405 TI - Simulation-Based Learning Strategies to Teach Undergraduate Students Basic Surgical Skills: A Systematic Review. AB - OBJECTIVE: We aimed to identify and critically appraise all literature surrounding simulation-based learning (SBL) courses, to assess their relevance as tools for undergraduate surgical education, and create a design framework targeted at standardizing future SBL. METHODS: We performed a systematic review of the literature using a specific keyword strategy to search at MEDLINE database. RESULTS: Of the 2371 potentially eligible titles, 472 were shortlisted and only 40 explored active interventions in undergraduate medical education. Of those, 20 were conducted in the United States, 9 in Europe and 11 in the rest of the world. Nineteen studies assessed the effectiveness of SBL by comparing students' attributes before and after interventions, 1 study assessed a new tool of surgical assessment and 16 studies evaluated SBL courses from the students' perspectives. Of those 40 studies, 12 used dry laboratory, 7 wet laboratory, 12 mixed, and 9 cadaveric SBL interventions. The extent to which positive results were obtained from dry, wet, mixed, and cadaveric laboratories were 75%, 57%, 92%, and 100%, respectively. Consequently, the SBL design framework was devised, providing a foundation upon which future SBL interventions can be designed such that learning outcomes are optimized. CONCLUSIONS: SBL is an important step in surgical education, investing in a safer and more efficient generation of surgeons. Standardization of these efforts can be accelerated with SBL design framework, a comprehensive guide to designing future interventions for basic surgical training at the undergraduate level. PMID- 29422406 TI - Longitudinal Change in Central Corneal Thickness in the Tema Eye Survey. PMID- 29422407 TI - Reply. PMID- 29422408 TI - Special Considerations for Diagnosing Behavior Problems in Older Pets. AB - Aging is a complex process that involves changes in sensory perception, cognition, and physical strength. Physiologic, metabolic, and emotional changes of the aging process can lead to behavioral problems in older pets. Treatment of behavior problems in older pets requires a multimodal therapeutic approach. Frequent follow-up visits are required to monitor pets and comment on prognosis. Clients should be informed of the prognosis and should be educated to evaluate pain, discomfort, and general quality of life of the aging pet. PMID- 29422409 TI - Computer therapy for the anxiety and depression disorders is effective, acceptable and practical health care: An updated meta-analysis. AB - BACKGROUND: A 2010 meta-analysis of internet-delivered CBT (iCBT) RCTs argued 'computer therapy for the anxiety and depressive disorders was effective, acceptable and practical health care' without data on effectiveness or practicality in routine practice. METHODS: Databases, reviews and meta-analyses were searched for randomised controlled trials of cCBT or iCBT versus a control group (care as usual, waitlist, information control, psychological placebo, pill placebo, etc.) in people who met diagnostic criteria for major depression, panic disorder, social anxiety disorder or generalised anxiety disorder. Number randomised, superiority of treatment versus control (Hedges'g) on primary outcome measure, length of follow-up, follow up outcome, patient adherence and satisfaction/harm were extracted; risk of bias was assessed. A search for studies on effectiveness of iCBT in clinical practice was conducted. RESULTS: 64 trials were identified. The mean effect size (efficacy) was g = 0.80 (NNT 2.34), and benefit was evident across all four disorders. Improvement was maintained at follow-with good acceptability. Research probity was good, and bias risk low. In addition, nine studies comparing iCBT with traditional face-to-face CBT and three comparing iCBT with bibliotherapy were identified. All three modes of treatment delivery appeared equally beneficial. The results of effectiveness studies were congruent with the results of the efficacy trials. LIMITATIONS: Studies variably measured changes in quality of life and disability, and the lack of comparisons with medications weakens the field. CONCLUSIONS: The conclusions drawn in the original meta-analysis are now supported: iCBT for the anxiety and depressive disorders is effective, acceptable and practical health care. PMID- 29422410 TI - Tissue Engineering 3D Neurovascular Units: A Biomaterials and Bioprinting Perspective. AB - Neurovascular dysfunction is a central process in the pathogenesis of stroke and most neurodegenerative diseases, including Alzheimer's disease. The multicellular neurovascular unit (NVU) combines the neural, vascular and extracellular matrix (ECM) components in an important interface whose correct functioning is critical to maintain brain health. Tissue engineering is now offering new tools and insights to advance our understanding of NVU function. Here, we review how the use of novel biomaterials to mimic the mechanical and functional cues of the ECM, coupled with precisely layered deposition of the different cells of the NVU through 3D bioprinting, is revolutionising the study of neurovascular function and dysfunction. PMID- 29422411 TI - Discovering Cell-Adhesion Peptides in Tissue Engineering: Beyond RGD. AB - As an alternative to natural extracellular matrix (ECM) macromolecules, cell adhesion peptides (CAPs) have had tremendous impact on the design of cell culture platforms, implants, and wound dressings. However, only a handful of CAPs have been utilized. The discrepancy in ECM composition strongly affects cell behavior, so it is paramount to reproduce such differences in synthetic systems. This Opinion article presents strategies inspired from high-throughput screening techniques implemented in drug discovery to exploit the potential of a growing CAP library. These strategies are expected to promote the use of a broader spectrum of CAPs, which in turn could lead to improved cell culture models, implants, and wound dressings. PMID- 29422412 TI - Nanotechnology-Based Strategies for siRNA Brain Delivery for Disease Therapy. AB - Small interfering RNA (siRNA)-based gene silencing technology has demonstrated significant potential for treating brain-associated diseases. However, effective and safe systemic delivery of siRNA into the brain remains challenging because of biological barriers such as enzymatic degradation, short circulation lifetime, the blood-brain barrier (BBB), insufficient tissue penetration, cell endocytosis, and cytosolic transport. Nanotechnology offers intriguing potential for addressing these challenges in siRNA brain delivery in conjunction with chemical and biological modification strategies. In this review, we outline the challenges of systemic delivery of siRNA-based therapy for brain diseases, highlight recent advances in the development and engineering of siRNA nanomedicines for various brain diseases, and discuss our perspectives on this exciting research field for siRNA-based therapy towards more effective brain disease therapy. PMID- 29422413 TI - Which method of chest compression should be used when resuscitating a newborn? PMID- 29422414 TI - Adapting international simulation-based educational methods: Localization for medical culture and educational characteristics. PMID- 29422415 TI - Lived Experience as a Distinct Information Source: A Case Study to Improve E Health Products for Adults With Type 1 or 2 Diabetes Starting Insulin. PMID- 29422417 TI - Characterization of van der Waals type bimodal,- lambda,- meta- and spinodal phase transitions in liquid mixtures, solid suspensions and thin films. AB - The perfect gas law is used as a reference when selecting state variables (P, V, T, n) needed to characterize ideal gases (vapors), liquids and solids. Van der Waals equation of state is used as a reference for models characterizing interactions in liquids, solids and their mixtures. Van der Waals loop introduces meta- and unstable states between the observed gas (vapor)-liquid P-V transitions at low T. These intermediate states are shown to appear also between liquid liquid, liquid-solid and solid-solid phase transitions. First-order phase transitions are characterized by a sharp discontinuity of first-order partial derivatives (P, S, V) of Helmholtz and Gibbs free energies. Second-order partial derivatives (KT, B, CV, CP, E) consist of a static contribution relating to second-order phase transitions and a relaxation contribution representing the degree of first-order phase transitions. Bimodal (first-order) and spinodal (second-order) phase boundaries are used to separate stable phases from metastable and unstable phases. The boundaries are identified and quantified by partial derivatives of molar Gibbs free energy or chemical potentials with respect to P, S, V and composition (mole fractions). Molecules confined to spread Langmuir monolayers or adsorbed Gibbs monolayers are characterized by equation of state and adsorption isotherms relating to a two-dimensional van der Waals equation of state. The basic work of two-dimensional wetting (cohesion, adsorption, spreading, immersion), have to be adjusted by a horizontal surface pressure in the presence of adsorbed vapor layers. If the adsorption is extended to liquid films a vertical surface pressure (Pi) may be added to account for the lateral interaction, thus restoring PV = PiAh dependence of thin films. Van der Waals attraction, Coulomb repulsion and structural hydration forces contribute to the vertical surface pressure. A van der Waals type coexistence of ordered (dispersed) and disordered (aggregated) phases is shown to exist when liquid vapor is confined in capillaries (condensation-liquefaction-evaporation and flux). This pheno-menon can be experimentally illustrated with suspended nano sized particles (flocculation-coagulation-peptisation of colloidal sols) being confined in sample holders of varying size. The self-assembled aggregates represent critical self-similar equilibrium structures corres-ponding to rate determining complexes in kinetics. Overall, a self-consistent thermodynamic framework is established for the characterization of two- and three-dimensional phase separations in one-, two- and three-component systems. PMID- 29422416 TI - Incidence and predictors of lesion-specific ischemia by FFRCT: Learnings from the international ADVANCE registry. AB - BACKGROUND: To date, the clinical utility of coronary computed tomography angiography (CTA)-derived fractional flow reserve (FFRCT) has been limited to trials and single center experiences. We herein report the incidence of abnormal FFRCT (<=0.80) and the relationship of lesion-specific ischemia to subject demographics, symptoms, and degree of stenosis in the multicenter, prospective ADVANCE registry. METHODS: One thousand patients with suspected angina having documented coronary artery disease on coronary CTA and clinically referred for FFRCT were prospectively enrolled in the registry. Patient demographics, symptom status, coronary CTA and FFRCT findings were recorded. Univariate and multivariate analyses were performed to investigate the predictors related to abnormal FFRCT. RESULTS: FFRCT data were analyzed in 952 patients (95.2%). Overall, 51.1% patients had a positive FFRCT value (<=0.80). Patients with >=3 risk factors had a significantly higher rate of abnormal FFRCT than those with <3 risk factors (60.2% vs. 43.9%, p = 0.0001). On multivariate analysis, baseline diabetes (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.04-2.21, p = 0.030) and hypertension (OR 1.56, 95%CI 1.14-2.14, p = 0.005) were both predictive of abnormal FFRCT. In addition, >70% stenosis was significantly associated with low FFRCT (OR 31.16, 95%CI 12.25-79.22, p < 0.0001) vs. <30% stenosis. Notably, stenosis 30-49% vs. <30% had an increased likelihood of ischemia (OR 3.74, 95%CI 1.52-9.17, p < 0.0001). CONCLUSIONS: In this real-world registry, CT angiographic stenosis severity in addition to baseline cardiovascular risk factors conferred an increased likelihood of an abnormal FFRCT. Importantly, however, mild CT angiographic stenoses were noted to have an increased hazard for ischemia and the converse holding true for more severe stenoses as well. PMID- 29422418 TI - Incorporation of Urinary Prostate Cancer Antigen 3 and TMPRSS2:ERG into Prostate Cancer Prevention Trial Risk Calculator. AB - BACKGROUND: The Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) is a commonly used risk tool for predicting the outcome on biopsy based on the established risk factors. OBJECTIVE: To determine whether incorporation of the novel urinary markers prostate cancer antigen 3 (PCA3) and TMPRSS2:ERG (T2:ERG) into the PCPTRC improves its discrimination, accuracy, and clinical net benefit. DESIGN, SETTING, AND PARTICIPANTS: Since PCA3 and T2:ERG were not measured as part of the PCPTRC, a Bayesian modeling approach was used to combine data where the markers were measured in a Michigan cohort with the PCPTRC as prior probabilities to form an updated PCPTRC. This update was compared to the existing PCPTRC on an independent Early Detection Research Network cohort in terms of discrimination, calibration, and decision curve analysis. RESULTS AND LIMITATIONS: Among the 1225 Michigan biopsies, 57.7%, 24.0%, and 18.3% were negative, with low- and high-grade (Gleason grade>=7) prostate cancer, respectively. Evaluated on the Early Detection Research Network validation set comprising 854 biopsies, areas under the curve (95% confidence interval) for predicting high-grade cancer in the 854 biopsies comprising the validation set were 70.0% (66.0-74.0%), 76.4% (72.8-80.0%), and 77.1% (73.6-80.6%) for the PCPTRC alone, with PCA3 added, and PCA3 and T2:ERG added, respectively. Net benefit was improved for the updated PCPTRC, while calibration was not. Limitations are that the updated PCPTRC is based on two different cohorts, the PCPT and Michigan, and that 20% of the validation set came from the Michigan center. More validation is required; hence, the updated risk tool is posted online. CONCLUSIONS: Incorporation of PCA3 into the PCPTRC improved validation on an independent cohort, whereas T2:ERG offered negligible utility in addition to PCA3. PATIENT SUMMARY: After passing external validation, prostate cancer antigen 3 has been added to the online Prostate Cancer Prevention Trial Risk Calculator for use by patients in deciding whether to proceed to biopsy. TMPRSS2:ERG did not improve prediction on the external validation set, but is included for further validation. PMID- 29422419 TI - Impact of Renal Hilar Control on Outcomes of Robotic Partial Nephrectomy: Systematic Review and Cumulative Meta-analysis. AB - CONTEXT: During robotic partial nephrectomy (RPN), various techniques of hilar control have been described, including on-clamp, early unclamping, selective/super-selective clamping, and completely-unclamped RPN. OBJECTIVE: To evaluate the impact of various hilar control techniques on perioperative, functional, and oncological outcomes of RPN for tumors. EVIDENCE ACQUISITION: We conducted a systematic literature review and meta-analysis of all comparative studies on various hilar control techniques during RPN using PubMed, Scopus, and Web of Science according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement, and Methods and Guide for Effectiveness and Comparative Effectiveness Review of the Agency for Healthcare Research and Quality. Cumulative meta-analysis of comparative studies was conducted using Review Manager 5.3. EVIDENCE SYNTHESIS: Of 987 RPN publications in the literature, 19 qualified for this analysis. Comparison of off-clamp versus on clamp RPN (n=9), selective clamping versus on-clamp RPN (n=3), super selective clamping versus on-clamp RPN (n=5), and early unclamped versus on-clamp (n=3) were reported. Patients undergoing RPN using off-clamp, selective/super selective, or early unclamp techniques had higher estimated blood loss compared with on-clamp RPN (weight mean difference [WMD]: 47.83, p=0.000, WMD: 41.06, p=0.02, and WMD: 37.50, p=0.47); however, this did not seem clinically relevant, since transfusion rates were similar (odds ratio [OR]: 0.98, p=0.95, OR: 0.72, p=0.7, and OR: 1.36, p=0.33, respectively). All groups appeared similar with regards to hospital stay, transfusions, overall and major complications, and positive cancer margin rates. Short- and long-term renal functional outcomes appeared superior in the off-clamp and super selective clamp groups compared with the on-clamp RPN cohort. CONCLUSIONS: Off-clamp, selective/super selective clamp, and early unclamp hilar control techniques are safe and feasible approaches for RPN surgery, with similar perioperative and oncological outcomes compared with on clamp RPN. Minimizing global renal ischemia may provide superior renal function preservation. However, higher quality data are necessary for definitive conclusions in this regard. PATIENT SUMMARY: The objective of partial nephrectomy is to treat the cancer while maximizing renal function preservation. Clamping the main vessels is done primarily to reduce the blood loss during partial nephrectomy; however, vascular clamping can compromise kidney function. In order to avoid clamping, various techniques have been described. Our analysis showed that techniques that avoid main renal artery clamping during RPN are associated with better renal function preservation, yet deliver non-inferior perioperative and oncological outcomes as compared with RPN procedures that clamp the main vessels. PMID- 29422420 TI - Botulinum Toxin Versus Neural Stimulation. AB - Botulinum toxin and nerve stimulation are viable options for overactive bladder refractory to pharmacotherapy. Treatment choice depends on multiple factors including associated symptoms, bladder function, and health economics. Decision making should be individualised to the particular situation taking into account patient preference. PMID- 29422421 TI - Two-year process evaluation of a pilot program to increase elementary children's physical activity during school. AB - The purpose of this study was to examine implementation processes in elementary classrooms during a 2-year (Fall 2014 to Spring 2016) pilot intervention program, Partnerships for Active Children in Elementary Schools (PACES). We examined (a) the effect of PACES on the extent of movement integration (MI) and (b) changes in teachers' perceptions regarding MI. Purposively selected classrooms (grades 1-3) across four schools (3 intervention, 1 control) participated in the study. The sample included classroom teachers (N = 12) in Fall 2014 and Spring 2015, but the number of participants dropped to eight in Fall 2015 and Spring 2016. PACES consisted of three partnership approaches (a virtual community of practice, community-based participatory research, and university service learning) intended to increase the extent of MI in the intervention classrooms. We collected process data using the System for Observing Student Movement in Academic Routines and Transitions (SOSMART) and teacher interviews. PACES did not significantly impact the extent of observed MI. Interviews indicated that the intervention had both strengths and limitations. Building interpersonal support for teachers is important to their use of MI. A different measurement schedule (e.g., collecting MI data each day of the school week) may be required to more thoroughly capture MI instances. PMID- 29422422 TI - Tablet-based interventions for individuals with ASD: Evidence of generalization and maintenance effects. AB - BACKGROUND: Despite positive effects of and established empirical evidence for tablet-based interventions for individuals with autism spectrum disorder (ASD), it is not known whether such findings can be applicable to maintenance and generalization effects of those interventions. AIMS: This systematic review evaluated peer-reviewed single-case experimental design (SCED) studies concerning evidence of generalization and maintenance effects of tablet-based interventions for individuals with ASD. METHODS: To evaluate the methodological rigor of the literature in terms of generalization and maintenance effects, the authors adopted four of the basic design standards developed by What Works Clearinghouse (WWC; Kratochwill et al., 2010/2014). In addition, the authors used Tau-U effect size measure and attempted to calculate effect sizes differentiated by the type of generalization and maintenance teaching strategies. RESULTS: A total of 21 studies assessed generalization and/or maintenance effects. In the first evaluation of evidence of generalization and maintenance effects, it was found that more than half of the studies included in this review collected interobserver agreement (IOA) on at least 20% of sessions across all generalization and maintenance conditions and met the minimum quality thresholds of IOA. Meanwhile, less than one third of the studies included more than three data points in each generalization and maintenance condition. With regard to maintenance of effects, about half of the reviewed studies did not report the latency to the maintenance measure, which may hamper the assessment of the clinical and practical significance of the effect of the tablet-based intervention. In the second evaluation, the omnibus Tau-U effect size for baseline to generalization comparisons resulted in a moderate effect. For the contrasts between intervention and generalization comparisons resulted in a small effect. The omnibus Tau-U effect size for baseline and maintenance comparisons resulted in a strong effect. For the contrasts between intervention to maintenance comparisons, the omnibus Tau-U effect size resulted in a small effect. CONCLUSIONS AND IMPLICATION: Findings in this review suggest that efforts should be made to establish a system for appraising generalization and maintenance procedures in SCED studies. In addition, future studies should investigate if tablet-based interventions are truly effective in creating sustainable behavioral change in individuals with ASD. PMID- 29422423 TI - Use of artesunate in non-malarial indications. AB - INTRODUCTION: Artesunate and other artemisinin derivatives are used in various infectious and non-infectious diseases. We aimed to analyze available data on artesunate and artemisinin derivatives activity in humans and their potential clinical benefits in non-malarial indications. MATERIAL AND METHODS: Literature review performed on PubMed and the Cochrane Library databases using the PRISMA method. We analyzed studies published in English from January 2008 to August 2017 using the same indicators of drug efficacy. RESULTS: We included 19 studies performed in humans (1 meta-analysis, 1 literature review, 4 randomized controlled trials, 3 prospective controlled trials, 3 prospective uncontrolled trials, 2 exploratory phase 1 or 2 trials, 1 case series, and 4 case reports). Artesunate and artemisinin derivatives demonstrated efficacy in the treatment of schistosomiasis in combination with praziquantel (P=0.003). Artesunate monotherapy was less effective than praziquantel alone (P<0.001) probably because its activity only affects the early stages of Schistosoma parasites. Artesunate monotherapy could be interesting as a chemoprophylactic drug against schistosomiasis (P<0.001). Findings seem promising but are still controversial in the treatment of multidrug-resistant CMV infections. Studies do not conclude on artesunate and artemisinin derivatives efficacy in the treatment of cervix, breast, colorectal, and lung cancers. CONCLUSION: Artesunate and artemisinin derivatives in combination with praziquantel were effective against schistosomiasis, and could be used as a chemoprophylactic drug alone. They could be interesting as anti-CMV and anti-tumor treatment. Additional trials in humans are required to assess the efficacy of artesunate and artemisinin derivatives in diseases other than malaria. PMID- 29422424 TI - [First case of mcr-1 ESBL-producing K. pneumoniae cross-transmission in France]. PMID- 29422425 TI - Utility of Clinical Parameters and Multiparametric MRI as Predictive Factors for Differentiating Uterine Sarcoma From Atypical Leiomyoma. AB - OBJECTIVES: The objective of this study was to find clinical parameters and qualitative and quantitative magnetic resonance imaging (MRI) features for differentiating uterine sarcoma from atypical leiomyoma (ALM) preoperatively and to calculate predictive values for uterine sarcoma. MATERIALS AND METHODS: Data from 60 patients with uterine sarcoma and 88 patients with ALM confirmed by surgery and pathology were collected. Clinical parameters, qualitative MRI features, diffusion-weighted imaging with apparent diffusion coefficient values, and quantitative parameters of dynamic contrast-enhanced MRI of these two tumor types were compared. Predictive values for uterine sarcoma were calculated using multivariable logistic regression. RESULTS: Patient clinical manifestations, tumor locations, margins, T2-weighted imaging signals, mean apparent diffusion coefficient values, minimum apparent diffusion coefficient values, and time signal intensity curves of solid tumor components were obvious significant parameters for distinguishing between uterine sarcoma and ALM (all P <.001). Abnormal vaginal bleeding, tumors located mainly in the uterine cavity, ill defined tumor margins, and mean apparent diffusion coefficient values of <1.272 * 10-3 mm2/s were significant preoperative predictors of uterine sarcoma. When the overall scores of these four predictors were greater than or equal to 7 points, the sensitivity, the specificity, the accuracy, and the positive and negative predictive values were 88.9%, 99.9%, 95.7%, 97.0%, and 95.1%, respectively. CONCLUSIONS: The use of clinical parameters and multiparametric MRI as predictive factors was beneficial for diagnosing uterine sarcoma preoperatively. These findings could be helpful for guiding treatment decisions. PMID- 29422426 TI - The presence of papillary features in thyroid nodules diagnosed as atypia of undetermined significance or follicular lesion of undetermined significance increases cancer risk and should influence treatment. AB - BACKGROUND: The objective of this study was to evaluate the influence of papillary features on risk of malignancy (ROM) within the Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance (AUS-FLUS) Bethesda System for Reporting Thyroid Cytopathology (BSRTC) diagnostic category. METHODS: A Retrospective review of cases with an AUS-FLUS diagnosis that underwent a thyroidectomy was carried out, and cases were subcategorized based upon the presence of papillary features. RESULTS: For the entire study population there were 93 (22%) of 427 FNAB specimens that had an AUS-FLUS diagnosis, and a 32% associated ROM. Papillary features were identified in 44 FNAB specimens (47% of the AUS-FLUS cases or 10% of the entire study population), and when present had a 45% ROM. The 49 FNAB specimens (53%) that did not exhibit papillary features had a significantly lower ROM (20%) than those that did have papillary features (p = 0.0069). CONCLUSIONS: The presence of papillary features in a thyroid FNAB with an AUS-FLUS diagnosis is common, and is associated with a higher ROM than is currently suggested by the BSRTC. PMID- 29422427 TI - Society of Interventional Radiology Position Statement on Catheter-Directed Therapy for Acute Pulmonary Embolism. PMID- 29422428 TI - Clinical implementation of contrast-enhanced four-dimensional dual-energy computed tomography for target delineation of pancreatic cancer. AB - BACKGROUND AND PURPOSE: The accurate delineation of pancreatic tumor with respiratory motion is challenging. This study demonstrates the application of contrast-enhanced four-dimensional dual-energy computed tomography (CE-4D-DECT) for tumor delineation and assesses the objective and subjective image quality. MATERIAL AND METHODS: Twelve patients underwent CE-4D-DECT, and quantitative spectral analysis was performed on the resulting virtual monochromatic images (VMI) to determine the optimal VMI (O-VMI) with the highest contrast-to-noise ratio (CNR). The objective value of the CNR between pancreatic parenchyma and tumor, and the subjective measurement with five-point scale were compared between O-VMI, standard VMI (S-VMI, 77 keV) and single energy CT (SECT, 120 kVp). RESULTS: The CNR was the highest in the VMI at 60 keV, and the corresponding CNR in the O-VMI (3.4) was significantly higher (p < 0.05) than that in the S-VMI (2.4) and the SECT (2.7). The overall mean subjective measurements among 4 radiation oncologists were higher for the O-VMI over the S-VMI and SECT with respect to overall image quality (4.0, 3.3 and 3.7, respectively), tumor enhancement (3.4, 2.6 and 3.2, respectively), and vessel delineation (4.2, 3.6 and 4.2, respectively). CONCLUSIONS: The O-VMI derived from the CE-4D-DECT demonstrated its superiority over the S-VMI and SECT in depicting pancreatic tumor. PMID- 29422429 TI - In-vitro development of vitrified-warmed bovine oocytes after activation may be predicted based on mathematical modelling of cooling and warming rates during vitrification, storage and sample removal. AB - Heat transfer during cooling and warming is difficult to measure in cryo-devices; mathematical modelling is an alternative method that can describe these processes. In this study, we tested the validity of one such model by assessing in-vitro development of vitrified and warmed bovine oocytes after parthenogenetic activation and culture. The viability of oocytes vitrified in four different cryo devices was assessed. Consistent with modelling predictions, oocytes vitrified using cryo-devices with the highest modelled cooling rates had significantly (P < 0.05) better cleavage and blastocyst formation rates. We then evaluated a two step sample removal process, in which oocytes were held in nitrogen vapour for 15 s to simulate sample identification during clinical application, before being removed completely and warmed. Oocytes exposed to this procedure showed reduced developmental potential, according to the model, owing to thermodynamic instability and devitrification at relatively low temperatures. These findings suggest that cryo-device selection and handling, including method of removal from nitrogen storage, are critical to survival of vitrified oocytes. Limitations of the study include use of parthenogenetically activated rather than fertilized ova and lack of physical measurement of recrystallization. We suggest mathematical modelling could be used to predict the effect of critical steps in cryopreservation. PMID- 29422430 TI - [How I do... salpingectomy or adnexectomy during vaginal hysterectomy in a safe manner?] PMID- 29422431 TI - Dupilumab for the Treatment of Atopic Dermatitis. AB - Atopic dermatitis (AD) is a common, chronic, inflammatory skin disorder with high physical and emotional burden. AD usually starts in early childhood and has a heterogeneous course. Emerging evidence suggests that IL-4 and IL-13 are key cytokines in the immunopathogenesis of AD. Dupilumab is a monoclonal antibody directed against IL-4 receptor alpha subunit, that blocks both IL-4 and IL-13 signaling. Data from Phase I-III studies revealed that dupilumab, administered as monotherapy or with topical corticosteroids, is effective and well tolerated in the treatment of adult patients with moderate-to-severe AD. A large proportion of patients receiving dupilumab had significant improvements in multiple efficacy indexes, including Eczema Area and Severity Index, Investigator's Global Assessment and SCORing Atopic Dermatitis scores. These results introduce a new era of targeted therapies in the management of AD. PMID- 29422432 TI - Erratum. PMID- 29422433 TI - Editorial Comment. PMID- 29422434 TI - Reply to comment on the article "Novel fluorene-based supramolecular sensor for selective detection of amoxicillin in water and blood". PMID- 29422435 TI - The Catch to Confidentiality: The Use of Electronic Health Records in Adolescent Health Care. AB - PURPOSE: This study aims to understand pediatric health-care providers' expectations and the practices they employ to protect confidentiality in electronic health records (EHRs) and subsequently how EHRs affect the documentation and dissemination of information in the course of health-care delivery to adolescent minors. METHODS: Twenty-six pediatric health-care providers participated in in-depth interviews about their experiences using EHRs to understand a broad spectrum of expectations and practices guiding the documentation and dissemination of information in the EHR. A thematic analysis of interviews was conducted to draw findings and conclusions. RESULTS: Two themes and several subthemes emerged centering on how EHRs affected confidentiality expectations and practices. Participants expressed confidentiality concerns due to the EHR's longevity as a legacy record, its multidimensional uses, and increased access by users (theme 1). These concerns affected practices for protecting adolescent confidentiality within the EHR (theme 2). Practices included selectively omitting or concealing information and utilizing sets of personal and collective codes designed to alert providers or teams of providers to confidential information within a patient's record. CONCLUSIONS: EHRs create new and unresolved challenges for pediatric health care as they alter expectations of confidentiality and the documentation and dissemination of information within the record. This is particularly relevant in the course of care to adolescent minors as EHRs may compromise the tenuous balance providers maintain between protecting confidentiality and effective documentation within the record. PMID- 29422436 TI - Impact of E-Cigarette Minimum Legal Sale Age Laws on Current Cigarette Smoking. AB - PURPOSE: The purpose of this study was to use individual-level data to examine the relationship between e-cigarette minimum legal sale age (MLSA) laws and cigarette smoking among U.S. adolescents, adjusting for e-cigarette use. METHODS: In 2016 and 2017, we regressed (logistic) current (past 30-day) cigarette smoking (from 2009-2014 National Youth Tobacco Surveys [NYTS]) on lagged (laws enacted each year counted for the following year) and unlagged (laws enacted January-June counted for that year) state e-cigarette MLSA laws prohibiting sales to youth aged <18 or <19 years (depending on the state). Models were adjusted for year and individual- (e-cigarette and other tobacco use, sex, race/ethnicity, and age) and state-level (smoke-free laws, cigarette taxes, medical marijuana legalization, income, and unemployment) covariates. RESULTS: Cigarette smoking was not significantly associated with lagged MLSA laws after adjusting for year (odds ratio [OR] = .87, 95% confidence interval [CI]: .73-1.03; p = .10) and covariates (OR = .85, .69-1.03; p = .10). Unlagged laws were significantly and negatively associated with cigarette smoking (OR = .84, .71-.98, p = .02), but not after adjusting for covariates (OR = .84, .70-1.01, p = .07). E-cigarette and other tobacco use, sex, race/ethnicity, age, and smoke-free laws were associated with cigarette smoking (p <.05). Results unadjusted for e-cigarette use and other tobacco use yielded a significant negative association between e-cigarette MLSA laws and cigarette smoking (lagged: OR = .78, .64-.93, p = .01; unlagged: OR = .80, .68-.95, p = .01). CONCLUSIONS: After adjusting for covariates, state e cigarette MLSA laws did not affect youth cigarette smoking. Unadjusted for e cigarette and other tobacco use, these laws were associated with lower cigarette smoking. PMID- 29422437 TI - Effect of cold pack therapy for management of burn scar pruritus: A pilot study. AB - PURPOSE: Pruritus, a common, chronically disabling condition is often refractory to treatment. The pruritus sensation is mediated in the spinal cord and post-burn pruritus is considered a form of neuropathic pain. We investigated cold pack therapy as a treatment modality for post-burn pruritus. METHODS: We studied 23 patients with severe pruritus scoring at least 5 on the visual analogue scale (VAS) and refractory to antihistamine and gabapentin administration. Each cold pack therapy lasted more than 20min. Patients participated in more than three sessions daily for 4 consecutive weeks. The numerical rating scale (NRS), 5-D Itch Scale, Leuven Itch Scale, and perfusion units were evaluated before, within 30min after, 2, and 4 weeks cold pack therapy. RESULTS: In all patients, the NRS was 9.37+/-1.47 pre-therapy, 3.48+/-2.19 at 2 weeks, and 2.78+/-2.13 at 4 weeks following therapy, the pre-scores being significantly different (p<0.001). Pruritus severity and consequences scores (Leuven Itch Scale) were improved after therapy compared to pre-therapy. Perfusion unit (PU) scores were statistically insignificant compared to PU scores measured before the application of cold pack therapy. Degree, direction, and disability scores (5-D Itch scale) significantly differed (p<.05). CONCLUSION: Cold pack therapy, a non-invasive, non pharmacological treatment modality significantly reduces post-burn pruritus and could be useful in burn patients. PMID- 29422438 TI - Effect of luteinizing hormone on goat theca cell apoptosis and steroidogenesis through activation of the PI3K/AKT pathway. AB - Luteinizing hormone (LH) is a glycoprotein that regulates the function of ovarian follicular cells. Theca cells (TCs) also have a key role in follicular growth and atresia. The effects and intracellular signaling mechanisms were investigated of LH on apoptosis and steroidogenesis in goat gonadotropin-independent follicular (1.0-4.0 mm) TCs. The results indicated that LH increased androstenedione secretion and relative abundance of CYP17A1 and BCL2 mRNA in the TCs, whereas LH in combination with LY294002, a PI3K/AKT inhibitor, decreased LH-induced function. The apoptosis ratio and expression of the BAX gene in TCs were less with LH treatment, and the extent of this inhibition was decreased by suppressing the PI3K/AKT pathway. In conclusion, results of the present study indicate LH regulates apoptosis and steroidogenesis in goat TCs by activating the PI3K/AKT pathway. PMID- 29422439 TI - Factors Influencing Fluid Milk Waste in a Breakfast in the Classroom School Breakfast Program. AB - OBJECTIVE: To determine predictors of fluid milk waste in a Breakfast in the Classroom School Breakfast Program. DESIGN: Cross-sectional with 3 repeated measures/classroom. SETTING: Elementary schools in a medium-sized, low-income, urban school district. PARTICIPANTS: Twenty third- through fourth-grade classrooms across 6 schools. MAIN OUTCOMES: Dependent variables include percentage of total and served milk wasted. Independent variables included observed daily menu offerings, program factors, and teacher and student behavior. ANALYSIS: Descriptive statistics were used to characterize variables across classrooms and schools. Multilevel mixed-effects models were used to test associations between predictors and outcomes of interest. P <= .05 was considered statistically significant. RESULTS: Total milk waste increased 12% when juice was offered and 3% for each additional carton of unserved milk. Teacher encouragement to take and/or consume breakfast was associated with a 5% and 9% increase in total and served milk waste, respectively. When students were engaged in other activities in addition to eating breakfast, total milk waste decreased 10%. CONCLUSIONS AND IMPLICATIONS: Beverage offerings were predictive of greater total milk waste. Teacher and student behavior also appeared to influence milk consumption. Findings suggest that specific changes to School Breakfast Program implementation policies and practices could have an important role in waste mitigation. PMID- 29422440 TI - GYG1 causing progressive limb girdle myopathy with onset during teenage years (polyglucosan body myopathy 2). AB - An 84-year-old lady with slowly progressive limb and axial muscle weakness with onset in her teens was referred for genetic investigations. Targeted next generation sequencing (NGS) revealed a homozygous mutation GYG1 in exon5:c.487delG:p.D163fs, confirming the diagnosis of Polyglucosan Body Myopathy 2 (PGBM2). Retrospective review of muscle pathology revealed a florid vacuolar myopathy with histochemical and ultrastructural features consistent with a polyglucosan storage myopathy. No cardiac symptoms were reported. Our case is consistent with the core phenotype of GYG1-related PGBM2 apart from an early onset of weakness without cardiac symptoms. The presence of alpha-amylase resistant PAS-positive material in skeletal muscle biopsy of patients with slowly progressive limb girdle muscle weakness should prompt the search for GYG1 mutations. This case highlights the combined role of muscle pathology and NGS in the molecular resolution of patients with undiagnosed neuromuscular conditions. PMID- 29422441 TI - Ambient air pollution the risk of stillbirth: A prospective birth cohort study in Wuhan, China. AB - BACKGROUND: Recent studies suggest that ambient air pollution exposure during pregnancy is associated with stillbirth occurrence. However, the results on the associations between ambient air pollutants and stillbirths are inconsistent and little is known about the gestational timing of sensitive periods for the effects of ambient air pollutants exposure on stillbirth. OBJECTIVE: This study aimed to examine whether exposure to high levels of ambient air pollutants in a Chinese population is associated with an increased risk of stillbirth, and determine the gestational period when the fetus is most susceptible. METHODS: We conducted a population-based cohort study in Wuhan, China, involving 95,354 births between June 10, 2011 and June 9, 2013. The exposure assessments were based on the daily mean concentrations of air pollutants obtained from the exposure monitor nearest to the pregnant women's residence. Logistic regression analyses were performed to determine the associations between stillbirths and exposure to each of the air pollutants at different pregnancy periods with adjustment for confounding factors. RESULTS: Stillbirth increased with a 10 MUg/m3 increase in particulate matter 2.5 (PM2.5) in each stage of pregnancy, and a significant association between carbon monoxide (CO) exposure and stillbirth was found during the third trimester (adjusted odds ratio (aOR): 1.01, 95% confidence interval (CI): 1.00 1.01) and in the entire pregnancy (aOR: 1.18, 95% CI: 1.04-1.34). Furthermore, an increased risk of stillbirth in the third trimester was associated with a 10 MUg/m3 increase in PM10 (aOR: 1.08, 95% CI: 1.04-1.11), nitrogen dioxide (NO2) (aOR: 1.13, 95% CI: 1.07-1.21) and sulfur dioxide (SO2) (aOR: 1.26, 95% CI: 1.16 1.35). However, no positive association was observed between ozone exposure and stillbirth. In the two-pollutant models, PM2.5 and CO exposures were found to be consistently associated with stillbirth. CONCLUSIONS: Our study revealed that exposure to high levels of PM2.5, PM10, SO2, NO2 and CO increases the risk of stillbirth and the most susceptible gestational period to ambient air pollution exposure was in the third trimester. Further toxicological and prospective cohort studies with improved exposure assessments are needed to confirm the causal link between air pollutants and stillbirth. PMID- 29422443 TI - Eggs and Magnetism: New Approaches for Schistosomiasis Diagnosis. AB - To date, reliable techniques that can provide accurate information on the local and global prevalence of schistosomiasis are still associated with high costs or labour-intensive processes. Here we discuss old and new concepts for diagnostic approaches, and we highlight structural properties of schistosome eggshells that result in their affinity for magnetic materials as a new diagnostic approach. PMID- 29422442 TI - Pallidal deep brain stimulation modulates excessive cortical high beta phase amplitude coupling in Parkinson disease. AB - OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are equally efficacious in the management of Parkinson disease (PD). Studies of STN-DBS have revealed a therapeutic reduction in excessive cortical beta-gamma phase-amplitude coupling (PAC). It is unclear whether this is specific to STN-DBS and potentially mediated by modulation of the hyperdirect pathway or if it is a generalizable mechanism seen with DBS of other targets. Moreover, it remains unclear how cortical signals are differentially modulated by movement versus therapy. To clarify, the effects of GPi-DBS and movement on cortical beta power and beta-gamma PAC were examined. METHODS: Right sensorimotor electrocorticographic signals were recorded in 10 PD patients undergoing GPi-DBS implantation surgery. We evaluated cortical beta power and beta-gamma PAC during blocks of rest and contralateral hand movement (finger tapping) with GPi-DBS off and on. RESULTS: Movement suppressed cortical low beta power (P = 0.008) and high beta-gamma PAC (P = 0.028). Linear mixed effect modeling (LMEM) showed that power in low and high beta bands are differentially modulated by movement (P = 0.022). GPi-DBS also results in a significant suppression of high beta-gamma PAC but without power modulation in either beta sub-band (P = 0.008). Cortical high beta-gamma PAC is significantly correlated with severity of bradykinesia (Rho = 0.59, P = 0.045) and changes proportionally with therapeutic improvement (Rho = 0.61, P = 0.04). CONCLUSIONS: Similar to STN DBS, GPi-DBS reduces motor cortical beta-gamma PAC, like that also reported with dopaminergic mediations, suggesting it is a generalizable symptom biomarker in PD, independent of therapeutic target or proximity to the hyperdirect pathway. PMID- 29422444 TI - Opportunistic but Lethal: The Mystery of Paramoebae. AB - Paramoebae are enigmatic single-celled eukaryotes that can be opportunistic pathogens of marine animals. For example, amoebic gill disease ravages farmed salmonids worldwide, causing tens of millions of dollars in losses annually. Although paramoebae can be found associated with animals ranging from fish and lobster to molluscs and sea urchins, how and how often they actually cause disease is unknown. Here we review recent progress towards understanding the biology and ecology of paramoebid species and the eukaryotic endosymbionts that live inside them. Genomic and transcriptomic sequence data serve as a platform upon which future research on paramoebiasis can build. PMID- 29422446 TI - Molecular detection and phylogenetic analysis of Anaplasma marginale and Anaplasma centrale amongst transhumant cattle in north-eastern Uganda. AB - There is little molecular data from Anaplasma marginale and Anaplasma centrale isolates from cattle in Uganda. Between November 2013 and January 2014, blood was collected from 240 cattle in 20 randomly-selected herds in two districts of the Karamoja Region in north-eastern Uganda. A duplex quantitative real-time polymerase chain reaction (qPCR) assay was used to detect and determine the prevalence of A. marginale (targeting the msp1beta gene) and A. centrale (targeting the groEL gene). The qPCR assay revealed that most cattle (82.9%; 95% confidence interval [CI] 78.2-87.7%) were positive for A. marginale DNA, while fewer cattle (12.1%; 95% CI 7.9-16.2%) were positive for A. centrale DNA. A mixed effects logistic regression model showed that the age of cattle was significantly associated with A. centrale infection, while the prevalence of A. marginale varied significantly according to locality. The near full-length 16S ribosomal RNA (16S rRNA) gene and the heat shock protein gene, groEL, for both Anaplasma species were amplified from a selection of samples. The amplicons were cloned and the resulting recombinants sequenced. We found three novel A. marginale 16S rRNA variants, seven A. marginale groEL gene sequence variants and two A. centrale groEL gene sequence variants. Phylogenetic trees were inferred from sequence alignments of the 16S rRNA gene and GroEL amino acid sequences determined here and published sequences using maximum likelihood, Bayesian inference and parsimony methods Phylogenetic analyses classified the 16S rRNA gene and GroEL amino acid sequences into one clade for A. marginale and a separate clade for A. centrale. This study reveals a high prevalence and sequence variability of A. marginale and A. centrale, and is the first report on the phylogenetic characterisation of A. marginale and A. centrale from cattle in Uganda using molecular markers. Sequence variation can be attributed to mobile pastoralism, communal grazing and grazing with wildlife. These data support future epidemiological investigations for bovine anaplasmosis in Uganda. PMID- 29422445 TI - Septic arthritis caused by Granulicatella adiacens after anterior cruciate ligament reconstruction. AB - Septic arthritis after knee arthroscopy is an extremely rare condition. A rate of 0.15-0.84% cases of postoperative infection is estimated in several series. The arthroscopy procedure most frequently related with an infectious complication is anterior cruciate ligament (ACL) reconstruction, with a prevalence of 0.3-1.7% cases. Staphylococcus sp. is the pathogen most commonly cultured. We describe a case of septic arthritis after ACL reconstruction. We found no published case of septic arthritis caused by this microorganism after knee arthroscopy. It is probably the first case published in the literature. PMID- 29422447 TI - High diversity of blood-associated parasites and bacteria in European wild cats in Bosnia and Herzegovina: A molecular study. AB - Wild felids may play a significant role in the transmission of various pathogens to domestic cats, in particular, but also to other animals and humans. However, since data on the occurrence of blood-borne organisms in European wild cats (Felis silvestris silvestris) are scarce, the present study aimed to provide an insight into the genetic diversity of the agents carried by this sylvatic species in Bosnia and Herzegovina and to elucidate their pathogenic impact. Tissue samples from 18 adult wild cats were collected and examined by PCR and histopathology. Five species of apicomplexan parasites belonging to three genera (Babesia sp., Cytauxzoon sp., Hepatozoon silvestris, H. felis, Hepatozoon sp.), as well as two different sequence types of undescribed hemotropic mycoplasmas (designated as type A and type B), were identified in 15 animals (83%). Histopathology revealed no relevant lesions associated with any of the agents detected. The results clearly showed that European wild cats can harbour a broad range of blood-associated parasites and bacteria. However, further studies are required to investigate the possible implication of hematophagous arthropod vectors in their transmission and to clarify the true pathogenic significance of these organisms. Direct transmission of the agents by bites should also be considered as an alternative, non-vectorial route of transmission in wild cats. PMID- 29422448 TI - Predictive value of Borrelia burgdorferi IgG antibody levels in patients referred to a tertiary Lyme centre. AB - A two-step testing strategy is recommended in serological testing for Lyme borreliosis; positive and indeterminate enzyme-linked immunosorbent assay (ELISA) results are confirmed with immunoblots. Several ELISAs quantify the concentration of antibodies tested, however, no recommendation exists for an upper cut-off value at which an IgG ELISA is sufficient and the immunoblot can be omitted. The study objective was to determine at which IgG antibody level an immunoblot does not have any additional predictive value compared to ELISA results. Data of adult patients who visited a tertiary Lyme centre between 2008 and 2014 were analysed. Both an ELISA (Enzygnost Lyme link VlsE IgG) and immunoblot (recomLine blot Borrelia) were performed. Clinical data were extracted from the patient's digital medical record. Positive predictive values (PPVs) for either previous or active infection with Borrelia burgdorferi s.l. were calculated for different cut-off ELISA IgG antibody levels where the immunoblot was regarded as reference test. In total, 1454 patients were included. According to the two-step test strategy, 486 (33%), 69 (5%) and 899 (62%) patients had positive, indeterminate and negative Borrelia IgG serology, respectively. At IgG levels of 500 IU/ml and higher, all immunoblots were positive, resulting in a 100% PPV (95% CI: 97.0-100). At IgG levels of 200 IU/ml and higher, the PPV was 99.3% (95% CI: 97.4-99.8). In conclusion, at IgG levels of 200 IU/ml and higher, an ELISA was sufficient to detect antibodies to Borrelia burgdorferi s.l. At those IgG levels, a confirmatory immunoblot may be omitted in patients referred to a tertiary Lyme centre. Before these results can be implemented in routine diagnosis of Lyme borreliosis, confirmation of the results is necessary in other patient populations and using other quantitative ELISAs and immunoblots. PMID- 29422449 TI - Attention Bias in Individuals with Addictive Disorders: Systematic Review Protocol. AB - BACKGROUND: Globally, substance disorders, particularly that of opiate use, cannabis use, and stimulant use disorders, are highly prevalent. Psychological treatments are an integral aspect of intervention, but a proportion of individuals still relapse despite having received such an intervention. Recently, the dual-process theory proposed that the unconscious processes of attention biases are responsible for these relapses. Prior meta-analyses have reported the presence of attention bias in alcohol and tobacco use disorders. More recent research has examined attention bias and its effectiveness in opiate use, cannabis use, and stimulant use disorder. The evidence syntheses to date have not examined whether attention bias is present in these disorders and could be subjected to manipulation. This is important information and would support the introduction of psychological interventions for attention bias for such patients. Such psychological interventions would help individuals maintain their abstinence and minimize the risk of relapse. OBJECTIVE: This paper aims to undertake a systematic review to synthesize the existing evidence for the presence of attention bias in all the disorders mentioned above, and to determine the clinical efficacy of attention bias modification. METHODS: A systematic review will be conducted. A search will be conducted on the respective databases up till 2017. Selection of the studies will be determined by the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Quality assessment of the included studies will be assessed using the Cochrane Risk of Bias tool. A narrative synthesis will be conducted, with a meta-analysis considered only if there are sufficient studies for statistical analysis. RESULTS: The results of the systematic review will be available 12 months after the publication of this protocol. CONCLUSIONS: This review is important as it will support the introduction of psychological interventions for attention bias for such patients. Such psychological interventions would help individuals maintain their abstinence and minimize the risk of relapse. PMID- 29422450 TI - Effect of Recruitment Methods on Response Rate in a Web-Based Study for Primary Care Physicians: Factorial Randomized Controlled Trial. AB - BACKGROUND: Low participation rates are one of the most serious disadvantages of Web-based studies. It is necessary to develop effective strategies to improve participation rates to obtain sufficient data. OBJECTIVE: The objective of this trial was to investigate the effect of emphasizing the incentive in the subject line of the invitation email and the day of the week of sending the invitation email on the participation rate in a Web-based trial. METHODS: We conducted a 2*2 factorial design randomized controlled trial. We contacted 2000 primary care physicians from members of the Japan Primary Care Association in January 2017 and randomly allocated them to 1 of 4 combinations of 2 subject lines (presence or absence of an emphasis on a lottery for an Amazon gift card worth 3000 yen or approximately US $30) and 2 delivery days (sending the invitation email on Tuesday or Friday). The primary outcome was the response rate defined as the number of participants answering the first page of the questionnaire divided by the number of invitation emails delivered. All outcomes were collected between January 17, 2017, and February 8, 2017. RESULTS: We analyzed data from 1943 out of 2000 participants after excluding those whose email addresses were invalid. The overall response rate was 6.3% (123/1943). There was no significant difference in the response rates between the 2 groups regarding incentive in the subject line: the risk ratio was 1.12 (95% CI 0.80 to 1.58) and the risk difference was 0.7% (95% CI -1.5% to 2.9%). Similarly, there was no significant difference in the response rates between the 2 groups regarding sending the email on Tuesday or Friday: the risk ratio was 0.98 (95% CI 0.70 to 1.38) and the risk difference was -0.1% (95% CI -2.3% to 2.1%). CONCLUSIONS: Neither emphasizing the incentive in the subject line of the invitation email nor varying the day of the week the invitation email was sent led to a meaningful increase in response rates in a Web-based trial with primary care physicians. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000025317; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000029121 (Archived by WebCite at http://www.webcitation. org/6wOo1jl9t). PMID- 29422451 TI - Influence of Radiofrequency Electromagnetic Fields on the Fertility System: Protocol for a Systematic Review and Meta-Analysis. AB - BACKGROUND: Due to the increased number of users of mobile phones, tablets, and other devices over the past few years, concerns about the potential impact of mobile phones on health are growing. The influence of mobile phone exposure on male fertility has been studied in recent years. Other research has shown that electromagnetic fields (EMFs) increase macrophages in the corpus luteum and growing follicles. Due to conflicting results among studies and since no systematic review has been performed to analyze the effects of radiofrequency EMF exposure from electronic devices on the fertility system in recent years, this evidence-based study is necessary. OBJECTIVE: The main objectives of this study are to determine the best evidence associated with the influence of radiofrequency EMFs on the fertility system and to provide insight into a potential mechanism using our observations. METHODS: In this systematic review, the databases and gray literature will be searched with no language and date limitation. The following databases will be searched: Cochrane Library, MEDLINE, PubMed, EMBASE, CINAHL, ProQuest, Scopus, Science Direct, Google Scholar, and other Persian databases. The combination of the Medical Subject Heading terms "radiofrequency electromagnetic" and "male reproductive system" or "female reproductive system" will be searched. Observational study designs will be included but case reports, case series, reviews, and letters to the editor will be excluded. Papers selected for retrieval will be evaluated by two independent referees for methodological validation before entering a review using the Newcastle-Ottawa Scale for nonrandomized studies and cohort studies. RESULTS: The results of this study will be submitted to a peer-reviewed journal for publication and also presented at PROSPERO. CONCLUSIONS: This systematic review will provide evidence-based data on the effect of radiofrequency EMFs on the fertility system. This article will also classify the harmful effect of radiofrequency waves on primary and secondary infertility. This study could be useful for decreasing infertility. This is important because the rate of infertility is growing, leading to negative outcomes for couples and the health care system. TRIAL REGISTRATION: PROSPERO CRD42017072462; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=72462 (Archived by WebCite at http://www.webcitation.org/6wjiE9R2q). PMID- 29422452 TI - Population Size Estimation of Gay and Bisexual Men and Other Men Who Have Sex With Men Using Social Media-Based Platforms. AB - BACKGROUND: Gay, bisexual, and other cisgender men who have sex with men (GBMSM) are disproportionately affected by the HIV pandemic. Traditionally, GBMSM have been deemed less relevant in HIV epidemics in low- and middle-income settings where HIV epidemics are more generalized. This is due (in part) to how important population size estimates regarding the number of individuals who identify as GBMSM are to informing the development and monitoring of HIV prevention, treatment, and care programs and coverage. However, pervasive stigma and criminalization of same-sex practices and relationships provide a challenging environment for population enumeration, and these factors have been associated with implausibly low or absent size estimates of GBMSM, thereby limiting knowledge about the dynamics of HIV transmission and the implementation of programs addressing GBMSM. OBJECTIVE: This study leverages estimates of the number of members of a social app geared towards gay men (Hornet) and members of Facebook using self-reported relationship interests in men, men and women, and those with at least one reported same-sex interest. Results were categorized by country of residence to validate official size estimates of GBMSM in 13 countries across five continents. METHODS: Data were collected through the Hornet Gay Social Network and by using an a priori determined framework to estimate the numbers of Facebook members with interests associated with GBMSM in South Africa, Ghana, Nigeria, Senegal, Cote d'Ivoire, Mauritania, The Gambia, Lebanon, Thailand, Malaysia, Brazil, Ukraine, and the United States. These estimates were compared with the most recent Joint United Nations Programme on HIV/AIDS (UNAIDS) and national estimates across 143 countries. RESULTS: The estimates that leveraged social media apps for the number of GBMSM across countries are consistently far higher than official UNAIDS estimates. Using Facebook, it is also feasible to assess the numbers of GBMSM aged 13-17 years, which demonstrate similar proportions to those of older men. There is greater consistency in Facebook estimates of GBMSM compared to UNAIDS-reported estimates across countries. CONCLUSIONS: The ability to use social media for epidemiologic and HIV prevention, treatment, and care needs continues to improve. Here, a method leveraging different categories of same-sex interests on Facebook, combined with a specific gay-oriented app (Hornet), demonstrated significantly higher estimates than those officially reported. While there are biases in this approach, these data reinforce the need for multiple methods to be used to count the number of GBMSM (especially in more stigmatizing settings) to better inform mathematical models and the scale of HIV program coverage. Moreover, these estimates can inform programs for those aged 13-17 years; a group for which HIV incidence is the highest and HIV prevention program coverage, including the availability of pre-exposure prophylaxis (PrEP), is lowest. Taken together, these results highlight the potential for social media to provide comparable estimates of the number of GBMSM across a large range of countries, including some with no reported estimates. PMID- 29422453 TI - Telehealth Rehabilitation for Cognitive Impairment: Randomized Controlled Feasibility Trial. AB - BACKGROUND: Nonpharmacological interventions are needed to support the function of older adults struggling with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and dementia due to Alzheimer disease (AD). Telerehabilitation aims to provide rehabilitation at a distance, but cognitive rehabilitation by videoconferencing has not been explored. OBJECTIVE: The objective of this study was to compare goal-oriented cognitive rehabilitation delivered in-person with videoconferencing to determine whether telehealth cognitive rehabilitation appears feasible. METHODS: Random assignment to in person or telehealth videoconferencing cognitive rehabilitation with a combined between-subjects, multiple baseline single-case experimental design, cognitive rehabilitation was delivered by a therapist to 6 participants with SCI (n=4), MCI (n=1), or dementia due to AD (n=1). RESULTS: Two of the 6 participants randomly assigned to the telehealth condition withdrew before beginning the intervention. For those who participated in the intervention, 6 out of 6 goals measured with the Canadian Occupational Performance Measure improved for those in the in-person group, and 7 out of 9 goals improved for those in the telehealth group. CONCLUSIONS: Delivery of cognitive rehabilitation by telehealth appeared feasible but required modifications such as greater reliance on caregivers and clients for manipulating materials. PMID- 29422455 TI - Variable selection based on clustering analysis for improvement of polyphenols prediction in green tea using synchronous fluorescence spectra. AB - Synchronous fluorescence spectra, combined with multivariate analysis were used to predict flavonoids content in green tea rapidly and nondestructively. This paper presented a new and efficient spectral intervals selection method called clustering based partial least square (CL-PLS), which selected informative wavelengths by combining clustering concept and partial least square (PLS) methods to improve models' performance by synchronous fluorescence spectra. The fluorescence spectra of tea samples were obtained and k-means and kohonen-self organizing map clustering algorithms were carried out to cluster full spectra into several clusters, and sub-PLS regression model was developed on each cluster. Finally, CL-PLS models consisting of gradually selected clusters were built. Correlation coefficient (R) was used to evaluate the effect on prediction performance of PLS models. In addition, variable influence on projection partial least square (VIP-PLS), selectivity ratio partial least square (SR-PLS), interval partial least square (iPLS) models and full spectra PLS model were investigated and the results were compared. The results showed that CL-PLS presented the best result for flavonoids prediction using synchronous fluorescence spectra. PMID- 29422454 TI - Enhancing Lifestyle Change in Cardiac Patients Through the Do CHANGE System ("Do Cardiac Health: Advanced New Generation Ecosystem"): Randomized Controlled Trial Protocol. AB - BACKGROUND: Promoting a healthy lifestyle (eg, physical activity, healthy diet) is crucial for the primary and secondary prevention of cardiac disease in order to decrease disease burden and mortality. OBJECTIVE: The current trial aims to evaluate the effectiveness of the Do Cardiac Health: Advanced New Generation Ecosystem (Do CHANGE) service, which is developed to assist cardiac patients in adopting a healthy lifestyle and improving their quality of life. METHODS: Cardiac patients (ie, people who have been diagnosed with heart failure, coronary artery disease, and/or hypertension) will be recruited at three pilot sites (Badalona Serveis Assistencials, Badalona, Spain [N=75]; Buddhist Tzu Chi Dalin General Hospital, Dalin, Taiwan [N=100] and Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands [N=75]). Patients will be assisted by the Do Something Different (DSD) program to change their unhealthy habits and/or lifestyle. DSD has been developed to increase behavioral flexibility and subsequently adopt new (healthier) habits. In addition, patients' progress will be monitored with a number of (newly developed) devices (eg, Fitbit, Beddit, COOKiT, FLUiT), which will be integrated in one application. RESULTS: The Do CHANGE trial will provide us with new insights regarding the effectiveness of the proposed intervention in different cultural settings. In addition, it will give insight into what works for whom and why. CONCLUSIONS: The Do CHANGE service integrates new technologies into a behavior change intervention in order to change the unhealthy lifestyles of cardiac patients. The program is expected to facilitate long-term, sustainable behavioral change. TRIAL REGISTRATION: Clinicaltrials.gov NCT03178305; https://clinicaltrials.gov/ct2/show/NCT03178305 (Archived by WebCite at http://www.webcitation.org/6wfWHvuyU). PMID- 29422456 TI - An introduction to optical super-resolution microscopy for the adventurous biologist. AB - Ever since the inception of light microscopy, the laws of physics have seemingly thwarted every attempt to visualize the processes of life at its most fundamental, sub-cellular, level. The diffraction limit has restricted our view to length scales well above 250 nm and in doing so, severely compromised our ability to gain true insights into many biological systems. Fortunately, continuous advancements in optics, electronics and mathematics have since provided the means to once again make physics work to our advantage. Even though some of the fundamental concepts enabling super-resolution light microscopy have been known for quite some time, practically feasible implementations have long remained elusive. It should therefore not come as a surprise that the 2014 Nobel Prize in Chemistry was awarded to the scientists who, each in their own way, contributed to transforming super-resolution microscopy from a technological tour de force to a staple of the biologist's toolkit. By overcoming the diffraction barrier, light microscopy could once again be established as an indispensable tool in an age where the importance of understanding life at the molecular level cannot be overstated. This review strives to provide the aspiring life science researcher with an introduction to optical microscopy, starting from the fundamental concepts governing compound and fluorescent confocal microscopy to the current state-of-the-art of super-resolution microscopy techniques and their applications. PMID- 29422457 TI - Effect of rare earth doping on optical and spectroscopic characteristics of BaZrO3:Eu3+,Tb3+ perovskites. AB - This paper reports structural investigations of rare earth doped BaZrO3 phosphors synthesized by Solid state reaction technique with varying concentrations of Eu3+ and Tb3+ from 0 mol% to 2 mol%. The synthesized phosphors show enhanced variable emissions in the visible region corresponding to different hypersensitive electronic transitions of Eu3+ and Tb3+ ions. With cubic structure confirmed in XRD analysis, the FESEM images show uniform grain connectivity and homogeneity of prepared samples. The TEM micrographs of the synthesized phosphors show agglomerated irregular structures. The synthesized phosphors were also subjected to FTIR, Raman, EDXS analysis along with studies of thermoluminescent and photoluminescent characteristics. On subjecting to 229 nm (UV) excitation, the phosphors show enhanced PL emissions corresponding to 571 nm (5D0-7F0), 591 nm (5D0-7F1), 615 nm (5D0-7F2) and 678 nm (5D0-7F4) hypersensitive transitions of Eu3+ ions and emission peaks at 489 nm (5D4-7F6), 539 nm (5D4-7F5), 589 nm (5D4 7F4) and 632 nm (5D4-7F3) accounting for electronic transitions of Tb3+ ions respectively. The computed average PL lifetime is 14.014 s. In the TL analysis, the second order of kinetics with the activation energy varying from 5.0 * 10-1 eV to 6.6 * 10-1 eV is reported. The maximum TL lifetime is estimated as 19.4985 min in the TL lifetime analysis. PMID- 29422458 TI - Probiotics in Caries Prevention. AB - Past few decades have seen a significant increase in the prevalence of dental caries at a global scale. To reduce the pervasiveness of cariogenic microflora, various efforts have been undertaken. However, completely eradicating caries associated microorganisms has been futile.1 Endogenous bacteria, such as Lactobacillus species, Streptococcus mutans, and Streptococcus sobrinus persisting in biofilms ferment carbohydrate and produce weak organic acids as by products. This, in turn, results in a drop in the local pH well below the critical level, resulting in demineralization of tooth.2. PMID- 29422459 TI - Antifungal Activity of Xylitol against Candida albicans: An in vitro Study. AB - AIM: The most common fungal infection among human population is candidiasis, the etiology of which is mostly Candida albicans. As a result of a disrupted balance of the normal flora or a compromised immune system, Candida species can become pathogenic. Various in vitro surveys have shown that glucose intake is a promoter of C. albicans growth, whereas in vivo studies have found that xylitol can decrease the risk of candidiasis and angular cheilitis. Hence, we aimed to evaluate for the first time the inhibitory effects of xylitol on C. albicans by assessing its minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC). MATERIALS AND METHODS: The standard strain of C. albicans was acquired. The fungi were incubated in supplemented brain-heart infusion broth for 48 hours at 37 degrees C. The MIC was measured according to the Clinical and Laboratory Standards Institute (CLSI) M100-S24 standard. Microdilution method was applied using 360-uL sterilized polystyrene flat-bottomed 96-well plates. The antimicrobial effects were examined by the microbroth dilution method according to the CLSI M100-S24 standard. RESULTS: The MIC of xylitol for C. albicans was found to be 20 * 104 MUg/mL. Furthermore, the concentration of 40 * 104 MUg/mL with a decrease of 99.95% in the colony-forming units (CFUs) of the microorganism was found to be the MFC of xylitol for C. albicans. CONCLUSION: According to the results of this survey, xylitol has considerable antimicrobial effects. Hence, this substance can be used as an effective element in gums, toothpastes, and antimicrobial mouthwashes, especially in patients with candidiasis. CLINICAL SIGNIFICANCE: By knowing the MIC and MFC of xylitol, this substance can be effectively used in products aimed to cure this fungal infection. PMID- 29422460 TI - Effect of Mouthrinses containing Olive Oil, Fluoride, and Their Combination on Enamel Erosion: An in vitro Study. AB - AIM: The aim of the study was to evaluate the effect of mouth-rinses containing olive oil, fluoride, and their combination on enamel erosion. MATERIALS AND METHODS: An in vitro study of 45 enamel specimens, which were prepared from 45 extracted teeth, was employed. Each specimen was subjected to 10 alternative demineralization and remineralization cycles. Remineralizing cycle includes 5 minutes exposure with one of the mouthrinse, and demineralizing cycle includes 3 minute exposure to 1% citric acid. Mean surface roughness (Ra) was measured from surfometry before and after cycles. Statistical tests used were Student's unpaired t-test and one-way analysis of variance (ANOVA), followed by Tukey's post hoc test. RESULTS: Among the three mouthrinses, Listerine and Xerostom showed maximum protection against erosion on enamel. The 2% olive oil mouthrinse showed the least protection against erosion on enamel. CONCLUSION: The study indicated that the Listerine and Xerostom mouthrinses are valuable preventive measures. CLINICAL SIGNIFICANCE: Mouthrinses are effective for lessening erosive demineralization and in aggregating remineralization of tooth surfaces which are the important factors to prevent enamel erosion. PMID- 29422461 TI - Effect of Green Tea Varnish on Depth of Root Caries. AB - AIM: Root caries is a common, debilitating condition particularly in the elderly population, which can lead to tooth loss. Evidence shows that green tea has cariostatic effects. Considering the gap of information on green tea varnish, this study aimed to assess the efficacy of green tea varnish in the prevention of root caries. MATERIALS AND METHODS: This in vitro experimental study was performed on 42 sound premolars. Two layers of acid-resistant nail varnish were applied on root surfaces except for a window of 1 * 4 mm. The teeth were randomly divided into three groups (n = 14). Group I (control) received no intervention. Group II received green tea varnish applied on the roots every 48 hours for 21 days. Group III received green tea varnish every 24 hours for 21 days. Sections of 40 MU thickness were prepared from the center of the window, and the depth of carious lesion was measured in three points with 500 MU distance from each other using polarized light microscope. Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 16 and non-parametric Kruskal-Wallis and Mann-Whitney U tests (alpha = 0.05). RESULTS: The mean (and standard deviation) depth of carious lesion was 54.30 +/- 28.64 (MUm), 0, and 0 in groups I, II, and III respectively. Control group showed the highest depth of caries. Groups II and III were not significantly different in this respect, but significant differences were noted in depth of caries between groups I and II and also groups I and III (p < 0.001). CONCLUSION: Based on the results, the green tea varnish may possess anticariogenic effects on root caries when applied every 24 or 48 hours over a 21 day period. Application of green tea varnish every 24 or 48 hours for 21 days may prevent root caries. CLINICAL SIGNIFICANCE: Application of green tea varnish can prevent root caries. PMID- 29422462 TI - Assessment of Retention and Resistance Form of Tooth Preparations for All Ceramic Restorations using Digital Imaging Technique. AB - AIM: This in vitro study evaluated the resistance form of die preparations for all ceramic restorations and, thereby, explored the concept of effective taper and its correlation between the ideal in theory and actual in the clinical situation by analyzing the digital images of the die preparations. MATERIALS AND METHODS: Scanned digital images of 114 die preparations for all ceramic restorations (n = 114) were collected from a dental laboratory. All the images were also analyzed digitally using Adobe Photoshop(r) software to analyze the degree of taper (angle of convergence) of each preparation and then applied the Zuckerman's circle, and the Lewis perpendicular methods were used to measure the resistance form. RESULTS: For the current study, the overall average degree of taper was found to be 20.9 degrees (range, 2-80 degrees ), which is more than what is recommended by most previous studies and also sharply greater than the textbook ideal of 3 to 6 degrees . Mean degree of taper for maxillary was 17.56 degrees (anterior-10.50 degrees , posterior-23.7 degrees ), and for mandibular teeth, it was 25.22 degrees (anterior-15 degrees , posterior- 28.45 degrees ). Out of the 64 analyzed images of maxillary teeth, 61 presented resistance form, while 3 were without it. Out of the 50 mandibular teeth analyzed, 38 possessed resistance form, whereas 12 were without. All the anterior teeth showed resistance form irrespective of the arch. CONCLUSION: The degree of taper showed a significant relationship with resistance and retention form, which was inversely proportional to each other. The recommended "degree of taper" is not always the clinically achievable as advocated in textbooks, as it is modified by various factors in the actual clinical situation. CLINICAL SIGNIFICANCE: The study provides scientific background regarding the relationship between the degree of taper with resistance and retention form, and the relationship was found to be inversely proportional to each other. The recommended "degree of taper" is not always the clinically achievable as advocated in textbooks, and it is modified by various modifying or limiting factors in the actual clinical situation. PMID- 29422463 TI - Effectiveness of Different Bristle Designs of Toothbrushes and Periodontal Status among Fixed Orthodontic Patients: A Double-blind Crossover Design. AB - AIM: The aim of the present study was to evaluate the effectiveness of different bristle designs of toothbrushes and the periodontal status among patients undergoing fixed orthodontic treatment. MATERIALS AND METHODS: This randomized controlled trial (RCT) consisted of 45 adolescents (comprising 20 males and 25 females) undergoing fixed orthodontic treatment. The study participants were randomly allocated to three groups, each group being assigned a locally available toothbrush with a particular design of toothbrush bristle. In the first test phase, group I study participants were allocated to toothbrush with flat bristles, group II study subjects were allocated to toothbrush with zigzag bristles, and group III study participants were allocated to toothbrush with crisscross bristles. The study participants were recalled after 4 weeks to check the effectiveness of the allocated toothbrushes. A washout period of 1 week was maintained to ensure that there was no carryover effect of the different bristle designs. In the second test phase, each patient used the opposite toothbrush bristle design (group I: toothbrush with zigzag bristles, group II: toothbrush with crisscross bristles, and group III: toothbrush with flat bristles). Plaque scores were measured using Turesky-Gilmore-Glickman modification of Quigley-Hein plaque index (PI). RESULTS: In both phase 1 and 2 of this RCT, toothbrush with crisscross bristles exhibited maximum plaque reduction among the three different bristle design toothbrushes following 30 days (p = 0.312 +/- 0.102 and 0.280 +/- 0.110, respectively), which was statistically significant. CONCLUSION: It was concluded that all the three designs of toothbrushes were effective in removing plaque in patients with fixed orthodontic appliances. But among the three different toothbrushes, toothbrush with crisscross bristles showed the highest mean plaque reduction. CLINICAL SIGNIFICANCE: Plaque accumulation around the orthodontic brackets and gingival margins is quite common among the fixed orthodontic patients, who encounter difficulty in maintaining good oral hygiene. Specially designed toothbrushes are very essential for effective plaque removal among the patients undergoing fixed orthodontic treatment. PMID- 29422464 TI - Structural and Morphological Evaluation of Presintered Zirconia following Different Surface Treatments. AB - AIM: The aim of this study was to evaluate the effect of different surface treatments on roughness, grain size, and phase transformation of presintered zirconia. MATERIALS AND METHODS: Surface treatments included airborne particle abrasion (APA) before and after sintering with different particles shape, size, and pressure (50 MUm Al2O3, 50 MUm glass beads, and ceramic powder). Thirty-five square-shaped presin-tered yttrium-stabilized tetragonal zirconia polycrystal (Y TZP) ceramic slabs (Zenostar ZR bridge, Wieland) were prepared (4 mm height * 10 mm width * 10 mm length) and polished with silicon carbide grit papers #800, 1000, 1200, 1500, and 2000 to ensure identical initial roughness. Specimens were divided into five groups according to surface treatment: group I (control): no surface treatment; group II: APA 50 MUm Al2O3 after sintering; group III: APA 50 MUm Al2O3 particles before sintering; group IV: APA 50 MUm glass bead particles before sintering; and group V: APA ceramic powder before sintering. Specimens were analyzed using scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray diffraction (XRD) analyses, and tested for shear bond strength (SBS). Data were statistically analyzed using one-way analysis of variance (ANOVA) followed by post hoc tests for multiple comparisons Tukey's test (a > 0.05). RESULTS: Air abrasion before sintering significantly increased the surface roughness when compared with groups I and III. The highest tetragonal to monoclinic (t-m) phase transformation (0.07%) was observed in group III, and a reverse transformation was observed in presintered groups (0.01%). Regarding bond strength, there was a significant difference between APA procedures pre- and postsintering. CONCLUSION: Air abrasion before sintering is a valuable method for increasing surface roughness and SBS. The abrasive particles' size and type used before sintering had a little effect on phase transformation. CLINICAL SIGNIFICANCE: Air abrasion before sintering could be supposed to be an alternative surface treatment method to air abrasion after sintering. PMID- 29422466 TI - Proliferative Index in Invasive Tumor Front of Oral Squamous Cell Carcinoma: A Potential Prognostic Indicator. AB - AIM: The aim of the study was to evaluate the proliferative index (PI) at their invasive front of oral cancer and their association with Bryne's grades of oral squamous cell carcinoma (OSCC) and compare the PI with lymph node metastasis, site of involvement, and habits. MATERIALS AND METHODS: The Ki-67 antigen expression was immunohistochemically evaluated in a total of 102 cases that included the histopathologically diagnosed archival specimens of OSCCs. They were subdivided by Bryne's histopathological grading into grade I (40 cases), grade II (32 cases), and grade III (30 cases). The nucleus with brown stain was considered positive. Cells were counted under 400* magnification. The proliferative activity thus determined was then expressed as a percentage of Ki-67 labeling index (Ki-67 LI) positive cells. RESULTS: A stepwise increase in the mean Ki-67 LI was found from grade I to III squamous cell carcinoma, thus correlating with the histological grading. In addition, there was a higher PI seen in cases associated with metastatic lymph node, which concords with the higher biologic aggressiveness and poor prognosis of the lesion. CONCLUSION: The present study shows a definitive correlation of Ki-67 antigen with the Bryne's histological grading, all the parameters of Bryne's grading for OSCC and lymph node status of the patient proving its association as an effective tool to grade the tumors and finally read the prognosis of the tumor. CLINICAL SIGNIFICANCE: Cell proliferation is regarded as one of the most important biologic mechanisms in oncogenesis. The role of cell proliferation in tumor progression has been inferred in studies concerned with human cancer by comparing the PI of normal tissue, preneoplastic and neoplastic lesions. The Ki-67 antigen-labeled cells can prove to be an effective aid to grade the tumors. It might be possible to standardize and objectify tumor grading among pathology laboratories. PMID- 29422465 TI - Estimation of Plasma Levels of Tumor Necrosis Factor-a, Interleukin-4 and 6 in Patients with Chronic Periodontitis and Type II Diabetes Mellitus. AB - INTRODUCTION: Both periodontitis and type II diabetes mellitus (T2DM) are common diseases with a multifactorial etiology and have influence of cytokines in their pathogenesis and thus may also influence each other. In recent times, more attention has been given to understanding the influences of these inflammatory cytokines which are a main part of oral chronic inflammation on systemic health of the individuals. Therefore, the aim of this study was to evaluate the plasma cytokine levels, specifically tumor necrosis factor-a (TNF-a), interleukin (IL) 6, and IL-4, in chronic periodontitis patients and T2DM patients, so as to investigate the influence of chronic periodontitis in systemic inflammation associated with diabetes mellitus. MATERIALS AND METHODS: The present study comprised a total sample size of 60 patients. A detailed history along with complete periodontal examination were done for each person. These patients were subdivided into four study groups with 15 subjects (n = 15) in each group: group I: healthy individuals, group II: chronic periodontitis, group III: diabetes mellitus without chronic periodontitis, and group IV: diabetes mellitus with chronic periodontitis. Venous blood was withdrawn for obtaining serum samples from the subjects. Hemoglobin A1c (HbAlc) levels were measured from the automated chromatography. Using enzyme-linked immunosorbent assay kit, TNF-a, IL-4, and IL 6 were measured. RESULTS: It was observed that the difference between almost all the results showed statistical significance. Not much of a difference was seen when TNF-a and IL-6 findings of group II were compared with group III. Furthermore, IL-4 also did not differ when group II was compared with group IV. CONCLUSION: The inflammatory cytokines together control the inflammation process and a balance is maintained. However, in patients with diabetes mellitus, this balance is interrupted, which affects the final development and progression of the disease. Thus, hyperglycemia may be partly associated with the severity of the periodontal status in diabetic patients. CLINICAL SIGNIFICANCE: Hyperglycemia thus may play a role in increasing the severity of the periodontal status in diabetic patients. Keeping such relationship in mind, better treatment modalities can be provided to the patients. PMID- 29422467 TI - Spirometric Assessment of Impact of Complete Dentures on Respiratory Performance: An in vitro Study. AB - INTRODUCTION: Edentulism is one of the debilitating states affecting a significant portion of the geriatric population. It is often considered as the ultimate marker for predicting the pressure and burden on oral health. Respiration is also a routine vital function running continuously through the human body and most commonly assessed by a spirometer. Hence, we planned the present study to assess the impact of complete dentures on the functioning of the respiratory system. MATERIALS AND METHODS: In the present study, a spirometric assessment of the effect of complete dentures on respiratory performance was done. A total of 100 subjects were included, and diagnostic spirometer was used for carrying out the spiro-metric test at different stages of each subject. The spirometric test was carried out at four different stages: In the absence of both the denture (AODs), with both the dentures (maxillary and mandibular) inserted in the patient's mouth (BDs), with only maxillary denture inserted in the oral cavity (UDs), and finally, by inserting only the mandibular dentures in the oral cavity (LDs). Forced vital capacity (FVC), peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV1), and forced expiratory flow between 25 and 75% (FEF25-75) were evaluated. All the results were compiled and assessed using Statistical Package for the Social Sciences (SPSS) software. RESULTS: Of the total 100 subjects included in the study, 42 were males and 58 were females. The mean FVC values of AOD, BD, LD, and UD group were 3.10, 3.02, 2.90, and 2.93 respectively. The mean PEF values of AOD, BD, LD, and UD group were 5.79, 5.60, 5.40, and 5.48 respectively; 2.39, 2.35, 2.33, and 2.32 were the mean FEV1 values observed in AOD, BD, LD, and UD group respectively. Statistically significant results were obtained while comparing AOD-FVC and BD-FVC and other oral conditions. CONCLUSION: Spirometric values of respiratory functional tests in edentulous patients might be unfavorably affected by wearing complete dentures. CLINICAL SIGNIFICANCE: Since subjects without complete dentures exhibited a maximum value of respiratory functional test, respiratory exercise protocols should also be carried in denture-wearing edentulous patients for increasing the performance of the respiratory system. PMID- 29422468 TI - Surface Characterization and Cell Adhesion of Different Zirconia Treatments: An in vitro Study. AB - AIM: The aim of this study was to characterize the surface of zirconia subjected to different treatments and evaluate its effect on cell adhesion and proliferation. MATERIALS AND METHODS: A total of 80 zirconia disks were divided into four groups (n = 20) according to the surface treatments used: group I: as sintered (AS), no surface treatment applied; group II: abrasion treatment applied using Rocatec (ROC; 3M ESPE) system with silica-coated alumina powder of grit size 110 MUm; group III: erbium, chromium:yttrium, scandium, gallium, garnet (Er, Cr:YSGG) laser (LAS; BIOLASE) was used at a frequency of 20 Hz and output power of 3 W; and group IV: specimens were subjected to the selective infiltration etching (SIE) technique. Surface characterization was evaluated for the different groups (roughness, hardness, and morphology), and cell behavior (adhesion and proliferation) was tested (a = 0.05). RESULTS: The ROC group reported a significant increase in surface roughness (2.201 +/- 0.352) and Vickers hardness (1758 +/- 16.6) compared with the other surface treatments. The SIE surface treated group reported a significantly higher number of cells (64.5 +/- 2.6 and 53.5 +/- 2.2 respectively) compared with the other surface-treated groups. CONCLUSION: The SIE is a promising surface treatment for zirconia that significantly enhances cell adhesion and osseointegration. CLINICAL SIGNIFICANCE: The SIE treatment of zirconia implants may help in a faster and better osseointegration. PMID- 29422469 TI - Microtensile Bond Strength of Polyacid-modified Composite Resin to Irradiated Primary Molars. AB - AIM: This study evaluated the influence of various doses of radiotherapy on the microtensile bond strength (pTBS) of compomer resin to dentin and enamel in primary molars. MATERIALS AND METHODS: Thirty-five intact primary molars were collected and divided into seven groups. Teeth were irradiated with doses from 10 to 60 Gy, except for the control group. Compomer restorations were performed, and enamel-compomer resin beams and dentin-compomer resin beams were tested at a crosshead speed of 1 mm/min. RESULTS: No statistically significant difference was found between the irradiated tooth enamel and the control group (F = 1.1468; p = 0.194). However, statistically significant differences were evident among the dentin groups (F = 11.050; p < 0.001). CONCLUSION: Radiation may not cause a significant difference in the pTBS of compomer resin to primary tooth enamel, but appears to dose dependently decrease its bond strength to primary tooth dentin. CLINICAL SIGNIFICANCE: Radiotherapy may affect the success rate of compomer fillings in primary teeth, especially in deeper cavities with exposed dentin. PMID- 29422470 TI - Influences of Light-emitting Diode Illumination Bleaching Technique on Nanohardness of Computer-aided Design and Computer-aided Manufacturing Ceramic Restorative Materials. AB - AIM: This study evaluated the effect of light-emitting diode (LED) illumination bleaching technique on the surface nanohardness of various computer-aided design and computer-aided manufacturing (CAD/CAM) ceramic materials. MATERIALS AND METHODS: Twenty disk-shaped samples (width, length, and thickness = 10, 15, and 2 mm) were prepared from each of the ceramic materials for CAD/CAM, including LavaTM Ultimate (LV), Vita Enamic(r) (En) IPS e.max(r) CAD (Me), inCoris(r) TZI (IC), and Prettau(r) zirconia (Pr). The samples from each type of ceramic were randomly divided into two groups based on the different bleaching techniques to be used on them, using 35% hydrogen peroxide with and without LED illumination. The ceramic disk samples were bleached according to the manufacturer's instruction. Surface hardness test was performed before and after bleaching using nanohardness tester with a Berkovich diamond indenter. RESULTS: The respective Vickers hardness number upon no bleaching and bleaching without or with LED illumination [mean +/- standard deviation (SD)] for each type of ceramic were as follows: 102.52 +/- 2.09, 101.04 +/- 1.18, and 98.17 +/- 1.15 for LV groups; 274.96 +/- 5.41, 271.29 +/- 5.94, and 268.20 +/- 7.02 for En groups; 640.74 +/- 31.02, 631.70 +/- 22.38, and 582.32 +/- 33.88 for Me groups; 1,442.09 +/- 35.07, 1,431.32 +/- 28.80, and 1,336.51 +/- 34.03 for IC groups; and 1,383.82 +/- 33.87, 1,343.51 +/- 38.75, and 1,295.96 +/- 31.29 for Pr groups. The results indicated surface hardness reduction following the bleaching procedure of varying degrees for different ceramic materials. Analysis of variance (ANOVA) revealed a significant reduction in surface hardness due to the effect of bleaching technique, ceramic material, and the interaction between bleaching technique and ceramic material (p < 0.05). CONCLUSION: Bleaching resulted in a diminution of the surface hardness of dental ceramic for CAD/CAM. Using 35% hydrogen peroxide bleaching agent with LED illumination exhibited more reduction in surface hardness of dental ceramic than what was observed without LED illumination. CLINICAL SIGNIFICANCE: Clinicians should consider protection of the existing restoration while bleaching. PMID- 29422471 TI - Evaluation of the Flexural Strength of Submicron Hybrid Composite using Different Fabrication Methods: An in vitro Study. AB - AIM: The aim of this study is to perform three-point bend test on submicron hybrid composite fabricated with direct and indirect veneer technique. MATERIALS AND METHODS: A total of 20 maxillary anterior teeth were selected, and labial reduction of 0.5 to 0.75 mm with a chamfered finish line for veneer preparation was done. Teeth were divided into two groups depending on fabrication technique being used: group I-veneers fabricated with light and group II-veneers fabricated with light and heat (PHOTOPOL). Specimens were tested under universal testing machine (UTM) where load was applied at a crosshead speed of 1 mm/min with a pointer of 1 mm diameter. Data were statistically analyzed. RESULTS: The results showed highly significant difference between the two groups with the mean value of group I (246.7 +/- 2.285 N) and group II (531.1 +/- 4.411 N). CONCLUSION: The curing mechanism involving light and heat increases the fracture resistance of the veneers. CLINICAL SIGNIFICANCE: Within the limitations of this study, the results led to the conclusion that the association of common composites with a simple postcure heat treatment may be an alternative for current indirect composite systems, although more studies are needed to assess other properties of the composites for this application. PMID- 29422472 TI - Evaluation of Hemoglobin Concentration and Hematocrit Values in Temporomandibular Joint Ankylosis Patients in Comparison to Nonankylosed Patients. AB - AIM: The aim of this study is to find if there is any correlation between the hematological parameters and temporomandibular joint (TMJ) ankylosis and severity of the disease in such patients when compared with the nonankylosed patients. MATERIALS AND METHODS: A total of 70 patients with age ranging from 10 to 40 years were included in the study after excluding the subjects according to the inclusion criteria. We categorized the subjects into two major groups: group I: control (nonankylosed/ healthy subjects) and group II: study group (ankylosed subjects) with each group containing 35 subjects (n = 35) respectively. A detailed personal and medical history was obtained. The pharynx diameter was also recorded for each patient, and blood investigations using venous blood were done, which included hemoglobin concentration and hematocrit values. RESULTS: The results of study population showed a mean age of 22 +/- 2.2 years. The most common etiology reported was trauma (65.7%) followed by infections, in which Noma was the most common one (80%). The difference of the mean values for hemoglobin and hematocrit concentration, between both the groups, was found to be statistically significant (p < 0.0001). Furthermore, a positive correlation was observed between the hemoglobin concentration and duration of ankylosis. CONCLUSION: This study was an attempt to find a relation between the hemoglobin and hematocrit values in TMJ ankylosis patients so that the clinical treatment and management of such patients during surgeries be improved and may be beneficial for the patient. CLINICAL SIGNIFICANCE: Temporomandibular joint ankylosis patients have to undergo complex surgical treatment, where the risk of excessive blood loss is high. Therefore, considering the complications of blood transfusions, such as infections and other risk factors, these patients can be good subjects for autologous blood transfusions, which help in improvement of the overall well-being of the patient. PMID- 29422473 TI - Comparison of Preoperative and Perioperative Antibiotic Prophylaxis Regimen in Compound Facial Fractures. AB - AIMS AND OBJECTIVES: Intraoperative antibiotics may be effective in elective surgery; there may be an advantage to starting antibiotics preoperatively when there is already an infective focus, such as compound facial fractures. The purpose of this study is to compare preoperative and intraoperative antibiotic prophylaxis in compound facial fractures. MATERIALS AND METHODS: This is a prospective study conducted over a period of 2 years on 50 patients, who underwent open reduction and rigid internal fixation. The patients were assigned to two groups. The patients in group I received antibiotics at the time of admission. The patients in group II received antibiotics perioperatively at the time of induction of general anesthesia. Postoperatively, the patients were evaluated for the reduction of pain and the presence of infection by assessing the local presence of erythema, swelling, a rise in temperature, and purulent discharge, if any, on a predefined proforma. RESULTS: A total of 72 fractures were assessed in 50 patients. There was an overall reduction of pain in both the groups. Wound healing status was found to be satisfactory in both the groups. CONCLUSION: Wound status and infection rate were evaluated in patients of both the groups. In the study, there was no difference between the two groups on the predecided parameters whether the antibiotics were given either preoperatively or perioperatively. CLINICAL SIGNIFICANCE: It is very essential to have a sound knowledge of the use of antibiotic therapy effectively to prevent the overuse of it and, thereby, help avoid developing resistance to antibiotics in patients. PMID- 29422474 TI - Effect of Bleaching Mouthwash on Force Decay of Orthodontic Elastomeric Chains. AB - INTRODUCTION: Force decay elastomeric chains are significant, and it is a clinical problem. AIM: The aim of this study was to evaluate the effects of bleaching agent in the mouthwash on the force decay of orthodontic chains. MATERIALS AND METHODS: In this experimental study, 160 gray closed elastomeric chains were randomly divided into three groups (one control and two test groups). Four loops of chains were stretched for 25 mm on custom-made jig. Control group specimens were immersed in artificial saliva during the test period. Test group specimens were immersed twice a day for 30 seconds in the whitening (LISTERINE(r) HEALTHY WHITETM) and daily sodium fluoride (LISTERINE(r) TOTAL CARE ZERO) mouthwashes. All specimens were immersed in artificial saliva at 37 degrees C. Force was measured at different time points (initial, 1, 7, 14, 21, 28 days). Statistical analysis was performed by two-way analysis of variance (ANOVA) and Bonferroni methods (a = 0.05). RESULTS: Force of elastomeric chains was decreased dramatically in all groups during the experiment. After 24 hours, force was decreased by 42.18, 48.34, and 53.38% in control group, daily, and bleaching mouthwash groups respectively. The corresponding numbers after 4 weeks were 66.30, 76.73, and 86.48. The difference between three groups at days 1 and 28 was statistically significant (p < 0.05). CONCLUSION: Within the limitations of the current in vitro study, bleaching and sodium fluoride mouthwashes could cause force decay of orthodontic elastomeric chains. Whitening mouthwash is more weakening for elastomeric chains. CLINICAL SIGNIFICANCE: Use of whitening mouthwash by orthodontic patients could decrease the force of elastomeric chains, so it could be recommended to use them for a short time. PMID- 29422475 TI - Clinical Evaluation of Microhybrid Composite and Glass lonomer Restorative Material in Permanent Teeth. AB - AIM: The aim of this study was to clinically compare glass ionomer cement (GIC) with microhybrid composite resin used in class I cavities on permanent teeth over a period of 9 months. MATERIALS AND METHODS: A total of 40 teeth with class I cavities were divided into two groups (n = 20) and restored with GIC (EQUIA; GC) and microhybrid resin composite (Amelogen Plus; Ultradent). Restorations were evaluated at *4.5 magnification using the United States Public Health Service (USPHS) criteria every 3 months. Statistical analysis was performed using the Fisher's exact test (a < 0.05). RESULTS: The data obtained reported no statistical significance difference between both groups in regard to anatomical shape, color, postoperative sensitivity, secondary caries, material handling, adaptation, and marginal staining. CONCLUSION: The results of this clinical study showed that GIC (EQUIA; GC) can be used for the restoration of permanent teeth and may be more appropriate for certain clinical situations than the resin composite material. CLINICAL SIGNIFICANCE: EQUIA (GIC) is a viable alternative to resin composite in restoring class I cavities in permanent teeth. PMID- 29422476 TI - Middle Mesial and Middle Distal Canals in Mandibular First Molar. AB - BACKGROUND: Root canal anatomy is a complex entity. The main objective of root canal treatment is to get rid of the infection and have a good apical and coronal seal with an appropriate filling. Inability to achieve thorough cleaning and shaping followed by three-dimensional obturation of the root canal system usually causes root canal treatment failure. For this reason, clinicians should be aware of these anatomical variations to achieve successful treatment. AIM: The aim of this article is to report on the successful treatment and follow-up of mandibular first molar with additional middle mesial (MM) and middle distal (MD) canals. CASE REPORT: A 29-year-old white male patient reported with a complaint of pain in relation with tooth #19. On clinical examination, diagnosis of symptomatic irreversible pulpitis with symptomatic apical periodontitis and condensing osteitis was made and nonsurgical root canal treatment was planned. Initially, two mesial and two distal canals were located, and the patient was planned for the obturation in the second visit. The complaint of mild persistent symptoms gave a possibility of additional canals. Under the dental operating microscope and selective troughing on the floor of the pulp chamber with ultrasonic tips, additional canals were located as MM and MD canals. CONCLUSION: Leaving some area of the root canal system untreated is found to be one of the main reasons for root canal treatment failure. Dentists should take advantage of new tools, such as dental operating microscope and ultrasonic tips to be able to locate and treat the hidden and unusual anatomy. CLINICAL SIGNIFICANCE: Mandibular first molar with six canals is very rare to encounter. Clinician should have a thorough knowledge of these unusual anatomy to avoid treatment failure due to incomplete disinfection of the root canal system. PMID- 29422477 TI - Parental Presence/Absence in the Dental Operatory as a Behavior Management Technique: A Review and Modified View. AB - INTRODUCTION: Parental presence/absence in the dental operatory (also called: Parent-in-parent-out technique) is an extremely controversial aspect of the nonpharmacological BMTs. Historically, dentists used to exclude parents from dental operatory to avoid their interference with the dentist's aptitude to build a rapport and relationship with the child, hence increasing the child management problems by disrupting treatment and making the dentist unfocused and uncomfortable. AIM: The purpose of this article is to review and emphasize on the importance of parental presence/absence in the dental operatory, especially in a certain age group, as a behavior management technique (BMT) in pediatric dentistry, and to present a modified view of this technique. RESULTS: This article reviews the current literature concerning behavior management in pediatric dentistry. It includes a medline database search and review of the comprehensive textbooks in pediatric dentistry. Some recommendations were based on the opinions of experienced researchers and clinicians. CONCLUSION: Parent-in parent-out technique in dental operatory is advocated to gain emotional support and avoid the effect of traumatic separation, especially in younger children or special health-care needs patients. CLINICAL SIGNIFICANCE: The parent-in-parent out technique in dental operatory is underused, or misused. This article clarifies the proper use of this technique along with a minor modification to it to make it more effective on young apprehensive dental patients. PMID- 29422478 TI - Angiogenesis and Fibrogenesis in Oral Submucous Fibrosis: A Viewpoint. AB - : Oral submucous fibrosis (OSF) is characterized by excessive fibrosis of submucosa. The degree of vascularity in OSF has always been a matter of debate. Angiogenesis is the key mechanism involved in regeneration and repair. It also plays an important role in various pathologic conditions. Angiogenesis may contribute to the progression of fibrosis in fibrotic disorders. Inhibition of pathological angiogenesis is considered to be a new strategy for the treatment of various fibrotic disorders. In OSF, angiogenesis can be related to progression fibrosis. This article briefly describes the role of angiogenesis in pathogenesis of fibrosis in OSF and the importance of inhibition of pathologic angiogenesis in its prevention and treatment. CLINICAL SIGNIFICANCE: Understanding the association between angiogenesis and fibrogenesis can help in developing new therapeutic strategies for treatment of OSF. PMID- 29422479 TI - Nonopioid drugs for pain. PMID- 29422480 TI - Comparison table: Some nonopioid analgesics for pain. PMID- 29422481 TI - Investigation of Adipose Tissue Fatty Acid Composition in Men with Uronephrolithiasis and Metabolic Syndrome. AB - BACKGROUND Fatty acids (FA) and their metabolites are closely related to some mechanisms involved in the development of uronephrolithiasis. The aim of this study was to evaluate the relationship between FA composition and type of kidney stones. MATERIAL AND METHODS Abdominal adipose tissue fatty acid methyl esters of 71 men with nephrolithiasis were identified by GC/MS, and the type of kidney stones was identified using FTIR infrared spectroscopy. Patients were divided into groups according to diagnosis of metabolic syndrome (MS) and type of kidney stone. The composition of FA was compared within different groups of patients with different types of kidney stones and between the patients and healthy individuals (control group) (n=100). RESULTS Individuals with nephrolithiasis had a significantly higher level of monounsaturated fatty acids (MUFA) and a lower level of polyunsaturated fatty acids (PUFA) versus healthy individuals. Patients with MS had a higher level of 18: 1omega9 and a lower level of 16: 1omega7 than patients without MS. Individuals with nephrolithiasis, but without MS, had a higher level of saturated fatty acids (SFA) compared to controls. The level of PUFA was higher in the control group (p<0.0001) compared to individuals with uronephrolithiasis, with or without MS. PUFA, omega - 6 PUFA, and 18: 2omega6 were higher in patients with calcium-based kidney stones without MS versus patients with uric acid kidney stones with MS. CONCLUSIONS The levels of MUFA were significantly higher and the levels of PUFA were significantly lower in patients with uronephrolithiasis compared to controls. PMID- 29422482 TI - Management of Hypothenar Hammer Syndrome A Case Report. AB - BACKGROUND Hypothenar hammer syndrome is a relatively rare disease process caused by repetitive stress or injury to the hypothenar eminence leading to chronic injury to the ulnar artery. This chronic stress (usually as a result of occupational or sport activities) may result in arterial constriction or thickening, which may lead to thrombosis or aneurysm formation. A review of current literature revealed that reports related to management of hypothenar hammer syndrome are limited. CASE REPORT A 33-year-old male without significant past medical history presented with left hand/digit pain, skin discoloration, and coolness of the hand/digits after a mechanical accident experienced 12 hours prior to presentation. Angiography confirmed reduced flow in the ulnar and radial artery with significant spasm of the ulnar artery. Treatment consisted of heparin, nitroglycerin, and papaverine with rapid resolution of symptoms. The patient was discharged on anticoagulation and a calcium channel blocker, with scheduled follow-up. CONCLUSIONS Hypothenar hammer syndrome is a rare disease process which manifests in certain occupations and activities that put undue stress on the hypothenar area. The use of angiography for definitive diagnosis and the use of anticoagulation and calcium channel blockers for treatment should continue to be studied to determine a standard treatment regimen. PMID- 29422483 TI - The Effects of Isopropyl Methylphosphono-Fluoridate (IMPF) Poisoning on Tumor Growth and Angiogenesis in BALB/C Mice. AB - BACKGROUND Acetylcholinesterase (AChE) and cholinergic receptors have an important role in the immune system and angiogenesis. This work evaluated the effects of isopropyl methylphosphonofluoridate (IMPF), an irreversible inhibitor of AChE, on tumor growth and selected parameters associated with tumor angiogenesis. MATERIAL AND METHODS Experiments were performed on male BALB/c mice exposed to IMPF (study group) or saline buffer (control group) and inoculated with L-1 sarcoma; the number of new blood vessels (TIA test) and the level of alphavbeta3 integrin (131I-MAb-antibeta3 assay) were analyzed at seven, 14, or 21 days after implantation of the tumor cells. RESULTS The IMPF poisoning affected tumor angiogenesis (TIA test). There was a statistically significant increase in the number of newly forming blood vessels in the group subjected to IMPF and inoculated with tumor cells. CONCLUSIONS This study showed that IMPF had a significant effect on the regulation of lymphocyte-induced angiogenesis and the modulation of angiogenic and pro-inflammatory cytokines secretion. The observed effects suggest involvement of neuronal and/or non-neuronal cholinergic signaling pathway. PMID- 29422484 TI - Spiral sockets for various types of stumps in transhumeral amputees: a case series. AB - BACKGROUND: Fitting a stump prosthesis is difficult in transhumeral amputees because of the stump's conical form. Shoulder harnesses for suspension can cause neck and shoulder pain. We developed a novel spiral socket transhumeral prosthesis to overcome these difficulties. We investigated its safety and effects in transhumeral amputees. CASE REPORT: Five transhumeral amputees with a mean age of 50.8+/-23.8 (range, 19-75 years) were fitted with the spiral socket between April 2013 and February 2017. Spiral sockets can adapt to changes in the shape of the stump, even in early stages when stump shape can change. It can also adapt to an hourglass-shaped stump. CLINICAL REHABILITATION IMPACT: The novel spiral socket transhumeral prosthesis might be useful for socket-stump adaptation at various stages after amputation. It may also be used for irregularly shaped stumps and can possibly prevent secondary complications, including neck and shoulder pain and skin disorders. PMID- 29422485 TI - Is the word "osteoporosis" a reason for kinesiophobia? AB - BACKGROUND: Osteoporosis is a systemic skeletal disease that causes weakening of the bones which increases the risk of fractures. Especially hip fractures lead to substantial physical, psychological, social and economic burden both for the patients and the governments. Exercises and physically active life style are essential preventive and therapeutic approaches for osteoporosis. Kinesiophobia is an irrational fear of movement due to the belief of susceptibility to injury. It is associated with lower levels of physical activity. Having a diagnosis of osteoporosis without an adequate education about the disease may lead to kinesiophobia in patients due to an illogical belief about increasing possibility of falls and related fractures during physical activity. AIM: To evaluate relationship between the diagnosis of osteoporosis and kinesiophobia. DESIGN: Case-control study. SETTING: Division of Rheumatology, Department of Rehabilitation, University Hospital. POPULATION: Fifty-four subjects with osteoporosis and fifty-four healthy subjects who were age- and gender-matched. METHODS: Demographic data of subjects (age, gender, weight, height, body mass index, disease duration) were recorded. The Tampa Kinesiophobia Scale (TKS) was applied to determine the level of fear of movement. Hospital Anxiety and Depression Scale (HADS) was used to evaluate mood status. The Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO-41) was performed to assess health related quality of life. Scores were compared between groups by Mann Whitney U test. Correlation between kinesiophobia and QUALEFFO-41 scores was performed by Spearman rank correlation. RESULTS: Subjects with osteoporosis had higher level of kinesiophobia than healthy control subjects. There was no significant difference in HADS scores between the groups. QUALEFFO 41 total score was worse in subjects with osteoporosis than those in healthy subjects. There was a significant correlation between QUALEFFO-41 total score and kinesiophobia score in subjects with osteoporosis. CONCLUSIONS: Subjects with osteoporosis have higher levels of kinesiophobia compared to age and gender matched healthy subjects. Kinesiophobia may affect the quality of life in subjects with osteoporosis. CLINICAL REHABILITATION IMPACT: As physical activity is essential for bone and general health, individuals should be educated and counseled about osteoporosis and the importance of physical activity to overcome kinesiophobia. PMID- 29422486 TI - Evaluating the functional outcomes of ultrasound-guided botulinum toxin type A injections using the Euro-musculus approach for upper limb spasticity treatment in post-stroke patients: an observational study. AB - BACKGROUND: Ultrasound-guided botulinum toxin type A injection is an effective treatment for spasticity. Euro-musculus spasticity approach is a new method for administering injections to the correct point of the correct muscle. The clinical outcomes of this practical approach are not yet available in the literature. AIM: The purpose of this study was to evaluate the effects on spasticity and the functional outcomes of ultrasound guided botulinum toxin type A injections via the Euro-musculus spasticity approach to treat upper limb spasticity in post stroke patients. DESIGN: Observational study. SETTING: Inpatient post-stroke patients. POPULATION: Twenty-five post-stroke patients with post-stroke upper limb spasticity were recruited. METHODS: The ultrasound-guided botulinum toxin type A injections were administered into the spastic target muscles using the Euro-musculus spasticity approach, and all of the patients were enrolled in rehabilitation programs after the injections. This research included the innervation zone and injection site figures and ultrasound images of each muscle in the upper limb. The degree of spasticity was assessed via the Modified Ashworth Scale and the upper limb motor function via the Fugl Meyer Upper Extremity Scale at the baseline and 4 and 12 weeks after the botulinum toxin type A injection. RESULTS: Significant decreases in the Modified Ashworth Scale scores of the upper limb flexor muscle tone measured 4 and 12 weeks after the botulinum toxin type A injection were found when compared to the baseline scores (P<0.025). When compared with the baseline Fugl Meyer Upper Extremity subgroup scores, the sitting position, wrist and total scores at 4 and 12 weeks were significantly improved (P<0.025). However, only the Fugl Meyer Upper Extremity hand scores were significantly improved 12 weeks after the injection (P<0.025). CONCLUSIONS: Ultrasound-guided botulinum toxin type A injection via the Euro-musculus spasticity approach is a practical and effective method for administering injections to the correct point of the correct muscle. Ultrasound-guided botulinum toxin type A injections combined with rehabilitation programs decrease spasticity and improve the upper extremity motor functions in stroke patients. CLINICAL REHABILITATION IMPACT: This new approach for ultrasound-guided botulinum toxin type A injection is very practical and effective method for upper extremity spasticity. PMID- 29422487 TI - No tension between assembly models of super massive black hole binaries and pulsar observations. AB - Pulsar timing arrays are presently the only means to search for the gravitational wave stochastic background from super massive black hole binary populations, considered to be within the grasp of current or near-future observations. The stringent upper limit from the Parkes Pulsar Timing Array has been interpreted as excluding (>90% confidence) the current paradigm of binary assembly through galaxy mergers and hardening via stellar interaction, suggesting evolution is accelerated or stalled. Using Bayesian hierarchical modelling we consider implications of this upper limit for a range of astrophysical scenarios, without invoking stalling, nor more exotic physical processes. All scenarios are fully consistent with the upper limit, but (weak) bounds on population parameters can be inferred. Recent upward revisions of the black hole-galaxy bulge mass relation are disfavoured at 1.6sigma against lighter models. Once sensitivity improves by an order of magnitude, a non-detection will disfavour the most optimistic scenarios at 3.9sigma. PMID- 29422488 TI - Phenotyping field-state wheat root system architecture for root foraging traits in response to environment*management interactions. AB - An important aspect of below-ground crop physiology is its root foraging performance, which is inherently related to root system architecture (RSA). A 2 yr field experiment was conducted and the field-state wheat RSA was phenotyped for root foraging trait (RFT). Four RSA-derived traits, i.e. Root horizontal angle (RHA), axial root expansion volume (AREV), RSA convex hull volume (CHV) and effective volume per unit root length (EVURL), were analyzed for RFTs in response to environment * management interactions. Results showed a dynamical RHA process but without statistical difference both within crop seasons and tillage treatments. AREV increased with root developmental stages, revealing an overall better root performance in the first year. However, tillage treatments did not induce observed difference within both crop seasons. CHV varied drastically from year to year and between tillage treatments, correlating well to the root length, but not with RHA. EVURL was both sensitive to tillage treatments and crop seasons, being a potential indicator for RFT. Above all, tillage effect on RFT was statistically far less than that induced by crop seasons. Pro/E assisted modeling can be used as an effective means for phenotyping integrated, RSA derived, RFTs for root foraging response to induced environment * management interactions. PMID- 29422489 TI - Simple model of saturable localised surface plasmon. AB - Localised surface plasmons (LSPs) are now applied to various fields, such as bio sensing, solar cell, molecular fluorescence enhancement and quantum-controlled devices at nanometre scale. Recent experiments show that LSPs are optically saturated by high-intensity light. Absorption saturation arises as a result of strong optical nonlinearity and cannot be explained by the conventional boson model of LSPs. Here, we propose a simple model of saturable LSPs using an effective dipole approximation. The strategy is to directly compare the classical linear optical response of an LSP with that obtained from a saturable quantum two level system in the limit of weak excitation. The second quantization can then be performed by replacing a classical polarizability with a quantum dipole operator. Taking an ellipsoidal nanometal as an example, we analyse in detail the optical response of a single ellipsoidal nanometal to validate our model. Our numerical results show that the plasmon resonance frequency and spectral linewidth decrease as the aspect ratio of the ellipsoid increases, which is similar to the size dependence observed in early experiments. PMID- 29422490 TI - Dibutyl phthalate alters the metabolic pathways of microbes in black soils. AB - Dibutyl phthalate (DBP) is well known as a high-priority pollutant. This study explored the impacts of DBP on the metabolic pathways of microbes in black soils in the short term (20 days). The results showed that the microbial communities were changed in black soils with DBP. In nitrogen cycling, the abundances of the genes were elevated by DBP. DBP contamination facilitated 3'-phosphoadenosine-5' phosphosulfate (PAPS) formation, and the gene flux of sulfate metabolism was increased. The total abundances of ABC transporters and the gene abundances of the monosaccharide-transporting ATPases MalK and MsmK were increased by DBP. The total abundance of two-component system (TCS) genes and the gene abundances of malate dehydrogenase, histidine kinase and citryl-CoA lyase were increased after DBP contamination. The total abundance of phosphotransferase system (PTS) genes and the gene abundances of phosphotransferase, Crr and BglF were raised by DBP. The increased gene abundances of ABC transporters, TCS and PTS could be the reasons for the acceleration of nitrogen, carbon and sulfate metabolism. The degrading-genes of DBP were increased markedly in soil exposed to DBP. In summary, DBP contamination altered the microbial community and enhanced the gene abundances of the carbon, nitrogen and sulfur metabolism in black soils in the short term. PMID- 29422491 TI - Targeting estrogen receptor beta (ERbeta) for treatment of ovarian cancer: importance of KDM6B and SIRT1 for ERbeta expression and functionality. AB - Estrogen receptor (ER) beta has growth inhibitory and chemo drug potentiating effect on ovarian cancer cells. We studied the dependence of ERbeta function on the presence of KDM6B and SIRT1 in human ovarian cancer cells in vitro. Activation of ERbeta with the subtype-selective agonist KB9520 resulted in significant inhibition of human ovarian cancer cell growth. KB9520-activated ERbeta had an additive effect on growth inhibition in combination with cisplatin and paclitaxel, respectively. Loss of KDM6B expression had a negative effect on ERbeta function as a ligand-dependent inhibitor of ovarian cancer cell growth. In contrast, loss or inhibition of SIRT1 deacetylase activity restored ligand activated ERbeta functionality. Presented data suggest that selective targeting of ERbeta with an agonist potentiate chemotherapy efficacy for the treatment of ovarian cancer and that downregulation or inhibition of SIRT1 may further enhance its therapeutic effect. PMID- 29422492 TI - A quantum optical study of thresholdless lasing features in high-beta nitride nanobeam cavities. AB - Exploring the limits of spontaneous emission coupling is not only one of the central goals in the development of nanolasers, it is also highly relevant regarding future large-scale photonic integration requiring energy-efficient coherent light sources with a small footprint. Recent studies in this field have triggered a vivid debate on how to prove and interpret lasing in the high-beta regime. We investigate close-to-ideal spontaneous emission coupling in GaN nanobeam lasers grown on silicon. Such nanobeam cavities allow for efficient funneling of spontaneous emission from the quantum well gain material into the laser mode. By performing a comprehensive optical and quantum-optical characterization, supported by microscopic modeling of the nanolasers, we identify high-beta lasing at room temperature and show a lasing transition in the absence of a threshold nonlinearity at 156 K. This peculiar characteristic is explained in terms of a temperature and excitation power-dependent interplay between zero-dimensional and two-dimensional gain contributions. PMID- 29422494 TI - Central Composite Design Optimization of Zinc Removal from Contaminated Soil, Using Citric Acid as Biodegradable Chelant. AB - Citric acid (CA) was evaluated in terms of its efficiency as a biodegradable chelating agent, in removing zinc (Zn) from heavily contaminated soil, using a soil washing process. To determine preliminary ranges of variables in the washing process, single factor experiments were carried out with different CA concentrations, pH levels and washing times. Optimization of batch washing conditions followed using a response surface methodology (RSM) based central composite design (CCD) approach. CCD predicted values and experimental results showed strong agreement, with an R2 value of 0.966. Maximum removal of 92.8% occurred with a CA concentration of 167.6 mM, pH of 4.43, and washing time of 30 min as optimal variable values. A leaching column experiment followed, to examine the efficiency of the optimum conditions established by the CCD model. A comparison of two soil washing techniques indicated that the removal efficiency rate of the column experiment (85.8%) closely matching that of the batch experiment (92.8%). The methodology supporting the research experimentation for optimizing Zn removal may be useful in the design of protocols for practical engineering soil decontamination applications. PMID- 29422493 TI - Impact of Drinking Water Fluoride on Human Thyroid Hormones: A Case- Control Study. AB - The elevated fluoride from drinking water impacts on T3, T4 and TSH hormones. The aim was study impacts of drinking water fluoride on T3, T4 and TSH hormones inYGA (Yazd Greater Area). In this case- control study 198 cases and 213 controls were selected. Fluoride was determined by the SPADNS Colorimetric Method. T3, T4 and TSH hormones tested in the Yazd central laboratory by RIA (Radio Immuno Assay) method. The average amount of TSH and T3 hormones based on the levels of fluoride in two concentration levels 0-0.29 and 0.3-0.5 (mg/L) was statistically significant (P = 0.001 for controls and P = 0.001 for cases). In multivariate regression logistic analysis, independent variable associated with Hypothyroidism were: gender (odds ratio: 2.5, CI 95%: 1.6-3.9), family history of thyroid disease (odds ratio: 2.7, CI 95%: 1.6-4.6), exercise (odds ratio: 5.34, CI 95%: 3.2-9), Diabetes (odds ratio: 3.7, CI 95%: 1.7-8), Hypertension (odds ratio: 3.2, CI 95%: 1.3-8.2), water consumption (odds ratio: 4, CI 95%: 1.2-14). It was found that fluoride has impacts on TSH, T3 hormones even in the standard concentration of less than 0.5 mg/L. Application of standard household water purification devices was recommended for hypothyroidism. PMID- 29422495 TI - Patterns of sexual size dimorphism in horseshoe bats: Testing Rensch's rule and potential causes. AB - Rensch's rule, stating that sexual size dimorphism (SSD) becomes more evident and male-biased with increasing body size, has been well supported for taxa that exhibit male-biased SSD. Bats, primarily having female-biased SSD, have so far been tested for whether SSD allometry conforms to Rensch's rule in only three studies. However, these studies did not consider phylogeny, and thus the mechanisms underlying SSD variations in bats remain unclear. Thus, the present study reviewed published and original data, including body size, baculum size, and habitat types in 45 bats of the family Rhinolophidae to determine whether horseshoe bats follow Rensch's rule using a phylogenetic comparative framework. We also investigated the potential effect of postcopulatory sexual selection and habitat type on SSD. Our findings indicated that Rensch's rule did not apply to Rhinolophidae, suggesting that SSD did not significantly vary with increasing size. This pattern may be attributable interactions between weak sexual selection to male body size and strong fecundity selection for on female body size. The degree of SSD among horseshoe bats may be attributed to a phylogenetic effect rather than to the intersexual competition for food or to baculum length. Interestingly, we observed that species in open habitats exhibited greater SSD than those in dense forests, suggesting that habitat types may be associated with variations in SSD in horseshoe bats. PMID- 29422496 TI - Opioid Antagonists and the A118G Polymorphism in the MU-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype. AB - This corrects the article DOI: 10.1038/npp.2016.60. PMID- 29422497 TI - Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence. AB - This corrects the article DOI: 10.1038/npp.2017.205. PMID- 29422498 TI - Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study. AB - This corrects the article DOI: 10.1038/npp.2017.48. PMID- 29422499 TI - Single-Subject Anxiety Treatment Outcome Prediction using Functional Neuroimaging. AB - This corrects the article DOI: 10.1038/npp.2013.328. PMID- 29422500 TI - The tumour microenvironment creates a niche for the self-renewal of tumour promoting macrophages in colon adenoma. AB - Circulating CCR2+ monocytes are crucial for maintaining the adult tissue-resident F4/80hiMHCIIhi macrophage pool in the intestinal lamina propria. Here we show that a subpopulation of CCR2-independent F4/80hiMHCIIlow macrophages, which are the most abundant F4/80hi cells in neonates, gradually decline in number in adulthood; these macrophages likely represent the fetal contribution to F4/80hi cells. In colon adenomas of ApcMin/+ mice, F4/80hiMHCIIlow macrophages are not only preserved, but become the dominant subpopulation among tumour-resident macrophages during tumour progression. Furthermore, these pro-tumoural F4/80hiMHCIIlow and F4/80hiMHCIIhi macrophages can self-renew in the tumour and maintain their numbers mostly independent from bone marrow contribution. Analyses of colon adenomas indicate that CSF1 may be a key facilitator of macrophage self renewal. In summary, the tumour microenvironment creates an isolated niche for tissue-resident macrophages that favours macrophage survival and self-renewal. PMID- 29422501 TI - LARP7 family proteins have conserved function in telomerase assembly. AB - Understanding the intricacies of telomerase regulation is crucial due to the potential health benefits of modifying its activity. Telomerase is composed of an RNA component and reverse transcriptase. However, additional factors required during biogenesis vary between species. Here we have identified fission yeast Lar7 as a member of the conserved LARP7 family, which includes the Tetrahymena telomerase-binding protein p65 and human LARP7. We show that Lar7 has conserved RNA-recognition motifs, which bind telomerase RNA to protect it from exosomal degradation. In addition, Lar7 is required to stabilise the association of telomerase RNA with the protective complex LSm2-8, and telomerase reverse transcriptase. Lar7 remains a component of the mature telomerase complex and is required for telomerase localisation to the telomere. Collectively, we demonstrate that Lar7 is a crucial player in fission yeast telomerase biogenesis, similarly to p65 in Tetrahymena, and highlight the LARP7 family as a conserved factor in telomere maintenance. PMID- 29422502 TI - Glucose repression can be alleviated by reducing glucose phosphorylation rate in Saccharomyces cerevisiae. AB - Microorganisms commonly exhibit preferential glucose consumption and diauxic growth when cultured in mixtures of glucose and other sugars. Although various genetic perturbations have alleviated the effects of glucose repression on consumption of specific sugars, a broadly applicable mechanism remains unknown. Here, we report that a reduction in the rate of glucose phosphorylation alleviates the effects of glucose repression in Saccharomyces cerevisiae. Through adaptive evolution under a mixture of xylose and the glucose analog 2 deoxyglucose, we isolated a mutant strain capable of simultaneously consuming glucose and xylose. Genome sequencing of the evolved mutant followed by CRISPR/Cas9-based reverse engineering revealed that mutations in the glucose phosphorylating enzymes (Hxk1, Hxk2, Glk1) were sufficient to confer simultaneous glucose and xylose utilization. We then found that varying hexokinase expression with an inducible promoter led to the simultaneous utilization of glucose and xylose. Interestingly, no mutations in sugar transporters occurred during the evolution, and no specific transporter played an indispensable role in simultaneous sugar utilization. Additionally, we demonstrated that slowing glucose consumption also enabled simultaneous utilization of glucose and galactose. These results suggest that the rate of intracellular glucose phosphorylation is a decisive factor for metabolic regulations of mixed sugars. PMID- 29422503 TI - LARP7-like protein Pof8 regulates telomerase assembly and poly(A)+TERRA expression in fission yeast. AB - Telomerase is a reverse transcriptase complex that ensures stable maintenance of linear eukaryotic chromosome ends by overcoming the end replication problem, posed by the inability of replicative DNA polymerases to fully replicate linear DNA. The catalytic subunit TERT must be assembled properly with its telomerase RNA for telomerase to function, and studies in Tetrahymena have established that p65, a La-related protein 7 (LARP7) family protein, utilizes its C-terminal xRRM domain to promote assembly of the telomerase ribonucleoprotein (RNP) complex. However, LARP7-dependent telomerase complex assembly has been considered as unique to ciliates that utilize RNA polymerase III to transcribe telomerase RNA. Here we show evidence that fission yeast Schizosaccharomyces pombe utilizes the p65-related protein Pof8 and its xRRM domain to promote assembly of RNA polymerase II-encoded telomerase RNA with TERT. Furthermore, we show that Pof8 contributes to repression of the transcription of noncoding RNAs at telomeres. PMID- 29422504 TI - Low-Loss Photonic Reservoir Computing with Multimode Photonic Integrated Circuits. AB - We present a numerical study of a passive integrated photonics reservoir computing platform based on multimodal Y-junctions. We propose a novel design of this junction where the level of adiabaticity is carefully tailored to capture the radiation loss in higher-order modes, while at the same time providing additional mode mixing that increases the richness of the reservoir dynamics. With this design, we report an overall average combination efficiency of 61% compared to the standard 50% for the single-mode case. We demonstrate that with this design, much more power is able to reach the distant nodes of the reservoir, leading to increased scaling prospects. We use the example of a header recognition task to confirm that such a reservoir can be used for bit-level processing tasks. The design itself is CMOS-compatible and can be fabricated through the known standard fabrication procedures. PMID- 29422505 TI - Independent estimates of marine population connectivity are more concordant when accounting for uncertainties in larval origins. AB - Marine larval dispersal is a complex biophysical process that depends on the effects of species biology and oceanography, leading to logistical difficulties in estimating connectivity among populations of marine animals with biphasic life cycles. To address this challenge, the application of multiple methodological approaches has been advocated, in order to increase confidence in estimates of population connectivity. However, studies seldom account for sources of uncertainty associated with each method, which undermines a direct comparative approach. In the present study we explicitly account for the statistical uncertainty in observed connectivity matrices derived from elemental chemistry of larval mussel shells, and compare these to predictions from a biophysical model of dispersal. To do this we manipulate the observed connectivity matrix by applying different confidence levels to the assignment of recruits to source populations, while concurrently modelling the intrinsic misclassification rate of larvae to known sources. We demonstrate that the correlation between the observed and modelled matrices increases as the number of observed recruits classified as unknowns approximates the observed larval misclassification rate. Using this approach, we show that unprecedented levels of concordance in connectivity estimates (r = 0.96) can be achieved, and at spatial scales (20-40 km) that are ecologically relevant. PMID- 29422506 TI - Landscape genomics and pathway analysis to understand genetic adaptation of South African indigenous goat populations. AB - In Africa, extensively raised livestock populations in most smallholder farming communities are exposed to harsh and heterogeneous climatic conditions and disease pathogens that they adapt to in order to survive. Majority of these livestock species, including goats, are of non-descript and uncharacterized breeds and their response to natural selection presented by heterogeneous environments is still unresolved. This study investigated genetic diversity and its association with environmental and geographic conditions in 194 South African indigenous goats from different geographic locations genotyped on the Illumina goat SNP50K panel. Population structure analysis revealed a homogeneous genetic cluster of the Tankwa goats, restricted to the Northern Cape province. Overall, the Boer, Kalahari Red, and Savanna showed a wide geographic spread of shared genetic components, whereas the village ecotypes revealed a longitudinal distribution. The relative importance of environmental factors on genetic variation of goat populations was assessed using redundancy analysis (RDA). Climatic and geographic variables explained 22% of the total variation while climatic variables alone accounted for 17% of the diversity. Geographic variables solitarily explained 1% of the total variation. The first axis (Model I) of the RDA analysis revealed 329 outlier SNPs. Landscape genomic approaches of spatial analysis method (SAM) identified a total of 843 (1.75%) SNPs, while latent factor mixed models (LFMM) identified 714 (1.48%) SNPs significantly associated with environmental variables. Significant markers were within genes involved in biological functions potentially important for environmental adaptation. Overall, the study suggested environmental factors to have some effect in shaping the genetic variation of South African indigenous goat populations. Loci observed to be significant and under selection may be responsible for the adaption of the goat populations to local production systems. PMID- 29422507 TI - Mosquito community influences West Nile virus seroprevalence in wild birds: implications for the risk of spillover into human populations. AB - Mosquito community composition plays a central role in the transmission of zoonotic vector-borne pathogens. We evaluated how the mosquito community affects the seroprevalence of West Nile virus (WNV) in house sparrows along an urbanisation gradient in an area with the endemic circulation of this virus. We sampled 2544 birds and 340829 mosquitoes in 45 localities, analysed in 15 groups, each containing one urban, one rural and one natural area. WNV seroprevalence was evaluated using an epitope-blocking ELISA kit and a micro virus-neutralization test (VNT). The presence of WNV antibodies was confirmed in 1.96% and 0.67% of birds by ELISA and VNT, respectively. The VNT-seropositive birds were captured in rural and natural areas, but not in urban areas. Human population density was zero in all the localities where VNT-positive birds were captured, which potentially explains the low incidence of human WNV cases in the area. The prevalence of neutralizing antibodies against WNV was positively correlated with the abundance of the ornithophilic Culex perexiguus but negatively associated with the abundance of the mammophilic Ochlerotatus caspius and Anopheles atroparvus. These results suggest that the enzootic circulation of WNV in Spain occurs in areas with larger populations of Cx. perexiguus and low human population densities. PMID- 29422508 TI - SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF 2alpha. AB - One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme usually repressed in the tumor milieu. Here we show that specific SOD3 re-expression in tumor-associated endothelial cells (ECs) increases doxorubicin (Doxo) delivery into and chemotherapeutic effect on tumors. Enhanced SOD3 activity fostered perivascular nitric oxide accumulation and reduced vessel leakage by inducing vascular endothelial cadherin (VEC) transcription. SOD3 reduced HIF prolyl hydroxylase domain protein activity, which increased hypoxia-inducible factor-2alpha (HIF-2alpha) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2alpha ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2alpha levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy. PMID- 29422509 TI - Identifying Phase-Amplitude Coupling in Cyclic Alternating Pattern using Masking Signals. AB - Judiciously classifying phase-A subtypes in cyclic alternating pattern (CAP) is critical for investigating sleep dynamics. Phase-amplitude coupling (PAC), one of the representative forms of neural rhythmic interaction, is defined as the amplitude of high-frequency activities modulated by the phase of low-frequency oscillations. To examine PACs under more or less synchronized conditions, we propose a nonlinear approach, named the masking phase-amplitude coupling (MPAC), to quantify physiological interactions between high (alpha/lowbeta) and low (delta) frequency bands. The results reveal that the coupling intensity is generally the highest in subtype A1 and lowest in A3. MPACs among various physiological conditions/disorders (p < 0.0001) and sleep stages (p < 0.0001 except S4) are tested. MPACs are found significantly stronger in light sleep than deep sleep (p < 0.0001). Physiological conditions/disorders show similar order in MPACs. Phase-amplitude dependence between delta and alpha/lowbeta oscillations are examined as well. delta phase tent to phase-locked to alpha/lowbeta amplitude in subtype A1 more than the rest. These results suggest that an elevated delta alpha/lowbeta MPACs can reflect some synchronization in CAP. Therefore, MPAC can be a potential tool to investigate neural interactions between different time scales, and delta-alpha/lowbeta MPAC can serve as a feasible biomarker for sleep microstructure. PMID- 29422510 TI - TGFbeta1 reinforces arterial aging in the vascular smooth muscle cell through a long-range regulation of the cytoskeletal stiffness. AB - Here we report exquisitely distinct material properties of primary vascular smooth muscle (VSM) cells isolated from the thoracic aorta of adult (8 months) vs. aged (30 months) F344XBN rats. Individual VSM cells derived from the aged animals showed a tense internal network of the actin cytoskeleton (CSK), exhibiting increased stiffness (elastic) and frictional (loss) moduli than those derived from the adult animals over a wide frequency range of the imposed oscillatory deformation. This discrete mechanical response was long-lived in culture and persistent across a physiological range of matrix rigidity. Strikingly, the pro-fibrotic transforming growth factor beta1 (TGFbeta1) emerged as a specific modifier of age-associated VSM stiffening in vitro. TGFbeta1 reinforced the mechanical phenotype of arterial aging in VSM cells on multiple time and length scales through clustering of mechanosensitive alpha5beta1 and alphavbeta3 integrins. Taken together, these studies identify a novel nodal point for the long-range regulation of VSM stiffness and serve as a proof-of-concept that the broad-based inhibition of TGFbeta1 expression, or TGFbeta1 signal transduction in VSM, may be a useful therapeutic approach to mitigate the pathologic progression of central arterial wall stiffening associated with aging. PMID- 29422511 TI - Ultrafast ion sieving using nanoporous polymeric membranes. AB - The great potential of nanoporous membranes for water filtration and chemical separation has been challenged by the trade-off between selectivity and permeability. Here we report on nanoporous polymer membranes with an excellent balance between selectivity and permeability of ions. Our membranes are fabricated by irradiating 2-MUm-thick polyethylene terephthalate Lumirror(r) films with GeV heavy ions followed by ultraviolet exposure. These membranes show a high transport rate of K+ ions of up to 14 mol h-1 m-2 and a selectivity of alkali metal ions over heavy metal ions of >500. Combining transport experiments and molecular dynamics simulations with a polymeric nanopore model, we demonstrate that the high permeability is attributable to the presence of nanopores with a radius of ~0.5 nm and a density of up to 5 * 1010 cm-2, and the selectivity is ascribed to the interaction between the partially dehydrated ions and the negatively charged nanopore wall. PMID- 29422512 TI - Depiction of pneumothoraces in a large animal model using x-ray dark-field radiography. AB - The aim of this study was to assess the diagnostic value of x-ray dark-field radiography to detect pneumothoraces in a pig model. Eight pigs were imaged with an experimental grating-based large-animal dark-field scanner before and after induction of a unilateral pneumothorax. Image contrast-to-noise ratios between lung tissue and the air-filled pleural cavity were quantified for transmission and dark-field radiograms. The projected area in the object plane of the inflated lung was measured in dark-field images to quantify the collapse of lung parenchyma due to a pneumothorax. Means and standard deviations for lung sizes and signal intensities from dark-field and transmission images were tested for statistical significance using Student's two-tailed t-test for paired samples. The contrast-to-noise ratio between the air-filled pleural space of lateral pneumothoraces and lung tissue was significantly higher in the dark-field (3.65 +/- 0.9) than in the transmission images (1.13 +/- 1.1; p = 0.002). In case of dorsally located pneumothoraces, a significant decrease (-20.5%; p > 0.0001) in the projected area of inflated lung parenchyma was found after a pneumothorax was induced. Therefore, the detection of pneumothoraces in x-ray dark-field radiography was facilitated compared to transmission imaging in a large animal model. PMID- 29422513 TI - Genetic relatedness reveals total population size of white sharks in eastern Australia and New Zealand. AB - Conservation concerns exist for many sharks but robust estimates of abundance are often lacking. Improving population status is a performance measure for species under conservation or recovery plans, yet the lack of data permitting estimation of population size means the efficacy of management actions can be difficult to assess, and achieving the goal of removing species from conservation listing challenging. For potentially dangerous species, like the white shark, balancing conservation and public safety demands is politically and socially complex, often leading to vigorous debate about their population status. This increases the need for robust information to inform policy decisions. We developed a novel method for estimating the total abundance of white sharks in eastern Australia and New Zealand using the genetic-relatedness of juveniles and applying a close-kin mark recapture framework and demographic model. Estimated numbers of adults are small (ca. 280-650), as is total population size (ca. 2,500-6,750). However, estimates of survival probability are high for adults (over 90%), and fairly high for juveniles (around 73%). This represents the first direct estimate of total white shark abundance and survival calculated from data across both the spatial and temporal life-history of the animal and provides a pathway to estimate population trend. PMID- 29422514 TI - Do physicians measure patients' blood pressure, and are those measurements reliable? AB - To determine how and how often blood pressure (BP) measurement is performed in health institutions. The researchers observed whether or not 84 physicians performed BP measurement. Immediately after BP measurement by the physician, this was repeated by the researchers in a manner compatible with HT guidelines. The physicians' and researchers' BP measurement results were compared. Physicians measured BP in only 37% (427) of 1130 consecutive patient examinations. None of the physicians "BP measurements were fully compatible with the guidelines" BP measurement recommendations. Physicians who performed measurements determined the same SBP and DBP as the researchers in 34.3% of patients. Hypertension was determined in 18.9% of patients in clinics in which BP measurement was not performed by physicians. Not all physicians in our study measured BP, and the great majority of those who did failed to measure it reliably. We think that it is therefore vitally important for physicians across the world to receive regular, repeated, and effective training in the importance of BP measurement and how to perform it correctly. PMID- 29422516 TI - Terawatt-scale optical half-cycle attosecond pulses. AB - Extreme-ultravoilet (XUV) attosecond pulses with durations of a few tens of attosecond have been successfully applied for exploring ultrafast electron dynamics at the atomic scale. But their weak intensities limit the further application in demonstrating nonlinear responses of inner-shell electrons. Optical attosecond pulses will provide sufficient photon flux to initiate strong field processes. Here we proposed a novel method to generate an ultra-intense isolated optical attosecond pulse through relativistic multi-cycle laser pulse interacting with a designed gas-foil target. The underdense gas target sharpens the multi-cycle laser pulse, producing a dense layer of relativistic electrons with a thickness of a few hundred nanometers. When the dense electron layer passes through an oblique foil, it emits single ultra-intense half-cycle attosecond pulse in the visible and ultraviolet spectral range. The emitted pulse has a peak intensity exceeding 1018 W/cm2 and full-width-half-maximum duration of 200 as. The peak power of this attosecond light source reaches 2 terawatt. The proposed method relaxes the single-cycle requirement on the driving pulse for isolated attosecond pulse generation and significantly boosts the peak power, thus it may open up the route to new experiments tracking the nonlinear response of inner-shell electrons as well as nonlinear attosecond phenomena investigation. PMID- 29422515 TI - Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification. AB - Hey2 gene mutations in both humans and mice have been associated with multiple cardiac defects. However, the currently reported localization of Hey2 in the ventricular compact zone cannot explain the wide variety of cardiac defects. Furthermore, it was reported that, in contrast to other organs, Notch doesn't regulate Hey2 in the heart. To determine the expression pattern and the regulation of Hey2, we used novel methods including RNAscope and a Hey2 CreERT2 knockin line to precisely determine the spatiotemporal expression pattern and level of Hey2 during cardiac development. We found that Hey2 is expressed in the endocardial cells of the atrioventricular canal and the outflow tract, as well as at the base of trabeculae, in addition to the reported expression in the ventricular compact myocardium. By disrupting several signaling pathways that regulate trabeculation and/or compaction, we found that, in contrast to previous reports, Notch signaling and Nrg1/ErbB2 regulate Hey2 expression level in myocardium and/or endocardium, but not its expression pattern: weak expression in trabecular myocardium and strong expression in compact myocardium. Instead, we found that FGF signaling regulates the expression pattern of Hey2 in the early myocardium, and regulates the expression level of Hey2 in a Notch1 dependent manner. PMID- 29422517 TI - Role of Precursor Carbides for Graphene Growth on Ni(111). AB - Surface X-ray Diffraction was used to study the transformation of a carbon supersaturated carbidic precursor toward a complete single layer of graphene in the temperature region below 703 K without carbon supply from the gas phase. The excess carbon beyond the 0.45 monolayers of C atoms within a single Ni2C layer is accompanied by sharpened reflections of the |4772| superstructure, along with ring-like diffraction features resulting from non-coincidence rotated Ni2C-type domains. A dynamic Ni2C reordering process, accompanied by slow carbon loss to subsurface regions, is proposed to increase the Ni2C 2D carbide long-range order via ripening toward coherent domains, and to increase the local supersaturation of near-surface dissolved carbon required for spontaneous graphene nucleation and growth. Upon transformation, the intensities of the surface carbide reflections and of specific powder-like diffraction rings vanish. The associated change of the specular X-ray reflectivity allows to quantify a single, fully surface covering layer of graphene (2 ML C) without diffraction contributions of rotated domains. The simultaneous presence of top-fcc and bridge-top configurations of graphene explains the crystal truncation rod data of the graphene-covered surface. Structure determination of the |4772| precursor surface-carbide using density functional theory is in perfect agreement with the experimentally derived X-ray structure factors. PMID- 29422519 TI - Exercise-induced hippocampal neurogenesis: 5-HT3 receptor antagonism by antipsychotics as a potential limiting factor in Schizophrenia. PMID- 29422518 TI - Receptor for advanced glycation end-products and ARDS prediction: a multicentre observational study. AB - Acute respiratory distress syndrome (ARDS) prediction remains challenging despite available clinical scores. To assess soluble receptor for advanced glycation end products (sRAGE), a marker of lung epithelial injury, as a predictor of ARDS in a high-risk population, adult patients with at least one ARDS risk factor upon admission to participating intensive care units (ICUs) were enrolled in a multicentre, prospective study between June 2014 and January 2015. Plasma sRAGE and endogenous secretory RAGE (esRAGE) were measured at baseline (ICU admission) and 24 hours later (day one). Four AGER candidate single nucleotide polymorphisms (SNPs) were also assayed because of previous reports of functionality (rs1800625, rs1800624, rs3134940, and rs2070600). The primary outcome was ARDS development within seven days. Of 500 patients enrolled, 464 patients were analysed, and 59 developed ARDS by day seven. Higher baseline and day one plasma sRAGE, but not esRAGE, were independently associated with increased ARDS risk. AGER SNP rs2070600 (Ser/Ser) was associated with increased ARDS risk and higher plasma sRAGE in this cohort, although confirmatory studies are needed to assess the role of AGER SNPs in ARDS prediction. These findings suggest that among at-risk ICU patients, higher plasma sRAGE may identify those who are more likely to develop ARDS. PMID- 29422520 TI - Lithium treatment and mechanisms of aging. PMID- 29422521 TI - The pulvinar nucleus and antidepressant treatment: dynamic modeling of antidepressant response and remission with ultra-high field functional MRI. AB - Functional magnetic resonance imaging (fMRI) successfully disentangled neuronal pathophysiology of major depression (MD), but only a few fMRI studies have investigated correlates and predictors of remission. Moreover, most studies have used clinical outcome parameters from two time points, which do not optimally depict differential response times. Therefore, we aimed to detect neuronal correlates of response and remission in an antidepressant treatment study with 7 T fMRI, potentially harnessing advances in detection power and spatial specificity. Moreover, we modeled outcome parameters from multiple study visits during a 12-week antidepressant fMRI study in 26 acute (aMD) patients compared to 36 stable remitted (rMD) patients and 33 healthy control subjects (HC). During an electrical painful stimulation task, significantly higher baseline activity in aMD compared to HC and rMD in the medial thalamic nuclei of the pulvinar was detected (p = 0.004, FWE-corrected), which was reduced by treatment. Moreover, clinical response followed a sigmoid function with a plateau phase in the beginning, a rapid decline and a further plateau at treatment end. By modeling the dynamic speed of response with fMRI-data, perigenual anterior cingulate activity after treatment was significantly associated with antidepressant response (p < 0.001, FWE-corrected). Temporoparietal junction (TPJ) baseline activity significantly predicted non-remission after 2 antidepressant trials (p = 0.005, FWE-corrected). The results underline the importance of the medial thalamus, attention networks in MD and antidepressant treatment. Moreover, by using a sigmoid model, this study provides a novel method to analyze the dynamic nature of response and remission for future trials. PMID- 29422522 TI - Evolution and stabilization of subnanometric metal species in confined space by in situ TEM. AB - Understanding the behavior and dynamic structural transformation of subnanometric metal species under reaction conditions will be helpful for understanding catalytic phenomena and for developing more efficient and stable catalysts based on single atoms and clusters. In this work, the evolution and stabilization of subnanometric Pt species confined in MCM-22 zeolite has been studied by in situ transmission electron microscopy (TEM). By correlating the results from in situ TEM studies and the results obtained in a continuous fix-bed reactor, it has been possible to delimitate the factors that control the dynamic agglomeration and redispersion behavior of metal species under reaction conditions. The dynamic reversible transformation between atomically dispersed Pt species and clusters/nanoparticles during CO oxidation at different temperatures has been elucidated. It has also been confirmed that subnanometric Pt clusters can be stabilized in MCM-22 crystallites during NO reduction with CO and H2. PMID- 29422523 TI - The Importance of Phonons with Negative Phase Quotient in Disordered Solids. AB - Current understanding of phonons is based on the phonon gas model (PGM), which is best rationalized for crystalline materials. However, most of the phonons/modes in disordered materials have a different character and thus may contribute to heat conduction in a fundamentally different way than is described by PGM. For the modes in crystals, which have sinusoidal character, one can separate the modes into two primary categories, namely acoustic and optical modes. However, for the modes in disordered materials, such designations may no longer rigorously apply. Nonetheless, the phase quotient (PQ) is a quantity that can be used to evaluate whether a mode more so shares a distinguishing property of acoustic vibrations manifested as a positive PQ, or a distinguishing property of an optical vibrations manifested as negative PQ. In thinking about this characteristic, there is essentially no intuition regarding the role of positive vs. negative PQ vibrational modes in disordered solids. Given this gap in understanding, herein we studied the respective contributions to thermal conductivity for several disordered solids as a function of PQ. The analysis sheds light on the importance of optical like/negative PQ modes in structurally/compositionally disordered solids, whereas in crystalline materials, the contributions of optical modes are usually small. PMID- 29422524 TI - Evolution of enzymes with new specificity by high-throughput screening using DmpR based genetic circuits and multiple flow cytometry rounds. AB - Genetic circuit-based biosensors are useful in detecting target metabolites or in vivo enzymes using transcription factors (Tx) as a molecular switch to express reporter signals, such as cellular fluorescence and antibiotic resistance. Herein, a phenol-detecting Tx (DmpR) was employed as a critical tool for enzyme engineering, specifically for the rapid analysis of numerous mutants with multiple mutations at the active site of tryptophan-indole lyase (TIL, EC 4.1.99.1). Cellular fluorescence was monitored cell-by-cell using flow cytometry to detect the creation of phenolic compounds by a new tyrosine-phenol-lyase (TPL, EC 4.1.99.2). In the TIL scaffold, target amino acids near the indole ring (Asp137, Phe304, Val394, Ile396 and His463) were mutated randomly to construct a large diversity of specificity variations. Collection of candidate positives by cell sorting using flow cytometry and subsequent shuffling of beneficial mutations identified a critical hit with four mutations (D137P, F304D, V394L, and I396R) in the TIL sequence. The variant displayed one-thirteenth the level of TPL activity, compared with native TPLs, and completely lost the original TIL activity. The findings demonstrate that hypersensitive, Tx-based biosensors could be useful critically to generate new activity from a related template, which would alleviate the current burden to high-throughput screening. PMID- 29422525 TI - Effects of water flow on submerged macrophyte-biofilm systems in constructed wetlands. AB - The effects of water flow on the leaf-biofilm interface of Vallisneria natans and Hydrilla verticillata were investigated using artificial plants as the control. Water flow inhibited the growth of two species of submerged macrophytes, reduced oxygen concentrations in plant leaves and changed oxygen profiles at the leaf biofilm interface. The results from confocal laser scanning microscopy and multifractal analysis showed that water flow reduced biofilm thickness, changed biofilm topographic characterization and increased the percentages of single colony-like biofilm patches. A cluster analysis revealed that the bacterial compositions in biofilms were determined mainly by substrate types and were different from those in sediments. However, water flow increased the bacterial diversity in biofilms in terms of operational taxonomic unit numbers and Shannon Indices. Our results indicated that water flow can be used to regulate the biomass, distribution and bacterial diversities of epiphytic biofilms in constructed wetlands dominated by submerged macrophytes. PMID- 29422526 TI - Optimal compressed representation of high throughput sequence data via light assembly. AB - The most effective genomic data compression methods either assemble reads into contigs, or replace them with their alignment positions on a reference genome. Such methods require significant computational resources, but faster alternatives that avoid using explicit or de novo-constructed references fail to match their performance. Here, we introduce a new reference-free compressed representation for genomic data based on light de novo assembly of reads, where each read is represented as a node in a (compact) trie. We show how to efficiently build such tries to compactly represent reads and demonstrate that among all methods using this representation (including all de novo assembly based methods), our method achieves the shortest possible output. We also provide an lower bound on the compression rate achievable on uniformly sampled genomic read data, which is approximated by our method well. Our method significantly improves the compression performance of alternatives without compromising speed. PMID- 29422527 TI - Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer. AB - The unique oncogene duet of coexisting BRAF V600E and TERT promoter mutations are widely found to be a robust genetic background promoting human cancer aggressiveness, but the mechanism is unclear. Here, we demonstrate that the BRAF V600E/MAP kinase pathway phosphorylates and activates FOS, which in turn acts as a transcription factor to bind and activate the GABPB promoter, increasing GABPB expression and driving formation of GABPA-GABPB complex; the latter selectively binds and activates mutant TERT promoter, upregulating TERT expression. Elevated TERT functions as a strong oncoprotein, robustly promoting aggressive behaviors of cancer cells and tumor development. We thus identify a molecular mechanism for the activation of mutant TERT by the BRAF V600E/MAP kinase pathway, in which FOS as a transcriptional factor of GABPB promoter plays a key role in functionally bridging the two oncogenes in cooperatively promoting oncogenesis, providing important cancer biological and clinical implications. PMID- 29422528 TI - Epothilone B Speeds Corneal Nerve Regrowth and Functional Recovery through Microtubule Stabilization and Increased Nerve Beading. AB - The successful restoration of corneal innervation and function after a corneal injury is a clinically challenging issue. Structural and functional recovery after a nerve injury involves a complex series of steps in which microtubules play a key role. The aim of the current study was to investigate the effects of epothilone B (EpoB), a microtubule-stabilizing agent, on corneal innervation and the functional recovery of the corneal nerve in mice after corneal epithelial abrasion. The pretreatment of mice with EpoB has a remarkable effect on the stabilization of beta-III tubulin, as demonstrated by substantial increases in the visualization of beta-III tubulin, nerve beading, corneal reinnervation, and reaction to stimuli. Furthermore, a pharmacokinetic analysis showed that EpoB remains at a high concentration in the cornea and the trigeminal ganglion for at least 6 days after administration. In addition, the administration of EpoB at 24 hours after corneal abrasion has a marked therapeutic effect on nerve regrowth and functional recovery. In conclusion, EpoB treatment may have therapeutic utility for improving corneal reinnervation and restoring sensitivity following corneal injury. PMID- 29422529 TI - A critical role of E2F transcription factor 2 in proinflammatory cytokines dependent proliferation and invasiveness of fibroblast-like synoviocytes in rheumatoid Arthritis. AB - As a transcription factor, E2F2 participates in regulation of numerous genes. To investigate the role and mechnism of E2F2 in RA, expression of E2F2 in synovial tissue was detected. Proliferation, invasion, and secretion of inflammatory cytokines were measured after E2F2 was knocked-down in RASFs by siRNA transfection. Induction of TNF-alpha, IL-6, and LPS on expression and nuclear translocation of E2F2, and signal pathways involved in the process were tested. ChIP was used to investigate direct binding of NF-kB to the promoter of E2F2, and E2F2 to the promoter of IL-6. The correlation between mRNA levels of E2F2 and IL 6 or TNF-alpha in secreted in supernatant of RASFs were also investigated. As a result, silencing E2F2 could inhibit the proliferation and invasion of RASFs. LPS, IL-6 can stimulate the expression of E2F2 in RASFs both via the NF-kB pathway, while TNF-alpha via the ERK pathway. TNF-alpha can facilitate the nuclear translocation of E2F2 and TNF-alpha can bind to promoter of E2F2, and then E2F2 can bind to the promoter of IL-6 directly. Significant correlations was found between levels of E2F2 and IL-6/TNF-alpha in synoviocytes of RA patients. Our findings indicate that E2F2 may play an important role in pathogenesis of RA. PMID- 29422530 TI - People Can Create Iconic Vocalizations to Communicate Various Meanings to Naive Listeners. AB - The innovation of iconic gestures is essential to establishing the vocabularies of signed languages, but might iconicity also play a role in the origin of spoken words? Can people create novel vocalizations that are comprehensible to naive listeners without prior convention? We launched a contest in which participants submitted non-linguistic vocalizations for 30 meanings spanning actions, humans, animals, inanimate objects, properties, quantifiers and demonstratives. The winner was determined by the ability of naive listeners to infer the meanings of the vocalizations. We report a series of experiments and analyses that evaluated the vocalizations for: (1) comprehensibility to naive listeners; (2) the degree to which they were iconic; (3) agreement between producers and listeners in iconicity; and (4) whether iconicity helps listeners learn the vocalizations as category labels. The results show contestants were able to create successful iconic vocalizations for most of the meanings, which were largely comprehensible to naive listeners, and easier to learn as category labels. These findings demonstrate how iconic vocalizations can enable interlocutors to establish understanding in the absence of conventions. They suggest that, prior to the advent of full-blown spoken languages, people could have used iconic vocalizations to ground a spoken vocabulary with considerable semantic breadth. PMID- 29422531 TI - Circulating miRNAs as diagnostic biomarkers for adolescent idiopathic scoliosis. AB - The aetiology of adolescent idiopathic scoliosis (AIS) has been linked to many factors, such as asymmetric growth, neuromuscular condition, bone strength and genetic background. Recently, epigenetic factors have been proposed as contributors of AIS physiopathology, but information about the molecular mechanisms and pathways involved is scarce. Regarding epigenetic factors, microRNAs (miRNAs) are molecules that contribute to gene expression modulation by regulating important cellular pathways. We herein used Next-Generation Sequencing to discover a series of circulating miRNAs detected in the blood samples of AIS patients, which yielded a unique miRNA biomarker signature that diagnoses AIS with high sensitivity and specificity. We propose that these miRNAs participate in the epigenetic control of signalling pathways by regulating osteoblast and osteoclast differentiation, thus modulating the genetic background of AIS patients. Our study yielded two relevant results: 1) evidence for the deregulated miRNAs that participate in osteoblast/osteoclast differentiation mechanisms in AIS; 2) this miRNA-signature can be potentially used as a clinical tool for molecular AIS diagnosis. Using miRNAs as biomarkers for AIS diagnostics is especially relevant since miRNAs can serve for early diagnoses and for evaluating the positive effects of applied therapies to therefore reduce the need of high risk surgical interventions. PMID- 29422532 TI - Type IV collagen alpha6 chain is a regulator of keratin 10 in keratinization of oral mucosal epithelium. AB - Keratinized mucosa is of fundamental importance to maintain healthy gingival tissue, and understanding the mechanisms of oral mucosa keratinization is crucial to successfully manage healthy gingiva. Previous studies have shown a strong involvement of the basement membrane in the proliferation and differentiation of epithelial cells. Therefore, first, to identify the keratinized mucosa-specific basement membrane components, immunohistochemical analysis for the six alpha chains of type IV collagen was performed in 8-week-old mice. No difference in the expression pattern of type IV collagen alpha1(IV) and alpha2(IV) chains was observed in the keratinized and non-keratinized mucosa. Interestingly, however, type IV collagen alpha5(IV) and alpha6(IV) chains specifically were strongly detected in the keratinized mucosa. To analyze the functional roles of the type IV collagen isoform alpha6(IV) in oral mucosa keratinization, we analyzed Col4a6 knockout mice. Epithelial developmental delay and low levels of KRT10 were observed in new-born Col4a6-knockout mice. Additionally, in vitro experiments with loss-of function analysis using human gingival epithelial cells confirmed the important role of alpha6(IV) chain in epithelial keratinization. These findings indicate that alpha112:alpha556 (IV) network, which is the only network that includes the alpha6(IV) chain, is one regulator of KRT10 expression in keratinization of oral mucosal epithelium. PMID- 29422533 TI - Gift, honorary or guest authorship. PMID- 29422535 TI - Locating multiple diffusion sources in time varying networks from sparse observations. AB - Data based source localization in complex networks has a broad range of applications. Despite recent progress, locating multiple diffusion sources in time varying networks remains to be an outstanding problem. Bridging structural observability and sparse signal reconstruction theories, we develop a general framework to locate diffusion sources in time varying networks based solely on sparse data from a small set of messenger nodes. A general finding is that large degree nodes produce more valuable information than small degree nodes, a result that contrasts that for static networks. Choosing large degree nodes as the messengers, we find that sparse observations from a few such nodes are often sufficient for any number of diffusion sources to be located for a variety of model and empirical networks. Counterintuitively, sources in more rapidly varying networks can be identified more readily with fewer required messenger nodes. PMID- 29422534 TI - IL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation. AB - Epigenetic modifications affect the differentiation of T cell subsets and the pathogenesis of autoimmune diseases, but many mechanisms of epigenetic regulation of T cell differentiation are unclear. Here we show reduced expression of the transcription factor RFX1 in CD4+ T cells from patients with systemic lupus erythematosus, which leads to IL-17A overexpression through increased histone H3 acetylation and decreased DNA methylation and H3K9 tri-methylation. Conditional deletion of Rfx1 in mice exacerbates experimental autoimmune encephalomyelitis and pristane-induced lupus-like syndrome and increases induction of Th17 cells. In vitro, Rfx1 deficiency increases the differentiation of naive CD4+ T cells into Th17 cells, but this effect can be reversed by forced expression of Rfx1. Importantly, RFX1 functions downstream of STAT3 and phosphorylated STAT3 can inhibit RFX1 expression, highlighting a non-canonical pathway that regulates differentiation of Th17 cells. Collectively, our findings identify a unique role for RFX1 in Th17-related autoimmune diseases. PMID- 29422536 TI - Impact of different ionization states of phosphorylated Serine-65 on ubiquitin structure and interactions. AB - The covalent attachment of ubiquitin (Ub) or Ub chains to cellular proteins is a versatile post-translational modification involved in a variety of eukaryotic cellular events. Recently, the post-translational modification of Ub itself by phosphorylation has emerged as an important component of the Ub-signaling system. Specifically, Ub phosphorylation at serine-65 was shown to activate parkin mediated mitochondrial quality control. However, the impact of phosphorylation on Ub structure and interactions is poorly understood. Here we investigate the recently reported structural changes in Ub upon serine-65 phosphorylation, namely, the equilibrium between a native-like and a novel, alternate conformer of phosphorylated Ub (pUb). We show that this equilibrium is pH-dependent, and the two pUb conformers are linked to the different charge states of the phosphate group. We examined pUb binding to a known Ub-receptor and found that the alternate conformer is binding incompetent. Furthermore, serine-65 phosphorylation affects the conformational equilibrium of K48-linked Ub dimers. Lastly, our crystal structure of S65D Ub and NMR data indicate that phosphomimetic mutations do not adequately reproduce the salient features of pUb. Our results suggest that the pH-dependence of the conformations and binding properties of phosphorylated Ub and polyUb could provide an additional level of modulation in Ub-mediated signaling. PMID- 29422537 TI - Influences of organic carbon speciation on hyporheic corridor biogeochemistry and microbial ecology. AB - The hyporheic corridor (HC) encompasses the river-groundwater continuum, where the mixing of groundwater (GW) with river water (RW) in the HC can stimulate biogeochemical activity. Here we propose a novel thermodynamic mechanism underlying this phenomenon and reveal broader impacts on dissolved organic carbon (DOC) and microbial ecology. We show that thermodynamically favorable DOC accumulates in GW despite lower DOC concentration, and that RW contains thermodynamically less-favorable DOC, but at higher concentrations. This indicates that GW DOC is protected from microbial oxidation by low total energy within the DOC pool, whereas RW DOC is protected by lower thermodynamic favorability of carbon species. We propose that GW-RW mixing overcomes these protections and stimulates respiration. Mixing models coupled with geophysical and molecular analyses further reveal tipping points in spatiotemporal dynamics of DOC and indicate important hydrology-biochemistry-microbial feedbacks. Previously unrecognized thermodynamic mechanisms regulated by GW-RW mixing may therefore strongly influence biogeochemical and microbial dynamics in riverine ecosystems. PMID- 29422538 TI - Dose and slice thickness evaluation with nMAG gel dosimeters in computed tomography. AB - Computed tomography (CT) has been widely used in clinical diagnosis. It is important to estimate radiation dose and perform image quality assurance procedures for CT scans. In this study, nMAG gel dosimeters were used to simultaneously measure the 300-mm weighted CT dose index (CTDI) and slice sensitivity profile (SSP) for multiple detector CT (MDCT). Magnetic resonance imaging (MRI) was performed on the irradiated gel to create R2-dose response curves for the tube voltages of 120 and 140 kVp. The gel dosimeters were loaded in three home-made cylindrical phantoms to obtain CTDI100 and CTDI300. The full width at half maximum (FWHM) for 2, 5, 10, 14.4, and 38.4-mm slice thicknesses was measured and compared with the result obtained by radiochromic films. The difference in weighted CTDI100 obtained by the gel dosimeter and ionization chamber was less than 1%. The CTDI efficiency at 120 and 140 kVp was in the range of 80.1%-82.5%. The FWHM of SSP measured by the gel dosimeter matched very well with the nominal slice thickness. The use of nMAG gel dosimeters combined with the home-made cylindrical phantoms can provide 300-mm weighted CTDI and slice thickness information, showing potential for quality assurance and clinical applications in MDCT. PMID- 29422539 TI - A Global Perspective on Sulfur Oxide Controls in Coal-Fired Power Plants and Cardiovascular Disease. AB - Sulfur oxides (SOx), particularly SO2 emitted by coal-fired power plants, produce long-term risks for cardiovascular disease (CVD). We estimated the relative risks of CVD and ischemic heart disease (IHD) attributable to SOx emission globally. National SOx reduction achieved by emissions control systems was defined as the average SOx reduction percentage weighted by generating capacities of individual plants in a country. We analyzed the relative risk of CVD incidence associated with national SOx reduction for 13,581 coal-fired power-generating units in 79 countries. A 10% decrease in SOx emission was associated with 0.28% (males; 95%CI = -0.39%~0.95%) and 1.69% (females; 95%CI = 0.99%~2.38%) lower CVD risk. The effects on IHD were > 2 times stronger among males than females (2.78%, 95%CI = 1.99%~3.57% vs. 1.18%, 95%CI = 0.19%~2.17%). Further, 1.43% (males) and 8.00% (females) of CVD cases were attributable to suboptimal SOx reduction. Thus, enhancing regulations on SOx emission control represents a target for national and international intervention to prevent CVD. PMID- 29422540 TI - Boosting lithium storage in covalent organic framework via activation of 14 electron redox chemistry. AB - Conjugated polymeric molecules have been heralded as promising electrode materials for the next-generation energy-storage technologies owing to their chemical flexibility at the molecular level, environmental benefit, and cost advantage. However, before any practical implementation takes place, the low capacity, poor structural stability, and sluggish ion/electron diffusion kinetics remain the obstacles that have to be overcome. Here, we report the synthesis of a few-layered two-dimensional covalent organic framework trapped by carbon nanotubes as the anode of lithium-ion batteries. Remarkably, upon activation, this organic electrode delivers a large reversible capacity of 1536 mAh g-1 and can sustain 500 cycles at 100 mA g-1. Aided by theoretical calculations and electrochemical probing of the electrochemical behavior at different stages of cycling, the storage mechanism is revealed to be governed by 14-electron redox chemistry for a covalent organic framework monomer with one lithium ion per C=N group and six lithium ions per benzene ring. This work may pave the way to the development of high-capacity electrodes for organic rechargeable batteries. PMID- 29422541 TI - Micronization potentiates curcumin's anti-seizure effect and brings an important advance in epilepsy treatment. AB - Epilepsy is one of the most common neurological diseases, and current antiepileptic drugs fail to suppress seizure occurrence in around one third of epileptic patients. Curcumin is a phytochemical with promising effects on epilepsy treatment. However, its application has been hindered by its low bioavailability. In order to improve curcumin's anti-seizure properties, increasing its bioavailability, here we proposed to micronize the compound through supercritical carbon dioxide processing, a suitable green chemistry technique to prepare and modify material properties. Here we investigated the anti-seizure potential of the classical antiepileptic drug valproate, curcumin in its natural state, and micronized curcumin in a PTZ-induced seizure model in zebrafish (Danio rerio). Concerning seizure development, valproate, curcumin and micronized curcumin showed protective effects, slowing seizure development both in larvae and adult animals. Nevertheless, considering the occurrence of the tonic-clonic seizure stage, only valproate and micronized curcumin reduced it, both in larvae and adult zebrafish, unlike non-processed curcumin. Our obtained results are very promising, since micronized curcumin showed effects that are similar to a classic antiepileptic drug, reducing seizure occurrence and slowing seizure progression. PMID- 29422542 TI - Protection of nigral dopaminergic neurons by AAV1 transduction with Rheb(S16H) against neurotoxic inflammation in vivo. AB - We recently reported that adeno-associated virus serotype 1 (AAV1) transduction of murine nigral dopaminergic (DA) neurons with constitutively active ras homolog enriched in brain with a mutation of serine to histidine at position 16 [Rheb(S16H)] induced the production of neurotrophic factors, resulting in neuroprotective effects on the nigrostriatal DA system in animal models of Parkinson's disease (PD). To further investigate whether AAV1-Rheb(S16H) transduction has neuroprotective potential against neurotoxic inflammation, which is known to be a potential event related to PD pathogenesis, we examined the effects of Rheb(S16H) expression in nigral DA neurons under a neurotoxic inflammatory environment induced by the endogenous microglial activator prothrombin kringle-2 (pKr-2). Our observations showed that Rheb(S16H) transduction played a role in the neuroprotection of the nigrostriatal DA system against pKr-2-induced neurotoxic inflammation, even though there were similar levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF alpha) and interleukin-1-beta (IL-1beta), in the AAV1-Rheb(S16H)-treated substantia nigra (SN) compared to the SN treated with pKr-2 alone; the neuroprotective effects may be mediated by the activation of neurotrophic signaling pathways following Rheb(S16H) transduction of nigral DA neurons. We conclude that AAV1-Rheb(S16H) transduction of neuronal populations to activate the production of neurotrophic factors and intracellular neurotrophic signaling pathways may offer promise for protecting adult neurons from extracellular neurotoxic inflammation. PMID- 29422543 TI - Poly(rC) binding protein 2 acts as a negative regulator of IRES-mediated translation of Hr mRNA. AB - During the hair follicle (HF) cycle, HR protein expression is not concordant with the presence of the Hr mRNA transcript, suggesting an elaborate regulation of Hr gene expression. Here we present evidence that the 5' untranslated region (UTR) of the Hr gene has internal ribosome entry site (IRES) activity and this activity is regulated by the binding of poly (rC) binding protein 2 (PCBP2) to Hr mRNA. Overexpression and knockdown of PCBP2 resulted in a decrease in Hr 5' UTR IRES activity and an increase in HR protein expression without changing mRNA levels. We also found that this regulation was disrupted in a mutant Hr 5' UTR that has a mutation responsible for Marie Unna hereditary hypotrichosis (MUHH) in both mice and humans. These findings suggest that Hr mRNA expression is regulated at the post-transcriptional level via IRES-mediated translation control through interaction with PCPB2, but not in MUHH. PMID- 29422544 TI - Mutational signatures and chromosome alteration profiles of squamous cell carcinomas of the vulva. AB - Vulvar squamous cell carcinoma (SCC) consists of two different etiologic categories: human papilloma virus (HPV)-associated (HPV (+)) and HPV-non associated (HPV (-)). There have been no genome-wide studies on the genetic alterations of vulvar SCCs or on the differences between HPV (+) and HPV (-) vulvar SCCs. In this study, we performed whole-exome sequencing and copy number profiling of 6 HPV (+) and 9 HPV (-) vulvar SCCs and found known mutations (TP53, CDKN2A and HRAS) and copy number alterations (CNAs) (7p and 8q gains and 2q loss) in HPV (-) SCCs. In HPV (+), we found novel mutations in PIK3CA, BRCA2 and FBXW7 that had not been reported in vulvar SCCs. HPV (-) SCCs exhibited more mutational loads (numbers of nonsilent mutations and driver mutations) than HPV (+) SCCs, but the CNA loads and mutation signatures between HPV (+) and HPV (-) SCCs did not differ. Of note, 40% and 40% of the 15 vulvar SCCs harbored PIK3CA and FAT1 alterations, respectively. In addition, we found that the SCCs harbored kataegis (a localized hypermutation) in 2 HPV (+) SCCs and copy-neutral losses of heterozygosity in 4 (one HPV (+) and 3 HPV (-)) SCCs. Our data indicate that HPV (+) and HPV (-) vulvar SCCs may have different mutation and CNA profiles but that there are genomic features common to SCCs. Our data provide useful information for both HPV (+) and HPV (-) vulvar SCCs and may aid in the development of clinical treatment strategies. PMID- 29422545 TI - Silencing of peroxiredoxin II by promoter methylation is necessary for the survival and migration of gastric cancer cells. AB - Peroxiredoxin (Prx), a family of ubiquitous thiol peroxidases, functions as a redox signaling regulator that controls cellular H2O2 in mammalian cells and has recently received attention for being overexpressed in various cancer types. In this study, we show that Prx type II (PrxII) is rather silenced in gastric cancer cells. PrxII expression is severely downregulated in 9 out of the 28 gastric cancer cell lines. Strikingly, PrxII expression is completely lost in three cell lines, MKN28, MKN74 and SNU484. Loss of PrxII expression is due to DNA methyltransferase 1-dependent methylation at the promoter region of the PrxII gene. Restoration of PrxII expression using a retroviral system markedly reduces the colony-forming ability and migratory activity of both MKN28 and SNU484 cells by inhibiting Src kinase. Mechanistically, PrxII peroxidase activity is essential for regulating gastric cancer cell migration. Bioinformatics analysis from The Cancer Genome Atlas stomach cancer data (STAD) revealed significantly low PrxII expression in gastric cancer patients and a negative correlation between PrxII expression and methylation levels. More importantly, low PrxII expression also strongly correlates with poor survival in cancer patients. Thus our study suggests that PrxII may be the first thiol peroxidase that simultaneously regulates both survival and metastasis in gastric cancer cells with high clinical relevance. PMID- 29422546 TI - A comparative study of growth: different body weight trajectories in three species of the genus Eublepharis and their hybrids. AB - An extensive research effort is devoted to the evolution of life-histories and processes underlying the variation in adult body weight; however, in this regard, some animal taxa remain neglected. Here we report rates and timing of growth recorded in two wild-derived populations of a model lizard species, Eublepharis macularius (M, W), other two related species, i.e., E. angramainyu (A) and E. sp. (D), and their between-species hybrids. We detected clear differences among the examined species/populations, which can be interpreted in the terms of "fast - slow" continuum of life-history strategies. The mean asymptotic body size was the highest in A and further decreased in the following order: M, W, and D. In contrast, the growth rate showed an opposite pattern. Counter-intuitively, the largest species exhibited the slowest growth rates. The final body size was determined mainly by the inflexion point. This parameter reflecting the duration of exponential growth increased with mean asymptotic body size and easily overcompensated the effect of decreasing growth rates in larger species. Compared to the parental species, the F1 and backcross hybrids exhibited intermediate values of growth parameters. Thus, except for the case of the F2 hybrid of MxA, we failed to detect deleterious effects of hybridization in these animals with temperature sex determination. PMID- 29422547 TI - Concurrent Presence of Obstructive Sleep Apnea and Elevated Homocysteine Levels Exacerbate the Development of Hypertension: A KoGES Six-year Follow-up Study. AB - Accumulating evidence has revealed that obstructive sleep apnea (OSA) and high homocysteine (Hcy) levels play important roles in the increased risk of hypertension and cardiovascular disease. We investigated whether the presence of elevated Hcy levels among individuals with OSA increase the risk of hypertension in a cohort study. A total of 1825 participants were selected from the cohort study. A high homocysteine level (Hcy) was defined as those in the 75th percentile of Hcy levels of the study cohort. The prevalence of hypertension was higher among subjects with OSA and high Hcy levels than among the other groups stratified by the presence of OSA and high Hcy levels. The incidence of hypertension at 6-year follow-up was: Hcy[-]/OSA[-] vs. Hcy[+]/OSA[-] vs. Hcy[ ]/OSA[+] vs. Hcy[+]/OSA[+], 14.2% vs. 19.8% vs. 24.2% vs. 36.1%. After adjusting for confounding factors, subjects with OSA and high Hcy levels had a 1.86-fold risk of developing hypertension compared to those without OSA and high Hcy levels. Moderate to severe OSA group with the highest tertile of Hcy levels had a 2.31-fold increased risk of developing hypertension. Interaction between Hcy and OSA on development of hypertension was significant, suggesting that these conditions may constitute an important determinant. PMID- 29422549 TI - Author Correction: Midbrain circuit regulation of individual alcohol drinking behaviors in mice. AB - The original version of this Article contained an error in the spelling of the author Scott Edwards, which was incorrectly given as Scott Edward. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29422550 TI - Flexible and Accurate Simulation of Radiation Cooling with FETD Method. AB - Thermal management and simulation are becoming increasingly important in many areas of engineering applications. There are three cooling routes for thermal management, namely thermal conduction, thermal convection and thermal radiation, among which the first two approaches have been widely studied and applied, while the radiation cooling has not yet attracted much attention in terrestrial environment because it usually contributes less to the total amount of thermal dissipation. Thus the simulation method for radiation cooling was also seldom noticed. The traditional way to simulate the radiation cooling is to solve the thermal conduction equation with an approximate radiation boundary condition, which neglects the wavelength and angular dependence of the emissivity of the object surface. In this paper, we combine the heat conduction equation with a rigorous radiation boundary condition discretized by the finite-element time domain method to simulate the radiation cooling accurately and flexibly. Numerical results are given to demonstrate the accuracy, flexibilities and potential applications of the proposed method. The proposed numerical model can provide a powerful tool to gain deep physical insight and optimize the physical design of radiation cooling. PMID- 29422548 TI - Africa-wide evaluation of host biomarkers in QuantiFERON supernatants for the diagnosis of pulmonary tuberculosis. AB - We investigated host-derived biomarkers that were previously identified in QuantiFERON supernatants, in a large pan-African study. We recruited individuals presenting with symptoms of pulmonary TB at seven peripheral healthcare facilities in six African countries, prior to assessment for TB disease. We then evaluated the concentrations of 12 biomarkers in stored QuantiFERON supernatants using the Luminex platform. Based on laboratory, clinical and radiological findings and a pre-established algorithm, participants were classified as TB disease or other respiratory diseases(ORD). Of the 514 individuals included in the study, 179(34.8%) had TB disease, 274(51.5%) had ORD and 61(11.5%) had an uncertain diagnosis. A biosignature comprising unstimulated IFN-gamma, MIP-1beta, TGF-alpha and antigen-specific levels of TGF-alpha and VEGF, identified on a training sample set (n = 311), validated by diagnosing TB disease in the test set (n = 134) with an AUC of 0.81(95% CI, 0.76-0.86), corresponding to a sensitivity of 64.2%(95% CI, 49.7-76.5%) and specificity of 82.7%(95% CI, 72.4-89.9%). Host biomarkers detected in QuantiFERON supernatants can contribute to the diagnosis of active TB disease amongst people presenting with symptoms requiring investigation for TB disease, regardless of HIV status or ethnicity in Africa. PMID- 29422551 TI - Phase contrast scanning transmission electron microscopy imaging of light and heavy atoms at the limit of contrast and resolution. AB - Using state of the art scanning transmission electron microscopy (STEM) it is nowadays possible to directly image single atomic columns at sub-A resolution. In standard (high angle) annular dark field STEM ((HA)ADF-STEM), however, light elements are usually invisible when imaged together with heavier elements in one image. Here we demonstrate the capability of the recently introduced Integrated Differential Phase Contrast STEM (iDPC-STEM) technique to image both light and heavy atoms in a thin sample at sub-A resolution. We use the technique to resolve both the Gallium and Nitrogen dumbbells in a GaN crystal in [[Formula: see text]] orientation, which each have a separation of only 63 pm. Reaching this ultimate resolution even for light elements is possible due to the fact that iDPC-STEM is a direct phase imaging technique that allows fine-tuning the microscope while imaging. Apart from this qualitative imaging result, we also demonstrate a quantitative match of ratios of the measured intensities with theoretical predictions based on simulations. PMID- 29422552 TI - Bone: A novel androgen-vitamin D link. PMID- 29422553 TI - Metabolism: NONO - the link between hepatic metabolism and feeding. PMID- 29422554 TI - Mediators of episodic memory decay across the adult life span. AB - The ability to remember the details of our own experiences declines gradually as we get old. The reason for this decay has been attributed to several factors besides age, such as education, nutrient intake and health status. However, the influence of these factors has mainly been examined individually and rarely together. Here we identify those factors that jointly act as mediators of episodic memory decay across the adult life span. We examined source memory in a lifespan sample of 1557 healthy adults. A total of 70 physical, biological and lifestyle variables were measured and introduced into a structural equation model as potential mediators that intervene between age and source memory. Only 14 mediator variables reliably mediated source memory decay; notably, eight of these variables have an effect on the cardiovascular system. The model unequivocally highlights that the mediators that may impair cardiovascular functioning also impact brain resources involved in episodic memory. We identified the factors that are relevant to episodic memory decline when they interact together as occurs in real life. PMID- 29422555 TI - Temporal downregulation of the polyubiquitin gene Ubb affects neuronal differentiation, but not maturation, in cells cultured in vitro. AB - Reduced levels of cellular ubiquitin (Ub) pools due to disruption of the polyubiquitin gene Ubb lead to dysregulation of neural stem cell (NSC) differentiation and impaired neuronal maturation in cells isolated from Ubb -/- mouse embryonic brains. However, it is currently unknown whether Ub is required for the specific stage of neuronal development or whether it plays a pleiotropic role throughout the process. To answer this question, we aimed to downregulate Ubb expression temporally during neuronal development, which could not be achieved in Ubb -/- cells. Therefore, we exploited lentivirus-mediated knockdown (KD) of Ubb at different stages of neuronal development, and investigated their phenotypes. Here, we report the outcome of Ubb KD on two independent culture days in vitro (DIV): DIV1 and DIV7. We observed that NSCs did not differentiate properly via Ubb KD on DIV1, but the maturation of already differentiated neurons was intact via Ubb KD on DIV7. Intriguingly, Ubb KD activated Notch signaling when it had been suppressed, but exerted no effect when it had already been activated. Therefore, our study suggests that Ub plays a pivotal role in NSC differentiation to suppress Notch signaling, but not in the subsequent maturation stages of neurons that had already been differentiated. PMID- 29422557 TI - Preparing for emergencies. AB - A ten year experience of medical emergencies at Birmingham Dental Hospital. PMID- 29422560 TI - Aesthetic possibilities in removable prosthodontics. Part 2: start with the face not the teeth when rehearsing lip support and tooth positions. AB - Even dentures exhibiting superb aesthetics are of no use if they visibly move during speech and social intercourse. In this, the second paper of three on removable denture aesthetics, we describe impression making and shaping the wax occlusal record rims. Not only are the impressions important for producing dentures with maximum retention, stability and support, but their extensions and the thickness of their borders have a decisive influence on lip support and profile. This article shows how the contours of the definitive impressions and the wax rims are developed so as to prescribe the overall form of the replacement gums and teeth. Properly trimmed rims are in essence an early three-dimensional rehearsal, an opportunity for developing the patient's preferred lip support and natural positioning of the denture teeth at subsequent stages. They can also give an early indication of what speech will be like with the new dentures. Without this 3D clinical information, laboratory technicians have to guess where to put the teeth and have little option but to fall back on the stereotypes of their textbook training. PMID- 29422566 TI - NHS dentistry: Historically weak. PMID- 29422568 TI - Conference report: 'So you want to be an orthodontist'. PMID- 29422571 TI - An apple a day keeps the...periodontist away? AB - A randomised study in young subjects of the effects of eating extra fruit or nuts on periodontal inflammation. PMID- 29422567 TI - Patient safety: Preventing aspiration. PMID- 29422572 TI - BAD science: Homeopathy - can the undetectable cure? PMID- 29422573 TI - Fluoride varnish application. PMID- 29422574 TI - Erratum. AB - This corrects the article DOI: 10.1038/sj.bdj.2018.4. PMID- 29422575 TI - Sugar, snacks and energy drinks in the spotlight. PMID- 29422581 TI - Honours and awards: A call for action. PMID- 29422576 TI - Neighbourhood incidence rate of paediatric dental extractions under general anaesthetic in South West England. AB - Introduction Extraction of decayed teeth is the most common reason for UK children aged 5-9 years to receive a general anaesthetic. Inequalities in oral health are well recognised, but is under-explored in dental general anaesthesia (DGA).Methods Secondary analysis of routinely collected data from three local authorities in South West England was used to assess: 1) dental activities recorded for children <18 years attending NHS general dental practitioners (GDP); 2) the incidence rate of DGA and disease severity among <16-year-olds; and 3) individual and neighbourhood factors associated with higher rates of child DGA, and greater severity of disease.Results Among 208,533 GDP appointments, rates of preventive action were low where 1/7 included fluoride varnish but 1/5 included permanent fillings. The incidence rate of DGA was 6.6 admissions for every 1,000 children, rising to 12.4/1,000 among 5-9-year-olds. A total of 86 (7.6%) children had previously received a DGA at the same hospital. Area deprivation was strongly associated with higher rates of DGA, but rates of DGA remained high in less deprived areas. No associations were observed between number of teeth removed and socio-economic status.Conclusion Too many children are receiving DGA, and too few preventive actions are recorded by GDPs. Area-based inequalities in DGA were apparent, but wealthy areas also experienced substantial childhood dental decay. PMID- 29422583 TI - Notice of elections to the Country Councils of the British Dental Association. PMID- 29422582 TI - In this together. PMID- 29422585 TI - Saving Smiles Trauma Toolkit launched. PMID- 29422586 TI - Oral health: A broader psychosocial approach. PMID- 29422589 TI - The vision thing. PMID- 29422590 TI - Struggling to communicate? AB - Are dental students well-equipped to deal with difficult communication situations? PMID- 29422591 TI - Radiology: New regulations. PMID- 29422599 TI - Immunotherapy: Viral reprogramming. PMID- 29422597 TI - From genetics to the clinic: a translational perspective on follicular lymphoma. AB - Follicular lymphoma (FL) is the most frequent indolent B cell lymphoma and is still considered to be incurable. In recent years, whole-exome sequencing studies of large cohorts of patients have greatly improved our knowledge of the FL mutational landscape. Moreover, the prolonged evolution of this disease has enabled some insights regarding the early pre-lymphoma lesions as well as the clonal evolution after treatment, allowing an evolutionary perspective on lymphomagenesis. Deciphering the earliest initiating lesions and identifying the molecular alterations leading to disease progression currently represent important goals; accomplishing these could help identify the most relevant targets for precision therapy. PMID- 29422598 TI - Genetic insights into the morass of metastatic heterogeneity. AB - Tumour heterogeneity poses a substantial problem for the clinical management of cancer. Somatic evolution of the cancer genome results in genetically distinct subclones in the primary tumour with different biological properties and therapeutic sensitivities. The problem of heterogeneity is compounded in metastatic disease owing to the complexity of the metastatic process and the multiple biological hurdles that the tumour cell must overcome to establish a clinically overt metastatic lesion. New advances in sequencing technology and clinical sample acquisition are providing insights into the phylogenetic relationship of metastases and primary tumours at the level of somatic tumour genetics while also illuminating fundamental mechanisms of the metastatic process. In addition to somatically acquired genetic heterogeneity in the tumour cells, inherited population-based genetic heterogeneity can profoundly modify metastatic biology and further complicate the development of effective, broadly applicable antimetastatic therapies. Here, we examine how genetic heterogeneity impacts metastatic disease and the implications of current knowledge for future research endeavours and therapeutic interventions. PMID- 29422600 TI - Efficient green light-emitting diodes based on quasi-two-dimensional composition and phase engineered perovskite with surface passivation. AB - Perovskite light-emitting diodes (LEDs) are attracting great attention due to their efficient and narrow emission. Quasi-two-dimensional perovskites with Ruddlesden-Popper-type layered structures can enlarge exciton binding energy and confine charge carriers and are considered good candidate materials for efficient LEDs. However, these materials usually contain a mixture of phases and the phase impurity could cause low emission efficiency. In addition, converting three dimensional into quasi-two-dimensional perovskite introduces more defects on the surface or at the grain boundaries due to the reduction of crystal sizes. Both factors limit the emission efficiency of LEDs. Here, firstly, through composition and phase engineering, optimal quasi-two-dimensional perovskites are selected. Secondly, surface passivation is carried out by coating organic small molecule trioctylphosphine oxide on the perovskite thin film surface. Accordingly, green LEDs based on quasi-two-dimensional perovskite reach a current efficiency of 62.4 cd A-1 and external quantum efficiency of 14.36%. PMID- 29422601 TI - No evidence of ongoing evolution in replication competent latent HIV-1 in a patient followed up for two years. AB - The persistence of infected T cells harbouring intact HIV proviruses is the barrier to the eradication of HIV. This reservoir is stable over long periods of time despite antiretroviral therapy. There has been controversy on whether low level viral replication is occurring at sanctuary sites periodically reseeding infected cells into the latent reservoir to account its durability. To study viral evolution in a physiologically relevant population of latent viruses, we repeatedly performed virus outgrowth assays on a stably treated HIV positive patient over two years and sequenced the reactivated latent viruses. We sought evidence of increasing sequence pairwise distances with time as evidence of ongoing viral replication. 64 reactivatable latent viral sequences were obtained over 103 weeks. We did not observe an increase in genetic distance of the sequences with the time elapsed between sampling. No evolution could be discerned in these reactivatable latent viruses. Thus, in this patient, the contribution of low-level replication to the maintenance of the latent reservoir detectable in the blood compartment is limited. PMID- 29422602 TI - Acidic organelles mediate TGF-beta1-induced cellular fibrosis via (pro)renin receptor and vacuolar ATPase trafficking in human peritoneal mesothelial cells. AB - TGF-beta1, which can cause renal tubular injury through a vacuolar-type H+-ATPase (V-ATPase)-mediated pathway, is induced by the glucose degradation product methylglyoxal to yield peritoneal injury and fibrosis. The present study investigated the roles of V-ATPase and its accessory protein, the (pro)renin receptor, in peritoneal fibrosis during peritoneal dialysis. Rats daily administered 20 mM methylglyoxal intraperitoneally developed significant peritoneal fibrosis after 7 days with increased expression of TGF-beta and V ATPase, which was reduced by the inhibition of V-ATPase with co-administration of 100 mM bafilomycin A1. The (pro)renin receptor and V-ATPase were expressed in acidic organelles and cell membranes of human peritoneal mesothelial cells. TGF beta1 upregulated the expression of collagens, alpha-SMA, and EDA-fibronectin, together with ERK1/2 phosphorylation, which was reduced by inhibition of V ATPase, (pro)renin receptor, or the MAPK pathway. Fibronectin and the soluble (pro)renin receptor were excreted from cells by acidic organelle trafficking in response to TGF-beta1; this excretion was also suppressed by inhibition of V ATPase. Soluble (pro)renin receptor concentrations in effluents of patients undergoing peritoneal dialysis were associated with the dialysate-to-plasma ratio of creatinine. Together, these results demonstrate a novel fibrosis mechanism through the (pro)renin receptor and V-ATPase in the acidic organelles of peritoneal mesothelial cells. PMID- 29422603 TI - REM sleep respiratory behaviours mental content in narcoleptic lucid dreamers. AB - Breathing is irregular during rapid eye-movement (REM) sleep, whereas it is stable during non-REM sleep. Why this is so remains a mystery. We propose that irregular breathing has a cortical origin and reflects the mental content of dreams, which often accompany REM sleep. We tested 21 patients with narcolepsy who had the exceptional ability to lucid dream in REM sleep, a condition in which one is conscious of dreaming during the dream and can signal lucidity with an ocular code. Sleep and respiration were monitored during multiple naps. Participants were instructed to modify their dream scenario so that it involved vocalizations or an apnoea, -two behaviours that require a cortical control of ventilation when executed during wakefulness. Most participants (86%) were able to signal lucidity in at least one nap. In 50% of the lucid naps, we found a clear congruence between the dream report (e.g., diving under water) and the observed respiratory behaviour (e.g., central apnoea) and, in several cases, a preparatory breath before the respiratory behaviour. This suggests that the cortico-subcortical networks involved in voluntary respiratory movements are preserved during REM sleep and that breathing irregularities during this stage have a cortical/subcortical origin that reflects dream content. PMID- 29422605 TI - Microstructure and phases of deposited metal of SUPER304H steel under high temperature Persistent stress. AB - In order to investigate the high temperature rupture property of deposited metal of SUPER304H steel, the high temperature tensile test was carried out, and the microstructure transformation of deposited metal of SUPER304H steel under high temperature persistent stress were studied. Most of the solidification subgrain boundaries dissolve. The effect of the high temperature enduring on the microstructure is not obvious. Temperature and time are the main factors that influence the change of microstructure. Under the action of high temperature stress, the corrosion resistance of austenite decreases significantly due to the occurrence of chromium deficiency. With the persistent stress of 200 MPa, the precipitated phase of deposited metal is Nb (C, N), M23C6, NbCrN phase, and a certain amount of alpha phase is precipitated in the deposited metal with a persistent stress of 78 MPa. The precipitation of M23C6 phase is the main reason for the decrease of the corrosion resistance, especially the decrease of the corrosion resistance. PMID- 29422606 TI - Conserved, unstructured regions in Pseudomonas aeruginosa PilO are important for type IVa pilus function. AB - Pseudomonas aeruginosa uses long, thin fibres called type IV pili (T4P) for adherence to surfaces, biofilm formation, and twitching motility. A conserved subcomplex of PilMNOP is required for extension and retraction of T4P. To better understand its function, we attempted to co-crystallize the soluble periplasmic portions of PilNOP, using reductive surface methylation to promote crystal formation. Only PilODelta109 crystallized; its structure was determined to 1.7 A resolution using molecular replacement. This new structure revealed two novel features: a shorter N-terminal alpha1-helix followed by a longer unstructured loop, and a discontinuous beta-strand in the second alphabetabeta motif, mirroring that in the first motif. PISA analysis identified a potential dimer interface with striking similarity to that of the PilO homolog EpsM from the Vibrio cholerae type II secretion system. We identified highly conserved residues within predicted unstructured regions in PilO proteins from various Pseudomonads and performed site-directed mutagenesis to assess their role in T4P function. R169D and I170A substitutions decreased surface piliation and twitching motility without disrupting PilO homodimer formation. These residues could form important protein-protein interactions with PilN or PilP. This work furthers our understanding of residues critical for T4aP function. PMID- 29422607 TI - Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca2+-dependent manner. AB - Muscle contraction, which is initiated by Ca2+, results in precise sliding of myosin-based thick and actin-based thin filament contractile proteins. The interactions between myosin and actin are finely tuned by three isoforms of myosin binding protein-C (MyBP-C): slow-skeletal, fast-skeletal, and cardiac (ssMyBP-C, fsMyBP-C and cMyBP-C, respectively), each with distinct N-terminal regulatory regions. The skeletal MyBP-C isoforms are conditionally coexpressed in cardiac muscle, but little is known about their function. Therefore, to characterize the functional differences and regulatory mechanisms among these three isoforms, we expressed recombinant N-terminal fragments and examined their effect on contractile properties in biophysical assays. Addition of the fragments to in vitro motility assays demonstrated that ssMyBP-C and cMyBP-C activate thin filament sliding at low Ca2+. Corresponding 3D electron microscopy reconstructions of native thin filaments suggest that graded shifts of tropomyosin on actin are responsible for this activation (cardiac > slow-skeletal > fast-skeletal). Conversely, at higher Ca2+, addition of fsMyBP-C and cMyBP-C fragments reduced sliding velocities in the in vitro motility assays and increased force production in cardiac muscle fibers. We conclude that due to the high frequency of Ca2+ cycling in cardiac muscle, cardiac MyBP-C may play dual roles at both low and high Ca2+. However, skeletal MyBP-C isoforms may be tuned to meet the needs of specific skeletal muscles. PMID- 29422608 TI - Accelerated invagination of vacuoles as a stress response in chronically heat stressed yeasts. AB - When exposed to sublethal high temperatures, budding yeast cells can survive for a period of time; however, a sufficient amount of ubiquitin is necessary for this survival. To understand the nature of the stress, we examined the morphological changes in yeast cells, focusing on the vacuoles. Changes in vacuolar morphology were notable, and ruffled vacuolar membranes, accelerated invaginations of vacuolar membranes, and vesicle-like formations were observed. These changes occurred in the absence of Atg1, Atg9 or Ivy1 but appeared to require endosomal sorting proteins, such as Vps23, Vps24 or Pep12. Furthermore, the serial sections of the vacuoles analysed using an electron microscopic analysis revealed that spherical invaginated structures were linked together in a vacuole. Because degradation of cell surface proteins is induced from heat stress, fusion of endosomal and vacuolar membranes might occur frequently in heat-stressed cells, and yeast cells might be able to cope with a rapid increase in vacuolar surface area by such invaginations. PMID- 29422604 TI - Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. AB - In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 * 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 * 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 * 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 * 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 * 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene. PMID- 29422609 TI - Stimuli-responsive hydroxyapatite liquid crystal with macroscopically controllable ordering and magneto-optical functions. AB - Liquid crystals are mostly formed by self-assembly of organic molecules. In contrast, inorganic materials available as liquid crystals are limited. Here we report the development of liquid-crystalline (LC) hydroxyapatite (HAp), which is an environmentally friendly and biocompatible biomineral. Its alignment behavior, magneto-optical properties, and atomic-scale structures are described. We successfully induce LC properties into aqueous colloidal dispersions of rod shaped HAp by controlling the morphology of the material using acidic macromolecules. These LC HAp nanorod materials are macroscopically oriented in response to external magnetic fields and mechanical forces. We achieve magnetic modulation of the optical transmission by dynamic control of the LC order. Atomic scale observations using transmission electron microscopy show the self-organized inorganic/organic hybrid structures of mesogenic nanorods. HAp liquid crystals have potential as bio-friendly functional materials because of their facile preparation, the bio-friendliness of HAp, and the stimuli-responsive properties of these colloidal ordered fluids. PMID- 29422610 TI - Coordinated activation of a cluster of MMP genes in response to UVB radiation. AB - Ultraviolet (UV) B radiation is a dangerous environmental stressor, which can lead to photoaging, inflammation, immune suppression and tumour formation. A recent report has shown the transcriptional activation of several skin-specific genes including matrix metalloproteases (MMPs) in response to UV irradiation. Here, we use a novel human keratinocyte model, HKerE6SFM, to demonstrate that UVB activates the transcription of most members of the 11q22.3 MMP gene cluster including MMP13, MMP12, MMP3, MMP1 and MMP10. Curiously, the expression of the well-characterized UVB-inducible MMP9, which is located outside of the cluster, remains unchanged. In accordance with the increased expression of the MMP gene cluster upon UVB irradiation, RNA polymerase II showed increased occupancy at their promoters following UVB irradiation. The results also demonstrate increased acetylated histone H3K9 levels at the promoters of the MMP13, MMP12, MMP3, MMP1 and MMP10 genes. These findings suggest a coordinated transcriptional activation of genes in the MMP cluster at 11q22.3 and that acetylation of histone H3 at lysine 9 has an important role in the UVB-dependent enhancement of transcription of MMP genes in this region. PMID- 29422611 TI - Decitibine improve the efficiency of anti-PD-1 therapy via activating the response to IFN/PD-L1 signal of lung cancer cells. AB - IFN-gamma-induced PD-L1 expression represents the existence of tumor-specific T cells, which predicts high-response rate to anti-PD-1/L1 therapy, but loss-of function of IFN signals (e.g., JAK mutation) induces adaptive immune resistance in patients with low-response rate. Interferon regulatory factors (IRF) are frequently epigenetic silenced in carcinogenesis, while the role of methylation in anti-PD-1/L1 therapy remains unclear. We here investigated the methylation status of IFN-gamma related genes IRF1/8 and IFN-alpha/beta-related genes IRF3/7 in lung cancer tissues and found that only highly methylated IRF1 and 7 negatively correlated to cd274 (coding PD-L1) expression, similar to JAK mutation. Interestingly, decitibine (DAC) as methylation inhibitor could hypomethylate IRF1/7 to restore PD-L1 level. Meanwhile, IRF7 enhanced constitutive PD-L1 expression, which was independent of IFN-gamma though directly promote transcription of PD-L1, leading to abrogating cytotoxic T lymphocytes (CTLs) generation which could be restored by anti-PD-L1 antibody, or siRNA-IRF7. The supplement of DAC to anti-PD-1 therapy in vivo improve the efficiency of anti tumor with less methylated IRF1/7, more interferon-related genes expression (e.g., CXCL9) and IFN-gamma/CD8+ T-cells infiltrations, suggesting that additional treatment of DAC could rescue the ability to response to IFN in lung cancer patients with anti-PD-1/L1 therapy resistance. PMID- 29422612 TI - Csde1 binds transcripts involved in protein homeostasis and controls their expression in an erythroid cell line. AB - Expression of the RNA-binding protein Csde1 (Cold shock domain protein e1) is strongly upregulated during erythropoiesis compared to other hematopoietic lineages. Csde1 expression is impaired in the severe congenital anemia Diamond Blackfan Anemia (DBA), and reduced expression of Csde1 in healthy erythroblasts impaired their proliferation and differentiation. To investigate the cellular pathways controlled by Csde1 in erythropoiesis, we identified the transcripts that physically associate with Csde1 in erythroid cells. These mainly encoded proteins involved in ribogenesis, mRNA translation and protein degradation, but also proteins associated with the mitochondrial respiratory chain and mitosis. Crispr/Cas9-mediated deletion of the first cold shock domain of Csde1 affected RNA expression and/or protein expression of Csde1-bound transcripts. For instance, protein expression of Pabpc1 was enhanced while Pabpc1 mRNA expression was reduced indicating more efficient translation of Pabpc1 followed by negative feedback on mRNA stability. Overall, the effect of reduced Csde1 function on mRNA stability and translation of Csde1-bound transcripts was modest. Clones with complete loss of Csde1, however, could not be generated. We suggest that Csde1 is involved in feed-back control in protein homeostasis and that it dampens stochastic changes in mRNA expression. PMID- 29422614 TI - Micro-computed tomography for the quantification of blocked fibers in hemodialyzers. AB - A novel technique based on micro-CT scanning is developed to quantify coagulation in fibers of hemodialyzers. This objectivation is needed to allow accurate assessment of thrombogenicity of dialyzers used during hemodialysis, for example when comparing different strategies to avoid coagulation and/or fiber blocking. The protocol allowed imaging at a resolution of 25 um, making it possible to count the open, non-coagulated fibers in a non-invasive way. In 3 fresh, non-used FX600 hemodialyzers, patent fiber counts were extremely consistent (10748 +/- 2). To illustrate the potential of this technique, different dialysis parameters currently used as surrogates for fiber blocking were evaluated during 20 hemodialysis sessions. After dialysis, the FX600 dialyzers were visually scored for clotting, dried and subsequently weighed and scanned. The number of patent fibers (10003 [8763,10330], range 534-10692) did not correlate with any of the recorded surrogate parameters. Micro-CT scanning is a feasible, objective, non invasive, accurate and reproducible tool for quantification of the degree of fiber blocking in a hemodialyzer after use, making it a potential gold standard for use in studies on fiber blocking during renal replacement therapies. PMID- 29422613 TI - Cx26 drives self-renewal in triple-negative breast cancer via interaction with NANOG and focal adhesion kinase. AB - Tumors adapt their phenotypes during growth and in response to therapies through dynamic changes in cellular processes. Connexin proteins enable such dynamic changes during development, and their dysregulation leads to disease states. The gap junction communication channels formed by connexins have been reported to exhibit tumor-suppressive functions, including in triple-negative breast cancer (TNBC). However, we find that connexin 26 (Cx26) is elevated in self-renewing cancer stem cells (CSCs) and is necessary and sufficient for their maintenance. Cx26 promotes CSC self-renewal by forming a signaling complex with the pluripotency transcription factor NANOG and focal adhesion kinase (FAK), resulting in NANOG stabilization and FAK activation. This FAK/NANOG-containing complex is not formed in mammary epithelial or luminal breast cancer cells. These findings challenge the paradigm that connexins are tumor suppressors in TNBC and reveal a unique function for Cx26 in regulating the core self-renewal signaling that controls CSC maintenance. PMID- 29422615 TI - House dust mite and Cockroach specific Immunoglobulin E sensitization is associated with diabetes mellitus in the adult Korean population. AB - Immunoglobulin E (IgE) is known to activate mast cells. Prior studies have shown that mast cells contribute to diet-induced obesity and diabetes mellitus (DM). We aimed to determine whether adults with IgE sensitization were at risk of DM. We performed assays regarding serum total IgE and allergen-specific IgE levels against the house dust mite, the cockroach, and the dog on 1,528 adults randomly sampled from every age and gender group in various districts. The total and three allergen-specific IgE levels were positively correlated with fasting glucose level and insulin resistance. Subjects with increased levels of total IgE (>100 kU/L), compared to those without, had an odds ratio (OR) of 1.72 (95% confidence interval [95% CI], 1.17-2.54) for DM after adjusting for various covariates. Further controlling for previous allergic disease did not attenuate the association between total IgE level and DM. Subjects sensitized to the house dust mite (OR 1.63, 95% CI, 1.03-2.59) and the cockroach (OR 2.27, 95% CI, 1.40-3.66) were also at increased risk of DM. We found a strong positive association between IgE sensitization and DM in a general Korean population, suggesting that IgE may be an important independent risk factor for metabolic diseases in Koreans. PMID- 29422617 TI - Publisher Correction: A Co3O4-CDots-C3N4 three component electrocatalyst design concept for efficient and tunable CO2 reduction to syngas. AB - The original HTML version of this Article omitted to list Yeshayahu Lifshitz as a corresponding author and incorrectly listed Shuit-Tong Lee as a corresponding author.Correspondingly, the original PDF version of this Article incorrectly stated that "Correspondence and requests for materials should be addressed to X.J. (email: xin.jiang@uni-siegen.de), or to Y.L. (email: yangl@suda.edu.cn), or to S.-T.L. (email: shayli@technion.ac.il), or to Z.K. (email: zhkang@suda.edu.cn)", instead of the correct "Correspondence and requests for materials should be addressed to X.J. (email: xin.jiang@uni-siegen.de), or to Y. Liu (email: yangl@suda.edu.cn), or to Y. Lifshitz (email: shayli@technion.ac.il), or to Z.K. (email: zhkang@suda.edu.cn)".This has now been corrected in the PDF and HTML versions of the Article. PMID- 29422616 TI - Identification of T helper (Th)1- and Th2-associated antigens of Cryptococcus neoformans in a murine model of pulmonary infection. AB - Cryptococcosis, caused by Cryptococcus neoformans, has been demonstrated to be controlled by T helper (Th)1 cells while Th2 cells are associated with fungal growth and dissemination. Although cryptococcal immunoreactive protein antigens were previously identified, their association with Th1 or Th2 immune responses was not provided. In mice, Th1-dependent IFN-gamma induces the production of IgG2a, whereas the Th2 cytokine IL-4 stimulates the expression of IgG1 rendering each isotype an indicator of the underlying Th cell response. Therefore, we performed an immunoproteomic study that distinguishes Th1- and Th2-associated antigens by their reactivity with Th1-dependent IgG2a or Th2-dependent IgG1 antibodies in sera from C. neoformans-infected wild-type mice. We additionally analysed sera from Th2-prone IL-12-deficient and Th1-prone IL-4Ralpha-deficient mice extending the results found in wild-type mice. In total, ten, four, and three protein antigens associated with IgG1, IgG2a, or both isotypes, respectively, were identified. Th2-associated antigens represent promising candidates for development of immunotherapy regimens, whereas Th1-associated antigens may serve as candidates for vaccine development. In conclusion, this study points to intrinsic immunomodulatory effects of fungal antigens on the process of Th cell differentiation based on the identification of cryptococcal protein antigens specifically associated with Th1 or Th2 responses throughout mice of different genotypes. PMID- 29422618 TI - Large uniaxial magnetostriction with sign inversion at the first order phase transition in the nanolaminated Mn2GaC MAX phase. AB - In 2013, a new class of inherently nanolaminated magnetic materials, the so called magnetic MAX phases, was discovered. Following predictive material stability calculations, the hexagonal Mn2GaC compound was synthesized as hetero epitaxial films containing Mn as the exclusive M-element. Recent theoretical and experimental studies suggested a high magnetic ordering temperature and non collinear antiferromagnetic (AFM) spin states as a result of competitive ferromagnetic and antiferromagnetic exchange interactions. In order to assess the potential for practical applications of Mn2GaC, we have studied the temperature dependent magnetization, and the magnetoresistive, magnetostrictive as well as magnetocaloric properties of the compound. The material exhibits two magnetic phase transitions. The Neel temperature is T N ~ 507 K, at which the system changes from a collinear AFM state to the paramagnetic state. At T t = 214 K the material undergoes a first order magnetic phase transition from AFM at higher temperature to a non-collinear AFM spin structure. Both states show large uniaxial c-axis magnetostriction of 450 ppm. Remarkably, the magnetostriction changes sign, being compressive (negative) above T t and tensile (positive) below the T t . The sign change of the magnetostriction is accompanied by a sign change in the magnetoresistance indicating a coupling among the spin, lattice and electrical transport properties. PMID- 29422619 TI - Anisotropic Friedel oscillations in graphene-like materials: The Dirac point approximation in wave-number dependent quantities revisited. AB - Friedel oscillations of the graphene-like materials are investigated theoretically for low and intermediate Fermi energies. Numerical calculations have been performed within the random phase approximation. It was demonstrated that for intra-valley transitions the contribution of the different Dirac points in the wave-number dependent quantities is determined by the orientation of the wave-number in k-space. Therefore, identical contribution of the different Dirac points is not automatically guaranteed by the degeneracy of the Hamiltonian at these points. Meanwhile, it was shown that the contribution of the inter-valley transitions is always anisotropic even when the Dirac points coincide with the Fermi level (E F = 0). This means that the Dirac point approximation based studies could give the correct physics only at long wave length limit. The anisotropy of the static dielectric function reveals different contribution of the each Dirac point. Additionally, the anisotropic k-space dielectric function results in anisotropic Friedel oscillations in graphene-like materials. Increasing the Rashba interaction strength slightly modifies the Friedel oscillations in this family of materials. Anisotropy of the dielectric function in k-space is the clear manifestation of band anisotropy in the graphene-like systems. PMID- 29422621 TI - Publisher Correction: Desumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathway. AB - In the originally published version of this Article, the positions of the final two authors in the author list were inadvertently inverted during the production process. This error has now been corrected in both the PDF and HTML versions of the Article. PMID- 29422620 TI - Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance. AB - Multidrug resistance is a major challenge to cancer chemotherapy. The multidrug resistance phenotype is associated with the overexpression of the adenosine triphosphate (ATP)-driven transmembrane efflux pumps in cancer cells. Here, we report a lipid membrane-coated silica-carbon (LSC) hybrid nanoparticle that targets mitochondria through pyruvate, to specifically produce reactive oxygen species (ROS) in mitochondria under near-infrared (NIR) laser irradiation. The ROS can oxidize the NADH into NAD+ to reduce the amount of ATP available for the efflux pumps. The treatment with LSC nanoparticles and NIR laser irradiation also reduces the expression and increases the intracellular distribution of the efflux pumps. Consequently, multidrug-resistant cancer cells lose their multidrug resistance capability for at least 5 days, creating a therapeutic window for chemotherapy. Our in vivo data show that the drug-laden LSC nanoparticles in combination with NIR laser treatment can effectively inhibit the growth of multidrug-resistant tumors with no evident systemic toxicity. PMID- 29422622 TI - Extreme rejuvenation and softening in a bulk metallic glass. AB - Rejuvenation of metallic glasses, bringing them to higher-energy states, is of interest in improving their plasticity. The mechanisms of rejuvenation are poorly understood, and its limits remain unexplored. We use constrained loading in compression to impose substantial plastic flow on a zirconium-based bulk metallic glass. The maximum measured effects are that the hardness of the glass decreases by 36%, and its excess enthalpy (above the relaxed state) increases to 41% of the enthalpy of melting. Comparably high degrees of rejuvenation have been reported only on microscopic scales at the centre of shear bands confined to low volume fractions. This extreme rejuvenation of a bulk glass gives a state equivalent to that obtainable by quenching the liquid at ~1010 K s-1, many orders of magnitude faster than is possible for bulk specimens. The contrast with earlier results showing relaxation in similar tests under tension emphasizes the importance of hydrostatic stress. PMID- 29422623 TI - Identification of novel cell-impermeant fluorescent substrates for testing the function and drug interaction of Organic Anion-Transporting Polypeptides, OATP1B1/1B3 and 2B1. AB - Organic Anion-Transporting Polypeptides are multispecific membrane proteins that regulate the passage of crucial endobiotics and drugs across pharmacological barriers. OATP1B1 and OATP1B3 have been described to play a major role in the hepatic uptake of statins, antivirals and various chemotherapeutics; whereas the pharmacological role of the ubiquitously expressed OATP2B1 is less well characterized. According to current industry standards, in vitro testing for susceptibility to OATP1B1 and 1B3 mediated transport is recommended for drug candidates that are eliminated in part via the liver. Here we show that human OATP1B1, 1B3 and 2B1 transport a series of commercially available viability dyes that are generally believed to be impermeable to intact cells. We demonstrate that the intracellular accumulation of Zombie Violet, Live/Dead Green, Cascade Blue and Alexa Fluor 405 is specifically increased by OATPs. Inhibition of Cascade Blue or Alexa Fluor 405 uptake by known OATP substrates/inhibitors yielded IC50 values in agreement with gold-standard radioligand assays. The fluorescence-based assays described in this study provide a new tool for testing OATP1B/2B1 drug interactions. PMID- 29422625 TI - Evaluation of the Heshang Cave stalagmite calcium isotope composition as a paleohydrologic proxy by comparison with the instrumental precipitation record. AB - With their merits of precise dating and sensitivity to climate changes, laminated stalagmites are an important terrestrial archive for reconstructions of paleohydrological changes. In particular, the Ca isotope composition (delta44/42Ca) of the Heshang Cave stalagmite has been documented to record a precipitation decrease during the 8.2 ka event in central China. As an extension, this study directly compares near-annual resolution delta44/42Ca data with an instrumental precipitation record to evaluate the fidelity of delta44/42Ca as a paleohydrologic proxy on annual to decade timescales. Over the period 1881-2001 AD, the delta44/42Ca values correlate significantly with both precipitation from a nearby weather station and the dryness/wetness index in the middle Yangtze River, with a stronger correlation on decadal smoothed data. These results clearly show that the delta44/42Ca ratio from stalagmites is an effective proxy for paleohydrological changes on a decadal timescale. More study is encouraged to refine understanding of stalagmite Ca isotope ratios and hydrological conditions and their application in paleohydrologic reconstructions. PMID- 29422624 TI - Deep-sea hydrothermal vents as natural egg-case incubators at the Galapagos Rift. AB - The discovery of deep-sea hydrothermal vents in 1977 challenged our views of ecosystem functioning and yet, the research conducted at these extreme and logistically challenging environments still continues to reveal unique biological processes. Here, we report for the first time, a unique behavior where the deep sea skate, Bathyraja spinosissima, appears to be actively using the elevated temperature of a hydrothermal vent environment to naturally "incubate" developing egg-cases. We hypothesize that this behavior is directly targeted to accelerate embryo development time given that deep-sea skates have some of the longest egg incubation times reported for the animal kingdom. Similar egg incubating behavior, where eggs are incubated in volcanically heated nesting grounds, have been recorded in Cretaceous sauropod dinosaurs and the rare avian megapode. To our knowledge, this is the first time incubating behavior using a volcanic source is recorded for the marine environment. PMID- 29422627 TI - The influence of the peripheral cortisol fluctuation on the success rate of adrenal venous sampling. AB - In this retrospective study, we aimed to estimate the influence of fluctuating peripheral plasma cortisol concentration (PCC) on the success rate of non stimulated adrenal venous sampling (AVS) and to demonstrate its fluctuating pattern. Overall, 107 consecutive patients with primary aldosteronism undergoing AVS between July 2015-January 2017 were included. The peripheral vein was sampled at 4 separate time points during the procedure: after femoral puncture, during left adrenal sampling, during right adrenal sampling, and before procedural ending. The selectivity index (SI) was calculated using the highest, the lowest, and the simultaneous sampled peripheral PCC. The highest and lowest peripheral PCC significantly differed (p < 0.001) ranging from a 113% increase to a 55% decrease, respectively, and significant correlation between the degree of the peripheral PCC fluctuation and the inter-sampling time length was found (p < 0.001). There was significant difference in the success rate of the groups using different peripheral PCC: highest and lowest (SI cutoff value 2 and 3), highest and simultaneous (2 and 3), and lowest and simultaneous (3). Altogether, we found significant variation of the peripheral PCC during AVS and the success rate for non-stimulated AVS altered significantly using the peripheral PCC at different time points. PMID- 29422626 TI - Protein interactomes of protein phosphatase 2A B55 regulatory subunits reveal B55 mediated regulation of replication protein A under replication stress. AB - The specific function of PP2A, a major serine/threonine phosphatase, is mediated by regulatory targeting subunits, such as members of the B55 family. Although implicated in cell division and other pathways, the specific substrates and functions of B55 targeting subunits are largely undefined. In this study we identified over 100 binding proteins of B55alpha and B55beta in Xenopus egg extracts that are involved in metabolism, mitochondria function, molecular trafficking, cell division, cytoskeleton, DNA replication, DNA repair, and cell signaling. Among the B55alpha and B55beta-associated proteins were numerous mitotic regulators, including many substrates of CDK1. Consistently, upregulation of B55alpha accelerated M-phase exit and inhibited M-phase entry. Moreover, specific substrates of CDK2, including factors of DNA replication and chromatin remodeling were identified within the interactomes of B55alpha and B55beta, suggesting a role for these phosphatase subunits in DNA replication. In particular, we confirmed in human cells that B55alpha binds RPA and mediates the dephosphorylation of RPA2. The B55-RPA association is disrupted after replication stress, consistent with the induction of RPA2 phosphorylation. Thus, we report here a new mechanism that accounts for both how RPA phosphorylation is modulated by PP2A and how the phosphorylation of RPA2 is abruptly induced after replication stress. PMID- 29422629 TI - Isolating, characterising and identifying a Cry1Ac resistance mutation in field populations of Helicoverpa punctigera. AB - Transgenic cotton expressing insecticidal proteins from Bacillus thuringiensis (Bt) has been grown in Australia for over 20 years and resistance remains the biggest threat. The native moth, Helicoverpa punctigera is a significant pest of cotton. A genotype causing resistance to Cry1Ac in H. punctigera was isolated from the field and a homozygous line established. The phenotype is recessive and homozygous individuals possess 113 fold resistance to Cry1Ac. Individuals that carry Cry1Ac resistance genes are rare in Australia with a frequency of 0.033 being detected in field populations. RNAseq, RT-PCR and DNA sequencing reveals a single nucleotide polymorphism at a splice site in the cadherin gene as the causal mutation, resulting in the partial transcription of the intron and a premature stop codon. Analysis of Cry1Ac binding to H. punctigera brush border membrane vesicles showed that it is unaffected by the disrupted cadherin gene. This suggests that the major Cry1Ac target is not cadherin but that this molecule plays a key role in resistance and therefore the mode of action. This work adds to our knowledge of resistance mechanisms in H. punctigera and the growing literature around the role of cadherin in the mode of action of Cry1 type Bt proteins. PMID- 29422630 TI - Publisher Correction: Role of outer surface probes for regulating ion gating of nanochannels. AB - The original version of this Article contained an error in Fig. 3. The scale bars in Figs 3c and 3d were incorrectly labelled as 50 MUA. In the correct version, the scale bars are labelled as 0.5 MUA. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29422628 TI - Self-assembly of emissive supramolecular rosettes with increasing complexity using multitopic terpyridine ligands. AB - Coordination-driven self-assembly has emerged as a powerful bottom-up approach to construct various supramolecular architectures with increasing complexity and functionality. Tetraphenylethylene (TPE) has been incorporated into metallo supramolecules to build luminescent materials based on aggregation-induced emission. We herein report three generations of ligands with full conjugation of TPE with 2,2':6',2"-terpyridine (TPY) to construct emissive materials. Due to the bulky size of TPY substituents, the intramolecular rotations of ligands are partially restricted even in dilute solution, thus leading to emission in both solution and aggregation states. Furthermore, TPE-TPY ligands are assembled with Cd(II) to introduce additional restriction of intramolecular rotation and immobilize fluorophores into rosette-like metallo-supramolecules ranging from generation 1-3 (G1-G3). More importantly, the fluorescent behavior of TPE-TPY ligands is preserved in these rosettes, which display tunable emissive properties with respect to different generations, particularly, pure white-light emission for G2. PMID- 29422631 TI - Electrically tunable perfect light absorbers as color filters and modulators. AB - Methods for spectrally controlling light absorption in optoelectronic devices have attracted considerable attention in recent years. It is now well known that a Fabry-Perot nanocavity comprising thin semiconductor and metal films can be used to absorb light at selected wavelengths. The absorption wavelength is controlled by tailoring the thickness of the nanocavity and also by nanostructure patterning. However, the realization of dynamically tuning the absorption wavelength without changing the structural geometry remains a great challenge in optoelectronic device development. Here it is shown how an ultrathin n-type doped indium antimonide integrated into a subwavelength-thick optical nanocavity can result in an electrically tunable perfect light absorber in the visible and near infrared range. These absorbers require simple thin-film fabrication processes and are cost effective for large-area devices without resorting to sophisticated nanopatterning techniques. In the visible range, a 40 nm spectral shift can be attained by applying a reasonable bias voltage to effect the color change. It is also shown that these electrically tunable absorbers may be used as optical modulators in the infrared. The predicted (up to) 95.3% change in reflectance, transforming the device from perfectly absorbing to highly reflective, should make this technology attractive to the telecommunication (switching) industry. PMID- 29422632 TI - The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd. AB - Mycobacterial energy metabolism currently attracts strong attention as new target space for development of anti-tuberculosis drugs. The imidazopyridine Q203 targets the cytochrome bcc complex of the respiratory chain, a key component in energy metabolism. Q203 blocks growth of Mycobacterium tuberculosis at nanomolar concentrations, however, it fails to actually kill the bacteria, which may limit the clinical applicability of this candidate drug. In this report we show that inhibition of cytochrome bd, a parallel branch of the mycobacterial respiratory chain, by aurachin D invoked bactericidal activity of Q203. In biochemical assays using inverted membrane vesicles from Mycobacterium tuberculosis and Mycobacterium smegmatis we found that inhibition of respiratory chain activity by Q203 was incomplete, but could be enhanced by inactivation of cytochrome bd, either by genetic knock-out or by inhibition with aurachin D. These results indicate that simultaneously targeting the cytochrome bcc and the cytochrome bd branch of the mycobacterial respiratory chain may turn out as effective strategy for combating M. tuberculosis. PMID- 29422633 TI - Long-Term Study of Heart Rate Variability Responses to Changes in the Solar and Geomagnetic Environment. AB - This long-term study examined relationships between solar and magnetic factors and the time course and lags of autonomic nervous system (ANS) responses to changes in solar and geomagnetic activity. Heart rate variability (HRV) was recorded for 72 consecutive hours each week over a five-month period in 16 participants in order to examine ANS responses during normal background environmental periods. HRV measures were correlated with solar and geomagnetic variables using multivariate linear regression analysis with Bonferroni corrections for multiple comparisons after removing circadian influences from both datasets. Overall, the study confirms that daily ANS activity responds to changes in geomagnetic and solar activity during periods of normal undisturbed activity and it is initiated at different times after the changes in the various environmental factors and persist over varying time periods. Increase in solar wind intensity was correlated with increases in heart rate, which we interpret as a biological stress response. Increase in cosmic rays, solar radio flux, and Schumann resonance power was all associated with increased HRV and parasympathetic activity. The findings support the hypothesis that energetic environmental phenomena affect psychophysical processes that can affect people in different ways depending on their sensitivity, health status and capacity for self-regulation. PMID- 29422635 TI - Diabetes: Quantifying genetic susceptibility in T1DM - implications for diagnosis after age 30. PMID- 29422634 TI - Biogenic corrosion inhibitor on mild steel protection in concentrated HCl medium. AB - Turbinaria ornata (TO) extract was tested as green corrosion inhibitor on mild steel (MS) coupons in conc. HCl medium with an efficiency of 100% at 25 g l-1 during 5 min exposure. Antibacterial efficacy performed against 16 S rDNA identified marine biofilming bacteria (MBB) and human pathogenic bacteria (HPB). Maximum inhibition growth was 16 mm on MBB observed in Bacillus megaterium (MBF14 - AB894827) and 20 mm on HPB in Escherichia coli (B5 - NCIM 2931). Similarly, minimum of 10 mm on MBB witnessed in Pseudomonas sp., (MBF9 - AB894829). Toxicity studies proved 50.0% LC50 at 500 MUg ml-1 in 24 hrs, whereas Balanus amphitrite resulted in 100% mortality within 12 hrs. Results including weight loss, potentiodynamic polarization and electrochemical impedance spectroscopy, FT-IR and GC-MS confirm 10-Octadecaonic acid as a major corrosion inhibitor from T. ornata and is discovered as a novel antifoulant. Anticorrosion formulation will become available soon. PMID- 29422636 TI - Childhood epilepsy and ADHD comorbidity in an Indian tertiary medical center outpatient population. AB - This study aimed to assess the prevalence of Attention Deficit Hyperactivity Disorder (ADHD) and its characteristics and risk factors in children with epilepsy at a tertiary medical center in New Delhi. Children with active epilepsy, aged 6 to 12 years, were assessed for ADHD using DSM-IV-TR criteria. Epilepsy and psychiatric characteristics, sociodemographic indicators, and use of antiepileptic drugs were analyzed for differences between the ADHD and non-ADHD groups. Among the 73 children with epilepsy, 23% (n = 17) had comorbid ADHD, of whom 59% (n = 10) had predominantly inattentive type, 35% (n = 6) combined type, and 6% (n = 1) predominantly hyperactive-impulsive type. Lower IQ scores, epileptiform EEG activity, not attending school, and male sex were significantly associated with comorbid ADHD in children with epilepsy. Groups were similar in terms of age, socioeconomic indicators, family history of psychiatric disorders, seizure frequency in the last six months, seizure etiology, and seizure type. Epilepsy is a common pediatric neurological condition with frequent psychiatric comorbidities, including ADHD. Specialists should collaborate to optimize treatment for children with epilepsy and ADHD, especially for families in developing countries where the burden of disease can be great. PMID- 29422638 TI - Evidence of thermophilisation and elevation-dependent warming during the Last Interglacial in the Italian Alps. AB - Thermophilisation is the response of plants communities in mountainous areas to increasing temperatures, causing an upward migration of warm-adapted (thermophilic) species and consequently, the timberline. This greening, associated with warming, causes enhanced evapotranspiration that leads to intensification of the hydrological cycle, which is recorded by hydroclimate sensitive archives, such as stalagmites and flowstones formed in caves. Understanding how hydroclimate manifests at high altitudes is important for predicting future water resources of many regions of Europe that rely on glaciers and snow accumulation. Using proxy data from three coeval speleothems (stalagmites and flowstone) from the Italian Alps, we reconstructed both the ecosystem and hydrological setting during the Last Interglacial (LIG); a warm period that may provide an analogue to a near-future climate scenario. Our speleothem proxy data, including calcite fabrics and the stable isotopes of calcite and fluid inclusions, indicate a +4.3 +/- 1.6 degrees C temperature anomaly at ~2000 m a.s.l. for the peak LIG, with respect to present-day values (1961-1990). This anomaly is significantly higher than any low-altitude reconstructions for the LIG in Europe, implying elevation-dependent warming during the LIG. The enhanced warming at high altitudes must be accounted for when considering future climate adaption strategies in sensitive mountainous regions. PMID- 29422637 TI - Ethyl-substitutive Thioflavin T as a highly-specific fluorescence probe for detecting G-quadruplex structure. AB - G-quadruplex has attracted considerable attention due to their prevalent distribution in functional genomic regions and transcripts, which can importantly influence biological processes such as regulation of telomere maintenance, gene transcription and gene translation. Artificial receptor study has been developed for accurate identification of G-quadruplex from DNA species, since it is important for the G-quadruplex related basic research, clinical diagnosis, and therapy. Herein, fluorescent dye ThT-E, a derivative of the known fluorescence probe Thioflavin T (ThT), was designed and synthesized to effectively differentiate various G-quadruplex structures from other nucleic acid forms. Compared with methyl groups in ThT, three ethyl groups were introduced to ThT-E, which leads to strengthened affinity, selectivity and little inducing effect on the G-quadruplex formation. More importantly, ThT-E could be served as a visual tool to directly differentiate G-quadruplex solution even with naked eyes under illumination of ultraviolet light. Thus, this probe reported herein may hold great promise for high-throughput assay to screen G-quadruplex, which may widely apply to G-quadruplex-based potential diagnosis and therapy. PMID- 29422640 TI - Mutational landscape of goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix is distinct from typical carcinoids and colorectal adenocarcinomas. AB - There is limited data on the spectrum of molecular alterations in goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix. We used next generation sequencing to determine mutations of potential pathogenetic and therapeutic significance in this rare group of tumors. Adequate DNA was successfully extracted in 34/46 cases and the final group included 18 goblet cell carcinoids and 16 adenocarcinoma ex goblet cell carcinoids. Illumina TruSeqTM was used for sequencing exons of a custom 282 gene panel using an Illumina HiSeq 2000. All cases had a minimum coverage depth of at least 50 reads. After filtering through the Exome Sequencing Project, the number of mutations per case ranged from 0-9 (mean:3). The mutational burden in adenocarcinoma ex goblet cell carcinoids was significantly higher than goblet cell carcinoids (mean 5 vs. 3; p < 0.05) but the spectrum of alterations overlapped between the two groups. The most frequent mutations included ARID1A (4/34), ARID2 (4/34), CDH1 (4/34), RHPN2 (4/34), and MLL2 (3/34). Some mutations typically seen in conventional colorectal adenocarcinomas were also identified but with much lower frequency (APC :4/34; KRAS :2/34). MLL2 and KRAS mutations were only seen in adenocarcinoma ex goblet cell carcinoids and TP53 mutations were limited to poorly differentiated adenocarcinoma ex goblet cell carcinoids (2/34). Copy number changes could be evaluated in 15/34 cases and showed low copy number gains in CDKN1B (6/15) and NFKBIA (6/15), among others. The overlapping molecular alterations suggest that goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids are best considered two grades of differentiation of the same tumor rather than two distinct histological types. Mutations in TP53, CDH1 and MLL2 mutations were predominantly present in the adenocarcinoma ex goblet cell carcinoid group consistent with transformation to a higher grade lesion. The unique mutational profile also offers an explanation for the poor chemosensitivity in these tumors and highlights the need for developing new targeted therapies. PMID- 29422639 TI - Ileal pouch of ulcerative colitis and familial adenomatous polyposis patients exhibit modulation of autophagy markers. AB - Total retocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgery of choice for patients with ulcerative colitis (UC) that are refractory to clinical treatment. Pouchitis is one of the most common complications after this procedure. Defects in autophagy have been reported in inflammatory bowel diseases. However, there are no studies on the IP. Therefore, we studied markers for autophagy in the IP mucosa of UC and FAP patients comparing them to controls with a normal distal ileum. Sixteen patients with IP in "J" shape, asymptomatic and with endoscopically normal IP were evaluated. The control group consisted of eight patients with normal colonoscopy. There was a significant decrease in the transcriptional levels of ATG5, MAP1LC3A and BAX in the FAP group. There was also a decrease in the protein level of Beclin-1 in the UC and FAP compared to the control group. Although the LC3II levels by immunoblot were higher in the UC group, LC3/p62 co-localization were lower in the immunofluorescence analysis in the UC and FAP compared to the control group. Corroborating these results, there was an increase of p62 by immunoblot in the UC group. These findings indicated a modulation of macroautophagy markers in the IP, which may explain the mucosa inflammation predisposition. PMID- 29422641 TI - Impact of Synaptic Device Variations on Pattern Recognition Accuracy in a Hardware Neural Network. AB - Neuromorphic systems (hardware neural networks) derive inspiration from biological neural systems and are expected to be a computing breakthrough beyond conventional von Neumann architecture. Interestingly, in neuromorphic systems, the processing and storing of information can be performed simultaneously by modulating the connection strength of a synaptic device (i.e., synaptic weight). Previously investigated synaptic devices can emulate the functionality of biological synapses successfully by utilizing various nano-electronic phenomena; however, the impact of intrinsic synaptic device variability on the system performance has not yet been studied. Here, we perform a device-to-system level simulation of different synaptic device variation parameters in a designed neuromorphic system that has the potential for unsupervised learning and pattern recognition. The effects of variations in parameters such as the weight modulation nonlinearity (NL), the minimum-maximum weight (G min and G max ), and the weight update margin (DeltaG) on the pattern recognition accuracy are analyzed quantitatively. These simulation results can provide guidelines for the continued design and optimization of a synaptic device for realizing a functional large-scale neuromorphic computing system. PMID- 29422642 TI - In Silico Non-Homologous End Joining Following Ion Induced DNA Double Strand Breaks Predicts That Repair Fidelity Depends on Break Density. AB - This work uses Monte Carlo simulations to investigate the dependence of residual and misrepaired double strand breaks (DSBs) at 24 hours on the initial damage pattern created during ion therapy. We present results from a nanometric DNA damage simulation coupled to a mechanistic model of Non-Homologous End Joining, capable of predicting the position, complexity, and repair of DSBs. The initial damage pattern is scored by calculating the average number of DSBs within 70 nm from every DSB. We show that this local DSB density, referred to as the cluster density, can linearly predict misrepair regardless of ion species. The models predict that the fraction of residual DSBs is constant, with 7.3% of DSBs left unrepaired following 24 hours of repair. Through simulation over a range of doses and linear energy transfer (LET) we derive simple correlations capable of predicting residual and misrepaired DSBs. These equations are applicable to ion therapy treatment planning where both dose and LET are scored. This is demonstrated by applying the correlations to an example of a clinical proton spread out Bragg peak. Here we see a considerable biological effect past the distal edge, dominated by residual DSBs. PMID- 29422643 TI - RNA-seq transcriptome analysis of breast cancer cell lines under shikonin treatment. AB - Shikonin is a naphthoquinone isolated from the dried root of Lithospermum erythrorhizon, an herb used in Chinese medicine. Although several studies have indicated that shikonin exhibits antitumor activity in breast cancer, the mechanism of action remains unclear. In the present study, we performed transcriptome analysis using RNA-seq and explored the mechanism of action of shikonin in regulating the growth of different types of breast cancer cells. The IC50 of shikonin on MCF-7, SKBR-3 and MDA-MB-231 cells were 10.3 MUMU, 15.0 MUMU, 15.0 MUMU respectively. Our results also demonstrated that shikonin arrests the progression of cell cycle and induces apoptosis in MDA-MB-231 cells. Using RNA seq transcriptome analysis, we found 38 common genes that significantly express in different types of breast cancer cells under shikonin treatment. In particular, our results indicated that shikonin induces the expression of dual specificity phosphatase (DUSP)-1 and DUSP2 in both RNA and protein levels. In addition, shikonin also inhibits the phosphorylation of JNK and p38, the downstream signaling molecules of DUSP1 and DUSP2. Therefore, our results suggest that shikonin induces the expression of DUSP1 and DUSP2 which consequently switches off JNK and p38 MAPK pathways and causes cell cycle arrest and apoptosis in breast cancer cells. PMID- 29422645 TI - Stroke: Expanding the thrombectomy time window after stroke. PMID- 29422644 TI - Advances in therapy for spinal muscular atrophy: promises and challenges. AB - Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease modifying therapy for SMA by US and European authorities - the antisense oligonucleotide nusinersen. At the same time, promising data from early-stage clinical trials of SMN1 gene therapy have indicated that additional therapeutic options are likely to emerge for patients with SMA in the near future. However, the approval of nusinersen has generated a number of immediate and substantial medical, ethical and financial implications that have the potential to resonate beyond the specific treatment of SMA. Here, we provide an overview of the rapidly evolving therapeutic landscape for SMA, highlighting current achievements and future opportunities. We also discuss how these developments are providing important lessons for the emerging second generation of combinatorial ('SMN plus') therapies that are likely to be required to generate robust treatments that are effective across a patient's lifespan. PMID- 29422646 TI - Alzheimer disease: APOE epsilon4 affects cognitive decline but does not block benefits of healthy lifestyle. PMID- 29422649 TI - Dielectric Jump and Negative Electrostriction in Metallosupramolecular Ionic Crystals. AB - In natural ionic solids, cationic and anionic species are alternately arranged to minimize electrostatic energy. Aggregation of identical ionic species is commonly prohibited due to the repulsive, long-range nature of Coulombic interactions. Recently, we synthesized unique ionic solids, [AuI4CoIII2(dppe)2(D-pen)4]X2.nH2O (dppe = 1,2-bis(diphenylphosphino)ethane, D-pen = D-penicillaminate), in which complex cations are self-assembled into a cationic supramolecular octahedron, while monovalent or divalent inorganic anions are aggregated into an anomalous anionic cluster accommodating several water molecules. This quite unusual aggregation manner originates from various molecular-level non-Coulombic interactions such as hydrogen bonds and CH-pi interactions; thus, this class of ionic solids is referred to as non-Coulombic ionic solids, abbreviated as NCISs. Herein, we report that the NCISs with a peculiar charge-separated (CS) structure in a cubic lattice show a negative, isotropic electrostriction phenomenon that has never been found in any ionic solids, as well as an anomalously large relaxer like dielectric jump phenomenon reaching to an application level of epsilon'/epsilon0 ~ 105. The appearance of these phenomena was explained by the cooperative dynamics of inorganic anions and dipolar water molecules in the pliable anionic clusters that are surrounded by a rather robust cationic metallosupramolecular framework with a meso-scopic scale. PMID- 29422647 TI - Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2alpha. AB - Spatiotemporal regulation of tumor immunity remains largely unexplored. Here we identify a vascular niche that controls alternative macrophage activation in glioblastoma (GBM). We show that tumor-promoting macrophages are spatially proximate to GBM-associated endothelial cells (ECs), permissive for angiocrine induced macrophage polarization. We identify ECs as one of the major sources for interleukin-6 (IL-6) expression in GBM microenvironment. Furthermore, we reveal that colony-stimulating factor-1 and angiocrine IL-6 induce robust arginase-1 expression and macrophage alternative activation, mediated through peroxisome proliferator-activated receptor-gamma-dependent transcriptional activation of hypoxia-inducible factor-2alpha. Finally, utilizing a genetic murine GBM model, we show that EC-specific knockout of IL-6 inhibits macrophage alternative activation and improves survival in the GBM-bearing mice. These findings illustrate a vascular niche-dependent mechanism for alternative macrophage activation and cancer progression, and suggest that targeting endothelial IL-6 may offer a selective and efficient therapeutic strategy for GBM, and possibly other solid malignant tumors. PMID- 29422651 TI - Impact of erroneous meal insulin bolus with dual-hormone artificial pancreas using a simplified bolus strategy - A randomized controlled trial. AB - Postprandial glucose control remains challenging for patients with type 1 diabetes (T1D). A simplified meal bolus approach with a dual-hormone (insulin and glucagon) closed-loop system (DH-CLS) has been tested; yet, the impact of categorization errors with this strategy is unknown. The objective was to compare, in a randomized controlled inpatient trial, DH-CLS with the simplified meal bolus approach for two different meals properly categorized or overestimated. We tested, in patients with T1D, the simplified strategy with two standardized breakfasts (n = 10 per meal) adequately categorized or overestimated: (1) 75 g and (2) 45 g of carbohydrate. No difference was observed for percentage of time <4.0 mmol/L over a 4-hour post-meal period (primary outcome; median [IQR]: 0[0-0] vs. 0[0-0] for both comparisons, p = 0.47 and 0.31 for the 75 g and 45 g meals, respectively). Despite higher meal insulin boluses with overestimation for both meals (9.2 [8.2-9.6] vs. 8.1 [7.3-9.1] U and 8.4 [7.2-10.4] vs. 4.8 [3.7-5.6] U; p < 0.05), mean glycemia, percentage of time in target range and glucagon infusion did not differ. Additional scenarios were tested in silico with comparable results. These results suggest that the DH-CLS with a simplified meal bolus calculation is probably able to avoid hypoglycemia in the event of meal size misclassification. PMID- 29422650 TI - Evaluating the potential of endothelial cells derived from human induced pluripotent stem cells to form microvascular networks in 3D cultures. AB - A major translational challenge in the fields of therapeutic angiogenesis and regenerative medicine is the need to create functional microvasculature. The purpose of this study was to assess whether a potentially autologous endothelial cell (EC) source derived from human induced pluripotent stem cells (iPSC-ECs) can form the same robust, stable microvasculature as previously documented for other sources of ECs. We utilized a well-established in vitro assay, in which endothelial cell-coated (iPSC-EC or HUVEC) beads were co-embedded with fibroblasts in a 3D fibrin matrix to assess their ability to form stable microvessels. iPSC-ECs exhibited a five-fold reduction in capillary network formation compared to HUVECs. Increasing matrix density reduced sprouting, although this effect was attenuated by distributing the NHLFs throughout the matrix. Inhibition of both MMP- and plasmin-mediated fibrinolysis was required to completely block sprouting of both HUVECs and iPSC-ECs. Further analysis revealed MMP-9 expression and activity were significantly lower in iPSC-EC/NHLF co cultures than in HUVEC/NHLF co-cultures at later time points, which may account for the observed deficiencies in angiogenic sprouting of the iPSC-ECs. Collectively, these findings suggest fundamental differences in EC phenotypes must be better understood to enable the promise and potential of iPSC-ECs for clinical translation to be realized. PMID- 29422648 TI - Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity. AB - Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins. We also show that naturally acquired purified antibodies against key transmission blocking epitopes of Pfs48/45 and Pfs230 are mechanistically involved in TRA, whereas sera depleted of these antibodies retain high-level, complement independent TRA. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes. PMID- 29422653 TI - Synthesis of light needles with tunable length and nearly constant irradiance. AB - We introduce a new method for producing optical needles with tunable length and almost constant irradiance based on the evaluation of the on-axis power content of the light distribution at the focal area. According to theoretical considerations, we propose an adaptive modulating continuous function that presents a large derivative and a zero value jump at the entrance pupil of the focusing system. This distribution is displayed on liquid crystal devices using holographic techniques. In this way, a polarized input beam is shaped and subsequently focused using a high numerical aperture (NA) objective lens. As a result, needles with variable length and nearly constant irradiance are produced using conventional optics components. This procedure is experimentally demonstrated obtaining a 53lambda-long and 0.8lambda-wide needle. PMID- 29422652 TI - RAGE-aptamer attenuates deoxycorticosterone acetate/salt-induced renal injury in mice. AB - The mineralocorticoid receptor (MR) and its downstream signaling play an important role in hypertensive renal injury. The interaction of advanced glycation end products (AGE) with their receptor (RAGE) is involved in the progression of renal disease. However, the pathological crosstalk between AGE RAGE axis and MR system in kidney derangement remains unclear. We screened DNA aptamer directed against RAGE (RAGE-apt) in vitro and examined its effects on renal injury in uninephrectomized deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mice. RAGE, GTP-bound Rac-1 (Rac1), and MR were co-localized in the podocytes of DOCA mice. The deletion of RAGE gene significantly inhibited mesangial matrix expansion and tubulointerstitial fibrosis in DOCA mice, which was associated with the reduction of glomerular oxidative stress, MR, Rac1, and urinary albumin excretion (UAE) levels. RAGE-apt attenuated the increase in carboxymethyllysine (CML), RAGE, nitrotyrosine, Rac1, and MR levels in the kidneys and reduced UAE in DOCA mice. Aldosterone (Aldo) increased nitrotyrosine, CML, and RAGE gene expression in murine podocytes, whereas CML stimulated MR and Rac1 levels, which were blocked by RAGE-apt. The present study indicates the crosstalk between the AGE-RAGE axis and Aldo-MR system, suggesting that RAGE-apt may be a novel therapeutic tool for the treatment of MR-associated renal diseases. PMID- 29422654 TI - High-throughput immune repertoire analysis with IGoR. AB - High-throughput immune repertoire sequencing is promising to lead to new statistical diagnostic tools for medicine and biology. Successful implementations of these methods require a correct characterization, analysis, and interpretation of these data sets. We present IGoR (Inference and Generation Of Repertoires)-a comprehensive tool that takes B or T cell receptor sequence reads and quantitatively characterizes the statistics of receptor generation from both cDNA and gDNA. It probabilistically annotates sequences and its modular structure can be used to investigate models of increasing biological complexity for different organisms. For B cells, IGoR returns the hypermutation statistics, which we use to reveal co-localization of hypermutations along the sequence. We demonstrate that IGoR outperforms existing tools in accuracy and estimate the sample sizes needed for reliable repertoire characterization. PMID- 29422655 TI - Glycogen synthase protects neurons from cytotoxicity of mutant huntingtin by enhancing the autophagy flux. AB - Healthy neurons do not store glycogen while they do possess the machinery for the glycogen synthesis albeit at an inactive state. Neurons in the degenerating brain, however, are known to accumulate glycogen, although its significance was not well understood. Emerging reports present contrasting views on neuronal glycogen synthesis; a few reports demonstrate a neurotoxic effect of glycogen while a few others suggest glycogen to be neuroprotective. Thus, the specific role of glycogen and glycogen synthase in neuronal physiology is largely unexplored. Using cellular and animal models of Huntington's disease, we show here that the overexpression of cytotoxic mutant huntingtin protein induces glycogen synthesis in the neurons by activating glycogen synthase and the overexpressed glycogen synthase protected neurons from the cytotoxicity of the mutant huntingtin. Exposure of neuronal cells to proteasomal blockade and oxidative stress also activate glycogen synthase to induce glycogen synthesis and to protect against stress-induced neuronal death. We show that the glycogen synthase plays an essential and inductive role in the neuronal autophagic flux, and helps in clearing the cytotoxic huntingtin aggregate. We also show that the increased neuronal glycogen inhibits the aggregation of mutant huntingtin, and thus could directly contribute to its clearance. Finally, we demonstrate that excessive autophagy flux is the molecular basis of cell death caused by the activation of glycogen synthase in unstressed neurons. Taken together, our results thus provide a novel function for glycogen synthase in proteolytic processes and offer insight into the role of glycogen synthase and glycogen in both survival and death of the neurons. PMID- 29422657 TI - Personalizing Androgen Suppression for Prostate Cancer Using Mathematical Modeling. AB - Using a dataset of 150 patients treated with intermittent androgen suppression (IAS) through a fixed treatment schedule, we retrospectively designed a personalized treatment schedule mathematically for each patient. We estimated 100 sets of parameter values for each patient by randomly resampling each patient's time points to take into account the uncertainty for observations of prostate specific antigen (PSA). Then, we identified 3 types and classified patients accordingly: in type (i), the relapse, namely the divergence of PSA, can be prevented by IAS; in type (ii), the relapse can be delayed by IAS later than by continuous androgen suppression (CAS); in type (iii) IAS was not beneficial and therefore CAS would have been more appropriate in the long run. Moreover, we obtained a treatment schedule of hormone therapy by minimizing the PSA of 3 years later in the worst case scenario among the 100 parameter sets by searching exhaustively all over the possible treatment schedules. If the most frequent type among 100 sets was type (i), the maximal PSA tended to be kept less than 100 ng/ml longer in IAS than in CAS, while there was no statistical difference for the other cases. Thus, mathematically personalized IAS should be studied prospectively. PMID- 29422656 TI - Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin. AB - Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and usually progresses from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain partially understood. Here, we use Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status in healthy, AK and cSCC epidermis samples. Importantly, we show that AK methylation patterns already display classical features of cancer methylomes and are highly similar to cSCC profiles. Further analysis identifies typical features of stem cell methylomes, such as reduced DNA methylation age, non-CpG methylation, and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature is detected only in half of the samples, while the other half shows patterns more closely related to healthy epidermis. These findings suggest the existence of two subclasses of AK and cSCC emerging from distinct keratinocyte differentiation stages. PMID- 29422658 TI - Hainan mantle plume produced late Cenozoic basaltic rocks in Thailand, Southeast Asia. AB - Intraplate volcanism initiated shortly after the cessation of Cenozoic seafloor spreading in the South China Sea (SCS) region, but the full extent of its influence on the Indochina block has not been well constrained. Here we present major and trace element data and Sr-Nd-Pb-Hf isotope ratios of late Cenozoic basaltic lavas from the Khorat plateau and some volcanic centers in the Paleozoic Sukhothai arc terrane in Thailand. These volcanic rocks are mainly trachybasalts and basaltic trachyandesites. Trace element patterns and Sr-Nd-Pb-Hf isotopic compositions show that these alkaline volcanic lavas exhibit oceanic island basalt (OIB)-like characteristics with enrichments in both large-ion lithophile elements (LILE) and high field strength elements (HFSEs). Their mantle source is a mixture between a depleted Indian MORB-type mantle and an enriched mantle type 2 (EMII). We suggest that the post-spreading intraplate volcanism in the SCS region was induced by a Hainan mantle plume which spread westwards to the Paleozoic Sukhothai arc terrane. PMID- 29422659 TI - How is genetic testing evaluated? A systematic review of the literature. AB - Given the rapid development of genetic tests, an assessment of their benefits, risks, and limitations is crucial for public health practice. We performed a systematic review aimed at identifying and comparing the existing evaluation frameworks for genetic tests. We searched PUBMED, SCOPUS, ISI Web of Knowledge, Google Scholar, Google, and gray literature sources for any documents describing such frameworks. We identified 29 evaluation frameworks published between 2000 and 2017, mostly based on the ACCE Framework (n = 13 models), or on the HTA process (n = 6), or both (n = 2). Others refer to the Wilson and Jungner screening criteria (n = 3) or to a mixture of different criteria (n = 5). Due to the widespread use of the ACCE Framework, the most frequently used evaluation criteria are analytic and clinical validity, clinical utility and ethical, legal and social implications. Less attention is given to the context of implementation. An economic dimension is always considered, but not in great detail. Consideration of delivery models, organizational aspects, and consumer viewpoint is often lacking. A deeper analysis of such context-related evaluation dimensions may strengthen a comprehensive evaluation of genetic tests and support the decision-making process. PMID- 29422660 TI - Deep intronic variation in splicing regulatory element of the ERCC8 gene associated with severe but long-term survival Cockayne syndrome. AB - Cockayne syndrome is an autosomal recessive multisystem disorder characterized by intellectual disability, microcephaly, severe growth failure, sensory impairment, peripheral neuropathy, and cutaneous sensitivity. This rare disease is linked to disease-causing variations in the ERCC6 (CSB) and ERCC8 (CSA) genes. Various degrees of severity have been described according to age at onset and survival, without any clear genotype-phenotype correlation. All types of nucleotide changes have been observed in CS genes, including splice variations mainly affecting the splice site consensus sequences. We report here the case of two brothers from a consanguineous family presenting a severe but long-term survival phenotype of Cockayne syndrome. We identified in the patients a homozygous deep intronic nucleotide variation causing the insertion of a cryptic exon in the ERCC8 (CSA) transcript, by modifying intronic regulatory elements important for exon definition. The pathogenesis of the nucleotide variant NG_009289.1(NM_000082.3):c.173+1119G>C was validated in vitro with a reporter minigene system. To our knowledge, these are the first Cockayne patients described with this kind of disease-causing variation, though molecular mechanism underlying early onset symptoms and unexpected slow raise of progression of the disease remain to be elucidated. PMID- 29422662 TI - Contemporary and historical oceanographic processes explain genetic connectivity in a Southwestern Atlantic coral. AB - Understanding connectivity patterns has implications for evolutionary and ecological processes, as well as for proper conservation strategies. This study examined population genetic structure and migration patterns of the coral Mussismilia hispida, one of the main reef builders in the Southwestern Atlantic Ocean. For this, 15 sites were sampled along its entire distributional range employing 10 microsatellite loci. M. hispida was divided into five genetically differentiated populations by Structure analysis. Population structure and migration estimates are consistent with present-day oceanographic current patterns, zones of upwelling and historical sea-level changes. The Central Region and Oceanic Islands populations had the highest genetic diversity, were possibly the main sources of migrants for other populations and presented mutual migrant exchange. This mutual exchange and the high diversity of Oceanic Islands, a peripherical population, is highly interesting and unexpected, but can be explained if these sites acted as refugia in past low sea-level stance. This is the first connectivity study in the region using hyper-variable markers and a fine sampling scale along 3,500 km. These results enlighten the population dynamics of an important reef building species and shows how oceanographic processes may act as barriers to dispersal for marine species, providing valuable information for management strategies. PMID- 29422661 TI - Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics. AB - Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 * 10-8) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180:C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 * 10-6) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 * 10-95). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking. PMID- 29422663 TI - Multiparameter Analysis of Gas Transport Phenomena in Shale Gas Reservoirs: Apparent Permeability Characterization. AB - The large amount of nanoscale pores in shale results in the inability to apply Darcy's law. Moreover, the gas adsorption of shale increases the complexity of pore size characterization and thus decreases the accuracy of flow regime estimation. In this study, an apparent permeability model, which describes the adsorptive gas flow behavior in shale by considering the effects of gas adsorption, stress dependence, and non-Darcy flow, is proposed. The pore size distribution, methane adsorption capacity, pore compressibility, and matrix permeability of the Barnett and Eagle Ford shales are measured in the laboratory to determine the critical parameters of gas transport phenomena. The slip coefficients, tortuosity, and surface diffusivity are predicted via the regression analysis of the permeability data. The results indicate that the apparent permeability model, which considers second-order gas slippage, Knudsen diffusion, and surface diffusion, could describe the gas flow behavior in the transition flow regime for nanoporous shale. Second-order gas slippage and surface diffusion play key roles in the gas flow in nanopores for Knudsen numbers ranging from 0.18 to 0.5. Therefore, the gas adsorption and non-Darcy flow effects, which involve gas slippage, Knudsen diffusion, and surface diffusion, are indispensable parameters of the permeability model for shale. PMID- 29422665 TI - Application of Bayes' to the prediction of referral decisions made by specialist optometrists in relation to chronic open angle glaucoma. AB - PURPOSE: To determine the accuracy of a Bayesian learning scheme (Bayes') applied to the prediction of clinical decisions made by specialist optometrists in relation to the referral refinement of chronic open angle glaucoma. METHODS: This cross-sectional observational study involved collection of data from the worst affected or right eyes of a consecutive sample of cases (n = 1,006) referred into the West Kent Clinical Commissioning Group Community Ophthalmology Team (COT) by high street optometrists. Multilevel classification of each case was based on race, sex, age, family history of chronic open angle glaucoma, reason for referral, Goldmann Applanation Tonometry (intraocular pressure and interocular asymmetry), optic nerve head assessment (vertical size, cup disc ratio and interocular asymmetry), central corneal thickness and visual field analysis (Hodapp-Parrish-Anderson classification). Randomised stratified tenfold cross validation was applied to determine the accuracy of Bayes' by comparing its output to the clinical decisions of three COT specialist optometrists; namely, the decision to discharge, follow-up or refer each case. RESULTS: Outcomes of cross-validation, expressed as means and standard deviations, showed that the accuracy of Bayes' was high (95%, 2.0%) but that it falsely discharged (3.4%, 1.6%) or referred (3.1%, 1.5%) some cases. CONCLUSIONS: The results indicate that Bayes' has the potential to augment the decisions of specialist optometrists. PMID- 29422664 TI - Pof8 is a La-related protein and a constitutive component of telomerase in fission yeast. AB - Telomerase reverse transcriptase (TERT) and the non-coding telomerase RNA subunit (TR) constitute the core of telomerase. Here we now report that the putative F box protein Pof8 is also a constitutive component of active telomerase in fission yeast. Pof8 functions in a hierarchical assembly pathway by promoting the binding of the Lsm2-8 complex to telomerase RNA, which in turn promotes binding of the catalytic subunit. Loss of Pof8 reduces TER1 stability, causes a severe assembly defect, and results in critically short telomeres. Structure profile searches identified similarities between Pof8 and telomerase subunits from ciliated protozoa, making Pof8 next to TERT the most widely conserved telomerase subunits identified to date. PMID- 29422666 TI - Response to: 'Comment on: 'How to defuse a demographic time bomb: the way forward?' PMID- 29422667 TI - Comment on: 'How to defuse a demographic time bomb: the way forward?' PMID- 29422668 TI - Electrical terahertz modulator based on photo-excited ferroelectric superlattice. AB - The transmission and dielectric spectra of ferroelectric STO/PT superlattice on Si substrate under simultaneous external optical and electric field were investigated and compared at room temperature. Results found that when with an optical field, the electric field realized an effective modulation on the transmission, which displayed a diode property. In addition, a comprehensive model combined with Debye relaxation and Lorentz model was used to analyze the dielectric spectra, variation of the soft mode with external field was put emphasis on exploring. PMID- 29422669 TI - Genetic control of meristem arrest and life span in Arabidopsis by a FRUITFULL APETALA2 pathway. AB - Monocarpic plants have a single reproductive cycle in their lives, where life span is determined by the coordinated arrest of all meristems, or global proliferative arrest (GPA). The molecular bases for GPA and the signaling mechanisms involved are poorly understood, other than systemic cues from developing seeds of unknown nature. Here we uncover a genetic pathway regulating GPA in Arabidopsis that responds to age-dependent factors and acts in parallel to seed-derived signals. We show that FRUITFULL (FUL), a MADS-box gene involved in flowering and fruit development, has a key role in promoting meristem arrest, as GPA is delayed and fruit production is increased in ful mutants. FUL directly and negatively regulates APETALA2 expression in the shoot apical meristem and maintains the temporal expression of WUSCHEL which is an essential factor for meristem maintenance. PMID- 29422670 TI - Alterations of specific chromatin conformation affect ATRA-induced leukemia cell differentiation. AB - Chromatin conformation plays a key role in regulating gene expression and controlling cell differentiation. However, the whole-genome chromatin conformation changes that occur during leukemia cell differentiation are poorly understood. Here, we characterized the changes in chromatin conformation, histone states, chromatin accessibility, and gene expression using an all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation model. The results showed that the boundaries of topological associated domains (TADs) were stable during differentiation; however, the chromatin conformations within several specific TADs were obviously changed. By combining H3K4me3, H3K27ac, and Hi-C signals, we annotated the differential gene-regulatory chromatin interactions upon ATRA induction. The gains and losses of the gene-regulatory chromatin interactions are significantly correlated with gene expression and chromatin accessibility. Finally, we found that the loss of GATA2 expression and DNA binding are crucial for the differentiation process, and changes in the chromatin structure around the GATA2 regulate its expression upon ATRA induction. This study provided both statistical insights and experimental details regarding the relationship between chromatin conformation changes and transcription regulation during leukemia cell differentiation, and the results suggested that the chromatin conformation is a new type of potential drug target for cancer therapy. PMID- 29422672 TI - Nonlinear effects for three-terminal heat engine and refrigerator. AB - The three-terminal heat device that consists of an electronic cavity and couples to a heat bath is studied both as a heat engine and as a refrigerator. We investigate the characteristic performance in the linear and nonlinear regime for both setups. It is our focus here to analyze how the efficiency of the heat engine and coefficient of performance of the refrigerator are affected by the nonlinear transport. With such considerations, the maximum efficiency and power are then optimized for various energy levels, temperatures and other parameters. PMID- 29422671 TI - Site-specific phosphorylation of TRANSPARENT TESTA GLABRA1 mediates carbon partitioning in Arabidopsis seeds. AB - Seed development is dependent on nutrients, such as a source of carbon, supplied by the parent plant. It remains largely unknown how these nutrients are distributed to zygotic and maternal tissues to coordinate storage of reserve compounds and development of protective tissues like seed coat. Here we show that phosphorylation of TRANSPARENT TESTA GLABRA1 (TTG1) is regulated by SHAGGY-like kinases 11/12 (SK11/12) and that this mediates carbon flow to fatty acid synthesis and seed coat traits in Arabidopsis seeds. SK11/12 phosphorylate TTG1 at serine 215, thus preventing TTG1 interaction with TRANSPARENT TESTA2. This compromises recruitment of TTG1 to the GLABRA2 locus and downregulates GLABRA2 expression, which enhances biosynthesis of fatty acids in the embryo, but reduces production of mucilage and flavonoid pigments in the seed coat. Therefore, site specific phosphorylation of TTG1 by SK11/SK12 regulates carbon partitioning between zygotic and maternal sinks in seeds. PMID- 29422673 TI - Small molecule anionophores promote transmembrane anion permeation matching CFTR activity. AB - Anion selective ionophores, anionophores, are small molecules capable of facilitating the transmembrane transport of anions. Inspired in the structure of natural product prodigiosin, four novel anionophores 1a-d, including a 1,2,3 triazole group, were prepared. These compounds proved highly efficient anion exchangers in model phospholipid liposomes. The changes in the hydrogen bond cleft modified the anion transport selectivity exhibited by these compounds compared to prodigiosin and suppressed the characteristic high toxicity of the natural product. Their activity as anionophores in living cells was studied and chloride efflux and iodine influx from living cells mediated by these derivatives was demonstrated. These compounds were shown to permeabilize cellular membranes to halides with efficiencies close to the natural anion channel CFTR at doses that do not compromise cellular viability. Remarkably, optimal transport efficiency was measured in the presence of pH gradients mimicking those found in the airway epithelia of Cystic Fibrosis patients. These results support the viability of developing small molecule anionophores as anion channel protein surrogates with potential applications in the treatment of conditions such as Cystic Fibrosis derived from the malfunction of natural anion transport mechanisms. PMID- 29422674 TI - Soil salinity and matric potential interaction on water use, water use efficiency and yield response factor of bean and wheat. AB - We studied the effects of soil matric potential and salinity on the water use (WU), water use efficiency (WUE) and yield response factor (Ky), for wheat (Triticum aestivum cv. Mahdavi) and bean (Phaseoulus vulgaris cv. COS16) in sandy loam and clay loam soils under greenhouse conditions. Results showed that aeration porosity is the predominant factor controlling WU, WUE, Ky and shoot biomass (Bs) at high soil water potentials. As matric potential was decreased, soil aeration improved, with Bs, WU and Ky reaching maximum value at -6 to -10 kPa, under all salinities. Wheat WUE remained almost unchanged by reduction of matric potential under low salinities (EC <= 8 dSm-1), but increased under higher salinities (EC >= 8 dSm-1), as did bean WUE at all salinities, as matric potential decreased to -33 kPa. Wheat WUE exceeds that of bean in both sandy loam and clay loam soils. WUE of both plants increased with higher shoot/root ratio and a high correlation coefficient exists between them. Results showed that salinity decreases all parameters, particularly at high potentials (h = -2 kPa), and amplifies the effects of waterlogging. Further, we observed a strong relationship between transpiration (T) and root respiration (Rr) for all experiments. PMID- 29422675 TI - The model of circulating immune complexes and interleukin-6 improves the prediction of disease activity in systemic lupus erythematosus. AB - Systemic Lupus Erythematosus (SLE) is an autoimmune disease resulting in autoantibody production, immune complex deposition, and complement activation. The standard biomarkers such as anti-dsDNA and complements (C3 and C4) do not always correlate with active clinical SLE. The heterogeneity of SLE patients may require additional biomarkers to designate disease activity. Ninety SLE patients participated in this study. Evaluation of disease activity was achieved with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and modified SLEDAI-2K. The measured serum biomarkers were anti-dsDNA, C3, C4, ESR, interleukin-6 (IL-6), and circulating immune complexes (CIC). IL-6, ESR and CIC significantly increased in active clinical SLE. Complement, anti-dsDNA, ESR and CIC correlated with SLEDAI-2K while only anti-dsDNA, CIC, ESR and IL-6 correlated with modified SLEDAI-2K. A combination of biomarkers gave a higher odds ratio (OR) than any single biomarker. A combination of IL-6 or CIC exhibited the highest OR (OR = 7.27, 95%CI (1.99-26.63), p = 0.003) while either complement or anti-dsDNA showed a moderate odds ratio (OR = 3.14, 95%CI (1.16-8.48), p = 0.024) of predicting clinical active SLE. The combination of CIC and IL-6 strongly predicts active clinical SLE. CIC and IL-6 can be used in addition to standard biomarkers to determine SLE activity. PMID- 29422676 TI - Pro-apoptotic liposomes-nanobubble conjugate synergistic with paclitaxel: a platform for ultrasound responsive image-guided drug delivery. AB - Recently, liposomes-microbubble conjugates have emerged as a promising ultrasound (US)-responsive platform for cancer therapeutics. However, these are limited by their size in terms of tumor penetration. Additionally, there have been no attempts to enhance the smartness of such conjugates which have been used only as passive carriers. The present study explores submicron sized (756 +/- 180.0 nm), US-responsive, phosphatidylserine (PS)-based paclitaxel-liposomes-nanobubble conjugates (PSPLBC) with an additional pro-apoptotic effect towards enhanced anti cancer efficacy and image-guidance. The developed PSPLBC underwent cavitation in response to US-trigger, exhibiting in vitro pulsatile release with a 10-fold increase in cellular internalization as compared to control. The PS-containing formulations were found to be pro-apoptotic and exhibited strong synergism between PS and paclitaxel (Combination Index, CI < 0.1). This resulted in significantly high anti-tumor efficacy both in vitro and in vivo conditions (98.3 +/- 0.8% tumor growth inhibition, TGI). Significant reduction in tumor proliferation index and MVD, as well as significant increase in apoptosis, were observed for the treated tumor sections. Further, the intravenous (i.v.) administration of PSPLBC enhanced the tumor US-contrast by 2-fold as compared to SonoVue. These results, show the potential of PSPLBC as a promising non-invasive, pro-apoptotic, smart DDS for US-responsive, image-guided cancer therapeutics. PMID- 29422677 TI - Transformable masks for colloidal nanosynthesis. AB - Synthetic skills are the prerequisite and foundation for the modern chemical and pharmaceutical industry. The same is true for nanotechnology, whose development has been hindered by the sluggish advance of its synthetic toolbox, i.e., the emerging field of nanosynthesis. Unlike organic chemistry, where the variety of functional groups provides numerous handles for designing chemical selectivity, colloidal particles have only facets and ligands. Such handles are similar in reactivity to each other, limited in type, symmetrically positioned, and difficult to control. In this work, we demonstrate the use of polymer shells as adjustable masks for nanosynthesis, where the different modes of shell transformation allow unconventional designs beyond facet control. In contrast to ligands, which bind dynamically and individually, the polymer masks are firmly attached as sizeable patches but at the same time are easy to manipulate, allowing versatile and multi-step functionalization of colloidal particles at selective locations. PMID- 29422678 TI - Clinical Translation of Tethered Confocal Microscopy Capsule for Unsedated Diagnosis of Eosinophilic Esophagitis. AB - Esophagogastroduodenoscopy (EGD) is a widely used procedure, posing significant financial burden on both healthcare systems and patients. Moreover, EGD is time consuming, sometimes difficult to tolerate, and suffers from an imperfect diagnostic yield as the limited number of collected biopsies does not represent the whole organ. In this paper, we report on technological and clinical feasibility of a swallowable tethered endomicroscopy capsule, which is administered without sedation, to image large regions of esophageal and gastric mucosa at the cellular level. To demonstrate imaging capabilities, we conducted a human pilot study (n = 17) on Eosinophilic Esophagitis (EoE) patients and healthy volunteers from which representative cases are presented and discussed. Results indicate that, compared to endoscopic biopsy, unsedated tethered capsule endomicroscopy obtains orders of magnitude more cellular information while successfully resolving characteristic tissue microscopic features such as stratified squamous epithelium, lamina propria papillae, intraepithelial eosinophils, and gastric cardia and body/fundic mucosa epithelia. Based on the major import of whole organ, cellular-level microscopy to obviate sampling error and the clear cost and convenience advantages of unsedated procedure, we believe that this tool has the potential to become a simpler and more effective device for diagnosing and monitoring the therapeutic response of EoE and other esophageal diseases. PMID- 29422681 TI - Melancholic Response to War Destruction and the Emergence of a Group Assumption of Post-Ness. AB - What psychological response does war and forced displacement evoke in victims? How do survivors of war communicate their experiences to their children? Finally, what culture does the psychological response to loss shape? Using data collected through interviews, psychological consultations, and children's drawings from two sources-the ongoing Syrian civil war and the Bosnian war of 1992-1995, this paper suggests that the experience of the war generation becomes the organizing axis of their identity and that of their children. It seeks to demonstrate that survivor parents communicate their experience of loss through gesture, act, and object rather than through a coherent narrative. Whereas survivor children use metaphoric and metonymic readings of their parents' everyday performance in order to construct meaning and form their identities as descendants of a given family. This paper argues that such an identity is characterized by ambivalence towards the self and towards others, melancholic longing for an idealized pre-war past, and the impossibility of letting it go. PMID- 29422679 TI - Effects of the Ketogenic diet in overweight divers breathing Enriched Air Nitrox. AB - Central Nervous System Oxygen Toxicity (CNS-OT) is one of the most harmful effects of Enriched Air Nitrox (EAN) diving. Protective factors of the Ketogenic Diet (KD) are antioxidant activity, the prevention of mitochondrial damage and anti-inflammatory mechanisms. We aimed to investigate if a short-term KD may reduce oxidative stress and inflammation during an hyperoxic dive. Samples from six overweight divers (mean +/- SD, age: 55.2 +/- 4.96 years; BMI: 26.7 +/- 0.86 kg/m2) were obtained a) before and after a dive breathing Enriched Air Nitrox and performing 20-minute mild underwater exercise, b) after a dive (same conditions) performed after 7 days of KD. We measured urinary 8-isoprostane and 8-OH-2 deoxyguanosine and plasmatic IL-1beta, IL-6 and TNF-alpha levels. The KD was successful in causing weight loss (3.20 +/- 1.31 Kgs, p < 0.01) and in limiting lipid peroxidation (3.63 +/- 1.16 vs. 1.11 +/- 0.22; p < 0.01) and inflammatory response (IL-1beta = 105.7 +/- 25.52 vs. 57.03 +/- 16.32, p < 0.05; IL-6 = 28.91 +/- 4.351 vs. 14.08 +/- 1.74, p < 0.001; TNF-alpha = 78.01 +/- 7.69 vs. 64.68 +/- 14.56, p < 0.05). A short-term KD seems to be effective in weight loss, in decreasing inflammation and protective towards lipid peroxidation during hyperoxic diving. PMID- 29422683 TI - Never again! Trauma disrupts the experience of time. PMID- 29422684 TI - Somatic Countertransference as Evidence of Adhesive Identification in a Severely Traumatized Woman. AB - This paper discusses the use of somatic countertransference as a means of learning about the patient, about projective and adhesive identification and about the object relating nature of the most traumatized and withdrawn part of the personality. It assumes an elemental knowledge of British Object Relations and uses clinical material to illustrate the hypotheses that somatic countertransference is an indicator of a very elemental communication occurring from the aspect of the psyche that is united in a body mind or mind body. The paper assumes that this body mind was object seeking at birth and perhaps before. Because these early aspects of the personality are non verbal and non conceptual, the analyst must rely not only on the verbal material in a session but on the emotional and sensual experiences within the transference and the countertransference. Such reliance requires a faith in one's own intuition without a certainty that one is "right." Because speaking of such early experience is difficult, often writers and analysts appear more certain than they are. This is a hazard of this type of analytic work. What I am writing about is conjecture or imagination or dream, but I am suggesting that such dream work is a valuable tool for analysis. PMID- 29422685 TI - Ethical Presence in the Psychoanalytic Encounter and the Role of Apology. AB - This paper discusses aspects of ethical presence in psychoanalysis, and the possible use of apology in the therapeutic process. The author roughly delineates two periods in the history of psychoanalysis regarding the ethical dimension-the early classical period which is influenced by Freud's ethics of honesty, which gradually evolves towards the more recent intersubjectively-influenced period, necessitating the assimilation of an ethics of relationships. It is suggested that explicit theorizing of the ethical dimension into psychoanalysis offers added value to its effectiveness, and a framework is presented for combining relational, intersubjectively informed ethical dialogue, with contributions of classical technique, enriching the therapeutic potential of psychoanalytic work. PMID- 29422686 TI - Binocular Vision in the Total Situation. AB - This paper investigates the concept of "total situation" which, even though introduced into psychoanalytic thinking via sister disciplines, such as sociology, the neurosciences, etc., has gradually acquired a relatively prominent position in current therapeutic practice. It is used as a metaphor for the envelopment of the unfolding transferential and related events in the analytic process. Irrespective of whether one focuses on the individual analytic condition or the group-analytic one, contemporary psychoanalytic perspectives include both the bi-personal unconscious interactions and the various levels of the total situation in their conceptualizations of the nature of the process. Such a complex approach in conceptualization can only be achieved through the so-called binocular vision of the analyst. PMID- 29422689 TI - On an additive partial correlation operator and nonparametric estimation of graphical models. AB - We introduce an additive partial correlation operator as an extension of partial correlation to the nonlinear setting, and use it to develop a new estimator for nonparametric graphical models. Our graphical models are based on additive conditional independence, a statistical relation that captures the spirit of conditional independence without having to resort to high-dimensional kernels for its estimation. The additive partial correlation operator completely characterizes additive conditional independence, and has the additional advantage of putting marginal variation on appropriate scales when evaluating interdependence, which leads to more accurate statistical inference. We establish the consistency of the proposed estimator. Through simulation experiments and analysis of the DREAM4 Challenge dataset, we demonstrate that our method performs better than existing methods in cases where the Gaussian or copula Gaussian assumption does not hold, and that a more appropriate scaling for our method further enhances its performance. PMID- 29422688 TI - LC-MS/MS-based quantitative study of the acyl group- and site-selectivity of human sirtuins to acylated nucleosomes. AB - Chromatin structure and gene expression are dynamically regulated by posttranslational modifications of histones. Recent advance in mass spectrometry has identified novel types of lysine acylations, such as butyrylation and malonylation, whose functions and regulations are likely different from those of acetylation. Sirtuins, nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, catalyze various deacylations. However, it is poorly understood how distinct sirtuins regulate the histone acylation states of nucleosomes that have many lysine residues. Here, we provide mass spectrometry-based quantitative information about the acyl group- and site-selectivity of all human sirtuins on acylated nucleosomes. The acyl group- and site-selectivity of each sirtuin is unique to its subtype. Sirt5 exclusively removes negatively-charged acyl groups, while Sirt1/2/3/6/7 preferentially remove hydrophobic acyl groups; Sirt1 and Sirt3 selectively remove acetyl group more than butyryl group, whereas Sirt2 and Sirt6 showed the opposite selectivity. Investigating site-selectivity for active sirtuins revealed acylated lysines on H4 tails to be poor substrates and acylated H3K18 to be a good substrate. Furthermore, we found Sirt7 to be a robust deacylase of H3K36/37, and its activity reliant on nucleosome-binding at its C terminal basic region. All together, our quantitative dataset provides a useful resource in understanding chromatin regulations by histone acylations. PMID- 29422690 TI - Misclassified group-tested current status data. AB - Group testing, introduced by Dorfman (1943), has been used to reduce costs when estimating the prevalence of a binary characteristic based on a screening test of [Formula: see text] groups that include [Formula: see text] independent individuals in total. If the unknown prevalence is low and the screening test suffers from misclassification, it is also possible to obtain more precise prevalence estimates than those obtained from testing all [Formula: see text] samples separately (Tu et al., 1994). In some applications, the individual binary response corresponds to whether an underlying time-to-event variable [Formula: see text] is less than an observed screening time [Formula: see text], a data structure known as current status data. Given sufficient variation in the observed [Formula: see text] values, it is possible to estimate the distribution function [Formula: see text] of [Formula: see text] nonparametrically, at least at some points in its support, using the pool-adjacent-violators algorithm (Ayer et al., 1955). Here, we consider nonparametric estimation of [Formula: see text] based on group-tested current status data for groups of size [Formula: see text] where the group tests positive if and only if any individual's unobserved [Formula: see text] is less than the corresponding observed [Formula: see text]. We investigate the performance of the group-based estimator as compared to the individual test nonparametric maximum likelihood estimator, and show that the former can be more precise in the presence of misclassification for low values of [Formula: see text]. Potential applications include testing for the presence of various diseases in pooled samples where interest focuses on the age-at-incidence distribution rather than overall prevalence. We apply this estimator to the age at-incidence curve for hepatitis C infection in a sample of U.S. women who gave birth to a child in 2014, where group assignment is done at random and based on maternal age. We discuss connections to other work in the literature, as well as potential extensions. PMID- 29422691 TI - Optimal stratification in outcome prediction using baseline information. AB - A common practice in predictive medicine is to use current study data to construct a stratification procedure, which groups subjects according to baseline information and forms stratum-specific prevention or intervention strategies. A desirable stratification scheme would not only have small intra-stratum variation but also have a clinically meaningful discriminatory capability. We show how to obtain optimal stratification rules with such desirable properties from fitting a set of regression models relating the outcome to baseline covariates and creating scoring systems for predicting potential outcomes. We propose that all available optimal stratifications be evaluated with an independent dataset to select a final stratification. Lastly, we obtain inferential results for this selected stratification scheme with a holdout dataset. When only one study of moderate size is available, we combine the first two steps via crossvalidation. Extensive simulation studies are used to compare the proposed stratification strategy with alternatives. We illustrate the new proposal using an AIDS clinical trial for binary outcomes and a cardiovascular clinical study for censored event time outcomes. PMID- 29422692 TI - On inverse probability-weighted estimators in the presence of interference. AB - We consider inference about the causal effect of a treatment or exposure in the presence of interference, i.e., when one individual's treatment affects the outcome of another individual. In the observational setting where the treatment assignment mechanism is not known, inverse probability-weighted estimators have been proposed when individuals can be partitioned into groups such that there is no interference between individuals in different groups. Unfortunately this assumption, which is sometimes referred to as partial interference, may not hold, and moreover existing weighted estimators may have large variances. In this paper we consider weighted estimators that could be employed when interference is present. We first propose a generalized inverse probability-weighted estimator and two Hajek-type stabilized weighted estimators that allow any form of interference. We derive their asymptotic distributions and propose consistent variance estimators assuming partial interference. Empirical results show that one of the Hajek estimators can have substantially smaller finite-sample variance than the other estimators. The different estimators are illustrated using data on the effects of rotavirus vaccination in Nicaragua. PMID- 29422693 TI - Bayesian inference on quasi-sparse count data. AB - There is growing interest in analysing high-dimensional count data, which often exhibit quasi-sparsity corresponding to an overabundance of zeros and small nonzero counts. Existing methods for analysing multivariate count data via Poisson or negative binomial log-linear hierarchical models with zero-inflation cannot flexibly adapt to quasi-sparse settings. We develop a new class of continuous local-global shrinkage priors tailored to quasi-sparse counts. Theoretical properties are assessed, including flexible posterior concentration and stronger control of false discoveries in multiple testing. Simulation studies demonstrate excellent small-sample properties relative to competing methods. We use the method to detect rare mutational hotspots in exome sequencing data and to identify North American cities most impacted by terrorism. PMID- 29422694 TI - Principal component analysis and the locus of the Frechet mean in the space of phylogenetic trees. AB - Evolutionary relationships are represented by phylogenetic trees, and a phylogenetic analysis of gene sequences typically produces a collection of these trees, one for each gene in the analysis. Analysis of samples of trees is difficult due to the multi-dimensionality of the space of possible trees. In Euclidean spaces, principal component analysis is a popular method of reducing high-dimensional data to a low-dimensional representation that preserves much of the sample's structure. However, the space of all phylogenetic trees on a fixed set of species does not form a Euclidean vector space, and methods adapted to tree space are needed. Previous work introduced the notion of a principal geodesic in this space, analogous to the first principal component. Here we propose a geometric object for tree space similar to the [Formula: see text]th principal component in Euclidean space: the locus of the weighted Frechet mean of [Formula: see text] vertex trees when the weights vary over the [Formula: see text]-simplex. We establish some basic properties of these objects, in particular showing that they have dimension [Formula: see text], and propose algorithms for projection onto these surfaces and for finding the principal locus associated with a sample of trees. Simulation studies demonstrate that these algorithms perform well, and analyses of two datasets, containing Apicomplexa and African coelacanth genomes respectively, reveal important structure from the second principal components. PMID- 29422695 TI - Bayesian Local Extremum Splines. AB - We consider shape restricted nonparametric regression on a closed set [Formula: see text], where it is reasonable to assume the function has no more than H local extrema interior to [Formula: see text]. Following a Bayesian approach we develop a nonparametric prior over a novel class of local extremum splines. This approach is shown to be consistent when modeling any continuously differentiable function within the class considered, and is used to develop methods for testing hypotheses on the shape of the curve. Sampling algorithms are developed, and the method is applied in simulation studies and data examples where the shape of the curve is of interest. PMID- 29422696 TI - Exploring the Mother-Adolescent Relationship as a Promotive Resource for Sexual and Gender Minority Youth. AB - Research often analyzes gender minority youth and sexual minority youth as a single group, a practice that obscures differences in how gender identity and sexual orientation shape health. The present study uses intersectionality to explore similarities and differences in the relationships between minority stress theory variables in a sample of 28 gender minority and 135 sexual minority youth of color. We also explore the mother-adolescent relationship as a potential promotive resource for minority stress research with youth. Results find few differences in minority stressors, promotive resources, or health between sexual and gender minority youth. However, different patterns in the correlations between stressors, resources, and health were observed for each group, underscoring the need for researchers to consider sexual and gender minority youth as distinct groups. Furthermore, study findings suggest that the maternal relationship may be an important promotive resource for both sexual and gender minority youth. PMID- 29422697 TI - Tandem synthesis of 1-formyl-1,2,3-triazoles. AB - A tandem method for preparing 4-formyl-1,2,3-triazoles via a two-step one-pot acetal cleavage/CuAAC reaction was developed. Using this method, 4-formyl-1,2,3 triazole analogs with both electron-withdrawing and electron-donating substituents were prepared in good yield and purity. Expansion of this method to a three-step tandem reaction that incorporates an additional step of azide substitution was also successful, circumventing the need for organic azide isolation. This one-pot method, noteworthy in its simplicity and mild conditions, utilizes practical, readily available reactants and relies on protic solvent to promote acid-catalyzed acetal cleavage. PMID- 29422698 TI - STEM crisis or STEM surplus? Yes and yes. AB - The last decade has seen considerable concern regarding a shortage of science, technology, engineering, and mathematics (STEM) workers to meet the demands of the labor market. At the same time, many experts have presented evidence of a STEM worker surplus. A comprehensive literature review, in conjunction with employment statistics, newspaper articles, and our own interviews with company recruiters, reveals a significant heterogeneity in the STEM labor market: the academic sector is generally oversupplied, while the government sector and private industry have shortages in specific areas. PMID- 29422699 TI - Social network members who engage in activities with older adults: Do they bring more social benefits than other members? AB - Active participation in social activities is important for the well-being of older adults. This study explored benefits of active social engagement by evaluating whether relationships that comprise active involvement (e.g., co engagement in activities) bring more social benefits (i.e., social support, companionship, positive social influence) than other relationships that do not involve co-engagement. A total of 133 adults ages 60 years and older living in a rural Midwestern city in the United States were interviewed once and provided information on 1,740 social network members. Among 1,506 social relationships in which interactions occurred at least once a month, 52% involved engagement in social activities together and 35% involved eating together regularly. Results of the generalized linear mixed model showed that relationships involving co engagement were significantly more likely to also convey social support (i.e., emotional, instrumental, informational), companionship, and social influence (encouragement for healthy behaviors) than relationships that do not involve co engagement. Having more network members who provide companionship was associated with higher sense of environmental mastery, positive relations with others, and satisfaction with social network. Interventions may focus on maintaining and developing such social relationships and ensuring the presence of social settings in which co-engagement can occur. Future research may explore whether increasing co-engagement leads to enhanced sense of companionship and psychological well being. PMID- 29422700 TI - A cross-species comparison of abnormal behavior in three species of singly-housed old world monkeys. AB - Abnormal behavior occurs in a number of captive nonhuman primate species and is often used as an indicator of welfare. However, reported levels of abnormal behavior often vary across species, making general welfare judgments difficult. The purpose of this study was to assess differences in levels of abnormal behavior and associated risk factors across three species of Old World monkeys in order to identify similarities and differences across species. The subjects were 415 (109 females) cynomolgus macaques (Macaca fascicularis), 365 (181 females) rhesus macaques (Macaca mulatta), and 331 (187 females) baboons (Papio hamadryas) that had been singly-housed for 30-120 days. A 5-min observation using one-zero sampling recorded the presence or absence of abnormal behavior for each animal. Macaques exhibited higher levels of abnormal behavior than baboons (29% vs. 14%; chi2(1) = 24.849, p < 0.001), but there was no difference between macaque species (30% vs. 28%; chi2(1) = 0.263, p = 0.608). Risk factors also varied. Overall, males exhibited greater levels of motor stereotypies (b = 0.425, p < 0.05), females greater levels of abnormal appetitive behavior (b = 1.703, p < 0.05), and older animals greater levels of self-directed behavior (b = 0.065, p < 0.05). However, macaques exhibited greater levels of motor stereotypy (b = 2.527, p < 0.001) and self-directed behavior (b = 2.968, p < 0.005) than did baboons. There was also a genus * sex interaction for abnormal appetitive behavior (b = -2.379, p < 0.01) and a genus * age interaction for motor stereotypy (b = -0.167, p < 0.05). These results demonstrate that differences in abnormal behavior exist across closely-related primate species. Therefore, a single species cannot be used generally as a model for abnormal behavior or animal welfare. PMID- 29422701 TI - Do Strict Land Use Regulations Make Metropolitan Areas More Segregated by Income? AB - Problem research strategy and findings: Income segregation has risen in each of the last four decades in U.S. metropolitan areas, which can have lifelong impacts on the health, economic productivity, and behaviors of residents. Although it is widely assumed that local land use regulations-such as minimum lot sizes and growth controls-exclude low-income households from wealthier neighborhoods, the empirical research is surprisingly limited. We examine the relationship between land use regulation and segregation by income using new measures for the 95 biggest cities in the United States. We find that density restrictions are associated with the segregation of the wealthy and middle income, but not the poor. We also find that more local pressure to regulate land use is linked to higher rates of income segregation, but that more state control is connected to lower-income segregation. Takeaway for practice: Density restrictions do drive urban income segregation of the rich, not the poor, but should be addressed because rich enclaves create significant metropolitan problems. Planners at the local level need assistance from regional and state efforts to ameliorate income segregation. Inclusionary housing requirements have a greater potential to reduce income segregation than bringing higher-income households into lower-income parts of the city. Finally, comprehensive and consistent data on the impacts of local land use regulations should be collected to inform future research and planning practice. PMID- 29422702 TI - Adapting the Ideas of Translational Science for Translational Family Science. AB - Family science has been doing translational science since before it came into vogue. Nevertheless, the field has been subjected to the same forces in the broader academy that have created a widening chasm between discovery and practice. Thus, the primary objective of this article is to translate the principles, concepts, and models of translational science to solidify an identity for family science and help the field move forward in broader academic, care delivery, and policy arenas. Alternative models of translational science, primarily from biomedicine but also from other disciplines, are reviewed and critically analyzed, and core concepts and principles are isolated, elaborated, and applied to family science. Family science's long-standing commitment to the doctrine of evidence-based practice, and its ongoing endorsement of the principles of scientific duality and multidisciplinary utility, places it in a preeminent position for using the zeitgeist of translational science to move forward. Nonetheless, the field has important epistemological, practical, professional, and curricular steps to complete to better position itself as a distinct and valued body of scientists. Ultimately, we argue that embracing the principles, concepts, and models of translational science should be leveraged by family science to help brand itself as a unique and essential social science field for enhancing the human condition. PMID- 29422703 TI - Responding to Infertility: Lessons From a Growing Body of Research and Suggested Guidelines for Practice. AB - Infertility is a common, yet often misunderstood, experience. Infertility is an important topic for family scientists because of its effects on families; its relevance to research in related areas, such as fertility trends and reproductive health; and its implications for practitioners who work with individuals and couples experiencing infertility. In this review, we focus on common misperceptions in knowledge and treatment of infertility and highlight insights from recent research that includes men, couples, and people with infertility who are not in treatment. The meaning of parenthood, childlessness, awareness of a fertility problem, and access to resources are particularly relevant for treatment seeking and psychosocial outcomes. On the basis of insights from family science research, we provide specific guidelines for infertility practice within broader social contexts such as trends in health care, education, employment, and relationships. Guidelines are presented across three areas of application: infertility education for individuals, families, and practitioners; steps to support the emotional well-being of those affected by infertility; and understanding of treatment approaches and their implications for individuals and couples. PMID- 29422704 TI - FRAX(r) Fracture Risks Are Associated with Coronary Artery Calcification Score. AB - Purpose: To examine the association between fracture risk assessment tool (FRAX) scores and coronary artery calcification (CAC) score in adults. Methods: The medical records of 81 adults who underwent both coronary computed tomography and bone mineral density (BMD) studies in a package during their health exams were reviewed at a regional hospital in Southern Taiwan. Data collected included health history, anthropomorphic characteristics, clinical laboratory results, and BMD. Fracture risk was determined using FRAX. Univariate and multivariate linear regression analysis were used to assess the association between CAC score and 10 year probability of hip fracture (HF) and major osteoporotic fracture (MOF) determined by FRAX. Results: The mean age of the patients was 55.8 years, and 63.0% were male. Univariate linear regression analysis showed that increases in MOF and HF risks, as measured by FRAX, were significantly and positively associated with CAC score. Multiple linear regression analysis adjusting for potential confounders showed that CAC score remained significantly associated with four FRAX indicators, including right MOF (r = 0.45, P < 0.001), left MOF (r = 0.31, P = 0.021), right HF (r = 0.38, P = 0.001), and left HF (r = 0.23, P = 0.049). Conclusions: Increased risks of MOF and HF as determined by FRAX were significantly and independently associated with CAC score. PMID- 29422705 TI - Does Free Public Health Care Increase Utilization and Reduce Spending? Heterogeneity and Long Term Effects. AB - Zambia removed user fees in publicly supported-government and faith based- health facilities in 54 out of 72 districts in 2006. This was extended to rural areas of previously unaffected districts in 2007. The natural experiment provided by the step-wise implementation of the removal policy and five waves of nationally representative household survey data enables us to study the impact of the removal policy on utilization and household health expenditure. We find that the policy increased overall use of health services in the short term and the effects were sustained in the long term. The increases were higher for individuals whose household heads were unemployed or had no or less education. The policy also led to a small shift in care seeking from private to publicly supported facilities, an effect driven primarily by individuals whose household heads were either formally employed or engaged in farming. The likelihood of incurring any spending reduced, although this weakened slightly in the long term. At the same time, there was an upward pressure on conditional health expenditure, i.e., expenditure was higher after removal of fees for those who incurred any spending. Hence, total (unconditional) household health expenditure was not significantly affected. PMID- 29422706 TI - WOMEN'S AGE AT FIRST MARRIAGE AND LONG-TERM ECONOMIC EMPOWERMENT IN EGYPT. AB - Sustainable Development Goal (SDG) 5 calls on nations to promote gender equality and to empower women and girls. SDG5 also recognizes the value of women's economic empowerment, entailing equal rights to economic resources and full participation at all levels in economic decisions. Also according to SDG5, eliminating harmful practices-such as child marriage before age 18-is a prerequisite for women's economic empowerment. Using national data for 4,129 married women 15-43 years who took part in the Egypt Labor Market Panel Survey (ELMPS 1998-2012), we performed autoregressive, cross-lagged panel analyses to assess whether women's first marriage in adulthood (at 18 years or older, as reported in 2006), was positively associated with their long-term post-marital economic empowerment, measured as their engagement in market work and latent family economic agency in 2012. Women's first marriage in adulthood had positive unadjusted associations with their market work and family economic agency in 2012. These associations persisted after accounting for market work and family economic agency in 2006, pre-marital resources for empowerment, and cumulative fertility. Policies to discourage child marriage may show promise to enhance women's long-term post-marital economic empowerment. PMID- 29422707 TI - Why and How Should Graduate Students in Audiology Be Taught and Trained in Counseling. PMID- 29422708 TI - I Have to/Get to Teach Counseling: Now What? A Personal Essay. AB - Faculty receiving the assignment to teach a course in counseling to Au.D. students often have limited background in teaching the requisite skills and knowledge associated with counseling. A period of self-reflection regarding transferable skills for counseling as well as guidance from colleagues may assist in developing core concepts for the content of the class. Theoretical underpinnings, understanding and respecting patient values, and listening and valuing are significant perspectives for students to develop as they approach the broad content of a counseling course. PMID- 29422709 TI - Counseling Skill Development in Audiology: Clinical Instruction Considerations. AB - Audiologists play a critical role in supporting patients as they provide diagnostic information about their hearing and in the delivery of treatment services. Graduate training related to counseling, however, varies among programs in the extent students are prepared to engage effectively and intentionally with patients. Instruction is needed to provide students with a framework that supports their ability to learn and implement evidence-based counseling services. This article addresses the impact patients can experience when counseling gaps exist, shares clinical instruction strategies that can support students' acquisition of counseling skills, and discusses considerations for integration of counseling education into graduate training programs. PMID- 29422710 TI - Developing Foundational Counseling Skills for Addressing Adherence Issues in Auditory Rehabilitation. AB - Successfully getting patients with confirmed hearing loss to use hearing aids is a major challenge for hearing health care professionals. Treatment adherence has been defined as the active involvement of patients in collaborating with health care providers to plan and manage treatment regimens. Counseling patients with hearing loss on adherence to recommendations of hearing aid uptake and utilization is dependent upon building a patient-centered therapeutic relationship during the initial diagnostic evaluation. The purpose of this article is to provide resources, tools, and engaging learning activities for training students on the development of a hierarchy of counseling skills: informational counseling (e.g., checking comprehension and problem clarification), communication skills (e.g., promotion of shared-communication space, congruence, listening with the third ear, unconditional positive regard, and empathy), and health behavior change (e.g., Motivational Interviewing and the Teach-Back Method) that are prerequisites for addressing treatment adherence. PMID- 29422711 TI - Opportunities for Audiologists to Use Patient-Centered Communication during Hearing Device Monitoring Encounters. AB - Patient-centered care incorporates patient's priorities, values, and goals. Audiologists can increase patient engagement when they use patient-centered principles during communication. Recent research, however, has revealed counseling gaps in audiology that could be detrimental to the intervention process. The present study sought to understand the extent patient-centered communication strategies were used during hearing device monitoring visits by analyzing audio recordings. Counseling portions of the appointments were transcribed using conversation analysis. Missed opportunities were observed, including not validating patients' emotional concerns, providing technical responses to emotional concerns, providing information without determining patient desire for the information, and not engaging the patient in a shared planning process. Training opportunities to enhance audiological services will be discussed. PMID- 29422712 TI - Performance Feedback to Increase Use of Counseling Skills. AB - Counseling is a critical component of audiological care and when implemented purposefully can yield multiple benefits for patients. Professional guidelines indicate that counseling is within the scope of practice for audiologists, yet research has shown that audiologists feel unprepared and are not comfortable providing adjustment counseling. This may be due to inadequate counseling training in audiology graduate programs. To identify ways to address this counseling training gap, this study examined the use of performance feedback to increase counseling skills among audiology graduate students. In this study, participants ( n = 5) were recorded during clinical session encounters, and recordings were coded for time spent counseling. A licensed clinical psychologist reviewed the recordings and provided individual performance feedback to participants over the course of the study. Time spent counseling increased by the end of the study, although improvement varied across participants. Results suggest that performance feedback can be used as a method to increase counseling skills in audiology students. However, factors, such as participant motivation, feedback timing, and prerequisite counseling skills, may influence response to feedback. More research is needed on ways to maximize gains from feedback, as well as other methods to improve counseling skills in audiology students. PMID- 29422713 TI - Teaching Patient-Centered Counseling Skills for Assessment, Diagnosis, and Management of Benign Paroxysmal Positional Vertigo. AB - Audiologists are an integral part of the management of those with dizziness and vestibular disorders. However, little research has been performed on counseling approaches for patients who present with dizziness as a primary concern. Accordingly, it is important that audiology students are provided with didactic and experiential learning opportunities for the assessment, diagnosis, and management of this population. Benign paroxysmal positional vertigo is the most common vestibular disorder among adults. Doctor of Audiology students, at a minimum, should be provided with learning opportunities for counseling patients with this particular disorder. Implementation of patient-centered counseling is applied across various parts of the patient encounter from initial intake to treatment and patient education. The purpose of this article is to present the available evidence and to apply widely accepted theories and techniques to counseling those with benign paroxysmal positional vertigo. Didactic resources and experiential learning activities are provided for use in coursework or as a supplement to clinical education. PMID- 29422714 TI - Counseling in Audiology: Au.D. Students' Perspectives and Experiences. AB - Counseling in audiology is an important aspect of service delivery. How audiologists interact with patients and foster counseling relationships to help patients and families understand and live with hearing loss can impact outcomes of audiological interventions. Currently, variability exists in how graduate training programs are teaching counseling skills, and the extent to which counseling skills development is supported in clinical experiences is unclear. This article seeks to explore the perspectives related to the importance of counseling and counseling training experiences received through clinical instruction of Au.D. students beginning their final year of study, to identify where counseling training might be limited, and to examine how counseling skills might be better supported. Findings revealed that students generally appreciate the importance of counseling in audiology. Data suggest that how students are supported in developing counseling skills appears to be variable and unstructured. PMID- 29422715 TI - Didactic Content and Experiential Aging Simulation for Developing Patient Centered Strategies and Empathy for Older Adults. AB - The number of people over 65 years of age is increasing, and many of those individuals will have sensorineural hearing loss in addition to other chronic health conditions. Future hearing health care providers need to be sensitive to the needs of elderly patients. The purpose of this article is to describe an experiential learning curriculum used in the Doctor of Audiology program in the Department of Communication Sciences and Disorders at the University of Oklahoma Health Sciences Center. The curriculum uses simulations of sensory disorders common in the elderly to transform knowledge and active experience into patient centered, empathetic counseling skills and strategies to use with older adults with hearing loss. PMID- 29422716 TI - Recognizing and Reacting to Risk Signs for Patient Suicide. AB - Evidence-based suggestions for developing an effective clinician-client relationship built upon trust and honesty will be shared, as well as a review of relevant scope of practice issues for audiologists. Audiologists need to be prepared if a patient threatens self-harm. Many patients do not spontaneously report their suicidal thoughts and intentions to their care providers, so we need to be alert to warning signs. Information about the strongest predictors of suicide, how to ask about suicidal intentions, and how to assess the risk of suicide will be presented. Although it is our responsibility to recognize suicidal tendencies and have a plan for preventive intervention, it is not our responsibility to conduct a suicide evaluation. Tips for collecting critical information to be provided to qualified professionals will be shared, as well as additional information about how and to whom to disclose this information. A list of suicide warning signs will be reviewed as well as some additional suggestions for how to react when a patient discloses his or her suicidal intent. A review of available resources (for both the patient and the clinician) will be provided, along with instructions for how and when it is appropriate to access them. PMID- 29422718 TI - What's in Your Teaching Toolbox? AB - Educators are faced with an array of tools available to enhance learning outcomes in the classroom and clinic. These tools range from those that are very simple to those that are sufficiently complex to require an investment in learning time. This article summarizes a collection of teaching tools, ordered by the time involved in learning proficient use. Simple tools described include specific online blogs providing support for faculty and student writing and a simple method to capture and download videos from YouTube for classroom use. More complex tools described include a Web-based application for custom-created animated videos and an interactive audience polling system. Readers are encouraged to reflect on the tools most appropriate for use in their own teaching toolbox by considering the requisite time to proficiency and suitability to address desired learner outcomes. PMID- 29422717 TI - Teaching Counseling Microskills to Audiology Students: Recommendations from Professional Counseling Educators. AB - To provide the highest quality services, audiologists incorporate counseling into their professional practice. This article, written by professional counselors, highlights the distinction between services provided by professional counselors (i.e., psychotherapy) and counseling microskills used by all health and rehabilitation professionals. Effective application of counseling microskills facilitates a strong therapeutic alliance, which research shows contributes to positive therapeutic outcomes. Counseling microskills should be taught early in graduate programs, because they serve as the foundation for the therapeutic alliance and allow for more effective application of other therapeutic interventions. The four most critical counseling microskills for audiologists are active listening, nonverbal communication, silence, and empathy. These skills should be taught using experiential learning activities (i.e., classroom role play and use of simulated patients) that incorporate practice, repetition, and feedback. Students should be evaluated on their ability to perform counseling microskills using a detailed grading rubric. Instructors should deliver feedback on these skills with care to reduce potential negative reactions. Ultimately, effectively teaching counseling microskills in graduate programs can improve students' ability to facilitate the therapeutic alliance and facilitate better health outcomes for patients. PMID- 29422719 TI - Burnout in HIV/AIDS Volunteers: A Socio-Cultural Analysis among Latino Gay, Bisexual Men, and Transgender People. AB - Understanding factors associated with burnout among HIV/AIDS volunteers has long ranging implications for community organizations and prevention. Using a cross sectional sample of Latino gay/bisexual men and transgender people (N=309), we assess potential correlates of burnout identified by multiple theories, including factors associated with volunteering (experiences, motives) and contextual factors (stigma, sense of community). Reporting negative volunteering experiences was positively associated with burnout, while being motivated by personal HIV/AIDS experiences and having a greater sense of GLBT community was negatively related to burnout. The study highlights central challenges and opportunities to retain volunteers from marginalized communities. PMID- 29422720 TI - Proform-Antecedent Linking in Individuals with Agrammatic Aphasia: A Test of the Intervener Hypothesis. AB - Purpose: To evaluate processing and comprehension of pronouns and reflexives in individuals with agrammatic (Broca's) aphasia and age-matched control participants. Specifically, we evaluate processing and comprehension patterns in terms of a specific hypothesis -- the Intervener Hypothesis - that posits that the difficulty of individuals with agrammatic (Broca's) aphasia results from similarity-based interference caused by the presence of an intervening NP between two elements of a dependency chain. Methods: We used an eye tracking-while listening paradigm to investigate real-time processing (Experiment 1) and a sentence-picture matching task to investigate final interpretive comprehension (Experiment 2) of sentences containing proforms in complement phrase and subject relative constructions. Results: Individuals with agrammatic aphasia demonstrated a greater proportion of gazes to the correct referent of reflexives relative to pronouns and significantly greater comprehension accuracy of reflexives relative to pronouns. Conclusions: These results provide support for the Intervener Hypothesis, previous support for which comes from studies of Wh- questions and unaccusative verbs, and we argue that this account provides an explanation for the deficits of individuals with agrammatic aphasia across a growing set of sentence constructions. The current study extends this hypothesis beyond filler gap dependencies to referential dependencies and allows us to refine the hypothesis in terms of the structural constraints that meet the description of the Intervener Hypothesis. PMID- 29422721 TI - Advances in Neural Engineering for Rehabilitation. PMID- 29422723 TI - Electrochemical study on the corrosion resistance of plasma nanocoated 316L stainless steel in albumin- and lysozyme-containing electrolytes. AB - The physiological corrosion resistance of plasma nanocoated 316L stainless steel was studied in protein-containing electrolytes using electrochemical methods. Plasma nanocoatings with thicknesses of 20-30 nm were deposited onto 316L stainless steel coupons in a glow discharge of trimethylsilane (TMS) or its mixture with oxygen gas under various gas ratios. The surface chemistries of the plasma nanocoatings were characterized using Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Corrosion properties of the plasma nanocoated 316L stainless steel coupons were assessed using potentiodynamic polarization, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) in phosphate-buffered saline (PBS) electrolytes that contain bovine serum albumin (BSA) or lysozyme. It was found that BSA adsorption on the plasma nanocoated 316L coupons was heavily favored. BSA adsorption on the plasma nanocoating surfaces could block charge-transfer reactions between the electrolyte and 316L substrate, and thus stabilize the 316L substrates from further corrosion. In contrast, lysozyme adsorption on the plasma nanocoated specimens was not as pronounced and mildly influenced the corrosion properties of the plasma nanocoated 316L stainless steel. PMID- 29422722 TI - Sleeping in a Brave New World: Opportunities for Improving Learning and Clinical Outcomes through Targeted Memory Reactivation. AB - Neuroscientific insights into learning and memory have mostly concerned input and output, but intervening processing during the time between acquisition and retrieval is also critical. Indeed, intervening memory reactivation may regulate memory longevity, and a growing body of evidence implicates sleep in changing memory storage. For example, subtle auditory stimulation can be used experimentally to selectively encourage memory reactivation during sleep, which thereby improves learning. Much remains to be elucidated about how learning depends on sleep. Nevertheless, this methodology for modifying memory storage during sleep offers new opportunities for reinforcing learning to enhance clinical outcomes in conjunction with therapies engaged during waking. A variety of such possibilities must now be carefully investigated. Likewise, brain rhythms can be entrained to enhance sleep functions, facilitating further progress in understanding the neurophysiological basis of memory processing during sleep. Ultimately, empirical evidence may reveal the extent to which the way we behave when awake is a function of what our brains do when we are asleep. Through such research efforts, an advanced understanding of memory and sleep may allow us to both make better use of our time asleep and take steps toward better health. PMID- 29422724 TI - Effect of Continuous versus Intermittent Subglottic Suctioning on Tracheal Mucosa by the Mallinckrodt TaperGuard Evac Oral Tracheal Tube in Intensive Care Unit Ventilated Patients: A Prospective Randomized Study. AB - Background and Aims: A risk of tracheal mucosa injury induced by subglottic suctioning has been raised. Therefore, this prospective randomized study aims to compare the effect of continuous suctioning of subglottic secretions versus intermittent suctioning of subglottic secretions (CSSS vs. ISSS) secretions on tracheal mucosa in front of the suctioning port of the endotracheal tube. Patients and Methods: Patients requiring intubation or reintubation in Intensive Care Unit with an expected ventilation duration > 24 h were eligible. Participants received CSSS at -20 mmHg or ISSS at -100 mmHg during 15 s and no suction during 8 s. The effect on tracheal mucosa in front of the suction port was assessed after intubation (T0) and before extubation (T1) using bronchoscopy. Tracheal mucosa damages were graded into five categories (no injury, erythema, edema, ulceration, or necrosis). The occurrence (no injury observed at T0 but present at T1) or the worsening (injury observed at T0 exacerbating at T1) was studied. Results: Seventy-three patients were included and 53 patients (CSSS, n = 26 and ISSS, n = 27) were evaluable on the primary endpoint. The occurrence or worsening of tracheal mucosal damages did not differ between the two groups (CSSS, n = 7 [27%] vs. ISSS, n = 5 [17%], P = 0.465). Daily average volume of suctioned secretion was higher with ISSS (74 +/- 100 ml vs. 20 +/- 25 ml, P < 0.001). Impossibility to aspirate was higher with CSSS (0.14 +/- 0.16 per day vs. 0.03 +/- 0.07 per day, P < 0.001). Conclusions: Our results suggest that tracheal mucosal damages did not differ between CSSS and ISSS. The aspirated volume was higher and impossibility to aspirate was lower with ISSS. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01555229. PMID- 29422725 TI - Clinical Profile, Intensive Care Unit Course, and Outcome of Patients Admitted in Intensive Care Unit with Chikungunya. AB - Objective: Chikungunya is generally a mild disease, rarely requiring Intensive Care Unit (ICU) admission. However, certain populations may develop organ dysfunction necessitating ICU admission. The purpose of the study was to assess the clinical profile and course of chikungunya patients admitted to the ICU, and to ascertain factors linked with poor outcome. Methods: All patients with chikungunya admitted to ICU were included in the study. Admission Acute Physiology and Chronic Health Evaluation (APACHE) II score and sequential organ failure assessment (SOFA) score were calculated. Primary outcome measured was 28 day mortality and secondary outcomes measured were length of hospital and ICU stay and the need for vasopressor support, renal replacement therapy (RRT), and mechanical ventilation (MV). Logistic regression analysis was performed to identify factors predicting mortality. Results: The most common complaints were fever (96.67%) and altered sensorium (56.67%). Mean admission APACHE II and SOFA scores were 17.28 +/- 7.9 and 7.15 +/- 4.2, respectively. Fifty-one patients had underlying comorbidities. Vasopressors were required by 46.76%; RRT by 26.67%, and MV by 58.33%, respectively. The 28-day mortality was 36.67%. High APACHE II score (odds ratio: 1.535; 95% confidence interval: 1.053-2.237; P = 0.026) and need for dialysis (odds ratio: 833.221; 95% confidence interval: 1.853 374,664.825; P = 0.031) could independently predict mortality. Conclusions: Patients with chikungunya fever may require ICU admission for organ failure. They are generally elderly patients with underlying comorbidities. Despite aggressive resuscitation and organ support, these patients are at high risk of death. Admission APACHE II score and need for dialysis may predict patients at higher risk of death. PMID- 29422726 TI - Audit of Postoperative Surgical Intensive Care Unit Admissions. AB - Objective: The objective of this study was to conduct an audit of Surgical Intensive Care Unit (SICU) for identifying the admission risk factors and evaluating the outcomes of postoperative surgical patients. Design: This was a prospective, observational study. Setting: This study was conducted at SICU of a 1500-bedded tertiary care university hospital in Western India. Subject and Methods: Two hundred and forty patients admitted to the SICU postoperatively over a period of 15 months. Results: Planned and unplanned postoperative SICU admission rate was 4.45% and 0.09% of the 5284 patients operated. Indications for planned admissions included preoperative medical illnesses, anticipated blood loss, and anticipated mechanical ventilation while unpredicted intraoperative hypotension was the principal cause of unplanned admittance. Univariate analysis for two groups of the American Society of Anesthesiologists (ASA) physical status indicated that advanced age, high American College of Cardiology/American Heart Association (ACC/AHA) surgical risk, emergency surgery, planned admissions, and mortality were related to high ASA class. Analysis for ACC/AHA surgical risk showed association of high ACC/AHA surgical risk with advanced age, male gender, high ASA physical status, emergency surgery, planned admissions, and mortality. High mortality was observed in patients with SICU stay of >7 days (75.86%) and readmitted cases (72.73%). Conclusion: The need for postoperative critical care is significantly higher in males, elderly, patients with poor preoperative risk stratification scores, preexisting medical illness, major intraoperative hemorrhage, hypotension requiring inotropic support, perioperative respiratory problems and patients undergoing abdominal, trauma, and emergent surgeries. A larger study inclusive of other surgical subspecialties would aid in optimal decision-making for admissions to the SICU. PMID- 29422727 TI - Pattern and Outcome of Obstetric Admissions into the Intensive Care Unit of a Southeast Nigerian Hospital. AB - Background and Aims: Although pregnancy and labor are considered physiological processes, the potential for catastrophic complications is constant and may develop rapidly. There is growing evidence that admission of high-risk patients into the Intensive Care Unit (ICU) is associated with a reduction in maternal mortality. This study was aimed at reviewing all obstetric patients admitted into the ICU. Materials and Methods: This was a retrospective study of all obstetric patients who were admitted into the ICU between January 1, 2012, and December 31, 2013. Results: There were 89 obstetric patients admitted and managed at the ICU out of 5176 deliveries, thereby accounting for 1 admission in 58 deliveries. Majority of the patients were between 26 and 30 years, primiparous, and unbooked. The indications for ICU admission in this study were ruptured uterus (36.0%), eclampsia (22.5%), obstetric hemorrhage (19.1%), septicemia (10.1%), severe preeclampsia (6.7%), and obstructed labor (6.7%). The maternal and perinatal mortality was 13.5% and 47.2%, respectively. Maternal unbooked status was significantly associated with maternal mortality (P < 0.05). Conclusion: Ruptured uterus was the most common indication for ICU admission in the center. Maternal mortality was significantly associated with unbooked status. This underscores the importance of booking for antenatal care, prompt presentation at the hospital during emergencies, skilled birth attendance, and provision of adequate facilities for the management of critical obstetric cases in this environment. PMID- 29422729 TI - Outcome of Patients Admitted to a Tertiary Referral Intensive Care Unit with Urosepsis Needing Source Control. AB - Introduction: Urosepsis is one of the common causes of admission to the Intensive Care Unit (ICU). It has traditionally been treated with antibiotics, but surgical management with Double J [DJ] ureteral stents is gaining popularity. This study compares patients with complicated urosepsis who underwent surgical source control by ureteral stenting with those managed medically. Materials and Methods: The study enrolled patients admitted to a tertiary adult ICU with a diagnosis of urosepsis over a period of 2 years. The primary outcomes were renal replacement therapy (RRT) requirement and ICU mortality. The secondary outcomes were ICU and hospital length of stay, ventilator-free days, and inotrope free days. Patients were divided those with obstructive and nonobstructive urinary tract infection (UTI). Results: A total of 58 patients met the criteria, of who 32 had obstructive UTI and were included in Group A, with the remaining 26 with nonobstructive UTI comprised Group B. In Group A, 27 patients underwent source control with ureteral DJ stenting, three patients recovered with medical management, and two who were advised source control did not consent to the procedure. Seventeen patients in Group A and seven patients in Group B required RRT (P = 0.044). There was no significant difference in ICU mortality, hospital mortality, and 28 days survival between the two groups. Conclusion: With early source control, obstructive UTI outcomes were comparable to nonobstructive UTI. However, despite undergoing ureteric stenting, more patients with obstructive UTI required RRT than those with nonobstructive UTI. PMID- 29422728 TI - Multicenter Observational Study to Evaluate Epidemiology and Resistance Patterns of Common Intensive Care Unit-infections. AB - Background: There is limited data regarding the microbiology of Intensive Care Unit (ICU)-acquired infections, such as ventilator-associated pneumonia (VAP), catheter-associated urinary tract infections (CAUTI), and catheter-related bloodstream infections (CRBSI) from India. Objectives: To explore the microbiology and resistance patterns of ICU-acquired infections and evaluate their outcomes. Materials and Methods: This was a multicenter observational study, conducted by Indian Society of Critical Care Medicine (MOSER study) between August 2011 and October 2012. Patients in the ICU >=48 h with any ICU acquired infection within 14 days of index ICU stay were included. Patient demographics, relevant clinical, and microbiological details were collected. Follow-up until hospital discharge or death was done, and 6-month survival data were collected. Results: Of the 381 patients included in the study, 346 patients had 1 ICU infection and 35 had more than one ICU infection. Among patients with single infections, 223 had VAP with Acinetobacter being the most common isolate. CAUTI was seen in 42 patients with Klebsiella as the most common organism. CRBSI was seen in 81 patients and Klebsiella was the most common causative organism. Multidrug resistance was noted in 87.5% of Acinetobacter, 75.5% of Klebsiella, 61.9% of Escherichia coli, and 58.9% of Pseudomonas isolates, respectively. Staphylococcus constituted only 2.4% of isolates. Mortality rates were 26%, 11.9%, and 34.6% in VAP, CAUTI, and CRBSI, respectively. Conclusion: VAP is the most common infection followed by CRBSI and CAUTI. Multidrug-resistant Gram negative bacteria are the most common organisms. Staphylococcus aureus is uncommon in the Indian setting. PMID- 29422730 TI - Acute Renal Failure Adversely Affects Survival in Pediatric Dengue Infection. AB - Aims: Dengue is currently one of the most important mosquito-borne viral infections. Acute renal failure (ARF) is a serious complication among children suffering from dengue infection. Subjects and Methods: A retrospective cohort review of baseline characteristics, disease outcomes, and risk factors of dengue infected patients, with and without renal failure (RF), were compared. Results: Among 97 children with dengue, 13.4% had RF (estimated glomerular filtration rate <60 ml/min/1.73 m2) at presentation. In comparison to all children (100%) of RF cohort, only 32% children of non-RF cohort (P < 0.0001) were suffering either from dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). The 7-day survival rate was 61.5% (8/13) among RF group as compared to 96.4% (81/84) in non RF group (P < 0.001). When a fraction of patients who needed vasopressor support were significantly higher in RF cohort (70% vs. 14% for RF and non-RF, respectively, P < 0.001), requirement of mechanical ventilation (15% vs. 11%, P = 0.67) was comparable in both cohorts. Conclusions: DHF/DSS is an independent risk factor for the development of ARF in patients with dengue infection. Mortality rate is high once RF develops in these children. PMID- 29422731 TI - Role of Correction Factor in Minimizing Errors While Calculating Electrolyte Values between Blood-gas Analyzer and Laboratory Autoanalyzer: A Comparative Study. AB - Aims: Electrolytes are charged elements that play important functions in the body. They are measured by both arterial blood-gas (ABG) analyzers and autoanalyzers (AA). In this study, we tried to find out the correction factor for sodium and potassium to establish the concordance between ABG and AA values. Materials and Methods: We prospectively studied 100 samples of patients, and for validation of the result, we applied our result on 30 patients later. 1.5 ml of blood collected in the 2.0 ml syringe preflushed with heparin and analyzed using blood-gas analyzer (ABG). Another sample was sent, to central laboratory, where serum Na+ and K+ concentrations were analyzed. Means, standard deviations, and coefficients of variation with Karl Pearson's correlation coefficients were found out. Deming regression analysis was performed and Bland-Altman plots were also constructed. Results: The mean sodium and potassium were 130.27 +/- 7.85 mmol/L and 3.542 +/- 0.76 mmol/L using ABG and 139.28 +/- 7.89 mmol/L and 4.196 +/- 0.72 mmol/L using AA. Concordance between ABG and AA is done by adding the correction factor: for sodium, correction factor is 9.01, standard error = 1.113, class interval = 6.815-11.205; and for potassium (K+), correction factor is 0.654, standard error = 0.1047, class interval = 0.4475-0.8605. Conclusion: The instrument type and calibration methods differ in different hospitals, so it is important that each center conducts an in-hospital study to know the correction factor before installation of an ABG, and the factor should be used accordingly to minimize all errors. PMID- 29422732 TI - An Interesting Presentation of Pheochromocytoma. AB - Pheochromocytoma is a rare cause of hypertension, but it could have severe consequences if not recognized and treated appropriately. Pheochromocytoma classically presents with paroxysms of hypertension and adrenergic symptoms including classic triad of episodic headache, sweating, and tachycardia. The clinical presentation of pheochromocytoma can mimic a number of other medical conditions including migraine, cardiac arrhythmias, myocardial infarction, and stroke, thus making the diagnosis of pheochromocytoma difficult, and treatment is directed toward presenting issue rather than underlying problem in such patients. We present a case of a 41-year-old male patient who presented with cerebellar infarct and found to have aortic thrombi and later developed acute myocardial infaction during same hospitalization. To the best of our knowledge, this is the first reported case of this kind. PMID- 29422733 TI - Quad Fever: Treatment through Lowering of Ambient Temperature. AB - Hyperpyrexia is a rare and at times fatal condition seen in an Intensive Care Unit setup. We encountered a case of a 65-year-old patient with road traffic accident presenting with dorsal spine fracture at D10 level. He underwent decompression and fusion for the same. He developed hyperpyrexia of sudden onset on the 10th day of admission with no source of infection and adequate broad spectrum antibiotic coverage with adequate thrombo-embolic prevention in place. The patient showed no response to antipyretic agents and other cooling methods. The origin of hyperthermia was idiopathic, and we speculate that the cause was secondary to hyperthermic thermoregulatory dysfunction often quoted as "quad fever," seen in spinal cord injury. We present a brief review of literature and the importance of early identification and treatment of this potentially fatal condition. PMID- 29422734 TI - Cardiotoxic Effects of Raw Opium. AB - While opioid drug toxicity and side effects of long-term opioid use during medical care are well studied, there is little information regarding effects of ingestion of raw opium. Characterization of the effects to a particular alkaloid is difficult since raw opium contains a number of alkaloids. Here, we present a case of poisoning due to ingestion of raw opium leading to severe myocardial suppression. PMID- 29422735 TI - Successful Use of Ketamine for Burst Suppression in Super Refractory Status Epilepticus Following Substance Abuse. AB - Status epilepticus is frequently encountered in neuro Intensive Care Units. It is a medical emergency and if not treated promptly can lead to severe brain damage and even death. Here, we present the case of a 18-year-old male with uncontrolled and unrelenting seizures with a rare etiology requiring ketamine infusion for burst suppression as it was resistant to thiopentone and midazolam infusions. The management of this case is presented in detail. PMID- 29422736 TI - Phlegmasia Cerulea Dolens Following Heparin-Induced Thrombocytopenia. AB - The authors present a case of a 49-year-old woman who underwent coronary artery bypass grafting after suffering from an acute coronary syndrome and later developed phlegmasia cerulea dolens with heparin-induced thrombocytopenia (HIT) and HIT thrombosis (HITT). PMID- 29422737 TI - Heart Rate Variability in Children Following Drowning Injury. AB - Heart rate variability (HRV) has been used as prognostic tool in various disorders in pediatric and adult patients. In our study we aimed to evaluate heart rate variability indices and their association with neurological outcome in three children with anoxic brain injury following drowning. Three children included in the study were admitted following drowning and required mechanical ventilation and targeted temperature management. All physiologic data, including electrocardiography (ECG) and EEG were collected for a period of 3-5 days after enrollment. ECG signals were analyzed in both time and frequency domains. The spectral power of the low-frequency (LF) band (0.04-0.15 Hz) and that of the high frequency (HF) band (0.15-0.4 Hz), the standard deviation of the average R to R ECG intervals (SDANN) were calculated. Mean low-frequency/high-frequency power ratios (LF/HF) were compared using a two-tailed t-test and ANOVA with Tukey Kramer multiple comparisons. The power in the LF band, the LF/HF power ratio, and the SDANN, were lower in children who had a poor outcome, and during periods of isoelectric or burst suppression EEG patterns. PMID- 29422739 TI - Quiz. PMID- 29422738 TI - Epidemiology and Antifungal Susceptibility of Candida Species Isolated from Urinary Tract Infections: A Study from an Intensive Care Unit of a Tertiary Care Hospital. PMID- 29422740 TI - Electrons in Biology. PMID- 29422742 TI - Impact of Yoga on Periodontal Disease and Stress Management. AB - Background: Yoga is considered to be one of the most important, effective, and valuable tools available for man to overcome various physical and psychological problems. Stress contributes significantly to the pathogenesis of periodontal diseases; hence, it becomes important to reduce the level of stress for prevention and management of diseases. Aims and Objectives: The present study was aimed: (1) To understand and analyze the possibilities of employing yogic practices in the treatment of periodontal disease along with conventional dental therapy, (2) to understand the effect of stress on periodontal treatment outcome, (3) to evaluate the efficacy of yoga in the management of periodontal disease with reference to stress. Materials and Methods: An outpatient department-based parallel group randomized study was performed with standard treatment for periodontal disease yoga therapy as Group II and only standard treatment as Group I. Periodontal health status was recorded using indices of modified plaque index (PI), bleeding on probing (BOP), probing depth, and clinical attachment loss (CAL). The Cohen's perceived stress questionnaire was also used to determine stress severity. The yogic intervention consists of lectures and practical sessions on asanas, pranayama, kriyas, and meditation. Results: Repeated measure analysis of variance revealed a significant difference (P < 0.001) in all the outcome variables with respect to time in both groups. It was observed that mean PI score reduced by 1.35 in Group II as compared to 0.54 in Group I, mean probing pocket depth reduced by 1.60 in Group II as compared to only 0.68 in Group I, and mean CAL score reduced by 1.60 in Group II as compared to 0.68 in Group I. Similarly, Cohen's perceived stress scale score also reduced by 18.76 points in Group II as compared to only 2.58 points in Group I, BOP also shows better improvement in Group II with a reduction of 0.68 as compared to reduction of only 0.08 in Group I. The results obtained ascertained the role of yoga in stress reduction in periodontal disease. Conclusion: Although yoga does not play a direct role in improving periodontal disease, it accelerates the treatment outcomes by combating the stress which is a major factor affecting the treatment of periodontal disease. PMID- 29422741 TI - Cardiopulmonary and Metabolic Effects of Yoga in Healthy Volunteers. AB - Background: Yoga the spiritual union of mind with the divine intelligence of the universe aims to liberate a human being from conflicts of body-mind duality. Beneficial cardiovascular and pulmonary effects of yoga are in par with aerobic exercise, even amounting to replace the exercise model. We conducted an interventional study in healthy volunteers, to analyze the impact of short-term yoga training on cardiovascular, pulmonary, autonomic function tests, lipid profile, and thyroid function tests. Materials and Methods: A sample of fifty new recruits attending the district yoga center was subject to 75 min yoga practice a day for 41 days. Basal values of cardiovascular, pulmonary, autonomic function tests, lipid profile, and thyroid function tests were recorded before yoga training and were reassessed for postyoga changes after 41 days. Results: After yoga practice there was a significant reduction in the resting heart rate, systolic blood pressure, diastolic blood pressure, and mean blood pressure of the participants. Effects on autonomic function tests were variable and inconclusive. There was a significant increase in forced vital capacity, forced expiratory volume in 1 s, and peak expiratory flow rate after yoga. A significant reduction in body mass index was observed. Effects on metabolic parameters were promising with a significant reduction in fasting blood sugar level, serum total cholesterol, serum triglycerides serum low-density lipoprotein levels, and significant increase in high-density lipoprotein. There was no significant change in thyroid function tests after yoga. Conclusion: Short-term yoga practice has no effect on thyroid functions. Yoga practice was found beneficial in maintaining physiological milieu pertaining to cardiovascular and other metabolic parameters. PMID- 29422743 TI - Sleep Quality and Body Composition Variations in Obese Male Adults after 14 Weeks of Yoga Intervention: A Randomized Controlled Trial. AB - Background: Obesity is a big challenge all over the world. It is associated with many noncommunicable diseases. Yoga known to be add-on treatment may be effective for obesity control. Aim: To assess the effect of integrated approach of yoga therapy (IAYT) for body composition and quality of sleep in adult obese male. Subjects and Methods: A randomized controlled trial was conducted for 14 weeks on obese male of urban setting. Eighty individuals were randomly divided into two groups, i.e., yoga group (n = 40; age; 40.03 +/- 8.74 years, body mass index [BMI] 28.7 +/- 2.35 kg/m2) and control group (age; 42.20 +/- 12.06 years, BMI 27.70 +/- 2.05 kg/m2). The IAYT was imparted to yoga group for 11/2 hour for 5 days in a week for 14 weeks. The control group continued their regular activities. The body composition by InBody R20 and sleep quality by Pittsburgh Sleep Quality Index (PSQI) were assessed. Statistical analysis was done for within and between groups using SPSS version 21. The correlation analysis was done on the difference in pre-post values. Results: The results showed that weight (P = 0.004), BMI (P = 0.008), bone mass (P = 0.017), obesity degree (P = 0.005), and mineral mass (P = 0.046) were improved in yoga group and no change in control group (P > 0.05). The global score of PSQI improved (P = 0.017) in yoga group alone. Conclusion: The results indicate the beneficial effects of IAYT on body composition and sleep quality in obese males. The yoga practice may reduce obesity with the improvement in quality of life. PMID- 29422744 TI - Investigation of Yoga Pranayama and Vedic Mathematics on Mindfulness, Aggression and Emotion Regulation. AB - Background: Competitive examinations, particularly in mathematics, have made emotional stress a major problem for preuniversity students, emotions like aggression toward fellow students and teachers increase. Mindfulness is a quality that reduces both emotional stress and aggression, so increasing mindfulness should be helpful. Aims: To study the effects of Yoga Pranayama (YP) and Vedic Mathematics (VM) on mindfulness, aggression, and emotion regulation. Methods: Participants were 12th graders attending a preuniversity college in Chikkamagaluru, India, of both genders. Exclusion criteria included major psychological problems. Three classes were arbitrarily assigned to one of three interventions, which consisted of 15 days each of 30 min daily instruction in YP, Group 1, VM, Group 2, or 30 min ordinary class work, Group 3, the control group. Assessments were made using the Mindfulness Attention Awareness Scale, the Nonphysical Aggression Scale from Pittsburgh Youth Study, and the Emotion Regulation Questionnaire. Statistical Analysis Used: SPSS 19.0. Results: Mindfulness, aggression, and negative emotional regulation changed significantly for the YP group, while mindfulness alone improved significantly for the VM group. No group changed on positive emotion regulation. Controls apparently improved on aggression. An interesting post hoc correlation analysis is also reported, among other things directly linking increased mindfulness to decreased aggression. Conclusions: The study showed positive effects of traditional methods of decreasing emotional pressure on students facing preuniversity mathematics examinations. Increasing mindfulness is considered a way of increasing emotion regulation, so the failure of this study to provide evidence for that is of interest. PMID- 29422745 TI - Assessment for Efficacy of Additional Breathing Exercises Over Improvement in Health Impairment Due to Asthma Assessed using St. George's Respiratory Questionnaire. AB - Background: Breathing exercises have been described to be useful in asthma management by few researchers in the past. Objective: To assess the efficacy of breathing exercises (Pranayamas) added to regular optimal medications in asthma patients in improving health impairment using St. George's Respiratory Questionnaire (SGRQ). Methods: Sixty stable asthma patients (34 females) receiving optimal treatment at our institute for 3 months or more as per the Global Initiative for Asthma guidelines were included in the study. They performed seven breathing exercises under supervision at yoga center of our institute for 3 months in addition to their regular medications. SGRQ (1 month symptoms version) was used to assess the quality of life before and after breathing exercises intervention for following subsets: Symptom score, activity score, impact score, and total score to assess the efficacy of breathing exercises. Results: Of 60 asthma patients, 34 were females and 26 were males, and their mean age was 25.45 +/- 5.41 years. Their baseline spirometric values were as follow: Forced expiratory volume in 1 s (FEV1) - 2.492 +/- 0.358 L and peak expiratory flow rate (PEFR) - 283.82 +/- 51.12 L/min. The SGRQ scores after breathing exercises intervention decreased from 45.98 +/- 5.61 to 38.78 +/- 4.92 for symptom subset, from 15.45 +/- 3.33 to 12.34 +/- 2.39 for activity subset, from 17.95 +/- 4.22 to 12.12 +/- 3.82 for impact subset, and from 25.83 +/- 8.31 to 19.20 +/- 7.09 for total scores. All these reductions were statistically highly significant (P < 0.001). Decrease in symptoms, activity, and total SGRQ scores each was significantly correlated with FEV1, FEV1/forced vital capacity (FVC) ratio, and PEFR; decrease in impact score was significantly related only with FEV1/FVC ratio. Conclusions: Breathing exercises significantly decreased all component scores of SGRQ, signifying a global improvement in health impairment due to asthma; this improvement was in addition to that was achieved with optimal asthma therapy alone. PMID- 29422746 TI - Diabetes Mellitus Type 2 and Yoga: Electro Photonic Imaging Perspective. AB - Background: Yoga is the most popular form of alternative medicine for the management of diabetes mellitus type 2. The electro-photonic imaging (EPI) is another contribution from alternative medicine in health monitoring. Aim: To evaluate diabetes from EPI perspective. Objectives: (1) Compare various EPI parameters in normal, prediabetic and diabetic patients. (2) Find difference in controlled and uncontrolled diabetes. (3) Study the effect of 7 days diabetes specific yoga program. Materials and Methods: For the first objective, there were 102 patients (normal 29, prediabetic 13, diabetic 60). In the second study, there were 60 patients (controlled diabetes 27, uncontrolled diabetes 33). The third study comprised 37 patients. EPI parameters were related to general health as well to specific organs. Results: In the first study, significant difference was observed between (1) Diabetics and normal: average intensity 5.978, form coefficient 3.590, immune organs 0.281 all P < 0.001; (2) Diabetics and prediabetics: average intensity 6.676, form coefficient 4.158, immune organs 5.890 P < 0.032; (3) Normal and prediabetes: immune organs (-6.171 P = 000). In the second study, remarkable difference was in the immune organs (0.201, P = 0.031). In the pre- and post-study, the mean difference was: area 630.37, form coefficient 1.78, entropy 0.03, liver 0.24, pancreas 0.17, coronary vessels 0.11, and left kidney 29, with all P < 0.02. Conclusion: There is a significant difference in EPI parameters between normal, prediabetics and diabetics, the prominent being average intensity, form coefficient, and immune organs. Between controlled and uncontrolled diabetes, immune organs show significant change. Intervention of yoga results in change in most parameters. PMID- 29422747 TI - Yoga in Print Media: Missing the Heart of the Practice. AB - Background: Popular media typically portray yoga as an exercise or posture practice despite the reality that yoga comprised eight practices (called limbs) including ethical behavior, conscious lifestyle choices, postures, breathing, introspection, concentration, meditation, and wholeness. Aim: This study assessed the comprehensiveness of yoga practice as represented in articles in the popular yoga magazine, Yoga Journal. It explored the degree to which articles referenced each of the eight limbs of yoga and other contents (e.g., fitness, spirituality). Materials and Methods: Six coders were trained to reliably and independently review 702 articles in 33 Yoga Journal issues published between 2007 and 2014, coding for the limbs of yoga and other contents. Results: Breathing and postures were most frequently referenced, which were covered in 48.7% and 40.1% of articles. Internal practices were covered in 36.5% of articles with introspection being the most and concentration the least commonly referred to internal practices. Ethical and lifestyle practices were least frequently covered (5.2% and 6.8%). Since 2007, coverage of postures steadily increased, whereas contents related to the other limbs steadily decreased. The most frequent other contents related to fitness (31.7%), spirituality (20.8), and relationships (18.7%) coverage of these did not change across time. Conclusions: Representation of yoga in articles contained in the most popular yoga magazine is heavily biased in favor of physical practices. Recommendations are offered about how to shift media representation of yoga to make the heart of the practice more accessible to individuals who could experience health benefits but currently feel excluded from the practice. PMID- 29422748 TI - Effectiveness of Music Therapy on Focused Attention, Working Memory and Stress in Type 2 Diabetes: An Exploratory Study. AB - Cognitive deficits are reported in diabetes mellitus type 2 (DM2). Previous research has shown that music-based intervention can not only reduce hyperglycemia but also target cognitive functions as well as stress. The aim of this exploratory study was to understand the effect of active participation in music therapy (MT) on the cognitive deficits of DM2 patients. MT of twenty sessions was carried out with three participants with DM2. Serum cortisol, perceived stress, Color Trail Test (1 and 2), and verbal n-back (1 and 2) tests were used to measure the outcomes. Feedback was taken for the subjective ratings and satisfaction of the participants. Stress and cortisol reduced and focused attention and working memory improved in varying degrees. Subjectively, participants reported having benefitted from the intervention. This is the first attempt to investigate the effect of music-based intervention on cognitive function in DM2 patients using case study approach. PMID- 29422749 TI - Outcomes of Scleral-fixated Intraocular-lens in Children with Idiopathic Ectopia Lentis. AB - PURPOSE: The purpose of the study was to review the safety and stability of scleral-fixated intraocular lens (IOL) 2 years after implantation in children with idiopathic ectopia lentis (EL). METHODS: This retrospective case series enrolled children with EL managed between 2011 and 2015 at a tertiary eye hospital in the eastern of Saudi Arabia. Data were collected on age, gender, vision, isolated or syndromic pathology, intraoperative and postoperative complications, spherical equivalent refraction, and final best-corrected visual acuity (BCVA). RESULTS: The series included 18 eyes of 11 children with EL (6 males and 5 females). There were 7 bilateral and 4 unilateral cases. The median age was 3.5 years (25% quartile 1 year; range: 1-8 years). Preoperatively, fixation was absent in 3 eyes, 8 eyes were fixating but vision could not be recorded. In the remaining seven eyes, median distant visual acuity was 0.1 (25% quartile: 0.08). The median postoperative follow-up was 24 months (25% quartile, 7 months). Complications included two eyes with iris capture and one eye with lens subluxation requiring re-implantation. Postoperative BCVA was better than 20/60 in 15 (83%) eyes. At last follow-up, 6 eyes required myopic correction, 1 eye was emmetropic, and 11 eyes were hypermetropic. One eye with glaucoma was managed medically. CONCLUSION: Scleral fixated IOL in eyes of young children with EL had good visual outcomes and high stability. However, there is a high incidence of residual refractive error. PMID- 29422751 TI - Cataract and Glaucoma Surgery: Endoscopic Cyclophotocoagulation versus Trabeculectomy. AB - PURPOSE: To compare the efficacy and safety of endoscopic cyclophotocoagulation (ECP) versus trabeculectomy with mitomycin C (trab) in combination with cataract surgery. MATERIALS AND METHODS: We evaluated the 6-month results of patients undergoing phacoemulsification (phaco) with either ECP or trab. The primary outcome was mean intraocular pressure (IOP) at 6 months; secondary outcomes were change in glaucoma medications, visual acuity, intraocular inflammation, and postoperative complications. Complete success was a target IOP of <21 mmHg and >6 mmHg without glaucoma medications. Qualified success was target IOP achieved through glaucoma medications. RESULTS: We evaluated 53 eyes of 53 patients; 24 (45.3%) eyes were treated with ECP-phaco and 29 (54.7%) with trab-phaco. At 6 months, there was no significant difference in mean IOP of the two groups (ECP phaco 14.2 +/- 3.6 mmHg; trab-phaco 13.0 +/- 2.5 mmHg; P = 0.240). Six (25.0%) ECP-phaco eyes and 20 (69.0%) trab-phaco eyes achieved complete success (P = 0.002). Qualified success was achieved in 18 (75.0%) ECP-phaco eyes and 9 (31.0%) trab-phaco eyes (P = 0.002). The mean reduction of medication from baseline was significant (ECP-phaco 1.2 +/- 1.1; trab-phaco 2.1 +/- 1.5; P = 0.020). ECP-phaco resulted in more IOP spikes on the 1st postoperative day (P = 0.040) and more anterior cellular reaction at 1 week and 1 month compared to trab-phaco (P < 0.05). The rate of postoperative complications was not significantly different between groups. CONCLUSION: At 6 months, ECP-phaco demonstrated similar improvements in IOP and visual acuity compared to trab-phaco. However, ECP-phaco patients had higher incidences of immediate postoperative IOP spikes and anterior chamber inflammation as well as requiring additional medications postoperatively. PMID- 29422750 TI - Keratoconus Asymmetry between Both Eyes Based on Corneal Tomography. AB - PURPOSE: To characterize the asymmetry between both eyes in patients with keratoconus based on corneal tomography. MATERIALS AND METHODS: All patients with keratoconus who presented to the eye clinic at Jordan University Hospital between January 2008 and November 2011 were included in the study. Using computerized corneal tomography, the keratometric values and indices of both eyes of participants with keratoconus and normal controls were compared. For both eyes to be considered symmetrical, the difference between the mean curvature power (Km), flat curvature power (K1), or steep curvature power (K2) in both eyes was equal to or <2.5 diopters, and the difference between the thinnest corneal points was equal to or <25.0 MUm between both eyes. RESULTS: Ninety-eight patients with keratoconus and 49 normal participants were evaluated. The mean age of the participants was 26.3 +/- 6.6 years. The results showed two populations of patients with keratoconus: one with asymmetrical corneas who were more affected by the disease and another with symmetrical corneas. As the disease severity increased, the differences between the two eyes increased for patients with the asymmetrical form, while both corneas of patients with the symmetrical form were similar. CONCLUSIONS: Corneal tomography identified two forms of keratoconus: symmetrical and asymmetrical. The latter tended to be more severe and occurred in a younger age group. Questions remain about whether the two keratoconic forms are specific to the Middle Eastern population and whether there are ethnic or demographic forms of the disease. PMID- 29422752 TI - Epidemiology and Clinical Features of Thyroid-associated Orbitopathy in Accra. AB - PURPOSE: Thyroid-associated orbitopathy (TAO), a clinical manifestation of Graves' disease, is an autoimmune disorder of the orbital and periorbital tissue. Data on the epidemiology and clinical presentation of TAO in Africa are generally scarce and unavailable in Ghana. We investigated the epidemiology and clinical features of TAO among patients with thyroid disorders attending the Korle Bu Teaching Hospital, Accra. SUBJECTS AND METHODS: This was a descriptive cross sectional study of patients diagnosed with thyroid disorders which was conducted at the endocrine and orbital clinics of the Korle Bu Teaching Hospital. Diagnosis was based on clinical features and confirmed by a thyroid function test. Data collected and analyzed included demography, systemic and ocular features of thyroid disorder, and thyroid function tests. RESULTS: Of the 194 patients with thyroid disorders recruited, 117 (60.30%) had TAO. The mean age was 45.22 years (standard deviation: 13.90). The male:female ratio was 1:4.45. The most common ocular symptoms were "bulging eyes" (76/65.00%) and "puffy eyelid" (62/53.00%), and the common signs were eyelid retraction (97/82.91%) and proptosis (80/68.38%). Mild TAO was diagnosed in 64.96% of patients with only 6.84% having the severe form. The outcomes of the thyroid function test, thyroid disorder, and severity of TAO did not record any statistically significant differences. CONCLUSIONS: The epidemiology is similar to those reported from other parts of the world, but the ocular presentation seems to be milder than in Caucasians. PMID- 29422753 TI - Investigating the Visual Status Of Preschool Children in Riyadh, Saudi Arabia. AB - PURPOSE: The purpose of the study was to explore the vision status of preschool children aged 3-6 years in Al Riyadh and to identify children at risk of amblyopia. MATERIALS AND METHODS: This was a cross-sectional population-based study. Visual acuity (VA) was measured using 15-line Lea symbols, refractive error was assessed using the Mohindra near retinoscopy technique, and peak contrast sensitivity (CS) was measured with the aid of the numerical CS test. We recruited 335 children, with their parents' written consent, from 14 kindergartens. RESULTS: A total of 335 children were recruited; 42 children (13%) exhibited reduced VA (Median [interquartile ranges (IQRs)], 0.00 [0.01]); most were emmetropic (87.7%). Myopia (4.2%), hyperopia (8.1%), and astigmatism (20%) were also observed. Most children had normal CSs. About 14% of children were at risk of amblyopia. It has been observed that 26% of families have some kind of refractive error. CONCLUSIONS: It is important to perform vision screening of preschoolers. Early detection of abnormalities in refractive errors could help to minimize the effect of visual impairment. PMID- 29422754 TI - Comparative Evaluation of Corneal Endothelium in Diabetic Patients Undergoing Phacoemulsification. AB - PURPOSE: To determine if phacoemulsification with intraocular lens implantation has a greater impact on the corneal endothelium of type 2 diabetic patients as compared to nondiabetics. MATERIALS AND METHODS: This study compared the endothelial status in 60 diabetics with good glycemic control and 60 nondiabetics before and after uneventful phacoemulsification. Central corneal endothelial cell density, percentage hexagonality and percentage coefficient of variation (%CV) were measured using a specular microscope. RESULTS: Data were age and sex matched. Diabetics showed significantly higher loss in endothelial cell count as compared to nondiabetics. At the end of 3 months, there was a decline of 157 endothelial cell (standard deviation [SD] 90) in the diabetic group and 121 (SD 50) in the control group. This was statistically significant (P = 0.008). Furthermore, the diabetics showed a slower recovery trend in the endothelial healing response as evidenced by lower change in the %CV. The change in %CV was 4.5 in the control group and 3.1 in diabetic group which was statistically significant (P = 0.016). Significant correlation was found between energy used and change in endothelial count as well as %CV in nondiabetics only. CONCLUSION: In spite of good glycemic control, diabetics have significantly more endothelial damage in comparison to nondiabetics with similar nuclear grading and phaco energy used. This warrants a more careful use of phaco energy in diabetics. PMID- 29422755 TI - Comparison of the Efficacy of Carboxymethylcellulose 0.5%, Hydroxypropyl-guar Containing Polyethylene Glycol 400/Propylene Glycol, and Hydroxypropyl Methyl Cellulose 0.3% Tear Substitutes in Improving Ocular Surface Disease Index in Cases of Dry Eye. AB - PURPOSE: To compare the efficacy of carboxymethylcellulose 0.5% (CMC), hydroxypropyl-guar containing polyethylene glycol 400/propylene glycol (PEG/PG), and hydroxypropyl methylcellulose 0.3% (HPMC) as tear substitutes in patients with dry eye. METHODS: A retrospective evaluation of cases presenting with symptoms of dry eye from July 2014 to June 2015 was done. Patients with Ocular Surface Disease Index (OSDI) scoring >12 were included in the study. Parameters such as age, gender, Schirmer test (ST), and tear film breakup time (TBUT) were recorded on day 0, week 1, and week 4. For analysis, cases were divided into three groups; Group 1 - CMC, Group 2 - PEG/PG, and Group 3 - HPMC. RESULTS: Overall, 120 patients were included in the study. Demographic data and baseline characteristics were comparable among the groups. Group 2 had significant improvement in percentage change in OSDI (weeks 0-1, 0-4, and 1-4, P = 0.00), TBUT (weeks 0-1, P = 0.01; 0-4, P = 0.006; and 1-4, P = 0.007), and in ST (weeks 0-1, P = 0.02; 0-4, P = 0.002; and 1-4, P = 0.008) compared to Group 1 at all follow-ups. Group 3 had improvements similar to Group 2, but it was not at all follow-ups (improvement in percentage change OSDI [weeks 0-1, 0-4, and 1-4, P = 0.00], TBUT [weeks 0-1, P = 0.10; 0-4, P = 0.03; and 1-4, P = 0.04], and in ST [weeks 0-1, P = 0.007; 0-4, P = 0.03; and 1-4, P = 0.12]). No significant difference was found between Groups 2 and 3. CONCLUSIONS: Hydroxypropyl-guar containing PEG/PG and HPMC as tear substitutes are better than CMC. While HPMC was comparable to PEG/PG in subjective improvement, the objective improvement was not consistent. PMID- 29422756 TI - Assessment of Annual Diabetic Eye Examination Using Telemedicine Technology Among Underserved Patients in Primary Care Setting. AB - CONTEXT: Digital retinal imaging with the application of telemedicine technology shows promising results for screening of diabetic retinopathy in the primary care setting without requiring an ophthalmologist on site. AIMS: We assessed whether the establishment of telemedicine technology was an effective and efficient way to increase completion of annual eye examinations among underserved, low-income (Medicaid) diabetic patients. SETTINGS AND DESIGN: A cross-sectional study in a primary care setting. SUBJECTS AND METHODS: Health care claims data were collected before the establishment of telemedicine technology in 2010 and after its implementation in 2012 for Medicaid patients at East Baltimore Medical Center (EBMC), an urban health center that is part of Johns Hopkins Health System. STATISTICAL ANALYSIS USED: The primary outcome measure was the compliance rate of patients with diabetic eye examinations; calculated as the number of diabetic patients with a completed telemedicine eye examination, divided by the total number of diabetic patients. RESULTS: In 2010, EBMC treated 213 Medicaid diabetic patients and in 2012 treated 228 Medicaid patients. In 2010, 47.89% of patients completed their annual diabetic eye examination while in 2012 it was 78.07% (P < 0.001). After adjustment for age, gender, HgBA1C, disease severity, using resource utilization band score as a proxy, and medication possession ratio; telemedicine technology significantly increased the compliance (odds ratio: 4.98, P < 0.001). CONCLUSIONS: Adherence to annual eye examinations is low in the studied Medicaid diabetic population. Telemedicine technology in a primary care setting can increase compliance with annual eye examinations. PMID- 29422757 TI - Aeromonas Salmonicida as a Causative Agent for Postoperative Endophthalmitis. AB - We report a case of a 55-year-old female who presented with pain, redness, and profound visual loss in her right eye 2 weeks after cataract surgery. An ophthalmic examination showed light perception vision, corneal edema with severe anterior chamber reaction and hypopyon, exudative membranes on the anterior lens surface, and dense vitreous exudates. Under the impression of acute postoperative exogenous endophthalmitis, immediate pars plana vitrectomy with culture of vitreous aspirate and intravitreal antibiotic injections were performed. Bacterial growth was observed on culture plates and broths which were identified as Aeromonas salmonicida by VITEK 2 compact system. So far, no report has been published regarding endophthalmitis due to A. salmonicida. Here, we present the first report of A. salmonicida isolated from the ocular specimen. PMID- 29422758 TI - Localized Trichiasis Causing Focal Full-Thickness Corneal Edema, Endothelial Cell Loss, and Corneal Scarring Requiring Penetrating Keratoplasty. AB - The purpose of the study was to report a case of focal trichiasis causing full thickness corneal edema, scarring, and endothelial cell loss requiring penetrating keratoplasty (PK). A 66-year-old male was referred for trichiasis of the right upper eyelid corresponding to an area of full-thickness corneal edema. No keratic precipitates or guttata was noted. Specular microscopy showed diffuse endothelial cell loss. He was treated with topical steroids and acyclovir with epilation of lashes. Anterior chamber paracentesis was negative for varicella zoster virus, cytomegalovirus, and herpes simplex virus. The patient developed diffuse stromal scarring with a decrease in vision and ultimately underwent PK with preceding eyelid repair. To the best of our knowledge, we present the first reported case of chronic trichiasis causing full-thickness corneal edema, scarring, and endothelial cell loss requiring PK. PMID- 29422759 TI - Cytomegalovirus Retinitis as a Presenting Feature of Multisystem Disorder: Dyskeratosis Congenita. AB - Cytomegalovirus (CMV) retinitis is an opportunistic infection commonly seen in disorders that affect the immune system of the body such as acquired immunodeficiency syndrome and hematological malignancies such as leukemia/lymphoma or organ transplantation. The occurrence of CMV retinitis in the absence of such condition should be thoroughly investigated, as it is a strong indicator of poor immune competence. We here report an interesting case of CMV retinitis as a presenting feature of rare multisystem disorder "Dyskeratosis congenita." PMID- 29422760 TI - Demographic and Clinical Features of Pediatric Uveitis at a Tertiary Referral Center in Iran. PMID- 29422761 TI - Modeling subject-specific nonautonomous dynamics. AB - We consider modeling non-autonomous dynamical systems for a group of subjects. The proposed model involves a common baseline gradient function and a multiplicative time-dependent subject-specific effect that accounts for phase and amplitude variations in the rate of change across subjects. The baseline gradient function is represented in a spline basis and the subject-specific effect is modeled as a polynomial in time with random coefficients. We establish appropriate identifiability conditions and propose an estimator based on the hierarchical likelihood. We prove consistency and asymptotic normality of the proposed estimator under a regime of moderate-to-dense observations per subject. Simulation studies and an application to the Berkeley Growth Data demonstrate the effectiveness of the proposed methodology. PMID- 29422762 TI - One-Step Generalized Estimating Equations with Large Cluster Sizes. AB - Medical studies increasingly involve a large sample of independent clusters, where the cluster sizes are also large. Our motivating example from the 2010 Nationwide Inpatient Sample (NIS) has 8,001,068 patients and 1049 clusters, with average cluster size of 7627. Consistent parameter estimates can be obtained naively assuming independence, which are inefficient when the intra-cluster correlation (ICC) is high. Efficient generalized estimating equations (GEE) incorporate the ICC and sum all pairs of observations within a cluster when estimating the ICC. For the 2010 NIS, there are 92.6 billion pairs of observations, making summation of pairs computationally prohibitive. We propose a one-step GEE estimator that 1) matches the asymptotic efficiency of the fully iterated GEE; 2) uses a simpler formula to estimate the ICC that avoids summing over all pairs; and 3) completely avoids matrix multiplications and inversions. These three features make the proposed estimator much less computationally intensive, especially with large cluster sizes. A unique contribution of this paper is that it expresses the GEE estimating equations incorporating the ICC as a simple sum of vectors and scalars. PMID- 29422763 TI - Long-Term Average Spectral (LTAS) Measures of Dysarthria and Their Relationship to Perceived Severity. AB - This study investigated the relationship between measures of Long-Term Average Spectrum (LTAS) for speakers with Parkinson's disease (PD) and Multiple Sclerosis (MS) and scaled estimates of perceived speech severity. Perceived severity was operationally defined as listeners' overall impression of voice, resonance, articulatory precision, and prosody without regard to intelligibility. Healthy control talkers were also studied. Speakers were audio recorded while reading Harvard Sentences and the Grandfather Passage. Using TF32 (Milenkovic, 2005), the LTAS was computed for sentences. Coefficients of the first four moments were used to characterize energy across the speech spectrum. Supplemental acoustic measures of articulatory rate, vocal intensity, and fundamental frequency also were obtained. Three speech-language pathologists scaled speech severity for the reading passages. Results indicated no group differences in acoustic measures. The absolute magnitude of correlations between LTAS moment coefficients and perceptual estimates of scaled severity within and across speaker groups ranged from .16 to .53, with the strongest correlations for the PD group. These results suggest that the LTAS may prove useful in conjunction with perceptual judgments to document speech spectral changes related to treatment or disease progression. Findings further suggest that different acoustic models of severity are likely needed for dysarthria secondary to PD and dysarthria secondary to MS. PMID- 29422764 TI - Integrated Theory- and Data-driven Feature Selection in Gene Expression Data Analysis. AB - The exponential growth of high dimensional biological data has led to a rapid increase in demand for automated approaches for knowledge production. Existing methods rely on two general approaches to address this challenge: 1) the Theory driven approach, which utilizes prior accumulated knowledge, and 2) the Data driven approach, which solely utilizes the data to deduce scientific knowledge. Both of these approaches alone suffer from bias toward past/present knowledge, as they fail to incorporate all of the current knowledge that is available to make new discoveries. In this paper, we show how an integrated method can effectively address the high dimensionality of big biological data, which is a major problem for pure data-driven analysis approaches. We realize our approach in a novel two step analytical workflow that incorporates a new feature selection paradigm as the first step to handling high-throughput gene expression data analysis and that utilizes graphical causal modeling as the second step to handle the automatic extraction of causal relationships. Our results, on real-world clinical datasets from The Cancer Genome Atlas (TCGA), demonstrate that our method is capable of intelligently selecting genes for learning effective causal networks. PMID- 29422765 TI - Preadolescents' Relationships with Pet Dogs: Relationship Continuity and Associations with Adjustment. AB - Research on human-animal interaction in children has been studied in isolation rather than integrated with core theories of children's relationships. This study is one of the first to examine how children's relationships with pet dogs are related to their human relationships (parent-child attachments, friendships) and to child adjustment, and to include observational assessment of children's interactions with their pet dog. Children (9 to 11 years old, n = 99) completed questionnaires regarding relationships with pet dogs, parents, and friends. Half the children were observed interacting with their pet dog. Children and teachers reported children's adjustment. Children who felt closer to their dogs were more securely attached to mothers and fathers, and reported more positive qualities and less conflict with friends. Children with more secure attachments to mothers, and greater companionship with dogs, interacted more with their dogs. Parental attachment and friendship quality, but not the pet dog relationship, were related to child adjustment. PMID- 29422766 TI - Inhibition of YAP ameliorates choroidal neovascularization via inhibiting endothelial cell proliferation. AB - Purpose: Age-related macular degeneration (AMD) is the leading cause of central visual loss among patients over the age of 55 years worldwide. Neovascular-type AMD (nAMD) accounts for approximately 10% of patients with AMD and is characterized by choroidal neovascularization (CNV). The proliferation of choroidal endothelial cells (CECs) is one important step in the formation of new vessels. Transcriptional coactivator Yes-associated protein (YAP) can promote the proliferation of multiple cancer cells, corneal endothelial cells, and vascular smooth muscle cells, which participate in angiogenesis. This study intends to reveal the expression and functions of YAP during the CNV process. Methods: In the study, a mouse CNV model was generated by laser photocoagulation. YAP expression was detected with western blotting and immunohistochemistry. YAP siRNA and ranibizumab, a VEGF monoclonal antibody, were injected intravitreally in CNV mice. The YAP and VEGF expression levels after injection were detected with western blotting. The incidence and leakage area of CNV were measured with fundus fluorescein angiography, choroidal flat mounting, and hematoxylin and eosin (HE) staining. Immunofluorescent double staining was used to detect YAP cellular localization with CD31 (an endothelial cell marker) antibody. Proliferating cell nuclear antigen (PCNA) expression in CNV mice without or with YAP siRNA intravitreal injection and the colocalization of PCNA and CD31 were measured with western blotting and immunofluorescent double staining, respectively. Results: YAP expression increased following laser exposure, in accordance with vascular endothelial growth factor (VEGF) expression. YAP siRNA and ranibizumab decreased VEGF expression and the incidence and leakage area of CNV. YAP was localized in the vascular endothelium within the CNV site. Additionally, after laser exposure, YAP siRNA inhibited the increased expression of PCNA, which was colocalized with endothelial cells. Conclusions: This study showed that YAP upregulation promoted CNV formation by upregulating the proliferation of endothelial cells, providing evidence for the molecular mechanisms of CNV and suggesting a novel molecular target for nAMD treatment. PMID- 29422767 TI - Acceleration of the formation of biofilms on contact lens surfaces in the presence of neutrophil-derived cellular debris is conserved across multiple genera. AB - Purpose: We have previously shown that invasive strains of Pseudomonas aeruginosa exploit the robust neutrophil response to form biofilms on contact lens surfaces and invade the corneal epithelium. The present study investigated the ability of multiple bacterial genera, all commonly recovered during contact lens-related infectious events, to adhere to and form biofilms on contact lens surfaces in the presence of neutrophils. Methods: Five reference strains from the American Type Culture Collection were used: P. aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia, Staphylococcus aureus, and Staphylococcus epidermidis. Each bacterial strain was incubated overnight with or without stimulated human neutrophils in the presence of an unworn contact lens. Standard colony counts and laser scanning confocal microscopy of BacLight-stained contact lenses were used to assess bacterial viability. Three-dimensional modeling of lens-associated biofilms with Imaris software was used to determine the biofilm volume. Lenses were further examined using scanning electron microscopy. Results: Less than 1% of the starting inoculum adhered to the contact lens surface incubated with bacteria alone. There were no differences in adhesion rates to contact lens surfaces between bacteria in the absence of neutrophils for either the Gram-negative or Gram-positive test strains. Bacterial adhesion to contact lens surfaces was accelerated in the presence of human neutrophils for all test strains. This effect was least evident with S. epidermidis. There was also an increase in the number of viable bacteria recovered from contact lens surfaces (p<0.001 for the Gram-negative and Gram-positive test strains, respectively) and in biofilm volume (p<0.001 for the Gram-negative test strains, p = 0.005 for S. aureus). Conclusions: These results show that in addition to P. aeruginosa, other bacteria commonly encountered during contact lens wear possess the capacity to utilize neutrophil-derived cellular debris to facilitate colonization of the lens surface. These data suggest that this phenomenon is conserved among multiple genera. Thus, during contact lens wear, the presence of inflammation and the accumulation of neutrophil debris under the posterior lens surface likely contribute to colonization of the lens. Further studies are needed to correlate these findings with risk for infection in an animal model. PMID- 29422768 TI - Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation. AB - Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results: Best corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions: The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype-phenotype correlations. PMID- 29422770 TI - Ex uno, multis: taxonomic revision in Navarretia divaricata (Polemoniaceae) and the recognition of four additional cryptic or near-cryptic species. AB - Navarretia divaricata, endemic to western North America and most recently considered a single species with two subspecies, was re-examined in light of field work, DNA sequences, comparative morphology, and a review of herbarium specimens including types. From these studies, we lectotypify the material on which N. divaricata is based, elevate N. divaricata subsp. vividior, which is an allotetraploid, to species rank (as N. vividiorcomb. et stat. nov.), and recognize three additional species: N. modocensissp. nov., N. aeroidessp. nov., and N. torreyellasp. nov.Navarretia modocensis, the diploid paternal progenitor of N. vividior, is morphologically cryptic with respect to its allotetraploid offspring and difficult to distinguish on herbarium sheets. Navarretia aeroides, the diploid maternal progenitor of N. vividior, is nearly cryptic, but more easily distinguished from both N. modocensis and N. vividior by its smaller, more glandular inflorescences. Navarretia torreyella is readily distinguished from all of these species, but has been generally mistaken for N. divaricata subsp. vividior given its colored corolla tube and rare co-occurrence with the other vividior-like species. Conservation assessments, an identification key, and table of comparative morphological features are provided for each species, emended descriptions for N. divaricata and N. vividior, and a discussion of the syntypes for Gilia divaricata Torr. ex A.Gray. PMID- 29422771 TI - Reduction of the Hawaiian genus Platydesma into Melicope section Pelea (Rutaceae) and notes on the monophyly of the section. AB - Platydesma, an endemic genus to the Hawaiian Islands containing four species, has long been considered of obscure origin. Recent molecular phylogenetic studies have unequivocally placed Platydesma within the widespread genus Melicope as sister to the rest of the Hawaiian species of Melicope. This makes submerging Platydesma into Melicope necessary. We make the necessary new combinations: Melicope cornuta (Hillebr.) Appelhans, K.R. Wood & W.L. Wagner, M. cornuta var. decurrens (B.C.Stone) Appelhans, K.R. Wood & W.L. Wagner, M. remyi (Sherff) Appelhans, K.R. Wood & W.L. Wagner, and M. rostrata (Hillebr.) Appelhans, K.R. Wood & W.L. Wagner. An additional species that has been recognized within Platydesma should now be recognized under its original name M. spathulata A. Gray. All Hawaiian species belong to Melicope section Pelea. Our molecular phylogenetic studies also showed that in addition to merging Platydesma into section Pelea, five species described from New Caledonia need to be excluded from the section in order to achieve monophyly of section Pelea. PMID- 29422772 TI - The association between infant and young child feeding practices and diarrhoea in Tanzanian children. AB - Background: Diarrhoea is a leading cause of child mortality in Tanzania. The association between optimal infant feeding practices and diarrhoea has been reported elsewhere, but the evidence has been limited to promote and advocate for strategic interventions in Tanzania. This study examined the association between infant and young child feeding (IYCF) practices and diarrhoea in Tanzanian children under 24 months. Methods: The study used the Tanzania Demographic and Health Survey data to estimate the prevalence of diarrhoea stratified by IYCF practices. Using multivariable logistic regression modelling that adjusted for confounding factors and cluster variability, the association between IYCF practices and diarrhoea among Tanzanian children was investigated. Results: Diarrhoea prevalence was lower in infants aged 0-5 months whose mothers engaged in exclusive breastfeeding (EBF) and predominant breastfeeding (PBF) compared to those who were not exclusively and predominantly breastfed. Infants aged 6-8 months who were introduced to complementary foods had a higher prevalence of diarrhoea compared to those who received no complementary foods, that is, infants who were exclusively breastfed at 6-8 months. Infants who were exclusively and predominantly breastfed were less likely to experience diarrhoea compared to those who were not exclusively and predominantly breastfed [adjusted odds ratio (AOR) 0.31, 95% confidence interval (CI) 0.16-0.59, P < 0.001 for EBF and AOR = 0.30, 95% CI 0.10-0.89, P = 0.031 for PBF]. In contrast, infants aged 6-8 months who were introduced to complementary foods were more likely to experience diarrhoea compared to those who received no complementary foods (AOR = 2.91, 95% CI 1.99-4.27, P < 0.001). Conclusions: The study suggests that EBF and PBF were protective against diarrhoeal illness in Tanzanian children, while the introduction of complementary foods was associated with the onset of diarrhoea. Strengthening IYCF (facility- and community-based) programmes would help to improve feeding behaviours of Tanzanian women and reduce diarrhoea burden in children under 2 years. PMID- 29422769 TI - A genome-wide association study of corneal astigmatism: The CREAM Consortium. AB - Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results: The meta analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55*10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism. PMID- 29422773 TI - What determines medical students' career preference for general practice residency training?: a multicenter survey in Japan. AB - Background: Few studies have systematically explored factors affecting medical students' general practice career choice. We conducted a nationwide multicenter survey (Japan MEdical Career of Students: JMECS) to examine factors associated with students' general practice career aspirations in Japan, where it has been decided that general practice will be officially acknowledged as a new discipline. Methods: From April to December 2015, we distributed a 21-item questionnaire to final year medical students in 17 medical schools. The survey asked students about their top three career preferences from 19 specialty fields, their demographics and their career priorities. Multivariable logistic regression was used to determine the effect of each item. Results: A total of 1264 responses were included in the analyses. The top three specialty choice were internal medicine: 833 (65.9%), general practice: 408 (32.3%), and pediatrics: 372 (29.4%). Among demographic factors, "plan to inherit other's practice" positively associated with choosing general practice, whereas "having physician parent" had negative correlation. After controlling for potential confounders, students who ranked the following items as highly important were more likely to choose general practice: "clinical diagnostic reasoning (adjusted odds ratio (aOR): 1.65, 95% CI 1.40-1.94)", "community-oriented practice (aOR: 1.33, 95% CI 1.13-1.57)", and" involvement in preventive medicine (aOR: 1.18, 95% CI 1.01-1.38)". On the contrary, "acute care rather than chronic care", "mastering advanced procedures", and "depth rather than breadth of practice" were less likely to be associated with general practice aspiration. Conclusions: Our nationwide multicenter survey found several features associated with general practice career aspirations: clinical diagnostic reasoning; community-oriented practice; and preventive medicine. These results can be fundamental to future research and the development of recruitment strategies. PMID- 29422774 TI - A comparison of symptoms and quality of life before and after nasal septoplasty and radiofrequency therapy of the inferior turbinate. AB - Background: The primary goal of this study is to compare pre- and postoperative symptoms and health related quality of life (HQOL) in 57 patients who underwent septoplasty (group-1), 56 patients who underwent septoplasty combined with radiofrequency therapy of inferior turbinates (RFIT) (group-2) and 58 patients who underwent RFIT alone (group-3). The secondary goal is to investigate if the change in symptoms and HQOL differed between these three patient groups after surgery. Methods: All patients reported symptoms on a visual analogue scale (VAS) and HQOL on Sino-Nasal-Outcome-Test-20 (SNOT-20) and Short-Form-Health-Survey-36 (SF-36) before and 6 months after surgery. The pre- and postoperative scores and improvement were compared within and between the three patient groups. Results: Preoperatively the three patient groups had a fairly similar symptom burden and HQOL, except for group-1 which reported more symptoms of oral breathing than group-3 (p < 0.01) and group-3 which reported more problems in the ear/facial- subset of SNOT-20 and in the general-mental-health-domain of SF-36 than group-1 (p < 0.01).Postoperatively all patient groups reported improved symptom scores of nasal obstruction, nasal discharge, snoring, oral breathing and reduced general health (p < 0.01), and better HQOL (p < 0.05). Patients in group-2 had less symptoms of nasal obstruction than group-3 (p < 0.05). Postoperative symptom score for nasal obstruction was 29.1 (SD67.6) in group-1, 27.5 (SD22.5) in group 2 and 37.2 (SD24.8) in group-3. Revision cases reported more nasal obstruction postoperatively; 41.3 (SD27) than non revision cases; 28.6 (SD24) (p < 0.01).The HQOL after surgery was about the same in all three patient groups, but we found that patients with comorbidities as sleep apnea and asthma reported worse HQOL than other patients (p < 0.01). Conclusion: Surgical treatment of nasal obstruction led to less symptoms and better HQOL for all three patient groups. Comparing the postoperative scores between the patient groups we find that all groups reached the same level of HQOL. Regarding symptoms, the patients who underwent septoplasty combined with RFIT reported postoperatively less nasal obstruction than patients who underwent RFIT alone which may indicate that a combined procedure of septoplasty and RFIT is better than RFIT alone to treat nasal obstruction. Furthermore, revision cases, patients with sleep apnea and asthma patients seem to have poorer outcome after surgery than other patients. Both disease specific and general QOL instruments add valuable information for identifying factors influencing outcome. PMID- 29422775 TI - Down regulation of G protein-coupled receptor 137 expression inhibits proliferation and promotes apoptosis in leukemia cells. AB - Background: G protein-coupled receptors (GPR) are involved in a wide range of physiological processes, some of which, however, can be hijacked by tumor cells. Over-expression of G protein-coupled receptors 137 (GPR137) are associated with the growth of tumor cells, but under-expression of GPR137 has shown to inhibit cell proliferation in several different types of cancers. Currently, the role of GPR137 in leukemia is still unclear. In this study, the effect of under expression of GPR137 on inhibiting the proliferation of leukemia cells is explored, to identify a novel target for leukemia treatment. Materials and methods: In this study, lentivirus-mediated RNA interference (RNAi) was employed to investigate the role of GPR137 in two leukemia cell lines K562 and HL60. The gene expression of GPR137 was analyzed by RT-PCR and its protein expression was determined by Western blot. Flow cytometry and Annexin V/7-AAD Apoptosis Detection Kit was used respectively in cell cycle and apoptosis analysis. The protein expression of CyclinD1, CDK4, BCL-2 and caspase-3 were also determined. Results: There was high level of constitutive expression of GPR137 in leukemia cancer cell lines K562 and HL60. Lentivirus-mediated RNAi could significantly down-regulate gene and protein expression of GPR137 in both cell lines. Down regulation of GPR137 was associated with the reduction in proliferation rate and colony forming capacity. In addition, down regulation of GPR137 arrested cells in the G0/G1 phase of cell cycle and induced apoptosis in both leukemia cell lines K562 and HL60. Conclusions: The expression of GPR137 is associated with the proliferation of leukemia cell lines. Down regulation of GPR137 could inhibit proliferation and promote apoptosis in leukemia cells, which makes it a promising bio-marker and therapeutic target to treat patients with leukemia. PMID- 29422776 TI - Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles. AB - Background: p53 is a tumor suppressor and key regulator of glycolysis in cancer cells, however highly mutated in tumors. In ovarian cancer, studies concerning p53 mutations focus on the DNA binding domain since the majority of hotspot mutations affects this region. Yet, mutations in other regions such as the proline rich domain may also affect the protein's expression and activity. The aim of this study is to investigate the effect of various positions of mutations in TP53 gene on glycolysis, apoptosis and transcription of p53 target genes. Methods: Mutations frequency and their effect on p53 expression were assessed by PCR-SSCP, sequencing and immunohistochemistry on 30 ovarian cancer biopsies. Six tumors were cultured, as well as SK-OV-3, OVCAR-3 and Igrov-1. SK-OV-3 cells were transfected with 2 TP53 mutants. p53 transcriptional activity was assayed by qPCR, apoptosis by flow cytometry and glycolysis by glucose and lactate measurements, with quantification of glycolytic enzymes expression. Results: Our results showed a high frequency of the P72R mutant, associated with p53 overexpression in the ovarian biopsies. However, P72R mutant cells showed similar apoptosis and glycolysis as WT cells. DNA binding domain mutations decreased the transcriptional activity of the protein and increased glucose consumption and lactate production. Conclusion: Despite the overexpression of the P72R mutated protein in the biopsies, it showed a similar apoptotic activity and glucose regulation ability as WT p53. Knowing that p53 expression status is used for chemotherapeutic approaches and prognosis in ovarian cancer, the results obtained highlight the importance of locating TP53 mutations. PMID- 29422777 TI - Imiquimod inhibits growth and induces differentiation of myeloid leukemia cell lines. AB - Background: The antitumoral effects of different Toll-like receptor (TLRs) agonists is mediated by activating immune responses to suppress tumors growth, although TLR ligands may also have a direct effect on tumoral cells. Given that TLR signaling induces hematopoietic cell differentiations this may serve as a novel differentiation therapeutic approach for AML. Methods: We investigated the effects of agonists for the ten human TLRs on the proliferation, apoptosis, cell cycle and differentiation of ten different types of myeloid leukemia cell lines (HL-60, U-937, KG-1, KG-1a, K-562, Kasumi-1, EOL-1, NB4, MOLM-13 and HEL). Proliferation was measured using the CellTiter 96(r) Aqueous One Solution Cell Proliferation Assay (Promega). Staining and analysis with a flow cytometer was used to identify cell cycle progression and apoptosis. Differentiation was measured by staining cells with the EuroFlowTM antibody panel for AML and analyzed by flow cytometry. FlowJo software was used to analyze the cytometric data. In all experiments, statistical significance was determined by a two-tailed t test. Results: The activation of particular TLRs on some cell lines can induce growth inhibition and Imiquimod (a TLR 7 agonist) was the most effective agonist in all leukemic cell lines examined. Imiquimod was able to induce apoptosis, as well as to induce cell cycle alteration and upregulation of myeloid differentiation markers on some of the cell lines tested. Conclusions: Our results, together with the known efficacy of Imiquimod against many tumor entities, suggest that Imiquimod can be a potential alternative therapy to AML. This drug has a direct cytotoxic effect on leukemic cells, has the potential to induce differentiation, and can also stimulate the activation of cellular immune responses anti-AML. PMID- 29422778 TI - Cost-effectiveness of tiotropium versus omalizumab for uncontrolled allergic asthma in US. AB - Background: A significant minority of asthma patients remain uncontrolled despite the use of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA). A number of add-on therapies, including monoclonal antibodies (namely omalizumab) and more recently tiotropium bromide have been recommended for this subgroup of patients. The purpose of this study was to assess the cost-effectiveness of tiotropium versus omalizumab as add-on therapies to ICS + LABA for patients with uncontrolled allergic asthma. Methods: A probabilistic Markov model of asthma was created. Total costs (in 2013 US $) and health outcomes of three interventions including standard therapy (ICS + LABA), add-on therapy with tiotropium, and add on therapy with omalizumab, were calculated over a 10-year time horizon. Future costs and quality-adjusted life years (QALYs) were discounted at the rate of 3%. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at willingness-to-pay value of $50,000. Results: The 10-year discounted costs and QALYs for standard therapy were $38,432 and 6.79, respectively. The corresponding values for add-on therapy with tiotropium and with omalizumab were $41,535 and 6.88, and $217,847 and 7.17, respectively. The incremental cost-effectiveness ratios (ICER) of add-on therapy with tiotropium versus standard therapy, and omalizumab versus tiotropium were $34,478/QALY, and $593,643/QALY, respectively. The model outcomes were most sensitive to the costs of omalizumab but were robust against other assumptions. Conclusions: Although omalizumab had the best health outcomes, add-on therapy with tiotropium was a cost-effective alternative to omalizumab and standard therapy for uncontrolled allergic asthma at willingness to-pay of $50,000/QALY. PMID- 29422779 TI - How Social Media is Changing the Practice of Regional Anesthesiology. AB - Purpose of Review: This review summarizes the current applications of social media in regional anesthesiology, describes ways that specific platforms may promote growth, and briefly discusses limitations and future directions. Recent findings: Although Facebook users outnumber Twitter users, the latter has been better studied in regional anesthesiology and may have the advantages of speed and expansion of reach. Highly tweeted publications are more likely to be cited in the medical literature, and twitter-enhanced journal clubs facilitate communication regarding important articles with international colleagues. In both the United States and internationally, Twitter has been shown to enhance the anesthesiology conference experience, changing communication among attendees and non-attendees. YouTube and podcasts are quickly finding a niche in regional anesthesiology for just-in-time training and continuing professional development. Summary: Social media use is rapidly growing in regional anesthesiology, and benefits include global interaction and knowledge translation within the specialty and with the general public. PMID- 29422780 TI - Real-Time In Vivo Intraocular Pressure Monitoring using an Optomechanical Implant and an Artificial Neural Network. AB - Optimized glaucoma therapy requires frequent monitoring and timely lowering of elevated intraocular pressure (IOP). A recently developed microscale IOP monitoring implant, when illuminated with broadband light, reflects a pressure dependent optical spectrum that is captured and converted to measure IOP. However, its accuracy is limited by background noise and the difficulty of modeling non-linear shifts of the spectra with respect to pressure changes. Using an end-to-end calibration system to train an artificial neural network (ANN) for signal demodulation we improved the speed and accuracy of pressure measurements obtained with an optically probed IOP-monitoring implant and make it suitable for real-time in vivo IOP monitoring. The ANN converts captured optical spectra into corresponding IOP levels. We achieved an IOP-measurement accuracy of +/-0.1 mmHg at a measurement rate of 100 Hz, which represents a ten-fold improvement from previously reported values. This technique allowed real-time tracking of artificially induced sub-1 s transient IOP elevations and minor fluctuations induced by the respiratory motion of the rabbits during in vivo monitoring. All in vivo sensor readings paralleled those obtained concurrently using a commercial tonometer and showed consistency within +/-2 mmHg. Real-time processing is highly useful for IOP monitoring in clinical settings and home environments and improves the overall practicality of the optical IOP-monitoring approach. PMID- 29422781 TI - The intersection between masculinity and health among rural immigrant Latino men. AB - Latino men experience health disparities in STI/HIV, diabetes, hypertension, and cancer. Gender roles likely play a role in risk behaviors and outcomes; however, there has been little focus on masculinity in Latino men. We conducted 20 semi structured interviews with Latino men living in North Carolina. The interviews, conducted by a trained bilingual/bicultural Latino male, prompted discussion around work, family, and stress. Four themes were identified: masculine roles of being a family provider and protector, sources of stress, family responsibility and interconnectedness to health, and coping mechanism. For Latino men, masculinity may have both positive and negative influences on health. For example, the role of family provider may contribute to coping and be a stressor simultaneously. Future research should examine masculinity as a positive and a negative health influence and the additional impacts of gender roles on mens' health. PMID- 29422782 TI - The Role of Ovarian Hormones and the Medial Amygdala in Sexual Motivation. AB - Purpose: Although research into the neurobiology of sexual desire in women is active, relatively little is understood about the origins of sexual motivation in women. The purpose of our review is to discuss factors that influence a central sexual motivate state and generalized arousal as potential drivers of sexual motivation in women and female rats. Recent Findings: Sexual motivation is the product of interactions of the central motive state and salient sexually-relevant cues. Ovarian hormones and generalized arousal influence the central motive state, and endogenous levels of estradiol and progesterone correlate with sexual motivation and behavior in women. The amygdala is a key integratory site for generalized arousal and sexual sensory stimulation, which could then increase sexual motivation through its downstream projections. Summary: Our model of enhanced female sexual motivation suggests that the combined effects of dopamine and progesterone receptor activation in the medial amygdala increases the incentive properties of a sexual stimulus. Further study into the interactions of ovarian hormones and mediators of generalized arousal on the processing of sexually-relevant cues informs our understanding of the neurobiology of female sexual motivation and could lead to the development of therapeutics to treat the dysfunctions of sexual desire in women. PMID- 29422783 TI - Enterobacter cloacae, an Emerging Plant-Pathogenic Bacterium Affecting Chili Pepper Seedlings. AB - A previously unreported bacterial disease on chili pepper (Capsicum annuum L.) seedlings affecting as many as 4% of seedlings was observed in greenhouses in Chihuahua, Mexico (Delicias and Meoqui counties). Initial lesions appeared as irregular small spots on leaves and brown necrosis at margins tips were observed. Later, the spots became necrotic with a chlorotic halo. Advanced disease was associated with defoliation. A Gram negative, rod-shaped bacterium was isolated from diseased chili pepper seedlings. Three inoculation methods revealed that isolated strains produce foliage symptoms, similar to those observed in naturally infected seedlings. Pathogenic strains that caused symptoms in inoculated seedlings were re-isolated and identified to fulfill koch's postulate. Polyphasic approaches for identification including biochemical assays (API 20E and 50CH), carbon source utilization profiling (Biolog) and 16S rDNA, hsp60 and rpoB sequence analysis were done. Enterobacter cloacae was identified as the causal agent of this outbreak on chili pepper seedlings. PMID- 29422784 TI - Genome-Wide Analysis of Type VI System Clusters and Effectors in Burkholderia Species. AB - Type VI secretion system (T6SS) has been discovered in a variety of gram-negative bacteria as a versatile weapon to stimulate the killing of eukaryotic cells or prokaryotic competitors. Type VI secretion effectors (T6SEs) are well known as key virulence factors for important pathogenic bacteria. In many Burkholderia species, T6SS has evolved as the most complicated secretion pathway with distinguished types to translocate diverse T6SEs, suggesting their essential roles in this genus. Here we attempted to detect and characterize T6SSs and potential T6SEs in target genomes of plant-associated and environmental Burkholderia species based on computational analyses. In total, 66 potential functional T6SS clusters were found in 30 target Burkholderia bacterial genomes, of which 33% possess three or four clusters. The core proteins in each cluster were specified and phylogenetic trees of three components (i.e., TssC, TssD, TssL) were constructed to elucidate the relationship among the identified T6SS clusters. Next, we identified 322 potential T6SEs in the target genomes based on homology searches and explored the important domains conserved in effector candidates. In addition, using the screening approach based on the profile hidden Markov model (pHMM) of T6SEs that possess markers for type VI effectors (MIX motif) (MIX T6SEs), 57 revealed proteins that were not included in training datasets were recognized as novel MIX T6SE candidates from the Burkholderia species. This approach could be useful to identify potential T6SEs from other bacterial genomes. PMID- 29422785 TI - Analysis of Genetic and Pathogenic Diversity of Ralstonia solanacearum Causing Potato Bacterial Wilt in Korea. AB - The Ralstonia solanacearum species complex (RSSC) can be divided into four phylotypes, and includes phenotypically diverse bacterial strains that cause bacterial wilt on various host plants. This study used 93 RSSC isolates responsible for potato bacterial wilt in Korea, and investigated their phylogenetic relatedness based on the analysis of phylotype, biovar, and host range. Of the 93 isolates, twenty-two were identified as biovar 2, eight as biovar 3, and sixty-three as biovar 4. Applied to the phylotype scheme, biovar 3 and 4 isolates belonged to phylotype I, and biovar 2 isolates belonged to phylotype IV. This classification was consistent with phylogenetic trees based on 16S rRNA and egl gene sequences, in which biovar 3 and 4 isolates clustered to phylotype I, and biovar 2 isolates clustered to phylotype IV. Korean biovar 2 isolates were distinct from biovar 3 and 4 isolates pathologically as well as genetically - all biovar 2 isolates were nonpathogenic to peppers. Additionally, in host-determining assays, we found uncommon strains among biovar 2 of phylotype IV, which were the tomato-nonpathogenic strains. Since tomatoes are known to be highly susceptible to RSSC, to the best of our knowledge this is the first report of tomato-nonpathogenic potato strains. These results imply the potential prevalence of greater RSSC diversity in terms of host range than would be predicted based on phylogenetic analysis. PMID- 29422786 TI - Hydrogen Cyanide Produced by Pseudomonas chlororaphis O6 Exhibits Nematicidal Activity against Meloidogyne hapla. AB - Root-knot nematodes (Meloidogyne spp.) are parasites that attack many field crops and orchard trees, and affect both the quantity and quality of the products. A root-colonizing bacterium, Pseudomonas chlororaphis O6, possesses beneficial traits including strong nematicidal activity. To determine the molecular mechanisms involved in the nematicidal activity of P. chlororaphis O6, we constructed two mutants; one lacking hydrogen cyanide production, and a second lacking an insecticidal toxin, FitD. Root drenching with wild-type P. chlororaphis O6 cells caused juvenile mortality in vitro and in planta. Efficacy was not altered in the fitD mutant compared to the wild-type but was reduced in both bioassays for the mutant lacking hydrogen cyanide production. The reduced number of galls on tomato plants caused by the wild-type strain was comparable to that of a standard chemical nematicide. These findings suggest that hydrogen cyanide-producing root colonizers, such as P. chlororaphis O6, could be formulated as "green" nematicides that are compatible with many crops and offer agricultural sustainability. PMID- 29422788 TI - First Isolation and Molecular Characterization of Bacteriophages Infecting Acidovorax citrulli, the Causal Agent of Bacterial Fruit Blotch. AB - Bacteriophages of Acidovorax citrulli, the causal agent of bacterial fruit blotch, were isolated from 39 watermelon, pumpkin, and cucumber leaf samples collected from various regions of Korea and tested against 18 A. citrulli strains. Among the six phages isolated, ACP17 forms the largest plaque, and exhibits the morphology of phages in the Myoviridae family with a head diameter of 100 +/- 5 nm and tail length of 150 +/- 5 nm. ACP17 has eclipse and latent periods of 25 +/- 5 min and 50 +/- 5 min, respectively, and a burst size of 120. The genome of ACP17 is 156,281 base pairs with a G + C content of 58.7%, 263 open reading frames, and 4 transfer RNA genes. Blast search and phylogenetic analysis of the major capsid protein showed that ACP17 has limited homology to two Stentrophomonas phages, suggesting that ACP17 is a new type of Myoviridae isolated from A. citrulli. PMID- 29422789 TI - Detection of Co-Infection of Notocactus leninghausii f. cristatus with Six Virus Species in South Korea. AB - Co-infection with two virus species was previously reported in some cactus plants. Here, we showed that Notocactus leninghausii f. cristatus can be co infected with six different viruses: cactus mild mottle virus (CMMoV)-Nl, cactus virus X (CVX)-Nl, pitaya virus X (PiVX)-Nl, rattail cactus necrosis-associated virus (RCNaV)-Nl, schlumbergera virus X (SchVX)-Nl, and zygocactus virus X (ZyVX) Nl. The coat protein sequences of these viruses were compared with those of previously reported viruses. CMMoV-Nl, CVX-Nl, PiVX-Nl, RCNaV-Nl, SchVX-Nl, and ZyVX-Nl showed the greatest nucleotide sequence homology to CMMoV-Kr (99.8% identity, GenBank accession NC_011803), CVX-Jeju (77.5% identity, GenBank accession LC12841), PiVX-P37 (98.4% identity, GenBank accession NC_024458), RCNaV (99.4% identity, GenBank accession NC_016442), SchVX-K11 (95.7% identity, GenBank accession NC_011659), and ZyVX-B1 (97.9% identity, GenBank accession NC_006059), respectively. This study is the first report of co-infection with six virus species in N. leninghausii f. cristatus in South Korea. PMID- 29422787 TI - Effect of Producing Different Phenazines on Bacterial Fitness and Biological Control in Pseudomonas chlororaphis 30-84. AB - Pseudomonas chlororaphis 30-84 is a biological control agent selected for its ability to suppress diseases caused by fungal pathogens. P. chlororaphis 30-84 produces three phenazines: phenazine-1-carboxylic acid (PCA), 2-hydroxy-phenazine 1-carboxylic acid (2OHPCA) and a small amount of 2-hydroxy-phenazine (2OHPHZ), and these are required for fungal pathogen inhibition and wheat rhizosphere competence. The two, 2-hydroxy derivatives are produced from PCA via the activity of a phenazine-modifying enzyme encoded by phzO. In addition to the seven biosynthetic genes responsible for the production of PCA, many other Pseudomonas strains possess one or more modifying genes, which encode enzymes that act independently or together to convert PCA into other phenazine derivatives. In order to understand the fitness effects of producing different phenazines, we constructed isogenic derivatives of P. chlororaphis 30-84 that differed only in the type of phenazines produced. Altering the type of phenazines produced by P. chlororaphis 30-84 enhanced the spectrum of fungal pathogens inhibited and altered the degree of take-all disease suppression. These strains also differed in their ability to promote extracellular DNA release, which may contribute to the observed differences in the amount of biofilm produced. All derivatives were equally important for survival over repeated plant/harvest cycles, indicating that the type of phenazines produced is less important for persistence in the wheat rhizosphere than whether or not cells produce phenazines. These findings provide a better understanding of the effects of different phenazines on functions important for biological control activity with implications for applications that rely on introduced or native phenazine producing populations. PMID- 29422790 TI - HR-Mediated Defense Response is Overcome at High Temperatures in Capsicum Species. AB - Resistance to Tomato spotted wilt virus isolated from paprika (TSWV-Pap) was overcome at high temperatures (30 +/- 2 degrees C) in both accessions of Capsicum annuum S3669 (Hana Seed Company) and C. chinense PI15225 (AVRDC Vegetable Genetic Resources). S3669 and PI15225, which carrying the Tsw gene, were mechanically inoculated with TSWV-Pap, and then maintained in growth chambers at temperatures ranging from 15 +/- 2 degrees C to 30 +/- 2 degrees C (in 5 degrees C increments). Seven days post inoculation (dpi), a hypersensitivity reaction (HR) was induced in inoculated leaves of PI152225 and S3669 plants maintained at 25 degrees C +/- 2 degrees C. Meanwhile, necrotic spots were formed in upper leaves of 33% of PI15225 plants maintained at 30 +/- 2 degrees C, while systemic mottle symptoms developed in 50% of S3669 plants inoculated. By 15 dpi, 25% of S3669 plants had recovered from systemic mottling induced at 30 +/- 2 degrees C. These results demonstrated that resistance to TSWV-Pap can be overcome at higher temperatures in both C. chinense and C. annuum. This is the first study reporting the determination of temperatures at which TSWV resistance is overcome in a C. annuum genetic resource expressing the Tsw gene. Our results indicated that TSWV resistance shown from pepper plants possess the Tsw gene could be overcome at high temperature. Thus, breeders should conduct evaluation of TSWV resistance in pepper cultivars at higher temperature than 30 degrees C (constant temperature). PMID- 29422791 TI - Reduced Bacterial Wilt in Tomato Plants by Bactericidal Peroxyacetic Acid Mixture Treatment. AB - Peroxyacetic acid mixture Perosan, composed of peroxyacetic acid, hydrogen peroxide and acetic acid, was evaluated for eco-friendly management of tomato bacterial wilt by Ralstonia pseudosolanacearum. Perosan drastically suppressed in vitro growth of R. pseudosolanacearum in liquid cultures in dose- and incubation time-dependent manners. Higher perosan doses (0.1 and 1%) caused lowered pH and phytotoxicity to detached leaves of two tomato cultivars Cupirang and Benekia 220 in aqueous solution. Treatment with 0.01% of Perosan delayed wilting symptom significantly in the detached leaves of two cultivars inoculated with R. pseudosolanacearum (107 cfu/ml). Soil drenching of 5% Perosan solution in pots caused severe tissue collapse of tomato seedlings at the four-week-old stage of two tomato cultivars. Treatment with 1% Perosan by soil-drenching significantly reduced bacterial wilt in the tomato seedlings of two cultivars. These findings suggest that Perosan treatment can be applied to suppress bacterial wilt during tomato production. PMID- 29422792 TI - Can histologic remission be a better prognostic factor and therapeutic target beyond endoscopic mucosal healing in patients with ulcerative colitis? PMID- 29422793 TI - Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: risk assessment. AB - Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised 2 parts: risk of TB infection Recommendaduring anti-TNF therapy, and screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment. PMID- 29422794 TI - Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 2: management. AB - Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised 3 parts: management of latent TB in preparation for anti-TNF therapy, monitoring during anti-TNF therapy, and management of an active TB infection after anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment. PMID- 29422796 TI - Quality indicators in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic, debilitating, and expensive condition affecting millions of people globally. There is significant variation in the quality of care for patients with IBD across North America, Europe, and Asia; this variation suggests poor quality of care due to overuse, underuse, or misuse of health services and disparity of outcomes. Several initiatives have been developed to reduce variation in care delivery and improve processes of care, patient outcomes, and reduced healthcare costs. These initiatives include the development of quality indicator sets to standardize care across organizations, and learning health systems to enable data sharing between doctors and patients, and sharing of best practices among providers. These programs have been variably successful in improving patient outcomes and reducing healthcare utilization. Further studies are needed to demonstrate the long-term impact and applicability of these efforts in different geographic areas around the world, as regional variations in patient populations, societal preferences, and costs should inform local quality improvement efforts. PMID- 29422797 TI - Quality is the key for emerging issues of population-based colonoscopy screening. AB - Colonoscopy is currently regarded as the gold standard and preferred method of screening for colorectal cancer (CRC). However, the benefit of colonoscopy screening may be blunted by low participation rates in population-based screening programs. Harmful effects of population-based colonoscopy screening may include complications induced by colonoscopy itself and by sedation, psychosocial distress, potential over-diagnosis, and socioeconomic burden. In addition, harmful effects of colonoscopy may increase with age and comorbidities. As the risk of adverse events in population-based colonoscopy screening may offset the benefit, the adverse events should be managed and monitored. To adopt population based colonoscopy screening, consensus on the risks and benefits should be developed, focusing on potential harm, patient preference, socioeconomic considerations, and quality improvement of colonoscopy, as well as efficacy for CRC prevention. As suboptimal colonoscopy quality is a major pitfall of population-based screening, adequate training and regulation of screening colonoscopists should be the first step in minimizing variations in quality. Gastroenterologists should promote quality improvement, auditing, and training for colonoscopy in a population-based screening program. PMID- 29422795 TI - Immunological pathogenesis of inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory state of the gastrointestinal tract and can be classified into 2 main clinical phenomena: Crohn's disease (CD) and ulcerative colitis (UC). The pathogenesis of IBD, including CD and UC, involves the presence of pathogenic factors such as abnormal gut microbiota, immune response dysregulation, environmental changes, and gene variants. Although many investigations have tried to identify novel pathogenic factors associated with IBD that are related to environmental, genetic, microbial, and immune response factors, a full understanding of IBD pathogenesis is unclear. Thus, IBD treatment is far from optimal, and patient outcomes can be unsatisfactory. As result of massive studying on IBD, T helper 17 (Th17) cells and innate lymphoid cells (ILCs) are investigated on their effects on IBD. A recent study of the plasticity of Th17 cells focused primarily on colitis. ILCs also emerging as novel cell family, which play a role in the pathogenesis of IBD. IBD immunopathogenesis is key to understanding the causes of IBD and can lead to the development of IBD therapies. The aim of this review is to explain the pathogenesis of IBD, with a focus on immunological factors and therapies. PMID- 29422798 TI - Association of endoscopic and histological remission with clinical course in patients of ulcerative colitis. AB - Background/Aims: The therapeutic goal for treating ulcerative colitis (UC) patients has shifted to achieving mucosal healing over the past few years. However, at present, limited data is available on the correlation between endoscopic findings and histological remission in patients with endoscopic mucosal healing. Methods: This was a prospective observational study conducted over a period of 18 months (January 2014 to June 2015) at Dayanand Medical College and Hospital, Ludhiana, Punjab, India. Patients diagnosed with UC who had been in clinical remission (n=76) for at least 6 months were evaluated for endoscopic remission. Those in endoscopic remission (Mayo score <=1; 46/76, 60.5%) were subjected to multiple biopsies from the rectosigmoid region and histological remission, which was then defined as grade 0/1 as per the Geboes criteria. Results: Of the 46 patients in endoscopic remission (age, 18-73 years; male:female=1.5:1.0), majority had E1 (proctitis) disease (21/46, 45.6%) followed by E2 (left sided colitis) (18/46, 39.1%) and E3 disease (pancolitis) (7/46, 15.2%) at baseline. Histological remission was noted in 67.3% (31/46) of the patients, while 32.7% (15/46) still retained the histologically active disease in the form of infiltration of the lamina propria by eosinophils and neutrophils (13/15, 86.6%), cryptitis (14/15, 93.3%), and crypt abscesses (8/15, 53.3%). On follow-up, after 1 year, 87.1% (27/31) of the patients who had been in histological remission remained clinically asymptomatic, while 12.9% (4/31) had relapsed. Among the 15 histologically active patients, 46.6% (7/15) remained in clinical remission, while 53.3% (8/15) had relapsed. Conclusions: Histological remission, rather than endoscopic remission, predicts a sustained clinical remission and allows monitoring of therapy for the subsequent disease course in patients with UC. PMID- 29422799 TI - Comparison of time until elective intestinal resection regarding previous anti tumor necrosis factor exposure: a Brazilian study on patients with Crohn's disease. AB - Background/Aims: The use of anti-tumor necrosis factor (anti-TNF) agents seems to reduce surgical rates and delay surgical procedures in prospective trials and population-based studies in the management of Crohn's disease (CD). This study aimed to identify whether preoperative anti-TNF agents influence the time from diagnosis to surgery. Methods: An observational retrospective cohort study was conducted on patients with CD submitted to intestinal resections due to complications or medical therapy failure in a period of 7 years. The patients were allocated into 2 groups according to their previous exposure to anti-TNF agents in the preoperative period. Epidemiological aspects regarding age at diagnosis, smoking, perianal disease, and preoperative conventional therapy were considered. A Kaplan-Meier survival analysis was used to outline possible differences between the groups regarding the time to surgery. Results: A total of 123 patients were included (71 and 52 with and without previous exposure to biologics, respectively). The overall time to surgery was 108+/-6.9 months (maximum, 276 months). The survival estimation revealed no difference in the mean time to intestinal resection between the groups (99.78+/-10.62 months in the patients without and 114.01+/-9.07 months in those with previous anti-TNF use) (log-rank P=0.35). There was no significant difference in the time to surgery regarding perianal CD (P=0.49), smoking (P=0.63), preoperative azathioprine (P=0.073) and steroid use (P=0.58). Conclusions: The time from diagnosis to surgery was not influenced by the preoperative use of anti-TNF therapy in this cohort of patients. PMID- 29422800 TI - Are Truelove and Witts criteria for diagnosing acute severe colitis relevant for the Indian population? A prospective study. AB - Background/Aims: Truelove and Witts criteria have been used to define acute severe colitis since the 1950s. However, hemoglobin (an additional criterion of the definition) levels in the general population in developing countries are lower than in the population of developed countries. We aimed to determine the relevance of Truelove and Witts criteria in the Indian population. Methods: Consecutive patients with acute severe colitis satisfying the Truelove and Witts criteria, hospitalized at a single center between April 2015 and December 2016 were included. All patients received intravenous corticosteroids and 16 required colectomy. The hemoglobin levels at admission were subsequently excluded from the classification criteria, and the effect this had on the criteria for diagnosis was determined. Results: Out of 61 patients of acute severe colitis diagnosed according to the original Truelove and Witts criteria, 12 patients (20%) had 1 additional criterion, 33 (54%) had 2 additional criteria and 16 (26%) had 3 or more additional criteria in addition to 6 or more blood stained stools on admission. On excluding hemoglobin as an additional criterion from the Truelove and Witts definition, all patients still met the criteria for acute severe colitis. Conclusions: Truelove and Witts criteria can be used to define acute severe colitis in India, despite lower mean hemoglobin in the native population. PMID- 29422801 TI - Efficacy of restarting anti-tumor necrosis factor alpha agents after surgery in patients with Crohn's disease. AB - Background/Aims: The efficacy of anti-tumor necrosis factor alpha (anti-TNFalpha) antibodies for postoperative Crohn's disease (CD) in patients who were treated with these agents prior to surgery is largely unknown. Methods: CD patients who underwent intestinal resection and received anti-TNFalpha agents after surgery were divided into 2 groups according to the presence or absence of preoperative anti-TNFalpha treatment: anti-TNFalpha restart group or anti-TNFalpha naive group. Endoscopic recurrence after surgery was examined according to the preoperative conditions, including administration of anti-TNFalpha agents before surgery. Results: Thirty-six patients received anti-TNFalpha antibody after surgery: 22 in the anti-TNFalpha restart group and 14 in the anti-TNFalpha naive group. Endoscopic recurrence after surgery was more frequently observed in the anti-TNFalpha restart group than in the anti-TNFalpha naive group (68% vs. 14%, P<0.001). Multivariate analysis revealed the following significant risk factors of endoscopic recurrence after surgery: anti-TNF restart group (odds ratio [OR], 28.10; 95% CI, 3.08-722.00), age at diagnosis <23 years (OR, 24.30; 95% CI, 1.67 1,312.00), serum albumin concentration at surgery <3.3 g/dL (OR, 34.10; 95% CI, 1.72-2,804.00), and presence of inflammation outside of the surgical site (OR, 21.40; 95% CI, 1.02-2,150.00). Treatment intensification for patients with endoscopic recurrence in the anti-TNFalpha restart group showed limited responses, with only 1 of 12 patients achieving endoscopic remission. Conclusions: The efficacy of restarting anti-TNFalpha antibody treatment after surgery was limited, and treatment intensification or a change to different classes of biologics should be considered for those patients. PMID- 29422802 TI - Efficacy and safety of the adalimumab biosimilar Exemptia as induction therapy in moderate-to-severe ulcerative colitis. AB - Background/Aims: Data on the efficacy and safety of the adalimumab biosimilar Exemptia are limited. Methods: Patients with moderate-to-severe active steroid refractory ulcerative colitis (UC) treated at Dayanand Medical College and Hospital, India were offered cyclosporine A, biologicals or biosimilars, or surgery. A retrospective analysis was conducted on patients who were treated with the adalimumab biosimilar, Exemptia. These patients were administered an induction dosing schedule of 160 mg Exemptia at week 0, 80 mg at week 2, and then 40 mg every other week from week 4 to 8. The clinical response and remission were assessed at week 8 using Mayo score. Results: A total of 29 patients (62.1% male; mean age, 34.9 +/- 9.7 years) with moderate-to-severe steroid-refractory active UC (mean disease duration, 6.3+/-5.1 years; pancolitis in 9 patients [31.1%]; left-sided colitis in 20 patients [68.9%]) were treated with the Exemptia induction dosing schedule. The mean Mayo score at presentation was 8.2+/-1.4. At week 8, clinical response was observed in 7 patients (24.1%), whereas clinical remission was observed only in 1 patient (3.5%). Among the non-responders (n=21), 4 patients required colectomy, 1 died, 1 was lost to follow-up, 10 were offered fecal microbiota transplant, 3 were administered infliximab, and 2 patients were administered cyclosporine and tacrolimus, respectively. Four patients (13.8%) developed extrapulmonary tuberculosis. Conclusions: The adalimumab biosimilar Exemptia has limited efficacy for the attainment of clinical response and remission in moderate-to-severe steroid-refractory UC, with a significant risk of acquisition or reactivation of tuberculosis in developing countries such as India. PMID- 29422803 TI - Distribution of cytomegalovirus genotypes among ulcerative colitis patients in Okinawa, Japan. AB - Background/Aims: To determine the prevalence of glycoprotein B (gB), glycoprotein N (gN), and glycoprotein H (gH) genotypes of human cytomegalovirus (HCMV) superimposed on ulcerative colitis (UC) patients in Japan. Methods: Four archived stool samples and 7-archived extracted DNA from stool samples of 11 UC patients with positive multiplex polymerase chain reaction (PCR) results for HCMV were used UL55 gene encoding gB, UL73 gene encoding gN, and UL75 gene encoding gH were identified by PCR. Genotypes of gB and glycoprotein N were determined by sequencing. Results: Among 11 samples, 8 samples were amplified through PCR. gB, gN, and gH genotypes were successfully detected in 3 of 8 (37.5%), 4 of 8 (50%), and 8 of 8 (100%), respectively. The distribution of gB and gN genotypes analyzed through phylogenetic analysis were as follows: gB1 (2/3, 66.7%), gB3 (1/3, 33.3%), gN3a (2/4, 50%), and gN3b (2/4, 50%). Other gB genotypes (gB2 and gB4) and gN genotypes (gN1, gN2, and gN4) were not detected in this study. Out of successfully amplified 8 samples of gH genotype, gH1 and gH2 were distributed in 12.5% and 75% samples, respectively. Only 1 sample revealed mixed infection of gH genotype. The distribution of gH1 and gH2 differed significantly (1:6, P<0.05) in UC patients. The distribution of single gH genotype also revealed significant difference in UC patients who were treated with immunosuppressive drug (P<0.05). Conclusions: In this study, gB1, gN3, and gH2 gene were determined as the most frequently observed genotypes in UC patients, which suggest that there might be an association between these genotypes of HCMV and UC. PMID- 29422804 TI - An analysis of dietary fiber and fecal fiber components including pH in rural Africans with colorectal cancer. AB - Background/Aims: Colorectal cancer (CRC) is now a major public health problem with heavy morbidity and mortality in rural Africans despite the lingering dietary fiber-rich foodstuffs consumption. Studies have shown that increased intake of dietary fiber which contribute to low fecal pH and also influences the activity of intestinal microbiota, is associated with a lowered risk for CRC. However, whether or not the apparent high dietary fiber consumption by Africans do not longer protects against CRC risk is unknown. This study evaluated dietary fiber intake, fecal fiber components and pH levels in CRC patients. Methods: Thirty-five subjects (CRC=21, control=14), mean age 45 years were recruited for the study. A truncated food frequency questionnaire and modified Goering and Van Soest procedures were used. Results: We found that all subjects consumed variety of dietary fiber-rich foodstuffs. There is slight preponderance in consumption of dietary fiber by the control group than the CRC patients. We also found a significant difference in the mean fecal neutral detergent fiber, acid detergent fiber, hemicellulose, cellulose and lignin contents from the CRC patients compared to the controls (P<0.05). The CRC patients had significantly more fecal pH level than the matched apparently healthy controls (P=0.017). Conclusions: The identified differences in the fecal fiber components and stool pH levels between the 2 groups may relate to CRC incidence and mortality in rural Africans. There is crucial need for more hypothesis-driven research with adequate funding on the cumulative preventive role of dietary fiber-rich foodstuffs against colorectal cancer in rural Africans "today." PMID- 29422805 TI - Rapid and accurate diagnosis of Clostridium difficile infection by real-time polymerase chain reaction. AB - Background/Aims: The incidence and severity of Clostridium difficile infection (CDI) have increased worldwide, resulting in a need for rapid and accurate diagnostic methods. Methods: A retrospective study was conducted to compare CDI diagnosis methods between January 2014 and December 2014. The stool samples, which were obtained in presumptive CDI patients, were compared for their diagnostic accuracy and rapidity, including real-time polymerase chain reaction (PCR) of toxin genes, C. difficile toxin assay, and culture for C. difficile. Results: A total of 207 cases from 116 patients were enrolled in this study and 117 cases (56.5%) were diagnosed as having CDI. Among the 117 cases, the sensitivities of real-time PCR, C. difficile toxin assay, and culture for C. difficile were 87.2% (102 cases; 95% CI, 80.7%-92.8%), 48.7% (57 cases; 95% CI, 41.0%-59.8%), and 65.0% (76 cases; 95% CI, 60.2%-78.5%), respectively (P<0.005). Notably, 34 cases (29.0%) were diagnosed with CDI by real-time PCR only. The time required to obtain results was 2.27 hours (136.62+/-82.51 minutes) for real-time PCR, 83.67 hours (5,020.66+/-3,816.38 minutes) for toxin assay, and 105.79 hours (6,347.68+/-3,331.46 minutes) for culture (P<0.005), respectively. Conclusions: We confirmed that real-time PCR of toxin genes is the most effective diagnostic method for accurate and early diagnosis of CDI. It also helps to diagnose hypervirulent CDI, such as ribotype 027 infection. PMID- 29422806 TI - Topographic, histological and molecular study of aberrant crypt foci identified in human colon in different clinical groups. AB - Background/Aims: Aberrant crypt foci (ACF) are early microscopic lesions of the colonic mucosa, which can be detected by magnified chromoendoscopy. Herein, we have investigated whether ACF identified in different clinical groups can be differentiated based on their characteristics. Methods: Macroscopically unremarkable mucosal flaps were collected from 270 fresh colectomies and divided into 3 clinical groups: colorectal carcinoma (group A), disease controls having known pre-neoplastic potential (group Bc), and disease controls without risk of carcinoma development (group Bn). Topographic and histologic analysis, immunohistochemistry, and molecular studies (high-resolution melt curve analysis, real-time polymerase chain reaction, and Sanger sequencing) were conducted for certain neoplasia-associated markers. Results: ACF were seen in 107 cases, out of which 72 were left colonic ACF and 35 right colonic ACF (67.2% vs. 32.7%, P=0.02). The overall density of left colonic ACF was 0.97/cm, which was greater than the right colonic ACF density of 0.81/cm. Hypercrinia was present in 41 out of 72 left colonic ACF and in 14 out of 35 right colonic ACF (P=0.01). Immunohistochemical expression of p53 was also greater in left colonic ACF than in right colonic ACF (60.5% vs. 38.2%, P=0.03). However, ACF identified among the 3 clinical groups did not show any distinguishing topographic, histological, or genetic changes. Conclusions: Left colonic ACF appear to be high-risk based on their morphological and prototypic tumor marker signature. ACF identified in different clinical groups do not show significant genotypic or topographic differences. Further detailed genetic studies are required to elucidate them further. PMID- 29422807 TI - Three-year colonoscopy surveillance after polypectomy in Korea: a Korean Association for the Study of Intestinal Diseases (KASID) multicenter prospective study. AB - Background/Aims: Colonoscopic surveillance is currently recommended after polypectomy owing to the risk of newly developed colonic neoplasia. However, few studies have investigated colonoscopy surveillance in Asia. This multicenter and prospective study was undertaken to assess the incidence of advanced adenoma based on baseline adenoma findings at 3 years after colonoscopic polypectomy. Methods: A total of 1,323 patients undergoing colonoscopic polypectomy were prospectively assigned to 3-year colonoscopy surveillance at 11 tertiary endoscopic centers. Relative risks for advanced adenoma after 3 years were calculated according to baseline adenoma characteristics. Results: Among 1,323 patients enrolled, 387 patients (29.3%) were followed up, and the mean follow-up interval was 31.0+/-9.8 months. The percentage of patients with advanced adenoma on baseline colonoscopy was higher in the surveillance group compared to the non surveillance group (34.4% vs. 25.7%). Advanced adenoma recurrence was observed in 17 patients (4.4%) at follow-up. The risk of advanced adenoma recurrence was 2 times greater in patients with baseline advanced adenoma than in those with baseline non-advanced adenoma, though the difference was not statistically significant (6.8% [9/133] vs. 3.1% [8/254], P=0.09). Advanced adenoma recurrence was observed only in males and in subjects aged >=50 years. In contrast, adenoma recurrence was observed in 187 patients (48.3%) at follow-up. Male sex, older age (>=50 years), and multiple adenomas (>=3) at baseline were independent risk factors for adenoma recurrence. Conclusions: A colonoscopy surveillance interval of 3 years in patients with baseline advanced adenoma can be considered appropriate. PMID- 29422808 TI - Clinical outcomes of surveillance colonoscopy for patients with sessile serrated adenoma. AB - Background/Aims: Sessile serrated adenomas (SSAs) are known to be precursors of colorectal cancer (CRC). The proper interval of follow-up colonoscopy for SSAs is still being debated. We sought to determine the proper interval of colonoscopy surveillance in patients diagnosed with SSAs in South Korea. Methods: We retrospectively reviewed the medical records of patients diagnosed with SSAs who received 1 or more follow-up colonoscopies. The information reviewed included patient baseline characteristics, SSA characteristics, and colonoscopy information. Results: From January 2007 to December 2011, 152 SSAs and 8 synchronous adenocarcinomas were identified in 138 patients. The mean age of the patients was 62.2 years and 60.1% patients were men. SSAs were located in the right colon (i.e., from the cecum to the hepatic flexure) in 68.4% patients. At the first follow-up, 27 SSAs were identified in 138 patients (right colon, 66.7%). At the second follow-up, 6 SSAs were identified in 65 patients (right colon, 66.7%). At the 3rd and 4th follow-up, 21 and 11 patients underwent colonoscopy, respectively, and no SSAs were detected. The total mean follow-up duration was 33.9 months. The mean size of SSAs was 8.1+/-5.0 mm. SSAs were most commonly found in the right colon (126/185, 68.1%). During annual follow-up colonoscopy surveillance, no cancer was detected. Conclusions: Annual colonoscopy surveillance is not necessary for identifying new CRCs in all patients diagnosed with SSAs. In addition, the right colon should be examined more carefully because SSAs occur more frequently in the right colon during initial and follow-up colonoscopies. PMID- 29422809 TI - Fecal microbiota transplantation for recurrent Clostridium difficile infection in a patient with ulcerative colitis. AB - Fecal microbiota transplantation (FMT) has been reported as a safe and effective therapy in patients with refractory and recurrent Clostridium difficile infection (CDI). FMT has also been reported as a promising therapy in patients with ulcerative colitis (UC). Both, CDI and UC, are believed to be caused by dysbiosis, such as altered compositions or decreased diversity of the intestinal microbiota. This report describes a patient with UC in remission with a second recurrent episode of CDI, who was treated with FMT. A single FMT performed via colonoscopy completely resolved the patient's diarrhea and eradicated C. difficile bacteriologically without any severe complications. Molecular biological analysis of the patient's fecal microbiota showed that FMT could dramatically change the altered composition of intestinal microbiota and restore its diversity. Despite the restoration of the intestinal microbiota, FMT could not prevent a relapse of UC in this patient. However, it improved the intestinal symptoms of CDI and could prevent further recurrences of CDI. PMID- 29422810 TI - A case of pemphigus vulgaris associated with ulcerative colitis. AB - Pemphigus vulgaris is an autoimmune bullous disorder characterized by the production of autoantibodies against the intercellular space of the epithelium. It has rarely been reported in association with inflammatory bowel disease. Ulcerative colitis is one of the forms of inflammatory bowel disease. A 62-year old woman who had been treated for ulcerative colitis for 16 years developed pruritic bullae on the skin of her face and body. Histological findings and direct immunofluorescence examination of the skin showed pemphigus vulgaris. She was treated with systemic steroids, mesalazine, and azathioprine. Her cutaneous lesions have remained in remission and her ulcerative colitis has remained well controlled. The relationship between pemphigus vulgaris and ulcerative colitis is unclear. An autoimmune response has been suspected in the pathogenesis of ulcerative colitis. Pemphigus vulgaris is also associated with an autoimmune mechanism. To our knowledge, this is the first case of ulcerative colitis associated with pemphigus vulgaris reported in Korea. The association may be causal. PMID- 29422811 TI - Duodenal amyloidosis secondary to ulcerative colitis. AB - Amyloidosis is defined as the extracellular deposition of non-branching fibrils composed of a variety of serum-protein precursors. Secondary amyloidosis is associated with several chronic inflammatory conditions, such as rheumatologic or intestinal diseases, familial Mediterranean fever, or chronic infectious diseases, such as tuberculosis. Although the association of amyloidosis with inflammatory bowel disease is known, amyloidosis secondary to ulcerative colitis (UC) is rare. A 36-year-old male patient with a 15-year history of UC presented with nausea, vomiting, and abdominal pain. He had been treated with infliximab for 6 years. At the time of admission, he had been undergoing treatment with mesalazine and adalimumab since the preceding 5 months. Esophagogastroduodenoscopy showed mucosal erythema, edema, and erosions with geographic ulcers at the 2nd and 3rd portions of the duodenum. Duodenal amyloidosis was diagnosed using polarized light microscopy and Congo red stain. Monoclonal gammopathy was not detected in serum and urine tests, while the serum free light chain assay result was not specific. An increase in plasma cells in the bone marrow was not found. Secondary amyloidosis due to UC was suspected. The symptoms were resolved after glucocorticoid therapy. PMID- 29422812 TI - Hyperbaric oxygen therapy for pyoderma gangrenosum associated with ulcerative colitis. AB - Pyoderma gangrenosum (PG), an ulcerating skin condition, is rare in patients with ulcerative colitis (UC). We report a case of successful treatment of PG in a patient with UC using hyperbaric oxygen therapy (HBOT). The patient had UC that was in remission following treatment with mesalazine and azathioprine therapy. After visiting an orthopedic clinic, the patient opted for treatment with antibiotics and daily dressing of the ulcerative skin lesions, while azathioprine was discontinued. However, the lesions did not improve. Two months later, the patient visited a dermatologist who diagnosed the lesions as PG, and he was admitted to our unit. Surgical debridement and HBOT were performed by a plastic surgeon in the emergency department. After 3 months of HBOT and topical treatment, the patient's PG completely resolved. His UC was still in remission with mesalazine alone. HBOT may be an effective and safe alternative treatment for PG associated with UC, particularly in patients in whom anti-tumor necrosis factor agents are unnecessary. PMID- 29422813 TI - A rare cause of gastrointestinal hemorrhage. PMID- 29422814 TI - T-cell immune response against cytomegalovirus in peripheral blood and colonic mucosa from ulcerative colitis and Crohn's disease patients. PMID- 29422818 TI - Circulating angiostatin serum level in patients with systemic sclerosis. AB - Introduction: Systemic sclerosis (SSc) is achronic connective tissue disease characterized by microangiopathy with inadequate angiogenesis. Angiostatin (AS) is a potent antiangiogenic factor specifically inhibiting proliferation and inducing apoptosis of vascular endothelial cells. Aim: To evaluate the level of angiostatin in the serum of patients with SSc. Material and methods: Serum levels of AS were measured in 20 SSc patients and 12 healthy controls. Results: A statistically significant difference in the serum levels of AS in SSc patients was observed compared to the control group (636.51 vs. 869.20 ng/ml; p = 0.012). Significant correlations between limited and disseminated SSc (lSSc/dSSc) were not found, however, a difference between lSSc and the control group was demonstrated (620.00 vs. 869.20 ng/ml; p = 0.011). The serum level of AS was not associated positively with organ changes caused by SSc. However, a statistically significant lower serum level of AS was observed in patients with SSc and no esophageal (p = 0.008) or pulmonary changes (p = 0.007) compared to the control group. Conclusions: Our results reveal significant differences in AS level in SSc patients compared to the healthy controls, and suggest that a low level of AS may occur as a result of impaired angiogenesis. PMID- 29422817 TI - Current applications of high-frequency ultrasonography in dermatology. AB - The era of ultrasounds in dermatology started in 1979, when pioneering use of 15 MHz by Alexander and Miller in measuring the skin thickness was introduced. Since then, some new applications of high-frequency ultrasonography (HF-USG) have emerged providing the clinicians with an extra hand in their everyday practice. The main advantages of HF-USG include the possibility of real-time imaging, measurements of morphological and physiological aspects of the skin, safety associated with the use of non-ionizing media as well as the lack of contraindications to its performance. Currently the main clinical use of HF-USG in dermatology regards preoperative assessment of the depth of invasion in melanomas and basal cell carcinomas. The ultrasound image analysis allows noninvasive follow-up of inflammatory skin diseases, like atopic dermatitis, psoriasis and may be used for monitoring effectiveness of therapy in skin lymphomas and sclerotic skin diseases. PMID- 29422815 TI - The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part III: Polymorphisms of genes involved in Tregs' activation and function. AB - Regulatory T cells (Tregs) represent a cell type that promotes immune tolerance to autologous components and maintains immune system homeostasis. The abnormal function of Tregs is relevant to the pathogenesis of several skin diseases like psoriasis, atopic dermatitis, systemic lupus erythematosus, cutaneous T-cell lymphomas, and skin cancer and is also important in rheumatoid arthritis, diabetes and other autoimmune diseases. In this review, we will summarize the role of mutations and/or polymorphisms of genes involved in Tregs development, and functions in the pathogenesis of selected skin diseases. PMID- 29422816 TI - The use of stem cells in aesthetic dermatology and plastic surgery procedures. A compact review of experimental and clinical applications. AB - The aim of this paper was to collect currently available data related to the use of stem cells in aesthetic dermatology and plastic surgery based on a systemic review of experimental and clinical applications. We found that the use of stem cells is very promising but the current state of art is still not effective. This situation is connected with not fully known mechanisms of cell interactions, possible risks and side effects. We think that there is a big need to create and conduct different studies which could resolve problems of stem cells use for implementation into aesthetic dermatology and plastic surgery. PMID- 29422819 TI - Increasing rate of daptomycin non-susceptible strains of Staphylococcus aureus in patients with atopic dermatitis. AB - Introduction: Daptomycin is a cyclic lipopeptide that is bactericidal against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) strains. Daptomycin exerts its antimicrobial effect by a calcium-dependent interaction with the cytoplasmic membrane resulting in depolarization, ion loss and rapid cell death. Unfortunately, loss of daptomycin susceptibility in S. aureus in the clinical setting has been noted. Aim: To evaluate the susceptibility profile to daptomycin among S. aureus strains isloted from patients with atopic dermatitis (AD). Another point was to correlate the results obtained by broth microdilution method and Etest, which is commonly applied in clinical setting. Material and methods: One hundred patients with the diagnosis of atopic dermatitis were microbiologically assessed for the carriage of S. aureus. Antimicrobial susceptibility tests were performed using broth microdilution (BMD) and Etests for daptomycin. Results: Staphylococcus aureus strains were isolated from the majority of our patients, either from the skin (73%) or the anterior nares (75%). Six of the 100 nasal swabs (6%) and 5 of the 100 skin swabs (5%) were positive for methicillin-resistant Staphylococcus aureus (MRSA). A total of 81 of 148 (54.7%) daptomycin non-susceptible isolates of S. aureus were identified by BMD. Only 19 of 81 were also classified as non susceptible by Etest. Conclusions: Clinicians and microbiologists should be aware of the possibility of the emergence of daptomycin non-susceptibility (or increase in minimal inhibitory concentration) during prolonged therapy and closely monitor the susceptibility of persisting isolates that might be recovered during therapy. PMID- 29422820 TI - Decolonization of Staphylococcus aureus in patients with atopic dermatitis: a reason for increasing resistance to antibiotics? AB - Introduction: Exacerbation of atopic dermatitis can be associated with bacterial infection. The skin of patients is colonized with Staphylococcus aureus in 90% of cases. An attempt has been made to demonstrate that eradication significantly reduces the severity of the disease. Studies indicate the efficacy of topical antibiotics, topical corticosteroids and calcineurin inhibitors. Due to increasing resistance to drugs and the defective antimicrobial peptide profile, decolonization is virtually impossible. Aim: To determine the prevalence of S. aureus colonization among patients with atopic dermatitis and to assess antimicrobial susceptibility of isolated strains to antibiotics, especially fusidic acid and mupirocin. Material and methods: One hundred patients with atopic dermatitis and 50 healthy subjects were microbiologically assessed for the carriage of S. aureus. Antimicrobial susceptibility tests were performed using the broth-microdilution method for antibiotics: ampicillin, ciprofloxacin, daptomycin, erythromycin, fusidic acid, linezolid, lincomycin, mupirocin, tetracycline and vancomycin. Results: Staphylococcus aureus strains were isolated from the majority of our patients, either from the skin (71%) or the anterior nares (67%). In the present study, 10% of isolations represented methicillin resistant S. aureus (MRSA). Antibiotics exhibited diverse activities against clinical isolates of S. aureus. Among those tested, the highest rates of resistance were shown for ampicillin - 58.5%, lincomycin - 37.5% and erythromycin - 31.0%. Enhanced resistance levels were expressed to mupirocin (17.5%) and fusidic acid (15.5%). Conclusions: According to the increasing rate of resistance and quick recolonization after discontinuation of the treatment, chronic use of topical antibiotics is not recommended and should be limited to exacerbation of atopic dermatitis with clinical signs of bacterial infection. PMID- 29422821 TI - Twenty years' observation of subcutaneous pollen allergoid immunotherapy efficacy in adults. AB - Introduction: It is valuable to determine the long-term efficacy of allergen specific immunotherapy (SIT) and whether it can cure allergy. Aim: For this study, patients were prospectively observed for 20 years after completion of SIT to determine its effectiveness. Material and methods: A total of 1006 patients who underwent SIT for pollen allergy were observed for 20 years to assess the efficacy of SIT. The rhinitis symptom score (RSS) and asthma symptom score (ASS) were measured after SIT completion. The possibility of allergy cure was estimated based on three sets of criteria: group A - neither symptoms nor intake of medication during the analysis period, group B - no symptoms during the analysis period (but possible medication intake), and group C - at most one mild symptom during the analysis period. Results: After SIT, approximately 25% of patients showed complete relief of allergy symptoms and had no need for symptomatic drug treatment during the pollen season. The level of effectiveness of SIT was similar throughout the treatment period. During the observation period after SIT, RSS ranged from 1.51 to 1.82, and ASS ranged from 1.22 to 1.29. The treatment effect at 10 and 20 years after SIT was comparable, regardless of whether criterion A or B was used. However, the effect of SIT using criterion C was lower than those using criteria A and B for the analyzed time points. Conclusions: For this study cohort, SIT had a long-term effect that did not depend significantly on the duration of immunotherapy against pollen. PMID- 29422822 TI - Thyroid function and thyroid autoantibodies in patients with chronic spontaneous urticaria. AB - Introduction: Chronic urticaria (CU) is a skin disease caused by autoantibodies against high affinity immunoglobulin E (IgE) receptor and against IgE. It is characterized by hives, erythematous wheals and redness present minimum twice a week for at least 6 weeks. It is observed that there is a strong association between CU and autoimmune diseases, such as autoimmune thyroiditis (AT). Aim: To verify the frequency of AT in patients suffering from chronic spontaneous urticaria (CSU) and to confirm the coexistence of CU and AT in the Polish population. Material and methods: One hundred and forty-eight patients with CSU were included to the study. The presence of anti-thyroperoxydase antibodies (anti TPO) and anti-thyroglobulin antibodies (anti-Tg) was checked and thyrotropin (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) concentration was measured. Results were compared with outcomes in a group of 35 patients with no history of skin disease. Results: Thirty-three patients were diagnosed with AT. Frequency of elevated anti-TPO (p = 0.0045) and anti-Tg (p = 0.013) levels was much higher in patients with CU. A comparison of the current study and previous ones was conducted. In a group with CU, there was a higher risk of elevated anti TPO (OR = 6.69) and anti-Tg (OR = 6.01) levels. Conclusions: There is a statistically significant difference in the presence of AT between the patients with CU and the whole population. Doctors should consider examining patients with CU for AT. Adequate therapy and guidance for patients could be implemented at an early stage of thyroid disease and help induce remission of skin disorders. PMID- 29422824 TI - The relationship between body mass index and increased airway reactivity based on methacholine challenge test results. AB - Introduction: According to the reports of the United States National Bureau of Statistics regarding the prevalence of obesity among adults and children and also asthma outbreak, the relationship between asthma and obesity in developed countries is taken into consideration. Aim: Relationship between body mass index and increased airway reactivity based on methacholine challenge test results. Material and methods: It was a retrospective cross-sectional study done on 256 patients who were referred to the lung clinic of the Imam Khomeini Hospital of Ahvaz with symptoms of hypersensitivity of the airways. The patients, who had normal spirometry, were examined by the methacholine challenge test and then they were divided in two groups with positive and negative test results. Results: The patients of this study were 12-84 years old and their average age was 36.3 +/ 12.1 years. Their mean body mass index (BMI) was 28 +/-4.7 kg/m2 in the group with positive methacholine and 26.7 +/-4.9 kg/m2 in the group with negative methacholine (p = 0.04). It was shown that there has been a statistically significant relationship between BMI and positive methacholine challenge test results (apart from confounding effects of other variables). It seems that the positivity rate of methacholine test rises by 1.06 with an increase in BMI by each unit (p < 0.05). Conclusions: According to the results of this study, it can be said that in high BMI there is a statistically significant association between gender (female) and a positive methacholine challenge test result; but there is no statistically significant association between the methacholine dose and BMI. PMID- 29422823 TI - Anaphylaxis in Poland: the epidemiology and direct costs. AB - Introduction: Epidemiological data on anaphylaxis have been underestimated both in Poland and worldwide. Aim: To evaluate the prevalence of anaphylaxis in Poland, including a classification by gender, age and residential region. Material and methods: The data used in the analysis were derived from two sources, the National Health Fund records of healthcare services for 2008-2015 (official statistics) and a questionnaire-based survey conducted in 2015 on a sample of 305 allergists practicing in different regions of Poland. Results: In 2015, 3144 people received treatment for anaphylactic shock (T78.0, T78.2, T80.5, T88.6) with an estimated prevalence rate of anaphylaxis of 8.2 per 100,000 (8.4 for females and 7.9 for males). The highest prevalence rate was found for women aged 50-54 years (14.5 per 100,000). There was a very large difference in the prevalence of anaphylaxis between rural and urban areas (13.1 vs. 0.8 per 100,000). In 2015, the Polish NHF spent PLN 3.5 million (EUR 835,000) on the management of anaphylaxis. Of the allergists surveyed, 73% had been currently managing patients who had experienced anaphylactic shock. The most common causes of anaphylaxis included insect venom (41.4%), food (29.8%) and drugs (17.4%). Conclusions: A central anaphylaxis registry should be established in Poland. This is the only approach that would allow collecting a wide range of reliable information on the cases, management and consequences of anaphylaxis. Ongoing management of patients who have experienced anaphylactic shock should be improved. PMID- 29422825 TI - Long non-coding RNA expression profiling in the lesional tissue and derived fibroblasts of keloid. AB - Introduction: Long non-coding RNA (lncRNA) plays a key role in various disorders. However, its role in keloid is still unclear. Aim: We explored differentially expressed (DE) lncRNAs and mRNAs between keloid tissue (KT)s and normal tissue (NT)s, as well as keloid fibroblast (KFB)s and normal fibroblast (NFB)s, respectively. Material and methods: We use KTs and NTs from the chest of 5 patients, and 3 pairs of KFBs and NFBs, to perform microarray respectively. Gene ontology and pathway analyses were conducted by online software DAVID (Database for Annotation, Visualization and Integrated Discovery). The validation of targeted lncRNAs were conducted by qRT-PCR in enlarged samples (79 KTs and 21 NTs). Results: We identified 3680 DE-lncRNAs in tissue essay, and 1231 DE-lncRNAs in cell essay. Furthermore, we found that many lncRNAs and their relative mRNAs were regulated simultaneously in keloid. We identified that ENST00000439703 and uc003jox.1 were up-regulated in both of the above essays through comparing the results of lncRNA screening between tissue essay and cell essay; the results were confirmed through qRT-PCR in enlarged samples. Conclusions: Our study demonstrates that numerous lncRNAs are involved in the pathogenesis and development of the keloid. PMID- 29422826 TI - Role of plasma growth factor in the healing of chronic ulcers of the lower legs and foot due to ischaemia in diabetic patients. AB - Introduction: It has been demonstrated that plasma growth factor (PGF) responsible for proliferation of smooth muscle cells and fibroblasts significantly shortens treatment duration. Aim: To determine the role of human growth factor in the healing of ulcers due to ischaemic diabetic foot syndrome (DFS) following previous angioplasty of the blood vessels of the lower leg and foot. Material and methods: The study group included 50 patients with ischaemic diabetic foot complicated by lower leg ulcers in which angioplasty of the stenotic arteries in the distal lower leg and foot was performed. It has been assumed that the area of the ulcer cannot exceed 5 cm2. Following surgical debridement, each patient received platelet-rich plasma in the form of dressings applied on an ulcer, followed by hydrocolloid dressings. Each dressing was replaced after 10 days, and this procedure was repeated after 20 and 30 days of treatment. The control group included 50 patients with ischaemic diabetic foot complicated by an ulcer up to 5 cm2. Angioplasty of the lower leg arteries was also performed in this group. However, after surgical debridement, wounds were covered with hydrocolloid dressings. Results: After 3 months of combined treatment, all wounds in the study group healed whereas in the control group, only wounds of the smallest size healed. Conclusions: Combined treatment of ulcers due to ischaemic DFS with endovascular procedures to re-establish blood flow to the vessels and dressings with autologous platelet-rich plasma significantly shortens the healing time. PMID- 29422827 TI - Incomplete excision of basal cell carcinoma (BCC) in the head and neck region: to wait, or not to wait? AB - Introduction: Recurrence rates for incompletely excised basal cell carcinoma (BCC) vary widely in the literature. Clinical observation is a commonly accepted method of follow up, however such management of these lesions still remains controversial. Aim: To evaluate the rate and factors associated with the recurrence of BCC of the head and neck region after incomplete excision. Material and methods: Medical records of 135 patients with 156 incompletely excised BCCs of the head and neck region were analyzed retrospectively. The primary outcome was the rate of recurrence. Additionally, a correlation of recurrence to clinical and morphological factors was analyzed. Results: Recurrence occurred in 72 (46%) lesions. The mean interval to recurrence was 20 months. In each category of factors, the highest relative risk of recurrence was correlated to: location on the scalp - 2.27, diameter over 2 cm - 1.21, nodular clinical form - 1.29, morpheaform histopathological type - 1.67, recurrent lesion - 1.88, irradicality of excision in the lateral margin - 1.24 and closure of the skin defect with the split-thickness skin graft - 1.42 relative risk. Conclusions: Observation is an acceptable management option as less than a half of incompletely excised BCCs recurred and needed further treatment. As 85% of recurrences occur within 3 years after operation, clinical observation should be particularly careful during this period, however long-term recurrence should not be underestimated. PMID- 29422828 TI - Vitamin D status in recurrent aphthous stomatitis. AB - Introduction: Recurrent aphthous stomatitis (RAS) is a common chronic inflammatory oral mucosa disease with an unknown cause. However, dysregulation of the immune response seems to play an important role in this disease. Aim: To evaluate the vitamin D status in RAS patients and its effects on RAS severity, given the likely immunomodulatory function of vitamin D in the human organism. Material and methods: Sixty-six patients with RAS and 66 controls were examined. Immunomodulatory or immunosuppressive treatment and other ulcerative oral diseases were used as exclusion criteria. The severity of RAS was assessed according to the clinical classification of the disease, the number of lesions per flare-up and the length of intervals between the attacks. The serum vitamin D level was established in each participant. Results: The mean serum vitamin D (25(OH)D) levels were found to be 16.81 ng/ml in the study group and 19.22 ng/ml in the control group, with no statistically significant difference between the two groups. In the study group, 5 (7.6%) participants were diagnosed with the "normal" vitamin D levels, while 16 (24.2%) had "insufficient" levels and 45 (68.2%) had "deficient" levels. The corresponding distribution in the control group was 8 (12.1%), 18 (27.3%) and 40 (60.6%), respectively. There was no statistical significance in the difference of vitamin D deficits between the study and the control groups. No correlation was detected between the severity of RAS and the serum vitamin D level. Conclusions: Vitamin D does not seem to be a trigger factor for RAS occurrence and does not appear to influence the severity of the disease in the studied group. PMID- 29422829 TI - Granulomatous skin disease with a histological pattern of palisading granuloma - an atypical facial necrobiosis lipoidica or more? PMID- 29422830 TI - Skin dissemination of myeloma. PMID- 29422831 TI - Transformation of primary cutaneous follicle centre lymphoma into primary cutaneous diffuse large B-cell lymphoma of other type. PMID- 29422832 TI - One week of exposure to sunlight induces progerin expression in human skin. PMID- 29422833 TI - Common lesions in a rare entity - Gardner's syndrome. PMID- 29422834 TI - Clinical internship at the Department of Dermatology, Venereology and Allergology, Medical University of Gdansk. PMID- 29422835 TI - Nanoparticle-Encapsulated Curcumin Inhibits Diabetic Neuropathic Pain Involving the P2Y12 Receptor in the Dorsal Root Ganglia. AB - Diabetic peripheral neuropathy results in diabetic neuropathic pain (DNP). Satellite glial cells (SGCs) enwrap the neuronal soma in the dorsal root ganglia (DRG). The purinergic 2 (P2) Y12 receptor is expressed on SGCs in the DRG. SGC activation plays an important role in the pathogenesis of DNP. Curcumin has anti inflammatory and antioxidant properties. Because curcumin has poor metabolic stability in vivo and low bioavailability, nanoparticle-encapsulated curcumin was used to improve its targeting and bioavailability. In the present study, our aim was to investigate the effects of nanoparticle-encapsulated curcumin on DNP mediated by the P2Y12 receptor on SGCs in the rat DRG. Diabetic peripheral neuropathy increased the expression levels of the P2Y12 receptor on SGCs in the DRG and enhanced mechanical and thermal hyperalgesia in rats with diabetes mellitus (DM). Up-regulation of the P2Y12 receptor in SGCs in the DRG increased the production of pro-inflammatory cytokines. Up-regulation of interleukin-1beta (IL-1beta) and connexin43 (Cx43) resulted in mechanical and thermal hyperalgesia in rats with DM. The nanoparticle-encapsulated curcumin decreased up-regulated IL 1beta and Cx43 expression and reduced levels of phosphorylated-Akt (p-Akt) in the DRG of rats with DM. The up-regulation of P2Y12 on SGCs and the up-regulation of the IL-1beta and Cx43 in the DRG indicated the activation of SGCs in the DRG. The nano-curcumin treatment inhibited the activation of SGCs accompanied by its anti inflammatory effect to decrease the up-regulated CGRP expression in the DRG neurons. Therefore, the nanoparticle-encapsulated curcumin treatment decreased the up-regulation of the P2Y12 receptor on SGCs in the DRG and decreased mechanical and thermal hyperalgesia in rats with DM. PMID- 29422836 TI - Early Alterations in Operant Performance and Prominent Huntingtin Aggregation in a Congenic F344 Rat Line of the Classical CAGn51trunc Model of Huntington Disease. AB - The transgenic rat model of Huntington disease expressing a fragment of mutant HTT (tgHD rat) has been thoroughly characterized and reproduces hallmark symptoms of human adult-onset HD. Pursuing the optimization of this model for evaluation of translational therapeutic approaches, the F344 inbred rat strain was considered as advantageous genetic background for the expression of the HD transgenic construct. In the present study, a novel congenic line of the SPRDtgHD transgenic model of HD, carrying 51 CAG repeats, was generated on the F344 rat genetic background. To assess the behavioral phenotype, classical assays investigating motor function, emotion, and sensorimotor gating were applied, along with automated screening of metabolic and activity parameters as well as operant conditioning tasks. The neuropathological phenotype was analyzed by immunohistochemistry and ex vivo magnetic resonance imaging. F344tgHD rats displayed markedly reduced anxiety-like behavior in the social interaction test and elevated impulsivity traits already at 3 months of age. Neuropathologically, reduced striatal volume and pronounced aggregation of mutant huntingtin in several brain regions were detected at later disease stage. In conclusion, the congenic F344tgHD model reproduces key aspects of the human HD phenotype, substantiating its value for translational therapeutic approaches. PMID- 29422837 TI - Signatures of Altered Gene Expression in Dorsal Root Ganglia of a Fabry Disease Mouse Model. AB - Fabry disease is an X-linked lysosomal storage disorder with involvement of the nervous system. Accumulation of glycosphingolipids within peripheral nerves and/or dorsal root ganglia results in pain due to small-fiber neuropathy, which affects the majority of patients already in early childhood. The alpha galactosidase A deficient mouse proved to be an adequate model for Fabry disease, as it shares many symptoms including altered temperature sensitivity and pain perception. To characterize the signatures of gene expression that might underlie Fabry disease-associated sensory deficits and pain, we performed one-color based hybridization microarray expression profiling of DRG explants from adult alpha galactosidase A deficient mice and age-matched wildtype controls. Protein-protein interaction (PPI) and pathway analyses were performed for differentially regulated mRNAs. We found 812 differentially expressed genes between adult alpha galactosidase A deficient mice and age-matched wildtype controls, 506 of them being upregulated, and 306 being downregulated. Among the enriched pathways and processes, the disease-specific pathways "lysosome" and "ceramide metabolic process" were identified, enhancing reliability of the current analysis. Novel pathways that we identified include "G-protein coupled receptor signaling" and "retrograde transport" for the upregulated genes. From the analysis of downregulated genes, immune-related pathways, autoimmune, and infection pathways emerged. The current analysis is the first to present a differential gene expression profile of DRGs from alpha-galactosidase A deficient mice, thereby providing knowledge on possible mechanisms underlying neuropathic pain related symptoms in Fabry patients. Therefore, the presented data provide new insights into the development of the pain phenotype and might lead to new treatment strategies. PMID- 29422838 TI - KCC2-dependent Steady-state Intracellular Chloride Concentration and pH in Cortical Layer 2/3 Neurons of Anesthetized and Awake Mice. AB - Neuronal intracellular Cl- concentration ([Cl-]i) influences a wide range of processes such as neuronal inhibition, membrane potential dynamics, intracellular pH (pHi) or cell volume. Up to date, neuronal [Cl-]i has predominantly been studied in model systems of reduced complexity. Here, we implemented the genetically encoded ratiometric Cl- indicator Superclomeleon (SCLM) to estimate the steady-state [Cl-]i in cortical neurons from anesthetized and awake mice using 2-photon microscopy. Additionally, we implemented superecliptic pHluorin (SE-pHluorin) as a ratiometric sensor to estimate the intracellular steady-state pH (pHi) of mouse cortical neurons in vivo. We estimated an average resting [Cl ]i of 6 +/- 2 mM with no evidence of subcellular gradients in the proximal somato dendritic domain and an average somatic pHi of 7.1 +/- 0.2. Neither [Cl-]i nor pHi were affected by isoflurane anesthesia. We deleted the cation-Cl- co transporter KCC2 in single identified neurons of adult mice and found an increase of [Cl-]i to approximately 26 +/- 8 mM, demonstrating that under in vivo conditions KCC2 produces low [Cl-]i in adult mouse neurons. In summary, neurons of the brain of awake adult mice exhibit a low and evenly distributed [Cl-]i in the proximal somato-dendritic compartment that is independent of anesthesia and requires KCC2 expression for its maintenance. PMID- 29422839 TI - Exercise-Induced Fatigue Impairs Bidirectional Corticostriatal Synaptic Plasticity. AB - Exercise-induced fatigue (EF) is a ubiquitous phenomenon in sports competition and training. It can impair athletes' motor skill execution and cognition. Corticostriatal synaptic plasticity is considered to be the cellular mechanism of movement control and motor learning. However, the effect of EF on corticostriatal synaptic plasticity remains elusive. In the present study, using field excitatory postsynaptic potential recording, we found that the corticostriatal long-term potentiation (LTP) and long-term depression (LTD) were both impaired in EF mice. To further investigate the cellular mechanisms underlying the impaired synaptic plasticity in corticostriatal pathway, whole-cell patch clamp recordings were carried out on striatal medium spiny neurons (MSNs). MSNs in EF mice exhibited increased spontaneous excitatory postsynaptic current (sEPSC) frequency and decreased paired-pulse ratio (PPR), while with normal basic electrophysiological properties and normal sEPSC amplitude. Furthermore, the N-methyl-D-aspartate (NMDA)/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) ratio of MSNs was reduced in EF mice. These results suggest that the enhanced presynaptic glutamate (Glu) release and downregulated postsynaptic NMDA receptor function lead to the impaired corticostriatal plasticity in EF mice. Taken together, our findings for the first time show that the bidirectional corticostriatal synaptic plasticity is impaired after EF, and suggest that the aberrant corticostriatal synaptic plasticity may be involved in the production and/or maintenance of EF. PMID- 29422840 TI - Mechanisms Underlying Serotonergic Excitation of Callosal Projection Neurons in the Mouse Medial Prefrontal Cortex. AB - Serotonin (5-HT) selectively excites subpopulations of pyramidal neurons in the neocortex via activation of 5-HT2A (2A) receptors coupled to Gq subtype G-protein alpha subunits. Gq-mediated excitatory responses have been attributed primarily to suppression of potassium conductances, including those mediated by KV7 potassium channels (i.e., the M-current), or activation of non-specific cation conductances that underlie calcium-dependent afterdepolarizations (ADPs). However, 2A-dependent excitation of cortical neurons has not been extensively studied, and no consensus exists regarding the underlying ionic effector(s) involved. In layer 5 of the mouse medial prefrontal cortex, we tested potential mechanisms of serotonergic excitation in commissural/callosal (COM) projection neurons, a subpopulation of pyramidal neurons that exhibits 2A-dependent excitation in response to 5-HT. In baseline conditions, 5-HT enhanced the rate of action potential generation in COM neurons experiencing suprathreshold somatic current injection. This serotonergic excitation was occluded by activation of muscarinic acetylcholine (ACh) receptors, confirming that 5-HT acts via the same Gq-signaling cascades engaged by ACh. Like ACh, 5-HT promoted the generation of calcium-dependent ADPs following spike trains. However, calcium was not necessary for serotonergic excitation, as responses to 5-HT were enhanced (by >100%), rather than reduced, by chelation of intracellular calcium with 10 mM BAPTA. This suggests intracellular calcium negatively regulates additional ionic conductances gated by 2A receptors. Removal of extracellular calcium had no effect when intracellular calcium signaling was intact, but suppressed 5-HT response amplitudes, by about 50%, when BAPTA was included in patch pipettes. This suggests that 2A excitation involves activation of a non-specific cation conductance that is both calcium-sensitive and calcium-permeable. M-current suppression was found to be a third ionic effector, as blockade of KV7 channels with XE991 (10 MUM) reduced serotonergic excitation by ~50% in control conditions, and by ~30% with intracellular BAPTA present. Together, these findings demonstrate a role for at least three distinct ionic effectors, including KV7 channels, a calcium-sensitive and calcium-permeable non-specific cation conductance, and the calcium-dependent ADP conductance, in mediating serotonergic excitation of COM neurons. PMID- 29422841 TI - Detecting Pilot's Engagement Using fNIRS Connectivity Features in an Automated vs. Manual Landing Scenario. AB - Monitoring pilot's mental states is a relevant approach to mitigate human error and enhance human machine interaction. A promising brain imaging technique to perform such a continuous measure of human mental state under ecological settings is Functional Near-InfraRed Spectroscopy (fNIRS). However, to our knowledge no study has yet assessed the potential of fNIRS connectivity metrics as long as passive Brain Computer Interfaces (BCI) are concerned. Therefore, we designed an experimental scenario in a realistic simulator in which 12 pilots had to perform landings under two contrasted levels of engagement (manual vs. automated). The collected data were used to benchmark the performance of classical oxygenation features (i.e., Average, Peak, Variance, Skewness, Kurtosis, Area Under the Curve, and Slope) and connectivity features (i.e., Covariance, Pearson's, and Spearman's Correlation, Spectral Coherence, and Wavelet Coherence) to discriminate these two landing conditions. Classification performance was obtained by using a shrinkage Linear Discriminant Analysis (sLDA) and a stratified cross validation using each feature alone or by combining them. Our findings disclosed that the connectivity features performed significantly better than the classical concentration metrics with a higher accuracy for the wavelet coherence (average: 65.3/59.9 %, min: 45.3/45.0, max: 80.5/74.7 computed for HbO/HbR signals respectively). A maximum classification performance was obtained by combining the area under the curve with the wavelet coherence (average: 66.9/61.6 %, min: 57.3/44.8, max: 80.0/81.3 computed for HbO/HbR signals respectively). In a general manner all connectivity measures allowed an efficient classification when computed over HbO signals. Those promising results provide methodological cues for further implementation of fNIRS-based passive BCIs. PMID- 29422842 TI - Estimation of Neuromuscular Primitives from EEG Slow Cortical Potentials in Incomplete Spinal Cord Injury Individuals for a New Class of Brain-Machine Interfaces. AB - One of the current challenges in human motor rehabilitation is the robust application of Brain-Machine Interfaces to assistive technologies such as powered lower limb exoskeletons. Reliable decoding of motor intentions and accurate timing of the robotic device actuation is fundamental to optimally enhance the patient's functional improvement. Several studies show that it may be possible to extract motor intentions from electroencephalographic (EEG) signals. These findings, although notable, suggests that current techniques are still far from being systematically applied to an accurate real-time control of rehabilitation or assistive devices. Here we propose the estimation of spinal primitives of multi-muscle control from EEG, using electromyography (EMG) dimensionality reduction as a solution to increase the robustness of the method. We successfully apply this methodology, both to healthy and incomplete spinal cord injury (SCI) patients, to identify muscle contraction during periodical knee extension from the EEG. We then introduce a novel performance metric, which accurately evaluates muscle primitive activations. PMID- 29422844 TI - Acrodermatitis Continua of Hallopeau with Bone Resorption in an 8-Year-Old Patient: A Case Report. AB - Acrodermatitis continua of Hallopeau (ACH) is an uncommon inflammatory disease manifesting as sterile pustular eruption of the fingers and toes. The disease is of a chronic relapsing nature and is often refractory to treatment. With longstanding disease, osteitis with consequent bone resorption of the underlying phalanges can occur, leading to disability. While the incidence of ACH is rare in children, complications like osteolysis have not been reported previously in this age group. In this paper, we report the case of an 8-year-old boy with severe ACH complicated by bone resorption. PMID- 29422843 TI - Cutaneous Metastases from Salivary Duct Carcinoma of the Submandibular Gland. AB - Salivary duct carcinoma is a rare and highly aggressive malignant neoplasm that frequently metastasises to other organs, but cutaneous metastasis is uncommon. There are only 6 cases reported in the literature with metastases to the skin and in all cases the tumour originates from the parotid gland. We present a case of skin metastases from the submandibular gland that was mistaken for basal cell carcinoma. To the best of our knowledge, this is the first reported case of salivary duct carcinoma arising from the submandibular gland with cutaneous metastases. PMID- 29422845 TI - Myointimal Hyperplasia in a Patient with Neuromyelitis Optica (Devic's Disease) after the Creation of an Arteriovenous Graft. AB - Neuromyelitis optica, also known as Devic's disease, is an autoimmune disorder that leads to the inflammation and demyelination of nerves. Devic's disease primarily affects the optic nerve and spinal cord, but can lead to a significant loss of function throughout the body if not treated with steroid therapy or plasmapheresis. We recently saw a 62-year-old patient who received plasmapheresis for Devic's disease through a PTFE arteriovenous graft in her left arm. Her graft clotted without warning, and percutaneous thrombolysis was not successful. A new vascular access was achieved with the use of an immediate-cannulation PTFE graft, and the patient received plasmapheresis immediately after her operation. However, the patient returned within 2 weeks with a thrombosed graft. Extensive myointimal fibrosis was noted within the brachial artery and axillary vein during a graft thrombectomy. Subsequent placement of a new arteriovenous fistula in her contralateral arm was eventually successful. Myointimal fibrosis may be a sequela of symptomatic antibody-positive Devic's disease, and avoidance of synthetic materials may be indicated in this patient population to avoid exacerbation of an autoimmune response. PMID- 29422846 TI - Statokinetic Dissociation (Riddoch Phenomenon) in a Patient with Homonymous Hemianopsia as the First Sign of Posterior Cortical Atrophy. AB - We report a 60-year-old woman with posterior cortical atrophy (PCA) who presented with left homonymous hemianopsia persisting for 5 years; the patient's condition was observed using static, but not kinetic, perimetry. This statokinetic dissociation of hemianopsia, which is often called Riddoch syndrome, might have been caused by a dysfunction of the right primary visual and visual association cortices, representing a functional imbalance within a disturbed visual cortex. In patients with PCA and visual field defects, both static and kinetic perimetry may be useful for understanding the extent of degeneration in the visual cortex, in addition to examinations of unilateral neglect. PMID- 29422847 TI - Intraoperative Rupture of Unruptured Cerebral Aneurysm during Craniotomy: A Case Report. AB - An unruptured aneurysm was incidentally found in the right middle cerebral artery in a 67-year-old woman. During an attempt to turn the temporalis muscle for surgical clipping, systolic blood pressure suddenly increased. After opening the dura mater, we found a subarachnoid hemorrhage and severe brain swelling. We promptly expanded the craniotomy area to reach the aneurysm while pulling part of the frontal lobe to apply a clip. We retrospectively analyzed the aneurysm using computational fluid dynamics. Our analysis suggests that the rupture of the aneurysm occurred at a location with very low wall shear stress. PMID- 29422848 TI - MRI Signal Abnormalities of the Inferior Olivary Nuclei in Spinocerebellar Ataxia Type 2. AB - Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant spinocerebellar degeneration, associated with extended repeats of the trinucleotide CAG in the ATXN2 gene on the long arm of chromosome 12. Magnetic resonance imaging (MRI) of SCA2 showed significant atrophies of the brainstem, middle cerebellar peduncles, and cerebellum. We report two genetically proven SCA2 patients who showed hypertrophy of the inferior olivary nuclei on proton density- and T2-weighted MRI. This pattern has never been reported in patients with SCA1, SCA3, or SCA6, and may make it possible to differentiate SCA2 from other hereditary spinocerebellar ataxias. PMID- 29422849 TI - Stroke Chameleons Manifesting as Distinct Radial Neuropathies: Expertise Can Hasten the Diagnosis. AB - Objective: Stroke chameleons encompass an atypical group of syndromes that do not initially appear to be cerebrovascular accidents. The objective of this study was to report patients with different lesions of central origin clinically presenting as wrist drop and with a semiology similar to that produced by peripheral lesions of the radial nerve at different topographical levels. Methods: This is a case series study of patients presenting with wrist drop during the acute phase of stroke who were assessed by clinical examination and CT and MRI brain scans. Results: Three cases presenting as monoparesis were evaluated. In all patients, the MRI revealed restricted diffusion in the pre- and post-central gyrus. Electromyography showed that the functionality of the radial, median, and ulnar nerves were intact in all three cases. The monoparesis resolved completely within 1 month of rehabilitation therapy, and no evidence of recurrent or new events was reported during the 6-month follow-up after stenting. Conclusion: The central message of this study is that when acute onset symptoms are present in a relatively old patient with vascular risk factors, stroke should be considered as the possible aetiology until proven otherwise, and the appropriate steps should be taken to avoid a delay in the treatment and to improve outcomes. PMID- 29422850 TI - A Native Haitian Woman with Unverricht-Lundborg Disease. AB - Unverricht-Lundborg disease (ULD) is an autosomal recessive progressive myoclonic epilepsy. The prevalence is highest in specific European countries and North Africa. Affected individuals have myoclonic and tonic-clonic seizures and a variable degree of ataxia and cognitive impairment. We report a native Haitian woman with ULD who was wheelchair bound due to nearly continuous myoclonic seizures exacerbated by activity and emotional distress. The seizures and their dramatic increase with volitional activity were recorded during video electroencephalography monitoring. Rational antiepileptic drug therapy controlled the seizures well enough for the patient to achieve a level of independence she had not experienced in over 25 years. PMID- 29422851 TI - STN DBS for Advanced Parkinson Disease Simultaneously Alleviates Cluster Headache. AB - Background: STB DBS (deep brain stimulation of the subthalamic nucleus) is commonly used to treat advanced Parkinson disease (PD) while posterior hypothalamic DBS for cluster headache (CH) remains experimental. Methods: We present a case where a middle-aged man was diagnosed with both CH and PD and received medical treatment for both. The patient was treated with bilateral STN DBS after developing side effects related to L-dopa. Findings: STN DBS not only alleviated PD symptoms but also the CH, and hence the CH treatment could be withdrawn. During follow-up PD progressed but the effect on CH symptoms was sustained. Conclusions: The anatomical proximity of the medial STN and hypothalamus, their similar connectivity via the hyperdirect pathway, and the autonomic effects of STN DBS could explain symptom relief for both PD and CH. PMID- 29422852 TI - Recurrent Stroke in a Young Woman with a Single Pulmonary Arteriovenous Fistula: An Unusual Association. AB - Introduction: Cryptogenic stroke is present in about 40% of ischemic stroke patients. Extracardiac shunt related to pulmonary arteriovenous fistula (PAVF) could be a rare potential risk factor for embolic stroke. Most PAVFs are multiple, congenital, and associated with hereditary conditions. On the other hand, isolated PAVFs are rare conditions and an uncommon cause of cryptogenic stoke. Case Report: We describe a case of a young woman without history of respiratory diseases or vascular risk factors, who presented with acute onset of transitory aphasia and right hemiplegia. She had a history of a transient ischemic attack, 3 years before, and migraine headaches. Brain MRI showed an acute cortical ischemic lesion and a chronic ischemic lesion. Diagnostic workup with transcranial Doppler ultrasonography revealed a significant right-to-left shunt with curtain pattern, and echocardiogram did not show structural abnormalities. An isolated small PAVF was diagnosed on pulmonary angiogram. Despite the rare association between isolated small PAVF and stroke, we decided to treat it with coil embolization because of recurrence of stroke, cortical lesions suggestive of embolic source, significant right-left shunt, and risk of future complications. Conclusions: This case highlights the importance of search, identification, and interpretation of causes of cryptogenic strokes to better choose therapy to reduce the stroke recurrence risk. Although unusual, PAVF detection is a treatable cause of stroke and the therapeutic decisions should take into account the characteristics of the PAVF and the degree of suspicion regarding the cause-effect relationship between PAVF and stroke. PMID- 29422853 TI - Persistent Hemichorea and Caudate Atrophy in Untreated Diabetic Striatopathy: A Case Report. AB - Background: Neurological complications of diabetes and hyperglycemia are relatively common but the specific manifestations can vary widely. Diabetic striatal disease or "diabetic striatopathy" is an uncommon condition usually thought to result from hyperglycemic injury to the basal ganglia, producing a hyperkinetic movement disorder, usually choreiform in nature. Symptoms are generally reversible with treatment of the hyperglycemia. Case Description: We report the case of a 57-year-old woman presenting with a unilateral choreoathetosis of the left upper extremity, persistent for 4 years. Contemporaneous imaging demonstrated severe atrophy of the right caudate nucleus, while imaging obtained at the onset of symptoms was consistent with a right diabetic striatopathy. Symptoms improved with the use of dopamine antagonists and benzodiazepines. Conclusion: Although generally considered to be fully reversible, this case demonstrates that diabetic striatopathy can result in permanent structural lesions with persistent symptoms if left untreated. PMID- 29422854 TI - Reversible Cerebral Vasoconstriction Syndrome due to Atovaquone. AB - A 72-year-old Japanese woman with rheumatoid arthritis whose activity decreased with previous treatments had recurrent thunderclap headaches during an atovaquone regimen for the treatment of pneumocystis pneumonia. The recurrent headaches disappeared after discontinuation of the drug. Brain magnetic resonance images showed multiple cerebral vasoconstrictions of cerebral arteries with vasogenic cerebral white matter edema, which diminished several weeks later. We diagnosed the patient's headaches as reversible cerebral vasoconstriction syndrome due to atovaquone. PMID- 29422855 TI - Lacrimal Caruncle Nevus with Papilloma. AB - Purpose: The aim of this article is to report a case of lacrimal caruncle nevus with papilloma. Methods: This is a case report of a 39-year-old female with a progressively enlarging pigmented lesion on the left lacrimal caruncle. She had been aware of a raised whitish wart on the top of this pigmented lesion for several months before her initial visit. Slit lamp examination revealed a papillomatous lesion over a well-circumscribed, pigmented lesion on the left lacrimal caruncle. Results: The histopathological examination of the excised tumor disclosed 2 characteristic findings, which include nests of nevus cells within the dermis and papillomatous structures which had fibrovascular cores overlying squamous cell epithelia with variable levels of acanthosis. The findings were consistent with an intradermal nevus and a papilloma arising from the conjunctival epithelium of the nevus. Conclusion: This is the first case report of a lacrimal caruncle nevus with papilloma. The clinical history and pathological findings of this case underscore the fact that an intradermal nevus primarily occurred on the lacrimal caruncle, after which a papilloma arose from the epithelium of the nevus as a consequence of human papillomavirus autoinoculation. PMID- 29422856 TI - Refractive Lens Exchange with Multifocal Intraocular Lens for Treatment of Chronic Intermittent Spasm of the Near Reflex. AB - We report the case of an emmetropic 32-year-old female with decreased uncorrected visual acuity and diplopia due to intermittent episodes of spasm of the near reflex. Neurologic, general, and ophthalmic examination could not find an organic cause. Attempts at spontaneous recovery, psychogenic therapy, and cycloplegic therapy were unsuccessful and the symptoms persisted for almost 5 years, leading to psychogenic distress. Final treatment with refractive lens exchange and implantation of a toric trifocal intraocular lens resolved the spasm of the near reflex, resulting in an uncorrected distance and near visual acuity of 20/20. PMID- 29422857 TI - Application of Arterial Spin Labelling in Detecting Retinal Ischemia. AB - Purpose: Here, we have tried to quantify the chorioretinal blood perfusion in patients who are clinically identified to be suffering from retinal ischemia using arterial spin labelling (ASL) MRI. Method: Four participants, diagnosed with retinal ischemia based on their structural OCT and angiography test, were then scanned using anatomical MRI as well as ASL. We optimized MR parameters to maximize resolution and target fixation, blinking, and breathing ques to minimize motion artifacts. Results: Participants had a maximum of ~50 mL/100 mL/min of blood perfusion, which is below the normal values of ~200 mL/100 mL/min. It also appeared that thinning of the choroid contributes more to the measured decreased chorioretinal perfusion, compared to slowed arterial filling time. Conclusion: Decreased chorioretinal perfusion is a multifactorial event and has been implicated in several posterior eye pathologies. Based on our current results, it seems that ischemia of the eye could be due to anatomy (tissue volume) and/or functionality (arterial flow). PMID- 29422858 TI - Unilateral Keratoconus after Chronic Eye Rubbing by the Nondominant Hand. AB - Introduction: To report the development of unilateral keratoconus in a healthy male after persistent unilateral eye rubbing by the nondominant hand which was not needed for professional activities. Methods: Observational case report. Results: A 60-year-old male was first seen in our clinic due to decreased vision in his left eye. Slit-lamp biomicroscopy of the left eye revealed Vogt's striae, stromal thinning, and a stromal scar. Corneal topography showed a stage 4 keratoconus. Clinical examination and corneal topography of the right eye were normal. Medical history revealed a habit of chronic eye rubbing only in the left eye because of the right hand being occupied for professional needs. During follow-up of 5 years, Scheimpflug images of the right eye stayed normal while the left eye showed a stable cone. Discussion: This case report supports the hypothesis of mechanical fatigue of the cornea due to repetitive shear stress on the surface caused by eye-rubbing. PMID- 29422859 TI - Successful Subcutaneous Allergen-Specific Immunotherapy in Refractory Atopic Keratoconjunctivitis: A Case Report. AB - Purpose: We report a case of refractory atopic keratoconjunctivitis (AKC) which was successfully treated with subcutaneous immunotherapy (SCIT). Case Report: A 22-year-old woman presented with severe allergic conjunctivitis for one and a half year. She failed to respond to conventional topical anti-allergic medications, topical corticosteroid, as well as topical cyclosporine A. Therefore, oral corticosteroids had to be prescribed to control the exacerbation for 1 year. Due to refractory AKC and to avoid long-term corticosteroid use, we referred her to an allergy clinic for considering the role of SCIT. Allergology investigations showed positive skin prick test and strongly elevated serum specific IgE to Dermatophagoides farinae (Der f) and Dermatophagoides pteronyssinus (Der p). She received a conventional protocol of SCIT using Der f and Der p allergen extracts. Results: The patient's ocular signs and symptoms were dramatically improved 2 months after the initiation of SCIT, and oral corticosteroids could be discontinued within 3 months of the treatment. She was maintained with mast cell stabilizers and preservative-free tears without any episodes of exacerbation. Conclusions: SCIT may contribute to successful outcomes in controlling symptoms and preventing exacerbation in AKC patient. It should be considered as an alternative or even a primary treatment for patients with refractory AKC. However, the optimal SCIT protocol must be discussed with an allergist on an individual basis for the best outcome. PMID- 29422860 TI - Chronic Central Serous Chorioretinopathy-Like Maculopathy as Atypical Presentation of Chorioretinal Folds. AB - Purpose: The purpose of this case report was to present the clinical data and management of a 69-year-old female patient with chorioretinal folds who developed chronic central serous chorioretinopathy-like maculopathy. Case Presentation: A 69-year-old female patient presented with a recent-onset slight decrease in visual acuity in her left eye. Her past ocular history was clear. Regarding her medical history, she had only hypertension, treated with per os medications. The patient underwent a complete ophthalmological examination. At presentation, the visual acuity was 6/6 in the right eye and 6/7.5 in the left eye. Intraocular pressure was 16 mm Etag in both eyes. On fundoscopy, chorioretinal folds were noticed in the left eye. Spectral-domain optical coherence tomography, fluorescein angiography, and indocyanine green angiography confirmed the diagnosis of chronic central serous chorioretinopathy-like maculopathy in the left eye, since other causes of chorioretinal folding were excluded. The right eye was normal. No treatment was given to the patient, and at the 6-month follow up there was improvement in visual acuity, which was 6/6, and decreased subretinal fluid. Conclusions: Central serous chorioretinopathy-like maculopathy should be taken into account for the differential diagnosis of patients with chorioretinal folds. PMID- 29422861 TI - The Turkish Medicines and Medical Devices Agency: Comparison of Its Registration Process with Australia, Canada, Saudi Arabia, and Singapore. AB - Introduction: Regulatory agency comparisons can be of more value and facilitate improvements if conducted among countries with common challenges and similar health agency characteristics. A study was conducted to compare the registration review model used by the Turkish Medicines and Medical Devices Agency (Turkiye Ilac ve Tibbi Cihaz Kurumu; TITCK) with those of four similar-sized regulatory agencies to identify areas of strength and those requiring further improvement within the TITCK in relation to the review process as well as to assess the level of adherence to good review practices (GRevP) in order to facilitate the TITCK progress toward agency goals. Methods: A questionnaire was completed and validated by the TITCK to collect data related to agency organizational structure, regulatory review process and decision-making practices. Similar questionnaires were completed and validated by Australia's Therapeutic Goods Administration (TGA), Health Canada, Singapore's Health Science Authority (HSA), and the Saudi Arabia Food and Drug Administration (SFDA). Results: The TITCK performs a full review for all new active substance (NAS) applications. Submission of a Certificate of Pharmaceutical product (CPP) with an application is not required; however, evidence of approval in another country is required for final authorization by the TITCK. Pricing data are not required by the TITCK at the time of submission; however, pricing must be completed to enable products to be commercially available. Mean approval times at the TITCK exceeded the agency's overall target time suggesting room for improved performance, consistency, and process predictability. Measures of GRevP are in place, but the implementation by the TITCK is not currently formalized. Discussion: Comparisons made through this study enabled recommendations to the TITCK that include streamlining the good manufacturing practice (GMP) process by sharing GMP inspection outcomes and certificates issued by other authorities, thus avoiding the delays by the current process; removing the requirement for prior approval or CPP; introducing shared or joint reviews with other similar regulatory authorities; formally implementing and monitoring GRevP; defining target timing for each review milestone; redefining the pricing process; and improving transparency by developing publicly available summaries for the basis of approval. PMID- 29422862 TI - Geraniol Pharmacokinetics, Bioavailability and Its Multiple Effects on the Liver Antioxidant and Xenobiotic-Metabolizing Enzymes. AB - Geraniol is a natural monoterpene showing anti-inflammatory, antioxidant, neuroprotective and anticancer effects. No pharmacokinetic and bioavailability data on geraniol are currently available. We therefore performed a systematic study to identify the permeation properties of geraniol across intestinal cells, and its pharmacokinetics and bioavailability after intravenous and oral administration to rats. In addition, we systematically investigated the potential hepatotoxic effects of high doses of geraniol on hepatic phase I, phase II and antioxidant enzymatic activities and undertook a hematochemical analysis on mice. Permeation studies performed via HPLC evidenced geraniol permeability coefficients across an in vitro model of the human intestinal wall for apical to basolateral and basolateral to apical transport of 13.10 +/- 2.3 * 10-3 and 2.1 +/- 0.1?* 10-3 cm/min, respectively. After intravenous administration of geraniol to rats (50 mg/kg), its concentration in whole blood (detected via HPLC) decreased following an apparent pseudo-first order kinetics with a half-life of 12.5 +/- 1.5 min. The absolute bioavailability values of oral formulations (50 mg/kg) of emulsified geraniol or fiber-adsorbed geraniol were 92 and 16%, respectively. Following emulsified oral administration, geraniol amounts in the cerebrospinal fluid of rats ranged between 0.72 +/- 0.08 MUg/mL and 2.6 +/- 0.2 MUg/mL within 60 min. Mice treated with 120 mg/kg of geraniol for 4 weeks showed increased anti-oxidative defenses with no signs of liver toxicity. CYP450 enzyme activities appeared only slightly affected by the high dosage of geraniol. PMID- 29422863 TI - N-n-Butyl Haloperidol Iodide, a Derivative of the Anti-psychotic Haloperidol, Antagonizes Hypoxia/Reoxygenation Injury by Inhibiting an Egr-1/ROS Positive Feedback Loop in H9c2 Cells. AB - Early growth response-1 (Egr-1), a transcription factor which often underlies the molecular basis of myocardial ischemia/reperfusion (I/R) injury, and oxidative stress, is key to myocardial I/R injury. Silent information regulator of transcription 1(SIRT1) not only interacts with and is inhibited by Egr-1, but also downregulates reactive oxygen species (ROS) via the Forkhead box O1(FOXO1)/manganese superoxide dismutase (Mn-SOD) signaling pathway. N-n-butyl haloperidol iodide (F2), a new patented compound, protects the myocardium against myocardial I/R injury in various animal I/R models in vivo and various heart derived cell hypoxia/reoxygenation (H/R) models in vitro. In addition, F2 can regulate the abnormal ROS/Egr-1 signaling pathway in cardiac microvascular endothelial cells (CMECs) and H9c2 cells after H/R. We studied whether there is an inverse Egr-1/ROS signaling pathway in H9c2 cells and whether the SIRT1/FOXO1/Mn-SOD signaling pathway mediates this. We verified a ROS/Egr-1 signaling loop in H9c2 cells during H/R and that F2 protects against myocardial H/R injury by affecting SIRT1-related signaling pathways. Knockdown of Egr-1, by siRNA interference, reduced ROS generation, and alleviated oxidative stress injury induced by H/R, as shown by upregulated mitochondrial membrane potential, increased glutathione peroxidase (GSH-px) and total SOD anti-oxidative enzyme activity, and downregulated MDA. Decreases in FOXO1 protein expression and Mn-SOD activity occurred after H/R, but could be blocked by Egr-1 siRNA. F2 treatment attenuated H/R-induced Egr-1 expression, ROS generation and other forms of oxidative stress injury such as MDA, and prevented H/R-induced decreases in FOXO1 and Mn-SOD activity. Nuclear co-localization between Egr-1 and SIRT1 was increased by H/R and decreased by either Egr-1 siRNA or F2. Therefore, our results suggest that Egr-1 inhibits the SIRT1/FOXO1/Mn-SOD antioxidant signaling pathway to increase ROS and perpetuate I/R injury. F2 inhibits induction of Egr-1 by H/R, thereby activating SIRT1/FOXO1/Mn-SOD antioxidant signaling and decreasing H/R-induced ROS, demonstrating an important mechanism by which F2 protects against myocardial H/R injury. PMID- 29422864 TI - Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models. AB - Objectives: Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but nevertheless 30% of patients experience MTX inefficacy. Our aim was to develop a clinical pharmacogenetic model to predict which RA patients will not respond to MTX monotherapy. We also assessed whether this model can be generalized to other populations by validating it on a group of Serbian RA patients. Methods: In 110 RA Slovenian patients, data on clinical factors and 34 polymorphisms in MTX pathway were analyzed by Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression to select variables associated with the disease activity as measured by Disease Activity Score (DAS28) score after 6 months of MTX monotherapy. A clinical pharmacogenetic index was constructed from penalized regression coefficients with absolute value above 0.05. This index was cross-validated and also independently validated on 133 Serbian RA patients. Results: A clinical pharmacogenetic index for prediction of DAS28 after 6 months of MTX monotherapy in Slovenian RA patients consisted of DAS28 score at diagnosis, presence of erosions, MTX dose, Solute Carrier Family 19 Member 1 (SLC19A1) rs1051266, Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) rs2306283, Thymidylate Synthase (TYMS), and Adenosine Monophosphate Deaminase 1 (AMPD1) rs17602729. It correctly classified 69% of Slovenian patients as responders or nonresponders and explained 30% of variability in DAS28 after 6 months of MTX monotherapy. Testing for validity in another population showed that it classified correctly only 22.5% of Serbian RA patients. Conclusions: We developed a clinical pharmacogenetic model for DAS28 after 6 months of MTX monotherapy in Slovenian RA patients by combining clinical and genetic variables. The clinical pharmacogenetic index developed for Slovenian patients did not perform well on Serbian patients, presumably due to the differences in patients' characteristics and clinical management between the two groups. PMID- 29422865 TI - Dietary Safety Assessment of Flk1-Transgenic Fish. AB - Genetic engineering, also called genetic modification, is facing with growing demands of aquaculture and aquatic products. Although various genetically modified (GM) aquatics have been generated, it is important to evaluate biosafety of GM organisms on the human health before entering into our food chain. For this purpose, we establish a zebrafish wild adult feeding Flk1-transgenic larvae model to examine the predatory fish's histology in multiple tissues, and the global gene expression profile in the liver. 180 days of feeding trial show that there are no significantly morphological changes in intestine, liver, kidney, and sex gonads between fish fed with Flk1 transgenic fish diet (TFD) and fish fed with regular food meal (RFM). However, a characteristic skin spot and autofluorescence increase in the theca of follicle are observed in F1 generation of TFD fish. Liver RNA-sequencing analyses demonstrate that 53 out of 56712 genes or isoforms are differentially transcribed, and mostly involved in proteolysis in extracellular region. According to GO enrichment terms these deregulated genes function in catalytic activity, steroid storing, lipid metabolic process and N Glycan biosynthesis. These results suggest that a long term of Flk1-transgenic fish diet could alter certain metabolic pathways and possibly cause related tissue deformation. Compared to the previous reports, our feasible transgenic dietary assess system could evaluate subchronic and potential health impact of transgenic fish diet by combining multi-tissue histology and liver transcriptome analyses. PMID- 29422866 TI - The Balance of [Formula: see text] Secretion vs. Reabsorption in the Endometrial Epithelium Regulates Uterine Fluid pH. AB - Uterine fluid contains a high concentration of [Formula: see text] which plays an essential role in sperm capacitation and fertilization. In addition, the [Formula: see text] concentration in uterine fluid changes periodically during the estrous cycle. It is well-known that the endometrial epithelium contains machineries involving the apical SLC26 family anion exchangers for secreting [Formula: see text] into the uterine fluid. In the present study, we find for the first time that the electroneutral Na+/[Formula: see text] cotransporter NBCn1 is expressed at the apical membrane of the endometrial epithelium. The protein abundance of the apical NBCn1 and that of the apical SLC26A4 and SLC26A6 are reciprocally regulated during the estrous cycle in the uterus. NBCn1 is most abundant at diestrus, whereas SLC26A4/A6 are most abundant at proestrus/estrus. In the ovariectomized mice, the expression of uterine NBCn1 is inhibited by beta estradiol, but stimulated by progesterone, whereas that of uterine SLC26A4/A6 is stimulated by beta-estradiol. In vivo perfusion studies show that the endometrial epithelium is capable of both secreting and reabsorbing [Formula: see text]. Moreover, the activity for [Formula: see text] secretion by the endometrial epithelium is significantly higher at estrus than it is at diestrus. The opposite is true for [Formula: see text] reabsorption. We conclude that the endometrial epithelium simultaneously contains the activity for [Formula: see text] secretion involving the apical SLC26A4/A6 and the activity for [Formula: see text] reabsorption involving the apical NBCn1, and that the acid-base homeostasis in the uterine fluid is regulated by the finely-tuned balance of the two activities. PMID- 29422867 TI - Actin Cytoskeleton Affects Schwann Cell Migration and Peripheral Nerve Regeneration. AB - Actin cytoskeleton regulates many essential biological functions, including cellular development, shape, polarity, and motility. The organization of actin cytoskeleton has also been associated with numerous physiological and pathological conditions, for instance, the elongation of axonal growth cone during peripheral nerve regeneration. However, the spatio-temporal expression patterns of actin cytoskeleton-related genes and the specific roles of actin cytoskeleton following peripheral nerve injury have not been fully revealed. To address this question, we made rat sciatic nerve crush surgery, collected injured sciatic nerve stumps, analyzed RNA deep sequencing outcomes, and specifically studied two significantly involved canonical pathways that were related with actin, actin cytoskeleton signaling and regulation of actin-based motility by Rho. By using bioinformatic tools and qRT-PCR, We identified and validated differentially expressed genes in these two signaling pathways. Moreover, by applying actin polymerization inhibitor cytochalasin D to sciatic nerve crushed rats, we studied the in vivo effect of cytochalasin D and demonstrated that inhibiting actin polymerization would delay the migration of Schwann cells and hinder the repair and regeneration of injured peripheral nerves. Overall, our data revealed the changes of actin cytoskeleton-related genes following peripheral nerve injury and stated the importance of actin cytoskeleton during peripheral nerve regeneration. PMID- 29422868 TI - Relationship between Aortic Compliance and Impact of Cerebral Blood Flow Fluctuation to Dynamic Orthostatic Challenge in Endurance Athletes. AB - Aorta effectively buffers cardiac pulsatile fluctuation generated from the left ventricular (LV) which could be a mechanical force to high blood flow and low resistance end-organs such as the brain. A dynamic orthostatic challenge may evoke substantial cardiac pulsatile fluctuation via the transient increases in venous return and stroke volume (SV). Particularly, this response may be greater in endurance-trained athletes (ET) who exhibit LV eccentric remodeling. The aim of this study was to determine the contribution of aortic compliance to the response of cerebral blood flow fluctuation to dynamic orthostatic challenge in ET and age-matched sedentary (SED) young healthy men. ET (n = 10) and SED (n = 10) underwent lower body negative pressure (LBNP) (-30 mmHg for 4 min) stimulation and release the pressure that initiates a rapid regain of limited venous return and consequent increase in SV. The recovery responses of central and middle cerebral arterial (MCA) hemodynamics from the release of LBNP (~15 s) were evaluated. SV (via Modeflow method) and pulsatile and systolic MCA (via transcranial Doppler) normalized by mean MCA velocity (MCAv) significantly increased after the cessation of LBNP in both groups. ET exhibited the higher ratio of SV to aortic pulse pressure (SV/AoPP), an index of aortic compliance, at the baseline compared with SED (P < 0.01). Following the LBNP release, SV was significantly increased in SED by 14 +/- 7% (mean +/- SD) and more in ET by 30 +/ 15%; nevertheless, normalized pulsatile, systolic, and diastolic MCAv remained constant in both groups. These results might be attributed to the concomitant with the increase in aortic compliance assessed by SV/AoPP. Importantly, the increase in SV/AoPP following the LBNP release was greater in ET than in SED (P < 0.01), and significantly correlated with the baseline SV/AoPP (r = 0.636, P < 0.01). These results suggest that the aortic compliance in the endurance athletes is able to accommodate the additional SV and buffer the potential increase in pulsatility at end-organs such as the brain. PMID- 29422869 TI - The Effect of Bed Rest and Hypoxic Environment on Postural Balance and Trunk Automatic (Re)Actions in Young Healthy Males. AB - Prolonged inactivity, such as bed rest induces several detrimental changes within a short timeframe. Impaired postural balance and responses of trunk muscles to (un)expected perturbations were both shown to be impaired after bed rest. Certain populations (e.g., astronauts) are exposed to hypoxic environment in addition to inactivity, similar to bed rest. While the isolated negative effects of hypoxia on postural balance have been observed before, no study to date has examined the combined effects of hypoxia and bed rest on postural balance or trunk muscle responses. In this study, we examined the effects of 21-day exposure to three conditions: (i) bed rest in hypoxic environment (HBR), (ii) bed rest in normoxic environment (NBR), and (iii) ambulatory hypoxic environment (HAMB). Fourteen healthy male subjects crossed over between conditions in a randomized order, with a 4-month break between conditions to ensure full recovery. Most body sway parameters indicated a similar deterioration of postural balance following both HBR and NBR. Similarly, both anticipatory and reactive responses of the trunk muscles (m. erector spinae and m. multifidus) were impaired after HBR and NBR to a similar degree and mostly unchanged after HAMB. Certain body sway parameters were impaired after HAMB, confirming that hypoxia alone can undermine postural balance. On the other hand, some trunk responses were improved after HAMB. In conclusion, the results of our study confirmed previous findings on negative effects of bed rest, but showed little or no additional effect of hypoxia during bed rest. Physical activity during bed rest is encouraged to preserve neuromuscular functions of the trunk. While the HBR condition in our study resembled conditions during space missions, our results could be relevant to other populations, such as patients with pulmonary diseases exposed to bed rest. PMID- 29422870 TI - Patients with Chronic Obstructive Pulmonary Disease Suffer from Worse Periodontal Health-Evidence from a Meta-Analysis. AB - Background and Objective: It is widely accepted that there is an association between chronic obstructive pulmonary disease (COPD) and periodontitis. However, whether the periodontal status of the COPD patients is worse than that of the non COPD subjects is seldom assessed. The findings currently available are inconsistent, some even contradictory. Therefore, we performed this meta-analysis to compare the periodontal health status of COPD patients and non-COPD subjects. Methods: PubMed and Embase were searched for all of the eligible studies which comparing the periodontal status between COPD patients and non-COPD subjects. The results of periodontal parameters in each study were extracted and the mean differences and 95% confidence intervals (CIs) for each parameter were calculated to determine their overall effects. Results: In total, 14 studies involving 3348 COPD patients and 20612 non-COPD controls were included and 9 periodontal indexes were analyzed. The mean differences (95% CIs) between COPD and non-COPD subjects for probing depth, clinical attachment loss, level of alveolar bone loss, plaque index, oral hygiene index, bleeding index, bleeding on probing, gingival index, and remaining teeth were 0.261 (0.020-0.501), 0.480 (0.280-0.681), 0.127 (0.000 0.254), 0.226 (0.043-0.408), 0.802 (0.326-1.279), 0.241 (-0.106 to 0.588), 6.878 (5.489-8.266), 0.364 (0.036-0.692), and -3.726 (-5.120 to -2.331), respectively. Conclusion: In summary, this meta-analysis demonstrates that the COPD patients suffer from worse periodontal health status, indicated by deeper periodontal pockets, high level of clinical attachment loss, worse oral hygiene, more inflammation and bleeding in the gingival tissue, and lower number of remaining teeth. Nevertheless, considering the limitations in our meta-analysis, more high quality, and well-designed studies focusing on the periodontal health of the COPD patients are required to validate our conclusion. PMID- 29422871 TI - Age-Related Vascular Changes Affect Turbulence in Aortic Blood Flow. AB - Turbulent blood flow is implicated in the pathogenesis of several aortic diseases but the extent and degree of turbulent blood flow in the normal aorta is unknown. We aimed to quantify the extent and degree of turbulece in the normal aorta and to assess whether age impacts the degree of turbulence. 22 young normal males (23.7 +/- 3.0 y.o.) and 20 old normal males (70.9 +/- 3.5 y.o.) were examined using four dimensional flow magnetic resonance imaging (4D Flow MRI) to quantify the turbulent kinetic energy (TKE), a measure of the intensity of turbulence, in the aorta. All healthy subjects developed turbulent flow in the aorta, with total TKE of 3-19 mJ. The overall degree of turbulence in the entire aorta was similar between the groups, although the old subjects had about 73% more total TKE in the ascending aorta compared to the young subjects (young = 3.7 +/- 1.8 mJ, old = 6.4 +/- 2.4 mJ, p < 0.001). This increase in ascending aorta TKE in old subjects was associated with age-related dilation of the ascending aorta which increases the volume available for turbulence development. Conversely, age-related dilation of the descending and abdominal aorta decreased the average flow velocity and suppressed the development of turbulence. In conclusion, turbulent blood flow develops in the aorta of normal subjects and is impacted by age-related geometric changes. Non-invasive assessment enables the determination of normal levels of turbulent flow in the aorta which is a prerequisite for understanding the role of turbulence in the pathophysiology of cardiovascular disease. PMID- 29422872 TI - Myocardial CKIP-1 Overexpression Protects from Simulated Microgravity-Induced Cardiac Remodeling. AB - Human cardiovascular system has adapted to Earth's gravity of 1G. The microgravity during space flight can induce cardiac remodeling and decline of cardiac function. At present, the mechanism of cardiac remodeling induced by microgravity remains to be disclosed. Casein kinase-2 interacting protein-1 (CKIP 1) is an important inhibitor of pressure-overload induced cardiac remodeling by decreasing the phosphorylation level of HDAC4. However, the role of CKIP-1 in the cardiac remodeling induced by microgravity is unknown. The purpose of this study was to determine whether CKIP-1 was also involved in the regulation of cardiac remodeling induced by microgravity. We first detected the expression of CKIP-1 in the heart from mice and monkey after simulated microgravity using Q-PCR and western blotting. Then, myocardial specific CKIP-1 transgenic (TG) and wild type mice were hindlimb-suspended (HU) to simulate microgravity effect. We estimated the cardiac remodeling in morphology and function by histological analysis and echocardiography. Finally, we detected the phosphorylation of AMPK, ERK1/2, and HDAC4 in the heart from wild type and CKIP-1 transgenic mice after HU. The results revealed the reduced expression of CKIP-1 in the heart both from mice and monkey after simulated microgravity. Myocardial CKIP-1 overexpression protected from simulated microgravity-induced decline of cardiac function and loss of left ventricular mass. Histological analysis demonstrated CKIP-1 TG inhibited the decreases in the size of individual cardiomyocytes of mice after hindlimb unloading. CKIP-1 TG can inhibit the activation of HDAC4 and ERK1/2 and the inactivation of AMPK in heart of mice induced by simulated microgravity. These results demonstrated CKIP-1 was a suppressor of cardiac remodeling induced by simulated microgravity. PMID- 29422873 TI - Neurofeedback Training for Psychiatric Disorders Associated with Criminal Offending: A Review. AB - Background: Effective treatment interventions for criminal offenders are necessary to reduce risk of criminal recidivism. Evidence about deviant electroencephalographic (EEG)-frequencies underlying disorders found in criminal offenders is accumulating. Yet, treatment modalities, such as neurofeedback, are rarely applied in the forensic psychiatric domain. Since offenders usually have multiple disorders, difficulties adhering to long-term treatment modalities, and are highly vulnerable for psychiatric decompensation, more information about neurofeedback training protocols, number of sessions, and expected symptom reduction is necessary before it can be successfully used in offender populations. Method: Studies were analyzed that used neurofeedback in adult criminal offenders, and in disorders these patients present with. Specifically aggression, violence, recidivism, offending, psychopathy, schizophrenia, attention-deficit hyperactivity disorder (ADHD), substance-use disorder (SUD), and cluster B personality disorders were included. Only studies that reported changes in EEG-frequencies posttreatment (increase/decrease/no change in EEG amplitude/power) were included. Results: Databases Psychinfo and Pubmed were searched in the period 1990-2017 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, resulting in a total of 10 studies. Studies in which neurofeedback was applied in ADHD (N = 3), SUD (N = 3), schizophrenia (N = 3), and psychopathy (N = 1) could be identified. No studies could be identified for neurofeedback applied in cluster B personality disorders, aggression, violence, or recidivism in criminal offenders. For all treatment populations and neurofeedback protocols, number of sessions varied greatly. Changes in behavioral levels ranged from no improvements to significant symptom reduction after neurofeedback training. The results are also mixed concerning posttreatment changes in targeted EEG-frequency bands. Only three studies established criteria for EEG-learning. Conclusion: Implications of the results for the applicability of neurofeedback training in criminal offender populations are discussed. More research focusing on neurofeedback and learning of cortical activity regulation is needed in populations with externalizing behaviors associated with violence and criminal behavior, as well as multiple comorbidities. At this point, it is unclear whether standard neurofeedback training protocols can be applied in offender populations, or whether QEEG-guided neurofeedback is a better choice. Given the special context in which the studies are executed, clinical trials, as well as single-case experimental designs, might be more feasible than large double-blind randomized controls. PMID- 29422874 TI - Temporal Features of the Differentiation between Self-Name and Religious Leader Name among Christians: An ERP Study. AB - Existing neuroimaging studies have shown that religion, as a subjective culture, can influence self-referential processing. However, the time course of this impact remains unclear. The present study examined how Christians process their own names, the name of their religious leader (i.e., Jesus), and a famous person's name (i.e., Yao Ming). Behavioral and EEG data were recorded while the participants performed a name-color judgment task for these three names. The behavioral data showed no significant differences in reaction time or accuracy among the names. However, the ERP data showed that the P200 and P300 amplitudes elicited by the self-name and religious leader name were larger than those elicited by the famous name. Furthermore, the self-name also elicited a larger P300 amplitude than the religious leader name did. These results suggested that both the self-name and the religious leader name were processed preferentially due to their important social value for the self as compared to a generally famous name. Importantly, the dissociation between the self-name and the religious leader name was observed at a high-order cognitive stage, which might be attributed to their different roles in one's self-concept. PMID- 29422875 TI - Delay of Gratification, Delay Discounting and their Associations with Age, Episodic Future Thinking, and Future Time Perspective. AB - The delay of gratification (DoG) in children is widely investigated with an experimental procedure originally called the "marshmallow test," whereas the studies on self-regulation (SR) in adolescents and adults usually use self-report questionnaires. Delay discounting (DD) measures simplify the DoG procedure and focus on monetary rewards. The aim of this study was to investigate age differences in DoG and DD from childhood to old age using a test that is suitable for both children and adults. Furthermore, investigations were conducted on the association between DoG/DD and two future orientation constructs [future time perspective (FTP) and episodic future thinking (EFT)] as well as age differences in these constructs. Participants from five age groups (9-14, 18-25, 35-55, 65 80, 80+) participated in the study (N = 96). While we found no age difference for DoG, DD was the lowest [i.e., self-control (SC) was the highest] in young/middle adults; however, it was the highest (i.e., SC was the lowest) in children and old/oldest adults. Furthermore, we found significant age differences for DD and FTP. As predicted, there were strong correlations between DoG and FTP and between DD and FTP, but not between DoG/DD and EFT. These results indicate that age differences in SR vary across the measures used. Individuals who generally think and act in a future-oriented manner have a stronger ability to delay gratification. PMID- 29422876 TI - Editorial: Twenty Years After the Iowa Gambling Task: Rationality, Emotion, and Decision-Making. PMID- 29422878 TI - "It's Your Problem. Deal with It." Performers' Experiences of Psychological Challenges in Music. AB - Musicians need to deal with a range of challenges during their performance career and in response to these have reported a number of conditions that impact on their performance. Although social support from peers and teachers has been identified as part of the process of dealing with these challenges, little is understood about musicians' coping methods, beliefs and their attitudes toward support. Therefore, this study aimed to explore (a) performers' previous experiences of psychological challenges, (b) the types of support they used and, (c) how this might inform future support programs in learning environments. Fifteen interviews were conducted with pre-elite (n = 5) transitioning elite (n = 3) and established elite performers (n = 7) in order to elicit data on psychological challenges, coping, beliefs and preferences for support. Inductive content analysis suggested that elite performers in this sample reported positive health habits, philosophical views of performance, health and life, positive anxiety reappraisal, and use of various psychological strategies, albeit without being explicitly aware of it. The need for various professional skills (e.g., communication, business, self-management, and organizational skills) was emphasized by all participants. Transition into conservatoire was marked by severe psychological challenges, disorders and trauma. Primary sources of support included friends, family and self-help literature. Professional help was predominantly sought for physical problems. The impact of teachers was paramount, yet securing good teachers was considered a matter of "luck." The most negative aspects recounted included abusive teachers, unsupportive environments, social comparison, competition, and disillusionment after entering the profession. Participants believed that talent could be developed and also valued wellbeing in relation to performance. Positive effects of late specialization on social development and professional skills were also mentioned. Implications and suggestions are discussed. PMID- 29422877 TI - Association between Children's Physical Activity and Parental Practices Enhancing Children's Physical Activity: The Moderating Effects of Children's BMI z-Score. AB - Objective: Parental practices that aim at increasing children's physical activity were found to be related to children's physical activity. So far, however, the association between these two sets of variables was studied without considering the moderating role of children's BMI z-score, which may determine the effectiveness of parental practices. The present study aims at filling this void. Design: Longitudinal data were collected among 879 dyads of children (6-11 years old) and their parents. Seven parental physical activity practices were assessed at baseline. Physical activity, body mass, and height (measured among children) were assessed twice (at baseline and 7-month follow-up). Body mass and height were measured objectively. Seven moderation analyses were conducted. Results: Six parental practices emerged to predict physical activity of children: collaborative social control, overall support, stimulation to be active, general encouragement for physical activity, positive social control, and modeling. Children's BMI z-score moderated three associations. The relationships between parental positive social control, overall parental support, and general parental encouragement for physical activity (at baseline), and children's physical activity (at follow-up) were significant only among children with low and medium BMI z-score. In turn, collaborative social control and modeling predicted children's physical activity at the follow-up regardless child's BMI z-score. Conclusions: Parental positive social control or overall parental support may be ineffective in children with higher body mass who are in need to increase their physical activity. PMID- 29422879 TI - Relating to the Speaker behind the Voice: What Is Changing? AB - We introduce therapeutic techniques that encourage voice hearers to view their voices as coming from intentional agents whose behavior may be dependent on how the voice hearer relates to and interacts with them. We suggest that this approach is effective because the communicative aspect of voice hearing might fruitfully be seen as explanatorily primitive, meaning that the agentive aspect, the auditory properties, and the intended meaning (interpretation) are all necessary parts of the experience, which contribute to the impact the experience has on the voice hearer. We examine the experiences of a patient who received Relating Therapy, and explore the kinds of changes that can result from this therapeutic approach. PMID- 29422880 TI - The View from the Trees: Nocturnal Bull Ants, Myrmecia midas, Use the Surrounding Panorama While Descending from Trees. AB - Solitary foraging ants commonly use visual cues from their environment for navigation. Foragers are known to store visual scenes from the surrounding panorama for later guidance to known resources and to return successfully back to the nest. Several ant species travel not only on the ground, but also climb trees to locate resources. The navigational information that guides animals back home during their descent, while their body is perpendicular to the ground, is largely unknown. Here, we investigate in a nocturnal ant, Myrmecia midas, whether foragers travelling down a tree use visual information to return home. These ants establish nests at the base of a tree on which they forage and in addition, they also forage on nearby trees. We collected foragers and placed them on the trunk of the nest tree or a foraging tree in multiple compass directions. Regardless of the displacement location, upon release ants immediately moved to the side of the trunk facing the nest during their descent. When ants were released on non foraging trees near the nest, displaced foragers again travelled around the tree to the side facing the nest. All the displaced foragers reached the correct side of the tree well before reaching the ground. However, when the terrestrial cues around the tree were blocked, foragers were unable to orient correctly, suggesting that the surrounding panorama is critical to successful orientation on the tree. Through analysis of panoramic pictures, we show that views acquired at the base of the foraging tree nest can provide reliable nest-ward orientation up to 1.75 m above the ground. We discuss, how animals descending from trees compare their current scene to a memorised scene and report on the similarities in visually guided behaviour while navigating on the ground and descending from trees. PMID- 29422881 TI - Encouragement-Induced Real-World Upper Limb Use after Stroke by a Tracking and Feedback Device: A Study Protocol for a Multi-Center, Assessor-Blinded, Randomized Controlled Trial. AB - Introduction: Retraining the paretic upper limb after stroke should be intense and specific to be effective. Hence, the best training is daily life use, which is often limited by motivation and effort. Tracking and feedback technology have the potential to encourage self-administered, context-specific training of upper limb use in the patients' home environment. The aim of this study is to investigate post-intervention and long-term effects of a wrist-worn activity tracking device providing multimodal feedback on daily arm use in hemiparetic subjects beyond 3 months post-stroke. Methods and analysis: A prospective, multi center, assessor-blinded, Phase 2 randomized controlled trial with a superiority framework. Sixty-two stroke patients will be randomized in two groups with a 1:1 allocation ratio, stratified based on arm paresis severity (Fugl-Meyer Assessment Upper Extremity subscale <32 and >=32). The experimental group receives a wrist worn activity tracking device providing multimodal feedback on daily arm use for 6 weeks. Controls wear an identical device providing no feedback. Sample size: 31 participants per group, based on a difference of 0.75+/-1.00 points on the Motor Activity Log-14 Item Version, Amount of Use subscale (MAL-14 AOU), 80% power, two sided alpha of 0.05, and a 10% attrition rate. Outcomes: primary outcome is the change in patient-reported amount of daily life upper limb use (MAL-14 AOU) from baseline to post-intervention. Secondary outcomes are change in upper limb motor function, upper limb capacity, global disability, patient-reported quality of daily life upper limb use, and quality of life from baseline to post-intervention and 6-week follow-up, as well as compliance, activity counts, and safety. Discussion: The results of this study will show the possible efficacy of a wrist worn tracking and feedback device on patient-reported amount of daily life upper limb use. Ethics and dissemination: The study is approved by the Cantonal Ethics Committees Zurich, and Northwest and Central Switzerland (BASEC-number 2017 00948) and registered in https://clinicaltrials.gov (NCT03294187) before recruitment started. This study will be carried out in compliance with the Declaration of Helsinki, ICH-GCP, ISO 14155:2011, and Swiss legal and regulatory requirements. Dissemination will include submission to a peer-reviewed journal, patient and healthcare professional magazines, and congress presentations. PMID- 29422883 TI - Detecting Cortical Spreading Depolarization with Full Band Scalp Electroencephalography: An Illusion? AB - Introduction: There is strong evidence suggesting detrimental effects of cortical spreading depolarization (CSD) in patients with acute ischemic stroke and severe traumatic brain injury. Previous studies implicated scalp electroencephalography (EEG) features to be correlates of CSD based on retrospective analysis of EEG epochs after having detected "CSD" in time aligned electrocorticography. We studied the feasibility of CSD detection in a prospective cohort study with continuous EEG in 18 patients with acute ischemic stroke and 18 with acute severe traumatic brain injury. Methods: Full band EEG with 21 silver/silver chloride electrodes was started within 48 h since symptom onset. Five additional electrodes were used above the infarct. We visually analyzed all raw EEG data in epochs of 1 h. Inspection was directed at detection of the typical combination of CSD characteristics, i.e., (i) a large slow potential change (SPC) accompanied by a simultaneous amplitude depression of >1Hz activity, (ii) focal presentation, and (iii) spread reflected as appearance on neighboring electrodes with a delay. Results: In 3,035 one-hour EEG epochs, infraslow activity (ISA) was present in half to three quarters of the registration time. Typically, activity was intermittent with amplitudes of 40-220 uV, approximately half was oscillatory. There was no specific spatial distribution. Relevant changes of ISA were always visible in multiple electrodes, and not focal, as expected in CSD. ISA appearing as "SPC" was mostly associated with an amplitude increase of faster activities, and never with suppression. In all patients, depressions of spontaneous brain activity occurred. However, these were not accompanied by simultaneous SPC, occurred simultaneously on all channels, and were not focal, let alone spread, as expected in CSD. Conclusion: With full band scalp EEG in patients with cortical ischemic stroke or traumatic brain injury, we observed various ISA, probably modulating cortical excitability. However, we were unable to identify unambiguous characteristics of CSD. PMID- 29422882 TI - Disrupted Brain Intrinsic Networks and Executive Dysfunction in Cirrhotic Patients without Overt Hepatic Encephalopathy. AB - Objective: Patients with cirrhosis often exhibit cognitive deficits, particularly executive dysfunction, which is considered a predictor of overt hepatic encephalopathy (OHE). We examined brain intrinsic networks associated with executive function to investigate the neural basis of this cognitive deficiency in cirrhosis. Methods: Resting-state functional MRI data were acquired from 20 cirrhotic patients and 18 healthy controls. Seed-based correlation analysis was used to identify the three well-known networks associated with executive function, including executive control (ECN), default mode (DMN), and salience (SN) networks. Functional connectivity (FC) within each network was compared between groups and correlated with patient executive performance (assessed by the Stroop task). Results: Patients showed decreased FC between the ECN seed (right dorsolateral prefrontal cortex) and several regions (including right middle/inferior frontal gyrus, left inferior frontal gyrus, bilateral inferior/superior parietal lobules, bilateral middle/inferior temporal gyrus, and right medial frontal gyrus), between the DMN seed [posterior cingulate cortex (PCC)] and several regions (including bilateral medial frontal gyrus, bilateral anterior cingulate cortex, bilateral superior frontal gyrus, bilateral precuneus/PCC, left supramarginal gyrus, and left middle temporal gyrus), and between the SN seed (right anterior insula) and right supramarginal gyrus. FC strength in the ECN and SN was negatively correlated with patient performance during the Stroop task. Conclusion: Disrupted functional integration in the core brain cognitive networks, which is reflected by reductions in FC, occurs before OHE bouts and may play an important role in the neural mechanism of executive dysfunction associated with cirrhosis. PMID- 29422884 TI - Redox Sensing within the Genus Shewanella. AB - A novel bacterial behavior called congregation was recently described in Shewanella oneidensis MR-1 as the accumulation of cells around insoluble electron acceptors (IEA). It is the result of a series of "run-and-reversal" events enabled by modulation of swimming speed and direction. The model proposed that the swimming cells constantly sense their surroundings with specialized outer membrane cytochromes capable of extracellular electron transport (EET). Up to this point, neither the congregation nor attachment behavior have been studied in any other strains. In this study, the wild type of S. oneidensis MR-1 and several deletion mutants as well as eight other Shewanella strains (Shewanella putrefaciens CN32, S. sp. ANA-3, S. sp. W3-18-1, Shewanella amazonensis SB2B, Shewanella loihica PV-4, Shewanella denitrificans OS217, Shewanella baltica OS155, and Shewanella frigidimarina NCIMB400) were screened for the ability to congregate. To monitor congregation and attachment, specialized cell-tracking techniques, as well as a novel cell accumulation after photo-bleaching (CAAP) confocal microscopy technique were utilized in this study. We found a strong correlation between the ability of strain MR-1 to accumulate on mineral surface and the presence of key EET genes such as mtrBC/omcA (SO_1778, SO_1776, and SO_1779) and gene coding for methyl-accepting protein (MCPs) with Ca+ channel chemotaxis receptor (Cache) domain (SO_2240). These EET and taxis genes were previously identified as essential for characteristic run and reversal swimming around IEA surfaces. CN32, ANA-3, and PV-4 congregated around both Fe(OH)3 and MnO2. Two other Shewanella spp. showed preferences for one oxide over the other: preferences that correlated with the metal content of the environments from which the strains were isolated: e.g., W3-18-1, which was isolated from an iron-rich habitat congregated and attached preferentially to Fe(OH)3, while SB2B, which was isolated from a MnO2-rich environment, preferred MnO2. PMID- 29422885 TI - Community Composition and Transcriptional Activity of Ammonia-Oxidizing Prokaryotes of Seagrass Thalassia hemprichii in Coral Reef Ecosystems. AB - Seagrasses in coral reef ecosystems play important ecological roles by enhancing coral reef resilience under ocean acidification. However, seagrass primary productivity is typically constrained by limited nitrogen availability. Ammonia oxidation is an important process conducted by ammonia-oxidizing archaea (AOA) and bacteria (AOB), yet little information is available concerning the community structure and potential activity of seagrass AOA and AOB. Therefore, this study investigated the variations in the abundance, diversity and transcriptional activity of AOA and AOB at the DNA and transcript level from four sample types: the leaf, root, rhizosphere sediment and bulk sediment of seagrass Thalassia hemprichii in three coral reef ecosystems. DNA and complementary DNA (cDNA) were used to prepare clone libraries and DNA and cDNA quantitative PCR (qPCR) assays, targeting the ammonia monooxygenase-subunit (amoA) genes as biomarkers. Our results indicated that the closest relatives of the obtained archaeal and bacterial amoA gene sequences recovered from DNA and cDNA libraries mainly originated from the marine environment. Moreover, all the obtained AOB sequences belong to the Nitrosomonadales cluster. Nearly all the AOA communities exhibited higher diversity than the AOB communities at the DNA level, but the qPCR data demonstrated that the abundances of AOB communities were higher than that of AOA communities based on both DNA and RNA transcripts. Collectively, most of the samples shared greater community composition similarity with samples from the same location rather than sample type. Furthermore, the abundance of archaeal amoA gene in rhizosphere sediments showed significant relationships with the ammonium concentration of sediments and the nitrogen content of plant tissue (leaf and root) at the DNA level (P < 0.05). Conversely, no such relationships were found for the AOB communities. This work provides new insight into the nitrogen cycle, particularly nitrification of seagrass meadows in coral reef ecosystems. PMID- 29422886 TI - Screening Phosphorylation Site Mutations in Yeast Acetyl-CoA Carboxylase Using Malonyl-CoA Sensor to Improve Malonyl-CoA-Derived Product. AB - Malonyl-coenzyme A (malonyl-CoA) is a critical precursor for the biosynthesis of a variety of biochemicals. It is synthesized by the catalysis of acetyl-CoA carboxylase (Acc1p), which was demonstrated to be deactivated by the phosphorylation of Snf1 protein kinase in yeast. In this study, we designed a synthetic malonyl-CoA biosensor and used it to screen phosphorylation site mutations of Acc1p in Saccharomyces cerevisiae. Thirteen phosphorylation sites were mutated, and a combination of three site mutations in Acc1p, S686A, S659A, and S1157A, was found to increase malonyl-CoA availability. ACC1S686AS659AS1157A expression also improved the production of 3-hydroxypropionic acid, a malonyl-CoA derived chemical, compared to both wild type and the previously reported ACC1S659AS1157A mutation. This mutation will also be beneficial for other malonyl CoA-derived products. PMID- 29422888 TI - Klebsiella pneumoniae Carbapenemase Producers in South Korea between 2013 and 2015. AB - Between 2014 and 2015, the Klebsiella pneumoniae carbapenemase (KPC) was becoming endemic in South Korea. To assess this period of transition, we analyzed KPC producers in terms of molecular epidemiology. A total of 362 KPC-producing Enterobacteriaceae strains, including one from 2013, 13 from 2014, and 348 from 2015, were actively collected from 60 hospitals throughout the peninsula. Subtypes of KPC were determined by PCR and direct sequencing, and isotypes of Tn4401 (the transposon flanking the blaKPC gene) were specified by PCR using isotype-specific primers and direct sequencing. Sporadic occurrence of KPC producing Enterobacteriaceae was initially observed around Seoul, which is the most crowded district of the country, and these strains rapidly disseminated in 2014, to the other parts of the country in 2015. The bacterial clones responsible for the extreme epidemiological transition were K. pneumoniae ST307 (46.2%) and ST11 (21.3%). Less frequently, E. coli (4.7%), Enterobacter spp. (1.4%), and other Enterobacteriaceae members (1.7%) producing the enzyme were identified. The blaKPC-2 gene bracketed by Tn4401a (72.1%) was the most prevalent mobile genetic element responsible for the dissemination, and the same gene carried either by Tn4401b (2.2%) or Tn4401c (6.6%) was identified at a lesser frequency. The genes blaKPC-3 (1.6%) and blaKPC-4 (6.4%), both flanked by Tn4401b, were occasionally identified. This study showed endemic dissemination of KPC producers in 2015 due to a clonal spread of two K. pneumoniae strains. Further systemic surveillance is needed to monitor dissemination of KPC-producers. PMID- 29422887 TI - Therapeutic Targeting of the Staphylococcus aureus Accessory Gene Regulator (agr) System. AB - Staphylococcus aureus can cause numerous different diseases, which has been attributed to its large repertoire of virulence factors, many of which are under the control of the accessory gene regulator (agr) quorum sensing system. Under conditions of high cell density, agr increases the production of many virulence factors, decreases expression of several colonization factors, and is intimately associated with the pathogenesis and biofilm formation of S. aureus. This review summarizes our current understanding of the molecular mechanisms underlying agr quorum sensing and the regulation of agr expression. The discussion also examines subgroups of agr and their association with different diseases, and concludes with an analysis of strategies for designing drugs and vaccines that target agr to combat S. aureus infections. PMID- 29422889 TI - Cordycepin, a Characteristic Bioactive Constituent in Cordyceps militaris, Ameliorates Hyperuricemia through URAT1 in Hyperuricemic Mice. AB - Recently, we've reported the anti-hyperuricemic effects of Cordyceps militaris. As a characteristic compound of C. militaris, we hypothesized that cordycepin may play a role in preventing hyperurecimia. Remarkably, cordycepin produced important anti-hyperuricemic actions, decreasing SUA (serum uric acid) to 216, 210, and 203 MUmol/L (P < 0.01) at 15, 30, and 60 mg/kg in comparison of hyperuricemic control (337 MUmol/L), closing to normal control (202 MUmol/L). Elisa, RT-PCR and western blot analysis demonstrated that the actions may be attributed to its downregulation of uric acid transporter 1 (URAT1) in kidney. Serum creatinine levels and blood urine nitrogen and liver, kidney, and spleen coefficients demonstrated that cordycepin may not impact liver, renal, and spleen functions. In addition, we used computational molecular simulation to investigate the binding mechanism of cordycepin. Of which, van der Waals interaction dominated the binding. Residues TRP290, ARG17, ALA408, GLY411, and MET147 contributed mainly on nonpolar energy. This provided the theoretical guidance to rationally design and synthesis novel URAT1 inhibitors. PMID- 29422890 TI - Embelin Restores Carbapenem Efficacy against NDM-1-Positive Pathogens. AB - The emergence and spread of carbapenemase in Gram-negative pathogens poses an enormous threat to global public health. New Delhi metallo-beta-lactamase-1 (NDM 1) inactivates nearly every class of beta-lactam antibiotics, including carbapenem; however, there is no clinically useful NDM-1 inhibitor. Embelin, an important ingredient in traditional herbal medicine, has anti-tumor effects. The current study is the first to discover and examine the inhibitory activity of embelin against beta-lactamase NDM-1. The IC50 of embelin was 2.1 +/- 0.2 MUM when tested against NDM-1 carbapenemase. Most regions of the embelin molecule were buried within NDM-1's active site, and the hydroxyl group of embelin interacted directly with the metal ion Zn2+, as shown by molecular dynamic simulation. Systematic analysis of the antibacterial activities of embelin and antibiotics demonstrated that embelin restored meropenem activity against a panel of NDM-positive pathogens, such as Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Based on these results, embelin could be a promising carbapenem adjuvant candidate against NDM-1-producing bacterial strains. PMID- 29422891 TI - Neuroinflammation: Microglia and T Cells Get Ready to Tango. AB - In recent years, many paradigms concerning central nervous system (CNS) immunology have been challenged and shifted, including the discovery of CNS draining lymphatic vessels, the origin and functional diversity of microglia, the impact of T cells on CNS immunological homeostasis and the role of neuroinflammation in neurodegenerative diseases. In parallel, antigen presentation outside the CNS has revealed the vital role of antigen-presenting cells in maintaining tolerance toward self-proteins, thwarting auto-immunity. Here, we review recent findings that unite these shifted paradigms of microglial functioning, antigen presentation, and CNS-directed T cell activation, focusing on common neurodegenerative diseases. It provides an important update on CNS adaptive immunity, novel targets, and a concept of the microglia T-cell equilibrium. PMID- 29422892 TI - Cathepsin G Is Expressed by Acute Lymphoblastic Leukemia and Is a Potential Immunotherapeutic Target. AB - Cathepsin G (CG) is a myeloid azurophil granule protease that is highly expressed by acute myeloid leukemia (AML) blasts and leukemia stem cells. We previously identified CG1 (FLLPTGAEA), a human leukocyte antigen-A2-restricted nonameric peptide derived from CG, as an immunogenic target in AML. In this report, we aimed to assess the level of CG expression in acute lymphoid leukemia (ALL) and its potential as an immunotherapeutic target in ALL. Using RT-PCR and western blots, we identified CG mRNA and protein, respectively, in B-ALL patient samples and cell lines. We also examined CG expression in a large cohort of 130 patients with ALL via reverse-phase protein array (RPPA). Our data show that CG is widely expressed by ALL and is a poor prognosticator. In addition to endogenous expression, we also provide evidence that CG can be taken up by ALL cells. Finally, we demonstrate that patient ALL can be lysed by CG1-specific cytotoxic T lymphocytes in vitro. Together, these data show high expression of CG by ALL and implicate CG as a target for immunotherapy in ALL. PMID- 29422893 TI - Immunosuppressive Mesenchymal Stromal Cells Derived from Human-Induced Pluripotent Stem Cells Induce Human Regulatory T Cells In Vitro and In Vivo. AB - Despite mesenchymal stromal cells (MSCs) are considered as a promising source of cells to modulate immune functions on cells from innate and adaptive immune systems, their clinical use remains restricted (few number, limited in vitro expansion, absence of a full phenotypic characterization, few insights on their in vivo fate). Standardized MSCs derived in vitro from human-induced pluripotent stem (huIPS) cells, remediating part of these issues, are considered as well as a valuable tool for therapeutic approaches, but their functions remained to be fully characterized. We generated multipotent MSCs derived from huiPS cells (huiPS-MSCs), and focusing on their immunosuppressive activity, we showed that human T-cell activation in coculture with huiPS-MSCs was significantly reduced. We also observed the generation of functional CD4+ FoxP3+ regulatory T (Treg) cells. Further tested in vivo in a model of human T-cell expansion in immune deficient NSG mice, huiPS-MSCs immunosuppressive activity prevented the circulation and the accumulation of activated human T cells. Intracytoplasmic labeling of cytokines produced by the recovered T cells showed reduced percentages of human-differentiated T cells producing Th1 inflammatory cytokines. By contrast, T cells producing IL-10 and FoxP3+-Treg cells, absent in non-treated animals, were detected in huiPS-MSCs treated mice. For the first time, these results highlight the immunosuppressive activity of the huiPS-MSCs on human T cell stimulation with a concomitant generation of human Treg cells in vivo. They may favor the development of new tools and strategies based on the use of huiPS cells and their derivatives for the induction of immune tolerance. PMID- 29422894 TI - The B-Cell Follicle in HIV Infection: Barrier to a Cure. AB - The majority of HIV replication occurs in secondary lymphoid organs (SLOs) such as the spleen, lymph nodes, and gut-associated lymphoid tissue. Within SLOs, HIV RNA+ cells are concentrated in the B-cell follicle during chronic untreated infection, and emerging data suggest that they are a major source of replication in treated disease as well. The concentration of HIV RNA+ cells in the B-cell follicle is mediated by several factors. Follicular CD4+ T-cell subsets including T-follicular helper cells and T-follicular regulatory cells are significantly more permissive to HIV than extrafollicular subsets. The B cell follicle also contains a large reservoir of extracellular HIV virions, which accumulate on the surface of follicular dendritic cells (FDCs) in germinal centers. FDC-bound HIV virions remain infectious even in the presence of neutralizing antibodies and can persist for months or even years. Moreover, the B-cell follicle is semi-immune privileged from CTL control. Frequencies of HIV- and SIV-specific CTL are lower in B-cell follicles compared to extrafollicular regions as the majority of CTL do not express the follicular homing receptor CXCR5. Additionally, CTL in the B-cell follicle may be less functional than extrafollicular CTL as many exhibit the recently described CD8 T follicular regulatory phenotype. Other factors may also contribute to the follicular concentration of HIV RNA+ cells. Notably, the contribution of NK cells and gammadelta T cells to control and/or persistence of HIV RNA+ cells in secondary lymphoid tissue remains poorly characterized. As HIV research moves increasingly toward the development of cure strategies, a greater understanding of the barriers to control of HIV infection in B-cell follicles is critical. Although no strategy has as of yet proven to be effective, a range of novel therapies to address these barriers are currently being investigated including genetically engineered CTL or chimeric antigen receptor T cells that express the follicular homing molecule CXCR5, treatment with IL-15 or an IL-15 superagonist, use of bispecific antibodies to harness the killing power of the follicular CD8+ T cell population, and disruption of the follicle through treatments such as rituximab. PMID- 29422895 TI - Tunneling Nanotubes: Intimate Communication between Myeloid Cells. AB - Tunneling nanotubes (TNT) are dynamic connections between cells, which represent a novel route for cell-to-cell communication. A growing body of evidence points TNT towards a role for intercellular exchanges of signals, molecules, organelles, and pathogens, involving them in a diverse array of functions. TNT form among several cell types, including neuronal cells, epithelial cells, and almost all immune cells. In myeloid cells (e.g., macrophages, dendritic cells, and osteoclasts), intercellular communication via TNT contributes to their differentiation and immune functions. Importantly, TNT enable myeloid cells to communicate with a targeted neighboring or distant cell, as well as with other cell types, therefore creating a complex variety of cellular exchanges. TNT also contribute to pathogen spread as they serve as "corridors" from a cell to another. Herein, we addressed the complexity of the definition and in vitro characterization of TNT in innate immune cells, the different processes involved in their formation, and their relevance in vivo. We also assess our current understanding of how TNT participate in immune surveillance and the spread of pathogens, with a particular interest for HIV-1. Overall, despite recent progress in this growing research field, we highlight that further investigation is needed to better unveil the role of TNT in both physiological and pathological conditions. PMID- 29422897 TI - Fowl Adenovirus Serotype 4 SD0828 Infections Causes High Mortality Rate and Cytokine Levels in Specific Pathogen-Free Chickens Compared to Ducks. AB - Hydropericardium syndrome and inclusion body hepatitis, together called hydropericardium-hepatitis syndrome, are acute infectious diseases found in chickens. These diseases are caused primarily by fowl adenovirus serotype 4 (FAdV 4) strains. In this study, we isolated a FAdV-4 strain (SD0828) from clinically diseased chickens and phylogenetically analyzed the L1 loops of the hexon protein sequences in 3-week-old specific pathogen-free chickens and ducks infected intramuscularly and orally, determining differences in the pathogenicity by observing clinical signs and gross and histological lesions. We also detected the viral load in tissue samples. Postinfection necropsy showed that all chickens but no ducks exhibited typical necropsy lesions. Additionally, all chickens infected intramuscularly died within 2 days postinfection (dpi), and all those infected orally died within 5 dpi, whereas no infected ducks died before 28 dpi. Quantitative real-time polymerase chain reaction analysis was used to determine the viral load in the tissues of hearts, livers, spleens, lungs, and kidneys and in cloacal cotton swabs from infected chickens and ducks at 1, 2, 3, 5, 7, 14, 21, and 28 dpi. The greatest number of viral DNA copies was found in the livers of infected chickens, yet no virus was found in any samples from infected ducks. In addition, the viral load increased over time in both chicken and duck embryo fibroblasts (CEFs and DEFs, respectively); in the former, replication speed was significantly greater than in the latter. Innate immune responses were also studied, both in vivo and in vitro. In CEFs, DEFs, and chickens infected intramuscularly, but not in infected ducks, mRNA expression levels of proinflammatory cytokines (interleukin-6 and -8) and interferon-stimulated genes (Mx and OAS) were significantly upregulated. Although some cytokines showed significant upregulation in the oral chickens, most did not change significantly. Finally, the duck retinoic acid-inducible gene I and its caspase activation and recruitment domain both had significant antiviral functions in CEFs, particularly after 24 h postinfection. Taken together, this research provides new insights into the interactions between FAdV-4 and the innate immune systems of studied hosts (chickens and ducks). PMID- 29422896 TI - Clearance of Apoptotic Cells by Tissue Epithelia: A Putative Role for Hepatocytes in Liver Efferocytosis. AB - Toxic substances and microbial or food-derived antigens continuously challenge the liver, which is tasked with their safe neutralization. This vital organ is also important for the removal of apoptotic immune cells during inflammation and has been previously described as a "graveyard" for dying lymphocytes. The clearance of apoptotic and necrotic cells is known as efferocytosis and is a critical liver function to maintain tissue homeostasis. Much of the research into this form of immunological control has focused on Kupffer cells, the liver resident macrophages. However, hepatocytes (and other liver resident cells) are competent efferocytes and comprise 80% of the liver mass. Little is known regarding the mechanisms of apoptotic and necrotic cell capture by epithelia, which lack key receptors that mediate phagocytosis in macrophages. Herein, we discuss recent developments that increased our understanding of efferocytosis in tissues, with a special focus on the liver parenchyma. We discuss the impact of efferocytosis in health and in inflammation, highlighting the role of phagocytic epithelia. PMID- 29422898 TI - Cyclic AMP Pathway Suppress Autoimmune Neuroinflammation by Inhibiting Functions of Encephalitogenic CD4 T Cells and Enhancing M2 Macrophage Polarization at the Site of Inflammation. AB - Although it has been demonstrated that cAMP pathway affect both adaptive and innate cell functions, the role of this pathway in the regulation of T-cell mediated central nervous system (CNS) autoimmune inflammation, such as in experimental autoimmune encephalomyelitis (EAE), remains unclear. It is also unclear how cAMP pathway affects the function of CD4 T cells in vivo at the site of inflammation. We found that adenylyl cyclase activator Forskolin besides inhibition of functions autoimmune CD4 T cells also upregulated microRNA (miR) 124 in the CNS during EAE, which is associated with M2 phenotype of microglia/macrophages. Our study further established that in addition to direct influence of cAMP pathway on CD4 T cells, stimulation of this pathway promoted macrophage polarization toward M2 leading to indirect inhibition of function of T cells in the CNS. We demonstrated that Forskolin together with IL-4 or with Forskolin together with IL-4 and IFNgamma effectively stimulated M2 phenotype of macrophages indicating high potency of this pathway in reprogramming of macrophage polarization in Th2- and even in Th1/Th2-mixed inflammatory conditions such as EAE. Mechanistically, Forskolin and/or IL-4 activated ERK pathway in macrophages resulting in the upregulation of M2-associated molecules miR-124, arginase (Arg)1, and Mannose receptor C-type 1 (Mrc1), which was reversed by ERK inhibitors. Administration of Forskolin after the onset of EAE substantially upregulated M2 markers Arg1, Mrc1, Fizz1, and Ym1 and inhibited M1 markers nitric oxide synthetase 2 and CD86 in the CNS during EAE resulting in decrease in macrophage/microglia activation, lymphocyte and CD4 T cell infiltration, and the recovery from the disease. Forskolin inhibited proliferation and IFNgamma production by CD4 T cells in the CNS but had rather weak direct effect on proliferation of autoimmune T cells in the periphery and in vitro, suggesting prevalence of indirect effect of Forskolin on differentiation and functions of autoimmune CD4 T cells in vivo. Thus, our data indicate that Forskolin has potency to skew balance toward M2 affecting ERK pathway in macrophages and indirectly inhibit pathogenic CD4 T cells in the CNS leading to the suppression of autoimmune inflammation. These data may have also implications for future therapeutic approaches to inhibit autoimmune Th1 cells at the site of tissue inflammation. PMID- 29422899 TI - Sensing Bacterial-Induced DNA Damaging Effects via Natural Killer Group 2 Member D Immune Receptor: From Dysbiosis to Autoimmunity and Carcinogenesis. AB - The human genome is constantly exposed to exogenous and endogenous DNA damaging factors that frequently cause DNA damages. Unless repaired, damaged DNA can result in deleterious mutations capable of causing malignant transformation. Accordingly, cells have developed an advanced and effective surveillance system, the DNA damage response (DDR) pathway, which maintains genetic integrity. In addition to well-defined outcomes, such as cell cycle arrest, apoptosis, and senescence, another consequence of DDR activation is the induction of natural killer group 2 member D ligands (NKG2D-Ls) on the surface of stressed cells. Consequently, NKG2D-Ls-expressing cells are recognized and eliminated by NKG2D receptor-expressing immune cells, including NK cells, and various subsets of T cells. Recent pieces of evidence indicate that commensal microbial imbalance (known as dysbiosis) can trigger DDR activation in host cells, which may result in sustained inflammatory responses. Therefore, dysbiosis can be seen as an important source of DNA damage agents that may be partially responsible for the overexpression of NKG2D-Ls on intestinal epithelial cells that is frequently observed in patients with inflammatory bowel disease and other disorders associated with altered human microbiota, including the development of colorectal cancer. In this article, we discuss recent evidence that appears to link an altered human microbiota with autoimmunity and carcinogenesis via the activation of DDR signals and the induction of NKG2D-Ls in stressed cells. PMID- 29422900 TI - Role of SLC7A5 in Metabolic Reprogramming of Human Monocyte/Macrophage Immune Responses. AB - Amino acids (AAs) are necessary nutrients which act not only as building blocks in protein synthesis but also in crucial anabolic cellular signaling pathways. It has been demonstrated that SLC7A5 is a critical transporter that mediates uptake of several essential amino acids in highly proliferative tumors and activated T cells. However, the dynamics and relevance of SLC7A5 activity in monocytes/macrophages is still poorly understood. We provide evidence that SLC7A5 mediated leucine influx contributes to pro-inflammatory cytokine production via mTOR complex 1 (mTORC1)-induced glycolytic reprograming in activated human monocytes/macrophages. Moreover, expression of SLC7A5 is significantly elevated in monocytes derived from patients with rheumatoid arthritis (RA), a chronic inflammatory disease, and was also markedly induced by LPS stimulation of both monocytes and macrophages from healthy individuals. Further, pharmacological blockade or silencing of SLC7A5 led to a significant reduction of IL-1beta downstream of leucine-mediated mTORC1 activation. Inhibition of SLC7A5-mediated leucine influx was linked to downregulation of glycolytic metabolism as evidenced by the decreased extracellular acidification rate, suggesting a regulatory role for this molecule in glycolytic reprograming. Furthermore, the expression of SLC7A5 on circulating monocytes from RA patients positively correlated with clinical parameters, suggesting that SLC7A5-mediated AA influx is related to inflammatory conditions. PMID- 29422901 TI - Identification of a Potential Common Ancestor for Mammalian Cross-Presenting Dendritic Cells in Teleost Respiratory Surfaces. AB - Dendritic cells (DCs) are highly specialized antigen-presenting cells that bridge innate and adaptive immune responses in vertebrates, being key modulators in the initiation of specific responses. Although teleost fish present the main elements of a fully developed adaptive immune system, not many studies have focused on identifying specific DC subsets in teleost species. Previous work from our group identified in rainbow trout (Oncorhynchus mykiss) skin a DC subpopulation co expressing CD8alpha and major histocompatibility complex II beta on the cell surface. Interestingly, these CD8+ DCs expressed common unique markers of mammalian cross-presenting DCs, a DC subset with an important role in antigen presentation and activation of CD8+ T cytotoxic lymphocytes. In this study, we have identified a similar DC subset in rainbow trout gills that also transcribes molecules uniquely expressed on diverse mammalian cross-presenting DC populations such as CD8, CD103, CD141, Batf3, IFN regulatory protein 8, and toll-like receptor 3. Hence, we have undertaken a broad phenotypic and functional characterization of this new DC subset that includes the confirmation of novel capacities for DCs in teleost, such an IgM-binding capacity and responsiveness to CD40 ligand. Furthermore, our results show that in gills, this DC subset shows some different phenotypic and functional characteristics when compared with their homologs in the skin, suggesting an adaptation of the cells to different mucosal tissues or different maturation status depending on their location. Our findings contribute to increase our knowledge on fish cross-presenting DCs, an important cell population to take into account for the future design of mucosal vaccination strategies. PMID- 29422902 TI - T Cells Engaging the Conserved MHC Class Ib Molecule Qa-1b with TAP-Independent Peptides Are Semi-Invariant Lymphocytes. AB - The HLA-E homolog in the mouse (Qa-1b) is a conserved MHC class Ib molecule presenting monomorphic peptides to germline-encoded natural killer receptor CD94/NKG2A. Previously, we demonstrated the replacement of this canonical peptide by a diverse peptidome upon deficiency of the TAP peptide transporter. Analysis of this Qa-1b-restricted T cell repertoire against these non-mutated neoantigens revealed characteristics of conventional hypervariable CD8+ T cells, but also of invariant T cell receptor (TCR)alphabeta T cells. A shared TCR Valpha chain was used by this subset in combination with a variety of Vbeta chains. The TCRs target peptide ligands that are conserved between mouse and man, like the identified peptide derived from the transcriptional cofactor Med15. The thymus selection was studied in a TCR-transgenic mouse and emerging naive CD8+ T cells displayed a slightly activated phenotype, as witnessed by higher CD122 and Ly6C expression. Moreover, the Qa-1b protein was dispensable for thymus selection. Importantly, no self-reactivity was observed as reported for other MHC class Ib restricted subsets. Naive Qa-1b restricted T cells expanded, contracted, and formed memory cells in vivo upon peptide vaccination in a similar manner as conventional CD8+ T cells. Based on these data, the Qa-1b restricted T cell subset might be positioned closest to conventional CD8+ T cells of all MHC class Ib populations. PMID- 29422903 TI - Autoantibodies in Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death worldwide, is characterized by irreversible airflow limitation based on obstructive bronchiolitis, emphysema, and chronic pulmonary inflammation. Inhaled toxic gases and particles, e.g., cigarette smoke, are major etiologic factors for COPD, while the pathogenesis of the disease is only partially understood. Over the past decade, an increasing body of evidence has been accumulated for a link between COPD and autoimmunity. Studies with clinical samples have demonstrated that autoantibodies are present in sera of COPD patients and some of these antibodies correlate with specific disease phenotypes. Furthermore, evidence from animal models of COPD has shown that autoimmunity against pulmonary antigens occur during disease development and is capable of mediating COPD-like symptoms. The idea that autoimmunity could contribute to the development of COPD provides a new angle to understand the pathogenesis of the disease. In this review article, we provide an advanced overview in this field and critically discuss the role of autoantibodies in the pathogenesis of COPD. PMID- 29422904 TI - Emerging Role of Immunity in Cerebral Small Vessel Disease. AB - Cerebral small vessel disease (CSVD) is one of the main causes of vascular dementia in older individuals. Apart from risk containment, efforts to prevent or treat CSVD are ineffective due to the unknown pathogenesis of the disease. CSVD, a subtype of stroke, is characterized by recurrent strokes and neurodegeneration. Blood-brain barrier (BBB) impairment, chronic inflammatory responses, and leukocyte infiltration are classical pathological features of CSVD. Understanding how BBB disruption instigates inflammatory and degenerative processes may be informative for CSVD therapy. Antigens derived from the brain are found in the peripheral blood of lacunar stroke patients, and antibodies and sensitized T cells against brain antigens are also detected in patients with leukoaraiosis. These findings suggest that antigen-specific immune responses could occur in CSVD. This review describes the neurovascular unit features of CSVD, the immune responses to specific neuronal and glial processes that may be involved in a distinct mechanism of CSVD, and the current evidence of the association between mechanisms of inflammation and interventions in CSVD. We suggest that autoimmune activity should be assessed in future studies; this knowledge would benefit the development of effective therapeutic interventions in CSVD. PMID- 29422905 TI - Immunomodulatory Properties of Carvone Inhalation and Its Effects on Contextual Fear Memory in Mice. AB - A complex network of interactions exists between the immune, the olfactory, and the central nervous system (CNS). Inhalation of different fragrances can affect immunological reactions in response to an antigen but also may have effects on the CNS and cognitive activity. We performed an exploratory study of the immunomodulatory ability of a series of compounds representing each of the 10 odor categories or clusters described previously. We evaluated the impact of each particular odor on the immune response after immunization with the model antigen ovalbumin in combination with the TLR3 agonist poly I:C. We found that some odors behave as immunostimulatory agents, whereas others might be considered as potential immunosuppressant odors. Interestingly, the immunomodulatory capacity was, in some cases, strain-specific. In particular, one of the fragrances, carvone, was found to be immunostimulatory in BALB/c mice and immunosuppressive in C57BL/6J mice, facilitating or impairing viral clearance, respectively, in a model of a viral infection with a recombinant adenovirus. Importantly, inhalation of the odor improved the memory capacity in BALB/c mice in a fear-conditioning test, while it impaired this same capacity in C57BL/6J mice. The improvement in memory capacity in BALB/c was associated with higher CD3+ T cell infiltration into the hippocampus and increased local expression of mRNA coding for IL-1beta, TNF-alpha, and IL-6 cytokines. In contrast, the memory impairment in C57BL/6 was associated with a reduction in CD3 numbers and an increase in IFN-gamma. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals. These results highlight the potential of studying odors as therapeutic agents for CNS-related diseases. PMID- 29422906 TI - The Complement System in Dialysis: A Forgotten Story? AB - Significant advances have lead to a greater understanding of the role of the complement system within nephrology. The success of the first clinically approved complement inhibitor has created renewed appreciation of complement-targeting therapeutics. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition in renal diseases and kidney transplantation. Although, complement has been known to be activated during dialysis for over four decades, this area of research has been neglected in recent years. Despite significant progress in biocompatibility of hemodialysis (HD) membranes and peritoneal dialysis (PD) fluids, complement activation remains an undesired effect and relevant issue. Short-term effects of complement activation include promoting inflammation and coagulation. In addition, long-term complications of dialysis, such as infection, fibrosis and cardiovascular events, are linked to the complement system. These results suggest that interventions targeting the complement system in dialysis could improve biocompatibility, dialysis efficacy, and long-term outcome. Combined with the clinical availability to safely target complement in patients, the question is not if we should inhibit complement in dialysis, but when and how. The purpose of this review is to summarize previous findings and provide a comprehensive overview of the role of the complement system in both HD and PD. PMID- 29422907 TI - Constitutive Expression of miR408 Improves Biomass and Seed Yield in Arabidopsis. AB - miR408 is highly conserved among different plant species and targets transcripts encoding copper-binding proteins. The function of miR408 in reproductive development remains largely unclear despite it being known to play important roles during vegetative development in Arabidopsis. Here, we show that transgenic Arabidopsis plants overexpressing MIR408 have altered morphology including significantly increased leaf area, petiole length, plant height, flower size, and silique length, resulting in enhanced biomass and seed yield. The increase in plant size was primarily due to cell expansion rather than cell proliferation, and was consistent with higher levels of myosin gene expression and gibberellic acid (GA) measured in transgenic plants. In addition, photosynthetic rate was significantly increased in the MIR408-overexpressing plants, as manifested by higher levels of chloroplastic copper content and plastocyanin (PC) expression. In contrast, overexpression of miR408-regulated targets, Plantacyanin and Laccase 13, resulted in reduced biomass production and seed yield. RNA-sequencing revealed that genes involved in primary metabolism and stress response were preferentially enriched in the genes upregulated in MIR408-overexpressing plants. These results indicate that miR408 plays an important role in regulating biomass and seed yield and that MIR408 may be a potential candidate gene involved in the domestication of agricultural crops. PMID- 29422908 TI - Domestication Origin and Breeding History of the Tea Plant (Camellia sinensis) in China and India Based on Nuclear Microsatellites and cpDNA Sequence Data. AB - Although China and India are the two largest tea-producing countries, the domestication origin and breeding history of the tea plant in these two countries remain unclear. Our previous study suggested that the tea plant includes three distinct lineages (China type tea, Chinese Assam type tea and Indian Assam type tea), which were independently domesticated in China and India, respectively. To determine the origin and historical timeline of tea domestication in these two countries we used a combination of 23 nSSRs (402 samples) and three cpDNA regions (101 samples) to genotype domesticated tea plants and its wild relative. Based on a combination of demographic modeling, NewHybrids and Neighbour joining tree analyses, three independent domestication centers were found. In addition, two origins of Chinese Assam type tea were detected: Southern and Western Yunnan of China. Results from demographic modeling suggested that China type tea and Assam type tea first diverged 22,000 year ago during the last glacial maximum and subsequently split into the Chinese Assam type tea and Indian Assam type tea lineages 2770 year ago, corresponding well with the early record of tea usage in Yunnan, China. Furthermore, we found that the three tea types underwent different breeding histories where hybridization appears to have been the most important approach for tea cultivar breeding and improvements: a high proportion of the hybrid lineages were found to be F2 and BCs. Collectively, our results underscore the necessity for the conservation of Chinese Assam type tea germplasm and landraces as a valuable resource for future tea breeding. PMID- 29422909 TI - Depletion of Arabidopsis ACYL-COA-BINDING PROTEIN3 Affects Fatty Acid Composition in the Phloem. AB - Oxylipins are crucial components in plant wound responses that are mobilised via the plant vasculature. Previous studies have shown that the overexpression of an Arabidopsis acyl-CoA-binding protein, AtACBP3, led to an accumulation of oxylipin containing galactolipids, and AtACBP3pro::BETA-GLUCURONIDASE (GUS) was expressed in the phloem of transgenic Arabidopsis. To investigate the role of AtACBP3 in the phloem, reverse transcription-polymerase chain reaction and western blot analysis of phloem exudates from the acbp3 mutant and wild type revealed that the AtACBP3 protein, but not its mRNA, was detected in the phloem sap. Furthermore, micrografting demonstrated that AtACBP3 expressed from the 35S promoter was translocated from shoot to root. Subsequently, AtACBP3 was localised to the companion cells, sieve elements and the apoplastic space of phloem tissue by immunogold electron microscopy using anti-AtACBP3 antibodies. AtACBP3pro::GUS was induced locally in Arabidopsis leaves upon wounding, and the expression of wound responsive jasmonic acid marker genes (JASMONATE ZIM-DOMAIN10, VEGETATIVE STORAGE PROTEIN2, and LIPOXYGENASE2) increased more significantly in both locally wounded and systemic leaves of the wild type in comparison to acbp3 and AtACBP3-RNAi. Oxylipin-related fatty acid (FA) (C18:2-FA, C18:3-FA and methyl jasmonate) content was observed to be lower in acbp3 and AtACBP3-RNAi than wild-type phloem exudates using gas chromatography-mass spectrometry. Experiments using recombinant AtACBP3 in isothermal titration calorimetry analysis showed that medium- and long-chain acyl-CoA esters bind (His)6-AtACBP3 with KD values in the micromolar range. Taken together, these results suggest that AtACBP3 is likely to be a phloem-mobile protein that affects the FA pool and jasmonate content in the phloem, possibly by its binding to acyl-CoA esters. PMID- 29422910 TI - Population Genetic Structure in Glyphosate-Resistant and -Susceptible Palmer Amaranth (Amaranthus palmeri) Populations Using Genotyping-by-sequencing (GBS). AB - Palmer amaranth (Amaranthus palmeri) is a major weed in United States cotton and soybean production systems. Originally native to the Southwest, the species has spread throughout the country. In 2004 a population of A. palmeri was identified with resistance to glyphosate, a herbicide heavily relied on in modern no-tillage and transgenic glyphosate-resistant (GR) crop systems. This project aims to determine the degree of genetic relatedness among eight different populations of GR and glyphosate-susceptible (GS) A. palmeri from various geographic regions in the United States by analyzing patterns of phylogeography and diversity to ascertain whether resistance evolved independently or spread from outside to an Arizona locality (AZ-R). Shikimic acid accumulation and EPSPS genomic copy assays confirmed resistance or susceptibility. With a set of 1,351 single nucleotide polymorphisms (SNPs), discovered by genotyping-by-sequencing (GBS), UPGMA phylogenetic analysis, principal component analysis, Bayesian model-based clustering, and pairwise comparisons of genetic distances were conducted. A GR population from Tennessee and two GS populations from Georgia and Arizona were identified as genetically distinct while the remaining GS populations from Kansas, Arizona, and Nebraska clustered together with two GR populations from Arizona and Georgia. Within the latter group, AZ-R was most closely related to the GS populations from Kansas and Arizona followed by the GR population from Georgia. GR populations from Georgia and Tennessee were genetically distinct from each other. No isolation by distance was detected and A. palmeri was revealed to be a species with high genetic diversity. The data suggest the following two possible scenarios: either glyphosate resistance was introduced to the Arizona locality from the east, or resistance evolved independently in Arizona. Glyphosate resistance in the Georgia and Tennessee localities most likely evolved separately. Thus, modern farmers need to continue to diversify weed management practices and prevent seed dispersal to mitigate herbicide resistance evolution in A. palmeri. PMID- 29422911 TI - Ecological and Genetic Divergences with Gene Flow of Two Sister Species (Leucomeris decora and Nouelia insignis) Driving by Climatic Transition in Southwest China. AB - Understanding of the processes of divergence and speciation is a major task for biodiversity researches and may offer clearer insight into mechanisms generating biological diversity. Here, we employ an integrative approach to explore genetic and ecological differentiation of Leucomeris decora and Nouelia insignis distributed allopatrically along the two sides of the biogeographic boundary 'Tanaka Line' in Southwest China. We addressed these questions using ten low-copy nuclear genes and nine plastid DNA regions sequenced among individuals sampled from 28 populations across their geographic ranges in China. Phylogenetic, coalescent-based population genetic analyses, approximate Bayesian computation (ABC) framework and ecological niche models (ENMs) were conducted. We identified a closer phylogenetic relationship in maternal lineage of L. decora with N. insignis than that between L. decora and congeneric Leucomeris spectabilis. A deep divergence between the two species was observed and occurred at the boundary between later Pliocene and early Pleistocene. However, the evidence of significant chloroplast DNA gene flow was also detected between the marginal populations of L. decora and N. insignis. Niche models and statistical analyses showed significant ecological differentiation, and two nuclear loci among the ten nuclear genes may be under divergent selection. These integrative results imply that the role of climatic shift from Pliocene to Pleistocene may be the prominent factor for the divergence of L. decora and N. insignis, and population expansion after divergence may have given rise to chloroplast DNA introgression. The divergence was maintained by differential selection despite in the face of gene flow. PMID- 29422912 TI - A New Mechanistic Model for Viral Cross Protection and Superinfection Exclusion. AB - Plants pre-infected with a mild variant of a virus frequently become protected against more severe variants of the same virus through the cross protection phenomenon first discovered in 1929. Despite its widespread use in managing important plant virus diseases, the mechanism of cross protection remains poorly understood. Recent investigations in our labs, by analyzing the whole-plant dynamics of a turnip crinkle virus (TCV) population, coupled with cell biological interrogation of individual TCV variants, revealed possible novel mechanisms for cross protection and the closely related process of superinfection exclusion (SIE). Our new mechanistic model postulates that, for RNA viruses like TCV, SIE manifests a viral function that denies progeny viruses the chance of re replicating their genomes in the cells of their "parents," and it collaterally targets highly homologous superinfecting viruses that are indistinguishable from progeny viruses. We further propose that SIE may be evolutionarily selected to maintain an optimal error frequency in progeny genomes. Although primarily based on observations made with TCV, this new model could be broadly applicable to other viruses as it provides a molecular basis for maintaining virus genome fidelity in the face of the error-prone nature of virus replication process. PMID- 29422914 TI - Empagliflozin Increases Short-Term Urinary Volume Output in Artificially Induced Syndrome of Inappropriate Antidiuresis. AB - Objective: Syndrome of inappropriate antidiuresis (SIADH) is the predominant cause of hyponatremia, but treatment options are unsatisfying. SGLT2 inhibitors increase urinary glucose excretion with concomitant osmotic diuresis. We therefore hypothesized SGLT2-inhibitors as a novel treatment for SIADH. Design: Double-blind placebo-controlled randomised crossover study in 14 healthy volunteers. Methods: We induced an artificial SIADH model by administration of desmopressin and overhydration. Afterwards, empagliflozin 25 mg or placebo was given in random order. The main outcomes were total urinary excretion, glucosuria, and the area under the curve (AUC) of serum sodium concentration. Outcome measures were obtained 2-8 hours after administration of study drug. Results: 14 participants (64% males), BMI 23 kg/m2 (+/-2.4), aged 28.6 years (+/ 9), completed the study. Empagliflozin led to significantly increased total urinary excretion (579.3 ml (+/-194.8) versus 367.3 ml (+/-158.8); treatment effect 158 ml (CI 48.29, 267.74), p = 0.017) due to glucosuria (74.18 mmol (+/ 22.3) versus 0.12 mmol (+/-0.04); treatment effect (log scale) 2.85 (CI 2.75, 2.96), p < 0.001). There was no difference in the AUC of serum sodium concentration (treatment effect 0.2 (CI -7.38, 6.98), p = 0.96). Conclusion: In our SIADH model, empagliflozin increased urinary excretion due to osmotic diuresis. Due to the short treatment duration, serum sodium levels remained unchanged. Real-live studies are needed to further examine empagliflozin as a new treatment for SIADH. PMID- 29422913 TI - Identifying Potential Plasmodium vivax Sporozoite Stage Vaccine Candidates: An Analysis of Genetic Diversity and Natural Selection. AB - Parasite antigen genetic diversity represents a great obstacle when designing a vaccine against malaria caused by Plasmodium vivax. Selecting vaccine candidate antigens has been focused on those fulfilling a role in invasion and which are conserved, thus avoiding specific-allele immune responses. Most antigens described to date belong to the blood stage, thereby blocking parasite development within red blood cells, whilst studying antigens from other stages has been quite restricted. Antigens from different parasite stages are required for developing a completely effective vaccine; thus, pre-erythrocyte stage antigens able to block the first line of infection becoming established should also be taken into account. However, few antigens from this stage have been studied to date. Several P. falciparum sporozoite antigens are involved in invasion. Since 77% of genes are orthologous amongst Plasmodium parasites, P. vivax sporozoite antigen orthologs to those of P. falciparum might be present in its genome. Although these genes might have high genetic diversity, conserved functionally-relevant regions (ideal for vaccine development) could be predicted by comparing genetic diversity patterns and evolutionary rates. This study was thus aimed at searching for putative P. vivax sporozoite genes so as to analyse their genetic diversity for determining their potential as vaccine candidates. Several DNA sequence polymorphism estimators were computed at each locus. The evolutionary force (drift, selection and recombination) drawing the genetic diversity pattern observed was also determined by using tests based on polymorphism frequency spectrum as well as the type of intra- and inter-species substitutions. Likewise, recombination was assessed both indirectly and directly. The results showed that sporozoite genes were more conserved than merozoite genes evaluated to date. Putative domains implied in cell traversal, gliding motility and hepatocyte interaction had a negative selection signal, being conserved amongst different species in the genus. PvP52, PvP36, PvSPATR, PvPLP1, PvMCP1, PvTLP, PvCelTOS, and PvMB2 antigens or functionally restricted regions within them would thus seem promising vaccine candidates and could be used when designing a pre-erythrocyte and/or multi-stage vaccine against P. vivax to avoid allele-specific immune responses that could reduce vaccine efficacy. PMID- 29422915 TI - Epidemiological Features of Clostridium difficile Colonizing the Intestine of Jordanian Infants. AB - Clostridium difficile is commonly found in the intestine of infants without causing any disease. This study investigated the most important epidemiological features of C. difficile strains colonizing intestine of Jordanian infants. A total of 287 fecal samples were collected from infants admitted to the Jordan University Hospital (JUH) over the period of 2015. Samples were cultured for C. difficile and their growth was identified using microbiological culture and PCR. The overall C. difficile colonization rate among hospitalized and nonhospitalized infants was 37/287 (12.9%). Neonates were less colonized than other infants (8.7% verses 19.5%). Colonization of the infants with C. difficile toxigenic strains (TcdA and TcdB) was observed in 54% of the isolates, whereas those colonized with nontoxigenic strains were 46% and only one isolate was positive for binary toxin. Breast feeding of infants is a significant factor associated with decreased colonization with C. difficile. All C. difficile strains were susceptible to vancomycin and metronidazole, while high resistance rate to ciprofloxacin (78.4%) and less resistance rate to erythromycin (29.7%) were detected among the isolates. The results showed that 40.5% of the isolates carried mutated gyrA and gyrB genes which have cross-resistance to ciprofloxacin and moxifloxacin. This study represents useful epidemiological features about C. difficile colonizing intestine of infants living in a developing country. PMID- 29422916 TI - A Particular Use of Endobag(r): Extraction of Rectal Foreign Bodies. AB - Introduction: The incidence of foreign bodies (FBs) in the rectum has recently increased. FB removal by the transanal way or by colonoscopy is generally feasible and only in few cases surgery is strictly necessary. Due to FB dimensions or rectum and colon anatomy, sometimes it may represent a challenge. Materials and Methods: Two cases of FB inserted in the rectum were treated in our institute. They underwent surgery using Endobag, a laparoscopic surgical device. The device was inserted through the anus in order to catch and remove the FB. Results: Both the procedures were easily performed, without any complication. Conclusions: The use of Endobag seems to be a good and effective way to remove FB from rectum. PMID- 29422918 TI - Psychiatry Investigation: 15 Years of Challenges. PMID- 29422917 TI - Neural Differentiation Is Inhibited through HIF1alpha/beta-Catenin Signaling in Embryoid Bodies. AB - Extensive research in the field of stem cells and developmental biology has revealed evidence of the role of hypoxia as an important factor regulating self renewal and differentiation. However, comprehensive information about the exact hypoxia-mediated regulatory mechanism of stem cell fate during early embryonic development is still missing. Using a model of embryoid bodies (EBs) derived from murine embryonic stem cells (ESC), we here tried to encrypt the role of hypoxia inducible factor 1alpha (HIF1alpha) in neural fate during spontaneous differentiation. EBs derived from ESC with the ablated gene for HIF1alpha had abnormally increased neuronal characteristics during differentiation. An increased neural phenotype in Hif1alpha-/- EBs was accompanied by the disruption of beta-catenin signaling together with the increased cytoplasmic degradation of beta-catenin. The knock-in of Hif1alpha, as well as beta-catenin ectopic overexpression in Hif1alpha-/- EBs, induced a reduction in neural markers to the levels observed in wild-type EBs. Interestingly, direct interaction between HIF1alpha and beta-catenin was demonstrated by immunoprecipitation analysis of the nuclear fraction of wild-type EBs. Together, these results emphasize the regulatory role of HIF1alpha in beta-catenin stabilization during spontaneous differentiation, which seems to be a crucial mechanism for the natural inhibition of premature neural differentiation. PMID- 29422919 TI - Is Psychiatry Ready to Move? PMID- 29422920 TI - Validation of the Korean Version of the Delirium Motor Subtype Scale. AB - Objective: The Delirium Motor Subtype Scale (DMSS) is a validated and reliable instrument developed from various methods previously used to assess delirium motor subtypes. It focuses on pure motor disturbances with a relative specificity for delirium. The aim of this study was to investigate the validity and reliability of a Korean version of the DMSS (K-DMSS). Methods: We recruited 145 patients who were older than 60 years and had been referred for psychiatric consultation for delirium. These patients were evaluated using the K-DMSS, Liptzin & Levkoff criteria, and the Korean version of the Delirium Rating Scale Revised-98 (K-DRS-R98) to compare delirium motor subtypes. Results: The internal consistency of the K-DMSS in assessing delirium motor subtypes was acceptable (Cronbach's alpha=0.79). Delirium motor subtypes identified with the K-DMSS and K DRS-R98 showed almost perfect agreement (Cohen's Kappa=0.81), while those identified with the K-DMSS and Liptzin & Levkoff criteria showed substantial agreement (Cohen's Kappa=0.78). Conclusion: Our results suggest that the K-DMSS is a valid and reliable tool for identifying delirium subtypes. PMID- 29422921 TI - Developing the Symptoms and Functional Impairment Rating Scale: A Multi Dimensional ADHD Scale. AB - Objective: This research developed a practical, multi-dimensional attention deficit hyperactivity disorder (ADHD) rating scale (i.e., the Symptoms and Functional Impairment Rating Scale, SFIRS) for Chinese children, aged 6-12 years, with ADHD. Methods: The structural validity, criterion validity, internal consistency, and test-retest reliability of the scale were evaluated. Item screening was conducted with 412 ADHD patients and 322 developmentally typical controls. Results: The scale includes 44 items, divided among Hyperactivity Impulsivity, Self-Control, Inattention, Self-Management, Academic Performance, and Social Interaction. The six-factor model showed good data fit, with each factor significantly correlated with its corresponding criterion (r=0.690-0.841). The Cronbach's alpha of the full scale was 0.976. Total score test-retest reliability was r=0.816 (p<0.01). Conclusion: The SFIRS thus demonstrated good reliability and validity and may be used to assess ADHD among children aged 6-12 years in China. PMID- 29422923 TI - Effects of Anxiety Sensitivity and Hearing Loss on Tinnitus Symptom Severity. AB - Objective: The aim of the present study was to examine the relative role of anxiety sensitivity and hearing loss on the tinnitus symptoms severity in a large clinical sample of patients with tinnitus. Methods: A total of 1,705 patients with tinnitus who visited the tinnitus clinic underwent the pure-tone audiometric testing and a battery of self-report questionnaires. Multiple linear regression analyses were performed to identify the relationship of anxiety sensitivity and hearing loss to tinnitus symptoms severity. Results: Both anxiety sensitivity and hearing loss were a significant association with of annoyance (anxiety sensitivity beta=0.11, p=0.010; hearing loss beta=0.09, p=0.005) and THI score (anxiety sensitivity beta=0.21, p<0.001; hearing loss beta=0.10, p<0.001) after adjusting for confounding factors. Meanwhile, the awareness time (beta=0.19, p<0.001) and loudness (beta=0.11, p<0.001) of tinnitus was associated with only the hearing loss but not with anxiety sensitivity. Conclusion: Our results indicate that both hearing loss and anxiety sensitivity were associated with increased tinnitus symptom severity. Furthermore, these associations could be different according to the characteristics of tinnitus symptoms. PMID- 29422922 TI - Is the Relationship between Depression and C Reactive Protein Level Moderated by Social Support in Elderly?-Korean Social Life, Health, and Aging Project (KSHAP). AB - Objective: To investigate the buffering effects of social support as an effects modifier in the association between depression and inflammation in the elderly. Methods: We analyzed the Korean Social Life, Health, and Aging Project (KSHAP) for questionnaire, clinical, and laboratory data of 530 older adults living in a rural community. Multivariate regression models were used to investigate the association between depressive symptoms and C-reactive protein level (CRP), a marker of inflammation, at varying levels of social support. Results: Social support affected the association between depressive symptoms and CRP level in both sexes. However, the direction of effects modification was different for men and women. In men, a higher CRP level was significantly associated with depressive symptoms only among those with lower support from a spouse or family members. By contrast, in women, the association was significant only among subgroups with higher spousal or family support. Social support from neighbors or friends did not affect the depression-inflammation relationship in men but modestly affected the relationship in women. Conclusion: Our findings suggest that social support may have a buffering effect in the relationship between depression and inflammation in elderly Koreans. But the influence of social support may run in different directions for men and women. PMID- 29422924 TI - Young Schema Questionnaire: Factor Structure and Specificity in Relation to Anxiety in Chinese Adolescents. AB - Objective: The goal of this study was to examine the factor structure of Young Schema Questionnaire-short form (YSQ-SF) in a sample of Chinese adolescents, and to explore which maladaptive schemas were associated with anxiety symptoms. Methods: YSQ-SF was administered to 983 nonclinical Chinese adolescents aged 13 17 years. Confirmatory factor analyses with weighted least squares means and variance adjusted estimation were conducted to examine the factor structure of YSQ-SF. Stepwise regression analyses were performed to identify schemas associated with anxiety symptoms. Results: A bifactor model with 15 correlated factors fitted the data better than other priori defined models. Stepwise regressions showed Vulnerability to harm, Abandonment, Emotional inhibition, Subjugation, and Unrelenting standards schemas were associated with anxiety symptoms. Furthermore, different anxiety symptoms were associated with common and distinctive schemas. Conclusion: Maladaptive schemas were already stably formed in Chinese adolescents, however there's no robust evidence for the existence of domain. The explanatory value of maladaptive schemas for understanding psychopathology of anxiety in adolescence is discussed. PMID- 29422925 TI - The Effects of Discrimination Experience on Life Satisfaction of North Korean Refugees: Mediating Effect of Stress. AB - Objective: This study investigated the mediation effect of stress between the experience of discrimination and life satisfaction among North Korean refugees who resettled in South Korea. The findings of the current study provide empirical evidence for the need of social interventions to mitigate adverse effects of stress on North Korean refugees who are subject to social discrimination on a daily basis. Methods: In this study, we included 500 subjects among 2,138 North Korean refugees who took refuge in South Korea in 2007. The interview started from April 6th 2009 and finished on May 25th 2009. We conducted moderator effect analysis with Path analysis was conducted because we confirm the experience of discrimination was affected by life satisfaction and stress can affected life satisfaction as a moderator. Results: The experience of discrimination significantly affects stress and stress significantly affects life satisfaction. However, the experience of discrimination was not directly related to life satisfaction. The more stress the study respondents experienced, the lower the life satisfaction they reported. Conclusion: The present finding suggests that the effects of discriminating experiences on the life satisfaction of North Korean refugees in South Korea were mediated by their own perceived stress. PMID- 29422926 TI - Reliability and Validity of a New Comprehensive Tool for Assessing Challenging Behaviors in Autism Spectrum Disorder. AB - Objective: The purpose of this study was to examine the validity and reliability of the Korean Comprehensive Scale for the Assessment of Challenging Behavior in Developmental Disorders (K-CSCB). Methods: In total, the parents of 189 patients with autism spectrum disorder (ASD) and 168 controls completed the K-CSCB, the Behavior Problems Inventory (BPI) and Child Behavior Checklist (CBCL). The reliability and validity of the K-CSCB was investigated. Results: The K-CSCB was found to be a reliable instrument (Cronbach's alpha=0.97). There was a significant difference between the ASD and control groups in all subscale scores. Scores on the K-CSCB subscales were significantly correlated with those on the BPI and CBCL. The diagnostic validity was 97.7%, and the cut-off score with the highest sensitivity and specificity was 12.5 points. Conclusion: The K-CSCB is the first tool in Korean to assess problematic behavior in individuals with ASD, and this study shows that it is a valid and reliable instrument. We expect the K CSCB to be widely used in clinical and research settings. PMID- 29422927 TI - Mediating Effect of Resilience on the Association between Emotional Neglect and Depressive Symptoms. AB - Objective: Previous studies have reported that childhood maltreatment experiences could induce biological and psychological vulnerability in depressive disorders. However, it is still unclear that type-specific effects of childhood maltreatment on psychological resilience, depressive symptoms and interactions among childhood maltreatment experiences, resilience, and depressive symptoms. Methods: A total of 438 medical students were included in the study. The Childhood Trauma Questionnaire-Short Form, the Conner-Davidson Resilience Scale, and the Beck Depression Inventory were used for measuring childhood maltreatment experiences, psychological resilience, and depressive symptoms, respectively. We investigated the effects of childhood maltreatment experiences on resilience and depressive symptoms using correlation analysis. In addition, we analyzed the mediating effect of resilience on the association between childhood maltreatment and symptoms of depression. Results: Among childhood maltreatment, emotional neglect was a significant predictor of the scores of low resilience and high depressive symptoms in both gender groups (all ps<0.05). Furthermore, resilience was found to be a mediator connecting emotional neglect experiences with depressive symptoms. Conclusion: Our results suggest that emotional neglect has detrimental effects on mood and resilience, and clinicians need to focus on the recovery of resilience when they deal with depressive symptoms in victims of childhood maltreatment. PMID- 29422928 TI - Education as a Protective Factor Moderating the Effect of Depression on Memory Impairment in Elderly Women. AB - Objective: The cognitive reserve theory explicates individual differences observed in the clinical manifestation of dementia despite similar brain pathology. Education, a popular proxy of the cognitive reserve, has been shown to have protective effects delaying the onset of clinical symptoms including memory. This study was conducted to test whether education can moderate the negative effect of depressive mood on memory performance in elderly women residing in the community. Methods: 29 elderly "unschooled" female (less than 6 years of formal education) and 49 "schooled" female (6 or more years) people were compared with regard to association between depressive mood and verbal memory functioning, which were measured by the Geriatric Depression Scale and the Elderly Verbal Learning Test, respectively. Results: The results showed that completing or receiving more than primary school education significantly reduced the negative association between depressive mood and memory performance. Participants who did not complete primary schooling showed a decline in memory test scores depending on the level of depressive mood; whereas participants who have completed or received more than primary education displayed relatively stable memory function despite varying level of depressive mood. Conclusion: Our findings imply that education in early life may have protective effects against memory impairment related to elderly depression. PMID- 29422929 TI - A Sleep Education and Hypnotics Reduction Program for Hospitalized Patients at a General Hospital. AB - Objective: We applied a program of sleep education and hypnotics reduction for inpatients (the i-sleep program). This study explored whether the i-sleep program is effective for reducing the prescription rate of sleeping pills to inpatients in a general hospital. Methods: We estimated the proportion of inpatients prescribed hypnotics at admission to and discharge from the hospital, excluding pediatric care units, before (2014) and after (2015) the program. In addition, we estimated the proportion of inpatients prescribed sleeping pills among all inpatients on the first day of each month of 2014 and 2015. Results: The proportion of inpatients prescribed hypnotics as discharge medication among inpatients who had been prescribed them at the time of admission decreased significantly, from 57.0% to 46.8%, after the i-sleep program (RR=0.82, 95% CI: 0.79-0.86). The proportion of inpatients newly prescribed sleeping pills after admission to the hospital did not significantly decrease (1.97% to 2.00%; RR=1.01, 95% CI: 0.96-1.07). The mean prescription rate of sleeping pills per day was 8.18% in 2014 and 7.78% in 2015. Conclusion: The i-sleep program reduced the proportion of inpatients who continued to take sleeping pills from admission until discharge, although it did't reduce the prescription rate per day. PMID- 29422931 TI - Treatment of Children and Adolescents with Attention Deficit Hyperactivity Disorder and/or Tourette's Disorder with Clonidine Extended Release. AB - We aimed to assess the effectiveness and safety of clonidine extended release (ER) treatment in Korean youth with ADHD and/or Tourette's disorder. We retrospectively reviewed the medical records of 29 children and adolescents treated with clonidine ER. The effectiveness were retrospectively measured at baseline and after 4 and 12 weeks based on the Clinical Global Impression Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scores. Safety was evaluated at each visit based on spontaneous reports from the subjects or from their parents/guardians. Significant decreases in the CGI-S scores for both ADHD (F=23.478, p<0.001, partial eta2=0.540) and tic symptoms (F=15.137, p<0.001, partial eta2=0.443) were noted over 12 weeks. The most common adverse event was somnolence (n=9, 31.0%) and life-threatening adverse effects were not observed. Our results provide preliminary evidence for the effectiveness and safety of clonidine ER. PMID- 29422930 TI - Haplotype Association of the MAP2K5 Gene with Antipsychotics-Induced Symptoms of Restless Legs Syndrome among Patients with Schizophrenia. AB - Objective: Restless legs syndrome (RLS) is considered a genetic disease and, following a genome-wide association study conducted in 2007, the mitogen activated protein kinase 5 (MAP2K5) gene has been regarded as the promising candidate gene for RLS. The present study investigated whether polymorphisms of MAP2K5 are associated with antipsychotics-induced RLS in schizophrenia. Methods: We assessed antipsychotics-induced RLS symptoms in 190 Korean schizophrenic patients using the diagnostic criteria of the International Restless Legs Syndrome Study Group. Five single-nucleotide polymorphisms (SNPs) of MAP2K5 were genotyped. We investigated genetic and haplotypic associations of these five SNPs with the risk of antipsychotics-induced RLS symptoms. Results: We divided the 190 subjects into 2 groups: 1) those with RLS symptoms (n=96) and 2) those without RLS symptoms (n=94). There were no significant intergroup differences in the distributions of the genotypes and alleles of the rs1026732, rs11635424, rs12593813, rs4489954, and rs3784709 SNPs. However, the haplotype analysis showed that the G-G-G-G-T (rs1026732-rs11635424-rs12593813-rs4489954-rs3784709) haplotype was associated with RLS symptoms (permutation p=0.033). Conclusion: These data suggest that a haplotype of MAP2K5 polymorphisms confers increased susceptibility to antipsychotics-induced RLS symptoms in schizophrenic patients. PMID- 29422932 TI - Is the Prevalence of the Deficit Syndrome in Schizophrenia Higher than Estimated? Results of a Meta-Analysis. AB - The primary and enduring presence of negative symptoms observed in a relatively homogeneous subgroup of patients with schizophrenia led to the concept of deficit syndrome (DS). Until date, it is considered that 20-25% of schizophrenia cohorts have DS. The aim of this meta-analysis was to determine the current prevalence of DS, including international and most recent studies. Thirteen observational studies met the inclusion criteria, comprising 2092 patients from eight countries. Pooled proportion of the DS subgroup was 32.64%, higher than previously reported. Based on our outcomes, up to one-third of patients with schizophrenia might have idiopathic and stable negative symptoms. This significant proportion of patients should be well represented in clinical trial's samples. PMID- 29422933 TI - Comment on "Clinical Dementia Rating Orientation Score as an Excellent Predictor of the Progression to Alzheimer's Disease in Mild Cognitive Impairment". PMID- 29422934 TI - Engineered human pluripotent stem cell-derived cardiac cells and tissues for electrophysiological studies. AB - Human cardiomyocytes (CMs) do not proliferate in culture and are difficult to obtain for practical reasons. As such, our understanding of the mechanisms that underlie the physiological and pathophysiological development of the human heart is mostly extrapolated from studies of the mouse and other animal models or heterologus expression of defective gene product(s) in non-human cells. Although these studies provided numerous important insights, much of the exact behavior in human cells remains unexplored given that significant species differences exist. With the derivation of human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSCs) from patients with underlying heart disease, a source of human CMs for disease modeling, cardiotoxicity screening and drug discovery is now available. In this review, we focus our discussion on the use of hESC/ iPSC derived cardiac cells and tissues for studying various heart rhythm disorders and the associated pro-arrhythmogenic properties in relation to advancements in electrophysiology and tissue engineering. PMID- 29422935 TI - Effectiveness of Acupuncture for Early Recovery of Bowel Function in Cancer: A Systematic Review and Meta-Analysis. AB - Objectives: The aim of this study was to evaluate the effects of acupuncture therapy to reduce the duration of postoperative ileus (POI) and to enhance bowel function in cancer patients. Methods: A systematic search of electronic databases for studies published from inception until January 2017 was carried out from six databases. Randomized controlled trials (RCTs) involving the use of acupuncture and acupressure for POI and bowel function in cancer patients were identified. Outcomes were extracted from each study and pooled to determine the risk ratio and standardized mean difference. Results: 10 RCTs involving 776 cancer patients were included. Compared with control groups (no acupuncture, sham acupuncture, and other active therapies), acupuncture was associated with shorter time to first flatus and time to first defecation. A subgroup analysis revealed that manual acupuncture was more effective on the time to first flatus and the time to first defecation; electroacupuncture was better in reducing the length of hospital stay. Compared with control groups (sham or no acupressure), acupressure was associated with shorter time to first flatus. However, GRADE approach indicated a low quality of evidence. Conclusions: Acupuncture and acupressure showed large effect size with significantly poor or inferior quality of included trials for enhancing bowel function in cancer patients after surgery. Further well-powered evidence is needed. PMID- 29422936 TI - Fuzheng Quxie Decoction Ameliorates Learning and Memory Impairment in SAMP8 Mice by Decreasing Tau Hyperphosphorylation. AB - Hyperphosphorylation of the microtubule-associated protein, tau, is critical to the progression of Alzheimer's disease (AD). Fuzheng Quxie Decoction (FQD), a Chinese herbal complex, is an effective clinical formula used to treat AD. In the current study, we employed high-performance liquid chromatography and liquid chromatography tandem mass spectrometry to identify the components of FQD. Three major components (ginsenoside Rg1, ginsenoside Re, and coptisine) were detected in the brain of FQD-fed mice, indicating their ability to cross the blood-brain barrier. We further evaluated the efficacy of FQD on Senescence-Accelerated Mice Prone-8 (SAMP8) mice. FQD significantly ameliorated learning and memory deficits in SAMP8 mice on the Morris Water Maze, decreasing escape latency (p < 0.01) and increasing swim time within the original platform-containing quadrant (p < 0.05). Further, FQD increased the number of neurons and intraneuronal Nissl bodies in the hippocampal CA1 region. FQD also decreased the expression of phosphorylated tau protein and increased the expression of protein phosphatase 2A (PP2A) and the N-methyl-D-aspartate receptor subunit, NR2A (p < 0.01). Our results indicate that FQD improves the learning and memory ability of SAMP8 mice. Moreover, our findings suggest that the protective effect of FQD is likely mediated through an inhibition of hippocampal tau hyperphosphorylation via NMDAR/PP2A-associated proteins. PMID- 29422937 TI - Effects and Mechanism of Huannao Yicong Decoction Extract on the Ethology of Transgenic APP/PS1 Mice. AB - To investigate the mechanism of Huannao Yicong Decoction (HYD) extract on improving of learning memory of transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) mice, we randomly divided 60 transgenic APP/PS1 mice of 3 months old into 4 groups: the model group, the Donepezil group, the HYD-L group, and the HYD-H group, with 15 C57BL/6J mice of the same genetic background as the control group. These mice were gavaged for 6 months in a row. The results showed that the latency was significantly shortened and the number of passing through the original platform was increased. HYD extract can increase the amount of neurons and improve the morphological structure of Nissl body obviously. The gamma-secretase activity and the expression of phosphorylated APP, Abeta1-40, and Abeta1-42 in hippocampal CA1 were significantly decreased. The expressions of protein and mRNA of PEN-2 and CREB in hippocampal were significantly downregulated. These results demonstrated that HYD extract can improve the memory ability of transgenic APP/PS1 mice, which was related to the protection of neurons and structure of Nissl body, reducing cleavage of APP and production of Abeta and inhibiting the activity of gamma-secretase by decreasing CREB activity because of downregulated expression of PEN-2. PMID- 29422938 TI - Porphyromonas gingivalis, a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in mice. AB - Background: A possible relationship between periodontitis and Alzheimer's disease (AD) has been reported. However, there is limited information on the association between the Porphyromonas gingivalis (P. gingivalis) periodontal infection and the pathological features of AD. The hypothesis that P. gingivalis periodontal infection may cause cognitive impairment via age-dependent neuroinflammation was tested. Results: Thirty 4-week-old (young) female C57BL/6 J mice were randomly divided into two groups, the control group and the experimental group. Thirty 12 month-old (middle-aged) were grouped as above. The mouth of the mice in the experimental group was infected with P. gingivalis. Morris water maze(MWM) was performed to assess the learning and memory ability of mice after 6 weeks. Moreover, the expression levels of the pro-inflammatory cytokines TNF-alpha, IL 6, and IL-1beta in the mice brain tissues were determined by Quantitative real time polymerase chain reaction (qRT-PCR), Enzyme Linked Immunosorbent Assay(ELISA) and immunohistochemistry. Our results showed that the learning and memory abilities of the middle-aged P. gingivalis infected mice were impaired. Moreover, the expression levels of the pro-inflammatory cytokines TNF-alpha, IL 6, and IL-1beta in the brain tissues of the middle-aged P. gingivalis infected mice were increased. Conclusions: These results suggest that P. gingivalis periodontal infection may cause cognitive impairment via the release of the pro inflammatory cytokines TNF-alpha, IL-6, and IL-1beta in the brain tissues of middle-aged mice. PMID- 29422939 TI - Associations between fatty acid oxidation, hepatic mitochondrial function, and plasma acylcarnitine levels in mice. AB - Background: The 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial beta-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARalpha). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels. Methods: C57BL/6 mice were divided in 4 groups of 10 mice and fed a control low-fat diet, low-fat diets with 0.4% (w/w) TTP, 0.4% TTA or a combination of these two fatty acids for three weeks (n = 10). At sacrifice, beta-oxidation and oxidative phosphorylation (OXPHOS) capacity was analysed in fresh liver samples. Hepatic mitochondria were studied using transmission electron microscopy. Lipid classes were measured in plasma, heart and liver, acylcarnitines were measured in plasma, and gene expression was measured in liver. Results: The TTP diet resulted in hepatic lipid accumulation, plasma L-carnitine and acetylcarnitine depletion and elevated palmitoylcarnitine and non-esterified fatty acid levels. No significant lipid accumulation was observed in heart. The TTA supplement resulted in enhanced hepatic beta oxidation, accompanied by an increased level of acetylcarnitine and palmitoylcarnitine in plasma. Analysis of mitochondrial respiration showed that TTP reduced oxidative phosphorylation, while TTA increased the maximum respiratory capacity of the electron transport system. Combined treatment with TTP and TTA resulted in a profound stimulation of genes involved in the PPAR response and L-carnitine metabolism, and partly prevented triacylglycerol accumulation in the liver concomitant with increased peroxisomal beta-oxidation and depletion of plasma acetylcarnitines. Despite an increased number of mitochondria in the liver of TTA + TTP fed mice, the OXPHOS capacity was significantly reduced. Conclusion: This study indicates that fatty acid beta oxidation directly affects mitochondrial respiratory capacity in liver. As plasma acylcarnitines reflected the reduced mitochondrial beta-oxidation in TTP-fed mice, they could be useful tools to monitor mitochondrial function. As mitochondrial dysfunction is a major determinant of metabolic disease, this supports their use as plasma markers of cardiovascular risk in humans. Results however indicate that high PPAR activation obscures the interpretation of plasma acylcarnitine levels. PMID- 29422940 TI - Strength-based assessment for future violence risk: a retrospective validation study of the Structured Assessment of PROtective Factors for violence risk (SAPROF) Japanese version in forensic psychiatric inpatients. AB - Background: The Structured Assessment of PROtective Factors for violence risk (SAPROF) was recently developed as a strength-based addition to the risk assessment of future violent behavior. We examined the interrater reliability and predictive accuracy of the SAPROF for violence in forensic mental health inpatient units in Japan. Methods: This retrospective record study provides an initial validation of the SAPROF in a Japanese sample of 95 forensic psychiatric inpatients from a complete 2008-2013 cohort. Violent outcomes were assessed 6 and 12 months after hospitalization. Results: We observed moderate-to-good interrater reliability for the SAPROF total score and the internal factors, motivational factors, external factors, and the Final Protection Judgment scores. According to a receiver operating characteristic analysis, the SAPROF total score and all subscale scores predicted violence at both 6 and 12 months after hospitalization with high accuracy. Furthermore, the predictive validity of a combination of the SAPROF with the Historical Clinical Risk Management-20 (HCR-20) outperformed that of the HCR-20 alone. Conclusions: The results provide evidence of the value of considering protective factors in the assessment of future violence risk among Japanese forensic psychiatric inpatients. The SAPROF might allow for a more balanced assessment of future violence risk in places where the population rates of violent crime are low, such as Japan, but a validation study in a different setting should confirm this. Moreover, future studies should examine the effectiveness of treatment and promoting community re-integration on motivating patients and treatment staff. PMID- 29422941 TI - Role of Graph Architecture in Controlling Dynamical Networks with Applications to Neural Systems. AB - Networked systems display complex patterns of interactions between components. In physical networks, these interactions often occur along structural connections that link components in a hard-wired connection topology, supporting a variety of system-wide dynamical behaviors such as synchronization. While descriptions of these behaviors are important, they are only a first step towards understanding and harnessing the relationship between network topology and system behavior. Here, we use linear network control theory to derive accurate closed-form expressions that relate the connectivity of a subset of structural connections (those linking driver nodes to non-driver nodes) to the minimum energy required to control networked systems. To illustrate the utility of the mathematics, we apply this approach to high-resolution connectomes recently reconstructed from Drosophila, mouse, and human brains. We use these principles to suggest an advantage of the human brain in supporting diverse network dynamics with small energetic costs while remaining robust to perturbations, and to perform clinically accessible targeted manipulation of the brain's control performance by removing single edges in the network. Generally, our results ground the expectation of a control system's behavior in its network architecture, and directly inspire new directions in network analysis and design via distributed control. PMID- 29422942 TI - RNA-binding protein immunoprecipitation as a tool to investigate plant miRNA processing interference by regulatory proteins of diverse origin. AB - Background: Due to the nature of viral RNA genomes, RNA viruses depend on many RNA-binding proteins (RBP) of viral and host origin for replication, dissemination and evasion of host RNA degradation pathways. Some viruses interfere with the microRNA (miRNA) pathway to generate better fitness. The development of an adjusted, reliable and sensitive ribonucleoprotein immunoprecipitation (RIP) assay is needed to study the interaction between RBP of different origin (including viral origin) and miRNA precursors. The method could be further applied to transiently expressed heterologous proteins in different plant species. Results: Here we describe a modified RIP assay applied to nuclear epitope-tagged proteins of heterologous origin and transiently expressed in Nicotiana benthamiana. The assay includes a combination of optimized steps as well as the careful selection of control samples and rigorous data analysis. It has proven efficient to detect and quantify miRNA processing intermediates associated with regulatory proteins. Conclusions: The RIP method described here provides a reliable tool to study the interaction of RBPs, such as transiently expressed regulatory proteins with lowly represented host RNA, as is the case of miRNA precursors. This modified method was efficiently adjusted to recover nuclear proteins and reduce unspecific background. The purification scheme optimized here for GFP-tagged proteins can be applied to a wide array of RBPs. The subsequent application of next-generation sequencing technologies will permit to sequence and characterize all RNA species bound in vivo by a given RBP. PMID- 29422944 TI - Encouraging Spatial Talk: Using Children's Museums to Bolster Spatial Reasoning. AB - Longitudinal spatial language intervention studies have shown that greater exposure to spatial language improves children's performance on spatial tasks. Can short naturalistic, spatial language interactions also evoke improved spatial performance? In this study, parents were asked to interact with their child at a block wall exhibit in a children's museum. Some parents were instructed to emphasize formal shape terms, others to emphasize spatial goals, and some were not provided scripts. Children were presented with a series of spatial reasoning tasks before and after this parental interaction, and the amount and type of spatial language during the training session was coded for parents and children. We found that (a) parents significantly increased their spatial language use when prompted, (b) children and parents used different types of spatial language in each of the scripted conditions, and PMID- 29422943 TI - Mathematical Modeling of Biofilm Structures Using COMSTAT Data. AB - Mathematical modeling holds great potential for quantitatively describing biofilm growth in presence or absence of chemical agents used to limit or promote biofilm growth. In this paper, we describe a general mathematical/statistical framework that allows for the characterization of complex data in terms of few parameters and the capability to (i) compare different experiments and exposures to different agents, (ii) test different hypotheses regarding biofilm growth and interaction with different agents, and (iii) simulate arbitrary administrations of agents. The mathematical framework is divided to submodels characterizing biofilm, including new models characterizing live biofilm growth and dead cell accumulation; the interaction with agents inhibiting or stimulating growth; the kinetics of the agents. The statistical framework can take into account measurement and interexperiment variation. We demonstrate the application of (some of) the models using confocal microscopy data obtained using the computer program COMSTAT. PMID- 29422945 TI - Differences between the antibiotic prescribing pattern of newly arrived refugees in Germany and the German population. AB - The number of refugees arriving in Europe increased dramatically in 2015, challenging the German health system. Amongst others, the treatment of infectious diseases is an important topic in refugee healthcare. A high prevalence of multi drug-resistant organisms has been identified among the refugee population. Still, little is known about the prescription of antibiotic medication for refugees. We conducted a descriptive analysis of all antibiotics prescribed to newly arrived refugees who were treated as outpatients between 10/01/2014 and 09/30/2015 in Erlangen, an average sized German town. The City's invoicing documents were used to collect data on prescriptions written for refugees. Basic penicillins, aminopenicillins with beta-lactamase inhibitor and cephalosporins constituted the largest proportion of antibiotics prescribed in the adult refugee group. Of these, both aminopenicillins with beta-lactamase-inhibitor as well as basic penicillins were prescribed significantly more often compared to non-refugees. We conclude that the high percentage of prescriptions of aminopenicillins with beta lactamase inhibitor is striking and should be further investigated. PMID- 29422946 TI - Evaluating the communities care program: best practice for rigorous research to evaluate gender based violence prevention and response programs in humanitarian settings. AB - Background: Gender-based violence (GBV) is a significant issue for women and girls in humanitarian settings. Innovative primary prevention programs are being developed and implemented with existing response programs to change harmful social norms that sustain GBV in humanitarian settings. Social norms are expectations of how women, men, girls and boys should behave, who should have power and control over behavior, and how families and communities value women and girls and support their rights and opportunities. Methods: The United Nations Children's Fund (UNICEF) led Communities Care program is a primary prevention and response program designed from the understanding that within the context of conflict and displacement, there is an opportunity for positive change in social norms that support gender equity, and decrease GBV. The goal is to support communities in humanitarian settings to create healthy, safe and peaceful environments with quality response services for women and girls by transforming harmful social norms that uphold violence into norms that promote dignity, equity, and non-violence. Conclusion: This manuscript will highlight the use of best practices in GBV research to rigorously evaluate the Communities Care program in two diverse in humanitarian settings, Somalia and South Sudan. PMID- 29422947 TI - Enhancing methane production from lignocellulosic biomass by combined steam explosion pretreatment and bioaugmentation with cellulolytic bacterium Caldicellulosiruptor bescii. AB - Background: Biogas production from lignocellulosic biomass is generally considered to be challenging due to the recalcitrant nature of this biomass. In this study, the recalcitrance of birch was reduced by applying steam-explosion (SE) pretreatment (210 degrees C and 10 min). Moreover, bioaugmentation with the cellulolytic bacterium Caldicellulosiruptor bescii was applied to possibly enhance the methane production from steam-exploded birch in an anaerobic digestion (AD) process under thermophilic conditions (62 degrees C). Results: Overall, the combined SE and bioaugmentation enhanced the methane yield up to 140% compared to untreated birch, while SE alone contributed to the major share of methane enhancement by 118%. The best methane improvement of 140% on day 50 was observed in bottles fed with pretreated birch and bioaugmentation with lower dosages of C. bescii (2 and 5% of inoculum volume). The maximum methane production rate also increased from 4-mL CH4/g VS (volatile solids)/day for untreated birch to 9-14-mL CH4/g VS/day for steam-exploded birch with applied bioaugmentation. Bioaugmentation was particularly effective for increasing the initial methane production rate of the pretreated birch yielding 21-44% more methane than the pretreated birch without applied bioaugmentation. The extent of solubilization of the organic matter was increased by more than twofold when combined SE pretreatment and bioaugmentation was used in comparison with the methane production from untreated birch. The beneficial effects of SE and bioaugmentation on methane yield indicated that biomass recalcitrance and hydrolysis step are the limiting factors for efficient AD of lignocellulosic biomass. Microbial community analysis by 16S rRNA amplicon sequencing showed that the microbial community composition was altered by the pretreatment and bioaugmentation processes. Notably, the enhanced methane production by pretreatment and bioaugmentation was well correlated with the increase in abundance of key bacterial and archaeal communities, particularly the hydrolytic bacterium Caldicoprobacter, several members of syntrophic acetate oxidizing bacteria and the hydrogenotrophic Methanothermobacter. Conclusion: Our findings demonstrate the potential of combined SE and bioaugmentation for enhancing methane production from lignocellulosic biomass. PMID- 29422949 TI - Combinatorial pretreatment and fermentation optimization enabled a record yield on lignin bioconversion. AB - Background: Lignin valorization has recently been considered to be an essential process for sustainable and cost-effective biorefineries. Lignin represents a potential new feedstock for value-added products. Oleaginous bacteria such as Rhodococcus opacus can produce intracellular lipids from biodegradation of aromatic substrates. These lipids can be used for biofuel production, which can potentially replace petroleum-derived chemicals. However, the low reactivity of lignin produced from pretreatment and the underdeveloped fermentation technology hindered lignin bioconversion to lipids. In this study, combinatorial pretreatment with an optimized fermentation strategy was evaluated to improve lignin valorization into lipids using R. opacus PD630. Results: As opposed to single pretreatment, combinatorial pretreatment produced a 12.8-75.6% higher lipid concentration in fermentation using lignin as the carbon source. Gas chromatography-mass spectrometry analysis showed that combinatorial pretreatment released more aromatic monomers, which could be more readily utilized by lignin degrading strains. Three detoxification strategies were used to remove potential inhibitors produced from pretreatment. After heating detoxification of the lignin stream, the lipid concentration further increased by 2.9-9.7%. Different fermentation strategies were evaluated in scale-up lipid fermentation using a 2.0 l fermenter. With laccase treatment of the lignin stream produced from combinatorial pretreatment, the highest cell dry weight and lipid concentration were 10.1 and 1.83 g/l, respectively, in fed-batch fermentation, with a total soluble substrate concentration of 40 g/l. The improvement of the lipid fermentation performance may have resulted from lignin depolymerization by the combinatorial pretreatment and laccase treatment, reduced inhibition effects by fed-batch fermentation, adequate oxygen supply, and an accurate pH control in the fermenter. Conclusions: Overall, these results demonstrate that combinatorial pretreatment, together with fermentation optimization, favorably improves lipid production using lignin as the carbon source. Combinatorial pretreatment integrated with fed-batch fermentation was an effective strategy to improve the bioconversion of lignin into lipids, thus facilitating lignin valorization in biorefineries. PMID- 29422948 TI - Processivity and enzymatic mechanism of a multifunctional family 5 endoglucanase from Bacillus subtilis BS-5 with potential applications in the saccharification of cellulosic substrates. AB - Background: Presently, enzymes still constitute a major part of the cost of biofuel production from lignocellulosic biomass. Processive endoglucanases, which possess both endoglucanase and exoglucanase activity, have the potential to reduce the costs of biomass saccharification when used together with commercial cellulases. Therefore, the exploration of new processive endoglucanases has attracted much attention with a view to accelerating the industrialization of biofuels and biochemicals. Results: The endoglucanase EG5C and its truncated form EG5C-1 from Bacillus subtilis BS-5 were expressed and characterized. EG5C was a typical endoglucanase, comprised of a family 5 catalytic domain and family 3 carbohydrate-binding domain, and which had high activity toward soluble cellulosic substrates, but low activity toward insoluble cellulosic substrates. Importantly, the truncated form EG5C-1 was a processive endoglucanase that hydrolyzed not only carboxymethyl cellulose (CMC), but also insoluble cellulosic substrates. The hydrolytic activities of EG5C-1 towards CMC, phosphoric acid swollen cellulose (PASC), p-nitrophenyl-beta-d-cellobioside, filter paper and Avicel are 4170, 700, 2550, 405 and 320 U/MUmol, respectively. These data demonstrated that EG5C-1 had higher activity ratio of exoglucanase to endoglucanase than other known processive endoglucanases. When PASC was degraded by EG5C-1, the ratio of soluble to insoluble reducing sugars was about 3.7 after 3 h of incubation with cellobiose and cellotriose as the main products. Importantly, EG5C-1 alone was able to hydrolyze filter paper and PASC. At 5% substrate concentration and 10 FPU/g PASC enzyme loading, the saccharification yield was 76.5% after 60 h of incubation. Replacement of a phenylalanine residue (F238) by an alanine at the entrance/exit of the substrate binding cleft significantly reduces the ability of EG5C-1 to degrade filter paper and Avicel, but this mutation has little impact on CMCase activity. The processivity of this mutant was also greatly reduced while its cellulose binding ability was markedly enhanced. Conclusions: The processive endoglucanase EG5C-1 from B. subtilis BS-5 exhibits excellent properties that render it a suitable candidate for use in biofuel and biochemical production from lignocellulosic biomass. In addition, our studies also provide useful information for research on enzyme processivity at the molecular level. PMID- 29422951 TI - Impact of regionalisation of a national rheumatic heart disease registry: the Ugandan experience. AB - Objectives: Rheumatic heart disease (RHD) remains a major driver of cardiovascular morbidity and mortality in low-resource settings. Registry-based care for RHD has been advocated as a powerful tool to improve clinical care and track quality metrics. Data collected through an RHD registry may also reveal epidemiological and geospatial trends, as well as insight into care utilisation. Uganda established a central RHD registry at the country's only tertiary cardiac centre in 2010. In 2014 RHD care and registry enrolment expanded to the Western region and in 2015 to the North. Here, we examine the geographical distribution of RHD cases in Uganda and the impact of registry expansion. Methods: A retrospective search of the Ugandan national RHD registry was preformed to capture all cases of acute rheumatic fever or clinical RHD from January 2010 through July 2016. A geospatial analysis revealed that the density of detected cases (cases/100 000 district residents) reflected proximity to an RHD registry enrolment centre. Regionalisation improved the number of cases detected in the regions of expansion and improved retention of patients in care. Results and conclusions: RHD appears to have uniform distribution throughout Uganda with geographical clustering surrounding RHD registry enrolment centres reflecting access to care, rather than differences in prevalence. Higher rates of case detection and improved retention in care with regionalisation highlight the urgent need for decentralisation of cardiovascular services. Future studies should examine sustainable models for cardiovascular care delivery, including task shifting of clinical care and echocardiography and use of telemedicine. PMID- 29422952 TI - Gender differences in the use of primary prevention ICDs in New Zealand patients with heart failure. AB - Objective: Women have been under-represented in randomised clinical trials for primary prevention implantable cardioverter defibrillators (ICDs), and there are concerns about the efficacy of devices between genders. Our study aimed to investigate gender differences in the use of primary prevention ICD in patients with heart failure from the northern region of New Zealand. Methods: Patients with heart failure with systolic dysfunction who received primary prevention ICD/cardiac resynchronisation therapy-defibrillator (CRT-D) in the northern region of New Zealand from 1 January 2007 to 1 June 2015 were included. Complications, mortality and hospitalisation events were reviewed. Results: Of the 385 patients with heart failure implanted with ICD/CRT-D, women comprised 15.1% (n=58), and no change in utilisation of these devices was observed over the study period among women. Women were more likely to have non-ischaemic cardiomyopathy and have higher perioperative complications (8.6% vs 2.5%, P=0.02), with non-significant higher trend towards increased lead displacement (5.2% vs 1.8%, P=0.12). Women appeared to have lower all-cause (10.3% vs 18.7%, P=0.12), cardiovascular (5.2% vs 11.9%, P=0.13) and heart failure (3.5% vs 7.9%, P=0.22) mortalities but was not statistically significant. There were no gender differences in all-cause (70.7% vs 67%, P=0.58) or heart failure (19% vs 25%, P=0.32) readmissions. Conclusion: Perioperative complications were significantly more common in women referred for ICD/CRT-D. Although there has been a significant increase in ICD implantation rates, gender differences in the use of these devices still exist in New Zealand, in keeping with the demographics of ischaemic heart disease and systolic dysfunction between genders. PMID- 29422950 TI - A feasible diagnostic approach for the translocation carrier from the indication of products of conception. AB - Background: Chromosome translocations are rare but frequently associated with infertility. The objective of this study is to investigate the feasibility of using chromosomal microarray analysis (CMA) on products of conception (POC) samples as an indicator of parental balanced translocation. From January 2011 to December 2016, CMA using Affymetrix CytoscanTM750K array was performed on 1294 POC samples in our hospital. Karyotyping and fluorescence in situ hybridization (FISH) using parental blood samples were performed to validate the origin of subchromosomal copy number variations (CNVs). Results: In the 1294 cases of POCs, we detected CNVs of terminal duplication and deletion that imply unbalanced translocation derivatives in 16 cases, and accurate diagnosis with the parental study was made in all the cases by karyotyping and/or FISH. In 10/16 (62.5%) of these cases, CNVs were inherited from one carrier parent of balanced translocation (Cases 1 to 10), while 6/16 (37.5%) cases occurred de novo (Cases 11 to 16). Conclusion: This study clearly illustrated the importance of the utilization of CMA on POC, followed by parental karyotyping and FISH to better characterize CNVs. This approach is especially useful for couples in whom one partner carries a cryptic/submicroscopic balanced translocation but has an apparently normal karyotype. PMID- 29422953 TI - Acute myocardial infarction in a young male. PMID- 29422954 TI - Genetic exchange in eukaryotes through horizontal transfer: connected by the mobilome. AB - Background: All living species contain genetic information that was once shared by their common ancestor. DNA is being inherited through generations by vertical transmission (VT) from parents to offspring and from ancestor to descendant species. This process was considered the sole pathway by which biological entities exchange inheritable information. However, Horizontal Transfer (HT), the exchange of genetic information by other means than parents to offspring, was discovered in prokaryotes along with strong evidence showing that it is a very important process by which prokaryotes acquire new genes. Main body: For some time now, it has been a scientific consensus that HT events were rare and non relevant for evolution of eukaryotic species, but there is growing evidence supporting that HT is an important and frequent phenomenon in eukaryotes as well. Conclusion: Here, we will discuss the latest findings regarding HT among eukaryotes, mainly HT of transposons (HTT), establishing HTT once and for all as an important phenomenon that should be taken into consideration to fully understand eukaryotes genome evolution. In addition, we will discuss the latest development methods to detect such events in a broader scale and highlight the new approaches which should be pursued by researchers to fill the knowledge gaps regarding HTT among eukaryotes. PMID- 29422956 TI - MDM2 binding protein as a predictor of metastasis and a novel prognostic biomarker in patients with gastric cancer. AB - MDM2 binding protein (MTBP) has been revealed to be involved in cancer progression and metastasis. However, the role and clinical implication of MTBP expression in gastric cancer (GC) remains poorly understood. The present study aimed to investigate the clinicopathological significance of MTBP and the prognostic determinant in GC. The expression level of MTBP was examined in cancerous and matched adjacent noncancerous gastric mucosa tissues by reverse transcription-quantitative polymerase chain reaction and western blotting. MTBP expression levels were evaluated by immunohistochemical analysis of tissue microarrays for 352 patients, and association between the expression levels and prognosis in patients with GC were investigated. Kaplan-Meier analysis and Cox's regression models were used to investigate the associations between MTBP expression and prognosis of GC patients. The results of the present study revealed decreased MTBP mRNA (P=0.005) and protein (P=0.001) expression levels in tumor tissue compared with in matched adjacent normal tissue mucosa. MTBP expression level in GC was associated with gender (P=0.026), lymph node metastasis (P<0.001), distant metastasis (P=0.026) and pathological tumor-node metastasis stage (P<0.001). Kaplan-Meier survival analysis demonstrated that patients with high MTBP expression levels exhibited longer survival times compared with patients with low MTBP expression levels. The multivariate logistic regression analysis revealed that MTBP was independently associated with the presence of lymph node [OR, 0.282; 95% confidence interval (CI), 0.161-0.494; P<0.001] and distant metastasis (OR, 0.365; 95% CI, 0.138-0.965; P=0.042). Furthermore, the multivariate Cox analysis revealed that low MTBP expression level was significantly associated with longer overall survival time and was recognized as an independent prognostic factor of patient's survival. MTBP expression level was significantly associated with progression and metastasis in GC, suggesting that MTBP may be used as a predictive marker for patient prognosis of GC. PMID- 29422955 TI - Mechanism of Supplemental Activator and Reducing Agent Atom Transfer Radical Polymerization Mediated by Inorganic Sulfites: Experimental Measurements and Kinetic Simulations. AB - The mechanism of atom transfer radical polymerization (ATRP) mediated by sodium dithionite (Na2S2O4), with CuIIBr2/Me6TREN as catalyst (Me6TREN: tris[2 (dimethylamino)ethyl]amine)) in ethanol/water mixtures, was investigated experimentally and by kinetic simulations. A kinetic model was proposed and the rate coefficients of the relevant reactions were measured. The kinetic model was validated by the agreement between experimental and simulated results. The results indicated that the polymerization followed the SARA ATRP mechanism, with a SO2*- radical anion derived from Na2S2O4, acting as both supplemental activator (SA) of alkyl halides and reducing agent (RA) for CuII/L to regenerate the main activator CuI/L. This is similar to the reversible-deactivation radical polymerization (RDRP) procedure conducted in the presence of Cu0. The electron transfer from SO2*-, to either CuIIBr2/Me6TREN or R-Br initiator, appears to follow an outer sphere electron transfer (OSET) process. The developed kinetic model was used to study the influence of targeted degree of polymerization, concentration of CuIIBr2/Me6TREN and solubility of Na2S2O4 on the level of polymerization control. The presence of small amounts of water in the polymerization mixtures slightly increased the reactivity of the CuI/L complex, but markedly increased the reactivity of sulfites. PMID- 29422957 TI - Ribosome biogenesis mediates antitumor activity of flavopiridol in CD44+/CD24- breast cancer stem cells. AB - Flavopiridol is a synthetically produced flavonoid that potently inhibits the proliferation of human tumor cell lines. Flavopiridol exerts strong antitumor activity via several mechanisms, including the induction of cell cycle arrest and apoptosis, and the modulation of transcriptional regulation. The aim of the present study was to determine the effect of flavopiridol on a subpopulation of cluster of differentiation (CD)44+/CD24- human breast cancer MCF7 stem cells. The CD44+/CD24- cells were isolated from the MCF7 cell line by fluorescence-activated cell sorting and treated with 100, 300, 500, 750 and 1,000 nM flavopiridol for 24, 48 and 72 h. Cell viability and proliferation assays were performed to determine the inhibitory effect of flavopiridol. Gene expression profiling was analyzed using Illumina Human HT-12 v4 Expression BeadChip microarray. According to the results, the half maximal inhibitory concentration (IC50) value of flavopiridol was 500 nM in monolayer cells. Flavopiridol induced growth inhibition and cytotoxicity in breast cancer stem cells (BCSCs) at the IC50 dose. The present study revealed several differentially regulated genes between flavopiridol-treated and untreated cells. The result of the pathway analysis revealed that flavopiridol serves an important role in translation, the ribosome biogenesis pathway, oxidative phosphorylation, the electron transport chain pathway, carbon metabolism and cell cycle. A notable result from the present study is that ribosome-associated gene expression is significantly affected by flavopiridol treatment. The data of the present study indicate that flavopiridol exhibits antitumor activity against CD44+/CD24- MCF7 BCSCs through different mechanisms, mainly by inhibiting translation and the ribosome biogenesis pathway, and could be an effective chemotherapeutic molecule to target and kill BCSCs. PMID- 29422958 TI - Expression and function of tetraspanin 1 in esophageal carcinoma. AB - The present study explored the expression of tetraspanin 1 (TSPAN1) in esophageal carcinoma (EC) and its association with clinicopathological factors. TSPAN1 small interfering RNA (siRNA) was designed to target the TSPAN1 gene in Eca-109 cells in order to explore the biological function of TSPAN1 in the proliferation and apoptosis of EC. The results demonstrated that the level of TSPAN1 expression in EC tissue was significantly increased compared with that in adjacent normal tissue (P<0.001). TSPAN1 expression was also associated with histological differentiation, depth of invasion, lymph node metastasis (all P<0.05) and Ki-67 (P<0.01). However, no association was observed between TSPAN expression and gender, age or location (P>0.05). In addition, silencing TSPAN1 markedly inhibited proliferation while increasing the apoptosis rate of Eca-109 cells, which was demonstrated by detecting the expression of the cell proliferation associated gene Ki-67 and the apoptotic gene caspase-3 (P<0.05). Taken together, these results indicated that TSPAN1 functions as a tumor-associated gene in EC through promoting cell proliferation and suppressing apoptosis, and siRNA technology may provide an advanced alternative in the development of therapeutics for EC. PMID- 29422959 TI - Implication of atypical supraclavicular F18-fluorodeoxyglucose uptake in patients with breast cancer: Association between brown adipose tissue and breast cancer. AB - It has been reported that F18-fluorodeoxyglucose (FDG) uptake in the neck and supraclavicular lesions represents activated brown adipose tissue (BAT). In the present study, the association between BAT activity, detected by FDG-positron emission tomography (PET), and the clinicopathological features of patients with breast cancer was investigated. The cases of 156 consecutive patients with breast cancer who underwent FDG-PET preoperatively were analyzed. The distribution and intensity of atypical FDG uptake in the neck and/or supraclavicular region was reviewed. The intensity was graded as follows: 1, weak; 2, moderate; and 3, intense. Among the 156 patients, 70 (44.9%) exhibited grade 1 intensity, 65 (41.7%) exhibited grade 2 intensity and 21 (13.5%) exhibited grade 3 intensity. The intensity of FDG was significantly associated with human epidermal growth factor receptor 2 (HER2) expression and progesterone expression. Among the 156 patients, 6 (3.8%) had recurrent disease. Multivariate analysis revealed that showing a low grade of atypical FDG uptake was the only independent risk factor of short-term recurrence, and none of the patients with recurrent disease had atypical FDG uptake that may reflect the activation of BAT. These results indicated that the presence of BAT is associated with HER2 expression and the absence of BAT may be a prognostic factor for breast cancer. PMID- 29422960 TI - Mecambridine induces potent cytotoxic effects, autophagic cell death and modulation of the mTOR/PI3K/Akt signaling pathway in HSC-3 oral squamous cell carcinoma cells. AB - Plant secondary metabolites including alkaloids, demonstrate a complex diversity in their molecular scaffolds and exhibit tremendous pharmacological potential as anti-cancerous therapeutics. The present study aimed to evaluate the anticancer activity of a natural alkaloid, mecambridine, against human oral squamous cell carcinoma (OSCC). An MTT assay was used to evaluate cytotoxic effects of mecambridine on HSC-3 oral squamous cell carcinoma cells. Effects of mecambridine on autophagy-associated proteins were analyzed by western blotting. Effects on reactive oxygen species (ROS) and mitochondrial membrane potential were assessed by flow cytometry. Results indicated that mecambridine exhibited an IC50 value of 50 uM and exerted its cytotoxic effects in a dose dependent manner on OSCC HSC-3 cells. Furthermore, it was observed that mecambridine decreases cell viability and induces autophagy in a dose-dependent manner. The underlying mechanism for the induction of autophagy was demonstrated to be associated with ROS-mediated alterations in mitochondrial membrane potential and modulation of the mechanistic target of rapamycin/phosphoinositide 3-kinase/protein kinase B (m-TOR/PI3K/Akt) signaling pathway in HSC-3 at the IC50. In conclusion, the present study suggests that mecambridine exhibits substantial anticancer activity against OSCC HSC-3 cells by induction of autophagy and modulates the expression of the mTOR/PI3K/Akt signaling cascade which is considered a potential target pathway for anti-cancer agents. PMID- 29422961 TI - MicroRNA-100 suppresses human gastric cancer cell proliferation by targeting CXCR7. AB - microRNAs (miRs) are a class of small non-coding RNAs that have been demonstrated to have a crucial role in tumorigenesis of human cancers, including gastric cancer (GC). Previous results have established that miR-100 participated in the development of GC; however, the underlying mechanism remains largely unknown. The preesent study utilized reverse transcription-quantitative polymerase chain reaction to analyze the expression of miR-100 in GC tissues and adjacent normal tissues. The present results indicated that the expression of miR-100 was downregulated in GC tissues when compared to the adjacent normal tissues. Furthermore, low miR-100 expression was observed to be associated with lymph node metastasis, tumor diameter and tumor stage. In addition, Kaplan-Meier analysis revealed that patients with low miR-100 expression tended to have a shorter overall survival. The miR-100 was further identified as an independent prognostic factor for overall survival. Notably, the levels of chemokine (CXC motif) receptor 7 (CXCR7) were inversely correlated with miR-100 in GC cell lines. Furthermore, miR-100 overexpression or CXCR7 depletion decreased in vitro GC cell proliferation. Bioinformatics analysis indicated that miR-100 may bind to the 3' untranslated region of CXCR7 to prevent the initiation of protein translation. Thus, miR-100 may function as a tumor suppressor in GC, partly by regulating the expression of CXCR7, and the regulation of miR-100 expression may be a potential strategy for the treatment of GC patients. PMID- 29422963 TI - Expression of microRNA-184 in glioma. AB - The aim of the present study was to examine the expression of microRNA (miRNA) 184 in gliomas with different pathological grades, and its effect on survival prognosis. For the present study, 40 participants were selected with different pathological grades of glioma tissues with grade I (n=10), grade II (n=8), grade III (n=16), and grade IV (n=6). In addition, 10 cases of normal brain tissue (obtained by decompression because of traumatic brain injury) were selected. RT PCR and immunohistochemical techniques were used to detect the expression level and intensity of miRNA-184 in different grades of glioma tissues. The length of survival of miRNA-184-positive patients was analyzed. miRNA-184 mRNA expression was found in normal tissues and tumor tissues, and the expression in tumor tissues was significant (P<0.05). Statistically significant differences of miRNA 184 expression were observed among different grades (P<0.05). miRNA-184 expression increased with the increase of grade level. The differences in expression across grade levels was statistically significant (P<0.05). A positive expression was not related to the pathological types of glioma cells. The median survival time of patients with miRNA-184-positive expression was significantly shorter than that of the negative expression group (P<0.05). miRNA-184 is highly expressed in gliomas, which is positively correlated with pathological grade, and is not correlated with pathological type, and negatively correlated with survival time. Thus, miRNA-184 is a potentially important molecular marker for glioma. PMID- 29422962 TI - Metformin and cancer: An existing drug for cancer prevention and therapy. AB - Metformin is a standard clinical drug used to treat type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome. Recently, epidemiological studies and meta analyses have revealed that patients with T2DM have a lower incidence of tumor development than healthy controls and that patients diagnosed with cancer have a lower risk of mortality when treated with metformin, demonstrating an association between metformin and tumorigenesis. In vivo and in vitro studies have revealed that metformin has a direct antitumor effect, which may depress tumor proliferation and induce the apoptosis, autophagy and cell cycle arrest of tumor cells. The mechanism underpinning the antitumor effect of metformin has not been well established. Studies have demonstrated that reducing insulin and insulin like growth factor levels in the peripheral blood circulation may lead to the inhibition of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin (mTOR) signaling or activation of AMP-activated protein kinase, which inhibits mTOR signaling, a process that may be associated with the antitumor effect of metformin. The present review primarily focuses on the recent progress in understanding the function of metformin in tumor development. PMID- 29422964 TI - Association of mast cell infiltration with gastric cancer progression. AB - The present study aimed to determine the expression of mast cells, C-C motif chemokine ligand 2 (CCL-2) and C-C motif chemokine receptor 2 (CCR2) in gastric cancer tumor tissue; and the association of mast cells with the proliferation, migration, invasion and apoptosis of gastric cancer cells. In addition, whether the stem cell factor (SCF)/c-Kit pathway was associated with the secretion of CCL 2 by gastric cancer cells was explored. Flow cytometry analysis and immunohistochemistry were used to observe the relative number of mast cells, and reverse transcription-quantitative polymerase chain reaction and western blot analysis were utilized to determine the expression of CCL-2 and CCR2 mRNA and protein. Following the co-culture of the mast cell line HMC-1 and the gastric cancer cell line BGC-823, a Transwell assay was used to validate the effect of mast cells on the migration and invasion of gastric cancer cells. Furthermore, Cell Counting kit-8 and dual acridine orange/ethidium bromide fluorescent staining assays were performed to determine the proliferation and apoptosis of gastric cancer cells, following co-culture with mast cells. The expression of SCF and c-Kit were also determined with a western blot analysis. A specific phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, was used to test the effect of PI3K inhibition on the secretion of CCL-2 in gastric cancer. The results demonstrated that the proportion of infiltrating mast cells, and the mRNA/protein expression of CCL-2 and CCR2, were significantly increased in tumor tissue relative to adjacent tissues. In addition, the migration and invasion of gastric cancer cells were significantly increased when mast cells were used as an attractant. When co-cultured with mast cells, the viability of gastric cancer cells was significantly increased and H2O2-induced apoptosis was inhibited. In gastric cancer tissue samples, the expression of SCF, c-Kit and phosphorylated (p)-Akt protein were significantly increased compared with normal adjacent tissues. It was hypothesized that SCF/c-Kit signaling pathway was activated by PI3K-Akt, resulting in an increase in the expression of CCL-2 mRNA and protein. Furthermore, it was demonstrated that CCL-2 mRNA and protein expression was significantly inhibited by treatment with the PI3K inhibitor wortmannin. Additionally, wortmannin intervention significantly inhibited gastric cancer cell migration and invasion. Therefore, the results of the present study demonstrated that mast cells may promote gastric cancer cell proliferation, migration and invasion, and inhibit apoptosis. In addition, the activation of the SCF/c-Kit signaling pathway was identified to promote the expression of CCL-2, which is associated with the development and metastasis of gastric cancer. PMID- 29422965 TI - Upregulation of Bcl2 in NSCLC with acquired resistance to EGFR-TKI. AB - Lung cancer has the highest incidence and mortality rate worldwide among all malignancy-associated mortalities, of which non-small cell lung cancer accounts for 80% of all cases. Resistance against epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) develops following 8-12 months of disease progression, and is a critical issue. HCC827 cell lines with resistance to EGFR TKIs were successfully screened. The half maximal inhibitory concentration values were 1,000-fold higher than the values for the parental HCC827 cell line, thereby demonstrating cross-resistance against the same family of TKIs. The expression of B-cell lymphoma 2 (Bcl2) was markedly increased in the resistant clones, as well as in the patient biopsies. The phosphatase and tensin homolog phosphoinositide 3 kinase signaling axis is a potential mechanism for acquiring resistance, and therefore targeting Bcl2 may be a useful strategy for further investigations. PMID- 29422966 TI - Inhibition of breast cancer cell survival by Xanthohumol via modulation of the Notch signaling pathway in vivo and in vitro. AB - Natural compounds derived from plants have been an important source of numerous clinically useful anticancer agents. Nevertheless, limited studies indicate that xanthohumol (XN), a major prenylated flavonoid in hop plants (Humulus lupulus), may possess anticarcinogenic properties. The purpose of the present study was to clarify the antitumorigenic effects and the underlying mechanism of XN on breast cancer in vivo and in vitro. A 4T1 breast tumor mouse model was used in the present study to investigate XN suppression of tumor growth as detected by tumorigenicity assays in vivo. In addition, in vitro studies revealed that XN significantly decreased cell viability, induced G0/G1 cell cycle arrest and apoptosis in MCF-7 and MDA-MB-231 cells, as confirmed by an MTT assay, flow cytometry and western blot analysis, indicating anticarcinogenic activity of XN against breast cancer. Furthermore, immunohistochemistry was performed to confirm the inactivation of the Notch signaling pathway, Notch 1 and Ki-67, in vivo; consistently, XN caused decreased activation of the Notch signaling pathway and apoptotic regulators B-cell lymphoma-2 (Bcl-2), Bcl-extra large and caspase 3, as determined by western blot analysis in vitro. This study suggests that XN may potentially be useful as a chemopreventive agent during breast hyperplasia and carcinogenesis, acting via the regulation of Notch associated apoptotic regulators in vivo and in vitro. PMID- 29422967 TI - Effects of Grb2-associated binding protein 2-specific siRNA on the migration and invasion of MG-63 osteosarcoma cells. AB - To investigate the association between the expression of growth factor receptor binding protein 2-associated binding protein 2 (Gab2) in human osteosarcoma as well as the effects of Gab2 on invasion and metastasis, human MG-63 osteosarcoma cells were transfected with small interfering (si)RNA plasmid. Gab2 protein and mRNA expression levels were detected using western blotting and reverse transcription-polymerase chain reaction, respectively. The cell migration and invasion abilities were detected using in vitro chemotaxis and invasion assays, respectively, following siRNA vector expression. Gab2 was markedly expressed in MG-63 cells. The Gab2 protein and mRNA expression levels of the cells transfected with Gab2 siRNA (siGab2/MG-63) were reduced compared with those of the cells transfected with scrambled siRNA (Scr/MG-63). The chemotaxis assay demonstrated that the migration capacity of siGab2/MG-63 cells induced by 10 ug/l epidermal growth factor, was significantly reduced compared with that of the MG-63 and Scr/MG-63 cells (P<0.01). In comparison with Scr/MG-63 and MG-63 cells, a reduced number of siGab2/MG-63 cells invaded the Matrigel matrix, demonstrating that the in vitro invasion capacity was significantly decreased (P<0.01). Decreasing Gab2 expression levels using siRNA interference inhibited the migration and invasion ability of human MG-63 osteosarcoma cells. PMID- 29422968 TI - Clinical value of CagA, c-Met, PI3K and Beclin-1 expressed in gastric cancer and their association with prognosis. AB - Gastric cancer (GC) is the fourth most common type of malignant tumor worldwide, and causes the second highest number of cancer-associated mortalities in 2012. Gastric tumorigenesis is a multistep and multifactorial process. In the present study, tissue microarray and immunohistochemistry analysis were used to detect cytotoxin-associated gene A (CagA), c-Met, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and Beclin-1 expression in 121 GC tumors and 120 normal gastric tissues. The clinical relevance and prognostic implications of CagA, c-Met, PI3K and Beclin-1 expression in GC patients were analyzed. Furthermore, the Cox proportional hazards model was performed to indicate the independent prognostic factors for GC patients, including various clinicopathological parameters and CagA, c-Met, PI3K and Beclin-1 expression. The results indicated that CagA positive H. pylori infection, c-Met, PI3K and Beclin-1 may have major roles in the oncogenesis, invasion and lymph node metastasis of GC. The disease-free survival rate was negatively associated with the expression of c-Met and CagA in tissues, and was positively associated with Beclin-1 expression. Overall survival was also negatively associated with the expression of c-Met and PI3K, and was positively associated with Beclin-1 expression. This indicated that c-Met and Beclin-1 may be independent and efficient biomarkers for predicting the DFS of patients with GC. Furthermore, in CagA-positive H. pylori infection-associated GC, c-Met expression was significantly upregulated and Beclin-1 expression was significantly downregulated. CagA-positive H. pylori infection therefore associated with the c-Met signaling pathway and the suppression of autophagy in the neoplasia, invasion and metastasis of GC. PMID- 29422969 TI - MicroRNA-544 promotes colorectal cancer progression by targeting forkhead box O1. AB - Dysregulation of microRNAs has been confirmed to serve an important role in cancer development and progression. However, the role of microRNA (miR)-544 in colorectal cancer progression remains unknown. In the present study, it was observed that the expression level of miR-544 was increased in breast cancer cell lines and tissues using the quantitative polymerase chain reaction. Overexpression of miR-544 promoted cell proliferation and invasion in colorectal cancer, whereas inhibition of miR-544 suppressed colorectal cancer progression as determined using MTT, colony formation and Transwell assays. Furthermore, forkhead box O1 (FOXO1) was a direct target of miR-544. FOXO1 mediated miR-544 regulated colorectal cancer progression and cell cycle distribution. In conclusion, the results of the present study revealed that miR-544 serves an important role in promoting human colorectal cancer cell progression. PMID- 29422970 TI - Increased copy number of mitochondrial DNA predicts poor prognosis of esophageal squamous cell carcinoma. AB - Change in mitochondrial DNA (mtDNA) copy number has been reported in esophageal squamous cell carcinoma (ESCC). However, its prognostic implication in ESCC remains largely unknown. Using reverse transcription-quantitative PCR assay, the mtDNA copy number was assessed in a cohort of patients with ESCC (n=141) and normal esophageal tissues (n=45), and the association between variable mtDNA levels and clinical outcomes of patients with ESCC were studied. Data revealed that ESCC patients exhibited an increased mtDNA content compared to control subjects. Furthermore, increased mtDNA content was associated with a significantly increased risk of cancer-associated mortality. This molecular event was associated with poorer survival in patients with ESCC, and was an independent predictor of patient survival. Data demonstrated that increased mtDNA content is a common genetic event in ESCC and may be a predictive factor of poor prognosis for ESCC patients. PMID- 29422971 TI - Novel and simple method of double-detection using fluorescence in situ hybridization and fluorescence immunostaining of formalin-fixed paraffin-embedded tissue sections. AB - The importance of fluorescence in situ hybridization (FISH) for pathological diagnosis has been increasing. However, the procedures utilized for a conventional FISH method with formalin-fixed paraffin-embedded tissue sections are complicated and it is difficult to perform as a routine laboratory test. In addition, there are difficulties with differentiation of targeted cells in observations with a fluorescence microscope. The present study reported a novel method that utilizes FISH in combination with fluorescence immunostaining as a simple double-detection technique that addresses these problems. Using this novel method, various genetic aberrations, as well as protein overexpression were easily visualized in isologous sections. In particular, FISH signals with our method clearly identify target cells in samples with poor differentiation between tumor cells coexisting with normal cells. It is proposed that this simple technique is widely applicable as a routine laboratory test and future developments are expected. PMID- 29422972 TI - Detection of circulating tumor cells in pulmonary venous blood for resectable non small cell lung cancer. AB - Intraoperative manipulation causes circulating tumor cell (CTC) shedding into the blood and accelerates metastasis in non-small cell lung cancer (NSCLC). The present study was conducted to assess the degree of dissemination resulting from surgery and to explore the biological features of CTCs. In patients with NSCLC who underwent complete resection, the pulmonary vein (PV) was isolated and stapled following thoracotomy. The number of CTCs retained per 7.5 ml PV blood (CTC-PV) and peripheral blood were detected. Following hematopoietic cell depletion, a xenograft assay was performed using the CTC-PV. A total of 32 consecutive patients were enrolled in the study, the majority of whom had CTCs in their PV blood (n=29, 90.6%). Circulating tumor microemboli (CTM) were identified in 12 patients (37.5%). The CTC-PV and CTM-PV counts were positively correlated with tumor size (P=0.012 and P=0.028, respectively). Patients with small tumors (<3.0 cm) also had considerable CTC-PV and CTM-PV. A total of 8 patients received platinum-based chemotherapy prior to surgery. The CTC-PV and CTM-PV counts in patients with partial response were significantly lower than those in patients with stable disease or who did not receive induction therapy (P=0.025 and P=0.044, respectively). The enriched CTC-PV from 3 patients were injected into 3 immunodeficient mice, and 1 mouse developed a xenograft tumor. To conclude, the present study indicates that intraoperative manipulation contributes to the hematogenous dissemination of tumorigenic CTCs and CTM. Lobectomy is recommended for lung cancer of any tumor size and stage according to oncological principles, in addition to ligating the PV, if possible, prior to any other treatment. PMID- 29422973 TI - Chloroquine affects autophagy to achieve an anticancer effect in EC109 esophageal carcinoma cells in vitro. AB - Esophageal carcinoma is a malignancy that severely threatens human health, with a high incidence rate and a low 5-year survival rate. Resistance to chemotherapy frequently emerges during its treatment, partly due to the induction of autophagy. Therefore, targeting autophagy may be a promising therapeutic approach for the treatment of esophageal carcinoma. In the present study, it was investigated how chloroquine (CQ) can influence the growth ability and biological behaviors of EC109 esophageal squamous carcinoma cells in vitro, as well as the potential molecular mechanisms behind its activity. It was demonstrated that CQ could suppress the growth and proliferation of EC109 cells in a time- and dose dependent manner; migration and colony formation abilities were also inhibited by CQ. Furthermore, subsequent to the exposure to CQ, the number of autophagosomes was clearly increased in EC109 cells overexpressing green fluorescent protein tagged-light chain (LC)3 when observed by fluorescence microscopy. Protein expression of the endogenous autophagy markers LC3-II and p62 was elevated subsequent to CQ treatment, whereas the expression of proteins from the protein kinase B/mechanistic target of rapamycin target of rapamycin pathway was inhibited. This suggested that CQ could induce the formation of autophagosomes in the initiation of autophagy, but inhibit the degradation of autophagosomes in a later stage of autophagy. The overall effect was that autophagic cell death was activated by CQ, as confirmed by flow cytometry. Overall, the anticancer effect of chloroquine on EC109 was revealed to be mediated through modulating autophagy, and this may produce promising therapeutic benefits for esophageal carcinoma. PMID- 29422974 TI - Low risk HPV-6E6 induces apoptosis in bone marrow-derived dendritic cells. AB - The present study assessed the subcellular localization and apoptotic potential of low-risk human papilloma virus 6E6 (HPV-6E6), expressed in bone marrow-derived dendritic cells (DCs). DCs were obtained from C57BL/6 mice and transfected with a pGFP-6E6 plasmid. The subcellular localization of E6 was determined by tracing green fluorescent protein (GFP) using fluorescence microscopy. Apoptosis was assessed by staining nuclei with DAPI and performing an apoptosis-based flow cytometry assay. The co-localization of E6 and p53 was also investigated using confocal microscopy. In addition, the expression of apoptosis-associated proteins was analyzed using immunoblotting. The results of the present study demonstrated that low-risk HPV-6E6 is predominantly localized in the cytoplasm of DCs. Furthermore, p53 was upregulated in DCs transfected with pGFP-6E6 and co localized with GFP-6E6 in the cytoplasm. DCs transfected with a control pGFP plasmid did not undergo apoptosis, whereas cells transfected with pGFP-6E6 did, as indicated by the presence of cell debris and condensation of the nuclei. Furthermore, the expression of apoptosis-associated proteins, including p53, BCL2 associated X apoptosis regulator (Bax), BCL2 homologous antagonist/killer (Bak) and cytochrome c, were significantly higher in DCs expressing low-risk E6 than in control cells. Therefore, the current study demonstrated that low-risk HPV-6E6 is predominantly located in the cytoplasm of DCs and induces apoptosis. This may be an important mechanism that explains why low-risk HPV is unable to induce malignant transformation. PMID- 29422975 TI - Assessment of PI3K/AKT/PTEN signaling pathway activity in colorectal cancer using quantum dot-conjugated antibodies. AB - In certain patients with advanced colorectal cancer, loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity is observed. PTEN is a major gatekeeper gene of the AKT serine/threonine kinase (AKT) signaling pathway responsible for the proliferative activity of cells. The assessment of AKT activity may be a prognostic factor or a predictor of response to the targeted therapies against particular signaling proteins. To precisely identify the cause and the place of the pathway deregulation, it is necessary to identify phosphorylation states and concentrations of several proteins located at different levels of the regulatory cascade. In the present study, we propose the simultaneous use of specific antibodies conjugated with different quantum dots to highlight the nature of AKT/PKB cascade deregulation in patients with colorectal cancer and the loss of PTEN expression in tumor tissue. Fifty patients with colorectal cancer of no specific location were enrolled in the study. The expression of the PTEN protein, and concentrations of phosphorylated/activated forms of 3-Phosphoinositide-dependent kinase 1 (PDK1) and AKT were assessed using quantum dot-conjugated antibodies. In patients with a diminished or complete loss of the PTEN expression in the tumor tissue increased levels of activated/phosphorylated forms of PDK1 (Phospho-PDK1-Ser241) and AKT (Phospho-AKT Thr308) proteins were found, which are responsible for the permanent activation of the phosphoinositide 3-kinase/AKT/PTEN signaling pathway in certain cases of colorectal cancer. PMID- 29422976 TI - Erratum: Safety and feasibility of laparoscopic intersphincteric resection for a lower rectal tumor. AB - [This corrects the article DOI: 10.3892/ol.2017.6664.]. PMID- 29422977 TI - Organic Matter in Cosmic Dust. AB - Organics are observed to be a significant component of cosmic dust in nearly all environments were dust is observed. In many cases only remote telescope observations of these materials are obtainable and our knowledge of the nature of these materials is very basic. However, it is possible to obtain actual samples of extraterrestrial dust in the Earth's stratosphere, in Antarctic ice and snow, in near-Earth orbit, and via spacecraft missions to asteroids and comets. It is clear that cosmic dust contains a diverse population of organic materials that owe their origins to a variety of chemical processes occurring in many different environments. The presence of isotopic enrichments of D and 15N suggests that many of these organic materials have an interstellar/protosolar heritage. The study of these samples is of considerable importance since they are the best preserved materials of the early Solar System available. PMID- 29422979 TI - All-Optical Imaging of Gold Nanoparticle Geometry Using Super-Resolution Microscopy. AB - We demonstrate the all-optical reconstruction of gold nanoparticle geometry using super-resolution microscopy. We employ DNA-PAINT to get exquisite control over the (un)binding kinetics by the number of complementary bases and salt concentration, leading to localization accuracies of ~5 nm. We employ a dye with an emission spectrum strongly blue-shifted from the plasmon resonance to minimize mislocalization due to plasmon-fluorophore coupling. We correlate the all-optical reconstructions with atomic force microscopy images and find that reconstructed dimensions deviate by no more than ~10%. Numerical modeling shows that this deviation is determined by the number of events per particle, and the signal-to background ratio in our measurement. We further find good agreement between the reconstructed orientation and aspect ratio of the particles and single-particle scattering spectroscopy. This method may provide an approach to all-optically image the geometry of single particles in confined spaces such as microfluidic circuits and biological cells, where access with electron beams or tip-based probes is prohibited. PMID- 29422978 TI - DNA methylation alterations in iPSC- and hESC-derived neurons: potential implications for neurological disease modeling. AB - Background: Genetic predisposition and epigenetic alterations are both considered to contribute to sporadic neurodegenerative diseases (NDDs) such as Parkinson's disease (PD). Since cell reprogramming and the generation of induced pluripotent stem cells (iPSCs) are themselves associated with major epigenetic remodeling, it remains unclear to what extent iPSC-derived neurons lend themselves to model epigenetic disease-associated changes. A key question to be addressed in this context is whether iPSC-derived neurons exhibit epigenetic signatures typically observed in neurons derived from non-reprogrammed human embryonic stem cells (hESCs). Results: Here, we compare mature neurons derived from hESC and isogenic human iPSC generated from hESC-derived neural stem cells. Genome-wide 450 K-based DNA methylation and HT12v4 gene array expression analyses were complemented by a deep analysis of selected genes known to be involved in NDD. Our studies show that DNA methylation and gene expression patterns of isogenic hESC- and iPSC derived neurons are markedly preserved on a genome-wide and single gene level. Conclusions: Overall, iPSC-derived neurons exhibit similar DNA methylation patterns compared to isogenic hESC-derived neurons. Further studies will be required to explore whether the epigenetic patterns observed in iPSC-derived neurons correspond to those detectable in native brain neurons. PMID- 29422980 TI - Facile Synthesis of Indium Sulfide/Flexible Electrospun Carbon Nanofiber for Enhanced Photocatalytic Efficiency and Its Application. AB - Heterojunction system has been proved as one of the best architectures for photocatalyst owing to extending specific surface area, expanding spectral response range, and increasing photoinduced charges generation, separation, and transmission, which can provide better light absorption range and higher reaction site. In this paper, Indium Sulfide/Flexible Electrospun Carbon Nanofiber (In2S3/CNF) heterogeneous systems were synthesized by a facile one-pot hydrothermal method. The results from characterizations of SEM, TEM, XRD, Raman, and UV-visible diffuse reflectance spectroscopy displayed that flower-like In2S3 was deposited on the hair-like CNF template, forming a one-dimensional nanofibrous network heterojunction photocatalyst. And the newly prepared In2S3/CNF photocatalysts exhibit greatly enhanced photocatalytic activity compared to pure In2S3. In addition, the formation mechanism of the one dimensional heterojunction In2S3/CNF photocatalyst is discussed and a promising approach to degrade Rhodamine B (RB) in the photocatalytic process is processed. PMID- 29422982 TI - The Opioid Crisis: Our Acupuncture Challenges and Responsibilities. PMID- 29422983 TI - 3rd American Traditional Chinese Medicine Association Congress Goes to Washington. PMID- 29422981 TI - Axisymmetric Contact Problem for a Flattened Cell: Contributions of Substrate Effect and Cell Thickness to the Determination of Viscoelastic Properties by Using AFM Indentation. AB - Nanoindentation technology has proven to be an effective method to investigate the viscoelastic properties of biological cells. The experimental data obtained by nanoindentation are frequently interpreted by Hertz contact model. However, in order to validate Hertz contact model, some studies assume that cells have infinite thickness which does not necessarily represent the real situation. In this study, a rigorous contact model based upon linear elasticity is developed for the interpretation of indentation tests of flattened cells. The cell, normally bonded to the Petri dish, is initially treated as an elastic layer of finite thickness perfectly fixed to a rigid substrate. The theory of linear elasticity is utilized to solve this contact issue and then the solutions are extended to viscoelastic situation which is regarded as a good indicator for mechanical properties of biological cells. To test the present model, AFM-based creep test has been conducted on living human hepatocellular carcinoma cell (SMMC 7721 cell) and its fullerenol-treated counterpart. The results indicate that the present model could not only describe very well the creep behavior of SMMC-7721 cells, but also curb overestimation of the mechanical properties due to substrate effect. PMID- 29422984 TI - How Do You Treat Back Pain in Your Practice? Part 2. PMID- 29422985 TI - Abstracts and Commentaries on Key Articles in the Literature. PMID- 29422986 TI - Radical Scavenger Capacity of Jabuticaba Fruit (Myrciaria cauliflora) and Its Biological Effects in Hypertensive Rats. AB - Jabuticaba is an exotic fruit native to Brazil that has been arousing medicinal interest. Using chemical (HPLC-PDA, resonance mass spectra, and NMR), electroanalytical (differential pulse voltammetry, radical scavenging assay), and pharmacological (in vivo and in vitro) approaches, we have identified its bioactive compounds and hypotensive effects on hypertensive rats. The hydroalcoholic extract of jabuticaba (HEJ) presents a great quantity of phenolic compounds, and several molecules with hydroxyl groups present high efficiency as an antioxidant. The treatment with HEJ (100 and 300 mg/kg/day, for four weeks) presented hypotensive effects on L-NAME-induced hypertensive rats, possibly improving the nitric oxide bioavailability because of its high antioxidant potential. Furthermore, renal and cardiac hypertrophies were also attenuated after the HEJ treatment. Moreover, the vascular responses to contractile and dilating agonists were improved with the HEJ treatment, which is also able to induce nitric oxide production in endothelial cells. PMID- 29422987 TI - Insulin-Like Growth Factor (IGF) Binding Protein-2, Independently of IGF-1, Induces GLUT-4 Translocation and Glucose Uptake in 3T3-L1 Adipocytes. AB - Insulin-like growth factor binding protein-2 (IGFBP-2) is the predominant IGF binding protein produced during adipogenesis and is known to increase the insulin stimulated glucose uptake (GU) in myotubes. We investigated the IGFBP-2-induced changes in basal and insulin-stimulated GU in adipocytes and the underlying mechanisms. We further determined the role of insulin and IGF-1 receptors in mediating the IGFBP-2 and the impact of IGFBP-2 on the IGF-1-induced GU. Fully differentiated 3T3-L1 adipocytes were treated with IGFBP-2 in the presence and absence of insulin and IGF-1. Insulin, IGF-1, and IGFBP-2 induced a dose dependent increase in GU. IGFBP-2 increased the insulin-induced GU after long term incubation. The IGFBP-2-induced impact on GU was neither affected by insulin or IGF-1 receptor blockage nor by insulin receptor knockdown. IGFBP-2 significantly increased the phosphorylation of PI3K, Akt, AMPK, TBC1D1, and PKCzeta/lambda and induced GLUT-4 translocation. Moreover, inhibition of PI3K and AMPK significantly reduced IGFBP-2-stimulated GU. In conclusion, IGFBP-2 stimulates GU in 3T3-L1 adipocytes through activation of PI3K/Akt, AMPK/TBC1D1, and PI3K/PKCzeta/lambda/GLUT-4 signaling. The stimulatory effect of IGFBP-2 on GU is independent of its binding to IGF-1 and is possibly not mediated through the insulin or IGF-1 receptor. This study highlights the potential role of IGFBP-2 in glucose metabolism. PMID- 29422988 TI - Differential Susceptibility of Germ and Leydig Cells to Cadmium-Mediated Toxicity: Impact on Testis Structure, Adiponectin Levels, and Steroidogenesis. AB - This study investigated the relationship between germ and Leydig cell death, testosterone, and adiponectin levels in cadmium-mediated acute toxicity. Cadmium chloride was administered in a single dose to five groups of rats: G1 (0.9% NaCl) and G2 to G5 (0.67, 0.74, 0.86, and 1.1 mg Cd/kg). After 7 days, the animals were euthanized, and the testosterone and testes were analyzed. Dose-dependent Cd accumulation in the testes was identified. At 0.86 and 1.1 mg/kg, animals exhibited marked inflammatory infiltrate and disorganization of the seminiferous epithelium. While Leydig cells were morphologically resistant to Cd toxicity, massive germ cell death and DNA oxidation and fragmentation were observed. Although numerical density of Leydig cells was unchanged, testosterone levels were significantly impaired in animals exposed to 0.86 and 1.1 mg Cd/kg, occurring in parallel with the reduction in total adiponectins and the increase in high-molecular weight adiponectin levels. Our findings indicated that Leydig and germ cells exhibit differential microstructural resistance to Cd toxicity. While germ cells are a primary target of Cd-induced toxicity, Leydig cells remain resistant to death even when exposed to high doses of Cd. Despite morphological resistance, steroidogenesis was drastically impaired by Cd exposure, an event potentially related to the imbalance in adiponectin production. PMID- 29422989 TI - Regulatory role of long non-coding RNAs during reproductive disease. AB - Long non-coding RNA (lncRNA) is a group of RNAs with broad biogenesis, which are longer than 200 nt and highly conserved in their secondary and tertiary structures. lncRNA that broadly participates in varied physiological processes in organisms has abundant biological function and can regulate expression of target genes at transcriptional, post-transcriptional and epigenetic levels. LncRNAs can also affect the development of diseases, and therefore be used to diagnose and treat diseases. With new sequencing and microarray techniques, hundreds of lncRNAs involved in reproductive disorders have been identified, but their functions in these disorders are undefined. In this paper, we reviewed the studies on how lncRNAs participate in the development of reproductive disorders, hoping our outcome can instruct the future study and provide new biomarkers and therapies for reproductive disorders. PMID- 29422990 TI - Polycystic ovary syndrome in mitochondrial disorders due mtDNA or nDNA variants. AB - OBJECTIVES: Whether polycystic ovary syndrome (PCOS) is associated with mtDNA or nDNA mutations causing mitochondrial disorders (MIDs) or not is under debate. This review aims at summarising and discussing previous and recent findings concerning the frequency, diagnosis, and treatment of PCOS in MIDs. METHODS: Systematic literature review using appropriate search terms. RESULTS: Currently, no reports are available which document a causal relation between PCOS and specific or non-specific MIDs. However, reports about the presence of various mtDNA point mutations, mtDNA deletions, and mtDNA depletion in females with PCOS have been published by a single Chinese group, without being confirmed by other study groups. Arguments against a causal relation between these mtDNA variants and PCOS are that all variants were homoplasmic and that none of the patients carrying any of these variants presented with a phenotype characterised by features other than PCOS or diabetes. CONCLUSIONS: Currently, there is no evidence that PCOS is a phenotypic feature of MIDs. mtDNA variants reported by a single centre in association with PCOS need to be confirmed by multicentre studies. In case of hereditary PCOS, whole exome (genome) sequencing is recommended. PMID- 29422991 TI - Preeclampsia is associated with hypermethylation of IGF-1 promoter mediated by DNMT1. AB - Previous studies have demonstrated a dynamic epigenetic regulation of genes expression in placenta trophoblasts and a dynamic imbalance of DNA methylation and hydroxymethylation. Reduced IGF-1 has been observed in preeclampsia. This study was to investigate the interactive roles between IGF-1 and the global DNA methylation/hydroxymethylation, and the status of DNA methylation/hydroxymethylation and associated enzymes such as DNMTs and TETs in peeeclamptic placentas and hypoxic trophoblasts. It was found that IGF-1 was decreased in preeclamptic placentas and hypoxic trophoblasts when compared to the control group using immunohistochemisty, western blot, qRT-PCR and ELISA. Pyrophosphate sequencing showed IGF-1 promoter was significantly hypermethylated in preeclamptic placentas, which was responsible for reduced IGF-1 expression. Preeclamptic placentas and hypoxic trophoblasts were hypermethylated and hypohydroxymethylated accompanied by remarkably higher 5mC, DNMT1 and DNMT3b, and lower DNMT3a, 5hmC, TET1, TET2 and TET3 detected by immunohistochemisty, western blot, qRT-PCR and ELISA. Pearson's correlation confirmed a statistically significant negative correlation between IGF-1 and DNMT1. Furthermore, both treatment with 5-Aza-dc and DNMT1-siRNA significantly increased the expression of IGF-1 in HTR8 cells, indicating the potential mechanism of DNMT1-mediated DNA methylation in IGF-1 regulation. However, IGF-1 didn't change DNA methylation or hydroxymethylation. These findings suggest that preeclampsia is associated with hypermethylation of IGF-1 promoter mediated by DNMT1 and provide new insights into the diagnosis and treatment of preeclampsia. PMID- 29422992 TI - Pyrroloquinoline quinone plays an important role in rescuing Bmi-1-/- mice induced developmental disorders of teeth and mandible--anti-oxidant effect of pyrroloquinoline quinone. AB - To investigate whether pyrroloquinoline quinine (PQQ) plays an important role in rescuing Bmi-1-/- mice induced developmental disorders of teeth and mandible by regulating oxidative stress. We fed Bmi-1-/- mice a diet supplemented with PQQ (BKO+PQQ), BKO mice with normal diet (BKO) and wild type mice with normal diet (WT) as controls. We compared the differences of dental, mandibular phenotype by means of X-ray photography, micro CT scanning and three-dimensional reconstruction, HE staining, histochemistry, immunoistohemistry, TUNEL staining, Western blot and Flow cytometry in three groups of animals. Results showed that BKO+PQQ mice increased morphology of teeth and mandible, decreased X-ray transmittance, and increased bone density compared with BKO mice. Results also showed that the teeth volume and the dentin sialoprotein (DSP) immunopositive areas, the cortical thickness, alveolar bone volume, osteoblast number and activity, and alkaline phosphatase (ALP), Osteocalcin (OCN) and type I collagen (Col 1) were all reduced significantly in BKO mice compared with their wild-type littermates, whereas these parameters were increased significantly in BKO+PQQ mice compared with BKO mice. Our study indicated that, compared BKO mice, PCNA positive cells percentage of mandibular first molar epithelial root sheath area significantly increased in BKO+PQQ mice, and TUNEL positive cells percentage was significantly decreased. Further studies showed that supplemental PQQ played a role in anti-osteoporosis of teeth and mandible by up-regulating anti-oxidant capacity, inhibiting oxidative stress and reducing DNA damage, down-regulating CDKI proteins levels, and decreasing cell apoptosis. This study demonstrated that PQQ played an important role in rescuing mandible osteoporosis and disorder of teeth development in BKO mice by promoting osteoblastic bone formation of mandibular alveolar bone, inhibiting osteoclastic bone resorption, promoting odontoblast cell proliferation of epithelial root sheath area, inhibiting cell apoptosis, scavenging ROS. PMID- 29422993 TI - Mesenteric injection of adipose-derived mesenchymal stem cells relieves experimentally-induced colitis in rats by regulating Th17/Treg cell balance. AB - Efficient delivery routes are critical for the effectiveness of adipose-derived mesenchymal stem cells (ADMSCs) in treating inflammatory bowel disease (IBD). Conventional ADMSC delivery routes include local, intravenous and intraperitoneal injection. Whether mesenteric injection has potential in IBD treatment remains unknown. In the present study, we investigated the therapeutic effects of mesenteric injection of ADMSCs in a trinitrobenzene sulfonic acid-induced rat IBD model and explored whether this treatment affected T helper 17 (Th17)/regulatory T (Treg) cell ratio. The results showed that mesenteric injection of ADMSCs markedly reduced signs of colitis, colon shortening, weight loss and pathological damage. The treatment also decreased serum tumor necrosis factor alpha concentration, increased serum tumor necrosis factor alpha-stimulated gene protein 6 concentration, and augmented repair via proliferation (assessed by evaluating Ki-67 levels) in colonic tissue. Moreover, mesenteric injection of ADMSCs reduced interleukin (IL)-17A and IL-6 mRNA expression, and increased IL-10 and transforming growth factor-beta mRNA expression in colonic tissue. Protein analyses indicated that mesenteric injection of ADMSCs was associated with increased expression of forkhead box P3+ and IL-10 as well as decreased expression of retinoid-related orphan receptor lambdat and IL-17. Additionally, the treatment inhibited phosphorylation of signal transducer and activator of transcription (STAT) 3 and activated phosphorylation of STAT5. Taken together, these results suggest that mesenteric injection of ADMSCs is a promising approach to treating trinitrobenzene sulfonic acid-induced IBD, and achieves its therapeutic effect by regulating the pro/anti-inflammatory Th17/Treg cell balance. PMID- 29422994 TI - Effect of low-intensity pulsed ultrasound on the biological behaviors of bone marrow mesenchymal stem cells on titanium with different surface topographies. AB - The use of low-intensity pulsed ultrasound (LIPUS) is a promising approach to promote osteogenesis. However, few studies have reported the influence of this technique on the osseointegration of endosseous implants, especially regarding different implant topographies. We focused on how the initial interaction between cells and the titanium surface is enhanced by LIPUS and the potential regulatory mechanisms. The bone marrow mesenchymal stem cells (BMSCs) of rats were cultured on two types of titanium surfaces (polished surface, Flat and large grain blast acid etched, SLA) under LIPUS stimulation or control conditions. The cell proliferation on the implant surfaces was significantly promoted by LIPUS, which stimulated the increase in the number of microfilaments, pseudopodia formed and extracellular matrix mineralization nodules compared with those in the control group. The expression of osteogenesis-related genes, including OPN, OCN, BMP-2, ALP, Runx2 and Col-1, were up-regulated on all the surfaces by LIPUS stimulation. Our findings suggest that LIPUS enhances osteoblast differentiation from BMSCs on titanium surfaces. The use of LIPUS might be a potential adjuvant treatment to improve the osseointegration process. PMID- 29422995 TI - Inhibition of nuclear factor kappa B pathway protects myocardial ischemia/reperfusion injury in rats under treatment with abnormal savda munziq. AB - OBJECTIVE: Uighur medicine Abnormal Savda Munziq (ASMq) shows cardioprotective effect in myocardial ischemia/reperfusion injury (IRI) in animal models, but the molecular mechanism of this effect is not clear. The present study investigates the regulation of nuclear factor kappa B (NF-kappa B) pathway by ASMq in IRI rat models. METHODS: Male Sprague-Dawley rats were divided into three groups: the NF kappaB gene knockout group (n = 5); the NF-kappaB transgenic group (n = 8); and the control group (n = 5). All rats were treated with ASMq for 21 days before underwent IRI surgical procedure. Blood and tissue samples were collected for the RT-PCR, ELISA, western blot and other examination. RESULTS: Expression of NF kappaB p65mRNA and protein were down-regulated in the NF-kappaB knockout rats but up-regulated in the transgenic rats comparing with the controls (P<0.05). The upstream NF-kappaB kinase expressions, the downstream inflammatory cytokines, and the myocardial injury markers were all changed in accordance with the NF-kappaB gene modification (all P values <0.05). AMSq treatment relieved IRI in the NF kappaB knockout rats. CONCLUSION: Inhibition on NF-kappaB signaling pathway may alleviate IRI in rats under ASMq treatment. PMID- 29422996 TI - Melatonin regulates CRE-dependent gene transcription underlying osteoblast proliferation by activating Src and PKA in parallel. AB - Several studies have indicated a relationship between melatonin and idiopathic scoliosis, including our previous work which demonstrated that melatonin can inhibit osteoblast proliferation; however, the mechanism remains unclear. Here, we utilized a MTT assay to show that melatonin significantly reduces osteoblast proliferation in a concentration-and time-dependent manner. Through a combination of techniques, including real-time PCR, MTT assays, immunofluorescence, and luciferase assays, we confirmed that melatonin-induced changes in phosphorylated cAMP response element-binding protein (CREB) reduced transcriptional activity in a melatonin receptor-dependent manner. Surprisingly, treatment of osteoblasts with the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059 up-regulated other cascades upstream of CREB. We next treated cells with PKA and Src inhibitors and observed that melatonin can also activate the protein kinase A (PKA) and Src pathways. To examine whether Src is upstream from the cAMP-PKA pathway, we measured cAMP levels in response to melatonin with and without a Src inhibitor (PP2) and found that PP2 had no additional effect. Therefore, the transcription-dependent mechanisms involved in CREB phosphorylation, along with melatonin, activated Src via a parallel signaling pathway that was separate from that of PKA. Finally, we transfected osteoblasts with lentiviral CREB short hairpin (sh) RNAs and found a decrease in the expression of proliferating cell nuclear antigen (PCNA) and osteoblast proliferation. These results suggest that CREB and PCNA are downstream targets of melatonin signaling, and that the down-regulation of CREB, which is regulated via PKA and Src pathways, contributes to the melatonin-induced inhibition of osteoblast proliferation. PMID- 29422997 TI - HucMSC exosomes-delivered 14-3-3zeta enhanced autophagy via modulation of ATG16L in preventing cisplatin-induced acute kidney injury. AB - The clinical application of cisplatin is restricted by its side effects of nephrotoxicity. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-ex) have an important effect in tissue injury repair. Our previous work discovered that pretreatment with human umbilical cord mesenchymal stem cell derived exosomes (hucMSC-ex) alleviated cisplatin-induced acute kidney injury (AKI) by activating autophagy both in vitro and in vivo. In this study, we further explored the mechanisms of hucMSC-ex in autophagy for preventing cisplatin-induced nephrotoxicity. We discovered that 14-3-3zeta was contained in hucMSC-ex, and knockdown and overexpression 14-3-3zeta reduced and enhanced the autophagic activity respectively. Furthermore, Knockdown of 14-3-3zeta alleviated the preventive effect of hucMSC-ex. In contrast, overexpression of 14-3-3zeta enhanced the effect. Further results confirmed that hucMSC-ex increased ATG16L expression and that 14-3-3zeta interacted with ATG16L, promoting the localization of ATG16L at autophagosome precursors. In this study, we revealed that hucMSC-ex delivered 14-3-3zeta interacted with ATG16L to activate autophagy. Our findings suggest that 14-3-3zeta is a novel mechanism for MSC-exosomes-activated autophagy and provides a new strategy for the prevention of cisplatin-induced nephrotoxicity. PMID- 29422998 TI - Black tea and D. candidum extracts play estrogenic activity via estrogen receptor alpha-dependent signaling pathway. AB - In recent years, phytoestrogens have been shown as useful selective estrogen receptor modulators. The estrogen-like effects of black tea (BT) and D. candidum (DC), as well as the combination of the two herbs, have remained largely elusive. This study aims to investigate the phytoestrogenic effect of BT and DC extract, and the possible mechanism. The effects on T47D (ER+ cell line) proliferation were evaluated by using MTT assay. The S phase proportion of ER+ cells was determined by using flow cytometry. The estrogen antagonist ICI 182,780 was applied to block the ER function. The activation of ER-mediated PI3K/AKT and ERK signal pathways were observed by using western blot. Expression of ERalpha and PGR, as well as PS2 and Cyclin D1 were detected by using western blot and real time quantitative PCR. Firstly, our results found that BT and DC extracts promoted cell proliferation in ER-positive cells, and this effect was ER dependent. Besides, BT and DC extracts increased the S-phase cell number. Next, PI3K, AKT and ERK pathways below ER were activated by phytoestrogen treatment, and this activation was blocked by the ER antagonist. Moreover, prolonged BT and DC treatments increased the expression of ESR1 and PGR. Consistently, the mRNA levels of not only ESR1 and PGR but also estrogen-dependent effectors ps2 and cyclin D1, were increased by phytoestrogens and blocked by ICI 182,780. Taken Together, BT and DC extracts have phytoestrogenic effects, and this may provide new ideas and experimental basis for the development and application of phytoestrogens. PMID- 29422999 TI - Potassium bromate-induced kidney damage in rats and the effect of gum acacia thereon. AB - Potassium bromate (KBrO3) is used in many countries in cosmetic and food industries. In this work, we investigated in male Sprague-Dawley rats, the effect of four graded oral doses of KBrO3 (5, 15, 45 and 135 mg/kg/day for 28 days) on renal function tests, inflammation, oxidative damage, and apoptosis, as well as on histopathology, using several traditional and novel renal injury biomarkers in plasma, urine and renal tissues. We also tested the possible ameliorative action of the renoprotective prebiotic agent gum acacia (GA) on the actions of KBrO3 when given concomitantly with it in the drinking water at a concentration of 15%w/v. Taken together, the results indicated that treatment with KBrO3 at the 45 and 135 mg/kg doses caused a significant dose-dependent nephrotoxicity, as evident by the measured renal structural and functional indices and biomarkers of toxicity. GA co-treatment significantly abated most of the indices and biomarkers of the renal toxicity caused by KBrO3, suggesting a beneficial effect and its possible inclusion in edible products where KBrO3 is still used. PMID- 29423000 TI - Silencing long noncoding RNA PVT1 inhibits tumorigenesis and cisplatin resistance of colorectal cancer. AB - Long noncoding RNA plasmacytoma variant translocation 1 (PVT1) plays pivotal roles in tumorigenesis of many cancers, including colorectal cancer (CRC). However, the clinical significance and the biological functions of PVT1 in CRC remain largely unknown. In this study, we found that PVT1 was highly expressed in CRC tissues and cell lines compared with the corresponding non-cancerous samples and normal colon epithelial cells. Clinically, increased expression of PVT1 was positively correlated with tumor size, advanced histological stages, metastases, poor prognosis, and cisplatin resistance of CRC patients. In vitro studies showed that PVT1 silencing inhibited the proliferation, migration, invasion, and apoptosis escape of CRC cells. Knockdown of PVT1 in cisplatin-resistant CRC cells induced proliferation inhibition and apoptosis, whereas overexpression of PVT1 increased proliferation and decreased apoptosis of CRC cells. Mechanically, the levels of drug resistance-associated molecules, including multidrug resistance 1 and multidrug resistance protein 1, as well as the expression of anti-apoptotic Bcl-2 were significantly downregulated whereas the levels of pro-apoptotic Bax and cleaved caspase-3 were increased in PVT1-silenced cisplatin-resistant CRC cells. However, ectopic expression of PVT1 in CRC cells reversed the expressions of the molecules mentioned above. In addition, PVT1 overexpression in CRC cells significantly promoted cisplatin resistance in vivo. Collectively, these results demonstrated that PVT1 is a significant regulator in tumorigenesis and cisplatin resistance of CRC and provided evidence that PVT1 may be a promising target for CRC therapy. PMID- 29423001 TI - Hypoxia increases amyloid-beta level in exosomes by enhancing the interaction between CD147 and Hook1. AB - Hypoxia promotes the accumulation of amyloid-beta (Abeta), which is related to the pathogenesis of Alzheimer's disease (AD). CD147 is considered as an additional subunit of gamma-secretase regulated by hypoxia, and has been identified in exosomes. Abeta is also found in exosomes that participate in the intercellular communication and amyloids propagation. This study was to investigate the role of CD147 in hypoxia-induced accumulation of Abeta in exosomes. Our results showed that hypoxia increased the levels of Abeta40 and Abeta42 in exosomes and enhanced the interaction between CD147 and Hook1 in SH SY5YAPP695 cells. Moreover, hypoxia increased the interaction between amyloid precursor protein (APP) and CD147 as well as the expression of CD147 in isolated membrane. After we interfered the interaction between CD147 and Hook1 by decreasing Rab22a expression, the hypoxia induced Abeta accumulation in exosomes was significantly suppressed. In addition, the increased interaction between CD147 and Hook1 was further confirmed in hypoxia exposed C57BL/6 mice. Our findings reveal that hypoxia may increase exosome Abeta level by enhancing the interaction between CD147 and Hook1. PMID- 29423002 TI - NDUFA4 enhances neuron growth by triggering growth factors and inhibiting neuron apoptosis through Bcl-2 and cytochrome C mediated signaling pathway. AB - Dandy-Walker malformation (DWM) is the most prevalent congenital malformation in cerebellum, however, pathological mechanism of DWM has not been fully clarified. This study aims to investigate effects of NDUFA4 on growth of neurons. LV5-NDUFA4 and LV3-NDUFA4-RNAi lentivirus were constructed and transfected to neurons. Ciclosporin A, together with the two lentivirus were applied to neurons to observe neuron growth, apoptosis, and related protein expression. MTT assay was used to observe neuron growth. Apoptosis was detected by using flow cytometry assay. Real-time PCR was utilized to examine NDUFA4 mRNA expression. Western blot and immunohistochemistry assay were used to detect nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), brain fibroblast growth factor (bFGF) and cytochrome C (Cyt C) expression. Results indicated that NDUFA4 significantly enhanced neuron activity and inhibited neuron apoptosis (P<0.05). NDUFA4 significantly increased Bcl-2 and decreased cleave caspase-3 expression compared to normal control group (P<0.05). NDUFA4 up-regulated growth factors, including NGF, BDNF, bFGF and Cyt C and inhibited Cyt C expression. NDUFA4 interfere inhibits antagonistic effect of ciclosporin A on apoptosis and decrease up regulative effect of ciclosporin A on neuron growth. NDUFA4 over-expression enhances antagonistic effect of ciclosporin A on apoptosis and increases up regulative effect of ciclosporin A on neuron growth. In conclusion, NDUFA4 enhances neuron growth by triggering NGF, BDNF and bFGF expression, inhibits neuron apoptosis by increasing Bcl-2 expression and decreasing cyto C expression. Meanwhile, NDUFA4 regulates the antagonistic effect of ciclosporin A on apoptosis and the up-regulative effect of ciclosporin A on neuron growth. PMID- 29423003 TI - Direct conversion of human fibroblasts into functional Leydig-like cells by SF-1, GATA4 and NGFI-B. AB - The reprogramming of fibroblasts to induced pluripotent stem cells raises the possibility that a somatic cell can be reprogrammed to an alternative, differentiated fate without first becoming a stem/progenitor cell. Recent work has shown that fibroblasts can be reprogrammed to other, terminally differentiated cells with a combination of several transcription factors. Here, we report that a combination of four developmental transcription factors; GATA4, SF-1, NGFI-B, and COUP TF2; efficiently reprogrammed human foreskin fibroblasts into functional induced Leydig-like cells (iLCs). The iLCs expressed Leydig specific markers and secreted testosterone in vitro. We found that GATA4 and SF-1 were particularly critical for Leydig-specific markers expression and that GATA4, SF-1, and NGFI-B were necessary to generate functional iLCs that secreted testosterone. These findings demonstrate that fibroblasts can be directly converted into iLCs with a few, defined factors and may provide insight into potential therapies to treat testosterone deficiency. PMID- 29423004 TI - Herpes zoster chronification to postherpetic neuralgia induces brain activity and grey matter volume change. AB - OBJECTIVE: Herpes zoster (HZ) can develop into postherpetic neuralgia (PHN), which is a chronic neuropathic pain (NP). Whether the chronification from HZ to PHN induced brain functional or structural change is unknown and no study compared the changes of the same brains of patients who transited from HZ to PHN. We minimized individual differences and observed whether the chronification of HZ to PHN induces functional and pain duration dependent grey matter volume (GMV) change in HZ-PHN patients. METHODS: To minimize individual differences induced error, we enrolled 12 patients with a transition from HZ to PHN. The functional and structural changes of their brains between the two states were identified with resting-state functional MRI (rs-fMRI) technique (i.e., the regional homogeneity (ReHo) and fractional aptitude of low-frequency fluctuation (fALFF) method) and the voxel based morphometry (VBM) technology respectively. The correlations between MRI parameters (i.e., DeltaReHo, DeltafALFF and DeltaVBM) and Deltapain duration were analyzed too. RESULTS: Compared with HZ brains, PHN brains exhibited abnormal ReHo, fALFF and VBM values in pain matrix (the frontal lobe, parietal lobe, thalamus, limbic lobe and cerebellum) as well as the occipital lobe and temporal lobe. Nevertheless, the activity of vast area of cerebellum and frontal lobe significantly increased while that of occipital lobe and limbic lobe showed apparent decrease when HZ developed to PHN. In addition, PHN brain showed decreased GMV in the frontal lobe, the parietal lobe and the occipital lobe but increased in the cerebellum and the temporal lobe. Correlation analyses showed that some of the ReHo, fALFF and VBM differential areas (such as the cerebellum posterior lobe, the thalamus extra-nuclear and the middle temporal gyrus) correlated well with Deltapain duration. CONCLUSIONS: HZ chronification induced functional and structural change in cerebellum, occipital lobe, temporal lobe, parietal lobe and limbic lobe. These changes may be correlated with HZ-PHN chronification. In addition, these changes could be reasons of refractory chronic pain of PHN. PMID- 29423005 TI - Transcription factor Phf19 positively regulates germinal center reactions that underlies its role in rheumatoid arthritis. AB - The Polycomb Repressive Complex 2 (PRC2) component PHD Finger Protein 19 (phf19) gene has been identified to be associated with rheumatoid arthritis (RA) risk. Here we show that Phf19 is highly expressed in murine germinal centers (GCs) and RA patients. To investigate the function of Phf19 in lymphocytes, we generated RAG1-deficient mice reconstituted with Phf19 or control-vector transduced bone marrow (BM) cells. Lymphogenesis in primary lymphoid tissues of Phf19-RM is normal, however, Phf19-RM form enlarged GCs and generate more antibody-secreting cells (ASCs). Overexpression of Phf19 promotes proliferation and survival of GC B cells and Tfh cells in vivo. The uncovered Phf19-dependent targets include the genes encoding cyclin D2, the prosurvival factor Bcl-xL and CD40-CD40 ligand axis, their regulation by Phf19 could partially elucidate the advantages observed in Phf19-overexpressing GCs. Our results underscore an unrecognized but critical function for Phf19 in GCs formation and antibody generation, and implicate the potential role of Phf19 in RA pathogenesis. PMID- 29423007 TI - miR-132 suppresses the migration and invasion of lung cancer cells by blocking USP9X-induced epithelial-mesenchymal transition. AB - miR-132, a microRNA, has been reported to be down-regulated in several human cancers and is related with tumor progression; however, its function in non-small cell lung cancer (NSCLC) progression remains unclear. This study aimed to investigate the putative role of miR-132 in the metastasis of NSCLC. We determined the function of miR-132 in the migration and invasion of a NSCLC cell line in vitro using a miR-132 inhibitor and mimic. Our results showed overexpression of miR-132 significantly inhibited the migration and invasion of NSCLC cells in vitro. We then identified USP9X as a potential target of miR-132, and demonstrated miR-132 could regulate the expression of USP9X at both the mRNA and protein level. miR-132 could directly bind to the 3' untranslated region (3' UTR) of USP9X. Inhibition of USP9X by its inhibitor WP1130 reduced the migration and invasion of NSCLC cells. Furthermore, USP9X inhibition also reversed the increased migration and invasion mediated by miR-132 inhibition. We found USP9X inhibition up-regulated expression of the epithelial-mesenchymal transition (EMT) marker E-cadherin, but down-regulated vimentin expression. A similar effect was seen with miR-132 overexpression, while the opposite effect occurred with miR-132 knockdown. USP9X inhibition reversed the miR-132 inhibitor-induced vimentin up regulation and E-cadherin down-regulation. Taken together, these results indicate miR-132 prohibits the migration and invasion of NSCLC cells via targeting USP9X induced EMT. Our data provides further evidence for the critical role of miR-132 and USP9X in regulating cell invasion and migration of NSCLC. PMID- 29423006 TI - Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis. AB - To investigate the clinical efficacy and safety of umbilical cord mesenchymal stem cell (UCMSC) transplantation for treating multiple sclerosis (MS), the patients with MS were recruited and treated with UCMSC. The procedure of preparing UCMSC was in accordance with the standards formulated by the International Society for Cell Biology. Cell surface markers, multiple differentiation potential and safety of UCMSC for transplantation were detected. The number of cells in each infusion was 1 to 2*106 cells/kg. Patients were recruited in accordance with the standards of the International Mesenchymal Stem Cells Transplantation Study Group. After treatment, the clinical therapeutic effects including symptoms, vital signs, clinical attacks, magnetic resonance imaging (MRI), neurological function scores and adverse reactions such as fever, dizziness, and vascular irritation were monitored and evaluated. In addition, the regulatory effects of UCMSC on immune system of patients were also assessed. The results showed that the patients' symptoms were improved after UCMSC transplantation. No clinical attacks occurred during transplantation. MRI revealed a reduced number of foci and Expanded Disability Status Scale scores were decreased. Some of patients had adverse reactions after transplantation. These adverse effects were not serious and lasted short duration, thus no intervention was conducted and let it be eliminated by itself. The mRNA expression of CD86, IL-2, CTLA-4, and HLADRB1 in peripheral blood was significantly decreased after UCMSC transplantation (P < 0.05). Based on our present studies, UCMSCs would be considered as a safe and alternative option for treatment of MS. PMID- 29423008 TI - Generation of an acute retinal photoreceptor degeneration model in rabbits. AB - PURPOSE: To assess the appropriate dose of sodium nitroprusside for establishing acute retinal photoreceptor degeneration models in rabbits. METHODS: Sodium nitroprusside (SNP) was delivered intravitreously. Sixteen New Zealand White rabbits are divided into four groups randomly: 0.1 mM, 0.25 mM, 0.5 mM SNP intravitreal injection group (experimental groups), and normal saline intravitreal injection group (control group). Assessments included weight, anterior segment photography, fundus photography, Hematoxylin-eosin staining, immunofluorescence, multi-focal electroretinogram (mfERG) and pupillary direct light reflex were performed at baseline and day 28 after injection. The spectral domain optical coherence tomography (SD-OCT) and full field electroretinogram (fERG) were performed at baseline and day 1, 3, 7, 14, 21 and 28 after injection. RESULTS: No complications and no significant different in weight were found among all groups. No obvious change was found by slit lamp and fundus photography after injection in all groups. In SD-OCT exams, a time-dependent and dose-dependent injury of photoreceptor was found in SNP injection groups (P<0.05). The thickness of inner nuclear and plexiform layer was significantly decreased in 0.5 mM group. HE staining and immunofluorescence present the photoreceptor damage at the posterior pole (0.1, 0.25, 0.5 mM groups) and periphery (0.5 mM group). fERG and mfERG showed significant dose-dependent responses depression in SNP injection groups (P<0.05). The pupillary direct light reflex in SNP groups declined significantly at day 28th than pre-injection (P<0.05). CONCLUSIONS: Sodium nitroprusside of 0.1 mM and 0.25 mM can lead to monolayer photoreceptor degeneration at posterior pole in rabbits and the lesion is stable at 1 month after SNP injection. PMID- 29423009 TI - Negatively-charged aerosol improves burn wound healing by promoting eNOS dependent angiogenesis. AB - Aerosols exist in the form of liquid or solid particles that stably suspending in air. Our previous studies have found that aerosol can accelerate chronic wound healing. However, the biological effects of aerosol in burn wound healing and the underlying molecular mechanism remain unclear. This study aimed to investigate the effects of aerosol on the healing of deep partial-thickness burn wounds and its regulatory mechanisms. By employing a self-controlled model of rats, we demonstrated that aerosol treatment not only increased the healing rate, but also improved the healing quality of deep partial-thickness burn wounds. Besides, the excessive inflammatory responses in the burn wounds were inhibited, and the angiogenesis was increased after aerosol treatment. It did so by upregulating the expression of eNOS/NO, as well as the VGEF expression during the wound healing process. Our results demonstrate that the function of aerosol in promoting burn wound healing is achieved by activating eNOS/NO pathway. PMID- 29423010 TI - Inhibition of N-acetyltransferase 10 using remodelin attenuates doxorubicin resistance by reversing the epithelial-mesenchymal transition in breast cancer. AB - Development of resistance to doxorubicin-based chemotherapy limits curative effect in breast cancer (BC). N-acetyltransferase 10 (NAT10), a nucleolar protein involved in histone acetylation, is overexpressed in several cancers. We investigated whether NAT10 is involved in doxorubicin resistance in BC and explored the potential mechanisms. Remodelin, a NAT10 inhibitor, and a NAT10 small interfering RNA (siRNA) were used to inhibit NAT10; both remodelin and the NAT10 siRNA reduced cell viability and attenuated doxorubicin resistance in four BC cell lines. Remodelin and doxorubicin synergistically reduced cell viability, though knockdown of NAT10 and remodelin did not exert a synergistic effect in doxorubicin-treated cells. Remodelin upregulated E-cadherin and downregulated vimentin, canonical markers of the epithelial-mesenchymal transition (EMT), whereas doxorubicin had the opposite effects. Moreover, both remodelin and knockdown of NAT10 reversed the doxorubicin-induced EMT. Finally, when the EMT was blocked using a siRNA targeting Twist, remodelin could not alleviate doxorubicin resistance. Collectively, these findings demonstrate that inhibition of NAT10 attenuates doxorubicin resistance by reversing the EMT in BC. This represents a novel mechanism of doxorubicin resistance in BC and indicates remodelin may have potential clinical value to increase the efficacy of doxorubicin-based chemotherapy in BC. PMID- 29423011 TI - Luteolin alleviates NLRP3 inflammasome activation and directs macrophage polarization in lipopolysaccharide-stimulated RAW264.7 cells. AB - Pure plant extract luteolin has been demonstrated to possess numerous biological effects. However, the specific effect of luteolin on macrophage polarization and NOD-like receptor protein 3 (NLRP3) inflammasome activation has not been documented. In this study, Cultured RAW264.7 cells were treated with or without luteolin in the presence or absence of LPS. Subsequently, cell viability was tested by CCK-8 assay. Total reactive oxygen species (ROS) were measured by flow cytometry. NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), caspase-1, inducible nitric oxide synthase (iNOS) and Arginase (Arg-1) protein expression was detected using western blotting. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the level of TNF-alpha, IL-18, and Interleukin 1beta (IL-1beta). Increased production of ROS and expression of NLRP3, ASC, caspase-1, IL-18 and IL-1beta proteins were observed in RAW264.7 cells incubated with LPS and were effectively inhibited by 2 MUM luteolin. Furthermore, 2 MUM luteolin pretreatment enhanced the expression of M2 macrophage markers (Arg-1 and IL-10), and decreased the expression of markers associated with M1 macrophage polarization (TNF-alpha, IL-6 and iNOS). These results indicated that low-dose luteolin inhibits NLRP3 inflammasomes activation and promotes macrophage polarization toward an M2 phenotype, which provides new evidence for the anti inflammation activity of luteolin. PMID- 29423012 TI - CCDC26 knockdown enhances resistance of gastrointestinal stromal tumor cells to imatinib by interacting with c-KIT. AB - Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are involved in diseases such as cancer. However, little is known about the role of lncRNAs in gastrointestinal stromal tumors (GIST). In the present study, we explored the biological function of the lncRNA coiled-coil domain-containing 26 (CCDC26) in imatinib resistance of GIST. We found that human GIST-882 cells with lower CCDC26 expression were less sensitive to imatinib compared with GIST-T1 cells with higher CCDC26 expression. CCDC26 expression decreased in a time-dependent manner in the presence of imatinib. Moreover, small interfering RNA (siRNA) knockdown of CCDC26 increased GIST cell sensitivity to imatinib. The RNA pull-down experiment showed that CCDC26 can interact with c-KIT and that CCDC26 knockdown can upregulate c-KIT expression. We also found that inhibiting c-KIT induced resistance to imatinib. Lastly, we proved that inhibiting c-KIT can reverse CCDC26 knockdown-mediated imatinib resistance in GIST. We suggest that CCDC26 knockdown can induce imatinib resistance in GIST cells by downregulating c-KIT expression. Our results provide a novel insight into imatinib resistance in GIST. PMID- 29423013 TI - LED enhances anti-inflammatory effect of luteolin (3',4',5,7-tetrahydroxyflavone) in vitro. AB - Neuroinflammation is a complex pathological process usually results from abnormal microglial activation, thus, intervention in a microglial stimulation pathway could be a promising approach for the treatment of neurodegenerative diseases. Luteolin is an important bioflavonoid possesses anti-inflammatory properties, which is widely studied over these years. Light emitting diode (LED) therapy is reported to be a potential therapeutic strategy for many diseases including neurodegenerative diseases. However, little is known about the anti-inflammatory effect of LED therapy on activated microglial cells, even less is known whether there is a synergistic anti-inflammatory effect exist in LED and luteolin therapy. In this study, we aimed to confirm the anti-inflammatory effect of luteolin and LED combination therapy in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. We showed that luteolin inhibited LPS-induced cytotoxicity, tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production through modulation of p38 and extracellular signal-regulated kinase (ERK) signaling in BV2 cells. In addition, LED therapy enhanced the anti-inflammatory effect of luteolin. These results suggest that a synergistic effect between luteolin and LED could be a new effective therapy in relieving neuroinflammation. PMID- 29423014 TI - The prognosis role of AJCC/UICC 8th edition staging system in gastric cancer, a retrospective analysis. AB - OBJECTIVE: The present study was designed to investigate whether AJCC/UICC 8th edition staging system precisely differentiated patients with different prognosis of gastric cancer (GC). METHODS: There were 540 GC cases included in this study. Stratification was done according to the 7th and 8th AJCC/UICC tumor-node metastasis (TNM) staging systems. Detailed comparison was conducted between two editions in terms of the sub-classification of pN3 stage, redefinitions of stage III, homogeneity, discrimination power, predictive accuracy, and complexity. RESULTS: Compared to the 7th edition, the 8th TNM staging system performed better by incorporating pN3a and pN3b into the final stage of GC (P<0.001), had better stage grouping homogeneity (P<0.001), prognostic value (area under the curve, AUC value was 0.809), and comparable discrimination power. CONCLUSIONS: AJCC 8th TNM staging system showed improved efficiency in GC prognosis. PMID- 29423015 TI - Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells. AB - Chemoresistance in gastric cancer is the leading cause of tumor recurrence and poses a substantial therapeutic challenge. The stem cell biomarker CD133 has been implicated in drug resistance of tumor-initiating cells in a number of cancers including gastric cancer. Therefore, we investigated the molecular mechanism of CD133-associated multidrug resistance in gastric cancer cells. Using CD133 overexpressing and knockdown gastric cancer cell lines, we demonstrated that loss of CD133 significantly increased the growth inhibition of chemotherapeutic agents; whereas, overexpression significantly reduced growth inhibition. Furthermore, CD133 knockdown significantly reduced the enzymatic activity of phosphatidylinositol-3 kinase (PI3K) and the expression of P-glycoprotein (P-gp), B-cell lymphoma 2 (BCL2), and phosphorylated-protein kinase B (p-AKT), but elevated the expression of BCL2 associated X (BAX). Conversely, overexpression of CD133 significantly increased PI3K enzymatic activity, expression of P-gp, BCL2, and p-AKT, and decreased BAX expression. The PI3K/AKT inhibitor LY294002 mirrored the effects of loss of CD133; whereas, the PI3K/AKT activator epidermal growth factor reproduced the effects of CD133 overexpression. To identify the interaction between CD133 and PI3K, we used site-directed mutagenesis to mutate individual tyrosine residues of CD133. We found that binding between CD133 and p85, the regulatory subunit of PI3K, was significantly reduced when tyrosine 852 was mutated. In summary, we have demonstrated that CD133 activates the PI3K/AKT signal transduction pathway through direct interaction with PI3K-p85, resulting in multidrug resistance of gastric cancer cells. These results suggest that the interaction between CD133 and PI3K-p85 may offer a novel therapeutic target in multidrug resistant gastric cancer. PMID- 29423016 TI - Exendin-4 promotes the osteogenic differentiation of osteoblasts via the Hedgehog/Gli1 signaling pathway. AB - This study aimed to investigate the effect and mechanisms of Exendin-4 mediated Hedgehog/Gli1 signaling pathway on the differentiation of osteoblasts in mouse. The alkaline phosphate activity, alizarin red staining and expression of Gli1, GLP-1R, Hedgehog, Runx2 and osteocalcin were analyzed using PCR and Western blot analysis after treating the osteoblastic cell line MC3T3-E1 with Exendin-4. Osteoblasts were treated with Gli1-siRNA and Hedgehog receptor antagonist Cyclopamine (Cy) and analyzed for their impact on the Hedgehog/Gli1 signaling pathway. Our results showed that optimal treatment of Exendin-4 was 7 days at 10 7 mol/L. Exendin-4 significantly promoted osteoblast formation in the cell line in a dose-dependent manner and up-regulated the expression of GLP-1R, Hedgehog and Gli1. Gli1-siRNA significantly down regulated the expression of Gli1 and Runx2, and offset Exendin-4-induced osteoblast differentiation. Similarly, Cy offset Exendin-4-induced Gli1 up-regulation. It is clear that Exendin-4 can promote the osteogenic differentiation of osteoblasts through Hedgehog/Gli1 signaling pathway. PMID- 29423017 TI - Aerosolized deferoxamine administration in mouse model of bronchopulmonary dysplasia improve pulmonary development. AB - Bronchopulmonary dysplasia (BPD) is the most common complication in preterm newborns. It occurs due to early exposure to high-oxygen and ventilation therapy. The mechanisms of disrupted alveolarization and vascular development associated with BPD were unclear. Deferoxamine (DFO) has been reported to reduce mortality and lung injury in mice after chlorine exposure. The effect of DFO in the treatment of BPD has not been explored. This study aimed to investigate the effect of aerosolized DFO administration in a mouse model of BPD. A mouse model of oxygen-induced BPD was established by postnatal hyperoxia (75% oxygen for 7 days) and DFO [17 mg/(kg.day)] (BPD+D) or aerosolized vehicle (BPD+V) administered for 14 days. The mice were anesthetized and sacrificed after 14 days treatment before removing the lungs for analysis. An exogenous continuous aerosol of DFO exerted a biological effect on BPD mice. The BPD+DFO group showed a better weight gain compared with the BPD+V group. Furthermore, the treatment of DFO exhibited a reduced pathological severity and increase expression of hypoxia inducible factor (HIF)-1alpha and CD31, and activated downstream vascular endothelial growth factor (VEGF)-induced angiogenesis. The results showed that C57BL/6 mice exposed to hyperoxic environment and treated with aerosolized of DFO solution, obviously promoted the pulmonary vascularization and alveolarization. The HIF-1alpha/VEGF signaling pathway mediated this process. The findings indicated that treatment with an exogenous continuous aerosol of DFO might be a potential therapeutic strategy for BPD. PMID- 29423018 TI - Erratum: Targeting gut microbiota: a potential promising therapy for diabetic kidney disease. AB - [This corrects the article on p. 4009 in vol. 8, PMID: 27829988.]. PMID- 29423020 TI - Targeting lipogenesis in the treatment of metabolic diseases and cancer. PMID- 29423019 TI - The role of 18F-fluorodeoxyglucose positron emission tomography in the management of patients with pancreatic adenocarcinoma. AB - Pancreatic cancer continues to have a grim prognosis with 5-year survival rates at less than 5 %. It is a particularly challenging health problem given these poor survival outcomes, aggressive tumor biology, and late onset of symptoms. Most patients present with advanced unresectable cancer however, margin-negative resection provides a rare chance for cure for patients with resectable disease. The standard imaging modality for the diagnosis and management of pancreatic cancer is contrast-enhanced multidetector computed tomography. Remarkable advances in CT technology have led to improvements in the ability to detect small tumors and intricate vasculature involvement by the tumor, yet CT is still restricted to providing a morphological portrait of the tumor. Diagnosis can be challenging due to similar appearance of certain benign and malignant disease. Distant metastatic disease can be silent on CT leading to improper staging, and thus management, of certain patients. Furthermore, radiation-induced fibrosis and necrosis complicate assessment of treatment response by CT alone. F fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is becoming a prevalent tool employed by physicians to improve accuracy in these clinical scenarios. Malignant transformation causes a high metabolic activity of cancer cells. 18F-FDG-PET captures this functional activity of malignancies by capturing areas with high glucose utilization rates. Imaging function rather than morphological appearance, 18F-FDG-PET has a unique role in the management of oncology patients with the ability to detect regions of tumor involvement that may be silent on conventional imaging. Literature on the sensitivity and specificity of 18F-FDG-PET fails to reach a consensus, and improvements resulting in hybridization of 18F-FDG-PET and CT imaging techniques are preliminary. Here we review the potential role of 18F-FDG-PET and PET/CT in improving accuracy in the initial evaluation and subsequent steps in the management of pancreatic cancer patients. PMID- 29423021 TI - Association of p53 and mitochondrial gene with chemosensitization by metformin in ovarian cancer. AB - Objective: This study aims to investigate the association of p53 and D-loop gene with drug resistance and sensitization induced by metformin in ovarian cancer. Results: Metformin suppresses cells in a time-dependent manner, but the inhibition does not change with the dose of metformin. This suggests that within a certain range of concentration in the body, metformin has a constant inhibitory effect on cells; and the long-term use of metformin yields a better effect. Conclusions: Metformin enhances the sensitivity of drug-resistant ovarian cancer cells to chemotherapy. Methods: The third passage cells of 17 cancerous ovarian tissues, which were successfully passaged five times, were used as the study objects; and the SKOV3 cell line was used as the positive control. After three adaptations, cells were cultured for 72 hours in an orthogonal experiment using drugs that were used for adaptation. Then, the inhibitory rate on cells in the experimental group was observed by CCK8 assay, in order to study the sensitization effect of metformin in different chemotherapies of ovarian cancer. PMID- 29423022 TI - Comprehensive analysis of gene expression and DNA methylation datasets identify valuable biomarkers for rheumatoid arthritis progression. AB - Rheumatoid arthritis (RA) represents a common systemic autoimmune disease which lays chronic and persistent pain on patients. The purpose of our study is to identify novel RA-related genes and biological processes/pathways. All the datasets of this study, including gene expression and DNA methylation datasets of RA and OA samples, were obtained from the free available database, i.e. Gene Expression Omnibus (GEO). We firstly identified the differentially expressed genes (DEGs) between RA and OA samples through the limma package of R programming software followed by the functional enrichment analysis in the Database for Annotation, Visualization and Integrated Discovery (DAVID) for the exploring of potential involved biological processes/pathways of DEGs. For DNA methylation datasets, we used the IMA package for their normalization and identification of differential methylation genes (DMGs) in RA compared with OA samples. Comprehensive analysis of DEGs and DMGs was also conducted for the identification of valuable RA-related biomarkers. As a result, we obtained 394 DEGs and 363 DMGs in RA samples with the thresholds of |log2fold change|> 1 and p-value < 0.05, and |delta beta|> 0.2 and p-value < 0.05 respectively. Functional analysis of DEGs obtained immune and inflammation associated biological processes/pathways. Besides, several valuable biomarkers of RA, including BCL11B, CCDC88C, FCRLA and APOL6, were identified through the integrated analysis of gene expression and DNA methylation datasets. Our study should be helpful for the development of novel drugs and therapeutic methods for RA. PMID- 29423023 TI - Infliction of proteotoxic stresses by impairment of the unfolded protein response or proteasomal inhibition as a therapeutic strategy for mast cell leukemia. AB - The intensity and duration of endoplasmic reticulum (ER) stress converts the unfolded protein response (UPR) from an adaptive into a terminal response. The first regulates homeostasis, the latter triggers apoptosis. Cells that rapidly proliferate and possess developed secretory capabilities, such as leukemia cells, depend on an efficiently operating UPR to maintain proteostasis. Activation of terminal UPR by either blockade of adaptive UPR or exaggeration of ER stress has been explored as a novel approach in cancer therapy. For mast cell leukemia (MCL) the efficacy of both approaches, by utilizing the KITV560G,D816V-positive MCL cell line HMC-1.2, was investigated. We show that HMC-1.2 cells display a tonic activation of the IRE1alpha arm of the UPR, which constitutively generates spliced XBP1. Inhibition of IRE1alpha by different types of inhibitors (MKC-8866, STF-083010, and KIRA6) suppressed proliferation at concentrations needed for blockade of IRE1alpha-mediated XBP1 splicing. At higher concentrations, these inhibitors triggered an apoptotic response. Blocking the proteasome by bortezomib, which confers an exaggerated UPR, resulted in a marked cytotoxic response. Bortezomib treatment also caused activation of the kinase JNK, which played a pro-proliferative and anti-apoptotic role. Hence, the combination of bortezomib with a JNK inhibitor synergized to induce cell death. In summary, the UPR can be addressed as an effective therapeutic target against KITD816V-positive MCL. PMID- 29423024 TI - A novel multiplex detection array revealed systemic complement activation in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is one of the most common tumors within the oral cavity. Early diagnosis and prognosis tools are urgently needed. This study aimed to investigate the activation of the complement system in OSCC patients as potential biomarker. Therefore, an innovative complement activation array was developed. Characterized antibodies detecting the complement activation specific epitopes C3a, C5a and sC5b-9 along with control antibodies were implemented into a suspension bead array. Human serum from a healthy (n = 46) and OSCC patient (n = 57) cohort were used to investigate the role of complement activation in oral tumor progression. The novel multiplex assay detected C3a, C5a and sC5b-9 from a minimal sample volume of human tears, aqueous humor and blood samples. Limits of detection were 0.04 ng/mL for C3a, 0.03 ng/mL for C5a and 18.9 ng/mL for sC5b-9, respectively. Biological cut-off levels guaranteed specific detections from serum. The mean serum concentration of a healthy control cohort was 680 ng/mL C3a, 70 ng/mL C5a and 2247 ng/mL sC5b-9, respectively. The assay showed an intra assay precision of 2.9-6.4% and an inter-assay precision of 9.2-18.2%. Increased systemic C5a (p < 0.0001) and sC5b-9 (p = 0.01) concentrations in OSCC patients were determined using the validated multiplex complement assay. Higher C5a concentrations correlated with tumor differentiation and OSCC extension state. Systemic sC5b-9 determination provided a novel biomarker for infiltrating tumor growth and C3a levels were associated with local tumor spreading. Our study suggests that systemic complement activation levels in OSCC patients may be useful to assess disease progression. PMID- 29423025 TI - Methylseleninic acid induces NAD(P)H:quinone oxidoreductase-1 expression through activation of NF-E2-related factor 2 in Chang liver cells. AB - Selenium has been reported to induce the expression of some cytoprotective enzymes, which may account for its chemoprotective and chemopreventive effects. However, it remains largely unresolved whether these effects are exerted by selenium itself or mediated by its metabolite(s). In the present study, methylseleninic acid (MSeA), a monomethylated selenium, induced the expression of NAD(P)H:quinone oxidoreductase-1 (NQO-1) in human Chang liver cells. Expression of NQO-1 and other antioxidant/stress response genes is primarily regulated by the transcription factor NF-E2-related factor2 (Nrf2). Exposure of human Chang liver cells to MSeA (3 MUM) increased nuclear translocation of Nrf2 and binding to antioxidant response elements. Silencing Nrf2 markedly reduced the MSeA induced NQO-1 expression. In comparison with embryonic fibroblasts from Nrf2 wild type mice, those from Nrf2 knockout mice failed to induce NQO-1 expression when treated with MSeA. Moreover, MSeA treatment enhanced ubiquitination of Keap1, but repressed Nrf2 ubiquitination. Pretreatment of cells with dithiothreitol abrogated the MSeA-induced NQO-1 expression, suggesting that MSeA causes Keap1 thiol modification. MSeA-induced NQO-1 upregulation was attenuated in cells harbouring the mutant Keap1 in which the cysteine 151 residue was replaced by serine. Oral administration of MSeA (1 mg/kg) by gavage to mice induced hepatic NQO-1 expression. Similar to MSeA, methylselenol generated from selenomethionine by methioninase activity induced NQO-1 expression. In conclusion, MSeA, the immediate precursor of methylselenol, upregulates the expression of NQO-1 via the Keap1-Nrf2 signaling. The above findings suggest that biological activities of selenium are dependent on the nature of the metabolites as well as the type of ingested selenium formulations. PMID- 29423026 TI - Effect of calcium salt of long-chain fatty acids and alfalfa supplementation on performance of Holstein bulls. AB - The purpose of this study was to assess the effects of calcium salt of long-chain fatty acids (CSFA) and alfalfa on beef cattle in the late fattening. 48 Holstein bulls were selected and randomly divided into 4 groups, feeding four dietary that Leymus chinensis with (LC) or with no (LN) 2.4% CSFA, and alfalfa replaced 50% Leymus chinensis with (AC) or with no (AN) 2.4% CSFA. The results indicated that alfalfa improved the feed conversion rate (P < 0.05). CSFA increased serum low density lipoprotein cholesterol, and reduced the cooking loss of Longissimus muscle (P < 0.05). CSFA and alfalfa reduced Acetate/Propionate. Alfalfa and CASF had significant additive effects on the apparent digestibility of dry matter, crude protein, neutral detergent fiber, acid detergent fiber, organic matter and rumen fermentation for acetate, isobutyrate, butyrate, isovalerate, total volatile fatty acids (P < 0.05). CSFA increased microbial diversity index when compared with alfalfa (P < 0.05), but no significant differences were detected in bacterial genera abundances among diets. The relative abundances of rumen bacterial genera have significant correlation with apparent digestibility of nutrients, rumen fermentation characteristics and serum biochemical parameters (P < 0.05). These results comprehensively evaluated the additive effects of alfalfa and CSFA on the application in Holstein bulls. PMID- 29423027 TI - Targeting the T-Lak cell originated protein kinase by OTS964 shrinks the size of power-law coded heterogeneous glioma stem cell populations. AB - Glioblastoma resists chemoradiotherapy, then, recurs to be a fatal space occupying lesion. The recurrence is caused by re-growing cell populations such as glioma stem cells (GSCs), suggesting that GSC populations should be targeted. This study addressed whether a novel anti-cancer drug, OTS964, an inhibitor for T LAK cell originated protein kinase (TOPK), is effective in reducing the size of the heterogeneous GSC populations, a power-law coded heterogeneous GSC populations consisting of glioma sphere (GS) clones, by detailing quantitative growth properties. We found that OTS964 killed GS clones while suppressing the growth of surviving GS clones, thus identifying clone-eliminating and growth disturbing efficacies of OTS964. The efficacies led to a significant size reduction in GS populations in a dose-dependent manner. The surviving GS clones reconstructed GS populations in the following generations; the recovery of GS populations fits a recurrence after the chemotherapy. The recovering GS clones resisted the clone-eliminating effect of OTS964 in sequential exposure during the growth recovery. However, surprisingly, the resistant properties of the recovered GS clones had been plastically canceled during self-renewal, and then the GS clones had become re-sensitive to OTS964. Thus, OTS964 targets GSCs to eliminate them or suppress their growth, resulting in shrinkage of the power-law coded GSC populations. We propose a therapy focusing on long-term control in recurrence of glioblastoma via reducing the size of the GSC populations by OTS964. PMID- 29423028 TI - Increased risk of testis failure in testicular germ cell tumor survivors undergoing radiotherapy. AB - Testicular germ cell tumors (TGCTs) are prevalent in males of reproductive age. Among the available therapeutic choices, pelvic radiotherapy (RT) and simple surveillance (SURV) are usually pursued. However, RT is considered to have life threatening effects on testicular functions. In this study we sought to clarify this issue by evaluating sperm parameters and sex hormones in 131 TGCTs RT treated-patients at both baseline (T0) and 12 (T1) and 24 months (T2) of follow up. An age-matched group of 61 SURV patients served as control. Sperm parameters were comparable between SURV and RT at T0. The RT group showed a significant reduction of all sperm parameters at T1 (all P values < 0.05 vs T0 and vs SURV at T1) and increased levels of sperm aneuploidies, with some degree of recovery at T2. On the other hand, despite normal levels of total testosterone being detected in both groups, luteinizing hormone (LH) levels in the RT group progressively increased at T1 and T2 with a relative risk of developing subclinical hypogonadism of 3.03 (95% CI: 1,50-6,11) compared to SURV. Again, compared to SURV, exposure to RT was associated with a 5.78 fold (95% CI: 2,91-11,48) risk of developing vitamin D insufficiency. These data suggest a likely RT-dependent impairment of the Leydig cell compartment. PMID- 29423029 TI - Recombinant frizzled1 protein attenuated cardiac hypertrophy after myocardial infarction via the canonical Wnt signaling pathway. AB - Postinfarct cardiac hypertrophy is an independent risk factor for heart failure and sudden death. Regression of cardiac hypertrophy has emerged as a promising strategy in the treatment of myocardial infarction (MI). Here we hypothesized that frizzled1 (FZD1), a receptor of the canonical Wnt signaling pathway, is a novel mediator of ischemia-associated cardiac hypertrophy. MI was induced in mice by left anterior descending (LAD) coronary occlusion. One week after MI, the expression of FZD1 was found to be notably increased in the left ventricles (LVs) of the MI-mice compared to shams. Mouse recombinant FZD1 protein (RFP) was subcutaneously injected in the mice to provoke autoimmunization response. Anti FZD1 antibody titer was significantly increased in the plasma of RFP-treated mice. RFP significantly mitigated the MI-induced cardiac hypertrophy and improved cardiac function in the MI mouse hearts. Moreover, increased heart and LV weights, myocardial size and the expression of beta-myosin heavy chain in the MI mice were also found to be attenuated by RFP. FZD1 was found to be significantly up-regulated in hypoxia-treated neonatal rat cardiomyocytes (NRCMs). Silencing FZD1 by siRNA transfection notably repressed the hypoxia-induced myocardial hypertrophy in NRCMs. Mechanistically, activation of canonical Wnt signaling induced by MI, e.g., beta-catenin and glycogen synthase kinase-3beta, was restrained in the LVs of the MI-mice treated by RFP, these inhibition on canonical Wnt signaling was further confirmed in hypoxic NRCMs transfected with FZD1 siRNA. In conclusion, immunization of RFP attenuated cardiac hypertrophy and improved cardiac function in the MI mice via blocking the canonical Wnt signaling pathway. PMID- 29423030 TI - Targeting dual specificity protein kinase TTK attenuates tumorigenesis of glioblastoma. AB - Accumulating evidence has proved that glioma stem-like cells (GSCs) are responsible for tumorigenesis, treatment resistance, and subsequent tumor recurrence in glioblastoma (GBM). In this study, we identified dual specificity protein kinase TTK (TTK) as the most up-regulated and differentially expressed kinase encoding genes in GSCs. Functionally, TTK was essential for in vitro clonogenicity and in vivo tumor propagation in GSCs. Clinically, TTK expression was highly enriched in GBM, moreover, was inversely correlated with a poor prognosis in GBM patients. Mechanistically, mitochondrial fission regulator 2 (MTFR2) was identified as one of the most correlated genes to TTK and transcriptionally regulated TTK expression via activation of TTK promoter. Collectively, MTFR2-dependent regulation of TTK plays a key role in maintaining GSCs in GBM and is a potential novel druggable target for GBM. PMID- 29423031 TI - Quantitative analysis of prompt gamma ray imaging during proton boron fusion therapy according to boron concentration. AB - The purpose of this study is to evaluate the prompt gamma ray imaging technique according to the clinical boron concentration range during proton boron fusion therapy (PBFT). To acquire a prompt gamma ray image from 32 projections, we simulated four head single photon emission computed tomography and a proton beam nozzle using a Monte Carlo simulation. We used modified ordered subset expectation maximization reconstruction algorithm with a graphic processing unit for fast image acquisition. Boron concentration was set as 20 to 100 MUg at intervals of 20 MUg. For quantitative analysis of the prompt gamma ray image, we acquired an image profile drawn through two boron uptake regions (BURs) and calculated the contrast value, signal-to-noise ratio (SNR), and difference between the physical target volume and volume of the prompt gamma ray image. The relative counts of prompt gamma rays were noticeably increased with increasing boron concentration. Although the intensities on the image profiles showed a similar tendency according to the boron concentration, the SNR and contrast value were improved with increasing boron concentration. This study suggests that a tumor monitoring technique using prompt gamma ray detection can be clinically applicable even if the boron concentration is relatively low. PMID- 29423033 TI - Prognostic significance of ST6GalNAc-1 expression in patients with non-metastatic clear cell renal cell carcinoma. AB - Background: Sialyltransferase ST6GalNAc-1 is highly expressed in tumor cells and associated with tumor aggressiveness and poor prognosis. In the present study, we aimed to investigate the clinical and prognostic significance of sialyltransferase ST6GalNAc-1 in patients with non-metastatic ccRCC. Results: High expression of ST6GalNAc-1 in tumor tissue was an independent prognostic factor for overall survival (p<0.001) and recurrence free survival (p<0.001) in multivariate analysis. The nomograms could give better prediction for overall survival and recurrence free survival in ccRCC patients. Methods: 264 patients diagnosed with non-metastatic clear cell renal cell carcinoma were enrolled in the present study. Immunohistochemical staining was performed on tissue microarrays to evaluate the intratumoral ST6GalNAc-1 expression. Kaplan-Meier method and Cox proportional hazard model were applied to assess the prognostic value of ST6GalNAc-1. Nomograms were generated to refine individual risk stratification in ccRCC patients. Conclusion: ST6GalNAc-1 was an independent adverse prognostic factor for both overall survival and recurrence free survival in patients with non-metastatic ccRCC. PMID- 29423032 TI - Small non-coding RNA profiling in human biofluids and surrogate tissues from healthy individuals: description of the diverse and most represented species. AB - The role of non-coding RNAs in different biological processes and diseases is continuously expanding. Next-generation sequencing together with the parallel improvement of bioinformatics analyses allows the accurate detection and quantification of an increasing number of RNA species. With the aim of exploring new potential biomarkers for disease classification, a clear overview of the expression levels of common/unique small RNA species among different biospecimens is necessary. However, except for miRNAs in plasma, there are no substantial indications about the pattern of expression of various small RNAs in multiple specimens among healthy humans. By analysing small RNA-sequencing data from 243 samples, we have identified and compared the most abundantly and uniformly expressed miRNAs and non-miRNA species of comparable size with the library preparation in four different specimens (plasma exosomes, stool, urine, and cervical scrapes). Eleven miRNAs were commonly detected among all different specimens while 231 miRNAs were globally unique across them. Classification analysis using these miRNAs provided an accuracy of 99.6% to recognize the sample types. piRNAs and tRNAs were the most represented non-miRNA small RNAs detected in all specimen types that were analysed, particularly in urine samples. With the present data, the most uniformly expressed small RNAs in each sample type were also identified. A signature of small RNAs for each specimen could represent a reference gene set in validation studies by RT-qPCR. Overall, the data reported hereby provide an insight of the constitution of the human miRNome and of other small non-coding RNAs in various specimens of healthy individuals. PMID- 29423034 TI - Schisandrol B and schisandrin B inhibit TGFbeta1-mediated NF-kappaB activation via a Smad-independent mechanism. AB - Aberrant transforming growth factor beta1 (TGFbeta1) signaling plays a pathogenic role in the development of vascular fibrosis. We have reported that Schisandra chinensis fruit extract (SCE), which has been used as a traditional oriental medicine, suppresses TGFbeta1-mediated phenotypes in vascular smooth muscle cells (VSMCs). However, it is still largely unknown about the pharmacologic effects of SCE on various TGFbeta1 signaling components. In this study, we found that SCE attenuated TGFbeta1-induced NF-kappaB activation and nuclear translocation in VSMCs. Among the five active ingredients of SCE that were examined, schisandrol B (SolB) and schisandrin B (SchB) most potently suppressed TGFbeta1-mediated NF kappaB activation. In addition, SolB and SchB effectively inhibited IKKalpha/beta activation and IkappaBalpha phosphorylation in TGFbeta1-treated VSMCs. The pharmacologic effects of SolB and SchB on NF-kappaB activation were independent of the Smad-mediated canonical pathway. Therefore, our study demonstrates that SCE and its active constituents SolB and SchB suppress TGFbeta1-mediated NF kappaB signaling pathway in a Smad-independent mechanism. Our results may help further investigations to develop novel multi-targeted therapeutic strategies that treat or prevent vascular fibrotic diseases. PMID- 29423035 TI - LITAF is a potential tumor suppressor in pancreatic cancer. AB - Early diagnosis of pancreatic cancer, one of the most deadly cancers with low survival rates, is difficult, and effective biomarkers are urgently needed. Lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF) has been recently proposed as a potential tumor suppressor gene in several types of cancer. Here, we analyzed the biological function of LITAF in pancreatic cancer. The LITAF gene and protein levels were decreased in pancreatic tumor tissues compared with their paired adjacent non-cancerous tissues. In addition, patients with the lower LITAF protein expression had lower disease-free survival rates. The decreased LITAF expression correlated with LITAF promoter hypermethylation in pancreatic cancer cells and tissues. Moreover, promoter demethylation dose dependently increased the LITAF transcription. Importantly, LITAF demethylation suppressed proliferation and cell cycle progression, and enhanced apoptosis of pancreatic cancer cells. Together, our results indicate that LITAF functions as a tumor suppressor gene in pancreatic cancer cells, and might serve as a novel biomarker for early diagnosis of pancreatic cancer. PMID- 29423037 TI - The structure of the binary methyltransferase-SAH complex from Zika virus reveals a novel conformation for the mechanism of mRNA capping. AB - Zika virus, a flavivirus like Dengue and West Nile viruses, poses a significant risk as a pathogen in the category of emerging infectious diseases. Zika infections typically cause nonspecific, mild symptoms, but can also manifest as a neurological disorder like Guillain-Barre syndrome. Infection in pregnant women is linked to microcephaly in newborn infants. The methyltransferase domain of the non-structural protein 5 is responsible for two sequential methylations of the 5' RNA cap. This is crucial for genome stability, efficient translation, and escape from the host immune response. Here we present the crystal structures of the Zika methyltransferase domain in complex with the methyl-donor SAM and its by-product SAH. The methyltransferase-SAH binary complex presents a new conformation of a "closed" or "obstructed" state that would restrict the binding of new RNA for capping. The combination and comparison of our new structures with recently published Zika methyltransferase structures provide a first glimpse into the structural mechanism of Zika virus mRNA capping. PMID- 29423036 TI - Salvaged allogeneic hematopoietic stem cell transplantation for pediatric chemotherapy refractory acute leukemia. AB - There is an ongoing debate concerning the performance of salvaged allogeneic hematopoietic stem cell transplantation (allo-HSCT) in pediatric patients with acute refractory leukemia, in whom the prognosis is quite dismal. Few studies have ever been conducted on this subject. This may be partly due to missed opportunities by majority of the patients in such situations. To investigate the feasibility, evaluate the efficiency, and identify the prognostic factors of allo HSCT in this sub-setting, the authors performed a single institution-based retrospective analysis. A total of 44 patients, of whom 28 had acute myeloid leukemia (AML), 13 had acute lymphocytic leukemia (ALL), and 3 had mixed phenotype leukemia (MPL), were enrolled in this study. With a median follow-up of 19 months, the estimated 2-year overall survival (OS) and progression free survival (PFS) were 34.3% (95% CI, 17.9-51.4%) and 33.6% (95% CI, 18.0-50.1%), respectively. The estimated 2-year incidence rates of relapse and non-relapse mortality (NRM) were 43.8% (95% CI 26.4-60.0%) and 19.6% (95% CI 9.1-32.9%), respectively. The estimated 100-day cumulative incidence of acute graft versus host disease (aGvHD) was 43.6% (95% CI 28.7-57.5%), and the 1-year cumulative incidence of chronic GvHD (cGvHD) was 45.5% (95% CI 30.5-59.3%). Compared with the previous studies, the multivariate analysis in this study additionally identified that female donors and cGvHD were associated with lower relapse and better PFS and OS. Male recipients, age younger than 10 years, a diagnosis of ALL, and the intermediate-adverse cytogenetic risk group were associated with increased relapse. On the contrary, extramedullary disease (EMD) and aGvHD were only linked to worse PFS. These data suggested that although only one-third of the patients would obtain PFS over 2 years, salvaged allo-HSCT is still the most reliable and best therapeutic strategy for refractory pediatric acute leukemia. If probable, choosing a female donor, better management of aGvHD, and induction of cGvHD promotes patient survival. PMID- 29423038 TI - Suppression of FGFR3- and MYC-dependent oncogenesis by tubacin: association with HDAC6-dependent and independent activities. AB - Fibroblast growth factor receptor 3 (FGFR3) is amplified, translocated or mutated in a number of different human cancer types, but most commonly in bladder cancers. We previously found that the accumulation of FGFR3 is dependent on histone deacetylase 6 (HDAC6). Here we show that HDAC6 loss or inhibition reduces FGFR3 accumulation in cells made tumorigenic by ectopic expression of a mutant activated version of FGFR3 together with the MYC oncoprotein and in a bladder cancer cell line whose tumorigenicity is dependent on expression of a translocated version of FGFR3. In tumor xenoplant assays, HDAC6 deficiency or small molecule inhibition by the selective HDAC6 inhibitors tubacin or tubastatin A was found to significantly impede tumor growth. However, tubacin was more effective at inhibiting tumor growth than tubastatin A or HDAC6 deficiency. The superior anti-tumor activity of tubacin was linked to its ability to not only inhibit accumulation of mutant FGFR3, but also to cause robust downregulation of MYC and cyclin D1, and to induce a DNA damage response and apoptosis. Neither HDAC6 deficiency nor treatment with tubastatin A altered MYC or cyclin D1 levels, and neither induced a DNA damage response or apoptosis. Thus while tubacin and tubastatin A inhibit HDAC6 with similar selectivity and potency, our results reveal unique HDAC6-independent activities of tubacin that likely contribute to its potent anti-tumor activity. PMID- 29423039 TI - Hypoxia-inducible factor-1alpha activates transforming growth factor-beta1/Smad signaling and increases collagen deposition in dermal fibroblasts. AB - Hypoxia of local tissue occurs during the scar formation; however, the degree of ischemia and hypoxia in the central areas of keloids is more serious than those in normal scars. Hypoxia-induced factor (HIF), is one of the main cellular responses to hypoxia, allowing cells to adapt to low-oxygen conditions. We investigated the correlation among hypoxia, transforming growth factor-beta1/Smad signaling and collagen deposition. Hypoxia up-regulated TGF-beta1, Smad2/3, p Smad2/3, Smad4, and total collagen in both normal and keloid fibroblasts via HIF 1alpha, which was attenuated by HIF-1alpha inhibition, but TbetaRII levels were not significantly altered. Silencing Smad4 under hypoxia decreased the mRNA and protein levels of HIF-1alpha, suggesting up-regulated Smad4 may also plays a role in promoting HIF-1alpha. Finally, we examined the role of the TGF-beta1/Smad pathway in collagen deposition. When TbetaRII was inhibited by ITD-1 under hypoxic conditions, p-Smad2/3 levels and collagen deposition decreased. When inhibited TbetaRII by siRNA under normoxia, the levels of p-Smad2/3, Smad4 and collagen deposition also decreased. This result demonstrated that hypoxia promoted TGF-beta1/Smad signaling via HIF-1alpha and that both HIF-1alpha and the TGF-beta1/Smad signaling promotes collagen deposition in hypoxia, which is an important mechanism of keloid formation. PMID- 29423040 TI - Systematic analysis of gene expression alterations and clinical outcomes of STAT3 in cancer. AB - Accumulated studies have provided controversial evidences of prognostic value for signal transducer and activator of transcription proteins 3 (STAT3) in cancers. To address this inconsistency, we performed a systematic analysis to determine whether STAT3 can serve as a prognostic marker in human cancers. STAT3 expression was assessed using Oncomine analysis. cBioPortal, Kaplan-Meier Plotter, and Prognoscan were performed to identify the prognostic roles of STAT3 in human cancers. The copy number alteration, mutation, interactive analysis, and visualize the altered networks were performed by cBioPortal. We found that STAT3 was more frequently overexpressed in lung, ovarian, gastric, blood and brain cancers than their normal tissues and its expression might be negatively related with the prognosis. In addition, STAT3 mutation mainly occurred in uterine cancer and existed in a hotspot in SH2 domain. Those findings suggest that STAT3 might serve as a diagnostic and therapeutic target for certain types of cancer, such as lung, ovarian, gastric, blood and brain cancers. However, future research is required to validate our findings and thus promote the clinical utility of STAT3 in those cancers prognosis evaluation. PMID- 29423042 TI - Reduced QSOX1 enhances radioresistance in nasopharyngeal carcinoma. AB - Radioresistance is a major cause leads to treatment failure in nasopharyngeal carcinoma (NPC). In our previous study, we identified that QSOX1 is a differentially expressed protein in NPC cell lines with variable radiosensitivities. The present study aimed to investigate the biological behavior of QSOX1 in nasopharyngeal carcinoma (NPC) and its effect on radiosensitivity. The levels of QSOX1 detected by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) in radioresistant NPC patient sera and tissue samples were markedly lower than those in radiosensitive samples. Small hairpin RNAs (shRNAs) were employed to knock down endogenous QSOX1 expression in CNE-2 cells, and then, radiosensitivity, apoptosis, migration and invasion were assessed using colony formation, Cell Counting Kit-8 (CCK-8), flow cytometry, and transwell assays, respectively. Tumor growth and radioresistance were also evaluated using a xenograft model in nude mice. The shRNA-mediated knockdown of QSOX1 significantly increased cell survival under irradiation (IR) and weakened radiosensitivity, which was likely due to a reduction in the cell apoptosis rate after IR. Moreover, QSOX1 silencing led to the suppression of cellular migration and invasion. Similar results were obtained with the xenograft mouse model. Thus, targeting QSOX1 will provide a new avenue for increasing the sensitivity of NPC to radiotherapy. PMID- 29423041 TI - Individual and combined effect of TP53, MDM2, MDM4, MTHFR, CCR5, and CASP8 gene polymorphisms in lung cancer. AB - Lung cancer (LC) is the second common and with the highest mortality oncological disease. Specific biomarkers for its diagnostics, treatment, and prognosis are still under the investigations. Aim of our study was to evaluate the relationship between the polymorphisms of TP53 pathway genes TP53, MDM2, MDM4, the polymorphisms of HPV-associated genes MTHFR, CASP8, CCR5, and HPV infection with survival of LC patients. SNPs were genotyped using PCR-RFLP. qRT-PCR was used to detect, identify, and quantify HPV. No statistically significant differences were detected between individual SNPs and patient survival with stage I-IV LC. Cluster analysis of SNPs in genes MDM4 A/A, CCR5 wt/Delta32, MTHFR C/T, MDM2 T/T showed possible association with the worse survival. Patients who were diagnosed with C/T polymorphic variant of gene MTHFR tend not to survive stage III-IV LC (P = .12). There is a tendency between MDM2 gene T/T variant and worse survival of patients diagnosed with late stage LC (P = .11). HPV infection is very rear among LC patients (3 of 92). Overall, there is a link, although statistically insignificant, between specific SNPs and LC patient survival frequency and time, meanwhile the combination of specific SNPs showed a statistically significant measure. In conclusion, we determined statistically significant (P = .04) link between the poor survival of LC patients after surgery and the combination of polymorphic variants C/T of the MTHFR and T/T of the MDM2 genes, whereas individually these SNPs do not show significant relationship with the survival of patients after surgery. PMID- 29423043 TI - Greater low-density lipoprotein cholesterol variability is associated with increased progression to dialysis in patients with chronic kidney disease stage 3. AB - Increasing evidence suggests that lipid variability may be a predictor of cardiovascular events. However, few studies have evaluated the association between lipid variability and renal outcomes in patients with moderate-to advanced chronic kidney disease (CKD). Therefore, the aims of this study were to assess whether lipid variability is associated with progression to dialysis in patients with CKD stage 3-5, and to evaluate the risk factors of lipid variability. This longitudinal study enrolled 725 patients with CKD stage 3-5. Intra-individual lipid variability was defined as the standard deviations (SDs) of lipid levels. The renal end-point was defined as commencing dialysis. During a mean follow-up period of 3.2 years, 208 patients (28.7%) started dialysis. The patients with CKD stage 3 with high low-density lipoprotein (LDL) cholesterol SD (per 1 mg/dL; hazard ratio, 1.035; 95% confidence interval, 1.003 to 1.067; p = 0.003) were associated with an increased risk of progression to dialysis, however this association was not seen in the patients with CKD stage 4 or 5. Furthermore, in the patients with CKD stage 3, a high urine protein-to-creatinine ratio (p < 0.001) and the use of statins (p < 0.001) were significantly associated with an increased LDL-cholesterol SD. Greater LDL-cholesterol variability was associated with an increased risk of progression to dialysis in patients with CKD stage 3, but not in those with CKD stage 4 or 5. These findings support the potential role of aggressive lipid control on clinical outcomes and highlight its importance in patients with CKD stage 3. PMID- 29423044 TI - Global view of a drug-sensitivity gene network. AB - An important challenge in drug development is to gain insight into the mechanism of drug sensitivity. Looking for insights into the global relationships between drugs and their sensitivity genes would be expected to reveal mechanism of drug sensitivity. Here we constructed a drug-sensitivity gene network (DSGN) based on the relationships between drugs and their sensitivity genes, using drug screened genomic data from the NCI-60 cell line panel, including 181 drugs and 1057 sensitivity genes, and 1646 associations between them. Through network analysis, we found that two drugs that share the same sensitivity genes tend to share the same Anatomical Therapeutic Chemical classification and side effects. We then found that the sensitivity genes of same drugs tend to cluster together in the human interactome and participate in the same biological function modules (pathways). Finally, we noticed that the sensitivity genes and target genes of the same drug have a significant dense distance in the human interactome network and they were functionally related. For example, target genes such as epidermal growth factor receptor gene can activate downstream sensitivity genes of the same drug in the PI3K/Akt pathway. Thus, the DSGN would provide great insights into the mechanism of drug sensitivity. PMID- 29423045 TI - Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway. AB - Chronic myeloid leukemia (CML) is a myeloproliferative pathology, originating from the hematopoietic cancer stem cells (hCSCs) due to the Bcl-Abl Philadelphia chromosome transformation. However, targeting these hCSCs as an effective anti CML strategy is relatively less explored. Ovatodiolide (Ova) is a natural diterpenoid isolate of Anisomeles indica with broad anticancer activity. In this study, we investigated the anti-hCSCs potential of Ova against CD34+/CD38-, CD34+/CD38+, and unsorted K562 cell lines using flow cytometry, western blot, RT PCR, genomic mapping, and tumorsphere formation assays. We demonstrated that compared to unsorted K562 and CD34+/CD38+, CD34+/CD38- cells were significantly enriched with Oct4, Sox2, CD133, Bcr-Abl, p-CrkL and p-Stat5 protein and/or mRNA. Furthermore, we showed that Ova alone or by enhancing the therapeutic potential of Imatinib, reduced the viability of CML cell lines, dose-dependently, irrespective of the cancer stemness, as well as markedly inhibit the Bcr-Abl, p CrkL, Stat5, and MDR protein expression levels in CD34+ cells. Mechanistic investigations revealed a significant up-regulation of hsa-miR-155, which resulted in the reduction of dysregulating the PIK3CA expression in Ova-treated K562 CD34+/CD38- cells. Additionally, Ova alone or in combination with Imatinib suppressed the hCSC traits of the CD34+/CD38- cells, resulting in loss of their ability to form tumorspheres, enhanced apoptosis, increase in the Bax/Bcl-2 ratio, and dysregulation of the PI3K/AKT/mTOR signaling pathway. Together, these results demonstrate the PI3K/AKT/mTOR signaling-mediated anti-hCSC effect of Ova in CML, as well as suggest a likely role for Ova as a small molecule PI3K/mTOR dual inhibitor, thus, extending its potential benefit to other mTOR-mediated pathologies. PMID- 29423046 TI - Vitexin induces apoptosis by suppressing autophagy in multi-drug resistant colorectal cancer cells. AB - Cancer treatment is limited due to the diverse multidrug resistance acquired by cancer cells and the collateral damage caused to adjacent normal cells by chemotherapy. The flavonoid compound vitexin exhibits anti-oxidative, anti inflammatory and anti-tumor activity. This study elucidated the antitumor effects of vitexin and its underlying mechanisms in a multi-drug resistant human colon cancer cell line (HCT-116DR), which exhibits higher levels of multidrug-resistant protein 1 (MDR1) expression as compared with its parental cell line (HCT-116). Here, we observed that vitexin suppressed MDR-1 expression and activity in HCT 116DR cells and showed cytotoxic effect in HCT-116DR cells by inhibiting autophagy and inducing apoptosis in a concentration-dependent manner. Additionally, vitexin treatment caused cleavage of caspase-9 and caspase-3, and upregulated the expression of the pro-apoptotic proteins, BID and Bax. Moreover, the expression of autophagy-related proteins, such as ATG5, Beclin-1 and LC3-II, was markedly reduced by vitexin treatment. Furthermore, in vivo experiments showed that vitexin induced apoptosis and suppressed tumor growth in HCT-116DR xenograft model. These results revealed that vitexin induced apoptosis through suppression of autophagy in vitro and in vivo and provide insight into the therapeutic potential of vitexin for the treatment of chemo-resistant colorectal cancer. PMID- 29423047 TI - BAFF and APRIL expression as an autoimmune signature of membranous nephropathy. AB - Background: Based on the fact that B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have a regulatory role in B cell biology, excessive levels of these cytokines can promote autoimmune pathogenesis. However, the expression and implication remain unresolved in cases of membranous nephropathy (MN). Results: The plasma BAFF levels of the primary MN patients were higher than those of healthy controls but lower than those of secondary MN patients, whereas the APRIL levels were similar between the MN patients and healthy controls. The BAFF levels were higher in relapse cases, whereas the APRIL levels were higher in the patients who did not experience remission compared with the counterpart patients. The ectopic expression of BAFF and APRIL was observed in the glomeruli or circulating B cells of MN patients, and this high expression trend was similar to that of lupus patients. Conclusions: Expression profile of BAFF and APRIL in MN is similar to that of other autoimmune disease, which affects the kidney outcomes. Methods: Plasma BAFF and APRIL levels were measured upon kidney biopsy in patients with primary (n = 89) and secondary MN (n = 13), and the results were compared with the levels in healthy controls (n = 111). The kidney outcomes (e.g., remission and relapse) were traced for the median of 3 years. Aberrant expression of the cytokines was evaluated in the kidney and circulating B cells using immunohistochemistry and flow cytometry analyses, respectively. PMID- 29423048 TI - Specific alterations in gut microbiota are associated with prognosis of Budd Chiari syndrome. AB - Gut microbiota is associated with liver diseases. However, gut microbial characteristics of Budd-Chiari syndrome (B-CS) have not been reported. Here, by MiSeq sequencing, gut microbial alterations were characterized among 37 health controls, 20 liver cirrhosis (LC) patients, 31 initial B-CS patients (B-CS group), 33 stability patients after BCS treatment (stability group) and 23 recurrent patients after BCS treatment (recurrence group). Gut microbial diversity was increased in B-CS versus LC. Bacterial community of B-CS clustered with controls but separated from LC. Operational taxonomic units (OTUs) 421, 502 (Clostridium IV) and 141 (Megasphaera) were unique to B-CS. Genera Escherichia/Shigella and Clostridium XI were decreased in B-CS versus controls. Moreover, nine genera, mainly including Bacteroides and Megamonas, were enriched in B-CS versus LC. Notably, Megamonas could distinguish B-CS from LC with areas under the curve (AUCs) of 0.7904. Microbial function prediction revealed that L amino acid transport system activity was decreased in B-CS versus both LC and controls. Furthermore, OTUs 27 (Clostridium XI), 137 (Clostridium XIVb) and 40 (Bacteroides) were associated with B-CS stability. Importantly, genus Clostridium XI was enriched in stability group versus both recurrence group and B-CS group. Also, PRPP glutamine biosynthesis was reduced in stability group versus recurrence group, but was enriched in stability group versus B-CS group. In conclusion, specific microbial alterations associated with diagnosis and prognosis were detected in B-CS patients. Correction of gut microbial alterations may be a potential strategy for B-CS prevention and treatment. PMID- 29423049 TI - Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer. AB - Potassium ion (K+) channels have been recently found to play a critical role in cancer biology. Despite that pharmacologic manipulation of ion channels is recognized as an important therapeutic approach, very little is known about the effects of targeting of K+ channels in cancer. In this study, we demonstrate that use of the Kv11.1 K+ channel activator NS1643 inhibits tumor growth in an in vivo model of breast cancer. Tumors exposed to NS1643 had reduced levels of proliferation markers, high expression levels of senescence markers, increased production of ROS and DNA damage compared to tumors of untreated mice. Importantly, mice treated with NS1643 did not exhibit significant cardiac dysfunction. In conclusion, pharmacological stimulation of Kv11.1 activity produced arrested TNBC-derived tumor growth by generating DNA damage and senescence without significant side effects. We propose that use of Kv11.1 channels activators could be considered as a possible pharmacological strategy against breast tumors. PMID- 29423050 TI - Enhanced anti-tumor efficacy and mechanisms associated with docetaxel-piperine combination- in vitro and in vivo investigation using a taxane-resistant prostate cancer model. AB - Docetaxel (DTX) is widely used for metastatic castrated resistant prostate cancer, but its efficacy is often compromised by drug resistance associated with low intracellular concentrations. Piperine (PIP) could enhance the bioavailability of other drugs via the inhibition of CYPs and P-gp activities. Thus, we hypothesize a positive effect with the DTX-PIP combination on the anti tumor efficacy and intra-tumor DTX concentrations in taxane-resistant prostate cancer. ICR-NOD/SCID mice implanted with taxane-resistant human prostate cancer cells were administrated with saline as well as PIP and DTX separately or in combination. The tumor growth was monitored together with intra-tumor concentrations of DTX. The inhibitory effects on CYPs and P-gp were further assessed in mouse liver microsome and MDCK-MDR1 cells. Compared with DTX alone, DTX-PIP combination significantly inhibited the tumor growth (114% vs. 217%, p = 0.002) with corresponding significantly higher intra-tumor DTX concentrations (5.854 +/- 5.510 ng/ml vs. 1.312 +/- 0.754 ng/mg, p = 0.037). The percentage of DTX metabolism was significantly decreased from 28.94 +/- 1.06% to 18.14 +/- 2.22% in mouse liver microsome after administration of PIP for two weeks. DTX accumulation in MDCK-MDR1 cell was significantly enhanced in the presence of PIP. Further microarray analysis revealed that PIP inhibited P-gp as well as CYP1B1 gene expression and induced a significant gene expression change relating to inflammatory response, angiogenesis, cell proliferation, or cell migration. In conclusion, DTX-PIP combination significantly induces activity against taxane resistant prostate tumor. Such effect appeared to be attributed to the inhibitory effect of PIP on CYPs and P-gp activity as well as gene expression changes relating to tumorigenesis and cellular responses. PMID- 29423051 TI - Del17p does not always significantly influence the survival of B-cell chronic lymphoproliferative disorders. AB - B-cell chronic lymphoproliferative disorders (B-CLPD) comprise several entities with indolent clinical manifestations but heterogeneous survival. Cytogenetic aberrations are now the standard prognostic predictors in chronic lymphocytic leukemia (CLL) but have been less investigated in other subtypes of B-CLPD. In this study, we detected cytogenetic aberrations by fluorescence in situ hybridization (FISH) in 875 B-CLPD patients, based on a panel probes locating at 13q14, 11q22, 17p13 and CEP12. We identified del17p acted as the independent adverse cytogenetic predictor for overall survival (OS) in CLL. Del13q, del11q and del17p were adverse factors for OS in Waldenstrom's macroglobulinemia in the univariate analysis but lost their role in the multivariate analysis. Trisomy 12 acted as an independent poor factor for both marginal zone lymphoma (MZL) and unclassified B-CLPD (BCLPD-U) subtype. Del17p did not impact survival in MZL and BCLPD-U patients. These contrasting results indicate different roles of the same cytogenetic aberrations in the pathogenesis of each B-CLPD subtype. As del17p contributed to the poorest survival in CLL and desired extraordinary treatment strategy, the imitation of CLL strategy to other B-CLPD with del17p should be carefully advocated based on this study. PMID- 29423052 TI - MAGE-A11 is activated through TFCP2/ZEB1 binding sites de-methylation as well as histone modification and facilitates ESCC tumor growth. AB - Recently, we have reported that the product of Melanoma Antigens Genes (MAGE) family member MAGE-A11 is an independent poor prognostic marker for esophageal squamous cell carcinoma (ESCC). However, the reason how MAGE-A11 is activated in ESCC progression still remains unclear. In the current study, we demonstrated that DNA methylation and the subsequent histone posttranslational modifications play crucial roles in the regulation of MAGE-A11 in ESCC progression. We found that the methylation rate of TFCP2/ZEB1 binding site on MAGE-A11 promoter in ESCC tissues and cells is higher than the normal esophageal epithelial tissues and cells. Transcription factors TFCP2 and ZEB1 directly bind MAGE-A11 promoter and regulate the endogenous MAGE-A11 expression in a methylation-dependent manner in ESCC cells. Following MAGE-A11 promoter methylation, the methyl-CpG-binding protein MeCP2 was found to bind the methylated MAGE-A11 promoter to mediate histone deactylation by recruiting HDAC1 and HDAC2. Simultaneously, histone inactivation marks including H3K27me3 as well as H3K9me3 were increased, whereas histone activation mark H3K4me3 was decreased. HDAC inhibitor Trichostatin A (TSA) increased DNA methylase inhibitor Decitabine (DAC)-induced MAGE-A11 expression. siRNA-mediated knockdown of histone methltransferase EZH2 or DZNep (a EZH2 inhibitor) treatment increased DAC-induced MAGE-A11 expression. Our results indicate that MAGE-A11 is activated through DNA demethylation, histone acetylation and histone methylation in ESCC, and its activation promotes ESCC tumor growth. PMID- 29423053 TI - Thiotepa-busulfan-fludarabine compared to busulfan-fludarabine for sibling and unrelated donor transplant in acute myeloid leukemia in first remission. AB - Background: A preparatory regimen consisting of thiotepa-busulfan-fludarabine (TBF) has been associated with reduced relapse in patients with haematological malignancies after haploidentical and cord blood transplants; however, few data exist regarding TBF conditioning in sibling (MSD) and unrelated donor (URD) transplants for AML. Results: Among patients receiving a myeloablative (MAC) regimen, TBF-MAC was associated with significantly lower relapse (HR 0.47, p = 0.005) however higher non-relapse mortality (NRM, HR 2.69, p < 10-4) as compared to BF. This led to similar leukemia-free (LFS) and overall survival (OS) between the two regimens (LFS: p = 0.6; OS: p = 0.27). When we selected TBF-MAC patients receiving busulfan 9.6 mg/kg, NRM resulted still higher but no more significantly different as compared to BF-MAC with busulfan 12.8 mg/kg (HR 1.53, p = 0.12); despite the lower busulfan dose, relapse remained inferior with TBF-MAC (HR 0.45, p = 0.01), however no difference in survival could be demonstrated (LFS: p = 0.31; OS: 0.82). Among patients receiving a reduced-intensity (RIC) regimen, similar outcome was observed with TBF-RIC and BF-RIC (LFS: p = 0.77; OS: p = 0.88). Conclusions: TBF-MAC as conditioning regimen for transplant from MSD and URD in AML patients in first remission provided stronger anti-leukemic activity but higher NRM as compared to BF-MAC, thus leading to similar survival. TBF-MAC with busulfan 9.6 mg/kg was associated with low relapse and acceptable NRM, however again with no survival benefit. TBF-RIC and BF-RIC resulted in comparable outcome. Methods: We conducted a registry-based study comparing outcomes of patients with AML in first remission undergoing transplant from MSD or URD prepared with either TBF (n = 212) or BF (n = 2698) conditioning. PMID- 29423054 TI - Copy number profiles of paired primary and metastatic colorectal cancers. AB - Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC). In this study, we compared the copy number profiles of paired primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. Paired primary and metastatic tumors from 16 patients and their adjacent normal tissue samples were analyzed using single nucleotide polymorphism arrays. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 188 genes known to be somatically altered in CRC and 24 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. The genomic differences between the tumor and paired metastases revealed an average copy number discordance of 22.0%. The pairs of tumor samples collected prior to treatment revealed significantly higher copy number differences compared to post-therapy liver metastases (P = 0.014). Loss of heterozygosity acquired in liver metastases was significantly higher in previously treated liver metastasis samples compared to treatment naive liver metastasis samples (P = 0.003). Amplification of the clinically actionable genes ERBB2, FGFR1, PIK3CA or CDK8 was observed in the metastatic tissue of 4 patients but not in the paired primary CRC. These examples highlight the intra-patient genomic discrepancies that can occur between metastases and the primary tumors from which they arose. We propose that precision medicine strategies may therefore identify different actionable targets in metastatic tissue, compared to primary tumors, due to substantial genomic differences. PMID- 29423055 TI - Hyperplastic thymus with increased angiogenesis is correlated with elevated serum thyroglobulin level in differentiated thyroid cancer patients with TENIS syndrome. AB - Aims: To investigate the association between angiogenetic activity of hyperplastic thymus and serum thyroglobulin (Tg) level in differentiated thyroid carcinoma patients with thyroglobulin (Tg)-elevated Negative Iodine Scintigraphy (TENIS) Syndrome. Methods: A cohort of 30 consecutive patients who underwent total thyroidectomy followed by radioiodine ablation and had TENIS syndrome received integrin alphavbeta3 targeted imaging with 99mTc-HYNIC-PEG4-E[PEG4 c(RGDfk)]2 (99mTc-3PRGD2). The correlation of angiogenetic activity of the thymus and the serum Tg levels was evaluated in patients with enlarged thymus. Results: Enlarged thymus was detected in 9 out of the 30 TENIS patients and all hyperplastic thymus showed an increased accumulation of the tracer (median tumor/background ratio: 2.8). Five of them had only mediastinal uptake and surgical removal of the mediastinal mass in one provided histopathologic evidence of thymic tissue. The other four were not assigned further treatment and were free of disease in the follow-up, though their stimulated Tg levels consistently increased. Four out of the 9 patients showed 99mTc-3PRGD2 uptake outside the mediastinum were assigned surgery followed by radioiodine treatment. Their stimulated Tg levels decreased after iodine ablation, but not drop back to normal. A significant linear correlation was observed between serum Tg levels and the degree of angiogenesis in the hyperplastic thymus. Conclusions: The angiogenetic activity in hyperplastic thymus was related with the consistently elevated serum Tg levels in TENIS syndrome patients. Based on the existing literature and current data, we propose further intervention for patients with RGD uptake outside thymus, while close follow-up for patients with only mediastinal uptake. PMID- 29423056 TI - Role of ZNF224 in c-Myc repression and imatinib responsiveness in chronic myeloid leukemia. AB - The transcription factor ZNF224 plays a key proapoptotic role in chronic myelogenous leukemia (CML), by modulating Wilms Tumor protein 1 (WT1) dependent apoptotic genes transcription. Recently, we demonstrated that Bcr-Abl signaling represses ZNF224 expression in Bcr-Abl positive CML cell lines and in CML patients. Interestingly, Imatinib and second-generation tyrosine kinase inhibitors specifically increase ZNF224 expression. On the other hand, Bcr-Abl positively modulates, via JAK2 activation, the expression of the c-Myc oncogene, which is required for Bcr-Abl oncogenic transformation in CML. Consequently, JAK2 inhibitors represent promising molecular therapeutic tools in CML. In this work, we demonstrate that ZNF224 is a novel transcriptional repressor of c-Myc in CML. We also show that ZNF224 induction by Imatinib and AG490, a specific JAK2 inhibitor, is responsible for the transcriptional repression of c-MYC, thus highlighting the crucial role of the ZNF224/c-Myc axis in Imatinib responsiveness. Interestingly, we also report that ZNF224 is induced by AG490 in Imatinib-resistant CML cells, leading to c-Myc repression and apoptosis induction. These findings suggest that the development of molecular tools able to induce ZNF224 expression could provide promising means to bypass Imatinib resistance in CML. PMID- 29423057 TI - Interleukin-34 sustains pro-tumorigenic signals in colon cancer tissue. AB - Interleukin-34 (IL-34), a cytokine produced by a wide range of cells, binds to the macrophage colony-stimulating factor receptor (M-CSFR-1) and receptor-type protein-tyrosine phosphatase zeta (PTP-z) and controls myeloid cell differentiation, proliferation and survival. various types of cancers over express IL-34 but the role of the cytokine in colorectal cancer (CRC) remains unknown. We here investigated the expression and functional role of IL-34 in CRC. A more pronounced expression of IL-34 was seen in CRC samples as compared to matched normal/benign colonic samples and this occurred at both RNA and protein level. Immunohistochemical analysis of CRC tissue samples showed that both cancer cells and lamina propria mononuclear cells over-expressed IL-34. Additionally, CRC cells expressed both M-CSFR-1 and PTP-z, thus suggesting that CRC cells can be responsive to IL-34. Indeed, stimulation of DLD-1 cancer cells with IL-34, but not with MSCF1, enhanced the cell proliferation and cell invasion without affecting cell survival. Analysis of intracellular signals underlying the mitogenic effect of IL-34 revealed that the cytokine enhanced activation of ERK1/2 and pharmacologic inhibition of ERK1/2 abrogated IL-34-driven cell proliferation. Consistently, IL-34 knockdown in HT-29 cells with a specific IL-34 antisense oligonucleotide reduced ERK1/2 activation, cell proliferation and enhanced the susceptibility of cells to Oxaliplatin-induced death. This is the first study showing up-regulation of IL-34 in CRC and suggesting a role for this cytokine in colon tumorigenesis. PMID- 29423058 TI - MUC1 induces M2 type macrophage influx during postpartum mammary gland involution and triggers breast cancer. AB - The microenvironment of postpartum mammary gland involution (PMI) has been linked to the increased risk of breast cancer and poor outcome of patients. Nevertheless the mechanism underlying regulates the microenvironment remains largely unknown. MUC1, which is abnormally overexpressed in most breast cancer, is physiologically expressed in PMI. Using MUC1 cytoplasm domain (MUC1-CD) transgenic mice, we reveal that the overexpression of MUC1-CD in mammary epithelial cells increases M2 type macrophage infiltration in PMI. By sustain activating p50, MUC1 upregulates M2 macrophage chemo-attractants and the anti-apoptotic protein Bcl xL. Because of the tumor promotional microenvironments and reduced apoptosis, MUC1-CD delays PMI process and results in atypical phenotype in multiparous mice mammary. This finding is further supported by the positive association between the expression of MUC1 and p50 in Luminal A and Luminal B subtypes through analyzing breast cancer databases. Taken together, our study demonstrates that MUC1-CD plays an important role in regulating microenvironment of PMI and promoting postpartum mammary tumorigenicity, providing novel prevention and treatment strategies against postpartum breast cancer. PMID- 29423059 TI - Brain- and brain tumor-penetrating disulfiram nanoparticles: Sequence of cytotoxic events and efficacy in human glioma cell lines and intracranial xenografts. AB - There is great interest in repurposing disulfiram (DSF), a rapidly metabolizing nontoxic drug, for brain cancers and other cancers. To overcome the instability and low therapeutic efficacy, we engineered passively-targeted DSF-nanoparticles (DSFNPs) using biodegradable monomethoxy (polyethylene glycol) d,l-lactic-co glycolic acid (mPEG-PLGA) matrix. The physicochemical properties, cellular uptake and the blood brain-barrier permeability of DSFNPs were investigated. The DSFNPs were highly stable with a size of ~70 nm with a >90% entrapment. Injection of the nanoparticles labeled with HITC, a near-infrared dye into normal mice and tumor bearing nude mice followed by in vivo imaging showed a selective accumulation of the formulation within the brain and subcutaneous tumors for >24 h, indicating an increased plasma half-life and entry of DSF into desired sites. The DSFNPs induced a potent and preferential killing of many brain tumor cell lines in cytotoxicity assays. Confocal microscopy showed a quick internalization of the nanoparticles in tumor cells followed by initial accumulation in lysosomes and subsequently in mitochondria. DSFNPs induced high levels of ROS and led to a marked loss of mitochondrial membrane potential. Activation of the MAP-kinase pathway leading to a nuclear translocation of apoptosis-inducing factor and altered expression of apoptotic and anti-apoptotic proteins were also observed. DSFNPs induced a powerful and significant regression of intracranial medulloblastoma xenografts compared to the marginal efficacy of unencapsulated DSF. Together, we show that passively targeted DSFNPs can affect multiple targets, trigger potent anticancer effects, and can offer a sustained drug supply for brain cancer treatment through an enhanced permeability retention (EPR). PMID- 29423061 TI - Chronic activation profile of circulating CD8+ T cells in Sezary syndrome. AB - Sezary syndrome (SS) is a leukemic variant of cutaneous T cell lymphoma (CTCL), and the neoplastic CD4+ T cells of SS patients undergo intense clonal proliferation. Although Sezary cells have been studied extensively, studies on adaptive immunity regarding CD8+T cells are scarce. This study aimed to investigate activation marker expression in CD8+ T cells according to the differentiation stages and IL-7/IL7Ralpha axis responses of patients with SS. Moreover, this study aimed to verify the soluble forms of CD38, sCD127 and IL-7 in serum. Although the SS patients of our cohort had reduced numbers of CD8+ T cells, they exhibited higher percentages of CD8+CD38+ T cells, mainly effector/memory CD8+ T cells, than the control group. In contrast, down-regulated expression of the activation markers CD127/IL-7R and CD26 was found in the CD8+ T cells of SS patients. High serum levels of sCD38 and sCD127 and scarce serum levels of IL-7 were detected, emphasizing the immune activation status of SS patients. Moreover, CD8+ T cells from SS patients exhibited IL-7 unresponsiveness to STAT5 phosphorylation and Bcl-2 expression, and IL-7 priming partially restored IFNgamma production. Our findings showed a chronic activation profile of CD8+ T cells, as an attenuated cytotoxic profile and impaired IL-7 responsiveness was observed, suggesting chronic activation status of CD8+ T cells in SS patients. PMID- 29423060 TI - Novel cooperative pathway of c-Myc and Furin, a pro-protein convertase, in cell proliferation as a therapeutic target in ovarian cancers. AB - c-Myc is a master regulator of various oncogenic functions in many types of human cancers. However, direct c-Myc-targeted therapy has not been successful in the clinic. Here, we explored a novel therapeutic target, which shows synthetic lethality in c-Myc-driven ovarian cancers, and examined the molecular mechanism of the synthetic lethal interaction. By high throughput siRNA screening with a library of 6,550 genes, Furin, a pro-protein convertase, was identified as the top hit gene. Furin inhibition by siRNA or a Furin inhibitor significantly suppressed cell proliferation in high c-Myc-expressing ovarian cancer cells compared with low c-Myc-expressing cells. Conversely, Furin overexpression in the presence of high c-Myc significantly promoted cell proliferation compared with only c-Myc or Furin overexpression. Notch1, one of the Furin substrates, was upregulated by c-Myc, and Notch1 cleaved by Furin increased cell proliferation of high c-Myc-expressing ovarian cancer cells. Notch1 was involved in the cooperative pathway of c-Myc and Furin in cell proliferation. In clinical ovarian cancer specimens, co-expression of c-Myc and Furin correlated with poor survival. In conclusion, we found that c-Myc cooperates with Furin to promote cell proliferation. Furin may be a promising therapeutic target in c-Myc-driven ovarian cancer. PMID- 29423062 TI - Drug-induced ciliogenesis in pancreatic cancer cells is facilitated by the secreted ATP-purinergic receptor signaling pathway. AB - Malignant transformation of cells is often accompanied by the loss of the primary cilium, a protruding microtubule-based sensory organelle, suggesting that it plays an "onco-suppressive" role. Therefore, restoration of the primary cilium is being explored as a new therapeutic approach to attenuate tumor growth. Recently, several commonly used chemotherapeutic drugs have been identified to induce the primary cilium in pancreatic cancer cells. The mechanisms by which these drugs re express the cilium remain, however, enigmatic. Here, evaluation of a panel of diverse ciliogenic drugs on pancreatic cancer cell models revealed a significant positive relationship between drug-induced extracellular ATP, released through pannexin channels, and the extent of primary cilium induction. Moreover, cilium induction by these drugs was hampered in the presence of the ATP degrading enzyme, apyrase, and in the presence of the pan-purinergic receptor inhibitor, suramin. Our findings reveal that ciliogenic drug-induced re-expression of the primary cilium in pancreatic cancer cells is, at least in certain contexts, dependent on a hitherto unrecognized autocrine/paracrine loop involving the extracellular ATP-purinergic receptor signaling pathway that can be exploited in a therapeutic approach targeting at restoring the primary cilium. PMID- 29423063 TI - LncRNA Gas5 acts as a ceRNA to regulate PTEN expression by sponging miR-222-3p in papillary thyroid carcinoma. AB - Accumulating evidence demonstrates that the long non-coding RNA Growth Arrest Specific 5 (Gas5) has practical significance in cancer progression and metastasis. However, its role and function in papillary thyroid carcinoma (PTC) remains unknown. In this study, we aimed to explore the potential involvement of Gas5 in papillary thyroid carcinogenesis and to highlight the emerging roles of ceRNAs in the biological regulation of PTC cells. The results suggested that Gas5 was markedly downregulated in both PTC tissues and PTC cell lines. Over expression of Gas5 remarkably suppressed PTC cells proliferation in vitro and inhibited the growth of tumor cells in vivo likewise. Furthermore, Gas5 was identified as a target of miR-222-3p which was aberrantly high in PTC cells. Enhanced expression of miR-222-3p promoted the proliferation of PTC cells while knocking down miR-222-3p could inhibit it. The advanced effects of miR-222-3p on the proliferation of PTC cells could be partly reversed by the upregulation of Gas5 expression. Furthermore, we validated that Gas5 increased the protein level of the PTEN, one of miR-222-3p's targets, which further activated PTEN/AKT pathway. Taken together, our study identified a tumor suppressive role of Gas5 in PTC cells acting as a ceRNA, effectively becoming a sink for miR-222-3p, modulating the expression of PTEN, which lead to PTEN/AKT pathway activation and proliferation suppression. This finding may offer a new potential therapeutic strategy for PTC. PMID- 29423064 TI - Melatonin attenuated brain death tissue extract-induced cardiac damage by suppressing DAMP signaling. AB - We tested the hypothesis that melatonin prevents brain death (BD) tissue extract (BDEX)-induced cardiac damage by suppressing inflammatory damage-associated molecular pattern (DAMP) signaling in rats. Six hours after BD induction, levels of a DAMP component (HMGB1) and inflammatory markers (TLR-2, TLR-4, MYD88, IkappaB, NF-kappaB, IL-1beta, IFN-gamma, TNF-alpha and IL-6) were higher in brain tissue from BD animals than controls. Levels of HMGB1 and inflammatory markers were higher in BDEX-treated H9C2 cardiac myoblasts than in cells treated with healthy brain tissue extract. These increases were attenuated by melatonin but re induced with luzindole (all P < 0.001). Additional male rats (n = 30) were divided into groups 1 (negative control), 2 (healthy brain tissue extract implanted in the left ventricular myocardium [LVM]), 3 (BDEX-LVM), 4 (BDEX-LVM + melatonin), and 5 (BDEX-LVM + melatonin + luzindole). Collagen deposition/fibrosis and LVM levels of MTR2, HMGB1, inflammatory markers, oxidative stress, apoptosis, mitochondrial damage and DNA damage were highest in group 3, lowest in groups 1 and 2, and higher in group 5 than in group 4. Heart function and LVM levels of MTR1 and anti-inflammatory, mitochondrial-integrity and anti-oxidative markers exhibited a pattern opposite that of the inflammatory markers in the five groups (all P < 0.0001). These results indicate melatonin inhibits BDEX-induced cardiac damage by suppressing the DAMP inflammatory axis. PMID- 29423065 TI - Phosphatase of regenerating liver-3 is expressed in acute lymphoblastic leukemia and mediates leukemic cell adhesion, migration and drug resistance. AB - Phosphatase of regenerating liver-3 (PRL-3/PTP4A3) is upregulated in multiple cancers, including BCR-ABL1- and ETV6-RUNX-positive acute lymphoblastic leukemia (ALL). With this study, we aim to characterize the biological role of PRL-3 in B cell ALL (B-ALL). Here, we demonstrate that PRL-3 expression at mRNA and protein level was higher in B-ALL cells than in normal cells, as measured by qRT-PCR or flow cytometry. Further, we demonstrate that inhibition of PRL-3 using shRNA or a small molecular inhibitor reduced cell migration towards an SDF-1alpha gradient in the preB-ALL cell lines Reh and MHH-CALL-4. Knockdown of PRL-3 also reduced cell adhesion towards fibronectin in Reh cells. Mechanistically, PRL-3 mediated SDF-1alpha stimulated calcium release, and activated focal adhesion kinase (FAK) and Src, important effectors of migration and adhesion. Finally, PRL-3 expression made Reh cells more resistance to cytarabine treatment. In conclusion, the expression level of PRL-3 was higher in B-ALL cells than in normal cells. PRL-3 promoted adhesion, migration and resistance to cytarabine. PRL-3 may represent a novel target in the treatment of B-ALL. PMID- 29423066 TI - Interferon beta protects against avascular osteonecrosis through interleukin 6 inhibition and silent information regulator transcript-1 upregulation. AB - Synovitis of the affected joint is a common in avascular osteonecrosis (AVN). Increased levels of pro-inflammatory cytokine interleukin-6 (IL-6) have been reported in AVN, but the mechanism of this increase remains unclear. Silent information regulator transcript-1 (SIRT1), an NAD-dependent deacetylase, inhibits the release of inflammatory cytokines. Interferon beta (IFN-beta) has clear anti-inflammatory properties. We sought to investigate the effects of IFN beta treatment on AVN and to evaluate the specific signal pathway relating to IL 6 and SIRT1 affected during AVN. Using a dissection microscope, AVN was surgically induced in the distal femurs of mice. Exogenous IFN-beta was administered to the model mice. The effects of exogenous IFN-beta on AVN model mice were assessed using hematoxylin eosin and safranin-O staining, and bone resorption activity was measured using tartrate-resistant acid phosphatase (TRAP) and CD68 staining. Western blots, real-time RT-PCR, and immunohistochemical staining were performed to evaluate the production of SIRT1 and IL-6 in tissues. The RAW 264.7 cell line and bone marrow derived osteoclasts treated with exogenous IFN-beta. Histological findings indicated well preserved trabecular bone and decreased osteoclast bone resorption activity in IFN-beta treated mice compared with mice in the AVN group. Treatment with IFN-beta increased SIRT1 expression and inhibited secretion of IL-6 in this AVN mouse model. IFN-beta decreased IL-6 secretion by activating SIRT1 in the RAW 264.7 cell and bone marrow derived osteoclasts. Our work suggests that IFN-beta could be used to treat AVN and that both SIRT1 and IL-6 are useful targets for treating patients with AVN. PMID- 29423067 TI - Inhibition of tumor growth by cancer vaccine combined with metronomic chemotherapy and anti-PD-1 in a pre-clinical setting. AB - Tumor microenvironment (TME) is characterized by multiple immune suppressive mechanisms able to suppress anti-tumor effector cell immunity. Combinatorial strategies, including vaccine and immunomodulatory drugs, need to be developed for improved immunotherapy efficacy. A novel combinatorial approach was assessed in C57BL/6 mice injected with mouse melanoma B16F10 cells. A multi-peptide vaccine (PEPT) was combined with a low dose metronomic chemotherapy (MCT) and an anti-PD-1 checkpoint inhibitor (CI). Statistical analysis were performed with the unpaired two-sided Student's t-test and ANOVA. Animals treated with the multi peptide vaccine combined with MCT or CI showed remarkable delay in tumor growth and prolonged survival as compared to control groups. The multi-pronged combination including PEPT+MCT+CI was able to prolong survival in all mice and inhibit tumor growth in 66.6% of mice. All animals which did not show tumor growth were re-challenged with the same melanoma cells and one of them showed complete tumor growth inhibition. The anti-tumor effect was associated with strong T cell immune response to vaccine mutated peptides and significant reduction of regulatory T cells. The combination of a vaccine with MCT and CI was highly efficient in potentiating the vaccine's anti-tumor effects. The approach is highly promising to be moved into clinical trial. PMID- 29423068 TI - FoxM1 and beta-catenin predicts aggressiveness in Middle Eastern ovarian cancer and their co-targeting impairs the growth of ovarian cancer cells. AB - Epithelial ovarian cancer (EOC) is a highly lethal disease with poor prognosis especially in advanced stage tumor. Emerging evidence has reported that aberrant upregulation of FoxM1 and beta-catenin are closely associated with aggressiveness of human cancer. However, interplay between these factors in the aggressiveness of EOC is not fully illustrated. In this study, we show that FoxM1 is frequently increased in Middle Eastern EOC and associated with high proliferative index (p = 0.0007) and high grade tumor (p = 0.0024). Interestingly, FoxM1 is significantly associated with elevated nuclear beta-catenin and the concomitant increase of FoxM1 and beta-catenin is associated with advanced stage of EOC by immunohistochemical analysis of 261 samples of Saudi patients with EOC. Functional analysis showed that beta-catenin is a direct transcriptional target of FoxM1 in EOC cell lines. FoxM1 inhibition either by specific inhibitor, thiostrepton or siRNA suppressed beta-catenin expression, whereas overexpression of FoxM1 increased nuclear beta-catenin expression. We identified two FoxM1 binding sites in the beta-catenin promoter that specifically bound to FoxM1 protein. Down-regulation of FoxM1 using thiostrepton induced apoptosis and inhibited cell migration/invasion in EOC cells. Moreover, co-inhibition of FoxM1 by thiostrepton and beta-catenin by FH535 significantly and synergistically inhibited EOC cell growth in vitro and in vivo. Collectively, our findings confer that co-targeting FoxM1/beta-catenin signaling cascade may be a promising molecular therapeutic choice in advanced EOC. PMID- 29423069 TI - Combined effects of PLK1 and RAS in hepatocellular carcinoma reveal rigosertib as promising novel therapeutic "dual-hit" option. AB - Inhibition of RAS-RAF-ERK-signaling is a major mechanism mediated by the multi kinase inhibitors sorafenib and regorafenib, the only effective therapeutic approaches for advanced hepatocellular carcinoma (HCC). This underlines the importance of RAS-RAF-ERK-signaling in HCC. Most RAS isoforms were not yet described to play crucial roles in HCC. However, several studies indicate that the HRAS isoform can function as potent oncogene in HCC, but pharmacologic RAS inhibition has not yet been investigated. Moreover, the cell cycle promoting polo like kinase 1 (PLK1) is an increasingly recognized therapeutic target in HCC that can be activated by RAS-RAF-signaling. A recently developed small molecule inhibitor, ON-01910 ("rigosertib", RGS), was shown to interfere with both RAS- and PLK1-signaling. The aim of this study was to analyze the effects of RGS in HCC and to assess PLK1 and HRAS expression in HCC. RGS treatment reduced cell proliferation and induced cell cycle arrest in human HCC cell lines in vitro. Moreover, RGS strongly inhibited both ERK- and AKT-activation in HCC cells, indicating disruption of RAS-signaling. Analysis of HCC patient data showed that PLK1 and HRAS expression levels are upregulated during HCC development and in advanced HCC, respectively. High expression levels of PLK1 significantly correlated with poor patient survival. Moreover, high expression of both PLK1 and HRAS revealed combined effects on patient outcome. This underscores the importance of these genes and associated pathways in HCC. We newly demonstrate the therapeutic potential of RGS in HCC by inhibition of both PLK1 activation and major RAS-pathways, revealing a novel therapeutic "dual-hit" approach for HCC. PMID- 29423070 TI - Salinomycin inhibits cholangiocarcinoma growth by inhibition of autophagic flux. AB - Introduction: Cholangiocarcinoma is characterized by aggressive tumor growth, high recurrence rates, and resistance against common chemotherapeutical regimes. The polyether-antibiotic Salinomycin is a promising drug in cancer therapy because of its ability to overcome apoptosis resistance of cancer cells and its selectivity against cancer stem cells. Here, we investigated the effectiveness of Salinomycin against cholangiocarcinoma in vivo, and analyzed interference of Salinomycin with autophagic flux in human cholangiocarcinoma cells. Results: Salinomycin reduces tumor cell viability, proliferation, migration, invasion, and induced apoptosis in vitro. Subcutaneous and intrahepatic cholangiocarcinoma growth in vivo was inhibited upon Salinomycin treatment. Analysis of autophagy reveals inhibition of autophagic activity. This was accompanied by accumulation of mitochondrial mass and increased generation of reactive oxygen species. Conclusions: This study demonstrates the effectiveness of Salinomycin against cholangiocarcinoma in vivo. Inhibition of autophagic flux represents an underlying molecular mechanism of Salinomycin against cholangiocarcinoma. Methods: The two murine cholangiocarcinoma cell lines p246 and p254 were used to analyze tumor cell proliferation, viability, migration, invasion, and apoptosis in vitro. For in vivo studies, murine cholangiocarcinoma cells were injected into syngeneic C57-BL/6-mice to initiate subcutaneous cholangiocarcinoma growth. Intrahepatic tumor growth was induced by electroporation of oncogenic transposon plasmids into the left liver lobe. For mechanistic studies in human cells, TFK-1 and EGI-1 were used, and activation of autophagy was analyzed after exposure to Salinomycin. PMID- 29423071 TI - A spliced form of CD44 expresses the unique glycan that is recognized by the prostate cancer specific antibody F77. AB - Prostate cancer is the most common cancer occurring in men in the United States. The monoclonal antibody F77 that was originally developed in our laboratory recognizes mainly glycolipids as well as O-linked glycosylation on proteins in prostate cancer cells. We have identified a spliced form of glycoprotein CD44 as one critical protein expressing the F77 antigen. The F77-specific glycosylation occurs on multiple potential glycosylation sites on the CD44 protein encoded by the fourteenth exon. CD44 is a tumor stem cell marker and is known to induce tumor stemness and metastasis. Knockdown of CD44 or FUT1 genes dramatically reduced F77-induced apoptosis in prostate cancer cell lines. We developed an ELISA using both a CD44 antibody and F77 to identify the special form of glycosylated CD44 from prostate cancer cells as well as from serum samples of prostate cancer patients. These results reveal a CD44-dependent mechanism for F77 to induce tumor cell apoptosis, and a new strategy for the detection of glycosylated CD44 proteins secreted by prostate cancer cells. PMID- 29423072 TI - Epithelial-mesenchymal crosstalk induces radioresistance in HNSCC cells. AB - Objective: Epithelial-mesenchymal crosstalk (EMC) contributes to tumor progression, chemoresistance and acquisition of a mesenchymal phenotype (EMT) of cancer cells. This study aims to investigate the effects of EMC on radioresistance in head and neck squamous cell carcinoma (HNSCC) cells. Methods: In tumor cell lines, the response of HNSCC cells, stimulated with EMC conditioned medium (CM), to irradiation was evaluated with viability and clonogenic assays. Dose modifying factors (DMF) were calculated from the results of clonogenic assays. Potential pathways involved in radioresistance were analyzed with quantitative Real-Time PCR and western blot. Results: CM significantly reduced the doubling time of SCC-25 cells (from 32.8 hours to 16.8 hours, p=0.0001) and Detroit 562 cells (from 88.5 hours to 29.6 hours, p=0.014). Further it increased clonogenic survival after irradiation. The DMF of CM was 2.04 +/- 0.43 (mean +/- standard deviation) for SCC-25 cells (p=0.015) and 2.14 +/- 0.34 for Detroit 562 cells (p=0.008). Treatment with CM more than tripled the ERCC1 and survivin gene expression in SCC-25 cells. Conclusion: EMC induced pathways involved in cell survival and DNA repair and led to increased radioresistance in HNSCC cells. PMID- 29423073 TI - Cognition, serum BDNF levels, and BDNF Val66Met polymorphism in type 2 diabetes patients and healthy controls. AB - Background and aims: Type 2 diabetes (T2DM) is associated with cognitive deficits. However, their pathophysiological mechanisms are still unknown. Recent study suggests that brain-derived neurotrophic factor (BDNF) is correlated with cognitive deficits in T2DM patients. This study was to determine whether altered serum BDNF levels and cognitive deficits depended on the BDNF Val66Met polymorphism in T2DM. Results: The BDNF Val66Met polymorphism may not contribute directly to the susceptibility to T2DM. The total and nearly all index scores (all p < 0.01) except for the attention and visuospatial/constructional indexes (both p > 0.05) of RBANS were markedly decreased in T2DM compared with healthy controls. Serum BDNF levels were significantly lower in patients than that in controls (p < 0.001), and BDNF was positively associated with delayed memory in patients (p < 0.05). The Met variant was associated with worse delayed memory performance among T2DM patients but not among normal controls. Moreover, serum BDNF was positively associated with delayed memory among Met homozygote patients (beta = 0.29, t = 2.21, p = 0.033), while serum BDNF was negatively associated the RBANS total score (beta = -0.92, t = -3.40, p = 0.002) and language index (beta = -1.17, t = -3.54, p = 0.001) among Val homozygote T2DM patients. Conclusions: BDNF gene Val66Met variation may be associated with cognitive deficits in T2DM, especially with delayed memory. The association between lower BDNF serum levels and cognitive impairment in T2DM is dependent on the BDNF Val66Met polymorphism. Methods: We recruited 311 T2DM patients and 346 healthy controls and compared them on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), serum BDNF levels, and the BDNF Val66Met polymorphism. PMID- 29423074 TI - Inhibition of integrin beta1-mediated oncogenic signalling by the antitumor microRNA-29 family in head and neck squamous cell carcinoma. AB - Due to their aggressive behavior, local recurrence and distant metastasis, survival rate of advanced stage of the patients with head and neck squamous cell carcinoma (HNSCC) is very poor. Currently available epidermal growth factor receptor (EGFR)-targeted therapies are not considered curative for HNSCC. Therefore, novel approaches for identification of therapeutic targets in HNSCC are needed. All members of the miRNA-29 family (miR-29a, miR-29b, and miR-29c) were downregulated in HNSCC tissues by analysis of RNA-sequencing based microRNA (miRNA) expression signature. Ectopic expression of mature miRNAs demonstrated that the miR-29 family inhibited cancer cell migration and invasion by HNSCC cell lines. Comprehensive gene expression studies and in silico database analyses were revealed that integrin beta1 (ITGB1) was regulated by the miR-29 family in HNSCC cells. Overexpression of ITGB1 was confirmed in HNSCC specimens, and high expression of ITGB1 significantly predicted poor survival in patients with HNSCC (p = 0.00463). Knockdown of ITGB1 significantly inhibited cancer cell migration and invasion through regulating downstream of ITGB1-mediated oncogenic signalling. In conclusion, regulation of the antitumor miR-29 family affected integrin-mediated oncogenic signalling to modulate HNSCC pathogenesis; these molecules may be novel therapeutic targets for HNSCC. PMID- 29423075 TI - Polymorphisms of long non-coding RNA HOTAIR with breast cancer susceptibility and clinical outcomes for a southeast Chinese Han population. AB - Hox transcript antisense intergenic RNA (HOTAIR) is a well-known long non-coding RNA (lncRNA) which participates in tumorigenesis and progress of multiple cancers. However, the associations among polymorphisms on HOTAIR, breast cancer (BC) susceptibility and clinical outcomes have remained obscure. In this case control study, we assessed the interaction between three lncRNA HOTAIR single nucleotide polymorphisms (SNPs) (rs1899663, rs4759314 and rs7958904) on the risk and clinical outcome of breast cancer in a Chinese Han population. In total, 969 breast cancer cases and 970 healthy controls were enrolled in this study. Associations among genotypes, BC risk and survival were evaluated by univariate and multivariate logistic regression to estimate the odds ratio (OR), hazard ratio (HR) and its 95% confidence interval (CI). The disease-free survival (DFS) and overall survival (OS) was calculated by the Kaplan-Meier method. We found that the T allele of rs1899663 and C allele of rs7958904 both achieved significant differences between cases and controls in the single locus analyses (P = 0.017 and 0.010, respectively). Multivariate analyses also revealed the rs1899663 TT genotype and rs7958904 CC genotype were both at higher risk of breast cancer compared with the GG homozygotes (OR = 2.08, 95% CI = 1.20-3.60 and OR = 1.45, 95% CI = 1.01-2.08, respectively). In survival analysis, we observed that the T allele of rs1899663 presented significant differences for both DFS (HR = 1.64, 95% CI = 1.12-2.40) and OS (HR = 2.10, 95% CI = 1.29-3.42) in younger subjects (age <= 40). Our findings may provide new insights into the associations among the genetic susceptibility, the fine classifications and the prognosis of breast cancer. Further studies with larger sample size and functional research should also be conducted to validate our findings and better elucidate the underlying biological mechanisms. PMID- 29423076 TI - Androgen receptor/let-7a signaling regulates breast tumor-initiating cells. AB - Androgen receptor (AR) is an important transcriptional factor, which is frequently expressed in invasive breast cancer and correlates patients' prognosis. Our previous results indicate AR activation may increase let-7a expression in breast cancer cells, while let-7, a tumor suppressor, is reported to inhibit breast tumor-initiating cells (T-IC). The study aims to explore the effects of AR/let-7a signaling on breast T-IC and its regulatory mechanism. The results revealed that the expression of AR was significantly associated with let 7a and CD44+/24-/low especially in estrogen receptor positive (ER+) breast cancer tissues. The expression of AR and let-7a indicated better outcome, while patients with CD44+/24-/low phenotype had worse prognosis. AR activation induced by dihydrotestosterone (DHT) prevented cells proliferation, migration, invasion and self-renewal capacities in ER+ breast cancer cells, via transcriptional up regulation of let-7a. In addition, AR could inhibit tumorigenesis and metastasis of ER+ breast cancer cells in the serial xenotranplanted animal models. Our data suggested that AR/let-7a signaling could inhibit the biological behavior of tumor initiating cells (T-IC) in ER+AR+ breast cancers, which might become a new therapeutic target. PMID- 29423077 TI - Integrating the dysregulated inflammasome-based molecular functionome in the malignant transformation of endometriosis-associated ovarian carcinoma. AB - The coexistence of endometriosis (ES) with ovarian clear cell carcinoma (CCC) or endometrioid carcinoma (EC) suggested that malignant transformation of ES leads to endometriosis associated ovarian carcinoma (EAOC). However, there is still lack of an integrating data analysis of the accumulated experimental data to provide the evidence supporting the hypothesis of EAOC transformation. Herein we used a function-based analytic model with the publicly available microarray datasets to investigate the expression profiling between ES, CCC, and EC. We analyzed the functional regularity pattern of the three type of samples and hierarchically clustered the gene sets to identify key mechanisms regulating the malignant transformation of EAOC. We identified a list of 18 genes (NLRP3, AIM2, PYCARD, NAIP, Caspase-4, Caspase-7, Caspase-8, TLR1, TLR7, TOLLIP, NFKBIA, TNF, TNFAIP3, INFGR2, P2RX7, IL-1B, IL1RL1, IL-18) closely related to inflammasome complex, indicating an important role of inflammation/immunity in EAOC transformation. We next explore the association between these target genes and patient survival using Gene Expression Omnibus (GEO), and found significant correlation between the expression levels of the target genes and the progression free survival. Interestingly, high expression levels of AIM2 and NLRP3, initiating proteins of inflammasomes, were significantly correlated with poor progression-free survival. Immunohistochemistry staining confirmed a correlation between high AIM2 and high Ki-67 in clinical EAOC samples, supporting its role in disease progression. Collectively, we established a bioinformatic platform of gene-set integrative molecular functionome to dissect the pathogenic pathways of EAOC, and demonstrated a key role of dysregulated inflammasome in modulating the malignant transformation of EAOC. PMID- 29423078 TI - Molecular mechanisms of calcium signaling in the modulation of small intestinal ion transports and bicarbonate secretion. AB - Background and Purpose: Although Ca2+ signaling may stimulate small intestinal ion secretion, little is known about its critical role and the molecular mechanisms of Ca2+-mediated biological action. Key Results: Activation of muscarinic receptors by carbachol(CCh) stimulated mouse duodenal Isc, which was significantly inhibited in Ca2+-free serosal solution and by several selective store-operated Ca2+ channels(SOC) blockers added to the serosal side of duodenal tissues. Furthermore, we found that CRAC/Orai channels may represent the molecular candidate of SOC in intestinal epithelium. CCh increased intracellular Ca2+ but not cAMP, and Ca2+ signaling mediated duodenal Cl- and HCO3- secretion in wild type mice but not in CFTR knockout mice. CCh induced duodenal ion secretion and stimulated PI3K/Akt activity in duodenal epithelium, all of which were inhibited by selective PI3K inhibitors with different structures. CCh induced Ca2+ signaling also stimulated the phosphorylation of CFTR proteins and their trafficking to the plasma membrane of duodenal epithelial cells, which were inhibited again by selective PI3K inhibitors. Materials and Methods: Functional, biochemical and morphological experiments were performed to examine ion secretion, PI3K/Akt and CFTR activity of mouse duodenal epithelium. Ca2+ imaging was performed on HT-29 cells. Conclusions and Implications: Ca2+ signaling plays a critical role in intestinal ion secretion via CRAC/Orai-mediated SOCE mechanism on the serosal side of epithelium. We also demonstrated the molecular mechanisms of Ca2+ signaling in CFTR-mediated secretion via novel PI3K/Akt pathway. Our findings suggest new perspectives for drug targets to protect the upper GI tract and control liquid homeostasis in the small intestine. PMID- 29423079 TI - Therapeutic effect of nerve growth factor on canine cerebral infarction evaluated by MRI. AB - To explore therapeutic effect of nerve growth factor (NGF) on cerebral infarction by establishing canine middle cerebral artery occlusion (MCAO) infarct model. The magnetic resonance imaging (MRI) technology was used to study effects of NGF on cerebral infarction, and the results of MRI indexes (such as diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI)) were compared with the results of pathology, cell biology and molecular biology. The clinical manifestations of the canine infarction model treated by NGF were significantly improved within 7 days compared with control group. The therapeutic evaluation of NGF effect could be determine by canine cerebral infarction treated by NGF within 6 hours according to DWI and PWI. From 6 hours to 7 days, therapeutic evaluation of NGF could be determine by T1WI, T2WI and FLAIR. DWI and PWI could find the change of cerebral ischemia at the early stage, provide advantages for qualitative diagnosis of early-stage cerebral infarction and observation of efficacy in early treatment, initially showing that their great potential for NGF role on cerebral ischemia and mechanism. PMID- 29423080 TI - Downregulation of N6-methyladenosine binding YTHDF2 protein mediated by miR-493 3p suppresses prostate cancer by elevating N6-methyladenosine levels. AB - Recent evidence suggests that m6A modifications regulate the progressions of several types of tumors. YTHDF2, an m6A reader, has been implicated in the regulation of hepatocellular carcinoma (HCC). miR-493-3p has been defined as tumor suppressor that inhibits the progressions of several types of cancers. However, the functions and mechanisms of YTHDF2 and the indirect m6A regulated role of miR-493-3p in prostate cancer (PCa) remains to be elusive. In this study, immuno-histochemical (IHC) staining and chromogenic in situ hybridization (CISH) were performed to find YTHDF2 was frequently upregulated but miR-493-3p was downregulated in both PCa tissues and cell lines (DU-145 and PC3) which was negatively correlated with each other. Knock down of YTHDF2 significantly elevated m6A levels, and inhibited the cell proliferation and migration of DU-145 and PC3 cell lines. The dual-luciferase reporter assay confirmed YTHDF2 as the direct target of miR-493-3p. In addition, forced expression of miR-493-3p consistently elevated the m6A levels and inhibited proliferation and migration with the knock down of YTHDF2. In contrast, overexpression of YTHDF2 and inhibition of miR-493-3p conversely reduced m6A levels. Additionally, the rescue experiments revealed that inhibition of miR-493-3p abrogated the suppression of proliferation and migration induced by si-YTHDF2. To conclude, YTHDF2 and miR-493 3p, as two crucial m6A regulators, are involved in the progression of PCa by indirectly modulating m6A levels. In view of these promising results, YTHDF2 and miR-493-3p may provide new insights into the carcinogenesis and new potential therapeutic targets for PCa. PMID- 29423081 TI - PM2.5 inhalation induces intracranial atherosclerosis which may be ameliorated by omega 3 fatty acids. AB - Background: Intracranial atherosclerosis (ICA) a major health problem. This study investigated whether inhalation of fine airborne particulate matters (PM2.5) causes ICA and whether omega-3 fatty acids (O3FA) attenuated the development of ICA. Results: Twelve but not 6 week exposure significantly increased triglycerides (TG) in normal chow diet (NCD), while PM2.5 enhanced all lipid profiles (TG, low density lipoprotein (LDL) and cholesterol (CHO)) after both 6 and 12-week exposure with high-cholesterol diet (HCD). PM2.5 exposure for 12 but not 6 weeks significantly induced middle cerebral artery (MCA) narrowing and thickening, in association with the enhanced expression of inflammatory cytokines, (interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), interferon gamma (IFN-gamma)), vascular cell adhesion molecule 1 (VCAM-1) and inducible nitric oxide synthase (iNOS). O3FA significantly attenuated vascular alterations, even without favorable changes in lipid profiles, in association with reduced expression of IL 6, TNF-alpha, MCP-1, IFN-gamma, VCAM-1 and iNOS in brain vessels. Conclusions: PM2.5 exposure for 12 weeks aggravates ICA in a dietary model (HCD + short-term L NAME), which may be mediated by vascular inflammation. O3FA dietary supplementation prevents ICA development and inflammatory reaction in cerebral vessels. Methods: Adult Sprague-Dawly rats were under filtered air (FA) or PM2.5 exposure with NCD or HCD for 6 or 12 weeks. Half of the HCD rats were treated with O3FA (5 mg/kg/day) by gavage. A total of 600 mg NG-nitro-L-arginine methyl ester (L-NAME, 3 mg/mL) per rat was administered over two weeks as supplementation in the HCD group. Blood lipids, including LDL, CHO, TG and high density lipoprotein (HDL), were measured at 6 and 12 weeks. ICA was determined by lumen diameter and thickness of the MCA. Inflammatory markers, IL-6, TNF-alpha, MCP-1, IFN-gamma, VCAM-1 and iNOS were assessed by real-time PCR for mRNA and Western blot for protein expression. PMID- 29423082 TI - Reduced recruitment of 53BP1 during interstrand crosslink repair is associated with genetically inherited attenuation of mitomycin C sensitivity in a family with Fanconi anemia. AB - The Fanconi anemia (FA) pathway is implicated in the repair of DNA interstrand crosslinks (ICL). In this process, it has been shown that FA factors regulate the choice for DNA double strand break repair towards homologous recombination (HR). As this mechanism is impaired in FA deficient cells exposed to crosslinking agents, an inappropriate usage of non-homologous end joining (NHEJ) leads to the accumulation of toxic chromosomal abnormalities. We studied a family with two FANCG patients and found a genetically inherited attenuation of mitomycin C sensitivity resulting in-vitro in an attenuated phenotype for one patient or in increased resistance for two healthy relatives. A heterozygous mutation in ATM was identified in these 3 subjects but was not directly linked to the observed phenotype. However, the attenuation of ICL sensitivity was associated with a reduced recruitment of 53BP1 during the course of ICL repair, and increased HR levels. These results further demonstrate the importance of favoring HR over NHEJ for the survival of cells challenged with ICLs. PMID- 29423083 TI - Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models. AB - Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity in vitro and in vivo. BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs), and increase of the MMPs inhibitor (TIMP-2) expression. Moreover, in our animal experiment, intraperitoneal administration of 10 mg/kg/day BA suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without obvious side effects. Furthermore, histological and immunohistochemical analyses showed a decrease in MMP-9 positive cells, MMP-2 positive cells and Ki-67 positive cells and an increase in cleaved caspase-3 positive cells upon BA administration. Notably, BA reduced the number of myeloid derived suppressor cells (MDSCs) in the lungs and tumors. Interestingly, in our caudal vein model, BA also obviously suppressed 4T1 tumor pulmonary metastases. These findings suggested that BA might be a potential agent for inhibiting the growth and metastasis of breast cancer. PMID- 29423084 TI - Similarity and difference in tumor-infiltrating lymphocytes in original tumor tissues and those of in vitro expanded populations in head and neck cancer. AB - Though adoptive tumor-infiltrating lymphocyte (TIL) therapy has been explored in clinical trials for many years, there is little information for the clonotype composition between TILs in original tumor tissues and TILs that were in vitro expanded and infused to cancer patients. To investigate the similarity/difference in TILs in original tumor tissues and those of in vitro expanded populations in squamous cell carcinoma of head and neck (SCCHN) as well as their correlation with somatic mutations in cancer cells, we performed whole exome analysis, expression profile analysis of immune-related genes, and T cell receptor (TCR) analysis of original TILs and in vitro expanded TILs in 8 surgically-resected HPV negative fresh tumors with SCCHN. We found an unusually high number of non synonymous somatic mutations (4290, 1779 and 901 mutations) in three SCCHN tumors, in which we identified mutations in mismatch repair genes, MSH2 or MSH4, or a DNA polymerase gene, POLE. Interestingly, dominant TCR clonotypes of expanded CD8+ TILs derived from these three tumors revealed high similarity to those in original tumors while for remaining tumors with the lower mutational load, we found that T cell clonotypes between TILs in original tumor tissues and those expanded in vitro were almost entirely different. Our findings might provide clinically useful information for identification of tumor-antigen specific T cell clones that may lead to further improvement of adoptive TIL therapy for SCCHN patients. PMID- 29423085 TI - The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth. AB - Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAFV600E mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 uM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma. PMID- 29423086 TI - MiR-27b directly targets Rab3D to inhibit the malignant phenotype in colorectal cancer. AB - MiRNAs, as oncogenes or as anti-oncogenes, play critically regulated roles in the initiation and progression of colorectal cancer at posttranscriptional level. However, the underlying functions of miR-27b in colorectal cancer remain largely unexplored. Here, we demonstrated miR-27b is significantly down-regulated in colorectal cancer tissues, and decreased miR-27b expression was closely associated with shorter overall survival of patients with colorectal cancer. By gain- and loss-of-function studies, we showed miR-27b remarkably suppressed cell proliferation and invasion of colorectal cancer. Furthermore, luciferase reporter assay identified Rab3D was the direct functional target of miR-27b. And Rab3D partly reversed the suppression of cell proliferation and invasion caused by miR 27b mimics. Finally, the animal experiment showed miR-27b plays a crucial role on colorectal cancer progression by targeting Rab3D. Taken together, our study implied miR-27b inhibits cell growth and invasion by targeting Rab3D, and miR-27b is a potential biomarker for prognosis and therapeutic target in colorectal cancer. PMID- 29423087 TI - Design of miRNA sponges for MDV-1 as a therapeutic strategy against lymphomas. AB - Lymphomas are solid-type tumors containing lymphoid cells. Some of latent herpesvirus infections established in B and/or T-lymphocytes could result in the formation of lymphomas. Marek's disease virus serotype 1 (MDV-1) is an avian herpes virus causing to lymphoproliferative tumors in birds, known as Marek's disease (MD). MD has often been used as an ideal biological model for studying the pathogenesis of lymphoma diseases caused by viruses. Therefore, we used it as a research subject to study the effect of miRNA sponges on its tumorigenicity, and to develop the theoretical basis for a new anti-tumor small molecule. The miRNA sponges designed in this study specifically bind to and degrade the miRNAs of meq gene cluster of MDV-1, including miR-M2-3p, miR-M3-5p, miR-M5-3p, miR-M9 5p and miR-M12-3p.qPCR results showed that the knockdown efficiency was 85.03%, 74.97%, 47.06%, 75.33% and 62.55%, respectively. EDU staining and CCK-8 results showed that miRNA sponges inhibited the proliferation of MDV-1 transformed MSB-1 cells in vitro, and the proliferation rate of miRNA sponges-treated cells was about 50% of the control group. DAPI staining and Annxin V-FITC/PI double staining showed that miRNA sponges induced apoptosis in MSB-1 cells, and the apoptotic rate was increased by about 27.87% compared with the control group. The results of transwell showed that miRNA sponges could inhibit the invasion of MSB 1 cells in vitro, and the inhibitory rate was about 64.52%. The soft agar assay showed that miRNA sponges could inhibit the tumorigenic ability of MSB-1 cells in vitro, and the inhibitory rate was about 66.44%.The 60-days animal study showed that miRNA sponges could alleviate the growth inhibition of MSB-1 cells (about 14.78%) and reduce the mortality (about 16.00%). In addition, the tumor formation rate was 0 (8-12% in the control group).This study suggests that miRNA sponges can serve as an effective anti-tumor small molecule for the tumors caused by herpesvirus, with potential clinical implications. PMID- 29423088 TI - Identification of survivin as a promising target for the immunotherapy of adult B cell acute lymphoblastic leukemia. AB - B-cell acute lymphoblastic leukemia (B-ALL) is a rare heterogeneous disease characterized by a block in lymphoid differentiation and a rapid clonal expansion of immature, non-functioning B cells. Adult B-ALL patients have a poor prognosis with less than 50% chance of survival after five years and a high relapse rate after allogeneic haematopoietic stem cell transplantation. Novel treatment approaches are required to improve the outcome for patients and the identification of B-ALL specific antigens are essential for the development of targeted immunotherapeutic treatments. We examined twelve potential target antigens for the immunotherapy of adult B-ALL. RT-PCR indicated that only survivin and WT1 were expressed in B-ALL patient samples (7/11 and 6/11, respectively) but not normal donor control samples (0/8). Real-time quantitative (RQ)-PCR showed that survivin was the only antigen whose transcript exhibited significantly higher expression in the B-ALL samples (n = 10) compared with healthy controls (n = 4)(p = 0.015). Immunolabelling detected SSX2, SSX2IP, survivin and WT1 protein expression in all ten B-ALL samples examined, but survivin was not detectable in healthy volunteer samples. To determine whether these findings were supported by the analyses of a larger cohort of patient samples, we performed metadata analysis on an already published microarray dataset. We found that only survivin was significantly over-expressed in B-ALL patients (n = 215) compared to healthy B-cell controls (n = 12)(p = 0.013). We have shown that survivin is frequently transcribed and translated in adult B-ALL, but not healthy donor samples, suggesting this may be a promising target patient group for survivin-mediated immunotherapy. PMID- 29423089 TI - Rs2459976 in ZW10 gene associated with congenital heart diseases in Chinese Han population. AB - Congenital heart diseases (CHD) are a large group of prevalent and complex anatomic malformations of the heart, with the genetic basis remaining largely unknown. Since genes or factors associated with the differentiation of human embryonic stem (HES) cells would affect the development of all embryonic tissues, including cardiac progenitor cells, we postulated their potential roles in CHD. In this study, we focused on ZW10, a kinetochore protein involved in the process of proper chromosome segregation, and conducted comparative studies between CHD patients and normal controls matched in gender and age in Chinese Han populations. We identified three variations in the ZW10 gene, including rs2885987, rs2271261 and rs2459976, which all had high genetic heterozygosity. Association analysis of these genetic variations with CHD showed correlation between rs2459976 and the risk of CHD. We conclude that rs2459976 in the ZW10 gene is associated with CHD in Chinese Han populations. PMID- 29423090 TI - Efficacy of assessing circulating cell-free DNA using a simple fluorescence assay in patients with triple-negative breast cancer receiving neoadjuvant chemotherapy: a prospective observational study. AB - This study aims to assess cell-free DNA (CFD) by a fluorescence assay as a biomarker for early prediction of a pathologic complete response (pCR) and relapse in patients with triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy. Patients with clinical stage II or III TNBC scheduled for neoadjuvant chemotherapy were prospectively enrolled. All patients underwent four cycles of Adriamycin plus cyclophosphamide (AC), followed by four cycles of cisplatin or docetaxel chemotherapy and surgery. Blood samples were obtained before the initial chemotherapy (baseline-CFD) and after four AC neoadjuvant chemotherapy cycles (AC-CFD) to evaluate CFD levels. In total, 72 patients who met the inclusion criteria were enrolled. The mean baseline-CFD and AC-CFD levels were 239 +/- 68 and 210 +/- 66 ng/mL, respectively, with a significant decline in the CFD levels after AC neoadjuvant chemotherapy (P = 0.001). In the 33.6-month median follow-up, 18 cases of relapse were reported. A ROC curve analysis of baseline-CFD was performed to determine the predictive value for relapse, and an area under the curve of 0.62 (95% CI, 0.46-0.78) at 264 ng/mL was obtained. Patients with baseline-CFD >264 ng/mL were at a higher risk of relapse than those with baseline-CFD <=264 ng/mL (HR, 2.84; 95% CI, 1.11-7.24; P = 0.029). Multivariate analysis established baseline-CFD as an independent predicting factor for relapse (HR, 3.74; 95% CI, 1.32-10.53; P = 0.013). In conclusion, baseline-CFD measured by a fluorescence assay might be a potential biomarker to predict relapse, which could be useful for risk stratification of TNBC. PMID- 29423091 TI - Catalpol protects mice against Lipopolysaccharide/D-galactosamine-induced acute liver injury through inhibiting inflammatory and oxidative response. AB - The purpose of this study was to investigate the protective effect of catalpol on Lipopolysaccharide (LPS)/D-galactosamine (D-gal)-induced acute liver injury in mice. The mouse model was established by injection of LPS and D-gal. Catalpol (2.5, 5, 10 mg/kg) were pretreated intraperitoneally 1 h before LPS and D-gal. The survival rate, AST, ALT, MDA, MPO activity, hepatic tissue histology, TNF alpha level, and NF-kappaB activation were assayed. The results revealed that catalpol dose-dependently elevated the survival rate. Furthermore, catalpol reduced the activities of AST, ALT, MDA, and MPO. The production of TNF-alpha was also inhibited by treatment of catalpol. In addition, catalpol inhibited LPS/D gal-induced NF-kappaB activation. The expression of Nrf2 and HO-1 were up regulated by treatment of catalpol. These results indicated that pretreatment with catalpol could attenuate LPS/D-gal-induced acute liver injury in mice and the underlying mechanism may due to the inhibition of NF-kappaB signaling pathway and the activation of Nrf2 signaling pathway. PMID- 29423092 TI - Nucleoside reverse transcriptase inhibitor-induced rat oocyte dysfunction and low fertility mediated by autophagy. AB - Low fertility is one of the most common side effects caused by nucleoside reverse transcriptase inhibitors (NRTIs), whereas the molecular mechanism underlying this process were largely unclear. This study was conducted to investigate whether autophagy plays a role in NRTIs-induced oocyte dysfunction and low fertility in female rat. Both in vivo and in vitro experiments were conducted. For the in vivo experiment, female adult Sprague-Dawley rats were subjected to zidovudine (AZT) and lamivudine (3TC) intragastric treatment for 3, 6, 9, and 12 weeks; a control was also set. Oocytes were collected for maturation evaluation, in vitro fertilization and mitochondrial function assays, and apoptosis and autophagy analysis. For the in vitro experiment, oocytes were collected and assigned to the control, 3-methyladenine (3-MA, an effective autophagy inhibitor), AZT, AZT+3-MA, 3TC, and 3TC+3-MA groups. The oocytes were cultured with the abovementioned drugs for 24, 48, and 72 h and then, subjected to the same assays as in the in vivo study. The results showed a significant time-dependent decrease in oocyte maturation-related maker levels, oocyte cleavage rate, blastocyst formation rate, mitochondrial DNA copy number and adenosine triphosphate level, and apoptosis, and a significant increase in the reactive oxygen species levels (all P-values < 0.05), in both the in vivo and the in vitro experiments. These changes, except for the changes in the oocyte maturation-related markers, were partially attenuated by 3-MA. In conclusion, we demonstrated that NRTIs can cause rat oocyte dysfunction and low fertility, and this damage was, at least partially, mediated by autophagy. PMID- 29423093 TI - Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells. AB - Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-ribose) polymerases (PARPis) and histone deacetylases (HDACis) are clinically active anti-tumor drugs. We hypothesized that their combination would be synergistically cytotoxic to leukemia and lymphoma cells. Exposure of AML and lymphoma cell lines to the combination of the PARPi niraparib (Npb), the HMA decitabine (DAC) and the HDACi romidepsin (Rom) or panobinostat (Pano) synergistically inhibited cell proliferation by up to 70% via activation of the ATM pathway, increased production of reactive oxygen species, decreased mitochondrial membrane potential, and activated apoptosis. Addition of the DNA alkylating agents busulfan (Bu) and/or melphalan enhanced the anti proliferative/cytotoxic effects of the triple-drug combination. [Npb+DAC+Rom] significantly increased the level of chromatin-bound PARP1 and DNMT1 and caused acetylation of DNA repair proteins, including Ku70, Ku80, PARP1, DDB1, ERCC1 and XPF/ERCC4. This three-drug combination down-regulated the components of the nucleosome-remodeling deacetylase (NuRD) complex, which is involved in DNA-damage repair. Addition of Bu to this combination further enhanced these effects on NuRD. The trapping of PARP1 and DNMT1 to chromatin, acetylation of DNA repair proteins, and down-regulation of NuRD may all have increased double-strand DNA break (DSB) formation as suggested by activation of the DNA-damage response, concomitantly resulting in tumor cell death. Similar synergistic cytotoxicity was observed in blood mononuclear cells isolated from patients with AML and lymphoma. Our results provide a rationale for the development of [Npb+DAC+Rom/Pano] combination therapies for leukemia and lymphoma patients. PMID- 29423094 TI - Differential regulation of the androgen receptor by protein phosphatase regulatory subunits. AB - The Androgen Receptor (AR) is a key molecule in the development, maintenance and progression of prostate cancer (PC). However, the relationship between the AR and co-regulatory proteins that facilitate AR activity in castrate resistant settings remain understudied. Here we show that protein phosphatase 1 regulatory subunits, identified from a phosphatase RNAi screen, direct PP1 catalytic subunits to a varied yet significant response in AR function. As such, we have characterised the PP1beta holoenzyme, myosin phosphatase (MLCP), as a novel ligand independent regulator of the AR. Sustained MLCP activity through down-regulation of the MLCP inhibitory subunit, PPP1R14C, results in impaired AR nuclear translocation, protein stability and transcriptional activity in distinct models of PC progression, culminating in restoration of a non-malignant prostate genotype. Phenotypically, a marked reduction in cell proliferation and migration, characterised by G1 cell cycle arrest is observed, confirming PP1 holoenzyme disruption as a novel treatment approach in PC. PMID- 29423095 TI - Decrease in PSCA expression caused by Helicobacter pylori infection may promote progression to severe gastritis. AB - SNP rs2294008 in Prostate Stem Cell Antigen (PSCA) and decreased PSCA expression are associated with gastric cancer. The objective of this study is to investigate the role of rs2294008 and PSCA expression in the gastritis-gastric cancer carcinogenic pathway. We conducted a case-control association study of H. pylori infected gastritis and gastric cancer. rs2294008 was associated with the progression to chronic active gastritis (P = 9.4 * 10-5; odds ratio = 3.88, TT + TC vs CC genotype), but not with H. pylori infection per se nor with the progression from active gastritis to gastric cancer. We also assessed the association of rs2294008 with PSCA mRNA expression in the gastric mucosa at various disease stages and found that rs2294008 was associated with PSCA expression (P = 1.3 * 10-12). H. pylori infection (P = 5.1 * 10-8) and eradication therapy (P < 1 * 10-11) resulted in the reduced and increased PSCA expression, respectively, indicating negative regulation of PSCA expression by H. pylori infection. PSCA expression was decreased in severe gastritis compared with mild gastritis only among T allele carriers. Our findings revealed the regulation of PSCA expression by host genetic variation and bacterial infection might contribute to gastritis progression after H. pylori infection. PMID- 29423096 TI - Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts. AB - Purpose: There is a need for adjuvant/neo-adjuvant treatment strategies to prevent metastatic relapse in soft tissue sarcoma (STS). Tumor hypoxia is associated with a high-risk of metastasis and is potentially targetable. This study aimed to derive and validate a hypoxia mRNA signature for STS for future biomarker-driven trials of hypoxia targeted therapy. Materials and Methods: RNA sequencing was used to identify seed genes induced by hypoxia in seven STS cell lines. Primary tumors in a training cohort (French training) were clustered into two phenotypes by seed gene expression and a de novo hypoxia signature derived. Prognostic significance of the de novo signature was evaluated in the training and two independent validation (French validation and The Cancer Genome Atlas) cohorts. Results: 37 genes were up-regulated by hypoxia in all seven cell lines, and a 24-gene signature was derived. The high-hypoxia phenotype defined by the signature was enriched for well-established hypoxia genes reported in the literature. The signature was prognostic in univariable analysis, and in multivariable analysis in the training (n = 183, HR 2.16, P = 0.0054) and two independent validation (n = 127, HR 3.06, P = 0.0019; n = 258, HR 2.05, P = 0.0098) cohorts. Combining information from the de novo hypoxia signature and a genome instability signature significantly improved prognostication. Transcriptomic analyses showed high-hypoxia tumors had more genome instability and lower immune scores. Conclusions: A 24-gene STS-specific hypoxia signature may be useful for prognostication and identifying patients for hypoxia-targeted therapy in clinical trials. PMID- 29423097 TI - Primary breast diffuse large B-cell lymphoma: a population-based study from 1975 to 2014. AB - Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin's lymphoma with limited data. In this study, a population-based study of primary breast DLBCL in the United States was performed to determine its incidence trends, prognostic factors, survival, the role of surgery as well as the comparison with nodal DLBCL. 1021 patients diagnosed with breast DLBCL were identified in the Surveillance, Epidemiology, and End Results (SEER) cancer registries from 1973-2014. The incidence of both breast and nodal DLBCL increased over time. Patients with breast DLBCL were older, mainly women, diagnosed at earlier stages and had lower prevalence in white and black races compared with nodal DLBCL. Multivariate analysis revealed older age (>= 70 years old) and advanced stage as independent predictors of worse OS. Independent predictor of better DSS were younger age (< 70 years old), early stage and diagnosis after 2000. When analyzed according to age, stage, race, tumor laterality and year of diagnosis, the overall survival did not benefit from surgery except in patients diagnosed between 2001-2010 and the surgery rate decreased overtime. Compared with nodal DLBCL, breast DLBCL patients exhibited a better outcome. In conclusion, breast DLBCL is a rare tumor with increasing incidence and improved survival over the last four decades. The introduction of rituximab seems to improve the outcome of breast DLBCL. Further studies are needed to advance our understanding of breast DLBCL and optimize the treatment strategy. PMID- 29423099 TI - Investigation on outcomes and bacterial distributions of liver cirrhosis patients with gram-negative bacterial bloodstream infection. AB - Objective: The study aimed at analyzing the epidemiology and outcomes of liver cirrhosis patients undergoing gram-negative bacterial bloodstream infection. Results: Totally 508 eligible patients were collected, with 25.79% 30-day mortality, and 58.86% patients were confirmed as nosocomial infection. The most common isolates were Escherichia coli (48.29%) and Klebsiella pneumoniae (19.29%), and multidrug-resistant isolates accounted for 36.61%. The bacterial distributions were similar between survivors and non-survivors (P>0.05), but showed close association with acquisition sites of infection (P<0.05). Nosocomial infection (HR=1.589, 95% CI=1.004-2.517), Child-Pugh grade (HR=2.471, 95% CI=1.279-4.772), septic shock (HR=1.966, 95% CI=1.228-3.146), complications (HR=3.529, 95% CI=2.140-5.818), and WBC (HR=1.065, 95% CI=1.018-1.114) were independent indicators for 30-day mortality. beta-lactamase inhibitor antibiotics exerted a high antibacterial activity. Methods: The inpatients with liver cirrhosis developed gram-negative bacterial bloodstream infection were collected. The clinical characteristics, bacterial distribution and drug sensitivity results of patients were compared according to their 30-day survival status and acquisition sites of infections. Cox regression model was applied to evaluate the risk factors for 30-day mortality. Conclusion: Escherichia coli and Klebsiella pneumoniae are frequently isolated from gram-negative bacterial bloodstream infection episodes in cirrhosis patients. Acquisition site of infection can influence clinical characteristics and etiological distribution. beta-lactamase inhibitor antibiotics may be the first choice for empirical treatments. PMID- 29423098 TI - Impact of STAT3 phosphorylation in glioblastoma stem cells radiosensitization and patient outcome. AB - Glioblastoma (GBM) represents the most common and lethal primary malignant brain tumor. The standard treatment for glioblastoma patients involves surgical resection with concomitant radio and chemotherapy. Despite today's clinical protocol, the prognosis for patients remains very poor with a median survival of 15 months. Tumor resistance and recurrence is strongly correlated with a subpopulation of highly radioresistant and invasive cells termed Glioblastoma Stem Cells (GSCs). The transcription factor STAT3 has been found to be constitutively activated in different tumors including GBM and enhanced tumor radioresistance. In this study, we assessed radiosensitization of GSC lines isolated from patients by inhibition of STAT3 activation using Stattic or WP1066. We showed that inhibitor treatment before cell irradiation decreased the surviving fraction of GSCs suggesting that STAT3 inhibition could potentiate radiation effects. Finally, we investigated STAT3 activation status on 61 GBM clinical samples and found a preferential phosphorylation of STAT3 on Serine727 (pS727). Moreover, we found that pS727 was associated with a significant lower overall patient survival and progression-free survival but not pY705. Taken together, our results suggest that pS727-STAT3 could be a potential prognostic marker and could constitute a therapeutic target to sensitize highly radioresistant GSCs. PMID- 29423100 TI - Proteomic profiling of antibody-inducing immunogens in tumor tissue identifies PSMA1, LAP3, ANXA3, and maspin as colon cancer markers. AB - We hypothesized that cancer tissue immunogens - antigens capable of inducing specific antibody production in patients - are promising targets for development of precision diagnostics and humoral immunotherapies. We developed an innovative immuno-proteomic strategy and identified new immunogenic markers of colon cancer. Proteins from cancers and matched normal tissues were separated by 2D gel electrophoresis and blotted with serum antibodies from the same patients. Antibody-reactive proteins were sequenced by mass spectrometry and validated by Western blotting and immunohistochemistry. 170 serum antibody-reactive proteins were identified only in cancerous but not matched normal. Among these, proteasome subunit alpha type 1 (PSA1), leucine aminopeptidase 3 (LAP3), annexin A3 (ANXA3), and maspin (serpin B5) were reproducibly found in tissues from three patients. Differential expression patterns were confirmed in samples from eight patients with various stages of colon adenocarcinoma and liver metastases. These tumor resident proteins and/or their associated serum antibodies may be promising markers for colon cancer screening and early diagnosis. Furthermore, tumor tissue specific antibodies could potentially be exploited as immunotherapeutic targets against cancer. More generally, proteomic profiling of antibody-inducing cancer associated immunogens represents a powerful generic method for uncovering the tumor antigen-ome, i.e., the totality of immunogenic tumor-associated proteins. PMID- 29423102 TI - Optimal time of tumour response evaluation and effectiveness of hypofractionated proton beam therapy for inoperable or recurrent hepatocellular carcinoma. AB - Objective: To evaluate the optimal time of tumour response and effectiveness of hypofractionated proton beam therapy (PBT) for hepatocellular carcinoma (HCC). Results: Overall, treatment was well tolerated with no grade toxicity >=3. Of 71 patients, 66 patients (93%) eventually reached complete response (CR) after PBT: 93.9% (62 of 66) of patients who reached CR within 12 months, and the remaining 4 patients (6.1%) reached CR at 12.5, 16.2, 19.1 and 21.7 months, respectively. The three-year local progression-free survival (LPFS), relapse-free survival (RFS) and OS rates were 89.9%, 26.8%, and 74.4%, respectively. Multivariate analysis revealed that the tumour response was an independent prognostic factor for LPFS, RFS, and OS. Conclusion: Most CR was achieved within 1 year after PBT and further salvage treatments in PBT field might be postponed up to approximately 18-24 months. Hypofractionated PBT could be good alternative for HCC patients who are unsuitable for surgical or invasive treatments with curative intent. Materials and Methods: Seventy-one inoperable or recurrent HCC patients underwent hypofractionated PBT using 66 GyE in 10 fractions. The tumour responses were defined as the maximal tumour response observed during the follow-up period using the modified Response Evaluation Criteria in Solid Tumors criteria. PMID- 29423101 TI - Up-regulation of hexokinase II contributes to rituximab-chemotherapy resistance and is a clinically relevant target for therapeutic development. AB - In order to identify cellular pathways associated with therapy-resistant aggressive lymphoma, we generated rituximab-resistant cell lines (RRCL) and found that the acquirement of rituximab resistance was associated with a deregulation in glucose metabolism and an increase in the apoptotic threshold leading to chemotherapy resistance. Hexokinase II (HKII), the predominant isoform overexpressed in cancer cells, has dual functions of promoting glycolysis as well as inhibiting mitochondrial-mediated apoptosis. We found that RRCL demonstrated higher HKII levels. Targeting HKII resulted in decreased mitochondrial membrane potential, ATP production, cell viability; and re-sensitization to chemotherapy agents. Analyzed gene expression profiling data from diffuse large B-cell lymphoma patients, high-HKII levels were associated with a shorter progression free survival (PFS) and/or overall survival (OS). Our data suggest that over expression of HKII is associated with resistance to rituximab and chemotherapy agents in aggressive lymphoma and identifies this enzyme isoform as a potential therapeutic target. PMID- 29423103 TI - Metformin induces distinct bioenergetic and metabolic profiles in sensitive versus resistant high grade serous ovarian cancer and normal fallopian tube secretory epithelial cells. AB - Metformin is a widely used agent for the treatment of diabetes and infertility, however, it has been found to have anti-cancer effects in a variety of malignancies including high grade serous ovarian cancer (HGSC). Studies describing the mechanisms by which metformin affects HGSC are ongoing, but detailed analysis of its effect on the cellular metabolism of both HGSC cells and their precursor, normal fallopian tube secretory epithelial cells (FTSECs), is lacking. We addressed the effects of metformin and the more potent biguanide, phenformin, on HGSC cell lines and normal immortalized FTSECs. Cell proliferation assays identified that FTSECs and a subset of HGSC cell lines are relatively resistant to the anti-proliferative effects of metformin. Bioenergetic and metabolomic analyses were used to metabolically differentiate the metformin sensitive and metformin-resistant cell lines. Bioenergetically, biguanides elicited a significant decrease in mitochondrial respiration in all HGSC cells and FTSECs. However, biguanides had a greater effect on mitochondrial respiration in metformin sensitive cells. Metabolomic analysis revealed that metformin and phenformin generally induce similar changes in metabolic profiles. Biguanide treatment led to a significant increase in NADH in FTSECs and HGSC cells. Interestingly, biguanide treatment induced changes in the levels of mitochondrial shuttle metabolites, glycerol-3-phopshate (G3P) and aspartate, specifically in HGSC cell lines and not in FTSECs. Greater alterations in G3P or aspartate levels were also found in metformin sensitive cells relative to metformin resistant cells. These data identify bioenergetic and HGSC-specific metabolic effects that correlate with metformin sensitivity and novel metabolic avenues for possible therapeutic intervention. PMID- 29423104 TI - Clinical outcomes and differential effects of PI3K pathway mutation in obese versus non-obese patients with cervical cancer. AB - The purpose of this study was to evaluate the effect of obesity and obesity associated factors on the outcomes of patients with cervical cancer. Outcomes were evaluated in 591 patients with FIGO Ib to IV cervical cancer treated uniformly with definitive radiation. Patients were stratified into 3 groups based upon pretreatment Body Mass Index (BMI): A <= 18.5; B 18.6 - 34.9; and C >= 35. The 5-year freedom from failure rates were 58, 59, and 73% for BMI groups A, B, and C (p = 0.01). Overall survival rates were 50, 59, and 68%, respectively (p = 0.02). High expression of phosphorylated AKT (pAKT) was associated with poor outcomes only in non-obese patients. Obese patients with PI3K pathway mutant tumors had a trend toward favorable outcomes, while a similar effect was not observed in non-obese patients. Compared to similar tumors from non-obese hosts, PIK3CA and PTEN mutant tumors from obese patients failed to express high levels of phosphorylated AKT and its downstream targets. These results show that patients with obesity at the time of diagnosis of cervical cancer exhibit improved outcomes after radiation. PI3K/AKT pathway mutations are common in obese patients, but are not associated with activation of AKT signaling. PMID- 29423105 TI - Transcriptome profiling identified differentially expressed genes and pathways associated with tamoxifen resistance in human breast cancer. AB - Tamoxifen (TAM) resistance is an important clinical problem in the treatment of breast cancer. In order to identify the mechanism of TAM resistance for estrogen receptor (ER)-positive breast cancer, we screened the transcriptome using RNA-seq and compared the gene expression profiles between the MCF-7 mamma carcinoma cell line and the TAM-resistant cell line TAMR/MCF-7, 52 significant differential expression genes (DEGs) were identified including SLIT2, ROBO, LHX, KLF, VEGFC, BAMBI, LAMA1, FLT4, PNMT, DHRS2, MAOA and ALDH. The DEGs were annotated in the GO, COG and KEGG databases. Annotation of the function of the DEGs in the KEGG database revealed the top three pathways enriched with the most DEGs, including pathways in cancer, the PI3K-AKT pathway, and focal adhesion. Then we compared the gene expression profiles between the Clinical progressive disease (PD) and the complete response (CR) from the cancer genome altas (TCGA). 10 common DEGs were identified through combining the clinical and cellular analysis results. Protein-protein interaction network was applied to analyze the association of ER signal pathway with the 10 DEGs. 3 significant genes (GFRA3, NPY1R and PTPRN2) were closely related to ER related pathway. These significant DEGs regulated many biological activities such as cell proliferation and survival, motility and migration, and tumor cell invasion. The interactions between these DEGs and drug resistance phenomenon need to be further elucidated at a functional level in further studies. Based on our findings, we believed that these DEGs could be therapeutic targets, which can be explored to develop new treatment options. PMID- 29423106 TI - The vascular disrupting agent combretastatin A-4 phosphate causes prolonged elevation of proteins involved in heme flux and function in resistant tumor cells. AB - Vascular disrupting agents (VDAs) represent a promising class of anti-cancer drugs for solid tumor treatment. Here, we aim to better understand the mechanisms underlying tumor reccurrence and treatment resistance following the administration of a VDA, combretastatin A-4 phosphate (CA4P). Firstly, we used photoacoustic tomography to noninvasively map the effect of CA4P on blood oxygen levels throughout subcutaneous non-small cell lung cancer (NSCLC) tumors in mice. We found that the oxygenation of peripheral tumor vessels was significantly decreased at 1 and 3 hours post-CA4P treatment. The oxygenation of the tumor core reduced significantly at 1 and 3 hours, and reached anoxia after 24 hours. Secondly, we examined the effect of CA4P on the levels of proteins involved in heme flux and function, which are elevated in lung tumors. Using immunohistochemistry, we found that CA4P substantially enhanced the levels of enzymes involved in heme biosynthesis, uptake, and degradation, as well as oxygen utilizing hemoproteins. Furthermore, measurements of markers of mitochondrial function suggest that CA4P did not diminish mitochondrial function in resistant tumor cells. These results suggest that elevated levels of heme flux and function contribute to tumor regrowth and treatment resistance post-VDA administration. PMID- 29423107 TI - Pulmonary sarcomatoid carcinoma: University of Cincinnati experience. AB - Objectives: To review the outcomes of treatment in patients with pulmonary sarcomatoid carcinoma (PSC) treated at the University of Cincinnati Medical Center (UCMC). Results: There was no significant difference in survival of patients treated with chemotherapy alone (median, 256 days) compared to patients not undergoing treatment (median, 205.5 days). Patients who underwent surgery and adjuvant chemotherapy showed a trend in improvement of survival (median, 457.6 days). Patients requiring only surgery had the longest OS of 713.5 days. Conclusions: Systemic chemotherapy alone did not improve survival in patients with PSC. Surgery provides the greatest overall survival benefit and adjuvant chemotherapy may also improve survival. Methods: From 2000 to 2014, twenty-five patients with pathologically confirmed PSC were treated at UCMC. The outcomes were retrospectively analyzed by treatment with overall survival (OS) as the endpoint. PMID- 29423108 TI - Cancer immunogenomic approach to neoantigen discovery in a checkpoint blockade responsive murine model of oral cavity squamous cell carcinoma. AB - Head and neck squamous cell carcinomas (HNSCC) are an ideal immunotherapy target due to their high mutation burden and frequent infiltration with lymphocytes. Preclinical models to investigate targeted and combination therapies as well as defining biomarkers to guide treatment represent an important need in the field. Immunogenomics approaches have illuminated the role of mutation-derived tumor neoantigens as potential biomarkers of response to checkpoint blockade as well as representing therapeutic vaccines. Here, we aimed to define a platform for checkpoint and other immunotherapy studies using syngeneic HNSCC cell line models (MOC2 and MOC22), and evaluated the association between mutation burden, predicted neoantigen landscape, infiltrating T cell populations and responsiveness of tumors to anti-PD1 therapy. We defined dramatic hematopoietic cell transcriptomic alterations in the MOC22 anti-PD1 responsive model in both tumor and draining lymph nodes. Using a cancer immunogenomics pipeline and validation with ELISPOT and tetramer analysis, we identified the H-2Kb-restricted ICAM1P315L (mICAM1) as a neoantigen in MOC22. Finally, we demonstrated that mICAM1 vaccination was able to protect against MOC22 tumor development defining mICAM1 as a bona fide neoantigen. Together these data define a pre-clinical HNSCC model system that provides a foundation for future investigations into combination and novel therapeutics. PMID- 29423109 TI - HLA class I loss and PD-L1 expression in lung cancer: impact on T-cell infiltration and immune escape. AB - Immune-checkpoint inhibitors show encouraging results in cancer treatment, but the clinical benefit is limited exclusively to a subset of patients. We analyzed the density and composition of tumor T-cell infiltration in non-small-cell lung carcinoma (NSCLC) in relation to PD-L1 and HLA class I (HLA-I) expression. We found that positive HLA-I expression, independently on PD-L1 status, is the key factor determining the increased density of the immune infiltrate. When both markers were analyzed simultaneously, we identified four phenotypes of HLA-I and PD-L1 co-expression. They demonstrated different patterns of tumor infiltration and clinicopathologic characteristics, including the tumor size and lymphatic spread. All HLA-I+/PD-L1+ tumors had a high degree of intratumoral infiltration with CD8+T-lymphocytes, whereas HLA-I loss was associated with a significantly reduced number of tumor infiltrating T-lymphocytes mostly restrained in the stroma surrounding the tumor nest. HLA-I-negative/PD-L1-positive tumors had bigger size (T) and lower grade of infiltration with CD8+T-cells. It represents a cancer immune escape phenotype that combines two independent mechanisms of immune evasion: loss of HLA-I and upregulation of PD-L1. Using GCH-array analysis of human lung cancer cell lines we found that the loss of heterozygosity (LOH) with complete or partial deletion of HLA-I genes is the principal mechanism of HLA-I alterations. This irreversible defect, which could potentially decrease the clinical efficacy of lung cancer immunotherapy, appears to be underestimated. In conclusion, our results suggest that the analysis of HLA-I is very important for the selection of potential responders to cancer immunotherapy. PMID- 29423110 TI - Potential for subsets of wt-NPM1 primary AML blasts to respond to retinoic acid treatment. AB - Acute myeloid leukemia (AML) has high mortality rates, perhaps reflecting a lack of understanding of the molecular diversity in various subtypes and a lack of known actionable targets. There are currently 12 open clinical trials for AML using combination therapeutic modalities including all-trans retinoic acid (RA). Mutant nucleophosmin-1, proposed as a possible marker for RA response, is the criterion for recruiting patients in three active RA phase 3 clinical trials. We tested the ability of RA alone or in combination with either bosutinib (B) or 6 formylindolo(3,2-b) carbazole (F) to induce conversion of 12 de novo AML samples toward a more differentiated phenotype. We assessed levels of expression of cell surface markers associated with differentiation, aldehyde dehydrogenase activity, and glucose uptake activity. Colony formation capacity was reduced with the combined treatment of RA and B or F, and correlated with modulation of a c Cbl/Lyn/c-Raf-centered signalsome. Combination treatment was in most cases more effective than RA alone. Based on their responses to the treatments, some primary leukemic samples cluster closer to HL-60 cells than to other primary samples, suggesting that they may represent a hitherto undefined AML subtype that is potentially responsive to RA in a combination differentiation therapy. PMID- 29423111 TI - Effect of NET-1 siRNA conjugated sub-micron bubble complex combined with low frequency ultrasound exposure in gene transfection. AB - The present study evaluated the effect of NET-1 siRNA-conjugated sub-micron bubble (SMB) complexes combined with low-frequency ultrasound exposure in gene transfection. The NET-1 gene was highly expressed level in SMMC-7721 human hepatocellular carcinoma cell line. The cells were divided into seven groups and treated with different conditions. The groups with or without low-frequency ultrasound exposure, groups of adherent cells, and suspension cells were separated. The NET-1 siRNA-conjugated SMB complexes were made in the laboratory and tested by Zetasizer Nano ZS90 analyzer. Flow cytometry was used to estimate the transfection efficiency and cellular apoptosis. Western blot and quantitative real-time polymerase chain reaction (qPCR) were used for the estimation of the protein and mRNA expressions, respectively. Transwell analysis determined the migration and invasion capacities of the tumor cells. The results did not show any difference in the transfection efficiency between adherent and suspension cells. However, the NET-1 siRNA-SMB complexes combined with low-frequency ultrasound exposure could enhance the gene transfection effectively. In summary, the NET-1 siRNA-SMB complexes appeared to be promising gene vehicle. PMID- 29423112 TI - Ophiopogonin B sensitizes TRAIL-induced apoptosis through activation of autophagy flux and downregulates cellular FLICE-like inhibitory protein. AB - Tumor necrosis factor related apoptosis-inducing ligand (TRAIL), a type II transmembrane protein, belongs to the TNF superfamily. Compared to other family members, TRAIL is a promising anti-cancer agent that can selectively induce apoptosis of various types of transformed cells and xenografts, with negligible cytotoxicity against normal tissues. Ophiopogonin B is a bioactive ingredient of Radix Ophiopogon japonicus, which is frequently used in traditional Chinese medicine to treat cancer. In this study, we report that Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is the key determinant mediating TRAIL resistance in A549 cells and Ophiopogonin B downregulates c-FLIP and enhances TRAIL-induced apoptosis by activating autophagy flux. In addition, treatment with Ophiopogonin B resulted in a slight increase in the conversion of LC3-I to LC3-II and significantly decreased p62 expression levels in a dose dependent manner. This indicates that Ophiopogonin B induces autophagy flux activation in human lung cancer cells. Inhibiting autophagy flux by applying a specific inhibitor ATG5 siRNA with Ophiopogonin B mediated enhancement of TRAIL effects. These data demonstrate that downregulation of c-FLIP by Ophiopogonin B enhances TRAIL-induced tumor cell death by activating autophagy flux in TRAIL resistant A549 cells, and also suggests that Ophiopogonin B combined with TRAIL may be a successful therapeutic strategy for TRAIL-resistant lung cancer cells. PMID- 29423113 TI - CKS1 expression in melanocytic nevi and melanoma. AB - Cyclin-dependent kinase subunit 1 (Cks1) regulates the degradation of p27, an important G1-S inhibitor, which is up regulated by MAPK pathway activation. In this study, we sought to determine whether Cks1 expression is increased in melanocytic tumors and correlates with outcome and/or other clinicopathologic prognostic markers. Cks1 expression was assessed by immunohistochemistry in 298 melanocytic lesions. The frequency and intensity of cytoplasmic and nuclear expression was scored as a labeling index and correlated with clinico pathological data. Nuclear Cks1 protein was found in 63% of melanocytic nevi, 89% primary and 90% metastatic melanomas with mean labeling index of 7 +/- 16, 19 +/- 20, and 30 +/- 29, respectively. While cytoplasmic Cks1 was found in 41% of melanocytic nevi, 84% primary and 95% metastatic melanomas with mean labeling index of 18 +/- 34, 35 +/- 34, and 52 +/- 34, accordingly. Histologic stepwise model of tumor progression, defined as progression from benign nevi to primary melanomas, to melanoma metastases, revealed a significant increase in nuclear and cytoplasmic Cks1 expression with tumor progression. Nuclear and cytoplasmic Cks1 expression correlated with the presence of ulceration, increased mitotic rate, Breslow depth, Clark level, tumor infiltrating lymphocytes and gender. However, other well-known prognostic factors (age, anatomic site, and regression) did not correlate with any type of Cks1 expression. Similarly, increasing nuclear expression of Cks1 significantly correlated with worse overall survival. Thus, Cks1 expression appears to play a role in the progression of melanoma, where high levels of expression are associated with poor outcome. Cytoplasmic expression of Cks1 might represent high turnover of protein via the ubiquination/proteosome pathway. PMID- 29423114 TI - Germline polymorphism of interferon-lambda3 is clinically associated with progression of renal cell carcinoma. AB - Renal cell carcinoma (RCC) is an immunogenic tumor that shows a metabolic shift to aerobic glycolysis. The immune system can have opposing host-protective and tumor-promoting effects, and aerobic glycolysis suppresses antitumor immunity. In addition to immunostimulatory effect, increasing numbers of studies have revealed that interferon (IFN) is also involved in promoting immunosuppression. Since various single nucleotide polymorphisms (SNPs) can influence the outcome of anticancer therapy, we investigated SNPs for IFN-lambda3, a new member of IFN family, in 53 patients with metastatic RCC who underwent cytoreductive nephrectomy. The 16 patients who were heterozygous/homozygous for the minor alleles of SNPs for IFN-lambda3 had a significantly worse response to sequential vascular endothelial growth factor-targeting therapy (P = 0.0029) and shorter survival (P = 0.0033) compared with the 37 patients possessing the major alleles of SNPs for IFN-lambda3. In these 16 patients, the primary tumor showed elevated glucose uptake on positron emission tomography with [18F] fluorodeoxyglucose (P = 0.0160) and increased expression of programmed cell death 1 (PD-1)-ligand 1 (PD L1) and phosphorylated serine/threonine kinase Akt (P = 0.0006 and P = 0.0043, respectively) compared to the tumors of the patients without these alleles. Since IFN-induced PD-L1 expression on either tumor cells or tumor-infiltrating mononuclear cells can trigger immunosuppression due to crosstalk between cancer cells and T cells, IFN-lambda3 polymorphism might be linked to the immunosuppressive effects of IFNs in cancer. Although this retrospective study lacks mechanistic insight, our findings suggest that IFN-lambda3 polymorphism might be relevant to the progression of RCC. PMID- 29423116 TI - A plasma telomeric cell-free DNA level in unaffected women with BRCA1 or/and BRCA2 mutations: a pilot study. AB - Plasma cell-free DNA (cfDNA) is a small DNA fragment circulating in the bloodstream originating from both non-tumor- and tumor-derived cells. A previous study showed that a plasma telomeric cfDNA level decreases in sporadic breast cancer patients compared to controls. Tumor suppressor gene products including BRCA1 and BRCA2 (BRCA1&2) play an important role in telomere maintenance. In this study, we hypothesized that the plasma telomeric cfDNA level is associated with the mutation status of BRCA1&2 genes. To test this hypothesis, we performed plasma telomeric cfDNA quantitative PCR (qPCR)-based assays to compare 28 women carriers of the BRCA1&2 mutation with age-matched controls of 28 healthy women. The results showed that the plasma telomeric cfDNA level was lower in unaffected BRCA1&2 mutation carriers than in age-matched controls from non-obese women (BMI < 30), while there was no association between unaffected BRCA1&2 mutation carriers and age-matched controls in obese women (BMI > 30). Moreover, the plasma telomeric cfDNA level applied aptly to the Tyrer-Cuzick model in non-obese women. These findings suggest that circulating cfDNA may detect dysfunctional telomeres derived from cells with BRCA1&2 mutations and, therefore, its level is associated with breast cancer susceptibility. This pilot study warrants further investigation to elucidate the implication of plasma telomeric cfDNA levels in relation to cancer and obesity. PMID- 29423115 TI - Association between CYP17 T-34C rs743572 and breast cancer risk. AB - Association between CYP17 T-34C (rs743572) polymorphism and breast cancer (BC) risk was controversial. In order to derive a more definitive conclusion, we performed this meta-analysis. We searched in the databases of PubMed, EMBASE and Cochrane for eligible publications. Pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association between CYP17 T-34C polymorphism and breast cancer risk. Forty-nine studies involving 2,7104 cases and 3,4218 control subjects were included in this meta-analysis. In overall, no significant association between CYP17 T-34C polymorphism and breast cancer susceptibility was found among general populations. In the stratified analysis by ethnicity and source, significant associations were still not detected in all genetic models; besides, limiting the analysis to studies with controls in agreement with HWE, we also observed no association between CYP17 T 34C polymorphism and breast cancer risk. For premenopausal women, we didn't detect an association between rs743572 and breast cancer risk; however, among postmenopausal women, we observed that the association was statistically significant under the allele contrast genetic model (OR = 1.10, 95% CI = 1.03 1.17, P = 0.003), but not in other four models. In conclusion, rs743572 may increase breast cancer risk in postmenopausal individuals, but not in premenopausal folks and general populations. PMID- 29423117 TI - Oxidative stress promotes exit from the stem cell state and spontaneous neuronal differentiation. AB - Reactive oxygen species (ROS) play important roles in fundamental cellular processes such as proliferation and survival. Here we investigated the effect of oxidative stress on stem cell maintenance and neuronal differentiation in a human embryonic stem cell (hESC) model, Ntera2 (NT2). CM-H2DCFDA and DHE assays confirmed that the oxidizing agent paraquat could induce a high level of ROS in NT2 cells. Quantitative PCR, Western blotting and immunocytochemistry showed that paraquat-induced oxidative stress suppressed the expression of stemness markers, including NANOG, OCT4 and TDGF1, whereas it enhanced the spontaneous expression of neuronal differentiation markers such as PAX6, NEUROD1, HOXA1, NCAM, GFRA1 and TUJ1. The treated cells even exhibited a strikingly different morphology from control cells, extending out long neurite-like processes. The neurogenic effect of ROS on stem cell behaviour was confirmed by the observations that the expression of neuronal markers in the paraquat-treated cells was suppressed by an antioxidant while further enhanced by knocking down Nrf2, a key transcription factor associated with antioxidant signaling. Lastly, paraquat dose-dependently activated the neurogenic MAPK-ERK1/2, which can be reversed by the MEK1/2 inhibitor SL327. Our study suggests that excessive intracellular ROS can trigger the exit from stem cell state and promote the neuronal differentiation of hESCs, and that MAPK-ERK1/2 signaling may play a proactive role in the ROS-induced neuronal differentiation of hESCs. PMID- 29423118 TI - The efficacy and safety of anti-PD-1/PD-L1 antibody therapy versus docetaxel for pretreated advanced NSCLC: a meta-analysis. AB - Antibodies against the immune checkpoint proteins PD-1 and PD-L1 are novel therapeutic drugs for the treatment of advanced non-small cell lung cancer (NSCLC). Many clinical trials involving these drugs achieved breakthroughs in patients previously treated for advanced NSCLC. However, the results of these clinical studies are not consistent. In this report, we performed a meta-analysis to assess the efficacy and safety of anti-PD-1/PD-L1 antibodies compared with docetaxel treatment for advanced NSCLC patients from 5 randomized clinical trials. We demonstrated that the patients in anti-PD-1/PD-L1 antibody therapy groups had significantly longer overall survival (OS) (HR = 0.69, 95% CI 0.63 0.75, P < 0.05) and progression-free survival (PFS) (HR = 0.76, 95% CI 0.63-0.92, P < 0.05) than those in chemotherapy groups, especially PD-L1 positive patients. Anti-PD-1/PD-L1 antibodies improved the objective response rate (ORR) compared with docetaxel (OR = 1.64, 95% CI 1.19-2.26, p < 0.05). In addition, the anti-PD 1/PD-L1 antibody therapy had fewer treatment-related adverse events (AEs) (OR = 0.33, 95% CI 0.28-0.39, P < 0.05) than docetaxel, especially the grade >=3 AEs (OR = 0.18, 95% CI 0.12-0.28, P < 0.001). In conclusion, our study revealed that, compared with docetaxel, anti-PD-1/PD-L1 antibody therapy improved clinical efficacy and safety in previously treated advanced NSCLC patients. This therapy may be a promising treatment for advanced NSCLC patients. PMID- 29423119 TI - Meta-analysis of three genome-wide association studies identifies two loci that predict survival and treatment outcome in breast cancer. AB - The majority of breast cancers are driven by the female hormone oestrogen via oestrogen receptor (ER) alpha. ER-positive patients are commonly treated with adjuvant endocrine therapy, however, resistance is a common occurrence and aside from ER-status, no unequivocal predictive biomarkers are currently in clinical use. In this study, we aimed to identify constitutional genetic variants influencing breast cancer survival among ER-positive patients and specifically, among endocrine-treated patients. We conducted a meta-analysis of three genome wide association studies comprising in total 3,136 patients with ER-positive breast cancer of which 2,751 had received adjuvant endocrine therapy. We identified a novel locus (rs992531 at 8p21.2) associated with reduced survival among the patients with ER-positive breast cancer (P = 3.77 * 10-8). Another locus (rs7701292 at 5q21.3) was associated with reduced survival among the endocrine-treated patients (P = 2.13 * 10-8). Interaction analysis indicated that the survival association of rs7701292 is treatment-specific and independent of conventional prognostic markers. In silico functional studies suggest plausible biological mechanisms for the observed survival associations and a functional link between the putative target genes of the rs992531 and rs7701292 (RHOBTB2 and RAB9P1, respectively). We further explored the genetic interaction between rs992531 and rs7701292 and found a significant, treatment-specific interactive effect on survival among ER-positive, endocrine-treated patients (hazard ratio = 6.97; 95% confidence interval, 1.79-27.08, Pinteraction= 0.036). This is the first study to identify a genetic interaction that specifically predicts treatment outcome. These findings may provide predictive biomarkers based on germ line genotype informing more personalized treatment selection. PMID- 29423120 TI - The prognostic value of p62 in solid tumor patients: a meta-analysis. AB - p62, as a scaffolding/adaptor protein, is involved in multiple physiological processes include inflammation, autophagy and mitosis. However, the influence of p62 in cancer patients has not been comprehensively investigated. Moreover, the prognostic value of p62 for the survival of patients with solid tumors remains controversial. In this present meta-analysis, twenty suitable articles were identified from PubMed, EMBASE and Web of Science, Nature databases, including 4271 patients. A random-effect or fixed-effect model was adopted to correlate p62 expression with different outcome measured in entire tumors. Combined with results of hazard ratios (HRs) and 95% confidence intervals (CIs), we concluded that higher expression of p62 is associated with poorer overall survival (OS) (HR: 2.22, 95% CI: 1.82-2.71, P < 0.05), disease-free survival (DFS) (HR = 2.48, 95% CI: 1.78-3.46, P < 0.05) and even certain clinicopathological parameters, such as lymph node metastasis (RR = 1.21, 95% CI: 1.06-1.37) and clinical stages (RR = 1.27, 95% CI: 1.12-1.45), in cancer patients. Consequently, our data showed that p62 might be an effective poor prognostic factor for patients with various solid tumors. PMID- 29423122 TI - Why research in primary care is important. PMID- 29423121 TI - Which type of congenital malformations is significantly increased in singleton pregnancies following after in vitro fertilization/intracytoplasmic sperm injection: a systematic review and meta-analysis. AB - It is inconclusive nowadays for which type of congenital malformations(CMs) is increased in singleton pregnancies following after in vitro fertilization(IVF)/intracytoplasmic sperm injection(ICSI) compared with those after spontaneous conception; furthermore, a complete overview is missing. We conducted a meta-analysis of cohort studies to assess the risk of specific CMs associated with IVF/ICSI singleton pregnancies. Unrestricted searches were conducted, with an end date parameter of 1 June 2017, of PubMed, Embase, Google Scholar, Cochrane Libraries, and Chinese databases. Either a fixed- or a random effects model was used to calculate the overall combined risk estimates. Subgroup and sensitivity analyses were performed to explore potential heterogeneity moderators when significant heterogeneity was observed. Sixteen cohort studies with a total of 129,648 IVF/ICSI and 5,491,949 spontaneously conceived singleton births fulfilled the inclusion criteria. The IVF/ICSI singleton pregnancies had a significantly increased risk of cleft lip and/or palate (OR = 1.34 [95% CI: 1.07 1.69]; I2 = 0%), eye, ear, face and neck (odd ratios [OR] = 1.20 [95% CI: 1.04 1.39]; I2 = 15%), chromosomal (OR = 1.23 [95% CI: 1.07-1.40]; I2 = 32%), respiratory (OR = 1.28 [95% CI: 1.01-1.64]; I2 = 37%), digestive (OR = 1.46 [95% CI: 1.29-1.65]; I2 = 0%), musculoskeletal (OR = 1.47 [95% CI: 1.25-1.72]; I2 = 64%), urogenital (OR = 1.43 [95% CI: 1.18-1.72]; I2 = 62%), and circulatory (OR = 1.39 [95% CI: 1.23-1.58]; I2 = 46%) system malformations. Relevant heterogeneity moderators have been identified by subgroup analysis. Sensitivity analysis yielded consistent results. No evidence of publication bias was observed. In conclusion, the IVF/ICSI singleton pregnancies are associated with higher risks for most specific CMs. Clinicians should provide appropriate information to counseling IVF/ICSI patients. PMID- 29423123 TI - Self-efficacy of foot care behaviour of elderly patients with diabetes. AB - Introduction: Elderly patients with diabetes are at a high risk of contracting diabetic foot problems. Self-efficacy is essential to help improve foot care behaviour. Aim: To identify levels of self-efficacy and foot care behaviour and their relationship with demographic characteristics in elderly patients with diabetes. Methods: A cross-sectional study was conducted in two general hospitals in Malaysia from May to June 2015. Diabetes patients aged 60 years with specific inclusion criteria were invited to participate in this study. The respondents were interviewed using a set of validated questionnaires. Data were analysed with descriptive and inferential statistics (multiple linear regression) using Statistical Package for the Social Sciences version 20.0. Results: Levels of foot self-efficacy (mean+31.39; standard deviation=7.76) and foot care behaviour (mean=25.37; SD=5.88) were high. There was a positive significant relationship between foot self-efficacy (beta = 0.41, p < 0.001) and gender (beta = 0.30, p < 0.001) with foot care behaviour. Conclusion: Self-efficacy can be incorporated in diabetes education to improve foot care behaviour. High-risk patients should be taught proper foot inspection and protection as well as the merits of skin care to prevent the occurrence of diabetic foot problems. PMID- 29423124 TI - Gestational diabetes mellitus: The prevalence, associated factors and foeto maternal outcome of women attending antenatal care. AB - Objective: The aim of the study is to determine the prevalence of gestational diabetes mellitus (GDM), its associated risk factors, foeto-maternal outcomes and prevalence of postnatal diabetes mellitus (DM). Methods: This is a cross sectional study using retrospective data from existing antenatal records of new antenatal women who registered at 72 public health clinics in Selangor in January 2014. Results: A total of 745 antenatal records were reviewed. The prevalence of GDM women was 27.9% (n = 184). GDM risks were higher in women aged 35 years old and above and in those with maternal obesity. GDM women had a higher risk of having a non-spontaneous vaginal delivery compared to non-GDM women. The prevalence of postnatal DM among GDM mother was 12.1%. Working GDM mothers were at higher risk of developing postnatal DM. Conclusion: The prevalence of GDM among newly registered women attending antenatal public health care in Selangor was higher than previous studies. Health care personnel need to be vigilant in screening women with risk factors. PMID- 29423125 TI - Management of T1DM in children and adolescents in primary care. AB - The Clinical Practice Guidelines on the Management of Type 1 Diabetes Mellitus in Children & Adolescents was developed by a multidisciplinary development group and approved by the Ministry of Health Malaysia in 2015. A systematic review of 15 clinical questions was conducted using the evidence retrieved mainly from MEDLINE and Cochrane databases. Critical appraisal was done using the Critical Appraisal Skills. Recommendations were formulated on the accepted 136 evidences using the principles of Grading Recommendations, Assessment, Development and Evaluation tailored to the local setting. Type 1 diabetes mellitus is a chronic disease, which usually occurs at an early age, and is associated with various complications including retinopathy, nephropathy, neuropathy and cardiovascular morbidity. Good glycaemic control early in the disease results in lower frequency of chronic diabetes complications, which in turn reduces the healthcare cost. Accurate classification of diabetes and optimum management with the aim to achieve glycaemic targets is of utmost importance. PMID- 29423126 TI - A rare case of a sharp foreign body on the vocal cord. AB - A foreign body (FB) in the upper aerodigestive tract is a common clinical problem that presents as as acute emergency. Sharp FB, such as fish bone or chicken bone, commonly lodges in the tonsil, base of tongue, vallecula or pyriform fossa. Dislodgement of a FB into the laryngopharynx is very rare and specifically onto the vocal cord is extremely uncommon. This case report illustrates a rare case of a sharp FB that was dislodged into the airway and stuck on to the right vocal cord, which was removed under local anaesthesia. PMID- 29423127 TI - Bezold's abscess: A rare complication of acute otitis media. AB - Otitis media is a common disease encountered in the primary practice. Most cases are successfully treated with antibiotics without any sequelae. Because of these, potential serious complications of otitis media may be overlooked. We report a rare case of Bezold's abscess, as a complication of otitis media and discuss its pathophysiology and management. PMID- 29423128 TI - An association of myasthenia gravis with Hashimoto's thyroiditis in a patient with a multinodular goitre. AB - Introduction: The association of myasthenia gravis (MG) with other autoimmune diseases including autoimmune thyroid disease (ATD) is well recognised, although rare. The occurrence of both diseases can occur in two ways: either disease preceding the other, or concurrently. The presentation of MG in association with ATD can range from ocular to generalised disease. Case Summary: A 26-year-old Malay female with persistent hyperthyroidism secondary to Hashimoto's thyroiditis in multinodular goitre was diagnosed with generalised MG after 2 years. She presented with right eye ptosis (ocular) and difficulty in swallowing and chewing (bulbar). The diagnosis of MG was confirmed by fatigability testing, electromyography and the presence of AChR antibodies. Her symptoms showed improvement with pyridostigmine (Mestinon) 60 mg 6-hourly. Her antithyroid drug was tapered down according to her thyroid function test. Throughout a year of follow-ups, her hyperthyroidism and fatigability symptoms improved with treatment. She was later counselled for total thyroidectomy and thymectomy. Conclusion: Myasthenia gravis and hyperthyroidism may present with similar symptoms such as dysphagia due to neuromuscular weakness or fatigue. When the diseases occur together, one of the diagnoses may be missed. Therefore, the occurrence of new symptoms in a patient with underlying ATD should should trigger the early identification of other autoimmune diseases by primary care doctors. PMID- 29423129 TI - In the finger it lingers. PMID- 29423130 TI - Targeted Blue Nanoparticles as Photoacoustic Contrast Agent for Brain Tumor Delineation. AB - Distinguishing a tumor from non-neoplastic tissue is a challenging task during cancer surgery. Several attempts have been made to use visible or fluorescent agents to aid in the visualization of a tumor during surgery. We describe a novel method to delineate brain tumors, using a highly sensitive photoacoustic imaging technique that is enhanced by tumor-targeting blue nanoparticles serving as a contrast agent. Experiments on phantoms and on rat brains, ex vivo, demonstrate the high sensitivity of photoacoustic imaging in delineating tumors containing contrast agent at a concentration much lower than needed for visualization by the naked eye. The limit of detection of the system for the nanoparticles is about 0.77 MUg/mL in water (equivalent to 0.84 MUmol/L Coomassie Blue dye). The present exploratory study suggests that photoacoustic imaging, when used with strongly optical absorbing contrast agents, could facilitate cancer surgery intraoperatively by revealing the distribution and extent of the tumor. PMID- 29423131 TI - Oscillatory rhythm of reward: anticipation and processing of rewards in children with and without autism. AB - Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, and multiple theories have emerged concerning core social deficits. While the social motivation hypothesis proposes that deficits in the social reward system cause individuals with ASD to engage less in social interaction, the overly intense world hypothesis (sensory over-responsivity) proposes that individuals with ASD find stimuli to be too intense and may have hypersensitivity to social interaction, leading them to avoid these interactions. Methods: EEG was recorded during reward anticipation and reward processing. Reward anticipation was measured using alpha asymmetry, and post-feedback theta was utilized to measure reward processing. Additionally, we calculated post-feedback alpha suppression to measure attention and salience. Participants were 6- to 8-year olds with (N = 20) and without (N = 23) ASD. Results: Children with ASD showed more left-dominant alpha suppression when anticipating rewards accompanied by nonsocial stimuli compared to social stimuli. During reward processing, children with ASD had less theta activity than typically developing (TD) children. Alpha activity after feedback showed the opposite pattern: children with ASD had greater alpha suppression than TD children. Significant correlations were observed between behavioral measures of autism severity and EEG activity in both the reward anticipation and reward processing time periods. Conclusions: The findings provide evidence that children with ASD have greater approach motivation prior to nonsocial (compared to social) stimuli. Results after feedback suggest that children with ASD evidence less robust activity thought to reflect evaluation and processing of rewards (e.g., theta) compared to TD children. However, children with ASD evidence greater alpha suppression after feedback compared to TD children. We hypothesize that post-feedback alpha suppression reflects general cognitive engagement-which suggests that children with ASD may experience feedback as overly intense. Taken together, these results suggest that aspects of both the social motivation hypothesis and the overly intense world hypothesis may be occurring simultaneously. PMID- 29423133 TI - Facial expression recognition as a candidate marker for autism spectrum disorder: how frequent and severe are deficits? AB - Background: Impairments in social communication are a core feature of Autism Spectrum Disorder (ASD). Because the ability to infer other people's emotions from their facial expressions is critical for many aspects of social communication, deficits in expression recognition are a plausible candidate marker for ASD. However, previous studies on facial expression recognition produced mixed results, which may be due to differences in the sensitivity of the many tests used and/or the heterogeneity among individuals with ASD. To ascertain whether expression recognition may serve as a diagnostic marker (which distinguishes people with ASD from a comparison group) or a stratification marker (which helps to divide ASD into more homogeneous subgroups), a crucial first step is to move beyond identification of mean group differences and to better understand the frequency and severity of impairments. Methods: This study tested 46 individuals with ASD and 52 age- and IQ-matched typically developing (TD) participants on the Films Expression Task, which combines three key features of real-life expression recognition: naturalistic facial expressions, a broad range of simple and complex emotions, and short presentation time. Test-retest reliability was assessed in 28 individuals who did not participate in the main study and revealed acceptable reliability (ICC r = .74). Results: Case-control comparisons showed highly significant mean group differences for accuracy (p = 1.1 * 10- 10), with an effect size (Cohen's d = 1.6), more than twice as large as the mean effect size reported in a previous meta-analysis (Uljarevic and Hamilton, 2012, J Autism Dev Disord). The ASD group also had significantly increased mean reaction times overall (p = .00015, d = .83) and on correct trials (p = .0002, d = .78). However, whereas 63% of people with ASD showed severe deficits (they performed below two standard deviations of the TD mean, a small subgroup (15.3%) performed normally (within one standard deviation of the mean). Conclusion: These findings indicate that the majority of people with ASD have severe expression recognition deficits and that the Films Expression Test is a sensitive task for biomarker research in ASD. Future work is needed to establish whether ASD subgroups with and without expression recognition deficits differ from one another in terms of their symptom profile or neurobiological underpinnings. PMID- 29423132 TI - Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons. AB - Background: The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Method: Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcriptome analysis. We identified 20 genes unique to AS neurons, 120 genes unique to 15q duplication, and 3 shared transcripts that were differentially expressed in DPSC neurons vs controls. Results: Copy number correlated with gene expression for most genes across the 15q11.2-q13.1 critical region. Two thirds of the genes differentially expressed in 15q duplication neurons were downregulated compared to controls including several transcription factors, while in AS differential expression was restricted primarily to the 15q region. Here, we show significant downregulation of the transcription factors FOXO1 and HAND2 in neurons from 15q duplication, but not AS deletion subjects suggesting that disruptions in transcriptional regulation may be a driving factor in the autism phenotype in Dup15q syndrome. Downstream analysis revealed downregulation of the ASD associated genes EHPB2 and RORA, both genes with FOXO1 binding sites. Genes upregulated in either Dup15q cortex or idiopathic ASD cortex both overlapped significantly with the most upregulated genes in Dup15q DPSC derived neurons. Conclusions: Finding a significant increase in both HERC2 and UBE3A in Dup15q neurons and significant decrease in these two genes in AS deletion neurons may explain differences between AS deletion class and UBE3A specific classes of AS mutation where HERC2 is expressed at normal levels. Also, we identified an enrichment for FOXO1-regulated transcripts in Dup15q neurons including ASD-associated genes EHPB2 and RORA indicating a possible connection between this syndromic form of ASD and idiopathic cases. PMID- 29423134 TI - The bidirectional association between sleep problems and autism spectrum disorder: a population-based cohort study. AB - Background: Sleep difficulties are prevalent in children with autism spectrum disorder (ASD). The temporal nature of the association between sleep problems and ASD is unclear because longitudinal studies are lacking. Our aim is to clarify whether sleep problems precede and worsen autistic traits and ASD or occur as a consequence of the disorder. Methods: Repeated sleep measures were available at 1.5, 3, 6, and 9 years of age in 5151 children participating in the Generation R Study, a large prospective birth cohort in the Netherlands. Autistic traits were determined with the Pervasive Developmental Problems score (PDP) of the Child Behavior Checklist (CBCL) at 1.5 and 3 years and the Social Responsiveness Scale (SRS) at 6 years. This cohort included 81 children diagnosed with ASD. Results: Sleep problems in early childhood were prospectively associated with a higher SRS score, but not when correcting for baseline PDP score. By contrast, a higher SRS score and an ASD diagnosis were associated with more sleep problems at later ages, even when adjusting for baseline sleep problems. Likewise, a trajectory of increasing sleep problems was associated with ASD. Conclusions: Sleep problems and ASD are not bidirectionally associated. Sleep problems do not precede and worsen autistic behavior but rather co-occur with autistic traits in early childhood. Over time, children with ASD have an increase in sleep problems, whereas typically developing children have a decrease in sleep problems. Our findings suggest that sleep problems are part of the construct ASD. PMID- 29423135 TI - Altered reward system reactivity for personalized circumscribed interests in autism. AB - Background: Neurobiological research in autism spectrum disorders (ASD) has paid little attention on brain mechanisms that cause and maintain restricted and repetitive behaviors and interests (RRBIs). Evidence indicates an imbalance in the brain's reward system responsiveness to social and non-social stimuli may contribute to both social deficits and RRBIs. Thus, this study's central aim was to compare brain responsiveness to individual RRBI (i.e., circumscribed interests), with social rewards (i.e., social approval), in youth with ASD relative to typically developing controls (TDCs). Methods: We conducted a 3T functional magnetic resonance imaging (fMRI) study to investigate the blood oxygenation-level-dependent effect of personalized circumscribed interest rewards versus social rewards in 39 youth with ASD relative to 22 TDC. To probe the reward system, we employed short video clips as reinforcement in an instrumental incentive delay task. This optimization increased the task's ecological validity compared to still pictures that are often used in this line of research. Results: Compared to TDCs, youth with ASD had stronger reward system responses for CIs mostly within the non-social realm (e.g., video games) than social rewards (e.g., approval). Additionally, this imbalance within the caudate nucleus' responsiveness was related to greater social impairment. Conclusions: The current data support the idea of reward system dysfunction that may contribute to enhanced motivation for RRBIs in ASD, accompanied by diminished motivation for social engagement. If a dysregulated reward system indeed supports the emergence and maintenance of social and non-social symptoms of ASD, then strategically targeting the reward system in future treatment endeavors may allow for more efficacious treatment practices that help improve outcomes for individuals with ASD and their families. PMID- 29423136 TI - Pyrimidine Nucleotides Containing a (S)-Methanocarba Ring as P2Y6 Receptor Agonists. AB - Both agonists and antagonists of the UDP-activated P2Y6 receptor (P2Y6R) have been proposed for therapeutic use, in conditions such as cancer, inflammation, neurodegeneration and diabetes. Uracil nucleotides containing a South bicyclo[3.1.0]hexane ((S)-methanocarba) ring system in place of the ribose ring were synthesized and shown to be potent P2Y6R agonists in a calcium mobilization assay. The (S)-methanocarba modification was compatible with either a 5-iodo or 4 methoxyimino group on the pyrimidine, but not with a alpha,beta-methylene 5' diphosphate. (S)-Methanocarba dinucleotide potency was compatible with a N4 methoxy modification on the proximal nucleoside that is assumed to bind at the P2Y6R similarly to UDP; (N)-methanocarba was preferred on the distal nucleoside moiety. This suggests that the distal dinucleotide P2Y6R binding site prefers a ribose-like group that can attain a (N) conformation, rather than (S). Dinucleotide binding was modeled by homology modeling, docking and molecular dynamics simulations, which suggested the same ribose conformational preferences found empirically. PMID- 29423137 TI - Mouse Obox and Crxos modulate preimplantation transcriptional profiles revealing similarity between paralogous mouse and human homeobox genes. AB - Background: ETCHbox genes are eutherian-specific homeobox genes expressed during preimplantation development at a time when the first cell lineage decisions are being made. The mouse has an unusual repertoire of ETCHbox genes with several gene families lost in evolution and the remaining two, Crxos and Obox, greatly divergent in sequence and number. Each has undergone duplication to give a double homeodomain Crxos locus and a large cluster of over 60 Obox loci. The gene content differences between species raise important questions about how evolution can tolerate loss of genes implicated in key developmental events. Results: We find that Crxos internal duplication occurred in the mouse lineage, while Obox duplication was stepwise, generating subgroups with distinct sequence and expression. Ectopic expression of three Obox genes and a Crxos transcript in primary mouse embryonic cells followed by transcriptome sequencing allowed investigation into their functional roles. We find distinct transcriptomic influences for different Obox subgroups and Crxos, including modulation of genes related to zygotic genome activation and preparation for blastocyst formation. Comparison with similar experiments performed using human homeobox genes reveals striking overlap between genes downstream of mouse Crxos and genes downstream of human ARGFX. Conclusions: Mouse Crxos and human ARGFX homeobox genes are paralogous rather than orthologous, yet they have evolved to regulate a common set of genes. This suggests there was compensation of function alongside gene loss through co-option of a different locus. Functional compensation by non orthologous genes with dissimilar sequences is unusual but may indicate underlying distributed robustness. Compensation may be driven by the strong evolutionary pressure for successful early embryo development. PMID- 29423140 TI - Maximum cosmesis for patients with primary hyperparathyroidism: a case for larger incisions. AB - While minimally invasive parathyroidectomy is an advantage to many properly selected patients, longer incisions and even wide skin resection may be optimal in a select few. We present an 80-year-old woman with primary hyperparathyroidism and bothersome excess neck skin and subcutaneous fat. The parathyroid adenoma was easily excised through a vertically-oriented cervical excision that removed an ellipse of fat and skin. Midline wound closure with a small Z-plasty to avoid wound tethering facilitated a cosmetic closure well within the surgical capabilities of endocrine surgeons. This technique is useful for select patients and their surgeons and may avoid the expense of cosmetic surgery. We offer this controversial case to highlight the pros and cons of maximizing efficient surgical care to our endocrine surgery patients. PMID- 29423138 TI - Developmental constraint through negative pleiotropy in the zygomatic arch. AB - Background: Previous analysis suggested that the relative contribution of individual bones to regional skull lengths differ between inbred mouse strains. If the negative correlation of adjacent bone lengths is associated with genetic variation in a heterogeneous population, it would be an example of negative pleiotropy, which occurs when a genetic factor leads to opposite effects in two phenotypes. Confirming negative pleiotropy and determining its basis may reveal important information about the maintenance of overall skull integration and developmental constraint on skull morphology. Results: We identified negative correlations between the lengths of the frontal and parietal bones in the midline cranial vault as well as the zygomatic bone and zygomatic process of the maxilla, which contribute to the zygomatic arch. Through gene association mapping of a large heterogeneous population of Diversity Outbred (DO) mice, we identified a quantitative trait locus on chromosome 17 driving the antagonistic contribution of these two zygomatic arch bones to total zygomatic arch length. Candidate genes in this region were identified and real-time PCR of the maxillary processes of DO founder strain embryos indicated differences in the RNA expression levels for two of the candidate genes, Camkmt and Six2. Conclusions: A genomic region underlying negative pleiotropy of two zygomatic arch bones was identified, which provides a mechanism for antagonism in component bone lengths while constraining overall zygomatic arch length. This type of mechanism may have led to variation in the contribution of individual bones to the zygomatic arch noted across mammals. Given that similar genetic and developmental mechanisms may underlie negative correlations in other parts of the skull, these results provide an important step toward understanding the developmental basis of evolutionary variation and constraint in skull morphology. PMID- 29423141 TI - Salmonella typhimurium: a rare cause of mesh-related infection. AB - The use of mesh in the management of abdominal wall hernias has significantly reduced the incidences of hernia recurrences. The placement of synthetic meshes to reinforce the abdominal wall is not without caveats. Synthetic meshes are associated with a risk of infection. Common causative microorganisms for mesh related infection range from a diversity of gram positive, gram negative and anaerobic bacteria. However, non-typhoidal Salmonella spp. mesh-related infection remains poorly described in the literature. In this case, we report the management of an immunocompromised patient who developed Salmonella typhimurium mesh-related infection that was complicated by abscess formation. PMID- 29423139 TI - Divergent axial morphogenesis and early shh expression in vertebrate prospective floor plate. AB - Background: The notochord has organizer properties and is required for floor plate induction and dorsoventral patterning of the neural tube. This activity has been attributed to sonic hedgehog (shh) signaling, which originates in the notochord, forms a gradient, and autoinduces shh expression in the floor plate. However, reported data are inconsistent and the spatiotemporal development of the relevant shh expression domains has not been studied in detail. We therefore studied the expression dynamics of shh in rabbit, chicken and Xenopus laevis embryos (as well as indian hedgehog and desert hedgehog as possible alternative functional candidates in the chicken). Results: Our analysis reveals a markedly divergent pattern within these vertebrates: whereas in the rabbit shh is first expressed in the notochord and its floor plate domain is then induced during subsequent somitogenesis stages, in the chick embryo shh is expressed in the prospective neuroectoderm prior to the notochord formation and, interestingly, prior to mesoderm immigration. Neither indian hedgehog nor desert hedgehog are expressed in these midline structures although mRNA of both genes was detected in other structures of the early chick embryo. In X. laevis, shh is expressed at the beginning of gastrulation in a distinct area dorsal to the dorsal blastopore lip and adjacent to the prospective neuroectoderm, whereas the floor plate expresses shh at the end of gastrulation. Conclusions: While shh expression patterns in rabbit and X. laevis embryos are roughly compatible with the classical view of "ventral to dorsal induction" of the floor plate, the early shh expression in the chick floor plate challenges this model. Intriguingly, this alternative sequence of domain induction is related to the asymmetrical morphogenesis of the primitive node and other axial organs in the chick. Our results indicate that the floor plate in X. laevis and chick embryos may be initially induced by planar interaction within the ectoderm or epiblast. Furthermore, we propose that the mode of the floor plate induction adapts to the variant topography of interacting tissues during gastrulation and notochord formation and thereby reveals evolutionary plasticity of early embryonic induction. PMID- 29423142 TI - Subtle presentation of jejunal lipomata with intussusception in a young adult. AB - Lipomas of gastrointestinal (GI) tract could occur at any anatomical level and represent 1-2% of all GI tumours. Amongst them, <2% are noted in jejunum and almost all in later decade of life with varied and non-specific symptoms. Their intussusception is even rarer and mostly present with full obstructive symptoms. Herein, we would like to report a successfully treated case of subtle jejunal lipomata with intussusception in an otherwise healthy a 21-year-old female. PMID- 29423143 TI - Metachronous metastatic colonic small cell carcinoma and recurrent adenocarcinoma in a patient with ulcerative colitis. AB - Colonic small cell carcinomas (SCCs) are rare, aggressive tumors characterized by early metastasis and poor prognosis. We describe a 39-year-old man with a history of ulcerative colitis and left colon adenocarcinoma resected at an outside institution who presented with hematochezia and proctalgia. Work-up revealed left colon SCC with liver metastases. After his excellent response to neoadjuvant chemotherapy, we performed synchronous proctocolectomy and right hepatectomy. Final pathologic evaluation revealed colonic primary SCC and recurrent adenocarcinoma with metastatic SCC to the liver; lymph nodes were positive for metastatic SCC and adenocarcinoma. SCC recurrence ultimately developed in the liver. To the best of our knowledge, this is the second reported case of surgical management of SCC of the colon with liver metastasis and the first report of synchronous excision. Despite superb response to neoadjuvant therapy and young patient age, caution is needed in surgical resection for SCC of the colon given the high recurrence risk. PMID- 29423145 TI - Management of Abdomino-scrotal hydrocele (ASH)/Scrotal-inguino-retroperitoneal (SIR) hydrocele in a renal transplant patient. AB - Abdomino-scrotal hydrocele (ASH) is a very rare clinical entity. It is an unusual condition, in which there is an hourglass communication between a large hydrocele and the retroperitoneal space, through the inguinal canal. First described by Dupuytren in 1834 and defined by Bickle in 1919, the condition is rarely seen. Surgical management usually involves excision of the sac as the definitive treatment option. The pathogenesis of ASH remains unclear and numerous theories have been postulated. We favour the term scrotal-inguino-retroperitoneal (SIR) hydrocele as a more accurate description. The paper presents a unique case of a 24-year-old gentleman, with a functioning kidney transplant, who developed a large ASH/SIR hydrocele that required a midline laparotomy to fenestrate the sac. PMID- 29423144 TI - Nasal hemangiopericytoma successfully treated with a combination of rIL-2 and extranasal approaches. AB - Hemangiopericytomas (HPCs) are uncommon vascular tumors originating from extracapillary cells called pericytes, and rarely occur in the nose or paranasal sinuses. We treated a 57-year-old man with nasal HPC who presented with nasal obstruction and hemorrhage. Nasal endoscopy showed a readily bleeding mass between the right nasal septum and inferior turbinate. Enhanced CT revealed a heterogeneous mass lesion with an enhancement effect that filled the right nasal cavity. A biopsy specimen was proved to exhibit a HPC histopathology. Recombinant interleukin-2 (rIL-2) was administered with a measurement of natural killer cell (NK cell) activity. Afterwards, wide excision with an extranasal approach was performed. The use of rIL-2 caused not only increased NK cell activity but also a reduction in the tumor size. With a combination of rIL-2 and wide excision with extranasal approaches, no local recurrence or metastasis has occurred over the last 4 years. PMID- 29423146 TI - A record-breaking lung metastasis from renal cell carcinoma 37 years after nephrectomy. AB - Development of distant metastases from renal cell carcinoma (RCC) is a frequent occurrence and, in nearly 95% of the cases, secondary lesions present within 5 years following nephrectomy. We performed a left pneumonectomy for a peri-hilar lung mass in an 81-year-old man with history of kidney cancer, resected 37 years earlier. Histopathological examination revealed a solitary lung metastasis from RCC, relapsed after an extraordinary 37-year time interval. To the best of our knowledge, this remarkable case represents the longest time interval between radical nephrectomy for RCC and the occurrence of a pulmonary metastasis. After an uneventful post-operative recovery, there are no signs of disease recurrence at a 3-year follow-up. The possibility of a lung metastasis should be taken into account in patients with history of RCC who present with pulmonary nodules, even decades after treatment of the primary neoplasm. PMID- 29423147 TI - Epididymo-orchitis causing testicular infarction: a serious complication of a common disorder. AB - One of the most common differentials for the acute scrotum is an epididymo orchitis (EO), which can mimic the presentation of testicular torsion. We present a case of a 37-year-old man presented to the Emergency department with a 3-day history of progressive left testicular pain. A Doppler ultrasound was done which revealed increased flow to the left testicle with no evidence of testicular torsion and he was discharged. He was re-admitted with worsening pain and a repeat scan showed that the penile arterial diastolic flow had reversed, indicating testicular infarction. This was confirmed at exploration and an orchidectomy was performed. EO causing severe complications is an uncommon manifestation of a common disorder. Features suggesting a lack of response to antibiotics include sepsis, pronounced scrotal oedema, severe testicular pain and scrotal wall inflammation. The presence of a positive urine culture has also been highlighted as a poor prognostic factor. PMID- 29423148 TI - Multiple lobar intracerebral hemorrhage and cerebral amyloid angiopathy in the setting of ApoE ?2: a case report of the disease course and call for improved treatment modalities. AB - We describe a case of multiple cerebral amyloid angiopathy-associated intracerebral hemorrhages (ICH) occurring at multi-focal lobar sites of the brain. A review and discussion of the current literature on the importance of Apolipoprotein E (ApoE) genotyping in prediction of ICH outcome and recurrence follows. PMID- 29423149 TI - Splenic hematoma as a consequence of pneumoperitoneum. AB - Splenic injury is a rare but serious complication of bariatric surgical procedures. Given that the need for dissection of the gastrosplenic ligament during bariatric surgical procedures, splenic injury is not unfathomable. While most subcapsular splenic hematomas may be self-limiting, continued expansion may result in splenic rupture and should, therefore, be handled with great care. With the growing rate of bariatric surgical procedures worldwide, inadvertent intra operative splenic injury may become a more prevalent surgical complication. We report that the first documented case of subcapsular hematoma and associated gas collection following laparoscopic sleeve gastrectomy, as well as, a proposed mechanism for the radiographic findings and potential complications. PMID- 29423150 TI - Sub-capsular effusion of liver as a rare complication of ventriculoperitoneal shunt in a child. AB - The most common procedure to deal with hydrocephalus is ventriculoperitoneal (VP) shunt. The purpose of the shunt is to drain cerebrospinal fluid from cerebral ventricles to abdominal cavity. Many complications of VP shunts have been reported such as infection, obstruction, overdrainage. Abdominal complications occur in ~15-25% of VP shunts in pediatric patients, such as peritonitis, hernia, abscess, perforated colon, perforated bladder and abdominal pseudocyst. However, sub-capsular effusion of liver is a rare complication of VP shunt. In this case report, We described an unusual case of VP shunt complication in a 2-year-old child who presented with intermittent fever and abdominal pain. PMID- 29423151 TI - A case of Bouveret's syndrome treated with gastrojejunal anastomosis. AB - Bouveret's syndrome is a rare cause of proximal gallstone ileus with obstruction of duodenum or gastric outlet. We report a case of an 87-year-old female patient presented with 1 week history of vomiting whose plain radiograms showed ileus and pneumobilia. The abdominal computed tomography confirmed pneumobilia and revealed free air and leakage of oral contrast agent in the hepatic hilum and subhepatic space and an impacted gallstone in the third portion of the duodenum. The patient underwent exploratory laparotomy, which showed that the duodenal perforation was circumvallated, and a side-to-side retrocolic gastrojejunal anastomosis was performed in order to surpass the impacted gallstone. Removal of the impacted gallstone through enterotomy or gastrotomy or endoscopic lithotripsy is the usual treatment of Bouveret's syndrome. However, gastrojejunal bypass may be a treatment option when the patient undergoes laparotomy and the gallstone is impacted in the third or fourth portion of the duodenum. PMID- 29423152 TI - Suppurative appendicitis presenting acute scrotal pain: a rare condition may confuse surgeons. AB - Scrotal pain presentation has many differential diagnoses such as testicular torsion is surgical emergency. For this reason, it is necessary for surgeons to differentiate between diseases for choosing the best treatment approach. We have reported a rare condition of 19-year-old male case had an atypical scrotal pain presentation of appendicitis. He was admitted to emergency service with 4 days history of pain in abdomen and testis. In physical examination, there is tenderness in right lower quadrant, right inguinal region and scrotum. Testicular torsion and appendicitis were roll-out in sonography. Because of low sensitivity of sonography in diagnose of appendicitis and high suspicious of surgeons, the case was candidate for an open appendectomy surgery. Acute suppurative appendicitis that presenting testicular pain is rare for making the best diagnosis and prevents multiple surgeries in such cases, cooperation of urology, general surgery and radiology specialists with high index of suspicion is required. PMID- 29423153 TI - Cardiac tamponade communicating with a posterior mediastinal chylocele after esophagectomy. AB - A 75-year-old male received neoadjuvant chemotherapy for locally advanced squamous cell carcinoma of the mid-thoracic esophagus, followed by right transthoracic esophagectomy with extended mediastinal lymphadenectomy. Cardiac tamponade developed on postoperative Days 1 and 13, for which emergency ultrasound-guided drainage was required. Pericardial drainage fluid became chylous after administration of polymeric formula. A computed tomography scan demonstrated the presence of a retrocardiac fluid collection, encompassed by the left pulmonary vein and left atrium, descending aorta and vertebral column. Based on these findings, the diagnosis of chylopericardial tamponade communicating with a posterior mediastinal chylocele was made. The ligation of the thoracic duct was successfully performed via the left-sided thoracoscopic approach on postoperative Day 20 and the clinical course after the second operation was uneventful. The possible mechanisms of this exceptionally rare complication after esophagectomy were discussed. PMID- 29423154 TI - Temporopolar bridging veins during anteromedial temporal strip placement: a case report on complication avoidance?. AB - Introduction: Surgery for temporal lobe epilepsy is proven to be beneficial in the treatment of medically refractory temporal lobe epilepsy. Subdural electrode strips are commonly passed in a blind fashion, allowing additional EEG coverage without requiring larger exposure. However, this increases risk of complication, specifically through vascular injury. Case report: We present a case of a 22-year old male with medically refractory epilepsy. During passage of an anterior medial temporal strip electrode, resistance was encountered despite multiple attempts and redirection. This strip was abandoned. During the subsequent resection operation, a large temporopolar bridging vein complex was noted and photographed precisely where we encountered resistance. Conclusion: Although much frequently less encountered than paramedian subdural strips, anterior medial temporal strip subdural electrodes may indeed injure large bridging veins. As subdural strips are passed where bony exposure is minimal, potential disastrous complications may arise if extreme caution is not used. PMID- 29423155 TI - Successful surgical treatment for huge retroperitoneal liposarcoma involving the pancreas, right kidney, abdominal aorta and inferior vena cava. AB - Retroperitoneal liposarcoma is a rare neoplasm that often involves other organs and major blood vessels. Complete surgical resection with negative margins is the only potential curative treatment. Here, we report the case of a patient with a large retroperitoneum liposarcoma that was removed by resection of the descending abdominal aorta and infrahepatic inferior vena cava, right nephrectomy and pancreatoduodenectomy following creation of an extra anatomical femoro-femoral crossover bypass after left axillo-left femoral bypass. The patient developed leg edema for a few weeks after surgery but this condition was gradually resolved with diuretics. Otherwise, no serious postoperative complication was observed, and the patient was discharged at 37 days after surgery. There has been no evidence of recurrence for 16 months. In conclusion, radical surgical resection is a possible therapeutic option for retroperitoneal liposarcoma involving major vessels or other organs, and may improve survival if negative resection margins can be achieved. PMID- 29423156 TI - Knotless suture allows for successful thoracoscopic diaphragm plication. AB - Diaphragm paralysis can cause significant shortness of breath. This condition can be treated with diaphragm plication. We illustrate two cases where we used a knotless suture and total portal thoracoscopic technique to successfully plicate the diaphragm. A 70-year-old female with right-sided and a 44-year-old male with left-sided diaphragm paralysis. Both patients had a sniff test that showed paradoxical movement of the diaphragm. The port placements during the procedure were different due to the laterality but both patients had three 5-mm ports and one 12-mm port for the procedure. Plication was performed using the Endo Stitch knotless suture. Both patients went home on post-operative Day 1 without any complications. After 1 month, both patients had significant improvement in shortness of breath with resolution of the diaphragm elevation. PMID- 29423157 TI - Acute cholecystitis in a parastomal hernia causing a small bowel obstruction. AB - A parastomal hernia is the abnormal protrusion of intra-abdominal tissue and organs through a defect in the abdominal wall around an ostomy. Commonly, they involve intra-abdominal fat, omentum or bowel. However, there are rare cases that involve other organs. We present the case of an 89-year-old gentleman with a gallbladder in his parastomal hernia. Due to his acute cholecystitis, the distended gallbladder compressed adjacent bowel loops in the parastomal hernia, resulting in a mechanical bowel obstruction. The patient was treated with antibiotics and a nasogastric tube. As his cholecystitis resolved his ostomy function returned. PMID- 29423158 TI - Endoscopic management of duodeno-ileal fistula secondary to diffuse B-cell lymphoma. AB - Lymphoma arising in the gastrointestinal tract is relatively common and can affect multiple sites. The development of a gastrointestinal fistula secondary to lymphoma is very rare and has not previously been reported between the duodenum and ileum. This is the first reported care where a fistula secondary to lymphoma has been treated by an endoscopic covered duodenal stent occluding the defect rather than surgical intervention. This strategy permitted early commencement of curative intent chemotherapy which led to tumour shrinkage and fistula closure. PMID- 29423159 TI - Pubic and inguinal venous collaterals mimic inguinal hernia. AB - Herein we report a case of a 38-year-old men who presented with acute suprapubic pain caused by a tubular, hypoechoic, non-compressible, inguinal mass with no flow evident on color Doppler sonography. The history of the patient, the clinical signs of local inflammation and tenderness on palpation as well as the results of the Doppler ultrasound examination led to the diagnose of an inguinal hernia with bowl incarceration. However, due to a remaining uncertainty whether a bilateral or unilateral hernia was immanent and whether the bowl incarceration was caused by a right or left sided hernia the on-call surgeon initiated a computed tomography (CT) scan. Surprisingly, this CT scan revealed extensive suprapubic venous collaterals with thrombophlebitis that mimicked a bilateral inguinal hernia secondary to an acute unilateral femoral vein thrombosis. Instead of undergoing surgery the patient was treated with antibiotics, pain killer and heparin and was discharged from hospital after 8 days. PMID- 29423160 TI - Stricturoplasty-a bowel-sparing option for long segment small bowel Crohn's disease. AB - Stricturoplasty is a surgical option for management of severe stricturing Crohn's disease of the small bowel. It avoids the need for small bowel resection and the associated metabolic complications. This report contrasts the indications and technical aspects of two different stricturoplasty techniques. Case 1 describes an extensive Michelassi (side-to-side isoperistaltic) stricturoplasty performed for a 100 cm segment of diseased small bowel in a 45-year-old patient. Case 2 describes the performance of 12 Heineke-Mikulicz stricturoplasties in a 23-year old patient with multiple short fibrotic strictures. PMID- 29423161 TI - Infective endocarditis, embolic stroke and splenic abscess: a case report. AB - We present the case of a patient presenting with embolic stroke secondary to aortic valve endocarditis, additionally complicated by splenic abscess, successfully treated by emergent valve replacement followed by delayed, robotic splenectomy. PMID- 29423162 TI - Middle aortic syndrome with renal artery stenosis. AB - A 39-year lady referred to Vascular Surgery OPD from Cardiology with uncontrolled hypertension, non- functional left kidney and absent bilateral femoral pulses. Investigations revealed middle aortic syndrome with non-functional left kidney with bilateral renal artery stenosis. She successfully underwent bypass of stenotic segment with polyester graft from descending thoracic aorta to left common iliac artery with reverse saphenous vein graft interposed between polyester and right renal artery. PMID- 29423163 TI - Metastatic Epicardial Leiomyoma with uncertain malignant potential. AB - A 49-year-old female with history of uterine leiomyoma and intermittent shortness of breath presented to the emergency department with new onset of tachycardia and chest pain. Subsequent cardiac work up revealed hypoechoic mass compressing the right ventricle. Computer tomography guided biopsy for tissue characterization revealed a benign spindle cell tumor. Surgical resection of a large epicardial tumor was undertaken. The histologic examination of the tumor was consistent with Estrogen and Progesterone positive leiomyoma of uncertain malignant potential. To the authors' knowledge, this is the first case report of a metastasizing epicardial leiomyoma that exhibits an unknown malignant potential. This case brings together common gynecologic disorder with complex thoracic surgery diagnosis and management. Differential diagnosis of cardiac tumors in patients with history of uterine leiomyoma should include metastasizing leiomyoma. The mainstay of therapy is surgical resection with immediate symptom relieve. PMID- 29423164 TI - Cutaneous metastasis of a primary oesophageal adenocarcinoma to the right cheek. AB - This case report details of a case of cutaneous metastasis from a primary adenocarcinoma of the oesophagus to the right cheek. A 67-year-old male was referred to the maxillofacial department with a 2-3 week history of non-painful swelling of the cheek. A diagnosis of infected sebaceous cyst was made and drainage was attempted with adjunctive antibiotic therapy. Follow up appointments showed no improvement a biopsy was taken. Histology reported presence of metastatic adenocarcinoma, suggesting the gastrointestinal tract as the primary site. An MRI scan was performed showing an oesophageal mass. Treatment options were discussed with the patient, including surgery, radiotherapy and chemotherapy. Unfortunately, the advanced nature of the primary lesion meant his care was mainly palliative in nature. Clinicians must have a high index of suspicion regarding non-healing cutaneous lesions. Timely investigations in the will help to diagnose the primary cause of the lesion. PMID- 29423165 TI - Surgical management of digital ischemia caused by constriction band formation in a patient with ichthyosis vulgaris. AB - Ichthyosis is a broad and loosely defined group of hereditary and acquired disorders characterized by filaggrin dysfunction and impaired epidermal homeostasis that results in dry, scaly and thickened skin. Individuals with truncation mutations in the profilaggrin gene coding for filaggrin are strongly predisposed to severe forms of ichthyosis. The phenotypical expression of ichthyosis caused by the same genotypical mutation can vary considerably in severity and in regards to how much constricting scar tissue develops. Here, we report a case of digital ichthyosis threatening the neurovascular integrity to the small finger to discuss the importance of early diagnosis and role of Z plasty flaps in the surgical treatment of constriction band formation. PMID- 29423166 TI - Endoscopic use of EpiFix-dehydrated Human Amnion/Chorion Membrane (dHACM) allograft in patients with Gastric Leak following Sleeve Gastrectomy. AB - Leak following laparoscopic sleeve gastrectomy is one of the most feared complications and its management can be difficult and frustrating for patients and physicians involved. Using multimodality approach and having variable options to plan management for patients presenting with leak following bariatric surgery can be advantageous for physicians. The use of endoscopic injection of EpiFix dehydrated Human Amnion/Chorion Membrane (dHACM) allograft can be a novel adjunct in facilitating healing of the leak site by iatrogenic introduction of tissue growth factors, cytokines and building connective tissue matrix. PMID- 29423167 TI - A rare case of massive lower gastrointestinal bleeding from a ruptured splenic artery aneurysm. AB - Splenic artery aneurysms (SAAs) are an extremely rare cause of asymptomatic massive lower gastrointestinal bleeding with less than a handful of patients surviving such a presentation. A 24-year-old female presented in shock after multiple episodes of massive rectal bleeding. Imaging revealed a heterogeneous mass arising from the tail of the pancreas eroding into the splenic flexure of the colon. Further episodes of bleeding led to an exploratory laparotomy. Intraoperatively, a suspected neoplastic process arising from the tail of the pancreas with contiguous involvement of the splenic flexure of the colon and the greater curvature of the stomach was noted. Distal pancreaticosplenectomy, gastric wedge resection with segmental colectomy and primary anastomosis were performed. Histology revealed a SAA with rupture into the colon. This case report shows that en-bloc resection of a ruptured SAA can be performed with success in the emergency setting. PMID- 29423168 TI - Intramuscular granular cell tumor of the gluteal region. AB - Granular cell tumors are uncommon, usually benign neoplasms, mainly observed in the head and neck region, chest wall and upper extremities. These tumors account for ~0.5% of all soft-tissue tumors. Less than 2% are malignant. These are associated with poor prognosis. Clinical signs suspicious for malignancy are large size, rapid growth, invasion, recurrence and metastasis. Malignancy is confirmed by histological examination. We present the case of a 79-year-old patient with a 6-month history of a rapidly growing mass in the left gluteal region giving the clinical impression of a malignant tumor. The patient underwent surgical excision of the tumor and the pathology report revealed a granular cell tumor. In difficult cases, multidisciplinary approach is necessary for appropriate diagnosis and management. PMID- 29423169 TI - A rare case of spinal cord compression due to cervical spine metastases from paraganglioma of the jugular foramen-how should it be treated? AB - Paragangliomas are benign neoplasms that arise from the autonomic nervous system and the associated paraganglia. Although benign, they have been shown to possess metastatic potential. Involvement of the spine is rare. Even rarer is considered the involvement of the cervical spine. We report a case of a patient with a history of an extra-adrenal non-functional paraganglioma of the jugular foramen which was initially treated with intra-arterial embolization. After a 3-year disease-free follow-up, the patient was presented with symptoms of spinal cord compression due to spinal metastases in C2 and C3 vertebrae. The patient was then treated with surgical decompression and external beam radiation. Therapeutic management with additional treatment options is now under discussion by a multidisciplinary team. Paraganglioma of the jugular foramen with spinal metastasis is an uncommon presentation where increased physician awareness and long-term follow-up are mandatory for all patients with history of paraganglioma. PMID- 29423170 TI - Paediatric aneurysmal bone cyst: not as easy as ABC. AB - Aneurysmal bone cysts (ABCs) are expansile cystic lesions that can affect any bone of the body. Whilst these lesions are histologically benign, the lesions are locally aggressive and can affect the integrity of the affected bone as well as surrounding structures. ABCs arising in the head and neck region, particularly the paranasal sinuses are rare and they are limited to case reports in the literature. Due to the proximity of critical anatomical structures and the visual apparatus, the potential complications can be devastating. The present article discusses both the clinical and radiological findings of an ABC arising from the ethmoid sinuses in a 6-year-old child and the potentially challenging diagnosis with its complex ensuing surgical management. The identification of an ABC arising in the paranasal sinuses is both a diagnostic and surgical challenge and ideally requires complex management in a joint paediatric ENT and craniofacial unit. PMID- 29423171 TI - Intraosseous papillary intralymphatic angioendothelioma (PILA): one new case and review of the literature. AB - Background: Papillary intralymphatic angioendothelioma (PILA) is a locally aggressive, rarely metastasizing vascular tumor, generally occurring in the soft tissues, with less than 40 cases described in the literature and only three cases reported in bone. Case presentation: We describe the case of a 51-year-old male with an intraosseous PILA of the proximal edge of his left clavicle and two other lesions evident on imaging. The patient was treated with marginal resection of the clavicle lesion but was lost to follow-up 1 month after surgery. Conclusions: PILA can also occur in bone, albeit very rarely, and has to be considered in the differential diagnosis of vascular bone tumors. PMID- 29423172 TI - Equine dietary supplements: an insight into their use and perceptions in the Irish equine industry. AB - Background: Nutritional supplements are frequently used by horse owners/caregivers to supplement their horse(s) diets. Some work has been done to identify the types of supplements fed and the reasons for doing so; however, this has been predominantly disciple-specific and with little focus on participants' perceptions of supplement testing and regulation. The aim of this study was to gain an insight into the use and perceptions of equine dietary supplements in the Irish equestrian industry. Methods: An online survey was designed to ascertain the following information: demographics, types of supplements fed and reasons for use, factors that influenced respondents' choice of supplement, where advice was sought and perceptions of testing and regulation of equine supplements. Results: The survey yielded 134 responses, 70% non-professionals and 30% professionals. A greater percentage of professionals included supplements in their horse(s) diets (98%) compared to non-professionals (86%). Almost 70% of professionals fed more than two supplements, whereas 80% of non-professionals reported to feed only one supplement. Joint supplements were most commonly fed by all respondents (22%) followed by calming supplements (13%). The enhancement of performance (35%) and prevention of joint disorders (34%) were the most common reasons reported by respondents for using a supplement. Over 53% of respondents sought advice on choosing a supplement from their feed merchant, followed by their veterinarian (46%). Veterinary recommendation was given as the most influential factor when choosing a supplement by 90% of respondents, followed by cost (69%). Most (93%) respondents thought that feed supplements had to meet legal standards, with each batch analysed for quality (72%) and the supplement tested on horses before being launched on to the market (92%). Conclusion: This study has identified the main types of supplements used in the Irish equestrian industry along with the reasons for their use. However, it has also highlighted major misperceptions in how supplements are tested before being launched for sale and further work on this aspect of the findings would be beneficial. PMID- 29423174 TI - Chronic pain in refugee torture survivors. PMID- 29423173 TI - Cardiopulmonary exercise testing (CPET) in the United Kingdom-a national survey of the structure, conduct, interpretation and funding. AB - Background: Cardiopulmonary exercise testing (CPET) is an exercise stress test with concomitant expired gas analysis that provides an objective, non-invasive measure of functional capacity under stress. CPET-derived variables predict postoperative morbidity and mortality after major abdominal and thoracic surgery. Two previous surveys have reported increasing utilisation of CPET preoperatively in England. We aimed to evaluate current CPET practice in the UK, to identify who performs CPET, how it is performed, how the data generated are used and the funding models. Methods: All anaesthetic departments in trusts with adult elective surgery in the UK were contacted by telephone to obtain contacts for their pre-assessment and CPET service leads. An online survey was sent to all leads between November 2016 and March 2017. Results: The response rate to the online survey was 73.1% (144/197) with 68.1% (98/144) reporting an established clinical service and 3.5% (5/144) setting up a service. Approximately 30,000 tests are performed a year with 93.0% (80/86) using cycle ergometry. Colorectal surgical patients are the most frequently tested (89.5%, 77/86). The majority of tests are performed and interpreted by anaesthetists. There is variability in the methods of interpretation and reporting of CPET and limited external validation of results. Conclusions: This survey has identified the continued expansion of perioperative CPET services in the UK which have doubled since 2011. The vast majority of CPET tests are performed and reported by anaesthetists. It has highlighted variation in practice and a lack of standardised reporting implying a need for practice guidelines and standardised training to ensure high-quality data to inform perioperative decision making. PMID- 29423175 TI - Measuring coverage of essential maternal and newborn care interventions: An unfinished agenda. PMID- 29423176 TI - Measuring coverage of essential maternal and newborn care interventions: An unfinished agenda to define the data matrix for action in maternal and newborn health. PMID- 29423177 TI - Immunization practices in low birth weight infants from rural Haryana, India: Findings from secondary data analysis. AB - Background: Low birth weight (LBW) infants constitute a vulnerable subset of infants with impaired immunity in early life. In India, there is scarcity of studies that focus on immunization practices in such infants. This analysis aimed to examine immunization practices in LBW infants with the intention to identify areas requiring intervention. Methods: Data on immunization status of LBW infants enrolled in an individually randomized, double-masked, placebo-controlled trial of neonatal vitamin A supplementation were analysed. Study outcomes were full immunization by one year of age and delayed vaccination with DPT1 and DPT3. Multivariable logistic regression was performed to identify factors associated with the outcome(s). Findings: Out of 10 644 LBW infants enrolled in trial, immunization data were available for 10 517 (98.8%). Less than one-third (29.7%) were fully immunized by one year of age. Lowest wealth quintile (adjusted odds ratio (AOR) 0.39, 95% confidence interval (CI) 0.32-0.47), Muslim religion (AOR 0.41, 95% CI 0.35-0.48) and age of mother <20 years (AOR 0.62, 95% CI 0.52-0.73) were associated with decreased odds of full immunization. Proportion of infants with delayed vaccination for DPT1 and DPT3 were 52% and 81% respectively. Lowest wealth quintiles (AOR 1.51, 95% CI 1.25-1.82), Muslim religion (AOR 1.41, 95% CI 1.21-1.65), mother aged <20 years (AOR 1.31, 95% CI 1.11-1.53) and birth weight <2000 g (AOR 1.20, 95% CI 1.03-1.40) were associated with higher odds of delayed vaccination for DPT-1. Maternal education (>=12 years of schooling) was associated with high odds of full immunization (AOR 2.39, 95% CI 1.97-2.91) and low odds of delayed vaccination for both DPT-1 (AOR 0.59, 95% CI 0.49-0.73) and DPT-3 (AOR 0.57, 95% CI 0.43-0.76). Conclusion: In this population, LBW infants are at a risk of delayed and incomplete immunization and therefore need attention. The risks are even higher in identified subgroups that should specifically be targeted. PMID- 29423178 TI - Gap between contact and content in maternal and newborn care: An analysis of data from 20 countries in sub-Saharan Africa. AB - Background: Over the last decade, coverage of maternal and newborn health indicators used for global monitoring and reporting have increased substantially but reductions in maternal and neonatal mortality have remained slow. This has led to an increased recognition and concern that these standard globally agreed upon measures of antenatal care (ANC), skilled birth attendance (SBA) and postnatal care (PNC) only capture the level of contacts with the health system and provide little indication of actual content of services received by mothers and their newborns. Over this period, large household surveys have captured measures of maternal and newborn care mainly through questions assessing contacts during the antenatal, delivery and postnatal periods along with some measures of content of care. This study aims to describe the gap between contact and content as a proxy for quality- of maternal and newborn health services by assessing level of co-coverage of ANC and PNC interventions. Methods: We used Demographic and Health Surveys (DHS) data from 20 countries between 2010 and 2015. We analysed the proportion of women with at least 1 and 4+ antenatal care visit, who received 8 interventions. We also assessed the percentage of newborns delivered with a skilled birth attendant who received 7 interventions. We ran random effect logistic regression to assess factors associated with receiving all interventions during the antenatal and postnatal period. Results: While on average 51% of women in the analysis received four ANC visits with at least one visit from a skilled health provider, only 5% of them received all 8 ANC interventions. Similarly, during the postnatal period though two-thirds (65%) of births were attended by a skilled birth attendant, only 3% of newborns received all 7 PNC interventions. The odds of receiving all ANC and PNC interventions were higher for women with higher education and higher wealth status. Conclusion: The gap between coverage and content as a proxy of quality of antenatal and postnatal care is excessively large in all countries. In order to accelerate maternal and newborn survival and achieve Sustainable Development Goals, increased efforts are needed to improve both the coverage and quality of maternal and newborn health interventions. PMID- 29423179 TI - Measuring postnatal care contacts for mothers and newborns: An analysis of data from the MICS and DHS surveys. AB - Background: The postnatal period represents a vulnerable phase for mothers and newborns where both face increased risk of morbidity and death. WHO recommends postnatal care (PNC) for mothers and newborns to include a first contact within 24 hours following the birth of the child. However, measuring coverage of PNC in household surveys has been variable over time. The two largest household survey programs in low and middle-income countries, the UNICEF-supported Multiple Indicator Cluster Surveys (MICS) and USAID-funded Demographic and Health Surveys (DHS), now include modules that capture these measures. However, the measurement approach is slightly different between the two programs. We attempt to assess the possible measurement differences that might affect comparability of coverage measures. Methods: We first review the standard questionnaires of the two survey programs to compare approaches to collecting data on postnatal contacts for mothers and newborns. We then illustrate how the approaches used can affect PNC coverage estimates by analysing data from four countries; Bangladesh, Ghana, Kygyz Republic, and Nepal, with both MICS and DHS between 2010-2015. Results: We found that tools implemented todate by MICS and DHS (up to MICS round 5 and up to DHS phase 6) have collected PNC information in different ways. While MICS dedicated a full module to PNC and distinguishes immediate vs later PNC, DHS implemented a more blended module of pregnancy and postnatal and did not systematically distinguish those phases. The two survey programs differred in the way questions on postnatal care for mothers and newbors were framed. Subsequently, MICS and DHS surveys followed different methodological approach to compute the global indicator of postnatal contacts for mothers and newborns within two days following delivery. Regardless of the place of delivery, MICS estimates for postnatal contacts for mothers and newbors appeared consistently higher than those reported in DHS. The difference was however, far more pronounced in case of newborns. Conclusions: Difference in questionnaires and the methodology adopted to measure PNC have created comparability issues in the coverage levels. Harmonization of survey instruments on postnatal contacts will allow comparable and better assessment of coverage levels and trends. PMID- 29423180 TI - Evidence from household surveys for measuring coverage of newborn care practices. AB - Background: Aside from breastfeeding, there are little data on use of essential newborn care practices, such as thermal protection and hygienic cord care, in high mortality countries. These practices have not typically been measured in national household surveys, often the main source for coverage data in these settings. The Every Newborn Action Plan proposed early breastfeeding as a tracer for essential newborn care due to data availability and evidence for the benefits of breastfeeding. In the past decade, a few national surveys have added questions on other practices, presenting an opportunity to assess the performance of early breastfeeding initiation as a tracer indicator. Methods: We identified twelve national surveys between 2005-2014 that included at least one indicator for immediate newborn care in addition to breastfeeding. Because question wording and reference populations varied, we standardized data to the extent possible to estimate coverage of newborn care practices, accounting for strata and multistage survey design. We assessed early breastfeeding as a tracer by: 1) examining associations with other indicators using Pearson correlations; and 2) stratifying by early breastfeeding to determine differences in coverage of other practices for initiators vs non-initiators in each survey, then pooling across surveys for a meta-analysis, using the inverse standard error as the weight for each observation. Findings: Associations between pairs of coverage indicators are generally weak, including those with breastfeeding. The exception is drying and wrapping, which have the strongest association of any two interventions in all five surveys where measured; estimated correlations for this range from 0.47 in Bangladesh's 2007 DHS to 0.83 in Nepal's 2006 DHS. The contrast in coverage for other practices by early breastfeeding is generally small; the greatest absolute difference was 6.7%, between coverage of immediate drying for newborns breastfed early compared to those who were not. Conclusions: Early initiation of breastfeeding is not a high performing tracer indicator for essential newborn care practices measured in previous national surveys. To have informative data on whether newborns are getting life-saving services, standardized questions about specific practices, in addition to breastfeeding initiation, need to be added to surveys. PMID- 29423181 TI - Skilled attendant at birth and newborn survival in Sub-Saharan Africa. AB - Background: Recent studies have shown higher neonatal mortality among births delivered by a skilled attendant at birth (SAB) compared to those who were not in sub-Saharan African countries. Deaths during the neonatal period are concentrated in the first 7 days of life, with about one third of these deaths occurring during the first day of life. We reassessed the relationship between SAB and neonatal mortality by distinguishing deaths on the first day of life from those on days 2-27. Methods: We used data on births in the past five years from recent demographic and health survey (DHS) between 2010 and 2014 in 20 countries in sub Saharan Africa. The main categorical outcome was 1) newborns who died within the first day of birth (day 0-1), 2) newborns who died between days 2-27, and 3) newborns who survived the neonatal period. We ran generalized linear mixed model with multinomial distribution and random effect for country on pooled data. Additionally, we ran a separate model restricted to births with SAB and assessed the association of receipt of seven antenatal care (ANC) and two immediate postnatal care interventions on risk of death on days 0-1 and days 2-27. These variables were assessed as proxy of quality of antenatal and postnatal care. Results: We found no statistically significant difference in risk of death on first day of life between newborns with SAB compared to those without. However, after the first day of life, newborns delivered with SAB were 16% less likely to die within 2-27 days than those without SAB (OR = 0.84, 95% CI = 0.71-0.99). Among births with skilled attendant, those who were weighed at birth and those who were initiated early on breastfeeding were significantly less likely to die on days 0-1 (respectively OR = 0.42 95% CI = 0.29-0.62 and OR = 0.24, 95% CI 0.18 0.31) or on days 2-27 (OR = 0.60, 95% CI = 0.45-0.81 and OR = 0.59, 95% CI = 47 0.74, respectively). Newborns whose mothers received an additional ANC intervention had no improved survival chances during days 0-1 of life. However, there was significant association on days 2-27 where newborns whose mothers received an additional ANC interventions had higher survival chances (OR = 0.95, 95% CI = 0.93-0.98). Conclusion: Findings demonstrate the vulnerability of newborns immediately after birth, compounded with insufficient quality of care. Improving the quality of care around the time of birth will significantly improve survival and therefore accelerate reduction in neonatal mortality in sub-Saharan African countries. Improved approaches for measuring skilled attendant at birth are also needed. PMID- 29423182 TI - The importance of skin-to-skin contact for early initiation of breastfeeding in Nigeria and Bangladesh. AB - Background: Skin-to-skin contact (SSC) between mother and newborn offers numerous protective effects, however it is an intervention that has been under-utilized. Our objectives are to understand which newborns in Bangladesh and Nigeria receive SSC and whether SSC is associated with the early initiation of breastfeeding. Methods: Demographic and Health Survey (DHS) data were used to study the characteristics of newborns receiving SSC for non-facility births in Nigeria (DHS 2013) and for both facility and non-facility births in Bangladesh (DHS 2014). Multivariable logistic regression was used to study the association between SSC and early initiation of breastfeeding after controlling for key socio demographic, maternal and newborn-related factors. Results: Only 10% of newborns in Nigeria and 26% of newborns in Bangladesh received SSC. In the regression models, SSC was significantly associated with the early initiation of breastfeeding in both countries (OR = 1.42, 95% CI 1.15-1.76 for Nigeria; OR = 1.27, 95% CI 1.04-1.55, for Bangladesh). Findings from the regression analysis for Bangladesh revealed that newborns born by Cesarean section had a 67% lower odds of early initiation of breastfeeding than those born by normal delivery (OR = 0.33, 95% CI 0.26-0.43). Also in Bangladesh newborns born in a health facility had a 30% lower odds of early initiation of breastfeeding than those born in non facility environments (OR = 0.70, 95% CI 0.53-0.92). Early initiation of breastfeeding was significantly associated with parity, urban residence and wealth in Nigeria. Geographic area was significant in the regression analyses for both Bangladesh and Nigeria. Conclusions: Coverage of SSC is very low in the two countries, despite its benefits for newborns without complications. SSC has the potential to save newborn lives. There is a need to prioritize training of health providers on the implementation of essential newborn care including SSC. Community engagement is also needed to ensure that all women and their families regardless of residence, socio-economic status, place or type of delivery, understand the benefits of SSC and early initiation of breastfeeding. PMID- 29423183 TI - Does postnatal care have a role in improving newborn feeding? A study in 15 sub Saharan African countries. AB - Background: Breastfeeding is known as a key intervention to improve newborn health and survival while prelacteal feeds (liquids other than breastmilk within 3 days of birth) represents a departure from optimal feeding practices. Recent programmatic guidelines from the WHO and UNICEF outline the need to improve newborn feeding and points to postnatal care (PNC) as a potential mechanism to do so. This study examines if PNC and type of PNC provider are associated with key newborn feeding practices: breastfeeding within 1 day and prelacteal feeds. Methods: We use data from the Demographic and Health Surveys for 15 sub-Saharan African countries to estimate 4 separate pooled, multilevel, logistic regression models to predict the newborn feeding outcomes. Findings: PNC is significantly associated with increased breastfeeding within 1day (OR = 1.35, P < 0.001) but is not associated with PLFs (OR = 1.04, P = 0.195). PNC provided by nurses, midwives and untrained health workers is also associated with higher odds of breastfeeding within 1 day of birth (OR = 1.39, P < 0.001, (OR = 1.95, P < 0.001) while PNC provided by untrained health workers is associated with increased odds of PLFs (OR = 1.20, P = 0.017). Conclusions: PNC delivered through customary care may be an effective strategy to improve the breastfeeding within 1 day but not to discourage PLFs. Further analysis should be done to examine how these variables operate at the country level to produce finer programmatic insight. PMID- 29423184 TI - Postnatal care for newborns in Bangladesh: The importance of health-related factors and location. AB - Background: Bangladesh achieved Millennium Development Goal 4, a two thirds reduction in under-five mortality from 1990 to 2015. However neonatal mortality remains high, and neonatal deaths now account for 62% of under-five deaths in Bangladesh. The objective of this paper is to understand which newborns in Bangladesh are receiving postnatal care (PNC), a set of interventions with the potential to reduce neonatal mortality. Methods: Using data from the Bangladesh Maternal Mortality Survey (BMMS) 2010 we conducted logistic regression analysis to understand what socio-economic and health-related factors were associated with early postnatal care (PNC) by day 2 and PNC by day 7. Key variables studied were maternal complications (during pregnancy, delivery or after delivery) and contact with the health care system (receipt of any antenatal care, place of delivery and type of delivery attendant). Using data from the BMMS 2010 and an Emergency Obstetric and Neonatal Care (EmONC) 2012 needs assessment, we also presented descriptive maps of PNC coverage overlaid with neonatal mortality rates. Results: There were several significant findings from the regression analysis. Newborns of mothers having a skilled delivery were significantly more likely to receive PNC (Day 7: OR = 2.16, 95% confidence interval (CI) 1.81, 2.58; Day 2: OR = 2.11, 95% 95% CI 1.76). Newborns of mothers who reported a complication were also significantly more likely to receive PNC with odds ratios varying between 1.3 and 1.6 for complications at the different points along the continuum of care. Urban residence and greater wealth were also significantly associated with PNC. The maps provided visual images of wide variation in PNC coverage and indicated that districts with the highest PNC coverage, did not necessarily have the lowest neonatal mortality rates. Conclusion: Newborns of mothers who had a skilled delivery or who experienced a complication were more likely to receive PNC than newborns of mothers with a home delivery or who did not report a complication. Given that the majority of women in Bangladesh have a home delivery, strategies are needed to reach their newborns with PNC. Greater focus is also needed to reach poor women in rural areas. Engaging community health workers to conduct home PNC visits may be an interim strategy as Bangladesh strives to increase skilled delivery coverage. PMID- 29423185 TI - Does health facility service environment matter for the receipt of essential newborn care? Linking health facility and household survey data in Malawi. AB - Background: Health facility service environment is an important factor for newborns survival and well-being in general and in particular in high mortality settings such as Malawi where despite high coverage of essential interventions, neonatal mortality remains high. The aim of this study is to assess whether the quality of the health service environment at birth is associated with quality of care received by the newborn. Methods: We used data from the Malawi Millennium Development Goals Endline household survey conducted as part of MICS survey program and Service Provision Assessment Survey carried out in 2014. The analysis is based on 6218 facility births that occurred during the past 2 years. Descriptive statistics, bivariate and multivariate random effect models are used to assess the association of health facility service readiness score for normal deliveries and newborn care with newborns receiving appropriate newborn care, defined for this analysis as receiving 5 out of 6 recommended interventions during the first 2 days after birth. Results: Newborns in districts with top facility service readiness score have 1.5 higher odds of receiving appropriate newborn care (adjusted odds ratio (aOR) = 1.52, 95% confidence interval CI = 1.19 1.95, P = 0.001), as compared to newborns in districts with a lower facility score after adjusting for potential confounders. Newborns in the Northern region were two times more likely to receive 5 newborn care interventions as compared to newborns in the Southern region (aOR = 2.06, 95% CI = 1.50-2.83, P < 0.001). Living in urban or rural areas did not have an impact on receiving appropriate newborn care. Conclusions: There is need to increase the level of service readiness across all facilities, so that all newborns irrespective of the health facility, district or region of delivery are able to receive all recommended essential interventions. Investments in health systems in Malawi should concentrate on increasing training and availability of health staff in facilities that offer normal delivery and newborn care services at all levels in the country. PMID- 29423186 TI - Assessment of health facility capacity to provide newborn care in Bangladesh, Haiti, Malawi, Senegal, and Tanzania. AB - Background: Despite the importance of health facility capacity to provide comprehensive care, the most widely used indicators for global monitoring of maternal and child health remain contact measures which assess women's use of services only and not the capacity of health facilities to provide those services; there is a gap in monitoring health facilities' capacity to provide newborn care services in low and middle income countries. Methods: In this study we demonstrate a measurable framework for assessing health facility capacity to provide newborn care using open access, nationally-representative Service Provision Assessment (SPA) data from the Demographic Health Surveys Program. In particular, we examine whether key newborn-related services are available at the facility (ie, service availability, measured by the availability of basic emergency obstetric care (BEmOC) signal functions, newborn signal functions, and routine perinatal services), and whether the facility has the equipment, medications, training and knowledge necessary to provide those services (ie, service readiness, measured by general facility requirements, equipment, medicines and commodities, and guidelines and staffing) in five countries with high levels of neonatal mortality and recent SPA data: Bangladesh, Haiti, Malawi, Senegal, and Tanzania. Findings: In each country, we find that key services and commodities needed for comprehensive delivery and newborn care are missing from a large percentage of facilities with delivery services. Of three domains of service availability examined, scores for routine care availability are highest, while scores for newborn signal function availability are lowest. Of four domains of service readiness examined, scores for general requirements and equipment are highest, while scores for guidelines and staffing are lowest. Conclusions: Both service availability and readiness tend to be highest in hospitals and facilities in urban areas, pointing to substantial equity gaps in the availability of essential newborn care services for rural areas and for people accessing lower level facilities. Together, the low levels of both service availability and readiness across the five countries reinforce the vital importance of monitoring health facility capacity to provide care. In order to save newborn lives and improve equity in child survival, not only does women's use of services need to increase, but facility capacity to provide those services must also be enhanced. PMID- 29423187 TI - Prevalence of chronic obstructive pulmonary disease (COPD) in China in 1990 and 2010. AB - Background: Chronic obstructive pulmonary disease (COPD) is set to become the third most frequent cause of death and also the third largest cause of global morbidity by 2020. In China, where the population is aging rapidly, COPD has become one of the leading causes of disability and a large economic burden. An epidemiological assessment of the COPD in China is required, with a focus on the number of cases living with disease, main determinants of the disease and time trends. Methods: We systematically searched large Chinese bibliographic databases and English databases to identify spirometry-based epidemiological studies of the prevalence of COPD in China diagnosed according to GOLD criteria. We estimated age- and gender-specific prevalence of COPD using a multilevel mixed-effect logistic regression. We also presented the time trends of COPD between 1990 and 2010 by age, gender and setting (urban vs rural). Findings: In 1990, the prevalence of COPD ranged from 0.49% (95% CI = 0.29-0.85) in <20 years group to 20.95% (95% CI = 14.04-27.04) in> = 80 years group, and the crude prevalence for China was 2.70% (95% CI = 1.86-3.51). In 2010, the prevalence in <20 years was 0.55% (95% CI = 0.37-1.04) and in> = 80 years was 22.89% (95% CI = 18.13-28.96), with the crude prevalence for China of 3.84% (95% CI = 3.30-4.77). The COPD prevalence in males was about two-fold higher than in females, and it increased with increasing age. Between 1990-2010, the total number of Chinese people living with COPD increased by 66.73%, from 30.90 million (95% CI = 21.28-40.02) in 1990 to 51.52 million (95% CI = 44.26-63.93) in 2010. This increase was most striking in middle age, and greater in females than in males from 30 years up to 64 years. Our estimates, which used an independent approach to acquiring data and development of analytical methods, and were based on a more complete data set, are remarkably similar to those produced recently by the GBD 2013 collaboration, differing by only about 5% in the estimated number of COPD cases in 1990 and by 1% in 2010. Conclusions: COPD is a highly prevalent disease in China and its importance is growing steadily. The number of people living with COPD has increased substantially between 1990 and 2010. COPD is more frequent in males and in rural areas. Optimised primary and secondary prevention and treatment is urgently needed to counter this growing trend. Improved epidemiological studies will be required to assist development of more effective strategies of prevention and treatment of COPD in China in the next decade and beyond. PMID- 29423188 TI - Availability of brands of six essential medicines in 124 pharmacies in Maharashtra. AB - Background: The aim of this study is to assess the availability and rational use of six essential medicines in private retail outlets in Maharashtra state. The study focuses on the range of brands for each medicine, and the availability of these brands in the pharmacies. The medicines were chosen because they are included in the World Health Organization's (WHO) essential medicines list (EML), the Indian national and Maharashtra state medicines list, and are all included in existing Indian public health initiatives and national disease control programmes. Methods: Data was gathered on the availability of the medicines and the range and frequency of brands in 124 private retail pharmacies between January and May 2012. As there is currently no centralised database in India of available pharmaceutical brands, we collected data on the range of products of the 6 essential medicines available in the Indian market by consulting three open access Indian pharmaceutical databases, CIMS India, Medindia, and Medguide, and the commercial database, Pharmatrac; we compared this data with the results of the survey. The six essential medicines used in this study are: artemisinin (malaria), lamivudine (HIV/AIDS), rifampicin (tuberculosis control), oxytocin (reproductive health), fluoxetine (mental health) and metformin (diabetes). Results: The study found that for each of the selected medicines there were multiple approved products listed in Indian databases, 2186 in total. The Pharmatrac database lists only 1359 brands of the selected medicines; 978 (72%) of these had zero sales in 2011-2012. Our survey found very low availability of the brands: 17% Pharmatrac marketed brands (163/978) and 12% of all Pharmatrac brands (163/1359) were available. Metformin was the only medicine with high availability in the study pharmacies at 91%, Rifampacin was the second highest at 64.5%; the other four medicines were available in less than half the pharmacies. A small number of brands were dominating the market. Conclusion: the survey shows that market competition has generated a large number of brands of the six study medicines but this has not translated into sufficient availability of these medicines in the study pharmacies. The data calls for a review of available brands, taking into consideration levels of sale and grounds for approval, and the setting up of a centralised database of registered pharmaceutical products. PMID- 29423189 TI - Early neonatal mortality in twin pregnancy: Findings from 60 low- and middle income countries. AB - Background: Around the world, the incidence of multiple pregnancies reaches its peak in the Central African countries and often represents an increased risk of death for women and children because of higher rates of obstetrical complications and poor management skills in those countries. We sought to assess the association between twins and early neonatal mortality compared with singleton pregnancies. We also assessed the role of skilled birth attendant and mode of delivery on early neonatal mortality in twin pregnancies. Methods: We conducted a secondary analysis of individual level data from 60 nationally-representative Demographic and Health Surveys including 521 867 singleton and 14 312 twin births. We investigated the occurrence of deaths within the first week of life in twins compared to singletons and the effect of place and attendance at birth; also, the role of caesarean sections against vaginal births was examined, globally and after countries stratification per caesarean sections rates. A multi level logistic regression was used accounting for homogeneity within country, and homogeneity within twin pairs. Results: Early neonatal mortality among twins was significantly higher when compared to singleton neonates (adjusted odds ratio (aOR) 7.6; 95% confidence interval (CI) = 7.0-8.3) in these 60 countries. Early neonatal mortality was also higher among twins than singletons when adjusting for birth weight in a subgroup analysis of those countries with data on birth weight (n = 20; less than 20% of missing values) (aOR = 2.8; 95% CI = 2.2-3.5). For countries with high rates (>15%) of caesarean sections (CS), twins delivered vaginally in health facility had a statistically significant (aOR = 4.8; 95% CI = 2.4-9.4) increased risk of early neonatal mortality compared to twins delivered through caesarean sections. Home twin births without SBA was associated with increased mortality compared with delivering at home with SBA (aOR = 1.3; 95% CI = 1.0-1.8) and with vaginal birth in health facility (aOR = 1.7; 95% CI = 1.4 2.0). Conclusions: Institutional deliveries and increased access of caesarian sections may be considered for twin pregnancies in low- and middle- income countries to decrease early adverse neonatal outcomes. PMID- 29423190 TI - Antibiotic use in a tertiary healthcare facility in Ghana: a point prevalence survey. AB - Background: The global rise and spread of antibiotic resistance is limiting the usefulness of antibiotics in the prevention and treatment of infectious diseases. The use of antibiotic stewardship programs guided by local data on prescribing practices is a useful strategy to control and reduce antibiotic resistance. Our objective in this study was to determine the prevalence and indications for use of antibiotics at the Korle-Bu Teaching Hospital Accra, Ghana. Methods: An antibiotic point prevalence survey was conducted among inpatients of the Korle-Bu Teaching Hospital between February and March 2016. Folders and treatment charts of patients on admission at participating departments were reviewed for antibiotics administered or scheduled to be administered on the day of the survey. Data on indication for use were also collected. Prevalence of antibiotic use was determined by dividing the number of inpatients on antibiotics at the time of survey by the total number of patients on admission. Results: Of the 677 inpatients surveyed, 348 (51.4%, 95% CI, 47.6-55.2) were on treatment with antibiotics. Prevalence was highest among Paediatric surgery where 20/22 patients (90.9%, 95% CI, 70.8-98.9) were administered antibiotics and lowest among Obstetrics patients with 77/214 (36%, 95% CI, 29.5-42.8). The indications for antibiotic use were 245/611 (40.1%) for community-acquired infections, 205/611 (33.6%) for surgical prophylaxis, 129/611 (21.1%) for healthcare associated infections and 33/611 (5.4%) for medical prophylaxis. The top five antibiotics prescribed in the hospital were metronidazole 107 (17.5%), amoxicillin-clavulinic acid 82 (13.4%), ceftriaxone 17(12.1%), cefuroxime 61 (10.0%), and cloxacillin 52 (8.5%) respectively. Prevalence of meropenem and vancomycin use was 12(2%) and 1 (.2%) respectively. The majority of patients 181 (52%) were being treated with two antibiotics. Conclusion: This study indicated a high prevalence of antibiotic use among inpatients at the Korle-Bu Teaching Hospital. Metronidazole was the most commonly used antibiotic; mainly for surgical prophylaxis. There is the need to further explore factors contributing to the high prevalence of antibiotic use and develop strategies for appropriate antibiotic use in the hospital. PMID- 29423191 TI - Bioaerosol concentrations generated from toilet flushing in a hospital-based patient care setting. AB - Background: In the United States, 1.7 million immunocompromised patients contract a healthcare-associated infection, annually. These infections increase morbidity, mortality and costs of care. A relatively unexplored route of transmission is the generation of bioaerosols during patient care. Transmission of pathogenic microorganisms may result from inhalation or surface contamination of bioaerosols. The toilet flushing of patient fecal waste may be a source of bioaerosols. To date, no study has investigated bioaerosol concentrations from flushing fecal wastes during patient care. Methods: Particle and bioaerosol concentrations were measured in hospital bathrooms across three sampling conditions; no waste no flush, no waste with flush, and fecal waste with flush. Particle and bioaerosol concentrations were measured with a particle counter bioaerosol sampler both before after a toilet flushing event at distances of 0.15, 0.5, and 1 m from the toilet for 5, 10, 15 min. Results: Particle concentrations measured before and after the flush were found to be significantly different (0.3-10 MUm). Bioaerosol concentrations when flushing fecal waste were found to be significantly greater than background concentrations (p-value = 0.005). However, the bioaerosol concentrations were not different across time (p value = 0.977) or distance (p-value = 0.911) from the toilet, suggesting that aerosols generated may remain for longer than 30 min post flush. Toilets produce aerosol particles when flushed, with the majority of the particles being 0.3 MUm in diameter. The particles aerosolized include microorganisms remaining from previous use or from fecal wastes. Differences in bioaerosol concentrations across conditions also suggest that toilet flushing is a source of bioaerosols that may result in transmission of pathogenic microorganisms. Conclusions: This study is the first to quantify particles and bioaerosols produced from flushing a hospital toilet during routine patient care. Future studies are needed targeting pathogens associated with gastrointestinal illness and evaluating aerosol exposure reduction interventions. PMID- 29423192 TI - Synergistic effect of eugenol with Colistin against clinical isolated Colistin resistant Escherichia coli strains. AB - Background: Bacterial infections have become more challenging to treat due to the emergence of multidrug-resistant pathogenic bacteria. Combined antibiotics prove to be a relatively effective method to control such resistant strains. This study aim to investigate synergistic activity of eugenol combined with colistin against a collection of clinical isolated Escherichia coli (E.coli) strains, and to evaluate potential interaction. Methods: Antimicrobial susceptibility, minimum inhibitory concentration (MIC) and fractional inhibitory concentration index (FICI) of the bacteria were determined by disk diffusion assay, broth microdilution method and checkerboard assay, respectively. The mcr-1 mRNA expression was measured by Real-time PCR. To predict possible interactions between eugenol and MCR-1, molecular docking assay was taken. Results: For total fourteen strains including eight colistin-resistant strains, eugenol was determined with MIC values of 4 to 8 MUg/mL. Checkerboard dilution test suggested that eugenol exhibited synergistic activity when combined with colistin (FICI ranging from 0.375 to 0.625). Comparison analysis of Real-time PCR showed that synergy could significantly down-regulate expression of mcr-1 gene. A metal ion coordination bond with catalytic zinc atom and a hydrogen bond with crucial amino acid residue Ser284 of MCR-1 were observed after molecular docking, indicating antibacterial activity and direct molecular interactions of eugenol with MCR-1 protein. Conclusions: Our results demonstrated that eugenol exhibited synergistic effect with colistin and enhanced its antimicrobial activity. This might further contribute to the antibacterial actions against colistin-resistant E.coli strains. Graphical abstract: Synergistic effect of eugenol with colistin against colistin-resistant Escherichia coli isolates. PMID- 29423194 TI - Women and renal replacement therapy in Europe: lower incidence, equal access to transplantation, longer survival than men. AB - In 2018, World Kidney Day (WKD) and International Women's Day coincide. The WKD editorial focuses on women's kidney health. The European Renal Association European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2015 summary provides an excellent snapshot of renal replacement therapy (RRT) epidemiology and women in Europe. The WKD editorial reports a lower incidence of RRT in women in major registries and potential limitations to women's access to transplantation. What is the situation in Europe? In Europe, the incidence of RRT is also lower in women: 38% of incident RRT patients are women. Does it represent milder chronic kidney disease (CKD) in women or barriers to RRT access? The question arises from the higher prevalence of CKD Stages G3-G5 in women than in men. However, in some European countries, such as Spain, non-dialysis CKD Stages G4-G5 is less frequent in women than in men, recapitulating the difference in RRT incidence. In the ERA-EDTA Registry, the incidence of transplantation as a first modality on Day 1 was slightly higher for women and survival on RRT was similar for women and men in the first 3 months, but an intergender gap favouring women increased as RRT vintage increased. However, women on RRT are worse off regarding survival when compared with women in the general population than men on RRT compared with men in the general population. In conclusion, the ERA-EDTA Registry Annual Report 2015 and European epidemiology data suggest a lower incidence of end-stage kidney disease in women, no gender differences in access to transplantation and better RRT survival in women. PMID- 29423193 TI - Alzheimer's disease hypothesis and related therapies. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause for dementia. There are many hypotheses about AD, including abnormal deposit of amyloid beta (Abeta) protein in the extracellular spaces of neurons, formation of twisted fibers of tau proteins inside neurons, cholinergic neuron damage, inflammation, oxidative stress, etc., and many anti-AD drugs based on these hypotheses have been developed. In this review, we will discuss the existing and emerging hypothesis and related therapies. PMID- 29423195 TI - International Society of Nephrology's 0by25 initiative (zero preventable deaths from acute kidney injury by 2025): focus on diagnosis of acute kidney injury in low-income countries. AB - In developing countries with limited medical infrastructure, preservation and recovery of renal function following acute kidney injury (AKI) is difficult. In conjunction with clinical presentation, rapid measurement of renal function is essential for early diagnosis and management. Especially in low- and middle income countries, simple interventions such as hydration and avoidance of toxins have the highest probability of recovery. In such contexts, measurement of urine volume and osmolality and serum creatinine with point-of-care devices and saliva urea nitrogen dipsticks can be valuable. This review aims to identify currently available methodologies to assist in reaching the ambitious goal of the 0by25 initiative to eliminate all preventable deaths from AKI by 2025. PMID- 29423196 TI - Renal recovery after severe acute kidney injury in critically ill myeloma patients: a retrospective study. AB - Background: Despite substantial improvements in the management of multiple myeloma, renal failure remains an important burden that tremendously impairs prognosis. The purpose of this study was to describe the characteristics and to establish prognostic factors of renal recovery in myeloma patients admitted to the intensive care unit (ICU) for acute kidney injury (AKI) Stage 3 treated with renal replacement therapy (RRT). Methods: A retrospective single-centre cohort study was performed, including consecutive myeloma patients admitted to one medical ICU between 1 January 2007 and 1 September 2015 and treated with RRT. Patients were evaluated 60 days after initiation of RRT and divided into three groups: alive without dialysis, alive and dialysis-dependent or deceased. A univariate analysis was performed to identify factors associated with renal recovery (alive without dialysis 60 days after initiation of RRT). Results: Fifty patients were included in the study. Mean age was 63 (interquartile range: 58-70) years and 32 (64%) were male. Patients were admitted to the ICU 4 (1-7) years after the diagnosis of myeloma. Twenty-one (42%) had already been treated with high-dose therapy combined with autologous stem cell transplantation. Baseline renal function evaluated by estimated glomerular filtration rate (GFR) before ICU admission was 63 (44-90) mL/min/1.73 m2. The mean SOFA score at Day 1 was 7 (4 8). The three main reasons for ICU admission were AKI (n = 31, 62%), acute pulmonary oedema (n = 17, 32%) and sepsis (n = 10, 20%). During ICU stay, RRT was implemented in all patients, 16 (32%) patients required invasive mechanical ventilation and 12 (24%) received vasopressors. The mean ICU and hospital length of stay were 6 (1-7) and 28 (13-34) days, respectively. At Day 60, 23 (46%) patients were alive without dialysis, 17 (32%) had died and 10 (20%) were still undergoing dialysis. Among the 23 patients who recovered, the mean duration of dialysis was 6 (2-18) days and renal function was not significantly different from baseline [estimated GFR at baseline = 65 (25-74) mL/min/1.73 m2 versus 63 (56-70) mL/min/1.73 m2 at Day 60, P = 0.70]. By univariate analysis, two factors were associated with nonrecovery of renal function at Day 60: a history of high dose therapy combined with autologous stem cell transplantation [odds ratio (OR) = 6.1, 95% confidence interval (CI) 1.7-21.6; P = 0.008] and a proteinuria at ICU admission >370 mg/mmol creatinine (OR = 4.2, 95% CI 1.1-17; P = 0.02). None of the other variables related to the haematological malignancy or to the ICU stay was associated with renal recovery at Day 60. Conclusions: AKI Stage 3 in critically ill myeloma patients was associated with a lower than expected hospital mortality. Patients with a high level of proteinuria and a history of high-dose therapy combined with autologous stem cell transplantation were less likely to recover their renal function at Day 60. Key words: dialysis, intensive care, multiple myeloma, prognosis, proteinuria. PMID- 29423197 TI - The potential role of complements in cocaine-induced thrombotic microangiopathy. AB - Thrombotic microangiopathy (TMA) is a rare disorder characterized by microvascular injury and occlusion resulting in tissue ischemia and dysfunction. TMA occurs in a variety of settings including cocaine use. Although cocaine is widely used in the United States, cocaine-associated TMA is only rarely reported. Therefore, other factors may predispose cocaine users to the development of TMA. Emerging evidence indicates that cocaine activates complements. Therefore, complement activation may contribute to the development of cocaine-induced TMA. Here, we report a cocaine user who presented with renal failure. Renal biopsy demonstrated TMA. Laboratory tests revealed reduced serum complement C3 and normal complement C4 levels indicative of alternative complement activation. We postulate that complement activation is involved in the pathogenesis of cocaine induced TMA. PMID- 29423198 TI - MicroRNAs: a new avenue to understand, investigate and treat immunoglobulin A nephropathy? AB - IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis worldwide. Up to 30% of cases develop the progressive form of the disease, eventually requiring renal replacement therapy. Diagnosis and risk stratification relies on an invasive kidney biopsy and management options are limited, with recurrence following renal transplantation being common. Thus the quest to understand the pathophysiology of IgAN has been one of great importance. MicroRNAs (miRs) are short nucleotides that suppress gene expression by hybridizing to the 3' untranslated region of messenger RNA (mRNAs), promoting mRNA degradation or disrupting translation. First discovered in 1993, miRs have since been implicated in a number of chronic conditions, including cancer, heart disease and kidney disease. The mounting interest in the field of miRs has led to fascinating developments in the field of nephrology, ranging from their roles as biomarkers for disease to the development of miR antagonists as avenues for treatment. The translational potential for miRs in IgAN is thus well grounded and may represent a paradigm shift in current approaches to the disease. This review aims to summarize the literature with regard to miRs and their roles in IgAN. PMID- 29423201 TI - Rituximab-induced serum sickness in the treatment of idiopathic membranous nephropathy. AB - We report a case of rituximab-induced serum sickness in a 50-year-old female with idiopathic membranous nephropathy. Presentation was characterized by a widespread rash 1 week after rituximab administration followed by fever and profound haemodynamic instability, mimicking sepsis. Symptoms resolved over 48 h, although adjunct antibiotics, steroids and inotropes were used. This case is notable for being the first reaction with rituximab for a renal indication as well as the severity of presentation. PMID- 29423200 TI - Idiopathic membranous nephropathy in patients with diabetes mellitus: a diagnostic and therapeutic quandary! AB - Background: Proteinuria and renal dysfunction is common in diabetic patients and may occur due to variety of causes. Nondiabetic renal diseases (NDRD) account for 30% of the renal biopsies, and idiopathic membranous nephropathy (iMN) is a common non diabetic glomerular disease that can exist alone or in combination with diabetic nephropathy (DN). Immunosuppressants used in iMN may be associated with complications of worsening glycemic control and recurrent infections. There is a paucity of literature on the clinical course, outcomes and treatment adverse effects of patients with iMN and diabetes. Methods: We retrospectively analyzed the data of all diabetics, evaluated for NDRD and found to have iMN, between January 2000 and June 2015 in our institute. Results: A total of 134 patients with diabetes were biopsied for NDRD and 16 patients had iMN. Mean +/- standard deviation age was 54 +/- 11.77 years and the median duration of diabetes was 9.4 years. Twelve patients had isolated iMN and four patients had iMN coexisting with DN. Response rates of 18%, 35.71% and 63.63% were seen with Modified Ponticelli (MP) regimen, tacrolimus and mycophenolate mofetil (MMF), respectively. Five patients developed treatment-related adverse effects significant enough to necessitate a treatment change. Worsening glycemic control was the most common side effect. Adverse effects were less with the MMF compared with the MP regimen and tacrolimus. Conclusion: Patients with iMN coexisting with diabetes exhibit a poor response to the MP regimen. Treatment-related toxicity is less common with MMF in comparison with the MP regimen and tacrolimus-based regimen. An almost similar response was noted with MMF and tacrolimus-based regimen but there was more withdrawal from treatment due to toxicities observed in the latter. PMID- 29423202 TI - Azithromycin suppressed relapses of idiopathic nephrotic syndrome in a child. AB - Long-term immunosuppressive therapy with severe adverse effects is indispensable to maintain disease remission in frequently relapsing nephrotic syndrome (NS) in children. Hence, development of new therapy with less toxicity for relapses of NS is required. We demonstrated a case of a 2-year-old boy with frequently relapsing NS, whose frequent relapses were successfully treated with azithromycin. Azithromycin treatment prevented the need for long-term immunosuppressive therapy in this case. Azithromycin could be a new treatment option for relapse of NS, with few adverse effects, in selected cases. PMID- 29423199 TI - IgA nephropathy in Greece: data from the registry of the Hellenic Society of Nephrology. AB - Background: Natural history, predisposing factors to an unfavourable outcome and the effect of various therapeutic regimens were evaluated in a cohort of 457 patients with immunoglobulin A nephropathy (IgAN) and follow-up of at least 12 months. Methods: Patients with normal renal function and proteinuria <1 g/24 h as well as those with serum creatinine (SCr) >2.5 mg/dL and/or severe glomerulosclerosis received no treatment. Patients with normal or impaired renal function and proteinuria >1 g/24 h for >6 months received daily oral prednisolone or a 3-day course of intravenous (IV) methylprednisolone followed by oral prednisolone per os every other day or a combination of prednisolone and azathioprine. The clinical outcome was estimated using the primary endpoints of end-stage renal disease and/or doubling of baseline SCr. Results: The overall 10 year renal survival was 90.8%, while end-stage renal disease and doubling of baseline SCr developed in 9.2% and 14.7% of patients, respectively. Risk factors related to the primary endpoints were elevated baseline SCr, arterial hypertension, persistent proteinuria >0.5 g/24 h and severity of tubulointerstial fibrosis. There was no difference in the clinical outcome of patients treated by the two regimens of corticosteroids; nevertheless, remission of proteinuria was more frequent in patients who received IV methylprednisolone (P = 0.000). The combination of prednisolone with azathioprine was not superior to IV methylprednisolone followed by oral prednisolone. Side effects related to immunossuppressive drugs were observed in 12.8% of patients. Conclusion: The clinical outcome of patients with IgAN was related to the severity of clinical and histological involvement. The addition of azathioprine to a corticosteroid based regimen for IgAN does not improve renal outcome. PMID- 29423203 TI - Causes and predictors of mortality in biopsy-proven lupus nephritis: the Sarawak experience. AB - Background: Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus that can be fatal if left untreated. The causes and prognostic predictors of mortality in LN have been well studied in developed countries but evidence is lacking for developing countries. The objective of this study was to investigate the causes and predictors of mortality in a cohort of Malaysian patients with biopsy-proven LN. Methods: We retrospectively studied all patients with biopsy-proven LN treated in Sarawak General Hospital during the period of 2000-15. Demographic data, clinical features and outcomes were collected. Cox regression analysis was carried out to determine the independent predictors of mortality. Results: There was a total of 250 patients with 259 renal biopsies available for our analysis. Our patients were of multi-ethnic origins with a female predominance (90%). Their mean +/- standard deviation age was 37.7 +/- 12.8 years. The patients had a mean disease duration of 135.6 +/- 81.9 months. Nephrotic syndrome was the most common presentation (29.6%) and acute renal failure was evident at initial presentation in 16% of patients. Class IV LN was the predominant biopsy class within the cohort (66.8%). The majority of patients achieved remission (81.2%) and had normal renal function (83.9%) at the last follow-up. The 5-, 10-, 15- and 20-year survival rates for our cohort were 93%, 88%, 82% and 77%, respectively. There were 37 deaths (14.8%), of which the main causes were: infection and flare (52.7%), infection alone (25.0%) and other causes (22.3%). Independent predictors of mortality in our cohort of LN patients were: the presence of acute kidney injury at presentation [hazard ratio (HR) 3.41; confidence interval (CI) 1.50-7.76], failure to achieve remission at 1-year post-induction therapy (HR 2.99; CI 1.35-6.65) and non-compliance with treatment (HR 1.89; CI 1.22-2.96). Age, ethnicity, class of LN and type of immunosuppressant used were not predictive of mortality. Conclusions: Survival and renal outcomes in our LN cohort were comparable to most LN studies reported worldwide. Both flare and infection remained the main causes of death. The presence of acute renal failure at presentation, failure to achieve remission at 1 year post-treatment and non-compliance with treatment were independent prognostic predictors of mortality in LN. PMID- 29423204 TI - Practical approaches to the management of autosomal dominant polycystic kidney disease patients in the era of tolvaptan. AB - Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease worldwide. The renal phenotype is characterized by progressive cystic enlargement of the kidneys leading to a decline in renal function, hypertension and often end-stage renal disease (ESRD). Supportive care with blood pressure control and management of pain, urinary infections and renal stone disease has, until recently, been the mainstay of treatment. With the recent approval of tolvaptan for use in ADPKD, the disease progression may now be targeted specifically. Algorithms that guide treatment initiation have been proposed but a more pragmatic and patient-individualized approach is often needed to make decisions regarding therapy. It is highly important to identify ADPKD patients with rapidly progressive disease who are likely to benefit most from this treatment and avoid treatment in patients that are unlikely to reach ESRD. Methods and Results: Here we present a series of cases of ADPKD patients in whom therapy with tolvaptan has been considered and report the rationale for the treatment decisions based on available lifestyle, clinical, biochemical, radiological and genetic data. Conclusions: These cases provide a discussion for the use of tolvaptan in ADPKD within the nephrology clinic and allow insights into the practicalities of using this therapy outside of clinical trials. PMID- 29423205 TI - CKD-MBD KDIGO guidelines: how difficult is reaching the 'target'? AB - Patients with chronic kidney disease (CKD) are affected by mineral and bone disorder (MBD), resulting in abnormalities in serum calcium (Ca), phosphorous (P) and parathyroid hormone (PTH). Changes in mineral metabolism have also been associated with higher rates of both all-cause and cardiovascular-related mortality. The majority of haemodialysis patients are also deficient in the endogenous hormone 1,25-dihydroxyvitamin D (calcitriol), often contributing to increased secondary hyperparathyroidism (SHPT) and consequently to abnormal levels of Ca, P and PTH. Thus P overload and SHPT are well-known targets of medical treatments, such as P binders, vitamin D and calcimimetics, although with still limited evidence-based advantages in terms of survival. The tough hedge that is still keeping nephrologists far from a conclusive and winning approach against CKD-MBD is reasonably related to the still partial comprehension of the molecular pathways involved in a complex, multifactorial and extreme process. PMID- 29423206 TI - Achievement of Kidney Disease: Improving Global Outcomes mineral and bone targets between 2010 and 2014 in incident dialysis patients in France: the Photo-Graphe3 study. AB - Background: Abnormal serum phosphate, calcium and parathyroid hormone (PTH) levels in patients with chronic kidney disease (CKD) undergoing haemodialysis have been associated with poor survival. The French Phosphorus and Calcium Observatory (Photo-Graphe(r) 3) aimed to estimate the percentage of CKD patients achieving the three Kidney Disease: Improving Global Outcomes (KDIGO) targets about optimal serum phosphate, calcium and PTH over a 3.5-year follow-up period. Methods: This was a prospective, multicentre, epidemiological observational study conducted with nephrologists in France, selected using a clustering approach. Eligible patients were adults undergoing intermittent haemodialysis or haemodiafiltration therapy started within the preceding 12 months. Data about clinical events, serum biochemistry and treatment were collected once every 6 months for 2.5 years and 12 months thereafter. Results: Overall, 9010 incident patients were included (men, 63%; median age, 71 years) of whom 7515 (83.4%) were treated by haemodialysis and 1495 (16.6%) by haemodiafiltration. None had a history of fracture or revascularization while 89 (1%) patients had a history of parathyroidectomy >6 months. Overall, 874 (10%) patients received a kidney graft, 2183 (24%) died and 1148 (13%) were lost to follow-up. The proportion achieving the three KDIGO targets increased significantly from 11% to 16% (P < 0.0001) until Year 2, but remained stable afterwards. The percentage of incident dialysis patients with normal serum phosphate (P < 0.0001) or normal serum calcium (P < 0.0001) levels increased significantly over time, while no significant change was observed for those with controlled PTH. Conclusion: Less than 20% of patients achieved the KDIGO recommendations although their proportion increased slightly over time. PMID- 29423207 TI - Old and new calcimimetics for treatment of secondary hyperparathyroidism: impact on biochemical and relevant clinical outcomes. AB - Secondary hyperparathyroidism (SHPT) is associated with increased bone turnover, risk of fractures, vascular calcifications, and cardiovascular and all-cause mortality. The classical treatment for SHPT includes active vitamin D compounds and phosphate binders. However, achieving the optimal laboratory targets is often difficult because vitamin D sterols suppress parathyroid hormone (PTH) secretion, while also promoting calcium and phosphate intestinal absorption. Calcimimetics increase the sensitivity of the calcium-sensing receptor, so that even with lower levels of extracellular calcium a signal can still exist, leading to a decrease of the set-point for systemic calcium homeostasis. This enables a decrease in plasma PTH levels and, consequently, of calcium levels. Cinacalcet was the first calcimimetic to be approved for clinical use. More than 10 years since its approval, cinacalcet has been demonstrated to effectively reduce PTH and improve biochemical control of mineral and bone disorders in chronic kidney patients. Three randomized controlled trials have analysed the effects of treatment with cinacalcet on hard clinical outcomes such as vascular calcification, bone histology and cardiovascular mortality and morbidity. However, a final conclusion on the effect of cinacalcet on hard outcomes remains elusive. Etelcalcetide is a new second-generation calcimimetic with a pharmacokinetic profile that allows thrice-weekly dosing at the time of haemodialysis. It was recently approved in Europe, and is regarded as a second opportunity to improve outcomes by optimizing treatment for SHPT. In this review, we summarize the impact of cinacalcet with regard to biochemical and clinical outcomes. We also discuss the possible implications of the new calcimimetic etelcalcetide in the quest to improve outcomes. PMID- 29423208 TI - Sevelamer reduces endothelial inflammatory response to advanced glycation end products. AB - Background: Advanced glycation end products (AGEs) have been related to the pathogenesis of cardiovascular diseases (CVD), chronic kidney disease (CKD) and diabetes mellitus. We sought to investigate the binding capacity of sevelamer to both AGEs and uremic serum in vitro and then test this pharmaceutical effect as a potential vascular anti-inflammatory strategy. Methods: AGEs were prepared by albumin glycation and characterized by absorbance and electrophoresis. Human endothelial cells were incubated in culture media containing AGEs and uremic serum with or without sevelamer. Receptor for advanced glycation end product (RAGE) expression was evaluated through immunocytochemistry and western blot to explore the interactions between AGEs and the endothelium. Inflammatory and endothelial dysfunction biomarkers, such as interleukin 6 (IL-6) and IL-8, monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and serum amyloid A (SAA) were also measured in cell supernatant. The chemotactic property of the supernatant was evaluated. Results: AGEs significantly induced the expression of RAGE, inflammatory and endothelial activation biomarkers [IL-6, (P < 0.005); IL-8, MCP-1, PAI-1 and SAA (P < 0.001)] and monocyte chemotaxis as compared with controls. In addition, AGEs increased the levels of inflammatory biomarkers, which were observed after 6 h of endothelial cell incubation with uremic serum [IL-6 (P < 0.001) IL-8, MCP-1 and PAI-1 (P < 0.05)]. On the other hand, after 6 h of endothelial cell treatment with sevelamer, RAGE expression (P < 0.05) and levels of inflammatory biomarkers [IL-6 and IL-8 (P < 0.001), MCP-1 (P < 0.01), PAI-1 and SAA (P < 0.005)] significantly decreased compared with the AGEs/uremic serum treatment alone. Conclusions: Sevelamer decreased both endothelial expression of RAGE and endothelial dysfunction biomarkers, induced by AGEs, and uremic serum. Further studies are necessary for a better understanding of the potential protective role of sevelamer on uremic serum and AGEs-mediated endothelial dysfunction. PMID- 29423209 TI - Quality of care and practice patterns in anaemia management at specialist kidney clinics in Ireland: a national study. AB - Background: Although anaemia is a common complication of advanced chronic kidney disease (CKD), knowledge of quality of care and management practices in specialist clinics varies. We examined anaemia practices at specialist nephrology clinics within the Irish health system and evaluated the opinions of practicing nephrologists. Methods: A multicentre cross-sectional study was conducted at specialist nephrology clinics across six geographic regions in Ireland. Clinical characteristics and treatment practices were evaluated in a sample of 530 patients with CKD. An accompanying national survey questionnaire captured opinions and treatment strategies of nephrologists on anaemia management. Results: The prevalence of anaemia [defined as haemoglobin (Hb) <12.0 g/dL] was 37.8%, which increased significantly with advancing CKD (from 21% to 63%; P < 0.01) and varied across clinical sites (from 36% to 62%; P < 0.026). Iron deficiency (ID) was present in 46% of all patients tested and 86% of them were not on treatment. More than 45% of anaemic patients were not tested for ID. Respondents differed in their selection of clinical guidelines, threshold targets for erythropoiesis-stimulating agent (ESA) and intravenous iron therapy and anaemia management algorithms were absent in 47% of the clinics. The unexpectedly low rates of ESA use (4.7%) and iron therapy (10.2%) in clinical practice were in contrast to survey responses where 63% of nephrologists indicated ESA therapy initiation when Hb was <10.0 g/dL and 46% indicated commencement of iron therapy for ferritin <150 ng/mL. Conclusion: This study highlights substantial variability in the management of anaemia and ID at specialist nephrology clinics with low testing rates for ID, high rates of anaemia and ID and underutilization of effective treatments. Variability in the adoption and implementation of different clinical guidelines was evident. PMID- 29423210 TI - The European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2015: a summary. AB - Background: This article summarizes the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry's 2015 Annual Report. It describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2015 within 36 countries. Methods: In 2016 and 2017, the ERA EDTA Registry received data on patients who were undergoing RRT for ESRD in 2015, from 52 national or regional renal registries. Thirty-two registries provided individual patient-level data and 20 provided aggregated-level data. The incidence, prevalence and survival probabilities of these patients were determined. Results: In 2015, 81 373 individuals commenced RRT for ESRD, equating to an overall unadjusted incidence rate of 119 per million population (pmp). The incidence ranged by 10-fold, from 24 pmp in Ukraine to 232 pmp in the Czech Republic. Of the patients commencing RRT, almost two-thirds were men, over half were aged >=65 years and a quarter had diabetes mellitus as their primary renal diagnosis. Treatment modality at the start of RRT was haemodialysis for 85% of the patients, peritoneal dialysis for 11% and a kidney transplant for 4%. By Day 91 of commencing RRT, 82% of patients were receiving haemodialysis, 13% peritoneal dialysis and 5% had a kidney transplant. On 31 December 2015, 546 783 individuals were receiving RRT for ESRD, corresponding to an unadjusted prevalence of 801 pmp. This ranged throughout Europe by more than 10-fold, from 178 pmp in Ukraine to 1824 pmp in Portugal. In 2015, 21 056 kidney transplantations were performed, equating to an overall unadjusted transplant rate of 31 pmp. This varied from 2 pmp in Ukraine to 94 pmp in the Spanish region of Cantabria. For patients commencing RRT during 2006-10, the 5-year unadjusted patient survival probabilities on all RRT modalities combined was 50.0% (95% confidence interval 49.9-50.1). PMID- 29423211 TI - Depressive affect in incident hemodialysis patients. AB - Background: The prevalence of depressive affect is not well defined in the incident hemodialysis (HD) population. We investigated the prevalence of and associated risk factors and hospitalization rates for depressive affect in incident HD patients. Methods: We performed a prospective investigation using the Patient Health Questionnaire 2 (PHQ2) depressive affect assessment. From January to July of 2013 at 108 in-center clinics randomly selected across tertiles of baseline quality measures, we contacted 577 and 543 patients by telephone for depressive affect screening. PHQ2 test scores range from 0 to 6 (scores >=3 suggest the presence of depressive affect). The prevalence of depressive affect was measured at 1-30 and 121-150 days after initiating HD; depressive affect risk factors and hospitalization rates by depressive affect status at 1-30 days after starting HD were computed. Results: Of 1120 contacted patients, 340 completed the PHQ2. In patients screened at 1-30 or 121-150 days after starting HD, depressive affect prevalence was 20.2% and 18.5%, respectively (unpaired t-test, P = 0.7). In 35 patients screened at both time points, there were trends for lower prevalence of depressive affect at the end of incident HD, with 20.0% and 5.7% of patients positive for depressive affect at 1-30 and 121-150 days, respectively (paired t-test, P = 0.1). Hospitalization rates were higher in patients with depressive affect during the first 30 days, exhibiting 1.5 more admissions (P < 0.001) and 10.5 additional hospital days (P = 0.008) per patient-year. Females were at higher risk for depressive affect at 1-30 days (P = 0.01). Conclusions: The prevalence of depressive affect in HD patients is high throughout the incident period. Rates of hospital admissions and hospital days are increased in incident HD patients with depressive affect. PMID- 29423212 TI - Chronic kidney disease, kidney transplantation and oxidative stress: a new look to successful kidney transplantation. AB - Oxidative stress plays a key role in the pathophysiological process of uremia and its complications, particularly in cardiovascular disease. The level of oxidative stress markers is known to increase as chronic kidney disease progresses and correlates significantly with the level of renal function. Hemodialysis and peritoneal dialysis are major modes of renal replacement therapy for end-stage renal disease patients, but unfortunately they are also accompanied by increased oxidative stress. Successful kidney transplantation, however, results in near normalization of the antioxidant status and lipid metabolism by eliminating free radicals despite the surge of oxidative stress caused by the surgical procedure and ischemic injury to the organ during the operation. This success is associated with both improved renal function, reduced cardiovascular complications and overall improved morbidity and mortality. Measuring oxidative stress markers such as malondialdehyde is promising in predicting allograft survival and delayed graft function. PMID- 29423213 TI - Cardiovascular effects of metabolic syndrome after transplantation: convergence of obesity and transplant-related factors. AB - Children are at increased risk of developing metabolic syndrome (MS) after kidney transplantation, which contributes to long-term cardiovascular (CV) morbidities and decline in allograft function. While MS in the general population occurs due to excess caloric intake and physical inactivity, additional chronic kidney disease and transplant-related factors contribute to the development of MS in transplant recipients. Despite its significant health consequences, the interplay of the individual components in CV morbidity in pediatric transplant recipients is not well understood. Additionally, the optimal methods to detect early CV dysfunction are not well defined in this unique population. The quest to establish clear guidelines for diagnosis is further complicated by genetic differences among ethnic groups that necessitate the development of race-specific criteria, particularly with regard to individuals of African descent who carry the apolipoprotein L1 variant. In children, since major CV events are rare and traditional echocardiographic measures of systolic function, such as ejection fraction, are typically well preserved, the presence of CV disease often goes undetected in the early stages. Recently, new noninvasive imaging techniques have become available that offer the opportunity for early detection. Carotid intima media thickness and impaired myocardial strain detected by speckle tracking echocardiography or cardiac magnetic resonance are emerging as early and sensitive markers of subclinical CV dysfunction. These highly sensitive tools may offer the opportunity to elucidate subtle CV effects of MS in children after transplantation. Current knowledge and future directions are explored in this review. PMID- 29423215 TI - Development of genome engineering technologies in cattle: from random to specific. AB - The production of transgenic farm animals (e.g., cattle) via genome engineering for the gain or loss of gene functions is an important undertaking. In the initial stages of genome engineering, DNA micro-injection into one-cell stage embryos (zygotes) followed by embryo transfer into a recipient was performed because of the ease of the procedure. However, as this approach resulted in severe mosaicism and has a low efficiency, it is not typically employed in the cattle as priority, unlike in mice. To overcome the above issue with micro injection in cattle, somatic cell nuclear transfer (SCNT) was introduced and successfully used to produce cloned livestock. The application of SCNT for the production of transgenic livestock represents a significant advancement, but its development speed is relatively slow because of abnormal reprogramming and low gene targeting efficiency. Recent genome editing technologies (e.g., ZFN, TALEN, and CRISPR-Cas9) have been rapidly adapted for applications in cattle and great results have been achieved in several fields such as disease models and bioreactors. In the future, genome engineering technologies will accelerate our understanding of genetic traits in bovine and will be readily adapted for bio medical applications in cattle. PMID- 29423214 TI - Use of gene-editing technology to introduce targeted modifications in pigs. AB - Pigs are an important resource in agriculture and serve as a model for human diseases. Due to their physiological and anatomical similarities with humans, pigs can recapitulate symptoms of human diseases, making them a useful model in biomedicine. However, in the past pig models have not been widely used partially because of the difficulty in genetic modification. The lack of true embryonic stem cells in pigs forced researchers to utilize genetic modification in somatic cells and somatic cell nuclear transfer (SCNT) to generate genetically engineered (GE) pigs carrying site-specific modifications. Although possible, this approach is extremely inefficient and GE pigs born through this method often presented developmental defects associated with the cloning process. Advancement in the gene-editing systems such as Zinc-Finger Nucleases (ZFNs), Transcription activator-like effector nucleases (TALENs), and the Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) system have dramatically increased the efficiency of producing GE pigs. These gene editing systems, specifically engineered endonucleases, are based on inducing double-stranded breaks (DSBs) at a specific location, and then site-specific modifications can be introduced through one of the two DNA repair pathways: non homologous end joining (NHEJ) or homology direct repair (HDR). Random insertions or deletions (indels) can be introduced through NHEJ and specific nucleotide sequences can be introduced through HDR, if donor DNA is provided. Use of these engineered endonucleases provides a higher success in genetic modifications, multiallelic modification of the genome, and an opportunity to introduce site specific modifications during embryogenesis, thus bypassing the need of SCNT in GE pig production. This review will provide a historical prospective of GE pig production and examples of how the gene-editing system, led by engineered endonucleases, have improved GE pig production. We will also present some of our current progress related to the optimal use of CRISPR/Cas9 system during embryogenesis. PMID- 29423216 TI - Dietary proline supplementation alters colonic luminal microbiota and bacterial metabolite composition between days 45 and 70 of pregnancy in Huanjiang mini pigs. AB - Background: Pregnancy is associated with important changes in gut microbiota composition. Dietary factors may affect the diversity, composition, and metabolic activity of the intestinal microbiota. Among amino acids, proline is known to play important roles in protein metabolism and structure, cell differentiation, conceptus growth and development, and gut microbiota re-equilibration in case of dysbiosis. Results: Dietary supplementation with 1% proline decreased (P < 0.05) the amounts of Klebsiella pneumoniae, Peptostreptococcus productus, Pseudomonas, and Veillonella spp. in distal colonic contents than that in the control group. The colonic contents of Butyrivibrio fibrisolvens, Bifidobacterium sp., Clostridium coccoides, Clostridium coccoides-Eubacterium rectale, Clostridium leptum subgroup, Escherichia coli, Faecalibacterium prausnitzii, Fusobacterium prausnitzii, and Prevotella increased (P < 0.05) on d 70 of pregnancy as compared with those on d 45 of pregnancy. The colonic concentrations of acetate, total straight-chain fatty acid, and total short-chain fatty acids (SCFA) in the proline-supplemented group were lower (P < 0.05), and butyrate level (P = 0.06) decreased as compared with the control group. Almost all of the SCFA displayed higher (P < 0.05) concentrations in proximal colonic contents on d 70 of pregnancy than those on d 45 of pregnancy. The concentrations of 1,7-heptyl diamine (P = 0.09) and phenylethylamine (P < 0.05) in proximal colonic contents were higher, while those of spermidine (P = 0.05) and total bioamine (P = 0.06) tended to be lower in the proline-supplemented group than those in the control group. The concentrations of spermidine, spermine, and total bioamine in colonic contents were higher (P < 0.05) on d 70 of pregnancy than those measured on d 45 of pregnancy. In contrast, the concentration of phenylethylamine was lower (P < 0.05) on d 70 than on d 45 of pregnancy. Conclusion: These findings indicate that L-proline supplementation modifies both the colonic microbiota composition and the luminal concentrations of several bacterial metabolites. Furthermore, our data show that both the microbiota composition and the concentrations of bacterial metabolites are evolving in the course of pregnancy. These results are discussed in terms of possible implication in terms of luminal environment and consequences for gut physiology and health. PMID- 29423218 TI - Women decision-making capacity and intimate partner violence among women in sub Saharan Africa. AB - Background: Violence against women is a common form of human rights violation, and intimate partner violence (IPV) appears to be the most significant component of violence. The aim of this study was to examine the association between women decision-making capacity and IPV among Women in Sub-Saharan Africa. The study also looked at how socio-demographic factors also influence IPV among Women in Sub-Saharan Africa. Methods: The study made use of pooled data from most recent Demographic and Health Survey (DHS) conducted from January 1, 2010, and December 3, 2016, in 18 countries in Sub-Saharan Africa. For the purpose of the study, only women aged 15-49 were used (N = 84,486). Univariate and multivariate logistic regression models were used to investigate the relationship between the explanatory variables and the outcome variable. Results: The odds of reporting ever experienced IPV was higher among women with decision-making capacity [AOR = 1.35; CI = 1.35-1.48]. The likelihood of experiencing IPV was low among young women. Women who belong to other religious groups and Christians were more likely to experience IPV compared to those who were Muslims [AOR = 1.73; CI = 1.65-1.82] and [AOR = 1.87; CI = 1.72-2.02] respectively. Women who have partners with no education [AOR = 1.11; CI = 1.03-1.20], those whose partners had primary education [AOR = 1.34; CI = 1.25-1.44] and those whose partners had secondary education [AOR = 1.22; CI = 1.15-1.30] were more likely to IPV compared to those whose partners had higher education. The odds of experiencing IPV were high among women who were employed compared to those who were unemployed [AOR = 1.33; CI = 1.28-1.37]. The likelihood of the occurrence of IPV was also high among women who were cohabiting compared to those who were married [AOR = 1.16; CI = 1.10-1.21]. Women with no education [AOR = 1.37; CI = 1.24-1.51], those with primary education [AOR = 1.65; CI = 1.50-1.82] and those with secondary education [AOR = 1.50; CI = 1.37-1.64] were more likely to experience IPV compared to those with higher education. Finally, women with poorest wealth status [AOR = 1.28; CI = 1.20-1.37], those with poorer wealth status [AOR = 1.24; CI = 1.17-1.32], those with middle wealth status [AOR = 1.27; CI = 1.20-1.34] and those with richer wealth status [AOR = 1.11; CI = 1.06-1.17] were more likely to IPV compared to women with richest wealth status. Conclusion: Though related socio-demographic characteristics and women decision-making capacity provided an explanation of IPV among women in sub-Saharan Africa, there were differences in relation to how each socio-demographic variable predisposed women to IPV in Sub-Saharan Africa. PMID- 29423219 TI - The effect of protein supplementation on body muscle mass and fat mass in post bariatric surgery: a randomized controlled trial (RCT) study protocol. AB - Background: Severe weight loss through means of bariatric surgery has been associated with loss of muscle mass due to lack of absorption of protein. The aim of this RCT is to investigate the effectiveness of protein supplementation in reducing the risk of developing protein malnutrition and muscle wasting in post bariatric surgery patients in Qatar. Methods and analysis: The study was based at the Department of bariatric and metabolic surgery, Doha metropolitan and regional areas. It is envisaged that approximately 160 post-bariatric surgery patients will be randomized and followed up for 6 months. These will be males and females obese (BMI >35) Qatari patients between the aged 18-60 years. Subjects with renal or liver disease and those with past history of bariatric surgery will be excluded. By the completion of the trial, patients who took less than 80% of the supplement will be further excluded from the final analysis. Protein supplement (Cubitan,Protein, Nutricia, Netherlands) that contain daily intake of 20 g of protein to be taken orally 3 times a day throughout the study period. The placebo group will receive identical ampule containing zero-protein with exact instructions as per the intervention group. Body weight, muscle and fat mass, total protein, albumin, vit B12, Magnesium and Zinc will be measured at baseline and every follow up/study visit. Study variables will be compared between the 2 groups at different stages of the trial, including baseline, using Sample T-test (paired and unpaired) and the significance level will be confirmed with the 95% confidence interval with alpha error set to 0.05. Ethics and dissemination: Protein supplementation for post-bariatric patients is not yet a standard procedure at Hamad Medical Corporation in Qatar and requires an RCT to establish evidence-based clinical practice guidelines. This study was approved by the Hamad Medical Corporation IRB and MRC committees (approval no. 16433/16). Trial registration: ClinicalTrials.gov NCT03147456 (registration date: 18 April 2017). Strengths and limitations of this study: One major strength of our study is that our population is a distinctive population (Qatari Obese patients) where results from international studies may not apply to the local and unique context. A local study like ours will provide healthcare providers in Qatar an opportunity to ensure good clinical practice and healthy and sustainable weight loss following bariatric surgery.The well-designed double-blinded RCT will almost certainly provide us with the evidence-based clinical practice guideline that we seek as health professionals.One limitation of our study is the slight discrepancy in caloric content of the intervention and the placebo (250 cal and 100 cal, respectively). However, it is the intervention that has the higher caloric content, in which case it may not influence the results in the direction of our hypothesis that protein supplementation leads to lower fat mass and higher muscle mass.Another limitation is that the use of the intervention and the placebo are not objectively measured. However, all efforts will be made to ensure compliance and reporting of consumption of products.A third limitation could be loss to follow up. Participants may cease to participate, particularly, once they have lost "sufficient' weight and gained the fitness to consume any type of foods they desire. This is common in late stages of post-bariatric surgery (beyond 3 months). We feel that this may be a challenge, particularly in reference to our specific population. However, such findings albeit negative, should serve in improving the clinical practice delivered by healthcare providers. PMID- 29423217 TI - Primordial germ cell-mediated transgenesis and genome editing in birds. AB - Transgenesis and genome editing in birds are based on a unique germline transmission system using primordial germ cells (PGCs), which is quite different from the mammalian transgenic and genome editing system. PGCs are progenitor cells of gametes that can deliver genetic information to the next generation. Since avian PGCs were first discovered in nineteenth century, there have been numerous efforts to reveal their origin, specification, and unique migration pattern, and to improve germline transmission efficiency. Recent advances in the isolation and in vitro culture of avian PGCs with genetic manipulation and genome editing tools enable the development of valuable avian models that were unavailable before. However, many challenges remain in the production of transgenic and genome-edited birds, including the precise control of germline transmission, introduction of exogenous genes, and genome editing in PGCs. Therefore, establishing reliable germline-competent PGCs and applying precise genome editing systems are critical current issues in the production of avian models. Here, we introduce a historical overview of avian PGCs and their application, including improved techniques and methodologies in the production of transgenic and genome-edited birds, and we discuss the future potential applications of transgenic and genome-edited birds to provide opportunities and benefits for humans. PMID- 29423220 TI - Mixing modes in a population-based interview survey: comparison of a sequential and a concurrent mixed-mode design for public health research. AB - Background: Population-based surveys currently face the problem of decreasing response rates. Mixed-mode designs are now being implemented more often to account for this, to improve sample composition and to reduce overall costs. This study examines whether a concurrent or sequential mixed-mode design achieves better results on a number of indicators of survey quality. Methods: Data were obtained from a population-based health interview survey of adults in Germany that was conducted as a methodological pilot study as part of the German Health Update (GEDA). Participants were randomly allocated to one of two surveys; each of the surveys had a different design. In the concurrent mixed-mode design (n = 617) two types of self-administered questionnaires (SAQ-Web and SAQ-Paper) and computer-assisted telephone interviewing were offered simultaneously to the respondents along with the invitation to participate. In the sequential mixed mode design (n = 561), SAQ-Web was initially provided, followed by SAQ-Paper, with an option for a telephone interview being sent out together with the reminders at a later date. Finally, this study compared the response rates, sample composition, health indicators, item non-response, the scope of fieldwork and the costs of both designs. Results: No systematic differences were identified between the two mixed-mode designs in terms of response rates, the socio demographic characteristics of the achieved samples, or the prevalence rates of the health indicators under study. The sequential design gained a higher rate of online respondents. Very few telephone interviews were conducted for either design. With regard to data quality, the sequential design (which had more online respondents) showed less item non-response. There were minor differences between the designs in terms of their costs. Postage and printing costs were lower in the concurrent design, but labour costs were lower in the sequential design. No differences in health indicators were found between the two designs. Modelling these results for higher response rates and larger net sample sizes indicated that the sequential design was more cost and time-effective. Conclusions: This study contributes to the research available on implementing mixed-mode designs as part of public health surveys. Our findings show that SAQ-Paper and SAQ-Web questionnaires can be combined effectively. Sequential mixed-mode designs with higher rates of online respondents may be of greater benefit to studies with larger net sample sizes than concurrent mixed-mode designs. PMID- 29423221 TI - A phase I clinical trial of dTCApFs, a derivative of a novel human hormone peptide, for the treatment of advanced/metastatic solid tumors. AB - The aim of the present phase I first-in-human study was to investigate the safety/efficacy of dTCApFs (a novel hormone peptide that enters cells through the T1/ST2 receptor), in advanced/metastatic solid tumors. The primary objective of this open-label dose-escalation study was to determine the safety profile of dTCApFs. The study enrolled patients (aged >=18 years) with pathologically confirmed locally advanced/metastatic solid malignancies, who experienced treatment failure or were unable to tolerate previous standard therapy. The study included 17 patients (64% male; median age, 65 years; 47% colorectal cancer, 29% pancreatic cancer). The patients received 1-3 cycles of escalating dTCApFs doses (6-96 mg/m2). The mean number +/- standard deviation of treatment cycles/patient was 3.2+/-1.4; no dose-limiting toxicities were observed up to a dose of 96 mg/m2, and the maximum tolerated dose was not reached. Half-life, maximal plasma concentration, and dTCApFs exposure were found to be linearly correlated with dose. Five patients were treated for >=3 months (12, 24, 48 mg/m2) and experienced stable disease throughout the treatment period, and 1 experienced pathological complete response. Analysis of serum biomarkers revealed decreased levels of angiogenic factors at dTCApFs concentrations of 12-48 mg/m2, increased levels of anticancer cytokines, and induction of the endoplasmic reticulum (ER) stress biomarker GRP78/BiP. Efficacy and biomarker data suggest that patients whose tumors were T1/ST2-positive exhibited a better response to dTCApFs. In conclusion, dTCApFs was found to be safe/well-tolerated, and potentially efficacious, with linear pharmacokinetics. Consistent with preclinical studies, the mechanism through which dTCApFs exerts anticancer effects appears to involve induction of ER stress, suppression of angiogenesis, and activation of the innate immune response. However, further studies are warranted. PMID- 29423222 TI - Clinicopathological characteristics of disseminated carcinomatosis of the bone marrow in breast cancer patients. AB - Disseminated carcinomatosis of the bone marrow (DCBM) is characterized by diffuse infiltrative growth of tumor cells in the bone marrow and is associated with systemic hematological disorders. Bone marrow metastases from breast cancer are not rare, and they may lead to serious life-threatening conditions when there is an associated hematological disorder. Therefore, DCBM necessitates a definitive diagnosis and prompt systemic therapy. We herein present 4 such cases and a review of the previous relevant literature. Bone marrow biopsy is an effective method for diagnosing DCBM, and it may also be useful for selecting the optimal therapy. The malignant cells in the bone marrow biopsy specimens from all 4 patients were negative for progesterone receptor expression, and in 1 case, human epidermal growth factor receptor 2/neu expression was discordant between the primary tumor and the bone marrow metastases. Patients with DCBM often require granulocyte colony-stimulating factor and/or blood transfusions due to a DCBM related hematological disorder. Although systemic chemotherapy for DCBM may temporarily exacerbate the need for hematological support, systemic chemotherapy may be effective for DCBM in breast cancer patients. In our experience, endocrine therapy has also been proven effective for DCBM. The aim of the present study was to review the clinical characteristics and the treatments used in 4 breast cancer patients with DCBM. PMID- 29423223 TI - Meta-analysis of diffusion-weighted imaging for predicting locoregional failure of chemoradiotherapy in patients with head and neck squamous cell carcinoma. AB - The purpose of this study was to evaluate the accuracy of diffusion-weighted imaging (DWI) for predicting locoregional failure of chemoradiotherapy in patients with head and neck squamous cell carcinoma (HNSCC). A comprehensive search was conducted through the EMBASE, PubMed and Cochrane Library databases for relevant publications. Stata software was used to calculate the pooled sensitivity, specificity, likelihood ratios and diagnostic odds ratios, and to construct a summary receiver operating characteristics (sROC) curve for DWI. A total of 9 studies comprising 421 patients were included. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 0.82 [95% confidence interval (CI): 0.72-0.88], 0.70 (95% CI: 0.62-0.77), 2.7 (95% CI: 2.1-3.6), 0.26 (95% CI: 0.17-0.41), and 10.48 (95% CI: 5.35-20.53), respectively. The area under the sROC curve was 0.84 (95% CI: 0.81 0.87). Therefore, DWI appears to be a promising imaging modality for predicting local failure of chemoradiotherapy in patients with HNSCC. PMID- 29423224 TI - Which environments matter in studies of early life developmental plasticity? PMID- 29423225 TI - Maternal pelvic dimensions and neonatal size: Implications for growth plasticity in early life as adaptation. AB - Patterns of fetal growth predict non-communicable disease risk in adult life, but fetal growth variability appears to have a relatively weak association with maternal nutritional dynamics during pregnancy. This challenges the interpretation of fetal growth variability as 'adaptation'. We hypothesized that associations of maternal size and nutritional status with neonatal size are mediated by the dimensions of the maternal pelvis. We analysed data on maternal height, body mass index (BMI) and pelvic dimensions (conjugate, inter-spinous and inter-cristal diameters) and neonatal gestational age, weight, length, thorax girth and head girth (n = 224). Multiple regression analysis was used to identify independent maternal predictors of neonatal size, and the mediating role of neonatal head girth in these associations. Pelvic dimensions displaced maternal BMI as a predictor of birth weight, explaining 11.6% of the variance. Maternal conjugate and inter-spinous diameters predicted neonatal length, thorax girth and head girth, whereas inter-cristal diameter only predicted neonatal length. Associations of pelvic dimensions with birth length, but not birth weight, were mediated by neonatal head girth. Pelvic dimensions predicted neonatal size better than maternal BMI, and these associations were mostly independent of maternal height. Sensitivity of fetal growth to pelvic dimensions reduces the risk of cephalo-pelvic disproportion, potentially a strong selective pressure during secular trends in height. Selection on fetal adaptation to relatively inflexible components of maternal phenotype, rather than directly to external ecological conditions, may help explain high levels of growth plasticity during late fetal life and early infancy. PMID- 29423227 TI - Silica exposure and work-relatedness evaluation for occupational cancer in Korea. AB - Crystalline silica has been classified as a definite carcinogen (Group 1) causing lung cancer by the International Agency for Research on Cancer (IARC). In Korea, crystalline silica has been the most common causal agent for workers to apply to the Korea Workers' Compensation and Welfare Service (KWCWS). We used KWCWS data to evaluate workers' crystalline silica exposure levels according to their occupations and industries, and reviewed research papers describing the dose response relationship between cumulative exposure levels and lung cancer incidence. In addition, we reviewed lung cancer cases accepted by the KWCWS, and suggest new criteria for defining occupational cancer caused by crystalline silica in Korea. Rather than confining to miners, we propose recognizing occupational lung cancer whenever workers with pneumoconiosis develop lung cancer, regardless of their industry. Simultaneous exposure and lag time should also be considered in evaluations of work-relatedness. PMID- 29423226 TI - Linking autoimmunity to the origin of the adaptive immune system. AB - In jawed vertebrates, the adaptive immune system (AIS) cooperates with the innate immune system (IIS) to protect hosts from infections. Although targeting non-self components, the AIS also generates self-reactive antibodies which, when inadequately counter-selected, can give rise to autoimmune diseases (ADs). ADs are on the rise in western countries. Why haven't ADs been eliminated during the evolution of a ~500 million-year old system? And why have they become more frequent in recent decades? Self-recognition is an attribute of the phylogenetically more ancient IIS and empirical data compellingly show that some self-reactive antibodies, which are classifiable as elements of the IIS rather then the AIS, may protect from (rather than cause) ADs. Here, we propose that the IIS's self-recognition system originally fathered the AIS and, as a consequence of this relationship, its activity is dampened in hygienic environments. Rather than a mere breakdown or failure of the mechanisms of self-tolerance, ADs might thus arise from architectural constraints. PMID- 29423228 TI - Does formaldehyde have a causal association with nasopharyngeal cancer and leukaemia? AB - Background: The South Korean criteria for occupational diseases were amended in July 2013. These criteria included formaldehyde as a newly defined occupational carcinogen, based on cases of "leukemia or nasopharyngeal cancer caused by formaldehyde exposure". This inclusion was based on the Internal Agency for Research on Cancer classification, which classified formaldehyde as definite human carcinogen for nasopharyngeal cancer in 2004 and leukemia in 2012. Methods: We reviewed reports regarding the causal relationship between occupational exposure to formaldehyde in Korea and the development of these cancers, in order to determine whether these cases were work-related. Results: Previous reports regarding excess mortality from nasopharyngeal cancer caused by formaldehyde exposure seemed to be influenced by excess mortality from a single plant. The recent meta-risk for nasopharyngeal cancer was significantly increased in case control studies, but was null for cohort studies (excluding unexplained clusters of nasopharyngeal cancers). A recent analysis of the largest industrial cohort revealed elevated risks of both leukemia and Hodgkin lymphoma at the peak formaldehyde exposure, and both cancers exhibited significant dose-response relationships. A nested case-control study of embalmers revealed that mortality from myeloid leukemia increased significantly with increasing numbers of embalms and with increasing formaldehyde exposure. The recent meta-risks for all leukemia and myeloid leukemia increased significantly. In South Korea, a few cases were considered occupational cancers as a result of mixed exposures to various chemicals (e.g., benzene), although no cases were compensated for formaldehyde exposure. The peak formaldehyde exposure levels in Korea were 2.70-14.8 ppm in a small number of specialized studies, which considered anatomy students, endoscopy employees who handled biopsy specimens, and manufacturing workers who were exposed to high temperatures. Conclusion: Additional evidence is needed to confirm the relationship between formaldehyde exposure and nasopharyngeal cancer. All lymphohematopoietic malignancies, including leukemia, should be considered in cases with occupational formaldehyde exposure. PMID- 29423230 TI - Review of carcinogenicity of hexavalent chrome and proposal of revising approval standards for an occupational cancers in Korea. AB - Background: The objective of this study is to suggest revised recognition standards for occupational disease due to chromium (VI) by reflecting recent domestic and international research works and considering domestic exposure status with respect to target organs, exposure period, and cumulative exposure dose in relation to the chromium (VI)-induced occupational disease compensation. Methods: In this study, the reports published by major international institutions such as World Health Organization (WHO) International Agency for Research on Cancer (IARC) (2012), Occupational Safety and Health Administration (OSHA) (2006), National Institute for Occupational Safety and Health (NIOSH) (2013), American Conference of Governmental Industrial Hygienists (ACGIH) (2004), National Toxicology Program (NTP) (2014), and Agency for Toxic Substances and Disease Registry (ASTDR) (2012) were reviewed and the recent research works searched by PubMed were summarized. Results: Considering the recent research works and the domestic situation, only lung cancer is conserved in the legislative bill in relation to chromium (VI), and the exposure period is not included in the bill. Nasal and paranasal sinus cancer was excluded from the list of cancers that are compensated as the chromium (VI)- induced occupational disease, while lung cancer remains in the list. In the view of legislative unity, considering the fact that only the cancers having sufficient evidence are included in the conventional list of cancers compensated as occupational disease, nasal and paranasal sinus cancer having limited evidence were excluded from the list.The exposure period was also removed from the legislative bill due to the insufficient evidence. Recent advices in connection with cumulative exposure dose were proposed, and other considerable points were provided with respect to individual occupational relevance. Conclusions: It is suggested that the current recognition standard which is "Lung cancer or nasal and paranasal sinus cancer caused by exposure to chromium (VI) or compounds thereof (exposure for two years or longer), or nickel compounds" should be changed to "Lung cancer caused by exposure to chromium (VI) or compounds thereof, and lung cancer or nasal and paranasal sinus cancer caused by exposure to nickel compounds". PMID- 29423229 TI - Recognition criteria for occupational cancers in relation to hepatitis B virus and hepatitis C virus in Korea. AB - The goal of this study was to review the scientific basis for the recognition of occupational cancer, in relation to hepatitis viral infections in Korea. Most Hepatitis B virus (HBV) infections in Korea occur as vertical infections, but these are decreasing rapidly due to vaccination. Hepatitis C virus (HCV) is known to be transmitted through parenteral routes, but the transmission route is often unclear. Most occupational infections of hepatitis virus involve accidental injuries of medical institution workers while using virus-contaminated medical devices. Many cohort studies and case-control studies have consistently reported that HBV and HCV infection increases the risk of hepatocellular carcinoma (HCC) and the strength of this association is high. Non-Hodgkin's lymphoma appears to be associated with HCV. Cholangiocarcinoma, pancreatic cancer, leukemia, and thyroid cancer are considered to be less related or unrelated to epidemiological causation. There are no uniform international specific criteria for occupational cancer caused through occupational exposure to a hepatitis virus. In establishing appropriate standards applicable to Korea, there should be sufficient consideration of latency, virus exposure levels and frequency, and other cancers, apart from HCC. In conclusion, we recommend keeping the current specific criteria. However, if a worker is injured at work when using a sharp medical device, and HBV and HCV viral infections are confirmed through serologic tests; if the worker is diagnosed as having a chronic HBV or HCV infection, a subsequent HCC (or Non-Hodgkin's lymphoma following chronic HCV infection) can then be considered highly related to the worker's occupation. PMID- 29423231 TI - Histological, hormonal and transcriptomic reveal the changes upon gibberellin induced parthenocarpy in pear fruit. AB - Phytohormones play crucial roles in fruit set regulation and development. Here, gibberellins (GA4+7), but not GA3, induced pear parthenocarpy. To systematically investigate the changes upon GA4+7 induced pear parthenocarpy, dynamic changes in histology, hormone and transcript levels were observed and identified in unpollinated, pollinated and GA4+7-treated ovaries. Mesocarp cells continued developing in both GA4+7-treated and pollinated ovaries. In unpollinated ovaries, mesocarp cells stopped developing 14 days after anthesis. During fruit set process, GA4+7, but not GA1+3, increased after pollination. Abscisic acid (ABA) accumulation was significantly repressed by GA4+7 or pollination, but under unpollinated conditions, ABA was produced in large quantities. Moreover, indole-3 acetic acid biosynthesis was not induced by GA4+7 or pollination treatments. Details of this GA-auxin-ABA cross-linked gene network were determined by a comparative transcriptome analysis. The indole-3-acetic acid transport-related genes, mainly auxin efflux carrier component genes, were induced in both GA4+7 treated and pollinated ovaries. ABA biosynthetic genes of the 9-cis epoxycarotenoid dioxygenase family were repressed by GA4+7 and pollination. Moreover, directly related genes in the downstream parthenocarpy network involved in cell division and expansion (upregulated), and MADS-box family genes (downregulated), were also identified. Thus, a model of GA-induced hormonal balance and its effects on parthenocarpy were established. PMID- 29423232 TI - A roadmap for breeding orphan leafy vegetable species: a case study of Gynandropsis gynandra (Cleomaceae). AB - Despite an increasing awareness of the potential of "orphan" or unimproved crops to contribute to food security and enhanced livelihoods for farmers, coordinated research agendas to facilitate production and use of orphan crops by local communities are generally lacking. We provide an overview of the current knowledge on leafy vegetables with a focus on Gynandropsis gynandra, a highly nutritious species used in Africa and Asia, and highlight general and species specific guidelines for participatory, genomics-assisted breeding of orphan crops. Key steps in genome-enabled orphan leafy vegetables improvement are identified and discussed in the context of Gynandropsis gynandra breeding, including: (1) germplasm collection and management; (2) product target definition and refinement; (3) characterization of the genetic control of key traits; (4) design of the 'process' for cultivar development; (5) integration of genomic data to optimize that 'process'; (6) multi-environmental participatory testing and end user evaluation; and (7) crop value chain development. The review discusses each step in detail, with emphasis on improving leaf yield, phytonutrient content, organoleptic quality, resistance to biotic and abiotic stresses and post-harvest management. PMID- 29423233 TI - Organellar genome assembly methods and comparative analysis of horticultural plants. AB - Although organellar genomes (including chloroplast and mitochondrial genomes) are smaller than nuclear genomes in size and gene number, organellar genomes are very important for the investigation of plant evolution and molecular ecology mechanisms. Few studies have focused on the organellar genomes of horticultural plants. Approximately 1193 chloroplast genomes and 199 mitochondrial genomes of land plants are available in the National Center for Biotechnology Information (NCBI), of which only 39 are from horticultural plants. In this paper, we report an innovative and efficient method for high-quality horticultural organellar genome assembly from next-generation sequencing (NGS) data. Sequencing reads were first assembled by Newbler, Amos, and Minimus software with default parameters. The remaining gaps were then filled through BLASTN search and PCR. The complete DNA sequence was corrected based on Illumina sequencing data using BWA (Burrows Wheeler Alignment tool) software. The advantage of this approach is that there is no need to isolate organellar DNA from total DNA during sample preparation. Using this procedure, the complete mitochondrial and chloroplast genomes of an ornamental plant, Salix suchowensis, and a fruit tree, Ziziphus jujuba, were identified. This study shows that horticultural plants have similar mitochondrial and chloroplast sequence organization to other seed plants. Most horticultural plants demonstrate a slight bias toward A+T rich features in the mitochondrial genome. In addition, a phylogenetic analysis of 39 horticultural plants based on 15 protein-coding genes showed that some mitochondrial genes are horizontally transferred from chloroplast DNA. Our study will provide an important reference for organellar genome assembly in other horticultural plants. Furthermore, phylogenetic analysis of the organellar genomes of horticultural plants could accurately clarify the unanticipated relationships among these plants. PMID- 29423234 TI - Reference quality assembly of the 3.5-Gb genome of Capsicum annuum from a single linked-read library. AB - Linked-Read sequencing technology has recently been employed successfully for de novo assembly of human genomes, however, the utility of this technology for complex plant genomes is unproven. We evaluated the technology for this purpose by sequencing the 3.5-gigabase (Gb) diploid pepper (Capsicum annuum) genome with a single Linked-Read library. Plant genomes, including pepper, are characterized by long, highly similar repetitive sequences. Accordingly, significant effort is used to ensure that the sequenced plant is highly homozygous and the resulting assembly is a haploid consensus. With a phased assembly approach, we targeted a heterozygous F1 derived from a wide cross to assess the ability to derive both haplotypes and characterize a pungency gene with a large insertion/deletion. The Supernova software generated a highly ordered, more contiguous sequence assembly than all currently available C. annuum reference genomes. Over 83% of the final assembly was anchored and oriented using four publicly available de novo linkage maps. A comparison of the annotation of conserved eukaryotic genes indicated the completeness of assembly. The validity of the phased assembly is further demonstrated with the complete recovery of both 2.5-Kb insertion/deletion haplotypes of the PUN1 locus in the F1 sample that represents pungent and nonpungent peppers, as well as nearly full recovery of the BUSCO2 gene set within each of the two haplotypes. The most contiguous pepper genome assembly to date has been generated which demonstrates that Linked-Read library technology provides a tool to de novo assemble complex highly repetitive heterozygous plant genomes. This technology can provide an opportunity to cost-effectively develop high-quality genome assemblies for other complex plants and compare structural and gene differences through accurate haplotype reconstruction. PMID- 29423235 TI - Genomic and transcriptomic alterations following intergeneric hybridization and polyploidization in the Chrysanthemum nankingense*Tanacetum vulgare hybrid and allopolyploid (Asteraceae). AB - Allopolyploid formation involves two major events: interspecific hybridization and polyploidization. A number of species in the Asteraceae family are polyploids because of frequent hybridization. The effects of hybridization on genomics and transcriptomics in Chrysanthemum nankingense*Tanacetum vulgare hybrids have been reported. In this study, we obtained allopolyploids by applying a colchicine treatment to a synthesized C. nankingense*T. vulgare hybrid. Sequence-related amplified polymorphism (SRAP), methylation-sensitive amplification polymorphism (MSAP), and high-throughput RNA sequencing (RNA-Seq) technologies were used to investigate the genomic, epigenetic, and transcriptomic alterations in both the hybrid and allopolyploids. The genomic alterations in the hybrid and allopolyploids mainly involved the loss of parental fragments and the gain of novel fragments. The DNA methylation level of the hybrid was reduced by hybridization but was restored somewhat after polyploidization. There were more significant differences in gene expression between the hybrid/allopolyploid and the paternal parent than between the hybrid/allopolyploid and the maternal parent. Most differentially expressed genes (DEGs) showed down-regulation in the hybrid/allopolyploid relative to the parents. Among the non-additive genes, transgressive patterns appeared to be dominant, especially repression patterns. Maternal expression dominance was observed specifically for down-regulated genes. Many methylase and methyltransferase genes showed differential expression between the hybrid and parents and between the allopolyploid and parents. Our data indicate that hybridization may be a major factor affecting genomic and transcriptomic changes in newly formed allopolyploids. The formation of allopolyploids may not simply be the sum of hybridization and polyploidization changes but also may be influenced by the interaction between these processes. PMID- 29423236 TI - A comprehensive proteomic analysis of elaioplasts from citrus fruits reveals insights into elaioplast biogenesis and function. AB - Elaioplasts of citrus peel are colorless plastids which accumulate significant amounts of terpenes. However, other functions of elaioplasts have not been fully characterized to date. Here, a LC-MS/MS shotgun technology was applied to identify the proteins from elaioplasts that were highly purified from young fruit peel of kumquat. A total of 655 putative plastid proteins were identified from elaioplasts according to sequence homology in silico and manual curation. Based on functional classification via Mapman, ~50% of the identified proteins fall into six categories, including protein metabolism, transport, and lipid metabolism. Of note, elaioplasts contained ATP synthase and ADP, ATP carrier proteins at high abundance, indicating important roles for ATP generation and transport in elaioplast biogenesis. Additionally, a comparison of proteins between citrus chromoplast and elaioplast proteomes suggest a high level of functional conservation. However, some distinctive protein profiles were also observed in both types of plastids notably for isoprene biosynthesis in elaioplasts, and carotenoid metabolism in chromoplasts. In conclusion, this comprehensive proteomic study provides new insights into the major metabolic pathways and unique characteristics of elaioplasts and chromoplasts in citrus fruit. PMID- 29423237 TI - Metabolic analyses reveal different mechanisms of leaf color change in two purple leaf tea plant (Camellia sinensis L.) cultivars. AB - Purple-leaf tea plants, as anthocyanin-rich cultivars, are valuable materials for manufacturing teas with unique colors or flavors. In this study, a new purple leaf cultivar "Zixin" ("ZX") was examined, and its biochemical variation and mechanism of leaf color change were elucidated. The metabolomes of leaves of "ZX" at completely purple, intermediately purple, and completely green stages were analyzed using ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF-MS). Metabolites in the flavonoid biosynthetic pathway remained at high levels in purple leaves, whereas intermediates of porphyrin and chlorophyll metabolism and carotenoid biosynthesis exhibited high levels in green leaves. In addition, fatty acid metabolism was more active in purple leaves, and steroids maintained higher levels in green leaves. Saponin, alcohol, organic acid, and terpenoid-related metabolites also changed significantly during the leaf color change process. Furthermore, the substance changes between "ZX" and "Zijuan" (a thoroughly studied purple-leaf cultivar) were also compared. The leaf color change in "Zijuan" was mainly caused by a decrease in flavonoids/anthocyanins. However, a decrease in flavonoids/anthocyanins, an enhancement of porphyrin, chlorophyll metabolism, carotenoid biosynthesis, and steroids, and a decrease in fatty acids synergistically caused the leaf color change in "ZX". These findings will facilitate comprehensive research on the regulatory mechanisms of leaf color change in purple-leaf tea cultivars. PMID- 29423238 TI - Chromosome-scale scaffolding of the black raspberry (Rubus occidentalis L.) genome based on chromatin interaction data. AB - Black raspberry (Rubus occidentalis L.) is a niche fruit crop valued for its flavor and potential health benefits. The improvement of fruit and cane characteristics via molecular breeding technologies has been hindered by the lack of a high-quality reference genome. The recently released draft genome for black raspberry (ORUS 4115-3) lacks assembly of scaffolds to chromosome scale. We used high-throughput chromatin conformation capture (Hi-C) and Proximity-Guided Assembly (PGA) to cluster and order 9650 out of 11,936 contigs of this draft genome assembly into seven pseudo-chromosomes. The seven pseudo-chromosomes cover ~97.2% of the total contig length (~223.8 Mb). Locating existing genetic markers on the physical map resolved multiple discrepancies in marker order on the genetic map. Centromeric regions were inferred from recombination frequencies of genetic markers, alignment of 303 bp centromeric sequence with the PGA, and heat map showing the physical contact matrix over the entire genome. We demonstrate a high degree of synteny between each of the seven chromosomes of black raspberry and a high-quality reference genome for strawberry (Fragaria vesca L.) assembled using only PacBio long-read sequences. We conclude that PGA is a cost-effective and rapid method of generating chromosome-scale assemblies from Illumina short read sequencing data. PMID- 29423239 TI - In-school adolescents' weight status and blood pressure profile in South-western Nigeria: urban-rural comparison. AB - Background: Obesity is a risk factor for hypertension. The study observed the relationship between adolescent weight status and blood pressure (BP) and the determinants of the BP pattern in urban and rural areas. Methods: This was a cross-sectional study of 1000 randomly selected respondents (500 from urban and 500 from rural areas) who had anthropometry and BP measurements done. The pattern of BP measurements based on the weight status by location was observed. Statistical inferences were drawn via Chi-square and logistic regression. Results: The mean age for all the respondents was 13.73 years +/-2.04 (13.63 +/- 2.05 for urban and 13.82 +/- 2.03 for rural). Systolic and diastolic BP generally increased with increasing respondents' age, with mean pressures higher in urban areas. About 3% were obese, while 7.7% were overweight. The overall prevalence of high BP was 4.1%, with two-thirds coming from urban areas. On logistic regression analysis, the significant variables associated with high BP include being female (AOR 2.067, 95%CI1.007-4.243, p = 0.048), overweight (AOR 5.574, 95%CI 2.501 12.421, p = 0.0001) and obese (AOR 12.437, 95%CI 4.636-33.364, p = 0.0001). Conclusion: High BP was associated with being female, overweight and obesity in both urban and rural areas. Urgent measures are needed to address increasing prevalence of overweight and obesity among adolescents and consequent high blood pressure. PMID- 29423240 TI - Rapid increase of overweight and obesity among primary school-aged children in the Caribbean; high initial BMI is the most significant predictor. AB - Background: To examine predictors of increasing overweight among children in two developing countries. Methods: Primary school children (6-10 y at baseline, n = 336) and their caregivers.Longitudinal data were collected in 2012, with follow up 18 months later. Data on children's height, weight and dietary intake were collected within 8 primary public schools in Trinidad and 7 schools in St. Kitts. Caregivers' demographic and anthropometric data were also collected. Results: At baseline, children's age and sex and caregivers' BMI, age, and marital status and reported dietary intake were similar across all weight groups. The incidence of overweight and obesity among children was 8.8% and 8.1%, respectively. Dietary intake at baseline was not related to becoming overweight or obese. Similarly there were no differences in reported intake among children who became overweight or obese except that they consumed fewer fruits (0.54+/-0.92 vs. 0.98+/-1.66, p = 0.017). Misreporting of energy intake was higher among overweight/obese children as compared to those who were not overweight/obese (27% vs. 17%, p = 0.047). The baseline predictors of increasing BMI (adjusted) of the children were older age, higher baseline BMI z-score and higher height-for-age (HFA) z-score; caregiver BMI, children's energy intake (with adjustment for misreporting) did not predict changes in children's BMI. Conclusions: The increasing prevalence of overweight/obesity among children is a serious problem in the Caribbean. Heavier children are at elevated risk of continued rapid increase in their weight status, pointing to the need for early intervention. PMID- 29423242 TI - A novel loss-of-function mutation in HACE1 is linked to a genetic disorder in a patient from India. AB - A large number of congenital disorders are very rare and localized to rural areas in India, a country that practices both endogamy and consanguinity. Recent advances in genomics can aid in the identification of causative genomic elements when exploring therapeutic interventions and developing neonatal screening to assign novel functions. Here, we report a novel loss-of-function mutation (p.Trp370*) in the HACE1 gene that is associated with a rare congenital neurodevelopmental disorder in a boy from a remote village in southern India. PMID- 29423243 TI - Overview of the Health and Retirement Study and Introduction to the Special Issue. AB - Twenty five years ago, the largest academic behavioral and social science project ever undertaken in the U.S. began: the Health and Retirement Study (HRS). The HRS is an invaluable publicly available dataset for investigating work, aging, and retirement and informing public policy on these issues. This biennial longitudinal study began in 1992 and has studied more than 43,000 individuals and produced almost 4000 journal articles, dissertations, books, book chapters, and reports to date. The purpose of this special issue of Work, Aging and Retirement is to describe the HRS and highlight relevant research that utilizes this rich and complex dataset. First, we briefly describe the background that led to the development of the HRS. Then we summarize key aspects of the study, including its development, sampling, and methodology. Our review of the content of the survey focuses on the aspects of the study most relevant to research on worker aging and retirement. Next, we identify key strengths and important limitations of the study and provide advice to current and future HRS data users. Finally, we summarize the articles in this Special Issue (all of which use data from the HRS) and how they advance our knowledge and understanding of worker aging and retirement. PMID- 29423241 TI - Novel rare variations in genes that regulate developmental change in N-methyl-d aspartate receptor in patients with schizophrenia. AB - The mechanism underlying the vulnerability to developing schizophrenia (SCZ) during adolescence remains elusive. Hypofunction of N-methyl-d-aspartate receptors (NMDARs) has been implicated in the pathophysiology of SCZ. During development, the composition of synaptic NMDARs dramatically changes from NR2B containing NMDARs to NR2A-containing NMDARs through the phosphorylation of NR2B S1480 or Y1472 by CDK5, CSNK2A1, and EphB2, which plays a pivotal role in the maturation of neural circuits. We hypothesized that the dysregulation of developmental change in NMDARs could be involved in the onset of SCZ. Using next generation sequencing, we re-sequenced all the coding regions and splice sites of CDK5, CSNK2A1, and EphB2 in 474 patients with SCZ and 475 healthy controls. Variants on the database for human control subjects of Japanese origin were removed and all the nonsynonymous and nonsense variants were validated using Sanger sequencing. Four novel variants in CDK5 were observed in patients with SCZ but were not observed in controls. The total number of variants, however, was not significantly different between the SCZ and control groups (P=0.062). In silico analyses predicted P271T to be damaging. Further genetic research using a larger sample is required to examine whether CDK5 is involved in the pathophysiology of SCZ. PMID- 29423244 TI - The importance of language. PMID- 29423245 TI - Refractory pain following hip arthroscopy: evaluation and management. AB - With increased knowledge and understanding of hip pathology, hip arthroscopy is rapidly becoming a popular treatment option for young patients with hip pain. Despite improved clinical and radiographic outcomes with arthroscopic treatment, some patients may have ongoing pain and less than satisfactory outcomes. While the reasons leading to failed hip arthroscopy are multifactorial, patient selection, surgical technique and rehabilitation all play a role. Patients with failed hip arthroscopy should undergo a thorough history and physical examination, as well as indicated imaging. A treatment plan should then be developed based on pertinent findings from the workup and in conjunction with the patient. Depending on the etiology of failed hip arthroscopy, management may be nonsurgical or surgical, which may include revision arthroscopic or open surgery, periacetabular osteotomy or joint arthroplasty. Revision surgery may be appropriate in settings including, but not limited to, incompletely treated femoroacetabular impingement, postoperative adhesions, heterotopic ossification, instability, hip dysplasia or advanced degeneration. PMID- 29423246 TI - The role of the ligamentum teres in the adult hip: redundant or relevant? A review. AB - The ligamentum teres (LT) has traditionally been described as a redundant structure with no contribution to hip biomechanics or function. There has been renewed interest in the LT as a source of hip pathology due to the high prevalence of LT pathology observed at the time of hip arthroscopy. The LT acts a secondary stabilizer to supplement the work of the capsular ligaments and works in a sling-like manner to prevent subluxation of the hip at the extremes of motion. The presence of free nerve endings within the LT indicates a definite role in pain generation, with the LT undergoing various mechanical and histological adaptations to hip pathology. PMID- 29423247 TI - Periacetabular osteotomy for developmental hip dysplasia with labral tears: is arthrotomy or arthroscopy required? AB - Patients with developmental dysplasia of the hip (DDH) who undergo periacetabular osteotomy (PAO) often have labral tears. The objective of this retrospective study was to compare PAO alone with PAO combined with arthrotomy or arthroscopy in DDH patients who had a full-thickness labral tear on magnetic resonance imaging. In total, 47 hips in the PAO group (PAO) were compared with 60 hips in the PAO with concomitant arthrotomy or arthroscopy (PAO-A) with respect to Hip Disability and Osteoarthritis Outcome Score (HOOS), modified Harris Hip Score (mHHS), Visual Analog Scale (VAS), clinical and radiographic outcomes at a median of 29 months. Reoperation rate and complications were compared between two groups of treatment. The PAO group was younger than the PAO-A group (25.2 +/- 9.7 versus 31.3 +/- 8.3). The PAO group was more likely to have worse dysplasia: lateral center edge angle (7.6 degrees +/-9.63 degrees versus 10.8 degrees +/-6.85 degrees ) and anterior center edge angle (4 degrees +/-12.92 degrees versus 10.8 degrees +/-9.92 degrees ). The PAO group had a higher preoperative mHHS (65.2 +/- 15.3 versus 57.8 +/- 14.8) and HOOS (66.3 +/- 17.5 versus 55.8 +/- 20.1). There were no significant differences in final functional outcome scores across treatment groups: mHHS (PAO; 86.8 +/- 12.4 versus PAO-A, 83.3 +/- 17.2), HOOS (86.5 +/- 13.3 versus 82.5 +/- 16.8) and VAS (2.5 +/- 2.8 versus 2.5 +/- 3.1). There was no difference in reoperation rate between two groups (6.4% versus 11.6%, P = 0.51). The overall complication rate was lower in the PAO group (26% versus 68%), but major complications were comparable. On the basis of our data, we were not able to conclusively demonstrate a clear benefit for the routine treatment of all labral tears; however, arthrotomy or arthroscopy may play a role in some conditions. PMID- 29423248 TI - Capsular augmentation in Colonna arthroplasty for the management of chronic hip dislocation. AB - Colonna capsular arthroplasty represents an option for the management of chronic hip dislocation in young patients with dysplasia. In the appropriate patient, modern capsular arthroplasty procedures may provide an opportunity for hip preservation in patients with preserved femoral head cartilage and not appropriate for total hip arthroplasty. Here, we review our experience with surgical dislocation of the hip and capsular arthroplasty in a 27-year-old female with congenital hip dysplasia and chronic superior hip dislocation. Due to inadequate native capsular tissue, a decellularized dermal allograft was used for interposition and capsular arthroplasty augmentation. The femoral head with preserved articular cartilage was reduced into the enlarged native acetabulum using a parachute technique to hold the allograft in position. Post-operatively, the patient was placed in a hip abduction brace and made non-weight bearing for six weeks. A conservative physical therapy protocol was implemented to allow gradual increase in weight bearing and range of motion over the first 12 weeks post-operatively. PMID- 29423249 TI - Muscle-tendon-related pain in 100 patients with hip dysplasia: prevalence and associations with self-reported hip disability and muscle strength. AB - The primary aim was to identify muscle-tendon-related pain in 100 patients with hip dysplasia. The secondary aim was to test whether muscle-tendon-related pain is associated with self-reported hip disability and muscle strength in patient with hip dysplasia. One hundred patients (17 men) with a mean age of 29 years (SD 9) were included. Clinical entity approach was carried out to identify muscle tendon-related pain. Associations between muscle-tendon-related pain and self reported hip disability and muscle strength were tested with multiple regression analysis, including adjustments for age and gender. Self-reported hip disability was recorded with the Copenhagen Hip and Groin Outcome Score (HAGOS), and muscle strength was assessed with a handheld dynamometer. Iliopsoas- and abductor related pain were most prevalent with prevalences of 56% (CI 46; 66) and 42% (CI 32; 52), respectively. Adductor-, hamstrings- and rectus abdominis-related pain were less common. There was a significant inverse linear association between muscle-tendon-related pain and self-reported hip disability ranging from -3.35 to - 7.51 HAGOS points in the adjusted analysis (P < 0.05). Besides the association between muscle-tendon-related pain and hip extension a significant inverse linear association between muscle-tendon-related pain and muscle strength was found ranging from -0.11 to - 0.12 Nm/kg in the adjusted analysis (P < 0.05). Muscle tendon-related pain exists in about half of patients with hip dysplasia with a high prevalence of muscle-tendon-related pain in the iliopsoas and the hip abductors and affects patients' self-reported hip disability and muscle strength negatively. PMID- 29423250 TI - Labral augmentation with ligamentum capitis femoris: presentation of a new technique and preliminary results. AB - Preservation of an intact labrum and reconstruction of a deficient or worn acetabular labrum are accepted techniques in modern hip surgery. If the remaining labrum is very thin, its intact tip can be preserved and its volume restored with a ligamentum teres graft. Technique and preliminary results of this augmentation technique are presented. Labral augmentation was performed in 16 hips (11 rights) in 16 patients (7 males, mean age 29 years) during surgical dislocation for treatment of femoroacetabular impingement. The acetabular index, lateral center edge angle, asphericity angle and acetabular retroversion index were determined on preoperative X-rays and magnetic resonance imaging. The pre- and postoperative Merle d'Aubigne and Postel score (MdA) was calculated and the Oxford Hip Score (OHS) obtained after 1 year. There were seven Grade 1 and nine Grade 0 hips (Tonnis classification). Mean lateral center edge was 29 degrees . The mean acetabular index was 1.85 degrees . Mean asphericity angle was 62.5 degrees . Mean acetabular retroversion index was 23.4%. Mean MdA improved from 14.5 preoperatively to 17 at 1 year (P < 0.0001). Mean OHS after 1 year was 42. Previous surgery was a risk factor for inferior results: OHS was 44.5 in hips without versus 26 in hips with previous surgery. Mean MdA improved from 15 to 17.5 in patients without previous surgery versus 14 to 16 for the group with previous surgery. Augmentation of the labrum using ligamentum teres shows good clinical results after 1 year. Patients with previous hip surgery had inferior results. PMID- 29423251 TI - Outcomes of intra-articular corticosteroid injections for adolescents with hip pain. AB - Intra-articular injection of corticosteroid and anesthetic (CSI) is a useful diagnostic tool for hip pain secondary to labral tears or femoroacetabular impingement (FAI). However, the effectiveness of CSI as a stand-alone treatment for hip pain in adolescents is unknown. The purpose of this study is to evaluate the use of CSI for the treatment of hip pain and determine factors that may affect outcomes after injection. Retrospective analysis of 18 patients and 19 hips that underwent fluoroscopic guided hip injection for the treatment of pain at a single institution from 2012 to 2015 was carried out in this study. Mean age at the time of injection was 15.1 years (range 13-17) with mean follow-up of 29.4 months. Fifty-two percent (10/19 hips) went on to surgery after the injection. Average time to surgical conversion was 12.8 months after CSI. Cam or pincer morphologies were present in 90% (9/10 hips) of the operative group. Patients with FAI were more likely to need surgery than patients without bony abnormalities (RR= 10, 95% CI 1.6-64.2, P = 0.0001). There was no difference in the presence of labral tears in the operative and non-operative groups (100% versus 89%, P = 0.47). For adolescents without bony abnormalities, 90% improved with CSI alone and did not require further treatment within 2.4 years. Fluoroscopic guided corticosteroid hip injection may have limited efficacy for the treatment of hip pain secondary to FAI in adolescents. However, for patients without osseous deformity, CSI may offer prolonged improvement of symptoms even in the presence of labral tears. PMID- 29423252 TI - Extracapsular local infiltration analgesia in hip arthroscopy: a retrospective study. AB - Many hip arthroscopy patients experience significant pain in the immediate postoperative period. Although peripheral nerve blocks have demonstrated efficacy in alleviating some of this pain, they come with significant costs. Local infiltration analgesia (LIA) may be a significantly cheaper and efficacious treatment modality. Although LIA has been well studied in hip and knee arthroplasty, its efficacy in hip arthroscopy is unclear. The purpose of this retrospective study is to determine the efficacy of a single extracapsular injection of bupivacaine-epinephrine during hip arthroscopy in reducing the rate of elective postoperative femoral nerve blocks. A retrospective review of 100 consecutive patients who underwent primary hip arthroscopy at a single medical center was performed. The control group consisted of 50 patients before the implementation of the current LIA protocol, whereas another 50 patients received a 20-ml extracapsular injection of 0.25% bupivacaine-epinephrine under direct arthroscopic visualization after capsular closure. In the post-anesthesia care unit (PACU), patients were offered a femoral nerve block for uncontrolled pain. The rate of femoral nerve block, and total opioid consumption, was compared between groups. The proportion of patients receiving elective femoral nerve blocks was significantly less in the LIA group (34%) as compared with the control group (56%; P = 0.027). There was no significant difference in total PACU opioid consumption between groups (P = 0.740). The decreased utilization of postoperative nerve blocks observed in the LIA group suggests that LIA may improve postoperative pain management and should be considered as a potentially cost-effective tool in pain management in hip arthroscopy patients. Level of Evidence: III. PMID- 29423253 TI - Clinical outcomes of patients with symptomatic acetabular rim fractures after arthroscopic FAI treatment. AB - This study aims to investigate the influence of the acetabular rim fractures on outcomes of hip arthroscopy at minimum 2-year follow-up. Between January 2009 and August 2012, data were prospectively collected on all patients undergoing hip arthroscopy. Anatomic findings, including presence of rim fractures, were recorded intraoperatively. Patients were assessed preoperatively and at 3 months, 1 year and minimum 2 years postoperatively with four patient-reported outcome measures: modified Harris Hip Score, Non-Arthritic Hip Score, Hip Outcome Score Activities of Daily Living and Hip Outcome Score-Sport Specific Subscales. Pain was estimated using a visual analog scale. Satisfaction was measured on a scale from 0 to 10. Patients with rim fractures were identified and retrospectively matched to a control group based on gender, BMI category, and age at surgery within 3 years and compared in terms of demographic factors, intraoperative findings, procedures and outcomes. Twenty-one patients with rim fractures were matched to a control group of 21 patients with symptomatic femoroacetabular impingement without rim fractures. No significant differences were detected with respect to demographic characteristics, surgical procedures (besides the removal of rim fractures), or in terms of preoperative, postoperative, or improvement in patient-reported outcome scores and satisfaction. The presence or absence of an acetabular rim fracture does not significantly influence clinical outcomes at minimum 2-year follow-up after hip arthroscopy. Case-control study design is used in this study. PMID- 29423254 TI - Outcomes following arthroscopic hip segmental labral reconstruction using autologous capsule tissue or indirect head of the rectus tendon. AB - The purpose of this study was to determine the outcomes following segmental labral reconstruction (labral defects measuring <1 cm) using a segment of capsular tissue or a segment of the indirect head of rectus femoris tendon. Eleven patients (five females and six males) underwent segmental labral reconstruction using a segment of capsule (eight patients) or indirect head of rectus tendon (three patients) by a single surgeon from March 2005 to October 2012. The average age of the patients was 35 years old (range, 20-51 years). Data collected included the pre- and post-operative Hip Outcome Score (HOS-ADL and HOS SS), the modified Harris Hip Score and patient satisfaction rate (1 = unsatisfied, 10 = very satisfied), complications, necessity of revision hip arthroscopy and conversion to total hip arthroplasty. Average follow-up time was at 62 months (range, 9-120 months). No patient required revision hip arthroscopy or converted to total hip arthroplasty. The HOS-ADL significantly improved from 73 to 89 (P < 0.05). The HOS-SS showed significant improvement from 52 to 79 and the modified Harris Hip Score significantly improved from 66 to 89. Median patient satisfaction rate was 9 out of 10 (range, 3-10). In a small sample, the arthroscopic hip segmental labral reconstruction showed significant improvement in patient-reported outcomes. This treatment provides an option in cases of small labrum defects (<1 cm) or deficits in patients while providing improved function and high patient satisfaction. PMID- 29423255 TI - Labral cuff refixation in the hip: rationale and operative technique for preserving the chondrolabral interface for labral repair: a case series. AB - Arthroscopic labral 'takedown' and refixation is utilized to permit adequate visualization and resection of the acetabular rim deformity, in patients with pincer or mixed femoroacetabular impingement. Deficiencies exist in present techniques, which include disruption of vital anatomical support and vascular structures to the labrum and chondrolabral junction, drill or anchor articular penetration risk, bunching, elevation and instability of the labrum. A new operative technique is described which preserves the important chondrolabral interface, accurately restoring the 'flap seal' of the acetabular labrum while minimizing vascular disruption and reducing the risk of drill and anchor penetration. A prospective series of 123 consecutive cases of pincer or mixed femoroacetabular impingement, treated with arthroscopic labral cuff refixation and preservation of the chondrolabral interface, is reported; operative technique and 2-year outcomes are presented. PMID- 29423257 TI - What the papers say. PMID- 29423256 TI - Clinical presentation of intra-articular osteoid osteoma of the hip and preliminary outcomes after arthroscopic resection: a case series. AB - Intra-articular osteoid osteoma (IAOO) of the hip is a relatively rare diagnosis, but one that can closely mimic symptomatic presentation of femoroacetabular impingement (FAI). Although there are multiple case reports of osteoid osteoma (OO) in the hip, we present the largest case series of hip IAOO treated with hip arthroscopy and discuss limited patient-reported outcomes after treatment with hip arthroscopy. We retrospectively identified patients diagnosed with IAOO of the hip with confirmatory computed tomography, magnetic resonance imaging or biopsy diagnoses of OO. We analyzed lesion location, main presenting symptoms, symptom duration and treatment undertaken. For the patients who underwent hip arthroscopy for treatment of their IAOO, we reviewed patient-reported outcome scores when available. Forty patients with confirmed IAOO were identified. Thirteen underwent excision with hip arthroscopy. The most common presenting symptom was groin pain. In limited patients who had pre- and post-operative outcome scores, we found significant improvements in modified Harris Hip Score (mHHS), Hip Outcome Score-Activity of Daily Living (HOS-ADL) and international Hip Outcomes Tool (iHot33) scores. Compared with patients undergoing hip arthroscopy for FAI alone, baseline mHHS, HOS-ADL, Hip Outcome Score-Sport Specific Subscale and iHot33 scores were almost identical. We found that the presenting symptoms of hip IAOO closely mimic symptomatic FAI, including groin pain and anterior hip pain, so it is important to keep IAOO of the hip in the differential diagnosis of hip pain. Based on our experience, arthroscopy can be an effective treatment option for excision of intra-articular OO and is especially effective in patients with concomitant FAI in treating both pathologies. PMID- 29423258 TI - An intervention for pulmonary rehabilitators to develop a social identity for patients attending exercise rehabilitation: a feasibility and pilot randomised control trial protocol. AB - Background: Chronic obstructive pulmonary disease (COPD) is a degenerative condition that can impair health-related quality of life (HRQoL). A number of self-management interventions, employing a variety of behavioural change techniques (BCTs), have been adopted to improve HRQoL for COPD patients. However, a lack of attention has been given to group management interventions with an emphasis on incorporating BCTs into rehabilitators' practice. This study aims to pilot and feasibly explore a social identity group management intervention, delivered by COPD rehabilitation staff to patients attending exercise pulmonary rehabilitation. Doing so will help inform the plausibility of the intervention before conducting a full trial to evaluate its effectiveness to improve HRQoL. Methods: This is a two-centre, randomised cross-over controlled trial. Two pulmonary rehabilitation centres based in the UK will be randomly allocated to two treatment arms (standard care and intervention). Outcome measurements relating to HRQoL and social identity will be completed pre- and post-exercise rehabilitation. Focus group interviews will be conducted at the end of exercise rehabilitation to capture participants' contextualised experiences of the intervention. COPD rehabilitators will undertake semi-structured interviews at the end of the trial to garner their holistic perspectives of intervention fidelity and implementation. Discussion: This is the first study to adopt a social identity approach to develop a rehabilitator-led, group management intervention for COPD patients attending exercise pulmonary rehabilitation. The results of this study will provide evidence for the feasibility and sample size requirements to inform a larger study, which can ascertain the intervention's effectiveness for improving HRQoL for COPD patients. Trial registration: ClinicalTrials.gov NCT02288039. Date 31 October 2014. PMID- 29423259 TI - Comprehensive geriatric assessment pilot of a randomized control study in a Swedish acute hospital: a feasibility study. AB - Background: Comprehensive geriatric assessment (CGA) represent an important component of geriatric acute hospital care for frail older people, secured by a multidisciplinary team who addresses the multiple needs of physical health, functional ability, psychological state, cognition and social status. The primary objective of the pilot study was to determine feasibility for recruitment and retention rates. Secondary objectives were to establish proof of principle that CGA has the potential to increase patient safety. Methods: The CGA pilot took place at a University hospital in Western Sweden, from March to November 2016, with data analyses in March 2017. Participants were frail people aged 75 and older, who required an acute admission to hospital. Participants were recruited and randomized in the emergency room. The intervention group received CGA, a person-centered multidisciplinary team addressing health, participation, and safety. The control group received usual care. The main objective measured the recruitment procedure and retention rates. Secondary objectives were also collected regarding services received on the ward including discharge plan, care plan meeting and hospital risk assessments including risk for falls, nutrition, decubitus ulcers, and activities of daily living status. Result: Participants were recruited from the emergency department, over 32 weeks. Thirty participants were approached and 100% (30/30) were included and randomized, and 100% (30/30) met the inclusion criteria. Sixteen participants were included in the intervention and 14 participants were included in the control. At baseline, 100% (16/16) intervention and 100% (14/14) control completed the data collection. A positive propensity towards the secondary objectives for the intervention was also evidenced, as this group received more care assessments. There was an average difference between the intervention and control in occupational therapy assessment - 0.80 [95% CI 1.06, - 0.57], occupational therapy assistive devices - 0.73 [95% CI 1.00, - 0.47], discharge planning -0.21 [95% CI 0.43, 0.00] and care planning meeting 0.36 [95% CI-1.70, -0.02]. Controlling for documented risk assessments, the intervention had for falls - 0.94 [95% CI 1.08, - 0.08], nutrition - 0.87 [95% CI 1.06, - 0.67], decubitus ulcers - 0.94 [95% CI 1.08, - 0.80], and ADL status - 0.80 [95% CI 1.04, - 0.57]. Conclusion: The CGA pilot was feasible and proof that the intervention increased safety justifies carrying forward to a large-scale study. Trial registration: Clinical Trials ID: NCT02773914. Registered 16 May 2016. PMID- 29423260 TI - A heel-strike real-time auditory feedback device to promote motor learning in children who have cerebral palsy: a pilot study to test device accuracy and feasibility to use a music and dance-based learning paradigm. AB - Background: Cerebral palsy (CP) is a developmental disorder of movement and posture that occurs due to damage to the developing nervous system. As part of therapy, wearable sensors that trigger interactive feedback may provide multi sensory guidance and motivation. A prototype of a heel-strike real-time feedback system has been developed which records the number of heel strikes during gait and indicates successful heel contact through real-time auditory feedback. The first aim of this feasibility study was to test the prototype accuracy.Since the end user for this device is a child, the device should be esthetically appealing and sufficiently motivating for children to perform repetitive challenging therapeutic movements. The second aim of this study was to collect feedback from the subjects with regard to the device usability and understand if the bell sound used as feedback used was motivating enough for children to continue using the prototype. This would help us in developing the next generation of the device. Methods: The prototype was tested with typically developing children and children who have CP. The accuracy in detecting heel strikes was calculated. As part of the study, the subjects were also asked questions to test the device compliance and acceptability of the musical beats with the pediatric population. Results: The device accuracy in identifying heel strikes is 97.44% (95% CI 96.31, 98.88%). The subjects did not show any hesitation to put on the device and the sound feedback motivated them to move. Based on this pilot study, a minimum age limit of 5 years is appropriate and the intervention study should be conducted for no more than 30 min per week. Conclusions: The pilot study showed that a main study can be conducted to test auditory feedback as an intervention to promote motor learning in children who have cerebral palsy. No adverse event or safety issues were reported in the feasibility study. PMID- 29423261 TI - Prognosis of patients with apparent treatment-resistant hypertension-a feasibility study. AB - Background: Most cases of hypertension can be effectively treated with lifestyle changes together with medications, but within this population lies a group with more difficult to treat hypertension-those with apparent treatment-resistant hypertension (aTRH). The American Heart Association and the UK National Institute for Health and Care Excellence have both highlighted the need for further research into the prognosis of patients with resistant hypertension, both apparent and true. Methods: In 16 practices affiliated to a university research network, 646 patients had been identified with apparent treatment-resistant hypertension. To inform a planned full cohort study of these patients, we conducted a feasibility study within three practices to determine participation of practices and patients, availability of outcome measures and data collection times. Results: All three practices fully participated and 205/210 (98%) patients were followed up for a median of 23 months. Thirty-five outcome events of interest occurred-the most common was the new onset of retinopathy (9 cases). Eight percent (17/210) had the main composite outcome of death or serious incident cardiovascular event. Of the six patients who died, identification of cause of death was possible from practice records in five; the national General Register Office was successfully used for the final patient. There were 123 admissions, both day and overnight, recorded in 94 individual patients. Average manual systolic blood pressure measurements improved from baseline by 5 mmHg to 138 (SD 19) mmHg; diastolic remained the same at 75 (SD 12) mmHg. Average eGFR increased from 58.8 (SD17.4) to 66 (SD19.7) mls/min/1.73m2. The average time for data collection per patient was 12 mins. Conclusions: This study demonstrates that the proposed methodology for a full cohort study within general practice of patients with apparent treatment hypertension is both acceptable to practices and feasible. An adequately powered subsequent follow-up study of the entire cohort appears possible. PMID- 29423262 TI - A fully absorbable biomimetic polymeric micelle loaded with cisplatin as drug carrier for cancer therapy. AB - cis-dichlorodiammineplatinum(II) (CDDP)-loaded polymeric micelles for cancer therapy have been developed to reduce the serious side effects of cisplatin CDDP. Herein, polymeric micelles incorporated with cisplatin are prepared based on the complexation between CDDP and hydrophilic poly (L-glutamic acid)-b-poly (2 methacryloyloxyethyl phosphorylcholine) (PLG-b-PMPC) diblock copolymers. These CDDP-loaded micelles possess an average size of 91 nm with narrow distribution, providing remarkable stability in media containing proteins. The release of CDDP from the micelles is faster at pH 5.0 and pH 6.0 than that at pH 7.4 and in a sustained manner without initial burst release. In addition, there is almost no difference in cellular uptake between these CDDP-loaded micelles and free CDDP. Moreover, in vitro cytotoxicity test shows they possess high efficacy to kill 4T1 cells as compared with free drug. Thus, PLG-b-PMPC copolymer might be a promising carrier for CDDP incorporating in cancer therapy. PMID- 29423263 TI - Evaluation of repeated exposure systemic toxicity test of PVC with new plasticizer on rats via dual parenteral routes. AB - Systemic toxicity caused by repeated exposure to both polar and nonpolar leachables of di(2-ethylhexyl)-1,2-cyclohexane plasticized polyvinyl chloride (PVC) was evaluated with dual routes of parenteral administration method on rats in the study. Experimental group and control group were designed by researchers. Tail intravenous injection with 0.9% sodium chloride injection extracts and intraperitoneal injection with corn oil extracts were conducted to the experimental rats while tail intravenous injection with 0.9% sodium chloride Injection and intraperitoneal injection with corn oil were conducted to the control rats. After 14 days, blood specimens were collected for clinical pathology (hematology and clinical chemistry) analysis. Selected organs were weighed and a histopathological examination was conducted. As a result, compared with the control animals, there were no toxicity-related changes on the parameters above. The results show that the rats do not show obvious systemic toxicity reaction caused by repeated exposure with dual routes of parenteral administration method on rats after administration with both polar and nonpolar exacts of di(2-ethylhexyl)-1,2-cyclohexane plasticized PVC simultaneously up for 14 days. PMID- 29423264 TI - A biomimetic and pH-sensitive polymeric micelle as carrier for paclitaxel delivery. AB - As nano-scale drug delivery systems, smart micelles that are sensitive to specific biological environment and allowed for target site-triggered drug release by reversible stabilization of micelle structure are attractive. In this work, a biocompatible and pH-sensitive copolymer is synthesized through bridging poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC) block and poly (D, L lactide) (PLA) block by a benzoyl imine linkage (Blink). Biomimetic micelles with excellent biocompatibility based on such PLA-Blink-PMPC copolymer are prepared as carriers for paclitaxel (PTX) delivery. Due to the rapid breakage of the benzoyl imine linkage under acidic condition, the micelle structure is disrupted with accelerated PTX release. Such pH-sensitive triggered drug release behavior in synchronization with acidic conditions at tumor site is helpful for improving the utilization of drug and facilitating antitumor efficacy. These micelles can be used as promising drug delivery systems due to their biocompatible and smart properties. PMID- 29423265 TI - A high-throughput study on endothelial cell adhesion and growth mediated by adsorbed serum protein via signaling pathway PCR array. AB - The purpose of this paper is to utilize the signaling pathway polymerase chain reaction (PCR) arrays to investigate the activation of two important biological signaling pathways in endothelial cell adhesion and growth mediated by adsorbed serum protein on the surface of bare and titanium nitride (TiN)-coated nickel titanium (NiTi) alloys. First, the endothelial cells were cultured on the bare and TiN-coated NiTi alloys and chitosan films as control for 4 h and 24 h, respectively. Then, the total RNA of the cells was collected and the PCR arrays were performed. After that, the differentially expressed genes in the transforming growth factor beta (TGF-beta) signaling pathway and the regulation of actin cytoskeleton pathway were screened out; and the further bioinformatics analyses were performed. The results showed that both TGF-beta signaling pathway and regulation of actin cytoskeleton pathway were activated in the cells after 4 h and 24 h culturing on the surface of bare and TiN-coated NiTi alloys compared to the chitosan group. The activated TGF-beta signaling pathway promoted cell adhesion; the activated regulation of actin cytoskeleton pathway promoted cell adhesion, spreading, growth and motility. In addition, the activation of both pathways was much stronger in the cells cultured for 24 h versus 4 h, which indicated that cell adhesion and growth became more favorable with longer time on the surface of two NiTi alloy materials. PMID- 29423266 TI - Promoting proliferation and differentiation of BMSCs by green tea polyphenols functionalized porous calcium phosphate. AB - In this article, we proposed a facile protocol to functionalize porous calcium phosphate ceramics (PCPC) using dietary tea polyphenols (TP). TP molecules was attracted and anchored by Ca2+ ions from the surface of CPC. These TP molecules modulated the nucleation and crystallization of calcium phosphate nanorods assemblies on the surface of PCPC. Our results prove that these calcium phosphate nanorods assemblies accompanies functional groups of TP make PCPC/TP effectively promote proliferation and differentiation of bone mesenchymal stem cells (BMSCs). We inferred that these calcium phosphate nanorods assemblies might change the surface microenvironment of PCPC, which is critical to promote the proliferation and differentiation of BMSCs. Compared with naked PCPC, PCPC/TP obviously increased BMP2, ErK/MAPK and JNK/MAPK level and mineralization capacity of cells (ALP level). PMID- 29423268 TI - Interaction between body mass index and serum uric acid in relation to blood pressure in community-dwelling Japanese men. AB - Background: Few data is available on the association between body mass index (BMI), serum uric acid (SUA) levels and blood pressure (BP) categories in the disease continuum, when efforts for its prevention may be applicable. Methods: We performed a cross-sectional study to examine the association between BMI, SUA and BP in a community-dwelling sample of Japanese men. Individuals not on antihypertensive and uric acid lowering medications, and aged 50 to 90 years [817men aged 66 +/- 9 (mean +/- standard deviation) years] were recruited for the survey during a community based annual medical check-up. The main outcome was the presence of prehypertension [systolic BP (SBP) 120-139 mmHg and/or diastolic BP (DBP) 80-89 mmHg] and hypertension [SBP >= 140 and /or DBP >= 90]. Results: In participants with a BMI of < 21.0 kg/m2, increased SUA levels were positively associated with SBP and DBP, but in those with a BMI of >= 21.0 kg/m2, increased SUA levels were negatively associated with SBP and DBP. The interaction between BMI and SUA as well as BMI and SUA was a significant and independent determinant for both SBP (beta = - 1.125, p = 0.001) and DBP (beta = - 0.995, p = 0.005). Among participants, the respective prevalence of normotension, prehypertension, and hypertension was 19.5% and 53.7%, and 19.8%. The prevalence of normotension and prehypertension decreased with increasing BMI and the prevalence of hypertension increased with increasing BMI. In participants with a BMI >= 21.0 kg/m2, the adjusted-odds ratio of SUA for hypertension was 0.75 (95% CI, 0.59 0.95) compared with normotension and 0.82 (0.70-0.96) compared with prehypertension. In those with a BMI of < 21.0 kg/m2, these associations were not shown. Conclusion: BMI may modify the association between SUA and blood pressure status among community-dwelling men. PMID- 29423267 TI - The material and biological characteristics of osteoinductive calcium phosphate ceramics. AB - The discovery of osteoinductivity of calcium phosphate (Ca-P) ceramics has set an enduring paradigm of conferring biological regenerative activity to materials with carefully designed structural characteristics. The unique phase composition and porous structural features of osteoinductive Ca-P ceramics allow it to interact with signaling molecules and extracellular matrices in the host system, creating a local environment conducive to new bone formation. Mounting evidence now indicate that the osteoinductive activity of Ca-P ceramics is linked to their physicochemical and three-dimensional structural properties. Inspired by this conceptual breakthrough, many laboratories have shown that other materials can be also enticed to join the rank of tissue-inducing biomaterials, and besides the bones, other tissues such as cartilage, nerves and blood vessels were also regenerated with the assistance of biomaterials. Here, we give a brief historical recount about the discovery of the osteoinductivity of Ca-P ceramics, summarize the underlying material factors and biological characteristics, and discuss the mechanism of osteoinduction concerning protein adsorption, and the interaction with different types of cells, and the involvement of the vascular and immune systems. PMID- 29423269 TI - TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling. AB - The mammalian target of rapamycin (mTOR) pathway is commonly activated in human cancers. The activity of mTOR complex 1 (mTORC1) signaling is supported by the intracellular positioning of cellular compartments and vesicle trafficking, regulated by Rab GTPases. Here we showed that tuftelin 1 (TUFT1) was involved in the activation of mTORC1 through modulating the Rab GTPase-regulated process. TUFT1 promoted tumor growth and metastasis. Consistently, the expression of TUFT1 correlated with poor prognosis in lung, breast and gastric cancers. Mechanistically, TUFT1 physically interacted with RABGAP1, thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promoted mTORC1 signaling. In addition, expression of TUFT1 predicted sensitivity to perifosine, an alkylphospholipid that alters the composition of lipid rafts. Perifosine treatment altered the positioning and trafficking of cellular compartments to inhibit mTORC1. Our observations indicate that TUFT1 is a key regulator of the mTORC1 pathway and suggest that it is a promising therapeutic target or a biomarker for tumor progression. PMID- 29423271 TI - Dual roles of endothelial FGF-2-FGFR1-PDGF-BB and perivascular FGF-2-FGFR2 PDGFRbeta signaling pathways in tumor vascular remodeling. AB - Perivascular cells are important cellular components in the tumor microenvironment (TME) and they modulate vascular integrity, remodeling, stability, and functions. Here we show using mice models that FGF-2 is a potent pericyte-stimulating factor in tumors. Mechanistically, FGF-2 binds to FGFR2 to stimulate pericyte proliferation and orchestrates the PDGFRbeta signaling for vascular recruitment. FGF-2 sensitizes the PDGFRbeta signaling through increasing PDGFRbeta levels in pericytes. To ensure activation of PDGFRbeta, the FGF-2-FGFR1 siganling induces PDGF-BB and PDGF-DD, two ligands for PDGFRbeta, in angiogenic endothelial cells. Thus, FGF-2 directly and indirectly stimulates pericyte proliferation and recruitment by modulating the PDGF-PDGFRbeta signaling. Our study identifies a novel mechanism by which the FGF-2 and PDGF-BB collaboratively modulate perivascular cell coverage in tumor vessels, thus providing mechanistic insights of pericyte-endothelial cell interactions in TME and conceptual implications for treatment of cancers and other diseases by targeting the FGF-2 FGFR-pericyte axis. PMID- 29423270 TI - ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells. AB - Loss of organelle homeostasis is a hallmark of aging. However, it remains elusive how this occurs at gene expression level. Here, we report that human mesenchymal stem cell (hMSC) aging is associated with dysfunction of double-membrane organelles and downregulation of transcription factor ATF6. CRISPR/Cas9-mediated inactivation of ATF6 in hMSCs, not in human embryonic stem cells and human adipocytes, results in premature cellular aging, characteristic of loss of endomembrane homeostasis. Transcriptomic analyses uncover cell type-specific constitutive and stress-induced ATF6-regulated genes implicated in various layers of organelles' homeostasis regulation. FOS was characterized as a constitutive ATF6 responsive gene, downregulation of which contributes to hMSC aging. Our study unravels the first ATF6-regulated gene expression network related to homeostatic regulation of membrane organelles, and provides novel mechanistic insights into aging-associated attrition of human stem cells. PMID- 29423272 TI - Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates. AB - Somatic or de novo mutations of Additional sex combs-like 1 (ASXL1) frequently occur in patients with myeloid malignancies or Bohring-Opitz syndrome, respectively. We have reported that global loss of Asxl1 leads to the development of myeloid malignancies and impairs bone marrow stromal cell (BMSC) fates in mice. However, the impact of Asxl1 deletion in the BM niche on hematopoiesis remains unclear. Here, we showed that BMSCs derived from chronic myelomonocytic leukemia patients had reduced expression of ASXL1, which impaired the maintaining cord blood CD34+ cell colony-forming capacity with a myeloid differentiation bias. Furthermore, Asxl1 deletion in the mouse BMSCs altered hematopoietic stem and progenitor cell (HSC/HPC) pool and a preferential myeloid lineage increment. Immunoprecipitation and ChIP-seq analyses demonstrated a novel interaction of ASXL1 with the core subunits of RNA polymerase II (RNAPII) complex. Convergent analyses of RNA-seq and ChIP-seq data revealed that loss of Asxl1 deregulated RNAPII transcriptional function and altered the expression of genes critical for HSC/HPC maintenance, such as Vcam1. Altogether, our study provides a mechanistic insight into the function of ASXL1 in the niche to maintain normal hematopoiesis; and ASXL1 alteration in, at least, a subset of the niche cells induces myeloid differentiation bias, thus, contributes the progression of myeloid malignancies. PMID- 29423273 TI - CD24-p53 axis suppresses diethylnitrosamine-induced hepatocellular carcinogenesis by sustaining intrahepatic macrophages. AB - It is generally assumed that inflammation following diethylnitrosamine (DEN) treatment promotes development of hepatocellular carcinoma (HCC) through the activity of intrahepatic macrophages. However, the tumor-promoting function of macrophages in the model has not been confirmed by either macrophage depletion or selective gene depletion in macrophages. Here we show that targeted mutation of Cd24 dramatically increased HCC burden while reducing intrahepatic macrophages and DEN-induced hepatocyte apoptosis. Depletion of macrophages also increased HCC burden and reduced hepatocyte apoptosis, thus establishing macrophages as an innate effector recognizing DEN-induced damaged hepatocytes. Mechanistically, Cd24 deficiency increased the levels of p53 in macrophages, resulting in their depletion in Cd24-/- mice following DEN treatment. These data demonstrate that the Cd24-p53 axis maintains intrahepatic macrophages, which can remove hepatocytes with DNA damage. Our data establish a critical role for macrophages in suppressing HCC development and call for an appraisal of the current dogma that intrahepatic macrophages promote HCC development. PMID- 29423274 TI - A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection. AB - Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease-disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy. PMID- 29423276 TI - Finding and engaging patients and the public to work collaboratively on an acute infection microbiology research public panel. AB - Plain English summary: In 2015 a microbiology team in Bristol joined a European research project that aims to develop new antibiotics to fight drug resistant infections. The microbiology team were convinced of the benefits of patient and public involvement, but had found it difficult to find former patients to work with on earlier microbiology research. This paper describes how the team overcame this challenge to successfully recruit a PPI panel to develop PPI within the European project.The advice from people with experience in public involvement was to decide what criteria were desirable for panel membership, think about what the work of the panel might involve and how long the project will go on. The team decided that experience of suffering a serious acute infection would qualify people to comment on this project. Next, the team needed to identify ways of finding people to join the PPI panel.The microbiology research team tried different ways to approach potential panel members. These included distributing flyers at public research events, sending emails to potentially interested people, posting a message on the hospital Facebook page and approaching eligible people known to the team. A direct approach was the most successful method - either by email, mail or in person. Ultimately 16 people were selected to form the panel. Key factors for success were planning what the work of the panel might be, perseverance despite early lack of success, and one person having overall responsibility for setting up the panel, with the support of the whole team. Abstract: Background In 2015 the microbiology research team became involved in a large European programme of research aiming to bring new antimicrobial drugs onto the market to combat the increasing problem of multi-drug resistant infection. With the purpose of developing patient and public involvement (PPI) in this project, the team decided to recruit a PPI panel to work with. The microbiology team had previously worked with a PPI panel on other research, but had found it difficult to recruit members. Methods Steps taken to recruit the panel were as follows:Advice was sought from people experienced in co-ordinating public involvement in research.One person in the team had overall responsibility but the whole research team was committed and met regularly.Two of the team undertook training in group facilitation and connecting with the public.Decisions were made about the criteria for inclusion into the panel, what tasks we envisaged for the panel, the length of and frequency of meetings.Advertising the involvement opportunity through flyers, social media, emails and direct contact with possible panel recruits known to the research team.Relevant documents such as a Role Profile and expression of interest form were drafted.An initial public meeting was planned for all who had shown interest in the panel.The expression of interest form was used for us to select as broad a group as possible.. Results Two out of three people who were approached directly and known by team members expressed interest in joining the panel (66%). Three out of seven members of a former panel were next (43%), then 10 out of 25 spinal infection clinic patients (40%), and finally 12 people responded to an email sent to 1261 foundation trust members (1%). No-one who was approached by indirect methods e.g. flyers or advertising on Facebook, expressed interest in the panel. Sixteen people were eventually selected for the panel. Conclusions It is possible to recruit a patient and public involvement panel for research in a discipline as challenging as microbiology. Good planning and the commitment of the research team were key to success. PMID- 29423277 TI - A phenotype centric benchmark of variant prioritisation tools. AB - Next generation sequencing is a standard tool used in clinical diagnostics. In Mendelian diseases the challenge is to discover the single etiological variant among thousands of benign or functionally unrelated variants. After calling variants from aligned sequencing reads, variant prioritisation tools are used to examine the conservation or potential functional consequences of variants. We hypothesised that the performance of variant prioritisation tools may vary by disease phenotype. To test this we created benchmark data sets for variants associated with different disease phenotypes. We found that performance of 24 tested tools is highly variable and differs by disease phenotype. The task of identifying a causative variant amongst a large number of benign variants is challenging for all tools, highlighting the need for further development in the field. Based on our observations, we recommend use of five top performers found in this study (FATHMM, M-CAP, MetaLR, MetaSVM and VEST3). In addition we provide tables indicating which analytical approach works best in which disease context. Variant prioritisation tools are best suited to investigate variants associated with well-studied genetic diseases, as these variants are more readily available during algorithm development than variants associated with rare diseases. We anticipate that further development into disease focussed tools will lead to significant improvements. PMID- 29423275 TI - A roadmap towards personalized immunology. AB - Big data generation and computational processing will enable medicine to evolve from a "one-size-fits-all" approach to precise patient stratification and treatment. Significant achievements using "Omics" data have been made especially in personalized oncology. However, immune cells relative to tumor cells show a much higher degree of complexity in heterogeneity, dynamics, memory-capability, plasticity and "social" interactions. There is still a long way ahead on translating our capability to identify potentially targetable personalized biomarkers into effective personalized therapy in immune-centralized diseases. Here, we discuss the recent advances and successful applications in "Omics" data utilization and network analysis on patients' samples of clinical trials and studies, as well as the major challenges and strategies towards personalized stratification and treatment for infectious or non-communicable inflammatory diseases such as autoimmune diseases or allergies. We provide a roadmap and highlight experimental, clinical, computational analysis, data management, ethical and regulatory issues to accelerate the implementation of personalized immunology. PMID- 29423278 TI - Comparative analysis of choroidal thickness in third trimester pregnant women. AB - Background: The impact of pregnancy on the choroid is still under investigation. The aim of this study is to compare choroidal thickness measurements of healthy pregnant women in the third trimester and healthy non-pregnant women using spectral-domain optical coherence tomography (OCT). Methods: This cross-sectional study included 122 eyes of 61 women, divided into two groups: 27 healthy pregnant women in the third trimester and 34 age-matched healthy non-pregnant women. Choroidal thickness was measured using Enhanced Depth Imaging OCT at ten different locations: at the fovea and every 500 um from the fovea up to 2500 um temporally and up to 2000 um nasally. Results: There were no significant differences in the ten measurements of choroidal thickness comparing both groups. Mean subfoveal choroidal thickness was 304.1 + 9.6 um in the control group and 318.1 + 15.6 um in the pregnant women group (p = 0.446). There was also no statistically significant association between gestational age and choroidal thickness measurements in the healthy pregnant women group. Conclusions: Our study showed no statistically difference in choroidal thickness between healthy non-pregnant women and healthy pregnant women in the third trimester. PMID- 29423279 TI - Physiotherapy for people with mental health problems in Sub-Saharan African countries: a systematic review. AB - Background: There is a need for psychosocial interventions to address the escalating mental health burden in Sub-Saharan Africa (SSA). Physiotherapists could have a central role in reducing the burden and facilitating recovery within the multidisciplinary care of people with mental health problems. The aim of this systematic review was to explore the role of physiotherapists within the current mental health policies of SSA countries and to explore the current research evidence for physiotherapy to improve functional outcomes in people with mental health problems in SSA. Methods: The Mental Health Atlas and MiNDbank of the World Health Organization were screened for the role of physiotherapy in mental health plans. Next, we systematically searched PubMed from inception until August 1st, 2017 for relevant studies on physiotherapy interventions in people with mental health problems in SSA. The following search strategy was used: "physiotherapy" OR "physical therapy" OR "rehabilitation" AND "mental" OR "depression" OR "psychosis" OR "schizophrenia" OR "bipolar" AND the name of the country. Results: The current systematic review shows that in 22 screened plans only 2 made reference to the importance of considering physiotherapy within the multidisciplinary treatment. The current evidence (N studies = 3; n participants = 94) shows that aerobic exercise might reduce depression and improve psychological quality of life, self-esteem, body image and emotional stress in people with HIV having mental health problems. In people with depression moderate to high but not light intensity aerobic exercise results in significantly less depressive symptoms (N = 1, n = 30). Finally, there is evidence for reduction in post-traumatic stress symptoms (avoidance and arousal), anxiety and depression following body awareness related exercises (N = 1, n = 26). Conclusions: Our review demonstrated that physiotherapy is still largely neglected in the mental health care systems of SSA. This is probably due to poor knowledge of the benefits of physiotherapy within mental health care by policymakers, training institutes, and other mental health care professionals in SSA. Based on the current scientific evidence, this paper recommends the adoption of physiotherapy within mental health care services and investment in research and in training of professionals in SSA. PMID- 29423281 TI - Occurrence of sudden paraplegia during follow-up period of thoracic vertebral compression fracture in a case with spinal epidural lipomatosis. AB - Introduction: Spinal epidural lipomatosis (SEL) involves hypertrophy of fat tissue in the extradural space, often associated with long-term corticosteroid therapy. Sometimes it causes severe spinal cord compression and the patient gradually becomes symptomatic. However, sudden onset of neurological deterioration is extremely rare. Case presentation: We herein present a case of sudden paraplegia in a patient with thoracic SEL at 2 months after thoracic vertebral fracture, whose symptoms were consistent with a lesion at the same level as the SEL. Computed tomography scan showed no remarkable change in the degree of vertebral fracture at the time of neurological deterioration. We performed immediate decompression surgery and found hemorrhage and granulation tissue at the level of the fracture and removed it with the epidural fat tissue. The hematoma and granulation tissue were thought to be the cause of the acute deterioration. The patient recovered gradually from the paraplegia. Discussion: Sudden paraplegia with SEL at the time of vertebral fracture has previously been reported, but this is the first report of SEL with delayed onset of paraplegia after an initial diagnosis of coexisting vertebral fracture. PMID- 29423280 TI - Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation. AB - The severe worldwide shortage of donor organs, and severe pathologies placing patients at high risk for rejecting conventional cornea transplantation, have left many corneal blind patients untreated. Following successful pre-clinical evaluation in mini-pigs, we tested a biomaterials-enabled pro-regeneration strategy to restore corneal integrity in an open-label observational study of six patients. Cell-free corneal implants comprising recombinant human collagen and phosphorylcholine were grafted by anterior lamellar keratoplasty into corneas of unilaterally blind patients diagnosed at high-risk for rejecting donor allografts. They were followed-up for a mean of 24 months. Patients with acute disease (ulceration) were relieved of pain and discomfort within 1-2 weeks post operation. Patients with scarred or ulcerated corneas from severe infection showed better vision improvement, followed by corneas with burns. Corneas with immune or degenerative conditions transplanted for symptom relief only showed no vision improvement overall. However, grafting promoted nerve regeneration as observed by improved touch sensitivity to near normal levels in all patients tested, even for those with little/no sensitivity before treatment. Overall, three out of six patients showed significant vision improvement. Others were sufficiently stabilized to allow follow-on surgery to restore vision. Grafting outcomes in mini-pig corneas were superior to those in human subjects, emphasizing that animal models are only predictive for patients with non-severely pathological corneas; however, for establishing parameters such as stable corneal tissue and nerve regeneration, our pig model is satisfactory. While further testing is merited, we have nevertheless shown that cell-free implants are potentially safe, efficacious options for treating high-risk patients. PMID- 29423282 TI - The Austrian Spinal Cord Injury Study: a registry for patients living with a traumatic spinal cord injury. AB - Study design: Establishing the structure of a prospective spinal cord injury (SCI) patient registry. Objectives: To develop a registry for patients with traumatic spinal cord injury (tSCI) in Austria as a base for addressing research questions, improving patient outcomes, and establishing a platform for future clinical trials. Settings: Coordinating institution: Paracelsus Medical University Salzburg, Austria; participating partners are located in nine states in Austria. Methods: The Austrian Spinal Cord Injury Study (ASCIS) collects longitudinal data on simple forms within a 7-stage follow-up examination timeline. Results: The implementation of the ASCIS in 2012 created the first nationwide SCI patient registry in Austria. ASCIS is currently implemented in 17 trauma hospitals in 9 Austrian states, and over 150 individuals with acute tSCI have been registered to date. As in Austria, the structure of the health-care system does not involve a specialized SCI center covering the primary health care and the rehabilitation care, major challenges have to be overcome to involve all participating primary centers and rehabilitation centers, which perform tSCI patient care, for ASCIS. Through implementing ASCIS, a network of SCI clinicians and researchers, which is now beginning to support translational research and to initiate clinical trials for patients with tSCI, has formed. Conclusions: ASCIS is uniquely positioned in Austria to capture detailed information from the early acute to the chronic phases of tSCI, to provide this information also to bigger and translational settings, and to connect researchers and clinicians to facilitate clinical research on tSCI. PMID- 29423283 TI - The anal exam and SCI. PMID- 29423284 TI - Pulse article: How do you do the international standards for neurological classification of SCI anorectal exam? AB - Study Design: Online survey of spinal cord injury (SCI) practitioners. Objectives: Determine provider understanding and routine performance of International Standards for Neurologic Classification of Spinal Cord Injury (ISNCSCI) anorectal examination. Setting: International online questionnaire. Methods: A descriptive survey was developed to assess current performance of the ISNCSCI anorectal exam. Information about this survey was disseminated through social email and international societies between the months of March and April 2017. Results: Two hundred and fifteen SCI practitioners completed the survey. Of these, 157 (73%) were specialists in physical medicine and rehabilitation, 32 (15%) were physical therapists, 6 were neurologists, 6 were orthopedists, and 3 were neurosurgeons. Of responders, 90% routinely personally performed the anal exam of the ISNCSCI, of whom, 42 placed firm pressure against the anal sphincter, 58 placed firm pressure against the rectal wall, and 87 placed firm pressure against the anal sphincter and rectal wall as part of the exam. On a routine basis, 74% tested sensation at the junction of the anal sphincter and skin, 82% had the patient attempt to squeeze their finger, and 50% performed the bulbocavernosus reflex. Conclusions: Marked inconsistency exists in the performance of the ISNCSCI anal examination. Researchers and clinicians need more education about the performance of the examination. Consideration should be given for the components of deep rectal sensation and anal pressure to be separately documented in the neurologic exam and for researchers to focus separately on recovery of sacral function vs. ambulatory function in clinical trials. PMID- 29423286 TI - Acute visual loss in a patient with spinal cord injury. AB - Introduction: Patients with spinal cord injury (SCI), especially those with injury at and above T6, are prone to transient episodes of hypertension induced by noxious triggers below the level of SCI, known as autonomic dysreflexia (AD). An uncommonly reported presentation of AD is posterior reversible encephalopathy syndrome (PRES). Case Presentation: A 50-year-old male with the history of paraplegia from SCI presented with sepsis secondary to baclofen pump and urinary tract infections. On hospital day 4, he developed acute bilateral vision loss. The next morning he had a generalized-tonic-clonic seizure followed by cardiac arrest, with return of spontaneous circulation following resuscitation. Magnetic resonance imaging brain demonstrated multifocal areas of hyperintensity on T2 fluid-attenuated inversion recovery sequence, most pronounced in the occipital lobes. Systolic blood pressures (SBP) were under 180 mmHg throughout hospital stay but above his baseline (SBP 90 mmHg). PRES was diagnosed on the basis of clinical and radiologic evidence. With strict blood pressure (BP) control, there was resolution of visual abnormalities, headaches, encephalopathy, and seizures. Discussion: Although PRES has been most commonly described in malignant hypertension, it can be seen in patients with normotension or moderate hypertension who have low baseline BPs, such as patients with SCI. These patients are prone to AD due to imbalanced sympathetic outflow to vasculature below the level of injury caused by noxious stimulus. This results in massive regional vasoconstriction leading to an uncontrolled rise in BP above baseline. This episode of PRES could have been prevented by identifying patient's risk, recognizing early signs and potential triggers of AD, and implementing aggressive treatment of the underlying noxious stimuli. PMID- 29423285 TI - Spinal arteriovenous fistula coexisting within a spinal lipoma: report of two cases. AB - Introduction: Spinal lipoma and spinal arteriovenous fistula (sAVF) are different pathologies and their co-existence is extremely rare. Here we reported two cases of adult-onset sAVF occurring within a spinal lipoma and with review the literature in an attempt to identify the mechanisim of and optimal treatment of this condition. Case presentation: Case 1 was a 51-year-old man who was treated by embolization of the feeding artery and ligation of the draining vein. Case 2 was a 53-year-old man who was treated by embolization and resection of the tumor containing the shunt zone. In both cases, symptoms improved after surgery. However, in Case 1, angiography at 1 month after the surgery revealed recurrence of the arteriovenous shunt. Discussion: A literature search revealed only nine other similar case reports. All cases, including ours occurred in adults. In almost all cases, the shunt was located within the spinal lipoma. Pathologic examination revealed venous hypertension, but no evidence of congenital vascular malformation. Given that lipomas release angiogenic factors, the presence of a spinal lipoma may indicate its involvement in the development of acquired sAVF. Our two cases might represent a new subtype of sAVF. Based on our experiences, we recommend resection of the tumor containing the shunt for the management of sAVF. PMID- 29423287 TI - Late neurological complications due to laminar hook compression in idiopathic scoliosis surgery. AB - Introduction: To provide a review of unusual neurological complications occurring years after spinal instrumentation surgery. Case Presentation: The authors analyzed the cases of three patients with adolescent idiopathic scoliosis who presented with delayed neurological symptoms (later than 12 months postoperatively) following spinal deformity surgery using Texas Scottish Rite Hospital (TSRH) hook-rod instrumentation. One case presented with conus medullaris syndrome while the last two were rare cases of posterior cord syndrome due to a dislodged laminar hook at the thoracolumbar transition. Discussion: In all three cases, the neurological symptoms were due to direct laminar hook compression. Metallosis was observed extra-spinally around the hook-rod construct but not at the sublaminar site. The dislodged laminar hook responsible for the symptoms was situated at the concavity of the curve with the blade-tip pointing downwards. Symptomatic improvement was observed in all patients following complete hardware removal. Conscientious long-term follow-up of patients undergoing posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) is important in order to recognize late neurological deficits directly related to instrumentation. Anamnesis and physical examination are key for initial assessment and diagnosis, while myelography and computed tomography (CT) images are of great help to confirm the site of spinal compression. Removal of the dislodged laminar hooks after PSF with TSRH instrumentation in AIS cases can potentially improve neurological symptoms. PMID- 29423288 TI - It's time to focus on autonomic function after spinal cord injury. PMID- 29423289 TI - Neuropathic pain in a rehabilitation setting after spinal cord injury: an interpretative phenomenological analysis of inpatients' experiences. AB - Study design: Qualitative, semi-structured interviews. Objectives: Neuropathic pain (NP) can be psychologically and physically debilitating, and is present in approximately half of the spinal cord injured (SCI) population. However, under half of those with NP are adherent to pain medication. Understanding the impact of NP during rehabilitation is required to reduce long-term impact and to promote adherence to medication and psychoeducation recommendations. Setting: United Kingdom. Methods: Five males and three females with SCI and chronic NP, resident in rehabilitation wards at a specialist SCI center in the United Kingdom, took part. Semi-structured interviews were conducted with participants less than 15 months post-SCI (mean = 8.4 months). Verbatim transcripts were subject to interpretative phenomenological analysis (IPA). Results: Three super-ordinate themes were identified, mediating pain and adherence: (1) the dichotomy of safety perceptions; (2) adherence despite adversity; and (3) fighting the future. Analyses suggest that experience of the rehabilitation setting and responsiveness of care shapes early distress. Attitudes to medication and psychosocial adjustment are relevant to developing expectations about pain management. Conclusions: Enhancing self-efficacy, feelings of safety in hospital, and encouraging the adoption of adaptive coping strategies may enhance psychosocial and pain-related outcomes, and improve adherence to medication. Encouraging adaptive responses to, and interpretation of, pain, through the use of interventions such as coping effectiveness training, targeted cognitive behavioral pain management, and acceptance-based interventions such as mindfulness, is recommended in order to reduce long-term reliance on medication. PMID- 29423290 TI - A forgotten 19th century surgeon: Richard Anthony Stafford (1797-1854), FRCS. PMID- 29423291 TI - Revision surgery for degenerative spinal deformity: a case report and review of the literature. AB - Introduction: Management of spinal degenerative deformities always represents a challenge for the spinal surgeon. Case presentation: We report a case of revision surgery for adult scoliosis, focusing of most common errors in pre-surgical management and criteria for reoperation. We analyzed the spino-pelvic parameters on the standing whole-spine X-ray and the role of sagittal balance. To restore 45 degrees of lumbar lordosis, we performed a L3 Pedicle Subtraction Osteotomy (PSO), along with L2-L3 and L3-L4 eXtreme Lateral Interbody Fusion (XLIF). Discussion: In cases of adult scoliosis, careful preoperative planning is necessary in an attempt to avoid difficult, expensive, and high-risk additional procedures. PMID- 29423292 TI - Thermodysregulation in persons with spinal cord injury: case series on use of the autonomic standards. AB - Introduction: The ability to maintain core body temperature (Tcore) within a narrow range (37 +/- 0.6 degrees C), despite exposure to a wide range of ambient temperatures, is essential in order to provide an optimal environment for vital organs, the central nervous system (CNS), and cellular processes to function. High-level (above T6) spinal cord injury (SCI) interrupts the autonomic nervous system's ability to carry out hypothalamic regulation of thermoregulatory mechanisms for both heat dissipation and conservation. This interruption leaves persons with high-level SCI vulnerable to hyper and hypothermia even during exposure to relatively mild ambient temperatures. The goal of the Autonomic Standards is to enable the clinician to quickly identify those individuals with SCI who may be most at risk for thermoregulatory dysfunction. Case presentation: Case 1: Heat Exhaustion, Case 2: Heat Stroke in absence of CNS symptoms, Case 3: Heat Exhaustion. Discussion: The three cases demonstrate the signs and symptoms that may accompany hyperthermia in persons with SCI. The onset may be quite rapid and the condition persistent, despite ambient temperatures being much less intense than expected to be necessary to induce similar conditions in able-bodied (AB) persons. The responses of the persons in the case studies to the temperature regulation and autonomic control of sweating sections of the Autonomic Standards would identify them as being vulnerable and warrant providing appropriate exposure guidelines and precautions to them and their caregivers. PMID- 29423293 TI - Using the autonomic standards to assess orthostatic hypotension in persons with SCI: a case series. AB - Introduction: Spinal cord injury (SCI) creates a complex and unique syndrome of medical issues related to disruption of somatic and autonomic pathways. Among these impaired control of blood pressure (BP) can significantly impede patients' activities of daily living. The International Standards for the Assessment of Autonomic Function after SCI (ISAFSCI) is used to document the impact of SCI on resting BP (abnormal if below 90 mmHg) and the presence or absence of orthostatic hypotension (OH), defined as a symptomatic or asymptomatic decrease in BP (>/=20/10 mmHg) upon moving to an upright position. Case presentation: Case 1 documents the adverse influence of prescribed medications (antidepressants for neuropathic pain) on OH; case 2 describes the influence of bladder management on cardiovascular instability (autonomic dysreflexia and subsequent OH); case 3 describes the association between spasticity and OH; case 4 describes OH associated with a Valsalva maneuver. Discussion: Impaired control of BP can stem from a combination of medical issues and autonomic dysfunction in persons with SCI. Management strategies for OH will vary depending on the stage of the SCI, the root cause of the OH and other confounding medical conditions. Non pharmacological treatment should be considered as a first line of intervention and consideration should be given to cessation of potentially contributory medications prior to implementing pharmaceutical interventions. The systematic use of ISAFSCI by clinicians is recommended to document BP irregularities and to describe the effects of treatment strategies aimed at improving BP control in the SCI population. PMID- 29423294 TI - A profile of traumatic spinal cord injury and medical complications in Latvia. AB - Study design: A single centre retrospective study. Objectives: To collect data and analyse the epidemiological profile of traumatic spinal cord injury and its medical complications during the subacute rehabilitation period. Setting: Spinal Cord Injury Rehabilitation Programme of the National Rehabilitation Centre, 'Vaivari', Jurmala, Latvia. Methods: Information was collected in 2015 from the medical records of 134 patients with a traumatic spinal cord injury admitted for primary rehabilitation between January 2011 and December 2014. Results: During this period, the median age of patients with a traumatic spinal cord injury was 39.5 years, and the male to female ratio was 5:1. The leading causes of traumatic spinal cord injuries were falls (37%), road traffic accidents (29%), sport and leisure activities (19%), other cause (8%), unidentified causes (5%), and assault (2%). The most common medical complications were pain (77%), spasticity (48%), urinary tract infections (45%), pressure ulcers (25%), and orthostatic hypotension (14%). Conclusions: Preventive measures in Latvia should be aimed primarily to address falls, road traffic accidents, and sport and leisure activities in the young male population. Medical complications are varied, and they are an important factor following traumatic spinal cord injury. The results obtained in this study comply with the data from studies in countries of the Baltic and North Sea regions of Europe. PMID- 29423295 TI - TRPA1 polymorphisms in chronic and complete spinal cord injury patients with neuropathic pain: a pilot study. AB - Study design: Pilot study. Objectives: Single-nucleotide polymorphisms (SNPs) in TRPA1 gene are related to the etiology of chronic pain. The study is a pilot study with the primary objective of analyzing these SNPs in Spanish patients with chronic and complete spinal cord injury (SCI) and neuropathic pain (NPP). Setting: Asepeyo Hospital Department of Chronic and Complete SCI. Methods: Twelve patients with chronic and complete SCI and NPP, and 12 patients with chronic and complete SCI with no pain were reviewed. International Spinal Cord Injury Pain Classification (LANSS) and visual analog score (VAS) were chosen to classify pain syndrome. SNPs were identified by melting analysis after DNA amplification with real-time fluorescence PCR. Results: There were differences in rs11988795 variant: GG homozygous (p = 0.01) and G allele (p = 0.001) were more frequent in SCI patients with no pain. There were differences in rs13255063 variant: TT homozygous were prevalent (p = 0.03) in patients with NPP. Conclusions: Until now this is the first study to show a description of TRPA1 SNPs in Spanish patients with chronic and complete SCI and NPP. These results suggest that GG genotype in rs11988795 variant and G allele could be protective factors against NPP. TT genotype in rs13255063 variant could be a risk factor for NPP. Neuropathic pain after spinal cord injuries may have genetic contributions. PMID- 29423296 TI - Acute spontaneous thoracic epidural hematoma, triggered by weight-lifting training, in a retired sportsman: case report and literature review. AB - Introduction: Spontaneous spinal epidural hematoma (SSEH) is a rare clinical entity, most often with acute symptomatic spinal cord compression and potentially permanent neurologic deficits. SSEH usually has surgical solutions and a good outcome after hematoma evacuation. Case presentation: A 61-year-old professional weight-lifting coach presented to the emergency department with sudden back pain, rapidly progressive paraparesis, and neurogenic bladder, after an intense training, 5 h previously. Magnetic resonance imaging revealed a ventral thoracic epidural hematoma with significant compression at Th3-Th6. Surgical procedure was performed within the first 12 h: decompressive laminectomy from Th3 to Th7 vertebral levels and near total epidural hematoma removal. The patient improved rapidly from Th5 AIS-C to Th7 AIS-D paraplegia with independent ambulation, after the intervention. The rehabilitation program led to further improvement of the neurologic deficits and a favorable outcome, to AIS-E. Discussion: Weightlifting has been reported as SSEH precipitating factor in young athletes. Our case is unique however, because the athlete was older. The underlying pathophysiological mechanism is represented by intravenous pressure changes and bleeding of the epidural venous plexus during a prolonged Valsalva maneuver, induced by strenuous, repeated efforts. Spondylosis, hypertension, and low doses of aspirin were incriminated as risk factors for SSEH. Prompt diagnosis, emergent decompressive intervention, early rehabilitation, and secondary prophylaxis were essential for a good outcome. PMID- 29423297 TI - Excision of a centrally based ventral intradural extramedullary tumor of the cervical spine through a direct posterior approach. AB - Introduction: Intradural extramedullary (IDEM) tumors of the cervical spine are removed through an assortment of surgical approaches including: dorsolateral, ventrolateral, and anterior or transoral. Historically, midline ventral IDEM tumors are ostensibly thought to be unfavorable candidates for removal through a direct posterior approach. A case report of a patient with a ventrally based centrally located meningioma in the upper cervical spine (C2/C3) that was removed with direct posterior approach is described. Case presentation: A 51-year-old male presented with cervicalgia and radiating scapular pain following a remote motor vehicle collision. A ventrally located meningioma in relation to the C2 body was noted on MRI. Management of this patient included obtaining adequate exposure through a posterior approach, complete tumor excision, and maintenance of cervical spine stability. Cervical stability was maintained following total unilateral facetectomy and application of instrumentation from C1-C3. Discussion: Subsequent to tumor removal, the patient had complete resolution of his cervicalgia, headaches, and scapular pain by his two month follow-up appointment. Although adhesions can make total resection difficult, a posterior approach can grant adequate access to midline ventral meningiomas. Cervical spine stability, tumor location, infection risk, and surgeon familiarity with the approach should all be weighed in decision-making. PMID- 29423298 TI - Upper extremity motor training of a subject with initially motor complete chronic high tetraplegia using constraint-induced biofeedback therapy. AB - Introduction: The purpose of this case study was to determine if a subject with chronic high tetraplegia (C3 AIS A) could learn to use an initially paralyzed upper extremity on the basis of training procedures alone. Case presentation: Initially, an AIS examination revealed no purposive movement below the neck other than minimal shoulder movement. Training was carried out weekly over 39 months. Training began based on electromyographic biofeedback; the electrical activity of a muscle (biceps or triceps) was displayed visually on a computer monitor and the subject was encouraged to progressively increase the magnitude of the response in small increments on a trial-by-trial basis (i.e., shaping). When small, overt movements began to appear; these were, in turn, shaped so that their excursion progressively increased. Training then progressed to enable lifting the arm with the aid of the counterweight of a Swedish Help Arm. Mean movement excursions in the best session were: internal rotation 52.5 cm; external rotation 26.9 cm; shoulder extension 22.1 cm; shoulder flexion 15.2 cm; pronation/supination 120 degrees ; extension of index finger (D2) 2.5 cm. Movements were initially saltatory, becoming smoother over time. With the Swedish Help Arm, the subject was able to lift her hand an average of 24.3 cm in the best session with 0.7 kg counterweight acting at the wrist (1.9 J of work). Discussion: Results suggest in preliminary fashion the effectiveness of this approach for improving upper extremity function after motor complete high tetraplegia. Thus, future studies are warranted. Possible mechanisms are discussed. PMID- 29423299 TI - Managing bowel and bladder impairments in sacral chordoma patients: a case-based approach. AB - Introduction: Chordomas are primary bone tumors that occur in the axial spine and most commonly in the sacrum. Because of their location, chordomas can affect bowel and bladder continence resulting in either an upper or a lower motor neuron functional pattern. Case presentation: We present two cases describing chordoma's impact on bowel and bladder function and the management plan used for improvement. Discussion: The accurate identification of an upper or lower motor neuron pattern in the setting of chordoma aims to significantly improve management of bowel and bladder impairment. PMID- 29423300 TI - Prediction of sexual function following spinal cord injury: a case series. AB - Introduction: Spinal Cord Injury (SCI) affects sexual response based on the level and degree of completeness of injury. By using the International Standards for the Neurologic Classification of SCI in conjunction with lumbo-sacral reflexes these effects can be predicted. The International Standards for the Assessment of Autonomic Function after SCI (ISAFSCI) document the impact of SCI on sexual responses including psychogenic and reflex arousal (erection or lubrication), orgasm, ejaculation, and sensation of menses. Responses are described based upon a 0 to 2 scale with 0 being absent, 1 altered, and 2 normal response. Additionally, the lesion is described as supraconal, conal or infraconal. Case presentation: We present 4 representative cases of the impact of SCI on sexual responses and course of treatment. Case 1 describes a complete supraconal lesion above T6 with upper motor neuron syndrome. Case 2 describes a supraconal complete lesion including the T11-L2 segment. Case 3 describes an infraconal (cauda equina) lesion with lower motor neuron syndrome. Case 4 is theoretical and describes a supraconal lesion above T6 with upper motor neuron syndrome, partial sensation in T11-L2 dermatomes, and other medical comorbidities. Discussion: Neurologic examination combined with reflex testing allows prediction of sexual responses after SCI. It would be useful for version 2.0 of the ISAFSCI to assist clinicians in determining the anticipated changes, whether their patients are functioning as anticipated sexually after SCI or whether other concerns also require treatment. PMID- 29423301 TI - Lower urinary tract autonomic dysfunction evaluation in spinal cord injury patients: an applied example. AB - Introduction: The International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) is a measure for motor-sensory dysfunction following spinal cord injury (SCI) but does not assess the autonomic nervous system dysfunction. The International Standards to document remaining Autonomic Dysfunction after Spinal Cord Injury (ISAFSCI) has been recommended to study autonomic dysfunction in such patients. We present a case presentation to demonstrate how to use the ISAFSCI and ISCoS urodynamics data set in persons with SCIs. Case presentation: A 24-year-old caucasian male presents with T4 ASIA SCI. We followed the patient over the course of 18 months. We present his clinical picture at different stages and how to apply ISAFSCI and ISCoS urodynamic data set to this patient. Discussion: The ISAFSCI and ISCoS urodynamics data sets are important tools in the repertoire of the clinician assessing autonomic dysfunction in persons with SCIs. They allow efficient clinical assessment of patients and standard communication between clinical care providers. PMID- 29423302 TI - Health status of regularly physically active persons with spinal cord injury. AB - Study design: A non-controlled cross-sectional study. Objectives: To make a descriptive examination of health status in persons with paraplegia and tetraplegia who exercise regularly according to Canadian guidelines. Settings: Sunnaas Rehabilitation Hospital and the Norwegian School of Sport Sciences. Methods: Eighteen persons (men/women = 9/9), aged 41-72 years with spinal cord injury (SCI), who exercise regularly were included. Post-injury years ranged from 4 to 48 years. Clinical examination of body composition, bone mineral density (BMD), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusion capacity (DLCO), cardiorespiratory fitness (VO2max), and self reported quality of life (QOL) obtained by questionnaire was performed. Lung function results are presented as % predicted and VO2max as absolute values relative to body weight. All results are given as median and range. Results: Persons with paraplegia (n = 13) were defined as overweight with fat mass 42% (25 51). BMD 1.047 g cm-2 (0.885-1.312) was within normal range. FVC 95% predicted (60-131), FEV1 90% predicted (61-119), DLCO 77% predicted (56-103), and VO2max 16.66 ml kg-1 min-1 (12.15-25.28) defined good aerobic capacity according to age controlled reference values (18). Persons with tetraplegia (n = 5) were slightly overweight with fat mass 35% (26-47). BMD 1.122 g cm-2 (1.095-1.299) was within normal range. FVC 72% predicted (46-91), FEV1 75% predicted (43-83), DLCO 67% predicted (56-84), and VO2max 16.70 ml kg-1 min-1 (9.91-21.01) defined excellent aerobic capacity according to reference values (18). QOL was ranked as median 7.5 (0-10 scale). Conclusions: Persons with SCI who exercise regularly following the Canadian guidelines responded with rather positive associations for health outcomes. Additional research is needed to strengthen our findings. PMID- 29423303 TI - Pulse article: Survey on the current usage of the International Standards for the Assessment of Autonomic Function after Spinal Cord Injury (ISAFSCI). AB - Study design: Online questionnaire. Objectives: To identify the awareness, and current use, of the International Standards for the Assessment of Autonomic Function after SCI (ISAFSCI) and suggest necessary revisions. Setting: An international collaboration of committee members. Methods: A survey was drafted and consensus achieved among members of the International Standards Committee of the ASIA. The questionnaire was posted on SurveyMonkey for 2 months. A survey link was posted on the ASIA and ISCoS websites, and committee members circulated the survey to colleagues with the goal of obtaining a wide-spread international response. Results: A total of 173 providers responded. About half (n = 84) of the respondents used the standards in some form. Forty-four percent (n = 72) felt they knew the difference between the standards and the data sets. Among 135 responses on the usefulness of the ISAFSCI, the bladder, bowel, and sexual function sections, and the heart rate, respiratory rate, blood pressure, and sudomotor sections for use in patients with tetraplegia were reported as most useful. Comments revealed that respondents would like more explanation regarding specific definitions of components of the standards, how/when to use the ISAFSCI, and how the ISAFSCI may assist in clinical care. Conclusion: The ISAFSCI is used by a subset of SCI clinicians. Some find the standards useful, while others are unaware of the utility of the ISAFSCI to prevent morbidity and assist in documentation of autonomic recovery post SCI. Further clarification regarding the definition of various disorders, and how and why to use the ISAFSCI in the SCI population, is needed. PMID- 29423304 TI - Alarming blood pressure changes during routine bladder emptying in a woman with cervical spinal cord injury. AB - Introduction: Many individuals with high-level spinal cord injury (SCI) experience secondary conditions such as autonomic dysreflexia (AD), which is a potentially life-threatening condition comprising transient episodes of hypertension up to 300 mmHg. AD may be accompanied by symptoms and signs such as headache, flushing, and sweating. Delay in AD recognition and management is associated with increased incidence of cardiovascular events and disease. As it is commonly triggered by bladder distension, AD continues to be a major concern for individuals living with SCI, both on a daily basis and in the long-term. Case presentation: A 58-year-old woman with C3 AIS B SCI presented with low resting blood pressure (BP) at 100/64 mmHg. She reported frequent episodes of AD that were most commonly attributed to urinary bladder filling. During our testing session, her systolic BP rose to 130 mmHg, at which point her care aide stepped in to utilize the Crede maneuver, which was part of her daily routine for bladder emptying. Application of suprapubic pressure further elevated her systolic BP to 230 mmHg. Throughout the episode of AD, the participant experienced a pounding headache and erythema above the LOI. Discussion: Clinical guidelines for bladder management after SCI recommend avoiding the Crede maneuver due to potential complications such as hernia or bruising. This current case report demonstrates the additional risk of inducing AD and dangerously high BP elevation. PMID- 29423305 TI - Autonomic dysreflexia caused by cervical stenosis. AB - Introduction: Autonomic dysreflexia (AD) is a well-known sequela of high spinal cord injuries (SCI). The characteristic episodic presentation is one of increased sympathetic tone: diaphoresis, hypertension, tachycardia, or reflex bradycardia. The episodes are triggered by visceral sensations and can last days to weeks. Case presentation: This report presents the case of a 73-year-old male with cervical stenosis, with a longstanding history of "hot flashes" accompanied by dizziness, flushing and diaphoresis, and palpitations. The patient was evaluated extensively by cardiology, endocrinology, and neurology with no treatable pathology determined aside from the patient's cervical stenosis. The patient was diagnosed with autonomic dysreflexia caused by cervical spinal stenosis and underwent anterior cervical decompression and fusion (ACDF) at the stenotic C5-C6 level. He found near complete resolution of his autonomic symptoms. Discussion: We hypothesize that the cervical compression caused a disruption in the regulatory control of the sympathetic preganglionic neurons resulting in the autonomic symptoms. Although numerous studies exist of patients with a traumatic onset of AD, to the best of our knowledge, this is the first case report in the literature of autonomic symptoms that stemmed from cervical stenosis. The purpose of this case report is to alert clinicians to a potential association between AD and spinal stenosis, which may exist outside the realm of SCI. PMID- 29423306 TI - International standards to document remaining autonomic Function in persons with SCI and neurogenic bowel dysfunction: Illustrative cases. AB - Introduction: Neurogenic bowel dysfunction (NBD) is a highly prevalent problem after spinal cord injury, with potential for significant impact on health and quality of life. The international standards to document remaining autonomic function after SCI were developed to standardize communication between professionals regarding neurogenic bowel and other autonomic function after SCI. To improve understanding of the bowel subsection, illustrative cases are presented. Case presentation: Three cases are presented which illustrate differences in presentation and scoring of the elements in the data set based upon varying injury severity and location. Discussion: Determination of neurologic level of injury is insufficient for assessment of autonomic function and there is no direct method of assessment. Hence, surrogate makers are needed. The bowel subsection of the International standards to document remaining autonomic function in persons with SCI is an easy-to-use tool for this purpose. PMID- 29423307 TI - The importance of the bulbocavernosus reflex. AB - The BCR consists of the contraction of the bulbocavernosus muscle in response to squeezing the glans penis or clitoris, and is mediated through the pudendal nerve. In case of a complete lesion, the presence of BCR is indicative of intact S2-S4 spinal reflex arcs and loss of supraspinal inhibition, determining an upper motor neuron (UMN) lesion, its absence a lower motor neuron (LMN) lesion. The BCR further helps distinguish conus medullaris from cauda equina syndromes. Sensory or motor function in the most caudal sacral segments, not BCR, defines the sacral sparing as part of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Sphincter dysfunctions are addressed in the International Standards for the Assessment of Autonomic Function after SCI (ISAFSCI). However, the ISAFSCI does not include the BCR, and is not part of the ISNCSCI. Yet, determination of the type of lesion, UMN or LMN, is very useful for the clinicians, and has important prognostic and therapeutic implications for bowel, bladder, and sexual function: UMN lesions are associated with detrusor and rectum hyperactivity, reflex erection and ejaculation, while the opposite is seen in patients with LMN lesions. BCR is complementary to the voluntary contraction of the external anal sphincter and should be added to ISNCSCI and ISAFSCI classifications, which should ultimately benefit patient care and research activities. PMID- 29423308 TI - The anorectal exam is unnecessary! PMID- 29423309 TI - The importance of the anal exam in neurologic classification of spinal cord injury. AB - The examination of the sensation of the anal orifice and the contraction of the external anal sphincter, either voluntarily or reflexly, has always been an integral part of the International Standards for Neurologic Classification of Spinal Cord Injury (ISNCSCI). Yet the importance of this component has been defended and challenged. This paper compares these two points of view as expressed by Previnaire and Marino, respectively. Both authors make important points but as the papers do not address the same aspect of the anal exam, room for further refinement of ISNCSCI both regarding the details of the exam and the use of components of the exam for prognostication of neurologic recovery is apparent. PMID- 29423310 TI - Audio-visual distraction as an adjunct to standby anaesthesia in persons with paraplegia: a case series of five operations. AB - Introduction: Persons with paraplegia present complex challenges to anaesthetists. Complications experienced by these patients can require major orthoplastic surgery such as excision of infected bone and soft tissue due to pressure sores and soft tissue reconstruction. Anaesthetic strategies deemed both safe and acceptable to this population are essential. Case presentation: We report a case series of five procedures in four patients with complete chronic spinal cord injury (CSCI) who underwent operations in lateral position under standby anaesthesia and audio-visual distraction (AVD) with minimal sedation. Patients' experience was formally assessed as part of the ongoing AVD service evaluation in our institution. All stated that they were not concerned in the operating theatre and felt "comfortable" or "very comfortable" throughout. All patients rated the experience as "better" than their previous experience with general anaesthesia and felt "very satisfied" with their anaesthetic. Importantly, all patients would recommend sedation with AVD to other patients. Discussion: To our knowledge, this is the first report of AVD application as an adjunct to standby anaesthesia during major surgery in persons with paraplegia. Patient feedback was extremely positive, therefore it is likely that by making standby anaesthesia more acceptable to patients the use of AVD could reduce anaesthetic risk in this complex patient group. PMID- 29423311 TI - Life after personalized adaptive locomotor training: a qualitative follow-up study. AB - Study Design: Qualitative follow-up study. Objectives: Intensive locomotor training can improve physical and psychological functioning for individuals with spinal cord injury. Few studies have examined long-term effects of locomotor training. Specifically, there is a lack of qualitative follow-up that provide insight into participants' perceptions of the effects of locomotor training on level of function and daily life. This study aimed to gain insight into participants' perceptions of intensive locomotor training and whether participation influenced the level of function and community living 1-2 years after training. Setting: Tertiary rehabilitation facility in Ontario, Canada. Methods: Participants were six individuals who had lived with spinal cord injury between 1.9 and 2.7 years at the time of the interviews and had completed locomotor training during the subacute phase of injury. Semi-structured interviews explored participants' daily experiences and level of function after locomotor training. Interviews were analyzed using thematic analysis. Results: Three themes were identified. (1) Outcomes: Personalized Adapted Locomotor Training led to transferable gains from the program to daily functioning and eased transitions out of the rehabilitation hospital. (2) Continuing the rehabilitation journey: following disappointment after training ended, recovery was perceived incomplete regardless of current functional status. Endeavors were now directed to maintaining gains achieved during the program. (3) Challenges: since discharge from Personalized Adapted Locomotor Training, participants identified changes in their psychological well-being and the risk of falls as challenges. Conclusions: Personalized Adapted Locomotor Training was a positive experience. The identified challenges present future opportunities for the improved delivery of intensive locomotor training programs. PMID- 29423312 TI - Epidemiological profile of spinal cord injuries at a tertiary rehabilitation center in Kuwait. AB - Study design: Retrospective, descriptive study. Objective: To describe the epidemiological profile of patients with spinal cord injury (SCI) in Kuwait. Setting: Physical Medicine and Rehabilitation Hospital, Kuwait. Methods: Review of medical records of 241 adult patients with SCI admitted during the period 2010 2015. The data collected included gender, age, etiology, neurological and vertebral level of injury and American Spinal Injury Association impairment scale (AIS). Results: There were 155 (64.3%) traumatic SCI (TSCI) and 86 (35.7%) non traumatic SCI (NTSCI) patients. In TSCI, the male to female ratio was 4.3:1, and in NTSCI it was 1.5:1. Road traffic accident was the most common cause of TSCI (52.9%), followed by fall from height (32.9%). Acute disc prolapse was the most common cause of NTSCI (29.1%), followed by degenerative disc disease (26.7%) and tumors (17.4%). Paraplegia (41.3%) was more common in TSCI, the level of injury being thoracic in 61% of cases. Cauda equina syndrome was the most common presentation in NTSCI (40.7%). Conclusion: Road traffic accident was found to be the main cause of TSCI in Kuwait, whereas acute and degenerative disc lesions were the leading causes in NTSCI. Prevention strategies should be directed toward these causes to reduce the incidence of SCI in Kuwait. PMID- 29423313 TI - Kilimanjaro porter spines. PMID- 29423314 TI - Adverse cognitive effect of gabapentin in individuals with spinal cord injury: preliminary findings. AB - Study design: Prospective observational cohort study. Objectives: To assess the effects of gabapentin on neuropsychological variables including memory, attention, and executive function in individuals with spinal cord injury. Setting: Santa Clara Valley Medical Center inpatient spinal cord injury unit. Methods: Ten patients (three females, seven males) with traumatic spinal cord injury underwent testing, with a mean age of 35.6 years (range 19-59, SD +/ 15.74). There were five patients with tetraplegia and five with paraplegia. Nine tests to assess neuropsychological function and two tests to assess pain were performed at 1 week post initiation of therapy, and at 4 weeks post initiation of therapy. The neuropsychological tests assessed aspects of memory, attention, and executive function. Results: The average score for six out of the nine neuropsychological items administered at 1 week post initiation of gabapentin displayed a decrease in cognitive function when compared to baseline. The average score for five out of nine neuropsychological items improved from 1 week post initiation of treatment to 4 weeks post initiation of treatment. Conclusions: Gabapentin therapy is associated with a tangible decline in memory, executive function, and attention in individuals with spinal cord injury. However, owing to small sample size, loss of patient follow-up at the 4 week post-treatment assessment, and lack of a control group, we cannot definitively state that any decreases in cognition are solely attributable to treatment with gabapentin. PMID- 29423315 TI - Temporal evolution of a patient with a spinal dural arteriovenous fistula on serial MRI. AB - Introduction: A spinal dural arteriovenous fistula is a rare type of vascular malformation. If left untreated, these fistulas can result in significant neurological deficits secondary to spinal cord infarct or hemorrhage. Case presentation: A 70-year-old female with a longstanding history of episodic progressive bilateral lower extremity weakness and sensory disturbances was previously misdiagnosed with multiple sclerosis. Imaging revealed a T2 signal change from T7 to the conus with associated signal change and she subsequently underwent a T10-L1 laminectomy for clip ligation of a spinal dural arteriovenous fistula. Here we present the clinical and radiographic progression of one patient with a spinal dural arteriovenous fistula. Discussion: Spinal dural arteriovenous fistulas are a rare but treatable cause of myelopathy, so it is important to understand its natural progression and radiologic findings as it is frequently misdiagnosed. PMID- 29423316 TI - Spinal cord injury with central cord syndrome from surfing. AB - Introduction: Central cord syndrome (CCS) is an injury to the center of the spinal cord. It is well known as a hyperextension injury, but it has never been described as a surfing injury. Our report describes this injury in detail. Case presentation: A 35-year-old male novice surfer presented to the emergency department with acute tetraplegia following falling off his surfboard and hitting sea floor at a shallow beach break. He was rescued by a fellow surfer while floating in the sea and unable to raise his head above sea level. Upon arrival at the hospital, tetraplegia and sensory deficits were noted. Radiological investigations showed advanced spinal stenosis at C4-6 levels. T2 magnetic resonance imaging (MRI) demonstrated myelopathy at C5-C6 level. He was diagnosed as having central cord syndrome, treated conservatively, and regained near full neurologic recovery after a month of rehabilitation. Discussion: Unique sport activities lead to unique injuries. It is important to accurately describe these injuries in order to create protective measures against them. Neurologic injuries in surfers are uncommon. With low-energy trauma, surfer's myelopathy is still the most common diagnosis, but central cord syndrome should be in the differential diagnosis. PMID- 29423317 TI - Design and production of conjugate vaccines against S. Paratyphi A using an O linked glycosylation system in vivo. AB - Enteric fever, mainly caused by Salmonella enterica serovar Paratyphi A, remains a common and serious infectious disease worldwide. As yet, there are no licensed vaccines against S. Paratyphi A. Biosynthesis of conjugate vaccines has become a promising approach against bacterial infection. However, the popular biosynthetic strategy using N-linked glycosylation systems does not recognize the specialized O-polysaccharide structure of S. Paratyphi A. Here, we describe an O-linked glycosylation approach, the only currently available glycosylation system suitable for an S. Paratyphi A conjugate vaccine. We successfully generated a recombinant S. Paratyphi A strain with a longer O-polysaccharide chain and transformed the O-linked glycosylation system into the strain. Thus, we avoided the need for construction of an O-polysaccharide expression vector. In vivo assays indicated that this conjugate vaccine could evoke IgG1 antibody to O antigen of S. Paratyphi A strain CMCC 50973 and elicit bactericidal activity against S. Paratyphi A strain CMCC 50973 and five other epidemic strains. Furthermore, we replaced the peptides after the glycosylation site (Ser) with an antigenic peptide (P2). The results showed that the anti-lipopolysaccharide antibody titer, bactericidal activity of serum, and protective effect during animal challenge could be improved, indicating a potential strategy for further vaccine design. Our system provides an easier and more economical method for the production of S. Paratyphi A conjugate vaccines. Modification of the glycosylation site sequon provides a potential approach for the development of next-generation "precise conjugate vaccines." PMID- 29423320 TI - Pattern of Contrast Sensitivity Changes in Acute Central Serous Chorioretinopathy. AB - Purpose: To evaluate contrast sensitivity (CS) changes in acute central serous chorioretinopathy (CSC). Methods: Visual acuity (VA), CS, and subretinal fluid (SRF) were evaluated monthly for 6 months. Treatment was considered at 3 months in case of persistent SRF. Results: Twelve of 20 eyes (60%) had spontaneous SRF resolution within 4 months. Five of 8 patients with delayed SRF resolution received either focal laser or photodynamic therapy. The CS was impaired in all spatial frequencies at baseline. There was a negative correlation between the baseline SRF thickness and CS at 3 and 6 cycles per degree (cpd). The CS improved significantly at the time of fluid resolution (p = 0.001) and continued to improve in 3 and 6 cpd. The CS at 6 cpd did not recover if compared to a normal fellow eye at 6 months (p = 0.018). The CS of 12 cpd at 6 months was superior in the spontaneous resolution group. Conclusion: The impaired CS gradually improved as the SRF reduced at all spatial frequencies. CS at 3 and 12 cpd continued to improve after complete fluid resolution. Despite an excellent final VA, the CS at 6 months did not regain its normal value. PMID- 29423319 TI - Improvement of long-term memory access with a pro-dopamine regulator in an elderly male: Are we targeting dopamine tone? AB - With aging, there is decline in both short-term and long-term memory. This effect is magnified by epigenetic insults on specific, dopamine- related genes (e.g., DRD2, DAT1) as well as by impaired or reduced mRNA transcription. In addition, long-term memory ability is positively correlated with dopamine function and there is evidence that aging is associated with a reduction in brain dopamine D2 receptors, with an acceleration seen in aging-induced dementia. As a result, the authors tested the acute effect of a Pro-Dopamine Regulator (KB220Z, liquid Nano variant) on an aspect of long-term memory performance in a 77-year-old, highly functional male, using the Animal Naming Test (ANT). An improvement in long-term memory retrieval had initially been noted during the subject's follow-up neurology exam, after he had been, for other reasons, taking KB220z. The patient had been given a number of ANTs by his primary and, later, another neurologist, from 2013 to 2016. Because the number of ANT observations was small (N = 7 with two groups) and the data uncorrelated, a non-parametric Wilcoxon-Mann-Whitney test was performed to test mean differences. After KB220z, the patient had much higher scores (p = 0.04762) on the ANT vs. when not taking it. His scores increased from the 30th percentile (pre-test) to the 76th percentile, after the first administration of KB220z and, later, to the 98th percentile, after a second administration of KB220z, six months later. The results indicate that KB220z, given acutely, increased a form of long-term memory retrieval in a highly functional, elderly male. Larger, double-blind, randomized controlled studies are encouraged. PMID- 29423318 TI - Pregnancy and infection: using disease pathogenesis to inform vaccine strategy. AB - Vaccination is the mainstay of preventative medicine for many infectious diseases. Pregnant women, unborn fetuses, and neonates represent three at-risk populations that can be simultaneously protected by strategic vaccination protocols. Because the pathogenesis of different infectious microbes varies based on tissue tropism, timing of infection, and host susceptibility, the goals of immunization are not uniform across all vaccines. Mechanistic understanding of infectious disease pathogenesis and immune responses is therefore essential to inform vaccine design and the implementation of appropriate immunization protocols that optimize protection of pregnant women, fetuses, and neonates. PMID- 29423321 TI - Hypertension in Non-Type 2 Diabetes in Isfahan, Iran: Incidence and Risk Factors. AB - Objective: To estimate the incidence of and risk factors for the development of hypertension (HTN) in people with T1D using routinely collected data. Method: The mean 16-year incidence of HTN was measured among 1,167 (557 men and 610 women) nonhypertensive patients with T1D from Isfahan Endocrine and Metabolism Research Center outpatient clinics, Iran. HTN was defined as a systolic blood pressure (BP) of 140 mm Hg or higher and/or a diastolic BP 90 mm Hg or higher and/or use of antihypertensive medications. The mean (standard deviation [SD]) age of participants was 20.6 years (10.5 years) with a mean (SD) duration of diabetes of 3.6 years (4.8 years) at registration. Results: The prevalence of HTN at baseline was 9.7% (95% CI: 8.2, 11.5). Among the 1,167 patients free of HTN at registration who attended the clinic at least twice in the period 1992-2016, the incidence of HTN was 9.6 (8.0 women and 11.3 men) per 1000 person-years based on 18,870 person-years of follow-up. Multivariate analyses showed that male gender, older age, higher triglyceride, and higher systolic BP were significantly and independently associated with the development of HTN in this population. Conclusion: These findings will help the identification of those patients with T1D at particular risk of HTN and strongly support the case for vigorous control of BP in patients with T1D. PMID- 29423322 TI - A Pediatric Case of Diffuse Alveolar Hemorrhage Secondary to Poststreptococcal Glomerulonephritis. AB - This report summarizes a case of a 4-year-old girl with poststreptococcal glomerulonephritis and diffuse alveolar hemorrhage, an atypical presentation in this age group and type of vasculitic disease. We propose that her rapid improvement in clinical status was due to her treatment, continuous renal replacement therapy (CRRT). This mechanism would have impacted recovery by removing factors such as endothelial microparticles, superantigens, and immune complexes that have been postulated as the pulmonary-renal link. This may be an interesting avenue of exploration going forward given the lack of evidence in treating such conditions and emergence of CRRT. PMID- 29423323 TI - Use of CytoSorb in Traumatic Amputation of the Forearm and Severe Septic Shock. AB - Severe trauma associated with later disability and mortality still constitutes a major health and socioeconomic problem throughout the world. While primary morbidity and mortality are mostly related to initial injuries and early complications, secondary lethality is strongly linked to the development of systemic inflammatory response syndrome, sepsis, and ultimately multiple organ dysfunction syndrome. We herein report on a 49-year-old male patient who was admitted to the hospital after a traumatic amputation of his right forearm that was cut off while working on a landfill. After initial treatment for shock, he received immediate replantation and was transferred to the ICU. Due to the anticipated risk of a complex infection, continuous renal replacement therapy in combination with CytoSorb was initiated. During the course of the combined treatment, a rapid improvement in hemodynamics was noticed, as well as a significant reduction of IL-6 and lactate levels. Despite a recurring septic episode and the necessity for amputation, the patient clinically stabilized and underwent complete recovery. The early treatment with a combination of CVVHDF and CytoSorb was accompanied by an attenuation of the systemic inflammatory reaction, which subsided without major or permanent organ damage, despite the impressive pathogen spectrum and the pronounced local damage. PMID- 29423324 TI - A False Positive I-131 Metastatic Survey Caused by Radioactive Iodine Uptake by a Benign Thymic Cyst. AB - Thyroid carcinoma is the most common endocrine malignancy in the United States with increasing incidence and diagnosis but stable mortality. Differentiated thyroid cancer rarely presents with distant metastases and is associated with a low risk of morbidity and mortality. Despite this, current protocols recommend remnant ablation with radioactive iodine and evaluation for local and distant metastasis in some patients with higher risk disease. There are several case reports of false positive results of metastatic surveys that are either normal physiologic variants or other pathological findings. Most false positive findings are associated with tissue that has physiologic increased uptake of I-131, such as breast tissue or lung tissue; pathological findings such as thymic cysts are also known to have increased uptake. Our case describes a rare finding of a thymic cyst found on a false positive I-131 metastatic survey. The patient was taken for surgical excision and the final pathology was a benign thymic cyst. Given that pulmonary metastases of differentiated thyroid cancer are rare, thymic cysts, though also rare, must be part of the differential diagnosis for false positive findings on an I-131 survey. PMID- 29423325 TI - Uterine Rupture after Laparoscopic Myomectomy in Two Cases: Real Complication or Malpractice? AB - We describe two cases of uterine rupture in pregnancy after laparoscopic myomectomy and analyze all the aetiological factors involved in this circumstance according to the recent literature, focusing above all on the surgical procedures and the characteristics of the excised myomas. The two cases of uterine rupture in pregnancy following laparoscopic myomectomy occurred at 36 and 18 weeks of gestation, respectively. Both women had undergone laparoscopic multiple myomectomy and uterine rupture occurred along the isthmic myomectomy scars, despite the fact that compliance with all the recent technical surgical recommendations for the previous laparoscopic multiple myomectomy had been fully observed. In our cases we identified the isthmic localization, size of the excised myomas (>=4 cm), and individual characteristics of the healing process as possible risk factors for "a real complication." Larger studies and robust case control analyses are needed to draw reliable conclusions; special care should be paid when performing laparoscopic myomectomy in women planning a later pregnancy. PMID- 29423326 TI - Multiple Tophaceous Gout of Hand with Extensor Tendon Rupture. AB - A 45-year-old man presented with painless subcutaneous masses bilaterally on his hands and loss of motion or contracture of the fingers. Initially, drug therapy to reduce the serum uric acid was administered and was expected to reduce the tophi. However, during observation at the clinic, spontaneous rupture of an extensor tendon occurred, and surgical repair of the tendon and resection of the masses were performed. Surgical exploration of the right hand showed hypertrophic white-colored crystal deposits that both surrounded and invaded the extensor digitorum communis of the index finger, which was ruptured. Histopathologic examination of the specimen demonstrated findings consistent with gouty tophi. Tophaceous gout can induce a rupture of tendons during clinical observation, and surgical resection of the tophi might be needed to prevent ruptures. PMID- 29423327 TI - Resistance Training and Stroke: A Critical Analysis of Different Training Programs. AB - The aim of this study was to carry out a literature review on the overall benefits of resistance training (RT) after stroke and undertake a critical analysis of the resistance exercise programs surveyed (rest interval between sets and exercises, number of sets, number of repetitions, intensity, duration of training, and weekly frequency). To obtain articles for the review, we searched PubMed, Google Scholar, and Physiotherapy Evidence Database (PEDro). Inclusion criteria were considered using the PICO (population, intervention, control/comparison, and outcome variables) model. The following characteristics were recorded for all articles: type of study, author, year of publication, participants (time after stroke, sample size, and age), benefits of RT, and structured resistance exercise programs. Positive effects of training were found on anxiety status, quality of life, muscle hypertrophy, cognitive function, strength, and muscle power. Only 5 studies described the main variables of RT in detail. Lack of control of some variables of RT may negatively affect the results of this practice. The findings of the present study may further inform health and physical conditioning professionals on the importance and necessity of using the main variables in the search for benefits for individuals with stroke. PMID- 29423329 TI - Geotechnical considerations for concurrent pillar recovery in close-distance multiple seams. AB - Room-and-pillar mining with pillar recovery has historically been associated with more than 25% of all ground fall fatalities in underground coal mines in the United States. The risk of ground falls during pillar recovery increases in multiple-seam mining conditions. The hazards associated with pillar recovery in multiple-seam mining include roof cutters, roof falls, rib rolls, coal outbursts, and floor heave. When pillar recovery is planned in multiple seams, it is critical to properly design the mining sequence and panel layout to minimize potential seam interaction. This paper addresses geotechnical considerations for concurrent pillar recovery in two coal seams with 21 m of interburden under about 305 m of depth of cover. The study finds that, for interburden thickness of 21 m, the multiple-seam mining influence zone in the lower seam is directly under the barrier pillar within about 30 m from the gob edge of the upper seam. The peak stress in the interburden transfers down at an angle of approximately 20 degrees away from the gob, and the entries and crosscuts in the influence zone are subjected to elevated stress during development and retreat. The study also suggests that, for full pillar recovery in close-distance multiple-seam scenarios, it is optimal to superimpose the gobs in both seams, but it is not necessary to superimpose the pillars. If the entries and/or crosscuts in the lower seam are developed outside the gob line of the upper seam, additional roof and rib support needs to be considered to account for the elevated stress in the multiple-seam influence zone. PMID- 29423328 TI - Audiovisual Biofeedback-Based Trunk Stabilization Training Using a Pressure Biofeedback System in Stroke Patients: A Randomized, Single-Blinded Study. AB - The purpose of this study was to assess the effects of audiovisual biofeedback based trunk stabilization training using a pressure biofeedback system (PBS) in stroke patients. Forty-three chronic stroke patients, who had experienced a stroke more than 6 months ago and were able to sit and walk independently, participated in this study. The subjects were randomly allocated to an experimental group (n = 21) or a control group (n = 22). The experimental group participated in audiovisual biofeedback-based trunk stabilization training for 50 minutes/day, 5 days/week, for 6 weeks. The control group underwent trunk stabilization training without any biofeedback. The primary outcome of this study was the thickness of the trunk muscles. The secondary outcomes included static sitting balance ability and dynamic sitting balance ability. The thickness of the trunk muscles, static sitting balance ability, and dynamic sitting balance ability were significantly improved in the experimental group compared to the control group (p < 0.05). The present study showed that trunk stabilization training using a PBS had a positive effect on the contracted ratio of trunk muscles and balance ability. By providing audiovisual feedback, the PBS enables accurate and effective training of the trunk muscles, and it is an effective method for trunk stabilization. PMID- 29423330 TI - mTOR signaling in skeletal development and disease. AB - The mammalian/mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that integrates inputs from nutrients and growth factors to control many fundamental cellular processes through two distinct protein complexes mTORC1 and mTORC2. Recent mouse genetic studies have established that mTOR pathways play important roles in regulating multiple aspects of skeletal development and homeostasis. In addition, mTORC1 has emerged as a common effector mediating the bone anabolic effect of Igf1, Wnt and Bmp. Dysregulation of mTORC1 could contribute to various skeletal diseases including osteoarthritis and osteoporosis. Here we review the current understanding of mTOR signaling in skeletal development and bone homeostasis, as well as in the maintenance of articular cartilage. We speculate that targeting mTOR signaling may be a valuable approach for treating skeletal diseases. PMID- 29423332 TI - Effect of Fish Oil vs. Resolvin D1, E1, Methyl Esters of Resolvins D1 or D2 on Diabetic Peripheral Neuropathy. AB - Objective: Fish oil is enriched in omega-3 polyunsaturated fatty acids primarily eicosapentaenoic and docosahexaenoic fatty acids. Metabolites of these two polyunsaturated fatty acids include the E and D series resolvins. Omega-3 polyunsaturated fatty acids and resolvins have been reported to have anti inflammatory and neuroprotective properties. The objective of this study was to evaluate the efficacy of menhaden oil, a fish oil derived from the menhaden, resolvins D1 and E1 and the methyl esters of resolvins D1 and D2 on diabetic peripheral neuropathy. Hypothesis being examined was that the methyl esters of resolvins D1 and D2 would be move efficacious than resolvins D1 or E1 due to an extended half-life. Methods: A model of type 2 diabetes in C57BL/6J mice was created through a combination of a high fat diet followed 8 weeks later with treatment of low dosage of streptozotocin. After 8 weeks of untreated hyperglycemia type 2 diabetic mice were treated for 8 weeks with menhaden oil in the diet or daily injections of 1 ng/g body weight resolvins D1, E1 or methyl esters of resolvins D1 or D2. Afterwards, multiple neurological endpoints were examined. Results: Menhaden oil or resolvins did not improve hyperglycemia. Untreated diabetic mice were thermal hypoalgesic, had mechanical allodynia, reduced motor and sensory nerve conduction velocities and decreased innervation of the cornea and skin. These endpoints were significantly improved with menhaden oil or resolvin treatment. However, the methyl esters of resolvins D1 or D2, contrary to our hypothesis, were generally less potent than menhaden oil or resolvins D1 or E1. Conclusion: These studies further support omega-3 polyunsaturated fatty acids derived from fish oil via in part due to their metabolites could be an effective treatment for diabetic neuropathy. PMID- 29423333 TI - Enolase and Acute Spinal Cord Injury. PMID- 29423334 TI - Pre-pregnancy Body Mass Index and Third-Trimester Depressive Symptoms in a Healthy Privately Insured Sample. AB - Objectives While being overweight (body mass index [BMI] >25) prior to pregnancy is linked to antenatal depression, whether weight is confounded by socioeconomic and/or medical risks is unclear. Study Design We assessed 66 healthy privately insured pregnant women at M = 35.0 +/- 3.3 weeks for symptoms of depression (Inventory for Depressive Symptoms-Self-Report (IDS-SR 30), lifetime history of depression and other psychiatric conditions (Mini International Neuropsychiatric Interview), and pre-pregnancy BMI derived from pre-pregnancy weight (by recall) and directly measured height. Pre-pregnancy overweight (BMI > 25) and antenatal depression (score of mild or greater [14] on the IDS-SR 30) were assessed using logistic regression, controlling for past major depressive disorder (MDD) and demographic factors showing significant between group differences. Results Pre pregnancy overweight ( n = 17; 25.8%) was associated with an increased risk of third trimester depression, independent of past MDD and marital status (odds ratio = 7.47; 95% confidence interval [2.09-26.68]; B (standard error) = 2.010 [0.650]). Conclusion Replication in a larger sample is suggested to confirm an independent effect of pregravid overweight on third trimester depression. PMID- 29423335 TI - Development and Application of Cancer Stem Cell-Targeted Vaccine in Cancer Immunotherapy. PMID- 29423336 TI - Myoclonic Jerks, Exposure to Many Cats, and Neurotoxoplasmosis in an Immunocompetent Male. AB - Background: Myoclonic jerks are due to sudden, brief, involuntary muscle contractions, positive myoclonus, or brief cessation of ongoing muscular activity, negative myoclonus, and may be difficult to recognize. Case Report: We describe an immunocompetent, adult, male patient with sleep-related, multifocal, myoclonic jerks and neurotoxoplasmosis with abnormal cerebrospinal fluid but normal brain imaging. There was complete resolution of the myoclonus with antitoxoplasmosis therapy after 1 week, and no relapse after 1 year. Discussion: Neurotoxoplasmosis may be subtle in presentation, difficult to diagnose, and more common than realized, and it is being increasingly implicated in epileptogenesis in humans. PMID- 29423337 TI - Istradefylline for Restless Legs Syndrome Associated with Parkinson's Disease. PMID- 29423338 TI - Static and Dynamic Cognitive Reserve Proxy Measures: Interactions with Alzheimer's Disease Neuropathology and Cognition. AB - Objective: Years of education are the most common proxy for measuring cognitive reserve (CR) when assessing the relationship between Alzheimer's disease (AD) neuropathology and cognition. However, years of education may be limited as a CR proxy given that it represents a specific timeframe in early life and is static. Studies suggest that measures of intellectual function provide a dynamic estimate of CR that is superior to years of education since it captures the effect of continued learning over time. The present study determined whether dynamic measures of CR were better predictors of episodic memory and executive function in the presence of AD pathology than a static measure of CR. Methods: Subjects examined died with a pre-mortem clinical diagnosis of no cognitive impaired, mild cognitive impairment and mild to moderate AD. CERAD and Braak stage were used to stratify the sample by AD pathology severity. Linear regression analyses using CR by CERAD and CR by Braak stage interaction terms were used to determine whether Extended Range Vocabulary Test (ERVT) scores or years of education were significantly associated with episodic memory composite (EMC) and executive function composite (EFC) performance. All models were adjusted for clinical diagnosis, age at death, gender, APOE e4 carrier status and Braak stage. Results: For episodic memory, years of education by CERAD interaction were not statistically significant (beta=-0.01, SE=0.01, p=0.53). By contrast, ERVT interaction with CERAD diagnosis was statistically significant (beta=-0.03, SE=0.01, p=0.004). Among the models using Braak stages, none of the CR by pathology interactions were associated with EMC or EFC. Conclusion: Results suggest that a dynamic rather than a static measure is a better indicator of CR and that the relationship between CR and cognition is dependent upon the severity of select AD criteria. PMID- 29423339 TI - Interventional Cultural and Language Assistance Program: Associations between Cultural and Linguistic Factors and Satisfaction with Cancer Care. AB - Addressing language and cultural nuance is required to improve the quality of care among all patients. The tenth version of the National Standards for Culturally and Linguistically Appropriate Services in Health Care (CLAS) recommends implementing ongoing assessments to integrate specific actions into measurement and continuous quality improvement activities. To this end, we have created the Interventional Cultural and Language Assistance Program (ICLAP). As part of ICLAP, we conducted a cross-sectional needs assessment survey with 564 consecutive patients receiving outpatient Positron emission tomography-computed tomography (PET/CT) imaging at a comprehensive cancer center in the five most prevalent languages of New York City: English, Spanish, Russian, Chinese, and Arabic. The purpose of this study is to describe the language assistance characteristics and needs of a sample of patients receiving care in the cancer center. We examined the relationship between race, ethnicity, birthplace, communication and language assistance characteristics and the satisfaction with the care received. Our results show that race and ethnicity, birthplace, cultural beliefs, language assistance, and communication characteristics were all factors associated with patients' satisfaction with care, illustrating that there is an unmet need among cancer patients to have cultural and linguistic sensitive services. PMID- 29423340 TI - The Effects of Glaucoma Drainage Devices on Oxygen Tension, Glycolytic Metabolites, and Metabolomics Profile of Aqueous Humor in the Rabbit. AB - Purpose: Glaucoma drainage device (GDD) implantation can lead to corneal decompensation. We evaluated changes over time in oxygen tension and in the metabolic environment of the aqueous humor after GDD implantation in the rabbit eye. Methods: Ahmed Glaucoma Valves were implanted in the left eyes of eight male New Zealand white rabbits. Right eyes were used as a control. Oxygen tension was measured immediately before surgery and at 1 and 2 months postoperation. Aqueous humor was collected from the surgical and control eyes at 1, 2, and 5 months postoperation. Aqueous humor samples collected at 1 and 5 months postoperation were selected for broad-spectrum metabolomics analysis using ultra-performance liquid chromatography-time of flight-mass spectrometry (UPLC TOF-MS). Multivariate analysis methods were used to identify metabolite profiles that separated the surgical and control eye at 1 and 5 months. Results: There was a significant decrease in oxygen tension in aqueous humor of the surgical eyes (9 mm Hg, 95% confidence interval [CI]: -14.7 to -3.5). Differences in the metabolic profiles between the surgical and control eye at 1 and 5 months were observed, as were differences for the surgical eye at 1 and 5 months. In addition, a metabolite profile was identified that differentiated the surgical eyes at 1 and 5 months. Conclusion: Changes in the oxygen tension and metabolic intermediates occur within the aqueous humor as early as 1 month after GDD implantation. Translational Relevance: Corneal decompensation following GDD implantation could be secondary to disruption of the normal aqueous circulation, resulting in hypoxia and an altered metabolic profile. Alterations to the GDD design might minimize aqueous disruption and prevent corneal decompensation. PMID- 29423341 TI - Three-Dimensional Analysis of Peeled Internal Limiting Membrane Using Focused Ion Beam/Scanning Electron Microscopy. AB - Purpose: To reevaluate the effect of internal limiting membrane peeling during vitrectomy on the Muller cell damage, we examined the ultrastructure of the internal limiting membrane by using focused ion beam/scanning electron microscopy (FIB/SEM). Methods: A total of 12 internal limiting membranes obtained during surgery in both the macular hole and the idiopathic epiretinal membrane groups were processed for observation by FIB/SEM. Three-dimensional structures of the internal limiting membrane were analyzed. Results: The number of cell fragments in the macular hole group was 5.07 +/- 1.03 per unit area of internal limiting membrane (100 MUm2). The total volume of cell fragments was 3.54 +/- 1.24 MUm3/100 MUm2. In contrast, the number of cell fragments in the epiretinal membrane group was 12.85 +/- 3.45/100 MUm2, and the total volume of cell fragments was 10.45 +/- 2.77 MUm3/100 MUm2. Data for both values were significantly higher than those observed in the macular hole group (P = 0.0024 and P = 0.0022, respectively, Mann-Whitney U test). No statistical difference was found for the mean volume of the cell fragment between the two groups. Conclusions: All of the internal limiting membrane examined in this study showed cell fragments on the retinal surface of the internal limiting membrane. As compared with macular hole, epiretinal membrane exhibited a higher number and total volume of cell fragments, indicating that internal limiting membrane peeling for epiretinal membrane might have a higher risk of causing inner retinal damage. Translational Relevance: FIB/SEM was a useful tool for three-dimensional quantitative analysis of the internal limiting membrane. PMID- 29423342 TI - Establishing Reference Ranges of Hematological Parameters from Malian Healthy Adults. AB - Introduction: Measurement of immuno-hematological parameters has been historically helpful in the diagnosis and treatment monitoring of many infectious diseases and cancers. However, these parameters have not yet been established in many developing countries where patient care strongly relies on such low-cost tests. This study describes the immuno-hematological parameter ranges for Malian healthy adults. Methods: A cross sectional study was conducted from August 2004 to May 2013. We included 213 healthy volunteers (173 male and 40 female), aged between 18-59 years. Median, 2.5 and 97.5 percentile ranges for each immuno hematological parameter are presented. Results: In our study population, the hematological parameters' ranges were mostly different to the universal established ranges. We found in our population a Median white blood cell (WBC) count of 5200 cells/MUL [3237.5-11900], Red Blood Cell (RBC) count of 4.94 10^6 [3.56-6.17], hemoglobin (Hb) of 14.2 g/dL [12.2-17.38], platelet count (Plt) of 275 10^3/MUL [145.4-614.4], lymphocytes 2050/MUL [1200-3800], neutrophils 2200/MUL [1040-6220]; monocytes 200/MUL [100-660]; eosinophils 131/MUL [0-1026]; CD4 902 cells/MUL [444-1669] and CD8 485 cells/MUL [0-1272]. We found significant gender differences in RBC, Hb level and MPV. However, RBC and Hb were higher in males median values compared to females (median values) (p<0.001), whereas the Mean platelet volume lower values (MPV) in males than females (P<0.047). The hemoglobin level for some West African countries (Mali, Burkina Faso, Togo, and Nigeria) ranged from 13.5 to 15.1 g/dL for males and 12 to 13 g/dL for females. However in East and Southern Africa, the values were anywhere from 14.1 to 16.1 for males and 11.2 to 14.4 for females. Conclusion: Our data may help physicians to better define hematological abnormalities in patients. They may also be used to define new "normal hematological values" in Malian population or in the whole West African population. PMID- 29423331 TI - Transforming growth factor-beta in stem cells and tissue homeostasis. AB - TGF-beta 1-3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix (ECM). The biological functions of TGF-beta in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-beta in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-beta is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-beta ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-beta signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-beta is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-beta. PMID- 29423343 TI - Rumination and Psychopathology: Are Anger and Depressive Rumination Differentially Associated with Internalizing and Externalizing Psychopathology? AB - Existing literature on rumination has predominately focused on depressive rumination; thus, there is little research directly comparing different forms of rumination as correlates of psychopathological outcomes. The present study investigated anger and depressive rumination as correlates of internalizing and externalizing psychopathology. Cross-sectional confirmatory factor analyses on data from 764 young adults from the Colorado Longitudinal Twin Study indicated that anger and depressive rumination were separable at the latent variable level, and were both associated with lifetime symptoms of internalizing and externalizing psychopathology. However, depressive rumination was more strongly associated with psychopathology than was anger rumination. Further analysis indicated that depressive rumination was independently associated with internalizing psychopathology, whereas associations between anger rumination and psychopathology were predominately due to shared variance with depressive rumination. Anger rumination was independently associated with externalizing psychopathology in women and was inversely associated with internalizing psychopathology in men. This result supports the clinical relevance of ruminative thought processes and the potential differential utility of anger and depressive content for understanding internalizing and externalizing psychopathology. PMID- 29423344 TI - Ant mosaics in Bornean primary rain forest high canopy depend on spatial scale, time of day, and sampling method. AB - Background: Competitive interactions in biological communities can be thought of as giving rise to "assembly rules" that dictate the species that are able to co exist. Ant communities in tropical canopies often display a particular pattern, an "ant mosaic", in which competition between dominant ant species results in a patchwork of mutually exclusive territories. Although ant mosaics have been well documented in plantation landscapes, their presence in pristine tropical forests remained contentious until recently. Here we assess presence of ant mosaics in a hitherto under-investigated forest stratum, the emergent trees of the high canopy in primary tropical rain forest, and explore how the strength of any ant mosaics is affected by spatial scale, time of day, and sampling method. Methods: To test whether these factors might impact the detection of ant mosaics in pristine habitats, we sampled ant communities from emergent trees, which rise above the highest canopy layers in lowland dipterocarp rain forests in North Borneo (38.8 60.2 m), using both baiting and insecticide fogging. Critically, we restricted sampling to only the canopy of each focal tree. For baiting, we carried out sampling during both the day and the night. We used null models of species co occurrence to assess patterns of segregation at within-tree and between-tree scales. Results: The numerically dominant ant species on the emergent trees sampled formed a diverse community, with differences in the identity of dominant species between times of day and sampling methods. Between trees, we found patterns of ant species segregation consistent with the existence of ant mosaics using both methods. Within trees, fogged ants were segregated, while baited ants were segregated only at night. Discussion: We conclude that ant mosaics are present within the emergent trees of the high canopy of tropical rain forest in Malaysian Borneo, and that sampling technique, spatial scale, and time of day interact to determine observed patterns of segregation. Restricting sampling to only emergent trees reveals segregatory patterns not observed in ground-based studies, confirming previous observations of stronger segregation with increasing height in the canopy. PMID- 29423346 TI - Relative evolutionary rate inference in HyPhy with LEISR. AB - We introduce LEISR (Likehood Estimation of Individual Site Rates, pronounced "laser"), a tool to infer relative evolutionary rates from protein and nucleotide data, implemented in HyPhy. LEISR is based on the popular Rate4Site (Pupko et al., 2002) approach for inferring relative site-wise evolutionary rates, primarily from protein data. We extend the original method for more general use in several key ways: (i) we increase the support for nucleotide data with additional models, (ii) we allow for datasets of arbitrary size, (iii) we support analysis of site-partitioned datasets to correct for the presence of recombination breakpoints, (iv) we produce rate estimates at all sites rather than at just a subset of sites, and (v) we implemented LEISR as MPI-enabled to support rapid, high-throughput analysis. LEISR is available in HyPhy starting with version 2.3.8, and it is accessible as an option in the HyPhy analysis menu ("Relative evolutionary rate inference"), which calls the HyPhy batchfile LEISR.bf. PMID- 29423345 TI - Linking pangenomes and metagenomes: the Prochlorococcus metapangenome. AB - Pangenomes offer detailed characterizations of core and accessory genes found in a set of closely related microbial genomes, generally by clustering genes based on sequence homology. In comparison, metagenomes facilitate highly resolved investigations of the relative distribution of microbial genomes and individual genes across environments through read recruitment analyses. Combining these complementary approaches can yield unique insights into the functional basis of microbial niche partitioning and fitness, however, advanced software solutions are lacking. Here we present an integrated analysis and visualization strategy that provides an interactive and reproducible framework to generate pangenomes and to study them in conjunction with metagenomes. To investigate its utility, we applied this strategy to a Prochlorococcus pangenome in the context of a large scale marine metagenomic survey. The resulting Prochlorococcus metapangenome revealed remarkable differential abundance patterns between very closely related isolates that belonged to the same phylogenetic cluster and that differed by only a small number of gene clusters in the pangenome. While the relationships between these genomes based on gene clusters correlated with their environmental distribution patterns, phylogenetic analyses using marker genes or concatenated single-copy core genes did not recapitulate these patterns. The metapangenome also revealed a small set of core genes that mostly occurred in hypervariable genomic islands of the Prochlorococcus populations, which systematically lacked read recruitment from surface ocean metagenomes. Notably, these core gene clusters were all linked to sugar metabolism, suggesting potential benefits to Prochlorococcus from a high sequence diversity of sugar metabolism genes. The rapidly growing number of microbial genomes and increasing availability of environmental metagenomes provide new opportunities to investigate the functioning and the ecology of microbial populations, and metapangenomes can provide unique insights for any taxon and biome for which genomic and sufficiently deep metagenomic data are available. PMID- 29423347 TI - Deficient mismatch repair and RAS mutation in colorectal carcinoma patients: a retrospective study in Eastern China. AB - Objectives: To investigate the frequency and prognostic role of deficient mismatch repair (dMMR) and RAS mutation in Chinese patients with colorectal carcinoma. Methods: Clinical and pathological information from 813 patients were reviewed and recorded. Expression of mismatch repair proteins was tested by immunohistochemistry. Mutation analyses for RAS gene were performed by real-time polymerase chain reaction. Correlations of mismatch repair status and RAS mutation status with clinicopathological characteristics and disease survival were determined. Results: The overall percentage of dMMR was 15.18% (121/797). The proportion of dMMR was higher in patients <50 years old (p < 0.001) and in the right side of the colon (p < 0.001). Deficient mismatch repair was also associated with mucinous production (p < 0.001), poor differentiation (p < 0.001), early tumor stage (p < 0.05) and bowel wall invasion (p < 0.05). The overall RAS mutation rate was 45.88%, including 42.56% (346/813) KRAS mutation and 3.69% (30/813) NRAS mutation (including three patients with mutations in both). KRAS mutation was significantly associated with mucinous production (p < 0.05), tumor stage (p < 0.05) and was higher in non-smokers (p < 0.05) and patients with a family history of colorectal carcinoma (p < 0.05). Overall, 44.63% (54/121) dMMR tumors harbored KRAS mutation, however, dMMR tumors were less likely to have NRAS mutation. Moreover, dMMR, KRAS and NRAS mutation were not prognostic factors for stage I-III colorectal carcinoma. Conclusions: This study confirms that the status of molecular markers involving mismatch repair status and RAS mutation reflects the specific clinicopathological characteristics of colorectal carcinoma. PMID- 29423348 TI - Sea cucumbers reduce chromophoric dissolved organic matter in aquaculture tanks. AB - Background: Mono-specific aquaculture effluents contain high concentrations of nutrients and organic matter, which affect negatively the water quality of the recipient ecosystems. A fundamental feature of water quality is its transparency. The fraction of dissolved organic matter that absorbs light is named chromophoric dissolved organic matter (CDOM). A sustainable alternative to mono-specific aquaculture is the multitrophic aquaculture that includes species trophically complementary named "extractive" species that uptake the waste byproducts. Sea cucumbers are recognized as efficient extractive species due to the consumption of particulate organic matter (POM). However, the effects of sea cucumbers on CDOM are still unknown. Methods: During more than one year, we monitored CDOM in two big-volume tanks with different trophic structure. One of the tanks ( holothurian) only contained around 810 individuals of Anemonia sulcata, whereas the other tank (+holothurian) also included 90 individuals of Holothuria tubulosa and Holothuria forskali. We routinely analyzed CDOM absorption spectra and determined quantitative (absorption coefficients at 325 nm) and qualitative (spectral slopes) optical parameters in the inlet waters, within the tanks, and in their corresponding effluents. To confirm the time-series results, we also performed three experiments. Each experiment consisted of two treatments: +holothurians (+H) and -holothurians (-H). We set up three +H tanks with 80 individuals of A. sulcata and 10 individuals of H. tubulosa in each tank and four -H tanks that contained only 80 individuals of A. sulcata. Results: In the time series, absorption coefficients at 325 nm (a325) and spectral slopes from 275 to 295 nm (S275-295) were significantly lower in the effluent of the +holothurian tank (average: 0.33 m-1 and 16 um-1, respectively) than in the effluent of the holothurian tank (average: 0.69 m-1 and 34 um-1, respectively), the former being similar to those found in the inlet waters (average: 0.32 m-1 and 22 um-1, respectively). This reduction in the absorption of the dissolved organic matter appears to be mediated by the POM consumption by holothurians. The experiments confirmed the results observed in the time-series. The a325 and S275-295 values were significantly lower in the treatment with holothurians than in the treatment without holothurians indicating a reduction in the concentration of chromophoric organic compounds, particularly of low molecular weight. Discussion: Consequently, sea cucumbers appear to improve water transparency in aquaculture tanks. The underlying mechanism of this improvement might be related to the POM consumption by holothurians, which reduces the concentration of CDOM derived from POM disaggregation or to the direct assimilation of dissolved compounds of low molecular weight as chromophoric amino acids. PMID- 29423349 TI - Complex versus simple models: ion-channel cardiac toxicity prediction. AB - There is growing interest in applying detailed mathematical models of the heart for ion-channel related cardiac toxicity prediction. However, a debate as to whether such complex models are required exists. Here an assessment in the predictive performance between two established large-scale biophysical cardiac models and a simple linear model Bnet was conducted. Three ion-channel data-sets were extracted from literature. Each compound was designated a cardiac risk category using two different classification schemes based on information within CredibleMeds. The predictive performance of each model within each data-set for each classification scheme was assessed via a leave-one-out cross validation. Overall the Bnet model performed equally as well as the leading cardiac models in two of the data-sets and outperformed both cardiac models on the latest. These results highlight the importance of benchmarking complex versus simple models but also encourage the development of simple models. PMID- 29423350 TI - Primary Psychiatric Disorder Masking the Diagnosis of Neuropsychiatric Lupus in a Patient with Altered Mental Status: A Case Report. AB - Neuropsychiatric systemic lupus erythematosus (NPSLE) has a wide variety of neurologic and psychiatric features. NPSLE symptoms and the psychotic features of primary psychiatric disorders often overlap with each other. These psychotic features often mask and delay the diagnosis of NPSLE. We present the case of a 59 year-old female previously diagnosed with bipolar disorder and generalized anxiety disorder presenting with altered mental status (AMS), subsequently diagnosed with neuropsychiatric lupus. Initially, medication overdose was suspected as an empty bottle of trazodone was found beside her. Obtaining an appropriate history was difficult due to the patient's altered mental status and absence of family members at bedside. The patient was found to have an elevated gamma gap, and further workup was pursued. Subsequently, positive antinuclear antibody (ANA) and anti-double stranded DNA antibody (anti-dsDNA) was detected. During the hospitalization, she was found to meet the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria for systemic lupus erythematosus (SLE). Lumbar puncture with cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis, elevated protein with no bacteria and likely a non-infectious process. Magnetic resonance imaging (MRI) spectroscopy of the brain revealed a reversal of normal Hunter's angle, with elevated choline-to creatine ratio within the white matter, and a lactate peak, which may be present in neuropsychiatric lupus. The patient was diagnosed with SLE with neuropsychiatric manifestations. Consequently, a kidney biopsy was obtained showing Class IV diffuse proliferative glomerulonephritis with fibrillary component likely related to lupus nephritis. The patient was started on treatment for neuropsychiatric lupus, which includes treatment for lupus nephritis with high dose pulse methylprednisolone. The anti-dsDNA titers decreased from 81 to 15 IU/ml and the patient displayed a gradual improvement in her mental status. She was started on cyclophosphamide while inpatient and discharged with the combination of cyclophosphamide, prednisone, along with rheumatology follow-up. This case stresses the importance of ruling out organic causes of AMS before diagnosing patients with a psychiatric disorder. Not every patient with SLE will meet the criteria for diagnosis at the same point in time; hence, it is important to obtain an appropriate history and physical examination to support such diagnosis. We believe our patient had a neuropsychiatric manifestation of SLE, which demonstrates the importance to keep this diagnosis in the list of differentials when assessing a patient presenting with AMS. PMID- 29423351 TI - Hemangiopericytoma in the Olfactory Groove: A Rare and Unusual Presentation. AB - Intracranial hemangiopericytomas (HPCs) are solitary fibrous tumors of the smooth muscle and the mesenchymal origin. While meningiomas located within the olfactory groove are common, an HPC in this location has never been reported previously. Here we describe the rare presentation of a differentiated HPC masquerading as an olfactory groove meningioma in a 33-year-old female presenting with the progressive headaches, anosmia, and visual field disturbances. Following resection, the histopathological analysis confirmed a grade II HPC. A preoperative understanding of the radiographic differences between the meningiomas and HPCs may confirm the treatment planning. An HPC must be considered in the differential diagnosis of the tumors located within the olfactory groove. PMID- 29423352 TI - Effects of Soft Drinks on Resting State EEG and Brain-Computer Interface Performance. AB - Motor imagery-based (MI based) brain-computer interface (BCI) using electroencephalography (EEG) allows users to directly control a computer or external device by modulating and decoding the brain waves. A variety of factors could potentially affect the performance of BCI such as the health status of subjects or the environment. In this study, we investigated the effects of soft drinks and regular coffee on EEG signals under resting state and on the performance of MI based BCI. Twenty-six healthy human subjects participated in three or four BCI sessions with a resting period in each session. During each session, the subjects drank an unlabeled soft drink with either sugar (Caffeine Free Coca-Cola), caffeine (Diet Coke), neither ingredient (Caffeine Free Diet Coke), or a regular coffee if there was a fourth session. The resting state spectral power in each condition was compared; the analysis showed that power in alpha and beta band after caffeine consumption were decreased substantially compared to control and sugar condition. Although the attenuation of powers in the frequency range used for the online BCI control signal was shown, group averaged BCI online performance after consuming caffeine was similar to those of other conditions. This work, for the first time, shows the effect of caffeine, sugar intake on the online BCI performance and resting state brain signal. PMID- 29423353 TI - Dissociative electron attachment to coordination complexes of chromium: chromium(0) hexacarbonyl and benzene-chromium(0) tricarbonyl. AB - Here we report the results of dissociative electron attachment (DEA) to gas-phase chromium(0) hexacarbonyl (Cr(CO)6) and benzene-chromium(0) tricarbonyl ((eta6 C6H6)Cr(CO)3) in the energy range of 0-12 eV. Measurements have been performed utilizing an electron-molecular crossed beam setup. It was found that DEA to Cr(CO)6 results (under the given experimental conditions) in the formation of three fragment anions, namely [Cr(CO)5]-, [Cr(CO)4]-, and [Cr(CO)3]-. The predominant reaction channel is the formation of [Cr(CO)5]- due to the loss of one CO ligand from the transient negative ion. The [Cr(CO)5]- channel is visible via two overlapping resonant structures appearing in the energy range below 1.5 eV with a dominant structure peaking at around 0 eV. The peak maxima of the fragments generated by the loss of two or three CO ligands are blue-shifted and the most intense peaks within the ion yield curves appear at 1.4 eV and 4.7 eV, respectively. (eta6-C6H6)Cr(CO)3 shows a very rich fragmentation pattern with decomposition leading to the formation of seven fragment anions. Three of them are generated from the cleavage of one, two or three CO ligand(s). The energy of the peak maxima of the [(C6H6)Cr(CO)2]-, [(C6H6)Cr(CO)]-, and [(C6H6)Cr]- fragments is shifted towards higher energy with respect to the position of the respective fragments generated from Cr(CO)6. This phenomenon is most likely caused by the fact that chromium-carbonyl bonds are stronger in the heteroleptic complex (eta6-C6H6)Cr(CO)3 than in homoleptic Cr(CO)6. Besides, we have observed the formation of anions due to the loss of C6H6 and one or more CO units. Finally, we found that Cr-, when stripped of all ligands, is generated through a high-energy resonance, peaking at 8 eV. PMID- 29423354 TI - Complex functional and epithetic rehabilitation after ablation of recurrent retroauricular basal cell carcinoma - a case study. AB - The reconstruction of extended defects of the concha poses a complex challenge for plastic surgeons. In cases of subtotal ablation, an alternative method designed especially for elderly oncological patients consists of epithetic rehabilitation. However, inserting an implant-retained concha epithesis proves challenging in patients with antecedents of deep resections involving the mastoid process. In the present case study, we report on the long-term treatment course (2009-2017) of a 79-year-old male patient suffering from a recurrent basal cell carcinoma of the retroauricular region. Following tumor resection, along with lateral mastoidectomy, reconstruction, and adjuvant radiotherapy, functional and esthetic deficits primarily due to peripheral facial nerve palsy were successfully managed using a multistep procedure. The procedure was completed by inserting an implant-retained concha epithesis, resulting in improved quality of life. Due to prior lateral mastoidectomy, ultra-short implants (4 mm) were inserted, partially at atypical positions. For maintaining healthy periimplant soft tissue, aftercare comprised cold plasma treatment. This oncologic case demonstrates the therapeutic necessity of using a broad spectrum of reconstructive procedures, along with their limitations, in a critical anatomic region. Specific features include the presentation of a workflow using ultra short implants in a compromised mastoid region. Surgeons should consider alternative implant positions in the event of any compromised mastoid process. A particular emphasis has been put on meticulous aftercare to preserve healthy periimplant soft tissues. PMID- 29423355 TI - Coverage of the scrotum after Fournier's gangrene. AB - Background: Fournier's gangrene is a necrotizing fasciitis caused by mixed aerobic and anaerobic bacteria and results in loss of skin and subcutaneous tissue in the perineal area. Coverage of testis varies from closure of the defect primarily, burying inside the thigh, using the remnants of the scrotum for tissue expansion and coverage by flaps. In this manuscript, scrotal advancement flaps and pudendal thigh flaps were used for coverage of the testis unilaterally or bilaterally according to the size of the defect following Fournier gangrene. Patients and methods: From June 2015 to March 2017, twelve cases were admitted to our department. The patients' ages ranged from 37-59 years and they all had suffered from Fournier's gangrene in the perineal area. Results: Of the twelve cases, two cases showed penile involvement. A skin graft was used for coverage of the penile shaft with excellent take. Four cases were closed primarily. This was applied to cases where loss of skin was less than 50%. The rest of the cases were reconstructed by pudendal thigh flap. The reconstructed cases were covered by bilateral pudendal thigh flap (4 cases) and unilateral pudendal thigh flap (4 cases). The follow-up extended up to 16 months. Conclusion: Scrotal advancement flap was suitable for small and medium size defects due to the elasticity of the scrotal skin. Pudendal thigh flap was efficient for the reconstruction of large defects of the scrotum. PMID- 29423356 TI - Stem Cell Therapies for the Resolution of Radiation Injury to the Brain. AB - Purpose of review: To encapsulate past and current research efforts focused on stem cell transplantation strategies to resolve radiation-induced cognitive dysfunction. Recent Findings: Transplantation of human stem cells in the irradiated brain was first shown to resolve radiation-induced cognitive dysfunction in a landmark paper by Acharya et al., appearing in PNAS in 2009. Since that time, work from the same laboratory as well as other groups have reported on the beneficial (as well as detrimental) effects of stem cell grafting after cranial radiation exposure. Improved learning and memory found many months after engraftment has since been associated with a preservation of host neuronal morphology, a suppression of neuroinflammation, improved myelination and increased cerebral blood flow. Interestingly, many (if not all) of these beneficial effects can be demonstrated by substituting stem cells with microvesicles derived from human stem cells during transplantation, thereby eliminating many of the more long-standing concerns related to immunorejection and teratoma formation. Summary: Stem cell and microvesicle transplantation into the irradiated brain of rodents has uncovered some unexpected benefits that hold promise for ameliorating many of adverse neurocognitive complications associated with major cancer treatments. Properly developed, such approaches may provide much needed clinical recourse to millions of cancer survivors suffering from the unintended side effects of their cancer therapies. PMID- 29423357 TI - Reaching consensus: a review on sexual health training modules for professional capacity building. AB - Background: Professional capacity building (PCB) is the focus point in health related subjects.The present study was conducted to systematically review the existing sexual health training modules for health care providers. Methods: The following keywords were used to search: training, education, professional capacity, practitioner, sexual health, skill education, module, course, package and curriculum.The term MESH is referred to Medical Subject Headings and the following databases were investigated: MEDLINE, EMBASE, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library and Web of Science, Scopus, Google Scholar, SID,Magiran, and Iranmedex. All articles from 1980 to 2015 were extracted. Online modules were excluded. Considering that lesson plan was the basis of instruction, the modules were selected based on the characteristics of the lesson plans. Results: A total number of 38 published training modules in the field of sexuality we redetermined. In total, more than half of the modules (58%) were designed for medical doctor sand allied health professionals and the remaining (42%) were for nurses and midwives. Almost all the modules (97%) were introduced and utilized in developed countries, and only 3% were disseminated in developing countries. Conclusion: There are invaluable modules to build professional capacity in the field of sexual health. As a number of modules have been designed for nurses and midwifes, as the first-line health care providers, the use of these groups in sexual counseling and empowerment for sexual health is essential. No sexual health training program was designed in Iran. Therefore, designing such modules according to Iranian culture is strongly recommended. PMID- 29423359 TI - Evaluating the adoption of evidence-based practice using Rogers's diffusion of innovation theory: a model testing study. AB - Background: Despite the emergence and development of evidence-based practice (EBP) in recent years, its adoption continues to be limited. This study used Rogers's diffusion of innovation theory to identify the factors that advance EBP adoption, determine the process by which such adoption occurs, and develop an EBP adoption model. Methods: This descriptive correlational study with model testing design conducted in 2015.Data were collected from 482 individuals (322 nurses and 160 nursing students) applying a demographic information questionnaire, a standard scale for the perception EBP attributes, an EBP scale, and an individual innovation inventory. The relationships between variables we reexamined by path analysis. Results: The results showed that EBP adoption had a significant positive relationship with individual innovation (r = 0.578, P < 0.001), knowledge (r = 0.657, P < 0.001), attitude (r = 0.623,P < 0.001), and age (r = 0.357, P < 0.001). The findings of path analysis indicated that the goodness of fit indices such as goodness of fit index (GFI) = 0.999, comparative fit index (CFI)= 0.999, root mean square error of approximation (RMSEA) = 0.036 were in the ideal ranges.Knowledge (total effect=0.309, P < 0.001), attitude (total effect = 0.372, P = 0.002), and work experience (total effect=0.321, P = 0.003) had the highest coefficient in the model. Conclusion: The results suggested that EBP adoption was influenced by various factors, such as individual innovation, attitude, knowledge, and the perception of EBP attributes. Among these factors, attitude had the greatest effect on EBP adoption. The findings can serve as a guide for the identification of factors that effectively influence EBP adoption. They can also be used as bases for the design of training programs intended to enhance the adoption of EBP. PMID- 29423358 TI - Using the PRECEDE-PROCEED model for an online peer-to-peer suicide prevention and awareness for depression (SPAD) intervention among African American college students: experimental study. AB - Background: Suicide rates are high among African American students because they are at a greater risk of depression. A commonly used suicide prevention approach is the gatekeeper training. However, gatekeeper training is neither evidence based nor has it been identified as culturally-appropriate for African American college students. Therefore, the purpose of this study was to develop and evaluate an online peer-to-peer PRECEDE-PROCEED model based depression awareness and suicide prevention program that was culturally appropriate for African American college students. Methods: The setting was a predominantly Black institution in southern USA. A pre-experimental repeated measures one group design was used to measure changes in peer educators' (n = 29) predisposing factors regarding knowledge, skills and attitudes pertaining to depression, reinforcing factors or receiving support from peers, healthcare professionals and teachers to help someone with depression, enabling factors or sureness of finding organizations to help someone with depression, and behavior for helping someone with depression at pretest, posttest and 1-month follow-up. A posttest only one group design was also used to measure effect on predisposing factors and behavior of students (n = 300) trained by peer educators. Results: There were statistically significant improvements in attitudes related to depression as disease (P = 0.003; eta2 = 0.39), attitudes about managing depression (P = 0.0001; eta2 = 0.30), skills(P = 0.0001; eta2 = 0.41), reinforcing factors (P = 0.018; eta2 = 0.13), enabling factors (P = 0.0001;eta2 = 0.31), and behavior (P = 0.016; eta2 = 0.14). Changes in knowledge about depression and attitudes about helping people with depression were not statistically significant over time for peer educators. The peer-to-peer training was not completely effective in transferring corresponding changes for students trained by peers. Conclusion: The program was effective for peer educators but peers could not significantly influence other students in all domains. This study provides a starting point toward evidencebased approaches for health promotion interventionists addressing depression awareness and suicide prevention among African American college students. PMID- 29423360 TI - Use of ethnic spices by adults in the United States: An exploratory study. AB - Background: The use of complementary and alternative medicine (CAM) therapies has increased in the United States, but little is known about consumers' perceptions of use of such therapies. The purpose of this study was to assess knowledge, perceptions, and predictors of spice use for health promotion among adults in the Midwestern US. Methods: UUsing a cross-sectional study design, adults in the Midwestern US (n = 703) completed a valid and reliable survey which was pilot tested with a small convenience sample of adults (n = 38). The study variables included demographic profile, spice use behavior, perceptions about efficacy of spices, and willingness to use spices. Data were analyzed using SPSS to compute descriptive (e.g. percent and frequencies) and inferential statistics (i.e. logistic regression analyses). Results: Almost half of the participants were interested in learning about health benefits of spices (48%), indicated friends and family members as sources of information on spices (50%),and were willing to use spices as CAM therapies (51%). Most (>50%) of the participants were familiar with or had used eight out of the 10 listed spices. The majority of participants (54%)were currently using one or more spices on a daily basis and believed that ginger (64%), garlic(58%), and cinnamon (56%) could promote good health and wellness. In logistic regression analysis, age, gender (odds ratios [OR] = 1.44 and OR = 1.56), income (OR = 1.77), health status(OR = 2.01), and recommendations from healthcare providers (OR = 5.31 and OR = 3.96) were significant predictors of current spice use and willingness to use spices. Conclusion: Individuals in our study did not use many ethnic spices and were unaware of potential health benefits of spices. Greater awareness of ethnic spices for disease prevention and health promotion are needed in this population. PMID- 29423361 TI - The influence of common method bias on the relationship of the socio-ecological model in predicting physical activity behavior. AB - Background: The purpose of this study was to evaluate the extent, if any, that the association between socio-ecological parameters and physical activity may be influenced by common method bias (CMB). Methods: This study took place between February and May of 2017 at a Southeastern University in the United States. A randomized controlled experiment was employed among 119 young adults.Participants were randomized into either group 1 (the group we attempted to minimize CMB)or group 2 (control group). In group 1, CMB was minimized via various procedural remedies,such as separating the measurement of predictor and criterion variables by introducing a time lag (temporal; 2 visits several days apart), creating a cover story (psychological), and approximating measures to have data collected in different media (computer-based vs. paper and pencil) and different locations to control method variance when collecting self-report measures from the same source. Socio-ecological parameters (self-efficacy; friend support; family support)and physical activity were self-reported. Results: Exercise self-efficacy was significantly associated with physical activity. This association (beta = 0.74, 95% CI: 0.33-1.1; P = 0.001) was only observed in group 2 (control), but not in group 1 (experimental group) (beta = 0.03; 95% CI: -0.57-0.63; P = 0.91). The difference in these coefficients (i.e., beta = 0.74 vs. beta = 0.03) was statistically significant (P = 0.04). Conclusion: Future research in this field, when feasible, may wish to consider employing procedural and statistical remedies to minimize CMB. PMID- 29423362 TI - Subjective well-being among Latino day laborers: Examining the role of religiosity, social networks, and cigarette use. AB - Background: Latino day laborers (LDLs) experience chronic stressors, that adversely affects their subjective well-being (SWB). The purpose of the study was to determine whether LDLs' sociodemographic characteristics, religiosity, social networks, and cigarette use were significantly associated with SWB. Methods: AApproximately 150 LDLs from 4 informal day laborer sites in Dallas and Arlington, Texas, participated in the cross-sectional survey. Informed consent was obtained from all participants and data on SWB were collected face-to-face from April 2013 through July 2013. Results: Most respondents were of Mexican ancestry, (n = 112; 75%), were foreign-born (n = 140; 93%), and undocumented (n = 108; 72%). LDLs reported a mean satisfaction with life score of 19.07 (SD=8.52). Thirty percent of LDLs reported not smoking any cigarettes in the past 30 days. However, 20% reported smoking 20-39 cigarettes, while another 20% reported smoking 40 or more cigarettes in the past 30 days. Hierarchical multiple regression results indicated that marital status (beta = 0.13, P <= 0.05), connectedness to friends (beta = 0.21, P <= 0.001), the influence of religion on life (beta = 0.57, P <= 0.01), frequency of attendance to religious institution (beta = 0.11, P <= 0.005), and cigarette use (beta = -0.15, P <= 0.05) were significantly associated with the SWB appraisals of LDLs. Conclusion: These findings show that LDLs are resilient and rely on noneconomic factors to enhance their perceived quality of life. The results underscore the need to identify pathways to improve SWB among LDLs. Doing so may address the broader mental health and occupational health disparities gaps that affect LDLs. PMID- 29423363 TI - Development and psychometric properties of a Calcium Intake Questionnaire based on the social cognitive theory (CIQ-SCT) for Iranian women. AB - Background: Osteoporosis is common among women which may be mostly due to the low intake of calcium. This article reports the development, cultural adaptation and psychometric properties of a Calcium Intake Questionnaire based on the social cognitive theory (CIQ-SCT)among Iranian women. Methods: In 2016, this cross sectional study was carried out among 400 younger than 50 years old women in Isfahan, Iran. After literature review, a preliminary 35-item questionnaire was developed. Then, forward-backward translation and cultural adaptation of the tool was conducted. Content Validity Index confirmed by an expert panel and Face Validity was evaluated in a pilot study. Exploratory and confirmatory factor analyses (EFA &CFA) were conducted on the calibration and validation sample, respectively. Reliability was also assessed using internal consistency test. Results: After determining content and face validity, 20 items with 5 factors (self-efficacy,outcome expectations, social support and self-regulation) were obtained. Cronbach alpha for the instrument was found to be 0.901. In EFA, we identified a 4-factor model with a total variance of 72.3%. The results related to CFA (CMIN/DF=1.850, CFI =0.946, TLI=0.938, RMSEA=0.069[90% CI: 0.057-0.081]) indicated that the model was fit to the social cognitive theory. Self regulation was detected as the best predictor for calcium intake. Conclusion: The CIQ-SCT showed acceptable levels of reliability and validity in explaining the calcium intake based on the constructs of social cognitive theory. Further psychometric testing is recommended in different population to approve the external validity of the instrument. PMID- 29423364 TI - Promoting evidence informed policymaking for maternal and child health in Nigeria: lessons from a knowledge translation workshop. AB - Background: Knowledge translation (KT) is a process that ensures that research evidence gets translated into policy and practice. In Nigeria, reports indicate that research evidence rarely gets into policymaking process. A major factor responsible for this is lack of KT capacity enhancement mechanisms. The objective of this study was to improve KT competence of an implementation research team (IRT), policymakers and stakeholders in maternal and child health to enhance evidence-informed policymaking. Methods: This study employed a "before and after" design, modified as an intervention study. The study was conducted in Bauchi, north-eastern Nigeria. A three-day KT training workshop was organized and 15 modules were covered including integrated and end-of-grant KT; KT models, measures, tools and strategies; priority setting; managing political interference; advocacy and consensus building/negotiations; inter-sectoral collaboration; policy analysis, contextualization and legislation. A 4-point Likert scale pre-/post-workshop questionnaires were administerd to evaluate the impact of the training, it was designed in terms of extent of adequacy; with "grossly inadequate" representing 1 point, and "very adequate" representing 4 points. Results: A total of 45 participants attended the workshop. There was a noteworthy improvement in the participants' understanding of KT processes and strategies. The range of the preworkshop mean of participants knowledge of modules taught was from 2.04-2.94, the range for the postworkshop mean was from 3.10-3.70 on the 4-point Likert scale. The range of percentage increase in mean for participants' knowledge at the end of the workshop was from 13.3%-55.2%. Conclusion: The outcome of this study suggests that using a KT capacity building programme e.g., workshop, health researchers, policymakers and other stakeholders can acquire capacity and skill that will facilitate evidence-to-policy link. PMID- 29423365 TI - Exploring the feelings of Iranian women of reproductive age about health care seeking behavior: a qualitative study. AB - Background: Despite the important role of feelings in health care seeking behavior (HCSB), this subject has not yet been adequately investigated. HCSB related feelings begin with the onset of disease symptoms and persist in different forms after treatment. The aim of current study was to explore the feelings that women of reproductive age experience when they seek health care. Methods: In this deductive, qualitative content analysis, participants were selected by purposeful sampling. Semi-structured, in-depth interviews with 17 women of reproductive age and 5 health care staffs in Qom, Iran were carried out until data saturation was achieved. Qualitative data were concurrently analyzed by deductive content analysis, using the Health Promotion Model (HPM). The MAXQDA10 software was used to manage qualitative data analysis. Results: Three main categories were drawn from data to explain the HCSB-related feelings of participants consisting of (1) feeling of inner satisfaction with the treatment with 2 subcategories including "peace of mind" and "feeling alive", (2) multiple roles of fear with 5 subcategories including "fear about the consequences of delay", "fear of having hidden diseases", "fear of unknown experiences", "fear of hearing bad news" and "fear of medical errors" and (3)uncomfortable feelings with 3 subcategories including "feeling uneasy when attending health facility", "feeling embarrassed" and "feeling worthless due to dealing the doctor". Conclusion: This study revealed that the inner feelings of women varied widely, ranging from positive or motivating feelings to negative or inhibitory ones, given their experiences with the formal health care system and the current situation of medical and health services. Highlighting patients' perceived inner satisfaction and reducing fear and uncomfortable feelings by adopting culture based practical strategies can enhance women's HCSB. PMID- 29423366 TI - What determines psychological well-being among Iranian female adolescents? Perceived stress may overshadow all determinants. AB - Background: Mental health problems, as one of the most neglected issues among adolescents,are common during adolescence and emerging adulthood. The aim of present study was to investigate the determinants of psychological well being among female adolescents in Tabriz,Iran. Methods: In this cross-sectional study, multi-stage cluster sampling was employed to recruit 289 female high school students to participate in the study during 2013-2014. A 3-section questionnaire was applied to collect data. Hierarchical linear regression analysis was applied to illustrate the variations in psychological wellbeing score on the basis of socio-demographic and psychological variables. Results: Self-efficacy, hopefulness, happiness and life satisfaction were positively correlated (r> 0.400) and perceived stress was negatively associated with psychological well being (r =-0.689). In the first model, satisfaction with family lifestyle (beta = 0.168, P < 0.001) and perceived stress (beta = -0.470, P < 0.001) were the most significant positive and negative predictors for psychological wellbeing, respectively (R2 = 0.595, P < 0.001). In the second model (step 6),physical activity (beta = -0.109, P < 0.019), have/had boyfriend (beta = 0.237, P < 0.001), hopefulness(beta = -0.130, P < 0.05) and happiness (-beta = 0.387, P < 0.001) were significant predictors for perceived stress (R2 = 0.453, P < 0.001). Conclusion: Considering the various behavioral, mental and social predictors of psychological wellbeing, it seems that perceived stress has overshadowed the influence of a majority of the other factors. Such influence may be due to the specific cultural and context-based rules enforced for female adolescents in the Iranian community. PMID- 29423367 TI - Management of severe childhood pneumonia by day care approach in developing countries. AB - Background: Pneumonia is a major cause of child mortality among children under 5 years, worldwide. Pneumonia infection may be caused by bacteria, viruses, or fungi in single or in both lungs. According to recent criteria developed by the World Health Organization(WHO) in September (2013), pneumonia can be classified into severe pneumonia, pneumonia and no pneumonia. Most of the deaths occur from severe pneumonia. Methods: Disease management of severe childhood pneumonia requires early identification,prompt referral and the availability of intensive quality care. Under 5 years old children with severe pneumonia should receive day care, with antibiotic treatment, feeding, and supportive care with similar 24 hour hospital treatment. Results: Considering that difficulties, International Centre for Diarrheal Disease Research,Bangladesh (ICDDR, B) initiated Day Care Approach (DCA) model, as an innovative, safe,effective and less expensive alternative to hospital management of severe childhood pneumonia.A 24 months old girl came to the health care center with severe breathing difficulty, cough,history of fever and head nodding. The management described below was continued daily until there was clinical improvement; no fever, no fast breathing, no lower chest wall in drawing, no danger signs, no rales on auscultation, and no hypoxemia. Conclusion: Considering the WHO case management protocol for severe pneumonia, DCA recommends that diagnosis of severe pneumonia should be based primarily on visible clinical parameters. On that basis, severe childhood pneumonia can be successfully managed at daycare clinics including for children with hypoxemia who is required prolong (4-6 hours) oxygen therapy. PMID- 29423368 TI - Multifaceted interventions to reduce acute exacerbations in elderly asthmatics. AB - Background: Although many risk factors are known to be associated with poor asthma outcomes in the elderly, the literature on the effect of risk factor control on asthma outcomes in the elderly is very sparse. Objective: To evaluate the role of multifaceted interventions in reducing acute exacerbations in elderly asthmatics. Methods: A total of 100 subjects were randomly selected from our prospective cohort of elderly asthmatics aged 65 years or older and were provided multifaceted intervention for 1 year. Our multifaceted interventions included repeated education on asthma and inhaler technique for patients and their caregivers, provision of an action plan to cope with acute exacerbations, short message service to prevent follow-up losses, and oral replacement of magnesium. The primary outcome was an acute asthma exacerbation rate compared to the previous year. Results: Ninety-two subjects completed this study, although only 58 subjects continued to take magnesium. Compared to the previous year, the acute asthma exacerbation rate showed a significant reduction from 67% to 50% (p = 0001) and significant improvement was observed in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) (p = 0.04, p = 0.036 for each). Interestingly, a subgroup analysis revealed that predicted value of FEV1 increased significantly in subjects who continued to take magnesium from 79.6% to 87.1% (p = 0.008). Conclusion: To reduce acute exacerbations in elderly asthmatics, a multifaceted approach in increase medical awareness, proficiency and adherence to inhaler, assistance of caregivers and correction of micronutrients deficiency is likely to be effective. In addition, a continuous oral replacement of magnesium may increase FEV1 in elderly asthmatics. PMID- 29423369 TI - Combination of omalizumab and bee venom immunotherapy: does it work? AB - Bee venom immunotherapy (b-VIT) can be combined with omalizumab therapy in order to suppress systemic reactions developing due to b-VIT itself. Omalizumab acts as a premedication and gains time for the immunotherapy to develop its immunomodulatory effects. However, the combination of omalizumab and b-VIT is not always effective enough. Herein we present a patient in whom successful immunotherapy cannot be achieved with combination of omalizumab to b-VIT. PMID- 29423370 TI - Jellyfish ingestion was safe for patients with crustaceans, cephalopods, and fish allergy. PMID- 29423371 TI - Identification of a thermal stable allergen in yam (Dioscorea opposita) to cause anaphylaxis. AB - Yam (Dioscorea opposita) is commonly consumed in East Asia, but allergic reaction to this plant food is rare. To date, there is no report of anaphylactic reaction after ingestion of cooked yam. We described 3 cases with anaphylaxis after eating boiled yam and 1 present with oral allergy syndrome as well. Basophil activation test in patients showed positive reactivity to boiled yam extract. In immunoblotting, a 30-kDa protein was recognized by all patients' sera and a 17 kDa band was detected by 1 patient. N-terminal amino acid revealed the 30-kDa IgE reacted band was DB3S, dioscorin in Dioscorea tuber. It promoted us that DB3S was a thermal stable oral allergen to trigger anaphylactic reaction and oral allergy syndrome in cooked yam (D. opposita) allergy. Patients with this plant food allergy should avoid both raw and well-cooked yam. PMID- 29423372 TI - Optimal control of asthma improved eosinophilic otitis media. AB - Background: Eosinophilic otitis media (EOM) is often associated with comorbid asthma. The middle ear cavity is part of the upper airway. Therefore, EOM and asthma can be considered to be a crucial part of the "one airway, one disease" phenomenon. Based on the concept of one airway, one disease in the context of allergic rhinitis and asthma, optimal level of inhalation therapy for better asthma control leads to improvement in allergic rhinitis. Objective: We conducted a pilot study to determine whether appropriate strengthening of inhalation therapy for asthma is effective for EOM. Methods: Fifteen patients with EOM and comorbid asthma were enrolled in this study. Eight patients were randomly selected and administered appropriately strengthened inhalation therapy for asthma (strengthened group). The effect of the therapy on EOM was assessed by comparing a questionnaire for ear symptoms, clinical characteristic score, pure tone audiometry, blood tests and temporal bone computed tomography (CT) examination before and after the therapy. Seven other EOM + asthma patients without the above mentioned therapy were included as controls. Results: In the strengthened group, the score of ear symptoms, clinical characteristics score, peripheral blood eosinophil count, CT score, and air conduction hearing level improved significantly after strengthening the inhalation therapy, but not in the control group. The lung function tests (forced vital capacity [%predicted], forced expiratory volume in 1 second [FEV1] [L], and FEV1 [%predicted]) significantly increased in the strengthened group after the therapy, but not in the control group. Conclusion: In this study we demonstrated that EOM improved along with improved lung function when appropriately optimal inhalation therapy was implemented in patients with EOM and asthma. Administration of optimizing therapy for asthma might be effective for concomitant EOM. PMID- 29423373 TI - Changes in basophil activation during immunotherapy with house dust mite and mugwort in patients with allergic rhinitis. AB - Background: The basophil activation test (BAT) is a promising tool for monitoring allergen-specific immunotherapy responses. Objective: We aimed to investigate the changes in basophil activation in response to the inhalant allergens of house dust mite (HDM) and mugwort pollen during immunotherapy in patients with allergic rhinitis. Methods: We enrolled patients with allergic rhinitis who were to receive subcutaneous immunotherapy for the inhalant allergens HDM or mugwort. A BAT was performed to assess CD63 upregulation in response to allergen stimulation using peripheral blood collected from the patients prior to immunotherapy and at 3, 6, 12, and 24 months after beginning immunotherapy. Rhinitis symptoms were evaluated using the rhinitis quality of life questionnaire (RQLQ) at 1-year intervals. Results: Seventeen patients (10 with HDM sensitivity, 3 with mugwort sensitivity, and 4 with sensitivity to both HDM and mugwort) were enrolled in the study. Basophil reactivity to HDM did not change significantly during 24 months of immunotherapy. However, a significant reduction in basophil reactivity to mugwort was observed at 24-month follow-up. There was no significant association between the change in clinical symptoms by RQLQ and the change in basophil reactivity to either allergen. The change in allergen-specific basophil reactivity to HDM was well correlated with the change in nonspecific basophil activation induced by anti-FcepsilonRI antibody, although basophil reactivity to anti-FcepsilonRI antibody was not significantly reduced during immunotherapy. Conclusion: Suppression of CD63 upregulation in the BAT was only observed with mugwort at 2-year follow-up. However, the basophil response did not reflect the clinical response to immunotherapy. PMID- 29423374 TI - The International Study of the Allergic Rhinitis Survey: outcomes from 4 geographical regions. AB - Background: Allergic rhinitis (AR) is a global health problem and is characterised by one or more symptoms, including sneezing, itching, nasal congestion and rhinorrhea. Objective: We investigated the features of AR and the physician's approach to the management of AR patients in four geographical regions. Methods: In this cross-sectional study, a questionnaire survey concerning AR was completed by Honorary and Corresponding Members of the Italian Society of Rhinology from different countries among 4 world geographical regions Asia, Europe, the Americas, and Africa. Results: The prevalence of AR was reported to be 15%-25%. Children and adolescents, as well as young adults, were the age groups more affected by AR with comorbidities of asthma, sinusitis, conjunctivitis, and nasal polyposis. Nasal symptoms of AR were more intense in the spring (51.92%) and autumn (28.85%). The most common aero-allergens were pollen and mites (67.31%), animal dander and pollutants (23.08%), and fungal allergens (21.15%). Allergen-specific immunotherapy was prescribed for both perennial and seasonal allergens (32.69%) via sublingual swallow (46.15%) and subcutaneous (32.69%) routes. For the AR patients, the most prescribed drugs were intranasal corticosteroids (86.54%) and oral H1-antihistamines (82.69%). Conclusion: A network of experts can improve our knowledge concerning AR epidemiology, and together with guidelines, could assist practitioners and otolaryngologists in standardising the diagnosis and treatment of AR. PMID- 29423376 TI - A whole new world: Asia Pacific Allergy online-only. PMID- 29423375 TI - Time trends of the prevalence of allergic diseases in Korea: A systematic literature review. AB - The prevalence of allergic diseases has increased dramatically in recent decades, and are now considered major chronic diseases at the global level. The increasing burden of allergic diseases has led to numerous worldwide and local researchers to investigate the time trends in its prevalence and identify its driving factors. Environmental changes such as urbanization and industrialization have been suggested to explain the increasing prevalence, but recent reports from Western countries suggest that this prevalence has reached a plateau or even possibly, started to decrease. However, such environmental changes are still occurring in many Asia-Pacific countries, including Korea, and it is speculated that the peak in allergy epidemics has yet to come. The present systematic literature review aimed to explore the time trends in the prevalence of allergic diseases in Korea and to identify the unmet needs for facilitating further studies. PMID- 29423377 TI - Accuracy of serum-specific IgE test with microfluidic array enzyme-linked immunosorbent assay for diagnosing inhalant allergen sensitization in asthma and/or rhinitis allergy patients in Jakarta, Indonesia. AB - Background: Asthma and allergic rhinitis are a global health burden. Inhalant allergens worsen the symptoms and clinical manifestations of asthma and allergic rhinitis. Skin prick test is the gold standard for diagnosing allergen sensitization but is associated with some limitations. In contrast, in vitro serum-specific immunoglobulin E (SSIgE) test is convenient and is not associated with an anaphylactic risk. Objective: The present study compared the accuracy of the SSIgE test by using microfluidic array enzyme-linked immunosorbent assay (ELISA) with that of the skin prick test for diagnosing inhalant allergen sensitization in patients with asthma and/or allergic rhinitis. Methods: This diagnostic study included patients with asthma and/or allergic rhinitis. Of these, 100 patients underwent the SSIgE test for diagnosing sensitization to house dust mites (Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Blomia tropicalis), dog dander, cat dander, and cockroach allergen. All the patients also underwent the skin prick test for diagnosing allergen sensitization. The sensitivity, specificity, predictive value, and likelihood ratio (LR) of the SSIgE test were evaluated for each allergen. Results: Sensitivity of the SSIgE test for diagnosing house dust mite sensitization was 48%-77%, with the highest sensitivity (77%) observed for diagnosing D. farinae sensitization. Specificity of the SSIgE test for diagnosing house dust mite sensitization was 64%-95%, with the highest specificity (95%) observed for diagnosing B. tropicalis sensitization. Although the SSIgE test showed high specificity and LR+ for diagnosing cockroach allergen sensitization, it showed low sensitivity (12%). Moreover, the SSIgE test showed high specificity (89%) but low sensitivity (3%) for diagnosing dog dander sensitization and high specificity (88%) but low sensitivity (10%) for diagnosing cat dander sensitization. Conclusion: The SSIgE test using microfluidic array ELISA shows moderate accuracy for diagnosing house dust mite sensitization and low accuracy for diagnosing cockroach allergen and dog and cat dander sensitization. PMID- 29423378 TI - Evaluation of the stability of maxillary expansion using cone-beam computed tomography after segmental Le Fort I osteotomy in adult patients with skeletal Class III malocclusion. AB - Objective: The aim of this study is to quantitatively evaluate the stability of the skeletal and dental widths using cone-beam computed tomography (CBCT) after segmental Le Fort I osteotomy in adult patients with skeletal Class III malocclusion requiring maxillary expansion. Methods: In total, 25 and 36 patients with skeletal Class III malocclusion underwent Le Fort I osteotomy (control group) and segmental Le Fort I osteotomy (experimental group), respectively. Coronal CBCT images were used to measure the dental and skeletal widths before (T1) and after (T2) surgery and at the end of treatment (T3). The correlation between the extent of surgery and the amount of relapse in the experimental group was also determined. Results: In the control group, the dental width exhibited a significant decrease of 0.70 +/- 1.28 mm between T3 and T2. In the experimental group, dental and skeletal expansion of 1.83 +/- 1.66 and 2.55 +/- 1.94 mm, respectively, was observed between T2 and T1. The mean changes in the dental and skeletal widths between T3 and T2 were -1.41 +/- 1.98 and -0.67 +/- 0.72 mm, respectively. There was a weak correlation between the amount of skeletal expansion during segmental Le Fort I osteotomy and the amount of postoperative skeletal relapse in the experimental group. Conclusions: Maxillary expansion via segmental Le Fort I osteotomy showed good stability, with a skeletal relapse rate of 26.3% over approximately 12 months. Our results suggest that a greater amount of expansion requires greater efforts for the prevention of relapse. PMID- 29423379 TI - Identification and Characterization of Blood and Neutrophil-Associated Microbiomes in Patients with Severe Acute Pancreatitis Using Next-Generation Sequencing. AB - Infectious complications are a leading cause of death for patients with severe acute pancreatitis (SAP). Yet, our knowledge about details of the blood microbial landscape in SAP patients remains limited. Recently, some studies have reported that the peripheral circulation harbors a diverse bacterial community in healthy and septic subjects. The objective of this study was to examine the presence of the blood bacterial microbiome in SAP patients and its potential role in the development of infectious complications. Here we conducted a prospective observational study on a cohort of 50 SAP patients and 12 healthy subjects to profile the bacterial composition in the blood. The patients were subgrouped into uninfected (n = 17), infected (n = 16), and septic (n = 17) cases. Applying 16S rDNA-based next-generation sequencing technique, we investigated blood and neutrophil-associated microbiomes in SAP patients, and assessed their connections with immunological alterations. Based on the sequencing data, a diverse bacterial microbiota was found in peripheral blood and neutrophils from the healthy and SAP subjects. As compared to healthy controls, the blood and neutrophil-associated microbiomes in the patients were significantly altered, with an expansion in Bacteroidetes and Firmicutes as well as a decrease in Actinobacteria. Variations in the microbiome composition in patients were associated with immunological disorders, including altered lymphocyte subgroups, elevated levels of serum cytokines and altered proteomic profiles of neutrophils. However, no significant compositional difference was observed between the patient subgroups, implying that the microbiota alterations might not be linked to presence/absence of infectious complications in SAP. Together, we present an initial description of the blood and neutrophil-associated bacterial profiles in SAP patients, offering novel evidence for the existence of the blood microbiome. Identification of the blood microbiome provides novel insights into characteristics and diagnostics of bacteremia in the patients. Further study is required to assess the possible implications of the blood microbiome in health and diseases. PMID- 29423380 TI - Firewalls Prevent Systemic Dissemination of Vectors Derived from Human Adenovirus Type 5 and Suppress Production of Transgene-Encoded Antigen in a Murine Model of Oral Vaccination. AB - To define the bottlenecks that restrict antigen expression after oral administration of viral-vectored vaccines, we tracked vectors derived from the human adenovirus type 5 at whole body, tissue, and cellular scales throughout the digestive tract in a murine model of oral delivery. After intragastric administration of vectors encoding firefly luciferase or a model antigen, detectable levels of transgene-encoded protein or mRNA were confined to the intestine, and restricted to delimited anatomical zones. Expression of luciferase in the form of multiple small bioluminescent foci in the distal ileum, cecum, and proximal colon suggested multiple crossing points. Many foci were unassociated with visible Peyer's patches, implying that transduced cells lay in proximity to villous rather than follicle-associated epithelium, as supported by detection of transgene-encoded antigen in villous epithelial cells. Transgene-encoded mRNA but not protein was readily detected in Peyer's patches, suggesting that post transcriptional regulation of viral gene expression might limit expression of transgene-encoded antigen in this tissue. To characterize the pathways by which the vector crossed the intestinal epithelium and encountered sentinel cells, a fluorescent-labeled vector was administered to mice by the intragastric route or inoculated into ligated intestinal loops comprising a Peyer's patch. The vector adhered selectively to microfold cells in the follicle-associated epithelium, and, after translocation to the subepithelial dome region, was captured by phagocytes that expressed CD11c and lysozyme. In conclusion, although a large number of crossing events took place throughout the intestine within and without Peyer's patches, multiple firewalls prevented systemic dissemination of vector and suppressed production of transgene-encoded protein in Peyer's patches. PMID- 29423381 TI - Targeted Delivery of GP5 Antigen of PRRSV to M Cells Enhances the Antigen Specific Systemic and Mucosal Immune Responses. AB - Efficient delivery of antigens through oral immunization is a first and critical step for successful induction of mucosal immunity, which can provide protection against pathogens invading the mucosa. Membranous/microfold cells (M cells) within the mucosa can transcytose internalized antigen without degradation and thus play an important role in initiating antigen-specific mucosal immune responses through inducing secretory IgA production. In this research, we modified poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) with Ulex europaeus agglutinin 1 (UEA-1) and successfully prepared an oral vaccine delivery system, UEA-1/PLGA NPs. PLGA NPs were prepared using a standard double emulsion solvent evaporation technique, which can protect the entrapped PRRSV DNA vaccine [pcDNA3.1-SynORF5 (synthetic ORF5)] or subunit vaccine ORF5-encoded glycoprotein (GP5) from exposure to the gastrointestinal (GI) tract and release the plasmids in a controlled manner. With UEA-1 modification, the UEA-1/PLGA NPs can be effectively transported by M-cells. We investigated immune response induced by UEA-1/PLGA-SynORF5 or UEA-1/PLGA-GP5 following inoculation in mice and piglets. Compared with PLGA-SynORF5 or PLGA-GP5 NPs, UEA-1/PLGA-SynORF5, or UEA-1/PLGA-GP5 NPs stimulated significantly increased serum IgG levels and augmented intestinal IgA levels in mice and piglets (P < 0.05). Our findings indicate UEA-1/PLGA NPs can be applied as a promising and universally robust oral vaccine delivery system. PMID- 29423382 TI - Polymorphisms in Protein Tyrosine Phosphatase Non-receptor Type 2 and 22 (PTPN2/22) Are Linked to Hyper-Proliferative T-Cells and Susceptibility to Mycobacteria in Rheumatoid Arthritis. AB - A shared genetic pre-disposition, chronic inflammation, and treatment with similar biologics between Rheumatoid arthritis (RA) and Crohn's disease (CD) have intrigued us to investigate whether the two disorders share trigger association or possible causation. We hypothesized earlier that Single Nucleotide Polymorphisms (SNPs) in the negative regulators Protein Tyrosine Phosphatase Non receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response, susceptibility to environmental triggers, and continued apoptosis as seen in chronic inflammation in RA and CD. To test the hypothesis, peripheral leukocytes samples from 132 consented subjects were genotyped for 9 SNPs in PTPN2/22 using TaqManTM genotyping. The effect of the SNPs on PTPN2/22 and IFN-gamma expression was determined using real time PCR. T-cell proliferation and response to phytohematoagglutonin (PHA) mitogen and mycobacterial antigens were determined by BrdU proliferation assay. Blood samples were also analyzed for the Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene by nPCR. Out of 9 SNPs examined, heterozygous (TC) or minor (CC) alleles of PTPN2:rs478582 occurred in 79% RA compared to 60% healthy controls (p-values <= 0.05; OR = 2.28). Similarly, heterozygous (GA) or minor (AA) alleles of PTPN22:rs2476601 occurred in 29% RA compared to 6% healthy controls (p-values <= 0.05; OR = 5.90). PTPN2/22 expression in RA was decreased by 1.2-fold compared to healthy controls. PTPN2:rs478582 upregulated IFN-gamma in RA by 1.5-fold. Combined PTPN2:rs478582 and PTPN22:rs2476601 increased T-cell proliferation by 2.7-fold when treated with PHA. Surprisingly, MAP DNA was detected in 34% of RA samples compared to 8% healthy controls, (p-values <= 0.05, OR = 5.74). RA samples with PTPN2:rs478582 and/or PTPN22:rs2476601 were more positive for MAP than samples without polymorphisms. Combined occurrence of PTPN2:rs478582 and PTPN22:rs2476601 in association with the presence of MAP has significantly increased T-cell response and elevated IFN-gamma expression in RA samples. The data suggest that genetic polymorphisms may play vital role in T-cell regulation, susceptibility to mycobacteria and ultimately response to treatment. This is the first study to report the detection of MAP DNA in the blood of RA patients; further studies are needed using larger number of samples. PMID- 29423383 TI - Biodistribution of 99mTc-MAA on SPECT/CT performed for 90Y radioembolization therapy planning: a pictorial review. AB - Purpose: To evaluate the frequency of 99mTc-MAA uptake in extrahepatic organs during 90Y radioembolization therapy planning. Methods: This retrospective case series of 70 subjects who underwent 99mTc-MAA hepatic artery perfusion studies between January 2014 and July 2016 for 90Y radioembolization therapy planning at our institution involved direct image review for all subjects, with endpoints recorded: lung shunt fraction, extrahepatic radiotracer uptake, time from MAA injection to imaging. Results: Combined planar and SPECT/CT imaging findings in the 70 subjects demonstrated lung shunt fraction measurements of less than 10% in 53 (76%) subjects and greater than 10% in 17 (24%) subjects. All patients demonstrated renal cortical uptake, 23 (33%) demonstrated salivary gland uptake, 23 (33%) demonstrated thyroid uptake, and 32 (46%) demonstrated gastric mucosal uptake, with significant overlap between these groups. The range of elapsed times between MAA injection and initial imaging was 41-138 min, with a mean of 92 min. There was no correlation between time to imaging and the presence of extrahepatic radiotracer uptake at any site. Conclusions: During hepatic artery perfusion scanning for 90Y radioembolization therapy planning, extrahepatic uptake is common, particularly in the kidney, salivary gland, thyroid and gastric mucosa, and is hypothesized to result from breakdown of 99mTc-MAA over time. Given the breakdown to smaller aggregates and ultimately pertechnetate, this should not be a contraindication to actual Y-90 microsphere therapy. Although we found no correlation between time to imaging and extrahepatic uptake, most of our injection to imaging times were relatively short. PMID- 29423385 TI - Association of the Anxiety/Depression with Nutrition Intake in Stroke Patients. AB - Stroke patients often experience a walking dysfunction caused by decreased mobility, weakened muscular strength, abnormal posture control, and cognitive dysfunction. Anxiety/depression is the most important and prevalent neuropsychiatric complication of stroke survivors. Brain injury and the presence of malnutrition after stroke contribute to metabolic status and clinical outcome of patients. We examined the level of nutrition intake in stroke patients according to their degree of anxiety/depression. The data were obtained from 2013 to 2015 through the Korea National Health and Nutrition Examination Survey (KNHANES). Study subjects were categorized to either a group having no problem of anxiety/depression (n = 274) or a group having a problem of anxiety or depression (n = 104). The EuroQoL-5 Dimensions Health Questionnaire (EQ-5D) index score was derived from the first description of an individual health status based on the EQ 5D classification system, including mobility, self-care, usual daily activities, pain/discomfort, and anxiety/depression. The mean age was 67.4 years in the normal group and 68.0 years in the anxiety or depression group. In the anxiety or depression group, 39.4% were men vs. 53.3% in the normal group. The total energy intake (p = 0.013), riboflavin (p = 0.041), and niacin (p = 0.038) was significantly higher in stroke patients with no anxiety/depression than those in stroke patients with having an anxiety/depression. The group having no problem of anxiety/depression had significantly higher EQ-5D index compared to the group having a problem of anxiety/depression group (p < 0.001) had. The results suggest the association between nutrition intake, usual activities and pain/discomfort status in the stroke patients with having an anxiety/depression. PMID- 29423386 TI - Erythrocyte Membrane Unsaturated (Mono and Poly) Fatty Acids Profile in Newly Diagnosed Basal Cell Carcinoma Patients. AB - Studies have reported different changes in the fatty acid composition of red blood cell (RBC) total lipids in patients with various types of cancer. It has been indicated that n-3/n-6 ratio plays a key role in the general consequence of skin photocarcinogenesis. However, to our knowledge there was no study examining the unsaturated fatty acid profile in basal cell carcinoma (BCC) patients. So, we explore the fatty acid composition of RBCs in newly diagnosed BCC patients in a hospital-based case-control study. This study has been conducted on new case BCC patients in Razi Hospital, Tehran, Iran. Fatty acid concentration in erythrocyte membranes defined as relative values after extraction, purification and preparation, by gas chromatography.Analysis revealed that heptadecenoic acid (p = 0.010) and oleic acid (p < 0.001) was significantly higher in BCC patients in comparison with control group. Among polyunsaturated fatty acids (PUFAs), linoleic acid (LA), and arachidonic acid (AA) were significantly higher in BCC patients (p < 0.001). It has been indicated that n-3 was significantly lower (p = 0.040) and n-6 was significantly higher (p = 0.002) in BCC patients. In addition, total PUFA (p < 0.001) and n-6 PUFAs/n-3 PUFAs (p = 0.002) were significantly higher in BCC patients compared to the control group. Here we indicated that new case BCC patient had significantly higher n-6 PUFA and lower n-3 along with other differences in unsaturated fatty acid in comparison with healthy subjects. Our study provides evidence that lipids are important in BCC development. PMID- 29423384 TI - Perspectives in Lipocalin-2: Emerging Biomarker for Medical Diagnosis and Prognosis for Alzheimer's Disease. AB - Lipocalin-2 (LCN2), a secreted glycoprotein belonging to the lipocalin superfamily was reported to participate in various biological processes including cell migration, cell survival, inflammatory responses, and insulin sensitivity. LCN2 is expressed in the multiple tissues such as kidney, liver, uterus, and bone marrow. The receptors for LCN2 were additionally found in microglia, astrocytes, epithelial cells, and neurons, but the role of LCN2 in the central nervous system (CNS) has not been fully understood yet. Recently, in vitro, in vivo, and clinical studies reported the association between LCN2 and the risk of Alzheimer's disease (AD). Here, we reviewed the significant evidences showing that LCN2 contributes to the onset and progression of AD. It may suggest that the manipulation of LCN2 in the CNS would be a crucial target for regulation of the pathogenesis and risk of AD. PMID- 29423387 TI - The Effect of Soluble Fiber Supplementation on Metabolic Syndrome Profile among Newly Diagnosed Type 2 Diabetes Patients. AB - Diets with high fiber content improve most metabolic syndrome (MetS) profile in non-diabetic individuals, but there is scarce information about the role of fiber intake in patients with the MetS and diabetes. The objective of this study is to determine whether soluble fiber supplementation improve MetS profile for 8 weeks of intervention in newly diagnosed type 2 diabetes (T2D) adult patients. After one week of dietary stabilization phase, 36 newly diagnosed T2D patients were stratified to different strata according to sex, age, fasting blood sugar (FBS), and waist circumference (WC). Then they were randomly allocated into 2 groups. The psyllium group (n = 18) received 10.5 g of psyllium daily for 8 weeks. The control group (n = 18) maintained their regular diet for 8 weeks. Soluble fiber supplementation showed significant reduction in the majority of MetS profile; FBS (43.55 mg/dL, p < 0.001), triglyceride (37.89 mg/dL, p < 0.001), total cholesterol (20.32 mg/dL, p < 0.001), systolic blood pressure (7.50 mmHg, p < 0.001), diastolic blood pressure (2.78 mmHg, p = 0.013), and WC (2.54 cm, p < 0.001) in the intervention group compared with the control group after 8 weeks of intervention. The high-density lipoprotein cholesterol was reduced in both groups, but this reduction was insignificant. The improvement in the MetS profile was enhanced by combining psyllium to the normal diet. Consumption of foods containing moderate amounts of these fibers may improve MetS profile in newly diagnosed T2D patients. This study was registered in Current Controlled Trials (PHRC/HC/28/15). PMID- 29423388 TI - Dietary Intake of Thiamine in Migraine Patients and Healthy Subjects: a Case Control Study. AB - The migraine headache is a disease related to the neurovascular system, which affects 10%-20% of people, worldwide. Recent evidences suggested a relation between thiamine status and migraine headaches. The current study was undertaken to assess dietary intake of the thiamine in migraine patients and to evaluate its association with the frequency of migraine attacks. In a case-control design, the current study was performed on 50 migraine patients and 50 healthy people, 20-60 years old in Isfahan, Iran, in 2017. Information about dietary intake was collected by Food frequency questionnaire and analyzed using the Nutritionist version 4 (N4) software (Tinuviel Software). Information about the history of disease was collected by demographic questionnaire. Analysis of covariance and independent t-test were used for data analysis and p value less than 0.05 was considered significant. Mean age, weight, height, and body mass index of participants were 35.1 +/- 9.8 years, 65.3 +/- 10.4 kg, 162.5 +/- 8.4 cm, and 24.7 +/- 4.0 kg/m2, respectively. Dietary intake of thiamine among the migraine patients was lower than that in the healthy participants (p < 0.001). Migraine patients with the high frequency attacks had significantly lower intake of thiamine compared with moderate frequency attacks group (p = 0.010), however, it was not significant after adjusting for energy intake (p = 0.410, p = 0.240). Dietary intake of thiamine in migraine patients was not significantly different in comparing with healthy subjects. In addition, no significant correlation between thiamine intake and the frequency of migraine attacks was observed. PMID- 29423389 TI - Food Elimination Diet and Nutritional Deficiency in Patients with Inflammatory Bowel Disease. AB - Certain types of foods are common trigger for bowel symptoms such as abdominal discomfort or pain in patients with inflammatory bowel disease (IBD). But indiscriminate food exclusions from their diet can lead extensive nutritional deficiencies. The aim of this study was to investigate nutritional status, food restriction and nutrient intake status in IBD patients. A total 104 patients (food exclusion group: n = 49; food non-exclusion group: n = 55) participated in the survey. The contents were examined by 3 categories: 1) anthropometric and nutritional status; 2) diet beliefs and food restriction; and 3) nutrient intake. The malnutrition rate was significantly higher in the food exclusion group (p = 0.007) compared to food non-exclusion group. Fifty-nine percent of patients in the food exclusion group held dietary beliefs and reported modifying their intake according to their dietary belief. The most common restricted food was milk, dairy products (32.7%), raw fish (24.5%), deep-spicy foods (22.4%), and ramen (18.4%). The mean daily intake of calcium (p = 0.002), vitamin A (p < 0.001), and zinc (p = 0.001) were significantly lower in the food exclusion group. Considering malnutrition in IBD patients, nutrition education by trained dietitians is necessary for the patients to acquire disease-related knowledge and overall balanced nutrition as part of strategies in treating and preventing nutrition deficiencies. PMID- 29423390 TI - Dual Effects of High Protein Diet on Mouse Skin and Colonic Inflammation. AB - Chronic inflammation is a major etiology of cancer. Accumulating epidemiological and experimental evidences suggest that intake of high protein diet (HPD) is associated with colitis-associated colon cancer, however, most of the studies were confined in colon. Systemic influence of HPD on inflammation indices in different tissues of an organism has never been studied. We therefore investigated the effect of HPD on mouse skin and colonic inflammation using the well characterized inflammation induction protocol in both tissues (12-O tetradecanoylphorbol-13-acetate [TPA] for skin and dextran sodium sulfate [DSS] for colon). ICR mice were grouped to normal diet (ND, 20% casein) or HPD (50% casein) groups. In each diet group, mice were treated with either vehicle (acetone or H2O), TPA, TPA and DSS, or DSS. Experimental diet was fed for total 4 weeks. After 1 week of diet feeding, 6.5 nmol of TPA was topically applied twice a week for 2 weeks on the shaved mouse dorsal skin. Drinking water containing 2% DSS was administered for 7 days at the final week of experiment. The results showed that TPA-induced skin hyperplasia, epidermal cell proliferation, and cyclooxygenase-2 (COX-2) expression were reduced in HPD group compared to ND group. In contrast, HPD increased DSS-induced colon mucosal hyperplasia, colonocyte proliferation, COX-2 expression, and plasma nitric oxide compared to ND group. This suggests that HPD exerts differential effect on different tissue inflammation which implies efficacy of protein intervention to human also should be monitored more thoroughly. PMID- 29423391 TI - A Nutrition Intervention Focused on Weight Management Through Lifestyle Improvements in Prediabetic Subjects. AB - We reported the cases in order to evaluate the effects of individualized nutrition interventions for enhancing self-management abilities of prediabetic subjects. We conducted four nutrition interventions for weight control in two subjects with high-risk of type 2 diabetes. The first subject was a 53-year-old housewife, and the second subject was a 46-year-old male office worker. The subjects visited the medical center 4 times during the study period, and the lifestyle interventions were advised by a clinical team comprised physicians, clinical dietitians, and nurses. In particular, nutrition intervention to achieve weight loss focused on enhancing motivation and problem-solving skills to improve self-management ability. As a result, both subjects achieved weight loss by the time of their last visits. These two case studies, which differed in terms of sex, occupation, and dietary habits showed the importance of individualized nutrition intervention and forming an intimate relationship based on trust centered on prediabetic subjects. In conclusion, systematic collaboration within the clinical team is necessary, and social infrastructure should be prepared to fully realize the benefits of a systematic intervention program. PMID- 29423392 TI - Neurochemical Alterations in Sudden Unexplained Perinatal Deaths-A Review. AB - Sudden unexpected perinatal collapse is a major trauma for the parents of victims. Sudden infant death syndrome (SIDS) is unexpected and mysterious death of an apparently healthy neonate from birth till 1 year of age without any known causes, even after thorough postmortem investigations. However, the incidence of sudden intrauterine unexplained death syndrome (SIUDS) is seven times higher as compared with SIDS. This observation is approximated 40-80%. Stillbirth is defined as death of a fetus after 20th week of gestation or just before delivery at full term without a known reason. Pakistan has the highest burden of stillbirth in the world. This basis of SIDS, SIUDS, and stillbirths eludes specialists. The purpose of this study is to investigate factors behind failure in control of these unexplained deaths and how research may go ahead with improved prospects. Animal models and physiological data demonstrate that sleep, arousal, and cardiorespiratory malfunctioning are abnormal mechanisms in SIUDS risk factors or in newborn children who subsequently die from SIDS. This review focuses on insights in neuropathology and mechanisms of SIDS and SIUDS in terms of different receptors involved in this major perinatal demise. Several studies conducted in the past decade have confirmed neuropathological and neurochemical anomalies related to serotonin transporter, substance P, acetylcholine alpha7 nicotine receptors, etc., in sudden unexplained fetal and infant deaths. There is need to focus more on research in this area to unveil the major curtain to neuroprotection by underlying mechanisms leading to such deaths. PMID- 29423393 TI - Commentary: Fear of Massive Deportations in the United States: Social Implications on Deprived Pediatric Communities. PMID- 29423394 TI - A Program for Weaning Children from Enteral Feeding in a General Pediatric Unit: How, for Whom, and with What Results? AB - Objective: To describe a series of children who were hospitalized for a tube weaning program in the general pediatric ward of a pediatric tertiary university hospital: describe our method, to determine the success rate of our inpatient pediatric tube weaning program, and search for relevant factors linked to its success or failure. Method: We analyzed the medical files of consecutive children who were hospitalized for gastric-tube weaning over an 8-year period. We analyzed outcomes in terms of feeding and growth with at least 2 years of data. Success (weaning within 3 months) and failure were compared by characteristics of children. Results: We included 37 children (29 females) with mean (SD) age 31.4 (21) months. Most had a severe medical history (30% prematurity; 50% intrauterine growth restriction, 50% neurological and genetic anomalies). The weaning program was successful for half of the children. Factors linked to success of the program were female sex (p = 0.0188), normal neurodevelopment (p = 0.0016), nasogastric tube (p = 0.0098), and with <24 months on EF before the stay (p = 0.0309). Discussion: Comparing the efficiency of various methods and results among teams was difficult, which indicates the need to establish consensus about the outcome criteria. We confirm the need for these types of stays and programs. PMID- 29423395 TI - Plasma Prekallikrein: Its Role in Hereditary Angioedema and Health and Disease. AB - Plasma prekallikrein (PK) has a critical role in acute attacks of hereditary angioedema (HAE). Unlike C1 inhibitor, its levels fall during HAE attacks with resultant cleaved high-molecular-weight kininogen. Cleavage of high-molecular weight kininogen liberates bradykinin, the major biologic peptide that promotes the edema. How prekallikrein initially becomes activated in acute attacks of HAE is not known. PK itself is negatively associated with cardiovascular disease. High prekallikrein is associated with accelerated vascular disease in diabetes and polymorphisms of prekallikrein that reduce high-molecular-weight kininogen binding are associated with protection from cardiovascular events. Prekallikrein deficient mice have reduced thrombosis risk and plasma kallikrein (PKa) inhibition is associated with reduced experimental gastroenterocolitis and arthritis in rodents. In sum, prekallikrein and its enzyme PKa are major targets in HAE providing much opportunity to improve the acute and chronic management of HAE. PKa inhibition also may be a target to ameliorate cardiovascular disease, thrombosis risk, and inflammation as in enterocolitis and arthritis. PMID- 29423397 TI - Age Is Relative-Impact of Donor Age on Induced Pluripotent Stem Cell-Derived Cell Functionality. AB - Induced pluripotent stem cells (iPSCs) avoid many of the restrictions that hamper the application of human embryonic stem cells: limited availability of source material due to legal restrictions in some countries, immunogenic rejection and ethical concerns. Also, the donor's clinical phenotype is often known when working with iPSCs. Therefore, iPSCs seem ideal to tackle the two biggest tasks of regenerative medicine: degenerative diseases with genetic cause (e.g., Duchenne's muscular dystrophy) and organ replacement in age-related diseases (e.g., end-stage heart or renal failure), especially in combination with recently developed gene-editing tools. In the setting of autologous transplantation in elderly patients, donor age becomes a potentially relevant factor that needs to be assessed. Here, we review and critically discuss available data pertinent to the questions: How does donor age influence the reprogramming process and iPSC functionality? Would it even be possible to reprogram senescent somatic cells? How does donor age affect iPSC differentiation into specialised cells and their functionality? We also identify research needs, which might help resolve current unknowns. Until recently, most hallmarks of ageing were attributed to an accumulation of DNA damage over time, and it was thus expected that DNA damage from a somatic cell would accumulate in iPSCs and the cells derived from them. In line with this, a decreased lifespan of cloned organisms compared with the donor was also observed in early cloning experiments. Therefore, it was questioned for a time whether iPSC derived from an old individual's somatic cells would suffer from early senescence and, thus, may not be a viable option either for disease modelling nor future clinical applications. Instead, typical signs of cellular ageing are reverted in the process of iPSC reprogramming, and iPSCs from older donors do not show diminished differentiation potential nor do iPSC-derived cells from older donors suffer early senescence or show functional impairments when compared with those from younger donors. Thus, the data would suggest that donor age does not limit iPSC application for modelling genetic diseases nor regenerative therapies. However, open questions remain, e.g., regarding the potential tumourigenicity of iPSC-derived cells and the impact of epigenetic pattern retention. PMID- 29423396 TI - Chaperonin of Group I: Oligomeric Spectrum and Biochemical and Biological Implications. AB - Chaperonins play various physiological roles and can also be pathogenic. Elucidation of their structure, e.g., oligomeric status and post-translational modifications (PTM), is necessary to understand their functions and mechanisms of action in health and disease. Group I chaperonins form tetradecamers with two stacked heptameric rings. The tetradecamer is considered the typical functional complex for folding of client polypeptides. However, other forms such as the monomer and oligomers with smaller number of subunits than the classical tetradecamer, also occur in cells. The properties and functions of the monomer and oligomers, and their roles in chaperonin-associated diseases are still incompletely understood. Chaperonin I in eukaryotes occurs in various locations, not just the mitochondrion, which is its canonical place of residence and function. Eukaryotic Chaperonin I, namely Hsp60 (designated HSP60 or HSPD1 in humans) has, indeed, been found in the cytosol; the plasma-cell membrane; on the outer surface of cells; in the intercellular space; in biological liquids such as lymph, blood, and cerebrospinal fluid; and in secretions, for instance saliva and urine. Hsp60 has also been found in cell-derived vesicles such as exosomes. The functions of Hsp60 in all these non-canonical locales are still poorly characterized and one of the questions not yet answered is in what form, i.e., monomer or oligomer, is the chaperonin present in these non-canonical locations. In view of the steady increase in interest on chaperonopathies over the last several years, we have studied human HSP60 to determine its role in various diseases, its locations in cells and tissues and migrations in the body, and its post-translational modifications that might have an impact on its location and function. We also carried out experiments to characterize the oligomeric status of extramitochondrial of HSP60 in solution. Here, we provide an overview of our results, focusing on the oligomeric equilibrium and stability of the various forms of HSP60 in comparison with GroEL. We also discuss post-translational modifications associated with anti-cancer drugs to indicate the potential of Hsp60 in Medicine, as a biomarker and etiopathogenic factor. PMID- 29423398 TI - Differing Roles of the Face and Voice in Early Human Communication: Roots of Language in Multimodal Expression. AB - Seeking roots of language, we probed infant facial expressions and vocalizations. Both have roles in language, but the voice plays an especially flexible role, expressing a variety of functions and affect conditions with the same vocal categories-a word can be produced with many different affective flavors. This requirement of language is seen in very early infant vocalizations. We examined the extent to which affect is transmitted by early vocal categories termed "protophones" (squeals, vowel-like sounds, and growls) and by their co-occurring facial expressions, and similarly the extent to which vocal type is transmitted by the voice and co-occurring facial expressions. Our coder agreement data suggest infant affect during protophones was most reliably transmitted by the face (judged in video-only), while vocal type was transmitted most reliably by the voice (judged in audio-only). Voice alone transmitted negative affect more reliably than neutral or positive affect, suggesting infant protophones may be used especially to call for attention when the infant is in distress. By contrast, the face alone provided no significant information about protophone categories. Indeed coders in VID could scarcely recognize the difference between silence and voice when coding protophones in VID. The results suggest that partial decoupling of communicative roles for face and voice occurs even in the first months of life. Affect in infancy appears to be transmitted in a way that audio and video aspects are flexibly interwoven, as in mature language. PMID- 29423399 TI - CoeViz: A Web-Based Integrative Platform for Interactive Visualization of Large Similarity and Distance Matrices. AB - Similarity and distance matrices are general data structures that describe reciprocal relationships between the objects within a given dataset. Commonly used methods for representation of these matrices include heatmaps, hierarchical trees, dimensionality reduction, and various types of networks. However, despite a well-developed foundation for the visualization of such representations, the challenge of creating an interactive view that would allow for quick data navigation and interpretation remains largely unaddressed. This problem becomes especially evident for large matrices with hundreds or thousands objects. In this work, we present a web-based platform for the interactive analysis of large (dis )similarity matrices. It consists of four major interconnected and synchronized components: a zoomable heatmap, interactive hierarchical tree, scalable circular relationship diagram, and 3D multi-dimensional scaling (MDS) scatterplot. We demonstrate the use of the platform for the analysis of amino acid covariance data in proteins as part of our previously developed CoeViz tool. The web platform enables quick and focused analysis of protein features, such as structural domains and functional sites. PMID- 29423400 TI - Seasonal Microbial Conditions of Locally Made Yoghurt (Shalom) Marketed in Some Regions of Cameroon. AB - The microbial conditions of locally made yoghurt (shalom) marketed in three areas of Cameroon were evaluated during the dry and rainy seasons alongside three commercial brands. A total of ninety-six samples were collected and the microbial conditions were based on total aerobic bacteria (TEB), coliforms, yeasts, and moulds counts as well as the identification of coliforms and yeasts using identification kits. Generally, there was a significant increase (p <= 0.05) in total aerobic and coliform counts (especially samples from Bamenda), but a decrease in yeast and mould counts of the same samples during the rainy season when compared to those obtained during the dry season. These counts were mostly greater than the recommended standards. Twenty-one Enterobacteriaceae species belonging to 15 genera were identified from 72 bacterial isolates previously considered as all coliforms. Pantoea sp. (27.77%) was highly represented, found in 41% (dry season) and 50% (rainy season) of samples. In addition, sixteen yeast species belonging to 8 genera were equally identified from 55 yeast isolates and Candida sp. (76.36%) was the most represented. This result suggests that unhygienic practices during production, ignorance, warmer weather, duration of selling, and inadequate refrigeration are the principal causes of higher levels of contamination and unsafe yoghurts. PMID- 29423401 TI - Association between Genetic Polymorphism and Risk of von Willebrand Disease in Pakistan. AB - von Willebrand disease (VWD) is an inherited, genetically and clinically heterogeneous hemorrhagic disorder. The most common cause of this disease is mutation in the gene that encodes protein von Willebrand factor (VWF) which is responsible for blood clotting. The current study was designed to investigate the role of genetic polymorphisms with the onset of VWD in population of Pakistan. Three exonic variants (c.3445T>C; c.4975C>T; c.7603C>T) from VWF gene were used for the genotyping purpose. The current study employed a case-control association design involving 43 VWD patients and 100 healthy controls from Pakistani population. The genetic reason of VWD was investigated using the allele specific PCR. The significant (P < 0.05) allelic association was found between all three exonic variants and VWD. The CT genotype of these variants was noticed to be associated with significantly higher risk of VWD [odds ratio (95% CI): 14.7 (4.546-47.98), 26.71 (7.281-97.98), and 21.5 (5.806-80.01) for c.3445T>C, c.4975C>T, and c.7603C>T, resp.] while genotypes CC (c.4975C>T) and TT (c.3445T>C and c.7603C>T) were having protective effect against the disease. However, replicated studies are needed for elaborating the role of these SNPs. PMID- 29423402 TI - Is Esophageal Temperature Better to Estimate Brain Temperature during Target Temperature Management in a Porcine Model of Cardiopulmonary Resuscitation? AB - Brain temperature monitoring is important in target temperature management for comatose survivors after cardiac arrest. Since acquisition of brain temperature is invasive and unrealistic in scene of resuscitation, we tried to sought out surrogate sites of temperature measurements that can precisely reflect cerebral temperature. Therefore, we designed this controlled, randomized animal study to investigate whether esophageal temperature can better predict brain temperature in two different hypothermia protocols. The results indicated that esophageal temperature had a stronger correlation with brain temperature in the early phase of hypothermia in both whole and regional body cooling protocols. It means that esophageal temperature was considered as priority method for early monitoring once hypothermia is initiated. This clinical significance of this study is as follows. Since resuscitated patients have unstable hemodynamics, collecting temperature data from esophagus probe is cost-efficient and easier than the catheter in central vein. Moreover, it can prevent the risk of iatrogenic infection comparing with deep vein catheterization, especially in survivors with transient immunoexpressing in hypothermia protocol. PMID- 29423403 TI - The Role of Antibiotic Prophylaxis in Reducing Bacterial Contamination of Autologous Bone Graft Collected from Implant Site. AB - The aim of this study was to evaluate if antibiotic prophylaxis reduces the bacterial contamination of bone particles collected directly from the burs used for implant site preparation. Thirty-four patients underwent the surgical procedures for a total of 34 implant sites. One 1 gr. tablet of amoxicillin + clavulanic acid was given to the test group 12 hours and 1 hour before the surgery. The control group did not take antibiotic prophylaxis. Bone particles were collected and centrifuged. The suspensions were subjected to serial dilutions and each dilution was examined twice using a spatulation technique in Trypticase Soy Agar (TSA), in Sabouraud Dextrose Agar, and in Mitis Salivarius Agar (MSA). The number of colonies was calculated and the identification of various microorganisms was made. The most represented species, in both groups of patients, belonged to the "oral Streptococci." For TSA, the test and control groups differed significantly (p = 0.018). Conversely, there was no significant difference for MSA (p = 0.201) and for the number of bacterial species isolated in the samples of the two groups of patients (p = 0.898). The antibiotic prophylaxis reduced, but did not cancel, the risk of infection of the autogenous particulate bone graft. This trial is registered with IRCT2017102537002N1. PMID- 29423404 TI - A Modified 2D Multiresolution Hybrid Algorithm for Ultrasound Strain Imaging. AB - Ultrasound elastography is an imaging modality to evaluate elastic properties of soft tissue. Recently, 1D quasi-static elastography method has been commercialized by some companies. However, its performance is still limited on high strain level. In order to improve the precision of estimation during high compression, some algorithms have been proposed to expand the 1D window to a 2D window for avoiding the side-slipping. But they are usually more computationally expensive. In this paper, we proposed a modified 2D multiresolution hybrid method for displacement estimation, which can offer an efficient strain imaging with stable and accurate results. A FEM phantom with a stiffer circular inclusion is simulated for testing the algorithm. The elastographic contrast-to-noise rate (CNRe) is calculated for quantitatively comparing the performance of the proposed algorithm with conventional 1D elastography using phase zero estimation and the 1D elastography using downsampled (d-s) baseband signals. Results show that the proposed method is robust and performs similarly as other algorithms in low strain but is superior when high level strain is applied. Particularly, the CNRe of our algorithm is 15 times higher than original method under 4% strain level. Furthermore, the execution time of our algorithm is five times faster than other algorithms. PMID- 29423405 TI - Quantitative Assessment of Blood Pressure Measurement Accuracy and Variability from Visual Auscultation Method by Observers without Receiving Medical Training. AB - This study aimed to quantify blood pressure (BP) measurement accuracy and variability with different techniques. Thirty video clips of BP recordings from the BHS training database were converted to Korotkoff sound waveforms. Ten observers without receiving medical training were asked to determine BPs using (a) traditional manual auscultatory method and (b) visual auscultation method by visualizing the Korotkoff sound waveform, which was repeated three times on different days. The measurement error was calculated against the reference answers, and the measurement variability was calculated from the SD of the three repeats. Statistical analysis showed that, in comparison with the auscultatory method, visual method significantly reduced overall variability from 2.2 to 1.1 mmHg for SBP and from 1.9 to 0.9 mmHg for DBP (both p < 0.001). It also showed that BP measurement errors were significant for both techniques (all p < 0.01, except DBP from the traditional method). Although significant, the overall mean errors were small (-1.5 and -1.2 mmHg for SBP and -0.7 and 2.6 mmHg for DBP, resp., from the traditional auscultatory and visual auscultation methods). In conclusion, the visual auscultation method had the ability to achieve an acceptable degree of BP measurement accuracy, with smaller variability in comparison with the traditional auscultatory method. PMID- 29423406 TI - Clinicopathological Characteristics, Treatment, and Prognosis of Rarely Primary Epididymal Adenocarcinoma: A Review and Update. AB - Primary epididymal adenocarcinoma (PEA) is exceedingly rare. Only 22 cases had been published worldwide by 2008; nearly 80% of these cases were reported before 2007. In order to investigate the current clinical status of PEA, we search for relevant literatures with "epididymis and adenocarcinoma" and "epididymal and adenocarcinoma" as keywords published between January 1997 and November 2017 in PubMed. As a result, 17 cases are identified. We review these cases and summarize new and important perspectives about the clinicopathological characteristics, diagnosis, treatment, and prognosis of PEA in the present review. PMID- 29423407 TI - Periprosthetic Joint Infection of Shoulder Arthroplasties: Diagnostic and Treatment Options. AB - Periprosthetic joint infection (PJI) is one of the most frequent reasons for painful shoulder arthroplasties and revision surgery of shoulder arthroplasties. Cutibacterium acnes (Propionibacterium acnes) is one of the microorganisms that most often causes the infection. However, this slow growing microorganism is difficult to detect. This paper presents an overview of different diagnostic test to detect a periprosthetic shoulder infection. This includes nonspecific diagnostic tests and specific tests (with identifying the responsible microorganism). The aspiration can combine different specific and nonspecific tests. In dry aspiration and suspected joint infection, we recommend a biopsy. Several therapeutic options exist for the treatment of PJI of shoulder arthroplasties. In acute infections, the options include leaving the implant in place with open debridement, septic irrigation with antibacterial fluids like octenidine or polyhexanide solution, and exchange of all removable components. In late infections (more than four weeks after implantation) the therapeutic options are a permanent spacer, single-stage revision, and two-stage revision with a temporary spacer. The functional results are best after single-stage revisions with a success rate similar to two-stage revisions. For single-stage revisions, the microorganism should be known preoperatively so that specific antibiotics can be mixed into the cement for implantation of the new prosthesis and specific systemic antibiotic therapy can be applied to support the surgery. PMID- 29423409 TI - The Influence of Suprascapular Notch Shape on the Visualization of Structures in the Suprascapular Notch Region: Studies Based on a New Four-Stage Ultrasonographic Protocol. AB - Evaluation of the morphology of the suprascapular notch region is important from a clinical point of view because it is the most common site of suprascapular nerve compression and injury. A group of 120 patients underwent ultrasound examination of the suprascapular notch region according to our original four stage "step-by-step" protocol. The notches were classified based on their morphology and measurements like maximal depth (MD) and superior transverse diameter (STD) as follows: type I-MD is longer than STD, type II-MD and STD are equal, type III-STD is longer than MD, and in type IV/V-notches only the bony margin was visualized without depression. Both suprascapular notches were fully visualized in 115 of 120 patients. The type III suprascapular notch was the most prevalent (64.2%), followed by type IV/V (18.7%), type I (11.1%), and type II (6.0%). Color Doppler analysis allowed the suprascapular artery to be recognized in all visualized notches. The suprascapular vein was visible in 176 notches and the suprascapular nerve in 150. Notches containing both suprascapular nerve and vein were significantly wider and shallower than average. As the suprascapular artery is the most easily recognised structure in the area, it may serve as a useful landmark of the suprascapular notch. PMID- 29423408 TI - "Naturalization" of Routine Assisted Reproductive Technologies by In Vitro Culture of Embryos with Microvibration: Sex Ratio, Body Length, and Weight of 2,456 Live-Birth Deliveries after Transfer of 9,624 Embryos In Vitro Cultured in Static System and with Microvibration. AB - Aim was to determine whether there is any difference in the sex ratio, body length, and body weight of 2,456 deliveries after transfer of 9,624 embryos derived using in vitro culture under static and mechanical microvibration conditions. Pronuclear embryos from 4435 patients were cultured in vitro under two different conditions: without (n = 4821) and with mechanical agitation (n = 4803). Sex ratio, body length, and weight of 2,456 live-birth deliveries after transfer of 9,624 embryos were noted. The proportion of males at birth was significantly associated with mode of in vitro culture of embryos only among women aged 40 years and older. The rate "body length" was significantly associated with mode of in vitro culture of embryos only among women aged 29 and younger. In the same time, among twins, this ratio positively associated with in vitro culture of embryos under microvibration only among women aged 30-34 years as well as >=40 years and negatively among women aged 35-39 years. It was concluded that birth weight of infants was positively associated with mode of in vitro culture of embryos under microvibration among women of all age groups. This trial registration number is ISRCTN13773904, registered 6 April 2016. PMID- 29423410 TI - Endothelial Glycocalyx Layer: A Possible Therapeutic Target for Acute Lung Injury during Lung Resection. AB - Background: Shedding of the endothelial glycocalyx layer (EGL) is known to occur during major surgery, but its degradation associated with minimally invasive video-assisted thoracoscopy (VATS) remains unclear. We investigated if serum biomarkers of EGL disruption were elevated during VATS lobectomy, and whether the urinary trypsin inhibitor (UTI) ulinastatin exerted a protective effect during this procedure. Materials and Methods: Sixty ASA II-III lung cancer patients undergoing elective VATS lobectomy were divided equally into UTI and control groups. UTI group patients received intravenous UTI during surgery. Serum levels of syndecan-1 and heparan sulfate were examined before (T0) and at the end of surgery (T1). Serum albumin and hemoglobin were measured before surgery (BOD) and on the first postoperative day (POD1). Results: In control group, syndecan-1 levels were significantly elevated at T1 compared with T0 (3.77 +/- 3.15 versus 4.28 +/- 3.30, P = 0.022*) and increased even more significantly in patients whose surgery lasted >3 h (3.28 +/- 2.84 versus 4.31 +/- 3.39, P = 0.003**). Serum albumin levels on POD1 were significantly lower in control group compared with UTI group (32.63 +/- 4.57 versus 35.76 +/- 2.99, P = 0.031*). Conclusion: EGL degradation occurs following VATS lobectomy. UTI can alleviate this shedding, thus helping preserve normal vascular permeability. Trail Registration: This trial is registered with ChiCTR-IOC-17010416 (January 13, 2017). PMID- 29423411 TI - HPV Status and Its Correlation with BCL2, p21, p53, Rb, and Survivin Expression in Breast Cancer in a Chinese Population. AB - Despite recent evidence, the role of human papillomavirus (HPV) in breast carcinogenesis is controversial. The correlations of HPV infection with the clinicopathological features of breast cancer and the expression of cell cycle/apoptosis-associated proteins have not been well elucidated. In this study, we sought to determine the prevalence of high-risk HPVs (HR-HPVs) infection and BCL2, p21, p53, Rb, and survivin expression in breast cancer patients and to investigate the relationship of HPV with these cancer-related proteins, in an attempt to clarify the potential mechanism of HPV in breast cancer pathogenesis. HPV presence in 81 fresh breast cancer tissues was determined by hybrid capture 2 (HC2) assay, and expression of BCL2, p21, p53, Rb, and survivin was detected by immunohistochemistry. Here we showed that fourteen (17.3%) patients were HR-HPV positive. HPV infection demonstrated no significant correlation with the clinicopathological characteristics of breast cancer. HPV-positive tumors showed significantly higher BCL2 and lower p53 expression than HPV-negative tumors. Expression of p21, Rb, and survivin was not associated with HPV status. Our results suggest a possible role of HR-HPV in breast cancer carcinogenesis, in which BCL2 and p53 may be involved. PMID- 29423412 TI - Physical Activity in Adolescents and Young Adults with Cerebral Palsy. AB - The aim of this study was to examine the level of physical activity in adults with cerebral palsy (CP) and to analyse its relationship with physical activity as adolescents, pain, and gross motor function. A prospective cohort study was performed using data from the Swedish National CP Registry (CPUP) for all 129 individuals born in 1991-1993 living in Skane and Blekinge who reported to CPUP at 14-16 years of age. Physical activity as adult was analysed relative to physical activity as adolescents, pain, and the Gross Motor Function Classification System (GMFCS). Seventy-one individuals at GMFCS I-V were followed up as adults and included in the analyses. Of these, 65% were physically active, but only 56% performed physical activity at least once a week. Their physical activity as adults differed relative to their physical activity as adolescents (p = 0.011) but not to pain or GMFCS. Being physically active as an adolescent doubled the probability of being active as an adult (OR 2.1; p = 0.054), indicating that physical activity in adults with CP is related to their physical activity as adolescents. Therefore, interventions to increase physical activity among adolescents with CP are likely also to improve physical activity in adulthood. PMID- 29423413 TI - Direct Bilirubin Levels and Risk of Metabolic Syndrome in Healthy Chinese Men. AB - Background: Serum bilirubin is a potent endogenous antioxidant with anti inflammatory properties. Several cross-sectional studies have reported that bilirubin was negatively associated with metabolic syndrome. However, in recent longitudinal studies, the relations between bilirubin and metabolic syndrome are inconsistent. Moreover, previous studies mainly focused on serum total bilirubin which is the sum of direct bilirubin and indirect bilirubin. For these reasons, the longitudinal effect of bilirubin subtypes on incident metabolic syndrome was evaluated in Chinese men. Methods: The study cohort involved 1339 Chinese men without metabolic syndrome. Metabolic syndrome was defined by the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) criteria, using BMI for the replacement of waist circumference. Results: There are 117 incident metabolic syndrome cases (8.7%) during 5 years of follow-up among 1339 metabolic syndrome-free participants at baseline. After adjusting for age, drinking, smoking, physical activity, TG, and LDL-C, the odd ratios (ORs) and 95% confidence intervals (CIs) for MetS incidence in the second, third, and fourth quartiles versus the first quartile of DBil concentration were 1.00 (0.61-1.63), 0.57 (0.32-1.02), and 0.51 (0.28-0.92) (Ptrend = 0.031), respectively. Conclusions: Our findings support the negative association between direct bilirubin and incident metabolic syndrome in healthy Chinese men over 5-year period. PMID- 29423414 TI - The Impact of Age on Clinical Outcomes of Coronary Artery Bypass Grafting: Long Term Results of a Real-World Registry. AB - The aim of this retrospective multicenter registry study was to investigate age dependent trends in mortality, long-term survival, and comorbidity over time in patients who underwent isolated CABG from 2003 to 2015. The percentage of patients < 60 years of age was 18.9%. Female sex, chronic pulmonary disease, extracardiac arteriopathy, and neurologic dysfunction disease were significantly less frequent in this younger population. The prevalence of BMI >= 30, previous myocardial infarction, preoperative severe depressed left ventricular ejection fraction, and history of previous PCI were significantly higher in this population. After PS matching, at 5 years, patients < 60 years of age reported significantly lower overall mortality (p < 0.0001), cardiac-related mortality (p < 0.0001), incidence of acute myocardial infarction (p = 0.01), and stroke rates (p < 0.0001). Patients < 60 years required repeated revascularization more frequently than older patients (p = 0.05). Patients < 60 who underwent CABG had a lower risk of adverse outcomes than older patients. Patients < 60 have a different clinical pattern of presentation of CAD in comparison with more elderly patients. These issues require focused attention in order to design and improve preventive strategies aiming to reduce the impact of specific cardiovascular risk factors for younger patients, such as diet, lifestyle, and weight control. PMID- 29423415 TI - Corrigendum to "Protective Effects of the Mushroom Lactarius deterrimus Extract on Systemic Oxidative Stress and Pancreatic Islets in Streptozotocin-Induced Diabetic Rats". AB - [This corrects the article DOI: 10.1155/2015/576726.]. PMID- 29423416 TI - Risk of Type 2 Diabetes Mellitus following Gestational Diabetes Pregnancy in Women with Polycystic Ovary Syndrome. AB - Background: This study examines gestational diabetes mellitus (GDM) in women with polycystic ovary syndrome (PCOS) and the risk of type 2 diabetes mellitus (DM) following GDM pregnancy. Methods: A cohort of 988 pregnant women with PCOS who delivered during 2002-2005 was examined to determine the prevalence and predictors of GDM, with follow-up through 2010 among those with GDM to estimate the risk of DM. Results: Of the 988 pregnant women with PCOS, 192 (19%) developed GDM. Multivariable predictors of GDM included older age, Asian race, prepregnancy obesity, family history of DM, preconception metformin use, and multiple gestation. Among women with PCOS and GDM pregnancy, the incidence of DM was 2.8 (95% confidence interval (CI) 1.9-4.2) per 100 person-years and substantially higher for those who received pharmacologic treatment for GDM (6.6 versus 1.5 per 100 person-years, p < 0.01). The multivariable adjusted risk of DM was fourfold higher in women who received pharmacologic treatment for GDM (adjusted hazard ratio 4.1, 95% CI 1.8-9.6). The five-year incidence of DM was 13.1% overall and also higher in the pharmacologic treatment subgroup (27.0% versus 7.1%, p < 0.01). Conclusions: The strongest predictors of GDM among women with PCOS included Asian race and prepregnancy obesity. Pharmacologic treatment of GDM is associated with fourfold higher risk of subsequent DM. PMID- 29423417 TI - Reduced sB7-H3 Expression in the Peripheral Blood of Systemic Lupus Erythematosus Patients. AB - Both membrane-bound and soluble forms of costimulatory molecules play important roles in immune-regulatory networks. B7-H3, a member of the B7 family, has been found with aberrant expression in tumors and infectious disease. However, the significance of sB7-H3 expression in systemic lupus erythematosus (SLE) has not been investigated. Using the peripheral blood of 78 SLE patients, we established a comprehensive database containing clinical data and relevant laboratory tests. We found that sB7-H3 expression in SLE patients was significantly lower compared with the healthy individuals. In addition, sB7-H3 levels in the patients were positively correlated with the disease activity as indicated by SLE disease activity index score, rashes, fever, and inflammatory cytokines. Moreover, sB7-H3 was associated with the counts of red blood cells and hemoglobin. Our findings suggest that sB7-H3 might counteract the aberrant immune response and potentially serve as a monitoring indicator of disease progression and therapeutic target in SLE treatment. PMID- 29423419 TI - Zero-Adjective Contrast in Much-less Ellipsis: The Advantage for Parallel Syntax. AB - This paper explores the processing of sentences with a much less coordinator (I don't own a pink hat, much less a red one). This understudied ellipsis sentence, one of several focus-sensitive coordination structures, imposes syntactic and semantic conditions on the relationship between the correlate (a pink hat) and remnant (a red one). We present the case of zero-adjective contrast, in which an NP remnant introduces an adjective without an overt counterpart in the correlate (I don't own a hat, much less a red one). Although zero-adjective contrast could in principle ease comprehension by limiting the possible relationships between the remnant and correlate to entailment, we find that zero-adjective contrast is avoided in production and taxing in online processing. Results from several studies support a processing model in which syntactic parallelism is the primary guide for determining contrast in ellipsis structures, even when violating parallelism would assist in computing semantic relationships. PMID- 29423418 TI - Synergistic Effects of Cabozantinib and EGFR-Specific CAR-NK-92 Cells in Renal Cell Carcinoma. AB - The chimeric antigen receptor-modified immune effector cell (CAR-T and CAR-NK) therapies are newly developed adoptive treatments of cancers. However, their therapeutic efficacy against solid tumors is limited. Combining CAR-T or CAR-NK cells with chemotherapeutic drugs to treat solid tumor may be a promising strategy. We developed an epidermal growth factor- (EGFR-) specific third generation CAR. NK-92 cells were modified with the CAR by lentivirus infection. The specific killing ability of the CAR-modified NK-92 cells (CAR-NK-92) against renal cell carcinoma (RCC) cell lines was confirmed in vitro. The synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells were investigated in vitro and in vivo. Our results showed that the CAR-NK-92 cells lyse RCC cells in an EGFR-specific manner. Treatment with cabozantinib could increase EGFR and decrease PD-L1 membrane surface expression in RCC cells and enhance the killing ability of CAR-NK-92 cells against the RCC cells in vitro. Furthermore, the CAR NK-92 cells show synergistic therapeutic efficacy with cabozantinib against human RCC xenograft models. Our results provided the basis for combination with chemotherapy as a novel strategy for enhancing the therapeutic efficacy of CAR modified immune effector cells for solid tumors. PMID- 29423420 TI - Trends in Kindergarten Rates of Vaccine Exemption and State-Level Policy, 2011 2016. AB - Background: Kindergarten-entry vaccination requirements have played an important role in controlling vaccine-preventable diseases in the United States. Forty eight states and the District of Colombia offer nonmedical exemptions to vaccines, ranging in stringency. Methods: We analyzed state-level exemption data from 2011 to 2012 through 2015 to 2016 school years. States were categorized by exemption ease and type of exemption allowed. We calculated nonmedical exemption rates for each year in the sample and stratified by exemption ease, type, and 2 trend categories: 2011-12 through 2012-13 and 2013-14 through 2015-16 school years. Using generalized estimating equations, we created regression models estimating (1) the average annual change in nonmedical exemption rates and (2) relative differences in rates by state classification. Results: The nonmedical exemption rate was higher during the 2013-2014 through 2015-2016 period (2.25%) compared to 2011-2012 through 2012-2013 (1.75%); more importantly, the average annual change in the latter period plateaued. The nonmedical exemption rate in states allowing philosophical and religious exemptions was 2.41 times as high as in states allowing only religious exemptions (incidence rate ratio = 2.41; 95% confidence interval, 1.71-3.41). Conclusions: There was an increase in nonmedical exemption rates through the 2012-2013 school year; however, rates stabilized through the 2015-2016 school year, showing an important shift in trend. PMID- 29423421 TI - An Updated Review of Iclaprim: A Potent and Rapidly Bactericidal Antibiotic for the Treatment of Skin and Skin Structure Infections and Nosocomial Pneumonia Caused by Gram-Positive Including Multidrug-Resistant Bacteria. AB - New antibiotics are needed because of the increased morbidity and mortality associated with multidrug-resistant bacteria. Iclaprim, a bacterial dihydrofolate reductase inhibitor, not currently approved, is being studied for the treatment of skin infections and nosocomial pneumonia caused by Gram-positve bacteria, including multidrug-resistant bacteria. Iclaprim showed noninferiority at -10% to linezolid in 1 of 2 phase 3 studies for the treatment of complicated skin and skin structure infections with a weight-based dose (0.8 mg/kg) but did not show noninferiority at -10% to linezolid in a second phase 3 study. More recently, iclaprim has shown noninferiority at -10% to vancomycin in 2 phase 3 studies for the treatment of acute bacterial skin and skin structure infections with an optimized fixed dose (80 mg). A phase 3 study for the treatment of hospital acquired bacterial and ventilator-associated bacterial pneumonia is upcoming. If, as anticipated, iclaprim becomes available for the treatment of skin and skin structure infections, it will serve as an alternative to current antibiotics for treatment of severe infections. This article will provide an update to the chemistry, preclinical, pharmacology, microbiology, clinical and regulatory status of iclaprim. PMID- 29423422 TI - Acute Appendicitis as the Initial Clinical Presentation of Primary HIV-1 Infection. AB - We report a case of an adolescent who presented at our emergency department with acute abdominal pain. While the initial diagnosis was acute appendicitis, a secondary and coincidental diagnosis of primary HIV-1 infection was made. Concurrent and subsequent clinical and molecular biology findings form the basis of our argument that primary HIV-1 infection was the cause of acute appendicitis in this individual. PMID- 29423423 TI - Rapid Reversal of Complete Binocular Blindness With High-Dose Corticosteroids and Lumbar Drain in a Solid Organ Transplant Recipient With Cryptococcal Meningitis and Immune Reconstitution Syndrome: First Case Study and Literature Review. AB - Blindness is a rare, devastating, usually permanent complication of cryptococcal meningitis (CM). We present the first case of complete vision loss in a solid organ transplant recipient with CM treated with placement of a lumbar drain who had a dramatic visual recovery that started after 3 doses of high-dose steroids. PMID- 29423424 TI - What Will It Take to Reduce HIV Incidence in the United States: A Mathematical Modeling Analysis. AB - Background: The National HIV/AIDS Strategy has set ambitious goals to improve the epidemic in the United States. However, there is a paucity of usable program level benchmarks tied to population-level epidemiologic goals. Our objective was to define tangible benchmarks for annual rates along the care continuum that are likely to translate to meaningful reductions in incidence. Methods: We used a validated mathematical model of HIV transmission and care engagement to characterize care continuum parameters that would translate into 50% reductions in incidence by 2025, compared with a base case scenario of the current US care continuum. We generated a large pool of simulations in which rates of screening, linkage, and retention in care were varied across wide ranges to evaluate permutations that halved incidence by 2025. Results: Among all simulations, 7% achieved a halving of incidence. It was impossible for our simulations to achieve this target if the annual rate of disengagement from care exceeded 20% per year, even at high rates of care reengagement. When retention in care was 95% per year and people living with HIV (PLWH) out of care reengaged within 1.5 years (on average), the probability of halving incidence by 2025 was approximately 90%. Conclusions: HIV programs should aim to retain at least 95% of PLWH in care annually and reengage people living with HIV into care within an average of 1.5 years to achieve the goal of halving HIV incidence by 2025. PMID- 29423425 TI - Mouse Corneal Stroma Fibroblast Primary Cell Culture. AB - This protocol is developed for primary cell culture of cornea stromal keratocytes isolated from neonatal mouse eyeballs. It provides an optimal condition to isolate stromal keratocytes which maintain high viability for cell culture. PMID- 29423426 TI - Bioluminescence Resonance Energy Transfer (BRET) Assay for Determination of Molecular Interactions in Living Cells. AB - The bioluminescence resonance energy transfer (BRET) assay can be used as an indicator of molecular approximation and/or interaction. A significant resonance energy transfer signal is generated when the acceptor, having the appropriate spectral overlap with the donor emission, is approximated with the donor. In the example provided, proteins tagged with bioluminescent Renilla luciferase (Rlu) as donor and yellow fluorescent protein (YFP) as acceptor were co-expressed in cells. This pair of donor and acceptor have an approximate Forster distance of 4.4 nm, providing the optimal working distance (Dacres et al., 2010). This technique can be used to explore the time-course of specific molecular interactions that occur in living cells. PMID- 29423427 TI - Rapid IFM Dissection for Visualizing Fluorescently Tagged Sarcomeric Proteins. AB - Sarcomeres, the smallest contractile unit of muscles, are arguably the most impressive actomyosin structure. Yet a complete understanding of sarcomere formation and maintenance is missing. The Drosophila indirect flight muscle (IFM) has proven to be a very valuable model to study sarcomeres. Here, we present a protocol for the rapid dissection of IFM and analysis of sarcomeres using fluorescently tagged proteins. PMID- 29423428 TI - What's Your "Street Race"? Leveraging Multidimensional Measures of Race and Intersectionality for Examining Physical and Mental Health Status Among Latinxs. AB - Using the 2015 Latino National Health and Immigration Survey (N= 1,197) we examine the relationship between physical and mental health status and three multidimensional measures of race: 1) "street race," or how you believe other "Americans" perceive your race at the level of the street; 2) socially assigned race or what we call "ascribed race," which refers to how you believe others usually classify your race in the U.S.; and 3) "self-perceived race," or how you usually self-classify your race on questionnaires. We engage in intersectional inquiry by combining street race and gender. We find that only self-perceived race correlates with physical health and that street race is associated with mental health. We also find that men reporting their street race as Latinx1 or Arab were associated with higher odds of reporting worse mental health outcomes. One surprising finding was that, for physical health, men reporting their street race as Latinx were associated with higher odds of reporting optimal physical health. Among women, those reporting their street race as Mexican were associated with lower odds of reporting optimal physical health when compared to all other women; for mental health status, however, we found no differences among women. We argue that "street race" is a promising multidimensional measure of race for exploring inequality among Latinxs. PMID- 29423429 TI - The FDA "Deeming Rule" and Tobacco Regulatory Research. AB - In May 2016, the Food and Drug Administration extended its tobacco regulatory authorities to other products meeting the definition of a tobacco product (Deeming Rule). This authority now includes, but is not limited to, electronic nicotine delivery systems (ENDS), such as electronic cigarettes, as well as all cigars, pipes, and hookahs (waterpipes). The FDA's Center for Tobacco Products has been able to fund research projects addressing these newly deemed tobacco products through a variety of mechanisms, including partnership with the Tobacco Regulatory Science Program, National Institutes of Health. In building the evidence base to inform the regulation of and communications about new and emerging tobacco products, it is important for investigators to be mindful of the goals of tobacco regulatory science, ie, scientific inquiry specifically to inform potential regulatory decisions and actions to protect the public's health. Having solid scientific evidence will allow the FDA to make the most appropriate regulatory decisions regarding newly deemed products. PMID- 29423430 TI - Neuron specific enolase is a potential target for regulating neuronal cell survival and death: implications in neurodegeneration and regeneration. PMID- 29423431 TI - Relationship between Risk Behavior for Eating Disorders and Dental Caries and Dental Erosion. AB - The aim of this study was to evaluate whether there is an association between risk behavior for eating disorders (EDs) and dental erosion and caries. A controlled cross-sectional study was conducted in Brazil, involving 850 randomly selected female adolescents. After evaluating risk behavior for eating disorders through the Bulimic Investigatory Test of Edinburgh, 12 adolescents were identified with severe risk behavior for EDs and matched to 48 adolescents without such risk. Dental examinations, anthropometric measurements, and eating habits and oral hygiene were performed. Adolescents with high severity eating disorder condition were not more likely to show dental caries (p = 0.329; OR = 2.2, 95% CI: 0.35-13.72) or dental erosion (p = 0.590; OR = 2.33; 95% CI: 0.56 9.70). Adolescents with high body mass index (BMI) were five times more likely to have high severity eating disorder condition (p = 0.031; OR = 5.1; 95% CI: 1.61 23.07). Therefore, high severity risk behavior for EDs was not significantly associated with dental caries and dental erosion. However, high BMI was a risk factor for developing eating disorders and should be an alert for individuals with this condition. PMID- 29423432 TI - Complications and outcomes of routine endoscopy in the very elderly. AB - Background and study aims: In Japan, the elderly population has been increasing annually. The number of elderly patients for whom esophagogastroduodenoscopy (EGD) and colonoscopy (CS) is indicated also has been rising. The aim of this study was to evaluate the safety and efficacy of routine endoscopy in a cohort of octogenarians aged 85 years and older - defined by the World Health Organization as the very elderly. Patients and methods: A total of 5,586 patients underwent EGDs, and 2,484 patients underwent CSs performed at the Keio University Hospital from January to September 2014. One hundred eighty-five EGDs and 70 of the CS were performed in the very elderly. Six hundred nine EGDs and 262 CS were performed on younger patients (aged forties). Statistical analysis was performed by univariate and multivariate analyses. Results: On univariate analysis, the rate of adverse events (AEs) in the very elderly was significantly higher compared to the younger group (6.3 % vs. 1.1 %; P < 0.01). Moreover, the very elderly cohort received substantial therapeutic intervention as compared to the younger (16.9 % vs. 6.9 %; P < 0.01). On multivariate analysis, independent risk factors of AEs included: very elderly patients (odds ratio (OR) 3.30, 95 % confidence interval (CI) 1.05 - 10.35), inpatients (OR 3.22, 95 % CI 1.34 - 7.74), and use of pethidine hydrochloride prescription (OR 3.44, 95 % CI 1.51 - 7.81). Conclusions: Routine endoscopy in the very elderly incurs a significant risk of AEs, particularly when combined with pethidine hydrochloride prescription. PMID- 29423433 TI - Adenoma recurrence after endoscopic mucosal resection: propensity score analysis of old and new colonoscopes and Sydney recurrence tool implementation. AB - Background and study aims: Risk factors for colorectal adenoma recurrence after endoscopic mucosal resection (EMR) have been well documented. We assessed the efficacy of the newer 190 colonoscope versus the standard 180 colonoscope for complete resection of lateral spreading lesions. Patients and methods: A single center, retrospective study of patients who underwent EMR with Olympus 180 or 190 colonoscopes from January 1, 2010 to September 30, 2016. We included patients with lesions >= 20 mm and surveillance colonoscopy (SC1) after index EMR. A propensity score approach with inverse probability weighting was used to control for potential confounders. A secondary aim was to identify risk factors for recurrence and assess the applicability of the Sydney EMR recurrence tool (SERT) by grading each lesion of our cohort and analyzing associations with recurrence. Results: Two hundred ninety-one lesions met inclusion criteria for the study. Odds ratio (OR) for recurrence with the 190 colonoscope was 1.06 ( P = .85). Adenoma size ( P = .02) and use of argon plasma coagulation (APC; P < .001) were risk factors for recurrence. Lesions with SERT scores > 0 had a higher recurrence risk during follow-up (32 % vs 21 %; OR 1.71; P = .05). Lesions with SERT scores = 0 reached a plateau for recurrence at 12 and 18 months in Kaplan Meier curves. Conclusions: The use of 190 colonoscopes did not measurably affect adenoma recurrence at SC1. Recurrence was associated with adenoma size, complementary APC for resection, and SERT scores > 0. Lesions with SERT scores = 0 that remain negative for recurrence at 18 months may return to routine surveillance. PMID- 29423434 TI - Prospective evaluation of EUS-guided fine needle biopsy in pancreatic mass lesions. AB - Background and study aim : Due to the scarcity of specific data on endoscopic ultrasound (EUS)-guided fine-needle biopsies (SharkCore) FNB in the evaluation of pancreatic lesions, we performed a prospective study of the diagnostic performance of EUS SharkCore FNB in patients with pancreatic lesions. The aim of this study was to evaluate the diagnostic accuracy. Patients and methods : Single center prospective study of 41 consecutive patients referred for EUS-FNB from October 2015 to April 2016 at our center. EUS-FNB was obtained in a predefined setting regarding the procedure and pathological evaluation. Data regarding demographics, lesion, technical parameters, and diagnostic accuracy were obtained. Results : The study included 41 consecutive patients (22 males (54 %); median age 68 years). The average size of the lesions was 28 mm (median: 30 mm). A diagnostic specimen was identified in 40 (98 %) cases during microscopy with an average of 2.4 passes. The route was trans-duodenal in 20 cases (49 %). The histological diagnosis of the specimens was malignant in 29 cases (71 %), benign in 8 (20 %), suspicious in 2 (5 %), atypical in 1 (2 %) and in 1 (2 %) no material for microscopic evaluation was obtained. This led to a diagnostic accuracy of 93 %, sensitivity of 91 % and a specificity of 100 %. 2 cases (5 %) of self-limiting bleeding were observed. The diagnosis at follow up was malignant in 32 (78 %) of the patients. Conclusions : EUS-FNB of pancreatic mass lesions with the SharkCore needle produced specimens with a diagnostic accuracy of 93 %. The procedure was safe and easy to perform, and these data support the use of EUS FNB in a routine setting. PMID- 29423435 TI - Usefulness of a multifunctional snare designed for colorectal hybrid endoscopic submucosal dissection (with video). AB - : Since colorectal endoscopic submucosal dissection (ESD) remains technically difficult, hybrid ESD was developed as an alternative therapeutic option to achieve en bloc resection of relatively large lesions. In this feasibility study, we evaluated the safety and efficacy of hybrid colorectal ESD using a newly developed multifunctional snare. From June to August 2016, we prospectively enrolled 10 consecutive patients with non-pedunculated intramucosal colorectal tumors 20 - 30 mm in diameter. All of the hybrid ESD steps were performed using the "SOUTEN" snare. The knob-shaped tip attached to the loop top helps to stabilize the needle-knife, making it less likely to slip during circumferential incision and enables partial submucosal dissection. All of the lesions were curatively resected by hybrid ESD, with a short mean procedure time (16.1 +/- 4.8 minutes). The mean diameters of the resected specimens and tumors were 30.5 +/- 4.9 and 26.0 +/- 3.5 mm, respectively. No perforations occurred, while delayed bleeding occurred in 1 patient. In conclusion, hybrid ESD using a multifunctional snare enables easy, safe, and cost-effective resection of relatively large colorectal tumors to be achieved. STUDY REGISTRATION: UMIN000022545. PMID- 29423436 TI - Extended cold snare polypectomy for small colorectal polyps increases the R0 resection rate. AB - Background and study aims: Despite widespread use of cold snare polypectomy (CSP), the R0 resection rate is not well documented. We perform extended CSP, resecting polyps with a > 1 mm circumferential margin. The aim of this study is to compare the R0 resection rate of extended CSP with conventional CSP and to assess safety. Patients and methods : From April 2014 to September 2016, 712 non pedunculated colorectal polyps, < 10 mm in size, resected using CSP from 316 patients were retrospectively analyzed. Results: We divided lesions into conventional CSP (n = 263) and extended CSP groups (n = 449). The baseline characteristics of these two groups were not significantly different in univariate or multivariate analyses. Sessile polyps comprised 94 % (668/712), and the remaining were flat-elevated polyps. Mean size of polyps (+/-standard deviation) was 4.2 +/- 1.5 mm. The most frequent pathology was low grade adenoma (97 %, 689/712). The R0 resection rate was significantly higher in the extended CSP group (439/449 [98 %]) than in the conventional CSP group (222/263 [84 %], P < 0.001). There was no delayed bleeding or perforation in either group (conventional CSP group, 0/263, 95 % confidence interval: 0.0 - 1.4 % and extended CSP group, 0/449, 95 % confidence interval: 0.0 - 0.8 %). Conclusions: Extended CSP results in a higher R0 resection rate compared with conventional CSP. Extended CSP did not result in a higher rate of delayed bleeding or perforation. Extended CSP is a safe and promising procedure for endoscopic resection of non-pedunculated colorectal polyps < 10 mm in size. PMID- 29423437 TI - Fast and Slow Oscillations Recruit Molecularly-Distinct Subnetworks of Lateral Hypothalamic Neurons In Situ. AB - Electrical signals generated by molecularly-distinct classes of lateral hypothalamus (LH) neurons have distinct physiological consequences. For example, LH orexin neurons promote net body energy expenditure, while LH non-orexin neurons [VGAT, melanin-concentrating hormone (MCH)] drive net energy conservation. Appropriate switching between such physiologically-opposing LH outputs is traditionally thought to require cell-type-specific chemical modulation of LH firing. However, it was recently found that, in vivo, the LH neurons are also physiologically exposed to electrical oscillations of different frequency bands. The role of the different physiological oscillation frequencies in firing of orexin vs non-orexin LH neurons remains unknown. Here, we used brain slice whole-cell patch-clamp technology to target precisely-defined oscillation waveforms to individual molecularly-defined classes LH cells (orexin, VGAT, MCH, GAD65), while measuring the action potential output of the cells. By modulating the frequency of sinusoidal oscillatory input, we found that high-frequency oscillations (gamma, ~30-200 Hz) preferentially silenced the action potential output orexinLH cells. In contrast, low frequencies (delta-theta, ~0.5-7 Hz) similarly permitted outputs from different LH cell types. This differential control of orexin and non-orexin cells by oscillation frequency was mediated by cell-specific, impedance-unrelated resonance mechanisms. These results substantiate electrical oscillations as a novel input modality for cell-type specific control of LH firing, which offers an unforeseen way to control specific cell ensembles within this highly heterogeneous neuronal cluster. PMID- 29423438 TI - Breast cancer risk factors and mammographic density among high-risk women in urban China. AB - Elevated mammographic density (MD) is an established breast cancer risk factor. Studies examining relationships between MD and breast cancer risk factors are limited in China, where established breast cancer risk factors are less prevalent but dense breasts are more prevalent than Western countries. This study included 11,478 women (45-69 years; 36% premenopausal) participating in an ongoing national cancer screening program in 11 urban provinces in China and predicted as having high-risk for breast cancer. Polytomous logistic regression was performed to assess associations between MD and risk factors by comparing each higher Breast Imaging Reporting and Data System (BI-RADS) category (2, 3, or 4) to the lowest category (BI-RADS, 1). We found associations of increasing age, body mass index, weight, postmenopausal status, and parity with lower MD. Higher levels of education, increasing height, and later first birth were associated with higher MD. These associations did not vary by menopausal status. Additionally, the association between longer period of breastfeeding and lower MD was seen among postmenopausal women only (Pinteraction = 0.003). Having first-degree relatives with breast cancer diagnosed before 50 years was associated with lower MD only among premenopausal women (Pinteraction = 0.061). We found effects of established breast cancer risk factors on MD showed similar directions in Chinese and Western women, supporting the hypothesis that MD represents cumulative exposure to breast cancer risk factors over the life course. Our findings help to understand the biological basis of the association of MD with breast cancer risk and have implications for breast cancer prevention research in China. PMID- 29423439 TI - Photocarrier generation from interlayer charge-transfer transitions in WS2 graphene heterostructures. AB - Efficient interfacial carrier generation in van der Waals heterostructures is critical for their electronic and optoelectronic applications. We demonstrate broadband photocarrier generation in WS2-graphene heterostructures by imaging interlayer coupling-dependent charge generation using ultrafast transient absorption microscopy. Interlayer charge-transfer (CT) transitions and hot carrier injection from graphene allow carrier generation by excitation as low as 0.8 eV below the WS2 bandgap. The experimentally determined interlayer CT transition energies are consistent with those predicted from the first-principles band structure calculation. CT interactions also lead to additional carrier generation in the visible spectral range in the heterostructures compared to that in the single-layer WS2 alone. The lifetime of the charge-separated states is measured to be ~1 ps. These results suggest that interlayer interactions make graphene-two-dimensional semiconductor heterostructures very attractive for photovoltaic and photodetector applications because of the combined benefits of high carrier mobility and enhanced broadband photocarrier generation. PMID- 29423440 TI - Optimal information networks: Application for data-driven integrated health in populations. AB - Development of composite indicators for integrated health in populations typically relies on a priori assumptions rather than model-free, data-driven evidence. Traditional variable selection processes tend not to consider relatedness and redundancy among variables, instead considering only individual correlations. In addition, a unified method for assessing integrated health statuses of populations is lacking, making systematic comparison among populations impossible. We propose the use of maximum entropy networks (MENets) that use transfer entropy to assess interrelatedness among selected variables considered for inclusion in a composite indicator. We also define optimal information networks (OINs) that are scale-invariant MENets, which use the information in constructed networks for optimal decision-making. Health outcome data from multiple cities in the United States are applied to this method to create a systemic health indicator, representing integrated health in a city. PMID- 29423441 TI - Revealing the detailed path of sequential deposition for metal halide perovskite formation. AB - Sequential deposition has been extensively used for the fabrication of perovskite solar cells. Nevertheless, fundamental aspects of the kinetics of methylammonium lead iodide perovskite formation remain obscure. We scrutinize the individual stages of the reaction and investigate the crystallization of the lead iodide film, which occurs before the intercalation of methylammonium iodide commences. Our study identifies the presence of mixed crystalline aggregates composed of perovskite and lead iodide during intercalation and structural reorganization. Furthermore, Ostwald ripening occurs in the film for reaction times beyond the point of conversion to perovskite. Using cross-sectional confocal laser scanning microscopy for the first time, we reveal that lead iodide in the over-layer and at the bottom of the mesoporous layer converts first. We identify unreacted lead iodide trapped in the mesoporous layer for samples of complete conversion. We acquire kinetic data by varying different parameters and find that the Avrami models best represent them. The model facilitates the rapid estimation of the reaction time for complete conversion for a variety of reaction conditions, thereby ascertaining a major factor previously determined by extensive experimentation. This comprehensive picture of the sequential deposition is essential for control over the perovskite film quality, which determines solar cell efficiency. Our results provide key insights to realize high-quality perovskite films for optoelectronic applications. PMID- 29423442 TI - Neyman-Pearson classification algorithms and NP receiver operating characteristics. AB - In many binary classification applications, such as disease diagnosis and spam detection, practitioners commonly face the need to limit type I error (that is, the conditional probability of misclassifying a class 0 observation as class 1) so that it remains below a desired threshold. To address this need, the Neyman Pearson (NP) classification paradigm is a natural choice; it minimizes type II error (that is, the conditional probability of misclassifying a class 1 observation as class 0) while enforcing an upper bound, alpha, on the type I error. Despite its century-long history in hypothesis testing, the NP paradigm has not been well recognized and implemented in classification schemes. Common practices that directly limit the empirical type I error to no more than alpha do not satisfy the type I error control objective because the resulting classifiers are likely to have type I errors much larger than alpha, and the NP paradigm has not been properly implemented in practice. We develop the first umbrella algorithm that implements the NP paradigm for all scoring-type classification methods, such as logistic regression, support vector machines, and random forests. Powered by this algorithm, we propose a novel graphical tool for NP classification methods: NP receiver operating characteristic (NP-ROC) bands motivated by the popular ROC curves. NP-ROC bands will help choose alpha in a data-adaptive way and compare different NP classifiers. We demonstrate the use and properties of the NP umbrella algorithm and NP-ROC bands, available in the R package nproc, through simulation and real data studies. PMID- 29423444 TI - Tailoring optical metamaterials to tune the atom-surface Casimir-Polder interaction. AB - Metamaterials are fascinating tools that can structure not only surface plasmons and electromagnetic waves but also electromagnetic vacuum fluctuations. The possibility of shaping the quantum vacuum is a powerful concept that ultimately allows engineering the interaction between macroscopic surfaces and quantum emitters such as atoms, molecules, or quantum dots. The long-range atom-surface interaction, known as Casimir-Polder interaction, is of fundamental importance in quantum electrodynamics but also attracts a significant interest for platforms that interface atoms with nanophotonic devices. We perform a spectroscopic selective reflection measurement of the Casimir-Polder interaction between a Cs(6P3/2) atom and a nanostructured metallic planar metamaterial. We show that by engineering the near-field plasmonic resonances of the metamaterial, we can successfully tune the Casimir-Polder interaction, demonstrating both a strong enhancement and reduction with respect to its nonresonant value. We also show an enhancement of the atomic spontaneous emission rate due to its coupling with the evanescent modes of the nanostructure. Probing excited-state atoms next to nontrivial tailored surfaces is a rigorous test of quantum electrodynamics. Engineering Casimir-Polder interactions represents a significant step toward atom trapping in the extreme near field, possibly without the use of external fields. PMID- 29423443 TI - Demonstration of universal parametric entangling gates on a multi-qubit lattice. AB - We show that parametric coupling techniques can be used to generate selective entangling interactions for multi-qubit processors. By inducing coherent population exchange between adjacent qubits under frequency modulation, we implement a universal gate set for a linear array of four superconducting qubits. An average process fidelity of F = 93% is estimated for three two-qubit gates via quantum process tomography. We establish the suitability of these techniques for computation by preparing a four-qubit maximally entangled state and comparing the estimated state fidelity with the expected performance of the individual entangling gates. In addition, we prepare an eight-qubit register in all possible bitstring permutations and monitor the fidelity of a two-qubit gate across one pair of these qubits. Across all these permutations, an average fidelity of F = 91.6 +/- 2.6% is observed. These results thus offer a path to a scalable architecture with high selectivity and low cross-talk. PMID- 29423445 TI - Wafer-scale, layer-controlled organic single crystals for high-speed circuit operation. AB - Two-dimensional (2D) layered semiconductors are a novel class of functional materials that are an ideal platform for electronic applications, where the whole electronic states are directly modified by external stimuli adjacent to their electronic channels. Scale-up of the areal coverage while maintaining homogeneous single crystals has been the relevant challenge. We demonstrate that wafer-size single crystals composed of an organic semiconductor bimolecular layer with an excellent mobility of 10 cm2 V-1 s-1 can be successfully formed via a simple one shot solution process. The well-controlled process to achieve organic single crystals composed of minimum molecular units realizes unprecedented low contact resistance and results in high-speed transistor operation of 20 MHz, which is twice as high as the common frequency used in near-field wireless communication. The capability of the solution process for scale-up coverage of high-mobility organic semiconductors opens up the way for novel 2D nanomaterials to realize products with large-scale integrated circuits on film-based devices. PMID- 29423446 TI - Plasmonic nanostructures through DNA-assisted lithography. AB - Programmable self-assembly of nucleic acids enables the fabrication of custom, precise objects with nanoscale dimensions. These structures can be further harnessed as templates to build novel materials such as metallic nanostructures, which are widely used and explored because of their unique optical properties and their potency to serve as components of novel metamaterials. However, approaches to transfer the spatial information of DNA constructions to metal nanostructures remain a challenge. We report a DNA-assisted lithography (DALI) method that combines the structural versatility of DNA origami with conventional lithography techniques to create discrete, well-defined, and entirely metallic nanostructures with designed plasmonic properties. DALI is a parallel, high-throughput fabrication method compatible with transparent substrates, thus providing an additional advantage for optical measurements, and yields structures with a feature size of ~10 nm. We demonstrate its feasibility by producing metal nanostructures with a chiral plasmonic response and bowtie-shaped nanoantennas for surface-enhanced Raman spectroscopy. We envisage that DALI can be generalized to large substrates, which would subsequently enable scale-up production of diverse metallic nanostructures with tailored plasmonic features. PMID- 29423447 TI - Development and Experimental Evaluation of Concurrent Control of a Robotic Arm and Continuum Manipulator for Osteolytic Lesion Treatment. AB - This paper presents the development and evaluation of concurrent control of a robotic system for less-invasive treatment of osteolytic lesions behind an acetabular implant. This system implements safety constraints including a remote center of motion (RCM), virtual walls, and joint limits while operating through the screw holes of the acetabular implant. The formulated linear constrained optimization problem ensures these constraints are satisfied while maintaining precise control of the tip of a Continuum Dexterous Manipulator (CDM) attached to a positioning robot. Experiments evaluated the performance of the tip control method within an acetabular cup. The controller reliably reached a series of goal points with a mean error of 0.42 mm and a worst-case error of straying 1.0 mm from our path. PMID- 29423448 TI - Understanding Word Reading Difficulties in Children With SLI. AB - Children with specific language impairment (SLI) often show considerable reading difficulties. Research has revealed two primary reading profiles among children with SLI: (a) one of poor word reading and decoding skills and associated reading comprehension difficulties, and (b) one involving relatively strong word reading skills but poor comprehension. This article reviews studies characterizing these two subtypes of SLI, discusses their current clinical implications, and suggests important directions for future study. PMID- 29423449 TI - Primary Pleomorphic Liposarcoma of Fallopian Tube with Recurrence: A Case Report and Review of the Literature. AB - Background: Liposarcoma, which develops in adipose tissue, is one of the most common soft tissue sarcomas. It appears mostly in the lower limbs, particularly in the thigh and limb girdles, followed by the upper extremities, thoracoabdominal wall, and the internal trunk and retroperitoneum. Pleomorphic liposarcoma (PLS), a rare subtype of liposarcoma is considered a highgrade malignancy. Case presentation: We present a case of primary PLS in the left fallopian tube of a 47-year-old female. Ten months previously, she was diagnosed with PLS of the left fallopian tube in another hospital and had a wide excision of left fallopian tube mass, including total abdominal hysterectomy and bilateral salpingo-oophorectomy for left fallopian tube PLS. Presently, she has developed a recurrence and metastasis of PLS in the pelvic and abdominal cavities. Conclusion: This may be the first case of primary fallopian tube PLS, wherein the prognosis of this patient was poor due to the high-grade malignancy of PLS. PMID- 29423450 TI - Color Doppler Ultrasound in Uterine Arterial Embolization. AB - Objective: To observe and analyze the effect of color doppler ultrasonography (CDU) in uterine arterial embolization (UAE). Methods: 160 cases of patients with uterine fibroid were selected in this study. CDU were performed on all patients before UAE as well as 5-9 days and 3-6 months after UAE, so as to observe the shape, size and ultrasonogram of the uterus and uterine fibroid, and the blood flow changes of the uterine fibroid. In addition, analysis was carried out on the improvement of the clinical symptoms 3 months to 6 months after UAE. Results: 5-9 days and 3-6 months after UAE, the blood flow of uterine fibroid was significantly reduced or even disappeared, with P <0.05; according to the observation carried out 3-6 months after UAE, irregular menstruation and uterine fibroid compression were significantly relieved; the uterine size and the uterine fibroid volume were significantly decreased;high-level echo was generated inside of the uterine fibroid, which was then gradually reduced into slightly higher echo, equal echo and low echo. High-level echo was found around the uterine fibroid. Conclusion: It is safe and reliable for the patients with symptomatic uterine fibroid to take UAE. The application of CDU can also provide a good basis and has great significance. PMID- 29423451 TI - Effects of Out-of-hospital Continuing Nursing on Schizophrenia Patients' Rehabilitation and Quality of Life. AB - Objective: This paper aims to explore specific effects of out-of-hospital continuing nursing on schizophrenia patients' health rehabilitation and quality of life, and further improve application and popularization of out-of-hospital continuing nursing. Methods: The 180 schizophrenia patients discharged from our hospital from March 2014 to March 2016 were selected as the subjects. The patients were divided into two groups according to the randomized double-blind method. Both groups received routine discharge guidance, and the observation group received out-of-hospital continuing nursing on this basis. Questionnaires and scales were used to compare differences of the two groups after discharge from hospital, such as medication compliance, recurrence rate of schizophrenia, awareness of health knowledge and quality of life. Results: After 6 months of nursing for the observation group, complete medication compliance rate was 71.11% (64/90), awareness rate of schizophrenia-related health knowledge was 96.67% (87/90), and recurrence rate was 8.89% (8/90). For the control group, complete medication compliance rate was 45.56% (41/90), awareness rate of schizophrenia related knowledge was 46.67% (42/90) and the recurrence rate of disease was 26.67% (24/90). Hence, the observation group enjoys significant advantages compared with the control group. Statistical analysis (P <0.05) showed statistical significance; In addition, life quality scores showed that the quality of life of the observation group was obviously better than the control group; the difference was statistically significant (P <0.05). Conclusion: Out-of hospital continuing nursing for schizophrenia patients after discharge can effectively improve medication compliance, awareness rate of health knowledge, effectively reduce incidence of schizophrenia and improve the quality of life of patients. Thus, the nursing concept and related methods are worthy of publicity and application in a wider range. PMID- 29423452 TI - Improving biosensing activity to carcinoembryonic antigen with orientated single domain antibodies. AB - Carcinoembryonic antigen (CEA), also referred as CEACAM5, is integral to the adhesion process during cancer invasion and metastasis and is one of the most widely used tumor markers for assisting the diagnosis of cancer recurrence and cancer metastasis. Antibodies against CEA molecules have been developed for detection and diagnostic applications following tumor removal. Single domain antibodies (sdAbs) against CEA isolated from dromedary and llama exhibited high specificity in binding to tumor cells. However, because these CEA sdAbs were not designed to be orientated when conjugated to surface sensors, there is potential for significant improvements in their activity and limit of detection. Herein we modified the CEA sdAbs with two different C-terminal fusions designed to aid with orientation by way of the tail's charge and biotin binding. A fusion which incorporated the C-terminus addition of a positively charged tail (B5-GS3K) improved biosensor sensitivity to CEA while also retaining the sub-nanomolar binding affinity and thermal stability of the unmodified sdAb. Using our fabricated surfaces on bare gold chips and a multiplexed surface plasmon resonance imager (SPRi), we quantified the specific binding activities, defined as the percentage of bound epitopes to the total immobilized, of the sdAb fusions and anti-CEA mAb. Our results demonstrate that monovalent B5-GS3K exhibited significantly improved binding activity, approximately 3-fold higher than bivalent mAb. PMID- 29423453 TI - Recognizing Whispered Speech Produced by an Individual with Surgically Reconstructed Larynx Using Articulatory Movement Data. AB - Individuals with larynx (vocal folds) impaired have problems in controlling their glottal vibration, producing whispered speech with extreme hoarseness. Standard automatic speech recognition using only acoustic cues is typically ineffective for whispered speech because the corresponding spectral characteristics are distorted. Articulatory cues such as the tongue and lip motion may help in recognizing whispered speech since articulatory motion patterns are generally not affected. In this paper, we investigated whispered speech recognition for patients with reconstructed larynx using articulatory movement data. A data set with both acoustic and articulatory motion data was collected from a patient with surgically reconstructed larynx using an electromagnetic articulograph. Two speech recognition systems, Gaussian mixture model-hidden Markov model (GMM-HMM) and deep neural network-HMM (DNN-HMM), were used in the experiments. Experimental results showed adding either tongue or lip motion data to acoustic features such as mel-frequency cepstral coefficient (MFCC) significantly reduced the phone error rates on both speech recognition systems. Adding both tongue and lip data achieved the best performance. PMID- 29423454 TI - Predicting Intelligible Speaking Rate in Individuals with Amyotrophic Lateral Sclerosis from a Small Number of Speech Acoustic and Articulatory Samples. AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurological disease that affects the speech motor functions, resulting in dysarthria, a motor speech disorder. Speech and articulation deterioration is an indicator of the disease progression of ALS; timely monitoring of the disease progression is critical for clinical management of these patients. This paper investigated machine prediction of intelligible speaking rate of nine individuals with ALS based on a small number of speech acoustic and articulatory samples. Two feature selection techniques - decision tree and gradient boosting - were used with support vector regression for predicting the intelligible speaking rate. Experimental results demonstrated the feasibility of predicting intelligible speaking rate from only a small number of speech samples. Furthermore, adding articulatory features to acoustic features improved prediction performance, when decision tree was used as the feature selection technique. PMID- 29423455 TI - The 'state' of tobacco: Perceptions of tobacco among Appalachian youth in Kentucky. AB - INTRODUCTION: In Appalachia, youth tobacco-use rates remain higher than the U.S. national average. Past research has indicated that several factors are related to high rates of tobacco use among Appalachian youth (e.g. low socioeconomic status, rural lifestyles). Of the Appalachian states, Kentucky has one of the highest rates of youth tobacco use. The aim of this study was to explore views of tobacco among Kentucky youth living in Appalachian counties. METHODS: In Fall 2014 - Spring 2015, focus group interviews were conducted with middle and high school students (N=109) in Appalachian counties in Kentucky. Each focus group session included open-ended questions and was conducted by trained facilitators. Focus group transcriptions and field notes were analyzed for themes. RESULTS: Study participants described an entrenched culture of tobacco. Three themes exemplified this culture. First, adult behavior served to enable youth tobacco use (e.g. teachers ignoring dip use in class, adults smoking with youth). Second, tobacco is easily accessible to youth (e.g. restrictions on youth sales are often ignored, family members provide). Third, symbols of tobacco are prevalent (e.g. festivals celebrating tobacco heritage, tobacco barns, and tobacco marketing logos). CONCLUSIONS: Youth participants described a deeply rooted tobacco culture, which they believed was unlikely to change. Additional studies and health education efforts are needed in these rural communities. Further, stricter enforcement of tobacco sales and marketing restrictions may be helpful in protecting this vulnerable population. PMID- 29423456 TI - Unraveling mechanisms of toxicant-induced oxidative stress in cardiovascular disease. AB - To date, numerous clinical studies examining correlations between oxidative stress biomarkers and cardiovascular diseases (CVD) have repeatedly suggested a role for oxidant injury in the pathogenesis of diseases such as atherosclerosis. Despite this, antioxidant supplementation trials have not demonstrated a reduction in disease progression. Nevertheless, small animal and epidemiological studies have linked exposures to certain toxicants with increased CVD risk involving putative oxidative stress mechanisms. A few prototypical vascular toxicants will be discussed as examples of toxicants that likely act via oxidative stress mechanisms. For discussion, we will classify these toxicants as those that induce direct (e.g., arsenic, nucleoside reverse transcriptase inhibitors) versus indirect (particulate matter, ozone) oxidative stress mechanisms, and those that likely induce CVD through both direct and indirect mechanisms (cigarette smoke). Finally, new findings in oxidative stress research, including the emerging importance of reactive sulfur species, hydrogen peroxide as a presumed endothelium-derived hyperpolarizing factors, etc., will be discussed, as well as the need to determine the role of toxicants in modulating these newly identified pathways. Moreover, given the lack of success in conclusively demonstrating the roles of oxidative stress in CVD risk stratification, research probing the roles of toxicant exposures in propagating CVD pathogenesis may be a novel approach for more conclusively delineating the causal role of oxidative stress in CVD initiation and progression. PMID- 29423458 TI - Posterior Ciliary Artery Occlusion. AB - Objective: To compare the severity of ischemic damage following posterior ciliary artery (PCA) occlusion in old, atherosclerotic, hypertensive monkeys to that in young monkeys. Design: Experimental study. Subjects: Seven eyes of normal, healthy rhesus monkeys and 8 of old, atherosclerotic, hypertensive monkeys. Methods: By lateral orbitotomy, all PCAs were cut behind the eyeball in both groups of animals. The fundus and the optic disc were evaluated by repeated ophthalmoscopy, color fundus photography and fluorescein fundus angiography, before and immediately after cutting the PCAs and serially thereafter during the follow-up period. Main Outcome Measures: Severity of acute ischemic damage to the choroidal, outer retinal and optic nerve head. Results: Cutting all the PCAs resulted in the development of ischemic infarction of the choroid, retinal pigment epithelium, outer part of the retina and the optic nerve head within 24 hours, in both groups of animals. The severity of the various ischemic fundus and retinal lesions and of the optic disc during the acute phase showed no statistically significant differences between the two groups of animals. Fluorescein fundus angiography soon after cutting the PCAs showed no filling of the entire choroid and the optic disc in both groups of animals. On follow-up for up to about 3 months, in both groups, the white opacity of the infract in the fundus seen during the acute phase gradually resolved in about 2-3 weeks, leaving greyish, granular, depigmented fundus, unmasking of the large choroidal vessels and optic atrophy; fluorescein angiography revealed gradual restoration of the choroidal blood flow and unmasking of the big choroidal vessels. Conclusions: The study showed that the severity of ischemic damage following occlusion of all the PCAs was similar in both the young healthy and the old, atherosclerotic, hypertensive monkeys. This is in contrast to the findings of our similar study dealing with central retinal artery occlusion, where the young suffered much severe ischemic damage than the old. PMID- 29423457 TI - Recent Advances in Neural Electrode-Tissue Interfaces. AB - Neurotechnology is facing an exponential growth in the recent decades. Neural electrode-tissue interface research has been well recognized as an instrumental component of neurotechnology development. While satisfactory long-term performance was demonstrated in some applications, such as cochlear implants and deep brain stimulators, more advanced neural electrode devices requiring higher resolution for single unit recording or microstimulation still face significant challenges in reliability and longevity. In this article, we review the most recent findings that contribute to our current understanding of the sources of poor reliability and longevity in neural recording or stimulation, including the material failure, biological tissue response and the interplay between the two. The newly developed characterization tools are introduced from electrophysiology models, molecular and biochemical analysis, material characterization to live imaging. The effective strategies that have been applied to improve the interface are also highlighted. Finally, we discuss the challenges and opportunities in improving the interface and achieving seamless integration between the implanted electrodes and neural tissue both anatomically and functionally. PMID- 29423459 TI - Apo E4 Alleles and Impaired Olfaction as Predictors of Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common form of dementia that affects more than 5 million Americans. It is the only disease among the 10 causes of death that cannot be slowed or cured, thus raising the need for identification of early preclinical markers that could be the focus of preventative efforts. Although evidence is escalating that abnormalities in olfactory structure and function precede AD development and early cognitive impairments by one or more decades, the importance of olfaction is largely overlooked in AD, and such testing is not routinely performed in neurology clinics. Nevertheless, research using the olfactory model, has begun to advance our understanding of the preclinical pathophysiology of AD. Notably, an interesting series of studies is beginning to illuminate the relationship between Apolipoprotein E (ApoE) epsilon4 polymorphism and olfactory dysfunction and late-onset Alzheimer's disease. In this article, we reviewed present research on the significance of ApoE and olfaction to AD, summarized current studies on the associations and mechanisms of ApoE and olfactory dysfunction, and highlighted important gaps for future work to further advance the translational application of the olfactory paradigm to early, preclinical diagnosis and treatment of AD. PMID- 29423460 TI - Risk of Cardiovascular Outcomes among Psoriasis Patients Treated with Biologics and Other Systemic Agents. AB - Background: The risk for cardiovascular events associated with systemic therapies for psoriasis, including biologics, is unclear. Methods: We used administrative data from Medicare 2006 through 2011 to identify psoriasis patients who initiated systemic treatments. We estimated incidence rates of hospitalized myocardial infarction, stroke, and a composite cardiovascular disease outcome, adjusting for potentially confounding factors. Results: There were 28,878 initiations of psoriasis treatments. Rates of myocardial infarction were highest for methotrexate (10.32/1000 patient-years, 95%CI 8.55-12.46) and numerically lower for biologics. Patterns were similar for stroke and the composite cardiovascular disease outcome. After multivariable adjustment, there were no significant differences between systemic therapies for any of the outcomes studied. Conclusions: In this cohort of predominantly older psoriasis patients, there was no elevated nor protective risk of cardiovascular or stroke events associated with systemic therapies for psoriasis compared to conventional treatments. PMID- 29423462 TI - From open-shell singlet diradicaloids to polyradicaloids. AB - In this Feature Article, we highlight our recent efforts toward stable open-shell singlet diradicaloids and polyradicaloids. A brief review on the historical works in the area is introduced first, followed by discussion on the fundamental electronic and physical properties of open-shell singlet diradicaloids. Then, the structure-diradical character relationships based on our recently developed diradicaloids are presented. Next, the challenges and solutions toward stable polyradicaloids and 3D pi-conjugated diradicaloids are discussed. Finally, their preliminary material applications are introduced and a perspective view of the area is given. PMID- 29423463 TI - Rigorous analysis of Casimir and van der Waals forces on a silicon nano optomechanical device actuated by optical forces. AB - Nano-optomechanical devices have enabled a lot of interesting scientific and technological applications. However, due to their nanoscale dimensions, they are vulnerable to the action of Casimir and van der Waals (dispersion) forces. This work presents a rigorous analysis of the dispersion forces on a nano optomechanical device based on a silicon waveguide and a silicon dioxide substrate, surrounded by air and driven by optical forces. The dispersion forces are calculated using a modified Lifshitz theory with experimental optical data and validated by means of a rigorous 3D FDTD simulation. The mechanical nonlinearity of the nanowaveguide is taken into account and validated using a 3D FEM simulation. The results show that it is possible to attain a no pull-in critical point due to only the optical forces; however, the dispersion forces usually impose a pull-in critical point to the device and establish a minimal initial gap between the waveguide and the substrate. Furthermore, it is shown that the geometric nonlinearity effect may be exploited in order to avoid or minimize the pull-in and, therefore, the device collapse. PMID- 29423465 TI - Dually responsive gold-iron oxide heterodimers: merging stimuli-responsive surface properties with intrinsic inorganic material features. AB - We demonstrate a versatile approach for the preparation of dually responsive smart inorganic heterostructures (HSs) with the potential for exploitation in nanomedicine. We utilize Au-FexOy dimers as templates for generating smart inorganic HSs with a pH-responsive coating and a thermo-responsive coating attached to iron oxide and gold nanoparticles (NPs), respectively. First, a thiol modified thermo-responsive (PNIPAAM-co-PEGA) polymer could be selectively attached to the gold domain by ligand exchange. The sequential attachment of a catechol-modified initiator to the iron oxide surface enables the in situ polymerization of a pH-responsive (PDMAEA) polymer. As hereby shown, the presence of the two distinct polymer domains on each NP subdomain enables each side of the HS to be loaded with different agents. Indeed, by a gel electrophoresis experiment we demonstrate the loading of siRNA on the pH-responsive polymer and the loading of Nile Blue dye, used as a drug model molecule, on the thermo responsive polymer. The smart HSs exhibited good biocompatibility and downregulated GFP production when loaded with anti-GFP siRNA molecules. In addition, an investigation of the magnetic relaxivity times revealed that the high R2 relaxivity values of the HSs suggest their potential as contrast agents in magnetic resonance imaging (MRI) applications. PMID- 29423461 TI - How to perform Contrast-Enhanced Ultrasound (CEUS). AB - "How to perform contrast-enhanced ultrasound (CEUS)" provides general advice on the use of ultrasound contrast agents (UCAs) for clinical decision-making and reviews technical parameters for optimal CEUS performance. CEUS techniques vary between centers, therefore, experts from EFSUMB, WFUMB and from the CEUS LI-RADS working group created a discussion forum to standardize the CEUS examination technique according to published evidence and best personal experience. The goal is to standardise the use and administration of UCAs to facilitate correct diagnoses and ultimately to improve the management and outcomes of patients. PMID- 29423464 TI - Inertial-ordering-assisted droplet microfluidics for high-throughput single-cell RNA-sequencing. AB - Single-cell RNA-seq reveals the cellular heterogeneity inherent in the population of cells, which is very important in many clinical and research applications. Recent advances in droplet microfluidics have achieved the automatic isolation, lysis, and labeling of single cells in droplet compartments without complex instrumentation. However, barcoding errors occurring in the cell encapsulation process because of the multiple-beads-in-droplet and insufficient throughput because of the low concentration of beads for avoiding multiple-beads-in-a droplet remain important challenges for precise and efficient expression profiling of single cells. In this study, we developed a new droplet-based microfluidic platform that significantly improved the throughput while reducing barcoding errors through deterministic encapsulation of inertially ordered beads. Highly concentrated beads containing oligonucleotide barcodes were spontaneously ordered in a spiral channel by an inertial effect, which were in turn encapsulated in droplets one-by-one, while cells were simultaneously encapsulated in the droplets. The deterministic encapsulation of beads resulted in a high fraction of single-bead-in-a-droplet and rare multiple-beads-in-a-droplet although the bead concentration increased to 1000 MUl-1, which diminished barcoding errors and enabled accurate high-throughput barcoding. We successfully validated our device with single-cell RNA-seq. In addition, we found that multiple-beads-in-a-droplet, generated using a normal Drop-Seq device with a high concentration of beads, underestimated transcript numbers and overestimated cell numbers. This accurate high-throughput platform can expand the capability and practicality of Drop-Seq in single-cell analysis. PMID- 29423466 TI - Magnetic N-doped Co-carbon composites derived from metal organic frameworks as highly efficient catalysts for p-nitrophenol reduction reaction. AB - Magnetic nitrogenous cobalt-carbon composites were synthesized via calcination of N-ZIF-67, where metal and N atoms were introduced into the conductive carbon matrix formed during carbonization of N-ZIF-67, and were applied, as catalysts, in the reduction reaction of p-nitrophenol, assisted by NaBH4. Characterization of the prepared composites was carefully performed using SEM, TEM, XRD, SQUID magnetometric analysis, XPS and nitrogen adsorption/desorption measurements. Compared to Co@C, which was similarly prepared, the N-Co@C catalyst exhibits much better catalytic activity for the reduction of 4-nitrophenol to 4-aminophenol. The pseudo-first-order rate constant for the N-Co@C catalyst is 4.47 times greater than that for the Co@C catalyst, and its stability shows little change after five reaction cycles. The superior catalytic properties of the N-Co@C catalyst are due to the presence of N moieties. Leaching out the cobalt cores was induced using FeCl3 and HCl to see what the active centers were. The results show that the majority of the catalytic activity is associated with the metal cores. PMID- 29423467 TI - An automated microfluidic DNA microarray platform for genetic variant detection in inherited arrhythmic diseases. AB - In this study, we developed an automated microfluidic DNA microarray (AMDM) platform for point mutation detection of genetic variants in inherited arrhythmic diseases. The platform allows for automated and programmable reagent sequencing under precise conditions of hybridization flow and temperature control. It is composed of a commercial microfluidic control system, a microfluidic microarray device, and a temperature control unit. The automated and rapid hybridization process can be performed in the AMDM platform using Cy3 labeled oligonucleotide exons of SCN5A genetic DNA, which produces proteins associated with sodium channels abundant in the heart (cardiac) muscle cells. We then introduce a graphene oxide (GO)-assisted DNA microarray hybridization protocol to enable point mutation detection. In this protocol, a GO solution is added after the staining step to quench dyes bound to single-stranded DNA or non-perfectly matched DNA, which can improve point mutation specificity. As proof-of-concept we extracted the wild-type and mutant of exon 12 and exon 17 of SCN5A genetic DNA from patients with long QT syndrome or Brugada syndrome by touchdown PCR and performed a successful point mutation discrimination in the AMDM platform. Overall, the AMDM platform can greatly reduce laborious and time-consuming hybridization steps and prevent potential contamination. Furthermore, by introducing the reciprocating flow into the microchannel during the hybridization process, the total assay time can be reduced to 3 hours, which is 6 times faster than the conventional DNA microarray. Given the automatic assay operation, shorter assay time, and high point mutation discrimination, we believe that the AMDM platform has potential for low-cost, rapid and sensitive genetic testing in a simple and user-friendly manner, which may benefit gene screening in medical practice. PMID- 29423468 TI - Investigation of charge transfer at the TiO2-MBA-Au interface based on surface enhanced Raman scattering: SPR contribution. AB - Charge transfer (CT) at the interfaces between titanium dioxide (TiO2) and gold (Au) is investigated by surface-enhanced Raman scattering (SERS) spectroscopy probed by a sandwiched molecule 4-mercaptobenzoic acid (4-MBA). For the first time, the contribution of surface plasmon resonance (SPR) to CT is studied by tuning the surface plasmon absorption of Au nanorods (NRs) from 530 nm to 793 nm. Moreover, the degrees of CT in the TiO2-MBA-Au assemblies are calculated and the maximum degree of CT is obtained when the excitation laser wavelength is resonant with the SPR absorption of the assemblies. Accordingly, we propose a CT pathway in these semiconductor-molecule-metal assemblies, and the mechanism by which SPR contributes to the CT at the interfaces is discussed. This study has established a simple and effective way of studying the influence of SPR on interfacial CT by using SERS, which is beneficial for further investigations on interfacial charge transfers. Our findings will have significant importance for the improvement of photoelectric devices and photocatalytic efficiency. PMID- 29423469 TI - A novel fluorescent probe based on biphenyl and rhodamine for multi-metal ion recognition and its application. AB - At present, the design of multi ion sensing receptors is a new area of research due to their potential application in the recognition of analytes. Herein, a novel fluorescent probe for the detection of multi metal ions was designed and synthesized based on the fluorophores of biphenyl and rhodamine. Probe 1 exhibits multiple fluorescence responses to various metal ions (Zn2+, Al3+, Cr3+ and Fe3+) and is accompanied by different optical signal outputs. Moreover, the interference between the target ions can also be effectively solved by the introduction of probe 2 and the addition of the corresponding anions. Probe 1 was also successfully used to detect trace metal ions in real water samples and silicone plate test strips were prepared for the rapid qualitative detection of target metal ions. In addition, in order to better understand the multiple response mechanism of probe 1, geometry optimizations and electronic calculations were carried out at the B3LYP/6-31G*/LANL2DZ level of theory. And harmonic vibrational frequency calculations were also carried out to ensure that all optimized structures were at energy minima on the potential energy surface. PMID- 29423470 TI - A "turn-off" red-emitting fluorophore for nanomolar detection of heparin. AB - A simple fluorophore bearing a diethylaminocoumarin donor and a pyridinium acceptor was synthesized and utilized for the ultra-sensitive detection of heparin. The synthesized dicationic push-pull coumarin derivative emits strongly in the red-region (665 nm) and detects nanomolar concentrations (14.8 nM to 148 nM) of heparin in HEPES buffer and FBS serum solutions. The dication exhibits excellent fluorescence selectivity and sensitivity towards heparin over its analogues such as chondroitin 4-sulfate (CS), hyaluronic acid (HA) and dextran. This fluorescence assay is a convenient, sensitive method for monitoring heparin levels in biological samples. These findings were confirmed using coarse-grained Monte Carlo simulations, which provide us with a rationale for the selective binding of heparin. PMID- 29423471 TI - Experimental and kinetic modeling investigation of rich premixed toluene flames doped with n-butanol. AB - n-Butanol is a promising renewable biofuel and has a lot of advantages as a gasoline additive compared with ethanol. Though the combustion of pure n-butanol has been extensively investigated, the chemical structures of large hydrocarbons doped with n-butanol, especially for aromatic fuels, are still insufficiently understood. In this work, rich premixed toluene/n-butanol/oxygen/argon flames were investigated at 30 Torr with synchrotron vacuum ultraviolet photoionization mass spectrometry (SVUV-PIMS). The blending ratio of n-butanol was varied from 0 to 50%, while the equivalence ratio was maintained at a quite rich value (1.75) for the purpose of studying the influence of n-butanol on the aromatic growth process. Flame species including radicals, reactive molecules, isomers and polycyclic aromatic hydrocarbons (PAHs) were identified and their mole fraction profiles were measured. A kinetic model of toluene/n-butanol combustion was developed from our recently reported toluene and n-butanol models. It is observed that the production of most toluene decomposition products and larger aromatics was suppressed as the blending ratio of n-butanol increases. Meanwhile, the addition of n-butanol generally enhanced the formation of most observed C2-C4 hydrocarbons and C1-C4 oxygenated species. The rate of production (ROP) analysis and experimental observations both indicate that the interaction between toluene and n-butanol in their decomposition processes mainly occurs at the formation of small intermediates, e.g. acetylene and methyl. In particular, the interaction between toluene and n-butanol in methyl formation influences the formation of large monocyclic aromatics such as ethylbenzene, styrene and phenylacetylene, making their maximum mole fractions decay slowly upon increasing the blending ratio of n-butanol compared with toluene and benzyl. The increase of the blending ratio of n-butanol reduces the formation of key PAH precursors such as benzyl, fulvenallenyl, benzene, phenyl and propargyl, which leads to a remarkable reduction in the formation of PAHs. PMID- 29423472 TI - Influence of Pb element on the catalytic properties of {P4Mo6}-polyoxometalate for redox reactions. AB - To introduce Pb element into the crystal framework of a polyoxoanion, a series of hybrid compounds were synthesized and characterized: (H2bpp)5[PbMn(H2O)2]2H2{Mn[Mo6O12(OH)3(HPO4)3(PO4)]2}2.8H2O (1), (H2bpp)3[PbM(H2O)2]2H6{M[Mo6O12(OH)3(HPO4)3(PO4)]2}2.6H2O (M = Ni (2), Co (3)) and (H2bpp)3[PbCd(H2O)2]2H6{Cd[Mo6O12(OH)3(HPO4)3(PO4)]2}2.4H2O (4) (bpp = 1,3 bis(4-pyridyl)propane). Crystal structures were determined and characterized by IR, TG, XPS and single-crystal X-ray diffraction. Hybrids 1-4 have similar compositions; the inorganic moiety has a high-dimensional polyanionic arrangement formed from bi-metallic {PbM} subunits covalently bridging negative {M(P4Mo)2} clusters; the organic moiety is made up of protonated bpp cations that surround anionic clusters through many complex supramolecular interactions. Experimental results showed that the introduction of Pb can modulate the electrochemical properties of crystal materials, leading to the more reversible redox process of {M(P4Mo6)2}-based hybrids. Hybrids 1-4 were employed as heterogeneous catalysts for redox reactions to evaluate their activity involving the transfer of electrons. It was found that these kinds of hybrids were catalytically active in the reduction reaction of [Fe(CN)6]3- (+S2O32-) -> [Fe(CN)6]4-, but were inactive for Cr(vi) (+HCOOH) -> Cr(iii) at 25-70 degrees C. The effect of temperature on the catalytic ability of hybrids was studied, and it was found that 50 degrees C was the optimal reaction condition for the four compounds to catalyze [Fe(CN)6]3- -> [Fe(CN)6]4-. The reduction percentages of Fe(iii) in 270 min were about 95.7% (1), 76.95% (2), 89.39% (3) and 80.8% (4). The well-defined polyanionic structure with tunable structural features might be beneficial for exploring the mechanism of catalytic redox reactions at the molecular level. PMID- 29423474 TI - Enhanced hydrogen spillover to fullerene at ambient temperature. AB - Enhanced hydrogen spillover on molecular fullerene C60, which represents extremely curved graphene sheets, is experimentally demonstrated around ambient temperature. Since the spillover hydrogen is strongly attracted by C60, the increase of C60 mass can be directly confirmed by mass spectroscopy. PMID- 29423473 TI - Enhanced catalytic activity for CO oxidation by the metal-oxide perimeter of TiO2/nanostructured Au inverse catalysts. AB - We report the effect of metal-oxide interfaces on CO oxidation catalytic activity with inverse TiO2-nanostructured Au catalysts. The inverse nanocatalysts were prepared by depositing TiO2via the liquid-phase immersion method on electrochemically synthesized Au nanostructure supports. The catalytic performance for CO oxidation was investigated using various amounts of Ti (i.e. 0.1-1.0 wt%) on two different morphologies of Au nanostructures (i.e. nanoporous and nanorod). In comparing the different Au morphologies, we found an overall higher TOF and lower activation energy for the TiO2/nanoporous Au than those for the TiO2/nanorod Au. In addition, the CO oxidation activity increased as the Ti content increased up to 0.5 wt% probably due to active TiO2-Au interface sites enhancing CO oxidation via the supply of adsorption sites or charge transfer from TiO2 to Au. However, a higher titania content (i.e. 1.0 wt% TiO2) resulted in decreased activity caused by high surface coverage of TiO2 decreasing the number of TiO2-Au interface sites. These results implied that the perimeter area of the metal-oxide interface played a significant role in determining the catalytic performance for CO oxidation. PMID- 29423475 TI - Exploring the structure evolution and core/ligand structure patterns of a series of large sized thiolate-protected gold clusters Au145-3N(SR)60-2N (N = 1-8): a first principles study. AB - The atomic structures of many atomically precise nanosized ligand protected gold clusters have been resolved recently. However, the determination of the atomic structures of large sized ligand protected gold clusters containing metal atoms over ~100 is still a grand challenge. The lack of structural information of these larger sized clusters has greatly hindered the understanding of the structure evolution and structure-property relations of ligand protected gold nanoclusters. In this work, we theoretically studied the structure evolution of a series of large sized Au145-3N(SR)60-2N (N = 1-8) clusters based on an "[Au2@Au(SR)2] fragmentation" pathway starting from a model Au145(SR)60 cluster. Through comprehensively searching the atomic structure of various clusters and evaluating their stabilities by means of first principles calculations, the stabilization mechanism of experimentally reported Au130(SR)50 and Au133(SR)52 clusters is first rationalized. Our studies indicated that Au130(SR)50 and Au133(SR)52 are two critical sized clusters on which the gold cores underwent configuration transitions between decahedral and icosahedral cores. The energy comparisons of various cluster isomer structures indicated that the Au130(SR)50, Au127(SR)48, Au124(SR)46 and Au121(SR)44 clusters favored a decahedral core, while the Au133(SR)52, Au136(SR)54, Au139(SR)56, and Au142(SR)58 clusters preferred icosahedral gold cores. Furthermore, we also find that the cuboctahedral gold core is less stable in the cluster size region between ~120 and ~140 gold atoms. The optical absorption properties and relative thermodynamic stabilities of the Au145-3N(SR)60-2N (N = 1-8) clusters are also surveyed by density functional theory (DFT) and time-dependent DFT calculations. PMID- 29423476 TI - Knots modify the coil-stretch transition in linear DNA polymers. AB - We perform single-molecule DNA experiments to investigate the relaxation dynamics of knotted polymers and examine the steady-state behavior of knotted polymers in elongational fields. The occurrence of a knot reduces the relaxation time of a molecule and leads to a shift in the molecule's coil-stretch transition to larger strain rates. We measure chain extension and extension fluctuations as a function of strain rate for unknotted and knotted molecules. The curves for knotted molecules can be collapsed onto the unknotted curves by defining an effective Weissenberg number based on the measured knotted relaxation time in the low extension regime, or a relaxation time based on Rouse/Zimm scaling theories in the high extension regime. Because a knot reduces a molecule's relaxation time, we observe that knot untying near the coil-stretch transition can result in dramatic changes in the molecule's conformation. For example, a knotted molecule at a given strain rate can experience a stretch-coil transition, followed by a coil-stretch transition, after the knot partially or fully unties. PMID- 29423477 TI - Low-surface-area nitrogen doped carbon nanomaterials for advanced sodium ion batteries. AB - A low-surface-area nitrogen-doped carbon nanomaterial was prepared via a facile annealing method, which shows good Na-ion storage ability (334 mA g-1) and coulombic efficiency due to its mixed charge-discharge mechanism and unique structural features. PMID- 29423478 TI - B(C6F5)3-catalyzed transfer hydrogenations of imines with Hantzsch esters. AB - Highly efficient transfer hydrogenations of imines were realized with as low as 0.1 mol% of B(C6F5)3 by using Hantzsch esters as a hydrogen source, furnishing a variety of amines in 80-99% yields. For the asymmetric transfer hydrogenations, up to 38% ee was obtained with chiral diene-derived boron Lewis acids. PMID- 29423480 TI - Strain-induced modulations of electronic structure and electron-phonon coupling in dense H3S. AB - A ~200 K superconducting phase in dense hydrogen sulfide is an important milestone for the development of novel superconductors with high critical temperature. Here, we systematically studied the effect of uniaxial strain on the electronic and superconducting properties in dense H3S using density functional calculations. Our theoretical results show that inducing strain is an effective tool to control the electronic Fermi surface topology, logarithmic average frequency, and electron-phonon coupling parameter of dense H3S. Thus, uniaxial strain induces sensitive and considerable changes in superconducting critical temperature, which stem from the energy-level shifts and softening lattice vibrations. PMID- 29423479 TI - Tandem copper and gold nanoclusters for two-color ratiometric explosives detection. AB - We report a sensory platform for the determination of common explosive species (e.g., TNT, PETN, RDX) based on the differential response from two different luminescent metal nanoclusters. In particular, whereas the red emission from bovine serum albumin-protected gold nanoclusters was strongly quenched by nitro-, nitrate-, and nitroamine-containing explosive organic molecules, blue-emitting glutathione-capped copper nanoclusters proved inert to quenching by these same analytes, instead showing evidence for aggregation-induced emission enhancement (AIEE). As a result, this discrete gold/copper nanocluster pairing provides a dual-probe, ratiometric (red-to-blue) system signaling the presence of TNT and other common explosives. This strategy opens up new potential for nanocluster based analyte signaling, with implications to fluorescence resonance energy transfer (FRET) strategies as well. PMID- 29423481 TI - Controllable synthesis of lanthanide Yb3+ and Er3+ co-doped AWO4 (A = Ca, Sr, Ba) micro-structured materials: phase, morphology and up-conversion luminescence enhancement. AB - Lanthanide ion (Yb3+, Er3+) co-doped AWO4 (A = Ca, Sr, Ba) up-conversion (UC) luminescent materials have been synthesized using a hydrothermal method and characterized by various microstructural and optical techniques. The results indicate that AWO4:Yb3+,Er3+ samples have an identical body-centered tetragonal scheelite structure with different morphologies, including CaWO4:Yb3+,Er3+ microspheres, dumbbell-like SrWO4:Yb3+,Er3+ and bipyramid-like BaWO4:Yb3+,Er3+. These samples exhibit visible emissions via an UC process under near-infrared (NIR) light (980 nm) excitation. Interestingly, the UC luminescence properties of AWO4:Yb3+,Er3+ can be prominently increased after combination with fluorescent carbon dots (CDs) to form CDs@AWO4:Yb3+,Er3+ composites. Compared to the corresponding samples without combination with CDs, the UC emission intensities of CDs@CaWO4:Yb3+,Er3+, CDs@SrWO4:Yb3+,Er3+ and CDs@BaWO4:Yb3+,Er3+ composites increase about three, six and seven fold in the green emission area, and two, three and four fold in the red emission area, respectively. The mechanism of UC luminescence enhancement is probably that the loss of non-radiative transitions from the higher energy levels to the lower excited levels could be effectively reduced through the energy capture by the CD energy levels. The fluorescence enhancement for Yb3+ and Er3+ co-doped AWO4 through combination with CDs provides a simple strategy for the tungstate system and other UC luminescent host systems. PMID- 29423482 TI - Surface-enhanced Raman scattering on organic-inorganic hybrid perovskites. AB - Surface-enhanced Raman scattering (SERS) on organic-inorganic hybrid perovskites is explored and for the first time the SERS activity (EF >= 104) of the nanostructured CH3NH3PbBr3 has been proved. Here, the SERS profile displays high similarity with the normal Raman spectra and the enhancement mechanism is discussed according to the charge transfer contribution. PMID- 29423483 TI - Halide and hydroxide anion binding in water. AB - The formation of halide and hydroxide anion complexes with two ligands L1 (3,6 bis(morpholin-4-ylmethyl)-1,2,4,5-tetrazine) and L2 (3,6-bis(morpholin-4-ylethyl) 1,2,4,5-tetrazine) was studied in aqueous solution, by means of potentiometric and ITC procedures. In the solid state, HF2-, Cl- and Br- complexes of H2L22+ were analysed by single crystal XRD measurements. Further information on the latter was obtained with the use of density functional theory (DFT) calculations in combination with the polarizable continuum model (PCM). The presence of two halide or bifluoride HF2- (F-H-F-) anions forming anion-pi interactions, respectively above and below the ligand tetrazine ring, is the leitmotiv of the [(H2L2)X2] (X = HF2, Cl, Br, I) complexes in the solid state, while hydrogen bonding between the anions and protonated morpholine ligand groups contributes to strengthen the anion-ligand interaction, in particular in the case of Cl- and Br . In contrast to the solid state, only the anion : ligand complexes of 1 : 1 stoichiometry were found in solution. The stability of these complexes displays the peculiar trend I- > F- > Br- > Cl- which was rationalized in terms of electrostatic, hydrogen bond, anion-pi interactions and solvent effects. DFT calculations performed on [(H2L2)X]+ (X = F, Cl, Br, I) in PCM water suggested that the ligand assumes a U-shaped conformation to form one anion-pi and two salt bridge interactions with the included anions and furnished structural information to interpret the solvation effects affecting complex formation. The formation of hydroxide anion complexes with neutral (not protonated) L1 and L2 molecules represents an unprecedented case in water. The stability of the [L(OH)]- (L = L1, L2) complexes is comparable to or higher than the stability of halide complexes with protonated ligand molecules, their formation being promoted by largely favourable enthalpic contributions that prevail over unfavourable entropic changes. PMID- 29423484 TI - Nickel-catalyzed C-O bond reduction of aryl and benzyl 2-pyridyl ethers. AB - The reduction of aryl and benzyl 2-pyridyl ethers with sodium isopropoxide was carried out via nickel-catalyzed C-OPy bond cleavage, giving reductive products in reasonable to excellent yields. This method allowed the 2-pyridyloxy group to be directly removed with high efficiency, mild reaction conditions, and good compatibility of functional groups. PMID- 29423485 TI - Thermoelectric properties of Ag-doped CuS nanocomposites synthesized by a facile polyol method. AB - We report the first thermoelectric properties of Cu1-xAgxS, x = 0-0.75 nanocomposites, synthesized by using a facile polyol method. Systematic characterizations using powder XRD, Rietveld refinement of XRD, EDAX, XPS and Raman spectroscopy confirmed their single phase, hexagonal crystal structure with the space group P63/mmc, nominal elemental composition, valence states of the constituent elements and stoichiometric nature. The TEM images showing the CuS formation of nearly perfect hexagonal disk-like particles of average thickness 26.7 nm and breadth ranging in a few hundreds of nanometers with nanorods stacked from these hexagonal nanodisks (NDs) elongated along the c axis corroborate the FESEM images. Attributed to structural phase transition, an anomaly at 55 K is clearly observed in both the thermopower and Hall resistivity data. By increasing x, a systematic reduction in thermal conductivity was observed near 300 K. Consequently, a 50% enhancement in figure of merit was observed for Cu0.9Ag0.1S as compared to pure CuS at 300 K. These results therefore are expected to provide a new direction in improving ZT near 300 K. PMID- 29423486 TI - Natural product gelators and a general method for obtaining them from organisms. AB - Since the late 1980s, low molecular weight gelators (LMWGs) based on different classes of natural products have been reported. Until 2011, pure natural LMWGs (i.e., natural product gelators, NPGs) were not found. However, today only five NPGs are reported. We think that this may be due to the lack of awareness about the importance of NPGs and suitable methods to discover new NPGs. Here we illustrate the potential significance of NPGs, and present a general and efficient method for obtaining NPGs from organisms, which provides specific and important guidance to researchers for easy discovery of new NPGs from organisms in the future. Using this method, we screened a total of 64 kinds of organisms (including plants, animals and fungi), and 6 extracts with a gelation ability were tracked and isolated to yield six new NPGs. These new NPGs include new types of NPGs such as tricyclic triterpenes (1) and tetracyclic triterpenes (2), and new classes of NPGs such as steroids (4 and 5) and glycosides (6), which greatly expand the class of NPGs in the LMWG field. PMID- 29423487 TI - The emergence of aqueous chemiluminescence: new promising class of phenoxy 1,2 dioxetane luminophores. AB - The majority of known chemiluminescent compounds produce light through oxidation dependent mechanisms. The unique notion of triggering chemiluminescence by a chemical reaction other than oxidation was first introduced by Schaap in 1987 with the development of chemically and enzymatically activated phenoxy dioxetanes. Such dioxetanes are distinctive among chemiluminescent molecules since the oxidized high-energy species, the dioxetane, is stable for years at room temperature. Light emission is selectively activated by deprotection of the phenol-protecting group. The chemiluminescence quantum yields of such dioxetanes are relatively high in organic solvents like DMSO. In aqueous solution, however, light emission efficiency drops by approximately 10 000-fold due to energy loss to water molecules. As we sought to understand the low light emission efficiency in water, we realized that the dioxetane chemiexcitation leads to the release of an excited state benzoate molecule, which is a very weak emitter under aqueous conditions. Thus, we reasoned that emission in aqueous solution could be enhanced, if the emissive nature of the excited benzoate formed in water is improved. Introduction of an electron-withdrawing acrylic group at the ortho position of the phenol donor resulted in an excited benzoate species that emits light with high efficiency in aqueous solutions. A striking 3000-fold increase in chemiluminescence emission was observed by simply using an acrylonitrile substituent on the dioxetane probe. For the first time, scientists now have an effective single-entity chemiluminescent probe that can be used to evaluate biological processes. This discovery promoted us to develop numerous highly efficient chemiluminescent probes for detection of different enzymes and analytes in aqueous solution. We anticipate that further studies in this direction will lead to even better chemiluminescence probes with quantum yield emissions that are even higher than that of the luciferin/luciferase system. In this Feature Article, we describe the insights that led us to develop these unprecedented luminophores and the historical perspective that led to the current generation of chemiluminescent phenoxy-dioxetane probes. PMID- 29423488 TI - How to distinguish between interacting and noninteracting molecules in tunnel junctions. AB - Recent experiments demonstrate a temperature control of the electric conduction through a ferrocene-based molecular junction. Here we examine the results in view of determining means to distinguish between transport through single-particle molecular levels or via transport channels split by Coulomb repulsion. Both transport mechanisms are similar in molecular junctions given the similarities between molecular intralevel energies and the charging energy. We propose an experimentally testable way to identify the main transport process. By applying a magnetic field to the molecule, we observe that an interacting theory predicts a shift of the conductance resonances of the molecule whereas in the noninteracting case each resonance is split into two peaks. The interaction model works well in explaining our experimental results obtained in a ferrocene-based single-molecule junction, where the charge degeneracy peaks shift (but do not split) under the action of an applied 7-Tesla magnetic field. This method is useful for a proper characterization of the transport properties of molecular tunnel junctions. PMID- 29423489 TI - A pH- and temperature-responsive bioresorbable injectable hydrogel based on polypeptide block copolymers for the sustained delivery of proteins in vivo. AB - Sustained delivery of protein therapeutics is limited owing to the fragile nature of proteins. Despite its great potential, delivery of proteins without any loss of bioactivity remains a challenge in the use of protein therapeutics in the clinic. To surmount this shortcoming, we report a pH- and temperature-responsive in situ-forming injectable hydrogel based on comb-type polypeptide block copolymers for the controlled delivery of proteins. Polypeptide block copolymers, composed of hydrophilic polyethylene glycol (PEG), temperature-responsive poly(gamma-benzyl-l-glutamate) (PBLG), and pH-responsive oligo(sulfamethazine) (OSM), exhibit pH- and temperature-induced sol-to-gel transition behavior in aqueous solutions. Polypeptide block copolymers were synthesized by combining N carboxyanhydride-based ring-opening polymerization and post-functionalization of the chain-end using N-hydroxy succinimide ester activated OSM. The physical properties of polypeptide-based hydrogels were tuned by varying the composition of temperature- and pH-responsive PBLG and OSM in block copolymers. Polypeptide block copolymers were non-toxic to human embryonic kidney cells at high concentrations (2000 MUg mL-1). Subcutaneous administration of polypeptide block copolymer sols formed viscoelastic gel instantly at the back of Sprague-Dawley (SD) rats. The in vivo gels exhibited sustained degradation and were found to be bioresorbable in 6 weeks without any noticeable inflammation at the injection site. Anionic characteristics of hydrogels allow efficient loading of a cationic model protein, lysozyme, through electrostatic interaction. Lysozyme-loaded polypeptide block copolymer sols readily formed a viscoelastic gel in vivo and sustained lysozyme release for at least a week. Overall, the results demonstrate an elegant approach to control the release of certain charged proteins and open a myriad of therapeutic possibilities in protein therapeutics. PMID- 29423490 TI - Stable coordination complexes of alpha-diimines with Nb(v) and Ta(v) halides. AB - Uncommon examples of coordination compounds of high valent transition metals with alpha-diimines were obtained and characterized by IR and NMR spectroscopy, X-ray diffraction and/or DFT analysis. The 1 : 1 molar reactions of NbF5 with a selection of alpha-diimines afforded the ionic compounds [NbF4(DADR)2][NbF6] (DADR = DADDip, 1a; DADXyl, 1b; DADMes, 1c) in 80-90% yields. The addition of DADDip to NbOCl3 gave NbOCl3(DADDip), 7 (62% yield). [MBr4(DADDip)][MBr6] (M = Nb, 7a; M = Ta, 7b) were afforded in moderate yields from MBr5 and DADDip. The reactions of NbCl5 with DADDip and DADXyl proceeded with non-selective activation of the organic substrate affording complex mixtures of products, including the quinoxalinium salt [{2,6-C6H3(CHMe2)2}N(CH)2NCC(CHMe2)(CH)3C][NbCl6], 2, the Nb(iv) coordination complex NbCl4(DADDip), 3, the N-(monoprotonated) alpha diimine salts [DADDip(H)][MCl6], 4a-b, and the iminomethyl-imidazolium [(2,6 C6H3Me2)NCHCHN(2,6-C6H3Me2)CCHN(2,6-C6H3Me2)][NbCl6], 5. PMID- 29423491 TI - Solvent-dependent dual fluorescence of the push-pull system 2-diethylamino-7 nitrofluorene. AB - The solvent-dependent excited state behavior of the molecular push-pull system 2 diethylamino-7-nitrofluorene has been explored using femtosecond transient absorption spectroscopy in combination with density functional theory calculations. Several excited state minima have been identified computationally, all possessing significant intramolecular charge transfer character. The experimentally observed dual fluorescence is suggested to arise from a planar excited state minimum and another minimum reached by twisting of the aryl nitrogen bond of the amino group. The majority of the excited state population, however, undergo non-radiative transitions and potential excited state deactivation pathways are assessed in the computational investigation. A third excited state conformer, characterized by twisting around the aryl-nitrogen bond of the nitro group, is reasoned to be responsible for the majority of the non radiative decays and a crossing between the excited state and ground state is localized. Additionally, ultrafast intersystem crossing is observed in the apolar solvent cyclohexane and rationalized to occur via an El-Sayed assisted transition from one of the identified excited state minima. The solvent thus determines more than just the fluorescence lifetime and shapes the potential energy landscape, thereby dictating the available excited state pathways. PMID- 29423492 TI - DFT methods applied to answer the question: how accurate is the ligand acidity constant method for estimating the pKa of transition metal hydride complexes MHXL4 when X is varied? AB - Density functional theory (DFT) is used to calculate the relative free energies of deprotonation of the isomers of iron-group hydride complexes MHXL4 where M = Fe, Ru, Os, L4 = (CO)4 or (PMe2CH2CH2PMe2)2 for a wide range of anionic ligands X. The free energies of the most stable isomers are used to calculate relative pKa values where Ka refers to the acid dissociation constant for the equilibrium MHXL4 -> [MXL4]- + H+. These are used to test the proposal that the pKa for a given metal complex in THF can be simply calculated by adding the contributions to the total pKa value from each ligand L; these are called ligand acidity constants (LAC) AL used in the LAC equation [R. H. Morris, J. Am. Chem. Soc., 2014, 136, 1948-1959]. The AL are calculated using AL = 0.2 as a reference for the hydride ligand. The AL of certain less polarizable X ligands are found to be fairly constant (+/-1 to +/-2 units) and consistent with the proposed LAC method for a range of the complexes considered: 2 for Me-, 1 for OH-, 1 for NH2-, 0 for B(OCH2CH2O-)-, -1 for OMe-, -2 for SH- and -2 for SMe-. Other ligands have more variable AL values (+/-3 to +/-5 units) because of high polarizability or other reasons: 1 for OtBu-, -1 for F-, -2 for BMe2-, -2 for NMe2-, -3 for Cl-, -3 for PMe2-, -3 for Br-, -5 for I-, -6 for CN- and -12 for SiCl3-. Iodide stabilizes the anion [MIL4]- more than does fluoride in [MFL4]- making iodide the more acidifying ligand despite its lower electronegativity. DFT is also used to validate the charge correction in the LAC equation. PMID- 29423493 TI - A 3D neutral chalcogenide framework built from a supertetrahedral T3 cluster and a metal complex for the electrocatalytic oxygen reduction reaction. AB - Herein we report a new 3D neutral chalcogenide framework constructed by using a supertetrahedral T3 cluster ([Mn2Ga4Sn4S20]) as the building unit and a metal complex ([Mn(dach)2], dach = 1,2-diaminocyclohexane) as the linker. Significantly, the obtained material exhibits high-efficiency electrocatalytic oxygen reduction activity with quasi-four-electron transfer and a small Tafel slope, much better than that of commercial Pt/C (10 wt%). PMID- 29423495 TI - Identification of a new substrate effect that enhances the electrocatalytic activity of dendritic tin in CO2 reduction. AB - In this study, a selective Sn based catalytic system that electrochemically reduces CO2 to formate has been developed based on a new substrate effect. Dendritic Sn catalysts were synthesised by hydrogen gas bubble assisted electrodeposition on Pt, Cu, Sn or In substrates and applied to electrocatalytic reduction of CO2. The four substrates exhibit a hydrogen evolution activity that follows the order Pt > Cu > Sn > In. However, the Cu supported dendritic Sn catalyst provides the best selectivity towards formate formation (67.3% at -0.95 V vs. RHE). A substrate induced local pH change is proposed as the origin of formate selectivity. This was confirmed by the bulk electrolysis results obtained from two electrolyte solutions with different buffer capacities. The high buffer capacity phosphate buffer electrolyte solution provides minimal local pH change while an electrolyte with a low buffer capacity such as NaHCO3 maximises this effect to enhance the selectivity towards formate. The strategy reported here does not only focus on the catalyst, but also takes into consideration the local chemical environment. Hence, this work provides an optimal approach to improving the catalytic performance of electrocatalysts for electrochemical CO2 reduction. PMID- 29423494 TI - EGCG evokes Nrf2 nuclear translocation and dampens PTP1B expression to ameliorate metabolic misalignment under insulin resistance condition. AB - As a major nutraceutical component of green tea (-)-epigallocatechin-3-gallate (EGCG) has attracted interest from scientists due to its well-documented antioxidant and antiobesity bioactivities. In the current study, we aimed to investigate the protective effect of EGCG on metabolic misalignment and in balancing the redox status in mice liver and HepG2 cells under insulin resistance condition. Our results indicated that EGCG accelerates the glucose uptake and evokes IRS-1/Akt/GLUT2 signaling pathway via dampening the expression of protein tyrosine phosphatase 1B (PTP1B). Consistently, ectopic expression of PTP1B by Ad PTP1B substantially impaired EGCG-elicited IRS-1/Akt/GLUT2 signaling pathway. Moreover, EGCG co-treatment stimulated nuclear translocation of Nrf2 by provoking P13K/AKT signaling pathway and thus modulated the downstream expressions of antioxidant enzymes such as HO-1 and NQO-1 in HepG2 cells. Furthermore, knockdown Nrf2 by small interfering RNA (siRNA) notably enhanced the expression of PTP1B and blunt EGCG-stimulated glucose uptake. Consistent with these results, in vivo study revealed that EGCG supplement significantly ameliorated high-fat and high fructose diet (HFFD)-triggered insulin resistance and oxidative stress by up regulating the IRS-1/AKT and Keap1/Nrf2 transcriptional pathways. Administration of an appropriate chemopreventive agent, such as EGCG, could potentially serve as an additional therapeutic intervention in the arsenal against obesity. PMID- 29423496 TI - Real time monitoring of the minute dynamic variation at the crude oil-water interface. AB - Quantitative recording of the minute dynamic variation at an oil-water interface is always a great challenge. Dual polarization interferometry (DPI) presents an approach in monitoring the variations of mass, thickness, and density at the interface with high resolution. In this study, a planar crude oil-water interface was established by spin-coating on a DPI chip surface. Different concentrations of sodium dodecyl sulphate (SDS) and polyacrylamide (PAM) were injected into the interface. The absorption of free SDS molecules, in low concentrations, can be interpreted as a two-step absorption. With the existence of micelles in higher concentrations, the crude oil molecules tend to be taken away by the micelles. The absorptions of the polymers at the interface are different from SDS. The crude oil can hardly be taken away by the polymers. Instead, the hydrophobic segments of polymers insert into the oil film and hydrophilic groups stretch into the solution. PMID- 29423497 TI - Mixed-metal clusters with a {Re3Mo3Se8} core: from a polymeric solid to soluble species with multiple redox transitions. AB - Cluster compounds based on a new {Re3Mo3Se8}n core were obtained and studied. The polymeric solid K6[Re3Mo3Se8(CN)4(CN)2/2] (1) containing 24 cluster valence electrons (CVE) was isolated as a result of high-temperature reaction. Water soluble salts K5[Re3Mo3Se8(CN)6].11H2O (2) and Cs5[Re3Mo3Se8(CN)6].H2O (3) were prepared from compound 1. Crystal structures of the diamagnetic compounds 2 and 3 contain a cluster anion [Re3Mo3Se8(CN)6]5- with a 22-electronic core {Re3Mo3Se8}+. Metathesis reaction followed by recrystallization from CH3CN yielded paramagnetic salt (Ph4P)4[Re3Mo3Se8(CN)6].2CH3CN (4) containing the {Re3Mo3Se8}2+ core with 21 CVE. Cyclic voltammetry of the solution of 4 displayed three quasi-reversible waves with E1/2 = -0.325, -0.818 and -1.410 V vs. Ag/AgCl electrode indicating the presence of [Re3Mo3Se8(CN)6]4-/5-/6-/7- transitions. Electronic structure calculations showed that both mer- and fac-isomers of [Re3Mo3Se8(CN)6]n- clusters undergo great distortion when the number of CVE decreases. PMID- 29423498 TI - A route to diastereomerically pure phenylglycine thioester peptides: crucial intermediates for investigating glycopeptide antibiotic biosynthesis. AB - Non-ribosomal peptides contain an array of amino acid building blocks that can present challenges for the synthesis of important intermediates. Here, we report the synthesis of glycopeptide antibiotic (GPA) thioester peptides that retains the crucial stereochemical purity of the terminal phenylglycine residue, which we show is essential for the enzymatic GPA cyclisation cascade. PMID- 29423499 TI - Design and synthesis of metal hydroxide three-dimensional inorganic cationic frameworks. AB - Three-dimensional (3D) cationic frameworks are rare but crucial host materials with vast industrial applications. However, the controlled synthesis of 3D inorganic cationic framework (ICF) materials still remains a challenge. Here, we develop a new strategy to construct 3D inorganic cationic frameworks by octahedral metal-hydroxide (M(OH)6) unit induced reconstruction of layered rare earth hydroxides. Based on this strategy, a large family (>187 members) of 3D-ICF with a general formula: RE12(OH)18((RE1-x-y,MxM'y)(OH)6)4.ACl6 (RE = Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y; M = Al, Cr; M' = Mg, Al, Cr, Mn, Fe, Co, Ni, Cu, Zn; A = Na, K) were achieved. This newly constructed strategy would greatly promote the development of 3D inorganic cationic materials. Furthermore, the discovery of this new family of cationic frameworks would pave the way for the potential application of cationic materials in different sorts of fields. PMID- 29423500 TI - Low-Dose Atropine for Myopia Control: Considering All the Data. PMID- 29423502 TI - Medical Student Knowledge of Human Papillomavirus-Positive Head and Neck Cancer. PMID- 29423501 TI - Association of Sulindac and Erlotinib vs Placebo With Colorectal Neoplasia in Familial Adenomatous Polyposis: Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for colorectal polyps and cancer. A combination of sulindac and erlotinib led to a 71% reduction in duodenal polyp burden in a phase 2 trial. Objective: To evaluate effect of sulindac and erlotinib on colorectal adenoma regression in patients with FAP. Design, Setting, and Participants: Prespecified secondary analysis for colorectal adenoma regression was carried out using data from a double-blind, randomized, placebo-controlled trial, enrolling 92 patients with FAP, conducted from July 2010 to June 2014 in Salt Lake City, Utah. Interventions: Patients were randomized to sulindac, 150 mg twice daily, and erlotinib, 75 mg daily (n = 46), vs placebo (n = 46) for 6 months. Main Outcomes and Measurements: The total number of polyps in the intact colorectum, ileal pouch anal anastomosis, or ileo-rectum were recorded at baseline and 6 months. The primary outcomes were change in total colorectal polyp count and percentage change in colorectal polyps, following 6 months of treatment. Results: Eighty-two randomized patients (mean [SD] age, 40 [13] years; 49 [60%] women) had colorectal polyp count data available for this secondary analysis: 22 with intact colon, 44 with ileal pouch anal anastomosis and 16 with ileo-rectal anastomosis; 41 patients received sulindac/erlotinib and 41 placebo. The total colorectal polyp count was significantly different between the placebo and sulindac-erlotinib group at 6 months in patients with net percentage change of 69.4% in those with an intact colorectum compared with placebo (95% CI, 28.8%-109.2%; P = .009). Conclusion and Relevance: In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum. Trial Registration: clinicaltrials.gov Identifier: NCT01187901. PMID- 29423503 TI - Association Between Circulating Tumor DNA and Pseudoprogression in Patients With Metastatic Melanoma Treated With Anti-Programmed Cell Death 1 Antibodies. AB - Importance: Longitudinal circulating tumor DNA (ctDNA) has been shown to predict response and survival in patients with metastatic melanoma treated with anti programmed cell death 1 (PD-1) antibodies. Pseudoprogression, defined as radiologic finding of disease progression prior to response, has been a challenge to clinicians. Objective: To establish whether ctDNA at baseline and up to week 12 of treatment can differentiate between the radiologic findings of pseudoprogression and true progression in patients with metastatic melanoma. Design, Setting, and Participants: This explorative biomarker study examined circulating BRAF and NRAS mutations in a cohort of 125 patients with melanoma receiving PD-1 antibodies alone or in combination with ipilimumab between July 3, 2014, and May 24, 2016. Pseudoprogression was defined retrospectively as radiologic progression not confirmed as progressive disease at the next radiologic assessment. Plasma samples of ctDNA at baseline and while receiving treatment were taken for analysis prospectively over the first 12 weeks of treatment. Favorable ctDNA profile (undetectable ctDNA at baseline or detectable ctDNA at baseline followed by >10-fold decrease) and unfavorable ctDNA profile (detectable ctDNA at baseline that remained stable or increased) were correlated with response and prognosis. Main Outcomes and Measures: Early differentiation of pseudoprogression from true progression using longitudinal ctDNA profile. Results: According to guidelines by Response Evaluation Criteria in Solid Tumors (RECIST), progressive disease occurred in 29 of the 125 patients (23.2%). Of the 29 patients, 17 (59%) were 65 years or younger, 18 (62%) were men, 9 (31%) had pseudoprogression, and 20 (69%) had true progression. Of the 9 patients (7%) with confirmed pseudoprogression, all patients had a favorable ctDNA profile. At a median follow-up of 110 weeks, 7 of 9 patients (78%) were alive. All but 2 patients with true progression had an unfavorable ctDNA profile. Sensitivity of ctDNA for predicting pseudoprogression was 90% (95% CI, 68%-99%) and specificity was 100% (95% CI, 60%-100%). The 1-year survival for patients with RECIST-defined progressive disease and favorable ctDNA was 82% vs 39% for unfavorable ctDNA (hazard ratio [HR], 4.8; 95% CI, 1.6-14.3; P = .02). Overall survival was longer in patients with a partial response (54 of 125 patients [43%]) compared with patients with progressive disease and a favorable ctDNA profile (11 of 125 patients [9%]; HR, 0.09; 95% CI, 0.01-0.80; P < .01). Conclusions and Relevance: The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies. Results of this blood test performed at regular intervals during systemic treatment reflect tumor biology and have potential as a powerful biomarker to predict long-term response and survival. PMID- 29423504 TI - Nonlinear Dynamics of Dacron Aortic Prostheses Conveying Pulsatile Flow. AB - This study addresses the dynamic response to pulsatile physiological blood flow and pressure of a woven Dacron graft currently used in thoracic aortic surgery. The model of the prosthesis assumes a cylindrical orthotropic shell described by means of nonlinear Novozhilov shell theory. The blood flow is modeled as Newtonian pulsatile flow, and unsteady viscous effects are included. Coupled fluid-structure Lagrange equations for open systems with wave propagation subject to pulsatile flow are applied. Physiological waveforms of blood pressure and velocity are approximated with the first eight harmonics of the corresponding Fourier series. Time responses of the prosthetic wall radial displacement are considered for two physiological conditions: at rest (60 bpm) and at high heart rate (180 bpm). While the response at 60 bpm reproduces the behavior of the pulsatile pressure, higher harmonics frequency contributions are observed at 180 bpm altering the shape of the time response. Frequency-responses show resonance peaks for heart rates between 130 bpm and 200 bpm due to higher harmonics of the pulsatile flow excitation. These resonant peaks correspond to unwanted high frequency radial oscillations of the vessel wall that can compromise the long term functioning of the prosthesis in case of significant physical activity. Thanks to this study, the dynamic response of Dacron prostheses to pulsatile flow can be understood as well as some possible complications in case of significant physical activity. PMID- 29423505 TI - Laboratory Eligibility Criteria as Potential Barriers to Participation by Black Men in Prostate Cancer Clinical Trials. PMID- 29423506 TI - Trend Analysis on Reoperation After Lumpectomy for Breast Cancer-Reply. PMID- 29423507 TI - Retinal Pigment Epithelium Tears in a 67-Year-Old Man. PMID- 29423510 TI - Low-Dose Atropine for Myopia Control-Reply. PMID- 29423509 TI - Outcomes of Onabotulinum Toxin A Treatment for Adductor Spasmodic Dysphonia and Laryngeal Tremor. AB - Importance: The relative outcomes of onabotulinum toxin A injections for treatment of adductor spasmodic dysphonia (ADSD), ADSD with lateral laryngeal tremor (ADSD+LT), and lateral LT without ADSD are unclear. Objective: To compare the outcomes of onabotulinum toxin A treatment on ADSD, ADSD+LT, and lateral LT without ADSD. Design, Setting, and Participants: A retrospective cohort study was conducted from January 1, 1990, to September 30, 2016, at a tertiary referral voice center. Participants included 817 patients treated with onabotulinum toxin A injections for diagnosis of ADSD, ADSD+LT, and lateral LT without ADSD. Exposure: Injection of onabotulinum toxin A into the thyroarytenoid/lateral cricoarytenoid muscle complex. Main Outcomes and Measures: Data from patient diaries were used to evaluate patient-perceived effectiveness of onabotulinum toxin A injection. Primary outcomes were (1) patient-reported good voice days (voice breaks or tremor minimized to patient satisfaction) and (2) percentage of injections in which maximal voice quality was reached (significant or complete reduction in vocal tremor or spasms during a treatment cycle). Multivariate analysis of variance tests compared differences in outcomes between groups. Subanalysis was performed to compare outcomes in patients with isolated LT with those who had mixed tremor (lateral with concomitant anterior-posterior and/or vertical components). Results: Of 817 patients treated with onabotulinum toxin A injections for laryngeal movement disorders, 548 patients (12 771 injection sessions) met inclusion criteria (ADSD: n = 328, ADSD+LT: n = 77, lateral LT without ADSD: n = 143). Of these, 408 (80.8%) were women; mean (SD) age was 57.2 (13.7) years. Among patients with tremor, those with isolated LT had better outcomes than those with mixed tremor. In adjusted analysis, good voice days in patients with ADSD, ADSD+LT, and lateral LT without ADSD were 81.1, 75.4, and 71.3 days, respectively (partial eta2, 0.05; 95% CI, 0.01-0.09). The percentage of maximally beneficial injections was 88.1% for ADSD, 83.4% for ADSD+LT, and 70.4% for LT without ADSD (partial eta2, 0.12; 95% CI, 0.06-0.17). Conclusions and Relevance: Onabotulinum toxin A injections into the thyroarytenoid/lateral cricoarytenoid muscle complex are an effective treatment for ADSD, ADSD+LT, and LT without ADSD; however, the greatest effectiveness was observed among patients with ADSD. Defining tremor directionality may help to prognosticate the effectiveness of onabotulinum toxin A injection among patients presenting with tremor components. PMID- 29423508 TI - Association of Retinopathy of Prematurity With Low Levels of Arachidonic Acid: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Mice with oxygen-induced retinopathy fed matched diets except for omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) vs omega-6 LC-PUFAs demonstrate relative antiangiogenic and neuroprotective associations of omega-3 LC-PUFAs. However, supplementing preterm infants with LC-PUFAs has been inconsistent in reducing major preterm morbidities. However, few studies measured serum lipid levels after supplementation. Objective: To examine the associated risk of retinopathy of prematurity (ROP) from the levels of circulating omega-3 and omega-6 LC-PUFAs. Design, Setting, and Participants: This longitudinal clinical study was a further analysis of serum lipid levels from a randomized controlled trial cohort of 90 infants born at gestational age (GA) less than 28 weeks. From April 4, 2013, to September 22, 2015, cord blood samples, followed by venous blood samples, were obtained at birth and at 1, 7, 14, and 28 days after birth and then at postmenstrual age (PMA) 32, 36, and 40 weeks at the neonatal intensive care unit at Sahlgrenska University Hospital in Goteborg, Sweden. Main Outcomes and Measures: Serum phospholipid fatty acids were transmethylated and measured by gas chromatography-mass spectrometry. Mann-Whitney test, logistic regression Spearman rank correlation, and receiver operating characteristic curve analysis were used to compare differences between infants with no ROP and infants who developed ROP. Results: Serum levels from 78 infants (43 male [55%]; mean [SD] GA, 25.5 [1.4] weeks) with a known ROP outcome were evaluated. Lower area under the curve (AUC) of arachidonic acid (AA) (20:4 omega-6) was seen in infants with a later diagnosis of ROP compared with infants with no ROP in the first month of life (mean, 34.05 [95% CI, 32.10-36.00] vs 37.15 [95% CI, 34.85-39.46]; P < .05). In addition, lower levels of AA at 32 weeks' PMA were seen in infants with later severe ROP compared with in those without ROP (mean, 7.06 [95% CI, 6.60-7.52] vs 8.74 [95% CI, 7.80-9.67]; P < .001). In logistic modeling, low postnatal serum levels of AA and GA at birth identified with a sensitivity greater than 90% of infants who developed ROP. Conclusions and Relevance: Low postnatal levels of the omega-6 LC-PUFAs (AA) are strongly associated with ROP development. Evaluating postnatal AA fraction after birth in addition to GA may be useful for ROP prediction. Trial Registration: clinicaltrials.gov Identifier: NCT02760472. PMID- 29423511 TI - Corrections. PMID- 29423512 TI - Trend Analysis on Reoperation After Lumpectomy for Breast Cancer. PMID- 29423513 TI - Association of Contact Lens Adherence With Visual Outcome in the Infant Aphakia Treatment Study: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Although contact lenses have been used for decades to optically correct eyes in children after cataract surgery, there has never been a prospective study looking at contact lens adherence in children with aphakia, to our knowledge. Objective: To evaluate contact lens adherence and its association with visual outcome in a cohort of children treated for unilateral cataract surgery. Design, Setting, and Participants: Secondary analysis of a multicenter randomized clinical trial of 57 infants born from August 22, 2004, to April 25, 2008, who were randomized to 1 of 2 treatments and followed up to age 5 years. Data analysis was performed from August 9, 2016, to December 7, 2017. Interventions: Unilateral cataract extraction and randomization to implantation of an intraocular lens vs contact lens to correct aphakia. Main Outcomes and Measures: Contact lens adherence was assessed by a 48-hour recall telephone interview that was administered every 3 months starting 3 months after surgery to age 5 years. A traveling examiner assessed visual acuity in patients at aged 4.5 years. Adherence to prescribed contact lens use was estimated as the mean percentage of waking hours as reported in 2 or more interviews for each year of life. Results: Of 57 infants who were randomized to contact lens treatment, 32 (56%) were girls, and 49 (86%) were white. A total of 872 telephone interviews were completed. In year 1, a median of 95% participants wore their contacts lenses nearly all waking hours (interquartile range [IQR], 84%-100%); year 2, 93% (IQR, 85%-99%); year 3, 93% (IQR, 85%-99%); year 4, 93% (IQR, 75%-99%); and year 5, 89% (IQR, 71%-97%). There was a tendency for poorer reported adherence at older ages (F = 3.86, P < .001). No differences were identified when the results were analyzed by sex, insurance coverage, or age at cataract surgery. Using linear regression, children who wore the contact lens for a greater proportion of waking hours during the entire study period tended to have better visual acuity at age 4.5 years, even after accounting for adherence to patching (partial correlation = -0.026; P = .08). Conclusions and Relevance: These results confirm that it is possible to achieve a high level of aphakic contact lens adherence over a 5-year period in children. Trial Registration: clinicaltrials.gov Identifier: NCT00212134. PMID- 29423514 TI - Concurrent Chemoradiotherapy for Stage IIIB Cervical Cancer-Global Impact Through Power. PMID- 29423515 TI - Atezolizumab (MPDL3280A) Monotherapy for Patients With Metastatic Urothelial Cancer: Long-term Outcomes From a Phase 1 Study. AB - Importance: Atezolizumab (anti-programmed death ligand 1) has demonstrated safety and activity in advanced and metastatic urothelial carcinoma, but its long-term clinical profile remains unknown. Objective: To report long-term clinical outcomes with atezolizumab therapy for patients with metastatic urothelial carcinoma. Design, Setting, and Participants: Patients were enrolled in an expansion cohort of an ongoing, open-label, phase 1 study. Median follow-up was 37.8 months (range, >0.7 to 44.4 months). Enrollment occurred between March 2013 and August 2015 at US and European academic medical centers. Eligible patients had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status 0 to 1, and a representative tumor sample. Programmed death ligand 1 expression on immune cells was assessed (VENTANA SP142 assay). Interventions: Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence, or loss of clinical benefit. Main Outcomes and Measures: Primary outcome was safety. Secondary outcomes included objective response rate, duration of response, and progression-free survival. Response and overall survival were assessed in key baseline subgroups. Results: Ninety-five patients were evaluable (72 [76%] male; median age, 66 years [range, 36-89 years]). Forty-five (47%) received atezolizumab as third-line therapy or greater. Nine patients (9%) had a grade 3 to 4 treatment-related adverse event, mostly within the first treatment year; no serious related adverse events were observed thereafter. One patient (1%) discontinued treatment due to a related event. No treatment-related deaths occurred. Responses occurred in 26% (95% CI, 18%-36%) of patients. Median duration of response was 22.1 months (range, 2.8 to >41.0 months), and median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months). Median overall survival was 10.1 months (95% CI, 7.3-17.0 months); 3-year OS rate was 27% (95% CI, 17%-36%). Response occurred in 40% (95% CI, 26%-55%; n = 40) and 11% (95% CI, 4%-25%; n = 44) of patients with programmed death ligand 1 expression of at least 5% tumor-infiltrating immune cells (IC2/3) or less than 5% (IC0/1), respectively. Median overall survival in patients with IC2/3 and IC0/1 was 14.6 months (95% CI, 9.0 months to not estimable) and 7.6 months (95% CI, 4.7 to 13.9 months), respectively. Conclusions and Relevance: Atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma population in this long-term study. Trial Registration: clinicaltrials.gov Identifier: NCT01375842. PMID- 29423516 TI - International Medical Graduates-A Critical Component of the Global Health Workforce. PMID- 29423517 TI - The Prematurity of Recommending Particular Polyunsaturated Fatty Acid Supplements for Retinopathy of Prematurity. PMID- 29423520 TI - Cisplatin Chemoradiotherapy vs Radiotherapy in FIGO Stage IIIB Squamous Cell Carcinoma of the Uterine Cervix: A Randomized Clinical Trial. AB - Importance: The evidence for concurrent chemoradiotherapy (CT-RT) in International Federation of Gynecology and Obstetrics (FIGO) stage IIIB squamous cell carcinoma of the uterine cervix is not robust. This study reports the final results of a randomized clinical trial of concurrent cisplatin-based CT-RT and radiotherapy alone (RT) in women with FIGO stage IIIB squamous cell carcinoma of the uterine cervix. Objective: To investigate the benefit of concurrent CT-RT in FIGO stage IIIB squamous cell carcinoma of the uterine cervix. Design, Setting, and Participants: This phase 3 open-label randomized clinical trial accrued 850 women in Mumbai, India, between July 7, 2003, and September 22, 2011. Of 2121 screened, 850 women with FIGO stage IIIB squamous cell carcinoma of the uterine cervix suitable for concurrent cisplatin chemotherapy were randomly assigned to CT-RT and RT using block randomization (1:1). The data were updated for a minimum follow-up period of 5 years until December 2016. The final analyses were performed in February and March 2017. This single-institution study was conducted at a tertiary cancer center setting. Interventions: Randomization to receive RT (RT arm), comprising a combination of external beam RT (50 Gy in 25 fractions over 5 weeks) and brachytherapy, or to receive in addition to the same RT concurrent weekly cisplatin chemotherapy (40 mg/m2 per week) (CT-RT arm). Main Outcomes and Measures: The primary end point was 5-year disease-free survival (DFS), defined as the time between the date of randomization and the date of any recurrence or death (whichever occurred first) in the intent-to-treat population. Results: This trial included 424 women assigned to CT-RT (mean [SD] age, 49.4 [7.9] years) and 426 women assigned to RT (mean [SD] age, 49.3 [7.9] years). At a median follow-up of 88 months (interquartile range, 61.3-113.1 months), there were 222 recurrences and 213 deaths in the CT-RT arm and 252 recurrences and 243 deaths in the RT arm. The 5-year DFS was significantly higher in the CT-RT arm (52.3%; 95% CI, 52.2%-52.4%) compared with the RT arm (43.8%; 95% CI, 43.7% 43.9%), with a hazard ratio for relapse or death of 0.81 (95% CI, 0.68-0.98) (P = .03). Similarly, the 5-year overall survival (OS) was significantly higher in the CT-RT arm (54.0%; 95% CI, 53.9%-54.1%) compared with the RT arm (46.0%; 95% CI, 45.9%-46.1%), with a hazard ratio for death of 0.82 (95% CI, 0.68-0.98; P = .04). After adjusting for prognostic factors, CT-RT continued to be significantly superior to RT for DFS and OS. There was a higher incidence of acute hematological adverse effects in the CT-RT arm. Conclusions and Relevance: Chemoradiotherapy using weekly cisplatin results in significantly better DFS and OS compared with RT in women with stage IIIB squamous cell carcinoma of the uterine cervix. This study provides level 1 evidence in the largest clinical trial reported so far in favor of concurrent weekly cisplatin chemotherapy in this setting. Trial Registration: clinicaltrials.gov Identifier: NCT00193791. PMID- 29423522 TI - Societal Identification of Facial Paralysis and Paralysis Location. AB - Importance: When able to identify facial paralysis, members of society regard individuals with facial paralysis differently. They perceive a decrease in attractiveness, more negative affect, and lower quality of life. However, the ability of lay people in society to accurately identify the presence of facial paralysis has not yet been defined. Objective: To determine societal members' ability to (1) identify paralysis in varying degrees of paralysis severity and (2) localize the defect on the face. Design, Setting, and Participants: A prospective observational study conducted in an academic tertiary referral center using a group of 380 casual observers was carried out. Main Outcomes and Measures: Surveys were designed containing smiling and repose images of normal faces and faces with unilateral facial paralysis of 3 severity levels (low, medium, and high) as categorized by House-Brackmann (HB) grade. The photographs were then shown to casual observers in a web-based survey. After reviewing both normal faces and faces with varying degrees of paralysis, they then indicated (1) whether paralysis was present and (2) if so, where the paralysis was on the face. Results: A total of 380 participants (267 [70.3%] women and 113 [29.7%] men with a mean [SD] age of 29 [12] years) successfully completed the survey, viewing 2860 facial photographs in aggregate. The accuracy rate of identifying paralysis increased from low-grade through high-grade paralysis. Facial paralysis was identified in 249 (34.6%) of 719 facial photographs with low-grade paralysis, 448 (63.2%) of 709 with medium-grade paralysis, and 696 (96.7%) of 720 with high grade paralysis (chi2 = 912.6, P < .001); 6.2% (44/731) of normal faces were incorrectly identified as having paralysis (chi2 = 912.6, P < .001). Participants correctly localized paralysis in 157 (63.0%) of 249 low-grade photographs, 307 (68.5%) of 448 medium-grade photographs, and 554 (79.6%) of 696 high-grade photographs (chi2 = 32.5, P < .001). In general, participants tended to identify facial paralysis more accurately in smiling vs repose faces (48.6% vs 20.6%, 92.4% vs 33.7%, and 96.7% vs 96.6% in low-, medium-, and high-grade paralysis, respectively) (chi2 = 62.2, P < .001; chi2 = 262.6, P < .001; chi2 = 0.0, P = .96, respectively). Conclusions and Relevance: The ability of individuals to identify the presence of facial paralysis increased as paralysis severity increased. Further, smiling increased accurate identification. However, even when individuals can identify paralysis, they are not necessarily able to accurately localize the paralysis on a face. This may speak to a phenomenon in which perception of a facial defect comes from a holistic interpretation of a face, rather than a clinically accurate specification of the defect location. These findings are important in the future counseling of patients. Level of Evidence: NA. PMID- 29423523 TI - Filarialike Parasite Under the Internal Limiting Membrane. PMID- 29423521 TI - Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial. AB - Importance: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. Objective: To determine if continuous blockade of EGFR by Sym004 has survival benefit. Design, Setting, and Participants: Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator's choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. Interventions: Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator's choice of treatment (arm C). Main Outcomes and Measures: Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. Results: A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n = 160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). Conclusions and Relevance: Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. Trial Registration: clinicaltrialsregister.eu Identifier: 2013-003829-29. PMID- 29423526 TI - Long working hours and depressive symptoms: systematic review and meta-analysis of published studies and unpublished individual participant data. AB - Objectives This systematic review and meta-analysis combined published study level data and unpublished individual-participant data with the aim of quantifying the relation between long working hours and the onset of depressive symptoms. Methods We searched PubMed and Embase for published prospective cohort studies and included available cohorts with unpublished individual-participant data. We used a random-effects meta-analysis to calculate summary estimates across studies. Results We identified ten published cohort studies and included unpublished individual-participant data from 18 studies. In the majority of cohorts, long working hours was defined as working >=55 hours per week. In multivariable-adjusted meta-analyses of 189 729 participants from 35 countries [96 275 men, 93 454 women, follow-up ranging from 1-5 years, 21 747 new-onset cases), there was an overall association of 1.14 (95% confidence interval (CI) 1.03-1.25] between long working hours and the onset of depressive symptoms, with significant evidence of heterogeneity (I 2=45.1%, P=0.004). A moderate association between working hours and depressive symptoms was found in Asian countries (1.50, 95% CI 1.13-2.01), a weaker association in Europe (1.11, 95% CI 1.00-1.22), and no association in North America (0.97, 95% CI 0.70-1.34) or Australia (0.95, 95% CI 0.70-1.29). Differences by other characteristics were small. Conclusions This observational evidence suggests a moderate association between long working hours and onset of depressive symptoms in Asia and a small association in Europe. PMID- 29423527 TI - A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays. AB - The (developmental) neurotoxicity hazard is still unknown for most chemicals. Establishing a test battery covering most of the relevant adverse outcome pathways may close this gap, without requiring a huge animal experimentation program. Ideally, each of the assays would cover multiple mechanisms of toxicity. One candidate test is the human LUHMES cell-based NeuriTox test. To evaluate its readiness for larger-scale testing, a proof of concept library assembled by the U.S. National Toxicology Program (NTP) was screened. Of the 75 unique compounds, seven were defined as specifically neurotoxic after the hit-confirmation phase and additional ten compounds were generally cytotoxic within the concentration range of up to 20 micromolar. As complementary approach, the library was screened in the PeriTox test, which identifies toxicants affecting the human peripheral nervous system. Of the eight PeriTox hits, five were similar to the NeuriTox hits: rotenone, colchicine, diethylstilbestrol, berberine chloride, and valinomycin. The unique NeuriTox hit, methyl-phenylpyridinium (MPP+) is known from in vivo studies to affect only dopaminergic neurons (which LUHMES cells are). Conversely, the known peripheral neurotoxicant acrylamide was picked up in the PeriTox, but not in the NeuriTox assay. All of the five common hits had also been identified in the published neural crest migration (cMINC) assay, while none of them emerged as cardiotoxicant in a previous screen using the same library. These comparative data suggest that complementary in vitro tests can pick up a broad range of toxicants, and that multiple test results might help to predict organ specificity patterns. PMID- 29423528 TI - Cellular functions of stem cell factors mediated by the ubiquitin-proteasome system. AB - Stem cells undergo partitioning through mitosis and separate into specific cells of each of the three embryonic germ layers: endoderm, mesoderm, and ectoderm. Pluripotency, reprogramming, and self-renewal are essential elements of embryonic stem cells (ESCs), and it is becoming evident that regulation of protein degradation mediated by the ubiquitin-proteasome system (UPS) is one of the key cellular mechanisms in ESCs. Although the framework of that mechanism may seem simple, it involves complicated proteolytic machinery. The UPS controls cell development, survival, differentiation, lineage commitment, migration, and homing processes. This review is centered on the connection between stem cell factors NANOG, OCT-3/4, SOX2, KLF4, C-MYC, LIN28, FAK, and telomerase and the UPS. Herein, we summarize recent findings and discuss potential UPS mechanisms involved in pluripotency, reprogramming, differentiation, and self-renewal. Interactions between the UPS and stem cell transcription factors can apply to various human diseases which can be treated by generating more efficient iPSCs. Such complexes may permit the design of novel therapeutics and the establishment of biomarkers that may be used in diagnosis and prognosis development. Therefore, the UPS is an important target for stem cell therapeutic product research. PMID- 29423530 TI - Life is not black and white, nor just Shades of Gray. PMID- 29423529 TI - Structure and function of Zika virus NS5 protein: perspectives for drug design. AB - Zika virus (ZIKV) belongs to the positive-sense single-stranded RNA-containing Flaviviridae family. Its recent outbreak and association with human diseases (e.g. neurological disorders) have raised global health concerns, and an urgency to develop a therapeutic strategy against ZIKV infection. However, there is no currently approved antiviral against ZIKV. Here we present a comprehensive overview on recent progress in structure-function investigation of ZIKV NS5 protein, the largest non-structural protein of ZIKV, which is responsible for replication of the viral genome, RNA capping and suppression of host interferon responses. Structural comparison of the N-terminal methyltransferase domain and C terminal RNA-dependent RNA polymerase domain of ZIKV NS5 with their counterparts from related viruses provides mechanistic insights into ZIKV NS5-mediated RNA replication, and identifies residues critical for its enzymatic activities. Finally, a collection of recently identified small molecule inhibitors against ZIKV NS5 or its closely related flavivirus homologues are also discussed. PMID- 29423533 TI - RETRACTED ARTICLE: Biologically validating the measurement of oxytocin in western lowland gorilla (Gorilla gorilla gorilla) urine and saliva using a commercial enzyme immunoassay. PMID- 29423531 TI - Tissue expression pattern of ABCG transporter indicates functional roles in reproduction of Toxocara canis. AB - Toxocara canis is a zoonotic parasite with worldwide distribution. ATP-binding cassette (ABC) transporters are integral membrane proteins which involve in a range of biological processes in various organisms. In present study, the full length coding sequence of abcg-5 gene of T. canis (Tc-abcg-5) was cloned and characterized. A 633 aa polypeptide containing two conserved Walker A and Walker B motifs was predicted from a continuous 1902 nt open reading frame. Quantitative real-time PCR was employed to determine the transcriptional levels of Tc-abcg-5 gene in adult male and female worms, which indicated high mRNA level of Tc-abcg-5 in the reproductive tract of adult female T. canis. Tc-abcg-5 was expressed to produce rabbit polyclonal antiserum against recombinant TcABCG5. Indirect fluorescence immunohistochemical assays were carried out to detect the tissue distribution of TcABCG5, which showed predominant distribution of TcABCG5 in the uterus (especially in the germ cells) of adult female T. canis. Tissue transcription and expression pattern of Tc-abcg-5 indicated that Tc-abcg-5 might play essential roles in the reproduction of this parasitic nematode. PMID- 29423532 TI - Novel Core-Interlayer-Shell DOX/ZnPc Co-loaded MSNs@ pH-Sensitive CaP@PEGylated Liposome for Enhanced Synergetic Chemo-Photodynamic Therapy. AB - PURPOSE: This work was intended to develop novel doxorubicin (DOX)/zinc (II) phthalocyanine (ZnPc) co-loaded mesoporous silica (MSNs)@ calcium phosphate (CaP)@PEGylated liposome nanoparticles (NPs) that could efficiently achieve collaborative anticancer therapy by the combination of photodynamic therapy (PDT) and chemotherapy. The interlayer of CaP could be utilized to achieve pH-triggered controllable drug release, promote the cellular uptake, and induce cell apoptosis to further enhance the anticancer effects. METHODS: MSNs were first synthesized as core particles in which the pores were diffusion-filled with DOX, then the cores were coated by CaP followed by the liposome encapsulation with ZnPc to form the final DOX/ZnPc co-loaded MSNs@CaP@PEGylated liposome. RESULTS: A core interlayer-shell MSNs@CaP@PEGylated liposomes was developed as a multifunctional theranostic nanoplatform. In vitro experiment indicated that CaP could not only achieve pH-triggered controllable drug release, promote the cellular uptake of the NPs, but also generate high osmotic pressure in the endo/lysosomes to induce cell apoptosis. Besides, the chemotherapy using DOX and PDT effect was achieved by the photosensitizer ZnPc. Furthermore, the MSNs@CaP@PEGylated liposomes showed outstanding tumor-targeting ability by enhanced permeability and retention (EPR) effect. CONCLUSIONS: The novel prepared MSNs@CaP@PEGylated liposomes could serve as a promising multifunctional theranostic nanoplatform in anticancer treatment by synergic chemo-PDT and superior tumor-targeting ability. PMID- 29423534 TI - Glenohumeral osteoarthritis: frequency of underlying diagnoses and the role of arm dominance-a retrospective analysis in a community-based musculoskeletal practice. AB - Patients with shoulder pain are commonly seen in adult primary care, and are typically referred to musculoskeletal specialists when their symptoms are persistent. Rotator cuff disorders (RCD) most commonly underlie non-traumatic shoulder pain in adults, and glenohumeral osteoarthritis (GHOA) has been considered to be relatively uncommon (Nakagawa et al., J Shoulder Elb Surg 8:580 584, 1999). Our impression has been that GHOA affects significant numbers of patients, is less well studied, and may be under recognized. Among adults referred to a musculoskeletal practice for shoulder pain evaluation, we determined the relative numbers of patients with a clinical diagnosis of RCD and GHOA by age and by gender, assessed the role of handedness in GHOA, and the proportion of patients with underlying conditions (versus primary or idiopathic GHOA). We also assessed the frequency of progression to operative management over a defined time interval. This is a retrospective case series of patients presenting to a musculoskeletal referral practice for shoulder pain. Patients with a clinical diagnosis of GHOA were identified with electronic medical records, and then assessed for demographic data, physical measures, comorbidities, and progression to surgical intervention within 2 years. Among non traumatic shoulder pain patients presenting to our practice during a 9-month period in 2013, RCD was diagnosed in 984 patients, and GHOA was diagnosed in 209 patients. 152 of the GHOA patients (73%) had primary (idiopathic) GHOA, without associated inflammatory conditions or cuff arthropathy. Primary GHOA affected the dominant arm in 38.7%, the non-dominant arm in 33.8%, and was bilateral in 27.5%. Patients diagnosed with primary GHOA were older than those with RCD (69.8 +/- 12.2 vs 57.1 +/- 15.1; p = 0.0001). Women represented 54% of cases of primary GHOA, and their presentation age was older than men (72.9 +/- 11.2 vs 66.1 +/- 12.4; p = 0.0005). Primary GHOA patients had a mean BMI of 31.0 +/- 6.3, 48.7% had hyperlipidemia and 57.2% had hypertension. 24.3% were treated surgically within 2 years of follow-up. GHOA is a significant cause of shoulder pain in older age groups, and the majority of these patients have primary (idiopathic) GHOA. Primary GHOA affects dominant and non-dominant arms at similar rates, suggesting that anatomical and/or systemic factors are more important than overuse in GHOA pathogenesis. Given the prominence of GHOA in older age groups, changes in population demographics, and limitations of non-operative treatment, continued increases in shoulder replacement surgery are likely. Efforts to further understand GHOA pathogenesis and develop new, more effective therapies are advocated. PMID- 29423535 TI - The population impact of rheumatic and musculoskeletal diseases in relation to other non-communicable disorders: comparing two estimation approaches. AB - The aim of this study was to quantify the population impact of rheumatic and musculoskeletal diseases (RMDs) with other non-communicable diseases (NCDs), using two complementary strategies: standard multivariate models based on global burden of disease (GBD)-defined groups vs. empirical mutually exclusive patterns of NCDs. We used cross-sectional data from the Portuguese Fourth National Health Survey (n = 23,752). Six GBD-defined groups were included: RMDs, chronic obstructive pulmonary disease or asthma, cancer, depression, diabetes or renal failure, and stroke or myocardial infarction. The empirical approach comprised the patterns "low disease probability", "cardiometabolic conditions", "respiratory conditions" and "RMDs and depression". As recommended by the outcome measures in rheumatology (OMERACT) initiative, health outcomes included life impact, pathophysiological manifestations, and resource use indicators. Population attributable fractions (PAF) were computed for each outcome and bootstrap confidence intervals (95% CI) were estimated. Among GBD-defined groups, RMDs had the highest impact across all the adverse health outcomes, from frequent healthcare utilization (PAF 7.8%, 95% CI 6.2-9.3) to negative self-rated health (PAF 18.1%, 95% CI 15.4-20.6). In the empirical approach, patterns "cardiometabolic conditions" and "RMDs and depression" had similar PAF estimates across all adverse health outcomes, but "RMDs and depression" showed significantly higher impact on chronic pain (PAF 8.9%, 95% CI 7.6-10.3) than the remaining multimorbidity patterns. RMDs revealed the greatest population impact across all adverse health outcomes tested, using both approaches. Empirical patterns are particularly interesting to evaluate the impact of RMDs in the context of their co-occurrence with other NCDs. PMID- 29423536 TI - Risk assessment of metachronous squamous cell carcinoma after endoscopic resection for esophageal carcinoma based on the genetic polymorphisms of alcoholdehydrogense-1B aldehyde dehydrogenase-2: temperance reduces the risk. AB - BACKGROUND: Metachronous multiple squamous cell carcinoma (SCC) of the esophagus and the head and neck is commonly observed in patients who have previously undergone endoscopic resection (ER) for SCC of the esophagus (ESCC). We evaluated the risk for developing metachronous SCC following ER for ESCC based on the genetic polymorphisms for alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) as well as the alcohol consumption and smoking habits. METHODS: We studied 158 patients who underwent ER for ESCC (median follow-up 80 months). Genotyping of ADH1B/ALDH2 was performed using saliva sampling. The alcohol consumption and smoking histories of the patients before and after the ER were documented. RESULTS: Multivariate analyses revealed that inactive heterozygous ALDH2 [hazard ratio (HR) 2.25] and alcohol consumption after ER (HR 1.94) were independently associated with the risk of developing secondary SCC. Moreover, inactive heterozygous ALDH2 (HR 4.39) and alcohol consumption after the ER (HR 2.82) were independently associated with the risk of a third SCC. We analyzed 110 patients who had a history of moderate or heavy alcohol consumption before the ER. The 3-year cumulative incidence rates of secondary SCC in the temperance (n = 65) and non-temperance groups (n = 45) were 14.0 and 42.1% (p = 0.0002). Further, the 5-year cumulative incidence rates of a third SCC in the temperance and non-temperance groups were 0 and 15.6% (p = 0.0011), respectively. In addition, the 7-year cumulative incidence rates of a fourth SCC in the temperance and non-temperance groups were 0 and 15.3% (p = 0.0015), respectively. CONCLUSIONS: Continued alcohol consumption is an important risk factor for the onset of metachronous SCC and is a risk factor for the third and subsequent SCCs. Strict advice in favor of temperance is crucial. PMID- 29423537 TI - Short-Term Exposure to Lambda-Cyhalothrin Negatively Affects the Survival and Memory-Related Characteristics of Worker Bees Apis mellifera. AB - Pesticides are considered one of the major contemporary stressors of honey bee health. In this study, the effects of short-term exposure to lambda-cyhalothrin on lifespan, learning, and memory-related characteristics of Apis mellifera were systematically examined. Short-term exposure to lambda-cyhalothrin in worker bees reduced lifespan, affected learning and memory performance, reduced the homing ability, and influenced the expression levels of two learning and memory-related genes of A. mellifera. This research identifies the nature of the sublethal effects of lambda-cyhalothrin on bees and the level of exposure that can be harmful to bee health. This new information will assist in establishing guidelines for the safe use of lambda-cyhalothrin in the field. PMID- 29423539 TI - Clinical prognostic value of the isocitrate dehydrogenase 1 single-nucleotide polymorphism rs11554137 in glioblastoma. AB - The presence of the single-nucleotide polymorphism (SNP) rs11554137:C>T in the IDH1 gene is associated with a significantly lower survival in acute myeloid leukemia patients. The impact of its presence in glioblastoma on patient survival is unclear. We retrospectively reviewed 171 adult (> 18 years of age) patients treated at a single, tertiary academic center for supratentorial glioblastoma (WHO grade IV) between 2013 and 2017. We conducted Kaplan-Meier overall and progression free survival analyses based on the IDH1 and IDH2 gene status of patients' glioblastoma (IDH wild type, mutant, and IDH1 rs11554137:C>T SNP). Multivariate Cox survival analyses were conducted accounting for age at diagnosis, preoperative Karnofsky performance status score, treatment (extent of resection, postoperative radiotherapy, and temozolomide), IDH gene variant, and MGMT promoter methylation status. Presence of rs11554137:C>T SNP in glioblastoma samples did not correlate with presence of IDH1 mutation. Patients with rs11554137:C>T SNP did not have histories of prior lower-grade gliomas. Patients with IDH mutant glioblastoma had a distinctly higher survival profile than both rs11554137:C>T SNP and IDH wild type glioblastomas. No survival difference was noted between patients with glioblastoma harboring the SNP and patients with IDH wild type glioblastoma. In this study, clinical prognostication in glioblastoma patients was largely dependent on the classification of IDH mutant and wild type glioblastoma, and not on the presence of IDH1 rs11554137:C>T SNP in the tumor. PMID- 29423538 TI - Genomic analysis of synchronous intracranial meningiomas with different histological grades. AB - Although meningioma is the most common primary tumor of the central nervous system, the mechanism of progression from benign to atypical or anaplastic grade remains elusive. The present case reports the genomic evaluation of two synchronous meningiomas with different histological grades (benign and atypical) in the same patient. Under the assumption that the atypical tumor may have progressed from the benign tumor, the clonal origin of the lesions was investigated to identify genomic events responsible for the oncogenic process of evolution to higher grades in meningioma. A 59 year-old female patient was diagnosed with two synchronous meningiomas with different histological grades, benign and atypical. Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analysis of both tumors were done. WES analysis showed that each meningioma harbored distinct mutation profiles, and RNA-seq analysis revealed distinct gene expression profiles between the two tumors. The only apparent common genetic abnormality found in both tumors was the loss of heterozygosity of chromosome 22, raising the possibility that this event is the initial step in tumor formation, after which distinct subsequent mutations lead to the evolvement of two separate tumors of different grades. The result provides additional evidence on previous reports suggesting separate, independent mechanism of progression into higher grades in meningioma. PMID- 29423540 TI - Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma? AB - Glioblastomas are malignant brain tumors with poor prognosis. Lately, data from clinical studies assessing the role of co-medications in different cancer types suggested reduced mortality and potential anti-tumor activity for statins, angiotensin-I converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (sartans). Here, we analysed the association of co-treatment with statins, ACEI or sartans with outcome in a cohort of 810 patients enrolled in the phase III CENTRIC and phase II CORE trials on the role of the integrin antagonist, cilengitide, in newly diagnosed glioblastoma with or without O6 methylguanine DNA methyltransferase (MGMT) promoter methylation. Progression-free survival (PFS) and overall survival (OS) were analysed for each medication in the pooled patient group. No association was found for co-medication with either drug for PFS or OS. Median OS was 22.1 (statins) versus 22.2 (control) months (HR 1.06, 95% CI 0.81-1.39, p = 0.69), 20.4 (ACEI) versus 22.6 (control) months (HR 1.25, 95% CI 0.96-1.62, p = 0.10), and 21.7 (sartans) versus 22.3 (control) months (HR 0.86, 95% CI 0.61-1.21, p = 0.38). None of the comparisons showed a signal for different PFS or OS when analyses were controlled for MGMT promoter methylation or treatment group (TMZ/RT -> TMZ vs. RT + CIL + TMZ -> TMZ + CIL). This secondary analysis of two large glioblastoma trials thus was unable to detect evidence for an association of the use of statins, ACEI or sartans with outcome in patients with newly diagnosed glioblastoma. These data challenge the rationale for prospective studies on the possible role of these non-tumor specific drugs within the concept of drug repurposing. PMID- 29423541 TI - Autoantibody to apolipoprotein A-1 in hepatitis C virus infection: a role in atherosclerosis? AB - BACKGROUND/PURPOSE: One to three per cent of the world's population has hepatitis C virus (HCV) infection, which is not only a major cause of liver disease and cancer but also associated with an increased risk of atherosclerosis, despite an ostensibly favourable lipid profile. Autoantibodies are frequent in HCV infection and emerging evidence shows that autoantibodies could be valuable for cardiovascular disease (CVD) risk stratification. This study investigated a novel independent biomarker of CVD, autoantibodies to apolipoprotein A-1 (anti-apoA-1 IgG) and lipids in patients with chronic HCV before, during and after direct acting anti-viral (DAA) therapy. METHODS: Eighty-nine blinded serum samples from 27 patients with advanced chronic HCV were assayed for lipids and anti-apoA-1 IgG by ELISA. RESULTS: Pre-treatment HCV viral load correlated with high-density lipoprotein cholesterol (HDL-C, r = 0.417; p = 0.042) and negatively with apolipoprotein (apo)B (r = - 0.497; p = 0.013) and markers of CVD risk, the apoB/apoA-1 ratio (r = - 0.490; p = 0.015) and triglyceride level (TG)/HDL-C ratio (r = - 0.450; p = 0.031). Fourteen (52%) of 27 patients had detectable anti apoA-1 IgG autoantibodies pre-treatment; only two became undetectable with virological cure. Autoantibody-positive sera had lower apoA-1 (p = 0.012), HDL-C (p = 0.009) and total cholesterol (p = 0.006) levels. CONCLUSIONS: This is the first report of the presence of an emerging biomarker for atherosclerosis, anti apoA-1 IgG, in some patients with HCV infection. It may be induced by apoA-1 on the surface of HCV lipoviral particles. The autoantibodies inversely correlate with apoA-1 and HDL levels and may render HDL dysfunctional. Whether these hypothesis-generating findings have clinical implications in HCV patients requires further study. PMID- 29423542 TI - Evaluation of growth hormone response to GHRH plus arginine test in children with idiopathic short stature: role of peak time. AB - PURPOSE: To describe the course of growth hormone response to growth hormone releasing hormone (GHRH) plus arginine provocative test in children with idiopathic short stature (ISS) and to evaluate the role of peak time. METHODS: A retrospective study was performed analyzing 344 GHRH plus arginine provocative tests performed in children and adolescents with short stature. Serum GH levels were measured at four-time points (T0', T30', T45' and T60') and GH peak was defined as the maximum value at any time point. Mean (T30'-T60') GH value and area under the curve (AUC) were calculated. RESULTS: When analyzing the time of peak at the provocative test, the most frequent peak time was T45' (53.8%) in the ISS group, with no differences in gender, age, and pubertal stage. Analyzing GHD subjects, the most frequent time of peak was T30 (50%). Analyzing the whole population, the GH T0' levels were significantly lower in subjects with the GH peak at T45' than those with the GH peak at T30' (1.7 +/- 2.0 vs. 3.2 +/- 4.0, p < 0.001). In subjects with GH peak at T45', the value of GH peak, AUC and mean GH were significantly higher than in those with GH peak at T30' and T60'. A direct correlation was found between the value of GH peak and growth velocity SDS (r = 0.127, p = 0.04) and a negative one between GH peak and GH level at T0' (r = - 0.111, p = 0.04), even when adjusted for gender, age, pubertal stage and BMI Z score. CONCLUSIONS: The time peak at 45 min seems to be associated with a better response to the test considering GH peak, mean and AUC. Patients with a GH peak at 30 min more probably could have a derangement in GH secretion showing worst growth pattern and/or a GH deficiency and should be carefully observed. PMID- 29423543 TI - Same-Day Preventive Embolization and Surgical Excision of Carotid Body Tumor. PMID- 29423545 TI - Improved walking distance and range of motion predict patient satisfaction after TKA. AB - PURPOSES: The focus in the evaluation of total knee arthroplasty has shifted from objective measures of implant position and knee function, to patient-reported outcome measures (PROMs). The relation between these two measures was investigated and the possibility of prediction of the patient satisfaction level was evaluated by defining thresholds for improvement of (1) range of motion (ROM), (2) 6-min walk test (6MWT), (3) sit-to-stand test (STS) and (4) quadriceps force after TKA? METHODS: Fifty-seven patients were prospectively tested at preoperative and 6 months postoperative intervals. The ROM, 6MWT, STS-test and quadriceps force were evaluated. Two clusters were created based on the postoperative KOOS, OKS and the satisfaction subscore of the new KSS, cluster 1 consisted of patients with good to excellent PROMs, cluster 2 of patients with poorer PROMs. Patients in each cluster were more similar to each other than to those in the other cluster. Receiver operating characteristic (ROC)-curve analysis was used to identify thresholds for the functional outcomes that established cluster allocation. Multiple logistic regression was used to define a model to predict cluster allocation. RESULTS: Patients with high postoperative PROMs (cluster 1 allocation) showed higher postoperative functional outcomes (p < 0.05). Thresholds for the improvement of ROM (>= 5 degrees , OR 6.3, 95% CI 1.23 31.84), 6MWT (>= 50 m, OR 8.2, 95% CI 1.61-42.18) STS (>= 1.05 s, OR 3, 95% CI 0.56-16.07) and normalized Q4 force (>= 1.5 N/BMI, OR 2.5, 95% CI 0.49-12.89) were found to be predictors of cluster allocation. A model to predict the cluster allocation contained gender, ROM improvement and 6MWT improvement (sensitivity 91.1%, specificity 75%). CONCLUSIONS: Thresholds for improvement of functional parameters can predict the patient satisfaction cluster. Patients, who are male, improve on the 6-min walk test with 50 m or more and have an increased range of motion of 5 degrees or more, compared to the preoperative situation, are 6-8 times more likely of being satisfied after TKA. These tests are easy to use in clinical practice and can predict the level of patient satisfaction after TKA. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 29423544 TI - High-intensity interval training in hypoxia does not affect muscle HIF responses to acute hypoxia in humans. AB - PURPOSE: The myocellular response to hypoxia is primarily regulated by hypoxia inducible factors (HIFs). HIFs thus conceivably are implicated in muscular adaptation to altitude training. Therefore, we investigated the effect of hypoxic versus normoxic training during a period of prolonged hypoxia ('living high') on muscle HIF activation during acute ischaemia. METHODS: Ten young male volunteers lived in normobaric hypoxia for 5 weeks (5 days per week, ~ 15.5 h per day, FiO2: 16.4-14.0%). One leg was trained in hypoxia (TRHYP, 12.3% FiO2) whilst the other leg was trained in normoxia (TRNOR, 20.9% FiO2). Training sessions (3 per week) consisted of intermittent unilateral knee extensions at 20-25% of the 1 repetition maximum. Before and after the intervention, a 10-min arterial occlusion and reperfusion of the leg was performed. Muscle oxygenation status was continuously measured by near-infrared spectroscopy. Biopsies were taken from m. vastus lateralis before and at the end of the occlusion. RESULTS: Irrespective of training, occlusion elevated the fraction of HIF-1alpha expressing myonuclei from ~ 54 to ~ 64% (P < 0.05). However, neither muscle HIF-1alpha or HIF-2alpha protein abundance, nor the expression of HIF-1alpha or downstream targets selected increased in any experimental condition. Training in both TRNOR and TRHYP raised muscular oxygen extraction rate upon occlusion by ~ 30%, whilst muscle hyperperfusion immediately following the occlusion increased by ~ 25% in either group (P < 0.05). CONCLUSION: Ten minutes of arterial occlusion increased HIF-1alpha-expressing myonuclei. However, neither normoxic nor hypoxic training during 'living high' altered muscle HIF translocation, stabilisation, or transcription in response to acute hypoxia induced by arterial occlusion. PMID- 29423547 TI - BPDAI and ABSIS correlate with serum anti-BP180 NC16A IgG but not with anti-BP230 IgG in patients with bullous pemphigoid. AB - Bullous pemphigoid (BP) is an autoimmune bullous disease characterized by autoantibody production against BP180 and BP230. Two scoring systems have been validated for BP including: Bullous Pemphigoid Disease Area Index (BPDAI) and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). In this study, we investigated correlations between both scoring systems and either anti-BP180 NC16A or anti-BP230 values. BPDAI and ABSIS were used to measure disease activity in 95 BP patients at Razi Hospital in Tehran, Iran. ELISA was performed on patient sera to identify any significant relationship between anti-BP180 NC16A/anti-BP230 values and BP disease activity. The two scores showed a strong correlation (rho = 0.73; p value < 0.0001). Anti-BP180 NC16A values correlated with BPDAI (rho = 0.49, p value = 0.0001), ABSIS (rho = 0.47, p value < 0.0001), and BPDAI-Pruritus scores (rho = 0.29, p value < 0.005). There was a strong correlation between anti-BP180 NC16A values and the ABSIS Skin score (rho = 0.58, p value < 0.0001), and a moderate correlation with erosion/blister BPDAI score (rho = 0.48, p value < 0.001) and urticaria/erythema BPDAI score (rho = 0.27, p value = 0.009). Anti-BP230 values did not demonstrate any relationship with either scores or their subcomponents. Both scoring systems demonstrated moderate validity. Mucosal components did not show any correlation with anti-BP antibodies and are disproportionately presented in both BP scoring tools. PMID- 29423548 TI - Detection and genetic characterization of bovine kobuvirus from calves in Egypt. AB - Kobuviruses are small non-enveloped RNA viruses that probably cause diarrhea in cattle and swine. Since its discovery in 2003, few studies have addressed bovine kobuvirus (BKoV; a species of Aichivirus B) infections. BKoV has been reported in Europe, Asia, and South America, suggesting a worldwide distribution. To investigate the presence of BKoV in Egypt, 36 fecal specimens from diarrheic calves in two different Egyptian provinces (Cairo and Sharkia) were screened by RT-PCR and 24 (66.7%) were found positive for BKoV. RNA from one of the positive samples (BKoV/Egy-1/KY407744) was subjected to next-generation sequencing to determine the complete BKoV genome sequence. When compared to the only recorded BKoV genome sequence (BKoV/U-1/AB084788), the studied strain showed 94 amino acid (aa) substitutions through its entire polyprotein (2463 aa), one nucleotide (nt) insertion and one nt deletion in the 2B gene and 4-nt deletions in the UTRs (2 each). Additionally, five VP1 and seven 3D sequences were obtained from other samples by using RT-PCR and Sanger sequencing. A discrepancy in the phylogenetic topography of VP1 and 3D was observed, where the Egyptian VP1 sequences were classified as a distinct cluster within the proposed lineage 1 (genotype A), which also contained strains from the UK, Brazil, and Japan. While, the 3D sequences from Cairo were related to those of Chinese strains unlike Sharkia ones that were more closer to Korean strains. To the best of our knowledge, this is the first detection and genomic characterization of BKoV in Egypt or indeed Africa. PMID- 29423546 TI - Association between incision technique for hamstring tendon harvest in anterior cruciate ligament reconstruction and the risk of injury to the infra-patellar branch of the saphenous nerve: a meta-analysis. AB - PURPOSE: To determine how the incision technique for hamstring tendon (HT) harvest in anterior cruciate ligament (ACL) reconstruction affects the risk of injury to the IPBSN and clinical outcome. METHODS: A systematic literature search of the MEDLINE/Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL) and EBSCOhost electronic databases and clinicaltrials.gov for unpublished studies was performed to identify comparative studies investigating injury to the IPBSN after HT ACL reconstruction by comparing at least two different incision techniques. Data were extracted for the number of patients with evidence of any neurologic deficit corresponding to injury to the IPBSN, area of sensory deficit, the Lysholm score and patient satisfaction. The mean difference (MD) in study outcome between incision groups was assessed. The relative risk (RR) and the number needed to treat (NNT) were calculated. The Chi-square and Higgins' I2 tests were applied to test heterogeneity. Data were pooled using a Mantel Haenszel random-effects model if the statistical heterogeneity was > 50% and a fixed-effects model if the statistical heterogeneity was < 50%. The risk of bias was evaluated according to the Cochrane Database questionnaire and the quality of evidence was graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. RESULTS: A total of eight studies (three randomized controlled trials (RCTs) and five comparative studies) were included, of which six compared vertical and oblique incisions, one horizontal and vertical incisions, and one compared all three techniques. HT harvest was performed through a vertical incision in 329 patients, through an oblique incision in 195 patients and through a horizontal incision in 151 patients. Considering the meta-analysis of the RCTs, the performance of a vertical incision significantly increased the risk of causing IPBSN deficiency compared with both oblique and horizontal incision [RR 1.65 (CI 1.10-2.49, p = 0.02) and RR 2.45 (CI 1.73-3.47, p < 0.0001), respectively]. A significantly larger area of sensory deficit was found with vertical incisions compared with oblique ones, with an MD of 22.91 cm2 (95% CI 7.73-38.08; p = 0.04). No significant differences were found between the incision techniques in relation to patient-reported outcomes. The same trend was obtained after the performing a meta-analysis of all eight included studies. The quality of evidence in this meta-analysis was determined as "low" to "moderate", mostly due to inadequate methods of randomization and high heterogeneity among the included studies. CONCLUSION: The performance of a vertical incision to harvest HTs for ACL reconstruction significantly increased the risk of iatrogenic injury to the IPBSN compared with both oblique and horizontal incisions. LEVEL OF EVIDENCE: Level I-III, meta-analysis of comparative studies. PMID- 29423549 TI - Genomic characteristics of vB_PpaP_PP74, a T7-like Autographivirinae bacteriophage infecting a potato pathogen of the newly proposed species Pectobacterium parmentieri. AB - Bacteriophage vB_PpaP_PP74 (PP74) is a novel virulent phage that infects members of the species Pectobacterium parmentieri, a newly established species of soft rot-causing bacteria in the family Pectobacteriaceae, derived from potato specific Pectobacterium wasabiae. vB_PpaP_PP74 was identified as a member of the family Podoviridae by transmission electron microscopy. The phage has a 39,790-bp dsDNA genome containing 50 open reading frames (ORFs). Because of the absence of genes encoding toxins or lysogeny factors, PP74 may be considered a candidate phage for pathogen biocontrol applications. The genome layout is similar to genomes of T7-like phages within the subfamily Autographivirinae, and therefore, functions can be attributed to most of ORFs. However, the closest nucleotide sequence homologs of phage PP74 are unclassified Escherichia phages. Based on phylogenetic analysis, vB_PpaP_PP74 is a sensu lato T7-like phage, but it forms a distant subgenus group together with homologous enterobacterial phages. PMID- 29423550 TI - Resilience concepts in psychiatry demonstrated with bipolar disorder. AB - BACKGROUND: The term resilience describes stress-response patterns of subjects across scientific disciplines. In ecology, advances have been made to clearly distinguish resilience definitions based on underlying mechanistic assumptions. Engineering resilience (rebound) is used for describing the ability of subjects to recover from adverse conditions (disturbances), and is the rate of recovery. In contrast, the ecological resilience definition considers a systemic change: when complex systems (including humans) respond to disturbances by reorganizing into a new regime (stable state) where structural and functional aspects have fundamentally changed relative to the prior regime. In this context, resilience is an emergent property of complex systems. We argue that both resilience definitions and uses are appropriate in psychology and psychiatry, but although the differences are subtle, the implications and uses are profoundly different. METHODS: We borrow from the field of ecology to discuss resilience concepts in the mental health sciences. RESULTS: In psychology and psychiatry, the prevailing view of resilience is adaptation to, coping with, and recovery (engineering resilience) from adverse social and environmental conditions. Ecological resilience may be useful for describing vulnerability, onset, and the irreversibility patterns of mental disorders. We discuss this in the context of bipolar disorder. CONCLUSION: Rebound, adaptation, and coping are processes that are subsumed within the broader systemic organization of humans, from which ecological resilience emanates. Discerning resilience concepts in psychology and psychiatry has potential for a mechanistically appropriate contextualization of mental disorders at large. This might contribute to a refinement of theory and contextualize clinical practice within the broader systemic functioning of mental illnesses. PMID- 29423552 TI - Laparoscopic management of large hiatal hernia: mesh method with the use of ProGrip mesh versus standard crural repair. AB - BACKGROUND: Primary repair of large hiatal hernia is associated with a high recurrence rate. The use of mesh can lead to a reduce of recurrence rate. Despite this reduction, the type of mesh used and the placement technique are controversial. In our study, we used a new type of non-absorbable, self-fixating mesh to reinforce the cruroplasty. The aim of the present study was to compare the long-term results of laparoscopic treatment of large hiatal hernia with mesh reinforcement versus simple crura repair. METHODS: This study was performed on 98 gastroesophageal reflux disease patients who underwent Nissen fundoplication with mesh-augmented crura repair and fundoplication with standard crura repair. We used non-absorbable laparoscopic self-fixating mesh by ProGripTM. All patients were separated into the mesh group (n = 50) and non-mesh group (n = 48). The groups were evaluated according to the following criteria: dysphagia, patients' symptomatic outcome judgment according to The Gastroesophageal Reflux Disease Health Related Quality of Life (GERD-HRQL) questionnaire and patients' satisfaction, hiatal hernia recurrence according to upper endoscopy and a barium contrast swallow study. Follow-up was completed in 95 (97%) patients with a mean follow-up duration of 54 months (range 12-62 months). RESULTS: Mean operative time was not significantly different (p = 0.30302). During the 48 months of follow-up, one recurrence occurred in the mesh group and eight recurrences appeared in the non-mesh group (p = 0.027). Patient satisfaction was significantly higher in the mesh group (p = 0.004). The mesh group had a more significant improvement in GERD-HRQL score (p < 0.0001) compared to the non-mesh group. CONCLUSION: In conclusion, this study confirms that laparoscopic repair of large hiatal hernias is effective and durable over a long period of time. Reinforcement of crura repair with ProGripTM mesh is safe and can prevent anatomical recurrences. PMID- 29423551 TI - High preoperative modified frailty index has a negative impact on short- and long term outcomes of octogenarians with gastric cancer after laparoscopic gastrectomy. AB - BACKGROUND: The proportion of elderly patients who undergo surgery has rapidly increased. However, clinical indicators that predict outcomes are limited. Frailty is thought to estimate physiological reserves, although its use has not been evaluated in laparoscopic surgical patients. This study aimed to evaluate the significance of preoperative modified frailty index (PMFI) in octogenarians undergoing a laparoscopic gastrectomy. METHODS: We reviewed prospectively collected data from 119 patients with gastric cancer (GC) aged 80 years or older who underwent a radical laparoscopic gastrectomy (RLG) between January 2007 and December 2012. Three baseline frailty traits were measured using routine preoperative laboratory data: albumin < 3.4 g/dL, haematocrit < 35%, and creatinine > 2 mg/dL. Patients were categorized by the number of positive traits as follows: low preoperative modified frailty index (LPMFI): 0-2 traits and high preoperative modified frailty index (HPMFI): 3 traits. We compared patient characteristics, operative outcomes, pathological results, morbidity, and survival. RESULTS: A total of 43 (36.1%) patients were considered HPMFI, and 76 (63.9%) patients were considered LPMFI. HPMFI was associated with an increased risk of postoperative complications (HPMFI group: odds ratio 2.506; 95% CI, 1.113 5.643, P = 0.027). With a median follow-up of 39.0 months, the 3-year overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS) rates for the entire cohort were 47.9, 34.3, and 51.7%, respectively. Significant differences were observed in OS (HPMFI group, 37.2%; LPMFI group, 53.9%; P = 0.038) and RFS (HPMFI group, 23.3%; LPMFI group, 40.5%; P = 0.012) between the groups, but no difference was found for CSS (HPMFI group, 43.5%; LPMFI group, 56.4%; P = 0.078). CONCLUSIONS: HPMFI based on an easily calculable preoperative measure may be useful for predicting postoperative complications and have a negative impact on 3-year OS and RFS after an RLG in octogenarians. Therefore, HPMFI can serve as a low-cost, simple screen for high-risk individuals who might suffer more than expected during the postoperative period after an RLG. PMID- 29423553 TI - Force-based learning curve tracking in fundamental laparoscopic skills training. AB - BACKGROUND: Within minimally invasive surgery (MIS), structural implementation of courses and structured assessment of skills are challenged by availability of trainers, time, and money. We aimed to establish and validate an objective measurement tool for preclinical skills acquisition in a basic laparoscopic at home training program. METHODS: A mobile laparoscopic simulator was equipped with a state-of-the-art force, motion, and time tracking system (ForceSense, MediShield B.V., Delft, the Netherlands). These performance parameters respectively representing tissue manipulation and instrument handling were continuously tracked during every trial. Proficiency levels were set by clinical experts for six different training tasks. Resident's acquisition and development of fundamental skills were evaluated by comparing pre- and post-course assessment measurements and OSATS forms. A questionnaire was distributed to determine face and content validity. RESULTS: Out of 1842 captured attempts by novices, 1594 successful trials were evaluated. A decrease in maximum exerted absolute force was shown in comparison of four training tasks (p <= 0.023). Three of the six comparisons also showed lower mean forces during tissue manipulation (p <= 0.024). Lower instrument handling outcomes (i.e., time and motion parameters) were observed in five tasks (resp. (p <= 0.019) and (p <= 0.025)). Simultaneously, all OSATS scores increased (p <= 0.028). Proficiency levels for all tasks can be reached in 2 weeks of at home training. CONCLUSIONS: Monitoring force, motion, and time parameters during training showed to be effective in determining acquisition and development of basic laparoscopic tissue manipulation and instrument handling skills. Therefore, we were able to gain insight into the amount of training needed to reach certain levels of competence. Skills improved after sufficient amount of training at home. Questionnaire outcomes indicated that skills and self-confidence improved and that this training should therefore be part of the regular residency training program. PMID- 29423554 TI - Performance of a second generation pulmonary capnotracking system for continuous monitoring of cardiac output. AB - Technologies for minimally-invasive cardiac output measurement in patients during surgery remain little used in routine practice. We tested a redeveloped system based on CO2 elimination (VCO2) by the lungs for use in ventilated patients, which can be seamlessly integrated into a modern anesthesia/monitoring platform, and provides automated, continuous breath-by-breath cardiac output monitoring. A prototype measurement system was constructed to measure VCO2 and end-tidal CO2 concentration with each breath. A baseline measurement of non-shunt cardiac output was made during a brief oscillating change in ventilator rate, according to the differential CO2 Fick approach and repeated at 5-10 min intervals. Continuous breath-by-breath monitoring of cardiac output was performed between these intervals from measurement of VCO2, using a derivation of the Fick equation applied to pulmonary CO2 elimination and cardiac output displayed in real time. Measurements were compared with simultaneous measurements by thermodilution in 50 patients undergoing cardiac surgery or liver transplantation. Overall mean bias [sd] for agreement in cardiac output measurement was - 0.3 [1.1] L/min, percentage error +/- 38.7%, intraclass correlation coefficient = 0.91. Concordance in measurement of changes of at least 15% in cardiac output was 81.4%, with a mean angular bias of - 1.7 degrees , and radial limits of agreement of +/- 76.2 degrees on polar plot analysis. The accuracy and precision compared favourably to other clinical techniques. The method is relatively seamless and automated and has potential for continuous, cardiac output monitoring in ventilated patients during anesthesia and critical care. PMID- 29423555 TI - Second Malignancies after Hematopoietic Stem Cell Transplantation. AB - OPINION STATEMENT: Second malignancies are a rare but well-defined late complication after autologous and allogeneic hematopoietic stem-cell transplantation (SCT). Solid malignancies occur in up to 15% of patients 15 years after SCT with myeloablative conditioning, with no plateau in the incidence rates. They are responsible for 5-10% of late deaths after SCT. The incidence is increased with advanced age at SCT. The major risk factors are the use of total body irradiation, which is associated with adenocarcinomas and with chronic graft versus-host disease which is associated with squamous cell cancers. There is less data on the incidence of second malignancies after reduced-intensity conditioning, but it may not be lower. The types of solid tumors reported in excess include melanoma and other skin cancers; cancers of the oral cavity and head and neck, brain, liver, uterine cervix, thyroid, breast, lung; and possibly gastrointestinal cancers. Therapy-related myeloid neoplasms (t-MN) are more common after autologous SCT and may be related mostly to pre-transplant therapies. Post-transplant lymphoproliferative disease is donor-cell-derived lymphoma that is more common after allogeneic SCT with T-cell depletion or intensive immune-suppression state. Second malignancies are most often treated similarly to the standard therapy for similar malignancies. Lifelong cancer screening and prevention interventions are required for all transplantation survivors. PMID- 29423557 TI - Strategies to Support the Education Goals of Youth and Young Adults with Serious Mental Health Conditions: A Case Study. AB - This manuscript describes efforts to support youth and young adults living with serious mental health conditions (SMHC) as they pursue their education goals. Case studies were conducted with three supported education initiatives across the US. Data were collected through individual interviews and focus groups. Key ingredients exist across various settings (e.g., mental health, post-secondary education) to support the pursuit of education goals for students living with SMHC, while individual settings have unique circumstances to address. Findings can inform stakeholders of relevant core components and implementation strategies across settings that support education goals for students with SMHCs. PMID- 29423556 TI - Psychosocial Predictors of Change in Depressive Symptoms Following Gastric Banding Surgery. AB - OBJECTIVE: The aim of this study is to identify psychosocial variables associated with the relationship between weight loss and change in depressive symptoms following gastric banding surgery. METHODS: Ninety-nine adults completed self report questionnaires assessing depressive symptoms and other psychosocial variables (self-esteem, body image dissatisfaction, perceived physical health, and perceived weight-based stigmatisation) prior to gastric-band surgery and monthly for 6-month post-surgery. RESULTS: Weight, depressive symptoms, and other psychosocial variables improved significantly 1-month post-surgery and remained lower to 6 months. Weight loss from baseline to 1- and 6-months post-surgery significantly correlated with change in depressive symptoms. Body image dissatisfaction and self-esteem accounted for some of the variance in change in depressive symptoms from baseline to 1-month and baseline to 6-months post surgery. CONCLUSIONS: Depressive symptoms improved significantly and rapidly after bariatric surgery, and body image dissatisfaction and self-esteem predicted change in depressive symptoms. Interventions targeting body image and self-esteem may improve depressive symptoms for those undergoing weight loss interventions. PMID- 29423558 TI - Automated sleep staging of OSAs based on ICA preprocessing and consolidation of temporal correlations. AB - An automated sleep staging based on analyzing long-range time correlations in EEG is proposed. These correlations, indicating time-scale invariant property or self similarity at different time scales, are known to be salient dynamical characteristics of stage succession for a sleeping brain even when the subject suffers a destructive disorder such as Obstructive Sleep Apnea (OSA). The goal is to extract a set of complementary features from cerebral sources mapped onto the scalp electrodes or from a number of denoised EEG channels. For this purpose, source localization/extraction and noise reduction approaches based on Independent Component Analysis were used prior to correlation analysis. Feature extracted segments were then classified in one of the five classes including WAKE, STAGE1, STAGE2, SWS and REM via an ensemble neuro-fuzzy classifier. Some techniques were employed to improve the classifier's performance including Scaled Conjugate Gradient Method to speed up learning the ANFIS classifiers, a pruning algorithm to eliminate irrelevant fuzzy rules and the 10-fold cross-validation technique to train and test the system more efficiently. The performance of classification for two strategies including (1) feature extraction from effective cerebral sources and (2) feature extraction from selected channels of denoised EEG signals was compared and contrasted in terms of training errors and test accuracies. The first and second strategies achieved 92.23 and 88.74% agreement with human expert respectively which indicates the effectiveness of the staging system based on cerebral sources of activity. Our results further indicate that the misclassification rates were almost below 10%. The proposed automated sleep staging system is reliable due to the fact that it is based on the underlying dynamics of sleep staging which is less likely to be affected by sleep fragmentations occurred repeatedly in OSA. PMID- 29423559 TI - Mind the gap: results of a multispecialty survey on coordination of care for peri procedural anticoagulation. AB - To understand how physicians from various specialties perceive coordination of care when managing peri-procedural anticoagulation. Cross-sectional survey of cardiologists, gastroenterologists, and primary care physicians (PCPs) in an integrated health system (N = 251). The survey began with a vignette of a patient with atrial fibrillation co-managed by his PCP, cardiologist, and an anticoagulation clinic who must hold warfarin for a colonoscopy. Respondents' experiences and opinions around responsibilities and institutional support for managing peri-procedural anticoagulation were elicited using multiple choice questions. We examined differences in responses across specialties using Chi square analysis. The response rate was 51% (n = 127). 52% were PCPs, 28% cardiologists, and 21% gastroenterologists. Nearly half (47.2%) of respondents believed that the cardiologist should be primarily responsible for managing peri procedural anticoagulation, while fewer identified the PCP (25.2%), anticoagulation clinic (21.3%), or gastroenterologist (6.3%; p = 0.09). Respondents across specialties had significantly different approaches to deciding how to manage the clinical case presented (p < 0.001). Most cardiologists (60.0%) would decide whether to offer bridging without consulting with other providers or clinical resources, while most PCPs would decide after consulting clinical resources (57.6%). Gastroenterologists would most often (46.2%) defer the decision to another provider. A majority of all three specialties agreed that their institution could do more to help manage peri-procedural anticoagulation, and there was broad support (88.1%) for anticoagulation clinics' managing all aspects of peri-procedural anticoagulation. Providers across specialties agree that their institution could do more to help manage peri-procedural anticoagulation, and overwhelmingly support anticoagulation clinics' taking responsibility. PMID- 29423560 TI - Re: Dabigatran overdose: a case report of acute hepatitis. Extracorporeal treatment. PMID- 29423561 TI - Colistin causes profound morphological alteration but minimal cytoplasmic membrane perforation in populations of Escherichia coli and Pseudomonas aeruginosa. AB - Whilst colistin (polymyxin E) represents the last mainstream treatment option for multidrug-resistant Gram-negative pathogens, details of its mechanism of action remain to be fully resolved. In this study, the effects of sub-inhibitory, inhibitory-bactericidal, and supra-bactericidal levels of colistin on the membrane integrity and morphology of Escherichia coli and Pseudomonas aeruginosa were investigated using potassium loss, flow cytometry, and scanning electron microscopy (SEM). Supra-bactericidal colistin concentrations induced just 4-12% intracellular potassium loss from bacteria after 24 h. Flow cytometry data suggested colistin might alter cell arrangement, and SEM confirmed the antibiotic causes bacterial aggregation. Filamentation was not detected in either species at any concentration or time-point up to 24 h. These results argue against the hypotheses that colistin kills bacteria by puncturing the cytoplasmic membrane or disrupting DNA synthesis. The colistin-induced bacterial aggregation detected has implications for the interpretation of MBC, time-kill, and other test results obtained with this antibiotic. PMID- 29423562 TI - Polynucleotide phosphorylase is involved in the control of lipopeptide fengycin production in Bacillus subtilis. AB - Bacillus subtilis is a wealth source of lipopeptide molecules such as iturins, surfactins and fengycins or plipastatins endowed with a range of biological activities. These molecules, designated secondary metabolites, are synthesized via non-ribosomal peptides synthesis (NRPS) machinery and are most often subjected to a complex regulation with involvement of several regulatory factors. To gain novel insights on mechanism regulating fengycin production, we investigated the effect of the fascinating polynucleotide phosphorylase (PNPase), as well as the effect of lipopeptide surfactin. Compared to the wild type, the production of fengycin in the mutant strains B. subtilis BBG235 and BBG236 altered for PNPase has not only decreased to about 70 and 40%, respectively, but also hampered its antifungal activity towards the plant pathogen Botrytis cinerea. On the other hand, mutant strains BBG231 (srfAA-) and BBG232 (srfAC-) displayed different levels of fengycin production. BBG231 had registered an important decrease in fengycin production, comparable to that observed for BBG235 or BBG236. This study permitted to establish that the products of pnpA gene (PNPase), and srfAA- (surfactin synthetase) are involved in fengycin production. PMID- 29423563 TI - New insights into the metabolic potential of the phototrophic purple bacterium Rhodopila globiformis DSM 161T from its draft genome sequence and evidence for a vanadium-dependent nitrogenase. AB - Rhodopila globiformis: is the most acidophilic anaerobic anoxygenic phototrophic purple bacterium and was isolated from a warm acidic sulfur spring in Yellowstone Park. Its genome is larger than genomes of other phototrophic purple bacteria, containing 7248 Mb with a G + C content of 67.1% and 6749 protein coding and 53 RNA genes. The genome revealed some previously unknown properties such as the presence of two sets of structural genes pufLMC for the photosynthetic reaction center genes and two types of nitrogenases (Mo-Fe and V-Fe nitrogenase), capabilities of autotrophic carbon dioxide fixation and denitrification using nitrite. Rhodopila globiformis assimilates sulfate and utilizes the C1 carbon substrates CO and methanol and a number of organic compounds, in particular, sugars and aromatic compounds. It is among the few purple bacteria containing a large number of pyrroloquinoline quinone-dependent dehydrogenases. It has extended capacities to resist stress by heavy metals, demonstrates different resistance mechanisms to antibiotics, and employs several toxin/antitoxin systems. PMID- 29423564 TI - Interpretation of ambiguous facial affect in adults with attention deficit/hyperactivity disorder. AB - In addition to impairments in cognitive functioning, attention deficit/hyperactivity disorder (ADHD) is associated with deficits in interpersonal functioning as well which are assumed to stem from a distorted perception or interpretation of affective information. While previous research suggests that the decoding of negatively valenced facial stimuli is impaired, less is known about the potential interpretation biases in ADHD which are linked to other externalizing psychopathologies. The present study investigated interpretation biases in adults with ADHD (N = 65) and controls (N = 49) using ambiguous facial stimuli (angry/happy, angry/fearful, fearful/happy blends) with different proportions of each emotion. Participants indicated the dominant emotion and rated the perceived intensity of each image. While impaired processing of fearful expressions was evident in the ADHD group, the results of the current study do not provide support for an interpretation bias in adults with ADHD. These findings suggest that interpretation biases may be restricted to aggressive psychopathology and cannot be generalized to individuals with ADHD. PMID- 29423565 TI - Formation of chelate structure between His-Met dipeptide and diaqua-cisplatin complex; DFT/PCM computational study. AB - Interaction of cisplatin in activated diaqua-form with His-Met dipeptide is explored using DFT approach with PCM model. First the conformation space of the dipeptide is explored to find the most stable structure (labeled 0683). Several functionals with double-zeta basis set are used for optimization and obtained order of conformers is confirmed by the CCSD(T) single-point calculations. Supermolecular model is used to determine reaction coordinate for the replacement of aqua ligands consequently by N-site of histidine and S-site of methionine and reversely. Despite the monoadduct of Pt-S(Met) is thermodynamically less stable this reaction passes substantially faster (by several orders of magnitude) than coordination of cisplatin to histidine. The consequent chelate formation occurs relatively fast with energy release up to 12 kcal mol-1. PMID- 29423566 TI - Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review. AB - Spastic paraplegia 35 (SPG35) is a recessive condition characterized by childhood onset, progressive course, complicated by dystonia, dysarthria, cognitive impairment, and epilepsy. Mutations in the FA2H gene have been described in several families, leading to the proposal of a single entity, named fatty acid hydrolase-associated neurodegeneration (FAHN). Several reports have described a polymorphic radiological picture with white matter lesions of various degrees and a distinct form of neurodegeneration with brain iron accumulation. While we reviewed the pertinent literature, we also report three new patients with SPG35, highlighting the possible absence of white matter lesions even after a long neuroimaging follow-up. Three-dimensional modeling of the mutated proteins was helpful to elucidate the role of the site of mutations and the correlation with the residual enzyme activity as determined in cultured skin fibroblasts. PMID- 29423567 TI - [Diagnostic management of fever]. AB - Fever is a symptom of a wide range of diseases. Its diagnostic management is of crucial importance, whereby the interface between general practitioner and hospital plays an important role. The family practitioner is of particular importance in the detection of life-threatening or complex situations involving fever. The diagnostic algorithm presented here can serve as the basis for rapid and targeted diagnostics. Good communication between the doctor and the hospital doctor is mandatory. PMID- 29423568 TI - A Two-Phase Approach to Developing SNAP: an iPhone Application to Support Appointment Scheduling and Management for Women with a BRCA Mutation. AB - Professional organizations provide surveillance guidelines for BRCA1 and BRCA2 (BRCA) carriers with intact breasts and/or ovaries to facilitate early cancer detection. However, literature indicates adherence to surveillance guidelines is inconsistent at best. Using the Messaging Model for Health Communication Campaigns framework, we undertook a two-phase formative research approach to develop an intervention to promote adherence to surveillance guidelines. Discussion groups identified preferred intervention format and function in phase I. Findings indicated carriers desired a phone application (app) to assist with surveillance management and appointment tracking. Thus, an iPhone app for carriers to track appointments based on published surveillance guidelines was developed. In phase II, we obtained feedback from BRCA carriers via a survey during a prototype demonstration at a regional conference. Participants in phase II wanted reminder capabilities and the ability to add and modify information fields. This feedback informed intervention modifications, resulting in the Scheduling Necessary Advised Procedures (SNAP) iPhone app currently being pilot tested by BRCA carriers throughout the USA. PMID- 29423569 TI - Time Costs for Genetic Counseling in Preconception Carrier Screening with Genome Sequencing. AB - Advances in technology and the promise of personalized health care are driving greater use of genome sequencing (GS) for a variety of clinical scenarios. As health systems consider adopting GS, they need to understand the impact of GS on the organization and cost of care. While research has documented a dramatic decrease in the cost of sequencing and interpreting GS, few studies have examined how GS impacts genetic counseling workloads. This study examined the time needed to provide genetic counseling for GS in the context of preconception carrier screening. Genetic counselors prospectively reported on the time spent in the results disclosure process with 107 study participants who were part of the NextGen study. We found that the median time for results disclosure was 64 min (ranged from 5 to 229 min). Preparation work was the most time-consuming activity. Qualitative data from journal entries, debrief interviews with genetic counselors, and detailed case conference notes provided information on factors influencing time for results disclosure and implications for practice. Results suggest that expanded carrier screening could require significant increases in genetic counseling time, unless we are able to generate new resources to reduce preparation work or develop other strategies such as the creation of new models to deliver this type of service. PMID- 29423570 TI - Perceived Changes to Obstetric Care and the Integration of Personal and Professional Life as a Pregnant Prenatal Genetic Counselor. AB - The impact of practicing as a prenatal genetic counselor while pregnant is unclear given the limited amount of published literature on this issue. To address this gap in knowledge, a total of 215 current and past prenatal genetic counselors provided insights regarding this personal yet professional juncture through completion of an online survey that allowed for both close-ended and open ended responses. While participants agreed that experiencing pregnancy affected their perspectives and counseling in several ways, this paper focuses on one particular finding-that of the changes in their own obstetric care perceived by genetic counselors while working within the prenatal setting and being pregnant themselves. As a result of these changes, considerations about when to disclose a pregnancy to colleagues along with how to integrate personal and professional needs as a pregnant prenatal genetic counselor surfaced. Additional findings, practice implications, and research recommendations are discussed. PMID- 29423571 TI - Novel Therapies for Older Adults With Acute Lymphoblastic Leukemia. AB - PURPOSE OF REVIEW: Older adults with acute lymphoblastic leukemia (ALL) have worse survival compared to their younger counterparts. Here, we review the reasons for the poorer outcomes of older patients with ALL and also summarize the current and future therapeutic approaches to ALL in the elderly population. RECENT FINDINGS: The poor outcomes of older adults with ALL are driven largely by lack of tolerance to standard-dose chemotherapy, which leads to unacceptably high rates of myelosuppression-related deaths. Recent studies have shown promising results with the use of low-intensity or chemotherapy-free regimens in older patients with ALL, which are able to retain efficacy without excess toxicity. Novel antibody constructs such as inotuzumab ozogamicin and blinatumomab as well as potent later-generation tyrosine kinase inhibitors such as ponatinib hold significant promise in the management of ALL in the older adult. Innovative combination strategies may further improve the outcomes of these patients. PMID- 29423572 TI - Integrating predictive frameworks and cognitive models of face perception. AB - The idea of a "predictive brain"-that is, the interpretation of internal and external information based on prior expectations-has been elaborated intensely over the past decade. Several domains in cognitive neuroscience have embraced this idea, including studies in perception, motor control, language, and affective, social, and clinical neuroscience. Despite the various studies that have used face stimuli to address questions related to predictive processing, there has been surprisingly little connection between this work and established cognitive models of face recognition. Here we suggest that the predictive framework can serve as an important complement of established cognitive face models. Conversely, the link to cognitive face models has the potential to shed light on issues that remain open in predictive frameworks. PMID- 29423573 TI - Can automaticity be verified utilizing a perceptual load manipulation? AB - A variety of studies tried to examine the fundamental question of whether specific processing is "automatic," that is, occurs without attention, by manipulating attention toward stimuli via the set-size manipulation of perceptual load. The present paper invites re-extermination of this common methodology of altering the perceptual load of a relevant task to manipulate attention toward peripheral stimuli. Four main arguments that propose alternative interpretations to the notion of automaticity in this line of studies are discussed, suggesting that automaticity cannot be verified utilizing manipulation of load, and outlining a plan for moving forward. PMID- 29423574 TI - Investigation of drought-vulnerable regions in North Korea using remote sensing and cloud computing climate data. AB - Drought is one of the most severe natural disasters in the world and leads to serious challenges that affect both the natural environment and human societies. North Korea (NK) has frequently suffered from severe and prolonged droughts since the second half of the twentieth century. These droughts affect the growing conditions of agricultural crops, which have led to food shortages in NK. However, it is not easy to obtain ground data because NK is one of the most closed-off societies in the world. In this situation, remote sensing (RS) techniques and cloud computing climate data (CCCD) can be used for drought monitoring in NK. RS-derived drought indices and CCCD were used to determine the drought-vulnerable regions in the spring season in NK. After the results were compared and discussed, the following conclusions were derived: (1) 10.0% of the total area of NK is estimated to be a drought-vulnerable region. The most susceptible regions to drought appear in the eastern and western coastal regions, far from BaekDu-DaeGan (BDDG), while fewer drought regions are found near BDDG and the Nahngrim Mountains. The drought-vulnerable regions are the coastal regions of South Hamgyong Province, North Hamgyong Province, South Pyongan Province, and South Hwanghae Province. The latter region is the food basket of NK. (2) In terms of land cover, the drought-vulnerable regions mainly consisted of croplands and mixed forest. PMID- 29423575 TI - Normalized STEAM-based diffusion tensor imaging provides a robust assessment of muscle tears in football players: preliminary results of a new approach to evaluate muscle injuries. AB - OBJECTIVES: To assess acute muscle tears in professional football players by diffusion tensor imaging (DTI) and evaluate the impact of normalization of data. METHODS: Eight football players with acute lower limb muscle tears were examined. DTI metrics of the injured muscle and corresponding healthy contralateral muscle and of ROIs drawn in muscle tears (ROItear) in the corresponding healthy contralateral muscle (ROIhc_t) in a healthy area ipsilateral to the injury (ROIhi) and in a corresponding contralateral area (ROIhc_i) were compared. The same comparison was performed for ratios of the injured (ROItear/ROIhi) and contralateral sides (ROIhc_t/ROIhc_i). ANOVA, Bonferroni-corrected post-hoc and Student's t-tests were used. RESULTS: Analyses of the entire muscle did not show any differences (p>0.05 each) except for axial diffusivity (AD; p=0.048). ROItear showed higher mean diffusivity (MD) and AD than ROIhc_t (p<0.05). Fractional anisotropy (FA) was lower in ROItear than in ROIhi and ROIhc_t (p<0.05). Radial diffusivity (RD) was higher in ROItear than in any other ROI (p<0.05). Ratios revealed higher MD and RD and lower FA and reduced number and length of fibre tracts on the injured side (p<0.05 each). CONCLUSIONS: DTI allowed a robust assessment of muscle tears in athletes especially after normalization to healthy muscle tissue. KEY POINTS: * STEAM-based DTI allows the investigation of muscle tears affecting professional football players. * Fractional anisotropy and mean diffusivity differ between injured and healthy muscle areas. * Only normalized data show differences of fibre tracking metrics in muscle tears. * The normalization of DTI-metrics enables a more robust characterization of muscle tears. PMID- 29423576 TI - Subclinical changes in MRI-determined right ventricular volumes and function in subjects with prediabetes and diabetes. AB - OBJECTIVES: The aim of this study was to assess subclinical changes in right ventricular volumes and function in subjects with prediabetes and diabetes and controls without a history of cardiovascular disease. METHODS: Data from 400 participants in the KORA FF4 study without self-reported cardiovascular disease who underwent 3-T whole-body MRI were obtained. The right ventricle was evaluated using the short axis and a four-chamber view. Diabetes was defined according to WHO criteria. Associations between glucose tolerance and right ventricular parameters were assessed using multivariable adjusted linear regression models. RESULTS: Data from 337 participants were available for analysis. Of these, 43 (13%) had diabetes, 87 (26%) had prediabetes, and 207 (61%) were normoglycaemic controls. There was a stepwise decrease in right ventricular volumes in men with prediabetes and diabetes in comparison with controls, including right ventricular end-diastolic volume (beta = -20.4 and beta = -25.6, respectively; p <= 0.005), right ventricular end-systolic volume (beta = -12.3 and beta = -12.7, respectively; p <= 0.037) and right ventricular stroke volume (beta = -8.1 and beta = -13.1, respectively, p <= 0.016). We did not observe any association between prediabetes or diabetes and right ventricular volumes in women or between prediabetes or diabetes and right ventricular ejection fraction in men and women. CONCLUSIONS: This study points towards early subclinical changes in right ventricular volumes in men with diabetes and prediabetes. KEY POINTS: * MRI was used to detect subclinical changes in right ventricular parameters. * Diabetes mellitus is associated with right ventricular dysfunction. * Impairment of right ventricular volumes seems to occur predominantly in men. PMID- 29423577 TI - EndoRectal ProctoPexy (ERPP) for recurrent semi-circumferential rectal polyp. PMID- 29423578 TI - Effective use of ustekinumab for prepouch ileitis without improvement of concomitant pouchitis. PMID- 29423579 TI - Ultrasound-guided bilateral rectus sheath block reduces early postoperative pain after laparoscopic gynecologic surgery: a randomized study. AB - PURPOSE: Rectus sheath block (RSB) is an anterior abdominal wall block that reduces postoperative pain associated with midline incisions. This study aims to investigate the effect of ultrasound-guided bilateral RSB (US-BRSB) on postoperative pain and analgesic consumption in patients undergoing laparoscopic gynecologic surgery. METHODS: Sixty patients who underwent laparoscopic gynecologic surgery were allocated to RSB (n = 30) or control (n = 30) group. A bilateral US-BRSB procedure (30 ml of 0.25% ropivacaine) was performed after induction of general anesthesia in the RSB group. The control group proceeded the surgery without sham block. All patients received fentanyl-based intravenous patient-controlled analgesia and rescue analgesics upon demand. Pain was scored by a blinded observer using a verbal numerical rating scale (VNRS) at rest while coughing at 0, 1, 6, 12, 24, and 48 h after postanesthesia care unit (PACU) admission. The primary outcome was the total number of rescue analgesics used in the 48-h postoperative period. RESULTS: At 0 h, VNRS were lower in the RSB group than in the control, both at rest (median VNRS 4.5 vs. 5, p = 0.02) and while coughing (median VNRS 6 vs. 7, p = 0.004). At 6 h, VNRS scores were lower in the RSB group than in the control while coughing (median VNRS 3 vs. 5, p = 0.01). Fentanyl use as rescue analgesics in the PACU was significantly lower in the RSB group than in the control (27.7 +/- 32.1 vs. 53.3 +/- 33.7 ug, respectively; p = 0.004). At 48 h postoperatively, the total number of rescue analgesics administered were significantly fewer in the RSB group than in the control (2.5 +/- 2.5 vs. 3.9 +/- 2.6, respectively; p = 0.04). CONCLUSION: US-BRSB reduces the immediate postoperative pain and opioid consumption during the early postoperative period. CLINICALTRIALS. GOV IDENTIFIER: NCT02476799, https://clinicaltrials.gov/ct2/show/NCT02476799 . PMID- 29423582 TI - A retrospective review of 48 individuals, including 12 families, molecularly diagnosed with hereditary leiomyomatosis and renal cell cancer (HLRCC). AB - Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by autosomal dominant germline mutations in the fumarate hydratase (FH) gene and is characterized by cutaneous leiomyomas, uterine leiomyomas and aggressive renal malignancies. We conducted a retrospective chart review to characterize the patients referred to our Regional Genetics Program for assessment of HLRCC from 2004 to mid-2016. Forty-eight of 69 (69.5%) referred individuals were positive for a pathogenic or likely pathogenic variant in FH; they had an average age of 39.1 years. There were 11 different FH variants among them. As expected, the most sensitive indications for a positive genetic test were papillary renal cell carcinoma (RCC) at a young age (5/5; 100%) and multiple cutaneous leiomyomas (18/19; 95%). However, only twenty-two of 48 (46%) individuals with a positive molecular test had cutaneous leiomyomas, which is considerably lower than previously reported and supports the likelihood of ascertainment bias in previous reports. Notably, we have experience with 1 large family in which there were no cutaneous leiomyomas across a large age range. We confirm that multiple cutaneous leiomyomas and papillary RCCs at a young age have a high positive predictive value for a molecular diagnosis of HLRCC, but that cutaneous leiomyomas are less prevalent in HLRCC than previously understood, and therefore the condition is likely to be under-ascertained. Our understanding of the phenotypic spectrum of HLRCC is still evolving. PMID- 29423580 TI - Regression of albuminuria and its association with incident cardiovascular outcomes and mortality in type 1 diabetes: the FinnDiane Study. AB - AIMS/HYPOTHESIS: Our aim was to assess regression of albuminuria and its clinical consequences in type 1 diabetes. METHODS: The analysis included 3642 participants from the Finnish Diabetic Nephropathy (FinnDiane) Study with a 24 h urine sample and a history of albuminuria available at baseline. A total of 2729 individuals had normal AER, 438 a history of microalbuminuria and 475 a history of macroalbuminuria. Regression was defined as a change from a higher category of albuminuria pre-baseline to a lower category in two out of the three most recent urine samples at baseline. The impact of regression on cardiovascular events (myocardial infarction, stroke, coronary procedure) and mortality was analysed over a follow-up of 14.0 years (interquartile range 11.9-15.9). RESULTS: In total, 102 (23.3%) individuals with prior microalbuminuria and 111 (23.4%) with prior macroalbuminuria had regressed at baseline. For individuals with normal AER as a reference, the age-adjusted HRs (95% CI) for cardiovascular events were 1.42 (0.75, 2.68) in individuals with regression from microalbuminuria, 2.62 (1.95, 3.54) in individuals with sustained microalbuminuria, 3.15 (2.02, 4.92) in individuals with regression from macroalbuminuria and 5.49 (4.31, 7.00) in individuals with sustained macroalbuminuria. Furthermore, for all-cause and cardiovascular mortality rates, HRs in regressed individuals were comparable with those with sustained renal status at the achieved level (i.e. those who did not regress but remained at the most advanced level of albuminuria noted pre baseline). CONCLUSIONS/INTERPRETATION: Progression of diabetic nephropathy confers an increased risk for cardiovascular disease and premature death. Notably, regression reduces the risk to the same level as for those who did not progress. PMID- 29423581 TI - Hypoglycaemia in type 1 diabetes: technological treatments, their limitations and the place of psychology. AB - Advances in technology allowing improved insulin delivery and glucose monitoring can significantly reduce the burden of hypoglycaemia when used appropriately. However, limitations of the current technology, and the skills, commitment and motivation required to use them, mean that it does not work for all people. Education and informed professional support are key to success. In the context of problematic hypoglycaemia, data suggest that newer technology has lower efficacy and uptake in those with most need. Identifying the causes of hypoglycaemia and understanding some of the underlying behavioural drivers may prove useful and psycho-educational strategies may be effective in selected individuals. Ultimately, as in many spheres of medicine, successful management of problematic hypoglycaemia depends upon matching the right treatment to the right individual. PMID- 29423583 TI - Beliefs About Child TV Viewing in Low-Income Mexican American Parents of Preschoolers: Development of the Beliefs About Child TV Viewing Scale (B-TV). AB - Objectives Parental beliefs about child television viewing may affect the way parents regulate child television viewing. Despite this, little research has focused on the development of measures of parental beliefs about child television viewing, particularly among ethnic minority parents and parents of young children. This study's objective was to develop and test a culturally-based measure of parental beliefs about television viewing in low-income Mexican American mothers of preschoolers. Methods Using a cross-sectional study design, 22 items reflecting parental beliefs about influences of TV on children were developed and assessed for psychometric properties in a sample of 312 low-income Mexican American mothers of preschoolers. Results Using exploratory factor analysis, we identified four factors reflecting four domains of parental beliefs: positive general beliefs, positive sleep-related beliefs, positive functional beliefs, and negative general beliefs. Internal reliabilities were acceptable (Cronbach's alpha = 0.70-0.89) for all factors except negative general beliefs (Cronbach's alpha = 0.61). Positive sleep-related beliefs and Positive Functional Beliefs were correlated with children's average daily hours of TV (r = 0.16, p < .01; r = 0.22, p < .001, respectively) and with mother's average daily hours of TV (r = 0.14, p < .05; r = 0.22, p < .001, respectively), providing initial support for construct validity. Conclusions for Practice The Beliefs about Child TV viewing scale measures four domains of parental beliefs regarding child TV viewing, and has good initial reliability and validity for three factors. Future use will allow investigators to conduct more in-depth evaluations on the influence of parental beliefs on the way parents shape their child's use of the TV. PMID- 29423584 TI - Interpregnancy Interval and Risk of Adverse Pregnancy Outcomes: A Register-Based Study of 328,577 Pregnancies in Denmark 1994-2010. AB - Objectives To investigate the associations of interpregnancy interval (IPI) with miscarriage, stillbirth, preterm delivery and small for gestational age delivery. Methods The study population comprised all women who had a live birth and at least one subsequent pregnancy in Denmark during the period from 1994 to 2010 (N = 328,577). Linear regression was used to estimate risk differences for miscarriage, stillbirth, preterm delivery and small for gestational age delivery according to IPI. Results The results were heterogeneous: the risk of miscarriage increased monotonically with the length of the IPI. Compared to women with IPIs of 18-23 months, women with IPIs of 0-5 months experienced 18.7 (13.1-24.2) fewer miscarriages per 1000 pregnancies, while women with IPIs of >= 60 months experienced 28.7 (23.4-34.0) more miscarriages per 1000 pregnancies. We found that women with IPIs of >= 60 months had 1.7 (0.4-3.0) more stillbirths per 1000 births compared to women with IPIs of 18-23 months. U-shaped associations were seen for preterm delivery and small for gestational age delivery with women with IPIs of 18-23 months experiencing the lowest risks of these outcomes. Conclusions for Practice The heterogeneity in associations between IPI and adverse pregnancy outcomes suggests that different mechanisms of action may be at play at various times in the antepartum period. While the finding for miscarriage suggests that fecundity is an important determinant for IPI, the findings for preterm delivery and small for gestational age delivery suggest the coexistence of the maternal depletion syndrome mechanism and the physiological regression mechanism and the finding for stillbirth speaks against a strict maternal depletion syndrome explanation. PMID- 29423585 TI - Dental Service Utilization Among Children in the Child Welfare System. AB - OBJECTIVE: To examine predisposing, enabling, and need-related factors associated with dental utilization by children involved with the child welfare system (CWS). METHODS: Data were analyzed from the National Survey of Child and Adolescent Well Being (NSCAW; Wave II), a national probability sample of children (2-17 years) following a welfare assessment during 2008-2009 (n = 2806). Caregiver-reported child receipt of dental services in the past year was the outcome in weighted logistic regression models. RESULTS: Two-thirds of children had a recent dental visit. Older children (OR 2.95, 95% CI 2.06,4.21 for ages 6-11; OR 2.47, CI 1.82, 3.37 for ages 12-17, compared to ages 2-5) were more likely to have visited the dentist, as were children of more educated caregivers (OR 1.68; CI 1.20, 2.36 for high school, OR 2.45; CI 1.71, 3.52 for more than high school). Children without a usual source of care (OR 0.50; CI 0.27, 0.94) and those living with non biological parents had lower odds of a recent visit (OR 0.64; CI 0.43, 0.97). Children with dental problems were twice as likely to have a recent visit (OR 2.02; CI 1.21, 3.38), while children with unmet needs who could not afford care had lower odds of utilizing services (OR 0.28; CI 0.16, 0.46). CONCLUSIONS FOR PRACTICE: Many children in the CWS, especially younger children (ages 2-5), did not have a reported dental visit in the past year. Cost was a barrier, and caregiver status was associated with the likelihood of obtaining dental care. Health and social service providers should refer these children for dental care. PMID- 29423586 TI - Relationship Between Postpartum Depression and Psychological and Biological Variables in the Initial Postpartum Period. AB - Objectives The aims of this study were to evaluate the predictive relationship between psychological symptomatology 24 h postpartum and depression 4 months postpartum, and analyze the relationship between estradiol and postpartum mood. Methods Two hundred women participated in an assessment 24 h postpartum and gave a blood sample for estradiol analysis. One hundred eleven of these women completed the second assessment 4 months postpartum. The Beck Depression Inventory II and the Scale of State-Trait Anxiety were used to assess psychological symptoms. Results At 24 h postpartum, symptoms of depression, trait anxiety, and state anxiety were all significantly correlated with each other. Depression at 24 h postpartum was the only significant independent predictor of depression at 4 months postpartum, explaining 28.7% of the variance. No statistically significant relationship was found between levels of estradiol and mood. Symptoms of depression immediately postpartum thus appear to be a predictor of postpartum depression. Conclusions for Practice These results suggest that early postpartum psychological evaluation of the mother, and intervention as warranted, might prevent or lessen postpartum depression. PMID- 29423587 TI - A Qualitative Assessment of Community Attitudes and Barriers to Family Planning Use in the Trifinio Region of Southwest Guatemala. AB - Introduction Our aim was to identify beliefs about and specific barriers to use of birth spacing methods that married and cohabitating women in the Trifinio Sur Oeste region of Guatemala report in order to design future family planning educational programs. Methods We conducted key informant interviews with community health workers and focus groups with married or cohabitating women. We used inductive and deductive coding to identify common themes. Using these themes, we created explanatory models for decision-making context and identified barriers to family planning use, community educational needs, and potential interventions. Results Thirty-seven women, aged 20-47 years, with an average of 3.5 children and a 2nd grade education level, were included in focus groups. Women had accurate knowledge about benefits of birth spacing however had poor knowledge of family planning methods. Most common barriers included lack of spousal approval, difficulty accessing contraceptive methods, lack of knowledge, and fear of adverse effects. Women were interested in increased education for men, adolescents, and themselves. Discussion Targeted education for women, men, and adolescents is needed to improve family planning uptake in the Trifinio region. Programming should focus on increasing knowledge and acceptability of birth spacing methods and increasing constructive dialogue among couples. PMID- 29423588 TI - Maternal and Child Health Among Female Firefighters in the U.S. AB - Objectives Despite increasing attention to the occupational impact of firefighting, little is known specific to the health of women firefighters. In particular, quantitative data is lacking on the impact firefighting has on maternal and child health for women who become pregnant while working as firefighters. Methods A total of 1821 women firefighters responded to requests to complete a self-report survey of questions about pregnancy. Women answered questions about their departments' policies and practices and their own experiences of pregnancy. Those participants who reported a pregnancy while serving as a firefighter were asked detailed questions about their pregnancy and outcomes. Results Female firefighters reported that nearly a quarter of their first pregnancies while in the fire service ended in miscarriage and that increased to a third of pregnancies by the fourth. Rates of pre-term delivery also were high among this population. Conclusions Findings have important implications for policy and practice among women who become pregnant while actively serving in the fire service. PMID- 29423591 TI - Inhibitory effect of bofutsushosan (fang feng tong sheng san) on glucose transporter 5 function in vitro. AB - Bofutsushosan (BTS; fang feng tong sheng san in Chinese) is a formula in traditional Japanese Kampo medicine and Chinese medicine comprising eighteen crude drugs, and is used to treat obesity and metabolic syndrome. Fructose is contained in refreshing beverages as high-fructose corn syrup, and is associated with obesity. Fructose is absorbed via glucose transporter 5 (GLUT5) in the intestine. Therefore, the inhibition of GLUT5 is considered to be a target of obesity drugs. We evaluated the inhibitory effects of BTS extract and its constituents on fructose uptake using Chinese hamster ovary K1 cells, i.e., cells stably expressing GLUT5. Boiled water extract of BTS significantly suppressed GLUT5 function in a concentration-dependent manner without cytotoxicities. Among 18 components of BTS, the boiled water extracts of the rhizome of Zingiber officinale, the root and rhizome of Saposhnikovia divaricata, and the root of Platycodon grandiflorum exhibited significant inhibitory effects on fructose uptake with IC50 values of 314, 119 and 475 ug/ml, respectively. Among the constituents of the rhizome of Z. officinale extract, 6-gingerol significantly inhibited GLUT5 with an IC50 value of 39 uM, while 6-shogaol exhibited a significant but weak inhibition on GLUT5 at 100 uM. One of the mechanisms of action of BTS may be the inhibition of fructose absorption in the intestine, and one of the active components of BTS is the rhizome of Z. officinale and 6 gingerol. PMID- 29423589 TI - Thalidomide potentiates etoposide-induced apoptosis in murine neuroblastoma through suppression of NF-kappaB activation. AB - PURPOSE: Treatment for high-risk neuroblastoma is still challenging. The purpose of the present study was to determine whether thalidomide suppresses etoposide induced NF-kappaB activation and thus potentiates apoptosis in murine neuroblastoma. METHODS: A murine neuroblastoma cell line, C1300, and A/J mice were used in this study. We evaluated NF-kappaB activation after using etoposide with or without thalidomide by quantitative analysis of NF-kappaB by ELISA and by Western blot analysis of IkappaB phosphorylation in vitro and in vivo. Induction of apoptosis was evaluated by Western blot analysis of the apoptotic signals caspase-3, 8, and 9 in vitro and by TUNEL assays in vivo. We also evaluated the efficacy of the combination of etoposide and thalidomide by assessing tumor growth and mouse survival in vivo. RESULTS: Etoposide activated NF-kappaB in C1300 cells. This activation was suppressed by thalidomide and IkappaB was re upregulated. The apoptotic signals were enhanced by the combination of thalidomide and etoposide compared with etoposide alone in vitro, which was consistent with TUNEL assays. The combination of etoposide and thalidomide also slowed tumor growth and mouse survival. CONCLUSION: Thalidomide potentiates etoposide-induced apoptosis in murine neuroblastoma by suppressing NF-kappaB. PMID- 29423590 TI - Rigenolides D-H, norsecoiridoid and secoiridoids from Gentiana rigescens Franch. AB - Five new compounds, rigenolides D-H (1-5), were isolated from the aerial parts of Gentiana rigescens Franch. Their structures were assigned by detailed spectroscopic analyses and chemical conversions. Rigenolides D (1) and E (2) were elucidated to be a secoiridoid and a norsecoiridoid, respectively, possessing a dienone moiety in common. Rigenolides F-H (3-5) were assigned as acylated secoiridoid glucosides. PMID- 29423592 TI - The functional link between tail-pinch-induced food intake and emotionality and its possible role in stress coping in rats. AB - Tail pinch facilitates eating in rats. We investigated an unidentified link between tail-pinch-induced eating behavior and individual emotionality in male Sprague-Dawley rats. Anxiety-like behavior was assessed on the elevated plus maze (EPM) and in the open field test (OFT). Tail-pinch-induced eating was observed as follows: After a 30-min habituation period, the tail pinch was applied for 5 min, followed by a 30-min recovery period. During the habituation and recovery periods, rats were allowed to access food ad libitum. During the recovery period, 14 of 24 rats ate more food than during the habituation period. Thus, we named them "high responders" and the others as "low responders". The food intake was significantly greater, while the times spent in the open arms in the EPM and in the center area in the OFT were significantly shorter in high responders than in low responders. This result suggests that the rats consuming more food after mild stress have higher anxiety. PMID- 29423594 TI - Treatment of EGFR T790M-Positive Non-Small Cell Lung Cancer. AB - The treatment of lung cancer has changed dramatically with the development of tyrosine kinase inhibitors (TKIs) that target sensitizing somatic mutations of the epidermal growth factor receptor (EGFR). Despite remarkable initial responses, patients eventually develop progressive disease, with the most common cause of resistance to first-line EGFR TKIs being the acquired T790M mutation. Various third-generation EGFR TKIs have been developed to specifically target this acquired mutation, of which osimertinib is currently the only approved agent. In addition, the eagerly anticipated data from the FLAURA study recently found improved efficacy with increased progression-free survival (PFS) with osimertinib compared to standard of care first-generation EGFR TKIs in the first line setting. Of note, osimertinib has also demonstrated promising efficacy in patients with known brain metastases. However, as patients invariably develop resistance during treatment with osimertinib, most commonly with the development of triple mutated EGFR (sensitizing mutations/T790M/C797S), which is resistant to all existing EGFR TKIs, efforts are currently ongoing to develop new strategies or novel compounds to specifically target this resistance mechanism. PMID- 29423593 TI - Tumor Hypoxia As an Enhancer of Inflammation-Mediated Metastasis: Emerging Therapeutic Strategies. AB - Metastasis is the leading cause of cancer-related deaths. Recent research has implicated tumor inflammation as a promoter of metastasis. Myeloid, lymphoid, and mesenchymal cells in the tumor microenvironment promote inflammatory signaling amongst each other and together with cancer cells to modulate sustained inflammation, which may enhance cancer invasiveness. Tumor hypoxia, a state of reduced available oxygen present in the majority of solid tumors, acts as a prognostic factor for a worse outcome and is known to have a role in tumor inflammation through the regulation of inflammatory mediator signals in both cancer and neighboring cells in the microenvironment. Multiple methods to target tumor hypoxia have been developed and tested in clinical trials, and still more are emerging as the impacts of hypoxia become better understood. These strategies include mechanistic inhibition of the hypoxia inducible factor signaling pathway and hypoxia activated pro-drugs, leading to both anti-tumor and anti-inflammatory effects. This prompts a need for further research on the prevention of hypoxia mediated inflammation in cancer. Hypoxia-targeting strategies seem to have the most potential for therapeutic benefit when combined with traditional chemotherapy agents. This paper will serve to summarize the role of the inflammatory response in metastasis, to discuss how hypoxia can enable or enhance inflammatory signaling, and to review established and emerging strategies to target the hypoxia-inflammation-metastasis axis. PMID- 29423596 TI - Characterization of the NISTmAb Reference Material using small-angle scattering and molecular simulation : Part II: Concentrated protein solutions. AB - Protein-protein interactions in monoclonal antibody solutions are important for the stability of a therapeutic drug and directly influence viscosity in concentrated protein solutions. This study describes the use of small-angle scattering to estimate protein-protein interactions at high concentrations of the IgG1 NISTmAb reference material and validate colloidal models for interacting molecules. In particular, we studied the colloidal stability of the NISTmAb at high protein concentrations and analyzed protein-protein interactions upon adding sodium chloride and its effect on viscosity. Isotropic colloidal models for interacting molecules were combined with an ensemble of atomistic structures from molecular simulation to account for the flexibility of the NISTmAb in solution. In histidine formulation buffer, net repulsive electrostatic interactions are important for the colloidal stability of the NISTmAb at high concentrations. Addition of sodium chloride increased the viscosity of the NISTmAb and decreased the colloidal stability due to charge screening of the repulsive interactions. The interactions at high concentrations (up to ~ 250 mg/mL) were consistent with those from light scattering at low concentrations (below ~ 20 mg/mL). However, in the presence of sodium chloride, the screening of charges was less pronounced with increasing protein concentration and the interactions approached those of the repulsive hard-sphere models. Additionally, we studied the NISTmAb under frozen conditions using in situ neutron scattering to analyze the crowded state as proteins are excluded from the water-rich phase. In the frozen samples, where protein concentration can reach hundreds of mg/mL in the protein-rich phase, sodium chloride did not affect the molecular spacing and crowding of the NISTmAb. Graphical Abstract Net repulsive interactions in concentrated NISTmAb solutions assessed by small-angle neutronscattering. PMID- 29423597 TI - ABC presents bioanalysis and environmental analysis. PMID- 29423595 TI - Alpha-Emitters and Targeted Alpha Therapy in Oncology: from Basic Science to Clinical Investigations. AB - Alpha-emitters are radionuclides that decay through the emission of high linear energy transfer alpha-particles and possess favorable pharmacologic profiles for cancer treatment. When coupled with monoclonal antibodies, peptides, small molecules, or nanoparticles, the excellent cytotoxic capability of alpha-particle emissions has generated a strong interest in exploring targeted alpha-therapy in the pre-clinical setting and more recently in clinical trials in oncology. Multiple obstacles have been overcome by researchers and clinicians to accelerate the development of targeted alpha-therapies, especially with the recent improvement in isotope production and purification, but also with the development of innovative strategies for optimized targeting. Numerous studies have demonstrated the in vitro and in vivo efficacy of the targeted alpha-therapy. Radium-223 (223Ra) dichloride (Xofigo(r)) is the first alpha-emitter to have received FDA approval for the treatment of prostate cancer with metastatic bone lesions. There is a significant increase in the number of clinical trials in oncology using several radionuclides such as Actinium-225 (225Ac), Bismuth-213 (213Bi), Lead-212 (212Pb), Astatine (211At) or Radium-223 (223Ra) assessing their safety and preliminary activity. This review will cover their therapeutic application as well as summarize the investigations that provide the foundation for further clinical development. PMID- 29423598 TI - Qualification of NISTmAb charge heterogeneity control assays. AB - The NISTmAb is a monoclonal antibody Reference Material from the National Institute of Standards and Technology; it is a class-representative IgG1kappa intended serve as a pre-competitive platform for harmonization and technology development in the biopharmaceutical industry. The publication series of which this paper is a part describes NIST's overall control strategy to ensure NISTmAb quality and availability over its lifecycle. In this paper, the development and qualification of methods for monitoring NISTmAb charge heterogeneity are described. Capillary zone electrophoresis (CZE) and capillary isoelectric focusing (CIEF) assays were optimized and evaluated as candidate assays for NISTmAb quality control. CIEF was found to be suitable as a structural characterization assay yielding information on the apparent pI of the NISTmAb. CZE was found to be better suited for routine monitoring of NISTmAb charge heterogeneity and was qualified for this purpose. This paper is intended to provide relevant details of NIST's charge heterogeneity control strategy to facilitate implementation of the NISTmAb as a test molecule in the end user's laboratory. Graphical Abstract Representative capillary zone electropherogram of the NIST monoclonal antibody (NISTmAb). The NISTmAb is a publicly available research tool intended to facilitate advancement of biopharmaceutical analytics. PMID- 29423599 TI - Establishment of pressurized-liquid extraction by response surface methodology approach coupled to HPLC-DAD-TOF-MS for the determination of phenolic compounds of myrtle leaves. AB - Myrtus communis L. (myrtle) is native to the Mediterranean region and Western Asia. Its leaves have demonstrated its potential effect towards different bioactivities like anti-diabetic, anti-diarrheic, anti-ulcer, anti-cancer, among others. These activities have been associated with its phenolic content. In this sense, the aim of this work has been to develop a new pressurized-liquid extraction procedure (PLE), by using a response surface methodology (RSM), to evaluate the phenolic composition from myrtle leaves by HPLC-DAD-TOF-MS. Previously, different solvents such as methanol, ethanol, and acetone/water mixtures were tested by using ultrasound-assisted extraction (UAE) in order to select the most suitable one. Subsequently, a Box-Behnken design (BBD) was performed according to the effect of ethanol/water ratio (50, 75, and 100% (v/v)), temperature (50, 125, and 200 degrees C), and extraction time (5, 18, and 30 min). The optimal conditions achieved with the established method were 71% ethanol/water, 137 degrees C, and 19 min. The analysis of the obtained extracts by HPLC-DAD-TOF-MS allowed the characterization of 15 new compounds in myrtle leaves. Finally, high amounts of gallic and ellagic acid were found in the optimized PLE extracts (3.31 +/- 0.03 and 3.88 +/- 0.09 mg/g leaf dry weight (d.w.), respectively), and PLE reported greater recovery of total phenolic compounds than UAE (30 +/- 1 and 22.4 +/- 0.6 mg/g leaf d.w., respectively). PMID- 29423600 TI - Characterization of the NISTmAb Reference Material using small-angle scattering and molecular simulation : Part I: Dilute protein solutions. AB - Both conformational and colloidal stability of therapeutic proteins must be closely monitored and thoroughly characterized to assess the long-term viability of drug products. We characterized the IgG1 NISTmAb reference material in its histidine formulation buffer and report our findings on the higher order structure and interactions of NISTmAb under a range of conditions. In this paper we present the analysis of experimental small-angle scattering data with atomistic molecular simulations to characterize the monodisperse dilute solution of NISTmAb. In part II we describe the characterization of the NISTmAb at high protein concentration (Castellanos et al. 2018). The NISTmAb was found to be a flexible protein with a radius of gyration of 49.0 +/- 1.2 A in histidine formulation buffer using a variety of neutron and X-ray scattering measurements. Scattering data were then modeled using molecular simulation. After building and validating a starting NISTmAb structure from the Fc and Fab crystallographic coordinates, molecular dynamics and torsion-angle Monte Carlo simulations were performed to explore the configuration space sampled in the NISTmAb and obtain ensembles of structures with atomistic detail that are consistent with the experimental data. Our results indicate that the small-angle scattering profiles of the NISTmAb can be modeled using ensembles of flexible structures that explore a wide configuration space. The NISTmAb is flexible in solution with no single preferred orientation of Fc and Fab domains, but with some regions of configuration space that are more consistent with measured scattering profiles. Analysis of inter-domain atomistic contacts indicated that all ensembles contained configurations where residues between domains are <= 4 A, although few contacts were observed for variable and C H 3 regions. Graphical Abstract Heavy atom self contact maps of the NISTmAb indicate a highly-flexible structure. PMID- 29423601 TI - The 2017 Nobel Prize in Chemistry: cryo-EM comes of age. AB - The 2017 Nobel Prize in Chemistry was awarded to Jacques Dubochet, Joachim Frank, and Richard Henderson for "developing cryo-electron microscopy (cryo-EM) for the high-resolution structure determination of biomolecules in solution." This feature article summarizes some of the major achievements leading to the development of cryo-EM and recent technological breakthroughs that have transformed the method into a mainstream tool for structure determination. PMID- 29423602 TI - Clinical care review systems in healthcare: a systematic review. AB - BACKGROUND: Clinical care review is the process of retrospectively examining potential errors or gaps in medical care, aiming for future practice improvement. The objective of our systematic review is to identify the current state of care review reported in peer-reviewed publications and to identify domains that contribute to successful systems of care review. METHODS: A librarian designed and conducted a comprehensive literature search of eight electronic databases. We evaluated publications from January 1, 2000, through May 31, 2016, and identified common domains for care review. Sixteen domains were identified for further abstraction. RESULTS: We found that there were few publications that described a comprehensive care review system and more focus on individual pathways within the overall systems. There is inconsistent inclusion of the identified domains of care review. CONCLUSION: While guidelines for some aspects of care review exist and have gained traction, there is no comprehensive standardized process for care review with widespread implementation. PMID- 29423603 TI - Sex-Differences in Children Referred for Assessment: An Exploratory Analysis of the Autism Mental Status Exam (AMSE). AB - The autism mental status exam is an eight-item observational assessment that structures the way we observe and document signs and symptoms of ASD. Investigations of test performance indicate strong sensitivity and specificity using gold-standard assessment as reference standard. This study aims to explore potential sex differences in AMSE test performance and observations of 123 children referred for autism assessment. Results indicates more language deficits in females with ASD than in males with ASD and less sensory symptoms in females compared to males with ASD. The AMSE performance is similar in identifying ASD and non-ASD in females compared to males. Less disruptive behaviors in females, might cause a need for a bigger hit to other areas of development to raise concern. PMID- 29423604 TI - Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1). AB - In a non-selected sample of children with Neurofibromatosis type 1 (NF1) the prevalence rate of autism spectrum disorder (ASD) and predictive value of an observational (ADOS)-and questionnaire-based screening instrument were assessed. Complete data was available for 128 children. The prevalence rate for clinical ASD was 10.9%, which is clearly higher than in the general population. This prevalence rate is presumably more accurate than in previous studies that examined children with NF1 with an ASD presumption or solely based on screening instruments. The combined observational- and screening based classifications demonstrated the highest positive predictive value for DSM-IV diagnosis, highlighting the importance of using both instruments in children with NF1. PMID- 29423606 TI - Identification of Symptoms of Autism Spectrum Disorders in the Second Year of Life at Day-Care Centres by Day-Care Staff: Step One in the Development of a Short Observation List. AB - Early symptoms of ASD develop through the second year of life, making a stable ASD diagnosis possible at 24 months of age. However, in general, children with ASD have their diagnosis at an older age. This retrospective study, including 30 children with ASD and 30 control children aged 3-6 years, explored the possibility of developing a short observation list to be used in day care settings for children 12-24 months of age. From 73 symptoms selected from published screeners and observation tools, we were able to construct a list of six symptoms that retrospectively differentiated children with ASD from typically developing children at 12-24 months of age when recalled by day-care personnel. PMID- 29423605 TI - An International Clinical Study of Ability and Disability in Autism Spectrum Disorder Using the WHO-ICF Framework. AB - This is the fourth international preparatory study designed to develop International Classification of Functioning, Disability and Health (ICF, and Children and Youth version, ICF-CY) Core Sets for Autism Spectrum Disorder (ASD). Examine functioning of individuals diagnosed with ASD as documented by the ICF-CY in a variety of clinical settings. A cross-sectional study was conducted, involving 11 units from 10 countries. Clinical investigators assessed functioning of 122 individuals with ASD using the ICF-CY checklist. In total, 139 ICF-CY categories were identified: 64 activities and participation, 40 body functions and 35 environmental factors. The study results reinforce the heterogeneity of ASD, as evidenced by the many functional and contextual domains impacting on ASD from a clinical perspective. PMID- 29423607 TI - Brief Report: Social Functioning Predicts Externalizing Problem Behaviors in Autism Spectrum Disorder. AB - Individuals with ASD often display externalizing behaviors, which have been associated with lower quality of life in adulthood. Social difficulties have been hypothesized to underlie externalizing problems among individuals with ASD (Klin and Volkmar in Asperger Syndrome, 340-366, 2000), but this has never been tested empirically. We examined whether socialization abilities predicted externalizing problems assessed by parent report in a group of 29 individuals with ASD (age range 7-16 years) and 29 TD individuals matched for IQ, age, and gender. Socialization scores accounted for 50% of the variance in externalizing behaviors among individuals with ASD, but not in TD children. These findings have implications for intervention, and suggest that targeting social difficulties might provide a better means to addressing externalizing problems. PMID- 29423608 TI - A Systematic Review of Group Social Skills Interventions, and Meta-analysis of Outcomes, for Children with High Functioning ASD. AB - Group social skills interventions (GSSIs) are a commonly offered treatment for children with high functioning ASD. We critically evaluated GSSI randomised controlled trials for those aged 6-25 years. Our meta-analysis of outcomes emphasised internal validity, thus was restricted to trials that used the parent report social responsiveness scale (SRS) or the social skills rating system (SSRS). Large positive effect sizes were found for the SRS total score, plus the social communication and restricted interests and repetitive behaviours subscales. The SSRS social skills subscale improved with moderate effect size. Moderator analysis of the SRS showed that GSSIs that include parent-groups, and are of greater duration or intensity, obtained larger effect sizes. We recommend future trials distinguish gains in children's social knowledge from social performance. PMID- 29423609 TI - The Prevalence and Psychopathological Correlates of Sibling Bullying in Children with and without Autism Spectrum Disorder. AB - Using data from a prospective population based study, the prevalence and psychopathological correlates of sibling bullying in children with and without autism spectrum disorder (ASD) were estimated. There were 475 children with ASD and 13,702 children without ASD aged 11 years. Children with ASD were more likely to be bullied by their siblings compared to those without ASD. They were also more likely than those without ASD to both bully and be bullied by their siblings, which was associated with lower prosocial skills as well as more internalizing and externalizing problems compared to those not involved in any sibling bullying. Interventions to improve social and emotional outcomes in children with ASD should focus on both the affected and the unaffected sibling. PMID- 29423610 TI - Repurposed drugs for use in Parkinson's disease. PMID- 29423612 TI - Bronislaw Onuf-Onufrowicz (1863-1928). PMID- 29423611 TI - Up-to-date knowledge about the association between multiple sclerosis and the reactivation of human endogenous retrovirus infections. AB - BACKGROUND: Although existing studies show that reactivation of the human endogenous retrovirus (HERVs) plays a leading role in multiple sclerosis (MS) progression, the practitioners are yet to establish effective approaches for managing MS without jeopardizing the patients' immune systems. AIM: To provide up to-date knowledge on the specific roles played by the reactivation of the HERVs in the pathogenesis of MS. MATERIALS AND METHODS: A systematic review of 70 peer reviewed journals accessed via PubMed was conducted. The searches generated more than 600 sources that were evaluated based on three step in and exclusion criteria. The selected sources were critically analyzed vis-a-vis the paper's hypothesis which posits that the HERVs reactivation does not directly cause the MS, but triggers a demyelination process by promoting the pathogenic effects of the retroviruses. The paper further documents the advancements in the therapeutic applications resulting from the immunohistological analysis and pathological studies aimed at minimizing the adverse consequences of the HERVs reactivation. RESULTS AND DISCUSSIONS: Only three out of the 70 reviewed sources did not find provide evidence linking the reactivation of HERV and MS progression. On the other hand, overwhelming pieces of evidence confirm that the reactivations often drive the demyelinating plaques by initiating microglial inflammation. Pathological examinations reveal that the inflammatory monocytes (Ly6ChiCCR2 + CX3CR1lo) trigger the reactivation of the malignant T cells that are responsible for the progression of MS. These findings are promoting new discoveries as far as managing MS is concerned. PMID- 29423613 TI - Anti-Sez6l2 antibody detected in a patient with immune-mediated cerebellar ataxia inhibits complex formation of GluR1 and Sez6l2. PMID- 29423614 TI - MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein. AB - Antibodies against the myelin oligodendrocyte glycoprotein (MOG-Ab) can be detected in various pediatric acquired demyelinating syndromes (ADS). Here, we analyze the spectrum of neuroradiologic findings in children with MOG-Ab and a first demyelinating event. The cerebral and spinal MRI of 69 children with different ADS was assessed in regard to the distribution and characteristics of lesions. Children with acute disseminated encephalomyelitis (n = 36) or neuromyelitis optica spectrum disorder (n = 5) presented an imaging pattern characterized predominantly by poorly demarcated lesions with a wide supra- and infratentorial distribution. Younger children also tended to have poorly defined and widespread lesions. The majority of patients with an isolated optic neuritis (n = 16) only presented small non-specific brain lesions or none at all. A longitudinally extensive transverse myelitis mainly affecting the cervical, and less often so the thoracic, lumbar, and conus regions, was detected in 31 children. The three children of our cohort who were then finally diagnosed with multiple sclerosis had at onset already demarcated white matter lesions as well as transverse myelitis. In conclusion, children with MOG seropositive ADS present disparate, yet characteristic imaging patterns. These patterns have been seen to correlate to the disease entity as well as to age of symptom onset. PMID- 29423615 TI - Defining spasticity: a new approach considering current movement disorders terminology and botulinum toxin therapy. AB - Spasticity is a symptom occurring in many neurological conditions including stroke, multiple sclerosis, hypoxic brain damage, traumatic brain injury, tumours and heredodegenerative diseases. It affects large numbers of patients and may cause major disability. So far, spasticity has merely been described as part of the upper motor neurone syndrome or defined in a narrowed neurophysiological sense. This consensus organised by IAB-Interdisciplinary Working Group Movement Disorders wants to provide a brief and practical new definition of spasticity-for the first time-based on its various forms of muscle hyperactivity as described in the current movement disorders terminology. We propose the following new definition system: Spasticity describes involuntary muscle hyperactivity in the presence of central paresis. The involuntary muscle hyperactivity can consist of various forms of muscle hyperactivity: spasticity sensu strictu describes involuntary muscle hyperactivity triggered by rapid passive joint movements, rigidity involuntary muscle hyperactivity triggered by slow passive joint movements, dystonia spontaneous involuntary muscle hyperactivity and spasms complex involuntary movements usually triggered by sensory or acoustic stimuli. Spasticity can be described by a documentation system grouped along clinical picture (axis 1), aetiology (axis 2), localisation (axis 3) and additional central nervous system deficits (axis 4). Our new definition allows distinction of spasticity components accessible to BT therapy and those inaccessible. The documentation sheet presented provides essential information for planning of BT therapy. PMID- 29423616 TI - Frequency and predictors of post-stroke delirium in PRospective Observational POLIsh Study (PROPOLIS). AB - Delirium is the most common and serious neurobehavioral complication in acute hospital admissions. Some patients develop signs of delirium but do not meet all diagnostic criteria. Stroke is a major risk factor for delirium. The aim of this prospective study was to build a predictive model for delirium and subsyndromal post-stroke delirium. Patients with stroke were screened for delirium during the first 7 days after admission. Delirium was diagnosed according to DSM-V criteria. Baseline demographic, biochemical, stroke-related data, medications used, neurological deficit, and premorbid cognitive and functional impairment were assessed. 750 consecutive stroke patients (71.75 +/- 13.13 years) were recruited; 203 (27.07%) had delirium. In predictive model for delirium MoCA score and white blood count on admission, neglect, vision deficits, physical impairment, and higher comorbidity prior to stroke had the highest predictive value. Subsyndromal delirium was diagnosed in 60 patients. MoCA score and potassium level on admission, and urinary tract infection during hospitalization had the highest predictive value for its development. Delirium occurs in one-fourth of admissions due to stroke; subsyndromal delirium is less prevalent and affects less than one per ten patients. The hyperactive form is the most rare type of delirium. The factors best predicting delirium are easily assessed in everyday practice and their co-occurrence in patients with stroke should alert the treating physician of high risk of delirium. PMID- 29423618 TI - Organotypic Models of Lung Cancer. AB - Human lung cancer is one of the leading causes of death worldwide, with nearly 2 million of new cases diagnosed each year, often too late for a successful therapeutic intervention. In this chapter, organotypic models of lung cancer will be reviewed. Ex vivo tissue explants, spheroids, organoids, and novel bioengineering approaches are currently being used to study human lung cancer. Although there is no ideal method that will fully recapitulate the complex human lung architecture, the three-dimensional (3D) organotypic models described here represent a major advance from classical two-dimensional (2D) tissue culture models. Organotypic tissue cultures are better at predicting in vivo tissue responses to anticancer drugs or carcinogenic toxins. In addition, there is also a possibility to use these systems as part of personalized medicine (e.g., to assist clinicians in selecting appropriate therapeutic choices based on individual patient-derived tissue responses to drugs in vitro). There is still a need for improvement in the 3D culture systems, such as automation for high throughput testing and reduction of costs. However, given the large number of failed clinical trials due to safety or efficacy reasons, more attention should be given to these more physiologically relevant 3D organotypic tissue culture models. PMID- 29423617 TI - Human T-cell lymphotropic virus (HTLV)-associated encephalopathy: an under recognised cause of acute encephalitis? Case series and literature review. AB - Human T-cell lymphotropic virus (HTLV)-1-associated myelopathy (HAM) is well described. Clinical features are predominantly consistent with cord pathology, though imaging and autopsy studies also demonstrate brain inflammation. In general, this is subclinical; however, six cases have previously been reported of encephalopathy in HTLV-1-infected patients, without alternative identified aetiology. We describe three further cases of encephalitis in the UK HAM cohort (n = 142), whereas the annual incidence of acute encephalitis in the general population is 0.07-12.6 per 100,000. Clinical features included reduced consciousness, fever/hypothermia, headaches, seizures, and focal neurology. Investigation showed: raised CSF protein; pleocytosis; raised CSF:peripheral blood mononuclear cell HTLV-1 proviral load ratio; and MRI either normal or showing white matter changes in brain and cord. Four of the six previous case reports of encephalopathy in HTLV-infected patients also had HAM. Histopathology, reported in three, showed perivascular predominantly CD8+ lymphocytic infiltrates in the brain. One had cerebral demyelination, and all had cord demyelination. We have reviewed the existing six cases in the literature, together with our three new cases. In all seven with HAM, the spastic paraparesis deteriorated sub acutely preceding encephalitis. Eight of the nine were female, and four of the seven treated with steroids improved. We propose that HTLV-associated encephalopathy may be part of the spectrum of HTLV-1-induced central nervous system disease. PMID- 29423619 TI - Smoking is not associated with higher prevalence of JC virus in MS patients. AB - John Cunningham virus (JCV) causes rare, but potentially life-threatening progressive multifocal leukoencephalopathy (PML) in natalizumab-treated multiple sclerosis (MS) patients. Beside JCV index, there is currently no other factor for further risk stratification. Because smoking was reported as potential risk factor for several viral and bacterial infections, we aimed to investigate whether smoking could increase the risk for JCV infection in MS patients. We screened our database of the MS Clinic of the Department of Neurology, Medical University of Innsbruck, Austria, for patients with known smoking status and test result for anti-JCV antibody index as determined by two-step ELISA at Unilabs, Copenhagen, Denmark. In a representative cohort of 200 MS patients with a rate of 36% current smokers plus 6% former smokers, we were not able to detect any association between smoking and JCV status. Furthermore, there was no association between smoking status and anti-JCV antibody index. Smoking does not seem to be a risk factor for JCV infection in MS patients and, therefore, does not represent a suitable marker for PML-risk stratification under treatment with natalizumab. PMID- 29423620 TI - Important Gaps in HIV Knowledge, Attitudes and Practices Among Young Asylum Seekers in Comparison to the General Population. AB - Migrants are disproportionately affected by HIV in many European countries, including Finland. We aimed to compare the HIV-related knowledge, attitudes and practices (KAP) of young asylum seekers to those of the general young adult population. Two cross-sectional surveys were conducted among 20- to 25-year-old young adults: The TIE study among asylum seekers (n = 47) and the World AIDS Day 2014 study among the general population (n = 485). Important gaps in HIV KAP were identified especially among the young asylum seekers. For the general young adult population, previous HIV testing was associated with female gender, better HIV knowledge and increased sexual activity. Health education concerning HIV needs to be further enforced among young adults in Finland. Due to poorer HIV knowledge, young asylum seekers might be especially vulnerable to HIV. The asylum process is a window of opportunity for health education and HIV testing. PMID- 29423621 TI - Uterine Transplant: A Risk to Life or a Chance for Life? AB - Being inherently different from any other lifesaving organ transplant, uterine transplantation does not aim at saving lives but supporting the possibility to generate life. Unlike the kidneys or the liver, the uterus is not specifically a vital organ. Given the non-lifesaving nature of this procedure, questions have been raised about its feasibility. The ethical dilemma revolves around whether it is worth placing two lives at risk related to surgery and immunosuppression, amongst others, to enable a woman with absolute uterine factor infertility to experience the presence of an organ enabling childbirth. In the year 2000, the first uterine transplantation, albeit unsuccessful, was performed in Saudi Arabia from where it has spread to the rest of the world including Sweden, the United States and now recently India. The procedure is, however, still in the preclinical stages and several ethical, legal, social and religious concerns are yet to be addressed before it can be integrated into the clinical setting as standard of care for women with absolute uterine factor infertility. PMID- 29423622 TI - Capsule Commentary on Landon et al., "Trends in Diabetes Treatment and Monitoring Among Medicare Beneficiaries". PMID- 29423625 TI - Capsule Commentary on Ratcliffe et al., "Service and Education: the Association Between Workload, Patient Complexity, and Teaching on Internal Medicine Inpatient Services". PMID- 29423623 TI - Women's Healthcare Utilization Following Routine Screening for Past-Year Intimate Partner Violence in the Veterans Health Administration. AB - BACKGROUND: Experience of intimate partner violence (IPV) can have adverse health impacts and has been associated with elevated rates of healthcare service utilization. Healthcare encounters present opportunities to identify IPV-related concerns and connect patients with services. The Veterans Health Administration (VHA) conducts IPV screening within an integrated healthcare system. OBJECTIVE: The objectives of this study were to compare service utilization in the 6 months following IPV screening between those screening positive and negative for past year IPV (IPV+, IPV-) and to examine the timing and types of healthcare services accessed among women screening IPV+. DESIGN: A retrospective chart review was conducted for 8888 female VHA patients across 13 VHA facilities who were screened for past-year IPV between April 2014 and April 2016. MAIN MEASURES: Demographic characteristics (age, race, ethnicity, marital status, veteran status), IPV screening response, and healthcare encounters (based on visit identification codes). KEY RESULTS: In the 6 months following routine screening for past-year IPV, patients screening IPV+ were more likely to utilize outpatient care (aOR = 1.85 [CI 1.26, 2.70]), including primary care or psychosocial care, and to have an inpatient stay (aOR = 2.09 [CI 1.23, 3.57]), compared with patients screening IPV-. Among those with any utilization, frequency of outpatient encounters within the 6-month period following screening was higher among those screening IPV+ compared with those screening IPV-. The majority of patients screening positive for past-year IPV returned for an outpatient visit within a brief time frame following the screening visit (> 70% within 14 days, >95% within 6 months). More than one in four patients screening IPV+ had an emergency department visit within the 6 months following screening. CONCLUSIONS: Women who screen positive for past year IPV have high rates of return to outpatient visits following screening, presenting opportunities for follow-up support. Higher rates of emergency department utilization and inpatient stays among women screening IPV+ may indicate adverse health outcomes related to IPV experience. PMID- 29423626 TI - Dangers and Opportunities of Direct-to-Consumer Advertising. PMID- 29423624 TI - Treatment Initiation for New Episodes of Depression in Primary Care Settings. AB - BACKGROUND: Depression is prevalent and costly, but despite effective treatments, is often untreated. Recent efforts to improve depression care have focused on primary care settings. Disparities in treatment initiation for depression have been reported, with fewer minority and older individuals starting treatment. OBJECTIVE: To describe patient characteristics associated with depression treatment initiation and treatment choice (antidepressant medications or psychotherapy) among patients newly diagnosed with depression in primary care settings. DESIGN: A retrospective observational design was used to analyze electronic health record data. PATIENTS: A total of 241,251 adults newly diagnosed with depression in primary care settings among five health care systems from 2010 to 2013. MAIN MEASURES: ICD-9 codes for depression, following a 365-day period with no depression diagnosis or treatment, were used to identify new depression episodes. Treatment initiation was defined as a completed psychotherapy visit or a filled prescription for antidepressant medication within 90 days of diagnosis. Depression severity was measured with Patient Health Questionnaire (PHQ-9) scores on the day of diagnosis. KEY RESULTS: Overall, 35.7% of patients with newly diagnosed depression initiated treatment. The odds of treatment initiation among Asians, non-Hispanic blacks, and Hispanics were at least 30% lower than among non-Hispanic whites, controlling for all other variables. The odds of patients aged >= 60 years starting treatment were half those of patients age 44 years and under. Treatment initiation increased with depression severity, but was only 53% among patients with a PHQ-9 score of >= 10. Among minority patients, psychotherapy was initiated significantly more often than medication. CONCLUSIONS: Screening for depression in primary care is a positive step towards improving detection, treatment, and outcomes for depression. However, study results indicate that treatment initiation remains suboptimal, and disparities persist. A better understanding of patient factors, and particularly system-level factors, that influence treatment initiation is needed to inform efforts by heath care systems to improve depression treatment engagement and to reduce disparities. PMID- 29423627 TI - General Internists in Pursuit of Diagnostic Excellence in Primary Care: a #ProudtobeGIM Thread That Unites Us All. PMID- 29423628 TI - Keys to career success: resources and barriers identified by early career academic hospitalists. PMID- 29423629 TI - Marital Status and Mothers' Time Use: Childcare, Housework, Leisure, and Sleep. AB - Assumptions that single mothers are "time poor" compared with married mothers are ubiquitous. We tested theorized associations derived from the time poverty thesis and the gender perspective using the 2003-2012 American Time Use Surveys (ATUS). We found marital status differentiated housework, leisure, and sleep time, but did not influence the amount of time that mothers provided childcare. Net of the number of employment hours, married mothers did more housework and slept less than never-married and divorced mothers, counter to expectations of the time poverty thesis. Never-married and cohabiting mothers reported more total and more sedentary leisure time than married mothers. We assessed the influence of demographic differences among mothers to account for variation in their time use by marital status. Compositional differences explained more than two-thirds of the variance in sedentary leisure time between married and never-married mothers, but only one-third of the variance between married and cohabiting mothers. The larger unexplained gap in leisure quality between cohabiting and married mothers is consistent with the gender perspective. PMID- 29423630 TI - Yeast-based genotoxicity tests for assessing DNA alterations and DNA stress responses: a 40-year overview. AB - By damaging DNA molecules, genotoxicants cause genetic mutations and also increase human susceptibility to cancers and genetic diseases. Over the past four decades, several assays have been developed in the budding yeast Saccharomyces cerevisiae to screen potential genotoxic substances and provide alternatives to animal-based genotoxicity tests. These yeast-based genotoxicity tests are either DNA alteration-based or DNA stress-response reporter-based. The former, which came first, were developed from the genetic studies conducted on various types of DNA alterations in yeast cells. Despite their limited throughput capabilities, some of these tests have been used as short-term genotoxicity tests in addition to bacteria- or mammalian cell-based tests. In contrast, the latter tests are based on the emergent transcriptional induction of DNA repair-related genes via activation of the DNA damage checkpoint kinase cascade triggered by DNA damage. Some of these reporter assays have been linked to DNA damage-responsive promoters to assess chemical carcinogenicity and ecotoxicity in environmental samples. Yeast-mediated genotoxicity tests are being continuously improved by increasing the permeability of yeast cell walls, by the ectopic expression of mammalian cytochrome P450 systems, by the use of DNA repair-deficient host strains, and by integrating them into high-throughput formats or microfluidic devices. Notably, yeast-based reporter assays linked with the newer toxicogenomic approaches are becoming powerful short-term genotoxicity tests for large numbers of compounds. These tests can also be used to detect polluted environmental samples, and as effective screening tools during anticancer drug development. PMID- 29423631 TI - Identification of the streptothricin and tunicamycin biosynthetic gene clusters by genome mining in Streptomyces sp. strain fd1-xmd. AB - The genus Streptomyces have been highly regarded for their important source of natural products. Combined with the technology of genome sequencing and mining, we could identify the active ingredients from fermentation broth quickly. Here, we report on Streptomyces sp. strain fd1-xmd, which was isolated from a soil sample collected in Shanghai. Interestingly, the fermentation broth derived from this strain demonstrated broad-spectrum antimicrobial activity against gram positive bacteria, gram-negative bacteria, and eukaryotes. To identify the antimicrobial substances and their biosynthetic gene clusters, we sequenced the fd1-xmd strain and obtained a genome 7,929,999 bp in length. The average GC content of the chromosome was 72.5 mol%. Knockout experiments demonstrated that out of eight biosynthetic gene clusters we could identify, two are responsible for the biosynthesis of the antibiotics streptothricin (ST) and tunicamycin (TM). The ST biosynthetic gene cluster from fd1-xmd was verified via successful heterologous expression in Streptomyces coelicolor M1146. ST production had a yield of up to 0.5 g/L after the optimization of culture conditions. This study describes a novel producer of ST and TM and outlines the complete process undertaken for Streptomyces sp. strain fd1-xmd genome mining. PMID- 29423632 TI - Murine model to follow hyphal development in invasive pulmonary aspergillosis. AB - Aspergillus fumigatus is an opportunistic pathogen, the leading cause of invasive and disseminated aspergillosis in systemic immunocompromised patients, and an important cause of mortality. The aim of the present study was to adapt a pulmonary aspergillosis murine model, to determine pathodynamical parameters quantitatively, and to follow the progression of fungal infection in vivo. The nasal inoculation of Aspergillus conidia in mice previously subjected to immunosuppression with cyclophosphamide (CP) turned out to be a more suitable model than that of immunosuppressed with hydrocortisone (HC). The following parameters were found to correlate quantitatively with the progress of the infection: (i) survival rate, (ii) weight loss of mice, (iii) infected focal plaque size, (iv) hyphal density, (v) hyphal length distribution of A. fumigatus, and the (vi) the histopathological status and scores. These parameters will be essential elements for the development of antifungal drugs and therapies, and important for the investigation of the pathogenicity in different strains of A. fumigatus. PMID- 29423633 TI - Nickel oxide (NiO) nanoparticles disturb physiology and induce cell death in the yeast Saccharomyces cerevisiae. AB - The increasing use of nanoparticles (NPs) has spurred concerns about their toxic effects. This work aimed to assess the potential hazards of nickel oxide (NiO) NPs using the yeast Saccharomyces cerevisiae as a cell model. Yeast cells exposed for 6 h to 100 mg/L NiO NPs presented reduced metabolic activity (esterase activity and FUN-1 dye processing) and enhanced accumulation of reactive oxygen species. NiO NPs induced the loss of cell viability in a dose-dependent manner. Study of the dissolution of NiO NPs in aqueous media, together with the toxicological data, suggests that the nickel released by the NPs cannot explain all the toxic effects observed in S. cerevisiae caused by the NPs. Transmission electron microscopy observations revealed that NiO NPs were adsorbed onto cell surface but did not enter into yeast cells. Isogenic mutants (cwp1? and cwp2?) with increased cell wall porosity did not display enhanced susceptibility to NiO NPs compared to the wild type strain. Our results suggest that NiO NPs exert their toxic effect by an indirect mechanism. This work contributes to knowledge of the potential hazards of NiO NPs and to the elucidation of their mechanisms of toxic action. PMID- 29423634 TI - Critical steps in carbon metabolism affecting lipid accumulation and their regulation in oleaginous microorganisms. AB - Oleaginous microorganisms are able to convert numerous agro-industrial and municipal wastes into storage lipids (single cell oil (SCO)) and are therefore considered as potential biofuel producers. While from an environmental and technological point of view the idea to convert waste materials into fuels is very attractive, the production cost of SCO is not currently competitive to that of conventional oils due to the low productivity of oleaginous microorganisms in combination with the high fermentation cost. Current strategies used to optimize the lipid-accumulating capacity of oleaginous microorganisms include the overexpression of genes encoding for key enzymes implicated in fatty acid and triacylglycerol synthesis, such as ATP-dependent citrate lyase, acetyl-CoA carboxylase, malic enzyme, proteins of the fatty acid synthase complex, glycerol 3-phosphate dehydrogenase and various acyltransferases, and/or the inactivation of genes encoding for enzymes implicated in storage lipid catabolism, such as lipases and acyl-CoA oxidases. Furthermore, blocking, even partially, pathways competitive to lipid biosynthesis (e.g., those involved in the accumulation of storage polysaccharide or organic acid and polyol excretion) can also increase lipid-accumulating ability in oleaginous microorganisms. Methodologies, such as adaptive laboratory evolution, can be included in existing workflows for the generation of strains with improved lipid accumulation capacity. In our opinion, efforts should be focused in the construction of strains with high carbon uptake rates and a reprogrammed coordination of the individual parts of the oleaginous machinery that maximizes carbon flux towards lipogenesis. PMID- 29423635 TI - Damage to offshore production facilities by corrosive microbial biofilms. AB - In offshore production facilities, large amounts of deaerated seawater are continuously injected to maintain pressure in oil reservoirs and equivalent volumes of fluids, composed of an oil/gas, and water mixture are produced. This process, brewing billions of liters of biphasic fluids particularly rich in microorganisms, goes through complex steel pipeline networks that are particularly prone to biofilm formation. Consequently, offshore facilities are frequently victims of severe microbiologically influenced corrosion. Understanding of microbiologically influenced corrosion is constantly growing. In the laboratory, the inventory of potentially corrosive microorganisms is increasing and microbial biochemical and bioelectrical processes are now recognized to be involved in corrosion. However, understanding of corrosive multispecies biofilms and the complex metabolic processes associated with corrosion remains a considerable challenge as simple laboratory biofilms comprising pure or defined mixed cultures poorly represent the complexity of in situ biofilms. Complementary, antagonistic, and parallel microbial pathways occur within the complex microbial and inorganic matrix of the biofilms which can lead to high corrosion rates. This mini-review explores models of microbiologically influenced corrosion and places them in the context of the multispecies biofilms observed in situ. Consequences of mitigation strategies on biofilm corrosiveness and dispersal are also discussed. PMID- 29423636 TI - The use of extracellular DNA as a proxy for specific microbial activity. AB - The ubiquity and relevance of extracellular DNA (exDNA) are well-known and increasingly gaining importance in many fields of application such as medicine and environmental microbiology. Although sources and types of exDNA are manifold, ratios of specific DNA-molecules inside and outside of living cells can give reliable information about the activity of entire systems and of specific microbial groups or species. Here, we introduce a method to discriminate between internal (iDNA), as well as bound and free exDNA, and evaluate various DNA fractions and related ratios (ex:iDNA) regarding their applicability to be used as a fast, convenient, and reliable alternative to more tedious RNA-based activity measurements. In order to deal with microbial consortia that can be regulated regarding their activity, we tested and evaluated the proposed method in comparison to sophisticated dehydrogenase- and RNA-based activity measurements with two anaerobic microbial consortia (anaerobic fungi and syntrophic archaea and a microbial rumen consortium) and three levels of resolution (overall activity, total bacteria, methanogenic archaea). Furthermore, we introduce a 28S rRNA gene-specific primer set and qPCR protocol, targeting anaerobic fungi (Neocallimastigomycota). Our findings show that the amount of actively released free exDNA (fDNA) strongly correlates with different activity measurements and is thus suggested to serve as a proxy for microbial activity. PMID- 29423638 TI - A new configuration of cannulated screw fixation in the treatment of vertical femoral neck fractures. AB - PURPOSE: The treatment of vertical femoral neck fractures in young patients is a worldwide challenge. The purpose of this study is to introduce a new configuration of cannulated screw fixation in vertical femoral neck fractures by comparing with using ordinary cannulated compression screw (OCCS) alone biomechanically and clinically. MATERIAL AND METHOD: Biomechanically, 20 synthetic femur models of femoral neck fractures with 20 degrees of VN angle were divided into two groups. The first group was fixed with three ordinary cannulated compression screws defined as OCCS group; the second group was fixed with two Headless Cannulated Compression Screws (HCCS) plus an OCCS, defined as combination group and tested for axial stiffness and load to failure. Clinically, a prospective study was designed with 59 patients who have vertical femoral neck fractures and were treated with cannulated screw, including 31 patients with three ordinary cannulated compression screws alone and 28 patients with an ordinary cannulated compression screw plus two headless cannulated compression screws. RESULTS: Biomechanically, our results showed that there was no significant difference of axial stiffness between OCCS group and combination group (109.92 +/- 10.81 vs. 123.49 +/- 15.13 N/mm, P = 0.145). But, the maximum load to failure of the combination group performed significant advantages than that of the OCCS group (446.85 +/- 76.25 vs. 302.92 +/- 80.46 N, P = 0.007). Clinically, the rates of fixation failure in the group treated with OCCS alone were 41.9%, while in the group treated with two types of screws were14.3% (P = 0.048). CONCLUSION: Our results suggested that using new configuration of an OCCS plus two HCCSs improved the outcome of vertical femoral neck fractures (FNF) patients compared to those using OCCS alone, which provides a new choice for treatment of FNF. PMID- 29423637 TI - Complementary expression of calcium binding proteins delineates the functional organization of the locomotor network. AB - Neuronal networks in the spinal cord generate and execute all locomotor-related movements by transforming descending signals from supraspinal areas into appropriate rhythmic activity patterns. In these spinal networks, neurons that arise from the same progenitor domain share similar distribution patterns, neurotransmitter phenotypes, morphological and electrophysiological features. However, subgroups of them participate in different functionally distinct microcircuits to produce locomotion at different speeds and of different modalities. To better understand the nature of this network complexity, here we characterized the distribution of parvalbumin (PV), calbindin D-28 k (CB) and calretinin (CR) which are regulators of intracellular calcium levels and can serve as anatomical markers for morphologically and potential functionally distinct neuronal subpopulations. We observed wide expression of CBPs in the adult zebrafish, in several spinal and reticulospinal neuronal populations with a diverse neurotransmitter phenotype. We also found that several spinal motoneurons express CR and PV. However, only the motoneuron pools that are responsible for generation of fast locomotion were CR-positive. CR can thus be used as a marker for fast motoneurons and might potentially label the fast locomotor module. Moreover, CB was mainly observed in the neuronal progenitor cells that are distributed around the central canal. Thus, our results suggest that during development the spinal neurons utilize CB and as the neurons mature and establish a neurotransmitter phenotype they use CR or/and PV. The detailed characterization of CBPs expression, in the spinal cord and brainstem neurons, is a crucial step toward a better understanding of the development and functionality of neuronal locomotor networks. PMID- 29423639 TI - Trends in total elbow arthroplasty: a nationwide analysis in Germany from 2005 to 2014. AB - PURPOSE: To date, there has been no study investigating the epidemiology and the changes over time, especially regarding indications, in total elbow replacement in Germany. METHODS: Using German procedure classification system (OPS) codes as well as the associated ICD codes, a retrospective analysis from 2005 to 2014 of the data provided by the Federal Statistical Office of Germany was performed. Total elbow arthroplasties (TEAs) were evaluated for admitting diagnoses, sex, and age of patient and distribution of constraint versus unconstraint prostheses. Furthermore, the number and indications of revision elbow arthroplasty (REA) and explantations were identified. RESULTS: From 2005 to 2014, a total of 3872 patients underwent TEA in Germany. This represents a rise of 84% in this period. Almost 77% of the arthroplasties were performed in females, and over 45% were implanted in patients before the age of 70. During the study, a significant increase in TEA performed on patients for trauma from 12 to 42% and concomitantly, a decrease for the arthritis subgroup from 20 to 2.6% could be revealed. Additionally, almost a doubling of REA in that period could be detected (10.3 to 17.1%). The main revision indication could be found in mechanical complications, such as aseptic loosening (72.1%). Conversely, the number of explantations decreased (12.4 to 5.8%). CONCLUSION: During the study period, the number of TEA performed in Germany nearly doubled. Over the years, the most common indication for total elbow arthroplasty changed from inflammatory arthritis to trauma sequel. Further database analysis may help to identify populations at risk and specify reasons for revisions. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 29423640 TI - Effectiveness of custom-made foot orthoses for treating forefoot pain: a systematic review. AB - PURPOSE: Pain in and around the metatarsal heads, the metatarsal phalangeal joints and the surrounding soft tissues is called metatarsalgia. Non-operative treatment of metatarsalgia includes foot orthoses. Foot orthoses may be classified as standard or custom-made. A systematic review was carried out to determine whether custom-made foot orthoses are effective for treating forefoot pain. METHODS: The MEDLINE, CINAHL, The Cochrane Library and PEDro databases were searched for relevant articles reporting patients undergoing treatment for forefoot pain by means of custom-made foot orthoses. Two reviewers independently reviewed all titles and abstracts and extracted the available data. The study eligibility criteria were randomised controlled clinical trials that included participants with forefoot pain treated with custom-made foot orthoses and that reported levels of forefoot pain after the use of orthoses. The data consisted of patient demographics, pathologies related to forefoot pain, type of foot orthoses used, follow-up period and clinical outcomes. RESULTS: Nine studies were selected which had a total of 487 participants. The pathologies evaluated were rheumatoid arthritis, hallux abductus valgus and isolated and secondary metatarsalgia. The use of custom-made foot orthoses was the intervention that exerted the most significant reduction of the level of pain in the forefoot in most of the studies. CONCLUSIONS: The use of custom-made foot orthoses improved the level of forefoot pain in rheumatoid arthritis, hallux abductus valgus and secondary metatarsalgia as it increases sole pressures. PMID- 29423643 TI - Rehabilitation and Re-socialization of Criminals in Iranian Criminal Law. AB - One of the concerns that always remain for the repentant criminal is the condition for his return to society. This concern may be so strong and effective that the criminal may seclude from the society due to the fear of its consequences and may return to crime. Therefore, paying attention to eliminating the social effect of the criminal conviction of criminals can return security to society and return the repentant criminals to normal life. So, all military and social institutions are effective in the re-socialization, in such a way that the re-socialization of criminals requires the provision of social platforms that starts with their own family and expands to society. The main concern of this research is how we can provide the favorable conditions for the re-socialization of repentant criminals that effectively realize the socialization goals. The Islamic Penal Code initiatives in 2013, despite the gaps in this regard, partly help to achieve such goals, but they are not enough. Therefore, the present article focused on the criminals' re-socialization and tried to raise the criminals' re-socialization both socially and criminally. The method was descriptive analytical. The result showed that the Islamic Penal Code, adopted in 2013 on the period of the subsequent effects, needs to be reformed, and the effective social institutions should be raised orderly in such a case. PMID- 29423641 TI - Functional Transcripts Indicate Phylogenetically Diverse Active Ammonia Scavenging Microbiota in Sympatric Sponges. AB - Symbiotic ammonia scavengers contribute to effective removal of ammonia in sponges. However, the phylogenetic diversity and in situ activity of ammonia scavenging microbiota between different sponge species are poorly addressed. Here, transcribed ammonia monooxygenase genes (amoA), hydrazine synthase genes (hzsA), and glutamine synthetase genes (glnA) were analyzed to reveal the active ammonia-scavenging microbiota in the sympatric sponges Theonella swinhoei, Plakortis simplex, and Phakellia fusca, and seawater. Archaeal amoA and bacterial glnA transcripts rather than bacterial amoA, hzsA, and archaeal glnA transcripts were detected in the investigated sponges and seawater. The transcribed amoA genes were ascribed to two Thaumarchaeota ecotypes, while the transcribed glnA genes were interspersed among the lineages of Cyanobacteria, Tectomicrobia, Poribacteria, Alpha-, Beta-, Gamma-, and Epsilonproteobacteria. In addition, transcribed abundances of archaeal amoA and bacterial glnA genes in these sponges have been quantified, showing significant variation among the investigated sponges and seawater. The transcriptome-based qualitative and quantitative analyses clarified the different phylogenetic diversity and transcription expression of functional genes related to microbially mediated ammonia scavenging in different sympatric sponges, contributing to the understanding of in situ active ecological functions of sponge microbial symbionts in holobiont nitrogen cycling. PMID- 29423644 TI - Moral Objections and Fear of Hell: An Important Barrier to Suicidality. AB - This review explores the literature to test the hypothesis that 'moral objections to suicide (MOS), especially the conviction of going to hell after committing suicide, exert a restraining effect on suicide and suicidality.' Medline and PsycInfo were searched using all relevant search terms; all relevant articles were selected, rated and reviewed. Fifteen cross-sectional studies were available on this topic, and raise sufficient evidence to confirm a restraining effect of MOS, and sparse data on fear of hell. MOS seem to counteract especially the development of suicidal intent and attempts, and possibly the lethality of suicidal attempts. A differential pattern of influence of MOS on the suicidal continuum is suggested. PMID- 29423645 TI - The Inverse U-Shaped Religion-Health Connection Among Israeli Jews. AB - A growing body of evidence indicates an association between religion and health. However, few have studied the connection between the extent of an individual's religiosity and his health. Analysis of the 2004 Israel National Health Survey was performed. Religiosity was self-identified using five continuous categories, distinctive to Israeli Jews. Bivariate and multivariate analyses examined the relationship between the extent of Religious commitment and several health outcomes. The relationship took the shape of an inverse U function: Israeli Jews in the middle religiously have the worst physical and mental health status on both unadjusted and adjusted bases. Israeli Jews exhibit a non-trivial connection between religiosity and health whereby the most Secular and the most Religious individuals seem to be healthier than individuals in between. PMID- 29423646 TI - Equivalent success and complication rates of tunneled common femoral venous catheter placed in the interventional suite vs. at patient bedside. AB - BACKGROUND: Femoral tunneled central line placement in the pediatric population offers an alternative means for intravenous (IV) access, but there is concern for higher complication and infection rates when placed at bedside. OBJECTIVE: To describe the complications and infection outcomes of primary femoral tunneled central venous catheter placement in the interventional radiology suite compared to the portable bedside location at a single tertiary pediatric institution. MATERIALS AND METHODS: We conducted a retrospective review comparing interventional radiology suites vs. bedside primary tunneled common femoral vein central line placement (January 2014 to December 2015). We identified 244 primary femoral placements in pediatric patients, ages 1 day to 18 years, using our electronic medical record and collected into a Research Electronic Data Capture. We compared categorical variables using the Fisher exact test. We compared continuous variables using the Wilcoxon rank test. RESULTS: In total, 2,375 pediatric patients received peripherally inserted and central lines; 244 of these were primary femoral tunneled central venous catheters (in 140 boys and 104 girls). In 140 children (mean age: 206 days), lines were inserted in the interventional radiology (IR) suite (technical success of 100%), with 14 (10.0%) complications including infection (n=7), malposition (n=2), bleeding (n=0), thrombosis (n=1) and line occlusion (n=4). The infection rate was 2.1 per 1,000 line days. In 104 children (mean age: 231 days), lines were placed at bedside (technical success 100%) with 14 (13.3%) complications including infection (n=3), malposition (n=5), bleeding (n=0), thrombosis (n=2) and line occlusion (n=4). The infection rate was 0.78 per 1,000 line days. The total line days were 7,109, of which 3,258 were in the IR suite and 3,851 in the bedside group. There was no statistical significance for complication rate (P=0.55) or infection rate (P=0.57) between bedside and interventional suite placements. CONCLUSION: In a cohort of children receiving primary femoral tunneled central venous catheters, the complication and infection rates in a bedside setting are not significantly increased compared to the lines placed in an IR suite. The perception of increased infection and complications from bedside-placed tunneled central venous catheters appears to be hyperbolized. PMID- 29423647 TI - Image-guided placement of percutaneous de novo low-profile gastrojejunostomy tubes in the pediatric population: a study of feasibility and efficacy. AB - BACKGROUND: De novo low-profile gastrojejunostomy tubes in pediatric patients offer less external catheter bulk and decreased propensity for dislodgement as children become more mobile. While small cohort studies have evaluated de novo placement of coaxial, adjustable-length, percutaneous gastrojejunostomy (GJ) tubes in children, placement of de novo low-profile GJ tubes in pediatric patients has not been analyzed. OBJECTIVE: This study evaluates technical feasibility, safety and clinical efficacy of percutaneous, retrograde placement of de novo low-profile GJ tubes in infants and children. MATERIALS AND METHODS: Following institutional review board approval, all de novo low-profile GJ tube placements in patients were retrospectively reviewed between May 2014 and May 2017. Technical parameters of fluoroscopy time, tube size, T-fasteners and complications were recorded. Clinical data, including age, indication, weight gain and complications, were analyzed. RESULTS: Thirty-four de novo low-profile GJ tubes were placed in 34 patients (median age: 9.4 months, range: 2 months-11.8 years; median pre-procedural weight: 7.5 kg, range: 2.9-31.6 kg). Twenty-one 14 Fr and 13 16-Fr GJ tubes were placed with technical success rate of 100%. Average weight gain 3 months' post procedure was 1.1 kg (range: 0.3-4.8 kg) and average weight percentile for age increase was 9.6% (range: -48.9% to 53.5%). One major complication occurred following balloon inflation within the tract causing pain requiring urgent replacement of the GJ tube. Minor complications occurred in 11 patients (32%): accidental dislodgement (n=9), skin irritation (n=4), tube dysfunction (n=2), leakage (n=2) and tube migration into the esophagus (n=1). CONCLUSION: Percutaneous, antegrade, image-guided placement of de novo low profile GJ tubes is technically feasible, safe and clinically efficacious in appropriately selected pediatric patients. PMID- 29423648 TI - An integrated structure- and pharmacophore-based MMP-12 virtual screening. AB - MMP-12 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades elastin. The main pathologic role of MMP-12 overexpression was suggested to be associated with pathogenesis mechanism of inflammatory respiratory diseases and atherosclerosis. An integrated ligand- and structure based virtual screening was employed in hope of finding inhibitors with new scaffolds and selectivity for MMP-12. Seven compounds among 18 experimentally tested compounds had a measurable effect on the inhibition of MMP-12 enzyme. Our results demonstrated the applicability of the developed pharmacophore model and selected crystal structure (PDB code: 3F17) to discover new MMP-12 inhibitors. The receptor structure was selected based on cross-docking results. Here, we report the discovery of new class of MMP-12 inhibitors that could be used for lead optimization. For the inhibition of MMP-12, the significance of its interactions with the catalytic residues Glu219 and Ala182 was emphasized through the inspection of the docking poses. PMID- 29423649 TI - Pretreatment neutrophil-to-lymphocyte ratio is associated with outcome of advanced-stage cancer patients treated with immunotherapy: a meta-analysis. AB - BACKGROUND: To investigate the association between pretreatment blood neutrophil to-lymphocyte ratio (NLR) and clinical outcomes for advanced-stage cancer patients treated with immunotherapy. METHODS: We conducted a comprehensive literature search to assess the relationship between pretreatment blood NLR and overall survival (OS) or progression-free survival (PFS) in advanced-stage cancer patients treated with immunotherapy. Published data including hazard ratios (HRs) and related 95% confidence interval (CI) were extracted. Pooled estimates of treatment outcomes were calculated using RevMan 5.3.5. RESULTS: Twenty-seven studies with 4647 patients were included in the current study. The pooled results suggested that high pretreatment blood NLR was correlated with significant shorter OS (HR = 1.98, 95% CI 1.66-2.36, P < 0.001) and PFS (HR = 1.78, 95% CI 1.48-2.15, P < 0.001). Subgroup analysis stratified by study targets revealed that anti-VEGF/VEGFR therapy (HR = 2.04, 95% CI 1.61-2.60, P < 0.001) and immune checkpoints blockade (HR = 2.16, 95% CI 1.86-2.51, P < 0.001) were significantly associated with inferior OS while other targets (HR = 1.63, 95% CI 0.89-2.99, P = 0.120) were not associated with OS. There was no correlation between distinct NLR cutoff values and OS ([Formula: see text] = 0.218, P = 0.329) or PFS benefit ([Formula: see text] = - 0.386, P = 0.140). Of note, HRs of PFS showed significant correlation with HRs of OS ([Formula: see text] = 0.656, P = 0.015). CONCLUSION: Elevated pretreatment blood NLR was a promising prognostic and predictive biomarker for advanced-stage cancer patients treated with immunotherapy. PMID- 29423650 TI - PRIM: An Efficient Preconditioning Iterative Reweighted Least Squares Method for Parallel Brain MRI Reconstruction. AB - The most recent history of parallel Magnetic Resonance Imaging (pMRI) has in large part been devoted to finding ways to reduce acquisition time. While joint total variation (JTV) regularized model has been demonstrated as a powerful tool in increasing sampling speed for pMRI, however, the major bottleneck is the inefficiency of the optimization method. While all present state-of-the-art optimizations for the JTV model could only reach a sublinear convergence rate, in this paper, we squeeze the performance by proposing a linear-convergent optimization method for the JTV model. The proposed method is based on the Iterative Reweighted Least Squares algorithm. Due to the complexity of the tangled JTV objective, we design a novel preconditioner to further accelerate the proposed method. Extensive experiments demonstrate the superior performance of the proposed algorithm for pMRI regarding both accuracy and efficiency compared with state-of-the-art methods. PMID- 29423651 TI - Genetic and functional analysis of SHROOM1-4 in a Chinese neural tube defect cohort. AB - Neural tube defects (NTDs), which include spina bifida and anencephaly, are the second most common form of human structural congenital malformations. While it is well established that SHROOM3 plays a pivotal role in the complex morphogenetic processes involved in neural tube closure (NTC), the underlying genetic contributions of SHROOM gene family members in the etiology of human NTDs remain poorly understood. Herein, we systematically investigated the mutation patterns of SHROOM1-4 in a Chinese population composed of 343 NTD cases and 206 controls, using targeted next-generation sequencing. Functional variants were further confirmed by western blot and the mammalian two-hybrid assays. Loss of function (LoF) variants were identified in SHROOM3. We observed 1.56 times as many rare [minor allele frequency (MAF) < 0.01] coding variants (p = 2.9 * 10-3) in SHROOM genes, and 4.5 times as many rare D-Mis (deleterious missense) variants in SHROOM2 genes in the NTD cases compared with the controls. D-Mis variants of SHROOM2 (p.A1331S; p.R1557H) were confirmed by Sanger sequencing, and these variants were determined to have profound effects on gene function that disrupted their binding with ROCK1 in vitro. These findings provide genetic and molecular insights into the effects of rare damaging variants in SHROOM2, indicating that such variants of SHROOM2 might contribute to the risk of human NTDs. This research enhances our understanding of the genetic contribution of the SHROOM gene family to the etiology of human NTDs. PMID- 29423653 TI - Pathway-induced allelic spectra of diseases in the presence of strong genetic effects. AB - Complex diseases are frequently modeled as following an additive model that excludes both intra- and inter-locus interaction, while at the same time reports on non-additive biological structures are ample, prominently featuring numerous metabolic and signaling pathways. Using extensive forward population simulations, we explored the impact of three basic pathway motifs on the relationship between epidemiological parameters, including disease prevalence, relative risk, sibling recurrence risk as well as causal variant number and allele frequency. We found that some but not all pathway motifs can shift the relationships between these parameters in comparison to the classical additive liability threshold model. The strongest deviations were observed with linear, cascade-like motifs that form an integral part of many reported pathways. We also modeled maturity-onset diabetes of the young (MODY) as a combination of different basic pathway motifs and observed a good concordance in epidemiological parameter values between our simulated data under this model and those reported in the literature. Given the widespread nature of pathways, including those in the etiology of human diseases, our results re-emphasize the need for non-additive interaction modeling of genetic variants to become an additional standard approach in analyzing human genetic data. PMID- 29423652 TI - Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes. AB - Increasing evidence implicates mitochondrial dysfunction in aging and age-related conditions. But little is known about the molecular basis for this connection. A possible cause may be mutations in the mitochondrial DNA (mtDNA), which are often heteroplasmic-the joint presence of different alleles at a single locus in the same individual. However, the involvement of mtDNA heteroplasmy in aging and age related conditions has not been investigated thoroughly. We deep-sequenced the complete mtDNA genomes of 356 Framingham Heart Study participants (52% women, mean age 43, mean coverage 4570-fold), identified 2880 unique mutations and comprehensively annotated them by MITOMAP and PolyPhen-2. We discovered 11 heteroplasmic "hot" spots [NADH dehydrogenase (ND) subunit 1, 4, 5 and 6 genes, n = 7; cytochrome c oxidase I (COI), n = 2; 16S rRNA, n = 1; D-loop, n = 1] for which the alternative-to-reference allele ratios significantly increased with advancing age (Bonferroni correction p < 0.001). Four of these heteroplasmic mutations in ND and COI genes were predicted to be deleterious nonsynonymous mutations which may have direct impact on ATP production. We confirmed previous findings that healthy individuals carry many low-frequency heteroplasmy mutations with potentially deleterious effects. We hypothesize that the effect of a single deleterious heteroplasmy may be minimal due to a low mutant-to-wildtype allele ratio, whereas the aggregate effects of many deleterious mutations may cause changes in mitochondrial function and contribute to age-related diseases. The identification of age-related mtDNA mutations is an important step to understand the genetic architecture of age-related diseases and may uncover novel therapeutic targets for such diseases. PMID- 29423654 TI - The evolution of relative trait size and shape: insights from the genitalia of dung beetles. AB - Insects show relatively little genital variation within species compared to extraordinary and often rapid diversification among species. It has been suggested that selection for reproductive isolation through differences in genital shape might explain this phenomenon. This hypothesis predicts that populations diverge faster in genital shape than in genital size. We tested this prediction in males from 10 dung beetle species with known phylogenetic relationships from the genus Onthophagus (Coleoptera: Scarabaeidae), including four species for which we were able to sample multiple populations. Specifically, we compared intra- and interspecific differentiation in shape and relative sizes of genitalia and calculated their respective evolutionary rates. We compared these rates to two similarly sized non-genital traits, the head and the fore tibia. We found significant intraspecific variation in genital shape in all four species for which multiple populations were sampled, but for three of them we also identified significant relative size variation. We also found that genital shape evolved at higher rates than relative genital size. Genital shape evolved faster than head shape, but not fore-tibia shape. However, shapes of all measured structures evolved faster than their relative size. We discuss the functional constraints that may bias the developmental evolution of relative size and shape of genitalia and other morphological traits. PMID- 29423655 TI - Xerophyta viscosa Aldose Reductase, XvAld1, Enhances Drought Tolerance in Transgenic Sweetpotato. AB - Sweetpotato is a significant crop which is widely cultivated particularly in the developing countries with high and stable yield. However, drought stress is a major limiting factor that antagonistically influences the crop's productivity. Dehydration stress caused by drought causes aggregation of reactive oxygen species (ROS) in plants, and aldose reductases are first-line safeguards against ROS caused by oxidative stress. In the present study, we generated transgenic sweetpotato plants expressing aldose reductase, XvAld1 isolated from Xerophyta viscosa under the control of a stress-inducible promoter via Agrobacterium mediated transformation. Our results demonstrated that the transgenic sweetpotato lines displayed significant enhanced tolerance to simulated drought stress and enhanced recuperation after rehydration contrasted with wild-type plants. In addition, the transgenic plants exhibited improved photosynthetic efficiency, higher water content and more proline accumulation under dehydration stress conditions compared with wild-type plants. These results demonstrate that exploiting the XvAld1 gene is not only a compelling and attainable way to improve sweetpotato tolerance to drought stresses without causing any phenotypic imperfections but also a promising gene candidate for more extensive crop improvement. PMID- 29423656 TI - RNA-binding protein Rbpms is represented in human retinas by isoforms A and C and its transcriptional regulation involves Sp1-binding site. AB - Rbpms (RNA-binding protein with multiple splicing) is a member of the RRM (RNA Recognition Motif) family of RNA-binding proteins, which is expressed as multiple alternatively spliced transcripts encoding different protein isoforms. We have shown earlier that Rbpms expression in the retina is restricted to retinal ganglion cells (RGCs), and have characterized this gene as a marker for RGCs. The aim of this study was to identify isoforms representing Rbpms in human retinas and to analyze its transcriptional regulation. We found that Rbpms is expressed as transcription variants 1 and 3 encoding isoforms A and C, respectively. These isoforms are encoded by the same first 6 exons but have different C-terminal ends encoded by exon 8 in variant 1 and exon 7 in variant 3. Computational analysis of the Rbpms 5' untranslated and flanking regions reveals the presence of three CpG islands and four predicted promoter regions (PPRs). The effect of PPR 1 (- 1672/- 1420) and PPR2 (- 330/- 79) on transcriptional activation was minimal, whereas PPR 3 (- 73/+ 177) and PPR4 (+ 274/+ 524) induced the expression by ~ 7 and ninefold compared to control, respectively. The maximum activity, a 30-fold increase above the control level, was obtained from the construct containing both PPRs 3 and 4. Site-directed mutagenesis of several cis-elements within PPR3 and PPR4 including five for Sp1, one for AP1, and two for NF-kB showed that mutation of the first three and especially the first GC box resulted in a threefold downregulation of gene expression. AP1, NF-kB, and two downstream Sp1 sites had no significant effect on expression level. The possible involvement of the GC box 1 at position - 54 in transcriptional regulation of Rbpms was corroborated by EMSA, which showed formation of a DNA-protein complex in the presence of the oligonucleotide corresponding to this Sp1-binding site. PMID- 29423658 TI - Effects of contaminants of emerging concern on Myzus persicae (Sulzer, Hemiptera: Aphididae) biology and on their host plant, Capsicum annuum. AB - Many countries are utilizing reclaimed wastewater for agriculture as water demands due to drought, rising temperatures, and expanding human populations. Unfortunately, wastewater often contains biologically active, pseudopersistant pharmaceuticals, even after treatment. Runoff from agriculture and effluent from wastewater treatment plants also contribute high concentrations of pharmaceuticals to the environment. This study assessed the effects of common pharmaceuticals on an agricultural pest, the aphid Myzus persicae (Sulzer, Hemiptera: Aphididae). Second instar nymphs were transferred to bell peppers (Capsicum annuum) that were grown hydroponically. Treatment plants were spiked with contaminants of emerging concern (CECs) at environmentally relevant concentrations found in reclaimed wastewater. M. persicae displayed no differences in population growth or microbial community differences due to chemical treatments. Plants, however, displayed significant growth reduction in antibiotic and mixture treatments, specifically in wet root masses. Antibiotic treatment masses were significantly reduced in the total and root wet masses. Mixture treatments displayed an overall reduction in plant root wet mass. Our results suggest that the use of reclaimed wastewater for crop irrigation would not affect aphid populations, but could hinder or delay crop production. PMID- 29423657 TI - QTL delineation for five fiber quality traits based on an intra-specific Gossypium hirsutum L. recombinant inbred line population. AB - Gossypium hirsutum L. is the most important fiber crop worldwide and contributes to more than 95% of global cotton production. Marker-assisted selection (MAS) is an effective approach for improving fiber quality, and quantitative trait loci (QTL) mapping of fiber quality traits is important for cotton breeding. In this study, a permanent intra-specific recombinant inbred line (RIL) population containing 137 families was used for fiber quality testing. Based on a previously reported high-density genetic map with an average marker distance of 0.63 cM, 186 additive QTLs were obtained for five fiber quality traits over five consecutive years, including 39 for fiber length (FL), 36 for fiber strength (FS), 50 for fiber uniformity (FU), 33 for micronaire (MC) and 28 for fiber elongation (FE). Three stable QTLs, qMC-A4-1, qMC-D2-3 and qFS-D9-1, were detected in four datasets, and another eight stable QTLs, qMC-A4-2, qMC-D11-2, qFU-A9-1, qFU-A10 4, qFS-D11-1, qFL-D9-2, qFL-D11-1 and qFE-A3-2, were detected in three datasets. The annotated genes in these 11 stable QTLs were collected, and these genes included many transcription factors with functions during fiber development. 33 QTL coincidence regions were found, and these involved nearly half of the total QTLs. Four chromosome regions containing at least 6 QTLs were promising for fine mapping. In addition, 41 pairs of epistatic QTLs (e-QTLs) were screened, including 6 for FL, 30 for FS, 2 for FU and 3 for MC. The identification of stable QTLs adds valuable information for further QTL fine mapping and gene positional cloning for fiber quality genetic detection and provides useful markers for further molecular breeding in enhancing fiber quality. PMID- 29423659 TI - Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence. AB - This article summarises the current evidence on the risk of venous thromboembolism (VTE) with the use of antipsychotics. An increasing number of observational studies indicate an elevated risk of VTE in antipsychotic drug users. Although the use of certain antipsychotics has been associated with VTE, current data can neither conclusively verify differences in occurrence rates of VTE between first- and second-generation antipsychotics or between individual compounds, nor identify which antipsychotic drugs have the lowest risk of VTE. The biological mechanisms involved in the pathogenesis of this adverse drug reaction are still to be clarified but hypotheses such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinaemia and hyperprolactinaemia have been suggested. Risk factors associated with the underlying psychiatric disorder may at least partly explain the increased risk. Physicians should be aware of this potentially serious and even sometimes fatal adverse drug reaction and should consider discontinuing or switching the antipsychotic treatment in patients experiencing a VTE. Even though supporting evidence is limited, prophylactic antithrombotic treatment should be considered in risk situations for VTE. PMID- 29423660 TI - Targeting Suppressive Oligonucleotide to Lymph Nodes Inhibits Toll-like Receptor 9-Mediated Activation of Adaptive Immunity. AB - PURPOSE: This paper aims to investigate the immunoinhibitory properties of a lymph nodes-targeting suppressive oligonucleotide (ODN) for the potential treatment of autoimmune diseases or chronic inflammation. METHODS: Synthetic suppressive ODN engineered with an albumin-binding diacyl lipid at the 5' terminal (lipo-ODN) was synthesized. In vitro and in vivo experiments were designed to compare the immune suppressive properties of lipo-ODN and unmodified ODN. Cellular uptake and distribution, inhibition of Toll-like receptor (TLR) activation, lymph nodes (LN) draining, and the suppression of antigen-specific immune responses in an ovalbumin protein model was investigated. RESULTS: Compared to unmodified ODN, lipid functionalized suppressive ODN demonstrated enhanced cellular uptake and TLR-9 specific immune suppression in TLR reporter cells. Additionally, injection of a low dose of lipid-modified suppressive ODN, but not the unconjugated ODN, accumulated in the draining LNs and exhibited potent inhibition of antigen-specific CD8+ T cell and B cell responses in vivo. CONCLUSIONS: Targeting suppressive ODN to antigen presenting cells (APCs) in the local LNs is an effective approach to amplify the immune modulation mediated by ODN containing repetitive TTAGGG motif. This approach might be broadly applicable to target molecular adjuvants to the key immune cells in the LNs draining from disease site, providing a simple strategy to improve the efficacy of many molecular immune modulators. PMID- 29423661 TI - Health Implications of Climate Change: a Review of the Literature About the Perception of the Public and Health Professionals. AB - PURPOSE OF REVIEW: Through a systematic search of English language peer-reviewed studies, we assess how health professionals and the public, worldwide, perceive the health implications of climate change. RECENT FINDINGS: Among health professionals, perception that climate change is harming health appears to be high, although self-assessed knowledge is low, and perceived need to learn more is high. Among the public, few North Americans can list any health impacts of climate change, or who is at risk, but appear to view climate change as harmful to health. Among vulnerable publics in Asia and Africa, awareness of increasing health harms due to specific changing climatic conditions is high. Americans across the political and climate change opinion spectra appear receptive to information about the health aspects of climate change, although findings are mixed. Health professionals feel the need to learn more, and the public appears open to learning more, about the health consequences of climate change. PMID- 29423663 TI - Submicron Protein Particle Characterization using Resistive Pulse Sensing and Conventional Light Scattering Based Approaches. AB - PURPOSE: Characterizing submicron protein particles (approximately 0.1-1MUm) is challenging due to a limited number of suitable instruments capable of monitoring a relatively large continuum of particle size and concentration. In this work, we report for the first time the characterization of submicron protein particles using the high size resolution technique of resistive pulse sensing (RPS). METHODS: Resistive pulse sensing, dynamic light scattering and size-exclusion chromatography with in-line multi-angle light scattering (SEC-MALS) are performed on protein and placebo formulations, polystyrene size standards, placebo formulations spiked with silicone oil, and protein formulations stressed via freeze-thaw cycling, thermal incubation, and acid treatment. RESULTS: A method is developed for monitoring submicron protein particles using RPS. The suitable particle concentration range for RPS is found to be approximately 4 * 107-1 * 1011 particles/mL using polystyrene size standards. Particle size distributions by RPS are consistent with hydrodynamic diameter distributions from batch DLS and to radius of gyration profiles from SEC-MALS. RPS particle size distributions provide an estimate of particle counts and better size resolution compared to light scattering. CONCLUSION: RPS is applicable for characterizing submicron particles in protein formulations with a high degree of size polydispersity. Data on submicron particle distributions provide insights into particles formation under different stresses encountered during biologics drug development. PMID- 29423664 TI - Current Management and Future Opportunities for Peritoneal Metastases: Peritoneal Mesothelioma. AB - PURPOSE: Diffuse malignant peritoneal mesothelioma (MPM) is a rare and ultimately fatal cancer that was first described just over a century ago. It is a diffuse malignancy arising from the mesothelial lining of the peritoneum; morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity. METHODS: The purpose of this article is to review the current state-of-the-science related to the diagnosis, staging, and treatment of MPM. RESULTS: The condition afflicts men and women equally and the peak incidence is between 55 and 60 years of age although it can arise in the young and elderly. Patients afflicted with MPM most commonly present with nonspecific abdominal symptoms that usually lead to diagnosis when the condition is relatively advanced. Historically, median overall survival for MPM patients without treatment is < 1 year. The couplet of systemic pemetrexed and cisplatin has an overall response rate of approximately 25% and a median overall survival of approximately 1 year. CONCLUSION: The available data, almost all retrospective in nature, have shown that in selected patients, operative cytoreduction (CRS) and regional chemotherapy administered as hyperthermic intraoperative peritoneal chemotherapy (HIPEC) or early postoperative intraperitoneal chemotherapy (EPIC) is associated with long-term survival. Studies on the molecular biology of MPM have yielded new insights relating to the potentially important role of the phosphoinsitide-3-kinase/mammalian target of rapamycin (PI3 K/mTOR) pathways and immune checkpoint inhibitors that may translate into new therapeutic options for patients with diffuse MPM. PMID- 29423662 TI - Environmental Exposures and Neuropsychiatric Disorders: What Role Does the Gut Immune-Brain Axis Play? AB - PURPOSE OF REVIEW: Evidence is growing that environmental exposures-including xenobiotics as well as microbes-play a role in the pathogenesis of many neuropsychiatric disorders. Underlying mechanisms are likely to be complex, involving the developmentally sensitive interplay of genetic/epigenetic, detoxification, and immune factors. Here, we review evidence supporting a role for environmental factors and disrupted gut-immune-brain axis function in some neuropsychiatric conditions. RECENT FINDINGS: Studies suggesting the involvement of an altered microbiome in triggering CNS-directed autoimmunity and neuropsychiatric disturbances are presented as an intriguing example of the varied mechanisms by which environmentally induced gut-immune-brain axis dysfunction may contribute to adverse brain outcomes. The gut-immune-brain axis is a burgeoning frontier for investigation of neuropsychiatric illness. Future translational research to define individual responses to exogenous exposures in terms of microbiome-dependent skew of the metabolome, immunity, and brain function may serve as a lens for illumination of pathways involved in the development of CNS disease and fuel discovery of novel interventions. PMID- 29423665 TI - A Meta-Analysis of the Effectiveness of Different Cortical Targets Used in Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Obsessive-Compulsive Disorder (OCD). AB - Randomised and sham-controlled trials (RCTs) of repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) have yielded conflicting results, which may be due to the variability in rTMS parameters used. We performed an updated systematic review and meta-analysis on the effectiveness of rTMS for the treatment of OCD and aimed to determine whether certain rTMS parameters, such as cortical target, may be associated with higher treatment effectiveness. After conducting a systematic literature review for RCTs on rTMS for OCD through to 1 December 2016 using MEDLINE, PubMed, Web of Science, PsycINFO, Google, and Google Scholar, we performed a random-effects meta-analysis with the outcome measure as pre-post changes in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores. To determine whether rTMS parameters may have influenced treatment effectiveness, studies were further analysed according to cortical target, stimulation frequency, and length of follow-up. Data were obtained from 18 RCTs on rTMS in the treatment of OCD. Overall, rTMS yielded a modest effect in reducing Y-BOCS scores with Hedge's g of 0.79 (95% CI = 0.43-1.15, p < 0.001). Stimulation of the supplementary motor area yielded the greatest reductions in Y BOCS scores relative to other cortical targets. Subgroup analyses suggested that low frequency rTMS was more effective than high frequency rTMS. The effectiveness of rTMS was also greater at 12 weeks follow-up than at four weeks follow-up. Our meta-analysis implies that low frequency rTMS applied over the supplementary motor area may offer the greatest effectiveness in the treatment of OCD. The therapeutic effects of rTMS also appear to persist post-treatment and may offer beneficial long-term effectiveness. With our findings, it is suggested that future large-scale studies focus on the supplementary motor area and include follow-up periods of 12 weeks or more. PMID- 29423668 TI - Editorial: Pediatric Ophthalmology - Part II. PMID- 29423666 TI - Consciousness: a unique way of processing information. AB - In this article, I argue that consciousness is a unique way of processing information, in that: it produces information, rather than purely transmitting it; the information it produces is meaningful for us; the meaning it has is always individuated. This uniqueness allows us to process information on the basis of our personal needs and ever-changing interactions with the environment, and consequently to act autonomously. Three main basic cognitive processes contribute to realize this unique way of information processing: the self, attention and working memory. The self, which is primarily expressed via the central and peripheral nervous systems, maps our body, the environment, and our relations with the environment. It is the primary means by which the complexity inherent to our composite structure is reduced into the "single voice" of a unique individual. It provides a reference system that (albeit evolving) is sufficiently stable to define the variations that will be used as the raw material for the construction of conscious information. Attention allows for the selection of those variations in the state of the self that are most relevant in the given situation. Attention originates and is deployed from a single locus inside our body, which represents the center of the self, around which all our conscious experiences are organized. Whatever is focused by attention appears in our consciousness as possessing a spatial quality defined by this center and the direction toward which attention is focused. In addition, attention determines two other features of conscious experience: periodicity and phenomenal quality. Self and attention are necessary but not sufficient for conscious information to be produced. Complex forms of conscious experiences, such as the various modes of givenness of conscious experience and the stream of consciousness, need a working memory mechanism to assemble the basic pieces of information selected by attention. PMID- 29423667 TI - Paeoniflorin Inhibits Migration and Invasion of Human Glioblastoma Cells via Suppression Transforming Growth Factor beta-Induced Epithelial-Mesenchymal Transition. AB - Paeoniflorin (PF) is a polyphenolic compound derived from Radix Paeoniae Alba thathas anti-cancer activities in a variety of human malignancies including glioblastoma. However, the underlying mechanisms have not been fully elucidated. Epithelial to mesenchymal transition (EMT), characterized as losing cell polarity, plays an essential role in tumor invasion and metastasis. TGFbeta, a key member of transforming growth factors, has been demonstrated to contribute to glioblastoma aggressiveness through inducing EMT. Therefore, the present studies aim to investigate whether PF suppresses the expression of TGFbeta and inhibits EMT that plays an important role in anti-glioblastoma. We found that PF dose dependently downregulates the expression of TGFbeta, enhances apoptosis, reduces cell proliferation, migration and invasion in three human glioblastoma cell lines (U87, U251, T98G). These effects are enhanced in TGFbeta siRNA treated cells and abolished in cells transfected with TGFbeta lentiviruses. In addition, other EMT markers such as snail, vimentin and N-cadherin were suppressed by PF in these cell lines and in BALB/c nude mice injected with U87 cells. The expression of MMP2/9, EMT markers, are also dose-dependently reduced in PF treated cells and in U87 xenograft mouse model. Moreover, the tumor sizes are reduced by PF treatment while there is no change in body weight. These results indicate that PF is a potential novel drug target for the treatment of glioblastoma by suppression of TGFbeta signaling pathway and inhibition of EMT. PMID- 29423669 TI - Normative Data of Thyroid Gland Volume in South Indian Neonates and Infants. AB - OBJECTIVE: To establish normative ultrasound data for thyroid gland volume in South Indian neonates and infants and compare with abnormal sonological features of thyroid in congenital hypothyroidism (CH) to explore thyroid ultrasound utility as a supportive screening tool to newborn screening programs for early detection of CH. METHODS: In view of impact of geo ethnic factors, varying growth velocities and body mass indices of human population worldwide, specific regional, age and gender related reference data for thyroid gland size and volume are vital. This study was an offshoot of ICMR pilot New Born Screening (NBS) project for CH. Formula used for thyroid volume estimation was ellipsoidal formula D1 x D2 x D3 * 0.523. It was a prospective observational study. The neonates who screened negative for Thyroid Stimulating Hormone (TSH) with repeat normal serum TSH and free thyroxine were selected. One hundred fifty seven infants were enrolled which included 99 boys and 58 girls. The study population included children in age groups from 3 d to 1 y six months. RESULTS: Data analysis was done by descriptive method and unpaired t test. Mean thyroid volume was 0.26 ml with 0.27 ml in boys and 0.24 ml in girls. Statistically significant "p value" was noted in single lobe measurements among boys and girls. CONCLUSIONS: Thyroid gland volume normative data play a key role in evaluation of thyroid sonological abnormalities in CH and there is effective utility of ultrasound as a supportive diagnostic and prognostic screening tool for early detection of CH. PMID- 29423670 TI - Primary Biliary Cholangitis- Autoimmune Hepatitis Overlap Syndrome. PMID- 29423671 TI - The glycosyltransferase ST6Gal-I is enriched in cancer stem-like cells in colorectal carcinoma and contributes to their chemo-resistance. AB - PURPOSE: Presence of cancer stem cells (CSCs) contributes to tumor outgrowth, chemo-resistance and relapse in some cancers including colorectal carcinoma (CRC). The current characterization methods of CSCs in CRC only allows enrichment of CSCs but not their purification. Recent reports showed that ST6 beta galactoside alpha-2,6-sialyltransferase 1 (ST6Gal-I) plays an essential role in protecting tumor cells against harsh environment like oxidative stress and nutrient deprivation. Therefore, whether ST6Gal-I may be highly expressed in CSCs or whether it may enhance resistance of tumor cells to chemotherapy deserves exploration. METHOD: ST6Gal-I levels were determined in CRC specimens, compared to paired normal colorectal tissue, and examined in CD133+ vs CD133- CRC cells, and CD44+ vs CD44- CRC cells. ST6Gal-I levels and their association with patient survival were examined. In vivo, 2 CRC cell lines Caco-2 and SW48 were transduced with two lentiviruses, one lentivirus carrying a green fluorescent protein reporter and a luciferase reporter under a cytomegalovirus promoter to allow tracing tumor cells by both fluorescence and luciferase activity, and one lentivirus carrying a nuclear red fluorescent protein under the control of ST6Gal I promoter to allow separation of ST6Gal-I+ vs ST6Gal-I- CRC cells. Tumor sphere formation, resistance to fluorouracil-induced apoptosis, and frequency of tumor formation after serial adoptive transplantation were done on ST6Gal-I+ vs ST6Gal I- CRC cells. RESULT: ST6Gal-I levels were significantly upregulated in clinically obtained CRC specimens, compared to paired normal colorectal tissue. Poorer patient survival was detected in ST6Gal-I-high CRC, compared to ST6Gal-I low subjects. Higher levels of ST6Gal-I were detected in CD133+ CRC cells than CD133- CRC cells, and in CD44+ CRC cells than in CD44- CRC cells. Compared to ST6Gal-I- CRC cells, ST6Gal-I+ CRC cells generated significantly more tumor spheres in culture, were more resistant to fluorouracil-induced apoptosis likely through upregulating cell autophagy, and generated tumor more frequently after serial adoptive transplantation. CONCLUSION: ST6Gal-I may be highly expressed in the cancer stem-like cells in CRC and enhances cancer cell resistance to chemotherapy. PMID- 29423674 TI - Intravenous Infusion of Human Adipose Tissue-Derived Mesenchymal Stem Cells to Treat Type 1 Diabetic Mellitus in Mice: An Evaluation of Grafted Cell Doses. AB - Mesenchymal stem cell (MSC) transplantation is a novel treatment for diabetes mellitus, especially type 1 diabetes. Many recent publications have demonstrated the efficacy of MSC transplantation on reducing blood glucose and increasing insulin production in both preclinical and clinical trials. However, the investigation of grafted cell doses has been lacking. Therefore, this study aimed to evaluate the different doses of MSCs on treatment of type 1 diabetes in mouse models. MSCs were isolated and expanded from human adipose tissue. Streptozotocin (STZ)-induced diabetic mice were divided into two groups that were intravenously transfused with two different doses of human MSCs: 106 or 2.106 cells/mouse. After transplantation, both grafted and placebo mice were monitored weekly for their blood glucose levels, glucose and insulin tolerance, pancreatic structural changes, and insulin production for 56 days after transplantation. The results showed that the higher dose of MSCs (2.106 cells/mouse) remarkably reduced death rate. The death rates were 50%, 66%, and 0% in placebo group, low-dose (1.106 MSCs) group, and high-dose (2.106 MSCs) group, respectively, after 56 days of treatment. Moreover, blood glucose levels were lower for the high-dose group compared to other groups. Glucose and insulin tolerance, as well as insulin production, were significantly improved in mice transplanted with 2.106 cells. The histochemical analyses also support these results. Thus, a higher (e.g., 2.106) dose of MSCs may be an effective dose for treatment of type 1 diabetes mellitus. PMID- 29423673 TI - Stromal expression of JNK1 and VDR is associated with the prognosis of esophageal squamous cell carcinoma. AB - PURPOSE: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, and its outcome is poor. The purpose of this study was to determine the association between JNK1 and vitamin D receptor (VDR) expression and the prognosis of ESCC. METHODS: Immunohistochemical staining was conducted on ESCC tissue microarrays (362 pairs of ESCC and normal esophagus tissues). The epithelial and stromal expression levels of c-jun NH2-terminal kinase 1 (JNK1) and VDR were scored and correlated with the ESCC characteristics. Laser-capture based quantitative RT-PCR was performed on ESCC tissues. The effects of JNK1 and VDR on ESCC cell proliferation and migration were analyzed in vitro by transient transfection, and protein changes were evaluated by immunoblotting. RESULTS: Both JNK1 and VDR were reduced in ESCC epithelial cells in comparison with the normal esophagus, but the expression of JNK1 and VDR in ESCC stromal tissues, not epithelial cells, was strongly associated with the survival time of ESCC patients. Functional studies showed that increased JNK1 suppressed cancer cell proliferation, mobility, and migration, which were linked to the alterations of VDR and metastasis-associated proteins. CONCLUSION: JNK1 and VDR act as tumor suppressors, and their stromal expression levels are associated with prognosis in esophageal squamous cell carcinoma. PMID- 29423675 TI - The Robust Potential of Mesenchymal Stem Cell-Loaded Constructs for Hard Tissue Regeneration After Cancer Removal. AB - Malignant bone tumors, although quite rare, are one of the causes of death in children and adolescents. Surgery as a common and primary treatment for removal of virtually bone cancer cause large bone defects. Thus, restoration of hard tissues like bone and cartilage after surgical tumor resection needs efficient therapeutic approaches. Tissue engineering (TE) is a powerful approach which has provided hope for restoration, maintenance, or improvement of damaged tissues. This strategy generally supplies a three-dimensional scaffold as an active substrate to support cell recruitment, infiltration, and proliferation for neo tissues. The scaffold mimics the natural extracellular matrix (ECM) of tissue which needs to be regenerated. The use of potent cell sources such as mesenchymal stem cells (MSCs) has also led to remarkable progresses in hard tissue regeneration. Combination of living cells and various biomaterials have continuously evolved over the past decades to improve the process of regeneration. This chapter describes various strategies used in TE and highlights recent advances in cell-loaded constructs. We herein focus on cell-based scaffold approach utilized in hard tissue engineering and parameters determining a clinically efficient outcome. Also, we attempt to identify the potential as well as shortcomings of pre-loaded scaffolds for future therapeutic applications. PMID- 29423677 TI - Rash management and treatment persistence of cancer patients treated with epidermal growth factor receptor inhibitors in the Truven MarketScan(r) research database. AB - PURPOSE: Rash toxicity is a common, expected class effect of epidermal growth factor receptor (EGFR) inhibitors. Although rash management is practiced, it is not well characterized in the real-world setting. We describe the management of rash that developed while receiving EGFR-inhibitor therapy and how rash affects treatment duration, using Truven MarketScan(r) Research Database, a US medical claims database. METHODS: Adult patients who received EGFR-inhibitor treatment between 2004 and 2015 after a diagnosis of colon, head and neck, lung, breast, or thyroid cancer were identified. Descriptive analyses were conducted to describe occurrence of rash during the EGFR-inhibitor treatment period, EGFR-inhibitor treatment persistence and management of rash, including treatment and cost. RESULTS: Of 44,533 eligible patients, 4649 (10.4%) had records of rash during the EGFR-inhibitor treatment period, and of patients experiencing rash, 2891 (62.2%) received prescription drugs for rash treatment. Treatment persistence with an EGFR inhibitor was longer among patients experiencing rash compared with no rash (median 178 vs. 80 days for EGFR-TKIs, 85 vs. 57 days for EGFR-monoclonal antibodies), especially among patients with rash who were treated for rash (208 days for EGFR-tyrosine kinase inhibitors, 104 days for EGFR- monoclonal antibodies). Annualized cost during EGFR-inhibitor treatment was lowest among patients not experiencing rash (US$185,619), followed by rash patients receiving drugs for rash management (US$215,561), and highest among rash patients not treated for rash (US$267,105). CONCLUSION: Our findings suggest that management of EGFR inhibitor-associated rash could be important for EGFR-inhibitor treatment persistence. PMID- 29423676 TI - Heat shock transcriptional factor mediates mitochondrial unfolded protein response. AB - For maintenance of cytoplasmic protein quality control (PQC), cytoplasmic heat shock proteins (HSPs) negatively control heat shock transcriptional factor (HSF) in a negative feedback loop. However, how mitochondrial protein quality control (mtPQC) is maintained is largely unknown. Here we present evidence that HSF directly monitors mtPQC in the budding yeast Saccharomyces cerevisiae. Mitochondrial HSP70 (Ssc1) negatively regulated HSF activity. Importantly, HSF was localized not only in the nucleus but also on mitochondria. The mitochondrial localization of HSF was increased by heat shock and compromised by SSC1 overexpression. Furthermore, the mitochondrial protein translocation system downregulated HSF activity. Finally, mtPQC modulated the mtHSP genes SSC1 and MDJ1 via HSF, and SSC1 overexpression compromised mitochondrial function. These findings illustrate a model in which HSF directly monitors mtPQC. PMID- 29423678 TI - Quality of life trajectories during the first year following hematopoietic cell transplantation: an inception cohort study. AB - BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) affects quality of life (QOL). Patient-reported outcomes examine symptoms, side effects, distress, and physical and social problems, but positive outcomes have been ignored. This inception cohort study followed people over the first year following HCT to document positive and negative outcomes. METHODS: People with hematologic cancers treated by HCT completed complementary self-report instruments at four milestones: (a) pre-transplant (N = 88); (b) engraftment (N = 80); (c) short-term post-discharge (N = 60); and (d) long-term post-discharge (N = 45). We examined symptoms, side effects, illness intrusiveness, depressive symptoms, positive and negative affect, and self-esteem. We compared QOL in HCT with diverse published values. RESULTS: QOL deteriorated following HCT. Most variables returned to baseline by short-term post-discharge, but self-esteem and illness intrusiveness required more time. Illness intrusiveness at 1 year post discharge was higher in HCT than other cancer groups; negative affect, too, was higher, but HCT survivors also reported higher positive affect. HCT and other cancer survivors reported similar depressive symptom levels. Compared to healthy people, HCT survivors reported more severe depressive symptoms, but similar positive and negative affect. CONCLUSIONS: QOL changes dramatically following HCT. People report more interference with valued activities and interests after 1 year than survivors of other cancers, but depressive symptoms are not higher. Positive and negative affect are equivalent to healthy community residents. Continued involvement in psychologically meaningful activities may preserve QOL. PMID- 29423679 TI - Predictors of enrollment in individual- and couple-based lifestyle intervention trials for cancer survivors. AB - PURPOSE: To utilize data from lifestyle intervention pilot studies for cancer survivors to elucidate demographic, disease-related, and health behavior factors that might predict enrollment in this type of research. Additionally, factors were differentially compared based on intervention design (i.e., individual versus couple-based). METHODS: Secondary data analysis was conducted regarding predictors of enrollment into lifestyle intervention studies, including Healthy Moves Weight Loss (individual participants, screened n = 89, enrolled n = 30) and Healthy Moves Couples (survivors and their partners, screened n = 197, enrolled n = 23). Due to small sample sizes, common in pilot studies, random forest analyses were used to maximize information yielded by the data. RESULTS: Results identified numerous important predictors of enrollment in individual and couple based lifestyle interventions. Percent energy from fat and physical activity minutes were identified as important predictors for both recruitment methods. Age, cancer site, and marital status were important predictors of enrollment in the individual-based intervention. Weight, fiber consumption, and disease-related symptom severity and interference were important predictors of enrollment in the couple-based intervention. CONCLUSION: Although there was some overlap in predictors for enrollment between studies, many differential predictors were identified between individual versus couple-based study designs for lifestyle intervention in cancer survivors. Future lifestyle intervention studies for cancer survivors may benefit from targeting different predictors of enrollment based on study design to optimize recruitment. Additionally, understanding predictors may allow certain barriers to enrollment (i.e., symptom burden) to be directly addressed, making lifestyle intervention research more feasible and acceptable to difficult-to-recruit survivors. PMID- 29423680 TI - Changes in upper extremity function, ADL, and HRQoL in colorectal cancer patients after the first chemotherapy cycle with oxaliplatin: a prospective single-center observational study. AB - PURPOSE: Oxaliplatin, an important chemotherapeutic agent in colorectal cancer, causes chemotherapy-induced peripheral neuropathy (CIPN), for which prophylactic or therapeutic interventions are lacking. We aimed to investigate changes in upper extremities, activities of daily living (ADL), and health-related quality of life (HRQoL) parameters after the first chemotherapy cycle. METHODS: Thirty eight colorectal cancer patients scheduled to receive the leucovorin, 5' fluorouracil, oxaliplatin (FOLFOX) therapy or the capecitabine, oxaliplatin (CAPOX) therapy, participated. Patients underwent objective assessment of sensory function, muscular strength, and manual dexterity and answered the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the Disabilities of the Arm, Shoulder, and Hand-Disability/Symptom (DASH-DS) questionnaires for subjective assessment. The CIPN was assessed at baseline and prior to the second drug cycle. RESULTS: Light touch sensation in both hands worsened significantly after the first drug cycle, though no significant changes were observed in muscular strength and manual dexterity. The QLQ-C30 analysis showed that Physical Functioning, Role Functioning, Nausea and Vomiting, and Dyspnea were significantly worse, whereas Emotional Functioning was improved. The DASH-DS analysis revealed significant worsening of dysfunction and subjective symptoms. CONCLUSIONS: Our results suggest that light touch sensation may worsen even in the absence of multiple chemotherapy cycles. Even if arm and hand function (muscular strength and manual dexterity) is apparently intact, patients may experience dysfunction and decreased HRQoL. For preserving or improving patients' ADL and HRQoL, it is imperative to provide support at chemotherapy initiation. PMID- 29423681 TI - Factors that shape preference for acupuncture or cognitive behavioral therapy for the treatment of insomnia in cancer patients. AB - PURPOSE: Patient preference is an essential component of patient-centered supportive cancer care; however, little is known about the factors that shape preference for treatment. This study sought to understand what factors may contribute to patient preference for two non-pharmacological interventions, acupuncture or cognitive behavioral therapy for insomnia (CBT-I). METHODS: We conducted individual, open-ended, semi-structured interviews among cancer survivors who had completed active treatment and met the diagnostic criteria for insomnia disorder. Two forms of codes were used for analysis: a priori set of codes derived from the key ideas and a set of codes that emerged from the data. RESULTS: Among 53 participants, the median age was 60.7 (range 27-83), 30 participants (56.6%) were female, and 18 (34%) were non-white. We identified three themes that contributed to an individual's treatment preference: perception of the treatment's evidence base, experience with the treatment, and consideration of personal factors. Participants gave preference to the treatment perceived as having stronger evidence. Participants also reflected on positive or negative experiences with both of the interventions, counting their own experiences, as well as those of trusted sources. Lastly, participants considered their own unique circumstances and factors such as the amount of work involved, fit with personality, or fit with their "type" of insomnia. CONCLUSIONS: Knowledge of the evidence base, past experience, and personal factors shaped patient preference regardless of whether they accurately represent the evidence. Acknowledging these salient factors may help inform patient-centered decision making and care. PMID- 29423682 TI - Locally advanced oral squamous cell carcinoma patients treated with photobiomodulation for prevention of oral mucositis: retrospective outcomes and safety analyses. AB - PURPOSE: The well-established clinical efficacy of photobiomodulation (PBM) therapy in management of oral mucositis (OM) is leading to increasing use in oncology care. This protection and enhanced repair of damage to mucosal tissue have led to the question of the potential effects of PBM therapy on pre-malignant and malignant cells. The purpose of this study was to examine the outcome of cancer therapy and incidence of tumor recurrence in locally advanced oral squamous cell carcinoma (OSCC) patients treated with PBM therapy for OM. METHODS: A retrospective clinical analysis of 152 advanced OSCC patients treated with prophylactic PBM therapy for radiotherapy-induced OM from January 2009 to December 2014 was conducted. RESULTS: Of the 152 OSCC patients treated with PBM therapy in this study, 19 (12.5%) had stage III and 133 (87.5%) had stage IV tumors. Of these, 52 (34.2%) received initial treatment with surgery followed by adjuvant radiotherapy, 94 (61.8%) with exclusive chemoradiation, and 6 (4%) with induction chemotherapy followed by surgery and radiotherapy. After a mean follow up of 40.84 (+/- 11.71) months, the overall survival and disease-free survival rates were 46.7 and 51.8%, respectively. Forty-five (29.6%) patients developed local-regional recurrence, 10 (6.57%) patients developed distant relapse, and 19 (12.5%) developed new (second) primary tumors. CONCLUSIONS: Clinicopathological features and survival outcomes in the PBM-treated patients were similar to previously published data for conventional treatments in patients with advanced OSCC. In this study, prophylactic use of PBM therapy did not impact treatment outcomes of the primary cancer, recurrence or new primary tumors, or survival in advanced OSCC patients. PMID- 29423684 TI - Small Things, Micro-Affirmations and Helpful Professionals Everyday Recovery Orientated Practices According to Persons with Mental Health Problems. AB - The aim of this study is to present concrete descriptions of the content in the construction of helpful relationships with staff, according to users. Starting with the re-occurring concept of the meaning of "little things" in recovery studies, a literature review was done. A thematic analysis shows that small things play an important role in improving a person's sense of self. Small things seem to be an invisible but effective parts of a recovery-orientated practice, but they might be defined as unprofessional and their efficacy negated. PMID- 29423683 TI - A phase I study of afatinib for patients aged 75 or older with advanced non-small cell lung cancer harboring EGFR mutations. AB - This phase I trial was conducted to determine the maximum tolerated dose (MTD) and recommended dose of afatinib for phase II trial in elderly patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The study used a standard 3 + 3 dose escalation design. Patients aged 75 years or older with advanced NSCLC harboring EGFR mutations were enrolled. The doses of afatinib, which were given once daily, were planned as follows: level 1, 20 mg/day; level 2, 30 mg/day; level 3, 40 mg/day. Dose-limiting toxicity (DLT) was defined as grade 4 hematologic, persistent grade > 2 diarrhea for > 2 days despite concomitant medications or grade 3 non hematologic toxicity. DLT was evaluated during day 1-28. Fifteen patients were enrolled. Patient characteristics were: male/female 3/12; median age 79 (range 75 87); PS 0/1, 2/13. Six patients have been treated at levels 1 and 3, and three patients at level 2. At level 1, one of six patients experienced grade 3 rush, grade 3 anorexia, and grade 3 infection as DLTs. At level 2, none of three patients experienced a DLT. At level 3, two patients developed grade 3 diarrhea, one of whom also experienced grade 3 anorexia. Most frequent adverse events of any grade were diarrhea, paronychia, rush, and nausea. Most patients at level 2 and 3 required dose reduction in 3 months. MTD was defined as 40 mg/day, and recommended dose for phase II study in elderly patients was 30 mg/day. PMID- 29423685 TI - Subchronic methionine load induces oxidative stress and provokes biochemical and histological changes in the rat liver tissue. AB - The aim of this study was to assess the effects of L-cysteine (Cys) (7 mg/kg) and N-acetyl-L-cysteine (NAC) (50 mg/kg) in the rat liver caused by subchronic i.p. application of methionine (Met) (0.8 mmol/kg) during 21 days. Malondialdehyde (MDA) concentration, glutathione content (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and acetylcholinesterase (AchE) activities were determined in the liver tissue and activities of liver enzymes (AST, ALT, ALP, and GGT) and concentrations of total proteins and albumin were determinated in plasma/serum. Catalase, superoxide dismutase, and acetylcholinesterase activities were increased by Cys and NAC. Met caused periportal mononuclear infiltration and rare focal necrosis of hepatocytes. In Cys- and NAC-supplemented groups, intracellular edema and microvesicular fatty changes without necrosis were noticed. We observed decrease of AST, ALT, and ALP activity in the methionine-treated group. Our results indicate that Cys and NAC application can increase activity of antioxidative enzymes and prevent intensive histological changes in liver in condition of subchronic methionine exposure. PMID- 29423687 TI - Inducing negative affect using film clips with general and eating disorder related content. AB - The aim of the present study was to select appropriate film clips with a general vs. eating disorder (ED)-related content to induce negative affect. More specifically, the study examined the subjective emotional experience (valence, arousal, anxiety, induction of somatic symptoms, and ability to control reactions during film clips) of Greek-Cypriot university students (N = 79) in response to three types of film clips: general unpleasant, ED-specific unpleasant, and emotionally neutral. In addition, the study aimed to compare the emotional reactions to the aforementioned clips between two groups of participants differing on their risk for ED (high vs. low). Preliminary results indicate the clips with general content ("The Champ") and with ED-specific content ("Binge eating") that are most effective in inducing negative affect and differentiating between risk groups. These clips provide an effective method for emotion induction that can be used for assessing the emotional experience of individuals with ED symptoms, since their emotional experience is significantly implicated in the development and maintenance of their symptoms (Merwin, Clin Psychol Sci Pract 18(3):208-214, 2011).Level of evidence No level of evidence, Experimental Study. PMID- 29423686 TI - TGF-beta1 Regulation of P-JNK and L-Type Calcium Channel Cav1.2 in Cortical Neurons. AB - Central nervous system (CNS) diseases can cause a series of neuronal lesions, which may be improved by the anti-apoptotic neuroprotection of transforming growth factor-beta 1 (TGF-beta1). In neurons, L-type Ca2+ channels (LTCC) are mainly composed of Cav1.2 subunits. Given the implication of TGF-beta1 in numerous CNS diseases, we examined the neuroprotective effects of TGF-beta1 on the Cav1.2 channel in the CNS. To simulate acute mechanical traumatic brain injury (TBI), we used a needle to create parallel scratches across plates, which were cultured for 9 h. Meanwhile, Fluo4-AM-loaded laser scanning confocal microscopy with a dual wavelength of 488 nm/530 nm was employed to determine intracellular calcium concentrations ([Ca2+]i). We found that MAPK inhibitors impede TGF-beta1-induced cell viability and that TGF-beta1 recovered from the trauma-induced cell viability in neurons. Cav1.2 production was significantly decreased in the TGF-beta1-treated (10 ng/mL) neurons. At this TGF-beta1 concentration, Cav1.2 was significantly down-regulated in a time-dependent manner after 12 h. Moreover, TGF-beta1 partially recovered the protein levels of Cav1.2 that were reduced by TBI. TGF-beta1 significantly inhibited the fluorescence intensity of [Ca2+]i increased by KCl and delayed the time of the peak [Ca2+]i. The observed effects of TGF-beta1 on Cav1.2 were regulated by MAPK inhibitors. The observed effects of TGF-beta1 on P-JNK were also impeded by pre-incubation with the LTCC inhibitor (10 MUM) nimodipine in trauma-injured neurons. Altogether, TGF-beta1 regulated LTCCs through a mechanism dependent on MEK, JNK1/2 and p38 MAPK signal pathways in cortical neurons. Thus, we suggest the involvement of this mechanism in cell viability. PMID- 29423689 TI - Development of a new adsorbent from pumpkin husk by KOH-modification to remove copper ions. AB - Heavy metal pollution in watercourses is a major environmental problem throughout the world due to rapid population growth, industrialization, and economic development. Considering this, the present study aimed to develop a new adsorbent from pumpkin husk (PH) by KOH modification to remove copper (Cu2+) ions and to explore its adsorptive potential. The sorption studies of Cu2+ on KOH-modified PH were carried out as functions of particle size, solution pH, adsorbent dose, temperature, initial metal concentration, and contact time. The sorption capacity of KOH-modified PH was found to be higher than that of raw PH, as 19.4 and 10.2 mg g-1, respectively. Morphology and surface structures of adsorbents were characterized by determination of zero point charge, a Fourier transform infrared spectrometer (FTIR-ATR) spectra, and a scanning electron microscopy (SEM) of PH powders before and after the sorption of Cu2+. The pHzpc of PH was found to be 5.0. FTIR-ATR analyses indicated that amino, amide, hydroxyl, carboxyl, and oxygenated groups of PH play an important role in the sorption process. Sorption isotherm, kinetic, and thermodynamic parameters of Cu2+ on KOH-modified PH were studied. The kinetic process was well represented by the Logistic model. The maximum sorption was found as 73.16 mg g-1 according to the well-fitting of Langmuir isotherm. Results of sorption and thermodynamic studies indicated that the process was exothermic, being feasible, and spontaneous. KOH-modified PH as an eco-friendly adsorbent had great potential to remove Cu2+ ions from aquatic system. PMID- 29423688 TI - Conceptualizing body dissatisfaction in eating disorders within a self discrepancy framework: a review of evidence. AB - Body dissatisfaction, the negative subjective evaluation of one's body, is associated with many negative psychological and physical health consequences. One conceptualization of body dissatisfaction includes an experience of discrepancy between perceived actual and ideal body shapes. This paper reviews the literature on three facets of body dissatisfaction from the framework of self-discrepancy theory: perceptions of current weight, ideal body weight, and the relative importance of conforming to ideals. We review components of body dissatisfaction among healthy individuals and eating-disordered individuals. We also address the conceptualization's relationship among body dissatisfaction, weight history, and dieting to expand the impact of body dissatisfaction research and to provide more information on the nature and treatment of eating disorders. PMID- 29423691 TI - Quantitative assessment of human-induced impacts based on net primary productivity in Guangzhou, China. AB - Urban expansion and land cover change driven primarily by human activities have significant influences on the urban eco-environment, and together with climate change jointly alter net primary productivity (NPP). However, at the spatiotemporal scale, there has been limited quantitative analysis of the impacts of human activities independent of climate change on NPP. We chose Guangzhou city as a study area to analyze the impacts of human activities on NPP, as well as the spatiotemporal variations of those impacts within three segments, using a relative impact index (RII) based on potential NPP (NPPp), actual NPP (NPPact), and NPP appropriation due to land use/land cover change (NPPlulc). The spatial patterns and dynamics of NPPact and NPPlulc were evaluated and the impacts of human activities on NPP during the process of urban sprawl were quantitatively analyzed and assessed using the RII. The results showed that NPPact and NPPlulc in the study area had clear spatial heterogeneity, between 2001 and 2013 there was a declining trend in NPPact while an increasing trend occurred in NPPlulc, and those trends were especially significant in the 10-40-km segment. The results also revealed that more than 91.0% of pixels in whole study region had positive RII values, while the lowest average RII values were found in the > 40-km segment (39.03%), indicating that human activities were not the main cause for the change in NPP there; meanwhile, the average RII was greater than 65.0% in the other two, suggesting that they were subjected to severe anthropogenic disturbances. The RII values in all three segments of the study area increased, indicating an increasing human interference. The 10-40-km buffer zone had the largest slope value (0.5665), suggesting that this segment was closely associated with growing human disturbances. Particularly noteworthy is the fact that the > 40-km segment had a large slope value (0.3323) and required more conservation efforts. Based on the above results, we suggest that continuous efforts may be necessary to improve the intensity of protection and management in the urban environment of Guangzhou. PMID- 29423690 TI - Exposure to aged crumb rubber reduces survival time during a stress test in earthworms (Eisenia fetida). AB - Solid waste management struggles with the sustainable disposal of used tires. One solution involves shredding used tires into crumb rubber and using the material as infill for artificial turf. However, crumb rubber contains hydrocarbons, organic compounds, and heavy metals, and it travels into the environment. Earthworms living in soil contaminated with virgin crumb rubber gained 14% less body weight than did earthworms living in uncontaminated soil, but the impact of aged crumb rubber on the earthworms is unknown. Since many athletic fields contain aged crumb rubber, we compared the body weight, survivorship, and longevity in heat and light stress for earthworms living in clean topsoil to those living in topsoil contaminated with aged crumb rubber. We also characterized levels of metals, nutrients, and micronutrients of both soil treatments and compared those to published values for soil contaminated with virgin crumb rubber. Consistent with earlier research, we found that contaminated soil did not inhibit microbial respiration rates. Aged crumb rubber, like new crumb rubber, had high levels of zinc. However, while exposure to aged crumb rubber did not reduce earthworm body weight as did exposure to new crumb rubber, exposure to aged crumb rubber reduced earthworm survival time during a stress test by a statistically significant 38 min (16.2%) relative to the survival time for worms that had lived in clean soil. Aged crumb rubber and new crumb rubber appear to pose similar toxic risks to earthworms. This study suggests an environmental cost associated with the current tire-recycling solution. PMID- 29423692 TI - Long-term distribution and habitat changes of protected wildlife: giant pandas in Wolong Nature Reserve, China. AB - Changes in wildlife habitat across space and time, and corresponding changes in wildlife space use, are increasingly common phenomenon. It is critical to study and understand these spatio-temporal changes to accurately inform conservation strategy and manage wildlife populations. These changes can be particularly large and complex in areas that face pressure from human development and disturbance but are also under protection and/or restoration regimes. We analyzed changes in space use and habitat suitability of giant pandas in Wolong Nature Reserve, China, over three decades using kernel density, spatio-temporal analysis of moving polygons (STAMP), and MaxEnt methods, and data from three national censuses. Between 2001 and 2012, there was a slight retraction in total range, and more area of significant space use decreases than increases. Habitat suitability varied spatially and temporally, with a 4.1% decrease in average suitability between 1987 and 2001 and a 3.5% increase in average suitability in between 2001 and 2012. Elevation and bamboo were the most important habitat predictors across the three censuses. Human and natural disturbance variables such as distance to household and the distance to landslide variable in the 4th census were also important predictors, and likely also negatively influenced important habitat variables such as bamboo and forest cover. We were able to measure changes in space utilization and habitat suitability over a large time scale, highlighting the achievements and challenges of giant panda conservation. Long-term monitoring of the changes in distribution and habitat of threatened species, and an analysis of the drivers behind these changes such as undergone here, are important to inform the management and conservation of the world's remaining wildlife populations. PMID- 29423693 TI - Water infrastructure and well-being among First Nations, Metis and Inuit individuals in Canada: what does the data tell us? AB - This paper documents the association between water and sanitation infrastructure and health indicators in Canada for First Nations, Metis and Inuit individuals living on and off-reserve in Canada. We use two data sources: the Aboriginal Peoples Survey and a survey conducted in a First Nations community in northern Manitoba-St. Theresa Point First Nation. We find statistically significant relationships between water infrastructure and health status in both sources of data. In particular, among individuals living off-reserve, contaminated water is associated with a 5-7% lower likelihood of reporting good self-rated health and a 4% higher probability of reporting a health condition or stomach problem. Those in St. Theresa Point First Nation without running water are four times more likely to report an illness relative to those with running water. Off-reserve, this likely suggests a need for improved public education on the management of private water supplies and more frequent water testing. Our case study suggests that further investment in water/sanitation infrastructure and housing is needed in the community. PMID- 29423694 TI - Attitudes to climate change, perceptions of disaster risk, and mitigation and adaptation behavior in Yunlin County, Taiwan. AB - Issues that are associated with climate change have global importance. Most related studies take a national or regional perspective on the impact of climate change. Taiwan is constrained by its geographical conditions, which increase its vulnerability to climate change, especially in its western coastal areas. The county that is most affected by climate change is Yunlin. In 2013-2014, projects that were sponsored by Taiwan's government analyzed the relationship among synthesized vulnerability, ecological footprint (EF) and adaptation to climate change and proposed 15 categories of synthesized vulnerability and EF values. This study further examines the relationship between vulnerability and EF values and examines how residents of four townships-Linnei, Sihu, Mailiao, and Huwei cope with the effects of climate change. This study investigates whether the residents of the four townships vary in their attitudes to climate change, their perceptions of disaster risk, and their behavioral intentions with respect to coping with climate change. The structural equation model (SEM) is used to examine the relationships among attitudes to climate change, perceptions of disaster risk, and the behavioral intentions of residents in townships with various vulnerabilities to climate change. The results that are obtained using the SEM reveal that climate change mitigation/adaptation behavior is affected by attitudes to climate change and perceptions of disaster risk. However, the effects of attitudes and perceptions on mitigation and adaptation that are mediated by place attachment are not statistically significant. PMID- 29423695 TI - Assessment of atrazine toxicity to the estuarine phytoplankter, Dunaliella tertiolecta (Chlorophyta), under varying nutrient conditions. AB - Anthropogenic inputs of chemical environmental contaminants are frequently associated with developing harmful algal blooms, but little is known about how estuarine phytoplankton assemblages respond to multiple, co-occurring chemical stressors in chronically disturbed habitats. The goals of this research were to establish a robust protocol for testing the effects of atrazine on estuarine phytoplankton, and then to use that protocol to compare the effects of atrazine exposure with and without nutrient enrichment on a cosmopolitan estuarine/marine alga, Dunaliella tertiolecta (Chlorophyta). Atrazine sensitivity in nutrient replete media (96-h growth inhibition [Formula: see text]) was 159.16 MUg l-1, but sensitivity was influenced by exposure duration, and inhibitory effects of herbicide on algal growth decreased under imbalanced nutrient regimes and low nitrogen and phosphorus supplies. These findings advance knowledge about how nutrient regimes and herbicides interact to control estuarine phytoplankton population dynamics. PMID- 29423696 TI - Treatment of soak liquor and bioelectricity generation in dual chamber microbial fuel cell. AB - The discharge of untreated soak liquor from tannery industry causes severe environmental pollution. This study is characterizing the soak liquor as a substrate in the microbial fuel cell (MFC) for remediation along with electricity generation. The dual chamber MFC was constructed and operated. Potassium permanganate was used as cathode solution and carbon felt electrode as anodic and cathodic material, respectively. The soak liquor was characterized by electrochemical studies viz., cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and polarization studies, respectively. The removal percentage of protein, lipid, and chemical oxygen demand (COD) were measured before and after treatment with MFC. The results of MFC showed a highest current density of 300 mA/cm2 and a power density of 92 mW/m2. The removal of COD, protein, and lipid were noted as 96, 81, and 97% respectively during MFC process. This MFC can be used in tannery industries for treating soak liquor and simultaneous electricity generation. PMID- 29423697 TI - Probing the toxic mechanism of bisphenol A with acid phosphatase at the molecular level. AB - As an endocrine-disrupting chemical, bisphenol A (BPA), can affect normal endocrine function of hormone. This paper studied the toxic effect of BPA on acid phosphatase at the molecular level by multi-spectroscopic measurements, molecular docking, and enzyme activity experiment. BPA could enhance the fluorescence intensity, change the structure, and cause an increased hydrophobicity of acid phosphatase. Hydrogen bond interaction and van der Waals forces were the main forces to generate the BPA-acid phosphatase complex on account of the negative DeltaH (- 36.92 kJ mol-1) and DeltaS (- 50.78 J mol-1 K-1). BPA led to the loosening and unfolding of protein structure and extending the peptide strands, as revealed by UV-vis absorption and CD spectra. Based on the enzyme activity experiment, BPA could decrease the activity of the acid phosphatase by entering the active site of the enzyme. The molecular docking model showed that BPA could bind into the cavity of acid phosphatase and interact with Tyr A252 and a hydrogen bond (1.47 A) was formed in the binding process. This work suggested the structures and functions of acid phosphatase were both affected by BPA. PMID- 29423698 TI - Assessment of progeny concentrations of 222Rn/220Rn and their related doses using deposition-based direct progeny sensors. AB - Indoor radon and thoron concentrations in the domestic environment result in natural radiation exposure to the public due to the inhalation of their short lived decay products. Keeping this in view, the annual effective dose and other radiation risks due to radon/thoron progenies have been calculated. In this study, newly developed time deposition-based progeny sensors (DTPS/DRPS) were used for long-term passive determination of progeny concentrations in the environment of Jammu and Kashmir, Himalayas, India. The total equilibrium equivalent radon (EECRA + U) and thoron (EECTA + U) concentrations ("A" and "U" referring to attached and unattached fractions) were found to vary from 5 to 38 Bq m-3 with an average value of 18 Bq m-3 and from 0.48 to 5.49 Bq m-3 with an average value of 1.69 Bq m-3, respectively. The aerosol concentration, equilibrium factors, and unattached fractions for radon and thoron progeny have been estimated in normal living conditions and their dependence on each others have also been studied. The annual equilibrium factor for radon and thoron progeny has been determined from the calculated data. The estimated annual effective dose due to radon progeny (0.34 to 2.42 mSv y-1) and thoron progeny (0.13 to 1.54 mSv y-1) is found to be below the world's recommended level. Based on measurements of mean values of the unattached fraction, dose conversion factors (DCFs) in units of mSv per working level month (WLM) has been calculated and the average calculated values of DCFs are 24, 10, and 13 mSv WLM-1. The variability of equilibrium factor and radon/thoron progeny with different seasons, ventilation conditions, and types of houses were also analyzed. PMID- 29423699 TI - Occurrence and molecular characterization of Giardia duodenalis cysts and Cryptosporidium oocysts in raw water samples from the Rimac River, Peru. AB - Giardia and Cryptosporidium are potentially pathogenic protozoa which are ubiquitous in ambient surface water. The present study included 60 samples of surface water from three sampling sites from the Rimac River, Lima and Callao, Peru, to detect the occurrence of Giardia spp. and Cryptosporidium spp. and to perform molecular characterization of specimens found. Water samples were concentrated using the membrane filtration technique, and following elution, cysts and oocysts were visualized by direct immunofluorescence assay (IFA). For molecular characterization, tpi and bg gene fragments and 18S rRNA were amplified by nested PCR for Giardia and Cryptosporidium, respectively, followed by sequencing and phylogenetic analysis. Giardia cysts were found in 93.3% of the analyzed samples, whereas Cryptosporidium oocysts were detected in 15%. The positivity of the Giardia cysts was 86.6% (n = 26) in 2014, while Cryptosporidium oocysts were not detected. In 2015, both protozoa were found in raw water samples, with all 30 samples collected positive for Giardia cysts (100.0%) and 9 positive for Cryptosporidium oocysts (30.0%). Oocysts were detected in 20.0% of water samples from sites 1 (mean 5.25 oocysts/L) and 2 (mean 52.3 oocysts/L), while at site 3, oocysts were detected in 50.0% of raw water samples (mean 193.6 oocysts/L). The presence of Giardia duodenalis assemblage A was confirmed in several samples by the phylogenetic positioning of the bg and tpi genes, and the sub-assemblage AII was predominant (8/9). Sequencing for Cryptosporidium resulted in profiles compatible with Cryptosporidium hominis, Cryptosporidium meleagridis, and Cryptosporidium baileyi. This is the first time that the presence of G. duodenalis assemblage A/sub-assemblage AII and Cryptosporidium species has been reported in surface water samples in Peru. These Cryptosporidium species and the Giardia duodenalis assemblage are associated with human disease which highlights the potential risk to public health and the need to increase environmental monitoring measures to protect this water body. PMID- 29423702 TI - Linburg-Comstock variation: histoanatomy and classification of the connection between flexor pollicis longus and flexor digitorum profundus to the index finger. AB - PURPOSE: The aim of the study was to investigate the anatomy and histology of Linburg-Comstock variation, or the anomalous connection between flexor pollicis longus and flexor digitorum profundus to the index finger, in Thai population. METHODS: One hundred and thirty cadaveric upper limbs were dissected. Skin and superficial fascia on the anterior distal forearm and hand were removed. The tendons of the flexor pollicis longus and flexor digitorum profundus to the index finger were identified for the possible occurrence of the intertendinous connection. For histological analysis, selected specimens were sampled, and were stained with hematoxylin and eosin. RESULTS: Out of 130 dissected upper limbs, interconnection between the two tendons was found in 32 limbs (25%). The connection was classified into three types including fibrous, tendinous, and musculotendinous. In 29 cases (22%), the connection was simply the thickening of synovial sheath between the two tendons. In two cases (1%) the connection was found as an additional tendinous slip of dense regular collagen bundles running from the flexor pollicis longus to flexor digitorum profundus of the index. In one case (1%), there was an aberrant reversed musculotendinous unit running from flexor pollicis longus, and later joined the first lumbrical. CONCLUSIONS: This study provides a detailed anatomo-histological description of the interconnection between flexor pollicis longus and flexor digitorum profundus to the index finger. Its etiology could either be congenital or secondarily acquired. Surgeons should be aware of this connection for better diagnosis, surgical planning and treatment of diseased hands. PMID- 29423703 TI - Bilateral 'coronoid foramina' with accessory foramina on the 'lateral aspect of ramus' of mandible: an unseen variance discovery in humans. AB - The normal flexibility in morphology and topography of body structures may be termed as an anatomical variation. This manuscript, aims to present a unique discovery of 'coronoid foramina' bilaterally along with bilateral accessory foramina over the 'lateral aspect of the ramus of the mandible' which has never been seen or documented in the literature so far in a live patient. It is noteworthy to realize a trait of phylogenetic context in these discoveries. PMID- 29423700 TI - Effect of water and ionic liquids on biomolecules. AB - The remarkable progress in the field of ionic liquids (ILs) in the last two decades has involved investigations on different aspects of ILs in various conditions. The nontoxic and biocompatible nature of ILs makes them a suitable substance for the storage and application of biomolecules. In this regard, the aqueous IL solutions have attracted a large number of studies to comprehend the role of water in modulating various properties of biomolecules. Here, we review some of the recent studies on aqueous ILs that concern the role of water in altering the behavior of ILs in general and in case of biomolecules solvated in ILs. The different structural and dynamic effects caused by water have been highlighted. We discuss the different modes of IL interaction that are responsible for stabilization and destabilization of proteins and enzymes followed by examples of water effect on this. The role of water in the case of nucleic acid storage in ILs, an area which has mostly been underrated, also has been emphasized. Our discussions highlight the fact that the effects of water on IL behavior are not general and are highly dependent on the nature of the IL under consideration. Overall, we aim to draw attention to the significance of water dynamics in the aqueous IL solutions, a better understanding of which can help in developing superior storage materials for application purposes. PMID- 29423704 TI - Correction to: Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation. AB - The article "Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation", written by Yasemen Cihan, Nele Kanzelmeyer, Jens Drube, Martin Kreuzer, Christian Lerch, Imke Hennies, Kerstin Froede, Murielle Verboom. PMID- 29423705 TI - Chemotherapeutic Agents and the Risk of Ischemia and Arterial Thrombosis. AB - PURPOSE OF REVIEW: Numerous chemotherapeutic agents have been associated with the development of ischemia and arterial thrombosis. As newer therapies have been developed to treat cancer, some of these chemotherapy drugs have been implicated in the development of vascular disease. In this review, we will summarize the most common chemotherapeutic drug classes that may play a role in the development of ischemic heart disease. RECENT FINDINGS: Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors have a number of cardiovascular toxicities. The possible mechanisms of action of these drugs leading to ischemic complications are varied but include endothelial dysfunction, platelet aggregation, reduced levels of nitrous oxide (NO), and elevated levels of reactive oxygen species (ROS), and vasospasm. While some drugs act through multiple pathways that result in the development of ischemic heart disease, others such as the antimetabolites and antimicrotubules appear to primarily cause vasospasm. Furthermore, while aromatase inhibitors increase the risk of heart disease in comparison to tamoxifen in large studies, this finding likely occurs because of a protective role of tamoxifen on cardiovascular risk factors rather than a direct effect of aromatase inhibitors. Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors can lead to ischemic complications in patients with cancer. Many of these drugs have proven to be effective in improving cancer prognosis, but their possible cardiovascular effects have to be carefully monitored and treated. Treatment of ischemic complications in the setting of cancer therapy should focus on the optimal medical management of known cardiovascular risk factors and follow an evidence-based approach. PMID- 29423706 TI - Active optical sensor assessment of spider mite damage on greenhouse beans and cotton. AB - The two-spotted spider mite, Tetranychus urticae Koch, is an important pest of cotton in mid-southern USA and causes yield reduction and deprivation in fiber fitness. Cotton and pinto beans grown in the greenhouse were infested with spider mites at the three-leaf and trifoliate stages, respectively. Spider mite damage on cotton and bean canopies expressed as normalized difference vegetation index indicative of changes in plant health was measured for 27 consecutive days. Plant health decreased incrementally for cotton until day 21 when complete destruction occurred. Thereafter, regrowth reversed decline in plant health. On spider mite treated beans, plant vigor plateaued until day 11 when plant health declined incrementally. Results indicate that pinto beans were better suited as a host plant than cotton for rearing T. urticae in the laboratory. PMID- 29423707 TI - Effect of reproductive disorders on productivity and reproductive efficiency of dromedary she-camels in relation to cytokine concentration. AB - This experiment was conducted to study the effect of reproductive disorders on reproductive efficiency and milk production in relation with pro-inflammatory cytokines in dromedary she-camels. Total of 20 late pregnant Maghrabi she-camels, aging 6-9 years, weighing 420-550 kg, and between the second and third parities were divided into two groups. Animals in the first group (n = 12) showed normal reproductive status (G1) at parturition, while those in the second one (n = 8) were suffered from reproductive disorders after parturition (G2). Results showed that during pre-partum, red blood cells (RBCs) count decreased (P <= 0.05), while white blood cells (WBCs), packed cell volume (PCV) value, and neutrophils percentage increased (P <= 0.05) in G2 than in G1. Percentages of monocytes, basophils, and eosinophils as well as hemoglobin concentration did not differ significantly (P >= 0.05) in G1 and G2. During postpartum period, the same results were noticed in addition to increase (P <= 0.05) in eosinophil and decrease (P <= 0.05) in basophils percentages. During prepartum period, concentration of total proteins, albumin (AL) and IGF-1decreased (P <= 0.05), cholesterol concentration, and activity of AST and ALT were higher (P <= 0.05) in G2 than in G1. Globulin (GL), AL: GL ratio, glucose, urea-N, creatinine, and triglyceride concentrations did not differ significantly in G1 and G2. During postpartum period, the same results were noticed with decrease (P <= 0.05) in GL and glucose concentrations in G2 as compared to G1. Concentration of all pro inflammatory cytokines, including IL-6, IL-10, and IFN-gamma, was higher (P <= 0.05) in G2 than in G1 at different peri-parturient times. Milk yield, days in milk, protein and lactose percentages, and IgG concentration were higher (P <= 0.05) in G1 than in G2. Fat, total solids, solid non-fat, and ash percentages did not show any significant differences between both groups. Reproductive traits, including length of estrous cycle, duration of estrous period, number of services/conception, gestation period, days open, and conception rate, were higher (P < 0.05) in G1 than in G2. From the present study can be concluded that pro-inflammatory cytokines may be a necessary test for the early diagnosis to prevent related disease in dromedary camels suffering from reproductive disorders. This study indicated strong relationship between hematological parameters and concentration of blood biochemicals and cytokines with reproductive efficiency in camels, which may be helpful in elucidating the adverse effects associated with reproductive disorders. PMID- 29423708 TI - Knowledge, attitude, and practices on usage, disposal, and effect of plastic bags on sheep and goats. AB - The objective of this study was to evaluate knowledge, attitudes, and practices of people in the Nairobi and Kajiado Counties, Kenya, on the usage, disposal, and effect of plastic waste on sheep and goats (shoats). A semi-structured questionnaire was used to collect data from 384 respondents in four communities in the two counties. Most of the people irrespective of their age, occupation, and educational status used plastic bags of some type on a daily basis. A high proportion of the respondents (37.0%, 142) used plastic bags because of the low cost. Approximately, 79.1% (304) disposed used plastic bags in open dumps. A total of 147 (38.3%) households kept shoats. Out of these, 38.1% (56) purchased feed and also allowed their animals to roam. Most of them (45.3%, 174) thought that lack of feed for the animals was the main reason why shoats roam and scavenge at refuse dump sites and road sides. A large proportion of the respondents (44.5%, 143) mentioned death of animals as the ultimate consequence of ingestion of waste plastic bags. Though, the respondents were aware that indiscriminate disposal of used plastic bags could result in death of the animals from which they derive their livelihoods, they nevertheless continued with the practice. There is a need for a paradigm shift in the way and manner plastic bags are used and disposed. PMID- 29423709 TI - An ascomycota coculture in batch bioreactor is better than polycultures for cellulase production. AB - Efficient hydrolysis of holocellulose depends on a proper balance between cellulase (endoglucanase, exoglucanase, beta-glucosidase) and xylanase activities. The present study aimed to induce the production of cellulases and xylanases using liquid cultures (one, two, three, and four fungal strains on the same bioreactor) of wild strains of Trichoderma harzianum, Aspergillus niger, and Fusarium oxysporum. The strains were identified by amplification and analysis of the ITS rDNA region and the obtained sequences were deposited in Genbank. Enzymes (endoglucanase, exoglucansae, beta-glucosidase, and xylanase activities) and the profile of extracellular protein isoforms (SDS-PAGE) produced by different fungal combinations (N = 14) were analyzed by Pearson's correlation matrix and principal component analysis (PCA). According to our results, induction of endoglucanase (19.02%) and beta-glucosidase (6.35%) were obtained after 4 days when A. niger and F. oxysporum were cocultured. The combination of A. niger-T. harzianum produced higher endoglucanase in a shorter time than monocultures. On the contrary, when more than two strains were cultured in the same reactor, the relationships of competition were established, trending to diminish the amount of enzymes and the extracellular protein isoforms produced. The xylanase production was sensible to stress produced by mixed cultures, decreasing their activity. This is important when the aim is to produce cellulase-free xylanase. In addition, exoglucanase activity did not change in the combinations tested. PMID- 29423710 TI - Intravenous cocaine self-administration in a panel of inbred mouse strains differing in acute locomotor sensitivity to cocaine. AB - RATIONALE: Initial sensitivity to drugs of abuse often predicts subsequent use and abuse, but this relationship is not always observed in human studies. Moreover, studies examining the relationship between initial locomotor sensitivity and the rewarding and reinforcing effects of drugs in animal models have also been equivocal. Understanding the relationship between initial drug effects and propensity to continue use, potentially resulting in the development of a substance use disorder, may help to identify key targets for prevention and treatment. OBJECTIVES: We examined intravenous cocaine self-administration in a set of mouse strains that were previously identified to be at the phenotypic extremes for cocaine-induced locomotor activation to determine if initial locomotor sensitivity predicted acquisition, extinction, dose response, or progressive ratio (PR) breakpoint. METHODS: We selected eight inbred mouse strains based on locomotor sensitivity to 20 mg/kg cocaine. These strains, designated as low and high responders, were tested in an intravenous self administration paradigm that included acquisition of 0.5 mg/(kg*inf) under a FR1 schedule, extinction, re-acquisition, dose response to 0.125, 0.25, 0.5, 1, and 2 mg/(kg*inf), and progressive ratio. RESULTS: We observed overall differences in self-administration behavior between high and low responders. Low responders self administered less cocaine and had lower breakpoints under the PR schedule. However, we also observed strain differences within each group. Self administration in the low responder, LG/J, more closely resembled the behavior of the high-responding group, and the high responder, P/J, had self-administration behavior that more closely resembled the low-responding group. CONCLUSIONS: We conclude that acute cocaine-induced locomotor activation does predict self administration behavior, but in a strain-specific manner. These data support the idea that genetic background influences the relationship among addiction-related behaviors. PMID- 29423711 TI - A protocol for obtaining DNA barcodes from plant and insect fragments isolated from forensic-type soils. AB - Soil is often collected from a suspect's tire, vehicle, or shoes during a criminal investigation and subsequently submitted to a forensic laboratory for analysis. Plant and insect material recovered in such samples is rarely analyzed, as morphological identification is difficult. In this study, DNA barcoding was used for taxonomic identifications by targeting the gene regions known to permit discrimination in plants [maturase K (matK) and ribulose 1,5-biphosphate carboxylase (rbcL)] and insects [cytochrome oxidase subunit I (COI)]. A DNA barcode protocol suitable for processing forensic-type biological fragments was developed and its utility broadly tested with forensic-type fragments (e.g., seeds, leaves, bark, head, legs; n, 213) isolated from soils collected within Virginia, USA (n, 11). Difficulties with PCR inhibitors in plant extracts and obtaining clean Sanger sequence data from insect amplicons were encountered during protocol development; however, the final protocol produced sequences specific to the expected locus and taxa. The overall quantity and quality of DNA extracted from the 213 forensic-type biological fragments was low (< 15 ng/MUL). For plant fragments, only the rbcL sequence data was deemed reliable; thus, taxonomic identifications were limited to the family level. The majority of insect sequences matched COI in both GenBank and Barcode of Life DataSystems; however, they were identified as an undescribed environmental contaminant. Although limited taxonomic information was gleaned from the forensic-type fragments processed in this study, the new protocol shows promise for obtaining reliable and specific identifications through DNA barcoding, which could ultimately enhance the information gleaned from soil examinations. PMID- 29423712 TI - Correction to: Cone beam computed tomography and ultrasonography imaging of benign intraosseous jaw lesion: a prospective radiopathological study. AB - In the original version of this article, '123 lytic intraosseous jaw lesions diagnosed in 112 patients' was incorrectly presented as '123 lytic intraosseous jaw lesions diagnosed in 121 patients' and 'an average age of 31.7 +/- 15.4 (range, 6-72)' was incorrectly presented as 'average age of 15.4 +/- 31.7 (range, 6-72)'. PMID- 29423714 TI - Wastewater Treatment Energy Recovery Potential For Adaptation To Global Change: An Integrated Assessment. AB - Approximately 20% of wastewaters globally do not receive treatment, whereas wastewater discharges are projected to increase, thereby leading to excessive water quality degradation of surface waters on a global scale. Increased treatment could help alleviate water quality issues by constructing more treatment plants; however, in many areas there exist economic constraints. Energy recovery methods including the utilization of biogas and incineration of biosolids generated during the treatment process may help to alleviate treatment costs. This study explores the potential for investments in energy recovery from wastewater to increase treatment levels and thus improve surface water quality. This was done by examining the relationships between nutrient over-enrichment, wastewater treatment, and energy recovery at a global scale using system dynamics simulation as part of the ANEMI integrated assessment model. The results show that a significant amount of energy can be recovered from wastewater, which helps to alleviate some of the costs of treatment. It was found that wastewater treatment levels could be increased by 34%, helping to offset the higher nutrient loading from a growing population with access to improved sanitation. The production of renewable natural gas from biogas was found to have the potential to prolong the depletion of natural gas resources used to produce electricity and heat. It is recommended that agricultural nutrient discharges be better managed to help reduce nutrient over-enrichment on global scale. To increase the utility of the simulation, a finer spatial scale should be used to consider regional treatment, economic, and water quality characteristics. PMID- 29423713 TI - Effects of a sodium fluoride- and phytate-containing dentifrice on remineralisation of enamel erosive lesions-an in situ randomised clinical study. AB - OBJECTIVE: The objective of this work was to evaluate effects of a dentifrice containing sodium fluoride (1150 ppm F) and the organic polyphosphate phytate (0.85% w/w of the hexa-sodium salt) on in situ remineralisation of early enamel erosive lesions and resistance to subsequent demineralisation. MATERIALS AND METHODS: Subjects (n = 62) wore palatal appliances holding eight bovine enamel specimens with pre-formed erosive lesions. They brushed their natural teeth with the phytate test dentifrice (TD); a positive control dentifrice (PC, 1150 ppm fluoride as NaF); a reference dentifrice (RD, disodium pyrophosphate + 1100 ppm fluoride as NaF) or a negative control dentifrice (NC, fluoride-free) in a randomised, double-blind, crossover design. Specimens were removed at 2, 4 and 8 h post-brushing and exposed to an ex vivo acid challenge. Surface microhardness (Knoop) was measured at each stage. The primary efficacy variable was relative erosion resistance (RER); other variables included the surface microhardness recovery (SMHR), acid resistance ratio (ARR) and enamel fluoride uptake (EFU). RESULTS: After 4 h, the results for RER, ARR and EFU were in the order PC > TD = RD > NC with PC > TD = RD = NC for SMHR. Results at 2 and 8 h were generally consistent with the 4 h data. Mineralisation progressed over time. Dentifrices were generally well-tolerated. CONCLUSIONS: In this in situ model, addition of phytate or pyrophosphate to a fluoride dentifrice inhibited the remineralising effect of fluoride. Both formulations still delivered fluoride to the enamel and inhibited demineralisation, albeit to a lesser extent than a polyphosphate-free dentifrice. CLINICAL RELEVANCE: Addition of phytate or pyrophosphate to a fluoride dentifrice may reduce its net anti-erosive properties. PMID- 29423715 TI - Modeling and simulation of bone mineral density in Japanese osteoporosis patients treated with zoledronic acid using tartrate-resistant acid phosphatase 5b, a bone resorption marker. AB - : Annual intravenous administration of zoledronic acid is used in the treatment of osteoporosis. A mathematical model was developed to predict bone mineral density up to 2 years after two annual doses of zoledronic acid from the early values of a bone resorption marker in osteoporosis patients. INTRODUCTION: The measurement of bone mineral density (BMD) has been used as a surrogate marker instead of the observation of incident fractures to detect the efficacy of treatment. However, this method requires a long time to obtain significant changes. On the other hand, bone resorption markers respond to bone resorption inhibitors within a few weeks. Therefore, the aim of this study was to develop a mathematical model predicting long-term BMD after two annual doses of zoledronic acid (ZOL) using the early response of a bone resorption marker in osteoporosis patients. METHODS: The model was constructed using 3410 tartrate-resistant acid phosphatase 5b (TRACP-5b) serum concentrations and 1146 lumbar spine (L2-L4) BMD values from 306 patients with primary osteoporosis. A mathematical model was developed to describe the time-dependent profiles of TRACP-5b and BMD. RESULTS: The percentage changes from baseline of the BMD (%BMD) at up to 2 years were predicted from patients' baseline BMD and baseline and 12-week TRACP-5b values by the model obtained. The simulated 90% prediction interval almost covered the observed %BMD distribution at each time point, and the predictions were comparable to the observed %BMD. CONCLUSIONS: This is the first model to predict BMD for up to 2 years following two annual doses of ZOL using patients' background characteristics and the early response of TRACP-5b. This model allows us to inform patients at the initial stage of ZOL treatment of their predicted response to treatment. PMID- 29423716 TI - Neutrophil-lymphatic interactions during acute and chronic disease. AB - The lymphatic system aids in osmoregulation through tissue fluid transport, but is also designed to support communication between cells of the innate and adaptive immune systems. During inflammation, changes within the lymphatics can result in an altered response to infection. Neutrophils have been described as one key cell type that facilitates antigen capture and presentation within the lymphatic system, enabling an effective adaptive immune response. Disruption of neutrophil recruitment during inflammation, due to alterations in lymphatics, is a growing area of study due to their key role in infection resolution. In this review, we discuss the currently known methods by which neutrophils are recruited to the lymphatic system and what subsequent effects they have on resident and recruited cells within the lymph vessels and nodes. We also discuss the changes in neutrophil activation and recruitment during chronic inflammatory diseases and their relationship to lymphatic dysfunction. PMID- 29423717 TI - We must harness technology to deliver the musculoskeletal disease epidemiology that is urgently needed across sub-Saharan Africa. PMID- 29423718 TI - Disease severity impacts the relationship of apelin with arterial function in patients with rheumatoid arthritis. AB - Apelin can improve arterial function by enhancing the expression of endothelial nitric oxide synthase but this effect depends markedly on endothelial integrity. We hypothesized that inflammation influences the potential impact of apelin on arterial function in rheumatoid arthritis (RA). We assessed the associations of apelin concentrations with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic pressure (CSP), central pulse pressure (CPP), peripheral pulse pressure (PPP), pulse pressure amplification (PPamp), and forward wave pressure (Pf)) among 170 RA patients without cardiovascular disease. In multivariable regression models, apelin concentrations were not independently associated with arterial function measures (p >= 0.15) in all patients. Inflammation markers were not consistently associated with apelin levels but joint deformity counts, Disease Activity Score in 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) impacted apelin pressure pulsatility relations (interaction p <= 0.05). In stratified analysis, apelin was associated with CSP (partial r = - 0.33, p = 0.01), CPP (partial r = - 0.26, p = 0.04), PPamp (partial r = 0.27, p = 0.03), and Pf (partial r = - 0.33, p = 0.01) in patients without but not with joint deformities; apelin was related to CSP (partial r = - 0.24, p = 0.05) in those with a DAS28 joint < 2.8 (median value) (partial r = - 0.24, p = 0.05) but not >= 2.8, and to CSP (partial r = - 0.36, p = 0.003) in those with an erythrocyte sedimentation rate < 13 mm/h (median value) but not >= 13 mm/h. Apelin is associated with reduced pressure pulsatility in RA patients without but not with a high inflammatory burden. A loss of apelin protective effects on arterial function may contribute to the link between RA severity and cardiovascular risk. PMID- 29423719 TI - Adults with incident accelerated knee osteoarthritis are more likely to receive a knee replacement: data from the Osteoarthritis Initiative. AB - We aimed to determine if knees with incident accelerated knee osteoarthritis (AKOA) were more likely to receive a knee replacement (KR) than those with common knee osteoarthritis (KOA) or no KOA. We conducted a nested cohort study using data from baseline and the first 9 years of the Osteoarthritis Initiative (OAI). Eligible knees had no radiographic KOA at baseline (Kellgren-Lawrence [KL] < 2). We classified 3 groups using KL grades from the first 8 years of the OAI: 1) AKOA: knee progressed to advance-stage KOA (KL 3/4) in <= 4 years, 2) common KOA: knee increased in KL grade (excluding AKOA), and 3) No KOA: no change in KL grade by 8 years. The outcome was a KR (partial or total) at or before the 9-year OAI visit. We conducted a logistic regression with generalized linear mixed model and adjusted for age, body mass index, and sex. Overall, 14% of knees with AKOA received a KR by the 9th year compared with 1% and < 1% of those with common or no KOA, respectively. Knees that developed AKOA were > 80x and ~ 25x more likely to receive a KR than knees with no KOA or incident common KOA (adjusted odds ratio = 25.08; 95% confidence interval = 9.63-65.34). In conclusion, approximately 1 in 7 knees that develop AKOA received a KR; however, KRs were rare in the OAI among other knees with no radiographic KOA at baseline. Urgent steps are needed to identify adults at high-risk for AKOA and develop prevention strategies regarding the modifiable risk factors. PMID- 29423720 TI - Association of interferon regulatory factor 5 (IRF5) gene polymorphisms with juvenile idiopathic arthritis. AB - Interferon regulatory factor 5 (IRF5) is a member of IRF family which induce signaling pathways and are involved in modulation of cell growth, differentiation, apoptosis, and immune system activity. Juvenile idiopathic arthritis (JIA) is an auto-inflammatory syndrome where the inflammatory markers are believed to play a fundamental role in its pathogenesis. In this study, we aimed to assess the association of IRF5 gene polymorphisms with susceptibility of JIA in Iranian population. Three IRF5 single-nucleotide polymorphisms (rs10954213 A/G, rs2004640 G/T, and rs3807306 G/T) were genotyped using TaqMan assays in 55 patients with JIA and 63 matched healthy individuals. The frequency of the IRF5 rs2004640 T allele was significantly higher (69 vs 45%, P value = 0.0013) in JIA group as compared to control. The frequency of the IRF5 rs 2004640 G allele was significantly higher in the control group in comparison to JIA group (54 vs 32%, P value = 0.001). Allele and genotype frequencies of the rs10954213 and rs3807306 did not show any significant difference between JIA and control group. IRF5 rs 2004640 T allele can be considered as a risk factor for the development of JIA and presence of rs 2004640 G may be act as protective factor. PMID- 29423721 TI - Reliability, validity, and cross-cultural adaptation of the Turkish version of the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire. AB - Up to 98% of rheumatoid arthritis (RA) patients experienced fatigue. It is an important physical and cognitive symptom which has overwhelming, uncontrollable, and unpredictable affects throughout their whole life. RA fatigue composes of complex and multi-dimensional components which are pain, stress, depression, inflammation, and disability. The acknowledgement of fatigue is important, and fatigue should be measured in all RA trials alongside the core set. The aim of this study was to determine reliability and validity of Turkish version of Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire in RA patients. One hundred RA patients were evaluated in the study. Exclusion criteria were determined as patients with cognitive impairment, illiterate patients, unable to understand and speak Turkish, under the age of 18, and over the age of 75. To validate Turkish version of Bristol Rheumatoid Arthritis Fatigue Multi Dimensional Questionnaire (BRAF-MDQ) (BRAF-MDQ-T), all participants answered BRAF MDQ-T, Multidimensional Assessment of Fatigue (MAF) scale, and Short Form-36 vitality (SF-36 VT). BRAF-MDQ-T was applied again 7 days later for test-retest reliability. Validity, internal consistency, and test-retest results were based on a sample of 100 patients. Internal consistency reliability of BRAF-MDQ-T was Cronbach alpha = 0.95 which was excellent. The correlation between the total scores of the BRAF-MDQ-T scale and the total scores of MAF-T was statistically significant (r = 0.82, p < 0.001). The correlation between the total scores of the BRAF-MDQ-T scale and the subscale scores of SF-36 VT was statistically significant (r = - 0.64, p < 0.001). The BRAF-MDQ-T is a valid and reliable scale for the assessment of fatigue in Turkish rheumatoid arthritis patients. PMID- 29423722 TI - Correction to: Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations. AB - Page 4, right column, under section heading "In-Vitro Aerosol Performance", line 11. PMID- 29423723 TI - Post-operative extra-spinal etiologies of sciatic nerve impingement. AB - Sciatica is a highly prevalent cause of morbidity, commonly resulting from intra spinal pathological processes. Many cases can have extra-spinal etiologies and can be clinically challenging. Certain scenarios should suggest an extra-spinal etiology, particularly total and revision hip arthroplasty, surgical hip dislocation, hip arthroscopy, and surgery in the lithotomy position. We review the post-operative clinical scenarios where sciatic neuropathy may occur, along with the pertinent imaging findings. PMID- 29423724 TI - Superficial acral fibromyxoma: a case report with radiological review. AB - Superficial acral fibromyxoma is a benign, slow-growing soft-tissue neoplasm that has a predilection for the peripheries. Although considered benign, its risk of recurrence warrants consideration in the radiological differential diagnoses of acral tumors. To our knowledge, there has been minimal literature studying the radiological features of this entity. We present a case report with a discussion focusing on its clinical and radiological findings. PMID- 29423725 TI - The impact of body mass index on quantitative 24-h urine chemistries in stone forming patients: a systematic review and meta-analysis. AB - To study the impact of body mass index (BMI) on quantitative 24-h urine chemistries in stone forming patients and to explore how overweight and obesity contribute to urolithiasis. A systematic search of PubMed, EMBASE, Cochrane Library, and Web of Science was performed in July 2017 and updated in October 2017 to detect relevant studies. After that, we screened all the relevant articles in accordance with the predetermined inclusion and exclusion criteria. Data of eligible studies were extracted, and then, a meta-analysis was conducted via RevMan 5.3 software. Nine studies, involving 5965 stone forming patients who underwent 24-h urine collection for chemistry analysis, were included in our analysis. BMI was used to clarify the body size. BMI >= 25 kg/m2 group, including overweight and obesity patients, erected more calcium (WMD 34.44 mg; 95% CI 11.33 57.55; p = 0.003), oxalate (WMD 3.44 mg; 95% CI 1.40-5.49; p = 0.001), urate (WMD 97.71 mg; 95% CI 63.05-132.38; p < 0.00001), and sodium (WMD 26.64 mg; 95% CI 18.23-35.05; p < 0.00001) in 24 h than BMI < 25 kg/m2 group. However, the BMI < 25 kg/m2 group showed higher pH of urine (WMD 0.12; 95% CI 0.04-0.20; p = 0.004). There was no significant difference in 24-h urine volume (WMD - 29.30 ml; 95% CI 122.03 to - 63.42; p = 0.54), citrate (WMD - 34.03 mg; 95% CI - 72.88 to 4.82; p = 0.09), magnesium (WMD - 4.50 mg; 95% CI - 10.48 to 1.48; p = 0.14), phosphate (WMD - 89.38 mg; 95% CI - 219.23 to 40.47; p = 0.18), and creatinine (WMD - 191.98 mg; 95% CI - 395.35 to 11.38; p = 0.06) between the two groups. All the results kept the same tendency when gender was taken in consideration. Sensitivity analysis generated similar results. The current evidence suggested that patients with BMI >= 25 kg/m2 erected more promotions but not inhibitors of urolithiasis than those with BMI < 25 kg/m2, which increased the risk of urolithiasis in overweight and obesity individuals. PMID- 29423726 TI - Prevalence and Sex-Specific Distribution of Cardiovascular Risk Factors in University Students in an Urban-Rural Environment of the Democratic Republic of the Congo. AB - A recent qualitative study on health promotion in non-communicable diseases in Sub-Saharan University students suggested sex differences in knowledge and beliefs concerning a healthy lifestyle. However, the extent to which this is reflected in sex-specific distribution of cardiovascular risk factors among Sub Saharan African students have not been fully evaluated. The objective of this study was to assess the prevalence and the sex-specific distribution of some modifiable cardiovascular risk factors among students at University of Kikwit in the Democratic Republic of the Congo. This cross-sectional descriptive study included 780 students (62.2% men) at the University of Kikwit between January and March of 2016. Data on physical measurements, lifestyle factors, and medical history were collected. The median age (interquartile range) of the students was 23 years (21-25 years). The modifiable cardiovascular risk factors identified were: alcohol consumption (53.1%), overweight (16.4%), general obesity (1.9%), abdominal obesity (10.4%), tobacco consumption (8.1%), hypertension (7.6%) and high pulse pressure (6.4%). Compared to women, men had a higher prevalence of hypertension (9.9 vs. 3.7%; p = 0.002), tobacco consumption (10.7 vs. 3.7%; p = 0.001), and alcohol consumption (58.4 vs. 44.4%; p < 0.001). In contrast, abdominal obesity was more predominant in women than in men (23.1 vs. 2.7%; p < 0.001). This study suggests a sex-specific distribution of several modifiable cardiovascular risk factors in students at the University of Kikwit. Design of sex-specific, student-targeted health promotion programs may be warranted to reduce the prevalence of risk factors and the subsequent burden of cardiovascular diseases. PMID- 29423727 TI - Collagen Damage Location in Articular Cartilage Differs if Damage is Caused by Excessive Loading Magnitude or Rate. AB - Collagen damage in articular cartilage is considered nearly irreversible and may be an early indication of cartilage degeneration. Surface fibrillation and internal collagen damage may both develop after overloading. This study hypothesizes that damage develops at these different locations, because the distribution of excessive strains varies with loading rate as a consequence of time-dependent cartilage properties. The objective is to explore whether collagen damage could preferentially occur superficially or internally, depending on the magnitude and rate of overloading. Bovine osteochondral plugs were compressed with a 2 mm diameter indenter to 15, 25, 35 and 45 N, and at 5, 60 and 120 mm/min. Surface fibrillation and internal collagen damage were graded by four observers, based on histology and staining of collagen damage. Results show that loading magnitude affects the degree of collagen damage, while loading rate dominates the location of network damage: low rates predominantly damage superficial collagen, while at high rates, internal collagen damage occurs. The proposed explanation for the rate-dependent location is that internal fluid flows govern the time-dependent internal tissue deformation and therewith the location of overstained and damaged areas. This supports the hypothesis that collagen damage development is influenced by the time-dependent material behaviour of cartilage. PMID- 29423728 TI - Ballroom dancing as physical activity for patients with cancer: a systematic review and report of a pilot project. AB - BACKGROUND: Physical activity has positive effects on cancer patients. Dancing addresses diverse bio-psycho-social aspects. Our aim was to assess the evidence on ballroom dancing and to develop the setting for a pilot project. METHODS: We performed a systematic review, extracted the data and designed a pilot training based on standard curricula. We included cancer patients during or after therapy. Training duration was 90 min with one regular pause and individual pauses as needed. RESULTS: We retrieved two systematic reviews and six controlled studies. Types of dancing varied. Only one study used ballroom dancing. Dance training might improve well-being, physical fitness, fatigue and coping during and after therapy. Yet, evidence is scarce and data to derive the effect size are lacking; 27 patients and their partners took part in the pilot training. Patients and partners needed more time to learn the steps than is planned in regular ballroom classes. Participants were very satisfied with the adaptation of the training to their physical strength and estimated the training in a sheltered group. No side effects occurred. In spite of a high rate of participants reporting fatigue, 90 min of physical activity with only a few minutes of rest were manageable for all participants. CONCLUSION: Ballroom dancing may offer benefits for patients with respect to quality of life. Cancer patients prefer sheltered training setting and curricula of regular ballroom classes must be adapted for cancer patients. Strict curricula might reduce motivation and adherence and exclude patients with lower or variable fitness. PMID- 29423729 TI - A Genome Comparison of T7-like Podoviruses That Infect Caulobacter crescentus. AB - Bacteriophages remain an understudied component of bacterial communities. Therefore, our laboratory has initiated an effort to isolate large numbers of bacteriophages that infect Caulobacter crescentus to provide an estimate of the diversity of bacteriophages that infect this common environmental bacterium. The majority of the new isolates are phicbkviruses, a genus of giant viruses that appear to be Caulobacter specific. However, we have also isolated several Podoviruses with icosahedral heads and small tails. One of these Podoviruses, designated Lullwater, is similar to two previously isolated Caulobacter phages, Cd1 and Percy. All three have genomes that are approximately 45 kb and contain approximately 30 genes. The gene order is conserved among the three genomes with one of the genes coding for a DNA polymerase that has homology to the family of T7 DNA polymerases. Phylogenetic trees based on either the DNA polymerase or the RNA polymerase amino acid sequences suggests that the three phages represent a new branch of the T7virus tree. Based on these similarities, we concluded that Cd1, Lullwater, and Percy comprise a new group in the T7virus genus. PMID- 29423730 TI - Tellurite Resistance in Shiga Toxin-Producing Escherichia coli. AB - Potassium tellurite (K2TeO3) is an effective selective agent for O157:H7 Shiga toxin-producing Escherichia coli (STEC), whereas tellurite resistance in non-O157 STEC is variable with information on O45 minimal. High-level K2TeO3 resistance in STEC is attributable to the ter gene cluster with terD an indicator of the cluster's presence. Polymerase chain reactions for terD and K2TeO3 minimum inhibitory concentration (MIC) determinations in broth cultures were conducted on 70 STEC and 40 non-STEC control organisms. Sixty-six STEC strains (94.3%) were terD+ compared to 28 control organisms (70.0%; P < 0.001). The prevalence of terD in O103 STEC strains was 70%, whereas in all other serogroups it was >= 90%. The K2TeO3 geometric mean MIC ranking for STEC serogroups from highest to lowest was O111 > O26 > O145 > O157 > O103 > O121 = O45. The K2TeO3 geometric mean MIC was significantly higher in terD+ than in terD- STEC, but not in terD+ versus terD- control strains. Resistance to K2TeO3 (MIC >= 25 mg/L) was exhibited by 65/66 terD+ and 0/4 terD- STEC strains, compared to 12/28 terD+ and 8/12 terD- control strains. These results confirm previous studies showing the significantly higher prevalence of the ter gene cluster in STEC strains, and the relationship between these genes and K2TeO3 resistance in STEC and especially intimin (eae)-positive STEC, in contrast to non-STEC organisms. O45 and O121 STEC, although frequently terD positive, on average had significantly lower levels of K2TeO3 resistance than O26, O111, and O145 STEC. PMID- 29423731 TI - HIV Persistence in Adipose Tissue Reservoirs. AB - PURPOSE OF REVIEW: The purpose of this review is to examine the evidence describing adipose tissue as a reservoir for HIV-1 and how this often expansive anatomic compartment contributes to HIV persistence. RECENT FINDINGS: Memory CD4 T cells and macrophages, the major host cells for HIV, accumulate in adipose tissue during HIV/SIV infection of humans and rhesus macaques. Whereas HIV and SIV proviral DNA is detectable in CD4 T cells of multiple fat depots in virtually all infected humans and monkeys examined, viral RNA is less frequently detected, and infected macrophages may be less prevalent in adipose tissue. However, based on viral outgrowth assays, adipose-resident CD4 T cells are latently infected with virus that is replication-competent and infectious. Additionally, adipocytes interact with CD4 T cells and macrophages to promote immune cell activation and inflammation which may be supportive for HIV persistence. Antiviral effector cells, such as CD8 T cells and NK/NKT cells, are abundant in adipose tissue during HIV/SIV infection and typically exceed CD4 T cells, whereas B cells are largely absent from adipose tissue of humans and monkeys. Additionally, CD8 T cells in adipose tissue of HIV patients are activated and have a late differentiated phenotype, with unique TCR clonotypes of less diversity relative to blood CD8 T cells. With respect to the distribution of antiretroviral drugs in adipose tissue, data is limited, but there may be class-specific penetration of fat depots. The trafficking of infected immune cells within adipose tissues is a common event during HIV/SIV infection of humans and monkeys, but the virus may be mostly transcriptionally dormant. Viral replication may occur less in adipose tissue compared to other major reservoirs, such as lymphoid tissue, but replication competence and infectiousness of adipose latent virus are comparable to other tissues. Due to the ubiquitous nature of adipose tissue, inflammatory interactions among adipocytes and CD4 T cells and macrophages, and selective distribution of antiretroviral drugs, the sequestration of infected immune cells within fat depots likely represents a major challenge for cure efforts. PMID- 29423734 TI - ? PMID- 29423735 TI - ? PMID- 29423733 TI - Effectiveness of time of sowing and cultivar choice for managing climate change: wheat crop phenology and water use efficiency. AB - Climate change (CC) presents a challenge for the sustainable development of wheat production systems in Australia. This study aimed to (1) quantify the impact of future CC on wheat grain yield for the period centred on 2030 from the perspectives of wheat phenology, water use and water use efficiency (WUE) and (2) evaluate the effectiveness of changing sowing times and cultivars in response to the expected impacts of future CC on wheat grain yield. The daily outputs of CSIRO Conformal-Cubic Atmospheric Model for baseline and future periods were used by a stochastic weather generator to derive changes in mean climate and in climate variability and to construct local climate scenarios, which were then coupled with a wheat crop model to achieve the two research aims. We considered three locations in New South Wales, Australia, six times of sowing (TOS) and three bread wheat (Triticum aestivum L.) cultivars in this study. Simulation results show that in 2030 (1) for impact analysis, wheat phenological events are expected to occur earlier and crop water use is expected to decrease across all cases (the combination of three locations, six TOS and three cultivars), wheat grain yield would increase or decrease depending on locations and TOS; and WUE would increase in most of the cases; (2) for adaptation considerations, the combination of TOS and cultivars with the highest yield varied across locations. Wheat growers at different locations will require different strategies in managing the negative impacts or taking the opportunities of future CC. PMID- 29423732 TI - Lipids in the Stomach - Implications for the Evaluation of Food Effects on Oral Drug Absorption. AB - Food effects on oral drug bioavailability can have significant impact on the provision of safe and reliable oral pharmacotherapy. A mechanistic understanding of the events that contribute to the occurrence of food effects is therefore critical. An increased oral bioavailability is often seen for poorly water soluble drugs after co-administration with lipids, including lipids in food, and is commonly explained by the ability of lipids to enhance drug solubility in intestinal luminal fluids. In contrast, the impact of lipids on drug solubilisation in the stomach has received less attention. This is in spite of the fact that lipid digestion is initiated in the stomach by human gastric lipase and that gastric events also initiate emulsification of lipids in the gastrointestinal tract. The stomach therefore acts to 'pre-process' lipids for subsequent events in the intestine and may significantly affect downstream events at intestinal drug absorption sites. In this article, the mechanisms by which lipids are processed in the stomach are reviewed and the potential impact of these processes on drug absorption discussed. Attention is also focused on in vitro methods that are used to assess gastric processing of lipids and their application to better understand food effects on drug release and absorption. PMID- 29423736 TI - iTemplate: A template-based eye movement data analysis approach. AB - Current eye movement data analysis methods rely on defining areas of interest (AOIs). Due to the fact that AOIs are created and modified manually, variances in their size, shape, and location are unavoidable. These variances affect not only the consistency of the AOI definitions, but also the validity of the eye movement analyses based on the AOIs. To reduce the variances in AOI creation and modification and achieve a procedure to process eye movement data with high precision and efficiency, we propose a template-based eye movement data analysis method. Using a linear transformation algorithm, this method registers the eye movement data from each individual stimulus to a template. Thus, users only need to create one set of AOIs for the template in order to analyze eye movement data, rather than creating a unique set of AOIs for all individual stimuli. This change greatly reduces the error caused by the variance from manually created AOIs and boosts the efficiency of the data analysis. Furthermore, this method can help researchers prepare eye movement data for some advanced analysis approaches, such as iMap. We have developed software (iTemplate) with a graphic user interface to make this analysis method available to researchers. PMID- 29423737 TI - Aggressive and Multidisciplinary Local Approach to Iterative Recurrences of Colorectal Liver Metastases. AB - BACKGROUND: Liver resection (LR) of colorectal metastases is associated with high recurrence risk. Aggressive local retreatment is advocated, but further recurrences may occur. Poor is known about presentation, treatment, and outcome of iterative recurrences. METHODS: A series of 323 consecutive patients undergoing first LR in the period 2004-2013 was reviewed. Patients with recurrence were included. Any local treatment (surgery, radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT)) was analyzed. If first recurrence (1st Rec) was treated, further recurrences and treatments were considered. RESULTS: Overall, 206 (63.8%) patients had 1st Rec; 105 (51.0%) were treated (72 surgery, 19 RFA, 14 SBRT). Among treated patients, 78.1% had 2nd Rec, 74.4% 3rd Rec, 72.2% 4th Rec. Liver involvement progressively decreased (from 81.6 to 30.8%), and pulmonary one increased (from 23.3 to 53.8%). The proportion of treated patients remained stable (1st Rec = 51%, 2nd Rec = 55%, 3rd Rec = 56.3%, 4th Rec = 69.2%): surgery and RFA decreased (from 35.4 to 23.1%; from 9.2 to 0%) and SBRT increased (from 6.8 to 46.2%). Overall, 105 patients received 205 treatments (133 operations in 80 patients). Surgery had the best local disease control: at 2 years 93.4% versus RFA 56.4% (p = 0.0008) and SBRT 74.0% (p = 0.051). In comparison with chemotherapy, recurrence treatment improved survival after 1st Rec (3-year survival 62.9 vs. 13.4%, p < 0.0001), 2nd Rec (61.3 vs. 22.5%, p < 0.0001), and 3rd Rec (2-year survival 88.9 vs. 30.8%, p = 0.005). CONCLUSIONS: Aggressive local treatment of recurrent metastases may improve survival, even in the case of iterative recurrences and extrahepatic lesions. Surgery is the standard, but a multidisciplinary approach should be adopted to enlarge the pool of treatable patients. PMID- 29423739 TI - 14-French Pigtail Catheters for Traumatic Hemothorax/Hemopneumothorax: Size Does Not Matter: Reply. PMID- 29423738 TI - Prognostic Factors of Salvage Esophagectomy for Residual or Recurrent Esophageal Squamous Cell Carcinoma After Definitive Chemoradiotherapy. AB - BACKGROUND: The aim of this study was to confirm prognostic factors for salvage esophagectomy for remnant or recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy. STUDY DESIGN: We retrospectively analyzed clinicopathological backgrounds of 50 patients who underwent salvage esophagectomy between April 2005 and January 2016. Salvage esophagectomy comprised 40 three-incision esophagectomies, two transhiatal esophagectomies and eight pharyngolaryngoesophagectomies. Independent prognostic factors for overall survival were assessed using Cox regression analysis of the factors. RESULTS: Salvage esophagectomy remains a highly invasive surgery and correlated with a higher incidence of all morbidities of Clavien-Dindo classification (CDc) >=II, severe morbidities of CDc >= IIIb, any pulmonary morbidities and chylorrhea, compared with those in patients without preoperative definitive chemoradiotherapy. Cox regression analysis suggested that R0 resection (hazard ratio [HR] 6.39; 95% confidence interval [CI] 2.03-9.68, P = 0.002), absence of severe complications (HR 4.97; 95% CI 1.70-14.81, P = 0.004) and early pStage (0 II) (HR 3.42; 95% CI 1.24-10.12, P = 0.018) were independent prognostic factors for salvage esophagectomy. CONCLUSIONS: Salvage esophagectomy remains correlated with a high incidence of postoperative complications. Avoiding non-curative surgery and reducing the incidence of severe postoperative complications are important if patients are to receive prognostic benefit of this highly invasive surgery. PMID- 29423741 TI - Correction to: Does Surgery Without Lugol's Solution Pretreatment for Graves' Disease Increase Surgical Morbidity? AB - In the original article, Mathieu Bonal's last name was spelled incorrectly. It is correct as reflected here. The original article has also been updated. PMID- 29423740 TI - Segmentectomy Versus Lobectomy for Radiologically Pure Solid Clinical T1a-bN0M0 Lung Cancer. AB - BACKGROUND: Segmentectomy for radiologically pure solid tumors is still controversial because these tumors are more aggressive in malignancy than those with ground-glass opacity. This study aimed to determine the feasibility of intentional segmentectomy for pure solid small-sized lung cancer. METHODS: We retrospectively analyzed 96 radiologically pure solid tumors in clinical T1a bN0M0 lung cancer. Patients whose tumor was located at a central region or right middle lobe were excluded. Forty-four patients who underwent lobectomy were compared with 52 those who underwent segmentectomy. Segmentectomy got converted to lobectomy if lymph node metastases or inadequate surgical margin was confirmed. Factors affecting survival were assessed using Cox regression. Propensity score stratification analysis was also performed. RESULTS: Eight patients (8%) were identified as a histological type other than adenocarcinoma or squamous cell carcinoma. Moreover, 14 patients (14%) displayed lymph node metastasis. Among those who underwent segmentectomy, nine patients (16%) were converted to lobectomy due to lymph node metastasis or inadequate surgical margin. The 3-year recurrence-free survival rates were 84.1 and 82.2% in patients who underwent segmentectomy and lobectomy, respectively (P = 0.745). In addition, the recurrence-free survival was not statistically significant between segmentectomy and lobectomy, as determined via multivariable Cox regression analysis (hazard ratio 1.11; 95% confidence interval 0.40-3.06), even after propensity score stratification (hazard ratio 1.17; 95% confidence interval 0.38 3.65). CONCLUSIONS: Segmentectomy with intraoperative assessment of lymph node metastasis and adequate surgical margin may be a feasible surgical procedure for pure solid tumors in clinical T1a-bN0M0 lung cancer. PMID- 29423742 TI - The Effect of Preoperative Pneumonia on Postsurgical Mortality and Morbidity: A NSQIP Analysis. AB - BACKGROUND: Currently, only indirect evidence suggests that preoperative pneumonia is a significant risk factor for poor postsurgical outcomes. Although this relationship is clinically intuitive, this is the first study that aims to quantify the extent to which pneumonia impacts morbidity and mortality. The objective of this study was to determine the impact of preoperative pneumonia on 30-day mortality and morbidity among both elective and emergency surgical patients. METHODS: We conducted a retrospective cohort study using 2008-2012 data from the American College of Surgeons National Surgical Quality Improvement Program database. Patients with preoperative pneumonia were matched to controls without preoperative pneumonia. Patient demographics and postoperative outcomes were extracted from the database, including 30-day mortality, specific morbidities (wound, cardiac, respiratory, urinary, central nervous system, thromboembolism and sepsis), composite morbidity, number of blood transfusions and number of patients that returned to the OR. Mortality and composite morbidity were further stratified. RESULTS: We obtained data for 137,174 patients, of whom 6933 (0.50%) had preoperative pneumonia. Overall, 6111 were successfully matched to 24,444 patients with no pneumonia. Postoperative mortality and composite morbidity were both higher in patients with pneumonia than in those without pneumonia, with an odds ratio of 1.37 (95% CI 1.26-1.48) and 1.68 (95% CI 1.58 1.79), respectively. CONCLUSION: Preoperative pneumonia significantly increased the rate of postoperative morbidity and mortality across several surgical settings and patient groups. It is our recommendation that elective surgery be delayed until after the pneumonia resolves. PMID- 29423743 TI - Synthetic biology of polyketide synthases. AB - Complex reduced polyketides represent the largest class of natural products that have applications in medicine, agriculture, and animal health. This structurally diverse class of compounds shares a common methodology of biosynthesis employing modular enzyme systems called polyketide synthases (PKSs). The modules are composed of enzymatic domains that share sequence and functional similarity across all known PKSs. We have used the nomenclature of synthetic biology to classify the enzymatic domains and modules as parts and devices, respectively, and have generated detailed lists of both. In addition, we describe the chassis (hosts) that are used to assemble, express, and engineer the parts and devices to produce polyketides. We describe a recently developed software tool to design PKS system and provide an example of its use. Finally, we provide perspectives of what needs to be accomplished to fully realize the potential that synthetic biology approaches bring to this class of molecules. PMID- 29423745 TI - In reply to "Commentary to: Endoscopic and clinical benefits of hyaluronic acid in children with chronic adenoiditis and middle ear disease", by Zhengcai Lou. AB - Some considerations will be expressed in consideration of the commentary previously published. In particular, we underline that no other medications were administered to the patients during the study period and any clinical evaluation was postponed in case of acute upper respiratory tract infection in the previous 14 days. We strongly advocate antibiotic treatment during any acute otitis media episode, and we agree that topically administered hyaluronic acid should be considered as a supporting treatment, "complementary to traditional therapies" in children with recurrent disease. PMID- 29423746 TI - Reply to the letter to the author concerning: 'Does adenoid hypertrophy affect disease severity in children with allergic rhinitis?' PMID- 29423747 TI - Relationship between swallowing-related quality of life and fiberoptic endoscopic evaluation of swallowing in patients who underwent open partial horizontal laryngectomy. AB - BACKGROUND: Several studies have previously analyzed the relationship between QOL and signs of dysphagia in patients treated for head and neck cancer and have reported heterogeneous findings. To the best of our knowledge, no study has previously investigated this relationship among patients who underwent open partial horizontal laryngectomy (OPHL). The aim of the study is to determine if patient-reported swallowing-related QOL can discriminate between safe and unsafe swallowing in OPHL patients. METHODS: 92 type I, type II, and type III OPHL patients at least 6 months postoperatively were recruited. Fiberoptic endoscopic evaluation of swallowing (FEES) was conducted using liquids, semisolids, and solids. FEES recordings were assessed through the penetration-aspiration scale, the pooling score and the dysphagia outcome and severity scale. All patients completed the MD Anderson dysphagia inventory (MDADI). Kruskal-Wallis test and post-hoc Mann Whitney U test were performed to compare MDADI scores among different level of airway invasion, post-swallow pharyngeal residue's degree and overall dysphagia severity. ROC curves were generated to determine diagnostic accuracy of the MDADI. RESULTS: Statistically significant differences in MDADI scores were found between level of airway invasion with semisolids and solids, degree of pharyngeal residue with solids, and severity of dysphagia. MDADI showed significant diagnostic accuracy only in the detection of moderate/severe pharyngeal residue and severe dysphagia; however, sensitivity and specificity were low. CONCLUSIONS: Investigating patients' perception of swallowing impairment and swallowing-related QOL is not sufficient to discriminate safe and unsafe swallowing in OPHL patients. PMID- 29423748 TI - Evaluation of the success of obstructive sleep apnea surgery using criteria based on long-term symptoms and incident hypertension. AB - OBJECTIVE: To identify appropriate success criteria, based on long-term symptoms and incident hypertension, after surgery for obstructive sleep apnea (OSA). METHODS: This observational cohort study included 97 adult OSA patients (90 men) who underwent surgical treatment at our tertiary medical center. Subjective symptoms [witnessed sleep apnea and snoring, and Epworth sleepiness scale (ESS) scores] were evaluated through a telephone survey, and incident hypertension was assessed from medical records. The subjects were divided into success and failure groups according to seven different criteria, and data were analyzed to identify the criteria that could significantly differentiate the success from failure groups. RESULTS: The participants had a mean age of 48.8 +/- 11.9 years and a mean preoperative body mass index of 26.5 +/- 3.5 kg/m2. The mean preoperative and postoperative apnea-hypopnea index (AHI) values were 36.1/h and 19.4/h, respectively. The mean follow-up duration was 77.0 +/- 31.1 months. Postoperative witnessed apnea, snoring, and the ESS scores decreased significantly compared to preoperative scores in both the success and failure groups based on most of the seven criteria. Among the seven criteria, success and failure groups based on a postoperative AHI cutoff of 15 or 20/h differed significantly in witnessed apnea, snoring, or ESS scores. Kaplan-Meier survival analysis based on incident hypertension revealed that no criterion could significantly distinguish between the two groups. CONCLUSIONS: Our results suggest that some of the success criteria analyzed may be more useful in differentiating between success and failure groups after surgery, in terms of long-term improvement of subjective OSA related symptoms. PMID- 29423749 TI - Swallowing evaluation after surgery for obstructive sleep apnea syndrome: uvulopalatopharyngoplasty vs. expansion pharyngoplasty. AB - PURPOSE: To evaluate the effect of pharyngeal surgery on swallowing pattern in patients with obstructive sleep apnea syndrome (OSAS), and to compare two surgical techniques: uvulopalatopharyngoplasty (UPPP) and expansion pharyngoplasty (EP), through videofluoroscopy. METHODS: Longitudinal prospective cohort, in a tertiary referral center. 17 adult patients were enrolled this study, divided into two groups: patients who underwent UPPP (n = 10) or EP (n = 7). Swallowing videofluoroscopy (for both liquid and pasty consistences) was assessed at three different periods: before surgery, and at 14 and 28 days following surgery. Comparisons were performed between pre- and post-operative (PO) swallowing conditions in the same patient, and between surgical techniques. RESULTS: Asymptomatic OSAS patients already presented altered swallowing pattern before surgery. Both surgical procedures led to an increased hyoid movement time and an increased frequency of laryngeal penetration in early PO during liquid ingestion. For pasty consistency, both techniques reduced velum movement time and increased pharyngeal transit time and the rate of stasis in hypopharynx. All these parameters reached or tended to reach the pre-operative indices at day PO 28. CONCLUSIONS: OSAS patients show sub-clinical changes in swallowing pattern before surgery. Both surgical techniques are related to transitory changes in swallowing biomechanics. Complete or partial reversal to pre-operative swallowing parameters occurs 1 month after both surgery techniques. PMID- 29423750 TI - The Requirement for Increasingly Effective Societal Cancer Control Efforts. PMID- 29423751 TI - Oviposition-like central pattern generators in pregenital segments of male and female grasshoppers. AB - Grasshoppers produce an extraordinary oviposition behavior that is associated with multiple specializations of the skeletal and neuromuscular systems in the posterior abdomen, including a central pattern generator (CPG) in the female's terminal abdominal ganglion. Two pairs of shovel-shaped appendages, the ovipositor valves on the abdomen tip, excavate the soil for deposition of eggs. By contrast, the sexually monomorphic pregenital region of the abdomen is without appendages. Morphological homologues of ovipositor muscles and efferent neurons in the eighth abdominal segment are nevertheless present in pregenital segments of males and females. In both sexes, a robust rhythmic motor program was induced in pregenital segments by the same experimental methods used to elicit oviposition digging. The activity, recorded extracellularly, was oviposition-like in burst period (5-6 s) and homologous muscle phase relationships, and it persisted after sensory inputs were removed, indicating the presence of pregenital CPGs. The abdomen exhibited posterior-going waves of activity with an intersegmental phase delay of approximately 1 s. These results indicate that serially homologous motor systems, including functional CPGs, provided the foundation for the evolution of oviposition behavior. PMID- 29423752 TI - Exogenous GA3 application altered morphology, anatomic and transcriptional regulatory networks of hormones in Eucalyptus grandis. AB - Gibberellins (GAs) play a key role in plant growth and development including cell elongation, cell expansion, and xylem differentiation. Eucalyptus are the world's most widely planted hardwood trees providing fiber and energy. However, the roles of GAs in Eucalyptus remain unclear and their effects on xylem development remain to be determined. In this study, E. grandis plants were treated with 0.10 mg L-1 GA3 and/or paclobutrazol (PAC, a GA inhibitor). The growth of shoot and root were recorded, transverse sections of roots and stems were stained using toluidine blue, and expression levels of genes related to hormone response and secondary cell wall biosynthesis were analyzed by quantitative real-time PCR. The results showed that GA3 dramatically promoted the length of shoot and root, but decreased the diameter of root and stem. Exogenous GA3 application also significantly promoted xylem development in both stem and root. Expression analysis revealed that exogenous GA3 application altered the transcript levels of genes related to the GA biosynthetic pathway and GA signaling, as well as genes related to auxin, cytokinin, and secondary cell wall. These findings suggest that GAs may interact with other hormones (such as auxin and cytokinin) to regulate the expression of secondary cell wall biosynthesis genes and trigger xylogenesis in Eucalyptus plants. PMID- 29423753 TI - Granivory from native rodents and competition from an exotic invader strongly and equally limit the establishment of native grasses. AB - Seed predation and resource competition are fundamental biotic filters that affect the assembly of plant communities, yet empirical studies rarely assess their importance relative to one another. Here, we used rodent exclosures and experimental seed additions to compare how rodent granivory and resource competition affected the net establishment of an exotic invader (Bromus tectorum) and two native bunchgrasses (Pseudoroegneria spicata and Elymus elymoides) in the Great Basin Desert, USA. Rodent granivory limited the establishment of both native grasses, but had no significant effect on B. tectorum. Competition from B. tectorum limited the establishment of both native grasses, but neither native grass imposed a significant competitive effect on B. tectorum. Interestingly, we found that rodent granivory and B. tectorum competition limited the establishment of native grasses to the same extent, suggesting that these biotic interactions may impose equally important barriers to the local establishment of P. spicata and E. elymoides. By evaluating the strength of multiple biotic interactions in simultaneous, coordinated experiments, we can understand their relative contributions to community-level patterns. PMID- 29423754 TI - Root-colonizing bacteria enhance the levels of (E)-beta-caryophyllene produced by maize roots in response to rootworm feeding. AB - When larvae of rootworms feed on maize roots they induce the emission of the sesquiterpene (E)-beta-caryophyllene (EbetaC). EbetaC is attractive to entomopathogenic nematodes, which parasitize and rapidly kill the larvae, thereby protecting the roots from further damage. Certain root-colonizing bacteria of the genus Pseudomonas also benefit plants by promoting growth, suppressing pathogens or inducing systemic resistance (ISR), and some strains also have insecticidal activity. It remains unknown how these bacteria influence the emissions of root volatiles. In this study, we evaluated how colonization by the growth-promoting and insecticidal bacteria Pseudomonas protegens CHA0 and Pseudomonas chlororaphis PCL1391 affects the production of EbetaC upon feeding by larvae of the banded cucumber beetle, Diabrotica balteata Le Conte (Coleoptera: Chrysomelidae). Using chemical analysis and gene expression measurements, we found that EbetaC production and the expression of the EbetaC synthase gene (tps23) were enhanced in Pseudomonas protegens CHA0-colonized roots after 72 h of D. balteata feeding. Undamaged roots colonized by Pseudomonas spp. showed no measurable increase in EbetaC production, but a slight increase in tps23 expression. Pseudomonas colonization did not affect root biomass, but larvae that fed on roots colonized by P. protegens CHA0 tended to gain more weight than larvae that fed on roots colonized by P. chlororaphis PCL1391. Larvae mortality on Pseudomonas spp. colonized roots was slightly, but not significantly higher than on non-colonized control roots. The observed enhanced production of EbetaC upon Pseudomonas protegens CHA0 colonization may enhance the roots' attractiveness to entomopathogenic nematodes, but this remains to be tested. PMID- 29423755 TI - PROMIS depression measures perform similarly to legacy measures relative to a structured diagnostic interview for depression in cancer patients. AB - PURPOSE: To assess the convergent validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) depression measures relative to legacy measures and criterion validity against a structured diagnostic interview for depression in an oncology sample. METHODS: 132 oncology/haematology outpatients completed the PROMIS Depression Computer Adaptive Test (PROMIS-D-CAT) and PROMIS Depression Short Form (PROMIS-D-SF) along with seven legacy measures: Beck Depression Inventory (BDI); Centre for Epidemiological Studies Depression (CES D); Depression, Anxiety and Stress Scale; Hospital Anxiety and Depression Scale; Patient Health Questionnaire; Distress Thermometer and PSYCH-6. Correlations, area under the curve (AUC) and diagnostic accuracy statistics were calculated with Structured Clinical Interview as the gold standard. RESULTS: Both PROMIS measures correlated with all legacy measures at p < .001 (rho = 0.589-0.810) and all AUCs (> 0.800) were comparable. At the cut-off points for mild depression of 53, the PROMIS measures had sensitivity (0.83 for PROMIS-D-CAT and 0.80 for PROMIS-D-SF) similar to or better than 6/7 legacy measures with high negative predictive value (> 90%). At cut-off points of 60 for moderate depression, PROMIS measures had specificity > 90%, similar to or better than all legacy measures and positive predictive value >= 0.50 (similar to 5/7 legacy measures). CONCLUSIONS: The convergent and criterion validity of the PROMIS depression measures in cancer populations was confirmed, although the optimal cut-off points are not established. PROMIS measures were briefer than BDI-II and CES-D but do not offer any advance in terms of diagnostic accuracy, reduced response burden or cost over other legacy measures of depression in oncology patients. PMID- 29423756 TI - Scale development with small samples: a new application of longitudinal item response theory. AB - PURPOSE: Measurement development in hard-to-reach populations can pose methodological challenges. Item response theory (IRT) is a useful statistical tool, but often requires large samples. We describe the use of longitudinal IRT models as a pragmatic approach to instrument development when large samples are not feasible. METHODS: The statistical foundations and practical benefits of longitudinal IRT models are briefly described. Results from a simulation study are reported to demonstrate the model's ability to recover the generating measurement structure and parameters using a range of sample sizes, number of items, and number of time points. An example using early-phase clinical trial data in a rare condition demonstrates these methods in practice. RESULTS: Simulation study results demonstrate that the longitudinal IRT model's ability to recover the generating parameters rests largely on the interaction between sample size and the number of time points. Overall, the model performs well even in small samples provided a sufficient number of time points are available. The clinical trial data example demonstrates that by using conditional, longitudinal IRT models researchers can obtain stable estimates of psychometric characteristics from samples typically considered too small for rigorous psychometric modeling. CONCLUSION: Capitalizing on repeated measurements, it is possible to estimate psychometric characteristics for an assessment even when sample size is small. This allows researchers to optimize study designs and have increased confidence in subsequent comparisons using scores obtained from such models. While there are limitations and caveats to consider when using these models, longitudinal IRT modeling may be especially beneficial when developing measures for rare conditions and diseases in difficult-to-reach populations. PMID- 29423757 TI - Comparing the validity and responsiveness of the EQ-5D-5L to the Oxford hip and knee scores and SF-12 in osteoarthritis patients 1 year following total joint replacement. AB - PURPOSE: (1) To assess responsiveness of the EQ-5D-5L compared to Oxford hip and knee scores and the SF-12 in osteoarthritis patients undergoing total hip (THR) or knee (TKR) replacement surgery; (2) to compare distribution and anchor-based methods of assessing responsiveness. METHODS: Questionnaires were mailed to consecutive patients following surgeon referral for primary THR or TKR and 1 year post-surgery. We assessed effect size (ES), standardized response mean (SRM), and standard error of measurement (SEM). Minimum important difference (MID) was the mean change in patients reporting somewhat better in hip or knee, health in general, and those who were satisfied with surgery (5-point scales). Responders were compared using MID versus 1 and 2SEM. RESULTS: The sample of 537 (50% TKR) was composed of 56% female with a mean age of 64 years (SD 10). EQ-5D-5L ES was 1.86 (THR) and 1.19 (TKR) compared to 3.00 and 2.05 for Oxford scores, respectively. MID for the EQ-5D-5L was 0.22 (THR) and 0.20 (TKR) for patients who rated their hip or knee as somewhat better. There was a wide variation in the MID and the percentage of responders, depending on the joint, method of assessment, and the outcome measure. The percent agreement of responder classification using 2SEM vs. MID ranged from 79.6 to 99.6% for the EQ-5D-5L and from 69.4 to 94.8% for the Oxford scores. CONCLUSIONS: Responsiveness of the EQ-5D-5L was acceptable in TKR and THR. Caution should be taken in interpreting responder to TJR based on only one method of assessment. PMID- 29423758 TI - Impact of pre-transplantation minimal residual disease determined by multiparameter flow cytometry on the outcome of AML patients with FLT3-ITD after allogeneic stem cell transplantation. AB - In this study, using multiparameter flow cytometry (FCM), we investigate the impact of minimal residual disease prior to transplantation (pre-MRD) on the transplant outcomes of AML patients with fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutation. A total of 20 patients who received HLA-matched sibling donor transplantation (MSDT) and 63 patients who received unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) were enrolled. Patients were classified into four groups based on the status of pre-FCM: group 1 with positive pre-FCM before MSDT, group 2 with negative pre-FCM before MSDT, group 3 with positive pre-FCM before haplo-HSCT, and group 4 with positive pre-FCM before haplo-HSCT. The results showed that patients in group 1 had the highest cumulative incidence of relapse (2-year CIR, 75.0%), the lowest leukemia-free survival (2-year LFS, 33.3%), and the overall survival (2-year OS, 25.0%) among all four groups. The other three groups of patients had comparable CIR (2-year CIR: group 2 vs. 3 vs. 4, 12.5% vs. 31.3% vs. 22.2%, P > 0.05) and LFS (2-year LFS: group 2 vs. 3 vs. 4, 87.5% vs. 62.5% vs. 66.5%, P > 0.05). Multivariate analysis indicated that disease status (> CR) and pre-MRD were associated with a higher CIR and a lower LFS when patients were classified by pre MRD and transplant type. Our results suggested that AML patients with FLT3-ITD were able to be separated into high-risk and low-risk relapse groups based on pre MRD, as determined by multiparameter FCM. Haplo-HSCT might overcome the negative impact of pre-MRD on patient outcomes compared to MSDT. These results require further investigation in prospective study with large numbers of cases. PMID- 29423759 TI - Geospatial approaches to cancer control and population sciences at the United States cancer centers. AB - PURPOSE: Geospatial, contextual, and multilevel research is integral to cancer prevention and control. NCI-designated Cancer Centers are at the forefront of cancer research; therefore, this paper sought to review the geospatial, contextual, and multilevel research at these cancer centers. METHODS: Investigators used PubMed and Web of Science to compile geospatial publications from 1971 to February 2016 with cancer center-affiliated authors. Relevant abstracts were pulled and classified by six geospatial approaches, eight geospatial scales, and eight cancer sites. RESULTS: The searches identified 802 geospatial, contextual, and multilevel publications with authors affiliated at 60 of the 68 NCI-designated Cancer Centers. Over 90% were published after 2000. Five cancer centers accounted for approximately 50% of total publications, and 30 cancer centers accounted for over 85% of total publications. Publications covered all geospatial approaches and scales to varying degrees, and 90% dealt with cancer. CONCLUSIONS: The NCI-designated Cancer Center network is increasingly pursuing geospatial, contextual, and multilevel cancer research, although many cancer centers still conduct limited to no research in this area. Expanding geospatial efforts to research programs across all cancer centers will further enrich cancer prevention and control. Similar reviews may benefit other domestic and international cancer research institutions. PMID- 29423760 TI - Non-communicable chronic diseases and timely breast cancer screening among women of the Eastern Caribbean Health Outcomes Research Network (ECHORN) Cohort Study. AB - PURPOSE: The Caribbean population faces a growing burden of multiple non communicable chronic diseases (NCDs). Breast cancer is the leading cause of cancer death for women in the Caribbean. Given the substantial burden of NCDs across the region, cancer prevention and control strategies may need to be specifically tailored for people with multiple co-morbidities. Preventive screening, such as timely mammography, is essential but may be either facilitated or hampered by chronic disease control. The main objective of this study is to examine the relationship between a chronic disease and timely breast cancer screening. METHODS: We conducted a cross-sectional data analysis using baseline data from the Eastern Caribbean Health Outcomes Research Network (ECHORN) Cohort Study-ECS. Our independent variables were presence of chronic diseases (hypertension or diabetes), defined as having been told by a clinical provider. Our dependent variable was timely screening mammography, as defined by receipt of mammography within the past 2 years. We examined bivariate and multivariate associations of covariates and timely screening mammography. RESULTS: In our sample (n = 841), 52% reported timely screening mammography. Among those with timely screening, 50.8% reported having hypertension, and 22.3% reported having diabetes. In our bivariate analyses, both diabetes and hypertension were associated with timely screening mammography. In partially adjusted models, we found that women with diabetes were significantly more likely to report timely screening mammography than women without diabetes. In our fully adjusted models, the association was no longer significant. Having a usual source of healthcare and a woman's island of residence were significantly associated with timely screening mammography (p < 0.05). CONCLUSIONS: We found that half of eligible women received timely screening mammography. Diabetes and hypertension, though common, are not associated with timely screening mammography. Usual source of care remains an important factor to timely breast cancer screening. PMID- 29423761 TI - Comparative safety and efficacy of insulin degludec with insulin glargine in type 2 and type 1 diabetes: a meta-analysis of randomized controlled trials. AB - AIMS: To determine the safety and efficacy of insulin degludec versus glargine in patients with type 1 (T1D) and type 2 (T2D) diabetes mellitus. METHODS: Databases were searched until July 5, 2017. We included randomized controlled trials comparing degludec with glargine in diabetic patients, each with a minimum of 16 weeks of follow-up. RESULTS: Eighteen trials with 16,791 patients were included. Degludec was associated with a statistically significant reduction in risk for all confirmed hypoglycemia at the maintenance treatment period [estimated rate ratio (ERR) 0.81; 95% confidence interval (CI) 0.72-0.92; P = 0.001], nocturnal confirmed hypoglycemia at the entire (ERR 0.71; 95% CI 0.63-0.80; P < 0.001) and maintenance treatment period (ERR 0.65; 95% CI 0.59-0.71; P < 0.001), all irrespective of the pooled diabetic populations and follow-up durations. The differences in the rate of hypoglycemia were more pronounced in nocturnal period and maintenance period and in T2D than T1D patients. Degludec reduced the incidence of severe hypoglycemia in T2D [ERR 0.65; (0.52; 0.89); P = 0.005] but not T1D patients. HbA1c concentration was slightly higher in degludec over glargine but was not clinically relevant [estimated treatment difference (ETD) 0.03; 95% CI - 0.00 to 0.06%; P = 0.06]. Fasting plasma glucose level was lower in degludec-treated patients (ETD - 0.28 mmol/L; 95% CI - 0.44 to - 0.11 mmol/L; P = 0.001). Several subgroup analyses showed largely consistent findings. The rates of adverse events including total mortality and cardiovascular events were not significantly different between two treatment strategies. CONCLUSIONS: Insulin degludec appears to have better safety in reducing hypoglycemic events with similar efficacy compared with insulin glargine. PMID- 29423764 TI - Rapid enumeration of CD4 + T lymphocytes using an integrated microfluidic system based on Chemiluminescence image detection at point-of-care testing. AB - An integrated microfluidic system has been developed for rapid enumeration of CD4 + T lymphocytes at point-of-care (POC) settings. A concise microfluidic chip, which consists of three separate chambers, respectively, for reaction, detection and waste storage, is developed to automate CD4 detection. To simplify CD4 + T lymphocyte enumeration, a single polycarbonate bead immobilized with CD4 antibody is adopted by the microfluidic chip to capture the CD4 antigen in the lysed testing sample. Desired performance is achieved by actuating the single bead for efficient mixing, as well as transferring it between different reaction chambers to reduce non-specific reaction. A controllable external magnetic field is applied to drive the single bead with a built-in ferrous core for different purposes. Chemiluminescence reaction is implemented in an independent chamber to reduce non-specific binding of enzyme. A simple flow control strategy is adopted to conveniently release the waste reagent into the waste storage chamber by just opening the vent hole without actively pumping. A sensitive CCD camera is used to collect the reaction signal by taking picture from the single bead, and then the signal intensity is further analyzed for CD4 + T lymphocyte enumeration. Experimental results show that rapid, convenient, accurate and low-cost CD4 + T lymphocyte enumeration can be obtained with the developed microfluidic system at POC test. PMID- 29423763 TI - Associations Between Practice-Related Changes in Motor Performance and Muscle Activity in Healthy Individuals: A Systematic Review. AB - BACKGROUND: A well-learned motor skill is characterized by the efficient activation of muscles that are involved in movement execution. However, it is unclear if practice-related changes in motor performance correlate with those in quantitative markers of muscle activity and if so, whether the association is different with respect to the investigated muscle (i.e., agonist and antagonist) and quantitative myoelectric parameter. Thus, we conducted a systematic review and characterized associations between practice-related changes in motor performance and muscle activity in healthy individuals. METHODS: A computerized systematic literature search was performed in the electronic databases PubMed, Web of Science, and SPORTDiscus up to September 2017 to capture all relevant articles. A systematic approach was applied to evaluate the 1670 articles identified for initial review. Studies were included only if they investigated healthy subjects aged 6 years and older and tested at least one measure of motor performance (e.g., error score, movement time) and quantitative muscle activity (i.e., amplitude domain: iEMG [integrated electromyography], RMS [root mean square]; time domain: duration of muscle activity, time to peak muscle activation). In total, 24 studies met the inclusionary criteria for review. The included studies were coded for the following criteria: age, learning task, practice modality, and investigated muscles (i.e., agonist and antagonist). Correlation coefficients for the relationship of motor performance changes with changes in electromyography (EMG) amplitude, and duration were extracted, transformed (i.e., Fisher's z-transformed rz value), aggregated (i.e., weighted mean rz value), and back-transformed to r values. To increase sample size, we additionally extracted pre and post practice data for motor performance and myoelectric variables and calculated percent change values as well as associations between both. Correlations were classified according to their magnitude (i.e., small r <= 0.69, medium r <= 0.89, large r >= 0.90). RESULTS: Five studies reported correlation coefficients for the association between practice-related alterations in motor performance and EMG activity. We found small associations (range r = 0.015-0.50) of practice-related changes in motor performance with measures of agonist and antagonist EMG amplitude and duration. A secondary analysis (17 studies) that was based on the calculation of percent change values also revealed small correlations for changes in motor performance with agonist (r = - 0.25, 11 studies) and antagonist (r = - 0.24, 7 studies) EMG amplitude as well as agonist (r = 0.46, 8 studies) and antagonist (r = 0.29, 5 studies) EMG duration. CONCLUSIONS: Our systematic review showed small-sized correlations between practice-related changes in motor performance and agonist and antagonist EMG amplitude and duration in healthy individuals. These findings indicate that practice-related changes can only partly be explained by quantitative myoelectric measures. Thus, future studies investigating biomechanical mechanisms of practice-related changes in motor performance should additionally include qualitative measures of muscle activity (e.g., timing of muscle activity, level of coactivation) and other biomechanical variables (i.e., kinetics, kinematics). PMID- 29423762 TI - Clinical and Novel Biomarkers in the Management of Prostate Cancer. AB - OPINION STATEMENT: Clinical outcomes in prostate cancer after initial screening and treatment for organ-confined disease and in advanced stage after drug intervention can be heterogeneous. Serum prostate-specific antigen which has a modest value as a screening biomarker while widely used in practice in all subsequent stages has limitations for prognostication or prediction of drug efficacy. Recent advances in genomic sciences and the identification of the mutational landscape of organ-confined and advanced-stage disease have contributed to the development of molecular biomarker profiling in addition to serum prostate-specific antigen. Genomic biomarkers are in development for application to screening for lethal disease subtypes, monitoring of disease recurrence after initial treatments, prognostication, as well as for prediction of drug efficacy. The application of translational molecular profiling in prostate cancer has the potential to enhance clinical management and outcomes in the future. Molecular biomarkers in development in organ-confined disease include both DNA- and RNA-based candidate and pathway-based biomarkers. In advanced-stage disease, molecular biomarker profiling has emerged for identifying therapeutic targets, prediction of drug efficacy, and for prognostication of survival that includes germline single nucleotide profiling and somatic aberrations including copy number variation and mutations and RNA-based profiling. This review summarizes the current state of clinical biomarkers used in practice, their limitations, and novel molecular biomarkers being developed for several clinical endpoints in early- and late-stage cancer. PMID- 29423765 TI - Open letter to journal editors on: International Consensus Radiochemistry Nomenclature Guidelines. PMID- 29423766 TI - The patient's perioperative perspective during the treatment of obstructive sleep apnea: a pilot study. AB - PURPOSE: This study aims to determine patients' pre-operative and post-operative experiences relating to surgical treatment for obstructive sleep apnea (OSA), while understanding how patients' perceptions influence their outcome and satisfaction. METHODS: This is a phenomenological qualitative study using a semi structured interview to evaluate patients who failed continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea and underwent airway surgery. Meaningful codes from the interviews were organized into overarching themes of patient experiences. The same surgeon in a tertiary care otolaryngology practice treated all patients. All patients underwent a modified or traditional uvulopalatopharyngoplasty (UPPP) between 2009 and 2013. Patients were diagnosed with OSA by polysomnogram and had failed CPAP use. Patients were interviewed regarding their experience with OSA, CPAP, and surgery. Thematic saturation was reached after 17 patients. RESULTS: Six themes exemplify patient's experience of OSA and treatment: (1) OSA impacted patients personally and professionally, (2) CPAP discomfort limited its therapeutic use, (3) patients had personal motivations for undergoing surgery, (4) patient knowledge influenced their perceptions, (5) post-operative challenges exceeded patient expectations, and (6) post-operative outcomes reflected positive effect on patients. CONCLUSIONS: Patients' experiences prior to surgery can largely influence their perceived outcome and satisfaction. Post-operative sleep studies may not capture the full outcome of the patients' response to surgery. This study suggests that the patient's subjective reported outcomes should be used in conjunction with objective post-operative sleep studies. PMID- 29423767 TI - Patient understanding of discharge instructions in the emergency department: do different patients need different approaches? AB - BACKGROUND: Previous studies have demonstrated that patients have poor understanding of the discharge instructions provided from the emergency department (ED). The aims of this study are to determine if patient factors, such as income and level of education, correlate with patient understanding of discharge instructions and to explore if different patient populations prefer different resources for receiving discharge instructions. METHODS: We conducted live observations of physicians providing discharge instructions in the ED to 100 patients followed by a patient survey to determine their understanding in four domains (diagnosis, treatment plan, follow-up instructions, and return to ED (RTED) instructions) and collect patient demographics. We enrolled patients over the age of 18 being discharged home. We excluded non-English- or French-speaking patients and those with significant psychiatric history or cognitive impairment. We performed a two-way ANOVA analysis of patient factors and patient understanding. RESULTS: We found that patients had poor understanding of discharge instructions, ranging from 24.0% having poor understanding of their follow-up plan to 64.0% for RTED instructions. Almost half (42%) of patients did not receive complete discharge instructions. Lower income was correlated with a significant decrease in patient understanding of discharge diagnosis (p = 0.01) and RTED instructions (p = 0.04). Patients who did not complete high school trended towards lower levels of understanding of their diagnosis and treatment plan (p = 0.06). Lower income patients had a preference for receiving a follow-up phone call by a nurse, while higher income patients preferred online resources. CONCLUSIONS: Lower income patients and those who have not completed high school are at a higher risk of poor understanding discharge instructions. As new technological solutions emerge to aid patient understanding of discharge instructions, our study suggests they may not aid those who are at the highest risk of failing to understand their instructions. PMID- 29423768 TI - Diversity patterns and isolation of Planctomycetes associated with metalliferous deposits from hydrothermal vent fields along the Valu Fa Ridge (SW Pacific). AB - The microbial diversity associated with diffuse venting deep-sea hydrothermal deposits is tightly coupled to the geochemistry of the hydrothermal fluids. Previous 16S rRNA gene amplicon sequencing (metabarcoding) of marine iron hydroxide deposits along the Arctic Mid Ocean Ridge, revealed the presence of diverse bacterial communities associated with these deposits (Storesund and Ovreas in Antonie van Leeuwenhoek 104:569-584, 2013). One of the most abundant and diverse phyla detected was the enigmatic Planctomycetes. Here we report on the comparative analyses of the diversity and distribution patterns of Planctomycetes associated with metalliferous deposits from two diffuse-flow hydrothermal vent fields (Mariner and Vai Lili) from the Valu Fa Ridge in the Southwestern Pacific. Metabarcoding of 16S rRNA genes showed that the major prokaryotic phyla were Proteobacteria (51-73% of all 16S rRNA gene reads), Epsilonbacteraeota (0.5-19%), Bacteriodetes (5-17%), Planctomycetes (0.4-11%), Candidatus Latescibacteria (0-5%) and Marine Benthic Group E (Hydrothermarchaeota) (0-5%). The two different sampling sites differed considerably in overall community composition. The abundance of Planctomycetes also varied substantially between the samples and the sites, with the majority of the sequences affiliated with uncultivated members of the classes Planctomycetacia and Phycisphaerae, and other deep branching lineages. Seven different strains affiliated with the order Planctomycetales were isolated, mostly from the Vai Lili samples, where also the highest Planctomycetales diversity was seen. Most of the isolates were affiliated with the genera Gimesia, Rhodopirellula and Blastopirellula. One isolate was only distantly related to known cultured, but uncharacterized species within the Pir4 group. This study shows that the deep-sea Planctomycetes represent a very heterogeneous group with a high phylogenetic diversity and a substantial potential for novel organism discovery in these deep ocean environments. PMID- 29423769 TI - Repeat computed tomography scans among inter-facility transferred major trauma patients in Oklahoma, 2009-2015. AB - PURPOSE: Computed tomography (CT) scans play a vital role in the diagnosis and evaluation of trauma patients. Repeat CT scans occurred often among transferred trauma patients. The objective was to describe CT use and identify patient- and hospital-level factors associated with repeat CT scans among inter-facility transferred major trauma patients. METHODS: A retrospective cohort study was conducted using data extracted from the Oklahoma State Trauma Registry between 2009 and 2015. Both bivariate and multivariate analyses were employed to assess the factors associated with repeat CT scans. RESULTS: During the 7-year study period, 8678 major trauma patients were transferred between acute-care hospitals in Oklahoma. Among them, 4311 patients had at least one repeat CT scan. Head CT scans were the most commonly performed as well as repeated. Bivariate analysis showed that differences in repeat CT scans were associated with age, injury type, injury severity score, head injury severity, revised trauma score, payer source, transport mode to referring facilities, and facility levels at the 5% level. Multivariate analysis showed the odds of repeat CT scans were higher for adult and geriatric patients, patients with blunt injuries, severely injured patients, patients with severe head injuries, patients with a good revised trauma score, patients discharged alive, and mode to referring facilities. CONCLUSIONS: Our study demonstrated that inter-facility transfers within an organized rural trauma system often underwent repeat CT scans. The large proportion of patients with multiple and repeated CT scans should underline the importance of trauma systems evaluating the necessity of CT scans, image-sharing capability, and obtaining appropriate scans in order to optimize use. Overall, reducing unnecessary CT scans should be an essential part of trauma care quality improvement efforts. PMID- 29423770 TI - Preparticipation screening in athletes, the role of sports cardiology and the impact of the camera. PMID- 29423771 TI - Inherited cardiomyopathies and sports participation. AB - Competitive sports activity is associated with an increased risk of sudden cardiovascular death in adolescents and young adults with inherited cardiomyopathies. Many young subjects aspire to continue competitive sport after a diagnosis of cardiomyopathy and the clinician is frequently confronted with the problem of eligibility and the request of designing specific exercise programs. Since inherited cardiomyopathies are the leading cause of sudden cardiovascular death during sports performance, a conservative approach implying disqualification of affected athletes from most competitive athletic disciplines is recommended by all the available international guidelines. On the other hand, we know that the health benefits of practicing recreational sports activity can overcome the potential arrhythmic risk in these patients, provided that the type and level of exercise are tailored on the basis of the specific risk profile of the underlying cardiomyopathy. This article will review the available evidence on the sports-related risk of sudden cardiac death and the recommendations regarding eligibility of individuals affected by inherited cardiomyopathies for sports activities. PMID- 29423772 TI - Syndesmis Francois, 1886 (Rhabdocoela: Umagillidae): a revisitation, with a synopsis and an identification key to species, and new molecular evidence for ascertaining the phylogeny of the group. AB - Syndesmis Francois, 1886 is a genus of umagillid turbellarians comprising species which are typically endosymbionts of echinoids, i.e. sea urchins. This group is likely key in addressing the issue of transition between a free-living and a parasitic mode of life in the Platyhelminthes. Accordingly, its phylogeny should be considered for detailed analysis, namely by addressing molecular evidence for its different species. At the present time, a revisitation of Syndesmis is required and fully justified by the following lines of argument: (i) the body of knowledge on Syndesmis is large, but the information is scattered through many different works in the literature; (ii) for about 60 years, it was a common practice to assign the umagillids isolated from sea urchins as a single species, i.e. the type-species, Syndesmis echinorum Francois, 1886, which was later split into several species on morphological grounds; and (iii) the type-species - for which no molecular information is available - was redescribed and new species were described in recent years but the generic diagnosis of Syndesmis was not emended accordingly. The present state of art additionally justifies the necessity of (i) an updated synopsis of species and (ii) an identification key to the 26 species described from different hosts and geographical locations. All these aspects define the aims of the present study. It is proposed that S. antillarum is attributed to Stunkard & Corliss (1951) and not to Powers (1936). PMID- 29423773 TI - A new species of Isospora Schneider, 1881 (Apicomplexa: Eimeriidae) from the twist-necked turtle Platemys platycephala (Schneider) (Testudines: Chelidae) in Brazil. AB - A new coccidian species of the genus Isospora Schneider 1881 (Apicomplexa, Eimeriidae) is reported from a single specimen of chelid turtle, Platemys platycephala (Schneider, 1792), obtained in a flooded area of the Amazonian municipality of Altamira, in Para State, northern Brazil. The oocysts of Isospora platemysi n. sp. are subspheroidal, 19.0-24.0 * 22.5-18.5 (22.6 * 20.8) um in size [length/width ratio 1.0-1.1 (1.1)], with a colourless wall, 1.0-1.9 (1.4) wide, with two smooth layers; polar granule is present, oocyst residuum and micropyle are both absent. The sporocyst is ovoidal, 10.0-12.1 * 8.0-10.0 (11.0 * 9.1) um [length/width ratio 1.1-1.3 (1.2), with a knob-like Stieda body. Sub Stieda body is present, rounded irregular-trapezoidal; para-Stieda body is absent. Sporocyst residuum is dispersed and composed of granules of differing sizes. This is only the fifth record of Isospora in chelonians, and the first report of a coccidian parasite of the genus Platemys. PMID- 29423776 TI - Full recovery from drummer's dystonia with foot and arm symptoms after stereotactic ventro-oral thalamotomy: a case report. AB - Ventro-oral (Vo) thalamotomy is effective in patients with focal task-specific dystonias (FTSDs), but only in those with upper-limb symptoms. We describe a patient with drummer's dystonia who completely recovered after Vo thalamotomy. A 37-year-old man who started playing drums at 14 began having difficulty performing fine movements with his right foot when drumming at 22. He experienced right hand cramps while drumming 3 months before visiting our hospital. He was diagnosed with FTSD. Left Vo thalamotomy was performed, which led to complete improvement of symptoms. Vo thalamotomy may be effective for FTSD patients with upper- and lower-extremity symptoms. PMID- 29423775 TI - A class of semiparametric cure models with current status data. AB - Current status data occur in many biomedical studies where we only know whether the event of interest occurs before or after a particular time point. In practice, some subjects may never experience the event of interest, i.e., a certain fraction of the population is cured or is not susceptible to the event of interest. We consider a class of semiparametric transformation cure models for current status data with a survival fraction. This class includes both the proportional hazards and the proportional odds cure models as two special cases. We develop efficient likelihood-based estimation and inference procedures. We show that the maximum likelihood estimators for the regression coefficients are consistent, asymptotically normal, and asymptotically efficient. Simulation studies demonstrate that the proposed methods perform well in finite samples. For illustration, we provide an application of the models to a study on the calcification of the hydrogel intraocular lenses. PMID- 29423774 TI - Revision: prognostic impact of baseline glucose levels in acute myocardial infarction complicated by cardiogenic shock-a substudy of the IABP-SHOCK II trial. AB - BACKGROUND: Limited data from observational retrospective studies suggest an association between glucose levels and prognosis of patients with cardiogenic shock (CS). The aim of this study was to investigate the prognostic role of glucose at admission in patients with acute myocardial infarction (AMI) complicated by CS included in the largest CS trial to date, the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial. METHODS AND RESULTS: In the IABP-SHOCK II-trial, patients with CS complicating AMI undergoing early revascularization were randomized to a therapy with vs. without IABP support. Primary and secondary endpoints were mortality within 30 days and 1 year, respectively. Glucose levels were examined at admission. Glucose levels were available in 513 patients. In total, 33.7% of the patients had known diabetes. Patients with diabetes had higher glucose levels compared to those without diabetes (median [interquartile range (IQR)] 13.1 mmol/L [IQR 9.5-18.3] vs. 10.8 mmol/L [IQR 7.8-15.4], p = 0.0003). Patients with glucose concentrations above the median (11.5 mmol/L) had higher 30-day and 1-year mortality compared to those below the median (47.7 vs. 36.5%, p = 0.004; 57.7 vs. 47.1%, p = 0.011, respectively). This negative prognostic impact of increased glucose levels remained significant in multivariate adjustment and was not influenced even after adjustment for the presence or absence of diabetes mellitus. CONCLUSIONS: In patients with CS complicating AMI, increased glucose concentration at admission was an independent predictor for mortality at 30-days and 1-year, independently of the diabetic state. PMID- 29423777 TI - Pandora's box. AB - Suitcases or other containers are occasionally involved in forensic investigations. If there is a suspicion that human remains are hidden inside such a container, medico-legal examinations are required. However, these containers are occasionally locked. Forced opening of a locked suitcase or container may cause damage to its contents. Additionally, the safety of the investigator has to be considered as such containers may be booby-trapped or contain other hazardous material. An overview of the contents before opening is desirable in order to avoid the possibility of encountering a Pandora's box. In forensic medicine, an established approach to examine the inside of a body before opening at autopsy is postmortem computed tomography (CT). However, there may be a reluctance to use this approach for suitcases or containers with metallic components because of the assumption that severe metal artifacts will result in inadequate images. In this article, we present a forensic case in which a CT scan of a metallic suitcase was performed in order to examine its contents. Additionally, we performed an experimental scan of a conventional safe in order to determine if CT is able to reveal the contents of such a highly radiopaque storage box. PMID- 29423778 TI - A homemade furnace. Influence of occupational skills in a fire-related planned complex suicide. AB - The term "planned complex suicide" means the combination of more than one method of suicide, planned to prevent failure of the first method to ensure a fatal outcome. Professional skills and tools are sometimes used to plan and perpetrate the suicide. A case of planned complex suicide of a mechanical engineer working with furnaces in a tube factory is herein reported. The suicide was committed in a rudimental furnace set up in the victim's apartment using his professional skills, by assembling furniture, mattresses, books and flammable liquid present in the house. Three-dimensional models of the crime scene before and after the realization of the "homemade furnace" are proposed. The discussion will focus on the importance of a comprehensive analysis of the professional background of the victim to infer the manner of death for the identification of complex and occupation-related suicides. PMID- 29423779 TI - Preferential Geographic Distribution Pattern of Abiotic Stress Tolerant Rice. AB - Crop productivity and stability of the food system are threatened by climate change, mainly through the effects of predicted abiotic stresses. Despite extensive research on abiotic stress tolerance in the past decades, the successful translation of these research to fields/farmers is scarce. The impelling demand of climate resilient varieties, and the poor translation of research into the field despite the availability of high throughput technologies lead us to critically analyse a neglected aspect of current abiotic stress tolerance research. Although environmental factors play the most important role in the development of adaptive traits of plants, most abiotic stress tolerance research ignores eco-geographic aspects of highly stress tolerant accessions. In this review, we critically examined the geographic distribution pattern of highly tolerant rice accessions of all major abiotic stresses along with one micronutrient deficiency. Remarkably, we identified a shared geographic distribution pattern of highly tolerant accessions for all abiotic stresses including zinc deficiency despite the sparseness of highly tolerant accessions. The majority of these tolerant accessions predominately originated from Bangladesh centred narrow geographic region. We therefore analysed the climatic and agro-ecological features of Bangladesh. Considering the threat of climate change on global food security and poverty, urgent concerted research efforts are necessary for the development of climate resilient rice varieties utilizing the technological advancement, know-hows, and the preferential distribution pattern of abiotic stress tolerant rice. PMID- 29423780 TI - Do Risk Prediction Models for Postoperative Delirium Consider Patients' Preoperative Medication Use? AB - BACKGROUND: Medicines are potentially modifiable risk factors for postoperative delirium. However, the extent to which preoperative medicines are included in risk prediction models (RPMs) is unknown. OBJECTIVE: This systematic review aimed to assess the extent of inclusion of preoperative medications in RPMs for postoperative delirium. METHODS: Articles were systematically searched from MEDLINE, EMBASE and CINAHL using Medical Subject Headings (MeSH) where possible and keywords for postoperative delirium and prediction model. Studies published until May 2017 with a primary outcome of postoperative delirium that developed an RPM containing preoperative patient information were considered. Where a study had two cohorts, a derivation and a validation cohort, findings from the derivation cohort were extracted and reported. RESULTS: Eighteen prospective and one retrospective cohort studies were included for review. Of the 19 studies, only nine considered preoperative medication data, with medications appearing as predictor variables in five models. There was wide variability in the factors included in the final models, with the most frequent predictors being age and cognitive impairment, appearing in 13 (68%) and 11 (58%) RPMs, respectively. CONCLUSION: While medications are commonly cited risk factors for delirium, they are not adequately considered when developing RPMs. Future studies aiming to develop an RPM for postoperative delirium should include preoperative medication data as a potential predictor variable because of the modifiable nature of medication use and its impact on other factors commonly in models, such as cognition. PMID- 29423781 TI - Older Patients' Compliance with Drug Storage Recommendations. AB - BACKGROUND: Whereas storage conditions are regulated and closely monitored in every stage of the drug supply chain before drug dispensing, it is unknown if patients store drugs at home according to storage recommendations. OBJECTIVE: The objective of this study was to investigate how older patients store their prescription drugs at home and to what extent they comply with drug storage recommendations. METHODS: We conducted a cross-sectional study between October 2015 and March 2016. Forty-four participating Dutch community pharmacies selected four home-dwelling patients (aged >= 65 years) using at least one prescription drug. A complete drug inventory at patients' homes was performed. Drugs were considered to fulfill the storage recommendation when these met all drug quality (Q) and information (I) criteria: adequately stored according to drug product label storage recommendations for temperature, light, humidity (Q1); expiry date not passed (Q2); integer primary package (Q3); drug identifiability (I1); drug package insert or information leaflet availability (I2). RESULTS: One hundred and seventy patients [53.5% female, mean age 74.9 (standard deviation 7.3) years] were included and 1133 prescription drugs stored at home were registered. More than half of the patients (51.2%) complied with all storage quality and information criteria. Assessment of the individual criteria showed that 76.4% of patients were compliant with criterion Q1 while 90.6, 95.3, 97.1 and 71.2% of patients complied with criteria Q2, Q3, I1 and I2, respectively. 53.2% of drugs that should be kept refrigerated according to storage criterion Q1 were not stored between 2 and 8 degrees C. CONCLUSION: This study illustrates that more than half of the older patients comply with general drug storage recommendations. PMID- 29423782 TI - Deep blue dot corneal degeneration: confocal characteristics. AB - PURPOSE: To discuss the clinical features, differential diagnosis and the novel confocal microscopic findings noted in the rare 'deep blue dot corneal degeneration'. METHODS: Observational case report. RESULTS: Slit-lamp biomicroscopic examination revealed bilateral, numerous, circular to oval discrete blue opacities at the level of deep stroma and fine grey linear opacities at the level of mid to deep stroma. Confocal microscopy demonstrated two types of corresponding hyper-reflective extracellular lesions: oval deposit like, most concentrated at a depth of 430-480 u and needle-like at the depth 330 370 u. CONCLUSIONS: Deep blue dot corneal degeneration is a rare entity where blue deposits of amyloid are seen in the deep corneal stroma. It should be considered as a differential diagnosis when an old-aged person presents with good vision and the above mentioned findings. PMID- 29423783 TI - Peyronie's disease and Dupuytren's contracture secondary to topical timolol. AB - INTRODUCTION: Topical beta-blockers are a proven and safe medication used in the treatment of glaucoma and ocular hypertension. Local and systemic side effects are, however, well documented. Systemic side effects can include severe cardio respiratory impairment, endocrine dysfunction, as well as headache and hyper somnolence. Disorders involving fibrosis such as Peyronie's disease, Dupuytren's contracture, and retroperitoneal fibrosis are rarely described in the literature. CASE REPORT: We describe a case of a 55-year-old male patient undergoing treatment for ocular hypertension with topical timolol 0.25% to both eyes, who subsequently developed both Peyronie's disease and Dupuytren's contracture. To our knowledge, this is the first case of Dupuytren's contracture secondary to the use of topical timolol. CONCLUSIONS: Whilst uncommon, beta-blockers are known to be associated with such fibrotic conditions and have been reported with the use of topical timolol. This case serves to increase the current understanding of this association. PMID- 29423784 TI - Ocular surface squamous neoplasia in a setting of fungal keratitis: a rare co occurrence. AB - PURPOSE: To describe a rare co-occurrence of ocular surface squamous neoplasia (OSSN) in a patient with microbial keratitis. METHODS: Case report. RESULTS: We describe a 68-years female who developed ocular surface squamous neoplasia (OSSN) in an eye with culture proven severe fungal keratitis of 5 months duration, which progressed to endophthalmitis. She was managed with extended enucleation for left eye. Histopathology examination was consistent with squamous cell carcinoma of ocular surface with no corneal stromal/scleral/anterior chamber involvement. She received adjuvant chemotherapy with topical Interferon alpha2b (3 cycles) for positive margins. Six months after treatment, she is completely tumor free. CONCLUSION: Co-occurrence of OSSN and chronic fungal keratitis is rare. We recommend that patients with chronic ocular infections should be examined and followed closely for abnormally thickened limbal areas. PMID- 29423785 TI - Damage to the inferior oblique muscle branch of the oculomotor nerve: a complication during orbital fat decompression. AB - PURPOSE: To present patients who suffered damage to the inferior oblique muscle branch of the oculomotor nerve during orbital fat decompression. METHODS: This study was a retrospective chart review of all patients who underwent orbital decompression surgery between April 2009 and June 2016 by the authors. RESULTS: Among 414 sides from 226 consecutive patients who underwent orbital decompression, the inferior oblique muscle branch was injured in two sides (0.5%) of two patients. Both patients showed hypotropia and incyclotropia immediately after surgery. Within 6 months of injury, ocular deviation on primary gaze had mostly resolved after conservative treatment. None of the patients underwent strabismus surgery. Postoperative computed tomographic images demonstrated that the affected branch was indistinct 3-4 mm posterior to the inferior oblique muscle. CONCLUSIONS: This report indicates that injury to the inferior oblique muscle nerve branch can occur at a point posterior to the inferior oblique muscle during orbital fat decompression; however, the resulting ocular deviation improves considerably within 6 months of injury. PMID- 29423786 TI - Comparison of ARMS2/LOC387715 A69S and CFH Y402H risk effect in wet-type age related macular degeneration: a meta-analysis. AB - PURPOSE: We designed this meta-analysis to pool studies which have analyzed both CFH (Y402H or I62V) and ARMS2 A69S in the same samples to compare the effect of CFH and ARMS2 in neovascular AMD. METHODS: Relevant studies identified and reviewed separately in order to select those for inclusion. Included studies had genotype data of studied groups for both ARMS2 A69S and CFH. To modify the heterogeneity in the variables, we used random effects model. Meta-analysis was performed using STATA. Funnel plot and Egger's regression test used for evaluation of the possible publication bias. RESULTS: Overall, we included 6676 neovascular AMD cases and 7668 controls. Pooled overall odds ratios (ORs) (95% CI) for neovascular AMD/control were ARMS2 A69S: OR = 2.35 (2.01-2.75) for GT versus GG; OR = 8.57 (6.91-10.64) for TT versus GG; CFH Y402H: OR = 1.94 (1.73 2.18) for CT versus TT; OR = 4.89 (3.96-6.05) for CC versus TT. ARMS2 A69S genotype OR/CFH Y402H genotype OR (homogeneous genotypes): Asia = 2.14, Europe: 1.87, America: 1.82, Middle East: 3.56, pooled: 1.75. ARMS2 A69S genotype OR/CFH Y402H genotype OR (heterogeneous genotypes): Asia = 0.93, Europe: 1.39, America: 2.06, Middle East: 1.20, pooled: 1.21. ARMS2 A69S risk genotypes have stronger predisposing effect on neovascular AMD compared to CFH Y402H risk genotypes. CONCLUSION: Our inclusion criteria to select those studies which have analyzed the effect of these two loci in the same case-control samples showed much stronger effect of ARMS2 A69S in neovascular AMD compared to the CFH Y402H. PMID- 29423787 TI - Human Immunodeficiency Virus Infection, Antiretroviral Therapy, and Statin: a Clinical Update. AB - PURPOSE OF REVIEW: This clinical update is intended to focus in relationship between HIV infection and use of antiretroviral therapy (ART) and statin. RECENT FINDINGS: Though ART significantly changed the course of HIV infection, it is related to numerous side effects principally to the lipid profile. In this way, statins became one of the most used lipid-lowering therapies in this population. In our clinical update, we evaluated studies that demonstrate the relationship and molecular mechanisms that HIV infection and ART use trigger dyslipidemia and also the use of statin to reduce this condition. We have demonstrated that use of statin can be used in dyslipidemic HIV-infected people as long as there is no drug interaction with ART. Recently, studies using rosuvastatin have shown greater effects when compared to the other statins. PMID- 29423788 TI - Evaluation of extraction methods for methylated cell-free fetal DNA from maternal plasma. AB - PURPOSE: Recently, fetal placenta-specific epigenetic regions (FSERs) have been identified for quantification of cell-free fetal DNA (cff-DNA) for non-invasive prenatal testing (NIPT). The aim of this study was to evaluate the efficiencies of a column-based kit and magnetic bead-based kit for quantification of methylated FSERs from maternal plasma. METHODS: Maternal plasma was extracted from normal pregnant women within the gestational age of 10~13 weeks (n = 24). Total cell-free DNA (cf-DNA) was extracted using a column-based kit and magnetic bead-based kit from the plasma of the same pregnant woman, respectively. Methylated FSERs were enriched from the extracted total cf-DNA using a methyl-CpG binding domain-based protein method. The four FSERs were simultaneously quantified by multiplex real-time polymerase chain reaction. RESULTS: Methylated FSERs were detected in all samples extracted from both kits. However, the amplification of FSERs showed significant differences in the extraction efficiency of methylated FSERs between the two extraction methods. The Ct values of methylated FSERs extracted using the column-based kit were significantly lower than those obtained using the magnetic bead-based kit (P < 0.001 for all FSERs). The quantity of methylated FSERs was significantly higher for extracted DNA using the column-based kit than that extracted using the magnetic bead-based kit (P < 0.001 for all FSERs). Time and cost for the process of extraction were similar for the column kit and magnetic bead-based kit. CONCLUSIONS: Our findings demonstrate that the column-based kit was more effective than the magnetic bead based kit for isolation of methylated FSERs from maternal plasma as assessed by FSER detection. PMID- 29423789 TI - Do trained reproductive endocrinologists perform better than their trainees? Comparing clinical pregnancy rates and live birth rates after transfer of single fresh blastocysts. AB - PURPOSE: To compare clinical pregnancy rates and live birth rates of single blastocyst transfers performed by attending physicians or fellows in reproductive endocrinology and infertility program. METHODS: Retrospective study in an academic reproductive center. We evaluated 932 fresh single blastocyst transfer cycles performed by fellows in training (389 embryo transfers) and by attending physicians (543 embryo transfers). RESULTS: There were no differences in the baseline characteristics and IVF cycle parameters between patients who had transfers performed by fellows or attending physicians. Transfers performed by attending physicians or fellows resulted in similar CPR (46.5 vs. 42.9%, p = 0.28) and LBR (38.3 vs. 34.2%, p = 0.11). Multivariate logistic regression analysis showed that even after adjusting for possible confounders (age, gravity, parity, baseline FSH, antral follicle count, dose of gonadotropins, stimulation protocol, and quality of embryo transferred), CPR (OR 0.81, CI 0.62-1.07) and LBR (OR 0.79, CI 0.6-1.05) in the two groups were comparable. CONCLUSION: Clinical pregnancy rate and live birth rate after embryo transfer performed by attending staffs or fellows are comparable. This finding reassures fellowship programs that allowing fellows to perform embryo transfers does not compromise the outcome. PMID- 29423790 TI - Identification of Disease Susceptibility Alleles in the Next Generation Sequencing Era. AB - The development of next generation sequencing (NGS) technologies has transformed the study of human genetic variation. In less than a decade, NGS has facilitated the discovery of causal mutations in both rare, monogenic diseases and common, heterogeneous disorders, leading to unprecedented improvements in disease diagnosis and treatment strategies. Given the rapid evolution of NGS platforms, it is now possible to analyze whole genomes and exomes quickly and affordably. Further, emerging NGS applications, such as single-cell sequencing, have the power to address specific issues like somatic variation, which is yielding new insights into the role of somatic mutations in cancer and late-onset diseases. Despite limitations associated with current iterations of NGS technologies, the impact of this approach on identifying disease-causing variants has been significant. This chapter provides an overview of several NGS platforms and applications and discusses how these technologies can be used in concert with experimental and computational strategies to identify variants with a causative effect on disease development and progression. PMID- 29423791 TI - Induced Pluripotent Stem Cells in Disease Modeling and Gene Identification. AB - Experimental modeling of human inherited disorders provides insight into the cellular and molecular mechanisms involved, and the underlying genetic component influencing, the disease phenotype. The breakthrough development of induced pluripotent stem cell (iPSC) technology represents a quantum leap in experimental modeling of human diseases, providing investigators with a self-renewing and, thus, unlimited source of pluripotent cells for targeted differentiation. In principle, the entire range of cell types found in the human body can be interrogated using an iPSC approach. Therefore, iPSC technology, and the increasingly refined abilities to differentiate iPSCs into disease-relevant target cells, has far-reaching implications for understanding disease pathophysiology, identifying disease-causing genes, and developing more precise therapeutics, including advances in regenerative medicine. In this chapter, we discuss the technological perspectives and recent developments in the application of patient-derived iPSC lines for human disease modeling and disease gene identification. PMID- 29423792 TI - Development of Targeted Therapies Based on Gene Modification. AB - With the advent of next-generation sequencing (NGS) and the demand for a personalized healthcare system, the fields of precision medicine and gene therapy are advancing in new directions. There is a push to identify genes that contribute to disease development, either alone or in conjunction with other genes or environmental factors, and then design targeted therapies based on this knowledge, rather than the traditional approach of treating generalized symptoms with pharmaceuticals in a one-size-fits-all manner. Identification of genes that contribute to disease pathogenesis and progression is critical for the maturation of the precision medicine field. Concomitant with a better understanding of disease pathology, precision medicine approaches can be adopted with greater confidence and are expected to lead to a new standard for clinical practice. In this chapter, we provide a brief introduction to precision medicine, discuss the importance of identifying genes and genetic variants that contribute to disease development and progression, offer examples of approaches that can be applied to treat specific diseases, and present some of the current challenges and limitations of precision medicine. PMID- 29423793 TI - What Can We Learn About Human Disease from the Nematode C. elegans? AB - Numerous approaches have been taken in the hunt for human disease genes. The identification of such genes not only provides a great deal of information about the mechanism of disease development, but also provides potential avenues for better diagnosis and treatment. In this chapter, we review the use of the nonmammalian model organism C. elegans for the identification of human disease genes. Studies utilizing this relatively simple organism offer a good balance between the ability to recapitulate many aspects of human disease, while still offering an abundance of powerful cell biological, genetic, and genomic tools for disease gene discovery. C. elegans and other nonmammalian models have produced, and will continue to produce, key insights into human disease pathogenesis. PMID- 29423794 TI - Microbiome Sequencing Methods for Studying Human Diseases. AB - Over the last decade, biologists have come to appreciate that the human body is inhabited by thousands of bacterial species in diverse communities unique to each body site. Moreover, due to high-throughput sequencing methods for microbial characterization in a culture-independent manner, it is becoming evident that the microbiome plays an important role in human health and disease. This chapter focuses on the most common form of bacterial microbiome profiling, targeted amplicon sequencing of the 16S ribosomal RNA (rRNA) subunit encoded by 16S rDNA. We discuss important features for designing and performing microbiome experiments on human specimens, including experimental design, sample collection, DNA preparation, and selection of the 16S rDNA sequencing target. We also provide details for designing fusion primers required for targeted amplicon sequencing and selecting the most appropriate high-throughput sequencing platform. We conclude with a review of the fundamental concepts of data analysis and interpretation for these kinds of experiments. Our goal is to provide the reader with the essential knowledge needed to undertake microbiome experiments for application to human disease research questions. PMID- 29423795 TI - The Emerging Role of Long Noncoding RNAs in Human Disease. AB - Only a small fraction of the human genome corresponds to protein-coding genes. Historically, the vast majority of genomic sequence was dismissed as transcriptionally silent, but recent large-scale investigations have instead revealed a rich array of functionally significant elements, including non-protein coding transcripts, within the noncoding regions of the human genome. Long noncoding RNAs (lncRNAs), a class of noncoding transcripts with lengths >200 nucleotides, are pervasively transcribed in the genome, and have been shown to bind DNA, RNA, and protein. LncRNAs exert effects through a variety of mechanisms that include guiding chromatin-modifying complexes to specific genomic loci, providing molecular scaffolds, modulating transcriptional programs, and regulating miRNA expression. An increasing number of experimental studies are providing evidence that lncRNAs mediate disease pathogenesis, thereby challenging the concept that protein-coding genes are the sole contributors to the development of human disease. This chapter highlights recent findings linking lncRNAs with human diseases of complex etiology, including hepatocellular carcinoma, Alzheimer's disease, and diabetes. PMID- 29423796 TI - Identification of Disease-Related Genes Using a Genome-Wide Association Study Approach. AB - Genome-wide association studies (GWAS) provide a hypothesis-free approach to discover genetic variants contributing to the risk of a certain disease or disease-related trait. Ongoing efforts to annotate the human genome have helped to localize disease-causing variants and point to mechanisms by which genetic variants might exert functional effects. By integrating bioinformatics approaches with in vivo and in vitro genomic strategies to predict and subsequently validate the functional roles of GWAS-identified variants, disease-related pathways can be characterized, providing new possibilities for therapeutic intervention. Here, we describe a basic workflow, from sample preparation to data analysis, for performing a GWAS to identify disease genes. We also discuss resources for the annotation and interpretation of GWAS results. PMID- 29423797 TI - Whole Genome Library Construction for Next Generation Sequencing. AB - With the rapid evolution of genomics technologies over the past decade, whole genome sequencing (WGS) has become an increasingly accessible tool in biomedical research. WGS applications include analysis of genomic DNA from single individuals, multiple related family members, and tumor/normal samples from the same patient in the context of oncology. A number of different modalities are available for performing WGS; this chapter focuses on wet lab library construction procedures for complex short insert WGS libraries using the KAPA Hyper Prep Kit (Kapa Biosystems), and includes a discussion of appropriate quality control measures for sequencing on the Illumina HiSeq2000 platform. Additional modifications to the protocol for long insert WGS library construction, to assess structural alterations and copy number changes, are also described. PMID- 29423798 TI - Whole Exome Library Construction for Next Generation Sequencing. AB - Whole exome sequencing (WES) is a DNA sequencing strategy that provides a survey of base substitutions across coding genomic locations and other regions of interest. As the coding portion of the genome encompasses only 1-2% of the entire genome, this approach represents a more cost-effective strategy to detect DNA alterations that may alter protein function, compared to whole genome sequencing. Although the research community has and is currently delineating the functional implications of sequence changes in noncoding regions of the genome, WES is a currently available assay that provides valuable information for both discovery research and precision medicine applications. In this chapter, we present a WES library preparation protocol using the KAPA Hyper Prep Kit with Agilent SureSelect Human All Exon V5+UTR probes that demonstrates high DNA-to-library conversion efficiency for sequencing on the Illumina HiSeq platform. PMID- 29423799 TI - Optimized Methodology for the Generation of RNA-Sequencing Libraries from Low Input Starting Material: Enabling Analysis of Specialized Cell Types and Clinical Samples. AB - RNA sequencing (RNA-seq) has become an important tool for examining the role of the transcriptome to biological processes. While RNA-seq has been widely adopted as a popular approach in many experimental designs, from gene discovery to mechanistic validation of targets, technical issues have largely limited the use of this technique to abundantly available sample sources. However, RNA-seq is becoming increasingly utilized for more specialized applications, such as flow cytometry-sorted cells and clinical specimens, due to protocol advances enabling the use of very low input material ranging from 10 pg to 10 ng of total RNA or 1 1000 intact cells. In this chapter, we present an optimized and detailed approach to RNA-seq for use with low abundance samples. PMID- 29423800 TI - Using Fluidigm C1 to Generate Single-Cell Full-Length cDNA Libraries for mRNA Sequencing. AB - Single-cell RNA sequencing has evolved into a benchmark application to study cellular heterogeneity, advancing our understanding of cellular differentiation, disease progression, and gene regulation in a multitude of research areas. The generation of high-quality cDNA, an important step in the experimental workflow when generating sequence-ready libraries, is critical to maximizing data quality. Here we describe a strategy that uses a microfluidic device (i.e., the C1TM IFC) to synthesize full-length cDNA from single cells in a fully automated, nanoliter scale format. The device also facilitates confirmation of the presence of a single, viable cell and recording of phenotypic information, quality control measures that are crucial for streamlining downstream data processing and enhancing overall data validity. PMID- 29423801 TI - MiSeq: A Next Generation Sequencing Platform for Genomic Analysis. AB - MiSeq, Illumina's integrated next generation sequencing instrument, uses reversible-terminator sequencing-by-synthesis technology to provide end-to-end sequencing solutions. The MiSeq instrument is one of the smallest benchtop sequencers that can perform onboard cluster generation, amplification, genomic DNA sequencing, and data analysis, including base calling, alignment and variant calling, in a single run. It performs both single- and paired-end runs with adjustable read lengths from 1 * 36 base pairs to 2 * 300 base pairs. A single run can produce output data of up to 15 Gb in as little as 4 h of runtime and can output up to 25 M single reads and 50 M paired-end reads. Thus, MiSeq provides an ideal platform for rapid turnaround time. MiSeq is also a cost-effective tool for various analyses focused on targeted gene sequencing (amplicon sequencing and target enrichment), metagenomics, and gene expression studies. For these reasons, MiSeq has become one of the most widely used next generation sequencing platforms. Here, we provide a protocol to prepare libraries for sequencing using the MiSeq instrument and basic guidelines for analysis of output data from the MiSeq sequencing run. PMID- 29423802 TI - Methods for CpG Methylation Array Profiling Via Bisulfite Conversion. AB - DNA methylation is a key factor in epigenetic regulation, and contributes to the pathogenesis of many diseases, including various forms of cancers, and epigenetic events such X inactivation, cellular differentiation and proliferation, and embryonic development. The most conserved epigenetic modification in plants, animals, and fungi is 5-methylcytosine (5mC), which has been well characterized across a diverse range of species. Many technologies have been developed to measure modifications in methylation with respect to biological processes, and the most common method, long considered a gold standard for identifying regions of methylation, is bisulfite conversion. In this technique, DNA is treated with bisulfite, which converts cytosine residues to uracil, but does not affect cytosine residues that have been methylated, such as 5-methylcytosines. Following bisulfite conversion, the only cytosine residues remaining in the DNA, therefore, are those that have been methylated. Subsequent sequencing can then distinguish between unmethylated cytosines, which are displayed as thymines in the resulting amplified sequence of the sense strand, and 5-methylcytosines, which are displayed as cytosines in the resulting amplified sequence of the sense strand, at the single nucleotide level. In this chapter, we describe an array-based protocol for identifying methylated DNA regions. We discuss protocols for DNA quantification, bisulfite conversion, library preparation, and chip assembly, and present an overview of current methods for the analysis of methylation data. PMID- 29423803 TI - miRNA Quantification Method Using Quantitative Polymerase Chain Reaction in Conjunction with C q Method. AB - MicroRNAs are small noncoding RNAs that function to regulate gene expression. In general, miRNAs are posttranscriptional regulators that imperfectly bind to the 3'untranslated region (3'UTR) of target mRNAs bearing complementary sequences, and target more than half of all protein-coding genes in the human genome. The dysregulation of miRNA expression and activity has been linked with numerous diseases, including cancer, cardiovascular diseases, neurodegenerative disorders, and diabetes. To better understand the relationship between miRNAs and human disease, a variety of techniques have been used to measure and validate miRNA expression in many cells, tissues, body fluids, and organs. For many years, quantitative polymerase chain reaction (qPCR) has been the gold standard for measuring relative gene expression, and is now also widely used to assess miRNA abundance. In this chapter, we describe a quick protocol for miRNA extraction, reverse transcription, qPCR, and data analysis. PMID- 29423804 TI - Primary Airway Epithelial Cell Gene Editing Using CRISPR-Cas9. AB - The adaptation of the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated endonuclease 9 (CRISPR-Cas9) machinery from prokaryotic organisms has resulted in a gene editing system that is highly versatile, easily constructed, and can be leveraged to generate human cells knocked out (KO) for a specific gene. While standard transfection techniques can be used for the introduction of CRISPR-Cas9 expression cassettes to many cell types, delivery by this method is not efficient in many primary cell types, including primary human airway epithelial cells (AECs). More efficient delivery in AECs can be achieved through lentiviral-mediated transduction, allowing the CRISPR-Cas9 system to be integrated into the genome of the cell, resulting in stable expression of the nuclease machinery and increasing editing rates. In parallel, advancements have been made in the culture, expansion, selection, and differentiation of AECs, which allow the robust generation of a bulk edited AEC population from transduced cells. Applying these methods, we detail here our latest protocol to generate mucociliary epithelial cultures knocked out for a specific gene from donor-isolated primary human basal airway epithelial cells. This protocol includes methods to: (1) design and generate lentivirus which targets a specific gene for KO with CRISPR-Cas9 machinery, (2) efficiently transduce AECs, (3) culture and select for a bulk edited AEC population, (4) molecularly screen AECs for Cas9 cutting and specific sequence edits, and (5) further expand and differentiate edited cells to a mucociliary airway epithelial culture. The AEC knockouts generated using this protocol provide an excellent primary cell model system with which to characterize the function of genes involved in airway dysfunction and disease. PMID- 29423805 TI - RNA Interference to Knock Down Gene Expression. AB - RNA interference (RNAi) is a biological process by which double-stranded RNA (dsRNA) induces sequence-specific gene silencing by targeting mRNA for degradation. As a tool for knocking down the expression of individual genes posttranscriptionally, RNAi has been widely used to study the cellular function of genes. In this chapter, I describe procedures for using gene-specific, synthetic, short interfering RNA (siRNA) to induce gene silencing in mammalian cells. Protocols for using lipid-based transfection reagents and electroporation techniques are provided. Potential challenges and problems associated with the siRNA technology are also discussed. PMID- 29423806 TI - Using Luciferase Reporter Assays to Identify Functional Variants at Disease Associated Loci. AB - The genomic era, highlighted by large scale, genome-wide association studies (GWAS) for both common and rare diseases, have identified hundreds of disease associated variants. However, most of these variants are not disease causing, but instead only provide information about a potential proximal functional variant through linkage disequilibrium. It is critical that these functional variants be identified, so that their role in disease risk can be ascertained. Luciferase assays are an invaluable tool for identifying and characterizing functional variants, allowing investigations of gene expression, intracellular signaling, transcription factors, receptor activity, and protein folding. In this chapter, we provide an overview of the different ways that luciferase assays can be used to validate functionality of a variant. PMID- 29423807 TI - Physiologic Interpretation of GWAS Signals for Type 2 Diabetes. AB - This chapter reviews both statistical and physiologic issues related to the pathophysiologic effects of genetic variation in the context of type 2 diabetes. The goal is to review current methodologies used to analyze disease-related quantitative traits for those who do not have extensive quantitative and physiologic background, as an attempt to bridge that gap. We leverage mathematical modeling to illustrate the strengths and weaknesses of different approaches and attempt to reinforce with real data analysis. Topics reviewed include phenotype selection, phenotype specificity, multiple variant analysis via the genetic risk score, and consideration of multiple disease-related phenotypes. Type 2 diabetes is used as the example, not only because of the extensive existing knowledge at the genetic, physiologic, clinical, and epidemiologic levels, but also because type 2 diabetes has been at the forefront of complex disease genetics, with many examples to draw from. PMID- 29423808 TI - Identification of Genes for Hereditary Hemochromatosis. AB - Hereditary hemochromatosis (HH) is one of the most common genetically transmitted conditions in individuals of Northern European ancestry. The disease is characterized by excessive intestinal absorption of dietary iron, resulting in pathologically high iron storage in tissues and organs. If left untreated, HH can damage joints and organs, and eventually lead to death. There are four main classes of HH, as well as five individual molecular subtypes, caused by mutations in five genes, and the approaches implemented in the discovery of each HH type have specific histories and unique aspects. In this chapter, we review the genetics of the different HH types, including the strategies used to detect the causal variants in each case and the manner in which genetic variants were found to affect iron metabolism. PMID- 29423810 TI - The Rise and Fall and Rise of Linkage Analysis as a Technique for Finding and Characterizing Inherited Influences on Disease Expression. AB - For many years, family-based studies using linkage analysis represented the primary approach for identifying disease genes. This strategy is responsible for the identification of the greatest number of genes proven to cause human disease. However, technical advancements in next generation sequencing and high throughput genotyping, coupled with the apparent simplicity of association testing, led to the rejection of family-based studies and of linkage analysis. At present, genetic association methods, using case-control comparisons, have become the exclusive approach for detecting disease-related genes, particularly those underlying common, complex diseases. In this chapter, we present a historical overview of linkage analysis, including a description of how the approach works, as well as its strengths and weaknesses. We discuss how the transition from family-based studies to population comparison association studies led to a critical loss of information with respect to genetic etiology and inheritance, and we present historical and contemporary examples of linkage analysis "success stories" in identifying genes contributing to the development of human disease. Currently, linkage analysis is re-emerging as a useful approach for identifying disease genes, determining genetic parameters, and resolving genetic heterogeneity. We posit that the combination of linkage analysis, association testing, and high throughput sequencing provides a powerful approach for identifying disease-causing genes. PMID- 29423809 TI - Identification of Driver Mutations in Rare Cancers: The Role of SMARCA4 in Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT). AB - Cancer is a complex genetic disease that can arise through the stepwise accumulation of mutations in oncogenes and tumor suppressor genes in a variety of different tissues. While the varied landscapes of mutations driving common cancer types such as lung, breast, and colorectal cancer have been comprehensively charted, the genetic underpinnings of many rare cancers remain poorly defined. Study of rare cancers faces unique methodological challenges, but collaborative enterprises that incorporate next generation sequencing, reach across disciplines (i.e., pathology, genetic epidemiology, genomics, functional biology, and preclinical modeling), engage advocacy groups, tumor registries, and clinical specialists are adding increasing resolution to the genomic landscapes of rare cancers. Here we describe the approaches and methods used to identify SMARCA4 mutations, which drive development of the rare ovarian cancer, small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and point to the broader relevance of this paradigm for future research in rare cancers. PMID- 29423812 TI - Correction to: Functional near-infrared spectroscopy (fNIRS) brain imaging of multi-sensory integration during computerized dynamic posturography in middle aged and older adults. AB - In the original publication, Figs. 2 and 3 are not placed in the correct order. Figure 2 should be replaced by Fig. 3 and Fig. 3 should be replaced by Fig. 2. PMID- 29423811 TI - Face stimulus eliminates antisaccade-cost: gaze following is a different kind of arrow. AB - When a person suddenly looks in a certain direction, others seem to shift their attention to the same, looked-at, location. This common observation, that gaze-of another seems to trigger reflexive shifts of attention within an observer, has been demonstrated in various studies. Yet just how reflexive it truly is, is an on-going controversy. Unlike most studies in which gaze cues were distractors in a cueing paradigm, the current study used gaze cues as triggers in a mixed pro- and anti-saccade task and a Posner-like discrimination task. In a set of two experiments, we investigated whether attention triggered by gaze-of-another differs from attention triggered by peripheral (exogenous) and arrow stimuli. In the first experiment, gaze cues resulted in slowed saccadic responses and in the elimination of the anti-saccade-cost associated with reflexive orienting. Pro saccades triggered by peripheral cues had significantly fewer errors and shorter reaction times than anti-saccades. However, there was no significant difference between pro and anti-saccades triggered by gaze cues. Thus, counter to expectations, gaze did not produce reflexive shifts of overt attention. The second experiment showed that attention triggered by gaze cues is no different from attention triggered by biologically irrelevant arrow cues. They both eliminated the anti-saccade-cost and displayed prolonged reaction times. However, manual discrimination RTs showed no significant differences between gaze and peripheral cues. Together, these results suggest that neither gaze nor arrow cues trigger reflexive shifts of overt attention. PMID- 29423813 TI - Exosomes in Pancreatic Cancer: from Early Detection to Treatment. AB - BACKGROUND: Pancreatic cancer (PC) remains one of the most fatal forms of cancer worldwide with incidence nearly equal to mortality. This is often attributed to the fact that diagnosis is often not made until later disease stages when treatment proves difficult. Efforts have been made to reduce the mortality of PC through improvements in early screening techniques and treatments of late-stage disease. Exosomes, small extracellular vesicles involved in cellular communication, have shown promise in helping understand PC disease biology. METHODS: In this review, we discuss current studies of the role of exosomes in PC physiology, and their potential use as diagnostic and treatment tools. RESULTS: Exosomes have a role in diagnosing pancreatic cancer and in understanding tumor biology including migration, proliferation, chemoresistance, immunosuppression, cachexia and diabetes, and have a potential role in therapy for pancreatic cancer. CONCLUSIONS: Exosomal analysis is beneficial in demonstrating mechanisms behind PC growth and metastasis, immunosuppression, drug resistance, and paraneoplastic conditions. Furthermore, the use of exosomes can be beneficial in detecting early-stage PC and exosomes have potential applications as therapeutic targets. PMID- 29423814 TI - Connectivity-based characterisation of subcortical grey matter pathology in frontotemporal dementia and ALS: a multimodal neuroimaging study. AB - Frontotemporal dementia (FTD) phenotypes have distinctive and well-established cortical signatures, but their subcortical grey matter profiles are poorly characterised. The comprehensive characterisation of striatal and thalamic pathology along the ALS-FTD spectrum is particularly timely, as dysfunction of frontostriatal and cortico-thalamic networks contribute to phenotype-defining cognitive, behavioral, and motor deficits. Ten patients with behavioral-variant FTD, 11 patients with non-fluent-variant primary progressive aphasia, 5 patients with semantic-variant primary progressive aphasia, 14 ALS-FTD patients with C9orf72 hexanucleotide expansions, 12 ALS-FTD patients without hexanucleotide repeats, 36 ALS patients without cognitive impairment and 50 healthy controls were included in a prospective neuroimaging study. Striatal, thalamic, hippocampal and amygdala pathology was evaluated using volume measurements, density analyses and connectivity-based segmentation. Significant volume reductions were identified in the thalamus and putamen of non-fluent-variant PPA patients. Marked nucleus accumbens and hippocampal atrophy was observed in the behavioral-variant FTD cohort. Semantic-variant PPA patients only exhibited volumetric changes in the left hippocampus. C9-positive ALS-FTD patients showed preferential density reductions in thalamic sub-regions connected to motor and sensory cortical areas. C9-negative ALS-FTD patients exhibited striatal pathology in sub-regions projecting to rostral-motor and executive cortical areas. The bulk of striatal and thalamic pathology in non-fluent-variant PPA patients was identified in foci projecting to motor areas. Subcortical density alterations in svPPA patients were limited to basal ganglia regions with parietal projections. Striatal and thalamic changes in FTD exhibit selective, network-defined vulnerability patterns mirroring cortical pathology. Multi-modal cortico-basal imaging analyses confirm that the subcortical grey matter profiles of FTD phenotypes are just as distinct as their cortical signatures. Our findings support emerging concepts of network-wise degeneration, preferential circuit vulnerability and disease propagation along connectivity patterns. PMID- 29423815 TI - Ayurvedic and herbal medicine-induced liver injury: It is time to wake up and take notice. PMID- 29423816 TI - Anaphylactoid Reactions to Intravenous N-Acetylcysteine during Treatment for Acetaminophen Poisoning. AB - BACKGROUND: Anaphylactoid reactions to intravenous (IV) N-acetylcysteine (NAC) are well-recognized adverse events during treatment for acetaminophen (APAP) poisoning. Uncertainty exists regarding their incidence, severity, risk factors, and management. We sought to determine the incidence, risk factors, and treatment of anaphylactoid reactions to IV NAC in a large, national cohort of patients admitted to hospital for acetaminophen overdose. METHODS: This retrospective medical record review included all patients initiated on the 21-h IV NAC protocol for acetaminophen poisoning in 34 Canadian hospitals between February 1980 and November 2005. The primary outcome was any anaphylactoid reaction, defined as cutaneous (urticaria, pruritus, angioedema) or systemic (hypotension, respiratory symptoms). We examined the incidence, severity and timing of these reactions, and their association with patient and overdose characteristics using multivariable analysis. RESULTS: An anaphylactoid reaction was documented in 528 (8.2%) of 6455 treatment courses, of which 398 (75.4%) were cutaneous. Five hundred four (95.4%) reactions occurred during the first 5 h. Of 403 patients administered any medication for these reactions, 371 (92%) received an antihistamine. Being female (adjusted OR 1.24 [95%CI 1.08, 1.42]) and having taken a single, acute overdose (1.24 [95%CI 1.10, 1.39]) were each associated with more severe reactions, whereas higher serum APAP concentrations were associated with fewer reactions (0.79 [95%CI 0.68, 0.92]). CONCLUSION: Anaphylactoid reactions to the 21-h IV NAC protocol were uncommon and involved primarily cutaneous symptoms. While the protective effects of higher APAP concentrations are of interest in understanding the pathophysiology, none of the associations identified are strong enough to substantially alter the threshold for NAC initiation. PMID- 29423818 TI - Crystal Structure of Carbonic Anhydrase II in Complex with an Activating Ligand: Implications in Neuronal Function. AB - Carbonic anhydrase (CA) plays a key role in neuronal signaling, providing bicarbonate and proton ions for GABAergic and glutamatergic neuronal function. Activation of CA isoforms expressed in neurons have been shown to have implications in the prognosis of Alzheimer's disease and dementia, while inhibitors of CAs are clinically used in the treatment of epilepsy, emphasizing the importance of this family of enzymes in both disease and normal neuronal function. Previously, compounds have been reported to enhance activity of CAs in an aging rat model, but their mechanism of action was not known. We report the 1.6 A resolution structure of an imidazole-based CA activator in complex with the ubiquitously-expressed human CA II. Based on the structure, a proposed mechanism of CA activation by the compound and its potential applications in the neurobiology of aging are discussed. PMID- 29423817 TI - Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT6 Receptor Antagonist SB-399885. AB - Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT6 receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister hooded rats (weaned on post-natal days 21-24 and housed individually or in groups of 3-4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a 2-week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFalpha levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms. PMID- 29423820 TI - [Biomarker-based diagnostics of Alzheimer's disease : Concept of suspected non Alzheimer pathology]. AB - In the field of prodromal Alzheimer's disease biomarker-based diagnostics are becoming increasingly more important. Unclear biomarker constellations, such as suspected non-Alzheimer pathology (SNAP) can lead to diagnostic and prognostic uncertainty. The use of biomarker-based research criteria in the clinical routine is therefore not without problems. Despite sometimes contradictory findings it appears to be nearly certain that the biomarker constellation of SNAP indicates an increased risk of progression to dementia, at least in patients with mild cognitive deficits (MCI). This article discusses the prognostic implications of a SNAP result and the diagnostic and prognostic problems of biomarker-based diagnostic criteria are presented based on the SNAP. PMID- 29423819 TI - Inhibiting Effect of Zinc Oxide Nanoparticles on Advanced Glycation Products and Oxidative Modifications: a Potential Tool to Counteract Oxidative Stress in Neurodegenerative Diseases. AB - Advanced glycation end products (AGEs) are implicated in several central nervous system (CNS) pathologies including Alzheimer and Parkinson's diseases. In the face-off of AGE menace, we have attempted to investigate the zinc oxide nanoparticle (ZnONP) role in inhibition of AGE formation. Synthesized ZnONPs were used to investigate the inhibitory effects on AGE formation. The inhibitory effects of ZnONPs on AGE formation were determined by biophysical immunological and biochemical techniques. The results showed that ZnONP is a potential anti glycating agent inhibiting AGE formation as well as protecting the protein structure from change. Therefore, our findings suggest ZnONPs may be used as a therapeutic in resolving the AGE role in CNS-related complications. PMID- 29423821 TI - The emerging role of stereotactic radiotherapy in gastrointestinal malignancies: a review of the literature and analysis from the Irish perspective. AB - Primary and secondary malignancies of the liver and pancreas result in significant morbidity and mortality, with increasing incidence and increasing demands on health services worldwide. Surgery is the only curative single modality of treatment and remains the gold standard. Unfortunately, up to 80% of the patients present with unresectable disease, and so, alternative efficacious local and systemic treatments are needed. Technologic advances in radiotherapy over recent decades have meant that precision high-dose treatment with stereotactic body radiotherapy (SBRT) has emerged as a viable cost-effective outpatient-based treatment in the management of these difficult to treat abdominal malignancies. This article reviews the current indications for SBRT in these settings, comparing it with other treatments including surgery, chemotherapy, radiofrequency ablation, and trans-arterial chemoembolisation. We also review the current use of abdominal SBRT and future projections in the Irish healthcare setting. PMID- 29423822 TI - Barriers to the medication error reporting process within the Irish National Ambulance Service, a focus group study. AB - BACKGROUND: Incident reporting is vital to identifying pre-hospital medication safety issues because literature suggests that the majority of errors pre hospital are self-identified. In 2016, the National Ambulance Service (NAS) reported 11 medication errors to the national body with responsibility for risk management and insurance cover. The Health Information and Quality Authority in 2014 stated that reporting of clinical incidents, of which medication errors are a subset, was not felt to be representative of the actual events occurring. Even though reporting systems are in place, the levels appear to be well below what might be expected. Little data is available to explain this apparent discrepancy. AIMS: To identify, investigate and document the barriers to medication error reporting within the NAS. METHODS: An independent moderator led four focus groups in March of 2016. A convenience sample of 18 frontline Paramedics and Advanced Paramedics from Cork City and County discussed medication errors and the medication error reporting process. The sessions were recorded and anonymised, and the data was analysed using a process of thematic analysis. RESULTS: Practitioners understood the value of reporting errors. Barriers to reporting included fear of consequences and ridicule, procedural ambiguity, lack of feedback and a perceived lack of both consistency and confidentiality. The perceived consequences for making an error included professional, financial, litigious and psychological. CONCLUSION: Staff appeared willing to admit errors in a psychologically safe environment. Barriers to reporting are in line with international evidence. Time constraints prevented achievement of thematic saturation. Further study is warranted. PMID- 29423823 TI - Blunt testicular trauma - is surgical exploration necessary? AB - OBJECTIVES: EAU and AUA guidelines recommend urgent surgical exploration in cases of suspected testicular rupture. However, the management of rupture to other encapsulated organs (e.g. kidney) is primarily non-operative. The aim of this study was to evaluate the conservative management of blunt scrotal trauma. METHODS: Standard practice in our Level II trauma centre is to manage all blunt scrotal injuries conservatively with analgesia, antibiotics and scrotal support. Ultrasonography is performed where testicular injury or haematocoele is suspected clinically. All patients are offered a 3 month follow-up appointment. A retrospective chart review was performed on all patients who underwent ultrasonography for blunt scrotal trauma between 1998 and 2014. Each patient was contacted by telephone to assess for testicular atrophy. RESULTS: Thirty-seven consecutive patients were identified for inclusion in the study. Twenty-three patients (62%) were diagnosed with significant testicular injury (rupture of tunica albuginea or large haematocele). All were managed conservatively regardless of ultrasound findings. Four patients had evidence of testicular atrophy at their three month follow up appointment. None reported chronic pain or required delayed orchidectomy. Four patients later underwent repair of an asymptomatic post-traumatic hydrocoele. CONCLUSIONS: Our experience shows that blunt scrotal trauma can be safely managed conservatively and may reduce the risk of atrophy compared to case series where the testis was surgically explored. PMID- 29423824 TI - Attitudes of Irish patients with chronic pain towards medicinal cannabis. AB - BACKGROUND: Medicinal cannabis use is topical in the media in Ireland. A recent Health Products Regulatory Authority review, however, has recommended against its use for patients with chronic pain. This is despite evidence for its effectiveness in this patient's cohort and the inadequate pain management of these patients. AIM: The aim of this study was to evaluate the attitudes of Irish patients with chronic pain towards medicinal cannabis. METHODS: After institutional ethics committee approval, a 12-item questionnaire (excluding demographics) was randomly assigned to patients attending a chronic pain clinic (University Hospital Limerick). The questionnaire was designed to incorporate patient's attitudes on a variety of medicinal cannabis related topics. RESULTS: Ninety-six adult patients were surveyed. 88.54% agreed that cannabis should be legalised for chronic pain medicinal purposes. 80.21% believed it would have health benefits for them and 73.96% agreed it would be socially acceptable to use cannabis for this purpose. 33.33% perceived cannabis to be addictive while 68.75% would be willing to try it if prescribed by a medical professional. CONCLUSIONS: The study highlights the attitudes of chronic pain patients in Ireland towards medicinal cannabis. It shows their desire to have medical cannabis legalised for chronic pain and that they view it as a reasonable pain management option. PMID- 29423825 TI - Non-operative treatment of appendicitis: public perception and decision-making. AB - BACKGROUND: Appendectomy has for many years been the accepted treatment of appendicitis. In recent years, non-operative management of appendicitis (NOTA) has been reported as an effective treatment option. AIMS: We aimed to assess the perspectives of public hospital attendees regarding the diagnosis and treatment options for appendicitis. METHODS: We conducted a cross-sectional survey of outpatients over a 10-week period (December 2016-March 2017). The questionnaire contained an information sheet and consent form and included open, closed and multiple-choice questions. RESULTS: Two hundred forty-four participants (159 female, 85 male) were surveyed. A high level of awareness of appendicitis as a surgical emergency existed amongst the participants. The primary reason participants were reluctant to receive non-operative treatment was a fear of their appendix "bursting" if not removed. CONCLUSIONS: Participant knowledge levels were variable with many concerned that non-operated appendicitis would always perforate. Perceptions of treatment were variable with some believing surgery was an absolute requirement and others preferring antibiotics due to the belief that NOTA is complication-free. PMID- 29423826 TI - Help Wanted: Medical Educators in Addiction Psychiatry. PMID- 29423827 TI - Making Feedback Meaningful: Using Student and Supervisor Feedback. PMID- 29423828 TI - Standardized Patients in Clinical Psychology and Psychotherapy: a Scoping Review of Barriers and Facilitators for Implementation. AB - OBJECTIVES: The use of simulated and standardized patients (SP) is widely accepted in the medical field and, from there, is beginning to disseminate into clinical psychology and psychotherapy. The purpose of this study was therefore to systematically review barriers and facilitators that should be considered in the implementation of SP interventions specific to clinical psychology and psychotherapy. METHODS: Following current guidelines, a scoping review was conducted. The literature search focused on the MEDLINE, PsycINFO and Web of Science databases, including Dissertation Abstracts International. After screening for titles and abstracts, full texts were screened independently and in duplicate according to our inclusion criteria. For data extraction, a pre-defined form was piloted and used. Units of meaning with respect to barriers and facilitators were extracted and categorized inductively using content-analysis techniques. From the results, a matrix of interconnections and a network graph were compiled. RESULTS: The 41 included publications were mainly in the fields of psychiatry and mental health nursing, as well as in training and education. The detailed category system contrasts four supercategories, i.e., which organizational and economic aspects to consider, which persons to include as eligible SPs, how to develop adequate scenarios, and how to authentically and consistently portray mental health patients. CONCLUSIONS: Publications focused especially on the interrelation between authenticity and consistency of portrayals, on how to evoke empathy in learners, and on economic and training aspects. A variety of recommendations for implementing SP programs, from planning to training, monitoring, and debriefing, is provided, for example, ethical screening of and ongoing support for SPs. PMID- 29423829 TI - Hepatocellular carcinoma in Gaucher disease: an international case series. AB - Gaucher disease (GD) is associated with an increased risk for malignancies. Next to hematological malignancies, the development of solid tumors in several organs has been described. The liver is one of the major storage sites involved in GD pathogenesis, and is also affected by liver-specific complications. In this case series, we describe 16 GD type 1 (GD1) patients from eight different referral centers around the world who developed hepatocellular carcinoma (HCC). Potential factors contributing to the increased HCC risk in GD patients are studied. Eleven patients had undergone a splenectomy in the past. Liver cirrhosis, one of the main risk factors for the development of HCC, was present in nine out of 14 patients for whom data was available. Three out of seven examined patients showed a transferrin saturation > 45%. In these three patients the presence of iron overload after histopathological examination of the liver was shown. Chronic hepatitis C infection was present in three of 14 examined cases. We summarized all findings and made a comparison to the literature. We recommend that GD patients, especially those with prior splenectomy or iron overload, be evaluated for signs of liver fibrosis and if found to be monitored for HCC development. PMID- 29423832 TI - [Glaucoma beyond intraocular pressure : New approaches]. PMID- 29423831 TI - Targeted versus untargeted omics - the CAFSA story. AB - BACKGROUND: In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches. METHODS AND RESULTS: First, we studied five of the six CAFSA patients initially described. Besides increased CSF free sialic acid concentrations, three patients presented with markedly decreased 5 methyltetrahydrofolate (5-MTHF) CSF concentrations. Exome sequencing identified a homozygous POLG mutation in two affected sisters, but failed to identify a causative gene in the three sporadic patients with high sialic acid but low 5 MTHF. Using targeted mass spectrometry, we confirmed that free sialic acid was increased in the CSF of a third known POLG-mutated patient. We then pursued pathophysiological analyses of CAFSA using mass spectrometry-based metabolomics on CSF from two sporadic CAFSA patients as well as 95 patients with an unexplained encephalopathy and 39 controls. This led to the identification of a common metabotype between the two initial CAFSA patients and three additional patients, including one patient with Kearns-Sayre syndrome. Metabolites of the CSF metabotype were positioned in a reconstruction of the human metabolic network, which highlighted the proximity of the metabotype with acetyl-CoA and carnitine, two key metabolites regulating mitochondrial energy homeostasis. CONCLUSION: Our genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either through POLG mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome. PMID- 29423830 TI - Biochemical markers and neuropsychological functioning in distal urea cycle disorders. AB - Urea cycle disorders often present as devastating metabolic conditions, resulting in high mortality and significant neuropsychological damage, despite treatment. The Urea Cycle Disorders Longitudinal Study is a natural history study that collects data from regular clinical follow-up and neuropsychological testing. This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and primary neuropsychological endpoints in three distal disorders, argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Laboratory results and test scores from neuropsychological evaluations were assessed in 145 study participants, ages 3 years and older, with ASD (n = 64), ASA (n = 65) and ARGD (n = 16). Mean full scale IQ was below the population mean of 100 +/- 15 for all groups: (ASD = 79 +/- 24; ASA = 71 +/- 21; ARGD = 65 +/- 19). The greatest deficits were noted in visual performance and motor skills for all groups. While ammonia levels remain prominent as prognostic biomarkers, other biomarkers may be equally valuable as correlates of neuropsychological functioning. Cumulative exposure to the biomarkers included in the study proved to be highly sensitive indicators of neuropsychological outcomes, even when below the cut-off levels generally considered toxic. Blood levels of biomarkers obtained on the day of neuropsychological evaluations were not correlated with measures of functioning for any disorder in any domain. The importance of cumulative exposure supports early identification and confirms the need for well controlled management of all biochemical abnormalities (and not just ammonia) that occur in urea cycle disorders. PMID- 29423833 TI - Assessment of improved buccal permeation and bioavailability of felodipine microemulsion-based cross-linked polycarbophil gel. AB - The oral bioavailability of felodipine (FEL) is very low, i.e., about 15%. This could be due to low water solubility and hepatic first-pass effect. The objective of the present study was to develop FEL microemulsion-based gel, to bypass the first pass effect, for buccal delivery. The optimized FEL microemulsion (OPT-MEF) was used to prepare buccoadhesive gels, with varying concentrations of hydroxypropyl methylcellulose (HPMC) E4M and polycarbophil (PCP), and evaluated. The cross-linking of the PCP gelling agent was done by adjusting the pH with a neutralizing agent, triethanolamine (TEA). The formulations, namely drug suspension, OPT-MEF, microemulsion-based buccal gel containing 1% w/v (MEF-E4M1), 2% w/v (MEF-E4M2), and 3% w/v (MEF-E4M3) of HPMC K4M and 1% w/v (MEF-PCP1), 2% w/v (MEF-PCP2), and 3% w/v (MEF-PCP3) of PCP were prepared and optimized on the basis of ex vivo permeation study, mucoadhesion force, and viscosity. The optimized buccal gel (MEF-PCP1) showed significantly higher (p < 0.01) permeation flux (J = 0.44 +/- 0.16 mg/cm2/h), when compared with the drug suspension (J = 0.17 +/- 0.14 mg/cm2/h). The permeation enhancement ratio of MEF-PCP1 was found to be 2.59 times higher than that of the aqueous suspension of the drug. The texture profile analysis of MEF-PCP1 was performed which showed spreadability (3.2 mJ), extrudability (151.8 mJ), hardness (13.8 g), and adhesiveness (41.0 g), and results indicated good spreadability and adhesiveness. The rheological study revealed the pseudoplastic flow behavior of MEF-PCP1 buccal gel. The Cmax value 9.21 +/- 2.88 MUg/ml of MEF-PCP1 gel was found to be significantly higher (P < 0.01) compared to the same dose administered by oral route (Cmax value 3.51 +/- 1.74 MUg/ml). The relative bioavailability (Fr) of the optimized MEF-PCP1 buccal gel was about 397.39% higher than that of oral route. In conclusion, consistent and effective buccal gel containing optimized FEL-loaded microemulsion, with improved buccal permeation and pharmacokinetic parameters was developed successfully to improve the bioavailability of FEL. PMID- 29423835 TI - Re: Sussman RD, Hill FC, Koch GE, Patel V, Venkatesan K (2017) Novel pericatheter retrograde urethrogram technique is a viable method for postoperative urethroplasty imaging. Int Urol Nephrol 49(12):2157-2165. doi:10.1007/s11255-017 1701-0. PMID- 29423834 TI - Factors predicting success after microsurgical vasovasostomy. AB - PURPOSE: To identify factors predicting success and analyze critically the status of microsurgical double-layer vasovasostomy using predictive models. METHODS: A cohort of 263 patients treated at our institution for vasectomy reversal between 1986 and 2010 was included in our study, and the literature was reviewed. Inclusion criteria were previous bilateral vasectomy and presence of at least two postoperative semen analyses; patients reporting pregnancy without a postoperative semen analysis were excluded. A double-layer, microscope-assisted, tension-free anastomosis vasovasostomy was performed approximating mucosa to mucosa and muscle to muscle with a 10-0 non-absorbable suture. A multivariate logistic regression backward stepwise model was used to predict combined success, and a predictive model was calculated with remaining variables. RESULTS: Mean age was of 41.6 years (SD 7.1); mean duration of obstruction 7.2 years (SD 6.7). On multivariate analysis, uni- or bilateral granuloma and Silber grade of I-III were variable identified predicting higher probability to success (OR 3.105; 95% CI 1.108-8.702; p = 0.031 and OR 4.795; 95% CI 2.117-10.860; p < 0.001, respectively). CONCLUSIONS: Based on our results, some factors predicting success after vasovasostomy surgery are known but others remain unknown; our predictive model may easily predict patency and success after this surgery and offers a concrete assistance in counseling patients. PMID- 29423836 TI - Response to Letter to Editor on: Novel pericatheter retrograde urethrogram technique is a viable method for postoperative urethroplasty imaging. PMID- 29423839 TI - Molecular, Neuronal, and Behavioral Effects of Ethanol and Nicotine Interactions. AB - Ethanol and nicotine can modulate the activity of several neurotransmitter systems and signalling pathways. Interactions between ethanol and nicotine can also occur via common molecular targets including nicotinic acetylcholine receptors (nAChRs). These effects can induce molecular and synaptic adaptations that over time, are consolidated in brain circuits that reinforce drug-seeking behavior, contribute to the development of withdrawal symptoms during abstinence and increase the susceptibility to relapse. This chapter will discuss the acute and chronic effects of ethanol and nicotine within the mesolimbic reward pathway and brain circuits involved in learning, memory, and withdrawal. Individual and common molecular targets of ethanol and nicotine within these circuits are also discussed. Finally, we review studies that have identified potential molecular and neuronal processes underlying the high incidence of ethanol and nicotine co use that may contribute to the development of ethanol and nicotine co-addiction. PMID- 29423837 TI - Analysis of hedgehog signaling in periocular sebaceous carcinoma. AB - PURPOSE: Sebaceous carcinoma (SC) is a clinical masquerader of benign conditions resulting in significant eye morbidity, sometimes leading to extensive surgical treatment including exenteration, and even mortality. Little is known about the genetic or molecular basis of SC. This study identifies the involvement of Hedgehog (Hh) signaling in periocular SC. METHODS: Fifteen patients with periocular SC patients were compared to 15 patients with eyelid nodular basal cell carcinoma (nBCC; a known Hh tumor), alongside four normal individuals as a control for physiological Hh expression. Expression of Patched 1 (PTCH1), Smoothened (SMO), and glioma-associated zinc transcription factors (Gli1 and Gli2) were assessed in histological sections using immunohistochemistry and immunofluorescence (IF) techniques. Antibody specificity was verified using Western-blot analysis of a Gli1 over-expressed cancer cell line, LNCaP-Gli1. Semi quantification compared tumors and control tissue using IF analysis by ImageJ software. RESULTS: Expression of the Hh pathway was observed in SC for all four major components of the pathway. PTCH1, SMO, and Gli2 were more significantly upregulated in SC (P < 0.01) compared to nBCC. Stromal expression of PTCH1 and Gli2 was observed in SC (P < 0.01). In contrast, stromal expression of these proteins in nBCC was similar or down-regulated compared to physiological Hh controls. CONCLUSIONS: The Hh signaling pathway is significantly more upregulated in periocular SC compared to nBCC, a known aberrant Hh pathway tumor. Furthermore, the stroma of the SC demonstrated Hh upregulation, in particular Gli2, compared to nBCC. Targeting of this pathway may be a potential treatment strategy for SC. PMID- 29423838 TI - Evaluating displacement of lamina cribrosa following glaucoma surgery. AB - PURPOSE: The purpose of the study is to assess the displacement of lamina cribrosa (LC) and prelaminar tissue area (PTA) changes following trabeculectomy and non-penetrating deep sclerectomy (NPDS) using spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging technology. METHODS: A total of 30 patients underwent glaucoma surgery. Sixteen patients underwent trabeculectomy, and 14 patients undertook NPDS. Serial horizontal B-scan images of optic nerve head (ONH) were obtained using SD-OCT preoperatively, and at 2 week, 1-, 3-, and 6-month postoperative visit (6 pv). LC displacement magnitude and PTA changes were determined from selected B-scan images. Correspondingly, OCT retinal nerve fiber layer (RNFL) parameters were measured. RESULTS: Intraocular pressure (IOP) decreased from 27.4 +/- 10.3 mmHg (mean +/- standard deviation) to 10.2 +/- 4.0 mmHg (P = 0.011) and from 19.9 +/- 4.0 mmHg to 11.9 +/- 3.6 mmHg (P = 0.012) at 6 pv, for trabeculectomy and NPDS, respectively. There was a significant decrease in the LC depth from a baseline glaucomatous LC displacement of 468.0 +/- 142.4 to 397.6 +/- 125.2 MUm in the trabeculectomy group (P = 0.001) and from 465.2 +/- 129.6 to 412.0 +/- 122.4 MUm in the NPDS group (P = 0.029) at 6 pv. The PTA differed between the procedures at baseline (P = 0.002), but was not statistically significant postoperatively. Multivariate analysis for all patients including age, magnitude of IOP reduction, baseline glaucomatous LC displacement, magnitude of LC displacement, and the type of surgery revealed that only the magnitude of LC displacement was associated with significant RNFL thinning on average (r2 = 0.162, P = 0.027) and in the following sectors: temporal superior (r2 = 0.197, P = 0.014), temporal (r2 = 0.150, P = 0.034), and nasal superior (r2 = 0.162, P = 0.027). CONCLUSIONS: Decrease in the LC depth after NPDS surgery can be observed at 6 pv. Regardless of the performed procedure, magnitude of LC displacement is associated with significant, focal RNFL thinning. PMID- 29423841 TI - Treatment of flat and elevated pigmented disorders with a 755-nm alexandrite picosecond laser: clinical and histological evaluation. AB - The novel picosecond lasers, initially developed for faster tattoo removal, have also shown great efficacy in endogenous pigmentary disorders. To describe the efficacy and safety profile of an alexandrite (755-nm) picosecond laser in a wide range of pigmented flat and elevated cutaneous lesions. A retrospective study was performed in which we collected all the clinical images of patients treated with the 755-nm alexandrite picosecond laser for 12 months (November 2016-November 2017). Clinical features were obtained from their medical charts. Patients treated for tattoo removal were excluded. All the images were analyzed by three blind physicians attending to a visual analogue scale (VAS) from 0 to 5 (0, no change; 1, 1-24% clearance; 2, 25-49% clearance; 3, 50-74% clearance; 4, 75-99% clearance; 5, complete clearance). Patient satisfaction was obtained from a subjective survey including four items: very satisfied, satisfied, non-satisfied, and totally dissatisfied. Thirty-seven patients were included (12 males; 25 females). The mean age of the study was 42.35 years. Twenty-five patients (68%) were treated for different pigmented flat disorders such as solar and mucosal lentigines (5), stasis dermatitis (4), or nevus of Ota (4), among other diagnoses. Twelve patients (32%) were treated for epidermal elevated lesions such as warts (5), epidermal nevi (2), and seborrheic keratosis (3), among other elevated lesions. Mean number of laser treatment was 3.02 sessions while mean follow-up after last laser treatment was 4.02 months. Mean VAS score of the three observers was 3.44 (61% of clearance) for pigmentary flat disorders and 3.60 (67%) for elevated lesions. Adverse effects reported were mild blistering in the first 2-5 days following laser treatment in some of the patients. Overall satisfaction among the patients included was high. The novel 755-nm picosecond alexandrite laser is effective not only for the resolution of pigmented flat lesions of different nature but also for the treatment of the more difficult elevated pigmented lesions. PMID- 29423840 TI - Evaluation of the therapeutic effects of led (lambda627 +/- 10 nm) on the initial phase of ankle sprain treatment: a randomised placebo-controlled clinical trial. AB - Various therapies for the treatment of sprains have emerged as advances occur in biomedical engineering and photobiology. Therapy with coherent and non-coherent light is a treatment modality for various musculoskeletal injuries. The main certified phototherapy benefits are the reduction of nociceptive processes and the modulation of the inflammatory process, among others. The objective of this study was to analyse the changes caused by the use of light-emitting diodes (LED) (lambda627 +/- 10 nm) with an energy density of 10 J/cm2 in 40 subjects divided into two groups (20 placebo and 20 LED). All of the volunteers had acute ankle sprains by inversion of grade II treated with the PRICE (protection, rest, ice, compression and elevation) technique and were treated for 6 days with LED therapy and LED therapy turned off (placebo). Pain assessment was performed on the 1st, 3rd and 6th days using the visual analogue scale (VAS) of pain, the McGill Pain Questionnaire and volumetry. The group treated with LED showed statistically decreased pain compared to the placebo group in both the VAS (85.79 vs 55.73%) and McGill questionnaire (83.33 vs 52.52%). The reduction of oedema in the LED group on the 3rd and 6th days after therapy was statistically superior to that in the placebo (p < 0.0001). Based on the results of this study, treatment with LED, using the tested dose, is effective for pain and oedema in the initial phase of ankle sprains. PMID- 29423842 TI - Preparation of Solutions and Reagents. AB - The ability to prepare accurate solutions, reagents, and buffers will determine the outcome of a successful experiment. Much time and effort spent in a lab will consist of making solutions, reagents, and buffers. This chapter introduces and refreshes the skill of making solutions including: molarity (M) concentration, percentage (%) concentration, mass/volume concentrations, X-factor concentration, working concentrations from stock solutions, conversions from percentage (%) to molarity (M) concentration, and conversions from molarity (M) to percentage (%) concentration. Basic formulas and examples for how to make solution concentrations are covered. PMID- 29423843 TI - Analysis of Fission Yeast Single DNA Molecules on the Megabase Scale Using DNA Combing. AB - DNA combing enables the quantitative analysis of DNA replication, DNA recombination, DNA-protein interaction, and DNA methylation along genomic single DNA molecules at 1 kb resolution. However, DNA combing has been restricted to short 200-500 kb long DNA fragments, which introduces significant bias in data analysis. An improved DNA combing methodology that allows to routinely image Mb scale single DNA molecules and occasionally up to full-length fission yeast chromosomes is presented in this chapter. DNA combing of Mb-scale single DNA molecules can be applied to accurately measure the dynamic properties of DNA replication such as the rate of origin firing, replication fork velocity, fork directionality and the frequency of fork blockage. In addition, Mb-scale single DNA molecules enable the quantitative analysis of complex genomic rearrangements including gross chromosomal translocations, repetitive DNA sequences, large deletions, and duplications, which are difficult to investigate with deep sequencing strategies. PMID- 29423844 TI - Chromatin Immunoprecipitation-Polymerase Chain Reaction (ChIP-PCR) Detects Methylation, Acetylation, and Ubiquitylation in S. pombe. AB - The distribution of modified histones within the fission yeast Schizosaccharomyces pombe genome is ultimately dependent upon the transcriptional activity and in turn influences the ability of the polymerases to bind and progress through the chromatin template. The Chromatin Immunoprecipitation Polymerase Chain Reaction (ChIP-PCR) method currently provides the highest resolution, accuracy, and reproducibility to characterize histones modifications within a defined region of the genome. The following protocol details the method applied to S. pombe. PMID- 29423845 TI - Primer Design and Inverse PCR on Yeast Display Antibody Selection Outputs. AB - The display of antibodies on the surface of Saccharomyces cerevisiae cells enables the high-throughput and precise selection of specific binders for the target antigen. The recent implementation of next-generation sequencing (NGS) to antibody display screening provides a complete picture of the entire selected polyclonal population. As such, NGS overcomes the limitations of random clones screening, but it comes with two main limitations: (1) depending upon the platform, the sequencing is usually restricted to the variable heavy chain domain complementary determining region 3 (HCDR3), or VH gene, and does not provide additional information on the rest of the antibody gene, including the VL; and (2) the sequence-identified clones are not physically available for validation. Here, we describe a rapid and effective protocol based on an inverse-PCR method to recover specific antibody clones based on their HCDR3 sequence from a yeast display selection output. PMID- 29423847 TI - Total RNA Isolation and Quantification of Specific RNAs in Fission Yeast. AB - The fission yeast, Schizosaccharomyces pombe, is an important model organism for investigations of gene regulation. Essential to such studies is the ability to quantify the levels of a specific RNA. We describe a protocol for the isolation and quantification of RNA in S. pombe using reverse-transcription followed by quantitative PCR. In this procedure, the cells are lysed using zirconia beads, then total RNA is selectively isolated away from proteins and DNA using the Trizol reagent. Contaminating DNA is then removed from the RNA by using TURBO DNase, which is easily inactivated and requires no subsequent clean-up step. The RNA is then reverse transcribed into cDNA using random nine-mers and oligo dT primers . Quantitative PCR using SYBR green is then performed to quantify RNA levels. This protocol has been tested on several S. pombe genotypes and generates highly reproducible results. PMID- 29423846 TI - Molecular Cloning and Characterization of Small Viral Genome in Fission Yeast. AB - Fission yeast is a single-cell eukaryote that has been used extensively as a model organism to study cell biology and virology of higher eukaryotes including plants and humans. In particular, it is a very well-tested model to study evolutionary highly conserved cellular activities such as cell proliferation, cell cycle regulation, and cell death. Some of the advantages of using fission yeast as a surrogate system: easy to carry out functional and genome-wide analysis of small viral genome, easy to maintain in the laboratory with a relatively short doubling time. It is genetically amendable and can be used to test the effect of gain-of-function or loss-of-function of a gene product. Here, we describe a streamlined and large-scale molecular cloning strategy for genome wide characterization of small viruses in fission yeast. PMID- 29423848 TI - Analysis of Reverse Transcribed mRNA Using PCR and Polyacrylamide Gel Electrophoresis. AB - The patterns of gene expression in the fission yeast Schizosaccharomyces pombe under various experimental conditions form the basis of any transcriptomic study. We describe a method involving reverse transcription of the mRNA, Polymerase Chain Reaction (PCR), and the subsequent separation of the products onto Urea Polyacrylamide gel that can be used to study the gene expression patterns in the fission yeast. The method described is cost effective and reproducible with satisfactory resolution of expressed transcripts in the gel. The method has the following essential steps: total RNA isolation and purification, cDNA synthesis from mRNAs, PCR amplification of cDNAs, visualization of PCR products, re amplification and cloning of the differentially expressed PCR products, sequencing the confirmed clones, and finally cDNA library screening to isolate the genes of interest. The technique is also popularly known as Differential Display Reverse Transcription (DDRT-PCR). After its invention in 1992, a number of modifications have been introduced to optimize the technique and specifically to reduce the major problem of "false positives." Since understanding of specific gene expression patterns that regulate developmental and stress responses is a major concern of biology, DDRT-PCR has become a very popular molecular technique during the past two decades. PMID- 29423849 TI - The No-Nonsens SDS-PAGE. AB - The discontinuous polyacrylamide gel electrophoresis system devised by Laemmli (Nature 227:680-685, 1970) has not only been used in numerous laboratories but has also been modified in several ways since its birth. In our laboratories, we use a modified Laemmli SDS-PAGE system for following protein purification as well as for analysis of certain protein-protein interactions, mainly involving filametous actin. PMID- 29423850 TI - Crystallization of Recombinant alpha-Actinin and Related Proteins. AB - When it comes to crystallization each protein is unique. It can never be predicted beforehand in which condition the particular protein will crystallize or even if it is possible to crystallize. Still, by following some simple checkpoints the chances of obtaining crystals are increased. The primary checkpoints are purity, stability, concentration, and homogeneity. High-quality protein crystals are needed. This protocol will allow an investigator to: clone, express, and crystallize a protein of interest. PMID- 29423851 TI - Estimation of GFP-Nucleoporin Amount Based on Fluorescence Microscopy. AB - Cellular structures and biomolecular complexes are not simply assemblies of proteins, but are organized with defined numbers of protein molecules in precise locations. Thus, evaluating the spatial localization and numbers of protein molecules is of fundamental importance in understanding cellular structures and functions. The amounts of proteins of interest have conventionally been determined by biochemical methods. However, biochemical measurements based on the population average have limitations: it is sometimes difficult to determine the amounts of insoluble proteins or low expression proteins localized in small portions of the cell. In contrast, microphotometric measurements using fluorescence microscopes enable us to detect the amounts of such proteins in situ in a particular subcellular region. Here, we describe a method to measure the amounts of fluorescently tagged proteins by fluorescence microscopy, and present an example of an application to nuclear pore proteins in the fission yeast Schizosaccharomyces pombe. PMID- 29423852 TI - Antibody Pull-Down Experiments in Fission Yeast. AB - Proteins act as executors for almost all kinds of cellular processes. The majority of proteins achieve their proper functions through interacting with other proteins. Knowing the binding partners of a protein is instrumental for understanding its function. The antibody pull-down method is a powerful and common approach to detect protein-protein interactions. Here, an antibody pull down protocol is described for detecting protein-protein interactions in fission yeast Schizosaccharomyces pombe. PMID- 29423853 TI - Preparation of Cell Lysates of Fission Yeast for Immunoprecipitation. AB - Immunoprecipitation is one of the most important and widely used techniques for the detection and purification of a protein of interest. Thanks to highly specific interaction between antigen and antibody, a target protein is purified and concentrated effectively. To obtain reasonable amounts of a target protein, it is crucially important to prepare total cell lysates in which the target protein is present in a soluble form. Here, we describe methods to prepare total cell lysates of fission yeast, which are then used directly for immunoprecipitation. We also describe some tips to select reagents for preparing buffers having a substantial impact on protein solubility, because there is essentially no reagent that can accommodate the full range of proteins having different characteristics. PMID- 29423854 TI - Wide-band Electrical Impedance Spectroscopy (EIS) Measures S. pombe Cell Growth in vivo. AB - This chapter describes a microfluidic device that enables immobilization and culturing of single rod-shaped S. pombe cells in a stand-up mode. The wide-band electrical impedance spectroscopy (EIS) has been integrated in the microfluidic device to continuously measure cell growth of single S. pombe cells. Cell growth curves showing cellular and intracellular features at high spatiotemporal resolution can be obtained from EIS signals. The features include longitudinal cell elongation in the G2 phase, mitosis, and cell division during an entire cell cycle of S. pombe cells. Microfluidics-based EIS systems provide, hence, a tool for dynamic single-cell studies. PMID- 29423855 TI - In Situ Chromatin-Binding Assay Using Epifluorescent Microscopy in S. pombe. AB - Chromatin-associated proteins play critical roles in many cellular processes, including gene expression, epigenetic regulation, DNA repair, recombination, and replication. Especially, epigenetic landscape, shaped by a variety of chromatin binding proteins, is dynamic and regulated in a context-dependent manner. In situ chromatin-binding assay is a powerful but simple tool to investigate how proteins, such as epigenetic components, associate with chromatin. This approach relies on the fact that chromatin bound proteins are more resistant to detergent extraction. Here, we describe a protocol for the in situ chromatin-binding assay used in Schizosaccaromyces pombe. PMID- 29423856 TI - High-Frequency Lithium Acetate Transformation of Schizosaccharomyces pombe. AB - The introduction of ectopic DNA, such as plasmids, into yeast cells has for decades been a critical protocol for the study of this eukaryotic model system. We describe here an efficient transformation procedure for use in the fission yeast Schizosaccharomyces pombe. This method relies on chemical agents (lithium acetate, and polyethylene glycol) and temperature stresses, which ultimately facilitate transfer of the genetic material through the cell wall and plasma membrane without significant impact on the transferred DNA or the recipient cell. Using this protocol, we consistently see transformation efficiencies between 1.0 * 103 and 1.0 * 104 transformants per microgram of the plasmid with 108 S. pombe cells. The principal benefits and advantages of this method are its simplicity, efficiency, and relative speed of completion. PMID- 29423857 TI - Tetrad Dissection in Fission Yeast. AB - Tetrad dissection is a powerful tool in yeast genetics that allows the analysis of products of a single meiosis. With just a few tetrads, it is possible to determine linkage, identify unique phenotypes associated with double mutants, or assess specific meiotic defects. Strains are crossed on nitrogen-limiting medium for 3 days. With the help of a micromanipulator, ripe asci are isolated to spots 5 mm apart on a YES plate. Incubation at 36 degrees C for about 3-5 h is necessary for the ascus walls to break down. Once the spores are released, they are individually placed in a row containing four tetrad products, separated by 5 mm. The spores are then put in the appropriate temperature for the cross until colonies form, and phenotypes are assessed by replica plating or microscopic analysis. PMID- 29423858 TI - Random Spore Analysis in Fission Yeast. AB - Random spore analysis (RSA) is a tool that allows for the screening of a large number of meiotic products. It requires only a limited effort, and is often the method of choice for constructing strains with unambiguous genotypes. It is also useful to identify the frequency of rare events. Strains are crossed on a nitrogen-limiting medium for three days. Mated cells are observed under the microscope to check for the presence of ripe asci. To release spores from their ascus, a sample of the cross is taken from the mating plate and resuspended in an enzyme solution overnight at 25-29 degrees C. Spores are then counted using a hemocytometer before plating an appropriate number. Incubation at the appropriate temperature follows until colonies form. PMID- 29423859 TI - Duplication and Transformation of the Schizosaccharomyces pombe Collection of Deletion Strains. AB - We present an efficient and organized method of lithium acetate and polyethylene glycol-based transformation of plasmid DNA into the commercially available collection of Schizosaccharomyces pombe with single-gene deletions. We also describe how to prepare a duplicate collection of the deletion strains in order to preserve the longevity of the master set. These protocols are adapted to the 96-well format of the 3004 strains of the Version 2.0 Bioneer set but can also be used for later releases of the collection. This transformation method typically yields efficiencies in the range between 1.0 * 103 and 1.0 * 104 transformants per microgram of plasmid DNA. However, some deletion strains transformed with significantly lower efficiencies. We provide a list of these difficult-to transform strains. Applications for this methodology include the transformation of the deletion set with plasmids necessary for genetic screens. PMID- 29423860 TI - Schizosaccharomyces pombe Biotechnological Applications in Winemaking. AB - The traditional way of producing wine is through the use of Saccharomyces cerevisiae in order to convert glucose and fructose into alcohol. In the case of red wines, after this alcoholic fermentation lactic bacteria Oenococus oeni is used to stabilize wine from a microbiological point of view by converting malic acid into lactic acid that it is not a microbiological substract. The yeast species Schizosaccharomyces pombe was traditionally considered spoilage yeast. Nevertheless, during the last decade it started to be used due to its unique malic acid deacidification ability to reduce the harsh acidity of wines from northern Europe, by converting malic acid to ethanol and CO2 without producing lactic acid as lactic bacteria does. Additionally, during the last years, S. pombe has started to be used to solve the problems of modern winemaking industry such as increasing food quality or food safety. Some of those new uses, different from its traditional malic acid deacidification, are: high autolytic polysaccharides release, gluconic acid reduction, urease activity that make impossible ethyl carbamate (toxic compound) formation, high pyruvic acid production, that is related to color improvement, and removing lactic bacteria subtracts while avoiding biogenic amines (toxic compounds such as histamine) formation. PMID- 29423861 TI - Schizosaccharomyces pombe Isolation Protocol. AB - This chapter describes a methodology to isolate yeast strains from Schizosaccharomyces pombe species. The method is based on a selective differential medium that notably facilitates the isolation of S. pombe. The main difficulty in isolating microorganisms from this genus is their extremely low incidence in nature when they are compared to other microorganisms. The proposed methodology allows isolating and selecting strains from this species for industrial purposes. Methodologies allows detecting the presence of those yeasts when they are considered spoilage microorganisms. Several selective-differential agents based on the basic physiological characteristics of S. pombe species are exposed during the chapter introduction and the use is properly justified. Some of those representative characteristics are its extraordinary resistance to high sugar concentrations, sulfur dioxide, sorbic acid, benzoic acid, acetic acid, or their unique malo-ethanolic fermentation ability. The proposed selective medium is mainly based on S. pombe resistance to the antibiotic actidione and the unusual tolerance to the inhibitory agent benzoic acid compared to possible microorganisms that could produce false-positive results during an isolation process. In addition, malic acid is proposed as the main differential factor due to the exclusive ability of this species to metabolize malic acid into ethanol. This fact allows the detection of malic acid degradation. Cloramphenicol is used to inhibit bacteria growth and liquid media to avoid fungi development. PMID- 29423862 TI - Establishing in vitro-in vivo correlation for antibody drug conjugate efficacy: a PK/PD modeling approach. AB - The objective of this manuscript was to establish in vitro-in vivo correlation (IVIVC) between the in vitro efficacy and in vivo efficacy of antibody drug conjugates (ADCs), using a PK/PD modeling approach. Nineteen different ADCs were used to develop IVIVC. In vitro efficacy of ADCs was evaluated using a kinetic cell cytotoxicity assay. The cytotoxicity data obtained from in vitro studies was characterized using a novel mathematical model, parameter estimates from which were used to derive an in vitro efficacy matrix for each ADC, termed as 'in vitro tumor static concentration' (TSCin vitro). TSCin vitro is a theoretical concentration at continuous exposure of which the number of cells will neither increase nor decrease, compared to the initial cell number in the experiment. The in vivo efficacy of ADCs was evaluated using tumor growth inhibition (TGI) studies performed on human tumor xenograft bearing mice. The TGI data obtained from in vivo studies was characterized using a PK/PD model, parameter estimates from which were used to derive an in vivo efficacy matrix for each ADC, termed as 'in vivo tumor static concentration' (TSCin vivo). TSCin vivo is a theoretical concentration if one were to maintain in the plasma of a tumor bearing mouse, the tumor volume will neither increase nor decrease compared to the initial tumor volume. Comparison of the TSCin vitro and TSCin vivo values from 19 ADCs provided a linear and positive IVIVC. The Spearman's rank correlation coefficient for TSCin vitro and TSCin vivo was found to be 0.82. On average TSCin vivo was found to be ~ 27 times higher than TSCin vitro. The reasonable IVIVC for ADCs suggests that in vitro efficacy data was correctly able to differentiate ADCs for their in vivo efficacy. Thus, IVIVC can be used as a tool to triage ADC molecules in the discovery stage, thereby preventing unnecessary scaling-up of ADCs and waste of time and resources. An ability to predict the concentration of ADC that is efficacious in vivo using the in vitro data can also help in optimizing the experimental design of preclinical efficacy studies. As such, the novel PK/PD modeling method presented here to establish IVIVC for ADCs holds promise, and should be evaluated further using diverse set of cell lines and anticancer agents. PMID- 29423863 TI - A framework for 2-stage global sensitivity analysis of GastroPlusTM compartmental models. AB - Parameter sensitivity and uncertainty analysis for physiologically based pharmacokinetic (PBPK) models are becoming an important consideration for regulatory submissions, requiring further evaluation to establish the need for global sensitivity analysis. To demonstrate the benefits of an extensive analysis, global sensitivity was implemented for the GastroPlusTM model, a well known commercially available platform, using four example drugs: acetaminophen, risperidone, atenolol, and furosemide. The capabilities of GastroPlus were expanded by developing an integrated framework to automate the GastroPlus graphical user interface with AutoIt and for execution of the sensitivity analysis in MATLAB(r). Global sensitivity analysis was performed in two stages using the Morris method to screen over 50 parameters for significant factors followed by quantitative assessment of variability using Sobol's sensitivity analysis. The 2-staged approach significantly reduced computational cost for the larger model without sacrificing interpretation of model behavior, showing that the sensitivity results were well aligned with the biopharmaceutical classification system. Both methods detected nonlinearities and parameter interactions that would have otherwise been missed by local approaches. Future work includes further exploration of how the input domain influences the calculated global sensitivity measures as well as extending the framework to consider a whole-body PBPK model. PMID- 29423864 TI - Femoral cortical thickness influences the pattern of proximal femoral periprosthetic fractures with a cemented stem. AB - INTRODUCTION: Periprosthetic fractures of the proximal femur place a significant burden on the patients who endure them, as well as the medical health system that supports them. The purpose of this study was to determine whether femoral cortical thickness, as an absolute measurement, is a predictor of periprosthetic fracture pattern. METHOD: A cohort of 102 patients who had sustained a periprosthetic hip fracture were retrospectively identified. This included 58 males and 44 females with a mean age of 79.8 years. The femoral periprosthetic fracture pattern was classified based on the Vancouver classification system. Stem fixation was recorded and femoral cortical thickness measured. Patients were grouped into cemented and cementless stems. The relationship between cortical thickness and periprosthetic fracture pattern was assessed using the primary stem fixation method. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold in the cortical thickness that predicted fracture pattern. Multinomial logistic regression analysis was used to adjust for confounding variables to assess the independent influence of cortical thickness on the risk of sustaining a Vancouver type A, B or C. RESULTS: There were 65 (63.7%) patients in the cemented group and 37 (36.3%) in the cementless group. The pattern of periprosthetic fractures around cemented stems was significantly (p < 0.001) influenced by the femoral cortical thickness, with a thinner cortical thickness associated with a type A fracture pattern. In contrast, no association between femoral cortical thickness and fracture pattern assessment was demonstrated in the cementless group (p = 0.82 Chi square). Comparing the rate of type A fracture patterns between the groups illustrated a significantly decreased risk in the cemented group with a cortical thickness of > 7 mm (odds ratio 0.03, p < 0.001). ROC curve analysis of the cemented group demonstrated a threshold value of 6.3 mm, offering a sensitivity of 83.3% and a specificity of 78.9% in predicting an A type fracture. Using this threshold, patients with a cortical thickness of 6.3 mm or less were significantly more likely to sustain a Vancouver type A fracture (OR 18.9, 95% CI 2.0-166.7, p < 0.001) when compared to patients with a cortical thickness of > 6.3 mm. In contrast, the ROC curve analysis did not find cortical thickness to be a predictor of fracture pattern in the cementless group. When adjusting for confounding variables, multinomial logistic regression demonstrated a cortical thickness of 6.3 mm or less was a significant predictor of a type A fracture (OR 3.28, 95% CI 1.06-10.16, p = 0.04) relative to those sustaining a type B fracture. CONCLUSION: Cortical thickness was found to influence the periprosthetic fracture pattern around cemented femoral stems, but this was not observed with cementless stems. Type A fracture patterns were significantly more likely to occur with a cortical thickness of 6.3 mm or less around cemented stems. PMID- 29423865 TI - Short-term outcomes of subacromial injection of combined corticosteroid with low volume compared to high-volume local anesthetic for rotator cuff impingement syndrome: a randomized controlled non-inferiority trial. AB - BACKGROUND: In symptomatic tendinosis, a corticosteroid injection into the subacromial space is a palliative treatment option. This study compares high volumes (10 cc) of local anesthetic (LA) combined with triamcinolone acetate (TA) with low volumes (4 cc) of LA combined with TA to see whether the latter would provide similar pain, function and complication outcomes for subacromial injections in patients with impingement syndrome. MATERIALS AND METHODS: This single-center, randomized, single-blind, non-inferiority trial included patients with shoulder pain and positive multiple clinical tests supporting the diagnosis of impingement syndrome. All 52 patients received subacromial injections, with either high-volume corticosteroid injections (HCI) (10 mL total volume of 1% lidocaine plus 40 mg TA) in 26 patients or low-volume corticosteroid injections (LCI) (4 mL total volume of 1% lidocaine plus 40 mg TA) in 26 patients. The demographic data were reported with the primary outcomes being VAS and WORC scores measured at 30 min, then 2 and 8 weeks after receiving the injections. A non-inferiority margin of 13% was assumed. RESULTS: Fifty-two patients (26 patients per group) were enrolled in the HCI and LCI. Mean VAS and WORC scores of HCI and LCI at baseline were 6.96, 33.85, 6.81 and 36.54, respectively. The mean VAS measured at 30 min, 2 and 8 weeks was 4.04, 2.08 and 1.20, respectively, in HCI group and 2.65, 1.95 and 1.26, respectively, in LCI group. The mean WORC at 2 and 8 weeks was 67.46 and 81.74, respectively, in HCI group and 65.42 and 80.12 in LCI group. These were not statistically significantly different (P > 0.05 in all). CONCLUSION: Corticosteroid injections can be used in the treatment of subacromial impingement syndrome. Low-volume (4 cc) corticosteroid injections have non-inferior pain results for VAS score when compared with high-volume (10 cc) corticosteroid injections. CLINICALTRIALS.GOV: NCT03120923. LEVEL OF EVIDENCE: Level I. PMID- 29423866 TI - Conservative treatment of distal fractures after the age of 65: a review of literature. AB - The goal of this study was to evaluate the role of conservative treatment of distal radius fractures in the elderly since 2000. Our series included 22 articles, of which 3 reviews, 2 meta-analyses, 6 descriptive series of conservative treatment, 10 series comparing surgical and conservative treatments and 1 series comparing different types of conservative treatments. The reduction was performed by closed reduction in 7 cases and by traction in 3 cases. A short arm cast was used in 8 cases and a long-arm cast in 4 cases for an average length of 6 weeks. The indications of conservative treatment were varied: AO type A fractures in 2 cases, type C fractures in 1 case, types A and C in 8 cases and types A, B and C in 3 cases. No article reported any significant difference between surgical and conservative treatments in terms of DASH or PRWE, whereas strength was sometimes improved when surgical treatment was used. Radiological results were always better after surgical treatment. The rate of complications varied greatly, greater, equally or lower compared to conservative treatment depending on the series. All in all, there is no consensus to assert that a conservative treatment is more justified than a surgical treatment to treat distal radius fractures after the age of 65. Most authors consider that the long term clinical outcome is identical and that the radiological result is better after surgical treatment. The fact that the fixation of a distal radius fracture by a volar locking plate after 65 years speeds up the recovery remains to be proven. PMID- 29423867 TI - Uncemented Thompson's hemiarthroplasty: safe, palliative and cost-effective surgery in the infirm patient-a consecutive series of 1445 cases. AB - BACKGROUND: Guidelines on the management of displaced intracapsular fractures recommend using an Orthopaedic Data Evaluation Panel-rated cemented implant. Prior to the National Institute for Health and Care Excellence guidelines, uncemented implants were commonly used in the UK. METHODS: We retrospectively examined the outcomes of patients with uncemented Thompson's hemiarthroplasties at our unit, between April 2005 and December 2010. Patients who underwent revision surgery before December 2011 were identified. Implant survival calculation utilised the primary outcome of revision to total hip arthroplasty, revision hemiarthroplasty or excision arthroplasty. Patients who died post operatively were identified and censored. RESULTS: A total of 1445 patients received uncemented Thompson's implant. Patient mean age was 82 years with 76% female. Forty-six (3.2%) patients required revision with 15% performed within 30 days of surgery and 62% within 1 year. Reasons for revision were infection (0.83%), acetabular erosion (0.83%) and loosening (0.62%). Twenty-seven patients (59% of total revisions) underwent revision to THA, 14 (30%) to excision arthroplasty and 5 (11%) to revision hemiarthroplasty. Cumulative survival rate was 98% at 1 year and 95% at 5 years. Thirty-day mortality was 7.1%. One-year mortality was 28.1%. CONCLUSION: Current guidelines strongly favour cemented hemiarthroplasty. Recognition that fractured hip patients are a non-homogeneous group is important. In patients with limited life expectancy, an uncemented Thompson is a quick, simple, palliative solution to early mobilisation. Correct surgical technique avoids using cement in this cohort, which is most vulnerable to bone cement implantation syndrome. Cost-effective resource utilisation with an increasingly elderly population remains a surgical responsibility. PMID- 29423868 TI - Acetone-Butanol-Ethanol Production from Waste Seaweed Collected from Gwangalli Beach, Busan, Korea, Based on pH-Controlled and Sequential Fermentation Using Two Strains. AB - The optimal conditions for acetone-butanol-ethanol (ABE) production were evaluated using waste seaweed from Gwangalli Beach, Busan, Korea. The waste seaweed had a fiber and carbohydrate, content of 48.34%; these are the main resources for ABE production. The optimal conditions for obtaining monosaccharides based on hyper thermal (HT) acid hydrolysis of waste seaweed were slurry contents of 8%, sulfuric acid concentration of 138 mM, and treatment time of 10 min. Enzymatic saccharification was performed using 16 unit/mL Viscozyme L, which showed the highest affinity (Km = 1.81 g/L). After pretreatment, 34.0 g/L monosaccharides were obtained. ABE fermentation was performed with single and sequential fermentation of Clostridium acetobutylicum and Clostridium tyrobutyricum; this was controlled for pH. A maximum ABE concentration of 12.5 g/L with YABE 0.37 was achieved using sequential fermentation with C. tyrobutyricum and C. acetobutylicum. Efficient ABE production from waste seaweed performed using pH-controlled culture broth and sequential cell culture. PMID- 29423872 TI - Streptococcus salivarius meningitis: a spontaneous case in a 74-year-old man. PMID- 29423873 TI - An unusual phenocopy of the HANAC syndrome without genetic involvement of COL4A1/COL4A2. PMID- 29423874 TI - [What is actually adult spinal deformity? : Development, classification, and indications for surgical treatment]. AB - BACKGROUND: Adult spinal deformity (ASD) is a complex entity that has had emerging significance for spine surgeons in the last decade. Sagittal and/or coronary deformities can have a high impact (disability, pain) on the quality of patients' life. Radiologic diagnostics determine the common spinopelvic parameters as the basis for classification of ASD. TREATMENT: Conservative treatment options may be sufficient in mild cases. The deformity's complexity frequently demands the entire spectrum of methods and techniques in spinal surgery. This article gives an overview on the development of the ASD, the correct classification as well as the indication for surgical therapy. PMID- 29423875 TI - Emergency Medicine in the Kingdom of Bahrain. AB - It has been more than a decade since emergency medicine became recognized as a specialty in the Kingdom of Bahrain. In the last fifteen years emergency medicine has widely established itself and developed rapidly in the Kingdom. The three main emergency departments are: Salmanyia Medical Complex (SMC), Royal Medical Services of Bahrain Defence Force (RMS-BDF) and King Hamad University Hospital (KHUH) are now fully equipped and operated by a majority of board certified emergency physicians.Standardized protocols, and the Central National Ambulance will be established in the near future, and the ambulances will offer both basic and advanced life support by trained nurses and paramedics.Emergency Medicine residency training programs were established in the main three hospitals in Bahrain for the Arab Board Certification initially, while currently only two hospitals, BDF hospital and KHUH are recognized as training centers for the Saudi Board Residency Program.This article will focus on many aspects related to emergency medicine in the Kingdom of Bahrain including: history of health care systems in Bahrain, hospitals and primary care, disaster management, Emergency medical services (EMS), hospital-based emergency care, training in emergency medicine and universities. We aim to present Bahrain's past and existing emergency medicine experience, our perspective about the existing challenges faced by the specialty, and the future plans for the advancement of emergency medicine in the Kingdom. PMID- 29423876 TI - Ureteroscopic holmium laser-assisted retrograde nephrostomy access: a novel approach to percutaneous stone removal. AB - INTRODUCTION AND OBJECTIVES: Percutaneous nephrolithotomy remains a challenging procedure primarily due to difficulties obtaining access. Indeed, few urologists obtain their own access due to difficulties using a fluoroscopic or ultrasonic based antegrade puncture technique. Herein we report the first experience using holmium laser energy to obtain access in a retrograde fashion. METHODS: After a pretreatment week of tamsulosin 0.4 mg/day (one center only) and following a documented sterile urine, a total of ten patients underwent retrograde holmium laser-assisted endoscopic-guided nephrostomy access in a prone split leg position. RESULTS: In nine of ten patients, ureteroscopic guided, holmium laser access via an upper pole posterior calyx was achieved. In one patient, the laser tract could not be safely dilated and antegrade endoscopic and fluoroscopic guided access was performed. The mean operative time was 202 min; the mean fluoroscopy time was 32 s (6/9 cases). The mean pre-operative stone volume was 14,420 mm3. CT imaging on post-operative day 1 revealed 6/6 patients had residual stone fragments with total mean volume of 250 mm3 (96% reduction); there were no residual fragments in three patients who were evaluated with non-CT radiographic imaging (KUB). There was a single complication requiring angioembolization due to a subcapsular hematoma with associated secondary tearing of an inter-polar vessel remote from the nephrostomy site. CONCLUSIONS: Holmium laser-assisted endoscopic guided retrograde access in a prone split-leg position was successfully performed at two institutions. The accuracy of nephrostomy placement and lessening of fluoroscopy time are two potential benefits of this approach. PMID- 29423878 TI - Ginger rhizome enhances the anti-inflammatory and anti-nociceptive effects of paracetamol in an experimental mouse model of fibromyalgia. AB - BACKGROUND: The dried rhizome of ginger has been widely used for more than 2500 years in folk medicine for the treatment of various diseases that involve inflammation or are caused by oxidative stress. AIMS: This study was designed to compare the anti-nociceptive and anti-inflammatory effect of dried powdered ginger rhizome (GR) and paracetamol (APAP) on an experimental mouse model of fibromyalgia syndrome (FMS) induced by intermittent cold stress (ICS). METHODS: Forty-eight female C57BL/6 J mice were used for the experiments. The animals were allocated in six groups (n = 8). Each group received one of the following treatments for 8 weeks: healthy control, ICS group, ICS + APAP (40 mg/Kg/day), ICS + GR (0.5%); ICS + GR (1%), and ICS + GR (0.5%) + APAP (40 mg/Kg/day). After treatment, symptoms of FMS were induced by intermittent cold stress (ICS). RESULTS AND CONCLUSIONS: GR consumption improved mechanical and thermal allodynia and mechanical hyperalgesia and improved behavioural changes related to cognitive disturbances, anxiety, and depression. In addition, GR also significantly decreased the inflammatory response of proinflammatory mediators such as NO, PGE2, TXB2, and IL-1beta in LPS-stimulated macrophages. The effects of APAP were significantly enhanced by co-administration with GR. These findings provide evidence that the daily consumption of GR enhances the anti-nociceptive effect of APAP in mice, improves other cognitive disturbances associated with chronic pain, and reduces the inflammatory state generated in an experimental FMS model. PMID- 29423879 TI - Non-human primate research of basal ganglia and movement disorders: advances and challenges. PMID- 29423877 TI - NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease. AB - A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis. PMID- 29423881 TI - The curious tale of perioperative precision medicine: a story of hydroxocobalamin and cardiac surgery-associated vasoplegia. PMID- 29423880 TI - Micropharmacology: An In Silico Approach for Assessing Drug Efficacy Within a Tumor Tissue. AB - Systemic chemotherapy is one of the main anticancer treatments used for most kinds of clinically diagnosed tumors. However, the efficacy of these drugs can be hampered by the physical attributes of the tumor tissue, such as tortuous vasculature, dense and fibrous extracellular matrix, irregular cellular architecture, tumor metabolic gradients, and non-uniform expression of the cell membrane receptors. This can impede the transport of therapeutic agents to tumor cells in sufficient quantities. In addition, tumor microenvironments undergo dynamic spatio-temporal changes during tumor progression and treatment, which can also obstruct drug efficacy. To examine ways to improve drug delivery on a cell to-tissue scale (single-cell pharmacology), we developed the microscale pharmacokinetics/pharmacodynamics (microPKPD) modeling framework. Our model is modular and can be adjusted to include only the mathematical equations that are crucial for a biological problem under consideration. This modularity makes the model applicable to a broad range of pharmacological cases. As an illustration, we present two specific applications of the microPKPD methodology that help to identify optimal drug properties. The hypoxia-activated drugs example uses continuous drug concentrations, diffusive-advective transport through the tumor interstitium, and passive transmembrane drug uptake. The targeted therapy example represents drug molecules as discrete particles that move by diffusion and actively bind to cell receptors. The proposed modeling approach takes into account the explicit tumor tissue morphology, its metabolic landscape and/or specific receptor distribution. All these tumor attributes can be assessed from patients' diagnostic biopsies; thus, the proposed methodology can be developed into a tool suitable for personalized medicine, such as neoadjuvant chemotherapy. PMID- 29423882 TI - Growth promotion of Euglena gracilis by ferulic acid from rice bran. AB - A significant growth promotion of Euglena gracilis was achieved by simply adding ferulic acid from rice bran without diminishing the accumulation of valuable products like paramylon. E. gracilis is a freshwater microalga that is widely applied in cosmetics, food, medicine, and supplements, and it is considered a potential source of biofuel. It is therefore important to enhance its yield at a lower cost for its commercial viability. Introducing a growth regulator derived from agro waste is considered a cheaper and safer strategy to improve biomass productivity compared with other alternatives such as implementing genetic engineering or adding nutrients and plant hormones as growth stimulator. The effect of ferulic acid derived from rice bran on the growth and metabolism of E. gracilis was investigated in this study. To aid in the dissolution of ferulic acid, 1% dimethyl sulfoxide (DMSO) was added to Cramer-Myers medium. Ferulic acid could alleviate the inhibitory effect of DMSO and significantly promoted the growth of E. gracilis. It was found that cell density was 2.5 times greater than that of the control group and 3.6 times greater than that of the negative control group when 500 mg/L of ferulic acid was added. In addition, the photosynthetic pigment content, especially chlorophyll a, increased with increasing ferulic acid concentrations. The total paramylon production would also be enhanced by ferulic acid since the number of cells increased without reducing the cellular content of paramylon. PMID- 29423883 TI - Prescribing Immunoglobulin Replacement Therapy for Patients with Non-classical and Secondary Antibody Deficiency: an Analysis of the Practice of Clinical Immunologists in the UK and Republic of Ireland. AB - BACKGROUND: Immunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled. METHODS: Under the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers. RESULTS: In order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 MUg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months. CONCLUSIONS: There was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination. PMID- 29423884 TI - Learning curve of totally thoracoscopic pulmonary segmentectomy. AB - Totally thoracoscopic pulmonary segmentectomy (TTPS) is a feasible and safe technique that requires advanced thoracoscopic skills and knowledge of pulmonary anatomy. However, data describing the learning curve of TTPS have yet to be obtained. In this study, 128 patients who underwent TTPS between September 2010 and December 2013 were retrospectively analyzed to evaluate the learning curve and were divided chronologically into three phases, namely, ascending phase (A), plateau phase (B), and descending phase (C), through cumulative summation (CUSUM) for operative time (OT). Phases A, B, and C comprised 39, 33, and 56 cases, respectively. OT and blood loss decreased significantly from phases A to C (P < 0.01), and the frequency of intraoperative bronchoscopy for target bronchus identification decreased gradually (A, 8/39; B, 4/33; C, 3/56; P = 0.06). No significant differences were observed in demographic factors, conversion, complications, hospital stay, and retrieved lymph nodes among the three phases. Surgical outcomes and techniques improved with experience and volume. CUSUMOT indicated that the learning curve of TTPS should be more than 72 cases. PMID- 29423885 TI - Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: a prospective randomized double-blind sham-controlled multi-center study. AB - PURPOSE: To evaluate the safety and efficacy of radiofrequency (RF) ablation of the basivertebral nerve (BVN) for the treatment of chronic low back pain (CLBP) in a Food and Drug Administration approved Investigational Device Exemption trial. The BVN has been shown to innervate endplate nociceptors which are thought to be a source of CLBP. METHODS: A total of 225 patients diagnosed with CLBP were randomized to either a sham (78 patients) or treatment (147 patients) intervention. The mean age within the study was 47 years (range 25-69) and the mean baseline ODI was 42. All patients had Type I or Type II Modic changes of the treated vertebral bodies. Patients were evaluated preoperatively, and at 2 weeks, 6 weeks and 3, 6 and 12 months postoperatively. The primary endpoint was the comparative change in ODI from baseline to 3 months. RESULTS: At 3 months, the average ODI in the treatment arm decreased 20.5 points, as compared to a 15.2 point decrease in the sham arm (p = 0.019, per-protocol population). A responder analysis based on ODI decrease >= 10 points showed that 75.6% of patients in the treatment arm as compared to 55.3% in the sham control arm exhibited a clinically meaningful improvement at 3 months. CONCLUSION: Patients treated with RF ablation of the BVN for CLBP exhibited significantly greater improvement in ODI at 3 months and a higher responder rate than sham treated controls. BVN ablation represents a potential minimally invasive treatment for the relief of chronic low back pain. These slides can be retrieved under Electronic Supplementary Material. PMID- 29423886 TI - Paraplegic patients: how to measure balance and what is normal or functional? AB - PURPOSE: To review the current understanding and data of sagittal balance and alignment considerations in paraplegic patients. METHODS: A PubMed literature search was conducted to identify all relevant articles relating to sagittal alignment and sagittal balance considerations in paraplegic and spinal cord injury patients. RESULTS: While there are numerous studies and publications on sagittal balance in the ambulatory patient with spinal deformity or complex spine disorders, there is paucity of the literature on "normal" sagittal balance in the paraplegic patients. Studies have reported significantly alterations of the sagittal alignment parameters in the non-ambulatory paraplegic patients compared to ambulatory patients. The variability of the alignment changes is related to the differences in the level of the spinal cord injury and their differences in the activations of truncal muscles to allow functional movements in those patients, particularly in optimizing sitting and transferring. Surgical goal in treating paraplegic patients with complex pathologies should not be solely directed to achieve the "normal" radiographic parameters of sagittal alignment in the ambulatory patients. The goal should be to maintain good coronal balance to allow ideal sitting position and to preserve motion segment to optimize functions of paraplegia patients. CONCLUSION: Current available literature data have not defined normal sagittal parameters for paraplegic patients. There are significant differences in postural sagittal parameters and muscle activations in paraplegic and non-spinal cord injury patients that can lead to differences in sagittal alignment and balance. Treatment goal in spine surgery for paraplegic patients should address their global function, sitting balance, and ability to perform self-care rather than the accepted radiographic parameters for adult spinal deformity in ambulatory patients. PMID- 29423887 TI - Reoperation within 2 years after lumbar interbody fusion: a multicenter study. AB - PURPOSE: Posterior lumbar interbody fusion (PLIF)/transforaminal lumbar interbody fusion (TLIF) can have complications that require reoperation. The goal of the study was to identify risk factors for reoperation within 2 years after PLIF/TLIF. METHODS: A retrospective analysis of a prospective multicenter database was performed for patients who underwent PLIF/TLIF. A total of 1363 patients (689 males and 674 females) were identified, with an average age of 65.9 years old. Comorbidities, perioperative ASA grade, and operative factors were compared between patients with and without reoperation. Risk factors for reoperation were identified in multivariate logistic analysis. RESULTS: There were 38 reoperations within 2 years after PLIF/TLIF (2.8%). The original surgical procedures were open PLIF (n = 26), open TLIF (n = 10), and minimally invasive surgery (n = 2). Reoperation was due to adjacent segment degeneration (ASD) (n = 10), surgical site infection (SSI) (n = 9), screw misplacement (n = 6), postoperative epidural hematoma (n = 6), pseudoarthrosis (n = 4), and cage protrusion (n = 3). Number of levels fused and dural tear were significantly associated with reoperation. In analysis of complications requiring reoperation, SSI was related to diabetes mellitus and dural tear, and postoperative epidural hematoma was related to fusion of two or more levels, EBL, and operation time. In multivariate logistic regression, fusion of two or more levels (HR 2.19) was significantly associated with reoperation. CONCLUSION: Surgical invasiveness, as reflected by number of fused levels, operation time, EBL and dural tear, was associated with reoperation. Fusion of two or more levels is a strong risk factor for reoperation within 2 years after initial PLIF/TLIF. These slides can be retrieved under Electronic Supplementary Material. PMID- 29423888 TI - Posterolateral cervical transpedicular corpectomy for the surgical management of metastatic tumor. AB - Management of metastatic spinal disease in the upper cervical spine can be particularly challenging. Depending on the level of the lesion and the patient's anatomy, multiple anterior approaches have been described for resection of the cancer, followed by posterior fixation and instrumentation. Although a single stage posterolateral approach is now well established for thoracic pathology, less is known about the applicability of these principles when applied as an approach to the cervical spine. The authors present here a case using a posterolateral transpedicular approach for corpectomy and graft placement for circumferential reconstruction as a treatment of metastatic disease in the cervical spine to illustrate the feasibility of this technique, especially in the setting where the patient's anatomy or pathology may impede an anterior or combined circumferential approach. PMID- 29423890 TI - Professor Tafu Yu: an eminent agricultural scientist and outstanding educator of our nation. PMID- 29423889 TI - Origins of antidromic activity in sensory afferent fibers and neurogenic inflammation. AB - Neurogenic inflammation results from the release of biologically active agents from the peripheral primary afferent terminal. This release reflects the presence of releasable pools of active product and depolarization-exocytotic coupling mechanisms in the distal afferent terminal and serves to alter the physiologic function of innervated organ systems ranging from the skin and meninges to muscle, bone, and viscera. Aside from direct stimulation, this biologically important release from the peripheral afferent terminal can be initiated by antidromic activity arising from five anatomically distinct points of origin: (i) afferent collaterals at the peripheral-target organ level, (ii) afferent collaterals arising proximal to the target organ, (iii) from mid-axon where afferents lacking myelin sheaths (C fibers and others following demyelinating injuries) may display crosstalk and respond to local irritation, (iv) the dorsal root ganglion itself, and (v) the central terminals of the afferent in the dorsal horn where local circuits and bulbospinal projections can initiate the so-called dorsal root reflexes, i.e., antidromic traffic in the sensory afferent. PMID- 29423891 TI - [Acute pain management in patients with drug dependence syndrome]. PMID- 29423893 TI - Identifying the Influence of Opponent Ranking and Game Characteristics on Alcohol Related Stadium Ejections. AB - Sporting events in the U.S., particularly college football games, provide an opportunity for high-risk alcohol consumption that can result in alcohol-related consequences and associated public safety issues. Policy implication and predicting alcohol-related misconduct at college football games has become a concern for university administrators. To address this issue, we explored the extent to which the profile of a game or opponent-whether that be operationalized by classification (e.g., in-state opponent, conference opponent) or opponent quality (e.g., top-25 status, ranking average)-influences the reported stadium ejections of a college football venue, and whether these associations existed beyond the influence of several noteworthy covariates (e.g., time of kickoff, attendance, temperature). We suggest that time of kickoff and opponent quality measures predicted increases of ejections from college football stadiums. We conclude by discussing policy implications for college athletic departments and university stakeholders. PMID- 29423892 TI - Total vs proximal gastrectomy for adenocarcinoma of the upper third of the stomach: a propensity-score-matched analysis of a multicenter western experience (On behalf of the Italian Research Group for Gastric Cancer-GIRCG). AB - BACKGROUND: The aim of this study is to compare surgical outcomes including postoperative complications and prognosis between total gastrectomy (TG) and proximal gastrectomy (PG) for proximal gastric cancer (GC). Propensity-score matching analysis was performed to overcome patient selection bias between the two surgical techniques. METHODS: Among 457 patients who were diagnosed with GC between January 1990 and December 2010 from four Italian institutions, 91 underwent PG and 366 underwent TG. Clinicopathologic features, postoperative complications, and survivals were reviewed and compared between these two groups retrospectively. RESULTS: After propensity-score matching had been done, 150 patients (75 TG patients, 75 PG patients) were included in the analysis. The PG group had smaller tumors, shorter resection margins, and smaller numbers of retrieved lymph nodes than the TG group. N stages and 5-year survival rates were similar after TG and PG. Postoperative complication rates after PG and TG were 25.3 and 28%, respectively, (P = 0.084). Rates of reflux esophagitis and anastomotic stricture were 12 and 6.6% after PG and 2.6 and 1.3% after TG, respectively (P < 0.001 and P = 0.002). 5-year overall survival for PG and TG group was 56.7 and 46.5%, respectively (P = 0.07). Survival rates according to the tumor stage were not different between the groups. Multivariate analysis showed that type of resection was not an independent prognostic factor. CONCLUSION: Although PG for upper third GC showed good results in terms of survival, it is associated with an increased mortality rate and a higher risk of reflux esophagitis and anastomotic stricture. PMID- 29423895 TI - Molecular Insights into the Roles of Rab Proteins in Intracellular Dynamics and Neurodegenerative Diseases. AB - In eukaryotes, the cellular functions are segregated to membrane-bound organelles. This inherently requires sorting of metabolites to membrane-limited locations. Sorting the metabolites from ribosomes to various organelles along the intracellular trafficking pathways involves several integral cellular processes, including an energy-dependent step, in which the sorting of metabolites between organelles is catalyzed by membrane-anchoring protein Rab-GTPases (Rab). They contribute to relaying the switching of the secretory proteins between hydrophobic and hydrophilic environments. The intracellular trafficking routes include exocytic and endocytic pathways. In these pathways, numerous Rab-GTPases are participating in discrete shuttling of cargoes. Long-distance trafficking of cargoes is essential for neuronal functions, and Rabs are critical for these functions, including the transport of membranes and essential proteins for the development of axons and neurites. Rabs are also the key players in exocytosis of neurotransmitters and recycling of neurotransmitter receptors. Thus, Rabs are critical for maintaining neuronal communication, as well as for normal cellular physiology. Therefore, cellular defects of Rab components involved in neural functions, which severely affect normal brain functions, can produce neurological complications, including several neurodegenerative diseases. In this review, we provide a comprehensive overview of the current understanding of the molecular signaling pathways of Rab proteins and the impact of their defects on different neurodegenerative diseases. The insights gathered into the dynamics of Rabs that are described in this review provide new avenues for developing effective treatments for neurodegenerative diseases-associated with Rab defects. PMID- 29423894 TI - Aloysia triphylla in the zebrafish food: effects on physiology, behavior, and growth performance. AB - Dietary supplements are commonly used by animals and humans and play key roles in diverse systems, such as the immune and reproductive systems, and in metabolism. Essential oils (EOs), which are natural substances, have potential for use in food supplementation; however, their effects on organisms remain to be elucidated. Here, we examine the effects of dietary Aloysia triphylla EO supplementation on zebrafish behavior, metabolism, stress response, and growth performance. We show that fish fed diets containing A. triphylla EO presented an anxiolytic response, with reduced exploratory activity and oxygen consumption; no changes were observed in neuroendocrine stress axis functioning and growth was not impaired. Taken together, these results suggest that the A. triphylla EO supplementation is a strong candidate for use in feed, since it ensures fish welfare (anxiolytic behavior) with decreased oxygen consumption. This makes it suitable for use in high-density production systems without causing damage to the neuroendocrine stress axis and without growth performance being impaired. PMID- 29423896 TI - Patterns of Non-injection Drug Use Associated with Injection Cessation among Street-Involved Youth in Vancouver, Canada. AB - Although abstinence from drug use is often a key goal of youth substance use treatment, transitioning to less harmful routes and types of drug use is desirable from both a clinical and public health perspective. Despite this, little is known about the trajectories of youth who inject drugs including changes in patterns of non-injection drug use. The At-Risk Youth Study (ARYS) is a longitudinal cohort of street-involved youth who use drugs in Vancouver, Canada. We used linear growth curve modeling to compare changes in non-injection drug use among participants who ceased injecting drugs for at least one 6-month period between September 2005 and May 2015 to matched controls who continued injecting over the same period. Of 387 eligible participants, 173 (44.7%) reported ceasing drug injection at least once. Non-injection drug use occurred during 160 (79.6%) periods of injection cessation. In adjusted linear growth curve analyses, the only non-injection drug use pattern observed to decrease significantly more than controls following injection cessation was daily crack/cocaine use (p = 0.024). With the exception of frequent crack/cocaine use, transitions out of injection drug use did not appear to coincide with increased reductions in patterns of non-injection drug use. Our findings indicate that most (80%) of the observed injection cessation events occurred in the context of ongoing substance use. Given that transitioning out of drug injection represents a significant reduction in risk and harm, efforts supporting vulnerable youth to move away from injecting may benefit from approaches that allow for ongoing non injection drug use. PMID- 29423898 TI - A Novel High-Molecular-Mass Bacteriocin Produced by Enterococcus faecium: Biochemical Features and Mode of Action. AB - Discovery of a novel bacteriocin is always an event in sciences, since cultivation of most bacterial species is a general problem in microbiology. This statement is reflected by the fact that number of bacteriocins is smaller for tenfold comparing to known antimicrobial peptides. We cultivated Enterococcus faecium on simplified medium to reduce amount of purification steps. This approach allows to purify the novel heavy weight bacteriocin produced by E. faecium ICIS 7. The novelty of this bacteriocin, named enterocin-7, was confirmed by N-terminal sequencing and by comparing the structural-functional properties with available data. Purified enterocin-7 is characterized by a sequence of amino acid residues having no homology in UniProt/SwissProt/TrEMBL databases: NH2 - Asp - Ala - His - Leu - Ser - Glu - Val - Ala - Glu - Arg - Phe - Glu - Asp - Leu - Gly. Isolated thermostable protein has a molecular mass of 65 kDa, which allows it to be classified into class III in bacteriocin classification schemes. Enterocin-7 displayed a broad spectrum of activity against some Gram-positive and Gram-negative microorganisms. Fluorescent microscopy and spectroscopy showed the permeabilizing mechanism of the action of enterocin-7, which is realized within a few minutes. PMID- 29423897 TI - The Role of Diet in Glaucoma: A Review of the Current Evidence. AB - Intraocular pressure (IOP) reduction by medications, laser, or surgery remains the mainstay of treatment in glaucoma. However, the role of complementary and alternative medicine (CAM) in glaucoma has received great interest from both patients and ophthalmologists. Previous evidence suggests that diet, a major domain of CAM, can influence an individual's IOP level. Furthermore, certain dietary components have been linked to the incidence and progression of glaucoma. In this review, we aim to provide a summary of the current evidence regarding the role of obesity, certain dietary components, and dietary supplements in glaucoma. PMID- 29423899 TI - Influence of control group therapy on the benefit from dose-dense chemotherapy in early breast cancer: a systemic review and meta-analysis. AB - PURPOSE: Results from clinical trials of adjuvant dose-dense chemotherapy in patients with breast cancer are inconsistent. METHODS: A systematic search of MEDLINE identified studies comparing the efficacy of dose-dense adjuvant chemotherapy to a standard treatment. The primary analysis included studies that used identical regimens in the experimental and control groups, but varied only dose density. A secondary analysis included studies that used either different drugs or doses in the experimental and the control groups. Hazard ratios (HRs) and 95% confidence intervals were computed for disease-free survival (DFS) and overall survival (OS) and pooled in a meta-analysis. Subgroup analyses and meta regression explored drug schedules utilized in control groups and the influence of clinicopathologic variables on benefit from dose-dense therapy. RESULTS: The primary analysis included 5 studies comprising 9819 patients while the secondary analysis included 6 studies comprising 9679 patients. Dose-dense treatment significantly improved DFS (HR 0.85, p < 0.001) and OS (HR 0.86, p = 0.008) in the primary analysis. Similar results were observed in the secondary analysis. Dose-dense schedule was important primarily in studies utilizing paclitaxel every 3 weeks as the control group (interaction p = 0.04 for DFS interaction p = 0.001 for OS). A significantly greater relative magnitude of benefit was observed in pre-menopausal women and those with nodal involvement, but there was no influence of hormone receptor status on results. CONCLUSIONS: Adjuvant dose-dense regimens improve breast cancer outcomes. It remains uncertain whether the observed benefit reflects the impact of dose density or the inferiority of paclitaxel every 3 weeks as a control group. PMID- 29423900 TI - Association between financial burden and adjuvant hormonal therapy adherence and persistent use for privately insured women aged 18-64 years in BCBS of Texas. AB - PURPOSE: The objective of this study is to understand an impact of financial burden on the adjuvant hormonal therapy (AHT) adherence and persistence for insured women aged 18-64 with early breast cancer in Texas. METHODS: We conducted a retrospective cohort study using claims data for population insured by Blue Cross Blue Shield of Texas from the year 2008 to 2013. Outcomes include adherence to adjuvant hormonal therapy, which was measured by medication possession ratio and persistence on AHT, which is the duration of time from initiation to discontinuation of therapy. Multivariate logistic regression models with repeated regional-level adjustments were used to explore the odds of AHT adherence. Cox proportional hazards model was conducted to assess time to the first 90+-day gap for persistence and a Kaplan-Meier curve were used to estimate probabilities to calculate the percentages of women who experienced 90+-day gaps in AHT. RESULTS: Of the 938 women in the cohort, 627 (66.8%) initiated the treatment. By year 1, 66.9% of women were adherent to the therapy, and by year 5, only 29% of those were adherent. The percentage of women with no gap in therapy greater than 90 days was 80.8%. Both higher out-of-pocket costs spent on all prescription drugs except AHT and AHT-specific out-of-pocket costs were negatively associated with adherence to AHT as well as continuing AHT as recommended. CONCLUSIONS: Financial burdens including both non-AHT medication and AHT-specific out-of-pocket costs were significantly associated with adherence and persistence to the therapy. PMID- 29423901 TI - Impact of physiological hormonal fluctuations on 18F-fluorodeoxyglucose uptake in breast cancer. AB - PURPOSE: Premenopausal physiologic steroid levels change cyclically, in contrast to steady state low levels seen in postmenopausal patients. The purpose of this study was to evaluate whether 18F-fluorodeoxyglucose (18F-FDG) uptake in breast cancer is influenced by physiological hormonal fluctuations. METHODS: A total of 160 primary invasive breast cancers from 155 females (54 premenopausal, 101 postmenopausal) who underwent 18F-FDG positron emission tomography/computed tomography before therapy were retrospectively analyzed. The maximal standardized uptake values (SUVmax) of tumors were compared with menstrual phases and menopausal status according to the following subgroups: 'luminal A-like,' 'luminal B-like,' and 'non-luminal.' Additionally, the effect of estradiol (E2) on 18F-FDG uptake in breast cancer cells was evaluated in vitro. RESULTS: Among premenopausal patients, SUVmax during the periovulatory-luteal phase was significantly higher than that during the follicular phase in luminal A-like tumors (n = 25, p = 0.004), while it did not differ between the follicular phase and the periovulatory-luteal phase in luminal B-like (n = 24) and non-luminal tumors (n = 7). Multiple regression analysis showed menstrual phase, tumor size, and Ki-67 index are independent predictors for SUVmax in premenopausal luminal A like tumors. There were no significant differences in SUVmax between pre- and postmenopausal patients in any of the subgroups. In in vitro studies, uptake in estrogen receptor-positive cells was significantly augmented when E2 concentration was increased from 0.01 to >= 1 nM. CONCLUSIONS: Our data suggest that 18F-FDG uptake may be impacted by physiological hormonal fluctuations during menstrual cycle in luminal A-like cancers, and that E2 could be partly responsible for these events. PMID- 29423902 TI - A Novel Substrate Radiotracer for Molecular Imaging of SIRT2 Expression and Activity with Positron Emission Tomography. AB - PURPOSE: The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues. PROCEDURES: A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10 fluorodecanoic groups (Kcat/Km 716.5 +/- 72.8, 615.4 +/- 50.5, 269.5 +/- 52.1/s mol, respectively). Radiosynthesis of 12- [18F]fluorododecanoic aminohexanoicanilide (12-[18F]DDAHA) was achieved by nucleophilic radiofluorination of 12-iododecanoic-AHA precursor. RESULTS: A significantly higher accumulation of 12-[18F]DDAHA was observed in MCF-7 and MDA-MB-435 cells in vitro as compared to U87, MiaPaCa, and MCF10A, which was consistent with levels of SIRT2 expression. Initial in vivo studies using 12-[18F]DDAHA conducted in a 9L glioma-bearing rats were discouraging, due to rapid defluorination of this radiotracer upon intravenous administration, as evidenced by significant accumulation of F-18 radioactivity in the skull and other bones, which confounded the interpretation of images of radiotracer accumulation within the tumor and other regions of the brain. CONCLUSIONS: The next generation of SIRT2-specific radiotracers resistant to systemic defluorination should be developed using alternative sites of radiofluorination on the aliphatic chain of DDAHA. A SIRT2 selective radiotracer may provide information about SIRT2 expression and activity in tumors and normal organs and tissues, which may help to better understand the roles of SIRT2 in different diseases. PMID- 29423904 TI - Case Presentation Commentary on "A case of longitudinal care of a patient with cardiac sarcoidosis". PMID- 29423903 TI - [11C]Harmine Binding to Brain Monoamine Oxidase A: Test-Retest Properties and Noninvasive Quantification. AB - PURPOSE: Inhibition of the isoform A of monoamine oxidase (MAO-A), a mitochondrial enzyme catalyzing deamination of monoamine neurotransmitters, is useful in treatment of depression and anxiety disorders. [11C]harmine, a MAO-A PET radioligand, has been used to study mood disorders and antidepressant treatment. However, [11C]harmine binding test-retest characteristics have to date only been partially investigated. Furthermore, since MAO-A is ubiquitously expressed, no reference region is available, thus requiring arterial blood sampling during PET scanning. Here, we investigate [11C]harmine binding measurements test-retest properties; assess effects of using a minimally invasive input function estimation on binding quantification and repeatability; and explore binding potentials estimation using a reference region-free approach. PROCEDURES: Quantification of [11C]harmine distribution volume (VT) via kinetic models and graphical analyses was compared based on absolute test-retest percent difference (TRPD), intraclass correlation coefficient (ICC), and identifiability. The optimal procedure was also used with a simultaneously estimated input function in place of the measured curve. Lastly, an approach for binding potentials quantification in absence of a reference region was evaluated. RESULTS: [11C]harmine VT estimates quantified using arterial blood and kinetic modeling showed average absolute TRPD values of 7.7 to 15.6 %, and ICC values between 0.56 and 0.86, across brain regions. Using simultaneous estimation (SIME) of input function resulted in VT estimates close to those obtained using arterial input function (r = 0.951, slope = 1.073, intercept = - 1.037), with numerically but not statistically higher test-retest difference (range 16.6 to 22.0 %), but with overall poor ICC values, between 0.30 and 0.57. CONCLUSIONS: Prospective studies using [11C]harmine are possible given its test-retest repeatability when binding is quantified using arterial blood. Results with SIME of input function show potential for simplifying data acquisition by replacing arterial catheterization with one arterial blood sample at 20 min post-injection. Estimation of [11C]harmine binding potentials remains a challenge that warrants further investigation. PMID- 29423905 TI - A case of longitudinal care of a patient with cardiac sarcoidosis. AB - Cardiac sarcoidosis has long been an evasive diagnosis with a spectrum of clinical presentations that extend from asymptomatic to ventricular arrhythmias and sudden cardiac death. The diagnosis has traditionally relied on histology which suffers from the low sensitivity of endomyocardial biopsy due to the patchy nature of the disease in addition to its invasive nature. Due to significant advancements in imaging, it is now possible to accurately identify cardiac sarcoidosis using non-invasive imaging modalities even without histological confirmation. Emerging guidelines are highlighting the role of multimodality imaging in the diagnosis and management of this challenging entity. We present the case of a 36-year-old man known to have sarcoidosis in which a variety of imaging modalities not only assisted in the diagnosis of cardiac sarcoidosis, but also played a key role in the monitoring of disease activity and response to therapy. PMID- 29423906 TI - Relationships between electrical and mechanical dyssynchrony in patients with left bundle branch block and healthy controls. AB - BACKGROUND: Abnormal electrical activation may cause dyssynchronous left ventricular (LV) contraction. In this study, we characterized and analyzed electrical and mechanical dyssynchrony in patient with left bundle branch block (LBBB) and healthy controls. METHODS: Myocardial perfusion imaging (MPI) data from 994 patients were analyzed. Forty-three patient fulfilled criteria for LBBB and 24 for controls. Electrical activation was characterized with vector electrocardiography (VECG) and LV function including mechanical dyssynchrony with ECG-gated MPI phase analysis. RESULTS: QRS duration (QRSd; r = 0.69, P < .001) and a few other VECG parameters correlated significantly with phase bandwidth (phaseBW) representing mechanical dyssynchrony. End-diastolic volume (EDV; r = 0.59, P < .001), ejection fraction and end-systolic volume correlated also with phaseBW. QRSd (beta = 0.47, P < .001) and EDV (beta = 0.36, P = .001) were independently associated with phaseBW explaining 55% of its variation. Sixty percent of patients with LBBB had significant mechanical dyssynchrony. Those patients had wider QRSd (159 vs 147 ms, P = .013) and larger EDV (144 vs 94 mL, P = .008) than those with synchronous LV contraction. Cut-off values for mechanical dyssynchrony seen in patients with LBBB were QRSd >= 165 ms and EDV >= 109 mL. CONCLUSIONS: Despite obvious conduction abnormality, LBBB is not always accompanied by mechanical dyssynchrony. QRSd and EDV explained 55% of variation seen in phaseBW. These two parameters were statistically different between LBBB cases with and without mechanical dyssynchrony. PMID- 29423907 TI - Correction to: Comparison of two software systems for quantification of myocardial blood flow in patients with hypertrophic cardiomyopathy. AB - The following information is missing from the Funding footnote on the first page of the published article: "This study was partly funded by NIH RO1 HL092985." The last/corresponding author is incorrectly listed on the first page of the published article: The correct name is Abraham MR. PMID- 29423908 TI - Vascular age for predicting cardiovascular risk: A novel clinical marker or just a mathematical permutation. PMID- 29423909 TI - Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain. AB - One carbon metabolism is regulated by the availability of nutrients known as methyl donors, and disruption of this pathway can affect multiple physiological systems. DNA methylation, critical for the regulation of gene expression, is linked to one carbon metabolism, and can be altered by perinatal diet. In this study, dams (n = 12/group) were fed HF or standard control (SC) diet through pregnancy and lactation, and male and female offspring were then fed either SC or methyl donor-supplemented diet (MDS) between 3 and 6 weeks of age (n = 20 26/group). Concentration of one carbon intermediates and other related metabolites were assessed within brain tissue (prefrontal cortex, PFC) through the use of mass spectrometry at 6 weeks of age. In addition, the expression of target genes and enzymes that participate in DNA methylation or are relevant to one carbon metabolism were measured. We found that MDS increases the concentration of folate intermediates in the PFC, and that this increase is blunted in male offspring from dams fed a HF diet. In addition, perinatal HF diet increased the concentration of cysteine in the PFC of both male and female offspring, consistent with oxidative stress. Furthermore, both maternal HF diet and postnatal MDS altered global DNA methylation in the PFC in males but not females. Collectively, these data demonstrate sex differences in changes in one carbon metabolites in the prefrontal cortex in response to early life high fat diet and methyl donor supplementation. Read the Editorial Highlight for this article on page 358. PMID- 29423910 TI - Kidney function monitoring and nonvitamin K oral anticoagulant dosage in atrial fibrillation. AB - BACKGROUND: Clinical practice guidelines recommend regular kidney function monitoring in atrial fibrillation patients on nonvitamin K oral anticoagulants (NOAC); however, information regarding compliance with these recommendations in daily life conditions is scarce. We sought to determine the compliance with kidney function monitoring recommendations in nonvalvular atrial fibrillation (NVAF) patients starting NOAC and its implication on the appropriateness of NOAC dosage. MATERIAL AND METHODS: This study involves the retrospective analysis of a multicentre registry including consecutive NVAF patients who started NOAC (n = 692). Drug dosage changes and serum creatinine determinations were recorded during 1-year follow-up. European Heart Rhythm Association criteria were used to define the appropriateness of kidney function monitoring as well as adequate NOAC dosage. RESULTS: During the follow-up (334 +/- 89 days), the compliance with kidney function monitoring recommendations was 61% (n = 425). After multivariate adjustment, age (OR * year: 0.92 (CI 95%: 0.89-0.95) P < .001), creatinine clearance (OR * mL/min: 1.02 (CI 95%: 1.01-1.03) P < .001) and adequate NOAC dosage at baseline (OR: 1.54 (CI 95%: 1.06-2.23), P = .024) were independent predictors of appropriate kidney function monitoring. Compliance with kidney function monitoring recommendations was independently associated with change to appropriate NOAC dose after 1 year (OR: 2.80 (CI 95%: 1.01-7.80), P = .049). CONCLUSIONS: Noncompliance with kidney function monitoring recommendations is common in NVAF patients starting NOAC, especially in elderly patients with kidney dysfunction. Compliance with kidney function monitoring recommendations was associated with adequate NOAC dosage at 1-year follow-up. Further studies are warranted to evaluate the implication of kidney function monitoring on prognosis. PMID- 29423911 TI - Planned birth at or near term for improving health outcomes for pregnant women with pre-existing diabetes and their infants. AB - BACKGROUND: Pregnant women with pre-existing diabetes (Type 1 or Type 2) have increased rates of adverse maternal and neonatal outcomes. Current clinical guidelines support elective birth, at or near term, because of increased perinatal mortality during the third trimester of pregnancy.This review replaces a review previously published in 2001 that included "diabetic pregnant women", which has now been split into two reviews. This current review focuses on pregnant women with pre-existing diabetes (Type 1 or Type 2) and a sister review focuses on women with gestational diabetes. OBJECTIVES: To assess the effect of planned birth (either by induction of labour or caesarean birth) at or near term gestation (37 to 40 weeks' gestation) compared with an expectant approach, for improving health outcomes for pregnant women with pre-existing diabetes and their infants. The primary outcomes relate to maternal and perinatal mortality and morbidity. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (15 August 2017), and reference lists of retrieved studies. SELECTION CRITERIA: We planned to include randomised trials (including those using a cluster-randomised design) and non-randomised trials (e.g. quasi randomised trials using alternate allocation) which compared planned birth, at or near term, with an expectant approach for pregnant women with pre-existing diabetes. DATA COLLECTION AND ANALYSIS: Two of the review authors independently assessed study eligibility. In future updates of this review, at least two of the review authors will extract data and assess the risk of bias in included studies. We will also assess the quality of the evidence using the GRADE approach. MAIN RESULTS: We identified no eligible published trials for inclusion in this review.We did identify one randomised trial which examined whether expectant management reduced the incidence of caesarean birth in uncomplicated pregnancies of women with gestational diabetes (requiring insulin) and with pre-existing diabetes. However, published data from this trial does not differentiate between pre-existing and gestational diabetes, and therefore we excluded this trial. AUTHORS' CONCLUSIONS: In the absence of evidence, we are unable to reach any conclusions about the health outcomes associated with planned birth, at or near term, compared with an expectant approach for pregnant women with pre-existing diabetes.This review demonstrates the urgent need for high-quality trials evaluating the effectiveness of planned birth at or near term gestation for pregnant women with pre-existing (Type 1 or Type 2) diabetes compared with an expectant approach. PMID- 29423912 TI - Implementing and Assessing a Standardized Protocol for Weaning Children Successfully From Extracorporeal Life Support. AB - Extracorporeal life support (ECLS) weaning is a complex interdisciplinary process with no clear guidelines. To assess ventricular and pulmonary function as well as hemodynamics including end-organ recovery during ECLS weaning, we developed a standardized weaning protocol. We reviewed our experience 2 years later to assess its feasibility and efficacy. In 2015 we established an inter-professional, standardized, stepwise protocol for weaning from ECLS. If the patient did not require further surgery, weaning was conducted bedside in the intensive care unit (ICU). Most of the weaning procedures are guided via echocardiography. Data acquisition began at baseline level, followed by four-step course (each step lasting 10 min), entailing flow-reduction and ending 30 min after decannulation. Moreover, data from the preprotocol era are presented. Between May 2015 and 2017, 26 consecutive patients (18 male), median age 177 days (2 days-20 years) required ECLS with median support of 4 (2-11) days. Excluding eight not weanable patients, 21 standardized weaning procedures were protocolled in the remaining 18 children. Our generally successful protocol-guided weaning rate (with at least 24-h survival) was 89%, with a discharge home rate of 58%. Practical application of the novel standard protocol seems to facilitate ECLS weaning and to improve its success rate. The protocol can be administered as part of standard bedside ICU assessment. PMID- 29423913 TI - Multivariate approaches for stability control of the olive oil reference materials for sensory analysis - part II: applications. AB - BACKGROUND: The organoleptic quality of virgin olive oil depends on positive and negative sensory attributes. These attributes are related to volatile organic compounds and phenolic compounds that represent the aroma and taste (flavour) of the virgin olive oil. The flavour is the characteristic that can be measured by a taster panel. However, as for any analytical measuring device, the tasters, individually, and the panel, as a whole, should be harmonized and validated and proper olive oil standards are needed. RESULTS: In the present study, multivariate approaches are put into practice in addition to the rules to build a multivariate control chart from chromatographic volatile fingerprinting and chemometrics. Fingerprinting techniques provide analytical information without identify and quantify the analytes. This methodology is used to monitor the stability of sensory reference materials. CONCLUSION: The similarity indices have been calculated to build multivariate control chart with two olive oils certified reference materials that have been used as examples to monitor their stabilities. This methodology with chromatographic data could be applied in parallel with the 'panel test' sensory method to reduce the work of sensory analysis. (c) 2018 Society of Chemical Industry. PMID- 29423914 TI - Hypertension: New perspective on its definition and clinical management by bedtime therapy substantially reduces cardiovascular disease risk. AB - Diagnosis of hypertension-elevated blood pressure (BP) associated with increased cardiovascular disease (CVD) risk-and its management for decades have been based primarily on single time-of-day office BP measurements (OBPM) assumed representative of systolic (SBP) and diastolic BP (DBP) during the entire 24 hours span. Around-the-clock ambulatory blood pressure monitoring (ABPM), however, reveals BP undergoes 24-hours patterning characterized in normotensives and uncomplicated hypertensives by striking morning-time rise, 2 daytime peaks one ~2-3 hours after awakening and the other early evening, small midafternoon nadir and 10-20% decline (BP dipping) in the asleep BP mean relative to the wake time BP mean. A growing number of outcome trials substantiate correlation between BP and target organ damage, vascular and other risks is greater for the ABPM derived asleep BP mean, independent and stronger predictor of CVD risk, than daytime OBPM or ABPM-derived awake BP. Additionally, bedtime hypertension chronotherapy, that is, ingestion of >=1 conventional hypertension medications at bedtime to achieve efficient attenuation of asleep BP, better reduces total CVD events by 61% and major events (CVD death, myocardial infarction, ischaemic and haemorrhagic stroke) by 67%-even in more vulnerable chronic kidney disease, diabetes and resistant hypertension patients-than customary on-awaking therapy that targets wake-time BP. Such findings of around-the-clock ABPM and bedtime hypertension outcome trials, consistently indicating greater importance of asleep BP than daytime OBPM or ambulatory awake BP, call for a new definition of true arterial hypertension plus modern approaches for its diagnosis and management. PMID- 29423915 TI - Sensory nerve degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser. AB - AIMS: Sensory nerve degeneration and consequent abnormal sensations are the earliest and most prevalent manifestations of familial amyloid polyneuropathy (FAP) due to amyloidogenic transthyretin (TTR). FAP is a relentlessly progressive degenerative disease of the peripheral nervous system. However, there is a lack of mouse models to replicate the early neuropathic manifestations of FAP. METHODS: We established human TTR knock-in mice by replacing one allele of the mouse Ttr locus with human wild-type TTR (hTTRwt ) or human TTR with the A97S mutation (hTTRA97S ). Given the late onset of neuropathic manifestations in A97S FAP, we investigated nerve pathology, physiology, and behavioural tests in these mice at two age points: the adult group (8 - 56 weeks) and the ageing group (> 104 weeks). RESULTS: In the adult group, nerve profiles, neurophysiology and behaviour were similar between hTTRwt and hTTRA97S mice. By contrast, ageing hTTRA97S mice showed small fibre neuropathy with decreased intraepidermal nerve fibre density and behavioural signs of mechanical allodynia. Furthermore, significant reductions in sural nerve myelinated nerve fibre density and sensory nerve action potential amplitudes in these mice indicated degeneration of large sensory fibres. The unaffected motor nerve physiology replicated the early symptoms of FAP patients, that is, sensory nerves were more vulnerable to mutant TTR than motor nerves. CONCLUSIONS: These results demonstrate that the hTTRA97S mouse model develops sensory nerve pathology and corresponding physiology mimicking A97S-FAP and provides a platform to develop new therapies for the early stage of A97S-FAP. PMID- 29423916 TI - Epiproteome profiling of cadmium-transformed human bronchial epithelial cells by quantitative histone post-translational modification-enzyme-linked immunosorbent assay. AB - Cadmium (Cd), a carcinogenic toxic metal, is pervasively distributed in the soil, water and air. Chronic exposure to Cd has been correlated to lung disease development including cancers. Although many studies have been conducted to investigate the proteome response of cells challenged with Cd, the epiproteomic responses (i.e., global histone post-translational modifications [PTMs]), particularly in human lung cells, are largely unexplored. Here, we provide an epiproteome profiling of human bronchial epithelial cells (BEAS-2B) chronically treated with cadmium chloride (CdCl2 ), with the aim of identifying global epiproteomic signatures in response to Cd epigenotoxicity. Total histone proteins from Cd-treated and untreated BEAS-2B cells were isolated and subject to quantitative histone PTM-enzyme-linked immunosorbent assay using 18 histone PTM antibodies. Our results unveiled that chronic Cd treatment led to the marked downregulation of H3K4me2 and H3K36me3 and upregulation of H3K9acS10ph, H4K5ac, H4K8ac and H4K12ac PTM marks. Cd-treated cells exhibit transformed cell properties as evidenced by enhanced cell migration and the ability of anchorage independent growth on soft agar. Notably, treatment of Cd-transformed cells with C646, a potent histone acetyltransferase inhibitor, suppressed the expression of mesenchymal marker genes and cell migration ability of these cells. Taken together, our studies provide for the first time the global epiproteomic interrogation of chronic Cd-exposed human lung cells. The identified aberrant histone PTM alterations associated with Cd-induced epigenotoxicity likely account for the epithelial-mesenchymal transition and neoplastic survival of these cells. PMID- 29423917 TI - Corrigendum to "the role of intracellular redox imbalance in nanomaterial induced cellular damage and genotoxicity: A review". PMID- 29423918 TI - Percutaneous endoscopic gastrostomy placement in paediatric Crohn's disease patients contributes to both improved nutrition and growth. AB - AIM: This paper describes the outcomes of gastrostomy feeding in patients with Crohn's disease (CD). METHODS: Patients with CD who attended the Royal Hospital for Children, Glasgow and received gastrostomy feeding for at least two years between 2003 and 2010 were identified from the clinical database. The data recorded included the anthropometric data, CD phenotype, the surgical technique that was used, complications, medication, feed type, median feed, calories, volume and clinical outcomes. RESULTS: The study identified 16 patients (14 male) who had a gastrostomy inserted using a pull technique at a median age of 12.6 years. Of these two required laparoscopic placement. Short-term complications lasting less than one month were experienced by nine (56%) patients and one (6%) experienced long-term complications. Anthropometry significantly improved at follow-up compared to baseline: at 12 months, the body mass index z-score was 1.11 (p = 0.005) and the weight z-score was 0.19 (p < 0.05). At 24 months, the height z-score was -1.03 (p = 0.04). The daily median volume and calories from feeds increased significantly from baseline to post-PEG insertion, from 400 to 738 mL and 705 to 860 kcal/day (p <= 0.01). CONCLUSION: Gastrostomy feeding for paediatric patients with CD was associated with improved nutrition, weight gain and growth outcomes. PMID- 29423919 TI - Ten-year retrospective clinicohistological study of cutaneous lupus erythematosus in Korea. AB - An understanding of the differences in clinical manifestations and laboratory abnormalities between subtypes of cutaneous lupus erythematosus (CLE) is still lacking. The purpose of this study was to analyze demographic, clinical and histological features of CLE according to three main presentation subsets: acute (ACLE), subacute (SCLE) and chronic (CCLE). A 10-year retrospective analysis was performed on data from patients who were diagnosed with CLE between March 2005 and September 2015 in a Korean tertiary referral dermatology clinic. We compared demographic data and clinical and histological findings between three different CLE groups. An overall sample of 220 patients with CLE consisted of 67 patients with ACLE, 25 patients with SCLE and 135 patients with CCLE. Patients with CCLE regardless of systemic lupus erythematosus (SLE) presence had lower prevalence of anemia, urinary abnormalities and elevated erythrocyte sedimentation rate. Furthermore, CCLE patients who only had skin lesions showed lower female predominance, lower extracutaneous manifestation, fewer laboratory and immunological abnormalities including low antinuclear antibody titers and the lowest positivity for C3, C4 and anti-dsDNA, anti-Ro, anti-Sm and anti-RNP antibodies, and more prominent perieccrine inflammation and dermal fibrosis in histological findings. Considering distinct cutaneous manifestations of LE, a comprehensive awareness of each CLE subtype is important for achieving a favorable prognosis through appropriate diagnosis and management. This study provides comparative clinical and histological profiles of patients with different CLE subtypes in Korea. PMID- 29423920 TI - Molecularly Imprinted Porous Aromatic Frameworks and Their Composite Components for Selective Extraction of Uranium Ions. AB - Selective extraction of uranium from water has attracted worldwide attention because the largest source of uranium is seawater with various interference ions (Na+ , K+ , Mg2+ , Ca2+ , etc.). However, traditional adsorbents encapsulate most of their functional sites in their dense structure, leading to problems with low selectivity and adsorption capacities. In this work, the tailor-made binding sites are first decorated into porous skeletons, and a series of molecularly imprinted porous aromatic frameworks are prepared for uranium extraction. Because the porous architecture provides numerous accessible sites, the resultant material has a fourfold increased ion capacity compared with traditional molecularly imprinted polymers and presents the highest selectivity among all reported uranium adsorbents. Moreover, the porous framework can be dispersed into commercial polymers to form composite components for the practical extraction of uranium ions from simulated seawater. PMID- 29423922 TI - Polymer-coated viral vectors: hybrid nanosystems for gene therapy. AB - The advantages and critical aspects of nanodimensional polymer-coated viral vector systems potentially applicable for gene delivery are reviewed. Various viral and nonviral vectors have been explored for gene therapy. Viral gene transfer methods, although highly efficient, are limited by their immunogenicity. Nonviral vectors have a lower transfection efficiency as a result of their inability to escape from the endosome. To overcome these drawbacks, novel nanotechnology-mediated interventions that involve the coating or modification of virus using polymers have emerged as a new paradigm in gene therapy. These alterations not only modify the tropism of the virus, but also reduce their undesirable interactions with the biological system. Also, co-encapsulation of other therapeutic agents in the polymeric coating may serve to augment the treatment efficacy. The viral particles can aid endosomal escape, as well as nuclear targeting, thereby enhancing the transfection efficiency. The integration of the desirable properties of both viral and nonviral vectors has been found beneficial for gene therapy by enhancing the transduction efficiency and minimizing the immune response. However, it is essential to ensure that these attempts should not compromise on the inherent ability of viruses to target and internalize into the cells and escape the endosomes. PMID- 29423921 TI - Vitamin C promotes oligodendrocytes generation and remyelination. AB - Oligodendrocyte-formed myelin sheaths play important roles in the neuronal functions in the central nervous system. In demyelinating diseases, such as Multiple Sclerosis, the myelin sheaths are damaged and the remyelinating process is somehow hindered. Restoration of the myelin sheaths requires the differentiation of the oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). To discover small molecule compounds that might promote the OPC to OL differentiation, a high-throughput screening system is established and L-ascorbyl-2-phosphate (As-2P), a stable form of Vitamin C (Vc), is found to greatly enhance the OPC to OL differentiation. As-2P promotes gradual expression of OL lineage markers, including O4, CNPase and MBP, in a dose- and time dependent manner. It also facilitates the formation of myelin sheaths in OPC neuron co-culture. As-2P also promotes the repair of the myelin sheaths in vivo and provides significant therapeutic effect in a cuprizone-mediated demyelination animal model. Interestingly, As-2P's function in promoting OPC differentiation is not related to its antioxidant activity. And an intracellular rather than an extracellular mechanism might be involved. Considering the safe use of Vc as a dietary supplement for many years, it might also be used as an alternative medicine for CNS demyelinating diseases. PMID- 29423923 TI - Stewardship opportunities in viral pneumonia: Why not the immunocompromised? AB - Antimicrobial management of viral pneumonia has proven to be a challenge in hospitalized immunocompromised patients. A host of factors contribute to the dilemma, such as diagnostic uncertainty, lack of organism identification, and clinical status of the patient. Respiratory virus panel (RVP) use was compared between 131 immunocompromised patients who received send-out (n = 56) vs in-house (n = 75) testing. Antimicrobial optimization interventions consisted of antiviral addition/discontinuation, antibiotic discontinuation/de-escalation, or modification of immunosuppressive regimen. After implementation of an in-house test with audit and feedback, turnaround time of the RVP was reduced from 46.7 to 5.5 hours (P < .001) and time to intervention was reduced from 52.1 to 13.9 hours (P < .001), yet the frequency of antimicrobial optimization interventions was unchanged (30.7% vs 35.7%). Differences were not observed in duration of empiric antibiotic therapy or length of stay. The overall discontinuation rate for patients tested with a RVP was low (4.6%), and those with positive RVP (n = 43) had antibiotics stopped in 14% of cases. Bacterial pneumonia coinfection was confirmed in 2 patients. Further systematic efforts should be taken to reduce antibiotic use in viral pneumonia and identify the major barriers in the immunocompromised population. PMID- 29423925 TI - Does public health system provide adequate financial risk protection to its clients? Out of pocket expenditure on inpatient care at secondary level public health institutions: Causes and determinants in an eastern Indian state. AB - : This study is undertaken to estimate the out of pocket expenditure (OOPE) for various diseases and its determinants at secondary level public health facilities in Odisha. METHODS: A cross-sectional survey was conducted among the inpatients utilising secondary level public health facilities in the 2 districts of Odisha. More than 80% of the inpatients were selected conveniently, and data on OOPE and socioeconomic status of patients were collected. The OOPE was estimated separately on surgery, nonsurgery, and child birth conditions. Ordinary least square regression models were developed to explain the factors determining OOPE. RESULTS: The mean OOPE for the secondary care facility was Indian National Rupee 3136.14, (95% CI: 2869.08-3403.19), of which, Indian National Rupee 1622.79 (95% CI: 1462.70-1782.89) was on medicine constituting 79% of total medical expenditure. The mean OOPE on surgery was highest followed by nonsurgery and child birth conditions. The OOPE is mainly influenced by caste and educational status of patients as revealed by the regression results. With increase in social status, the OOPE increases and the results are statistically significant. CONCLUSION: This evidence should be used to design financial strategies to reduce OOPE at secondary care public health facilities, which is largely due to medicine, diagnostic services, and transport expenditure. Efforts should be made to protect the interest of the poor, who utilise public health facility in a low resource setting in India. PMID- 29423924 TI - Timing of prenatal exposure to trauma and altered placental expressions of hypothalamic-pituitary-adrenal axis genes and genes driving neurodevelopment. AB - Prenatal maternal stress increases the risk for negative developmental outcomes in offspring; however, the underlying biological mechanisms remain largely unexplored. In the present study, alterations in placental gene expression associated with maternal stress were examined to clarify the potential underlying epi/genetic mechanisms. Expression levels of 40 selected genes involved in regulating foetal hypothalamic-pituitary-adrenal axis and neurodevelopment were profiled in placental tissues collected from a birth cohort established around the time of Superstorm Sandy. Objective prenatal traumatic stress was defined as whether mothers were exposed to Superstorm Sandy during pregnancy. Among the 275 mother-infant dyads, 181 dyads were delivered before Superstorm Sandy (ie, Control), 66 dyads were exposed to Superstorm Sandy during the first trimester (ie, Early Exposure) and 28 were exposed to Superstorm Sandy during the second or third trimester (ie, Mid-Late Exposure). Across all trimesters, expression of HSD11B2, MAOA, ZNF507 and DYRK1A was down-regulated among those exposed to Superstorm Sandy during pregnancy. Furthermore, trimester-specific differences were also observed: exposure during early gestation was associated with down regulation of HSD11B1 and MAOB and up-regulation of CRHBP; exposure during mid late gestation was associated with up-regulation of SRD5A3. The findings of the present study suggest that placental gene expression may be altered in response to traumatic stress exposure during pregnancy, and the susceptibility of these genes is dependent on the time of the exposure during pregnancy. Further studies should aim to clarify the biological mechanisms that underlie trimester-specific exposure by evaluating the differential impact on offspring neurodevelopment later in childhood. PMID- 29423926 TI - 3D Graphene Fibers Grown by Thermal Chemical Vapor Deposition. AB - 3D assembly of graphene sheets (GSs) is important for preserving the merits of the single-atomic-layered structure. Simultaneously, vertical growth of GSs has long been a challenge for thermal chemical vapor deposition (CVD). Here, vertical growth of the GSs is achieved in a thermal CVD reactor and a novel 3D graphene structure, 3D graphene fibers (3DGFs), is developed. The 3DGFs are prepared by carbonizing electrospun polyacrylonitrile fibers in NH3 and subsequently in situ growing the radially oriented GSs using thermal CVD. The GSs on the 3DGFs are densely arranged and interconnected with the edges fully exposed on the surface, resulting in high performances in multiple aspects such as electrical conductivity (3.4 * 104 -1.2 * 105 S m-1 ), electromagnetic shielding (60 932 dB cm2 g-1 ), and superhydrophobicity and superoleophilicity, which are far superior to the existing 3D graphene materials. With the extraordinary properties along with the easy scalability of the simple thermal CVD, the novel 3DGFs are highly promising for many applications such as high-strength and conducting composites, flexible conductors, electromagnetic shielding, energy storage, catalysis, and separation and purification. Furthermore, this strategy can be widely used to grow the vertical GSs on many other substrates by thermal CVD. PMID- 29423927 TI - Taxon sampling effects on the quantification and comparison of community phylogenetic diversity. AB - Ecologists are increasingly making use of molecular phylogenies, especially in the fields of community ecology and conservation. However, these phylogenies are often used without full appreciation of their underlying assumptions and uncertainties. A frequent practice in ecological studies is inferring a phylogeny with molecular data from taxa only within the community of interest. These "inferred community phylogenies" are inherently biased in their taxon sampling. Despite the importance of comprehensive sampling in constructing phylogenies, the implications of using inferred community phylogenies in ecological studies have not been examined. Here, we evaluate how taxon sampling affects the quantification and comparison of community phylogenetic diversity using both simulated and empirical data sets. We demonstrate that inferred community trees greatly underestimate phylogenetic diversity and that the probability of incorrectly ranking community diversity can reach up to 25%, depending on the dating methods employed. We argue that to reach reliable conclusions, ecological studies must improve their taxon sampling and generate the best phylogeny possible. PMID- 29423928 TI - Unexpected heterogeneity derived from Cas9 ribonucleoprotein-introduced clonal cells at the HPRT1 locus. AB - Single-cell cloning is an essential technique for establishing genome-edited cell clones mediated by programmable nucleases such as CRISPR-Cas9. However, residual genome-editing activity after single-cell cloning may cause heterogeneity in the clonal cells. Previous studies showed efficient mutagenesis and rapid degradation of CRISPR-Cas9 components in cultured cells by introducing Cas9 ribonucleoproteins (RNPs). In this study, we investigated how the timing for single-cell cloning of Cas9 RNP-transfected cells affected the heterogeneity of the resultant clones. We carried out transfection of Cas9 RNPs targeting several loci in the HPRT1 gene in HCT116 cells, followed by single-cell cloning at 24, 48, 72 hr and 1 week post-transfection. After approximately 3 weeks of incubation, the clonal cells were collected and genotyped by high-resolution microchip electrophoresis and Sanger sequencing. Unexpectedly, long-term incubation before single-cell cloning resulted in highly heterogeneous clones. We used a lipofection method for transfection, and the media containing transfectable RNPs were not removed before single-cell cloning. Therefore, the active Cas9 RNPs were considered to be continuously incorporated into cells during the precloning incubation. Our findings provide a warning that lipofection of Cas9 RNPs may cause continuous introduction of gene mutations depending on the experimental procedures. PMID- 29423929 TI - Introduction of an algorithm for planning of autologous fibular transfer in mandibular reconstruction based on individual bone curvatures. AB - BACKGROUND: Reconstruction of the mandible with autologous transplants is a challenging task and current computer-aided surgical planning remains cumbersome. Thus, the aim of the present study was to create an automated computational approach for this procedure. METHODS: The developed algorithm is based on curves following characteristic anatomical features. Geometrical data from a physiological mandible and a fibula were used to generate six different defects, and geometrical accordance was investigated to demonstrate the applicability of the method with different reconstruction parameters (n = 309). RESULTS: The method proved to be applicable, it recognized given clinical constraints and the values of accordance could be used to quantify the success of reconstructions. CONCLUSIONS: With the present approach, the complex three-dimensional task of mandibular reconstruction was simplified, and thus it allows implementation in clinical routine. The computational planning that is proposed may be used to design cutting guides or as geometrical input data for real-time navigated surgery. PMID- 29423930 TI - Saliva with reduced calcium and phosphorous concentrations: Effect on erosion dental lesions. AB - OBJECTIVES: To investigate whether saliva formulations with reduced calcium (Ca) and inorganic phosphorous (Pi) concentration would affect dental erosion caused by hydrochloric acid (HCl). METHODS: Enamel and root dentine bovine slabs were embedded, polished, and measured for surface Knoop microhardness (SMH). After reference areas were created, specimens were exposed to HCl solution (0.01 M; pH 2; 120 s) and immersed in artificial salivas (6 hr) containing three different Ca/Pi concentrations (n = 15), which simulate serum conditions of normo-, mild, or severe hypocalcemia. The control group was immersed in Ca/Pi-free saliva. The study protocol was carried out 2*/day for 5 days. Surface loss of enamel and root dentine was assessed using an optical profilometer, and SMH was remeasured for enamel. RESULTS: One-way analysis of variance (p < .001) and Tukey's test showed that enamel loss in groups subjected to artificial salivas that simulated mild or severe hypocalcemia did not differ from that resembling normocalcemia. %SMH was lower when saliva was mildly and normally concentrated in Ca/Pi (p < .001). Root dentine loss was higher in saliva simulating severe hypocalcemia than in those referring to mild, hypo-, and normocalcemia. CONCLUSIONS: Depending on the dental substrate, salivary formulations resembling serum hypocalcemia affected surface loss due to erosion and rehardening thereof. PMID- 29423931 TI - Electrogenerated Chemiluminescence Imaging of Electrocatalysis at a Single Au-Pt Janus Nanoparticle. AB - Noble metal nanoparticles are promising catalysts in electrochemical reactions, while understanding the relationship between the structure and reactivity of the particles is important to achieve higher efficiency of electrocatalysis, and promote the development of single-molecule electrochemistry. Electrogenerated chemiluminescence (ECL) was employed to image the catalytic oxidation of luminophore at single Au, Pt, and Au-Pt Janus nanoparticles. Compared to the monometal nanoparticles, the Janus particle structure exhibited enhanced ECL intensity and stability, indicating better catalytic efficiency. On the basis of the experimental results and digital simulation, it was concluded that a concentration difference arose at the asymmetric bimetallic interface according to different heterogeneous electron-transfer rate constants at Au and Pt. The fluid slip around the Janus particle enhanced local redox reactions and protected the particle surface from passivation. PMID- 29423932 TI - Protein translation, proteolysis and autophagy in human skeletal muscle atrophy after spinal cord injury. AB - AIM: Spinal cord injury-induced loss of skeletal muscle mass does not progress linearly. In humans, peak muscle loss occurs during the first 6 weeks postinjury, and gradually continues thereafter. The aim of this study was to delineate the regulatory events underlying skeletal muscle atrophy during the first year following spinal cord injury. METHODS: Key translational, autophagic and proteolytic proteins were analysed by immunoblotting of human vastus lateralis muscle obtained 1, 3 and 12 months following spinal cord injury. Age-matched able bodied control subjects were also studied. RESULTS: Several downstream targets of Akt signalling decreased after spinal cord injury in skeletal muscle, without changes in resting Akt Ser473 and Akt Thr308 phosphorylation or total Akt protein. Abundance of mTOR protein and mTOR Ser2448 phosphorylation, as well as FOXO1 Ser256 phosphorylation and FOXO3 protein, decreased in response to spinal cord injury, coincident with attenuated protein abundance of E3 ubiquitin ligases, MuRF1 and MAFbx. S6 protein and Ser235/236 phosphorylation, as well as 4E-BP1 Thr37/46 phosphorylation, increased transiently after spinal cord injury, indicating higher levels of protein translation early after injury. Protein abundance of LC3-I and LC3-II decreased 3 months postinjury as compared with 1 month postinjury, but not compared to able-bodied control subjects, indicating lower levels of autophagy. Proteins regulating proteasomal degradation were stably increased in response to spinal cord injury. CONCLUSION: Together, these data provide indirect evidence suggesting that protein translation and autophagy transiently increase, while whole proteolysis remains stably higher in skeletal muscle within the first year after spinal cord injury. PMID- 29423933 TI - Single-Nanoparticle Photoelectrochemistry at a Nanoparticulate TiO2 -Filmed Ultramicroelectrode. AB - An ultrasensitive photoelectrochemical method for achieving real-time detection of single nanoparticle collision events is presented. Using a micrometer-thick nanoparticulate TiO2 -filmed Au ultra-microelectrode (TiO2 @Au UME), a sub millisecond photocurrent transient was observed for an individual N719-tagged TiO2 (N719@TiO2 ) nanoparticle and is due to the instantaneous collision process. Owing to a trap-limited electron diffusion process as the rate-limiting step, a random three-dimensional diffusion model was developed to simulate electron transport dynamics in TiO2 film. The combination of theoretical simulation and high-resolution photocurrent measurement allow electron-transfer information of a single N719@TiO2 nanoparticle to be quantified at single-molecule accuracy and the electron diffusivity and the electron-collection efficiency of TiO2 @Au UME to be estimated. This method provides a test for studies of photoinduced electron transfer at the single-nanoparticle level. PMID- 29423935 TI - Corrigendum. PMID- 29423934 TI - Zoonotic disease transmission associated with feral cats in a metropolitan area: A geospatial analysis. AB - Feral cats raise public health concerns due to their large population numbers and ability to harbour pathogens that cause disease in people, pets, and wildlife. Information regarding the potential for feral cats to intersect with areas frequented by humans is lacking. This study examined the potential for feral cats and human territories to overlap in the Richmond metropolitan area of Central Virginia. Feral cats (n = 275) were trapped for monthly trap-neuter-release (TNR) clinics from July to November 2016. A geographic information system (GIS) was used to map feral cat trapping locations, elementary and preschools, public parks, and community gardens, and to evaluate the potential for cat interaction with these areas, presuming a maximum habitat radius of 0.44 miles. We found that 8.0% of feral cats in the Richmond metropolitan area had potential to range onto public elementary or preschool property, and 81.5% of feral cats trapped in Richmond City had potential to roam into one or more places of interest, including elementary and preschool grounds, public parks, and community gardens. This provides public health, veterinary, and human health professionals with important information that can be used to focus resources in an effort to reduce zoonosis associated with feral cat populations. PMID- 29423936 TI - Population pharmacokinetics of enoxaparin in early stage of paediatric liver transplantation. AB - AIMS: Preventing post-liver transplantation (LT) hepatic artery and portal vein thrombosis includes enoxaparin administration. Enoxaparin pharmacokinetics (PK) has not been investigated in children following LT. We described an enoxaparin PK model in 22 children the first week following LT. METHODS: Anti-Xa activity time courses were analysed using a nonlinear mixed effects approach with Monolix version 2016R. RESULTS: Anti-Xa activity time-courses were well described by a one-compartment model with first order absorption and elimination. Bodyweight prior to surgery (BWPREOP ) and the related postoperative variation (BW(t)) were the main covariates explaining CL and V between subject variabilities. Parameter estimates were CLi = CLTYP * (BWPREOP /70)3/4 ; Vi = VTYP * (BW(t)/70)1 ; where typical clearance (CLTYP ) and typical volume of distribution (VTYP ) were 1.23 l h-1 and 14.6 l, respectively. Standard dosing regimens of 50 IU kg-1 12 h-1 were insufficient to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 . Specifically, seven children (32%) never attained the target range during the whole period of treatment and all children were at least once underdosed. According to the final results, we simulated individualized dosing regimens within 4 h following the first administration. More than 100 IU kg-1 12 h-1 are suggested to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 from the first day. CONCLUSION: Thanks to this model, the initial and maintenance doses could be assessed to rapidly achieve the target range. Higher doses per kg, especially in the youngest children, are suggested. PMID- 29423937 TI - Mutually exclusive alternative splicing of pre-mRNAs. AB - Pre-mRNA alternative splicing is an important mechanism used to expand protein diversity in higher eukaryotes, and mutually exclusive splicing is a specific type of alternative splicing in which only one of the exons in a cluster is included in functional transcripts. The most extraordinary example of this is the Drosophila melanogaster Down's syndrome cell adhesion molecule gene (Dscam), which potentially encodes 38,016 different isoforms through mutually exclusive splicing. Mutually exclusive splicing is a unique and challenging model that can be used to elucidate the evolution, regulatory mechanism, and function of alternative splicing. The use of new approaches has not only greatly expanded the mutually exclusive exome, but has also enabled the systematic analyses of single cell alternative splicing during development. Furthermore, the identification of long-range RNA secondary structures provides a mechanistic framework for the regulation of mutually exclusive splicing (i.e., Dscam splicing). This article reviews recent insights into the identification, underlying mechanism, and roles of mutually exclusive splicing. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems. PMID- 29423938 TI - Effects of inspiratory muscle training in chronic heart failure patients: A systematic review and meta-analysis. AB - OBJECTIVE: The aim of this study was to evaluate the effects of inspiratory muscle training (IMT) in chronic heart failure (CHF) patients. DESIGN: We searched MEDLINE, EMBASE, Cochrane Library, CINHAL, and CBMdisc to collect controlled trials on the application of inspiratory muscle training in CHF patients from the establishment of these databases to November 2016. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data, and assessed the quality of literature. Meta analysis was conducted by software RevMan5.3. RESULTS: Eight studies involving 302 patients were identified. Meta-analysis indicated that IMT significantly improved PImax , VE /VCO2 slope and dyspnea (weighted mean difference [WMD] = 16.52, 95% CI: 13.87-19.17, P < .01; WMD = -5.78, 95% CI: -7.72 to -3.85, P < .01; SMD = -0.95, 95% CI: -1.5 to -0.39, P < .01), and descriptive results showed that long-term IMT (>=6 weeks) can improve the quality of life of CHF patients, and patients in IMT group also have a significant improvement in 6-minute walking distance test (6-MWD). CONCLUSION: IMT can improve pulmonary function, exercise tolerance, and quality of life of CHF patients and relieve the symptom of dyspnea. PMID- 29423939 TI - Human MAIT cells show metabolic quiescence with rapid glucose-dependent upregulation of granzyme B upon stimulation. AB - Mucosal-associated invariant T (MAIT) cells are a well-characterized innate-like T cell population abundant in the human liver, peripheral tissues and blood. MAIT cells serve in the first line of defense against infections, through engagement of their T cell receptor, which recognizes microbial metabolites presented on MR1, and through cytokine-mediated triggering. Typically, they show a quiescent memory phenotype but can undergo rapid upregulation of effector functions including cytolysis upon stimulation. T cells profoundly change their cellular metabolism during their maturation and activation. We sought to determine how MAIT cell metabolism may facilitate both the long-term memory phase in tissue and the transition to rapid effector function. Here, we show, by flow cytometric metabolism assays and extracellular flux analysis that, despite an effector memory profile, human MAIT cells are metabolically quiescent in a resting state comparable to naive and central memory T cells. Upon stimulation, they rapidly increase uptake of glucose and show a concomitant upregulation of the effector molecules notably granzyme B, which is impaired by inhibition of glycolysis with 2-deoxyglucose. These findings suggest that MAIT cells share some metabolic characteristics of both resting and effector T cell subsets, with a rapid transition upon triggering. Metabolic programming of this cell type may be of interest in understanding and modulating their function in infectious diseases and cancer. PMID- 29423940 TI - Superhierarchical Cobalt-Embedded Nitrogen-Doped Porous Carbon Nanosheets as Two in-One Hosts for High-Performance Lithium-Sulfur Batteries. AB - Lithium-sulfur (Li-S) batteries, based on the redox reaction between elemental sulfur and lithium metal, have attracted great interest because of their inherently high theoretical energy density. However, the severe polysulfide shuttle effect and sluggish reaction kinetics in sulfur cathodes, as well as dendrite growth in lithium-metal anodes are great obstacles for their practical application. Herein, a two-in-one approach with superhierarchical cobalt-embedded nitrogen-doped porous carbon nanosheets (Co/N-PCNSs) as stable hosts for both elemental sulfur and metallic lithium to improve their performance simultaneously is reported. Experimental and theoretical results reveal that stable Co nanoparticles, elaborately encapsulated by N-doped graphitic carbon, can work synergistically with N heteroatoms to reserve the soluble polysulfides and promote the redox reaction kinetics of sulfur cathodes. Moreover, the high surface-area pore structure and the Co-enhanced lithiophilic N heteroatoms in Co/N-PCNSs can regulate metallic lithium plating and successfully suppress lithium dendrite growth in the anodes. As a result, a full lithium-sulfur cell constructed with Co/N-PCNSs as two-in-one hosts demonstrates excellent capacity retention with stable Coulombic efficiency. PMID- 29423941 TI - Is health care infected by Baumol's cost disease? Test of a new model. AB - Rising health care costs are a policy concern across the Organisation for Economic Co-operation and Development, and relatively little consensus exists concerning their causes. One explanation that has received revived attention is Baumol's cost disease (BCD). However, developing a theoretically appropriate test of BCD has been a challenge. In this paper, we construct a 2-sector model firmly based on Baumol's axioms. We then derive several testable propositions. In particular, the model predicts that (a) the share of total labor employed in the health care sector and (b) the relative price index of the health and non-health care sectors should both be positively related to economy-wide productivity. The model also predicts that (c) the share of labor in the health sector will be negatively related and (d) the ratio of prices in the health and non-health sectors unrelated, to the demand for non-health services. Using annual data from 28 Organisation for Economic Co-operation and Development countries over the years 1995-2016 and from 14 U.S. industry groups over the years 1947-2015, we find little evidence to support the predictions of BCD once we address spurious correlation due to coincident trending and other econometric issues. PMID- 29423942 TI - Erythema elevatum diutinum-like vasculitis secondary to cocaine adulterated with levamisole. PMID- 29423944 TI - Impact of Mon2 monocyte-platelet aggregates on human coronary artery disease. AB - BACKGROUND: Monocyte-platelet aggregates (MPAs) form when Mon1, Mon2 or Mon3 monocyte subsets adhere to platelets. They are pathophysiologically linked to coronary artery disease (CAD). However, their individual roles in the occurrence of diffuse CAD remain unknown. MATERIALS AND METHODS: Peripheral blood from 50 patients with diffuse CAD, 40 patients with focal CAD and 50 age-matched patients with normal coronary arteries was analysed by flow cytometry to quantify MPAs associated with individual monocyte subsets. Cutaneous forearm microcirculation was assessed using laser Doppler flowmetry at rest and after iontophoresis of acetylcholine (endothelium-dependent vasodilation) and sodium nitroprusside (endothelium-independent vasodilation) at 100 MUA for 60 seconds. Patients with CAD had repeat assessment at 6 and 12 months. RESULTS: Baseline counts of MPAs with Mon2 subset (CD14++CD16+CC2+ monocytes) were significantly higher in patients with diffuse CAD compared to focal CAD (P = .001) and patients without CAD (P = .006). On multivariate regression, MPAs with Mon2 independently predicted diffuse CAD (odds ratio 1.10, 95% confidence interval 1.02-1.19, P = .01) and correlated negatively with endothelium-dependent microvascular vasodilation (r = -.37, P = .008), an association which persisted after adjustment for covariates. Longitudinal observation confirmed the persistence of an inverse relationship between MPAs with Mon2 and endothelium-dependent microvascular function. CONCLUSION: Monocyte-platelet aggregates with Mon2 are increased in patients with diffuse CAD and therefore could represent an important contributor to accelerated coronary atherosclerotic progression by a mechanism involving microvascular endothelial dysfunction. PMID- 29423943 TI - Effect of body condition score and reuse of progesterone-releasing intravaginal devices on conception rate following timed artificial insemination in Nelore cows. AB - This study had the aim of investigating the efficiency of timed artificial insemination (TAI) through the progesterone-releasing intravaginal device (PRID), used in new condition and for the second and third times in Nelore cows. The effects of device reuse and body condition score (BCS) on the conception rate (CR) were evaluated in 1,122 multiparous Nelore cows (mean BCS of 2.7 +/- 0.4), which were randomly distributed into three groups that received new (n = 330), once (n = 439) and twice used (n = 353) PRID. Among the 1,122 females that underwent TAI, 573 became pregnant, thus representing an overall CR of 51.06%. Cows with BCS between 2.75 and 4.0 had greater (p < .0001) CR (69.75%) than cows with BSC of 2.0-2.5 (32.98%). It was observed that the CR through using PRID was 60.00%, 51.71% and 41.93% for new, once and twice used PRID, respectively, with difference between all groups (p < .0001). Under tropical conditions, animals with BCS greater than 2.5 had a higher CR, and the CR decreased proportionally with the number of times that the PRID had been used. PMID- 29423945 TI - Skeletal growth, body composition, and metabolic risk among North Sudanese immigrant children. AB - OBJECTIVES: Children of immigrants and refugees from developing countries are at risk for poor growth that could contribute to adult chronic disease. This study describes the physical growth, bone growth, body composition, metabolic risks, physical activity, and food security of Sudanese children living in the United States. DESIGN AND SAMPLE: Cross-sectional descriptive study of 64 Sudanese children age 5-18. MEASURES: Bone mineral content (BMC), bone density (aBMD), and body composition (fat, lean mass, percent body fat) were measured using DXA. Lipids, insulin, glucose, and hs-CRP were analyzed using standardized laboratory methods. Food security was assessed with the U.S. Household Food Security Survey. Physical activity was measured through self-report questionnaire and pedometers. RESULTS: About 1/3 of children had low BMC and aBMD. Lean mass was low in 46%, and 32% were obese. Cholesterol, triglycerides, and HOMA-IR were elevated in 23.4%, 32.8%, and 15.6% of children, respectively; only 22% of children were physically active and 40% experienced food insecurity. CONCLUSION: Sudanese children may have unique risks related to low bone mass low muscle mass, high percent body fat metabolic biomarkers, inactivity, and food insecurity potentially contributing to adult osteoporosis, diabetes, and cardiovascular disease. PMID- 29423946 TI - Is stiffness related to athletic groin pain? AB - Athletic groin pain (AGP) is a common injury prevalent in field sports. One biomechanical measure that may be of importance for injury risk is stiffness. To date however, stiffness has not been examined in AGP. The primary aim was to determine whether AGP affects vertical and joint stiffness and if so, whether successful rehabilitation is associated with a change in stiffness. Sixty-five male patients with AGP and fifty male controls were recruited to this study. Assessment included a biomechanical examination of stiffness during a lateral hurdle hop test. Subjects with AGP were tested pre- and post-rehabilitation, while controls were tested once. AGP subjects were cleared for return to play in a median time of 9.14 weeks (5.14-29.0). Stiffness was significantly different at pre-rehabilitation in comparison with controls for four of the ten stiffness values examined: ankle plantar flexor, knee extensor, hip abductor, and vertical stiffness (P < .05, D = 0.36-0.79). Despite clearance for return to play, of these four variables, only hip abductor stiffness changed significantly from pre- to post-rehabilitation (P = .05, D = 0.35) to become non-significantly different to the uninjured group (P = .18, D = 0.26). These findings suggest that hip abductor stiffness may represent a target for AGP rehabilitation. Conversely, given the clearance for return to play, the lower sagittal plane and vertical stiffness in the AGP group in comparison with the uninjured controls likely represents either a compensatory mechanism to reduce the risk of further injury or a consequence of neuromuscular detraining. PMID- 29423947 TI - The effects of a CCR3 inhibitor, AXP1275, on allergen-induced airway responses in adults with mild-to-moderate atopic asthma. AB - BACKGROUND: CCR3 is the cognate receptor for major human eosinophil chemoattractants from the eotaxin family of proteins that are elevated in asthma and correlate with disease severity. OBJECTIVE: This proof-of-mechanism study examined the effect of AXP1275, an oral, small-molecule inhibitor of CCR3, on airway responses to inhaled allergen challenge. METHODS: Twenty-one subjects with mild atopic asthma and documented early and late asthmatic responses to an inhaled aeroallergen completed a randomized double-blind cross-over study to compare early and late allergen-induced asthmatic responses, methacholine PC20 , blood and sputum eosinophils and exhaled nitric oxide after 2 weeks of treatment with once-daily doses of AXP1275 (50 mg) or placebo. RESULTS: There was a significant increase in methacholine PC20 after 12 days of AXP1275 treatment compared to placebo (increase of 0.92 doubling doses versus 0.17 doubling doses, P = .01), but this protection was lost post-allergen challenge. There was no effect of AXP1275 on allergen-induced late asthmatic responses, or eosinophils in blood and sputum. The early asthmatic response and exhaled nitric oxide levels were slightly lower with AXP1275, but this did not reach statistical significance. The number of subjects who experienced treatment-emergent adverse events while receiving AXP1275 was comparable placebo. CONCLUSIONS & CLINICAL RELEVANCE: AXP1275 50 mg administered daily was safe and well tolerated, and there was no difference in the type, severity or frequency of treatment-emergent adverse events in subjects while receiving AXP1275 compared to placebo. AXP1275 increased the methacholine PC20 ; however, the low and variable exposure to APX1275 over a short treatment period may have contributed to poor efficacy on other outcomes. PMID- 29423948 TI - Age-related changes to the effects of electroconvulsive therapy in an elderly patient: a case report. PMID- 29423950 TI - Guideline-Directed Medical Therapy and Survival Following Hospitalization in Patients with Heart Failure. AB - BACKGROUND: Modification of guideline-directed medical therapy (GDMT) in hospitalized patients with heart failure (HF) has not been extensively evaluated. METHODS: The community surveillance arm of the Atherosclerosis Risk in Communities Study identified 6959 HF hospitalizations from 2005-2011. Predictors of GDMT modification and survival were assessed using multivariable logistic regression and Cox proportional hazards models. RESULTS: For 5091 hospitalizations, patient mean age was 75 years, 53% were female, 69% were white, and 81% had acute decompensated heart failure (ADHF). Regarding ejection fraction (EF), 31% of patients had HF with reduced EF (HFrEF), 24% had HF with preserved EF (HFpEF), and 44% were missing EF values. At admission, 52% of patients received angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), 66% beta-blockers (BBs), 9% aldosterone-receptor antagonists, 16% digoxin, 10% hydralazine, and 29% nitrates. Modification of GDMT occurred in up to 23% of hospitalizations. Significant predictors of GDMT initiation included ADHF and HFrEF; discontinuation of medications was observed with select comorbidities. In HFrEF, initiation of any GDMT was associated with reduced 1 year all-cause mortality (adjusted hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.23-0.71) as was initiation of ACEI/ARBs, BBs, and digoxin. Discontinuation of any therapy versus maintaining GDMT was associated with greater mortality (HR 1.30, 95% CI 1.02-1.66). Similar trends were observed in HFpEF. CONCLUSIONS: Our study suggests that GDMT initiation is associated with increased survival, and discontinuation of therapy is associated with reduced survival in hospitalized patients with HF. Future studies should be conducted to confirm the impact of GDMT therapy modification in this population. PMID- 29423951 TI - Early CALP2 expression and microglial activation are potential inducers of spinal IL-6 up-regulation and bilateral pain following motor nerve injury. AB - Previous work from our laboratory showed that motor nerve injury by lumbar 5 ventral root transection (L5-VRT) led to interleukin-6 (IL-6) over-expression in bilateral spinal cord, and that intrathecal administration of IL-6 neutralizing antibody delayed the induction of mechanical allodynia in bilateral hind paws. However, early events and upstream mechanisms underlying spinal IL-6 expression following L5-VRT require elucidation. The model of L5-VRT was used to induce neuropathic pain, which was assessed with von Frey hairs and the plantar tester in adult male Sprague-Dawley rats. Calpain-2 (CALP2, a calcium-dependent protease) knockdown or over-expression and microglia depletion were conducted intrathecally. Western blots and immunohistochemistry were performed to explore the possible mechanisms. Here, we provide the first evidence that both IL-6 and CALP2 levels are increased in lumbar spinal cord within 30 min following L5-VRT. IL-6 and CALP2 co-localized in both spinal dorsal horn (SDH) and spinal ventral horn. Post-operative (PO) increase in CALP2 in ipsilateral SDH was evident at 10 min PO, preceding increased IL-6 at 20 min PO. Knockdown of spinal CALP2 by intrathecal CALP2-shRNA administration prevented VRT-induced IL-6 overproduction in ipsilateral spinal cord and alleviated bilateral mechanical allodynia. Spinal microglia activation also played a role in early IL-6 up-regulation. Macrophage/microglia markers ED1/Iba1 were increased at 30 min PO, while glial fibrillary acidic protein (astrocyte) and CNPase (oligodendrocyte) markers were not. Increased Iba1 was detected as early as 20 min PO and peaked at 3 days. Morphology changed from a small soma with fine processes in resting cells to an activated ameboid shape. Depletion of microglia using Mac-1-saporin partially prevented IL-6 up-regulation and attenuated VRT-induced bilateral mechanical allodynia. Taken together, our findings provide evidence that increased spinal cord CALP2 and microglia cell activation may have early causative roles in IL-6 over-expression following motor nerve injury. Agents that inhibit CALP2 and/or microglia activation may therefore prove valuable for treating neuropathic pain. PMID- 29423949 TI - Genetic diversity of equine herpesvirus 1 isolated from neurological, abortigenic and respiratory disease outbreaks. AB - Equine herpesvirus 1 (EHV-1) causes respiratory disease, abortion, neonatal death and neurological disease in equines and is endemic in most countries. The viral factors that influence EHV-1 disease severity are poorly understood, and this has hampered vaccine development. However, the N752D substitution in the viral DNA polymerase catalytic subunit has been shown statistically to be associated with neurological disease. This has given rise to the term "neuropathic strain," even though strains lacking the polymorphism have been recovered from cases of neurological disease. To broaden understanding of EHV-1 diversity in the field, 78 EHV-1 strains isolated over a period of 35 years were sequenced. The great majority of isolates originated from the United Kingdom and included in the collection were low passage isolates from respiratory, abortigenic and neurological outbreaks. Phylogenetic analysis of regions spanning 80% of the genome showed that up to 13 viral clades have been circulating in the United Kingdom and that most of these are continuing to circulate. Abortion isolates grouped into nine clades, and neurological isolates grouped into five. Most neurological isolates had the N752D substitution, whereas most abortion isolates did not, although three of the neurological isolates from linked outbreaks had a different polymorphism. Finally, bioinformatic analysis suggested that recombination has occurred between EHV-1 clades, between EHV-1 and equine herpesvirus 4, and between EHV-1 and equine herpesvirus 8. PMID- 29423952 TI - A splice site variant in the SUV39H2 gene in Greyhounds with nasal parakeratosis. AB - Hereditary nasal parakeratosis (HNPK), described in the Labrador Retriever breed, is a monogenic autosomal recessive disorder that causes crusts and fissures on the nasal planum of otherwise healthy dogs. Our group previously showed that this genodermatosis may be caused by a missense variant located in the SUV39H2 gene encoding a histone 3 lysine 9 methyltransferase, a chromatin modifying enzyme with a potential role in keratinocyte differentiation. In the present study, we investigated a litter of Greyhounds in which six out of eight puppies were affected with parakeratotic lesions restricted to the nasal planum. Clinically and histologically, the lesions were comparable to HNPK in Labrador Retrievers. Whole genome sequencing of one affected Greyhound revealed a 4-bp deletion at the 5'-end of intron 4 of the SUV39H2 gene that was absent in 188 control dog and three wolf genomes. The variant was predicted to disrupt the 5'-splice site with subsequent loss of SUV39H2 function. The six affected puppies were homozygous for the variant, whereas the two non-affected littermates were heterozygous. Genotyping of a larger cohort of Greyhounds revealed that the variant is segregating in the breed and that this breed might benefit from genetic testing to avoid carrier * carrier matings. PMID- 29423953 TI - Does Intravenous Infusion Influence Diagnostic Ultrasound-Induced Pulmonary Capillary Hemorrhage? AB - OBJECTIVES: Pulmonary diagnostic ultrasound (US) can induce pulmonary capillary hemorrhage (PCH) in mammals. This singular biological effect of diagnostic US imaging was discovered more than 25 years ago but remains poorly understood. Our objective here was to investigate rapid infusion of intravenous fluids as a possible stressor for capillaries, which might enhance pulmonary diagnostic US induced PCH. METHODS: Rats were anesthetized with Telazol (Zoetis, Inc, Kalamazoo, MI), which yielded relatively low pulmonary diagnostic US-induced PCH, or Telazol and xylazine, which yielded relatively high pulmonary diagnostic US induced PCH. Groups of rats were not infused or infused either with normal saline, 10% mannitol, or 5% albumin. Rats were scanned in a warmed water bath with B-mode US for 5 minutes with a 7.6-MHz linear array set to different mechanical index values to obtain exposure response information. Pulmonary capillary hemorrhage was observed as comet tail artifacts in the image and measured on the lung surface. RESULTS: For Telazol anesthesia, all of the PCH results were very low, with no significant differences at the maximum output with an in situ peak rarefactional pressure amplitude of 2.1 MPa (on-screen mechanical index, 0.9). The addition of xylazine to the Telazol anesthetic significantly enhanced the PCH (P < .001) without infusion and likewise for the mannitol and albumin infusion. Saline infusion eliminated this enhancement, with significantly reduced PCH for Telazol-plus-xylazine anesthesia (P < .001); however, both mannitol and albumin infusion resulted in significantly more PCH than saline infusion (P < .01). CONCLUSIONS: These results show PCH dependence on the specific intravenous infusion fluid and illustrate the complex importance of physiologic parameters for US-induced PCH. PMID- 29423954 TI - An analytic approach for interpretable predictive models in high-dimensional data in the presence of interactions with exposures. AB - Predicting a phenotype and understanding which variables improve that prediction are two very challenging and overlapping problems in the analysis of high dimensional (HD) data such as those arising from genomic and brain imaging studies. It is often believed that the number of truly important predictors is small relative to the total number of variables, making computational approaches to variable selection and dimension reduction extremely important. To reduce dimensionality, commonly used two-step methods first cluster the data in some way, and build models using cluster summaries to predict the phenotype. It is known that important exposure variables can alter correlation patterns between clusters of HD variables, that is, alter network properties of the variables. However, it is not well understood whether such altered clustering is informative in prediction. Here, assuming there is a binary exposure with such network altering effects, we explore whether the use of exposure-dependent clustering relationships in dimension reduction can improve predictive modeling in a two step framework. Hence, we propose a modeling framework called ECLUST to test this hypothesis, and evaluate its performance through extensive simulations. With ECLUST, we found improved prediction and variable selection performance compared to methods that do not consider the environment in the clustering step, or to methods that use the original data as features. We further illustrate this modeling framework through the analysis of three data sets from very different fields, each with HD data, a binary exposure, and a phenotype of interest. Our method is available in the eclust CRAN package. PMID- 29423955 TI - New and emerging techniques for endoscopic treatment of Zenker's diverticulum: State-of-the-art review. AB - Zenker's diverticulum (ZD), or pharyngeal pouch, is an anatomical defect characterized by herniation of the posterior pharyngeal wall through Killian's dehiscence, and may result in dysphagia and regurgitation. Multiple therapeutic modalities including surgery, rigid and flexible endoscopy have been developed to manage ZD. Although surgical management with open and endoscopically assisted techniques have historically been the mainstay of ZD treatment, minimally invasive flexible endoscopic techniques, carried out under conscious sedation, are increasingly favored. Over the last two decades, the advent of new accessories and techniques have changed the landscape of endotherapy for ZD, with the current armamentarium including, but not limited to, endoscopic stapling, CO2 laser, argon plasma coagulation, needle knife, bipolar forceps, hook knife, clutch cutter, stag beetle knife, and submucosal tunneling endoscopic septum division. We hereby review the latest evidence to support the endoscopic management of ZD. PMID- 29423956 TI - Efficacy and safety of sarolaner against generalized demodicosis in dogs in European countries: a non-inferiority study. AB - BACKGROUND: Treatment of canine demodicosis can be challenging; new treatments are always being sought. OBJECTIVE: The efficacy of sarolaner was evaluated in comparison with a moxidectin/imidacloprid topical product against generalized demodicosis in dogs in a randomized, single-masked, multi-centre field study. ANIMALS: Client-owned dogs were treated monthly with oral sarolaner (n = 53) or with weekly/monthly topical moxidectin/imidacloprid (n = 28). METHODS: Mites were counted monthly in deep skin scrapings and the severity of skin lesions was evaluated. Dogs completed the study when no live mites were found on two consecutive monthly skin scrapings or on day 180 at the latest (study end). RESULTS: Parasitological cure, defined as the first time that no live mites were found in the skin scrapings, was achieved in 92.9% and 100% of the dogs after three and no more than five monthly treatments with sarolaner (respectively). In the moxidectin/imidacloprid group, 77.3% and 91.7% of the dogs were cured after three and six months, respectively. Parasitological cure rate for sarolaner was non-inferior to moxidectin/imidacloprid on day 60. Mite counts were reduced by 77.2%, 95.0%, 98.5%, 99.0%, 100% and 100% in the sarolaner group and by 68.0%, 88.4%, 91.1%, 92.7%, 73.9% and 82.2% in the moxidectin/imidacloprid group, on days 30, 60, 90, 120, 150 and 180, respectively, compared to pre-treatment counts. The skin lesions improved throughout the study; the total affected body surface decreased by 94% in the sarolaner and by 72% in the moxidectin/imidacloprid group. There were no treatment-related adverse events. CONCLUSIONS: Monthly oral administration of sarolaner was safe and highly effective in the treatment of generalized demodicosis in dogs. PMID- 29423957 TI - Sterculia and Brachychiton: a comprehensive overview on their ethnopharmacology, biological activities, phytochemistry and the role of their gummy exudates in drug delivery. AB - OBJECTIVES: Sterculia and Brachychiton are two related genera (Malvaceae) containing more than 300 species. Most of these species are ornamental trees that are native to Australia and widely cultivated in many countries. Different members of the two genera were used by various cultures for medicinal and economical purposes. This review sheds light on the medicinal values and chemical composition of various species of these two genera. KEY FINDINGS: Sterculia and Brachychiton species were used traditionally for the treatment of gastrointestinal disorders, microbial infection, skin diseases, inflammation and many other conditions. The seeds of various species were roasted and eaten by many traditional tribes. Plants from the two genera revealed their anti inflammatory, antioxidant, antimicrobial, antidiabetic, antiulcer, insecticidal and analgesic activity. These activities may be attributed to the presence of a wide range of secondary metabolites as flavonoids, phenolic acids, coumarins, terpenoids particularly sesquiterpenes and triterpenes in addition to sterols and fatty acids. Moreover, the gummy exudates obtained from some members of these genera played an important role in different pharmaceutical dosage forms and drug delivery systems. CONCLUSIONS: More research is recommended on other species of Sterculia and Brachychiton to discover new molecular entities with potential biological and economic values. PMID- 29423958 TI - Differences in the Temporal Typology of Alcohol Hangover. AB - BACKGROUND: At a group level, hangover severity during the day has been described to follow an inverted U-shaped curve, with gradually increasing severity scores that, after reaching a peak, gradually decrease toward zero. The aim of this study was to examine if and how individual drinkers' hangover severity scores vary during the day. METHODS: Data from a survey (Penning et al., ) in which 727 drinkers reported on their latest alcohol hangover were reanalyzed. The temporal pattern of each individual's hangover was first categorized as belonging to 1 of 6 types based on predefined temporal characteristics. RESULTS: Three dominant hangover patterns emerged as comprising more than 95% of the sample: (i) a continuous decline hangover (Severity Type 1 hangover, 54.5%), (ii) a steady state hangover (Severity Type 2 hangover, 19.1%), and (iii) an inverted U-shaped curve hangover (Severity Type 3 hangover, 21.8%). Of these 3 patterns, Severity Type 2 hangovers are associated with significantly less alcohol consumption and with having the lowest severity scores of individual hangover symptoms. Severity Type 1 hangovers are associated with having the highest severity of individual hangover symptoms. In line with significantly lower levels of alcohol consumption, Severity Type 2 hangovers were significantly more often observed in women when compared to men. Severity Type 1 hangovers were significantly more common in men than in women. Severity Type 3 hangovers, characterized by the increased presence of gastrointestinal complaints, were equally commonly experienced in men and women. CONCLUSIONS: This study revealed that the temporal pattern of hangover severity can follow marked interindividual variability. Three common temporal patterns were identified, which are uniquely related to the amount of alcohol consumed and the presence and severity of different individual hangover symptoms. Better understanding of individual differences in hangover typology may help to delineate mechanisms underlying alcohol hangover. PMID- 29423960 TI - Le hazard ou la necessite? Comorbid pathologies of neurodegenerative diseases. PMID- 29423959 TI - Low resilience to stress is associated with candidate gene expression alterations in the dopaminergic signalling pathway. AB - BACKGROUND: In stressful situations, a person's ability to appropriately complete tasks with minimal anxiety is known as stress resilience. Genetic variants in neuropeptide Y, Corticotropin releasing hormone receptor 1 (CRHR1), and serotonin transporter have been previously reported to be associated with low resilience, but the relationship between low resilience and the dopaminergic signalling pathway is not well understood. Here, we aimed to describe the association between comprehensive psychological characteristics and messenger RNA levels of dopamine receptor D1 (DRD1), dopamine receptor D2 (DRD2), dopamine receptor D3 (DRD3), dopamine receptor D4 (DRD4), dopamine receptor D5 (DRD5), COMT, Dopamine Beta-Hydroxylase (DBH), Tyrosine hydroxylase (TH), monoamine oxidase A (MAOM), dopa decarboxylase (DDC), dopamine transporter (DAT), serotonin transporter (5 HTT), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) genes based on peripheral blood samples from 400 subjects who react differently to major life event stressors. The blood samples were analyzed by quantitative real-time polymerase chain reaction. METHODS: Four hundred Iranian individuals (age range: 17-42 years) were selected from 18 of Iran's 31 provinces. They were divided into four groups: (i) group A, persons with normal reactions to major life-event stressors; (ii) group B, persons with acute stress reactions to major life-event stressors; (iii) group C, persons with normal reactions to crises/catastrophes; and (iv) group D, persons with acute stress reactions to crises/catastrophes. Individuals were divided into groups by a senior psychiatrist based on an unstructured interview, the 21-item Depression Anxiety Stress Scale, and Connor-Davidson Resilience Scale. RESULTS: We found that the upregulation of DRD1, DRD2, DRD3, DRD4, DBH, DAT, and BDNF and the downregulation of serotonin transporter, monoamine oxidase A, and COMT are associated with stress resilience, which is modulated by dopaminergic and serotonergic pathways. CONCLUSIONS: Gene expression variations were not only correlated with stress resilience, but they were also associated with other psychological parameters including personality, depression, anxiety, and intelligence. PMID- 29423961 TI - Pruritic arthropod bite-like papules in T-cell large granular lymphocytic leukaemia and chronic myelomonocytic leukaemia. AB - T-cell large granular lymphocytic leukaemia (T-LGLL) is a clinically indolent mature T-cell neoplasm characterized by a monoclonal population of CD3+ CD8+ cytotoxic T cells, which usually presents as neutropenia, anaemia and thrombocytopenia. Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic disorder with features of both a myeloproliferative neoplasm and myelodysplastic syndrome (MDS). Patients with CMML exhibit a persistent peripheral blood monocytosis in addition to myelodysplastic features. Because of the rarity of T-LGLL, its cutaneous manifestations are poorly documented, but include vasculitis, vasculopathy, persistent ulcerations, generalized pruritus and disseminated granuloma annulare. Various types of skin lesions have been observed in patients with CMML and reportedly occur in approximately 10% of cases. We report the extraordinary case of a patient with MDS who developed T LGLL, and subsequently the MDS progressed to CMML. The patient then developed diffuse arthropod bite-like papules and intractable pruritus. PMID- 29423962 TI - Systemic allergic contact dermatitis associated with topical diltiazem and/or cinchocaine. PMID- 29423963 TI - The omega-transaminase engineering database (oTAED): A navigation tool in protein sequence and structure space. AB - The omega-Transaminase Engineering Database (oTAED) was established as a publicly accessible resource on sequences and structures of the biotechnologically relevant omega-transaminases (omega-TAs) from Fold types I and IV. The oTAED integrates sequence and structure data, provides a classification based on fold type and sequence similarity, and applies a standard numbering scheme to identify equivalent positions in homologous proteins. The oTAED includes 67 210 proteins (114 655 sequences) which are divided into 169 homologous families based on global sequence similarity. The 44 and 39 highly conserved positions which were identified in Fold type I and IV, respectively, include the known catalytic residues and a large fraction of glycines and prolines in loop regions, which might have a role in protein folding and stability. However, for most of the conserved positions the function is still unknown. Literature information on positions that mediate substrate specificity and stereoselectivity was systematically examined. The standard numbering schemes revealed that many positions which have been described in different enzymes are structurally equivalent. For some positions, multiple functional roles have been suggested based on experimental data in different enzymes. The proposed standard numbering schemes for Fold type I and IV omega-TAs assist with analysis of literature data, facilitate annotation of omega-TAs, support prediction of promising mutation sites, and enable navigation in omega-TA sequence space. Thus, it is a useful tool for enzyme engineering and the selection of novel omega-TA candidates with desired biochemical properties. PMID- 29423964 TI - Atomically Dispersed Transition Metals on Carbon Nanotubes with Ultrahigh Loading for Selective Electrochemical Carbon Dioxide Reduction. AB - Single-atom catalysts (SACs) are the smallest entities for catalytic reactions with projected high atomic efficiency, superior activity, and selectivity; however, practical applications of SACs suffer from a very low metal loading of 1 2 wt%. Here, a class of SACs based on atomically dispersed transition metals on nitrogen-doped carbon nanotubes (MSA-N-CNTs, where M = Ni, Co, NiCo, CoFe, and NiPt) is synthesized with an extraordinarily high metal loading, e.g., 20 wt% in the case of NiSA-N-CNTs, using a new multistep pyrolysis process. Among these materials, NiSA-N-CNTs show an excellent selectivity and activity for the electrochemical reduction of CO2 to CO, achieving a turnover frequency (TOF) of 11.7 s-1 at -0.55 V (vs reversible hydrogen electrode (RHE)), two orders of magnitude higher than Ni nanoparticles supported on CNTs. PMID- 29423965 TI - An integrative review exploring the perceptions of patients and healthcare professionals towards patient involvement in promoting hand hygiene compliance in the hospital setting. AB - AIMS AND OBJECTIVES: To review patients' and healthcare professionals' perceptions of patient involvement in promoting hand hygiene compliance in the hospital setting. BACKGROUND: Initiatives continue to emphasise the importance of involving patients in their safety at the point of care. A patient-centred care approach aimed to empower patients to become active members of the healthcare team. However, understanding the perceptions of patients and healthcare professionals of patient involvement in promoting hand hygiene compliance among healthcare professionals has yet to be fully explored. DESIGN: Integrative literature review. METHODS: A five-stage review process informed by Whittemore and Knafl's methodology was conducted. MEDLINE and CINAHL were searched for papers published between January 2009-July 2017. Data were extracted manually, organised using NVivo 11 and analysed using thematic analysis. RESULTS: From an identified 240 papers, 19 papers were included in this review. Thematic analysis revealed two main themes with three related subthemes. Patients were willing to remind healthcare professionals (especially nurses) to wash their hands, healthcare professionals perception towards patients' involvement varied from one study to another. However, an overall positive attitude towards patient involvement was related to how patients asked and how healthcare professionals responded to being asked. CONCLUSION: There is limited evidence regarding patients' actual intention to ask healthcare professionals to wash their hands, and some evidence that patients are reluctant to do so. Further research is required to understand this area thoroughly, including which situations patients would feel more empowered to speak up. RELEVANCE TO CLINICAL PRACTICE: Simple messages promoting patient involvement may lead to complex reactions in both patients and healthcare professionals. It is unclear, yet how patients and staff react to such messages in clinical practice. There is a need for a deeper understanding of how they can work together to support harm free care. PMID- 29423966 TI - International investigation of neurocognitive and behavioral phenotype in 47,XXY (Klinefelter syndrome): Predicting individual differences. AB - 47,XXY (KS) occurs in 1:650 male births, though less than 25% are ever identified. We assessed stability of neurocognitive features across diverse populations and quantified factors mediating outcome. Forty-four boys from the Netherlands (NL) and 54 boys from the United States (US) participated. The Wechsler Intelligence Scales assessed intellectual functioning; the ANT program evaluated cognitive function; and the CBCL assessed behavioral functioning. ANOVA was used for group comparisons. Hierarchical regressions assessed variance explained by each independent variable: parental education, timing of diagnosis, testosterone, age, and nationality. Parental education, timing of diagnosis, and hormonal treatment all played an important role in neurocognitive performance. The observed higher IQ and better attention regulation in the US group as compared to the NL group was observed with decreased levels of behavioral problems in the US group. Cognitive measures that were different between the NL and US groups, i.e., attention regulation and IQ scores, were also significantly influenced by external factors including timing of diagnosis, testosterone treatment, and parental education. On the ANT, a cognitive phenotype of 47,XXY was observed, with similar scores on 9 out of the 10 ANT subtests for the NL and US groups. This study lays additional features to the foundation for an algorithm linking external variables to outcome on various neurodevelopmental measures. PMID- 29423968 TI - Expanding the Breadth of 4-Amino-1,8-naphthalimide Photophysical Properties through Substitution of the Naphthalimide Core. AB - Fluorescent sensors that illuminate specific molecules and chemical events allow the selective and sensitive study of the cellular environment. At the centre of this technology lies the fluorescent reporter molecule, and it is therefore crucial to provide a breadth of fluorophores with varying photophysical and biological behaviour. 4-Amino-1,8-naphthalimides are commonly employed in fluorescent sensors, but the narrow range of structural derivatives limits versatility of application. Here we report the synthesis and investigation of a set of twelve 4-amino-1,8-naphthalimides bearing an additional substituent on the aromatic core. Photophysical characterisation and time-dependent density functional theory studies provided insights into the structure-photophysical property relationships of these derivatives, which show an expanded range of emission wavelengths and other photophysical properties. These compounds could all be visualised within cells by confocal microscopy, showing cytoplasmic or lipid droplet localisation. Our studies have demonstrated that simple structural modification of 4-amino-1,8-naphthalimides provides derivatives with considerable breadth of behaviour that lend valuable versatility to the design of fluorescent sensors. PMID- 29423967 TI - Suvorexant is associated with a low incidence of delirium in critically ill patients: a retrospective cohort study. AB - BACKGROUND: Benzodiazepine use is a risk factor for the development of delirium in adult intensive care unit (ICU) patients. Suvorexant is an alternative to benzodiazepines to induce sleep, but the incidence of delirium in critically ill patients is unknown. We undertook this retrospective study to investigate the incidence of delirium in patients who receive suvorexant in the ICU. METHODS: This retrospective cohort study was conducted in a closed 12-bed ICU at a tertiary teaching hospital. Patients admitted to the ICU for 72 h or longer between January and June 2015 were evaluated for delirium using the Confusion Assessment Method for the Intensive Care Unit tool. We evaluated the incidence of delirium in patients who received suvorexant and those who did not. To adjust for confounding factors, multivariable logistic regression analysis was conducted. RESULTS: Study subjects included 118 patients, with a median age of 72 years and a median Acute Physiology and Chronic Health Evaluation II score of 18 points. Eighty-two patients (69.5%) were admitted after cardiovascular surgery. In the suvorexant group, there were fewer post-cardiovascular surgical patients and more medical patients. The duration of mechanical ventilation during ICU stay was longer in the suvorexant group, and sedatives and sleep inducers other than suvorexant were used more frequently in the suvorexant group. The incidence of delirium was 43.8% in the suvorexant group and 58.8% in the non-suvorexant group (P = 0.149). After adjustment for risk factors using multivariable logistic regression analysis, suvorexant was associated with a lower incidence of delirium (odds ratio = 0.23, 95% confidence interval: 0.07-0.73; P = 0.012). CONCLUSIONS: Suvorexant was associated with decreased odds of transitioning to delirium in critically ill patients. The use of suvorexant may lower the incidence of delirium in ICU patients. Future prospective studies are warranted. PMID- 29423969 TI - A Clinical Comparative Study of 3-Dimensional Accuracy between Digital and Conventional Implant Impression Techniques. AB - PURPOSE: To evaluate the accuracy of a digital implant impression technique using a TRIOS 3Shape intraoral scanner (IOS) compared to conventional implant impression techniques (pick-up and transfer) in clinical situations. MATERIALS AND METHODS: Thirty-six patients who had two implants (Implantium, internal connection) ranging in diameter between 3.8 and 4.8 mm in posterior regions participated in this study after signing a consent form. Thirty-six reference models (RM) were fabricated by attaching two impression copings intraorally, splinted with autopolymerizing acrylic resin, verified by sectioning through the middle of the index, and rejoined again with freshly mixed autopolymerizing acrylic resin pattern (Pattern Resin) with the brush bead method. After that, the splinted assemblies were attached to implant analogs (DANSE) and impressed with type III dental stone (Gypsum Microstone) in standard plastic die lock trays. Thirty-six working casts were fabricated for each conventional impression technique (i.e., pick-up and transfer). Thirty-six digital impressions were made with a TRIOS 3Shape IOS. Eight of the digitally scanned files were damaged; 28 digital scan files were retrieved to STL format. A coordinate-measuring machine (CMM) was used to record linear displacement measurements (x, y, and z coordinates), interimplant distances, and angular displacements for the RMs and conventionally fabricated working casts. CATIA 3D evaluation software was used to assess the digital STL files for the same variables as the CMM measurements. CMM measurements made on the RMs and conventionally fabricated working casts were compared with 3D software measurements made on the digitally scanned files. Data were statistically analyzed using the generalized estimating equation (GEE) with an exchangeable correlation matrix and linear method, followed by the Bonferroni method for pairwise comparisons (alpha = 0.05). RESULTS: The results showed significant differences between the pick-up and digital groups in all of the measured variables (p < 0.001). Concerning the transfer and digital groups, the results were statistically significant in angular displacement (p < 0.001), distance measurements (p = 0.01), and linear displacement (p = 0.03); however, between the pick-up and transfer groups, there was no statistical significance in all of the measured variables (interimplant distance deviation, linear displacement, and angular displacement deviations). CONCLUSIONS: According to the results of this study, the digital implant impression technique had the least accuracy. Based on the study outcomes, distance and angulation errors associated with the intraoral digital implant impressions were too large to fabricate well fitting restorations for partially edentulous patients. The pick-up implant impression technique was the most accurate, and the transfer technique revealed comparable accuracy to it. PMID- 29423970 TI - Autoinducer2 affects trimethoprim-sulfamethoxazole susceptibility in avian pathogenic Escherichia coli dependent on the folate synthesis-associate pathway. AB - Avian pathogenic Escherichia coli (APEC) causes airsacculitis, polyserositis, septicemia, and other mainly extraintestinal diseases in chickens, ducks, geese, pigeons, and other avian species, and is responsible for great economic losses in the avian industry. The autoinducer 2 (AI-2) quorum sensing system is widely present in many species of gram-negative and gram-positive bacteria and has been proposed to be involved in interspecies communication. In clinical APEC strains, whether or not AI-2 affects the expression of antibiotic-related genes has not been reported. In this study, we have reported that exogenous AI-2 increase the susceptibility of APEC strains to trimethoprim-sulfamethoxazole (SXT) in a folate synthesis-dependent pathway but not in the LsrR-dependent manner. Our results further explained that exogenous AI-2 can down regulate the transcription of the folate synthetase encoding genes folA and folC, and the folate synthesis-related genes luxS, metE, and metH. Gel shift assays confirmed that LsrR, the AI-2 receptor, did not bind to the promoters of folA and folC, suggesting that exogenous AI-2 might influence folate metabolism by a feedback inhibition effect but not in the LsrR-dependent pathway. This study might provide further information in the search for potential drug targets for prophylaxis of avian colibacillosis and for auxiliary antibiotics in the treatment of avian colibacillosis. PMID- 29423971 TI - Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability. AB - SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele. PMID- 29423973 TI - It's Time to Reverse our Thinking: The Reverse Translation Research Paradigm. PMID- 29423972 TI - The art and science of choosing efficacy endpoints for rare disease clinical trials. AB - An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression. For rare diseases, regulatory approval requires demonstration of clinical benefit, defined as how a patient, feels, functions, or survives, in at least one adequate and well-controlled pivotal study conducted according to Good Clinical Practice. In some cases, full regulatory approval can occur using a validated surrogate biomarker, while accelerated, or provisional, approval can occur using a biomarker that is likely to predict clinical benefit. Rare disease studies are small by necessity and require the use of endpoints with large effect sizes to demonstrate statistical significance. Understanding the quantitative factors that determine effect size and its impact on powering the study with an adequate sample size is key to the successful choice of endpoints. Interpreting the clinical meaningfulness of an observed change in an efficacy endpoint can be justified by statistical methods, regulatory precedence, and clinical context. Heterogeneous diseases that affect multiple organ systems may be better accommodated by endpoints that assess mean change across multiple endpoints within the same patient rather than mean change in an individual endpoint across all patients. PMID- 29423974 TI - Usefulness of Rapiplug in nipple reconstruction to improve nipple projection. AB - BACKGROUND: The final stage of breast reconstruction after mastectomy for breast cancer is nipple reconstruction. However, a consistent and reliable method resulting in the most ideal aesthetic results has yet to be clarified. This study analysed the long-term outcomes of nipple reconstruction using Rapiplug. METHODS: Forty-one patients who underwent immediate breast reconstruction after mastectomy between January 2014 and February 2017 were enrolled. Nipple reconstruction was performed with C-V flap and Hammond flap, and hat-shaped Rapiplug was implanted at the flap core. Nipple projection and width were measured and nipple reduction rates were calculated immediately after and at 3, 6, and 12 months after surgery. Patient satisfaction was surveyed at the 12-month follow-up and compared with patient characteristics and other variables. RESULTS: Forty-one nipple reconstructions were performed in 41 patients. Most post-operative adverse events were resolved with conservative management, and revision was performed in only one case. The mean nipple projections were 8.9 +/- 1.8, 7 +/- 1.8, 5.6 +/- 1.6 and 4.9 +/- 1.6 mm immediately, and 3, 6 and 12 months after surgery, respectively, and the mean reduction rate of nipple size with reference to the size immediately after surgery was 22.2%, 37.2% and 44.7% at 3, 6 and 12 months after surgery, respectively. Patient satisfaction was 82.9% in overall outcome, and 85.3% of projection was good or excellent. CONCLUSION: Rapiplug can improve the long-term preservation of nipple projection after nipple reconstruction and is considered to be consistent and reliable with good aesthetic outcomes and no severe complications. PMID- 29423975 TI - Targeted metabolomics reveals proline as a major osmolyte in the chemolithoautotroph Sulfurimonas denitrificans. AB - Chemoautotrophic bacteria belonging to the genus Sulfurimonas in the class Campylobacteria are widespread in many marine environments characterized by redox interfaces, yet little is known about their physiological adaptations to different environmental conditions. Here, we used liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in a targeted metabolomics approach to study the adaptations of Sulfurimonas denitrificans to varying salt concentrations that are found in its natural habitat of tidal mudflats. Proline was identified as one of the most abundant internal metabolites and its concentration showed a strong positive correlation with ionic strength, suggesting that it acts as an important osmolyte in S. denitrificans. 2,3 dihydroxypropane-1-sulfonate was also positively correlated with ionic strength, indicating it might play a previously unrecognized role in osmoregulation. Furthermore, the detection of metabolites from the reductive tricarboxylic acid cycle at high internal concentrations reinforces the importance of this pathway for carbon fixation in Campylobacteria and as a hub for biosynthesis. As the first report of metabolomic data for an campylobacterial chemolithoautotroph, this study provides data that will be useful to understand the adaptations of Campylobacteria to their natural habitat at redox interfaces. PMID- 29423977 TI - Measures for risk factor stratification to prevent suicide mortality in breast cancer patients. PMID- 29423976 TI - Innovation strategy management survey of the Chilean biomedical industry. Assessment of windows of opportunities to reduce technological gaps. AB - The convergence of different theories (ie, catch-up effect and windows of opportunities) allows for the interpretation of different "technological innovation gaps" in Chile's biomedical industry. It is common knowledge that Chile has always had an economy almost exclusively based on services, commodities, and mainly in the exploitation of natural resources with low value added. The literature confirms that countries that concentrate their economies on the knowledge, research, development, and commercialization of technology and innovation have a better and more stable growth rate in the medium and long run. The "Asian Tigers" are a good example of this. Analyzing the technological gaps that affect the Chilean biomedical industry, it is possible to find windows of opportunities to catch up. This could allow the country to take its knowledge, skills, and capabilities further, thus enabling Chile to not just depend on its unpredictable natural resources. For the first time, a quantitative diagnosis of the Chilean biomedical industry was made. This study considered the Chilean biomedical industry and its innovation and entrepreneurship environment, taking into account its productive capacities and its potential to make progress in technological innovation and, as a result, dramatically reducing technological gaps through windows of opportunities. PMID- 29423979 TI - Measures for risk factor stratification to prevent suicide mortality in breast cancer patients: A reply. PMID- 29423980 TI - Polymer Solar Cells with 90% External Quantum Efficiency Featuring an Ideal Light and Charge-Manipulation Layer. AB - Rapid progress in the power conversion efficiency (PCE) of polymer solar cells (PSEs) is beneficial from the factors that match the irradiated solar spectrum, maximize incident light absorption, and reduce photogenerated charge recombination. To optimize the device efficiency, a nanopatterned ZnO:Al2 O3 composite film is presented as an efficient light- and charge-manipulation layer (LCML). The Al2 O3 shells on the ZnO nanoparticles offer the passivation effect that allows optimal electron collection by suppressing charge-recombination loss. Both the increased refractive index and the patterned deterministic aperiodic nanostructure in the ZnO:Al2 O3 LCML cause broadband light harvesting. Highly efficient single-junction PSCs for different binary blends are obtained with a peak external quantum efficiency of up to 90%, showing certified PCEs of 9.69% and 13.03% for a fullerene blend of PTB7:PC71 BM and a nonfullerene blend, FTAZ:IDIC, respectively. Because of the substantial increase in efficiency, this method unlocks the full potential of the ZnO:Al2 O3 LCML toward future photovoltaic applications. PMID- 29423981 TI - Embedding routine health checks for adults with intellectual disabilities in primary care: practice nurse perceptions. AB - BACKGROUND: Adults with intellectual disabilities (IDs) have consistently poorer health outcomes than the general population. There is evidence that routine health checks in primary care may improve outcomes. We conducted a randomised controlled trial of practice nurse led health checks. Here, we report findings from the nested qualitative study. AIM: To explore practice nurse perceptions and experience of delivering an anticipatory health check for adults with IDs. DESIGN AND SETTING: Qualitative study in General Practices located in NHS Greater Glasgow and Clyde, Scotland, UK. METHOD: Eleven practice nurses from 11 intervention practices participated in a semi-structured interview. Analysis was guided by a framework approach. RESULTS: Practice nurses reported initially feeling 'swamped' and 'baffled' by the prospect of the intervention, but early misgivings were not realised. Health checks were incorporated into daily routines with relative ease, but this was largely contingent on existing patient engagement. The intervention was thought most successful with patients already well known to the practice. Chronic disease management models are commonly used by practice nurses and participants tailored health checks to existing practice. It emerged that few of the nurses utilised the breadth of the check instead modifying the check to respond to individual patients' needs. As such, already recognised 'problems' or issues dominated the health check process. Engaging with the health checks in this way appeared to increase the acceptability and feasibility of the check for nurses. There was universal support for the health check ethos, although some questioned whether all adults with IDs would access the health checks, and as a consequence, the long-term benefits of checks. CONCLUSION: While the trial found the intervention to be dominant over standard health care, the adjustments nurses made may not have maximised potential benefits to patients. Increasing training could further improve the benefits that health checks provide for people with IDs. PMID- 29423982 TI - Pulmonary actinomycosis masquerading as lung cancer: keep it in mind. PMID- 29423984 TI - Commentary on McDonald et al. (2018): Intranasal naloxone-from the laboratory to the real world. PMID- 29423983 TI - Commentary on Kerr et al. (2018): Marijuana, drug use, and mental health in the United States-a tale of two generations. PMID- 29423985 TI - Reflections on Addiction Research Centres and the Nurturing of Creativity. PMID- 29423987 TI - Commentary on Grubbs et al. (2018): Coming out as a pornography user-could societal acceptance decrease the prevalence of perceived addiction? PMID- 29423988 TI - Commentary on Nuyts et al. (2018): Education is the key to preventing growing inequalities in smoking prevalence. PMID- 29423989 TI - Corrigendum. PMID- 29423990 TI - Commentary on Pickering et al. (2018): Problems with measurement consistency unique to gambling or widespread in addictions? PMID- 29423991 TI - Fostering transparency in e-cigarette research synthesis: the utility and limitations of methodological hierarchies. PMID- 29423992 TI - Commentary on Chan et al. (2018): Cannabis use and educational level-which is the chicken and which is the egg? PMID- 29423993 TI - Cytokine gene polymorphism in denture stomatitis patients: A clinical study. AB - OBJECTIVE: This clinical study investigated the association between cytokine gene polymorphism and Candida growth in denture stomatitis (DS) patients. SUBJECTS AND METHODS: Saliva and blood samples of 160 complete denture wearers (80 healthy controls and 80 with DS) were collected for mycological and gene polymorphism testing, respectively. Salivary Candida growth and TNF-alpha, TGF-beta, IL-6, and IL-10 genotypes were investigated. Data were analyzed using Student's t test, Mann-Whitney U test, chi-square analysis, and continuity (yates) correction tests (p < .05). RESULTS: Candida albicans colony counts in saliva were significantly higher in the DS group and in the TNF-alpha GG genotype (p < .05). TGF-beta TC GG and TGF-beta CC GG haplotypes were significantly higher in DS and control groups, respectively (p < .05). C. albicans colony counts were significantly higher in control group in the TGF-beta TC GG haplotype (p < .05). Candida glabrata colony counts were significantly higher in the DS group than the control group in IL-6 GG genotype (p < .05). The difference between DS types in IL-6 genotypes was significant with lower expression level in DS type 3 than DS type 1 and also type 2 (p <= .01). CONCLUSION: The significant differences in some genotypes of the TNF-alpha, TGF-beta, and IL-6 in DS patients are promising in understanding the host defense in DS. PMID- 29423994 TI - Functional effects of synthetic cannabinoids versus Delta9 -THC in mice on body temperature, nociceptive threshold, anxiety, cognition, locomotor/exploratory parameters and depression. AB - Synthetic cannabinoids are psychoactive substances designed to mimic the euphorigenic effects of the natural cannabis. Novel unregulated compounds appear once older compounds become illegal. It has been previously reported that synthetic cannabinoids are different than Delta9 -tetrahydrocannabinol (Delta9 THC) as they have chemical structures unrelated to Delta9 -THC, different metabolism and, often, greater toxicity. This study aimed to investigate the effects of three novel synthetic cannabinoids and pure Delta9 -THC on body temperature, nociceptive threshold, anxiety, memory function, locomotor and exploratory parameters, and depression. We performed a battery of behavioural and motor tests starting 50 minutes post i.p. injection of each drug to adult ICR mice. The synthetic cannabinoids that were used are AB-FUBINACA, AB-CHMINACA and PB-22. All synthetic cannabinoids and Delta9 -THC caused hypothermia, but only Delta9 -THC induced a clear antinociceptive effect. All synthetic cannabinoids and Delta9 -THC caused decreased anxiety levels, spatial memory deficits and decreased exploratory behaviour as measured in the elevated plus maze, Y-maze and staircase paradigm, respectively. However, all synthetic cannabinoids but not Delta9 -THC demonstrated decreased locomotor activity in the staircase test. Moreover, only AB-FUBINACA and Delta9 -THC affected the gait balance and grip strength of the mice as was assessed by the latency time to fall from a rod. In the forced swimming test, PB-22 caused elevated depression-like behaviour while AB-FUBINACA induced a reversed effect. These results suggest varied effects among different synthetic cannabinoids and Delta9 -THC. Further studies are needed to characterize the overall effects and differences between these synthetic cannabinoids and Delta9 -THC. PMID- 29423995 TI - Gold Nanoclusters for Targeting Methicillin-Resistant Staphylococcus aureus In Vivo. AB - Widespread multidrug resistance caused by the abuse of antibiotics calls for novel strategies and materials. Gold nanoclusters (AuNCs) are scarcely explored for combating multidrug-resistant (MDR) bacteria in vivo. We herein synthesized a novel class of AuNCs, namely quaternary ammonium (QA) capped AuNCs (QA-AuNCs) as potent antibiotics selectively targeting MDR Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), in vivo. QA-AuNCs kill bacteria through a combined physicochemical mechanism, and show excellent therapeutic effects in both a skin infection model and a bacteremia model induced by MRSA. In addition, owing to their intense fluorescence, QA-AuNCs can be used for the discrimination of live/dead bacteria and bacteria counting, suggesting their potential for clinical theranostics. PMID- 29423996 TI - A Catalyst-Free Amination of Functional Organolithium Reagents by Flow Chemistry. AB - Reported is the electrophilic amination of functional organolithium intermediates with well-designed aminating reagents under mild reaction conditions using flow microreactors. The aminating reagents were optimized to achieve efficient C-N bond formation without using any catalyst. The electrophilic amination reactions of functionalized aryllithiums were successfully conducted under mild reaction conditions, within 1 minute, by using flow microreactors. The aminating reagent was also prepared by the flow method. Based on stopped-flow NMR analysis, the reaction time for the preparation of the aminating reagent was quickly optimized without the necessity of work-up. Integrated one-flow synthesis consisting of the generation of an aryllithium, the preparation of an aminating reagent, and their combined reaction was successfully achieved to give the desired amine within 5 minutes of total reaction time. PMID- 29423998 TI - Opposing expression gradients of calcitonin-related polypeptide alpha (Calca/Cgrpalpha) and tyrosine hydroxylase (Th) in type II afferent neurons of the mouse cochlea. PMID- 29423997 TI - Draft genome sequence of ramie, Boehmeria nivea (L.) Gaudich. AB - Ramie, Boehmeria nivea (L.) Gaudich, family Urticaceae, is a plant native to eastern Asia, and one of the world's oldest fibre crops. It is also used as animal feed and for the phytoremediation of heavy metal-contaminated farmlands. Thus, the genome sequence of ramie was determined to explore the molecular basis of its fibre quality, protein content and phytoremediation. For further understanding ramie genome, different paired-end and mate-pair libraries were combined to generate 134.31 Gb of raw DNA sequences using the Illumina whole genome shotgun sequencing approach. The highly heterozygous B. nivea genome was assembled using the Platanus Genome Assembler, which is an effective tool for the assembly of highly heterozygous genome sequences. The final length of the draft genome of this species was approximately 341.9 Mb (contig N50 = 22.62 kb, scaffold N50 = 1,126.36 kb). Based on ramie genome annotations, 30,237 protein coding genes were predicted, and the repetitive element content was 46.3%. The completeness of the final assembly was evaluated by benchmarking universal single copy orthologous genes (BUSCO); 90.5% of the 1,440 expected embryophytic genes were identified as complete, and 4.9% were identified as fragmented. Phylogenetic analysis based on single-copy gene families and one-to-one orthologous genes placed ramie with mulberry and cannabis, within the clade of urticalean rosids. Genome information of ramie will be a valuable resource for the conservation of endangered Boehmeria species and for future studies on the biogeography and characteristic evolution of members of Urticaceae. PMID- 29423999 TI - Electrophysiological evidence of low salience distractor interference during visual search. AB - Visual search displays often include distractors of lesser salience in addition to a target and one or more salient distractors. We investigated low salience distractor effects on the N2pc, an ERP component indexing the deployment of attention, and the Ptc, a component purported to reflect attentional disengagement. We hypothesized that salient distractors pull the attentional focus away from the target, which could lead to increased attentional processing of low salience distractors close to the target and salient distractor. Participants looked for a colored inverted T during a visual search task while ignoring an L of the same color at a fixed distance on an imaginary circle around fixation. There were four conditions: no additional gray (low salience) distractors, two additional gray distractors between color items, two additional gray distractors just outside the area delimited by the colored items, and four additional gray distractors inside and outside the attended region. The gray distractors impacted N2pc and Ptc amplitude and latency, indicating an effect of gray distractors on attentional processing. Also, additional gray distractors led to increasingly more deviation of the N2pc and Ptc waveforms from the baseline offered by the condition with no additional gray distractors. When we increased the difficulty to individuate the target, we observed more displacement of lateralized activity from the N2pc to the Ptc time window. We argue that distractor-related modulations likely result from increased variance in the latency of attentional engagement activity to the target instead of distractor inhibition or attentional disengagement. PMID- 29424000 TI - A threshold-free summary index of prediction accuracy for censored time to event data. AB - Prediction performance of a risk scoring system needs to be carefully assessed before its adoption in clinical practice. Clinical preventive care often uses risk scores to screen asymptomatic population. The primary clinical interest is to predict the risk of having an event by a prespecified future time t0 . Accuracy measures such as positive predictive values have been recommended for evaluating the predictive performance. However, for commonly used continuous or ordinal risk score systems, these measures require a subjective cutoff threshold value that dichotomizes the risk scores. The need for a cutoff value created barriers for practitioners and researchers. In this paper, we propose a threshold free summary index of positive predictive values that accommodates time-dependent event status and competing risks. We develop a nonparametric estimator and provide an inference procedure for comparing this summary measure between 2 risk scores for censored time to event data. We conduct a simulation study to examine the finite-sample performance of the proposed estimation and inference procedures. Lastly, we illustrate the use of this measure on a real data example, comparing 2 risk score systems for predicting heart failure in childhood cancer survivors. PMID- 29424002 TI - Perpetual complexity: predicting human CD8+ T-cell responses to pathogenic peptides. AB - The accurate prediction of human CD8+ T-cell epitopes has great potential clinical and translational implications in the context of infection, cancer and autoimmunity. Prediction algorithms have traditionally focused on calculated peptide affinity for the binding groove of MHC-I. However, over the years it has become increasingly clear that the ultimate T-cell recognition of MHC-I-bound peptides is governed by many contributing factors within the complex antigen presentation pathway. Recent advances in next-generation sequencing and immunnopeptidomics have increased the precision of HLA-I sub-allele classification, and have led to the discovery of peptide processing events and individual allele-specific binding preferences. Here, we review some of the discoveries that initiated the development of peptide prediction algorithms, and outline some of the current available online tools for CD8+ T-cell epitope prediction. PMID- 29424001 TI - Use of trimethoprim-sulfamethoxazole during pregnancy and risk of spontaneous abortion: a nested case control study. AB - AIMS: Data available on the fetal safety of trimethoprim-sulfamethoxazole (TMP SMX) exposure during pregnancy remains scarce and inconclusive. A previous study assessing the link between TMP-SMX exposure during pregnancy and the risk of spontaneous abortion (SA) did not control for protopathic bias and indication bias. METHODS: We conducted a nested control study (n = 77 429 pregnancies including 7039 cases of SA and 70 390 controls) within the Quebec Pregnancy Cohort. For each case of SA, we selected 10 controls at the index date that were matched on gestational age and year of pregnancy. TMP-SMX exposure was defined as either having filled at least one prescription between the first day of gestation (1DG) and the index date, or as having filled a prescription before pregnancy but with a duration overlapping the 1DG (102 pregnancies exposed to TMP-SMX, including 25 cases of SA and 77 controls). RESULTS: Adjusting for potential confounders, TMP-SMX exposure was associated with an increased risk of SA (AOR 2.94, 95% C 1.89-4.57, 25 exposed cases). Similar results were found after controlling for indication bias and protopathic bias. CONCLUSION: Given that this drug is widely use in HIV patients to prevent opportunistic infections and malaria, there is an urgent need to identify potential data sources in Africa for analysis of early pregnancy exposure to TMP-SMX. PMID- 29424003 TI - A retrospective case series of referrals to our psychodermatology clinic 2009 2016. PMID- 29424005 TI - The gift of time? School starting age and mental health. AB - Using linked Danish survey and register data, we estimate the causal effect of age at kindergarten entry on mental health. Danish children are supposed to enter kindergarten in the calendar year in which they turn 6 years. In a "fuzzy" regression-discontinuity design based on this rule and exact dates of birth, we find that a 1-year delay in kindergarten entry dramatically reduces inattention/hyperactivity at age 7 (effect size = -0.73), a measure of self regulation with strong negative links to student achievement. The effect is primarily identified for girls but persists at age 11. PMID- 29424004 TI - Substrate stiffness regulated migration and invasion ability of adenoid cystic carcinoma cells via RhoA/ROCK pathway. AB - OBJECTIVES: Human salivary adenoid cystic carcinoma (SACC) is one of the most common malignant tumours of the salivary gland and has strong migratory and invasive ability, which often lead to poor prognosis and lower survival rate. Tumour tissue tends to stiffen during solid tumour progression. This study aimed to investigate the influence of various substrate stiffness on the migration and invasion of SACC. METHODS: Salivary adenoid cystic carcinoma cell line ACC2 cells were cultured on polydimethylsiloxane substrates (PDMS) with varying stiffness for investigating the effects of substrate stiffness on the activities of MMPs and TIMPs. The underlying mechanism was also explored. RESULTS: When ACC2 cells were cultured on various stiffness of PDMS, the expressions of matrix metalloproteinases 2 (MMP2), MMP9, MMP14, RhoA, Rac1, Rho-associated protein kinase 1 (ROCK1) and ROCK2 were up-regulated with increasing substrate stiffness, whereas that of tissue inhibitor of matrix metalloproteinase 1 (TIMP1), TIMP2 and TIMP4 were down-regulated with increasing substrate stiffness. CONCLUSIONS: Our results showed that substrate stiffness regulated the activities of MMPs and TIMPs and then modulate migratory and invasive ability of ACC2 cells via RhoA/ROCK pathway. This work indicate that matrix stiffness played an important role in progression of SACC, which not only can help understand the strong invasive ability of SACC, but also suggested that therapeutically targeting matrix stiffness may help reduce migration and invasion of SACC and improve effective therapies. PMID- 29424006 TI - How to insert an internal seton for supralevator sepsis: an effective technique for complex fistulae. PMID- 29424007 TI - Inspiratory muscle training improves exercise capacity with thoracic load carriage. AB - Thoracic load carriage (LC) exercise impairs exercise performance compared to unloaded exercise, partially due to impaired respiratory mechanics. We investigated the effects of LC on exercise and diaphragmatic fatigue in a constant-load exercise task; and whether inspiratory muscle training (IMT) improved exercise capacity and diaphragmatic fatigue with LC. Twelve recreationally active males completed three separate running trials to exhaustion (Tlim ) at a fixed speed eliciting 70% of their VO2max . The first two trials were completed either unloaded (UL) or while carrying a 10 kg backpack (LC). Subjects then completed 6 weeks of either true IMT or placebo-IMT. Posttraining, subjects completed an additional LC trial identical to the pretraining LC trial. Exercise metabolic and ventilatory measures were recorded. Diaphragm fatigue was assessed as the difference between preexercise and postexercise twitch diaphragmatic pressure (Pdi, tw ), assessed by bilateral stimulation of the phrenic nerve with esophageal balloon-tipped catheters measuring intrathoracic pressures. Tlim was significantly shorter (P < 0.001) with LC compared with UL by 42.9 (29.1)% (1626.5 (866.7) sec and 2311.6 (1246.5) sec, respectively). The change in Pdi, tw from pre- to postexercise was significantly greater (P = 0.001) in LC (-13.9 (5.3)%) compared with UL (3.8 (6.5)%). Six weeks of IMT significantly improved Tlim compared to pretraining (P = 0.029, %Delta +29.3 (15.7)% IMT, -8.8 (27.2)% Placebo), but did not alter the magnitude of diaphragmatic fatigue following a run to exhaustion (P > 0.05). Minute ventilation and breathing mechanics were unchanged post-IMT (P > 0.05). Six weeks of flow-resistive IMT improved exercise capacity, but did not mitigate diaphragmatic fatigue following submaximal, constant-load running to volitional exhaustion with LC. PMID- 29424008 TI - Prophylactic Granisetron for post-spinal anesthesia shivering in Caesarean Section: a randomized controlled clinical study. AB - BACKGROUND: The serotonergic system is known to be involved in control of post anesthetic shivering. Our hypothesis was that prophylactic granisetrone (serotonin antagonist) might reduce incidence of post- spinal anesthesia shivering in cesarean section. METHODS: Parturient scheduled for elective Caesarean delivery under spinal anesthesia were allocated to receive 0.9% saline (Group I, n = 71), 1 mg granisetron (Group II, n = 69), or 0.7 mg granisetron (Group III, n = 72) before the spinal block. Assessment parameters included; hemodynamics, tympanic membrane temperature, neonatal Apgar score, shivering score, patient satisfaction scores about shivering prophylaxis and adverse effects. RESULTS: Clinically significant shivering was recorded in 55/71 patients (77.5%) in group I, 11/69 (15.9%) in group II and 21/72 (29.2%) in group III (P = 0.000). The intensity of shivering was significantly lower in patients who received granisetron 1 mg compared with granisetron 0.7 mg or saline (P = 0.000). Patients who received prophylactic granisetron 1 mg reported lower mean intraoperative arterial pressure and heart rate values and consumed higher doses of iv ephedrine compared with 0.7 mg granisetron or saline placebo (P < 0.05). Pruritus significantly decreased from (22.5%) in control group to (0%) in granisetron groups (P = 0.000). Nausea was reported in 8 vs. 10 and 4 in group I, II, and III respectively (P < 0.03). Sixteen vs. eight and six patients vomited in group I, II, and III respectively (P < 0.03). Higher patient satisfaction scores were recorded in group II (9.83 +/- 0.29, P < 0.03) and III (9.14 +/- 1.04, P < 0.04), compared with control group (8.23 +/- 1.14). CONCLUSION: Prophylactic granisetron effectively reduced incidence and severity of perioperative shivering in a dose-dependent manner, compared to placebo controls. PMID- 29424009 TI - Living on next to nothing: tree seedlings can survive weeks with very low carbohydrate concentrations. AB - The usage of nonstructural carbohydrates (NSCs) to indicate carbon (C) limitation in trees requires knowledge of the minimum tissue NSC concentrations at lethal C starvation, and the NSC dynamics during and after severe C limitation. We completely darkened and subsequently released seedlings of two deciduous and two evergreen temperate tree species for varying periods. NSCs were measured in all major organs, allowing assessment of whole-seedling NSC balances. NSCs decreased fast in darkness, but seedlings survived species-specific whole-seedling starch concentrations as low as 0.4-0.8% per dry matter (DM), and sugar (sucrose, glucose and fructose) concentrations as low as 0.5-2.0% DM. After re illumination, the refilling of NSC pools began within 3 wk, while the resumption of growth was delayed or restricted. All seedlings had died after 12 wk of darkness, and starch and sugar concentrations in most tissues were lower than 1% DM. We conclude that under the applied conditions, tree seedlings can survive several weeks with very low NSC reserves probably also using alternative C sources like lipids, proteins or hemicelluloses; lethal C starvation cannot be assumed, if NSC concentrations are higher than the minimum concentrations found in surviving seedlings; and NSC reformation after re-illumination occurs preferentially over growth. PMID- 29424010 TI - Excess weight in children and adolescents is associated with altered subendocardial blood supply among girls but not boys. AB - Subendocardial viability ratio (SEVR) is a reliable index of myocardial supply workload balance. This study sought to investigate whether overweight/obese children and adolescents have altered SEVR and to identify which are the associated factors. This cross-sectional study involved 789 individuals. Central haemodynamic was measured by radial applanation tonometry. Diastolic time was shorter (496 +/- 122 vs 537 +/- 140 ms, P = .014) and diastolic pressure-time index was lower (2681 +/- 412 vs 2814 +/- 423 mm Hg seconds, P = .024) in overweight/obese compared with eutrophic girls. SEVR was lower in girls than in boys (1.34 +/- 0.39 vs 1.48 +/- 0.41, P = .018) but only among overweight/obese. SEVR may be affected by small variations in the temporal determinants of cardiac cycle. PMID- 29424012 TI - True Low-Power Self-Locking Soft Actuators. AB - Natural double-layered structures observed in living organisms are known to exhibit asymmetric volume changes with environmental triggers. Typical examples are natural roots of plants, which show unique self-organized bending behavior in response to environmental stimuli. Herein, light- and electro-active polymer (LEAP) based actuators with a double-layered structure are reported. The LEAP actuators exhibit an improvement of 250% in displacement and hold an object three times heavier as compared to that in the case of conventional electro-active polymer actuators. Most interestingly, the bending motion of the LEAP actuators can be effectively locked for a few tens of minutes even in the absence of a power supply. Further, the self-locking LEAP actuators show a large and reversible bending strain of more than 2.0% and require only 6.2 mW h cm-2 of energy to hold an object for 15 min at an operating voltage of 3 V. These novel self-locking soft actuators should find wide applicability in artificial muscles, biomedical microdevices, and various innovative soft robot technologies. PMID- 29424011 TI - Efficacy of the 6-mm fully covered self-expandable metal stent during endoscopic ultrasound-guided hepaticogastrostomy as a primary biliary drainage for the cases estimated difficult endoscopic retrograde cholangiopancreatography: A prospective clinical study. AB - BACKGROUND AND AIM: Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is performed as an alternative to the percutaneous or surgical approach. Despite high success rates, the adverse events rate is high. Recently, we used 6-mm fully covered self-expandable metal stents to prevent adverse events and allow easy re intervention. The purposes were to evaluate the safety, feasibility, and clinical efficacy. METHODS: A prospective study to confirm the safety of EUS-HGS was carried out in six patients, followed by a trial to evaluate the feasibility and efficacy of EUS-HGS in approximately 12 additional patients. We permitted a total of 18 to 20 patients in consideration of possibility such as the deviation after providing informed consent. RESULTS: Twenty patients underwent EUS-HGS. No treatment-related adverse events described in the safety assessment criteria were seen. The technical and clinical success rates were 100% and 95%. The adverse event rate was 15%. Focal cholangitis was seen in two patients and fever in one patient. All cases were treated conservatively. Stent dysfunction was seen in 10 patients. The causes of stent dysfunction were biliary sludge (n = 6) and stent dislocation (n = 4). In nine cases, a new stent was easily inserted. Percutaneous drainage was selected in only one patient because of worsening general condition. CONCLUSIONS: The 6-mm fully covered self-expandable metal stent is safe and effective, especially for avoiding serious adverse events and allowing easy re intervention. (UMIN000006785). PMID- 29424013 TI - Cigarette smoking causes a worse long-term outcome in persistent atrial fibrillation following catheter ablation. AB - INTRODUCTION: Cigarette smoking contributes to the development of atrial fibrosis via nicotine. The impact of smoking on ablation results in persistent atrial fibrillation (AF) is unknown. We aimed to investigate the triggers and long-term outcome between smokers and nonsmokers in the patients with persistent AF after catheter ablation. METHODS: This study included 201 (177 males, 53 +/- 10 years old) patients who received index catheter ablation, including pulmonary vein isolation (PVI) and complex fractionated atrial electrograms (CFAEs) ablation for persistent AF, retrospectively. Electrophysiological characteristics at the index procedure and long-term outcome were investigated to determine the differences between smokers and nonsmokers. RESULTS: Baseline characteristics were similar between two groups. Pulmonary vein (PV) triggers were found in all patients in the two groups. There was a higher incidence of nonpulmonary vein (NPV) triggers in smokers than in nonsmokers (61% vs. 31%, P < 0.05). There were no differences of the long-term ablation outcomes between smokers and nonsmokers in Kaplan-Meier analysis. Smokers with PV plus right atrial NPV (RA-NPV) triggers had a higher incidence of recurrence (log-rank P < 0.05) than those without RA-NPV triggers, but not in nonsmokers, after a mean follow-up of 31 +/- 25 months. CONCLUSIONS: Smoking increases the incidence of NPV triggers in patients with persistent AF. Smokers who have RA-NPV triggers during index procedure do have a worse outcome after catheter ablation, indicating the harmful effects of nicotine to right atrium. PMID- 29424014 TI - Irish persons with intellectual disability moving from family care to residential accommodation in a period of austerity. AB - BACKGROUND: Ireland has a growing population of adult persons living with family carers, thereby increasing the demand for residential places. Simultaneously, government policy aimed to reprovision residents living in congregated settings but at a time when funding was curtailed due to the economic crisis. This study examines the movements of people into and among three types of residential options between 2009 and 2014. METHOD: A cohort of 20,163 persons recorded on the National Intellectual Disability Database in 2009 was identified and tracked to the 2014 database. RESULTS: An estimated 200 persons per annum (@1.6% of those living with families) moved from family care although the number of places available nationally fell by 9%. Moreover, transfers of existing residents into vacated places tended to exceed those from families. CONCLUSIONS: More people will have to continue living with their families and for longer if funding for new places remains curtailed. PMID- 29424015 TI - Direct Palladium-Catalyzed beta-Arylation of Lactams. AB - A direct and catalytic method is reported here for beta-arylation of N-protected lactams with simple aryl iodides. The transformation is enabled by merging soft enolization of lactams, palladium-catalyzed desaturation, Ar-X bond activation, and aryl conjugate addition. The reaction is operated under mild reaction conditions, is scalable, and is chemoselective. Application of this method to concise syntheses of pharmaceutically relevant compounds is demonstrated. PMID- 29424016 TI - Hollow PtPdRh Nanocubes with Enhanced Catalytic Activities for In Vivo Clearance of Radiation-Induced ROS via Surface-Mediated Bond Breaking. AB - Catalytic nanomaterials can be used extrinsically to combat diseases associated with a surplus of reactive oxygen species (ROS). Rational design of surface morphologies and appropriate doping can substantially improve the catalytic performances. In this work, a class of hollow polyvinyl pyrrolidone-protected PtPdRh nanocubes with enhanced catalytic activities for in vivo free radical scavenging is proposed. Compared with Pt and PtPd counterparts, ternary PtPdRh nanocubes show remarkable catalytic properties of decomposing H2 O2 via enhanced oxygen reduction reactions. Density functional theory calculation indicates that the bond of superoxide anions breaks for the energetically favorable status of oxygen atoms on the surface of PtPdRh. Viability of cells and survival rate of animal models under exposure of high-energy gamma radiation are considerably enhanced by 94% and 50% respectively after treatment of PtPdRh nanocubes. The mechanistic investigations on superoxide dismutase (SOD) activity, malondialdehyde amount, and DNA damage repair demonstrate that hollow PtPdRh nanocubes act as catalase, peroxidase, and SOD analogs to efficiently scavenge ROS. PMID- 29424017 TI - Perioperative Blood Management Strategies for Total Knee Arthroplasty. AB - Total knee arthroplasty (TKA) often causes a significant amount of blood loss with an accompanying decline in hemoglobin and may increase the frequency of allogeneic blood transfusion rates. Unfortunately, allogeneic blood transfusions have associated risks including postoperative confusion, infection, cardiac arrhythmia, fluid overload, increased length of hospital stay, and increased mortality. Other than reducing the need for blood transfusions, reducing perioperative blood loss in TKA may also minimize intra-articular hemorrhage, limb swelling, and postoperative pain, and increase the range of motion during the early postoperative period. These benefits improve rehabilitation success and increase patients' postoperative satisfaction. Preoperative anemia, coupled with intraoperative and postoperative blood loss, is a major factor associated with higher rates of blood transfusion in TKA. Thus, treatment of preoperative anemia and prevention of perioperative blood loss are the primary strategies for perioperative blood management in TKA. This review, combined with current evidence, analyzes various methods of blood conservation, including preoperative, intraoperative, and postoperative methods, in terms of their effectiveness, safety, and cost. Because many factors can be controlled to reduce blood loss and transfusion rates in TKA, a highly efficient, safe, and cost-effective blood management strategy can be constructed to eliminate the need for transfusions associated with TKA. PMID- 29424019 TI - Altering spacer material affects bone regeneration in the Masquelet technique in a rat femoral defect. AB - The Masquelet technique depends on pre-development of a foreign-body membrane to support bone regeneration with grafts over three times larger than the traditional maximum. To date, the procedure has always used spacers made of bone cement, which is the polymer polymethyl methacrylate (PMMA), to induce the foreign-body membrane. This study sought to compare (i) morphology, factor expression, and cellularity in membranes formed by PMMA, titanium, and polyvinyl alcohol sponge (PVA) spacers in the Masquelet milieu and (ii) subsequent bone regeneration in the same groups. Ten-week-old, male Sprague-Dawley rats were given an externally stabilized, 6 mm femur defect, and a pre-made spacer of PMMA, titanium, or PVA was implanted. All animals were given 4 weeks to form a membrane, and those receiving an isograft were given 10 weeks post-implantation to union. All samples were scanned with microCT to measure phase 1 and phase 2 bone formation. Membrane samples were processed for histology to measure membrane morphology, cellularity, and expression of the factors BMP2, TGFbeta, VEGF, and IL6. PMMA and titanium spacers created almost identical membranes and phase 1 bone. PVA spacers were uniformly infiltrated with tissue and cells and did not form a distinct membrane. There were no quantitative differences in phase 2 bone formation. However, PMMA induced membranes supported functional union in 6 of 7 samples while a majority of titanium and PVA groups failed to achieve the same. Spacer material can alter the membrane enough to disrupt phase 2 bone formation. The membrane's role in bone regeneration is likely more than just as a physical barrier. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 29424018 TI - Relation of quality of anticoagulation control with different management systems among patients with atrial fibrillation: Data from FANTASIIA Registry. AB - BACKGROUND: Anticoagulation control in patients with atrial fibrillation (AF) has a multidisciplinary approach although is usually managed by general practitioners (GP) or haematologists. The aim of our study was to assess the quality of anticoagulation control with vitamin K antagonists (VKAs) in relation to the responsible specialist in a "real-world" AF population. METHODS: We consecutively enrolled VKA anticoagulated patients included in the FANTASIIA Registry from 2013 to 2015. We analysed demographical, clinical characteristics and the quality of anticoagulation control according to the specialist responsible (ie GPs or haematologists). RESULTS: Data on 1584 patients were included (42.5% females, mean age 74.0 +/- 9.4 years): 977 (61.7%) patients were controlled by GPs and 607 (38.3%) by haematologists. Patients managed by GPs had higher previous heart disease (53.2% vs 43.3%, P < .001), heart failure (32.9% vs 26.5%, P < .008) and dilated cardiomyopathy (15.2% vs 8.7%, P < .001) with better renal function (69.3 +/- 24.7 vs 63.1 +/- 21.4 mL/min, P < .001) compared to patients managed by haematologists. There was no difference between groups in the type of AF, CHA2 DS2 -VASc or HAS-BLED scores, but patients with electrical cardioversion were more prevalent in GP group. The overall mean time in therapeutic range (TTR) assessed by Rosendaal method was 61.5 +/- 24.9%; 52.6% of patients had TTR<65% and 60% of patients had TTR<70%. TTR was significantly lower in patients controlled by haematologists than by GPs (63 +/- 24.4 vs 59.2 +/- 25.6, P < .005). CONCLUSIONS: About 60% of AF patients anticoagulated with VKAs had poor anticoagulation control (ie TTR<70%), and their management was only slightly better than when it is managed by general practitioners. PMID- 29424020 TI - Activation patterns of vasopressinergic and oxytocinergic brain regions following social play exposure in juvenile male and female rats. AB - Social play is a highly rewarding and motivated behavior predominately displayed by juveniles and expressed by nearly all mammalian species. Prior work suggested that the vasopressin (AVP) and oxytocin (OT) systems can regulate the expression of social play in sex-specific ways. Here we investigated whether there are sex differences in the recruitment of vasopressinergic and oxytocinergic brain regions following social play exposure in juvenile rats. Single-housed rats were allowed to play, in their home cage, with an age- and sex-matched unfamiliar conspecific for 10 min, or received similar handling but no partner. Double labeled fluorescent immunohistochemistry for Fos and either AVP or OT was completed in adjacent series of tissue to determine recruitment of AVP- and OT immunoreactive neurons in response to social play. Exposure to social play did not increase recruitment of AVP or OT neurons in the supraoptic (SO) or paraventricular (PVH) hypothalamic nuclei of either sex compared to the no-play control condition. Interestingly, there was a robust sex difference in SO recruitment, irrespective of social play condition, with males exhibiting twice the recruitment of SO-AVP and SO-OT neurons compared to females. Lastly, exposure to social play increased recruitment of the posterior bed nuclei of the stria terminalis (pBST) and the posterodorsal medial amygdalar nucleus (MEApd) compared to the no-play control condition, and this effect was most pronounced in females. Our findings revealed sex differences in the recruitment of brain regions (i) independent of play condition (i.e., SO) possibly representing a sex difference in the baseline levels of AVP and OT signaling required for typical functioning and (ii) specific to play condition (i.e., pBST, MEApd). In sum, this study provides further evidence that the neural substrates underlying social play behavior are sex-specific. This article is protected by copyright. All rights reserved. PMID- 29424021 TI - Combined assessment of attentional reserve and cognitive-motor effort under various levels of challenge with a dry EEG system. AB - A novel ERP approach was proposed to index variations in mental workload, particularly in attentional reserve, which is complementary to EEG spectral content thought to reflect mental effort. To our knowledge, no study has assessed mental effort and attentional reserve simultaneously in EEG gel-based and, importantly, dry systems, which are particularly well suited for real-world settings. Therefore, by systematically considering ERP, EEG spectral, and importantly the combination of both, this study examined if a small set of dry EEG electrodes could detect changes in both spectral and ERP metrics to assess the mental workload under various challenges with a similar fidelity to their gel based counterparts in a laboratory setting. By employing both EEG gel-based and dry systems, the ERP and spectral markers were computed while participants executed a visuomotor task under three levels of challenge. For both EEG systems, more challenging levels of difficulty were associated with concomitant changes in ERP amplitude, and spectral power reflected a reduction of the attentional reserve and an increase in cognitive-motor effort, respectively. Those variations in attentional reserve and cognitive-motor effort collectively indexed mental workload with nearly identical fidelity for both gel-based and dry EEG systems. These findings promise to assess the mental workload in situations where the use of dry EEG systems could be advantageously employed to examine human cognitive motor performance. PMID- 29424022 TI - Acenocoumarol as an alternative anticoagulant in a patient with warfarin-related nephropathy. AB - ADVERSE EVENT: Warfarin-related nephropathy. DRUG IMPLICATED: Warfarin. THE PATIENT: A 31-year-old female, managed with warfarin for rheumatic heart disease with atrial fibrillation. EVIDENCE THAT LINKS THE DRUG TO THE EVENT: There were no alternative causes of nephropathy that could have caused the adverse event in this patient. MANAGEMENT: Shifting the drug from warfarin to acenocoumarol. MECHANISM: Difference in renal elimination between warfarin and acenocoumarol. IMPLICATION FOR THERAPY: Clinicians should be aware of this rare adverse effect of warfarin, and acenocoumarol can be considered as an alternative therapy for this condition. HYPOTHESES TO BE TESTED: Further prospectively designed studies are needed to consider acenocoumarol as an alternative therapy in warfarin related nephropathy. PMID- 29424023 TI - Integrin alphaM activation and upregulation on esophageal eosinophils and periostin-mediated eosinophil survival in eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is an increasingly recognized allergic disease associated with dysphagia and esophageal fibrosis. We aimed to determine expression patterns of specific eosinophil integrins that promote eosinophilic infiltration of the esophageal epithelium, and to determine how key EoE-related cytokines influence eosinophil activation and survival. Esophageal and peripheral eosinophils were isolated from 20 adult subjects with EoE for immunophenotyping and integrin profiling using multicolor flow cytometry and immunohistochemistry. Expression signatures of eosinophil integrins were further assessed by immunohistochemistry using serial sections of esophageal biopsy specimens. Purified eosinophils were used to assess the effect of EoE-relevant cytokines and recombinant periostin on expression of known eosinophil integrins and eosinophil survival and activation. We found that resting eosinophils express high levels of the beta2-pairing integrins alphaL and alphaM, and lower levels of alpha4, alpha6 and alpha4beta7. The migration of peripheral eosinophils to the esophagus is characterized by the specific induction of alphaM, and a significant increase in the proportion of alphaM in high-activity conformation. Periostin, a secreted extracellular matrix protein that is significantly overexpressed in EoE, enhances eosinophil survival, and this effect is mediated by alphaM interaction. Integrin alphaM is a specific marker of activated tissue eosinophils in EoE, and promotes eosinophil survival through interactions with periostin. The ability of alphaMbeta2 to mediate eosinophil tissue residency via periostin represents a key mechanism for disease development and a potential therapeutic target in EoE. PMID- 29424024 TI - Impulse oscillometry measurement of distal airways obstruction in depleted uranium-exposed Gulf War veterans. AB - INTRODUCTION: A cohort of Gulf War I veterans who sustained exposure to depleted uranium undergoes biennial surveillance for potential uranium-related health effects. We performed impulse oscillometry and hypothesized that veterans with higher uranium body burdens would have more obstructive abnormalities than those with lower burdens. METHODS: We compared pulmonary function of veterans in high versus low urine uranium groups by evaluating spirometry and oscillometry values. RESULTS: Overall mean spirometry and oscillometry resistance values fell within the normal ranges. There were no significant differences between the high and low uranium groups for any parameters. However, more veterans were classified as having obstruction by oscillometry (42%) than spirometry (8%). CONCLUSIONS: While oscillometry identified more veterans as obstructed, obstruction was not uranium related. However, the added sensitivity of this method implies a benefit in wider surveillance of exposed cohorts and holds promise in identifying abnormalities in areas of the lung historically described as silent. PMID- 29424025 TI - Nrf2-mediated neuroprotection against oxygen-glucose deprivation/reperfusion injury by emodin via AMPK-dependent inhibition of GSK-3beta. AB - OBJECTIVES: Our study verified the neuroprotective properties of emodin against oxygen-glucose deprivation/reoxygenation (OGD/R) and demonstrated its mechanism. METHODS: Human neuronal SH-SY5Y cells were investigated by analysing cell viability, lactate dehydrogenase levels, expression of molecules related to apoptotic cell death, and using biochemical techniques, flow cytometry and Western blot assays. KEY FINDINGS: Emodin reduced OGD/R-lead to neurotoxicity in SH-SY5Y cells. OGD/R significantly increased levels of cleaved poly ADP ribose polymerase, cleaved caspase-3, cleaved caspase-9, p53, p21 and Bax protein. However, emodin treatment effectively inhibited these OGD/R-induced changes. Emodin treatment also increased HO-1 and NQO1 expression in a concentration- and time-dependent manner and caused antioxidant response element (ARE) transcription activity and nuclear Nrf2 accumulation. Emodin phosphorylated AMPK and GSK3beta, and pretreatment of cells with an AMPK inhibitor suppressed emodin-induced nuclear Nrf2 accumulation and HO-1 and NQO1 expression. AMPK inhibitor treatment decreased GSK3beta phosphorylation, suggesting that AMPK is upstream of GSK3beta, Nrf2, HO-1 and NQO1. Emodin's neuroprotective effect was completely blocked by HO 1, NQO1 and Nrf2 knock-down and an AMPK inhibitor, indicating the action of AMPK/GSK3beta/Nrf2/ARE in the neuroprotective effect of emodin subjected to OGD/R. CONCLUSIONS: Emodin treatment protected against OGD/R-lead to neurotoxicity by potentiating Nrf2/ARE-regulated neuroprotection through the AMPK/GSK3beta pathway, indicating that emodin may be useful for treating neurodegenerative disorders. PMID- 29424026 TI - Tough and Water-Insensitive Self-Healing Elastomer for Robust Electronic Skin. AB - An electronic (e-) skin is expected to experience significant wear and tear over time. Therefore, self-healing stretchable materials that are simultaneously soft and with high fracture energy, that is high tolerance of damage or small cracks without propagating, are essential requirements for the realization of robust e skin. However, previously reported elastomers and especially self-healing polymers are mostly viscoelastic and lack high mechanical toughness. Here, a new class of polymeric material crosslinked through rationally designed multistrength hydrogen bonding interactions is reported. The resultant supramolecular network in polymer film realizes exceptional mechanical properties such as notch insensitive high stretchability (1200%), high toughness of 12 000 J m-2 , and autonomous self-healing even in artificial sweat. The tough self-healing materials enable the wafer-scale fabrication of robust and stretchable self healing e-skin devices, which will provide new directions for future soft robotics and skin prosthetics. PMID- 29424029 TI - Corrigendum. PMID- 29424027 TI - Review: Relationship of type 2 diabetes to human brain pathology. AB - Type 2 diabetes (T2D) and Alzheimer's disease (AD) are both highly prevalent diseases worldwide, and each is associated with high-morbidity and high mortality. Numerous clinical studies have consistently shown that T2D confers a two-fold increased risk for a dementia, including dementia attributable to AD. Yet, the mechanisms underlying this relationship, especially nonvascular mechanisms, remain debated. Cerebral vascular disease (CVD) is likely to be playing a role. But increased AD neuropathologic changes (ADNC), specifically neuritic amyloid plaques (AP) and neurofibrillary tangles (NFT), are also posited mechanisms. The clinicopathological studies to date demonstrate T2D to be consistently associated with infarcts, particularly subcortical lacunar infarcts, but not ADNC, suggesting the association of T2D with dementia may largely be mediated through CVD. Furthermore, growing interest exists in insulin resistance (IR), particularly IR within the brain itself, which may be an associated but distinct phenomenon from T2D, and possibly itself associated with ADNC. Other mechanisms largely related to protein processing and efflux in the central nervous system with altered function in T2D may also be involved. Such mechanisms include islet amyloid polypeptide (or amylin) deposition, co-localized with beta amyloid and found in more abundance in the AD temporal cortex, blood-brain barrier breakdown and dysfunction, potentially related to pericyte degeneration, and disturbance of brain lymphatics, both in the glial lymphatic system and the newly discovered discrete central nervous system lymph vessels. Medical research is ongoing to further disentangle the relationship of T2D to dementia in the ageing human brain. PMID- 29424028 TI - A test for gene-environment interaction in the presence of measurement error in the environmental variable. AB - The identification of gene-environment interactions in relation to risk of human diseases has been challenging. One difficulty has been that measurement error in the exposure can lead to massive reductions in the power of the test, as well as in bias toward the null in the interaction effect estimates. Leveraging previous work on linear discriminant analysis, we develop a new test of interaction between genetic variants and a continuous exposure that mitigates these detrimental impacts of exposure measurement error in ExG testing by reversing the role of exposure and the diseases status in the fitted model, thus transforming the analysis to standard linear regression. Through simulation studies, we show that the proposed approach is valid in the presence of classical exposure measurement error as well as when there is correlation between the exposure and the genetic variant. Simulations also demonstrated that the reverse test has greater power compared to logistic regression. Finally, we confirmed that our approach eliminates bias from exposure measurement error in estimation. Computing times are reduced by as much as fivefold in this new approach. For illustrative purposes, we applied the new approach to an ExGWAS study of interactions with alcohol and body mass index among 1,145 cases with invasive breast cancer and 1,142 controls from the Cancer Genetic Markers of Susceptibility study. PMID- 29424030 TI - Efficacy of traction-assisted colorectal endoscopic submucosal dissection using a clip-and-thread technique: A prospective randomized study. AB - BACKGROUND AND AIM: Colorectal endoscopic submucosal dissection (ESD) remains challenging because of technical difficulties, long procedure time, and high risk of adverse events. To facilitate colorectal ESD, we developed traction-assisted colorectal ESD using a clip and thread (TAC-ESD) and conducted a randomized controlled trial to evaluate its efficacy. METHODS: Patients with superficial colorectal neoplasms (SCN) >=20 mm were enrolled and randomly assigned to the conventional-ESD group or to the TAC-ESD group. SCN <=50 mm were treated by two intermediates, and SCN >50 mm were treated by two experts. Primary endpoint was procedure time. Secondary endpoints were TAC-ESD success rate (sustained application of the clip and thread until the end of the procedure), self completion rate by the intermediates, and adverse events. RESULTS: Altogether, 42 SCN were analyzed in each ESD group (conventional and TAC). Procedure time (median [range]) for the TAC-ESD group was significantly shorter than that for the conventional-ESD group (40 [11-86] min vs 70 [30-180] min, respectively; P < 0.0001). Success rate of TAC-ESD was 95% (40/42). The intermediates' self completion rate was significantly higher for the TAC-ESD group than for the conventional-ESD group (100% [39/39] vs 90% [36/40], respectively; P = 0.04). Adverse events included one intraoperative perforation in the conventional-ESD group and one delayed perforation in the TAC-ESD group. CONCLUSION: Traction assisted colorectal endoscopic submucosal dissection reduced the procedure time and increased the self-completion rate by the intermediates (UMIN000018612). PMID- 29424031 TI - Ageing and healthcare expenditures: Exploring the role of individual health status. AB - In 1999, Zweifel, Felder, and Meiers questioned conventional wisdom on ageing and healthcare expenditure (HCE). According to these authors, the positive association between age and HCE is due to an increasing age-specific mortality and the high cost of dying. After a weighty academic debate, a new consensus was reached on the importance of proximity to death when analysing HCE. Nevertheless, the influence of individual health status remains unknown. The objective of our study is to analyse the influence individual health status has on HCE, when compared to proximity to death and demographic effects and considering a comprehensive view of healthcare services and costs. We examined data concerning different HCE components of N = 61,473 persons aged 30 to 95 years old. Using 2 part models, we analysed the probability of use and positive HCE. Regardless of the specific group of healthcare services, HCE at the end of life depends mainly on the individual health status. Proximity to death approximates individual morbidity when it is excluded from the model. The inclusion of morbidity generally improves the goodness of fit. These results provide implications for the analysis of ageing population and its impact on HCE that should be taken into account. PMID- 29424032 TI - A Self-Powered Sensor Mimicking Slow- and Fast-Adapting Cutaneous Mechanoreceptors. AB - Highly efficient human skin systems transmit fast adaptive (FA) and slow adaptive (SA) pulses selectively or consolidatively to the brain for a variety of external stimuli. The integrated analysis of these signals determines how humans perceive external physical stimuli. Here, a self-powered mechanoreceptor sensor based on an artificial ion-channel system combined with a piezoelectric film is presented, which can simultaneously implement FA and SA pulses like human skin. This device detects stimuli with high sensitivity and broad frequency band without external power. For the feasibility study, various stimuli are measured or detected. Vital signs such as the heart rate and ballistocardiogram can be measured simultaneously in real time. Also, a variety of stimuli such as the mechanical stress, surface roughness, and contact by a moving object can be distinguished and detected. This opens new scientific fields to realize the somatic cutaneous sensor of the real skin. Moreover, this new sensing scheme inspired by natural sensing structures is able to mimic the five senses of living creatures. PMID- 29424033 TI - Mitochondrial dysfunction in human skeletal muscle biopsies of lipid storage disorder. AB - Mitochondria regulate the balance between lipid metabolism and storage in the skeletal muscle. Altered lipid transport, metabolism and storage influence the bioenergetics, redox status and insulin signalling, contributing to cardiac and neurological diseases. Lipid storage disorders (LSDs) are neurological disorders which entail intramuscular lipid accumulation and impaired mitochondrial bioenergetics in the skeletal muscle causing progressive myopathy with muscle weakness. However, the mitochondrial changes including molecular events associated with impaired lipid storage have not been completely understood in the human skeletal muscle. We carried out morphological and biochemical analysis of mitochondrial function in muscle biopsies of human subjects with LSDs (n = 7), compared to controls (n = 10). Routine histology, enzyme histochemistry and ultrastructural analysis indicated altered muscle cell morphology and mitochondrial structure. Protein profiling of the muscle mitochondria from LSD samples (n = 5) (vs. control, n = 5) by high-throughput mass spectrometric analysis revealed that impaired metabolic processes could contribute to mitochondrial dysfunction and ensuing myopathy in LSDs. We propose that impaired fatty acid and respiratory metabolism along with increased membrane permeability, elevated lipolysis and altered cristae entail mitochondrial dysfunction in LSDs. Some of these mechanisms were unique to LSD apart from others that were common to dystrophic and inflammatory muscle pathologies. Many differentially regulated mitochondrial proteins in LSD are linked with other human diseases, indicating that mitochondrial protection via targeted drugs could be a treatment modality in LSD and related metabolic diseases. Cover Image for this Issue: doi: 10.1111/jnc.14177. PMID- 29424034 TI - Total and Toxocara canis larval excretory/secretory antigen- and allergen specific IgE in atopic and non-atopic dogs. AB - BACKGROUND: Total IgE concentrations are higher in dogs than in humans. Persistent Toxocara canis larval infection is prevalent in dogs and is associated with substantial specific antibody reactions. A correlation, however, between total IgE and T. canis-specific antibody levels in dogs has not been evaluated. OBJECTIVES: To determine the relationship between total IgE, T. canis-specific IgG and IgE, and allergen-specific IgE levels in atopic and non-atopic dogs, and to evaluate possible confounding factors. ANIMALS: Sera of 30 atopic and 30 non atopic client-owned dogs. METHODS: Total IgE, T. canis-specific antibody and allergen-specific IgE levels were evaluated by ELISA. RESULTS: Total IgE, T. canis-specific antibody and allergen-specific IgE levels were significantly higher in non-atopic compared to atopic dogs. A positive correlation was demonstrated between T. canis-specific IgG and T. canis-specific IgE; T. canis specific IgG and total IgE; T. canis-specific IgE and total IgE; and allergen specific IgE and total IgE. No differences were detected on the basis of age, gender, vaccination status; deworming or season between atopic and non-atopic dogs. Previous immunomodulatory treatment and cause of atopy did not influence antibody levels of atopic dogs. CONCLUSIONS: Toxocara canis-specific IgE appears to be a major component of total IgE in dogs. Total and T. canis-specific IgE levels are higher in non-atopic compared to atopic dogs. It is speculated that T. canis infection may have a protective effect against the development of canine atopic dermatitis and/or that elevations in total serum IgE level are often not associated with atopic dermatitis. PMID- 29424035 TI - Involvement of spinal cannabinoid receptors in the antipruritic effects of WIN 55,212-2, a cannabinoid receptor agonist. AB - BACKGROUND: Cannabinoids have been used for their analgesic and euphoric effects for millennia, but recently the antipruritic effects of cannabis have been discovered. Considering the similarities between pain and itch sensations, we hypothesized that cannabinoid receptors may play a role in the antipruritic effects of cannabinoids. AIM: To analyse the role of the spinal cannabinoid receptors, CB1 and CB2, in the antipruritic effects of the cannabinoid agonist WIN 55,212-2. METHODS: Male Balb/c mice weighing 20-30 g were used. Scratching behaviour in the mice was produced by injection of serotonin 5 MUg/50 MUL intradermally into the nape of the neck. Scratching of the site of injection by the hind paws was video-recorded for 30 min. After testing different doses of WIN 55,212-2 [1, 3 and 10 mg/kg intraperitoneally (IP)], the effects of the CB1 receptor antagonist, AM-251 [1 MUg/mouse administered intrathecally (IT)] and the CB2 receptor antagonist AM-630 (4 MUg/mouse IT) on the antipruritic effects of WIN 55,212-2 were studied using a rotarod apparatus. RESULTS: WIN 55,212-2 (1, 3 or 10 mg/kg IP) dose-dependently decreased serotonin-induced scratches. The receptor antagonist CB1 partially reversed the effects of WIN 55,212-2 (P < 0.05); whereas CB2 had no statistically significant effect. WIN 55,212-2 impaired motor function only at the highest dose given (10 mg/kg, P < 0.05). CONCLUSIONS: Our findings support prior researches indicating that cannabinoids exert antipruritic effects. Moreover, our results show that the antipruritic effects of cannabinoids are partially mediated by spinal CB1 receptors. PMID- 29424036 TI - Bioluminescence-based cytotoxicity assay for simultaneous evaluation of cell viability and membrane damage in human hepatoma HepG2 cells. AB - We have developed a bioluminescence-based non-destructive cytotoxicity assay in which cell viability and membrane damage are simultaneously evaluated using Emerald luciferase (ELuc) and endoplasmic reticulum (ER)-targeted copepod luciferase (GLuc-KDEL), respectively, by using multi-integrase mouse artificial chromosome (MI-MAC) vector. We have demonstrated that the time-dependent concentration response curves of ELuc luminescence intensity and WST-1 assay, and GLuc-KDEL luminescence intensity and lactate dehydrogenase (LDH) activity in the culture medium accompanied by cytotoxicity show good agreement in toxicant treated ELuc- and GLuc-KDEL-expressing HepG2 stable cell lines. We have clarified that the increase of GLuc-KDEL luminescence intensity in the culture medium reflects the type of cell death, including necrosis and late apoptosis, but not early apoptosis. We have also uncovered a strong correlation between GLuc-KDEL luminescence intensity in the culture medium and the extracellular release of high mobility group box 1 (HMGB1), a representative damage-associated molecular pattern (DAMP) molecule. The bioluminescence measurement assay using ELuc and GLuc-KDEL developed in this study can simultaneously monitor cell viability and membrane damage, respectively, and the increase of GLuc-KDEL luminescence intensity in the culture medium accompanied by the increase of cytotoxicity is an index of necrosis and late apoptosis associated with the extracellular release of DAMP molecules. PMID- 29424037 TI - Severity of OSAS, CPAP and cardiovascular events: A follow-up study. AB - BACKGROUND: Previous studies suggested obstructive sleep apnoea syndrome (OSAS) as a major risk factor for incident cardiovascular events. However, the relationship between OSAS severity, the use of continuous positive airway pressure (CPAP) treatment and the development of cardiovascular disease is still matter of debate. STUDY OBJECTIVES: The aim was to test the association between OSAS and cardiovascular events in patients with concomitant cardio-metabolic diseases and the potential impact of CPAP therapy on cardiovascular outcomes. METHODS: Prospective observational cohort study of consecutive outpatients with suspected metabolic disorders who had complete clinical and biochemical workup including polysomnography because of heavy snoring and possible OSAS. The primary endpoint was a composite of major adverse cardiovascular and cerebrovascular events (MACCE). RESULTS: Median follow-up was 81.3 months, including 434 patients (2701.2 person/years); 83 had a primary snoring, 84 had mild, 93 moderate and 174 severe OSAS, respectively. The incidence of MACCE was 0.8% per year (95% confidence interval [CI] 0.2-2.1) in primary snorers and 2.1% per year (95% CI 1.5-2.8) for those with OSAS. A positive association was observed between event free survival and OSAS severity (log-rank test; P = .041). A multivariable Cox regression analysis showed obesity (HR = 8.011, 95% CI 1.071-59.922, P = .043), moderate OSAS (vs non-OSAS HR = 3.853, 95% CI 1.069-13.879, P = .039) and severe OSAS (vs non-OSAS HR = 3.540, 95% CI 1.026-12.217, P = .045) as predictors of MACCE. No significant association was observed between CPAP treatment and MACCE (log-rank test; P = .227). CONCLUSIONS: Our findings support the role of moderate/severe OSAS as a risk factor for incident MACCE. CPAP treatment was not associated with a lower rate of MACCE. PMID- 29424038 TI - Workplace-related generational characteristics of nurses: A mixed-method systematic review. AB - AIMS: The aim of this study was to describe and summarize workplace characteristics of three nursing generations: Baby Boomers, Generations X and Y. BACKGROUND: Generational differences affect occupational well-being, nurses' performance, patient outcomes and safety; therefore, nurse managers, administrators and educators are interested increasingly in making evidence-based decisions about the multigenerational nursing workforce. DESIGN: Mixed-method systematic review. DATA SOURCES: Medline, CINAHL, PsycINFO and Scopus (January 1991-January 2017). REVIEW METHODS: (1) The Joanna Briggs Institute's method for conducting mixed-method systematic reviews; (2) the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and (3) the Enhancing Transparency in Reporting the Synthesis of Qualitative Research guidelines. The studies' methodological quality was assessed with the Mixed-Methods Appraisal Tool. Quantitative and mixed-method studies were transformed into qualitative methods using a convergent qualitative synthesis and qualitative findings were combined with a narrative synthesis. RESULTS: Thirty-three studies were included with three main themes and 11 subthemes: (1) Job attitudes (work engagement; turnover intentions, reasons for leaving; reasons, incentives/disincentives to continue nursing); (2) Emotion-related job aspects (stress/resilience; well-being/job satisfaction; affective commitment; unit climate; work ethic) and (3) Practice and leadership-related aspects (autonomy; perceived competence; leadership relationships and perceptions). Baby Boomers reported lower levels of stress and burnout than did Generations X and Y, different work engagement, factors affecting workplace well-being and retention and greater intention to leave compared with Generation Y, which was less resilient, but more cohesive. CONCLUSION: Although several studies reported methodological limitations and conflicting findings, generational differences in nurses' job attitudes, emotional, practice and leadership factors should be considered to enhance workplace quality. PMID- 29424039 TI - Organising nursing practice into care models that catalyse quality: A clinical nurse leader case study. AB - AIMS: To determine the power of a conceptual clinical nurse leader practice model to explain the care model's enactment and trajectory in real world settings. BACKGROUND: How nursing, organised into specific models of care, functions as an organisational strategy for quality is not well specified. Clinical nurse leader integrated care delivery is one emerging model with growing adoption. A recently validated clinical nurse leader practice model conceptualizes the care model's characteristics and hypothesizes their mechanisms of action. METHODS: Pattern matching case study design and mixed methods were used to determine how the care model's constructs were operationalized in one regional United States health system that integrated clinical nurse leaders into their care delivery system in 2010. RESULTS: The findings confirmed the empirical presence of all clinical nurse leader practice model constructs and provided a rich description of how the health system operationalized the constructs in practice. The findings support the hypothesized model pathway from Clinical Nurse Leader structuring to Clinical Nurse Leader practice and outcomes. CONCLUSION: The findings indicate analytic generalizability of the clinical nurse leader practice model. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing practice organised to focus on microsystem care processes can catalyse multidisciplinary engagement with, and consistent enactment of, quality practices. The model has great potential for transferability across diverse health systems. PMID- 29424041 TI - Neuropsychological differentiation of progressive aphasic disorders. AB - The differentiation of subtypes of primary progressive aphasia (PPA) remains challenging. We aimed to identify optimum neuropsychological measures for characterizing PPA, to examine the relationship between behavioural change and subtypes of PPA and to determine whether characteristic profiles of language, working memory, and behavioural changes occur in PPA. Forty-seven patients with PPA and multi-domain Alzheimer's disease (AD) together with 19 age-matched controls underwent a large battery of working memory and language tests. We found that simple tasks of sentence ordering, narrative production, and buccofacial praxis were particularly useful in differentiating non-fluent/agrammatic variant PPA (nfvPPA) from other PPA subtypes, whereas a test of single word comprehension was useful in detecting semantic dementia (SD). No individual tests were discriminating for logopenic variant PPA (lvPPA) relative to nfvPPA. LvPPA and multidomain AD exhibited similar language profiles. A principal components analysis revealed that characteristic PPA profiles extended beyond the realms of language, in particular, the presence of apraxia in nfvPPA, behavioural changes in SD, and working memory deficits in lvPPA. These findings suggest that not all tests are equally discriminatory for PPA and highlight the importance of a test profile in differentiating PPA. These results also support the view that lvPPA is a focal form of AD and emphasize the difficulties classifying lvPPA. PMID- 29424040 TI - Alpha event-related synchronization after eye closing differs in Alzheimer's disease and dementia with Lewy bodies: a magnetoencephalography study. AB - BACKGROUND: The electroencephalography (EEG) abnormalities found in patients with dementia with Lewy bodies (DLB) are conflicting. In this study, we used magnetoencephalography, which has higher spatial resolution than electroencephalography, to explore neurophysiological features of DLB that may aid in the differential diagnosis. METHODS: Six patients with DLB, 11 patients with Alzheimer's disease, and 11 age-matched normal subjects were recruited. We investigated alterations in the ratio of event-related synchronization (ERS) in the alpha band after eye-closing. RESULTS: Although the averaged ratio change of alpha ERS after eye-closing appeared predominantly in the posterior brain regions in all study groups, DLB patients had the weakest ratio change of alpha ERS. In particular, DLB patients exhibited a significantly reduced ratio change of alpha ERS in the bilateral inferior temporal gyrus, right occipital pole, and left parieto-occipital cortex compared to Alzheimer's disease patients or normal controls. CONCLUSION: Our findings indicated that a reduced ratio change of alpha ERS in the posterior brain regions elicited by eye-closing is a brain electromagnetic feature of DLB. PMID- 29424042 TI - Negative influence of pKa on activation energy barrier: A case study for double proton transfer reaction in inorganic acid dimers. AB - Strength of acid can be determined by means of pKa value. Attempts have been made to find a relationship between pKa and activation energy barrier for a double proton transfer (DPT) reaction in inorganic acid dimers. Negative influence of pKa is observed on activation energy (Ea ) which is contrary to the general convention of pKa . Four different levels of theories with two different basis sets have been used to calculate the activation energy barrier of the DPT reaction in inorganic acid dimers. A model based on first and second order polynomial has been created to find the relationship between activation energy for DPT reaction. (c) 2018 Wiley Periodicals, Inc. PMID- 29424043 TI - Sex differences in binge-like EtOH drinking, corticotropin-releasing hormone and corticosterone: effects of beta-endorphin. AB - Binge drinking is an increasingly common pattern of risky use associated with numerous health problems, including alcohol use disorders. Because low basal plasma levels of beta-endorphin (beta-E) and an increased beta-E response to alcohol are evident in genetically at-risk human populations, this peptide is thought to contribute to the susceptibility for disordered drinking. Animal models suggest that the effect of beta-E on consumption may be sex-dependent. Here, we studied binge-like EtOH consumption in transgenic mice possessing varying levels of beta-E: wild-type controls with 100% of the peptide (beta-E +/+), heterozygous mice constitutively modified to possess 50% of wild-type levels (beta-E +/-) and mice entirely lacking the capacity to synthesize beta-E ( /-). These three genotypes and both sexes were evaluated in a 4-day, two-bottle choice, drinking in the dark paradigm with limited access to 20% EtOH. beta-E deficiency determined sexually divergent patterns of drinking in that beta-E -/- female mice drank more than their wild-type counterparts, an effect not observed in male mice. beta-E -/- female mice also displayed elevated basal anxiety, plasma corticosterone and corticotropin-releasing hormone mRNA in the extended amygdala, and all of these were normalized by EtOH self-administration. These data suggest that a heightened risk for excessive EtOH consumption in female mice is related to the drug's ability to ameliorate an overactive anxiety/stress-like state. Taken together, our study highlights a critical impact of sex on neuropeptide regulation of EtOH consumption. PMID- 29424045 TI - Unilateral telangiectasia macularis eruptiva perstans with an unusual clinical presentation. PMID- 29424044 TI - Validation of daily urinary creatinine excretion measurement by muscle-creatinine equivalence. AB - BACKGROUND: Twenty-four-hour urinary creatinine excretion (24hUCrE) is strongly correlated with skeletal muscle mass (SMM). This study suggests how to exploit the power of the SMM-24hUCrE correlation to assess the accuracy of 24hUCrE measurement. METHODS: Four hundred and sixty-six men, a subgroup of participants in the 2002-2004 follow-up examination of the Olivetti Heart Study, performed a 24-h urine collection to measure 24hUCrE and underwent bioelectrical impedance analysis to evaluate SMM. Linear regression analysis between 24hUCrE and SMM was used to calculate the muscle-creatinine equivalence and to develop an equation to predict the 24hUCrE depending on SMM. The accuracy of the 24hUCrE measurement was assessed using the change in the SMM-24hUCrE correlation coefficient upon variation in the percentage deviation (%D) between the measured and predicted 24hUCrE. RESULTS: The calculated muscle-creatinine equivalence was 1 g of 24hUCrE = 22.73 kg of SMM. The %Ds and the corresponding SMM-24hUCrE correlation coefficients were as follows: %D = 3.0, r = .997; %D = 4.7, r = .989; %D = 8.1, r = .963; %D = 10.5, r = .940; %D = 12.6, r = .909; %D = 18.9, r = .825; %D = 25.8, r = .707; %D = 33.5, r = .595; %D = 41.4, r = .453. CONCLUSION: The increase in %D corresponds to a reduced correlation between muscle mass and creatinine excretion, which indicated a poor performance in the measurement of the 24hUCrE. For studies on single individuals, where small variations in 24hUCrE could be significant, a %D up to 12.6% is suggested; on the other hand, a wider %D interval could be acceptable for population studies. PMID- 29424046 TI - Highly Dispersed Metal Carbide on ZIF-Derived Pyridinic-N-Doped Carbon for CO2 Enrichment and Selective Hydrogenation. AB - Catalytic conversion of CO2 into chemicals is a critical issue for energy and environmental research. Among such reactions, converting CO2 into CO has been regarded as a significant foundation to generate a liquid fuels and chemicals on a large scale. In this work, zeolitic imidazolate framework-derived N-doped carbon-supported metal carbide catalysts (M/ZIF-8-C; M=Ni, Fe, Co and Cu) with highly dispersed metal carbide were prepared for selective CO2 hydrogenation. Under the same metal loadings, catalytic activity for CO2 hydrogenation to CO follows the order: Ni/ZIF-8-C~Fe/ZIF-8-C>Co/ZIF-8-C>Cu/ZIF-8-C. These catalysts are composed of carbide or metal supported on pyridinic N sites within the N doped carbon structure. ZIF-8-derived pyridinic nitrogen and carbide effect CO2 adsorption, whereas dispersed Ni or Fe carbide and metal species serve as an active site for CO2 hydrogenation. The supported Ni catalyst exhibits extraordinary catalytic performance, which results from high dispersion of the metal and exposure of the carbide. Based on high-sensitivity low-energy ion scattering (HS-LEIS) and line scan results, density functional theory (DFT) was used to understand reaction mechanism of selective CO2 hydrogenation over Ni/ZIF 8-C. The product CO is derived mainly from the direct cleavage of C-O bonds in CO2 * rather than decomposition of COOH*. The CO* desorption energy on Ni/ZIF-8-C is lower than that for further hydrogenation and dissociation. Comparison of Ni/ZIF-8-C with ZIF-8-C indicates that the combined effects of the highly dispersed metal or carbide and weak CO adsorption result in high CO selectivity for CO2 hydrogenation. PMID- 29424047 TI - Halogen Bond Catalyzed Bromocarbocyclization. AB - A halogen bond catalyzed bromo-carbocyclization of N-cinnamyl sulfonamides and O cinnamyl phenyl ethers has been developed. N-methyl 4-iodopyridinium triflate is used as the halogen-bonding organocatalyst and the reaction is highly chemoselective. This report represents the first proof-of-concept for halogen bonding organocatalyst-promoted electrophilic halogenation. Mechanistic study suggests the autocatalytic nature of this reaction. PMID- 29424048 TI - Fe2 O+ Cation Mediated Propane Oxidation by Dioxygen in the Gas Phase. AB - The mass-selected Fe2 O+ cation mediated propane oxidation by O2 was investigated by mass spectrometry and density functional theory calculations. In the reaction of Fe2 O+ with C3 H8 , H2 was liberated by C-H bond activation to give Fe2 OC3 H6+ . Interestingly, when a mixture of C3 H8 /O2 was introduced into the reactor, an intense signal that corresponded to the Fe2 O2+ cation was present; the experiments indicated that O2 was activated in its reaction with Fe2 O(C3 H6 )+ to give Fe2 O2+ and C3 H6 O (acetone or propanal). A Langmuir-Hinshelwood-like mechanism was adopted in the propane oxidation reaction by O2 on gas-phase Fe2 O+ cations. In comparison with the absence of Fe2 O2+ in the reaction of Fe2 O+ with O2 , the ligand effect of C3 H6 on Fe2 OC3 H6+ is important in the oxygen activation reaction. The theoretical results are consistent with the experimental observations. The propane oxidation by O2 in the presence of Fe2 O+ might be applied as a model for alkane and O2 activations over iron oxide catalysts, and the mechanisms and kinetic data are useful for understanding corresponding heterogeneous reactions. PMID- 29424050 TI - Salmonella and Campylobacter biofilm formation: a comparative assessment from farm to fork. AB - It takes several steps to bring food from the farm to the fork (dining table), and contamination with food-borne pathogens can occur at any point in the process. Campylobacter spp. and Salmonella spp. are the main microorganisms responsible for foodborne disease in the EU. These two pathogens are able to persist throughout the food supply chain thanks to their ability to form biofilms. Owing to the high prevalence of Salmonella and especially of Campylobacter in the food supply chain and the huge efforts of food authorities to reduce these levels, it is of great importance to fully understand their mechanisms of persistence. Diverse studies have evaluated the biofilm-forming capacity of foodborne pathogens isolated at different steps of food production. Nonetheless, the principal obstacle of these studies is to reproduce the real conditions that microorganisms encounter in the food supply chain. While there are a wide number of Salmonella biofilm studies, information on Campylobacter biofilms is still limited. A comparison between the two microorganisms could help to develop new research in the field of Campylobacter biofilms. Therefore, this review evaluates relevant work in the field of Salmonella and Campylobacter biofilms and the applicability of the data obtained from these studies to real working conditions. (c) 2018 Society of Chemical Industry. PMID- 29424049 TI - Astrocyte disruption of neurovascular communication is linked to cortical damage in an animal model of multiple sclerosis. AB - To elucidate mechanisms contributing to cortical pathology in multiple sclerosis (MS), we investigated neurovascular aberrations, in particular the association of astrocytes with cortical neurons and blood vessels, in mice induced with experimental autoimmune encephalomyelitis (EAE). Blood-brain barrier (BBB) dysfunction was evident by leakage of the tracer sodium fluorescein, along with reduced expression of claudin-5 by endothelial cells and desmin by pericytes. Immunohistological and ultrastructural analyses revealed detachment of the astroglial cell bodies from the blood vessels and loss of their connections with both the blood vessels and the neuronal synapses. Furthermore, examination of individual astrocytic processes at cortical layer IV, where well-defined neuronal columns (barrels) are linked to functional properties, revealed loss of astrocytic confinement to the functional neuronal boundaries. Thus, in contrast to the highly modulated patches of astrocyte processes in naive mice overlapping the barrel cores, in EAE-mice process distribution was uniform ignoring the barrel boundaries. These aberrations are attributed to the surrounding inflammation, indicated by T-cells presence in the cortex as well as in the subcortical white matter and the meninges. Immunomodulatory treatment with glatiramer acetate partially abrogated the neurovascular damage. These combined findings indicate that under inflammatory conditions, activated perivascular astrocytes fail in neuro-hemodynamic coupling, resulting in obstructed cross-talk between the blood vessels and the neurons. We propose that loss of cortical astrocytic regulation and fine-tuning between the blood supply and the neuronal needs contributes to the neurological impairment and cognitive decline occurring in EAE/MS as well as to the disease progression. PMID- 29424051 TI - Highly Efficient and Stable Flexible Perovskite Solar Cells with Metal Oxides Nanoparticle Charge Extraction Layers. AB - In this study, the fabrication of highly efficient and durable flexible inverted perovskite solar cells (PSCs) is reported. Presynthesized, solution-derived NiOx and ZnO nanoparticles films are employed at room temperature as a hole transport layer (HTL) and electron transport layer (ETL), respectively. The triple cation perovskite films are produced in a single step and for the sake of comparison, ultrasmooth and pinhole-free absorbing layers are also fabricated using MAPbI3 perovskite. The triple cation perovskite cells exhibit champion power conversion efficiencies (PCEs) of 18.6% with high stabilized power conversion efficiency of 17.7% on rigid glass/indium tin oxide (ITO) substrates (comparing with 16.6% PCE with 16.1% stabilized output efficiency for the flexible polyethylene naphthalate (PEN)/thin film barrier/ITO substrates). More interestingly, the durability of flexible PSC under simulation of operative condition is proved. Over 85% of the maximum stabilized output efficiency is retained after 1000 h aging employing a thin MAPbI3 perovskite (over 90% after 500 h with a thick triple cation perovskite). This result is comparable to a similar state of the art rigid PSC and represents a breakthrough in the stability of flexible PSC using ETLs and HTLs compatible with roll to roll production speed, thanks to their room temperature processing. PMID- 29424052 TI - Persistence of plasmid-mediated expression of transgenes in human mesenchymal stem cells depends primarily on CpG levels of both vector and transgene. AB - BACKGROUND: Gene therapy and cell modification for clinical applications using plasmid vectors are considered to be a safe and promising strategy. One of the major problems with plasmid vector-based constructs is a rapid decline of transgene expression in cells in vitro and in vivo. An important role of CpG motifs or bacterial vector backbone in expression silencing has been suggested. METHODS: To address the effects of CpG motifs on transgene expression maintenance in stem cells in vitro, we constructed a novel pMBR2 plasmid vector containing 13 CpG motifs only. pMBR2 constructs with CpG-free and CpG-replete firefly luciferase inserts were introduced into cultured human adipose-derived mesenchymal stem (MSCs) by electroporation, and luciferase expression levels were monitored for 3 weeks. RESULTS: The pMBR2 vector with CpG-free luciferase insert demonstrated the highest persistence of expression, whereas the wild-type luciferase insert containing 97 CpG motifs demonstrated lower expression maintenance in the same vector. In comparison, the same inserts in the CpG replete pCDNA3 vector demonstrated significantly lower expression levels and only a minimal persistence of expression. beta-galactosidase and enhanced green fluorescent protein genes inserted into pMBR2 vector also demonstrated higher expression levels and better maintenance compared to the same genes in pCDNA3 vector. CONCLUSIONS: The persistence of plasmid vector expression in human MSCs is determined primarily by CpG content of both vector and transgene. The data obtained in the present study indicate that the pMBR2 vector with a minimized number of CpG motifs is appropriate for extended plasmid-mediated expression of transgenes in MSCs and possibly other types of stem cells. PMID- 29424053 TI - Abstracts from the 2017 BDA Research Symposium, 6 December 2017, Birmingham, UK. Publication of this supplement has been supported by the British Dietetic Association. PMID- 29424054 TI - Chitin biological absorbable catheters bridging sural nerve grafts transplanted into sciatic nerve defects promote nerve regeneration. AB - AIMS: To investigate the efficacy of chitin biological absorbable catheters in a rat model of autologous nerve transplantation. METHODS: A segment of sciatic nerve was removed to produce a sciatic nerve defect, and the sural nerve was cut from the ipsilateral leg and used as a graft to bridge the defect, with or without use of a chitin biological absorbable catheter surrounding the graft. The number and morphology of regenerating myelinated fibers, nerve conduction velocity, nerve function index, triceps surae muscle morphology, and sensory function were evaluated at 9 and 12 months after surgery. RESULTS: All of the above parameters were improved in rats in which the nerve graft was bridged with chitin biological absorbable catheters compared with rats without catheters. CONCLUSIONS: The results of this study indicate that use of chitin biological absorbable catheters to surround sural nerve grafts bridging sciatic nerve defects promotes recovery of structural, motor, and sensory function and improves muscle fiber morphology. PMID- 29424055 TI - Characterization of Swedish Campylobacter coli clade 2 and clade 3 water isolates. AB - Campylobacter jejuni and Campylobacter coli are important bacterial enteropathogens. Poultry is the best-known reservoir for Campylobacter infection but natural bodies of water have also been shown to be important pathways for transmission. Campylobacter can survive in cold water but most of the studies have focused on C. jejuni only. In this paper, we take a closer look at the biology and water survival strategies of C. coli. Eight C. coli isolates cultivated from raw (incoming) surface water at water plants in Sweden were characterized using whole-genome sequencing and phenotypical assays. Phylogenetic analysis assigned the Swedish water isolates to clades 2 and 3, known to include C. coli of environmental origin. In addition, 53 earlier published sequences of C. coli clade 2 and 3 from environmental waters were included for in silico analyses. Generally, clade 2 isolates had larger genomes, which included a functional tricarballylate utilization locus, while clade 3 isolates contained different genes involved in oxidative stress as well as putative virulence factors. The Swedish water isolates of clade 2 formed large, blurry bacterial colonies on agar, whereas clade 3 colonies were smaller. All Swedish isolates were motile, but clade 3 isolates formed larger motility zones on soft agar, and none of these isolates produced biofilm. Although water survival varied between the analyzed isolates, there were hardly any clade-specific significant differences. Our results highlight the diversity of C. coli in general, and show differences in metabolic capabilities and ways to handle oxidative stress between clade 2 and 3 water isolates. PMID- 29424056 TI - Ultralong-Discharge-Time Biobattery Based on Immobilized Enzymes in Bilayer Rolled-Up Enzymatic Nanomembranes. AB - Glucose biofuel cells (GBFCs) are highly promising power sources for implantable biomedical and consumer electronics because they provide a high energy density and safety. However, it remains a great challenge to combine their high power density with reliable long-term stability. In this study, a novel GBFC design based on the enzyme biocatalysts glucose dehydrogenase, diaphorase, and bilirubin oxidase immobilized in rolled-up titanium nanomembranes is reported. The setup delivers a maximum areal power density of ~3.7 mW cm-2 and a stable power output of ~0.8 mW cm-2 . The power discharges over 452 h, which is considerably longer than reported previously. These results demonstrate that the GBFC design is in principle a feasible and effective approach to solve the long-term discharge challenge for implantable biomedical device applications. PMID- 29424057 TI - Beverage intake of Australian children and relationship with intake of fruit, vegetables, milk and body weight at 2, 3.7 and 5 years of age. AB - AIM: Describe the type and amount of beverages consumed by Australian children at age 2, 3.7 and 5; investigate the longitudinal relationship between intake of sweet beverages with fruits and vegetables or milk/alternatives, and body mass index (BMI) z-score. METHODS: Mothers in the NOURISH trial completed a single 24 hour recall of their child's intake, at age 2 (n = 515), 3.7 (n = 426) and 5 (n = 405). Anthropometry was measured by study staff. At each time point, proportion of children consuming at least one beverage on 24-hour recall from the following groups was determined; essential-cow's milk/alternatives, breast milk; non essential-formula, sweet beverages. For consumers, intake (grams) of each beverage and proportion total estimated energy intake was calculated. The longitudinal relationship between intake of sweet beverages, and fruit and vegetable intake (g/kg body weight), with BMI z-score at 2, 3.7 and 5 years was examined using structural equation modelling. A second model investigated relationship with intake of milk/alternatives. RESULTS: Sweet beverages were consumed by 38, 55 and 47% of children at each time point. Intake of sweet beverages strongly correlated between two and five years; however, intake was not associated with BMIz and did not appear to displace fruit and vegetable intake. Intake of cow's milk declined over time and was negatively associated with intake of sweet beverages at two and five years. CONCLUSIONS: Tracking of intake over time supports the notion that children's early experience of sweet tastes is a strong predictor of future intake. Limiting exposure to sweet beverages in early childhood remains an important strategy in the development of healthy food preferences and promotion of dietary quality. PMID- 29424058 TI - A realistic evaluation approach highlighted the success factors and difficulties of an innovative and comprehensive malnutrition programme in Madagascar. AB - AIM: Malnutrition has multiple causes, not just a lack of calories. We explored the successes and barriers of an innovative, comprehensive programme in Madagascar that educated mothers in particular about nutrition. METHODS: The outpatient programme in Antananarivo treats 2400 malnourished children from 6 to 59 months each year. The 35-day programme comprises health checks, cooking demonstrations, the distribution of enriched flour supplements and two food related games that are called Nutricartes and are based on boards and picture cards. In 2014, we involved 74 of the children's mothers in a realistic evaluation process, which investigates the mechanisms that produce a particular outcome in a given context. RESULTS: The mechanisms of success were the community based aspects of the programme, the kindness and equality displayed by the nutritional assistants and improved household budgeting and hygiene. Children ate better and improved their health, which reduced medical visits and costs. Finally, the mothers became proud of their achievements and told other mothers what they had learnt. Adherence was greatest when the women were on a minimum wage and strongly motivated. CONCLUSION: The effect of this multifaceted programme was that the mothers received sustainable education about healthy eating and improved childhood health and nutrition. PMID- 29424059 TI - Effective dose of dexmedetomidine as an adjuvant sedative to peripheral nerve blockade in elderly patients. AB - BACKGROUND: The median effective dose (ED50 ) of sedative dexmedetomidine adjuvant to peripheral nerve block (PNB) has not yet been verified in elderly patients. This study assessed the ED50 of intravenous dexmedetomidine for sedation in elderly patients who were undergoing total knee arthroplasty (TKA) with PNB. METHODS: Forty-two patients aged 65-85 years were included and stratified into two groups according to age: young-old group (aged 65-74 years) and middle-old group (aged 75-85 years). After the PNB was performed, a pre calculated dose of dexmedetomidine was administered for 10 min. The Observer's Assessment of Alertness/Sedation scale, bispectral index score, blood pressure and heart rate were recorded. ED50 values of dexmedetomidine for adequate sedation were estimated by the up-and-down method of Dixon and probit regression. RESULTS: The ED50 of single-dose dexmedetomidine adjuvant to PNB was 0.57 MUg/kg (95% confidence interval [CI], 0.47-0.65) in the young-old group and 0.38 MUg/kg (95% CI, 0.28-0.46) in the middle-old group. The ED50 of dexmedetomidine differed significantly between the two groups (P < 0.001). In addition, no significant adverse hemodynamic or hypoxemic effects were noted. CONCLUSION: We determined the ED50 for sedation using intravenous dexmedetomidine adjuvant to PNB in elderly patients. The ED50 of dexmedetomidine in the middle-old group decreased by 33% compared with that in the young-old group with a mean age difference of 11 years between the two groups. PMID- 29424060 TI - Monodisperse CNT Microspheres for High Permeability and Efficiency Flow-Through Filtration Applications. AB - Carbon nanotube (CNT)-based filters have the potential to revolutionize water treatment because of their high capacity and fast kinetics in sorption of organic, inorganic, and biological pollutants. To date, CNT filters either rely on CNTs dispersed in liquids, which are difficult to recover and cause safety concerns, or on CNT buckypaper, which offers high efficiency, but suffers from an intrinsic trade-off between filter permeability and capacity. Here, a new approach is presented that bypasses this trade-off and achieves buckypaper-like efficiency combined with filter-column-like permeability and capacity. For this, CNTs are first assembled into porous microspheres and then are packed into microfluidic column filters. These microcolumns exhibit large flow-through filtration efficiencies, while maintaining membrane permeabilities an order of magnitude larger then CNT buckypaper and specific permeabilities double that of activated carbon for similar flowrates (232 000 L m-2 h-1 bar-1 , 1.23 * 10-12 m2 ). Moreover, in a test to remove sodium dodecyl sulfate (SDS) from water, these microstructured CNT columns outperform activated carbon columns. This improved filtration efficiency and permeability is an important step toward a broader implementation of CNT-based filtration devices. PMID- 29424062 TI - Abrogation of fluid suppression in intracranial postcontrast fluid-attenuated inversion recovery magnetic resonance imaging: A clinical and phantom study. AB - Postcontrast, fluid-attenuated inversion recovery (FLAIR) sequences are reported to be of variable value in veterinary and human neuroimaging. The source of hyperintensity in postcontrast-T2 FLAIR images is inconsistently reported and has implications for the significance of imaging findings. We hypothesized that the main source of increased signal intensity in postcontrast-T2 FLAIR images would be due to gadolinium leakage into adjacent fluid, and that the resulting gadolinium-induced T1 shortening causes reappearance of fluid hyperintensity, previously nulled on precontrast FLAIR images. A retrospective, descriptive study was carried out comparing T2 weighted, pre- and postcontrast T1 weighted and pre- and postcontrast weighted T2 FLAIR images in a variety of intracranial diseases in dogs and cats. A prospective, experimental, phantom, in vitro study was also done to compare the relative effects of gadolinium concentration on T2 weighted, T1 weighted, and FLAIR images. A majority of hyperintensities on postcontrast-T2 FLAIR images that were not present on precontrast FLAIR images were also present on precontrast T2 weighted images, and were consistent with normal or pathological fluid filled structures. Phantom imaging demonstrated increased sensitivity of FLAIR sequences to low concentrations of gadolinium compared to T1 weighted sequences. Apparent contrast enhancement on postcontrast-T2 FLAIR images often reflects leakage of gadolinium across normal or pathology specific barriers into fluid-filled structures, and hyperintensity may therefore represent normal fluid structures as well as pathological tissues. Findings indicated that postcontrast-T2 FLAIR images may provide insight into integrity of biological structures such as the ependymal and subarachnoid barriers that may be relevant to progression of disease. PMID- 29424061 TI - Prospective diagnostic study on the use of narrow-band imaging on suspicious lesions during colonoscopy examination. AB - INTRODUCTION: Colonoscopy is the gold standard to detect colorectal neoplasm. Narrow-band imaging (NBI) has a good diagnostic accuracy to differentiate between neoplastic and non-neoplastic colorectal lesions. This study explores the diagnostic validity of NBI colonoscopy as well as its associated factors related to neoplastic and non-neoplastic colorectal lesions. METHODS: This study enrolled 100 patients in a single-center tertiary teaching hospital. Patients presented for screening colonoscopy, and those with suspicious colorectal lesions were included in this study. During colonoscopy, the most suspicious lesion in each patient was analyzed using the NBI system based on Sano's classification. Each lesion was biopsied for histopathological analysis, the gold standard. Endoscopic images were captured electronically. The sensitivity, specificity, and diagnostic accuracy of NBI colonoscopy were assessed. Other associated factors related to neoplastic and non-neoplastic lesions were analyzed accordingly. RESULTS: The sensitivity and specificity of the NBI were 88.2% and 71.9%, respectively. The area under the receiver-operator curve was 0.801, indicating that NBI has a good ability to differentiate between disease and non-disease. There are significant associations between histopathological examination outcomes and both presenting symptoms, especially weight loss, and lesion site, even after other variables were controlled (P < 0.05). CONCLUSION: The NBI system in colonoscopy was capable of distinguishing neoplastic from non-neoplastic colorectal lesions. It indicates an acceptable level of agreement with histopathology, the gold standard. However, the role of NBI in screening and surveillance in Malaysia still needs further evaluation and exploration. PMID- 29424063 TI - It is only fair: blood donors are more sensitive to violations of fairness norms than nondonors - converging psychometric and ultimatum game evidence. AB - BACKGROUND AND OBJECTIVES: The design of effective donor recruitment campaigns requires an accurate understanding of donor motivations. This requires cross validation of theoretically derived, psychometrically assessed motivations with behavioural preferences. Theoretical models suggest that blood donors should be more sensitive than nondonors to violations of fairness norms. Specifically, active blood donors, compared to nondonors, should endorse beliefs of reciprocal fairness, norms of both positive and negative reciprocity and reject more unfair offers in a behavioural economic game (the ultimatum game). This study is the first to test this hypothesis. MATERIALS AND METHODS: Two studies are reported. One experimental psychometric study (N = 400) and one behavioural economic game using the ultimatum game (N = 60). RESULTS: Consistent with the predictions, active and lapsed donors, compared to nondonors, were more likely to endorse beliefs of reciprocal fairness and active donors to endorse norms of both positive and negative reciprocity and reject more unfair offers in the ultimatum game. This pattern of motivations was unique to blood donors and not observed for other health (i.e. being on the organ donor register) and nonhealth (e.g. volunteering) prosociality. CONCLUSION: Blood donors have a heightened sensitivity to unfairness violations. This indicates a very clear and specific line for the development of interventions that align fairness, self-interest and reciprocity, for example voluntary reciprocal altruism (VRA). We also highlight the importance of establishing intervention development within a clinical trials model and emphasize why experimental work of this type is vital. PMID- 29424064 TI - Integrative Self-Sorting: One-Pot Synthesis of a Hetero[4]rotaxane from a Daisy Chain-Containing Hetero[4]pseudorotaxane. AB - The structural complexity of mechanically interlocked molecules are very attractive to chemists owing to the challenges they present. In this article, novel mechanically interlocked molecules with a daisy-chain-containing hetero[4]rotaxane motif were efficiently synthesized. In addition, a novel integrative self-sorting strategy is demonstrated, involving an ABB-type (A for host, dibenzo-24-crown-8 (DB24C8), and B for guest, ammonium salt sites) monomer and a macrocycle host, benzo-21-crown-7 (B21C7), in which the assembled species in hydrogen-bonding-supported solvent only includes a novel daisy-chain containing hetero[4]pseudorotaxane. The found self-sorting process involves the integrative recognition between B21C7 macrocycles and carefully designed components simultaneously containing two types of secondary ammonium ions and a host molecule, DB24C8 crown ether. The self-sorting strategy is integrative to undertake self-recognition behavior to form one single species of pseudorotaxane compared with the previous report. This self-sorting system can be used for the efficient one-pot synthesis of a daisy-chain-containing hetero[4]rotaxane in a good yield. The structure of hetero[4]rotaxane was confirmed by 1 H NMR spectroscopy and high-resolution electrospray ionization (HR-ESI) mass spectrometry. PMID- 29424065 TI - Trend and outcome of sepsis in children: A nationwide cohort study. AB - AIM: The aim of this study was to investigate the trend of incidence and outcome of paediatric sepsis in a population-based database. METHODS: Children with sepsis were identified from the 23 million nationwide health insurance claims database of Taiwan. Sepsis was defined by the presence of single ICD-9 code for severe sepsis or septic shock or a combination of ICD-9 codes for infection and organ dysfunction. We analysed the trend of incidence, mortality and source of infection in three age groups: infant (28 days to 1 year), child (1-9 years) and adolescent (10-18 years). RESULTS: From 2002 to 2012, we identified 38 582 paediatric patients with sepsis, of which 21.3% were infants, 52.8% were children and 25.8% were adolescents. The incidence of sepsis was 336.4 cases per 100 000 population in infants, 3.3 times higher than in children (101.5/100 000 cases) and 7.3 times higher than in adolescents (46.2/100 000 cases). While sepsis incidence decreased from 598.0 to 336.4 cases per 100 000 people in the infant population, it remained relatively unchanged in children and adolescents. For 90 day mortality, there were significant decreases in all three age groups (absolute decrease of 5.0% for infants, 3.7% for children and 14.4% for the adolescents). In the infant population, we observed a decrease in the incidence of lower respiratory tract infections, while the incidence of urinary tract infections remained unchanged. CONCLUSIONS: The incidence and mortality of sepsis among paediatric patients have decreased substantially between 2002 and 2012, especially among infants. The widespread use of Haemophilus influenzae and pneumococcal vaccines in infants could be a possible explanation. PMID- 29424066 TI - Untimely illness: When diagnosis does not match age-related expectations. AB - BACKGROUND: We explore the concept of "untimely diagnosis," where the onset of a long-term condition occurs at a life stage which does not conform to traditional expectations, focusing on two conditions (asthma and arthritis) typically associated with a particular life stage (childhood and older adulthood, respectively). Previous literature has focused on the meaning of chronic illness in terms of life history, and the biographical lens has been used in various ways to make sense of the experience. Less attention has been paid to the condition onset when it seems dissonant with chronological age. METHODS: Secondary analysis of two qualitative data sets (total 58 interviews) exploring the experiences of people with adult-onset asthma and young people diagnosed with arthritis. Data from the original interview transcripts relating to diagnosis and symptom recognition were re-analysed using a "candidacy" framework to examine how age and diagnosis intersect. RESULTS: People did not always assert their candidacy for either condition because of pre-conceived expectations around age. Similarly, health professionals sometimes failed to recognize patients' candidacy, instead pursuing "age-plausible" possibilities. In some cases, participants were proactive in suggesting a diagnosis to the health professional where diagnosis was delayed. CONCLUSION: The diagnosis of adult-onset asthma, and arthritis in young people, may be regarded as "untimely." We suggest that being diagnosed with what is perceived to be a "childhood" condition in adulthood, or "an older person's" condition in childhood, may be viewed as a "biographical paradox" and an "untimely breach" to the expected order. PMID- 29424067 TI - Drug-resistant epilepsy and topiramate: Plasma concentration and frequency of epileptic seizures. AB - Topiramate (TPM) is a second-generation antiepileptic drug (AED), acting on drug resistant epilepsy. The aim of the study was to evaluate the influence of the dose, use of other AEDs on TPM plasma concentration (Cp ), and frequency of epileptic seizures. A cross-sectional analytical study was developed with patients aged 18-60 years, for diagnosis of drug-resistant epilepsy, using TPM in monotherapy or associated with other AEDs. The following variables were analyzed: age, frequency of epileptic seizures, pharmacotherapeutic regimen with its respective doses, adherence to medication treatment, and adverse events score. Thirty-seven patients were included, 83.8% of the patients presented Cp below the therapeutic range. Multiple linear regression estimated that the increase of 1.0 mg/kg/d promoted an increase of 0.68 MUg/mL in TPMCp , while the use of inducers predicted a reduction of 2.97 MUg/mL (P < .001). Multiple Poisson regression predicts that an increase of 1.0 MUg/mL in TPMCp decreased the patient's chance of presenting seizures, and patients using AED inducers were about ten times more likely to present seizures than those who do not use (P < .001). In addition, for patients using AED inducers with Cp below the therapeutic range, the mean number of seizures per month was greater than those with Cp within the therapeutic range. The prescribed dose and the use of AED inducers influence Cp of TPM, likewise the low Cp of first-line AEDs and of the adjuvant in the treatment, TPM, as well as low TPM dose seem to affect the control of epileptic seizures. PMID- 29424068 TI - Mutations at multiple CDK phosphorylation consensus sites on Cdt2 increase the affinity of CRL4Cdt2 for PCNA and its ubiquitination activity in S phase. AB - CRL4Cdt2 ubiquitin ligase plays an important role maintaining genome integrity during the cell cycle. A recent report suggested that Cdk1 negatively regulates CRL4Cdt2 activity through phosphorylation of its receptor, Cdt2, but the involvement of phosphorylation remains unclear. To address this, we mutated all CDK consensus phosphorylation sites located in the C-terminal half region of Cdt2 (Cdt2-18A) and examined the effect on substrate degradation. We show that both cyclinA/Cdk2 and cyclinB/Cdk1 phosphorylated Cdt2 in vitro and that phosphorylation was reduced by the 18A mutation both in vitro and in vivo. The 18A mutation increased the affinity of Cdt2 to PCNA, and a high amount of Cdt2 18A was colocalized with PCNA foci during S phase in comparison with Cdt2-WT. Poly-ubiquitination activity to Cdt1 was concomitantly enhanced in cells expressing Cdt2-18A. Other CRL4Cdt2 substrates, Set8 and thymine DNA glycosylase, begin to accumulate around late S phase to G2 phase, but the accumulation was prevented in Cdt2-18A cells. Furthermore, mitotic degradation of Cdt1 after UV irradiation was induced in these cells. Our results suggest that CDK-mediated phosphorylation of Cdt2 inactivates its ubiquitin ligase activity by reducing its affinity to PCNA, an important strategy for regulating the levels of key proteins in the cell cycle. PMID- 29424069 TI - Development of a fibrosis index including hepatitis B virus basal core promoter A1762T mutation for pretherapeutic evaluation. AB - BACKGROUND AND AIM: Commonly used non-invasive fibrosis scores usually included serum transaminase levels in the equations, including Aspartate transaminase to Platelet Ratio Index (APRI) and fibrosis-4 (FIB-4). Transaminases fluctuated significantly in chronic hepatitis B patients with exacerbations, leading to unsteady score values. As such, here, we aim to develop a transaminase-free score suitable for pretherapeutic evaluation of fibrosis stages. METHODS: Firstly, 1082 treatment-naive chronic hepatitis B patients were enrolled and divided into modeling (n = 541) and verification (n = 541) cohorts. Secondly, 265 patients having received liver biopsy, with known Ishak fibrosis stages, were included for independent correlation. RESULTS: Cross-sectional analysis of 1082 patients revealed age-dependent variation of association between virological factors and cirrhosis. A fibrosis score including Anti-hepatitis B e antibody, Basal core promoter (BCP) A1762T mutation, and Platelet count Index (named ABPI) was derived from the modeling cohort. ABPI performed better than APRI and FIB-4 in the verification cohort for identifying cirrhotic patients (comparison of area under the receiver operating characteristic curves: ABPI vs APRI and FIB-4 = 0.785 vs 0.563 [P < 0.001] and 0.700 [P = 0.026], respectively). The performance of ABPI was even better in young (< 40 years old) hepatitis B patients (area under the receiver operating characteristic curves: 0.856 vs 0.402 [P < 0.001] and 0.599 [P = 0.009], respectively). Finally, in the independent cohort of 265 patients with known Ishak fibrosis stages, it was found that ABPI effectively distinguished between Ishak fibrosis stages 3 and > 3 and between 4 and > 4 (P < 0.001 for each). CONCLUSIONS: We developed a transaminase-free fibrosis score (ABPI) utilizing basal core promoter A1762T data, which outperformed APRI and FIB-4. PMID- 29424070 TI - Variability of perioperative mortality of hepatic resection in Australia. AB - BACKGROUND: Hepatic resection is a relatively young and complex specialized procedure. A strong relationship between volume and perioperative mortality has been reported internationally. However, there has been no multicentre study into hepatic resection in Australia. This retrospective, population-based cohort study was conducted to determine national, state and territory based volume and perioperative mortality rates (POMRs). METHODS: Australian Institute of Health and Welfare data was interrogated for the Australian Classification of Health Intervention codes for hepatic resection defined as extended hemi-hepatectomy (30421), hemi-hepatectomy (30418), segmental hepatic resection (30415) and sub segmental hepatic resection (30414). Logistic regression analysis was performed using the de-identified data to investigate trends and differences between states/territories. Mortality rates were risk adjusted for age, gender and public or private admission. The data set included patients who underwent hepatic resection in the financial years 2005/2006 to 2012/2013. RESULTS: The overall POMR for all types of hepatic resection was 1.6% (201/12 562). There was no significant change in POMR over time. However, there was significant variation between the states and territories with two states having significantly higher POMR for major hepatic resections (regional range: 1.3-3.8%). POMRs increased with age with the highest mortality seen in the 75-79 year age group. The POMR was lower in private than in public hospitals. CONCLUSION: The results of this study confirm that the overall Australian POMR for major hepatic resection is similar to results reported internationally. National and state/territory POMR has not varied significantly over time. The significant variation between states/territories warrants further investigation. PMID- 29424071 TI - Letters to the editor: Publish fast. PMID- 29424075 TI - Nanoisozymes: Crystal-Facet-Dependent Enzyme-Mimetic Activity of V2 O5 Nanomaterials. AB - Nanomaterials with enzyme-like activity (nanozymes) attract significant interest owing to their applications in biomedical research. Particularly, redox nanozymes that exhibit glutathione peroxidase (GPx)-like activity play important roles in cellular signaling by controlling the hydrogen peroxide (H2 O2 ) level. Herein we report, for the first time, that the redox properties and GPx-like activity of V2 O5 nanozyme depends not only on the size and morphology, but also on the crystal facets exposed on the surface within the same crystal system of the nanomaterials. These results suggest that the surface of the nanomaterials can be engineered to fine-tune their redox properties to act as "nanoisozymes" for specific biological applications. PMID- 29424076 TI - Achieving Insertion-Like Capacity at Ultrahigh Rate via Tunable Surface Pseudocapacitance. AB - The insertion/deinsertion mechanism enables plenty of charge-storage sites in the bulk phase to be accessible to intercalated ions, giving rise to at least one more order of magnitude higher energy density than the adsorption/desorption mechanism. However, the sluggish ion diffusion in the bulk phase leads to several orders of magnitude slower charge-transport kinetics. An ideal energy-storage device should possess high power density and large energy density simultaneously. Herein, surface-modified Fe2 O3 quantum dots anchored on graphene nanosheets are developed and exhibit greatly enhanced pseudocapacitance via fast dual-ion involved redox reactions with both large specific capacity and fast charge/discharge capability. By using an aqueous Na2 SO3 electrolyte, the oxygen vacancy-tuned Fe2 O3 surface greatly enhances the absorption of SO32- anions that majorly increase the surface pseudocapacitance. Significantly, the Fe2 O3 -based electrode delivers a high specific capacity of 749 C g-1 at 5 mV s-1 and retains 290 C g-1 at an ultrahigh scan rate of 3.2 V s-1 . With a novel dual-electrolyte design, a 2 V Fe2 O3 /Na2 SO3 //MnO2 /Na2 SO4 asymmetric supercapacitor is constructed, delivering a high energy density of 75 W h kg-1 at a power density of 3125 W kg-1 . PMID- 29424077 TI - Demographic factors in Swedish adults undergoing root filling and subsequent extraction of a maxillary first molar: a comparative study. AB - AIM: To study the demographics of Swedish adults who had received a root filling, followed by extraction during the following 5-6 years in comparison with subjects who had undergone a corresponding root filling with an uneventful outcome. METHODOLOGY: The root filled maxillary first molar was chosen as the comparison model. The Swedish Social Insurance Agency provided data on all teeth reported as root filled in Sweden during 2009. A comparison group, equally large as the study group, was constructed by randomly selecting subjects with root filled maxillary first molars, which had not subsequently been extracted, that is, an uneventful outcome. Demographic data on the subjects were obtained from Statistics Sweden: country of birth, disposable income, educational level, age, civil status and gender. Chi-square, t-tests and logistic regression were used for statistical analyses. RESULTS: In the year 2009, 36 139 maxillary first molar teeth were reported to have been root filled, 4362 (12.1%) of which were then recorded as extracted during the following 5-6 year period. Only minor intergroup differences were noted: 86.5% of the study group were Swedish-born, compared with 84.4% of the comparison group (P = 0.007). Women comprised 53.2% of the study group and 50.5% (P = 0.01) of the comparison group. There was an association between extractions and gender as well as age; men had a lower odds ratio (OR) for extraction OR, 0.87; confidence interval (CI), 0.80-0.95. For every additional year, the chance for extraction was higher OR, 1.01; CI, 1.01-1.01. No other significant differences were detected. CONCLUSIONS: There was only little or no demographic differences between the study group, comprising Swedish adults who had undergone root filling of one of their maxillary first molars in 2009 and subsequent extraction during the following 5-6 years, and the comparison group, with uneventful outcomes after a corresponding root filling. PMID- 29424078 TI - Tinkering at the margins: A response to Chanen. PMID- 29424079 TI - Bipolar disorders: Cornering debate. PMID- 29424080 TI - In Situ Oxidation Synthesis of p-Type Composite with Narrow-Bandgap Small Organic Molecule Coating on Single-Walled Carbon Nanotube: Flexible Film and Thermoelectric Performance. AB - Although composites of organic polymers or n-type small molecule/carbon nanotube (CNT) have achieved significant advances in thermoelectric (TE) applications, p type TE composites of small organic molecules as thick surface coating layers on the surfaces of inorganic nanoparticles still remain a great challenge. Taking advantage of in situ oxidation reaction of thieno[3,4-b]pyrazine (TP) into TP di N-oxide (TPNO) on single-walled CNT (SWCNT) surface, a novel synthesis strategy is proposed to achieve flexible films of TE composites with narrow-bandgap (1.19 eV) small molecule coating on SWCNT surface. The TE performance can be effectively enhanced and conveniently tuned by poly(sodium-p-styrenesulfonate) content, TPNO/SWCNT mass ratio, and posttreatment by various polar solvents. The maximum of the composite power factor at room temperature is 29.4 +/- 1.0 uW m-1 K-2 . The work presents a way to achieve flexible films of p-type small organic molecule/inorganic composites with clear surface coating morphology for TE application. PMID- 29424081 TI - Polarity-Dependent Isomerization of an Unsymmetrical Overcrowded Ethylene Promoted by Zwitterionic Contribution in the Twisted Isomer. AB - The twisted form of bianthrone is known as a metastable state provided by a photo induced or thermal-induced isomerization of the folded form, and thus prevents the isolation and the detailed analysis of its electronic structure. In this study, an unsymmetrical bianthrone (2), consisting of the electron-withdrawing anthrone and electron-donating acridane, have been synthesized and shown to exhibit a solvent-polarity-dependent isomerization reaction between the folded and twisted isomers. With increasing the polarity of the solvent, 2 showed an isomerization reaction from the folded form to the twisted form. The stabilization of the twisted isomer in polar solvents can be interpreted as proof of its relatively large zwitterionic character. The DMF solution of 2 displayed paramagnetically-broadened NMR signals from the thermally populated triplet state resulting from rotation of the weakened ethylenic double bond of the twisted isomer. PMID- 29424082 TI - A microRNA-1 gene, tci-miR-1-3p, is involved in cyflumetofen resistance by targeting a glutathione S-transferase gene, TCGSTM4, in Tetranychus cinnabarinus. AB - microRNA-1 (miR-1) is a well-studied conservative microRNA (miRNA) involved in immune responses in mammals and insects. However, little is known about its role in pesticide resistance in arthropods. In this study, we found that a microRNA belong to miR-1 family (tci-miR-1-3p) was significantly down-regulated in a cyflumetofen-resistant strain (CYR) of Tetranychus cinnabarinus compared with its homologous susceptible strain (SS), indicating an involvement of miR-1 in cyflumetofen resistance in mites. One glutathione S-transferase (GST) gene (TCGSTM4, a mu class GST gene), a candidate target gene of tci-miR-1-3p, was found to be significantly down-regulated when tci-miR-1-3p was over-expressed. The specific interaction between tci-miR-1-3p and the target sequence in the 3' untranslated region of TCGSTM4 was confirmed. A decrease or increase in tci-miR-1 3p abundance through feeding miRNA inhibitors or mimics significantly increased or decreased TCGSTM4 expressions at the mRNA and protein levels, respectively. In addition, an over-expression of tci-miR-1-3p resulted in a decrease in the tolerance of T. cinnabarinus to cyflumetofen in both SS and CYR strains, and vice versa. After decreasing TCGSTM4 transcription via RNA interference, T. cinnabarinus became more sensitive to cyflumetofen in both resistant and susceptible mites, and the change in mortality was greater in CYR than that in SS. Moreover, the recombinant TCGSTM4 could significantly decompose cyflumetofen, indicating that TCGSTM4 is a functional gene responsible for cyflumetofen resistance in mites. PMID- 29424083 TI - Multicenter reproducibility study of diffusion MRI and fiber tractography of the lumbosacral nerves. AB - BACKGROUND: Diffusion tensor imaging (DTI) has been applied in the lumbar and sacral nerves in vivo, but information about the reproducibility of this method is needed before DTI can be used reliably in clinical practice across centers. PURPOSE: In this multicenter study the reproducibility of DTI of the lumbosacral nerves in healthy volunteers was investigated. STUDY TYPE: Prospective control series. SUBJECTS: Twenty healthy subjects. FIELD STRENGTH/SEQUENCE: 3T MRI. 3D turbo spin echo, and 3.0 mm isotropic DTI scan. ASSESSMENT: The DTI scan was performed three times (twice in the same session, intrascan reproducibility, and once after an hour, interscan reproducibility). At site 2, 1 week later, the protocol was repeated (interweek reproducibility). Fiber tractography (FT) of the lumbar and sacral nerves (L3-S2) was performed to obtain values for fractional anisotropy, mean, axial, and radial diffusivity. STATISTICAL TESTS: Reproducibility was determined using the intraclass correlation coefficient (ICC), and power calculations were performed. RESULTS: FT was successful and reproducible in all datasets. ICCs for all diffusion parameters were high for intrascan (ranging from 0.70-0.85), intermediate for interscan (ranging from 0.61 0.73), and interweek reliability (ranging from 0.58-0.62). There were small but significant differences between the interweek diffusivity values (P < 0.0005). Depending on the effect size, nerve location, and parameter of interest, power calculations showed that sample sizes between 10 and 232 subjects are needed for cross-sectional studies. DATA CONCLUSION: We found that DTI and FT of the lumbosacral nerves have intermediate to high reproducibility within and between scans. Based on these results, 10-58 subjects are needed to find a 10% change in parameters in cross-sectional studies of the lumbar and sacral nerves. The small significant differences of the interweek comparison suggest that results from longitudinal studies need to be interpreted carefully, since small differences may also be caused by factors other than disease progression or therapeutic effects. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:951-963. PMID- 29424084 TI - Asymptomatic hyperkeratotic plaque on the vulva of a patient with lichen sclerosus. PMID- 29424085 TI - Achieving public and global health competencies: A teaching case study of Botswana's cervical cancer screening program. AB - OBJECTIVES: To design and implement a case study on the cervical cancer screening program in Botswana to teach public and global health competencies to undergraduate nursing students. DESIGN AND SAMPLE: The case study was developed following a review of the literature on the epidemiology and health policies of cervical cancer in Botswana, and an interview with an obstetrician/gynecologist engaged in both clinical practice and research in Botswana. The case study has been implemented over seven semesters to students enrolled in the Nursing in the Community course at the University of Pennsylvania. Approximately 75-100 students are enrolled each semester. MEASURES: Student's perceptions of epidemiologic skills gained and group functioning. Students responded to an open-ended question about lessons learned and offered suggestions to improve the learning experience. RESULTS: Faculty assessment of student deliverables demonstrated that students achieved the learning objectives and mastered necessary competencies. More than 70% (n = 69) of the students indicated that they acquired relevant skills at greater than a satisfactory level. Generally, students had great experiences working in groups measured across five dimensions: engagement/contribution, creativity/resilience, on task/works independently, social interaction/communication, and preparedness. However, isolated cases of poor group functioning were reported for engagement/contribution, and creativity/resilience. CONCLUSION: The case study, which has been revised with respect to length, content and group processes, has been valuable in educating undergraduate nursing students in a more engaging way that mimics real life public health nursing scenarios. Students achieved both public and global health competencies through participation in the case study. PMID- 29424086 TI - Circadian processes in the RNA life cycle. AB - The circadian clock drives daily rhythms of multiple physiological processes, allowing organisms to anticipate and adjust to periodic changes in environmental conditions. These physiological rhythms are associated with robust oscillations in the expression of at least 30% of expressed genes. While the ability for the endogenous timekeeping system to generate a 24-hr cycle is a cell-autonomous mechanism based on negative autoregulatory feedback loops of transcription and translation involving core-clock genes and their protein products, it is now increasingly evident that additional mechanisms also govern the circadian oscillations of clock-controlled genes. Such mechanisms can take place post transcriptionally during the course of the RNA life cycle. It has been shown that many steps during RNA processing are regulated in a circadian manner, thus contributing to circadian gene expression. These steps include mRNA capping, alternative splicing, changes in splicing efficiency, and changes in RNA stability controlled by the tail length of polyadenylation or the use of alternative polyadenylation sites. RNA transport can also follow a circadian pattern, with a circadian nuclear retention driven by rhythmic expression within the nucleus of particular bodies (the paraspeckles) and circadian export to the cytoplasm driven by rhythmic proteins acting like cargo. Finally, RNA degradation may also follow a circadian pattern through the rhythmic involvement of miRNAs. In this review, we summarize the current knowledge of the post-transcriptional circadian mechanisms known to play a prominent role in shaping circadian gene expression in mammals. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > RNA Editing and Modification RNA Export and Localization > Nuclear Export/Import. PMID- 29424087 TI - Can you detect early dementia from an email? A proof of principle study of daily computer use to detect cognitive and functional decline. AB - OBJECTIVE: To determine whether multiple computer use behaviours can distinguish between cognitively healthy older adults and those in the early stages of cognitive decline, and to investigate whether these behaviours are associated with cognitive and functional ability. METHODS: Older adults with cognitive impairment (n = 20) and healthy controls (n = 24) completed assessments of cognitive and functional abilities and a series of semi-directed computer tasks. Computer use behaviours were captured passively using bespoke software. RESULTS: The profile of computer use behaviours was significantly different in cognitively impaired compared with cognitively healthy control participants including more frequent pauses, slower typing, and a higher proportion of mouse clicks. These behaviours were significantly associated with performance on cognitive and functional assessments, in particular, those related to memory. CONCLUSION: Unobtrusively capturing computer use behaviours offers the potential for early detection of neurodegeneration in non-clinical settings, which could enable timely interventions to ultimately improve long-term outcomes. PMID- 29424088 TI - A review of measures used in the screening, assessment and diagnosis of dementia in people with an intellectual disability. AB - BACKGROUND: The increasing number of individuals with an intellectual disability who are at risk of developing dementia highlights the need to use measures with strong psychometric properties as part of the screening, assessment and diagnostic process. METHOD: Searches were made of clinical and good practice guidelines and English language journal articles sourced from Proquest, Web of Science and Scopus databases (up to July 2017) for tools which were designed or adapted for the purpose of helping to diagnose dementia in people with intellectual disability. RESULTS: Based on a detailed review of 81 articles and guidelines, the present authors identified 22 relevant tools (12 cognitive, 10 behaviour). These were reviewed in terms of their psychometric properties. CONCLUSIONS: A number of tools were found to be available for use with people with intellectual disability; however, few were specifically standardized for this purpose which also had comprehensive information about reliability and validity. PMID- 29424089 TI - Cardiovascular benefits of SGLT2 inhibition in diabetes and chronic kidney diseases. PMID- 29424090 TI - The host defense peptide LL-37 is detected in human parotid and submandibular/sublingual saliva and expressed in glandular neutrophils. AB - The human host defense peptide, LL-37, is an important player in the first line of defense against invading microorganisms. LL-37 and its precursor, hCAP18, have been detected in unstimulated whole saliva but no reports showing hCAP18/LL-37 in isolated, parotid, and/or submandibular/sublingual saliva have been presented. Here, we measured the levels of hCAP18/LL-37 in human parotid and submandibular/sublingual saliva and investigated the expression of hCAP18/LL-37 in parotid and submandibular gland tissue. Parotid and submandibular/sublingual saliva was collected from healthy volunteers, and the levels of hCAP18/LL-37 in saliva were analyzed by dot blot, ELISA, and western blotting. Cellular expression of hCAP18/LL-37 in human parotid and submandibular glands was investigated by immunohistochemistry. Immunoreactivity for hCAP18/LL-37 was detected in both parotid and submandibular/sublingual saliva of all individuals. The concentration of hCAP18/LL-37 was similar in parotid and submandibular/sublingual saliva, and was determined by densitometric scanning of each dot and normalization to the total protein concentration of each sample, and by ELISA. Double immunohistochemistry revealed that intravascular neutrophils of both parotid and submandibular glands express hCAP18/LL-37. For the first time, we demonstrate hCAP18/LL-37 in isolated human parotid and submandibular/sublingual saliva and expression of hCAP18/LL-37 in glandular intravascular neutrophils, indicating that neutrophils of the major salivary glands contribute to the LL-37 content of whole saliva. PMID- 29424091 TI - Quantitative differences detected in the histology of galls induced by the same aphid species in different varieties of the same host. AB - Plant galls are abnormal growths caused by an inducer that determines their morphology and anatomy. We qualitatively and quantitatively compared the histological anatomy of five aphid species (Paracletus cimiciformis, Forda marginata, Forda formicaria, Baizongia pistaciae and Geoica wertheimae) that induce galls in Pistacia terebinthus shrubs growing in Israel. We also quantitatively compared these galls to those that the aphids create on the same host in Spain. Histological study was conducted following methods described previously by the authors. Quantitative differences among the galls were found in five of 12 common anatomical traits: gall thickness, stomatal number in the epidermis-air, size of vascular bundles, distance of phloem ducts from the lumen and number of intraphloematic schizogenous ducts. Other structures were particular to one or some species: number of cracks in the epidermis-lumen, a sclereid layer, trichomes and microcrystal inclusions. Fisher's tests of combined probabilities showed that the galls induced in Israel were statistically different from those in Spain. In particular, the number of intraphloematic schizogenous ducts was higher in the galls induced in P. terebinthus in Israel. Such differences were also found in other traits related to defence of the gall inhabitant. In conclusion, while the gall shape and size are determined mainly by the cecidogenic insect, it seems that the host plant also plays an important role in determining the number/size of quantitative traits, in this case mainly protective structures. PMID- 29424092 TI - Characterization of rabies post-exposure prophylaxis in a region of the eastern Amazon, state of Para, Brazil, between 2000 and 2014. AB - Animal bites are a serious public health issue, and prevention strategies have been consistently documented worldwide. The aim of this study was to characterize human anti-rabies treatment in 11 counties of the Salgado microregion, Para state, Brazil, which borders the Bragantina microregion, where exposures of human rabies were reported in 2004 and 2005. A descriptive retrospective study was conducted using anti-rabies treatment notifications registered in the Information System for Notifiable Diseases (SINAN) database of the State Department of Public Health of Para (SESPA) from January 2000 to December 2014. In this period, 13,403 exposures were reported, with a growing annual trend (Y = 68.571x + 344.96). The years 2012 and 2013 presented the highest exposure incidence. Salinopolis was the county with the highest average annual incidence per 10,000 persons (62.83), followed by Sao Joao de Pirabas (43.28) and Sao Caetano de Odivelas (41.27). Most patients were males (59.6%) and were 1-19 years old (48.7%). The main species involved in aggressions were dogs (74.1%), followed by bats (13.1%) and cats (7.4%). Biting was the most common kind of exposure, mostly on the lower limbs (39.6%). This study shows that aggression by bats was the second most common cause of demand for the service in the region for the past 14 years. The low quality of records may increase the difficulty of rabies surveillance in Para. PMID- 29424093 TI - Taxus ingredients in the red arils of Taxus baccata L. determined by HPLC-MS/MS. AB - INTRODUCTION: Taxus baccata L. is an evergreen conifer whose plant parts are cardiotoxic. Only the red arils of the berries are described as non-toxic and taxane-free. OBJECTIVE: Extraction and HPLC-MS/MS methods were developed for the investigation of the Taxus compounds 3,5-dimethoxyphenol, 10-deacetylbaccatin III, baccatin III, cephalomannine, taxol A and taxinine M in the red arils of the yew berries. METHODOLOGY: A liquid-liquid extraction method for the red arils of the fruits from three yews were developed. An accurate (ESI+) HPLC-MS/MS method was performed for the simultaneous detection and determination of the target compounds in multiple reaction monitoring (MRM) mode. RESULTS: All Taxus agents obtained were detected in the red arils. Highest concentrations were determined for baccatin III and 10-deacetylbaccatin III. CONCLUSION: The developed quantitative method is reliable and selective and was successfully applied for quantification of selected Taxus ingredients in red arils of Taxus baccata. It was disproved that the red arils of the berries do not contain the selected Taxus compounds. PMID- 29424094 TI - Leg length, sitting height, and body proportions references for achondroplasia: New tools for monitoring growth. AB - Achondroplasia is the most common form of inherited disproportionate short stature. We report leg length, sitting height, and body proportion curves for achondroplasia. Seven centile format of sitting height, leg length, sitting height/leg length ratio, sitting height/height ratio, and head circumference/height ratio were estimated by the LMS method. The Q-test was applied to assess the goodness of fit. For comparison, centiles of sitting height and leg length were graphed using Argentine national growth references for achondroplasia and non-achondroplasia populations. The sample consisted of 342 children with achondroplasia (171 males, 171 females) aged 0-18 years. The median (interquartile range) number of measurements per child was 6 (3, 12) for sitting height and 8 (3, 13) for head circumference. Median leg length increased from 14 cm at age 1 week to 44 and 40 cm (males and females, respectively) in achondroplasia adolescents which is 3.5 cm shorter than non-achondroplasia children at age 1 week and, 38 cm shorter at adolescence. Median sitting height increased from 34 cm at birth to 86 and 81 in adolescents' boys and girls respectively, only 5 cm shorter than non-achondroplasia children. Sitting height/leg length decreased from 2.61 at birth to approximately 1.90 at adolescent. Median head circumference/height ratio decreased from 0.79 at birth to 0.46 at 18 years in both sexes. Growth of lower limbs is affected early in life and becomes more noticeable throughout childhood. The disharmonic growth between the less affected trunk and the severely affected limbs determine body disproportion in achondroplasia. PMID- 29424095 TI - DR. MICHAEL ("MIKE") WESLEY THOMAS (1948-2017). PMID- 29424096 TI - Low education and lack of spousal relationship are associated with dementia in older adults with diabetes mellitus in Nigeria. AB - BACKGROUND: The relationship between dementia and type 2 diabetes mellitus (T2DM) in older adults is well established in the literature. However, there have been few studies on this relationship in older adults living in low- and middle-income countries, and most demographic projections predict that older adult population will increase substantially in these regions by 2050. METHODS: In this study, older adults with T2DM attending a tertiary health facility were examined and compared with community-dwelling older adults without T2DM. The participants were assessed using the Consortium to Establish Registry for Alzheimer's Disease, the Stick Design Test, the 30-item Geriatric Depression Scale, and the Instrumental Activities of Daily Living Scale. Additionally, all the participants had a physical examination, including assessment of glycated haemoglobin, fasting blood glucose, lipid profile, and HIV status. A consensus diagnosis of dementia was made based on the criteria for dementia in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and the International Classification for Diseases, 10th edition. The data were analyzed using SPSS version 20 for Windows. RESULTS: This study included 224 diabetic patients and 116 controls. A total of 27 diabetic patients (12.1%) had dementia, 19 of whom were women. Of the 27 diabetic patients with dementia, 25 patients (92.6%) had Alzheimer's disease and 2 patients (7.4%) had mixed dementia (vascular dementia and Alzheimer's disease). Only one person among the controls had Alzheimer's type dementia. Dementia in the diabetic patients was significantly associated with advancing age, female gender, education level, duration of diabetes, and absence of a spouse. CONCLUSION: Dementia is common in older adults with T2DM in this low-resource setting, and the risk factors for dementia were similar to those reported in earlier studies in Western societies. PMID- 29424097 TI - Nanodiamonds for In Vivo Applications. AB - Due to their unique optical properties, diamonds are the most valued gemstones. However, beyond the sparkle, diamonds have a number of unique properties. Their extreme hardness gives them outstanding performance as abrasives and cutting tools. Similar to many materials, their nanometer-sized form has yet other unique properties. Nanodiamonds are very inert but still can be functionalized on the surface. Additionally, they can be made in very small sizes and a narrow size distribution. Nanodiamonds can also host very stable fluorescent defects. Since they are protected in the crystal lattice, they never bleach. These defects can also be utilized for nanoscale sensing since they change their optical properties, for example, based on temperature or magnetic fields in their surroundings. In this Review, in vivo applications are focused upon. To this end, how different diamond materials are made and how this affects their properties are discussed first. Next, in vivo biocompatibility studies are reviewed. Finally, the reader is introduced to in vivo applications of diamonds. These include drug delivery, aiding radiology, labeling, and use in cosmetics. The field is critically reviewed and a perspective on future developments is provided. PMID- 29424098 TI - Diagnosis of Compressed Nerve Root in Lumbar Disc Herniation Patients by Surface Electromyography. AB - OBJECTIVE: To establish a logistic regression model using surface electromyography (SEMG) parameters for diagnosing the compressed nerve root at L5 or S1 level in patients with lumbar disc herniation (LDH). METHODS: This study recruited 24 patients with L5 nerve root compression and 23 patients with S1 nerve root compression caused by LDH from May 2014 to May 2016. SEMG signals from the bilateral tibialis anterior and lateral gastrocnemius were measured. The root mean square (RMS), the RMS peak time, the mean power frequency (MPF), and the median frequency (MF) were analyzed. The accuracy, sensitivity, and specificity values were calculated separately. The areas under the curve (AUC) of the receiver-operating characteristic (ROC) curve and the kappa value were used to evaluate the accuracy of the SEMG diagnostic model. RESULTS: The accuracy of the SEMG model ranged from 85.71% to 100%, with an average of 93.57%. The sensitivity, specificity, AUC, and kappa value of the logistic regression model were 0.98 +/- 0.05, 0.92 +/- 0.09, 0.95 +/- 0.04 (P = 0.006), and 0.87 +/- 0.11, respectively (P = 0.001). The final diagnostic model was: P=1-11+ey; y = 10.76 - (5.95 * TA_RMS Ratio) - (0.38 * TA_RMS Peak Time Ratio) - (5.44 * 44 * LG_RMS Peak Time Ratio). L5 nerve root compression is diagnosed when P < 0.5 and S1 nerve root compression when P >= 0.5. CONCLUSIONS: The logistic regression model developed in this study showed high diagnostic accuracy in detecting the compressed nerve root (L5 and S1 ) in these patients with LDH. PMID- 29424099 TI - Analysis of SLCO1B1 and APOE genetic polymorphisms in a large ethnic Hakka population in southern China. AB - OBJECTIVE: Statins are the most widely used lipid-lowering drugs, which have a significant effect on the inhibition of cardiovascular disease. The efficacy and side effects of statins are associated with the polymorphisms of SLCO1B1 and APOE genes. The purpose of this study was to analyze the SLCO1B1 and APOE gene polymorphisms in the Hakka population of southern China. METHODS: A total of 3249 subjects including 2019 males and 1230 females participated in this study. Polymerase chain reaction (PCR)-fluorescence probe technique for polymorphisms analysis and analyzed the genotypes frequencies of SLCO1B1 and APOE genes. RESULTS: The frequencies of SLCO1B1 521T>C between men and women were statistically significant (SLCO1B1 521TT, chi2 = 8.431, P = .004; SLCO1B1 521TC, chi2 = 7.436, P = .007). The frequencies of haplotypes *1b/*1b (40.07%) and *1a/*1b (32.56%) of SLCO1B1 gene accounted for 72.63%, followed by *1b/*15(14.40%), *1a/*1a (5.82%), *1a/*15 (5.57%), *15/*15 (1.45%), and *1a/*5 (0.12%). The frequencies of haplotypes *1a/*15 and *1b/*1b of SLCO1B1 gene between men and women were statistically significant (*1a/*15, chi2 = 6.789, P = .009; *1b/*1b, chi2 = 3.998, P = .004). In this study, genotype E3/E3 accounted for 69.04%, followed by E3/E4 (16.19%), E2/E3 (11.60%), E2/E4 (1.35%), E4/E4 (1.08%), and E2/E2 (0.74%) in all subjects, in which E3 had the greatest allele frequency (82.93%), followed by E4 (9.85%) and E2 (7.22%). We found that 47 subjects carrying the SLCO1B1 521 (CC) polymorphism who had not any myopathy caused by statins. CONCLUSIONS: We analyzed the SLCO1B1 and APOE gene polymorphisms in the Hakka population of southern China. This study provides a reference for the individualized meditation for Hakka population in this area. PMID- 29424100 TI - 'Ease of interpretation' of cytological smears stained with modified ultrafast papanicolaou stain: Interobserver agreement and reproducibility. AB - BACKGROUND: Since its inception in 1995, the Ultrafast Papanicoloau (UFPAP) cytological stain has undergone a number of modifications to suit the local availability of reagents and cost in different set ups. However, the reported results have been uniformly encouraging. We designed a study to investigate the inter-observer agreement in 'perceived ease of interpretation' of cytological smears stained with Modified Ultrafast Papanicoloau stain (MUFPAP). METHODS: After a small pilot study, we prospectively stained air-dried fine needle aspirate smears (FNACs) and Body Fluid smears with the standardized MUFPAP stain. The MUFPAP stained slides were evaluated in tandem with other routine cytological stains as well as independently by two pathologists. Two rater kappa was used to determine the agreement. RESULTS: The study included 93 fluids and 34 FNACs. A vast majority of the cases stained with MUFPAP were rated 'better' than the routine stains in terms of 'overall ease of interpretation' with considerable agreement. The agreement tended to be better for FNACs than fluid specimens. Cases with malignant pathology demonstrated a perfect agreement (kappa = 1) between the raters in terms of 'overall ease of interpretation' (91.7% cases were rated 'very good' by each pathologist) when compared to cases with benign pathology (kappa = 0.52). Nuclear characteristics were appreciated with a better agreement than other parameters. CONCLUSION: Modified UFPAP stain appears to be quick, reliable, cost-effective alternative in cytology, especially for detecting malignant cells in smears with low cellularity. Its specific advantage is robust nuclear staining against a clear background. PMID- 29424101 TI - Sentinel lymph node mapping in liver resection for colorectal liver metastases. PMID- 29424102 TI - Complex care and contradictions of choice in the safety net. AB - This article explores the complicated and often-contradictory notions of choice at play in complex care management (CCM) programmes in the US healthcare safety net. Drawing from longitudinal data collected over two years of ethnographic fieldwork at urban safety-net clinics, our study examines the CCM goal of transforming frequent emergency department (ED) utilisers into 'active' patients who will reduce their service utilisation and thereby contribute to a more rational, cost-effective healthcare system. By considering our data alongside philosopher Annemarie Mol's (2008) conceptualisation of the competing logics of choice and care, we argue that these premises often undermine CCM teams' efforts to support patients and provide the care they need - not only to prevent medical crises, but to overcome socio-economic barriers as well. We assert that while safety-net CCM programmes are held accountable for the degree to which their patients successfully transform into self-managing, cost-effective actors, much of the care CCM staff provide in fact involves attempts to intervene on structural obstacles that impinge on patient choice. CCM programmes thus struggle between an economic imperative to get patients to make better health choices and a moral imperative to provide care in the face of systemic societal neglect. (A virtual abstract of this paper can be viewed at: https://www.youtube.com/channel/UC_979cmCmR9rLrKuD7z0ycA). PMID- 29424103 TI - Alternative activation of hedgehog pathway induced by ultraviolet B radiation: preliminary study. AB - BACKGROUND: There is still much ambiguity in studies of Sonic hedgehog (Shh) pathways and its dysregulation. Some studies concerning the role of the Shh pathway in basal cell carcinoma (BCC) have been conducted, but there is a lack of studies about Shh pathway dysregulation under the influence of ultraviolet (UV)B radiation. AIM: To evaluate skin expression of Shh, Ptch1, Ptch2, Smo and Gli1 proteins in BCCs with and without the influence of UVB radiation. METHODS: In total, 34 healthy controls (HCs) and 42 patients with nodular BCC were recruited into the study. Patients were divided into five groups (A-E), depending on UVB dose received and BCC status. In all skin specimens, expression of Shh, Ptch1, Ptch2, Smo and Gli1 protein was evaluated. RESULTS: Comparing the BCC group with the HC group, there was significantly higher expression of Shh, Ptch1, Ptch2, Smo and Gli1 proteins. Expression of Ptch2, Smo and Gli1 was increased in response to UVB doses of 3 MED (minimal erythema dose), whereas expression of Ptch1 and Shh was unaffected. CONCLUSION: The lack of change in expression of Shh and Ptch1 after exposure to UVB suggests that the Shh pathway may be activated through a noncanonical pathway under the influence of strong UVB doses. PMID- 29424104 TI - Experience of migrant care and needs for cultural competence training among public health workers in Korea. AB - OBJECTIVE: This study explored the experiences of public health workers (PHWs) providing health care for migrants living in Korea and clarified needs for cultural competence training. DESIGN AND SAMPLE: Twenty-six PHWs from five public health centers in Gwangju city, South Korea, participated in this exploratory qualitative study. METHODS: Five semi-structured focus group interviews of PHWs were conducted from September to December 2016. A directed content analysis approach was conducted using four categories: perceived characteristics of migrants, interaction between PHWs and migrants, interaction between PHWs and organizations/systems, and cultural competence training needs. RESULTS: PHWs perceived that migrants lacked autonomy in health decisions and awareness of health behaviors. PHWs experienced difficulties in communicating and in establishing trusting relationships. They found clients hard to reach and easy to miss, a lack of continuity in health care programs, and inadequate human and material resources. They preferred passive teaching methods to activity-based simulation. PHWs believed essential training should be provided through e learning to all PHWs, including management. CONCLUSION: PHWs reported experiencing multiple challenges from a lack of preparedness for culturally competent care and their clients' vulnerability. Development of cultural competence training is suggested through e-learning that reflects the PHWs' experiences and provides systematic support. PMID- 29424105 TI - Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition. AB - Colorectal cancer is a leading form of cancer in both males and females. Early detection of individuals at risk of colorectal cancer allows proper treatment and management of the disease to be implemented, which can potentially reduce the burden of colorectal cancer incidence, morbidity and mortality. In recent years, the role of genetic susceptibility factors in mediating predisposition to colorectal cancer has become more and more apparent. Identification of high frequency, low-penetrance genetic polymorphisms associated with the cancer has therefore emerged as an important approach which can potentially aid prediction of colorectal cancer risk. However, the overwhelming amount of genetic epidemiology data generated over the past decades has made it difficult for one to assimilate the information and determine the exact genetic polymorphisms that can potentially be used as biomarkers for colorectal cancer. This review comprehensively consolidates, based primarily on results from meta-analyses, the recent progresses in the search of colorectal cancer-associated genetic polymorphisms, and discusses the possible mechanisms involved. PMID- 29424107 TI - Diazadibora[1.1.1.1]m,p,m,p-cyclophanes: Ambipolar Conjugated Macrocycles with Different B-pi-N Embedded Patterns. AB - Are different B(boron)-pi-N(nitrogen) embedded patterns to bring about significant different (opto)electronic properties for the same macrocyclic molecular backbone? A series of B-pi-N-embedded alternate-meta-para-linked cyclophanes 1-3 have been prepared and characterized as a new class of ambipolar pi-conjugated B-pi-N macrocycles. The answer to the opening question is yes. These macrocycles revealed the intramolecular charge transfer in the oxidized states and the intriguing photophysical proprerties in accordance with the embedded patterns, suggesting the electronic structures are tunable by introducing multiple B-pi-N moieties. PMID- 29424106 TI - Seroprevalence of selected flaviviruses in free-living and captive capuchin monkeys in the state of Pernambuco, Brazil. AB - Mosquito-borne diseases such as dengue, yellow fever and, more recently, Chikungunya virus (CHIKV) and Zika virus (ZIKV) have a great impact in the public health. In addition, the presence of such viruses might have an impact on wild animal conservation as well as their possible role as animal reservoir. Here, we performed a serological survey searching for antibodies against a panel of flaviviruses [ZIKV, Dengue virus (DENV), Yellow Fever virus (YFV), West Nile virus (WNV), Saint Louis Encephalitis virus (SLEV), Ilheus virus (ILHV) and Rocio virus (ROCV)] using plaque reduction neutralization test (PRNT90 ) in both free ranging and captive capuchin monkeys (Sapajus flavius and Sapajus libidinosus). Captive and free-living monkeys were sampled between June 2015 and January 2016 in the state of Pernambuco, including in the border with State of Paraiba, the epicentre of the ZIKV epidemics in Brazil. We have found neutralizing antibodies for ZIKV, DENV-1, DENV-2, DENV-3, DENV-4, YFV, ILHV and SLEV in both S. flavius and S. libidinosus samples. No positives samples were found for ROCV and WNV. Our results suggest that these flaviviruses might be circulating in capuchin monkey in the studied region. The possible presence of these viruses represents a risk for public health, as well as for animal conservation, especially for S. flavius which is a critically endangered species, facing high risk of extinction. PMID- 29424108 TI - A field trial in Thailand of the efficacy of oral fluralaner for the treatment of dogs with generalized demodicosis. AB - BACKGROUND: Generalized demodicosis in dogs can be challenging to manage, especially in adult-onset cases. HYPOTHESIS/OBJECTIVES: This study evaluated the efficacy of oral fluralaner at the dose of 25-50 mg/kg for the treatment of canine generalized demodicosis. ANIMALS: Client-owned dogs from Bangkok, Thailand, diagnosed with generalized demodicosis according to published criteria. METHODS: Deep skin scrapings were performed at three to five affected areas to evaluate numbers of mites. Repeat examinations were performed monthly until parasitological cure; dogs were then followed up for two to 12 months. Parasitological cure was defined as two negative skin scrapings achieved one month apart. RESULTS: One hundred and fifteen dogs were included in the study, 73 with adult-onset demodicosis and 42 with juvenile-onset demodicosis. Twenty one dogs were lost to follow-up and 27 had one negative skin scraping but did not return. Sixty seven dogs (21 with juvenile-onset and 46 with adult-onset disease) reached parasitological cure, which occurred after two, three and four months in 63%, 85% and 100% (respectively) of dogs with adult-onset demodicosis, cumulatively, and after two and three months in 81% and 100% of dogs with juvenile-onset demodicosis. Underlying causes associated with adult-onset demodicosis included atopic dermatitis, neoplasia, metabolic diseases and idiopathy. No adverse effects of fluralaner were observed in any of the dogs. CONCLUSION: Fluralaner given at the label dose for flea and tick prevention is effective for the treatment of canine generalized demodicosis. PMID- 29424109 TI - Metamemory: A construct with diagnostic utility in a cognitive disorders clinic? PMID- 29424110 TI - Social media and loneliness among community-dwelling older adults. PMID- 29424111 TI - The influence of TNF inhibitors on dementia incidence in patients with rheumatoid arthritis; an analysis from the BSRBR-RA. PMID- 29424112 TI - From Diogenes syndrome to Asperger's syndrome? PMID- 29424113 TI - Effect of a Matter of Balance programme on avoidance behaviour due to fear of falling in older adults. AB - BACKGROUND: Fear of falling (FOF) is associated with restricted activities, increased risk of falling, and decreased quality of life. A Matter of Balance (AMOB) is an evidence-based programme designed to decrease FOF. The current study investigated the influence of the AMOB on activity avoidance caused by FOF in older adults using the Fear of Falling Avoidance Behavior Questionnaire (FFABQ), health-related quality of life, and a question regarding concerns about falling. METHODS: Participants of this quasi-experimental, one-group, pretest-post-test study design were older adults from community sites in the Phoenix, Arizona, metropolitan area. Participants attended the AMOB programme, which consisted of one weekly 2-h session for 8 weeks. At the beginning and end of the programme, participants completed the standard AMOB assessments, the FFABQ, the Centers for Disease Control Core Healthy Days Measure (CDC HRQOL-4), and a question regarding concerns about falling. RESULTS: Sixty-three participants completed the study; their mean +/- SD age was 75.3 +/- 7.1 years (range: 60.0-90.0 years), and 84.1% were women. The FFABQ scores decreased from baseline (24.4 +/- 12.7 points) to post-AMOB (20.1 +/- 11.9 points; t = 2.62, P = 0.01). No changes in any of the CDC HRQOL-4 questions were noted (CDC HRQOL-4 question (Q)1 (z = -1.41, P = 0.16), CDC HRQOL-4 Q2 and Q3 summary index (z = -1.60, P = 0.11), and CDC HRQOL-4 Q4 (z = -0.97, P = 0.33)). Concerns about falling decreased from baseline (3.4 +/ 0.9 points) to post-AMOB (2.8 +/- 0.8 points; z = -4.09, P < 0.001). CONCLUSION: Avoidance behaviour caused by FOF, as measured by the FFABQ, and concerns about falling decreased in community-dwelling older adults who participated in the AMOB. Findings support the efficacy of the AMOB for reducing both avoidance behaviour caused by FOF and concerns about falling through an approach that combines education and exercise. PMID- 29424114 TI - See one, do one, teach one: Is it enough? Yes. PMID- 29424115 TI - In this February issue. PMID- 29424117 TI - ACEM President response: Mandatory misrepresentation. AB - With the challenges of modern media, political agendas and the power of special interest and pressure groups, specialist medical colleges increasingly have a significant role to play in health advocacy, and to stand up for human rights. PMID- 29424119 TI - Copper-Catalyzed Heteroarylsilylation of Unactivated Olefins through Distal Heteroaryl Migration. AB - A copper-catalyzed protocol for heteroarylsilylation of unactivated olefins is disclosed herein. The addition of a silyl radical to an alkene triggers a subsequent intramolecular heteroaryl migration. Heteroaryl groups such as benzothiazolyl, thiazolyl, imidazolyl, and pyridyl showcase their migratory aptitudes. A variety of heteroaryl-substituted alkyl silanes are readily generated in synthetically useful yields. PMID- 29424118 TI - Ultraearly assessed reperfusion status after middle cerebral artery recanalization predicting clinical outcome. AB - OBJECTIVES: Mechanical thrombectomy has high evidence in stroke therapy; however, successful recanalization guarantees not a favorable clinical outcome. We aimed to quantitatively assess the reperfusion status ultraearly after successful middle cerebral artery (MCA) recanalization to identify flow parameters that potentially allow predicting clinical outcome. MATERIALS AND METHODS: Sixty-seven stroke patients with acute MCA occlusion, undergoing recanalization, were enrolled. Using parametric color coding, a post-processing algorithm, pre-, and post-interventional digital subtraction angiography series were evaluated concerning the following parameters: pre- and post-procedural cortical relative time to peak (rTTP) of MCA territory, reperfusion time, and index. Functional long-term outcome was assessed by the 90-day modified Rankin Scale score (mRS; favorable: 0-2). RESULTS: Cortical rTTP was significantly shorter before (3.33 +/ 1.36 seconds; P = .03) and after intervention (2.05 +/- 0.70 seconds; P = .003) in patients with favorable clinical outcome. Additionally, age (P = .005) and initial National Institutes of Health Stroke Scale score (P = .02) were significantly different between the patients, whereas reperfusion index and time as well as initially estimated infarct size were not. In multivariate analysis, only post-procedural rTTP (P = .005) was independently associated with favorable clinical outcome. 2.29 seconds for post-procedural rTTP might be a threshold to predict favorable clinical outcome. CONCLUSIONS: Ultraearly quantitative assessment of reperfusion status after successful MCA recanalization reveals post procedural cortical rTTP as possible independent prognostic value in predicting favorable clinical outcome, even determining a threshold value might be possible. In consequence, focusing stroke therapy on microcirculatory patency could be valuable to improve outcome. PMID- 29424120 TI - Longitudinal assessment of the impact of multiple switches between a biosimilar and its reference product on efficacy parameters. AB - Patients, physicians, and health care providers in Europe have more than 10 years of experience with biosimilars. However, there are still debates if switching between a biosimilar and its reference product influences the efficacy of the treatment. In this paper, we address this uncertainty by developing a formal statistical test that can be used for showing that switching has no negative impact on the efficacy of biosimilars. For that, we first introduce a linear mixed-effects model that is used for defining the null hypothesis (switching influences the efficacy) and the alternative hypothesis (switching has no influence on the efficacy). Using this as the foundation of our work, we propose several approaches for testing for changes in the efficacy of the treatment due to switching and discuss the properties of these tests in an extensive simulation study. It is shown that all these methods have advantages and disadvantages and the decision regarding which method is preferred depends on the expectation of a switching assessment. To demonstrate the applicability of the methods in practice, the approaches were applied to the data of the EGALITY study, which compares the reference product Enbrel(r) (Amgen) with the approved biosimilar Erelzi(r) (Sandoz). PMID- 29424121 TI - Donor understandings of blood and the body in relation to more frequent donation. AB - BACKGROUND AND OBJECTIVES: The INTERVAL trial aimed to find the optimum frequency of blood donation to enhance blood supplies and maintain donor health. This not only requires biological knowledge, but also an appreciation of donor perspectives, and how their experiences and beliefs might be central if any changes are ever to be made. To address this, trial participants were interviewed about their ideas of blood and the body in relation to their experiences of increased donation frequency. MATERIALS AND METHODS: Thirty in depth face-to-face interviews conducted with blood donors participating in the trial. RESULTS: Three key themes emerged: ideas about how blood and iron reserves are replenished, and what people did to facilitate this; beliefs about physiological differences relating to age and gender; and practical issues that affected the experience of donation. Overall, participants interviewed welcomed more frequent donation, despite a range of pragmatic concerns. CONCLUSION: Despite some practical obstacles, increased donation frequency aligned with participant's ideas about bodily replenishment, the value of donation, and their identity as enduring blood donors. They therefore supported the idea of increasing frequency of donation, independently of the biomedical evidence from the trial itself. PMID- 29424122 TI - Abstracts of the American Psychosocial Oncology Society 15th Annual Conference, 22-24 February 2018, Tucson, Arizona. PMID- 29424124 TI - Can a postnasal drip can be aspirated into the lungs? PMID- 29424123 TI - Mouse models of non-alcoholic steatohepatitis: A reflection on recent literature. AB - Non-alcoholic steatohepatitis (NASH) is strongly associated with overnutrition, insulin resistance, and predisposition to type 2 diabetes. To critically analyze the translational significance of currently used animal models of NASH, we reviewed articles published during the last 3 years that studied NASH pathogenesis using mouse models. Among 146 articles, 34 (23%) used models in which overnutrition was reported, and 36 (25%) demonstrated insulin resistance, with or without glucose intolerance. Half the articles contained no information on whether mice exhibited overnutrition or insulin resistance. While 75 papers (52%) reported > 2-fold increase of serum/plasma alanine aminotransferase (ALT) compared with controls, ALT levels were near normal or not reported in 48%. Liver pathology was assessed by a pathologist with an interest in liver pathology in 53% of articles published in gastroenterology/hepatology journals, versus 43-44% in other journals. While there appears to be a trend to use models that are potentially relevant to the pathogenesis of human NASH, journals currently publish data on mouse models in which overnutrition and insulin resistance do not occur, without ALT increase or appropriate analysis of NASH pathology. We recommend that investigators, reviewers, and journal editors carefully consider the validity of NASH models in current use and that moves are made to reach a consensus on what the minimal criteria should be. PMID- 29424125 TI - A High-Performance Optical Memory Array Based on Inhomogeneity of Organic Semiconductors. AB - Organic optical memory devices keep attracting intensive interests for diverse optoelectronic applications including optical sensors and memories. Here, flexible nonvolatile optical memory devices are developed based on the bis[1]benzothieno[2,3-d;2',3'-d']naphtho[2,3-b;6,7-b']dithiophene (BBTNDT) organic field-effect transistors with charge trapping centers induced by the inhomogeneity (nanosprouts) of the organic thin film. The devices exhibit average mobility as high as 7.7 cm2 V-1 s-1 , photoresponsivity of 433 A W-1 , and long retention time for more than 6 h with a current ratio larger than 106 . Compared with the standard floating gate memory transistors, the BBTNDT devices can reduce the fabrication complexity, cost, and time. Based on the reasonable performance of the single device on a rigid substrate, the optical memory transistor is further scaled up to a 16 * 16 active matrix array on a flexible substrate with operating voltage less than 3 V, and it is used to map out 2D optical images. The findings reveal the potentials of utilizing [1]benzothieno[3,2 b][1]benzothiophene (BTBT) derivatives as organic semiconductors for high performance optical memory transistors with a facile structure. A detailed study on the charge trapping mechanism in the derivatives of BTBT materials is also provided, which is closely related to the nanosprouts formed inside the organic active layer. PMID- 29424126 TI - Fewer peripheral asymmetrical cortical veins is a predictor of favorable outcome in MCA infarctions with SWI-DWI mismatch. AB - BACKGROUND: Outcome prediction of asymmetrical prominent cortical veins (APCVs) on infarction is still debated and may help in selecting patients for reperfusion treatment. PURPOSE: To explore the relationship between fewer peripheral APCVs and the outcome in the patients of acute/subacute middle cerebral artery (MCA) infarctions as well as the relationship between this sign and stenosis of ipsilateral MCA. STUDY TYPE: Retrospective case-control study. POPULATION: We enrolled 41 patients with MCA acute/subacute infarction. Compared to the low sign of cortical veins of contralateral hemisphere on susceptibility-weighted imaging (SWI), these patients were divided into fewer (n = 28) and prominent APCVs (n = 13) groups. FIELD STRENGTH/SEQUENCE: 3.0T conventional stroke sequences, including T1 -weighted imaging, T2 -weighted imaging, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI) (b = 0 and 1000 s/mm2 ), MR angiography (MRA), and SWI. ASSESSMENT: We explored the relationships between fewer peripheral APCVs sign and clinical outcome, as well as the relationship between this sign and the degree of ipsilateral MCA stenosis. STATISTICAL TESTS: Fisher's exact analysis, logistical regression, as well as Cohen's kappa coefficient were used for statistical analysis. RESULTS: Fewer and prominent peripheral APCVs were detected in 28 (56.10%) and 13 (43.90%) patients. In 28 patients with fewer peripheral APCVs, 23 patients (82.14%) had a favorable outcome (modified Rankin Scale [mRS] <=2), and five patients (17.76%) had an unfavorable outcome (mRS >2) (P = 0.010). In terms of MCA stenosis, the rate of normal and mild to moderate stenosis of MCA in the fewer APCVs group (82.14%) was higher than that in the prominent APCVs group (23.08%) (P < 0.001). More severe stenosis of ipsilateral MCA was found in patients with prominent APCVs group (76.92%) than that of fewer APCVs group (17.86%). The peripheral APCVs was positively correlated with the degree of MCA stenosis (r = 0.538, P < 0.001). DATA CONCLUSION: Fewer peripheral APCVs may suggest a favorable outcome in unilateral MCA infarction. The patency of ipsilateral MCA may correlate to fewer APCVs and favorable outcome. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;48:964-970. PMID- 29424127 TI - Intensive care unit nurses' knowledge of medication administration via enteral tubes. AB - BACKGROUND: Medication administration via enteral tubes is a complex and key application for which nurses in intensive care units are responsible. AIM: The aim of this study was to evaluate drug administrations via enteral tubes by nurses in intensive care units. METHODS: This research was conducted using a descriptive and cross-sectional research design. The study was conducted with 289 nurses at intensive care units in hospitals in Izmir, Turkey. The data of the study were collected with the 'Sociodemographic Information Form' and the 'Enteral Medication Administrations Questionnaire', which was designed in accordance with the literature and consists of questions on interventions before, during and following medication administrations via enteral tubes. RESULTS: It was found that more than half the nurses (62.3%) use nasogastric tubes for medication administrations and that all of them use the enteral way for the administration of medications in the form of tablets, while 58.8% use this method to administer the medications in the form of enteric-coated tablets. It was determined that approximately half the nurses (52.6%) apply more than one medication separately, and a majority (84.1%) use tap water to wash the enteral tube. CONCLUSIONS: Enteral medication administration practices are inconsistent. Some nurses use unsafe practices and may therefore compromise patient care. RELEVANCE TO CLINICAL PRACTICE: Conduction of education programmes on medication administration via enteral tubes for intensive care unit nurses is important in improving nurses' knowledge. PMID- 29424128 TI - Chiral Shell Core-Satellite Nanostructures for Ultrasensitive Detection of Mycotoxin. AB - Herein, the design of a DNA-based chiral biosensor is described utilizing the self-assembly of shell core-gold (Au) satellite nanostructures for the detection of mycotoxin, ochratoxin A (OTA). The assembly of core-satellite nanostructures based on OTA-aptamer binding exhibits a strong chiral signal with an intense circular dichroism (CD) peak. The integrity of the assembly of core-satellite nanostructures is limited to some extent in the presence of different levels of OTA. Correspondingly, the chiral intensity of assembly is weakened with increasing OTA concentrations, allowing quantitative determination of the target. The developed chiral sensor shows an excellent linear relationship between the CD signal and concentrations of OTA in the range of 0.1-5 pg mL-1 with a limit of detection as low as 0.037 pg mL-1 . The effectiveness of the biosensor in a sample of red wine is verified and a good recovery rate is obtained. These results suggest that the strategy has great potential for practical application. PMID- 29424129 TI - Micro Perfusion and Quantitative Analysis of the Femoral Head Intraosseous Artery. AB - The present study investigates the feasibility of micro perfusion of femoral head specimens from femoral neck fracture patients by the inferior retinacular arteries and performing intraosseous artery quantitative analysis of the femoral head. Twelve femoral neck fracture patients who had undergone conventional hip replacement surgery were included in this study. Femoral head specimen arteries were first dissected and exposed and then perfused by the inferior retinacular arteries and all the femoral heads underwent micro-CT scanning. After micro-CT scanning, a digital 3-D model was reconstructed to quantify the femoral head intraosseous arteries for comparison with a normal femoral head. The artery length density, artery volume density, and artery length/volume ratio were calculated separately and compared with normal femoral head parameters. Micro-CT scanning displayed the epiphyseal arterial network structure and their fine vascular branches in all 12 femoral neck fractures. Blood was supplied from the inferior retinacular artery to the epiphyseal arterial network then to all the fine blood vessels within the femoral head. No statistical differences were observed in femoral heads' intraosseous artery length densities or volume densities between the normal and femoral neck fracture specimens, while the artery length/volume ratio showed a statistical difference, and the ratio increased from 19 to 46. Micro perfusion of the femoral head by the inferior retinacular arteries is possible and can present the epiphyseal network and their fine arterial branches in pathologic conditions to provide a morphological basis for the study of femoral head disease. PMID- 29424130 TI - [Progress in fungal polyketide biosynthesis]. AB - Fungal polyketides display complex structures and variously biological activities. Their biosynthetic pathways generally contain novel enzyme-catalyzed reactions. This review provides a summary of recent research advances in molecular mechanism of the biosynthesis of fungal polyketides including highly reducing polyketide synthases (HR-PKSs), non-reducing polyketide synthases (NR PKSs), as well as polyketide-nonribosomal peptide synthase (PKS-NRPSs) and reducingnon- reducing polyketide synthase (HR-NR PKSs) hybrids. The elucidation of biosynthetic mechanism of many fungal polyketides provides guidance on the discovery of new biosynthetic gene cluster of fungal polyketide natural products and compounds with novel structures as well as their analogue. PMID- 29424131 TI - [Enzymatic production of arginine derivatives: a review]. AB - L-arginine (L-Arg) is an alkaline amino acid that possesses various function groups and acts as an important precursor for useful chemical synthesis. L-Arg derivatives are widely applied in pharmaceutical, food and cosmetic industries. Environment friendly and cost-effective production of L-Arg derivatives by enzymatic catalysis provides significant advantages over chemical synthesis and microbial fermentation. In this article, several typical L-Arg derivatives and their enzymatic production processes are highlighted. Furthermore, prospect is also addressed about enzymatic production of L-Arg derivatives. PMID- 29424132 TI - [Progress in lytic polysaccharide monooxygenase]. AB - Lignocellulose is the most abundant renewable biomass resource. Enzymatic breakdown of lignocellulose into oligosaccharides or monosaccharides is the key to exploit lignocellulosic biomass. However, traditional glycoside hydrolases are insufficient to degrade lignocellulose. The emergence of lytic polysaccharide monooxygenase, a novel enzyme for lignocellulose degradation, has enriched the deconstruction schema and accelerated the enzymatic conversion of polysaccharides, by introducing new chain breaks that allow hydrolases to initiate further degradation. Here, we review the discovery, classification and catalytic mechanism of the enzyme, as well as the methods for assaying its activity. The prospect for its application in feed additive, functional food and biofuel development is further discussed. PMID- 29424133 TI - [Recent advances in enzyme immobilization]. AB - Enzyme is an efficient and green biocatalyst, and widely used in many areas. Immobilized enzyme is superior to its free form in a variety of properties. Enzyme immobilization studies started in the 1970s in China. Till now, immobilized enzymes are widely applied in the fields of food, medical, energy, environmental management, among others. However, there are still some defects such as no universal method and the high cost. Therefore, based on the relatively mature traditional immobilization technologies, efforts have been made to innovate immobilization technologies. As a result, many new immobilization technologies focusing on new carriers and methods are continuously generated. Coupling with more than ten years' study on enzyme immobilization, we present here recent development and application of new immobilization technologies, as well as suggestions to future development of immobilization technology. PMID- 29424134 TI - [Active miniature inverted-repeat transposable elements transposon in plants: a review]. AB - Miniature inverted-repeat transposable elements transposon is a special transposon that could transpose by "cut-paste" mechanism, which is one of characteristics of DNA transposons. Otherwise, the copy number of MITEs is very high, which is one of characteristics of RNA transposons. Many MITE families have been reported, but little about active MITEs. We summarize recent advances in studying active MITEs. Most the MITEs belong to the Tourist-like family, such as mPing, mGing, PhTourist1, Tmi1 and PhTst-3. Additionally, DTstu1 and MITE-39 belong to Stowaway-like family, and AhMITEs1 belongs to Mutator-like family. Moreover, we summarize the structure (terminal inverse repeats and target site duplications), copy number, evolution pattern and transposition characteristics of these active MITEs, to provide the foundation for the identification of other active MITEs and subsequent research on MITE transposition and amplification mechanism. PMID- 29424135 TI - [Generation and characterization of recombinant classical swine fever virus C strain expressing the cap protein of porcine circovirus type 2]. AB - Classical swine fever (CSF), caused by classical swine fever virus (CSFV), is a devastating viral disease in swine, leading to significant economic losses to the pig husbandry. C-strain is one of the best modified live vaccines against CSF. The vaccine is highly safe and efficacious and can provide rapid and complete protection against essentially all genotypes of CSFV. Co-infections of pigs with CSFV and porcine circovirus type 2 (PCV2) occur frequently in the field, making it difficult to control the associated diseases. Here, a recombinant C-strain rHCLV-Cap expressing the Cap protein of PCV2 was constructed and evaluated in vitro and in vivo. The recombinant had comparable phenotypes to C-strain in cell cultures and rabbits. At ten days post-immunization, anti-E2, but not anti-Cap, antibodies were detected in the rabbits inoculated with the recombinant virus. Our study warrants further work to construct C-strain-based bivalent vaccines. PMID- 29424136 TI - [Improving glycolic acid yield by metabolic engineering in Escherichia coli]. AB - Glycolic acid is an important industrial compound. To improve glycolic acid yield, we knocked out ldhA (lactate dehydrogenase) in Escherichia coli MG1655 (DE3) to get the strain Mgly1. Then, we regulated expression levels of isocitrate lyase (aceA), glyoxylic acid reductase (ycdW) and isocitrate dehydrogenase kinase/phosphorylase (aceK) that are key enzymes of glycolate synthesis pathway. The yield of glycolic acid increased to 0.326 g/g glucose (38.3% of the theoretical yield) by overexpressing citrate synthase (gltA). Then we knocked out glcB and aceB (malate synthase) in Mgly1. The engineering strain Mgly335 was obtained and the yield of glycolic acid reached 0.522 g/g glucose (61.4% of the theoretical yield). PMID- 29424137 TI - [Isolation, purification and antitumor activity of Bacillomycin D from Bacillus amyloliquefaciems Q-426]. AB - Cyclic lipopeptide has extensive application prospect in the field of medicine due to its unique chemical structure and biological activity. This study aims to obtain high purity of cyclic lipopeptide monomer from Bacillus amyloliquefaciems strain Q-426, and illuminate preliminary antitumor mechanism of C-15 Bacillomycin D and C-16 Bacillomycin D. Firstly, crude cyclic lipopeptide solution was prepared by two-steps purification of acid precipitation and double-resins chromatography. In order to obtain purer product preparative HPLC was utilized to separate and purify cyclic lipopeptide. Component 1 and component 2 were detected as C-15 Bacillomycin D and C-16 Bacillomycin D by HPLC-MS and ESI-MS/MS. Secondly, the effect of C-15 Bacillomycin D, C-16 Bacillomycin D and their mixture (1:1, mol:mol) on cell proliferation was measured using human cancer cells (Hela, MG, Hep-G2 and HT-29). The cyclic peptide showed a dose dependent manner on the cell proliferation inhibition of Hela and MG cells. Finally, the results of the scratch wound healing assay and FACS analysis revealed that C-16 Bacillomycin D can effectively influence the cells migration and the cells treated with C-16 Bacillomycin D showed typical apoptotic morphology with the increase of drug concentration in the early apoptosis, late apoptosis percentage increased, and G0G1 arrest was induced significantly. PMID- 29424138 TI - [Cofactor engineering strategy for enhanced S-adenosylmethionine production in Saccharomyces cerevisiae]. AB - In order to study the role of cofactor engineering in enhancing the production of S-adenosylmethionine (SAM), we altered the form and concentration of cofactor in Saccharomyces cerevisiae through gene recombination. Effects of cofactor on product synthesis, carbon and energy metabolism were analyzed aiming to provide a theoretical basis for a successful metabolic engineering of SAM producing strains. Because NADPH metabolism in mitochondrion and cytoplasm of S. cerevisiae is relatively independent, the effect of intracellular NADPH availability on the production of SAM was studied in different compartments of S. cerevisiae BY4741. The expression of NADH kinase in mitochondria (POS5 encoded) and cytoplasm (POS5Delta17 encoded) was separately confirmed using a laser scanning confocal microscope. NADPH regulation strategy enhanced SAM production. Compared with the control strain, the intracellular SAM concentration of strain NBYSM-1 was increased by 3.28 times, and the intracellular SAM concentration of strain NBYSM 2 was increased by 1.79 times at 24 h fermentation. In addition, SAM titer and NADPH/NADP+ ratio in strain NBYSM-1 were significantly higher than that of strain NBYSM-2. Therefore, NADPH regulation strategy will be a valuable tool for SAM production and could further improve the synthesis of a large range of cofactor driven chemicals. PMID- 29424139 TI - [Enhancing thermostability of beta-amylase from Bacillus flexus CCTCC 2015368 based on in vitro molecular evolution]. AB - We used in vitro molecular evolution technology by error-prone PCR and high throughput screening to improve thermostability of Bacillus flexus CCTCC 2015368 beta-amylase. Mutant D476N with significant thermostability increase was selected by LB agar starch plate colorimetric assay and 96-well plate enzyme activity assay. The optimum pH was 6.5 for the mutant D476N, compared to 7.0 of the wild type. The optimal temperature was 55 C for both mutant D476N and the wild type. The T50 value of the mutant D476N was 4 C higher than that of the wild type. The half-life of mutant D476N at 55 C was 35 min, 95% higher than that of the wild type. The Km of the mutant D476N was 97.98 MUmol/L, 1.14 times of that of the wild type (85.86 MUmol/L). The thermostability of the mutant D476N was slightly lower than that of the wild type. The three-dimensional structure of wild type and mutant D476N was simulated by SWISS-MODEL and analyzed by PyMol software. The mutated amino acid residue Asn476 was located on the loop of protein surface. The molecular free energy(DeltaG) of D476N was calculated by MOE software was 106.0 kcal/mol, reduced by 10.3% compared to the wild enzyme. These results were consistent with the theory that the protein molecular free energy and thermostability were negatively correlated. PMID- 29424140 TI - [Expression characteristics of glutamine synthetase of wheat in Escherichia coli]. AB - Glutamine synthetase is a key enzyme in plant nitrogen assimilation. To study the structure of wheat glutamine synthetase isoenzymes, GS1, GSr, GSe, GS2 and GS2p of wheat were cloned into pET-21a, and the expression condition was optimized. Although wheat glutamine synthetase isoenzymes had 70%-80% amino acid sequence homology, the isoforms expressed with different characteristics. Induced at 30 degrees C, the most expression level of GSr, GSe and GS2 was after 3 h, and of GS1 was at the 7 h whereas no GS2p was expressed, and the GS isoenzymes showed different expression level, with the order of GS1 (22%)>GSr (15%)>GS2 (12%)>GSe (5%). GSe expressed as soluble protein, and GS1 expressed mainly as soluble protein whereas GSr and GS2 expressed as insoluble proteins. Induced at 30 degrees C for 3 h, mRNA transcript levels of GS isoforms were different, with the order of GSr (7.59)>GS2 (1.84)>GS2p (1.66)>GSe (1.46)>GS1 (1.00). The levels of mRNA transcription were not consistent with the level of the protein translation. The analysis of mRNA secondary structure showed the free energy of translation initiation region of glutamine synthetase isoforms was different, with the order of GS1 (14.4)GSr (13%)>GS2 (10%)>GSe (7%), and different activities with GS1>GSe>GS2, and the activity of GSr was not detected. The gene sequence of glutamine synthetase isoenzymes determines the amount, status and activity of proteins expressed in prokaryotic cells. PMID- 29424141 TI - [Adulteration detection of tea samples based on plant rbcL gene sequencing]. AB - Tea is one of the most popular drinks in the world, but counterfeit or adulterated tea can be found now and then on the tea market. The traditional methods dependent on sensory, physical and chemical tests cannot identify the composition of adulterated plant species accurately. We developed therefore a method for identification of adulterated plants in tea based on qualitative detection of plant rbcL (Ribulose 1,5-bisphosphate carboxylase-oxygenase large subunit) fragments, which involved amplification, sequencing and sequence analyses of rbcL fragments. Seven tea samples were analyzed with the established method. The results showed that Yueyanghuangcha (yellow tea) and Xinyangmaojian (green tea) were pure with only detection of the tea plant Camellia sinensis; Zhengshan Souzhong (black tea), Tieguanyin (oolong tea), Tailaoyinzhen (white tea), Liupao and Pu-erh (dark tea) were, to a certain extent, adulterated with non-Camellia sinensis plants. The method introduced in this study only requires a small amount of tea samples, easy to operate and reliable. It can be used to determine if any tea samples are adulterated. PMID- 29424142 TI - [Optimizing carbon/energy metabolism to enhance monellin production by Pichia pastoris]. AB - In heterologous protein productions by Pichia pastoris, methanol induction is generally initiated when cell density reaches very high level. However, this traditional strategy suffers with the problems of difficulty in DO control, toxic by-metabolites accumulation and low targeted protein titer. Therefore, initiating methanol induction at lower cell concentration is considered as an alternative strategy to overcome those problems. However, the methanol/energy regulation mechanisms of initiating induction at lower concentration are not clear and seldom reported. In this article, with monellin production as a prototype, we analyzed the methanol/energy metabolism in protein expression process using the strategies of initiating induction at both higher/lower cells concentrations. We attempted to interpret the advantages of the "alternative" strategy, via online measurements of methanol consumption, CO2 production and O2 uptake rates. When adopting this "alternative" strategy and maintaining temperature at 30 degrees C, carbon flux ratio directing into monellin precursors synthesis reached the highest level of 65%. In addition, monellin synthesis was completely associated with cell growth. PMID- 29424143 TI - [Analysis of transcriptional factors expression profile during dedifferentiation of liver cell cultured in vitro]. AB - Primary hepatocytes are widely used in drug metabolism and toxicity assessment. As the culture of primary hepatocytes in vitro is a process of dedifferentiation, hepatocytes lose normal metabolic detoxification function gradually. The mechanism of hepatocyte dedifferentiation has been not clear so far. TFs play an important role in the dedifferentiation and non-parenchymal cells can maintain the function of hepatocytes in vitro. However, the current methods cannot be used in effective identification and quantitative analysis of a large number of TFs. In this paper, the mo-culture system (only primary hepatocytes) and co-culture system (primary hepatocytes and non-parenchymal cells) were established. The cells were cultured for 24 h, 48 h, 72 h as monolayer. The changes of TFs during the culture were obtained by TOT (Transcription factor response elements on tip) transcription factor enrichment method and mass spectrometry. A total of 219 TFs were identified in three individual replicates. The result revealed that up regulated TFs were enriched in cell proliferation, death and immune response pathways, and down-regulated TFs were involved in metabolism pathway. The establishment of such culture-TFs identification system is of great significance to reveal the mechanism of primary hepatocyte dedifferentiation and crosstalk between hepatocytes and non-parenchymal cells. PMID- 29424144 TI - [Discussion on hot spot of femoral intertrochanteric fracture]. PMID- 29424145 TI - [Mid-term follow-up study of hip arthroplasty for internal fixation failure of femoral intertrochanteric fractures in the elderly]. AB - OBJECTIVE: To retrospective analysis the mid-term follow-up effect of hip joint replacement in elderly patients with failure of intertrochanteric fractures of the hip joint internal fixation. METHODS: From December 2008 to December 2011, 32 elderly patients underwent arthroplasty after intertrochanteric fracture fixation failure, of which, 4 death cases were excluded from the study, and the remaining 28 cases were in the study group. The age of patients ranged from 69 to 83 years old with a mean of 75 years old. The time from the internal fixation to the hip replacement were 8 to 72 months. Among them, 6 patients were Evans I type, 11 patients were Evans II type, 9 patients were Evans III type, and 2 patients were Evans IV type. Nine cases showed fracture of the lateral plate before operation, while 15 cases were femoral head screw cut-out and 4 cases were screw loosening. Harris score was used to compare the changes of hip function before operation with the final follow-up. Imaging results(X-ray) and erythrocyte sedimentation rate(ESR) were performed during the follow-up. RESULTS: All patients were followed up from 4 to 7 years with an average of 5.3 years. Pain was significantly reduced or disappeared in patients compared with pre-operation. And hip function was significantly improved. Two cases had moderate pain after the physical activity and 4 cases had mild pain after the physical activity. At the final follow-up, 19 patients resumed free walking, 8 patients required walking with walking sticks, and 1 patient needed walking aid. The Harris scores improved from preoperative 34.9+/-2.4 to 83.4+/-5.7 at the final follow-up, among them, 15 cases were classified as excellent, 10 as good, 2 as fair, and 1 as poor. X-ray examination showed no prosthesis loosening and sinking fracture. CONCLUSIONS: Salvage THA surgery could improve the hip function and the quality of life for old patients with intertrochanteric fracture fixation failure, and the middle term follow-up results support that. PMID- 29424146 TI - [Comparison of PFNA and InterTAN intramedullary nail in treating unstable femoral intertrochanteric fractures]. AB - OBJECTIVE: To compare the clinical effects of PFNA and InterTAN for the treatment of unstable intertrochanteric fractures in the elderly patients. METHODS: From April 2012 to February 2014, 113 elderly patients with unstable intertrochanteric fractures were treated by PFNA or InterTAN. There were 64 cases in PFNA group, including 25 males and 39 females with an average age of (73.3+/-6.5) years old (ranged, 66 to 85);while 49 cases in InterTAN group, including 20 males and 29 females with an average age of (74.2+/-5.4) years old (ranged, 65 to 85). According to the AO classification, there were 48 cases of type A2, 16 cases of type A3 in PFNA group and 37 cases of type A2, 12 cases with type A3 in InterTAN group. The time interval from injury ranged from 3 to 8 days with an average of 4.7+/-1.2. The blood loss, operation time, fluoroscopy time, lateral cortex fractures of the proximal femur, healing time of fracture, femoral shaft fractures, femoral head screw cut-out, necrosis of the femoral head, femoral neck shortening and Harris score of patients at the last follow-up were compared between the two groups. RESULTS: Fifty-eight patients in PFNA and 44 patients in InterTAN were followed up for 14 to 18 months with an average of 16.3+/-1.2. Wound healing was satisfying during the follow-up. Significant differences were observed between the two groups regarding the blood loss, operation time, fluoroscopy time. The complication rate of femoral shaft fractures, femoral head screw cut-out and femoral neck shortening in InterTAN group was less than that in PFNA group, showing significant difference between the two groups (P<0.05). At the latest follow-up, the average Harris scores were 90.7+/-5.1 in PFNA group and 90.4+/-3.9 in InterTAN group, there was no significant difference between the two groups(P>0.05). CONCLUSIONS: InterTAN with stronger anti-rotation function is more suitable for patients with early weight-bearing and it reduces the incidence rates of hip varus, femoral head screw cut-out and femoral neck shortening. However, for those patients with osteoporosis or unfit for surgery, PFNA is a good option. As the limited follow-up duration, long-term effects of the two surgical methods needs to be further observed and studied. PMID- 29424147 TI - [Effect of surgical timing of femoral intertrochanteric fractures on 1-year postoperative mortality in elderly]. AB - OBJECTIVE: To evaluate the effect of surgical timing of intertrochanteric fracture on 1-year postoperative mortality in elderly and analyze factors that influence 1-year postoperative mortality. METHODS: A retrospective search had been conducted to analyze 350 patients of intertrochanteric fracture from December 2012 to December 2014. The studied patients were divided into three groups such as the group of <72 h and the group of 72-96 h and the group of >96 h, which depended on the time of injury to surgery. The postoperative mortality was compared among the groups and causes of death in patients were evaluated after surgery. Multiple logistic regression was then used to distinguish independent effects on mortality. RESULTS: The one-year postoperative mortality of three groups(<72h, 72-96 h, >96 h)were significantly different and the rate of death was 1.8%, 8.1%, 10.3%. The one-year postoperative mortality of the group of <72 h was inferior to the group of 72-96 h and >96 h respectively(P<0.05). Age, preoperative coexist disease and surgical timing were dependent risk factors to one-year postoperative mortality(P<0.05, OR>1). CONCLUSIONS: The early surgery can diminish one year postoperative mortality, the patient who is older and has too many preoperative coexist diseases and is delayed to surgery has higher risk to die in one year after surgery. PMID- 29424149 TI - [Inversive LISS plate in treating intertrochanteric and subtrochanteric fractures combined with femoral shaft fractures]. AB - OBJECTIVE: To study clinical effects of inversive LISS(less invasive stabilization system, LISS) plate for the treatment of intertrochanteric and subtrochanteric fractures combined with femoral shaft fractures. METHODS: From January 2012 to January 2015, 24 patients with intertrochanteric and subtrochanteric fractures combined with femoral shaft fractures were treated with inversive LISS plate, included 16 males and 8 females with an average age of 62.5 years old ranged from 35 to 81 years old. There were 8 cases of traffic accident injuries, 3 cases of falling from high place, and 13 cases of falls injuries. The time from injury to operation was ranged from 2 to 12 days with an average of 5.2 days. The operation time, intraoperative blood loss and the length of hospitalization were analyzed. The fracture union was assessed by follow-up radiographs and hip functional recovery by Harris hip scoring. RESULTS: All patients were followed up for 16.2 months (ranged, 18 to 36 months). The mean operative time was (68.22+/-48.36) min;the mean blood loss was (256.28+/-182.46) ml;the mean time of hospitalization was(14.8+/-5.2) days. There were no complications such as deep infection, deep vein thrombosis, pulmonary embolism and bone nonunion during the follow up period. The bone healing was ranged from 3 to 8 months with an average of 4.8 months. The mean Harris score was 76.49+/ 12.28 at the final follow-up, 15 cases were classified as excellent, 6 as good and 3 as fair. CONCLUSIONS: Inversive LISS plate can be used in treating with intertrochanteric and subtrochanteric fractures combined with femoral shaft fractures, and should not emphasis on premature loading. PMID- 29424148 TI - [Clinical analysis of LPFP, PFNA and BPH in treating femoral intertrochanteric fractures in elderly patients]. AB - OBJECTIVE: To evaluate the clinical results of locking proximal femur plate(LPFP), proximal femoral nail antirotation(PFNA) and bipolar hemiarthroplasty(BPH) in the treatment of femoral intertrochanteric fractures in elderly patients. METHODS: Retrospective analysis of the 86 elderly patients with femoral intertrochanteric fractures during June 2011 and August 2016 were enrolled in this study. The patients were divided into 3 groups: 26 cases in LPFP group included 10 males and 16 females with an average age of (72.54+/-4.78) years old, 5 cases of type II of Evans, 12 cases of type III and 9 cases of type IV; 39 cases in PFNA group included 17 males and 22 females with an average age of 74.41+/-5.65, 11 cases of type II, 18 cases of type III and 10 cases of type IV; 21 cases in BPH group included 9 males and 12 females with an average age of 76.23+/-6.97, 1 case of type II, 10 cases of type III and 10 cases of type IV. The data of three groups were collected for statistical analysis on the following aspects: operation time, intraoperative blood loss, the length of hospital stay, postoperative complications and Harris score of the hip joint function. RESULTS: The wound healed well and no complication occurred. Eighty-four cases were follow up, while 2 cases were lost, the follow-up rate was 97.6%. The patients were followed up for 22 to 41 months with an average of 26.3 months. For comparison of operation time and time of the hospital stay, BPH group was shorter than the LPFP and PFNA group(F=19.782, 21.981, P<0.05). For comparison of the intraoperative blood loss, the BPH group was less blood loss than the LPFP and PFNA group(F=12.976, P<0.05), while there was no significant means between the LPFP and PFNA group(t=10.879, P>0.05). For comparison of the postoperative complications, LPFP group was higher than BHP and PFNA group(F=30.976, P<0.05), while there was no significant means between LPFP and PFNA group(t=9.902, P>0.05). For comparison of the Harris score of the hip joint at 1 year after operation, BPH and PFNA group were both higher than LPFP group(F=19.692, P<0.05), while there was no significant means between BPH and PFNA group (t=4.971, P>0.05). CONCLUSIONS: For elder patient with femoral intertrochanteric fracture, BPH could be the best optional for the shorter operation time and less complications. And the PFNA also could be optional choice for the patients while the LPFP was forbidden for the elder patients. PMID- 29424150 TI - [Treatment of Pipkin type I and II femoral head fractures through modified Smith Peterson approach and modified Hardinge approach-a case-control studies]. AB - OBJECTIVE: To compare clinical results of treatment of Pipkin type I and II femoral head fractures through modified Smith-Peterson(S-P) approach and modified Hardinge approach. METHODS: From July 2005 to July 2014, 42 patients with Pipkin type I and II femoral head fractures were treated with operation. A total of 23 patients in anterior group was treated with modified S-P approach including 17 males and 6 females with an average age of (29.3+/-9.4) years old, 5 cases of type I by excision of the fragement, 3 cases of type I and 15 cases of type II cases by fixation of the fragement. While a total of 19 patients in the lateral group was treated with modified Hardinge approach including 15 males and 4 females with an average age of (31.4+/-10.0) years old, 3 cases of type I by excision of the fragement, 4 cases of type I and 12 cases of type II by fixation of the fragement. Operative time, blood loss during operation and fracture healing time were observed and compared. The clinical and radiographic outcomes of the patients were measured using Thompson-Epstein scoring scale. The effect of hip reduction time of less than 6 h, 6 to12 h, and more than 12 h, the effect of surgery time within 24 h and more than 24 h after injury were compared. RESULTS: All patients were followed up from 24 to 60 months with an average of(30.29+/ 6.95) months. The operation time (61.96+/-12.22) min, blood loss (46.09+/-18.03) ml, and (74.74+/-10.06) min, blood loss (72.11+/-19.88) ml in lateral group in the anterior group were better than those of lateral group(P<0.05). In anterior group, fracture healing time was(12.22+/-1.70) weeks, the results were excellent in 8 cases, good in 10 cases, fair in 4 cases and poor in 1 case, the excellent and good rate was 78.3%, the incidence of avascular necrosis of femoral head was 8.69%(2/23), and the incidence of heterotopic ossification was 13.04%(3/23). While in lateral group, the fracture healing time was(12.42+/-1.95) weeks, the results were excellent in 6 cases, good in 7 cases, fair in 3 cases and poor in 3 cases, the excellent and good rate was 68.4%, the incidence of avascular necrosis of femoral head was 10.53%(2/19), and the incidence of heterotopic ossification was 5.26%(1/19). There was no significant difference in fracture healing time, postoperative effect and postoperative complications between the anterior group and lateral group(P<0.05). The effect of patients with reduction time of hip dislocation less than 12 h was significantly better than that of more than 12 h, there was no significant difference in the effect between reduction time within 6 h and 6 to 12 h. There was no significant difference in the outcome between surgical patients within 24 h and more than 24 h after injury. CONCLUSIONS: Dislocated hip of Pipkin type I and II femoral head fractures should be closed reduction within 6 h. If conditions are limited, the reduction time can be accepted within 12 h. Both of modified S-P approach and modified Hardinge approach are effective in treating Pipkin type I and II femoral head fractures, and can obtain excellent outcomes. Moreover, modified S-P approach has advantage of less trauma, less blood loss, shorter operative time. PMID- 29424151 TI - [Treatment of humeral shaft fractures in children with closed reduction and external fixation]. AB - OBJECTIVE: To explore the clinical effect of closed reduction and minimally invasive treatment of humeral shaft fractures in children. METHODS: From July 2011 to April 2015, 39 cases of pediatric humeral shaft fractures were treated by closed reduction and external fixation, including 27 males and 12 females with a mean age of 8.6 years old ranging from 3 to 14 years old. Time from injury to the treatment was 2 h to 7 days with an average of 2.7 days. There were 6 cases of upper fracture, 21 cases of middle fracture and 12 cases of lower fracture. All children were closed injury, appeared pain, swelling, local deformity and limited mobility and other symptoms after injury. X-ray examination showed humeral shaft fracture. Neer score of shoulder joint function and HSS score of elbow joint function were used to record and analyze the pain, function and activity of shoulder and elbow joint before and after treatment. RESULTS: All the 39 cases were followed up for 6 to 12 months with a mean of 8.6 months. Two cases appeared postoperative superficial infection of the needle, and healed after dress; other cases gained good pinhole healing. There were significant differences in the pain, function and activity of the shoulder of Neer score before and after the treatment (P<0.05). There were significant differences in the pain and function of the elbow of HSS before and after treatment (P<0.05). According to the evaluation of Neer score of shoulder function, the total score was 88.82+/-2.50, 29 cases were excellent, 9 cases were good, and 1 case was fair. According to the evaluation of HSS score of elbow joint function evaluation, the total score was 91.51+/-5.09, 30 cases were excellent, 7 cases were good, 2 cases were general. CONCLUSIONS: Manual closed reduction combined with external fixation for the treatment of humeral shaft fractures in children has advantages of less trauma, definite reduction effect, reliable fixation and benefit for early functional exercise of the shoulder and elbow joint. This therapy can be used as one of clinical methods for the treatment of humeral shaft fractures in children. PMID- 29424152 TI - [Application of the computer-assisted virtual reduction combined with 3D printing technique in acetabular fractures]. AB - OBJECTIVE: To investigate the computer-assisted virtual reduction combined with 3D printing technique as preoperative planning and assess their therapeutic effects. METHODS: Thirty-five cases of acetabular fracture treated by internal fixation from March 2011 and March 2014 were retrospectively analyzed. All patients underwent operations with internal fixations implanted. The patients were divided into 2 groups according whether they used the computer-assisted virtual reduction combined with 3D printing technology. Fifteen patients in the digital group included 9 males and 6 females with a mean age of (39.4+/-8.8) years old ranging from 22 to 58 years old;time from injury to the operation was (8.8+/-2.0) days;for Letournel-Judet classification, 4 cases were both column fracture, 5 cases were posterior wall fracture, 4 cases were T-fracture, 2 cases were posterior wall with transverse fracture. Twenty cases in the control group included 12 males and 8 females with a mean age of (38.7+/-13.1) years old ranging from 19 to 59 years old;time from injury to the operation was(8.2+/-2.3) days;for Letournel-Judet classification, 6 cases were both column fracture, 8 cases were posterior wall fracture, 3 cases were T-fracture, 3 cases were posterior wall with transverse fracture. The volume of intraoperative blood loss and blood transfusion, operative time, satisfaction rate of fracture reduction and excellent and good rate of d'Aubigne Postal function evaluation were compared between the two groups and statistical analysis was conducted. RESULTS: All the incisions healed without infection occurred. All the fractures healed without breakage or loosening of plates and screws. There was 1 case of postoperative nerve stimulation symptoms in each group. One patient in the digital group was found necrosis of the femoral head at 6 months after operation. One patient in the control group was found heterotopic ossification at 8 months after operation. All patients were follow-up for 13 to 28 months with an average of 17.6 months. The volume of intraoperative blood loss and blood transfusion in the digital group were significantly less than those in the control group(P<0.05). The operation time in the digital group was shorter than that in the control group(P<0.05). The excellent and good rates of fracture reduction were 92.9%(14/15) and 85%(17/20) in the digital group and the control group respectively, and there was no statistical significance (P>0.05). The excellent and good rates of Aubigne Postal function evaluation were 86.7%(13/15) and 80%(16/20) respectively, and there was no significant difference(P>0.05). CONCLUSIONS: The computer-assisted virtual reduction combined with 3D printing technique can reduce the operative time, volume of intraoperative blood loss and blood transfusion in acetabular surgeries for patients with acetabular fractures. The technique is an effective method for preoperative planning, which worth promoting. PMID- 29424153 TI - [Clinical application value and imaging diagnosis of stress fracture]. AB - OBJECTIVE: To discuss the imaging findings of stress fracture, in order to improve the ability of early diagnosis and early treatment of this disease. METHODS: The DR, CT and MRI imaging data of 336 cases of stress fracture from January 2010 to January 2016 were analyzed retrospectively. Early diagnosis ratio in stress fractures by three methods were analyzed using chi2-test. RESULTS: Early diagnosis ratio of three methods as follow: DR was 70.83%(238/332), CT was 55.93%(66/118), and MRI was 73.61%(53/72). There was statistical significance among three methods (chi2=10.15, P=0.006), the early diagnosis ratio of DR was higher than CT (chi2=8.765, P=0.003)and there was no statistical significance between DR and MRI (chi2=0.224, P=0.636). CONCLUSIONS: DR and MRI have better diagnosis of stress fractures while CT is not helpful in the early diagnosis. DR examination is preferred method due to its economical and convenient. MR is the important complement means, which can improve the early diagnosis ratio and provide imaging diagnosis basis for the clinical, so that the disease get early intervention and treatment. PMID- 29424154 TI - [Clinical study on the relationship between the displaced fracture of the inferior ramus of pubis and the posterior pelvic ring injury]. AB - OBJECTIVE: To investigate relation between displaced inferior ramus fractures and posterior pelvic ring injury. METHODS: From August 2012 to August 2015, 51 patients of pubic ramus fractures with complete record were retrospective reviewed including 27 males and 24 females with an average age of(49.1+/-19.0) years old ranging from 9 to 90 years old. The time from injury to treatment ranged from 0.3 to 48 hours with an average of 10.1 hours. According to Tile classification of pelvic fractures, 28 cases were type A, 17 cases were type B, 6 cases were type C. Pelvic radiographs and computed tomography scans were detailed and evaluated for whether there were posterior pelvic ring injury, meanwhile pubic rami fractures were divided into 4 groups as follow: displaced inferior ramus fractures group, undisplaced inferior ramus fractures group, displaced superior ramus fractures group, undisplaced superior ramus fractures group;the incidence rate of association of posterior pelvic ring injury was determined and compared. RESULTS: Twenty-six patients had displaced inferior ramus fractures, all of them (100%) were combined with posterior pelvic ring injury. Twenty patients had undisplaced inferior ramus fractures, 6 of them(30%)were combined with posterior pelvic ring injury. Twenty-eight patients had displaced superior ramus fractures, 22 of them(78.5%) were combined with posterior pelvic ring injury. Twelve patients had displaced superior ramus fractures, 5 of them(41.6%) were combined with posterior pelvic ring injury. Compared with undisplaced inferior ramus fractures group, there was statistic difference(P=0.028 8<0.05) on the incidence rate of posterior pelvic ring injury, there were no statistic difference(P=0.055 8>0.05;P=0.168 3>0.05) while compared with other undisplaced superior ramus fractures group and displaced superior ramus fractures group, but the incidence rate of association with posterior pelvic ring injury much higher than both of two groups (100% vs 41.6%, 78.5%). CONCLUSIONS: Displaced inferior pubic ramus fractures have the highest incidence rate of association with posterior pelvic ring injury, frequently prompted injury to the posterior pelvis. Displaced inferior ramus fractures were an indirect evidence of posterior pelvic injury. PMID- 29424155 TI - [Clinical observation on the effect of joint mobilization in treating elderly patients after distal radius fractures operation]. AB - OBJECTIVE: To investigate the effect of joint mobilization on postoperative wrist joint function, pain and grip strength for elderly patients with distal radius fracture. METHODS: From January 2015 to June 2016, a total of 67 elderly patients with distal radius fracture were randomly divided into routine exercise group and joint mobilization group. Among them, 37 patients in the routine exercise group underwent conventional distal radius fracture postoperative joint function exercise regimen, including 16 males and 21 females with a mean age of (67.8+/ 3.2) years old ranging from 60 to 72 years old;the injured side was dominant in 23 cases and non-dominant in 14 cases;injury mechanism was fall in 26 cases, traffic accident in 11 cases; for AO type, 6 cases were type B3, 18 cases were type C1, 7 cases were type C2, 6 cases was type C3. Other 30 patients in the joint mobilization group underwent joint mobilization on the basis of the routine exercise group including 14 males and 16 females with a mean age of (67.1+/-4.0) years old ranging from 61 to 74 years old; the injured side was dominant in 21 cases and non-dominant in 9 cases;injury mechanism was fall in 25 cases, traffic accident in 5 cases;for AO type, 8 cases were type B3, 13 cases were type C1, 6 cases were type C2, 9 cases were type C3. The wrist joint activity, Gartland Werley wrist joint function score, VAS pain score and grip strength were observed at 3 months afrer treatment. RESULTS: After 3 months' treatment, the VAS in the routine exercise group was higher than that of the joint mobilization group (P<0.05). The grip strength of affected side in both groups were lower than that of contralateral side, but the average grip strength of affected side in joint mobilization group was higher than that in routine exercise group(P<0.05). In routine exercise group, the average angle of flexion, extension, radial deviation were significantly higher than those of joint mobilization group(P<0.05). But ulnar deviation angle in routine exercise group compared with joint mobilization group had no significant difference (P>0.05). In the comparison of each item of Gartland-Werley, there was no significant difference between two groups in residual deformity and complication(P>0.05); the average score of subjective score, objective score and total score in routine exercise group were significantly higher than those of the joint mobilization group (P<0.05). The wrist function Gartland-Werley score in routine exercise group after treatment was excellent in 21 cases, good in 10, 6 in fair, while in joint mobilization group, excellent in 23, good in 6, fair in 1(P<0.05). CONCLUSIONS: The application of joint mobilization in the treatment of elderly patients with distal radius fracture can improve the joint activity and obtain better wrist function after surgery. PMID- 29424156 TI - [Particle impaction bone graft and plate internal fixation for the treatment of proximal femoral bone tumor or tumor lesion]. AB - OBJECTIVE: To evaluate the clinical feasibility of particle impaction bone graft and plate internal fixation for the treatment of proximal femoral bone tumors or tumor disease. METHODS: From January 2013 to January 2016 a total of 26 cases of the proximal femur bone tumors or tumor lesions, neither pathological fracture, were retrospectively analyzed, including 12 males and 14 females with an average age of 34.2 years old ranging from 8 to 62 years old. The pathologic result involved fibrous dysplasia in 11 cases, bone isolation bone cyst in 7 cases, giant cell tumors of bone in 3 cases, aneurysm sample bone cyst in 3 cases, non ossifying fibroma in 1 case, benign fibrous histiocytoma in 1 case. No biopsy of the lesion was performed before the operation. Postoperative lesions were sent to pathology. The operation was treated by particle impaction bone graft and plate internal fixation. RESULTS: All patients were followed up to resume normal life for 8 to 42 months with an average of 25 months. The function assessment referenced to the bone and soft tissue tumor association (MSTS). At the end of the last examination, the positive and lateral X-ray films of the femur showed no low density shadow in the margin of bone graft and bone graft, and the bone healing in the bone graft area was good. No recurrence or metastasis was found in all patients, and no loosening or deformation of the internal fixator occurred. The hip function was well restored and no fracture or deformity progressed in all patients. CONCLUSIONS: The tumor recurrence in the proximal femur is related to curettage and bone grafting. After the curettage, the residual tumor cells were treated by chemical and physical methods. By this method, the disease can be cured for a long time, and it can reduce the recurrence and resume the function of the hip joint. PMID- 29424157 TI - [Clinical observation of 5 cases of diabetes insipidus complicated with skeletal fluorosis]. AB - OBJECTIVE: To investigate the mechanism of diabetes insipidus complicated with skeletal fluorosis and the surgical treatment of spinal canal stenosis caused by skeletal fluorosis. METHODS: From January 2000 to November 2011, 5 patients with diabetes insipidus complicated with skeletal fluorosis were treated with drug and cervical or thoracic posterior decompression including 2 males and 3 females with age of 35, 45, 47, 49, 55 years old respectively. The symptoms was mainly limb motor sensory disturbance accompanied by polyuria and polyuria. Imaging showed that cervical and thoracic multi-segmental continuous spinal stenosis. It was diagnosed with diabetes insipidus according to the symptoms and laboratory tests. According to the symptoms, the vertebral with problems were located and treated by posterior laminectomy decompression or the expansive open-door laminectomy. The recovery of neurological symptoms were recorded and the operation result were evaluate by JOA score improvement rate. RESULTS: The wound healed well in 5 cases, and 1 case of cervical axial pain was improved after symptomatic treatment. Five patients were followed up for 2 to 6 years with an average of 4 years. Numbness of limb and weakness symptoms of follow-up patients were significantly improved, muscle strength and acupuncture hypothyroidism were significantly improved compared with preoperative, the JOA score was significantly improved. At the final follow-up, the improvement rate got excellent results in 2 cases, good in 2 and fair in 1. CONCLUSIONS: Long-term high intake of fluoride can cause skeletal fluorosis in patients with diabetes insipidus. The posterior decompression is effective for the majority of spinal canal stenosis caused by skeletal fluorosis. PMID- 29424158 TI - [Intramedullary nailing combined with cannulated screw in treating femoral condyles fractures]. AB - OBJECTIVE: To observe the clinical effects of retrograde intramedullary nailing and cannulated screws in the treatment of femoral condylar fracture. METHODS: From June 2009 to June 2015, 13 patients with femoral condyles fracture were treated by retrograde intramedullary nailing and cannulated screws including 6 males and 7 females with an average age of 46.1 years old ranging from 16 to 76 years old. There were 10 cases of closed fractures, 3 cases of open fraetures. According to AO classification criteriam, 4 cases were type C1, 7 cases were type C2, 2 cases were type C3. Postoperative reduction of fracture and the knee joint function recovery were observed. RESULTS: All patients were followed up for 12 to 36 months with a mean of 24 months. X-ray examination showed that the union time of fracture was 18 to 24 weeks, 21 weeks on average. There were no cases of loosening, breakage of internal fixators and re-fracture. Hospital for Special Surgery(HSS) knee score was 90.07+/-4.99 at 1 year after the operation. CONCLUSIONS: The clinical efficacy for retrograde intramedullary nailing and cannulated screw for the treatment of femoral condyles fracture was excellent. It can improve the anatomical reattachment rate and reduce the complications and promote the knee functional recovery. PMID- 29424159 TI - [Minimally invasive internal fixation of pelvic ring for type C pelvic fracture]. AB - OBJECTIVE: To evaluate the feasibility of minimally invasive internal fixation of pelvic anterior and posterior ring for the treatment of type C pelvic fracture, and to explore its operative techniques and therapeutic efficacy. METHODS: From December 2010 to December 2015, 18 patients with type C pelvic fracture were treated by reconstructive plates fixation through minimally invasive ilioinguinal approach for pelvic anterior ring injuries, and by invasive percutaneous sacroiliac joint screw fixation for pelvic posterior ring injuries. There were 11 males and 7 females ranging from 29 to 68 years old with an average age of 43.6 years old. According to Tile classification, there were 14 cases of type C1, 3 cases of type C2, 1 case of Type C3. To be specific, 12 cases with hemi-fracture of rami ossa pubis accompanied with fracture of the sacrum, 2 cases with hemi fracture of rami ossa pubis accompanied with sacro-iliac joint dislocation, 3 cases with bilateral-fracture of rami ossa pubis combined with pubic symphysis separation accompanied with single-fracture of the sacrum, 1 case with bilateral fracture of rami ossa pubis combined with bilateral-fracture of sacro-iliac joint were included. Operation time, intra-operative blood loss, injuries of lumbosacral nerves and iliac blood vessels, and fracture reduction were observed. RESULTS: All wounds were primary healing. No complications such as infection, deep venous thrombosis, injuries of lumbosacral nerves and iliaca vessels or heterotopic ossification occurred. According to Matta criterion of fracture reduction, 14 cases got excellent results, 3 good and 1 fair. Sixteen patients were followed up in a period varying from 6 to 33 months with 16.7 months on average. And according to functional score of Majeed, 13 cases obtained excellent results, 2 good and 1 fair, with an average score of 92.13+/-5.44. CONCLUSIONS: Internal fixation with reconstructive plates through the ilioinguinal approach and with percutaneous iliosacral screw for type C pelvic facture on pelvic anterior ring and pelvic posterior ring respectively have advantages of shorter operation time, smaller invasive trauma, less blood loss and etc. Thus, this technique is safe and practicable, yielding satisfying results. PMID- 29424160 TI - [Bone setting manipulative reduction for the treatment of children's distal radioulnar fracture and dorsal dislocation]. AB - OBJECTIVE: To observe the effect of different manipulative reduction for children's distal radioulnar fracture and dorsal dislocation. METHODS: From June 2013 to June 2014, 80 children with distal radioulnar fracture and dorsal dislocation were treated by bone setting manipulative reduction including 51 males and 29 females with an average age of 6.5 years old ranging from 3 to 14 years old. Time from injury to treatment was 1 h to 6 d, 31 cases were on the right, 49 cases were on the left. Among them, 45 cases were type I of overlapping displacement, 35 cases were type II. The displacement of the fracture was observed by clinical manifestations and X-ray examination. Under fluoroscopy, different techniques were used for reduction and fixation. After 3 weeks of over wrist fixation, the splints were overturned and fixed again for 1 to 2 weeks, then were removed. The wrist joint function was evaluated based on Dienst criteria. RESULTS: Eighty cases of fracture were successfully operated one time, all reached anatomic reduction or near anatomic reduction. Eighty children were followed up for 3 months to 1 year. All the fractures healed, and the healing time was 4 to 5 weeks with an average of 4.6 weeks. All patients removed the splint 3 months later, the results were excellent in 72 cases, good in 7 cases and fair in 1 case, the excellent and good rate was 98.75%. CONCLUSIONS: Bone setting manipulation for children's distal radioulnar fracture and dorsal dislocation can get good reduction. At 1 month after the removal of the splint, wrist function and finger strength gradually recovered and returned to normal after 3 months. PMID- 29424161 TI - [Application of convolute manipulation for the treatment of femoral fractures in children]. AB - OBJECTIVE: To discuss the application of convoluted manipulation in pediatric femoral fractures. METHODS: From March 2015 to October 2016, 12 children with femoral fractures were treated by Chinese traditional manipulation including 8 males and 4 females with an average age of 6 years old ranging from 1 to 12 years old. The causes of injury were falls in 10 cases and traffic accidents in 2 cases. Of which 1 case was transverse fractures, 4 cases were oblique fractures and 4 cases were spiral fractures, 2 cases were comminuted fracture, 1 case was greenstick fracture. All patients underwent manual reduction within 1 to 2 days, plus small splint with cedar bark, and parallel lower limb traction. RESULTS: All the 12 patients were followed up for 1-3 months, with an average of 2 months. All the 12 patients achieved clinical union, and the average healing time was 6 weeks. There was no obvious shortening and rotational angulation. At the last follow-up, Schatzker-Lambert distal femoral fracture evaluation results were excellent in 11 cases, good in 1 case. CONCLUSIONS: Convoluted manipulation is very important for reduction of femoral fractures in children, with the splint of cedar bark, satisfactory therapeutic effect can be achieved. PMID- 29424162 TI - [Ossifying parosteal lipoma beside the clavicle misdiagnosed as osteochondroma: a case report]. PMID- 29424163 TI - [Research progress on the effects of the tensile strain stimulation on proliferation differention and pericellular matrix of cartilage]. AB - Mechanical stimulation widely exists in the body and participates in adjusting biological behavior of many kinds of cells. As a common stress pattern in the body, the tensile strain widely exists in many organs, such as bone and cartilage, muscle tendon, cardiac and pulmonary vessels, and so on. In recent years, with the development of the researches of biomechanics, a variety of mechanical loading devices, which are used to simulate the complex mechanical stimulation in the body to provide the tensile strain including the isometric, uniaxial and various types of mechanical waveform, came into being. This is a huge boost to biomechanical research. Many researchers have found that the tensile strain stimulation can lead to the transformation of proliferation, differentiation and apoptosis of cells and change of cell matrix. However, for the same kind of cells, different kinds of tensile strain stimulation can lead to different and even the contrary results. In this paper, the effects of the tensile strain on the proliferation, differentiation and matrix of cartilage were reviewed. Understanding these characteristics will have important implications for the mechanism of cell proliferation and differentiation under the biomechanic stimulation and the prevention and treatment of diseases. PMID- 29424164 TI - [Research progress on the etiology and treatment of patellofemoral pain syndrome]. AB - Patellofemoral pain syndrome (PFPS) is one of the most common diseases that cause pain in the knee joint. At present, there is no specific diagnostic measure. The diagnosis of patellofemoral pain syndrome may be considered when imaging is performed without cartilage, ligament and soft tissue injuries. The etiology includes abnormalities of the patellar motion caused by various anatomical abnormalities, such as abnormal patellar position, increased Q angle, and excessive valgus foot. Dysfunction of the lower extremity muscles such as the imbalance of the four biceps and the dysfunction of the gluteal muscles also play an important role in the development of patellofemoral pain syndrome. At present, there are many treatments, and the exercises of four biceps exercises and hip abductor exercises are aimed at improving the dynamic stability of patella; The muscle patch and the patellar brace mainly reduce the pressure of the patellofemoral joint by improving the patellar trajectory; Foot orthopedic pads are used primarily in patients with valgus feet. After the conservative treatment is ineffective, the patellar lateral retinaculum can be loosened under arthroscopy. Because the patellofemoral pain syndrome is caused by the combined effects of various etiologies, a variety of treatments are helpful to improve the therapeutic effect. PMID- 29424165 TI - [Treatment for acute ankle joint injuries]. PMID- 29424166 TI - [Case-control study on reduction for external and posterior malleolar fractures combined with compressive articular surface through tibiafibular fractures region]. AB - OBJECTIVE: To compare clinical outcomes of external and posterior malleolar fractures associated with compressive articular surface through posteriorlateral incision and posteriormedial incision. METHODS: From January 2012 to January 2015, 52 patients with external and posterior malleolar fractures associated with compressive articular surface were treated by interfix. Among them, 24 patients were treated through posteriourlateral incision, including 16 males and 8 females, aged from 20 to 65 years old with an average of(35.2+/-6.4);28 patients were treated through posteromedi and posterior lateral incision, including 18 males and 10 females, aged from 22 to 62 years old with an average of(36.4+/ 4.8). Operation time, blood loss, length of incision, times of X-ray exposure and complications between two groups were recorded and compared, AOFAS scores were applied for evaluate clinical outcomes. RESULTS: All patients were followed up, group A were followed up from 13 to 55 months with an average of (27.5+/-2.5) months;group B were followed up from 12 to 54 months with an average of (28.5+/ 2.4) months. All fractures were obtained good reduction, and the healing time ranged from 10 to 16 weeks with an average of 12 weeks. Two patients in group B occurred incision infection, and 1 patient occurred screw loosening; while no incision infection occurred in group A, and 1 patient occurred screw loosening. There were statistical significance in operation time, blood loss, times of X-ray exposure and complications between two group;while no significant difference in ankle AOFAS score between two groups. CONCLUSIONS: Compared with reduction through achilles tendon, reduction for external and posterior malleolar fractures combined with compressive articular surface through tibiafibular fractures region has advantages of less blood loss, shorter operation time, less times of X-ray exposure, good recovery of ankle joint function, especially in treating external and posterior malleolar combined with compressive articular surface which could not obtained good reduction through normal pathway. PMID- 29424167 TI - [Manipulative reduction and percutaneous Kirschner wire internal fixation for grade IV supination-external rotation ankle fractures]. AB - OBJECTIVE: To investigate surgical skills and clinical effects of manipulative reduction and percutaneous Kirschner wire internal fixation in treating grade IV supination-external rotation ankle fractures. METHODS: From May 2013 to October 2016, 35 patients with grade IV supination-external rotation ankle fractures were treated with percutaneous Kirschner wire internal fixation, involving 22 males and 13 females with an average age of 38.2 years ranged from 18 to 65 years old. The time from injury to operation ranged from 2 h to 10 d with an average of 5 d. Reduction quality was assessed by Burwell-Charnley radiological criteria. Baird Jackson ankle scoring system was used to assess clinical effects. RESULTS: Thirty three patients were followed up from 10 to 28 months with an average of 14 months. Fracture healing time ranged from 10 to 18 weeks with an average of 12 weeks. According to Burwell-Charnley radiological criteria, 30 cases were obtained anatomic reduction, 3 cases moderate. According to Baird-Jackson ankle scoring system, total score was 93.8+/-5.4, 17 cases got excellent result, 12 good, 2 fair and 2 poor. CONCLUSIONS: Manipulative reduction and percutaneous Kirschner wire internal fixation in treating grade IV supination-external rotation ankle fractures has advantages of reliable efficacy, less complications. But higher require techniques were required for closed reduction. It is not suitable for severe crushed fracture and compressive articular surface fracture. PMID- 29424168 TI - [Treatment of chronic anterolateral ankle instability by reconstructing lateral ligament with semitendinosus autograft]. AB - OBJECTIVE: To investigate clinical effects of chronic anterolateral ankle instability by reconstructing lateral ligament with semitendinosus autograft. METHODS: From September 2014 to November 2016, 28 patients with chronic anterolateral ankle instability underwent lateral ligament reconstruction with semitendinosus autograft. Among them, including 20 males and 8 females with an average age of 28.6 years(18 to 47 years old). Preoperative complications were recorded. AOFAS and VAS score were used to evaluate clinical outcomes. RESULTS: Twenty-eight patients were followed up from 6 to 28 months with an average of 18.2. No iatrogenic fracture or infection occurred. There was no ankle instability or limited at the latest follow-up. AOFAS score was improved from 53.1+/-6.8 before operation to 90.4+/-5.9 at the latest follow-up , and had statistical difference(P<0.05); while VAS score was increased from 6.3+/-1.7 before operation to 0.8+/-0.5 at the lastest follow-up(P<0.05). CONCLUSIONS: Chronic anterolateral ankle instability by reconstructing lateral ligament with semitendinosus autograft has advantages of simple operation, good recovery, less compilations and good clinical effects. It is one of stable methods for the treatment of chronic anterolateral ankle instability. PMID- 29424169 TI - [Clinical efficiency and activity range of stiff knee by total knee arthroplasty]. AB - OBJECTIVE: To observe clinical effect and influencing factor of total knee arthroplasty (TKA) for the treatment of stiff knee. METHODS: From January 2010 to October 2014, 20 patients(25 knees) with stiff knee were treated with TKA. Among them, including 2 males(3 knees) and 18 females(22 knees), aged from 55 to 78 years old with an average of(64.5+/- 4.9) years old, the courses of disease ranged from 5 to 21 years with an average 8.3 years. Preoperative and postoperative HSS (hospital for special surgery knee score) score, activity range and complications were observed and compared. RESULTS: All patients were followed up from 12 to 69 months with an average of 35.3 months. Ten patients occurred complications after operation. HSS score was improved from 32.36+/-12.31 preoperatively to 80.70+/-18.52 postoperatively, and had statistical difference between two groups;7 knees obtained excellent results, 15 knees good and 3 knees moderate. Activity range was improved from(39.4+/-5.3) degrees preoperatively to (92.5+/-11.2) degrees at the latest follow up. CONCLUSIONS: Total knee arthroplasty for stiffness knees is feasible and could obtain satisfied activity range and function. PMID- 29424170 TI - [Risk factors of radius shortening in adult with distal radius fracture after conservative treatment]. AB - OBJECTIVE: To analyze the of risk factors of radius shortening in adult with distal radius fracture after conservative treatment by Logistic analysis. METHODS: From May 2009 to March 2015, 137 adults patients with distal radius fracture treated by conservative treatment were retrospective analyzed, and 36 patients occurred radius shortening, including 7 males and 29 females with an average age of (58.33+/-14.06) years old, 8 patients were type A, 34 patients were type B and 12 patients were type C according to fracture classification; 101 patients were without radius shortening, including 23 males and 78 females with an average age of (52.49+/-12.79) years old, 48 patients were type A, 34 patients were type B and 19 patients were type C according to fracture classification. Ages, gender, BMI , time from injuries to reduction, fracture classification, fixed form and loading time were collected and screened risk factors by Logistic analysis. RESULTS: All patients were followed up from 8 to 16 months. Ages, time from injuries to reduction, fracture classification, earlier loading could obviously affect radius shortening by univariate analysis, multivariate logistic analysis revealed the risk factor including ages [OR=1.045(1.008-1.083), P=0.015], time from injury to reduction[OR=2.853(1.178-6.909), P=0.020], fracture classification(Type C fracture was more relevant to radius shortening than other two type fractures)[OR=4.854(1.506-15.640), P=0.008], and earlier loading[OR=3.038(1.138-8.111), P=0.027]. CONCLUSIONS: Ages, time from injury to reduction, fracture classification, and earlier load are the risk factors of radius shortening, so corresponding preventive measures and appropriate treatment should be applied to according to different risk factor. PMID- 29424171 TI - [Retrograde interlocked intramedullary nailing with tibia bone graft fusion for the treatment of end-stage ankle arthritis]. AB - OBJECTIVE: To explore clinical outcomes of retrograde interlocked intramedullary nailing with tibia bone graft fusion in treating end-stage ankle arthritis. METHODS: From November 2014 to April 2016, 22 patients with end-stage ankle arthritis were treated with retrograde interlocked intramedullary nailing with tibia bone graft fusion, including 9 males and 13 females aged from 30 to 65 years old with an average of 48.5 years old. Seven patients had obvious varus deformity, and other 15 patients' appearance were normal. Operative time, blood loss, fracture healing time and complications were observed and compared, AOFAS and VAS score were applied for evaluate ankle joint function and pain degree before operation and 9 months after operation. RESULTS: All patients were followed up from 12 to 24 months with an average of 18.6 months. The incision were healed at stage I , and no complications occurred. Operative time ranged from 80 to 120 min with an average of 90 min;blood loss ranged from 15 to 50 ml with an average of 30 ml;fracture healing time was from 10 to 18 weeks with an average of 14 weeks. AOFAS score at 9 months after operation was 88.00+/-3.45, while 54.82+/-2.98 before operation, and there was statistical significance; 8 cases obtained excellent results, 12 good and 2 moderate. There was significant difference in VAS score between preoperative(3.96+/-1.27) and 9 months after operation(9.37+/-0.55). CONCLUSIONS: Retrograde interlocked intramedullary nailing with tibia bone graft fusion for the treatment of end-stage ankle arthritis has advantages of stable fixation, less trauma, less blood loss, bone union and rapid recovery of function, and could relieve pain obviously. PMID- 29424172 TI - [CT manifestation for excavated-type of rhomboid fossa of the clavicle]. AB - OBJECTIVE: To explore the manifestation of CT for excavated-type of rhomboid fossa of the clavicle. METHODS: Nine cases with rhomboid fossaes of the clavicle of 8 patients accepted CT and 1 case added MRI together;all 8 patients were male who aged from 17 to 70 years old with mean age of 42.5 years old;three dimensional reconstruction of all CTs were made, the distance between focus and inside end of clavicle and the size of all focus were measured respectively, then the position, shape, margin of focus were analyzed. RESULTS: All focuses located near the inside end of clavicle and the distances between focus and inside end of clavicle were lower than 2 cm and the mean value was 1.3 cm, the size of all focuses was from 1.05 to 3.45 cm and the mean value was 2.18 cm. All 9 focuses of 8 patients located in the posterior and nether edge of inside end of clavicle, 5 cases located in right and 4 cases located in left side(both right and left side occurred in 1 patient. Seven focuses showed "fishhook sign" and the rest 2 focuses were small and without fishhook shape;the cortex of clavicle of all 9 cases showed local minus and nearly marrow showed integrated sclerotic margin. Regular soft tissue as strip can be seen in 7 focuses and the rest small focuses without the symptom. CONCLUSIONS: CT could show certain characteristics for excavated-type of rhomboid fossa of the clavicle and certain value for its diagnosis and identification. PMID- 29424173 TI - [Meta analysis of clinical effects between intramedullary nail and volar plate internal fixation for distal radius fractures]. AB - OBJECTIVE: To evaluate curative effects of intramedullary nail and volar plate internal fixation for distal radius fractures. METHODS: The studies concerning about randomized controlled trial of intramedullary nail and volar plate internal fixation for distal radius fractures from create database to May, 2016 were searched from PubMed, Cochrane Library, Web of Science, CNKI, Wan Fang data and VIP. Information was screen and taken out according to inclusion and exclusion criteria, quality of literature was evaluated according to Cochrane Handbook evaluating system. Meta analysis was performed by RevMan 5.2 software. Postoperative grip strength, clinical effects(results of flexion and extension, pronation, supination, deflection of ulnar and radialis) , imaging evaluation (ulnar variance, radial height, volar tilting angle and radial inclination) and the incidence of postoperative complications were analyzed. RESULTS: Totally 6 RCT including 370 patients were chosen. According to the Meta analysis, there were no statistical differences in extension[MD=5.63, 95%CI(-7.01, 18.27), P=0.38], flexion[MD=3.10, 95%CI(-0.67, 6.86), P=0.11], pronation[MD=2.58, 95%CI( 0.49, 5.65), P=0.10], supination[MD=0.82, 95%CI(-1.89, 3.54), P=0.55], radial deviation[MD=-5.16, 95%CI(-14.42, 4.11), P=0.28], ulnar deviation[MD=0.19, 95%CI( 2.39, 2.77), P=0.88], ulnar variance[MD=-0.01, 95%CI(-0.43, 0.42), P=0.97], ulnar inclination[MD=-0.31, 95%CI(-1.37, 0.73), P=0.56], radial height[MD=-0.27, 95%CI( 0.98, 0.44), P=0.45], radial inclination[MD=0.29, 95%CI(-0.41, 0.99), P=0.42] and the incidence of postoperative complications[RR=0.71, 95%CI(0.46, 1.09), P=0.12] between intramedullary nail and volar plate internal fixation. CONCLUSIONS: Compared with volar plate internal fixation, intramedullary nail has the same effect in grip strength, clinical effect, but could not reduce the occurrence of postoperative complications. However, a large number of prospective randomized controlled study should be carried out to prove clinical effect of intramedullary nail for distal radius fractures. PMID- 29424174 TI - [A case control study of perpendicular or parallel double plate for the treatment of young and middle-aged patients with type C fractures of distal humerus]. AB - OBJECTIVE: To compare clinical outcomes of perpendicular or parallel double plate in treating type C fractures of distal humerus in adults. METHODS: From March 2009 and March 2013, 40 adult patients with type C distal humerus fractures were treated. The patients were divided into two groups according to fixed form. In perpendicular group(group A), there were 13 males and 9 females with a mean age of (37.56+/-9.24) years old(ranged 18 to 56);while in parallel plating group(group B), including 11 males and 7 females, with a mean age of (41.35+/ 9.03) year old(ranged 20 to 53). All fractures were fresh and closed without blood vessels or nerve damaged. Incision length, operating time, blood loss, hospital stay, preoperative and postoperative radiological change, range of activity of elbow joint, Mayo score, flexor and extensor elbow strength, and postoperative complications were observed and compared. RESULTS: All incisions were healed well. One patient occurred myositis ossificans between two groups. Two patients in group A and 1 patient in group B occurred elbow joint stiffness. All fractures were obtained bone union. Group A were followed up from 20 to 36 months with an average of (25.2+/-7.1) months, while group B were followed up from 18 to 35 months with an average of(24.3+/-6.0) months. There were significant differences in blood loss and operative time, while there was no obvious meaning in incision length, hospital stay, muscle strength, fracture healing time, range of activity of elbow joint. Mayo score of group A was 82.27+/ 10.43, 6 cases obtained excellent results, 12 good, 3 moderate and 1 poor;in group B was 81.94+/-12.02, 5 cases obtained excellent results, 9 good, 3 moderate and 1 poor;and there were no statistical significance between two groups. CONCLUSIONS: There was no significant differences in clinical effects between perpendicular and parallel double plate for adult patients with type C distal humerus fractures, while the operation should choose according to facture and proficiency of operator. PMID- 29424175 TI - [Experimental study on staphylococcal enterotoxin promoting tendon-bone healing after reconstruction of anterior cruciate ligament in rabbits]. AB - OBJECTIVE: To explore highly agglutinative staphylococcin (HAS) pomoting on tendon-bone healing after reconstruction of anterior cruciate ligament(ACL) in rabbits. METHODS: Animal model of ACL reconstruction in 24 mature New Zealand white rabbits(3 months, 2.56 kg on average, either gender) were established using autologous digital long extensor tendon and randomly classified into 2 groups(HAS and control group), 12 rabbits for each group. HAS group was separately injected 0.1ml highly agglutinative staphylococcin immediately into tendon-bone interface during the operation and 2 days after operation. Control group was injected with the same dose of physiological saline for 3 days. All animals were sacrificed at 4, 8, and 12 weeks after operation for histological examinations. The specimens were stained with hematoxylin-eosin, picric acid-sirius red, VEGF immunohistochemistry stain, and toluidine blue to histologically analysis the total pathology changes of the tendon-bone healing tissue, the tendon bone interface morphology classification, hyperplasia and arrangement of collagen fiber, vascularization and new bone formation, respectively. RESULTS: The Yamakado morphological interface results showed that the tissue healing at tendon bone interface of the HAS group was better than that of the control group. The histological examination revealed that on the 4th week after operation, the tendon-bone interface of HAS group was filled with fibrous connective tissue. The proliferated fibroblasts, chondroblasts and the angiogenesis were rich. On the 8th week after operation, the healing tissue at the bone-tendon interface had developed into dense connective tissue, the neo-vessels were very rich, the collagen fibers were formed abundantly, some Sharpey's fibers spanning parts of the tendon-bone interface. On the 12th week after operation, the transition zones were full of Sharpey's fibers;the neo-vessels were not as much as the 8th weeks, but new bone formation was further increased and immature fibrocartilage appeared. For quantitative histological analysis at 4, 8 and 12 weeks after operation, the proportion of neo-vessel area and the area of now bone formation of the HAS group were all significantly higher than those of the control group(P<0.05). CONCLUSIONS: Under the synergy of staphylococcal enterotoxin C and other active ingredients, Highly Agglutinative Staphylococcin can significantly improve the tendon-bone healing after ACL reconstruction in rabbit knees, which is expected to be a new method to improve the clinical results of ACL reconstruction. PMID- 29424176 TI - [Repairing diabetic rats with bone defect by VEGF165 gene modified adipose derived stem cells]. AB - OBJECTIVE: To explore repairing results of VEGF165 gene modified adipose-derived stem cells for diabetic rats with bone defect. METHODS: Seventy-eight male Wistar rats weighted 180 to 220 g were selected, 72 rats were established diabetic animal models by streptozotocin inducement method, blood glucose level was more than 16.7 mmol/L. Experimental animals were randomly divided into 5 groups, 6 rats in normal group and each 18 rats in other groups. VEGF165 gene modified adipose-derived stem cells were implanted into normal group with bone defect; single diabetic rats with bone defect were named as diabetic group;vascular endothelial growth factor implanted into single diabetic rats with bone defect named as growth factor group; adipose-derived stem cells implanted into diabetic rats with bone defect names as stem cell group; VEGF165 gene modified adipose derived stem cells implanted diabetic rats with bone defect named as experimental group. After combination of VEGF165-ADSCs (5*106) cells combined with gel sponge, implanted into diabetic rats with bone defect. On the forth week, general form of defect repairing tissue were observed by optical microscopy;local density of micro-vessel were detected by immunohistochemistry method; content of Ca, P and ALP of repairing callus were detected by IRIS Intrepid XSP inductively coupled plasma emission spectrometer. Efficacy of the VEGF165-ADSCs repairing function was evaluated by SPSS statistic software. RESULTS: Fluorescent staining results showed that expression of VEGF165 located on cytoplasm of ADSCs, expression percentage was more than 87%; general histology results showed that callus formation and quality was near to normal group, repairing results in diabetes group, growth factor group and stem cell group were poor. On the Forth week after implantation, content of Ca, P and ALP of repairing callus in experimental group were higher than those in growth group and stem cell group, and without significant differences compared with normal group; blood vessel density in experimental group was lower than normal group, but higher than other groups. CONCLUSIONS: VEGF165 gene modified adipose-derived stem cells for repairing diabetic rats with bone defect has advantages of osteogenesis and angiogenesis, and should be one of the effective method for repairing diabetic rats with bone defect. PMID- 29424177 TI - [Postoperative clinical effects of plantar pressure measurement system in treating the first ray hypermobility]. AB - OBJECTIVE: To explore plantar pressure measurement system in treating the first ray hypermobility. METHODS: From June 2013 to January 2014, 16 female patients (20 feet) with hallux valgus with unstable of the first sequence were treated by first tarsometatarsal joint fusion, aged from 42 to 52 years old with an average of(46.5+/-2.9) years old, the course of disease was from 3 to 5 years. Twenty healthy female(20 feet) were chosen as control group, and single side were only choose, aged from 41 to 55 years old with an average of(46.8+/-4.5) years old. Preoperative and postoperative AOFAS score was used to evaluate feet function. Plantar pressure measurement system were applied to compare peak value of the dynamic pressure and impulse indicators of affected feet and control normal feet from the first to the fifth head of metatarsal bone. RESULTS: All patients were followed up from 24 to 30 months with an average of 27.4 months. Hallux valgus deformity of affected feet were corrected, pain and swelling of the second head of metatarsal bone were disappeared. There were statistical differences in AOFAS score between preoperative (45.55+/-12.28) and postoperative (85.45+/-6.76). There were significant differences in peak pressure, pressure between affected feet and normal feet of the first and second head of metatarsal bone. Postoperative peak pressure, pressure of the first affected head of metatarsal bone were increased than that of before operation, but no differences compared with control group(P>0.05). Postoperative peak pressure, pressure of the second affected head of metatarsal bone were decreased before operation(P<0.05), but no meaning compared with control group(P>0.05). There were no significant differences compared between the forth and fifth affected head of metatarsal bone and control group(P>0.05). CONCLUSIONS: There were obvious differences in pressure of the first and second head of metatarsal bone patients with unstable of the first sequence, the first tarsometatarsal joint fusing could recover plantar pressure of the first and second head of metatarsal bone by plantar pressure measurement system. PMID- 29424178 TI - [Reconstruction of medial patellofemoral ligament with transposition of great adductor muscular tendon for the treatment of teenagers' recurrent patellar dislocation]. AB - OBJECTIVE: To investigate surgical method and clinical curative effects of medial patellofemoral ligament (MPFL) reconstruction with great adductor muscular tendon in treating teenagers' recurrent patellar dislocation. METHODS: From May 2012 to September 2014, 19 patients with recurrent dislocation of patellar, including 6 males and 13 females with an average of 16 years old (ranged from 13 to 17 years), the courses of disease ranged from 3 to 18 months(averaged 6 months). All patients were underwent great adductor muscular tendon transposition to reconstruct medial patellofemoral ligament. The curative effects were evaluated by preoperative and postoperative with Lysholm scores and Patellofemoral angle and Q angle. RESULTS: All patients were followed up from 12 to 18 months with an average of 16.5 months. Primary healing was achieved at stage I. No pain, swelling and patellar dislocation or subluxation occurred. Patellofemoral angle increased from preoperative (-3.8+/-4.9) degrees to (10.3+/-4.1) degrees postoperatively. Q angle decreased from preoperative(16.4+/-3.1) degrees to(10.5+/-1.2) degrees postoperatively; Lysholm scores were improved from preoperative (68.6+/-8.5) to (93.7+/-6.5) final follow-up (P<0.01), and 15 cases got excellent results, 3 good, and 1 fair. CONCLUSIONS: Reconstruction of medial patellofemoral ligament with transposition of great adductor muscular tendon could obviously recover stability of patellar, and it is one of the effective methods for the treatment of teenagers' recurrent patellar dislocation. PMID- 29424179 TI - [Minimally invasive percutaneous plate osteosynthesis for the treatment of acetabulum anterior column fracture with intact true pelvic brim]. AB - OBJECTIVE: To discuss feasibility and clinical effects of minimally invasive percutaneous plate osteosynthesis in treating acetabulum anterior column fracture with intact true pelvic brim. METHODS: From May 2013 to December 2015, 8 patients with acetabulum anterior column fracture with intact true pelvic brim were reviewed retrospectively. According to Judet-Letournel classification, all were simple unstable acetabulum anterior column fracture. Among them, there were 5 males and 3 females with an average age of 42.8 years old ranging from 22 to 63. The injury was caused by crush in 4 cases, smash of heavy object in 3 cases, and falling down in 1 case. The time from injury to operation was ranged from 5 to 19 days with an average of 9.5 days. Preoperative CT showed high anterior column fracture of acetabulum with intact true pelvic brim, the fracture separation was less than 1 cm. All the patients were treated with closed reduction and minimally invasive percutaneous plate osteosynthesis. The quality of fracture reduction, operation time, blood loss, fracture healing time, hip function and postoperative complications were observed and recorded. RESULTS: All patients were followed up from 10 to 19 months with an average of 14.5 months. The quality of reduction was classified as anatomical in 4 patients, imperfect in 3, poor in 1 by Matta's score system. The operation time was 30 to 80 min, averaged 51.3 min;the blood loss was 50 to 120 ml, averaged 86.2 ml; fracture healing time was 10 to 19 weeks, averaged 13.3 weeks. At the latest follow-up, the hip function was evaluated by Merle D'Aubigne scoring system, 5 cases got excellent results, 2 cases in good, and 1 case in fair. No vascular nerve injury, wound infection, bleeding, deep vein thrombosis and other complications occurred in 8 patients. CONCLUSIONS: Minimally invasive percutaneous plate osteosynthesis in treating acetabulum anterior column fracture with intact true pelvic brim has advantages of less trauma, less bleeding, quick recovery and good curative effect, and it is a good surgical procedures for acetabulum anterior column fracture. PMID- 29424180 TI - [Diagnosis and treatment of 4 patients with knee discoid medial meniscus under arthroscopic]. AB - OBJECTIVE: To explore clinical characteristics of 4 patients with knee discoid medial meniscus under arthroscopic. METHODS: From April 2012 to May 2015, 4 patients(4 knees) with knee discoid medial meniscus were treated with arthroscopic, including 1 male and 3 females, aged from 7 to 56 years old with an average of 26 years old. All patients were performed discoid meniscus plasty under arthroscopic. Postoperative symptoms and signs were observed, and clinical effects were evaluated by Lysholm knee scores. RESULTS: All patients were followed up from 6 to 20 months with an average of 12 months. At the latest follow-up, Lysholm scores were 83.5+/-10.0;2 knees got excellent results, 1 knee good, and 1 knee moderate. CONCLUSIONS: Knee discoid medial meniscus is easily missed diagnosis for atypical and early clinical symptoms , and seeing a doctor for obvious symptoms with meniscus tear, and could receive good curative effects after diagnosis as soon as possible. PMID- 29424181 TI - [Sever lumbar spinal stenosis with symptoms of perineum area only: a case report]. PMID- 29424182 TI - [A case report of extraskeletal chondroma on knee joint]. PMID- 29424183 TI - [Progress on rheumatoid arthritis in elderly]. AB - During choosing non-steroidal anti-inflammatory drugs(NSAIDs), risk factors should be evaluated in elder patients with rheumatoid arthritis. The present study focused on biological therapies, and elderly patients should be more concerned about the risk of infection when used it. Traditional Chinese medicine has advantages of obvious curative effect, especially for tripterygium wilfordii, large clinical trial on western and Chinese medical accurate drug strategies for old patients with rheumatoid arthritis. Old patients are easier to suffer from cardiac diseases and interstitial lung disease, rheumatoid arthritis could be controlled along with the treatment for coexistent disease. The incidence of rheumatoid arthritis in old patients is the same with other RA, and need to treat to target based on the aim of relieve pain and reduce activity of diseases, while the clinical charteristic and treatment target in elder patients with rheumatoid arthritis were not similar with other aged patient, so treatment standard target would vary with aging. Resent clinical studies excluded old patients, lead to lack of evidence-based medicine data. Clinical study for elder patients with rheumatoid arthritis are energetically carrying out, and could provide base and guide for clinical treatment. PMID- 29424184 TI - [Different sources of mesenchymal stem cells for the treatment of cartilage repair in knee joint]. AB - As propose of organ repair stem cell therapy technology, articular cartilage cannot be repaired by itself has become one of the research hotspots, repair of articular cartilage with mesenchymal stem cells has shown obvious advantages for the treatment. The scholars have made a preliminary study on the role of mesenchymal stem cells from different sources in the repair of knee articular cartilage, and with the combination of transplantation and cartilage tissue engineering, these technologies improved the human cartilage repair effect of bone marrow, adipose, synovium, cord blood derived stem cells, which achieved good clinical curative effect. Due to the different sources, the dominant and recessive factors, each stem cell will have certain advantages and disadvantages. At present, the clinical research is still in the experimental stage, there is no definite conclusion on which kind of stem cell or technology is more suitable for human cartilage repair. This requires the validation of large-scale or combining with new processing technology clinical trials and the long-term clinical effect, it also provides for the basis for further clinical research. PMID- 29424185 TI - Predictors of early failure and secondary patency in native arteriovenous fistulas for hemodialysis. AB - BACKGROUND: Native arteriovenous fistula (AVF) is considered the gold standard of vascular access for hemodialysis due to its longer survival, fewer complications, lower mortality and costs. Patency is important for effective dialysis treatment and this remains a challenge in nephrology. There are no well-defined prognostic factors for early and long-term AVF survival. The aim of this study was to evaluate comorbidity, analytical and ultrasound (US) variables as prognostic factors for early failure and AVF patency. METHODS: A prospective single-center cohort study was conducted with 5 years of follow-up. Inclusion criteria were patients with new native AVF creation between January 2011 and December 2015 and known vascular access survival data at the end of follow-up. Comorbidity (blood pressure, severe arteriopathy, diabetes, Charlson Index), and laboratory data (hemoglobin, calcium, phosphorus, PTH, ferritin, C-reactive protein), as well as US preoperative mapping (morphology and hemodynamic), were collected. End-points were early failure and secondary patency by Kaplan-Meier. RESULTS: The study included 117 patients with native AVF. Median age was 69+/-18 years and mainly of male gender (N.=70, 59.8%). Hypertension, diabetes and severe vascular disease were present in 65 (86.7%), 38 (50.7%) and 31 (41.3%). In 55 patients (47.8%) the AVF was in a distal location. Early failure was 19.7% and secondary patency at 5 years was 66.7%. Elderly age (P=0.034) and vein diameter (P=0.041) had an impact on early AVF failure. Radial (P=0.006) and ulnar peak systolic velocity (PSV) (P=0.018) showed predictive value in native AVF secondary patency rate. CONCLUSIONS: Predictors of early and late events are slightly different. Elderly age and vein diameter had greater impact on early AVF failure. However, distal arterial hemodynamics showed prognostic value in native AVF secondary patency rate. PMID- 29424186 TI - Spinal cord injury in endovascular thoracoabdominal aortic aneurysm repair: prevalence, risk factors and preventive strategies. AB - Thoracoabdominal aortic aneurysms are among the most challenging pathologic conditions vascular surgeons have to face. Endovascular treatment brought the prospect of being able to treat these complex aneurysms with less invasiveness and recent outcomes already challenge those of open repair. Plus, this technique offers a therapeutic option for patients who had none, due to significant comorbidities limiting open repair. Spinal cord injury is a major complication after complex aneurysm repair that dramatically affects patient's quality of life, even if technical success - aneurysm exclusion from circulation - has been achieved. Several strategies to prevent this terrible outcome have been developed, with remarkable success in narrowing down the number of patients who will suffer this complication. This comprehensive review covers how the standard of care for thoracoabdominal aortic aneurysms has evolved over time, how the understanding of spinal cord perfusion has changed in light of the collateral network concept, the risk factors associated with SCI, and details preventive strategies applied in current practice to lessen even further the frequency of spinal cord injury. Strategies covered go from the traditional adjuncts comprising hemodynamic control, neuroprotective drugs, neuromonitoring and cerebrospinal fluid drainage to emerging and innovative techniques such as near infrared spectroscopy, two-step repair, minimally-invasive selective segmental artery coil-embolization, temporary aneurysm sac perfusion, and techniques for earlier pelvic and lower limb reperfusion. PMID- 29424187 TI - Vascular malformations: classification, diagnosis and treatment. AB - INTRODUCTION: Vascular malformations are congenital lesions with complex clinical presentations and management. Their classification and treatment options have considerably changed throughout the years, with conflicting evidence in the literature. In this article, we aim to review the classification, diagnosis and treatment of the main vascular malformations. EVIDENCE ACQUISITION: A thorough non-systematic review of the literature was conducted using PubMed/Medline. Seventy-nine articles were selected and included, according to their scientific relevance and relation with the subject. EVIDENCE SYNTHESIS: Vascular malformations occur due to errors during vasculogenesis. They are present at birth, though they may not be apparent until later in life. These malformations are most frequently found in the head and neck, but can occur in any part of the body. They can be divided according to the predominant vessel type into arteriovenous, venous, capillary and lymphatic. Combined malformations occur when more than one type of vessel is present. Clinical presentation is variable and depends on the type of malformation, as well as location, size and relation with other structures. Symptoms such as ischemia, swelling, pain, thrombosis, deformity and functional impairment can be caused by these lesions. The diagnosis of vascular malformations is based in both clinical presentation and complementary imaging techniques, with special emphasis on magnetic resonance imaging. Depending on the malformation and clinical presentation, treatment may be medical or interventional, by means of either interventional techniques or surgery. CONCLUSIONS: Vascular malformations are a complex group of pathologies, with different clinical presentations and treatment options, and therefore management by a multi-disciplinary team is essential. Their cure is often challenging and when not possible, treatment should aim at symptomatic control and improvement of patient's quality of life. PMID- 29424188 TI - Revolving door respiratory patients: A rehabilitative perspective. AB - Rehabilitation is an integral component of care for patients affected by either acute or chronic pulmonary diseases. The key elements of rehabilitation treatment for critical respiratory patients are as follows: weaning from mechanical ventilation, respiratory therapy, physical reconditioning, and occupational therapy. It should be noted that patients affected by pulmonary diseases are prone to hospital re-admission due to frequent exacerbations, especially in cases with more severe stages of chronic obstructive pulmonary disease. A periodical worsening of clinical conditions is common in asthma, acute respiratory distress syndrome survivors, obstructive sleep apnea syndrome, and pulmonary fibrosis, as well as in patients with severe neuromuscular diseases. These patients are often identified as "revolving door patients". Pulmonary patients are typically forced to maintain bed rest, or at least spend most of their waking hours dealing with mobility limitations, due to various pathological conditions including dyspnea, fatigue, and poor tolerance of movements. Alterations in mood are common in pulmonary patients who experience a decreased quality of life and limited social interactions. These negative emotional and cognitive aspects can be a major limitation to the provision of care, because to enhance and facilitate a degree of autonomy, the patient must be cooperative and pro-active. PMID- 29424189 TI - Correlation of aspergillus skin hypersensitivity with the duration and severity of asthma. AB - Asthma is a significant health problem worldwide and Allergic Bronchopulmonary aspergillosis (ABPA) complicates the course of 1-2% of patients of asthma. Aspergillus skin hypersensitivity (AH) is the first step for diagnosis of ABPA. This study was conducted to know the correlation of AH with severity and duration of asthma. Patients, age >15 years, of asthma attending this hospital from January 2015 to December 2015 were included. Asthma was diagnosed clinically and confirmed with spirometry. Of 282 patients 206 patients were AH positive. The AST positivity in patients having severe asthma (96.8%) was higher than that in patients having mild (36.8%) and moderate asthma (80.4%). The median (IQR) duration of asthma of AH positive patients was 5.0 yrs. This study emphasized the need of ABPA screening by intradermal skin test especially in patients having severe asthma and/or those having asthma for longer duration in order for early diagnosis of ABPA. PMID- 29424190 TI - Association of HLA antigens with the clinical course of sarcoidosis and familial disease. AB - Patients with sarcoidosis usually have a benign course and a favourable prognosis. Although spontaneous remission is common, a progressive disease with a severe prognosis occurs in a small but significant number of patients. The aim of this study was to evaluate the potential significance of HLA antigens as a clinical marker on the outcome of sarcoidosis patients. We conducted a retrospective cohort study for HLA class I and II allels in 74 sarcoidosis patients and 72 healthy transplant donors. Bronchoscopy and bronchial biopsies were performed in each patient. Two or more positive bronchial biopsy samples revealing granulomatous inflammation was defined as diffuse while one positive biopsy sample was considered as limited endobronchial disease. Three or more extrapulmonary organ involvement was denoted as severe extrapulmonary disease. The patients were followed-up at least for eight years. Incidence of progressive disease was significantly high in patients with positive HLA-DRB1*07, DRB1*14 (p<0.05) and DRB1*15 (p <0.001) allels. HLA-DRB1*14 and DRB1*15 were associated with severe extrapulmonary organ involvement (p<0.001). HLA-DRB1 *14 (p<0.05) and DRB1*15 (p<0.001) were significantly more frequent in patients with diffuse endobronchial involvement. Incidence of familial disease was 14.8% with a 6.7% identical HLA typing. Presence of HLA class I and II allels may influence the severity and prognosis of sarcoidosis significantly. Apart from defining genetic susceptibility, HLA class I and class II allels appear to be relevant and crucial markers for the to predict the clinical outcome of sarcoidosis. Distinct heterogenity of sarcoidosis may arise from the particular presence of different allels in invidual patients. PMID- 29424191 TI - Minute ventilation to carbon dioxide output (V'E/V'CO2 slope) is the strongest death predictor before larger lung resections. AB - The minute ventilation to CO2 production ratio (V'E/V'CO2 slope) was recently identified as a mortality predictor after lung surgery, but the effect of the resection extent was not taken into account. The aim of this study was to investigate the role of V'E/V'CO2 slope as preoperative mortality predictor depending on the type of surgery performed. Retrospective analysis was performed on 263 consecutive patients evaluated before surgery for lung cancer. Death within 30 days and serious respiratory complications were considered. Univariate and multivariate regression analyses were used to identify independent predictors of death. Lobectomy or bilobectomy were performed in 186 patients with 29/186 (15.6%) serious pulmonary complications and 6/186 (3.2%) deaths. Pneumonectomy was performed in 77 patients with 14/77 (18.2%) serious complications and 5/77 (6.5%) deaths. Considering the whole group, the peak oxygen consumption (V'02peak, L/ min; z=-2.66, p<0.008, OR 0.007) and V'E/V'C02 slope (z=2.80, p<0.005, OR 1.14) were independent predictors of mortality whereas in pneumonectomies V'E/V'C02 slope (z=2.34, p<0.02, OR 1.22) was the only independent predictor of mortality. High V'E/V'CO2 slope, age and low V'02peak are predictors of death and severe complications after lung surgery. Before larger resections as pneumonectomies an increased V'E/V'CO2 slope represents the best mortality predictor. PMID- 29424192 TI - Varenicline in smokers with severe or very severe COPD after 24 weeks of treatment. A descriptive analysis: VALUE study. AB - A large number of COPD patients are smokers. The particular characteristics of this group as well as their need to quit usually require psychological counselling and pharmacological treatment to achieve abstinence and, often, intensively. Little information is available about this issue. The main objective of the study was to evaluate the effectiveness of varenicline after 24 weeks of treatment, with continuous abstinence between weeks 9 and 24. This study was a post-authorization, open label, observational study of prospective follow-up. Patients included were smokers with severe or very severe COPD criteria who were treated with varenicline for 24 weeks, i.e. with a 12-week extension over the usual treatment. The outcomes in the population of subjects completing 24 weeks of follow-up were at week 24: continuous abstinence 36.8%, 7 days point prevalence abstinence 65.7%, and continuous smoking 31.5%.The outcomes in the intention-to-treat population included at baseline were: continuous abstinence 17.7% of patients, 7 days point prevalence abstinence 31.6%, continuous smoking 15.1% and not valid/unknown 51.8%. The mean CAT score at week 24 was 15 and reduction from the baseline was 3.77 (paired T test, p<0.01). The most common adverse events reported were nausea, vivid dreams, stomach ache, insomnia, headache and vomiting. Patients included in VALUE were active smokers despite all of them had a severe COPD which suggests a very high degree of dependence. Although the study do not allow to infer the results to the global population of smokers with severe COPD, the outcomes have shown that, at 24 weeks follow up 36.8% of the patients were successful in quitting but from 79 patients enrolled initially only 17.7% quit. PMID- 29424193 TI - Changes in quality of life and functional capacity after lung transplantation: A single-center experience. AB - Lung transplantation (LT) increases the life expectancy of patients affected by end stage pulmonary disease; specifically, its ultimate aims are to improve survival and health related quality of life (HRQoL). The aim of the present longitudinal study was to determine the HRQoL trajectory and changes in functional capacity from time of entry in the waiting list for LT to 2 year after LT. The study included sixty-nine outpatients enrolled in a single medical center when they entered the waiting list for LT and who subsequently received it. They were then followed up over 2 years after LT. HRQoL was assessed by the physical and mental component summary (PCS and MCS) scores of the 36-item Short Form Health Survey (SF-36) and Saint George's Respiratory Questionnaire (SGRQ). Psychological distress was evaluated with the General Health Questionnaire (GHQ), and functional capacity was investigated using the six-minute walk test (6MWT) and forced expiratory volume (FEV1). Patients showed low SF-36 PCS (30.5+/-7.8) and SGRQ total (61.8+/-17.5) scores at entry in the waiting list, but exhibited significant changes over time after LT (p<0.001). Furthermore, patients who showed an increase of at least 50% in SF36 PCS and SGRQ scores at 6 months survived longer. Both FEV1 and 6MWT distance as well as GHQ scores significantly changed over time, with improvements occurring in the first 6 months after LT but no major changes thereafter. Out of the 69 patients enrolled, 32 died over a median follow-up of 51 months. Although mortality tended to be slightly higher for patients with lower HRQoL at the baseline assessment, this difference was not statistically significant. HRQoL evaluations appear critical in the follow-up of LT candidates, in particularly SGRQ, because of its specificity in targeting respiratory symptoms and functional wellbeing. PMID- 29424194 TI - Evaluation of endothelial function and cardiovascular risk in non-obese patients with slight degree of obstructive sleep apnea syndrome. AB - Recently, it has been clearly described an independent relationship between obstructive sleep apnea syndrome (OSAS) and cardiovascular risk, with underlying mechanisms also including endothelial dysfunction. We enrolled 32 consecutive non obese patients (mean age of 39.5+/-11.5 years), of which 16 with mild OSAS and 16 snoring without OSAS. Mild OSAS is defined by an AHI index between 5 and 15. We have investigated if whether there was a relationship between mild OSAS, endothelial function and carotid intima-media thickness (C-IMT). The population was divided into two groups: Group 1 (16 simple snorer patients with an average age of 39.4+/-12.1 years) and Group 2 (16 subjects with mild OSAS with an average age of 39.6+/-11.2 years). Each group underwent cardiovascular investigation including measurement of flow-mediated dilation (FMD) of the brachial artery and C-IMT. Both groups comprised non-obese subjects. Patients with mild OSAS had serum total cholesterol values statistically significantly higher than simple snores patients (178.6+/-24.9 vs 159.2+/-25.3; p=0.038). OSAS patients had also a trend towards higher values of maximum C-IMT compared to simple snorer patients (0.70+/-0.15 vs 0.65+/-0.16), although below the level of significance. Between the two groups, no difference was found for FMD values. The present results on mild OSAS strengthen the importance of a diagnosis of OSAS as soon as possible, in order to encourage all primary prevention interventions to correct risk factors responsible for disease progression and the occurrence of cardiovascular diseases, not excluding the use of therapies of non-invasive ventilation even in the early stages of the disease. PMID- 29424195 TI - Clinical features and prognostic significance of splenic involvement in sarcoidosis. AB - Sarcoidosis is a systemic disease characterized by noncasefied granulomas in various organs. Incidence of splenic disease is variable and is reported to occur in 6.7 to 77 percent of the patients. Firm data establishing the clinical features and the association of splenic involvement with prognosis in sarcoidosis is scant. The aim of our study was to investigate the clinical features and the consequence of splenic involvement on the prognostic outcome of sarcoidosis patients. We evaluated the clinical and laboratory findings in 82 sarcoidosis patients. Forty-two patients with splenic involvement were compared to 48 sarcoidosis patients without splenic disease in regard to laboratory findings, endobronchial disease, extrapulmonary organ involvement, and prognosis. Lung biopsy sample was considered positive if it demonstrated noncaseating granulomas with negative fungal and mycobacterial cultures. Splenic sarcoidosis was identified by ultrasound or computed tomography and was designated as limited, diffuse or without splenic involvement. Extrapulmonary organ sarcoidosis was classified as extensive and limited. Endobronchial disease was categorized as limited or diffuse involvement. The most commonly comprised organ was lung in 95% of the cases followed by lymph nodes, skin, eye, spleen and liver in the order of frequency. Splenic disease was diffuse in 22 patients. Of these patients, 14 had extensive extrapulmonary organ involvement while 16 had diffuse endobronchial disease. There was no significant difference between the three groups for FEV1, FVC, TLC, DLCO/VA, serum and 24h urinary calcium levels. Serum ACE was higher in patients with diffuse splenic involvement (p<0.001). Incidence of persistent chronic disease was significantly higher (p<0.001) in patients with diffuse splenic sarcoidosis. Extensive extrapulmonary organ involvement and diffuse endobronchial disease were more common (p<0.001) in this group. Extensive extrapulmonary organ involvement and diffuse endobronchial disease were more frequent in patients with diffuse splenic sarcoidosis. Patients with diffuse splenic granulomas had a worse prognosis than the patients without splenic involvement or patients with limited splenic disease. Diffuse splenic involvement emerges to be a significant risk factor for persistent chronic sarcoidosis. Extensive granuloma burden in an organ may be the decisive clinical marker for the prognostic outcome of sarcoidosis patients. PMID- 29424196 TI - Exercise-based cardiac rehabilitation in cardiac resynchronization therapy recipients: A primer for practicing clinicians. AB - Cardiac resynchronization therapy (CRT) is a therapeutic option of increasing importance for chronic heart failure (CHF) and criteria for implantation now concern a large amount of patient populations. As a consequence, subjects with ongoing CRT (or immediately after CRT implantation) are more often referred to Cardiac Rehabilitation (CR) programmes, and it has been recently estimated that about one third of CHF patients attending CR in Italy currently have this kind of device. The presence of CRT represents a modulating factor for exercise prescription and monitoring, since CRT patients may be considered per se as a target group for CR. Exercise therapy (ET) increases benefits from CRT on functional capacity, and recent evidence suggests an adjuvant role of ET in improving cardiovascular prognosis also. Both aerobic endurance and resistance training activities may involve CHF patients with CRT, while the potential role of aerobic interval training needs more studies and evidence. Prescription of an ET program should be associated with information regarding device programming and possible limiting factors associated with pacing therapy, tailoring of the basic principles of ET (in terms of type of exercise, intensity and program duration) in this patient group is mandatory. PMID- 29424197 TI - Pregabalin-induced first degree atrioventricular block in a young patient treated for pain from extrapulmonary tuberculosis. AB - Pregabalin, widely used in the treatment of several pain disorders, is usually well tolerated. Uncommonly, the drug may induce cardiac side effects, rarely prolongation of the PR interval. The latter has never been described in patients with healthy heart or normal renal function. We characterize a unique case of a young man with extrapulmonary tuberculosis and no detectable or known cardiac or kidney diseases, treated with pregabalin to control the severe pain due to the involvement of the spinal cord by the tuberculosis, showing an atrioventricular (AV) block due to pregabalin administration. The reported case emphasizes the need of monitoring PR interval during treatment with pregabalin, even in patients without background of cardiac or renal diseases. PMID- 29424198 TI - Aneurysmal rib cyst. AB - Thoracic cage is the site of development of various primary or metastatic tumors. An aneurysmal rib cyst is a benign tumor arising from the chest wall. Aneurysmal rib cyst is considered a rare surgical entity and its presence must be followed by removal for histology examination. We present here the case of an aneurysmal rib cyst to a young 33-year-old female. The tumor was presented as an expanding left anterior second rib mass during a self-breast examination. Chest x-ray showed a shadow on the left upper lung area and CT scan revealed a large multicystic mass in the anterolateral left 2nd rib protruding underneath the thoracic major muscle. We discuss the clinicopathological characteristics of this tumor and its surgical management along with a short literature review. PMID- 29424199 TI - Primary synchronous small and non-small cell lung cancer in the same lung lobe: A case report. AB - Synchronous multiple primary lung cancer (SMPLC) means tumours present at the same time, which are separate and have different histology. We present the case of a 66-year-old patient with a combination of small-cell lung carcinoma (SCLC) with adenocarcinoma in the same lobe with metastasis of SCLC in the mediastinal lymph node. This is a rare case. We performed a standard left upper video assisted thoracoscopic lobectomy with mediastinal lymphadenectomy and adjuvant therapy targeted to SCLC was administered. Despite advances in imaging methods and diagnostic procedures in pneumology a diagnosis of SMPLC is often discovered only intraoperatively or accidentally during the histological examination. Actually, no guidelines exist for the treatment protocol of such cases. Multiple methods of management of SMPLC, mainly complete anatomical resection with lymphadenectomy combined with chemotherapy or radiotherapy should be adopted according to the histologic types, staging and molecular testing of the tumours. These rare cases of SMPLC require individual treatment and multidisciplinary approach. PMID- 29424200 TI - Middle lobe syndrome: An exceptional presentation of concomitant lepidic adenocarcinoma and bronchial anthracofibrosis. AB - Lepidic adenocarcinoma previously known as bronchioloalveolar carcinoma (BAC) is a non-small cell lung cancer with an indolent presentation. Bronchial anthracofibrosis (BAF) is caused by long-standing exposure to biomass fuel smoke often in poorly ventilated kitchen. Middle lobe syndrome (MLS) due to BAF is not uncommon however, lepidic adenocarcinoma then known as BAC, presenting as MLS has been documented only once before in the Polish literature. A 68-year-old never smoker female with biomass fuel smoke exposure presented with cough and breathlessness. Imaging revealed MLS. Fiberoptic bronchoscopy visualised bluish black hyperpigmentation with narrowing and distortion of right middle lobe bronchus suggestive of BAF. Transbronchial biopsy confirmed presence of lepidic adenocarcinoma. To our knowledge, this is the first detailed description of lepidic adenocarcinoma and BAF presenting as MLS. PMID- 29424201 TI - Hereditary hyperhomocysteinemia associated with nephrotic syndrome complicated by artery thrombosis and chronic thromboembolic pulmonary hypertension: A case report. AB - We present here the case of a 30-year-old man with a long term history of nephrotic syndrome (NS) who developed an episode of acute left main pulmonary artery thrombosis complicated by a lung abscess. During the hospital admission was also identified a concomitant hyperhomocysteinemia. After an atypical resection of the left upper pulmonary lobe and the starting of long term anticoagulation the patient was discharged but did not attend the planned follow up visits until one year later when he was seen again for severe dyspnea and exercise intolerance. At this time chronic thromboembolic pulmonary hypertension (CTEPH) was diagnosed by lung perfusion scintigraphy and right heart catheterization. He initially refused the surgical treatment but, after six months, for the presence of worsening dyspnea was referred for bilateral pulmonary endarterectomy followed by a cardio-thoracic rehabilitation program. After a follow-up of seven years the patient is alive and in stable conditions. NS and hyperhomocysteinemia are both known risk factors for pulmonary embolism (PE), but their association with CTEPH is extremely rare. We discuss here the possible mechanisms linking these conditions. CTEPH must be suspected in any patient with NS, with or without hyperhomocysteinemia, and unexplained dyspnea. PMID- 29424202 TI - Quality of semen: a 6-year single experience study on 5680 patients. AB - BACKGROUND: The aim of our study was to evaluate the quality of semen of a large sample from general healthy population living in Italy, in order to identify possible variables that could influence several parameters of spermiogram. METHODS: We conducted a cross-sectional study from February 2010 to March 2015, collecting semen samples from the general population. Semen analysis was performed according to the WHO guidelines. The collected data were inserted in a database and processed using the software Stata 12. The Mann-Whitney Test was used to assess the relationship of dichotomus variables with the parameters of the spermiogram; Kruskal-Wallis Test for variables with more than two categories. We used also Robust regression and Spearman correlation to analyze the relationship between age and the parameters. RESULTS: We collected 5680 samples of semen. The mean age of our patients was 41.4 years old. Mann-Whitney Test showed that the citizenship (codified as "Italian/Foreign") influences some parameters: pH, vitality, number of spermatozoa, sperm concentration, with worse results for the Italian group. Kruskal-Wallis Test showed that the single nationality influences pH, volume, sperm motility A-B-C-D, vitality, morphology, number of spermatozoa, sperm concentration. Robust regression showed a relationship between age and several parameters: volume (P=0.04, R2=0.0007 beta: 0.06); sperm motility A (P<0.01; R2=0.0051; beta=0.02); sperm motility B (P<0.01; R2=0.02; beta=-0.35); sperm motility C (P<0.01; R2=0.01; beta=0.12); sperm motility D (P<0.01; R2=0.006; beta=0.2); vitality (P<0.01; R2=0.01; beta=-0.32); sperm concentration (P=0.01; R2=0.001; beta=0.19). CONCLUSIONS: Our patients had spermiogram's results quite better than the standard guidelines. Our study showed that the country of origin could be a factor influencing several parameters of the spermiogram in healthy population and through robust regression confirmed a strict correlation between age and these parameters. PMID- 29424203 TI - Clinicopathological significance of chemokine receptor CXCR4 expression in papillary thyroid carcinoma: a meta-analysis. AB - INTRODUCTION: Emerging evidence indicates that C-X-C chemokine receptor type 4(CXCR 4) is a candidate oncogene in several types of human tumors including papillary thyroid carcinoma (PTC). To investigate its expression impact on clinicopathological features, a meta-analysis was performed. EVIDENCE ACQUISITION: A comprehensive search in the PubMed, Embase and The Cochrane Library (up to March 14, 2017) was performed for relevant studies using multiple search strategies. Methodological quality of the studies was also evaluated. Odds ratios (ORs) were calculated and summarized. EVIDENCE SYNTHESIS: Final analysis was performed of 661 PTC patients from 8 eligible studies. The pooled OR indicated that CXCR4 expression was significantly higher in PTC than that in normal thyroid tissue and benign thyroid nodule (NTT/BTN) (OR=67.22, 95% CI: 32.85-137.55, P < 0.00001). In subgroup analysis, CXCR4 expression was associated with age (OR=1.55, 95% CI: 1.02-2.34, P=0.04), lympaocytic thyroiditis (OR=1.68, 95% CI: 1.06-2.67, P=0.03); CXCR4 expression was not found to be associated with gender (OR=1.02, 95% CI: 0.66-1.58, P=0.93), multiple (OR=0.91, 95% CI: 0.55 1.53, P=0.73), lymph node metastatic (LNM) (OR=1.98, 95% CI: 0.88-4.47, P=0.10) and TNM stage (OR=2.00, 95% CI: 0.49-8.16, P=0.34). A sensitivity analysis found out the study by Zhu et al. which impacted the pooled OR, after removing this study, a positive and relatively stable result conformed that CXCR4 expression was associated to LNM. CONCLUSIONS: The results of this meta-analysis suggest that CXCR4 expression is frequent and cancer-specific event in PTC. PMID- 29424204 TI - Relation between change in treatment for central diabetes insipidus and body weight loss. AB - BACKGOUND: Patients with central diabetes insipidus (CDI) are known to lose weight because their polydipsia interferes with their nutritional intake. We retrospectively examined weight changes in CDI patients when they switched from nasal to oral desmopressin. METHODS: Twenty-three patients with CDI were included. Weight change was defined as an increase or decrease of more than 3 kg or 3% body weight. As factors contributing to the weight change, we studied the patients' clinical characteristics and quality of life (QOL) scores as determined by our original questionnaire. RESULTS: Five patients showed a weight loss of 5.9 kg (2.4-9.0 kg), and two patients showed weight gain, while 16 out of 23 patients were weight neutral. When the patients with weight gain and weight neutral were analyzed together, the mean weight change was +0.3 kg (-0.5 to +1.1 kg). All the patients who lost weight had a BMI >= 22 kg/m2 (38% vs. 0%, p=0.027) and higher frequencies of abnormally high serum levels of AST (40% vs. 0%, p=0.005). The sum of the QOL scores was similar between the two groups, but higher in patients who lost weight after switching to oral desmopressin (43.3 +/-2.7) than in those who did not (38.2 +/-5.0, p=0.01). CONCLUSIONS: Switching the treatment from nasal to oral desmopressin may cause weight loss in patients with CDI who seemed to have polydipsia-associated weight gain. PMID- 29424205 TI - [Features of health disorders in miners employed at northern copper-nickel mines]. AB - The aim of the study was to assess the influence of different working conditions on the health of 1523 copper-nickel miners of the Kola High North. The low degree of mechanization of mining operations was established to be related to more higher levels of vibration, noise and physical overloads. The working in such conditions, when compared with high mining mechanization, leads to a decrease in the number of conditionally healthy workers (12% and 20.7%, p <0.001) an increase in the number of diseases in the one worker (2,94 +/- 0,10 and 2.13 +/- 0.07 cases, p <0,001), the increase of the risk of occupational diseases (OD) of the musculoskeletal (RR = 2.31) and nervous (RR = 2.07) systems, vibration disease (RR = 1.70), neuro-sensory hearing loss (RR = 1.90). Both at low and high degree of mechanization of mining operations the greatest risk of occupational diseases in noted in drifters (OR = 5.68), at that it was higher at hand mining than at mechanized mining (RR = 1.44). There was made a conclusion about the need to improve the complex of measures for the preservation of health in this group of workers, especially engaged in the performance of tunnel works. PMID- 29424206 TI - [Changes in morphologic indices of physical development of urban schoolchildren]. AB - The aim of the research was to assess the age variability of anthropometric parameters in schoolchildren of the city of Gomel examined with a 40-year interval. The authors of the article examined schoolchildren of secondary schools in Gomel. Over 2010-2012 the complex cross-sectional morphometrical examination was carried out on schoolchildren aged of 8-16 years without any significant health problems in the city of Gomel (a total of 3105, out of them there were 1452 boys and 1653 girls). The somatometrical program included body length and mass, chest circumference parameters. The absolute and relative parameters of their annual increases were calculated in schoolchildren, which made it possible to determine the periods of their relative acceleration and deceleration indices. The anthropometric data on schoolchildren of the city of Gomel obtained by V.Ya.Leontyev in 1973 and A.I. Kienya, V.A. Melnik over 1994-1996 were used for comparison. The comparative analysis of the gender and age dynamics of morphometric indices in schoolchildren of the city of Gomel aged of 8-16 years in 1973 and over 2010-2012 revealed the processes of acceleration (increase of body length and mass) in boys and asthenization (increase of body length and decrease of body mass) in girls at the beginning of the XXI century. The indices of the chest circumference before and after puberty period in the contemporary school boys and girls were lower, but in the puberty period being higher than in schoolchildren of the same age examined forty years ago. The authors developed, published and put into both practical public health of Belarus and educational process the Tables for the assessment of physical development of schoolchildren of the city of Gomel. PMID- 29424207 TI - [Shaping a healthy lifestyle as necessary condition for prevention of disorders and diseases of visual organ in younger schoolchildren]. AB - Purpose. Study of the lifestyle and identification of behavioral risk factors negatively affecting on the state of the visual organ in primary school children. Patients and methods. There was performed a questionnaire survey of parents of 384 younger schoolchildren in Moscow. Questionnaire specially designed by authors included questions relating to lifestyle and behavioral risk factors that affect vision. Results. More than 46% of the younger schoolchildren in the mode of the day have no daily walks in the fresh air, including during daylight hours in 51.6%; time daily needed for this age on air is spent by only 32.8% of schoolchildren. Among younger schoolchildren every day 57.2%, 44.8% and 39.5% spend longer time than needed for homework, TV and computer correspondingly; all the time only 9.4% keepproperfit at their desk, 15.6% at the computer, 20.8% - when watch television; 40.6% do not constantly comply with the requirements for proper illumination while watching TV; 45.8% sometimes read in lyingposition , 9.9% - in transport. Conclusion. Identified in junior schoolchildren of the city of Moscow a high prevalence of behavioral risk factors that negatively affect their visual organ and health in general, requires the elimination of these factors by means of hygienic education and shaping a healthy lifestyle in schoolchildren since 1st grade. PMID- 29424208 TI - [Assessment of the efficiency of prevention of iodine deficiency among the children's population of the city of Mezhdurechensk of the Kemerovo region]. AB - In the article there are presented results of a study of indices of ioduria in preschool kids and school children of the city of Mezhdurechensk (south of the Kemerovo region). 411 children aged of 3-17 years participated in the study. The median of ioduria on preschooler kids was 97,0 pg/l, and the proportion of urine samples with iodine levels less than 50 pg/l - 1,0%. The median of ioduria in school children is 98,0 pg/l, the percentage of urine samples with iodine levels less than 50 pg/l accounts for 1,3%. On average, on the population of children there was established that the percentage of urine samples with iodine levels from 50-100 pg/l (mild deficiency) was detected in 53,5% of children. Comparative analysis of indices of the level of ioduria according to data obtained in 2008 and 2014 in a group of school children showed that the measures taken to prevent diseases caused by iodine deficiency (the use of iodized salt in the diet of children and adolescents from organized groups on a regular basis) have given positive results. PMID- 29424209 TI - [Dynamics of indicators of physical development of preschool children of ufa]. AB - A comparative analysis of indicators ofphysical development ofpreschool children of Ufa for 1978, 1999 and 2014 showed mixed changes or no statistically reliable changes in the indicators in preschool children of different groups from 1978 to 1999. In the periodfrom 1999 to 2014 in some groups of preschool children revealed statistically reliable positive changes in the indices, whereas statistically reliable decrease of indicators was not. A favorable fact is also increase in comparison with 1999, the percentage of preschool children with harmonious physical development. PMID- 29424210 TI - [Features of consumption of vitamins and foods enriched with biologically active substances by Petersburgers]. AB - Purpose. To study and evaluate the use of vitamins and products enriched with biologically active substances by the residents of St. Petersburg. The study was conducted with the use of the questionnaire survey method of 1200 Petersburgers. Results. A third of residents (35.5 per cent) never used enriched food products in nutrition. The majority of St. Petersburgers (59.3%) when cooking do not use iodized salt or do it rarely. While the use of salt increases with the age. Inclusion of vitamins in the diet fails to be widely distributed among the citizens: monthly they are used by only 20.3% of citizen, 2 times a year - 28.2% and only during illness - 17.7%. One third of the population (33.8 percent) never takes vitamins in the form of tablets, syrups, solutions, etc. Conclusion. The analysis indicates the need to improve the nutrition of Petersburgers to reduce risk factors for diseases by improving health literacy in organized units for healthy nutrition on the base of Health Centers or clinics in St. Petersburg. PMID- 29424211 TI - [Application of the new culture medium for the isolation of Salmonella from water bodies to assess the epidemic safety of water use. Gigiena i Sanitaria (Hygiene and Sanitation, Russian)]. AB - There was developed a liquid storage medium for the isolation of bacteria of genus Salmonella from water bodies (The culture medium for the accumulation of Salmonella, ready to use, "RNS"), providing the accumulation of Salmonella from different serogroups, inhibiting the growth of accompanying microflora, allowing to obtain objective information about the extent of bacterial contamination of water bodies. Medium is by nature of a solution for microbiological purposes which is produced by mixing the components with consequentfiltration and sterilization. In an experimental way there were chosen optimal ratios of the nutrient medium ingredients: extract offodder yeast in an amount of 4.55.0 g/l, sodium hydroxide - to 1.3-1.4 g/l, potassium phosphate - 8.6-8.8 g/l. The medium is a sterile, clear liquid, green in color, medium pH is 6.4 to 6.8, amine nitrogen - from 0.05 to 0.1%. Designed medium for accumulation is sensitivity, it ensures the growth of the test strains of salmonella at seeding of single cells in that favorably differs from similar media used in public health practice at the present time. The smallest time for the accumulation of biomass of Salmonella accounts of 6 hours, the optimal time is 24 hours. Incubation of crops is produced at 37 degrees C. Cultures of Salmonella at seeding in the developed medium retain their biological properties. Developed medium in terms of sensitivity is superior to magnesian and selenite media. PMID- 29424212 TI - [Hygiene of the life activity of children and adolescents is the basis of welfare of young generation of Russians (to the 90th anniversary of the Department of hygiene of education - hygiene of children and adolescents of the Imperial Moscow University - 1st Moscow State University - 1st Moscow State Medical University - Moscow Medical Academy - First Moscow State Medical University named after I.M. Sechenov)]. PMID- 29424214 TI - [Technogenic environmental pollution and the public health: analysis and prognosis]. AB - Technogenic risk factors are very aggressive for a human health. Due to the progressive increase in environmental pollution the problem of the adverse impact of these factors on the health of both the human population as a whole, and individual groups every year is becoming increasingly important. At that the influence of anthropogenic pollution on the various manifestations of infectious pathology in the scientific literature is presented very modestly. In this paper there is presented a review of research devoted to the problem of the interrelationship of man-made pollution of the environment and public health. PMID- 29424213 TI - [Gas chromatography-mass spectrometric studies of volatile emissions from plants for the assessment of the effectiveness and chemical safety of the implementation of environment improving phytotechnologies]. AB - The chromato-mass-spectrometric studies of volatile emissions of fresh-cut roses have revealed the persistence of wide range of organic compounds. The most large content was consist of terpene hydrocarbons. The contribution of oxygen containing components (alcohols, ethers, aldehydes and ketones) varied in wide ranges in dependence on the content of the feeding solution. The significant part of plants ' volatiles has no hygienic norm. Among the substances released into the air space ofpremises with volatile emissions ofplants, a significant part has not hygienic standards. Purposeful change in composition of the mixture of volatile organic compounds released by the plants, in the combination with chemical-analytical control of the content of these substances by gas chromatography-mass spectrometry in terms of ecological and hygienic aspects may be useful in the development, use and determination of the optimal conditions of the implementation of environment improving phytotechnologies and evaluation of the efficacy and safety of their impact on public health. PMID- 29424215 TI - [Informative indices of the biocorrosion activity for the determination of the character of the aggression ground]. AB - Underground corrosion is referred to the most difficult types of corrosion in connection with that it is multifactorial and differs in progressive dynamics of the participation of each parameter in the process of destruction of the metal. With the aim of the evaluation of the informativeness of the index of the biocorrosion activity caused by the influence of various factors to determine the character of the soil aggressiveness in the district of pipeline laying there was studied the complex of microbiological and physical-chemical indices). There was determined the amount of sulfur cycle bacteria (autotrophic thiobacteria and sulphate-reducing bacteria), the total concentration of sulfur and iron in the soil samples adjacent to the surface of the underground pipelines in the territory of the Khanty-Mansi Autonomous District of Yugra, and the ratio of these indices with a specific electrical resistance of the soil. There was established the predominance ofsamples with weak aggressiveness of the soil (55.17% of cases), with the criterion ofbiocorrosion soil activity of 2,44 +/- 0,19. The results show significant differences in the thiobacteria content and mobile iron in the studied soil-ground samples. There was revealed a direct correlation of the average force of concentrations of identified bacteria and iron content in the soil. There was shown the necessity of the implementation of dynamic control and the development of methods of protection of metal structures to prevent biocorrosion in the design and in the process of the operation of the pipeline. PMID- 29424216 TI - [Fishes from the Volga-Caspian basin - vectors of pathogens of anthropozoonoses]. AB - In the Volga-Caspian region there is abundant variety of parasitic species from different systematic groups. Some species ofparasites can be pathogenic not only for fish, but also for human that is why studies on the infection rate of commercial fish species by agents of are very topical for today. The work presents materials on invasiveness by the sanitary-significant helminthes of sheat fish, pike-perch, perch, pike, bream, Caspian roach, red-eye, sabrefish, silver bream, anchovy and ordinary kilka, herring, Caspian shad, black-backed shad. In parasite cenoses of all studied representatives of ichthyofauna there were from one to four species of helminthes which are pathogenic for human and warm-blooded animals. The obtained data indicate to the functioning and active circulation of natural foci of invasion ofAnisacidosis, Eustrongylidosis, apophallosis, rossicotremosis, corynosomosis, opisthorchiasis and pseudamphistomosis in the delta and avan-delta of the Volga River, which, in turn, points to the sanitary trouble of the Volga Caspian region. PMID- 29424217 TI - [The content of petroleum products, benzo(a)pyrene and heavy metals in soils of yamalnenets autonomous district and heavy metals in the hair of children]. AB - The paper presents information about the content of benzo(a)pyrene in soil samples of petroleum products and the content of heavy metals (iron, copper, lead, arsenic, manganese, chromium, cadmium and mercury) in the soil and hair samples of children. Soil samples and hair were taken in October 2014 in the north-western part of the Yamal-Nenets Autonomous District. The values obtained were compared with the approximately permissible levels and maximum allowable concentrations adopted in the Russian Federation. Levels are determined compounds in the soil in general do not exceed the allowable concentrations. In hair samples there was noted marked exceeding of the recommended values for zinc, copper, chromium and iron 10%, 16.7%, 83.3% and 100% samples, respectively. The cause of the high iron content in the hair samples may be due to the quality of consumed water, which is characterized by low mineralization and high iron content. Increased chromium content of more than 80% of the hair samples can be caused, as in the case of iron, the quality of water consumed, but also a high proportion of local foods in the diet of people, rich by chromium. A conducted study on the state of the environment in the village, away from areas of hydrocarbon production, indicates to the low importance of anthropogenic impact. PMID- 29424218 TI - [The frequency of detection of non-polio enteroviruses in foul and fecal waste waters, water and some food products]. AB - In the Perm Territory from 2010 to 2014 155 samples offoul andfecal waste waters, 293 samples of surface water, 827 samples of supply net water, and 57 vegetable and fruit water-washes were examined for the RNA enterovirus agent with the use of polymerase chain reaction (PCR) method. In parallel 155 wastewater samples, 20 samples of surface water, and 4 samples of supply net water were examined for non polio enterovirus agent with the use of virological methods. In the samples of foul waste waters the RNA enterovirus agent was detected in 74.8 +/- 3.4%, and nonpolio enterovirus agent - in 65.1 +/- 3.8%. In the samples of surface water the RNA enterovirus agent was detected in 2.3 +/- 0.8%; in the area offoul and fecal waste waters the non-polio enterovirus agent was detected in 20.0 +/- 4.4% in the process of virological investigation of RNA-positive water samples. In supply net water the RNA enterovirus agent was detected in 0.8 +/- 0.3 %, on the surface of vegetables, fruits, and grapes - in 10.5 +/- 3.9 %. PMID- 29424219 TI - Creating new solutions to tackle old problems: the first ever evidence-based guidance on emergency risk communication policy and practice. PMID- 29424220 TI - The role of extended and whole genome sequencing for tracking transmission of measles and rubella viruses: report from the Global Measles and Rubella Laboratory Network meeting, 2017. PMID- 29424221 TI - [State of health of the population of the one out of oil and gas extraction regions of Kazakhstan]. AB - Research is conducted in the city of Aktau ofMangystau area in 2009-2011. The state of health of adult population of the city of Aktau and quality of atmospheric air were studied. Results of works revealed positive dynamics of a natural increase of the population. There is noted a high rate of birth rate, however infantile mortality has tendency to the gain. There were established the structure and leading indices of the incidence among the male andfemale population. The impurity of atmospheric air by chemicals was shown to have the direct impact on health of urban population. PMID- 29424222 TI - [Ecological and physiological assessment of the elemental status in the adult population of the Republic of Bashkortostan]. AB - The study of elemental status was carried out as a result of a multielement analysis of hair by ICP-MS within the framework of the Federal Program "National System of chemical and biological security of the Russian Federation, 2009-2014". This parameter is an index of the impact of the environment on the body. A total of 1,138 adult residents of the Republic of Bashkortostan (624 women and 514 men aged of25-50 years) were examined. The features of the element status of the adult population of the Republic were shown. The obtained data can be used as reference values of chemical elements in the hair of the adult population of the Republic of Bashkortostan. PMID- 29424223 TI - [Modern features of the formation of occupational diseases and insurance coverage on the example of the Republic of Bashkortostan]. AB - There was executed the analysis of morbidity and disability rate in workers with occupational diseases (poisoning) of the Republic ofBashkortostan for the periodfrom 2010 to 2014. There is reflected the sectoral distribution of the relative indices of the occupational morbidity. There are selected factors of labor and the labor process, promoting occupational diseases (OD). The leading place in the structure of primary morbidity is held by OD related to physical overload and functional overexertion of certain organs and systems; the second - by diseases associated with exposure to physicalfactors; the third - by diseases from exposure to workplace allergens. This is followed by illness (intoxications) caused by exposure to chemical factors, industrial aerosols. The share of OD from exposure to biological agents and professional tumors in total accounts for about 2.0% of all cases of OD revealed for the first time. PMID- 29424224 TI - Metastable Structures in Cluster Catalysis from First-Principles: Structural Ensemble in Reaction Conditions and Metastability Triggered Reactivity. AB - Reactivity studies on catalytic transition metal clusters are usually performed on a single global minimum structure. With the example of a Pt13 cluster under a pressure of hydrogen, we show from first-principle calculations that low energy metastable structures of the cluster can play a major role for catalytic reactivity and that hence consideration of the global minimum structure alone can severely underestimate the activity. The catalyst is fluxional with an ensemble of metastable structures energetically accessible at reaction conditions. A modified genetic algorithm is proposed to comprehensively search for the low energy metastable ensemble (LEME) structures instead of merely the global minimum structure. In order to reduce the computational cost of density functional calculations, a high dimensional neural network potential is employed to accelerate the exploration. The presence and influence of LEME structures during catalysis is discussed by the example of H covered Pt13 clusters for two reactions of major importance: hydrogen evolution reaction and methane activation. The results demonstrate that although the number of accessible metastable structures is reduced under reaction condition for Pt13 clusters, these metastable structures can exhibit high activity and dominate the observed activity due to their unique electronic or structural properties. This underlines the necessity of thoroughly exploring the LEME structures in catalysis simulations. The approach enables one to systematically address the impact of isomers in catalysis studies, taking into account the high adsorbate coverage induced by reaction conditions. PMID- 29424225 TI - Carbon-Nanotube-Wrapped Spider Silks for Directed Cardiomyocyte Growth and Electrophysiological Detection. AB - The combination of nanostructures with biomaterials offers great opportunities in constructing innovative functional devices such as biosensors and actuators. Here, we create a multifunctional fiber by wrapping a thin film of carbon nanotubes (CNTs) on naturally found spider silks, which shows great flexibility and conductivity. The hybrid CNT-silk fiber demonstrates intimate contact with cardiomyocytes and can direct the cell growth and simultaneously record potential signals evoked from cell beating. Cell activities reflected in the form of potential signals have been monitored clearly and reliably through the CNT-silk fibers without degradation over the long term. PMID- 29424226 TI - Improving Charge Injection via a Blade-Coating Molybdenum Oxide Layer: Toward High-Performance Large-Area Quantum-Dot Light-Emitting Diodes. AB - A solution-processed molybdenum oxide (MoO x) as the hole injection layer (HIL) by doctor-blade coating was developed to improve the efficiency and lifetime of red-emitting quantum-dot light-emitting diodes (QD-LEDs). It has been demonstrated that by adding isopropyl alcohol into the MoO x precursor during the doctor-blade coating process, the morphology, composition, and the surface electronic structure of the MoO x HIL could be tailored. A high-quality MoO x film with optimized charge injection was obtained, based on which all-solution processed highly efficient red-emitting QD-LEDs were realized by using a low-cost doctor-blade coating technique under ambient conditions. The red QD-LEDs exhibited the maximum current efficiency and external quantum efficiency of 16 cd/A and 15.1%, respectively. Moreover, the lifetime of red devices initializing at 100 cd/m2 was 3236 h under ambient conditions, which is about twice as long as those with a conventional poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) HIL. Large-area QD-LEDs with 4 in. emitting areas were fabricated with blade coating as well, which exhibit a high efficiency of 12.1 cd/A for red emissions. Our work paves a new way to the realization of efficient large-area QD-LEDs, and the processing and findings from this work can be expanded into next-generation lighting and flat-panel displays. PMID- 29424227 TI - Assessing Exposome Effects on Pregnancy through Urine Metabolomics of a Portuguese (Estarreja) Cohort. AB - This nuclear magnetic resonance metabolomics study compared the influence of two different central Portugal exposomes, one of which comprised an important source of pollutants (the Estarreja Chemical Complex, ECC), on the urinary metabolic trajectory of a cohort of healthy pregnant women (total n = 107). An exposome independent description of pregnancy metabolism was found to comprise a set of 18 metabolites reflecting expected changes in branched-chain amino acid catabolism and hormone and lipid metabolisms. In addition, a set of small changes in some metabolites was suggested to be exposome-dependent and characteristic of pregnant subjects from the Estarreja region. These results suggested that the Estarreja exposome may impact to a very low extent pregnancy metabolism, inducing slight changes in amino acid metabolism (alanine, glycine, and 3-hydroxyisobutyrate, possibly involved in valine metabolism), tricarboxylic acid (TCA) cycle (cis aconitate), diet, or gut microflora (furoylglycine) as well as allantoin, 2 hydroxyisobutyrate, and an unassigned resonance at delta 8.45. Furthermore, the urine of Estarreja subjects was found to generally contain higher levels of 4 hydroxyphenylacetate and lower levels of citrate. However, out of the above metabolites, only glycine and citrate seemed to correlate with the proximity to the ECC, with slightly relative higher levels of these compounds found for subjects living closer to the ECC. This suggested possible small effects of local pollutants on energy metabolism, with the remaining exposome-dependent metabolite changes most probably originating from other aspects of the local exposome such as diet and lifestyle. Despite the limitation of this study regarding the unavailability of objective environmental parameters for the period under study, our results confirm the usefulness of metabolomics of human urine to gauge exposome effects on human health and, particularly, during pregnancy. PMID- 29424228 TI - Insight into the Electro-Oxidation Mechanism of Glucose and Other Carbohydrates by CuO-Based Electrodes. AB - In this work, a new hypothesis for the electrocatalytic behavior of CuO electrodes is presented. Different from the established mechanism, here we discuss why CuIII species do not participate in the oxidation mechanism of carbohydrates. We show that hydroxyl ion adsorption and the semiconductive properties of the material play a more significant role in this process. The relationship between the flat band potential and the potential that begin oxidation suggests that the concentration of vacancies in the charge region acts upon the reactivity of the adsorbed hydroxyl ions through a partial charge transfer reaction. In the presence of carbohydrate molecules, the electron transfer is facilitated and involves the transfer of electrons from the adsorbed hydroxyl ions to the CuO film. This mechanism is fundamentally relevant since it helps the understanding of several experimental misleads. The results can also lead to obtaining better catalysts, since improvements in the material should focus on enhancing the semiconductive properties rather than the CuII/CuIII redox transition. The results shed light on different aspects of carbohydrate molecules oxidation that could lead to novel applications and possibly a better description of other semiconductor mechanisms in electrocatalysis. PMID- 29424229 TI - Condensed Tannin Changes along the Digestive Tract in Lambs Fed with Sainfoin Pellets or Hazelnut Skins. AB - The variable anthelmintic efficacy of condensed tannins (CT) against gastrointestinal nematodes may depend on CT concentration, composition, or fate along the digestive tract. We analyzed CT concentration and composition by acetone-HCl-butanol and thiolysis coupled to HPLC-MS in digesta and feces of lambs. Lambs had been infected with Haemonchus contortus and Trichostrongylus colubriformis and received sainfoin pellets and hazelnut skins of contrasting prodelphinidin/procyanidin ratios. The digesta and feces had lower CT concentrations than the original feeds but similar concentration patterns across the digestive compartments. The changes in assayable CT concentrations between rumen, abomasum, and small intestine may be due to complex formation between CT and other dietary components. However, the large CT disappearance (61-85%) from feed to feces could also indicate that CT may have been structurally modified, degraded, or absorbed during digestion. Interestingly, there were no changes in the structural features of assayable CT in the digesta. PMID- 29424230 TI - Laser-Induced Intersite Spin Transfer. AB - Laser pulses induce spin-selective charge flow that we show to generate dramatic changes in the magnetic structure of materials, including a switching of magnetic order from antiferromagnetic (AFM) to transient ferromagnetic (FM) in multisub lattice systems. The microscopic mechanism underpinning this ultrafast switching of magnetic order is dominated by spin-selective charge transfer from one magnetic sublattice to another. Because this spin modulation is purely optical in nature (i.e., not mediated indirectly via the spin-orbit interaction) this is one of the fastest means of manipulating spin by light. We further demonstrate this mechanism to be universally applicable to AFM, FM, and ferri-magnets in both multilayer and bulk geometry and provide three rules that encapsulate early-time magnetization dynamics of multisub-lattice systems. PMID- 29424231 TI - Monitoring the Surface Chemistry of Functionalized Nanomaterials with a Microfluidic Electronic Tongue. AB - Advances in nanomaterials have led to tremendous progress in different areas with the development of high performance and multifunctional platforms. However, a relevant gap remains in providing the mass-production of these nanomaterials with reproducible surfaces. Accordingly, the monitoring of such materials across their entire life cycle becomes mandatory to both industry and academy. In this paper, we use a microfluidic electronic tongue (e-tongue) as a user-friendly and cost effective method to classify nanomaterials according to their surface chemistry. The chip relies on a new single response e-tongue with association of capacitors in parallel, which consisted of stainless steel microwires coated with SiO2, NiO2, Al2O3, and Fe2O3 thin films. Utilizing impedance spectroscopy and a multidimensional projection technique, the chip was sufficiently sensitive to distinguish silica nanoparticles and multiwalled carbon nanotubes dispersed in water in spite of the very small surface modifications induced by distinct functionalization and oxidation extents, respectively. Flow analyses were made acquiring the analytical readouts in a label-free mode. The device also allowed for multiplex monitoring in an unprecedented way to speed up the tests. Our goal is not to replace the traditional techniques of surface analysis, but rather propose the use of libraries from e-tongue data as benchmark for routine screening of modified nanomaterials in industry and academy. PMID- 29424232 TI - Micelle-Enabled Photoassisted Selective Oxyhalogenation of Alkynes in Water under Mild Conditions. AB - Using micelles of FI-750-M, visible light, photocatalysts, and inexpensive halogenating reagents, such as N-bromosuccinimide and N-chlorosuccinimde, selective oxyhalogenations of alkynes were achieved in water under very mild conditions. No halogenation at the aromatic rings was detected, and control experiments revealed the radical pathway. The easily conducted protocol exhibited high reproducibility, was readily adjusted to gram scale, and allowed for recycling of reaction medium and catalyst. PMID- 29424233 TI - Quantitation of Oleuropein and Related Phenolics in Cured Spanish-Style Green, California-Style Black Ripe, and Greek-Style Natural Fermentation Olives. AB - Oleuropein, ligstroside, and related hydrolysis products are key contributors to olive bitterness, and several of these phenolics are implicated in the prevention of lifestyle age-related diseases. While table olive processing methods are designed to reduce oleuropein, the impact of processing on ligstroside and related hydrolysis products (e.g., oleacein, oleocanthal, hydroxytyrosol glucoside, ligstroside aglycone, and oleuropein aglycone) is relatively unknown. Herein, levels of these compounds were measured in Spanish-style green (SP), Californian-style black ripe (CA), and Greek-style natural fermentation (GK) olives using rapid ultrahigh-performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS). GK olives had the highest concentration of all compounds measured, with the exception of oleocanthal, which was highest in SP olives (0.081 mg kg-1 wet weight (w.wt)). CA olives had the lowest levels of most compounds measured, including ligstroside (0.115 mg kg-1 w.wt) and oleuropein (0.974 mg kg-1 w.wt). Hydroxytyrosol was the predominate compound in all three styles of commercial olives, with similar concentrations observed for GK and SP olives (134.329 and 133.685 mg kg-1 w.wt, respectively) and significantly lower concentrations observed for CA olives (19.981 mg kg-1 w.wt). PMID- 29424234 TI - Osteochondral Allograft Transplantation of the Knee in Patients with an Elevated Body Mass Index. AB - Objective To characterize the graft survivorship and clinical outcomes of osteochondral allograft transplantation (OCA) of the knee in patients with an elevated body mass index (BMI). Design Prospective data on 38 consecutive patients with a BMI >=30 kg/m2 treated with OCA from 2000 to 2015 were reviewed. Complications, reoperations, and patient responses to validated outcome measures were examined. Failures were defined by any removal/revision of the allograft or conversion to arthroplasty. Results Thirty-one knees in 31 patients (mean age, 35.4 years [range, 17-61 years]; 87% male) met the inclusion criteria. Mean BMI was 32.9 kg/m2 (range, 30-39 kg/m2). Mean chondral defect size was 6.4 cm2 (range, 1.0-15.3 cm2). Prior to OCA, 23 patients (74%) had undergone previous surgery to the ipsilateral knee. Mean duration of follow-up was 4.1 years (range, 2-11 years). After OCA, 5 knees (13%) underwent conversion to unicompartmental (1) or total (4) knee arthroplasty. Two- and 5-year graft survivorship were 87% and 83%, respectively. At final follow-up, clinically significant improvements were noted in the pain (49.3-72.6) and physical functioning (52.9-81.3) subscales of the Short Form-36 ( P <= 0.001), International Knee Documentation Committee subjective form (43.5-67.0; P = 0.002), Knee Outcome Survey-Activities of Daily Living (58.2-80.4; P = 0.002), and overall condition subscale of the Cincinnati Knee Rating System (4.7-6.9; P = 0.046). Conclusions OCA can be a successful midterm treatment option for focal cartilage defects of the knee in select patients with a BMI >=30 kg/m2. PMID- 29424235 TI - Should we be using digital technologies in the treatment of psychotic disorders? PMID- 29424237 TI - Greasing the wheels or a spanner in the works? Regulation of the cardiac sodium pump by palmitoylation. AB - The ubiquitous sodium/potassium ATPase (Na pump) is the most abundant primary active transporter at the cell surface of multiple cell types, including ventricular myocytes in the heart. The activity of the Na pump establishes transmembrane ion gradients that control numerous events at the cell surface, positioning it as a key regulator of the contractile and metabolic state of the myocardium. Defects in Na pump activity and regulation elevate intracellular Na in cardiac muscle, playing a causal role in the development of cardiac hypertrophy, diastolic dysfunction, arrhythmias and heart failure. Palmitoylation is the reversible conjugation of the fatty acid palmitate to specific protein cysteine residues; all subunits of the cardiac Na pump are palmitoylated. Palmitoylation of the pump's accessory subunit phospholemman (PLM) by the cell surface palmitoyl acyl transferase DHHC5 leads to pump inhibition, possibly by altering the relationship between the pump catalytic alpha subunit and specifically bound membrane lipids. In this review, we discuss the functional impact of PLM palmitoylation on the cardiac Na pump and the molecular basis of recognition of PLM by its palmitoylating enzyme DHHC5, as well as effects of palmitoylation on Na pump cell surface abundance in the cardiac muscle. We also highlight the numerous unanswered questions regarding the cellular control of this fundamentally important regulatory process. PMID- 29424238 TI - The Rise and Fall of Metronidazole for Clostridium difficile Infection. AB - Clostridium difficile is posing urgent health threats. Older studies have shown that metronidazole and vancomycin are equally effective in the treatment of Clostridium difficile infection (CDI). Given its inexpensive cost and low propensity to select antimicrobial resistant organisms, metronidazole became rapidly the drug of choice despite its pharmacokinetic limitations in the treatment of CDI. However, newer studies demonstrated that metronidazole is inferior to vancomycin, prompting clinicians to change their long-standing position on using metronidazole for mild to moderate infections and on reserving vancomycin for severe infections. Moving forward, metronidazole will fall out of favor in the treatment of CDI. PMID- 29424236 TI - Home-based pre-surgical psychological intervention for knee osteoarthritis (HAPPiKNEES): a feasibility randomized controlled trial. AB - OBJECTIVE: To determine the feasibility of conducting a trial of a pre-surgical psychological intervention on pain, function, and mood in people with knee osteoarthritis listed for total knee arthroplasty. DESIGN: Multi-centre, mixed methods feasibility randomized controlled trial of intervention plus usual care versus usual care. SETTING: Participants' homes or hospital. PARTICIPANTS: Patients with knee osteoarthritis listed for total knee arthroplasty and score >7 on either subscales of Hospital Anxiety and Depression Scale. INTERVENTION: Up-to 10 sessions of psychological intervention (based on cognitive behavioural therapy). MAIN MEASURES: Feasibility outcomes (recruitment and retention rates, acceptability of trial procedures and intervention, completion of outcome measures), and standardized questionnaires assessing pain, function, and mood at baseline, and four and six months post-randomisation. RESULTS: Of 222 people screened, 81 did not meet inclusion criteria, 64 did not wish to participate, 26 were excluded for other reasons, and 51 were randomized. A total of 30 completed 4-month outcomes and 25 completed 6-month outcomes. Modal number of intervention sessions completed was three (range 2-8). At 6-month follow-up, mood, pain, and physical function scores were consistent with clinically important benefits from intervention, with effect sizes ranging from small ( d = 0.005) to moderate ( d = 0.74), and significant differences in physical function between intervention and usual care groups ( d = 1.16). Feedback interviews suggested that participants understood the rationale for the study, found the information provided adequate, the measures comprehensive, and the intervention acceptable. CONCLUSION: A definitive trial is feasible, with a total sample size of 444 people. Pain is a suitable primary outcome, but best assessed 6 and 12 months post-surgery. PMID- 29424239 TI - Assessment of Cardiovascular Risk With Glucagon-Like Peptide 1 Receptor Agonists in Patients With Type 2 Diabetes Using an Alternative Measure to the Hazard Ratio. AB - BACKGROUND: Randomized clinical trials with the aim of evaluating the cardiovascular risks associated with glucagon-like peptide 1 (GLP-1) receptor agonists, lixisenatide, liraglutide, semaglutide, and exenatide, have been conducted. They showed different results among the agents, but the reason has not been explained. OBJECTIVE: To evaluate the cardiovascular risks associated with GLP-1 receptor agonists by using an alternative measure to the hazard ratio. METHODS: We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Four randomized clinical trials with cardiovascular events as a primary endpoint, ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide), were reevaluated by estimating the RMSTs for each of the agents and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. RESULTS: The differences of RMSTs (GLP-1 receptor agonist minus placebo: point estimate and 95% CI) for primary composite endpoint of cardiovascular events were 0 days [-14, 14] in ELIXA (1080 days follow-up), 20 days [6, 34] in LEADER (1620 days follow-up), 8 days [1, 15] in SUSTAIN-6 (672 days follow-up), and 11 days [-3, 26] in EXSCEL (1825 days follow-up). As for the risk of other cardiovascular outcomes, there were no substantial differences between GLP-1 receptor agonists and placebo. CONCLUSIONS: Liraglutide and semaglutide decrease the risk of major adverse cardiovascular events compared with placebo when using the difference in RMST. The previously reported result that GLP-1 receptor agonists do not increase the risk of cardiovascular outcomes compared with placebo is also confirmed. PMID- 29424240 TI - Report of in vitro antileishmanial properties of Iberian macroalgae. AB - Here is reported the anti Leishmania infantum activity of 48 hexane, CH2Cl2 and MeOH extracts from 16 macroalgae collected on the Iberian Coast. Seven hexane and CH2Cl2 Cystoseira baccata, Cystoseira barbata, Cystoseira tamariscifolia, Cystoseira usneoides, Dictyota spiralis and Plocamium cartilagineum extracts were active towards promastigotes (IC50 29.8-101.8 MUg/mL) inducing strong morphological alterations in the parasites. Hexane extracts of C. baccata and C. barbata were also active against intracellular amastigotes (IC50 5.1 and 6.8 MUg/mL, respectively). Fatty acids, triacylglycerols, carotenoids, steroids and meroterpenoids were detected by nuclear magnetic resonance (NMR), and gas chromatography in the Cystoseira extracts. These results suggest that Cystoseira macroalgae contain compounds with antileishmanial activity, which could be explored as scaffolds to the development of novel sources of antiparasitic derivatives. PMID- 29424241 TI - The challenges of fertility preservation in cancer patients: an interview with Michael Grynberg. AB - Michael Grynberg is an Obstetrician Gynecologist specialized in reproductive medicine. After 1 year as a visiting fellow in the Department of Reproductive Medicine at Cornell University, he returned to work in France as an Attending Physician in the Division of Reproductive Medicine at the University Hospital Antoine Beclere, Clamart, France. In 2011, he completed his PhD on the topic of the regulation of follicular growth and anti-Mullerian hormone production. Since 2014, he has been Professor of Reproductive Medicine and the Head of the Department of Reproductive Medicine and Fertility Preservation at the University Hospital Jean Verdier, Bondy, France. Since 2017, he has become the Head of the Department of Reproductive Medicine and Fertility Preservation at the University Hospital Antoine Beclere, Clamart, France. In addition, he is an active member of the basic research unit INSERM U 1133, University Paris Diderot-CNRS UMR 8251. His research interests initially include the assessment of ovarian follicular status and the regulation of anti-Mullerian hormone, a key peptide in the ovarian function. Over the past 5 years, he has expanded his field of research with oncofertility. Indeed, female fertility preservation has recently emerged in the field of reproductive medicine. He is a pioneer on this topic in France and has recently become the President of the French Society of Oncofertility. He, along with his colleagues, has published over 100 peer-reviewed articles in international journals and books. PMID- 29424244 TI - Social comparisons in adults with type 2 diabetes: Patients' reasons for target selection. AB - OBJECTIVE: To examine reasons for selecting a social comparison target (i.e. a specific other for relative self-evaluation), and their influence on affect and motivation for self-care, in type 2 diabetes (T2DM). DESIGN: Adults with T2DM (n = 180, MA1c = 7.6%) chose to read about one of four targets. Participants rated five reasons for their choice (strongly disagree - strongly agree), and rated affect and self-care motivation before and after reading. RESULTS: To boost confidence in my ability to manage diabetes was rated highest overall (ps < 0.01), though choosing worse-off (vs. better-off) targets was associated with to gain useful information about how to improve (p = 0.04, [Formula: see text] = 0.05). Selection in order to feel better worked for those who chose better-off targets; choosing worse-off targets for this purpose worsened mood and stress (ps < 0.04, [Formula: see text]s = 0.02). Choosing worse-off targets to learn about similar others reduced self-care motivation (p < 0.01, [Formula: see text] = 0.05). Selection in order to boost confidence showed increased motivation only among those who chose better-off targets (p = 0.01). CONCLUSIONS: Patients' reasons for a particular comparison are associated with short-term changes in affect and self-care motivation, and warrant greater empirical and clinical attention. PMID- 29424242 TI - Rce1: mechanism and inhibition. AB - Ras converting enzyme 1 (Rce1) is an integral membrane endoprotease localized to the endoplasmic reticulum that mediates the cleavage of the carboxyl-terminal three amino acids from CaaX proteins, whose members play important roles in cell signaling processes. Examples include the Ras family of small GTPases, the gamma subunit of heterotrimeric GTPases, nuclear lamins, and protein kinases and phosphatases. CaaX proteins, especially Ras, have been implicated in cancer, and understanding the post-translational modifications of CaaX proteins would provide insight into their biological function and regulation. Many proteolytic mechanisms have been proposed for Rce1, but sequence alignment, mutational studies, topology, and recent crystallographic data point to a novel mechanism involving a glutamate-activated water and an oxyanion hole. Studies using in vivo and in vitro reporters of Rce1 activity have revealed that the enzyme cleaves only prenylated substrates and the identity of the a2 amino residue in the Ca1a2X sequence is most critical for recognition, preferring Ile, Leu, or Val. Substrate mimetics can be somewhat effective inhibitors of Rce1 in vitro. Small-molecule inhibitor discovery is currently limited by the lack of structural information on a eukaryotic enzyme, but a set of 8-hydroxyquinoline derivatives has demonstrated an ability to mislocalize all three mammalian Ras isoforms, giving optimism that potent, selective inhibitors might be developed. Much remains to be discovered regarding cleavage specificity, the impact of chemical inhibition, and the potential of Rce1 as a therapeutic target, not only for cancer, but also for other diseases. PMID- 29424243 TI - FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer. AB - Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-alpha to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-alpha positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response. PMID- 29424245 TI - Surgical management of a thoracic extradural arachnoid cyst with communication to subarachnoid space through nerve root: a case report. AB - Spinal extradural cysts are uncommon and may cause cord and nerve root compression. The cysts usually appear in thoracic spine. We report a 29-year-old man with an extradural arachnoid cyst from T4 to T6. The cyst was communicated to the subarachnoid space through a fistula at the left T6 nerve root. To access the fistula, we had to unroof the foramen of left T6 nerve root which could lead to spinal instability. We decided to save the bony and soft tissue elements of the foramen at the mentioned thoracic spine level. Therefore, the cyst walls were excised and then the ostia of the cyst at the cystic side of the fistula was tightly closed. PMID- 29424247 TI - Corrigendum. PMID- 29424248 TI - Evaluation of changes in renal function in PARAMOUNT: a phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. AB - OBJECTIVES: To assess the effect of long-term pemetrexed maintenance therapy on patients' renal function. METHODS: In the PARAMOUNT phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays and treatment discontinuations associated with impaired renal function. RESULTS: Creatinine clearance >=45 mL/min was required before the start of any cycle. Patients on pemetrexed maintenance had a significantly higher percentage maximum increase in sCr over baseline versus placebo for the range of >=10% to >=90% increase (p < .05). The risk of experiencing renal events leading to dose delays and discontinuations was higher with higher increases in sCr but reversible in most patients. sCr increases of >=30% and >=40% were associated with gender (female), age (<70 years) and longer exposure to pemetrexed compared with placebo. Sixteen (4%) pemetrexed patients and 1 (1%) placebo patient discontinued treatment due to drug-related renal events; 13/16 (81%) of those pemetrexed patients had sCr increases >=30% and 7/13 (54%) had pre-existing conditions and/or were receiving nephrotoxic drugs. CONCLUSIONS: The appearance of renal events leading to dose delays and/or treatment discontinuations was associated with sCr increase of at least 30%. However, it was difficult to identify patients at a higher risk of treatment discontinuation due to a drug related renal event based only on changes in pre-maintenance laboratory values. PMID- 29424246 TI - Increased plasma FGF21 level as an early biomarker for insulin resistance and metabolic disturbance in obese insulin-resistant rats. AB - : Propose: To investigate the temporal relationship between plasma fibroblast growth factor 21 levels, insulin resistance, metabolic dysfunction and cardiac fibroblast growth factor 21 resistance in long-term high-fat diet-induced obese rats. METHODS: In total, 36 male Wistar rats were fed with either a normal diet or high-fat diet for 12 weeks. Blood was collected from the tail tip, and plasma was used to determine metabolic profiles and fibroblast growth factor 21 levels. Rats were sacrificed at weeks 4, 8 and 12, and the hearts were rapidly removed for the determination of cardiac fibroblast growth factor 21 signalling pathways. RESULTS: Body weight and plasma fibroblast growth factor 21 levels were increased after 4 weeks of consumption of a high-fat diet. At weeks 8 and 12, high-fat diet rats had significantly increased body weight and plasma fibroblast growth factor 21 levels, together with increased plasma insulin, HOMA index, area under the curve of glucose, plasma total cholesterol, plasma low-density lipoprotein cholesterol, serum malondialdehyde and cardiac malondialdehyde levels. However, plasma high-density lipoprotein cholesterol levels and cardiac fibroblast growth factor 21 signalling proteins (p-FGFR1 Tyr154, p-ERK1/2 Thr202/Tyr204 and p-Akt Ser473) were decreased, compared with normal diet rats. CONCLUSION: These findings suggest that plasma fibroblast growth factor 21 levels could be an early predictive biomarker prior to the development of insulin resistance, metabolic disturbance and cardiac fibroblast growth factor 21 resistance. PMID- 29424249 TI - Gender specific considerations in atrial fibrillation treatment: a review. AB - INTRODUCTION: Distinct differences in clinical presentation, utilization of therapy and outcome of atrial fibrillation (AF) management are observed in men vs women. This review focuses on our current knowledge on these sex-specific variations and how those impact the detection of AF and therapeutic decisions. Areas covered: The current article reviews reports illustrating gender-related differences in the incidence, prevalence, clinical presentations, different risk factors, pathophysiology, therapeutic strategies, procedural parameters in catheter ablation for AF and complications and long-term outcome of ablative therapy including arrhythmia recurrence and quality of life. Some of these areas have been investigated widely providing conclusive evidences, whereas others have many unanswered questions or conflicting findings that need clarifications. Expert opinion: Attainment of sinus rhythm and healthy quality of life as well as prevention of complications, especially stroke, are the main goals of AF management. Sex-specific variations are evident in many areas in the spectrum of AF that should be addressed by large population-based or randomized trials to facilitate customization of AF-therapy to maximize success in both genders. PMID- 29424250 TI - Graphene-based nanocomposites: synthesis and their theranostic applications. AB - Graphene, the mother of all carbon materials, has unlocked a new era of biomedical nanomaterials due to its exceptional biocompatibility, physicochemical and mechanical properties. It is a single atom thick, nanosized, two-dimensional structure and provides high surface area with adjustable surface chemistry to form hybrids. The present article provides a comprehensive review of ever expanding application of graphene nanomaterials with different inorganic and organic materials in drug delivery and theranostics. Methods of preparation of nanomaterials are elaborated and biological and physicochemical characteristics of biomedical relevance are also discussed. Graphene form nanomaterials with metallic nanoparticles offer multiscale application. First, graphene act as a platform to attach nanoparticles and provide excellent mechanical strength. Second, graphene improves efficacy of metallic nanoparticles in diagnostic, biosensing, therapeutic and drug delivery application. Graphene-based polymeric nanocomposites find wider application in drug delivery with flexibility to incorporate hydrophilic, hydrophobic, sensitive and macromolecules. In addition, grapheme quantum dots and graphene hybrids with inorganic nanocrystal and carbon nanotubes hybrids have shown interesting properties for diagnosis and therapy. Finally, we have pointed out research trends that may be more common in future for graphene-based nanomaterials. PMID- 29424251 TI - Care at specialized cancer centers among young adults with acute lymphoblastic leukemia in California. PMID- 29424252 TI - The Impact of Respite Programming on Caregiver Resilience in Dementia Care: A Qualitative Examination of Family Caregiver Perspectives. AB - Family members with a relative with dementia often experience what has been called the "unexpected career of caregiver" and face multifaceted, complex, and stressful life situations that can have important consequences. This exploratory study was designed to address this major public health challenge through the lens of caregiver resilience and caregiver respite programming. While many caregivers report that they derive significant emotional and spiritual rewards from their caregiving role, many also experience physical and emotional problems directly related to the stress and demands of daily care. One way to alleviate these demands is the growing respite care field, providing services in a variety of settings for caregiver. Through qualitative analysis from face-to-face interviews with 33 family caregivers of individuals with dementia, several themes emerged describing the path to caregiver resilience which include family dynamics, isolation, financial struggles, seeking respite, and acceptance. While much research focuses on a caregiving burden perspective, the innovation of the present study is applying the resilience framework to outcomes from respite programming. PMID- 29424253 TI - Molecular hydrogen upregulates heat shock response and collagen biosynthesis, and downregulates cell cycles: meta-analyses of gene expression profiles. AB - Molecular hydrogen exerts its effect on multiple pathologies, including oxidative stress, inflammation, and apoptosis. However, its molecular mechanisms have not been fully elucidated. In order to explore the effects of molecular hydrogen, we meta-analysed gene expression profiles modulated by molecular hydrogen. We performed microarray analysis of the mouse liver with or without drinking hydrogen water. We also integrated two previously reported microarray datasets of the rat liver into meta-analyses. We used two categories of meta-analysis methods: the cross-platform method and the conventional meta-analysis method (Fisher's method). For each method, hydrogen-modulated pathways were analysed by (i) the hypergeometric test (HGT) in the class of over-representation analysis (ORA), (ii) the gene set enrichment analysis (GSEA) in the class of functional class scoring (FCS), and (iii) the signalling pathway impact analysis (SPIA), pathway regulation score (PRS), and others in the class of pathway topology-based approach (PTA). Pathways in the collagen biosynthesis and the heat-shock response were up-regulated according to (a) HGT with the cross-platform method, (b) GSEA with the cross-platform method, and (c) PRS with the cross-platform method. Pathways in cell cycles were down-regulated according to (a) HGT with the cross platform method, (b) GSEA with the cross-platform method, and (d) GSEA with the conventional meta-analysis method. Because the heat-shock response leads to up regulation of collagen biosynthesis and a transient arrest of cell cycles, induction of the heat-shock response is likely to be a primary event induced by molecular hydrogen in the liver of wild-type rodents. PMID- 29424254 TI - A case of B-cell precursor acute lymphoblastic leukemia with IL3-IGH rearrangement revealed by thromboembolism and marked eosinophilia. PMID- 29424255 TI - The therapeutic potential of CETP inhibitors: a patent review. AB - INTRODUCTION: Epidemiological studies have identified that high levels of low density lipoprotein-cholesterol (LDL-C) and low levels of high-density lipoprotein-cholesterol (HDL-C) are two independent causes of cardiovascular disease (CVD). Statins, niacin and fibrate are used for the treatment of CVD. However, some defects are shown in the treatment process. Thus, there is a demand for better treatment strategies that confer preferable efficacy with fewer side effects. Cholesteryl ester transfer protein (CETP) promotes the movement of CEs from HDL to LDL and VLDL in exchange for triglycerides (TGs). Areas covered: In this review, we reviewed the development and therapeutic applications of CETP inhibitors. A comprehensive review of the patents and pharmaceutical applications between 2009 and 2017 has been highlighted. Expert opinion: Recently, CETP inhibitors have attracted considerable interest in atherosclerosis-related disease. There are four drugs (torcetrapib, anacetrapib, evacetrapib and dalcetrapib) that have been clinically evaluated in phase III clinical trials and showed promising results in raising HDL-C levels, but there were suboptimal performances in reducing the risk of cardiovascular events with all the compounds. The correlation between plasma HDL-C levels and CVD incidence needs further verification. The timeline is still long for CETP inhibitors to emerge from the treatment of CVD. PMID- 29424256 TI - Effect of coenzyme Q10 on mitochondrial respiratory proteins in trigeminal neuralgia. AB - Trigeminal neuralgia (TN) is the neuropathic pain. Mitochondrial dysfunction, increased oxidative stress, and inflammation demonstrated in chronic pain. Carbamazepine (CBZ) is the first-line drug for TN, however, it is still insufficient. Coenzyme Q10 (CoQ10) has been used as the additional supplement for pain therapy. Nonetheless, mitochondrial respiratory proteins, oxidative stress, and inflammation in TN, and the add-on effects of CoQ10 on those defects have never been investigated. CBZ-treated TN-patients, naive TN-patients, and control subjects were included. CBZ-treated TN-patients were randomised into two subgroups, received either CoQ10 or placebo for 2 months. Pain levels were evaluated, and peripheral blood mononuclear cells were isolated to determine the oxidative stress, mitochondrial oxidative phosphorylation (OXPHOS), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), and cytokines including TNF-alpha, IL-1beta and IL-18 mRNA expression. Pain scales, oxidative stress, and OXPHOS levels were greater in naive TN-patients than control, whereas the cytokine profiles were unchanged. Although pain scales were lower in CBZ-treated TN-patients than in naive TN-patients, oxidative stress, OXPHOS, and cytokine expression profiles were not different. PGC-1alpha levels found to be increased in CBZ-treated TN patients when compared with the naive group. CoQ10 supplement in CBZ-treated TN patients reduced pain scale and oxidative stress and increased antioxidants levels when compared with placebo group. However, OXPHOS, PGC-1alpha, and cytokines were not different between groups. These findings suggest that increased oxidative stress could be potentially involved in the pathogenesis of TN. CoQ10 supplements can reduce oxidative stress, leading to more effective pain reduction in TN patients being treated with CBZ. PMID- 29424257 TI - Romosozumab treatment in postmenopausal women with osteoporosis: a meta-analysis of randomized controlled trials. AB - AIM: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the safety and efficacy of romosozumab in the treatment of postmenopausal osteoporosis. METHOD: A comprehensive literature review was performed of PubMed, EMBASE, Cochrane Controlled Trials Registry, and Web of Science for RCTs. Outcome measures were changes in lumbar spine, total hip and femoral neck bone mineral density (BMD), incidence of fractures and adverse events. Six trials were finally included. RESULTS: Romosozumab resulted in a significantly lower risk of new vertebral fracture (relative risk (RR) 0.37, 95% confidence interval (CI) 0.18-0.77, p = 0.005, n = 5371), non-vertebral fracture (RR 0.78, 95% CI 0.66-0.92, p < 0.0001, n = 5635) and hip fracture (RR 0.59, 95% CI 0.44-0.79, p = 0.0004, n = 5635) compared with other therapies. The BMD was significantly increased at the lumbar spine (weighted mean difference (WMD) 13.33, 95% CI 11.41-15.25, p < 0.00001, n = 198), total hip (WMD 5.09, 95% CI 3.81-6.38, p < 0.00001, n = 184) and femoral neck (WMD 4.70, 95% CI 3.50-5.90, p < 0.00001, n = 175) compared with placebo. There was no significant difference in the incidence of adverse events in patients with romosozumab compared to other therapies (RR 1.00, 95% CI 0.98-1.02). CONCLUSION: In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment resulted in a significantly lower risk of fracture. Romosozumab 210 mg monthly showed the largest gains in BMD, and was generally well tolerated. PMID- 29424258 TI - Anti-leukemic treatment-induced neurotoxicity in long-term survivors of childhood acute lymphoblastic leukemia: impact of reduced central nervous system radiotherapy and intermediate- to high-dose methotrexate. AB - The aim of the study was to evaluate the long-term neurodevelopmental consequences of currently applied acute lymphoblastic leukemia (ALL) therapy containing chemotherapy alone or combined with 12 Gy radiotherapy. Seventy-nine children aged 6.3-21.7 years diagnosed with ALL and treated according to ALL IC BFM 2002 have been studied. The control group consisted of 23 children newly diagnosed with ALL. We assessed subcortical gray matter volume using automatic MRI segmentation and cognitive performance to identify differences between three therapeutic schemes and patients prior to treatment. Irradiated patients had smaller selected subcortical volumes than those treated with chemotherapy alone and than the controls, while the chemotherapy group had similar volumes as the control one. In neurocognitive assessment, irradiated children performed worse in major domains than the control group. There were no significant results for patients after high dose chemotherapy without radiotherapy. There was a significant relationship between full scale IQ together with verbal learning and volumes of hippocampus, amygdala, and pallidum. In all children treated for ALL, both decreased volume of selected subcortical structures and cognitive impairment were observed, especially in children who were irradiated. PMID- 29424259 TI - Increased oxidative damage of RNA in liver injury caused by hepatitis B virus (HBV) infection. AB - To evaluate the urinary levels of 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) in liver injury patients with hepatitis B virus (HBV) infection and to explore the relationship between urinary 8-oxo-dGsn or 8-oxo-Gsn and degree of liver damage. We enrolled 138 liver injury patients with HBV infection and 169 age- and sex-matched healthy controls in this study. A sensitive and accurate isotope-diluted liquid chromatograph mass spectrometer/mass spectrometer (LC-MS/MS) method was used to measure the urinary levels of 8-oxo-Gsn and 8-oxo-dGsn. Simultaneously, pathological analysis of liver biopsy tissues was carried out, and immunohistochemistry was carried out for 8-oxo-Guo, 8-oxo-dGuo and MTH1 protein in some liver injury tissues. We analysed the correlation between the degrees of inflammation and fibrosis and levels of 8-oxo-Gsn and 8-oxo-dGsn. We also analysed the levels of urinary 8-oxo Gsn and 8-oxo-dGsn with clinical data of HBeAg, HBsAg, and HBV genotype and detected the levels of plasma aspartate aminotransferase, alanine aminotransferase (AST), platelet, alkaline phosphatase, prothrombin time (PT) and HBV DNA, and calculated the aspartate amino transferase-to-platelet ratio index (APRI) score. Nonparametric correlations were used to evaluate the correlation between 8-oxo-Gsn, 8-oxo-dGsn or APRI and various laboratory biochemical indicators. Results showed that the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn in patients with liver injury were significantly higher than those of healthy controls (both p < .001). Urinary 8-oxo-Gsn was significantly associated with AST, APRI and PT (p = .013, p = .026 and p = .049). The receiver operating characteristic curves of 8-oxo-Gsn were 0.696 (0.632-0.759) and 0.731 (0.672 0.790) for inflammatory activity and fibrosis, respectively. Patients with higher levels of urinary 8-oxo-Gsn are more likely to have a high degree of fibrosis and urinary 8-oxo-Gsn may have a great potential in assessing liver fibrosis. PMID- 29424260 TI - Psychosocial work characteristics and long-term sickness absence due to mental disorders. AB - BACKGROUND: Psychosocial work characteristics are associated with all-cause long term sickness absence (LTSA). AIMS: This study investigated whether psychosocial work characteristics such as higher workload, faster pace of work, less variety in work, lack of performance feedback, and lack of supervisor support are prospectively associated with higher LTSA due to mental disorders. METHODS: Cohort study including 4877 workers employed in the distribution and transport sector in The Netherlands. Psychosocial work characteristics were included in a logistic regression model estimating the odds ratios (OR) and 95% confidence intervals (CI) of mental LTSA during 2-year follow-up. The ability of the regression model to discriminate between workers with and without mental LTSA was investigated with the area under the receiver operating characteristic curve (AUC). RESULTS: Tow thousand seven hundred and eighty-two (57%) workers were included in the analysis; 73 (3%) had mental LTSA. Feedback about one's performance (OR = 0.82; 95% CI 0.70-0.96) was associated with mental LTSA. A prediction model including psychosocial work characteristics poorly discriminated (AUC = 0.65; 95% CI 0.56-0.74) between workers with and without mental LTSA. CONCLUSIONS: Feedback about one's performance is associated with lower rates of mental LTSA, but it is not useful to measure psychosocial work characteristics to identify workers at risk of mental LTSA. PMID- 29424261 TI - The breast tumor microenvironment: role in cancer development, progression and response to therapy. AB - INTRODUCTION: Numerous clinical and pre-clinical studies have provided ample evidence supporting that the tumor microenvironment plays a significant role during breast cancer development, progression and in determining the therapeutic response. Areas covered: This review focuses on the evolving concept of the microenvironment as the critical participant in each step of the multi-stage process of malignant progression. Currently, only a small number of molecules form part of routine molecular diagnostics in breast caner, but microenvironment derived biomarkers are potential additions to existing predictive and prognostic marker panels. The authors discuss the dependency of the breast tumor cells on different components of the microenvironment for their survival, dissemination, dormancy and establishment in secondary sites to form overt metastasis, as well as the potential as a therapeutic target to improve breast cancer outcome. Expert commentary: Despite the importance in the development of breast cancer, the contribution of the microenvironment is not considered in routine diagnostic testing or informing therapeutic decisions. However, introduction of immunotherapy will increasingly require patient selection based on the stromal composition of the primary breast tumor. Better understanding of the role of specific microenvironment-derived molecules is likely to inform personalized therapy, leading to improved patient outcome. PMID- 29424262 TI - Cardiovascular Physiology and Disease in Youth-The Year That Was 2017. AB - The value of exercise studies in children often resides in defining differences, which might make growing youngsters unique from their mature adult counterparts. Many such physiological and behavioral developmental differences have been identified, emphasizing that children are not, physiologically speaking, simply small adults. The following 2 studies published in the past year were chosen for their importance in contributing to the insights into previously unexplored areas. The first study addresses the influence of exercise on physiological variability, an emerging field that offers to provide important insights into the nature of such responses. The second study concerns the effects of altitude on physiological responses to exercise, an area of considerable importance for the health and physical performance of pediatric athletes, climbers, and residents at high altitude. These studies exemplify the genre of investigations that are essential for advancing our understanding of the link between exercise with physical performance and the well-being of growing children and adolescents. PMID- 29424263 TI - Intraoperative Transesophageal Echocardiogram During Orthotopic Liver Transplantation: TEE to the Rescue! AB - Supported by a growing number of studies and case reports in the literature, perioperative use of TEE in non-cardiac cases has significantly increased the past two decades. The utility of TEE in monitoring hemodynamic, and diagnosing causes of hypotension refractory to conventional therapy, have made it an almost indispensible tool during major surgeries, such liver transplantation. Despite this fact, compared to the adult population, there is a lack of an equivalent amount of literature on the perioperative use of TEE in pediatric cases. In our case we report the utilization of TEE during a pediatric liver transplant, to diagnose a post reperfusion suprahepatic anastomosis stricture. In this case, the cooperation of the anesthesia, the surgical, and the cardiology teams, helped in resolving the case, allowing a positive outcome for the patient. To our knowledge, this is the first case describing the use of TEE during a pediatric liver transplant. PMID- 29424264 TI - Youth Resistance Training: The Good, the Bad, and the Ugly-The Year That Was 2017. AB - The good news is that a growing body of evidence recognizes resistance training as foundational to long-term physical development. Original research and reviews published in 2017 conclude that early exposure to developmentally appropriate resistance training can improve markers of health, increase muscular fitness, enhance physical literacy, and reduce the risk of injury in young athletes. Although the papers discussed in the commentary add to our understanding of the pleiotropic benefits of youth resistance training, they also raise concerns. As measures of muscular strength and power have been found to track from childhood to adulthood, the bad news is that youth with low levels of muscular fitness tend to become weak adults who are at increased risk for functional limitations and adverse health outcomes. Furthermore, global participation in youth resistance training is falling far short of public health recommendations, and these ugly trends will likely impact the health and well-being of future generations. A change in current attitudes and common practices is urgently needed to educate parents, practitioners, and clinicians about the potential benefits of resistance training for all children and adolescents, not only young athletes. PMID- 29424265 TI - Neural Oscillations Orchestrate Multisensory Processing. AB - At any given moment, we receive input through our different sensory systems, and this information needs to be processed and integrated. Multisensory processing requires the coordinated activity of distinct cortical areas. Key mechanisms implicated in these processes include local neural oscillations and functional connectivity between distant cortical areas. Evidence is now emerging that neural oscillations in distinct frequency bands reflect different mechanisms of multisensory processing. Moreover, studies suggest that aberrant neural oscillations contribute to multisensory processing deficits in clinical populations, such as schizophrenia. In this article, we review recent literature on the neural mechanisms underlying multisensory processing, focusing on neural oscillations. We derive a framework that summarizes findings on (1) stimulus driven multisensory processing, (2) the influence of top-down information on multisensory processing, and (3) the role of predictions for the formation of multisensory perception. We propose that different frequency band oscillations subserve complementary mechanisms of multisensory processing. These processes can act in parallel and are essential for multisensory processing. PMID- 29424266 TI - Silencing of lncRNA ZFAS1 inhibits malignancies by blocking Wnt/beta-catenin signaling in gastric cancer cells. AB - Gastric cancer is a common malignancy with high mortality. Long noncoding RNA (lncRNA) zinc finger antisense (ZFAS)1 is upregulated in gastric cancer specimens compared with the para-carcinoma tissues. The silencing of ZFAS1 inhibited the growth, proliferation, cell cycle progress, migration, invasion and epithelial mesenchymal transition (EMT), and enhanced the sensitivity to cis-platinum or paclitaxel in SGC7901 cells, as evidenced by the expression changes of proliferating cell nuclear antigen, Cyclin D1, Cyclin E, Cyclin B1, E-cadherin, N cadherin, vimentin, matrix metalloproteinase (MMP)-2 and MMP-14. The ZFAS1 also activated the Wnt/beta-catenin signaling. Subsequently, the ZFAS1 knockdown induced the inhibition of migration, invasion, EMT and resistance to chemotherapeutic reagens was reversed by the overexpression of beta-catenin. In summary, the silencing of ZFAS1 inhibited the growth, proliferation, cell cycle progress, migration, invasion, EMT and chemotherapeutic tolerance by blocking the Wnt/beta-catenin signaling in gastric cancer cells. PMID- 29424267 TI - Metabolism and Exercise During Youth-The Year That Was 2017. AB - Two publications were selected because they are excellent representations of studies examining different ends of the exercise-sedentary behavior continuum in young people. The first study is an acute response study with 13 mixed-sex, mid to late adolescents presenting complete data from 4 different randomized experimental crossover conditions for analyses. Continuous glucose monitoring showed that interrupting prolonged continuous sitting with body-weight resistance exercises reduced the postprandial glucose concentration compared with a time matched uninterrupted period of sitting. Furthermore, the effects of the breaks in sitting time were independent of the energy content of the standardized meals, but variations in the area under the glucose time curves expression were important. The second study adopted a chronic 12-week exercise training intervention design with a large sample of obese children and adolescents who were allocated randomly to high-intensity interval training (HIIT), moderate intensity continuous training, or nutritional advice groups. HIIT was the most efficacious for improving cardiorespiratory fitness compared with the other interventions; however, cardiometabolic biomarkers and visceral/subcutaneous adipose tissue did not change meaningfully in any group over the 12 weeks. Attrition rates from both HIIT and moderate-intensity continuous training groups reduce the validity of the exercise training comparison, yet this still provides a solid platform for future research comparisons using HIIT in young people. PMID- 29424268 TI - Bacterial quorum sensing in symbiotic and pathogenic relationships with hosts. AB - Gram-negative bacteria communicate with each other by producing and sensing diffusible signaling molecules. This mechanism is called quorum sensing (QS) and regulates many bacterial activities from gene expression to symbiotic/pathogenic interactions with hosts. Therefore, the elucidation and control of bacterial QS systems have been attracted increasing attention over the past two decades. The most common QS signals in Gram-negative bacteria are N-acyl homoserine lactones (AHLs). There are also bacteria that employ different QS systems, for example, the plant pathogen Ralstonia solanacearum utilizes 3-hydroxy fatty acid methyl esters as its QS signals. The QS system found in the endosymbiotic bacterium associated with the fungus Mortierella alpina, the development of an affinity pull-down method for AHL synthases, and the elucidation of a unique QS circuit in R. solanacearum are discussed herein. PMID- 29424269 TI - Comparative effects of ethylene inhibitors on Agrobacterium-mediated transformation of drought-tolerant wild watermelon. AB - Ethylene (C2H4), a phytohormone that is produced in response to both abiotic and biotic stresses, is an important factor influencing the efficiency of Agrobacterium-mediated transformation. In this study, effects of various ethylene inhibitors on the efficiency of Agrobacterium-mediated genetic transformation in drought-tolerant wild watermelon was comparatively examined. Consequently, in comparison to the application of chemical inhibitors such as AgNO3 and aminoethoxyvinylglycine (AVG), lower ethylene level was observed when the infecting Agrobacterium contained a gene for 1-aminocyclopropane-carboxylic acid (ACC) deaminase (acdS), which cleaves ethylene precursor ACC into alpha ketobutyrate and ammonia. GUS histochemical and spectrophotometric enzyme assays showed that acdS was more effective in enhancing gene transfer than the chemical ethylene inhibitors. Efficiency of transgenic shoots formation was higher in acdS and AVG-treated explants. These observations demonstrated that controlling the ethylene level during co-cultivation and shoot formation, particularly using the acdS-harboring Agrobacterium, is advantageous for enhancing the transformation efficiency in this plant. PMID- 29424271 TI - Inhibition of spinal MAPKs by scorpion venom peptide BmK AGAP produces a sensory specific analgesic effect. AB - Background Several studies have shown that scorpion venom peptide BmK AGAP has an analgesic activity. Our previous study also demonstrated that intraplantar injection of BmK AGAP ameliorates formalin-induced spontaneous nociceptive behavior. However, the effect of intrathecal injection of BmK AGAP on nociceptive processing is poorly understood. Methods We investigated the effects of intrathecal injection of BmK AGAP on spinal nociceptive processing induced by chronic constrictive injury or formalin. Thermal hyperalgesia and mechanical allodynia were measured using radiant heat and the von Frey filaments test. Formalin-induced spontaneous nociceptive behavior was also investigated. C-Fos expression was assessed by immunohistochemistry. Phosphorylated mitogen-activated protein kinase (p-MAPK) expression was monitored by Western blot assay. Results Intrathecal injection of BmK AGAP reduced chronic constrictive injury-induced neuropathic pain behavior and pain from formalin-induced inflammation, accompanied by decreased expression of spinal p-MAPKs and c-Fos protein. The results of combining low doses of different MAPK inhibitor (U0126, SP600125, or SB203580; 0.1 ug for each inhibitor) with a low dose of BmK AGAP (0.2 ug) suggested that BmK AGAP could potentiate the effects of MAPK inhibitors on inflammation-associated pain. Conclusion Our results demonstrate that intrathecal injection of BmK AGAP produces a sensory-specific analgesic effect via a p-MAPK dependent mechanism. PMID- 29424273 TI - Neuromuscular Physiology, Exercise, and Training During Youth-The Year That Was 2017. AB - The pressure for children to excel and succeed in sport continues to mount. Although resistance training for youth was in disfavor by many organizations even into the early 21st century, children's training programs are more closely resembling the volume and intensity of adult programs. The physiological maturation of adolescent youth may impact their response to advanced training programs. Furthermore, the pressure to specialize in specific sports rather than engage in a variety of sporting activities may affect not only training responses but also injury incidence. The highlighted articles first illustrate the training specific responses of prepeak and postpeak height velocity stage youth with more specific training stimuli needed for the postpeak height velocity stage youth. Second, individual sports tend to promote earlier and greater specialization compared with team sports, which tend to result in a higher proportion of overuse injuries. Based on the findings of these 2 studies, the planning and implementation of high-intensity training for youth, such as plyometrics, should take into consideration the physical maturation of the child and that the prevention of overuse injuries would benefit from a more varied participation in sports and activities. PMID- 29424272 TI - Lower hippocampal subfields volume in relation to anxiety in medication-overuse headache. AB - Background Hippocampus (HIP) was an important limbic structure, and concurrent emotion disorders may occur in medication-overuse headache patients. The aim of this study is to investigate altered HIP and HIP subfields volume in relation with the anxiety in medication-overuse headache patients using a state-of-the-art hippocampal segment method. Results The current study presented that a significant lower HIP and HIP subfields volume were identified in medication overuse headache compared with that in normal controls except right HIP tail, bilateral parasubiculums, and HIP fissure. The left HIP and right subiculum presented negative correlation with headache variables, and the right subiculum, Cornu Ammonis 4, granule cell layer of dentate gyrus, bilateral Cornu Ammonis 1, molecular layer, and whole HIP presented negative correlation with Hamilton Anxiety Scale score, which were further confirmed by the linear regression analysis with the exclusion of psychological variables and headache variables, respectively. Conclusions The lower HIP and HIP subfields volume were identified in medication-overuse headache patients, and negatively related with anxiety condition. The potential mechanism for the comorbidity medication-overuse headache and anxiety might be interpreted as the reciprocal causation relationship and co-occurrence relationship. PMID- 29424270 TI - TRPV1 gain-of-function mutation impairs pain and itch sensations in mice. AB - Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which can detect various noxious stimuli that cause pain, inflammation, hyperalgesia, and itch. TRPV1 knock-out mice show deficiency in nociception, but the in vivo effects of persistent activation of TRPV1 are not completely understood. Here, we generated TRPV1 knock-in mice with a G564S mutation. In the heterologous expression system, an electrophysiological study showed that the G564S mutation in mouse TRPV1 caused increased basal current and a leftward shift of voltage dependence. Intriguingly, using behavioral analysis, we found that knock-in mice showed a thermosensory defect, impaired inflammatory thermal pain, and capsaicin sensitivity. We also demonstrated an attenuated behavioral response to the pruritic agent histamine in the knock-in mice. Indeed, calcium imaging together with electrophysiology showed that the overactive mutant had decreased capsaicin sensitivity. Western blot analysis revealed that the G564S mutant reduced TRPV1 phosphorylation and cell membrane trafficking. Together, we have generated a mouse model with a gain-of-function mutation in Trpv1 gene and demonstrated that the pain and histamine-dependent itch sensations in these mice are impaired due to a decreased phosphorylation level and reduced membrane localization of TRPV1. PMID- 29424274 TI - Two Strategies for Qualitative Content Analysis: An Intramethod Approach to Triangulation. AB - The overarching aim of qualitative research is to gain an understanding of certain social phenomena. Qualitative research involves the studied use and collection of empirical materials, all to describe moments and meanings in individuals' lives. Data derived from these various materials require a form of analysis of the content, focusing on written or spoken language as communication, to provide context and understanding of the message. Qualitative research often involves the collection of data through extensive interviews, note taking, and tape recording. These methods are time- and labor-intensive. With the advances in computerized text analysis software, the practice of combining methods to analyze qualitative data can assist the researcher in making large data sets more manageable and enhance the trustworthiness of the results. This article will describe a novel process of combining two methods of qualitative data analysis, or Intramethod triangulation, as a means to provide a deeper analysis of text. PMID- 29424276 TI - Growth, Maturation, and Exercise During Youth-The Year That Was 2017. AB - For "The Year That Was 2017," I have selected 3 papers in the area of growth, maturation, and exercise during youth. The first paper has been chosen because it provides for the first time the relative age, maturation, and anthropometric biases on position allocation in elite youth soccer players participating in talent identification programs in professional soccer league. Specific anthropometrical attributes characterized playing positions with a bias toward these athletes who are comparatively tall and heavy for their age already in younger ages, whereas position-specific physical attributes do not become apparent until the later stages of talent development. The second paper was selected because it provides a unique perspective on the contributions of different types of sport activities to the development of soccer performance. This paper demonstrated that early specialization and concentration on one sport only during growth is not beneficial in elite youth soccer. In contrast, variable early sporting experience, and not different physiological parameters, facilitates subsequent soccer performance development. The third paper provided some evidence that the consequence of physical activity during adolescence can be far reaching as physical activity might not only predict academic success during compulsory basic education but also boost educational outcomes in adulthood. PMID- 29424275 TI - Sensing and regulation of cell volume - we know so much and yet understand so little: TRPV4 as a sensor of volume changes but possibly without a volume regulatory role? AB - Cellular volume changes lead to initiation of cell volume regulatory events, the molecular identity of which remains unresolved. We here discuss experimental challenges associated with investigation of volume regulation during application of large, non-physiological osmotic gradients. The TRPV4 ion channel responds to volume increase irrespectively of the molecular mechanism underlying cell swelling, and is thus considered a sensor of volume changes. Evidence pointing towards the involvement of TRPV4 in subsequent volume regulatory mechanisms is intriguing, yet far from conclusive. We here present an experimental setting with astrocytic cell swelling in the absence of externally applied osmotic gradients, and the lack of evidence for involvement of TRPV4 in this regulatory volume response. Our aim with these new data and the preceding discussion is to stimulate further experimental effort in this area of research to clarify the role of TRPV4 and other channels and transporters in regulatory volume responses. PMID- 29424277 TI - Integrating a Patient-Controlled Admission Program Into Mental Health Hospital Service: A Multicenter Grounded Theory Study. AB - Patient-controlled admissions (PCAs) enable mental health patients by means of a contract to initiate an admission at a mental health hospital unit without using traditional admission procedures. This study was part of a 3-year Danish multicenter project, and we explored how mental health professionals experienced and managed the implementation of a PCA program. The methodology was grounded theory and the sample included 26 participants. We performed a constant comparative analysis to explore the concerns, attitudes, and strategies of mental health professionals. We developed a model of how the mental health professionals strived to integrate PCA into clinical practice. The process was motivated by the idea of establishing a partnership with patients and involved two interrelated strategies to manage (a) the patient-related duties and (b) the admission contracts. The professionals moved from a phase of professional discomfort to a phase of professional awareness, and ended up with professional comprehension. PMID- 29424278 TI - Culture as a Double-Edged Sword: The Posttraumatic Experience of Indigenous Ethnic Minority Veterans. AB - The applicability of Western concepts regarding the treatment of trauma in soldiers from indigenous ethnic minority backgrounds has scarcely been researched. This study explored the subjective meaning of living with chronic posttraumatic stress disorder (PTSD) among indigenous Bedouin veterans of the Israel Defense Forces (IDF), who are of Arab ethnicity and Muslim faith. In depth, semistructured qualitative interviews were conducted with 10 Bedouin veterans suffering from PTSD and three Bedouin mental health clinicians working with this population. Two themes emerged: "I wanted to be like everyone else," referring to participants' experiences during their military service, and "Fluctuating between belonging and abandonment," referring to veterans' experiences of living with mental health problems in a traditional minority community. These findings highlight the importance of conducting a comprehensive inquiry into the complex cultural and social backgrounds of indigenous minority veterans suffering from PTSD, and the interplay between the conflicted identities and multiple "realities" they experience. PMID- 29424279 TI - Commentary on the Assessment and Interpretation of Pediatric Aerobic Fitness-The Year That Was 2017. AB - Three papers, which between them contribute to the current debate on the assessment and interpretation of pediatric aerobic fitness, were selected for commentary. The first paper (Children. 2017; 4:6; doi: 10.3390/children4010006 ) highlights the merits of clinical exercise testing and advocates the advancement of pediatric exercise testing through a rationale founded on demonstrated prognostic value of data obtained. It notes the lack of well-accepted definitions of exercise outcome variables in children and promotes the case for data harmonization across laboratories. The second paper (J Appl Physiol. 2017; 122: 997-1002) argues persuasively that the acceptance of peak oxygen uptake (peak [Formula: see text]) at the termination of an exercise test to voluntary exhaustion as a surrogate for a "true" maximal value (ie, [Formula: see text]) is no longer tolerable. The authors present a compelling case for the adoption of a follow-up verification test to unambiguously validate the achievement of [Formula: see text]. The third paper (Br J Sports Med. 2017; 1-10, doi: 10.1136/bjsports-2017-097982 ) compiles large, previously published datasets to provide a review of temporal trends in 20-m shuttle run test scores. The authors assert that temporal trends in 20-m shuttle run test performance provide meaningful insight into trends in population health. The commentary stresses the importance of scientific rigor in pediatric exercise testing, emphasizes the use of precise definitions when describing health-related variables, and cautions against the misuse of exercise outcome measures in recommendations relating to or impacting on young people's health and well-being. PMID- 29424281 TI - Induced phenylamide accumulation in response to pathogen infection and hormone treatment in rice (Oryza sativa). AB - Rice plants accumulate various specialized metabolites, including phenylamides, in response to pathogen attack. We prepared 25 phenylamides, and developed a method of analyzing them by multiple reaction monitoring with liquid chromatography coupled with tandem mass spectrometry. We analyzed phenylamides in rice leaves infected with Cochliobolus miyabeanus and Xanthomonas oryzae. The phenylamides induced included benzoyltryptamine, cinnamoyl-, p-coumaroyl-, feruloyl-, and benzoylserotonins, cinnamoyl and benzoyltyramines, feruloylagmatine, and feruloylputrescine. Some of the phenylamides exhibited antimicrobial activity against C. miyabeanus and X. oryzae, indicating that they are phytoalexins. Treatment with jasmonic acid, salicylic acid, 6 benzylaminopurine, and ethephone also induced phenylamide accumulation. The compositions of the induced amides varied depending on the plant hormone used, and cinnamoyltryptamine, cinnamoylserotonin, and cinnamoyltyramine were not induced by the plant hormones. These findings suggest that several plant hormones and additional factors are involved in phenylamide accumulation in response to pathogen infection in rice. PMID- 29424282 TI - Growth and differential salinity reduction between Portulaca oleracea and Eichhornia crassipes in experimental hydroponic units. AB - We evaluated the salinity reduction of the experimental saline solutions through ion uptake capacity of two plant species, purslane (PU) (Portulaca oleraceae) and water hyacinth (WH) (Eichhornia crassipes). These species were grown in experimental hydroponic units simulating a floating system. The hydroponic system contained treatments with three nutrient solutions identified as A1, A2, and A3 composed of fixed concentrations of macro and micronutrients to which three different concentrations of sodium chloride had been added. After the experimental period, physicochemical and volume changes in the saline nutrient solutions were evaluated. The relative growth rate results were similar for both plant species, but with lower consumption of hydroponic nutrient solutions by PU. Despite higher solution volume loss, regardless of the nutrient solution applied, WH had greater weekly estimated potential of reduction of macronutrients (calcium and magnesium; >50%); however, PU showed the best weekly potential reduction of sodium (36%) with solution A2. Therefore, both plants present potential to be used for salinity reduction in the natural conditions. PMID- 29424280 TI - The peel of Citrus kawachiensis (kawachi bankan) ameliorates microglial activation, tau hyper-phosphorylation, and suppression of neurogenesis in the hippocampus of senescence-accelerated mice. AB - We previously reported that the dried peel powder of Citrus kawachiensis, one of the citrus products of Ehime, Japan, exerted anti-inflammatory effects in the brain of a lipopolysaccharide-injected systemic inflammation animal model. Inflammation is one of the main mechanisms underlying aging in the brain; therefore, we herein evaluated the anti-inflammatory and other effects of the dried peel powder of C. kawachiensis in the senescence-accelerated mouse-prone 8 (SAMP8) model. The C. kawachiensis treatment inhibited microglial activation in the hippocampus, the hyper-phosphorylation of tau at 231 of threonine in hippocampal neurons, and ameliorated the suppression of neurogenesis in the dentate gyrus of the hippocampus. These results suggest that the dried peel powder of C. kawachiensis exert anti-inflammatory and neuroprotective effects. PMID- 29424284 TI - Puncturing the pipeline: Do technology companies alienate women in recruiting sessions? AB - A 'chilly' environment limits women's advancement through the educational pipeline leading to jobs in science and technology. However, we know relatively little about the environment women encounter after making it through the educational pipeline. Do technology companies create environments that may dampen women's interest at the juncture when they are launching their careers? Using original observational data from 84 recruiting sessions hosted by technology companies at a prominent university on the US West Coast, we find that company representatives often engage in behaviors that are known to create a chilly environment for women. Through gender-imbalanced presenter roles, geek culture references, overt use of gender stereotypes, and other gendered speech and actions, representatives may puncture the pipeline, lessening the interest of women at the point of recruitment into technology careers. PMID- 29424285 TI - Shifting syndromes: Sex chromosome variations and intersex classifications. AB - The 2006 'Consensus statement on management of intersex disorders' recommended moving to a new classification of intersex variations, framed in terms of 'disorders of sex development' or DSD. Part of the rationale for this change was to move away from associations with gender, and to increase clarity by grounding the classification system in genetics. While the medical community has largely accepted the move, some individuals from intersex activist communities have condemned it. In addition, people both inside and outside the medical community have disagreed about what should be covered by the classification system, in particular whether sex chromosome variations and the related diagnoses of Turner and Klinefelter's syndromes should be included. This article explores initial descriptions of Turner and Klinefelter's syndromes and their subsequent inclusion in intersex classifications, which were increasingly grounded in scientific understandings of sex chromosomes that emerged in the 1950s. The article questions the current drive to stabilize and 'sort out' intersex classifications through a grounding in genetics. Alternative social and historical definitions of intersex - such as those proposed by the intersex activists - have the potential to do more justice to the lived experience of those affected by such classifications and their consequences. PMID- 29424287 TI - Calcium alginate-based antimicrobial film dressings for potential healing of infected foot ulcers. AB - AIM: Diabetic foot ulcers are susceptible to infection and nonmedicated dressings are ineffective because they have no antimicrobial activity. This study aimed to develop antimicrobial films to deliver ciprofloxacin for treating bacterial infection. Results/methodology: Ciprofloxacin-loaded calcium alginate films were characterized for porosity, swelling, equilibrium water content, water absorption, water vapor transmission, evaporative water loss, moisture content, mechanical strength, adhesion, IR spectroscopy, scanning electron microscopy, x ray diffraction, drug release, cytotoxicity and antimicrobial activity against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Films were transparent, flexible, uniform, with ideal moisture handling, maximum drug release within 90 min, killing bacteria within 24 h and highly biocompatible with human keratinocyte cells. CONCLUSION: The results confirmed successful design of biocompatible dressings effective against Gram-positive and Gram-negative bacteria. [Formula: see text]. PMID- 29424288 TI - The Ellipta(r) in asthma and chronic obstructive pulmonary disease: device characteristics and patient acceptability. AB - Asthma and chronic obstructive pulmonary disease are primarily treated with inhaled medication, but delivery of that medication to its site of action is problematic; patients' ability to use inhalers will affect therapeutic response. Multiple inhaler devices are available but they are variably easy to use with consequent effects on compliance, intentional or otherwise. The Ellipta(r) device is a novel blister strip dry powder inhaler with medium resistance and a consistent delivered dose across a range of inspiratory flow rates. The Ellipta has proven easy to use and is preferred by patients across several evaluations and compared with other inhaler devices. The Ellipta is used to administer multiple inhaled medications, all in single daily-dose regimens, making it ideal for patients who struggle with complex inhaled therapy regimens. PMID- 29424289 TI - Influences of the vehicle in the spreading and release of betamethasone. AB - AIM: We compared the performances of two different commercial products both based on betamethasone and an antibiotic but using different pharmaceutical vehicles: a polymer and lipid-enriched cream and a conventional oil-in-water emulsion. METHODOLOGY: Evaluation was conducted on a reconstructed human epidermis model. Moreover, skin barrier properties and cutaneous hydration of the two vehicles were evaluated on 20 human healthy volunteers. RESULTS: Overall, the polymer and lipid-enriched formulation works as a film-forming product that retains the therapeutic agent for a long time, ensuring its penetration and absorption through the skin, and promoting skin hydration. CONCLUSION: The above characteristics are useful in the clinical setting, especially in the context of eczematous diseases with a strong xerotic component. PMID- 29424290 TI - Industry update: what is new in the field of therapeutic delivery? AB - The present industry update covers the period 1-30 November 2017. Sources of information include company press releases, regulatory and patent agencies' notices, scientific literature and various news websites. A number of companies reported positive clinical trial results for therapeutic candidates enabled by different delivery strategies including Vascular Therapies, Adapt and Altemia. November also saw the announcement of some significant collaborations and acquisitions; Cerenis Therapeutics acquired Lypro Biosciences, which gives them access to a proprietary drug delivery nanotechnology platform, NanoDisk(r), and Takeda announced a collaboration with Portal Instruments to develop a needle-free delivery device for its biological therapeutics. From a patenting perspective, Allergan's strategy of transferring the rights of some of their patents to Saint Regis Mohawk Tribe has drawn scrutiny (and criticism) from US Senators. PMID- 29424291 TI - Hydrogel formulations for biologicals: current spotlight from a commercial perspective. AB - Hydrogels are, from a commercial perspective especially because of their ease of production, attractive sustained-release systems for high potent immunoglobulins with short circulation half-lives. Hydrogel formulations can reduce the dosing frequency while maintaining therapeutically relevant drug concentrations locally as well as systemically. However, hydrogels have only limited loading capacities and release hydrophilic immunoglobulins typically within hours or days, whereas weeks or months would be more preferable. Despite an evident medical need, the call for novel depot formulations seems to go unheard. This special report explores sought-after hydrogel properties, discusses arguments for using established versus novel excipients and provides selected examples for hydrogel formulations of biologicals that have proceeded into clinical development. PMID- 29424292 TI - Cross-linked hyaluronan films loaded with acetazolamide-cyclodextrin triethanolamine complexes for glaucoma treatment. AB - AIM: This work aimed to design and characterize cross-linked hyaluronic acid itaconic acid films loaded with acetazolamide-hydroxypropyl beta cyclodextrin triethanolamine complexes. MATERIALS & METHODS: Films were cross-linked with itaconic acid and poly(ethyleneglycol)-diglycidylether. Biopharmaceutical properties were assessed by evaluating in vitro drug release rate, biocompatibility in a human corneal epithelial cell line, bioadhesiveness with pig gastric mucin, in vivo bioadhesion and efficacy. RESULTS: Showed good mechanical properties and oxygen permeability. Proliferation rate of corneal cells was affected by highest acetazolamide concentration. Bioadhesive interaction exhibited a water movement from pig mucin to the film; in vivo experiments showed strong bioadhesion for 8 h and hypotensive effect for almost 20 h. CONCLUSION: Experimental set showed promising performance and encouraged future studies to optimize formulation. [Formula: see text]. PMID- 29424297 TI - Use of immunotherapy to treat metastatic breast cancer. AB - This article reviews the principal attempts of immune-modulation or immune therapy in metastatic breast cancer. It considers their rationale and reports on results from the relevant key clinical trials. Immune-modulatory or immune stimulating cytokines used alone or combined with conventional therapies is among the principal approaches of immune manipulation in breast cancer. As this issue was recently reviewed by us, the aim of the current article is to discuss our updated and unpublished data on this topic. Overall survival in luminal (28 patients) and non-luminal (9 patients) molecular subtypes is 91 and 59 months respectively that is about two and half or three times longer than expected. Thereafter, we focus on monoclonal antibodies (mAb) based-therapies including novel strategies to overcome resistance to anti-HER2 mAb. The main vaccine platforms in different molecular subtypes and immune therapies in triple negative metastatic breast cancer (m-TNBC) are discussed in the last sections. Some phase III investigations have already changed the current clinical practice. In fact, pertuzumab plus trastuzumab and docetaxel is the recommended first line regimen in HER2 positive locally recurrent or metastatic breast cancer and bevacizumab plus paclitaxel or docetaxel is a reasonable option for m-TNBC. In some other observational or phase I/II studies on first-line trastuzumab plus chemotherapy and hormonal therapy and in that on HER2 peptide/protein vaccines promising although preliminary findings have been reported to be further validated. In the remaining studies, results were disappointing. In the future, finding new predictive biomarkers and exploring more suitable synergizing combinations, time and dose-dependent-scheduled sequences of currently and further investigated immunological approaches are main challenges. PMID- 29424295 TI - Chronic wasting disease management in ranched elk using rectal biopsy testing. AB - Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) affecting members of the cervid species, and is one of the few TSEs with an expanding geographic range. Diagnostic limitations, efficient transmission, and the movement of infected animals are important contributing factors in the ongoing spread of disease. Managing CWD in affected populations has proven difficult, relying on population reduction in the case of wild deer and elk, or quarantine and depopulation in farmed cervids. In the present study, we evaluated the effectiveness of managing endemic CWD in a closed elk herd using antemortem sampling combined with both conventional and experimental diagnostic testing, and selective, targeted culling of infected animals. We hypothesized that the real time quaking-induced conversion (RT-QuIC) assay, a developing amplification assay, would offer greater detection capabilities over immunohistochemistry (IHC) in the identification of infected animals using recto-anal mucosa associated lymphoid tissue (RAMALT). We further sought to develop a better understanding of CWD epidemiology in elk with various PRNP alleles, and predicted that CWD prevalence would decrease with targeted culling. We found that RT-QuIC identified significantly more CWD-positive animals than IHC using RAMALT tissues (121 vs. 86, respectively, out of 553 unique animals), and that longstanding disease presence was associated with an increasing frequency of less susceptible PRNP alleles. Prevalence of CWD increased significantly over the first two years of the study, implying that refinements in our management strategy are necessary to reduce the prevalence of CWD in this herd. PMID- 29424298 TI - Flavonoids in the Treatment of Alzheimer's and Other Neurodegenerative Diseases. AB - Flavonoids are phytochemicals present in almost all terrestrial plants and, as a consequence, in plant-based foods, and thus consumed by humans through diet. Recent evidences suggest that several flavonoids have positive effects against dementia and Alzheimer's disease, reversing age-related declines in neurocognitive performances. In this review, we provide a general classification of natural and synthetic flavonoids, a description of their physico-chemical properties, in particular their redox properties and stability, and an extensive overview about their biological activities and structure-activity relationship in the field of neurodegenerative diseases. In addition, a section will be dedicated to the synthetic strategies for the preparation of bioactive derivatives. This information will be essential for the design and development of new drugs that can improve brain functions. PMID- 29424299 TI - Medicinal Chemistry Updates on Bacterial Efflux Pump Modulators. AB - Antibiotic resistance is one of the most pressing health issues of our days. It can arise due to a multiplicity of factors, such as target modification, decrease in the drug uptake, changes in the metabolic pathways and activation of efflux pumps. The overexpression of efflux pumps is responsible for the extrusion of drugs, making antibiotic therapy fail, as the quantity of intracellular antibiotic is not enough to provide the desired therapeutic effect. Efflux pumps can be included in five families according to their composition, nature of substrates, energy source, and number of transmembrane spanning regions. The ABC superfamily are mainly found in Gram-positive bacteria, use ATP as an energy source, and only a limited number of ABC pumps confer multidrug resistance (MDR). On the other hand, the MFS family, most present in Gram-positive bacteria, and the RND family, characteristic of Gram-negative bacteria, are the most associated with antibiotic resistance. A wide variety of inhibitors have been disclosed for both families, from either natural or synthetic sources, or even drugs that are currently in therapy for other diseases. The other two families are the SMR, which are the smallest drug efflux proteins known, and the MATE family, whose pumps can also resort to the sodium gradient as an energy source. In this review, it is intended to present a comprehensive review of the classes of efflux pump inhibitors from the various sources, highlighting their structure-activity relationships, which can be useful for medicinal chemists in the pursuit of novel efflux pump inhibitors. PMID- 29424300 TI - Targeting the Folate Receptor: Improving Efficacy in Inorganic Medicinal Chemistry. AB - The discovery of the high-affinity, high-specificity folate receptor in mamalian kidney cells, coupled with the ability of folate to enter cells by folate receptor-mediated endocytosis and the subsequent elucidation of the folate receptor's overexpression in specific cancer cell types; heralded the arrival of the area of chemotherapeutic folate targeting. The application of purely organic folate-based small-molecule drug conjugates that selectively target the folate receptor, which is over expressed in several diseases such as cancer, is well established. The application of inorganic folate-targeted drugs offers significant potential to expand and enhance this therapeutic approach. From the data made available to date, it is apparent that this aspect of inorganic medicinal chemistry is in its youth but has the capability to contribute greatly to cancer research, both in therapy and diagnosis. The union of folate-receptor targeting and inorganic medicine may also lead to the development of treatments for disorders such as chronic-inflammation, tuberculosis, neurodegenerative disease and leishmaniasis. In this review, we summarize what is known about the coordination chemistry of folic acid and the therapeutic potential of such complexes. We also describe approaches adopted to conjugate platinum drugs to folate- or folate-carrier- systems and their prospective ability to overcome problems associated with unwanted side-effects and resistance by improving their delivery and/or selectivity. The literature pertaining to non-platinum metal complex conjugates with folic acid is also reviewed revealing that this is an area that offers significant potential to develop targeted therapeutic approaches in areas such as chemotherapy and molecular imaging for diagnostics. PMID- 29424301 TI - Novel therapeutic approaches in Rheumatoid Arthritis: Role of Janus Kinases Inhibitors. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis. Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug free remission is nowadays a realistic goal in the treatment of RA. However, despite the availability of multiple therapeutic options, up to 40% of patients do not respond to current treatments, including biologics. Small-molecule therapies offer an alternative to biological therapies for the treatment of inflammatory diseases. In the past 5 years, a number of small-molecule compounds targeting Janus kinases (JAKs) have been developed. Since JAKs are essential for cell signaling in immune cells, in particular controlling the response to many cytokines, their inhibitors quickly became a promising class of oral therapeutics that proved effective in the treatment of RA. Tofacitinib is the first Janus kinase (JAK) inhibitor approved for the treatment of RA, followed more recently by baricitinib. Several other JAK inhibitors, are currently being tested in phase II and III trials for the treatment of a different autoimmune diseases. Most of these compounds exhibit an overall acceptable safety profile similar to that of biologic agents, with infections being the most frequent adverse event. Apart from tofacitinib, safety data on other JAK inhibitors are still limited. Long term follow up and further research are needed to evaluate the general safety profile and the global risk of malignancy of these small molecules, although no clear association with malignancy has been reported to date. Here, we will review the main characteristics of JAK inhibitors, including details on their molecular targets and on the clinical evidences obtained so far in the treatment of RA. PMID- 29424302 TI - The Role of 5-HT1A Receptor in Cancer as a New Opportunity in Medicinal Chemistry. AB - The 5-HT1A receptor is a pharmacologically well characterized serotonin receptor subtype and it has long been investigated because of its involvement in several physiopathological mechanisms and treatment of neurological diseases like ansia and depression. Serotonin (5-HT) also shows many non-neural functions such as essential hypertension, embryogenesis, follicle maturation and behavior. Moreover, it exerts a growth factor function on different types of non-tumoral cells, and it was also found to be related to oncogenes. In fact, growth stimulatory activity of serotonin in different human tumor cells has been reported. Recently, new chemical molecules binding the 5-HT1A receptor have been described as novel therapeutic entities useful in neuroprotection, cognitive impairment, Parkinson's Disease, pain treatment, malignant carcinoid syndrome and cancer. It was widely demonstrated that 5-HT1A receptor is involved in the carcinogenesis and consequently in many human tumor types, such as prostate, bladder, small cell lung, colonrectal and cholangiocarcinoma. Furthermore, depending on the tumor type, 5-HT1A receptor antagonists were shown to be capable of blocking the 5HT-induced increase in tumor growth. In this review, we have focused our attention on each tumor type where the 5-HT1A receptor is involved, investigating the role of this molecular target and the different classes of compounds that have shown the capability to modulate it. The analyzed aspects could represent a hint for the medical chemists to develop novel molecules as selective 5-HT1A agents are useful in further elucidating the role of this therapeutic target. PMID- 29424303 TI - Antiplatelet for Coronary Artery Disease in Specific Condition "No Size Fits All". AB - Antiplatelet is the cornerstone therapy for patient with coronary artery disease. Several comorbidities can influence the efficacy and safety of antiplatelet agent. Diabetes mellitus is characterized by increased platelet reactivity and reduced response to antiplatelet. Elderly patients have both reduced response to antiplatelet and increased risk of bleeding. Patients with renal dysfunction also had decreased efficacy of antiplatelet accompanied with increased risk of bleeding. In patients with atrial fibrillation, the concomitant use of anticoagulant with antiplatelet poses an increased risk of bleeding. In patients with these comorbidities, caution should be stressed in selecting the best regimen of antiplatelet which translates the most optimal efficacy while minimizing the risk of adverse events. In this review, we will discuss the platelet changes in these comorbidities, current evidence of antiplatelet usage in these group of patients and current recommendation. PMID- 29424304 TI - Applications of Polymeric Nanoparticles in Oral Diseases: A Review of Recent Findings. AB - Polymeric nanoparticles are promising drug delivery systems due to their physicochemical properties, which may be explored to improve the treatment and prevention of several diseases, including oral conditions. Moreover, the pharmacological effects of polymers may be improved by nanostructuration. Therefore, this article provides a detailed review of the studies published between 2010 and 2017 covering the use of polymeric nanoparticles in the treatment and/or prevention of oral diseases. A brief description about the dental biofilm and oral diseases is presented in first part of the article. The following section includes an important discussion about the strategies studied to improve the treatment and prevention of these diseases using polymeric nanoparticles: (i) a better drug antibacterial effect, (ii) the release of the drug in a time-controlled way, (iii) the increase of drug uptake by cells, (iv) the cytotoxicity in tumor cells and solubility in water, and (v) mucoadhesive drug delivery systems. Furthermore, the composition and size of the polymeric nanoparticles explored by these strategies were described. Finally, in the last part of this review, the in vitro and in vivo results which demonstrate the effect of these systems in the treatment and/or prevention of the most prevalent oral disorders were highlighted: dental carious lesions, oral cancer, and periodontal and endodontic diseases. PMID- 29424305 TI - Selective Antiprotozoal Activity of Nitric Oxide-releasing Chitosan Nanoparticles Against Trypanosoma cruzi: Toxicity and Mechanisms of Action. AB - BACKGROUND: Chagas' disease, caused by Trypanosoma cruzi, was described for the first time over a hundred years ago. Nonetheless, clinically available drugs still lack effective and selective properties. Nitric oxide (NO) produced by activated macrophages controls the progression of disease by killing the parasite. METHODS AND RESULTS: Here, chitosan nanoparticles (CS NPs) were synthesized and mercaptosuccinic acid (MSA), the NO donor precursor, was encapsulated into CS NPs, forming MSA-CS NPs, which had hydrodynamic size of 101.0+/-2.535 nm. Encapsulated MSA was nitrosated forming NO donor S nitrosomercaptosuccinic acid-containing nanoparticles (S-nitroso-MSA-CS NPs). Kinetic data revealed a sustained release of NO from the nanoparticles. S-nitroso MSA-CS NPs inhibited epimastigote proliferation and trypomastigote viability of T. cruzi, with IC50=75.0+/-6.5 ug.mL-1 and EC50=25.0+/-5.0 ug.mL-1, respectively. Treatment of peritoneal macrophages with nanoparticles decreased the number of T. cruzi-infected cells and the average number of intracellular replicative amastigotes per infected cells. Besides, the results have showed a selective behaviour of S-nitroso-MSA-CS NPs to parasites. Morphological and biochemical changes induced by these NO-releasing nanoparticles, such as cell shrinkage, cell cycle arrest, mitochondrial membrane depolarization and phosphatidylserine exposure on cell surface indicate that epimastigotes death is associated to the apoptotic pathway. CONCLUSION: S-nitroso-MSA-CS NPs are promising nanocarriers for the treatment of Chagas's disease. PMID- 29424306 TI - Biologic Therapy in Psoriasis (Part I): Efficacy and Safety of Tumor Necrosis Factor- alpha Inhibitors. AB - BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory disorder, with an estimated global prevalence of 2-3%. Psoriasis is associated with an impaired health-related quality of life and a substantial economic burden. Biologics, which target the pathways involved in the pathogenesis of psoriasis, represent an established therapeutic approach for moderate-to-severe plaque psoriasis, with remarkable efficacy and safety profile extensively examined and monitored. METHODS: Biological therapies currently available can be divided into three main categories: the TNFalpha antagonists (infliximab, adalimumab, etanercept, golimumab, certolizumab pegol), the interleukin (IL)- 12/23 monoclonal antibody (ustekinumab), and IL-17 inhibitor (secukinumab, ixekizumab). RESULTS: In this section, we explore the complex role of TNFalpha in psoriasis as well as the efficacy and safety of TNFalpha inhibitors largely used in the management of the cutaneous disease. CONCLUSION: Dosing regimens, administration, pharmacodynamics profiles, efficacy, and safety of licensed anti-TNFalpha are here discussed in detail. PMID- 29424307 TI - New Developments in CRISPR Technology: Improvements in Specificity and Efficiency. AB - BACKGROUND: RNA-guided endonuclease as a versatile genome editing technology opened new windows in various fields of biology. The simplicity of this revolutionary technique provides a promising future for its application in a broad range of approaches from functional annotation of genes to diseases, to genetic manipulation and gene therapy. Besides the site-specific activity of Cas9 endonuclease, the unintended cleavage known as off-target effect is still a major challenge for this genome editing technique. METHODS: Various strategies have been developed to resolve this bottleneck including development of new softwares for designing optimized guide RNA (gRNA), engineering Cas9 enzyme, improvement in off-target detection assays, etc. Results: This review dedicated to discuss on methods that have been used for optimizing Cas9, specificity with the aim of improving this technology for therapeutic applications. CONCLUSION: In addition, the applications and novel breakthroughs in the field of CRISPR technology will be described. PMID- 29424309 TI - Editorial: Uveitis: Pathology, Molecular Mechanisms and Therapy. PMID- 29424308 TI - Staphylokinase Enzyme: An Overview of Structure, Function and Engineered Forms. AB - BACKGROUND: One of the most important causes of death in the modern lifestyle is acute ischemic stroke, which is related to thrombosis in the blood vessels. Staphylokinase (SAK), a fibrinolytic agent, which is produced mainly by Staphylococcus aureus, is an indirect activator of plasminogen and belongs to the third generation of fibrinolytic enzymes. METHODS: Considering the very low level of production and immunogenicity concerns of natural SAK produced by Staphylococcus aureus, attempts have been made to produce recombinant SAKs with high production levels, more fibrinolytic activities and low immunogenicity. RESULTS AND CONCLUSION: In this review, we summarized a number of expression systems based on recombinant DNA technology and protein-engineering approaches, which have been developed for the production of engineered recombinant SAK molecules with higher fibrinolytic activities and lower antigenicity. PMID- 29424310 TI - Elevated Interleukin 37 Expression Associated With Disease Activity in HLA-B27 Associated Anterior Uveitis and Idiopathic Anterior Uveitis. AB - BACKGROUND & OBJECTIVE: Interleukin 37 (IL-37) is an important regulator of the anti-inflammatory T-cell response. In this study, we investigated its expression and function in peripheral blood mononuclear cells (PBMCs) of patients with HLA B27 associated acute anterior uveitis (AAU) and idiopathic AAU. METHODS: 15 patients with HLA-B27-associated AAU, 10 patients with idiopathic AAU and 22 controls were recruited to this study from August 2013 to December 2016. Complete ophthalmological examinations were performed and clinical features were clearly documented. Blood samples were collected and peripheral blood mononuclear cells were extracted. IL-37 messenger RNA (mRNA) and protein expression in peripheral blood mononuclear cells (PBMCs) were examined by performing RT-PCRs and western blot, respectively. Cytokines in the supernatants of stimulated dendritic cells (DCs) with IL-37 were assayed by multiplex immunoassay. RESULTS: An increased level of IL-37 mRNA and protein expression by PBMCs was found in the patient group with clinically active AAU compared to controls. There was no significant difference in IL-37 mRNA and protein expression levels between HLA-B27 associated AAU and idiopathic AAU. IL-37 significantly inhibited the production of IL-1beta, IL-6, IL-10, IL-21, IL-23, TNF-alpha and IFN-gamma. IL-37 levels of mRNA and protein expression showed a significant positive correlation with disease activity. CONCLUSIONS: Elevated IL-37 expression is associated with disease activity in HLA-B27 associated AAU and idiopathic AAU. IL-37 can inhibit proinflammatory cytokine productions in AAU. Manipulation of IL-37 may offer a new therapeutic target for these entities. PMID- 29424311 TI - How To Deal With Uveitis Patients? AB - During the past nine years, our center has grown into the largest uveitis referral center in China. To deal with this increasing stream of patients we have developed a management system to coordinate communication with our patients, their referring ophthalmologists, consultations with other medical specialties and worldrenowned foreign uveitis specialists. We have established the biggest database of uveitis patients records allowing continuous analysis of clinical features and response to treatment of patients with various uveitis entities as well as the evaluation of the relevance of various ancillary tests performed in this patient group. The establishment of a specimen biobank has been shown to be instrumental in the research on the complex immunopathological mechanisms involved in this disease. The close interaction between patient care and clinical research under one roof has led to a novel understanding of disease mechanisms and will undoubtedly lead to a tailored treatment for this disease. PMID- 29424312 TI - Association of IL33 and IL1RAP Polymorphisms With Acute Anterior Uveitis. AB - BACKGROUND: AAU (acute anterior uveitis) is the most common entity of uveitis characterized by acute vision loss and violent sore eyes. IL-33 and IL-1RacP have been found to play crucial roles in the innate immune system. OBJECTIVE: In the present study, we investigated the association of IL33 and IL1RAP genes with AAU. METHOD: A total of 549 AAU patients and 1080 unrelated healthy controls were recruited for this study. Ten single nucleotide polymorphisms (SNPs) were genotyped using Sequenom Mass ARRAY technology. RESULTS: Our findings demonstrated that IL1RAP-rs3773978 significantly associated with AAU and could serve as a genetic risk marker in Chinese AAU patients. A significantly increased frequency of the A allele and AA homozygosity of IL1RAP-rs3773978 was observed in AAU patients compared with that in controls (p=0.001, pc=0.01, OR=1.282, 95% CI 1.106 to 1.487; p=0.0003, pc=0.003, OR=1.647, 95% CI 1.255 to 2.163, respectively). Further stratification analyses showed that the genetic correlation may differ depending on HLA-B27 status, AS (ankylosing spondylitis) status, attack times and laterality status. CONCLUSION: Our findings provide new insights that enhance the current knowledge of uveitis genetics by demonstrating the specific functional roles of IL1RAP and other IL-1 family genes in uveitis. PMID- 29424313 TI - Mesenchymal Stem Cells Inhibited Dendritic Cells Via the Regulation of STAT1 and STAT6 Phosphorylation in Experimental Autoimmune Uveitis. AB - PURPOSE: We have previously reported that MSCs inhibited experimental autoimmune uveitis (EAU) in rodent models induced by either uveitogenic antigens or antigen specific T cells. In this study, we explored the inhibitory mechanisms of MSCs on dendritic cells (DCs) in EAU. METHODS: We collected the DCs from the lymph nodes of MSC treated or untreated EAU rats, as well as bone marrow derived DCs cultured in vitro with or without MSC treatment. The levels of costimulatory molecules of CD80, CD86, CD40, OX40L and suppressors of cytokine signaling (SOCS1, SOCS2, and SOCS3) on these DCs were analyzed by flow Cytometry. The expression of CCR-7 and MMP-9 was examined by real time PCR and western blots. Total proteins of STAT1 and STAT6 signaling molecules and their phosphorylation were examined by western blots. ShRNA of STAT1 and STAT6 were respectively employed to explore the influence of STAT1 and STAT6 knockdown on DCs. RESULTS: MSC treatment down regulated the expression of CD80, CD86, CD40, and OX40L, as well as CCR-7 and MMP 9, but increased the levels of SOCS1, SOCS 2, and SOCS3 on DCs. STAT1 phosphorylation was reduced while STAT6 phosphorylation was enhanced in MSC treated DCs. Moreover, MSC treatment and STAT1 shRNA equally reduced CCR-7 and MMP-9 levels in DCs, and inhibited the proliferation of R16-specific T cells. In contrast, knockdown of STAT6 in DCs by STAT6 shRNA increased the expression of CD80 and CD86 and accelerated the proliferation of R16-specific T cells. CONCLUSION: MSCs inhibit DC maturation by regulating Stat1 and Stat6 phosphorylation in EAU. PMID- 29424314 TI - Pulmonary Delivery of Triptorelin Loaded in Pluronic Based Nanomicelles in Rat Model. AB - INTRODUCTION: Triptorelin, the synthetic analog of gonadotrophin-releasing hormone, is used for the treatment of sex hormone dependent diseases via parenteral administration. The aim of the present study was to investigate the possibility of triptorelin pulmonary delivery and preparation of a pulmonary nanocarrier delivery system for it. METHODS: Triptorelin was loaded in Pluronic F127 grafted poly (methyl vinyl ether-alt-maleic acid) nanomicelles by direct dissolution method. Effects of the processing variables including: drug/polymer ratio, temperature, stirring rate and time on the physicochemical properties of nanomicelles including zeta potential, particle size, drug entrapment efficiency and release profiles of triptorelin loaded nanomicelles were evaluated. For animal studies 24 Wistar rats were separated into four groups of six. Group 1 received blank nanomicelles, groups 2, 3 and 4 were treated with a single dose of 250 ug.kg-1 of triptorelin solution subcutaneously (sc), pulmonary spraying of triptorelin solution (250 ug.kg-1) and pulmonary spraying of triptorelin nanomicelles (250 ug.kg-1), respectively by microsprayer. RESULTS: The optimized micelles had particle size of 87.35 nm, zeta potential of -12.8 mV, entrapment efficiency of 84.36% and release efficiency of 65%. The area under the blood testosterone levels increment differed significantly (p<0.05) between pulmonary triptorelin nanomicelles and drug solution. The pharmacological activity of the simple solution was 59.38%, while it was 80.18% for the nanomicelles relative to sc route of administration with prolonged residence time. CONCLUSION: The results of this study show that not only triptorelin is absorbable from the lungs but also nanomicelles can significantly enhance its pulmonary absorption compared to its simple solution. PMID- 29424315 TI - Recent Approaches in the Development of Phytolipid Complexes as Novel Drug Delivery. AB - The imbalance of hydrophilicity and lipophilicity along with a large molecular size (due to a unique chemical structure) of natural compounds or plant actives poses a significant challenge for their absorption through a biological membrane and thus, alters the therapeutic efficacy. Therefore, it is desirable to have a novel approach for such formulation in order to improve the solubility and bioavailability of these phytoconstituents as a phospholipid complexation. Herbal drugs are precisely, embedded and bound by phospholipids to form vesicular structures which are amphoteric in nature. Thus, the phytolipid complex technology is unique, in the respect that it has a higher stability profile owing to its amphoteric nature or owing to its solubility in aqueous as well as oil media. It also exhibits a greater absorption and bioavailability, as the drug molecules are embedded in the pockets of the phytosomal assembly, therefore, with more drug loading capability, protection from the gastric environment, and subsequently inactivation in gastro-intestinal tract (GIT). Phytolipid complexes have a great potential in the field of medicine, pharmaceuticals and cosmetics due to improved pharmacokinetics and pharmacological attributes. The present review explores the various aspects of phytolipid complexes concerning the phospholipids, vesicles, choice of ingredients, phytolipid complexation, advantages, preparation methods and their applications. PMID- 29424316 TI - Anti-angiogenic activity of curcumin in cancer therapy: a narrative review. AB - Curcumin is a naturally occurring polyphenol isolated from Curcuma longa that has various pharmacological activities, including, anti-inflammatory, anti-oxidant and anti-cancer properties. The anticancer effect of curcumin is attributed to activation of apoptotic pathways in cancer cells, as well as inhibition of inflammation and angiogenesis in the tumour microenvironment and suppression of tumour metastasis. Angiogenesis, which is the formation of new blood vessels from pre-existing ones, is a fundamental step in tumour growth and expansion. Several reports have demonstrated that curcumin inhibits angiogenesis in a wide variety of tumour cells through the modulation of various cell signaling pathways which involve transcription factors, protein kinases, growth factors and enzymes. This review provides an updated summary of the various pathways and molecular targets that are regulated by curcumin to elicit its anti-angiogenic activity. PMID- 29424318 TI - The significance of pain in chronic venous disease and its medical treatment. AB - Chronic venous disease (CVeD) is a highly prevalent condition in the general population, and it has a significant impact on quality of life. While it is usually manifested by obvious signs, such as varicose veins and venous ulcers, other symptoms of the disease are less specific. Among the other symptoms, which include heaviness, swelling, muscle cramps and restless legs, pain is the symptom that most frequently compels CVeD patients to seek medical aid. However, there is a substantial discrepancy between pain severity and clinically detectable signs of CVeD, questioned by several opposing studies. Further evaluation is needed to clarify this subject, and to analyse whether pain development predicts objective CVeD progression. General management of CVeD starts with advising lifestyle changes, such as lowering body mass index and treating comorbidities. However, the mainstay of treatment is compression therapy, with the additional use of pharmacological substances. Venoactive drugs proved to be the drugs of choice for symptom alleviation and slowing the progression of CVeD, with micronized purified flavonoid fraction being the most effective one. Interventional therapy is reserved for advanced stages of the disease. PMID- 29424317 TI - Novel Hypolipidaemic Drugs: Mechanisms Of Action And Main Metabolic Effects. AB - Over the last 3 decades, hypolipidaemic treatment has significantly reduced both cardiovascular (CV) risk and events, with statins being the cornerstone of this achievement. Nevertheless, residual CV risk and unmet goals in hypolipidaemic treatment make novel options necessary. Recently marketed monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown the way towards innovation, while other ways of PCSK9 inhibition like small interfering RNA (Inclisiran) are already being tested. Other effective and well tolerated drugs affect known paths of lipid synthesis and metabolism, such as bempedoic acid blocking acetyl-coenzyme A synthesis at a different level than statins, pemafibrate selectively acting on peroxisome proliferator-activated receptor (PPAR)-alpha receptors and oligonucleotides against apolipoprotein (a). Additionally, other novel hypolipidaemic drugs are in early phase clinical trials, such as the inhibitors of apolipoprotein C-III, which is located on triglyceride (TG)-rich lipoproteins, or the inhibitors of angiopoietin-like 3 (ANGPTL3), that play a key role in lipid metabolism, aiming to beneficial effects on TG levels and glucose metabolism. Among others, gene therapy substituting the loss of essential enzymes is already used for lipoprotein lipase (LPL) deficiency in autosomal chylomicronaemia and is expected to eliminate the lack of low density lipoprotein (LDL) receptors in patients with homozygous familial hypercholesterolaemia. Experimental data of high-density lipoprotein (HDL) mimetics infusion therapy have shown a beneficial effect on atherosclerotic plaques. Thus, many novel hypolipidaemic drugs targeting different aspects of lipid metabolism are being investigated, although they need to be assessed in large trials to prove their CV benefit and safety. PMID- 29424319 TI - Caffeine inhibits angiogenesis in human glioblastoma cells via HIFs modulation. AB - Caffeine represents the most used psychoactive drug in the world acting as a non selective adenosine receptor antagonist. It exerts an anti-cancer role in glioblastoma multiforme (GBM). This neoplasia is characterized by extensive hypoxic foci triggering hypoxia-inducible factors (HIFs) expression. Among these factors, HIF-1alpha performs a crucial role in the induction of vascular endothelium growth factor (VEGF), a key player in angiogenesis and cell migration. In this work, we have investigated whether caffeine counteracts GBM progression by modulating hypoxic event. Our results have indicated that this psychostimulant drug significantly reduced HIF-1alpha and VEGF expression in GBM cells exposed to hypoxia. This effect is mediated through inhibition of PI3K/Akt and MAPK/ERK signaling pathways both implied in HIFs regulation. PMID- 29424320 TI - Reserpine induces apoptosis and cell cycle arrest in hormone independent prostate cancer cells through mitochondrial membrane potential failure. AB - Reserpine, an indole alkaloid commonly used for hypertension, is found in the roots of Rauwolfia serpentina. Although the root extract has been used for the treatment of cancer, the molecular mechanism of its anti-cancer activity on hormonal independent prostate cancer remains elusive. Therefore, we evaluated the cytotoxicity of reserpine and other indole alkaloids, yohimbine and ajmaline on prostate cancer cells (PC3) using MTT assay. We investigated the mechanism of apoptosis using a combination of techniques including acridine orange/ethidium bromide staining, high content imaging of Annexin V-FITC staining, flow cytometric quantification of the mitochondrial membrane potential and reactive oxygen species (ROS) and cell cycle analysis. Our results indicate that reserpine inhibits DNA synthesis by arresting the cells at the G2 phase and showed all standard sequential features of apoptosis including, destabilization of mitochondrial membrane potential, reduced production of reactive oxygen species and DNA ladder formation. Our in silico analysis further confirmed that indeed reserpine docks to the catalytic cleft of anti-apoptotic proteins substantiating our results. Collectively, our findings suggest that reserpine can be a novel therapeutic agent for the treatment of androgen-independent prostate cancer. PMID- 29424321 TI - Design, Synthesis and Biological Evaluation of Novel Urea and Thiourea Bearing thieno[3,2-d]-pyrimidines as PI3 Kinase Inhibitors. AB - BACKGROUND: Phosphatidylinositol-3-kinase alpha (PI3Kalpha) is a ubiquitous intracellular enzyme, mainly involved in intracellular signaling pathways, promotes cellular growth, proliferation, and differentiation. Therefore, inhibition of PI3K can be a hotspot in molecular targeted therapy for the treatment of cancer. METHODS: The present research work involves molecular docking studies performed to screen derivatives of urea and thiourea bearing thieno [3,2-d]-pyrimidines against the active site of PI3K enzyme using MOE.2008.10. The designed structures (6a-f) and (7a-j) were synthesized by the facile synthetic methods and evaluated for their anticancer activity against HT 29 and MCF-7 cell lines and inhibitory activity against PI3Kalpha enzyme. RESULTS: Among the tested compounds, 4-(4-(2-(3-(pyrimidin-2 yl)thioureido)ethyl)piperazin-1-yl)thieno[3,2- d]pyrimidine-6-carboxamide (7f) showed the highest anticancer activity against HT-29 and MCF-7 cell lines with IC50 values of 2.18 uM and 4.25 uM, respectively. Further, the same compound also exhibited potent PI3Kalpha inhibitory activity with IC50 value of 1.26 uM. CONCLUSION: Docking studies supported the initial pharmacophoric hypothesis and suggested a mode of interaction at the active binding site of PI3Kalpha, demonstrating that the target compounds were potential inhibitory agents for cancer therapy. PMID- 29424323 TI - Topical Delivery of Erythromycin Through Cubosomes for Acne. AB - BACKGROUND: Topical delivery is an attractive route for local and systemic treatment. The novel topical application has many advantages like averting the GI irritation, preventing the metabolism of drugs in the liver and increasing the bioavailability of the drug over the conventional dosage forms. OBJECTIVE: The aim of present work was to prepare and characterized erythromycin encapsulated cubosomes using different concentrations of glyceryl monooleate and poloxamer 407 by the emulsification method. METHODS: The prepared dispersion of cubosomes was characterized for surface morphology, particle size, entrapment efficiency and in vitro release. Further, optimized formulation was converted to cubosomal gel by incorporating carbopol 934 at different concentrations. The prepared gel was characterized for homogeneity, pH, viscosity, spreadibility, drug content and in vitro drug release study. RESULTS: The result of optimized cubosomes showed average particle size of 264.5+/-2.84nm and entrapment efficiency about 95.29+/ 1.32 % and the pH of optimized cubosomal was found to be 6.5, viscosity 2475 8901(cp), drug content 95.29% and the spreadability was found to be 11.74 gm.cm/sec. The in vitro drug release kinetics of optimized formulation was found to follow Korsmeyer peppas model having highest R2 value 0.835 and in vitro drug release of optimized erythromycin loaded cubosomal gel and plain drug gel in 24 hr was found to be 89.91+/-0.73 and 88.64+/-2.16, while in 36 hr plain drug gel and cubosomal gel showed drug release about 87.64+/-0.97 and 91.55+/-1.09, and sustained release was obtained after 24 hr in case of cubosomal gel. CONCLUSION: Thus, as a whole it can be concluded that erythromycin loaded cubosomes are effective in topically delivering drug in sustained and non-invasive manner for treatment and prevention of acne. PMID- 29424322 TI - TNF-alpha Polymorphisms and Maternal Depression in a Mexican Mestizo Population. AB - BACKGROUND: Depressive disorders are common during pregnancy. There is compelling evidence that the inflammatory response system is important in the pathophysiology of depression. Higher concentrations of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) in depressed subjects have been described. Because several polymorphisms in the TNF-alpha promoter region are known to affect its gene expression, the aim of this study was determine whether TNF-alpha - 857C/T, -308G/A, and -238G/A polymorphisms confer susceptibility to depression during pregnancy in a Mexican mestizo population. METHODS: This case control study involved 153 depressed pregnant women and 177 controls. Polymorphisms were genotyped using real-time PCR. Odds ratios (OR) and 95% confidence intervals adjusted by age, body mass index, number of pregnancies, months of pregnancy and number of abortions were used to estimate risk. RESULTS: The -857CT genotype was found to increase the risk for depression (OR= 1.73, 95% CI= 1.06-2.82). In contrast, the -238GA genotype reduced the risk (OR= 0.33, 95% CI= 0.14-0.72). The - 308G/A polymorphism was not associated with risk for depression. Finally, the C857-G308-A238 haplotype was associated with a decreased risk of depression (OR= 0.35, 95% CI= 0.15-0.82). CONCLUSION: Our results show for the first time an association between TNF-alpha -857C/T and -238G/A polymorphisms and prenatal depression in Mexican mestizo population. PMID- 29424324 TI - Nano-Medicine as a Newly Emerging Approach to Combat Human Immunodeficiency Virus (HIV). AB - BACKGROUND: Human Immuno deficiency Virus (HIV) infection has attained pandemic level due to its complexity on both the HIV infection cycle and on the targets for drug delivery. This limits medication and consequently requires prominent and promising drug delivery systems to be invented. Notably, various nanomaterial have been studied to enhance effective delivery of the antiretroviral drugs for HIV prevention, diagnosis and cure. Some of these nanomaterials are liposomes, dendrimers, inorganic nanoparticles (NPs), polymeric micelles, natural and synthetic polymers. OBJECTIVE: The present study aimed to review the recent progress in nanomedicine as a newly emerging approach to combat HIV. METHODS: The scientific data bases reviewed carefully to find both in vitro and in vivo studies representing the role of nonomedicine to combat HIV. RESULTS: Impressively, nanomedicine drug delivery systems have been commendable in various models ranging from in vitro to in vivo. It gives notion about the application of nano-carrier systems for the delivery of anti-retroviral drugs which ideally should provide better distribution to surpass Blood- Brain Barrier (BBB) and other tissue or to overcome innate barriers such as mucus. Considerably, nanomaterials such as dendrimers and many other inorganic NPs such as silver, gold, iron, and zinc can be used for HIV treatment by interfering in varying stages of HIV life cycle. Furthermore, NPs could best act as adjuvants, convoys during vaccine delivery, as intra-vaginal microbicides and for the early detection of HIV-1 p24 antigen. CONCLUSION: Nanomedicine may be a proper approach in HIV/AIDS therapy by means of offering lower dosage and side effect, better patient-to-patient consistency, bioavailability, target specificity and improved sensitivity of HIV diagnosis. PMID- 29424325 TI - [Pain in cancer]. AB - - Cancer patients often experience pain that has a significantly negative effect on their daily living.- This pain may be caused by the disease process itself, but may also be related to the treatment such as chemotherapy-induced neuropathic pain, chronic pain following surgery and post-amputation pain.- In this training article we will discuss the different aspects of cancer-related pain, based on various questions posed by general practitioners and internists.- Items that are discussed include measurement of pain, opioid therapy, opioid side effects, adjuvant medication, barriers that preclude proper treatment of pain, opioid tolerance and addiction, and interventional therapy.- Pain treatment in cancer patients requires a multidisciplinary team effort, with a central role for the patient. PMID- 29424326 TI - [Risk of vitamin K antagonists in cases of cerebral microbleeds]. AB - - Cerebral microbleeds are associated with a higher risk of intracerebral hemorrhage.- When microbleeds are detected, the possible underlying pathology should be considered; this includes cerebral amyloid angiopathy and other factors that increase the risk of haemorrhage, particularly hypertension. - No randomised trials have yet been conducted into haemorrhagic complications and cerebral infarctions in patients with microbleeds who take vitamin K antagonists. This means that it is not clear whether the intended prevention of cerebral infarctions outweighs the increased risk of haemorrhage associated with use of vitamin K antagonists by these patients.- When deciding whether or not an older patient should be given anticoagulants the following should be taken into consideration as well: comorbidities, polypharmacy, the risk of falls and the probability that the patient can be optimally titrated to vitamin K antagonists. If there is an increased risk of intracerebral haemorrhage but anticoagulants are indicated, direct oral anticoagulants (DOACs) might be preferable to vitamin K antagonists in patients with a history of cerebral microbleeds. PMID- 29424327 TI - [A woman with spontaneous neck pain]. AB - A 42-year-old woman presented with neck pain without previous trauma. On suspicion of spondylodiscitis, an MRI of the cervical spine was made. This MRI and an additional CT showed calcific tendinitis of the longus colli muscle, a self-limiting disorder. PMID- 29424328 TI - [Nurses to be preferred over physicians in elderly care?] AB - A thorough systematic literature review comparing care for the elderly provided by physicians and nurses with that provided by physicians alone finds a modest advantage for the first. The conclusion is that 'Physician substitution in healthcare for the aging population may achieve at least as good patient outcomes and process of care outcomes compared with care provided by physicians'. On closer inspection, the selected studies compare multidisciplinary care programmes including nursing staff with monodisciplinary physician care. The modest advantage found for the multidisciplinary programmes can be seen as support for the prevailing consensus that this is the way to go, but the conclusion that this is support for the substitution of physicians lacks evidence. Focus on cost effectiveness and/or the wish to accentuate the important role of highly trained nursing experts in modern care for older people may have affected the interpretation of the data. PMID- 29424329 TI - [The (un)predictability of coronary atherosclerosis]. AB - Coronary atherosclerosis is a common disease. The plaques developing inside coronary vessels may have serious consequences such as myocardial infarction. However, the course of this multifactorial and heterogeneous disease is difficult to predict and is different for each patient. Atherosclerosis is often described as a gradually progressive disease, but in addition to slow progression, a certain periodicity is often seen. There may be periods with more stability and periods of regression. Several processes are known to be involved in plaque development and their increasing vulnerability. We describe some of these processes in this article. Despite existing knowledge about these processes, atherosclerosis periodicity remains largely unexplained. More insight into this periodicity may potentially be relevant to the development of new therapies. Drug therapy to lower LDL-cholesterol is currently the cornerstone of treatment, in addition to lifestyle advice. PMID- 29424330 TI - [Fish-caused illness: notify food-related outbreaks to the Municipal Health Services]. AB - BACKGROUND: When two or more people fall ill after eating the same food, this is called an outbreak of food poisoning or food-related infection. In the Netherlands, physicians have to notify the Municipal Health Services (GGD) of such outbreaks. The GGD informs the Netherlands Food and Consumer Product Safety Authority (NVWA). CASE DESCRIPTION: Two clusters of scombroid poisoning (histamine poisoning in this case after eating tuna) occurred in one month. Due to the quick reporting of patients by physicians, the GGD and the NVWA immediately tracked down the source. In both clusters the NVWA confirmed high histamine levels in tuna. In reaction to these findings and the first cluster, the supplier recalled the tuna batch. This may have prevented other cases of food poisoning. In the second cluster, the implicated tuna batch had already been sold. CONCLUSION: Timely notification by physicians of food poisoning or food related outbreaks to the GGD enables swift tracing of the source and appropriate measures by the GGD and the NVWA.. PMID- 29424331 TI - [Hope-Simpson and shingles]. AB - Dr Robert Edgar Hope-Simpson (1908-2003) was a British general practitioner, who has laid the foundation for unravelling the pathogenesis of shingles. At the beginning of the 20th century, both conditions were known to be related, but the precise relationship was unclear. It was assumed that chickenpox could originate after infection by both a person with shingles or someone with chickenpox, but that both diseases were caused by different viruses. Through rigorous observations in his GP practice and during his field work on the island of Yell, Hope-Simpson developed his hypothesis about the - now scientifically accepted - pathogenesis of shingles. Hope-Simpson's work shows how accurate observations can lead to unexpected new insights and hypotheses. PMID- 29424332 TI - [A man who was unable to open his eyes]. AB - A 47-years-old man presented with the complaint that he could not open his eyes in the morning. Facial myxedema caused by hypothyroidism was evident. Pictures taken after treatment for six months with levothyroxine showed complete recovery. Myxedema is caused by accumulation of glycosaminoglycans in the dermis. PMID- 29424334 TI - Reactive gliosis mimicking tumor recurrence - a case series documenting MRI abnormalities and neuropathological correlates. AB - The aim of this study is to identify, in our center, all cases of foreign-body reactions to hemostatic agents or other prostheses resulting in a radiological suspicion of tumor recurrence. We interrogated our internal database to identify all such cases and systematically evaluated the MRI brain scans of patients: (i) at the time of initial tumor diagnosis, (ii) postoperatively, (iii) and at the time of suspected tumor recurrence. In addition, we reviewed each patient's operative notes and reviewed the histology of all cases following a second surgical intervention. In total, we identified 8 patients, 7 of whom had a WHO grade II glioma at initial surgery. We did not identify any distinguishing radiological abnormalities from the initial diagnostic brain scan to the suspected recurrence, and histologically all cases were characterized by extensive gliosis; with both macrophages and reactive astrocytes present throughout. The cause of gliosis was identified as being relating to hemostatic agents in 4 cases; in the other 4 cases, the foreign-body reaction was presumed to be caused be materials used in a craniotomy or cranioplasty. This study highlights the difficulty in radiologically diagnosing a foreign-body reaction and also identifies that such a gliotic reaction may occur as a consequence of exogenous materials used in a craniotomy or cranioplasty.?. PMID- 29424335 TI - Simple and rapid UPLC-MS/MS method for quantification of entecavir in human plasma: Application to a bioequivalence study?. AB - A simple and fast ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated to determine entecavir in human plasma with the stable isotopically labeled internal standard entecavir 13C215N. Samples (100 uL each) were pretreated by protein precipitation with methanol, and then separated on an ACQUITY UPLC BEH C18 analytical column (2.1 * 50 mm, 1.7 um) with a simple isocratic elution. The detection was operated by a positive ionization electrospray mass spectrometry in multiple reaction monitoring mode. The method had a short chromatographic run time of 2 minutes, and obtained sharp peaks of entecavir and the internal standard. Good linearity was found within 0.1 - 20 ng/mL. The intra- and inter-day precision and accuracy met the acceptance criteria, and no matrix effect was observed. This method was successfully applied in a bioequivalence study of two kinds of entecavir tablets in healthy Chinese volunteers. And the results showed that no significant differences were found between the test and reference preparations in pharmacokinetic parameters (p > 0.05) by ANOVA. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax, AUC0-tlast, and AUC0-infinity fell within the bioequivalence acceptance criteria (80 - 125%). No significant difference was found in tmax between the two preparations. The two one-sided t-tests showed that these two products were bioequivalent.?. PMID- 29424336 TI - A novel UMOD gene mutation associated with chronic kidney failure at a young age. AB - Autosomal dominant tubulointerstitial kidney disease (ADTKD) belongs to a group of renal hereditary disorders linked by common findings of tubulointerstitial disease and dominant inheritance. The renal clinical phenotype is characterized by chronic kidney disease, hyperuricemia, gout, and, inconstantly, renal cysts. Uromodulin (UMOD) gene mutations are related to the clinical phenotype of ADTKD UMOD. We describe here a novel heterozygous mutation of UMOD (c.249C>G; p.Cys83Trp) in an affected 9-year-old boy with progressive renal impairment and hyperuricemia. His mother is also affected and received renal transplantation at the age of 31 years. We assume that this variant is likely to be the causative mutation in this family as it segregates with the disease, it is not present in the genomic databases, and it is predicted to be damaging by the principal software tools. Considering the progressive renal impairment of our proband at an early age (serum creatinine elevation at the age of 6, hyperuricemia at the age of 9) and the early age at end-stage renal disease of his mother, we hypothesize that this variant is associated with a severe clinical phenotype.?. PMID- 29424338 TI - Post-prophylaxis monitoring of CMV following renal transplantation. PMID- 29424337 TI - Successful use of rituximab in glomerular basement membrane nephritis associated with HIV interstitial nephritis secondary to Castleman disease?. AB - We report a case of glomerular basement membrane crescentic glomerulonephritis and multicentric Castleman disease-associated interstitial nephritis in a patient with human immunodeficiency virus (HIV) infection. The patient received corticosteroids, cyclophosphamide, and plasmapheresis, and within 3 weeks, there was worsening thrombocytopenia, anemia, and renal function requiring initiation of hemodialysis. He then received 8 weekly doses of rituximab, and there was steady improvement in renal function, such that he stopped dialysis within 6 weeks and has remained in disease remission at 1-year follow-up. This is the first case report of acute kidney injury caused by both antiglomerular basement membrane disease and multicentric Castleman disease, with a favorable response to rituximab.?. PMID- 29424339 TI - Redescription of Paradiplozoon hemiculteri (Monogenea, Diplozoidae) from the type host Hemiculter leucisculus, with neotype designation. AB - Paradiplozoon hemiculteri (Ling, 1973), a member of the Diplozoidae, parasitizes the gills of Asian fish. Not only is the type material unavailable for this species, the original description was poor and somewhat conflicting, and adequate molecular data were not available. What is more, the available morphological and molecular data are inconsistent and fluctuate significantly. Here, we present a redescription of P. hemiculteri based on morphological and molecular data from new isolates collected from the type host, the sharpbelly Hemiculter leucisculus (Basilewsky, 1855), captured at the neotype locality (Shaoguan, Guangdong Province, southern China); a neotype for P. hemiculteri was designated from this collection. The length and width of the body, buccal suckers, pharynx, attachment clamps, sickle and the central hook handle were all measured and the shape of the anterior and posterior part of the median plate and anterior and posterior joining sclerites accurately documented. Phylogenetic analyses based on the sequences of the second rDNA internal transcribed spacer (ITS2) indicated that all new samples clustered together and differed clearly from sequences attributed to P. hemiculteri, which are deposited in GenBank. Our results confirm that P. hemiculteri is the only diplozoid that has demonstrably been found on the gills of H. leucisculus to date. PMID- 29424340 TI - Cavisoma magnum (Cavisomidae), a unique Pacific acanthocephalan redescribed from an unusual host, Mugil cephalus (Mugilidae), in the Arabian Gulf, with notes on histopathology and metal analysis. AB - Cavisoma magnum (Southwell, 1927) Van Cleave, 1931 was originally described from a sea bass, Serranus sp. and spotted surgeonfish, Ctenochaetus strigosus (Perciformes) off Sri Lanka before its more recent redescription from milkfish in the Philippines in 1995. These reports were based on only light infections of their host fishes. Of the few flathead grey mullets, Mugil cephalus (Mugilidae), that we examined in the Arabian Gulf, one fish was infected with 1,450 worms. One milkfish, Chanos chanos (Chanidae), from the same location in the Arabian Gulf, was also heavily infected with specimens of C. magnum. The descriptions of this unique large worm are revised and for the first time, we provide SEM images, new systematic observations, metal analysis of hooks showing extremely high levels of sulfur, and histopathology in the mullet intestinal tissue. Adjustments and corrections of previous descriptive accounts are made. The histopathology studies show extensive damage to the host intestinal tissue including epithelial necrosis, hemorrhaging and worm encapsulation. There is an extensive amount of host connective tissue surrounding the worm. Results of x-ray analysis displayed high levels of sulfur in proboscis hooks, especially at the tips and edges of these attachment structures. PMID- 29424333 TI - Pathogenesis of Proteus mirabilis Infection. AB - Proteus mirabilis, a Gram-negative rod-shaped bacterium most noted for its swarming motility and urease activity, frequently causes catheter-associated urinary tract infections (CAUTIs) that are often polymicrobial. These infections may be accompanied by urolithiasis, the development of bladder or kidney stones due to alkalinization of urine from urease-catalyzed urea hydrolysis. Adherence of the bacterium to epithelial and catheter surfaces is mediated by 17 different fimbriae, most notably MR/P fimbriae. Repressors of motility are often encoded by these fimbrial operons. Motility is mediated by flagella encoded on a single contiguous 54-kb chromosomal sequence. On agar plates, P. mirabilis undergoes a morphological conversion to a filamentous swarmer cell expressing hundreds of flagella. When swarms from different strains meet, a line of demarcation, a "Dienes line," develops due to the killing action of each strain's type VI secretion system. During infection, histological damage is caused by cytotoxins including hemolysin and a variety of proteases, some autotransported. The pathogenesis of infection, including assessment of individual genes or global screens for virulence or fitness factors has been assessed in murine models of ascending urinary tract infections or CAUTIs using both single-species and polymicrobial models. Global gene expression studies performed in culture and in the murine model have revealed the unique metabolism of this bacterium. Vaccines, using MR/P fimbria and its adhesin, MrpH, have been shown to be efficacious in the murine model. A comprehensive review of factors associated with urinary tract infection is presented, encompassing both historical perspectives and current advances. PMID- 29424341 TI - A new genus and species of the family Pennellidae (Copepoda, Siphonostomatoida) infecting the Pacific viperfish Chauliodus macouni. AB - A new genus and species of pennellid copepod, Protosarcotretes nishikawai n. g., n. sp., is described on the basis of an ovigerous female infecting a Pacific viperfish Chauliodus macouni collected from the deep-waters of Suruga Bay, Japan. The new genus exhibits the most plesiomorphic states in the first to fourth legs of pennellids, and is differentiated from two closely related pennellid genera Sarcotretes and Lernaeenicus by the morphology of the oral appendages. Two species of the genus Lernaeenicus are transferred to the new genus as Protosarcotretes multilobatus (Lewis, 1959) n. comb. and Protosarcotretes gnavus (Leigh-Sharpe, 1934) n. comb. The host specificity and life cycle of deep-sea pennellids are discussed. Sarcotretes scopeli Jungersen, 1911 and Cardiodectes bellottii (Richiardi, 1882) show low differentiated host-specificity, while P. nishikawai seems to be limited to the Stomiidae, which are rare hosts of pennellids, in contrast to the Myctophidae family. In the Pennellidae family, two patterns of the life cycle are found: with or without naupliar stages. PMID- 29424343 TI - Living-related renal transplantation in Hong Kong. PMID- 29424342 TI - YTH-RNA-binding protein prevents deleterious expression of meiotic proteins by tethering their mRNAs to nuclear foci. AB - Accurate and extensive regulation of meiotic gene expression is crucial to distinguish germ cells from somatic cells. In the fission yeast Schizosaccharomyces pombe, a YTH family RNA-binding protein, Mmi1, directs the nuclear exosome-mediated elimination of meiotic transcripts during vegetative proliferation. Mmi1 also induces the formation of facultative heterochromatin at a subset of its target genes. Here, we show that Mmi1 prevents the mistimed expression of meiotic proteins by tethering their mRNAs to the nuclear foci. Mmi1 interacts with itself with the assistance of a homolog of Enhancer of Rudimentary, Erh1. Mmi1 self-interaction is required for foci formation, target transcript elimination, their nuclear retention, and protein expression inhibition. We propose that nuclear foci formed by Mmi1 are not only the site of RNA degradation, but also of sequestration of meiotic transcripts from the translation machinery. PMID- 29424344 TI - Recent advances in breast cancer treatment. PMID- 29424345 TI - We need a stroke system. PMID- 29424346 TI - Emergency thrombectomy for acute ischaemic stroke: current evidence, international guidelines, and local clinical practice. AB - Acute ischaemic stroke due to large vessel occlusion leads to grave neurological morbidity and mortality. Conventional intravenous thrombolysis is ineffective in achieving timely reperfusion in this group of patients. The publication of five positive randomised controlled trials of emergency thrombectomy for acute ischaemic stroke in 2015 provided strong evidence to support endovascular reperfusion therapy and represented a paradigm shift in acute stroke management. In this article, we review the current evidence and international guidelines, and report on the findings of a survey study of the clinical practice and opinions of local neurologists, neurosurgeons, and interventional radiologists in emergency thrombectomy. We also discuss the controversies around thrombectomy treatment, local experience, and suggestions to incorporate thrombectomy in acute stroke treatment. PMID- 29424347 TI - Intravenous stroke thrombolysis after reversal of dabigatran effect by idarucizumab: first reported case in Hong Kong. PMID- 29424348 TI - Mesenteric fibromatosis: a rare cause of peritonitis. PMID- 29424349 TI - Therapeutic effects of N-acetyl-L-cysteine on liver damage induced by long-term CCl4 administration. AB - N-acetyl-L-cysteine (NAC) is a drug routinely used in several health problems, e.g. liver damage. There is some information emerged on its negative effects in certain situations. The aim of our study was to examine its ability to influence liver damage induced by long-term burden. We induced liver damage by CCl4 (10 weeks) and monitored the impact of parallel NAC administration (daily 150 mg/kg of b.w.) on liver morphology and some biochemical parameters (triacylglycerols, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, proteins, albumins and cholinesterase). NAC significantly decreased levels of bile acids and bilirubin in plasma and triacylglycerols in liver, all of them elevated by impairment with CCl4. Reduction of cholesterol induced by CCl4 was completely recovered in the presence of NAC as indicated by its elevation to control levels. NAC administration did not improve the histological parameters. Together with protective effects of NAC, we found also its deleterious properties: parallel administration of CCl4 and NAC increased triacylglycerols, ALT and AST activity and significantly increased plasma cholinesterase activity. We have observed nonsignificantly increased percentage of liver tissue fibrosis. Our results have shown that NAC administered simultaneously with liver damaging agent CCl4, exhibits not only protective, but also deleterious effects as indicated by several biochemical parameters. PMID- 29424350 TI - The contribution of noradrenergic nerves to the vasoconstrictor response during local cooling of leg and forearm skin in humans. AB - This study investigated the noradrenergic contribution during the cutaneous vasoconstrictor response to local cooling in the leg and forearm. On each limb, one site was perfused with Yoh/Prop to block the postsynaptic adrenoceptors and another with Lactated Ringer's (control) using microdialysis. Blood flow was measured by Laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF units divided by the mean arterial pressure. After baseline measures, skin was locally cooled to 24 degrees C. Basal CVC was similar at all sites in the leg and forearm (all p > 0.1). During the first 10 min of local cooling, CVC was reduced in the leg (p < 0.005) and unchanged in the forearm control sites (p = 0.2). Yoh/Prop induced an increased CVC in the leg and forearm to a similar level (39.2 +/- 11.5, and 41.3 +/- 3.3%CVC, respectively; p < 0.35). Late during local cooling, the vasoconstriction was attenuated in the leg and forearm at Yoh/Prop (-38.2 +/- 5.3 -37.1 +/- 5.3%CVC, respectively; p = 0.5) compared to control sites (-69.1 +/- 5.8 vs. -54.5 +/- 6.4%CVC, respectively; p < 0.005). Noradrenergic contribution was greater in the leg than the forearm during the late vasoconstrictor response (p = 0.006). These data indicate that the leg skin can induce greater vasoconstriction than forearm during local cooling, possibly via higher noradrenergic sensitivity in the leg skin. PMID- 29424351 TI - Ca2+-dependent calcineurin/NFAT signaling in beta-adrenergic-induced cardiac hypertrophy. AB - Ca2+ is an important mediator in the beta-adrenergic-induced cardiac hypertrophy. The beta-adrenergic stimulation alters the Ca2+ transient characteristics including its oscillation frequency, diastolic and systolic levels which lead to the CaN activation and subsequent NFAT-dependent hypertrophic genes transcription. Moreover, beta-adrenergic-induced alterations in PKA and GSK3beta kinase activities in both the cytosol and the nucleus regulate NFAT nuclear translocation and contribute in its hypertrophic response. Due to the complex nature of CaN/NFAT signaling in cardiac cells, we use a computational approach to investigate the beta-adrenergic-induced CaN/NFAT activation in the cardiac myocytes. The presented model predicts well the main physiological characteristics of CaN/NFAT signaling in accordance with the experimental observations. The presented model establishes the previous experimental and mathematical results on the principal role of Ca2+ oscillation frequency in the CaN/NFAT signaling and shows that increase in Ca2+ oscillation frequency enhances CaN activity and its sensitivity to low ISO concentrations. The model illustrates that in addition to the known ISO effect on Ca2+ transient amplitude, ISO-induced alterations in Ca2+ oscillation frequency, PKA and GSK3beta kinase activities also greatly affect the beta-adrenergic-induced NFAT activity. We also found that PKA has both pro-hypertrophic and anti-hypertrophic effects on NFAT activation and is the main kinase in ISO-induced NFAT activation. PMID- 29424352 TI - DNA-DOPE-gemini surfactants complexes at low surface charge density: from structure to transfection efficiency. AB - DNA condensation, structure and transfection efficiency of complexes formed by gemini surfactants alkane-alpha,omega-diyl-bis(dodecyldimethylammonium bromide)s (CnGS12, n = 3, 6 and 12 is the number of alkane spacer carbons), dioleoylphosphatidylethanolamine (CnGS12/DOPE = 0.3 mol/mol) and DNA at low surface charge density were investigated through different techniques. Small angle X-ray diffraction showed a condensed lamellar phase with marked dependence of DNA-DNA distance on (+/-) charge ratio. High ionic strength of hydrating medium screens the interaction DNA - CnGS12/DOPE and complexed DNA represented maximally ~ 45-60% of total DNA in the solution as derived from fluorescence and UV-VIS spectroscopy. The in vitro transfection efficiency of CnGS12/DOPE liposomes on mammalian HEK 293 cell line was spacer length-dependent. C12GS12/DOPE/DNA complexes exhibited the best transfection efficiency (~ 18% GFP expressing cells relative to all viable cells) accompanied by ~ 89% cell viability. PMID- 29424353 TI - Resuscitative therapy with erythropoietin reduces oxidative stress and inflammatory responses of vital organs in a rat severe fixed-volume hemorrhagic shock model. AB - Hemorrhagic shock (HS) still has a high mortality rate and none of the known resuscitative regimens completely reverse its adverse outcomes. This study investigated the effects of different models of resuscitative therapy on the healing of organ damage in a HS model. Male Wistar rats were randomized into six groups: Sham, without HS induction; HS, without resuscitation; HS+Blood, resuscitation with the shed blood; HS+Blood+NS, resuscitation with blood and normal saline; HS+Blood+RL, resuscitation with blood and Ringer's lactate; EPO, erythropoietin was added to the blood and RL. Blood and urine samples were obtained 3 h after resuscitation. Kidney, liver and brain tissue samples were harvested for multiple organ failure evaluation. Survival rate was the highest in the Sham, EPO and HS+Blood+RL groups compared to others. Plasma creatinine concentration, ALT, AST, urinary NAG activity and renal NGAL mRNA expression significantly increased in the HS+Blood+RL group compared to the Sham group. There was a significant increase in tissue oxidative stress markers and pro inflammatory cytokines in HS+Blood+RL group compared to the Sham rats. EPO had more protective effects on multiple organ failure compared to the HS+Blood+RL group. EPO, as a resuscitative treatment, attenuated HS-induced organ damage. It seems that it has a potential to be attractive for clinical trials. PMID- 29424354 TI - Stability studies of endocrine disrupting tributyltin and triphenyltin compounds in an artificial sea water model. AB - Triorganotins belong to toxic components present predominantly in antifouling paints for marine vessels. Tributyltin/triphenyltin at pico- or nanomolar concentrations in sea water are known to induce an irreversible sexual abnormality in females of over 190 marine species, an "imposex" phenomenon - the superimposition of male genitalia on a female. Moreover, trialkyltins and triaryltins function as potent nuclear retinoid X receptors (RXR) agonists. In mammals, triorganotin compounds induce immunosuppressive, metabolic, reproductive or developmental effects. Toxic effects of triorganotins warrant the need for monitoring of their long-lasting presence in the environment. This study brings novel data on the stability of two triorganotin compounds in artificial sea water model obtained by applying ultra-pressure liquid chromatography (UPLC) and gas chromatography-mass spectrometry (GC-MS) methods. Stability of tributyltin and triphenyltin chlorides was studied for 180 days and the degradation kinetic parameters were obtained. Tributyltin chloride was the less stable with the degradation kinetic parameters Kdeg = 0.00014 day-1 and t1/2 = 4950 days (13.6 years). Kdeg of the more stable triphenyltin chloride was determined to be Kdeg = 0.00006 day-1 with t1/2 = 11550 days (31.6 years). Since similar stability data of triorganotin compounds were not published previously, we report high stability for both tested compounds, which indicates a significant environmental problem when these substances enter sea water and later coastal sediments. PMID- 29424356 TI - Water-soluble quercetin modulates the choleresis and bile lipid ratio in rats. AB - Water-soluble analogue of quercetin, corvitin is used in patients with myocardial infarction as blocker of 5-lipoxygenase. However, its effects on secretion, lipid content and physico-chemical properties of bile have not been understood yet. We investigated the effect of corvitin, applied in different doses, on the level of bile flow, the content of bile free and esterified cholesterol, phospholipids, triacylglycerols, and free fatty acids. In order to determine stability of the bile colloidal system, we examined the relationship between different lipid components. The rats were injected intraportally with a bolus of corvitin. At doses of 2.5, 5, and 10 mg/kg, the latter increased bile flow and concentration of total cholates, as well as free fatty acids. Corvitin (5 mg/kg) elevated phospholipids and cholesterol content, but at a dose of 10 mg/kg it increased the concentration of bile cholesterol esters and triacylglycerols. Corvitin applied at doses of 2.5 and 10 mg/kg increased total cholates/cholesterol ratio, but at a dose of 10 mg/kg, the drug reduced cholesterol / esterified cholesterol ratio. The results suggest that corvitin exerts choleretic effect and improves stability of bile colloidal system. PMID- 29424357 TI - Action levels for airborne uranium in the workplace: chemical and radiological assessments. AB - A method is described for deriving two levels of action-an investigation level (IL) and an immediate action level (IAL)-for different forms and mixtures of the natural uranium (U) isotopes 234U, 235U, and 238U in air in the workplace. An IL indicates the need to confirm the validity of moderately elevated measurements of airborne U and adequacy of confinement controls and determine whether work limitations are appropriate. An IAL indicates that safeguards should be put into place immediately, including removal of workers from further exposure until conditions are acceptable. Derivations of ILs and IALs are based on latest radiation protection guidance, information on chemical toxicity of U, and biokinetic models for U. An action level (IL or IAL) is the more restrictive of two derived values, the action level based on U as a chemical hazard and the action level based on U as a radiation hazard. PMID- 29424355 TI - Cytotoxicity of propolis nanopreparations in cancer cell monolayers: multimode of action including apoptotsis and nitric oxide production. AB - Natural products are invaluable resource of anticancer drug discovery. They generally viewed as safe but weak, within the framework of nanotechnology, they can serve as template for potent anticancer drugs. We first evaluated the cytotoxic activity of different propolis extracts (water, 70% ethanol, absolute ethanol and hexane) in many cancer cell lines, then the solid nanoparticles from the organic solvent extracts were prepared and their cytotoxicity was evaluated as well. Finally, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes were prepared from the most cytotoxic organic solvent extract and their cytotoxicity was also evaluated. All results collectively showed that hexane extract and its solid nanoparticles as well as its liposomal form exhibited high cytotoxic activity. DPPC/DOPC-hexane extract cytotoxicity selectively depends on the cell line and DOPC liposomal form was characterized by reduced IC50 compared with the other preparations/extracts, the average IC50 value is 165.8 +/- 3 ug/ml. The antiproliferative activity of propolis was associated to multiple modes of actions including apoptosis and nitric oxide production and as indicated by the HPLC and FTIR results, it is functioning in many propolis ingredients rather than a single component and influenced by the presence of more lipophilic components within the extract and not by the extract mass yield. These results may have an impact on the multidrug resistivity issue. PMID- 29424358 TI - Dark matter in dwarf spheroidal galaxies and indirect detection: a review. AB - Indirect dark matter searches targeting dwarf spheroidal galaxies (dSphs) have matured rapidly during the past decade. This has been because of the substantial increase in kinematic data sets from the dSphs, the new dSphs that have been discovered, and the operation of the Fermi-LAT and many ground-based gamma-ray experiments. Here we review the analysis methods that have been used to determine the dSph dark matter distributions, in particular the 'J-factors', comparing and contrasting them, and detailing the underlying systematics that still affect the analysis. We discuss prospects for improving measurements of dark matter distributions, and how these interplay with future indirect dark matter searches. PMID- 29424359 TI - Motor unit number index (MUNIX) derivation from the relationship between the area and power of surface electromyogram: a computer simulation and clinical study. AB - OBJECTIVE: The motor unit number index (MUNIX) is a technique based on the surface electromyogram (sEMG) that is gaining acceptance as a method for monitoring motor neuron loss, because it is reliable and produces less discomfort than other electrodiagnostic techniques having the same intended purpose. MUNIX assumes that the relationship between the area of sEMG obtained at increasing levels of muscle activation and the values of a variable called 'ideal case motor unit count' (ICMUC), defined as the product of the ratio between area and power of the compound muscle action potential (CMAP) by that of the sEMG, is described by a decreasing power function. Nevertheless, the reason for this comportment is unknown. The objective of this work is to investigate if the definition of MUNIX could derive from more basic properties of the sEMG. APPROACH: The CMAP and sEMG epochs obtained at different levels of muscle activation from (1) the abductor pollicis brevis (APB) muscle of persons with and without a carpal tunnel syndrome (CTS) and (2) from a computer model of sEMG generation previously published were analysed. MAIN RESULTS: MUNIX reflects the power relationship existing between the area and power of a sEMG. The exponent of this function was smaller in patients with motor CTS than in the rest of the subjects. The analysis of the relationship between the area and power of a sEMG could aid in distinguishing a MUNIX reduction due to a motoneuron loss from that due to a loss of muscle fibre. SIGNIFICANCE: MUNIX is derived from the relationship between the area and power of a sEMG. This relationship changes when there is a loss of motor units (MUs), which partially explains the diagnostic sensibility of MUNIX. Although the reasons for this change are unknown, it could reflect an increase in the proportion of MUs of great amplitude. PMID- 29424360 TI - Dose equivalent transmission data for shielding industrial x-ray facilities up to 800 kV. AB - The transmission factors used to calculate radiation shielding around an industrial x-ray device are determined using the MCNP6 code. The transmission factors are given for high voltages ranging between 120 and 800 kV for lead and between 200 and 800 kV for concrete. In view of the high usage intensity of industrial devices, the transmission factors are evaluated up to 1.10-10. The parameters used in the classic equation of Archer et al are derived from the transmission data calculated here. This type of data exists in the literature, but only for voltages lower than 150 kV to meet the design demands for facilities used in the medical field. In addition, this study markedly supplements the existing data, in particular for industrial and research installations. PMID- 29424361 TI - Patterning of functional human astrocytes onto parylene-C/SiO2 substrates for the study of Ca2+ dynamics in astrocytic networks. AB - OBJECTIVE: Recent literature suggests that astrocytes form organized functional networks and communicate through transient changes in cytosolic Ca2+. Traditional techniques to investigate network activity, such as pharmacological blocking or genetic knockout, are difficult to restrict to individual cells. The objective of this work is to develop cell-patterning techniques to physically manipulate astrocytic interactions to enable the study of Ca2+ in astrocytic networks. APPROACH: We investigate how an in vitro cell-patterning platform that utilizes geometric patterns of parylene-C on SiO2 can be used to physically isolate single astrocytes and small astrocytic networks. MAIN RESULTS: We report that single astrocytes are effectively isolated on 75 * 75 um square parylene nodes, whereas multi-cellular astrocytic networks are isolated on larger nodes, with the mean number of astrocytes per cluster increasing as a function of node size. Additionally, we report that astrocytes in small multi-cellular clusters exhibit spatio-temporal clustering of Ca2+ transients. Finally, we report that the frequency and regularity of Ca2+ transients was positively correlated with astrocyte connectivity. SIGNIFICANCE: The significance of this work is to demonstrate how patterning hNT astrocytes replicates spatio-temporal clustering of Ca2+ signalling that is observed in vivo but not in dissociated in vitro cultures. We therefore highlight the importance of the structure of astrocytic networks in determining ensemble Ca2+ behaviour. PMID- 29424362 TI - Physics of SrTiO3-based heterostructures and nanostructures: a review. AB - This review provides a summary of the rich physics expressed within SrTiO3-based heterostructures and nanostructures. The intended audience is researchers who are working in the field of oxides, but also those with different backgrounds (e.g., semiconductor nanostructures). After reviewing the relevant properties of SrTiO3 itself, we will then discuss the basics of SrTiO3-based heterostructures, how they can be grown, and how devices are typically fabricated. Next, we will cover the physics of these heterostructures, including their phase diagram and coupling between the various degrees of freedom. Finally, we will review the rich landscape of quantum transport phenomena, as well as the devices that elicit them. PMID- 29424363 TI - From hadrons to quarks in neutron stars: a review. AB - In recent years our understanding of neutron stars has advanced remarkably, thanks to research converging from many directions. The importance of understanding neutron star behavior and structure has been underlined by the recent direct detection of gravitational radiation from merging neutron stars. The clean identification of several heavy neutron stars, of order two solar masses, challenges our current understanding of how dense matter can be sufficiently stiff to support such a mass against gravitational collapse. Programs underway to determine simultaneously the mass and radius of neutron stars will continue to constrain and inform theories of neutron star interiors. At the same time, an emerging understanding in quantum chromodynamics (QCD) of how nuclear matter can evolve into deconfined quark matter at high baryon densities is leading to advances in understanding the equation of state of the matter under the extreme conditions in neutron star interiors. We review here the equation of state of matter in neutron stars from the solid crust through the liquid nuclear matter interior to the quark regime at higher densities. We focus in detail on the question of how quark matter appears in neutron stars, and how it affects the equation of state. After discussing the crust and liquid nuclear matter in the core we briefly review aspects of microscopic quark physics relevant to neutron stars, and quark models of dense matter based on the Nambu Jona-Lasinio framework, in which gluonic processes are replaced by effective quark interactions. We turn then to describing equations of state useful for interpretation of both electromagnetic and gravitational observations, reviewing the emerging picture of hadron-quark continuity in which hadronic matter turns relatively smoothly, with at most only a weak first order transition, into quark matter with increasing density. We review construction of unified equations of state that interpolate between the reasonably well understood nuclear matter regime at low densities and the quark matter regime at higher densities. The utility of such interpolations is driven by the present inability to calculate the dense matter equation of state in QCD from first principles. As we review, the parameters of effective quark models-which have direct relevance to the more general structure of the QCD phase diagram of dense and hot matter-are constrained by neutron star mass and radii measurements, in particular favoring large repulsive density-density and attractive diquark pairing interactions. We describe the structure of neutron stars constructed from the unified equations of states with crossover. Lastly we present the current equations of state-called 'QHC18' for quark-hadron crossover-in a parametrized form practical for neutron star modeling. PMID- 29424364 TI - Performance evaluation of a direct-conversion flat-panel detector system in imaging and quality assurance for a high-dose-rate 192Ir source. AB - In high-dose-rate (HDR) brachytherapy, a direct-conversion flat-panel detector (d FPD) clearly depicts a 192Ir source without image halation, even under the emission of high-energy gamma rays. However, it was unknown why iridium is visible when using a d-FPD. The purpose of this study was to clarify the reasons for visibility of the source core based on physical imaging characteristics, including the modulation transfer functions (MTF), noise power spectral (NPS), contrast transfer functions, and linearity of d-FPD to high-energy gamma rays. The acquired data included: x-rays, [X]; gamma rays, [gamma]; dual rays (X + gamma), [D], and subtracted data for depicting the source ([D] - [gamma]). In the quality assurance (QA) test for the positional accuracy of a source core, the coordinates of each dwelling point were compared between the planned and actual source core positions using a CT/MR-compatible ovoid applicator and a Fletcher Williamson applicator. The profile curves of [X] and ([D] - [gamma]) matched well on MTF and NPS. The contrast resolutions of [D] and [X] were equivalent. A strongly positive linear correlation was found between the output data of [gamma] and source strength (r 2 > 0.99). With regard to the accuracy of the source core position, the largest coordinate difference (3D distance) was noted at the maximum curvature of the CT/MR-compatible ovoid and Fletcher-Williamson applicators, showing 1.74 +/- 0.02 mm and 1.01 +/- 0.01 mm, respectively. A d FPD system provides high-quality images of a source, even when high-energy gamma rays are emitted to the detector, and positional accuracy tests with clinical applicators are useful in identifying source positions (source movements) within the applicator for QA. PMID- 29424365 TI - The effects of a revised operational dose quantity on the response characteristics of neutron survey instruments. AB - The ICRU is considering revising the definition of ambient dose equivalent. This paper investigates the impacts of the proposed change on four designs of neutron survey instrument, the GNU, HSREM, LB6411 and Studsvik 2202D, in terms of their respective energy dependences of response and their performances in realistic workplace fields. In some circumstances the current designs of instrument still produce acceptable characteristics, but in general they may need to be re optimized to better match the requirements of the new operational quantity; to that end, a simple retrofit solution for the GNU is demonstrated. The performance criteria against which instruments are judged may also need to be revised to reflect the proposed change. PMID- 29424366 TI - Large-area few-layer hexagonal boron nitride prepared by quadrupole field aided exfoliation. AB - A quadrupole electric field-mediated exfoliation method is proposed to convert micron-sized hexagonal boron nitride (h-BN) powder into few-layer hexagonal boron nitride nanosheets (h-BNNS). Under optimum conditions (400 Hz, 40 V, 32 MUg ml-1, sodium deoxycholate, TAE medium), the h-BN powders (thickness >200 nm, horizontal scale ~10 MUm) are successfully exfoliated into 0.5-4 nm (1-10 layers) thick h BNNS with the same horizontal scale. Dynamic laser scattering and atomic force microscope data show that the yield is 47.6% (for the portion with the thickness of 0.5-6 nm), and all of the vertical sizes are reduced to smaller than 18 nm (45 layers). PMID- 29424367 TI - Simulating biological processes: stochastic physics from whole cells to colonies. AB - The last few decades have revealed the living cell to be a crowded spatially heterogeneous space teeming with biomolecules whose concentrations and activities are governed by intrinsically random forces. It is from this randomness, however, that a vast array of precisely timed and intricately coordinated biological functions emerge that give rise to the complex forms and behaviors we see in the biosphere around us. This seemingly paradoxical nature of life has drawn the interest of an increasing number of physicists, and recent years have seen stochastic modeling grow into a major subdiscipline within biological physics. Here we review some of the major advances that have shaped our understanding of stochasticity in biology. We begin with some historical context, outlining a string of important experimental results that motivated the development of stochastic modeling. We then embark upon a fairly rigorous treatment of the simulation methods that are currently available for the treatment of stochastic biological models, with an eye toward comparing and contrasting their realms of applicability, and the care that must be taken when parameterizing them. Following that, we describe how stochasticity impacts several key biological functions, including transcription, translation, ribosome biogenesis, chromosome replication, and metabolism, before considering how the functions may be coupled into a comprehensive model of a 'minimal cell'. Finally, we close with our expectation for the future of the field, focusing on how mesoscopic stochastic methods may be augmented with atomic-scale molecular modeling approaches in order to understand life across a range of length and time scales. PMID- 29424368 TI - Unusually large Stokes shift for a near-infrared emitting DNA-stabilized silver nanocluster. AB - In this paper we present a new near-IR emitting silver nanocluster (NIR-DNA-AgNC) with an unusually large Stokes shift between absorption and emission maximum (211 nm or 5600 cm-1). We studied the effect of viscosity and temperature on the steady state and time-resolved emission. The time-resolved results on NIR-DNA AgNC show that the relaxation dynamics slow down significantly with increasing viscosity of the solvent. In high viscosity solution, the spectral relaxation stretches well into the nanosecond scale. As a result of this slow spectral relaxation in high viscosity solutions, a multi-exponential fluorescence decay time behavior is observed, in contrast to the more mono-exponential decay in low viscosity solution. PMID- 29424369 TI - Comment on 'Deep convolutional neural network with transfer learning for rectum toxicity prediction in cervical cancer radiotherapy: a feasibility study'. AB - The application of machine learning (ML) presents tremendous opportunities for the field of oncology, thus we read 'Deep convolutional neural network with transfer learning for rectum toxicity prediction in cervical cancer radiotherapy: a feasibility study' with great interest. In this article, the authors used state of the art techniques: a pre-trained convolutional neural network (VGG-16 CNN), transfer learning, data augmentation, drop out and early stopping, all of which are directly responsible for the success and the excitement that these algorithms have created in other fields. We believe that the use of these techniques can offer tremendous opportunities in the field of Medical Physics and as such we would like to praise the authors for their pioneering application to the field of Radiation Oncology. That being said, given that the field of Medical Physics has unique characteristics that differentiate us from those fields where these techniques have been applied successfully, we would like to raise some points for future discussion and follow up studies that could help the community understand the limitations and nuances of deep learning techniques. PMID- 29424370 TI - Large-area synthesis and photoelectric properties of few-layer MoSe2 on molybdenum foils. AB - Compared with MoS2 and WS2, selenide analogs have narrower band gaps and higher electron mobilities, which make them more applicable to real electrical devices. In addition, few-layer metal selenides have higher electrical conductivity, carrier mobility and light absorption than the corresponding monolayers. However, the large-scale and high-quality growth of few-layer metal selenides remains a significant challenge. Here, we develop a facile method to grow large-area and highly crystalline few-layer MoSe2 by directly selenizing the Mo foil surface at 550 degrees C within 60 min under ambient pressure. The atomic layers were controllably grown with thicknesses between 3.4 and 6 nm, which just met the thickness range required for high-performance electrical devices. Furthermore, we fabricated a vertical p-n junction photodetector composed of few-layer MoSe2 and p-type silicon, achieving photoresponsivity higher by two orders of magnitude than that of the reported monolayer counterpart. This technique provides a feasible approach towards preparing other 2D transition metal dichalcogendes for device applications. PMID- 29424371 TI - Incidental thyroid carcinoma in patients with TIR1, TIR2 and TIR3 FNA. AB - AIM: The aim of our study was to evaluate the presence of incidental differentiated thyroid carcinomas, at final histological examination, in patients undergoing thyroidectomy or lobectomy for presumed benign pathology or in those with cytological diagnosis of indeterminate nodules (TIR3). MATERIAL OF STUDY: 457 patients who underwent surgery for benign disease and 179 patients with indeterminate FNA were included in our study. RESULTS: 77 out of 457 patients had the diagnosis of differentiated thyroid carcinoma. 29 out of 179 patients had the same diagnosis as previous ones, but not on the undetermined FNA nodule. In the most of the cases, the istotype was follicular variant of papillary carcinoma. DISCUSSION: The incidence of incidental carcinomas, approximately the same in the two groups of patients, respectively 16.8% and 16.2%, shows that there is still a group of patients with benign thyroid disease escaping a careful ultrasound evaluation and therefore a targeted FNA. Even in patients with indeterminate cytology, the presence of an incidental carcinoma suggests that on the one hand there has been an overestimation and on the other a non-recognition of the really suspect nodule. Although in most cases it is a microcarcinoma, we must not overlook the presence of many tumors at stage T3. CONCLUSIONS: Surely the analysis of the set of risk factors with a wider application of molecular biology surveys will in the future lead to better selection of patients to undergo surgery sooner than those that can be followed in follow up even for a longer period of time. KEY WORDS: Differentiated thyroid carcinoma, Fine needle aspiration, Incidental carcinoma. PMID- 29424372 TI - Desmoid tumor of the abdominal wall A case report and literature review. AB - BACKGROUND: Desmoid tumor is a rare soft tissues neoplasia characterized by local invasiveness and by a tendency towards local recurrence although not towards metastasization. DISCUSSION: Etiology is not clear. Desmoid tumors originate from the monoclonal proliferation of one mesenchymal cell and develop in the context of fascial, muscular and aponeurotic tissue. They are free of capsule and do not usually metastatize, although they do present a high risk of local recurrence CONCLUSION: In the absence of a systematic data collection and of a clear distinction, in the existing databases, between primitive and recurrent lesions and between lesions of different sites, there are no standard guidelines for a correct management of desmoids. KEY WORDS: Aggressive fibromatos Desmoid tumor, Soft tissue neoplasia. PMID- 29424374 TI - Retraction: Hacking on decoy-state quantum key distribution system with partial phase randomization. AB - This corrects the article DOI: 10.1038/srep04759. PMID- 29424375 TI - Thickness dependent Raman spectra and interfacial interaction between Ag and epitaxial graphene on 6H-SiC(0001). AB - Graphene as the thinnest material has an extremely large specific surface area, and thus the physical properties of graphene based devices should be sensitively dependent on the contacted metals. Moreover, the interfacial interaction between graphene and metals is complicated and it is difficult to probe. In this paper, epitaxial graphene is prepared by thermal decomposition of 6H-SiC(0001), and then Ag is deposited on it. It is found that the morphology and distribution of Ag particles on graphene domains are independent of the graphene thickness. The Ag particles induce the surface enhanced Raman scattering (SERS) effect and the doping effect in epitaxial graphene. The enhancement factor of SERS as well as the splitting of the G band and the shift of the 2D band decreases with increasing graphene thickness, which can be ascribed to the weakened interaction between Ag and EG. This is confirmed by the charge transfer between the Ag atom and epitaxial graphene on 6H-SiC predicted by first-principles calculations. The results are helpful to the design and development of graphene-based composites and devices. PMID- 29424376 TI - Nonanuclear Ni(ii) complexes in a [1-7-1] formation derived from asymmetric multidentate ligands: magnetic and electrochemical properties. AB - Nonanuclear Ni(ii) complexes, [Ni9(Ln)6(OH)6(H2O)6] (Ni9Ln, n = 1-4; H2Ln = 6 acetoacetyl-2-pyridinecarboxylic acid derivatives), were prepared via self assembly using the asymmetric multidentate ligands H2Ln. A corner-sharing tetrahedron-type structure, [Ni7(MU3-OH)6]8+, and terminal mononuclear units constitute the nonanuclear structure in a [1-7-1] formation. The electrochemical and magnetic properties of Ni9Ln were modulated by the introduction of various substituents in H2Ln. PMID- 29424373 TI - UPRmt regulation and output: a stress response mediated by mitochondrial-nuclear communication. AB - The mitochondrial network is not only required for the production of energy, essential cofactors and amino acids, but also serves as a signaling hub for innate immune and apoptotic pathways. Multiple mechanisms have evolved to identify and combat mitochondrial dysfunction to maintain the health of the organism. One such pathway is the mitochondrial unfolded protein response (UPRmt), which is regulated by the mitochondrial import efficiency of the transcription factor ATFS-1 in C. elegans and potentially orthologous transcription factors in mammals (ATF4, ATF5, CHOP). Upon mitochondrial dysfunction, import of ATFS-1 into mitochondria is reduced, allowing it to be trafficked to the nucleus where it promotes the expression of genes that promote survival and recovery of the mitochondrial network. Here, we discuss recent findings underlying UPRmt signal transduction and how this adaptive transcriptional response may interact with other mitochondrial stress response pathways. PMID- 29424377 TI - Highly efficient direct oxygen electro-reduction by partially unfolded laccases immobilized on waste-derived magnetically separable nanoparticles. AB - A biocatalytic system based on laccase functionalized waste-derived iron oxide nanoparticles (LAC-DA-Fe2O3) was designed by a mechanochemical approach and employed in the electrocatalytic reduction of oxygen. Full characterization of the obtained bioconjugates revealed that the protein adopted a partially unfolded state. The mentioned configuration, together with the geometry coordination changes along the T1 center can be further related to a high bioelectrocatalytic response. A current density up to 2.9 mA cm-2 has been achieved, which is among the highest values reported in literature for laccase functionalized nanomaterials. PMID- 29424378 TI - Atomistic and continuum scale modeling of functionalized graphyne membranes for water desalination. AB - Recent theoretical and experimental studies reported ultra-high water permeability and salt rejection in nanoporous single-layer graphene. However, creating and controlling the size and distribution of nanometer-scale pores pose significant challenges to application of these membranes for water desalination. Graphyne and hydrogenated graphyne have tremendous potential as ultra-permeable membranes for desalination and wastewater reclamation due to their uniform pore distribution, atomic thickness and mechano-chemical stability. Using molecular dynamics (MD) simulations and upscale continuum analysis, the desalination performance of bare and hydrogenated alpha-graphyne and gamma-{2,3,4}-graphyne membranes is evaluated as a function of pore size, pore geometry, chemical functionalization and applied pressure. MD simulations show that pores ranging from 20 to 50 A2 reject in excess of 90% of the ions for pressures up to 1 GPa. Water permeability is found to range up to 85 L cm-2 day-1 MPa-1, which is up to three orders of magnitude larger than commercial seawater reverse osmosis (RO) membranes and up to ten times that of nanoporous graphene. Pore chemistry, functionalization and geometry are shown to play a critical role in modulating the water flux, and these observations are explained by water velocity, density, and energy barriers in the pores. The atomistic scale investigations are complemented by upscale continuum analysis to examine the performance of these membranes in application to cross-flow RO systems. This upscale analysis, however, shows that the significant increase in permeability, observed from MD simulations, does not fully translate to current RO systems due to transport limitations. Nevertheless, upscale calculations predict that the higher permeability of graphyne membranes would allow up to six times higher permeate recovery or up to 6% less energy consumption as compared to thin-film composite membranes at currently accessible operating conditions. Significantly higher energy savings and permeate recovery can be achieved if higher feed-flow rates can be realized. PMID- 29424379 TI - Mechanochromic MOF nanoplates: spatial molecular isolation of light-emitting guests in a sodalite framework structure. AB - Mechanochromic materials have a wide range of promising technological applications, such as photonics-based sensors and smart optoelectronics. The examples of mechanochromic metal-organic framework (MOF) materials, however, are still relatively uncommon in the literature. Herein, we present a previously undescribed Guest@MOF system, comprising "Perylene@ZIF-8" nanoplates, which will undergo a reversible 442 nm ? 502 nm photoemission switching when subjected to a moderate level of mechanically-induced pressure at several tens of MPa. The nanoplates were constructed via high-concentration reaction (HCR) strategy at ambient conditions to yield a crystalline ZIF-8 framework hosting the luminous Perylene guests. The latter confined within the porous sodalite cages of ZIF-8. Remarkably, we show that in a solid-state condition, it is the spatial isolation and nano-partitioning of the luminescent guests that bestow the unique solution like optical properties measured in the host-guest assembly. As such, we demonstrate that switchable red- or blue-shifts of the visible emission can be accomplished by mechanically modifying the nanoscale packing of the nanoplates (e.g. monoliths, pellets). Theoretical calculations suggest that the elasticity of the host's sodalite cage coupled with the intermolecular weak interactions of the confined guest are responsible for the unique mechanochromic luminescence behavior observed. PMID- 29424380 TI - High-efficiency SrTiO3/TiO2 hetero-photoanode for visible-light water splitting by charge transport design and optical absorption management. AB - Herein, a two-pronged approach to obtain excellent visible-light performance of SrTiO3/TiO2 photoelectrodes for water oxidation is presented. More specifically, the combination of hetero-constructing SrTiO3 nanocubes and Cr3+/Ti3+ dual-doping has been demonstrated for achieving high efficiency of charge separation and extending photoresponse of TiO2 nanotube arrays from the UV to visible light region. As expected, this unique Cr-SrTiO3-x/Cr-TiO2-x photoanode exhibited remarkably improved PEC performance for water splitting (4.05 mA cm-2) under visible light irradiation, which is more than 100 times higher than that of pristine TiO2 nanotube arrays. Additionally, the photocurrent intensity as well as water splitting behavior remain constant even after long time irradiation, revealing its high PEC as well as structure stability. Thereby, the rational design of the interface charge transport and precise management of optical absorption endow the TiO2-based PEC system with excellent and stable visible light performance for water splitting. PMID- 29424381 TI - Liquid metal-based amalgamation-assisted lithography for fabrication of complex channels with diverse structures and configurations. AB - Numerous lab-on-a-chip applications benefit from channels with complex structures and configurations in the areas of tissue engineering and clinical diagnostics. The current fabrication approaches require time-consuming, complicated processes and bulky, expensive facilities. In this work, we propose a novel method for the fabrication of complex channels with the assistance of amalgamation of liquid metal with copper tape. This new technique enables the rapid fabrication of liquid metal molds with various dimensions and diverse structures. Two proof-of concept experiments were conducted to verify the utilization of this method. First, the channel replicated from the liquid metal mold is used to enhance the mixing performance of liquids flowing through the channel. Second, a channel with a semicircular cross-section is fabricated to achieve 3D focusing in a simple way. This proposed technique can be readily used for fabricating complex channels for a wide range of applications. PMID- 29424383 TI - Population dynamics of Aphis gossypii Glover and in sole and intercropping systems of cotton and cowpea. AB - Population dynamics of aphids have been studied in sole and intercropping systems. These studies have required the use of more precise analytical tools in order to better understand patterns in quantitative data. Mathematical models are among the most important tools to explain the dynamics of insect populations. This study investigated the population dynamics of aphids Aphis gossypii and Aphis craccivora over time, using mathematical models composed of a set of differential equations as a helpful analytical tool to understand the population dynamics of aphids in arrangements of cotton and cowpea. The treatments were sole cotton, sole cowpea, and three arrangements of cotton intercropped with cowpea (t1, t2 and t3). The plants were infested with two aphid species and were evaluated at 7, 14, 28, 35, 42, and 49 days after the infestations. Mathematical models were used to fit the population dynamics of two aphid species. There were good fits for aphid dynamics by mathematical model over time. The highest population peak of both species A. gossypii and A. craccivora was found in the sole crops, and the lowest population peak was found in crop system t2. These results are important for integrated management programs of aphids in cotton and cowpea. PMID- 29424382 TI - Harvesting Season and Botanical Origin Interferes in Production and Nutritional Composition of Bee Pollen. AB - We aimed to evaluate the frequency of bee pollen production, its botanical origin and chemical composition when collected in different seasons. Our results indicate that higher proteins (22.80 +/- 3.09%) and flavonoids (2789.87 +/- 1396.00 MUg 100g-1) levels were obtained in the winter season, which also showed greater pollen production (134.50 +/- 35.70 grams) and predominance of the Myrtaceae family. As for spring we found high concentrations of lipids (4.62 +/- 2.26%) and low ash content (2.22 +/- 0.39%). Regarding the amino acid composition and vitamin C content, we found no differences between the averages throughout the seasons. Our results highlight the importance of understanding not only the botanical origin and the chemical composition of bee pollen, but also the harvesting frequency of this product by bees, so that it becomes possible to supplement the colonies in times of natural food resources shortage. PMID- 29424384 TI - Hematological and biometric traits of tuvira Gymnotus inaequilabiatus (Valenciennes, 1839) (Gymnotiformes: Gymnotidae) from the Brazilian Pantanal. AB - This study describes the hematological and biometric characteristics of male and female Gymnotus species from the Pantanal, Mato Grosso do Sul state, Brazil. Fifty adult specimens of Gymnotus inaequilabiatus were weighed, measured, and then euthanized. Blood was collected by puncturing the celiac mesenteric vein to determine the hematocrit, hemoglobin content, number of erythrocytes, mean corpuscular volume, mean corpuscular hemoglobin concentration, glucose level, absolute value of leukocytes, and relative value of leukocytes and thrombocytes. Body weight and relative condition factor did not differ (P > 0.05) between the sexes, as well as erythrogram and the blood glucose values. Hematocrit ranged from 18.0% to 54.0%; hemoglobin from 1.1 to 14.7 g dL-1; number of erythrocytes from 0.2 * 106 to 3.8 *106 uL-1; MCV from 24.2 to 321.7 fL; and MCHC from 4.2 to 44.5 g dL-1. In the differential count were identified thrombocytes, lymphocytes, neutrophils, monocytes, basophils, immature leukocytes, and PAS-positive granular leukocyte (PAS-GL). Females had a higher percentage of immature leukocytes (P < 0.05) than males. Glucose levels, erythrogram, leukogram, and the morphology of defense cells are comparable to other fish species of the Pantanal. Thrombocytes were the most frequent defense cells, followed by lymphocytes and neutrophils. PMID- 29424385 TI - Bohnenblust-Hille inequalities: analytical and computational aspects. AB - The Bohnenblust-Hille polynomial and multilinear inequalities were proved in 1931 and the determination of exact values of their constants is still an open and challenging problem, pursued by various authors. The present paper briefly surveys recent attempts to attack/solve this problem; it also presents new results, like connections with classical results of the linear theory of absolutely summing operators, and new perspectives. PMID- 29424386 TI - The effect of Agaricus brasiliensis extract supplementation on honey bee colonies. AB - This study was done to discover any beneficial effect of a medicinal mushroom Agaricus brasiliensis extract on the honey bee. Firstly, a laboratory experiment was conducted on 640 bees reared in 32 single-use plastic rearing cups. A. brasiliensis extract proved safe in all doses tested (50, 100 and 150 mg/kg/day) irrespective of feeding mode (sugar syrup or candy). Secondly, a three-year field experiment was conducted on 26 colonies treated with a single dose of A. brasiliensis extract (100 mg/kg/day) added to syrup. Each year the colonies were treated once in autumn and twice in spring. The treatments significantly increased colony strength parameters: brood rearing improvement and adult population growth were noticed more often than the increase in honey production and pollen reserves. These positive effects were mainly observed in April. In conclusion, A. brasiliensis extract is safe for the bees and helps maintaining strong colonies, especially in spring. PMID- 29424387 TI - Yellow sweet potato flour: use in sweet bread processing to increase beta carotene content and improve quality. AB - Yellow sweet potato is mostly produced by small farmers, and may be a source of energy and carotenoids in the human diet, but it is a highly perishable crop. To increase its industrial application, yellow sweet potato flour has been produced for use in bakery products. This study aimed to evaluate the technological quality and the carotenoids content in sweet breads produced with the replacement of wheat flour by 0, 3, 6, and 9% yellow sweet potato flour. Breads were characterized by technological parameters and beta-carotene levels during nine days of storage. Tukey's test (p<0.05) was used for comparison between means. The increase in yellow sweet potato flour concentrations in bread led to a decrease of specific volume and firmness, and an increase in water activity, moisture, orange coloring, and carotenoids. During storage, the most significant changes were observed after the fifth day, with a decrease in intensity of the orange color. The beta-carotene content was 0.1656 to 0.4715 ug/g in breads with yellow sweet potato flour. This work showed a novel use of yellow sweet potato in breads, which brings benefits to consumers' health and for the agricultural business. PMID- 29424388 TI - Evaluation antibacterial and antibiofilm activity of the antimicrobial peptide P34 against Staphylococcus aureus and Enterococcus faecalis. AB - The adhesion ability of bacteria to abiotic surfaces has important implications in food industries, because these organisms can survive for long periods through the biofilm formation. They can be transferred from one place to another in the industry causing contamination of the food processing environment. In this study, the antibacterial and antibiofilm activities of the antimicrobial peptide P34, characterized as a bacteriocin-like substance (BLS P34) were tested against planktonic and sessile cells of Staphylococcus aureus and Enterococcus faecalis isolated from foods. The BLS P34 showed inhibitory effect against all planktonic cells of E. faecalis. The inhibition of biofilm formation and the eradication of pre-formed biofilm were evaluated with the crystal violet assay and with the reduction of 3-bromide [4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium. The BLS P34 promoted a reduction of percentage of adhered microbial cells on the surface, not being able to perform the complete elimination of biofilm formation. The metabolic activity of S. aureus biofilms decreased considerably between 41 95%. However, E. faecalis cells showed up metabolically stimulated. The BLS P34 has the potential antibiofilm for the species S. aureus. Studies suggest more detailed approaches to a better understanding of the interactions between the antimicrobial and bacterial cells within the biofilm structure. PMID- 29424390 TI - The behavior of Aphis gossypii and Aphis craccivora (Hemiptera: Aphididae) and of their predator Cycloneda sanguinea (Coleoptera: Coccinellidae) in cotton-cowpea intercropping systems. AB - The intercropping is an important cultural practice commonly used in pest management. It is based on the principle that increased plant diversity in the agro-ecosystem can lead to reductions of pest populations in the crop. The current study aimed to assess the impact the colored fiber cotton-cowpea intercropped systems on Aphis gossypii and Aphis craccivora and on their predator Cycloneda sanguinea and the losses and the dispersion behavior of these aphids and their predator in these cropping systems. The experiment had a randomized block experimental design with two bioassays and four treatments. The number of apterous and alate aphids (A. gossypii) per cotton plant was 1.46 and 1.73 or 1.97 and 2.19 times highest in the solid cotton system than that found in the cotton-cowpea intercropped systems (S1) and (S2), respectively. On the other hand, the cotton-cowpea intercropped systems (S1 and S2) reduced, respectively, in 43% and 31% the number of apterousA. gossypiiper cotton plant compared to the control. Implementing cotton-cowpea intercropped system in the S1 scheme reduced A. gossypii infestation, favored the multiplication of C. sanguinea, and allowed obtaining heavier open bolls. PMID- 29424389 TI - Effectiveness of Arbuscular Mycorrhizal Fungal Isolates from the Land Uses of Amazon Region in Symbiosis with Cowpea. AB - Arbuscular mycorrhizal fungi provide several ecosystem services, including increase in plant growth and nutrition. The occurrence, richness, and structure of arbuscular mycorrhizal fungi communities are influenced by human activities, which may affect the functional benefits of these components of the soil biota. In this study, 13 arbuscular mycorrhizal fungi isolates originating from soils with different land uses in the Alto Solimoes-Amazon region were evaluated regarding their effect on growth, nutrition, and cowpea yield in controlled conditions using two soils. Comparisons with reference isolates and a mixture of isolates were also performed. Fungal isolates exhibited a wide variability associated with colonization, sporulation, production of aboveground biomass, nitrogen and phosphorus uptake, and grain yield, indicating high functional diversity within and among fungal species. A generalized effect of isolates in promoting phosphorus uptake, increase in biomass, and cowpea yield was observed in both soils. The isolates of Glomus were the most efficient and are promising isolates for practical inoculation programs. No relationship was found between the origin of fungal isolate (i.e. land use) and their symbiotic performance in cowpea. PMID- 29424391 TI - Somatic embryogenesis in Carica papaya as affected by auxins and explants, and morphoanatomical-related aspects. AB - The aim of this study was to evaluate somatic embryogenesis in juvenile explants of the THB papaya cultivar. Apical shoots and cotyledonary leaves were inoculated in an induction medium composed of different concentrations of 2,4-D (6, 9, 12, 15 and 18 uM) or 4-CPA (19, 22, 25, 28 and 31 uM). The embryogenic calluses were transferred to a maturation medium for 30 days. Histological analysis were done during the induction and scanning electron microscopy after maturing. For both types of auxin, embryogenesis was achieved at higher frequencies with cotyledonary leaves incubated in induction medium than with apical shoots; except for callogenesis. The early-stage embryos (e.g., globular or heart-shape) predominated. Among the auxins, best results were observed in cotyledonary leaves induced with 4-CPA (25 uM). Histological analyses of the cotyledonary leaf derived calluses confirmed that the somatic embryos (SEs) formed from parenchyma cells, predominantly differentiated via indirect and multicellular origin and infrequently via synchronized embryogenesis. The secondary embryogenesis was observed during induction and maturation phases in papaya THB cultivar. The combination of ABA (0.5 uM) and AC (15 g L-1) in maturation medium resulted in the highest somatic embryogenesis induction frequency (70 SEs callus-1) and the lowest percentage of early germination (4%). PMID- 29424392 TI - Reproductive Biology of Varronia curassavica Jacq. (Boraginaceae). AB - Varronia curassavica, a subshrubby medicinal species associated with restinga in the Atlantic Forest, has been exploited by local people and the pharmaceutical industry. Indeed, restingas have experienced a continuous process of degradation, and thus, with species and ecosystem both at risk, efforts to support conservation actions are required. The present study aimed to evaluate aspects of V. curassavica reproductive biology. To accomplish this, morphological characterization was performed by monitoring flowering events. The availability of nectar and pollen, as well as the frequency and behavior of floral visitors and dispersers, was also evaluated. This species exhibits both heterostyly and protogyny. Anthesis is diurnal, and flowers last less than a day. The high number of flower and fruit abortions suggests that mechanisms, such as self incompatibility intra-morphs and easily detached flowers, contribute to reduced fruit production. The high diversity of floral visitors indicate a generalist pollination syndrome. Diptera, Hymenoptera and Lepidoptera were the main pollinators, and nectar was the main resource sought by these insects. Fruits were dispersed by birds and ants. It can be concluded that the interaction of V. curassavica with several species is a key factor in its own survival and for maintaining the biological diversity of restinga. PMID- 29424393 TI - Fatty acid composition from the marine red algae Pterocladiella capillacea (S. G. Gmelin) Santelices & Hommersand 1997 and Osmundaria obtusiloba (C. Agardh) R. E. Norris 1991 and its antioxidant activity. AB - This study evaluated the chemical composition and antioxidant activity of fatty acids from the marine red algae Pterocladiella capillacea (S. G. Gmelin) Santelices & Hommersand 1997 and Osmundaria obtusiloba (C. Agardh) R. E. Norris 1991. The gas chromatography mass spectrometry (GC-MS) identified nine fatty acids in the two species. The major fatty acids of P. capillacea and O. obtusiloba were palmitic acid, oleic acid, arachidonic acid and eicosapentaenoic acid. The DPPH radical scavenging capacity of fatty acids was moderate ranging from 25.90% to 29.97%. Fatty acids from P. capillacea (31.18%) had a moderate ferrous ions chelating activity (FIC), while in O. obtusiloba (17.17%), was weak. The ferric reducing antioxidant power (FRAP) of fatty acids from P. capillacea and O. obtusiloba was low. As for beta-carotene bleaching (BCB), P. capillacea and O. obtusiloba showed a good activity. This is the first report of the antioxidant activities of fatty acids from the marine red algae P. capillacea and O. obtusiloba. PMID- 29424394 TI - Serra Pelada: the first Amazonian Meteorite fall is a Eucrite (basalt) from Asteroid 4-Vesta. AB - Serra Pelada is the newest Brazilian eucrite and the first recovered fall from Amazonia (State of Para, Brazil, June 29th 2017). In this paper, we report on its petrography, chemistry, mineralogy and its magnetic properties. Study of four thin sections reveals that the meteorite is brecciated, containing basaltic and gabbroic clasts, as well of recrystallized impact melt, embedded into a fine medium grained matrix. Chemical analyses suggest that Serra Pelada is a monomict basaltic eucritic breccia, and that the meteorite is a normal member of the HED suite. Our results provide additional geological and compositional information on the lithological diversity of its parent body. The mineralogy of Serra Pelada consists basically of low-Ca pyroxene and high-Ca plagioclase with accessory minerals such as quartz, sulphide (troilite), chromite - ulvospinel and ilmenite. These data are consistent with the meteorite being an eucrite, a basaltic achondrite and a member of the howardite-eucrite-diogenite (HED) clan of meteorites which most likely are from the crust asteroid 4 Vesta. PMID- 29424395 TI - [Effect of a high-fat diet on cholesterol gallstone formation]. AB - BACKGROUND: It is known that some nutrients play an important role in the development of cholelithiasis. Cholesterol is carried by micelles and vesicles in the bile. During the first stage of gallstone formation, cholesterol crystals derive from thermodynamically unstable vesicles. AIM: To determine the effect of a high fat diet on blood lipids and bile composition, and its implication in the formation of gallstones. MATERIAL AND METHODS: Two groups of 15 BALB/c mice each, coming from the same litter, were treated with a control or with a high-fat diet (64% fat and 0.14% cholesterol). After two months, the animals were sacrificed, blood and bile samples were obtained. Serum glucose and the corresponding lipid profiles were measured. In bile samples, cholesterol and phospholipid levels were analyzed, and cholesterol transporters (vesicles and micelles) were separated by gel filtration chromatography. RESULTS: Treated animals showed an 87% increase in serum total cholesterol (p < 0.01), a 97% increase in HDL-cholesterol (p < 0.05) and a 140% increase in LDL-cholesterol (p < 0.05). No changes in serum triglycerides or glucose were observed. In bile, a 13% increase in biliary cholesterol (p < 0.05) was observed but no change in biliary phospholipids. Also, an increase in biliary vesicular transporters and an increase of cholesterol/phospholipid ratio in vesicular transporters were observed. CONCLUSIONS: A high fat diet may contribute to the formation of gallstones in our experimental model. PMID- 29424396 TI - [Quality of sleep and academic performance in high school students]. AB - BACKGROUND: Sleeping and studying are the day-to-day activities of a teenager attending school. AIM: To determine the quality of sleep and its relationship to the academic performance among students attending morning and afternoon shifts in a public high school. MATERIAL AND METHODS: Students of the first and second year of high school answered an interview about socio-demographic background, academic performance, student activities and subjective sleep quality; they were evaluated using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The interview was answered by 322 first year students aged 15 +/- 5 years attending the morning shift and 364 second year students, aged 16 +/- 0.5 years, attending the afternoon shift. The components: sleep latency, habitual sleep efficiency, sleep disturbance, drug use and daytime dysfunction were similar and classified as good in both school shifts. The components subjective sleep quality and duration of sleep had higher scores among students of the morning shift. The mean grades during the first semester of the students attending morning and afternoon shifts were 5.9 and 5.8, respectively (of a scale from 1 to 7). Among students of both shifts, the PSQI scale was associated inversely and significantly with academic performance. CONCLUSIONS: A bad sleep quality influences academic performance in these students. PMID- 29424397 TI - [Health and wellbeing of sexual minorities]. AB - BACKGROUND: Most of the information in Chile about health and wellbeing of sexual minorities refers to risk behaviors. AIM: To assess health and wellbeing in a sample of Chilean homosexual men and women. MATERIAL AND METHODS: Spanish versions of the Satisfaction With Life Scale and Outcome Questionnaire-45 (OQ-45) were answered by 191 homosexual women and 256 homosexual men aged 18 to 67 years, from four Chilean cities. RESULTS: Lesbian women have better levels of satisfaction with life and adjustment in personal relationships than homosexual men. Eight percent of respondents had suicidal thoughts in some moment of their life. CONCLUSIONS: The information gathered in this work could help in the development of mental health policies for sexual minorities. PMID- 29424398 TI - [Assessment of moral competence of physicians]. AB - BACKGROUND: Moral competence (MC) in physicians is fundamental, given the increasing complexity of medicine. The "Moral Competence Test" (MCT (c) Lind) evaluates this feature and its indicator is the C Index (CI). AIM: To explore moral competence and its associated factors among physicians working in Chile. MATERIAL AND METHODS: The MCT was answered by 236 physicians from two medical centers who voluntarily participated in the study. Besides the test, participants completed an encrypted form giving information about gender, years in practice and post-graduate studies. RESULTS: The average CI value of the participants was 20,9. Post-graduate studies had a significant positive influence on CI. There was a significant decrease in CI, between 16 and 20 years of professional exercise. Gender and the area of post-graduate studies did not have a significant influence. CONCLUSIONS: The studied physicians showed a wide range of CI which was positively affected by the postgraduate studies performed. The years of professional practice had a negative influence. Expanding training opportunities during professional practice could have a positive effect on CM as measured by CI. PMID- 29424399 TI - [Presence of intracellular Escherichia coli in patients with inflammatory bowel disease]. AB - BACKGROUND: Different strains of invasive Escherichia coli (E. coli), isolated from intestinal mucosa of patients, are related to the pathogenesis of inflammatory bowel diseases (IBD). AIM: To evaluate an association between intracellular E. coli and IBD; its clinical characteristics and use of steroids. MATERIAL AND METHODS: Sixty one patients with Crohn's disease and 83 with ulcerative colitis were studied. To determine the intracellular E. coli content, colonoscopy biopsies of these patients and 29 control subjects were processed using the gentamicin protection assay. Differences in the bacterial content between patient groups were evaluated using Mann-Whitney test, while the association between presence of E. coli with endoscopic activity, location/extension and use of corticosteroid as anti-inflammatory treatment were evaluated with Fisher's exact test or Chi-square test. RESULTS: E. coli strains were detected in 36.1, 39.3 and 10.3% of patients with ulcerative colitis, Crohn's disease and controls, respectively. The number of bacteria per biopsy in Crohn's disease and ulcerative colitis was significantly higher than in controls (p < 0.01 between patients and controls). In ulcerative colitis, significant associations were found between the presence of bacteria and disease location and use of corticosteroids. In Crohn's disease, no association was found. CONCLUSIONS: IBD are associated with the presence of intracellular E. coli strains in the intestinal mucosa, suggesting an alteration in the microbiota or loss of integrity of the epithelial barrier. The association of intracellular E. coli with clinical features and the use of corticosteroids in ulcerative colitis suggests that different factors could promote colonization or proliferation of these bacteria. PMID- 29424400 TI - [Validity of scales for the functional assessment of critically ill patients]. AB - The decrease in mortality in critical patient units led to an increase in intensive care unit acquired weakness (ICUAW), which significantly affects the functional performance and quality of life of patients. There are several scales that measure functionality in critical patients. The aim of this systematic review is to determine the criterion validity and reliability of the scales that evaluate functionality in critically ill adult patients. We considered studies in critically ill adult subjects of both genders that determined the psychometric properties of the scales that evaluate functionality. Six minutes' walk test (6MWT), timed up and go (TUG), the Medical Research Council sum score (MRC-SS), grip strength, discharge destination and need for rehabilitation at discharge were considered as gold standards. Three scales were identified: PFIT-s, Perme MS, and DEMMI. PFIT-s has a positive correlation with 6MWT, MRC-SS and grip strength, and a negative correlation with TUG. It also predicts the need for rehabilitation at discharge and discharge to the home. DEMMI has a positive correlation with MRC-SS. the interobserver reliability was evaluated in three articles, demonstrating an almost perfect association. The intraobserver agreement was considered good in one report. With this information, it is not possible to determine which is the instrument with better measurement properties. PMID- 29424401 TI - [Association between adverse childhood experiences with depression in adults consulting in primary care]. AB - BACKGROUND: Traumatic experiences during childhood may influence the development of mental disorders during adulthood. AIM: To determine clinical and psychosocial variables that are associated with a higher frequency of adverse childhood experiences (ACE) in patients who consult for depression in Primary Health Care clinics in Chile. MATERIAL AND METHODS: A socio-demographic interview, the mini international neuropsychiatric interview (MINI), a screening for ACE, a questionnaire for partner violence (PV), the Life Experiences Survey (LES) and the Hamilton Rating Scale for Depression (HRDS) were applied to 394 patients with major depression (87% women). RESULTS: Eighty two percent of patients had experienced at least one ACE and 43% of them reported three or more. Positive correlations were observed between the number of ACE and severity of depressive symptoms (r = 0.19; p < 0.01), psychiatric comorbidities (r = 0.23; p < 0.01), partner violence events (r = 0.31; p < 0.01), vital stressful events (r = 0.12; p < 0.01), number of depressive episodes (r = 0.16; p < 0.01), duration of the longer depressive episode (r = 0.12; p < 0.05) and suicidal tendency according to HDRS (r = 0.16; p < 0.01). An inverse correlation was observed between frequency of ACE and age at the first depressive episode (r = -0.12; p < 0.05). CONCLUSIONS: These data are consistent with the hypothesis that early trauma is associated with more severe and complex depressive episodes during adulthood. PMID- 29424402 TI - [Effects of high intensity interval training on blood pressure in hypertensive subjects]. AB - BACKGROUND: Exercise training may reduce blood pressure. AIM: To determine the effects of a high intensity interval training (HIIT) exercise protocol on systolic and diastolic blood pressure in hypertensive subjects. MATERIAL AND METHODS: Eleven men and 27 women aged 46.4 +/- 9.8 years were divided in two groups according to their blood pressure. Sixteen were classified as normotensive and 22 as hypertensive. All attended an exercise program with 3 sessions per week for a total of 24 sessions. Each session consisted of one minute of intense exercise performed on a stationary bike, followed by an inactive pause lasting two minutes. This cycle was repeated 10 times and it was thus called 1 * 2 * 10. Blood pressure, weight (kg) and body fat were assessed. RESULTS: In the hypertensive group, there was a significant reduction in systolic blood pressure from 145.4 +/- 9.0 to 118.3 +/- 15.6 mm Hg (p < 0.05). No significant change was observed in diastolic blood pressure (84.9 +/- 3.9 and 85.8 +/- 17.6 mmHg. Thus, there was a mean reduction in systolic pressure of 27. 7 +/- 18.9 mmHg. Therefore, 73% of patients achieved systolic pressures within normal range, without medication. CONCLUSIONS: The 1 * 2 * 10 exercise method is effective to improve and restore normal blood pressure in persons with hypertension in a period of two months and 24 sessions. PMID- 29424403 TI - [The effects of weight stigmatization on obese people and health care professionals]. AB - Weight stigmatization is defined as the devaluation of others based on weight, a visible and specific characteristic that cannot be hidden. The consequences of weight stigmatization have been studied in victims and healthcare providers. This narrative literature review describes the consequences of weight stigmatization in victims and healthcare practitioners. According to several studies, high levels of psychological dysfunction in victims coexist with negative stereotypes in healthcare professionals, since the latter are exposed to the same negative media messages about obesity. Thus, weight stigmatization contributes to increase the burden of obesity, since when obese patients perceive that they are discriminated by healthcare professionals, their unhealthy behaviors persist and they have a low adherence to obesity treatment and medical recommendations. PMID- 29424404 TI - [Endobronchial ultrasound-guided transbronchial needle aspiration]. AB - In the last years, several techniques have been developed to obtain a prompt diagnosis or rule out lung cancer. Endobronchial ultrasound- guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure with a high diagnostic yield for mediastinal and central pulmonary lesions. This procedure is especially useful for lung cancer diagnosis and mediastinal staging. Two different types of EBUS are currently available: Radial EBUS and lineal EBUS. Each one has technical differences together with a range of clinical indications. The aim of this review is to discuss about EBUS-TBNA and its current clinical indications, evidence about the accuracy of the procedure for lung cancer diagnosis and staging, and evaluation of the pathological and molecular studies (EGFR, ALK, and ROS1) obtained through EBUS-TBNA and rapid on-site evaluation (ROSE). PMID- 29424405 TI - [Satiation and satiety in the regulation of energy intake]. AB - The study of the factors that regulate high energy food intake is especially relevant nowadays due to the high prevalence of overweight and obesity. Food intake regulation can be divided in two basic processes, namely satiation and satiety. Satiation is the process that determines the moment in which feeding stops and regulates the amount of ingested food during a single meal. Satiety is the interval between meals and regulates the time elapsed between two meals. The longer the interval, the lower energy intake. Each of these processes are regulated by different factors, which are here reviewed. PMID- 29424406 TI - [Tribute to the teachers Cora Mayers Glehy and Alfredo Demaria Andreani]. AB - Dr. Cora Mayers Glehy, was the director of the Nursing School, head of the Department of Health Education of the General Health Office, a founding member of the Pediatric Society and Dr. Alfredo Demaria Andreani, was a prominent student leader, first sanitarian graduated in the University of John Hopkins, director of Health, professor of the Chair of Hygiene and Preventive Medicine. Both were brilliant academics of the Faculty of Medicine of the University of Chile in the early 1930's and great achievements were expected from them by the medical and university community. These hopes and longings were destroyed when they tragically ended their lives on the morning of a Monday, January 12, 1931. PMID- 29424407 TI - [The constructivist epistemological belief about scientific knowledge varies according to the year of training in medical students but not in students of other health careers]. AB - BACKGROUND: To optimize the teaching-learning process it is fundamental to know the representations that students have regarding knowledge. Epistemological beliefs are implicit theories that guide the practical actions of people. AIM: To characterize and compare epistemological beliefs regarding the nature and acquisition of scientific knowledge of health career students. MATERIAL AND METHODS: Between 2012 and 2013, 726 students coursing first, third or fifth year from six health careers answered a validated questionnaire that includes closed and open questions aimed to characterize their epistemological beliefs about scientific knowledge. RESULTS: Irrespective of the career, when students had to select predefined answers, most of them appeared as constructivists (61%). On the other hand, when they had to argue, the majority seemed objectivist (47%). First year medical students have the highest frequency of constructivist epistemological beliefs (56%). Paradoxically, the lowest percentage is found (34%) in the fifth year. The students of the health careers, in particular those of Medicine, recognize that knowledge is not acquired immediately (83%) and that its distribution is shared (92%). CONCLUSIONS: Discordance between selections and arguments suggests that epistemological sophistication is achieved declaratively but not practically. The lower proportion of students who presented constructivist beliefs in the fifth year compared to first year of Medicine could be associated with the pedagogical approaches used in the different cycles of the career. PMID- 29424408 TI - [Concept frame for curricular innovation in health care schools]. AB - We herein describe the conceptual dimension of the curricular innovation process carried out in the Faculty of Medicine of the University of Chile. We describe the context of innovation. The theoretical pertinence and relevance of a competence driven curriculum for health care professionals is discussed. The epistemological, ontological and didactic dimensions of the curricular innovation are examined. A main issue is the notion of competence and its significance in professional training. The curriculum is essentially considered as a moral endeavor, especially for health care professionals and their quest to improve the quality of life of the population. PMID- 29424409 TI - [Does therapeutic privilege have a place in modern medicine?] AB - During the last years, bioethical discussion has highlighted the role of the patients' autonomy, being informed consent its particular expression, about decisions that they should make about their own health. The Hippocratic tradition, the deontological positions of the Geneva Declaration of the World Medical Association and numerous codes of ethics in various countries, require that the physician, above all, should ensure patients' health. In this context the discussion on pros and cons for the so-called "therapeutic privilege" are discussed. The "therapeutic privilege" refers to the withholding of information by the clinician during the consent process in the belief that disclosure of this information would lead to harm or suffering of the patient. The circumstances and conditions in which this privilege can become valid are discussed. Special reference is made in order to respect multiculturalism and to the possibility of obtaining advice from health care ethics committees. The role of prudence in the doctor-patient relation must be highlighted. Disclosure of information should be subordinated and oriented to the integral well-being of the patient. PMID- 29424410 TI - [Diabetes mellitus caused by a mutation of glucokinase gene. Report of an affected family]. AB - Maturity-Onset Diabetes of the Young (MODY) refers to a heterogeneous group of monogenic diabetes. Unlike other types of MODY characterized by genetic defects in transcription factors, MODY 2 is triggered by metabolic alterations caused by mutations of glucokinase (GCK), the first enzyme of the glycolytic pathway. We report a three-generation Chilean family with multiple cases affected with this disease. The index case is a patient who presented severe neonatal hyperglycemia (831 mg/dl, without ketosis) requiring continuous infusion of insulin, which was suspended after 48 hours with normalization of blood glucose. Subsequently, continuous glucose monitoring at 4 months of age revealed 47% of tissue glucose levels above 140 mg/dl, with fasting glucose levels between 120 and 166 mg/dl. The genetic analysis revealed a previously reported mutation in heterozygous state of the GCK gene (c.148C>T; p.His50Tyr). This mutation was also identified in more than one affected relative in the last two generations, with a transmission pattern suggestive of dominant inheritance. GCK gene sequencing led to a correct molecular diagnosis of MODY 2 while bioinformatic analysis indicated the possible molecular causes of the enzyme dysfunction. The knowledge of the molecular diagnosis allowed an adequate medical treatment for this disease. PMID- 29424411 TI - [Blastic plasmacytoid dendritic cell neoplasm. Report of three cases]. AB - Blastic plasmacytoid dendritic cell neoplasm is a rare hematological malignancy derived from immature plasmacytoid dendritic cells. The tumor cells have an immature blastic appearance, and diagnosis is based on the expression of CD4, CD56 y CD123 in the absence of other lymphoid, natural killer, or myeloid antigens. The majority of affected individuals are older people with a mean age of 66 years. Male to female ratio is approximately 3:1. Common presentation includes cutaneous lesions followed by tumor dissemination. Treatment with conventional chemotherapy is ineffective and allogeneic hematopoietic stem cell transplantation is required to achieve remission. We report three male patients, aged 23, 27 and 51 years with the disease. All had multiple, infiltrated pink plaques and nodules on the skin of their face, neck and thorax, measuring 1 to 12 cm in diameter. All tumors were histologically characterized by a monotonous proliferation of medium size cells with blastic features. Tumor cells were positive for CD123, CD56, CD4 and CD7 in all cases. After a mean of follow-up of 14.6 months, one patient died of the disease, one patient is alive and the disease relapsed after 17 months of remission and one patient is alive with no evidence of the disease. PMID- 29424412 TI - [Treatment of heparin-induced thrombocytopenia with rivaroxaban. Case report]. AB - Heparin-induced thrombocytopenia (HIT) is immune-mediated. It occurs more frequently with unfractionated heparin (UFH) than with low molecular weight heparins (LMWH). It is associated with thromboembolic rather than hemorrhagic events, as opposed to thrombocytopenia of other etiologies. The key in therapy is the cessation of heparin and the start of another anticoagulant. We report a 58 years old female with HIT secondary to the use of Enoxaparin who was successfully managed with Rivaroxaban. Our goal is to report a novel therapy and provide the evidence that supports its use. PMID- 29424413 TI - [Acute polyradiculoneuropathy associated with human Herpes Virus 7 in an immunocompetent patient. Case report]. AB - Human herpes virus 7 (HHV-7) is a cause of encephalitis, meningitis and myeloradiculoneuropathy in adults who are immunocompetent or with immunosuppression. The involvement of the peripheral nervous system is always associated with myelitis. We report a case of acute polyradiculoneuropathy due to HHV-7, without involvement of central nervous system, in an immunocompetent patient. A 35-years-old man complained of lumbar pain radiating to both buttocks. On examination muscle strength and tendon reflexes were normal. He had asymmetric pinprick and light touch saddle hypoesthesia and also in the perineal region, dorsum and lateral aspect of the left foot. Magnetic resonance imaging showed mild thickening and contrast enhancement of cauda equina nerve roots. Polymerase chain reaction performed on cerebrospinal fluid was positive for HVV-7. Other inflammatory, infectious and neoplastic etiologies were ruled out. Lumbar pain and hypoesthesia improved progressively and neurological examination was normal after one month. He did not receive antiviral therapy. PMID- 29424414 TI - [Tithonus syndrome]. PMID- 29424415 TI - [Proposal of a method for establishing order of authorship in multicenter observational studies]. PMID- 29424416 TI - [Curricular training in global health in Chile: a pending challenge?] PMID- 29424417 TI - [Handbook for the Standardization of Clinical Studies in Chile: from conception to publication]. PMID- 29424418 TI - Extracellular matrix fragmentation in young, healthy cartilaginous tissues. AB - Although the composition and structure of cartilaginous tissues is complex, collagen II fibrils and aggrecan are the most abundant assemblies in both articular cartilage (AC) and the nucleus pulposus (NP) of the intervertebral disc (IVD). Whilst structural heterogeneity of intact aggrecan ( containing three globular domains) is well characterised, the extent of aggrecan fragmentation in healthy tissues is poorly defined. Using young, yet skeletally mature (18-30 months), bovine AC and NP tissues, it was shown that, whilst the ultrastructure of intact aggrecan was tissue-dependent, most molecules (AC: 95 %; NP: 99.5 %) were fragmented (lacking one or more globular domains). Fragments were significantly smaller and more structurally heterogeneous in the NP compared with the AC (molecular area; AC: 8543 nm2; NP: 4625 nm2; p < 0.0001). In contrast, fibrillar collagen appeared structurally intact and tissue-invariant. Molecular fragmentation is considered indicative of a pathology; however, these young, skeletally mature tissues were histologically and mechanically (reduced modulus: AC: ~ 500 kPa; NP: ~ 80 kPa) comparable to healthy tissues and devoid of notable gelatinase activity (compared with rat dermis). As aggrecan fragmentation was prevalent in neonatal bovine AC (99.5 % fragmented, molecular area: 5137 nm2) as compared with mature AC (95.0 % fragmented, molecular area: 8667 nm2), it was hypothesised that targeted proteolysis might be an adaptive process that modified aggrecan packing (as simulated computationally) and, hence, tissue charge density, mechanical properties and porosity. These observations provided a baseline against which pathological and/or age-related fragmentation of aggrecan could be assessed and suggested that new strategies might be required to engineer constructs that mimic the mechanical properties of native cartilaginous tissues. PMID- 29424421 TI - Physical restraint: perceptions of nurse managers, registered nurses and healthcare assistants. AB - AIM: To examine the perceptions of nurse managers, registered nurses and healthcare assistants of physical restraint use on older people in a long-term care setting in the Republic of Ireland. BACKGROUND: The use of physical restraint, although controversial, persists in long-term care settings, despite recommendations for restraint-free environments. Perception and attitude of staff can influence use of physical restraint. METHODS: A descriptive cross-sectional design was used. A total of 250 nursing and healthcare assistant staff were recruited. A questionnaire incorporating demographics and the Perceptions of Restraint Use Questionnaire was used. Descriptive and inferential statistical analyses were conducted. RESULTS: Mean age of respondents (n = 156) was 41 years, and the majority were female. Overall, a low level of importance was attached to the use of restraint. Nurse managers and registered nurses compared favourably with healthcare assistants who attached a higher importance to use of restraint. Across all three staff groups, greatest importance was attached to the use of physical restraint for reducing falls, followed by prevention of treatment interference. Restraint was least favoured as a means of impairment management. Education was not an explanatory factor in perceived importance of physical restraint use. CONCLUSION: Nurse managers and registered nurses are unlikely to use physical restraint. However, there is concern regarding perception of healthcare assistants on use of restraint. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Results from this study compare favourably with those in countries that have no policy on physical restraint use. Educational programmes alone are insufficient to address use of physical restraint. Attention to skill mix with adequate support for healthcare assistants in long-term care settings is recommended. PMID- 29424419 TI - Neurotransmitter diversity in pre-synaptic terminals located in the parvicellular neuroendocrine paraventricular nucleus of the rat and mouse hypothalamus. AB - Virtually all rodent neuroendocrine corticotropin-releasing-hormone (CRH) neurons are in the dorsal medial parvicellular (mpd) part of the paraventricular nucleus of the hypothalamus (PVH). They form the final common pathway for adrenocortical stress responses. Their activity is controlled by sets of GABA-, glutamate-, and catecholamine-containing inputs arranged in an interactive pre-motor network. Defining the nature and arrangement of these inputs can help clarify how stressor type and intensity information is conveyed to neuroendocrine neurons. Here we use immunohistochemistry with high-resolution 3-dimensional image analyses to examine the arrangement of single- and co-occurring GABA, glutamate, and catecholamine markers in synaptophysin-defined pre-synaptic terminals in the PVHmpd of unstressed rats and Crh-IRES-Cre;Ai14 transgenic mice: respectively, vesicular glutamate transporter 2 (VGluT2), vesicular GABA transporter (VGAT), dopamine beta-hydroxylase (DBH), and phenylethanolamine n-methyltransferase (PNMT). Just over half of all PVHmpd pre-synaptic terminals contain VGAT, with slightly less containing VGluT2. The vast majority of terminal appositions with mouse CRH neurons occur non-somatically. However, there are significantly more somatic VGAT than VGluT2 appositions. In the rat PVHmpd, about five times as many pre-synaptic terminals contain PNMT than DBH only. However, because epinephrine release has never been detected in the PVH, PNMT terminals may functionally be noradrenergic not adrenergic. PNMT and VGluT2 co-occur in some pre-synaptic terminals indicating the potential for co-transmission of glutamate and norepinephrine. Collectively, these results provide a structural basis for how GABA/glutamate/catecholamine interactions enable adrenocortical responses to fast onset interosensory stimuli, and more broadly, how combinations of PVH neurotransmitters and neuromodulators interact dynamically to control adrenocortical activity. PMID- 29424420 TI - Neuroanatomical details of the lateral neurons of Drosophila melanogaster support their functional role in the circadian system. AB - Drosophila melanogaster is a long-standing model organism in the circadian clock research. A major advantage is the relative small number of about 150 neurons, which built the circadian clock in Drosophila. In our recent work, we focused on the neuroanatomical properties of the lateral neurons of the clock network. By applying the multicolor-labeling technique Flybow we were able to identify the anatomical similarity of the previously described E2 subunit of the evening oscillator of the clock, which is built by the 5th small ventrolateral neuron (5th s-LNv ) and one ITP positive dorsolateral neuron (LNd ). These two clock neurons share the same spatial and functional properties. We found both neurons innervating the same brain areas with similar pre- and postsynaptic sites in the brain. Here the anatomical findings support their shared function as a main evening oscillator in the clock network like also found in previous studies. A second quite surprising finding addresses the large lateral ventral PDF-neurons (l-LNv s). We could show that the four hardly distinguishable l-LNv s consist of two subgroups with different innervation patterns. While three of the neurons reflect the well-known branching pattern reproduced by PDF immunohistochemistry, one neuron per brain hemisphere has a distinguished innervation profile and is restricted only to the proximal part of the medulla-surface. We named this neuron "extra" l-LNv (l-LNv x). We suggest the anatomical findings reflect different functional properties of the two l-LNv subgroups. PMID- 29424422 TI - Generalization of equivalence relations from photos to objects by preschool children. AB - Generalized equivalence classes are stimulus classes that consist of equivalent stimuli and other physically similar class-member stimuli. The present study evaluated whether preschool children would form equivalence classes among photos of abstract objects (2D) and show equivalence generalization to the corresponding objects (3D), printed photos (2D stimuli), and to black-and-white drawn pictures (2D stimuli). Six typically developing children were taught arbitrary relations to establish three 3-member equivalence classes with 2D stimuli presented on a computer screen. AB-AC baseline relations (for half of the participants) and AB BC relations (for the other half) were taught using a multiple-probe design to assess taught and tested relations. After class formation, three types of generalization probes were conducted: generalization to 3D stimuli, generalization between 2D (printed photos) and 3D stimuli, and generalization to drawn pictures (2D). All of the participants formed the equivalence classes. Two participants met the criterion for all three generalization probe types. Two participants presented mixed results across tests, and two participants did not exhibit equivalence generalization. The results demonstrated equivalence generalization from 2D to 3D stimuli in preschool children, although the variability across participants suggests that such generalization cannot be assumed a priori. PMID- 29424423 TI - Near-infrared spectroscopic models for analysis of winter pea (Pisum sativum L.) quality constituents. AB - BACKGROUND: Winter pea (Pisum sativum L.) grows well in a wide geographic region, both as a forage and cover crop. Understanding the quality constituents of this crop is important for both end uses; however, analysis of quality constituents by conventional wet chemistry methods is laborious, slow and costly. Near infrared reflectance spectroscopy (NIRS) is a precise, accurate, rapid and cheap alternative to using wet chemistry for estimating quality constituents. We developed and validated NIRS calibration models for constituent analysis of this crop. RESULTS: Of the 11 constituent models developed, nine constituents including moisture, dry-matter, total-nitrogen, crude protein, acid detergent fiber, neutral detergent fiber, AD-lignin, cellulose and non-fibrous carbohydrate had low standard errors and a high coefficient of determination (R2 = 0.88-0.98; 1 - VR, which is the coefficient of determination during cross-validation = 0.77 0.92) for both calibration and cross-validation, indicating their potential for quantitative predictability. The calibration models for ash (R2 = 0.65; 1 - VR = 0.46) and hemicellulose (R2 = 0.75; 1 - VR = 0.50) also appeared to be adequate for qualitative screening. Predictions of an independent validation set yielded reliable agreement between the NIRS predicted values and the reference values with low standard error of prediction (SEP), low bias, high coefficient of determination (r2 = 0.82-0.95), high ratios of performance to deviation (RPD = SD/SEP; 2.30-3.85) and high ratios of performance to interquartile distance (RPIQ = IQ/SEP; 2.57-7.59) for all 11 constituents. CONCLUSION: Precise, accurate and rapid analysis of winter pea for major forage and cover crop quality constituents can be performed at a low cost using the NIRS calibration models developed. (c) 2018 Society of Chemical Industry. PMID- 29424424 TI - Adult-specific insulin-producing neurons in Drosophila melanogaster. AB - Holometabolous insects undergo metamorphosis to reorganize their behavioral and morphological features into adult-specific ones. In the central nervous system (CNS), some larval neurons undergo programmed cell death, whereas others go through remodeling of axonal and dendritic arbors to support functions of re established adult organs. Although there are multiple neuropeptides that have stage-specific roles in holometabolous insects, the reorganization pattern of the entire neuropeptidergic system through metamorphosis still remains largely unclear. In this study, we conducted a mapping and lineage tracing of peptidergic neurons in the larval and adult CNS by using Drosophila genetic tools. We found that Diuretic hormone 44-producing median neurosecretory cells start expressing Insulin-like peptide 2 in the pharate adult stage. This neuronal cluster projects to the corpora cardiaca and dorsal vessel in both larval and adult stages, and also innervates an adult-specific structure in the digestive tract, the crop. We propose that the adult-specific insulin-producing cells may regulate functions of the digestive system in a stage-specific manner. Our study provides a neuroanatomical basis for understanding remodeling of the neuropeptidergic system during insect development and evolution. PMID- 29424425 TI - Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and CTLA-4 inhibitors). AB - Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on immune response, which is affected by sex difference, where both biological and sociological factors are involved. The role of sex in ICI trials has been overlooked. How sex correlates with ICI efficacy is incompletely understood. Clinical trials evaluating ICI versus other therapies in male and female patients were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression-free survival (PFS) were used. Six thousand and ninety-six patients from 11 trials were included. More improvement of OS was observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on the overall survival in melanoma patients versus NSCLC patients. Overall survival of patients treated with CTLA-4 inhibitor was more influenced by sex variable compared with PD-1 inhibitors. A significant sex-related efficacy difference was observed between female and male melanoma patients. Although male patients had longer OS and PFS than females when treated with ICIs versus controls, the difference was not significant. Sex difference should be more considered in future clinical trials, guidelines and clinical practice. PMID- 29424426 TI - Hormonal factors and pancreatic cancer risk in women: The Malmo Diet and Cancer Study. AB - The incidence of pancreatic cancer is leveling between sexes. Smoking, high age and heredity are established risk factors, but evidence regarding the influence of hormonal factors is unclear. In this study, we investigated the associations of reproductive factors, use of oral contraceptives (OC) and hormone replacement therapy (HRT) with pancreatic cancer risk in the Malmo Diet and Cancer Study, a prospective, population-based cohort encompassing 17,035 women. Up until 31 December 2015, 110 women were identified with incident pancreatic cancer through the Swedish Cancer Registry. Higher age at menarche was significantly associated with pancreatic cancer risk (age-adjusted [hazard ratio] HR = 1.17; 95% confidence interval [CI] 1.04-1.32, and fully adjusted HR = 1.17; 95% CI 1.04 1.32). Ever use of OC was not significantly associated with pancreatic cancer risk but ever use of HRT was significantly associated with a decreased risk of pancreatic cancer (age-adjusted HR = 0.47, 95% CI 0.23-0.97, and fully adjusted HR = 0.48, 95% CI 0.23-1.00), in particular use of estrogen-only regimen (age adjusted HR = 0.21; 95% CI 0.05-0.87 and fully adjusted HR = 0.22; 95% CI 0.05 0.90). Age at menopause or first childbirth, parity and breastfeeding history were not significantly associated with pancreatic cancer risk. Collectively, these findings suggest a protective role of female hormones against pancreatic cancer. Further studies are needed, and potential modifying genetic factors and indirect hazardous effects of smoking should also be considered. PMID- 29424427 TI - Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. AB - Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR-deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR-deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome. PMID- 29424428 TI - Volatile composition of Carignan noir wines from ungrafted and grafted onto Pais (Vitis vinifera L.) grapevines from ten wine-growing sites in Maule Valley, Chile. AB - BACKGROUND: Carignan noir is one of the minor and ancient varieties from the Chilean wine scenario that has had a resurgence as a result of to its rediscovered oenological potential when cultivated under the conditions of the interior dryland area. Under these growing conditions Carignan noir wines stand out as fruit driven and fresh compared to those originating from other growing areas. On the other hand, it is well known that wine aroma composition depends mainly on variety, viticultural management and winemaking. Thus, the present study aimed to investigate the volatile composition of wines from Carignan noir grapes originating from ungrafted and grafted onto Pais grapevines, in ten sites of the Maule Valley (Chile) during two consecutive vintages. RESULTS: Higher alcohols were the most abundant volatile compounds, whereas ethyl esters and beta damascenone were the most odoriferous compounds according to their odorant activity value. The dominant factor in Carignan noir wine volatile composition was season, whereas rootstock did not have a significant effect in differentiating the wines. In terms of climate, cold nights during the month prior to harvest correlated with higher linalool, alpha-terpineol and trans-3 hexen-1-ol content. The biologically effective degree-days index was inversely correlated with isoamyl acetate and 2-phenylethyl acetate content. Huglin's heliothermal and the average mean temperature of the warmest month indices were inversely correlated with ethyl vanillate, ethyl hexanoate and ethyl octanoate content. CONCLUSION: Site climate conditions were related to the accumulation of certain wine volatile compounds. This information may be useful for devising new Carignan noir vineyard management strategies when aiming to improve wine quality or adjust site selection approaches to maximize grape/wine volatile composition according to wine style. (c) 2018 Society of Chemical Industry. PMID- 29424429 TI - Multivariate approaches for stability control of the olive oil reference materials for sensory analysis - part I: framework and fundamentals. AB - BACKGROUND: Virgin olive oil is the only food product for which sensory analysis is regulated to classify it in different quality categories. To harmonize the results of the sensorial method, the use of standards or reference materials is crucial. The stability of sensory reference materials is required to enable their suitable control, aiming to confirm that their specific target values are maintained on an ongoing basis. Currently, such stability is monitored by means of sensory analysis and the sensory panels are in the paradoxical situation of controlling the standards that are devoted to controlling the panels. RESULTS: In the present study, several approaches based on similarity analysis are exploited. For each approach, the specific methodology to build a proper multivariate control chart to monitor the stability of the sensory properties is explained and discussed. CONCLUSION: The normalized Euclidean and Mahalanobis distances, the so called nearness and hardiness indices respectively, have been defined as new similarity indices to range the values from 0 to 1. Also, the squared mean from Hotelling's T2 -statistic and Q2 -statistic has been proposed as another similarity index. (c) 2018 Society of Chemical Industry. PMID- 29424430 TI - The stereotyped positioning of the generative cell associated with vacuole dynamics is not required for male gametogenesis in rice pollen. AB - During male gametogenesis in cereals, the generative cell undergoes a positioning process that parallels the dynamics of the central vacuole, which is believed to be associated with generative cell movement in the male gametophyte. However, the impact of the generative cell positioning and the central vacuole dynamics on male gametogenesis has remained poorly understood. Here, we report that OsGCD1 (GAMETE CELLS DEFECTIVE1) dysfunction influenced pollen development and disrupted pollen germination. Loss of function of OsGCD1 altered the central vacuole dynamics and the generative cell was mispositioned. Nevertheless, twin sperm cells were generated normally, indicating that gametogenesis does not rely on positional information as long as a generative cell is produced. The normal vacuole dynamics seems necessary only for pollen maturation and germination. Our findings also indicate that osgcd1 mutation resulted in rice male sterility in which pollen has full cell viability and generated normal gametes, but lacks the potential to germinate. PMID- 29424432 TI - Human metapneumovirus in hospitalized children less than 5 years of age in Pakistan. AB - Acute respiratory infection (ARI) is the second leading cause of death in children less than 5 years of age worldwide. Human Metapneumovirus (hMPV) is associated with around 5-7% of the total pneumonia admissions in children. The aim of this study was to determine the magnitude of hMPV associated hospitalizations among children, in Karachi, Pakistan. A 3 years prospective study was conducted at the Aga Khan University Hospital (AKUH), from August 2009 to June 2012. Children less than 5 years of age, admitted with ARIs, were enrolled. Throat swabs were collected and tested for hMPV using real-time PCR. Multivariable log binomial regression analysis was performed. Out of 1150 children enrolled, hMPV was detected among 84/1150 (7%). About 87% of the enrolled children presented with cough, followed by fever (73%), nasal congestion (69%) and shortness of breath (68%). Of the hMPV positive subjects, most (56/84, 67%) were less than 12 months of age. The most common diagnosis in hMPV positive infants was pneumonia, followed by asthma and bronchiolitis. HMPV was identified year round, with peaks during February and August. Sore throat was found to be significantly associated with the hMPV infection (Adjusted RR 2.23; 95%CI 1.42 3.52). The proportion of hMPV was higher among hospitalized infants with ARI. Pneumonia was the primary discharge diagnoses of patients who tested positive for hMPV. hMPV could be a target for future vaccine to further decrease the burden of ARI morbidity and possibly mortality in developing countries. PMID- 29424431 TI - Inhibitory and modulatory inputs to the vocal central pattern generator of a teleost fish. AB - Vocalization is a behavioral feature that is shared among multiple vertebrate lineages, including fish. The temporal patterning of vocal communication signals is set, in part, by central pattern generators (CPGs). Toadfishes are well established models for CPG coding of vocalization at the hindbrain level. The vocal CPG comprises three topographically separate nuclei: pre-pacemaker, pacemaker, motor. While the connectivity between these nuclei is well understood, their neurochemical profile remains largely unexplored. The highly vocal Gulf toadfish, Opsanus beta, has been the subject of previous behavioral, neuroanatomical and neurophysiological studies. Combining transneuronal neurobiotin-labeling with immunohistochemistry, we map the distribution of inhibitory neurotransmitters and neuromodulators along with gap junctions in the vocal CPG of this species. Dense GABAergic and glycinergic label is found throughout the CPG, with labeled somata immediately adjacent to or within CPG nuclei, including a distinct subset of pacemaker neurons co-labeled with neurobiotin and glycine. Neurobiotin-labeled motor and pacemaker neurons are densely co-labeled with the gap junction protein connexin 35/36, supporting the hypothesis that transneuronal neurobiotin-labeling occurs, at least in part, via gap junction coupling. Serotonergic and catecholaminergic label is also robust within the entire vocal CPG, with additional cholinergic label in pacemaker and prepacemaker nuclei. Likely sources of these putative modulatory inputs are neurons within or immediately adjacent to vocal CPG neurons. Together with prior neurophysiological investigations, the results reveal potential mechanisms for generating multiple classes of social context-dependent vocalizations with widely divergent temporal and spectral properties. PMID- 29424433 TI - Rituximab-Bendamustine (R-Benda) in MALT lymphoma complicating primary Sjogren syndrome (pSS). PMID- 29424435 TI - Diagnostic performance of the Sofia(r) influenza A+B fluorescent immunoassay in adult outpatients in Northern Taiwan. AB - To evaluate the diagnostic performance of the Sofia influenza A+B fluorescent immunoassay (Sofia FIA), we performed a prospective study at the Chang Gung Memorial Hospital in Taiwan from January 2012 to December 2013. Patients who presented at out-patient clinics or the emergency department with influenza-like illness were included. Upper respiratory tract specimens were collected from oropharynx or nasopharynx. Performance of the Sofia FIA was compared to that of the Formosa One Sure Flu A/B Rapid Test. A Real-time reverse transcriptase polymerase chain reaction assay (RT-PCR) and/or virus culture were used as reference standards. Of the 109 enrolled patients, the sensitivity, specificity, positive, and negative predictive values of the Sofia FIA to detect influenza A virus were 82%, 89%, 77%, and 89%, respectively. These parameters were 100% when the samples were from nasopharynx. The positive predictive value for influenza B virus detection was 29%. The sensitivity of the Sofia FIA for detection of influenza A virus was 93% between days 2 and 4 after onset of symptoms. For specimens with low viral loads (RT-PCR cycle threshold between 30 and 34.9), the sensitivity of The Sofia FIA was 83% (10/12). The Sofia FIA performed effectively in detecting influenza A virus infection. With nasopharyngeal samples, the performance was comparable to RT-PCR. Although influenza viral load typically decreases with time, the Sofia FIA was sensitive enough to identify influenza infecting patients presenting after several days of illness. However, a high false positive rate limits the assay's usefulness to identify influenza B virus infection. PMID- 29424436 TI - Predictors of Saudi nursing students' attitudes towards environment and sustainability in health care. AB - AIM: This study aimed to investigate the predictors of Saudi nursing students' attitudes towards the environment and sustainability in health care. BACKGROUND: With rising temperature and decreasing annual rainfall, Saudi Arabia is threatened by the harmful effects of climate change on its population. In response to these threats, the Ministry of Health adapted sustainable development and environmental preservation in their National E-Health strategy. INTRODUCTION: To implement these policies successfully, healthcare practitioners should be educated on how climate change could impact human health negatively. METHODS: A secondary analysis of 280 questionnaires from baccalaureate nursing students of a university in Hail City, Saudi Arabia, was completed. The New Ecological Paradigm (NEP) Scale and Sustainability Attitudes in Nursing Survey 2 (SANS-2) were used to investigate the predictors of student attitudes towards the environment and sustainable development in health care. RESULTS: The NEP score indicated moderate pro-environment attitudes, whereas the SANS-2 mean score showed very positive attitudes towards sustainability in health care. Learning about the environment and related issues in the nursing programme, raising climate change awareness and attending environment-related seminars and training positively influenced the environmental and sustainability attitudes of nursing students. DISCUSSION: Saudi nursing students moderately manifested pro-environment attitudes but exhibited extremely positive attitudes towards sustainability in health care. The results support the need to strengthen the education of nursing students about environmental and sustainability concepts and the inclusion of these topics in the nursing curricula. CONCLUSION: The study underscores the critical role of enriching the awareness of nursing students on environmental issues and concerns and sustainability in health care. IMPLICATIONS FOR NURSING AND NURSING POLICY: The findings of this study can support the inclusion of course contents, which deal specifically with environmental health and sustainability practices, in the creation of new policies directed towards curricular revision. PMID- 29424437 TI - Simulation for Predicting Effectiveness and Safety of New Cardiovascular Drugs in Routine Care Populations. AB - In the presence of heterogeneity of treatment effect (HTE), the average treatment effect from a randomized controlled trial (RCT) may not be applicable to different patients, such as those in observational settings. Our objective was to develop a novel approach that uses individual-level simulation to expand RCT results to target patient populations in the presence of HTE. For this purpose, we compared the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, and two observational studies that compared benefits and risks of dabigatran to warfarin in patients with atrial fibrillation. We developed a simulation model that replicates the rates of ischemic stroke and major bleeding observed in RE-LY using published outcome risk models and participants' baseline characteristics. We used our validated simulation model to predict what the results of the RCT would have been had it been conducted in populations similar to those in the observational studies. PMID- 29424434 TI - Immunolocalization of muscarinic M1 receptor in the rat medial prefrontal cortex. AB - The medial prefrontal cortex (mPFC) has been considered to participate in many higher cognitive functions, such as memory formation and spatial navigation. These cognitive functions are modulated by cholinergic afferents via muscarinic acetylcholine receptors. Previous pharmacological studies have strongly suggested that the M1 receptor (M1R) is the most important subtype among muscarinic receptors to perform these cognitive functions. Actually, M1R is abundant in mPFC. However, the proportion of somata containing M1R among cortical cellular types, and the precise intracellular localization of M1R remain unclear. In this study, to clarify the precise immunolocalization of M1R in rat mPFC, we examined three major cellular types, pyramidal neurons, inhibitory neurons, and astrocytes. M1R immunopositivity signals were found in the majority of the somata of both pyramidal neurons and inhibitory neurons. In pyramidal neurons, strong M1R immunopositivity signals were usually found throughout their somata and dendrites including spines. On the other hand, the signal strength of M1R immunopositivity in the somata of inhibitory neurons significantly varied. Some neurons showed strong signals. Whereas about 40% of GAD67-immunopositive neurons and 30% of parvalbumin-immunopositive neurons (PV neurons) showed only weak signals. In PV neurons, M1R immunopositivity signals were preferentially distributed in somata. Furthermore, we found that many astrocytes showed substantial M1R immunopositivity signals. These signals were also mainly distributed in their somata. Thus, the distribution pattern of M1R markedly differs between cellular types. This difference might underlie the cholinergic modulation of higher cognitive functions subserved by mPFC. PMID- 29424438 TI - T-bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1. AB - T-bet and Eomes are T-box transcription factors that drive the differentiation and function of cytotoxic lymphocytes such as NK cells. Their DNA-binding domains are highly similar, suggesting redundant transcriptional activity. However, while these transcription factors have different patterns of expression, the phenotype of loss-of-function mouse models suggests that they play distinct roles in the development of NK cells and other innate lymphoid cells (ILCs). Recent technological advances using reporter mice and conditional knockouts were fundamental in defining the regulation and function of these factors at steady state and during pathological conditions such as various types of cancer or infection. Here, we review these recent developments, focusing on NK cells as prototypical cytotoxic lymphocytes and their development, and also discuss parallels between NK cells and T cells. We also examine the role of T-bet and Eomes in human NK cells and ILC1s. Considering divergent findings on mouse and human ILC1s, we propose that NK cells are defined by coexpression of T-bet and Eomes, while ILC1s express only one of these factors, either T-bet or Eomes, depending on the tissue or the species. PMID- 29424439 TI - Divergent Response of Murine and Porcine Adipocytes to Stimulation of Browning Genes by 18-Carbon Polyunsaturated Fatty Acids and Beta-Receptor Agonists. AB - Long-chain fatty acids (LCFA) are known to activate brown and beige adipocytes. However, very little is known about the effects of the number and the position of double bonds in LCFA with the same length on brown fat-specific gene expression. To determine the specificity of LCFA in the regulation of these genes in different adipocyte models, fully differentiated 10T1/2, 3T3-L1, murine, or porcine primary adipocytes (obtained from the subcutaneous fat pad of C57BL/6 mice or Landrace * Yorkshire * Duroc crossbred piglets) were treated with 50 MUM of the following 18-carbon fatty acids: stearic acid (STA; 18:0), oleic acid (OLA; 18:1, Delta9), linoleic acid (LNA; 18:2, Delta9,12), alpha-linolenic acid (ALA; 18:3, Delta9,12,15), gamma-linolenic acid (GLA; 18:3, Delta6,9,12), or pinolenic acid (PLA; 18:3, Delta5,9,12) for 24 h with or without 4-h norepinephrine (NE) treatment. Expression levels of thermoregulatory markers were measured by quantitative real-time PCR. LNA, ALA, GLA, and PLA upregulated Ucp1 expression and tended to upregulate Pgc1a expression in murine primary adipocytes, but not in 10T1/2, 3T3-L1, and porcine primary adipocytes. In murine primary adipocytes, NE induced a higher expression of Ucp1 and Pgc1a than non-NE treated cells, and PLA augmented the NE effect. In 10T1/2 cells, NE upregulated Ucp1 and Pgc1a expression, but there was no fatty acid effect. However, 3T3-L1 cells were insensitive to both fatty acid and beta-adrenergic agonist stimulation. These results indicate that different adipocyte cell types have different levels of sensitivity to both LCFA and beta agonists in regard to induction of brown fat-specific gene expression. PMID- 29424440 TI - Apple S-RNase triggers inhibition of tRNA aminoacylation by interacting with a soluble inorganic pyrophosphatase in growing self-pollen tubes in vitro. AB - Apple exhibits S-RNase-based self-incompatibility (SI), in which S-RNase plays a central role in rejecting self-pollen. It has been proposed that the arrest of pollen growth in SI of Solanaceae plants is a consequence of the degradation of pollen rRNA by S-RNase; however, the underlying mechanism in Rosaceae is still unclear. Here, we used S2 -RNase as a bait to screen an apple pollen cDNA library and characterized an apple soluble inorganic pyrophosphatase (MdPPa) that physically interacted with S-RNases. When treated with self S-RNases, apple pollen tubes showed a marked growth inhibition, as well as a decrease in endogenous soluble pyrophosphatase activity and elevated levels of inorganic pyrophosphate (PPi). In addition, S-RNase was found to bind to two variable regions of MdPPa, resulting in a noncompetitive inhibition of its activity. Silencing of MdPPa expression led to a reduction in pollen tube growth. Interestingly, tRNA aminoacylation was inhibited in self S-RNase-treated or MdPPa silenced pollen tubes, resulting in the accumulation of uncharged tRNA. Furthermore, we provide evidence showing that this disturbance of tRNA aminoacylation is independent of RNase activity. We propose an alternative mechanism differing from RNA degradation to explain the cytotoxicity of the S RNase apple SI process. PMID- 29424441 TI - Intravenous iron isomaltoside improves hemoglobin concentration and iron stores in female iron-deficient blood donors: a randomized double-blind placebo controlled clinical trial. AB - BACKGROUND: This trial evaluated the efficacy and safety of intravenous (IV) iron isomaltoside (Monofer) in comparison with placebo in first-time female blood donors. STUDY DESIGN AND METHODS: The trial was a prospective, double blind, placebo-controlled, randomized, comparative, single-center trial of 85 first-time female blood donors. The subjects were randomly assigned 1:1 to either 1000 mg IV iron isomaltoside infusion or placebo. The primary endpoint of the trial was change in hemoglobin (Hb) from baseline to right before the third blood donation. RESULTS: The increase in Hb was significantly higher for iron isomaltoside compared with placebo right before both the second blood donation (p = 0.0327) and the third blood donation (primary endpoint, p < 0.0001). Improvements in other iron-related variables (plasma iron, plasma ferritin, transferrin saturation, and reticulocyte count) in favor of iron isomaltoside were also observed. The trial was not powered on patient-reported outcomes. However, improvements in iron stores and Hb levels after iron isomaltoside administration were supported by the fact that several of the fatigue symptoms scores showed numerical differences in favor of iron isomaltoside. There were no differences in side effects between the groups. CONCLUSION: In iron-deficient female blood donors a single IV iron isomaltoside administration resulted in an improvement in Hb concentration and iron stores and demonstrated a favorable safety profile comparable to placebo. PMID- 29424442 TI - Construction and evaluation of type III secretion system mutants of the catfish pathogen Edwardsiella piscicida. AB - Catfish is the largest aquaculture industry in the United States. Edwardsiellosis is considered one of the most significant problems affecting this industry. Edwardsiella piscicida is a newly described species within the genus Edwardsiella, and it was previously classified as Edwardsiella tarda. It causes gastrointestinal septicaemia, primarily in summer months, in farmed channel catfish in the south-eastern United States. In the current study, we adapted gene deletion methods used for Edwardsiella to E. piscicida strain C07-087, which was isolated from a disease outbreak in a catfish production pond. Four genes encoding structural proteins in the type III secretion system (T3SS) apparatus of E. piscicida were deleted by homologous recombination and allelic exchange to produce in-frame deletion mutants (EpDeltassaV, EpDeltaesaM, EpDeltayscR and EpDeltaescT). The mutants were phenotypically characterized, and virulence and vaccine efficacy were evaluated. Three of the mutants, EpDeltassaV, EpDeltayscR and EpDeltaesaM, were significantly attenuated compared to the parent strain (p < .05), but EpDeltaescT strain was not. Vaccination of catfish with the four mutant strains (EpDeltassaV, EpDeltaesaM, EpDeltayscR and EpDeltaescT) provided significant protection when subsequently challenged with wild-type strain. In conclusion, we report methods for gene deletion in E. piscicida and development of vaccine candidates derived from a virulent catfish isolate. PMID- 29424444 TI - A brief history of the AAPM: Celebrating 60 years of contributions to medical physics practice and science. PMID- 29424443 TI - Erratum: "Supplement 2 for the 2004 update of the AAPM Task Group No. 43 Report: Joint recommendations by the AAPM and GEC-ESTRO" [Med. Phys. Vol 44 (9), e297 e338 (2017)]. PMID- 29424446 TI - Diversity and seasonal abundances of mosquitoes at potential arboviral transmission sites in two different climate zones in Switzerland. AB - Pathogens of medical or veterinary significance that are transmitted by mosquitoes (Diptera: Culicidae) are (re-)emerging in Europe [e.g. West Nile virus (WNV), Dirofilaria nematodes]. Little is known about the spatiotemporal abundances of mosquito species in Switzerland. Therefore, mosquito population dynamics were investigated, focusing on areas of risk for sylvatic or synanthropic transmission, such as natural sites and suburban sites on either side of the Alpine crest. Repeated collections were made using Centers for Disease Control (CDC) traps, juvenile sampling and ovitrapping. A total of 122 831 mosquito specimens of 21 taxa were identified. Levels of mosquito species richness were similar at suburban sites and in natural zones in Switzerland. Mosquito abundances and seasonality were analysed with generalized linear mixed models based on 382 CDC trap samples (29 454 females) and revealed Aedes annulipes/cantans, Aedes geniculatus, Aedes japonicus, Aedes sticticus, Aedes vexans, Coquillettidia richiardii and Culex pipiens/torrentium as the dominant species overall. Abundances of these species were season-dependent in most cases. There was an effect of site with regard to abundance (higher in natural zones), but not with respect to seasonality. Together with data on vector competence and the host preferences of different species, the present data contribute to assessments of risk for pathogen transmission. For example, both natural and suburban environments seem feasible as sites for amplification cycles of WNV and transmission to mammals. PMID- 29424447 TI - Behavioural intervention to reduce resistance in those attending adult day care centres: PROCENDIAS study protocol for a randomized clinical trial. AB - AIM: This study evaluates the effectiveness of a behavioural intervention programme aimed at reducing the reluctance of dependent people to attend Adult Day Care Centres. We hope that reducing resistance will have a positive influence on the mental health of caregivers. BACKGROUND: Care centres offer important relief and rest services for family caregivers. Some caregivers report being affected by behavioural and psychological symptoms of dementia when they prepare dependents for the Care Centres, especially when these have dementia. Caregivers often report the need for information about how to manage the behaviour of the sick. Nurses in community healthcare units can investigate cases of patients who present resistance when attending care centres and can promote the use of interventions aimed at reducing this problem. DESIGN: Randomised controlled clinical trial. METHODS: The reference population will be care centre users in Salamanca (Spain) to select 120 family members responsible for the preparation and transfer of the care-recipient. Each participant will be randomised to an intervention group or control group (standard care). A baseline assessment and 6 months follow-up assessment will be performed (study approved in September 2016). INTERVENTION: The intervention group will consist of 8 sessions, one per week, each lasting 90 min. Each session will be run by a psychologist trained in behaviour analysis and will be tailored to the specific behavioural problems reported by the caregivers. DISCUSSION: The results of a previously published pilot study allow us to be optimistic about the possibilities of a brief intervention. PMID- 29424448 TI - Comparison of Ultrasound Elastography and Color Doppler Ultrasonography for Distinguishing Small Triple-Negative Breast Cancer From Fibroadenoma. AB - OBJECTIVES: To compare the performance of ultrasound elastography and color Doppler ultrasonography (US) in distinguishing small, oval, or round triple negative breast cancer from fibroadenoma and the influence on the further management decision at US. METHODS: In total, 131 biopsy-proven oval or round fibroadenomas (n = 68) and triple-negative breast cancers (n = 63) smaller than 2 cm were included. Three blinded readers assessed the images from US, elastography, and color Doppler imaging according to the Breast Imaging Reporting and Data System lexicon independently. Interobserver agreement was assessed, and sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve values for each data set were compared. Pathologic results were reference standards. RESULTS: The interobserver agreements were excellent (intraclass correlation coefficients, 0.856 for US, 0.948 for elastography, and 0.864 for color Doppler). The specificity and accuracy of US with elastography were increased compared with US alone or US with Doppler imaging without statistically significant differences in sensitivity. The average area under the curve for US with elastography (0.869) was increased compared with US alone (0.650) or US with color Doppler (0.576). CONCLUSIONS: Elastography is more useful than color Doppler imaging for distinguishing small, oval, or round triple negative breast cancer from fibroadenoma, and elastography can help avoid biopsy of benign masses. PMID- 29424449 TI - Viral eradication reduces both liver stiffness and steatosis in patients with chronic hepatitis C virus infection who received direct-acting anti-viral therapy. AB - BACKGROUND: Whether direct-acting anti-viral therapy can reduce liver fibrosis and steatosis in patients with chronic hepatitis C virus (HCV) infection is unclear. AIMS: To evaluate changes in liver stiffness and steatosis in patients with HCV who received direct-acting anti-viral therapy and achieved sustained virological response (SVR). METHODS: A total of 198 patients infected with HCV genotype 1 or 2 who achieved SVR after direct-acting anti-viral therapy were analysed. Liver stiffness as evaluated by magnetic resonance elastography, steatosis as evaluated by magnetic resonance imaging-determined proton density fat fraction (PDFF), insulin resistance, and laboratory data were assessed before treatment (baseline) and at 24 weeks after the end of treatment (SVR24). RESULTS: Alanine aminotransferase and homeostatic model assessment-insulin resistance levels decreased significantly from baseline to SVR24. Conversely, platelet count, which is inversely associated with liver fibrosis, increased significantly from baseline to SVR24. In patients with high triglyceride levels (>=150 mg/dL), triglyceride levels significantly decreased from baseline to SVR24 (P = 0.004). The median (interquartile range) liver stiffness values at baseline and SVR24 were 3.10 (2.70-4.18) kPa and 2.80 (2.40-3.77) kPa respectively (P < 0.001). The PDFF values at baseline and SVR 24 were 2.4 (1.7-3.4)% and 1.9 (1.3-2.8)% respectively (P < 0.001). In addition, 68% (19/28) of patients with fatty liver at baseline (PDFF >=5.2%; n = 28) no longer had fatty liver (PDFF <5.2%) at SVR24. CONCLUSION: Viral eradication reduces both liver stiffness and steatosis in patients with chronic HCV who received direct-acting anti-viral therapy (UMIN000017020). PMID- 29424450 TI - Mayo CALR mutation type classification guide using alpha helix propensity. PMID- 29424451 TI - Preoperative Axillary Ultrasound in the Selection of Patients With a Heavy Axillary Tumor Burden in Early-Stage Breast Cancer: What Leads to False-Positive Results? AB - OBJECTIVES: To determine whether imaging and clinicopathologic features could predict false-positive axillary ultrasound (US) results in the selection of patients with breast cancer who had a heavy axillary tumor burden (>=3 tumor involved nodes). METHODS: Among 788 patients with histologically confirmed invasive breast cancer at Ruijin Hospital from October 2014 to September 2015, 162 patients (cT1-T2, cN0) with 167 axillae had suspicious axillary US findings. Ultrasound findings were considered suspicious for metastasis if cortical thickening of greater than 3 mm or effacement of the fatty hilum was present. The false-positive rate of suspicious axillary US results for identifying 3 or more positive lymph nodes in the final pathologic examination was calculated. Univariate and multivariate analyses were used to evaluate imaging and clinicopathologic factors related to the false-positive results. RESULTS: Axillary US showed a false-positive rate of 60.5% (101 of 167) in the patients with breast cancer and a heavy nodal burden. By logistic regression analyses, we found false-positive axillary US results more frequently in patients who had a T1 stage tumor (P = .005), an estrogen receptor/progesterone receptor-negative tumor (P < .001), solitary suspicious nodes identified on axillary US (P < .001), and a cortical thickness of the most suspicious lymph node of 3.5 mm or less (P = .015). CONCLUSIONS: Imaging and clinicopathologic features can be used to identify axillae with less than 3 metastatic nodes in patients with early-stage breast cancer who have positive axillary US results. In the post-American College of Surgeons Oncology Group Z0011 trial era, conducting a secondary evaluation either clinically or by axillary imaging before the use of a US-guided biopsy of suspicious nodes can potentially avoid the additional morbidity of axillary lymph node dissection and reduce the preoperative workload. PMID- 29424452 TI - Evidence and mechanism by which upper partial fibulectomy improves knee biomechanics and decreases knee pain of osteoarthritis. AB - To investigate the change in short-term clinical outcomes and biomechanical properties of the knee in response to upper partial fibulectomy and to probe into the biomechanical mechanism underlying the clinical benefits of upper partial fibulectomy for medial compartment knee osteoarthritis (KOA). A total of 29 patients with medial compartment KOA underwent upper partial fibulectomy. Visual analog scale (VAS) pain, the hospital for special surgery knee score (HSS), hip knee-ankle (HKA) angle (measured in the frontal plane), and flexion/extension range of motion of the knee were assessed before and up to 6 months after surgery. Patients and 20 healthy controls were evaluated by 3D gait analysis and dynamic lower limb musculoskeletal analysis. Both VAS pain and HSS score were significantly improved (p < 0.001) one day after surgery and steadily improved during the subsequent 6 months. HKA angle improved (p = 0.025) immediately and remained stable by 3 months after surgery. The decreased overall peak KAM (decreased by 11.1%) and increased HKA angle (increased by 1.80 degrees from a more varus to more neutral alignment) of affected and operated side by 6 months after surgery were observed. Muscle activity of biceps femoris caput longum of affected and operated side increased immediately and was equivalent to healthy controls by 6 months after surgery (p = 0.007). This pilot study provides biomechanical evidence of benefit from partial upper fibulectomy and indicates a plausible rationale for the improvement in clinical symptoms. Long-term clinical outcomes and precise biomechanical mechanism of partial upper fibulectomy should be further investigated. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-10, 2018. PMID- 29424453 TI - Clinical and genetic features of the patients with X-Linked agammaglobulinemia from Turkey: Single-centre experience. AB - X-linked agammaglobulinemia is a primary immunodeficiency disorder resulting from BTK gene mutations. There are many studies in the literature suggesting contradictory ideas about phenotype-genotype correlation. The aim of this study was to identify the mutations and clinical findings of patients with XLA in Turkey, to determine long-term complications related to the disease and to analyse the phenotype-genotype correlation. Thirty-two patients with XLA diagnosed between 1985 and 2016 in Pediatric Immunology Department of Hacettepe University Ihsan Dogramaci Children's Hospital were investigated. A clinical survey including clinical features of the patients was completed, and thirty-two patients from 26 different families were included in the study. Getting early diagnosis and regular assessment with imaging techniques seem to be the most important issues for improving the health status of the patients with XLA. Early molecular analysis gives chance for definitive diagnosis and genetic counselling, but not for predicting the clinical severity and prognosis. PMID- 29424454 TI - Evaluation of SNAP cPL, Spec cPL, VetScan cPL Rapid Test, and Precision PSL Assays for the Diagnosis of Clinical Pancreatitis in Dogs. AB - BACKGROUND: The sensitivity, specificity, and agreement of 4 diagnostic assays (SNAP canine pancreatic lipase (cPL), specific cPL (Spec cPL), VetScan cPL Rapid Test, and Precision PSL) for pancreatitis in dogs have not been directly compared. HYPOTHESIS/OBJECTIVES: To determine the level of agreement among each of the 4 assays and a clinical suspicion score, level of agreement among the assays, and sensitivity and specificity of each assay in a clinically relevant patient group. ANIMALS: Fifty client-owned dogs with clinical signs of gastrointestinal disease. METHODS: Prospective study. History, physical examination, complete blood count, serum biochemistry, abdominal ultrasound examination, and the 4 diagnostic assays for pancreatitis were performed. Intraclass correlation coefficients (ICC) were used to determine the level of agreement between each assay and a clinical suspicion score determined by a panel of 5 board-certified veterinary internists. RESULTS: The ICC between the clinical suspicion score and the 4 assays were SNAP cPL, 0.61; Spec cPL, 0.68; VetScan cPL Rapid Test, 0.68; and Precision PSL, 0.60. The sensitivities of the assays ranged from 73.9 to 100.0%, whereas the specificities were SNAP cPL, 71.1-77.8%; Spec cPL, 74.1-81.1%; VetScan cPL Rapid Test, 76.9-83.8%; and Precision PSL, 64.0 74.3%. CONCLUSIONS AND CLINICAL IMPORTANCE: A good to excellent level of agreement was demonstrated among the 4 assays. The previously unreported sensitivity and specificity of the VetScan cPL Rapid Test were 73.9-83.3% and 76.9-83.8%, respectively. Results of any of the 4 diagnostic assays alone, in the absence of supporting clinical findings, are insufficient to establish a diagnosis of clinical pancreatitis in dogs. PMID- 29424455 TI - Predictive value of serum Golgi protein 73 for prominent hepatic necroinflammation in chronic HBV infection. AB - As a noninvasive marker, serum alanine aminotransferase (ALT) has limitations, because a large proportion of patients chronically infected with hepatitis B virus (HBV) suffer from severe hepatic necroinflammation, but have normal or mildly elevated ALT. In the present study, we aimed to investigate the potential value of serum Golgi protein 73 (GP73) in predicting significant hepatic necroinflamation among chronic HBV infected patients. A cohort of 497 chronic HBV infected patients was retrospectively recruited. Liver biopsy was performed in all patients and serum GP73 levels were measured by enzyme-linked immunosorbent assay. Serum GP73 increased in parallel with the increase in hepatic necroinflammatory activity grade (r = 0.682) and the stage of liver fibrosis (r = 0.539). The positive correlation of serum GP73 with the degree of hepatic necroinflammatory activity was statistically significant, while serum GP73 with the stage of liver fibrosis was weaker than that with hepatic necroinflammation. Furthermore, serum GP73 levels were significantly greater in patients with normal or mildly elevated ALT and significant hepatic necroinflammation (>=G2) than in patients with minimal to mild hepatic necroinflammation. The sensitivity and specificity of GP73 for the diagnosis of G2 hepatic necroinflammation was 42.35% and 95.0%, respectively, at a cut-off value of 88.38 ng/mL. When the cut-off value was set at 124.76 ng/mL, the sensitivity and specificity of GP73 for the diagnosis of G3 hepatic necroinflammation was 55.56% and 97.29%, respectively. These findings indicate that GP73 holds promise as an important candidate for diagnosing significant hepatic necroinflammation. PMID- 29424457 TI - A point-of-care diagnostic system to influenza viruses using chip-based ultra fast PCR. AB - In order to diagnose the infectious disease from clinical samples, the various protocols such as culturing microorganism, rapid diagnostic test using chromatographic method, ELISA, conventional PCR are developed. Since a novel strain of avian influenza can be cross-infected human as well as birds and livestock due to genetic reassortment, some strains of influenza such as H7N9 and H5N1 have emerged as a severe virus which can be threaten the health of poultry as well as human. Therefore, we explored the development of simultaneously and rapid diagnostic tool for seasonal influenza (A/H1N1, A/H3N2, B) and highly pathogenic avian influenza (A/H5N1, A/H7N9). We analyzed the unique nucleotide sequences of influenza types including three seasonal influenza, A/H7N9, and A/H5N1, and distinguished each type of influenza and diagnosed through One Step RT-PCR. In the results, Chip-based PCR technique can be diagnosed rapidly and directly from naked eye with EvaGreen the influenza also respiratory specimens within 23 min 15 s, including reverse transcription. The Chip-based PCR is a point-of-care system, and it is expected to reduce diagnosis time and to develop a diagnostic kit. Furthermore the Chip based PCR technique can be used for high risk pathogen in bioterror and/or biological warfare in the field. PMID- 29424456 TI - Characterization of Paroxysmal Gluten-Sensitive Dyskinesia in Border Terriers Using Serological Markers. AB - BACKGROUND: Paroxysmal gluten-sensitive dyskinesia (PGSD) in border terriers (BTs) results from an immunologic response directed against transglutaminase (TG)2 and gliadin. Recent evidence suggests that PGSD is only one aspect of a range of possible manifestations of gluten sensitivity in the breed. HYPOTHESIS/OBJECTIVES: Gluten sensitivity in BTs is a heterogeneous disease process with a diverse clinical spectrum; to characterize the phenotype of PGSD using TG2 and gliadin autoantibodies as diagnostic markers. ANIMALS: One hundred twenty-eight client-owned BTs with various disorders. METHODS: Prospective study. BTs with paroxysmal episodes and a normal interictal examination were phenotyped using footage of a representative episode and assigned to 3 groups: idiopathic epilepsy (IE), paroxysmal dyskinesia (PD), or other. Owners of each dog completed a questionnaire to obtain information regarding clinical signs. Healthy BTs formed a control group. Serum antibodies against TG2 and AGA were measured in all dogs. RESULTS: One hundred twenty-eight BTs were enrolled; 45 with PD, 28 with IE, 35 with other conditions, and 20 controls. Three overlapping phenotypes were identified; PD, signs suggestive of gastrointestinal disease, and dermatopathy. AGA-IgG concentrations were increased in PD, compared with IE (P = 0.012), controls (P < 0.0001) and other (P = 0.018) conditions. Anti-canine TG2-IgA concentrations were increased in PD, compared with IE (P < 0.0001), controls (P < 0.0001) and other (P = 0.012) conditions. Serological markers are highly specific for PGSD but lack sensitivity. CONCLUSIONS: PGSD appears part of a syndrome of gluten intolerance consisting of episodes of transient dyskinesia, signs suggestive of gastrointestinal disease, and dermatological hypersensitivity. PMID- 29424458 TI - Improving chemical shift encoding-based water-fat separation based on a detailed consideration of magnetic field contributions. AB - PURPOSE: To improve the robustness of existing chemical shift encoding-based water-fat separation methods by incorporating a priori information of the magnetic field distortions in complex-based water-fat separation. METHODS: Four major field contributions are considered: inhomogeneities of the scanner magnet, the shim field, an object-based field map estimate, and a residual field. The former two are completely determined by spherical harmonic expansion coefficients directly available from the magnetic resonance (MR) scanner. The object-based field map is forward simulated from air-tissue interfaces inside the field of view (FOV). The missing residual field originates from the object outside the FOV and is investigated by magnetic field simulations on a numerical whole body phantom. In vivo the spatially linear first-order component of the residual field is estimated by measuring echo misalignments after demodulation of other field contributions resulting in a linear residual field. Gradient echo datasets of the cervical and the ankle region without and with shimming were acquired, where all four contributions were incorporated in the water-fat separation with two algorithms from the ISMRM water-fat toolbox and compared to water-fat separation with less incorporated field contributions. RESULTS: Incorporating all four field contributions as demodulation steps resulted in reduced temporal and spatial phase wraps leading to almost swap-free water-fat separation results in all datasets. CONCLUSION: Demodulating estimates of major field contributions reduces the phase evolution to be driven by only small differences in local tissue susceptibility, which supports the field smoothness assumption of existing water fat separation techniques. PMID- 29424459 TI - Spin-lock imaging of 3-o-methyl-D glucose (3oMG) in brain tumors. AB - PURPOSE: To evaluate the ability of spin-lock imaging to detect the uptake of 3-o methyl-D-glucose (3oMG) in normal brain and brain tumors in animals. METHODS: Measurements of the longitudinal relaxation rate in the rotating frame (R1rho ) were made over a range of spin-lock powers in rat brains bearing 9L tumors. The dispersion of R1rho values was quantified by DeltaR1rho , the difference of R1rho values acquired with low and high locking powers. The glucose analogue 3oMG was administered intravenously and the differences of DeltaR1rho values ( DeltaR1rhodiff) before and as a function of time after administration were calculated to isolate the contribution of 3oMG to the dispersions, which at high fields primarily reflects chemical exchange effects. In addition, the ratio of image signals from low and high locking fields (the spin-lock ratio, SLR), which requires fewer acquisitions and varies directly with DeltaR1rho , was computed as an alternative measure of the variation with locking power, and changes in SLR (SLRdiff ) after 3oMG were evaluated. RESULTS: Both DeltaR1rhodiff and SLRdiff in tumors increased rapidly after injection, whereas intact brain showed a gradual increase up to 1 h. The DeltaR1rhodiff and SLRdiff were significantly different between tumors and contralateral normal tissues. CONCLUSION: Spin-lock methods can be used to detect 3oMG in vivo after injection, and appropriate analyses of MRI signals allow tumors to be distinguished from normal brain. PMID- 29424460 TI - Dual-polarity slice-GRAPPA for concurrent ghost correction and slice separation in simultaneous multi-slice EPI. AB - PURPOSE: A ghost correction strategy for Simultaneous Multi-Slice (SMS) EPI methods that provides improved ghosting artifact reduction compared to conventional methods is presented. Conventional Nyquist ghost correction methods for SMS-EPI rely on navigator data that contain phase errors from all slices in the simultaneously acquired slice-group. These navigator data may contain spatially nonlinear phase differences near regions of B0 inhomogeneity, which violates the linear model employed by most EPI ghost correction algorithms, resulting in poor reconstructions. METHODS: Dual-Polarity GRAPPA (DPG) was previously shown to accurately model and correct both spatially nonlinear and 2D phase errors in conventional single-slice EPI data. Here, an extension we call Dual-Polarity slice-GRAPPA (DPsG) is adapted to the slice-GRAPPA method and applied to SMS-EPI data for slice separation and ghost correction concurrently eliminating the need for a separate ghost correction step while also providing improved slice-specific EPI phase error correction. RESULTS: Images from in vivo SMS-EPI data reconstructed using DPsG in place of conventional Nyquist ghost correction and slice-GRAPPA are presented. DPsG is shown to reduce ghosting artifacts and provide improved temporal SNR compared to the conventional reconstruction. CONCLUSION: The proposed use of DPsG for SMS-EPI reconstruction can provide images with lower artifact levels, higher image fidelity, and improved time-series stability compared to conventional reconstruction methods. PMID- 29424461 TI - Dynamic B0 shimming of the human brain at 9.4 T with a 16-channel multi-coil shim setup. AB - PURPOSE: A 16-channel multi-coil shimming setup was developed to mitigate severe B0 field perturbations at ultrahigh field and improve data quality for human brain imaging and spectroscopy. METHODS: The shimming setup consisted of 16 circular B0 coils that were positioned symmetrically on a cylinder with a diameter of 370 mm. The latter was large enough to house a shielded 18/32-channel RF transceiver array. The shim performance was assessed via simulations and phantom as well as in vivo measurements at 9.4 T. The global and dynamic shimming performance of the multi-coil setup was compared with the built-in scanner shim system for EPI and single voxel spectroscopy. RESULTS: The presence of the multi coil shim did not influence the performance of the RF coil. The performance of the proposed setup was similar to a full third-order spherical harmonic shim system in the case of global static and dynamic slice-wise shimming. Dynamic slice-wise shimming with the multi-coil setup outperformed global static shimming with the scanner's second-order spherical-harmonic shim. The multi-coil setup allowed mitigating geometric distortions for EPI. The combination of the multi coil shim setup with the zeroth and first-order shim of the scanner further reduced the standard deviation of the B0 field in the brain by 12% compared with the case in which multi-coil was used exclusively. CONCLUSION: The combination of a multi-coil setup and the linear shim channels of the scanner provides a straightforward solution for implementing dynamic slice-wise shimming without requiring an additional pre-emphasis setup. PMID- 29424462 TI - Environmental and genetic control of cold tolerance in the Glanville fritillary butterfly. AB - Thermal tolerance has a major effect on individual fitness and species distributions and can be determined by genetic variation and phenotypic plasticity. We investigate the effects of developmental and adult thermal conditions on cold tolerance, measured as chill coma recovery (CCR) time, during the early and late adult stage in the Glanville fritillary butterfly. We also investigate the genetic basis of cold tolerance by associating CCR variation with polymorphisms in candidate genes that have a known role in insect physiology. Our results demonstrate that a cooler developmental temperature leads to reduced cold tolerance in the early adult stage, whereas cooler conditions during the adult stage lead to increased cold tolerance. This suggests that adult acclimation, but not developmental plasticity, of adult cold tolerance is adaptive. This could be explained by the ecological conditions the Glanville fritillary experiences in the field, where temperature during early summer, but not spring, is predictive of thermal conditions during the butterfly's flight season. In addition, an amino acid polymorphism (Ala-Glu) in the gene flightin, which has a known function in insect flight and locomotion, was associated with CCR. These amino acids have distinct biochemical properties and may thus affect protein function and/or structure. To our knowledge, our study is the first to link genetic variation in flightin to cold tolerance, or thermal adaptation in general. PMID- 29424464 TI - Comprehensive Guidance for Antibiotic Dosing in Obese Adults. PMID- 29424463 TI - Spin-lock imaging of early tissue pH changes in ischemic rat brain. AB - We have previously reported that the dispersion of spin-lattice relaxation rates in the rotating frame (R1rho ) of tissue water protons at high field can be dominated by chemical exchange contributions. Ischemia in brain causes changes in tissue pH, which in turn may affect proton exchange rates. Amide proton transfer (APT, a form of chemical exchange saturation transfer) has been shown to be sensitive to chemical exchange rates and able to detect pH changes non-invasively following ischemic stroke. However, the specificity of APT to pH changes is decreased because of the influence of several other factors that affect magnetization transfer. R1rho is less influenced by such confounding factors and thus may be more specific for detecting variations in pH. Here, we applied a spin locking sequence to detect ischemic stroke in animal models. Although R1rho images acquired with a single spin-locking amplitude (omega1 ) have previously been used to assess stroke, here we use DeltaR1rho , which is the difference in R1rho values acquired with two different locking fields to emphasize selectively the contribution of chemical exchange effects. Numerical simulations with different exchange rates and measurements of tissue homogenates with different pH were performed to evaluate the specificity of DeltaR1rho to detect tissue acidosis. Spin-lock and APT data were acquired on five rat brains after ischemic strokes induced via middle cerebral artery occlusions. Correlations between these data were analyzed at different time points after the onset of stroke. The results show that DeltaR1rho (but not R1rho acquired with a single omega1 ) was significantly correlated with APT metrics consistent with DeltaR1rho varying with pH. PMID- 29424465 TI - Clinical Utility of Plasma Fructosamine Concentration as a Hypoglycemic Biomarker during Early Lactation in Dairy Cattle. AB - BACKGROUND: Plasma fructosamine concentration ([FRA]) is a widely used long term hyperglycemic biomarker in humans and dogs, but its clinical usefulness as a hypoglycemic biomarker in dairy cattle is uncertain. OBJECTIVES: To evaluate the relationship between plasma [FRA] and glucose concentration ([gluc]) as well as indices of energy balance during early lactation in dairy cattle, and to characterize the influence of plasma total protein concentration ([TP]) and albumin concentration ([albumin]) on [FRA]. ANIMALS: Convenience sample comprising 103 periparturient Holstein-Friesian cattle. METHODS: Plasma [gluc], [TP], [albumin], and other clinicopathologic indices of energy status were determined periodically from Day 4 postpartum. Body condition score (BCS) was assessed, and backfat thickness (BFT) and longissimus dorsi muscle thickness (LDT) were measured ultrasonographically. Plasma [FRA] was measured at approximately 28 days postpartum. Associations between plasma [FRA] and study variables were evaluated using Spearman's rho and stepwise forward linear regression. Statistical significance was declared at P < 0.05. RESULTS: A positive association was detected between plasma [FRA] and mean plasma [gluc] from Days 4-28 postpartum (rs = +0.36, P < 0.001), and between plasma [FRA] and LDT (rs = +0.28, P = 0.007), BCS (rs = +0.23, P = 0.029), and BFT (rs = +0.21, P = 0.043). Multivariable regression identified a positive association between plasma [FRA] and mean plasma [gluc] and [albumin] from Days 4-28 postpartum. Correcting plasma [FRA] for [albumin] improved the association (rs = +0.46, P < 0.001) between plasma [FRA] and mean plasma [gluc]. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma [FRA] does not provide a clinically useful method for quantifying the magnitude of hypoglycemia or negative energy balance in dairy cows during early lactation. PMID- 29424466 TI - Differential local tissue permissiveness influences the final fate of GPR17 expressing oligodendrocyte precursors in two distinct models of demyelination. AB - Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreERT2 xCAG-eGFP mice) allowing to follow the final fate of GPR17+ cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP+ cells at damaged areas. However, only in the cuprizone model reacting GFP+ cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP+ cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti-inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery. PMID- 29424467 TI - Facilitation of Ca2+ -induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment. AB - Mitochondrial redox imbalance and high Ca2+ uptake induce the opening of the permeability transition pore (PTP) that leads to disruption of energy-linked mitochondrial functions and triggers cell death in many disease states. In this review, we discuss the major results from our studies investigating the consequences of NAD(P)-transhydrogenase (NNT) deficiency, and of statins treatment for mitochondrial functions and susceptibility to Ca2+ -induced PTP. We highlight the aggravation of high fat diet-induced fatty liver disease in the context of NNT deficiency and the role of antioxidants in the prevention of statins toxicity to mitochondria. PMID- 29424468 TI - Structure determination of butylone as a new psychoactive substance using chiroptical and vibrational spectroscopies. AB - Recently, there has been a worldwide substantial increase in the consumption of new psychoactive substances (NPS), compounds that mimic the structure of illicit drugs, such as amphetamines or ecstasy. The producers try to avoid the law by a slight modification of illicit structures, thereby developing dozens of temporarily legal NPS every year. The current trends in the detection and monitoring of such substances demand a fast and reliable analysis. Molecular spectroscopy represents a highly effective tool for the identification of NPS and chiroptical methods can provide further information on their 3D structure, which is the key for the determination of their biological activity. We present the first systematic study of NPS, specifically butylone, combining chiroptical and vibrational spectroscopies with ab initio calculations. According to density functional theory calculations, 6 stable lowest energy conformers of butylone were found and their molecular structure was described. For each conformer, the relative abundance based on the Boltzmann distribution was estimated, their population weighted spectra predicted and compared to the experimental results. Very good agreement between the experimental and the simulated spectra was achieved, which allowed not only the assignment of the absolute configuration, but also a precise description of the molecular structure. PMID- 29424469 TI - Effect of intensive blood pressure control in patients with type 2 diabetes mellitus over 9 years of follow-up: A subgroup analysis of high-risk ACCORDION trial participants. AB - Although guidelines recommend strict blood pressure (BP) control in patients with type 2 diabetes mellitus (T2DM) and elevated cardiovascular risk, the long-term effects of this approach are unknown. We investigated the effect of intensive BP control on clinical outcomes in patients with T2DM over 9 years of follow-up. We included Action to Control Cardiovascular Risk in Diabetes - Blood Pressure participants in the standard glucose control arm who had established cardiovascular disease, chronic kidney disease, were >=75 years of age or who had a 10-year coronary heart risk >=15%. Participants were randomized to either intensive (systolic BP < 120 mm Hg) or standard (systolic BP < 140 mm Hg) BP control for an average of 5 years. Observational follow-up occurred for an average of 4 years thereafter. After an average total follow-up of 9 years, intensive BP control reduced the composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke by 25% (hazard ratio, 0.75; 95% confidence interval, 0.60-0.95; P = .02). The overall benefit was driven by a reduction in nonfatal myocardial infarction (P = .01). In this post-hoc analysis, the benefits of a fixed-duration intensive BP control intervention in patients with T2DM persisted throughout 9 years of follow-up. PMID- 29424470 TI - Results of ACCORDIAN in ACCORD with lower blood pressure begetting lower mortality in patients with diabetes. PMID- 29424471 TI - Calcium imaging in Arabidopsis pollen cells using G-CaMP5. AB - Calcium (Ca2+ ) signaling has been implicated in pollen germination and pollen tube growth. To date, however, we still know very little about how exactly Ca2+ signaling links to various physiological subcellular processes during pollen germination and pollen tube growth. Given that Ca2+ signaling is tightly related to the cytosolic concentration and dynamics of Ca2+ , it is vital to trace the dynamic changes in Ca2+ levels in order to decode Ca2+ signaling. Here, we demonstrate that G-CaMP5 serves well as an indicator for monitoring cytosolic Ca2+ dynamics in pollen cells. Using this probe, we show that cytosolic Ca2+ changes dramatically during pollen germination, and, as reported previously, Ca2+ forms a tip-focused gradient in the pollen tube and undergoes oscillation in the tip region during pollen tube growth. In particular, using G-CaMP5 allowed us to capture the dynamic changes in the cytosolic Ca2+ concentration ([Ca2+ ]cyt ) in pollen tubes in response to various exogenous treatments. Our data suggest that G CaMP5 is a suitable probe for monitoring the dynamics of [Ca2+ ]cyt in pollen cells. PMID- 29424472 TI - Characterization of a satellite DNA in the genera Lacerta and Timon (Reptilia, Lacertidae) and its role in the differentiation of the W chromosome. AB - In this study, IMO-TaqI satDNA, previously isolated in several species of Lacertidae, was isolated and characterized from four species of the genus Lacerta and three of the genus Timon. The aim was to gain further insights into the evolutionary dynamics of this satDNA, its occurrence among lacertids and to understand if it plays any role in sex chromosome evolution in these seven species. The results here obtained highlighted the presence of this repetitive element in the genome of all the species investigated, thus indicating that IMO TaqI satDNA is evolutionary conserved among a wide variety of lacertids. In addition, this element was found to be very abundant in the constitutive heterochromatin of the W-sex chromosome of the four Lacerta species investigated. The occurrence of IMO-TaqI satDNA on Lacerta heterochromosome suggests that it is involved in the differentiation of the W chromosome by heterochromatinization, and the fact that it is absent in the W of other lacertids investigated seems to confirm that repetitive DNA sequences would remain randomly trapped into the sex chromosomes, undergoing amplification as a consequence of the suppression of recombination. PMID- 29424473 TI - Biocompatibility of composites based on chitosan, apatite, and graphene oxide for tissue applications. AB - Novel two-dimensional films and three-dimensional (3D) scaffolds based on chitosan (CHI), apatite (Ap), and graphene oxide (GO) were developed by an in situ synthesis in which self-assembly process was conducted to direct partial reduction of GO by CHI in acidic medium. Physical-chemical characterization was carried out by optical microscopy, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy. In vitro biological studies using murine fibroblast (MC3T3) and human neuroblastoma (SH-SY5Y) cell lines were also performed. Cell growth and adherence on composites was also checked using SEM. Live and death staining by confocal microscope and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2 (4-sulfophenyl)-2H-tetrazolium of the samples were investigated. The results confirmed the incorporation of both Ap and GO sheets, into CHI polymeric matrix. Furthermore, it was confirmed a physical integration between inorganic Ap and organic CHI and strong chemical interaction between CHI and GO in the obtained composites. SH-SY5Y cell line showed preferential adherence on CHI/GO films surface while MC3T3 cell line displayed a good compatibility for all 3D scaffolds. This study confirms the biocompatibility of materials based on CHI, Ap, and GO for future tissues applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1585-1594, 2018. PMID- 29424474 TI - A critical review of the application of polymer of low concern and regulatory criteria to fluoropolymers. AB - Per- and polyfluoroalkyl substances (PFAS) are a group of fluorinated substances that are in the focus of researchers and regulators due to widespread presence in the environment and biota, including humans, of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). Fluoropolymers, high molecular weight polymers, have unique properties that constitute a distinct class within the PFAS group. Fluoropolymers have thermal, chemical, photochemical, hydrolytic, oxidative, and biological stability. They have negligible residual monomer and oligomer content and low to no leachables. Fluoropolymers are practically insoluble in water and not subject to long-range transport. With a molecular weight well over 100 000 Da, fluoropolymers cannot cross the cell membrane. Fluoropolymers are not bioavailable or bioaccumulative, as evidenced by toxicology studies on polytetrafluoroethylene (PTFE): acute and subchronic systemic toxicity, irritation, sensitization, local toxicity on implantation, cytotoxicity, in vitro and in vivo genotoxicity, hemolysis, complement activation, and thrombogenicity. Clinical studies of patients receiving permanently implanted PTFE cardiovascular medical devices demonstrate no chronic toxicity or carcinogenicity and no reproductive, developmental, or endocrine toxicity. This paper brings together fluoropolymer toxicity data, human clinical data, and physical, chemical, thermal, and biological data for review and assessment to show that fluoropolymers satisfy widely accepted assessment criteria to be considered as "polymers of low concern" (PLC). This review concludes that fluoropolymers are distinctly different from other polymeric and nonpolymeric PFAS and should be separated from them for hazard assessment or regulatory purposes. Grouping fluoropolymers with all classes of PFAS for "read across" or structure-activity relationship assessment is not scientifically appropriate. Integr Environ Assess Manag 2018;14:316-334. (c) 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC). PMID- 29424475 TI - ANAPHASE PROMOTING COMPLEX/CYCLOSOME-mediated cyclin B1 degradation is critical for cell cycle synchronization in syncytial endosperms. AB - Although it is known that in most angiosperms mitosis in early endosperm development is syncytial and synchronized, it is unclear how the synchronization is regulated. We showed previously that APC11, also named ZYG1, in Arabidopsis activates zygote division by interaction and degradation of cyclin B1. Here, we report that the mutation in APC11/ZYG1 led to unsynchronized mitosis and over accumulation of cyclin B1-GUS in the endosperm. Mutations in two other APC subunits showed similar defects. Transgenic expression of stable cyclin B1 in the endosperm also caused unsynchronized mitosis. Further, downregulation of APC11 generated multi-nucleate somatic cells with unsynchronized mitotic division. Together, our results suggest that APC/C-mediated cyclin B1 degradation is critical for cell cycle synchronization. PMID- 29424476 TI - Cobalt-Catalyzed C-H Nitration of Indoles by Employing a Removable Directing Group. AB - A mild and efficient C(sp2 )-H nitration of 3-substituted indoles, by using the economical and non-toxic cobalt nitrate hexahydrate [Co(NO3 )2 ?6 H2 O] as a catalyst and tert-butyl nitrite (TBN) as the nitro source, is reported. This approach provides a unique methodology involving a site-selective C-N bond formation for preparation of C-2 substituted nitro indoles. Utilization of the tBoc as the removable directing group enhances the synthetic utility of the method. PMID- 29424477 TI - Association of lipoprotein-associated phospholipase A2 mass with asymptomatic cerebral artery stenosis. AB - Cerebral artery stenosis (CAS) is the most important causes of ischaemic stroke. Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays 2 diverse roles in atherosclerosis (pro-inflammatory and anti-inflammatory), and the association between Lp-PLA2 mass and cardiovascular or cerebrovascular events is inconsistent among previous studies. A cross-sectional study including 2012 North Chinese adults aged >=40 years was performed in 2010-2011 to investigate whether Lp-PLA2 mass is associated with asymptomatic cerebral artery stenosis (ACAS). Serum Lp PLA2 mass was determined by enzyme-linked immunosorbent assay (ELISA). All participants underwent transcranial Doppler (TCD) and bilateral carotid duplex ultrasound to evaluate intracranial artery stenosis (ICAS) and extracranial arterial stenosis (ECAS). The median serum Lp-PLA2 mass of the participants was 140.74 ng/mL (interquartile range: 131.79-158.07 ng/mL). The adjusted odds ratio (OR) when comparing the 4th quartile to the 1st quartile of Lp-PLA2 was 1.98 (95% confidence interval (CI): 1.42-2.78), 1.79 (95% CI: 1.08-2.94) and 1.87 (95% CI: 1.28-2.73) for the occurrence of ACAS, asymptomatic ECAS and asymptomatic ICAS, respectively, after controlling for vascular risk factors. These independently significant associations remained statistically significant in the male or elderly subgroups, but not in females or middle-aged participants. Lp-PLA2 mass is positively correlated with subclinical atherosclerosis determined by ACAS, ICAS and ECAS in North Chinese, particularly in male and older participants, suggesting that serum Lp-PLA2 mass might be potential biomarker for the detection of ACAS in the adults. PMID- 29424478 TI - Liver graft-to-spleen volume ratio as a useful predictive factor of the early graft function in children and young adults transplanted for biliary atresia: a retrospective study. AB - A graft volume/standard liver volume ratio (GV/SLV) > 35% or graft/recipient weight ratio (GRWR) > 0.8% has been considered as a standard criteria of graft selection. Even if the graft size meets these selection criteria, small-for-size syndrome can still occur depending on the portal venous flow (PVF). The aim of this study was to identify other factors contributing to portal hyperperfusion and the post-transplant course, focusing on the graft volume-to-spleen volume ratio (GV/SV). Thirty-seven BA patients who underwent living donor liver transplantation were reviewed retrospectively. First, we evaluated the preoperative factors contributing to portal hyperperfusion. Second, we evaluated the factors contributing to post-transplant complications, such as thrombocytopenia, hyperbilirubinemia, and coagulopathy. The GV/SLV was >35% in all cases; however, portal hyperperfusion (>=250 ml/min/100 g graft) was found in 12 recipients (35.3%). Furthermore, although the GRWR was >0.8% in over 90% of cases, portal hyperperfusion was found in 10 recipients (32.3%). In contrast, the GV/SV showed a significant correlation with the PVF after reperfusion. If the GV/SV was <0.88, about 80% of recipients developed portal hyperperfusion. Furthermore, the GV/SV also showed a significant correlation with post-transplant persistent thrombocytopenia and hyperbilirubinemia. The GV/SV < 0.88 predicts portal hyperperfusion, post-transplant persistent thrombocytopenia, and hyperbilirubinemia. PMID- 29424479 TI - Biomimetic peptide display from a polymeric nanoparticle surface for targeting and antitumor activity to human triple-negative breast cancer cells. AB - While poly(lactic-co-glycolic acid)-block-polyethylene glycol (PLGA-PEG) nanoparticles (NPs) can encapsulate drug cargos and prolong circulation times, they show nonspecific accumulation in off-target tissues. Targeted delivery of drugs to tumor tissue and tumor vasculature is a promising approach for treating solid tumors while enhancing specificity and reducing systemic toxicity. AXT050, a collagen-IV derived peptide with both antitumor and antiangiogenic properties, is shown to bind to tumor-associated integrins with high affinity, which leads to targeted accumulation in tumor tissue. AXT050 conjugated to PLGA-PEG NPs at precisely controlled surface density functions both as a targeting agent to human tumor cells and demonstrates potential for simultaneous antitumorigenic and antiangiogenic activity. These targeted NPs cause inhibition of adhesion and proliferation in vitro when added to human triple-negative breast cancer cells and microvascular endothelial cells through binding to integrin alphaV beta3 . Furthermore, we find an in vivo biphasic relationship between tumor targeting and surface coating density of NPs coated with AXT050. NPs with an intermediate level of 10% peptide surface coating show approximately twofold greater accumulation in tumors and lower accumulation in the liver compared to nontargeted PLGA-PEG NPs in a murine biodistribution model. Display of biomimetic peptides from NP surfaces to both target and inhibit cancer cells has the potential to enhance the activity of cancer nanomedicines. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1753-1764, 2018. PMID- 29424481 TI - Efficient Aliphatic C-H Bond Oxidation Catalyzed by Manganese Complexes with Hydrogen Peroxide. AB - A tetradentate nitrogen ligand containing a benzimidazole ring and an electron rich pyridine ring was developed, the resulting manganese complex exhibited good activity in the C-H oxidation of simple alkanes. In particular, cyclic aliphatic alkanes were transformed into ketones in very good yields (up to 89 %) by using environmentally benign H2 O2 as the terminal oxidant. This protocol was also applied successfully in benzylic C-H oxidation, giving the corresponding ketones with very good selectivities. In addition, tertiary C-H bond oxidation of complex molecules by the manganese complex showed potential utility for assembling alcohols with good selectivity in late-stage chemical synthesis. PMID- 29424480 TI - Predicting new-onset HF in patients undergoing coronary or peripheral angiography: results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study. AB - AIMS: Methods to identify patients at risk for incident HF would be welcome as such patients might benefit from earlier interventions. METHODS AND RESULTS: From a registry of 1251 patients referred for coronary and/or peripheral angiography, we sought to identify independent predictors of incident HF during follow-up and develop a clinical and biomarker strategy to predict this outcome. There were 991 patients free of prevalent HF at baseline. Cox proportional hazard models were developed to predict adjudicated diagnosis of incident HF. Model discrimination and reclassification were evaluated. At follow-up, 177 (18%) developed new-onset HF. Independent predictors of new-onset HF included five clinical variables (age, male sex, heart rate, history of atrial fibrillation/flutter, and history of hypertension) and two biomarkers (amino-terminal pro-B type natriuretic peptide and ST2). The c-statistic for the model without biomarkers was 0.69; including biomarkers increased the c-statistic to 0.76 (P < 0.001). A score was developed from the model. Patients in the highest score quintile had shortest time to incident HF compared with lower quintiles (log-rank P < 0.001). Following 100 bootstrap iterations, internal validation was confirmed with Harrell's c statistic of 0.77. Use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers at enrollment was associated with substantial attenuation of predictive value of the risk score. CONCLUSIONS: Patients undergoing coronary/peripheral angiographic procedures are a population at high risk for incident HF. We describe an accurate clinical and biomarker strategy for predicting incident HF and possibly intervening in such patients (NCT00842868). PMID- 29424483 TI - The Glycoproteomics-MS for Studying Glycosylation in Cardiac Hypertrophy and Heart Failure. AB - With recent advancements of analytical techniques and mass spectrometric instrumentations, proteomics has been widely exploited to study the regulation of protein expression associated with disease states. Many proteins may undergo abnormal change in response to the stimulants, leading to regulation of posttranslationally modified proteins. In this review, the physiological and pathological roles of protein glycosylation in cardiac hypertrophy is discussed, and how the signal pathways regulate heart function and leading to heart failure. The analytical methods for analysis of protein glycosylation, including glycans, glycosite, occupancy, and heterogeneity is emphasized. The rationale on glycoproteins as disease biomarkers is also discussed. The authors also propose potential research in this field and challenges in the diagnosis and treatment of this disease. PMID- 29424482 TI - Zinc Deficiency-Like Syndrome in Fleckvieh Calves: Clinical and Pathological Findings and Differentiation from Bovine Hereditary Zinc Deficiency. AB - BACKGROUND: Zinc deficiency-like (ZDL) syndrome is an inherited defect of Fleckvieh calves, with striking similarity to bovine hereditary zinc deficiency (BHZD). However, the causative mutation in a phospholipase D4 encoding gene (PLD4) shows no connection to zinc metabolism. OBJECTIVES: To describe clinical signs, laboratory variables, and pathological findings of ZDL syndrome and their utility to differentiate ZDL from BHZD and infectious diseases with similar phenotype. ANIMALS: Nine hospitalized calves with crusting dermatitis and confirmed mutation in PLD4 and medical records from 25 calves with crusting dermatitis or suspected zinc deficiency. METHODS: Prospective and retrospective case series. RESULTS: The 9 calves (age: 5-53 weeks) displayed a moderate to severe crusting dermatitis mainly on the head, ventrum, and joints. Respiratory and digestive tract inflammations were frequently observed. Zinc supplementation did not lead to remission of clinical signs in 4 calves. Laboratory variables revealed slight anemia in 8 calves, hypoalbuminemia in 6 calves, but reduced serum zinc concentrations in only 3 calves. Mucosal erosions/ulcerations were present in 7 calves and thymus atrophy or reduced thymic weights in 8 calves. Histologically, skin lesions were indistinguishable from BHZD. Retrospective analysis of medical records revealed the presence of this phenotype since 1988 and pedigree analysis revealed a common ancestor of several affected calves. CONCLUSIONS AND CLINICAL IMPORTANCE: ZDL syndrome should be suspected in Fleckvieh calves with crusting dermatitis together with diarrhea or respiratory tract inflammations without response to oral zinc supplementation. Definite diagnosis requires molecular genetic confirmation of the PLD4 mutation. PMID- 29424485 TI - Sub-epithelial connective tissue graft for the management of Miller's class I and class II isolated gingival recession defect: A systematic review of the factors influencing the outcome. AB - The aim of the present systematic review was to analyze the factors that affect the outcome of subepithelial connective tissue graft (SCTG) for managing Miller's class I and class II isolated gingival recession defect. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews were used. Quality assessments of selected articles were performed. Data on root surface condition, recession type defect, flap thickness, different flap designs, different harvesting techniques, presence/absence of the epithelial collar, graft thickness, flap tension, suturing techniques, and smoking-related outcomes on root coverage were assessed. The SCTG procedure provides the best root coverage outcomes for Miller's class I and class II recession. The critical threshold of flap thickness was found to be 1 mm. Maximum root coverage was achieved by envelope and modified tunnel technique. SCTG with the epithelial collar does not provide additional gains than SCTG without the epithelial collar. The thickness of SCTG for root coverage was found to be 1.5-2 mm. Greater flap tension and smoking adversely affect root coverage outcomes. Analysis of the factors discussed would be of key importance for technique selection, and a combined approach involving factors favoring outcomes of SCTG could be of clinical relevance in recession coverage. PMID- 29424484 TI - Acute heart failure following myocardial infarction: complement activation correlates with the severity of heart failure in patients developing cardiogenic shock. AB - AIMS: Heart failure (HF) is an impending complication to myocardial infarction. We hypothesized that the degree of complement activation reflects severity of HF following acute myocardial infarction. METHODS AND RESULTS: The LEAF trial (LEvosimendan in Acute heart Failure following myocardial infarction) evaluating 61 patients developing HF within 48 h after percutaneous coronary intervention treated ST-elevation myocardial infarction herein underwent a post hoc analysis. Blood samples were drawn from inclusion to Day 5 and at 42 day follow-up, and biomarkers were measured with enzyme immunoassays. Regional myocardial contractility was measured by echocardiography as wall motion score index (WMSI). The cardiogenic shock group (n = 9) was compared with the non-shock group (n = 52). Controls (n = 44) were age-matched and sex-matched healthy individuals. C4bc, C3bc, C3bBbP, and sC5b-9 were elevated in patients at inclusion compared with controls (P < 0.01). The shock group had higher levels compared with the non shock group for all activation products except C3bBbP (P < 0.05). At Day 42, all products were higher in the shock group (P < 0.05). In the shock group, sC5b-9 correlated significantly with WMSI at baseline (r = 0.68; P = 0.045) and at Day 42 (r = 0.84; P = 0.036). Peak sC5b-9 level correlated strongly with WMSI at Day 42 (r = 0.98; P = 0.005). Circulating endothelial cell activation markers sICAM-1 and sVCAM-1 were higher in the shock group during the acute phase (P < 0.01), and their peak levels correlated with sC5b-9 peak level in the whole HF population (r = 0.32; P = 0.014 and r = 0.30; P = 0.022, respectively). CONCLUSIONS: Complement activation discriminated cardiogenic shock from non-shock in acute ST-elevation myocardial infarction complicated by HF and correlated with regional contractility and endothelial cell activation, suggesting a pathogenic role of complement in this condition. PMID- 29424486 TI - Association between dental visiting and missing teeth: Estimation using propensity score adjustment. AB - AIM: The aim of the present study was to determine the association between dental visiting and missing teeth using propensity score (PS) adjustment to control for confounding bias, and to compare the estimates with those obtained from traditional regression models. METHODS: A population-based study was conducted on adults aged 35-54 years in India. Multistage stratified cluster random sampling was used. Data were collected through interviews and oral examinations. The exposure factor was 'dental visiting', and the outcome was number of missing teeth. Sociodemographic factors, oral hygiene practices, periodontal disease, and caries experience were the covariates. Inverse probability weight (IPW) calculated from the PS for dental visiting from a logistic regression model was used to balance the covariates. The association between dental visiting and missing teeth was estimated from log-binomial regression models with and without using IPW. RESULTS: Of the 873 participants, 77.7% visited a dentist. The >=1 missing teeth prevalence was 65.3%. Post-IPW adjustment covariate standardized bias between groups with or without dental visit was lower than the pre-IPW adjustment. Those who visited a dentist had an adjusted prevalence ratio of 2.40 when IPW was used, and 2.03 when IPW was not used. CONCLUSION: Dental visiting was strongly associated with missing teeth in this rural population. PMID- 29424487 TI - Streptococcus equi Infections in Horses: Guidelines for Treatment, Control, and Prevention of Strangles-Revised Consensus Statement. AB - This consensus statement update reflects our current published knowledge and opinion about clinical signs, pathogenesis, epidemiology, treatment, complications, and control of strangles. This updated statement emphasizes varying presentations in the context of existing underlying immunity and carrier states of strangles in the transmission of disease. The statement redefines the "gold standard" for detection of possible infection and reviews the new technologies available in polymerase chain reaction diagnosis and serology and their use in outbreak control and prevention. We reiterate the importance of judicious use of antibiotics in horses with strangles. This updated consensus statement reviews current vaccine technology and the importance of linking vaccination with currently advocated disease control and prevention programs to facilitate the eradication of endemic infections while safely maintaining herd immunity. Differentiation between immune responses to primary and repeated exposure of subclinically infected animals and responses induced by vaccination is also addressed. PMID- 29424488 TI - Lipopolysaccharide enhances TGF-beta1 signalling pathway and rat pancreatic fibrosis. AB - Pancreatic stellate cells (PSCs) play a critical role in fibrogenesis during alcoholic chronic pancreatitis (ACP). Transforming growth factor-beta1 (TGF beta1) is a key regulator of extracellular matrix production and PSC activation. Endotoxin lipopolysaccharide (LPS) has been recognized as a trigger factor in the pathogenesis of ACP. This study aimed to investigate the mechanisms by which LPS modulates TGF-beta1 signalling and pancreatic fibrosis. Sprague-Dawley rats fed with a Lieber-DeCarli alcohol (ALC) liquid diet for 10 weeks with or without LPS challenge during the last 3 weeks. In vitro studies were performed using rat macrophages (Mphis) and PSCs (RP-2 cell line). The results showed that repeated LPS challenge resulted in significantly more collagen production and PSC activation compared to rats fed with ALC alone. LPS administration caused overexpression of pancreatic TLR4 or TGF-beta1 which was paralleled by an increased number of TLR4-positive or TGF-beta1-positive Mphis or PSCs in ALC-fed rats. In vitro, TLR4 or TGF-beta1 production in Mphis or RP-2 cells was up regulated by LPS. LPS alone or in combination with TGF-beta1 significantly increased type I collagen and alpha-SMA production and Smad2 and 3 phosphorylation in serum-starved RP-2 cells. TGF-beta pseudoreceptor BAMBI production was repressed by LPS, which was antagonized by Si-TLR4 RNA or by inhibitors of MyD88/NF-kB. Additionally, knockdown of Bambi with Si-Bambi RNA significantly increased TGF-beta1 signalling in RP-2 cells. These findings indicate that LPS increases TGF-beta1 production through paracrine and autocrine mechanisms and that LPS enhances TGF-beta1 signalling in PSCs by repressing BAMBI via TLR4/MyD88/NF-kB activation. PMID- 29424489 TI - HSP27 associates with epithelial-mesenchymal transition, stemness and radioresistance of salivary adenoid cystic carcinoma. AB - Epithelial-mesenchymal transition (EMT) has been shown to associate with cancer stem cells and radioresistance. However, it is obscure whether EMT itself or specific EMT regulators play causal roles in these properties of salivary adenoid cystic carcinoma (SACC). Here, we exhibited that overexpression of HSP27 drove the migration and invasion, induced EMT, as well as mediated TGF-beta1-induced EMT in SACC cells, accompanying the up-regulation of Snail1 and Prrx1. Conversely, HSP27 silencing reduced the migration and invasion and contributed to MET of SACC cells. HSP27 indirectly down-regulates the expression of E-cadherin through activating Snail1 and Prrx1 expressions. Overexpression of Snail1 or Prrx1 restored the migration and invasion in HSP27 knockdown cells. Enforced expression of HSP27 enhanced colony formation, CD133+ /CD44+ population and radioresistance of SACC cell lines. In addition, HSP27 expression was positively associated with radioresistance and poor prognosis of SACC patients as well as with the expression of Prrx1 or Snail1 in SACC tissues. The data confirm an important function for HSP27 in SACC progression through regulating EMT and stemness, and they imply the possible association between EMT and radioresistance of SACC. PMID- 29424491 TI - Corrigendum: Extraction of Salinity-Gradient Energy by a Hybrid Capacitive-Mixing System. PMID- 29424490 TI - Effects of 2 years of caloric restriction on oxidative status assessed by urinary F2-isoprostanes: The CALERIE 2 randomized clinical trial. AB - Calorie restriction (CR) without malnutrition slows aging in animal models. Oxidative stress reduction was proposed to mediate CR effects. CR effect on urinary F2-isoprostanes, validated oxidative stress markers, was assessed in CALERIE, a two-year randomized controlled trial. Healthy volunteers (n = 218) were randomized to prescribed 25% CR (n = 143) or ad libitum control (AL, n = 75) stratifying the randomization schedule by site, sex, and BMI. F2-isoprostanes were quantified using LC-MS/MS in morning, fasted urine specimens at baseline, at 12 and 24 months. The primary measure of oxidative status was creatinine-adjusted 2,3-dinor-iPF(2alpha)-III concentration, additional measured included iPF(2alpha) III, iPF2a-VI, and 8,12-iso-iPF2a-VI. Intention-to-treat analyses assessed change in 2,3-dinor-iPF(2alpha)-III using mixed models assessing treatment, time, and treatment-by-time interaction effects, adjusted for blocking variables and baseline F2-isoprostane value. Exploratory analyses examined changes in iPF(2alpha)-III, iPF(2alpha)-VI, and 8,12-iso-iPF(2alpha)-VI. A factor analysis used aggregate information on F2-isoprostane values. In CR group, 2,3-dinor iPF(2alpha)-III concentrations were reduced from baseline by 17% and 13% at 12 and 24 months, respectively; these changes were significantly different from AL group (p < .01). CR reduced iPF(2alpha)-III concentrations by 20% and 27% at 12 and 24 months, respectively (p < .05). The effects were weaker on the VI-species. CR caused statistically significant reduction in isoprostane factor at both time points, and mean (se) changes were -0.36 (0.06) and -0.31 (0.06). No significant changes in isoprostane factor were at either time point in AL group (p < .01 between-group difference). We conclude that two-year CR intervention in healthy, nonobese men and women reduced whole body oxidative stress as assessed by urinary concentrations of F2-isoprostanes. PMID- 29424492 TI - Urgent care centre redirection: evaluation of a nurse-led intervention. AB - AIM: Patient redirection can help reduce service demand by providing information about more appropriate services. There is, however, no evidence about the effect of nurse-led patient redirection in urgent care centre settings. The aim of this project was to develop and evaluate a nurse-led patient 'self-care and redirection first' intervention in an urgent care centre (UCC). METHOD: Adopting a prospective observational design, the intervention was delivered to an opportunity sample of patients who attended a south London hospital UCC, between June and July 2014, and evaluated through patient interviews five to ten days after initial attendance. FINDINGS: 118 of the 1,710 people who attended the UCC participated in the intervention, of whom 81 (69%) were redirected to other services or home to self-care, and 37 were transferred to an emergency department. Of the 110 (93.2%) participants who completed the questionnaire, 97.2% were satisfied with the service. Only two accessed different services to those recommended, 72.2% ( n =85) said they would not reattend a UCC for a similar condition. CONCLUSION: Treating minor ailments in a UCC is an inefficient use of resources. A nurse-led self-care and redirection intervention can help divert patients with minor ailments to more appropriate services. Further evaluation of the effect of the intervention on service demand and costs is required. PMID- 29424493 TI - Is it safe to inject local anaesthetic with adrenaline into the pinna and external nose? AB - Adrenaline containing lidocaine preparations such as lignospan are routinely used in ear, nose and throat (ENT) care. Despite this, textbooks and internet resources warn against their use in peripheries, including the nose and ear. As a result, they are commonly avoided by other specialties, such as emergency medicine. This article reports on the findings of a review undertaken to assess the evidence of harm associated with using lignospan in the pinna and external nose. A literature search was carried out, and retrospective data were collected on all elective facial skin lesion surgery in the ENT department at the Great Western Hospital in Swindon between 2005 and 2015. Cases using lignospan in the pinna and nose were included. The literature search revealed no reports of ischaemic complications of the pinna or nose following use of lignospan, or similar preparation. Of the 1,409 cases collected, no ischaemic complications were recorded. The article concludes that adrenaline containing lidocaine preparations such as lignospan are safe for use in the pinna and nose, and should be considered for use in emergency departments. PMID- 29424494 TI - Accidents and ethics: a visual-narrative approach. AB - Emergency department (ED) attendances are continuing to rise, and medical and nursing teams are working under considerable strain. ED clinicians are used to thinking on their feet and possess the skills to multitask, and juggle ever changing and competing priorities against the clock. This article reports the findings of a study that enabled ED clinicians to take time out to reflect on some of the difficult decisions they make daily, and to ask whether they consider ethical principles in depth, and if they are of any practical help. Findings reveal that autonomy, beneficence, non-maleficence and distributive justice are evident in contemporary EDs, and clinicians need to be encouraged to incorporate ethical reasoning into their reflective practice. The term 'clinician' refers to doctors and nurses in this article. PMID- 29424495 TI - [Hygienic assessment of working conditions in the production of ferro-alloys]. AB - This work is devoted to the study of conditions of the work of employees of the modern ferro-alloy production, which was performed in the framework of the evaluation of working places at the Open Joint-Stock Company "Ferrokhrom", which is part of Joint-Stock Transnational Company "Kazchrom". The studies were performed with account of the full range of the list of working places, both in the main and auxiliary shops. The work activity of the workers from leading professional groups was established to be conjugate of the impact of the complex of unfavorable factors of occupational environment and labor process. There are given comprehensive measures to improve working conditions and health maintenance in workers from leading professional groups. PMID- 29424496 TI - [Peculiarities of air pollution in the production of continuous glass fiber]. AB - With the use of a one-stage method we have carried out hygienic studies of the air of work area of the production of continuous glass fiber. There was revealed the emission of epichlorohydrin, formaldehyde, ethane acid, hydrochloride, spray of mineral petroleum oil, fine glass fiber dust in air of the work area. There was established the combined effect of hazardous substances of unidirectional action with the summation effect on the body. Hazardous substances containing in glass fiber sizers in combination with dust of glass fiber against the background of microtraumatization of the hand skin contribute to the development of occupational skin neoplasms. The studies became the basis of the development of preventive measures aimed at the reduction of risks of the impact of the chemical factor impact on workers. PMID- 29424497 TI - [Hygienic assessment of the overwroughtness of educational activity in schoolchildren of 5-10 classes of secondary schools]. AB - The state of health in children and adolescents during the time of education in secondary schools is getting worse: the prevalence rate of functional disorders and chronic diseases is increasing. There was executed the assessment of the overwroughtness of the training-education process in secondary school institutions. The prior characteristics of the educational activity are: intellectual, sensory, emotional loads; their monotony and mode of educational activity, school work intensity. The system of indices of the overwroughtness of the education labour was formed with account ofpsycho-physiological characteristics of children's organism. There was performed the research of the overwroughtness of educational activity in 820 schoolchildren. The overwroughtness of the educational process was evaluated on the basis of chronometry research, questionnaire survey of teachers and parents, and with taking into account the organization of educational process. In questionnaire survey there were involved 52 teachers and 389 parents. The assessment of overwroughtness factors of the educational activity was carried out in 5-10th classes for academic disciplines: Russian Language, Literature, Mathematics, History, Geography, Foreign Languages. It was found that the characteristics of "mental load" in schoolchildren are established to be the one of the main limiting factors that allow to refer training activities to "overwroughted of first degree" (3.1 class). Sensory loads on the studied academic subjects are rated as the second class of overwroughtness and are "permissible." The monotony of loads was revealed to correspond to 1st and 2nd class of overwroughtness and is therefore an optimal or acceptable. Training activities in the traditional educational institution corresponds to the 2nd class of overwroughtness - "permissible." The arduousness of the educational process in an innovative school is rated as the third class of the first degree ofthe overwroughtness (3.1). According to results of the study of the arduousness of the educational labor the study of mathematics in grades 5-9 on indices of the mental load was noted to correspond to the 1st degree of arduous activity (3.1 class). The acceptable level of the arduousness of the training and educational labour in nearly all classes was established in the Russian language, Literature, History and Geography, Foreign language. High school students are established to be exposed to effects of emotional load more than mid-level students. There are developed proposals on the optimization of the learning process, allowing to reduce the level of intellectual, sensory, emotional load. PMID- 29424498 TI - [Lifestyle and health of students]. AB - The article presents the results of the evaluation of the most significant risk factors related to lifestyle and health of medical students of different courses andfaculties. The obtained data testify that out of the total number of factors that have a significant influence on the formation of bases of student's healthy lifestyle and health, the most typical are the mode of employment, the total workload, material well-being, living conditions of the majority of today's students, as well as the conditions of nutrition, physical activity, the presence or absence of such factors as smoking, frequency of consumption of alcoholic beverages. PMID- 29424499 TI - [Corrective effect of aromatherapy on indices of heart rate variability in students under exam stress conditions]. AB - There were investigated changes in indices of the activity of regulatory mechanisms of heart rhythm in student under exam stress conditions and the possibility of their correction with aid of aromatherapy. The examination stress was established to be accompanied by pronounced shifts of integral and spectral indices of heart rhythm in students, indicating to the activation of the sympathetic circuit of Autonomic Nervous System in conditions of examination stress. A positive, relaxation impact of the essential oil of orange on the investigated indices was also recorded. The latter is expressed by weakly pronounced changes or lack of them in data of integral and spectral heart rate indices in students from the experimental group, that indicates to the stabilizing effect of used ethereal oil on the psycho-physiological state of students in conditions of exam stress PMID- 29424500 TI - [Peculiarities of the psychological status of first-year students in terms of university education]. AB - Peculiarities There was performed the study of the mental status of first-year students enrolled in the Tuvan state University. There were detected levels of reactive and personal anxiety, adaptive capacity, the level of social and psychological adaptation and aggression. Adaptation potential in students is within limits of the satisfactory one, there was no detected person with poor adaptive capacity and failure of adaptation, that indicates to the genetically fixed ability of the students' body to adapt to living conditions. In a state of psychological adjustment there was revealed the more higher level of anxiety in Tuvan students, which is caused by the poor living conditions. More satisfactory condition is typical for the social and psychological adaptation, since in all students values of test scales are within normal limits.There were shown gender differences in adaptation and psychological status of students. Boys have more lower indices of indirect and verbal aggression, anger, resentment, suspicion, guilt. Girls are characterized by higher hostility, at that it even exceeds standard values. In the group of students with a high personal anxiety no differences in adaptive capacities were found, and in students with moderate personal anxiety there were significantly more boys with stress adaptation than girls. Analysis of the socio-psychological adaptation of first-year students shows that in all students values of the test scales are normal, but in young men, indices are higher that indicates to a more successful socialization in the environment of the university. Correlation analysis of indices of aggressiveness and socio-psychological adaptation revealed weak negative relationships between index of aggressiveness with maladaptiveness, non-acceptance of others, emotional comfort in boys. In girls "aggressiveness" positively correlates with the such indices as acceptance of others and adaptation. Factor analysis in young men revealed the first factor, labeled as maladjustment because it included indirect aggression, maladaptiveness, self-rejection, emotional discomfort and external control. In girls first factor combines indices: adaptability, self-acceptance, adaptation (integral), self-acceptance, emotional comfort, the desire to dominate and this factor was labeled as adaptation. PMID- 29424501 TI - [Effect of recultivated wastes of mining factories on children residing in the district of their location]. AB - Wastes and tailing ponds of Tyrnyauz tungsten and molybdenum factory are the main sources of heavy metal incoming into environment in Kabardino-Balkarian Republic. The factory was closed more than 10 years ago and the recultivation of it's tailing ponds, where accumulated hundreds of millions tones of wastes, was completed. The aim of this investigation was an assessment of their possible influence on children residing in the vicinity of these tailing ponds (village Bylym). Village Verhny Baksan located about 30 km upstream of the valley of the Baksan River was chosen as reference (pure) locality. As a results of the performed investigations we revealed that in drinking water of Bylym and Verhny Baksan concentrations of molybdenum were 2.10+/-0.42 pg/l and 0.31+/-0.15 pg/l correspondingly, which is remarkably lower than maximum permitted concentrations. The concentrations of Mo, Cu and Pb in children's hair in both villages were practically the same, which indicates to the absence of their accumulation in human organism. But the quantity of cells with cytogenetic disorders in buccal epithelial cells in children from Bylym was 4.1 times higher in comparison with the corresponding index of uncontaminated area. The obtained data demonstrate that genotoxic effect of remedied tailing ponds retains. PMID- 29424502 TI - [Differences in self-assessment of health and psychological wellbeing between healthy and unhealthy young adults]. AB - Self-assessment of health is the one out of the most important characteristics, which gives an idea about the health of the respondent as a psychophysiological continuum. The purpose of this study is to establish the relationship between indices of self-rated health and characteristics of the psychological well-being. Sample 344 young adults - students at an average age of 20.9 +/- 1.6 years. Methods. "Self-assessment of health" questionnaire was used; MOSSF36 questionnaire and "Psychological wellbeing scale" developed by K. Riff. Respondents were divided into groups: (1) without chronic diseases; (2) having one or more chronic diseases of any etiology. Results. The presence of chronic diseases was shown to negatively effect on the self-estimation of physical and psychological state. The significant positive correlation (p <0,001) between the perceived health and subjective well-being was found. Healthy individuals perceive the state of their own physical health and psychological wellbeing as unrelated to each other characteristics. In contrast, in cases with even mild chronic health problems there is pronounced the relationship between somatic and psychological health, which forms a complex of physical and psychological factors determining the general state of a person. PMID- 29424503 TI - [Comparative assessment of sanitary and epidemic importance of indicator coliform indices of drinking water quality]. AB - The used methodology of the scientific substantiation of indicators is in the establishment of the conformity of laws of vital activity of indicator and pathogenic microorganisms in the real conditions of the action of the complex of factors, including disinfecting agents. In the one water sample simultaneously there were determined both the general indicator (GICB), thermotolerant (TTCB), glucose positive (GPCB) coliform bacteria, E.coli. On the base of long-term research in the various regions of the Russian Federation, as well with bearing in mind the analysis of domestic and foreign data, comparing the water quality and the incidence of intestinal infections in population it is recommended to use the index of determination of the total number glucose positive coliform bacteria (GPCB), which brings together a much broader range of bacteria of the Enterobacteriaceae family in comparison with total coliform bacteria (TCB) and thermotolerant coliform bacteria (TTCB) and warrants the absence in the test volume of water as an indicator lactose positive (E.coli, TCB, TTCB) and pathogens (salmonella) and potentially pathogenic bacteria which do not ferment lactose. Proposed index of GPCB is shown to allow to assess epidemiological risks not only more accurate, but also more efficiently without increasing the cost performance of bacteriological research. PMID- 29424504 TI - [Research of the inactivation of pathogens in water under exposure to low temperature plasma]. AB - There was investigated the effect of barrier and spark discharge low temperature plasma on water containing the cells of Escherichia coli (Escherichia coli), hay bacillus (Bacillus subtilis) and yeast (Saccharomyces cerevisiae). There was shown a general decline in the concentration of viable microbial cells after the treatment of suspensions. There was especially marked the detrimental effect of the method on the viability of sanitary-indicative coliform bacteria in the water. PMID- 29424505 TI - Best videos of the year in 2017. PMID- 29424506 TI - Do we have enough evidences that make you safe to treat a man with hypogonadism one year after a radical prostatectomy for prostate cancer? | Opinion: YES. PMID- 29424507 TI - Do we have enough evidences that make you safe to treat a man with hypogonadism one year after a radical prostatectomy for prostate cancer? | Opinion: Not Yet. PMID- 29424508 TI - [Pilot tests using molecular diagnostic assay cervicovaginal infection during pregnancy]. AB - Background: The prevalence of cervicovaginal infections during pregnancy has been associated with adverse perinatal outcomes however, the actual approach used for diagnosis is not effective. The aim of this study was to compare the diagnosis of vaginal infections in pregnant women using clinical, molecular diagnostic and traditional microbiological culture in a pilot study, to determine the prevalence and association with the development of preterm labor. Materials and methods: We performed a nested cross-sectional study composed by 54 women in a cohort of pregnant women in Mexico City. Cervicovaginal infections were evaluated by clinical methods, microbiology culture and a commercially available molecular biology test. Results: Prevalence of cervicovaginal infections during pregnancy was estimated between 28% and 50% according to methodologies. Considering the clinical diagnosis of preterm labor as the gold standard, all diagnostic tests were poor as predictors of preterm labor. Conclusion: Traditional approaches to establish the significance of cervicovaginal infection in pregnancy are exhausted, so be sought new ways to understand this complex relationship. Meanwhile it is recommended to continue to use traditional methods to identify infections during pregnancy in both knowledge of new methods aimed at understanding these relationships are sophisticated. PMID- 29424509 TI - [Operative morbidity of the hidrodiseccion with epinefrina during the surgery for prolapse of pelvic organs]. AB - Objetive: To assess the effect of the hydrodissection on operative morbidity and operative time in patients undergoing vaginal surgery for pelvic organ prolapse. Material and methods: Experimental, prospective, longitudinal, comparative, randomized study: randomized controlled clinical. Randomly, 44 patients were assigned to receive management hydrodissection with epinephrine (Group 1= 22) or not hydrodissection (Group 2= 22) prior to the start of the surgical procedure. The variables analyzed were operative morbidity (defined as infection, hematoma and surgical postoperative bleeding requiring transfusion) and surgical time required to complete the procedure. Results: The average age was 58.1 years (+/- 9.3) in the group of hydrodissection and 63.0 years (+/- 10.6) in the group without hydrodissection (p = .111). The frequency of postoperative complications was similar enters both groups (p> .05) presenting only one case of postoperative hematoma in Group 1 and none in Group 2. The operative bleeding was significantly lower in the hydrodissection group (240.9 +/- 111.9 mL) compared with the group of non hydrodissection (324.1 +/- 104.9 mL). No significant difference in operative time was found (p = 0.67) compared with 135.5 (+/- 22.6) minutes in Group 1 and 139.3 (+/- 32.5) minutes. Conclusion: Hydrodissection with epinephrine compared with non Hydrodissection significantly reduces operative bleeding but no differences in operative morbidity and operative time in patients undergoing vaginal surgery in the management of pelvic organ prolapse. PMID- 29424510 TI - [Blood loss and use of blood products in cases of cesarean hysterectomy for placenta accrete]. AB - Background: Placenta accreta (abnormal insertion of the placenta or part of the myometrium ) endangers the lives of pregnant women. It is a public health problem because it can be complicated by obstetric hemorrhage , the latter being the main cause of maternal death worldwide. Objetive: To estimate the blood loss and the use of blood products in patients who underwent cesarean - hysterectomy for placenta accreta. Material and methods: A descriptive study was conducted in HGO UMAE CMNO IMSS in patients who underwent cesarean - hysterectomy for placenta accreta in a period of 4 years. Results: 106 cases of placenta accreta were studied, 23% had a massive bleeding of > 3000 cc. Packed red blood cells were transfused in 68% of events, fresh frozen plasma in platelet concentrates 29% and 6%. The history of uterine curettage was observed in 64 % and cesarean section 1 or 2 occasions in 76 % of cases. Conclusion: An early detection of placenta accreta in patients with risk factors to avoid emergency surgery is desired. Being prepared with blood products and appropriate use is a cornerstone in the management of this condition. The average blood loss was determined in cases of accreta in cesarean hysterectomy was 2523 milliliters. PMID- 29424511 TI - [Breast Cancer Survival: Clinical andPathological Prognostic Factors Analysis]. AB - Background: Breast cancer is the leading cause of cancer death in women in Mexico, is a heterogeneous disease, and knowledge of prognostic factors are critical in making treatment decisions. Objetive: determine the overall survival (OS) and disease-free survival (DFS) at 5 years, analyzed by risk groups. Material and methods: Patients diagnosed with breast treated at the Institute of Breast Diseases FUCAM from July 2005 to December 2014 were included. Simple frequencies were used for analysis of the general characteristics, and 5- year OS and DFS were analyzed using Kaplan-Meier curves. A subset analysis of the clinical stage and comparing survival in those patients diagnosed by mammography screening program was performed. Results: 4,902 patients with breast cancer were included, general clinical and pathological features are described and 3,762 patients were included for analysis of 5-year OS and DFS. The average age at diagnosis was 53.7 years; 13.3% were <40 years, which deleteriously reflects on the supervivencia global 76 vs 84% in >40. At diagnosis predominated locally advanced stages (45%), OS and DFS at 5 years was 96.8 +/- 0.6% and 93.4%+/-0.9 respectively for early stages, 74.6 +/- 1.7% and 68.7 +/- 2% for locally advanced and 35.9+/- 5.1% and 37.4 +/- 10.3% for metastatic tumors. Women diagnosed in the screening program had significantly better OS and DFS compared with symptomatic patients (95 and 93% vs 79 and 77%). For biological subtypes, OS and DFS was 89 and 84% for luminal, 81 and 81% for luminal Her +, 74 and 78% for pure Her 2, and 69 and 73% for triple negative. Conclusion: Knowledge of the prognostic factors that affect survival of patients with breast cancer is essential for categorizing risk groups and to individualize treatment in order to improve life expectancy. PMID- 29424512 TI - [External cephalic version]. AB - Objetives: To analyze the rate of successful external cephalic versions in our center and caesarean sections that would be avoided with the use of external cephalic versions. Material and methods: From January 2012 to March 2016 external cephalic versions carried out at our center, which were a total of 52. We collected data about female age, gestational age at the time of the external cephalic version, maternal body mass index (BMI), fetal variety and situation, fetal weight, parity, location of the placenta, amniotic fluid index (ILA), tocolysis, analgesia, and newborn weight at birth, minor adverse effects (dizziness, hypotension and maternal pain) and major adverse effects (tachycardia, bradycardia, decelerations and emergency cesarean section). Results: 45% of the versions were unsuccessful and 55% were successful. The percentage of successful vaginal delivery in versions was 84% (4% were instrumental) and 15% of caesarean sections. With respect to the variables studied, only significant differences in birth weight were found; suggesting that birth weight it is related to the outcome of external cephalic version. Probably we did not find significant differences due to the number of patients studied. Conclusion: For women with breech presentation, we recommend external cephalic version before the expectant management or performing a cesarean section. The external cephalic version increases the proportion of fetuses in cephalic presentation and also decreases the rate of caesarean sections. PMID- 29424514 TI - [Recurrent pregnancy loss: a literature review]. AB - Background: The definition of recurrent pregnancy loss varies according different authors and consensus: the American Society for Reproductive Medicine (ASRM) defines RPL when two or more pregnancy losses occur, and the European Society of Human Reproduction and Embryology (ESHRE) defines it as three or more pregnancy losses, not necessarily intrauterine. To this day, there is no uniform approach that serves as a guide in the diagnosis and treatment of this condition; this is why, in up to 50% of the cases of RPL, it will not be possible to identify the specific etiology. Objetive: To report on the recurrent pregnancy loss, in order to harmonize concepts and suggest a diagnosis and treatment for this condition approach. Method: The search strategy included, but was not limited to keywords like: recurrent abortion, infertility, habitual abortion, primary antiphospholipid syndrome, lupus anticoagulant, anti-cardiolipin antibodies and anti B2 glycoprotein I. PMID- 29424513 TI - [Comparison of pregnancy outcomes Caesarean techniques: modified Misgav-Ladach, Pfannenstiel-Kerr and Kerr-half infraumbilical]. AB - Background: In Mexico, the prevalence of caesarean section is 40.9% in the health sector, the techniques used are the traditional Pfannenstiel-Kerr and Kerr-half infraumbilical and little experience with this new technique Misgav-Ladach modified. Objetive: To compare pregnancy outcomes (surgical and fetal extraction time, bleeding, postoperative pain, surgical wound infection, maternal and fetal death) caesarean section techniques modified Misgav-Ladach, Pfannenstiel-Kerr and infraumbilical. Material and method: Clinical trial in primiparous women with term pregnancy treated at the Medical Unit of High Specialty 23 of the Mexican Social Security Institute, Monterrey, Nuevo Leon, Mexico. Misgav-Ladach caesarean Caesarean modified and Kerr, the latter subdivided into two groups: infraumbilical Pfannenstiel incision and incision half-Kerr two groups patients were randomized. Results: 137 gilts were studied, with term pregnancy and BMI between 19 and 24.9 kg / m2. Caesarean modified Misgav-Ladach 68 patients and 69 classical Kerr (35 Pfannenstiel-Kerr and 34 infraumbilical) was performed. The surgical time in minutes was lower with modified Misgav-Ladach: 27.8 +/- 8.0, Pfannenstiel-Kerr recorded 51.7 +/- 12.1 and 12.0 +/- infraumbilical media48.3 (p = 0.000). The time in seconds fetal extraction was lower in modified Misgav Ladach: 96.2 +/- 68.3, 474.9 +/- Pfannenstiel-Kerr 294.1 and 423.2 +/- 398.6 infraumbilical (p = 0.000). The trasoperatory milliliters bleeding was lower with modified Misgav-Ladach: 298.5 +/- 57.3, 354.3 +/- Pfannenstiel-Kerr 98.0 and 355.9 +/- 110.6 infraumbilical (p = 0.001). Postoperative pain assessed with the visual analog scale in the first 24 hours was lower with modified Misgav-Ladach: 4.4 +/- 1.9, 5.7 +/- Pfannenstiel-Kerr and IK 2.1 6.1 +/- 2.0 (p = 0.000). The start of the oral route and ambulation Nwas soon comparing modified Misgav-Ladach against Pfannenstiel-Kerr and Kerr-infraumbilical (p = 0.000). The prevalence of fever was 5.9% with modified Misgav-Ladach, 5.9% Pfannenstiel-Kerr and 32.4% withinfraumbilical-Kerr (p = 001). The discharge in hours was modified Misgav Ladach +/- 45.8 to 12.1 h, Pfannenstiel-Kerr 49.3 +/- 12.3 h and 58.5 infraumbilical-Kerr +/- 21.5 h (p = .000). In this study no maternal or fetal deaths were observed. Conclusion: Surgical time, bleeding, postoperative pain, better postoperative recovery and shorter hospital stays and less infection were significantly lower than with conventional techniques of caesarean Nsection or infraumbilical-Kerr technique. PMID- 29424515 TI - Coding Checkup: Determining the New Normal For Coding Accuracy in a Post-ICD-10 World. PMID- 29424516 TI - [Uterine arteriovenous malformation as cause of uterine bleeding of sudden onset. Doppler ultrasound utility, other imaging methods and the minimally invasive treatment]. AB - Background: Uterine arteriovenous malformation is a rare disorder that can cause sudden life-threatening vaginal bleeding. Objetive: To present the clinical features in addition to the use of office gynecologic ultrasound and other imaging techniques in the diagnosis and minimally-invasive treatment of a patient with sudden vaginal bleeding resulting from a uterine arteriovenous malformation. Case report: A 31 year old woman presented sudden onset vaginal bleeding requiring the transfusion of 3 units of red blood cells. An initial diagnosis of uterine arteriovenous malformation was made using an office gynecological ultrasound and Color Doppler sonography. The patient was referred to interventional radiology for confirmation of the diagnosis and patient care. The diagnosis and localization of the uterine arteriovenous malformation was confirmed using magnetic resonance imaging. Therapeutic management proceeded with superselective angiography and embolization of the supplying arteries resulting in immediate symptomatic resolution. Conclusion: The use of office gynecologic ultrasound in combination with other imaging techniques is an important tool in the diagnosis and localization of uterine arteriovenous malformation. Embolization of supplying arteries is considered a safe and effective therapeutic option due to advances in radiologic intervention techniques. Advantages of this procedure include a minimally-invasive technique, low morbidity and preservation of uterine function. PMID- 29424517 TI - [Peripartum cardiomyopathy: a case report]. AB - Background: Peripartum cardiomyopathy also known as cardiomyopathy associated with pregnancy, is rarely a cause of heart failure, it affects pregnant or puerperal women in the first 5 months. Although the first case reported was in 1849, it was recognized until 1930. In 2010 the European Society of Cardiology Working Group on peripartum cardiomyopathy, defined this pathology as an idiopathic cardiomyopathy that affects pregnant women between the third trimester and five months after delivery. Characterized by a left ventricular failure with an ejection fraction of <=45% and an end-diastolic dimension >=2.7 cm/m2 , in absence of an identifiable cause of heart failure. Case report: We report a case of a 39-year-old patient, diagnosed with a peripartum cardiomyopathy in the early puerperium, characterized by hypertension, tachycardia, dyspnea and oxygen desaturation. The transesophageal echocardiogram reported heart failure, a hypokinetic left ventricle and a ventricular failure with an ejection fraction <40%. We could not identify an other cause to justify heart failure. Multidisciplinary management was administered successfully. Conclusion: The importance of this article relies in the fact that eripartum cardiomyopathy has a high morbidity and mortality. The impact of this pathology is unknow in our country. Here we establish and discuss the multidisciplinary management held in our hospital with this specific patient in order to improve the prognosis on future occasions. PMID- 29424519 TI - ICD-10 Coding Audits Reveal Error Trends to Avoid. PMID- 29424518 TI - HIM Reimagined Outlines BOLD New Future for HIM Profession. PMID- 29424520 TI - Embrace the MIPS Additional Payment Adjustment for Exceptional Performance. PMID- 29424521 TI - Deep Eutectic Solvent-Assisted Preparation of Nitrogen/Chloride-Doped Carbon Dots for Intracellular Biological Sensing and Live Cell Imaging. AB - A novel approach for the preparation of dual-functional carbon dots, i.e., nitrogen- and chloride-doped carbon dots, abbreviated as N/Cl-CDs, is developed with the assistance of a choline chloride-glycerine deep eutectic solvent (DES). The carbon source is provided by urea and the DES serves as a solvent for controlling the preparation of CDs in the absence of water. The dual-element doped carbon dots are oxygen-rich with hydroxyl and amine groups. They exhibit an average particle size of ca. 3.88 nm and give rise to strong and pH-sensitive fluorescent emission at lambdaex/lambdaem = 340/430 nm with a quantum yield of 16.15 +/- 1.36%. It is particularly interesting to see that the fluorescence of N/Cl-CDs remains stable in a high-salinity matrix, providing vast potentials for treating real biological sample matrixes with high salinity. The N/Cl-CDs provide an optical probe for intracellular pH sensing and multicolor imaging in HeLa cells. In addition, the N/Cl-CDs show obvious fluorescence response to cytochrome c (cyt- c) with a detection limit of 3.6 mg L-1 (ca. 0.29 MUmol L-1) within in a range of 10-500 mg L-1, providing potentials for fluorescence detection of cyt- c as well as facilitating intracellular cyt- c imaging. PMID- 29424522 TI - Self-Assembled Tetrahedral DNA Nanostructures Promote Neural Stem Cell Proliferation and Neuronal Differentiation. AB - Stem cell-based therapy is considered a promising approach for the repair of nervous tissues. Neural stem cells (NSCs) cannot proliferate or differentiate efficiently; hence, different biomaterials have been explored to improve NSC proliferation and differentiation. However, these agents either had low bioavailability or poor biocompatibility. In this work, our group investigated the effects of tetrahedral DNA nanostructures (TDNs), a novel DNA biological material, on the self-renew and differentiation of neuroectodermal (NE-4C) stem cells. We observed that TDN treatment promoted self-renew of the stem cells via activating the Wnt/beta -catenin pathway. In addition, our findings suggested that NE-4C stem cells' neuronal differentiation could be promoted effectively by TDNs via inhibiting the notch signaling pathway. In summary, this is the first report about the effects of TDNs on the proliferation and differentiation of NE 4C stem cells and the results demonstrate that TDNs have a great potential in nerve tissue regeneration. PMID- 29424523 TI - Probing the Ionic and Electrochemical Phenomena during Resistive Switching of NiO Thin Films. AB - Ionic transport and electrochemical reactions underpin the functionality of the memory devices. NiO, as a promising transition metal oxide for developing resistive switching random access memory, has been extensively explored in the terms of the resistive switching. However, there is limited experimental evidence to visualize the ionic processes of the NiO under the external electrical field. In addition, the correlation between the ionic processes and the resistive switching has not been established. To close this gap and also to determine the role of the ionic processes in resistive switching of the NiO, in this study, a series of scanning probe microscopy techniques, including electrochemical strain microscopy (ESM), conductive atomic force microscopy, Kelvin probe force microscopy, and a newly developed first-order reversal curve-IV, are employed to measure the ESM response, the resistive switching performance, the work function, and the ionic dynamics of NiO, respectively. The results in this work have clearly visualized the ionic transport and electrochemical reactions of NiO when subjected to the electrical field. It has been found that the ionic processes and the resistive switching accompanied each other. Furthermore, it is found that the electrochemical reactions play a determinative role in the resistive switching of the NiO, and this electrochemically induced resistive switching performance can be explained by an integrated mechanism that has combined the filamentary and the interfacial effects underlying resistive switching. In addition to providing a better understanding of the resistive switching of NiO, this work also provides effective methods to probe the ionic processes and to correlate these ionic processes to the performance of functional materials. PMID- 29424524 TI - Second Near-Infrared Conjugated Polymer Nanoparticles for Photoacoustic Imaging and Photothermal Therapy. AB - Photothermal conversion in the second near-infrared (NIR-II) window allows deeper penetration and higher exposure to lasers, but examples of NIR-II photothermal agents are mainly formulated by inorganic compounds. In view of the underlying influence of inorganic materials, a novel NIR-II photothermal nanoagent based on a narrow band gap D-A conjugated polymer (TBDOPV-DT) with 2,2-bithiophene as the donor and thiophene-fused benzodifurandione-based oligo( p-phenylenevinylene) as the acceptor has been developed. More importantly, TBDOPV-DT nanoparticles (TBDOPV-DT NPs) are demonstrated to combine excellent photoacoustic imaging (PAI) and photothermal therapy (PTT) ability. TBDOPV-DT NPs exhibit dramatic photostability and heating reproducibility with a photothermal conversion efficiency of 50%. Especially, the NPs possess a remarkable PTT effect toward cancer cells in vitro and can eliminate tumor cells completely in vivo under 1064 nm laser irradiation, while no appreciable side effects have been observed. This study achieves PAI-guided cancer therapy and sheds light on the future of using organic polymer NPs for the NIR-II PTT of cancer. PMID- 29424525 TI - Ultralight and Highly Elastic Graphene/Lignin-Derived Carbon Nanocomposite Aerogels with Ultrahigh Electromagnetic Interference Shielding Performance. AB - Ultralight and highly elastic reduced graphene oxide (RGO)/lignin-derived carbon (LDC) composite aerogels with aligned micron-sized pores and cell walls are prepared using a facile freeze-drying method. The presence of a small fraction of LDC in the cell walls enhances the interfacial polarization effect while almost maintaining the amount of charge carriers and conductivity of the cell walls, greatly boosting the wave absorption capability of the cell walls. RGO/LDC aerogels also show a greater number of large cell walls with better integrity than RGO aerogels, further improving the multiple reflection ability of the aligned cell walls. Synergistic effects of the multiphase cell walls and the preferred microstructures of the RGO/LDC aerogels lead to their high electromagnetic interference (EMI) shielding effectiveness of 21.3-49.2 dB at an ultralow density of 2.0-8.0 mg/cm3. This corresponds to the surface-specific SE (SE divided by density and thickness) up to 53 250 dB.cm2/g, which is higher than the values reported for other carbon- and metal-based shields. Furthermore, the critical roles that microstructures play in determining the EMI shielding performance are directly revealed by comparing the shielding performance in directions parallel and normal to cell walls, as well as in an in situ compression process. PMID- 29424526 TI - Novel Amorphous Molybdenum Selenide as an Efficient Catalyst for Hydrogen Evolution Reaction. AB - Amorphous molybdenum selenide nanopowder, obtained by refluxing Mo(CO)6 and Se precursors in dichlorobenzene, shows several structural and electrochemical similarities to the amorphous molybdenum sulfide analogue. The molybdenum selenide displays attractive catalytic properties for the hydrogen evolution reaction in water over a wide range of pH. In a pH 0 solution, it operates with a small onset overpotential of 125 mV and requires an overpotential of 270 mV for generating a catalytic current of 10 mA/cm2. Compared with molybdenum sulfide, the selenide analogue is more robust in a basic electrolyte. Therefore, molybdenum selenide is a potential candidate for incorporating within an electrolyzer or a photoelectrochemical cell for water electrolysis in acidic, neutral, or alkaline medium. PMID- 29424527 TI - ROS-Activated Ratiometric Fluorescent Polymeric Nanoparticles for Self-Reporting Drug Delivery. AB - Reactive oxygen species (ROS)-responsive theranostic nanomedicines have attracted wide interest in recent years because ROS stress is implicated in some pathological disorders such as inflammatory diseases and cancers. In this article, we report a kind of innovative ROS-responsive theranostic polymeric nanoparticles that are able to load hydrophobic drugs and to fluorescently self report the in vitro or intracellular drug release under ROS triggering. The fluorescent nanoparticles were formed by amphiphilic block copolymers consisting of a poly(ethylene glycol) (PEG) segment and an oxidation-responsive hydrophobic block. The copolymers with different hydrophobic block lengths were synthesized by the atom transfer radical polymerization of a phenylboronic ester-containing acrylic monomer with a small fraction of a ROS-activatable 1,8-naphthalimide based fluorescent monomer, using PEG-Br as the macroinitiator. The copolymer nanoparticles were stable in neutral phosphate buffer but degraded upon H2O2 triggering, with the degradation rate depending on the hydrophobic block length and the concentration of H2O2. The degradation of nanoparticles was accompanied by a colorimetric change of the fluorophore from blue to green, which affords the nanoparticles the ability to detecting H2O2 by a ratiometric fluorescent approach. Moreover, the nanoparticles could encapsulate doxorubicin (DOX) and the H2O2-triggered DOX release was well associated with the change in ratiometric fluorescence. Confocal laser scanning microscope results reveal that the fluorescent nanoparticles were internalized into A549 cells through the endocytosis pathway. The ROS-stimulated degradation of the nanoparticles and intracellular DOX release and the fate of the degraded polymers could be monitored by ratiometric fluorescent imaging. Finally, the naked nanoparticles and the degradation products are cytocompatible, whereas the DOX-loaded ones exhibit concentration-dependent cytotoxicity. Of importance, the stimulation with exogenous H2O2 or lipopolysaccharide enhanced obviously the cell-killing capability of the DOX-loaded nanoparticles because of the ROS-enhanced intracellular DOX release. PMID- 29424528 TI - Aqueous Solvation of SmI3: A Born-Oppenheimer Molecular Dynamics Density Functional Theory Cluster Approach. AB - We report the results of Born-Oppenheimer molecular dynamics (BOMD) simulations on the aqueous solvation of the SmI3 molecule and of the bare Sm3+ cation at room temperature using the cluster microsolvation approach including 37 and 29 water molecules, respectively. The electronic structure calculations were done using the M062X hybrid exchange-correlation functional in conjunction with the 6-31G** basis sets for oxygen and hydrogen. For the iodine and samarium atoms, the Stuttgart-Koln relativistic effective-core potentials were utilized with their associated valence basis sets. When SmI3 is embedded in the microsolvation environment, we find that substitution of the iodine ions by water molecules around Sm(III) cannot be achieved due to an insufficient number of explicit water molecules to fully solvate the four separate metal and halogen ions. Therefore, we studied the solvation dynamics of the bare Sm3+ cation with a 29-water molecule model cluster. Through the Sm-O radial distribution function and the evolution of the Sm-O distances, the present study yields a very tightly bound first rigid Sm(III) solvation shell from 2.3 to 2.9 A whose integration leads to a coordination number of 9 water molecules and a second softer solvation sphere from 3.9 to 5 A with 12 water molecules. No water exchange processes were found. The theoretical EXAFS spectrum is in excellent agreement with the experimental spectrum for Sm(III) in liquid water. The strong differences between the solvation patterns of Sm(III) vs Sm(II) are discussed in detail. PMID- 29424529 TI - Phototriggered Mechanical Movement in A Bipyridinium-based Coordination Polymer Powered by Electron Transfer. AB - Photomechanical movement with a morphological deformation has been achieved in the crystalline state of a bipyridinium-based coordination polymer. The engine "heart" is the electron-deficient bipyridinium core sandwiched by electron-rich phenylcarboxylate components. The decorrelation of the CT state triggered by PET reaction in the engine "heart" promotes the occurrence of this mechanical movement. PMID- 29424530 TI - Helical Rod-like Phenylene Cages via Ruthenium Catalyzed Diol-Diene Benzannulation: A Cord of Three Strands. AB - p-Bromo-terminated oligo(p-phenylenevinylenes) emanating from a 1,3,5-benzene core are dihydroxylated and subjected to ruthenium catalyzed diol-diene benzannulation to form tripodal oligo(phenylenes). Copper- or nickel-mediated 3 fold reductive biaryl homocoupling delivers a series of triple-stranded phenylene cages of helical rod-like topology bearing 14, 17, and 20 benzene rings. PMID- 29424531 TI - Current Risk Assessment Frameworks Misjudge Risks of Hydrophobic Chemicals. PMID- 29424532 TI - Nanocrystals for Triplet Sensitization: Molecular Behavior from Quantum-Confined Materials. AB - Inorganic semiconductor quantum dot-molecular constructs represent an emerging class of materials functioning as triplet photosensitizers. Fundamental investigations into the exciton transfer/transduction processes at the interface of these hybrid materials have revealed parallels in the operable mechanisms to those established in purely molecular systems. The similarities in the governing energy migration mechanisms in these quantum-confined materials permit conventional photophysical strategies to be implemented in future research endeavors. This Viewpoint provides a perspective on this emerging field of inorganic quantum dots as photosensitizers, in particular the transfer of triplet excitons at the molecule-nanomaterial interface. The current state-of-the-art will be explored while highlighting areas of potential growth toward exploiting these materials in photofunctional solar energy conversion schemes. PMID- 29424533 TI - Effect of Binding on Enantioselectivity of Epoxide Hydrolase. AB - Molecular dynamics simulations and free energy calculations have been used to investigate the effect of ligand binding on the enantioselectivity of an epoxide hydrolase (EH) from Aspergillus niger. Despite sharing a common mechanism, a wide range of alternative mechanisms have been proposed to explain the origin of enantiomeric selectivity in EHs. By comparing the interactions of ( R)- and ( S) glycidyl phenyl ether (GPE) with both the wild type (WT, E = 3) and a mutant showing enhanced enantioselectivity to GPE (LW202, E = 193), we have examined whether enantioselectivity is due to differences in the binding pose, the affinity for the ( R)- or ( S)- enantiomers, or a kinetic effect. The two enantiomers were easily accommodated within the binding pockets of the WT enzyme and LW202. Free energy calculations suggested that neither enzyme had a preference for a given enantiomer. The two substrates sampled a wide variety of conformations in the simulations with the sterically hindered and unhindered carbon atoms of the GPE epoxide ring both coming in close proximity to the nucleophilic aspartic acid residue. This suggests that alternative pathways could lead to the formation of a ( S)- and ( R)-diol product. Together, the calculations suggest that the enantioselectivity is due to kinetic rather than thermodynamic effects and that the assumption that one substrate results in one product when interpreting the available experimental data and deriving E-values may be inappropriate in the case of EHs. PMID- 29424534 TI - Dianionic Phase-Transfer Catalyst for Asymmetric Fluoro-cyclization. AB - Inspired by the dicationic nature of the electrophilic fluorinating reagent, Selectfluor (1), we rationally designed a series of dicarboxylic acid precatalysts (2), which, when deprotonated, act as anionic phase-transfer catalysts for asymmetric fluorination of alkenes. Among them, 2a having the shortest linker moiety efficiently catalyzed unprecedented 6-endo-fluoro cyclization of various allylic amides, affording fluorinated dihydrooxazine compounds with high enantioselectivity (up to 99% ee). In addition to cyclic substrates, acyclic trisubstituted alkenes underwent the reaction with good diastereoselectivity, whereas low diastereoselectivity was observed for linear disubstituted alkenes. Results suggest that the reaction proceeds via a fluoro carbocation intermediate. PMID- 29424535 TI - Phosphorus Dimerization in Gallium Phosphide at High Pressure. AB - Using combined experimental and computational approaches, we show that at 43 GPa and 1300 K gallium phosphide adopts the super- Cmcm structure, here indicated with its Pearson notation oS24. First-principles enthalpy calculations demonstrate that this structure is more thermodynamically stable above ~20 GPa than previously proposed polymorphs. In contrast to other polymorphs, the oS24 phase shows a strong bonding differentiation and distorted fivefold coordination geometries of both P atoms. The shortest bond of the phase is a single covalent P P bond measuring 2.171(11) A at synthesis pressure. Phosphorus dimerization in GaP sheds light on the nature of the super- Cmcm phase and provides critical new insights into the high-pressure polymorphism of octet semiconductors. Bond directionality and anisotropy explain the relatively low symmetry of this high pressure phase. PMID- 29424536 TI - A Strategically Located Arg/Lys Residue Promotes Correct Base Paring During Nucleic Acid Biosynthesis in Polymerases. AB - Polymerases (Pols) synthesize the double-stranded nucleic acids in the Watson Crick (W-C) conformation, which is critical for DNA and RNA functioning. Yet, the molecular basis to catalyze the W-C base pairing during Pol-mediated nucleic acids biosynthesis remains unclear. Here, through bioinformatics analyses on a large data set of Pol/DNA structures, we first describe the conserved presence of one positively charged residue (Lys or Arg), which is similarly located near the enzymatic two-metal active site, always interacting directly with the incoming substrate (d)NTP. Incidentally, we noted that some Pol/DNA structures showing the alternative Hoogsteen base pairing were often solved with this specific residue either mutated, displaced, or missing. We then used quantum and classical simulations coupled to free-energy calculations to illustrate how, in human DNA Pol-eta, the conserved Arg61 favors W-C base pairing through defined interactions with the incoming nucleotide. Taken together, these structural observations and computational results suggest a structural framework in which this specific residue is critical for stabilizing the incoming (d)NTP nucleotide and base pairing during Pol-mediated nucleic acid biosynthesis. These results may benefit enzyme engineering for nucleic acid processing and encourage new drug discovery strategies to modulate Pols function. PMID- 29424537 TI - A New Bis(aquated) High Relaxivity Mn(II) Complex as an Alternative to Gd(III) Based MRI Contrast Agent. AB - Disclosed here are a piperazine, a pyridine, and two carboxylate groups containing pentadentate ligand H2pmpa and its corresponding water-soluble Mn(II) complex (1). DFT-based structural optimization implied that the complex had pentagonal bipyramidal geometry where the axial positions were occupied by two water molecules, and the equatorial plane was constituted by the ligand ON3O donor set. Thus, a bis(aquated) disc-like Mn(II) complex has been synthesized. The complex showed higher stability compared with Mn(II)-EDTA complex [log KMnL = 14.29(3)] and showed a very high r1 relaxivity value of 5.88 mM-1 s-1 at 1.41 T, 25 degrees C, and pH = 7.4. The relaxivity value remained almost unaffected by the pH of the medium in the range of 6-10. Although the presence of 200 equiv of fluoride and bicarbonate anions did not affect the relaxivity value appreciably, an increase in the value was noticed in the presence of phosphate anion due to slow tumbling of the complex. Cell viability measurements, as well as phantom MR images using clinical MRI imager, consolidated the possible candidature of complex 1 as a positive contrast agent. PMID- 29424539 TI - Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo. AB - Piperlongumine 1 increases reactive oxygen species (ROS) levels and preferably induces cancer cell apoptosis by triggering different pathways. However, the poor solubility of 1 limits its intensive investigation and clinical application. Ligustrazine possesses a water-soluble pyrazine skeleton and can inhibit proliferation and metastasis of cancer cells. We synthesized compound 3 by replacement of the trimethoxyphenyl of 1 with ligustrazine moiety and further introduced 2-Cl, -Br, and -I to 3 for synthesis of 4-6, respectively. Compound 4 possessed 14-fold greater aqueous solubility than 1 and increased ROS levels in colorectal cancer HCT-116 cells. Additionally, 4 preferably inhibited proliferation, migration, invasion, and heteroadhesion of HCT-116 cells. Treatment with 4 suppressed tumor growth and lung metastasis in vivo and prolonged the survival of tumor-bearing mice. Furthermore, 4 mitigated TGF-beta1 induced epithelial-mesenchymal transition and Wnt/beta-catenin activation by inhibiting the Akt and GSK-3beta phosphorylation in HCT-116 cells. Collectively, 4 displayed significant antiproliferation and antimetastasis activities, superior to 1. PMID- 29424538 TI - Development of a Targeted Mass-Spectrometry Serum Assay To Quantify M-Protein in the Presence of Therapeutic Monoclonal Antibodies. AB - M-protein diagnostics can be compromised for patients receiving therapeutic monoclonal antibodies as treatment in multiple myeloma. Conventional techniques are often not able to distinguish between M-proteins and therapeutic monoclonal antibodies administered to the patient. This may prevent correct response assessment and can lead to overtreatment. We have developed a serum-based targeted mass-spectrometry assay to detect M-proteins, even in the presence of three therapeutic monoclonal antibodies (daratumumab, ipilimumab, and nivolumab). This assay can target proteotypic M-protein peptides as well as unique peptides derived from therapeutic monoclonal antibodies. We address the sensitivity in M protein diagnostics and show that our mass-spectrometry assay is more than two orders of magnitude more sensitive than conventional M-protein diagnostics. The use of stable isotope-labeled peptides allows absolute quantification of the M protein and increases the potential of assay standardization across multiple laboratories. Finally, we discuss the position of mass-spectrometry assays in monitoring minimal residual disease in multiple myeloma, which is currently dominated by molecular techniques based on plasma cell assessment that requires invasive bone marrow aspirations or biopsies. PMID- 29424540 TI - Chiral Molecule-Enhanced Extinction Ratios of Quantum Dots Coupled to Random Plasmonic Structures. AB - Devices based on self-assembled hybrid colloidal quantum dots (CQDs) coupled with specific organic linker molecules are a promising way to simply realize room temperature, spectrally tunable light detectors. Nevertheless, this type of devices usually has low quantum efficiency. Plasmonics has been shown as an efficient tool in guiding and confining light at nanoscale dimensions. As plasmonic modes exhibit highly confined fields, they locally increase light matter interactions and consequently enhance the performance of CQD-based photodetectors. Recent publications presented experimental results of large extinction enhancement from a monolayer of CQDs coupled to random gold nanoislands using a monolayer of organic alkyl linkers. We report here that a twofold larger extinction enhancement in the visible spectrum is observed when a monolayer of helical chiral molecules connects the CQDs to the gold structure instead of a monolayer of achiral linkers. We also show that this effect provides insight into the chirality of the molecules within the monolayer. In future work, we plan to evaluate the potential of these results to be used in the construction of a more efficient and sensitive photon detector based on surface QDs, as well as to supply a simple way to map the chirality of a single chiral monolayer. PMID- 29424541 TI - Rhodium-Catalyzed Asymmetric Conjugate Alkynylation/Aldol Cyclization Cascade for the Formation of alpha-Propargyl-beta-hydroxyketones. AB - A rhodium-catalyzed conjugate alkynylation/aldol cyclization cascade was developed. Densely functionalized cyclic alpha-propargyl-beta-hydroxyketones were synthesized with simultaneous formation of a C(sp)-C(sp3) bond, a C(sp3)-C(sp3) bond, as well as three new contiguous stereocenters. The transformation was achieved with excellent enantio- and diastereoselectivities using BINAP as the ligand. The synthetic utility of the newly installed alkynyl moiety was exhibited by subjecting the products to an array of derivatizations. PMID- 29424542 TI - Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile. AB - Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone. PMID- 29424544 TI - Interplay between Caging and Bonding in Binary Concentrated Colloidal Suspensions. AB - When a liquid becomes dynamically arrested, a gel, a repulsive glass, or an attractive glass state will form. Bonding and caging mechanisms decide their static structures and dynamic properties. To better understand their interplay, the competition between bonding and caging in a binary mixture of polystyrene core/poly( N-isopropylacrylamide) shell (CS) microgels and sulfonated polystyrene (PSS) particles is studied. CS microgels have short-range attraction above the volume phase transition temperature, whereas PSS species experiences relatively long-range electrostatic repulsion. Adding more PSS into the binary mixture will, of course, increase the total effective volume fraction but lead to different properties in gel or glass states. For instance, in gels, it increases the localization length and weakens the gel, whereas in glass, it decreases the localization length and strengthens the glass. This thus implies that the static and dynamic properties of gels are mainly controlled by bonding and those of both repulsive and attractive glasses are governed by caging. On the other hand, increasing the temperature will decrease the effective volume fraction because of the volume phase transition of the CS microgels. A discontinuous repulsive glass to-liquid-to-gel transition can be observed when the PSS concentration is low, but a continuous repulsive glass-to-gel transition can also be observed with the increase of the PSS concentration. This may hint that glass transition and physical gelation share a similar mechanism, whereas the former has a longer relaxation time. PMID- 29424543 TI - Balancing Force Field Protein-Lipid Interactions To Capture Transmembrane Helix Helix Association. AB - Atomistic simulations have recently been shown to be sufficiently accurate to reversibly fold globular proteins and have provided insights into folding mechanisms. Gaining similar understanding from simulations of membrane protein folding and association would be of great medical interest. All-atom simulations of the folding and assembly of transmembrane protein domains are much more challenging, not least due to very slow diffusion within the lipid bilayer membrane. Here, we focus on a simple and well-characterized prototype of membrane protein folding and assembly, namely the dimerization of glycophorin A, a homodimer of single transmembrane helices. We have determined the free energy landscape for association of the dimer using the CHARMM36 force field. We find that the native structure is a metastable state, but not stable as expected from experimental estimates of the dissociation constant and numerous experimental structures obtained under a variety of conditions. We explore two straightforward approaches to address this problem and demonstrate that they result in stable dimers with dissociation constants consistent with experimental data. PMID- 29424545 TI - Copper-Catalyzed Aza-Michael Addition of 2-Aminobenzoate to beta-Substituted alpha,beta-Unsaturated Ketones: One-Pot Synthesis of 3-Carbonyl-2-Substituted Quinolin-4(1H)-ones. AB - We present a new and straightforward one-pot process for the synthesis of 3 carbonyl-4-quinolone derivatives through highly efficient Cu-catalyzed aza Michael addition of 2-aminobenzoates to beta-substituted alpha,beta-unsaturated ketones/cyclization/mild oxidation reactions. A broad range of new versatile 3 carbonyl-quinolin-4(1H)-ones is prepared from readily available chemicals under mild reaction conditions with short reaction times, producing good to excellent yields (up to 99%). PMID- 29424546 TI - Heteroatom-Directed Acylation of Secondary Alcohols To Assign Absolute Configuration. AB - Birman's HBTM catalyst is effective for the enantioselective acylation and kinetic resolution of benzylic secondary alcohols. The enantioselective acylation has now been extended to secondary alcohols bearing electron-withdrawing groups such as halides and other heteroatoms. The level of selectivity is modest to good and is sufficient for determining configuration using the competing enantioselective conversion method. A mathematical analysis identifies conditions for achieving maximum differences in conversion and, consequently, assigning configuration with greater confidence. The new method is effective for halohydrins and secondary-tertiary 1,2-diols and was used to confirm the configuration of two inoterpene natural products. PMID- 29424547 TI - Superstable Ultrathin Water Film Confined in a Hydrophilized Carbon Nanotube. AB - Fluids confined in a nanoscale space behave differently than in the bulk due to strong interactions between fluid molecules and solid atoms. Here, we observed water confined inside "open" hydrophilized carbon nanotubes (CNT), with diameter of tens of nanometers, using transmission electron microscopy (TEM). A 1-7 nm water film adhering to most of the inner wall surface was observed and remained stable in the high vacuum (order of 10-5 Pa) of the TEM. The superstability of this film was attributed to a combination of curvature, nanoroughness, and confinement resulting in a lower vapor pressure for water and hence inhibiting its vaporization. Occasional, suspended ultrathin water film with thickness of 3 20 nm were found and remained stable inside the CNT. This film thickness is 1 order of magnitude smaller than the critical film thickness (about 40 nm) reported by the Derjaguin-Landau-Verwey-Overbeek theory and previous experimental investigations. The stability of the suspended ultrathin water film is attributed to the additional molecular interactions due to the extended water meniscus, which balances the rest of the disjoining pressures. PMID- 29424548 TI - Triterpenic azines, a new class of compounds with selective cytotoxicity to leukemia cells CCRF-CEM. AB - AIM: From betulinic acid (1a), we synthesized 30-oxobetulinic acid (2a) that is highly cytotoxic against many cancer cell lines; however, its generic toxicity is the main obstacle in further development as cytostatic. Methodology & results: From 2a, we prepared a new class of compounds - nonsymmetrical azines and tested their in vitro cytotoxicity. All new azines with a free 28-COOH group (4a-4e) were highly and selectively cytotoxic against the T-lymphoblastic leukemia cell line CCRF-CEM and exhibited dose-dependent inhibition of RNA and DNA synthesis and other cell-cycle alterations, including the M-phase block. CONCLUSION: The potential use of azines (4a-4e) in drug development focused on hematological cancers is significantly higher than that of previously studied acids 1a and 2a. PMID- 29424549 TI - Variation in levels of non-starch polysaccharides and endogenous endo-1,4-beta xylanases affects the nutritive value of wheat for poultry. AB - 1. Endo-1,4-beta-xylanase is known to improve the nutritive value of wheat-based diets for poultry by degrading dietary arabinoxylans. However, broilers' response to supplementation of wheat-based diets with exogenous endo-1,4-beta-xylanase is not always observed. 2. In this study, 108 different wheat lots were analysed for levels of extract viscosity as well as for endogenous endo-1,4-beta-xylanase activity, and the impact of these two variables in animal performance was tested. 3. Results revealed that endogenous endo-1,4-beta-xylanase activity and extract viscosity content varied widely among different wheat lots. Thus, a trial was conducted to evaluate the efficacy of exogenous enzyme supplementation in broiler diets using wheats with different levels of extract viscosity and endogenous endo 1,4-beta-xylanase activity. 4. The data revealed that exogenous enzyme supplementation was only effective when the wheat present in the diet had high levels of extract viscosity (14.8 cP) with low endogenous endo-1,4-beta-xylanase activity (347.0 U/kg). Nevertheless, it is apparent that exogenous microbial xylanases reduce digesta extract viscosity and feed conversion ratio independently of the endogenous properties presented by different wheat lots. 5. The data suggest that extract viscosity and/or endogenous endo-1,4-beta-xylanase activity affect the response to enzyme supplementation by poultry fed on wheat based diets. PMID- 29424550 TI - Enhancing anticancer activity through the combination of bioreducing agents and triterpenes. AB - AIM: Triterpenes are natural compounds, whose wide biological activity predestines them for application as promising new chemotherapeutics. In this paper, we report the results of our investigations into the substitution of oleanolic acid with aromatic and nitroaromatic moieties acting as bioreducing agents. RESULTS: The process of reduction of nitro groups was investigated through cyclic voltammetry, UV-Vis and electron paramagnetic resonance spectroelectrochemistry. The cytotoxic activity against selected cancer cell lines was determined, showing a significant increase in cytotoxicity when the triterpene is equipped with a nitroaromatic moiety. CONCLUSION: We believe this approach to the functionalization is promising in terms of enhancing anticancer activity. We also indicate electrochemical techniques as advantageous preclinical screening methods for the identification of cytotoxic agents. PMID- 29424551 TI - Development of Infrared Library Search Prefilters for Automotive Clear Coats from Simulated Attenuated Total Reflection (ATR) Spectra. AB - A previously published study featuring an attenuated total reflection (ATR) simulation algorithm that mitigated distortions in ATR spectra was further investigated to evaluate its efficacy to enhance searching of infrared (IR) transmission libraries. In the present study, search prefilters were developed from transformed ATR spectra to identify the assembly plant of a vehicle from ATR spectra of the clear coat layer. A total of 456 IR transmission spectra from the Paint Data Query (PDQ) database that spanned 22 General Motors assembly plants and served as a training set cohort were transformed into ATR spectra by the simulation algorithm. These search prefilters were formulated using the fingerprint region (1500 cm-1 to 500 cm-1). Both the transformed ATR spectra (training set) and the experimental ATR spectra (validation set) were preprocessed for pattern recognition analysis using the discrete wavelet transform, which increased the signal-to-noise of the ATR spectra by concentrating the signal in specific wavelet coefficients. Attenuated total reflection spectra of 14 clear coat samples (validation set) measured with a Nicolet iS50 Fourier transform IR spectrometer were correctly classified as to assembly plant(s) of the automotive vehicle from which the paint sample originated using search prefilters developed from 456 simulated ATR spectra. The ATR simulation (transformation) algorithm successfully facilitated spectral library matching of ATR spectra against IR transmission spectra of automotive clear coats in the PDQ database. PMID- 29424552 TI - Differences in neuropsychiatric symptoms between nursing home residents with young-onset dementia and late-onset dementia. AB - OBJECTIVE: The aims of the current study are (1) to explore the differences in neuropsychiatric symptoms (NPS) between young-onset dementia (YOD) and late-onset dementia (LOD), and (2) to investigate whether the possible differences can be attributed to differences in dementia subtype, gender, psychotropic drug use (PDU), or dementia severity. METHOD: Three hundred and eighty-six nursing home (NH) residents with YOD and 350 with LOD were included. Multilevel modeling was used to compare NPS between the groups . Furthermore, dementia subtype, gender, PDU, and dementia severity were added to the crude multilevel models to investigate whether the possible differences in NPS could be attributed to these characteristics. RESULTS: Higher levels of apathy were found in NH residents with YOD. After the characteristics were added to the models, also lower levels of verbally agitated behaviors were found in YOD . CONCLUSION: We recommend that special attention be paid to interventions targeting apathy in YOD. Although no differences in other NPS were found, the PDU rates were higher in YOD, suggesting that the threshold for the use of PDU in the management of NPS is lower. This underscores the need for appropriate attention to non-pharmacological interventions for the management of NPS in YOD. PMID- 29424553 TI - Lower Sleep Duration Is Associated With Reduced Autobiographical Memory Specificity. AB - OBJECTIVE/BACKGROUND: Sleep can have an important influence on memory. However, it is unclear whether there is any relation between sleep quality and the specificity with which autobiographical memories are retrieved, a key factor associated with vulnerability for, and the presence of, depression and other psychiatric diagnoses. The present study provides the first investigation of the association between sleep quality and autobiographical memory specificity. PARTICIPANTS AND METHOD: Fifty-four unselected community participants completed the Autobiographical Memory Test (AMT) to assess memory specificity, while subjective and objective measures of total sleep time and sleep onset latency were provided through a daily diary and an actigraphy wristwatch worn for a week. Participants also completed questionnaires that measure known correlates of AMT specificity: the Ruminative Response Scale (RRS) and Beck Depression Inventory (BDI-II). RESULTS: Shorter sleep duration, measured using actigraphy, was associated with reduced autobiographical memory specificity. There was no evidence of an association between total sleep time recorded by self-report diaries, or of sleep onset latency recorded using actigraphy or diaries and memory specificity. The relation between actigraphy-assessed total sleep time and memory specificity was independent of the effects of rumination or depressive symptoms on these variables. CONCLUSIONS: Shorter sleep duration is associated with reduced memory specificity. Future research examining memory specificity and its association with psychopathology should consider the role of sleep quality around the time of memory recall in specificity. PMID- 29424554 TI - Predicting Postprobationary Job Performance of Police Officers Using CPI and MMPI 2-RF Test Data Obtained During Preemployment Psychological Screening. AB - We examined associations between prehire California Psychological Inventory (CPI) and prorated Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) scores (calculated from MMPI profiles) and supervisor ratings for a sample of 143 male police officers. Substantive scale scores in this sample were meaningfully lower than those obtained by the tests' normative samples in the case of the MMPI-2-RF and meaningfully higher in the case of the CPI (indicating less psychological dysfunction). Test scores from both instruments showed substantial range restriction, consistent with those produced by members of the police candidate comparison groups (Corey & Ben-Porath, 2014 ; Roberts & Johnson, 2001 ). After applying a statistical correction for range restriction, we found a number of meaningful associations between both CPI and MMPI-2-RF substantive scale scores and supervisor ratings. For the MMPI-2-RF, findings for scales from the emotional dysfunction and interpersonal functioning domains of the test were particularly strong. For the CPI, findings for scales indicating conformity with social norms, integrity, and tolerance were strong, as were the findings for an index indicating risk of termination. Hierarchical regression analyses showed that MMPI-2-RF and CPI scores complement each other, accounting for incremental variance in the prediction of job-related variables over and above each other. Implications of these findings for assessment science and practice are discussed. PMID- 29424555 TI - Videogames for Emotion Regulation: A Systematic Review. AB - INTRODUCTION: Emotion regulation (ER) supports multiple individual functions and promotes mental health and wellbeing. Among the tools that may be used to help people in managing their affective states, videogames are reaching attention and are showing positive effects. Yet, little is known about their effectiveness. OBJECTIVE: This study aims to assess the amount and quality of studies investigating the effects and modalities of the use of videogames for ER. MATERIALS AND METHODS: A systematic literature search according to PRISMA guidelines was performed. Subsequently, according to expert advice other few studies have been added. RESULTS: Twenty-three studies met the inclusion criteria and were included in the review; they can be categorized into three groups, namely (1) cross-sectional and qualitative studies, (2) experimental studies investigating the effects of videogame experience on ER and (3) ER intervention with serious games. DISCUSSION: Discussion of the reviewed studies highlights that frequent gaming with commercial games offers more opportunities for ER improvement (related to gameplay and enjoyment of fictional properties) than limited-time experiences, such as those supported by bespoke serious games. This research area is still in its infancy and findings need to be interpreted with caution; furthermore, future reviews are encouraged to include clinical populations. CONCLUSION: Videogames offer several opportunities for ER and a challenge for educational and psychological interventions. PMID- 29424556 TI - Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR). AB - OBJECTIVE: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin (ATTR) amyloidosis. PATIENTS AND METHODS: We performed a retrospective analysis of patients with biopsy-proven ATTRwt (wild-type transthyretin amyloid protein) and genopositive ATTR V122I (valine-to-isoleucine substitution at position 122 of the TTR gene) amyloidosis evaluated at the Amyloidosis Center at Boston University and Boston Medical Center between 1 January 2003 and 31 December 2016. RESULTS: There were a total of 226 patients with ATTRwt and ATTR V122I amyloidosis evaluated during the specified time frame with 155 and 71 patients in each cohort, respectively. Those with complete medical records, 140 patients with ATTRwt and 57 V1221 ATTRm subjects, were included in the analyses. Fifty-five patients (39%) in the ATTRwt cohort and 28 patients (49%) in the ATTR V122I cohort had an MGUS, as indicated by an abnormality in the serum-free light-chain ratio and/or serum immunofixation electrophoresis. CONCLUSION: These data confirm the high prevalence of coexistent MGUS with ATTR amyloidosis in this patient population, with an MGUS rate that is higher than the general population. These findings also highlight the importance of a thorough diagnostic evaluation in patients with amyloidosis to determine the precursor protein, as the clinical course and treatment of AL (light-chain amyloid protein) and ATTR amyloidosis are distinct. PMID- 29424558 TI - Corrigendum. PMID- 29424557 TI - Proteomic biomarkers for lung cancer progression. AB - AIM: Lung adenocarcinoma (LUAD) and lung squamous-cell carcinoma (LUSC) are two major subtypes of lung cancer and constitute about 70% of all the lung cancer cases. The patient's lifespan and living quality will be significantly improved if they are diagnosed at an early stage and adequately treated. METHODS & RESULTS: This study comprehensively screened the proteomic dataset of both LUAD and LUSC, and proposed classification models for the progression stages of LUAD and LUSC with accuracies 86.51 and 89.47%, respectively. DISCUSSION & CONCLUSION: A comparative analysis was also carried out on related transcriptomic datasets, which indicates that the proposed biomarkers provide discerning power for accurate stage prediction, and will be improved when larger-scale proteomic quantitative technologies become available. PMID- 29424559 TI - Bayesian Latent Class Analysis Tutorial. AB - This article is a how-to guide on Bayesian computation using Gibbs sampling, demonstrated in the context of Latent Class Analysis (LCA). It is written for students in quantitative psychology or related fields who have a working knowledge of Bayes Theorem and conditional probability and have experience in writing computer programs in the statistical language R . The overall goals are to provide an accessible and self-contained tutorial, along with a practical computation tool. We begin with how Bayesian computation is typically described in academic articles. Technical difficulties are addressed by a hypothetical, worked-out example. We show how Bayesian computation can be broken down into a series of simpler calculations, which can then be assembled together to complete a computationally more complex model. The details are described much more explicitly than what is typically available in elementary introductions to Bayesian modeling so that readers are not overwhelmed by the mathematics. Moreover, the provided computer program shows how Bayesian LCA can be implemented with relative ease. The computer program is then applied in a large, real-world data set and explained line-by-line. We outline the general steps in how to extend these considerations to other methodological applications. We conclude with suggestions for further readings. PMID- 29424560 TI - Validation of Montreal Cognitive Assessment-Basic in a sample of elderly Egyptians with neurocognitive disorders. AB - BACKGROUND AND OBJECTIVES: Montreal Cognitive Assessment-Basic (MoCA-B) is a modified version of the MoCA that is especially suitable for use in elderly subjects with low education. The Authors translated the tool into Arabic and they aimed at validation of this tool in a sample of elderly Egyptians. METHODS: The study included 93 patients, 60 years and older, fulfilling the DSM-5 criteria of Mild Neurocognitive Disorder (NCD) (39 patients) and Major Neurocognitive Disorder (54 patients) that were compared to 112 community dwelling elder subjects. All subjects were assessed using the MoCA-B, Mini-Mental State Examination (MMSE), and the Clinical Dementia Rating Scale (CDR) in addition to the required laboratory and radiological investigations. RESULTS: MoCA-B demonstrated good internal consistency (Cronbach's alpha = 0.915) and content validity in discrimination between normal and diseased subjects. It showed superior sensitivity and specificity when compared to MMSE in screening for Mild NCD (AUC MoCA-B = 0.988 versus MMSE = 0.939). The recommended cut-off was 21/22 with sensitivity of 92.5% and specificity of 98.2% for detecting Mild NCD and 16/17 with sensitivity of 90.7% and specificity of 97.4% for detecting Major NCD (dementia). CONCLUSION: The Arabic MoCA-B is a valid cognitive assessment tool in elderly Egyptian subjects. PMID- 29424561 TI - Resource or Hindrance? The benefits and costs of social support for functional difficulties and its implications for depressive symptoms. AB - OBJECTIVES: The impact of social support on the relationship between stress and well-being remains somewhat inconclusive, with work suggesting either null, buffering, or amplification effects. The current study investigated the conditions in which perceived social support is likely to act as a buffer or amplifier by considering individual differences in self-perceptions of aging. METHODS: Using data from two subsamples of the Wisconsin Longitudinal Study (graduates: 70-74 years, siblings: 40-92 years), we examined how perceived social support (emotional versus instrumental) and self-perceptions of aging (SPA) moderated the effect of functional limitations on depressive symptoms (DS). RESULTS: Although emotional support positively predicted DS, its effects did not depend on SPA. Instrumental support was associated with both increases and decreases in well-being that were dependent upon SPA. Functional limitations predicted more DS at both low and high levels of instrumental support when SPA were negative. However, when SPA were positive, low levels of social support were found to decrease depressive symptoms, and high levels were found to increase depressive symptoms. CONCLUSIONS: The impact of social social may enhance or deteriorate well-being, depending on how it interacts with self-evaluative beliefs. Findings offer insights as to the boundary conditions associated with the (positive) effects of social support and SPA, and highlight the need for continued research on the mechanisms associated these effects. PMID- 29424562 TI - Synthesis and antitumor evaluation of hybrids of 5,8-dioxo-5,8 dihydroisoquinoline-4-carboxylates and carbohydrates. AB - AIM: Cancer has emerged as a growing public health problem in many parts of the world. METHODOLOGY: We describe the synthesis of a series of carbohydrate-based isoquinoline-5,8-diones through the 1,4-addition reaction between 5,8-dioxo-5,8 dihydroisoquinoline and aminocarbohydrates. Halogenated quinones were also synthesized. Their inhibitory effects on the proliferation of human cancer cell lines were studied. RESULTS & CONCLUSION: The most promising compound, derived from isoquinoline-5,8-dione, containing ribofuranosidyl ring, was selectively active in vitro against H1299 cancer cells, with 1.7-fold higher activity than that of vinorelbine tartrate. This result suggests that the glycoconjugate in question may constitute a valuable lead compound to design and synthesize a more active and less toxic derivative with respect to the development of a new antitumor substance. PMID- 29424563 TI - Corrigendum. PMID- 29424564 TI - Oxidative stress impairs cGMP-dependent protein kinase activation and vasodilator stimulated phosphoprotein serine-phosphorylation. AB - Reactive oxygen species induce vascular dysfunction and hypertension by directly interacting with nitric oxide (NO) which leads to NO inactivation. In addition to a decrease in NO bioavailability, there is evidence that oxidative stress can also modulate NO signaling during hypertension. Here, we investigated the effect of oxidative stress on NO signaling molecules cGMP-dependent protein kinase (PKG) and vasodilator-stimulated phosphoprotein (VASP) which are known to mediate vasodilatory actions of NO. Male Sprague Dawley (SD) rats were provided with tap water (control), 30 mM L-buthionine sulfoximine (BSO, a pro-oxidant), 1 mM tempol (T, an antioxidant) and BSO + T for 3 wks. BSO-treated rats exhibited high blood pressure and oxidative stress. Incubation of mesenteric arterial rings with NO donors caused concentration-dependent relaxation in control rats. However, the response to NO donors was significantly lower in BSO-treated rats with a marked decrease in pD2. In control rats, NO donors activated mesenteric PKG, increased VASP phosphorylation and its interaction with transient receptor potential channels 4 (TRPC4) and inhibited store-operated Ca2+ influx. NO failed to activate these signaling molecules in mesenteric arteries from BSO-treated rats. Supplementation of BSO-treated rats with tempol reduced oxidative stress and blood pressure and normalized the NO signaling. These data suggest that oxidative stress can reduce NO-mediated PKG activation and VASP-TRPC4 interaction which leads to failure of NO to reduce Ca2+ influx in smooth muscle cells. The increase in intracellular Ca2+ contributes to sustained vasoconstriction and subsequent hypertension. Antioxidant supplementation decreases oxidative stress, normalizes NO signaling and reduces blood pressure. PMID- 29424565 TI - The PlusoptiX Photoscreener and the Retinomax Autorefractor as Community-based Screening Devices for Preschool Children. AB - PURPOSE: To compare the performance of the PlusoptiX S12 mobile photoscreener and the Retinomax K+3 Autorefractor as screening devices in preschool children. METHODS: Children ranging from 3 to 5 years of age from 11 San Diego County preschools underwent vision screening in their schools where ambient light could not always be controlled using both the Retinomax and the PlusoptiX. Cycloplegic refraction on the consented children was subsequently performed on the UCSD EyeMobile for children on-site at the school locations. RESULTS: A total of 321 children were screened with the PlusoptiX and Retinomax. The PlusoptiX referred 22% of children, of whom 70% of the referrals were read as "unable". The Retinomax referred 13% and there were no "unables". Similar results occurred in the cycloplegic-refracted 182 consented children-64% of the PlusoptiX referrals were read as "unable" . Only one third of these "unables" required glasses. Both devices referred the four children with amblyopia and one case of strabismus. However, PlusoptiX's 3 false negatives had amblyopia risk factors (ARFs) while the one Retinomax's false negative did not have ARFs. The Retinomax screening had 95% sensitivity and 94% specificity. The PlusoptiX screening had 86% sensitivity and 84% specificity. CONCLUSION: In this preschool population and environment, the PlusoptiX referred 63% more than the Retinomax in addition to a lower specificity and sensitivity. Adjusting PlusoptiX referral criteria might not substantially improve the specificity of the PlusoptiX due to the high numbers of "unables". PMID- 29424566 TI - Evaluation of the Tindouf Basin Region in Southern Morocco as an Analogue Site for Soil Geochemistry on Noachian Mars. AB - Locations on Earth that provide insights into processes that may be occurring or may have occurred throughout martian history are often broadly deemed "Mars analog environments." As no single locale can precisely represent a past or present martian environment, it is important to focus on characterization of terrestrial processes that produce analogous features to those observed in specific regions of Mars or, if possible, specific time periods during martian history. Here, we report on the preservation of ionic species in soil samples collected from the Tindouf region of Morocco and compare them with the McMurdo Dry Valleys of Antarctica, the Atacama Desert in Chile, the martian meteorite EETA79001, and the in situ Mars analyses from the Phoenix Wet Chemistry Laboratory (WCL). The Moroccan samples show the greatest similarity with those from Victoria Valley, Beacon Valley, and the Atacama, while being consistently depleted compared to University Valley and enriched compared to Taylor Valley. The NO3/Cl ratios are most similar to Victoria Valley and Atacama, while the SO4/Cl ratios are similar to those from Beacon Valley, Victoria Valley, and the Atacama. While perchlorate concentrations in the Moroccan samples are typically lower than those found in samples of other analog sites, conditions in the region are sufficiently arid to retain oxychlorines at detectable levels. Our results suggest that the Tindouf Basin in Morocco can serve as a suitable analogue for the soil geochemistry and subsequent aridification of the Noachian epoch on Mars. PMID- 29424567 TI - Neuropsychological assessment of adults with ADHD: A Delphi consensus study. AB - Within the clinical evaluation of adults with attention deficit hyperactivity disorder (ADHD), cognitive functions are often assessed to characterize individual cognitive problems and guide treatment planning. However, the composition of an adequate neuropsychological assessment battery remains difficult given the large number of cognitive functions that can be distinguished, the variety of available tools to assess these functions, as well as the cognitive heterogeneity that has been observed between individuals with ADHD. Twenty-seven clinicians and researchers experienced in working with adults with ADHD took part in the present study. This study employed the Delphi methodology in order to compose an assessment battery for the measurement of the most important neuropsychological functions by employing the most suitable measures to assess these functions. Consensus between experts was achieved on a ranking of 16 neuropsychological functions that are important for the neuropsychological assessment of adults with ADHD. Furthermore, measures were suggested to assess each of the neuropsychological functions. The assessment battery as composed in the present study may support research and clinical practice in the selection of appropriate functions and measures for the determination of the individual level of cognitive functioning and treatment planning of adults with ADHD. PMID- 29424568 TI - Validity of the DSM-5 Levels of Personality Functioning Scale-Self Report. AB - In this study we examined the structure, reliability, and validity of the Levels of Personality Functioning Scale-Self Report (LPFS-SR) in 3 large community samples. The LPFS-SR is a questionnaire with content that corresponds directly to the DSM-5 alternative model of personality disorders, Criterion A. We found that the LPFS-SR was highly reliable across a brief retest interval. LPFS-SR scores correlated substantially with a wide range of maladaptive personality traits, personality disorder constructs, and interpersonal problems. The LPFS-SR did not correlate as strongly with aspects of personality with less clear relations to distress and dysfunction. Data further support that identity, self-direction, intimacy, and empathy components of the LPFS-SR can be characterized by a single factor and have similar correlations with criterion variables, consistent with the hypothesis that DSM-5 Criterion A is a relatively homogeneous construct. Overall, these results support the validity of the LPFS-SR, highlight important issues in assessing personality pathology, and point toward novel avenues for research on personality disorder classification. PMID- 29424569 TI - Optimal metrics for identifying long term patterns of depression in older HIV infected and HIV-uninfected men who have sex with men. AB - OBJECTIVES: Center of Epidemiologic Studies-Depression Scale (CES-D) provides a snapshot of symptom severity at a single point in time. However, the best way of using CES-D to classify long-term depression is unclear. METHOD: To identify long term depression among HIV-infected and HIV-uninfected 50+ year-old men who have sex with men (MSM) with at least 5 years of follow-up, we compared sensitivities and specificities of CES-D-based metrics (baseline CES-D; four consecutive CES Ds; group-based trajectory models) thresholded at 16 and 20 to a clinician's evaluation of depression phenotype based on all available data including CES-D history, depression treatment history, drug use history, HIV disease factors, and demographic characteristics. RESULTS: A positive depressive phenotype prevalence was common among HIV-infected (prevalence = 33.1%) and HIV-uninfected MSM (prevalence = 23.2%). Compared to the depressive phenotype, trajectory models of CES-D>=20 provided highest specificities among HIV-infected (specificity = 99.9%, 95% Confidence Interval [CI]:99.4%-100.0%) and HIV-uninfected MSM (specificity = 99.0%, 95% CI:97.4%-99.7%). Highest sensitivities resulted from classifying baseline CES-D >= 16 among HIV-infected MSM (sensitivity = 75.0%, 95% CI:67.3% 81.7%) and four consecutive CES-Ds >= 16 among HIV-uninfected MSM (sensitivity = 81.0%, 95% CI:73.7%-87.0%). CONCLUSION: Choice of method should vary, depending on importance of false positive or negative rate for long-term depression in HIV infected and HIV-uninfected MSM. PMID- 29424570 TI - Upregulated galectin-3 is not a critical disease mediator of cardiomyopathy induced by beta2-adrenoceptor overexpression. AB - Preclinical studies have demonstrated that anti-galectin-3 (Gal-3) interventions are effective in attenuating cardiac remodeling, fibrosis, and dysfunction. We determined, in a transgenic (TG) mouse model of fibrotic cardiomyopathy, whether Gal-3 expression was elevated and whether Gal-3 played a critical role in disease development. We studied mice with fibrotic cardiomyopathy attributable to cardiac overexpression of human beta2-adrenoceptors (beta2-TG). Cardiac expression levels of Gal-3 and fibrotic or inflammatory genes were determined. The effect of Gal-3 inhibition in beta2-TG mice was studied by treatment with Gal-3 inhibitors ( N acetyllactosamine and modified citrus pectin) or by deletion of Gal-3 through crossing beta2-TG and Gal-3 knockout mice. Changes in cardiomyopathy phenotypes were assessed by echocardiography and biochemical assays. In beta2-TG mice at 3, 6, and 9 mo of age, upregulation of Gal-3 expression was observed at mRNA (~6- to 15-fold) and protein (~4- to 8-fold) levels. Treatment of beta2-TG mice with N acetyllactosamine (3 wk) or modified citrus pectin (3 mo) did not reverse cardiac fibrosis, inflammation, and cardiomyopathy. Similarly, Gal-3 gene deletion in beta2-TG mice aged 3 and 9 mo did not rescue the cardiomyopathy phenotype. In conclusion, the beta2-TG model of cardiomyopathy showed a robust upregulation of Gal-3 that correlated with disease severity, but Gal-3 inhibitors or Gal-3 gene deletion had no effect in halting myocardial fibrosis, remodeling, and dysfunction. Gal-3 may not be critical for cardiac fibrogenesis and remodeling in this cardiomyopathy model. NEW & NOTEWORTHY We showed a robust upregulation of cardiac galectin-3 (Gal-3) expression in a mouse model of cardiomyopathy attributable to cardiomyocyte-restricted transgenic activation of beta2 adrenoceptors. However, pharmacological and genetic inhibition of Gal-3 did not confer benefit in this model, implying that Gal-3 may not be a critical disease mediator of cardiac remodeling in this model. PMID- 29424572 TI - Atrial arrhythmias and autonomic dysfunction in rats exposed to chronic intermittent hypoxia. AB - Obstructive sleep apnea, which involves chronic intermittent hypoxia (CIH), is a major risk factor for developing atrial fibrillation (AF). Whether or not CIH alone alters cardiac mechanisms to support AF is unknown. This study investigated the effects of CIH on atrial electrophysiology and arrhythmia vulnerability and evaluated the role of autonomics in CIH promotion of AF. Adult male Sprague Dawley rats were exposed to 8 h/day of CIH or normoxia for 7 days. After exposure, rats were anesthetized for intracardiac electrophysiological experiments. Atrial effective refractory periods (AERPs) and AF inducibility were determined using programmed electrical stimulation and burst pacing in the absence and presence of autonomic receptor agonists and antagonists. Western blot analysis measured atrial protein expression of muscarinic M2, M3, and beta1 adrenergic receptors. Compared with normoxia-exposed control rats, CIH-exposed rats had enhanced AF vulnerability using both programmed electrical stimulation and burst pacing, accompanied by greater AERP responses to carbachol and propranolol, lesser responses to isoproterenol, and higher atrial M2 receptor protein levels. Enhanced atrial vulnerability was accentuated by carbachol and abolished by atropine, indicating that the AF-promoting effects of CIH depended principally on parasympathetic activation. Enhancement of atrial vulnerability and AERP shortening with cholinergic agonists in CIH-exposed rats is consistent with sensitivity to parasympathetic activation. Higher responses to adrenergic receptor blockade in CIH-exposed rats is consistent with sympathetic potentiation. These findings implicate CIH as an important mediator of enhanced AF susceptibility in obstructive sleep apnea and provide novel insights into the underlying mechanisms. NEW & NOTEWORTHY Our study demonstrates, for the first time, that chronic intermittent hypoxia alone enhances vulnerability to atrial arrhythmia induction, which depends principally on parasympathetic activation. Enhanced atrial vulnerability was accompanied by heightened electrophysiological responses of the atrial myocardium to carbachol and isoproterenol, dampened responses to propranolol, and increased atrial M2 receptor protein levels. PMID- 29424573 TI - A multi-method evaluation of interprofessional education for healthcare professionals caring for women during and after pregnancy. AB - This multi-method evaluation assessed the perceived impact of interprofessional workshops targeting enhanced collaboration between healthcare professionals who care for women during and after pregnancy. Current policy recommends partnership working to improve care for women and babies, however, there is little interprofessional education in this area. Five one-day workshops were delivered to 18 healthcare professionals (47.4% of the 38 healthcare professionals registered). The workshop was evaluated through questionnaires before and after the workshop measuring attitudes and willingness towards collaboration; observations of the workshops by a researcher and follow-up interviews 2 months' post-workshop to explore changes in practice. Workshops were attended by midwives, health visitors (trained nurses specialising in community care for children 0-5 years), dietitians, nurses, a general practitioner and a breastfeeding specialist. Attitudes and willingness to participate in interprofessional collaborative practice improved after the workshop. Observations made at the workshop included engaged participants who reported numerous barriers towards collaboration. Follow-up contact with 12 participants identified several examples of collaboration in practice resulting from workshop attendance. These findings suggest that the workshops influenced attendees to change their practice towards more collaborative working. Future work needs to confirm these results with more participants. PMID- 29424575 TI - Acknowledgment of Authors. PMID- 29424571 TI - Coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction. AB - There are multiple proposed mechanisms for the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). We hypothesized that coronary microvascular dysfunction is common in these patients. In a prospective, observational study, patients undergoing cardiac catheterization with HFpEF [left ventricular (LV) ejection fraction >= 50% and with clinical HF] were compared with similar patients without HFpEF. Patients with >=50% stenosis were excluded, and coronary flow reserve (CFR) and the index of microvascular resistance (IMR) were measured after adenosine administration using a guidewire, with CFR <= 2 and IMR >= 23 being abnormal. Baseline characteristics and CFR and IMR were compared in 30 HFpEF patients and 14 control subjects. Compared with control subjects, HFpEF patients were older (65.4 +/- 9.6 vs. 55.1 +/- 3.1 yr, P < 0.01), had higher numbers of comorbidities (4.4 +/- 1.5 vs. 2.6 +/- 1.9, P = 0.002), had higher median B-type natriuretic peptide [161 (interquartile range: 75-511) pg/dl vs. 37 (interquartile range: 18.5-111) pg/dl, P < 0.01], and had higher LV end diastolic pressure (17.8 +/- 4.2 vs. 8.4 +/- 4.2, P < 0.01). HFpEF patients had lower CFR (2.55 +/- 1.60 vs. 3.84 +/- 1.89, P = 0.024) and higher IMR (26.7 +/- 10.3 vs. 19.7 +/- 9.7 units, P = 0.037) than control subjects. Most (71.4%) control subjects had normal coronary physiology, whereas 36.7% of HFpEF patients had both abnormal CFR and IMR and another 36.7% had either abnormal CFR or IMR. In conclusion, this is the first study that has reported invasively determined CFR and IMR in HFpEF patients. We demonstrated the presence of four distinct coronary physiology groups in HFpEF patients. Investigation into the potential mechanisms for these findings is needed. NEW & NOTEWORTHY In this prospective observational study of patients with heart failure with preserved ejection fraction (HFpEF), we found that patients with HFpEF had more abnormalities of coronary flow and resistance than asymptomatic control patients, indicating that coronary microvascular dysfunction may play a role in the HFpEF disease process. PMID- 29424576 TI - Immunohistochemical and electron microscopic morphometric image analysis of hepatocellular carcinoma in association of HCV infection. AB - Early detection of hepatocellular carcinoma (HCC) is crucial for successful therapy. The present work examined the value of ultrastructural morphometric image analysis of hepatocyte nuclei in patients with chronic hepatitis C virus (HCV) versus HCC cases with chronic HCV and the corresponding surgical tumor-free safe margins (TFMs), to highlight any early predictive signs of neoplastic cellular transformation. This work also performed an immunohistochemical assessment of cytokeratin 19 (CK19) and Ki-67-positive cells to visualize any associated proliferative activity in the examined groups. The results showed significant decrease in the hepatocyte nuclear surface areas in the HCC and TFMs versus those in the HCV cases. The hepatocyte nucleolar surface area was significantly increased in the HCC cases versus that in the HCV cases. This increase was associated with a significant increase in Ki-67-positive cells in the HCC cases compared to those in the other groups. Conversely, the mean number of CK 19-positive cells was significantly reduced in the HCC cases compared to the cell numbers in TFMs and HCV cases with severe hepatic fibrosis. Liver progenitor cells (LPCs) were discerned in the reactive ductules and canaliculo ductular junctions that characterized TFMs. LPCs were sporadically distributed in the liver lobules and reactive bile ductules in the HCC samples. In conclusion, CK 19 represents an important marker for distinguishing between dysplastic and malignant liver nodules. Electron microscopic morphometric image analysis may be considered as adjunct factor for assessing hepatocyte malignant transformation. Wider scale studies are needed to authenticate these results. PMID- 29424577 TI - Traditional Gender Roles and the Stress-Alcohol Relationship among Latina/o College Students. AB - BACKGROUND: Latina/o college students have been shown to engage in more high risk drinking behavior than students from other ethnic minority groups, and are more likely to experience certain negative alcohol related consequences as a result of drinking. Previous research links stress to drinking among college students and indicates drinking occurs within a gendered context. Although this suggests an effect of gender role socialization, studies exploring these relationships among Latina/os are lacking. OBJECTIVES: To explore potential relationships of stress, gender role prescriptions of the heritage culture, and drinking among Latina/o college students. Specifically, to explore potential interactions between stress and multiple dimensions of machismo and marianismo as related to alcohol use. METHOD: Latina/o undergraduates (N = 248) completed a questionnaire. Self reported stress, quantity of alcohol consumption, and frequency of binge drinking were recorded for all participants. Gender role prescriptions were assessed via endorsement of two dimensions of machismo (men) or two dimensions of marianismo (women). RESULTS: Stress was positively related to general quantity for women. Each dimension of machismo was distinctly related to binge drinking for men. Significant interactions emerged between both machismo and marianismo and stress as related to both alcohol use outcomes. For women, the moderating pattern between marianismo and stress varied according to type of alcohol use. Conclusions/Importance: Gender role beliefs influence the relationship between stress and alcohol use among Latina/o college students. Future research should account for the intersection of gender and culture when considering the stress alcohol relationship. PMID- 29424578 TI - Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care Ontario guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement Summary. PMID- 29424580 TI - Antiemetics: American Society of Clinical Oncology Focused Guideline Update. PMID- 29424581 TI - Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline. PMID- 29424582 TI - Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. PMID- 29424579 TI - Nevirapine-induced liver lipid-SER inclusions and other ultrastructural aberrations. AB - Nevirapine (NVP) therapy is associated with a high risk of serious liver injury and skin rash. Treatment of Brown Norway rats with NVP causes an immune-mediated skin rash. Even though NVP does not cause serious liver injury in wildtype animals, incubation of hepatocytes with NVP leads to the release of presumably danger-associated molecular pattern molecules (DAMPs), which activate macrophages. In this study, we examined the liver biopsies of Brown Norway rats treated with NVP to determine the histologic correlate to the release of DAMPs by hepatocytes. In vivo, debris from necrotic hepatocytes and endothelial cells were present in the liver sinusoids, a condition that can trigger an immune response. In addition to mitochondrial, hepatocytic, and endothelial damage, the drug induced large hepatocytic inclusions composed of lipid droplets surrounded by concentric whorls of smooth endoplasmic reticulum (SER) cisternae-lipid-SER (LSER) inclusions, which were deposited in the sinusoids. NVP is lipid soluble, and these LSER inclusions may be sinks of NVP or its metabolites. LSERs are deposited in the blood stream where they may be picked up by lymph nodes and contribute to initiation of an immune response leading to serious liver injury or skin rash. LSERs migration from liver to the blood stream may signify a novel mechanism of drug exocytosis. PMID- 29424583 TI - Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. PMID- 29424584 TI - Recommendations for the Use of White Blood Cell Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. PMID- 29424585 TI - Informed Consent and Chemotherapy. PMID- 29424586 TI - Q&A From ASCO's Coding and Reimbursement Hotline. PMID- 29424587 TI - CAP: Making the Decision to Participate in Medicare's Alternative to Drug Purchasing. PMID- 29424588 TI - Elements of Successfully Integrating a Mid-Level Provider Into Practice. PMID- 29424589 TI - PLWC Expands Information to Help Your Patients Better Manage Side Effects of Cancer and Cancer Treatment. PMID- 29424591 TI - Preparing for a Seat at the Research Table: The National Breast Cancer Coalition Fund's Project LEAD. PMID- 29424590 TI - Your Clinical Practice Committee. PMID- 29424592 TI - Interview with Barry Straube, MD, Acting Chief Medical Officer for CMS: Coverage Decision Process Improves, but Cost-Controlling Measures Loom. PMID- 29424593 TI - Clinical Trial Participation Award Winners: Three Community Research Programs With Minority Recruitment Success. PMID- 29424594 TI - The Era of Accountability and Oncology: Carpe Diem. PMID- 29424595 TI - Growing a State Society: The Michigan Model. PMID- 29424597 TI - ASCO Undertakes Oncology Workforce Study. PMID- 29424596 TI - What Does a Fellow Need to Know to Build a Successful Academic Clinical Research Career?Advice From Monica Morrow, MD. PMID- 29424598 TI - Primary ductal adenocarcinoma of the lacrimal gland with changing genetic analysis mutations. AB - Primary ductal adenocarcinoma of the lacrimal gland is a rare but highly aggressive epithelial malignancy with a poor prognosis. Early diagnosis, along with genetic testing of these tumors, is imperative for proper management. We present a case of a 54-year-old man with decreasing vision over the past three years and increasing proptosis in his right eye over the past three months, secondary to a lacrimal gland mass diagnosed as primary ductal adenocarcinoma. The diagnosis was made using histological and immunohistochemical profiles (positivity for cytokeratin AE1/3, CAM5.2, androgen receptor, human epidermal growth factor receptor 2, and gross cystic disease fluid protein 15) seen in previous cases, alongside a tumor genetic profile that showed actionable mutations. Uniquely in this case, after failing traditional chemotherapy, repeat biopsy revealed a change in genetics with the malignancy no longer showing actionable mutations. These findings show that these immunohistochemical findings can act as diagnostic biomarkers, while genetic testing can reveal actionable mutations for targeted therapy. PMID- 29424599 TI - Screening of biomarkers for liver adenoma in low-dose-rate gamma-ray-irradiated mice. AB - PURPOSE: Chronic low-dose-rate (20 mGy/day) gamma-irradiation increases the incidence of hepatocellular adenomas (HCA) in female B6C3F1 mice. The purpose of this study is to identify potential serum biomarkers for these HCAs by a new approach. MATERIAL AND METHODS: Microarray analysis were performed to compare the gene expression profiles of HCAs from mice exposed to low-dose-rate gamma-rays with those of normal livers from non-irradiated mice. From the differentially expressed genes, those for possibly secretory proteins were selected. Then, the levels of the proteins in sera were analysed by ELISA. RESULTS: Microarray analysis identified 4181 genes differentially expressed in HCAs (>2.0-fold). From these genes, those for alpha-fetoprotein (Afp), alpha-1B-glycoprotein (A1bg) and serine peptidase inhibitor Kazal type-3 (Spink3) were selected as the genes for candidate proteins. ELISA revealed that the levels of Afp and A1bg proteins in sera significantly increased and decreased, respectively, in low-dose-rate irradiated mice with HCAs and also same tendency was observed in human patients with hepatocellular carcinomas. CONCLUSION: These results indicate that A1bg could be a new serum biomarker for liver tumor. This new approach of using microarray to select genes for secretory proteins is useful for prediction of novel tumor markers in sera. PMID- 29424600 TI - Comparison of the hepatic and thyroid gland effects of sodium phenobarbital and pregnenolone-16alpha-carbonitrile in wild-type and constitutive androstane receptor (CAR)/pregnane X receptor (PXR) knockout rats. AB - The hepatic and thyroid gland effects of the constitutive androstane receptor (CAR) activator sodium phenobarbital (NaPB) and the pregnane X receptor (PXR) activator pregnenolone-16alpha-carbonitrile (PCN) were examined in male Sprague Dawley wild-type (WT) and knockout (KO) rats lacking both hepatic CAR and PXR receptors (CAR KO/PXR KO rats). The treatment of WT rats for 7 d with 500 ppm NaPB in the diet and 100 mg/kg/d PCN by gavage resulted in increased relative liver weight, hepatocyte hypertrophy, increased hepatocyte replicative DNA synthesis (RDS) and induction of cytochrome P450 CYP2B and CYP3A subfamily enzymes. NaPB and PCN also induced thyroid gland follicular cell RDS and hepatic microsomal UDP-glucuronosyltransferase activity towards thyroxine as substrate. These effects were not observed in the liver and thyroid gland of CAR KO/PXR KO rats. Male C57BL/6 J (WT) and CAR KO/PXR KO mice were given 1000 ppm NaPB in the diet for 7 d. In WT, but not in CAR KO/PXR KO, mice NaPB treatment resulted in liver hypertrophy and induction of hepatocyte RDS and Cyp2b enzymes. These results suggest that the CAR KO/PXR KO rat and mouse models are useful experimental models for mode of action studies with rodent CAR activators. PMID- 29424601 TI - Thromboembolic complications following aminocaproic acid use in patients with hematologic malignancies. AB - Aminocaproic acid is frequently used in patients with hematologic malignancy that present with thrombocytopenia with or without hemorrhage. We conducted a retrospective study to evaluate the safety of aminocaproic acid in 109 patients with hematologic malignancies. Patients were included if aminocaproic acid had been administered for at least 24 hours for the prevention or treatment of thrombocytopenic hemorrhage. Our primary outcome was thromboembolic complications defined as arterial or venous thrombotic events objectively confirmed by imaging studies. Thromboembolic complications occurred in five patients (4.6%) and all were venous thromboses. Other than the underlying malignancy, these patients also had many concurrent risk factors including indwelling central venous catheters, which could have contributed to thromboses. In conclusion, in our population of patients with a variety of hematological malignancies, aminocaproic acid does not appear to be associated with a high incidence of thromboembolic complications. PMID- 29424602 TI - Geroderma osteodysplasticum: Histological features and the role of panel-based exome sequencing in diagnosis. AB - Geroderma osteodysplasticum (GO) has clinical and histological features that overlap with other causes of wrinkly skin. Here we present the case of a child diagnosed with GO following exome sequencing of a panel of genes covering the wide differential diagnosis. The histological features of the overlapping conditions are presented, highlighting the utility of panel testing for conditions of this type. This is relevant to many genetic conditions and can influence ongoing management as exemplified by this case. PMID- 29424603 TI - Wound Curriculum for Nurses. AB - The European Wound Management Association (EWMA) has just finalised the first curriculum in a series of several curricula intended for use in levels 5-7 of the European Qualifications Framework (EQF)1. The aim of these is to support a common approach to post-registration qualification in wound management for nurses across Europe. EWMA hopes and will work towards a close collaboration with European nurse organisations as well as educational institutions to implement these common curricula. PMID- 29424604 TI - Genetic markers of stable molecular remission in chronic myeloid leukemia after targeted therapy discontinuation. PMID- 29424605 TI - Adjuvant and Salvage Radiotherapy After Prostatectomy: American Society of Clinical Oncology Clinical Practice Guideline Endorsement Summary. PMID- 29424606 TI - Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline Summary. PMID- 29424607 TI - Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline Summary. PMID- 29424608 TI - Relations between Positive Temperament, Substance Use, and Internalizing Problems among Adolescents and Young Adults with and without Medical Conditions. AB - BACKGROUND: Substance use problems are prevalent during emerging adulthood and may be particularly harmful for individuals with medical conditions. Understanding the role of positive temperament in substance use for adolescents and young adults (AYAs) may facilitate the identification of intervention and prevention targets given the complex relations between positive emotions and substance use. OBJECTIVE: To examine whether components of positive temperament differentially relate to substance use in a sample of AYAs with and without medical conditions. Internalizing problems were examined as a secondary outcome given their comorbidity with substance use. METHOD: In a cross-sectional study that took place in 2015-2016, 494 AYAs (Mage = 19.30 years, SD = 1.33, 73% female) who were enrolled in college completed online questionnaires in a laboratory regarding their levels of positive temperament (i.e., high intensity pleasure and positive affect) as well as their substance use and internalizing problems. The primary analyses were conducted using structural equation modeling. RESULTS: For healthy AYAs, high intensity pleasure was positively associated with drug and alcohol use problems and positive affect was negatively associated with drug use problems. Among AYAs with medical conditions, high intensity pleasure was positively associated with alcohol use problems. Positive affect was negatively associated with internalizing problems for both groups. Conclusions/Importance: Findings identify paths between components of temperament and substance use and internalizing problems that may inform prevention and intervention efforts tailored to the unique and overlapping needs of AYAs with a range of healthcare demands. PMID- 29424609 TI - Effects of Mental Fatigue on Physical Endurance Performance and Muscle Activation Are Attenuated by Monetary Incentives. AB - Physical performance is impaired following cognitive control exertion. Incentives can ameliorate adverse carryover effects of cognitive control exertion but have not been investigated for physical endurance. This study examined the effect of monetary incentives on physical performance and muscle activation following exposure to a mentally fatiguing, cognitive control task. Participants (N = 82) performed two isometric endurance handgrip trials separated by a 12-min cognitive control manipulation using a 2 (high cognitive control [HCC]/low cognitive control [LCC]) * 2 (incentive/no incentive) design. Mental fatigue was significantly higher in the HCC conditions. Performance decreased in the HCC/no incentive condition but was unaffected in the HCC/incentive condition, which did not differ from the low cognitive control conditions. Electromyography data revealed increased muscle activation in the HCC/no incentive condition, which was also attenuated in the HCC/incentive condition. Findings show that incentives counteract the negative effects of HCC on physical endurance and alter central drive to motor units. PMID- 29424610 TI - OCT-guided management of subclinical recurrent retinoblastoma. AB - PURPOSE: Retinoblastoma (Rb) tumor recurrence in the papillary or macular region is a threat to life and visual prognosis respectively, making early detection indispensable. This study demonstrates the value of optical coherence tomography (OCT) in the early detection of subclinical tumor recurrence. METHODS: Since June 2012, hand-held SD-OCT (spectral domain Optical Coherence Tomography) of retro equatorial foci, the optic head nerve and macula, is systematically performed under anesthesia in children treated and followed for Rb. RESULTS: Between June 2012 and January 2017, 16 subclinical recurrent tumors in 14 children were detected only by OCT in flat pigmented scars (n = 9), in type 2 regression (n = 3), on the optic nerve head (n = 3), and as secondary retinal seeding (n = 1). CONCLUSION: OCT has become invaluable in the modern management of Rb. It allows not only early detection of a lesion before any tumor extension towards the macula or optic nerve head, but also the monitoring of the therapeutic response. PMID- 29424611 TI - State Affiliate News. PMID- 29424613 TI - Centers for Medicare & Medicaid Services Move Toward Pay-for-Performance. PMID- 29424612 TI - In the Wake of Medicare Modernization Act Changes, A Moral Wake-Up. PMID- 29424615 TI - Medicare Demonstration Recognizes Oncologist's Role in Managing Chemotherapy Side Effects. PMID- 29424614 TI - Refer Your Patients to PLWC.org , ASCO's Patient Information Web Site. PMID- 29424616 TI - Assessing Changes in Hospital Outpatient Cancer Care. PMID- 29424617 TI - Choosing a Private Practice: Q&A with Thomas A. Bensinger, MD, FACP. AB - The Focus on Fellows column will focus on how to get started in private practice. The columns may include a Q&A, articles written from a new practitioner's perspective, or advice from senior oncologists. The Q&A below is between a new practitioner and a more experienced one. PMID- 29424618 TI - Oncologists and the Stark Law. PMID- 29424619 TI - National Coalition for Cancer Survivorship: Advocating for Quality Cancer Care for All. PMID- 29424620 TI - Where Can Brain Tumor Patients Turn for Support and Information? PMID- 29424621 TI - Navigating Change with Oncology Resources. AB - This column is intended to provide oncology practitioners and their staff with important information about reimbursement, coding, coverage, and regulatory policies. Topic suggestions or questions for future issues should be sent to practice@asco.org . PMID- 29424622 TI - Alveolar bone remodeling after tooth extraction in irradiated mandible: An experimental study with canine model. AB - OBJECTIVES: The aim of the present study is to investigate the morphological and cellular changes in dental extraction socket that has been irradiated after the tooth extraction and to describe morphological characteristics of the osteocytes and osteocyte-lacunar-canalicular network (LCN) by scanning electron microscopy (SEM). MATERIAL AND METHODS: Five beagle dogs aged 1-2 years were used in this study. One side of each mandible was irradiated in two sessions and the other side of mandible (non-irradiated) served as a control. The mandible bone blocks were processed by bulk staining en bloc in basic fuchsin and the specimens were embedded routinely in polymethyl methacrylate resin without preliminary decalcification. All blocks were subjected to micro-CT imaging, after that the specimens were prepared for light microscopy and SEM. RESULTS: Alterations in bone macrostructure are minimal in irradiated bone, but the changes in LCN are clear. In the area of the tooth extraction socket, the connections of osteocytes to the vessels and to neighboring osteocytes were not observed both in irradiated and nonirradiated bone. However, osteoclasts were located in the bone surface entering inside to the bone between osteons. In the lamellar bone of lateral sides, a decrease in canalicular connections between osteocytes and periosteum was found in irradiated bone as compared to the non-irradiated side. CONCLUSIONS: The novelty of the present study is that radiation disrupts osteocytes and their dendrites. PMID- 29424623 TI - Interprofessional education day - an evaluation of an introductory experience for first-year students. AB - Interprofessional health care teams have been shown to improve patient safety and reduce medical errors, among other benefits. Introducing interprofessional concepts to students in full day events is an established model that allows students to learn together. Our group developed an academic day for first-year students devoted to an introductory interprofessional education (IPE) experience, 'IPE Day'. In total, 438 students representing medicine, dentistry, pharmacy and optometry gathered together, along with 25 facilitators, for IPE Day. Following the day's program, students completed the evaluation consisting of the Interprofessional Collaborative Competencies Attainment Survey and open-ended questions. Narrative responses were analyzed for content and coded using the Canadian Interprofessional Health Collaborative competency domains. Three hundred and eight evaluations were completed. Students reported increased self-ratings of competency across all 20 items (p < 0.05). Their comments were organized into the six domains: interprofessional communication, collaborative leadership, role clarification, patient-centred care, conflict resolution, and team functioning. Based on these findings, we suggest that this IPE activity may be useful for improving learner perceptions about their interprofessional collaborative practice competence. PMID- 29424624 TI - Algorithm of Laparoscopic Technique in Pediatric Inguinal Hernia: Results from Experience of 10 Years. AB - BACKGROUND: Many laparoscopic techniques have been evolved along years for pediatric inguinal hernia (PIH) with no standardization of technique. No single technique suits all varieties of hernia. PURPOSE: To propose an algorithm for allocation of PIH to laparoscopic technique based on internal ring (IR) diameter to improve outcomes. PATIENTS AND METHODS: Along 10 years, 459 cases with unilateral PIH were treated in Tanta University Hospital. In the first 5 years (phase I), 214 cases included then an algorithm for stratification was designed and applied in the second 5-year period (phase II), where 245 cases managed. This algorithm included evaluation of the hernia based on IR diameter as measured by the laparoscope from inside by a piece of suture. When the IR diameter is from 4 to 15 mm, complete sac disconnection is used. When IR diameter lies from 15 to 25 mm a purse string is added. When IR diameter is >2.5 cm or recurrent cases, the interrupted muscular arch repair after sac disconnection is used. RESULTS: In phase I, 170 boys and 44 girls from 6 to 180 months of age were treated. All cases managed by laparoscopy were 84 herniotomy, 82 by purse string, and 44 by interrupted muscular arch. In phase II, 180 boys and 65 girls from 3 to 180 months of age were included. Eighty were managed by herniotomy, 137 by purse string, and 25 by interrupted muscular arch. Recurrence rate decreased significantly in phase II. CONCLUSIONS: Application of Tanta algorithm reduces the recurrence rate significantly. The laparoscopic technique should be tailored according to criteria of each group of PIH to get the best outcome and reduced recurrence rate. PMID- 29424626 TI - Extraction of total phenolic content from Azadirachta indica or (neem) leaves: Kinetics study. AB - The objective of this work is to put forth the optimization and kinetics of total phenolic compounds extraction from Azadirachta indica leaves in a stirred batch extraction. Various experiential extraction parameters have been studied for maximum extraction of the total phenolic compounds. The maximum yield of total phenolic compounds was found to be 10.80 mg g-1 of dried neem powder under the optimized conditions. The extraction kinetics behavior followed first-order kinetics with diffusion coefficient ranged from 1.8 * 10-12 to 3.2 * 10-12 m2 s-1 for all sets. Activation energy (Ea) value for the extraction of the total phenolic compounds was found to be 22.87 kJ mol-1. The kinetic expression model developed by Spiro and Siddique showed a good agreement with the experimental outcomes. The obtained results can be used to scale up the operations for industrial purposes. PMID- 29424627 TI - Bioprospecting microbes for single-cell oil production from starchy wastes. AB - Production of lipid from oleaginous yeast using starch as a carbon source is not a common practice; therefore, the purpose of this investigation was to explore the capability of starch assimilating microbes to produce oil, which was determined in terms of biomass weight, productivity, and lipid yield. Saccharomyces pastorianus, Rhodotorula mucilaginosa, Rhodotorula glutinis, and fungal isolate Ganoderma wiiroense were screened for the key parameters. The optimization was also performed by one-factor-at-a-time approach. Considering the specific yield of lipid and cell dry weight yield, R. glutinis and R. mucilaginosa showed superiority over other strains. G. wiiroense, a new isolate, would also be a promising strain for starch waste utilization in terms of extracellular and intracellular specific yield of lipids. Extracellular specific yield of lipid was highest in R. glutinis culture (0.025 g g-1 of biomass) followed by R. mucilaginosa (0.022 g g-1 of biomass) and G. wiiroense (0.020 g g 1 of biomass). Intracellular lipid was again highest in R. glutinis (0.048 g g-1 of biomass). The most prominent fatty acid methyl esters among the lipid as detected by GC-MS were saturated lipids mainly octadecanoic acid, tetradecanoate, and hexadecanoate. Extracellular lipid produced on starch substrate waste would be a cost-effective alternative for energy-intensive extraction process in biodiesel industry. PMID- 29424628 TI - Letter to the Editor. Preoperative third ventricle shape and ETV. PMID- 29424629 TI - Parental satisfaction with being present in the operating room during the induction of anesthesia prior to pediatric neurosurgical intervention: a qualitative analysis. AB - OBJECTIVE Parental presence in the operating room during the induction of anesthesia (PPIA) has been shown to decrease parent and child anxiety and increase satisfaction with patient experience in outpatient otolaryngological procedures, such as tympanostomy tube placement. PPIA for other procedures, such as a major neurosurgical intervention, has been a practice at the authors' institutions for many years. This practice is not universally accepted across the United States, and the potential benefits for patients and families have not been formally evaluated. The aim of this study is to provide a qualitative analysis of parental and patient satisfaction with PPIA at the authors' institution. METHODS All patients younger than 18 years who underwent surgical intervention at the authors' institution between August 2013 and December 2015 were identified. All surgeries were performed by a single neurosurgeon. A random sample of 96 parents were contacted by telephone for a qualitative, semiscripted interview; 42 parents completed the interviews. The interview consisted of a validated satisfaction assessment in addition to a standardized open-ended questionnaire. Thematic analysis was performed until saturation was achieved, and responses were coded into the predominant themes. Member checking was performed, and a thick description was created. RESULTS The predominant themes identified with PPIA were 1) perception of induction as traumatizing or distressing to witness, 2) positive feelings regarding having been present, 3) satisfaction regarding the overall experience with surgery, 4) variable feelings in parents who decided not to attend induction, and 5) mixed feelings in the interactions with the care team. Parents expressed an array of positive, negative, and neutral impressions of the experience; however, overall, most experiences were positive. Most parents would choose PPIA again if their child required additional surgery. CONCLUSIONS This is the first study to evaluate the benefit of PPIA for pediatric neurosurgical patients. The results show a unique insight into medical communication and patient satisfaction with high-risk surgeries. PPIA may be able to help shape an environment of trust and increase satisfaction with perioperative care. PMID- 29424630 TI - James Edward Heath. PMID- 29424631 TI - Occurrence of infectious laryngotracheitis outbreaks in commercial layer hens detected by ELISA. AB - Infectious laryngotracheitis (ILT) is an acute respiratory disease of chickens and a cause of great economic loss in commercial layers. The aims of this study were to investigate the prevalence of ILT in the field outbreaks and to compare the characteristics of ILT-infected and free flocks of commercial layers. A total of 625 blood serum samples were collected from 25 different layer flocks. The presence of antibodies against infectious laryngotracheitis virus (ILTV) in each sample was determined by ELISA. Of the 625 serum samples, 266 (42.56%) were found to be positive for ILTV antibodies. A total of 16 (64%) flocks were detected ILT positive by ELISA method. The mortality of infected flocks was statistically higher (P < 0.05) than uninfected flocks. The egg production of positive flocks was lower than that of the free flocks, but this difference was not statistically significant. The average live weight of hens in infected flocks was lower (P > 0.05) than hens in free flocks. In conclusion, the results of this study indicated a high prevalence of ILT infection in the commercial layer flocks in Konya region, Turkey. In outbreaks, ILT significantly increased the mortality rate and decreased the average live weight in layer hens. PMID- 29424632 TI - Statistical optimization for lipase production from solid waste of vegetable oil industry. AB - The production of biofuel using thermostable bacterial lipase from hot spring bacteria out of low-cost agricultural residue olive oil cake is reported in the present paper. Using a lipase enzyme from Bacillus licheniformis, a 66.5% yield of methyl esters was obtained. Optimum parameters were determined, with maximum production of lipase at a pH of 8.2, temperature 50.8 degrees C, moisture content of 55.7%, and biosurfactant content of 1.693 mg. The contour plots and 3D surface responses depict the significant interaction of pH and moisture content with biosurfactant during lipase production. Chromatographic analysis of the lipase transesterification product was methyl esters, from kitchen waste oil under optimized conditions, generated methyl palmitate, methyl stearate, methyl oleate, and methyl linoleate. PMID- 29424633 TI - A convenient solid phase approach to obtain lipophilic 5'-phosphoramidate derivatives of DNA and RNA oligonucleotides. AB - This paper explores the potential of a modified phosphotriester approach to the synthesis of 5'-phosphoramidate derivatives of DNA and RNA oligonucleotides. The modification of 5'-deprotected support-bound oligonucleotides is done in two steps: i) conversion of the 5'-OH group of an oligonucleotide into an activated phosphodiester, and ii) treatment of the activated phosphodiester with an aminocompound. The approach is efficient and compatible with conventional solid phase oligonucleotide synthesis. It can be used for the conjugation of therapeutically relevant oligonucleotides with functional moieties or carrier constructions, which are to be removed after endocytosis. PMID- 29424634 TI - Optimization of the ANFIS using a genetic algorithm for physical work rate classification. AB - PURPOSE: Recently, a new method was proposed for physical work rate classification based on an adaptive neuro-fuzzy inference system (ANFIS). This study aims to present a genetic algorithm (GA)-optimized ANFIS model for a highly accurate classification of physical work rate. METHODS: Thirty healthy men participated in this study. Directly measured heart rate and oxygen consumption of the participants in the laboratory were used for training the ANFIS classifier model in MATLAB version 8.0.0 using a hybrid algorithm. A similar process was done using the GA as an optimization technique. RESULTS: The accuracy, sensitivity and specificity of the ANFIS classifier model were increased successfully. The mean accuracy of the model was increased from 92.95 to 97.92%. Also, the calculated root mean square error of the model was reduced from 5.4186 to 3.1882. The maximum estimation error of the optimized ANFIS during the network testing process was +/- 5%. CONCLUSION: The GA can be effectively used for ANFIS optimization and leads to an accurate classification of physical work rate. In addition to high accuracy, simple implementation and inter-individual variability consideration are two other advantages of the presented model. PMID- 29424635 TI - Application of medium optimization tools for improving recombinant human interferon gamma production from Kluyveromyces lactis. AB - The present study is focused upon improving biomass of Kluyveromyces lactis cells expressing recombinant human interferon gamma (hIFN-gamma), with the aim of augmenting hIFN-gamma concentration using statistical and artificial intelligence approach. Optimization of medium components viz., lactose, yeast extract, and trace elements were performed with Box-Behnken design (BBD) and artificial neural network linked genetic algorithm (ANN-GA) for maximizing biomass of recombinant K. lactis (objective function). The studies resulted over 1.5-fold improvement in the biomass concentration in a medium composed of 80 g/L lactose, 10.353 g/L yeast extract, and 15 mL/L trace elements as compared with initial biomass value. In the same study hIFN-gamma concentration reached 881 ug/L which was 2.28-fold higher as compared with initial hIFN-gamma concentration obtained in unoptimized medium. Further the batch fermentation study displayed mixed growth associated kinetics with the maximum hIFN-gamma production rate of 1.1 mg/L. BBD and ANN-GA, both optimization techniques predicted a higher lactose concentration was clearly beneficial for augmenting K. lactis biomass which in turn increased hIFN-gamma concentration. PMID- 29424637 TI - Hysterothylacium fabri (Nematoda: Raphidascarididae) in Mullus surmuletus (Perciformes: Mullidae) and Uranoscopus scaber (Perciformes: Uranoscopidae) from the Mediterranean. AB - Raphidascarididae are among the most abundant and widespread parasitic nematodes in the marine environment. The life-cycle of most raphidascaridid species is poorly known and information about their distribution and host range is lacking in many geographical areas, as is the taxonomy of several species. A study of larval and adult stages of Hysterothylacium fabri (Rudolphi, 1819) Deardorff and Overstreet, 1980 (Nematoda: Raphidascarididae) infecting the striped goatfish Mullus surmuletus Linnaeus, 1758 (Mullidae) and the Mediterranean stargazer Uranoscopus scaber Linnaeus, 1759 (Uranoscopidae) from the Ionian Sea (central Mediterranean) has been carried out by combining light and scanning electron microscopy observations and molecular analyses through polymerase chain reaction restriction fragment length polymorphism and sequencing of the ITS rDNA gene. Results indicate that U. scaber and M. surmuletus represent suitable definitive and intermediate/paratenic hosts of H. fabri, respectively, in the Mediterranean and highlight the importance of combining genetic and morphological data to study the taxonomy and epidemiology of parasites widely distributed in different fish species and aquatic ecosystems. PMID- 29424636 TI - Early Experience with Video-Assisted Thoracoscopic Anatomic Segmentectomy. AB - BACKGROUND: Anatomic segmentectomy for stage I nonsmall cell lung cancer (NSCLC) has potential advantages such as preserving pulmonary function and reducing postoperative complications. However, many surgeons are deterred from this procedure for its anatomical complexity. Therefore, we presented our early experience with video-assisted thoracoscopic surgery (VATS) anatomic segmentectomy compared with our most recent VATS lobectomy cases. PATIENTS AND METHODS: Forty patients with cT1aN0M0 (ground-glass opacity [GGO] rate >50%) NSCLC underwent VATS segmentectomy from January 2015 to December 2016. To compare the short-term postoperative outcomes, 47 patients, who underwent VATS lobectomy for cT1aN0M0 NSCLC (GGO rate <=50% and pure solid nodule) during the same period, were referred to as a control group. RESULTS: The two groups were similar in age, sex, preoperative pulmonary functional assessment, and associated comorbidities. The tumor size in the segmentectomy group was significantly smaller (median, 0.8 cm versus 1.4 cm, P < .001). Segmentectomy and lobectomy groups had similar operating time, estimated blood loss, duration of chest tube drainage, length of postoperative hospital stay, and postoperative major and minor morbidities. With regard to lymph node evaluation, lobectomy was associated with more lymph nodes (median, 12 versus 9 nodes, P < .001) and mediastinal nodal stations evaluated (median, 3 versus 3 stations, P < .001). CONCLUSIONS: With acceptable morbidity and mortality, VATS segmentectomy may be an acceptable option for the treatment of cT1aN0M0 (GGO rate >50%) NSCLC. PMID- 29424639 TI - Celebration, education and statistics! PMID- 29424638 TI - Perceived racial/ethnic discrimination, marketing, and substance use among young adults. AB - Perceived experiences of discrimination have been linked to negative health behaviors including tobacco, alcohol, and marijuana use across various racial/ethnic groups. Tobacco and alcohol marketing exposure have also been linked with substance use. This study examined the independent and interacting effects of perceived experiences of discrimination and exposure to alcohol and tobacco marketing, and receptivity to marijuana marketing on substance use in an online survey of a multiethnic sample of young adults in 6 metropolitan areas (n = 505). African Americans (mean (M) = 1.96, 9% 5CI [1.84, 2.09]) and Hispanics (M = 1.98, 95% CI [1.87, 2.09]) reported higher levels of perceived discrimination than Whites (M = 1.52, 95% CI [1.40, 1.64]), p < .001. African Americans had higher levels of exposure to tobacco and alcohol marketing; Hispanics reported higher levels of exposure to alcohol marketing and receptivity to marijuana promotion. Discrimination and marketing exposure were independently associated with higher odds of all 3 outcomes, controlling for covariates (AOR from 2.1 to 3.4 for discrimination; AOR from 1.4 to 13.8 for marketing). Models showed a significant interaction of discrimination and tobacco marketing on past 30-day cigarette use (F = 5.5; p = .02). Individuals with high levels of tobacco marketing exposure were likely to report high past 30-day cigarette use regardless of level of discrimination, while those with low exposure were only at increased risk of reporting cigarette use at higher levels of discrimination. Both perceived discrimination and marketing exposure play a role in substance use. Interventions should consider discrimination as a significant risk factor underlying vulnerability to substance use among young adults. PMID- 29424640 TI - Making sense of the p-value (part 1). PMID- 29424641 TI - Cost-effectiveness of using a collagen-containing dressing plus compression therapy in non-healing venous leg ulcers. AB - OBJECTIVE: To estimate whether collagen-containing dressings could potentially afford the UK's National Health Service (NHS) a cost-effective intervention for the management of non-healing venous leg ulcers (VLUs). METHOD: This was a modelling study performed from the perspective of the UK's NHS. A combination of published clinical outcomes, resource utilisation estimates and utilities for VLUs enabled the construction of a decision model, depicting the management of a chronic VLU with standard care or with a collagen-containing dressing plus compression therapy followed by standard care, over a period of 6 months. The model estimated the incremental cost-effectiveness of the two interventions in terms of the incremental cost per quality-adjusted life year (QALY) gained at 2015/16 prices. RESULTS: The treatment of VLUs of >6 months' duration with a collagen-containing dressing plus compression therapy followed by standard care, instead of standard care, is expected to increase the probability of healing from 0.11 to 0.49 by 6 months and increase health-related quality of life at 6 months from 0.331 to 0.373 QALYs per patient. Additionally, treatment with a collagen containing dressing plus compression therapy followed by standard care has the potential to reduce management costs by 40% over 6 months when compared with standard care (from L6328 to L3789 per patient). CONCLUSION: Within the study's limitations, including a collagen-containing dressing into a standard care protocol compared with standard care potentially affords the NHS a cost-effective (dominant) treatment since it improves outcomes for less cost. PMID- 29424642 TI - Restoring balance: biofilms and wound dressings. AB - Biofilms are responsible for stimulating and maintaining wound inflammation, increasing infection risk and delaying wound closure. Appropriate biofilm management is required to fight against local and systemic infection and to restore balance to the wound environment. The most effective way to remove biofilms involves the use of mechanical techniques, with the wound dressing representing an important component of this strategy. Wound dressing fibres, such as polyacrylate fibres, have been shown to be effective in affecting biofilm architecture by disrupting the biofilm matrix. This helps enhance the efficacy of antimicrobials, such as silver. Focusing an antibiofilm strategy on active agents alone does not constitute a sustainable approach to biofilm management. Furthermore, adding too many active chemicals into a wound can be highly detrimental to the wound bed, and potentially may have both short- and long-term biological concerns. Particular attention on the characteristics and key features of wound dressings is discussed in this paper. The aim of the paper is to review the ideal characteristics of wound dressings, in conjunction with antimicrobials, that are considered a fundamental part of an antibiofilm strategy and growing requirement for enhanced wound healing. PMID- 29424643 TI - An observational study of a superabsorbent polymer dressing evaluated by clinicians and patients. AB - OBJECTIVE: This open, non-comparative, multi-centre investigation examines the use of a new superabsorbent polymer (SAP) wound dressing used for exudate management (in medium-to-high exuding wounds) in a patient population with a variety of wound types. The primary objective of this study was to evaluate the fluid management capabilities of the dressing. METHOD: Both acute and chronic wounds with moderate-to-high exudate production levels were assessed (over a period of two weeks) as requiring exudate management, with a SAP dressing, Zetuvit Plus (designated Resposorb Super in Europe), as part of their normal treatment regimen. Clinicians recorded a subjective assessment of exudate management and its impact on periwound skin conditions. In addition, wound bed preparation, healing trajectory and pain level reduction were monitored to give an insight into the clinical implications of using this dressing. Data was also collected from clinicians and patients on clinical performance of the dressing. RESULTS: The SAP dressing achieved ratings of 'very good'/'good' (83% and 13%, respectively) in relation to its wound exudate handling properties. The dressing supported improved wound healing, reduced damage to and enhanced the status of the periwound skin. Pain levels were reduced and, as a consequence, patient reported outcomes were improved. Patients commented that the exudate handling capabilities of the dressing, its conformability and comfort allowed them to resume a semblance of normality in their life. All participating clinicians indicated that they would continue to use the SAP dressing. A sub-population cost analysis has highlighted that, when compared to alternative (historical) exudate management treatments, the SAP dressing was less expensive. The cost reduction arises from data that shows product use and frequency of dressing change (that impacts on nurse time) are both reduced. For the 10 patients evaluated, total costs were L2,491 and L1,312 before and during use, respectively; a saving of L1,179.00 (47%). CONCLUSION: The SAP dressing was well tolerated and shown to be effective in the management of moderate-to-high exudate. Consequently, the dressing supported improved healing, and reduced damage to periwound skin, leading to lower pain levels. Overall, both the patients and clinicians rated the SAP highly. PMID- 29424644 TI - Effectiveness of a monofilament wound debridement pad at removing biofilm and slough: ex vivo and clinical performance. AB - OBJECTIVE: Removal of slough and other devitalised tissue is an important step in biofilm-based wound care (BBWC) and wound bed preparation. Debridement is key to management of both slough and biofilm, and a number of methods are available to achieve this, including surgical/sharp and mechanical debridement. Developments have led to products indicated for debridement of wounds, including a sterile pad consisting of monofilament fibres. Our aim is to examine the effectiveness of a monofilament wound debridement pad (WDP), Debrisoft. METHOD: We assessed the WDP, in laboratory tests, for the removal of mature biofilm from porcine dermal tissue in an ex vivo model, and the clinical management of sloughy wounds that would benefit from debridement. We used the UPPER score to determine the superficial infection status. RESULTS: The WDP was effective in removing biofilm from porcine dermal tissue. A case series of 10 patients with chronic wounds suggested that the WDP was beneficial in the removal of slough. All chronic wounds had slough and were cleaned weekly, for four weeks, using the MDP to achieve improved healing and a clean wound bed. The average wound size decreased from 8.09cm2 at baseline to 2.3cm2 at week four, with three wounds healed completely. Exudate was reduced, and the UPPER score improved in every patient. CONCLUSION: These results indicate that the WDP effectively debrides biofilm and slough, and contributes to care that follows the principles of wound bed preparation and BBWC. PMID- 29424645 TI - Micrografting chronic lower extremity ulcers with mechanically disaggregated skin using a micrograft preparation system. AB - OBJECTIVE: The Rigenera system is a new standardised micrograft preparation system. It works by means of automated mechanical disaggregation of small tissue samples, extracting only the smallest cells (<50um). The aim of this study was to retrospectively evaluate patients affected by chronic ulcers and who were treated with the micrograft preparation method. METHOD: Chronic ulcers have been included regardless of the cause. The specimen was collected with a 3mm diameter biopsy punch and immediately dissociated by means of the Rigenera System. The obtained suspension was placed on a scaffold of equine collagen. RESULTS: We included 15 patients (four males, 11 females) with a mean age of 72.2+/-8.41 (mean+/-standard deviation) years. In seven patients the ulcers were related to the complications of diabetes, post-traumatic in a further three diabetic patients, vasculitis in one patient, and four patients had venous leg ulcers (VLUs). The median main diameter was 5.0cm and the median estimated area was 43.96cm2. The ulcers were present from a mean of 4.50+/-2.30 months before inclusion in this study. At the second week the wounds were reduced by 37.33%+/-19.35%, at the week eight, nine patients (60.0%) were healed, and at week 16, 13 (86.7%) were healed. The quality of scars was good and did not deteriorate at the six month follow-up. CONCLUSION: The simplicity of the approach, the minimal invasiveness of the specimen collection, and the good quality of scarring of healed wounds, confirmed in the follow-up, makes this micrograft preparation method a useful tool to use on large or complex wounds. PMID- 29424646 TI - Optic pathway-hypothalamic glioma hemorrhage: a series of 9 patients and review of the literature. AB - OBJECTIVE Hemorrhage (also known as apoplexy) in optic pathway gliomas (OPGs) is rare. Because of the variable presentations and low incidence of OPG hemorrhages, little is known about their clinical course and the best treatment options. The aim of this work was to review risk factors, clinical course, and treatment strategies of optic glioma hemorrhages in the largest possible number of cases. METHODS A total of 34 patients were analyzed. Nine new cases were collected, and 25 were identified in the literature. Data regarding demographics, radiological and histological features, treatment, and outcome were retrospectively reviewed. RESULTS The majority of patients were younger than 20 years. Only 3 patients were known to have neurofibromatosis. The histopathological diagnosis was pilocytic astrocytoma in the majority of cases. Five patients had intraorbital hemorrhages, whereas 29 patients had intracranial hemorrhage; the majority of intracranial bleeds were treated surgically. Six patients, all with intracranial hemorrhage, died due to recurrent bleeding, hydrocephalus, or surgical complications. No clear risk factors could be identified. CONCLUSIONS Intracerebral OPG hemorrhages have a fatal outcome in 20% of cases. Age, hormonal status, neurofibromatosis involvement, and histopathological diagnosis have been suggested as risk factors for hemorrhage, but this cannot be reliably established from the present series. The goals of surgery should be patient survival and prevention of further neurological and ophthalmological deterioration. PMID- 29424647 TI - Therapeutic electrical stimulation of injured peripheral nerve tissue using implantable thin-film wireless nerve stimulators. AB - OBJECTIVE Electrical stimulation of peripheral nerve tissue has been shown to accelerate axonal regeneration. Yet existing methods of applying electrical stimulation to injured peripheral nerves have presented significant barriers to clinical translation. In this study, the authors examined the use of a novel implantable wireless nerve stimulator capable of simultaneously delivering therapeutic electrical stimulation of injured peripheral nerve tissue and providing postoperative serial assessment of functional recovery. METHODS Flexible wireless stimulators were fabricated and implanted into Lewis rats. Thin film implants were used to deliver brief electrical stimulation (1 hour, 20 Hz) to sciatic nerves after nerve crush or nerve transection-and-repair injuries. RESULTS Electrical stimulation of injured nerves via implanted wireless stimulators significantly improved functional recovery. Brief electrical stimulation was observed to increase the rate of functional recovery after both nerve crush and nerve transection-and-repair injuries. Wireless stimulators successfully facilitated therapeutic stimulation of peripheral nerve tissue and serial assessment of nerve recovery. CONCLUSIONS Implantable wireless stimulators can deliver therapeutic electrical stimulation to injured peripheral nerve tissue. Implantable wireless nerve stimulators might represent a novel means of facilitating therapeutic electrical stimulation in both intraoperative and postoperative settings. PMID- 29424648 TI - Association of plasma D-dimer level with thromboembolic events after endovascular coil treatment of ruptured cerebral aneurysms. AB - OBJECTIVE Although endovascular therapy is favored for acutely ruptured intracranial aneurysms, hematological factors associated with acute subarachnoid hemorrhage (SAH) may predispose to procedure-related ischemic complications. The aim of this study was to evaluate whether an elevated level of plasma D-dimer, a parameter of hypercoagulation in patients with acute SAH, is correlated with increased incidence of thromboembolic events during endovascular coiling of ruptured aneurysms. METHODS The authors analyzed data from 103 cases of acutely ruptured aneurysms (in 103 patients) treated with endovascular coil embolization at a single institution. Factors associated with elevated D-dimer level on admission were identified. The authors also evaluated whether D-dimer elevation was independently correlated with increased incidence of perioperative thromboembolic events. RESULTS An elevated D-dimer concentration (>= 1.0 MUg/ml) on admission was observed in 70 (68.0%) of 103 patients. Increasing age (p < 0.001, Student t-test) and poor initial neurological grade representing World Federation of Neurosurgical Societies (WFNS) grade IV or V (p = 0.0018, chi square test) were significantly associated with D-dimer elevation. Symptomatic thromboembolic events occurred in 11 cases (10.7%). Elevated D-dimer levels on admission (OR 1.34, 95% CI 1.10-1.62, p = 0.0029) independently carried a higher risk of thromboembolic events after adjustment for potential angiographic confounders, including wide neck of the aneurysm and large aneurysm size. CONCLUSIONS Elevated D-dimer levels on admission of patients with acute SAH were significantly associated with increased incidence of thromboembolic events during endovascular coiling of ruptured aneurysms. PMID- 29424649 TI - Letter to the Editor. Focal cortical dysplasia type IIIa and isolated hippocampal sclerosis. PMID- 29424650 TI - Factors associated with burnout among US neurosurgery residents: a nationwide survey. AB - OBJECTIVE Excessive dissatisfaction and stress among physicians can precipitate burnout, which results in diminished productivity, quality of care, and patient satisfaction and treatment adherence. Given the multiplicity of its harms and detriments to workforce retention and in light of the growing physician shortage, burnout has garnered much attention in recent years. Using a national survey, the authors formally evaluated burnout among neurosurgery trainees. METHODS An 86 item questionnaire was disseminated to residents in the American Association of Neurological Surgeons database between June and November 2015. Questions evaluated personal and workplace stressors, mentorship, career satisfaction, and burnout. Burnout was assessed using the previously validated Maslach Burnout Inventory. Factors associated with burnout were determined using univariate and multivariate logistic regression. RESULTS The response rate with completed surveys was 21% (346/1643). The majority of residents were male (78%), 26-35 years old (92%), in a stable relationship (70%), and without children (73%). Respondents were equally distributed across all residency years. Eighty-one percent of residents were satisfied with their career choice, although 41% had at some point given serious thought to quitting. The overall burnout rate was 67%. In the multivariate analysis, notable factors associated with burnout included inadequate operating room exposure (OR 7.57, p = 0.011), hostile faculty (OR 4.07, p = 0.008), and social stressors outside of work (OR 4.52, p = 0.008). Meaningful mentorship was protective against burnout in the multivariate regression models (OR 0.338, p = 0.031). CONCLUSIONS Rates of burnout and career satisfaction are paradoxically high among neurosurgery trainees. While several factors were predictive of burnout, including inadequate operative exposure and social stressors, meaningful mentorship proved to be protective against burnout. The documented negative effects of burnout on patient care and health care economics necessitate further studies for potential solutions to curb its rise. PMID- 29424651 TI - Novel experimental surgical strategy to prevent traumatic neuroma formation by combining a 3D-printed Y-tube with an autograft. AB - OBJECTIVE Traumatic neuromas may develop after nerve injury at the proximal nerve stump, which can lead to neuropathic pain. These neuromas are often resistant to therapy, and excision of the neuroma frequently leads to recurrence. In this study, the authors present a novel surgical strategy to prevent neuroma formation based on the principle of centro-central anastomosis (CCA), but rather than directly connecting the nerve ends to an autograft, they created a loop using a 3D-printed polyethylene Y-shaped conduit with an autograft in the distal outlets. METHODS The 3D-printed Y-tube with autograft was investigated in a model of rat sciatic nerve transection in which the Y-tube was placed on the proximal sciatic nerve stump and a peroneal graft was placed between the distal outlets of the Y tube to form a closed loop. This model was compared with a CCA model, in which a loop was created between the proximal tibial and peroneal nerves with a peroneal autograft. Additional control groups consisted of the closed Y-tube and the extended-arm Y-tube. Results were analyzed at 12 weeks of survival using nerve morphometry for the occurrence of neuroma formation and axonal regeneration in plastic semi-thin sections. RESULTS Among the different surgical groups, the Y tube with interposed autograft was the only model that did not result in neuroma formation at 12 weeks of survival. In addition, a 13% reduction in the number of myelinated axons regenerating through the interposed autograft was observed in the Y-tube with autograft model. In the CCA model, the authors also observed a decrease of 17% in the number of myelinated axons, but neuroma formation was present in this model. The closed Y-tube resulted in minimal nerve regeneration inside the tube together with extensive neuroma formation before the entrance of the tube. The extended-arm Y-tube model clearly showed that the majority of the regenerating axons merged into the Y-tube arm, which was connected to the autograft, leaving the extended plastic arm almost empty. CONCLUSIONS This pilot study shows that our novel 3D-printed Y-tube model with interposed autograft prevents neuroma formation, making this a promising surgical tool for the management of traumatic neuromas. PMID- 29424652 TI - Letter to the Editor. Use of the ACS NSQIP Surgical Risk Calculator for prediction of adverse outcomes after neurosurgery. PMID- 29424653 TI - Seroprevalence of hepatitis B surface antigenemia and viral infectivity among liver cancer patients accessing care at a tertiary health facility in Southwest Nigeria. AB - INTRODUCTION: Hepatitis B virus (HBV) infection is a public health challenge globally, associated with hepatocellular carcinoma and known to be highly endemic in developing countries. Its comorbidity with cancer in infected patients poses greater challenge in their management. This study was therefore designed to determine the burden of HBV infection and its correlation among cancer patients assessing care in a tertiary health facility in southwest Nigeria. METHODOLOGY: A total of 122 plasma samples from consenting cancer patients were tested for Hepatitis B surface Antigen (HBsAg) using a commercial enzyme-linked immunosorbent (ELISA) assay and their plasma HBV DNA quantified by COBAS Amplicor HBV Monitor assay. Data were analyzed using SPSS version 21 and chi-square (chi2) test was used to determine association while p < 0.05 considered statistically significant. RESULTS: An overall HBsAg rate of 13.9% was found among the study population. The distribution of HBsAg positivity among the subjects with condition of cancer showed 9(23.7%) with chronic liver disease (CLD), 4(10.8%) in primary liver carcinoma (PLCC) and 4(8.5%) with pyrexia of unknown origin (PUO). The CLD group had highest viral infectivity (Mean=8324.3 Copies/Ml) and lowest among those with PLCC (468.4 Copies/Ml). The rate for HBsAg was higher in male (14.7%) than in their female (13.0%) counterparts with significant statistical association by gender (p>0.0314) and peaked (23.5%) among age group 20-29 years. CONCLUSION: This study identified high rate of HBV infection among the population and could be investigated as a predictor for cancer. This finding is vital in the management of cancer patients coinfected with HBV. PMID- 29424654 TI - Effects of work surface and task difficulty on neck-shoulder posture and trapezius activity during a simulated mouse task. AB - OBJECTIVES: The purpose of this study is to evaluate the influence of the work surface and task difficulty on the head, upper back and upper arm postures and activity of the descending trapezius during a simulated mouse task. METHODS: Healthy female university students (N = 15) were evaluated. The work surface was positioned at elbow height (EH) and above elbow height (AEH) and the task difficulty was set at low (LD) and high (HD) levels. The postures were recorded by inclinometers. Trapezius activity was normalized by the maximum voluntary isometric contraction (MVIC). RESULTS: Significantly higher head flexion was found at EH compared to the AEH condition, with an average difference of 2 degrees -5 degrees at the same difficulty level. The HD task significantly increased head (3 degrees -6 degrees ) and upper back flexion (6 degrees -7 degrees ) at the same table height. For upper arm elevation and trapezius activation, the AEH condition presented higher upper arm elevation (about 6 degrees -8 degrees ) and trapezius activity (0.8-1.4% of MVIC), regardless of the difficulty level of the task. CONCLUSIONS: Head posture was influenced by the table height and task difficulty; the upper back posture by high difficulty; and upper arm posture and trapezius activity were only influenced by table height. PMID- 29424655 TI - Decolorization of Reactive Red 159 by a consortium of photosynthetic bacteria using an anaerobic sequencing batch reactor (AnSBR). AB - This experiment aimed to decolorize Reactive Red 159 using a high potential of a consortium of purple nonsulfur bacteria (PNSB) with an application of response surface methodology through a central composite design in open system. The three factors of hydraulic retention time (HRT), sludge retention time (SRT) and dye concentration were applied to the design. The decolorization was operated in an anaerobic sequencing batch reactor until the system reached to a pseudosteady state for 30 cycles in each experiment. The optimal condition was 6,500 mg/L of Reactive Red 159 concentration with 20 days of SRT and 8 days of HRT, achieving dye effluent of 142.62 +/- 5.35 mg/L, decolorization rate of 264.54 +/- 7.13 mg/L/h and decolorization efficiency of 97.68 +/- 0.74%. The results revealed that PNSB efficiently decolorized the high concentration of Reactive Red 159 and they were a high potential of microorganisms for dyes contaminated wastewater treatment. PMID- 29424656 TI - From Peers to Lay Bystanders: Findings from a Decade of Naloxone Distribution in Pittsburgh, PA. AB - Distribution of the opioid overdose reversal drug naloxone has been central to efforts to combat the ongoing opioid epidemic in the United States. This report presents data from Prevention Point Pittsburgh (PPP), a public health advocacy and direct service organization that has operated an overdose prevention program (OPP) with naloxone distribution since 2005. The program initially provided naloxone training and distribution only to people who use opioids (PWUO). In 2015, a change to state law enabled PPP to provide naloxone to anyone in a position to respond to an opioid-related overdose. This report examines the characteristics and naloxone-related experiences of 1330 PWUO trained in overdose prevention and naloxone administration by PPP between January 1, 2006, and December 31, 2015, and compares rates of return for a naloxone refill by PWUO and the 619 non-users trained between January 1, 2015, and December 31, 2015. While larger numbers of individuals obtained naloxone after state law changed, PWUO especially heroin users-were significantly more likely to reverse an overdose and return to PPP for a naloxone refill. Based on these findings, we recommend that resource-limited, community-based organizations prioritize the distribution of naloxone to PWUO. PMID- 29424658 TI - Home care in Australia: an integrative review. AB - The home care sector comprises one of Australia's fastest growing workforces, yet few papers capture the overall landscape of Australian home care. This integrative review investigates home care with the aim of better understanding care recipients and their needs, funding, and regulation; care worker skills, tasks, demographics, employment conditions, and training needs. Over 2,700 pieces of literature were analyzed to inform this review. Results suggest sector fragmentation and a home care workforce who, although well-placed to improve outcomes for care recipients, are in need of better training and employment support. Suggestions for future research regarding Australian home care include studies that combine both aged and disability aspects of care, more research around care recipients, priority needs and strategies for addressing them, and how best to prepare home care workers for their roles. PMID- 29424659 TI - Schistosomes and Microfilarial Parasites in Magellanic Penguins. AB - The Magellanic Penguin ( Spheniscus magellanicus) is native to Argentina, Chile, and the Falkland/Malvinas Islands, and is a regular winter migrant in Uruguayan and Brazilian coastal waters. The species is known to be susceptible to a variety of gastrointestinal nematodes, cestodes, trematodes, and acanthocephalans, as well as renal trematodes and pulmonary nematodes. Schistosomes (Platyhelminthes, Trematoda, Schistosomatidae) and microfilariae (Nematoda, Secernentea, Onchocercidae) were histologically identified in Magellanic Penguins ( Spheniscus magellanicus) that died while under care at rehabilitation centers in southern Brazil. Phylogenetic analysis of the COI gene, ITS-1 region, 5.8S rRNA gene, ITS 2 region, and 28S rRNA gene sequences of the schistosome revealed that it is closely related to, but distinct from, a schistosome reported from the African Penguin ( Spheniscus demersus). The schistosomes from Magellanic and African Penguins were grouped with Gigantobilharzia huronensis, Gigantobilharzia melanoidis, and Dendritobilharzia pulvurenta; however, the lack of a clearly monophyletic origin precludes determining their genus. The incidental discovery of novel parasites during a study that did not specifically aim to investigate the occurrence of helminths underscores the value of histopathological examination as an exploratory diagnostic approach. PMID- 29424657 TI - Extracellular vesicles regulate immune responses and cellular function in intestinal inflammation and repair. AB - Tightly controlled communication among the various resident and recruited cells in the intestinal tissue is critical for maintaining tissue homeostasis, re establishment of the barrier function and healing responses following injury. Emerging evidence convincingly implicates extracellular vesicles (EVs) in facilitating this important cell-to-cell crosstalk by transporting bioactive effectors and genetic information in healthy tissue and disease. While many aspects of EV biology, including release mechanisms, cargo packaging, and uptake by target cells are still not completely understood, EVs contribution to cellular signaling and function is apparent. Moreover, EV research has already sparked a clinical interest, as a potential diagnostic, prognostic and therapeutic tool. The current review will discuss the function of EVs originating from innate immune cells, namely, neutrophils, monocytes and macrophages, as well as intestinal epithelial cells in healthy tissue and inflammatory disorders of the intestinal tract. Our discussion will specifically emphasize the contribution of EVs to the regulation of vascular and epithelial barrier function in inflamed intestines, wound healing, as well as trafficking and activity of resident and recruited immune cells. PMID- 29424660 TI - Associations between vitamin D and pulmonary function in chronic spinal cord injury. AB - CONTEXT/OBJECTIVE: Individuals with chronic spinal cord injury (SCI) have an increased risk of morbidity and mortality attributable to respiratory diseases. Previous studies in non-SCI populations suggest that vitamin D may be a determinant of respiratory health. Therefore, we sought to assess if lower vitamin D levels were associated with decreased pulmonary function in persons with chronic SCI. DESIGN: Cross-sectional study. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: 312 participants (260 men and 52 women) with chronic SCI recruited from VA Boston and the community participating in an epidemiologic study to assess factors influencing respiratory health. METHODS: Participants provided a blood sample, completed a respiratory health questionnaire, and underwent spirometry. Linear regression methods were used to assess cross-sectional associations between plasma 25-hydroxyviatmin D and spirometric measures of pulmonary function. OUTCOME MEASURES: Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC. RESULTS: Adjusted and unadjusted for a number of confounders, there was no significant association between plasma vitamin D levels and FEV1, FVC, or FEV1/FVC. For example, in fully adjusted models, each 10 ng/ml increase in vitamin D was associated with a 4.4 ml (95%CI -64.4, 73.2, P = 0.90) ml change in FEV1. Conclusion: There was no significant cross-sectional association between plasma vitamin D and FEV1, FVC, or FEV1/FVC in this cohort of individuals with chronic SCI. PMID- 29424661 TI - Preventive care among primary care patients living with spinal cord injury. AB - OBJECTIVE: Context/Objective: Family physicians may lack the knowledge or resources to adequately support patients with spinal cord injury (SCI). Our objectives were to determine patterns of preventive care for patients with SCI in a primary care setting (i.e. cancer screening, influenza vaccinations, general physicals, bone mineral density tests), and determine physicians' level of comfort with providing primary care to patients with SCI. DESIGN: i) Retrospective chart review, ii) Survey of physicians in the family practice. SETTING: Six primary care practice sites in Ontario, Canada. PARTICIPANTS: All adult rostered patients of the family practice with SCI; All family physicians in the six sites. OUTCOME MEASURES: Proportion of patients up-to-date on cancer screening, proportion of patients with influenza vaccinations, general physicals, bone mineral density tests; physicians' level of comfort with providing care to patients with SCI. RESULTS: Sixty patients were included in analyses. Rates of cancer screening were generally poor. The highest uptake was seen for cervical cancer screening, where 50% of eligible women were up-to-date on Pap tests. Only 36.7% of patients were up-to-date on colorectal cancer screening. Only 14 (23.3%) patients had a documented general physical exam in their electronic record. There was a recorded flu vaccination for 55% of patients, and of those, there was a median of 19 months since last vaccination. Fifteen physicians (21.4%) responded to the survey. Ten physicians reported at least one patient with SCI, with the maximum being 20 patients. Comfort level in managing SCI-relevant conditions varied and was lowest for spasticity, respiratory issues and autonomic dysreflexia, where only 27.3% of respondents had some level of comfort. CONCLUSION: There are many opportunities to improve the preventive care of patients living with SCI. PMID- 29424662 TI - Small RNA-Omics for Virome Reconstruction and Antiviral Defense Characterization in Mixed Infections of Cultivated Solanum Plants. AB - In plants, RNA silencing-based antiviral defense generates viral small RNAs (sRNAs) faithfully representing the viral genomes. We employed sRNA sequencing and bioinformatics (sRNA-omics) to characterize antiviral defense and to reconstruct the full genomic sequences and their variants in the evolving viral quasispecies in cultivated solanaceous plants carrying mixed infections. In naturally infected Solanum tuberosum (potato), one case study revealed a virome comprising Potato virus Y (genus Potyvirus) and Potato virus X (genus Potexvirus), which was reconstructed by de novo-assembling separate genome-size sRNA contigs. Another case study revealed a virome comprising NTN and O strains of Potato virus Y, whose sRNAs assembled in chimeric contigs, which could be disentangled on the basis of reference genome sequences. Both viromes were stable in vegetative potato progeny. In a cross-protection trial of Solanum lycopersicum (tomato), the supposedly protective mild strain CH2 of Pepino mosaic virus (genus Potexvirus) was tested for protection against strain LP of the same virus. Reciprocal mechanical inoculations eventually resulted in co-infection of all individual plants with CH2 and LP strains, reconstructed as separate sRNA contigs. LP invasions into CH2-preinfected plants and vice versa were accompanied by alterations of consensus genome sequences in viral quasispecies, indicating a potential risk of cross-protection measures. Additionally, the study also revealed, by reconstruction from sRNAs, the presence of the mechanically nontransmissible Southern tomato virus (genus Amalgavirus) in some plants. Our in depth analysis of sRNA sizes, 5'-nucleotide frequencies and hotspot maps revealed similarities in sRNA-generating mechanisms in potato and tomato, differential silencing responses to virome components and potential for sRNA-directed cross targeting between viral strains which could not, however, prevent the formation of stable viromes. PMID- 29424664 TI - A Chemotaxis-Like Pathway of Azorhizobium caulinodans Controls Flagella-Driven Motility, Which Regulates Biofilm Formation, Exopolysaccharide Biosynthesis, and Competitive Nodulation. AB - The genome of the Azorhizobium caulinodans ORS571 contains a unique chemotaxis gene cluster (che) including five chemotaxis genes: cheA, cheW, cheY1, cheB, and cheR. Analysis of the role of the chemotaxis cluster of A. caulinodans using deletion mutant strains revealed that CheA or the Che signaling pathway controls chemotaxis behavior and flagella-driven motility and plays important roles in formation of biofilms and production of extracellular polysaccharides (EPS). Furthermore, the deletion mutants (DeltacheA and DeltacheA-R) were defective in competitive adsorption and colonization on the root surface of host plants. In addition, a functional CheA or Che pathway promoted competitive nodulation on roots and stems. Interestingly, a nonflagellated mutant, DeltafliM, displayed a phenotype highly similar to that of the DeltacheA or DeltacheA-R mutant strains. These findings suggest that through controlling flagella-driven motility behavior, the chemotaxis signaling pathway in A. caulinodans coordinates biofilm formation, EPS, and competitive colonization and nodulation. PMID- 29424663 TI - A Large-Scale Mutational Analysis of Two-Component Signaling Systems of Lonsdalea quercina Revealed that KdpD-KdpE Regulates Bacterial Virulence Against Host Poplar Trees. AB - Poplar, which is a dominant species in plant communities distributed in the northern hemisphere, is commonly used as a model plant in forestry studies. Poplar production can be inhibited by infections caused by bacteria, including Lonsdalea quercina subsp. populi, which is a gram-negative bacterium responsible for bark canker disease. However, the molecular basis of the pathogenesis remains uncharacterized. In this study, we annotated the two-component signal transduction systems (TCSs) encoded by the L. quercina subsp. populi N-5-1 genome and identified 18 putative histidine kinases and 24 response regulators. A large scale mutational analysis revealed that 19 TCS genes regulated bacterial virulence against poplar trees. Additionally, the deletion of kdpE or overexpression of kdpD resulted in almost complete loss of bacterial virulence. We observed that kdpE and kdpD formed a bi-cistronic operon. KdpD exhibited autokinase activity and could bind to KdpE (Kd = 5.73 +/- 0.64 MUM). Furthermore, KdpE is an OmpR family response regulator. A chromatin immunoprecipitation sequencing analysis revealed that KdpE binds to an imperfect palindromic sequence within the promoters of 44 genes, including stress response genes Lqp0434, Lqp3037, and Lqp3270. A comprehensive analysis of TCS functions may help to characterize the regulation of poplar bark canker disease. PMID- 29424665 TI - Social comparisons and quality of life following a prostate cancer diagnosis. AB - PURPOSE: The objective was to explore the relationships among cognitive appraisals of prostate cancer (challenge, threat, and harm/loss), social comparisons, and quality of life in men previously diagnosed. Design, Sample, & Methods: Men who had participated in prostate cancer support groups completed a cross-sectional questionnaire (N = 189). Multivariable linear regression was used to evaluate social comparisons as mediators of quality of life while controlling for uncertainty and optimism. FINDINGS: Positive and negative social comparisons were parallel mediators of the relationships between challenge or threat appraisals and quality of life, while only negative social comparisons mediated the relationship between harm/loss appraisals and quality of life. CONCLUSIONS: These findings demonstrate the importance of social comparisons in accounting for the effect of cognitive appraisals of prostate cancer on quality of life among men in support groups. Implications for Psychosocial Providers: Interventions to improve quality of life could address reduction of maladaptive comparisons, a strategy that could be tailored based on the patient's appraisal of prostate cancer. PMID- 29424666 TI - The municipal solid waste management of La Paz (Bolivia): Challenges and opportunities for a sustainable development. AB - Municipal solid waste management (MSWM) is considered an important public health, economic and environmental concern, especially in developing countries. This paper introduces the situation of MSWM in La Paz (Bolivia) in 2016, and is based on the Wasteaware indicators and waste flow analysis, useful tools for classifying and comparing waste treatment and management plans among other countries. Taking into account the lack of technology in waste treatment and the presence of a developed informal sector, the paper analyses the main strengths and weak points for implementing a sustainable MSWM. The research conducted revealed that the MSWM of La Paz is not efficient with regard to collection, recycling (8%), financial sustainability, and equity of the service. At the same time, local Government and stakeholders are interested in implementing new MSWM methods for improving the current sanitary state of the city and many efforts were made over the last ten years. In general terms, La Paz could be considered as a good study area for developing plans for waste valorization, becoming an example for a low-middle income developing big city of Latin America. The study provided a few considerations about the affordability of the methodology applied and critically analyzed the case study proposed. PMID- 29424668 TI - Optimizing secretory expression of recombinant human interferon gamma from Kluyveromyces lactis. AB - Biosimilar/biotherapeutic production is becoming a major area of focus for a big chunk of biotechnology industry. Easy licensing and already approved status for clinical use have given it a boost. In the present study, recombinant human interferon gamma (IFNG) was expressed for the first time in Kluyveromyces lactis expression system and its expression was optimized by varying growth parameters and carbon source concentration with the aim of increasing recombinant protein production level. Human IFNG gene was cloned in the genomic DNA of K. lactis by homologous recombination and under unoptimized conditions in shake flask, IFNgamma protein was secreted in the fermentation medium at a level of 175 ug/L quantified by ELISA assay. After the optimization of expression conditions using one-variable-at-a-time technique, expression level was enhanced by 2.2-folds. Substrate inhibition studies revealed that up to 80 g/L of lactose is well tolerated by K. lactis cells for its growth but more than 80 g/L of lactose causes remarkable reduction in biomass production. PMID- 29424667 TI - Caregiver informational support in different patient care settings at end of life. AB - Caregivers of the terminally ill face many complicated tasks including providing direct patient care, communicating with clinicians, and managing the logistical demands of daily activities. They require instructive information at all points in the illness process and across several settings where patients receive end-of life care. This study examines how the setting where a patient receives end-of life care affects caregivers' informational support needs by thematically analyzing data from caregiver interviews and clinical observations. Caregivers providing care for patients at home received informational support related to meeting patients' mobility, medication, and nutritional needs. Caregivers who provided care remotely received informational support to navigate transitions between patient care settings or long-term care arrangements, including financial considerations and insurance logistics. The findings document that interventions designed to enhance information for caregivers should account for caregiving context and that health care providers should proactively and repeatedly assess caregiver information needs related to end-of-life patient care. PMID- 29424669 TI - Age and Sex Differences in Morningness/Eveningness Along the Life Span: A Cross Sectional Study in Spain. AB - Work psychology has noted the importance of considering the temporal dimension of behavior in organizations. Given that society widely operates on a 24-hr schedule, it is important to know how circadian typologies are distributed in the general population. In this study, diurnal preference was analyzed among 4,175 Spanish participants (61.3% women), 12-59 years old, who completed the Composite Scale of Morningness (Smith, Reilly, & Midkiff, 1989). Several measurement models of the CSM were analyzed using exploratory structural equation modeling and confirmatory factor analysis. The bifactor model showed the best fit, with a general factor (morningness/eveningness) and three subfactors (morningness, morning affect, and time of retiring). The age and sex factorial invariance of the bifactor model were tenable at the latent variance-covariance level. Next, age and sex differences analysis indicated a progressive increase in morningness with age, but over 40 years old, men were more morningness oriented than women were. These results indicate that morningness/eveningness can be considered a multidimensional construct and that psychosocial factors must be considered when estimating the prevalence of morningness/eveningness in different populations or countries. PMID- 29424670 TI - The impact of posttraumatic stress symptoms on social support and social conflict during hematopoietic stem cell transplant. AB - PURPOSE/OBJECTIVES: Social support and its relationship to psychological distress are of interest in hematopoietic stem cell transplant (HSCT) as patients are dependent on caregivers pre-, during, and posttransplant. Although social support is critical for managing stress and trauma, posttraumatic stress symptoms (PTSS) may erode social support and evoke conflict and abandonment within the support system. This study aimed to evaluate whether PTSS were associated with lower support and social conflict in a sample of patients undergoing HSCT. DESIGN/METHODS: Prospective relationships between PTSS, perceived social support, and social conflict were assessed in 88 participants across the first three months of HSCT (T0 Baseline; T1 +30; T2 +60; T3 +90). FINDINGS: When individuals experienced increase above their own average levels of PTSS, they reported concurrent increase in social conflict (p < .001) and subsequent increase in social support in the following month (p = .026). CONCLUSION/IMPLICATIONS: Results suggest PTSS during stem cell transplantation may evoke social conflict, but over time, the support system may recalibrate to be more supportive. Patients undergoing HSCT may benefit from family and social-level interventions that specifically target the incidence of interpersonal conflict as it unfolds during the initial stages of HSCT. PMID- 29424672 TI - Sacral pedicle subtraction osteotomy for an extreme case of positive sagittal balance: case report. AB - The importance of sagittal spinal balance and lumbopelvic parameters is now well understood. The popularization of various osteotomies, including Smith-Peterson, Ponte, and pedicle subtraction osteotomies (PSOs), as well as vertebral column resections, have greatly enhanced the spine surgeon's ability to recognize and effectively treat sagittal imbalance. Yet rare circumstances remain, most notably in distal kyphotic deformities and patients with extremely elevated pelvic incidences, where these techniques remain inadequate. In this article, the authors describe a patient with severe sagittal imbalance despite multiple prior anterior and posterior reconstructive surgeries in which a sacral PSO was performed with good results. A description of this technique as well as a brief review of the literature is provided. PMID- 29424673 TI - Nerve fascicle transfer using a part of the C-7 nerve for spinal accessory nerve injury. AB - OBJECTIVE Spinal accessory nerve (SAN) injury results in a series of shoulder dysfunctions and continuous pain. However, current treatments are limited by the lack of donor nerves as well as by undesirable nerve regeneration. Here, the authors report a modified nerve transfer technique in which they employ a nerve fascicle from the posterior division (PD) of the ipsilateral C-7 nerve to repair SAN injury. The technique, first performed in cadavers, was then undertaken in 2 patients. METHODS Six fresh cadavers (12 sides of the SAN and ipsilateral C-7) were studied to observe the anatomical relationship between the SAN and C-7 nerve. The length from artificial bifurcation of the middle trunk to the point of the posterior cord formation in the PD (namely, donor nerve fascicle) and the linear distance from the cut end of the donor fascicle to both sites of the jugular foramen and medial border of the trapezius muscle (d-SCM and d-Traps, respectively) were measured. Meanwhile, an optimal route for nerve fascicle transfer (NFT) was designed. The authors then performed successful NFT operations in 2 patients, one with an injury at the proximal SAN and another with an injury at the distal SAN. RESULTS The mean lengths of the cadaver donor nerve fascicle, d-SCM, and d-Traps were 4.2, 5.2, and 2.5 cm, respectively. In one patient who underwent proximal SAN excision necessitated by a partial thyroidectomy, early signs of reinnervation were seen on electrophysiological testing at 6 months after surgery, and an impaired left trapezius muscle, which was completely atrophic preoperatively, had visible signs of improvement (from grade M0 to grade M3 strength). In the other patient in whom a distal SAN injury was the result of a neck cyst resection, reinnervation and complex repetitive discharges were seen 1 year after surgery. Additionally, the patient's denervated trapezius muscle was completely resolved (from grade M2 to grade M4 strength), and her shoulder pain had disappeared by the time of final assessment. CONCLUSIONS NFT using a partial C-7 nerve is a feasible and efficacious method to repair an injured SAN, which provides an alternative option for treatment of SAN injury. PMID- 29424671 TI - Reproducibility, temporal stability, and functional correlation of diffusion MR measurements within the spinal cord in patients with asymptomatic cervical stenosis or cervical myelopathy. AB - OBJECTIVE The purpose of this study was to quantify the reproducibility, temporal stability, and functional correlation of diffusion MR characteristics in the spinal cord in patients with cervical stenosis with or without myelopathy. The association between longitudinal diffusion tensor imaging (DTI) measurements and serial neurological function assessment was explored at both the group and individual level. METHODS Sixty-six nonoperatively treated patients with cervical stenosis were prospectively followed (3 months to > 5 years) using synchronous serial MRI and functional outcome assessment. A total of 183 separate MRI examinations were performed, separated by at least 3 months, and each patient had a minimum of 2 MRI scans (range 2-5 scans). Anatomical and DTI measurements were performed within the spinal cord at the C1-2 region as well as at the area of highest compression. Coefficients of variance (COVs) were compared across measurements in both reference tissue and areas of compression for anatomical measurements, fractional anisotropy (FA), and mean diffusivity (MD). The correlation between diffusion MR measures at the site of compression and evaluations of neurological function assessed using the modified Japanese Orthopaedic Association (mJOA) scale at multiple time points was evaluated. RESULTS The COVs for anatomical measurements (Torg ratio and canal diameter) were between 7% and 10%. The median COV for FA measurements at the site of compression was 9%, and for reference tissue at C1-2 it was 6%. The median COV for MD at the site of compression was approximately 12%, and for reference tissue at C1-2 it was 10%. The FA and MD measurements of C1-2 averaged 0.61 and 0.91 MUm2/msec, respectively, whereas the FA and MD measurements at the site of compression averaged 0.51 and 1.26 MUm2/msec, respectively. Both FA (slope = 0.037; R2 = 0.3281, p < 0.0001) and MD (slope = -0.074; R2 = 0.1101, p = 0.0084) were significantly correlated with the mJOA score. The FA decreased by approximately 0.032 units per mJOA unit decrease (R2 = 0.2037, p < 0.0001), whereas the MD was increased by approximately 0.084 MUm2/msec for every mJOA unit decrease (R2 = 0.1016, p < 0.0001). CONCLUSIONS Quantitative DTI measurements of the spinal cord in patients with cervical stenosis with or without myelopathy have a median COV of 5%-10%, similar to anatomical measurements. The reproducibility of these measurements and significant correlation with functional outcome status suggest a potential role in the evaluation and longitudinal surveillance of nonoperatively treated patients. With respect to the specific DTI measurements, FA within the spinal cord appears slightly more sensitive to neurological function and more stable than measures of MD. Therefore, DTI of the spinal cord may be a clinically feasible imaging technique for longitudinally monitoring patients with cervical spondylotic myelopathy. PMID- 29424674 TI - Usefulness of corset adoption after single-level lumbar discectomy: a randomized controlled trial. AB - OBJECTIVE In this paper, the authors sought to verify whether corset adoption could improve the short-term and midterm outcome scores of patients after single level lumbar discectomy. METHODS A monocentric, randomized controlled trial of 54 consecutive patients who underwent single-level lumbar discectomy at the authors' institution was performed from September 2014 to August 2015. Patients were randomly assigned to use or not use a lumbar corset in the upright position. Patients with previous interventions for disc herniation or with concomitant canal or foraminal stenosis were excluded. The visual analog scale, Oswestry Disability Index, and Roland Morris Disability Questionnaire were used to compare groups at the 1- and 6-month follow-up time points. RESULTS No significant differences between the 2 groups were reported at either time point for any given outcome irrespective of the scale used. CONCLUSIONS Corset adoption does not improve the short-term and midterm outcomes of patients after single-level lumbar discectomy. PMID- 29424675 TI - Intradural spinal arachnoid cyst resection: implications of duraplasty in a large case series. AB - OBJECTIVE Optimal diagnosis and management strategies for intradural spinal arachnoid cysts (SACs) are still unresolved given the rare nature of this entity, with few large case series and virtually no statistical analyses of patient characteristics in the literature. Here, the authors studied a large patient cohort with these lesions to determine whether pre- or postoperative attributes could be used to aid in either diagnosis or prognosis. METHODS A chart review was completed at a single institution for the period from 2002 to 2016 to determine the preoperative characteristics and postoperative outcomes of 21 patients with exclusively intradural SACs. Patients were assessed for symptoms such as weakness, pain, sensory changes, bowel and/or bladder dysfunction, and gait changes. Postoperatively, patients were analyzed for symptom improvement, complication occurrence, and duration of follow-up. RESULTS Approximately two thirds of the patients in this series had developed SACs idiopathically, and the mean duration of symptoms prior to diagnosis was 15 months among all patients. A slight majority (57%) underwent CT myelography in the course of diagnosis, and a quarter of the patients had a syrinx. There was a statistically significant association between location of the SAC and number of presenting signs and symptoms; that is, patients with cysts in the lumbosacral region had more symptoms than those with cysts at the cervical or thoracic levels (p = 0.031). Overall, outcomes were largely positive, with approximately 60%-70% of patients experiencing postoperative improvement in symptoms, with motor weakness showing the highest response rate (71%) and pain symptoms the least likely to subside (50%). In the cohort with preoperative pain, those who had undergone expansile duraplasty were significantly more likely to experience relief of their pain symptoms (p = 0.028), which may have been a result of the superior restoration of cerebrospinal fluid pathways allowing for more adequate reduction in compression. CONCLUSIONS In this large case series on intradural SACs, new light has been shed on aspects of both pre- and postoperative care for patients with these rare lesions. Specifically, the authors revealed that lumbosacral intradural SACs may be associated with a higher disease burden and that patients who undergo expansile duraplasty may have an increased likelihood of experiencing postoperative pain relief. PMID- 29424676 TI - A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation. AB - OBJECTIVE Chemonucleolysis with condoliase has the potential to be a new, less invasive therapeutic option for patients with lumbar disc herniation (LDH). The aim of the present study was to determine the most suitable therapeutic dose of condoliase. METHODS Patients between 20 and 70 years of age with unilateral leg pain, positive findings on the straight leg raise test, and LDH were recruited. All eligible patients were randomly assigned to receive condoliase (1.25, 2.5, or 5 U) or placebo. The primary end point was a change in the worst leg pain from preadministration (baseline) to week 13. The secondary end points were changes from baseline in the following items: worst back pain, Oswestry Disability Index (ODI), SF-36, and neurological examination. For pharmacokinetic and pharmacodynamic analyses, plasma condoliase concentrations and serum keratan sulfate concentrations were measured. The safety end points were adverse events (AEs) and radiographic and MRI parameters. Data on leg pain, back pain, abnormal neurological findings, and imaging parameters were collected until week 52. RESULTS A total of 194 patients received an injection of condoliase or placebo. The mean change in worst leg pain from baseline to week 13 was -31.7 mm (placebo), -46.7 mm (1.25 U), -41.1 mm (2.5 U), and -47.6 mm (5 U). The differences were significant at week 13 in the 1.25-U group (-14.9 mm; 95% CI 28.4 to -1.4 mm; p = 0.03) and 5-U group (-15.9 mm; 95% CI -29.0 to -2.7 mm; p = 0.01) compared with the placebo group. The dose-response improvement in the worst leg pain at week 13 was not significant (p = 0.14). The decrease in the worst leg pain in all 3 condoliase groups was observed from week 1 through week 52. Regarding the other end points, the worst back pain and results of the straight leg raise test, ODI, and SF-36 showed a tendency for sustained improvement in each of the condoliase groups until week 52. In all patients at all time points, plasma condoliase concentrations were below the detectable limit (< 100 MUU/ml). Serum keratan sulfate concentrations significantly increased from baseline to 6 hours and 6 weeks after administration in all 3 condoliase groups. No patient died or developed anaphylaxis or neurological sequelae. Five serious AEs occurred in 5 patients (3 patients in the condoliase groups and 2 patients in the placebo group), resolved, and were considered unrelated to the investigational drug. Severe AEs occurred in 10 patients in the condoliase groups and resolved or improved. In the condoliase groups, back pain was the most frequent AE. Modic type 1 change and decrease in disc height were frequent imaging findings. Dose response relationships were observed for the incidence of adverse drug reactions and decrease in disc height. CONCLUSIONS Condoliase significantly improved clinical symptoms in patients with LDH and was well tolerated. While all 3 doses had similar efficacy, the incidence of adverse drug reactions and decrease in disc height were dose dependent, thereby suggesting that 1.25 U would be the recommended clinical dose of condoliase. Clinical trial registration no.: NCT00634946 (clinicaltrials.gov). PMID- 29424677 TI - Prospective assessment of the safety and early outcomes of sublaminar band placement for the prevention of proximal junctional kyphosis. AB - OBJECTIVE Proximal junctional kyphosis (PJK) can progress to proximal junctional failure (PJF), a widely recognized early and serious complication of multisegment spinal instrumentation for the treatment of adult spinal deformity (ASD). Sublaminar band placement has been suggested as a possible technique to prevent PJK and PJF but carries the theoretical possibility of a paradoxical increase in these complications as a result of the required muscle dissection and posterior ligamentous disruption. In this study, the authors prospectively assess the safety as well as the early clinical and radiological outcomes of sublaminar band insertion at the upper instrumented vertebra (UIV) plus 1 level (UIV+1). METHODS Between August 2015 and February 2017, 40 consecutive patients underwent either upper (T2-4) or lower (T8-10) thoracic sublaminar band placement at the UIV+1 during long-segment thoracolumbar arthrodesis surgery. Outcome measures were prospectively collected and uploaded to a web-based REDCap database specifically designed to include demographic, clinical, and radiological data. All patients underwent clinical assessment, as well as radiological assessment with anteroposterior and lateral 36-inch whole-spine standing radiographs both pre- and postoperatively. RESULTS Forty patients (24 women and 16 men) were included in this study. Median age at surgery was 64.0 years with an IQR of 57.7-70.0 years. Median follow-up was 12 months (IQR 6-15 months). Three procedure-related complications were noted, including 2 intraoperative cerebrospinal spinal fluid leaks and 1 transient neurological deficit. Median visual analog scale (VAS) scores for back pain significantly improved after surgery (preoperatively: 8.0, IQR 6.0-10.0; 1-year follow-up: 2.0, IQR 0.0-6.0; p = 0.001). Median Oswestry Disability Index (version 2.1a) scores also significantly improved after surgery (preoperatively: 56.0, IQR 45.0-64.0; 1-year follow-up: 46.0, IQR 22.2-54.0; p < 0.001). Sagittal vertical axis (preoperatively: 9.0 cm, IQR 5.3-11.6 cm; final follow-up: 4.7 cm, IQR 2.0-6.6 cm; p < 0.001), pelvic incidence-lumbar lordosis mismatch (24.7 degrees , IQR 11.2 degrees -31.2 degrees ; 7.7 degrees , IQR -1.2 degrees to 19.5 degrees ; p < 0.001), and pelvic tilt (28.7 degrees , IQR 20.4 degrees -32.6 degrees ; 17.1 degrees , IQR 10.8 degrees -25.2 degrees ; p < 0.001) were all improved at the final follow-up. While proximal junctional (PJ) Cobb angles increased overall at the final follow-up (preoperatively: 4.2 degrees , IQR 1.9 degrees -7.4 degrees ; final follow-up: 8.0 degrees , IQR 5.8 degrees 10.3 degrees ; p = 0.002), the significant increase was primarily noted starting at the immediate postoperative time point (7.2 degrees , IQR 4.4 degrees -11.8 degrees ; p = 0.001) and not beyond. Three patients (7.5%) developed radiological PJK (mean DeltaPJ Cobb 15.5 degrees ), while there were no instances of PJF in this cohort. CONCLUSIONS Sublaminar band placement at the UIV+1 during long segment thoracolumbar instrumented arthrodesis is relatively safe and is not associated with an increased rate of PJK. Moreover, no subjects developed PJF. Prospective large-scale and long-term analysis is needed to define the potential benefit of sublaminar bands in reducing the incidence of PJK and PJF following surgery for ASD. Clinical trial registration no.: NCT02411799 (clinicaltrials.gov). PMID- 29424679 TI - Effects of respite care training on respite provider knowledge and confidence, and outcomes for family caregivers receiving respite services. AB - Respite services are vital in supporting informal caregivers in need of a break from their caregiving duties. A respite training program aimed at developing respite provider competence and improving caregiver well-being was evaluated. Trainees experienced significant growth in their perceived respite knowledge and confidence to deliver respite from pretraining to posttraining. An objective core competency assessment confirmed posttraining knowledge in 10 core areas of respite. Family caregivers provided more favorable ratings on various measures of their well-being while receiving respite from a trained provider compared to before respite began and if respite were to end. Findings suggest that formal training prepares providers to deliver quality respite resulting in improved caregiver outcomes. PMID- 29424680 TI - Web-based alcohol intervention for nightclub patrons: Opposite effects according to baseline alcohol use disorder classification. AB - BACKGROUND: This study aimed to test the effectiveness of a Web-based intervention in preventing alcohol abuse among nightclub patrons. METHODS: A probabilistic sample of the patrons of 31 nightclubs in Sao Paulo, Brazil, was invited to participate in an online screening using the Alcohol Use Disorders Identification Test (AUDIT). A total of 1057 patrons met the inclusion criteria to participate in the randomized controlled trial, with data collection at 0, 3, 6, and 12 months. At baseline, participants were classified into 2 AUDIT score groups: a "high-risk" group (AUDIT >=8; 44%) and a "low-risk" group (AUDIT <8; 56%). In both groups, the intervention subgroup was exposed once to a personalized normative feedback screen with information on the participant's alcohol consumption and its potential consequences. RESULTS: After 12 months, no differences were found between the intervention and the control conditions in either risk group. In the "high-risk" group, there were significant reductions of both the AUDIT score and the prevalence of binge drinking (BD) over time in both the control and the intervention subgroups. In addition, an effect of the intervention was observed at 6 months, i.e., there was an estimated 13% reduction in the AUDIT score in favor of the intervention subgroup (odds ratio [OR] = 0.87; 95% confidence interval [CI]: 0.76, 1.00). In the "low-risk" group, both the control patrons and those receiving the intervention had increased AUDIT scores. CONCLUSION: The results suggest that the time effect of participating in the study may have had a beneficial outcome in reducing harmful drinking among patrons in the "high-risk" group. The intervention is not recommended to the "low risk" group. PMID- 29424681 TI - Social Discrimination and Health Care: A Multidimensional Framework of Experiences among a Low-Income Multiethnic Sample. AB - The study aims to describe the perceived discriminatory health care treatment experiences and its impact on care among minority urban-dwelling adults. Semistructured qualitative interviews (N = 51) were conducted with patients from community-based health care settings, and systematic, grounded theory approach was used. Three distinct themes emerged: (a) the sources of discriminatory experiences, (b) its impact on health care, and (c) the provider/organization recommendations to address discriminatory practices. The study highlights the relevance of perceived discrimination in avoidance of health care services, nonadherence to treatment, and adverse health-related sequelae by low-income urban-dwelling adults with little access to health care. PMID- 29424683 TI - Dynamic sporulation gene co-expression networks for Bacillus subtilis 168 and the food-borne isolate Bacillus amyloliquefaciens: a transcriptomic model. AB - Sporulation is a survival strategy, adapted by bacterial cells in response to harsh environmental adversities. The adaptation potential differs between strains and the variations may arise from differences in gene regulation. Gene networks are a valuable way of studying such regulation processes and establishing associations between genes. We reconstructed and compared sporulation gene co expression networks (GCNs) of the model laboratory strain Bacillus subtilis 168 and the food-borne industrial isolate Bacillus amyloliquefaciens. Transcriptome data obtained from samples of six stages during the sporulation process were used for network inference. Subsequently, a gene set enrichment analysis was performed to compare the reconstructed GCNs of B. subtilis 168 and B. amyloliquefaciens with respect to biological functions, which showed the enriched modules with coherent functional groups associated with sporulation. On basis of the GCNs and time-evolution of differentially expressed genes, we could identify novel candidate genes strongly associated with sporulation in B. subtilis 168 and B. amyloliquefaciens. The GCNs offer a framework for exploring transcription factors, their targets, and co-expressed genes during sporulation. Furthermore, the methodology described here can conveniently be applied to other species or biological processes. PMID- 29424684 TI - Genome analysis of clinical multilocus sequence Type 11 Klebsiella pneumoniae from China. AB - The increasing prevalence of KPC-producing Klebsiella pneumoniae strains in clinical settings has been largely attributed to dissemination of organisms of specific multilocus sequence types, such as ST258 and ST11. Compared with the ST258 clone, which is prevalent in North America and Europe, ST11 is common in China but information regarding its genetic features remains scarce. In this study, we performed detailed genetic characterization of ST11 K. pneumoniae strains by analyzing whole-genome sequences of 58 clinical strains collected from diverse geographic locations in China. The ST11 genomes were found to be highly heterogeneous and clustered into at least three major lineages based on the patterns of single-nucleotide polymorphisms. Exhibiting five different capsular types, these ST11 strains were found to harbor multiple resistance and virulence determinants such as the blaKPC-2 gene, which encodes carbapenemase, and the yersiniabactin-associated virulence genes irp, ybt and fyu. Moreover, genes encoding the virulence factor aerobactin and the regulator of the mucoid phenotype (rmpA) were detectable in six genomes, whereas genes encoding salmochelin were found in three genomes. In conclusion, our data indicated that carriage of a wide range of resistance and virulence genes constitutes the underlying basis of the high level of prevalence of ST11 in clinical settings. Such findings provide insight into the development of novel strategies for prevention, diagnosis and treatment of K. pneumoniae infections. PMID- 29424685 TI - Global morphogenetic flow is accurately predicted by the spatial distribution of myosin motors. AB - During embryogenesis tissue layers undergo morphogenetic flow rearranging and folding into specific shapes. While developmental biology has identified key genes and local cellular processes, global coordination of tissue remodeling at the organ scale remains unclear. Here, we combine in toto light-sheet microscopy of the Drosophila embryo with quantitative analysis and physical modeling to relate cellular flow with the patterns of force generation during the gastrulation process. We find that the complex spatio-temporal flow pattern can be predicted from the measured meso-scale myosin density and anisotropy using a simple, effective viscous model of the tissue, achieving close to 90% accuracy with one time dependent and two constant parameters. Our analysis uncovers the importance of a) spatial modulation of myosin distribution on the scale of the embryo and b) the non-locality of its effect due to mechanical interaction of cells, demonstrating the need for the global perspective in the study of morphogenetic flow. PMID- 29424686 TI - Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages. AB - The glucocorticoid receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis in mouse macrophages reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB-binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class; however, it effects repression by targeting distinct temporal events and components of transcriptional machinery. PMID- 29424687 TI - Architecture of the human mTORC2 core complex. AB - The mammalian target of rapamycin (mTOR) is a key protein kinase controlling cellular metabolism and growth. It is part of the two structurally and functionally distinct multiprotein complexes mTORC1 and mTORC2. Dysregulation of mTOR occurs in diabetes, cancer and neurological disease. We report the architecture of human mTORC2 at intermediate resolution, revealing a conserved binding site for accessory proteins on mTOR and explaining the structural basis for the rapamycin insensitivity of the complex. PMID- 29424688 TI - A sleep state in Drosophila larvae required for neural stem cell proliferation. AB - Sleep during development is involved in refining brain circuitry, but a role for sleep in the earliest periods of nervous system elaboration, when neurons are first being born, has not been explored. Here we identify a sleep state in Drosophila larvae that coincides with a major wave of neurogenesis. Mechanisms controlling larval sleep are partially distinct from adult sleep: octopamine, the Drosophila analog of mammalian norepinephrine, is the major arousal neuromodulator in larvae, but dopamine is not required. Using real-time behavioral monitoring in a closed-loop sleep deprivation system, we find that sleep loss in larvae impairs cell division of neural progenitors. This work establishes a system uniquely suited for studying sleep during nascent periods, and demonstrates that sleep in early life regulates neural stem cell proliferation. PMID- 29424689 TI - Sci-Hub provides access to nearly all scholarly literature. AB - The website Sci-Hub enables users to download PDF versions of scholarly articles, including many articles that are paywalled at their journal's site. Sci-Hub has grown rapidly since its creation in 2011, but the extent of its coverage has been unclear. Here we report that, as of March 2017, Sci-Hub's database contains 68.9% of the 81.6 million scholarly articles registered with Crossref and 85.1% of articles published in toll access journals. We find that coverage varies by discipline and publisher, and that Sci-Hub preferentially covers popular, paywalled content. For toll access articles, we find that Sci-Hub provides greater coverage than the University of Pennsylvania, a major research university in the United States. Green open access to toll access articles via licit services, on the other hand, remains quite limited. Our interactive browser at https://greenelab.github.io/scihu allows users to explore these findings in more detail. For the first time, nearly all scholarly literature is available gratis to anyone with an Internet connection, suggesting the toll access business model may become unsustainable. PMID- 29424690 TI - Dynamics of venom composition across a complex life cycle. AB - Little is known about venom in young developmental stages of animals. The appearance of toxins and stinging cells during early embryonic stages in the sea anemone Nematostella vectensis suggests that venom is already expressed in eggs and larvae of this species. Here, we harness transcriptomic, biochemical and transgenic tools to study venom production dynamics in Nematostella. We find that venom composition and arsenal of toxin-producing cells change dramatically between developmental stages of this species. These findings can be explained by the vastly different interspecific interactions of each life stage, as individuals develop from a miniature non-feeding mobile planula to a larger sessile polyp that predates on other animals and interact differently with predators. Indeed, behavioral assays involving prey, predators and Nematostella are consistent with this hypothesis. Further, the results of this work suggest a much wider and dynamic venom landscape than initially appreciated in animals with a complex life cycle. PMID- 29424691 TI - Pi-Pi contacts are an overlooked protein feature relevant to phase separation. AB - Protein phase separation is implicated in formation of membraneless organelles, signaling puncta and the nuclear pore. Multivalent interactions of modular binding domains and their target motifs can drive phase separation. However, forces promoting the more common phase separation of intrinsically disordered regions are less understood, with suggested roles for multivalent cation-pi, pi pi, and charge interactions and the hydrophobic effect. Known phase-separating proteins are enriched in pi-orbital containing residues and thus we analyzed pi interactions in folded proteins. We found that pi-pi interactions involving non aromatic groups are widespread, underestimated by force-fields used in structure calculations and correlated with solvation and lack of regular secondary structure, properties associated with disordered regions. We present a phase separation predictive algorithm based on pi interaction frequency, highlighting proteins involved in biomaterials and RNA processing. PMID- 29424693 TI - Improved Contrast-Enhanced Ultrasound Imaging With Multiplane-Wave Imaging. AB - Contrast-enhanced ultrasound (CEUS) imaging has great potential for use in new ultrasound clinical applications such as myocardial perfusion imaging and abdominal lesion characterization. In CEUS imaging, contrast agents (i.e., microbubbles) are used to improve contrast between blood and tissue because of their high nonlinearity under low ultrasound pressure. However, the quality of CEUS imaging sometimes suffers from a low signal-to-noise ratio (SNR) in deeper imaging regions when a low mechanical index (MI) is used to avoid microbubble disruption, especially for imaging at off-resonance transmit frequencies. In this paper, we propose a new strategy of combining CEUS sequences with the recently proposed multiplane-wave (MW) compounding method to improve the SNR of CEUS in deeper imaging regions without increasing MI or sacrificing frame rate. The MW CEUS method emits multiple Hadamard-coded CEUS pulses in each transmission event (i.e., pulse-echo event). The received echo signals first undergo fundamental bandpass filtering (i.e., the filter is centered on the transmit frequency) to eliminate the microbubble's second-harmonic signals because they cannot be encoded by pulse inversion. The filtered signals are then Hadamard decoded and realigned in fast time to recover the signals as they would have been obtained using classic CEUS pulses, followed by designed recombination to cancel the linear tissue responses. The MW-CEUS method significantly improved contrast-to tissue ratio and SNR of CEUS imaging by transmitting longer coded pulses. The image resolution was also preserved. The microbubble disruption ratio and motion artifacts in MW-CEUS were similar to those of classic CEUS imaging. In addition, the MW-CEUS sequence can be adapted to other transmission coding formats. These properties of MW-CEUS can potentially facilitate CEUS imaging for many clinical applications, especially assessing deep abdominal organs or the heart. PMID- 29424694 TI - Focused Ultrasound Steering for Harmonic Motion Imaging. AB - Harmonic motion imaging (HMI) is a radiation-force-based ultrasound elasticity imaging technique, which is designed for both tissue relative stiffness imaging and reliable high-intensity focused ultrasound treatment monitoring. The objective of this letter is to develop and demonstrate the feasibility of 2-D focused ultrasound (FUS) beam steering for HMI using a 93-element, FUS phased array. HMI with steered FUS beam was acquired in tissue-mimicking phantoms. The HMI displacement was imaged within the steering range of +/-1.7 mm laterally and +/-2 mm axially. Using the steered FUS beam, HMI can be used to image a larger tissue volume with higher efficiency and without requiring mechanical movement of the transducer. PMID- 29424695 TI - Body Joint Guided 3-D Deep Convolutional Descriptors for Action Recognition. AB - 3-D convolutional neural networks (3-D CNNs) have been established as a powerful tool to simultaneously learn features from both spatial and temporal dimensions, which is suitable to be applied to video-based action recognition. In this paper, we propose not to directly use the activations of fully connected layers of a 3-D CNN as the video feature, but to use selective convolutional layer activations to form a discriminative descriptor for video. It pools the feature on the convolutional layers under the guidance of body joint positions. Two schemes of mapping body joints into convolutional feature maps for pooling are discussed. The body joint positions can be obtained from any off-the-shelf skeleton estimation algorithm. The helpfulness of the body joint guided feature pooling with inaccurate skeleton estimation is systematically evaluated. To make it end to-end and do not rely on any sophisticated body joint detection algorithm, we further propose a two-stream bilinear model which can learn the guidance from the body joints and capture the spatio-temporal features simultaneously. In this model, the body joint guided feature pooling is conveniently formulated as a bilinear product operation. Experimental results on three real-world datasets demonstrate the effectiveness of body joint guided pooling which achieves promising performance. PMID- 29424692 TI - LRRTM1 underlies synaptic convergence in visual thalamus. AB - It has long been thought that the mammalian visual system is organized into parallel pathways, with incoming visual signals being parsed in the retina based on feature (e.g. color, contrast and motion) and then transmitted to the brain in unmixed, feature-specific channels. To faithfully convey feature-specific information from retina to cortex, thalamic relay cells must receive inputs from only a small number of functionally similar retinal ganglion cells. However, recent studies challenged this by revealing substantial levels of retinal convergence onto relay cells. Here, we sought to identify mechanisms responsible for the assembly of such convergence. Using an unbiased transcriptomics approach and targeted mutant mice, we discovered a critical role for the synaptic adhesion molecule Leucine Rich Repeat Transmembrane Neuronal 1 (LRRTM1) in the emergence of retinothalamic convergence. Importantly, LRRTM1 mutant mice display impairment in visual behaviors, suggesting a functional role of retinothalamic convergence in vision. PMID- 29424696 TI - Upper respiratory viral infections in patients with haematological malignancies after allogeneic haematopoietic stem cell transplantation: a retrospective study. AB - BACKGROUND: Community respiratory viruses (CRVs) are associated with upper respiratory viral infections (URI), pneumonia or life-threatening respiratory disease in patients with allogeneic haematopoietic stem cell transplantation (allo-HSCT). Our aim is to demonstrate our URI experience related to CRVs after allo-HSCT. METHODS: From January 2013 to November 2015, 39 post allo-HSCT patients with acute URI symptoms were included in the study. We evaluated CRVs by multiplex PCR from nasopharyngeal wash and throat swabs. RESULTS: The median age of the patients was 39 (range 20-67 years). A total of 25 patients (64%) had viral panel positivity at a median 140 days post-transplant (range 3-617 days). The most common agents detected were respiratory syncytial virus (32%) and parainfluenza (32%). The patients with viral panel positivity had significantly lower lymphocyte count (1.05*109/l versus 3.09*109/l; P=0.013). During follow-up, 20 patients (80%) were diagnosed with pneumonia. Patients with concurrent bacterial or fungal infections were more likely to have pneumonia (100% versus 68%; P=0.023). 10 patients (40%) died due to pneumonia and related complications. Lower lymphocyte counts and higher C-reactive protein levels at the time of viral panel positivity were risk factors for mortality (1.5*109/l versus 0.39*109/l, P=0.007; 74.2 versus 199.7, P=0.006). CONCLUSIONS: The viral panel was positive in 64% of patients with acute URI symptoms. Lower lymphocyte count was detected in CRV-positive patients. The onset of concomitant bacterial or fungal infections increased the risk of lower respiratory infection disease. Indeed, prospective studies should be designed for risks and outcomes of CRVs in allo-HSCT recipients. PMID- 29424698 TI - A promising oral fucoidan-based antithrombotic nanosystem: Development, activity and safety. AB - Fucoidan-loaded nanoparticles emerge as great candidates to oral anticoagulant therapy, due to increasing of bioavailability and circulation time of this natural anticoagulant. Crosslink between chitosan chains are performed using glutaraldehyde to confer higher gastric pH resistance to nanoparticle matrices. In this work, chitosan-fucoidan nanoparticles, without (NpCF) and with glutaraldehyde crosslink (NpCF 1% and NpCF 2%), were prepared to evaluate their anticoagulant, antithrombotic and hemorrhagic profile. Nanoparticles were characterized by average diameter, polydispersity index, zeta potential, Fourier transform infrared spectroscopy and fucoidan in vitro release. Anticoagulant and antithrombotic activities were determined by in vitro and in vivo models, respectively. Hemorrhagic profile was in vivo evaluated by tail bleeding assay. Preparations showed nanometric and homogeneous average diameters. Zeta potentials of NpCF and NpCF 1% were stable over gastrointestinal pH range, which was confirmed by low fucoidan release in gastric and enteric media. In pH 7.4, NpCF and NpCF 1% demonstrated fucoidan release of 65.5% and 60.6%, respectively, within the first 24 hours. In comparison to fucoidan, NpCF and NpCF 1% showed increased in vitro anticoagulant activity. A significant difference on oral antithrombotic profile of NpCF 1% was found in comparison to fucoidan. Bleeding profile of NpCF and NpCF 1% showed no differences to control group, indicating the safety of these systems. Surprisingly, oral antithrombotic profile of commercially available fucoidan, from Fucus vesiculosus, has not been previously determined, which reveals new possibilities. In this work, significant advances were observed in anticoagulant and antithrombotic profiles of fucoidan through the preparation of NpCF 1%. PMID- 29424699 TI - Cube-like Fe3O4@SiO2@Au@Ag magnetic nanoparticles: a highly efficient SERS substrate for detection of pesticide. AB - As a novel SERS nanocomposities, cube-like Fe3O4@SiO2@Au@Ag magnetic nanoparticles have been synthesized for the first time. Cube-like alpha-Fe2O3 NPs with uniform size can be achieved by optimizing reaction temperature and time. Firstly, the cube-like Fe3O4@SiO2 with good dispersity were achieved by calcining alpha-Fe2O3@SiO2 NPs in hydrogen atmosphere at 360 degrees C for 2.5 h, followed by self-assembling PEI shell via sonication. Furthermore, the Au@Ag particles can be densely assembled on the Fe3O4@SiO2 NPs to form the Fe3O4@SiO2@Au@Ag composite structure via strong Ag-N interaction. The obtained nanocomposites exhibit an excellent surface-enhanced Raman (SERS) behavior, reflected from low detection of limit (p-ATP) at 5*10-14 M level. Moreover, these nanocubes are used for detection of thiram and the detection limit can reach up to 5*10-11 M, while the rule of U.S. Environmental Protection Agency specifies that the residue in fruit must be lower than 7 ppm. Hence, the resulting substrate with high SERS activity has great practical potential applications in rapid detection of chemical, biological and environment pollutants with a simple portable Raman instrument at trace level. PMID- 29424697 TI - Patterns of efavirenz use as first-line antiretroviral therapy in the United States: 1999-2015. AB - BACKGROUND: Efavirenz has been a mainstay of antiretroviral therapy (ART) for over 15 years in the US. Its association with neuropsychiatric side effects may influence clinical prescribing and management. METHODS: We included HIV-infected adults enrolled in care at seven sites across the US, who initiated combination ART between 1999 and 2015. We examined the proportion initiating and continuing on efavirenz, overall and by mental health status. Log binomial and Cox models were used to estimate associations between mental health, clinical and sociodemographic characteristics and initiating or switching from efavirenz as first-line ART. RESULTS: Of the 8,230 participants included, 3,710 (45%) initiated efavirenz. In multivariable analyses, prior mono- or dual-ART, ART initiation after 2006, being female, intravenous drug use, antidepressant prescription, previous mental health diagnosis and baseline CD4+ T-cell count >350 cells/mm3 were inversely associated with initiating efavirenz. Participants initiating efavirenz had a faster time to a regimen switch, compared with those initiating an efavirenz-free regimen (P-value <0.01). Among efavirenz initiators, starting efavirenz in more recent time periods and a previous mental health diagnosis were associated with faster time to switching from efavirenz. Despite this, 40-50% of participants with a previous mental health diagnosis initiated and continued on efavirenz for much of the follow-up period. CONCLUSIONS: Multiple clinical factors, including mental health diagnoses, appeared to influence efavirenz use. While mental health diagnosis status and more recent treatment starts were associated with shorter duration of efavirenz therapy, a previous mental health diagnosis did not preclude efavirenz initiation or continuation in many participants. PMID- 29424700 TI - Fabrication of beta-CoV3O8 nanorods embedded in graphene sheets and their application for electrochemical charge storage electrode. AB - The fabrication of beta-CoV3O8 nanorods embedded in graphene sheets and their application as electrochemical charge storage electrodes is reported. From the surfactant treatment of raw graphite, graphene was directly prepared and its nanocomposite with beta-CoV3O8 nanorods distributed between graphene layers (beta CoV3O8-G) was synthesized by a hydrothermal method. When applied as an anode in lithium-ion batteries, the beta-CoV3O8-G anode exhibits greatly improved charge and discharge capacities of 790 and 627 mAh . g-1, respectively, with unexpectedly high initial efficiency of 82%. The observed discharge capacity reflected that at least 3.7 mol of Li+ is selectively accumulated within the beta CoV3O8 phase (LixCoV3O8, x > 3.7), indicative of significantly improved Li+ uptake when compared with aggregated beta-CoV3O8 nanorods. Moreover, very distinct peak plateaus and greatly advanced cycling performance are observed, showing more improved Li+ storage within the beta-CoV3O8 phase. As a supercapacitor electrode, moreover, our composite electrode exhibits very high peak pseudocapacitances of 2.71 F . cm-2 and 433.65 F . g-1 in the beta-CoV3O8 phase with extremely stable cycling performance. This remarkably enhanced performance in the individual electrochemical charge storage electrodes is attributed to the novel phase formation of beta-CoV3O8 and its optimized nanocomposite structure with graphene, which yield fast electrical conduction through graphene, easy accessibility of ions through the open multilayer nanosheet structure, and a relaxation space between the beta-CoV3O8-G. PMID- 29424701 TI - On the physics of dispersive electron transport characteristics in SnO2 nanoparticle-based dye sensitized solar cells. AB - The present study elucidates dispersive electron transport mediated by surface states in tin oxide (SnO2) nanoparticle-based dye sensitized solar cells (DSSCs). Transmission electron microscopic studies on SnO2 show a distribution of ~10 nm particles exhibiting (111) crystal planes with inter-planar spacing of 0.28 nm. The dispersive transport, experienced by photo-generated charge carriers in the bulk of SnO2, is observed to be imposed by trapping and de-trapping processes via SnO2 surface states present close to the band edge. The DSSC exhibits 50% difference in performance observed between the forward (4%) and reverse (6%) scans due to the dispersive transport characteristics of the charge carriers in the bulk of the SnO2. The photo-generated charge carriers are captured and released by the SnO2 surface states that are close to the conduction band-edge resulting in a very significant variation; this is confirmed by the hysteresis observed in the forward and reverse scan current-voltage measurements under AM1.5 illumination. The hysteresis behavior assures that the charge carriers are accumulated in the bulk of electron acceptor due to the trapping, and released by de-trapping mediated by surface states observed during the forward and reverse scan measurements. PMID- 29424702 TI - The effects of nanostructures on the mechanical and tribological properties of TiO2 nanotubes. AB - TiO2 nanotubes were prepared by anodization on Ti substrates with a diameter variation of 30-100 nm, and the structure of the nanotubes were studied using x ray diffraction and Raman spectroscopy, which confirmed the structure changes from the anatase phase to the rutile phase of TiO2 at a diameter below 50 nm. The tribological behaviors of TiO2 nanotubes were investigated with different diameters. The effectiveness of the rutile phase and the diameter size enhanced the frictional performance of TiO2 nanotubes. PMID- 29424703 TI - Temperature effects in contacts between a metal and a semiconductor nanowire near the degenerate doping. AB - We have investigated the nonlinear conductance in diffusion-doped Si:GaAs nanowires contacted by patterned metal films in a wide range of temperatures T. The wire resistance RW and the zero bias resistance RC, dominated by the contacts, exhibit very different responses to temperature changes. While RW shows almost no dependence on T, RC varies by several orders of magnitude as the devices are cooled from room temperature to T= 5 K. We develop a model that employs a sharp donor level very low in the GaAs conduction band and show that our observations are consistent with the model predictions. We then demonstrate that such measurements can be used to estimate carrier properties in nanostructured semiconductors and obtain an estimate for ND, the doping density in our samples. We also discuss the effects of surface states and dielectric confinement on carrier density in semiconductor nanowires. PMID- 29424704 TI - Charge screening-controlled Verwey phase transition in Fe3O4/SrTiO3 heterostructure. AB - Despite intensive investigations on the Verwey phase transition of Fe3O4 over half a century, the mechanism of this phase transition remains controversial and needs further research. In this work, we build the Fe3O4/SrTiO3 multiferroic heterostructure and investigate its temperature dependence of saturation magnetization under various electric fields. It is found that the charge screening effect not only influences the magnetization but also induces the temperature of Verwey phase transition shifting ~13 K. It suggests that the Verwey phase transition has certain correlations with the electron distribution and the change of the number of minority spin electrons in the trimerons plays a dominant role in the temperature shift of phase transition. PMID- 29424705 TI - Effect of heating parameters on sintering behaviors and properties of mullite whisker frameworks. AB - Mullite whisker frameworks were fabricated by vapor-solid reaction with SiO2, Al2O3 and AlF3 powders as the whisker forming agent at high temperatures. The effects of heating temperature and soaking time on the weight loss, liner shrinkage, porosity, microstructure and compressive strength were investigated. The results showed that with the increasing of the sintering temperature and soaking time, the weight loss and liner shrinkage of the samples increased and the porosities decreased due to the accelerated vapor-solid reaction, resulting in strong bonding and grain growth of the mullite frameworks. The compressive strength of the samples increased with increasing the sintering temperature from 1500 to 1650 degrees C, and decreased with the soaking time extended to more than 5 h for 1500 degrees C and 2 h for 1650 degrees C. A maximum compressive strength of 142 MPa at a porosity of 62.3% was obtained for the mullite whisker framework heated at 1500 degrees C for 5 h. The enhanced strength was attributed to the strong bonding strength and fine mullite grains resulting from a relative lower heating temperature and a modest soaking time. PMID- 29424706 TI - Tungsten diselenide for mode-locked erbium-doped fiber lasers with short pulse duration. AB - In this paper, a WSe2 film prepared by chemical vapor deposition (CVD) is transferred onto a tapered fiber, and a WSe2 saturable absorber (SA) is fabricated. In order to measure the third-order optical nonlinearity of the WSe2, the Z-scan technique is applied. The modulation depth of the WSe2 SA is measured as being 21.89%. Taking advantage of the remarkable nonlinear absorption characteristic of the WSe2 SA, a mode-locked erbium-doped fiber laser is demonstrated at 1557.4 nm with a bandwidth of 25.8 nm and signal to noise ratio of 96 dB. To the best of our knowledge, the pulse duration of 163.5 fs is confirmed to be the shortest compared with previous mode-locked fiber lasers based on transition-metal dichalcogenides SAs. These results indicate that WSe2 is a powerful competitor in the application of ultrashort pulse lasers. PMID- 29424707 TI - Quantitative investigation on the critical thickness of the dielectric shell for metallic nanoparticles determined by the plasmon decay length. AB - Inert dielectric shells coating the surface of metallic nanoparticles (NPs) are important for enhancing the NPs' stability, biocompatibility, and realizing targeting detection, but they impair NPs' sensing ability due to the electric fields damping. The dielectric shell not only determines the distance of the analyte from the NP surface, but also affects the field decay. From a practical point of view, it is extremely important to investigate the critical thickness of the shell, beyond which the NPs are no longer able to effectively detect the analytes. The plasmon decay length of the shell-coated NPs determines the critical thickness of the coating layer. Extracting from the exponential fitting results, we quantitatively demonstrate that the critical thickness of the shell exhibits a linear dependence on the NP volume and the dielectric constants of the shell and the surrounding medium, but only with a small variation influenced by the NP shape where the dipole resonance is dominated. We show the critical thickness increases with enlarging the NP sizes, or increasing the dielectric constant differences between the shell and surrounding medium. The findings are essential for applications of shell-coated NPs in plasmonic sensing. PMID- 29424708 TI - Protein coated gold nanoparticles as template for the directed synthesis of highly fluorescent gold nanoclusters. AB - Bovine serum albumin (BSA) modified gold nanoparticles (AuNPs) was selected as template for the synthesis of AuNPs@gold nanoclusters (AuNCs) core/shell nanoparticles, in which BSA not only acted as dual functions agent for both anchoring and reducing Au3+ ions, but also was employed as a bridge between the AuNPs and AuNCs. Optical properties of AuNPs@AuNCs core/shell nanoparticles were studied using UV-visible and fluorescence spectroscopy. The prepared AuNPs@AuNCs core/shell nanoparticles exhibited sphere size uniformity with improved monodispersity, excellent fluorescence and fluorescent stability. Compared with AuNCs, AuNPs@AuNCs core/shell nanoparticles possessed large size and strong fluorescence intensity due to the effect of AuNPs as core. Moreover, the mechanism of the AuNPs induced fluorescence changes of the core/shell nanoparticles was first explored. PMID- 29424709 TI - Influence of experimental parameters on iron oxide nanoparticles properties synthesized by thermal decomposition: size and nuclear magnetic resonance studies. AB - The study of the experimental conditions to synthetize monodisperse iron oxide nanocrystals prepared from the thermal decomposition of iron (III) acetylacetonate in the presence of surfactants and reducing agent was carried out. The influence of temperature, synthesis time and surfactant amounts on nanoparticle properties are reported. This investigation combines the relaxometric characterization and size properties. The relaxometric behavior of nanomaterials depends on the selected experimental parameters. The synthesis of iron oxide nanoparticles with a high relaxivity and a high saturation magnetization can be obtained with a short reaction time at high temperature. Moreover, the influence of surfactant concentrations determines the optimal value in order to produce iron oxide nanoparticles with a narrow size distribution. The optimized synthesis is rapid, robust and reproductive, and produces nearly monodisperse magnetic nanocrystals. PMID- 29424710 TI - Three-dimensional design and fabrication of reduced graphene oxide/polyaniline composite hydrogel electrodes for high performance electrochemical supercapacitors. AB - Graphene/polyaniline composite hydrogels (GH/PANI) were chemically synthesized by in situ polymerization of aniline monomer. Graphene hydrogels were obtained by a hydrothermal method and used in supercapacitors. The graphene/polyaniline composite hydrogel exhibits better electrochemical performance than the pure individual components as determined by cyclic voltammetry (CV), galvanostatic charge-discharge (GCD), and electrochemical impedance spectroscopic measurements. A remarkable specific capacitance (C sp) of 323.9 F g-1 was measured using CV at a scan rate of 2 mV s-1 at 25 degrees C. GCD measurements (311.3 F g-1) and electrochemical impedance analysis also support these results. The numbers were obtained at extremely high loading masses: 7.14 mg cm-2 for GH and GH/PANI synthesized at 0 degrees C, and 8.93 mg cm-2 for GH/PANI synthesized at 25 degrees C. The corresponding areal capacitances are 1.14, 1.75 and 2.78 F cm-2 for GH, and GH/PANI composite hydrogels synthesized at 0 degrees C and 25 degrees C, respectively. These values in F cm-2 are 3.80, 5.83 and 9.27 times higher than commercially available activated carbon supercapacitors (~0.3 F cm-2 for a two electrode system). Moreover, the GH/PANI composite synthesized at 25 degrees C exhibits excellent stability with 99% initial capacitance retention after 1000 charge/discharge cycles. GH/PANI composites synthesized at 0 degrees C and 25 degrees C therefore hold promise for use in supercapacitor device applications. PMID- 29424712 TI - Iron-filled multi-walled carbon nanotubes for terahertz applications: effects of interfacial polarization, screening and anisotropy. AB - Interface interactions in multicomponent nanoparticles can affect electromagnetic properties of an absorbing system. In this work, we investigate the electromagnetic response of multi-walled carbon nanotubes (MWCNTs) filled with iron-containing nanoparticles (ICNs) in the terahertz frequency range. MWCNTs with different iron content have been synthesized by aerosol-assisted catalytic chemical vapour deposition method from toluene containing a certain quantity of ferrocene used as a catalyst. According to the x-ray diffraction analysis, encapsulated ICNs were mainly in the form of iron carbide. Thin composite films were prepared from the iron-filled MWCNTs and polymethylmethacrylate (PMMA) by casting and stretching methods. The composites showed an enhanced permittivity and anisotropy in the transmittance spectra when iron content increased. This behaviour was related to the mechanism based on electrical conductivity and polarization of ICNs and ICN/MWCNT interfaces. Since terahertz field penetrates inside MWCNTs, the filling of their cavities can be a way of varying the electromagnetic properties of MWCNT-containing composites. PMID- 29424711 TI - Using the cavitation collapse time to indicate the extent of histotripsy-induced tissue fractionation. AB - Histotripsy is an ultrasonic tissue ablation method based on acoustic cavitation. It has been shown that cavitation dynamics change depending on the mechanical properties of the host medium. During histotripsy treatment, the target-tissue is gradually fractionated and eventually liquefied to acellular homogenate. In this study, the change in the collapse time (t col) of the cavitation bubble cloud over the course of histotripsy treatment is investigated as an indicator for progression of the tissue fractionation process throughout treatment. A 500 kHz histotripsy transducer is used to generate single-location lesions within tissue mimicking agar phantoms of varying stiffness levels as well as ex vivo bovine liver samples. Cavitation collapse signals are acquired with broadband hydrophones, and cavitation is imaged optically using a high-speed camera in transparent tissue-mimicking phantoms. The high-speed-camera-acquired measurements of t col validate the acoustic hydrophone measurements. Increases in t col are observed both with decreasing phantom stiffness and throughout histotripsy treatment with increasing number of pulses applied. The increasing trend of t col throughout the histotripsy treatment correlates well with the progression of lesion formation generated in tissue-mimicking phantoms (R 2 = 0.87). Finally, the increasing trend of t col over the histotripsy treatment is validated in ex vivo bovine liver. PMID- 29424713 TI - Do natural spring waters in Australia and New Zealand affect health? A systematic review. AB - Therapeutic use of spring waters has a recorded history dating back to at least 1550 BC and includes both bathing in and drinking such waters for their healing properties. In Australia and New Zealand the use of therapeutic spring waters is a much more recent phenomenon, becoming a source of health tourism from the late 1800s. We conducted a systematic review aimed at determining the potential health outcomes relating to exposure to Australian or New Zealand natural spring water. We found only low-level evidence of adverse health outcomes relating to this spring water exposure, including fatalities from hydrogen sulphide poisoning, drowning and primary amoebic meningoencephalitis. We found no studies that investigated the therapeutic use of these waters, compared with similar treatment with other types of water. From the broader literature, recommendations have been made, including fencing potentially harmful spring water, and having signage and media messages to highlight the potential harms from spring water exposure and how to mitigate the risks (e.g. not putting your head under water from geothermal springs). Sound research into the potential health benefits of Australian and New Zealand spring waters could provide an evidence base for the growing wellness tourism industry. PMID- 29424715 TI - Evaluation of a most probable number method for the enumeration of Legionella pneumophila from North American potable and nonpotable water samples. AB - This study compares the performance of a novel most probable number (MPN) method (LegiolertTM/Quanti-Tray(r)) with Standard Methods for the Examination of Water and Wastewater 9260 J for the enumeration of Legionella pneumophila from potable and nonpotable waters. Data from the study showed that Legiolert exhibited higher sensitivity for the detection of L. pneumophila for potable water and equivalent sensitivity for nonpotable water. The Legiolert medium had a high specificity with no false positive signals reported for either water type. The new method represents a significant improvement in usability and accuracy in the enumeration of L. pneumophila. PMID- 29424714 TI - A systematic literature review of the enabling environment elements to improve implementation of water safety plans in high-income countries. AB - Effective risk management helps ensure safe drinking water and protect public health. Even in high-income countries, risk management sometimes fails and waterborne disease, including outbreaks, occur. To help reduce waterborne disease, the WHO Guidelines for Drinking Water Quality recommend water safety plans (WSPs), a systematic preventive risk management strategy applied from catchment to consumer. Since the introduction of WSPs, international guidelines, national and state legislation, and local practices have facilitated their implementation. While various high-income OECD countries have documented successes in improving drinking water safety through implementing WSPs, others have little experience. This review synthesizes the elements of the enabling environment that promoted the implementation of WSPs in high-income countries. We show that guidelines, regulations, tools and resources, public health support, and context-specific evidence of the feasibility and benefits of WSPs are elements of the enabling environment that encourage adoption and implementation of WSPs in high-income countries. These findings contribute to understanding the ways in which to increase the uptake and extent of WSPs throughout high-income countries to help improve public health. PMID- 29424716 TI - Soil-transmitted helminth eggs assessment in wastewater in an urban area in India. AB - Water quality and sanitation are inextricably linked to prevalence and control of soil-transmitted helminth infections, a public health concern in resource-limited settings. India bears a large burden of disease associated with poor sanitation. Transformative onsite sanitation technologies are being developed that feature elimination of pathogens including helminth eggs in wastewater treatment. We are conducting third-party testing of multiple sanitation technology systems in Coimbatore (Tamil Nadu) India. To ensure stringent testing of the pathogen removal ability of sanitation technologies, the presence of helminth eggs in wastewater across the town of Coimbatore was assessed. Wastewater samples from existing test sites as well as desludging trucks servicing residential and non residential septic tanks, were collected. The AmBic methodology (based on washing, sieving, sedimenting and floating) was used for helminth egg isolation. We tested 29 different source samples and found a 52% prevalence of potentially infective helminth eggs. Identification and enumeration of helminth species is reported against the septage source (private residential vs. shared toilet facility) and total solids content. Trichuris egg counts were higher than those of hookworm and Ascaris from desludging trucks, whereas hookworm egg counts were higher in fresh wastewater samples. Surprisingly, no correlation between soil transmitted helminth eggs and total solids was observed. PMID- 29424717 TI - Presence of Waddlia chondrophila in hot water systems from non-domestic buildings in France. AB - The presence of Waddlia chondrophila has been related to respiratory tract infections and human and animal fetal death. Although several sources of infection have been suggested, the actual source remains unknown and limited information exists on the prevalence of W. chondrophila in the environment. This pathogen has been previously detected in well water but its presence has not been confirmed in water networks. Since these bacteria have been detected in water reservoirs, it has been hypothesized that they can access artificial water systems and survive until they find appropriate conditions to proliferate. In this work, their presence in water samples from 19 non-domestic water networks was tested by quantitative polymerase chain reaction (qPCR). Approximately half of the networks (47%) were positive for W. chondrophila and the overall results revealed 20% positive samples (12/59). Furthermore, most of the samples showed low concentrations of the pathogen (<200 genomic units/L). This finding demonstrates that W. chondrophila can colonize some water networks. Therefore, they must be considered as potential infection sources in future epidemiological studies. PMID- 29424718 TI - Caries affected by calcium and fluoride in drinking water and family income. AB - Water quality and socioeconomics influence caries in populations. This study broadens previous studies on how caries is associated with fluoride and calcium in drinking water and with family income by quantifying the combined effect of the three independent variables. The effects of calcium and fluoride can be described as independent effects of the two ions or, alternatively, in the form of saturation with respect to fluorite (CaF2). A general linear model describes this relationship with high significance and the model confirms the important protective effect of calcium and fluoride, independently against caries. From the model, the relative importance of fluoride and calcium to protect against caries is quantified. The relationship between caries and family income is also highly significant. It is illustrated how the linear model can be applied in planning and analyzing drinking water softening in relation to caries. PMID- 29424719 TI - Isolation, molecular characterization, and antibiotic resistance patterns of Vibrio parahaemolyticus isolated from coastal water in the Eastern Province of Saudi Arabia. PMID- 29424720 TI - The effect of sodium thiosulfate dechlorination on fecal indicator bacteria enumeration: laboratory and field data. AB - In microbiological water quality testing, sample dechlorination with sodium thiosulfate is recommended to ensure that results accurately reflect the water quality at sample collection. Nevertheless, monitoring institutions in low resource settings do not always dechlorinate samples, and there is limited research describing how this practice impacts drinking water quality results. The effect of dechlorination on indicator bacteria counts was evaluated by spiking laboratory water with five Escherichia coli (E. coli) concentrations (104-108 CFU/100 mL), chlorinating at six doses (0-0.6 mg/L), holding samples with and without sodium thiosulfate for 5-7 hours, and enumerating E. coli by membrane filtration with m-lauryl sulfate media. Additionally, sub-Saharan African water suppliers enumerated thermotolerant coliform by membrane filtration in paired chlorinated water samples collected with and without sodium thiosulfate. Across all E. coli and chlorine doses in the laboratory, and all field tests, samples held without sodium thiosulfate had lower bacteria counts (p < 0.001). Additionally, chlorinated water supply samples held without sodium thiosulfate had an 87.5% false negative rate. Results indicate the importance of dechlorinating microbiological water quality samples, discarding data from chlorinated samples collected without dechlorination, and reinforcing dechlorination recommendations in resource-limited environments to improve water safety management. PMID- 29424721 TI - Season matters when sampling streams for swine CAFO waste pollution impacts. AB - Concentrated (or confined) animal feed operations (CAFOs) are the principal means of livestock production in the United States, and such facilities pollute nearby waterways because of their waste management practices; CAFO waste is pumped from the confinement structure into a cesspit and sprayed on a field. Stocking Head Creek is located in eastern North Carolina, a state with >9,000,000 head of swine confined in CAFOs. This watershed contains 40 swine CAFOs; stream water quality was investigated at seven sites during 2016, with five sampling dates in early spring and five in summer. Geometric mean fecal coliform counts were in the thousands/100 mL at five sites in spring and all seven sites in summer. Excessive nitrate pollution was widespread with concentrations up to >11.0 mg N/L. Seasonality played an important role in pollutant concentrations. In North Carolina, spraying animal waste on adjoining fields is permissible from March 1 through September 30. Seasonal data showed significantly higher (p < 0.01) concentrations of conductivity, nitrate, total nitrogen, total organic carbon, and fecal bacteria in summer as opposed to early spring. Thus, sampling performed only in winter-early spring would significantly underestimate impacts from swine CAFO spray fields on nearby waterways. PMID- 29424722 TI - Pool water quality and prevalence of microbes in filter backwash from metro Atlanta swimming pools. AB - During the 2012 summer swim season, aquatic venue data and filter backwash samples were collected from 127 metro-Atlanta pools. Last-recorded water chemistry measures indicated 98% (157/161) of samples were from pools with >=1 mg/L residual chlorine without stabilized chlorine or >=2 mg/L with stabilized chlorine and 89% (144/161) had pH readings 7.2-7.8. These water quality parameters are consistent with the 2016 Model Aquatic Health Code (2nd edition) recommendations. We used previously validated real-time polymerase chain reaction assays for detection of seven enteric microbes, including Escherichia coli, and Pseudomonas aeruginosa. E. coli was detected in 58% (93/161) of samples, signifying that swimmers likely introduced fecal material into pool water. P. aeruginosa was detected in 59% (95/161) of samples, indicating contamination from swimmers or biofilm growth on surfaces. Cryptosporidium spp. and Giardia duodenalis were each detected in approximately 1% of samples. These findings indicate the need for aquatics staff, state and local environmental health practitioners, and swimmers to each take steps to minimize the risk of transmission of infectious pathogens. PMID- 29424723 TI - Assessing the spatial pattern of iron in well water from a small central Florida community. AB - Iron is one of the most common elements in the Earth's crust, which corresponds to it being a common constituent in drinking water supplies. Residents of Bithlo, an unincorporated community in east-central Florida, have observed that their drinking water tastes like metal and stains clothing and teeth. An evaluation of water samples collected from over 200 private drinking water wells revealed iron concentrations that exceeded the US Environmental Protection Agency's (EPA's) secondary standard of 0.3 mg/L. Households with and without point-of-entry treatment were found to have over three times (0.92 mg/L) and ten times (3.86 mg/L) more iron than the EPA's secondary standard, respectively. The human health based threshold of 4.2 mg/L established by the Centers for Disease Control and Prevention was exceeded in 38.6% of untreated residences. Community-wide statistical and spatial water-quality trends were developed by combining the collected well water quality data with historically available water quality reports. Spatial analyses revealed that greater than 99% of the Bithlo community's private household supplies would exceed the EPA's drinking water secondary standard. PMID- 29424724 TI - Assessment of diversity of adenovirus DNA polymerase gene in recreational waters facilitated by ultracentrifugal concentration. AB - Adenoviruses (AdV) are related to respiratory and gastrointestinal diseases in animals and human beings. Their wide genetic diversity in water bodies and their resistance to environmental conditions allow the use of AdV as a reliable marker for detection of fecal contamination. In this work, the diversity of AdV along Belo Stream - in the city of Caxias do Sul, Rio Grande do Sul, Brazil - was evaluated. Samples were compared in both concentrated and unconcentrated forms. The identification of different AdV species was performed by amplifying a partial sequence of the DNA polymerase gene. AdV was detected in 24 out of 55 concentrated samples (43.6%) and the following species were identified: human adenovirus (HAdV) species C (4/55; 7.2%), D (6/55; 10.9%), E (2/55; 3.6%), and F (9/55; 16.3%). AdV related to other mammalian hosts, such as bovine adenovirus (1/55, 1.8%) and murine adenovirus (2/55, 3.6%), have also been identified; 23.6% (13/55) of the unconcentrated samples were positive, and identified as HAdV species C (6/55, 10.9%), D (1/55, 1.8%), and F (6/55, 10.9%). Results obtained evidenced the presence and the great diversity of AdV, mainly of human origin, circulating in Belo Stream. As expected, the concentration step performed helped to detect AdV in more samples. PMID- 29424725 TI - Sodium hypochlorite dosage for household and emergency water treatment: updated recommendations. AB - Household water treatment with chlorine can improve the microbiological quality of household water and reduce diarrheal disease. We conducted laboratory and field studies to inform chlorine dosage recommendations. In the laboratory, reactors of varying turbidity (10-300 NTU) and total organic carbon (0-25 mg/L addition) were created, spiked with Escherichia coli, and dosed with 3.75 mg/L sodium hypochlorite. All reactors had >4 log reduction of E. coli 24 hours after chlorine addition. In the field, we tested 158 sources in 22 countries for chlorine demand. A 1.88 mg/L dosage for water from improved sources of <5 or <10 NTU turbidity met free chlorine residual criteria (<=2.0 mg/L at 1 hour, >=0.2 mg/L at 24 hours) 91-94% and 82-87% of the time at 8 and 24 hours, respectively. In unimproved water source samples, a 3.75 mg/L dosage met relaxed criteria (<=4.0 mg/L at 1 hour, >=0.2 mg/L after 24 hours) 83% and 65% of the time after 8 and 24 hours, respectively. We recommend water from improved/low turbidity sources be dosed at 1.88 mg/L and used within 24 hours, and from unimproved/higher turbidity sources be dosed at 3.75 mg/L and consumed within 8 hours. Further research on field effectiveness of chlorination is recommended. PMID- 29424726 TI - Inhibition of Daphnia magna's occurrence in drinking water treatment process by controlling its phototactic behavior. AB - Cladocera zooplankton as carriers of bacteria result in biological risk due to their occurrence in drinking water treatment systems. In this paper, bench-scale experiments were performed to investigate the inhibition effect on Daphnia magna (D. magna) by controlling its phototactic behavior. The results showed that UVA had a negative effect on the phototaxis of D. magna, indicating an active movement away from light source, while blue light was positive in inducing phototactic behavior. The water quality could influence the phototactic behavior of D. magna. When the turbidity value was higher than 10 NTU or total organic carbon (TOC) concentration was beyond 4 mg/L, the phototaxis of D. magna to UVA (25 MUw/cm2 intensity) or blue light (1,000 Lux intensity) was significantly weakened. It was difficult for D. magna to offset the effect of water flow by its phototactic movement when the flow rate was higher than 10 mm/s. According to the above results, with suitable process parameters in full-scale experiments, the occurrence of D. magna in the effluent of sedimentation tank and activated carbon filter was obviously inhibited by the UVA irradiation and blue light induction, respectively. PMID- 29424727 TI - Microbial source tracking in highly vulnerable karst drinking water resources. AB - Water resources situated in areas with underlying karst geology are particularly vulnerable to fecal pollution. In such vulnerable systems, microbial source tracking (MST) methods are useful tools to elucidate the pathways of both animal and human fecal pollution, leading to more accurate water use risk assessments. Here, we describe the application of a MST toolbox using both culture-dependent bacteriophage and molecular-dependent 16S rRNA assays at spring and well sites in the karstic St Imier Valley, Switzerland. Culture-dependent and molecular dependent marker performance varied significantly, with the 16S rRNA assays displaying greater sensitivity than their phage counterpart; HF183 was the best performing human wastewater-associated marker while Rum2Bac was the best performing ruminant marker. Differences were observed in pollution regimes between the well and spring sampling sites, with the spring water being more degraded than the well site. Our results inform the choice of marker selection for MST studies and highlight differences in microbial water quality between well and spring karst sites. PMID- 29424728 TI - The role of chemical products at low doses in preventing the proliferation of bacteria in dental unit waterlines: the ICX(r) experience. AB - In this study we evaluated (1) the efficacy of a protocol that combines hydrogen peroxide (shock treatment) and ICX(r) tablets (continuous treatment) for the control of microbial contamination in dental unit water lines, and (2) the in vitro antimicrobial activity of ICX(r) tablets on collection and wild strains isolated from dental chair output waters. To assess the treatment effectiveness, the microbial load in the output water samples of three dental chairs were investigated: one control chair received only shock treatment. In vitro bactericidal activity was tested against Staphylococcus aureus and Pseudomonas aeruginosa. Data obtained from samples collected from chairs treated with ICX(r) and shock treatment and data from the control chair did not differ significantly on the basis of microbial load. In the in vitro study, the product was unable to kill Gram-negative bacteria. These results show that the continuous introduction of ICX(r) was not effective in maintaining low counts of the heterotrophic bacteria in the output water of dental devices, and shock treatment may be needed more frequently than monthly. PMID- 29424729 TI - Sorbent-embedded sheets for safe drinking water in developing countries: a case study of lead(II) removal by a zeolite-embedded sheet. AB - Although many kinds of materials for water purification are known, easy-to-use methods that ensure the safety of drinking water for rural populations are not sufficiently available. Sorbent-embedded sheets provide methods for the easy removal of contaminants from drinking water in the home. As an example of such a sorbent-embedded sheet, we prepared a Linde type A (LTA) zeolite-embedded sheet (ZES) and examined its Pb(II) removal behaviour. Different amounts of LTA were added either as powder or as ZES to 0.3 mM Pb(NO3)2 solutions containing 2.5 mM Ca(NO3)2, in which the ratio of the negative charges in LTA to the positive charges in Pb(II) (LTA/Pb ratio) ranged from 1 to 20. After shaking, the mixtures were centrifuged to remove the powder, while the ZES was simply removed from the mixture by hand. The LTA powder removed more than 99% of the Pb(II) from the solution at all LTA/Pb ratios within 1 h, while the ZES removed >99% of the Pb(II) at LTA/Pb ratios of 2 and higher; at the highest LTA/Pb ratio of 20, the ZES removed >99% of the Pb(II) in 30 s. Therefore, the use of appropriate sorbent embedded sheets enable the facile removal of contaminants from water. PMID- 29424730 TI - First reported isolation of an emerging opportunistic pathogen (Elizabethkingia anophelis) from hospital water systems in Greece. AB - After the Elizabethkingia anophelis outbreak in Wisconsin, USA, an active search for the detection of the microorganism in hospital water systems from Central and Northern Greece was performed from June to December 2016. In total, 457 water samples from 11 hospitals were analyzed. Elizabethkingia spp. was detected in three samples collected from two hospitals, both of which are located in Northern Greece. Two of the three isolated strains were identified as Elizabethkingia anophelis. No cases of Elizabethkingia infection were reported in either hospital during 2016. This is the first reported isolation of the pathogen in water supply systems in Greece. PMID- 29424732 TI - Comment on "Association between CYP2C19 and ABCB1 polymorphisms and clopidogrel resistance in clopidogrel-treated Chinese patients". PMID- 29424731 TI - Efficacy of cardiac shock wave therapy in patients with stable angina: The design of randomized, triple blind, sham-procedure controlled study. AB - OBJECTIVE: Despite revascularization and optimal medical treatment (OMT), patients with angina often have a reduced quality of life due to inadequate relief from symptoms. Recent studies have shown that the application of shock waves may reduce angina symptoms and improve quality of life, exercise capacity, and myocardial perfusion due to the stimulation of angiogenesis. However, there is limited evidence due to small, single-arm, single-center studies of low to moderate quality. The purpose of this study is to evaluate the impact of cardiac shock wave therapy (CSWT) on exercise tolerance and angina symptoms in patients with coronary artery disease and objective evidence of myocardial ischemia who cannot undergo traditional revascularization and experience angina despite OMT in comparison to sham procedure. METHODS: We designed a randomized, triple-blind, placebo-controlled, multicentre trial (NCT02339454) to assess the efficacy of CSWT in addition to OMT in patients with stable angina and myocardial ischemia documented by exercise treadmill test (ETT). All patients were treated with stable doses of standard medical treatment 4 weeks before screening. An increase in the total exercise duration on ETT by >=90 s from the baseline at the end of the study was set as the primary endpoint. Secondary endpoints included angina class, Seattle angina questionnaire scores, symptoms, and ECG changes during stress test. Patients underwent nine sessions of CSWT or corresponding sham procedure applied to all segments of the left ventricle, within 9 weeks. Endpoint assessments were performed at 6-month follow-up. The imaging substudies assessed the potential of CSWT to reduce stress-induced myocardial ischemia detected by dobutamine stress echocardiography, cardiac single-photon emission computed tomography, and cardiac magnetic resonance imaging. RESULTS: At two centers, 72 of the 323 screened patients were randomized in two groups (ratio 1:1): active treatment and placebo control. Study patients were predominantly males (70.8%); the mean age of the patients was 68.4+/-8.3 years. Of these, 44 patients had angina Canadian Cardiovascular Society class III, and 66.7% of the patients had a history of myocardial infarction. CONCLUSION: Using sham applicators, blinding study participants, investigators, and endpoints assessors to the study data as well as centralized randomization ensures rigorous methodology and low risk of bias in this large randomized controlled CSWT study. PMID- 29424733 TI - Decreased FENDRR and LincRNA-p21 expression in atherosclerotic plaque. AB - OBJECTIVE: Cardiovascular diseases are the most important cause of mortality worldwide, particularly atherosclerosis. Recently, lncRNAs affecting atherosclerotic progression have been reported in vascular smooth muscle cells, endothelial cells, and monocytes, suggesting that lncRNAs play an important role in atherosclerosis. METHODS: In recent clinical studies, nowadays, it was determined that internal mammary bypass grafts are closest to ideal grafts in coronary artery bypass surgery. In this study, we used tissue samples taken from atherosclerotic coronary arteries and the internal mammary artery (IMA) during coronary artery bypass surgery. Using RT-PCR, we investigated the role of two lncRNAs, FENDRR and LincRNA-p21, by comparing their expression levels in coronary artery plaques and normal mammary arteries of 20 atherosclerotic patients. RESULTS: We found that the FENDRR and LincRNA-p21 expressions decreased by approximately 2 and 7 fold in coronary artery plaques, respectively, compared with those in IMA, which is known to have no plaque development. CONCLUSION: This study was the first to use mammary artery tissues of the same patients as a control and to study FENDRR expression. Our data may provide helpful insights regarding the association of lncRNAs and atherosclerosis. PMID- 29424734 TI - What we have learned from the European Heart Rhythm Association consensus document on device-detected subclinical atrial tachyarrhythmias. AB - Although various cardiac monitoring methods were developed to detect subclinical arrhythmias, guidelines do not address in detail the management of subclinical atrial fibrillation and tachyarrhythmias. The European Heart Rhythm Association recently published a consensus document that addresses the clinical importance, implications, and management of device-detected subclinical atrial tachyarrhythmias. This paper comprehensively reviews the diagnostic tools to detect subclinical atrial arrhythmias and discusses the pathophysiologic link between devicedetected subclinical atrial fibrillation and stroke. In this invited review, in the light of this paper and current scientific data, we aimed to summarize how to manage subclinical atrial arrhythmias. PMID- 29424736 TI - Management of scar-related atrial flutter in a patient with dextrocardia, inferior vena cava interruption, and azygos continuation. PMID- 29424735 TI - MicroRNAs in acute myocardial infarction: Evident value as novel biomarkers? AB - Traditional circulating biomarkers play a fundamental role in the diagnosis and prognosis of acute myocardial infarction (AMI). However, they have several limitations. microRNAs (miRs), a class of RNA molecules that do not encode proteins, function directly at the RNA level by inhibiting the translation of messenger RNAs. Due to their significant roles in disease development, they can be used as biomarkers. Accumulating evidence has revealed an attractive role of miRs as biomarkers of AMI and its associated symptoms, including vulnerable atherosclerotic plaques, and their role in disease diagnosis, platelet activation monitoring, and prognostic outcome prediction. This manuscript will highlight the recent updates regarding the involvement of miRs as biomarkers in AMI and emphasize their value in vulnerable atherosclerotic plaque prediction and monitoring of platelet activation. PMID- 29424737 TI - Catheter ablation of manifest posteroseptal accessory pathway associated with coronary sinus diverticula in a child with congenitally corrected transposition of the great arteries. PMID- 29424738 TI - Lead extraction: Definition standards. PMID- 29424739 TI - Author's Reply. PMID- 29424740 TI - Lead extraction and contrast venography. PMID- 29424741 TI - Author's Reply. PMID- 29424742 TI - Contrast-induced acute kidney injury/ contrast-induced nephropathy may be related to additional risk factors. PMID- 29424743 TI - Author's Reply. PMID- 29424744 TI - An unusual complication during reimplantation of implantable cardioverter defibrillator (ICD) after ICD leads extraction: Distal migration of anchoring sleeve. PMID- 29424745 TI - Ten years' clinical experience of cardiac myxoma: diagnosis, treatment, and clinical outcomes. PMID- 29424746 TI - Sudden cardiac death in physicians: an alarming problem in China. PMID- 29424747 TI - Functional paraganglioma in the right atrium. PMID- 29424748 TI - Spontaneous giant pseudoaneurysm in the upper segment of the aortic arch. PMID- 29424749 TI - An unusual cause of aortic regurgitation: accessory mitral valve. PMID- 29424750 TI - New Term. PMID- 29424751 TI - Lack of association of tumor necrosis factor superfamily member 4 (TNFSF4) gene polymorphisms (rs3850641 and rs17568) with coronary heart disease and stroke: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the association between the tumor necrosis factor superfamily member 4 (TNFSF4) gene polymorphisms and common cardiovascular and cerebrovascular diseases. METHODS: A literature-based search was conducted through databases including PubMed, EMBASE, Cochrane Library, CNKI, and WanFang data. Crude odds ratios (ORs) and 95% confidence intervals (CI) were calculated to estimate the strength of the association between TNFSF4 polymorphisms (rs3850641 and rs17568) and the risk of coronary heart disease (CHD) and stroke. RESULTS: Overall, 11 eligible studies were included in this meta-analysis. G allele was showed not to be associated with CHD and stroke, compared with A allele (rs3850641: OR=1.02, 95% CI=0.89-1.17; rs17568: OR=1.09, 95% CI=0.89 1.33). Genotypic analysis demonstrated that there was no significant association between the risk of CHD and stroke and rs3850641 [homozygous comparison (GG vs. AA): OR=1.05, 95% CI=0.74-1.50; heterozygous comparison (GA vs. AA): OR=1.00, 95% CI=0.88-1.13; recessive model (GG vs. GA+AA): OR=1.04, 95% CI=0.76-1.43; dominant model (GG+GA vs. AA): OR=1.01, 95% CI=0.88-1.17]. Similarly, no susceptibility between CHD and stroke and rs17568 polymorphism was uncovered (GG vs. AA: OR=1.04, 95% CI=0.74-1.46; GA vs. AA: OR=1.07, 95% CI=0.62-1.83; GG+GA vs. AA: OR=1.13, 95% CI=0.82-1.56; GG vs. GA+AA: OR=1.01, 95% CI=0.74-1.39). CONCLUSION: The present study demonstrated that there is no significant relationship between TNFSF4 gene polymorphism and cerebrovascular and cardiovascular diseases. PMID- 29424752 TI - CE: Original Research: An Investigation into the Safety of Oral Intake During Labor. AB - : : Purpose: The purpose of this study was to compare the maternal and neonatal outcomes among laboring women permitted ad lib oral intake with those permitted nothing by mouth except for ice chips. DESIGN: This was a quantitative retrospective observational cross-sectional study. SAMPLE: The initial data set consisted of all closed medical records for 2,817 women who were admitted to a suburban community hospital in the northeastern United States between January 2008 and December 2012. Some subjects' records were missing either covariate data or outcomes data, resulting in final sample sizes of 2,797 women (for comparison across covariates) and 2,784 women (for comparison across outcomes). METHODS: A deidentified limited data set was extracted from the electronic health record for descriptive and inferential comparisons between groups. Demographics and maternal comorbidities present on admission were compared between groups before data analysis. Outcome comparisons were obtained with traditional between-groups analysis and propensity score matching. RESULTS: The groups were found to be sufficiently equivalent for comparison. The group permitted nothing by mouth was significantly more likely to have unplanned cesarean section births than the group permitted ad lib oral intake. There were no significant differences in unplanned maternal ICU admissions postpartum, in neonate condition as determined by Apgar scores, or in the need for a higher level of care. Allowing women ad lib oral intake during labor caused no increase in morbidity, and there were no mortalities in either group. CONCLUSION: Allowing women ad lib oral intake during labor does not increase adverse maternal or neonatal outcomes. It stands to reason that allowing such intake could increase patient satisfaction. Further study is needed to determine what types of food and drink are most beneficial as well as what types are preferred. PMID- 29424753 TI - CE: Malnutrition in Older Adults. AB - : Older adults are at risk for compromised nutritional status because of physical changes associated with aging, as well as cognitive, psychological, and social factors such as dementia, depression, isolation, and limited income. Malnutrition negatively affects quality of life, increases health care costs, and increases the risk of short-term mortality. Nurses and other members of interdisciplinary health care teams play important roles in preventing malnutrition in community dwelling older adults and in older adults in long-term care settings. This article provides an overview of screening tools and interventions nurses can use to minimize the risk of malnutrition in older adults. PMID- 29424754 TI - Inaccurate data in meta-analysis 'Dietary patterns and colorectal cancer risk: a meta-analysis'. PMID- 29424755 TI - The Accuracy of Portable Ultrasound Bladder Scanner Measurements of Postvoid Residual Volume in Women With Pelvic Organ Prolapse. AB - OBJECTIVES: The purpose of this study was to evaluate the accuracy of portable bladder scanner postvoid residual (PVR) volume measurements in patients with pelvic organ prolapse. A secondary goal was to determine whether covariates such as bladder volume and stage of prolapse affect bladder scanner accuracy. STUDY DESIGN: Complex urodynamic studies were performed on 70 patients with stage II or greater prolapse. Complex urodynamic studies included measurement of maximum bladder capacity (MBC) as well as measurement of PVR by urethral catheterization before, and following, complex filling cystometry. For each catheterized PVR, a corresponding bladder scanner measurement was obtained; the primary outcome was the difference between these measurements. In addition, bladder scanner measurements of MBC were compared with MBC by urodynamic pump. Measurements were compared by paired t test. Linear regression was used to assess association between covariates and bladder scanner error. RESULTS: There was no significant difference between catheter and bladder scanner PVR at the initial (mean difference, 5.94 mL; 95% confidence interval [CI], -3.8 to 15.7) or final (mean difference, 1.37 mL; 95% CI, -10.9 to 13.6) measurements. Maximum bladder capacity measurements by bladder scanner were significantly smaller than catheterized measurements (mean difference, -21.3 mL; 95% CI, -40.3 to -2.3). Stage III/IV prolapse was associated with increased bladder scanner error (P = 0.03). CONCLUSIONS: The portable bladder scanner accurately measures PVR in patients with pelvic organ prolapse and could be considered as an alternative to catheterized assessment. However, stage III/IV prolapse is associated with increased bladder scanner error, which should be considered when determining appropriate candidates for bladder scanner PVR assessment.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29424756 TI - Pazopanib-Associated Transient Ischemic Attack. PMID- 29424757 TI - Survey of Core Trainees' Confidence in Electroconvulsive Therapy. AB - OBJECTIVES: The objective of the survey was to assess confidence in electroconvulsive therapy (ECT) in core psychiatry trainees across Scotland, looking at both theoretical and practical aspects of ECT. METHODS: A link to a 14 item electronic questionnaire was distributed to core trainees via deanery administrators. Most questions were based on the Royal College of Psychiatry's ECT guidelines. RESULTS: A total of 85 responses were analyzed from trainees at all 3 levels of core training and from all health boards across Scotland. Almost 90% of trainees felt that their ECT training was sufficient, with more senior trainees rating their training better than those in the first year of training. Trainees who had theoretical teaching before their practical sessions rated their training better than those with purely observational training. Most trainees felt confident delivering ECT under supervision, and nearly 75% of trainees felt confident preparing a patient for ECT. The areas in which trainees felt least confident were in practical aspects such as dosing protocols and electroencephalogram interpretation. CONCLUSIONS: While ECT training and trainee confidence in delivering ECT were generally good, there are variations in trainees' experience that could be addressed by having a standardized ECT training, including theoretical teaching and practical competencies, in line with current guidelines. Ideally, evidence of meeting the Royal College recommendations for ECT competencies could be made a compulsory aspect of core training in the United Kingdom. PMID- 29424758 TI - A 6-Year Follow-up Study of Vagus Nerve Stimulation Effect on Quality of Life in Treatment-Resistant Depression: A Pilot Study. AB - OBJECTIVES: Treatment-resistant depression (TRD) carries a major burden on those affected by this disease and significantly impacts their quality of life (QOL). Vagus nerve stimulation (VNS) has showed promising results on symptoms, but its impact on QOL remains underresearched. This study aims to evaluate the long-term effects of VNS on both QOL and clinical symptoms for TRD patients, through a naturalistic 6-year follow-up. METHOD: Outpatients with confirmed TRD were enrolled to receive VNS. None of the patients enrolled left the study or was lost at follow-up. Patients were evaluated at 1, 3, 6, 12, 24, 36, 48, 60, and 72 months for a total of 10 assessments using the 36 item Short Form questionnaire, Hamilton Rating Scale for Depression and Hamilton Anxiety Rating Scale. RESULTS: Ten patients were enrolled with a mean age of 50 years. This study shows a clinically and statistically significant improvement of the mental QOL (P = 0.012), physical QOL (P < 0.002), depressive symptoms (P < 0.001), and anxiety symptoms (P < 0.001). CONCLUSIONS: This long-term naturalistic study is the first to demonstrate that the therapeutic effect of VNS on TRD goes beyond clinical symptoms to improve the daily QOL of those affected. PMID- 29424759 TI - Clinical Improvement According to RAPID3 in Patients With Polymyalgia Rheumatica: A Longitudinal Analysis From Routine Care. PMID- 29424760 TI - Dengue-Triggered Kawasaki Disease: A Report of 2 Cases. PMID- 29424761 TI - Granulomatosis With Polyangiitis Associated With Mumps Viral Infection. PMID- 29424762 TI - Can Diagnostic and Therapeutic Arthrocentesis Be Successfully Performed in the Flexed Knee? AB - BACKGROUND/OBJECTIVE: The objective of this study was to determine whether the extended or flexed knee positioning was superior for arthrocentesis and whether the flexed knee positioning could be improved by mechanical compression. METHODS: Fifty-five clinically effusive knees underwent arthrocentesis in a quality improvement intervention: 20 consecutive knees in the extended knee position using the superolateral approach, followed by 35 consecutive knees in the flexed knee position with and without an external compression brace placed on the suprapatellar bursa. Arthrocentesis success and fluid yield in milliliters were measured. RESULTS: Fluid yield for the extended knee was greater (191% greater) than the flexed knee (extended knee, 16.9 +/- 15.7 mL; flexed knee, 5.8 +/- 6.3 mL; P < 0.007). Successful diagnostic arthrocentesis (>=2 mL) was 95% (19/20) in the extended knee and 77% (27/35) in the flexed knee (P = 0.08). After mechanical compression was applied to the suprapatellar bursa and patellofemoral joint of the flexed knee, fluid yields were essentially identical (extended knee, 16.9 +/- 15.7 mL; flexed knee, 16.7 +/- 11.3 mL; P = 0.73), as were successful diagnostic arthrocentesis (>=2 mL) (extended knee 95% vs. flexed knee 100%, P = 0.12). CONCLUSIONS: The extended knee superolateral approach is superior to the flexed knee for conventional arthrocentesis; however, the extended knee positioning and flexed knee positioning have identical arthrocentesis success when mechanical compression is applied to the superior knee. This new flexed knee technique for arthrocentesis is a useful alternative for patients who are in wheelchairs, have flexion contractures, cannot be supine, or cannot otherwise extend their knee. PMID- 29424763 TI - Atorvastatin-Induced Dermatomyositis: Resolution With Change in Statin? PMID- 29424764 TI - Introduction to the 2018 Taiwan Society of Plastic Surgery Supplement. PMID- 29424765 TI - Relationship Between Xanthelasma Palpebrarum and Hyperlipidemia. AB - BACKGROUND: Xanthelasma palpebrarum is a common periorbital lesion that occurs in middle-aged woman. Dyslipidemia was strongly associated with the occurrence of xanthelasma. Different treatment methods for xanthelasma were applied with comparable results. MATERIALS AND METHODS: This was a retrospective chart review series performed at a single institute. The surgical pathology of 69 patients who received surgical excision from 1994 to 2012 was obtained. In addition, International Classification of Diseases, Ninth Revision, Clinical Modification code of xanthelasma (374.51) of 44 patients who underwent nonsurgical treatment at an outpatient department was acquired from 2006 to 2012. The serum lipid levels, comorbidities, recurrence, and treatment methods were obtained and analyzed with Statistical Analysis System (SAS) 9.4. RESULTS: Of a total of 113 identified patients, 50 had lipid profile data. Of these 50 patients, 25 (50%) had dyslipidemia, which is higher than general population in Taiwan. The recurrence rate was 17.5%, and there was no statistical difference in the recurrence rate between the different treatment methods. CONCLUSIONS: Xanthelasma was found to be associated with dyslipidemia. Thus, we recommend patients with xanthelasma to check their lipid profile and receive diet control and lipid lowering medications for lipid abnormalities. PMID- 29424766 TI - Social Connectedness and Perceived Listening Effort in Adult Cochlear Implant Users: A Grounded Theory to Establish Content Validity for a New Patient-Reported Outcome Measure. AB - OBJECTIVES: Individuals with hearing loss often report a need for increased effort when listening, particularly in challenging acoustic environments. Despite audiologists' recognition of the impact of listening effort on individuals' quality of life, there are currently no standardized clinical measures of listening effort, including patient-reported outcome measures (PROMs). To generate items and content for a new PROM, this qualitative study explored the perceptions, understanding, and experiences of listening effort in adults with severe-profound sensorineural hearing loss before and after cochlear implantation. DESIGN: Three focus groups (1 to 3) were conducted. Purposive sampling was used to recruit 17 participants from a cochlear implant (CI) center in the United Kingdom. The participants included adults (n = 15, mean age = 64.1 years, range 42 to 84 years) with acquired severe-profound sensorineural hearing loss who satisfied the UK's national candidacy criteria for cochlear implantation and their normal-hearing significant others (n = 2). Participants were CI candidates who used hearing aids (HAs) and were awaiting CI surgery or CI recipients who used a unilateral CI or a CI and contralateral HA (CI + HA). Data from a pilot focus group conducted with 2 CI recipients were included in the analysis. The data, verbatim transcripts of the focus group proceedings, were analyzed qualitatively using constructivist grounded theory (GT) methodology. RESULTS: A GT of listening effort in cochlear implantation was developed from participants' accounts. The participants provided rich, nuanced descriptions of the complex and multidimensional nature of their listening effort. Interpreting and integrating these descriptions through GT methodology, listening effort was described as the mental energy required to attend to and process the auditory signal, as well as the effort required to adapt to, and compensate for, a hearing loss. Analyses also suggested that listening effort for most participants was motivated by a need to maintain a sense of social connectedness (i.e., the subjective awareness of being in touch with one's social world). Before implantation, low social connectedness in the presence of high listening effort encouraged self-alienating behaviors and resulted in social isolation with adverse effects for participant's well-being and quality of life. A CI moderated but did not remove the requirement for listening effort. Listening effort, in combination with the improved auditory signal supplied by the CI, enabled most participants to listen and communicate more effectively. These participants reported a restored sense of social connectedness and an acceptance of the continued need for listening effort. CONCLUSIONS: Social connectedness, effort reward balance, and listening effort as a multidimensional phenomenon were the core constructs identified as important to participants' experiences and understanding of listening effort. The study's findings suggest: (1) perceived listening effort is related to social and psychological factors and (2) these factors may influence how individuals with hearing loss report on the actual cognitive processing demands of listening. These findings provide evidence in support of the Framework for Understanding Effortful Listening a heuristic that describes listening effort as a function of both motivation and demands on cognitive capacity. This GT will inform item development and establish the content validity for a new PROM for measuring listening effort. PMID- 29424767 TI - Extracellular Vesicles from Human Liver Stem Cells Reduce Injury in an Ex Vivo Normothermic Hypoxic Rat Liver Perfusion Model. AB - BACKGROUND: The gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. Here, we aimed to explore the feasibility of a pharmacological intervention on isolated rat livers by using a combination of NMP and human liver stem cells-derived extracellular vesicles (HLSC-EV). METHODS: We established an ex vivo murine model of NMP capable to maintain liver function despite an ongoing hypoxic injury induced by hemodilution. Livers were perfused for 4 hours without (control group, n = 10) or with HLSC-EV (treated group, n = 9). Bile production was quantified; perfusate samples were collected hourly to measure metabolic (pH, pO2, pCO2) and cytolysis parameters (AST, alanine aminotransferase, lactate dehydrogenase). At the end of perfusion, we assessed HLSC-EV engraftment by immunofluorescence, tissue injury by histology, apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, tissue hypoxia-inducible factor 1-alpha, and transforming growth factor-beta 1 RNA expression by quantitative reverse transcription-polymerase chain reaction. RESULTS: During hypoxic NMP, livers were able to maintain homeostasis and produce bile. In the treated group, AST (P = 0.018) and lactate dehydrogenase (P = 0.032) levels were significantly lower than those of the control group at 3 hours of perfusion, and AST levels persisted lower at 4 hours (P = 0.003). By the end of NMP, HLSC-EV had been uptaken by hepatocytes, and EV treatment significantly reduced histological damage (P = 0.030), apoptosis (P = 0.049), and RNA overexpression of hypoxia-inducible factor 1-alpha (P < 0.0001) and transforming growth factor-beta 1 (P = 0.014). CONCLUSIONS: HLSC-EV treatment, even in a short-duration model, was feasible and effectively reduced liver injury during hypoxic NMP. PMID- 29424768 TI - Current Status of Surgical Incisions Used in Donors During Living Related Liver Transplantation-A Nationwide Survey in Japan. AB - BACKGROUND: Smaller surgical incisions have recently been introduced in living donor liver procurement. This study used national data from Japan to clarify the present status of surgical incisions in living donor liver procurement. METHODS: A nationwide, questionnaire-based survey related to 3121 donors and recipients was used. Donors were divided into 2 groups: left lateral segment graft (LLSG) procurement (n = 690) and other types (n = 2431). Incisions were classified into 6 types: type I, upper midline and bilateral subcostal; type II, upper midline and right subcostal; type III, upper midline and right subcostal to the right lateral margin of the abdominal rectus muscle; type IV, upper midline without laparoscopy; type V, upper midline with laparoscopy; and type VI, lower abdominal using the full laparoscopic technique. Types I, II, and III were regarded as standard, and types IV, V, and VI as small incisions. RESULTS: In LLSGs, blood transfusion and postoperative complication rates were significantly less frequent in the small incision group than in the standard group. In other graft types, there were no significant differences in blood transfusion, postoperative complication, and recipients' graft loss rates. The rates of wound extension during surgery were 2.8% and 2.1% in the small incision group in LLSGs and in other graft types, respectively. A small incision was adapted more frequently and postoperative complications were less common in high-volume centers. CONCLUSIONS: Various incisions have been adopted in living donor liver procurement. Donor safety and graft integrity appear to have been retained for donors receiving small incisions. PMID- 29424769 TI - Emotional Modulation of Pain and Spinal Nociception in Sexual Assault Survivors. AB - OBJECTIVE: Sexual assault (SA) is associated with an increased risk for chronic pain and affective distress. Given that emotional processes modulate pain (e.g., negative emotions enhance pain, positive emotions inhibit pain), increased pain risk in SA survivors could stem from a disruption of emotional modulation processes. METHODS: A well-validated affective picture-viewing paradigm was used to study emotional modulation of pain in 33 healthy, pain-free SA survivors and a control group of 33 healthy, pain-free individuals with no reported history of SA (matched on age, sex, race, and number of non-SA traumas). Unpleasant (mutilation), neutral, and pleasant (erotic) pictures were presented, while painful electrocutaneous stimulations were delivered at the ankle. Pain intensity ratings and nociceptive flexion reflex (NFR) magnitudes (a physiologic measure of spinal nociception) were recorded in response to electric stimuli. Multilevel models were used to analyze the data with group (SA versus non-SA) and content (mutilation, neutral, erotic) as independent variables. RESULTS: Both groups demonstrated similar emotional modulation of pain (FGroupbyContent(2,646.52) = 0.44, p = .65), but a main effect of group (FGroup(1,65.42) = 4.24, p = .043) indicated the SA group experienced more overall pain from electric stimuli (hyperalgesia). A significant group by content interaction for NFR (p = .035) indicated that emotional modulation of NFR was present for the non-SA group (FContentSimpleEffect(2,684.55) = 12.43, p < .001), but not the SA group (FContentSimpleEffect(2,683.38) = 1.71, p = .18). CONCLUSIONS: These findings suggest that SA survivors have difficulty emotionally engaging brain-to-spinal cord mechanisms to modulate spinal nociception. A disruption of descending inhibition plus hyperalgesia could contribute to comorbidity between sexual trauma and chronic pain. PMID- 29424770 TI - Endoscopic Repair of Persistent Oroantral Communications Using the Caldwell-Luc Approach. AB - In this article, a novel endoscopic technique used to close oro-antral fistulas will be described. In the technique described here, 24 cases were surgically treated between May 2011, and November 2014. Under endonasal endoscopic examination following partial inferior uncinectomy, the natural ostium of the maxillary sinus was identified; through this tract, a curved aspirator was advanced into the sinus. If present, we extracted endoscopically tissues causing obliteration of the ostium through the Caldwell-Luc antrostomy, taking care to preserve the integrity of the natural ostium. In the technique described here, endoscopic examination using the Caldwell-Luc approach, the inside of the maxillary sinus is explored fully, existing infection and polyps are eliminated locally, and natural patency of the maxillary sinus ostium can be achieved. The graft used to obliterate the oroantral fistula can be easily harvested from the bone of the anterior wall of the maxillary sinus by accessing the surgical entry tract. PMID- 29424771 TI - T-cell receptor activator of nuclear factor-kappaB ligand/osteoprotegerin imbalance is associated with HIV-induced bone loss in patients with higher CD4+ T cell counts. AB - OBJECTIVE: Higher incidence of osteopenia and osteoporosis underlie increased rates of fragility fracture in HIV infection. B cells are a major source of osteoprotegerin (OPG), an inhibitor of the key osteoclastogenic cytokine receptor activator of nuclear factor-kappaB ligand (RANKL). We previously showed that higher B-cell RANKL/OPG ratio contributes to HIV-induced bone loss. T-cell OPG production in humans, however, remains undefined and the contribution of T-cell OPG and RANKL to HIV-induced bone loss has not been explored. DESIGN: We investigated T-cell OPG and RANKL production in ART-naive HIV-infected and uninfected individuals in relation to indices of bone loss in a cross-sectional study. METHODS: T-cell RANKL and OPG production was determined by intracellular staining and flow cytometry, and plasma levels of bone resorption markers were determined by ELISA. RESULTS: We demonstrate for the first time in-vivo human T cell OPG production, which was significantly lower in HIV-infected individuals and was coupled with moderately higher T-cell RANKL production, resulting in a significantly higher T-cell RANKL/OPG ratio. T-cell RANKL/OPG ratio correlated significantly with BMD-derived z-scores at the hip, lumbar spine and femur neck in HIV-infected individuals with CD4 T-cell counts at least 200 cells/MUl but not in those with lower counts. CONCLUSION: Our data suggest that T cells may be a physiologically relevant source of OPG and T-cell RANKL/OPG imbalance is associated with HIV-induced bone loss in CD4 T-cell-sufficient patients. Both B and T lymphocytes may thus contribute to HIV-induced bone loss. PMID- 29424772 TI - Systematic identification of correlates of HIV infection: an X-wide association study. AB - OBJECTIVE: Better identification of at-risk groups could benefit HIV-1 care programmes. We systematically identified HIV-1 risk factors in two nationally representative cohorts of women in the Demographic and Health Surveys. METHODS: We identified and replicated the association of 1415 social, economic, environmental, and behavioral factors with HIV-1 status. We used the 2007 and 2013-2014 surveys conducted among 5715 and 15 433 Zambian women, respectively (688 shared factors). We used false discovery rate criteria to identify factors that are strongly associated with HIV-1 in univariate and multivariate models of the entire population, as well as in subgroups stratified by wealth, residence, age, and past HIV-1 testing. RESULTS: In the univariate analysis, we identified 102 and 182 variables that are associated with HIV-1 in the two surveys, respectively (79 factors were associated in both). Factors that were associated with HIV-1 status in full-sample analyses and in subgroups include being formerly married (adjusted OR 2007, 2.8, P < 10; 2013-2014 2.8, P < 10), widowhood (aOR 3.7, P < 10; and 4.2, P < 10), genital ulcers within 12 months (aOR 2.4, P < 10; and 2.2, P < 10), and having a woman head of the household (aOR 1.7, P < 10; and 2.1, P < 10), while owning a bicycle (aOR 0.6, P < 10; and 0.6, P < 10) and currently breastfeeding (aOR 0.5, P < 10; and 0.4, P < 10) were associated with decreased risk. Area under the curve for HIV-1 positivity was 0.76-0.82. CONCLUSION: Our X-wide association study identifies under-recognized factors related to HIV-1 infection, including widowhood, breastfeeding, and gender of head of the household. These features could be used to improve HIV-1 identification programs. PMID- 29424775 TI - Distribution and reduction magnitude of HIV-DNA burden in CD4+ T cell subsets depend on art initiation timing. AB - OBJECTIVE: The aim of our study was to analyze the dynamics of HIV-DNA levels in CD4 T-cell subsets in individuals starting successful dolutegravir-based regimens. DESIGN: Twenty-seven individuals with acute infection (AI, n = 8) or chronic infection (CI, n = 5) and patients in virological success (VS, n = 10) or virological failure (VF, n = 4) on antiretroviral therapy (ART) who initiated a dolutegravir-based regimen were enrolled (NCT02557997). METHODS: CD4 T-cells from baseline and week 48 of successful treatment were sorted into effector memory (TEM), transitional memory (TTM), central memory (TCM) and naive (TN) cell groups for total HIV-DNA measurements by qPCR. Bayesian methods were used to estimate the posterior probability of a HIV-DNA decrease more than 0.25 log copies/10 cells at week 48. RESULTS: All patients achieved HIV-RNA suppression at 48 weeks. At baseline and week 48, the highest contributions to the HIV-DNA-infected pool from CD4 T cells were observed in TTM cells in the AI group (62.4 and 60.2%, respectively), but in TCM cells for the CI, VS and VF groups (54.6 and 59.4%, 58.2 and 62.9%, 62.4 and 67.2%), respectively. HIV-DNA burden declined in all subsets after 48 weeks of treatment in the AI (probability (Pr) > 91%), CI (Pr > 52%) and VF (Pr > 52%) groups, but only in TEM cells in the VS group (Pr = 95%). CONCLUSION: Our study showed that dolutegravir-based treatment reduced the HIV DNA cellular burden in individuals from the AI, CI and VF groups, though the reduction levels differed between the patient subgroups. Early treated patients had the highest probability of HIV-DNA reduction. Interestingly, in the aviremic VS group, HIV-DNA reduction was limited to TEM cells. PMID- 29424774 TI - In what circumstances could nondaily preexposure prophylaxis for HIV substantially reduce program costs? AB - OBJECTIVES: To review the main factors influencing the costs of nondaily oral preexposure prophylaxis (PrEP) with tenofovir (+/-emtricitabine). To estimate the cost reductions possible with nondaily PrEP compared with daily PrEP for different populations (MSM and heterosexual populations). DESIGN: Systematic review and data triangulation. METHODS: We estimated the required number of tablets/person/week for dosing regimens used in the HPTN 067/ADAPT (daily/time driven/event-driven) and IPERGAY (on-demand) trials for different patterns of sexual intercourse. Using trial data, and behavioural and cost data obtained through systematic literature reviews, we estimated cost savings resulting from tablet reductions for nondaily versus daily oral PrEP, assuming 100% adherence. RESULTS: Among different populations being prioritized for PrEP, the median reported number of days of sexual activity varied between 0 and 2 days/week (0 1.5 days/week for MSM, 1-2 days/week for heterosexual populations). With 100% adherence and two or fewer sex-days/week, HPTN 067/ADAPT nondaily regimens reduced the number of tablets/week by more than 40% compared with daily PrEP. PrEP program costs were reduced the most in settings with high drug costs, for example, by 66-69% with event-driven PrEP for French/US populations reporting on average one sex-day/week. CONCLUSION: Nondaily oral PrEP could lower costs substantially (>50%) compared with daily PrEP, particularly in high-income countries. Adherence and efficacy data are needed to determine cost effectiveness. PMID- 29424773 TI - Vaginal microbiota and susceptibility to HIV. AB - : Bacterial vaginosis, characterized by the replacement of the Lactobacillus dominant microbiota with anaerobic bacteria and facultative Gram-negative rods, has been associated with adverse reproductive health outcomes including HIV acquisition. With the advent of newer molecular techniques, the vaginal microbiota can be investigated in more detail and the association with HIV examined more thoroughly. This review examines recent evidence suggesting that vaginal dysbiosis with increased microbial diversity, specific vaginal bacterial communities, and the presence and concentrations of some individual bacterial species, may increase HIV susceptibility. Potential mechanisms through which vaginal microbiota could impact HIV susceptibility are discussed. On the basis of the available data, this review finds that there is a modest, but growing, body of evidence linking vaginal microbiota to HIV susceptibility in women. The evidence could be strengthened through two main pathways. First, laboratory studies such as ex-vivo or animal experiments are needed to move from plausible mechanisms towards proven mechanisms that explain an effect of the vaginal microbiota on HIV susceptibility. Second, experimental evidence could directly test the hypothesis that sustaining optimal microbiota reduces HIV risk, though there are important obstacles to conducting such studies. Finally, this review examines strong evidence from a recent publication suggesting that deviations from an optimal vaginal microbiome, and particularly the presence of some bacterial communities with high relative abundance of Gardnerella vaginalis, reduces the efficacy of vaginal tenofovir-based microbicides. PMID- 29424777 TI - Impact of insurance coverage on HIV transmission potential among antiretroviral therapy-treated youth living with HIV. AB - OBJECTIVE: To identify the prevalence of high HIV transmission potential in a cohort of youth living with HIV (YLWH), and determine the impact of insurance coverage on potential for HIV transmission. DESIGN: Retrospective cohort study of antiretroviral therapy (ART)-treated YLWH at a US adolescent HIV clinic, 2002 2015. METHODS: The primary exposure was presence or absence of insurance, defined as private, public or pharmacy-only coverage. The primary outcome was high HIV transmission potential, defined as time-concurrent incident bacterial sexually transmitted infections (STI) (gonorrhea, chlamydia or syphilis) and HIV RNA greater than 1500 copies/ml. Marginal structural models adjusting for baseline demographic covariates, prior history of STI and time-varying retention in care assessed the relationship between insurance status and HIV transmission potential. RESULTS: Participants (n = 240) were followed for a median of 22 (IQR 8.1-49) months after ART initiation, and were predominately African-American men and transgender women who have sex with men, with a median age at HIV diagnosis of 19 years (IQR 17-21). We identified 37 (15%) participants with at least one episode of high HIV transmission potential. Insurance coverage was associated with a greater than 50% lower odds of high HIV transmission potential (aOR 0.46, 95% CI 0.26-0.84), and history of STI at or before entry to HIV care conferred more than three-fold higher odds of high transmission potential (aOR 3.21, 95% CI 1.55-6.63). CONCLUSION: We found 15% of YLWH to have episodic high HIV transmission potential despite receiving ART. Insurance coverage, including pharmacy-only benefits, was protective against transmission risk, suggesting a pivotal role for universal ART coverage in treatment as prevention. PMID- 29424776 TI - A prospective study of serum microbial translocation biomarkers and risk of AIDS related non-Hodgkin lymphoma. AB - BACKGROUND: Chronic immune activation is a harbinger of AIDS-associated non Hodgkin lymphoma (AIDS-NHL), yet the underlying basis is unclear. Microbial translocation, the passage of microbial components from the gastrointestinal tract into the systemic circulation, is a source of systemic immune activation in HIV infection and may be an important contributor to chronic B-cell activation and subsequent AIDS-NHL development. METHOD: We measured biomarkers of microbial translocation including bacterial receptors/antibodies, intestinal barrier proteins, and macrophage activation-associated cytokines/chemokines, in serum from 200 HIV-infected men from the Multicenter AIDS Cohort Study prior to their AIDS-NHL diagnosis (mean = 3.9 years; SD = 1.6 years) and 200 controls. Controls were HIV-infected men who did not develop AIDS-NHL, individually matched to cases on CD4 T-cell count, prior antiretroviral drug use, and recruitment year into the cohort. RESULTS: Biomarkers of bacterial translocation and intestinal permeability were significantly increased prior to AIDS-NHL. Lipopolysaccharide binding protein (LPB), fatty acid-binding protein 2 (FABP2), and soluble CD14 were associated with 1.6-fold, 2.9-fold, and 3.7-fold increases in AIDS-NHL risk for each unit increase on the natural log scale, respectively. Haptoglobin had a 2.1-fold increase and endotoxin-core antibody a 2.0-fold decrease risk for AIDS NHL (fourth versus first quartile). Biomarkers of macrophage activation were significantly increased prior to AIDS-NHL: B-cell activation factor (BAFF), IL18, monocyote chemoattractant protein-1 (MCP1), tumor necrosis factor-alpha (TNFalpha), and CCL17 had 2.2-fold, 2.0-fold, 1.6-fold, 2.8-fold, and 1.7-fold increases in risk for each unit increase on the natural log scale, respectively. CONCLUSION: These data provide evidence for microbial translocation as a cause of the systemic immune activation in chronic HIV infection preceding AIDS-NHL development. PMID- 29424778 TI - Persistence of memory B-cell and T-cell responses to the quadrivalent HPV vaccine in HIV-infected children. AB - OBJECTIVE: To determine the magnitude and persistence of quadrivalent human papillomavirus (HPV)16 and HPV18 B-cell and T-cell memory after three or four doses of quadrivalent HPV vaccine (QHPV) in HIV-infected children. METHODS: Seventy-four HIV-infected children immunized with four doses and 23 with three doses of QHPV had HPV16 and HPV18 IgG B-cell and IFNgamma and IL2 T-cell ELISPOT performed at 2, 3.5 and 4-5 years after the last dose. RESULTS: HPV16 and HPV18 T cell responses were similar in both treatment groups, with higher responses to HPV16 vs. HPV18. These HPV T-cell responses correlated with HIV disease characteristics at the study visits. Global T-cell function declined over time as measured by nonspecific mitogenic stimulation. B-cell memory was similar across treatment groups and HPV genotypes. There was a decline in HPV-specific B-cell memory over time that reached statistical significance for HPV16 in the four-dose group. CONCLUSION: B-cell and T-cell memory did not significantly differ after either three or four doses of QHPV in HIV-infected children. The clinical consequences of decreasing global T-cell function and HPV B-cell memory over time in HIV-infected children requires further investigation. PMID- 29424779 TI - Impact of aging and HIV infection on serologic response to seasonal influenza vaccination. AB - OBJECTIVE: To determine influence of age and HIV infection on influenza vaccine responses. DESIGN: Evaluate serologic response to seasonal trivalent influenza vaccine (TIV) as the immunologic outcome in HIV-infected (HIV+) and age-matched HIV negative (HIV-) adults. METHODS: During 2013-2016, 151 virologically controlled HIV+ individuals on antiretroviral therapy and 164 HIV- volunteers grouped by age as young (<40 years), middle aged (40-59 years) and old (>=60 years) were administered TIV and investigated for serum antibody response to vaccine antigens. RESULTS: At prevaccination (T0) titers were in seroprotective range in more than 90% of participants. Antibody titers increased in all participants postvaccination but frequency of classified vaccine responders to individual or all three vaccine antigens at 3-4 weeks was higher in HIV- than HIV+ adults with the greatest differences manifesting in the young age group. Of the three vaccine strains in TIV, antibody responses at T2 were weakest against H3N2 with those to H1N1 and B antigens dominating. Among the age groups, the titers for H1N1 and B were lowest in old age, with evidence of an age-associated interaction in HIV+ persons with antibody to B antigen. CONCLUSION: Greater frequencies of vaccine nonresponders are seen in HIV+ young compared with HIV- adults and the observed age-associated interaction for B antigen in HIV+ persons are supportive of the concept of premature immune senescence in controlled HIV infection. High-potency influenza vaccination recommended for healthy aging could be considered for HIV+ adults of all ages. PMID- 29424781 TI - Rethinking recycling nucleoside reverse transcriptase inhibitors in HIV treatment: learning from dual therapy studies. PMID- 29424780 TI - Insulin-like growth factor 1 inversely relates to monocyte/macrophage activation markers in HIV. AB - OBJECTIVE: Monocyte/macrophage activation is increased among people with HIV, and may contribute to the heightened risk of atherosclerosis and neurocognitive dysfunction in this population. Insulin-like growth factor 1 (IGF-1) has been shown to attenuate the innate immune response in animal models of atherosclerosis and inflammatory bowel disease. We investigated, for the first time, relationships of circulating IGF-1 with monocyte/macrophage-specific indices among HIV-infected individuals and uninfected controls. DESIGN: Observational. METHODS: One hundred and thirty-one HIV-infected patients and 65 well matched controls without known cardiac disease or viral hepatitis were recruited previously. IGF-1, expressed as a z-score relative to the age-adjusted and sex adjusted population mean, was related to log-transformed inflammatory markers within HIV and non-HIV groups. RESULTS: In HIV, IGF-1 inversely related to sCD163 (r = -0.28, P = 0.002), sCD14 (r = -0.29, P = 0.002), and high-sensitivity IL-6 (r = -0.27, P = 0.006). There was no association of IGF-1 with high-sensitivity CRP, MCP-1, IL-18, or LPS in HIV, or between IGF-1 and any inflammatory marker in controls. Relationships of IGF-1 with sCD163 and sCD14 remained significant in HIV after controlling for age, sex, smoking, BMI, visceral fat, statin use, viral load, and antiretroviral therapy. For every one-unit decline in IGF-1 z-score, sCD163 and sCD14 increased by 14% (95% CI, 0.23-29%) and 29% (95% CI, 1.4-63%), respectively. CONCLUSION: Low IGF-1 was robustly associated with high sCD163 and sCD14 in HIV. Prospective studies are needed to investigate augmentation of IGF-1 as a novel strategy to reduce monocyte/macrophage activation in this population. PMID- 29424782 TI - Social and structural factors associated with greater time with a plasma HIV-1 RNA viral load above log10(1500) copies/ml among illicit drug users. AB - OBJECTIVES: Although previous cross-sectional studies have identified correlates of detectable plasma HIV-1 RNA viral load (VL) among HIV-positive people who use drugs (PWUD), longitudinal factors associated with heightened HIV transmission potential have not been well described. Therefore, we longitudinally examined factors associated with amount of person-time spent above log10(1500) copies/ml plasma among HIV-positive PWUD in Vancouver, Canada. DESIGN: Data were derived from a long-running prospective cohort of HIV-positive PWUD linked to comprehensive clinical records including systematic VL monitoring. METHODS: We used generalized estimating equations modeling to longitudinally examine factors associated with person-time (in days) with a VL more than log10(1500) copies/ml plasma in the previous 180 days. RESULTS: Between December 2005 and May 2014, 845 PWUD were eligible and included in the study. Participants spent an average of 26.8% of observation time with a VL more than log10(1500) copies/ml. In multivariable analyses, homelessness (Adjusted Rate Ratio [ARR] = 1.45) and lack of social support (ARR = 1.27) were positively associated with person-time with a VL more than log10(1500) copies/ml. Older age (ARR = 0.97) and enrolment in addiction treatment (ARR = 0.75) were negatively associated with the outcome in multivariable analyses (all P < 0.05). CONCLUSION: Social and structural factors, including periods of homelessness or lacking in social support, were independently associated with greater amount of time with heightened HIV transmission potential. These findings suggest the need for targeted efforts to address modifiable contextual factors that contribute to increased risk of onward HIV transmission among PWUD. PMID- 29424783 TI - Repeat testing of low-level HIV-1 RNA: assay performance and implementation in clinical trials. AB - OBJECTIVE: Assess the performance of HIV-1 RNA repeat testing of stored samples in cases of low-level viremia during clinical trials. DESIGN: Prospective and retrospective analysis of randomized clinical trial samples and reference standards. METHODS: To evaluate assay variability of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test, v2.0, three separate sources of samples were utilized: the World Health Organization (WHO) HIV reference standard (assayed using 50 independent measurements at six viral loads <200 copies/ml), retrospective analysis of four to six aliquots of plasma samples from four clinical trial participants, and prospective repeat testing of 120 samples from participants in randomized trials with low-level viremia. RESULTS: The TaqMan assay on the WHO HIV-1 RNA standards at viral loads <200 copies/ml performed within the expected variability according to assay specifications. However, standards with low viral loads of 36 and 18 copies/ml reported values of >= 50 copies/ml in 66 and 18% of tests, respectively. In participants treated with antiretrovirals who had unexpected viremia of 50-200 copies/ml after achieving <50 copies/ml, retesting of multiple aliquots of stored plasma found <50 copies/ml in nearly all cases upon retesting (14/15; 93%). Repeat testing was prospectively implemented in four clinical trials for all samples with virologic rebound of 50-200 copies/ml (n = 120 samples from 92 participants) from which 42% (50/120) had a retest result of less than 50 copies/ml and 58% (70/120) retested >= 50 copies/ml. CONCLUSION: The TaqMan HIV-1 RNA assay shows variability around 50 copies/ml that affects clinical trial results and may impact clinical practice. In participants with a history of viral load suppression, unexpected low-level viremia may be because of assay variability rather than low drug adherence or true virologic failure. Retesting a stored aliquot of the same sample may differentiate between assay variability and virologic failure as the source of viremia. This retesting strategy could save time, money, and anxiety for patients and their providers, as well as decrease follow-up clinic visits without increasing the risk of virologic failure and resistance development. PMID- 29424784 TI - Adverse drug reactions to integrase strand transfer inhibitors. AB - OBJECTIVES: To describe and compare integrase strand transfer inhibitor (INSTI) adverse drug reactions (ADRs) for raltegravir, elvitegravir-cobicistat, and dolutegravir. DESIGN: Population-based, retrospective cohort. METHODS: Antiretroviral-experienced and naive persons at least 19 years old were included if they received their first prescription for raltegravir, elvitegravir cobicistat, or dolutegravir in British Columbia, Canada, in 2012-2014, and were followed for 2 years until 31 December 2016. The primary outcome was an ADR resulting in INSTI discontinuation. ADR rates and 95% confidence intervals (95% CIs) were calculated by Poisson method. Cox proportional-hazards regression estimated the hazard ratio for ADR-related INSTI discontinuation, adjusted for confounders. ADR symptoms were compared across INSTIs. RESULTS: There were 1344 persons contributing 1464 person-INSTI exposures. The cohort was predominantly male (79%) and antiretroviral therapy-experienced (85%). ADR events and unadjusted ADR rates (95% CI) per 100 person-years were raltegravir 24 of 551 (4.4%), 2.91 (1.95, 4.35); elvitegravir-cobicistat 38 of 394 (9.6%), 5.94 (4.32, 8.16); and dolutegravir 27 of 519 (5.2%), 2.96 (2.03, 4.31). The ADR rate for elvitegravir-cobicistat was double that of dolutegravir (adjusted hazard ratio 2.24, 95% CI 1.13, 4.44), but not significantly different for either dolutegravir or elvitegravir versus raltegravir. Elvitegravir-cobicistat-treated persons had a significantly higher proportion of gastrointestinal and general (fatigue, malaise) ADRs. Neuropsychiatric ADRs were more frequent with dolutegravir, but not significantly different between INSTIs. Among those switching between INSTIs, there was no apparent relationship between experiencing an ADR to one INSTI and subsequent intolerance to another. CONCLUSIONS: This study affirms INSTIs are well tolerated during routine clinical use. Consideration of differences in side effect profiles can inform antiretroviral therapy individualization. PMID- 29424785 TI - Bone density, microarchitecture, and tissue quality after 1 year of treatment with tenofovir disoproxil fumarate. AB - OBJECIVE: Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is used to assess bone health in HIV patients. DXA measures the amount of mineral, but not other key aspects of bone strength such as bone microarchitecture or bone quality. Trabecular bone score (TBS) and in-vivo microindentation directly measure trabecular microarchitecture and bone tissue quality, respectively. The aim of this study is to measure bone strength properties using these techniques. RESULTS: Forty naive HIV patients who were going to start antiretroviral therapy (ART), a single pill treatment with elvitegravir/cobicistat, tenofovir disoproxil fumarate (TDF), emtricitavine (FTC) were included. A significant reduction in BMD at spine (-3.25%, P < 0.001) and in femoral neck (-3.82%, P = 0.016) between baseline and 48 weeks of treatment were found. Bone microarchitecture score at the spine, as measured by TBS, also significantly decreased from 1.357 (0.09) to 1.322 (0.09) (-2.5%, P = 0.011) between baseline to 48 weeks of treatment. Microindentation (BMSi) values were significantly higher than at baseline [89.04 (4.2) versus 86.07 (6.1); 3.49%, P < 0.001] after 48 weeks of TDF-based ART treatment, indicating improved bone material properties CONCLUSION:: A significant decrease in BMD and TBS were observed after 1 year of TDF therapy. However, tissue quality significantly improved after 1 year of treatment, suggesting a recovery of bone material properties following the control of the infection despite the significant reduction of BMD. These techniques provide additional and necessary information to DXA about bone health in treated HIV patients, and because of its convenience and feasibility they could be routinely apply to assess bone in clinical practice. PMID- 29424787 TI - Major Depressive Disorder: Longitudinal Analysis of Impact on Clinical and Behavioral Outcomes in Uganda. AB - BACKGROUND: There is still wide variability in HIV disease course and other HIV related outcomes, attributable in part to psychosocial factors such as major depressive disorder (MDD), a subject that has received little attention in sub Saharan Africa. METHODS: Using a longitudinal cohort of 1099 HIV-positive antiretroviral therapy-naive persons, we investigated the impact of MDD on 4 HIV related negative outcome domains in Uganda. MDD was assessed using a Diagnostic Statistical Manual IV-based tool. Also collected were data on surrogate measures of the HIV-related outcome domains. Data were collected at the 3 time points of baseline, 6, and 12 months. Multiple regression and discrete time survival models were used to investigate the relationship between MDD and indices of the HIV outcomes. RESULTS: MDD was a significant predictor of "missed antiretroviral therapy doses" [adjusted odds ratio (aOR) = 4.75, 95% confidence interval (CI): 1.87 to 12.04, P = 0.001], "time to first visit to healthy facility" (aOR = 1.71; 95% CI: 1.07 to 2.73; P = 0.024), "time to first self-reported risky sexual activity" (aOR = 2.11, 95% CI: 1.27 to 3.49; P = 0.004) but not of "CD4 counts at months 6 and 12" (estimated effect 29.0; 95% CI: -7.8 to 65.7; P = 0.12), and "time to new WHO stage 3 or 4 clinical event" (aOR = 0.52, 95% CI: 0.12 to 2.20, P = 0.37). CONCLUSIONS: MDD significantly impacted 3 of the 4 investigated outcome domains. These results by demonstrating the adverse consequences of an untreated mental health disorder (MDD) on HIV-related outcomes further strengthen the need to urgently act on WHO's call to integrate mental health care in general HIV care. PMID- 29424786 TI - No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts. AB - OBJECTIVE: To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV positive adults with more than 500 CD4 cells/MUl. DESIGN: Randomized trial. METHODS: The START parent study randomized participants to commence immediate versus deferred ART until CD4 less than 350 cells/MUl. The START Neurology substudy used eight neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models. RESULTS: The 592 participants had a median age of 34 years; median baseline CD4 count was 629 cells/MUl; the mean follow-up was 3.4 years. ART was used for 94 and 32% of accrued person-years in the immediate and deferred groups, respectively. There was no difference between the immediate and deferred ART groups in QNPZ-8 change through follow-up [-0.018 (95% CI -0.062 to 0.027, P = 0.44)], or at any visit. However, QNPZ-8 scores increased in both arms during the first year, by 0.22 and 0.24, respectively (P < 0.001 for increase from baseline). CONCLUSION: We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4 cell counts above 500 cells/MUl. PMID- 29424788 TI - Prevalence of Primary Drug Resistance Against HIV-1 Integrase Inhibitors in Canada. PMID- 29424789 TI - Social Network Support and Decreased Risk of Seroconversion in Black MSM: Results of the BROTHERS (HPTN 061) Study. AB - BACKGROUND AND SETTING: Black men who have sex with men (BMSM) in the United States have disproportionately high HIV infection rates. Social networks have been shown to influence HIV risk behavior; however, little is known about whether they affect the risk of HIV seroconversion. This study uses data from the BROTHERS (HPTN 061) study to test whether contextual factors related to social networks are associated with HIV seroconversion among BMSM. METHODS: We analyzed data from the BROTHERS study (2009-2011), which examined a multicomponent intervention for BMSM in 6 US cities. We ran a series of Cox regression analyses to examine associations between time-dependent measures of network support (personal/emotional, financial, medical, and social participation) and time to HIV seroconversion. We ran unadjusted models followed by models adjusted for participant age at enrollment and study location. RESULTS: A total of 1000 BMSM tested HIV negative at baseline and were followed at 6- and 12-month study visits. Twenty-eight men tested HIV positive. In adjusted hazard ratio models, study participants who remained HIV negative had higher proportions of social network members who provided personal/emotional {0.92 [95% confidence interval (CI): 0.85 to 0.99]}, medical [0.92 (95% CI: 0.85 to 0.99)], or social participation [0.91 (95% CI: 0.86 to 0.97)] support. CONCLUSION: Findings suggest that the increased presence of social network support can be protective against HIV acquisition. Future research should explore the processes that link social network support with sexual and other transmission risk behaviors as a basis to inform HIV prevention efforts. PMID- 29424791 TI - A Special 50-Year Perspective on Our Field. PMID- 29424790 TI - Differences in Local and Systemic TFV PK Among Premenopausal Versus Postmenopausal Women Exposed to TFV 1% Vaginal Gel. AB - OBJECTIVE: We describe and compare the local and systemic pharmacokinetics (PK) of tenofovir (TFV) and TFV-diphosphate (TFV-DP) in healthy premenopausal (PRE) and postmenopausal (POST) women using TFV 1% gel and correlate local PK with other mucosal end points. METHODS: PRE (n = 20) and POST (n = 17) women used 2 doses of TFV 1% vaginal gel, separated by 2 hours. Blood and cervicovaginal samples were obtained 3 and 23 hours after the second dose. PRE women used gel in the follicular and luteal phases of the menstrual cycle. POST women used gel at baseline and again after approximately 2 months of treatment with 0.01% vaginal estradiol (E2) cream. RESULTS: Median TFV concentrations in cervicovaginal aspirate (ng/mL) and vaginal tissue (ng/mg) were significantly higher in PRE (4.3E10, 49.8) versus POST women (2.6E10, 2.2). POST women had significantly higher median molecular ratios of TFV-DP to TFV (3.7%) compared with PRE (0.19%). After vaginal E2 treatment, the local and systemic PK end points in POST women were generally similar to PRE women (all P values > 0.05). Importantly, median vaginal tissue TFV-DP concentrations (fmol/mg) among PRE, POST, and POST women after E2 therapy were similar (292.5, 463.3, and 184.6, respectively). Vaginal tissue TFV concentrations were significantly positively correlated with vaginal epithelial thickness, whereas vaginal tissue TFV-DP concentrations were positively correlated with density of vaginal CD4 and CD8 immune cells. CONCLUSIONS: The state of the cervicovaginal mucosa has a significant impact on local and systemic PK of a topically applied microbicide. PMID- 29424792 TI - In-Depth Characterization of the Effects of Cigarette Smoke Exposure on the Acute Trauma Response and Hemorrhage in Mice. AB - INTRODUCTION: Hemorrhagic shock accounts for a large amount of trauma-related mortality. The severity of trauma can be further aggravated by an additional blunt chest trauma (TxT), which independently contributes to mortality upon the development of an acute lung injury (ALI). Besides, cigarette smoke (CS) exposure before TxT enhanced posttraumatic inflammation, thereby aggravating ALI. We therefore aimed to characterize the impact of an acute and/or chronic lung injury on organ dysfunction in a murine model of traumatic hemorrhagic shock (HS). METHODS: After 3 weeks of CS exposure, anesthetized mice underwent HS with/without TxT. Hemorrhagic shock was implemented for 1 h followed by retransfusion of shed blood and intensive care therapy for 4 h including lung protective mechanical ventilation, fluid resuscitation, and noradrenaline titrated to maintain mean arterial pressure >=50 mmHg. Lung mechanics and gas exchange were assessed together with systemic hemodynamics, metabolism, and acid base status. Postmortem blood and tissue samples were analyzed for cytokine and chemokine levels, protein expression, mitochondrial respiration, and histological changes. RESULTS: CS exposure and HS alone coincided with increased inflammation, decreased whole blood sulfide concentrations, and decreased diaphragmatic mitochondrial respiration. CS-exposed mice, which were subjected to TxT and subsequent HS, showed hemodynamic instability, acute kidney injury, and high mortality. CONCLUSIONS: Chronic CS exposure per se had the strongest impact on inflammatory responses. The degree of inflammation was similar upon an additional TxT; however, mice presented with organ dysfunction and increased mortality rates. Hence, in mice the degree of inflammation may be dissociated from the severity of organ dysfunction or injury. PMID- 29424794 TI - Crocin Alleviates Myocardial Ischemia/Reperfusion-Induced Endoplasmic Reticulum Stress Via Regulation of MIR-34A/SIRT1/NRF2 Pathway. AB - Endoplasmic reticulum (ER) stress is associated with ischemia/reperfusion (I/R) induced cardiomyocyte apoptosis. Crocin could protect myocardial cells against I/R injury and suppress ER stress. This study aimed to explore the molecular mechanism of crocin related to ER stress in myocardial I/R injury. We found crocin alleviated I/R-induced cardiomyocyte apoptosis both in I/R-induced primary cardiomyocytes and in mouse models. The expression of Bax, active caspase 3, Glucose-regulated protein of 78 kDa (GRP78), and C/EBP homologous protein (CHOP) induced by I/R injury was reduced, whereas Bcl-2 expression was enhanced by crocin, the effect of which was abrogated by ER stress activator thapsigargin treatment. Crocin decreased miR-34a expression, while it increased Sirt1, Nrf2, and HO-1 levels, in I/R-induced cardiomyocytes. miR-34a overexpression reduced the expression of Sirt1, Nrf2, and HO-1; in contrast, the suppression of miR-34a up-regulated their expression. Sirt1 blocker nicotinamide and Nrf2 siRNA restrained the levels of GRP78, CHOP, Bax, and active caspase 3. The levels of apoptosis- and ER stress-related proteins, and the expression of miR-34a, Sirt1, Nrf2, and HO-1 in I/R-induced mouse models were consistent with those in vitro. Additionally, I/R-induced left ventricular dysfunction and infarct were attenuated by crocin in mice. In conclusion, crocin attenuates I/R-induced cardiomyocyte apoptosis via suppressing ER stress, which is regulated by the miR 34a/Sirt1/Nrf2 pathway. PMID- 29424793 TI - Regulators of Intestinal Epithelial Migration in Sepsis. AB - The gut is a continuously renewing organ, with cell proliferation, migration and death occurring rapidly under basal conditions. Since the impact of critical illness on cell movement from crypt base to villus tip is poorly understood, the purpose of this study was to determine how sepsis alters enterocyte migration. Wild type, transgenic and knockout mice were injected with 5-bromo-2'deoxyuridine (BrdU) to label cells in S phase before and after the onset of cecal ligation and puncture and were sacrificed at pre-determined endpoints to determine distance proliferating cells migrated up the crypt-villus unit. Enterocyte migration rate was decreased from 24-96 hours following sepsis. BrdU was not detectable on villi 6 days after sham laparotomy, meaning all cells had migrated the length of the gut and been exfoliated into its lumen. However, BrdU positive cells were detectable on villi 10 days after sepsis. Multiple components of gut integrity altered enterocyte migration. Sepsis decreased crypt proliferation, which further slowed enterocyte transit as mice injected with BrdU after the onset of sepsis (decreased proliferation) had slower migration than mice injected with BrdU prior to the onset of sepsis (normal proliferation). Decreasing intestinal apoptosis via gut-specific overexpression of Bcl-2 prevented sepsis-induced slowing of enterocyte migration. In contrast, worsened intestinal hyperpermeability by genetic deletion of JAM-A increased enterocyte migration. Sepsis therefore significantly slows enterocyte migration, and intestinal proliferation, apoptosis and permeability all affect migration time, which can potentially be targeted both genetically and pharmacologically. PMID- 29424795 TI - Evaluation of Vasopressin for Vasoplegic Shock in Patients With Preoperative Left Ventricular Dysfunction After Cardiac Surgery: A Propensity-Score Analysis. AB - PURPOSE: Postoperative vasoplegic shock after cardiac surgery seems to be a frequent complication with poor outcomes. We hypothesized that vasopressin may increase the risk of poor outcomes in patients with preoperative Left Ventricular Dysfunction (pLVD) rather than norepinephrine. The aim of this study was to assess whether vasopressin is superior to norepinephrine to improve outcomes in patients with pLVD after cardiac surgery. METHODS: This retrospective cohort study included 1,156 patients with postoperative vasoplegic shock (mean arterial pressure <65 mmHg resistant to fluid challenge and cardiac index >2.20 L/min m) and pLVD (left ventricular ejection fraction <=35%, left ventricular end diastolic diameter >=60 mm, New York Heart Association >=III) from 2007 to 2017. To address any indicated biases, we derived a propensity score predicting the functions of vasopressin (0.02-0.07 U/min) and norepinephrine (10-60 MUg/min) on postoperative vasoplegic shock. The primary outcomes were 30-day mortality, mechanical ventilation more than 48 h, cardiac reoperation, extracorporeal membrane oxygenation, stroke, and acute kidney injury, whereas the secondary outcomes included infection, septic shock, atrial fibrillation and ventricular arrhythmias. RESULTS: There were 338 patients (169 vasopressin and169 norepinephrine) with a similar risk profile in propensity score-matched cohort. In propensity-matched patients, the primary outcomes of vasopressin and norepinephrine showed no significant difference (50.89% vs. 58.58%, P = 0.155). However, compared with norepinephrine, secondary outcomes of vasopressin were increased due to the high rate of atrial fibrillation (11.83% vs. 20.12%, P = 0.038) and ventricular arrhythmias (14.20% vs. 24.85%, P = 0.014). CONCLUSIONS: Compared with norepinephrine, vasopressin could not improve the postoperative outcomes in patients with pLVD after cardiac surgery. Vasopressin should be cautious to be used as a first-line vasopressor agent in postcardiac vasoplegic shock. PMID- 29424796 TI - Activation of Sigma-1 Receptor by Cutamesine Attenuates Neuronal Apoptosis by Inhibiting Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in a Rat Model of Asphyxia Cardiac Arrest. AB - BACKGROUND: Global cerebral ischemic/reperfusion (I/R) injury after cardiac arrest (CA) is a major cause of mortality and morbidity in survivors of resuscitation. We utilized a rat model of asphyxia CA to explore the functional effects and mechanisms of Sigma-1 receptor (Sig-1R) activation in cerebral protection using the Sig-1R agonist cutamesine (SA-4503). METHODS: After resuscitation, the surviving rats were randomly divided into three groups (n = 18 each): (1) the CPR group (0.9% saline at 1 mL/kg); (2) the SA4503 low-dose group (1 mg/kg SA4503); and (3) the SA4503 high-dose group (2.5 mg/kg SA4503). The neurological deficit scores were recorded, and the cerebral cortex were harvested for western blotting. Mitochondrial transmembrane potential, ATP concentrations, calcium homeostasis, and mitochondrial ultrastructure were also studied. RESULTS: The SA4503 treatment groups exhibited improved neurological outcomes compared with the CPR group. The protein levels of caspase-3 and the endoplasmic reticulum stress markers CHOP and caspase-12 were lower in the SA4503 treatment groups compared with the CPR group. SA4503 treatment also normalized mitochondrial membrane potential, tissue ATP concentrations, intracellular Ca overload, and upregulated Sig-1R protein level compared with the CPR group. The SA4503 high dose treatment showed significant cerebral protective effects compared with the SA4503 low dose treatment. The therapeutic effect of SA4503 was dose-dependent. CONCLUSIONS: CA down-regulated Sig-1R protein expression. Activating Sig-1R using SA4503 protected against global cerebral I/R injury in a rat model of asphyxia CA by alleviating endoplasmic reticulum stress and mitochondrial dysfunction and eventually inhibiting neuronal apoptosis. PMID- 29424797 TI - Mutation in the ADNP gene associated with Noonan syndrome features. PMID- 29424798 TI - Group B Streptococcal Cellulitis and Necrotizing Fasciitis in Infants: A Systematic Review. AB - BACKGROUND: There is no consensus regarding approaches to infantile group B streptococcal (GBS) head and neck cellulitis and necrotizing fasciitis. We present a case of GBS necrotizing cellulitis and summarize the literature regarding the presentation and management of infantile head and neck GBS cellulitis and necrotizing fasciitis. METHODS: The literature was searched using PubMed, Web of Science, EMBASE and Medline (inception to April 2017) by 2 independent review authors. Inclusion criteria encompassed case reports or case series of infants less than 12 months of age with GBS cellulitis of the head and neck or with GBS necrotizing fasciitis without restriction to the head and neck. Data were extracted using tables developed a priori by 2 independent review authors, and discrepancies were resolved by consensus. RESULTS: An infant presenting at 33 days of age with GBS facial necrotizing fasciitis was successfully treated conservatively with antibiotics. Our literature search identified 40 infants with GBS head and neck cellulitis. Late-onset (98%), male gender (65%) and prematurity (58%) predominated. Penicillin is the main therapy used (97%). The 12 identified cases of necrotizing fasciitis were associated with polymicrobial etiology (36%) and broad-spectrum antibiotic use. Seventy-five percent required debridement, including 4 of 5 (80%) cases involving the head and neck. CONCLUSIONS: Skin and soft tissue involvement is an uncommon manifestation of late-onset GBS infection which requires antibiotic therapy and possibly surgical debridement cases with necrotizing fasciitis. PMID- 29424799 TI - Safety and Immunogenicity of the HPV-16/18 AS04-adjuvanted Vaccine in 4-6-year old Girls: Results to Month 12 From a Randomized Trial. AB - BACKGROUND: The burden of cervical cancer caused by human papillomavirus (HPV) is high in Latin America. The suboptimal HPV vaccination coverage in adolescents could be improved by pediatric immunization. HPV vaccination has not yet been reported in girls <9 years of age. METHODS: This ongoing phase III, controlled, randomized, single-blind, multicenter study conducted in Colombia, Mexico and Panama (NCT01627561) evaluated the safety and immunogenicity of AS04-HPV-16/18 vaccine in 4-6-year-old girls. Healthy girls (randomized 1:1) received either 2 doses of AS04-HPV-16/18 vaccine (HPV group, N=74) or 1 dose of each measles-mumps rubella and diphtheria-tetanus-acellular-pertussis vaccines (control group, N=74) 6 months apart. We report the safety and serum anti-HPV-16 and anti-HPV-18 antibodies (measured by enzyme-linked immunosorbent assay) up to 6 months postvaccination, that is, month (M) 12. RESULTS: Injection site pain was the most frequently reported solicited local symptom in HPV vaccinees. The incidence of other solicited and unsolicited symptoms after each vaccination was similar between the HPV and control group. Until M12, 1 girl in the HPV group and 2 in the control group reported serious adverse events; all serious adverse events were assessed as unrelated to study vaccines. No potential immune-mediated diseases were identified. All girls seroconverted for both antigens after 2 doses of AS04-HPV-16/18. In initially seronegative girls, anti-HPV-16 geometric mean concentrations were 20080.0 enzyme-linked immunosorbent assay units (EU)/mL at M7 and 3246.5 EU/mL at M12; anti-HPV-18 geometric mean concentrations were 10621.8 EU/mL at M7 and 1216.6 EU/mL at M12. CONCLUSIONS: Two-dose vaccination with AS04 HPV-16/18 was well tolerated and induced adequate antibody responses in 4-6-year old girls. PMID- 29424800 TI - Influenza Vaccination Coverage in Children With Neurologic Disorders and Their Siblings, July 2006 to June 2014. AB - Children with neurologic disorders are at high risk for influenza-associated complications. We identified 184,460 children 1-17 years of age with neurologic disorders and 204,966 siblings in a commercial insurance claims database from July 2006 to June 2014. Among children with neurologic disorders, coverage increased from 22.4% in 2006-2007 to 42.3% in 2013-2014, but remained suboptimal. A lower proportion of siblings were vaccinated. PMID- 29424801 TI - A Case of Nonfatal Torsade de Pointes Associated With Psychiatric Polypharmacy. PMID- 29424803 TI - Clozapine Associated With Microscopic Colitis in the Setting of Biopsy-Proven Celiac Disease. PMID- 29424802 TI - Predictors of Topiramate Tolerability in Heavy Cannabis-Using Adolescents and Young Adults: A Secondary Analysis of a Randomized, Double-Blind, Placebo Controlled Trial. AB - PURPOSE/BACKGROUND: Cannabis is the most commonly abused illicit drug and accounts for the greatest number of adolescent substance abuse treatment admissions. Despite urgent need for effective interventions, the best available psychosocial treatment options yield only modest effects. Topiramate showed promise as an adjunctive pharmacotherapy to a psychosocial intervention for cannabis misuse among adolescents and young adults in a recent clinical trial, but it was not well tolerated. This study investigated associations between clinical characteristics and side effects and dropout among adolescents and young adults randomized to topiramate. METHODS: This study involved secondary data analysis of a randomized placebo-controlled trial of topiramate for treating cannabis misuse (ages, 15-24 years; 50% female). We explored the interaction effects of baseline characteristics and medication condition (topiramate vs placebo) on treatment dropout. We also explored the relationship between side effects and dropout. FINDINGS/RESULTS: Higher cannabis problems were significantly associated with reduced hazard of dropout in the topiramate group (P = 0.048) and were nonsignificantly associated with increased hazard of dropout in the placebo group (P = 0.062). Results also showed that memory difficulties were an overwhelming predictor of dropout in the topiramate condition; 42% of participants who dropped out experienced memory difficulties, whereas none of those who remained in the study experienced these effects. IMPLICATIONS/CONCLUSIONS: By identifying who may most benefit from and tolerate this medication, treatment for substance use disorders can become more individualized and positive outcomes may be enhanced. PMID- 29424804 TI - No Effect of Adjunctive Minocycline Treatment on Body Metabolism in Patients With Schizophrenia. AB - PURPOSE/BACKGROUND: This study examined the effect of adjunctive minocycline on body metabolism in risperidone-treated patients with schizophrenia. METHODS/PROCEDURES: Each subject had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia and had been on stable dose of risperidone for at least 4 weeks. In a 16-week randomized, double blind, placebo-controlled study, subjects received either minocycline (200 mg/d) or placebo. Various metabolic parameters, including weight, waist circumference, fasting insulin, glucose, and lipids, were measured at baseline and week 16. FINDINGS/RESULTS: A total of 63 subjects with schizophrenia were enrolled in the study. Fifty-five patients completed week-16 assessments (27 in the minocycline group, 28 in the placebo group). There were no significant differences between the 2 groups in week 16 changes for body weight, body mass index, waist circumference, fasting insulin, glucose, and lipids (P's > 0.300). IMPLICATIONS/CONCLUSIONS: In the present study, adjunctive treatment of minocycline did not seem to improve body metabolism in patients with schizophrenia receiving risperidone. The implications for future studies were discussed. PMID- 29424806 TI - Intravenous Ketamine Relieves Pain and Depression After Traumatic Suicide Attempts: A Case Series. PMID- 29424805 TI - Effects of Alcohol on the Pharmacokinetics of Blonanserin and N-Deethylated Blonanserin in Healthy Chinese Subjects. AB - PURPOSE/BACKGROUND: Blonanserin is a novel antipsychotic drug approved for the treatment of schizophrenia in East Asia. The main objective of the present study was to investigate the effect of alcohol on the pharmacokinetic properties of blonanserin and its metabolite N-deethyl blonanserin in healthy Chinese male subjects under fasting conditions. METHODS/PROCEDURES: The study was designed as a randomized, open-label, crossover clinical investigation in 10 male volunteers, each of whom received 2 treatments under fasted conditions: treatment A, blonanserin (8 mg) with water, and treatment B, blonanserin (8 mg) with alcohol (1 mL/kg). FINDINGS/RESULTS: The average values of areas under the curve (AUCs) and mean peak plasma concentrations (Cmax) were noticeably increased by alcohol consumption. In treatment A, average values of AUC0-24h, AUC0-infinity, and Cmax were 3178 ng/h/L, 3879 ng/h/L, and 492 ng/L for blonanserin, and 1932 ng/h/L, 4208 ng/h/L, and 137 ng/L for N-deethylated blonanserin, respectively. In treatment B, AUC0-infinity and Cmax were both increased 2.4-fold for blonanserin and 1.4-fold and 1.7-fold, respectively, for N-deethylated blonanserin (P < 0.05). Compared with treatment A, clearance (Clz/F) of blonanserin and N deethylated blonanserin decreased significantly (2.4-fold and 1.7-fold, respectively) in treatment B (P < 0.05). Alcohol delayed the absorption and reduced the clearance of blonanserin, leading to a 1.8-fold increase in the time to reach Cmax (Tmax) and half life time (t1/2) (P < 0.05). IMPLICATIONS/CONCLUSIONS: Alcohol increased the bioavailability of blonanserin and N-deethyl blonanserin in healthy subjects and the marked effect of alcohol on blonanserin bioavailability should be taken into consideration in deciding dosing schedules in clinical therapy. PMID- 29424807 TI - Two-Year Methylphenidate Treatment of Mental Fatigue and Cognitive Function After a Traumatic Brain Injury: A Clinical Prospective Study. PMID- 29424808 TI - Leukocyte Telomere Length and Pancreatic Cancer Risk: Updated Epidemiologic Review. AB - Many risk factors have been firmly established for pancreatic cancer (PC), but the molecular processes by which known risk factors influence susceptibility to PC are not clear. There has been a recent upsurge of interest in the role of telomere length (TL), the protective DNA sequence repeats at chromosome ends, in pancreatic carcinogenesis. Given this heightened interest, we performed an in depth, focused, and up-to-date review of the epidemiological evidence linking leukocyte TL (LTL) with PC risk. We searched MEDLINE, Embase, and the Cochrane Library databases for all published studies on LTL and PC risk, up to May 2017. Five studies were identified for review: 4 nested case-control studies and 1 retrospective case-control study. Two studies found opposite associations between LTL and PC risk: 1 found a dose-response positive association and the other found a dose-response inverse association. Two studies also found a "U-shaped" association, whereas another reported a weak nonlinear relationship. We offer potential reasons for the conflicting findings including variation in study design, biospecimen characteristics, and differences in interlaboratory measurements of TL. Future studies should carefully control for risk factors of PC that are associated also with telomere attrition and investigate the role of genetic variation in TL maintenance. PMID- 29424810 TI - Human Fetal beta Islets Express Coagulation Factor XIII-A and Proteases Suggesting Amphicrine Regulation to Facilitate Islet Fusion. PMID- 29424809 TI - Intraductal Papillary Mucinous Neoplasms of the Pancreas: Current Understanding and Future Directions for Stratification of Malignancy Risk. AB - The incidence of intraductal papillary mucinous neoplasms (IPMNs) has been increasing over the past decade, mainly owing to increased awareness and the increased use of cross-sectional imaging. The Sendai and Fukuoka consensus guidelines provide us with clinical management guidelines and algorithms; however, the clinical management of IPMNs continues to be challenging. Our incomplete understanding of the natural history of the disease, and the events and pathways that permit progression to adenocarcinoma, result in difficulties predicting which tumors are high risk and will progress to invasive disease. In this review, we summarize the current management guidelines and describe ongoing efforts to more clearly stratify IPMNs by risk of malignancy and identify IPMNs with malignant potential or ongoing malignant transformation. PMID- 29424811 TI - Serum Osteopontin Is Associated With Organ Failure in Patients With Acute Pancreatitis. PMID- 29424812 TI - Etiology Is Linked to the Length of Admission in Patients With Acute Pancreatitis: Is Novel Endoscopy an Unrecognized Cause? PMID- 29424813 TI - Survival Benefits From Metformin Use in Pancreatic Cancer: A Systemic Review and Meta-analysis. PMID- 29424814 TI - Cytomegalovirus Infection in Pediatric Severe Ulcerative Colitis-A Multicenter Study from the Pediatric Inflammatory Bowel Disease Porto Group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition. AB - BACKGROUND: Data on the clinical course and outcomes of pediatric patients with cytomegalovirus (CMV) infection complicating acute severe ulcerative colitis (ASC) are very limited. The aim of our study was to compare outcomes of children with ASC who were CMV positive or CMV negative. METHODS: This was a multicenter retrospective case-controlled study, from centers affiliated with the Pediatric Inflammatory Bowel Disease Porto Group of European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. We included CMV-positive children hospitalized for ASC and compared their colectomy rate during hospitalization and up to 1 year thereafter, matched with CMV-negative controls. RESULTS: A total of 56 children were included; 15 CMV positive and 41 CMV negative. More CMV-positive patients were resistant to intravenous corticosteroids as compared with CMV negative (93% and 56% respectively, P = 0.009). Fourteen of the CMV-positive children (93%) were treated with ganciclovir [5/14 (36%) with 5 mg/kg and 9/14 (64%) with 10 mg/kg]. During hospitalization, 3 (20%) CMV-positive and 3 (7.8%) CMV-negative patients required colectomy (P = 0.17). By 12 months, 5 (33%) and 5 (13%) CMV-positive and CMV-negative patients required colectomy, respectively (P = 0.049); the significance was not retained on multivariate analysis. CONCLUSIONS: A higher prevalence of CMVpositivity was found in pediatric ulcerative colitis patients who required colectomy within 12 months of hospitalization for ASC. Further studies are needed to clarify the impact of CMV infection on the outcome of acute severe colitis in pediatric patients. PMID- 29424815 TI - Successful Treatment of Disseminated Cutaneous Leishmaniasis With Liposomal Amphotericin B and Miltefosine in an Eight-year-old Girl. AB - This case report presents an 8-year-old girl, from Fars province in Iran, diagnosed with cutaneous leishmaniasis in the form of multiple nodular, ulcerative and crusted lesions disseminated on the face, trunk and extremities. The result of direct smear of ulcers was positive for Leishmania parasite. The patient had no immunodeficiency or relevant family history making her susceptible for disseminated cutaneous leishmaniasis. The skin lesions failed to respond to multiple treatment courses of meglumine antimoniate or amphotericin B but were successfully treated with simultaneous miltefosine and liposomal amphotericin B. PMID- 29424816 TI - Recovery of CD4 T Cells in HIV/HCV Coinfected Children: Is it Really Impaired? PMID- 29424817 TI - Re: Recovery of CD4 T Cells in HIV/HCV Coinfected Children: Is it Really Impaired? PMID- 29424818 TI - Open Access: Is There a Predator at the Door? PMID- 29424819 TI - Temporal Bone Meningo-Encephalic-Herniation: Etiological Categorization and Surgical Strategy. AB - OBJECTIVE: To study the clinical presentation, intraoperative findings and surgical management in meningo-encephalic-herniation (MEH) based on the etiology. STUDY DESIGN: A retrospective clinical study and is a follow-up on the previously published report in 2009. SETTING: A quaternary referral otology and skull base center PATIENTS AND METHODS:: The inclusion criteria were intraoperatively verified MEH in patients with a minimum follow-up of 12 months, which yielded 262 operated ears. The data were extracted regarding demographics, laterality, clinical presentation, past surgeries, contralateral-ear condition, intraoperative findings, complications, recurrences, revision-surgeries, audiometric-data, and follow-up. RESULTS: The mean age at surgery was 49.7 years with the involvement of right-ear in 53.8% of patients. Lesions were categorized based on the etiology as chronic-otitis-media with/without cholesteatoma-MEH (COM/CHOL-MEH)-47.7%, iatrogenic-MEHs -20.9%; traumatic-MEHs -8% and spontaneous MEHs -23.3%. At presentation, hearing loss (100 and 98.2%) and otorrhea (65.6 and 49.1%) were predominant in COM/CHOL-MEHs and iatrogenic-MEHs, respectively. On the other hand, meningitis (23.9 and 14.3%) and cerebrospinal fluid-leak (52.4 and 42.8%) were more pronounced in spontaneous and traumatic MEHs, respectively. Surgical approaches included 1) transmastoid, 2) middle-cranial-fossa-approach, 3) combined, and 4) middle-ear-obliteration (MEO) techniques. A total of 52.8% of COM/CHOL-MEHs and 49.1% of iatrogenic-MEHs underwent MEO. Middle-cranial-fossa approach was predominantly used in spontaneous-MEHs (52.5%) and traumatic-MEHs (38.1%). The defect was mostly single (75.2%). Smaller, multiple, bilateral lesions were more common in spontaneous-MEHs with tegmen-tympani involvement (57.4%). CONCLUSION: Incorporating etiology into MEHs is a key-step that can be used as a guidance in choosing the right surgery. MEO is a part of armamentarium, and should be used whenever needed, if the objective is performing a definitive surgery. PMID- 29424820 TI - The Antioxidant Effect of Rosmarinic Acid by Different Delivery Routes in the Animal Model of Noise-Induced Hearing Loss. AB - HYPOTHESIS: Trans-tympanic Rosmarinic Acid (RA), as compared with the systemic administration, protects against noise-induced auditory hair cell and hearing losses in rats in vivo. BACKGROUND: ROS production, lipoperoxidative damage, and an imbalance of antioxidant defences play a significant role in noise-induced hearing loss. Several molecules with antioxidant properties have been tested to restore redox homeostasis; however, drug delivery system represents a challenge for their effectiveness. In our model, acute and intense noise exposure induces hearing loss, hair cell death, and oxidative stress, with an increase in superoxide production and over-expression of lipid peroxidation in cochlear structures. METHODS: RA was administrated in male Wistar rats by trans-tympanic (20 MUl) and systemic (10 mg/kg) modality. In systemic administration, RA was injected 1 hour before noise exposure and once daily for the following 3 days. ABRs were measured before and at days 1, 3, 7, and 30 after noise exposure. Rhodamine-phalloidin staining, dihydroethidium and 8-isoprostane immunostainings were performed to assess and quantify outer hair cells loss, superoxide production, and lipid peroxidation in the different experimental groups. RESULTS: Systemic RA administration significantly decreased noise-induced hearing loss and the improvement of auditory function was paralleled by a significant reduction in cochlear oxidative stress. The trans-tympanic modality of drug administration showed a similar degree of protection both at the functional and morphological levels. CONCLUSION: The effectiveness of RA given via trans-tympanic injection could be interesting for the future application of this minimally-invasive procedure in the treatment of ROS-induced hearing loss. PMID- 29424821 TI - Breaking the Myth of Central Neurological Complications in Stapedial Artery Surgery. PMID- 29424823 TI - Retrograde Mastoidectomy. PMID- 29424822 TI - Response to "Breaking the Myth of Central Neurological Complications in Stapedial Artery Surgery". PMID- 29424824 TI - Response to Letter to the Editor: "Long-Term Complications and Surgical Failures After Ossiculoplasty". PMID- 29424825 TI - A Case of Bilateral Atrophy of the Inferior Vestibular Nerves. AB - : We report a case of a 62-year-old woman who was found to have bilateral atrophy of the inferior vestibular nerves on magnetic resonance imaging (MRI) after presenting to our clinic with 6 years of intermittent vertigo and residual unsteadiness. The nerve atrophy may be associated with an episode of vestibular neuritis, a common cause of vertigo that exclusively involves the inferior vestibular nerve in less than 3% of cases. While MRI may demonstrate vestibular nerve enhancement in cases of acute vestibular neuritis, no single MRI finding has been demonstrated consistently among cases of acute or chronic vestibular neuritis. Physical therapy is likely an effective long-term treatment for this patient to achieve central compensation for symptomatic relief. PMID- 29424827 TI - Case Report: Invalidation of the Farnsworth D15 Test in Dichromacy Secondary to Practice. AB - SIGNIFICANCE: The Farnsworth D15 test can be subverted by patients even with severe red-green color deficiency. PURPOSE: To describe a case showing that perfect performance on the Farnsworth D15 is possible after practicing the test. CASE REPORT: A 23-year-old man presented for a comprehensive color vision evaluation. He had only minor complaints with regard to color vision and otherwise normal vision and ocular health. Based on anomaloscope findings, he was diagnosed with protanopia, a form of dichromacy in which the patient does not have any functional L cones, only S and M cones. The patient practiced the Farnsworth D15 test and returned for a follow-up visit in which he performed the test perfectly four times (i.e., twice in the regular order and twice using cap 15 as the pilot cap). In addition, the patient returned a year later and again performed the test perfectly, indicating long-term learning. CONCLUSIONS: All studies to date have shown that patients with dichromacy fail the Farnsworth D15 test. This case report shows that it is indeed possible for highly motivated patients to subvert the test through practice, and knowledge of this possibility is very important, especially in occupational testing. PMID- 29424826 TI - How Do Patients Respond to Genetic Testing for Age-related Macular Degeneration? AB - SIGNIFICANCE: The American Academy of Ophthalmology currently recommends against routine genetic testing for complex diseases such as age-related macular degeneration (AMD). The results of this study demonstrate that patients are very interested in predictive genetic testing for AMD, find the information useful, and make behavioral changes as a result of the information. PURPOSE: The goal of this project was to conduct a pilot AMD genomic medicine study. METHODS: Eligible patients were aged 50 to 65 years with no personal history of AMD. DNA samples were genotyped for five single-nucleotide polymorphisms (SNPs) in the CFH gene, one SNP in the ARMS-2 gene, one SNP in the C3 gene, and one SNP in the mitochondrial ND2 gene. A risk score was calculated utilizing a model based on odds ratios, lifetime risk of advanced AMD and known population prevalence of genotype, haplotype, and smoking risk. The study optometrist provided the patient's risk score and counseling for personal protective behaviors. Telephone interviews were conducted 1 to 3 months after the counseling visit. RESULTS: One hundred one subjects (85%) participated in the genetic testing; 78 (77.2%) were female. Follow-up interviews were conducted with 94 participants (93.1%). More than half (n = 48) of the participants said that they were motivated to participate in the study because they had a family member with AMD or another eye or genetic disorder. Despite low risk levels, many participants reported making changes as a result of the genetic testing. Twenty-seven people reported making specific changes, including wearing sunglasses and brimmed hat and taking vitamin supplements. Another 16 people said that they were already doing the recommended activities, including wearing glasses, quitting smoking, and/or taking vitamins. CONCLUSIONS: Interest in genetic testing for future risk of AMD was high in this population and resulted in support to continue current health behaviors or incentive to improve behaviors related to eye health. PMID- 29424828 TI - Subjective Ratings and Satisfaction in Contact Lens Wear. AB - SIGNIFICANCE: This study shows satisfaction in contact lens (CL) wear is influenced by both comfort and vision. Eighty-six percent of participants were willing to continue with trial CL wear if satisfied with both comfort and vision, dropping to 50% if either variable was unsatisfactory and 0% if both were unsatisfactory. PURPOSE: The aim of this study was to understand the relationship between subjective ratings and satisfaction with CL wear. METHODS: This was a retrospective analysis of two daily-disposable CL trials (delefilcon A, somofilcon A) on participants 40 years or younger followed over 3 months. Subjective ratings (numerical rating scale 1 to 10, 1-point step) collected at visits following baseline (2 weeks, 1 and 3 months) included comfort (insertion, during day, end of day), vision clarity, and binary response for satisfaction with comfort and vision (yes/no). Willingness to continue with trial CL was obtained at completion. RESULTS: There was no significant association of comfort on insertion with comfort satisfaction (odds ratio [OR], 1.2; P = .30); however, comfort during day (OR, 2.1; P < .001) and end of day (OR, 3.4; P < .001) was associated with comfort satisfaction. For comfort during day ratings of at least 8/10 and end of day of at least 6/10, 90% of participants were considered satisfied. There was a 14% increase in participants satisfied with comfort for each unit increase on the numerical rating scale from ratings of 3 to 8 for comfort during day and a 20% increase from ratings of 3 to 7 for comfort end of day. The percentage of satisfied participants reached its maximum at a lower end of day rating (8/10) compared with during day (10/10). The percentage of participants satisfied with vision reached its maximum (100%) at a vision rating of 9/10. CONCLUSIONS: Satisfaction in CL wear is influenced by both comfort and vision. A higher rating for comfort during the day compared with end of day is necessary for participants to attain satisfaction. PMID- 29424829 TI - Accommodative Function in Individuals with Autism Spectrum Disorder. AB - SIGNIFICANCE: Accommodative responses were significantly poorer in individuals with autism spectrum disorder (ASD) compared with age-matched typically developing control subjects, and hypoaccommodation was associated with reduced near visual acuity (NVA) and convergence. PURPOSE: Autism spectrum disorder is a neurodevelopmental disorder with a reported prevalence of 1.1 to 1.5%. Accommodative dysfunction has been noted in other developmental conditions including cerebral palsy and Down syndrome. The aim of this study was to investigate how accommodative accuracy and near visual function in ASD compared with typically developing control subjects. METHODS: This study investigated accommodative function in children with ASD, in conjunction with other vision measures with habitual refractive corrections. Accommodative accuracy was assessed using modified Nott dynamic retinoscopy. Individual accommodative demand and response were calculated incorporating residual refractive error (difference between cycloplegic and habitual refractive state). Near visual measures included NVA, near point of convergence, fusional reserves, and stereoacuity. Cycloplegic autorefraction confirmed refractive error. RESULTS: Accommodative responses were measured from 124 participants with ASD (6 to 17 years old) and 204 age-matched control subjects. There was no significant difference in the magnitude of residual refractive error between groups (P = .10). The prevalence of a clinically significant lag of accommodation was greater in the ASD group compared with control subjects (ASD = 17.4%, control subjects = 4.9%, chi = 13.04, P < .0001). Near visual acuity was significantly reduced in the ASD group with a clinically significant lag of accommodation (P < .01). A few participants (n = 24 control subjects, n = 14 ASD) had uncorrected or undercorrected refractive errors (spherical equivalent refractive error >=+2.00 D, >1.00 DC), and when these were removed from analysis, there was still an increased prevalence of hypoaccommodation in ASD (14.7%). CONCLUSIONS: Children with ASD were significantly more likely to have accommodative deficits (and associated near visual deficits) in their presenting refractive state than typically developing children. Appraisal of refractive error, accommodation, and NVA should be considered in visual assessment of children with ASD. PMID- 29424830 TI - What Is the Nature of the Reach and Grasp Deficit in Wet Age-related Macular Degeneration? AB - SIGNIFICANCE: Vision is paramount for motor actions directed toward objects. Vision allows not only the identification of objects and their shape and spatial location, but also the adaptation of our movement when it arrives on the object. These findings show that vision deficits, as in age-related macular degeneration (AMD), can lead to reaching and grasping deficits. PURPOSE: Few studies have investigated reaching and grasping in patients with AMD. They showed a deficit in the execution of motor actions in people with AMD, even though these people do not mention difficulties in their daily lives. The purpose of this study was to understand the nature of impairments in motor actions in patients. METHODS: We compared performance in two reach-and-grasp tasks determined by whether the participants (16 people with wet AMD and 17 age-matched control subjects) had time to look at the object before reaching and grasping it. RESULTS: The results show that the kinematic parameters of reach-and-grasp movements do not differ between groups when participants are provided time to look at the object before the movement. In contrast, performance in terms of movement duration, acceleration time, time to reach the maximum grip aperture, and the maximum velocity differ between patients and control subjects when the object is displayed immediately before the movement. CONCLUSIONS: The motor perturbations observed in people with AMD in previous studies seem to result from difficulties in target identification rather than from visuomotor deficits. PMID- 29424831 TI - Morphological analysis and quantitative evaluation of myopic maculopathy by three dimensional magnetic resonance imaging. AB - PurposeTo study the characteristic morphology and quantitatively evaluate the eye shape in different types of myopic maculopathy.MethodsA total of 103 eyes from 65 patients with high myopic maculopathy were examined by spectral-domain optical coherence tomography (SD-OCT) and three-dimensional magnetic resonance imaging (3D MRI). The participants were classified into two groups, namely myopic traction maculopathy (MTM) eyes and non-MTM eyes, with SD-OCT imaging. Volume renderings and morphology analysis of the 3D MRI of the eyeball were obtained. Quantitative analysis was achieved in the calculation of vitreous volume and the three-dimensional diameters of the eyeball in three cardinal axes. The eye shape distribution and the diameters of the eyeball were compared between the two groups. Eye shape distribution, vitreous volume, and eyeball diameter were compared between MTM and non-MTM eyes.ResultsThe MTM and non-MTM groups had a total of 68 and 35 eyes, respectively. A significant difference was found in the eye shape distribution (P<0.0001) between MTM and non-MTM eyes. Most of the MTM eyes had undergone a non-uniform expansion of the eyeball, whereas the non-MTM eyes had expanded uniformly. There was no significant difference (P>0.05) in either vitreous volume or other diameters between the two groups.ConclusionsNon uniform globe expansion and staphyloma formation might play an important role in the pathogenesis of MTM. PMID- 29424832 TI - Elusive drusen and changing terminology of AMD. AB - The first descriptions of ageing macula disorder (AMD), be it under other names, appeared in 1855 and 1868. The earliest accounts of AMD linked the presence of drusen with visual loss. It took a century before these connections between drusen and AMD were generally accepted by medical science and in clinical articles. The first signs of AMD appear in the region of the choriocapillaris, Bruch's membrane and the retinal pigment epithelium. The pathogenesis of drusen and of AMD is still uncertain. This is reflected in the wide variation in nomenclature of both, since the first publications. PMID- 29424833 TI - Understanding developmental plasticity as adaptation requires an inter generational perspective. AB - In this issue of Evolution, Medicine and Public Health, Lea and colleagues argue that there are major advantages to bringing together biomedical and evolutionary perspectives on plasticity. To develop this approach, they propose two contrasting scenarios for 'developmental plasticity as adaptation': that it reflects adjustments to resolve the effects of early 'constraints', or that it adjusts phenotype to ecological cues in anticipation of similar conditions in adulthood. Yet neither scenario highlights the unique role of maternal phenotype, mediated by maternal investment strategy, in generating such constraints or cues. Developmental plasticity is greatest during the period when all ecological influences on the offspring are transduced by maternal phenotype. If the offspring adapts during this period, then the target of that adaptation is to maternal phenotype. Ignoring the inter-generational source of early constraints or cues prevents development of a comprehensive adaptive framework, because developmental plasticity is fundamentally relevant to the fitness of both offspring and parents. PMID- 29424835 TI - Correction to: A cluster randomized controlled trial for child and parent weight management: children and parents randomized to the intervention group have correlated changes in adiposity. AB - [This corrects the article DOI: 10.1186/s40608-017-0175-z.]. PMID- 29424836 TI - Epigenetic reaction norms: possible but not inevitable. PMID- 29424837 TI - Erratum to "Frontal Lobe Dysfunction in a Depressed Patient Who Survived a Suicide Attempt by Jumping from the Bridge on the Han River". AB - [This corrects the article on p. 904 in vol. 14.]. PMID- 29424834 TI - Developmental plasticity: Bridging research in evolution and human health. AB - Early life experiences can have profound and persistent effects on traits expressed throughout the life course, with consequences for later life behavior, disease risk, and mortality rates. The shaping of later life traits by early life environments, known as 'developmental plasticity', has been well-documented in humans and non-human animals, and has consequently captured the attention of both evolutionary biologists and researchers studying human health. Importantly, the parallel significance of developmental plasticity across multiple fields presents a timely opportunity to build a comprehensive understanding of this phenomenon. We aim to facilitate this goal by highlighting key outstanding questions shared by both evolutionary and health researchers, and by identifying theory and empirical work from both research traditions that is designed to address these questions. Specifically, we focus on: (i) evolutionary explanations for developmental plasticity, (ii) the genetics of developmental plasticity and (iii) the molecular mechanisms that mediate developmental plasticity. In each section, we emphasize the conceptual gains in human health and evolutionary biology that would follow from filling current knowledge gaps using interdisciplinary approaches. We encourage researchers interested in developmental plasticity to evaluate their own work in light of research from diverse fields, with the ultimate goal of establishing a cross-disciplinary understanding of developmental plasticity. PMID- 29424838 TI - Erratum: Publisher Correction: A potent neutralizing antibody with therapeutic potential against all four serotypes of dengue virus. AB - [This corrects the article DOI: 10.1038/s41541-016-0003-3.]. PMID- 29424839 TI - Developmental plasticity: Friend or foe? AB - Developmental plasticity - the concept that adaptation to changing and unfavorable environmental conditions are possible but may come at the price of compromised health potentials - has evolutionary grounding as it facilitates survival but dissents with fundamental evolutionary principles in that it may advance the lesser fit. It is an important cornerstone of the Developmental Origins of Health and Disease (DOHaD). Unlike evolutionary adaptation developmental plasticity may be short-lived and restricted to one or few generations and inheritance is uncertain. Potential mechanisms include epigenetic modifications adopted in utero which may not transmit to the next generation; future insights may allow adjustments of the outcomes of developmental plasticity. PMID- 29424840 TI - Developmental plasticity: Need to go beyond naive thinking. PMID- 29424841 TI - Encapsulation of Ni/Fe3O4 heterostructures inside onion-like N-doped carbon nanorods enables synergistic electrocatalysis for water oxidation. AB - The rational modulation of composition and structure is critical for the development of robust and efficient oxygen evolution reaction (OER) catalysts for water splitting. In this study, an onion-like N-doped carbon nanorods hybrid (denoted as ONC) with encapsulated Ni/Fe3O4 heterostructures has been fabricated by the pyrolysis of an NiFe-based coordination polymer under a N2 atmosphere. The nanorod-like morphology is transferred from the polymer to the hybrids and generates ONC nanolayers encapsulated with core-shell Ni/Fe3O4 nanostructures. The synergistic effects between the ONC layers and the encapsulated Ni/Fe3O4 heterostructures result in high electronic conductivity due to the nitrogen-doped carbon with an appropriate level of defects and enlarged electrochemical surface area due to the well-defined mesoporous morphology. Compared with Ni@ONC, Fe3O4@ONC, NiFe2O4 and commercial RuO2 electrocatalysts, the as-prepared Ni/Fe3O4@ONC exhibits extraordinary electrocatalytic activity for water oxidation with an overpotential of merely 296 mV at 10 mA cm-2 and a small Tafel slope of 61 mV dec-1. This Ni/Fe3O4@ONC OER catalyst highlights the great potential of integrating hetero-composite nanocatalysts with hetero-atom doped nanocarbon supports for the development of high-performance electrocatalysts for renewable energy applications. PMID- 29424842 TI - CoV2O4: a novel anode material for lithium-ion batteries with excellent electrochemical performance. AB - This study reports the electrochemical applications of CoV2O4 as a novel anode for lithium-ion batteries. Ex situ analyses were performed to understand the conversion that transpires during the charge-discharge cycle. Also, the effects of different binders were analyzed. With the synergistic effect of Na carboxymethyl cellulose and styrene butadiene rubber (CMC and SBR), a reversible capacity of 727.5 mA h g-1 was obtained after 100 cycles which indicates potential applications of CoV2O4 in energy storage devices. PMID- 29424843 TI - Liquid-liquid displacement in slippery liquid-infused membranes (SLIMs). AB - Liquid-infused membranes inspired by slippery liquid-infused porous surfaces (SLIPS) have been recently introduced to membrane technology. The gating mechanism of these membranes is expected to give rise to anti-fouling properties and multi-phase transport capabilities. However, the long-term retention of the infusion liquid has not yet been explored. To address this issue, we investigate the retention of the infusion liquid in slippery liquid-infused membranes (SLIMs) via liquid-liquid displacement porometry (LLDP) experiments combined with microscopic observations of the displacement mechanism. Our results reveal that pores will be opened corresponding to the capillary pressure, leading to preferential flow pathways for water transport. The LLDP results further suggest the presence of liquid-lined pores in SLIM. This hypothesis is analyzed theoretically using an interfacial pore flow model. We find that the displacement patterns correspond to capillary fingering in immiscible displacement in porous media. The related physics regarding two-phase flow in porous media is used to confirm the permeation mechanism appearing in SLIMs. In order to experimentally observe liquid-liquid displacement, a microfluidic chip mimicking a porous medium is designed and a highly ramified structure with trapped infusion liquid is observed. The remaining infusion liquid is retained as pools, bridges and thin films around pillar structures in the chip, which further confirms liquid-lining. Fractal dimension analysis, along with evaluation of the fluid (non-wetting phase) saturation, further confirms that the fractal patterns correspond to capillary fingering, which is consistent with an invasion percolation with trapping (IPT) model. PMID- 29424844 TI - Dietary lipophilic iron alters amyloidogenesis and microglial morphology in Alzheimer's disease knock-in APP mice. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized pathologically by amyloid beta (Abeta) deposition, microgliosis, and iron dyshomeostasis. Increased labile iron due to homeostatic dysregulation is believed to facilitate amyloidogenesis. Free iron is incorporated into aggregating amyloid peptides during Abeta plaque formation and increases potential for oxidative stress surrounding plaques. The goal of this work was to observe how brain iron levels temporally influence Abeta plaque formation, plaque iron concentration, and microgliosis. We fed humanized APPNL-F and APPNL-G-F knock-in mice lipophilic iron compound 3,5,5-trimethylhexanoyl ferrocene (TMHF) and iron deficient diets for twelve months. TMHF elevated brain iron by 22% and iron deficiency decreased brain iron 21% relative to control diet. Increasing brain iron with TMHF accelerated plaque formation, increased Abeta staining, and increased senile morphology of amyloid plaques. Increased brain iron was associated with increased plaque-iron loading and microglial iron inclusions. TMHF decreased IBA1+ microglia branch length while increasing roundness indicative of microglial activation. This body of work suggests that increasing mouse brain iron with TMHF potentiates a more human-like Alzheimer's disease phenotype with iron integration into Abeta plaques and associated microgliosis. PMID- 29424845 TI - Cathodic electrochemical activation of Co3O4 nanoarrays: a smart strategy to significantly boost the hydrogen evolution activity. AB - Co(hydro)oxides show unsatisfactory catalytic activity for the hydrogen evolution reaction (HER) in alkaline media, and it is thus highly desirable but still remains a challenge to design and develop Co(hydro)oxide derived materials as superb hydrogen-evolving catalysts using a facile, rapid and less energy intensive method. Here, we propose a cathodic electrochemical activation strategy toward greatly boosted HER activity of a Co3O4 nanoarray via room-temperature cathodic polarization in sodium hypophosphite solution. After activation, the overpotential significantly decreases from 260 to 73 mV to drive a geometrical catalytic current density of 10 mA cm-2 in 1.0 M KOH. Notably, this activated electrode also shows strong long-term electrochemical durability with the retention of its catalytic activity at 100 mA cm-2 for at least 40 h. PMID- 29424846 TI - Probing the surface fine structure through electrochemical oscillations. AB - In the course of (electro)catalytic reactions, reversible and irreversible changes, namely the formation of adsorbed poisons, catalyst degradation, surface roughening, etc., take place at distinct time-scales. Reading the transformations on the catalyst surface from the measurement of the reaction rates is greatly desirable but generally not feasible. Herein, we study the effect of random surface defects on Pt(100) electrodes toward the electro-oxidation of methanol in acidic media. The surface defects are gently generated in situ and their relative magnitudes are reproducibly controlled. The system was characterized under conventional conditions and investigated under an oscillatory regime. Oscillatory patterns were selected according to the presence of surface defects, and a continuous transition from large amplitude/low frequency oscillations (type L) on smooth surfaces to small amplitude/high frequency oscillations (type S) on disordered surfaces was observed. Importantly, self-organized potential oscillations were found to be much more sensitive to the surface structure than conventional electrochemical signatures or even other in situ characterization methods. As a consequence, we proved the possibility of following the surface fine structure in situ and in a non-invasive manner by monitoring the temporal evolution of oscillatory patterns. From a mechanistic point of view, we describe the role played by surface defects and of the adsorbed and partially oxidized, dissolved species on the oscillations of type S and L. PMID- 29424847 TI - Design of highly selective ethanol dehydration nanocatalysts for ethylene production. AB - Rational design of catalysts for selective conversion of alcohols to olefins is key since product selectivity remains an issue due to competing etherification reactions. Using first principles calculations and chemical rules, we designed novel metal-oxide-protected metal nanoclusters (M13X4O12, with M = Cu, Ag, and Au and X = Al, Ga, and In) exhibiting strong Lewis acid sites on their surface, active for the selective formation of olefins from alcohols. These symmetrical nanocatalysts, due to their curvature, show unfavorable etherification chemistries, while favoring the olefin production. Furthermore, we determined that water removal and regeneration of the nanocatalysts is more feasible compared to the equivalent strong acid sites on solid acids used for alcohol dehydration. Our results demonstrate an exceptional stability of these new nanostructures with the most energetically favorable being Cu-based. Thus, the high selectivity and stability of these in-silico-predicted novel nanoclusters (e.g. Cu13Al4O12) make them attractive catalysts for the selective dehydration of alcohols to olefins. PMID- 29424848 TI - Correction: Physical and compositional analysis of differently cultured 3D human skin equivalents by confocal Raman spectroscopy. AB - Correction for 'Physical and compositional analysis of differently cultured 3D human skin equivalents by confocal Raman spectroscopy' by Y. Dancik, et al., Analyst, 2018, DOI: . PMID- 29424849 TI - Facile fabrication of shape-controlled CoxMnyObeta nanocatalysts for benzene oxidation at low temperatures. AB - We report a new strategy for the design and construction of CoxMnyObeta for C6H6 oxidation, a representative VOC. The nanostructures of CoxMnyObeta can be tuned from nanowires to needles, hollow/hierarchical microspheres and nanocubes. Moreover, different nanostructures of CoxMnyObeta show diverse textural/structural/surface properties, which in turn show strikingly different catalytic performances. Benefitting from its unique structural feature, nanocubic MnO2 exhibits a superior to considerably high activity for C6H6 oxidation at low temperatures. PMID- 29424850 TI - Synthesis and characterization of an Fe(i) cage complex with high stability towards strong H-acids. AB - The first synthesized and X-ray structurally characterized "classical" iron(i) dioximate showed an unrivaled stability towards strong acids, thus calling for a reassessment of the origins of the electrocatalytic activity of similar low valent cobalt and iron cage complexes with electron-withdrawing ribbed substituents, shown previously to be effective electrocatalysts of the HER. PMID- 29424851 TI - On the relationship between rutile/anatase ratio and the nature of defect states in sub-100 nm TiO2 nanostructures: experimental insights. AB - Black TiO2 is being widely investigated due to its superior optical activity and potential applications in photocatalytic hydrogen generation. Herein, the limitations of the hydrogenation process of TiO2 nanostructures are unraveled by exploiting the fundamental tradeoffs affecting the overall efficiency of the water splitting process. To control the nature and concentration of defect states, different reduction rates are applied to sub-100 nm TiO2 nanotubes, chosen primarily for their superiority over their long counterparts. X-Ray Photoelectron Spectroscopy disclosed changes in the stoichiometry of TiO2 with the reduction rate. UV-vis and Raman spectra showed that high reduction rates promote the formation of the rutile phase in TiO2, which is inactive towards water splitting. Furthermore, electrochemical analysis revealed that such high rates induce a higher concentration of localized electronic defect states that hinder the water splitting performance. Finally, incident photon-to-current conversion efficiency (IPCE) highlighted the optimum reduction rate that attains a relatively lower defect concentration as well as lower rutile content, thereby achieving the highest conversion efficiency. PMID- 29424852 TI - Determination of the packing model of a supramolecular nanofiber via mass-per length measurement and de novo simulation. AB - Herein, we report an example of using scanning transmission electron microscopy to determine the mass-per-length of supramolecular nanofibers. Together with the measurement of the diameter of nanofibers via transmission electron microscopy, we could estimate the packing density of assembling molecules along the nanofibers. A parallel unbiased de novo simulation screens and reveals the most plausible molecular packing pattern of small molecules along the supramolecular nanofibers. Remarkably, the simulated packing patterns and density correlate well with the experimental measurements. Unexpectedly, the naphthalene groups are likely facing outward, creating a hydrophobic surface, which is driven by the geometry of the hydrogelator molecule. Overall, this study establishes a complementary method to determine molecular arrangement along the supramolecular nanofibers, which is potentially useful for the guidance of rational design of biomaterials based on self-assembly. PMID- 29424853 TI - Ion distribution in dry polyelectrolyte multilayers: a neutron reflectometry study. AB - Ultrathin films of complexed polycation poly(diallyldimethylammonium), PDADMA, and polyanion poly(styrenesulfonate), PSS, were prepared on silicon wafers using the layer-by-layer adsorption technique. When terminated with PDADMA, all films had excess PDADMA, which was balanced by counterions. Neutron reflectivity of these as-made multilayers was compared with measurements on multilayers which had been further processed to ensure 1 : 1 stoichiometry of PDADMA and PSS. The compositions of all films, including polymers and counterions, were determined experimentally rather than by fitting, reducing the number of fit parameters required to model the reflectivity. For each sample, acetate, either protiated, CH3COO-, or deuterated, CD3COO-, served as the counterion. All films were maintained dry under vacuum. Scattering length density profiles were constrained to fit reflectivity data from samples having either counterion. The best fits were obtained with uniform counterion concentrations, even for stoichiometric samples that had been exposed to PDADMA for ca. 5 minutes, showing that surprisingly fast and complete transport of excess cationic charge occurs throughout the multilayer during its construction. PMID- 29424854 TI - Pyridinic-nitrogen highly doped nanotubular carbon arrays grown on a carbon cloth for high-performance and flexible supercapacitors. AB - Pyridinic-nitrogen highly doped nanotubular carbon (NTC) arrays with multimodal pores in the wall were synthesized via a one-step template strategy using 1,3,5 triamino-2,4,6-trinitrobenzene (TATB) as both carbon and nitrogen precursors and ZnO nanowire (ZnO NW) arrays grown on carbon clothes as templates for high performance supercapacitors (SCs). A strikingly high N-doping level of 14.3% and pyridine N (N-6) dominance as high as 69.1% of the total N content were achieved. Both the N content and N configuration can be well tailored by adjusting the carbonization temperatures of TATB. When directly applied as flexible SCs, the N doped NTC yields a high specific capacitance of 310.7 F g-1 (0.8 A g-1), a cycling retention ratio of 105.1% after 20 000 charge-discharge cycles, and excellent capacitance retention rates of 93.6%, 74.2%, and 53.6% at 8 A g-1, 40 A g-1, and 80 A g-1, respectively, as compared to the value at 0.8 g-1. TATB, as the only precursor of C and N, is expected to be of great significance for the further design and synthesis of N-doped sp2 carbon nanostructures with selective N configurations and controlled N content. PMID- 29424855 TI - ? PMID- 29424856 TI - ? PMID- 29424857 TI - ? PMID- 29424858 TI - ? PMID- 29424859 TI - ? PMID- 29424860 TI - ? PMID- 29424861 TI - ? PMID- 29424862 TI - ? PMID- 29424863 TI - Evolution of osteosynthesis : Historical review. PMID- 29424864 TI - Prognostic factors in rectal cancer: where is the evidence? AB - BACKGROUND: In rectal cancer, the 5 years survival is about 53 % for all stages: it remains low in spite of the progress of diagnostic and therapeutic tools. The aim of this work was to provide evidence based answers to the following question: what are the pre, intra and post operative prognostic factors in rectal cancer? METHODS: We have carried out a search in the following data bases: Pubmed, Embase, Cochrane and Scopus. The key words used were: " rectal cancer ", " adenocarcinoma ", " overall survival ", " disease-free survival ", " prognosis " and " evidence-based medicine ". The overall 5 years survival rate has been retained as primary outcome measure. Recurrence-free survival has been retained as secondary endpoint. Were included meta-analyses and systematic reviews of clinical trials dating back to less than six years. RESULTS: We retrieved 270 publications, 27 articles only met the above-mentioned eligibility criteria and thereof have been retained in this work. A high operating volume, a specialized surgeon in colorectal surgery, a total mesorectal excision, an adjuvant chemotherapy given within no more than 8 weeks following the curative resection improve prognosis in rectal cancer with level I of evidence. Anastomotic leak and diabetes worsen prognosis in rectal cancer with level I of evidence. Margin of surgical resection must be RO to improve prognosis in rectal cancer with level I of evidence. CONCLUSION: The main prognostic factors found in literature which we should keep in mind are those on which surgeons can act: neoadjuvant treatment, high operating volume of the surgeon, high tie of the inferior mesenteric artery, mesorectal excision , RO resection, improvement of the techniques of intersphincteric resection and techniques of anastomosis and adjuvant chemotherapy within less than 8 weeks when appropriate. PMID- 29424866 TI - Particularities of community- acquired pneumonia in the elderly. AB - BACKGROUND: Acute community-acquiredpneumonia in olderadults has averysevereprognosiswith a mortality rate whichcanreach 10%. Knowing the clinical, etiological, therapeutic and progressive features of thisdiseasecan help to establish management rulesthatcanimprove the prognosis. The aim of ourstudywas to compare the community-acquiredpneumonia profile in olderadults and youngerthem. METHODS: Retrospective comparative studyincluding patients hospitalized for community-acquiredpneumonia. Two groups of patients weredefined: group 1 subjectsagedbetween 18 and 64 years and group 2 subjectsaged 65 years and older. RESULTS: The meanage of elderlywas 76+/-6,18. COPD was five times more common in group 2 (p = 0.0001). Symptomsweredifferent in the two groups withpredominance of dyspnea in the group of elderly. Prognosisfactors scores (PSI and CURB_65) in elderlywerehighercompared to youngersubjects. Sputum culture wascontributory in third cases in both groups. Pseudomonas aeruginosawas the mostcommonpathogenidentified in the elderly. Empiricaltreatmentwas the mostprescribed in both groups. Evolution was more favorable in group 1 (p = 0.006). Complications, hospitalization in ICU and delay of recoveryweremostcommon in the group 2. CONCLUSION: Our studyconfirmedsomecharacteristics of community acquiredpneumonia in elderly; it has mostlyrevealed the importance of microbiological tests in this population. PMID- 29424865 TI - Right ventricular systolic echocardiographic parameters in dilated cardiomyopathy and prognosis. AB - BACKGROUND: Right ventricular (RV) dysfunction is associated with poor prognosis in patients with non-ischemic dilated cardiomyopathy. Several RV echocardiographic parameters have been proposed as sensitive markers to detect patients at risk. OBJECTIVE: To compare the predictive value of echographic parameters of RV systolic function for adverse outcomes in patients with non ischemic dilated cardiomyopathy. METHODS: Forty patients with non-ischemic dilated cardiomyopathy were included. Right ventricular systolic function assessed by Doppler echocardiography standard (RV fractional area change, Tei index, TAPSE and dp/dt), tissue Doppler (peak systolic velocity (Sa)) and Strain 2D of the RV. The primary endpoint was the occurrence of a major cardiovascular event. The follow-up extended for 6.2 months +/- 2,49. RESULTS: Eighteen patients reached the primary endpoint. TAPSE (HR 0.86 [0.74-0.99], p=0.04), Sa (HR 0.77 [0.62-0.95], p=0.01), Tei index (HR 1.06 [1.01-1.12], p=0.02) and strain of the lateral wall of the RV (HR 1.13 [1.04-1.23], p=0.004) were found to be independent predictors of major cardiovascular event. The cut-off thresholds for TAPSE, Sa, Tei index and strain of the lateral wall of th RV, defined using ROC curves were respectively 12,5mm ; 8,5cm/s ; 0,55 et -12. CONCLUSION: TAPSE, Sa, Tei index and strain of the lateral wall of the RV are independent predictors of major cardiovascular event in non ischemic dilated cardiomyopathy. PMID- 29424867 TI - Clinico-pathological and prognostic findings on 27 cases of medullary thyroid carcinoma. AB - INTRODUCTION: Medullary thyroid carcinoma is a rare tumor accounting for less than 10% of thyroid neoplasm. This tumor is characterized by important histological polymorphism which makes morphological diagnosis difficult and immunohistochemical study often necessary. OBJECTIVE: We aim to perform a retrospective review of clinical and pathological characteristics of medullary carcinoma. We will discuss the place of immunohistochemistry in the positive diagnosis and as a prognostic factor. METHODS: patients with thyroid medullary carcinoma diagnosed in department of pathology at carcinologic institute between 1998 and 2013 were retrospectively included. Clinic, radiologic and prognostic variables were assessed. Slides were reviewed for all the patients with confirmed tumors. RESULTS: Twenty-seven patients with CMT were identified. The average age was 55 years with predominance of males. The average consultation time was 16 months. The most common presentation symptom was a cervical lymph node. Total thyroidectomy was performed in 23 patients. Tumor was nodular and unique in 22 cases. The average size was 2.1 cm. CMT was of mixed type containing both medullary and papillary compound in four cases. Amyloid substance was present and abundant in 21cases. Positive staining for calcitonin was observed in 16 cases. Distant metastasis or metastatic lymph nodes was observed in eight cases with an average period of 42 months. Radiotherapy was performed in fifteen cases and two patients received chemotherapy. CONCLUSION: In the absence of amyloid deposits, immunohistochemical staining with calcitonin is useful to confirm the diagnosis. The prognosis of this entity is more pejorative than papillary thyroid carcinoma. PMID- 29424868 TI - Premature Birth, low Birth Weight and Birth Defects after assisted reproductive therapies. a 18-year comparative study. AB - BACKGROUND: As assisted reproductive therapies (ART) become more common in Tunisia, it was relevant to define the associated perinatal risks. The risk of multiple births and its correlate after ART were well admitted. We aimed to disclose whether ART were associated with increased perinatal risks in singletons and twins from ART comparatively with spontaneous conception. METHODS: A retrospective descriptive and comparative study including all newborns conceived by ART and admitted between 1998 and 2015 and spontaneous newborns selected randomly. We compared separately singletons and twins from ART and natural conception for premature birth (PB) and low birth weight (LBW). For birth defects (BD), we compared the two groups condensed. RESULTS: We identified 425 ART newborns and 322 controls. The risk of PB was statistically higher, in both ART singletons and twins than in controls. Among singletons, the use of ART was associated with statistically significant increased rates of LBW and VLBW. Among twins, this result was valuable only for VLBW. Newborns conceived with ART had a risk of BD that was three times higher than in controls. BD risk was statistically higher with ICSI (Intra Cytoplasm Sperm Injection), ovulation inductor and in vitro fertilization. BD risks were 2.4 times higher with ICSI than with all others therapies condensed. CONCLUSIONS: This study highlighted the increased perinatal risks even in singleton from ART comparatively with natural conception. The exact mechanisms underlying all these risks remain unclear. Further studies are required to prove the part of ART underlying parental factors, and sterility itself. PMID- 29424869 TI - The bone scintigraphy in the diagnosis and management in children with febrile osteoarticular pain. AB - BACKGROUND: Bone and joint infections are common diseases in pediatrics. They still are a public health problem in Tunisia. The diagnosis is based on clinical, biological, radiological and skeletal scintigraphy arguments. The purpose of this study is to determine the contribution of triple phase bone scan in the exploration of musculoskeletal pain febrile child. METHODS: This was a descriptive and retrospective study. It was conducted over a period of 5 years. It has interested all children explored in nuclear medicine department with suspected acute osteomyelitis (OMA) , osteoarthritis (OA) or septic arthritis (SA) referred from Orthopaedic Infantile service. All these patients had, alongside the conventional radiologic exams, a triple phase bone scan HMDP-Tc99m. RESULTS: We collected 62 patients. Among the selected diagnoses, there were: 22 OMA, 4 OA, 4 SA. The mean age of the patients was 5.58 years with a male predominance. The main reason for consultation was pain. Fever was >= 38 degrees C in 80 % of cases. The preferential localization was the lower limb (93.5 %). The quantitative and qualitative bone scan abnormalities objectified led to a correct diagnosis of: 18 OMA, 3 OA and 2 SA with a respectively estimated sensitivity and specificity of 76.6% and 90.6% in the all population. CONCLUSIONS: Bone scan demonstrates early abnormalities allowing osteoaricular infection diagnosis. It highlights the infection site, and draws a map of the lesions. Currently, imaging modalities differ in their availability, their cost, their input and diagnostic accuracy but they are complementary. PMID- 29424870 TI - The check-list in operating rooms, as perceived by tunisians caregivers. AB - BACKGROUND: The operating room is a high-risk environment for the patient and the healthcare professional and therefore their safety remains a priority in this unit. The checklist "patient safety in the operating room" showed, through the years, its effectiveness in promoting the quality of care and the patient safety. AIM: To explore the perception of operating theaters professionals on the use of the checklist. METHODS: This is a descriptive cross-sectional study among operating theaters professionals of the university hospitals in Sousse, Tunisia, and this during the period from 15 July 2015 until 15 September 2015. The measuring instrument used is derived from the validated questionnaire and proposed by the National Health Authority "individual questionnaire of opinion on the use of the checklist". RESULTS: 98.1% expressed agreement that the checklist improves safety culture and 97.2% say that it is an opportunity to avoid mistakes. 88.1% think that the checklist is an additional administrative burden. The whole study population (100%) confirms the usefulness of the checklist in improving patient safety in the operating room. CONCLUSION: Professionals operating theaters have expressed a positive attitude towards the checklist, however, its implementation raises some difficulties. PMID- 29424871 TI - Associated outcomes to fetal macrosomia: effect of maternal diabetes. AB - BACKGROUND: Fetal macrosomia is associated with an increased risk of adverse outcomes to both the mother and the infant. AIM: To determine maternal and neonatal outcomes associated to fetal macrosomia in diabetic and non- diabetic mothers. METHODS: It is a descriptive retrospective study conducted in Tunisia. We included in this study all patients who delivered newborns having a birth weight above 4kg during 2013. Multivariate analysis was performed using binary logistic regression to identify the complications associated to macrosomic pregnancies with diabetes. RESULTS: Among the 10186 deliveries registered during the study period, 821 mothers gave birth to macrosomic newborns. The prevalence of macrosomia was 8.1%, and macrosomic newborns who had a birth weight of 4500 g or greater were 1.06%. Macrosomia was significantly higher in males (p <10-3). The rate of cesarean delivery was 47.9%. The most frequent adverse maternal and neonatal outcomes were perineal tears (3.6%), post-partum hemorrhage (0.6%), shoulder dystocia (4.9%) and neonatal intensive care unit admission (7.6%).The proportion of maternal diabetes was 9.3%. Macrosomic pregnancies with diabetes appear to be significantly associated with cesarean delivery (OR=2.22), postpartum hemorrhage (OR=6.69) and neonatal intensive care unit admission (OR=4.18). CONCLUSION: Macrosomia increases the risk of maternal and perinatal morbidity particularly when it was associated to maternal diabetes. PMID- 29424872 TI - Inter observer reproducibility of SPECT-low dose CT in classifying indeterminate lesion on planar bone scan in oncologic diseases. AB - AIM: to assess the inter observer reproducibility of Single Photon Computed Tomography-Computerised Tomography (SPECT-CT) in classifying indeterminate foci of abnormal metabolism on planar bone scan (PBS), in oncologic diseases, in the limit of performance of a low dose CT. METHODS: 49 patients (27 men, 22 women) whose PBS showed indeterminate lesions underwent SPECT/CT. The mean age was 57 +/ 13 years (range 22-80 years). Lesions were classified as malignant, benign or indeterminate by two readers. Inter observer agreement was assessed by a weighted Kappa test. RESULTS: On PBS, readers identified 63 indeterminate lesions. SPECT CT showed 95 lesions (31,7% lesion detected more than PBS). Reviewer 1 becomes more confident in final diagnosis of 45 patients. 4 cases remained indeterminate. For the second reviewer, final reports were modified in 37 cases. The Kappa value was 0,74. Scintigraphic, morphologic imaging and follow up identified no false negative and 2 false positive. CONCLUSION: Despite the poor quality of images provided by a low dose scanner, side by side reading of SPECT-CT performs significantly better than planar bone scan for the detection and the classification of equivocal lesions with good inter reviewer agreement. PMID- 29424873 TI - Scheduled consultation in neurosurgery: Profile of patients admitted in the university hospital of Brazzaville. AB - INTRODUCTION: The determination of the types of neurosurgical pathologies in Sub Saharan Africa is essential to prepare the practitioner aiming to pursue that specialty in that area. The aim of our study was to determine the patient's epidemiological profile admitted in a scheduled neurosurgical consultation in the University Hospital of Brazzaville. METHODS: We performed a prospective and descriptive study in a population of patients admitted to the neurosurgical consultation by appointment, for a period of 27 months. The parameters evaluated were socio-anthropometric, diagnostic and evolutionary. RESULTS: We recorded in total 354 patients. The average age was 45.38 years with a sex ratio of 1.02. The majority of patients (72.31%) did not have health assurance. 83.05% of the cases were from the city of Brazzaville and its surroundings. The most common symptom in the consultation was lomboradiculalgia with 99 cases (27.96%). 80 patients (22.59%) had a lumbar spinal stenosis. Surgical indication was raised in 32 patients (9.03%). CONCLUSION: Lomboradiculalgia in lumbar spinal stenosis is the most frequent situation in the scheduled neurosurgical consultation. The low ratio of neurosurgeons and the socioeconomic level of the patients are the main barriers to optimal care of patients. PMID- 29424874 TI - Congenital diaphragmatic eventration complicated with neonatal gastric perforation. AB - Congenital diaphragm eventration is a rare and usually asymptomatic developmental defect. Neonatal gastric perforation is also a rare but lifethreatening condition. In our knowledge, the association of these two pathologies has been, exceptionally reported. We report a case who illustrates clinical and radiological features of this possible co-morbidity. A full-term male neonate was born from uneventful pregnancy and delivery. The antenatal scan was reported as normal. At birth, clinical exam was normal, no special resuscitation was necessary. The newborn was examined and admitted the 4th day of life for fever, tachypnea, cyanosis, hemodynamic shock and refusing feeds. Clinical examination suggested peritonitis. Chest radiography and ultrasonography suggested congenital hernia. A laparotomy was performed after a brief resuscitation and confirmed the presence of diaphragm eventration with gastric perforation. Suturing of gastric perforation with a diaphragmatic plication was performed with favorable evolution. PMID- 29424875 TI - Acute tubular necrosis following transurethral resection of the Prostate using Glycine as irrigating fluid. AB - Transurethral resection of the prostate is currently the gold standard for the surgical treatment of the benign prostatic hyperplasia. This surgery may lead transurethral resection of the prostate (TURP) syndrome and in some cases, acute tubular necrosis can develop. We report a patient who developed hyponatremia, hemolysis and oliguric acute renal failure as a major complication following TURP using glycine as irrigating fluid.A 64-year-old man was admitted for a prostate resection procedure. Physical examination revealed a healthy elderly man. Preoperative laboratory data showed serum sodium 140 mEq/L, blood urea nitrogen (BUN) 0.6 g/L, creatinine 0.7 mg/dL and hemoglobin 12.9 g/dL. Few hours after, the patient becomes incoherent and developed oliguria, nausea and vomiting. The laboratory data revealed rapidly elevating BUN and creatinine levels (BUN 2.4 g/L; creatinine 6.1 mg/dL), the serum sodium concentration decreased by 14 meq/L. A decreased hemoglobin level (7.4 g/dL) with an elevated lactate dehydrogenase level (665 U/L) was observed. Renal ultrasonography was normal. The diagnosis of acute tubular necrosis complicating TURP syndrome was retained. The hyponatremia was slowly corrected to 132 mmol/L by diuresis and fluid restriction. The renal function recovered after four hemodialysis sessions. Using glycine as an irrigant for TURP may cause hyponatremia, hemolysis and also acute renal failure, especially in patients with longer resection time. It is necessary to carry out every effort to shorten resection time and avoid extravasation during surgery. PMID- 29424876 TI - Insulin-induced edema: an unusual complication in a patient with diabetic ketosis. AB - The insulin-induced edema is a rare complication of insulin therapy. Two mechanisms are known, the sodium and water retention and vasoactive mediator's release. We report the case of a 32 years-old patient, with a history of diabetes for one month treated with metformin. He was hospitalized for diabetic ketosis and developed lower legs edema and scrotum edema, few hours after the insulin injections. Biologic tests showed hypoprotidemia without proteinuria and hyponatremia. The abdominal ultrasound showed a liver steatosis. Chest radiography was normal. Transthoracic echocardiography showed a moderate pericardial effusion. Edema resolved spontaneously one month later. Protidemia and natremia were normalized. The natural history of insulin-induced oedema was observed in our patient and the accountability of insulin is likely, but invetstigations are often needed to eliminate other causes of edemas. PMID- 29424877 TI - Hisian extrasystole mimicking second degree atrioventricular block. a case report. AB - Hisian extrasystoles originate from the His bundle. They are rare and usually misdiagnosed. In fact, they manifest on the EKG, with a p' wave located before, in or after the QRS complex. More rarely, the extrasystole blocks the propagation of the influx to the ventricles simulating a Mobitz II atrioventricular (AV) block. We report the case of a 36-Year-old woman with no medical History, suffering from presyncope and palpitations at rest. Her physical examination and EKG were normal. The 24-hour Holter monitoring showed some long periods with unexpected blocked p waves but with no significant pause. Considering her young age and the absence of causes of AV block, we performed an intracardiac electrophysiological study which showed hisian extrasystoles with normal conduction tissue properties at baseline and under flecainide. The diagnosis of hisian extrasystoles simulating Mobitz II AV block was made. A simple monitoring with beta-blockers therapy was recommended. Hisian extrasystoles may simulate first or second degree AV block with different therapeutic and prognostic implications. Nevertheless, these hisian extrasystoles may be the marker of a vulnerable AV conduction, long-term follow up should be considered. PMID- 29424878 TI - Synovial cell sarcoma: a rare laryngeal tumor. AB - Synovial cell sarcoma is a soft tissue tumor that occurs predominately in the lower limbs near the joints. Lesions of the head and neck are extremely rare. The larynx is the least frequent site with only about 20 cases reported in the literature. Treatment of these tumors is controversial and should follow the guidelines for other tumor sites. We report the case of a 37-year-old man with primary laryngeal synovial cell sarcoma, who was surgically managed by a narrow field laryngectomy. PMID- 29424879 TI - An unexpected cause of retroperitoneal gangrene. AB - Retroperitoneal Gangrene is a serious condition whose causes are many. We report three originally cases of anorectal suppuration complicated by retroperitoneal gangrene without Fournier's gangrene until there ever described in the literature. The diagnosis was made in all cases on CT because of atypical clinical presentation. The surgical approach was carried out in different ways to treat perineal and retroperitoneal lesions. PMID- 29424880 TI - Complex regional pain syndrome as an unusual cause of delirium in a dementia patient. PMID- 29424881 TI - Tumor of the kidney associated to acquired cystic renal disease. PMID- 29424882 TI - Paranoid schizophrenia in a woman with Marfan syndrome. PMID- 29424883 TI - Upregulation of LINC00346 in non-small cell lung cancer cells. PMID- 29424884 TI - Clinical research on one-third dose verteporfin photodynamic therapy in the treatment of chronic central serous chorioretinopathy. AB - OBJECTIVE: To observe the curative effect and safety of one-third dose Verteporfin photodynamic therapy (PDT) in the treatment of chronic central serous chorioretinopathy (CSC). PATIENTS AND METHODS: A total of 60 patients (68 eyes) treated in our hospital from January 2016 to December 2016 were selected in this study, and they were diagnosed with chronic CSC via fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT). Besides, patients were treated with one-third conventional dose Verteporfin PDT. The subfoveal choroidal thickness (SFCT), superior, inferior, nasal and temporal choroidal thickness at 1.5 mm away from macula central fovea, central choroidal capillary layer thickness, photoreceptor layer thickness, best corrected visual acuity (BCVA), subretinal fluid absorption, FFA and ICGA manifestations and complications of patients were observed and recorded before treatment and at 1, 3 and 6 months after treatment. RESULTS: After PDT via one third conventional dose of Verteporfin, patients were followed up for 1 month, 3 months, and 6 months. The SFCT of affected eyes was changed from (381.23 +/- 83.29) MUm before treatment to (385.31 +/- 90.89) MUm, (369.59 +/- 75.60) MUm and (374.08 +/- 102.81) MUm successively, and the differences were statistically significant (p < 0.001). Central choroidal capillary layer thickness and superior, inferior, nasal and temporal choroidal thickness at 1.5 mm away from macula central fovea (SCT1.5mm, ICT1.5mm, NCT1.5mm and TCT1.5mm) were significantly decreased at 1 month, 3 months and 6 months after treatment compared with those before treatment (p < 0.001). With the passage of time after treatment, the photoreceptor layer thickness of affected eyes was increased gradually, and the difference was statistically significant (F = 268.8, p < 0.0001). After PDT, BCVA had a statistically significant difference compared with that before treatment (p = 36.16, p < 0.001); BCVA at 3 months after treatment had no statistically significant difference compared with that at 6 months after treatment (p > 0.05). At 6 months after treatment, the subretinal fluid in 63 eyes (92.6%) completely subsided, and a little subretinal fluid was retained in 5 eyes (7.4%). FFA and ICGA showed the choroidal vessel dilatation in affected eyes after treatment and significantly improved moderate-advanced high fluorescein leakage compared with that before treatment. There were no obvious complications in the body and fundus during the follow-up period. CONCLUSIONS: One-third dose Verteporfin PDT can improve BCVA, stop or reduce the choroidal vasodilatation and leakage, accelerate the absorption of serous subretinal fluid, and help the recovery of photoreceptor layer of patients with chronic CSC, which is safe and reliable. PMID- 29424885 TI - Use of balloon catheter dilation vs. traditional endoscopic sinus surgery in management of light and severe chronic rhinosinusitis of the frontal sinus: a multicenter prospective randomized study. AB - OBJECTIVE: Chronic rhinosinusitis (CRS) of the frontal sinus is a complex pathological condition and many surgical techniques were described to treat this area endoscopically, like traditional endoscopic sinus surgery (ESS) and balloon catheter dilation (BCD). PATIENTS AND METHODS: We designed a multicenter prospective randomized study to assess the validity and safety of BCD vs. ESS in symptomatological chronic rhinosinusitis of the frontal sinus enrolling a population of 102 adult patients (64 men and 38 women; overall 148 frontal sinuses studied) with non-polypoid CRS. For a better evaluation of the disease, in our study we decided to analyze both radiological (Lund-McKay CT scoring modified by Zinreich) and symptomatological results (SNOT-20 questionnaire). We divided the population affected in two groups, one with light/mild frontal CRS and the other with moderate/severe frontal CRS, basing on radiological findings at Lund-MacKay modified by Zinreich score. Every group was divided in two subgroups, in one we used BCD and in the other we used traditional ESS. RESULTS: The current literature does not support the suggestion that indications for BCD and ESS are identical, and additional research is needed to determine the role for BCD in specific patient populations. The results showed a not statistically significative difference between BCD and conventional ESS of the frontal sinus in patients with light/mild CRS and in patients with moderate/severe CRS at Lund Mackay modified by Zinreich score. The same not statistically significative difference was observed comparing the results of SNOT-20 questionnaire in the group of light/mild frontal chronic rhinosinusitis. However, we noticed a statistically significant better outcome of SNOT-20 score in patients with moderate/severe chronic rhinosinusitis that underwent BCD of frontal sinus compared to ESS. CONCLUSIONS: BCD and ESS are two alternative weapons in the baggage of every endoscopic surgeon, even because they present similar outcomes, safeness and effectiveness both in light/mild and moderate/severe chronic rhinosinusitis of the frontal sinus. An interesting result of our study was the statistically significant better outcome of SNOT-20 score in patients that underwent BCD of frontal sinus for a moderate/severe CRS, compared to those that underwent a traditional ESS. PMID- 29424886 TI - MiR-599 as a potential biomarker for prognosis of glioma. AB - OBJECTIVE: MicroRNAs (miRNAs) have been demonstrated to play a central role in development and progression in various cancers including glioma. This study aimed to determine the expression level of miRR-599 in glioma and to further investigate its clinical significance. PATIENTS AND METHODS: The expression levels of miR-599 were evaluated in 184 paired of glioma and normal tissues by Real-time RT-PCR. The correlation between tumor miR-599 expression and the clinical and pathological features was analyzed using x2 test. Overall survival and progression-free survival curves were obtained using the Kaplan-Meier method. Cox regression analysis was conducted to analyze the prognostic value of miR-599. RESULTS: We observed that miR-599 expression was significantly downregulated in glioma compared with the adjacent noncancerous tissues (p < 0.01). Correlation analysis revealed that miR-599 downregulation was significantly correlated with KPS (p = 0.000), WHO grade (p = 0.003) and recurrence (p = 0.039). Moreover, Kaplan-Meier analysis confirmed that low miR-599 expression was related to decreased and overall survival (p = 0.002) and progression-free survival (p = 0.001). Then, multivariate analysis revealed that miR-599 was an independent prognostic indicator for overall survival (p = 0.006) and progression-free survival (p = 0.003). CONCLUSIONS: Our data, for the first time, demonstrated that miR-599 expression in glioma could be a useful prognostic marker. PMID- 29424887 TI - MiR-205 enhances cisplatin sensitivity of glioma cells by targeting E2F1. AB - OBJECTIVE: miR-205 has been previously identified as a diagnostic and prognostic factor in glioma. However, its exact functions in glioma remain unclear. The current research aimed to decipher the role of miR-205 in the development of cisplatin resistance in glioma cells. MATERIALS AND METHODS: miR-205 expressions in both cisplatin sensitive and resistant cell lines were compared by the Real time PCR method. The dose-response to cisplatin of U87/DDP cells was determined by MTT assay. Cell cycle and apoptosis were determined by flow cytometry, caspase 3/7 activity assay and Western blot assay. The direct repression of E2F1 by miR 205 was confirmed by luciferase assay and Western blot assay. RESULTS: miR-205 expression was decreased in cisplatin resistant glioma cell lines, and cisplatin treatment led to a decrease of miR-205 in glioma cells. Overexpression of miR-205 in U87/DDP restored its cisplatin sensitivity by enhancing apoptosis and G1/S cell cycle arrest; notably, all these effects were then partially abrogated by E2F1 overexpression. Luciferase assay and Western blot assay confirmed E2F1 as the direct target of miR-205 in U87/DDP cells. CONCLUSIONS: These findings suggest that down-regulation of miR-205 confers the cisplatin resistance in glioma cells via upregulation of E2F1. It might serve as a candidate for glioma therapy. PMID- 29424888 TI - Effect of TAGLN2 in the regulation of meningioma tumorigenesis and development. AB - OBJECTIVE: To explore the role of transgelin-2 TAGLN2 in the development and progression of meningioma and the potential regulatory. MATERIALS AND METHODS: TAGLN2 knockdown expression and overexpression in vitro models were constructed using lentivirus in meningioma cell line CH157; their corresponding transfection efficiencies were verified by qRT-PCR and Western Blot. Actions of TAGLN2 on the proliferation of meningioma cells were explored by CCK8 and colony formation assays. The effect of TAGLN2 on invasion of meningioma cells was analyzed by transwell cell invasion assay. Biological function of TAGLN2 on apoptosis of meningioma cells was determined by flow cytometry. Finally, Western Blot was used to investigate the detailed mechanism of TAGLN2 on regulating the biological functions of meningioma cells. RESULTS: After down-regulating the expression of TAGLN2, there were significantly decreased capacities of cells proliferation and colony formation of meningioma cells, meanwhile, cell invasion was significantly decreased but the apoptosis rate was increased. On the contrary, up-regulation of TAGLN2 expression, the proliferation, colony formation ability were significantly increased as well as the invasion capacity, whilst apoptosis rate was decreased. Western Blot showed that expressions of p-PI3K and p-AKT were inhibited after knockdown of TAGLN2, which were significantly increased after TAGLN2 was overexpressed. CONCLUSIONS: TAGLN2 can affect the proliferation, invasion and apoptosis of meningioma cells and may participate in the development of meningioma through regulating the PI3K/AKT signaling pathway. PMID- 29424889 TI - LncRNA colon cancer-associated transcript 1 (CCAT1) promotes proliferation and metastasis of ovarian cancer via miR-1290. AB - OBJECTIVE: Ovarian cancer is one of the leading causes of cancer-related death in women, but treatment remained unsatisfactory. Studies have shown that lncRNA colon cancer-associated transcript 1 (CCAT1) plays an important regulatory role in different cancers, but its role in ovarian cancer remained largely unclear. PATIENTS AND METHODS: Quantitative Real-time polymerase chain reaction (qRT-PCR) was applied to detect the expression of lncRNA CCAT1 in ovarian cancer and adjacent tissue, and analysis was applied to explore the relationship between expression and clinical characteristic. After lncRNA CCAT1 suppression, Cell Counting Kit-8 (CCK8) and wound-healing assay were used to detect the proliferation and metastasis ability of ovarian cancer, respectively. RESULTS: qRT-PCR showed that lncRNA CCAT1 was highly expressed in ovarian cancer tissue, compared with adjacent tissue. Moreover, we found that the expression of lncRNA CCAT1 was closely related to prognosis, tumor size, and lymph node metastasis. We also found that lncRNA CCAT1 could sponge miR-1290 in ovarian cancer. CONCLUSIONS: In this study, we found that lncRNA CCAT1 could sponge miR-1290 in ovarian cancer, and was closely related to prognosis, proliferation, and metastasis. PMID- 29424890 TI - miRNA211 induces apoptosis of cervical cancer SiHa cells via down-regulation of inhibitor of apoptosis proteins. AB - OBJECTIVE: Cervical cancer severely threatens patients' lives. MicroRNAs contribute to regulatory function in the growth and apoptosis of cells. The present study investigated the effect of miRNA211 on growth and apoptosis of cervical cancer SiHa cells. MATERIALS AND METHODS: miRNA211 and control miRNA were synthesized and transfected into cervical cancer SiHa cells. MTT assay and flow cytometry were used to study the effect of miRNA211 on growth and apoptosis of SiHa cells. RT-PCR and Western blot were used to detect the expression of inhibitor of apoptosis proteins (IAPs) at both mRNA and protein levels. Groups of miRNA (NC), miRNA211, miRNA+siRNA IAP, miRNA211+siRNA IAP were established and levels of IAP and caspase 3 from each group were measured after transfection. RESULTS: After transfection with miRNA211, the growth of SiHa cells was significantly inhibited and apoptosis of SiHa cells was induced, with the reduction of IAPs at both mRNA and protein levels (p<0.05). Knockdown of IAPs enhanced the apoptosis of SiHa cells that were induced by miRNA211, while the overexpression of limited the pro-apoptotic effect of miRNA211 on SiHa cells. CONCLUSIONS: MiRNA211 inhibits the growth of SiHa cells via down-regulation of IAPs. PMID- 29424891 TI - Autophagy suppresses the proliferation of renal carcinoma cell. AB - OBJECTIVE: To investigate the effetcs of autophagy on the proliferation of renal carcinoma (RCCs). MATERIALS AND METHODS: Authophagy related protein 7 (Atg7) overexpressing and knockdown RCC cell lines were established using lentiviral transfection and shRNA interference, respectively. (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide) (MTT) was used to determine the Cell growth rate, and western blot was used to determine the expression of protein. In order to establish xenograft animal models, stable transfected cells were injected into nude mice. After that those mice were used to detect the effect of autophagy on the growth of RCC in vivo. RESULTS: Atg7 overexpression could up-regulate the level of LC3II in RCC cell lines, while Atg7-knockdown suppressed the expression of light chain 3 II (LC3II) in RCC cell lines. Atg7-overexpression cells exhibited a decreased growth profile, while suppressing the expression of Atg7 could accelerate the growth of RCC formed tumors. CONCLUSIONS: Our data indicated that autophagy could suppress the growth of RCC cells in vivo and in vitro, and autophagy appeared to be a new therapeutic target for treating advanced renal cell carcinoma. PMID- 29424892 TI - A novel prognostic biomarker for cholangiocarcinoma: circRNA Cdr1as. AB - OBJECTIVE: Cholangiocarcinoma (CCA) is the second most common primary malignant hepatobiliary cancer worldwide. The circular RNA (circRNA) Cdr1as has been found to play critical roles in various cancers. However, the relationship between circRNA Cdr1as and CCA is still ambiguous. The aim of this study was to explore the expression level of Cdr1as in CCA and to further investigate the clinicopathological and prognostic value of Cdr1as. PATIENTS AND METHODS: We investigated the circRNA Cdr1as expression in 54 paired tumor and adjacent normal tissues of CCA patients by using quantitative Real-time PCR, and evaluated the relevance between Cdr1as expression level and the clinicopathological features. We further assessed the association of Cdr1as expression with overall survival and its prognostic efficacy. RESULTS: The expression of circRNA Cdr1as in tumor tissues was higher than that in adjacent normal tissues. The overexpression of Cdr1as was closely associated with the advanced TNM stage, lymph node invasion, and postoperative recurrence. The overall survival of CCA patients with high Cdr1as expression was worse than that of the CCA patients with low Cdr1as expression. According to multivariate analysis, the Cdr1as expression could be considered as an independent prognostic biomarker for cholangiocarcinoma with acceptable sensitivity and specificity. CONCLUSIONS: Our finding suggested that circRNA Cdr1as may serve as a potential vicious molecular biomarker to predict the aggressive tumor progression and worse prognosis for CCA patients. PMID- 29424893 TI - The ten commandments of chemoembolization: expert discussion and report from Mediterranean Interventional Oncology (MIOLive) congress 2017. AB - Transarterial therapies in the setting of primary and secondary liver malignancies are becoming an essential part of the oncology landscape. The mechanism of action of c-TACE is the induction of tumor necrosis due to the high concentration of the chemotherapeutic that is delivered only locally and to the embolic effect that causes ischemia and increased dwell time of the chemotherapeutic in the tumor. Recently, DEB-TACE has emerged as a variation of c TACE with the potential for the selective delivery of large amounts of drugs to the tumor for a prolonged period, thereby decreasing plasma levels of the chemotherapeutic agent and related systemic effects. There is an increasing consensus that compared with conventional lipiodol-based regimen, DEB-TACE offers standardized methodology, is more reproducible and is associated with improved response and significantly better safety profile. Using an easy to access point by point format, this manuscript summarizes the expert discussion from the Mediterranean Interventional Oncology Live Congress (MIOLive 2017) about the role of TACE in the treatment of liver tumors. PMID- 29424894 TI - Twist2 and CD24 expression alters renal microenvironment in obesity associated kidney cancer. AB - OBJECTIVE: Obesity emerged as a major public health problem worldwide, and prolonged condition with increased BMI causes various metabolic disorders include the development of kidney cancer. The metabolic changes alter the renal microenvironment and thereby promoting tumor. Hence, detailed studies of genes that regulate these this changes are keen to understand. MATERIALS AND METHODS: Initially, we successfully initiate kidney tumor using prolonged intake of a high fat diet in Wistar rats, which are confirmed with pathological changes observed through histological sectioning. The expression of Twist2 and CD24 was assessed using Immunohistology and Western Blotting in a different time interval of kidney cancer. RESULTS: The rats fed with high-fat diet for 8 months shows 1.5 times increased in body mass whereas rats fed with high-fat diet for 16 months shows triple the size when compared with controls. Histological sectioning confirms the development of lesions and proteinaceous casts in 8 months high-fat fed rats, whereas we observed the high proliferative mass of cells in 16 months high-fat fed rats. Interestingly, we also observed elevated expression of Twist2 in initial stages of kidney cancer, which are down-regulated in the latter stages of kidney cancer. The experiments with CD24 shows the gradual increase of the expression of CD24 as a tumor develops to the next level. CONCLUSIONS: The correlation between Twist2 and CD24 expression conclude that Twist2 overexpression in initial stage augments CD24 to express more in the latter stage of kidney cancer. Reversely, the overexpression of CD24 and down-regulation of Twist2 in later stages of kidney cancer suggest the CD24 expression is dependent on Twist2 expression level. PMID- 29424895 TI - Long noncoding RNA RUSC1-AS-N indicates poor prognosis and increases cell viability in hepatocellular carcinoma. AB - OBJECTIVE: This study aimed at exploring the expression and prognostic values of a novel long noncoding RNA RUSC1-AS-N in hepatocellular carcinoma (HCC), and to investigate the biological roles of RUSC1-AS-N in HCC cells. PATIENTS AND METHODS: RUSC1-AS-N expression in public available microarray data was analyzed. The expression of RUSC1-AS-N in our cohort containing 66 HCC tissues and paired adjacent non-cancerous hepatic tissues was measured by qRT-PCR. The correlation between RUSC1-AS-N expression and clinicopathological characteristics was evaluated by Pearson chi2-test. The prognostic value of RUSC1-AS-N was analyzed by Kaplan-Meier survival analysis. The biological roles of RUSC1-AS-N on HCC cell viability were evaluated by Glo cell viability assays and Ethynyl deoxyuridine incorporation assays. The effects of RUSC1-AS-N on HCC cell cycle were evaluated by fluorescence-activated cell sorting (FACS) analyses of propidium-iodide (PI) stained cells. The effects of RUSC1-AS-N on HCC cell apoptosis were evaluated by TdT-mediated dUTP nick end-labeling (TUNEL) assays. RESULTS: RUSC1-AS-N is upregulated in HCC tissues and associated with poor prognosis of HCC patients from GSE54238 and GSE40144. In our cohort, we further confirmed the upregulation of RUSC1-AS-N in HCC tissues. High expression of RUSC1-AS-N associates with large tumor size, vein invasion, encapsulation incompletion, advanced BCLC stage, and poor recurrence-free survival and overall survival. Functional assays revealed that RUSC1-AS-N knockdown markedly decreases cell viability, induces cell-cycle arrest and apoptosis of HCC cells. CONCLUSIONS: RUSC1-AS-N is upregulated and acts as an oncogene in HCC. RUSC1-AS-N may be a promising prognostic biomarker and therapeutic target for HCC. PMID- 29424896 TI - Silencing FOXA1 gene regulates liver cancer cell apoptosis and cell proliferation. AB - OBJECTIVE: Liver cancer emerged as a major health problem, and it accounts for leading cancer-related death worldwide. Due to recurrence and metastatic behavior, it is challenging to be controlled and managed. Understanding the regulative role of different proteins, which regulates liver cancer in various pathological stages, is essential to be investigated. In this study, we analyzed the correlation between Foxa1 suppression along with apoptosis and cancer stem cell proliferation. MATERIALS AND METHODS: CD133+ cells were used to induce the initial and advanced stage of liver cancer. Histology was used to study and confirm the tissue complications associated with initial, advanced and Foxa1 silenced liver cancer tissues. Immunohistochemistry and Western blotting were used to quantify Foxa1, CD133 expression. TUNEL assay was performed to study apoptosis. RESULTS: Initially using CD133+ cells, we successfully developed a mouse model with the initial and advanced stage of liver cancer upon 4 and 8 weeks incubation. Histologically, as the tumor progress, it shows more proliferative cells with disorganized tissue structure. Foxa1 silencing aids in recovering from initial liver cancer, but it has only limited effects with advanced liver cancer. The apoptosis process is enhanced in initial liver cancer, and Foxa1 silenced tissue when compared with the advanced stage of liver cancer. Foxa1 silencing also suppresses the cancer stem cell proliferation. CONCLUSIONS: Overall, our results reveal the critical role of Foxa1 in regulating apoptosis and liver cancer stem cells. PMID- 29424897 TI - The inhibitory effect of miR-375 targeting sp1 in colorectal cancer cell proliferation. AB - OBJECTIVE: Sp1 is a member of super zinc finger structure family that participates in cancer cells' apoptosis, proliferation, survival, and differentiation. This study detected the expressions of miR-375 and sp1 in colorectal cancer tissue and cells to analyze their impact on cell proliferation. PATIENTS AND METHODS: Colorectal cancer patients in our hospital were enrolled. HCT-116 cell was transfected with miR-375 mimics, mimics control, and miR-375 + sp1, respectively. RT-PCR and Western blot were applied to detect expressions of miR-375 and sp1 at mRNA and protein level in colorectal cancer tissue, para carcinoma tissue, and normal colorectal tissue. RT-PCR and Western blot were used to test levels of miR-375 and sp1 in HCT-116 cells after transfection. MTT assay was performed to determine HCT-116 cell proliferation. RESULTS: Our data showed that miR-375 was downregulated, while sp1 was overexpressed in colorectal cancer tissue compared with that in para-carcinoma tissue and normal control (p < 0.05). MiR-375 level was elevated, while sp1 mRNA was declined after miR-375 mimic transfection (p < 0.05). Compared with miR-375 mimic group, the levels of miR-375 and sp1 showed no difference in miR-375 + sp1 group (p > 0.05). Of note, the increase of MiR-375 and reduction of sp1 were in a time-dependent manner (p < 0.05). The cell proliferation rate in miR-375 mimic group was significantly decreased compared with that in mimic control and blank group (p < 0.05). The cell proliferation rate in miR-375 + sp1 group was significantly higher than that miR-375 group, but still lower than the control (p < 0.05). The proliferation rate gradually declined in a time-dependent manner (p < 0.05). CONCLUSIONS: MiR 375 was decreased and sp1 level was enhanced in colorectal cancer. MiR-375 suppresses the proliferation of colorectal cancer cells via the inhibition of sp1 expression at posttranscriptional level. PMID- 29424898 TI - Increased expression of miR-552 acts as a potential predictor biomarker for poor prognosis of colorectal cancer. AB - OBJECTIVE: MiR-552 has recently been identified to be involved in tumorigenesis of colorectal cancer (CRC). The aim of this study was to determine if miR-552 could serve as a prognosis indicator for patients with CRC. PATIENTS AND METHODS: MiR-552 expression levels were detected in 183 pairs of primary CRC and their matched non-tumor tissues by qPCR. The association between miR-552 expression and clinicopathological parameters was analyzed. The survival curves were calculated by the Kaplan-Meier method. Univariate and multivariate analyses were performed to explore the prognostic significance of miR-552 expression. RESULTS: We found that miR-552 expression was upregulated in CRC tumor tissues compared to their adjacent normal tissues (p < 0.01). Increased miR-552 expression was significantly associated with histological grade (p = 0.000), lymph nodes metastasis (p = 0.022) and TNM stage (p = 0.002). In addition, the patients with high miR-552 expression had a significantly worse 5-year overall survival rate than those with low miR-552 expression (p = 0.0036). Furthermore, according to univariate and multivariate analysis, elevated miR-552 was confirmed to be an independent prognostic factor for worse survival. CONCLUSIONS: The current results demonstrated that high miR-552 expression was associated with poor outcomes in patients with CRC. MiR-552 may be a potential prognostic biomarker and therapeutic target in CRC patients. PMID- 29424899 TI - Clinical prognostic value of A FOXM1 related long non-coding RNA expression in gastric cancer. AB - OBJECTIVE: The aim of this study was to explore FOXM1-related LncRNA 1(FRLnc1) expression level in gastric cancer (GC) and demonstrate its association with the prognosis. PATIENTS AND METHODS: A total of 173 GC patients from Affiliated Hospital of Jining Medical University were enrolled in the study. GC tissue samples were quantified for FRLnc1 expression level using quantitative PCR (qPCR) method. The relevance between FRLnc1 expression and clinicopathological features was determined by x2-test. The association between FRLnc1 expression and overall survival was estimated by the Kaplan-Meier method. Multivariate and univariate analysis were performed to explore whether FRLnc1 was an independent prognostic factor for GC patients. RESULTS: We found that FRLnc1 expression was higher in GC tissues than corresponding adjacent tissues (p < 0.01). Increased FRLnc1 expression was associated with depth of tumor (p = 0.004), differentiation degree (p = 0.032), distant metastasis (p = 0.007), TNM stage (p = 0.006) and lymph node metastasis (p = 0.012). More importantly, Kaplan-Meier survival analysis demonstrated that overall patient survival for those with low FRLnc1 expression was significantly longer than those patients with high FRLnc1 expression (p < 0.001). Multivariate analysis suggested that FRLnc1 expression was an independent prognostic marker for survival in patients with GC. CONCLUSIONS: The data presented in this work firstly suggested that FRLnc1 may be a prognostic predictor in GC. PMID- 29424900 TI - LncRNA CASC9 promotes tumorigenesis by affecting EMT and predicts poor prognosis in esophageal squamous cell cancer. AB - OBJECTIVE: The purpose of this study was to explore the clinical significance and biological function of long noncoding RNA CASC9 (CASC9) in esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Quantitative Real-time PCR (qRT-PCR) was used to determine the expression of CASC9 in ESCC tissues and cell lines. Receiver operating characteristic curves were used to evaluate the sensitivity and specificity of CASC9. The correlation between the CASC9 levels and the clinicopathological factors of the patients was also analyzed. Then, the survival was assessed by the Kaplan-Meier method and proportional hazards model. The effects of CASC9 on ESCC cells were evaluated by Cell Counting Kit-8 (CCK-8), migration and invasion. Finally, several EMT markers expression was detected by Western blot. RESULTS: We found that CASC9 was significantly upregulated in ESCC cell lines and clinical tissues. The CASC9 levels discriminated ESCC tissues from normal tissues with an area under the ROC curve (AUC) of 0.813. In addition, there is statistical significance between CASC9 expression level and tumor stage, lymph nodes metastasis, and clinical stage. Kaplan-Meier analysis indicated that high CASC9 expression had a significant impact on overall survival (p = 0.014) and disease-free survival (p = 0.0025). Moreover, CASC9 expression was an independent prognostic marker of overall survival and disease-free survival in a multivariate analysis. In vitro assay indicated that inhibition of CASC9 could suppress proliferation, migration, and invasion in ESCC. Further mechanistic studies found that aberrant CASC9 expression could modulate the expression levels of markers of EMT. CONCLUSIONS: Our data highlight the pivotal role of CASC9 as a novel diagnostic, prognostic biomarker and a potential therapeutic target of ESCC. PMID- 29424901 TI - LncRNA TUC338 promotes invasion of lung cancer by activating MAPK pathway. AB - OBJECTIVE: Lung cancer is highly heterogeneous and the 5-year survival rate is less than 15%. It is currently difficult to determine the heterogeneity of lung cancer and the underlying pathogenetic of metastasis. We aimed to investigate the effect of long non-coding RNA (lncRNA) TUC338 on the invasion of lung cancer by activating MAPK pathway and to understand the heterogeneity and metastasis mechanism of lung cancer. PATIENTS AND METHODS: The expression of lncRNA TUC338 in 42 samples of lung cancer and paracancerous tissues were accessed by RT-qPCR. The relationship between the expression of lncRNA and clinicopathological parameters was analyzed. After overexpressing and interfering with lncRNA TUC338, effects of lncRNA TUC338 on cell proliferation and invasion were determined by cell counting kit-8 (CCK8) and transwell assay. The protein expression was evaluated by Western blot. RESULTS: Higher expression of TUC338 in lung cancer was observed in comparison with that in paracancerous tissues. The survival time of TUC338 was correlated with the expression of TUC338. Clinical data analysis revealed that the expression of TUC338 was correlated with the overall survival, tumor size and lymph node metastasis in patients, but not with age and gender. After interfering and overexpressing TUC338, it was found that the activity of lung cancer cells was decreased, as well as the invasion ability after interference with TUC338. After overexpression of TUC338, we found that lung cancer cell activity increased, as well as the invasion ability. By Western blot, we found that TUC338 can promote the development of lung cancer through regulating MAPK pathway. CONCLUSIONS: TUC338 was overexpressed in lung cancer, and its expression may have a relationship to the prognosis of lung cancer. MAPK pathway was involved in the invasion of lung cancer regulated by TUC338. PMID- 29424902 TI - Regulatory role of CDX2 and NOX4 expression associated with recurrent nasopharyngeal carcinoma. AB - OBJECTIVE: Nasopharyngeal carcinoma (NPC) is a malignancy caused by Epstein-Barr virus (EBV). NPC is radiosensitive and has a high frequency of treatment failure due to metastasis, which results in recurrent nasopharyngeal carcinoma (rNPC). PATIENTS AND METHODS: In the present study, nasopharyngeal carcinoma biopsies were obtained from NPC and rNPC patients, as well as healthy controls, and reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and immunoblotting analyses were performed. RESULTS: The RTPCR data showed expression of CDX2 and NOX4 in rNPC biopsy samples but not in control or NPC samples. Immunohistochemical and immunoblotting analyses confirmed the expression of CDX2 and NOX4 in rNPC samples, but not in NPC biopsy samples. CONCLUSIONS: The finding concludes that an association of CDX2 and NOX4 expression with rNPC was noted; thus, these proteins may have value as prognostic indicators and may facilitate the development of novel therapeutics for rNPC patients. PMID- 29424903 TI - Low expression of miR-597 is correlated with tumor stage and poor outcome in breast cancer. AB - OBJECTIVE: MicroRNAs (miRNAs) have been reported to play important roles in the progression of breast cancer (BC). In the present study, we aimed to explore the association between miR-597 expression level and prognosis of BC. PATIENTS AND METHODS: The expression levels of miR-597 were measured using quantitative Real time polymerase chain reaction (qRT-PCR) analysis. The association between miR 597 expression and clinicopathological factors was analyzed. Differences in BC patient survival were determined using the Kaplan-Meier method and log-rank test. The prognostic value of miR-597 was further verified using the Cox proportional hazards regression model. RESULTS: Our data indicated that miR-597 was lowly expressed in BC compared with adjacent non-malignant tissues (p<0.001). Low miR 597 expression was observed to be closely associated with positive lymph node metastasis (p=0.001), higher TNM stage (p = 0.003), and poorer pathological differentiation (p=0.006). Furthermore, patients with lower levels of miR-597 expression had a shorter overall survival time than patients with higher miR-597 expression levels (p=0.009). In addition, multivariate Cox proportional hazards model analysis confirmed that miR-597 was an independent prognostic indicator of overall survival (p=0.005; HR 2.273; CI 95%, 1.117-4.291). CONCLUSIONS: We showed, for the first time, that decreased miR-597 expression suggested unfavorable prognosis for BC patients. PMID- 29424904 TI - miR-212-3p reduced proliferation, and promoted apoptosis of fibroblast-like synoviocytes via down-regulating SOX5 in rheumatoid arthritis. AB - OBJECTIVE: Several microRNAs have been reported to contribute the progression of rheumatoid arthritis (RA) due to the ectopic expression of miRNAs in fibroblast like synoviocytes (FLS). However, the function of miR-212-3p in RA still has not been mentioned before. PATIENTS AND METHODS: We obtained serum, synovial tissues, and FLS samples from RA patients and normal donors. Quantitative Real-time polymerase chain reaction (qRT-PCR) was used to analysis the expression level of miR-212-3p. By using miR-212-3p mimics and inhibitors, we detected the effects of miR-212-3p on cell proliferation, cell cycle, and apoptosis in RA-FLS. Dual luciferase and Western-blot were employed to verify the target of miR-212-3p. In addition, we over-expressed the SOX5 in miR-212-3p mimics treatment FLS to emphasize our results. RESULTS: The level of miR-212-3p in serum, synovial tissues, and FLS from RA patients was lower than these in relative normal group. Up-regulation of miR-212-3p inhibited cell proliferation, promoted cell apoptosis; however, knockdown of miR-212-3p promoted cell growth but reduced cell apoptotic rate. Furthermore, we found SOX5 as a direct target of miR-212-3p in RA FLS and up-regulation of SOX5 reversed the effects of miR-212-3p over-expression. CONCLUSIONS: miR-212-3p could reduce cell proliferation and promoted cell apoptosis of RA-FLS via repressing SOX5, which may provide a new biological target for RA treatment. PMID- 29424905 TI - Study the relevance between inflammatory factors and estradiol and their association with knee osteoarthritis in postmenopausal women. AB - OBJECTIVE: To investigate whether serum levels of inflammatory factors and estradiol (E2) are involved in the pathogenesis of postmenopausal women with knee osteoarthritis (OA). PATIENTS AND METHODS: 58 randomly patients diagnosed with postmenopausal knee OA that underwent orthopedic surgery from October 2013 to October 2016 in our hospital were selected. These patients, considered as the experimental group, according to the degree of cartilage damage, were divided into light, medium and heavy groups. 58 patients with menstrual disorders without knee OA were in the control group. 35 cases without osteoarthritis were included in the normal control group. Serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), erythrocyte sedimentation rate (ESR), high sensitive C- reactive protein (CRP), estradiol (E2) and IL-1, IL-6 and TNF-alpha levels in the synovial fluid of the experimental group were measured. RESULTS: The serum levels of IL-1, IL-6, TNF-alpha, and CRP in the normal control group, the control group and the experimental group were gradually increasing, the difference was statistically significant (p<0.05). The level of serum E2 was gradually decreasing (p<0.05); the difference of ESR between normal control group and control group had no significant difference (p>0.05), but the level of ESR in experimental group was higher than the normal control group and the control group (p<0.05). The serum levels of IL-1, TNF-alpha in experimental group of mild, moderate and severe sub-group were gradually increasing, the difference was statistically significant (p<0.05); while the level of IL-6 in the early, middle stage of OA increased significantly, and the late was reduced (p<0.05). The level of E2 was gradually decreased in the mild, moderate and severe sub-group of the experimental group, which had statistically significant difference (p<0.05). The level of serum E2 in the experimental group was positively correlated with the levels of IL-1, IL-6 and TNF-alpha in synovial fluid (p<0.05). CONCLUSIONS: The lack of estradiol is associated with the pathogenesis of OA in postmenopausal women, the inflammatory factors of IL-1, IL 6, TNF-alpha in postmenopausal increased in serum and synovial fluid may promote and aggravate the OA. PMID- 29424906 TI - Diagnostic value of various noninvasive indexes in the diagnosis of chronic hepatic fibrosis. AB - OBJECTIVE: Hepatic fibrosis is a repair response to chronic liver injury. This study evaluated the diagnostic value of various noninvasive indicators for hepatic fibrosis in patients with chronic liver disease. PATIENTS AND METHODS: 95 patients with liver biopsy were enrolled in this study. Routine clinical and laboratory examinations were collected, including age, sex, blood routine, biochemistry, serum fibrosis, and FibroTouch. APRI and FIB4 scores were calculated. The patients were grouped according to liver pathological staging to analyze the correlation between the fibrosis with serum fibrosis, APRI, FIB4 score, and FibroTouch. The receiver operator characteristics of S2, S3, and S4 were analyzed to calculate the area under the curve (AUC). RESULTS: No statistical difference was found on age, ALT, AST, GGT, BMI, TG, CHOL, and Glu (p > 0.05). Liver stiffness measurement (LSM), APRI, FIB4, PCIII, CIV, LN, and HA exhibited statistical significance (p < 0.05). Further correlation analysis showed that PCIII, IV-C, LN, APRI, LSM, and FIB4 were positively correlated with the stage of hepatic fibrosis (p < 0.05). ROC curve analysis demonstrated that LSM and FIB4 revealed good predictions of various stages of fibrosis in chronic liver disease with AUC greater than 0.7. The AUC of LSM in the diagnosis of liver cirrhosis (S4) reached 0.908. Its accuracy was influenced by liver inflammation. CONCLUSIONS: The LSM value in FibroTouch showed high coincidence rate with hepatic fibrosis staging. It is a valuable noninvasive method for assessing the progression of hepatic fibrosis in chronic liver disease. PMID- 29424907 TI - MiR-26a protects type II alveolar epithelial cells against mitochondrial apoptosis. AB - OBJECTIVE: This study aims to investigate the miR-26a effects on H2O2-induced apoptosis of Type II alveolar epithelial cells (AEC-II) and the potential mechanism. MATERIALS AND METHODS: AEC-II cells were treated with 0.5 mmol/L H2O2 to mimic cellular model of acute lung injury. Transmitting electron microscopy (TEM) was employed to observe the change of morphological structures. After infecting with miR-26a mimics, flow cytometry was performed to detect cell apoptosis. Western blot was also done to explore mitochondrial apoptosis-related markers: Caspase-3, B-cell lymphoma-2 (Bcl-2) and Bax. AEC-II cells treated with 0.5 mmol/L H2O2 exhibited significant cell apoptosis. Overexpression using miR 26a mimics partially reversed the effects of H2O2-induced apoptosis in AEC-II cells, evidenced by flow cytometry results. RESULTS: Further Western blot results revealed increased levels of Caspase-3 and Bax, and the decreased Bcl-2 level after infecting with miR-26a mimics, indicating miR-26a has protective effects against mitochondrial apoptosis in AEC-II cells. CONCLUSIONS: MiR-26a protected AEC-II cells against apoptosis via mitochondrial pathway. Thus, miR-26a promises to be a potential therapy in treatment of Acute Respiratory Distress Syndrome (ARDS). PMID- 29424908 TI - Hyperoxia induces the apoptosis of alveolar epithelial cells and changes of pulmonary surfactant proteins. AB - OBJECTIVE: To explore the changes of surfactant protein C, D (SP-C, SP-D) and apoptosis of alveolar epithelial cells (AEC) in the lung injury of neonatal rats induced by hyperoxia. MATERIALS AND METHODS: We divided neonatal rats within 24 hours into two groups randomly: the air group (n = 50) and the hyperoxia group (n = 50). Rats in the air group and hyperoxia group were bred conventionally and in tanks with normal pressure and 90% concentration of oxygen, respectively. On the 1st, 3rd, 7th, 10th, and 14th day after exposure, lung tissue of 8 rats in each group was collected and stained with hematoxylin and eosin (HE). We observed and recorded pathologic changes of lung tissue and detected apoptosis rate of alveolar epithelial cells by TUNEL (TdT-mediated dUTP nick end labeling). We detected the content of SP-C, SP-D in bronchoalveolar lavage fluid (BALF) by ELISA (enzyme-linked immunosorbent assay). RESULTS: In the air group, the alveolar formed gradually with equable size and regular shape during growth. While the amount of alveolar decreased gradually and we observed small vessels dilation and increasing hemorrhage as well as increasing interstitial cells and swollen lung tissue in the hyperoxia group. In the air group, the content of SP-C in the BALF reduced during growth. However, the content of SP-C in the hyperoxia group was lower than that in the air group on the first day, higher on the third day, reached the peak on the seventh day and began to decrease on the tenth day and more obviously on the fourteenth day. The level of SP-D in the air group declined gradually with growing. On the first day, the content of SP-D in the hyperoxia group was similar to that in the air group. It began to increase on the third day, reached its peak on the seventh day, and began to decrease on the tenth day, more obviously on the fourteenth day. CONCLUSIONS: Long-term exposure to hyperoxia inhibits the development of alveolar. The apoptosis of alveolar epithelial cells increased and the content of SP-C, SP-D in the lung tissue first increased and then decreased with the increase of exposure time. PMID- 29424909 TI - MiR-124 affects the apoptosis of brain vascular endothelial cells and ROS production through regulating PI3K/AKT signaling pathway. AB - OBJECTIVE: The apoptosis of vascular endothelial cells (VEC) is related to ischemic stroke. Phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT/PKB) signaling pathway can upregulate Bcl-2 expression, reduce reactive oxygen species (ROS) production, and induce apoptosis. The level of miR-124 was significantly increased after cerebral ischemia. This study aimed to investigate the role of miR-124 in regulating PI3K expression, brain VEC apoptosis, and ROS production. MATERIALS AND METHODS: The expressions of miR-124, PI3K, p-AKT, and Bcl-2 in brain VEC of rats from the sham group and middle cerebral artery occlusion (MCAO) group were tested. Bioinformatics analysis showed the complementary binding site between miR-124 and PI3K mRNA. ROS content and cell apoptosis were detected by flow cytometry. Rat brain VEC were cultured in vitro and treated by oxygen glucose deprivation (OGD) for 6 h. VECs were divided into four groups, including miR-NC, miR-124 inhibitor, pIRES2-blank, and pIRES2-PI3K groups, and were further treated by OGD. RESULTS: MiR-124 expression, ROS content, and cell apoptosis were markedly increased, whereas the levels of PI3K, p-AKT, and Bcl-2 were markedly reduced in rat VECs from MCAO group compared with that in the sham group. OGD treatment significantly induced VECs apoptosis, upregulated miR-124 expression and ROS content, and down-regulated the levels of PI3K, p-AKT, and Bcl-2. MiR-124 inhibitor or transfection of pIRES2-PI3K plasmid apparently enhanced PI3K, p-AKT, and Bcl-2 expressions, alleviated cell apoptosis and decreased ROS content in VECs induced by OGD. CONCLUSIONS: Our data demonstrated that miR-124 induced the apoptosis of brain vascular endothelial cells via the down-regulation of PI3K/AKT signaling pathway and promotion of ROS production. PMID- 29424910 TI - Correlations between blood uric acid and the incidence and progression of type 2 diabetes nephropathy. AB - OBJECTIVE: To investigate the relationships between blood uric acid (BUA) level and the incidence, progression and deterioration of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: A total of fifty patients with T2DM alone whose glycosylated hemoglobin (HbA1c) were under normal range (4-6.5%) at their admission to our hospital were randomly selected as diabetes mellitus (DM) group. Fifty patients with hyperuricemia alone were randomly selected as hyperuricemia (HUA) group. Fifty patients with T2DM complicated with hyperuricemia who were admitted to the hospital with HbAlc of 4 6.5% were randomly selected as diabetes mellitus hyperuricemia (DM-HUA) group. In addition, fifty healthy persons who passed the health examination were randomly selected as normal control (NC) group. The general data such as name and body mass index (BMI), metabolic-related indexes such as fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG) as well as kidney-related indexes such as blood urea nitrogen (BUN), creatinine (Cr) and albumin-creatinine-ratio (ACR) in four groups were tested and recorded at the same time. The interrelationships between uric acid (UA) and the above indexes were statistically analyzed. RESULTS: In DM-HUA group, serum TC, TG and low density lipoprotein (LDL) as well as urine ACE were greatly increased (p<0.05) compared with the other three groups, high-density lipoprotein (HDL) was significantly decreased compared with the remaining three groups (p<0.05), and BMI and Cr were increased compared with those in NC group and DM group (p<0.05). There were no significant differences in metabolic indexes and renal functions in DM group and HUA group. Compared with NC group, TC, LDL, serum beta2 macroglobulin and BMI in above two groups were greatly increased (p<0.05); BUN and Cr in HUA group were slightly higher than those in NC group (p<0.05). Multiple linear regression analysis showed that UA level was the main factor affecting ACR (R2=0.636, p<0.001). CONCLUSIONS: UA level is an independent risk factor for early renal disease in patients with T2DM, which can promote the progression and deterioration of renal disease in T2DM patients. PMID- 29424911 TI - Administration of vitamin D and high dose of omega 3 to sustain remission of type 1 diabetes. AB - OBJECTIVE: Two cases of Type 1 Diabetes (T1D) in pediatric subjects treated with supplementation with high dose vitamin D and omega 3 are reported. A similar pattern of remission of the disease was observed, resulting in restoration and subsequent persistence of optimal metabolic control, one and two years after T1D onset. Minimal basal insulin administration (0.1 IU/kg/die) in a single evening injection was required. The immunomodulatory and anti-inflammatory properties of the supplements were likely contributing to the observed effect. Similarities in genotyping and autoantibody patterns in these two cases could be of assistance to identify which subjects with T1D could benefit from this supplemental therapy. High dose vitamin D and omega 3 could be of assistance in childhood T1D therapy, to prolong preservation of endogenous insulin secretion in the absence of side effects. We do not know how long the state of remission can last, but these initial results are promising and represented a significant benefit for the two pediatric subjects treated. Larger controlled studies will determine the long term effect of this proposed supplementation and its possible cost-benefits, including reduction of hypoglycemic episodes and complications. PMID- 29424912 TI - The potential role of quantitative digital subtraction angiography in evaluating type B chronic aortic dissection during TEVAR: preliminary results. AB - OBJECTIVE: To evaluate the role of quantitative digital subtraction angiography (Q-DSA) with parametric color coding (PCC) in assessing patients with type B chronic thoracic aortic dissection (TBCAD) during thoracic endovascular aortic repair (TEVAR) procedures. PATIENTS AND METHODS: A total of 11 patients electively treated in our Department for a TBCAD were retrospectively enrolled. All cases were treated with TEVAR for false lumen aneurysm of the thoracic descending aorta. For digital subtraction angiography (DSA) series post processing, a newly implemented PCC algorithm was used to turn consecutive two dimensional images into a single color-coded picture (syngo iFLOW, Siemens AG, Forchheim, Germany). In consensus reading, two clinicians experienced in vascular imaging evaluated the DSA series in blinded assessment and compared them to the color-coded images. PCC was assessed for its accuracy in identifying the true and false lumen as well as whether it could provide improved visualization in pre deployment stent grafting and the final evaluation of treatment. RESULTS: PCC facilitated the visualization of the aortic dissection angioarchitecture in terms of contemporary true and false lumen vision in 81.8% of the cases. In 72.7% of the procedures, Q-DSA was estimated to improve aorta information assessment in terms of false lumen viewing, and it was possible to identify the proximal entry tear position in 45.4% of the cases. After stent graft deployment, in 72.7% of the cases (all 8 patients in which the aortic arch false lumen was visible in pre treatment), Q-DSA confirmed the absence of early false lumen reperfusion. CONCLUSIONS: Our results indicate that Q-DSA could be useful in the intraprocedural evaluation of patients with aortic dissection during TEVAR procedures without additional x-ray costs and contrast exposure. PMID- 29424913 TI - The targeted regulation of miR-26a on PTEN-PI3K/AKT signaling pathway in myocardial fibrosis after myocardial infarction. AB - OBJECTIVE: MiR-26a is involved in regulating myocardial remodeling and it is also related to organ fibrosis. Its role in myocardial fibrosis process is still controversy. As a definite target gene of miR-26a, phosphatase and tensin homology does on chromosome ten (PTEN) plays a role in regulating PTEN-PI3K/AKT signaling pathway. This study explored the function of miR-26a in regulating PTEN PI3K/AKT signaling pathway, MMP-9 expression, and myocardial fibrosis after acute myocardial infarction (AMI). MATERIALS AND METHODS: AMI model was established on Sprague-Dawley (SD) rats. Hydroxyproline, COL1A1, miR-26a, PTEN, p-AKT, and MMP-9 expressions in myocardial tissue at 1 week, 2 weeks, and 4 weeks after modeling were detected. Human cardiac fibroblasts (HCF) were cultured in vitro to detect miR-26a, PTEN, p-AKT, MMP-9, COL1A1, and alpha-SMA expressions in the process of myofibroblast differentiation (P1, P3, P5). HCF in P5 were transfected with miR 26a mimics or inhibitor to test miR-26a, PTEN, p-AKT, MMP-9, COL1A1, and alpha SMA expressions. RESULTS: Hydroxyproline, COL1A1, miR-26a, p-AKT, and MMP-9 overexpressed, while PTEN downregulated in myocardial tissue during the process of myocardial fibrosis after AMI. MiR-26a, PTEN, p-AKT, MMP-9, COL1A1, and alpha SMA expression gradually enhanced, while PTEN declined, following the process of HCF differentiating into myofibroblast. MiR-26a elevation suppressed PTEN expression, and increased p-AKT, MMP-9, COL1A1, and alpha-SMA levels. MiR-26a reduction significantly upregulated PTEN level, weakened PI3K/AKT signaling pathway activity, and declined MMP-9, COL1A1, and alpha-SMA protein expression. CONCLUSIONS: MiR-26a upregulation may play a role in myocardial fibrosis after AMI by suppressing PTEN, enhancing PI3K/AKT signaling pathway and MMP-9 levels. PMID- 29424914 TI - MicroRNA-298 regulates apoptosis of cardiomyocytes after myocardial infarction. AB - OBJECTIVE: To investigate the role and mechanism of micro ribonucleic acid (miR) 298 in myocardial apoptosis after myocardial infarction. MATERIALS AND METHODS: In vivo experiments, the rat model of myocardial infarction was established, and miR-298 was up-regulated via lentivirus with miR-298 overexpression. Cardiac function of rats was detected via echocardiography, Bcl-2 associated X protein (BAX) expressions in infarction border zone were detected via Real-time Quantitative PCR (qT-PCR) and Western blot, and TUNEL assay was used to detect the myocardial apoptosis. In vitro experiments, myocardial cells were isolated and cultured, an oxygen-glucose deprivation (OGD) model was established to mimicking the ischemic condition, the relationship between miR-298 and BAX was verified using luciferase reporter vector, lentivirus and small-interfering RNA (siRNA) in BAX. RESULTS: In vivo experiments showed that the miR-298 expression was down-regulated at 2 and 4 weeks after myocardial infarction. The up regulation of miR-298 significantly improved the cardiac function, decreased the expressions of BAX, reduced the myocardial apoptosis and inhibit the apoptosis proteins expression including cytochrome-c and cleaved caspase-3. In vitro experiments revealed that BAX was a target gene of miR-298 and further proof that miR-298 could inhibit the cytochrome-c and cleaved caspase-3 expression and myocardial apoptosis through BAX. CONCLUSIONS: MiR-298 can improve the myocardial apoptosis through the target gene BAX. PMID- 29424915 TI - Circulating miR-379 as a potential novel biomarker for diagnosis of acute myocardial infarction. AB - OBJECTIVE: Previous studies have demonstrated that microRNA-379 (miR-379) was involved in regulating cell proliferation. The present study aimed to investigate its potential role in the diagnosis of cute myocardium infarction (AMI). PATIENTS AND METHODS: Plasma samples from 30 patients with AMI and 30 healthy adults (non AMI controls) were collected. The abundance of circulating miR-379 was determined using quantitative Real-time PCR (qRT-PCR). Receiver-operator characteristic (ROC) analyses were performed by GraphPad Prism 5.0 and the areas under the curve (AUC) were calculated. The proliferative ability and cell cycle progression of vascular smooth muscle cell (VSMC) were measured by CCK-8 and flow cytometry, respectively. RESULTS: We found that the plasma miR-379 level was significantly decreased in patients with AMI compared with healthy people. Further studies demonstrated the miR-379 was negatively correlated with creatine kinase-MB (CK MB) and cTns in study subjects. Finally, ROC analysis revealed an AUC value of 0.751 in discriminating AMI patients from healthy controls. Function assay in vitro further indicated miR-379 inhibited cell proliferation and induced cell cycle G0/G1 arrest in VSMCs. CONCLUSIONS: Our results suggest that miR-379 may be a novel biomarker for the diagnosis of AMI by affecting VSMC cell function, which could be used in the early diagnosis of AMI. PMID- 29424916 TI - Role of surgical setting and patients-related factors in predicting the occurrence of postoperative pulmonary complications after abdominal surgery. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the role of surgical setting (urgent vs. elective) and approach (open vs. laparoscopic) in affecting postoperative pulmonary complications (PPCs) prevalence in patients undergoing abdominal surgery. PATIENTS AND METHODS: After local Ethical Committee approval, 409 patients who had undergone abdominal surgery between January and December 2014 were included in the final analysis. PPCs were defined as the development of one of the following new findings: respiratory failure, pulmonary infection, aspiration pneumonia, pleural effusion, pneumothorax, atelectasis on chest X-ray, bronchospasm or un-planned urgent re-intubation. RESULTS: PPCs prevalence was greater in urgent (33%) vs. elective setting (7%) (chi2 with Yates correction: 44; p=0.0001) and in open (6%) vs. laparoscopic approach (1.9%) (chi2 with Yates correction: 12; p=0.0006). PPCs occurrence was positively correlated with in-hospital mortality (Biserial Correlation r=0.37; p=0.0001). Logistic regression showed that urgent setting (p=0.000), Ariscat (Assess Respiratory Risk in Surgical Patients in Catalonia) score (p=0.004), and age (p=0.01) were predictors of PPCs. A cut-off of 23 for Ariscat score was also identified as determining factor for PPCs occurrence with 94% sensitivity and 29% specificity. CONCLUSIONS: Patients undergoing abdominal surgery in an urgent setting were exposed to a higher risk of PPCs compared to patients scheduled for elective procedures. Ariscat score fitted with PPCs prevalence and older patients were exposed to a higher risk of PPCs. Prospective studies are needed to confirm these results. PMID- 29424917 TI - The effect of curcumin on cell adhesion of human esophageal cancer cell. AB - OBJECTIVE: Esophageal cancer is the 8th most common cancers worldwide and the 6th most common cause of death among cancers. Curcumin has been reported to have the function of anti-inflammatory, antioxidant, anti-rheumatoid, and anti atherosclerosis role. It can also reduce lipid, eliminate free radicals and inhibit the growth of the tumor. Many reports had suggested that curcumin has shown great potential in the treatment of tumors by inducing apoptosis. Little is known about the effects of curcumin on cell adhesion of tumor cancer. Therefore, in this study, we attempted to look for a new approach to target resistant cells and improve efficacy without toxicity. MATERIALS AND METHODS: Human esophageal cancer cell line (Eca-109 cells) was cultured. Cell adhesion was detected under a microplate reader. Reactive oxygen species were measured using Fluostar Omega Spectrofluorimeter. SOD activity and GSH content in cells were detected by commercial determination kit. The expression of p-JAK, p-STAT3 and STAT3 were measured by Western blot and RT-PCR. RESULTS: Cell adhesion assay showed curcumin enhances cell-cell adhesion and cell-matrix adhesion in Eca-109 cells. ROS levels, SOD activity and total GSH content were detected and the results showed curcumin decreases intracellular ROS levels but increases SOD activity and total GSH content. Then, NAC (ROS inhibitor) and ICI (ER inhibitor) were pre-treated. Results showed ICI reversed the decreasing of intracellular ROS levels and the increasing of SOD activity and total GSH content affected by curcumin, but NAC had no such impact. Taken together, ER rather than ROS involves in cell adhesion affected by curcumin. Meanwhile, the downregulating of p-JAK, p-SATA3 and total STAT3 were caused by curcumin but NAC had no such influence. They were reversed by ICI, but NAC had no such influence. CONCLUSIONS: Curcumin could increase cell adhesion through inhibiting JAK/STAT3 mediated by ER in Eca-109. PMID- 29424918 TI - Highly expressed long non-coding RNA DUXAP10 promotes proliferation of ovarian cancer. AB - OBJECTIVE: To investigate the expression of long non-coding RNA DUXAP10 in ovarian cancer and its effect on ovarian cancer cell lines HO8910 and A2780 cells. MATERIALS AND METHODS: Search the microarray dataset from the Gene Expression Omnibus (GEO) database using the keywords "ovarian cancer" and "GPL570". The differentially expressed genes in ovarian cancer tissues and normal ovarian tissues were analyzed by bioinformatics. Normal ovarian epithelial cells IOSE386, ovarian cancer HEY, HO8910 and A2780 cell lines were cultured. Cell proliferation assay was detected by CCK8 method and cloning formation assay was done. Quantitative Real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of RNA. RESULTS: The results showed that the expression of DUXAP10 in ovarian cancer tissues was significantly higher than that in normal ovarian tissues, which was consistent with those of TCGA. Clinical data analysis showed that the expression level of DUXAP10 was correlated with tumor size and FIGO stage in clinical patients. Compared with the negative control group, the proliferation ability and cell cloning ability of HO8910 cells overexpressing DUXAP10 were significantly increased (p<0.001), while the proliferation and cell cloning ability of A2780 cells interfering with DUXAP10 were significantly decreased (p<0.001), indicating that DUXAP10 played a role in promoting the proliferation of ovarian cancer cells. CONCLUSIONS: DUXAP10 was significantly overexpressed in ovarian cancer tissues, and its expression was positively correlated with tumor size and FIGO stage in clinical patients. DUXAP10 promoted the proliferation of ovarian cancer cells and was expected to be a predictor and a potential therapeutic target of ovarian cancer. PMID- 29424919 TI - Ibrutinib presents antitumor activity in skin cancer and induces autophagy. AB - OBJECTIVE: Skin cancer is one of the most common malignancies in dermatology. Patient compliance and prognosis of skin cancer are poor. Ibrutinib, a Bruton's Tyrosine Kinase (BTK) inhibitor, is a new anticancer drug used to treat many cancers. Therefore, we aimed to explore the role of ibrutinib in the treatment of skin cancer. MATERIALS AND METHODS: Cell Counting Kit-8 (CCK8) and plate cloning assay were used to detect cell proliferation. Apoptosis was determined by flow cytometry. Western blotting analysis was used to analyze the expression of key proteins that regulated autophagy. Proliferation and apoptosis of skin cancer cells and induction of autophagy induced by ibrutinib were evaluated. RESULTS: CCK8 plate cloning assays showed that ibrutinib can gradually inhibit the skin cancer cell proliferation as the treatment time and dose increased. Results of flow cytometry showed that apoptosis in skin cancer cells were induced after ibrutinib treatment. Western blot showed that autophagy in skin cancer cells was found induced by ibrutinib and also related to the time and concentration of ibrutinib treatment. Combination treatment of ibrutinib and 3MA for skin cancer cells can significantly increase apoptosis. CONCLUSIONS: Ibrutinib has anti-tumor activity in skin cancer and can induce autophagy. Binding to autophagy inhibitors can promote ibrutinib's anti-skin cancer activity. Our experimental results provided new ideas for developing skin cancer drugs. PMID- 29424920 TI - Menopause: new frontiers in the treatment of urogenital atrophy. AB - OBJECTIVE: Urogenital atrophy is a degenerative process that may occur during menopause causing debilitating disorders and painful symptomatology. Estrogen therapy slows the onset of atrophy, but it requires ongoing therapy to maintain its effectiveness. To mitigate the degenerative evolutions associated with menopause, patients may benefit from new therapeutic approaches, such as the use of mesenchymal stem cells. Among the many sources, the adipose tissue is considered one of the smartest, due to its abundance and easy access. This study investigated the feasibility and potential benefits of using an autologous adipose tissue to treat the symptoms of urogenital atrophy. PATIENTS AND METHODS: In 2014, the first three women affected by post-menopausal urogenital atrophy were treated with injections of autologous and micro-fragmented adipose tissue (Lipogems(r)). Clinical outcomes were determined at 3, 6, 9, 12, 18, 24, and 36 months by evaluating vaginal dryness, burning, itching, stranguria, sensitivity, and dyspareunia. Pre- and 36 months post-op biopsies and vaginal discharge were also collected. RESULTS: The three women reported a significant improvement of the symptoms at 6 months with complete resolution at 9 months. This benefit, subjectively reported and confirmed by clinical evaluation, remained constant without recurrence at least until 36 months. Immunohistochemical analysis revealed a total recovery of vaginal vitality with production of glycogen, vasculature hyperplasia and regeneration of the epithelium and subcutaneous tissue at 36 months. The analysis of vaginal discharge showed a restoration of an acid pH with the colonization of lactobacilli. No postoperative complications nor adverse events were recorded. CONCLUSIONS: The results of these first three cases pointed to autologous and micro-fragmented adipose tissue as a safe, feasible and effective therapeutic approach for the treatment of post-menopausal urogenital atrophy. PMID- 29424921 TI - Role of long non-coding RNA SNHG1 in occurrence and progression of ovarian carcinoma. AB - OBJECTIVE: To investigate the expression of human long non-coding ribonucleic acid (lncRNA) small nucleolar RNA host gene 1 (SNHG1) in epithelial ovarian carcinoma tissues and its effects on the in vitro proliferation, apoptosis, invasion and metastasis of ovarian carcinoma cells, and to investigate its possible mechanism. PATIENTS AND METHODS: The expressions of SNHG1 in 20 pairs of epithelial ovarian carcinoma tissues and para-carcinoma normal tissues were detected by Real-time fluorescence quantitative polymerase chain reaction (qRT PCR). The expressions of SNHG1 in normal ovarian epithelial cells (IOSE25) and ovarian carcinoma cells (CAOV-3, SKOV-3, ES2 and A2780) were further detected. The knockdown efficiency of SNHG1 small interfering RNA (siRNA) in SKOV-3 cells was detected via qRT-PCR. Moreover, the effects of SNHG1 knockdown on proliferation, migration and apoptosis of SKOV-3 cells were detected by cell counting kit 8 (CCK8) proliferation assay, clone formation assay, transwell migration assay and flow cytometry. Finally, the expressions of apoptosis-related proteins, epithelial-mesenchymal transition (EMT)-related proteins and matrix metalloproteinases (MMPs) in control group and interference group were detected by Western blotting. RESULTS: The expression level of lncRNA SNHG1 in ovarian carcinoma tissues was significantly higher than that in para-carcinoma normal tissues. After lncRNA SNHG1 knockdown in SKOV-3 cells, the cell proliferation and clone formation abilities were significantly inhibited. The apoptosis assay proved that inhibiting lncRNA SNHG1 could promote the apoptosis of SKOV-3 cells. Besides, Western blotting revealed that the expressions of pro-apoptotic proteins in interference group were significantly upregulated compared with those in control group. Wound-healing assay and transwell migration assay showed that the down-regulation of lncRNA SNHG1 could inhibit the invasion and metastasis of SKOV 3 cells, whose mechanism was related to the inhibition of EMT process and down regulation of expressions of MMPs. CONCLUSIONS: LncRNA SNHG1 is highly expressed in ovarian carcinoma, which can promote the growth, invasion and metastasis of ovarian carcinoma cells. The down-regulation of SNHG1 can inhibit the proliferation, invasion and metastasis of SKOV-3 cells. Inhibiting the expression of SNHG1 may be a potentially effective means of treating ovarian carcinoma. PMID- 29424922 TI - MiR-182 affects renal cancer cell proliferation, apoptosis, and invasion by regulating PI3K/AKT/mTOR signaling pathway. AB - OBJECTIVE: PI3K/AKT/mTOR signaling pathway plays a crucial role in tumorigenesis and development. It was shown that mTOR overexpression was associated with the pathogenesis of renal cancer. Down-regulation of MiR-182 was found in renal carcinoma tissue. This study thus aims to investigate the influence of miR-182 in regulating mTOR expression and renal carcinoma cell proliferation, invasion, and apoptosis. PATIENTS AND METHODS: The targeted regulatory relationship between miR 182 and mTOR was tested by dual luciferase assay. Renal carcinoma tissue and benign renal tissue were collected to detect miR-182 and mTOR expressions. MiR 182, mTOR, p-mTOR, and Survivin levels were compared between HK-2 and A498 cells. Renal carcinoma A498 cells were divided into four groups, including miR-NC, anti miR-182 mimic, si-NC, and si-mTOR groups. Cell apoptosis and proliferation were evaluated by flow cytometry. Cell invasion was determined by transwell assay. RESULTS: Bioinformatics analysis revealed the complementary relationship between miR-182 and the 3'-UTR of mTOR mRNA. The level of miR-182 was significantly reduced, while mTOR expression was upregulated in renal carcinoma tissue compared with that in benign lesion, which was associated with TNM stage. MiR-182 expression was markedly declined, whereas mTOR, p-mTOR, and Survivin levels were apparently upregulated in A498 cells compared with that in HK-2 cells. The treatment of miR-182 mimic or si-mTOR transfection significantly downregulated mTOR, p-mTOR, and Survivin expressions, restrained cell proliferation and invasion, and enhanced cell apoptosis. CONCLUSIONS: The decreasing level of miR 182 plays a role in enhancing mTOR expression and promoting renal carcinoma pathogenesis. Overexpression of miR-182 inhibited mTOR expression and weakened cell proliferation and invasion, which provides leads to the future therapy of renal cancer. PMID- 29424923 TI - Cisplatin induces apoptosis of hepatocellular carcinoma LM3 cells via down regulation of XIAP. AB - OBJECTIVE: Cisplatin is an important anti-cancer drug. However, the molecular mechanism of cisplatin on inhibition of the proliferation of liver cancer cells is unclear. Thus, we aimed to investigate the regulatory role of cisplatin on the growth and apoptosis of hepatoma LM3 cells. MATERIALS AND METHODS: LM3 cells were treated with cisplatin (2 MUmol/L) for 48 h. MTT assay, flow cytometry, and caspase-3 activity assay were used to detect the growth, proliferation and apoptosis of LM3 cells. Western blot was applied to detect the expression of the inhibitor of apoptosis protein, XIAP. siRNA was used to knockdown the level of XIAP followed by cisplatin (2 MUmol/L) treatment, and then the apoptosis of LM3 cells was measured. RESULTS: The treatment of cisplatin significantly inhibited the growth but induced the apoptosis of LM3 cells. Cisplatin also downregulated the expression of XIAP. The downregulation of XIAP by using siRNA enhanced the apoptosis of LM3 cells induced by cisplatin. CONCLUSIONS: Downregulation of XIAP enhanced the proapoptotic effect of cisplatin on LM3 cells, suggesting that XIAP might be used as a potential target in the treatment of liver cancer. PMID- 29424924 TI - HuR, TTP, and miR-133b expression in NSCLC and their association with prognosis. AB - OBJECTIVE: This study sought to explore HuR, Thrombotic Thrombocytopenic Purpura (TTP), and microRNA 133b (miR-133b) expression levels in non-small cell lung cancer (NSCLC) patients and assess the relationship of expression with disease prognosis. PATIENTS AND METHODS: One hundred and ten paraffin-embedded and 33 fresh flash-frozen NSCLC samples, together with matched tumor adjacent normal tissue controls, were collected from patients between January 2013 and July 2015 in Yidu Central Hospital of Weifang. Twenty-nine patients provided both paraffin embedded and fresh frozen tissues. HuR and TTP protein expression levels were measured in 110 paraffin-embedded tumors and matched controls using immunohistochemistry, while miR-133b levels were measured using Real-time fluorescent quantitative PCR. RESULTS: Follow-up parameters included treatment response, relapse events, post-relapse treatment, disease free survival (DFS), and overall survival (OS). HuR expression was significantly different between tumor and matched controls (p < 0.0001). Cytoplasmic expression levels of HuR and TTP correlated with pTNM staging (p < 0.05). No significant correlation was observed between HuR and TTP expression and other clinical pathological factors (gender, age, tumor size, pathological subtype, differentiation status, lymph node metastasis, distant metastasis, and tumor invasiveness). MiR-133b expression correlated with tumor size (p = 0.015) and differentiation status (p = 0.013) in paraffin-embedded sections, but was only correlated with pTNM staging (p = 0.032) in frozen tissue samples. No significant difference in DFS nor OS was observed between 68 HuR-positive and 42 HuR-negative patients (DFS, Log Rank p = 0.712; OS, Log Rank p = 0.220). However, DFS and OS were significantly different between miR-133b high-expression and low-expression patients (DFS, Log Rank p = 0.048 < 0.05; OS, Log Rank p = 0.025 < 0.05). This indicates that miR-133b levels may have prognostic value. CONCLUSIONS: HuR expression was negatively correlated with TTP expression in NSCLC tissues. MiR-133b levels were downregulated in normal tissues compared to both paraffin and frozen tumor samples, and correlated with both HuR and TTP expression, which may affect the prognosis of NSCLC patients. PMID- 29424925 TI - New possible mechanisms of embolism formation when measuring vulnerability curves by air injection in a pressure sleeve. AB - Since 1988, researchers have exposed stems to positive pressures to displace water in vessels and measure the impact of applied pressure on hydraulic conductivity. The pressure-sleeve technique has been used in more than 60 publications to measure vulnerability curves (VCs), which are a measure of how water stress impacts the ability of plants to transport water because water stress induces embolism in vessels that blocks water flow. It is thought that the positive pressure in a sleeve required to induce 50% loss of conductivity (PLC), P50 , is the same magnitude as the tension that causes 50% PLC, T50 , where the tension can be induced by either bench-top dehydration or by a centrifuge technique. The unifying concept that P50 = T50 and that the entire VC is the same regardless of method is referred to as the air-seeding hypothesis. In the current study, we performed experiments to further test the air-seeding hypothesis in pressure sleeves and concluded that an "effervescence" mechanism caused embolism formation under positive pressure. This mechanism explains why VCs measured using positive pressure do not always match VCs obtained by other methods that induce water tension. PMID- 29424926 TI - Genomic structure and expression of alternative oxidase genes in legumes. AB - Mitochondria isolated from chickpea (Cicer arietinum) possess substantial alternative oxidase (AOX) activity, even in non-stressed plants, and one or two AOX protein bands were detected immunologically, depending on the organ. Four different AOX isoforms were identified in the chickpea genome: CaAOX1 and CaAOX2A, B and D. CaAOX2A was the most highly expressed form and was strongly expressed in photosynthetic tissues, whereas CaAOX2D was found in all organs examined. These results are very similar to those of previous studies with soybean and siratro. Searches of available databases showed that this pattern of AOX genes and their expression was common to at least 16 different legume species. The evolution of the legume AOX gene family is discussed, as is the in vivo impact of an inherently high AOX capacity in legumes on growth and responses to environmental stresses. PMID- 29424927 TI - Allogeneic hematopoietic stem cell transplantation for relapsed follicular lymphoma: A combined analysis on behalf of the Lymphoma Working Party of the EBMT and the Lymphoma Committee of the CIBMTR. AB - BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only potentially curative treatment option for relapsed follicular lymphoma (FL), yet questions remain about the optimal timing. This study analyzed long term outcomes and associated factors among recipients of allo-HCT with FL. METHODS: Patients with relapsed FL who underwent allo-HCT from 2001 to 2011 with a human leukocyte antigen (HLA)-matched donor were included. Outcome analyses for overall survival (OS), progression-free survival (PFS), transplant-related mortality (TRM), and disease relapse/progression were calculated. A multivariate analysis was performed to determine factors associated with outcomes, and a prognostic score for treatment failure was developed in a subset analysis of patients. RESULTS: In all, 1567 patients with relapsed FL were included; the median follow-up was 55 months. The 5-year probabilities of OS and PFS were 61% and 52%, respectively. The 5-year cumulative incidences of disease progression/relapse and TRM were 29% and 19%, respectively. Chemoresistant disease, older age, heavy pretreatment, poor performance status (PS), and myeloablative protocols were predictors for worse survival. The prognostic score, using age, lines of prior therapy, disease status, and PS, stratified patients into 3 groups-low, intermediate, and high risk-with 5-year PFS rates of 68%, 53%, and 46%, respectively, and 5-year OS rates of 80%, 62%, and 50%, respectively. CONCLUSIONS: Allo-HCT should be considered for patients with relapsed FL and available HLA-matched donors. Outcomes are better in earlier phases of the disease, and reduced-intensity conditioning should be preferred. The prognostic score presented here can assist in counseling patients and determining the time to proceed to transplantation. Cancer 2018;124:1733-42. (c) 2018 American Cancer Society. PMID- 29424928 TI - Native soils with their microbiotas elicit a state of alert in tomato plants. AB - Several studies have investigated soil microbial biodiversity, but understanding of the mechanisms underlying plant responses to soil microbiota remains in its infancy. Here, we focused on tomato (Solanum lycopersicum), testing the hypothesis that plants grown on native soils display different responses to soil microbiotas. Using transcriptomics, proteomics, and biochemistry, we describe the responses of two tomato genotypes (susceptible or resistant to Fusarium oxysporum f. sp. lycopersici) grown on an artificial growth substrate and two native soils (conducive and suppressive to Fusarium). Native soils affected tomato responses by modulating pathways involved in responses to oxidative stress, phenol biosynthesis, lignin deposition, and innate immunity, particularly in the suppressive soil. In tomato plants grown on steam-disinfected soils, total phenols and lignin decreased significantly. The inoculation of a mycorrhizal fungus partly rescued this response locally and systemically. Plants inoculated with the fungal pathogen showed reduced disease symptoms in the resistant genotype in both soils, but the susceptible genotype was partially protected from the pathogen only when grown on the suppressive soil. The 'state of alert' detected in tomatoes reveals novel mechanisms operating in plants in native soils and the soil microbiota appears to be one of the drivers of these plant responses. PMID- 29424929 TI - Three physiological parameters capture variation in leaf respiration of Eucalyptus grandis, as elicited by short-term changes in ambient temperature, and differing nitrogen supply. AB - We used instantaneous temperature responses of CO2 -respiration to explore temperature acclimation dynamics for Eucalyptus grandis grown with differing nitrogen supply. A reduction in ambient temperature from 23 to 19 degrees C reduced light-saturated photosynthesis by 25% but increased respiratory capacity by 30%. Changes in respiratory capacity were not reversed after temperatures were subsequently increased to 27 degrees C. Temperature sensitivity of respiration measured at prevalent ambient temperature varied little between temperature treatments but was significantly reduced from ~105 kJ mol-1 when supply of N was weak, to ~70 kJ mol-1 when it was strong. Temperature sensitivity of respiration measured across a broader temperature range (20-40 degrees C) could be fully described by 2 exponent parameters of an Arrhenius-type model (i.e., activation energy of respiration at low reference temperature and a parameter describing the temperature dependence of activation energy). These 2 parameters were strongly correlated, statistically explaining 74% of observed variation. Residual variation was linked to treatment-induced changes in respiration at low reference temperature or respiratory capacity. Leaf contents of starch and soluble sugars suggest that respiratory capacity varies with source-sink imbalances in carbohydrate utilization, which in combination with shifts in carbon-flux mode, serve to maintain homeostasis of respiratory temperature sensitivity at prevalent growth temperature. PMID- 29424930 TI - Inhaled mannitol for cystic fibrosis. AB - BACKGROUND: Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review. OBJECTIVES: To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences.Date of last search: 28 September 2017. SELECTION CRITERIA: All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment. DATA COLLECTION AND ANALYSIS: Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. The quality of the evidence was assessed using GRADE. MAIN RESULTS: Six studies (reported in 50 publications) were included with a total of 784 participants.Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population.Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole.While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies.Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non respirable mannitol groups; however, we judged this evidence to be of low to very low quality.For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF.For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations.In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa). AUTHORS' CONCLUSIONS: There is moderate quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa.The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice. PMID- 29424931 TI - Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology. AB - KEY POINTS: Ca2+ signalling in different cell types in exocrine pancreatic lobules was monitored simultaneously and signalling responses to various stimuli were directly compared. Ca2+ signals evoked by K+ -induced depolarization were recorded from pancreatic nerve cells. Nerve cell stimulation evoked Ca2+ signals in acinar but not in stellate cells. Stellate cells are not electrically excitable as they, like acinar cells, did not generate Ca2+ signals in response to membrane depolarization. The responsiveness of the stellate cells to bradykinin was markedly reduced in experimental alcohol-related acute pancreatitis, but they became sensitive to stimulation with trypsin. Our results provide fresh evidence for an important role of stellate cells in acute pancreatitis. They seem to be a critical element in a vicious circle promoting necrotic acinar cell death. Initial trypsin release from a few dying acinar cells generates Ca2+ signals in the stellate cells, which then in turn damage more acinar cells causing further trypsin liberation. ABSTRACT: Physiological Ca2+ signals in pancreatic acinar cells control fluid and enzyme secretion, whereas excessive Ca2+ signals induced by pathological agents induce destructive processes leading to acute pancreatitis. Ca2+ signals in the peri-acinar stellate cells may also play a role in the development of acute pancreatitis. In this study, we explored Ca2+ signalling in the different cell types in the acinar environment of the pancreatic tissue. We have, for the first time, recorded depolarization-evoked Ca2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the stellate cells. The stellate, like the acinar, cells are not electrically excitable as they do not generate Ca2+ signals in response to membrane depolarization. The principal agent evoking Ca2+ signals in the stellate cells is bradykinin, but in experimental alcohol-related acute pancreatitis, these cells become much less responsive to bradykinin and then acquire sensitivity to trypsin. Our new findings have implications for our understanding of the development of acute pancreatitis and we propose a scheme in which Ca2+ signals in stellate cells provide an amplification loop promoting acinar cell death. Initial release of the proteases kallikrein and trypsin from dying acinar cells can, via bradykinin generation and protease-activated receptors, induce Ca2+ signals in stellate cells which can then, possibly via nitric oxide generation, damage more acinar cells and thereby cause additional release of proteases, generating a vicious circle. PMID- 29424932 TI - Mechanisms of glacial-to-future atmospheric CO2 effects on plant immunity. AB - The impacts of rising atmospheric CO2 concentrations on plant disease have received increasing attention, but with little consensus emerging on the direct mechanisms by which CO2 shapes plant immunity. Furthermore, the impact of sub ambient CO2 concentrations, which plants have experienced repeatedly over the past 800 000 yr, has been largely overlooked. A combination of gene expression analysis, phenotypic characterisation of mutants and mass spectrometry-based metabolic profiling was used to determine development-independent effects of sub ambient CO2 (saCO2 ) and elevated CO2 (eCO2 ) on Arabidopsis immunity. Resistance to the necrotrophic Plectosphaerella cucumerina (Pc) was repressed at saCO2 and enhanced at eCO2 . This CO2 -dependent resistance was associated with priming of jasmonic acid (JA)-dependent gene expression and required intact JA biosynthesis and signalling. Resistance to the biotrophic oomycete Hyaloperonospora arabidopsidis (Hpa) increased at both eCO2 and saCO2 . Although eCO2 primed salicylic acid (SA)-dependent gene expression, mutations affecting SA signalling only partially suppressed Hpa resistance at eCO2 , suggesting additional mechanisms are involved. Induced production of intracellular reactive oxygen species (ROS) at saCO2 corresponded to a loss of resistance in glycolate oxidase mutants and increased transcription of the peroxisomal catalase gene CAT2, unveiling a mechanism by which photorespiration-derived ROS determined Hpa resistance at saCO2 . By separating indirect developmental impacts from direct immunological effects, we uncover distinct mechanisms by which CO2 shapes plant immunity and discuss their evolutionary significance. PMID- 29424933 TI - Hydraulics play an important role in causing low growth rate and dieback of aging Pinus sylvestris var. mongolica trees in plantations of Northeast China. AB - The frequently observed forest decline in water-limited regions may be associated with impaired tree hydraulics, but the precise physiological mechanisms remain poorly understood. We compared hydraulic architecture of Mongolian pine (Pinus sylvestris var. mongolica) trees of different size classes from a plantation and a natural forest site to test whether greater hydraulic limitation with increasing size plays an important role in tree decline observed in the more water-limited plantation site. We found that trees from plantations overall showed significantly lower stem hydraulic efficiency. More importantly, plantation-grown trees showed significant declines in stem hydraulic conductivity and hydraulic safety margins as well as syndromes of stronger drought stress with increasing size, whereas no such trends were observed at the natural forest site. Most notably, the leaf to sapwood area ratio (LA/SA) showed a strong linear decline with increasing tree size at the plantation site. Although compensatory adjustments in LA/SA may mitigate the effect of increased water stress in larger trees, they may result in greater risk of carbon imbalance, eventually limiting tree growth at the plantation site. Our results provide a potential mechanistic explanation for the widespread decline of Mongolian pine trees in plantations of Northern China. PMID- 29424934 TI - Effect of individual structured and qualified feedback on improving clinical performance of dental students in clinical courses-randomised controlled study. AB - AIM: Analysis of the effect of individual structured and qualified feedback (FB) on practical skills development of dental students during clinical courses. METHODS: Fifty-three final-year dental students at Jena University Hospital participated in this prospective randomised controlled interventional study. Two calibrated assessors evaluated 128 pre- and post-assessments of 4 different dental treatment steps performed by dental students during the integrated clinical course in restorative dentistry and prosthodontics and the clinical course paediatric dentistry. The assessment included direct observation, graded and non-grading evaluation and was documented with a specific FB assessment tool. Dental students in the intervention group (IG) received an elaborated, structured and qualified FB after the pre-assessment that focussed on individual strengths and weaknesses, providing specific suggestions for improvement and establishing a personal learning goal. Participants were randomly allocated to the IG and the control group (CG). RESULTS: In both groups, dental students significantly enhanced their performance, but the difference was higher in the IG than in the CG. Large effect sizes (ES) were observed in all observed items, but FB had largest effect size in improving technical skills (ES = 1.6), followed by management (ES = 1.3) and communication skills (ES = 0.8). Factors with the highest influence on FB in enhancing dental students' clinical performance were their insight into their own mistakes or omissions, the observed dental treatment step and the duration of FB. CONCLUSION: Individual structured and qualified FB is an effective method to enhance dental students' professional performances and to individually guide the learning process. PMID- 29424935 TI - The effect of extended hours dialysis on sleep quality in a randomised trial. AB - BACKGROUND: Poor sleep quality is common in haemodialysis patients and associated with worse outcomes. In this pre-specified analysis, we examined the impact of extended hours haemodialysis on sleep quality. METHODS: The ACTIVE Dialysis trial randomized 200 participants to extended (>=24 hours/week) or standard (target 12 15 hours) hours haemodialysis over 12 months. Sleep quality was measured in the Kidney Disease Quality of Life Short Form 1.3 (KDQOL-SF) by overall sleep quality score (0-10, 10 = "very good") and the sleep subscale (0-100, 100 = 'best possible sleep') every three months via blinded telephone interviewer. The average intervention effect was calculated by mixed linear regression adjusted by time point and baseline score. Factors predicting sleep quality were assessed by multivariate regression analysis. RESULTS: Overall sleep quality score and sleep subscale at baseline were similar in both groups (5.9 [95%CI 5.4-6.4] vs 6.3 [5.9 6.8]; 65.0 [60.9-69.1] vs 63.2 [59.1-67.3]; extended and standard hours respectively). Extended hours haemodialysis led to a non-significant improvement in overall sleep quality score (average intervention effect 0.44 (-0.01-0.89), p=0.053) and sleep subscale (average intervention effect 3.58 (-0.02-7.18), p= 0.051). Poor sleep quality was associated with being female and with current smoking. Sleep quality was positively associated with EuroQol-5D (EQ5D) and the SF-36 Physical Component and Mental Component Summary Scores but not with hospitalisations. CONCLUSIONS: Sleep quality was not significantly improved by extended hours dialysis in this study. Sleep quality is positively correlated with quality of life in haemodialysis patients and is poorer in women and current smokers. PMID- 29424936 TI - Checkpoint inhibitors in triple-negative breast cancer (TNBC): Where to go from here. AB - Advances in cancer immunotherapy and a growing body of research have focused on the role of the antitumor response in breast cancer. Triple-negative breast cancer (TNBC) is the most immunogenic breast cancer subtype, and there is strong evidence that tumor-infiltrating lymphocytes in TNBC have prognostic value and are associated with clinical outcome and improved survival. Evading antitumor immunity is a hallmark for the development and progression of cancer. Immunotherapy studies have focused on the role of the programmed cell death-1 (PD 1) receptor/programmed death-ligand 1 (PD-L1) pathway in maintaining immunosuppression in the tumor microenvironment. Blockade of the PD-1/PD-L1 axis has emerged as a promising therapeutic option to enhance antitumor immunity and is actively being investigated in TNBC, with encouraging results. In this article, the authors review the current literature on checkpoint inhibitors in TNBC with a focus on PD-1/PD-L1 antibodies and discuss combination strategies and novel approaches for improving antitumor immunity and clinical outcome. Cancer 2018;124:2086-103. (c) 2018 American Cancer Society. PMID- 29424937 TI - Pathogenesis of cranial neuropathies in Moebius syndrome: Electrodiagnostic orofacial studies. AB - INTRODUCTION: We designed a retrospective study of 59 patients with congenital sporadic nonprogressive bilateral facial and abducens palsies. METHODS: Examinations included needle electromyography (EMG) of facial and oral muscles, facial nerve motor latency and conduction velocity (FNCV), and blink responses (BR). RESULTS: Neurogenic EMG changes were found in 1 or more muscles in 55 of 59 patients, with no abnormal spontaneous activity. EMG changes were homogeneously neurogenic in 17 patients, homogeneously myopathic in 1 patient, and heterogeneous in 41 of 59 patients. Motor latency was increased according to recordings from 52 of 137 facial muscles. An increase of motor latency was not associated with neurogenic EMG (Fischer's test: right, P = 1; left, P = 0.76). FNCV was slowed in 19 of 36 patients. BR was absent bilaterally in 35 of 58 patients; when present, R1 and R2 latencies were normal. DISCUSSION: Our results support the hypothesis of an early developmental defect localized in motor cranial nerves with spared V-VII internuclear pathways. Muscle Nerve, 2018. PMID- 29424938 TI - Observational study shows that it is feasible to provide neuroprotective treatment for neonatal encephalopathy in low-income countries. AB - AIM: Perinatal asphyxia is one of the most frequent causes of neonatal morbidity and mortality worldwide, and 96% of the burden of neonatal encephalopathy occurs in low-income countries. This study investigated the feasibility of providing neuroprotective treatment for neonatal encephalopathy in low-income countries. METHODS: Neonates with a gestational age of at least 36 weeks, with signs of perinatal asphyxia, were included in this 2015 observational study in three hospitals in Kinshasa, capital of the Democratic Republic of Congo. Their characteristics were described, including the time to admission and Thompson score on admission. RESULTS: We found that 42 of 134 patients (31.3%) reached the hospital within six hours of birth with a Thompson score of at least seven on admission. Another 15 patients (11.2%) had a five-minute Apgar score of up to five, without a Thompson score, and were eligible for treatment. Of the 57 (42.5%) eligible patients, 31 were discharged (54.4%), 25 died (43.9%) and one (1.8%) remained in hospital at the end of the study. CONCLUSION: Interventional studies are feasible and necessary, especially in countries where the burden of neonatal encephalopathy is largest. A Thompson score of 7-15 might be a useful entry criterion for neuroprotective treatment in low-income countries. PMID- 29424939 TI - CLCN1 Myotonia congenita mutation with a variable pattern of inheritance suggests a novel mechanism of dominant myotonia. AB - INTRODUCTION: Mutations in CLCN1 cause recessive or dominant forms of myotonia congenita (MC). Some mutations have been found to exhibit both patterns of inheritance but the mechanism explaining this behavior is unknown. METHODS: A known recessive missense mutation, A493E, was identified in a family with dominant MC. The mutant p.A493E alone or in co-expression with wild-type (WT) ClC 1 was expressed in Xenopus oocytes. Currents were measured and biochemical assays were performed. RESULTS: The mutant showed no significant activity and reduced total and plasma membrane (PM) protein levels. Co-expression with the mutant reduced the activity and PM levels of an engineered lower expression variant of ClC-1, whereas no effect was observed on a higher expression variant. DISCUSSION: Our results suggest that the dominant effect of some CLCN1 mutations showing recessive or dominant inheritance patterns may be due to a dose-dependent defect in PM delivery of the WT channel. Muscle Nerve, 2018. PMID- 29424940 TI - Thymus imaging in myasthenia gravis: The relevance in clinical practice. AB - INTRODUCTION: The ability to distinguish between normal thymus, thymic hyperplasia, and thymoma should aid clinical management and decision making in patients with myasthenia gravis (MG). We sought to determine the accuracy of routine imaging in predicting thymic pathology. METHODS: We retrospectively analyzed records of patients with MG from the Oxford Myasthenia Centre registry who had undergone thymectomy. Each patient received 1 radiological diagnosis and 1 histological diagnosis. RESULTS: We included 106 patients. Radiological and histological diagnoses agreed in 73 (68.9%) patients. Sensitivity and specificity, respectively, were calculated for each radiological diagnosis as follows: thymoma 90% and 95.5%, hyperplasia 17.6% and 98.6%, and normal 96.9% and 60.8%. DISCUSSION: Routine chest computed tomography and MRI can effectively identify thymoma. However, they are not reliable tools to differentiate between thymic hyperplasia and normal thymus in patients with MG. Muscle Nerve, 2018. PMID- 29424942 TI - Tetrathiafulvalene-[2.2]paracyclophanes: Synthesis, crystal structures, and chiroptical properties. AB - Two racemic tetrathiafulvalene-[2.2]paracyclophane electron donors EDT-TTF [2.2]paracyclophane 1 and (COOMe)2 -TTF-[2.2]paracyclophane 2 have been synthesized via the phosphite mediated cross coupling strategy. Chiral HPLC allowed the optical resolution of the (RP ) and (SP ) enantiomers for both compounds. Solid-state structures of (RP )-1 and (rac)-2 have been determined by single crystal X-ray analysis. Intermolecular pi-pi and S***S interactions are disclosed in the packing. Single crystal X-ray analysis of (RP )-1 combined with experimental and theoretical circular dichroism spectra allowed the assignment of the absolute configuration of the enantiomers of 1 and 2. PMID- 29424941 TI - Simultaneous measurement of NAD metabolome in aged mice tissue using liquid chromatography tandem-mass spectrometry. AB - Nicotinamide adenine dinucleotide (NAD) is a major co-factor that mediates multiple biological processes including redox reaction and gene expression. Recently, NAD metabolism has received considerable attention because administration of NAD precursors exhibited beneficial effects against aging related metabolic disorders in animals. Although numerous studies have reported that NAD levels decline with aging in multiple animal tissues, the pathway and kinetics of NAD metabolism in aged organs are not completely understood. To determine the NAD metabolism upon aging, we developed targeted metabolomics based on an LC/MS/MS system. Our method is simple and applicable to crude biological samples, including culture cells and animal tissues. Unlike a conventional enzymatic cycling assay, our approach can determine NAD and NADH (reduced form of NAD) by performing a single sample preparation. Further, we validated our method using biological samples and investigated the alteration of the NAD metabolome during aging. Consistent with previous reports, the NAD levels in the liver and skeletal muscle decreased with aging. Further, we detected a significant increase in nicotinamide mononucleotide and nicotinamide riboside in the kidney upon aging. The LC/MS/MS-based NAD metabolomics that we have developed is extensively applicable to biomedical studies, and the results will present innovative ideas for the aging studies, especially for that of NAD metabolism. PMID- 29424943 TI - On the measurement of thin-ideal internalization: Implications for interpretation of risk factors and treatment outcome in eating disorders research. AB - OBJECTIVE: Although the Sociocultural Attitudes Towards Appearance Questionnaire (SATAQ) and Ideal Body Stereotype Scale (IBSS) are used interchangeably to assess thin ideal internalization, limited work has examined the assumption that the two measures index the same construct. METHOD: The current study utilized confirmatory factor analysis to examine whether these measures capture a single construct (one-factor), two constructs (two-factor), or both shared and unique constructs (bifactor). The SATAQ-4R-Internalization: Thin/Low Body Fat subscale and IBSS-Revised were administered to 1,114 college females. RESULTS: A bifactor model provided the best fit to the data. Further, the SATAQ-4R was more strongly related to disordered eating and body satisfaction than the IBSS-R. DISCUSSION: Results indicate that the two most commonly used measures of internalization capture both shared and unique constructs. While both measures appear to contribute to the assessment of a global internalization factor, the SATAQ-4R may be better suited to assess personal acceptance of and desire to achieve a thin body, while the IBSS-R may be better suited to assess an awareness or acknowledgement of broader sociocultural ideals (e.g., toned, shapely bodies). Continued psychometric investigation of the scales is recommended in order to ensure targeted assessment of the intended constructs. PMID- 29424944 TI - A simple distillation method to extract bromine from natural water and salt samples for isotope analysis by multi-collector inductively coupled plasma mass spectrometry. AB - RATIONALE: In natural samples bromine is present in trace amounts, and measurement of stable Br isotopes necessitates its separation from the matrix. Most methods described previously need large samples or samples with high Br/Cl ratios. The use of metals as reagents, proposed in previous Br distillation methods, must be avoided for multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) analyses, because of risk of cross-contamination, since the instrument is also used to measure stable isotopes of metals. METHODS: Dedicated to water and evaporite samples with low Br/Cl ratios, the proposed method is a simple distillation that separates bromide from chloride for isotopic analyses by MC-ICP-MS. It is based on the difference in oxidation potential between chloride and bromide in the presence of nitric acid. The sample is mixed with dilute (1:5) nitric acid in a distillation flask and heated over a candle flame for 10 min. The distillate (bromine) is trapped in an ammonia solution and reduced to bromide. Chloride is only distilled to a very small extent. The obtained solution can be measured directly by MC-ICP-MS for stable Br isotopes. RESULTS: The method was tested for a variety of volumes, ammonia concentrations, pH values and distillation times and compared with the classic ion-exchange chromatography method. The method more efficiently separates Br from Cl, so that samples with lower Br/Cl ratios can be analysed, with Br isotope data in agreement with those obtained by previous methods. CONCLUSIONS: Unlike other Br extraction methods based on oxidation, the distillation method presented here does not use any metallic ion for redox reactions that could contaminate the mass spectrometer. It is efficient in separating Br from samples with low Br/Cl ratios. The method ensures reproducible recovery yields and a long-term reproducibility of +/-0.110/00 (1 standard deviation). The distillation method was successfully applied to samples with low Br/Cl ratios and low Br amounts (down to 20 MUg). PMID- 29424945 TI - In vitro and in vivo investigation of a novel amniotic-based chitosan dressing for wound healing. AB - It is more than a decade that amniotic membrane has been used as a wound dressing because of its anti-inflammatory, anti-microbial, anti-fibrotic, anti-scarring properties, as well as its pain relieving and epithelialization promoting features. However, amniotic membrane had limited applications because it needs to suture in surgery, is highly fragile, firmly adhere to the wound and may cause bleeding and pain when changing the bandage. This study investigated the possibility of development of a novel amniotic-based chitosan gel dressing as a potential wound repair substrate with marked efficacy. In this experiment, amniotic gel prepared based on chitosan/PVP gel containing human amniotic membrane extract (AME-Gel) was investigated in terms of wound-healing efficacy and scar preventive effects in a rat burn model. The levels of re epithelialization and dermal regeneration were examined by histological assessment using H&E and Masson's trichrome staining. Also, we clarified the mechanism of healing and cytokine-releasing activities of AME as well as its effect on epithelization, angiogenesis, and fibroblast growth and migration. Our results revealed that AME-Gel induces epidermal and dermal regeneration at a shorter time through formation of granulation tissue, enhancement of fibroblast proliferation, and improvement of blood capillary formation concomitant with developing collagen bundles. Therefore, AME-Gel could be considered a simple and easy to be used as a biological dressing for any type of superficial burn wounds, without any adverse effects. PMID- 29424946 TI - Interference of transcription across H-NS binding sites and repression by H-NS. AB - Nucleoid-associated protein H-NS represses transcription by forming extended DNA H-NS complexes. Repression by H-NS operates mostly at the level of transcription initiation. Less is known about how DNA-H-NS complexes interfere with transcription elongation. In vitro H-NS has been shown to enhance RNA polymerase pausing and to promote Rho-dependent termination, while in vivo inhibition of Rho resulted in a decrease of the genome occupancy by H-NS. Here we show that transcription directed across H-NS binding regions relieves H-NS (and H-NS/StpA) mediated repression of promoters in these regions. Further, we observed a correlation of transcription across the H-NS-bound region and de-repression. The data suggest that the transcribing RNA polymerase is able to remodel the H-NS complex and/or dislodge H-NS from the DNA and thus relieve repression. Such an interference of transcription and H-NS mediated repression may imply that poorly transcribed AT-rich loci are prone to be repressed by H-NS, while efficiently transcribed loci escape repression. PMID- 29424947 TI - Monitoring of macrophage recruitment enhanced by Toll-like receptor 4 activation with MR imaging in nerve injury. AB - INTRODUCTION: Macrophage recruitment is critical for nerve regeneration after an injury. The aim of this study was to investigate whether ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle-based MRI could be used to monitor the enhanced macrophage recruitment by Toll-like receptor 4 (TLR4) activation in nerve injury. METHODS: Rats received intraperitoneal injections of either lipopolysaccharide (LPS) or phosphate buffered saline (PBS) or no injection (controls) after a sciatic nerve crush injury. After intravenous injection of the USPIOs (LPS and PBS groups) or PBS (control group), MRI was performed and correlated with histological findings. RESULTS: LPS group showed more remarkable hypointense signals on T2*-weighted imaging and lower T2 values in the crushed nerves than PBS group. The hypointense signal areas were associated with an enhanced recruitment of iron-loaded macrophages to the injured nerves. DISCUSSION: USPIO-enhanced MRI can be used to monitor the enhanced macrophage recruitment by means of TLR4 signal pathway activation in nerve injury. Muscle Nerve, 2018. PMID- 29424948 TI - Corrigendum to Ellerbrock et al. (2018) "Four in vivo g-ratio-weighted imaging methods: Comparability and repeatability at the group level". PMID- 29424949 TI - ICD-10 impact on ascertainment and accuracy of oral cleft cases as recorded by the Brazilian national live birth information system. AB - We compared Brazilian oral cleft (OC) frequencies between the population-based Brazilian System of Live Birth (SINASC) and the hospital-based Latin American Collaborative Study of Congenital Malformations (ECLAMC), trying to understand the paucity of cleft of lip and palate (CLP) in the first system. SINASC uses the International Classification of Disease version 10 (ICD-10) for congenital defects coding, ECLAMC uses ICD-8 with modifications. In SINASC, the CLP frequency was 1.7 per 10,000 (95% confidence limits 1.7-1.8), cleft lip (CL) 1.6 (1.5-1.7), and cleft palate (CP) 2.0 (1.9-2.1). In ECLAMC, the CLP frequency was 10.4 per 10,000 (9.0-12.1), CL 5.5 (4.5-6.7), and CP 4.4. (4.5-6.7). In SINASC, only 33% of the oral clefts were CLP, versus 51% in ECLAMC. Part of this discrepancy may have been due to the relative excess of CP and CL cases. Although congenital defect frequencies are usually lower in population than in hospital based registries, differences in the proportion of the main OC categories are not expected and are probably due to ICD-10 coding issues, such as lumping of unilateral CL and CL without other specifications. ICD-10 codes, whose deficiency for oral clefts is fully explained in the literature, lack modifiers for severity, or clinical subtypes. This paper shows the practical aspect of the ICD 10 system deficiency in capturing cleft lip and palate (CLP) subtypes, as demonstrated in SINASC covering three million births per year. Such errors are expected to occur in any registry that uses the ICD-10 coding system, and must be adjusted, given its relevance worldwide. PMID- 29424950 TI - Identification of candidate effector genes of Pratylenchus penetrans. AB - Pratylenchus penetrans is one of the most important species of root lesion nematodes (RLNs) because of its detrimental and economic impact in a wide range of crops. Similar to other plant-parasitic nematodes (PPNs), P. penetrans harbours a significant number of secreted proteins that play key roles during parasitism. Here, we combined spatially and temporally resolved next-generation sequencing datasets of P. penetrans to select a list of candidate genes aimed at the identification of a panel of effector genes for this species. We determined the spatial expression of transcripts of 22 candidate effectors within the oesophageal glands of P. penetrans by in situ hybridization. These comprised homologues of known effectors of other PPNs with diverse putative functions, as well as novel pioneer effectors specific to RLNs. It is noteworthy that five of the pioneer effectors encode extremely proline-rich proteins. We then combined in situ localization of effectors with available genomic data to identify a non coding motif enriched in promoter regions of a subset of P. penetrans effectors, and thus a putative hallmark of spatial expression. Expression profiling analyses of a subset of candidate effectors confirmed their expression during plant infection. Our current results provide the most comprehensive panel of effectors found for RLNs. Considering the damage caused by P. penetrans, this information provides valuable data to elucidate the mode of parasitism of this nematode and offers useful suggestions regarding the potential use of P. penetrans-specific target effector genes to control this important pathogen. PMID- 29424951 TI - Synthesis and Biological Evaluation of Fluorescent Bryostatin Analogues. AB - To investigate the cellular distribution of tumor-promoting vs. non-tumor promoting bryostatin analogues, we synthesized fluorescently labeled variants of two bryostatin derivatives that have previously shown either phorbol ester-like or bryostatin-like biological activity in U937 leukemia cells. These new fluorescent analogues both displayed high affinity for protein kinase C (PKC) binding and retained the basic properties of the parent unlabeled compounds in U937 assays. The fluorescent compounds showed similar patterns of intracellular distribution in cells, however; this argues against an existing hypothesis that various patterns of intracellular distribution are responsible for differences in biological activity. Upon further characterization, the fluorescent compounds revealed a slow rate of cellular uptake; correspondingly, they showed reduced activity for cellular responses that were only transient upon treatment with phorbol ester or bryostatin 1. PMID- 29424952 TI - Effects of resistance mutations of Pro197, Asp376 and Trp574 on the characteristics of acetohydroxyacid synthase (AHAS) isozymes. AB - BACKGROUND: Descurainia sophia L., a problematic weed in winter wheat fields in China, has developed high resistance to tribenuron-methyl. Amino acid substitutions at sites Pro197, Asp376 and Trp574 in the target acetohydroxyacid synthase (AHAS) were primarily responsible for D. sophia resistance to tribenuron methyl. In this study, purified subpopulations of D. sophia plants individually homozygous for a specific resistance mutation (Pro197Leu, Pro197His, Pro197Ser, Pro197Thr, Asp376Glu or Trp574Leu) in AHAS were generated, and the effects of resistance mutations on D. sophia resistance and AHAS characteristics were investigated. RESULTS: All resistance mutations in this study not only caused D. sophia to evolve 152- to 811-fold resistance to tribenuron-methyl but also greatly reduced AHAS sensitivity to tribenuron-methyl and increased AHAS binding affinity for the substrate pyruvate, which was primarily responsible for D. sophia resistance. The molecular docking results indicated that these resistance mutations altered AHAS binding affinity for tribenuron-methyl by reducing the hydrogen bonds and changing hydrophobic interactions. Compared with the wild-type AHAS, these resistance mutations exhibited no significant effects on AHAS feedback inhibition by branched-chain amino acids (BCAAs) at concentrations <0.08 mm. The altered AHAS sensitivity to feedback inhibition by BCAAs did not necessarily increase or decrease the free BCAAs in resistant D. sophia plants. CONCLUSION: The AHAS resistance mutations conferred D. sophia resistance to tribenuron-methyl by decreasing the binding affinity for tribenuron-methyl and/or increasing the binding affinity for pyruvate, but the mutations did not necessarily affect the biosynthesis of BCAAs in plants. (c) 2018 Society of Chemical Industry. PMID- 29424953 TI - Pseudo-double XEN: a complication of XEN45 stent placement technique. PMID- 29424954 TI - Discovery of a Short-Chain Dehydrogenase from Catharanthus roseus that Produces a New Monoterpene Indole Alkaloid. AB - Plant monoterpene indole alkaloids, a large class of natural products, derive from the biosynthetic intermediate strictosidine aglycone. Strictosidine aglycone, which can exist as a variety of isomers, can be reduced to form numerous different structures. We have discovered a short-chain alcohol dehydrogenase (SDR) from plant producers of monoterpene indole alkaloids (Catharanthus roseus and Rauvolfia serpentina) that reduce strictosidine aglycone and produce an alkaloid that does not correspond to any previously reported compound. Here we report the structural characterization of this product, which we have named vitrosamine, as well as the crystal structure of the SDR. This discovery highlights the structural versatility of the strictosidine aglycone biosynthetic intermediate and expands the range of enzymatic reactions that SDRs can catalyse. This discovery further highlights how a sequence-based gene mining discovery approach in plants can reveal cryptic chemistry that would not be uncovered by classical natural product chemistry approaches. PMID- 29424955 TI - Vision loss secondary to orbital extension of rhabdomyosarcoma in an adult. PMID- 29424956 TI - Sulfonamidation of Aryl and Heteroaryl Halides through Photosensitized Nickel Catalysis. AB - Herein we report a highly efficient method for nickel-catalyzed C-N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N-aryl and N-heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy-transfer mechanism wherein C-N bond reductive elimination occurs from a triplet excited NiII complex. Late-stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated. PMID- 29424957 TI - HNF1A variant, energy-reduced diets and insulin resistance improvement during weight loss: The POUNDS Lost trial and DIRECT. AB - AIM: To determine whether weight-loss diets varying in macronutrients modulate the genetic effect of hepatocyte nuclear factor 1alpha (HNF1A) rs7957197 on weight loss and improvement of insulin resistance. MATERIALS AND METHODS: We analysed the interaction between HNF1A rs7957197 and weight-loss diets with regard to weight loss and insulin resistance improvement among 722 overweight/obese adults from a 2-year randomized weight-loss trial, the POUNDS Lost trial. The findings were replicated in another independent 2-year weight loss trial, the Dietary Intervention Randomized Controlled Trial (DIRECT), in 280 overweight/obese adults. RESULTS: In the POUNDS Lost trial, we found that a high fat diet significantly modified the genetic effect of HNF1A on weight loss and reduction in waist circumference (P for interaction = .006 and .005, respectively). Borderline significant interactions for fasting insulin and insulin resistance (P for interaction = .07 and .06, respectively) were observed. We replicated the results in DIRECT. Pooled results showed similar significant interactions with weight loss, waist circumference reduction, and improvement in fasting insulin and insulin resistance (P values for interaction = .001, .005, .02 and .03, respectively). Greater decreases in weight, waist circumference, fasting insulin level and insulin resistance were observed in participants with the T allele compared to those without the T allele in the high-fat diet group (P = .04, .03 and .01, respectively). CONCLUSIONS: Our replicable findings provide strong evidence that individuals with the HNF1A rs7957197 T allele might obtain more benefits in weight loss and improvement of insulin resistance by choosing a hypocaloric and high-fat diet. PMID- 29424958 TI - Aerogels made of chitosan and chondroitin sulfate at high degree of neutralization: Biological properties toward wound healing. AB - In this study, highly neutralized, highly porous, and ultralight polymeric aerogels prepared from aqueous colloidal suspensions of chitosan (CS) and chondroitin sulfate (ChS) nanocomplexes, formulated as quasi-equimolar amounts of both, are described. These aerogels were designed as healing agents under the inspiration of minimizing the amount of matter applied to wounds, reducing the electrostatic potential of the material and avoiding covalent cross-linkers in order to decrease metabolic stress over wounds. Aerogels synthesized under these criteria are biocompatible and provide specific properties for the induction of wound healing. They do not affect neither the metabolic activity of cultured 3T3 fibroblasts nor the biochemical parameters of experimental animals, open wounds close significantly faster and, unlike control wounds, complete reepithelialization and scarring can be attained 14 days after surgery. Because of its hydration abilities, rapid adaptation to the wound bed and the early accelerator effect of wound closure, the CS/ChS aerogels appear to be functional inducers of the healing. Previous information show that CS/ChS aerogels improve wound bed quality, increase granulation tissue and have pain suppressive effect. CS/ChS aerogels are useful as safe, inexpensive and easy to handle materials for topical applications, such as skin chronic wounds. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2464-2471, 2018. PMID- 29424959 TI - Influence of family demographic factors on social communication questionnaire scores. AB - : This study examined the effect of demographic factors on Social Communication Questionnaire (SCQ) scores in children aged 30-68 months. Diagnoses of ASD were made after a gold standard evaluation that included the Autism Diagnostic Observation Schedule (ADOS), and the Autism Diagnostic Interview Revised (ADI-R). The relationship of demographic variables to SCQ scores was compared in two source populations: (a) children recruited from clinical and educational sources serving children who have ASD or other developmental disorders (CE) and (b) children recruited from birth certificates to represent the general population (BC). The impact of the demographic variables-child sex, child age, maternal language, maternal ethnicity, maternal education, maternal race, and household income-on total SCQ score were studied to examine their impact on the SCQ's performance. Demographic factors predicting the SCQ total score were used to generate ROCs. Factors that had a significant influence on SCQ performance were identified by examining the area under the ROCs. Optimal SCQ cut-points were generated for significant factors using the Youden's Index. Overall male sex, lower household income, lower maternal education and Black race predicted higher SCQ scores. In this sample, the most common optimum value for the SCQ cut-point across the different sociodemographic groups was 11. Autism Res 2018, 11: 695 706. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Screeners are used to help identify children who are more likely to have ASD than their peers. Ideally screeners should be accurate for different groups of children and families. This study examined how well the Social Communication Questionnaire (SCQ) predicts ASD. We found that male sex, lower household income, lower maternal education and Black race were associated with higher SCQ scores. In this study an SCQ cut-point of 11 worked best across the different sociodemographic groups in our sample. PMID- 29424960 TI - The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the rate of malignancy for atypia of undetermined significance subcategories. AB - BACKGROUND: The recent revision in terminology, with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) replacing noninvasive follicular variant of papillary thyroid carcinoma, has reclassified the clinically indolent tumor as nonmalignant. The objective of this study was to evaluate the impact of this change on the rate of malignancy (ROM) for subcategories of an atypia of undetermined significance (AUS) diagnosis on fine needle aspiration (FNA) cytology. METHODS: Consecutive thyroid FNAs interpreted as AUS over a period of 4 years were retrospectively analyzed. The ROM for AUS subcategories, including atypia of undetermined significance with nuclear atypia (AUS-N), atypia of undetermined significance with a microfollicular pattern (AUS F), atypia of undetermined significance with nuclear atypia and a microfollicular pattern (AUS-N/F), atypia of undetermined significance with Hurthle cells (AUS H), and atypia of undetermined significance, not otherwise specified (AUS-NOS), were analyzed. RESULTS: Of the 426 nodules interpreted as AUS, 244 were surgically excised. The incidence of NIFTP in each subcategory was as follows: 18% for AUS-N, 18% for AUS-F, 9% for AUS-N/F, 3% for AUS-H, and 0% for AUS-NOS. After the reclassification of NIFTP as nonmalignant, the ROM based on histologic follow-up significantly decreased from 43% to 26% for AUS-N (P < .001) and from 29% to 10% for AUS-F (P = .008). The ROM for AUS-N remained significantly higher than the ROM for AUS-F (P = .030). CONCLUSIONS: A subset of resected AUS nodules can be reclassified as NIFTP, and that significantly decreases the ROM, especially for AUS-N and AUS-F. Nonetheless, AUS-N still harbors a substantially higher ROM than AUS-F. Cancer Cytopathol 2018;126:309-16. (c) 2018 American Cancer Society. PMID- 29424961 TI - Global trends in mortality from malignant mesothelioma: Analysis of WHO mortality database (1994-2013). AB - BACKGROUND AND OBJECTIVE: Little is known about the extent to which asbestos use ban has affected global trends in malignant mesothelioma. This study investigated recent global mortality trends of malignant mesothelioma. METHODS: Data were collected from International Agency for Research on Cancer/World Health Organization mortality database to examine age-standardized, gender-specific mortality rates for malignant mesothelioma (ICD10-C45). Cross-sectional mortality rates (2009-2013) as well as trends over time (1994-2013) were also reported. Gender-specific annual percent change (APC) was calculated to examine trends over time for each country. RESULTS: Among the 30 countries with highest mesothelioma mortality in men, there is almost 10-fold variation in mortality rates during 2009-2013 ranging from 6.25 per 100 000 for United Kingdom to 0.64 per 100 000 in Portugal; whereas, among the 30 countries with highest mesothelioma mortality in women, there is a 4-fold variation in mortality rates during 2009-2013 ranging from 1.08 per 100 000 for United Kingdom to 0.26 per 100 000 in Ireland. Mortality rates were higher in men compared to women in 32 out of 35 evaluable countries. Among males and over the last 10 years of covered years, mesothelioma mortality was significantly declining in 9 countries (United Kingdom, Sweden, France, Germany, Netherlands, Canada, United States, Australia, and New Zealand); whereas, it was significantly rising in 5 countries (Poland, Spain, China-Hong Kong, Japan, and Republic of Korea). In the remaining countries, APC was stable. Among females and over the last 10 years of covered years, mesothelioma mortality was significantly declining in 1 country only (Italy); whereas, it was significantly rising in 3 countries (Poland, Argentina, and Republic of Korea). In the remaining countries, APC was stable. CONCLUSIONS: There is a worldwide variability in the burden and trends of mesothelioma mortality; and despite the ban on asbestos in many countries, mesothelioma still represents an important cause of mortality. PMID- 29424962 TI - Can gamma irradiation during radiotherapy influence the metal release process for biomedical CoCrMo and 316L alloys? AB - The extent of metal release from implant materials that are irradiated during radiotherapy may be influenced by irradiation-formed radicals. The influence of gamma irradiation, with a total dose of relevance for radiotherapy (e.g., for cancer treatments) on the extent of metal release from biomedical stainless steel AISI 316L and a cobalt-chromium alloy (CoCrMo) was investigated in physiological relevant solutions (phosphate buffered saline with and without 10 g/L bovine serum albumin) at pH 7.3. Directly after irradiation, the released amounts of metals were significantly higher for irradiated CoCrMo as compared to nonirradiated CoCrMo, resulting in an increased surface passivation (enhanced passive conditions) that hindered further release. A similar effect was observed for 316L showing lower nickel release after 1 h of initially irradiated samples as compared to nonirradiated samples. However, the effect of irradiation (total dose of 16.5 Gy) on metal release and surface oxide composition and thickness was generally small. Most metals were released initially (within seconds) upon immersion from CoCrMo but not from 316L. Albumin induced an increased amount of released metals from AISI 316L but not from CoCrMo. Albumin was not found to aggregate to any greater extent either upon gamma irradiation or in the presence of trace metal ions, as determined using different light scattering techniques. Further studies should elucidate the effect of repeated friction and fractionated low irradiation doses on the short- and long term metal release process of biomedical materials. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2673-2680, 2018. PMID- 29424963 TI - Programmable Self-Assembly of Heterometallic Palladium(II)-Copper(II) 1D Grid Chain using Dinuclear Palladium(II) Corners with Pyrazole-Carboxylic Acid Ligands. AB - A novel heterometallic diPdII -diCuII grid-chain, {[(bpy)4 Pd4 Cu2 L4 ](NO3 )4 }n (2; bpy=2,2'-bipyridine), was synthesized through a programmable self-assembly approach from the molecular corners [(bpy)2 Pd2 (HL)(L)](NO3 ) (1) as linkers with CuII nitrate by using the bifunctional H2 L ligand featuring primary (pyrazole) and secondary (benzoic acid) groups. Structural analysis revealed that 1D structure 2 consists of one [Cu2 (O2 CPh)4 ]n unit as a bridge and two [(bpy)2 Pd2 L2 ]n corners. Additionally, the catalytic effect of the heterometallic synergy on the Suzuki coupling reaction by using 2 was further explored. PMID- 29424965 TI - Prevalence and risk factors of drug-resistant extrapulmonary tuberculosis. AB - BACKGROUND: Physicians are usually aware of the occurrence of drug-resistant (DR) pulmonary tuberculosis (PTB), but lack concern about DR-extrapulmonary TB (EPTB). Data regarding the prevalence and risk factors of DR-EPTB remain limited. OBJECTIVES: To determine the prevalence and risk factors of DR-EPTB. METHODS: A retrospective study was performed in patients who had culture-proven Mycobacterium tuberculosis (MTB) from various specimens between January 2013 and December 2015. Patients were classified into three groups: PTB, EPTB and concomitant PTB and EPTB (PTB + EPTB). Clinical data, chest radiographic extent of disease and patterns of DR were collected. RESULTS: There were 1014 culture proven MTB specimens (716 pulmonary specimens and 298 extrapulmonary specimens) from 986 patients (648 PTB, 218 EPTB and 120 PTB + EPTB). The prevalences of isoniazid-, rifampicin- and multidrug-resistant EPTB were 7.8%, .5% and .5%, respectively, which were lower than those of PTB. When PTB and EPTB coexisted, a higher rate of DR-TB was observed than for PTB alone. Of 338 EPTB patients, the extent of radiographic disease was associated with isoniazid-, rifampicin- and multidrug-resistant TB. Previous history of TB and use of steroids/immunosuppressive drugs were also associated with rifampicin- and multidrug-resistant TB in multivariate analysis. CONCLUSIONS: The prevalence of DR-EPTB was high in patients who had concomitant PTB. Although the prevalences of rifampicin- and multidrug-resistant TB were low in isolated EPTB, the prevalence of isoniazid-resistant TB remained high. Therefore, drug susceptibility testing should be performed in EPTB patients, especially those who carry the aforementioned risk factors. PMID- 29424966 TI - The effects of bi-functional anti-adhesion scaffolds on flexor tendon healing in a rabbit model. AB - Progressive tendon adhesion is a major challenge in flexor tendon repair. The authors developed a bifunctional anti-adhesion scaffold and hypothesized that its application would reduce adhesion formation and deliver mesenchymal stem cells (MSCs) to enhance tendon healing. The scaffold was fabricated by an electrospinning machine before surface modification. The flexor tendons of 29 New Zealand rabbits underwent surgical repair and randomized to control, scaffold and scaffold loaded with MSC group. At 3 and 8 weeks post-surgery, range of motion (ROM), biomechanical properties, and histology were examined. There was no significant increase in ROM and biomechanical properties between the three groups. The histology showed successful delivery of MSCs but no significant difference in nuclear morphometry. This barrier delivers and retains MSCs within the tendon repair site. However, its sheet form and wrapping around the repair site may not be optimal for tendon healing. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2605-2614, 2018. PMID- 29424964 TI - Development of zwitterionic sulfobetaine block copolymer conjugation strategies for reduced platelet deposition in respiratory assist devices. AB - Respiratory assist devices, that utilize ~2 m2 of hollow fiber membranes (HFMs) to achieve desired gas transfer rates, have been limited in their adoption due to such blood biocompatibility limitations. This study reports two techniques for the functionalization and subsequent conjugation of zwitterionic sulfobetaine (SB) block copolymers to polymethylpentene (PMP) HFM surfaces with the intention of reducing thrombus formation in respiratory assist devices. Amine or hydroxyl functionalization of PMP HFMs (PMP-A or PMP-H) was accomplished using plasma enhanced chemical vapor deposition. The generated functional groups were conjugated to low molecular weight SB block copolymers with N-hydroxysuccinimide ester or siloxane groups (SBNHS or SBNHSi) that were synthesized using reversible addition fragmentation chain transfer polymerization. The modified HFMs (PMP-A SBNHS or PMP-H-SBNHSi) showed 80-95% reduction in platelet deposition from whole ovine blood, stability under the fluid shear of anticipated operating conditions, and uninhibited gas exchange performance relative to non-modified HFMs (PMP-C). Additionally, the functionalization and SBNHSi conjugation technique was shown to reduce platelet deposition on polycarbonate and poly(vinyl chloride), two other materials commonly found in extracorporeal circuits. The observed thromboresistance and stability of the SB modified surfaces, without degradation of HFM gas transfer performance, indicate that this approach is promising for longer term pre-clinical testing in respiratory assist devices and may ultimately allow for the reduction of anticoagulation levels in patients being supported for extended periods. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2681-2692, 2018. PMID- 29424967 TI - Predicting drug-induced arrhythmias by multiscale modeling. AB - Drugs often have undesired side effects. In the heart, they can induce lethal arrhythmias such as torsades de pointes. The risk evaluation of a new compound is costly and can take a long time, which often hinders the development of new drugs. Here, we establish a high-resolution, multiscale computational model to quickly assess the cardiac toxicity of new and existing drugs. The input of the model is the drug-specific current block from single cell electrophysiology; the output is the spatio-temporal activation profile and the associated electrocardiogram. We demonstrate the potential of our model for a low-risk drug, ranolazine, and a high-risk drug, quinidine: For ranolazine, our model predicts a prolonged QT interval of 19.4% compared with baseline and a regular sinus rhythm at 60.15 beats per minute. For quinidine, our model predicts a prolonged QT interval of 78.4% and a spontaneous development of torsades de pointes both in the activation profile and in the electrocardiogram. Our model reveals the mechanisms by which electrophysiological abnormalities propagate across the spatio-temporal scales, from specific channel blockage, via altered single cell action potentials and prolonged QT intervals, to the spontaneous emergence of ventricular tachycardia in the form of torsades de pointes. Our model could have important implications for researchers, regulatory agencies, and pharmaceutical companies on rationalizing safe drug development and reducing the time-to-market of new drugs. PMID- 29424968 TI - The Importance of Retaining Well-Trained and Experienced Coders. PMID- 29424969 TI - [Cost of family planning care in 10-19 years old teenagers]. AB - Objetives: To identify the costs of family planning care in adolescents. Material and methods: Longitudinal study of the cost of care for family planning carried out in 2015 in a group of individuals with age limits of 10 and 19 years in a unit first level of health care in the state of Queretaro, Mexico. The profile of use of family planning (FP) was created for the teen was performed services through counseling, provision of contraception and review of intrauterine device (IUD) in a year; cost projections for the population of adolescents and different coverage scenarios between 5 and 100% were made. Results: The average annual cost was 228.84 Mexican pesos. Ideally the identified cost was 2,708.94 pesos. The projection with 20 % coverage was 207,251,330 pesos. The average annual family planning consultations was 0.9. The most commonly used method was with medroxyprogesterone-estradiol at doses of 25 and 5 mg. Conclusion: The cost of planning in adolescents is low, taking into account the costs that the care of high-risk pregnancies and associated comorbidities. PMID- 29424970 TI - Annual HIPAA Training: A Preventive Measure. PMID- 29424971 TI - [Prevalence of HPV high-risk serotypes detected by PCR in patients with normal cervical cytology at the Hospital Regional Adolfo Lopez Mateos, ISSSTE]. AB - Background: Is fundamental to determine the prevalence of human papiloma virus (HVP) high-risk serotypes in local and regional population in order for health providers to offer patients, vaccines and treatments against specific population based serotypes. Objetive: To determine the prevalence of HPV High risk serotypes detected by PCR in patients with normal cytology from the ISSSTE Adolfo Lopez Mateos Regional Hospital. Methods: An observational, descriptive, prospective study was conducted from cervical cytologies and high risk HPV test by PCR in patients from the Regional Hospital Adolfo Lopez Mateos, ISSSTE, during the period January 2013-December 2015. Cases of patients with negative cervical cytology were included. Information about age, the result of cervical cytology and high risk HPV test by PCR was obtained. The overall prevalence of HPV infection and the most prevalent serotypes by age groups were calculated. Results: A total of 3258 cervical smears were performed, of which 2557 were negative (78.4%), from this, the global prevalence of HPV infection was 10.2% (n=262). We found that 1.8% (n = 45) of negative reports had HPV16 infection, 0.5% (n=13) had HPV18 and 8.9% (n = 227) were infected by Viral Pool of other high-risk serotypes. The prevalence of infection by viral pool of high risk serotypes was 11.5% in women <20 years, 12.9% in women between 20-29 years and 22.2% in women between 30-39 years. This prevalence was lower in patients older than 40 years (p<0.05). Conclusion: A higher prevalence of viral pool high risk serotypes was found in patients with normal cytology, than the HPV16 and HPV-8 prevalence, which was significantly higher in women younger than 40 years. PMID- 29424972 TI - Information Governance for Analytics Support: Remember the Life Cycle Component. PMID- 29424973 TI - Understanding User Needs for Interoperability: Defining Use Cases in eHealth. PMID- 29424974 TI - Case Study #6: Enterprise Information Management at Children's Health System of Texas. Updating Organizational Policies and Procedures for Information Governance. PMID- 29424975 TI - [Subsequent reoperation obstetric hysterectomy and selective ligation of hypogastric arteries]. AB - Background: Bleeding in pregnancy, childbirth or postpartum period is an emergency. Selective internal iliac (hypogastric) arteries ligation is a surgical therapy in selected cases of obstetric massive hemorrhage. It had proven to be safe. Objetive: To evaluate the risk for re-intervention for post-operatory bleeding in patients with obstetric hysterectomy and selective hypogastric arteries ligation. Material and method: Cross-sectional study including women diagnosed with obstetric hysterectomy with and without selective arterial ligation as a factor to assess the risk of re-intervention, from December 2013 to December 2014, at High Specialty Medical Unit 23 of Gynaecology and Obstetrics, in Monterrey, which is a tertiary care medical center. Those patients with 28 weeks of gestation or more were selected. The postoperative blood loss was quantified by open drainage system (Penrose). Results: We performed 88 hysterectomies in the study period. We included 45 women according to selection criteria. The average was 31.9 +/- 5.48 years old. Performing a selective hypogastric arteries ligation may be a protective factor (p<0.05) for re intervention as a consequence of postoperative bleeding. Conclusion: Selective arterial ligation is a factor that could help to prevent a re-intervention. A continuous training of physicians and residents of Gynecology and Obstetrics is essential to ensure the reduction in morbidity and maternal mortality. PMID- 29424976 TI - The Evolution of DRGs (2017 Update). PMID- 29424977 TI - [Use of growth hormone for in vitro fertilization]. AB - Background: Ovarian stimulation is the cornerstone in fertility treatments, it produces multifolicular development and in consequence, a greater pregnancy rate. Poor responder patients have bad outcomes in IVF, several medical approaches have been proposed in managing these patients, including Growth Hormone. Objetive: To report our results with the use of growth hormone and review published data. Material and method: Case series conducted from January 2013 to May 2015 in patients to Centro de Reproduccion PROCREA, Mexico City, poor responders according to the criteria of consensus Bologna cycles in fresh stimulation protocol Flare up, application of growth hormone as adjuvant, complete cycles of stimulation (stimulation, oocyte capture, and embryo transfer pregnancy test) and complete records. For statistical analysis, averages and percentages were used. Results: 40 cases were analyzed. Age and BMI were 39.1 +/- 2.1 years and 24.6 +/- 2.8 kg/m2, respectively. Total gonadotrophin dose was 2128.6 +/- 1078.9 UI, retrieved oocytes and fertilized eggs were 7.1 +/- 4.0 y 5.4 +/- 2.8 respectively. Fertilization rate was 76.3% and pregnancy rate was 59.5%. Conclusion: There is insufficient evidence for prescribing GH in all patients requiring IVF, nevertheless, in poor responder patients, there seems to be an improvement in egg quality leading to better fertilization and pregnancy rate, with no adverse effects. PMID- 29424978 TI - [Risk factors for cardiovascular disease in patients with hypertensive disorders during pregnancy. Experience of 10 years]. AB - Background: The 8 to 10% of pregnancies are affected with hypertensive disorders of pregnancy. They are the most common obstetric complication and present significant maternal and perinatal morbidity and mortality; but also these diseases go beyond pregnancy and determine a group of women with increased cardiovascular risk in your life futura. Cardiovascular disease remains the main cause of death in the Western world and women with a history of pregnancy hypertensive disease, are at increased risk of cardiovascular complications afterwards. Therefore, pregnancy is a unique physiological situation provides an opportunity to identify a group of women who will present cardiovascular risk factors later in life. Objetive: To determine the long-term cardiovascular risk factors (chronic hypertension, type 2 diabetes mellitus, metabolic syndrome) and thyroid dysfunction incidence in women who have previously been diagnosed with "hypertensive disorders of pregnancy". Material and methods: Case-control study with retrospective collection of information from women whose pregnancy and childbirth occurred between 2000 and 2010. Case: Patients with a diagnosis of "hypertensive diseases of pregnancy" (N = 134). Control: random sample of pregnant women who were not diagnosed with hypertensive state of pregnancy and whose gestation was spent in 2000 (n = 145). The mean follow-up of both groups was 10,78 years. We have applied parametric test (T-Student for independent samples), and for those variables that did not meet that condition, we have applied the U of Mann-Whitney test. The Chi-square test was used to compare qualitative variables and Fisher's exact test. For comparison between groups, model univariate logistic regression was performed. Results: The incidence of hypertension was 41,32% in patients with a history of hypertensive pregnancy disease, with a relative risk (RR) was 9,15. The incidence of type 2 diabetes mellitus was 5,17%. Dyslipidemia was diagnosed after at 43,53% with a RR of 3,7. Metabolic syndrome reached 16,83% in the cases population with a RR of 2,63. The incidence of hypothyroidism was 8,11%. Conclusion: Patients who were diagnosed with "hypertensive state of pregnancy" are a group of women at increased risk of developing cardiovascular risk factors later in life. PMID- 29424979 TI - [Pneumomediastinum associated with hyperemesis gravidarum: a case report]. AB - Background: The hyperemesis gravidarum is a severe illness of nauseas and vomit that is present in the first trimester of the pregnancy, it has an incidence of 0.3 to 2%, it has been associated to weight loss, electrolytic disturbances, ketonuria, dehydration and in very seldom cases spontaneous pneumomediastinum. Clinical case: A 21 years old female patient, primigest, in the first trimester of gestation, she started her disease with nauseas and vomiting more than 15 times during 6 hours period, odynophagia, dysphonia and pain in the cervical region, loss of 5 kilograms in the last month. The physical examination showed the patient in bad conditions, dehydration, neck with volume increased and emphysema subcutaneus, crakles until torax. Laboratory findings with hypokalemia, leukocytosis, acute kidney failure, and elevation of hepatic enzymes. The initial treatment was with intravenous fluids resuscitation, hydroelectrolytic balance restoration, antiemetic treatment and rest, it was taken TC of neck and torax, and was exclude any laryngeal and esophageal injury and perforation, but it showed air in the mediastinum. Conservative management with favorable evolution and completed resolution in 7 days. Conclusion: It is very important that the medical doctor must keep in mind the different diagnosis of and take an opportune decision in case of present those complications potentially fatal to the mother. PMID- 29424980 TI - [Primary intestinal parasitic fibroid, an incidental finding during gynecological laparoscopic surgery]. AB - Background: Uterine fibroids are the most frequent solid pelvic benign tumors in women. Their most common location is the uterine corpus, cervix and broad ligament but they can also be found in other areas, less commonly as extragenital locations and/or in a parasitic way. Clinical case: A 40 years old patient, who consulted for menorrhagia and dysmenorrhea on long evolution. On physical examination, the enlarged uterus, inflamated, hard consistency and normal mobility was identified. The sonographic features and location suggested a fibroid nodule type II (Wamsteker classification), which deformed the endometrial cavity. It was decided to perform the surgery and during the procedure the enlarged uterus, deformed at the expense of a localized fundal formation, like a intramural fibroid. By mobilizing the intestinal loops and change the position of the patient (Trendelenburg) a solid tumor, cranially separated from the internal genitals it was observed. In reviewing the insertion site, it was visualized that remained attached to antimesial of the jejunum. Total hysterectomy was performed with monopolar and bipolar energy, and vascular sealant. The postoperative was favorable, without complication. The pathological study reported a primary leiomyoma of the small intestine, while in the uterus of multiple myomas was confirmed. Conclusion: The parasitic fibroids are those located separately from the uterus that receive vascular irrigation from another organ or abdominopelvic structure. They are a very rare pathology. The diagnosis has made as an accidental event, during an abdominal surgery or during the differential diagnosis of a abdominopelvic tumor. The therapeutical choice depends on the clinical presentation, the location of the fibroid and the reproductive desires of the patient, most commonly recomending their surgycal removal. PMID- 29424981 TI - [Pelvic organ prolapse during pregnancy: treatment with vaginal pessary. A report of two cases]. AB - Background: Pelvic organ prolapse during pregnancy is a rare condition that may be associated with maternal and fetal complications. Objetive: To describe the experience of two cases of pelvic organ prolapse during pregnancy managed with vaginal pessary. Case report: The cases of two patients with grade 4 vaginal prolapse during pregnancy managed with vaginal pessary until the time of delivery are presented. The patients had improvement of their symptoms without complications related to prolapse or pessary use. Conclusion: Early recognition, monitoring and management of this condition are essential. The vaginal pessary is a good option for transient treatment and is associated with few complications. PMID- 29424982 TI - [Gatrointestinal stromal tumor: a case report]. AB - : Gastrointestinal stromal tumors are the most common mesenquimal neoplasms of the gastrointestinal tract. A preoperative diagnose of GIST it is very difficult to make, but up to 5% of the cases initially appear as a pelvic mass. Clinical case: 45-year-old patient attended in medical service by unspecific pain in the lower abdomen of several weeks of evolution. The abdominopelvic tomography evidence collection of 9*8 cm above of the uterus and sigma's right with air in the cavity, it is was compatible with pelvic abscess. Due to increased pain, we realized emergency exploratory laparotomy, which showed a 14 cm tumor, dependent of the small intestine, without ascites or involvement other organs of the digestive or reproductive tract. The excision of the tumor was successfully (non intraoperative rupture). The pathological study reported a bowel piece of 20 cm, in which a tumor of 14 cm with large central cavitation was identified. Histologically showed diffuse growth pattern and neoplastic epithelioid cells with low rate of mitosis (mitosis 1-2/5 mm2). The immunohistochemistry test reports strong expression of DOG-1 and focal expression in CD117 (c-kit), with very low proliferation index (Ki67). The molecular pathology study identified a mutation in exon 11, codon 557-558, the c-kit gene in the p.W557_K558del position. We use imatinib (400 mg/24 h) from the second month after surgery. Today keep in treatment, and clinical and laboratories following every month: in addition, to CT scans scheduled every 6 months. PMID- 29424983 TI - [Salpingectomy in ovarian cancer prevention: Evidence behind the hypothesis and surgical implications]. AB - Background: Over the last decade, evidence suggests the fallopian tubes are the origin of most of the high grade ovarian serous carcinomas. This type of carcinoma represents at least 50% of all the cases of epithelial ovarian cancer. Salpingectomy may lower the risk of high grade serous carcinoma. Removing the two fallopian tubes should be considered a strategy for risk reduction in patients who decide tubal sterilization or in patients with hysterectomy for benign disease. There are ongoing protocols that evaluate the ovarian hormonal production impact after prophilactic salpingectomy. In patients with BRCA1 and BRCA2 mutations, salpingo-oophorectomy is recommended usually between 35 to 40 years of age for BRCA 1 and between 40 and 45 years of age for BRCA 2. The oopherectomy done whithin these decades has the consequences and side effects of premature menopause, some physicians have suggested doing a two step procedure: perform a salpingectomy as soon as the patient has decided to have permanent birth control, and doing the ophoorectomy at the onset of menopause. The oncological safety of this approach is still under evaluation and is not recommended outside a protocol. PMID- 29424984 TI - [Features of White LED Daylight and human health]. AB - Today it is not enough to focus only on energy-saving concept, but it should be taken into account the complex changes in the human body when exposed to not only visual and psychological, but also biological components and led lighting. Such approach to the hygienic assessment of led lighting will help to reveal both how the risks of exposure are dangerous and to identify hygienic and constructional solutions in the development of LED lamps. Led lighting as a factor of stimulation of the human hormonal system can, along with metabolic syndrome, increase the risk of type 2 diabetes. PMID- 29424985 TI - [Scientific substantiation of sizes of sanitary protection zones of anthrax burial sites based on the comprehensive evaluation of risk factors]. AB - In the Russian Federation anthrax epizootics are still being registered among animals as well as epidemic foci of the population. This situation is linked to natural reservoirs of the pathogen - numerous anthrax burial sites which belong to class I of dangerous objects. In this connection, a one-kilometer sanitary protective zone is required according to current Russian Federation legislation. As a result, a significant land of the country is unsuitable for any agricultural use. Meanwhile, epizootologo-epidemiological observations indicate to that different anthrax burial sites differ in their characteristics and represent varying degrees of the risk. In connection with the development of the agricultural sector, intensive construction and the development of new and abandoned areas there is a need of creating unified approaches to assess the risk of anthrax burial sites, as well as to determine the size of sanitary protection zones based on the risk assessment. This article represents an original methodology to assess the actual danger of anthrax burial sites. It is based on a comprehensive multi-factor quantity-related risk assessment, described by a model that accounting the importance of each study for natural, social and biological factors. Undertaking this methodology allowed to reveal a degree of danger of anthrax burial sites located in different territories of the Russian Federation, and helped to substantiate the dimensions of their sanitary protection zones. PMID- 29424986 TI - [Comparative evaluation of the prevalence of congenital malformations de novo in newborns from radiation-contaminated territories of the Bryansk region (1999 2014)]. AB - On the basis of official statistics for 1999-2014 there was performed the comparative evaluation of the prevalence of congenital malformations de novo: polydactyly, reduction limb defects and multiple congenital malformations in newborns of radiation-contaminated areas of the Bryansk area residing in areas with the various density of radioactive contamination by long lived radionuclides cesium-137 (from 10.0 to 2523.4 kBq/m) and strontium-90 (from 0.7 to 42.5 kBq/m). The findings showed no statistically significant differences in the prevalence of polydactyly, reduction limb defects and multiple congenital malformations in newborns in the South-Western areas compared to medium regional values, although the maximum value of the amount of congenital malformations de novo is found in most radiation-contaminated areas. PMID- 29424987 TI - [Comparative evaluation of the efficacy of plants for disinfection of medical waste]. AB - There are presented results of the comparative evaluation of the effectiveness of plants for disinfection of medical waste which use 4 most common hardware technologies: treatment by saturated steam pressure, moist heat, microwave exposure and chemical disinfection with refinement. The efficiency ofplants using physical methods of influence was shown to be higher in comparison with hardware chemical disinfection. PMID- 29424988 TI - [Stress as an occupational risk factor among policemen of road patrol service]. AB - The hygienic evaluation of occupational factors which characterized working conditions of traffic policemen of road patrol service was performed. The authors found that along with high neuro-emotional occupational stress in traffic policemen, they exposed to unfavorable microclimate, higher level of noise, vibration and their work was classified as heavy. Also, traffic policemen presented subjective complaints about negative impact of polluted air of motorways on their health status. Prevalence of chronic diseases was analyzed in group of 431 traffic policemen. The authors revealed a leading role of the following diseases: musculoskeletal diseases, diseases of connective tissue, digestive diseases, diseases of the nerve system, circulation system; their portion in the morbidity structure was 86.0%. The association of these diseases with occupation was confirmed by the increasing of their incidence with increasing of length of duration of service. Calculation of indices of relative occupational risk showed (that especially important) the increase of the length of service led to the increase in the risk ofpathologies, in which stress played a significant role. In examined group, the authors revealed such diseases as hypertension, autonomous-vascular dystonia, gastric and duodenal ulcer. Risk of the development of these diseases in some age/length of service groups is classified as high and very high. Obtained results provide the evidence that measures aimed to the decrease of the exposure to occupational factors will promote prevention of stress-stipulated diseases among traffic policemen. PMID- 29424989 TI - Device or No Device? Coding IMPELLA/IABP External Ventricular Support and the Impact on MS-DRG Assignment. PMID- 29424990 TI - [The genetic component of chronic respiratory diseases in workers of foundry productions]. AB - Review of the literature shows that currently there is an accumulation of data on the genetic determination of individual susceptibility to adverse industrial factors. Material of the research were high molecular DNA samples isolated from epithelial mouth scrapings in 99 foundry workers. Study of polymorphic variants of interleukin genes was performed by means of the analysis ofproducts of amplification of specific regions of the genome. Homozygous genotype TNF-a ( 308A/G) was established to increase the relative risk of shaping of chronic respiratory diseases: with AA alleles - by 6.4 times and GG alleles - by 2.4 times, while the heterozygous genotype (AG) decreases - by 1. 9 times. Polymorphism of gene IL-1beta (+3953 T / C) had no significance for the development of respiratory disease. Genotyping interleukins, involved in the inflammatory responses of the bronchopulmonary tract, can be considered as an element ofprimary prevention in industries with a high risk for shaping of respiratory diseases. PMID- 29424991 TI - [Description of the life quality of contracted servicemen]. AB - There are presented results of a comprehensive study of the life quality of representatives of three reference groups of servicemen on contract: cadets of military high schools (n = 400), contracted servicemen of the units of power ministries and departments (n = 453), common soldiers and junior commanders (n = 357). The study was executed with the aid of the public survey, the performing of both psychological and functional load tests. This work is notable for the complexation of indices which characterize socio-hygienic, psychological and medical aspects of the life quality, life values, life satisfaction, and specific features of the military profession. Results of the study, which differ from the prior investigation by inclusion of indices characterizing the specific features of military-professional activity, lifestyle and spirituality, for the first time made it possible to assess the life quality related to health, taking into account the axiological values in life and important needs of the studied population. Changes in the life quality indices of contract servicemen were shown to be more sensitive to changes in their health than the traditional clinical laboratory and instrumental data, which allows to recommend a wide practical use of the monitoring the life quality for professional selection and medical support of the military service, including the implementation of measures on optimization of psychological climate in military units, and the personification of the complex of therapeutic-recreational measures. The results allow us to recommend to military medical commissions of military commissariats in the call of citizens for military service under contract to carry out studies of quality and lifestyle of recruits for the early detection of groups of risk for their health. The program of in-depth medical examinations of military-contract there is recommended to include research aimed at identifying adverse social and hygienic factors of service and living conditions, psychopathological personality traits, rehabilitation and psychological climate in a military collective, execution of a personalized set of therapeutic measures. PMID- 29424992 TI - The Ins and Outs of HCCs. PMID- 29424994 TI - [Factorial structure of physical performance in children aged of 7-8 years]. AB - The given research is devoted to the comprehensive investigation of physical working capability within the whole range of accessible loads in healthy schoolchildren aged of 7-8 years (n=159). During the working process there were identifiedfive important facts determining the structure ofpupils 'physical working capability in the researched aged group. They include common working capability, aerobic alactant working capability, anaerobic glycolytic working capability, aerobic power and aerobic volume. The pointed out facts except the fact of common working capability, are associated with the maximum, sub maximum, large and medium zones of relative capacity respectively. During the study there were found out the expressed differences between boys and girls according to the development level of aerobic and anaerobic components ofphysical working capability. Therewith the most substantial differences were observed concerning the variables characterizing the working capability in zones of large and medium power dealing predominantly with aerobic muscle activity power supply, and the least valuable ones - in accordance with working indices in the sub maximum power dealing with anaerobic glycolytic system. The received data can be applied in solving practical problems of hygienic rating and control ofphysical loads value of different relative power during the process of physical education as well as in prenosological diagnostics of children's health on the base of the evaluation of their organism's adaptative capabilities. PMID- 29424993 TI - [Hygienic standardization of 2-formylphenoxyethane acid in the air of the working zone Hygiene of Children and Adolescents]. AB - The toxic properties of 2-formylphenoxyethane acid for hygienic standardization in the air of the working zone were studied. DL of the substance under the introduction into the stomach for male rats, male and female mice was 5354, 3698 and 4322 mg/kg. This compound refers to moderately hazardous substances. No significant differences in species and gender sensitivity of animals to the substance were found. This compound possesses a strong ability to the accumulation: C accounts of 2.9. It has a marked irritating effect to the mucous membranes of eyes and the moderate impact to the skin. It has a toxic effect on the liver, kidneys, central nervous system. The threshold of acute inhalation effect (Lim) equals to 120.3 mg/m. It has no irritating effect to the respiratory tract at Lim level. The tentative safe exposure level of 2-formylphenoxyethane acid in the air of working zone equals to 1 mg/m. PMID- 29424995 TI - Artificial Intelligence Use in Healthcare Growing Fast. PMID- 29424996 TI - [Features of physical development of girls residing in the altai territory with the different level of the environmental load]. AB - There was performed the determination of the characteristics of the physical development of 660 girls aged of from 6 years 6 months to 17years 5 months 29 days, residing in the Blagoveshchenskiy and the Ust-Pristanskiy regions of the Altai Krai. The Blagoveshchenskiy region is characterized by a high level of ambient air pollution (potential of the atmospheric pollution accounts for 2.7 3.0). Sodium sulfate, sulfur dioxide, hydrogen sulfide, carbonic oxide, nitrogen dioxide, vanadium pentoxide, ammonia, manganese and its compounds, hexavalent chromium make the greatest contribution to the atmospheric pollution. The Ust Pristanskiy region is referred to the least polluted territories of the Altai Krai. Living conditions in the Blagoveshchenskiy region of the Altai Krai were found to influence on the girls ' physical and sexual development. The girls living in the Blagoveshchenskiy region show the pubertal growth spurt one year later, which is lasting longer. As a result, by the age of 17, measurements of the body and leg length are almost 6 cm higher in girls of the Blagoveshchenskiy region. 97% of the Blagoveshchenskiy region residents have pathological (trochanter index <= 1.85) and disevolutive (trochanter index = 1.86 - 1.91) types of age evolution which testifies to the thyroid and reproductive hormones deficiency. Among the residents of the Ust-Pristanskiy region, 80% have either normal values of the trochanter index (1.95 - 2.0) or slightly deviated from the norm (hypoevolutive, normoevolutive, and hyperevolutive types of age evolution). The level of the endocrine system diseases prevalence, nutrition and metabolic disorders among the teenagers of the Blagoveshchenskiy region are 2.5 times higher than in the rural area of the Altai Krai. The relative risk of the endocrine system diseases occurrence, nutrition disturbances and metabolic disorders in the teenagers of the Blagoveshchenskiy region equals to OR=1.87 (x=272.7, p<0.001). PMID- 29424997 TI - [Chrono Physiological characteristics of children of primary school age - the natives of the Middle Ob]. AB - Chronoreflexometric characteristics of the mental performance of children of primary school age - the natives of the Middle Ob were based on the statistical analysis of the latent period of time of a simple visual - motor responses. The results of a survey showed that the functional state of the nervous system of surveyed children ofprimary school age was at "reduced" and "greatly reduced" level of mental performance. This state is characterized by a weakening of attention, a sharp deterioration in time and accuracy parameters of activity and a significant decrease of efficiency on the whole. PMID- 29424998 TI - [Estimation of the influence of the design of school backpacks to posture regulation in children with different posture conditions]. AB - There was performed the study of the characteristics of the regulation of vertical posture in 42 children of 8-10 years old using school bags of different designs. According to medical examination 25 children have normal posture and 17 children had kyphotic one. The stability of the posture was estimated according to the average variance and the average velocity of the total center of gravity of the body, the area of the ellipse, and the quality of the equilibrium function with computer stabilography. Three models of school bags were used - with traditional, ergonomic and orthopedic back support. Vertical posture stability for children with impaired posture without school bag and when used with traditional and ergonomic back were significantly lower in comparison with children with normal posture. When the orthopedic back was used the stability impairment of the vertical posture in children with kyphotic posture was not observed. It is concluded that for the prevention of spinal deformity for students with kyphotic posture orthopedic school bags should be used. PMID- 29424999 TI - [Morbidity and content of microelements in the blood of school children residing near chromium enterprises]. AB - For the first time there was investigated the content of certain microelements in the blood of children of school age residing in the city of Aktobe (Kazakhstan), where the global giants, mining andprocessing chrome ore productions are located. There were determined blood levels of chromium, nickel, lead in children. There was shown the difference in the blood content of microelements in children, depending on region of residence and their correlation with the core indices of health and disease. PMID- 29425000 TI - [Dynamics of indices of physical development of preschool children of the city of Ufa]. AB - A comparative analysis of indices of physical development of preschool children of Ufa for 1978, 1999 and 2014 showed mixed changes or no statistically reliable changes in the indices in preschool children of different groups from 1978 to 1999. In the period from 1999 to 2014 in some groups of preschool children there were revealed statistically reliable positive changes in the indices, whereas there was no statistically reliable decrease of indices. A favorable fact is also the increment in the percentage of preschool children with harmonious physical development in the comparison with 1999. PMID- 29425001 TI - Solving the Health IT Interoperability Quagmire. PMID- 29425002 TI - [State of adaptive systems of the body in boys aged of 11-15 years in the process of their age development, pubertal maturation and in the dynamics of the school year]. AB - A comprehensive study of the functional state of the sympathoadrenal system (SAS) and adrenal cortex (AC) in boys aged of 11-15 years, was carried out depending on their age, puberty stage and academic year period, on the basis of indices of the daily adrenaline (A), noradrenaline (NA), 17-ketosteroids (17-KS) and 17 oxyketosteroids (17-OKS) excretion. A certain synchronism of the manifestation offunctional activity of the SAS mediator level, glucocorticoid and androgen AC function is determined as boys grow older and during their pubertal changes. At the same time the different dynamics of the studied indices in boys aged of from 14 to 15 years and by the V puberty stage is marked. During the academic year changes of hormone and hormonal metabolite excretion, having a different focus and intensity in the age groups were observed: a significant decrease of age NA excretion and androgen metabolite indices (at 15) of 14 and 15 year-old teenagers at the end of the academic year is found out, against the backdrop of a substantial and long-term increase of glucocorticoids (February, April), with their dangerous catabolic effect on a child's body and their depressing effect on the immune response. PMID- 29425003 TI - [Sedative effect of lavender during physical loads]. AB - There was investigated the dynamics of the functional state of the cardiovascular system of students after bicycle exercise load, followed by cold inhalation of lavender oil. Examinations were performed in the first half of the day at the same time, three times: 1) before exercise load (the state ofphysiological norm); 2) immediately after the load for 15minutes on the bike training apparatus "Proteus Pec 3320" in the third position, followed by aromatherapy; 3) at the 15 minute of the post-exercise load recovery period. Aromacorrection was executed by the method of cold inhalation. Registration and analysis of ECG by variation pulsometry was implemented by hardware-software complex, which combined the portable electrocardiograph of brand "Bio-Arm 001", a personal computer and software for automatic recording and analysis of ECG with the method of variation pulsometry according to parameters of the cardiac rhythm. In the absence of correction factors (control group) the work on a stationary bike was established to be accompanied by significant deviations of all investigated parameters of the heart rhythm, the majority of which persisted at the 15 minute of the post exercise load period also. Inhalation with the essential lavender oil (control group) under the bicycle load has a sedative effect on the activity of regulatory mechanisms of heart rhythm students. Releasing of the increased sympathetic influence on heart rate, initiated by the physical activity, it facilitates the rapid recovery of the functional state of the body in the post-exercise load period, thereby promoting its tolerance to effects of stress factors. PMID- 29425004 TI - Making the Call for Patient Experience: Using Health IT to Address Gaps in Patient Data-Sharing, Communication, and Interoperability. PMID- 29425006 TI - A Look Back on the ICD-10 Transition: CRISIS AVERTED OR IMAGINARY? PMID- 29425007 TI - [The improvement of methodical approaches of hygienic regulation of pesticides in water bodies]. AB - The article highlights the methodical features of hygienic regulation of pesticide preparation in water bodies, concretizes and supplements (specified) number of positions of the acting current methodical document on hygienic evaluation of new pesticides. From the position of the comprehensive hygienic standardization there are marked principles of the study of MPC for pesticides in water bodies, there is substantiated the expediency of expanding the arsenal of methods for determination of threshold concentrations of pesticides on the impact on organoleptic properties of water and sanitary regime of reservoirs, shows the role and importance of hydrolysis processes of active ingredients ofpesticides in water, which should be considered in the assessment of the impact of drugs on the processes of self-purification of water bodies. PMID- 29425005 TI - [Evaluation of antimutagenic properties of powdered malt and polymalt extracts with the use of micronucleus test]. AB - There were performed studies of the occurrence of cells with pathologies in the buccal epithelium of volunteers who consume drinks based on mixtures ofpowdered malt and polymalt extracts of buckwheat, peas, corn and barley. There was shown their impact on the stability of the genetic material of examined cases. There was established activation of apoptosis, which leads to the elimination of cells with cytogenetic deteriorations. Poliymalt extracts possess protective properties, contribute to the suppression ofprocesses offormation of cells with genetic disorders (micronuclei (from 4.38 +/- 0.67 %%, up to 2.53 +/- 0.39 %% after intake), protrusions (from 1,98 +/- 0,42 %%, up 0,85 +/- 0,25 %% after intake), incisures (from 3.34 +/- 0.44 %%, up 2.17 +/- 0.35 %% after intake), two cores (from 1.63 +/- 0.26 %%, up 0.65 +/- 0.21 %% after intake) and rid the body of aberrant cells, as evidenced by the increase in the number of cells with karyolysis (up to 5.98 +/- 0,91 %%, up 9.55 +/- 1.74 %% after intake), karyopyknosis (from 10.71 +/- 0.90 %%, up to 11.97 +/- 0.85 %% after intake) and perinuclear vacuoles (from 9.24 +/- 1.63 %%, up to 12.94 +/- 2.57 %% after intake). In women, anti-mutagenic effects ofpolymalt extracts are more pronounced than in men. Antimutagenic effects of extracts can be explained by the properties of contained in them B vitamins and sulfur-containing amino acids (cysteine and methionine). PMID- 29425008 TI - [Prevention of deteriorations of blood biochemical indices in experimental stress in rats]. AB - Results of the research of the impact of extract from the byproducts of guelder rose, containing a complexflavonoides (65% of dry weight), in the conditions of experimental a stress (vertical fixing of rats by a dorsal cervicalfold for 22 o'clock) are presented. The impact of a stress was shown to be followed by the gain in mass of adrenal glands by 42%. In blood serum there were noted marked hypertriglyceridemia, hypercholesterolemia, increased superoxide dismutase activity, decline in the number of reduced glutathione and anti-radical activity, the gain in lisofractions of phospholipids, decrease of phosphatidylcholine, phosphatidylethanolamine, cholesterol esters. Administration of the extract from the byproducts of guelder rose crushing promoted the normalization of indices of mass of adrenal glands and lipid metabolism in blood serum, was more effective, than a reference stress protector "Extract eleuterokokka(r)". The introduction of eleuterococcus was followed by the persistent both elevated level of cholesterol, free fatty acids, lisofraction of phospholipidsand low level offatty acids esters, cholesterol esters and a diphosphatidilglicerin. Byproducts of guelder rose were shown to represent a perspective view of raw materials for the producing of stress protective preparations. PMID- 29425009 TI - Improving Coding and Documentation Quality Through Real-Time Collaboration: Nurses and Coding Professionals Team Up to Tackle Documentation Issues. PMID- 29425010 TI - [Influence of beta - carotene on the spermatogenic epithelium and output dominant lethal muthations in rats under the exposure to hexavalent chromium]. AB - In adult rats exposed to hexavalent chromium (intraperitoneal injection of 0.028; 0.28 and 2.8 mg KCrO(kg bw/ day) during 48 days there is observed the decrease in the intensity of index of spermatogenesis, increase ofspermatids with micronuclei, intensifying of processes peroxidation of lipids in testis, resulted in the increase in the number of the abnormal spermatozoa and of percent of a fetal death. Simultaneous supplementation of beta-carotene in Cr (VI) exposed rats showed the increase of intensity index of spermatogenesis. Morphology of a sperm, intensity of processes peroxidation of lipids in testis and of number of viable embryos was restored. PMID- 29425011 TI - [Issues of occupational health in scientific works of Aleksey N. Sysin (to the 85th anniversary of the "A.N. Sysin Research Institute of Human Ecology and Environmental Health")]. AB - Research priorities of Alexei Nikolaevich Sysin (1879-1956) were faced to the study of issues of sanitary and epidemiological welfare of Russia. World- renowned hygienist scientist was the one of the pioneers in the field of general and communal hygiene, epidemiology and disinfection. Not little attention A.N. Sysin paid also to issues of occupational health, together with other scientists he laid the foundation of modern Occupational Health. The victory of the Great October Revolution has set before organizers and medical science scholars, among who was A.N. Sysin, new challenges in dealing with the many complex issues, including occupational health issues. Already in the first months of the new Republic he prepared dozens of directives, regulations and instructions, wrote a large number of draft laws for health services, developed the first regulations on the sanitary supervision of the country enterprises. The leading role in the emergence of many printed newspapers and magazines, books and bulletins on general issues in health, preventive medicine, hygiene, epidemiology, occupational health is belonged to A.N. Sysin. He published more than 250 scientific papers on various aspects of sanitary science: from the problems of epidemics of dangerous infections to the working and living conditions of different enterprises. A. N. Sysin paid a lot of attention to industrial injuries, problems of increscent occupational toxicology, the introduction of newest forms of general and personal protective equipment at the plant, modernization of the industrial equipment, issues of the shortened workday, labor of women and children - all kinds of sanitary measures and improvement of labor and living workers' conditions. PMID- 29425012 TI - Health Records All Access Pass. Patient Portals That Allow Viewing of Clinical Notes and Hospital Discharge Summaries: The University of Washington Opennotes Implementation Experience. PMID- 29425013 TI - Stopping Thieves in Their Tracks: What HIM Professionals Can Do To Mitigate Medical Identity Theft. PMID- 29425014 TI - ICD-10 Coding Productivity Study Highlights Emerging Standards. PMID- 29425015 TI - When Doctors and Patients Troll Each Other, PHI Protection Suffers. PMID- 29425016 TI - Controllable Electrochemical Synthesis of Copper Sulfides as Sodium-Ion Battery Anodes with Superior Rate Capability and Ultralong Cycle Life. AB - Sodium-ion batteries (SIBs) are prospective alternative to lithium-ion batteries for large-scale energy-storage applications, owing to the abundant resources of sodium. Metal sulfides are deemed to be promising anode materials for SIBs due to their low-cost and eco-friendliness. Herein, for the first time, series of copper sulfides (Cu2S, Cu7S4, and Cu7KS4) are controllably synthesized via a facile electrochemical route in KCl-NaCl-Na2S molten salts. The as-prepared Cu2S with micron-sized flakes structure is first investigated as anode of SIBs, which delivers a capacity of 430 mAh g-1 with a high initial Coulombic efficiency of 84.9% at a current density of 100 mA g-1. Moreover, the Cu2S anode demonstrates superior capability (337 mAh g-1 at 20 A g-1, corresponding to 50 C) and ultralong cycle performance (88.2% of capacity retention after 5000 cycles at 5 A g-1, corresponding to 0.0024% of fade rate per cycle). Meanwhile, the pseudocapacitance contribution and robust porous structure in situ formed during cycling endow the Cu2S anodes with outstanding rate capability and enhanced cyclic performance, which are revealed by kinetics analysis and ex situ characterization. PMID- 29425018 TI - Highly Photostable Near-IR-Excitation Upconversion Nanocapsules Based on Triplet Triplet Annihilation for in Vivo Bioimaging Application. AB - Triplet-triplet-annihilation-based upconversion (TTA-UC) imaging boasts a low excitation irradiance and an uncanny lack of autofluorescence interference. Because of these promising features, this approach has been the subject of intensifying investigation. Despite the ideal features, the classical approach of TTA-UC imaging suffers from some crucial drawbacks. A major deficiency of the system lies within its poor photostability, especially for a near-IR-excitation system. Here we report a reduction strategy to improve the TTA-UC photostability. The poor photostability of TTA-UC can be attributed to singlet oxygen generation by the sensitizer under irradiation. We control the singlet oxygen by including a reductive solvent, which consumes the singlet oxygen, thereby improving the TTA UC photostability. We also prepared TTA-UC nanocapsules with reductive solvent soybean oil inside. In comparison to nonreductive solvents such as toluene, our system shows a significant enhancement to the TTA-UC photostability. The prepared TTA-UC nanocapsules were then used for whole-animal deep imaging with a high signal-to-noise ratio. PMID- 29425017 TI - Optimum Preferential Oxidation Performance of CeO2-CuO x-RGO Composites through Interfacial Regulation. AB - Interfacial regulation offers a promising route to rationally and effectively design advanced materials for CO preferential oxidation. Herein, we initiated an interfacial regulation of CeO2-CuO x-RGO composites by adjusting the addition sequence of the components during the support formation. The presence of RGO along with the sequence tuning of the components is confirmed to survey the changes of the oxidation state of copper species, the content and distribution of the Cu+ site, and the synergistic interactions between Cu-Ce mixed oxides and reduced graphene oxide (RGO) over the catalysts. These catalysts were systematically characterized by inductively coupled plasma, X-ray diffraction, transmission electron microscopy/high-resolution transmission electron microscopy, hydrogen temperature-programmed reduction, X-ray photoelectron spectra, thermal gravimetric analysis, Raman spectra, and in situ diffuse reflectance infrared Fourier transform spectroscopy measurements. The results show that RGO is favorable for the generation of Cu+ and the dispersion of copper cerium species in the as-prepared catalysts. Furthermore, by multi-interfacial regulation of the CeO2-CuO x-RGO composites, the catalyst CeO2/CuO x-RGO exhibits a strikingly high catalytic oxidation activity at a low temperature coupled with a broader operation temperature window (i.e., CO conversion >99.0%, 140-220 degrees C) in the CO-selective oxidation reaction, which has been attributed to the high content of the active species Cu+ enriched on the surface, the highly dispersed copper oxide clusters subjected to a strong interaction with ceria, and the synergistic interactions between Cu-Ce mixed oxides and RGO. PMID- 29425019 TI - Electrospun Mat of Poly(vinyl alcohol)/Graphene Oxide for Superior Electrolyte Performance. AB - Here, we describe an electrospun mat of poly(vinyl alcohol) (PVA) and graphene oxide (GO) as a novel solid-state electrolyte matrix, which offers better performance retention upon drying after infiltrated with aqueous electrolyte. The PVA-GO mat overcomes the major issue of conventional PVA-based electrolytes, which is the ionic conductivity decay upon drying. After exposure to 45 +/- 5% relative humidity at 25 degrees C for 1 month, its conductivity decay is limited to 38.4%, whereas that of pure PVA mat is as high as 84.0%. This mainly attributes to the hygroscopic nature of GO and the unique nanofiber structure within the mat. Monolithic supercapacitors have been derived directly on the mat via a well-developed laser scribing process. The as-prepared supercapacitor offers an areal capacitance of 9.9 mF cm-2 at 40 mV s-1 even after 1 month of aging under ambient conditions, with a high device-based volumetric energy density of 0.13 mWh cm-3 and a power density of 2.48 W cm-3, demonstrating great promises as a more stable power supply for wearable electronics. PMID- 29425020 TI - Nature-Inspired 2D-Mosaic 3D-Gradient Mesoporous Framework: Bimetal Oxide Dual Composite Strategy toward Ultrastable and High-Capacity Lithium Storage. AB - In allusion to traditional transition-metal oxide (TMO) anodes for lithium-ion batteries, which face severe volume variation and poor conductivity, herein a bimetal oxide dual-composite strategy based on two-dimensional (2D)-mosaic three dimensional (3D)-gradient design is proposed. Inspired by natural mosaic dominance phenomena, Zn1-xCoxO/ZnCo2O4 2D-mosaic-hybrid mesoporous ultrathin nanosheets serve as building blocks to assemble into a 3D Zn-Co hierarchical framework. Moreover, a series of derivative frameworks with high evolution are controllably synthesized, based on which a facile one-pot synthesis process can be developed. From a component-composite perspective, both Zn1-xCoxO and ZnCo2O4 provide superior conductivity due to bimetal doping effect, which is verified by density functional theory calculations. From a structure-composite perspective, 2D-mosaic-hybrid mode gives rise to ladder-type buffering and electrochemical synergistic effect, thus realizing mutual stabilization and activation between the mosaic pair, especially for Zn1-xCoxO with higher capacity yet higher expansion. Moreover, the inside-out Zn-Co concentration gradient in 3D framework and rich oxygen vacancies further greatly enhance Li storage capability and stability. As a result, a high reversible capacity (1010 mA h g-1) and areal capacity (1.48 mA h cm-2) are attained, while ultrastable cyclability is obtained during high-rate and long-term cycles, rending great potential of our 2D-mosaic 3D-gradient design together with facile synthesis. PMID- 29425021 TI - Rational Design of Si@SiO2/C Composites Using Sustainable Cellulose as a Carbon Resource for Anodes in Lithium-Ion Batteries. AB - In this work, we propose a novel and facile route for the rational design of Si@SiO2/C anode materials by using sustainable and environment-friendly cellulose as a carbon resource. To simultaneously obtain a SiO2 layer and a carbon scaffold, a specially designed homogeneous cellulose solution and commercial Si nanopowder are used as the starting materials, and the cellulose/Si composite is directly assembled by an in situ regenerating method. Subsequently, Si@SiO2/C composite is obtained after carbonization. As expected, Si@SiO2 is homogeneously encapsulated in the cellulose-derived carbon network. The obtained Si@SiO2/C composite shows a high reversible capacity of 1071 mA h g-1 at a current density of 420 mA g-1 and 70% capacity retention after 200 cycles. This novel, sustainable, and effective design is a promising approach to obtain high performance and cost-effective composite anodes for practical applications. PMID- 29425022 TI - Photo-Induced Electron Transfer-Based Versatile Platform with G-Quadruplex/Hemin Complex as Quencher for Construction of DNA Logic Circuits. AB - G-quadruplex has been developed as an innovator for analytical chemistry and biomedicine due to its vibrant binding activity, structural polymorphism, and critical roles in biological regulation. Herein, a simple but versatile platform was obtained by integrating split G-quadruplex and fluorophore into a molecular beacon, where the photoinduced electron transfer could occur when the fluorophore approached the preformed G-quadruplex/hemin complexes. Such design subtly combined the G4 disruption-induced fluorescent turn-on strategy and the photoinduced electron transfer property into one platform for constructing the logic circuits. On the basis of such a universal platform, a series of binary logic gates (OR, INHIBIT, AND, and XOR), a combinatorial gate (INHIBIT-OR), and even a complex logic operation for discrimination of multiples of three from natural numbers less than ten have been successfully achieved only by employing such platform as work unit and single-strand DNAs as inputs. The set-reset function of this platform could be realized by alternatively introducing blocking and releasing strands. In addition, this platform could operate in a biological matrix stably and precisely. Therefore, such a universal platform lays the foundation for complicating the logic systems, realizing the biocomputing and also points out a new direction for target detection. PMID- 29425023 TI - Optimizing Micromixer Surfaces To Deter Biofouling. AB - Using computational modeling, we show that the dynamic interplay between a flowing fluid and the appropriately designed surface relief pattern can inhibit the fouling of the substrate. We specifically focus on surfaces that are decorated with three-dimensional (3D) chevron or sawtooth "micromixer" patterns and model the fouling agents (e.g., cells) as spherical microcapsules. The interaction between the imposed shear flow and the chevrons on the surface generates 3D vortices in the system. We pinpoint a range of shear rates where the forces from these vortices can rupture the bonds between the two mobile microcapsules near the surface. Notably, the patterned surface offers fewer points of attachment than a flat substrate, and the shear flows readily transport the separated capsules away from the layer. We contrast the performance of surfaces that encompass rectangular posts, chevrons, and asymmetric sawtooth patterns and thereby identify the geometric factors that cause the sawtooth structure to be most effective at disrupting the bonding between the capsules. By breaking up nascent clusters of contaminant cells, these 3D relief patterns can play a vital role in disrupting the biofouling of surfaces immersed in flowing fluids. PMID- 29425025 TI - Ultrasensitive Single-Molecule Enzyme Detection and Analysis Using a Polymer Microarray. AB - This report describes a novel method for isolating and detecting individual enzyme molecules using polymer arrays of picoliter microwells. A fluidic flow cell device containing an array of microwells is fabricated in cyclic olefin polymer (COP). The use of COP microwell arrays simplifies experiments by eliminating extensive device preparation and surface functionalization that are common in other microwell array formats. Using a simple and robust loading method to introduce the reaction solution, individual enzyme molecules are trapped in picoliter microwells and subsequently isolated and sealed by fluorinated oil. The sealing is stable for hours in the COP device. The picoliter microwell device can measure enzyme concentrations in the low-femtomolar range by counting the number of active wells using a digital read-out. These picoliter microwell arrays can also easily be regenerated and reused. PMID- 29425024 TI - Human Suction Blister Fluid Composition Determined Using High-Resolution Metabolomics. AB - Interstitial fluid (ISF) surrounds the cells and tissues of the body. Since ISF has molecular components similar to plasma, as well as compounds produced locally in tissues, it may be a valuable source of biomarkers for diagnostics and monitoring. However, there has not been a comprehensive study to determine the metabolite composition of ISF and to compare it to plasma. In this study, the metabolome of suction blister fluid (SBF), which largely consists of ISF, collected from 10 human volunteers was analyzed using untargeted high-resolution metabolomics (HRM). A wide range of metabolites were detected in SBF, including amino acids, lipids, nucleotides, and compounds of exogenous origin. Various systemic and skin-derived metabolite biomarkers were elevated or found uniquely in SBF, and many other metabolites of clinical and physiological significance were well correlated between SBF and plasma. In sum, using untargeted HRM profiling, this study shows that SBF can be a valuable source of information about metabolites relevant to human health. PMID- 29425026 TI - Label-Free Detection of Tetramolecular i-Motifs by Surface-Enhanced Raman Spectroscopy. AB - Surface-enhanced Raman spectroscopy (SERS) can probe DNA primary structure; however, the direct analysis of DNA secondary structure is still technically challenging. In this study, we developed a novel method based on introducing aluminum ion as the aggregation agent for silver nanoparticles, affording high quality SERS signals of tetramolecular DNA. Thus, the formation of tetramolecular i-motifs was precisely analyzed by SERS signals for the first time and structural features involving glycosidic torsion, protonated cytosine, and cytosine rings were investigated. Moreover, the number of intercalated base pairs in i-motifs were quantified based on the relative intensities of the characteristic SERS bands. The proposed approach would have widespread applications in DNA analysis, especially for detecting various DNA secondary structures. PMID- 29425027 TI - Metal-Organic Frameworks Mediated Synthesis of One-Dimensional Molybdenum Based/Carbon Composites for Enhanced Lithium Storage. AB - Molybdenum (Mo)-based compounds with properly engineered nanostructures usually possess improved reversible lithium storage capabilities, which offer great promise to boost the performance of lithium-ion batteries (LIBs). Nevertheless, a lack of efficient and high-yield methods for constructing rational nanostructures has largely restricted the application of these potentially important materials. Herein we demonstrate a metal-organic frameworks (MOFs) mediated strategy to successfully synthesize a series of one-dimensional Mo-based/carbon composites with distinct nanostructures. In this process, starting from well-designed MoO3 nanorods, the crystal control growth is first proposed that a layer of MOFs is achieved to be controllably grown on surfaces of MoO3, forming an obvious core shell structure, and then the adopted precursor can be in situ transformed into MoO2 or Mo2C which are both well confined in conductive porous carbons through direct carbonization at different temperatures, where the MOFs shell serve as both carbon sources and the reactant to react with MoO3 simultaneously. Benefiting from this design, all optimized products exhibit enhanced electrochemical performances when evaluated as anode materials for LIBs, especially the hollow MoO2/C and core-shell Mo2C/C electrodes, show best reversible capacities up to 810 and 530 mAh g-1 even after 600 cycles at a current density of 1 A g-1, respectively. So this work may broaden the application of MOFs as a kind of coating materials and elucidates the attractive lithium storage performances of molybdenum-based compounds. PMID- 29425028 TI - High-Throughput Cysteine Scanning To Identify Stable Antibody Conjugation Sites for Maleimide- and Disulfide-Based Linkers. AB - THIOMAB antibody technology utilizes cysteine residues engineered onto an antibody to allow for site-specific conjugation. The technology has enabled the exploration of different attachment sites on the antibody in combination with small molecules, peptides, or proteins to yield antibody conjugates with unique properties. As reported previously ( Shen , B. Q. , et al. ( 2012 ) Nat. Biotechnol. 30 , 184 - 189 ; Pillow , T. H. , et al. ( 2017 ) Chem. Sci. 8 , 366 370 ), the specific location of the site of conjugation on an antibody can impact the stability of the linkage to the engineered cysteine for both thio succinimide and disulfide bonds. High stability of the linkage is usually desired to maximize the delivery of the cargo to the intended target. In the current study, cysteines were individually substituted into every position of the anti HER2 antibody (trastuzumab), and the stabilities of drug conjugations at those sites were evaluated. We screened a total of 648 THIOMAB antibody-drug conjugates, each generated from a trastuzamab prepared by sequentially mutating non-cysteine amino acids in the light and heavy chains to cysteine. Each THIOMAB antibody variant was conjugated to either maleimidocaproyl-valine-citrulline-p aminobenzyloxycarbonyl-monomethyl auristatin E (MC-vc-PAB-MMAE) or pyridyl disulfide monomethyl auristatin E (PDS-MMAE) using a high-throughput, on-bead conjugation and purification method. Greater than 50% of the THIOMAB antibody variants were successfully conjugated to both MMAE derivatives with a drug to antibody ratio (DAR) of >0.5 and <50% aggregation. The relative in vitro plasma stabilities for approximately 750 conjugates were assessed using enzyme-linked immunosorbent assays, and stable sites were confirmed with affinity-capture LC/MS based detection methods. Highly stable conjugation sites for the two types of MMAE derivatives were identified on both the heavy and light chains. Although the stabilities of maleimide conjugates were shown to be greater than those of the disulfide conjugates, many sites were identified that were stable for both. Furthermore, in vitro stabilities of selected stable sites translated across different cytotoxic payloads and different target antibodies as well as to in vivo stability. PMID- 29425031 TI - Selective Inhibitors of Human Neuraminidase 3. AB - Human neuraminidases (NEU) are associated with human diseases including cancer, atherosclerosis, and diabetes. To obtain small molecule inhibitors as research tools for the study of their biological functions, we designed a library of 2 deoxy-2,3-didehydro- N-acetylneuraminic acid (DANA) analogues with modifications at C4 and C9 positions. This library allowed us to discover selective inhibitors targeting the human NEU3 isoenzyme. Our most selective inhibitor for NEU3 has a Ki of 320 +/- 40 nM and a 15-fold selectivity over other human neuraminidase isoenzymes. This inhibitor blocks glycolipid processing by NEU3 in vitro. To improve their pharmacokinetic properties, various esters of the best inhibitors were synthesized and evaluated. Finally, we confirmed that our best compounds exhibited selective inhibition of NEU orthologues from murine brain. PMID- 29425029 TI - Mechanistic Origins of Enzyme Activation in Human Glucokinase Variants Associated with Congenital Hyperinsulinism. AB - Human glucokinase (GCK) acts as the body's primary glucose sensor and plays a critical role in glucose homeostatic maintenance. Gain-of-function mutations in gck produce hyperactive enzyme variants that cause congenital hyperinsulinism. Prior biochemical and biophysical studies suggest that activated disease variants can be segregated into two mechanistically distinct classes, termed alpha-type and beta-type. Steady-state viscosity variation studies indicate that the kcat values of wild-type GCK and an alpha-type variant are partially diffusion limited, whereas the kcat value of a beta-type variant is viscosity-independent. Transient-state chemical quench-flow analyses demonstrate that wild-type GCK and the alpha-type variant display burst kinetics, whereas the beta-type variant lacks a burst phase. Comparative hydrogen-deuterium exchange mass spectrometry of unliganded enzymes demonstrates that a disordered active site loop, which folds upon binding of glucose, is protected from exchange in the alpha-type variant. The alpha-type variant also displays an increased level of exchange within a beta strand located near the enzyme's hinge region, which becomes more solvent-exposed upon glucose binding. In contrast, beta-type activation causes no substantial difference in global or local exchange relative to that of unliganded, wild-type GCK. Together, these results demonstrate that alpha-type activation results from a shift in the conformational ensemble of unliganded GCK toward a state resembling the glucose-bound conformation, whereas beta-type activation is attributable to an accelerated rate of product release. This work elucidates the molecular basis of naturally occurring, activated GCK disease variants and provides insight into the structural and dynamic origins of GCK's unique kinetic cooperativity. PMID- 29425032 TI - Floquet Study of Quantum Control of the Cis-Trans Photoisomerization of Rhodopsin. AB - Understanding how to control reaction dynamics of polyatomic systems by using ultrafast laser technology is a fundamental challenge of great technological interest. Here, we report a Floquet theoretical study of the effect of light induced potentials on the ultrafast cis-trans photoisomerization dynamics of rhodopsin. The Floquet Hamiltonian involves an empirical 3-state 25-mode model with frequencies and excited-state gradients parametrized to reproduce the rhodopsin electronic vertical excitation energy, the resonance Raman spectrum, and the photoisomerization time and efficiency as probed by ultrafast spectroscopy. We simulate the excited state relaxation dynamics using the time dependent self-consistent field method, as described by a 3-state 2-mode nuclear wavepacket coupled to a Gaussian ansatz of 23 vibronic modes. We analyze the reaction time and product yield obtained with pulses of various widths and intensity profiles, defining 'dressed states' where the perturbational effect of the pulses is naturally decoupled along the different reaction channels. We find pulses that delay the excited-state photoisomerization for hundreds of femtoseconds, and we gain insights on the underlying control mechanisms. The reported findings provide understanding of quantum control, particularly valuable for the development of ultrafast optical switches based on visual pigments. PMID- 29425030 TI - eIF2B Mechanisms of Action and Regulation: A Thermodynamic View. AB - Eukaryotic translation initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor of the GTPase eIF2, which brings the initiator Met-tRNAi to the ribosome in the form of the eIF2-GTP.Met-tRNAi ternary complex (TC). The activity of eIF2B is inhibited by phosphorylation of its substrate eIF2 by several stress induced kinases, which triggers the integrated stress response (ISR). The ISR plays a central role in maintaining homeostasis in the cell under various stress conditions, and its dysregulation is a causative factor in the pathology of a number of neurodegenerative disorders. Over the past three decades, virtually every aspect of eIF2B function has been the subject of uncertainty or controversy: from the catalytic mechanism of nucleotide exchange, to whether eIF2B only catalyzes nucleotide exchange on eIF2 or also promotes binding of Met tRNAi to eIF2-GTP to form the TC. Here, we provide the first complete thermodynamic analysis of the process of recycling of eIF2-GDP to the TC. The available evidence leads to the conclusion that eIF2 is channeled from the ribosome (as an eIF5.eIF2-GDP complex) to eIF2B, converted by eIF2B to the TC, which is then channeled back to eIF5 and the ribosome. The system has evolved to be regulated by multiple factors, including post-translational modifications of eIF2, eIF2B, and eIF5, as well as directly by the energy balance in the cell, through the GTP:GDP ratio. PMID- 29425033 TI - Copper Inhibition of Triplet-Induced Reactions Involving Natural Organic Matter. AB - The triplet excited state of natural organic matter (3NOM*) is an important reactive intermediate in sensitizing transformation of a wide range of environmentally relevant organic compounds, but the impact of trace metals on the fate and reactivity of 3NOM* is poorly understood. In this study, we investigate the effect of low concentrations of copper on 3NOM*-mediated oxidation (electron transfer) and energy transfer reactions. The oxidative efficiency of 3NOM* from Suwannee River NOM (SRNOM) and the widely used model triplet sensitizer 4 carboxybenzophenone were determined by measuring the photooxidation of 2,4,6 trimethylphenol (TMP). The pseudo-first-order photooxidation rate constants of TMP decreased markedly in the presence of trace amounts of Cu(II) (25-500 nM) with the decrease associated with the continuous reduction of the oxidation intermediates of TMP (i.e., TMP*(-H)) by the photochemically produced Cu(I). A kinetic model is developed that adequately describes the Cu inhibition effect in TMP photooxidation in irradiated SRNOM solutions. The 3NOM* energy transfer ability was assessed by measuring the isomerization of sorbic acid with the rate of this process markedly retarded in the presence of significantly higher (micromolar) concentrations of Cu(II) than previously used. This result is attributed to (i) decreased formation of high energy 3NOM* due to formation of Cu NOM complexes and (ii) increased loss of 3NOM* as a result of quenching by Cu. Since 3NOM* is the precursor to singlet oxygen (1O2) formation, the steady-state concentrations of 1O2 also decreased in the presence of micromolar concentrations of Cu(II) with the quenching rate constant of 3NOM* by Cu calculated to be 1.08 * 1010 M-1 s-1. PMID- 29425034 TI - Strategies to Explore and Develop Reversible Redox Reactions of Li-S in Electrode Architectures Using Silver-Polyoxometalate Clusters. AB - Investigations of the Ag (I)-substituted Keggin K3[H3AgIPW11O39] as a bifunctional Lewis acidic and basic catalyst are reported that explore the stabilization of Li2Sn moieties so that reversible redox reactions in S-based electrodes would be possible. Spectroscopic investigations showed that the Li2Sn moieties can be strongly adsorbed on the {AgIPW11O39} cluster, where the Ag(I) ion can act as a Lewis acid site to further enhance the adsorption of the S moieties, and these interactions were investigated and rationalized using DFT. These results were used to construct an electrode for use in a Li-S battery with a very high S utilization of 94%, and a coulometric capacity of 1580 mAh g-1. This means, as a result of using the AgPOM, both a high active S content, as well as a high areal S mass loading, is achieved in the composite electrode giving a highly stable battery with cycling performance at high rates (1050 and 810 mAh g 1 at 1C and 2C over 100 to 300 cycles, respectively). PMID- 29425035 TI - Efficiency at Maximum Power of Irreversible Engines with Asymmetric Nonlinear Flux-Force Relations. AB - The efficiency at maximum power (EMP) is investigated for classical irreversible thermal or chemical model engines. The heat or particle transport is governed by flux-force relations of the general power-law type. Special attention is given to engines that feature asymmetric transport laws, one for input (of heat or particles) and a different one for output. It is shown that in a couple of case studies, the EMP of such engines is close to the lowest of the two EMPs that would result for symmetric implementations of the transport laws. As a consequence, ideal efficiency at maximum power is only possible in the model in which both flux-force relations are of step-function type. PMID- 29425036 TI - Environmental Transformations and Algal Toxicity of Single-Layer Molybdenum Disulfide Regulated by Humic Acid. AB - The environmental transformations of nanomaterials are correlated with their behaviors and ecological risks. The applications of single-layer molybdenum disulfide (SLMoS2) have rapidly developed in environmental fields, but the potential transformations and biological effects of SLMoS2 remain largely unknown. This study revealed that humic acid (HA, over 10 mg/L) induced the scrolling of SLMoS2 with light irradiation over a 56-day incubation. The colloidal stability of SLMoS2 increased, and the aggregation ratio decreased from 0.59 +/- 0.07 to 0.08 +/- 0.01 nm/min after HA hybridization. Besides, compared with pristine SLMoS2, the chemical dissolution rate of SLMoS2 was up to 4.6-fold faster with HA exposure. These results demonstrate that HA affects the environmental fate and transformations of SLMoS2. SLMoS2-HA possessed a significantly widened direct band gap (2.06 eV) compared with that of SLMoS2 (1.8 eV). SLMoS2 acted as an electronic acceptor from HA, resulting in the separation of electron-hole pairs. Consequently, SLMoS2-HA exhibited stronger peroxidase like catalytic activity, which was approximately 2-fold higher than that of SLMoS2. Moreover, the morphology and layered structure of SLMoS2 changed, and the damage SLMoS2 inflicted on microalgae was significantly reduced. This work provides insights into the behaviors and related biological risks of SLMoS2 in aqueous environments. PMID- 29425038 TI - Discussion on Regression Methods Based on Ensemble Learning and Applicability Domains of Linear Submodels. AB - To develop a new ensemble learning method and construct highly predictive regression models in chemoinformatics and chemometrics, applicability domains (ADs) are introduced into the ensemble learning process of prediction. When estimating values of an objective variable using subregression models, only the submodels with ADs that cover a query sample, i.e., the sample is inside the model's AD, are used. By constructing submodels and changing a list of selected explanatory variables, the union of the submodels' ADs, which defines the overall AD, becomes large, and the prediction performance is enhanced for diverse compounds. By analyzing a quantitative structure-activity relationship data set and a quantitative structure-property relationship data set, it is confirmed that the ADs can be enlarged and the estimation performance of regression models is improved compared with traditional methods. PMID- 29425037 TI - Assessment and Reproducibility of Quantitative Structure-Activity Relationship Models by the Nonexpert. AB - Model reliability is generally assessed and reported as an intrinsic component of quantitative structure-activity relationship (QSAR) publications; it can be evaluated using defined quality criteria such as the Organisation for Economic Cooperation and Development (OECD) principles for the validation of QSARs. However, less emphasis is afforded to the assessment of model reproducibility, particularly by users who may wish to use model outcomes for decision making, but who are not QSAR experts. In this study we identified a range of QSARs in the area of absorption, distribution, metabolism, and elimination (ADME) prediction and assessed their adherence to the OECD principles, as well as investigating their reproducibility by scientists without expertise in QSAR. Here, 85 papers were reviewed, reporting over 80 models for 31 ADME-related endpoints. Of these, 12 models were identified that fulfilled at least 4 of the 5 OECD principles and 3 of these 12 could be readily reproduced. Published QSAR models should aim to meet a standard level of quality and be clearly communicated, ensuring their reproducibility, to progress the uptake of the models in both research and regulatory landscapes. A pragmatic workflow for implementing published QSAR models and recommendations to modellers, for publishing models with greater usability, are presented herein. PMID- 29425039 TI - E22G Pathogenic Mutation of beta-Amyloid (Abeta) Enhances Misfolding of Abeta40 by Unexpected Prion-like Cross Talk between Abeta42 and Abeta40. AB - Cross-seeding of misfolded amyloid proteins is postulated to induce cross-species infection of prion diseases. In sporadic Alzheimer's disease (AD), misfolding of 42-residue beta-amyloid (Abeta) is widely considered to trigger amyloid plaque deposition. Despite increasing evidence that misfolded Abeta mimics prions, interactions of misfolded 42-residue Abeta42 with more abundant 40-residue Abeta40 in AD are elusive. This study presents in vitro evidence that a heterozygous E22G pathogenic ("Arctic") mutation of Abeta40 can enhance misfolding of Abeta via cross-seeding from wild-type (WT) Abeta42 fibril. Thioflavin T (ThT) fluorescence analysis suggested that misfolding of E22G Abeta40 was enhanced by adding 5% (w/w) WT Abeta42 fibril as "seed", whereas WT Abeta40 was unaffected by Abeta42 fibril seed. 13C SSNMR analysis revealed that such cross-seeding prompted formation of E22G Abeta40 fibril that structurally mimics the seed Abeta42 fibril, suggesting unexpected cross talk of Abeta isoforms that potentially promotes early onset of AD. The SSNMR approach is likely applicable to elucidate structural details of heterogeneous amyloid fibrils produced in cross-seeding for amyloids linked to neurodegenerative diseases. PMID- 29425040 TI - Controlled Gas Uptake in Metal-Organic Frameworks with Record Ammonia Sorption. AB - Ammonia is a vital commodity in our food supply chain, but its toxicity and corrosiveness require advanced protection and mitigation. These needs are not met efficiently by current materials, which suffer from either low capacity or low affinity for NH3. Here, we report that a series of microporous triazolate metal organic frameworks containing open metal sites exhibit record static and dynamic ammonia capacities. Under equilibrium conditions at 1 bar, the materials adsorb up to 19.79 mmol NH3 g-1, more than twice the capacity of activated carbon, the industry standard. Under conditions relevant to personal protection equipment, capacities reach 8.56 mmol g-1, 27% greater than the previous best material. Structure-function relationships and kinetic analyses of NH3 uptake in isostructural micro- and mesoporous materials made from Co, Ni, and Cu reveal stability trends that are in line with the water substitution rates in simple metal-aquo complexes. Altogether, these results provide clear, intuitive descriptors that govern the static and dynamic uptake, kinetics, and stability of MOF sorbents for strongly interacting gases. PMID- 29425041 TI - Discovery of Intermediates of lacZ beta-Galactosidase Catalyzed Hydrolysis Using dDNP NMR. AB - Using dissolution dynamic nuclear polarization, the sensitivity of single scan solution state 13C NMR can be improved up to 4 orders of magnitude. In this study, the enzyme lacZ beta-galactosidase from Escherichia coli was subjected to hyperpolarized substrate, and previously unknown reaction intermediates were observed, including a 1,1-linked disaccharide. The enzyme is known for making 1,6 transglycosylation, producing products like allolactose, that are also substrates. To analyze the kinetics, a simple kinetic model was developed and used to determine relative transglycosylation and hydrolysis rates of each of the intermediates, and the novel transglycosylation intermediates were determined as better substrates than the 1,6-linked one, explaining their transient nature. These findings suggest that hydrolysis and transglycosylation might be more complex than previously described. PMID- 29425042 TI - Pushing the Limits of Structure-Based Models: Prediction of Nonglobular Protein Folding and Fibrils Formation with Go-Model Simulations. AB - The development of computational efficient models is essential to obtain a detailed characterization of the mechanisms underlying the folding of proteins and the formation of amyloid fibrils. Structure-based computational models (Go model) with Calpha or all-atom resolutions have been able to successfully delineate the mechanisms of folding of several globular proteins and offer an interesting alternative to computationally intensive simulations with explicit solvent description. Here, we explore the limits of Go-model predictions by analyzing the folding of the nonglobular repeat domain proteins Notch Ankyrin and p16INK4 and the formation of human islet amyloid polypeptide (hIAPP) fibrils. Folding trajectories of the repeat domain proteins revealed that an all-atom resolution is required to capture the folding pathways and cooperativity reported in experimental studies. The all-atom Go-model was also successful in predicting the free-energy landscape of hIAPP fibrillation, suggesting a "dock and lock" mechanism of fibril elongation. We finally explored how mutations can affect the co-assembly of hIAPP fibrils by simulating a heterogeneous system composed of wild-type and mutated hIAPP peptides. Overall, this study shows that all-atom Go model-based simulations have the potential of discerning the effects of mutations and post-translational modifications in protein folding and association and may help in resolving the dichotomy between experimental and theoretical studies on protein folding and amyloid fibrillation. PMID- 29425043 TI - Aptamer-Based Lateral Flow Test Strip for Rapid Detection of Zearalenone in Corn Samples. AB - An aptamer-based lateral flow test strip was developed for the detection of zearalenone (ZEN). This assay was based on the competition for the aptamer between ZEN and its complementary sequence. Several experimental conditions that could influence sensitivity have been investigated, including the concentration of aptamer and NaCl used in the probe preparation, the mole ratio of streptavidin and biotinylated DNA used in the preparation of test line and control line, and the loading quantity of gold nanoparticles-aptamer conjugates (AuNPs-Apt). Under the optimal experimental conditions, we successfully detected ZEN within a detection range of 5-200 ng/mL and the visual limit of detection of 20 ng/mL. This aptamer-based strip was successfully applied to the determination of ZEN in spiked corn samples, and the recoveries were from 93.4% to 114.2%. All detections can be achieved within 5 min. The results demonstrated that the developed aptamer based lateral flow test strip is a potential alternative tool for the rapid and sensitive detection of ZEN. PMID- 29425044 TI - Photo-Rechargeable Organo-Halide Perovskite Batteries. AB - Emerging autonomous electronic devices require increasingly compact energy generation and storage solutions. Merging these two functionalities in a single device would significantly increase their volumetric performance, however this is challenging due to material and manufacturing incompatibilities between energy harvesting and storage materials. Here we demonstrate that organic-inorganic hybrid perovskites can both generate and store energy in a rechargeable device termed a photobattery. This photobattery relies on highly photoactive two dimensional lead halide perovskites to simultaneously achieve photocharging and Li-ion storage. Integrating these functionalities provides simple autonomous power solutions while retaining capacities of up to 100 mAh/g and efficiencies similar to electrodes using a mixture of batteries and solar materials. PMID- 29425045 TI - Ag(I)-Catalyzed Synthesis of Azabicyclic Alkaloid Frameworks from Ketimine Tethered Ynones: Total Synthesis of Indolizidine 209D. AB - An efficient Ag(I)-catalyzed pi-acid activation method for the cyclization of cyclic ketimine-tethered ynones is reported. Various nitrogen-containing scaffolds commonly found in bioactive alkaloids can be prepared in high yields, and the utility of the method is demonstrated by a formal synthesis of (+/-) lasubine II and in a short total synthesis of (+/-)-indolizidine 209D. PMID- 29425046 TI - Electrochemical Generation of Diaza-oxyallyl Cation for Cycloaddition in an All Green Electrolytic System. AB - The electro-oxidative generation of diaza-oxyallyl cation and its application to the synthesis of diamine motifs has been explored. Because of the synergistic combination of anodic and cathodic reactions, the current electrochemical method not only avoids the use of a stoichiometric amount of chemical oxidant but also eliminates the need for supporting electrolyte and external base required for effective oxidation. PMID- 29425047 TI - Protein Adsorption and Layer Formation at the Stainless Steel-Solution Interface Mediates Shear-Induced Particle Formation for an IgG1 Monoclonal Antibody. AB - Passage of specific protein solutions through certain pumps, tubing, and/or filling nozzles can result in the production of unwanted subvisible protein particles (SVPs). In this work, surface-mediated SVP formation was investigated. Specifically, the effects of different solid interface materials, interfacial shear rates, and protein concentrations on SVP formation were measured for the National Institute of Standards and Technology monoclonal antibody (NISTmAb), a reference IgG1 monoclonal antibody (mAb). A stainless steel rotary piston pump was used to identify formulation and process parameters that affect aggregation, and a flow cell (alumina or stainless steel interface) was used to further investigate the effect of different interface materials and/or interfacial shear rates. SVP particles produced were monitored using flow microscopy or flow cytometry. Neutron reflectometry and a quartz crystal microbalance with dissipation monitoring were used to characterize adsorption and properties of NISTmAb at the stainless steel interface. Pump/shear cell experiments showed that the NISTmAb concentration and interface material had a significant effect on SVP formation, while the effects of interfacial shear rate and passage number were less important. At the higher NISTmAb concentrations, the adsorbed protein became structurally altered at the stainless steel interface. The primary adsorbed layer remained largely undisturbed during flow, suggesting that SVP formation at high NISTmAb concentration was caused by the disruption of patches and/or secondary interactions. PMID- 29425048 TI - Electro-optic Response in Germanium Halide Perovskites. AB - Electro-optic materials that can be solution-processed and provide high crystalline quality are sought for the development of compact, efficient optical modulators. Here we present density functional theory investigations of the linear electro-optic coefficients of candidate materials cesium and methylammonium germanium halide perovskites. As with their lead halide counterparts, these compounds can be solution-processed, but in contrast, they possess the noncentrosymmetric crystal structures needed to provide a linear electro-optic effect. We find substantial electro-optic responses from these compounds; in particular, for the r51 tensor element of CsGeI3, we predict an electro-optic coefficient of 47 pm.V-1 at the communications wavelength of 1550 nm, surpassing the strongest coefficient of LiNbO3 at 31 pm.V-1. The strong electro-optic responses of the germanium compounds are driven by high nonlinear susceptibilities and dynamics of the germanium atoms that ultimately arise from the distorted crystal structures. Alongside the electro-optic coefficient calculations, we provide the frequency responses for the linear and nonlinear electronic susceptibilities. PMID- 29425049 TI - Polysaccharide Submicrocarrier for Improved Pulmonary Delivery of Poorly Soluble Anti-infective Ciprofloxacin: Preparation, Characterization, and Influence of Size on Cellular Uptake. AB - The majority of the currently used and developed anti-infectives are poorly water soluble molecules. The poor solubility might lead to limited bioavailability and pharmacological action of the drug. Novel pharmaceutical materials have thus been designed to solve those problems and improve drug delivery. In this study, we propose a facile method to produce submicrocarriers (sMCs) by electrostatic gelation of anionic beta-cyclodextrin (abeta-CD) and chitosan. The average hydrodynamic size ranged from 400 to 900 nm by carefully adjusting polymer concentrations and N/C ratio. The distinct host-guest reaction of cyclodextrin derivative is considered as a good approach to enhance solubility, and prevent drug recrystallization, and thus was used to develop sMC to improve the controlled release profile of a poorly soluble and clinically relevant anti infective ciprofloxacin. The optimal molar ratio of ciprofloxacin to abeta-CD was found to be 1:1, which helped maximize encapsulation efficiency (~90%) and loading capacity (~9%) of ciprofloxacin loaded sMCs. Furthermore, to recommend the future application of the developed sMCs, the dependence of cell uptake on sMCs size (500, 700, and 900 nm) was investigated in vitro on dTHP-1 by both flow cytometry and confocal microscopy. The results demonstrate that, regardless of their size, an only comparatively small fraction of the sMCs were taken up by the macrophage-like cells, while most of the carriers were merely adsorbed to the cell surface after 2 h incubation. After continuing the incubation to reach 24 h, the majority of the sMCs were found intracellularly. However, the sMCs had been designed to release sufficient amount of drug within 24 h, and the subsequent phagocytosis of the carrier may be considered as an efficient pathway for its safe degradation and elimination. In summary, the developed sMC is a suitable system with promising perspectives recommended for pulmonary extracellular infection therapeutics. PMID- 29425050 TI - Estimated Excess Morbidity and Mortality Associated with Air Pollution above American Thoracic Society-recommended Standards, 2013-2015. American Thoracic Society and Marron Institute Report. PMID- 29425051 TI - Carbohydrate antigen 125: a promising tool for risk stratification in heart diseases. AB - All patients with heart diseases should undergo risk stratification to predict those who are at high risk for short- and long-term adverse outcomes. Carbohydrate antigen 125 (CA125) is a glycoprotein produced by mesothelium that has clinical role in ovarian cancer monitoring. However, as it is not specific for ovarian cells, CA125 could also be used in heart diseases to monitor congestion and inflammation. Pericarditis, atrial fibrillation, heart failure and coronary artery disease are some scenarios in which this biomarker was studied.CA125 identifies patients at high risk of rehospitalizations and death, in addition to being associated with hemodynamic data (ejection fraction and right atrial pressure). Hence, CA125 is a tool for risk stratification in heart diseases. PMID- 29425052 TI - Regulatory T Cells Subvert Mycobacterial Containment in Patients Failing Extensively Drug-Resistant Tuberculosis Treatment. AB - RATIONALE: The advent of extensively drug-resistant (XDR) tuberculosis (TB) and totally drug-resistant TB, with limited or no treatment options, has facilitated renewed interest in host-directed immunotherapy, particularly for therapeutically destitute patients. However, the selection and utility of such approaches depend on understanding the host immune response in XDR-TB, which hitherto remains unexplored. OBJECTIVES: To determine the host immunological profile in patients with XDR-TB, compared with drug-sensitive TB (DS-TB), using peripheral blood and explanted lung tissue. METHODS: Blood and explanted lung tissue were obtained from patients with XDR-TB (n = 31), DS-TB (n = 20), and presumed latent TB infection (n = 20). T-cell phenotype (T-helper cell type 1 [Th1]/Th2/Th17/regulatory T cells [Tregs]) was evaluated in all patient groups, and Treg function assessed in XDR-TB nonresponders by coculturing PPD-preprimed effector T cells with H37Rv-infected monocyte-derived macrophages, with or without autologous Tregs. Mycobacterial containment was evaluated by counting colony-forming units. MEASUREMENTS AND MAIN RESULTS: Patients failing XDR-TB treatment had an altered immunophenotype characterized by a substantial increase in the frequency (median; interquartile range) of CD4+CD25+FoxP3+ Tregs (11.5%; 5.9-15.2%) compared with DS-TB (3.4%; 1.6-5.73%; P < 0.001) and presumed latent TB infection (1.8%; 1.2-2.3%; P < 0.001), which was unrelated to disease duration. Tregs isolated from patients with XDR-TB suppressed T-cell proliferation (up to 90%) and subverted containment of H37Rv-infected monocyte derived macrophages (by 30%; P = 0.03) by impairing effector T-cell function through a mechanism independent of direct cell-to-cell contact, IL-10, TGF (transforming growth factor)-beta, and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). CONCLUSIONS: Collectively, these data suggest that Tregs may be contributing to immune dysfunction, and bacterial persistence, in patients with XDR-TB. The relevant cellular pathways may serve as potential targets for immunotherapeutic intervention. PMID- 29425053 TI - Identified Palliative Care Approach Needs with SPICT in Family Practice: A Preliminary Observational Study. AB - BACKGROUND: Identifying patients who require palliative care approach is challenging for family physicians, even though several identification tools have been developed for this purpose. OBJECTIVE: To explore the prevalence and characteristics of family practice patients who need palliative care approach as determined using Supportive and Palliative Care Indicators Tool (SPICTTM, April 2015) in Japan. DESIGN: Single-center cross-sectional study. SETTING/SUBJECTS: We enrolled all patients >=65 years of age who visited the chief researcher's outpatient clinic in October 2016. MEASUREMENTS: We used Japanese version of SPICT (SPICT-J) to identify patients who need palliative care approach. We assessed patients' backgrounds and whether they had undergone advance care planning with their family physicians. RESULTS: This study included 87 patients (61 females) with a mean age of 79.0 +/- 7.4 years. Eight patients (9.2%) were identified as needing palliative care approach. The mean age of patients who needed this approach was 82.3 +/- 8.3 years and main underlying conditions were heart/vascular disease (37.5%), dementia/frailty (25.0%), and respiratory disease (12.5%). Only two of eight patients identified as needing palliative care approach had discussed advance care planning with their family physicians. CONCLUSIONS: In family practice, 9.2% of outpatients >=65 years of age were identified as needing palliative care approach. Family physicians should carefully evaluate whether outpatients need palliative care approach. PMID- 29425055 TI - Caring for Life-Limiting Illness in Ethiopia: A Mixed-Methods Assessment of Outpatient Palliative Care Needs. AB - BACKGROUND: Palliative care aims to reduce physical suffering and the emotional, spiritual, and psychosocial distress of life-limiting illness. Palliative care is a human right, yet there are vast disparities in its provision: of the 40 million people globally in need of palliative care, less than 10% receive it, largely in high-income countries. There is a particular paucity of data on palliative care needs across the spectrum of incurable disease in Ethiopia. OBJECTIVES: The aims of this research were to assess the overall burden of life-limiting illness, the costs associated with life-limiting illness, and barriers to accessing palliative care in Ethiopia. DESIGN: Mixed-methods case-series. SETTING/SUBJECTS: One hundred adults (mean age: 43.7 +/- 14 years, 64% female) were recruited at three outpatient clinics (oncology, HIV, noncommunicable disease) and hospice patient homes in Ethiopia. MEASUREMENTS: Four internationally validated questionnaires were used to assess physical symptoms, psychosocial distress, and disability. In depth interviews gauged poverty level, costs of care, and end-of-life preferences. Qualitative data were analyzed by thematic content, quantitative data by standard descriptive, frequency and regression analyses. RESULTS: In oncology, 95.5% of the population endorsed moderate or severe pain, while 24% were not prescribed analgesia. Importantly, 80% of the noncommunicable disease population reported moderate or severe pain. The mean psychosocial distress score was 6.4/10. Severe disability was reported in 26% of the population, with mobility most affected. Statistically significant relationships were found between pain and costs, and pain and lack of well-being. Very high costs were reported by oncology patients. Oncology withstanding, the majority of subjects wished to die at home. Oncology patients cited pain control as the top reason they preferred a hospital death. CONCLUSION: There are extensive unmet palliative care needs in Ethiopia. Untreated pain and high costs of illness are the major contributors to psychosocial distress and financial crisis in this Ethiopian population. PMID- 29425054 TI - Cost-effectiveness analysis of routine 13-valent pneumococcal conjugate vaccinations in Chinese infants. AB - BACKGROUND: This study aimed to evaluate the cost-effectiveness of the 13-valent pneumococcal conjugate vaccine (PCV-13) compared to a no vaccination strategy in Chinese infants. METHODS: A Markov process model was developed to examine the outcomes of PCV-13 against a no vaccination strategy using data and assumptions adapted for relevance to China. Outcomes over a lifetime horizon are presented. One-way and probabilistic sensitivity analyses were performed to determine the uncertainty. RESULTS: Compared to no vaccination, a PCV-13 vaccination program would provide a gain of 0.009 additional quality-adjusted life years (QALYs) per subject. From the health care and societal perspectives, the incremental costs per QALY were $20,709 and 18,483, respectively. When herd effect was included, the cost effectiveness of the PCV-13 vaccination strategy was notably improved. The lower price of PCV-13 will improve the cost-effectiveness. CONCLUSIONS: The PCV-13 vaccination is likely to be cost-effective at the current Chinese prices and ceiling threshold ($8,382). PMID- 29425056 TI - Human brain trauma severity is associated with lectin complement pathway activation. AB - We explored the involvement of the lectin pathway of complement in post-traumatic brain injury (TBI) pathophysiology in humans. Brain samples were obtained from 28 patients who had undergone therapeutic contusion removal, within 12 h (early) or from >12 h until five days (late) from injury, and from five non-TBI patients. Imaging analysis indicated that lectin pathway initiator molecules (MBL, ficolin 1, ficolin-2 and ficolin-3), the key enzymes MASP-2 and MASP-3, and the downstream complement components (C3 fragments and TCC) were present inside and outside brain vessels in all contusions. Only ficolin-1 was found in the parenchyma of non-TBI tissues. Immunoassays in brain homogenates showed that MBL, ficolin-2 and ficolin-3 increased in TBI compared to non-TBI (2.0, 2.2 and 6.0 times) samples. MASP-2 increased with subarachnoid hemorrhage and abnormal pupil reactivity, two indicators of structural and functional damage. C3 fragments and TCC increased, respectively, by 3.5 - and 4.0-fold in TBI compared to non-TBI tissue and significantly correlated with MBL, ficolin-2, ficolin-3, MASP-2 and MASP-3 levels in the homogenates. In conclusion, we show for the first time the direct presence of lectin pathway components in human cerebral contusions and their association with injury severity, suggesting a central role for the lectin pathway in the post-traumatic pathophysiology of human TBI. PMID- 29425057 TI - Assessing health outcomes, quality of life, and healthcare use among school-age children with asthma. AB - OBJECTIVE: Asthma affects six million children in the United States. Most people can control their asthma symptoms with effective care, management, and appropriate medical treatment. Information on the relationship between asthma control and quality of life indicators and health care use among school-age children is limited. METHODS: Using the 2006-2010 combined Behavior Risk Factor Surveillance System Asthma Call-back Survey child data, we examined asthma control and asthma attack status among school-age (aged 5-17 years) children with asthma from 35 states and the District of Columbia. Multivariable logistic regression models were used to assess if having uncontrolled asthma and having >=1 asthma attacks affect quality of life (activity limitation and missed school days) and healthcare use (emergency department [ED] visits and hospitalizations). RESULTS: About one-third (36.5%) of the 8,484 respondents with current asthma had uncontrolled asthma and 56.8% reported >=1 asthma attack in the past year. Having uncontrolled asthma and having >=1 asthma attack were significantly associated with activity limitation (aPR = 1.43 and 1.74, respectively), missed school (1.45 and 1.68), ED visits (2.05 and 4.78), and hospitalizations (2.38 and 3.64). Long term control (LTC) medication use was higher among respondents with uncontrolled asthma (61.3%) than respondents with well-controlled asthma (33.5%). CONCLUSIONS: Having uncontrolled asthma is associated with reduced quality of life and increased health care use. However, only 61.3% of respondents with uncontrolled asthma use LTC medications. Increasing use of LTC medications among children with uncontrolled asthma could help improve quality of life and reduce health care use. PMID- 29425058 TI - A multiparametric analysis combining DCE-MRI- and IVIM -derived parameters to improve differentiation of parotid tumors: a pilot study. AB - AIM: To evaluate dynamic contrast-enhanced (DCE)-MRI and diffusion weighted (DW) MRI diagnostic value to differentiate Warthin tumors (WT) by pleomorphic adenomas (PA). MATERIALS & METHODS: Seven WT and seven PA were examined. DCE- and DW-MRI parameters were extracted from volumes of interest; volume of interest-based averages and standard deviations were calculated. Statistical analysis included: linear discriminant analysis, receiver operating characteristic curves, sensitivity and specificity. RESULTS: No single feature was able to differentiate WT by PA (p > 0.05); linear discriminant analysis analysis showed that a combination of all features or combinations of feature pairs (namely: Ktrans(std) & f(std), Ktrans(std) & D(std), kep(std) & D(std), MRE(av) & TTP(av)) might achieve sensitivity (SENS), specificity (SPEC) = 100%, with a slight reduction after cross-validation analysis (SENS = 0.875; SPEC = 1). CONCLUSION: Although preliminary and not conclusive, our results suggest that differentiation between WT and PA is possible through a multiparametric approach based on combination of DCE- and DW-MRI parameters. PMID- 29425059 TI - Prader-Willi syndrome and Angelman syndrome: Visualisation of the molecular pathways for two chromosomal disorders. AB - OBJECTIVES: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two syndromes that are caused by the same chromosomal deletion on 15q11.2-q13. Due to methylation patterns, different genes are responsible for the two distinct phenotypes resulting in the disorders. Patients of both disorders exhibit hypotonia in neonatal stage, delay in development and hypopigmentation. Typical features for PWS include hyperphagia, which leads to obesity, the major cause of mortality, and hypogonadism. In AS, patients suffer from a more severe developmental delay, they have a distinctive behaviour that is often described as unnaturally happy, and a tendency for epileptic seizures. For both syndromes, we identified and visualised molecular downstream pathways of the deleted genes that could give insight on the development of the clinical features. METHODS: This was done by consulting literature, genome browsers and pathway databases to identify molecular interactions and to construct downstream pathways. RESULTS: A pathway visualisation was created and uploaded to the open pathway database WikiPathways covering all molecular pathways that were found. CONCLUSIONS: The visualisation of the downstream pathways of PWS- and AS-deleted genes shows that some of the typical symptoms are caused by multiple genes and reveals critical gaps in the current knowledge. PMID- 29425060 TI - Measuring Development of Adolescent and Young Adult Cancer Patients: An Integrative Review of Available Instruments. AB - Adolescents and young adults (AYAs) 15-39 years old face unique challenges during cancer treatment as developmental and social needs are often disrupted to achieve cure. Developmentally appropriate supportive care for AYAs across the cancer trajectory is needed. The purpose of this review is to identify and describe instruments that measure AYA development across physical, psychological, and social domains, commenting on the instruments' psychometric properties and usefulness in clinical practice and research. A computerized literature search published in English from 1950 to January of 2017 was conducted utilizing the following databases: Mental Measurements Yearbook (MMY), Health and Psychosocial Instruments, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, and Google Scholar. The following instruments were identified and described: the Child Health and Illness Profile-Adolescent Edition (CHIP-AE); the Course of Life Questionnaire; the Developmental Task Questionnaire (DTQ); the Impact of Cancer scale for childhood survivors and AYAs (IOC-CS and IOC-AYA); the McCleery Scale of Adolescent Development (MSAD); and the Minneapolis-Manchester Quality of Life Adolescent and Young Adult Form (MMQL-AF and MMQL-YA). Among currently available instruments, the IOC-AYA and MMQL-AF were relevant to AYAs undergoing or completing cancer therapy. However, validation for the IOC-AYA occurred in cancer survivors off treatment so further psychometric evaluation is needed in AYAs currently undergoing cancer treatment. Furthermore, the MMQL-AF has been validated for use during active cancer treatment, but is limited to adolescents 13-20 years. Further research may be needed to create or refine instruments measuring the developmental impact in AYAs, particularly emerging adults undergoing active cancer treatment. PMID- 29425061 TI - Correction to: First Food Justice: Infant Feeding Disparities and the First Food System, by Morrell E. Breastfeed Med 2017;12(8):489-492. DOI: 10.1089/bfm.2017.0088. PMID- 29425062 TI - Microbiota regulate the development and function of the immune cells. AB - Microbiota is a group of microbes coexisting and co-evolving with the immune system in the host body for millions of years. There are mutual interaction between microbiota and the immune system. Immune cells can shape the populations of microbiota in the gut of animals and humans, and the presence of microbiota and the microbial products can regulate the development and function of the immune cells in the host. Although microbiota resides mainly at the mucosa, the effect of microbiota on the immune system can be both local at the mucosa and systemic through the whole body. At the mucosal sites, the presences of microbiota and microbial products have a direct effect on the immune cells. Microbiota induces production of effectors from immune cells, such as cytokines and inflammatory factors, influencing the further development and function of the immune cells. Experimental data have shown that microbial products can influence the activity of some key factors in signaling pathways. At the nonmucosal sites, such as the bone marrow, peripheral lymph nodes, and spleen, microbiota can also regulate the development and function of the immune cells via several mechanisms in mice, such as introduction of chromatin-level changes through histone acetylation and DNA methylation. Given the important effect of microbiota on the immune system, many immunotherapies that are mediated by immune system rely on gut microbiota. Thus, the study of how microbiota influences immune system bring a potential therapy prospect in preventing and treating diseases. PMID- 29425063 TI - Psychotropic Medication Patterns for American Indian Children in Foster Care. AB - OBJECTIVE: This study assesses the effects of race, age, sex, and time spent in foster care on rates of psychotropic medication use for children in foster care in 2012. METHODS: Using existing electronic records through county Social Service and Minnesota Medical Assistance databases, 626 children were identified using the inclusion criteria of having been in foster care for at least 30 days during 2012 in St. Louis County, Minnesota. All prescriptions for dispensed psychotropic medications were identified into the following classes: antidepressants, attention-deficit/hyperactivity disorder (ADHD) medications, antipsychotics, alpha-agonists, and other (including anticonvulsants/mood stabilizers, lithium, benzodiazepines, and sedative hypnotics). RESULTS: Overall, 26% of children were dispensed at least one psychotropic medication during the year with the percentage of children on medication for each race as follows: American Indian (AI) 23.3%, European American (EA) 29.2%, and African American (AA) 18.3%. AI children were significantly less likely to be dispensed any psychotropic medication and ADHD medication. EA children, males, and older children received psychotropic medications from significantly more classes than AI or AA children, females, and younger children. Males were significantly more likely to be dispensed alpha-agonists, antipsychotics, and ADHD medications. Increased time since placement into foster care was also significantly associated with increased dispensing rates of antidepressants, ADHD medication, and multiple medication classes. CONCLUSIONS: The results of this study show that non-EA children, in particular AI children, were dispensed psychotropics both overall and across different medication classes less often compared to other racial groups. While the reasons for this difference are not known, future studies are needed to address whether mental health needs of all children in foster care are being appropriately addressed, accounting for need and patient preference. PMID- 29425065 TI - Acknowledgment of Reviewers 2017. PMID- 29425066 TI - Whole Blood Gene Expression Profiling Predicts Severe Morbidity and Mortality in Cystic Fibrosis: A 5-Year Follow-Up Study. AB - RATIONALE: Cystic fibrosis pulmonary exacerbations accelerate pulmonary decline and increase mortality. Previously, we identified a 10-gene leukocyte panel measured directly from whole blood, which indicates response to exacerbation treatment. We hypothesized that molecular characteristics of exacerbations could also predict future disease severity. OBJECTIVES: We tested whether a 10-gene panel measured from whole blood could identify patient cohorts at increased risk for severe morbidity and mortality, beyond standard clinical measures. METHODS: Transcript abundance for the 10-gene panel was measured from whole blood at the beginning of exacerbation treatment (n = 57). A hierarchical cluster analysis of subjects based on their gene expression was performed, yielding four molecular clusters. An analysis of cluster membership and outcomes incorporating an independent cohort (n = 21) was completed to evaluate robustness of cluster partitioning of genes to predict severe morbidity and mortality. RESULTS: The four molecular clusters were analyzed for differences in forced expiratory volume in 1 second, C-reactive protein, return to baseline forced expiratory volume in 1 second after treatment, time to next exacerbation, and time to morbidity or mortality events (defined as lung transplant referral, lung transplant, intensive care unit admission for respiratory insufficiency, or death). Clustering based on gene expression discriminated between patient groups with significant differences in forced expiratory volume in 1 second, admission frequency, and overall morbidity and mortality. At 5 years, all subjects in cluster 1 (very low risk) were alive and well, whereas 90% of subjects in cluster 4 (high risk) had suffered a major event (P = 0.0001). In multivariable analysis, the ability of gene expression to predict clinical outcomes remained significant, despite adjustment for forced expiratory volume in 1 second, sex, and admission frequency. The robustness of gene clustering to categorize patients appropriately in terms of clinical characteristics, and short- and long-term clinical outcomes, remained consistent, even when adding in a secondary population with significantly different clinical outcomes. CONCLUSIONS: Whole blood gene expression profiling allows molecular classification of acute pulmonary exacerbations, beyond standard clinical measures, providing a predictive tool for identifying subjects at increased risk for mortality and disease progression. PMID- 29425067 TI - Protective and anti-inflammatory effects of hydroalcoholic leaf extract of Origanum vulgare on oxidative stress, TNF-alpha gene expression and liver histological changes in paraquat-induced hepatotoxicity in rats. AB - CONTEXT: Toxicity with paraquat can lead to serious damages to the liver. OBJECTIVE: The study investigates the protective effects of Origanum vulgare leaf extract against paraquat liver damage. MATERIAL AND METHODS: Rats were divided into six groups. Group 1, the control group; group 2, rats that received paraquat only; group 3, rats that received paraquat plus silymarin; and groups 4, 5, and 6 were treated with paraquat and O. vulgare leaf extract. Then, the serum and tissue parameters of the oxidative stress were examined. RESULTS: In group 2, paraquat caused a remarkable increase in the level of serum ALT, AST, ALP, lipid profiles, and liver TNF-alpha gene expression compared to group 1. The groups which received O. vulgare leaf extract exhibited significant ameliorations in abnormalities of paraquat-induced liver damage and serum biochemical parameters. CONCLUSION: O. vulgare leaf extract has inhibitory effects on paraquat-induced liver damage due to its antioxidant properties. PMID- 29425068 TI - STRC Gene Mutations, Mainly Large Deletions, are a Very Important Cause of Early Onset Hereditary Hearing Loss in the Czech Population. AB - INTRODUCTION: Hearing loss (HL) is the most common sensory deficit in humans. HL is an extremely heterogeneous condition presenting most frequently as a nonsyndromic (NS) condition inherited in an autosomal recessive (AR) pattern, termed DFNB. Mutations affecting the STRC gene cause DFNB type 16. Various types of mutations within the STRC gene have been reported from the U.S. and German populations, but no information about the relative contribution of STRC mutations to NSHL-AR among Czech patients is available. METHODS AND PATIENTS: Two hundred and eighty-eight patients with prelingual NSHL, either sporadic (n = 207) or AR (n = 81), who had been previously tested negative for the mutations affecting the GJB2 gene, were included in the study. These patients were tested for STRC mutations by a quantitative comparative fluorescent polymerase chain reaction (QF PCR) assay. In addition, 31 of the 81 NSHL-AR patients were analyzed by massively parallel sequencing using one of two different gene panels: 23 patients were analyzed by multiplex-ligation probe amplification (MLPA); and 9 patients by SNP microarrays. RESULTS: Causal mutations affecting the STRC gene (including copy number variations [CNVs] and point mutations) were found in 5.5% of all patients and 13.6% of the 81 patients in the subgroup with NSHL-AR. CONCLUSION: Our results provide strong evidence that STRC gene mutations are an important cause of NSHL-AR in Czech HL patients and are probably the second most common cause of DFNB. Large CNVs were more frequent than point mutations and it is reasonable to test them first by a QF-PCR method-a simple, accessible, and efficient tool for STRC CNV detection, which can be combined by MLPA. PMID- 29425070 TI - It's Time for Pediatric Oncology to Grow Up. PMID- 29425069 TI - Targeted Next-Generation Sequencing Reveals Novel RP1 Mutations in Autosomal Recessive Retinitis Pigmentosa. AB - BACKGROUND: Retinitis pigmentosa (RP) is a group of rare inherited retinal dystrophies that result in a progressive loss of vision. Molecular diagnosis of RP is difficult due to its phenotypic and genetic heterogeneities. AIMS: To investigate causative genetic mutations in a collection of RP cases: one Indian and two Chinese families with autosomal-recessive RP and two sporadic patients with RP. MATERIALS AND METHODS: A total of 163 genes, which have previously been found to be involved in inherited retinal disorders, were selected for targeted next-generation sequencing (NGS). Stringent NGS data analyses followed by confirmation using Sanger sequencing and segregation analyses were applied to evaluate all identified pathogenic mutations. RESULTS: Four novel frameshift mutations and two compound heterozygous mutations were identified in RP1. In addition, all mutations were found to co-segregate with the disease in the three familial cases; none of the mutations were detected in control samples. CONCLUSION: This study expands the mutational spectrums of RP1 for RP. PMID- 29425071 TI - The effects of probiotics in lactose intolerance: A systematic review. AB - Over 60 percent of the human population has a reduced ability to digest lactose due to low levels of lactase enzyme activity. Probiotics are live bacteria or yeast that supplements the gastrointestinal flora. Studies have shown that probiotics exhibit various health beneficial properties such as improvement of intestinal health, enhancement of the immune responses, and reduction of serum cholesterol. Accumulating evidence has shown that probiotic bacteria in fermented and unfermented milk products can be used to alleviate the clinical symptoms of lactose intolerance (LI). In this systematic review, the effectiveness of probiotics in the treatment of LI was evaluated using 15 randomized double-blind studies. Eight probiotic strains with the greatest number of proven benefits were studied. Results showed varying degrees of efficacy but an overall positive relationship between probiotics and lactose intolerance. PMID- 29425072 TI - The Job Market Outlook for Residency Graduates: Clear Weather Ahead for the Butterflies? PMID- 29425073 TI - Sensitive NPM1 Mutation Quantitation in Acute Myeloid Leukemia Using Ultradeep Next-Generation Sequencing in the Diagnostic Laboratory. AB - Context Detection of measurable residual disease after therapy is an important predictor of outcome in acute myeloid leukemia. Objective To investigate the feasibility of using next-generation sequencing (NGS) in the diagnostic laboratory to perform quantitative NPM1 mutation assessment using ultradeep (approximately 300 000*-500 000*) sequencing (NGS-q NPM1) as a method of assessing residual disease burden in patients with acute myeloid leukemia. Design A flexible NGS-based assay for the detection and quantitation of NPM1 mutations was developed by polymerase chain reaction amplification of target DNA sequences, sequencing on an Illumina (San Diego, California) MiSeq, and analyzing data with an in-house-designed bioinformatic pipeline. NGS-q NPM1 was compared with current NPM1 quantitation methods (real-time quantitative-polymerase chain reaction and multiparameter flow cytometry). Results The NGS-q NPM1 assay had a sensitivity of between 10-4 and 10-5 and showed high concordance and correlation with reference methodologies. Moreover, the NGS-q NPM1 assay was able to be integrated into the laboratory's existing, targeted amplicon-based sequencing workflow. Conclusions An NGS-based, quantitative NPM1-mutation assessment can be used to monitor patients with acute myeloid leukemia, and it has some practical advantages over existing modalities. PMID- 29425074 TI - IgA polymerization contributes to efficient virus neutralization on human upper respiratory mucosa after intranasal inactivated influenza vaccine administration. AB - Unlike the current injectable influenza vaccines, intranasally administered influenza vaccines induce influenza virus-specific IgA antibodies in the local respiratory mucosa as well as IgG antibodies in the systemic circulation. Our previous study showed that after five volunteers underwent intranasal administration with inactivated H3N2 or H5N1 vaccines, their IgA antibodies on the upper respiratory tract were present as monomers, dimers, and multimers (trimers and tetramers). Moreover, the multimers associated with the highest virus neutralizing activity. However, it has remained elusive whether a more practical intranasal vaccination strategy could induce the high-performance IgA multimers in the nasal mucosa. In the present study, volunteers were administered with two doses of the intranasal trivalent whole-virus inactivated influenza vaccine and showed that in nasal wash samples the amount of multimeric IgA correlated positively with virus neutralizing titers, indicating that the multimeric IgA antibodies play an important role in the antiviral activity at the nasal mucosa. Surface plasmon resonance analysis of the binding dynamics of nasal wash derived IgA monomers, dimers, and multimers against recombinant trimeric influenza virus HA showed that sample fractions containing IgA multimers dissociated from HA less well than sample fractions without IgA multimers. Thus, IgA multimers may "stick" to the antigen more tightly than the other structures. In summary, intranasal administration of two doses of multivalent inactivated influenza vaccines induced multimeric IgA. Multimerization of mucosal IgA antibodies conferred higher neutralizing activity against viruses in the nasal mucosa, possibly by increasing their cohesion to virus antigens. PMID- 29425075 TI - Outcomes of the Montana Asthma Home Visiting Program: A home-based asthma education program. AB - OBJECTIVE: Asthma is a common disease in children. Home-based, multi-trigger, multi-component interventions with an environmental focus have been shown to be effective to address asthma in children. The objective of this study was to assess the outcomes and feasibility of implementing a specific asthma home visiting (HV) program in a rural area. METHODS: Children aged 0-17 years with uncontrolled asthma were enrolled in an asthma HV program that included six contacts over a 12-month period delivered by a registered nurse specifically trained in asthma education and trigger removal in eleven counties in the rural state of Montana. Between June 2010 and December 2016, data on asthma symptoms and asthma self-management skills were collected at baseline and throughout the program. In June 2017, they were analyzed to assess changes in asthma control and quality of life over time among participants completing all six contacts. RESULTS: Since June 2010, 152 of 338 enrolled children completed all six contacts outlined in the program (45%). Participants who completed the program reported significant improvements in asthma control test scores, self-management skills, and self-efficacy related to asthma management. These results improved the longer participants remained in the program. CONCLUSIONS: These findings suggest that it is feasible to implement a 12-month HV program using local public health resources in a rural area as outcomes improved over this time period. PMID- 29425076 TI - Identifying and mitigating Sudden Unexpected Death in Epilepsy (SUDEP) risk factors. AB - INTRODUCTION: Sudden Unexpected Death in Epilepsy (SUDEP) is a significant cause of death for people with chronic epilepsy. Good practice guidance in the UK and the USA expect SUDEP to be discussed with the individual. The event rarity, methodological variance and lack of robust research into the pathological mechanisms, associated risk factors, and management strategies have created a challenge on how and what to discuss. There are some significant associations which allows for risk assessment and mitigation. Areas covered: The current understanding of static and modifiable risk factors for SUDEP and how to manage these more effectively are reviewed. Longitudinal risk may be assessed using standardised risk assessment tools which help in communicating risk. Technological advancement allows measurement of physiological parameters associated with seizures and risk of SUDEP using small wearable devices. Further evidence is needed to demonstrate such technologies are efficacious and safe. Expert commentary: Risk reduction should be an important part of epilepsy management and we suggest a Gold Standard of Care which healthcare professionals and services should aim for when approaching SUDEP risk management. A Minimum Standard of Care is also proposed that is practical to implement, that all people with epilepsy should expect to receive. PMID- 29425077 TI - The NISTmAb tryptic peptide spectral library for monoclonal antibody characterization. AB - We describe the creation of a mass spectral library composed of all identifiable spectra derived from the tryptic digest of the NISTmAb IgG1kappa. The library is a unique reference spectral collection developed from over six million peptide spectrum matches acquired by liquid chromatography-mass spectrometry (LC-MS) over a wide range of collision energy. Conventional one-dimensional (1D) LC-MS was used for various digestion conditions and 20- and 24-fraction two-dimensional (2D) LC-MS studies permitted in-depth analyses of single digests. Computer methods were developed for automated analysis of LC-MS isotopic clusters to determine the attributes for all ions detected in the 1D and 2D studies. The library contains a selection of over 12,600 high-quality tandem spectra of more than 3,300 peptide ions identified and validated by accurate mass, differential elution pattern, and expected peptide classes in peptide map experiments. These include a variety of biologically modified peptide spectra involving glycosylated, oxidized, deamidated, glycated, and N/C-terminal modified peptides, as well as artifacts. A complete glycation profile was obtained for the NISTmAb with spectra for 58% and 100% of all possible glycation sites in the heavy and light chains, respectively. The site-specific quantification of methionine oxidation in the protein is described. The utility of this reference library is demonstrated by the analysis of a commercial monoclonal antibody (adalimumab, Humira(r)), where 691 peptide ion spectra are identifiable in the constant regions, accounting for 60% coverage for both heavy and light chains. The NIST reference library platform may be used as a tool for facile identification of the primary sequence and post-translational modifications, as well as the recognition of LC-MS method-induced artifacts for human and recombinant IgG antibodies. Its development also provides a general method for creating comprehensive peptide libraries of individual proteins. PMID- 29425078 TI - Pre-Operative Skin Antisepsis with Chlorhexidine Gluconate and Povidone-Iodine to Prevent Port-Site Infection in Laparoscopic Cholecystectomy: A Prospective Study. AB - BACKGROUND: Skin preparation with antiseptic agents is commonly recommended for incisional site cleansing before surgery. We present the result of a prospective case series submitted to a scheduled pre-operative antiseptic procedure combining chlorhexidine gluconate and povidone-iodine before elective laparoscopic cholecystectomy. PATIENTS AND METHODS: Consecutive patients underwent pre operative standardized cleansing of the operation site combining chlorhexidine gluconate and povidone-iodine. Patients were reviewed one week and four weeks post-operatively. RESULTS: Post-operative infection was observed in seven patients (4.3%). All observed infections were port-site infections, always located at the level of the umbilical incision. In all cases infections involved skin and subcutaneous tissue. Staphylococcus aureus was isolated in five patients (71.4%) and miscellaneous aerobic gram-positive bacteria in two subjects (28.6%). Post-operative hospital stay was the only factor significantly associated with the development of port-site infections. CONCLUSIONS: Port-site infections are a common complication after elective laparoscopic cholecystectomy. The proposed pre operative disinfection procedure is effective in reducing port-site infections. Reducing hospital stay may contribute to limiting the occurrence of this complication. PMID- 29425079 TI - Cost-effectiveness analysis of different seasonal influenza vaccines in the elderly Italian population. AB - ABSRACT In the perspective of reaching at least 75% influenza vaccination coverage in the elderly and substantial budget constraints, Italian decision makers are facing important challenges in determining an optimal immunization strategy for this growing and particularly vulnerable population. Four different influenza vaccines are currently available for Italian older adults aged 65 years or above, namely trivalent inactivated vaccines (TIVs), MF59-adjuvanted TIV (MF59 TIV), intradermal TIV (ID-TIV) and quadrivalent inactivated vaccines (QIVs). The present study is the first to compare the cost-effectiveness profiles of virtually all possible public health strategies, including the aforementioned four vaccine formulations as well non-vaccination. For this purpose, a decision tree model was built ex novo; the analysis was conducted from the third-payer perspective in the timeframe of one year. All available vaccines were cost effective compared with non-vaccination. However, MF59-TIV had the most favorable economic profile in the Italian elderly population. Indeed, compared with non vaccination, it was deemed highly cost-effective with an incremental cost effectiveness ratio (ICER) of ?10,750 per quality-adjusted life year (QALY). The ICER was much lower (?4,527/QALY) when MF59-TIV was directly compared with TIV. ID-TIV and QIV were dominated by MF59-TIV as the former comparators were associated with greater total costs and lower health benefits. Both deterministic and probabilistic sensitivity analyses confirmed robustness of the base case results. From the economic perspective, MF59-TIV should be considered as a preferential choice for Italian older adults aged 65 years or above. PMID- 29425081 TI - Impacts of Federally Funded State Obesity Programs on Adult Obesity Prevalence in the United States, 1998-2010. AB - OBJECTIVES: From 2000 to 2010, the Division of Nutrition, Physical Activity, and Obesity (DNPAO) at the Centers for Disease Control and Prevention (CDC) funded 37 state health departments to address the obesity epidemic in their states through various interventions. The objective of this study was to investigate the overall impacts of CDC-DNPAO statewide intervention programs on adult obesity prevalence in the United States. METHODS: We used a set of an individual-level, interrupted time-series regression and a quasi-experimental analysis to evaluate the overall effect of CDC-DNPAO intervention programs before (1998-1999) and after (2010) their implementation by using data from CDC's Behavioral Risk Factor Surveillance System. RESULTS: States that implemented the CDC-DNPAO program had a 2.4% to 3.8% reduction in the odds of obesity during 2000-2010 compared with states without the program. The effect of the CDC-DNPAO program varied by length of program implementation. A quasi-experimental analysis found that states with longer program implementation did not necessarily have lower odds of obesity than states with shorter program implementation. CONCLUSIONS: Statewide obesity interventions can contribute to reduced odds of obesity in the United States. Future research should evaluate the CDC-DNPAO programs in relation to their goals, objectives, and other environmental obesity risk factors to inform future interventions. PMID- 29425080 TI - Receptor-Mediated Uptake of Phosphorothioate Antisense Oligonucleotides in Different Cell Types of the Liver. AB - Oligonucleotide therapeutics have emerged as a third distinct platform for drug discovery within the pharmaceutical industry. Five oligonucleotide-based drugs have been approved by the US FDA and over 100 oligonucleotides drugs are currently at different stages of human trials. Several of these oligonucleotide drugs are modified using the phosphorothioate (PS) backbone modification where one of the nonbridging oxygen atoms of the phosphodiester linkage is replaced with sulfur. In this review, we summarize our knowledge on receptor-mediated uptake of PS antisense oligonucleotides (ASOs) within different cell types of the liver-a privileged organ for the discovery of oligonucleotide-based therapeutics. PMID- 29425082 TI - Can a shared decision be wrong if made for the 'right' reasons? PMID- 29425083 TI - Having the COURAGE to include PCI in shared decision-making for stable angina. PMID- 29425084 TI - Finding balance: Optimizing medication prescribing in older patients. PMID- 29425085 TI - Medication management in older adults. AB - Managing medications is a major part of providing care to older adults. Polypharmacy is common in the elderly and is fraught with risks. A careful and systematic approach is needed for managing drug therapy in these patients, recognizing the patient's specific goals. PMID- 29425086 TI - Transient neurologic syndromes: A diagnostic approach. AB - Clinicians are often confronted with patients who have transient neurologic symptoms lasting seconds to hours. In many of these patients, their symptoms have gone away or returned to baseline by the time of evaluation, making the diagnosis even more challenging. Elements such as correlation of symptoms with vascular territory, prodromes, triggers, motor symptoms, confusion, and sleep behavior can guide the diagnostic workup. PMID- 29425087 TI - A 75-year-old with abdominal pain, hypoxia, and weak pulses in the left leg. PMID- 29425088 TI - PCI for stable angina: A missed opportunity for shared decision-making. AB - Percutaneous coronary intervention (PCI) continues to be frequently performed for patients with stable coronary artery disease, despite clear evidence that it provides minimal benefit over optimal medical therapy and entails small but not inconsequential risks. Many patients and doctors do not fully understand the risks and benefits of PCI, even when presented with the evidence, and this makes informed consent challenging. The best approach is shared decision-making, with doctor and patient together choosing the best treatment option after considering the evidence and the patient's preferences. PMID- 29425089 TI - Kidney transplant: New opportunities and challenges. AB - Progress in kidney transplant has improved survival while creating challenges. The pool of eligible patients is increasing, but organ supply remains inadequate. Waiting-list issues, adequate pretransplant assessment, judicious use of potent immunotherapy, and management of infections must be considered. PMID- 29425090 TI - Erythema ab igne. PMID- 29425091 TI - Gas under the right diaphragm. PMID- 29425092 TI - Paraneoplastic acral vascular syndrome. PMID- 29425094 TI - Cadmium Body Burden and Gestational Diabetes Mellitus: A Prospective Study. AB - BACKGROUND: Several studies have reported that cadmium (Cd) is associated with type 2 diabetes. However, little is known about Cd exposure and the risk of gestational diabetes mellitus (GDM). OBJECTIVE: We examined the association between Cd body burden in early pregnancy and the risk of GDM. METHODS: We conducted a prospective study of 2,026 pregnant women from a single tertiary medical center between 2013 and 2016 in Wuhan, China. Cd body burden was reflected by Cd concentrations in urine samples collected between gestational weeks 8 and 14. GDM was diagnosed according to International Association of Diabetes and Pregnancy Study Groups Consensus Panel (IADPSG) recommendations. RESULTS: The geometric mean of Cd concentrations in maternal urine of all pregnant women was 0.59MUg/L. A total of 198 (9.8%) women were diagnosed with GDM. After adjustment for potential confounders, the risk ratios (RRs) of GDM were 1.04 (95% CI: 0.74, 1.44) for the middle tertile of Cd levels and 1.36 (95%: CI: 0.98, 1.90) for the top tertile compared with the bottom tertile. In addition, we found a significant interaction between fetal sex and maternal Cd levels on the risk of GDM (p for interaction=0.03). Among women carrying male fetuses, the RR of GDM was 1.86 (95% CI: 1.14, 2.93) for the top tertile of Cd levels compared with the bottom tertile. CONCLUSIONS: To our knowledge, this is the first report of an association between urinary Cd levels in early pregnancy and GDM. Our findings suggest that Cd body burden increases the risk of GDM and that the association may be modified by fetal sex. https://doi.org/10.1289/EHP2716. PMID- 29425095 TI - Cleanup in the Gulf: Oil Spill Dispersants and Health Symptoms in Deepwater Horizon Responders. PMID- 29425097 TI - Molecular mechanism for inhibition of twinfilin by phosphoinositides. AB - Membrane phosphoinositides control organization and dynamics of the actin cytoskeleton by regulating the activities of several key actin-binding proteins. Twinfilin is an evolutionarily conserved protein that contributes to cytoskeletal dynamics by interacting with actin monomers, filaments, and the heterodimeric capping protein. Twinfilin also binds phosphoinositides, which inhibit its interactions with actin, but the underlying mechanism has remained unknown. Here, we show that the high-affinity binding site of twinfilin for phosphoinositides is located at the C-terminal tail region, whereas the two actin-depolymerizing factor (ADF)/cofilin-like ADF homology domains of twinfilin bind phosphoinositides only with low affinity. Mutagenesis and biochemical experiments combined with atomistic molecular dynamics simulations reveal that the C-terminal tail of twinfilin interacts with membranes through a multivalent electrostatic interaction with a preference toward phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), PI(4,5)P2, and PI(3,4,5)P3 This initial interaction places the actin binding ADF homology domains of twinfilin in close proximity to the membrane and subsequently promotes their association with the membrane, thus leading to inhibition of the actin interactions. In support of this model, a twinfilin mutant lacking the C-terminal tail inhibits actin filament assembly in a phosphoinositide-insensitive manner. Our mutagenesis data also reveal that the phosphoinositide- and capping protein-binding sites overlap in the C-terminal tail of twinfilin, suggesting that phosphoinositide binding additionally inhibits the interactions of twinfilin with the heterodimeric capping protein. The results demonstrate that the conserved C-terminal tail of twinfilin is a multifunctional binding motif, which is crucial for interaction with the heterodimeric capping protein and for tethering twinfilin to phosphoinositide-rich membranes. PMID- 29425096 TI - Function and maturation of the Fe-S center in dihydroxyacid dehydratase from Arabidopsis. AB - Dihydroxyacid dehydratase (DHAD) is the third enzyme required for branched-chain amino acid biosynthesis in bacteria, fungi, and plants. DHAD enzymes contain two distinct types of active-site Fe-S clusters. The best characterized examples are Escherichia coli DHAD, which contains an oxygen-labile [Fe4S4] cluster, and spinach DHAD, which contains an oxygen-resistant [Fe2S2] cluster. Although the Fe S cluster is crucial for DHAD function, little is known about the cluster coordination environment or the mechanism of catalysis and cluster biogenesis. Here, using the combination of UV-visible absorption and circular dichroism and resonance Raman and electron paramagnetic resonance, we spectroscopically characterized the Fe-S center in DHAD from Arabidopsis thaliana (At). Our results indicated that AtDHAD can accommodate [Fe2S2] and [Fe4S4] clusters. However, only the [Fe2S2] cluster-bound form is catalytically active. We found that the [Fe2S2] cluster is coordinated by at least one non-cysteinyl ligand, which can be replaced by the thiol group(s) of dithiothreitol. In vitro cluster transfer and reconstitution reactions revealed that [Fe2S2] cluster-containing NFU2 protein is likely the physiological cluster donor for in vivo maturation of AtDHAD. In summary, AtDHAD binds either one [Fe4S4] or one [Fe2S2] cluster, with only the latter being catalytically competent and capable of substrate and product binding, and NFU2 appears to be the physiological [Fe2S2] cluster donor for DHAD maturation. This work represents the first in vitro characterization of recombinant AtDHAD, providing new insights into the properties, biogenesis, and catalytic role of the active-site Fe-S center in a plant DHAD. PMID- 29425098 TI - Introduction to Metals in Biology 2018: Copper homeostasis and utilization in redox enzymes. AB - This 11th Thematic Metals in Biology Thematic Series deals with copper, a transition metal with a prominent role in biochemistry. Copper is a very versatile element, and both deficiencies and excesses can be problematic. The five Minireviews in this series deal with several aspects of copper homeostasis in microorganisms and mammals and the role of this metal in two enzymes, copper only superoxide dismutase and cytochrome c oxidase. PMID- 29425099 TI - Conserved cysteines in the finger domain of the epithelial Na+ channel alpha and gamma subunits are proximal to the dynamic finger-thumb domain interface. AB - The epithelial Na+ channel (ENaC) is a member of the ENaC/degenerin family of ion channels. In the structure of a related family member, the "thumb" domain's base interacts with the pore, and its tip interacts with the divergent "finger" domain. Between the base and tip, the thumb domain is characterized by a conserved five-rung disulfide ladder holding together two anti-parallel alpha helices. The ENaC alpha and gamma subunits' finger domains harbor autoinhibitory tracts that can be proteolytically liberated to activate the channel and also host an ENaC-specific pair of cysteines. Using a crosslinking approach, we show that one of the finger domain cysteines in the alpha subunit (alphaCys-263) and both of the finger domain cysteines in the gamma subunit (gammaCys-213 and gammaCys-220) lie near the dynamic finger-thumb domain interface. Our data suggest that the alphaCys-256/alphaCys-263 pair is not disulfide-bonded. In contrast, we found that the gammaCys-213/gammaCys-220 pair is disulfide-bonded. Our data also suggest that the gamma subunit lacks the terminal rung in the thumb domain disulfide ladder, suggesting asymmetry between the subunits. We also observed functional asymmetry between the alpha and gamma subunit finger-thumb domain interfaces; crosslinks bridging the alpha subunit finger-thumb interface only inhibited ENaC currents, whereas crosslinks bridging the gamma subunit finger-thumb interface activated or inhibited currents dependent on the length of the crosslinker. Our data suggest that reactive cysteines lie at the dynamic finger-thumb interfaces of the alpha and gamma subunits and may play a yet undefined role in channel regulation. PMID- 29425100 TI - The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling. AB - As a master regulator of endothelial cell function, vascular endothelial growth factor receptor-2 (VEGFR2) activates multiple downstream signaling pathways that are critical for vascular development and normal vessel function. VEGFR2 trafficking through various endosomal compartments modulates its signaling output. Accordingly, proteins that regulate the speed and direction by which VEGFR2 traffics through endosomes have been demonstrated to be particularly important for arteriogenesis. However, little is known about how these proteins control VEGFR2 trafficking and about the implications of this control for endothelial cell function. Here, we show that Rab GTPase-binding effector protein 2 (RABEP2), a Rab-effector protein implicated in arteriogenesis, modulates VEGFR2 trafficking. By employing high-resolution microscopy and biochemical assays, we demonstrate that RABEP2 interacts with the small GTPase Rab4 and regulates VEGFR2 endosomal trafficking to maintain cell-surface expression of VEGFR2 and VEGF signaling. Lack of RABEP2 also led to prolonged retention of VEGFR2 in Rab5 positive sorting endosomes, which increased VEGFR2's exposure to phosphotyrosine phosphatase 1b (PTP1b), causing diminished VEGFR2 signaling. Finally, the loss of RABEP2 increased VEGFR2 degradation by diverting VEGFR2 to Rab7-positive endosomes destined for the lysosome. These results implicate RABEP2 as a key modulator of VEGFR2 endosomal trafficking, and demonstrate the importance of RABEP2 and Rab4 for VEGFR2 signaling in endothelial cells. PMID- 29425102 TI - Designs and performance of three new microprocessor-controlled knee joints. AB - A crossover design study with a small group of subjects was used to evaluate the performance of three microprocessor-controlled exoprosthetic knee joints (MPKs): C-Leg 4, Plie 3 and Rheo Knee 3. Given that the mechanical designs and control algorithms of the joints determine the user outcome, the influence of these inherent differences on the functional characteristics was investigated in this study. The knee joints were evaluated during level-ground walking at different velocities in a motion analysis laboratory. Additionally, technical analyses using patents, technical documentations and X-ray computed tomography (CT) for each knee joint were performed. The technical analyses showed that only C-Leg 4 and Rheo Knee 3 allow microprocessor-controlled adaptation of the joint resistances for different gait velocities. Furthermore, Plie 3 is not able to provide stance extension damping. The biomechanical results showed that only if a knee joint adapts flexion and extension resistances by the microprocessor all known advantages of MPKs can become apparent. But not all users may benefit from the examined functions: e.g. a good accommodation to fast walking speeds or comfortable stance phase flexion. Hence, a detailed comparison of user demands and performance of the designated knee joint is mandatory to ensure a maximum in user outcome. PMID- 29425101 TI - Exceptional potency and structural basis of a T1249-derived lipopeptide fusion inhibitor against HIV-1, HIV-2, and simian immunodeficiency virus. AB - Enfuvirtide (T20) is the only viral fusion inhibitor approved for clinical use, but it has relatively weak anti-HIV activity and easily induces drug resistance. In succession to T20, T1249 has been designed as a 39-mer peptide composed of amino acid sequences derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV); however, its development has been suspended due to formulation difficulties. We recently developed a T20-based lipopeptide (LP-40) showing greatly improved pharmaceutical properties. Here, we generated a T1249-based lipopeptide, termed LP-46, by replacing its C-terminal tryptophan-rich sequence with fatty acid. As compared with T20, T1249, and LP-40, the truncated LP-46 (31 mer) had dramatically increased activities in inhibiting a large panel of HIV-1 subtypes, with IC50 values approaching low picomolar concentrations. Also, LP-46 was an exceptionally potent inhibitor against HIV-2, SIV, and T20-resistant variants, and it displayed obvious synergistic effects with LP-40. Furthermore, we showed that LP-46 had increased helical stability and binding affinity with the target site. The crystal structure of LP-46 in complex with a target surrogate revealed its critical binding motifs underlying the mechanism of action. Interestingly, it was found that the introduced pocket-binding domain in LP-46 did not interact with the gp41 pocket as expected; instead, it adopted a mode similar to that of LP-40. Therefore, our studies have provided an exceptionally potent and broad fusion inhibitor for developing new anti-HIV drugs, which can also serve as a tool to exploit the mechanisms of viral fusion and inhibition. PMID- 29425103 TI - Approaches for calibration and validation of near-infrared optical methods for oxygenation monitoring. AB - Pulse oximetry for arterial oxygenation monitoring and tissue oximetry for monitoring of cerebral oxygenation or muscle oxygenation are based on quantitative in vivo diffuse optical spectroscopy. However, in both cases the information on absolute or relative concentration of human tissue constituents and especially on hemoglobin oxygenation can often not be retrieved by model based analysis. An in vivo calibration against an accepted reference measurement can be a practical alternative. Pulse oximeters and most of commercial cerebral tissue oximeters rely on empirical calibration based on invasive controlled human desaturation studies. As invasive in vivo tests on healthy subjects are ethically disputable and should be limited to exceptional cases this calibration practice is unsatisfactory. We present the current status and problems of calibration and validation in pulse oximetry and cerebral tissue oximetry including the pros and cons of in vivo as well as in vitro methods. We emphasize various digital and physical phantom approaches and discuss the prospects of their application and possible further developments. PMID- 29425104 TI - Optimized angiotensin-converting enzyme activity assay for the accurate diagnosis of sarcoidosis. AB - BACKGROUND: Serum angiotensin-converting enzyme (ACE) activity determination can aid the early diagnosis of sarcoidosis. We aimed to optimize a fluorescent kinetic assay for ACE activity by screening the confounding effects of endogenous ACE inhibitors and interfering factors. Genotype-dependent and genotype independent reference values of ACE activity were established, and their diagnostic accuracies were validated in a clinical study. METHODS: Internally quenched fluorescent substrate, Abz-FRK(Dnp)P-OH was used for ACE-activity measurements. A total of 201 healthy individuals and 59 presumably sarcoidotic patients were enrolled into this study. ACE activity and insertion/deletion (I/D) genotype of the ACE gene were determined. RESULTS: Here we report that serum samples should be diluted at least 35-fold to eliminate the endogenous inhibitor effect of albumin. No significant interferences were detected: up to a triglyceride concentration of 16 mM, a hemoglobin concentration of 0.71 g/L and a bilirubin concentration of 150 MUM. Genotype-dependent reference intervals were considered as 3.76-11.25 U/L, 5.22-11.59 U/L, 7.19-14.84 U/L for II, ID and DD genotypes, respectively. I/D genotype-independent reference interval was established as 4.85-13.79 U/L. An ACE activity value was considered positive for sarcoidosis when it exceeded the upper limit of the reference interval. The optimized assay with genotype-dependent reference ranges resulted in 42.5% sensitivity, 100% specificity, 100% positive predictive value and 32.4% negative predictive value in the clinical study, whereas the genotype-independent reference range proved to have inferior diagnostic efficiency. CONCLUSIONS: An optimized fluorescent kinetic assay of serum ACE activity combined with ACE I/D genotype determination is an alternative to invasive biopsy for confirming the diagnosis of sarcoidosis in a significant percentage of patients. PMID- 29425105 TI - IL8 and IL16 levels indicate serum and plasma quality. AB - BACKGROUND: Longer pre-centrifugation times alter the quality of serum and plasma samples. Markers for such delays in sample processing and hence for the sample quality, have been identified. METHODS: Twenty cytokines in serum, EDTA plasma and citrate plasma samples were screened for changes in concentration induced by extended blood pre-centrifugation delays at room temperature. The two cytokines that showed the largest changes were further validated for their "diagnostic performance" in identifying serum or plasma samples with extended pre centrifugation times. RESULTS: In this study, using R&D Systems ELISA kits, EDTA plasma samples and serum samples with a pre-centrifugation delay longer than 24 h had an IL16 concentration higher than 313 pg/mL, and an IL8 concentration higher than 125 pg/mL, respectively. EDTA plasma samples with a pre-centrifugation delay longer than 48 h had an IL16 concentration higher than 897 pg/mL, citrate plasma samples had an IL8 concentration higher than 21.5 pg/mL and serum samples had an IL8 concentration higher than 528 pg/mL. CONCLUSIONS: These robust and accurate tools, based on simple and commercially available ELISA assays can greatly facilitate qualification of serum and plasma legacy collections with undocumented pre-analytics. PMID- 29425106 TI - Timeo apis mellifera and dona ferens: bee sting-induced Kounis syndrome. PMID- 29425107 TI - Screening for gestational diabetes in low-risk women: effect of maternal age. AB - Background Gestational diabetes mellitus (GDM) is on the rise globally and there are various screening guidelines with regard to patients' criteria. Materials and methods We conducted a prospective cross-sectional study to determine the prevalence of GDM amongst low-risk pregnant women above the age of 25 years. A modified glucose tolerance test (MGTT) was performed between 24 and 36 weeks of gestation. Women with GDM were divided into two groups for analysis: age between 25 and 34 years (group A) and above 35 years (group B). They were managed as per hospital protocol and followed-up until delivery. The women's demographic data, treatment and subsequent pregnancy outcomes were analysed. Results The overall prevalence of GDM in our low-risk women was 14%. GDM was less common in the younger age group (25-34 years) in comparison to those aged above 35 years (9.7% vs. 26.3%, p = 0.001). There was a non-significant increase in the induction of labour (IOL) rate amongst those aged below 35 years compared to the older group (46.7 % vs. 38.5%). The insulin requirement in the age group 25-34 years and above 35 years, were 6.7% and 23.1%, respectively. There was no significant difference between both age groups with regard to caesarean delivery, birth weight above the 95th centile and neonatal hypoglycaemia. Conclusion In low-risk women, the prevalence of GDM is significantly lower in those aged less than 35 years. Diagnosing GDM had resulted in the increment of IOL in this group, although with no significant increase in maternal and neonatal morbidity. PMID- 29425108 TI - Neck adipose tissue - tying ties in metabolic disorders. AB - Upper body adipose tissue accumulation has been associated with clustering of metabolic disorders and increased cardiovascular risk. Neck circumference (NC) indicated that subcutaneous adipose tissue (SAT) in that region is an independent pathogenic depot that might account for the additional risk missed by visceral adipose tissue (VAT). Neck adipose tissue (NAT) is not only one more ectopic depot but has several particular features that might modulate its metabolic role. Besides a controversial impact on obstructive apnea syndrome, neck fat encompasses carotid arteries as an important perivascular adipose tissue (PVAT) depot. With dysfunctional changes in obesity, physiologic vascular regulation is lost and inflammatory signals accelerate atherogenesis. Unexpected was the discovery of brown and beige adipocytes in the neck of human adults. When stimulated, brown adipose tissue (BAT) dissipates energy through thermogenesis and it is associated with other favorable metabolic effects. Moreover, the neck is the region where the browning mechanism was disclosed. With this unique plastic nature, NAT revealed multiple ties, challenging dynamics and potential new therapeutic targets that might have significant implications on metabolic outcomes and vascular risk. PMID- 29425109 TI - Student Experiences of High-stakes Testing for Progression in One Undergraduate Nursing Program. AB - Each year, thousands of students throughout the world are required to complete one or more high-stakes tests as a measure of competency in undergraduate nursing education. Currently, the trend in nursing education is to use high-stakes tests to establish program progression policies. However, use of these tests to block student progression is of serious concern. This article describes findings of a pilot study that used a phenomenographic approach to understand senior nursing students' experiences of completing multiple high-stakes tests for successful progression within one undergraduate nursing program. Eighteen graduating senior nursing students participated in the study via individual interviews. Students described a multitude of experiences, organized into five main categories of descriptions: high-stakes tests as a value; high-stakes tests as a stressor; high stakes tests as a high expectation; high-stakes tests as various inconsistencies; and high-stakes tests affecting the transfer of learning. Student perspectives with high-stakes testing contributed valuable insight lacking in the current nursing education literature. Findings suggested if high-stakes tests are to be used for program progression, it is imperative for nurse educators to convene and explore strategies to support student preparation and success with testing, and develop well-defined structures of teaching and learning for the delivery of course content. PMID- 29425110 TI - A Japanese patient with congenital central hypothyroidism caused by a novel IGSF1 mutation. AB - BACKGROUND: IGSF1 abnormality causes diverse symptoms, including congenital central hypothyroidism (CCH), prolactin hyposecretion, testicular enlargement and delayed puberty. CASE PRESENTATION: Here, we report a case of a male patient who visited our hospital with a chief complaint of abdominal pain and short stature, in whom we identified a novel IGSF1 mutation. He was closely examined because of chronic constipation since infancy, persistent abdominal pain at 14 years of age and marked short stature (-4.7 standard deviation [SD] for normal Japanese boys). He was diagnosed with CCH. Decreased prolactin (PRL) secretion was also observed. IGSF1 analysis revealed a novel mutation at the splicing donor site (c.2065+1G>A) in intron 11. In silico analysis predicted this mutation to be a non-functional splice donor site. After thyroid hormone replacement, his thyroid function, constipation and growth rate improved. CONCLUSIONS: This is the first report of a patient in whom constipation and short stature led to a diagnosis of CCH with a novel IGSF1 mutation. PMID- 29425111 TI - The safety of Lipistart, a medium-chain triglyceride based formula, in the dietary treatment of long-chain fatty acid disorders: a phase I study. AB - BACKGROUND: Children with long-chain fatty acid beta-oxidation disorders (LCFAOD) presenting with clinical symptoms are treated with a specialist infant formula, with medium chain triglyceride (MCT) mainly replacing long chain triglyceride (LCT). It is essential that the safety and efficacy of any new specialist formula designed for LCFAOD be tested in infants and children. METHODS: In an open-label, 21-day, phase I trial, we studied the safety of a new MCT-based formula (feed 1) in six well-controlled children (three male), aged 7-13 years (median 9 years) with LCFAOD (very long chain acyl CoA dehydrogenase deficiency [VLCADD], n=2; long chain 3-hydroxyacyl CoA dehydrogenase deficiency [LCHADD], n=2; carnitine acyl carnitine translocase deficiency [CACTD], n=2). Feed 1 (Lipistart; Vitaflo) contained 30% energy from MCT, 7.5% LCT and 3% linoleic acid and it was compared with a conventional MCT feed (Monogen; Nutricia) (feed 2) containing 17% energy from MCT, 3% LCT and 1.1% linoleic acid. Subjects consumed feed 2 for 7 days then feed 1 for 7 days and finally resumed feed 2 for 7 days. Vital signs, blood biochemistry, ECG, weight, height, food/feed intake and symptoms were monitored. RESULTS: Five subjects completed the study. Their median daily volume of both feeds was 720 mL (range 500-1900 mL/day). Feed 1 was associated with minimal changes in tolerance, free fatty acids (FFA), acylcarnitines, 3-hydroxybutyrate (3-HB), creatine kinase (CK), blood glucose, liver enzymes and no change in an electrocardiogram (ECG). No child complained of muscle pain or symptoms associated with LCFAOD on either feed. CONCLUSIONS: This is the first safety trial reported of an MCT formula specifically designed for infants and children with LCFAOD. In this short-term study, it appeared safe and well tolerated in this challenging group. PMID- 29425112 TI - Investigation into the effects of surface stripping ZnO nanosheets. AB - ZnO nanosheets are polycrystalline nanostructures that are used in devices including solar cells and gas sensors. However, for efficient and reproducible device operation and contact behaviour the conductivity characteristics must be controlled and surface contaminants removed. Here we use low doses of argon bombardment to remove surface contamination and make reproducible lower resistance contacts. Higher doses strip the surface of the nanosheets altering the contact type from near-ohmic to rectifying by removing the donor-type defects, which photoluminescence shows to be concentrated in the near-surface. Controlled doses of argon treatments allow nanosheets to be customised for device formation. PMID- 29425113 TI - Honoring the Past, Pursuing the Future. PMID- 29425114 TI - Dichloroisocoumarins with Potential Anti-Inflammatory Activity from the Mangrove Endophytic Fungus Ascomycota sp. CYSK-4. AB - Three new isocoumarins-dichlorodiaportintone (1), desmethyldichlorodiaportintone (2) and desmethyldichlorodiaportinol (3)-as well as six known analogues (4-9) were isolated from the culture of the mangrove endophytic fungus Ascomycota sp. CYSK-4 from Pluchea indica. Their structures were elucidated by analysis of spectroscopic data. The absolute configuration of compounds 1 and 2 were determined by the modified Mosher's method. Compound 2 showed significant anti inflammatory activity by inhibiting the production of NO in LPS-induced RAW 264.7 cells with IC50 value of 15.8 MUM, while compounds 1, 5, and 6 exhibited weak activities with IC50 values of 41.5, 33.6, and 67.2 MUM, respectively. In addition, compounds 1, 5, and 6 showed antibacterial effects against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter calcoaceticus with the MIC values in the range of 25-50 MUg.mL-1. PMID- 29425116 TI - Integrated Systems Approach Reveals Sphingolipid Metabolism Pathway Dysregulation in Association with Late-Onset Alzheimer's Disease. AB - Late-onset Alzheimer's disease (LOAD) and age are significantly correlated such that one-third of Americans beyond 85 years of age are afflicted. We have designed and implemented a pilot study that combines systems biology approaches with traditional next-generation sequencing (NGS) analysis techniques to identify relevant regulatory pathways, infer functional relationships and confirm the dysregulation of these biological pathways in LOAD. Our study design is a most comprehensive systems approach combining co-expression network modeling derived from RNA-seq data, rigorous quality control (QC) standards, functional ontology, and expression quantitative trait loci (eQTL) derived from whole exome (WES) single nucleotide variant (SNV) genotype data. Our initial results reveal several statistically significant, biologically relevant genes involved in sphingolipid metabolism. To validate these findings, we performed a gene set enrichment analysis (GSEA). The GSEA revealed the sphingolipid metabolism pathway and regulation of autophagy in association with LOAD cases. In the execution of this study, we have successfully tested an integrative approach to identify both novel and known LOAD drivers in order to develop a broader and more detailed picture of the highly complex transcriptional and regulatory landscape of age-related dementia. PMID- 29425117 TI - A Qualitative Exploration of the Role of Vape Shop Environments in Supporting Smoking Abstinence. AB - E-cigarettes are the most popular method of quitting smoking in England and most are purchased in specialist vape shops. This qualitative study explores how the vape shop environment is experienced by quitters to support smoking abstinence. Semi-structured qualitative interviews were conducted to elicit experiences of e cigarette use, including experiences of vape shops, in 40 people who had used e cigarettes in a quit attempt. Observations of six shops in a range of locations were also undertaken. Interview and observation data were analysed using inductive thematic analysis and triangulated. At an individual level, smoking abstinence was supported through shop assistants' attempts to understand customers' smoking preferences in order to: (i) tailor advice about the most appropriate product; and (ii) offer an ongoing point of contact for practical help. At an interpersonal level, shops offered opportunity to socialise and reinforce a vaping identity, although the environment was perceived as intimidating for some (e.g., new and female users). At a structural level, shops ensured easy access to products perceived to be good value by customers and had adapted to legislative changes. Vape shops can provide effective behavioural support to quitters to maintain smoking abstinence. Health professionals could capitalise on this through partnership working with shops, to ensure best outcomes for clients wanting to use e-cigarettes to quit smoking. PMID- 29425115 TI - Nonstructural Proteins of Alphavirus-Potential Targets for Drug Development. AB - Alphaviruses are enveloped, positive single-stranded RNA viruses, typically transmitted by arthropods. They often cause arthralgia or encephalitic diseases in infected humans and there is currently no targeted antiviral treatment available. The re-emergence of alphaviruses in Asia, Europe, and the Americas over the last decade, including chikungunya and o'nyong'nyong viruses, have intensified the search for selective inhibitors. In this review, we highlight key molecular determinants within the alphavirus replication complex that have been identified as viral targets, focusing on their structure and functionality in viral dissemination. We also summarize recent structural data of these viral targets and discuss how these could serve as templates to facilitate structure based drug design and development of small molecule inhibitors. PMID- 29425118 TI - Coordination-Enhanced Luminescence on Tetra-Phenylethylene-Based Supramolecular Assemblies. AB - Materials with aggregation-induced emission (AIE) properties have received increased attention recently due to their potential applications in light emitting devices, chemo/biosensors and biomedical diagnostics. In general, AIE requires the forced aggregation of the AIEgens induced by the poor solvent or close arrangement of AIEgens covalently attached to polymer chains. Here, we report two coordination-enhanced fluorescent supramolecular complexes featuring hierarchically restricted intramolecular motions via the self-assembly of tetraphenylethylene (TPE)-based tetra-dentate (La) and bidentate (Lb) ligands and the cis-Pd(en)(NO3)2 (en = ethylenediamine) unit. While the free ligands are non emissive in dilute solution and show typical AIE properties in both mixed solvent system and the solid state, the self-assembled complexes maintain their fluorescent nature in the solution state. In particular, the Pd4(La)2 complex shows remarkable 6-fold fluorescent enhancement over La in dilute solution. We anticipate that these kinds of coordination-enhanced emissive supramolecules will find applications in biomedical sensing or labeling. PMID- 29425119 TI - Silver Eco-Solvent Ink for Reactive Printing of Polychromatic SERS and SPR Substrates. AB - A new reactive ink based on a silver citrate complex is proposed for a photochemical route to surface-enhanced Raman spectroscopy active substrates with controllable extinction spectra. The drop-cast test of the ink reveals homogeneous nucleation of silver and colloid particle growth originating directly from photochemical in situ reduction in droplets, while the following evaporation of the deposited ink produces small nano- and micron-size particles. The prepared nanostructures and substrates were accurately characterized by electron microscopy methods and optical extinction spectroscopy. Varying the duration of UV irradiation allows tuning the morphology of individual silver nanoparticles forming hierarchical ring structures with numerous "hot spots" for most efficient Raman enhancement. Raman measurements of probe molecules of rhodamine 6G and methylene blue reached the largest signal enhancement of 106 by the resonance effects. PMID- 29425120 TI - A Plant-Based Dietary Intervention Improves Beta-Cell Function and Insulin Resistance in Overweight Adults: A 16-Week Randomized Clinical Trial. AB - The aim of this study was to test the effect of a plant-based dietary intervention on beta-cell function in overweight adults with no history of diabetes. Participants (n = 75) were randomized to follow a low-fat plant-based diet (n = 38) or to make no diet changes (n = 37) for 16 weeks. At baseline and 16 weeks, beta-cell function was quantified with a mathematical model. Using a standard meal test, insulin secretory rate was calculated by C-peptide deconvolution. The Homeostasis Model Assessment (HOMA-IR) index was used to assess insulin resistance while fasting. A marked increase in meal-stimulated insulin secretion was observed in the intervention group compared with controls (interaction between group and time, Gxt, p < 0.001). HOMA-IR index fell significantly (p < 0.001) in the intervention group (treatment effect -1.0 (95% CI, -1.2 to -0.8); Gxt, p = 0.004). Changes in HOMA-IR correlated positively with changes in body mass index (BMI) and visceral fat volume (r = 0.34; p = 0.009 and r = 0.42; p = 0.001, respectively). The latter remained significant after adjustment for changes in BMI (r = 0.41; p = 0.002). Changes in glucose-induced insulin secretion correlated negatively with BMI changes (r = -0.25; p = 0.04), but not with changes in visceral fat. Beta-cell function and insulin sensitivity were significantly improved through a low-fat plant-based diet in overweight adults. PMID- 29425122 TI - High Catalytic Efficiency of Nanostructured beta-CoMoO4 in the Reduction of the Ortho-, Meta- and Para-Nitrophenol Isomers. AB - Nanostructured beta-CoMoO4 catalysts have been prepared via the thermal decomposition of an oxalate precursor. The catalyst was characterized by infrared spectroscopy (FTIR), X-ray diffraction (XRD), Brunauer-Emmett-Teller method (BET), energy dispersive X-ray spectroscopy (EDX), and transmission electron microscopy (TEM). The efficiency of these nanoparticles in the reduction of ortho and meta-nitrophenol isomers (2-NP, 3-NP, and 4-NP) to their corresponding aminophenols was tested using UV-visible spectroscopy measurements. It was found that, with a beta-CoMoO4 catalyst, NaBH4 reduces 3-NP instantaneously, whilst the reduction of 2-NP and 4-NP is slower at 8 min. This difference is thought to arise from the lower acidity of 3-NP, where the negative charge of the phenolate could not be delocalized onto the oxygen atoms of the meta-nitro group. PMID- 29425121 TI - miR-214-Dependent Increase of PHLPP2 Levels Mediates the Impairment of Insulin Stimulated Akt Activation in Mouse Aortic Endothelial Cells Exposed to Methylglyoxal. AB - Evidence has been provided linking microRNAs (miRNAs) and diabetic complications, by the regulation of molecular pathways, including insulin-signaling, involved in the pathophysiology of vascular dysfunction. Methylglyoxal (MGO) accumulates in diabetes and is associated with cardiovascular complications. This study aims to analyze the contribution of miRNAs in the MGO-induced damaging effect on insulin responsiveness in mouse aortic endothelial cells (MAECs). miRNA modulation was performed by transfection of specific miRNA mimics and inhibitors in MAECs, treated or not with MGO. miRNA-target protein levels were evaluated by Western blot. PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulation by miR-214 was tested by luciferase assays and by the use of a target protector specific for miR-214 on PHLPP2-3'UTR. This study reveals a 4-fold increase of PHLPP2 in MGO-treated MAECs. PHLPP2 levels inversely correlate with miR-214 modulation. Moreover, miR-214 overexpression is able to reduce PHLPP2 levels in MGO-treated MAECs. Interestingly, a direct regulation of PHLPP2 is proved to be dependent by miR-214. Finally, the inhibition of miR-214 impairs the insulin dependent Akt activation, while its overexpression rescues the insulin effect on Akt activation in MGO-treated MAECs. In conclusion, this study shows that PHLPP2 is a target of miR-214 in MAECs, and identifies miR-214 downregulation as a contributing factor to MGO-induced endothelial insulin-resistance. PMID- 29425123 TI - Aspergillus fumigatus Detection and Risk Factors in Patients with COPD Bronchiectasis Overlap. AB - The role of Aspergillus fumigatus in the airways of chronic obstructive pulmonary disease (COPD) patients with bronchiectasis is currently unclear. We searched for a sensitive and noninvasive method for A. fumigatus detection in the sputum of COPD patients and addressed potential risk factors for its presence. Induced sputum samples of 18 COPD patients and 17 COPD patients with bronchiectasis were analyzed for the presence of A. fumigatus by culture, galactomannan detection, and PCR. Of the patients with COPD-bronchiectasis overlap, 23.5% had a positive culture for A. fumigatus versus 10.5% of COPD patients without bronchiectasis (p = 0.39). The median sputum galactomannan optical density index was significantly higher in patients with COPD and bronchiectasis compared with patients with COPD alone (p = 0.026) and ranged between the levels of healthy controls and A. fumigatus-colonized cystic fibrosis patients. Both the presence of bronchiectasis and the administration of systemic corticosteroids were associated with sputum galactomannan (p = 0.0028 and p = 0.0044, respectively) and showed significant interaction (p interaction = 0.022). PCR for Aspergillus was found to be a less sensitive method, but was critically dependent on the extraction technique. The higher sputum galactomannan levels suggest a more abundant presence of A. fumigatus in the airways of patients with COPD-bronchiectasis overlap compared with patients with COPD without bronchiectasis, particularly when systemic corticosteroids are administered. PMID- 29425125 TI - On the Cutting Performance of Segmented Diamond Blades when Dry-Cutting Concrete. AB - The objective of the present study is to analyze and compare the cutting performance of segmented diamond blades when dry-cutting concrete. A cutting criteria is proposed to characterize the wear of the blades by measuring the variation of the external diameter and the weight loss of the blade. The results exhibit the cutting blade SB-A, which has twice the density of diamonds and large contact area, exhibits less wear even though the material removal rate is higher compared with the other two cutting blades. Additionally, the surface topography of the different blades is evaluated to examine the impact of wear depending on the surface profile and the distribution of the diamonds in the blade's matrix. Large number of diamonds pull-out are found in blades type SB-C, which additionally shows the worst wear resistant capability. As a conclusion, the cutting efficiency of the blade is found to be related to the density of embedded diamonds and the type of the surface profile of the cutting blade after reaching the stop criteria. PMID- 29425124 TI - Evaluation of an Internally Controlled Multiplex Tth Endonuclease Cleavage Loop Mediated Isothermal Amplification (TEC-LAMP) Assay for the Detection of Bacterial Meningitis Pathogens. AB - Bacterial meningitis infection is a leading global health concern for which rapid and accurate diagnosis is essential to reduce associated morbidity and mortality. Loop-mediated isothermal amplification (LAMP) offers an effective low-cost diagnostic approach; however, multiplex LAMP is difficult to achieve, limiting its application. We have developed novel real-time multiplex LAMP technology, TEC LAMP, using Tth endonuclease IV and a unique LAMP primer/probe. This study evaluates the analytical specificity, limit of detection (LOD) and clinical application of an internally controlled multiplex TEC-LAMP assay for detection of leading bacterial meningitis pathogens: Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae. Analytical specificities were established by testing 168 bacterial strains, and LODs were determined using Probit analysis. The TEC-LAMP assay was 100% specific, with LODs for S. pneumoniae, N. meningitidis and H. influenzae of 39.5, 17.3 and 25.9 genome copies per reaction, respectively. Clinical performance was evaluated by testing 65 archived PCR-positive samples. Compared to singleplex real-time PCR, the multiplex TEC-LAMP assay demonstrated diagnostic sensitivity and specificity of 92.3% and 100%, respectively. This is the first report of a single-tube internally controlled multiplex LAMP assay for bacterial meningitis pathogen detection, and the first report of Tth endonuclease IV incorporation into nucleic acid amplification diagnostic technology. PMID- 29425126 TI - Moderating Effect of Residential History on the Effects of a Fatherhood Program on Parenting Skills Satisfaction among Nonresident African American Fathers. AB - Nonresident African American (AA) fathers sometimes face challenges to achieving satisfaction with their parenting skills, which may inhibit their motivations for parenting. Studies have found that residential history of fathers is associated with parental involvement; however, current fatherhood programs rarely consider the influence of different residential history on fathering. In the current study, we examined whether nonresident AA fathers' residential history with their sons moderated their parenting skills satisfaction after participating in the Fathers and Sons Program. Our results indicated that after controlling for fathers' pretest parenting skills satisfaction, age, education, marital status, employment, and ever lived with their son's mother; there was a moderating effect of residential history on the intervention's effects on posttest parenting skills satisfaction. The regression analyses showed that fathers in the intervention group who had lived with their son increased their parenting skills satisfaction more at posttest compared with fathers who had never lived with their sons. However, fathers in the comparison group who had lived with their sons had lower posttest parenting skills satisfaction. Future fatherhood programs for nonresident AA fathers should develop more nuanced group-specific interventions that consider residential history as a critical factor to enhance their parenting skills satisfaction as a strategy for improving father involvement. PMID- 29425127 TI - German Consumers' Attitude towards Selenium-Biofortified Apples and Acceptance of Related Nutrition and Health Claims. AB - The present study investigates consumers' acceptance of Se-biofortified apples, as well as Se health and nutrition claims that have been approved by the European Commission. Despite indications that such statements are more likely to be accepted if the carrier product itself has a healthy image, unprocessed fruits biofortified with Se have not been investigated in this context yet. Apples as the most frequently-consumed type of fresh fruit in Germany may offer the potential to improve the Se status of consumers when the produce is enriched with Se. Therefore, an online survey of 356 German adults was conducted to analyze different aspects that could affect the perception of and preference for the proposed product concept by consumers. The findings indicate a moderate acceptance of Se-biofortified apples, as well as of Se health and nutrition claims among the participants. Additional information about beneficial health effects of Se had a significant impact on consumer acceptance. People who regularly eat convenience food and prefer to buy apples at supermarkets were particularly attracted by the product idea. In conclusion, the results of the study indicate good prospects for a successful introduction of Se-rich apples in the German food market, if the produce is advertised with approved health and nutrition claims. PMID- 29425128 TI - The Complete Chloroplast Genome of Catha edulis: A Comparative Analysis of Genome Features with Related Species. AB - Qat (Catha edulis, Celastraceae) is a woody evergreen species with great economic and cultural importance. It is cultivated for its stimulant alkaloids cathine and cathinone in East Africa and southwest Arabia. However, genome information, especially DNA sequence resources, for C. edulis are limited, hindering studies regarding interspecific and intraspecific relationships. Herein, the complete chloroplast (cp) genome of Catha edulis is reported. This genome is 157,960 bp in length with 37% GC content and is structurally arranged into two 26,577 bp inverted repeats and two single-copy areas. The size of the small single-copy and the large single-copy regions were 18,491 bp and 86,315 bp, respectively. The C. edulis cp genome consists of 129 coding genes including 37 transfer RNA (tRNA) genes, 8 ribosomal RNA (rRNA) genes, and 84 protein coding genes. For those genes, 112 are single copy genes and 17 genes are duplicated in two inverted regions with seven tRNAs, four rRNAs, and six protein coding genes. The phylogenetic relationships resolved from the cp genome of qat and 32 other species confirms the monophyly of Celastraceae. The cp genomes of C. edulis, Euonymus japonicus and seven Celastraceae species lack the rps16 intron, which indicates an intron loss took place among an ancestor of this family. The cp genome of C. edulis provides a highly valuable genetic resource for further phylogenomic research, barcoding and cp transformation in Celastraceae. PMID- 29425129 TI - Suicidal Ideation among Youth Living in the Slums of Kampala, Uganda. AB - The purpose of this study is to examine the factors associated with suicidal ideation among youth living in the slums of Kampala, Uganda. Analyses are based on cross-sectional survey data, collected in 2014, of a convenience sample (n = 1134) of urban service-seeking youth participating in a Uganda Youth Development Link drop-in center. Logistic regression analyses were computed to determine the psychosocial factors associated with suicidal ideation. Among youth participants, 23.54% (n = 266) reported suicidal ideation in the past year. In the multivariable analysis, suicidal ideation was associated with being female (OR: 1.61; 95% CI: 1.15, 2.25), reporting one (OR: 1.51; 95% CI: 1.05, 2.18) or two deceased parents (OR: 1.55; 95% CI: 1.03, 2.35), ever living on the streets (OR: 2.65; 95% CI: 1.86, 3.79), problem drinking (OR: 1.83; 95% CI: 1.19, 2.80), sexually transmitted infection (OR: 1.59; 95% CI: 1.14, 2.21), ever being raped (OR: 1.49; 95% CI: 1.01, 2.20), and experiencing physical child abuse (OR: 2.40; 95% CI: 1.75, 3.27). Our findings underscore many unmet needs in this vulnerable population. However, strategies that specifically seek to address problem drinking-a modifiable risk factor for suicidal ideation-may be particularly warranted in this low-resource setting. PMID- 29425130 TI - The Influence of the Heat-Affected Zone Mechanical Properties on the Behaviour of the Welding in Transverse Plate-to-Tube Joints. AB - Eurocode 3 establishes the component method to analytically characterize the structural joints between beam and columns. When one of the members involved in the joint is a hollow section (i.e., a tube) there is a lack of information for the specific components present in the joint. There are two different ways to bridge the gap: experimental testing on the actual beam column joints involving tubular sections; or numerical modelization, typically by means of finite element analysis. For this second option, it is necessary to know the actual mechanical properties of the material. As long as the joint implies a welding process, there is a concern related to how the mechanical properties in the heat-affected zone (HAZ) influence the behavior of the joint. In this work, some coupons were extracted from the HAZ of the beam-column joint. The coupons were tested and the results were implemented in the numerical model of the joint, in an attempt to bring it closer to the experimental results of the tested joints. PMID- 29425131 TI - Phenotypic and Genotypic Analysis of Antimicrobial Resistance among Listeria monocytogenes Isolated from Australian Food Production Chains. AB - The current global crisis of antimicrobial resistance (AMR) among important human bacterial pathogens has been amplified by an increased resistance prevalence. In recent years, a number of studies have reported higher resistance levels among Listeria monocytogenes isolates, which may have implications for treatment of listeriosis infection where resistance to key treatment antimicrobials is noted. This study examined the genotypic and phenotypic AMR patterns of 100 L. monocytogenes isolates originating from food production supplies in Australia and examined this in the context of global population trends. Low levels of resistance were noted to ciprofloxacin (2%) and erythromycin (1%); however, no resistance was observed to penicillin G or tetracycline. Resistance to ciprofloxacin was associated with a mutation in the fepR gene in one isolate; however, no genetic basis for resistance in the other isolate was identified. Resistance to erythromycin was correlated with the presence of the ermB resistance gene. Both resistant isolates belonged to clonal complex 1 (CC1), and analysis of these in the context of global CC1 isolates suggested that they were more similar to isolates from India rather than the other CC1 isolates included in this study. This study provides baseline AMR data for L. monocytogenes isolated in Australia, identifies key genetic markers underlying this resistance, and highlights the need for global molecular surveillance of resistance patterns to maintain control over the potential dissemination of AMR isolates. PMID- 29425132 TI - Preliminary Investigation of Species Diversity of Rice Hopper Parasitoids in Southeast Asia. AB - Ongoing intensification of rice production systems in Southeast Asia is causing devastating yield losses each year due to rice hoppers. Their continuing development of immunity to resistant rice varieties and pesticide applications further complicates this problem. Hence, there is a high demand for biological control agents of rice hoppers. Egg parasitoid wasps are among the most important natural enemies of rice hoppers, such as Nilaparvata lugens and Nephotettix spp. However, our knowledge of their diversity is still very limited, due to their small size and the lack of available morphological information. Classifying these parasitoids is the first step to properly understanding their role in the rice agroecosystem. We used traditional morphological identification, as well as DNA sequencing of the 28S rRNA and the COI genes, to investigate the diversity of four important hopper egg parasitoid genera in the Philippines. Parasitoids of the genera Anagrus, Oligosita, Gonatocerus, and Paracentrobia were collected in eight study landscapes located in Luzon. Our findings illustrate that characterization of species diversity using morphological and molecular analyses were concordant only for the genus Paracentrobia. The genera Anagrus and Gonatocerus exhibited more genetic diversity than estimated with the morphological analysis, while the opposite was observed for Oligosita. This is the first study investigating the molecular diversity of rice hopper parasitoids in the Philippines. More research combining morphological, behavioral, and molecular methods, as well as the establishment of a comprehensive DNA database, are urgently needed to assess the performance and suitability of these organisms as biocontrol agents. PMID- 29425133 TI - Correction: Wen-I Liao, et al. Ac2-26, an Annexin A1 Peptide, Attenuates Ischemia Reperfusion-Induced Acute Lung Injury. Int. J. Mol. Sci. 2017, 18, 1771. AB - The authors would like to make a correction to their published paper [1][...]. PMID- 29425134 TI - OSCANN: Technical Characterization of a Novel Gaze Tracking Analyzer. AB - Eye-movement analysis has grown exponentially in recent decades. The reason is that abnormalities in oculomotor movements are usually symptoms of injuries in the nervous system. This paper presents a novel regulated solution named OSCANN. OSCANN aims at providing an innovative tool for the control, management and visualization of oculomotor neurological examinations. This solution utilizes an eye-tracker sensor based on video electro-oculography (VOG) technology to capture eye movements and store them in video files. Such a sensor can store images at a rate of 100 frames per second. A characterization study was performed using twenty-two volunteers (13 male, 9 female, ages 22-45 years, mean 29.3 years, SD = 6.7) to assess the accuracy and precision specifications of OSCANN during oculomotor movement analysis. The accuracy was evaluated based on the offset, whereas precision was estimated with Root Means Square (RMS). Such a study reported values lower than 0.4 ? and 0.03 ? of accuracy and precision, respectively. These results suggest that OSCANN can be considered as a powerful tool to measure oculomotor movement alterations involved in some neurological disease progression. PMID- 29425135 TI - Impact of Electrode Surface Morphology in ZnO-Based Resistive Random Access Memory Fabricated Using the Cu Chemical Displacement Technique. AB - Electrochemical-metallization-type resistive random access memories (ReRAMs) show promising performance as next-generation nonvolatile memory. In this paper, the Cu chemical displacement technique (CDT) is used to form the bottom electrode of ReRAM devices. Compared with conventional deposition methods, the Cu-CDT method has numerous advantages for ReRAM fabrication, including low cost, low temperature fabrication, and the provision of unconsolidated Cu film and large surface roughness. Moreover, the Cu-CDT method is a favorable candidate for overcoming the Cu etching problem and is thus suitable for fabricating ReRAM devices. Using this technique, the surface morphology of a thin Cu film can be easily controlled. The obtained results show that the electric fields during the Forming and SET operations decreased, and the on-state current increased in the RESET operation, as the Cu-CDT displacement time was increased. The Cu-CDT samples exhibited a low operation field, large memory window (>106), and excellent endurance switching cycle characteristics. Moreover, this paper proposes a model to explain the electrical characteristics of ReRAM, which are dependent on the surface morphology. PMID- 29425137 TI - Structure-Activity Relationship of Xanthones as Inhibitors of Xanthine Oxidase. AB - Polygala plants contain a large number of xanthones with good physiological activities. In our previous work, 18 xanthones were isolated from Polygala crotalarioides. Extented study of the chemical composition of the other species Polygala sibirica led to the separation of two new xanthones-3-hydroxy-1,2,6,7,8 pentamethoxy xanthone (A) and 6-O-beta-d-glucopyranosyl-1,7-dimethoxy xanthone (C)-together with 14 known xanthones. Among them, some xanthones have a certain xanthine oxidase (XO) inhibitory activity. Furthemore, 14 xanthones as XO inhibitors were selected to develop three-dimensional quantitative structure activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. The CoMFA model predicted a q2 value of 0.613 and an r2 value of 0.997. The best CoMSIA model predicted a q2 value of 0.608 and an r2 value of 0.997 based on a combination of steric, electrostatic, and hydrophobic effects. The analysis of the contour maps from each model provided insight into the structural requirements for the development of more active XO inhibitors. PMID- 29425136 TI - Urinary Arsenic in Human Samples from Areas Characterized by Natural or Anthropogenic Pollution in Italy. AB - Arsenic is ubiquitous and has a potentially adverse impact on human health. We compared the distribution of concentrations of urinary inorganic arsenic plus methylated forms (uc(iAs+MMA+DMA)) in four Italian areas with other international studies, and we assessed the relationship between uc(iAs+MMA+DMA) and various exposure factors. We conducted a human biomonitoring study on 271 subjects (132 men) aged 20-44, randomly sampled and stratified by area, gender, and age. Data on environmental and occupational exposure and dietary habits were collected through a questionnaire. Arsenic was speciated using chromatographic separation and inductively coupled mass spectrometry. Associations between uc(iAs+MMA+DMA) and exposure factors were evaluated using the geometric mean ratio (GMR) with a 90% confidence interval by stepwise multiple regression analysis. The 95th percentile value of uc(iAs+MMA+DMA) for the whole sample (86.28 ug/L) was higher than other national studies worldwide. A statistical significant correlation was found between uc(iAs+MMA+DMA) and occupational exposure (GMR: 2.68 [1.79-4.00]), GSTT gene (GMR: 0.68 [0.52-0.80]), consumption of tap water (GMR: 1.35 [1.02 1.77]), seafood (GMR: 1.44 [1.11-1.88]), whole milk (GMR: 1.34 [1.04-1.73]), and fruit/vegetables (GMR: 1.37 [1.03-1.82]). This study demonstrated the utility of uc(iAs+MMA+DMA) as a biomarker to assess environmental exposure. In a public health context, this information could be used to support remedial action, to prevent individuals from being further exposed to environmental arsenic sources. PMID- 29425138 TI - Facile Preparation of Nano-Bi2MoO6/Diatomite Composite for Enhancing Photocatalytic Performance under Visible Light Irradiation. AB - In this work, a new nano-Bi2MoO6/diatomite composite photocatalyst was successfully synthesized by a facile solvothermal method. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and UV-vis diffuse reflection spectroscopy (DRS) were employed to investigate the morphology, crystal structure, and optical properties. It was shown that nanometer-scaled Bi2MoO6 crystals were well-deposited on the surface of Bi2MoO6/diatomite. The photocatalytic activity of the obtained samples was evaluated by the degradation of rhodamine B (RhB) under the visible light (lambda > 420 nm) irradiation. Moreover, trapping experiments were performed to investigate the possible photocatalytic reaction mechanism. The results showed that the nano-Bi2MoO6/diatomite composite with the mass ratio of Bi2MoO6 to diatomaceous earth of 70% exhibited the highest activity, and the RhB degradation efficiency reached 97.6% within 60 min. The main active species were revealed to be h+ and*O2-. As a photocatalytic reactor, its recycling performance showed a good stability and reusability. This new composite photocatalyst material holds great promise in the engineering field for the environmental remediation. PMID- 29425139 TI - Spectral Analysis and Sensitive Waveband Determination Based on Nitrogen Detection of Different Soil Types Using Near Infrared Sensors. AB - Compared with the chemical analytical technique, the soil nitrogen acquisition method based on near infrared (NIR) sensors shows significant advantages, being rapid, nondestructive, and convenient. Providing an accurate grasp of different soil types, sensitive wavebands could enhance the nitrogen estimation efficiency to a large extent. In this paper, loess, calcium soil, black soil, and red soil were used as experimental samples. The prediction models between soil nitrogen and NIR spectral reflectance were established based on three chemometric methods, that is, partial least squares (PLS), backward interval partial least squares (BIPLS), and back propagation neural network (BPNN). In addition, the sensitive wavebands of four kinds of soils were selected by competitive adaptive reweighted sampling (CARS) and BIPLS. The predictive ability was assessed by the coefficient of determination R2 and the root mean square error (RMSE). As a result, loess ( 0.93 < R p 2 < 0.95 , 0.066 g / kg < RMSE p < 0.075 g / kg ) and calcium soil ( 0.95 < R p 2 < 0.96 , 0.080 g / kg < RMSE p < 0.102 g / kg ) achieved a high prediction accuracy regardless of which algorithm was used, while black soil ( 0.79 < R p 2 < 0.86 , 0.232 g / kg < RMSE p < 0.325 g / kg ) obtained a relatively lower prediction accuracy caused by the interference of high humus content and strong absorption. The prediction accuracy of red soil ( 0.86 < R p 2 < 0.87 , 0.231 g / kg < RMSE p < 0.236 g / kg ) was similar to black soil, partly due to the high content of iron-aluminum oxide. Compared with PLS and BPNN, BIPLS performed well in removing noise and enhancing the prediction effect. In addition, the determined sensitive wavebands were 1152 nm-1162 nm and 1296 nm 1309 nm (loess), 1036 nm-1055 nm and 1129 nm-1156 nm (calcium soil), 1055 nm, 1281 nm, 1414 nm-1428 nm and 1472 nm-1493 nm (black soil), 1250 nm, 1480 nm and 1680 nm (red soil). It is of great value to investigate the differences among the NIR spectral characteristics of different soil types and determine sensitive wavebands for the more efficient and portable NIR sensors in practical application. PMID- 29425140 TI - An Experimental Exploration of the Effects of Exposure to Images of Nature on Rumination. AB - Exposure to natural environments has been shown to have beneficial effects on mood. Rumination is a thinking style associated with negative mood, and sometimes depression, and is characterized by repetitive, intrusive thoughts, often with a negative emotional element. This study investigated whether exposure to nature, operationalized using photographs presented as a slideshow, could aid reduction in levels of state rumination. An experimental, within-between (Time x Condition) participant design was used; participants (n = 58) undertook a presentation task designed to induce rumination and influence mood. Participants were then randomly allocated to either: watch a slideshow of a natural environment, watch a slideshow of an urban environment, or wait patiently with no distractions. Data were collected at baseline, after the presentation, and after the slideshow. Environmental exposure had no effect on levels of rumination or negative mood, but did have a significant effect on levels of positive mood, 'being away', and 'fascination'. Positive mood declined in those who saw the urban slideshow, but remained the same in those who saw the nature slideshow, whilst levels of being away and fascination were highest in those who saw the nature slideshow. This study extends previous restorative environment research by exploring the effects of nature on rumination. PMID- 29425141 TI - Proposal for a Monitoring Concept for Veterinary Medicinal Products with PBT Properties, Using Parasiticides as a Case Study. AB - The aim of this work is to prepare a proposal for the post-authorization monitoring (PAM) of veterinary medicinal products (VMP), in particular parasiticides. Such a monitoring might especially be useful for parasiticides identified as Persistence Bioaccumulation Toxicity (PBT) substances, i.e., chemicals that are toxic (T), persist in the environment (P) and bioaccumulate (B) in food chains and, thus, pose a hazard to ecosystems. Based on a literature search, issues to be considered when performing such a PAM are discussed (e.g., residue analysis, compartments to be included, selection of organisms and the duration of monitoring studies). The outcome of this discussion is that-and despite that there are huge challenges in detail (e.g., in terms of analytical chemistry or taxonomy)-the technical performance of such a PAM is not the main problem, since most of the chemical and biological methods to be used are well known (partly even standardized) or could be adapted. However, it is very difficult to define in detail where and when a monitoring should be performed. The main problem is to link exposure to effects of a certain parasiticide in a way that any impact can directly be related to the use of this parasiticide. Therefore, a "Targeted Environmental Monitoring" (TEM) is proposed, which is essentially a combination between a field study and a PAM. PMID- 29425142 TI - Optimal Hydrogen Production Coupled with Pollutant Removal from Biodiesel Wastewater Using a Thermally Treated TiO2 Photocatalyst (P25): Influence of the Operating Conditions. AB - This work aimed to produce hydrogen (H2) simultaneously with pollutant removal from biodiesel wastewater by photocatalytic oxidation using a thermally-treated commercial titanium dioxide (TiO2) photocatalyst at room temperature (~30 degrees C) and ambient pressure. The effects of the operating conditions, including the catalyst loading level (1-6 g/L), UV light intensity (3.52-6.64 mW/cm2), initial pH of the wastewater (2.3-8.0) and reaction time (1-4 h), on the quantity of H2 production together with the reduction in the chemical oxygen demand (COD), biological oxygen demand (BOD) and oil and grease levels were explored. It was found that all the investigated parameters affected the level of H2 production and pollutant removal. The optimum operating condition for simultaneous H2 production and pollutant removal was found at an initial wastewater pH of 6.0, a catalyst dosage of 4.0 g/L, a UV light intensity of 4.79 mW/cm2 and a reaction time of 2 h. These conditions led to the production of 228 MUmol H2 with a light conversion efficiency of 6.78% and reduced the COD, BOD and oil and grease levels by 13.2%, 89.6% and 67.7%, respectively. The rate of pollutant removal followed a pseudo-first order chemical reaction with a rate constant of 0.008, 0.085 and 0.044 min-1 for the COD, BOD and oil and grease removal, respectively. PMID- 29425143 TI - Potential of Extracted Locusta Migratoria Protein Fractions as Value-Added Ingredients. AB - Although locusts can be sustainably produced and are nutrient rich, the thought of eating them can be hard to swallow for many consumers. This paper aims to investigate the nutritional composition of Locusta migratoria, including the properties of extracted locust protein, contributing to limited literature and product development opportunities for industry. Locusts sourced from Dunedin, New Zealand, contained a high amount of protein (50.79% dry weight) and fat (34.93%), which contained high amounts of omega-3 (15.64%), creating a desirably low omega 3/omega-6 ratio of 0.57. Three protein fractions including; insoluble locust fraction, soluble locust fraction, and a supernatant fraction were recovered following alkali isoelectric precipitation methodology. Initially, proteins were solubilised at pH 10 then precipitated out at the isoelectric point (pH 4). All fractions had significantly higher protein contents compared with the whole locust. The insoluble protein fraction represented 37.76% of the dry weight of protein recovered and was much lighter in colour and greener compared to other fractions. It also had the highest water and oil holding capacity of 5.17 mL/g and 7.31 mL/g, possibly due to larger particle size. The high supernatant yield (56.60%) and low soluble protein yield (9.83%) was unexpected and could be a result of experimental pH conditions chosen. PMID- 29425144 TI - Fully Solution-Processable Fabrication of Multi-Layered Circuits on a Flexible Substrate Using Laser Processing. AB - The development of printing technologies has enabled the realization of electric circuit fabrication on a flexible substrate. However, the current technique remains restricted to single-layer patterning. In this paper, we demonstrate a fully solution-processable patterning approach for multi-layer circuits using a combined method of laser sintering and ablation. Selective laser sintering of silver (Ag) nanoparticle-based ink is applied to make conductive patterns on a heat-sensitive substrate and insulating layer. The laser beam path and irradiation fluence are controlled to create circuit patterns for flexible electronics. Microvia drilling using femtosecond laser through the polyvinylphenol-film insulating layer by laser ablation, as well as sequential coating of Ag ink and laser sintering, achieves an interlayer interconnection between multi-layer circuits. The dimension of microvia is determined by a sophisticated adjustment of the laser focal position and intensity. Based on these methods, a flexible electronic circuit with chip-size-package light emitting diodes was successfully fabricated and demonstrated to have functional operations. PMID- 29425145 TI - Reduction and Removal of Chromium VI in Water by Powdered Activated Carbon. AB - Cr adsorption on wood-based powdered activated carbon (WPAC) was characterized by scanning electron microscopy coupled with energy dispersive spectroscopy (SEM EDS), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). The highest Cr(VI) adsorption (40.04%) was obtained under acidic conditions (pH 3), whereas Cr removal at pH 10 was only 0.34%. The mechanism of Cr(VI) removal from aqueous solutions by WPAC was based on the reduction of Cr(VI) to Cr(III) with the concomitant oxidation of C-H and C-OH to C-OH and C=O, respectively, on the surface of WPAC, followed by Cr(III) adsorption. Raman spectroscopy revealed a change in the WPAC structure in terms of the D/G band intensity ratio after Cr(VI) adsorption. SEM-EDS analysis showed that the oxygen/carbon ratio on the WPAC surface increased from 9.85% to 17.74%. This result was confirmed by XPS measurements, which showed that 78.8% of Cr adsorbed on the WPAC surface was in the trivalent state. The amount of oxygen-containing functional groups on the surface increased due to the oxidation of graphitic carbons to C-OH and C=O groups. PMID- 29425146 TI - Nanoparticle-Based Strategies to Treat Neuro-Inflammation. AB - Neuro-inflammation is a pivotal physio-pathological feature of brain disorders, including neurodegenerative diseases. As such, it is a relevant therapeutic target against which drugs have to be proposed. Targeting neuro-inflammation implies crossing the Blood-Brain Barrier (BBB) to reach the Central Nervous System (CNS). Engineered nanoparticles (ENPs) are promising candidates to carry and deliver drugs to the CNS by crossing the BBB. There are several strategies to design ENPs intended for crossing through the BBB. Herein, we first put nanotechnologies back in their historical context and introduce neuro inflammation and its consequences in terms of public health. In a second part, we explain how ENPs can get access to the brain and review this area by highlighting recent papers in the field. Finally, after pointing out potential guidelines for preclinical studies involving ENPs, we conclude by opening the debate on the questions of nanosafety and toxicity of these ENPs and in particular on ecotoxicity related to regulatory issues and public concerns. PMID- 29425147 TI - Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity. AB - Herb-drug interaction (HDI) limits clinical application of herbs and drugs, and inhibition of herbs towards uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has gained attention as one of the important reasons to cause HDIs. Sauchinone, an active lignan isolated from aerial parts of Saururus chinensis (Saururacease), possesses anti-oxidant, anti-inflammatory, and anti-viral activities. In pharmacokinetics of sauchinone, sauchinone is highly distributed to the liver, forming extensive metabolites of sauchinone via UGTs in the liver. Thus, we investigated whether sauchinone inhibited UGTs to explore potential of sauchinone-drug interactions. In human liver microsomes (HLMs), sauchinone inhibited activities of UGT1A1, 1A3, 1A6, and 2B7 with IC50 values of 8.83, 43.9, 0.758, and 0.279 MUM, respectively. Sauchinone also noncompetitively inhibited UGT1A6 and 2B7 with Ki values of 1.08 and 0.524 MUM, respectively. In in vivo interaction study using mice, sauchinone inhibited UGT2B7-mediated zidovudine metabolism, resulting in increased systemic exposure of zidovudine when sauchinone and zidovudine were co-administered together. Our results indicated that there is potential HDI between sauchinone and drugs undergoing UGT2B7 mediated metabolism, possibly contributing to the safe use of sauchinone and drug combinations. PMID- 29425148 TI - Effects of the Artificial Sweetener Neotame on the Gut Microbiome and Fecal Metabolites in Mice. AB - Although artificial sweeteners are widely used in food industry, their effects on human health remain a controversy. It is known that the gut microbiota plays a key role in human metabolism and recent studies indicated that some artificial sweeteners such as saccharin could perturb gut microbiome and further affect host health, such as inducing glucose intolerance. Neotame is a relatively new low caloric and high-intensity artificial sweetener, approved by FDA in 2002. However, the specific effects of neotame on gut bacteria are still unknown. In this study, we combined high-throughput sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics to investigate the effects of neotame on the gut microbiome and fecal metabolite profiles of CD-1 mice. We found that a four week neotame consumption reduced the alpha-diversity and altered the beta diversity of the gut microbiome. Firmicutes was largely decreased while Bacteroidetes was significantly increased. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis also indicated that the control mice and neotame-treated mice have different metabolic patterns and some key genes such as butyrate synthetic genes were decreased. Moreover, neotame consumption also changed the fecal metabolite profiles. Dramatically, the concentrations of multiple fatty acids, lipids as well as cholesterol in the feces of neotame-treated mice were consistently higher than controls. Other metabolites, such as malic acid and glyceric acid, however, were largely decreased. In conclusion, our study first explored the specific effects of neotame on mouse gut microbiota and the results may improve our understanding of the interaction between gut microbiome and neotame and how this interaction could influence the normal metabolism of host bodies. PMID- 29425149 TI - Dietary Phytoestrogen Intake is Inversely Associated with Hypertension in a Cohort of Adults Living in the Mediterranean Area. AB - BACKGROUND: Dietary polyphenols, including phytoestrogens are abundantly present in a balanced diet. Evidence for their role in preventing non-communicable diseases is emerging. METHODS: We examined the association between estimated habitual intakes of dietary phytoestrogens and hypertension in a cohort study. The baseline data included 1936 men and women aged 18 years and older. Intakes of total phytoestrogens, isoflavones, and lignans were calculated from validated food frequency questionnaire. Data on the polyphenols content in foods were retrieved from the Phenol-Explorer database. RESULTS: Individuals in the highest quartile of dietary phytoestrogens intake were less likely to be hypertensive (OR: 0.66, 95% CI: 0.44-0.98); moreover, the association showed a significant decreasing trend. Isoflavones and lignans were not associated with lower odds of hypertension; however, some individual compounds, such as biochanin A and pinoresinol showed an independent inverse association with hypertension. CONCLUSIONS: Dietary phytoestrogens are associated with lower likelihood of hypertension in adults living in the Mediterranean area. Future studies are needed to confirm the present findings (i.e., prospective cohort studies) and to better understand the mechanisms underlying such associations. PMID- 29425150 TI - Aethiopinolones A-E, New Pregnenolone Type Steroids from the East African Basidiomycete Fomitiporia aethiopica. AB - A mycelial culture of the Kenyan basidiomycete Fomitiporia aethiopica was fermented on rice and the cultures were extracted with methanol. Subsequent HPLC profiling and preparative chromatography of its crude extract led to the isolation of five previously undescribed pregnenolone type triterpenes 1-5, for which we propose the trivial name aethiopinolones A-E. The chemical structures of the aethiopinolones were determined by extensive 1D- and 2D-NMR, and HRMS data analysis. The compounds exhibited moderate cytotoxic effects against various human cancer cell lines, but they were found devoid of significant nematicidal and antimicrobial activities. PMID- 29425152 TI - Composite Laser Ceramics by Advanced Bonding Technology. AB - Composites obtained by bonding materials with the same crystal structure and different chemical compositions can create new functions that do not exist in conventional concepts. We have succeeded in bonding polycrystalline YAG and Nd:YAG ceramics without any interstices at the bonding interface, and the bonding state of this composite was at the atomic level, similar to the grain boundary structure in ceramics. The mechanical strength of the bonded composite reached 278 MPa, which was not less than the strength of each host material (269 and 255 MPa). Thermal conductivity of the composite was 12.3 W/mK (theoretical value) which is intermediate between the thermal conductivities of YAG and Nd:YAG (14.1 and 10.2 W/mK, respectively). Light scattering cannot be detected at the bonding interface of the ceramic composite by laser tomography. Since the scattering coefficients of the monolithic material and the composite material formed by bonding up to 15 layers of the same materials were both 0.10%/cm, there was no occurrence of light scattering due to the bonding. In addition, it was not detected that the optical distortion and non-uniformity of the refractive index variation were caused by the bonding. An excitation light source (LD = 808 nm) was collimated to 200 MUm and irradiated into a commercial 1% Nd:YAG single crystal, but fracture damage occurred at a low damage threshold of 80 kW/cm2. On the other hand, the same test was conducted on the bonded interface of 1% Nd:YAG YAG composite ceramics fabricated in this study, but it was not damaged until the excitation density reached 127 kW/cm2. 0.6% Nd:YAG-YAG composite ceramics showed high damage resistance (up to 223 kW/cm2). It was concluded that composites formed by bonding polycrystalline ceramics are ideal in terms of thermo mechanical and optical properties. PMID- 29425151 TI - Liver Transplantation for Alcoholic Liver Disease and Hepatocellular Carcinoma. AB - Hepatocellular carcinoma is one of the main important causes of cancer-related death and its mortality is increasingly worldwide. In Europe, alcohol abuse accounts for approximately half of all liver cancer cases and it will become the leading cause of hepatocellular carcinoma in the next future with the sharp decline of chronic viral hepatitis. The pathophysiology of alcohol-induced carcinogenesis involves acetaldehyde catabolism, oxidative stress and chronic liver inflammation. Genetic background plays also a significant role and specific patterns of gene mutations in alcohol-related hepatocellular carcinoma have been characterized. Survival is higher in patients who undergo specific surveillance programmes than in patients who do not. However, patients with alcohol cirrhosis present a significantly greater risk of liver decompensation than those with cirrhosis due to other aetiologies. Furthermore, the adherence to screening program can be suboptimal. Liver transplant for patients with Milan-in hepatocellular carcinoma represents the best possible treatment in case of tumour recurrence/progression despite loco-regional or surgical treatments. Long-term result after liver transplantation for alcohol related liver disease is good. However, cardiovascular disease and de novo malignancies can significantly hamper patients' survival and should be carefully considered by transplant team. In this review, we have focused on the evolution of alcohol-related hepatocellular carcinoma epidemiology and risk factors as well as on liver transplantation in alcoholic patients with and without hepatocellular carcinoma. PMID- 29425153 TI - Seaweed Bioactive Compounds against Pathogens and Microalgae: Potential Uses on Pharmacology and Harmful Algae Bloom Control. AB - Cyanobacteria are found globally due to their adaptation to various environments. The occurrence of cyanobacterial blooms is not a new phenomenon. The bloom forming and toxin-producing species have been a persistent nuisance all over the world over the last decades. Evidence suggests that this trend might be attributed to a complex interplay of direct and indirect anthropogenic influences. To control cyanobacterial blooms, various strategies, including physical, chemical, and biological methods have been proposed. Nevertheless, the use of those strategies is usually not effective. The isolation of natural compounds from many aquatic and terrestrial plants and seaweeds has become an alternative approach for controlling harmful algae in aquatic systems. Seaweeds have received attention from scientists because of their bioactive compounds with antibacterial, antifungal, anti-microalgae, and antioxidant properties. The undesirable effects of cyanobacteria proliferations and potential control methods are here reviewed, focusing on the use of potent bioactive compounds, isolated from seaweeds, against microalgae and cyanobacteria growth. PMID- 29425156 TI - Contribution of Polyphenol Oxidation, Chlorophyll and Vitamin C Degradation to the Blackening of Piper nigrum L. AB - Black pepper (Piper nigrum L.) is the most widely used spice in the world. Blackening is considered to be beneficial and important in the processing of black pepper because it contributes to its color and flavor. The purpose of this paper is to investigate polyphenol oxidation as well as the chlorophyll and vitamin C (VC) degradation in the blackening of Piper nigrum L. Black pepper was produced by four methods, and changes in polyphenols, chlorophyll and VC were studied by high performance liquid chromatography (HPLC) and ultraviolet-visible and visible (UV-Vis) spectrophotometry. The results show that polyphenol oxidase activity significantly decreased during the preparation of black pepper, and the concentrations of phenolic compounds, VC, and chlorophyll a and b also significantly decreased. Polyphenol oxidation and chlorophyll and VC degradation contribute to the blackening. A crude extract of phenolic compounds from black pepper was prepared by the system solvent method. The greater the polarity of the extraction solvent, the higher the extraction rates of the phenolic compounds and the total phenol content. Pepper phenolic compounds were analyzed by HPLC analysis. PMID- 29425154 TI - Laminated Copper Nanocluster Incorporated Antioxidative Paper Device with RGB System-Assisted Signal Improvement. AB - Paper-based analytical devices are an emerging class of lightweight and simple-to use analytical platform. However, challenges such as instrumental requirements and chemical reagents durability, represent a barrier for less-developed countries and markets. Herein, we report an advanced laminated device using red emitting copper nanocluster and RGB digital analysis for signal improvement. Upon RGB system assistance, the device signal-to-background ratio and the calibration sensitivity are highly enhanced under a filter-free setup. In addition, the calibration sensitivity, limit of detection, and coefficient of determination are on par with those determined by instrumental fluorescence analysis. Moreover, the limitation of using oxidation-susceptible fluorescent nanomaterials is overcome by the introduction of protecting tape barriers, antioxidative sheets, and lamination enclosing. The robustness of device is highly advanced, and the durability is prolonged to more than tenfold. PMID- 29425155 TI - Markers of Iron Status Are Associated with Risk of Hyperuricemia among Chinese Adults: Nationwide Population-Based Study. AB - BACKGROUND: Elevated serum uric acid (SUA) involved in iron metabolism, has been increasingly recognized as a risk factor for gout and cardiovascular diseases. The objective of this study was to examine the associations between markers of iron status with risk of hyperuricemia (HU) in Chinese adult population. METHODS: Data were extracted from the 2009 wave of the China Health and Nutrition Survey, consisting of 7946 apparently healthy adults. Serum ferritin (SF), transferrin, soluble transferrin receptors (sTfR), hemoglobin (Hb), high-sensitivity C reactive protein (hs-CRP), and SUA were measured. Diet was assessed with three consecutive 24 h recalls. Demographic characteristics, smoking status, alcohol consumption, and physical activities were investigated using a structured questionnaire. Multilevel mixed-effects models were constructed to estimate the associations of SF, transferrin, sTfR, and Hb with SUA and the risk of HU. RESULTS: The crude prevalence of HU was 16.1%. SF, transferrin, and Hb levels were positively associated with SUA and the risk of HU after adjustment for cluster effects and potential confounders (all p-trend < 0.05). Compared with participants in the lowest quartile of SF, those in the highest quartile had significantly higher SUA concentrations (beta = 0.899 mg/dL, 95% confidence interval (CI): 0.788, 1.010; p < 0.001) and higher risk of HU (odds ratio (OR) = 3.086, 95% CI: 2.450, 3.888; p < 0.001). Participants with the highest quartile of transferrin had significantly higher SUA concentrations (beta = 0.488 mg/dL, 95% CI: 0.389, 0.587; p < 0.001) and higher risk of HU (OR: 1.900; 95% CI: 1.579, 2.286; p < 0.001) when compared with those with the lowest quartile. In male participants, those in the highest quartile of Hb had significantly higher risk of HU when compared to the reference group (OR: 1.401, 95% CI: 1.104, 1.777; p < 0.01); however, this association was not found in female participants (OR: 1.093; 95% CI: 0.821, 1.455; p = 0.544). CONCLUSION: SF, transferrin, and Hb levels were positively associated with the risk of HU, and additional studies are needed to confirm the findings, as well as to elucidate their underlying mechanisms. PMID- 29425157 TI - Nectandra grandiflora By-Products Obtained by Alternative Extraction Methods as a Source of Phytochemicals with Antioxidant and Antifungal Properties. AB - Nectandra grandiflora Nees (Lauraceae) is a Brazilian native tree recognized by its durable wood and the antioxidant compounds of its leaves. Taking into account that the forest industry offers the opportunity to recover active compounds from its residues and by-products, this study identifies and underlines the potential of natural products from Nectandra grandiflora that can add value to the forest exploitation. This study shows the effect of three different extraction methods: conventional (CE), ultrasound-assisted (UAE) and microwave-assisted (MAE) on Nectandra grandiflora leaf extracts (NGLE) chemical yields, phenolic and flavonoid composition, physical characteristics as well as antioxidant and antifungal properties. Results indicate that CE achieves the highest extraction phytochemical yield (22.16%), but with similar chemical composition to that obtained by UAE and MAE. Moreover, CE also provided a superior thermal stability of NGLE. The phenolic composition of NGLE was confirmed firstly, by colorimetric assays and infrared spectra and then by chromatographic analysis, in which quercetin-3-O-rhamnoside was detected as the major compound (57.75-65.14%). Furthermore, the antioxidant capacity of the NGLE was not altered by the extraction methods, finding a high radical inhibition in all NGLE (>80% at 2 mg/mL). Regarding the antifungal activity, there was observed that NGLE possess effective bioactive compounds, which inhibit the Aspergillus niger growth. PMID- 29425158 TI - Free Vibration Analysis of Moderately Thick Orthotropic Functionally Graded Plates with General Boundary Restraints. AB - In this paper, a modified Fourier series method is presented for the free vibration of moderately thick orthotropic functionally graded plates with general boundary restraints based on the first-order shear deformation theory. Regardless of boundary restraints, displacements and rotations of each plate are described as an improved form of double Fourier cosine series and several closed-form auxiliary functions to eliminate all the boundary discontinuities and jumps. Exact solutions are obtained by the energy functions of the plates based on Rayleigh-Ritz method. The convergence and reliability of the current method and the corresponding theoretical formulations are verified by comparing the present results with those available in the literature, and numerous new results for orthotropic functionally graded (OFG) plates with general boundary restraints are presented. In addition, the effects of gradient index, volume fraction and geometric parameters on frequencies with general boundary restraints are illustrated. PMID- 29425160 TI - Elucidating Grinding Mechanism by Theoretical and Experimental Investigations. AB - Grinding is one of the essential manufacturing processes for producing brittle or hard materials-based precision parts (e.g., optical lenses). In grinding, a grinding wheel removes the desired amount of material by passing the same area on the workpiece surface multiple times. How the topography of a workpiece surface evolves with these passes is thus an important research issue, which has not yet been addressed elaborately. The present paper tackles this issue from both the theoretical and the experimental points of view. In particular, this paper presents the results of experimental and theoretical investigations on the multi pass surface grinding operations where the workpiece surface is made of glass and the grinding wheel consists of cBN abrasive grains. Both investigations confirm that a great deal of stochasticity is involved in the grinding mechanism, and the complexity of the workpiece surface gradually increases along with the number of passes. PMID- 29425159 TI - Genome-Wide Identification and Characterization of WD40 Protein Genes in the Silkworm, Bombyx mori. AB - WD40 proteins are scaffolding molecules in protein-protein interactions and play crucial roles in fundamental biological processes. Genome-wide characterization of WD40 proteins in animals has been conducted solely in humans. We retrieved 172 WD40 protein genes in silkworm (BmWD40s) and identified these genes in 7 other insects, 9 vertebrates and 5 nematodes. Comparative analysis revealed that the WD40 protein gene family underwent lineage-specific expansions during animal evolution, but did not undergo significant expansion during insect evolution. The BmWD40s were categorized into five clusters and 12 classes according to the phylogenetic classification and their domain architectures, respectively. Sequence analyses indicated that tandem and segmental duplication played minor roles in producing the current number of BmWD40s, and domain recombination events of multi-domain BmWD40s might have occurred mainly after gene duplication events. Gene Ontology (GO) analysis revealed that a higher proportion of BmWD40s was involved in processes, such as binding, transcription-regulation and cellular component biogenesis, compared to all silkworm genes annotated in GO. Microarray based analysis demonstrated that many BmWD40s had tissue-specific expression and exhibited high and/or sex-related expression during metamorphosis. These findings contribute to a better understanding of the evolution of the animal WD40 protein family and assist the study of the functions of BmWD40s. PMID- 29425161 TI - Perceived Environmental Factors Associated with Obesity in Libyan Men and Women. AB - Background: There is a lack of research pertaining to the links between built environment attributes and obesity in adults in the Eastern Mediterranean Region. In the Libyan context, no previous studies have been conducted to investigate this relationship. Therefore, the aim of this study was to examine associations between perceived neighbourhood built environmental attributes and obesity among Libyan men and women. The prevalence of overweight and obesity was also assessed. Methods: A cross-sectional study design was used for the population-based survey in Benghazi, Libya. A multi-stage cluster sampling technique was used to select Libyan adults from the Benghazi electoral register. The Physical Activity Neighbourhood Environment Scale (PANES) was used to measure participants' perception of neighbourhood environmental factors. Using the Tanita BC-601 Segmental Body Composition Monitor and a portable stadiometer, anthropometric measurements were taken at a mutually agreeable place by qualified nurses. Results: Four hundred and one Libyan adults were recruited (78% response rate). Participants were aged 20-65 years, 63% were female, and all had lived in Benghazi for over 10 years. The prevalence of obesity and overweight was 42.4% and 32.9% respectively. A significant association was found between BMI and 6 neighbourhood environment attributes, specifically: street connectivity, unsafe environment and committing crimes at night, and neighbourhood aesthetics. For men only, these were: access to public transport, access to recreational facilities, and unsafe environment and committing crimes during the day. The attribute 'residential density zones' was only significant for women. Conclusions: The study suggests that Libyan people are at risk of living in neighbourhoods with unsupportive environmental features of physical activity, which are likely to promote obesity of both genders. The findings of this study could inform Libyan health policies about interventions in the obesogenic environments that might slow the obesity epidemic and contain the public health crisis. This study suggests that further research is needed, within the Libyan context, to explore the impact of the neighbourhood environment attributes on contributing to increased obesity. PMID- 29425162 TI - Segmenting Proteins into Tripeptides to Enhance Conformational Sampling with Monte Carlo Methods. AB - This paper presents an approach to enhance conformational sampling of proteins employing stochastic algorithms such as Monte Carlo (MC) methods. The approach is based on a mechanistic representation of proteins and on the application of methods originating from robotics. We outline the general ideas of our approach and detail how it can be applied to construct several MC move classes, all operating on a shared representation of the molecule and using a single mathematical solver. We showcase these sampling techniques on several types of proteins. Results show that combining several move classes, which can be easily implemented thanks to the proposed approach, significantly improves sampling efficiency. PMID- 29425163 TI - Nanostructure and Corresponding Quenching Efficiency of Fluorescent DNA Probes. AB - Based on the fluorescence resonance energy transfer (FRET) mechanism, fluorescent DNA probes were prepared with a novel DNA hairpin template method, with SiO2 coated CdTe (CdTe/SiO2) core/shell nanoparticles used as the fluorescence energy donors and gold (Au) nanoparticles (AuNPs) as the energy acceptors. The nanostructure and energy donor/acceptor ratio in a probe were controlled with this method. The relationship between the nanostructure of the probes and FRET efficiency (quenching efficiency) were investigated. The results indicated that when the donor/acceptor ratios were 2:1, 1:1, and 1:2; the corresponding FRET efficiencies were about 33.6%, 57.5%, and 74.2%, respectively. The detection results indicated that the fluorescent recovery efficiency of the detecting system was linear when the concentration of the target DNA was about 0.0446-2.230 nmol/L. Moreover, the probes showed good sensitivity and stability in different buffer conditions with a low detection limit of about 0.106 nmol/L. PMID- 29425165 TI - Synthesis and Magnetic Properties of Stable Radical Derivatives Carrying a Phenylacetylene Unit. AB - A nitronyl nitroxide derivative, 2-phenylethynyl-4,4,5,5-tetramethyl-4,5-dihydro 1H-imidazol-1-oxyl-3-oxide (1), and two verdazyl derivatives carrying a phenylacetylene unit, 1,5-diphenyl-3-phenylethynyl-6-oxo-1,2,4,5-tetrazin-2-yl (2) and 1,5-diisopropyl-3-phenylethynyl-6-oxo-1,2,4,5-tetrazin-2-yl (3), were synthesized and their packing structures were studied by X-ray crystallographic analysis and magnetically characterized in the solid state. While 1 and 3 had an isolated doublet spin state, 2 formed an antiferromagnetically coupled pair (2J/kB = -118 K). Density functional theory (DFT) calculations reveal that the spin density polarized in the phenyl group decreases as the dihedral angle between the phenyl ring and radical plane increases. PMID- 29425164 TI - Association of Alpha Tocopherol and Ag Sulfadiazine Chitosan Oleate Nanocarriers in Bioactive Dressings Supporting Platelet Lysate Application to Skin Wounds. AB - Chitosan oleate was previously proposed to encapsulate in nanocarriers some poorly soluble molecules aimed to wound therapy, such as the anti-infective silver sulfadiazine, and the antioxidant alpha tocopherol. Because nanocarriers need a suitable formulation to be administered to wounds, in the present paper, these previously developed nanocarriers were loaded into freeze dried dressings based on chitosan glutamate. These were proposed as bioactive dressings aimed to support the application to wounds of platelet lysate, a hemoderivative rich in growth factors. The dressings were characterized for hydration capacity, morphological aspect, and rheological and mechanical behavior. Although chitosan oleate nanocarriers clearly decreased the mechanical properties of dressings, these remained compatible with handling and application to wounds. Preliminary studies in vitro on fibroblast cell cultures demonstrated good compatibility of platelet lysate with nanocarriers and bioactive dressings. An in vivo study on a murine wound model showed an accelerating wound healing effect for the bioactive dressing and its suitability as support of the platelet lysate application to wounds. PMID- 29425166 TI - Fast Focal Point Correction in Prism-Coupled Total Internal Reflection Scanning Imager Using an Electronically Tunable Lens. AB - Total internal reflection (TIR) is useful for interrogating physical and chemical processes that occur at the interface between two transparent media. Yet prism coupled TIR imaging microscopes suffer from limited sensing areas due to the fact that the interface (the object plane) is not perpendicular to the optical axis of the microscope. In this paper, we show that an electrically tunable lens can be used to rapidly and reproducibly correct the focal length of an oblique-incidence scanning microscope (OI-RD) in a prism-coupled TIR geometry. We demonstrate the performance of such a correction by acquiring an image of a protein microarray over a scan area of 4 cm2 with an effective resolution of less than 20 microns. The electronic focal length tuning eliminates the mechanical movement of the illumination lens in the scanning microscope and in turn the noise and background drift associated with the motion. PMID- 29425168 TI - Parametric Evaluation of Errors Using Isolated Dots for Movement Measurement by Image Cross-Correlation. AB - Digital Image Correlation (DIC) is a common tool for assessing the movement of objects in a scene. Among others, one of the most popular techniques consists of tracking a dotted texture imitating speckle patterns. In this work, we analyzed the individual dots that form this pattern in order to propose an optimum size, shape, and dynamic range that allows minimizing the tracking error. Tracking was accomplished by using normalized cross-correlation with peak interpolation in order to obtain subpixel accuracy. For the models here used, we show that dot radii of 30-40 px with 150 gray levels are enough to obtain an accurate subpixel tracking resolution. Also, we show that 0.002 px is the performance limit of this technique, being this limit in accordance with the experimentally achievable subpixel limit. PMID- 29425167 TI - "I Was Relieved to Know That My Baby Was Safe": Women's Attitudes and Perceptions on Using a New Electronic Fetal Heart Rate Monitor during Labor in Tanzania. AB - To increase labor monitoring and prevent neonatal morbidity and mortality, a new wireless, strap-on electronic fetal heart rate monitor called Moyo was introduced in Tanzania in 2016. As part of the ongoing evaluation of the introduction of the monitor, the aim of this study was to explore the attitudes and perceptions of women who had worn the monitor continuously during their most recent delivery and perceptions about how it affected care. This knowledge is important to identify barriers towards adaptation in order to introduce new technology more effectively. We carried out 20 semi-structured individual interviews post-labor at two hospitals in Tanzania. A thematic content analysis was used to analyze the data. Our results indicated that the use of the monitor positively affected the women's birth experience. It provided much-needed reassurance about the wellbeing of the child. The women considered that wearing Moyo improved care due to an increase in communication and attention from birth attendants. However, the women did not fully understand the purpose and function of the device and overestimated its capabilities. This highlights the need to improve how and when information is conveyed to women in labor. PMID- 29425169 TI - Monitoring of Soft Deposition Layers in Liquid-Filled Tubes with Guided Acoustic Waves Excited by Clamp-on Transducers. AB - The monitoring of liquid-filled tubes with respect to the formation of soft deposition layers such as biofilms on the inner walls calls for non-invasive and long-term stable sensors, which can be attached to existing pipe structures. For this task a method is developed, which uses an ultrasonic clamp-on device. This method is based on the impact of such deposition layers on the propagation of circumferential guided waves on the pipe wall. Such waves are partly converted into longitudinal compressional waves in the liquid, which are back-converted to guided waves in a circular cross section of the pipe. Validating this approach, laboratory experiments with gelatin deposition layers on steel tubes exhibited a distinguishable sensitivity of both wave branches with respect to the thickness of such layers. This allows the monitoring of the layer growth. PMID- 29425170 TI - Multi-Complementary Model for Long-Term Tracking. AB - In recent years, video target tracking algorithms have been widely used. However, many tracking algorithms do not achieve satisfactory performance, especially when dealing with problems such as object occlusions, background clutters, motion blur, low illumination color images, and sudden illumination changes in real scenes. In this paper, we incorporate an object model based on contour information into a Staple tracker that combines the correlation filter model and color model to greatly improve the tracking robustness. Since each model is responsible for tracking specific features, the three complementary models combine for more robust tracking. In addition, we propose an efficient object detection model with contour and color histogram features, which has good detection performance and better detection efficiency compared to the traditional target detection algorithm. Finally, we optimize the traditional scale calculation, which greatly improves the tracking execution speed. We evaluate our tracker on the Object Tracking Benchmarks 2013 (OTB-13) and Object Tracking Benchmarks 2015 (OTB-15) benchmark datasets. With the OTB-13 benchmark datasets, our algorithm is improved by 4.8%, 9.6%, and 10.9% on the success plots of OPE, TRE and SRE, respectively, in contrast to another classic LCT (Long-term Correlation Tracking) algorithm. On the OTB-15 benchmark datasets, when compared with the LCT algorithm, our algorithm achieves 10.4%, 12.5%, and 16.1% improvement on the success plots of OPE, TRE, and SRE, respectively. At the same time, it needs to be emphasized that, due to the high computational efficiency of the color model and the object detection model using efficient data structures, and the speed advantage of the correlation filters, our tracking algorithm could still achieve good tracking speed. PMID- 29425171 TI - Walking Outdoors during Seminars Improved Perceived Seminar Quality and Sense of Well-Being among Participants. AB - Low levels of physical activity and sedentary behaviour are a growing health problem globally. Physical inactivity is associated with increased risk of numerous ailments, cardiovascular disease and mortality. Our primary aim was to perform a feasibility study on how to incorporate physical activity among students and teachers in regular teaching activities. The second aim was to investigate how students and teachers perceived the differences between outdoor walking seminars and regular indoor seminars. By transforming an on-campus course into a blended course, we were able to conduct seminars outdoors in nearby nature while walking. These walking seminars were evaluated among 131 students and nine teachers leading the walking seminars. The responses to the student survey and teacher interviews indicate that discussions, sense of well-being and the general quality of the seminar improved, regardless of how physically active participants were the rest of the time. The study shows one way to increase physical activity with small means; in our case, a reorganization of how we prepared for the seminars which allowed for walking discussions. PMID- 29425172 TI - Hybrid Beamforming for Reduction of Inter-Beam Interference in Millimeter-Wave Cellular Systems. AB - In millimeter-wave (mm-wave) cellular systems, beamforming antennas are necessary at both the base station (BS) and mobile station (MS) to compensate for high attenuation in mm-wave frequency bands and to extend the transmission range. The beamforming antennas also allow each BS to serve a number of MSs simultaneously, providing a substantial gain in system capacity. In space-division multiple access (SDMA) systems, the challenge is the inter-beam interference (IBI) caused by adjacent beams that are formed by the BS in the same cell and BSs in neighboring cells. The beams that are formed toward MSs in each cell may generate significant interference to MSs in neighboring cells, especially for MSs at the cell boundary. In this paper, we propose four different digital precoding techniques (Type-1, Type-2, Type-3, and Type-4) to reduce IBI in mm-wave cellular systems with a hybrid beamformer. Simulation results show that the proposed techniques can reduce the IBI in mm-wave cellular systems effectively, compared with a single-cell multiuser case. PMID- 29425174 TI - Solid Particle Number Emission Factors of Euro VI Heavy-Duty Vehicles on the Road and in the Laboratory. AB - Particulate matter (PM), and in particular ultrafine particles, have a negative impact on human health. The contribution of vehicle PM emissions to air pollution is typically quantified with emission inventories, which need vehicle emission factors as input. Heavy-duty vehicles, although they represent a small percentage of the vehicle population in nearly every major country, contribute the majority of the on-road PM emissions. However, the published data of modern heavy-duty vehicle emissions are scarce, and for the newest Euro VI technologies, almost non existent. The main objective of this paper is to present Solid Particle Number (SPN) emission factors from Euro VI heavy-duty vehicles using diesel, Compressed Natural Gas (CNG), or Liquefied Natural Gas (LNG). Urban, rural and motorway (highway) emissions were determined on the road at various European cities using SPN Portable Emission Measurement Systems (PEMS). Additional tests on a heavy duty chassis dynamometer showed that the solid sub-23 nm fraction, which is not covered at the moment in the European regulation, is high, especially for CNG engines. The significant contribution of regeneration events and the effect of ambient temperature and engine cold-start on particle emissions were also discussed. PMID- 29425173 TI - Bioapplications of Cell-SELEX-Generated Aptamers in Cancer Diagnostics, Therapeutics, Theranostics and Biomarker Discovery: A Comprehensive Review. AB - Currently, functional single-stranded oligonucleotide probes, termed aptamers, generated by an iterative technology, Systematic Evolution of Ligands by Exponential Enrichment (SELEX), are utilized to selectively target molecules or cells with high affinity. Aptamers hold considerable promise as multifunctional molecules or conjugates for challenging nanotechnologies or bioapplications now and in the future. In this review, we first describe recent endeavors to select aptamers towards live cancer cells via cell-SELEX. We then introduce several characteristic applications of selected aptamers, especially in imaging, drug delivery and therapy. In part, these advances have been made possible via synthesis of aptamer-based nanomaterials, which, by their sizes, shapes, and physicochemical properties, allow such aptamer-nanomaterial complexes to function as signal reporters or drug carriers. We also describe how these aptamer-based molecular tools contribute to cancer biomarker discovery through high-affinity recognition of membrane protein receptors. PMID- 29425175 TI - Laser-Based Monitoring of CH4, CO2, NH3, and H2S in Animal Farming-System Characterization and Initial Demonstration. AB - In this paper, we present a system for sequential detection of multiple gases using laser-based wavelength modulation spectroscopy (WMS) method combined with a Herriot-type multi-pass cell. Concentration of hydrogen sulfide (H2S), methane (CH4), carbon dioxide (CO2), and ammonia (NH3) are retrieved using three distributed feedback laser diodes operating at 1574.5 nm (H2S and CO2), 1651 nm (CH4), and 1531 nm (NH3). Careful adjustment of system parameters allows for H2S sensing at single parts-per-million by volume (ppmv) level with strongly reduced interference from adjacent CO2 transitions even at atmospheric pressure. System characterization in laboratory conditions is presented and the results from initial tests in real-world application are demonstrated. PMID- 29425176 TI - Favipiravir and Ribavirin Inhibit Replication of Asian and African Strains of Zika Virus in Different Cell Models. AB - Zika virus (ZIKV) has recently emerged as a new public health threat. ZIKV infections have caused a wide spectrum of neurological diseases, such as Guillain Barre syndrome, myelitis, meningoencephalitis, and congenital microcephaly. No effective therapies currently exist for treating patients infected with ZIKV. Herein, we evaluated the anti-viral activity of favipiravir (T-705) and ribavirin against Asian and African strains of ZIKV using different cell models, including human neuronal progenitor cells (hNPCs), human dermal fibroblasts (HDFs), human lung adenocarcinoma cells (A549) and Vero cells. Cells were treated with favipiravir or ribavirin and effects on ZIKV replication were determined using quantitative real-time PCR and plaque assay. Our results demonstrate that favipiravir or ribavirin treatment significantly inhibited ZIKV replication in a dose-dependent manner. Moreover, favipiravir treatment of ZIKV-infected hNPCs led to reduced cell death, enhanced AKT pathway phosphorylation, and increased expression of anti-apoptotic factor B cell lymphoma 2. In conclusion, our results demonstrate conclusively that favipiravir inhibits ZIKV replication and prevents cell death, and can be a promising intervention for ZIKV-associated disease. PMID- 29425177 TI - Nano-Pore Size of Alumina Affects Osteoblastic Response. AB - The rapid development and application of nanotechnology to biological interfaces has impacted the bone implant field, allowing researchers to finely modulate the interface between biomaterials and recipient tissues. In the present study, oxidative anodization was exploited to generate two alumina surfaces with different pore diameters. The former displayed surface pores in the mean range of 16-30 nm, while in the latter pores varied from to 65 to 89 nm. The samples were characterized by Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersive X-ray spectroscopy (EDX) analysis prior to being tested with pre osteoblastic MC3T3-E1 cells. In vitro cell response was studied in terms of early cell adhesion, viability, and morphology, including focal adhesion quantification. Both the alumina samples promoted higher cell adhesion and viability than the control condition represented by the standard culture dish plastic. Osteogenic differentiation was assessed through alkaline phosphatase activity and extracellular calcium deposition, and it was found that of the two nano-surfaces, one was more efficient than the other. By comparing for the first time two nano-porous alumina surfaces with different pore diameters, our data supported the role of nano-topography in inducing cell response. Modulating a simple aspect of surface texture may become an attractive route for guiding bone healing and regeneration around implantable metals. PMID- 29425178 TI - Coordinated Interpersonal Behaviour in Collective Dance Improvisation: The Aesthetics of Kinaesthetic Togetherness. AB - Collective dance improvisation (e.g., traditional and social dancing, contact improvisation) is a participatory, relational and embodied art form which eschews standard concepts in aesthetics. We present our ongoing research into the mechanisms underlying the lived experience of "togetherness" associated with such practices. Togetherness in collective dance improvisation is kinaesthetic (based on movement and its perception), and so can be simultaneously addressed from the perspective of the performers and the spectators, and be measured. We utilise these multiple levels of description: the first-person, phenomenological level of personal experiences, the third-person description of brain and body activity, and the level of interpersonal dynamics. Here, we describe two of our protocols: a four-person mirror game and a 'rhythm battle' dance improvisation score. Using an interpersonal closeness measure after the practice, we correlate subjective sense of individual/group connectedness and observed levels of in-group temporal synchronization. We propose that kinaesthetic togetherness, or interpersonal resonance, is integral to the aesthetic pleasure of the participants and spectators, and that embodied feeling of togetherness might play a role more generally in aesthetic experience in the performing arts. PMID- 29425179 TI - Statistical Modelling of Temperature and Moisture Uptake of Biochars Exposed to Selected Relative Humidity of Air. AB - New experimental techniques, as well as modern variants on known methods, have recently been employed to investigate the fundamental reactions underlying the oxidation of biochar. The purpose of this paper was to experimentally and statistically study how the relative humidity of air, mass, and particle size of four biochars influenced the adsorption of water and the increase in temperature. A random factorial design was employed using the intuitive statistical software Xlstat. A simple linear regression model and an analysis of variance with a pairwise comparison were performed. The experimental study was carried out on the wood of Quercus pubescens, Cyclobalanopsis glauca, Trigonostemon huangmosun, and Bambusa vulgaris, and involved five relative humidity conditions (22, 43, 75, 84, and 90%), two mass samples (0.1 and 1 g), and two particle sizes (powder and piece). Two response variables including water adsorption and temperature increase were analyzed and discussed. The temperature did not increase linearly with the adsorption of water. Temperature was modeled by nine explanatory variables, while water adsorption was modeled by eight. Five variables, including factors and their interactions, were found to be common to the two models. Sample mass and relative humidity influenced the two qualitative variables, while particle size and biochar type only influenced the temperature. PMID- 29425180 TI - Comment from the Editor to the Special Issue: "Big Data and Precision Medicine Series I: Lung Cancer Early Diagnosis". AB - With this Editorial we want to present the Special Issue "Big Data and Precision Medicine Series I: Lung Cancer Early Diagnosis" to the scientific community, which aims to gather experts on the early detection of lung cancer in order to implement common efforts in the fight against cancer. PMID- 29425181 TI - Third International Electronic Conference on Medicinal Chemistry (ECMC-3). AB - The third International Electronic Conference on Medicinal Chemistry, organized and sponsored by MDPI AG, publisher, and the journal Pharmaceuticals, took place in November 2017 on the SciForum website (www.sciforum.net/conference/ecmc-3). Around 300 authors from 34 different countries participated at the event, which hosted more than 70 presentations, keynotes, videos, and posters. A short description of some works presented during that scientific meeting is disclosed in this report. PMID- 29425185 TI - Cave Pearl Data Logger: A Flexible Arduino-Based Logging Platform for Long-Term Monitoring in Harsh Environments. AB - A low-cost data logging platform is presented that provides long-term operation in remote or submerged environments. Three premade "breakout boards" from the open-source Arduino ecosystem are assembled into the core of the data logger. Power optimization techniques are presented which extend the operational life of this module-based design to >1 year on three alkaline AA batteries. Robust underwater housings are constructed for these loggers using PVC fittings. Both the logging platform and the enclosures, are easy to build and modify without specialized tools or a significant background in electronics. This combination turns the Cave Pearl data logger into a generalized prototyping system and this design flexibility is demonstrated with two field studies recording drip rates in a cave and water flow in a flooded cave system. This paper describes a complete DIY solution, suitable for a wide range of challenging deployment conditions. PMID- 29425184 TI - Bioreducible Polymer Micelles Based on Acid-Degradable Poly(ethylene glycol) poly(amino ketal) Enhance the Stromal Cell-Derived Factor-1alpha Gene Transfection Efficacy and Therapeutic Angiogenesis of Human Adipose-Derived Stem Cells. AB - Adipose-derived stem cells (ADSCs) have the potential to treat ischemic diseases. In general, ADSCs facilitate angiogenesis by secreting various pro-angiogenic growth factors. However, transplanted ADSCs have a low therapeutic efficacy in ischemic tissues due to their poor engraftment and low viability. Stromal cell derived factor-1alpha (SDF-1alpha) improves the survival rate of stem cells transplanted into ischemic regions. In this study, we developed acid-degradable poly(ethylene glycol)-poly(amino ketal) (PEG-PAK)-based micelles for efficient intracellular delivery of SDF-1alpha plasmid DNA. The SDF-1alpha gene was successfully delivered into human ADSCs (hADSCs) using PEG-PAK micelles. Transfection of SDF-1alpha increased SDF-1alpha, vascular endothelial growth factor, and basic fibroblast growth factor gene expression and decreased apoptotic activity in hADSCs cultured under hypoxic conditions in comparison with conventional gene transfection using polyethylenimine. SDF-1alpha-transfected hADSCs also showed significantly increased SDF-1alpha and VEGF expression together with reduced apoptotic activity at 4 weeks after transplantation into mouse ischemic hindlimbs. Consequently, these cells improved angiogenesis in ischemic hindlimb regions. These PEG-PAK micelles may lead to the development of a novel therapeutic modality for ischemic diseases based on an acid-degradable polymer specialized for gene delivery. PMID- 29425182 TI - The Effects of Carbohydrates, in Isolation and Combined with Caffeine, on Cognitive Performance and Mood-Current Evidence and Future Directions. AB - This review examines the effects of carbohydrates, delivered individually and in combination with caffeine, on a range of cognitive domains and subjective mood. There is evidence for beneficial effects of glucose at a dose of 25 g on episodic memory, but exploration of dose effects has not been systematic and the effects on other cognitive domains is not known. Factors contributing to the differential sensitivity to glucose facilitation include age, task difficulty/demand, task domain, and glucoregulatory control. There is modest evidence to suggest modulating glycemic response may impact cognitive function. The evidence presented in this review identifies dose ranges of glucose and caffeine which improve cognition, but fails to find convincing consistent synergistic effects of combining caffeine and glucose. Whilst combining glucose and caffeine has been shown to facilitate cognitive performance and mood compared to placebo or glucose alone, the relative contribution of caffeine and glucose to the observed effects is difficult to ascertain, due to the paucity of studies that have appropriately compared the effects of these ingredients combined and in isolation. This review identifies a number of methodological challenges which need to be considered in the design of future hypothesis driven research in this area. PMID- 29425183 TI - Role of the IL-23/IL-17 Axis in Psoriasis and Psoriatic Arthritis: The Clinical Importance of Its Divergence in Skin and Joints. AB - Psoriasis is a chronic systemic inflammatory disease causing erythematosus and scaly skin plaques; up to 30% of patients with psoriasis develop Psoriatic Arthritis (PsA), which is characterised by inflammation and progressive damage of the peripheral joints and/or the spine and/or the entheses. The pathogenic mechanisms driving the skin disorder in psoriasis and the joint disease in PsA are sustained by the activation of inflammatory pathways that can be overlapping, but also, at least partially, distinct. Cytokines members of the IL-23/IL-17 family, critical in the development of autoimmunity, are abundantly expressed within the cutaneous lesions but also seem to be involved in chronic inflammation and damage of the synovium though, as it will be here discussed, not in all patients. In this review, we will focus on the state of the art of the molecular features of psoriatic skin and joints, focusing on the specific role of the IL 23/IL-17 pathway in each of these anatomical districts. We will then offer an overview of the approved and in-development biologics targeting this axis, emphasising how the availability of the "target" in the diseased tissues could provide a plausible explanation for the heterogeneous clinical efficacy of these drugs, thus opening future perspective of personalised therapies. PMID- 29425186 TI - Effect of Ball Mill Treatment on the Physicochemical Properties and Digestibility of Protein Extracts Generated from Scallops (Chlamys farreri). AB - The effects of ball mill treatment (0, 2, 4, 6, 8, and 10 min) on the physicochemical and digestible properties of scallops (Chlamys farreri) protein (CFP) were investigated. The CFP particle size decreased with increasing ball milling time. The content of free sulfhydryl (SH) of CFP increased from 13.08 +/- 0.25 MUmol/g protein to 18.85 +/- 0.24 MUmol/g protein when the ball-milling time increased from 0 min to 10 min. A sharp increase of the surface hydrophobicity index (H0) from 48.53 +/- 0.27 to 239.59 +/- 0.37 was found when the ball-milling time increased from 0 min to 4 min. Furthermore, the foaming capacity increased from 46.08 +/- 6.12% to 65.11 +/- 1.05% with increasing ball-milling time from 0 min to 6 min, after which it reached a plateau. SDS-PAGE results showed that ball mill treatment did not change the primary structure of CFP. Digestible properties of BMCFP simulated gastrointestinal digestion as a function of ball mill treatment were analyzed by Tricine-SDS-PAGE and nitrogen recovery index. After 60 min of simulated human gastro digestion, nitrogen recovery index of CFP had a significant rise from 42.01 +/- 0.31% to 58.78 +/- 3.37% as the ball-milling time increased from 0 min to 6 min. Peptides from hydrolysates of Chlamys farreri protein (CFP) were identified by ultraperformance liquidchromatographysystem coupled to a Synapt Mass Quadrupole Time-of-Flight Mass Spectrometer (UPLC-Q-TOF MS). After 2 h and 4 h of simulated human duodenal digestion, the number of peptides with 7-10 amino acids length increased apparently with the ball-milling time increased. This study presents an approach to investigating the effect of the ball-milling process on the physicochemical and digestible properties of CFP, which may provide valuable information on the application of CFP as an ingredient in food products. PMID- 29425188 TI - A Longitudinal Study of Predictors for Adolescent Electronic Cigarette Experimentation and Comparison with Conventional Smoking. AB - Little is known of the predictors of electronic cigarette (e-cigarette) use among adolescents, even though the use is increasing. We studied here the predictors for e-cigarette experimentation (tried and tried more than twice) and compared them with predictors for conventional smoking. A baseline school survey was conducted in the Helsinki metropolitan area, Finland, in 2011 for seventh graders (12 to 13-year-olds). Response rate was 73%. The same students were followed up in 2014 (9th grade, 15 to 16-year-olds), N = 5742. Generalized linear mixed models controlling for school clustering were used. In the follow-up, 43.3% of boys and 25.6% of girls had tried e-cigarettes and 21.9% and 8.1% correspondingly more than twice. The strongest predictors for both genders were conventional smoking, drunkenness and energy drink use. Furthermore, poor academic achievement predicted e-cigarette experimentation for both genders, and for boys, participation in team sports was a predictor. The predictors for experimenting and for experimenting more than twice were very similar, except for boys' participation in team sports. They were also similar compared to the predictors of conventional smoking but the associations were weaker. To conclude, smoking and other addictive behaviors predict adolescents' experimentation with e cigarettes. Family's socioeconomic background had little significance. PMID- 29425187 TI - The Differential Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Cardiometabolic Risk Factors: A Systematic Review. AB - A large body of evidence supports the cardioprotective effects of the long-chain omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). There is increasing interest in the independent effects of EPA and DHA in the modulation of cardiometabolic risk factors. This systematic review aims to appraise the latest available evidence of the differential effects of EPA and DHA on such risk factors. A systematic literature review was conducted up to May 2017. Randomised controlled trials were included if they met strict eligibility criteria, including EPA or DHA > 2 g/day and purity >= 90%. Eighteen identified articles were included, corresponding to six unique studies involving 527 participants. Both EPA and DHA lowered triglyceride concentration, with DHA having a greater triglyceride-lowering effect. Whilst total cholesterol levels were largely unchanged by EPA and DHA, DHA increased high-density lipoprotein (HDL) cholesterol concentration, particularly HDL2, and increased low-density lipoprotein (LDL) cholesterol concentration and LDL particle size. Both EPA and DHA inhibited platelet activity, whilst DHA improved vascular function and lowered heart rate and blood pressure to a greater extent than EPA. The effects of EPA and DHA on inflammatory markers and glycaemic control were inconclusive; however both lowered oxidative stress. Thus, EPA and DHA appear to have differential effects on cardiometabolic risk factors, but these need to be confirmed by larger clinical studies. PMID- 29425189 TI - Taking Action on Air Pollution Control in the Beijing-Tianjin-Hebei (BTH) Region: Progress, Challenges and Opportunities. AB - Due to rapid urbanization, industrialization and motorization, a large number of Chinese cities are affected by heavy air pollution. In order to explore progress, remaining challenges, and sustainability of air pollution control in the Beijing Tianjin-Hebei (BTH) region after 2013, a mixed method analysis was undertaken. The quantitative analysis comprised an overview of air quality management in the BTH region. Semi-structured expert interviews were conducted with 12 stakeholders from various levels of government and research institutions who played substantial roles either in decision-making or in research and advising on air pollution control in the BTH region. The results indicated that with the stringent air pollution control policies, the air quality in BTH meets the targets of the Air Pollution Prevention and Control Action Plan. However, improvements vary across the region and for different pollutants. Although implementation has been decisive and was at least in parts effectively enforced, significant challenges remained with regard to industrial and traffic emission control, and national air quality limits continued to be significantly exceeded and competing development interests remained mainly unsolved. There were also concerns about the sustainability of the current air pollution control measures especially for industries due to the top-down enforcement, and the associated large burden of social cost including unemployment and social inequity resulting industrial restructuring. Better mechanisms for ensuring cross-sectoral coordination and for improved central-local government communication were suggested. Further suggestions were provided to improve the conceptual design and effective implementation of respective air pollution control strategies in BTH. Our study highlights some of the major hurdles that need to be addressed to succeed with a comprehensive air pollution control management for the Chinese mega-urban agglomerations. PMID- 29425190 TI - Acute Effects of Ambient PM2.5 on All-Cause and Cause-Specific Emergency Ambulance Dispatches in Japan. AB - Short-term health effects of ambient PM2.5 have been established with numerous studies, but evidence in Asian countries is limited. This study aimed to investigate the short-term effects of PM2.5 on acute health outcomes, particularly all-cause, cardiovascular, respiratory, cerebrovascular and neuropsychological outcomes. We utilized daily emergency ambulance dispatches (EAD) data from eight Japanese cities (2007-2011). Statistical analyses included two stages: (1) City-level generalized linear model with Poisson distribution; (2) Random-effects meta-analysis in pooling city-specific effect estimates. Lag patterns were explored using (1) unconstrained-distributed lags (lag 0 to lag 7) and (2) average lags (lag: 0-1, 0-3, 0-5, 0-7). In all-cause EAD, significant increases were observed in both shorter lag (lag 0: 1.24% (95% CI: 0.92, 1.56)) and average lag 0-1 (0.64% (95% CI: 0.23, 1.06)). Increases of 1.88% and 1.48% in respiratory and neuropsychological EAD outcomes, respectively, were observed at lag 0 per 10 ug/m3 increase in PM2.5. While respiratory outcomes demonstrated significant average effects, no significant effect was observed for cardiovascular outcomes. Meanwhile, an inverse association was observed in cerebrovascular outcomes. In this study, we observed that effects of PM2.5 on all cause, respiratory and neuropsychological EAD were acute, with average effects not exceeding 3 days prior to EAD onset. PMID- 29425191 TI - Effect of the Composition of Lanthanide Complexes on Their Luminescence Enhancement by Ag@SiO2 Core-Shell Nanoparticles. AB - Metal-enhanced luminescence of lanthanide complexes by noble metal nanoparticles has attracted much attention because of its high efficiency in improving the luminescent properties of lanthanide ions. Herein, nine kinds of europium and terbium complexes-RE(TPTZ)(ampca)3.3H2O, RE(TPTZ)(BA)3.3H2O, RE(phen)(ampca)3.3H2O, RE(phen)(PTA)1.5.3H2O (RE = Eu, Tb) and Eu(phen)(BA)3.3H2O (TPTZ = 2,4,6-tri(2-pyridyl)-s-triazine, ampca = 3-aminopyrazine-2-carboxylic acid, BA = benzoic acid, phen = 1,10-phenanthroline, PTA = phthalic acid)-have been synthesized. Meanwhile, seven kinds of core-shell Ag@SiO2 nanoparticles of two different core sizes (80-100 nm and 40-60 nm) and varied shell thicknesses (5, 12, 20, 30 and 40 nm) have been prepared. The combination of these nine types of lanthanide complexes and seven kinds of Ag@SiO2 nanoparticles provides an opportunity for a thorough investigation of the metal-enhanced luminescence effect. Luminescence spectra analysis showed that the luminescence enhancement factor not only depends on the size of the Ag@SiO2 nanoparticles, but also strongly relates to the composition of the lanthanide complexes. Terbium complexes typically possess higher enhancement factors than their corresponding europium complexes with the same ligands, which may result from better spectral overlap between the emission bands of Tb complexes and surface plasmon resonance (SPR) absorption bands of Ag@SiO2. For the complexes with the same lanthanide ion but varied ligands, the complexes with high enhancement factors are typically those with excitation wavelengths located nearby the SPR absorption bands of Ag@SiO2 nanoparticles. These findings suggest a combinatorial chemistry strategy is necessary to obtain an optimal metal-enhanced luminescence effect for lanthanide complexes. PMID- 29425192 TI - Correction: Phenome-wide heritability analysis of the UK Biobank. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006711.]. PMID- 29425193 TI - Accuracy of molecular biology techniques for the diagnosis of Strongyloides stercoralis infection-A systematic review and meta-analysis. AB - BACKGROUND: Strongyloides stercoralis infection is a neglected tropical disease which can lead to severe symptoms and even death in immunosuppressed people. Unfortunately, its diagnosis is hampered by the lack of a gold standard, as the sensitivity of traditional parasitological tests (including microscopic examination of stool samples and coproculture) is low. Hence, alternative diagnostic methods, such as molecular biology techniques (mostly polymerase chain reaction, PCR) have been implemented. However, there are discrepancies in the reported accuracy of PCR. METHODOLOGY: A systematic review with meta-analysis was conducted in order to evaluate the accuracy of PCR for the diagnosis of S. stercoralis infection. The protocol was registered with PROSPERO International Prospective Register of Systematic Reviews (record: CRD42016054298). Fourteen studies, 12 of which evaluating real-time PCR, were included in the analysis. The specificity of the techniques resulted high (ranging from 93 to 95%, according to the reference test(s) used). When all molecular techniques were compared to parasitological methods, the sensitivity of PCR was assessed at 71.8% (95% CI 52.2-85.5), that decreased to 61.8% (95% CI 42.0-78.4) when serology was added among the reference tests. Similarly, sensitivity of real-time PCR resulted 64.4% (95% CI 46.2-77.7) when compared to parasitological methods only, 56.5% (95% CI 39.2-72.4) including serology. CONCLUSIONS: PCR might not be suitable for screening purpose, whereas it might have a role as a confirmatory test. PMID- 29425194 TI - Evaluation of the WHO 2009 classification for diagnosis of acute dengue in a large cohort of adults and children in Sri Lanka during a dengue-1 epidemic. AB - BACKGROUND: Dengue is a leading cause of fever and mimics other acute febrile illnesses (AFI). In 2009, the World Health Organization (WHO) revised criteria for clinical diagnosis of dengue. METHODOLOGY/PRINCIPAL FINDINGS: The new WHO 2009 classification of dengue divides suspected cases into three categories: dengue without warning signs, dengue with warning signs and severe dengue. We evaluated the WHO 2009 classification vs physicians' subjective clinical diagnosis (gestalt clinical impression) in a large cohort of patients presenting to a tertiary care center in southern Sri Lanka hospitalized with acute febrile illness. We confirmed acute dengue in 388 patients (305 adults >= 18 years and 83 children), including 103 primary and 245 secondary cases, of 976 patients prospectively enrolled with AFI. At presentation, both adults and children with acute dengue were more likely than those with other AFI to have leukopenia and thrombocytopenia. Additionally, adults were more likely than those with other AFI to have joint pain, higher temperatures, and absence of crackles on examination whereas children with dengue were more likely than others to have sore throat, fatigue, oliguria, and elevated hematocrit and transaminases. Similarly, presence of joint pain, thrombocytopenia, and absence of cough were independently associated with secondary vs primary dengue in adults whereas no variables were different in children. The 2009 WHO dengue classification was more sensitive than physicians' clinical diagnosis for identification of acute dengue (71.5% vs 67.1%), but was less specific. However, despite the absence of on-site diagnostic confirmation of dengue, clinical diagnosis was more sensitive on discharge (75.2%). The 2009 WHO criteria classified almost 75% as having warning signs, even though only 9 (2.3%) patients had evidence of plasma leakage and 16 (4.1%) had evidence of bleeding. CONCLUSIONS/SIGNIFICANCE: In a large cohort with AFI, we identified features predictive of dengue vs other AFI and secondary vs primary dengue in adults versus children. The 2009 WHO dengue classification criteria had high sensitivity but low specificity compared to physicians' gestaldt diagnosis. Large cohort studies will be needed to validate the diagnostic yield of clinical impression and specific features for dengue relative to the 2009 WHO classification criteria. PMID- 29425195 TI - A natural agonist of mosquito TRPA1 from the medicinal plant Cinnamosma fragrans that is toxic, antifeedant, and repellent to the yellow fever mosquito Aedes aegypti. AB - Plants produce various secondary metabolites that offer a potential source of novel insecticides and repellents for the control of mosquito vectors. Plants of the genus Cinnamosma are endemic to, and widely-distributed throughout, the island of Madagascar. The barks of these species are commonly used in traditional medicines for treating a wide range of maladies. The therapeutic nature of the bark is thought to be associated with its enrichment of pungent drimane sesquiterpenes, which elicit antifeedant and toxic effects in some insects. Here we test the hypothesis that a bark extract of Cinnamosma fragrans (CINEX) and its major drimane sesquiterpenes are insecticidal, antifeedant, and repellent to Aedes aegypti, the principal mosquito vector of chikungunya, dengue, yellow fever, and Zika viruses. We demonstrate that CINEX is 1) toxic to larval and adult female mosquitoes, and 2) antifeedant and repellent to adult female mosquitoes. Moreover, we show that cinnamodial (CDIAL), a sesquiterpene dialdehyde isolated from CINEX, duplicates these bioactivities and exhibits similar toxic potency against pyrethroid-susceptible and -resistant strains of Ae. aegypti. Importantly, we show that CDIAL is an agonist of heterologously expressed mosquito Transient Receptor Potential A1 (TRPA1) channels, and the antifeedant activity of CDIAL is dampened in a TRPA1-deficient strain of Ae. aegypti (TRPA1-/-). Intriguingly, TRPA1-/- mosquitoes do not exhibit toxic resistance to CDIAL. The data indicate that modulation of TRPA1 is required for the sensory detection and avoidance of CDIAL by mosquitoes, but not for inducing the molecule's toxicity. Our study suggests that CDIAL may serve as a novel chemical platform for the development of natural product-based insecticides and repellents for controlling mosquito vectors. PMID- 29425196 TI - Validation of the ADAMO Care Watch for step counting in older adults. AB - BACKGROUND: Accurate measurement devices are required to objectively quantify physical activity. Wearable activity monitors, such as pedometers, may serve as affordable and feasible instruments for measuring physical activity levels in older adults during their normal activities of daily living. Currently few available accelerometer-based steps counting devices have been shown to be accurate at slow walking speeds, therefore there is still lacking appropriate devices tailored for slow speed ambulation, typical of older adults. This study aimed to assess the validity of step counting using the pedometer function of the ADAMO Care Watch, containing an embedded algorithm for measuring physical activity in older adults. METHODS: Twenty older adults aged >= 65 years (mean +/- SD, 75+/-7 years; range, 68-91) and 20 young adults (25+/-5 years, range 20-40), wore a care watch on each wrist and performed a number of randomly ordered tasks: walking at slow, normal and fast self-paced speeds; a Timed Up and Go test (TUG); a step test and ascending/descending stairs. The criterion measure was the actual number of steps observed, counted with a manual tally counter. Absolute percentage error scores, Intraclass Correlation Coefficients (ICC), and Bland Altman plots were used to assess validity. RESULTS: ADAMO Care Watch demonstrated high validity during slow and normal speeds (range 0.5-1.5 m/s) showing an absolute error from 1.3% to 1.9% in the older adult group and from 0.7% to 2.7% in the young adult group. The percentage error for the 30-metre walking tasks increased with faster pace in both young adult (17%) and older adult groups (6%). In the TUG test, there was less error in the steps recorded for older adults (1.3% to 2.2%) than the young adults (6.6% to 7.2%). For the total sample, the ICCs for the ADAMO Care Watch for the 30-metre walking tasks at each speed and for the TUG test were ranged between 0.931 to 0.985. CONCLUSION: These findings provide evidence that the ADAMO Care Watch demonstrated highly accurate measurements of the steps count in all activities, particularly walking at normal and slow speeds. Therefore, these data support the inclusion of the ADAMO Care Watch in clinical applications for measuring the number of steps taken by older adults at normal, slow walking speeds. PMID- 29425197 TI - How the microbiome challenges our concept of self. AB - Today, the three classical biological explanations of the individual self--the immune system, the brain, the genome--are being challenged by the new field of microbiome research. Evidence shows that our resident microbes orchestrate the adaptive immune system, influence the brain, and contribute more gene functions than our own genome. The realization that humans are not individual, discrete entities but rather the outcome of ever-changing interactions with microorganisms has consequences beyond the biological disciplines. In particular, it calls into question the assumption that distinctive human traits set us apart from all other animals--and therefore also the traditional disciplinary divisions between the arts and the sciences. PMID- 29425199 TI - Evidence of previous but not current transmission of chikungunya virus in southern and central Vietnam: Results from a systematic review and a seroprevalence study in four locations. AB - BACKGROUND: Arbovirus infections are a serious concern in tropical countries due to their high levels of transmission and morbidity. With the outbreaks of chikungunya (CHIKV) in surrounding regions in recent years and the fact that the environment in Vietnam is suitable for the vectors of CHIKV, the possibility of transmission of CHIKV in Vietnam is of great interest. However, information about CHIKV activity in Vietnam remains limited. METHODOLOGY: In order to address this question, we performed a systematic review of CHIKV in Vietnam and a CHIKV seroprevalence survey. The seroprevalence survey tested for CHIKV IgG in population serum samples from individuals of all ages in 2015 from four locations in Vietnam. PRINCIPAL FINDINGS: The four locations were An Giang province (n = 137), Ho Chi Minh City (n = 136), Dak Lak province (n = 137), and Hue City (n = 136). The findings give us evidence of some CHIKV activity: 73/546 of overall samples were seropositive (13.4%). The age-adjusted seroprevalences were 12.30% (6.58-18.02), 13.42% (7.16-19.68), 7.97% (3.56-12.38), and 3.72% (1.75-5.69) in An Giang province, Ho Chi Minh City, Dak Lak province, and Hue City respectively. However, the age-stratified seroprevalence suggests that the last transmission ended around 30 years ago, consistent with results from the systematic review. We see no evidence for on-going transmission in three of the locations, though with some evidence of recent exposure in Dak Lak, most likely due to transmission in neighbouring countries. Before the 1980s, when transmission was occurring, we estimate on average 2-4% of the population were infected each year in HCMC and An Giang and Hue (though transmision ended earlier in Hue). We estimate lower transmission in Dak Lak, with around 1% of the population infected each year. CONCLUSION: In conclusion, we find evidence of past CHIKV transmission in central and southern Vietnam, but no evidence of recent sustained transmission. When transmission of CHIKV did occur, it appeared to be widespread and affect a geographically diverse population. The estimated susceptibility of the population to chikungunya is continually increasing, therefore the possibility of future CHIKV transmission in Vietnam remains. PMID- 29425198 TI - Drosophila PLP assembles pericentriolar clouds that promote centriole stability, cohesion and MT nucleation. AB - Pericentrin is a conserved centrosomal protein whose dysfunction has been linked to several human diseases. It has been implicated in many aspects of centrosome and cilia function, but its precise role is unclear. Here, we examine Drosophila Pericentrin-like-protein (PLP) function in vivo in tissues that form both centrosomes and cilia. Plp mutant centrioles exhibit four major defects: (1) They are short and have subtle structural abnormalities; (2) They disengage prematurely, and so overduplicate; (3) They organise fewer cytoplasmic MTs during interphase; (4) When forming cilia, they fail to establish and/or maintain a proper connection to the plasma membrane-although, surprisingly, they can still form an axoneme-like structure that can recruit transition zone (TZ) proteins. We show that PLP helps assemble "pericentriolar clouds" of electron-dense material that emanate from the central cartwheel spokes and spread outward to surround the mother centriole. We propose that the partial loss of these structures may largely explain the complex centriole, centrosome and cilium defects we observe in Plp mutant cells. PMID- 29425200 TI - An agent-based model of tsetse fly response to seasonal climatic drivers: Assessing the impact on sleeping sickness transmission rates. AB - BACKGROUND: This paper presents the development of an agent-based model (ABM) to incorporate climatic drivers which affect tsetse fly (G. m. morsitans) population dynamics, and ultimately disease transmission. The model was used to gain a greater understanding of how tsetse populations fluctuate seasonally, and investigate any response observed in Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) disease transmission, with a view to gaining a greater understanding of disease dynamics. Such an understanding is essential for the development of appropriate, well-targeted mitigation strategies in the future. METHODS: The ABM was developed to model rHAT incidence at a fine spatial scale along a 75 km transect in the Luangwa Valley, Zambia. The model incorporates climatic factors that affect pupal mortality, pupal development, birth rate, and death rate. In combination with fine scale demographic data such as ethnicity, age and gender for the human population in the region, as well as an animal census and a sample of daily routines, we create a detailed, plausible simulation model to explore tsetse population and disease transmission dynamics. RESULTS: The seasonally-driven model suggests that the number of infections reported annually in the simulation is likely to be a reasonable representation of reality, taking into account the high levels of under-detection observed. Similar infection rates were observed in human (0.355 per 1000 person-years (SE = 0.013)), and cattle (0.281 per 1000 cattle-years (SE = 0.025)) populations, likely due to the sparsity of cattle close to the tsetse interface. The model suggests that immigrant tribes and school children are at greatest risk of infection, a result that derives from the bottom-up nature of the ABM and conditioning on multiple constraints. This result could not be inferred using alternative population-level modelling approaches. CONCLUSIONS: In producing a model which models the tsetse population at a very fine resolution, we were able to analyse and evaluate specific elements of the output, such as pupal development and the progression of the teneral population, allowing the development of our understanding of the tsetse population as a whole. This is an important step in the production of a more accurate transmission model for rHAT which can, in turn, help us to gain a greater understanding of the transmission system as a whole. PMID- 29425201 TI - A novel antibody surrogate biomarker to monitor parasite persistence in Trypanosoma cruzi-infected patients. AB - BACKGROUND: Trypanosoma cruzi parasite, the causative agent of Chagas disease, infects about six million individuals in more than 20 countries. Monitoring parasite persistence in infected individuals is of utmost importance to develop and evaluate treatments to control the disease. Routine screening for infected human individuals is achieved by serological assays; PCR testing to monitor spontaneous or therapy-induced parasitological cure has limitations due to the low and fluctuating parasitic load in circulating blood. The aim of the present study is to evaluate a newly developed antibody profiling assay as an indirect method to assess parasite persistence based on waning of antibodies following spontaneous or therapy-induced clearance of the infection. METHODOLOGY/PRINCIPAL FINDINGS: We designed a multiplex serology assay, an array of fifteen optimized T. cruzi antigens, to evaluate antibody diversity in 1654 serum samples from chronic Chagas patients. One specific antibody response (antibody 3, Ab3) showed a strong correlation with T. cruzi parasite persistence as determined by T. cruzi PCR positive results. High and sustained Ab3 signal was strongly associated with PCR positivity in untreated patients, whereas significant decline in Ab3 signals was observed in BZN-treated patients who cleared parasitemia based on blood PCR results. CONCLUSION/SIGNIFICANCE: Ab3 is a new surrogate biomarker that strongly correlates with parasite persistence in chronic and benznidazole-treated Chagas patients. We hypothesize that Ab3 is induced and maintained by incessant stimulation of the immune system by tissue-based and shed parasites that are not consistently detectable by blood based PCR techniques. Hence, a simple immunoassay measurement of Ab3 could be beneficial for monitoring the infectious status of seropositive patients. PMID- 29425202 TI - De novo transcriptome analysis of Bagarius yarrelli (Siluriformes: Sisoridae) and the search for potential SSR markers using RNA-Seq. AB - BACKGROUND: The yellow sisorid catfish (Bagarius yarrelli) is a carnivorous freshwater fish that inhabits the Honghe River, Lanchangjiang River and Nujiang River of southern China and other Southeast Asian countries. However, the publicly available genomic data for B. yarrelli are limited. METHODOLOGY AND PRINCIPAL FINDINGS: Illumina Solexa paired-end technology produced 1,706,456 raw reads from muscle, liver and caudal fin tissues of B. yarrelli. Nearly 5 Gb of data were acquired, and de novo assembly generated 14,607 unigenes, with an N50 of 2006 bp. A total of 9093 unigenes showed significant similarities to known proteins in public databases: 4477 and 6391 of B. yarrelli unigenes were mapped to the Gene Ontology (GO) and Clusters of Orthologous Groups (COG) databases, respectively. Moreover, 9635 unigenes were assigned to 242 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. In addition, 8568 microsatellites (simple sequence repeats, SSRs) were detected, and 31 pairs of polymorphic primers were characterized using wild populations of B. yarrelli from the Nujiang River, Yunnan Province, China. CONCLUSION/SIGNIFICANCE: These sequences enrich the genomic resources for B. yarrelli and will benefit future investigations into the evolutionary and biological processes of this and related Bagarius species. The SSR markers developed in this study will facilitate construction of genetic maps, investigations of genetic structures and germplasm polymorphism assessments in B. yarrelli. PMID- 29425203 TI - Neutralization of antibody-enhanced dengue infection by VIS513, a pan serotype reactive monoclonal antibody targeting domain III of the dengue E protein. AB - Dengue virus (DENV) infection imposes enormous health and economic burden worldwide with no approved treatment. Several small molecules, including lovastatin, celgosivir, balapiravir and chloroquine have been tested for potential anti-dengue activity in clinical trials; none of these have demonstrated a protective effect. Recently, based on identification and characterization of cross-serotype neutralizing antibodies, there is increasing attention on the potential for dengue immunotherapy. Here, we tested the ability of VIS513, an engineered cross-neutralizing humanized antibody targeting the DENV E protein domain III, to overcome antibody-enhanced infection and high but brief viremia, which are commonly encountered in dengue patients, in various in vitro and in vivo models. We observed that VIS513 efficiently neutralizes DENV at clinically relevant viral loads or in the presence of enhancing levels of DENV immune sera. Single therapeutic administration of VIS513 in mouse models of primary infection or lethal secondary antibody-enhanced infection, reduces DENV titers and protects from lethal infection. Finally, VIS513 administration does not readily lead to resistance, either in cell culture systems or in animal models of dengue infection. The findings suggest that rapid viral reduction during acute DENV infection with a monoclonal antibody is feasible. PMID- 29425204 TI - The aldehyde dehydrogenase 2 polymorphisms on neuropsychological performance in bipolar II disorder with or without comorbid anxiety disorder. AB - Anxiety disorders (ADs), the most common comorbid illnesses with bipolar disorder (BP) has been reported to associate with dopamine system. Dopamine, metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase 2 (ALDH2), and the distribution of the ALDH2*1/*1, and ALDH2*1/*2+ALDH*2/*2 alleles in the Han Chinese general population is relatively equal. The association between dopamine metabolic enzymes and cognitive performance in patients with bipolar II disorder (BP-II) comorbid with AD is unclear. This study proposed to explore the role of ALDH2 polymorphisms on neuropsychological performance between BP-II comorbid with or without AD. One hundred ninety-seven BP-II patients with and without a comorbid AD were recruited and compared with 130 healthy controls (HCs). A polymerase chain reaction and a restriction fragment length polymorphism analysis were used to determine genotypes for ALDH2, and study participants underwent neuropsychological tests. An interaction between AD comorbidity and the ALDH2 polymorphisms was found in different domain of cognitive dysfunction in the BP-II patients. The ALDH2 polymorphisms might have different effects on the neuropsychological performance of BP-II patients with and without comorbid AD. PMID- 29425205 TI - Absence without leave or leave without absence: Examining the interrelations among mind wandering, metacognition and cognitive control. AB - Despite the abundance of recent publications about mind wandering (i.e., off-task thought), its interconnection with metacognition and cognitive control has not yet been examined. In the current study, we hypothesized that these three constructs would show clear interrelations. Metacognitive capacity was predicted to correlate positively with cognitive control ability, which in turn was predicted to be positively related to resistance to mind wandering during sustained attention. Moreover, it was expected that participants with good metacognitive capacity would be better at the subjective recognition of behaviorally present mind wandering. Three tasks were used: The Sustained Attention to Response Task (SART) to measure mind wandering, a perceptual decision task with confidence ratings to measure metacognitive efficiency, and a conflict task to measure cognitive control. Structural Equation Modelling was used to test the interrelations among the three constructs. As expected, metacognitive efficiency was positively related to cognitive control ability. Surprisingly, there was a negative relation between metacognitive efficiency and the degree to which subjective mind wandering reports tracked the behavioral index of mind wandering. No relation was found between cognitive control and behavioral mind wandering. The results of the current work are the first to shed light on the interrelations among these three constructs. PMID- 29425206 TI - Genome-wide association study to identify candidate loci and genes for Mn toxicity tolerance in rice. AB - Manganese (Mn) is an essential micro-nutrient for plants, but flooded rice fields can accumulate high levels of Mn2+ leading to Mn toxicity. Here, we present a genome-wide association study (GWAS) to identify candidate loci conferring Mn toxicity tolerance in rice (Oryza sativa L.). A diversity panel of 288 genotypes was grown in hydroponic solutions in a greenhouse under optimal and toxic Mn concentrations. We applied a Mn toxicity treatment (5 ppm Mn2+, 3 weeks) at twelve days after transplanting. Mn toxicity caused moderate damage in rice in terms of biomass loss and symptom formation despite extremely high shoot Mn concentrations ranging from 2.4 to 17.4 mg g-1. The tropical japonica subpopulation was more sensitive to Mn toxicity than other subpopulations. Leaf damage symptoms were significantly correlated with Mn uptake into shoots. Association mapping was conducted for seven traits using 416741 single nucleotide polymorphism (SNP) markers using a mixed linear model, and detected six significant associations for the traits shoot manganese concentration and relative shoot length. Candidate regions contained genes coding for a heavy metal transporter, peroxidase precursor and Mn2+ ion binding proteins. The significant marker SNP-2.22465867 caused an amino acid change in a gene (LOC_Os02g37170) with unknown function. This study demonstrated significant natural variation in rice for Mn toxicity tolerance and the possibility of using GWAS to unravel genetic factors responsible for such complex traits. PMID- 29425208 TI - Estimation of linkage disequilibrium and analysis of genetic diversity in Korean chicken lines. AB - The development of genetic markers for animal breeding is an effective strategy to reduce the time and cost required to improve economically important traits. To implement genomic selection in the multibreed chicken population of Korea, an understanding of the linkage disequilibrium (LD) status of the target population is essential. In this study, we performed population genetic analyses to investigate LD decay, the effective population size, and breed diversity using 600K high-density single nucleotide polymorphism genotypes of 189 native chickens in 14 lines (including Korean native chicken, imported and adapted purebred and commercial chickens). The results indicated that commercial native chickens have less calculated LD (average, r2 = 0.13-0.26) and purebred native chickens have more calculated LD (average, r2 = 0.24-0.37) across the entire genome. The effective population sizes of the examined lines showed patterns opposite to those of population LD. The phylogeny and admixture analyses showed that commercial and purebred chickens were well distinguished, except for Rhode Island Red (RIR) purebred lines of NC (NIAS_RIR_C) and ND (NIAS_RIR_D). These lines are difficult to distinguish clearly because they originated from the same respective breeds. The results of this study may provide important information for the development of genetic markers that can be used in breeding to improve the economic traits of native chickens. PMID- 29425207 TI - The prevalence and trends of waterpipe tobacco smoking: A systematic review. AB - INTRODUCTION: Waterpipe tobacco smoking is harmful to health however its prevalence estimates remain uncertain. We aimed to systematically review the medical literature on waterpipe tobacco prevalence and trends. METHODS: We searched Medline, Embase and ISI Web of Science for 'waterpipe' and its synonyms, without using language or date restrictions. We included any measure of waterpipe tobacco smoking prevalence in jurisdictionally representative populations. We stratified findings by prevalence measure (past 30 day, ever, regular or occasional, daily, other or unspecified) and age (adults or youth). RESULTS: We included 129 studies reporting 355 estimates for 68 countries. In general, prevalence estimates among adults were highest in the Eastern Mediterranean, and among youth were about equal between Eastern Mediterranean and European regions. Past 30 day use was highest among Lebanese youth (37.2% in 2008), ever use was highest among Lebanese youth in 2002 and Lebanese university students in 2005 (both 65.3%), regular or occasional use was highest in among Iranian university students (16.3% in 2005), and daily use was highest among Egyptian youth (10.4% in 2005). Trend data were limited but most studies reported increased use over time, ranging from 0.3-1.0% per year among youth in the US to 2.9% per year among youth in Jordan (both for past 30 day use). Results were similar for ever use trends. Turkey (2.3% in 2008 to 0.8% in 2010) and Iraq (6.3% in 2008 and 4.8% in 2012) both witnessed decreased waterpipe use. CONCLUSION: Waterpipe tobacco smoking is most prevalent in Eastern Mediterranean and European countries, and appears higher among youth than adults. Continued surveillance will be important to assess and inform policy measures to control waterpipe tobacco use. PMID- 29425209 TI - Retinal genes are differentially expressed in areas of primary versus secondary degeneration following partial optic nerve injury. AB - BACKGROUND: Partial transection (PT) of the optic nerve is an established experimental model of secondary degeneration in the central nervous system. After a dorsal transection, retinal ganglion cells (RGCs) with axons in ventral optic nerve are intact but vulnerable to secondary degeneration, whereas RGCs in dorsal retina with dorsal axons are affected by primary and secondary injuries. Using microarray, we quantified gene expression changes in dorsal and ventral retina at 1 and 7 days post PT, to characterize pathogenic pathways linked to primary and secondary degeneration. RESULTS: In comparison to uninjured retina Cryba1, Cryba2 and Crygs, were significantly downregulated in injured dorsal retina at days 1 and 7. While Ecel1, Timp1, Mt2A and CD74, which are associated with reducing excitotoxicity, oxidative stress and inflammation, were significantly upregulated. Genes associated with oxygen binding pathways, immune responses, cytokine receptor activity and apoptosis were enriched in dorsal retina at day 1 after PT. Oxygen binding and apoptosis remained enriched at day 7, as were pathways involved in extracellular matrix modification. Fewer changes were observed in ventral retina at day 1 after PT, most associated with the regulation of protein homodimerization activity. By day 7, apoptosis, matrix organization and signal transduction pathways were enriched. Discriminant analysis was also performed for specific functional gene groups to compare expression intensities at each time point. Altered expression of selected genes (ATF3, GFAP, Ecel1, TIMP1, Tp53) and proteins (GFAP, ECEL1 and ATF3) were semi-quantitatively assessed by qRT-PCR and immunohistochemistry respectively. CONCLUSION: There was an acute and complex primary injury response in dorsal retina indicative of a dynamic interaction between neuroprotective and neurodegenerative events; ventral retina vulnerable to secondary degeneration showed a delayed injury response. Both primary and secondary injury resulted in the upregulation of numerous genes linked to RGC death, but differences in the nature of these changes strongly suggest that death occurred via different molecular mechanisms. PMID- 29425210 TI - Seasonality in trauma admissions - Are daylight and weather variables better predictors than general cyclic effects? AB - BACKGROUND: Trauma is a leading global cause of death, and predicting the burden of trauma admissions is vital for good planning of trauma care. Seasonality in trauma admissions has been found in several studies. Seasonal fluctuations in daylight hours, temperature and weather affect social and cultural practices but also individual neuroendocrine rhythms that may ultimately modify behaviour and potentially predispose to trauma. The aim of the present study was to explore to what extent the observed seasonality in daily trauma admissions could be explained by changes in daylight and weather variables throughout the year. METHODS: Retrospective registry study on trauma admissions in the 10-year period 2001-2010 at Oslo University Hospital, Ulleval, Norway, where the amount of daylight varies from less than 6 hours to almost 19 hours per day throughout the year. Daily number of admissions was analysed by fitting non-linear Poisson time series regression models, simultaneously adjusting for several layers of temporal patterns, including a non-linear long-term trend and both seasonal and weekly cyclic effects. Five daylight and weather variables were explored, including hours of daylight and amount of precipitation. Models were compared using Akaike's Information Criterion (AIC). RESULTS: A regression model including daylight and weather variables significantly outperformed a traditional seasonality model in terms of AIC. A cyclic week effect was significant in all models. CONCLUSION: Daylight and weather variables are better predictors of seasonality in daily trauma admissions than mere information on day-of-year. PMID- 29425211 TI - Effectiveness of a bioactive food compound in anthropometric measures of individuals with HIV/AIDS: A nonrandomized trial. AB - BACKGROUND: Highly Active Antiretroviral therapy (HAART) promotes anthropometric changes in lipid metabolism and glucose in patients with Human Immunodeficiency Virus (HIV). Functional foods play an important role on metabolism. Bioactive Food Compound (BFC) has shown effective results in changes arising from decompensated lipid metabolism due to the effects of HAART on HIV patients. From this perspective, the objective of this study is to evaluate anthropometric indicators and the body composition of patients undergoing HAART before and after consumption of BFC. METHODS: This is a prospective intervention with 180 individuals with HIV undergoing HAART. They formed two groups and were monitored for 3 months: the first group consisted of individuals who consumed BFC (n = 121) at the recommended daily intake of 40 g. The second group consisted of individuals who did not consume BFC (n = 59). We determined body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), conicity index (CI) and antiretroviral regimen used by the patients. RESULTS: The BMI among adults (p<0.001), the WC (p<0.001 and p<0.014 for men and women, respectively) and the CI (p = 0.001 and p<0.001 for men and women, respectively) increased at the end of the study in the group of individuals who did not consume BFC and remained stable in the BFC group. There were no changes in WHR in any of the groups evaluated. Regarding the antiretroviral regimens used, we observed that there was no difference between regimens as for BMI, WC, WHR and CI. CONCLUSIONS: The BFC consumed by HIV patients undergoing HAART allowed the maintenance of anthropometric measures without increasing the mean values of conicity index, suggesting that the consumption of this bioactive compound protects the individual against the development of metabolic syndrome (MeS) in patients infected with HIV undergoing antiretroviral therapy. PMID- 29425212 TI - Insulin resistance in lean and overweight non-diabetic Caucasian adults: Study of its relationship with liver triglyceride content, waist circumference and BMI. AB - AIMS: Insulin resistance is the pathophysiological precursor of type 2 diabetes mellitus (DM-2), and its relationship with non-alcoholic fatty liver disease (NAFLD) has been widely studied in patients with obesity or metabolic syndrome using not only ultrasound but also liver biopsies or proton magnetic resonance spectroscopy (H1-MRS) to assess liver fat content. In contrast, there are no studies on insulin resistance and NAFLD in lean or overweight Caucasian individuals using H1-MRS or liver biopsies for the quantification of hepatic triglyceride content. Our objectives were to study the presence of insulin resistance in lean and overweight Caucasian adults and investigate its possible relationship with liver triglyceride content, waist circumference (as proxy of visceral adiposity), BMI, and cardiometabolic risk factors. METHODS: A cross sectional study was conducted in 113 non-obese, non-diabetic individuals classified as overweight (BMI 25-29.9 kg/m2) or lean (BMI 19.5-24.9 kg/m2). Hepatic triglyceride content was quantified by 3T H1-MRS. NAFLD was defined as hepatic triglyceride content >5.56%. Insulin resistance (HOMA-IR), serum adiponectin, and tumor necrosis factor (TNF) were determined. RESULTS: HOMA-IR was significantly correlated with hepatic triglyceride content (r:0.76; p<0.0001). The lean-with-NAFLD group had significantly higher HOMA-IR (p<0.001) and lower serum adiponectin (p<0.05) than the overweight-without-NAFLD group. Insulin resistance was independently associated with NAFLD but not with waist circumference or BMI. Regression analysis showed hepatic triglyceride content to be the most important determinant of insulin resistance (p<0.01). CONCLUSIONS: Our findings suggest that NAFLD, once established, seems to be involved in insulin resistance and cardio-metabolic risk factors above and beyond waist circumference and BMI in non-obese, non-diabetic Caucasian individuals. PMID- 29425213 TI - A study on nonlinear estimation of submaximal effort tolerance based on the generalized MET concept and the 6MWT in pulmonary rehabilitation. AB - BACKGROUND: The six-minute walk test (6MWT) is considered to be a simple and inexpensive tool for the assessment of functional tolerance of submaximal effort. The aim of this work was 1) to background the nonlinear nature of the energy expenditure process due to physical activity, 2) to compare the results/scores of the submaximal treadmill exercise test and those of 6MWT in pulmonary patients and 3) to develop nonlinear mathematical models relating the two. METHODS: The study group included patients with the COPD. All patients were subjected to a submaximal exercise test and a 6MWT. To develop an optimal mathematical solution and compare the results of the exercise test and the 6MWT, the least squares and genetic algorithms were employed to estimate parameters of polynomial expansion and piecewise linear models. RESULTS: Mathematical analysis enabled to construct nonlinear models for estimating the MET result of submaximal exercise test based on average walk velocity (or distance) in the 6MWT. CONCLUSIONS: Submaximal effort tolerance in COPD patients can be effectively estimated from new, rehabilitation-oriented, nonlinear models based on the generalized MET concept and the 6MWT. PMID- 29425214 TI - Analyzing ecological restoration strategies for water and soil conservation. AB - The choice of areas for nature conservation involves the attempt to maximize the benefits, whether by carrying out an economic activity or by the provision of Ecosystem Services. Studies are needed to improve the understanding of the effect of the extent and position along the watershed of restored areas on soil and water conservation. This study aimed to understand how different restoration strategies might reflect in soil conservation and sediment retention. Using InVEST tool, sediment transport was simulated in a small 12 km2 watershed (Posses River, in Southeast Brazil), where one of first Brazilian Payment for Ecosystem Services (PES) projects is being carried out, comparing different hypothetical restoration strategies. With 25% of restoration, sediment export decreased by 78% for riparian restoration, and 27% for the steepest slopes restoration. On the other hand, the decrease in soil loss was lower for riparian restoration, with a 16% decrease, while the steepest slopes restoration reduced it by 21%. This mismatch between the reduction of sediment export and soil loss was explained by the fact that forest not only reduces soil loss locally but also traps sediment arriving from the upper parts of the watershed. While the first mechanism is important to provide soil stability, decreasing the risk of landslip, and to maintain agricultural productivity, the second can improve water quality and decrease the risk of silting, with positive effects on the water reservoirs at the outlet of the watershed. This suggests that Riparian and the Steepest Slopes restoration strategies are complementary in the sense of preventing sediments from reaching the water bodies as well as protecting them at their origin (with the reduction of erosion), so it will be advisable to consider the two types of restoration. PMID- 29425215 TI - Friend virus limits adaptive cellular immune responses by imprinting a maturation resistant and T helper type 2-biased immunophenotype in dendritic cells. AB - The murine Friend virus (FV) retrovirus model has been widely used to study anti viral immune responses, and virus-induced cancer. Here we analyzed FV immune evasion mechanisms on the level of dendritic cells (DC) essential for the induction of primary adaptive immune responses. Comparative quantitative proteome analysis of FV-infected DC (FV-DC) of different genotypes (BALB/c, C57BL/6) and non-infected DC revealed numerous genotype-independently regulated proteins rergulating metabolic activity, cytoskeletal rearrangements, and antigen processing/presentation. These alterations may promote virion production in FV DC. Stimulation of FV-DC with LPS resulted in strongly enhanced IL-10 production which was partially responsible for their attenuated T cell (CD4+, CD8+) stimulatory capacity. Stimulated FV-DC induced less IFN-gamma production in T cells required for cellular anti-viral responses, but more T helper cell type 2 (Th2)-associated cytokines (IL-4, IL-5, IL-13). We conclude that FV reprograms DC to promote viral spreading and immune deviation by imprinting a largely maturation-resistant, Th2-biased immunophenotype. PMID- 29425216 TI - First field evaluation of the optimized CE marked Abbott protocol for HIV RNA testing on dried blood spot in a routine clinical setting in Vietnam. AB - BACKGROUND: Viral load (VL) monitoring of HIV-infected patients in decentralized areas is limited due to logistic constraints. Dried Blood Spots (DBS) offer the opportunity to collect samples in remote area which can be easily transferred and tested at a central laboratory. The MOVIDA (Monitoring Of Viral load In Decentralized Area) project evaluated the performance of VL measurements on DBS using the new CE marked optimized Abbott protocol. METHODS: HIV-1 infected adults from three outpatient clinics in Hanoi (Vietnam) were enrolled into the study between 1 March and 13 April 2017. VL was measured on DBS using the optimized protocol provided by the manufacturer and compared to plasma VL as reference method on the Abbott m2000rt RealTime HIV-1 platform. Sensitivity was defined as the ability for DBS samples to correctly identify VL failure at the threshold of 1000 copies/mL of plasma, while specificity represented the ability to identify patients with a plasma HIV-RNA VL of <1000 copies/mL. RESULTS: A total of 203 patients were enrolled in the study, of which 152 (75%) were male. Median age was 38 [inter quartile range: 34-43] years. Of these patients, 37 were untreated, 38 on ART for <6 months and 117 were on ART for >=6 months. A strong correlation between VL results in plasma and from DBS was observed (rho = 0.95; p<0.001). Plasma VL was >=1000 copies/mL in 71 patients. The sensitivity of DBS was 90.1% (95% confidence interval [CI]: 80.7-95.9) and the specificity was 96.2% (95% CI: 91.4-98.8). CONCLUSIONS: The new optimized Abbott DBS protocol performed well in this study, meeting the WHO performance criteria for the use of DBS for HIV VL monitoring. Scaling up VL monitoring using DBS can be used to reach the last 90 in the UNAIDS targets of 90-90-90 to help end the AIDS epidemics. However, sensitivity remains the main challenge for manufacturers to prevent maintaining patients in virological failure on inefficient ART. PMID- 29425217 TI - Random measurement error: Why worry? An example of cardiovascular risk factors. AB - With the increased use of data not originally recorded for research, such as routine care data (or 'big data'), measurement error is bound to become an increasingly relevant problem in medical research. A common view among medical researchers on the influence of random measurement error (i.e. classical measurement error) is that its presence leads to some degree of systematic underestimation of studied exposure-outcome relations (i.e. attenuation of the effect estimate). For the common situation where the analysis involves at least one exposure and one confounder, we demonstrate that the direction of effect of random measurement error on the estimated exposure-outcome relations can be difficult to anticipate. Using three example studies on cardiovascular risk factors, we illustrate that random measurement error in the exposure and/or confounder can lead to underestimation as well as overestimation of exposure outcome relations. We therefore advise medical researchers to refrain from making claims about the direction of effect of measurement error in their manuscripts, unless the appropriate inferential tools are used to study or alleviate the impact of measurement error from the analysis. PMID- 29425218 TI - Body size estimation of self and others in females varying in BMI. AB - Previous literature suggests that a disturbed ability to accurately identify own body size may contribute to overweight. Here, we investigated the influence of personal body size, indexed by body mass index (BMI), on body size estimation in a non-clinical population of females varying in BMI. We attempted to disentangle general biases in body size estimates and attitudinal influences by manipulating whether participants believed the body stimuli (personalized avatars with realistic weight variations) represented their own body or that of another person. Our results show that the accuracy of own body size estimation is predicted by personal BMI, such that participants with lower BMI underestimated their body size and participants with higher BMI overestimated their body size. Further, participants with higher BMI were less likely to notice the same percentage of weight gain than participants with lower BMI. Importantly, these results were only apparent when participants were judging a virtual body that was their own identity (Experiment 1), but not when they estimated the size of a body with another identity and the same underlying body shape (Experiment 2a). The different influences of BMI on accuracy of body size estimation and sensitivity to weight change for self and other identity suggests that effects of BMI on visual body size estimation are self-specific and not generalizable to other bodies. PMID- 29425219 TI - The effect of floods on anemia among reproductive age women in Afghanistan. AB - This study uses biomarker information from the 2013 National Nutrition Survey Afghanistan and satellite precipitation driven modeling results from the Global Flood Monitoring System to analyze how floods affect the probability of anemia in Afghan women of reproductive age (15-49). In addition to establishing a causal relation between the two by exploiting the quasi-random variation of floods in different districts and periods, the analysis demonstrates that floods have a significant positive effect on the probability of anemia through two possible transmission mechanisms. The first is a significant effect on inflammation, probably related to water borne diseases carried by unsafe drinking water, and the second is a significant negative effect on retinol concentrations. Because the effect of floods on anemia remains significant even after we control for anemia's most common causes, we argue that the condition may also be affected by elevated levels of psychological stress. PMID- 29425220 TI - A new method of identifying target groups for pronatalist policy applied to Australia. AB - A country's total fertility rate (TFR) depends on many factors. Attributing changes in TFR to changes of policy is difficult, as they could easily be correlated with changes in the unmeasured drivers of TFR. A case in point is Australia where both pronatalist effort and TFR increased in lock step from 2001 to 2008 and then decreased. The global financial crisis or other unobserved confounders might explain both the reducing TFR and pronatalist incentives after 2008. Therefore, it is difficult to estimate causal effects of policy using econometric techniques. The aim of this study is to instead look at the structure of the population to identify which subgroups most influence TFR. Specifically, we build a stochastic model relating TFR to the fertility rates of various subgroups and calculate elasticity of TFR with respect to each rate. For each subgroup, the ratio of its elasticity to its group size is used to evaluate the subgroup's potential cost effectiveness as a pronatalist target. In addition, we measure the historical stability of group fertility rates, which measures propensity to change. Groups with a high effectiveness ratio and also high propensity to change are natural policy targets. We applied this new method to Australian data on fertility rates broken down by parity, age and marital status. The results show that targeting parity 3+ is more cost-effective than lower parities. This study contributes to the literature on pronatalist policies by investigating the targeting of policies, and generates important implications for formulating cost-effective policies. PMID- 29425221 TI - 18F-fluorocholine PET/CT in patients with occult biochemical recurrence of prostate cancer: Detection rate, impact on management and adequacy of impact. A prospective multicentre study. AB - AIM: To prospectively evaluate the clinical impact and the diagnostic performance of FCH-PET/CT in patients with occult biochemical recurrence of prostate cancer (PCa). MATERIALS AND METHODS: Results of 179 patients (mean PSA = 7.5ng/mL) with negative/inconclusive results of pelvic-MRI and of bone-scintigraphy were analysed. To determine the impact of FCH-PET/CT on diagnostic thinking and on patient management, the referring physicians prospectively filled-in a 1st and 2nd questionnaire related to patient's planned management before and after FCH PET/CT. Based on data from a 6-month follow-up after FCH-PET/CT, an independent assessor blinded to results of FCH-PET/CT determined the adequacy of management changes motivated by FCH-PET/CT. RESULTS: FCH-PET/CT localised foci evocative of recurrent PCa in 59% (105/179) of patients. Results of FCH-PET/CT motivated a change in scheduled patient management in 56% (100/179) of patients; which was considered as adequate in 89% (89/100) of patients. FCH-PET/CT also led to the detection of lung cancer in two patients. CONCLUSION: FCH PET/CT is a powerful tool to localise the sites of occult biochemical recurrence of PCa, leading to an adequate management change in half of patients. PMID- 29425222 TI - The safety and quality of pork and poultry meat imports for the common European market received at border inspection post Hamburg Harbour between 2014 and 2015. AB - Though imports of products of animal origin into the European Union (EU) have to comply with legal requirements and quality standards of the community, food consignment rejections at external EU borders have been increasing in recent years. This study explored microbiological metrics according to national target and critical values valid for samples at consumer level of 498 fresh poultry meat and 136 fresh pork filets from consignments subjected to physical checks during clearing at the border inspection post Hamburg harbour between January 2014 and December 2015 with ISO standard methods. Quantitative results indicated that critical thresholds for aerobic counts, Enterobacteriaceae, and E. coli were never surpassed. Merely for staphylococci, one poultry sample (0.2%) and 10 pork samples (9.3%) exceeded the critical limit (3.7 log cfu/g). However, qualitative analyses revealed that, Staphylococcus aureus was present in 16% and 10% of all poultry and pork samples, respectively, though no methicillin-resistant Staphylococcus aureus could be confirmed. Moreover, E. coli was present in 50% and 67% of all pork and poultry samples, respectively, and thereof 33 isolates were confirmed as extended-spectrum beta-lactamase-producing E. coli. Only 1.2% of the poultry samples were unacceptable due to the presence of Salmonella spp., whereas they were not detected in any pork sample. Campylobacter spp. were not detected in any sample. Though imported pork and poultry meat complies mostly with national market requirements, it might pose a potential risk to public health, especially for a direct or indirect foodborne transmission of imported, uncommon strains of zoonotic bacteria. PMID- 29425223 TI - MEA Viewer: A high-performance interactive application for visualizing electrophysiological data. AB - Action potentials can be recorded extracellularly from hundreds of neurons simultaneously with multi-electrode arrays. These can typically have as many as 120 or more electrodes. The brief duration of action potentials requires a high sampling frequency to reliably capture each waveform. The resulting raw data files are therefore large and difficult to visualize with traditional plotting tools. Common approaches to deal with the difficulties of data display, such as extracting spike times and performing spike train analysis, are useful in many contexts but they also significantly reduce data dimensionality. The use of tools which minimize data processing enable the development of heuristic perspective of experimental results. Here we introduce MEA Viewer, a high-performance open source application for the direct visualization of multi-channel electrophysiological data. MEA Viewer includes several high-performance visualizations, including an easily navigable overview of recorded extracellular action potentials from all data channels overlaid with spike timestamp data and an interactive raster plot. MEA Viewer can also display the two dimensional extent of action potential propagation in single neurons by signal averaging extracellular action potentials (eAPs) from single neurons detected on multiple electrodes. This view extracts and displays eAP timing information and eAP waveforms that are otherwise below the spike detection threshold. This entirely new method of using MEAs opens up novel research applications for medium density arrays. MEA Viewer is licensed under the General Public License version 3, GPLv3, and is available at http://github.com/dbridges/mea-tools. PMID- 29425224 TI - The foreign language effect on the self-serving bias: A field experiment in the high school classroom. AB - The rise of bilingual education triggers an important question: which language is preferred for a particular school activity? Our field experiment (n = 120) shows that students (aged 13-15) who process feedback in non-native English have greater self-serving bias than students who process feedback in their native Dutch. By contrast, literature on the foreign-language emotionality effect suggests a weaker self-serving bias in the non-native language, so our result adds nuance to that literature. The result is important to schools as it suggests that teachers may be able to reduce students' defensiveness and demotivation by communicating negative feedback in the native language, and teachers may be able to increase students' confidence and motivation by communicating positive feedback in the foreign language. PMID- 29425225 TI - An integrated strategy for improving contrast, durability, and portability of a Pocket Colposcope for cervical cancer screening and diagnosis. AB - INTRODUCTION: We have previously developed a portable Pocket Colposcope for cervical cancer screening in resource-limited settings. In this manuscript we report two different strategies (cross-polarization and an integrated reflector) to improve image contrast levels achieved with the Pocket Colposcope and evaluate the merits of each strategy compared to a standard-of-care digital colposcope. The desired outcomes included reduced specular reflection (glare), increased illumination beam pattern uniformity, and reduced electrical power budget. In addition, anti-fogging and waterproofing features were incorporated to prevent the Pocket Colposcope from fogging in the vaginal canal and to enable rapid disinfection by submersion in chemical agents. METHODS: Cross-polarization (Generation 3 Pocket Colposcope) and a new reflector design (Generation 4 Pocket Colposcope) were used to reduce glare and improve contrast. The reflector design (including the angle and height of the reflector sidewalls) was optimized through ray-tracing simulations. Both systems were characterized with a series of bench tests to assess specular reflection, beam pattern uniformity, and image contrast. A pilot clinical study was conducted to compare the Generation 3 and 4 Pocket Colposcopes to a standard-of-care colposcope (Leisegang Optik 2). Specifically, paired images of cervices were collected from the standard-of-care colposcope and either the Generation 3 (n = 24 patients) or the Generation 4 (n = 32 patients) Pocket Colposcopes. The paired images were blinded by device, randomized, and sent to an expert physician who provided a diagnosis for each image. Corresponding pathology was obtained for all image pairs. The primary outcome measures were the level of agreement (%) and kappa (kappa) statistic between the standard-of-care colposcope and each Pocket Colposcope (Generation 3 and Generation 4). RESULTS: Both generations of Pocket Colposcope had significantly higher image contrast when compared to the standard-of-care colposcope. The addition of anti-fog and waterproofing features to the Generation 3 and 4 Pocket Colposcope did not impact image quality based on qualitative and quantitative metrics. The level of agreement between the Generation 3 Pocket Colposcope and the standard-of-care colposcope was 75.0% (kappa = 0.4000, p = 0.0028, n = 24). This closely matched the level of agreement between the Generation 4 Pocket Colposcope and the standard-of-care colposcope which was also 75.0% (kappa = 0.4941, p = 0.0024, n = 32). CONCLUSION: Our results indicate that the Generation 3 and 4 Pocket Colposcopes perform comparably to the standard-of-care colposcope, with the added benefit of being low-cost and waterproof, which is ideal for use in resource-limited settings. Additionally, the reflector significantly reduces the electrical requirements of the Generation 4 Pocket Colposcope enhancing portability without altering performance compared to the Generation 3 system. PMID- 29425226 TI - Randomized controlled trial on promoting influenza vaccination in general practice waiting rooms. AB - BACKGROUND: Most of general practitioners (GPs) use advertising in their waiting rooms for patient's education purposes. Patients vaccinated against seasonal influenza have been gradually lessening. The objective of this trial was to assess the effect of an advertising campaign for influenza vaccination using posters and pamphlets in GPs' waiting rooms. METHODS AND FINDINGS: Registry based 2/1 cluster randomized controlled trial, a cluster gathering the enlisted patients of 75 GPs aged over 16 years. The trial, run during the 2014-2015 influenza vaccination campaign, compared patient's awareness from being in 50 GPs' standard waiting rooms (control group) versus that of waiting in 25 rooms from GPs who had received and exposed pamphlets and one poster on influenza vaccine (intervention group), in addition to standard mandatory information. The main outcome was the number of vaccination units delivered in pharmacies. Data were extracted from the SIAM-ERASME claim database of the Health Insurance Fund of Lille-Douai (France). The association between the intervention (yes/no) and the main outcome was assessed through a generalized estimating equation. Seventy five GPs enrolled 10,597 patients over 65 years or suffering from long lasting diseases (intervention/control as of 3781/6816 patients) from October 15, 2014 to February 28, 2015. No difference was found regarding the number of influenza vaccination units delivered (Relative Risk (RR) = 1.01; 95% Confidence interval: 0.97 to 1.05; p = 0.561). CONCLUSION: Effects of the monothematic campaign promoting vaccination against influenza using a poster and pamphlets exposed in GPs' waiting rooms could not be demonstrated. PMID- 29425227 TI - Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk: A case-control study in unselected white European populations. AB - Regular aspirin use is associated with reduced risk of colorectal cancer (CRC). Variation in aspirin's chemoprevention efficacy has been attributed to the presence of single nucleotide polymorphisms (SNPs). We conducted a meta-analysis using two large population-based case-control datasets, the UK-Leeds Colorectal Cancer Study Group and the NIH-Colon Cancer Family Registry, having a combined total of 3325 cases and 2262 controls. The aim was to assess 42 candidate SNPs in 15 genes whose association with colorectal cancer risk was putatively modified by aspirin use, in the literature. Log odds ratios (ORs) and standard errors were estimated for each dataset separately using logistic regression adjusting for age, sex and study site, and dataset-specific results were combined using random effects meta-analysis. Meta-analysis showed association between SNPs rs6983267, rs11694911 and rs2302615 with CRC risk reduction (All P<0.05). Association for SNP rs6983267 in the CCAT2 gene only was noteworthy after multiple test correction (P = 0.001). Site-specific analysis showed association between SNPs rs1799853 and rs2302615 with reduced colon cancer risk only (P = 0.01 and P = 0.004, respectively), however neither reached significance threshold following multiple test correction. Meta-analysis of SNPs rs2070959 and rs1105879 in UGT1A6 gene showed interaction between aspirin use and CRC risk (Pinteraction = 0.01 and 0.02, respectively); stratification by aspirin use showed an association for decreased CRC risk for aspirin users having a wild-type genotype (rs2070959 OR = 0.77, 95% CI = 0.68-0.86; rs1105879 OR = 0.77 95% CI = 0.69-0.86) compared to variant allele cariers. The direction of the interaction however is in contrast to that published in studies on colorectal adenomas. Both SNPs showed potential site-specific interaction with aspirin use and colon cancer risk only (Pinteraction = 0.006 and 0.008, respectively), with the direction of association similar to that observed for CRC. Additionally, they showed interaction between any non-steroidal anti-inflammatory drugs (including aspirin) use and CRC risk (Pinteraction = 0.01 for both). All gene x environment (GxE) interactions however were not significant after multiple test correction. Candidate gene investigation indicated no evidence of GxE interaction between genetic variants in genes involved in aspirin pathways, regular aspirin use and colorectal cancer risk. PMID- 29425228 TI - KSHV oral shedding and plasma viremia result in significant changes in the extracellular tumorigenic miRNA expression profile in individuals infected with the malaria parasite. AB - Kaposi's sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS). Both KSHV and HIV infections are endemic in Uganda, where KS is among the most common cancers in HIV-infected individuals. Recent studies examined the use of small RNAs as biomarkers of disease, including microRNAs (miRNAs), with viral and tumor-derived miRNAs being detected in exosomes from individuals with KSHV associated malignancies. In the current study, the host and viral extracellular mature miRNA expression profiles were analyzed in blood of KS-negative individuals in Uganda, comparing those with or without KSHV detectable from the oropharynx. We observed increased levels of cellular oncogenic miRNAs and decreased levels of tumor-suppressor miRNAs in plasma of infected individuals exhibiting oral KSHV shedding. These changes in host oncomiRs were exacerbated in people co-infected with HIV, and partially reversed after 2 years of anti retroviral therapy. We also detected KSHV miRNAs in plasma of KSHV infected individuals and determined that their expression levels correlated with KSHV plasma viremia. Deep sequencing revealed an expected profile of small cellular RNAs in plasma, with miRNAs constituting the major RNA biotype. In contrast, the composition of small RNAs in exosomes was highly atypical with high levels of YRNA and low levels of miRNAs. Mass spectrometry analysis of the exosomes revealed eleven different peptides derived from the malaria parasite, Plasmodium falciparum, and small RNA sequencing confirmed widespread plasmodium co infections in the Ugandan cohorts. Proteome analysis indicated an exosomal protein profile consistent with erythrocyte and keratinocyte origins for the plasma exosomes. A strong correlation was observed between the abundance of Plasmodium proteins and cellular markers of malaria. As Plasmodium falciparum is an endemic pathogen in Uganda, our study shows that co-infection with other pathogens, such as KSHV, can severely impact the small RNA repertoire, complicating the use of exosome miRNAs as biomarkers of disease. PMID- 29425229 TI - Schistosoma mansoni SmKI-1 serine protease inhibitor binds to elastase and impairs neutrophil function and inflammation. AB - Protease inhibitors have important function during homeostasis, inflammation and tissue injury. In this study, we described the role of Schistosoma mansoni SmKI-1 serine protease inhibitor in parasite development and as a molecule capable of regulating different models of inflammatory diseases. First, we determine that recombinant (r) SmKI-1 and its Kunitz domain but not the C-terminal region possess inhibitory activity against trypsin and neutrophil elastase (NE). To better understand the molecular basis of NE inhibition by SmKI-1, molecular docking studies were also conducted. Docking results suggest a complete blockage of NE active site by SmKI-1 Kunitz domain. Additionally, rSmKI-1 markedly inhibited the capacity of NE to kill schistosomes. In order to further investigate the role of SmKI-1 in the parasite, we designed specific siRNA to knockdown SmKI-1 in S. mansoni. SmKI-1 gene suppression in larval stage of S. mansoni robustly impact in parasite development in vitro and in vivo. To determine the ability of SmKI-1 to interfere with neutrophil migration and function, we tested SmKI-1 anti-inflammatory potential in different murine models of inflammatory diseases. Treatment with SmKI-1 rescued acetaminophen (APAP) mediated liver damage, with a significant reduction in both neutrophil recruitment and elastase activity. In the model of gout arthritis, this protein reduced neutrophil accumulation, IL-1beta secretion, hypernociception, and overall pathological score. Finally, we demonstrated the ability of SmKI-1 to inhibit early events that trigger neutrophil recruitment in pleural cavities of mice in response to carrageenan. In conclusion, SmKI-1 is a key protein in S. mansoni survival and it has the ability to inhibit neutrophil function as a promising therapeutic molecule against inflammatory diseases. PMID- 29425230 TI - Novel flowcytometry-based approach of malignant cell detection in body fluids using an automated hematology analyzer. AB - Morphological microscopic examinations of nucleated cells in body fluid (BF) samples are performed to screen malignancy. However, the morphological differentiation is time-consuming and labor-intensive. This study aimed to develop a new flowcytometry-based gating analysis mode "XN-BF gating algorithm" to detect malignant cells using an automated hematology analyzer, Sysmex XN-1000. XN-BF mode was equipped with WDF white blood cell (WBC) differential channel. We added two algorithms to the WDF channel: Rule 1 detects larger and clumped cell signals compared to the leukocytes, targeting the clustered malignant cells; Rule 2 detects middle sized mononuclear cells containing less granules than neutrophils with similar fluorescence signal to monocytes, targeting hematological malignant cells and solid tumor cells. BF samples that meet, at least, one rule were detected as malignant. To evaluate this novel gating algorithm, 92 various BF samples were collected. Manual microscopic differentiation with the May-Grunwald Giemsa stain and WBC count with hemocytometer were also performed. The performance of these three methods were evaluated by comparing with the cytological diagnosis. The XN-BF gating algorithm achieved sensitivity of 63.0% and specificity of 87.8% with 68.0% for positive predictive value and 85.1% for negative predictive value in detecting malignant cell positive samples. Manual microscopic WBC differentiation and WBC count demonstrated 70.4% and 66.7% of sensitivities, and 96.9% and 92.3% of specificities, respectively. The XN-BF gating algorithm can be a feasible tool in hematology laboratories for prompt screening of malignant cells in various BF samples. PMID- 29425231 TI - Structural and biochemical characterization of the biuret hydrolase (BiuH) from the cyanuric acid catabolism pathway of Rhizobium leguminasorum bv. viciae 3841. AB - Biuret deamination is an essential step in cyanuric acid mineralization. In the well-studied atrazine degrading bacterium Pseudomonas sp. strain ADP, the amidase AtzE catalyzes this step. However, Rhizobium leguminosarum bv. viciae 3841 uses an unrelated cysteine hydrolase, BiuH, instead. Herein, structures of BiuH, BiuH with bound inhibitor and variants of BiuH are reported. The substrate is bound in the active site by a hydrogen bonding network that imparts high substrate specificity. The structure of the inactive Cys175Ser BiuH variant with substrate bound in the active site revealed that an active site cysteine (Cys175), aspartic acid (Asp36) and lysine (Lys142) form a catalytic triad, which is consistent with biochemical studies of BiuH variants. Finally, molecular dynamics simulations highlighted the presence of three channels from the active site to the enzyme surface: a persistent tunnel gated by residues Val218 and Gln215 forming a potential substrate channel and two smaller channels formed by Val28 and a mobile loop (including residues Phe41, Tyr47 and Met51) that may serve as channels for co-product (ammonia) or co-substrate (water). PMID- 29425232 TI - Identification and characterization of influenza A viruses in selected domestic animals in Kenya, 2010-2012. AB - BACKGROUND: Influenza A virus subtypes in non-human hosts have not been characterized in Kenya. We carried out influenza surveillance in selected domestic animals and compared the virus isolates with isolates obtained in humans during the same period. METHODS: We collected nasal swabs from pigs, dogs and cats; oropharyngeal and cloacal swabs from poultry; and blood samples from all animals between 2010 and 2012. A standardized questionnaire was administered to farmers and traders. Swabs were tested for influenza A by rtRT-PCR, virus isolation and subtyping was done on all positive swabs. All sera were screened for influenza A antibodies by ELISA, and positives were evaluated by hemagglutination inhibition (HI). Full genome sequencing was done on four selected pig virus isolates. RESULTS: Among 3,798 sera tested by ELISA, influenza A seroprevalence was highest in pigs (15.9%; 172/1084), 1.2% (3/258) in ducks, 1.4% (1/72) in cats 0.6% (3/467) in dogs, 0.1% (2/1894) in chicken and 0% in geese and turkeys. HI testing of ELISA-positive pig sera showed that 71.5% had positive titers to A/California/04/2009(H1N1). Among 6,289 swabs tested by rRT PCR, influenza A prevalence was highest in ducks [1.2%; 5/423] and 0% in cats and turkeys. Eight virus isolates were obtained from pig nasal swabs collected in 2011 and were determined to be A(H1N1)pdm09 on subtyping. On phylogenetic analysis, four hemagglutinin segments from pig isolates clustered together and were closely associated with human influenza viruses that circulated in Kenya in 2011. CONCLUSION: Influenza A(H1N1)pdm09 isolated in pigs was genetically similar to contemporary human pandemic influenza virus isolates. This suggest that the virus was likely transmitted from humans to pigs, became established and circulated in Kenyan pig populations during the study period. Minimal influenza A prevalence was observed in the other animals studied. PMID- 29425233 TI - Introduction of a hydrolysis probe PCR assay for high-throughput screening of methicillin-resistant Staphylococcus aureus with the ability to include or exclude detection of Staphylococcus argenteus. AB - Many countries using sensitive screening methods for detection of carriage of methicillin-resistant Staphylococcus aureus (MRSA) have a sustained low incidence of MRSA infections. For diagnostic laboratories with high sample volumes, MRSA screening requires stability, low maintenance and high performance at a low cost. Herein we designed oligonucleotides for a new nuc targeted hydrolysis probe PCR to replace the standard in-house nuc SybrGreen PCR assay. This new, more time efficient, PCR assay resulted in a 40% increase in daily sample capacity, with maintained high specificity and sensitivity. The assay was also able to detect Staphylococcus aureus clonal cluster 75 (CC75) lineage strains, recently re classified as Staphylococcus argenteus, with a sensitivity considerably increased compared to our previous assay. While awaiting consensus if the CC75 lineage of S. aureus should be considered as S. argenteus, and whether methicillin-resistant S. argenteus should be included in the MRSA definition, many diagnostic laboratories need to update their MRSA assay sensitivity/specificity towards this lineage/species. The MRSA screening assay presented in this manuscript is comprised of nuc oligonucleotides separately targeting S. aureus and CC75 lineage strains/S. argenteus, thus providing high user flexibility for the detection of CC75 lineage strains/S. argenteus. PMID- 29425234 TI - Targeted liquid chromatography tandem mass spectrometry to quantitate wheat gluten using well-defined reference proteins. AB - Celiac disease (CD) is an inflammatory disorder of the upper small intestine caused by the ingestion of storage proteins (prolamins and glutelins) from wheat, barley, rye, and, in rare cases, oats. CD patients need to follow a gluten-free diet by consuming gluten-free products with gluten contents of less than 20 mg/kg. Currently, the recommended method for the quantitative determination of gluten is an enzyme-linked immunosorbent assay (ELISA) based on the R5 monoclonal antibody. Because the R5 ELISA mostly detects the prolamin fraction of gluten, a new independent method is required to detect prolamins as well as glutelins. This paper presents the development of a method to quantitate 16 wheat marker peptides derived from all wheat gluten protein types by liquid chromatography tandem mass spectrometry (LC-MS/MS) in the multiple reaction monitoring mode. The quantitation of each marker peptide in the chymotryptic digest of a defined amount of the respective reference wheat protein type resulted in peptide specific yields. This enabled the conversion of peptide into protein type concentrations. Gluten contents were expressed as sum of all determined protein type concentrations. This new method was applied to quantitate gluten in wheat starches and compared to R5 ELISA and gel-permeation high-performance liquid chromatography with fluorescence detection (GP-HPLC-FLD), which resulted in a strong correlation between LC-MS/MS and the other two methods. PMID- 29425236 TI - Correction: Variability and cost implications of three generations of the Roche LightCycler(r) 480. AB - [This corrects the article DOI: 10.1371/journal.pone.0190847.]. PMID- 29425235 TI - Evidence of chronic kidney disease in veterans with incident diabetes mellitus. AB - While chronic kidney disease (CKD) is regularly evaluated among patients with diabetes, kidney function may be significantly impaired before diabetes is diagnosed. Moreover, disparities in the severity of CKD in such a population are likely. This study evaluated the extent of CKD in a national cohort of 36,764 US veterans first diagnosed with diabetes between 2003 and 2013 and prior to initiating oral antidiabetic therapy. Evidence of CKD (any stage) at the time of diabetes diagnosis was determined using eGFR and urine-albumin-creatinine ratios, the odds of which were assessed using logistic regression controlling for patient characteristics. CKD was evident in 31.6% of veterans prior to being diagnosed with diabetes (age and gender standardized rates: 241.8 per 1,000 adults [overall] and 247.7 per 1,000 adult males), over half of whom had at least moderate kidney disease (stage 3 or higher). The odds of CKD tended to increase with age (OR: 1.88; 95% CI: 1.82-1.93), hemoglobin A1C (OR: 1.05; 95% CI: 1.04 1.06), systolic blood pressure (OR: 1.04; 95% CI: 1.027-1.043), and BMI (OR: 1.016; 95% CI: 1.011-1.020). Both Asian Americans (OR: 1.53; 95% CI: 1.15-2.04) and African Americans (OR: 1.11; 95% CI: 1.03-1.20) had higher adjusted odds of CKD compared to whites, and prevalence was highest in the Upper Midwest and parts of the Mid-South. Results suggest that evidence of CKD is common among veterans before a diabetes diagnosis, and certain populations throughout the country, such as minorities, may be afflicted at higher rates. PMID- 29425237 TI - Intragenic DNA methylation of PITX1 and the adjacent long non-coding RNA C5orf66 AS1 are prognostic biomarkers in patients with head and neck squamous cell carcinomas. AB - BACKGROUND: Patients with squamous cell cancer of the head and neck region (HNSCC) are at risk for disease recurrence and metastases, even after initial successful therapy. A tissue-based biomarker could be beneficial to guide treatment as well as post-treatment surveillance. Gene methylation status has been recently identified as powerful prognostic biomarker in HNSCC. We therefore evaluated the methylation status of the homeobox gene PITX1 and the adjacent long intergenic non-coding RNA (lincRNA) C5orf66-AS1 in publicly available datasets. METHODS: Gene methylation and expression data from 528 patients with HNSCC included in The Cancer Genome Atlas (TCGA, there obtained by using the Infinium HumanMethylation450 BeadChip Kit) were evaluated and methylation and expression levels of PITX1 and lincRNA C5orf66-AS1 was correlated with overall survival and other parameters. Thus, ten beads targeting PITX1 exon 3 and three beads targeting lincRNA C5orf66-AS1 were identified as significant candidates. The mean methylation of these beads was used for further correlation and the median was employed for dichotomization. RESULTS: Both PITX1 exon 3 and lincRNA C5orf66-AS1 were significantly higher methylated in tumor tissue than in normal adjacent tissue (NAT) (PITX1 exon 3: tumor tissue 58.1%, NAT: 31.7%, p<0.001; lincRNA C5orf66-AS1: tumor tissue: 27.4%, NAT: 18.9%, p<0.001). In a univariate analysis, hypermethylation of both loci was significantly associated with the risk of death (univariate: exon 3: Hazard ratio (HR): 4.97 [1.78-16.71], p = 0.010, lincRNA C5orf66-AS1: Hazard ratio (HR): 12.23 [3.01-49.74], p<0.001). PITX1 exon 3 and lincRNA C5orf66-AS1 methylation was also significantly correlated with tumor localization, T category, human papilloma virus (HPV)-negative and p16-negative tumors and tumor grade. Kaplan-Meier analysis showed, that lincRNA C5orf66-AS1 hypomethylation was significantly associated with overall survival (p = 0.001) in the entire cohort as well in a subgroup of HPV-negative tumors (p = 0.003) and in patients with laryngeal tumors (p = 0.022). CONCLUSION: Methylation status of PITX1 and even more so of lincRNA C5orf66-AS1 is a promising prognostic biomarker in HNSCC, in particular for HPV-negative patients. Further prospective evaluation is warranted. PMID- 29425238 TI - Host-parasite co-metabolic activation of antitrypanosomal aminomethyl benzoxaboroles. AB - Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in Trypanosoma brucei. We describe an oxidative enzymatic pathway composed of host semicarbazide sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds. PMID- 29425239 TI - Magnolol-mediated regulation of plasma triglyceride through affecting lipoprotein lipase activity in apolipoprotein A5 knock-in mice. AB - Hyperlipidemia is a risk factor of arteriosclerosis, stroke, and other coronary heart disease, which has been shown to correlate with single nucleotide polymorphisms of genes essential for lipid metabolism, such as lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5). In this study, the effect of magnolol, the main active component extracted from Magnolia officinalis, on LPL activity was investigated. A dose-dependent up-regulation of LPL activity, possibly through increasing LPL mRNA transcription, was observed in mouse 3T3-L1 pre-adipocytes cultured in the presence of magnolol for 6 days. Subsequently, a transgenic knock in mice carrying APOA5 c.553G>T variant was established and then fed with corn oil with or without magnolol for four days. The baseline plasma triglyceride levels in transgenic knock-in mice were higher than those in wild-type mice, with the highest increase occurred in homozygous transgenic mice (106 mg/dL vs 51 mg/dL, p<0.01). After the induction of hyperglyceridemia along with the administration of magnolol, the plasma triglyceride level in heterozygous transgenic mice was significantly reduced by half. In summary, magnolol could effectively lower the plasma triglyceride levels in APOA5 c.553G>T variant carrier mice and facilitate the triglyceride metabolism in postprandial hypertriglyceridemia. PMID- 29425240 TI - Correction: The paradox of HBV evolution as revealed from a 16th century mummy. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006750.]. PMID- 29425241 TI - A quick aphasia battery for efficient, reliable, and multidimensional assessment of language function. AB - This paper describes a quick aphasia battery (QAB) that aims to provide a reliable and multidimensional assessment of language function in about a quarter of an hour, bridging the gap between comprehensive batteries that are time consuming to administer, and rapid screening instruments that provide limited detail regarding individual profiles of deficits. The QAB is made up of eight subtests, each comprising sets of items that probe different language domains, vary in difficulty, and are scored with a graded system to maximize the informativeness of each item. From the eight subtests, eight summary measures are derived, which constitute a multidimensional profile of language function, quantifying strengths and weaknesses across core language domains. The QAB was administered to 28 individuals with acute stroke and aphasia, 25 individuals with acute stroke but no aphasia, 16 individuals with chronic post-stroke aphasia, and 14 healthy controls. The patients with chronic post-stroke aphasia were tested 3 times each and scored independently by 2 raters to establish test-retest and inter-rater reliability. The Western Aphasia Battery (WAB) was also administered to these patients to assess concurrent validity. We found that all QAB summary measures were sensitive to aphasic deficits in the two groups with aphasia. All measures showed good or excellent test-retest reliability (overall summary measure: intraclass correlation coefficient (ICC) = 0.98), and excellent inter rater reliability (overall summary measure: ICC = 0.99). Sensitivity and specificity for diagnosis of aphasia (relative to clinical impression) were 0.91 and 0.95 respectively. All QAB measures were highly correlated with corresponding WAB measures where available. Individual patients showed distinct profiles of spared and impaired function across different language domains. In sum, the QAB efficiently and reliably characterized individual profiles of language deficits. PMID- 29425242 TI - Generation of a monoclonal antibody recognizing the heavily glycosylated CD45 protein and its application on identifying circulating tumor cells. AB - Here, we provide direct evidence that using recombinant proteins expressed in eukaryotic cells as antigen is a practical way to generate monoclonal antibodies (mAbs) against heavily glycosylated proteins. Heavily glycosylated proteins are typically difficult targets for mAb generation, being limited by unsatisfactory affinity and low specificity. Using the heavily glycosylated CD45 protein as an example, we demonstrate the entire process of expressing the protein in eukaryotic cells and using it as an antigen to generate CD45-targeting mAbs in mice. The mAbs generated showed robust affinity and specificity, which are crucial factors for differentiate circulating tumor cells from white blood cells in human breast cancer patient samples. Only 1 cell fusion and 2 cyclic sub cloning steps were necessary before mAbs with satisfactory performance were obtained. PMID- 29425243 TI - An extended car-following model at un-signalized intersections under V2V communication environment. AB - An extended car-following model is proposed in this paper to analyze the impacts of V2V (vehicle to vehicle) communication on the micro driving behavior at the un signalized intersection. A four-leg un-signalized intersection with twelve streams (left-turn, through movement, and right turn from each leg) is used. The effect of the guidance strategy on the reduction of the rate of stops and total delay is explored by comparing the proposed model and the traditional FVD car following model. The numerical results illustrate that potential conflicts between vehicles can be predicted and some stops can be avoided by decelerating in advance. The driving comfort and traffic efficiency can be improved accordingly. More benefits could be obtained under the long communication range, low to medium traffic density, and simple traffic pattern conditions. PMID- 29425244 TI - Initiation, extension, and termination of RNA synthesis by a paramyxovirus polymerase. AB - Paramyxoviruses represent a family of RNA viruses causing significant human diseases. These include measles virus, the most infectious virus ever reported, in addition to parainfluenza virus, and other emerging viruses. Paramyxoviruses likely share common replication machinery but their mechanisms of RNA biosynthesis activities and details of their complex polymerase structures are unknown. Mechanistic and functional details of a paramyxovirus polymerase would have sweeping implications for understanding RNA virus replication and for the development of new antiviral medicines. To study paramyxovirus polymerase structure and function, we expressed an active recombinant Nipah virus (NiV) polymerase complex assembled from the multifunctional NiV L protein bound to its phosphoprotein cofactor. NiV is an emerging highly pathogenic virus that causes severe encephalitis and has been declared a global public health concern due to its high mortality rate. Using negative-stain electron microscopy, we demonstrated NiV polymerase forms ring-like particles resembling related RNA polymerases. We identified conserved sequence elements driving recognition of the 3'-terminal genomic promoter by NiV polymerase, and leading to initiation of RNA synthesis, primer extension, and transition to elongation mode. Polyadenylation resulting from NiV polymerase stuttering provides a mechanistic basis for transcription termination. It also suggests a divergent adaptation in promoter recognition between pneumo- and paramyxoviruses. The lack of available antiviral therapy for NiV prompted us to identify the triphosphate forms of R1479 and GS 5734, two clinically relevant nucleotide analogs, as substrates and inhibitors of NiV polymerase activity by delayed chain termination. Overall, these findings provide low-resolution structural details and the mechanism of an RNA polymerase from a previously uncharacterized virus family. This work illustrates important functional differences yet remarkable similarities between the polymerases of nonsegmented negative-strand RNA viruses. PMID- 29425246 TI - Concurrent credit portfolio losses. AB - We consider the problem of concurrent portfolio losses in two non-overlapping credit portfolios. In order to explore the full statistical dependence structure of such portfolio losses, we estimate their empirical pairwise copulas. Instead of a Gaussian dependence, we typically find a strong asymmetry in the copulas. Concurrent large portfolio losses are much more likely than small ones. Studying the dependences of these losses as a function of portfolio size, we moreover reveal that not only large portfolios of thousands of contracts, but also medium sized and small ones with only a few dozens of contracts exhibit notable portfolio loss correlations. Anticipated idiosyncratic effects turn out to be negligible. These are troublesome insights not only for investors in structured fixed-income products, but particularly for the stability of the financial sector. JEL codes: C32, F34, G21, G32, H81. PMID- 29425245 TI - Unique pharmacological properties of serotoninergic G-protein coupled receptors from cestodes. AB - BACKGROUND: Cestodes are a diverse group of parasites, some of them being agents of neglected diseases. In cestodes, little is known about the functional properties of G protein coupled receptors (GPCRs) which have proved to be highly druggable targets in other organisms. Notably, serotoninergic G-protein coupled receptors (5-HT GPCRs) play major roles in key functions like movement, development and reproduction in parasites. METHODOLOGY/PRINCIPAL FINDINGS: Three 5-HT GPCRs from Echinococcus granulosus and Mesocestoides corti were cloned, sequenced, bioinformatically analyzed and functionally characterized. Multiple sequence alignment with other GPCRs showed the presence of seven transmembrane segments and conserved motifs but interesting differences were also observed. Phylogenetic analysis grouped these new sequences within the 5-HT7 clade of GPCRs. Molecular modeling showed a striking resemblance in the spatial localization of key residues with their mammalian counterparts. Expression analysis using available RNAseq data showed that both E. granulosus sequences are expressed in larval and adult stages. Localization studies performed in E. granulosus larvae with a fluorescent probe produced a punctiform pattern concentrated in suckers. E. granulosus and M. corti larvae showed an increase in motility in response to serotonin. Heterologous expression revealed elevated levels of cAMP production in response to 5-HT and two of the GPCRs showed extremely high sensitivity to 5-HT (picomolar range). While each of these GPCRs was activated by 5-HT, they exhibit distinct pharmacological properties (5-HT sensitivity, differential responsiveness to ligands). CONCLUSIONS/SIGNIFICANCE: These data provide the first functional report of GPCRs in parasitic cestodes. The serotoninergic GPCRs characterized here may represent novel druggable targets for antiparasitic intervention. PMID- 29425247 TI - NetMiner-an ensemble pipeline for building genome-wide and high-quality gene co expression network using massive-scale RNA-seq samples. AB - Accurately reconstructing gene co-expression network is of great importance for uncovering the genetic architecture underlying complex and various phenotypes. The recent availability of high-throughput RNA-seq sequencing has made genome wide detecting and quantifying of the novel, rare and low-abundance transcripts practical. However, its potential merits in reconstructing gene co-expression network have still not been well explored. Using massive-scale RNA-seq samples, we have designed an ensemble pipeline, called NetMiner, for building genome-scale and high-quality Gene Co-expression Network (GCN) by integrating three frequently used inference algorithms. We constructed a RNA-seq-based GCN in one species of monocot rice. The quality of network obtained by our method was verified and evaluated by the curated gene functional association data sets, which obviously outperformed each single method. In addition, the powerful capability of network for associating genes with functions and agronomic traits was shown by enrichment analysis and case studies. In particular, we demonstrated the potential value of our proposed method to predict the biological roles of unknown protein-coding genes, long non-coding RNA (lncRNA) genes and circular RNA (circRNA) genes. Our results provided a valuable and highly reliable data source to select key candidate genes for subsequent experimental validation. To facilitate identification of novel genes regulating important biological processes and phenotypes in other plants or animals, we have published the source code of NetMiner, making it freely available at https://github.com/czllab/NetMiner. PMID- 29425248 TI - Electrooculography-based continuous eye-writing recognition system for efficient assistive communication systems. AB - Human-computer interface systems whose input is based on eye movements can serve as a means of communication for patients with locked-in syndrome. Eye-writing is one such system; users can input characters by moving their eyes to follow the lines of the strokes corresponding to characters. Although this input method makes it easy for patients to get started because of their familiarity with handwriting, existing eye-writing systems suffer from slow input rates because they require a pause between input characters to simplify the automatic recognition process. In this paper, we propose a continuous eye-writing recognition system that achieves a rapid input rate because it accepts characters eye-written continuously, with no pauses. For recognition purposes, the proposed system first detects eye movements using electrooculography (EOG), and then a hidden Markov model (HMM) is applied to model the EOG signals and recognize the eye-written characters. Additionally, this paper investigates an EOG adaptation that uses a deep neural network (DNN)-based HMM. Experiments with six participants showed an average input speed of 27.9 character/min using Japanese Katakana as the input target characters. A Katakana character-recognition error rate of only 5.0% was achieved using 13.8 minutes of adaptation data. PMID- 29425249 TI - Impact and cost-effectiveness of different vaccination strategies to reduce the burden of pneumococcal disease among elderly in the Netherlands. AB - BACKGROUND: Streptococcus pneumoniae causes morbidity and mortality among all ages in The Netherlands. To reduce this burden, infants in The Netherlands receive the 10-valent pneumococcal conjugated vaccine (PCV10), but older persons are not targeted. We assessed the impact and cost-effectiveness of vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23) or 13-valent PCV (PCV13) among all those aged 60, 65 or 70 and/or in combination with replacing PCV10 with PCV13 in the infant vaccination programme. METHODS: A static cost effectiveness model was parameterized including projected trends for invasive pneumococcal disease (IPD) and hospitalised community acquired pneumonia (CAP). The different strategies were evaluated using vaccine list prices and a 10-year time horizon. Incremental cost-effectiveness ratios (ICER) were calculated with the current strategy (infant vaccination program with PCV10) as reference. RESULTS: Compared to the reference, the largest impact on pneumococcal disease burden was projected with a combined use of PCV13 among infants and PPV23 at 60, 65 and 70 years, preventing 1,635 cases of IPD and 914 cases of CAP. The most cost-effective strategy was vaccinating with PPV23 at 70 years only with similar low ICERs at age 60 and 65. The impact of the use of PCV13 among infants depends strongly on the projected herd-immunity effect on serotype 19A. Vaccinating elderly with either PCV13 or PPV23 was dominated by PPV23 in all investigated scenarios, mainly due to the lower price of PPV23. CONCLUSION: Under the current assumptions, the best value for money is the use of PPV23 for elderly, with a single dose or at five year increment between age 60 to age 70. PMID- 29425251 TI - Is oxygen availability a limiting factor for in vitro folliculogenesis? AB - Transplantation of ovarian tissue for the preservation of fertility in oncological patients is becoming an accepted clinical practice. However, the risk of re-introducing tumour cells at transplantation has stirred an increased interest for complete in vitro folliculogenesis. This has not yet been achieved in humans possibly for the lack of knowledge on the environmental milieu that orchestrates folliculogenesis in vivo. The main aim of this study was to investigate the effect of oxygen availability on follicle health and growth during in vitro culture of ovarian tissue strips. To this end, a model was developed to predict the dissolved oxygen concentration in tissue under varying culture conditions. Ovarian cortical strips of bovine, adopted as an animal model, and human tissue were cultured in conventional (CD) and gas permeable (PD) dishes under different media column heights and gaseous oxygen tensions for 3, 6 and 9 days. Follicle quality, activation of primordial follicles to the primary stage, and progression to the secondary stage were analysed through histology. Follicle viability was assessed through a live-dead assay at the confocal scanning laser microscope. Findings showed a higher follicle quality and viability after culture of bovine ovarian strips in PD in adequate medium height and oxygen tensions. The best culture conditions found in the bovine were adopted for human ovarian strip culture and promoted a higher follicle quality, viability and progression. Overall, data demonstrated that modulation of oxygen availability in tissue plays a key role in maintaining follicles' health and their ability to survive and progress to the secondary stage during ovarian tissue in vitro culture. Such culture conditions could increase the yield of healthy secondary follicles for subsequent dissection and individual culture to obtain competent oocytes. PMID- 29425250 TI - 25-hydroxyvitamin D, influenza vaccine response and healthcare encounters among a young adult population. AB - BACKGROUND: Influenza causes significant morbidity and mortality; the pandemic in 2009-2010 was a reminder of the potential for novel strains and antigenic changes. Studies have shown that vitamin D deficiency may be associated with poor vaccine immunogenicity, therefore we sought to determine if there was a correlation between 25-hydroxyvitamin D [25(OH)D] and influenza vaccine response. METHODS: A retrospective observational study was conducted among young, healthy military members to evaluate the association between total 25(OH)D levels with post influenza vaccination antibody titers and healthcare encounters during the 2009-10 influenza season. Univariate analyses were performed to evaluate whether 25(OH)D levels are associated with baseline characteristics and post-vaccination antibody responses. Multivariable logistic regression models were utilized to determine the associations between antibody responses and 25(OH)D levels adjusting for possible confounders. RESULTS: A total of 437 subjects were studied. Most participants were young adults (91% were 18-39 years of age), 50% were male, and 56% resided in the southern U.S. Overall, 152 (34.8%) were vitamin D deficient, 167 (38.2%) insufficient, and 118 (27.0%) with normal 25(OH)D levels. There were no demographic differences by 25(OH)D category. Only 224 (51.3%) demonstrated a seroprotective anti-influenza post-vaccination titer, which did not vary by categorical 25(OH)D levels [vitamin D deficient vs. normal: OR 1.10 (0.68-1.78) and insufficient vs. normal: OR 1.25 (0.78-2.01)] or continuous vitamin D levels [OR 0.98 (0.84-1.15)]. There were also no associations with increased influenza like illnesses, respiratory diagnoses and healthcare encounters between the vitamin D groups. CONCLUSION: Vitamin D insufficiency and deficiency were highly prevalent despite evaluating a young, healthy adult population. There were no significant associations between 25(OH)D levels and post-vaccination antibody titers to influenza vaccine. Further studies are required to discover strategies to improve vaccine efficacy as well as to determine the role of 25(OH)D in vaccine immunity. PMID- 29425252 TI - Difference between beta1-adrenoceptor autoantibodies of human and animal origin Limitations detecting beta1-adrenoceptor autoantibodies using peptide based ELISA technology. AB - Cell-based analytics for the detection of the beta1-adrenoceptor autoantibody (beta1-AAB) are functional, yet difficult to handle, and should be replaced by easily applicable, routine lab methods. Endeavors to develop solid-phase-based assays such as ELISA to exploit epitope moieties for trapping autoantibodies are ongoing. These solid-phase-based assays, however, are often unreliable when used with human patient material, in contrast to animal derived autoantibodies. We therefore tested an immunogen peptide-based ELISA for the detection of beta1-AAB, and compared commercially available goat antibodies against the 2nd extracellular loop of human beta1-adrenoceptor (ADRB1-AB) to autoantibodies enriched from patient material. The functionality of these autoantibodies was tested in a cell based assay for comparison and their structural appearance was investigated using 2D gel electrophoresis. The ELISA showed a limit of detection for ADRB1-AB of about 1.5 nmol antibody/L when spiked in human control serum and only about 25 nmol/L when spiked in species identical (goat) matrix material. When applied to samples of human origin, the ELISA failed to identify the specific beta1-AABs. A low concentration of beta1-AAB, together with structural inconsistency of the patient originated samples as seen from the 2D Gel appearance, might contribute to the failure of the peptide based ELISA technology to detect human beta1-AABs. PMID- 29425253 TI - The KCa3.1 blocker TRAM34 reverses renal damage in a mouse model of established diabetic nephropathy. AB - Despite optimal control of hyperglycaemia, hypertension, and dyslipidaemia, the number of patients with diabetic nephropathy (DN) continues to grow. Strategies to target various signaling pathways to prevent DN have been intensively investigated in animal models and many have been proved to be promising. However, targeting these pathways once kidney disease is established, remain unsatisfactory. The clinical scenario is that patients with diabetes mellitus often present with established kidney damage and need effective treatments to repair and reverse the kidney damage. In this studies, eNOS-/- mice were administered with streptozotocin to induce diabetes. At 24 weeks, at which time we have previously demonstrated albuminuria and pathological changes of diabetic nephropathy, mice were randomised to receive TRAM34 subcutaneously, a highly selective inhibitor of potassium channel KCa3.1 or DMSO (vehicle) for a further 14 weeks. Albuminuria was assessed, inflammatory markers (CD68, F4/80) and extracellular matrix deposition (type I collagen and fibronectin) in the kidneys were examined. The results clearly demonstrate that TRAM34 reduced albuminuria, decreased inflammatory markers and reversed extracellular matrix deposition in kidneys via inhibition of the TGF-beta1 signaling pathway. These results indicate that KCa3.1 blockade effectively reverses established diabetic nephropathy in this rodent model and provides a basis for progressing to human studies. PMID- 29425255 TI - Response to Lea et al.'s developmental plasticity: Bridging research in evolution and human health. PMID- 29425254 TI - Conservation and lineage-specific rearrangements in the GOBP/PBP gene complex of distantly related ditrysian Lepidoptera. AB - General odorant binding proteins (GOBPs) and pheromone binding proteins (PBPs) form a monophyletic subfamily of insect odorant binding proteins (OBPs) specific for Lepidoptera, butterflies and moths. The GOBP/PBP genes include six subgroups (GOBP1-2, PBP-A-D) previously reported to form a complex arrayed in a conserved order in representative moths (superfamily Bombycoidea) and butterflies (Nymphalidae). Although our knowledge of lepidopteran genomes has increased greatly recently, the structure of the GOBP/PBP complex has been studied only for species that represent limited lineages of the highly diverged Ditrysia. To understand the evolution of this functionally important gene complex, we determined 69-149 kb genomic sequences that include GOBP2 and five PBP genes in three Ostrinia moths (Pyraloidea), O. nubilalis, O. furnacalis, and O. latipennis, using bacterial artificial chromosome (BAC) and fosmid clones. The structure of the GOBP2/PBP gene cluster was well conserved despite the different sex pheromone composition utilized by the three moths. Five expressed PBP genes in Ostrinia moths were the result of two duplications of PBP-A genes. Surprisingly, an allele containing a fusion gene between tandemly arrayed PBP-A genes was observed in O. nubilalis. We also revealed duplication and intra chromosomal translocation of the GOBP1 gene in P. xylostella by fluorescence in situ hybridization (FISH) analysis. Additionally, we compared the structure of the GOBP/PBP gene complex of seventeen species covering six superfamilies and twelve families of the lepidopteran clade, Ditrysia, and found the gene order was basically conserved despite the frequent occurrence of lineage-specific gains, losses, inversions and translocations of these genes, compared with their neighboring genes. Our findings support the hypothesis that the structure of the GOBP/PBP gene complex was already established in the common ancestor of Ditrysia. PMID- 29425256 TI - Dihydromyricetin improves type 2 diabetes-induced cognitive impairment via suppressing oxidative stress and enhancing brain-derived neurotrophic factor mediated neuroprotection in mice. AB - Type 2 diabetes mellitus (T2DM) leads to cognitive impairment (CI), but there have been no effective pharmacotherapies or drugs for cognitive dysfunction in T2DM. Dihydromyricetin (DHM) is a natural flavonoid compound extracted from the leaves of Ampelopsis grossedentata and has various pharmacological effects including anti-oxidant and anti-diabetes. Thus, we investigated the effects of DHM on CI in T2DM mouse model and its possible mechanism. To induce T2DM, mice were fed with high-sugar and high-fat diet for 8 weeks, followed by a low dose streptozotocin (STZ) administration. After the successful induction of T2DM mouse model, mice were treated respectively with equal volume of saline (T2DM group), 125 mg/kg/d DHM (L-DHM group), or 250 mg/kg/d DHM (H-DHM group). After 16 weeks of DHM administration, the body weight (BW), fasting blood glucose, blood lipids, intraperitoneal glucose tolerance (IPGT), and cognitive function were determined. Then, alterations in the expressions of oxidative stress markers and brain derived neurotrophic factor (BDNF) in the hippocampus were investigated. Our findings demonstrated that DHM could significantly ameliorate CI and reverse aberrant glucose and lipid metabolism in T2DM mice, likely through the suppression of oxidative stress and enhancement of BDNF-mediated neuroprotection. In conclusion, our results suggest that DHM is a promising candidate for the treatment of T2DM-induced cognitive dysfunction. PMID- 29425257 TI - Serum Prostate-Specific Antigen (PSA) Concentration, PSA Mass, and Obesity: A Mathematical Analysis. AB - Objectives: To provide a mathematical background for understanding the phenomenon of analyte hemodilution using a kinetic analysis. Methods: The first assumption for this analysis is that change in concentration of any analyte, such as prostate-specific antigen (PSA), is due to the flux of the analyte from an organ into the blood minus its flux from the blood. What results is a relatively simple differential equation that emphasizes the importance of plasma volume, organ mass, and two rate constants. Results: The analyses demonstrate how serum PSA can be affected by plasma volume as well as body mass and how hemodilution due to obesity can be at least partly corrected for by expressing PSA in units of total mass or total mass density. Conclusions: At a time when obesity is prevalent, expressing analytes in units of total mass may make them relate more closely to disease status and prognosis. PMID- 29425258 TI - Expression of Programmed Death Ligand 1 (PD-L1) in Posttreatment Primary Inflammatory Breast Cancers and Clinical Implications. AB - Objectives: Inflammatory breast carcinoma (IBC) is rare but is the most lethal type of breast cancer. Programmed death ligand 1 (PD-L1) expression in IBCs has been understudied. Methods: In this study, tissue microarrays of 68 IBCs were immunostained with a PD-L1 antibody using an antibody clone (28-8) and detection system approved by the US Food and Drug Administration for selecting patients with non-small cell lung cancer and melanoma for anti-PD-L1 therapy. Results: Positive PD-L1 expression was found in 25 (36.8%) of 68 samples but was not significantly associated with the clinicopathologic variables examined. Univariate analysis of overall survival (OS) revealed that worse OS was significantly associated with positive PD-L1, negative estrogen receptor, and triple-negative status. The 5-year OS rate was 36.4% for patients with PD-L1 positive IBC and 47.3% for those with PD-L1-negative IBC. In multivariate analyses, PD-L1 status remained a statistically independent predictor of OS. Conclusions: These findings indicate that PD-L1 inhibitors could potentially improve the clinical outcome of patients with PD-L1-positive IBC. PMID- 29425259 TI - Repeating Critical Hematology and Coagulation Values Wastes Resources, Lengthens Turnaround Time, and Delays Clinical Action. AB - Objectives: To determine the need and impact of repeating critical values in hematology and coagulation. Methods: We prospectively evaluated the need for repeating critical values. The cost of this practice was estimated using a workflow analysis. Retrospective chart review before and after removal of this process was performed to assess the clinical impact of removing this practice. Results: Over 95% of the repeated values remained critical and all but one of the repeats were within the expected analytical precision of the assays. The practice of repeating critical values delayed turnaround time for these results and wasted resources, most notably manpower. The delay associated with repeating hematology critical values resulted in delayed administration of blood product (RBC units). Conclusions: Repeating critical hematology and coagulation results was found to be an unnecessary process that wasted laboratory resources and lengthened turnaround time, delaying clinical intervention. PMID- 29425260 TI - Systematic Review of Non-ASCP Choosing Wisely Recommendations Relevant to Pathology and Laboratory Medicine. AB - Objectives: To determine non-American Society for Clinical Pathology pathology- and laboratory-related Choosing Wisely recommendations that drive effective test utilization in the laboratory. Methods: Data were collected via a two-part web based survey distributed to a broad sample of pathologists and laboratory professionals from a variety of institutions. Results: Pathologists' most relevant recommendation: "Do not transfuse more units of blood than absolutely necessary"; highest priority: "Do not transfuse more than the minimum number of RBC units necessary to relieve symptoms of anemia or to return a patient to a safe hemoglobin range (7-8 g/dL in stable, noncardiac inpatients)." Laboratory professionals' most relevant recommendation: "Avoid testing for a Clostridium difficile infection in the absence of diarrhea"; highest priority: "Do not routinely transfuse stable, asymptomatic hospitalized patients with a hemoglobin level greater than 7 to 8 g/dL." Conclusions: Most of the highest priority, most relevant recommendations among those surveyed concerned utilization of blood products and transfusion management. PMID- 29425261 TI - Timing of seed dispersal and seed dormancy in Brazilian savanna: two solutions to face seasonality. AB - Background and Aims : The relationship between fruiting phenology and seed dispersal syndrome is widely recognized; however, the interaction of dormancy classes and plant life-history traits in relation to fruiting phenology and seed dispersal is understudied. Here we examined the relationship between fruiting season and seed dormancy and how this relationship is modulated by dormancy classes, dispersal syndromes, seed mass and seed moisture content in a Brazilian savanna (cerrado). Methods : Dormancy classes (non-dormancy and physical, morphological, morphophysiological, physiological and physiophysical dormancy) of 34 cerrado species were experimentally determined. Their seed dispersal syndrome (autochory, anemochory, zoochory), dispersal season (rainy, dry, rainy-to-dry and dry-to-rainy transitions), seed mass and moisture contents, and the estimated germination date were also determined. Log-linear models were used to evaluate how dormancy and dormancy classes are related to dispersal season and syndrome. Key Results : The proportions of dormant and non-dormant species were similar in cerrado. The community-estimated germination date was seasonal, occurring at the onset of rainy season. Overall, anemochorous non-dormant species released seeds during the dry-to-rainy transition; autochorous physically dormant species dispersed seeds during the dry season and rainy-to-dry transition; zoochorous species dispersed non-dormant seeds during the dry and rainy seasons, while species with morphological, morphophysiological or physiological dormancy dispersed seeds in the transitional seasons. Seed mass differed among dispersal seasons and dormancy classes, but seed moisture content did not vary with dispersal syndrome, season or dormancy class. Conclusions : The beginning of the rainy season was the most favourable period for seed germination in cerrado, and the germination phenology was controlled by both the timing of seed dispersal and seed dormancy. Dormancy class was influenced by dispersal syndrome and season. Moreover, dormancy avoided seed germination during the rainy-to-dry transition, independently of dispersal syndrome. The variability of dormancy classes with dispersal syndrome allowed animal-dispersed species to fruit all year round, but seeds germinated only during the rainy season. Conversely, seasonally restricted wind-dispersal species dispersed and germinated their non-dormant seeds only in the rainy season. PMID- 29425262 TI - Application of a Fast Separation Method for Anti-diabetics in Pharmaceuticals Using Monolithic Column: Comparative Study With Silica Based C-18 Particle Packed Column. AB - Run time is a predominant factor in HPLC for quality control laboratories especially if there is large number of samples have to be analyzed. Working at high flow rates cannot be attained with silica based particle packed column due to elevated backpressure issues. The use of monolithic column as an alternative to traditional C-18 column was tested for fast separation of pharmaceuticals, where the results were very competitive. The performance comparison of both columns was tested for separation of anti-diabetic combination containing Metformin, Pioglitazone and Glimepiride using Gliclazide as an internal standard. Working at high flow rates with less significant backpressure was obtained with the monolithic column where the run time was reduced from 6 min in traditional column to only 1 min in monolithic column with accepted resolution. The structure of the monolith contains many pores which can adapt the high flow rate of the mobile phase. Moreover, peak symmetry and equilibration time were more efficient with monolithic column. PMID- 29425263 TI - Determinants of Optogenetic Cortical Spreading Depolarizations. AB - Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP). Focal illumination (470 nm, 1-10 mW) through intact skull using an optical fiber evokes power-dependent steady extracellular potential shifts and local elevations of extracellular [K+] that culminate in an SD when power exceeds a threshold. Using the model, we show that homozygous mice are significantly more susceptible to SD (i.e., lower light thresholds) than heterozygous ChR2 mice. Moreover, we show SD susceptibility differs significantly among cortical divisions (motor, whisker barrel, sensory, visual, in decreasing order of susceptibility), which correlates with relative channelrhodopsin-2 expression. Furthermore, the NMDA receptor antagonist MK-801 blocks the transition to SD without diminishing extracellular potential shifts. Altogether, our data show that the optogenetic SD model is highly suitable for examining physiological or pharmacological modulation of SD in acute and longitudinal studies. PMID- 29425264 TI - Reply to Suzuki and Saito. PMID- 29425265 TI - Assessment of Multiple Solvents for Extraction and Direct GC-MS Determination of the Phytochemical Inventory of Sansevieria Extrafoliar Nectar Droplets. AB - Considerable effort has been devoted to analytical determinations of sugar and amino acid constituents of plant nectars, with the primary aim of understanding their ecological roles, yet few studies have reported more exhaustive organic compound inventories of plant nectars or extrafoliar nectars. This work evaluated the efficacy of four solvents (ethyl acetate, dichloromethane, toluene and hexane) to extract the greatest number of organic compound classes and unique compounds from extrafoliar nectar drops produced by Sansevieria spp. Aggregation of the results from each solvent revealed that 240 unique compounds were extracted in total, with 42.5% of those detected in multiple extracts. Aliphatic hydrocarbons dominated in all but the ethyl acetate extracts, with 44 unique aliphatic hydrocarbons detected in dichloromethane (DCM) extracts, followed by 41, 19 and 8 in hexane, toluene and ethyl acetate extracts, respectively. Hexane extracted the most unique compounds (79), followed by DCM (73), ethyl acetate (56) and toluene (32). Integrated total ion chromatographic peak areas of extracted compound classes were positively correlated with numbers of unique compounds detected within those classes. In addition to demonstrating that multi solvent extraction with direct GC-MS detection is a suitable analytical approach for determining secondary nectar constituents, to the best of our knowledge, this study also represents: (i) the first attempt to inventory the secondary phytochemical constituents of Sansevieria spp. extrafoliar nectar secretions and (ii) the largest organic solvent extractable compound inventory reported for any plant matrix to date. PMID- 29425266 TI - Lipophilicity of New Anticancer 1,6- and 3,6-diazaphenothiazines by of Use RP TLC and Different Computational Methods. AB - The lipophilicity of new two series of anticancer active 10-substituted 1,6- and 3,6-diazaphenothiazines has been investigated using reversed-phase thin-layer chromatography. Their lipophilicity (RM0 and log PTLC) was determined with mixtures of acetone and Tris buffer as mobile phases. The relative lipophilicity parameter RM0 and specific hydrophobic surface area b were significantly intercorrelated showing congeneric classes of diazaphenothiazines. The parameter RM0 was transformed into parameter log PTLC by use of the calibration curve. The parameter log PTLC was compared with computationally calculated lipophilic parameters log Pcalcd. The lipophilicity was discussed with the structure elements and was correlated with molecular descriptors, ADME properties and in vitro anticancer activities. PMID- 29425267 TI - Global White Matter Diffusion Characteristics Predict Longitudinal Cognitive Change Independently of Amyloid Status in Clinically Normal Older Adults. AB - White matter degradation has been proposed as one possible explanation for age related cognitive decline. In the present study, we examined 2 main questions: 1) Do diffusion characteristics predict longitudinal change in cognition independently or synergistically with amyloid status? 2) Are the effects of diffusion characteristics on longitudinal cognitive change tract-specific or global in nature? Cognitive domains of executive function, episodic memory, and processing speed were measured annually (mean follow-up = 3.93 +/- 1.25 years). Diffusion tensor imaging and Pittsburgh Compound-B positron emission tomography were performed at baseline in 265 clinically normal older adults (aged 63-90). Tract-specific diffusion was measured as the mean fractional anisotropy (FA) for 9 major white matter tracts. Global diffusion was measured as the mean FA across the 9 white matter tracts. Linear mixed models demonstrated independent, rather than synergistic, effects of global FA and amyloid status on cognitive decline. After controlling for amyloid status, lower global FA was associated with worse longitudinal performance in episodic memory and processing speed, but not executive function. After accounting for global FA, none of the individual tracts predicted a significant change in cognitive performance. These findings suggest that global, rather than tract-specific, diffusion characteristics predict longitudinal cognitive decline independently of amyloid status. PMID- 29425268 TI - Prenatal Stress, Mood, and Gray Matter Volume in Young Adulthood. AB - This study aimed to determine whether prenatal stress, measured by the number of stressful life events during the first 20 weeks of pregnancy, might relate to mood dysregulation and altered brain structure in young adulthood. Participants included 93 young adults from a community-based birth cohort from the Czech Republic. Information on prenatal stress exposure was collected from their mothers in 1990-1992. Magnetic resonance imaging (MRI) and mood-related data were collected from the young adults in 2015. MRI analyses focused on overall gray matter (GM) volume and GM volume of cortical regions previously associated with major depression. Higher prenatal stress predicted more mood dysregulation, lower overall GM volume, and lower GM volume in mid-dorsolateral frontal cortex, anterior cingulate cortex, and precuneus in young adulthood. We observed no prenatal stress by sex interactions for any of the relations. We conclude that prenatal stress is an important risk factor that relates to worse mood states and altered brain structure in young adulthood irrespective of sex. Our results point to the importance and long-lasting effects of prenatal programming and suggest that offspring of mothers who went through substantial stress during pregnancy might benefit from early intervention that would reduce the odds of mental illness in later life. PMID- 29425269 TI - Effects of Intraspecific Genetic Variation and Prior Herbivory in an Old-Field Plant on the Abundance of the Specialist Aphid Uroleucon nigrotuberculatum (Hemiptera: Aphididae). AB - Intraspecific genetic variation in plants can contribute to the diversity and abundance of associated insects, though many questions remain about why some genotypes support more insects than others. Since plant secondary metabolites, which may be induced after insect attack, may potentially vary among genotypes, these compounds provide a possible explanation for insect abundance variation in plants with substantial genetic variation. In this study, we examined four genotypes of the old-field plant species Solidago altissima (L.; Asterales: Asteraceae) and asked if the abundance of the specialist aphid Uroleucon nigrotuberculatum (Olive; Hemiptera: Aphididae) was affected by genotype and previous foliage damage by a specialist beetle. We hypothesized that different genotypes and prior herbivory would result in different quantities of terpenes produced by S. altissima, and that terpenes would affect aphid abundance. We found evidence of foliar terpene induction in a greenhouse environment, and significant differences in terpene production among genotypes in a field setting, though prior damage had little effect on aphid abundance in the field. There were significant effects of genotypes on aphid abundance, as well as genotype effects on terpenes and foliar nutrients (leaf N and C:N). Noteworthy was a change in the allocation of particular terpenes among genotypes that related to aphid abundance. Our analyses demonstrated that phytochemicals, and especially terpenes, related to aphid abundance. This study adds to a previous finding that variation in leaf terpenes in S. altissima provides a partial explanation for variable abundance among genotypes of a specialist aphid, and suggests that differences in the allocation of compounds is important. PMID- 29425270 TI - System-Specific Patterns of Thalamocortical Connectivity in Early Brain Development as Revealed by Structural and Functional MRI. AB - The normal development of thalamocortical connections plays a critical role in shaping brain connectivity in the prenatal and postnatal periods. Recent studies using advanced magnetic resonance imaging (MRI) techniques in neonates and infants have shown that abnormal thalamocortical connectivity is associated with adverse neurodevelopmental outcomes. However, all these studies have focused on a single neuroimaging modality, overlooking the dynamic relationship between structure and function at this early stage. Here, we study the relationship between structural and functional thalamocortical connectivity patterns derived from healthy full-term infants scanned with diffusion-weighted MRI and resting state functional MRI within the first weeks of life (mean gestational age = 39.3 +/- 1.2 weeks; age at scan = 24.2 +/- 7.9 days). Our results show that while there is, in general, good spatial agreement between both MRI modalities, there are regional variations that are system-specific: regions involving primary sensory cortices exhibit greater structural/functional overlap, whereas higher order association areas such as temporal and posterior parietal cortices show divergence in spatial patterns of each modality. This variability illustrates the complementarity of both modalities and highlights the importance of multimodal approaches. PMID- 29425271 TI - Lyme Disease Testing in a High-Incidence State: Clinician Knowledge and Patterns. AB - Objectives: Lyme disease (LD) incidence is increasing, but data suggest some clinicians are not fully aware of recommended procedures for ordering and interpreting diagnostic tests. The study objective was to assess clinicians' knowledge and practices regarding LD testing in a high-incidence region. Methods: We distributed surveys to 1,142 clinicians in the University of Vermont Medical Center region, of which 144 were completed (12.6% response rate). We also examined LD laboratory test results and logs of calls to laboratory customer service over a period of 2.5 years and 6 months, respectively. Results: Most clinicians demonstrated basic knowledge of diagnostic protocols, but many misinterpreted Western blot results. For example, 42.4% incorrectly interpreted a positive immunoglobulin M result as an overall positive test in a patient with longstanding symptoms. Many also reported receiving patient requests for unvalidated tests. Conclusions: Additional education and modifications to LD test ordering and reporting systems would likely reduce errors and improve patient care. PMID- 29425272 TI - Endometriosis alters brain electrophysiology, gene expression and increases pain sensitization, anxiety, and depression in female mice. AB - Endometriosis is an estrogen-dependent inflammatory disorder among reproductive aged women associated with pelvic pain, anxiety, and depression. Pain is characterized by central sensitization; however, it is not clear if endometriosis leads to increased pain perception or if women with the disease are more sensitive to pain, increasing the detection of endometriosis. Endometriosis was induced in mice and changes in behavior including pain perception, brain electrophysiology, and gene expression were characterized. Behavioral tests revealed that mice with endometriosis were more depressed, anxious and sensitive to pain compared to sham controls. Microarray analyses confirmed by qPCR identified differential gene expression in several regions of brain in mice with endometriosis. In these mice, genes such as Gpr88, Glra3 in insula, Chrnb4, Npas4 in the hippocampus, and Lcn2 in the amygdala were upregulated while Lct, Serpina3n (insula), and Nptx2 (amygdala) were downregulated. These genes are involved in anxiety, locomotion, and pain. Patch clamp recordings in the amygdala were altered in endometriosis mice demonstrating an effect of endometriosis on brain electrophysiology. Endometriosis induced pain sensitization, anxiety, and depression by modulating brain gene expression and electrophysiology; the effect of endometriosis on the brain may underlie pain sensitization and mood disorders reported in women with the disease. PMID- 29425273 TI - Kpax3: Bayesian bi-clustering of large sequence datasets. AB - Motivation: Estimation of the hidden population structure is an important step in many genetic studies. Often the aim is also to identify which sequence locations are the most discriminative between groups of samples for a given data partition. Automated discovery of interesting patterns that are present in the data can help to generate new biological hypotheses. Results: We introduce Kpax3, a Bayesian method for bi-clustering multiple sequence alignments. Influence of individual sites will be determined in a supervised manner by using informative prior distributions for the model parameters. Our inference method uses an implementation of both split-merge and Gibbs sampler type MCMC algorithms to traverse the joint posterior of partitions of samples and variables. We use a large Rotavirus sequence dataset to demonstrate the ability of Kpax3 to generate biologically important hypotheses about differential selective pressures across a virus protein. Availability and implementation: Kpax3 is implemented as a Julia package and released under the MIT license. Source code and documentation are available at: https://github.com/albertopessia/Kpax3.jl. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29425274 TI - Trio a novel bovine high-fecundity allele: II. Hormonal profile and follicular dynamics underlying the high ovulation rate. AB - The newly discovered Trio high-fecundity allele produces multiple ovulations in cattle. This study evaluated (1) size and growth rates of follicles in Trio carriers during a synchronized follicular wave, induced by follicle aspiration; (2) follicle-stimulating hormone (FSH) patterns associated with the follicular wave; (3) size of corpora lutea (CL) and circulating progesterone; and (4) intrafollicular estradiol concentrations prior to normal deviation. Trio carriers had mean dominant follicles that were significantly smaller in diameter and volume than noncarriers. Onset of diameter deviation occurred at ~3 days after the last follicle aspiration in both genotypes despite Trio carriers having much smaller individual follicles. Follicles of Trio carriers grew at a slower rate than noncarrier follicles (~65% in mm/day or ~30% in mm3/day) resulting in much smaller individual dominant follicles (~25% volume). However, total dominant follicle volume, calculated as the sum of all dominant follicles in each animal, was similar in carriers and noncarriers of Trio throughout the entire follicular wave. Circulating FSH was greater in Trio carriers during the 24 h encompassing deviation. Trio carriers had significantly more ovulations than noncarriers, and individual CL volume was smaller, although total luteal tissue volume and circulating P4 were not different. Thus, increased ovulation rate in Trio carriers relates to smaller individual follicles (one-third the volume) near the time of deviation due to slower follicle growth rate, although time of deviation is similar, with increased circulating FSH near deviation leading to selection of multiple dominant follicles in Trio carriers with similar total follicle volume. PMID- 29425275 TI - Breast Hypertrophy, Reduction Mammaplasty, and Body Image. AB - Background: Body image dissatisfaction is one of the major factors that motivate patients to undergo plastic surgery. However, few studies have associated body satisfaction with reduction mammaplasty. Objectives: The aim of this study was to evaluate the impact of breast hypertrophy and reduction mammaplasty on body image. Methods: Breast hypertrophy patients, with reduction mammaplasty already scheduled between June 2013 and December 2015 (mammaplasty group, MG), were prospectively evaluated through the body dysmorphic disorder examination (BDDE), body investment scale (BIS), and breast evaluation questionnaire (BEQ55) tools. Women with normal-sized breasts were also evaluated as study controls (normal sized breast group, NSBG). All the participants were interviewed at the initial assessment and after six months. Data were analyzed before and after six months. Results: Each group consisted of 103 women. The MG group had a significant improvement in BDDE, BIS, and BEQ55 scores six months postoperatively (P <= 0.001 for the three instruments), whereas the NSBG group showed no alteration in results over time (P = 0.876; P = 0.442; and P = 0.184, respectively). In the intergroup comparison it was observed that the MG group began to invest more in the body, similarly to the NSBG group, and surpassed the level of satisfaction and body image that the women of the NSBG group had after the surgery. Conclusions: Reduction mammaplasty promoted improvement in body image of women with breast hypertrophy. Level of Evidence 2: PMID- 29425276 TI - Giant Cell Tumor of Bone in Patients 55 Years and Older: A Study of 34 Patients. AB - Objectives: Most giant cell tumors of bone (GCTs) occur in patients aged 20 to 40 years. We analyzed features of GCT in patients 55 years or older. Methods: GCTs were examined for fibrosis, matrix, cystic change, histiocytes, mitoses, and necrosis. Clinical/radiologic data were collected. Results: Thirty-four (5%) of 710 GCTs occurred in patients older than 55 years (14/20 male/female; 56-83 years) in long bones (n = 24), vertebrae (n = 6), pelvis (n = 3), and metacarpal (n = 1). Imaging was classic in 26 of 27 cases; one case appeared malignant. Morphologic patterns included fibrosis (n = 29), bone formation (n = 19), cystic change (n = 8), necrosis (n = 8), foamy histiocytes (n = 7), and secondary aneurysmal bone cyst formation (n = 1). Mitoses ranged from 0 to 18 per 10 high power fields. Six recurred; one patient developed metastasis. Four of five cases harbored H3F3A mutations. Conclusions: GCTs in patients 55 years or older share pathologic characteristics with those arising in younger adults. Fibrosis and reactive bone are common, potentially leading to diagnostic confusion in this population. No histologic features correlate with adverse outcome. PMID- 29425277 TI - Global analysis of an exponential model of cell proliferation for estimation of cell cycle duration in the root apical meristem of angiosperms. AB - Background and Aims: Information on cell cycle duration (T) in the root apical meristem (RAM) provides insight into root growth, development and evolution. We have previously proposed a simple method for evaluating T based on the dynamics of root growth (V), the number of cells in the RAM (Nm) and the length of fully elongated cells (l), which we named the rate-of-cell-production (RCP) method. Here, a global analysis was performed to confirm the reliability of this method in a range of angiosperm species and to assess the advantages of this approach. Methods: We measured V, Nm and l from live or fixed cleared primary roots of seedlings or adventitious roots of bulbs and used this information to estimate the average T values in 73 angiosperm species via the RCP method. The results were then compared with published data obtained using the classical but laborious and time-consuming 3H-thymidine method. Key Results: In most species examined, the T values obtained by the RCP method were nearly identical to those obtained by the 3H-thymidine method. Conclusions: The global analysis demonstrated that the relationship between the variables V, Nm and l in roots in the steady state of growth is correctly described by the equation T = (ln2 Nm l)V-1. Thus, the RCP method enables cell cycle duration in the RAM to be rapidly and accurately determined. This method can be performed using live or fixed roots for each individual cell type. The simplicity of the approach suggests that it will be widely used in phenomics, evolutionary ecology and other plant biology studies. PMID- 29425278 TI - Carotid Intima-Media Thickness and Silent Brain Infarctions in a Biracial Cohort: The Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Both hypertensive and atherosclerotic processes contribute to common carotid artery intima-media thickness (CCA-IMT). Elevated CCA-IMT may be indicative of subclinical cerebrovascular disease; however, its role in the absence of concomitant carotid artery plaque is uncertain, and few studies have examined associations in Black populations. MATERIALS AND METHODS: At cohort visit 3 (1993-1995) a subset of stroke-free participants (641 Blacks and 702 Whites, mean age 63) from the Atherosclerosis Risk in Communities (ARIC) study was imaged by brain MRI and carotid ultrasound. A CCA-IMT >0.9 mm was considered elevated. Asymptomatic brain lesions >=3 mm were considered silent brain infarctions (SBI). Subcortical SBI measuring 3 to <20 mm were considered lacunes. Associations between elevated CCA-IMT and SBI were analyzed with Poisson regression. RESULTS: Elevated CCA-IMT was identified in 168 participants (16% of Blacks, 10% of Whites), and SBI were observed in 156 (15% of Blacks, 8% of Whites). Elevated CCA-IMT was strongly related to anterior circulation SBI, posterior circulation SBI, and lacunes. After adjustments, elevated CCA-IMT remained associated with greater number of lacunes in Blacks ([prevalence ratio, PR] = 1.60; 95% confidence interval [CI]: 1.02-2.51), but not Whites (PR = 0.85; 95% CI: 0.35-2.04); P value for interaction = 0.12. Among Black participants without concomitant carotid plaque, elevated CCA-IMT was associated with twice the number of lacunes (PR = 2.00; 95% CI: 1.05-3.82). CONCLUSIONS: In older Black adults, elevated CCA-IMT is independently associated with lipohyalinosis of the cerebral small vessels, irrespective of concomitant carotid plaque and vascular risk factors. PMID- 29425279 TI - MiRNA-133a is involved in the regulation of postmenopausal osteoporosis through promoting osteoclast differentiation. AB - The important role of miR-133a in the progress and development of postmenopausal osteoporosis has been reported, however, the underlying mechanism is not clear yet. In this study, qRT-PCR analysis was performed to assess miR-133 expression in serum isolated from postmenopausal osteoporosis patients (PMOP) and healthy controls. Bone mineral density (BMD) was measured at the lumbar spine by dual energy X-ray absorptiometry (DXA). The results showed that miR-133a was significantly upregulated and negatively correlated with lumbar spine BMD in serum of postmenopausal osteoporotic women. The miR-133a mimic, miR-133a inhibitor, and the corresponding controls were transfected into RAW264.7 and THP 1 cells, respectively. TRAP-positive cells were counted and the protein expression of NFATc1, c-Fos and TRAP were detected by western blot analysis. We found that MiR-133a was upregulated during osteoclastogenesis, and overexpression of miR-133a promoted RANKL-induced differentiation of RAW264.7 and THP-1 cells into osteoclasts, whereas miR-133a knockdown showed the reversed results. In in vivo experiment, rats were bilaterally ovariectomized (OVX) and injected with antagomiR-133a or antagoNC, and were sacrificed for collecting serum and lumbar spine for ELISA, micro-computed Tomography (CT) and bone histomorphology analysis, respectively. It was found that, in OVX rats, miR-133a knockdown altered the levels of osteoclastogenesis-related factors in serum and increased lumbar spine BMD and changed bone histomorphology. Collectively, miRNA-133a is involved in the regulation of postmenopausal osteoporosis through promoting osteoclast differentiation. PMID- 29425280 TI - Early childhood undernutrition increases risk of hearing loss in young adulthood in rural Nepal. AB - Background: Prevalence of young adult hearing loss is high in low-resource societies; the reasons for this are likely complex but could involve early childhood undernutrition. Objective: We evaluated preschool childhood stunting, wasting, and underweight as risk factors for hearing loss in young adulthood in Sarlahi District, southern Nepal. Design: Ear health was assessed in 2006-2008 in a cohort of 2193 subjects aged 16-23 y, who as children <60 mo of age participated in a 16-mo placebo-controlled, randomized vitamin A supplementation trial from 1989 to 1991. At each of five 4-mo assessments, field staff measured children's weight, height, and mid-upper arm circumference (MUAC) and recorded validated parental history of ear discharge in the previous 7 d. Children were classified as stunted [<-2 z score height-for-age (HAZ)], underweight [<-2 z score weight-for-age (WAZ)], or wasted [<-2 z score MUAC-for-age (MUACAZ) or body mass index-for-age (BMIAZ)]. At follow-up, hearing was tested by audiometry and tympanometry, with hearing loss defined as pure-tone average >30dB in the worse ear (0.5, 1, 2, 4 kHz) and middle-ear dysfunction as abnormal tympanometric peak height (<0.3 or >1.4 mmho) or width (<50 or >110 daPa). Results: Hearing loss, present in 5.9% (95% CI: 5.01%, 7.00%) of subjects, was associated with early childhood stunting (OR: 1.64; 95% CI: 1.10, 1.45), underweight (OR: 1.70; 95% CI: 1.18, 2.44) and wasting by BMIAZ (OR: 1.88; 95% CI: 1.19, 2.97) and MUACAZ (OR: 2.14; 95% CI: 1.47, 3.12). Abnormal tympanometry, affecting 16.6% (95% CI: 15.06%, 18.18%), was associated with underweight (OR: 1.46; 95% CI: 1.16, 1.84) and wasting by BMIAZ (OR: 1.80; 95% CI: 1.32, 2.46) and MUACAZ (OR: 1.42; 95% CI: 1.10, 1.84), but not stunting (OR: 1.18; 95% CI: 0.93, 1.49) in early childhood. Highest ORs were observed for subjects with both hearing loss and abnormal tympanometry, ranging from 1.87 to 2.24 (all lower 95% CI >1.00). Conclusions: Early childhood undernutrition is a modifiable risk factor for early adulthood hearing loss. PMID- 29425281 TI - AT1 Receptor Antagonism Improves Structural, Functional, and Biomechanical Properties in Resistance Arteries in a Rodent Chronic Kidney Disease Model. AB - BACKGROUND: The renin-angiotensin system, in particular Angiotensin II (AngII), plays a significant role in the pathogenesis of hypertension in chronic kidney disease (CKD). Effects of chronic AT1 receptor antagonism were investigated in a genetic hypertensive rat model of CKD, the Lewis polycystic kidney (LPK) rat. METHODS: Mixed-sex LPK and Lewis control rats (total n = 31) were split between treated (valsartan 60 mg/kg/day p.o. from 4 to 18 weeks) and vehicle groups. Animals were assessed for systolic blood pressure and urine biochemistry, and after euthanasia, blood collected for urea and creatinine analysis, confirming the hypertensive and renal phenotype. Mesenteric resistance vasculature was assessed using pressure myography and histology. RESULTS: Valsartan treatment improved vascular structure in LPK rats, increasing internal and external diameter values and reducing wall thickness (untreated vs. treated LPK: 53.19 +/- 3.29 vs. 33.93 +/- 2.17 MUm) and wall-lumen ratios (untreated vs. treated LPK: 0.52 +/- 0.09 vs. 0.16 +/- 0.01, all P < 0.0001). Endothelium dysfunction, as measured by maximal response to acetylcholine (Rmax), was normalized with treatment (untreated vs. treated LPK: 69.56 +/- 4.34 vs. 103.05 +/- 4.13, P < 0.05), increasing the relative contributions of nitric oxide and endothelium derived hyperpolarization to vasorelaxation while downregulating the prostanoid contribution. Biomechanical properties also improved with treatment, as indicated by an increase in compliance, decrease in intrinsic stiffness and alterations in the artery wall composition, which included decreases in collagen density and collagen/elastin ratio. CONCLUSIONS: Our results highlight the importance of AngII as a driver of resistance vessel structural, functional, and biomechanical dysfunction and provide insight as to how AT1 receptor blockade exerts therapeutic efficacy in CKD. PMID- 29425282 TI - Presence and molecular characteristics of oxazolidinone resistance in staphylococci from household animals in rural China. AB - Objectives: To investigate the presence and molecular characteristics of oxazolidinone resistance genes cfr and optrA in staphylococci from household animals in rural China. Methods: Various samples were collected from household animals in 12 rural villages. Staphylococcal isolates showing florfenicol MICs >=10 mg/L were identified and screened for the presence of cfr and/or optrA. PCR positive isolates were characterized by antimicrobial susceptibility testing, S1 nuclease PFGE and Southern blotting. WGS data were analysed to identify the core genome phylogenetic profile of each isolate as well as the genetic environment of cfr and/or optrA. Results: Nine optrA-positive (seven Staphylococcus sciuri and two Staphylococcus simulans) and 10 cfr-positive staphylococci were identified from eight and five villages, respectively. The gene optrA was chromosomally encoded in all nine isolates, whereas cfr was located on a plasmid in one S. sciuri and three Staphylococcus saprophyticus and in the chromosomal DNA of single Staphylococcus cohnii and Staphylococcus lentus isolates and two S. sciuri isolates. The remaining two cfr-carrying Staphylococcus haemolyticus isolates were indistinguishable by PFGE. Most optrA- or cfr-carrying staphylococci also harboured phenicol, tetracycline and/or macrolide-lincosamide-streptogramin B resistance genes. Genetic environment analysis showed that, for the first time, optrA was associated with transposon Tn6261, while cfr was adjacent to both a tnp (transposase) gene and a Tn558 transposon. Conclusions: The current study reveals for the first time the wide distribution of oxazolidinone resistance genes optrA and cfr in household animals in rural areas of China and is the first identification of optrA in S. simulans isolates. PMID- 29425283 TI - Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model. AB - Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients. Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function. Methods: A population pharmacokinetic model was developed in NONMEM(r) 7.3 based on steady-state meropenem concentrations (CSS) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRCG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (CSS >=8 mg/L) and potentially increased likelihood of adverse drug reactions (CSS >32 mg/L). Results: In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P0.05 - P0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/3940 mg were required to reach a target CSS = 8 mg/L in 90% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5%) was associated with these doses. Conclusions: A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population. PMID- 29425284 TI - Chromosomal instability in women with primary ovarian insufficiency. AB - STUDY QUESTION: What is the prevalence of somatic chromosomal instability among women with idiopathic primary ovarian insufficiency (POI)? SUMMARY ANSWER: A subset of women with idiopathic POI may have functional impairment in DNA repair leading to chromosomal instability in their soma. WHAT IS KNOWN ALREADY: The formation and repair of DNA double-strand breaks during meiotic recombination are fundamental processes of gametogenesis. Oocytes with compromised DNA integrity are susceptible to apoptosis which could trigger premature ovarian aging and accelerated wastage of the human follicle reserve. Genomewide association studies, as well as whole exome sequencing, have implicated multiple genes involved in DNA damage repair. However, the prevalence of defective DNA damage repair in the soma of women with POI is unknown. STUDY DESIGN, SIZE, DURATION: In total, 46 women with POI and 15 family members were evaluated for excessive mitomycin-C (MMC)-induced chromosome breakage. Healthy fertile females (n = 20) and two lymphoblastoid cell lines served as negative and as positive controls, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a pilot functional study utilizing MMC to assess chromosomal instability in the peripheral blood of participants. A high-resolution array comparative genomic hybridization (aCGH) was performed on 16 POI patients to identify copy number variations (CNVs) for a set of 341 targeted genes implicated in DNA repair. MAIN RESULTS AND THE ROLE OF CHANCE: Array CGH revealed three POI patients (3/16, 18.8%) with pathogenic CNVs. Excessive chromosomal breakage suggestive of a constitutional deficiency in DNA repair was detected in one POI patient with the 16p12.3 duplication. In two patients with negative chromosome breakage analysis, aCGH detected a Xq28 deletion comprising the Centrin EF-hand Protein 2 (CETN2) and HAUS Augmin Like Complex Subunit 7 (HAUS7) genes essential for meiotic DNA repair, and a duplication in the 3p22.2 region comprising a part of the ATPase domain of the MutL Homolog 1 (MLH1) gene. LIMITATIONS REASONS FOR CAUTION: Peripheral lymphocytes, used as a surrogate tissue to quantify induced chromosome damage, may not be representative of all the affected tissues. Another limitation pertains to the MMC assay which detects homologous repair pathway defects and does not test deficiencies in other DNA repair pathways. WIDER IMPLICATIONS OF THE FINDINGS: Our results provide evidence for functional impairment of DNA repair in idiopathic POI, which may predispose the patients to other DNA repair related conditions such as accelerated aging and/or cancer susceptibility. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the National Institute of Child Health and Human Development. There were no competing interests to declare. PMID- 29425285 TI - Pattern-oriented modelling as a novel way to verify and validate functional structural plant models: a demonstration with the annual growth module of avocado. AB - Background and Aims: Functional-structural plant (FSP) models have been widely used to understand the complex interactions between plant architecture and underlying developmental mechanisms. However, to obtain evidence that a model captures these mechanisms correctly, a clear distinction must be made between model outputs used for calibration and thus verification, and outputs used for validation. In pattern-oriented modelling (POM), multiple verification patterns are used as filters for rejecting unrealistic model structures and parameter combinations, while a second, independent set of patterns is used for validation. Methods: To test the potential of POM for FSP modelling, a model of avocado (Persea americana 'Hass') was developed. The model of shoot growth is based on a conceptual model, the annual growth module (AGM), and simulates photosynthesis and adaptive carbon allocation at the organ level. The model was first calibrated using a set of observed patterns from a published article. Then, for validation, model predictions were compared with a different set of empirical patterns from various field studies that were not used for calibration. Key Results: After calibration, our model simultaneously reproduced multiple observed architectural patterns. The model then successfully predicted, without further calibration, the validation patterns. The model supports the hypothesis that carbon allocation can be modelled as being dependent on current organ biomass and sink strength of each organ type, and also predicted the observed developmental timing of the leaf sink source transition stage. Conclusions: These findings suggest that POM can help to improve the 'structural realism' of FSP models, i.e. the likelihood that a model reproduces observed patterns for the right reasons. Structural realism increases predictive power so that the response of an AGM to changing environmental conditions can be predicted. Accordingly, our FSP model provides a better but still parsimonious understanding of the mechanisms underlying known patterns of AGM growth. PMID- 29425286 TI - Central Neuropeptide Y Plays an Important Role in Mediating the Adaptation Mechanism Against Chronic Stress in Male Rats. AB - Exposure to continuous life stress often causes gastrointestinal (GI) symptoms. Studies have shown that neuropeptide Y (NPY) counteracts the biological actions of corticotrophin-releasing factor (CRF) and is involved in the termination of the stress response. However, in chronic repeated restraint stress (CRS) conditions, the actions of NPY on GI motility remain controversial. To evaluate the role of NPY in mediation of the adaptation mechanism and GI motility in CRS conditions, a CRS rat model was set up. Central CRF and NPY expression levels were analyzed, serum corticosterone and NPY concentrations were measured, and GI motor function was evaluated. The NPY Y1 receptor antagonist BIBP-3226 was centrally administered before stress loading, and on days 1 through 5 of repeated stress, the central CRF and the serum corticosterone concentrations were measured. In addition, gastric and colonic motor functions were evaluated. The elevated central CRF expression and corticosterone concentration caused by acute stress began to fall after 3 days of stress loading, whereas central NPY expression and serum NPY began to increase. GI dysmotility also returned to a normal level. Pretreatment with BIBP-3226 abolished the adaptation mechanism and significantly increased CRF expression and the corticosterone concentration, which resulted in delayed gastric emptying and accelerated fecal pellet output. Inhibited gastric motility and enhanced distal colonic motility were also recorded. CRS-produced adaptation, overexpressed central CRF, and GI dysmotility observed in acute restraint stress were restored to normal levels. Central NPY via the Y1 receptor plays an important role in mediating the adaptation mechanism against chronic stress. PMID- 29425288 TI - Does frequently inadequate adult care threaten the outcome of congenital heart disease after successful paediatric treatment? PMID- 29425289 TI - The numbers of 2- 5 and 6-9 mm ovarian follicles are inversely correlated in both normal women and in polycystic ovary syndrome patients: what is the missing link? AB - STUDY QUESTION: Is the negative correlation between the numbers of 2-5 and 6-9 mm follicles influenced by ovarian and/or metabolic parameter(s) in young control women and in patients with polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: Our study confirmed that the negative correlation between numbers of follicles sized 2-5 and 6-9 mm was stronger in PCOS than in young control women and was not linked to any ovarian or metabolic parameter. WHAT IS KNOWN ALREADY: Previous reports described a direct negative correlation between the number of small antral follicles (2-5 mm) and large antral follicle (6-9 mm) during the early follicular phase (cycle Days 2-5) in normal and PCOS women. Numerous factors, that could be either intrinsic to the ovary or secondary to metabolic influence and/or gonadotropin regulation, might account for this. STUDY DESIGN, SIZE, DURATION: Six hundred and thirty-nine patients with PCOS according to Rotterdam Criteria and 157 control women were recruited in this retrospective cross sectional study from January 2009 to January 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were obtained from a database of clinical, hormonal and ultrasound (U/S) features recorded consecutively in a single reproductive medicine centre. Univariate correlations between the various parameters were analysed by the Spearman's correlation test. All variables significantly related to the 2-5 and/or 6-9 mm follicle numbers were included in a principal component analysis (PCA) in order to structure the data and to obtain collections of uncorrelated variables, called principal components (PC), which are linear combinations of the original variables. MAIN RESULTS AND THE ROLE OF CHANCE: By univariate analysis, the 2-5 and 6-9 mm follicle numbers were strongly but negatively correlated in both populations. Many other variables were correlated to the 2-5 and/or 6-9 mm follicle numbers and to each other. By PCA, these relationships were gathered into four independent PCs in each population. In both groups, the 2-5 and 6-9 mm follicle numbers correlated strongly and inversely to a specific PC. Among the other variables tested, only serum oestradiol level correlated weakly to this PC in the control group. Two other uncorrelated PCs gathered relationships between variables linked to the metabolic status and the gonadotropin regulation both in control and PCOS women. Lastly, a fourth PC included relationships which linked to ovarian ageing in controls and to follicle dysregulation in patients with PCOS. LIMITATIONS, REASONS FOR CAUTION: Our controls did not represent the general population since they were recruited in an ART centre; we used a modified Rotterdam classification for PCOS using follicle count and/or serum AMH level with in-house thresholds to define the follicle excess; the AMH assay used is no longer commercially available. WIDER IMPLICATIONS OF THE FINDINGS: Factor(s) regulating specifically the equilibrium between the 2-5 and 6-9 mm follicle numbers still need(s) to be identified. More attention should be paid to the oocyte. STUDY FUNDING/COMPETING INTEREST(S): None. PMID- 29425287 TI - Perinatal Bisphenol A Exposure Increases Atherosclerosis in Adult Male PXR Humanized Mice. AB - Bisphenol A (BPA) is a base chemical used extensively in numerous consumer products, and human exposure to BPA is ubiquitous. Higher BPA exposure has been associated with an increased risk of atherosclerosis and cardiovascular disease (CVD) in multiple human population-based studies. However, the underlying mechanisms responsible for the associations remain elusive. We previously reported that BPA activates the xenobiotic receptor pregnane X receptor (PXR), which has proatherogenic effects in animal models. Because BPA is a potent agonist for human PXR but does not affect rodent PXR activity, a suitable PXR humanized apolipoprotein E-deficient (huPXR*ApoE-/-) mouse model was developed to study BPA's atherogenic effects. Chronic BPA exposure increased atherosclerosis in the huPXR*ApoE-/- mice. We report that BPA exposure can also activate human PXR signaling in the heart tubes of huPXR*ApoE-/- embryos, and perinatal BPA exposure exacerbated atherosclerosis in adult male huPXR*ApoE-/- offspring. However, atherosclerosis development in female offspring was not affected by perinatal BPA exposure. Perinatal BPA exposure did not affect plasma lipid levels but increased aortic and atherosclerotic lesional fatty acid transporter CD36 expression in male huPXR*ApoE-/- offspring. Mechanistically, PXR epigenetically regulated CD36 expression by increasing H3K4me3 levels and decreasing H3K27me3 levels in the CD36 promoter in response to perinatal BPA exposure. The findings from the present study contribute to our understanding of the association between BPA exposure and increased atherosclerosis or CVD risk in humans, and activation of human PXR should be considered for future BPA risk assessment. PMID- 29425290 TI - Performance of the Natural Mortality Factors of Aphis gossypii (Hemiptera: Aphididae) as a Function of Cotton Plant Variety and Phenology. AB - Natural mortality factors are responsible for regulating pest populations in the field. However, plant attributes such as the variety and phenological stage can influence the performance of these factors. Therefore, we investigated the performance of the natural mortality factors of Aphis gossypii (Glover; Hemiptera: Aphididae) as a function of the plant variety and phenology. To investigate the performance of these factors, we evaluated the mortality of A. gossypii caused by natural mortality factors for 2 yr in field conditions in transgenic (Bacillus thuringiensis/Roundup Ready) and non-transgenic cotton crops during vegetative, flowering, and fruiting stages. The natural mortality factors were affected similarly between the transgenic and non-transgenic plants; however, differences were observed in their performance, depending on the phenological stage of the cotton plant. Compared with other stages, predation was higher in the flowering stage, whereas the mortality caused by rainfall was higher in the vegetative stage. Coccinellid beetles were primarily responsible for the predation on A. gossypii. These findings highlight that the performance of the natural mortality factors of A. gossypii varied more as a function of the phenological stage of cotton than of the variety. PMID- 29425291 TI - GeneSeqToFamily: a Galaxy workflow to find gene families based on the Ensembl Compara GeneTrees pipeline. AB - Background: Gene duplication is a major factor contributing to evolutionary novelty, and the contraction or expansion of gene families has often been associated with morphological, physiological, and environmental adaptations. The study of homologous genes helps us to understand the evolution of gene families. It plays a vital role in finding ancestral gene duplication events as well as identifying genes that have diverged from a common ancestor under positive selection. There are various tools available, such as MSOAR, OrthoMCL, and HomoloGene, to identify gene families and visualize syntenic information between species, providing an overview of syntenic regions evolution at the family level. Unfortunately, none of them provide information about structural changes within genes, such as the conservation of ancestral exon boundaries among multiple genomes. The Ensembl GeneTrees computational pipeline generates gene trees based on coding sequences, provides details about exon conservation, and is used in the Ensembl Compara project to discover gene families. Findings: A certain amount of expertise is required to configure and run the Ensembl Compara GeneTrees pipeline via command line. Therefore, we converted this pipeline into a Galaxy workflow, called GeneSeqToFamily, and provided additional functionality. This workflow uses existing tools from the Galaxy ToolShed, as well as providing additional wrappers and tools that are required to run the workflow. Conclusions: GeneSeqToFamily represents the Ensembl GeneTrees pipeline as a set of interconnected Galaxy tools, so they can be run interactively within the Galaxy's user-friendly workflow environment while still providing the flexibility to tailor the analysis by changing configurations and tools if necessary. Additional tools allow users to subsequently visualize the gene families produced by the workflow, using the Aequatus.js interactive tool, which has been developed as part of the Aequatus software project. PMID- 29425292 TI - The mental health of sons and daughters of Australian Vietnam veterans. AB - Background: War service increases the risk of post-traumatic stress disorder (PTSD) to combatants, and has been shown to increase the risk of PTSD in their offspring. The extent to which there is an excess compared with the general population is not yet established, nor whether PTSD increases the risk of other psychiatric problems. Methods: A national sample of 133 sons and 182 daughters of a cohort of 179 Australian Vietnam veterans' families were assessed in person, using structured psychiatric interviews. The prevalence of trauma exposures, DSM IV (Diagnostic and Statistical Manual of Mental Disorders Fourth Edition) diagnoses and suicidality were compared with the Australian Bureau of Statistics' 2007 National Survey of Mental Health and Wellbeing data matched for age and sex. The risk of mental health problems potentially attributable to PTSD was also assessed. Results: Sons and daughters were more likely than population expectations to report exposures to natural disasters, fire or explosions and transport accidents, and sons more likely to report exposure to toxic chemicals whereas daughters were more likely to report sexual assault. Sons and daughters had higher prevalences of alcohol and other substance dependence, depression and anxiety, and PTSD, and children's PTSD was associated with substance dependence, depression and suicidal ideation. There were strong associations between children's PTSD and comorbid conditions of substance use disorders, depression and anxiety. Conclusions: Higher rates of mental health problems in veterans' families, together with comorbidity with PTSD and the link between veterans' and children's PTSD, suggest that the effects of trauma may continue into subsequent generations. PMID- 29425293 TI - Use of a wine yeast deletion collection reveals genes that influence fermentation performance under low-nitrogen conditions. AB - A deficiency of nitrogenous nutrients in grape juice can cause stuck and sluggish alcoholic fermentation, which has long been a problem in winemaking. Nitrogen requirements vary between wine yeast strains, and the ability of yeast to assimilate nitrogen depends on the nature and concentration of nitrogen present in the medium. In this study, a wine yeast gene deletion collection (1844 deletants in the haploid AWRI1631 background) was screened to identify genes whose deletion resulted in a reduction in the time taken to utilise all sugars when grown in a chemically defined grape juice medium supplemented with limited nitrogen (75 mg L-1 as a free amino acid mixture). Through micro-scale and laboratory-scale fermentations, 15 deletants were identified that completed fermentation in a shorter time than the wildtype (c.a. 15%-59% time reduction). This group of genes was annotated to biological processes including protein modification, transport, metabolism and ubiquitination (UBC13, MMS2, UBP7, UBI4, BRO1, TPK2, EAR1, MRP17, MFA2 and MVB12), signalling (MFA2) and amino acid metabolism (AAT2). Deletion of MFA2, encoding mating factor-a, resulted in a 55% decrease in fermentation duration. Mfa2Delta was chosen for further investigation to understand how this gene deletion conferred fermentation efficiency in limited nitrogen conditions. PMID- 29425294 TI - The RACE-3 is on: double-locking sinus rhythm by upstream and downstream therapy. PMID- 29425297 TI - Surgical repair of atrioventricular septal defects: incidence and mode of failure of the left atrioventricular valve. AB - OBJECTIVES: Our goal was to investigate the outcome of the left atrioventricular valve (LAVV) after repair of atrioventricular septal defects (AVSDs) by analysing the mechanisms of LAVV failure. METHODS: A retrospective investigation of 202 children with AVSD, operated on between 1992 and 2016, was performed. Analysis focused on freedom from reoperation for LAVV dysfunction, with specific attention to the modes of failure. RESULTS: The population consisted of 129 (64%) patients with complete AVSD (cAVSD) and 73 (36%) patients with partial AVSD (pAVSD), corrected at a median age of 3.9 (interquartile range 3.4) months and 29.0 (interquartile range 90.4) months, respectively. Within a median follow-up period of 5.9 (interquartile range 12.6) years, 27 (13.4%) patients required reoperation for LAVV failure, respectively, in 17 (13.2%) patients with cAVSD and 10 (13.9%) patients with pAVSD. Freedom from reoperation for LAVV at 10 years was 87 +/- 4% for cAVSD and 87 +/- 5% for pAVSD (P = 0.789). The failure mode was predominantly technical in cAVSD (71% vs 20% in pAVSD), whereas residual anatomical anomalies entailed more frequently LAVV regurgitation (LAVVR) in pAVSD (80% vs 29% in cAVSD) (P = 0.018). Cleft suture dehiscence (n = 8) and incomplete cleft closure (n = 6) were considered technical failures, whereas remnant distortions of the subvalvular apparatus (n = 9), small asymmetric bridging leaflet (n = 2), double orifice (n = 1) and additional cleft (n = 1) were considered anatomical lesions. The incidence of repair at the 1st reoperation was 92.6%. Eight patients needed a 2nd and 2 patients a 3rd repeat LAVV operation. Five patients finally ended with a mechanical prosthesis. CONCLUSIONS: In the long term, patients with AVSD are still subject to LAVV failure. Despite systematic cleft closure, patients with cAVSD develop LAVV failure mainly because of a recurrent/residual deficit at the cleft, amenable to technical improvement. Patients with pAVSD need increased attention for additional anatomical features of the LAVV at the time of primary repair. PMID- 29425295 TI - Prenatal Exposure to Unconventional Oil and Gas Operation Chemical Mixtures Altered Mammary Gland Development in Adult Female Mice. AB - Unconventional oil and gas (UOG) operations, which combine hydraulic fracturing (fracking) and directional drilling, involve the use of hundreds of chemicals, including many with endocrine-disrupting properties. Two previous studies examined mice exposed during early development to a 23-chemical mixture of UOG compounds (UOG-MIX) commonly used or produced in the process. Both male and female offspring exposed prenatally to one or more doses of UOG-MIX displayed alterations to endocrine organ function and serum hormone concentrations. We hypothesized that prenatal UOG-MIX exposure would similarly disrupt development of the mouse mammary gland. Female C57Bl/6 mice were exposed to ~3, ~30, ~ 300, or ~3000 MUg/kg/d UOG-MIX from gestational day 11 to birth. Although no effects were observed on the mammary glands of these females before puberty, in early adulthood, females exposed to 300 or 3000 MUg/kg/d UOG-MIX developed more dense mammary epithelial ducts; females exposed to 3 MUg/kg/d UOG-MIX had an altered ratio of apoptosis to proliferation in the mammary epithelium. Furthermore, adult females from all UOG-MIX-treated groups developed intraductal hyperplasia that resembled terminal end buds (i.e., highly proliferative structures typically seen at puberty). These results suggest that the mammary gland is sensitive to mixtures of chemicals used in UOG production at exposure levels that are environmentally relevant. The effect of these findings on the long-term health of the mammary gland, including its lactational capacity and its risk of cancer, should be evaluated in future studies. PMID- 29425296 TI - Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis. AB - Context: With the aging of the population and projected increase in osteoporotic fractures coupled with the declining use of osteoporosis medications, there is a compelling need for new approaches to treat osteoporosis. Given that age-related osteoporosis generally coexists with multiple other comorbidities (e.g., atherosclerosis, diabetes, frailty) that share aging as the leading risk factor, there is growing interest in the "Geroscience Hypothesis," which posits that manipulation of fundamental aging mechanisms will delay the appearance or severity of multiple chronic diseases because these diseases share aging as the underlying risk factor. In this context, one fundamental aging mechanism that has received considerable attention recently as contributing to multiple age-related morbidities is cellular senescence. This mini-review provides an overview on cellular senescence with a focus on its role in mediating age-related bone loss. Methods: This summary is based on the authors' knowledge of the field supplemented by a PubMed search using the terms "senescence," "aging," and "bone." Results: There is compelling evidence from preclinical models and supportive human data demonstrating an increase in senescent cells in the bone microenvironment with aging. These cells produce a proinflammatory secretome that leads to increased bone resorption and decreased bone formation, and approaches that either eliminate senescent cells or impair the production of their proinflammatory secretome have been shown to prevent age-related bone loss in mice. Conclusions: Targeting cellular senescence represents a novel therapeutic strategy to prevent not only bone loss but potentially multiple age-related diseases simultaneously. PMID- 29425298 TI - 'Man Up': the importance and strategy for placing male reproductive health centre stage in the political and research agenda. AB - Approximately 1 in 20 young men today have sperm counts low enough to impair fertility, whereas this may not have been the case historically. The cause(s) of such a decline in male reproductive health is unknown, despite it being a global health issue. Concomitantly, little progress has been made in answering fundamental questions in andrology or in developing new diagnostic tools or alternative management strategies to ICSI in infertile men. We advocate formulation of a detailed roadmap for male reproductive health to facilitate development of a research agenda that highlights the present unmet needs and key unanswered questions, and seeks to deliver effective funding and investment to address them. This vision we term 'a Male Reproductive Health Ecosystem'. PMID- 29425300 TI - Reply to Gasz. PMID- 29425299 TI - Stability of Ethyl Glucuronide, Ethyl Sulfate, Phosphatidylethanols and Fatty Acid Ethyl Esters in Postmortem Human Blood. AB - The lack of systematic studies on the stability of ethanol's non-oxidative metabolites in postmortem specimens restricts their use in forensic cases. This study aimed to compare the stability of ethyl glucuronide (EtG), ethyl sulfate (EtS), phosphatidylethanols (PEths) and fatty acid ethyl esters (FAEEs) in postmortem human blood. Three groups were established based on the level and source of ethanol: the blank group, the ethanol-spiked group and the ethanol positive group. Each group contained six blood samples from different corpses. The samples in each group were placed at 37, 25, 4 and -20 degrees C. Every 24 h for 7 days, 50 MUL was collected from each sample. The levels of EtG, EtS, PEths and FAEEs were determined by liquid chromatography-mass spectrometry, and their stability was evaluated. EtG was not detected in the blank group, but it was found in samples in the ethanol-spiked group placed at 37 degrees C, and it was degraded in the ethanol-positive group at 37 and 25 degrees C. EtS showed no change in any of the groups. PEths were not detected in the blank group, but formation was found in the ethanol-spiked group at all temperatures. In the ethanol-positive group, PEth levels fluctuated at 37 degrees C, decreased at 25 degrees C and increased at -20 degrees C. FAEEs were generated in the blank group and in the ethanol-spiked group at all temperatures. In the ethanol-positive group, FAEEs were degraded at 37 and 25 degrees C but were generated at 4 and -20 degrees C. EtS is a reliable biomarker of ethanol consumption, and EtG could be used as a biomarker at low temperatures (4 and -20 degrees C), but PEths and FAEEs are not appropriate biomarkers of ethanol consumption. PMID- 29425301 TI - Changes in physical and mental health functioning during retirement transition: a register-linkage follow-up study. AB - Background: Changes in health functioning over different retirement transitions are poorly understood. This study aimed to examine associations between transition into statutory, disability and part-time retirement, and changes in health functioning. Methods: Survey data were collected among ageing employees of the City of Helsinki, Finland, at three phases: (i) (2000-02), (ii) (2007) and (iii) (2012). Physical and mental health functioning were measured using the Short-Form 36 questionnaire at each phase. Retirees between phases 1 and 3 were identified from the national registers of the Finnish Centre for Pensions: full time statutory retirement (n = 1464), part-time retirement (n = 404), and disability retirement (n = 462). Generalized estimating equations were used to examine the associations. Results: Disability retirees had poorer pre- and post retirement health functioning compared to statutory and part-time retirees. Statutory and part-time retirement were associated with no or only small changes in physical health functioning during retirement transition (beta 0.1, 95% CI 0.3 to 0.5 and -1.0, -1.8 to -0.1, respectively), whereas a clear decline in functioning was observed among disability retirees (-4.3, -5.4 to -3.2). Mental health functioning improved during the retirement transition among statutory and part-time retirees (1.9, 1.4-2.4 and 2.0, 1.0-3.0, respectively), whereas no change was observed for disability retirees. Conclusions: Transition to disability retirement led to a decrease in physical health functioning, and statutory retirement to a slight improvement in mental health functioning. Evidence on changes in physical and mental health functioning during retirement transition process may provide useful information for interventions to promote healthy ageing. PMID- 29425302 TI - The influence of healthcare policy on the outcome parameters of myocardial revascularization procedures as opposed to geographical differences. PMID- 29425303 TI - Regulation of the positive transcriptional effect of PLZF through a non-canonical EZH2 activity. AB - The transcription factor PLZF (promyelocytic leukemia zinc finger protein) acts as an epigenetic regulator balancing self-renewal and differentiation of hematopoietic cells through binding to various chromatin-modifying factors. First described as a transcriptional repressor, PLZF is also associated with active transcription, although the molecular bases underlying the differences are unknown. Here, we reveal that in a hematopoietic cell line, PLZF is predominantly associated with transcribed genes. Additionally, we identify a new association between PLZF and the histone methyltransferase, EZH2 at the genomic level. We find that co-occupancy of PLZF and EZH2 on chromatin at PLZF target genes is not associated with SUZ12 or trimethylated lysine 27 of histone H3 (H3K27me3) but with the active histone mark H3K4me3 and active transcription. Removal of EZH2 leads to an increase of PLZF binding and increased gene expression. Our results suggest a new role of EZH2 in restricting PLZF positive transcriptional activity independently of its canonical PRC2 activity. PMID- 29425305 TI - USU's Pediatric Interest Group: Preparing the Next Generation of Military Pediatricians. PMID- 29425304 TI - Associations Between Serum Bone Biomarkers in Early Breast Cancer and Development of Bone Metastasis: Results From the AZURE (BIG01/04) Trial. AB - Background: Adjuvant therapies can prevent/delay bone metastasis development in breast cancer. We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis. Methods: Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type 1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type 1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE ISRCTN79831382) in early breast cancer. Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables. All statistical tests were two-sided. Results: When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = .006, P = .009, P = .008, respectively). Harrell's c-indices were a P1NP of 0.57 (95% confidence interval [CI] = 0.51 to 0.63), CTX of 0.57 (95% CI = 0.51 to 0.62), and 1-CTP of 0.57 (95% CI = 0.52 to 0.63). In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0.299 ng/mL), but not 1-CTP (>4.2 ng/mL), were also prognostic for future bone recurrence (P = .03, P = .03, P = .10, respectively). None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid. Conclusions: Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study. PMID- 29425307 TI - Concerns About Ankle Injury Prophylaxis and Acceptance of the Parachute Ankle Brace Among Jumpmaster Students. AB - Introduction: Several studies have shown that the parachute ankle brace (PAB) is safe, cost-effective, and reduces the rates of ankle injuries during military parachuting. However, the acceptability and usability of the PAB has not been well established in units that regularly do airborne exercises. Many anecdotal concerns in the past may be limiting common use. The purpose of the study is to ascertain the attitudes toward the PAB among experienced paratroopers. Methods: One hundred experienced paratroopers training to be jumpmasters at the Advanced Airborne School (Fort Bragg, NC) voluntarily responded to a 13-item, paper questionnaire to assess attitudes toward the PAB, its use, and concerns about future ankle injuries. The survey was offered to all 100 students enrolled in an Advanced Airborne School course. Results were input into an online database using Qualtrics and qualitative responses were evaluated for thematic content and categorized appropriately. Analysis was performed using Qualtrics and SPSS for descriptive statistics, two-sample t-tests, and chi-square tests. The Wilcoxon signed-rank test was used to evaluate Likert-type responses. Results: Of the 100 paratroopers who responded to the survey 32% had over 10 yr of military service, 58% had over 5 yr of service, and 32% had over 5 yr on active jump status. Results show that none of the respondents had ever used the PAB; 62% had never heard of the PAB, and 72% had never observed use of the PAB. A majority of respondents (87%) had never injured an ankle during a parachute landing fall (PLF), but 79% believed that an ankle injury could affect their career potential as a paratrooper. Almost one-half of the respondents (47%) had seen that ankle injuries affect another paratrooper's career. A third of the respondents (35%) said that they had concerns that would keep them from using the PAB, whereas 21% were uncertain, as they had never heard of it. Only 19% of the respondents were willing to use measures such as taping, lace-up bracing, semi-rigid brace inside a normal boot, specialized jump boot with stabilizing braces built in, or outside the-boot braces to prevent ankle injury. However, 40% said that they were likely to use these measures on jumps after experiencing an ankle injury. Discussion: Previous research clearly establishes the advantages of the PAB. None of the participants had ever used the PAB but expressed a fear about how an ankle injury might impact their future career potential. Yet half of the jumpmasters indicated a willingness to use prophylactic measures after an ankle injury. Conclusion: This survey assessed the attitude and knowledge related to the PAB among jumpmaster students. Results show that despite the benefits of the PAB, a negative attitude exists toward the PAB, and it is not currently being used. This survey clearly demonstrates the need either to educate paratroopers on the existence of the PAB or to explore other designs that may be more readily accepted in the airborne community. PMID- 29425306 TI - Interferon Treatment Duration in Patients With Chronic Delta Hepatitis and its Effect on the Natural Course of the Disease. AB - Background: Interferon is the only treatment option in chronic delta hepatitis (CDH). A CDH database (333 patients, 161 with interferon treatment history) was analyzed for effects of treatment duration on virologic response and clinical outcomes. Methods: Ninety-nine CDH patients who received at least 6 months of interferon were selected. Maintained virologic response (MVR) was defined as hepatitis D virus RNA negative for 2 years after treatment discontinuation. Cumulative median interferon treatment duration was 24 months (range 6-126 months), with a median of 2 courses (range 1-8). Post-treatment median follow-up was 55 months (24-225 months). Results: Thirty-five patients achieved MVR. Cumulative probability of MVR increased with treatment duration and reached 50% at 5 years. Patients with MVR were less likely to die from liver disease or develop complications compared to patients without MVR (P = .032, P = .006, respectively). Cirrhosis at baseline and no response to therapy (odds ratio 16.1 and 5.23, respectively) predicted an adverse endpoint. Hepatitis B surface antigen clearance occurred in 37% of patients with MVR. Conclusion: Viral response to interferon increases with treatment duration and favorably affects the natural course of disease. Interferon treatment duration has to be individualized with careful post-treatment assessment. PMID- 29425308 TI - INfORM: Inference of NetwOrk Response Modules. AB - Summary: Detecting and interpreting responsive modules from gene expression data by using network-based approaches is a common but laborious task. It often requires the application of several computational methods implemented in different software packages, forcing biologists to compile complex analytical pipelines. Here we introduce INfORM (Inference of NetwOrk Response Modules), an R shiny application that enables non-expert users to detect, evaluate and select gene modules with high statistical and biological significance. INfORM is a comprehensive tool for the identification of biologically meaningful response modules from consensus gene networks inferred by using multiple algorithms. It is accessible through an intuitive graphical user interface allowing for a level of abstraction from the computational steps. Availability and implementation: INfORM is freely available for academic use at https://github.com/Greco-Lab/INfORM. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29425309 TI - Influenza Vaccine Effectiveness and Age. PMID- 29425310 TI - Cost-Effectiveness Analysis of a Military Hearing Conservation Program. AB - Introduction: Occupational noise threatens U.S. worker health and safety and commands a significant financial burden on state and federal government worker compensation programs. Previous studies suggest that hearing conservation programs have contributed to reduced occupational hearing loss for noise-exposed workers. Many military personnel are overexposed to noise and are provided hearing conservation services. Select military branches require all active duty personnel to follow hearing conservation program guidelines, regardless of individual noise exposure. We evaluated the cost-effectiveness of a military hearing conservation program, relative to no intervention, in relation to cases of hearing loss prevented. Methods: We employed cost-effectiveness analytic methods to compare the costs and effectiveness, in terms of hearing loss cases prevented, of a military hearing conservation program relative to no program. We used costs and probability estimates available in the literature and publicly available sources. The effectiveness of the interventions was analyzed based on whether hearing loss occurred over a 20-yr time frame. Results: The incremental cost-effectiveness ratio of the hearing conservation program compared with no intervention was $10,657 per case of hearing loss prevented. Workers were 28% less likely to sustain hearing loss in our model when they received the hearing conservation program compared with no intervention, which reflected the greater effectiveness of the hearing conservation program. Cost-effectiveness results were sensitive to estimated values for the probability of acquiring hearing loss from both interventions and the cost of hearing protection. We performed a Monte Carlo probabilistic sensitivity analysis where we simultaneously varied all the model parameters to their extreme plausible bounds. When we ran 10,000 Monte Carlo iterations, we observed that the hearing conservation program was more cost effective in 99% of cases when decision makers were willing to pay $64,172 per case of hearing loss prevented. Conclusions: Conceding a lifetime cost for service-related compensation for hearing loss per individual of $64,172, the Department of Defense Hearing Conservation Program is an economically reasonable program relative to no intervention, if a case of hearing loss avoided costs $10,657. Considering the net difference of the costs and comparative benefits of both treatment strategies, providing a hearing conservation program for all active duty military workers may be a cost-effective intervention for the Department of Defense. PMID- 29425311 TI - Are Nonsense Alleles of Drosophila melanogaster Genes under Any Selection? AB - A gene which carries a bona fide loss-of-function mutation effectively becomes a functionless pseudogene, free from selective constraint. However, there is a number of molecular mechanisms that may lead to at least a partial preservation of the function of genes carrying even drastic alleles. We performed a direct measurement of the strength of negative selection acting on nonsense alleles of protein-coding genes in the Zambian population of Drosophila melanogaster. Within those exons that carry nonsense mutations, negative selection, assayed by the ratio of missense over synonymous nucleotide diversity levels, appears to be absent, consistent with total loss of function. In other exons of nonsense alleles, negative selection was deeply relaxed but likely not completely absent, and the per site number of missense alleles declined significantly with the distance from the premature stop codon. This pattern may be due to alternative splicing which preserves function of some isoforms of nonsense alleles of genes. PMID- 29425312 TI - Risk Factors for Early Intraocular Pressure Elevation After Cataract Surgery in a Cohort of United States Veterans. AB - Introduction: Cataract surgery is the most frequently performed surgery in the Veterans Health Administration (VHA). A well-known complication is a transient but potentially harmful elevation in intraocular pressure (IOP) within the 24-h postoperative period. The purpose of this study is to investigate the risk factors for IOP elevation 1 d after cataract surgery in a cohort of United States (US) veterans. Materials and Methods: The study included 784 patients who underwent cataract surgery between April 2013 and April 2016 at a single Veterans Affairs medical center in Providence, RI. One thousand one hundred thirty-seven cataract surgeries were considered in total. Institutional Review Board (IRB) approval was obtained through the Providence Veterans Affairs Medical Center (PVAMC). Logistic regression, adjusted for patients with bilateral surgeries, was used to evaluate risk factors for first postoperative day IOP elevation (>=28 mmHg). The main outcome measure was elevated IOP on postoperative day 1 (POD1) after cataract surgery. Results: The average patient age was 74 yr. Ninety-eight percent (1,110/1,137) of cases involved male patients; 75.3% (856/1,137) of the cataract surgeries were performed by resident surgeons. Type II diabetes mellitus (DM) was present in 41% (461/1,137), alpha-1 blocker use in 31% (358/1,137), ocular hypertension (ocular HTN) in 4% (44/1,137), and glaucoma in 11% (126/1,137) of cases. Twenty-two percent (232/1,137) of eyes had elevated IOP. Independent risk factors were a history of ocular HTN (OR: 8.74 [4.03-18.9]), glaucoma (OR: 3.54 [2.17-5.75]), a preoperative IOP >=22 mmHg (OR: 2.51 [1.12 5.62]), and complicated cataract surgery (OR: 2.45 [1.18-5.08]), defined as vitreous loss, anterior capsular tear (ACT), posterior capsular tear (PCT), or presence of zonular lysis. Conclusion: These findings suggest that cataract surgery patients with ocular HTN, glaucoma, a preoperative IOP >=22 mmHg, or significant intraocular complications may benefit from prophylactic ocular anti hypertensive medication. PMID- 29425313 TI - Multimorbidity in South Asian adults: prevalence, risk factors and mortality. AB - Background: We report the prevalence, risk factors and mortality associated with multimorbidity in urban South Asian adults. Methods: Hypertension, diabetes, heart disease, stroke and chronic kidney disease were measured at baseline in a sample of 16 287 adults ages >=20 years in Delhi, Chennai and Karachi in 2010-11 followed for an average of 38 months. Multimorbidity was defined as having >=2 chronic conditions at baseline. We identified correlates of multimorbidity at baseline using multinomial logistic models, and we assessed the prospective association between multimorbidity and mortality using Cox proportional hazards models. Results: The adjusted prevalence of multimorbidity was 9.4%; multimorbidity was highest in adults who were aged >=60 years (37%), consumed alcohol (12.3%), body mass index >=25 m/kg2 (14.1%), high waist circumference (17.1%) and had family history of a chronic condition (12.4%). Compared with adults with no chronic conditions, the fully adjusted relative hazard of death was twice as high in adults with two morbidities (hazard ratio [HR] = 2.3; 95% confidence interval [CI]: 1.6, 3.3) and thrice as high in adults with >=3 morbidities (HR = 3.1; 95% CI: 1.9, 5.1). Conclusion: Multimorbidity affects nearly 1 in 10 urban South Asians, and each additional morbidity carries a progressively higher risk of death. Identifying locally appropriate strategies for prevention and coordinated management of multimorbidity will benefit population health in the region. PMID- 29425314 TI - Trio, a novel bovine high fecundity allele: III. Acquisition of dominance and ovulatory capacity at a smaller follicle size. AB - The acquisition of dominance and ovulatory capacity was evaluated in follicles from cows that were carriers or half-sibling noncarriers of the Trio allele. Follicle size at acquisition of follicular dominance was determined by evaluating whether follicles ovulate after GnRH challenge (ovulatory capacity-experiment 1) and by determination of intrafollicular concentrations of estradiol and free insulin like growth factor 1 (IGF1) and relative mRNA expression of cytochrome P450 family 19 subfamily A member 1 (CYP19A1), luteinizing hormone/choriogonadotropin receptor (LHCGR), and pappalysin 1 (PAPPA, previously known as pregnancy-associated plasma protein A, pappalysin 1) in granulosa cells from follicles of different sizes (experiment 2). Ovulatory capacity developed in follicles at 8.3 mm (50% ovulatory capacity) in noncarriers but at smaller sizes (5.5 mm) in Trio carriers. Similarly, in experiment 2, follicles of Trio carriers acquired a dominant phenotype, as determined by intrafollicular estradiol and CYP19A1, LHCGR, and PAPPA mRNA expression in granulosa cells, at significantly smaller sizes but at a similar time after wave emergence. Overall, dominance/ovulatory capacity was acquired when follicles of Trio carriers were ~30% the size (volume basis) of follicles in noncarriers. In addition, follicles in Trio carriers appear to acquire dominance in a hierarchal manner, as demonstrated by the progressively greater number of follicles with a dominant phenotype between days 2 and 4 after wave emergence. Thus, results from this study provide further support for a physiological model in which selection of multiple follicles in Trio allele carriers is characterized by acquisition of dominance at a smaller follicle size but at a similar time in the follicular wave with multiple follicles acquiring dominance in a hierarchal sequence. PMID- 29425316 TI - The Problem of Unenforceable Surrogacy Contracts: Can Unjust Enrichment Provide a Solution? AB - The fact that surrogacy contracts are unenforceable can cause problems if a surrogate decides that she wishes to keep the child. When this happens, the intended parents cannot bring a claim in contract compelling her to give the baby up to them or even for the return of money paid to the surrogate. Intuitively, it appears unfair that the surrogate can keep the child and the money while the intended parents are left with nothing. However, enforcing such contracts could be oppressive to the surrogate and detrimental to the child's welfare. In this article, we consider whether the law unjust enrichment will allow for the return of money paid under such contracts. We argue that this branch of the law can provide a solution to the problem of unenforceable surrogacy contracts that strikes a fair balance between the interests of the surrogate and intended parents while also placing the child's lifelong welfare paramount. PMID- 29425315 TI - Residential eviction predicts initiation of or relapse into crystal methamphetamine use among people who inject drugs: a prospective cohort study. AB - Reports of increasing methamphetamine use among vulnerable populations may be attributed in part to the adaptive use of stimulants in response to the loss of stable housing through residential eviction. We employed multivariable recurrent event extended Cox regression to examine the independent association between recent evictions and initiation of or relapse into crystal methamphetamine use among people who inject drugs in Vancouver, Canada enrolled in two prospective cohort studies. In a multivariable analysis, eviction remained independently associated with methamphetamine initiation or relapse (adjusted hazard ratio = 1.90; 95% confidence interval: 1.31-2.75). Findings demonstrate the need to secure tenancies for drug-using populations to reduce harms. PMID- 29425318 TI - Albumin downregulates Klotho in tubular cells. AB - Background: Kidney tubular cells are the main sources of Klotho, a protein with phosphaturic action. Genetic Klotho deficiency causes premature cardiovascular aging in mice. Human chronic kidney disease (CKD) is characterized by acquired Klotho deficiency. Despite the lack of uremic toxin accumulation, Category G1 CKD [(normal glomerular filtration rate (GFR)] is already associated with decreased Klotho and with premature cardiovascular aging. Methods: We have explored whether albuminuria, a criterion to diagnose CKD when GFR is normal, may directly decrease Klotho expression in human CKD, preclinical models and cultured tubular cells. Results: In a CKD cohort, albuminuria correlated with serum phosphate after adjustment for GFR, age and sex. In this regard, urinary Klotho was decreased in patients with pathological albuminuria but preserved GFR. Proteinuria induced in rats by puromycin aminonucleoside and in mice by albumin overload was associated with interstitial inflammation and reduced total kidney Klotho messenger ribonucleic acid (mRNA) expression. Western blot disclosed reduced kidney Klotho protein in proteinuric rats and mice and immunohistochemistry localized the reduced kidney Klotho expression to tubular cells in proteinuric animals. In cultured murine and human tubular cells, albumin directly decreased Klotho mRNA and protein expression. This was inhibited by trichostatin A, an inhibitor of histone deacetylases, but unlike cytokine-induced Klotho downregulation, not by inhibitors of nuclear factor kappa-light-chain enhancer of activated B cells. Conclusions: In conclusion, albumin directly decreases Klotho expression in cultured tubular cells. This may explain, or at least contribute to, the decrease in Klotho and promote fibroblast growth factor 23 resistance in early CKD categories, as observed in preclinical and clinical proteinuric kidney disease. PMID- 29425319 TI - Changes in Temporary Disability Reporting Following the Implementation of the Army Medical Readiness Transformation. AB - Introduction: In November 2014, the U.S. Army held a readiness summit to address concerns about the accuracy of medical reporting systems. At the time, soldiers on temporary disability were tracked as a medical readiness classification (MRC) 3A or 3B. MRC 3A soldiers had a medical condition with recovery expected within 30 d and MRC 3B soldiers were expected to take longer than 30 d to recover. Both groups were considered "non-available" and presumably non-deployable. Starting June 1, 2016, with the implementation of the Army Medical Readiness Transformation, soldiers on temporary disability longer than 14 d began to be reported as MRC 3s and are considered "non-deployable." The purpose of this study is to compare the number of soldiers on temporary disability previously reported as MRC 3A and 3B to the number listed as MRC 3 under the new reporting system for a light infantry brigade and to quantify the types and relative percentage of medical conditions leading to temporary disability under the new system. Materials and Methods: This cross-sectional analysis was conducted between January 1 and December 31, 2016 at Fort Carson, Colorado and included all soldiers assigned to Second Brigade, Fourth Infantry Division. We calculated the average number and proportion of soldiers on temporary disability at any one time for the period prior to implementation of the new reporting system (January 1 through May 31, 2016) and compared this to the period after implementation on June 1, 2016. The difference between the two independent proportions was calculated along with the lower and upper limits of the 95% confidence interval for the difference. Results: Between January 1 and May 31, 2016, the average number of soldiers on temporary disability at any one time was 186, accounting for 4.3% of the authorized unit strength. After June 1, 2016, the average number increased to 244 or 5.7%. The difference in the proportion of temporary profiles was 1.4% (95% confidence interval 0.43-2.3%). From June 1 through December 31, 2016, 936 soldiers were placed on temporary disability. The majority was for orthopedic-related conditions (68.6%). Lower extremity (18.3%) and knee (17.5%) conditions were the two most common orthopedic issues. Behavioral health-related conditions (6.9%) and postoperative recovery (5.6%) were the next two most common categories. Conclusion: Implementation of the Army Medical Readiness Transformation resulted in a statistically significant increase in reported "non deployable" MRC 3 soldiers compared with the previous "non-available" MRC 3A/3B population. One possible reason for this relates to how temporary disability is reported under each system, especially for those soldiers with only mild limitations. Under the new system, musculoskeletal conditions accounted for the majority of disability. Important limitations include small sample sizes, a fluctuating denominator representing authorized unit strength, and that the study did not take into account seasonal variation and the operational cycle for the unit. Future studies should look at those conditions or soldier characteristics that can help guide commanders as they make deployability decisions and how to address wellness and injury prevention to mitigate the risk of soldiers going on temporary disability. PMID- 29425317 TI - Human Cervical Mucus Plugs Exhibit Insufficiencies in Antimicrobial Activity Towards Group B Streptococcus. AB - Preterm birth is a leading cause of neonatal mortality and lacks an effective therapy. Ascending microbial infections from the lower genital tract lead to infection of the placenta, amniotic fluid, and fetus causing preterm birth or stillbirth. Directly in the path of an ascending infection is the cervical mucus plug (CMP), a dense mucoid structure in the cervical canal with potential antimicrobial properties. In this study, we aimed to define the components of CMP responsible for antimicrobial activity against a common lower genital tract organism associated with preterm birth and stillbirths, namely, group B streptococcus (GBS). Using a quantitative proteomic approach, we identified antimicrobial factors in CMPs that were collected from healthy human pregnancies. However, we noted that the concentration of antimicrobial peptides present in the human CMPs were insufficient to directly kill GBS, and antimicrobial activity, when observed, was due to antibiotics retained in the CMPs. Despite this insufficiency, CMP proteins were able to activate leukocytes in whole blood resulting in increased rates of bacterial killing, suggesting a role for the CMP in enhancing complement-mediated killing or leukocyte activation. This study provides new insight into how the human CMP may limit ascending bacterial infection. PMID- 29425320 TI - Treatment for Uncomplicated Plasmodium falciparum Malaria in French Soldiers Deployed in Sub-Saharan Africa: Gaps Between Policy and Field Practice. AB - Background: Malaria prevention and treatment are big challenges for the French forces deployed in sub-Saharan Africa. Since December 2013, 1,800 French soldiers have been deployed at any one time in the Central African Republic in the framework of "Operation Sangaris" and European Union Force (EUFOR). Over the 2014 2015 period, about 500 cases of malaria were notified in these troops during the operation or after their return (annual incidence: 13.4 p.100 person-year). The recommendation to use dihydroartemisinin-piperaquine (DHA-PQ) as the first-line treatment for French soldiers suffering from uncomplicated Plasmodium falciparum malaria in endemic areas is not always followed in practice in the field by French military general practitioners (GPs). Methods: We conduced a retrospective Knowledge-Attitude-Practice study by self-administered questionnaire, to all military French doctors who were in mission in Central African Republic from January 2014 to July 2015 to try to understand what were the reasons for the GP not to prescribe DHA-PQ on the field. Findings: Thirty-six GPs (53%) answered to the questionnaire. Eighty-three percent of them knew about the recommendation to use DHA-PQ for un uncomplicated Pf malaria. Fifty-eight percent had a favorable attitude toward DHA-PQ. The factors associated with the prescription of another drug (Atovaquone-proguanil) were: the habit (odds ratio [OR] 0.1, confidence interval (CI) 0-0.6], the fact that Atovaquone-proguanil is more practical to use [OR 0.01, CI 0-0.1]. In practice, only 37.5% prescribed DHA-PQ the most of the time during their mission. Factors associated with a non-favorable attitude toward DHA-PQ were: the necessity to calculate a QTc interval during the treatment [OR 0.2, confidence interval 0-0.9], and the fact that DHA-PQ must be taken on an empty stomach [OR 0.3, CI 0.1-0.8]. GP who received a formation before their mission about malaria and treatment had a favorable attitude toward DHA-PQ. Discussion: There is very satisfactory knowledge by the military GPs stationed in the Central African Republic on both the recommendations and prescription of antimalarial drugs. The present study highlights some difficulties in implementing the recommendations in an operational context, notably factors limiting the prescription of DHA-PQ during military deployment (need for ECG monitoring, empty stomach, and lack of habit). Proposals can be made to improve the efficacy, tolerance, and practicability of malaria treatment in the field. The main focus should be a more flexible application of the French DHA-PQ risk management plan in the field, specific training and communication about DHA-PQ use, the generalization of ECG printing equipment in the field, and the switch from DHA-PQ to an alternative artemisinin-based combination therapy during deployments in malaria-endemic areas. PMID- 29425322 TI - Hepatitis Delta Enters a New Therapeutic Era. PMID- 29425323 TI - Long-Term Effectiveness of Gross-Total Resection for Symptomatic Spinal Cord Cavernous Malformations. AB - BACKGROUND: Intramedullary spinal cord cavernous malformations (CMs) account for 5% of all CMs in the central nervous system and 5% to 12% of all spinal cord vascular lesions, yet their optimal management is controversial. OBJECTIVE: To identify factors associated with the clinical progression of spinal cord CMs and quantify the range of surgical outcomes. METHODS: Retrospective observational cohort study of 32 patients who underwent open surgical resection for spinal CMs, the majority of which presented to a dorsal or lateral pial surface, from 1996 to 2017 at a single institution. We evaluated outcomes as clinically improved, worsened, or unchanged against preoperative baseline; Frankel and Aminoff-Logue disability grades were also calculated. RESULTS: Mean age at presentation was 44.2 (range, 0.5-77 yr). Symptoms included sensory deficits (n = 26, 81%), loss of strength/coordination (n = 16, 50%), pain (n = 16, 50%), and bladder/bowel dysfunction (n = 6, 19%). Thoracic (n = 16, 50%) and cervical CMs (n = 16, 50%) were equally common, with overall mean size of 7.1 mm (range, 1-20 mm). Functional outcomes at last follow-up, compared to preoperative status for patients with >6 mo of follow-up, were improved in 6 (23%), unchanged in 19 (73%), and worsened in 1 (4%) patients. Preoperative Frankel grade and improved Frankel grade immediately following resection were strongly associated with improvement from baseline at long-term followup (P < .01). CONCLUSION: Gross total resection of symptomatic spinal cord CMs can prevent further neurological decline. Our experience suggests excellent long-term outcomes and minimal surgical morbidity following resection. PMID- 29425324 TI - The Development of Wisdom: A Social Ecological Approach. AB - Objectives: This study examined the development of wisdom within the context of difficult life events (DLEs), and the importance of individuals and their social environments in this process of growth. Social support has long been studied in adulthood, yet less is known about the ways social transactions can promote wisdom. Method: Semi-structured interviews were conducted with men (n = 14) and women (n = 36), ages 56-91 years (M = 71.71; SD = 8.8) who described a DLE and how they coped with it. The analysis was guided by constructivist grounded theory. Results: DLEs included those from childhood through later life. When personal meaning was disrupted by adversity, the social environment played a key role in facilitating new perspectives that corresponded with aspects of wisdom: self-knowledge, compassion, comfort with uncertainty, and accepting complexity. Discussion: Wisdom is often studied as an individual characteristic, but this study highlighted the relevance of a social ecological perspective to understanding how wisdom development is also facilitated through social transactions. PMID- 29425321 TI - Splicing regulation by long noncoding RNAs. AB - Massive high-throughput sequencing techniques allowed the identification of thousands of noncoding RNAs (ncRNAs) and a plethora of different mRNA processing events occurring in higher organisms. Long ncRNAs can act directly as long transcripts or can be processed into active small si/miRNAs. They can modulate mRNA cleavage, translational repression or the epigenetic landscape of their target genes. Recently, certain long ncRNAs have been shown to play a crucial role in the regulation of alternative splicing in response to several stimuli or during disease. In this review, we focus on recent discoveries linking gene regulation by alternative splicing and its modulation by long and small ncRNAs. PMID- 29425325 TI - Selenzyme: enzyme selection tool for pathway design. AB - Summary: Synthetic biology applies the principles of engineering to biology in order to create biological functionalities not seen before in nature. One of the most exciting applications of synthetic biology is the design of new organisms with the ability to produce valuable chemicals including pharmaceuticals and biomaterials in a greener; sustainable fashion. Selecting the right enzymes to catalyze each reaction step in order to produce a desired target compound is, however, not trivial. Here, we present Selenzyme, a free online enzyme selection tool for metabolic pathway design. The user is guided through several decision steps in order to shortlist the best candidates for a given pathway step. The tool graphically presents key information about enzymes based on existing databases and tools such as: similarity of sequences and of catalyzed reactions; phylogenetic distance between source organism and intended host species; multiple alignment highlighting conserved regions, predicted catalytic site, and active regions and relevant properties such as predicted solubility and transmembrane regions. Selenzyme provides bespoke sequence selection for automated workflows in biofoundries. Availability and implementation: The tool is integrated as part of the pathway design stage into the design-build-test-learn SYNBIOCHEM pipeline. The Selenzyme web server is available at http://selenzyme.synbiochem.co.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29425326 TI - Test-Retest Reliabilty of Exercise-Induced Hypoalgesia After Aerobic Exercise. AB - Objective: Exercise increases pressure pain thresholds (PPTs) in exercising and nonexercising muscles, known as exercise-induced hypoalgesia (EIH). No studies have investigated the test-retest reliability of change in PPTs after aerobic exercise. Primary objectives were to compare the effect on PPTs after an incremental bicycling exercise compared with quiet rest and to investigate the relative and absolute test-retest reliability of the test stimulus (PPT) and the absolute and relative EIH response in exercising and nonexercising muscles. Setting: Laboratory. Methods: In two sessions, PPTs in the quadriceps and trapezius muscles were assessed before and after 15 minutes of quiet rest and 15 minutes of bicycling in 34 healthy subjects. Habitual physical activity was assessed by the International Physical Activity Questionnaire (IPAQ). Results: Bicycling increased PPTs in exercising and nonexercising muscles in both sessions (P < 0.05). The magnitude of the EIH response in the exercising muscle was, however, larger in the second compared with the first session (P < 0.015). PPTs showed excellent (intraclass correlation [ICC] >= 0.84) within-session and between-session test-retest reliability. The EIH response in exercising and nonexercising muscles demonstrated fair (ICC = 0.45) between-session relative test-retest reliability, but agreement in EIH responders between sessions was not significant (quadriceps: kappa = 0.24, P = 0.15; trapezius: kappa = 0.01, P = 0.97). Positive correlations between the IPAQ score and PPTs were found (quadriceps: r = 0.44, P = 0.009; trapezius: r = 0.31, P = 0.07) before exercise. No significant association was found between IPAQ and EIH. Conclusions: Incremental bicycling exercise increased PPTs with fair relative and absolute reliability of the EIH response. These data might have an impact on future studies investigating EIH and for clinicians designing exercise programs for pain relief. PMID- 29425327 TI - Sleep Disturbances in Chronic Pain: Neurobiology, Assessment, and Treatment in Physical Therapist Practice. AB - Among people with chronic pain, insomnia is highly prevalent, closely related to the mechanism of central sensitization, characterized by low-grade neuroinflammation, and commonly associated with stress or anxiety; in addition, it often does not respond effectively to drug treatments. This review article applies the current understanding of insomnia to clinical practice, including assessment and conservative treatment of insomnia in people with chronic pain. Cognitive-behavioral therapy for insomnia can be efficacious for improvements in sleep initiation, sleep maintenance, perceived sleep quality, and pain interference with daily functioning in people with chronic pain. A recent systematic review concluded that with additional training, physical therapist-led cognitive-behavioral interventions are efficacious for low back pain, allowing their implementation within the field. Cognitive-behavioral therapy for insomnia, as provided to people with chronic pain, typically includes education, sleep restriction measures, stimulus control instructions, sleep hygiene, and cognitive therapy. PMID- 29425328 TI - Advocating for an Enhanced Presence of Social Workers in Special Medical Needs Shelters during Emergencies. PMID- 29425329 TI - How Valid Are Assumptions About Re-emerging Smallpox? A Systematic Review of Parameters Used in Smallpox Mathematical Models. AB - Background: Globally eradicated in 1980, smallpox is listed as a category A bioterrorism agent. If smallpox were to re-emerge, it may be due to an act of bioterrorism or a laboratory accident, and the impact is likely to be severe. Preparedness against smallpox is subject to more uncertainty than other infectious diseases because it is eradicated, there is uncertainty about population immunity, and the current global health workforce has no practical experience or living memory of smallpox. In the event of re-emergence of smallpox, mathematical modeling plays a crucial role in improving the evidence base to inform preparedness, mitigation, and response activities. However, the predictions of mathematical models about outbreak magnitude and impact depend critically on the assumptions and disease parameters used. We aimed to identify modeling studies that would be applicable to re-emerging smallpox and to evaluate consistency and the certainty of the evidence published about the key parameters used. Methods: We conducted a systematic review using PRISMA criteria, of assumptions used in modeling studies on duration of latent, prodromal, and infectious period, as well as the choice of the basic reproduction number (R0) for re-emerging smallpox. We performed a literature search using PubMED, Scopus, Web of Science, and EMBASE and included peer-reviewed articles that focused on smallpox models, stated at least three of the aforementioned parameters and published in English. Findings: A total of 42 studies were selected for inclusion. There was general agreement on the duration of latent and prodromal periods, being 11-12 d (88%) and 3 d (59%), respectively. The duration of the infectious period varied from 4 to 20 d. Most models assumed 16 d (19%), 12 d (16.7%), and 8.6 d (12%) of infectiousness. In 25/34 studies, R0 ranged between 3 and 5, generally lower than the R0 calculated from past outbreaks. Discussion: Models of smallpox re-emergence also tend to use the same limited available historical data sources but assume a wide range of different estimates for key parameters. Models use very optimistic assumptions of decreased population immunity, despite high uncertainty about duration and magnitude of post vaccination immunity. This review reveals a paradox. A substantial proportion of the modern population is unvaccinated, never exposed to boosting from wild-type smallpox, or immunocompromised; furthermore, vaccine-induced immunity wanes over time. Failure to consider these factors in a model will lead to underestimating the true impact of a re-emergent smallpox epidemic in the contemporary population. PMID- 29425330 TI - Trigeminal Nerve Compression Without Trigeminal Neuralgia: Intraoperative vs Imaging Evidence. AB - BACKGROUND: While high-resolution imaging is increasingly used in guiding decisions about surgical interventions for the treatment of trigeminal neuralgia, direct assessment of the extent of vascular contact of the trigeminal nerve is still considered the gold standard for the determination of whether nerve decompression is warranted. OBJECTIVE: To compare intraoperative and magnetic resonance imaging (MRI) findings of the prevalence and severity of vascular compression of the trigeminal nerve in patients without classical trigeminal neuralgia. METHODS: We prospectively recruited 27 patients without facial pain who were undergoing microvascular decompression for hemifacial spasm and had undergone high-resolution preoperative MRI. Neurovascular contact/compression (NVC/C) by artery or vein was assessed both intraoperatively and by MRI, and was stratified into 3 types: simple contact, compression (indentation of the surface of the nerve), and deformity (deviation or distortion of the nerve). RESULTS: Intraoperative evidence of NVC/C was detected in 23 patients. MRI evidence of NVC/C was detected in 18 patients, all of whom had intraoperative evidence of NVC/C. Thus, there were 5, or 28% more patients in whom NVC/C was detected intraoperatively than with MRI (Kappa = 0.52); contact was observed in 4 of these patients and compression in 1 patient. In patients where NVC/C was observed by both methods, there was agreement regarding the severity of contact/compression in 83% (15/18) of patients (Kappa = 0.47). No patients exhibited deformity of the nerve by imaging or intraoperatively. CONCLUSION: There was moderate agreement between imaging and operative findings with respect to both the presence and severity of NVC/C. PMID- 29425331 TI - Modafinil in Forensic and Clinical Toxicology-Case Reports, Analytics and Literature. AB - Modafinil is used because of its wakefulness-promoting properties for treatment of diseases associated with extreme sleepiness (i.e., narcolepsy). Additionally, it is misused as a "cognitive enhancer" to increase alertness and to improve concentration. We present modafinil concentrations in serum samples in five cases of our routine work measured by high-performance liquid chromatography coupled with a photo diode array detector after solid-phase extraction. One sample was analyzed for clinical toxicology purposes. The other four were investigated for the police: three cases of driving under the influence of drugs and one case of bodily harm. Sample preparation consisted of solid-phase extraction using Bond Elut(r) C18 columns. Papaverine was used as internal standard. Chromatographic separation was carried out using a Polaris C18-A column in an isocratic run. Wavelengths used for UV-detection were 220 nm for modafinil and 239 nm for the internal standard, respectively. The method was validated with a reduced validation design for rare analytes. A six-point-calibration from 0.5 to 5.0 mg/L, covering the therapeutic range (0.9-3.3 mg/L), was used for quantification. Concentrations in serum were in the range of 1.3 to ~34 mg/L (median: 3.6 mg/L; mean: 9.0 mg/L). To our knowledge, there are only few publications concerning the serum concentrations of modafinil in cases of (suspected) misuse, forensic cases or intoxications. In our discussion, the serum concentrations we determined are compared with the levels described in the literature so far. PMID- 29425332 TI - Association between use of phthalate-containing medication and semen quality among men in couples referred for assisted reproduction. AB - STUDY QUESTION: Does phthalate exposure from prescription drugs affect semen quality? SUMMARY ANSWER: Exposure to phthalate-containing drugs is associated with poor semen quality. WHAT IS KNOWN ALREADY: Phthalates and their metabolites have been shown to disrupt the hormone signalling in animal studies. One study has shown associations between medicinal phthalate exposure and poor semen quality, suggesting similar effects in humans. STUDY DESIGN, SIZE, DURATION: We included 18 515 males with poor semen quality (cases) and 31 063 males with normal semen quality (controls) registered in the Danish IVF Registry from 2006 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Exposure to phthalate containing drugs was assessed from the Danish Register of Medicinal Product Statistics. Outcome measures were obtained at the first contact with the fertility clinic, and categorized according to the International Classification of Diseases (ICD-10). The association between current use of phthalate-containing medications <90 days prior to semen sampling and reduced semen quality was analysed using unconditional logistic regression, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 57 cases and 72 controls redeemed at least one prescription for a drug containing ortho phthalates in the 90 days before their first semen sample, yielding an adjusted odds ratio (OR) of 1.30 (95% CI: 0.91-1.85) for poor semen quality when compared to males exposed to phthalate-free generic drugs. Similarly, 81 cases and 78 controls exposed to a drug containing polymers had increased odds of poor semen quality (OR = 1.71, 95% CI: 1.24-2.35). Current exposure to polymer containing products from alimentary tract and metabolism drugs was associated with the highest OR of 2.80 (95% CI: 1.63-4.84). Comparing males exposed to drugs containing ortho-phthalates or polymers with males unexposed to prescription drugs, we found adjusted ORs of 1.32 (95% CI: 0.93-1.87) and 1.73 (95% CI: 1.26 2.36), respectively. We saw no clear relationship between degree of exposure and odds of poor semen quality. LIMITATIONS, REASONS FOR CAUTION: The reliance on ICD 10 based register data restricted our ability to relate phthalate exposure to detailed semen parameters. Furthermore, due to imperfections in the registry, we could only include the first semen sample and could not follow semen quality over time. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the likely negative effect of phthalate exposure from medicinal drugs on semen quality. As exposures from medicinal products are readily avoidable, our findings may be of relevance to regulatory authorities. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Odense University Hospital, Denmark (Grant number A1003). None of the authors declare conflict of interest. PMID- 29425333 TI - Taking an HPV vaccine research-tested intervention to scale in a clinical setting. AB - Research tested interventions are seldom ready for wide spread use. Successful intervention adaptation to clinical settings demands an iterative process with target audience feedback. We describe the adaptation process of implementing an NCI research tested HPV vaccine intervention, Women's Stories, to a community clinic context (Planned Parenthood). Five phases are described for the adaptation of content and the development of a health kiosk intervention delivery system: (a) informant interviews with the target audience of young adult, predominantly African-American women, (b) translating HPV vaccine decision narratives into prevention messages, (c) health kiosk interface design, (d) conducting a usability study of the health kiosk intervention product, and (e) conducting a waiting room observational study. Lessons learned and challenges in adapting prevention interventions to clinical settings are discussed. PMID- 29425334 TI - Bright environmental light ameliorates deficient subjective 'liking' in insomnia: an experience sampling study. AB - Study Objectives: Altered comfort sensing and reduced gray matter volume in the orbitofrontal cortex of the brain in people suffering from insomnia disorder (ID) suggest compromised processes of motivation and hedonia. The experience sampling (ES) method was used to evaluate whether, in naturalistic conditions, people with ID differ from those without sleep complaints with respect to subjective Wanting and Liking, two major dimensions of the reward system. Since light affects brain circuits involved in affect and reward, ES was combined with ambulatory monitoring of light intensity fluctuations to evaluate their effect on subjective Wanting and Liking. Methods: Participants with ID (n = 17, 12 females, 56.8 +/- 6.5 mean +/- standard deviation years of age) and matched controls without sleep complaints (n = 18, 12 females, 57.0 +/- 8.6 years of age) were probed by a smartphone alarm to log their subjective Wanting, Liking, and mood nine times a day for 7 days. Using an ambulatory light recorder, light intensity exposure was sampled simultaneously and averaged over the intervals between subsequent ES alarms. Mixed-effect models were used to evaluate how ID and varying light intensity affected subjective assessments. Results: The results indicated significantly lower subjective Liking and Wanting in people suffering from ID, particularly at low environmental light intensity. Conclusions: Wanting and Liking, rather than more commonly used mood adjectives, showed an increased sensitivity to detect deficient hedonic and reward processing in insomnia during everyday life. Deficient Liking may in part be rescued by exposure to bright environmental light. PMID- 29425335 TI - Wounded Healers: A Multistate Study of Licensed Social Workers' Behavioral Health Problems. AB - Studies indicate that helping professionals are disproportionately affected by behavioral health problems. Among social workers, the nature and scope of these problems are understudied. This article reports the findings of a 2015 survey of 6,112 licensed social workers in 13 states regarding their problems with mental health; alcohol, tobacco, and other drugs; and gambling. To ascertain whether these problems preceded or developed during their social work careers, the periods of time when these issues were experienced were identified. Results indicate that 40.2 percent of respondents reported mental health problems before becoming social workers, increasing to 51.8 percent during their social work career, with 28 percent currently experiencing such problems. Nearly 10 percent of the sample experienced substance use problems before becoming social workers, decreasing to 7.7 percent during their career. Analyses by race or ethnicity, sex, and age identified between-group differences in the prevalence of these problems. The article concludes with a discussion of the implications for the social work profession. PMID- 29425336 TI - Is Access to Outpatient Neurosurgery Affected by Narrow Insurance Networks? Results From Statewide Analysis of Marketplace Plans in Louisiana. AB - BACKGROUND: The main objective of the Affordable Care Act (ACA) was to make health insurance affordable to all Americans while addressing the lack of coverage for 48 million people. In the face of rapidly increasing enrollment and rising demand for inexpensive plans, insurance providers are limiting in-network physicians. Provider networks offering plans with limited in-network physicians have become known as "narrow networks." OBJECTIVE: To assesses the adequacy of ACA marketplace plans for outpatient neurosurgery in Louisiana. METHODS: The Marketplace Public Use Files were searched for all "silver" plans. A total of 7 silver plans were identified in Louisiana. Using the plans' online directories, a search of in-network neurosurgeons in Louisiana parishes with >100 000 population was performed. The primary outcome was lack of in-network neurosurgeon(s) in silver plans within 50 miles of selected zip code for each parish with >100 000 population. Plans without in-network neurosurgeon(s) are labeled as neurosurgeon deficient plans. RESULTS: Several plans in Louisiana are neurosurgeon deficient, ie no in-network neurosurgeon within 50 miles of the designated parish zip code. Company A's plan 3 is deficient in all 5 parishes, while company C and company D silver plans are deficient in 4 out of 14 (29%). Combined results from all counties and plans demonstrate that 43% (3 out of 7) of all silver plans in Louisiana are neurosurgeon deficient in at least 4 parishes with population >100 000. CONCLUSION: In Louisiana, narrow networks have limited access to neurosurgical care for those patients with ACA silver plans. PMID- 29425337 TI - Self-assembly of FUS through its low-complexity domain contributes to neurodegeneration. AB - Aggregation of fused in sarcoma (FUS) protein, and mutations in FUS gene, are causative to a range of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. To gain insights into the molecular mechanism whereby FUS causes neurodegeneration, we generated transgenic Drosophila melanogaster overexpressing human FUS in the photoreceptor neurons, which exhibited mild retinal degeneration. Expression of familial ALS-mutant FUS aggravated the degeneration, which was associated with an increase in cytoplasmic localization of FUS. A carboxy-terminally truncated R495X mutant FUS also was localized in cytoplasm, whereas the degenerative phenotype was diminished. Double expression of R495X and wild-type FUS dramatically exacerbated degeneration, sequestrating wild-type FUS into cytoplasmic aggregates. Notably, replacement of all tyrosine residues within the low-complexity domain, which abolished self assembly of FUS, completely eliminated the degenerative phenotypes. Taken together, we propose that self-assembly of FUS through its low-complexity domain contributes to FUS-induced neurodegeneration. PMID- 29425339 TI - CD28 co-stimulation is dispensable for the steady state homeostasis of intestinal regulatory T cells. AB - It is well-established that CD28 co-stimulation is required for the development and the proliferation of thymus-derived regulatory T cells (tTregs). Meanwhile, the role of CD28 co-stimulation in the homeostasis of peripherally derived Tregs (pTregs) remains unclear. To clarify this issue, we analyzed Tregs in small and large intestines (SI and LI), the principle sites of pTreg development. Interestingly, and different from in the thymus, Tregs were abundant in the intestines of CD28-/- mice, and most of them were phenotypically pTregs. We showed that CD28-/- naive T cells differentiated into pTregs in the LI after oral exposure to antigens and that CD28-/- pTregs in the LI had the same highly proliferative activity as CD28+/- cells. CD28-/- pTregs acquired these Treg specific features at transcriptional and epigenetics levels. On the other hand, some immune suppressive molecules were down-regulated in CD28-/- pTregs. Correspondingly, the suppressive activity of CD28-/- pTregs was weaker than CD28+/+ cells. These results indicate that the homeostasis of pTregs in the intestines is maintained even in the absence of CD28, whereas CD28 is required for the maximal suppressive activity of intestinal pTregs. PMID- 29425338 TI - Village health volunteers' individual social capital and caretakers' health service utilization for febrile children in Malaria-endemic villages in Papua New Guinea. AB - Background: Little is known about the association between the social capital of village health volunteers (VHVs) and their performance in relation to malarial care. Methods: Data came from 337 children and 13 VHVs working in Dagua, Papua New Guinea. The outcome variable was whether caretakers brought their children to health care services on the incidence of a febrile episode. The social capital of VHVs was assessed by inquiring about relationships with people in 25 social positions/roles. Results: Caretakers were more likely to bring their febrile children to health care services when they lived in a village whose VHVs frequently discussed their activities with people in positions/roles outside their village (prevalence ratio [PR]=1.47 [95% confidence interval {CI} 1.22 to 1.78]). On the other hand, caretakers were less likely to do so when their VHVs had known people in informal positions/roles inside their village (PR=0.85 [95% CI 0.77 to 0.93]) and when they discussed their activities with people in formal positions/roles inside their village (PR=0.76 [95% CI 0.61 to 0.95]). Conclusions: Our results suggest that the social interactions of VHVs with people in positions/roles outside the village may benefit residents while those with people in positions/roles inside the village might not necessarily benefit them. PMID- 29425340 TI - Clinical review of delafloxacin: a novel anionic fluoroquinolone. AB - Delafloxacin is a novel anionic fluoroquinolone (FQ) approved for treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by a number of Gram-positive and Gram-negative organisms including MRSA and Pseudomonas aeruginosa. The unique chemical structure of delafloxacin renders it a weak acid and results in increased potency in acidic environments. In Phase III studies, delafloxacin had similar outcomes to comparator regimens for treatment of ABSSSIs, and was well tolerated overall. Similar to other FQs, delafloxacin is available in both intravenous and oral formulations, but differs in that delafloxacin exerts a minimal effect on cytochrome P450 enzymes and on the corrected QT interval. This novel FQ has the potential to be utilized across a wide variety of clinical settings; however, post-marketing surveillance and long term safety and resistance data will be essential to identify optimal use scenarios. PMID- 29425341 TI - Fibroblast growth factor 23 is induced by an activated renin-angiotensin aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts. AB - Background: Fibroblast growth factor 23 (FGF23) is discussed as a new biomarker of cardiac hypertrophy and mortality in patients with and without chronic kidney disease (CKD). We previously demonstrated that FGF23 is expressed by cardiac myocytes, enhanced in CKD and induces cardiac hypertrophy via activation of FGF receptor 4 independent of its co-receptor klotho. The impact of FGF23 on cardiac fibrosis is largely unknown. Methods: By conducting a retrospective case-control study including myocardial autopsy samples from 24 patients with end-stage CKD and in vitro studies in cardiac fibroblasts and myocytes, we investigated the pro fibrotic properties of FGF23. Results: The accumulation of fibrillar collagens I and III was increased in myocardial tissue of CKD patients and correlated with dialysis vintage, klotho deficiency and enhanced cardiac angiotensinogen (AGT) expression. Using human fibrosis RT2 Profiler PCR array analysis, transforming growth factor (TGF)-beta and its related TGF-beta receptor/Smad complexes, extracellular matrix remodeling enzymes and pro-fibrotic growth factors were upregulated in myocardial tissue of CKD patients. FGF23 stimulated cell proliferation, migration, pro-fibrotic TGF-beta receptor/Smad complexes and collagen synthesis in cultured cardiac fibroblasts. In isolated cardiac myocytes, FGF23 enhanced collagen remodeling, expression of pro-inflammatory genes and pro survival pathways and induced pro-hypertrophic genes. FGF23 stimulated AGT expression in cardiac myocytes and angiotensin II and aldosterone, as components of the renin-angiotensin-aldosterone system (RAAS), induced FGF23 in cardiac myocytes. Conclusions: Our data demonstrate that activated RAAS induces FGF23 expression in cardiac myocytes and thereby stimulates a pro-fibrotic crosstalk between cardiac myocytes and fibroblasts, which may contribute to myocardial fibrosis in CKD. PMID- 29425343 TI - Prevalence and causes of musculoskeletal impairment in Mahabubnagar District, Telangana State, India: results of a population-based survey. AB - Background: Musculoskeletal impairments (MSI) are the leading contributor to global years lived with disability. Comparable epidemiological data on MSI is lacking, and are needed to inform health and rehabilitative services. This study aimed to estimate the prevalence and causes of MSI in Telangana State, India. Method: A population-based survey used probability proportionate to size and compact-segment sampling to select 51 clusters of 80 individuals (all ages). Participants were screened using seven questions and any participant who screened positive underwent standardized examination by a physiotherapist for MSI presence, severity and diagnosis. Data were also collected on vision and hearing impairment, depression and self-reported difficulties with physical functioning. Results: The prevalence of MSI was 19.6% (95% CI: 16.7-22.8%) and this increased with age. The majority (82%; 574/699) of MSI was classified as mild, 11% as moderate and 7% as severe. Over half (57%) of MSI diagnoses were acquired non traumatic causes, with degenerative joint disease being the most common. There was a high unmet need for physiotherapy services (3% attended vs. 40% recommended). One-fifth (21%) of MSI cases also had at least one of vision (10%) or hearing (11%) impairment or depression (3%). Conclusions: MSI is common among persons living in Mahabubnagar District, particularly older adults. These estimates can inform public health initiatives for the planning of health and rehabilitation services. PMID- 29425344 TI - DEWAX2 Transcription Factor Negatively Regulates Cuticular Wax Biosynthesis in Arabidopsis Leaves. AB - The aerial parts of terrestrial plants are covered with hydrophobic wax layers, which represent the primary barrier between plant cells and the environment and act to protect plants from abiotic and biotic stresses. Although total wax loads are precisely regulated in an environmental- or organ-specific manner, regulatory mechanisms underlying cuticular wax biosynthesis remain largely unknown. In this study, we characterized DEWAX2 (DECREASE WAX BIOSYNTHESIS2) which encodes an APETALA 2 (AP2)/ethylene response element-binding factor (ERF)-type transcription factor and is predominantly expressed in young seedlings, and rosette and cauline leaves. Total wax loads increased by approximately 12% and 16% in rosette and cauline leaves of dewax2, respectively, but were not significantly altered in the stems of dewax2 relative to the wild type (WT). The excess wax phenotype of dewax2 leaves was rescued upon expression of DEWAX2 driven by its own promoter. Overexpression of DEWAX2 decreased total wax loads by approximately 15% and 26% in the stems and rosette leaves compared with those of the WT, respectively. DEWAX2:eYFP (enhanced yellow fluorescent protein) was localized to the nucleus in Arabidopsis roots and hypocotyls. DEWAX2 possessed transcriptional repression activity in tobacco protoplasts. Transcriptome and quantitative real-time PCR analyses showed that the transcript levels of CER1, ACLA2, LACS1, LACS2 and KCS12 were down-regulated in DEWAX2 overexpression lines compared with the WT. Transient transcriptional assays showed that DEWAX2 represses the expression of its putative target genes. Quantitative chromatin immunoprecipitation-PCR revealed that DEWAX2 binds directly to the GCC motifs of the LACS1, LACS2, KCS12 and CER1 promoters. These results suggest that DEWAX2-mediated transcriptional repression may contribute to the total wax load in Arabidopsis leaves. PMID- 29425345 TI - Recurrent Central Serous Retinopathy with Permanent Visual Loss in a U.S. Naval Fighter Pilot. AB - Central serous retinopathy (CSR) is a disease process that involves accumulation of serous fluid within the macular retina. This fluid accumulation can temporarily or permanently disrupt vision and in many patients is often a recurrent problem. This case describes recurrent CSR in an experienced U.S. Naval F/A-18 fighter pilot. The patient had been troubled by recurrent CSR for several years which required him to be removed from a flying status. After several episodes and treatment with laser photocoagulation and finasteride, the patient's vision and disease process stabilized, but with permanent defective visual acuity in the right eye. There have been many case reports documenting CSR in active duty military aviators worldwide, including flying pilots who have residual permanent loss of visual acuity; however, this is the first U.S. Naval pilot who has been granted a waiver to return to unrestricted flight status with permanent defective visual acuity. PMID- 29425342 TI - Characterization of the rubber tree metallothionein family reveals a role in mitigating the effects of reactive oxygen species associated with physiological stress. AB - Metallothioneins (MTs) as reactive oxygen species (ROS) scavengers play important roles in stress response and heavy metal homeostasis. In Hevea brasiliensis (the para rubber tree that is the source of commercial natural rubber) and in other trees, the functions of MTs are not well understood. Latex exudes when the rubber tree is tapped. The flow of latex and its regeneration can be enhanced by tapping, wounding and ethylene treatment, all of which produce ROS as a by product. Here, we show the presence of four MT genes in H. brasiliensis, comprising three Type 2 (HbMT2, -2a and -2b) and one Type 3 (HbMT3L) isoforms, representing one of the smallest MT gene families among angiosperms. The four HbMTs exhibited distinct tissue expression patterns: HbMT2 and HbMT3L mainly in leaves, HbMT2a specifically in flowers and HbMT2b in diverse tissues. The expression of HbMT2b, an isoform present in latex, decreased significantly in the latex following the stress-inducing treatments of tapping, wounding and ethephon (an ethylene generator). The expressions of the leaf-abundant isoforms, HbMT2 and -3L were up-regulated following pathogenic fungus infection and high-temperature stress, but down-regulated by low-temperature stress. These reactions were consistent with multiple defense- and hormone-responsive cis-acting elements in the HbMT promoters. Nine transcription factors were shown to implicate in the high-temperature responsiveness of HbMT2 and -3L in leaves. Overexpression of HbMT2 in Escherichia coli enhanced the bacterium's tolerance to heavy metals and ROS, consistent with its predicted role as an ROS scavenger. Taken together, our results, along with other relevant studies, suggest an important role of HbMTs in latex regeneration as well as species adaptation via the regulation of ROS homeostasis. PMID- 29425346 TI - Temperature response of respiration and respiratory quotients of 16 co-occurring temperate tree species. AB - The forests of the northeastern US are globally, one of the fastest growing terrestrial carbon sinks due to historical declines in large-scale agriculture, timber harvesting and fire disturbance. However, shifting range distributions of tree species with warming air temperatures are altering forest community composition and carbon dynamics. Here, we focus on respiration, a physiological process that is strongly temperature and species dependent. We specifically examined the response of respiration (R; CO2 release) to temperature in 10 broadleaved and six conifer species, as well as the respiratory quotient (RQ; ratio of CO2 released to O2 consumed) of nine broadleaved species that co-occur in the Hudson Highlands Region of New York, USA. The relationships between these physiological measurements and associated leaf traits were also explored. The rates of respiration at 20 degrees C were 71% higher in northern-ranged broadleaved species when compared with both central- and southern-ranged species. In contrast, the rates of respiration at 20 degrees C in northern-ranged conifers were 12% lower than in central-ranged conifers. The RQ of broadleaved species increased by 14% as temperatures increased from 15 degrees C to 35 degrees C. When RQ values were pooled across temperature, northern-ranged broadleaved species had 12% and 9% lower RQ values than central, and southern ranged species, respectively, suggesting a reliance on alternative (non carbohydrate) substrates to fulfill respiratory demands. A Pearson correlation analysis of leaf traits and respiration revealed strong correlations between leaf nitrogen, leaf mass area and R for both broadleaved and conifer species. Our results elucidate leaf trait relationships with tree physiology and reveal the various form and function strategies for species from differing range distributions. Compounded with predicted range distribution shifts and species replacement, this may reduce the carbon storage potential of northeast forests. PMID- 29425347 TI - Jeroen Bax MD PhD President of the European Society of Cardiology: He is a little more than halfway through his 2-year term as President of the European Society of Cardiology (ESC), but Jeroen Bax can already hear the clock ticking. PMID- 29425348 TI - William G Stevenson MD: The electrophysiology cardiologist who has been involved with ventricular tachycardia since the 1980s and is still searching. PMID- 29425349 TI - Fuwai Hospital, Beijing, China: The World's Largest Cardiovascular Science Centre with more than 1200 beds. PMID- 29425350 TI - The Cardiomyopathy Research Group at Fuwai Hospital. PMID- 29425351 TI - An African cardiology summit: The World Heart Federation African Summit on Best Practices in Policy and Access to Care in 2017 concluded with the Khartoum Action Plan, to improve cardiovascular on the African continent. PMID- 29425352 TI - Women and Men Together in Recruit Training. AB - Introduction: Although men and women recruits to the Australian Army have trained in mixed-gender platoons since 1995, restrictions on women joining the combat arms were only removed in 2016. As part of a longitudinal study starting with recruit training, this article examined recruit records collected before 2016 with the aims of delineating (1) the relative performance of women versus men in mixed-gender platoons and (2) the relative performance of men in mixed-gender platoons versus all-male platoons. Materials and Methods: De-identified instructor ratings for 630 females and 4,505 males who completed training between 2011 and 2015 were obtained. Recruits were distributed across 128 platoons (averaging 41.6 members, SD = 8.3) of which 75% contained females, in proportions from 5% to 45%. These analyses were conducted under defense ethics approval DPR LREP 069-15. Results: Factor analyses revealed that instructor ratings generally loaded onto a single factor, accounting 77.2% of the variance. Consequently, a composite recruit performance score (range 1-5) was computed for 16 of 19 competencies. Analyses of the scores revealed that the distributions of the scores for females and males overlapped considerably. Observed effects were negligible to small in size. The distributions were all centered between 3.0 and 3.5. In mixed-gender platoons, 51% of the females and 52% of the males fell in this band, and 44% of recruits in all-male platoons had scores in this band. The lower three bands (1.0-3.0) contained a slightly greater proportion of females (18%) than males in either mixed-gender platoons (12%) or all-male platoons (12%). Conversely, the upper three bands (3.5-5.0) contained a slightly smaller percentage of females (31%) than males in either mixed-gender platoons (36%) or all-male platoons (44%). Although scores for females were reliably lower than those of males in mixed-gender platoons, chi2 (4) = 16.01, p < 0.01, the effect size (V = 0.07) did not reach the criterion for even a small effect (0.10). For male recruits, those in mixed-gender platoons had scores that were reliably lower than in all-male platoons, chi2 (4) = 48.38, p < 0.001; its effect size (V = 0.11) just exceeded the criterion for a small effect (0.10). Further analyses revealed that male scores had a near-zero correlation (r = -0.033) with the proportion of females in platoons (0-45%). Conclusion: This large-scale secondary analysis of instructor ratings of female and male recruits provides a platform for monitoring the integration of women into the combat arms. The analyses revealed nearly complete overlap in the performance of female versus male recruits. The detected gender-related differences were negligible to small in size. These small differences must be viewed with considerable caution. They may be artifacts of rater bias or other uncontrolled features of the rating system, which was designed for reporting individual recruit performance rather than aggregate analyses. Even with these limitations, this baseline snapshot of recruit performance suggests that, at recruit training, women and men are already working well together, which bodes well for their subsequent integration into the combat arms. PMID- 29425353 TI - Differential Dependence of GABAergic and Glutamatergic Neurons on Glia for the Establishment of Synaptic Transmission. AB - In the mammalian cortex, GABAergic and glutamatergic neurons represent 2 major neuronal classes, which establish inhibitory and excitatory synapses, respectively. Despite differences in their anatomy, physiology and developmental origin, both cell types require support from glial cells, particularly astrocytes, for their growth and survival. Recent experiments indicate that glutamatergic neurons also depend on astrocytes for synapse formation. However, it is not clear if the same holds true for GABAergic neurons. By studying highly pure GABAergic cell cultures, established through fluorescent activated cell sorting, we find that purified GABAergic neurons are smaller and have reduced survival, nevertheless they establish robust synaptic transmission in the absence of glia. Support from glial cells reverses morphological and survival deficits, but does little to alter synaptic transmission. In contrast, in cultures of purified glutamatergic neurons, morphological development, survival and synaptic transmission are collectively dependent on glial support. Thus, our results demonstrate a fundamental difference in the way GABAergic and glutamatergic neurons depend on glia for the establishment of synaptic transmission, a finding that has important implications for our understanding of how neuronal networks develop. PMID- 29425354 TI - A qualitative study of patient experiences of care in integrated behavioral health and primary care settings: more similar than different. AB - Integrated behavioral health and primary care is a patient-centered approach designed to address a person's physical, emotional, and social healthcare needs. Increasingly, practices are integrating care to help achieve the Quadruple Aim, yet no studies have examined, using qualitative methods, patients' experiences of care in integrated settings. The purpose of this study was to examine patients' experiences of care in community-based settings integrating behavioral health and primary care. This is a qualitative study of 24 patients receiving care across five practices participating in Advancing Care Together (ACT). ACT was a 4-year demonstration project (2010-2014) of primary care and community mental health centers (CMHCs) integrating care. We conducted in-depth interviews in 2014 and a multidisciplinary team analyzed data using an inductive qualitative descriptive approach. Nineteen patients described receiving integrated care. Both primary care and CMHC patients felt cared for when the full spectrum of their needs, including physical, emotional, and social circumstances, were addressed. Patients perceived personal, interpersonal, and organizational benefits from integrated care. Interactions with integrated team members helped patients develop and/or improve coping skills; patients shared lessons learned with family and friends. Service proximity, provider continuity and trust, and a number of free initial behavioral health appointments supported patient access to, and engagement with, integrated care. In contrast, patients' prior experience, provider "mismatch," clinician turnover, and restrictive insurance coverage presented barriers in accessing and sustaining care. Patients in both primary care and CMHCs perceived similar benefits from integrated care related to personal growth, improved quality, and access to care. Policy makers and practice leadership should attend to proximity, continuity, trust, and cost/coverage as factors that can impede or facilitate engagement with integrated care. PMID- 29425355 TI - An Initial Report of Sleep Disorders in Women in the U.S. Military. AB - Introduction: Sleep disorders are increasingly recognized in active duty service members (ADSM). While there are multiple studies in male ADSM, there are limited data regarding sleep disorders in women in the military. The purpose of this study was to characterize sleep disorders in female ADSM referred for clinical evaluation to provide a better understanding of this unique population. Materials and Methods: We conducted a retrospective review of female ADSM who underwent a sleep medicine evaluation and an attended polysomnogram (PSG). Demographic and polysomnogram variables, as well as medical records, were reviewed. Associated illnesses to include post-traumatic stress disorder, pain disorders, anxiety, and depression, were recorded. Results: The cohort consisted of 101 women. The average age was 33.9 +/- 9.0 years and body mass index was 27.3 +/- 4.5, with an average Epworth Sleepiness Scale score of 12.9 +/- 5.2, and Insomnia Severity Index score of 17.6 +/- 5.7. Overall, 36.6% were diagnosed with insomnia only, 14.9% with obstructive sleep apnea (OSA) only, and 34.7% met diagnostic criteria for both insomnia and OSA. The average apnea-hypopnea index for the entire cohort was 5.37 +/- 7.04/h whereas it was 10.34 +/- 3.14/h for those meeting diagnostic criteria for OSA. The women referred for sleep evaluations had the following rates of associated illnesses: pain disorders (59.4%), anxiety (48.5%), depression (46.5%), and post-traumatic stress disorder (21.8%). For patients with OSA, the relative risk of having post-traumatic stress disorder was 2.72 (95% confidence interval 1.16-6.39). Conclusions: Women in the U.S. military who have sleep disorders have a high rate of behavioral medicine and pain disorders. Interestingly, nearly 50% of active duty females referred for a sleep study have OSA while not necessarily manifesting the typical signs of obesity or increased age. The reasons for this finding are not completely understood, though factors related to military service may potentially contribute. The findings from our study indicate a need for increased awareness and evaluation of sleep disorders in women in the military, especially those with behavioral medicine disorders. PMID- 29425356 TI - UniProt: the universal protein knowledgebase. PMID- 29425357 TI - Novel Presentation of Fibroepithelioma of Pinkus on the Ear of a Patient Treated on a Panamanian Humanitarian Mission. AB - Fibroepithelioma of Pinkus (FEP) is traditionally classified as an unusual variant of basal cell carcinoma. It has non-specific clinical findings yet distinct histologic features. The diagnosis can be challenging for clinicians because it often mimics benign entities such as intradermal nevi. FEP typically occurs on the trunk, but many body sites can be involved including the head, neck, and genitalia. According to a PubMed search of articles indexed in MEDLINE using "Fibroepithelioma of Pinkus" and "ear" or "auricle," there are no reports of FEP specifically occurring on the ear. We describe the first case of FEP on the ear of a heavily sun-damaged male treated while on a military humanitarian mission to Panama. This case helps support the classification of FEP as a basal cell carcinoma variant and raises awareness for this entity as it may be encountered both on military humanitarian missions and in military clinics. PMID- 29425358 TI - Very Low Prevalence of Vaccine Human Papillomavirus Types Among 18- to 35-Year Old Australian Women 9 Years Following Implementation of Vaccination. AB - Introduction: A quadrivalent human papillomavirus vaccination program targeting females aged 12-13 years commenced in Australia in 2007, with catch-up vaccination of 14-26 year olds through 2009. We evaluated the program's impact on HPV prevalence among women aged 18-35 in 2015. Methods: HPV prevalence among women aged 18-24 and 25-35 was compared with prevalence in these age groups in 2005-2007. For women aged 18-24, we also compared prevalence with that in a postvaccine study conducted in 2010-2012. Results: For the 2015 sample, Vaccination Register-confirmed 3-dose coverage was 53.3% (65.0% and 40.3% aged 18 24 and 25-35, respectively). Prevalence of vaccine HPV types decreased from 22.7% (2005-2007) and 7.3% (2010-2012), to 1.5% (2015) (P trend < .001) among women aged 18-24, and from 11.8% (2005-2007) to 1.1% (2015) (P = .001) among those aged 25-35. Conclusions: This study, reporting the longest surveillance follow-up to date, shows prevalence of vaccine-targeted HPV types has continued to decline among young women. A substantial fall also occurred in women aged 25-35, despite lower coverage. Strong herd protection and effectiveness of less than 3 vaccine doses likely contributed to these reductions. PMID- 29425359 TI - Petal senescence: a hormone view. AB - Flowers are highly complex organs that have evolved to enhance the reproductive success of angiosperms. As a key component of flowers, petals play a vital role in attracting pollinators and ensuring successful pollination. Having fulfilled this function, petals senesce through a process that involves many physiological and biochemical changes that also occur during leaf senescence. However, petal senescence is distinct, due to the abundance of secondary metabolites in petals and the fact that petal senescence is irreversible. Various phytohormones are involved in regulating petal senescence, and are thought to act both synergistically and antagonistically. In this regard, there appears to be developmental point during which such regulatory signals are sensed and senescence is initiated. Here, we review current understanding of petal senescence, and discuss associated regulatory mechanisms involving hormone interactions and epigenetic regulation. PMID- 29425360 TI - Transcriptional Regulation of Arbuscular Mycorrhiza Development. AB - Arbuscular mycorrhiza (AM) is an ancient symbiosis between land plants and fungi of the glomeromycotina that is widespread in the plant kingdom. AM improves plant nutrition, stress resistance and general plant performance, and thus represents a promising addition to sustainable agricultural practices. In return for delivering mineral nutrients, the obligate biotrophic AM fungi receive up to 20% of the photosynthetically fixed carbon from the plant. AM fungi colonize the inside of roots and form highly branched tree-shaped structures, called arbuscules, in cortex cells. The pair of the arbuscule and its host cell is considered the central functional unit of the symbiosis as it mediates the bidirectional nutrient exchange between the symbionts. The development and spread of AM fungi within the root is predominantly under the control of the host plant and depends on its developmental and physiological status. Intracellular accommodation of fungal structures is enabled by the remarkable plasticity of plant cells, which undergo drastic subcellular rearrangements. These are promoted and accompanied by cell-autonomous transcriptional reprogramming. AM development can be dissected into distinct stages using plant mutants. Progress in the application of laser dissection technology has allowed the assignment of transcriptional responses to specific stages and cell types. The first transcription factors controlling AM-specific gene expression and AM development have been discovered, and cis-elements required for AM-responsive promoter activity have been identified. An understanding of their connectivity and elucidation of transcriptional networks orchestrating AM development can be expected in the near future. PMID- 29425361 TI - Quadrivalent human papillomavirus vaccination in boys and risk of autoimmune diseases, neurological diseases and venous thromboembolism. AB - Background: In recent years, human papillomavirus (HPV) vaccination of boys has been added to childhood vaccination programmes in several countries but, so far, no systematic population-based assessment with long-term follow-up has been undertaken of the relative incidence of adverse outcomes following HPV vaccination in this group. We investigated if quadrivalent HPV (qHPV) vaccination of 10-17-year-old boys is associated with any unusual risk of autoimmune diseases, neurological diseases or venous thromboembolism. Methods: We conducted a national cohort study of 568 410 boys born in Denmark 1988-2006 and followed for 4 million person-years during 2006-16, using nationwide registers to obtain individual-level information about received doses of the qHPV vaccine and hospital records for 39 autoimmune diseases, 12 neurological diseases and venous thromboembolism. For each outcome, we estimated incidence rate ratios (RRs) with 95% confidence intervals (CIs) according to qHPV vaccination status. Results: Altogether 7384 boys received at least one dose of the qHPV vaccine at age 10-17 years. Overall, RRs were close to unity for the combined groups of autoimmune diseases (RR = 0.96; 95% CI: 0.71-1.28, n = 46 cases in qHPV-vaccinated boys) and neurological diseases (RR = 0.67; 0.41-1.10, n = 16), as well as for venous thromboembolism (RR = 0.88; 0.33-2.35, n = 4). After taking multiple testing into account, none of the 52 individual outcomes studied appeared to occur in excess among qHPV-vaccinated boys. Conclusions: Although additional large-scale epidemiological studies are warranted, our findings provide population-based reassurance that qHPV vaccination of 10-17-year-old boys is unlikely to be associated with an elevated risk of autoimmune diseases, neurological diseases or venous thromboembolism. PMID- 29425362 TI - Time Factor and Disc Herniation Size: Are They Really Predictive for Outcome of Urinary Dysfunction in Patients With Cauda Equina Syndrome? AB - BACKGROUND: Timing of surgery and the importance of the size of disc prolapse in cauda equina syndrome (CES) remain controversial. OBJECTIVE: To investigate whether there is a relationship between postoperative urinary function, preoperative duration of neurogenic lower urinary tract dysfunction (NLUTD), and the level of canal compromise. METHODS: Seventy-one patients operated for CES were prospectively identified between 2010 and 2013. Fifty-two cases with preoperative NLUTD were included. The "Prolapse: Canal ratio" (PCR) was calculated as a proportion of cross-sectional area of disc prolapse on total cross-sectional area of spinal canal. RESULTS: Median of preoperative duration of NLUTD was 72 h (48; 132) and period from first assessment to surgery 10.5 h (7; 18.5). Urinary incontinence was seen in 46.2% of patients, 38.4% had painless retention and 15.4% had painful retention. In 38.5% of cases, urinary symptoms persisted for more than 20 mo postoperatively. There was no correlation between duration of preoperative NLUTD and urinary dysfunction persistence (P = .921). The outcome was not significantly influenced by having surgery more than the 48 h after presentation (P = .135). Preoperative incontinence persisted in 58% and painless retention in 30% of cases. The mean PCR was 0.6 +/- 0.18. There was no correlation between PCR and outcome (P = .537) even after adjusting for duration of preoperative NLUTD (P = .7264). CONCLUSION: No significant correlation was demonstrated between the preoperative duration of urinary dysfunction, the size of disc herniation relative to size of spinal canal, and postoperative urinary function in a large consecutive series of patients with CES. PMID- 29425363 TI - Trypanosoma cruzi Infection in Rhodnius pallescens (Heteroptera: Reduviidae) Infesting Coyol Palms in the Dry Arch of Panama. AB - Ecoepidemiological scenarios for Trypanosoma cruzi Chagas transmission are partially shaped by kissing bug vector ecology. The presence of Attalea butyracea Kunth, the 'royal palm', is a major risk factor for Chagas disease transmission in Panama given their frequent infestations by Rhodnius pallescens Barber, a major neotropical T. cruzi vector. It was assumed that in Panama this relationship was very close and unique, limiting the niche of R. pallescens to that of Att. butyracea. However, here we present observations about T. cruzi infected R. pallescens infesting coyol palms, Acrocomia aculeata Jacquin, in Pedasi district, Los Santos Province, Panama. Between May 2015 and August 2016, we sampled kissing bugs from 83 coyol palms using mice-baited traps placed at the crown of each palm during the dry and wet season. We collected 62 R. pallescens and one Eratyrus cuspidatus Stal kissing bugs. Using logistic regression, we found that the probability of kissing bug infestation in coyol palms increased during the rainy season, with infructescence number and palm height. We examined adult R. pallescens bugs (n = 30) and found T. cruzi in 67% of the samples. We were able to isolate and characterize T. cruzi from parasites present in the feces from R. pallescens, all parasites belonging to the TC I lineage. We found that green fronds number and house proximity increased T. cruzi infection probability in kissing bugs collected in coyol palms. These results highlight coyol palms as a potential risk factor for Chagas disease transmission in the dry arch of Panama. PMID- 29425364 TI - COMPARING LUNGS, LIVER AND KNEE MEASUREMENT GEOMETRIES AT VARIOUS TIMES POST INHALATION OF 239Pu AND 241Am. AB - In-vivo measurement of Pu/241Am in workers is carried out by placing suitable detector above lungs, liver and skeleton, as major fraction of Pu/Am is transferred to liver and skeleton, after its retention in entry organ. In this work, committed effective dose (CED) corresponding to minimum detectable activity for Type M and Type S 239Pu/241Am deposited in these organs are presented and a monitoring protocol of organ measurement giving lowest CED at different time intervals post inhalation is described. We have observed, for Type M compounds, lung measurement is most sensitive method during initial days after exposure. Liver measurement yields lowest CED between 100 and 5000 d and beyond that bone measurement gives lowest CED. For Type S compounds lung measurement remains most sensitive method even up to 10 000 d post inhalation. This study will be useful for the assessment of CED due to internally deposited 239Pu/241Am in the workers. PMID- 29425365 TI - Social Work and Prison Labor: A Restorative Model. AB - The prison industry is one of the fastest-growing industries in the United States, fueled largely by prison privatization. UN guidelines and U.S. federal policy outline standards for prison workers, but evidence suggests that protections have been ignored or circumvented. The current prison labor system allows corporations to profit from punishment that is disproportionately allocated to people of color and the poor. This article provides a critical analysis of prison labor policies in the United States and proposes a position for social workers on the ethical and restorative use of inmate labor. This model uses the framework of restorative justice to explore how successful models of social enterprise can benefit inmates and their communities. Meaningful prison enterprises may offer the ability to return resources to communities depleted by crime and incarceration, and to restore inmates to full citizenship. PMID- 29425366 TI - U.S. Marines' Perceptions of Environmental Factors Associated With Alcohol Binge Drinking. AB - Introduction: Alcohol misuse, in particular binge drinking, is a serious concern among military personnel because it is strongly associated with adverse consequences and has a deleterious effect on readiness. Although most alcohol misuse studies have focused on individual risk factors, studies are increasingly examining environmental influences and strategies for reducing alcohol risks. The purpose of this study is to address gaps in what is known about how service members' perceptions of environmental factors are related to binge drinking in the U.S. Marine Corps. Materials and Methods: The relationship between Marines' self-reports of environmental factors and alcohol binge drinking was assessed in this correlational study using data from three large Marine Corps installations drawn from the Department of Defense 2011 Health Related Behaviors Survey of Active Duty Military Personnel (N = 2,933). We proposed several directional hypotheses based on existing civilian and military studies of alcohol use and misuse, as well as health behavior theory. Results: Agreement with the statements that alcoholic beverages cost too much, that drinking might negatively affect one's military career, and that one's immediate supervisor and installation discourage alcohol use were independently associated with decreased odds of binge drinking (i.e., protective factors). Perceptions that alcoholic beverages are difficult to get was particularly protective; the odds of having binged were lower for participants who endorsed this belief than for those who did not. Perceptions that drinking is part of being in one's unit was a risk factor for binge drinking (odds ratio = 1.29). Conclusion: Even after accounting for strong sociodemographic correlates, binge drinking was independently associated with a number of environmentally oriented perceptions. Beliefs that alcohol is affordable and easy to access were the strongest environmental correlates of increased risk of binge drinking. Addressing the threat alcohol misuse poses to both Marines and mission readiness will likely require multiple strategies, including both policy and environmental changes. PMID- 29425367 TI - A Rapid, Handheld Device to Assess Respiratory Resistance: Clinical and Normative Evidence. AB - Introduction: Following reports of respiratory symptoms among service members returning from deployment to South West Asia (SWA), an expert panel recommended pre-deployment spirometry be used to assess disease burden. Unfortunately, testing with spirometry is high cost and time-consuming. The airflow perturbation device (APD) is a handheld monitor that rapidly measures respiratory resistance (APD-Rr) and has promising but limited clinical data. Its speed and portability make it ideally suited for large volume pre-deployment screening. We conducted a pilot study to assess APD performance characteristics and develop normative values. Materials and Methods: We prospectively enrolled subjects and derived reference equations for the APD from those without respiratory symptoms, pulmonary disease, or tobacco exposure. APD testing was conducted by medical technicians who received a 10-min in-service on its use. A subset of subjects performed spirometry and impulse oscillometry (iOS), administered by trained respiratory therapists. APD measures were compared with spirometry and iOS. Results: The total study population included 199 subjects (55.8% males, body mass index 27.7 +/- 6.0 kg/m2, age 49.9 +/- 18.7 yr). Across the three APD trials, mean inspiratory (APD-Ri), expiratory (APD-Re), and average (APD-Ravg) resistances were 3.30 +/- 1.0, 3.69 +/- 1.2, and 3.50 +/- 1.1 cm H2O/L/s. Reference equations were derived from 142 clinically normal volunteers. Height, weight, and body mass index were independently associated with APD-Ri, APD-Re, and APD-Ravg and were combined with age and gender in linear regression models. APD-Ri, APD-Re, and APD-Ravg were significantly inversely correlated with FEV1 (r = -0.39 to -0.42), FVC (r = -0.37 to -0.40), and FEF25-75 (r = -0.31 to -0.35) and positively correlated with R5 (r = 0.61-0.62), R20 (r = 0.50-0.52), X5 (r = 0.57 to -0.59), and FRES (r = 0.42-0.43). Bland-Altman plots showed that the APD Rr closely approximates iOS when resistance is normal. Conclusion: Rapid testing was achieved with minimal training required, and reference equations were constructed. APD-Rr correlated moderately with iOS and weakly with spirometry. More testing is required to determine whether the APD has value for pre- and post deployment respiratory assessment. PMID- 29425368 TI - Value Preferences of Social Workers. AB - The current study examines value preferences of social workers in Israel. Using a theoretical framework of person-environment fit paradigm and theory of values, the study compared social workers (N = 641, mean age = 37.7 years, 91 percent female) with a representative sample of Israeli Jews (N = 1,600, mean age = 44.2, 52 percent female). Questionnaires included personal value preferences and sociodemographic variables (gender, age, education, religiosity, and immigrant status). Multivariate analysis of covariance showed that value preferences of social workers differed significantly from those of the general population. Analyses of covariance showed that social workers reported a higher preference for self-transcendence and a lower preference for conservation and self enhancement values. Results have significance for the selection, training, and supervision of social workers. They suggest that it is important to assess to what extent selection processes for social workers are primarily recruiting social workers with shared values, thus creating an overly homogenous population of social workers. An understanding of personal value motivations can help social workers in their own process of self-development and growth, and to understand how the profession can fulfill their basic motivations. PMID- 29425370 TI - The Short-Sighted Sycophant's Selfie. PMID- 29425369 TI - Auditory stimulation of sleep slow oscillations modulates subsequent memory encoding through altered hippocampal function. AB - Study Objectives: Slow oscillations (SO) during sleep contribute to the consolidation of learned material. How the encoding of declarative memories during subsequent wakefulness might benefit from their enhancement during sleep is less clear. In this study, we investigated the impact of acoustically enhanced SO during a nap on subsequent encoding of declarative material. Methods: Thirty seven healthy young adults were studied under two conditions: stimulation (STIM) and no stimulation (SHAM), in counter-balanced order following a night of sleep restriction (4 hr time-in-bed [TIB]). In the STIM condition, auditory tones were phase-locked to the SO up-state during a 90 min nap opportunity. In the SHAM condition, corresponding time points were marked but tones were not presented. Thirty minutes after awakening, participants encoded pictures while undergoing fMRI. Picture recognition was tested 60 min later. Results: Acoustic stimulation augmented SO across the group, but there was no group level benefit on memory. However, the magnitude of SO enhancement correlated with greater recollection. SO enhancement was also positively correlated with hippocampal activation at encoding. Although spindle activity increased, this did not correlate with memory benefit or shift in hippocampal signal. Conclusions: Acoustic stimulation during a nap can benefit encoding of declarative memories. Hippocampal activation positively correlated with SO augmentation. PMID- 29425371 TI - An analysis of methods used to synthesize evidence and grade recommendations in food-based dietary guidelines. AB - Evidence-informed guideline development methods underpinned by systematic reviews ensure that guidelines are transparently developed, free from overt bias, and based on the best available evidence. Only recently has the nutrition field begun using these methods to develop public health nutrition guidelines. Given the importance of following an evidence-informed approach and recent advances in related methods, this study sought to describe the methods used to synthesize evidence, rate evidence quality, grade recommendations, and manage conflicts of interest (COIs) in national food-based dietary guidelines (FBDGs). The Food and Agriculture Organization's FBDGs database was searched to identify the latest versions of FBDGs published from 2010 onward. Relevant data from 32 FBDGs were extracted, and the findings are presented narratively. This study shows that despite advances in evidence-informed methods for developing dietary guidelines, there are variations and deficiencies in methods used to review evidence, rate evidence quality, and grade recommendations. Dietary guidelines should follow systematic and transparent methods and be informed by the best available evidence, while considering important contextual factors and managing conflicts of interest. PMID- 29425372 TI - Sleep deprivation and cerebrospinal fluid biomarkers for Alzheimer's disease. AB - Study Objectives: To investigate the cumulative effect of five consecutive nights of partial sleep deprivation (PSD) on a panel of cerebrospinal fluid (CSF) biomarkers in healthy adults. Methods: A randomized, cross-over study conducted at the University of Gothenburg. The participants (N = 13) were healthy adults (20-40 years of age) with a normal sleeping pattern. The participants underwent a baseline sleep period consisting of five nights with 8 hr spent in bed. A subsequent period with PSD consisted of five nights of maximum 4 hr of sleep per night. Four participants were also subjected to a prolonged period of PSD consisting of eight nights with 4 hr of sleep per night. Sleep was monitored by means of observation, actigraphy, and continuous polysomnographic recordings. CSF samples were collected by routine lumbar puncture after each period. CSF biomarkers included the 38, 40, and 42 amino acid-long Abeta isoforms, total-tau, phospho-tau, orexin, monoamine metabolites (3-methoxy-4-hydroxyphenylglycol, homovanillinic acid, and 5-hydroxyindoleacetic acid), neuron-derived biomarkers (neurofilament light, neuron-specific enolase, and fatty acid-binding protein), and astro- and microglia-derived biomarkers (glial fibrillary acidic protein, S 100B, and YKL-40). Results: PSD was associated with a 27 per cent increase in CSF orexin concentrations (p = 0.001). No PSD-related changes in CSF biomarkers for amyloid build-up in the brain, Alzheimer's disease (AD)-type neurodegeneration, or astroglial activation were observed. PSD led to a shortening of time spent in all sleep stages except slow-wave sleep (SWS). Conclusion: Five to eight consecutive nights of PSD, with preserved SWS, increased CSF orexin but had no effect on CSF biomarkers for amyloid deposition, neuronal injury, and astroglial activation. PMID- 29425374 TI - Epigenome-wide association study of DNA methylation in narcolepsy: an integrated genetic and epigenetic approach. AB - Narcolepsy with cataplexy, which is a hypersomnia characterized by excessive daytime sleepiness and cataplexy, is a multifactorial disease caused by both genetic and environmental factors. Several genetic factors including HLA DQB1*06:02 have been identified; however, the disease etiology is still unclear. Epigenetic modifications, such as DNA methylation, have been suggested to play an important role in the pathogenesis of complex diseases. Here, we examined DNA methylation profiles of blood samples from narcolepsy and healthy control individuals and performed an epigenome-wide association study (EWAS) to investigate methylation loci associated with narcolepsy. Moreover, data from the EWAS and a previously performed narcolepsy genome-wide association study were integrated to search for methylation loci with causal links to the disease. We found that (1) genes annotated to the top-ranked differentially methylated positions (DMPs) in narcolepsy were associated with pathways of hormone secretion and monocarboxylic acid metabolism. (2) Top-ranked narcolepsy-associated DMPs were significantly more abundant in non-CpG island regions and more than 95 per cent of such sites were hypomethylated in narcolepsy patients. (3) The integrative analysis identified the CCR3 region where both a single methylation site and multiple single-nucleotide polymorphisms were found to be associated with the disease as a candidate region responsible for narcolepsy. The findings of this study suggest the importance of future replication studies, using methylation technologies with wider genome coverage and/or larger number of samples, to confirm and expand on these results. PMID- 29425375 TI - Impact of Hypothermic Stress During Special Operations Training of Chilean Military Forces. AB - Introduction: The Chilean Army considers processes that can optimize physical capacities for responding to the impact of situations and given stressors. The study of the effect of hypothermia as a stressor agent (HSA) and its relationship with cardiovascular, hematological, anthropometric, endocrine, and immunological parameters has not been fully addressed experimentally in military populations. Objective: To identify the endocrine, hematological, cardiovascular, and immunological changes caused by HSA and to associate these variables with body composition and physical fitness in the military special operation courses of the Chilean Army. Materials and Methods: Forty-two male subjects were exposed to remain in cold water (10.6 degrees C) in the context of regular military operations training, the longest time of exposure was determined by individual volitional limits. The measurements were taken in pre-hypothermia conditions, then 2 d later under acute hypothermia condition, and finally during the course period of lesser physical and psychological stressors where the baseline measurements were taken. The statistical analysis consisted of testing normality of the distribution through the Shapiro-Wilk test, assessing the equality of variances through the Levene test, and variance analysis by applying the ANOVA test (analysis of variance). The Bonferroni test was used for multiple comparison correction and the Pearson test for correlations between two variables. The level of significance was of p < 0.05. Results: The main finding of this study is that HSA has a significant impact at the cardiovascular level and produces an increment in the cell population of the immune and hematologic systems. Significant hormonal changes were observed: ACTH (r = 0.50, p < 0.002), cortisol (r = 0.32, p < 0.03), free testosterone (r = 0.13, p < 0.002), total testosterone r = 0.31, p < 0.002), and anthropometrics (r = -0.51, p < 0.05). However, there is no significant correlation between physical fitness and HAS. Conclusions: All subjects experienced hypothermia stress elicited by immersion in cold water. This was evidenced by the decrease in core temperature as well as cardiovascular, endocrine, anthropometric, and immunological changes. Individual differences exist between subjects and their resistance to hypothermia in cold water. These differences are not explained by the physical fitness profile but rather respond to a greater body adiposity index and minor changes in the adrenocorticotropic hormone and cortisol hormone. An acute hypothermia stress condition also affects the anabolic/catabolic environment. Finally, HSA produces an increase in the cell population of the immune system. The authors believe that this study allows to standardize HSA exposure times during regular military operations training by identifying the physiological impacts under this extreme environment. At present, the availability of intra-abdominal temperature measurement apparatus with capsule thermometers raises the interest of corroborating the findings of the current study through the use of such measuring devices. Likewise, an interesting line of research for the future would be to compare the HSA against a psychological evaluation with the purpose of identifying the stress management mechanisms among subjects of these characteristics and include heart rate variability measurements as an indicator of sympathetic stress. PMID- 29425373 TI - Associations between change in sedentary behavior and outcome in standard behavioral weight loss treatment. AB - Sedentary behavior, particularly in prolonged periods, is an important determinant of health. Little research exploring changes in sedentary behavior during behavioral weight loss programs exists. This study evaluated the magnitude of changes in total and prolonged sedentary behavior and how these changes related to changes in weight and cardiovascular outcomes during a behavioral weight loss program. Participants (n = 450) in two lifestyle modification programs underwent assessments of sedentary behavior (by accelerometry), weight, waist circumference, blood pressure, and resting heart rate at baseline and after 6 months of treatment. Sedentary behavior was defined as both total and prolonged (>=30 continuous minutes) sedentary minutes/day. Reductions in total and prolonged sedentary time were significant and were accounted for by increases in moderate-to-vigorous physical activity (MVPA). Only changes in MVPA significantly predicted change in weight when entered into a model simultaneously with changes in sedentary behavior. Changes in total and prolonged sedentary time were not associated with changes in waist circumference, heart rate, or blood pressure. Change in sedentary time was not independently associated with change in health outcomes during a behavioral weight loss treatment. High variability in changes in sedentary time indicate that individual differences may be important to examine. Reducing sedentary time may not be powerful enough to impact these health outcomes above the effects of other changes made during these programs; alternatively, it may be that increasing focus in treatment on reducing sedentary time may engender greater decreases in sedentariness, which could lead to better health outcomes. PMID- 29425376 TI - "I Think I Can . . . Maybe I Can . . . I Can't": Social Work Women and Local Elected Office. AB - If women are more interested in running for office, it should be observable in MSW students. Not only are the majority of students women, but they have experienced a dramatic change in political fortunes within the last year. However, the 2016 election may be leading women to doubt their qualifications to run. Using survey data from 545 MSW students and 200 law students, this study considers how interested women are in running for office and what barriers they perceive to doing so. Results suggest that women in MSW programs were significantly more interested in running for local office (city council, school board, county commission) than women in law school. At the same time, women in MSW programs were significantly more likely to doubt their qualifications to run for local office, which significantly decreased their interest in running. Content analysis revealed that women felt this way because they did not believe they had the knowledge and experience to run for local office. These results suggest that field placements in political offices might be a way to provide women in MSW programs with knowledge and experience that increases their sense of qualification to run for local office. PMID- 29425378 TI - Government Cloud Computing Policies: Potential Opportunities for Advancing Military Biomedical Research. AB - Introduction: This position paper summarizes the development and the present status of Department of Defense (DoD) and other government policies and guidances regarding cloud computing services. Due to the heterogeneous and growing biomedical big datasets, cloud computing services offer an opportunity to mitigate the associated storage and analysis requirements. Having on-demand network access to a shared pool of flexible computing resources creates a consolidated system that should reduce potential duplications of effort in military biomedical research. Methods: Interactive, online literature searches were performed with Google, at the Defense Technical Information Center, and at two National Institutes of Health research portfolio information sites. References cited within some of the collected documents also served as literature resources. Results: We gathered, selected, and reviewed DoD and other government cloud computing policies and guidances published from 2009 to 2017. These policies were intended to consolidate computer resources within the government and reduce costs by decreasing the number of federal data centers and by migrating electronic data to cloud systems. Initial White House Office of Management and Budget information technology guidelines were developed for cloud usage, followed by policies and other documents from the DoD, the Defense Health Agency, and the Armed Services. Security standards from the National Institute of Standards and Technology, the Government Services Administration, the DoD, and the Army were also developed. Government Services Administration and DoD Inspectors General monitored cloud usage by the DoD. A 2016 Government Accountability Office report characterized cloud computing as being economical, flexible and fast. A congressionally mandated independent study reported that the DoD was active in offering a wide selection of commercial cloud services in addition to its milCloud system. Our findings from the Department of Health and Human Services indicated that the security infrastructure in cloud services may be more compliant with the Health Insurance Portability and Accountability Act of 1996 regulations than traditional methods. To gauge the DoD's adoption of cloud technologies proposed metrics included cost factors, ease of use, automation, availability, accessibility, security, and policy compliance. Conclusions: Since 2009, plans and policies were developed for the use of cloud technology to help consolidate and reduce the number of data centers which were expected to reduce costs, improve environmental factors, enhance information technology security, and maintain mission support for service members. Cloud technologies were also expected to improve employee efficiency and productivity. Federal cloud computing policies within the last decade also offered increased opportunities to advance military healthcare. It was assumed that these opportunities would benefit consumers of healthcare and health science data by allowing more access to centralized cloud computer facilities to store, analyze, search and share relevant data, to enhance standardization, and to reduce potential duplications of effort. We recommend that cloud computing be considered by DoD biomedical researchers for increasing connectivity, presumably by facilitating communications and data sharing, among the various intra- and extramural laboratories. We also recommend that policies and other guidances be updated to include developing additional metrics that will help stakeholders evaluate the above mentioned assumptions and expectations. PMID- 29425377 TI - Quality of life among men with low-risk prostate cancer during the first year following diagnosis: the PREPARE prospective cohort study. AB - As many as 40% of men diagnosed with prostate cancer have low-risk disease, which results in the need to decide whether to undergo active treatment (AT) or active surveillance (AS). The treatment decision can have a significant effect on general and prostate-specific quality of life (QOL). The purpose of this study was to assess the QOL among men with low-risk prostate cancer during the first year following diagnosis. In a prospective cohort study, we conducted pretreatment telephone interviews (N = 1,139; 69.3% response rate) with low-risk PCa patients (PSA <= 10, Gleason <= 6) and a follow-up assessment 6-10 months postdiagnosis (N = 1057; 93%). We assessed general depression, anxiety, and physical functioning, prostate-specific anxiety, and prostate-specific QOL at both interviews. Clinical variables were obtained from the medical record. Men were 61.7 (SD = 7.2) years old, 82% white, 39% had undergone AT (surgery or radiation), and 61.0% had begun AS. Linear regression analyses revealed that at follow-up, the AS group reported significantly better sexual, bowel, urinary, and general physical function (compared to AT), and no difference in depression. However, the AS group did report greater general anxiety and prostate-specific anxiety at follow-up, compared to AT. Among men with low-risk PCa, adjusting for pretreatment functioning, the AS group reported better prostate-related QOL, but were worse off on general and prostate-specific anxiety compared to men on AT. These results suggest that, within the first year postdiagnosis, men who did not undergo AT may require additional support in order to remain comfortable with this decision and to continue with AS when it is clinically indicated. PMID- 29425379 TI - Barriers to prompt TB diagnosis-a comparative study between northern Malawi and eastern rural China. AB - Background: Tuberculosis (TB) case detection in China has improved remarkably, partly benefiting from the reducing delay to TB care, whereas the timeliness of TB care in Malawi remains problematic. Methods: This study investigates barriers hindering timely TB diagnosis in Malawi and China, and attempts to share the experience in high burden countries. A cross-sectional study on TB diagnostic delay was conducted among 254 Malawian and 146 Chinese TB patients. Results: The medians of patient's delays were 22 and 20 days (p>0.05), and provider delays were 12 and 11.5 days (p>0.05) in Malawi and China, respectively. Malawian patients had a higher proportion (72.05% vs 67.12%) of patient's delay longer than 14 days (p=0.042), which was significantly associated with initial visits to lower-level health providers in the villages (aOR=1.989, 95% CI: 1.075-3.682), and patients conducting casual/piece work (aOR=3.318, 95% CI: 1.228-8.964). Initial healthcare visits at village level also led to longer provider delay in both Malawi (aOR=2.055, 1.211-3.487) and China (aOR=5.627, 2.218-14.276). Conclusion: Establishing a good communication and referral mechanism between different levels of health facilities is crucial to timely TB diagnosis. China's experience on pro-poor interventions could be useful to its Malawian counterpart and other similar settings with high TB burden. PMID- 29425380 TI - The distinguishing motor features of cataplexy: a study from video-recorded attacks. AB - Study Objectives: To describe the motor pattern of cataplexy and to determine its phenomenological differences from pseudocataplexy in the differential diagnosis of episodic falls. Methods: We selected 30 video-recorded cataplexy and 21 pseudocataplexy attacks in 17 and 10 patients evaluated for suspected narcolepsy and with final diagnosis of narcolepsy type 1 and conversion disorder, respectively, together with self-reported attacks features, and asked expert neurologists to blindly evaluate the motor features of the attacks. Video documented and self-reported attack features of cataplexy and pseudocataplexy were contrasted. Results: Video-recorded cataplexy can be positively differentiated from pseudocataplexy by the occurrence of facial hypotonia (ptosis, mouth opening, tongue protrusion) intermingled by jerks and grimaces abruptly interrupting laughter behavior (i.e. smile, facial expression) and postural control (head drops, trunk fall) under clear emotional trigger. Facial involvement is present in both partial and generalized cataplexy. Conversely, generalized pseudocataplexy is associated with persistence of deep tendon reflexes during the attack. Self-reported features confirmed the important role of positive emotions (laughter, telling a joke) in triggering the attacks, as well as the more frequent occurrence of partial body involvement in cataplexy compared with pseudocataplexy. Conclusions: Cataplexy is characterized by abrupt facial involvement during laughter behavior. Video recording of suspected cataplexy attacks allows the identification of positive clinical signs useful for diagnosis and, possibly in the future, for severity assessment. PMID- 29425381 TI - AUTOMATIC ACQUISITION OF CT RADIATION DOSE DATA: USING THE DIAGNOSTIC REFERENCE LEVEL FOR RADIATION DOSE OPTIMIZATION. AB - The present work describes that we try to construct a system that collects dose information that performed CT examination from multiple facilities and unified management. The results of analysis are compared with other National diagnostic reference level (DRL), and the results are fed back to each facility and the cause of the abnormal value is investigated for dose optimization. Medical information collected 139 144 tests from 33 CT devices in 13 facilities. Although the DRL of this study is lower than that of Japan DRL, it was higher than the DRL of each country. When collecting all the examination, it is thought that the variation of the dose due to the error other than the intended imaging site is large. In future, we should continue to collect information in order to DRL renewal and we also think that it is desirable to collect information on physique and detailed scan region as well. PMID- 29425383 TI - Dual Use of E-Cigarettes and Traditional Cigarettes Among Adolescents in Taiwan, 2014-2016. AB - Introduction: We investigated the use of electronic cigarettes (e-cigarettes) with traditional cigarettes among adolescents during 2014 to 2016 to identify risk factors for using e-cigarettes only, traditional cigarettes only, or both products. Methods: We used cross-sectional data from the Taiwan Global Youth Tobacco Survey, (conducted over a 3-year period by the Health Promotion Administration, Ministry of Health and Welfare, Taiwan), which is representative of tobacco use among adolescents aged 12-18 years. The outcome variable was smoking behavior. Dependent variables included gender, grade, monthly income/allowance, parents' educational level, parents' smoking status, close friends' smoking status, use of other tobacco products, contact with cigarette/e cigarette advertisements, and access to free cigarettes/e-cigarettes. Multinomial regression identify factors influencing the smoking behaviors of adolescents, as manifested in the use of traditional cigarettes only, e-cigarettes only, e cigarettes with traditional cigarettes, and nonsmoking. Results: When weighted to the population, the sample included 1723150 adolescents in 2014, 1691568 adolescents in 2015, and 1627216 adolescents in 2016. The rates averaged over three years were as follows: nonsmoking (91.6%), traditional cigarettes only (5.4%), e-cigarettes only (1.5%), and dual usage (1.6%). Among adolescents in Taiwan, the following were risk factors for dual use: male, older, high monthly allowance, smoking parents, smoking friends, use of other tobacco products, contact with cigarette advertisements, and access to free cigarettes. Conclusions: Our results revealed an increase in the number of adolescents using e-cigarettes with traditional cigarettes. We recommend that the government continue smoking cessation programs while maintaining control over advertisements and promotions for tobacco products. Implications: This is the first study to examine the dual use of e-cigarettes and traditional cigarettes among adolescents in Taiwan. This study identified the risk factors of using traditional cigarettes only, using e-cigarettes only, and the dual use of e-cigarettes and traditional cigarettes, with nonsmokers used as a reference group. This study examined the relationship between exposure to cigarette promotions and the use of various tobacco products including the dual use of e-cigarettes and traditional cigarettes, both of which have been disregarded in previous studies. PMID- 29425382 TI - The beneficial effect of weight reduction on adverse cardiovascular outcomes following bariatric surgery is attenuated in patients with obstructive sleep apnea. AB - Weight loss after bariatric surgery is associated with reduction in adverse cardiovascular outcomes; however, the impact of obstructive sleep apnea (OSA) on reduction of cardiovascular outcomes after bariatric surgery in morbidly obese patients is not known. We retrospectively assessed differences in cardiovascular events after laparoscopic adjustable gastric banding (LAGB)-induced weight loss in patients with and without OSA before and after propensity score matching for age, sex, body mass index (BMI), and major comorbidities between the two groups and determined predictors of poor outcomes. OSA was present in 222 out of 830 patients (27 per cent) who underwent LAGB between 2001 and 2011. Despite a similar reduction in BMI (20.0 and 20.8 per cent), a significantly higher percentage of cardiovascular events were observed in patients with than without OSA (35.6 vs 6.9 per cent; p < 0.001) at 3 years (mean follow-up 6.0 +/- 3.2; range: 0.5 to 13 years). The differences in the cumulative endpoint of new onset stroke, heart failure, myocardial infarction, venous thrombosis, and pulmonary embolism between the OSA and non-OSA groups were maintained after propensity matching. Patients with OSA treated with continuous positive airway pressure (CPAP) during sleep [n = 66] had lower cardiovascular event rates at 30 months compared with those not treated (p < 0.041). OSA (hazard ratio: 6.92, 95% CI: 3.39-14.13, p < 0.001) remained an independent predictor of cardiovascular events after multivariate analysis. Thus, patients with OSA, despite a similar initial weight loss after LAGB, had a higher incidence of cardiovascular events compared with a propensity-matched group without OSA. Treatment with CPAP appears to reduce such events. PMID- 29425384 TI - Variability in temperature dependence of stem CO2 efflux from Norway spruce trees. AB - This study presents results from continuous measurements of stem CO2 efflux carried out for seven experimental seasons (from May to October) in a young Norway spruce forest. The objectives of the study were to determine variability in the response of stem CO2 efflux to stem temperature over the season and to observe differences in the calculated relationship between stem temperature and CO2 efflux based on full growing season data or on data divided into periods according to stem growth rate. Temperature sensitivity of stem CO2 efflux (Q10) calculated for the established periods ranged between 1.61 and 3.46 and varied over the season, with the lowest values occurring in July and August. Q10 calculated using data from the full growing seasons ranged between 2.30 and 2.94 and was often significantly higher than Q10 calculated for the individual periods. Temperature-normalized stem CO2 efflux (R10) determined using Q10 from growing season data was overestimated when the temperature was below 10 degrees C and underestimated when the temperature was above 10 degrees C, compared with R10 calculated using Q10 established for the individual periods. The differences in daily mean R10 calculated by these two approaches ranged between -0.9 and 0.2 MUmol CO2 m-2 s-1. The results of this study confirm that long periods for determining the temperature dependence of stem CO2 efflux encompass different statuses of the wood (especially in relation to stem growth). This may cause bias in models using this relationship for estimating stem CO2 efflux as a function of temperature. PMID- 29425385 TI - Analysis of Accommodative Performance of a New Accommodative Intraocular Lens. AB - PURPOSE: To compare objective and subjective accommodation and visual acuities with a new accommodative intraocular lens (IOL) (Lumina; AkkoLens Clinical BV, Rijswijk, The Netherlands) with a monofocal IOL and young phakic eyes. METHODS: In this prospective, randomized controlled clinical investigation, patients aged 51 to 85 years with symptomatic cataract were enrolled in the study. A total of 25 eyes were implanted with the accommodative IOL and 18 eyes received the monofocal Acrysof SA60AT IOL (Alcon Laboratories, Inc., Fort Worth, TX). Each group included 4 bilateral patients. An additional 20 phakic eyes of young patients aged 19 to 29 years were used to assess the restoration of accommodation. Subjective and objective accommodative amplitudes were evaluated by defocus curves and the WAM-5500 open-field Auto Ref/Keratometer (Grand Seiko, Tokyo, Japan), respectively. RESULTS: The 1-year postoperative examination showed significantly better visual acuities with the accommodative IOL compared to the monofocal IOL, over a defocus range of -0.50 to -5.00 diopters (D) (P < 10-5), and revealed more than 50% of the visual acuities of the young phakic eyes at up to -3.50 D defocus. The depth of focus of the accommodative group exceeded that of the monofocal group by 2.52 +/- 0.03 D in a visual acuity range of 0.3 to 0.8 (decimal) (20/63 to 20/25 Snellen). Compared with the monofocal IOL, the accommodative IOL resulted in a similar uncorrected distance visual acuity of 0.99 +/- 0.12 (20/20 Snellen) (P > .79) and a significantly better uncorrected near visual acuity of 0.91 +/- 0.11 (20/22 Snellen) (P < 2.7 * 10-6). A significant correlation of 0.51 (P < 1.3 * 10-7) was found between the objective and subjective accommodative amplitudes with the accommodative IOL. CONCLUSIONS: Eyes implanted with the accommodative IOL showed similar amounts of objective and subjective accommodation. [J Refract Surg. 2018;34(2):78-83.]. PMID- 29425386 TI - Rotational Stability of Monofocal and Trifocal Intraocular Toric Lenses With Identical Design and Material but Different Surface Treatment. AB - PURPOSE: To compare the rotational stability, total misalignment, and visual and refractive outcomes achieved with a trifocal toric versus a monofocal toric intraocular lens (IOL). METHODS: In this prospective, interventional case series, eyes of patients consecutively scheduled for cataract surgery who had clinically relevant astigmatism were implanted with a FineVision Pod FT trifocal toric IOL or an Ankoris monofocal toric IOL (both PhysIOL SA, Liege, Belgium). Certain comorbidities, such as pseudoexfoliation syndrome, were allowed. IOL rotation and total misalignment were analyzed 15 minutes, 1 day, 1 week, 6 weeks, 6 months, and 1 year postoperatively. RESULTS: Seventy-one eyes of 53 patients were assessed: 37 eyes were implanted with the trifocal IOL and 34 eyes with the monofocal IOL. More IOL rotation occurred in the monofocal group compared to the trifocal group (mean 4.23 degrees +/- 4.64 degrees vs 2.55 degrees +/- 2.62 degrees ; P = .043, 12 months). Mean total misalignment was higher in the monofocal group (6.67 degrees +/- 6.59 degrees at 12 months vs 3.79 degrees +/ 3.59 degrees in the trifocal group) (P = .017). Postoperatively, more eyes achieved a refractive cylinder of 0.50 diopters or below in the trifocal group (65% at 12 months) than in the monofocal group, even in the monofocal subgroup analysis that excluded keratoconic eyes (42% at 12 months; P = .009). CONCLUSIONS: The monofocal and trifocal toric IOLs both appear to effectively reduce refractive astigmatism and provide good visual acuity in astigmatic patients having cataract surgery. The trifocal toric IOL offers better rotational stability than the monofocal IOL, probably due to the higher frictional coefficient of its surface. [J Refract Surg. 2018;34(2):84-91.]. PMID- 29425387 TI - Intraoperative Patient Experience and Postoperative Visual Quality After SMILE and LASIK in a Randomized, Paired-Eye, Controlled Study. AB - PURPOSE: To compare intraoperative and postoperative subjective patient experience after small incision lenticule extraction (SMILE) and femtosecond laser-assisted LASIK. METHODS: In a prospective, randomized, paired-eye, single masked clinical trial at Singapore National Eye Centre, 70 patients were randomly treated with SMILE and LASIK in each eye. The intraoperative questionnaire was completed immediately after surgery and included light perception and levels of anxiety, fear, and discomfort. The postoperative 1- and 3-month questionnaires evaluated severity of light sensitivity, eye discomfort, eye dryness, excessive tearing, gritty sensation, glare, halos, blurring, and fluctuations in vision. RESULTS: Average discomfort scores were higher during tissue manipulation in SMILE (1.9 +/- 0.9) than flap lifting in LASIK (1.59 +/- 0.8) (P = .020) but comparable during docking and laser application (P > .249). Fear scores were lower in SMILE than LASIK during docking (2.6 +/- 1.6 vs 3.4 +/- 1.9, P = .024) but similar during occasional blackout, laser application, and lenticule/flap manipulation (P > .364). Fear scores were generally higher in patients with intraoperative suction loss (n = 3). For SMILE, light sensitivity, eye discomfort, blurring, and fluctuations in vision improved from 1 to 3 months (P < .039). For LASIK, improvements were reported for light sensitivity, eye discomfort, eye dryness, gritty sensation, and fluctuations in vision from 1 to 3 months (P < .046). At 1 month, patients experienced more blurring after SMILE than LASIK (2.1 +/- 0.8 vs 1.8 +/- 0.7, P = .025), but with no differences in any of the visual symptoms at 3 months. CONCLUSIONS: Tissue manipulation may be more uncomfortable during SMILE than LASIK, but not more frightening. Subjective visual symptoms were comparable after 3 months. [J Refract Surg. 2018;34(2):92 99.]. PMID- 29425388 TI - Risk Factors for Epithelial Ingrowth Following Microkeratome-Assisted LASIK. AB - PURPOSE: To analyze the incidence and risk factors associated with epithelial ingrowth following uncomplicated microkeratome-assisted LASIK. METHODS: All patients who underwent microkeratome-assisted LASIK between January 2006 and December 2014 in a single surgical center were reviewed. Epithelial ingrowth cases were identified and associated factors were assessed. RESULTS: Overall, 149 (0.49%) of 30,574 cases developed epithelial ingrowth. The epithelial ingrowth group was older compared to controls (35.3 +/- 12.3 vs 31.7 +/- 10.3 years, P = .001) and had a higher percentage of moderate to high hyperopia (13.7% vs 5.3%, P < .001), early postoperative flap slippage requiring flap repositioning (9.4% versus 2.8%, P < .001), or flap lifting for enhancement (48.6% vs 4.3%, P < .001), were treated with a smaller optic zone (6 mm) (37.7% vs 15.2%, P < .001), with a Moria M2 microkeratome (Moria SA, Antony, France) (70.1% vs 55.5%, P = .02), by low volume surgeons (n < 1,000) (5.8% vs 1.3%, P < .001), in a lower operating room temperature (22.3 +/- 1.8 vs 22.8 +/- 1.6, P = .005), and with a greater maximum ablation depth (67.3 +/- 29.7 vs 57.3 +/- 30.3, P < .001). There was a high incidence of epithelial ingrowth in the enhancement group compared to primary LASIK (4.8% vs 0.2%, P < .001). The time between treatments (primary and enhanced LASIK) was significantly greater in the epithelial ingrowth group (mean: 1,110 +/- 870 vs 626 +/- 662 days, P < .001). There was a significant rise in epithelial ingrowth rates as time between primary and enhancement LASIK increased, peaking at 4 to 5 years (P < .001). In multivariate analysis, flap lifting for enhancement (odds ratio [OR] = 19.5, P < .001), 6-mm optic zone (OR = 2.2, P < .001), moderate to severe hyperopia (OR = 2.4, P = .005), greater ablation depth (OR = 1.005, P < .001), and low volume surgeon (OR = 3.9, P = .01) were associated with epithelial ingrowth (total R2 = 15.4). CONCLUSIONS: The potential risk factors described above may forewarn surgeons as to which individuals merit closer observation for this complication. [J Refract Surg. 2018;34(2):100-105.]. PMID- 29425389 TI - Factors Influencing Cyclotorsion During Photorefractive Keratectomy. AB - PURPOSE: To determine predictive factors for intra-operative cyclotorsion in photorefractive keratectomy (PRK). METHODS: A retrospective statistical analysis of medical records pertaining to 3,996 eyes undergoing PRK was conducted. Outcome measures of this study were the likely existence of statistically significant relations between diverse and potentially influential factors and the occurrence of intraoperative cyclotorsion. RESULTS: A total of 96% of examined medical records indicated some degree of cyclotorsion with the absolute mean intraoperative value of 1.38 degrees +/- 1.67 degrees (range: 0 degrees to 13.6 degrees ). Absolute mean cyclotorsion showed no significant correlation with age (r = 0.14, P = .37). Female patients had significantly higher degrees of cyclotorsion versus males (P < .001). Right and left eyes showed no significant difference in absolute mean torsion (P = .05). Higher diopters of refractive errors, hyperopia, more than 2.00 diopters of cylinder, high pulse numbers (r = 0.26), and use of the advanced personalized treatment ablation algorithm were all significantly related to higher degrees of torsion (P < .0001). Ablation depth (r = 0.13) and surgeon appeared to be dependent factors. CONCLUSIONS: Incidence of intraoperative cyclotorsion is high in eyes undergoing PRK and most of them will experience some degree of torsion. Several diverse factors (sex, refractive error diopters, hyperopia, high cylinder, pulse numbers, and ablation algorithm) were significant predictors for higher degrees of the observed torsion. [J Refract Surg. 2018;34(2):106-112.]. PMID- 29425390 TI - Corneal Apical Scar After Hyperopic Excimer Laser Refractive Surgery: Long-term Follow-up of Treatment With Sequential Customized Therapeutic Keratectomy. AB - PURPOSE: To evaluate long-term results of sequential customized therapeutic keratectomy (SCTK) in highly aberrated corneas with apical scars consequent to hyperopic excimer laser refractive surgery. METHODS: Fifteen eyes of 12 patients treated with SCTK for a corneal apical scar after hyperopic excimer laser refractive surgery were retrospectively evaluated. SCTK is a sequence of custom therapeutic excimer laser keratectomies where the results are monitored step-by step by intraoperative corneal topography. In the preoperative and postoperative course, corrected distance visual acuity (CDVA), corneal topography and aberrometry, Scheimpflug tomography, and anterior segment optical coherence tomography were compared before and after SCTK. RESULTS: The postoperative follow up comprised 7 patients with 1 year and 8 patients with more than 2 years of follow-up. Functional results showed a significant increase of CDVA from 0.36 +/- 0.31 to 0.14 +/- 0.25 logMAR at the last available follow-up. Mean sphere did not change significantly from the baseline, demonstrating that SCTK does not induce hyperopic shift. Higher order aberrations decreased significantly from 2.57 +/- 1.92 to 0.80 +/- 0.42 um at the last follow-up. Topographic indexes (irregular astigmatism index, surface asymmetry index, and surface regularity index) showed a significant improvement after SCTK. Pachymetry 3 months postoperatively showed no significant reduction during the entire follow-up in either minimum or central thickness. CONCLUSIONS: Long-term results demonstrate that SCTK can treat this sight-threatening complication of hyperopic excimer laser refractive surgery, achieving significant improvements in visual acuity and in many corneal morphological parameters. [J Refract Surg. 2018;34(2):113-120.]. PMID- 29425391 TI - Incidence and Outcomes of Optical Zone Enlargement and Recentration After Previous Myopic LASIK by Topography-Guided Custom Ablation. AB - PURPOSE: To report the incidence, visual and refractive outcomes, optical zone enlargement, and recentration using topography-guided CRS-Master TOSCA II software with the MEL 80 excimer laser (Carl Zeiss Meditec AG, Jena, Germany) after primary myopic laser refractive surgery. METHODS: Retrospective analysis of 73 eyes (40 patients) with complaints of night vision disturbances due to either a decentration or small optical zone following a primary myopic laser refractive surgery procedure using the MEL 80 laser. Multiple ATLAS topography scans were imported into the CRS-Master software for topography-guided ablation planning. The topography-guided re-treatment procedure was performed as either a LASIK flap lift, a new LASIK flap, a side cut only, or photorefractive keratectomy. Axial curvature maps were analyzed using a fixed grid and set of concentric circles superimposed to measure the topographic optical zone diameter and centration. Follow-up was 12 months. RESULTS: The incidence of use in the population of myopic treatments during the study period was 0.79% (73 of 9,249). The optical zone diameter was increased by 11% from a mean of 5.65 to 6.32 mm, with a maximum change of 2 mm in one case. Topographic decentration was reduced by 64% from a mean of 0.58 to 0.21 mm. There was a 44% reduction in spherical aberration, 53% reduction in coma, and 39% reduction in total higher order aberrations. A subjective improvement in night vision symptoms was reported by 93%. Regarding efficacy, 82% of eyes reached 20/20 and 100% reached 20/32 (preoperative CDVA was 20/20 or better in 90%). Regarding safety, no eyes lost two lines of CDVA and 27% gained one line. Regarding predictability, 71% of re-treatments were within +/ 0.50 diopters. CONCLUSIONS: Topography-guided ablation was effective in enlarging the optical zone, recentering the optical zone, and reducing higher order aberrations. Topography-guided custom ablation appears to be an effective method for re-treatment procedures of symptomatic patients after myopic LASIK. [J Refract Surg. 2018;34(2):121-130.]. PMID- 29425392 TI - Long-term Clinical Outcomes of Phototherapeutic Keratectomy in Corneas With Granular Corneal Dystrophy Type 2 Exacerbated After LASIK. AB - PURPOSE: To investigate the long-term clinical outcomes and recurrence patterns of phototherapeutic keratectomy (PTK) in patients with granular corneal dystrophy type 2 (GCD2) exacerbated after LASIK. METHODS: Fifty-one patients (76 eyes) with GCD2 exacerbated after LASIK who underwent PTK between January 2007 and February 2017 were included. Participants underwent ophthalmic examination, including slit lamp microscopy, corrected distance visual acuity (CDVA), slit-lamp photography, and Fourier domain optical coherence tomography at preoperative and postoperative visits. PTK was performed using VISX S4 IR (VISX, Inc., Santa Clara, CA). Visual acuity, complications, interval, and contributing factors of recurrence were evaluated. RESULTS: The follow-up period ranged from 1 to 108 months (mean: 35.22 months). The mean logMAR CDVA was 0.55 +/- 0.43 (Snellen equivalent 20/80) preoperatively and 0.09 +/- 0.43 (Snellen equivalent 20/25) at 3 months postoperatively. Forty-five (61.6%) eyes developed biomicroscopic recurrence at a mean of 18.6 months after PTK; 20 (27.4%) eyes developed significant recurrence at a mean of 31.3 months after PTK. The flap removal group demonstrated better CDVA at 3 years after surgery and lower recurrence and complication rates than the flap conservation group. Multivariate analysis revealed that flap removal remarkably reduced the risk of both any sign of and significant recurrence. CONCLUSIONS: PTK improved corneal transparency and visual acuity in patients with GCD2 exacerbated after LASIK, although GCD2 eventually recurred. PTK with flap removal was superior to PTK with flap conservation in terms of visual acuity, recurrence, and complications. [J Refract Surg. 2018;34(2):132-139.]. PMID- 29425393 TI - White Ring Sign and Sequential Segmental Terminal Lenticular Side Cut Dissection for Uneventful and Complete Lenticular Extraction in SMILE. PMID- 29425394 TI - Surface Ablation Re-treatments After SMILE. PMID- 29425395 TI - Estimation of LASIK Flap Thickness. PMID- 29425396 TI - Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors. AB - : Hepatitis C virus (HCV) genotype (gt) 3 is highly prevalent globally, with non gt3a subtypes common in Southeast Asia. Resistance-associated substitutions (RASs) have been shown to play a role in treatment failure. However, the role of RASs in gt3 is not well understood. We report the prevalence of RASs in a cohort of direct-acting antiviral treatment-naive, gt3-infected patients, including those with rarer subtypes, and evaluate the effect of these RASs on direct-acting antivirals in vitro. Baseline samples from 496 gt3 patients enrolled in the BOSON clinical trial were analyzed by next-generation sequencing after probe-based enrichment for HCV. Whole viral genomes were analyzed for the presence of RASs to approved direct-acting antivirals. The resistance phenotype of RASs in combination with daclatasvir, velpatasvir, pibrentasvir, elbasvir, and sofosbuvir was measured using the S52 DeltaN gt3a replicon model. The nonstructural protein 5A A30K and Y93H substitutions were the most common at 8.9% (n = 44) and 12.3% (n = 61), respectively, and showed a 10-fold and 11-fold increase in 50% effect concentration for daclatasvir compared to the unmodified replicon. Paired RASs (A30K + L31M and A30K + Y93H) were identified in 18 patients (9 of each pair); these combinations were shown to be highly resistant to daclatasvir, velpatasvir, elbasvir, and pibrentasvir. The A30K + L31M combination was found in all gt3b and gt3g samples. CONCLUSION: Our study reveals high frequencies of RASs to nonstructural protein 5A inhibitors in gt3 HCV; the paired A30K + L31M substitutions occur in all patients with gt3b and gt3g virus, and in vitro analysis suggests that these subtypes may be inherently resistant to all approved nonstructural protein 5A inhibitors for gt3 HCV. (Hepatology 2018). PMID- 29425397 TI - Cholangiocyte-derived exosomal long noncoding RNA H19 promotes cholestatic liver injury in mouse and humans. AB - : Cholestatic liver injury is an important clinical problem with limited understanding of disease pathologies. Exosomes are small extracellular vesicles released by a variety of cells, including cholangiocytes. Exosome-mediated cell cell communication can modulate various cellular functions by transferring a variety of intracellular components to target cells. Our recent studies indicate that the long noncoding RNA (lncRNA), H19, is mainly expressed in cholangiocytes, and its aberrant expression is associated with significant down-regulation of small heterodimer partner (SHP) in hepatocytes and cholestatic liver injury in multidrug resistance 2 knockout (Mdr2-/- ) mice. However, how cholangiocyte derived H19 suppresses SHP in hepatocytes remains unknown. Here, we report that cholangiocyte-derived exosomes mediate transfer of H19 into hepatocytes and promote cholestatic injury. Hepatic H19 level is correlated with severity of cholestatic injury in both fibrotic mouse models, including Mdr2-/- mice, a well characterized model of primary sclerosing cholangitis (PSC), or CCl4 -induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually up-regulated during disease progression in Mdr2-/ mice and patients with cirrhosis. H19-carrying exosomes from the primary cholangiocytes of wild-type (WT) mice suppress SHP expression in hepatocytes, but not the exosomes from the cholangiocytes of H19-/- mice. Furthermore, overexpression of H19 significantly suppressed SHP expression at both transcriptional and posttranscriptional levels. Importantly, transplant of H19 carrying serum exosomes of old fibrotic Mdr2-/- mice significantly promoted liver fibrosis (LF) in young Mdr2-/- mice. CONCLUSION: Cholangiocyte-derived exosomal H19 plays a critical role in cholestatic liver injury. Serum exosomal H19 represents a noninvasive biomarker and potential therapeutic target for cholestatic diseases. (Hepatology 2018). PMID- 29425398 TI - Do Parent Preferences for Child Conduct Problem Interventions Impact Parenting Outcomes? A Pilot Study in Community Children's Mental Health Settings. AB - A pilot, doubly randomized preference trial was conducted to investigate the impact of providing parents preferences on parenting outcomes. Families with children having conduct problems were randomly assigned to a choice group in which they received their preferred treatment among the four intervention options or a no-choice group in which they were randomized assigned to one of the four options. Results of mixed-effects models showed that parents in the choice group who selected Parent Management Training-Oregon Model (PMTO) had better parenting outcomes over time compared to parents in the choice group who selected child therapy. It highlights the importance of incorporating parent preferences in the delivery of evidence-based treatments. PMID- 29425399 TI - Probing Substrate Diffusion in Interstitial MOF Chemistry with Kinetic Isotope Effects. AB - Metal-organic frameworks (MOFs) have garnered substantial interest as platforms for site-isolated catalysis. Efficient diffusion of small-molecule substrates to interstitial lattice-confined catalyst sites is critical to leveraging unique opportunities of these materials as catalysts. Understanding the rates of substrate diffusion in MOFs is challenging, and few in situ chemical tools are available to evaluate substrate diffusion during interstitial MOF chemistry. Herein, we demonstrate nitrogen atom transfer (NAT) from a lattice-confined Ru2 nitride to toluene to generate benzylamine. We use the comparison of the intramolecular deuterium kinetic isotope effect (KIE), determined for amination of a partially deuterated substrate, with the intermolecular KIE, determined by competitive amination of a mixture of perdeuterated and undeuterated substrates, to establish the relative rates of substrate diffusion and interstitial chemistry. We anticipate that the developed KIE-based experiments will contribute to the development of porous materials for group-transfer catalysis. PMID- 29425400 TI - Journal of Orthopaedic Research(r) update, January 2018. PMID- 29425401 TI - Community structure, dispersal ability and functional profiling of microbiome existing in fat body and ovary of the brown planthopper, Nilaparvata lugens. AB - The endosymbionts play vital roles in growth, development and reproduction in insects. Yeast-like endosymbionts (YLSs) have been well studied in Nilaparvata lugens (N. lugens), but little is known about the tissue-specific bacterial microbiomes, especially on the microbial intersection among internal tissues. Here, the correlation of microbial composition, structure, dispersal ability and functional profiling were illuminated in two tissues, the fat body and ovary in N. lugens. A total of 11 phyla and 105 genera were captured from all samples; Firmicutes and Proteobacteria were the most predominant and accounted for more than 99% in all samples. However, the relative abundance of Firmicutes and Proteobacteria was significantly different in ovary and fat body through Fisher's Least Significant Difference test. Microbial diversity but not the richness index in the two tissues exhibited significant difference. Furthermore, the microbial community structure of the ovary and fat body were primarily determined by tissue quality. Firmicutes showed strong dispersal ability between ovary and fat body based on the quantitative null model assessing, indicating the frequent interaction of these microbiomes in the two tissues. In addition, the Kyoto Encyclopedia of Genes and Genomes pathways of microbial participation were delineated. The ten most abundant pathways counted for over 46% of the annotation and were shared between the two tissues, mainly containing Energy Metabolism and Amino Acid Metabolism/Biosynthesis. The results will provide insights into the correlation of microbial community structure between ovary and fat body of N. lugens. PMID- 29425402 TI - Alpha-fetoprotein in liver transplantation for hepatocellular carcinoma: The lower, the better. PMID- 29425403 TI - Direct and indirect effects of light pollution on the performance of an herbivorous insect. AB - Light pollution is a global disturbance with resounding impacts on a wide variety of organisms, but our understanding of these impacts is restricted to relatively few higher vertebrate species. We tested the direct effects of light pollution on herbivore performance as well as indirect effects mediated by host plant quality. We found that artificial light from streetlights alters plant toughness. Additionally, we found evidence of both direct and indirect effects of light pollution on the performance of an herbivorous insect, which indicates that streetlights can have cascading impacts on multiple trophic levels. Our novel findings suggest that light pollution can alter plant-insect interactions and thus may have important community-wide consequences. PMID- 29425404 TI - Nonstructural protein 5A/P32 deletion after failure of ledipasvir/sofosbuvir in hepatitis C virus genotype 1b infection. PMID- 29425405 TI - Tunable Crystallinity and Charge Transfer in Two-Dimensional G-Quadruplex Organic Frameworks. AB - DNA G-quadruplex structures were recently discovered to provide reliable scaffolding for two-dimensional organic frameworks due to the strong hydrogen bonding ability of guanine. Herein, 2,7-diaryl pyrene building blocks with high HOMO energies and large optical gaps are incorporated into G-quadruplex organic frameworks. The adjustable substitution on the aryl groups provides an opportunity to elucidate the framework formation mechanism; molecular non planarity is found to be beneficial for restricting interlayer slippage, and the framework crystallinity is highest when intermolecular interaction and non planarity strike a fine balance. When guanine-functionalized pyrenes are co crystallized with naphthalene diimide, charge-transfer (CT) complexes are obtained. The photophysical properties of the pyrene-only and CT frameworks are characterized by UV/Vis and steady-state and time-resolved photoluminescence spectroscopies, and by EPR spectroscopy for the CT complex frameworks. PMID- 29425407 TI - The importance of understanding the underlying physiology of exercise when designing exercise interventions for brain health. PMID- 29425408 TI - Layered Nano-TiO2 Based Treatments for the Maintenance of Natural Stones in Historical Architecture. AB - Layered treatments of natural stones based on dispersions of experimental nano TiO2 and commercial TEOS showing photocatalytic and self-cleaning properties were set up and tested. To enhance nano-TiO2 efficacy, a surface pre-treatment with tetraethyl orthosilicate was proposed to avoid the penetration of NPs into the crystalline porous substrates and to improve their adhesion to the stone. Two treatment applications (wet-on-wet and wet-on-dry) were compared, showing different results. A strong interaction Si-O-Ti was the key factor for the successful treatment, leaving the band gap and relevant properties of nano-TiO2 unaltered. The layered treatments were tested on a porous calcarenite (Noto stone) and a very compact marble (Carrara marble). The combined SiO2 -nano-TiO2 treatments can find application in suitable cases where a surface consolidation is needed, ensuring a depolluting and self-cleaning durable activity. PMID- 29425409 TI - A confirmatory examination of age-associated personality differences: Deriving age-related measurement-invariant solutions using ant colony optimization. AB - OBJECTIVE: The goal of this study was to examine age-associated personality differences using a measurement-invariant representation of the higher-order structure of the Five-Factor Model. METHOD: We reanalyzed the German NEO-PI-R norm sample (N = 11,724) and applied ant colony optimization in a multigroup confirmatory factor analysis setting in order to select three items per first order factor that would optimize model fit and measurement invariance across 18 age groups ranging from 16 to 65 years of age. RESULTS: Ant colony optimization substantially improved absolute and relative model fit under measurement invariance constraints. However, the results showed that even when selecting items, measurement invariance across a large age span could not be guaranteed. Strong measurement invariance for Extraversion and Agreeableness could not be established. The age-associated mean-level differences of the first-order factors of Neuroticism and Conscientiousness supported the maturity hypothesis. The mean levels of the first-order factors of Openness varied substantially from each other across age. CONCLUSIONS: Findings on age differences in personality can be particularly distorted in older age groups. Testing for and ensuring measurement invariance with item selection procedures can help solve this problem. The higher order structure of personality should be accounted for when personality development is examined. PMID- 29425411 TI - [In process]. PMID- 29425406 TI - Radical solutions: Principles and application of electron-based dissociation in mass spectrometry-based analysis of protein structure. AB - In recent years, electron capture (ECD) and electron transfer dissociation (ETD) have emerged as two of the most useful methods in mass spectrometry-based protein analysis, evidenced by a considerable and growing body of literature. In large part, the interest in these methods is due to their ability to induce backbone fragmentation with very little disruption of noncovalent interactions which allows inference of information regarding higher order structure from the observed fragmentation behavior. Here, we review the evolution of electron-based dissociation methods, and pay particular attention to their application in "native" mass spectrometry, their mechanism, determinants of fragmentation behavior, and recent developments in available instrumentation. Although we focus on the two most widely used methods-ECD and ETD-we also discuss the use of other ion/electron, ion/ion, and ion/neutral fragmentation methods, useful for interrogation of a range of classes of biomolecules in positive- and negative-ion mode, and speculate about how this exciting field might evolve in the coming years. PMID- 29425410 TI - Three-Component Activation/Alkynylation/Cyclocondensation (AACC) Synthesis of Enhanced Emission Solvatochromic 3-Ethynylquinoxalines. AB - 2-Substituted 3-ethynylquinoxaline chromophores can be readily synthesized by a consecutive activation-alkynylation-cyclocondensation (AACC) one-pot sequence in a three-component manner. In comparison with the previously published four component glyoxylation starting from electron-rich pi-nucleophiles, the direct activation of (hetero)aryl glyoxylic acids allows the introduction of substituents that cannot be directly accessed by glyoxylation. By introducing N,N dimethylaniline as a strong donor in the 2-position, the emission solvatochromicity of 3-ethynylquinoxalines can be considerably enhanced to cover the spectral range from blue-green to deep red-orange with a single chromophore in a relatively narrow polarity window. The diversity-oriented nature of the synthetic multicomponent reaction concept enables comprehensive investigations of structure-property relationships by Hammett correlations and Lippert-Mataga analysis, as well as the elucidation of the electronic structure of the emission solvatochromic pi-conjugated donor-acceptor systems by DFT and time-dependent DFT calculations with the PBEh1PBE functional for a better reproduction of the dominant charge-transfer character of the longest wavelength absorption band. PMID- 29425412 TI - [In process]. PMID- 29425413 TI - [In process]. PMID- 29425414 TI - [In process]. PMID- 29425415 TI - [In process]. PMID- 29425416 TI - [In process]. PMID- 29425417 TI - [In process]. PMID- 29425418 TI - [In process]. PMID- 29425419 TI - [In process]. PMID- 29425420 TI - [In process]. PMID- 29425421 TI - [In process]. PMID- 29425422 TI - [In process]. PMID- 29425423 TI - [In process]. PMID- 29425424 TI - [In process]. PMID- 29425425 TI - [In process]. PMID- 29425426 TI - [In process]. PMID- 29425427 TI - [In process]. PMID- 29425428 TI - [In process]. PMID- 29425429 TI - [In process]. PMID- 29425430 TI - [In process]. PMID- 29425431 TI - [In process]. PMID- 29425432 TI - [In process]. PMID- 29425433 TI - [In process]. PMID- 29425434 TI - [In process]. PMID- 29425435 TI - [In process]. PMID- 29425436 TI - [In process]. PMID- 29425437 TI - [In process]. PMID- 29425438 TI - High Mechanical Property of Laminated Electromechanical Sensors by Carbonized Nanolignocellulose/Graphene Composites. AB - Although widely used in nanocomposites, the effect of embedding graphene in carbonized nanolignocellulose substrates is less clear. We added graphene to a carbonized nanolignocellulose to change its mechanical and electromechanical properties. Here, the laminated carbonized nanolignocellulose/graphene composites were fabricated by carbonizing the nanolignocellulose/graphene composites prepared through mechanochemistry and flow-directed assembly process. The resulting composites exhibit excellent mechanical property with the ultimate bending strength of 25.6 +/- 4.2 MPa. It is observed reversible electrical resistance change in these composites with strain, which is associated with the tunneling conduction model. This type of high-strength conductive composite has great potential applications in load-bearing electromechanical sensors. PMID- 29425439 TI - Near-UV Water Splitting by Cu, Ni, and Co Complexes in the Gas Phase. AB - (2,2'-Bipyridine)M?O+ ions (M = Cu, Ni, Co) were generated by collision-induced dissociation and near-UV photodissociation of readily available [(2,2' bipyridine)MII(NO3)]+ ions in the gas phase, and their structure was confirmed by ion-molecule reactions combined with isotope labeling. Upon storage in a quadrupole ion trap, the (2,2'-bipyridine)M?O+ ions spontaneously added water, and the formed [(2,2'-bipyridine)M?O + H2O]+ complexes eliminated OH upon further near-UV photodissociation. This reaction sequence can be accomplished at a single laser wavelength in the range of 260-340 nm to achieve stoichiometric homolytic cleavage of gaseous water. Structures, spin states, and electronic excitations of the metal complexes were characterized by ion-molecule reactions using 2H and 18O labeling, photodissociation action spectroscopy, and density functional theory calculations. PMID- 29425441 TI - Nonthrombogenic Hydrogel Coatings with Carbene-Cross-Linking Bioadhesives. AB - Bioadhesives are a current unmet clinical need for mending of blood contacting soft tissues without inducing thrombosis. Recent development of carbene precursor bioadhesives with the advantages of on-demand curing, tuneable modulus, and wet adhesion have been synthesized by grafting diazirine onto poly (amidoamine) (PAMAM-G5) dendrimers. Herein, the structure activity relationships of platelet adhesion and activation is evaluated for the first time on the cured PAMAM-g diazirine bioadhesives. Three strategies were employed to prevent healthy human donor platelets from adhering and activating on light-cured bioadhesive surfaces: (1) Attenuation of cationic surface charge, (2) antifouling composites by incorporating heparin and alginate in uncured formulation, and (3) heparin wash of cured bioadhesive surface. Topographical imaging of cured and ethanol dehydrated bioadhesive surfaces was used to quantify the adhered and activated platelets with scanning electron microscopy, whose resolution allowed identification of round senescent, short dendritic, and long dendritic platelets. Cured surfaces of PAMAM-g-diazirine (15%) had 10300 +/- 500 adhered platelets mm 2 with 99.7% activation into short/long dendritic cells. Reduction of primary amines by higher degree of diazirine grafting or capping of free amines by acetylation reduces platelet adherence (2400 +/- 200 vs 3000 +/- 300, respectively). Physical incorporation of heparin and alginate in the formulations reduced the activated platelet; 1300 +/- 300 and 300 +/- 50, activated platelets mm-2, in comparison with additive free adhesive formulation. Similarly, heparin rinse of the surface of additive free bioadhesive reduced the activated platelet to platelets of heparin composites at 600 +/- 100 platelets mm-2. PAMAM-g diazirine (15%) bioadhesive retained the photocured mechanical properties and lap shear adhesion despite the addition of heparin and alginate additives. PMID- 29425440 TI - Tailoring Mechanically Tunable Strain Fields in Graphene. AB - There are a number of theoretical proposals based on strain engineering of graphene and other two-dimensional materials, however purely mechanical control of strain fields in these systems has remained a major challenge. The two approaches mostly used so far either couple the electrical and mechanical properties of the system simultaneously or introduce some unwanted disturbances due to the substrate. Here, we report on silicon micromachined comb-drive actuators to controllably and reproducibly induce strain in a suspended graphene sheet in an entirely mechanical way. We use spatially resolved confocal Raman spectroscopy to quantify the induced strain, and we show that different strain fields can be obtained by engineering the clamping geometry, including tunable strain gradients of up to 1.4%/MUm. Our approach also allows for multiple axis straining and is equally applicable to other two-dimensional materials, opening the door to investigating their mechanical and electromechanical properties. Our measurements also clearly identify defects at the edges of a graphene sheet as being weak spots responsible for its mechanical failure. PMID- 29425442 TI - Light-Harvesting Strategy during CO2-Dependent Photosynthesis in the Green Alga Chlamydomonas reinhardtii. AB - To maximize the efficiency of photosynthesis, photosynthetic organisms must properly balance their light-harvesting ability and CO2 utilization. However, the molecular mechanisms of light harvesting under various CO2 conditions remain unclear. To reveal these mechanisms, we performed new analysis on cells of the green alga Chlamydomonas reinhardtii under different CO2 conditions. The analysis combines three kinds of fluorometries: pulse-amplitude modulated fluorescence, steady-state fluorescence with absolute intensity, and time-resolved fluorescence. Under low CO2 conditions, the main regulatory mechanism was migration of a light-harvesting chlorophyll-protein complex (LHC) II from photosystem (PS) II to PSI. However, under CO2-deficient conditions with carbon supplementation, some of the LHCII separated from the PSI and aggregated with quenching. These different light-harvesting abilities of LHCII may play an important role in the regulation of light harvesting in C. reinhardtii under various CO2 conditions. PMID- 29425443 TI - Tumor Targeting with Novel Pyridyl 6-Substituted Pyrrolo[2,3- d]Pyrimidine Antifolates via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of De Novo Purine Nucleotide Biosynthesis. AB - Tumor-targeted specificities of 6-substituted pyrrolo[2,3- d]pyrimidine analogues of 1, where the phenyl side-chain is replaced by 3',6' (5, 8), 2',5' (6, 9), and 2',6' (7, 10) pyridyls, were analyzed. Proliferation inhibition of isogenic Chinese hamster ovary (CHO) cells expressing folate receptors (FRs) alpha and beta were in rank order, 6 > 9 > 5 > 7 > 8, with 10 showing no activity, and 6 > 9 > 5 > 8, with 10 and 7 being inactive, respectively. Antiproliferative effects toward FRalpha- and FRbeta-expressing cells were reflected in competitive binding with [3H]folic acid. Only compound 6 was active against proton-coupled folate receptor (PCFT)-expressing CHO cells (~4-fold more potent than 1) and inhibited [3H]methotrexate uptake by PCFT. In KB and IGROV1 tumor cells, 6 showed <1 nM IC50, ~2-3-fold more potent than 1. Compound 6 inhibited glycinamide ribonucleotide formyltransferase in de novo purine biosynthesis and showed potent in vivo efficacy toward subcutaneous IGROV1 tumor xenografts in SCID mice. PMID- 29425444 TI - Probing the Local Dielectric Constant of Plasmid DNA in Solution and Adsorbed on Chemically Graded Aminosilane Surfaces. AB - Nile Red dye was used to determine the dielectric constant, epsilon, of nonpolar microenvironments in double stranded DNA (ds-DNA) both in aqueous buffer solution and when adsorbed on amine-modified surfaces. The value of epsilon within the DNA decreased with increasing buffer concentration. Values of epsilon ~ 6.75 and ~3.00 were obtained in 0.1 mM phosphate buffered saline (PBS) and in 10 mM PBS, respectively. Similar effects were observed upon adsorption to chemically graded amine-modified silica surfaces. Under 1 mM buffer, epsilon was measured to be ~2.84 and ~1.90 at the low amine (high silica) and high amine (low silica) ends of the gradient, respectively. An increase in the buffer concentration again led to a decrease in epsilon, but only at the low amine end. It is concluded that high buffer concentrations and binding to an amine surface cause a condensation of the DNA, forming less polar microenvironments. These results provide important knowledge of the factors governing the polarity of DNA microenvironments to which intercalators bind. PMID- 29425445 TI - Highly Diastereoselective Palladium-Catalyzed Oxidative Carbocyclization of Enallenes Assisted by a Weakly Coordinating Hydroxyl Group. AB - A highly diastereoselective palladium-catalyzed oxidative carbocyclization borylation of enallenes assisted by a weakly coordinating hydroxyl group was developed. The reaction afforded functionalized cyclohexenol derivatives, in which the 1,3-relative stereochemistry is controlled (d.r. > 50:1). Other weakly coordinating oxygen-containing groups (ketone, alkoxide, acetate) also assisted the carbocyclization toward cyclohexenes. The reaction proceeds via a ligand exchange on Pd of the weakly coordinating group with a distant olefin group. The high diastereoselectivity of the hydroxyl-directed reaction could be rationalized by a face-selective coordination of the distant olefin. It was demonstrated that the primary coordination of the close-by oxygen-containing functionality was necessary for the reaction to occur and removal of this functionality shut down the reaction. PMID- 29425447 TI - Structural Comparison of Various Silkworm Silks: An Insight into the Structure Property Relationship. AB - Silkworm silk has attracted considerable attention in recent years due to its excellent mechanical properties, biocompatibility, and promising applications in biomedical sector. However, a clear understanding of the molecular structure and the relationship between the excellent mechanical properties and the silk protein sequences are still lacking. This study carries out a thorough comparative structural analysis of silk fibers of four silkworm species ( Bombyx mori, Antheraea pernyi, Samia cynthia ricini, and Antheraea assamensis). A combination of characterization techniques including scanning electron microscopy, mechanical test, synchrotron X-ray diffraction, Fourier transform infrared spectroscopy (FTIR), and NMR spectroscopy was applied to investigate the morphologies, mechanical properties, amino acid compositions, nanoscale organizations, and molecular structures of various silkworm silks. Furthermore, the structure property relationship is discussed by correlating the molecular structural features of silks with their mechanical properties. The results show that a high content of beta-sheet structures and a high crystallinity would result in a high Young's modulus for silkworm silk fibers. Additionally, a low content of beta sheet structures would result in a high extensibility. PMID- 29425446 TI - Transcriptome Analysis of Hepatopancreas from the Cr (VI)-Stimulated Mantis Shrimp ( Oratosquilla oratoria) by Illumina Paired-End Sequencing: Assembly, Annotation, and Expression Analysis. AB - Cr (VI), the pathogenicity factor, is widely known to cause toxic effects in living organisms. Given the economic importance of the mantis shrimp ( Oratosquilla oratoria), the understanding of impacts by Cr (VI) is considered important. In this study, transcriptome of mantis shrimp was characterized by a comparison between control and Cr (VI)-treated samples using RNA-seq approach. Totally, 88 234 826 bp and 13.24G clean reads were obtained. The total length and number of unigenes were 68 411 206 bp and 100 918, respectively. The maximal and average length of unigenes was 24 906 bp and 678 bp, respectively (N50, 798 bp). 7115 of these unigenes accounted for 7.05% of the total that were annotated in all databases. After annotation of assembled unigenes, 35 619 of them were assigned into 3 functional categories and 56 subcategories using Gene Ontology; 18 580 of them were assigned into 26 functional categories using Clusters of Orthologous Groups of proteins; 16 864 of them were assigned into 5 major categories and 32 subclasses using KEGG. Finally, 1730 genes were differentially expressed (DGEs), 9 up-regulated pathways (protein digestion and absorption, neuroactive ligand-receptor interaction, pancreatic secretion, tyrosine metabolism, amoebiasis, ECM-receptor interaction, riboflavin metabolism, amino sugar and nucleotide sugar metabolism and AGE-RAGE signaling pathway in diabetic complications) were significantly enriched ( q < 0.05), and one down-regulated pathway ( Staphylococcus aureus infection) was significantly enriched ( q < 0.05). Up-regulation of genes in pathways of protein digestion/absorption ( PepT1/SLC15A and ATP1B) and environment information processing ( COL1AS, COL4A; LAMA3_5, LAMB3; FN1 and TN) may imply the potentially positive toxicity resistance mechanisms. PMID- 29425448 TI - Design of Carrageenan-Based Heparin-Mimetic Gel Beads as Self-Anticoagulant Hemoperfusion Adsorbents. AB - The currently used hemoperfusion adsorbents such as activated carbon and ion exchange resin show dissatisfactory hemocompatibility, and a large dose of injected heparin leads to the increasing cost and the risk of systematic bleeding. Natural polysaccharide adsorbents commonly have good biocompatibility, but their application is restricted by the poor mechanical strength and low content of functional groups. Herein, we developed an efficient, self anticoagulant and blood compatible hemoperfusion adsorbent by imitating the structure and functional groups of heparin. Carrageenan and poly(acrylic acid) (PAA) cross-linked networks were built up by the combination of phase inversion of carrageenan and post-cross-linking of AA, and the formed dual-network structure endowed the beads with improved mechanical properties and controlled swelling ratios. The beads exhibited low protein adsorption amounts, low hemolysis ratios, low cytotoxicity, and suppressed complement activation and contact activation levels. Especially, the activated partial thromboplastin time, prothrombin time, and thrombin time of the gel beads were prolonged over 13, 18, and 4 times than those of the control. The self-anticoagulant and biocompatible beads showed good adsorption capacities toward exogenous toxins (560.34 mg/g for heavy metal ions) and endogenous toxins (14.83 mg/g for creatinine, 228.16 mg/g for bilirubin, and 18.15 mg/g for low density lipoprotein (LDL)), thus, highlighting their potential usage for safe and efficient blood purification. PMID- 29425449 TI - Selection for Cd Pollution-Safe Cultivars of Chinese Kale (Brassica alboglabra L. H. Bailey) and Biochemical Mechanisms of the Cultivar-Dependent Cd Accumulation Involving in Cd Subcellular Distribution. AB - Two pot experiments were conducted to compare and verify Cd accumulation capacities of different cultivars under Cd exposures (0.215, 0.543, and 0.925 mg kg-1 in Exp-1 and 0.143, 0.619, and 1.407 mg kg-1 in Exp-2) and Cd subcellular distributions between low- and high-Cd cultivars. Shoot Cd concentrations between the selected low- and high-Cd cultivars were 1.4-fold different and the results were reproducible. The proportions of Cd-in-cell-wall of shoots and roots were all higher in a typical low-Cd cultivar (DX102) than in a typical high-Cd cultivar (HJK), while those of Cd-in-chloroplast or Cd-in-trophoplast and Cd-in membrane-and-organelle were opposite. The proportions of Cd-in-vacuoles-and cytoplasm of roots in DX102 were always higher than in HJK under Cd stresses, while there was no clear pattern in those of shoots. These findings may help to reduce health risk of Cd from Chinese kale consumption and explained biochemical mechanisms of cultivar-dependent Cd accumulation among the species. PMID- 29425451 TI - Ionization and Single and Double Electron Capture in Proton-Ar Collisions. AB - Total cross sections for formation of H and H-, and electron production, in H+ + Ar collisions have been calculated at energies between 100 eV and 200 keV by employing two methods: for E < 10 keV, a semiclassical treatment with an expansion in a basis of electronic wave functions of the ArH+ quasimolecule and, for E > 10 keV, the switching-classical-trajectory-Monte Carlo method (s-CTMC). The semiclassical calculation involves transitions to molecular autoionizing states, calculated by applying a block-diagonalization technique. The s-CTMC method is adept to treat two-electron processes and yields total cross sections for H- formation in reasonably good agreement with the experimental data. Cross sections for electron- and H-production processes, which are dominated by one electron transitions, are in good agreement with the experimental data. PMID- 29425452 TI - Evaluation of the High-Field Orbitrap Fusion for Compound Annotation in Metabolomics. AB - Annotation of signals of interest represents a key point in mass spectrometry based metabolomics studies. The first level of investigation is the elemental composition, which can be deduced from accurately measured masses and isotope patterns. However, accuracy of these two parameters remains to be evaluated on last generation mass spectrometers to determine the level of confidence that can be used during the annotation process. In this context, we evaluated the performance of the Orbitrap Fusion mass spectrometer for the first time and demonstrated huge potential for metabolite annotation via elemental composition determination. This work was performed using a set of 50 standard compounds analyzed under LC/MS conditions in solvent and biological media. Accurate control of the number of trapped ions proved mandatory to avoid space charge effects, ensure sub-ppm mass accuracy (using external calibration), and reliable measurement of isotopic patterns at 500,000 resolution. On the basis of the results, we propose standard optimized experimental conditions for performing robust and accurate untargeted metabolomics on the Orbitrap Fusion at high mass measurement and mass spectral accuracy. PMID- 29425453 TI - Accelerating Chemical Discovery with Machine Learning: Simulated Evolution of Spin Crossover Complexes with an Artificial Neural Network. AB - Machine learning (ML) has emerged as a powerful complement to simulation for materials discovery by reducing time for evaluation of energies and properties at accuracy competitive with first-principles methods. We use genetic algorithm (GA) optimization to discover unconventional spin-crossover complexes in combination with efficient scoring from an artificial neural network (ANN) that predicts spin state splitting of inorganic complexes. We explore a compound space of over 5600 candidate materials derived from eight metal/oxidation state combinations and a 32-ligand pool. We introduce a strategy for error-aware ML-driven discovery by limiting how far the GA travels away from the nearest ANN training points while maximizing property (i.e., spin-splitting) fitness, leading to discovery of 80% of the leads from full chemical space enumeration. Over a 51-complex subset, average unsigned errors (4.5 kcal/mol) are close to the ANN's baseline 3 kcal/mol error. By obtaining leads from the trained ANN within seconds rather than days from a DFT-driven GA, this strategy demonstrates the power of ML for accelerating inorganic material discovery. PMID- 29425450 TI - Hydrophobic Collapse in N-Methylacetamide-Water Mixtures. AB - Aqueous N-methylacetamide solutions were investigated by polarization-resolved pump-probe and 2D infrared spectroscopy (2D IR), using the amide I mode as a reporter. The 2D IR results are compared with molecular dynamics simulations and spectral calculations to gain insight into the molecular structures in the mixture. N-Methylacetamide and water molecules tend to form clusters with "frozen" amide I dynamics. This is driven by a hydrophobic collapse as the methyl groups of the N-methylacetamide molecules cluster in the presence of water. Since the studied system can be considered as a simplified model for the backbone of proteins, the present study forms a convenient basis for understanding the structural and vibrational dynamics in proteins. It is particularly interesting to find out that a hydrophobic collapse as the one driving protein folding is observed in such a simple system. PMID- 29425454 TI - Surface-Assisted Dynamic Search Processes. AB - Many chemical and biological systems exhibit intermittent search phenomena when participating particles alternate between dynamic regimes with different dimensionalities. Here we investigate theoretically a dynamic search process of finding a small target on a two-dimensional surface starting from a bulk solution, which is an example of such an intermittent search process. Both continuum and discrete-state stochastic descriptions are developed. It is found that depending on the scanning length lambda, which describes the area visited by the reacting molecule during one search cycle, the system can exhibit three different search regimes: (i) For small lambda values, the reactant finds the target mostly via three-dimensional bulk diffusion; (ii) for large lambda values, the reactant molecule associates to the target mostly via surface diffusion; and (iii) for intermediate lambda values, the reactant reaches the target via a combination of three-dimensional and two-dimensional search cycles. Our analysis also shows that the mean search times have different scalings as a function of the size of the surface segment depending on the nature of the dynamic search regime. Search dynamics are also sensitive to the position of the target for large scanning lengths. In addition, it is argued that the continuum description underestimates mean search times and does not always correctly describe the most optimal conditions for the surface-assisted dynamic processes. The importance of our findings for real natural systems is discussed. PMID- 29425455 TI - Optimal HTS Fingerprint Definitions by Using a Desirability Function and a Genetic Algorithm. AB - The use of compound biological fingerprints built on data from high-throughput screening (HTS) campaigns, or HTS fingerprints, is a novel cheminformatics method of representing compounds by integrating chemical and biological activity data that is gaining momentum in its application to drug discovery, including hit expansion, target identification, and virtual screening. HTS fingerprints present two major limitations, noise and missing data, which are intrinsic to the high throughput data acquisition technologies and to the assay availability or assay selection procedure used for their construction. In this work, we present a methodology to define an optimal set of HTS fingerprints by using a desirability function that encodes the principles of maximum biological and chemical space coverage and minimum redundancy between HTS assays. We used a genetic algorithm to optimize the desirability function and obtained an optimal fingerprint that was evaluated for performance in a test set of 33 diverse assays. Our results show that the optimal HTS fingerprint represents compounds in chemical biology space using 25% fewer assays. When used for virtual screening, the optimal HTS fingerprint obtained equivalent performance, in terms of both area under the curve and enrichment factors, to full fingerprints for 27 out of 33 test assays, while randomly assembled fingerpints could achieve equivalent performance in only 23 test assays. PMID- 29425456 TI - Knowledge-Based Conformer Generation Using the Cambridge Structural Database. AB - Fast generation of plausible molecular conformations is central to molecular modeling. This paper presents an approach to conformer generation that makes extensive use of the information available in the Cambridge Structural Database. By using geometric distributions derived from the Cambridge Structural Database, it is possible to create biologically relevant conformations in the majority of cases analyzed. The paper compares the performance of the approach with previously published evaluations, and presents some cases where the method fails. The method appears to show significantly improved performance in reproduction of the conformations of structures observed in the Cambridge Structural Database and the Protein Data Bank as compared to other published methods of a similar speed. PMID- 29425457 TI - Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury. AB - Two 2-aminoimidazole-based inhibitors, LY3031207 (1) and LY3023703 (2), of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme were found to cause drug induced liver injury (DILI) in humans. We studied imidazole ring substitutions to successfully mitigate reactive metabolite (RM) formation. These studies support the conclusion that RM formation may play a role in the observations of DILI and the consideration of 2-aminoimidazoles as structure alerts, due to the high likelihood of bioactivation to generate RMs. PMID- 29425458 TI - Vanadium Oxide Thin Film Formation on Graphene Oxide by Microexplosive Decomposition of Ammonium Peroxovanadate and Its Application as a Sodium Ion Battery Anode. AB - Formation of vanadium oxide nanofilm-coated graphene oxide (GO) is achieved by thermally induced explosive disintegration of a microcrystalline ammonium peroxovanadate-GO composite. GO sheets isolate the microcrystalline grains and capture and contain the microexplosion products, resulting in the deposition of the nanoscale products on the GO. Thermal treatment of the supported nanofilm yields a sequence of nanocrystalline phases of vanadium oxide (V3O7, VO2) as a function of temperature. This is the first demonstration of microexplosive disintegration of a crystalline peroxo compound to yield a nanocoating. The large number of recently reported peroxide-rich crystalline materials suggests that the process can be a useful general route for nanofilm formation. The V3O7@GO composite product was tested as a sodium ion battery anode and showed high charge capacity at high rate charge-discharge cycling (150 mAh g-1 at 3000 mA g-1 vs 300 mAh g-1 at 100 mA g-1) due to the nanomorphology of the vanadium oxide. PMID- 29425459 TI - Tunable Physical Properties of Ethylcellulose/Gelatin Composite Nanofibers by Electrospinning. AB - In this work, the ethylcellulose/gelatin blends at various weight ratios in water/ethanol/acetic acid solution were electrospun to fabricate nanofibers with tunable physical properties. The solution compatibility was predicted based on Hansen solubility parameters and evaluated by rheological measurements. The physical properties were characterized by scanning electron microscopy, porosity, differential scanning calorimetry, thermogravimetry, Fourier transform infrared spectroscopy, and water contact angle. Results showed that the entangled structures among ethylcellulose and gelatin chains through hydrogen bonds gave rise to a fine morphology of the composite fibers with improved thermal stability. The fibers with higher gelatin ratio (75%), possessed hydrophilic surface (water contact angle of 53.5 degrees ), and adequate water uptake ability (1234.14%), while the fibers with higher ethylcellulose proportion (75%) tended to be highly water stable with a hydrophobic surface (water contact angle of 129.7 degrees ). This work suggested that the composite ethylcellulose/gelatin nanofibers with tunable physical properties have potentials as materials for bioactive encapsulation, food packaging, and filtration applications. PMID- 29425460 TI - Self-Organized Lattices of Nonlinear Optochemical Waves in Photopolymerizable Fluids: The Spontaneous Emergence of 3-D Order in a Weakly Correlated System. AB - Many of the extraordinary three-dimensional architectures that pattern our physical world emerge from complex nonlinear systems or dynamic populations whose individual constituents are only weakly correlated to each other. Shoals of fish, murmuration behaviors in birds, congestion patterns in traffic, and even networks of social conventions are examples of spontaneous pattern formation, which cannot be predicted from the properties of individual elements alone. Pattern formation at a different scale has been observed or predicted in weakly correlated systems including superconductors, atomic gases near Bose Einstein condensation, and incoherent optical fields. Understanding pattern formation in nonlinear weakly correlated systems, which are often unified through mathematical expression, could pave intelligent self-organizing pathways to functional materials, architectures, and computing technologies. However, it is experimentally difficult to directly visualize the nonlinear dynamics of pattern formation in most populations-especially in three dimensions. Here, we describe the collective behavior of large populations of nonlinear optochemical waves, which are poorly correlated in both space and time. The optochemical waves-microscopic filaments of white light entrapped within polymer channels-originate from the modulation instability of incandescent light traveling in photopolymerizable fluids. By tracing the three-dimensional distribution of optical intensity in the nascent polymerizing system, we find that populations of randomly distributed, optochemical waves synergistically and collectively shift in space to form highly ordered lattices of specific symmetries. These, to our knowledge, are the first three-dimensionally periodic structures to emerge from a system of weakly correlated waves. Their spontaneous formation in an incoherent and effectively chaotic field is counterintuitive, but the apparent contradiction of known behaviors of light including the laws of optical interference can be explained through the soliton-like interactions of optochemical waves with nearest neighbors. Critically, this work casts fundamentally new insight into the collective behaviors of poorly correlated nonlinear waves in higher dimensions and provides a rare, accessible platform for further experimental studies of these previously unexplored behaviors. Furthermore, it defines a self organization paradigm that, unlike conventional counterparts, could generate polymer microstructures with symmetries spanning all the Bravais lattices. PMID- 29425461 TI - Excited-State Dynamics of a DNA Duplex in a Deep Eutectic Solvent Probed by Femtosecond Time-Resolved IR Spectroscopy. AB - To better understand how the solvent influences excited-state deactivation in DNA strands, femtosecond time-resolved IR (fs-TRIR) pump-probe measurements were performed on a d(AT)9.d(AT)9 duplex dissolved in a deep eutectic solvent (DES) made from choline chloride and ethylene glycol in a 1:2 mol ratio. This solvent, known as ethaline, is a member of a class of ionic liquids capable of solubilizing DNA with minimal disruption to its secondary structure. UV melting analysis reveals that the duplex studied here melts at 18 degrees C in ethaline compared to 50 degrees C in aqueous solution. Ethaline has an excellent transparency window that facilitates TRIR measurements in the double-bond stretching region. Transient spectra recorded in deuterated ethaline at room temperature indicate that photoinduced intrastrand charge transfer occurs from A to T, yielding the same exciplex state previously detected in aqueous solution. This state decays via charge recombination with a lifetime of 380 +/- 10 ps compared to the 300 +/- 10 ps lifetime measured earlier in D2O solution. The TRIR data strongly suggest that the long-lived exciplex forms exclusively in the solvated duplex, and not in the denatured single strands, which appear to have little, if any, base stacking. The longer lifetime of the exciplex state in the DES compared to aqueous solution is suggested to arise from reduced stabilization of the charge transfer state, resulting in slower charge recombination on account of Marcus inverted behavior. PMID- 29425464 TI - Renin-angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B. AB - Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin-angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl4-induced liver fibrosis. Mice were treated with silymarin (30 mg.kg-1), perindopril (1 mg.kg-1), fosinopril (2 mg.kg-1), or losartan (10 mg.kg-1). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (alpha SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFkappaB) pathway by the inhibition of NFkappaB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFkappaBia) subsequently inhibited NFkappaB-induced TNF-alpha and TGF-beta1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis. PMID- 29425463 TI - Genome-Wide Association Study in African Americans with Acute Respiratory Distress Syndrome Identifies the Selectin P Ligand Gene as a Risk Factor. AB - RATIONALE: Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches. OBJECTIVES: To identify genetic susceptibility targets for ARDS. METHODS: A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort. MEASUREMENTS AND MAIN RESULTS: Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg-/- mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation. CONCLUSIONS: These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent. PMID- 29425462 TI - Challenges in Pulmonary Hypertension: Controversies in Treating the Tip of the Iceberg. A Joint National Institutes of Health Clinical Center and Pulmonary Hypertension Association Symposium Report. PMID- 29425465 TI - Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients. AB - RATIONALE: Aspiration of infective subglottic secretions causes ventilator associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP. OBJECTIVES: To characterize subglottic host defense dysfunction in mechanically ventilated patients in the ICU; to determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth. METHODS: Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 min); isolation and culture of primary subglottic epithelial cells from control patients; laboratory analysis of host innate immune defenses. MEASUREMENTS AND MAIN RESULTS: Twenty four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in the ICU was characterized by neutrophilic inflammation, significantly increased proinflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic impairment was reversible on treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium. CONCLUSIONS: Mechanical ventilation in the ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil function and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage. PMID- 29425467 TI - Picking the Right Fruit: Intersecting Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Discoveries with Epigenetics. PMID- 29425466 TI - Mesenchymal stem cells pretreated with melatonin ameliorate kidney functions in a rat model of diabetic nephropathy. AB - The aim of this study was to investigate the effect of a regenerative therapy comprising mesenchymal stem cells (MSCs) pretreated with melatonin (MT) as a new therapy for underlying diabetic nephropathy (DN) pathogenesis in a rat model, and its possible effect on autophagy protein Beclin-1. Forty adult male albino Wistar rats were distributed among 4 groups: (i) control, (ii) DN, (iii) MSC-treated, and (iv) treated with MSCs that were pre-incubated in-vitro with MT (5 MUmol.L-1 for 24 h; MSCs + MT). MSCs treatment significantly improved the renal functions and ameliorated the measured underlying DN pathogenesis and elevation of Beclin-1 protein levels compared with the DN group. In-vitro pretreatment of MSCs with MT enhanced proliferation and efficiency, and thus improved the kidney functions by increasing superoxide dismutase (SOD-1) and Beclin-1, and decreasing transforming growth factor (TGF-beta) markers in the kidney tissue, compared with the MSC group (P < 0.05). In conclusion: MSCs represent a promising target in DN management, and their effect can be intensified by pretreatment with MT. The elevated levels of Beclin-1 could be a mediator. PMID- 29425468 TI - Identifying small RNAs derived from maternal- and somatic-type rRNAs in zebrafish development. AB - rRNAs are non-coding RNAs present in all prokaryotes and eukaryotes. In eukaryotes there are four rRNAs: 18S, 5.8S, 28S, originating from a common precursor (45S), and 5S. We have recently discovered the existence of two distinct developmental types of rRNA: a maternal-type, present in eggs and a somatic-type, expressed in adult tissues. Lately, next-generation sequencing has allowed the discovery of new small-RNAs deriving from longer non-coding RNAs, including small-RNAs from rRNAs (srRNAs). Here, we systemically investigated srRNAs of maternal- or somatic-type 18S, 5.8S, 28S, with small-RNAseq from many zebrafish developmental stages. We identified new srRNAs for each rRNA. For 5.8S, we found srRNA consisting of the 5' or 3' halves, with only the latter having different sequence for the maternal- and somatic-types. For 18S, we discovered 21 nt srRNA from the 5' end of the 18S rRNA with a striking resemblance to microRNAs; as it is likely processed from a stem-loop precursor and present in human and mouse Argonaute-complexed small-RNA. For 28S, an abundant 80 nt srRNA from the 3' end of the 28S rRNA was found. The expression levels during embryogenesis of these srRNA indicate they are not generated from rRNA degradation and might have a role in the zebrafish development. PMID- 29425469 TI - Discordance Between Body Mass Index (BMI) and a Novel Body Composition Change Index (BCCI) as Outcome Measures in Weight Change Interventions. AB - OBJECTIVE: A general assumption is that the body mass index (BMI) reflects changes in fat mass (FM). However, it fails to distinguish the type of weight that is lost or gained-fat mass (FM) or fat-free mass (FFM). The BMI treats both changes the same although they have opposite health consequences. The objective of this study was to propose a more precise measure, a body composition change index (BCCI), which distinguishes between changes in FM and FFM, and this study compares it with using the BMI as an outcome measure. METHODS: Data were obtained from 3,870 subjects who had completed dual-energy x-ray absorptiometry (DEXA) total body scans at baseline and end-of-study when participating in a variety of weight-loss interventions. Since height remained constant in this adult cohort, changes in the BMI corresponded with scale weight changes (r = 0.994), allowing BMI changes to be converted to "lbs." to match the statistic used for calculation of the BCCI. The BCCI is calculated by scoring increases in FFM (lbs.) and decreases in FM (lbs.) as positive outcomes and scoring decreases in FFM and increases in FM as negative outcomes. The BCCI is the net sum of these calculations. Differences between scale weight changes and BCCI values were subsequently compared to obtain "discordance scores." RESULTS: Discordance scores ranged from 0.0 lbs. to >30.0 lbs. with a mean absolute value of between the two measures of 7.79 lbs. (99% confidence interval: 7.49-8.10, p <0.00001), SD = 7.4 lbs. Similar discordance scores were also found in subgroups of self-reported gender, ethnicity, and age. CONCLUSIONS: A significant difference of 7.79 lbs. was found between the BCCI and the BMI to evaluate the efficacy of weight loss interventions. If assessing changes in body composition is a treatment goal, use of the BMI could result in significantly erroneous conclusions. PMID- 29425470 TI - A Lean Pork-Containing Breakfast Reduces Hunger and Glycemic Response Compared to a Refined Carbohydrate-Containing Breakfast in Adults with Prediabetes. AB - OBJECTIVE: Replacing dietary refined carbohydrates (CHO) with protein may impact appetite and glucose and lipid metabolism in metabolically at-risk individuals. The objectives of this study were to assess the effects of consumption of a lean pork-containing, high-protein (pPro) breakfast versus a refined-CHO-rich breakfast for 2 weeks on appetite and cardiometabolic parameters in overweight or obese adults with prediabetes. METHODS: In this crossover study, overweight or obese men and women with prediabetes were provided with either a pPro breakfast meal or a refined-CHO breakfast meal to consume each day (2-week intervention, >= 2-week washout). On the last day of each period, fasting and postprandial glucose, insulin, and lipid values were assessed. Visual analog scales were used to evaluate appetite, mental energy, and focus; energy intake at a lunch meal was also evaluated. RESULTS: Data from 21 participants (13 females and 8 males) were analyzed and participants had a mean (+/- standard error of the mean) age of 44.4 +/- 3.1 years and body mass index of 30.4 +/- 0.9 kg/m2. Mean hunger net incremental area under the curve to 240 minutes postmeal (niAUC0-240 min) and desire to eat niAUC0-240 min were both significantly (p < 0.05) lower following the pPro breakfast intakes compared to the refined-CHO breakfast intakes. Mean incremental area under the curve to 240 minutes postmeal for glucose and insulin were significantly lower (p = 0.003 and p = 0.001, respectively) following the pPro breakfast versus refined-CHO breakfast, and mean percentage change from baseline for triglycerides (TG) at 120 minutes was also less pronounced, 10.0% +/ 6.8% versus 32.3% +/- 7.7%, respectively (p = 0.001). No other significant differences were observed for outcome variables. CONCLUSIONS: Intake of a higher protein, lean pork-containing breakfast may favorably impact appetite and lower postprandial glucose, insulin, and TG values, although longer-term studies are warranted. PMID- 29425471 TI - Antidiabetic Effect of Rosella-Stevia Tea on Prediabetic Women in Yogyakarta, Indonesia. AB - BACKGROUND: Rosella tea (Hibiscuss sabdariffa. Linn) with stevia sweetener (Stevia rebaudiana Bertoni) is a combined herbal drink that is expected to have antidiabetic effect by lowering glucose levels in people with diabetes and prediabetes. This research investigates the effect of rosella-stevia tea to decrease fasting blood glucose (FBG) and 2 hours postprandial blood glucose (2 hour postprandial BG) level in prediabetic women. METHOD: This is quasi experimental research with control and treatment (rosella-stevia tea) group. Each group consists of 12 prediabetic women aged 30-60 years. Rosella-stevia tea (5 g rosella powder, 125 mg stevia sweetener) was administered to the treatment group twice a day for 14 days. RESULT: Rosella-stevia tea consumption affects blood glucose levels. Rosella-stevia tea consumption significantly lowered the FBG level (from 111.25 +/- 7.20 mg/dL to 88.58 +/- 13.19 mg/dL; p < 0.01) but not the 2-hour postprandial BG level (from 123.25 +/- 37.61 mg/dL to 106.92 +/- 18.82 mg/dL). There are no significant differences in the control group (FBG level from 106.00 +/- 5.27 mg/dL to 102.08 +/- 8.36, and 2-hour postprandial BG level from 119.83 +/- 16.43 mg/dL to 128.00 +/- 23.54 mg/dL). CONCLUSION: Rosella-stevia tea consumption can lower the FBG level but not the 2-hour postprandial BG level in prediabetic women. PMID- 29425472 TI - The Use of Field Triage in Disaster and Mass Casualty Incidents: A Survey of Current Practices by EMS Personnel. AB - BACKGROUND: Mass casualty incident (MCI) triage and the use of triage tags to assign treatment priorities are not fully implemented despite emergency medical services (EMS) personnel training during drills and exercises. OBJECTIVES: To compare current field triage practices during both training and actual MCIs and identify any potential barriers to use. METHODS: During training sessions from November 2015 through March 2016, an anonymous survey was distributed to personnel in 3 distinct types of paid full-time EMS systems: Boston EMS (2 tiered, municipal third-service); Portland Fire Department (fire department-based ALS); and Stokes County EMS (county-based ALS) combined with Forsyth County EMS (county-based ALS). Data included personnel demographics and previous participation experiences in both drill and actual MCIs. Personnel with any prior MCI experience were queried regarding triage tag use and type of algorithm used. Data on barriers to use of triage tags and methods of communication of patient information were also collected. Descriptive statistics were used to analyze responses. RESULTS: Overall survey participation rate was 77.9% (464/596). Among all respondents, 38.7% (179/464) reported participating in both a drill and actual MCI's. In these cases, respondents reported less likely use of triage tags during actual MCI's compared to drills, (34.1 vs. 91.8%, p < 0.01), less likely to complete full triage (16.3 vs. 68.7%, p < 0.01) and less likely to employ geographical triage (56.8 vs. 90.4% p < 0.01). Verbal report was the most common communication method to hospitals (93.1%) when triage tags were not used. Responders reported proximity to the hospital as the most common reason for not using triage tags during an actual MCI (29.5%). CONCLUSIONS: Despite being a fundamental skill in MCI response, triage and other standard practices have not always been utilized in actual events despite training. EMS educators and disaster planners should consider strategies to better incorporate MCI practices during real world events. PMID- 29425473 TI - Beetroot Increases Muscle Performance and Oxygenation During Sustained Isometric Exercise, but Does Not Alter Muscle Oxidative Efficiency and Microvascular Reactivity at Rest. AB - OBJECTIVE: To examine the effects of beetroot juice (BRJ) on (i) in vivo skeletal muscle O2 consumption (mVO2) and microvascular reactivity at rest and (ii) muscle performance, muscle oxygenation, and mVO2 during sustained isometric handgrip exercise (IHG). METHODS: Sixteen young males consumed, randomly, a nitrate-rich (8.1 mmol BRJnitrate) or nitrate-depleted (BRJplacebo) BRJ. After 2.5 hours, they performed an occlusion-reperfusion maneuver at rest, a 3-minute sustained IHG, and a sustained IHG to exhaustion with arterial occlusion. Changes in muscle oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), microvascular red blood cell content (tHb), and mVO2 were measured using near-infrared spectroscopy. Force output was recorded. RESULTS: During occlusion, the O2Hb decline did not differ between BRJnitrate and BRJplacebo (magnitude: -30.3 +/- 1.6 vs. -31.1 +/- 1.5 DeltaMUMU; slope: -0.107 +/- 0.007 vs. -0.111 +/- 0.007 MUMU second-1). During reperfusion, all microvascular reactivity indices were not altered after BRJnitrate (e.g., O2Hbslope: 1.584 +/- 0.093 vs. 1.556 +/- 0.072 MUMU second-1). During the second and third minute of IHG, O2Hb and tHb were higher in BRJnitrate versus BRJplacebo (p < 0.05), and force output was higher during the third minute (10.8 +/- 0.7 vs. 9.5 +/- 1.2 kg; p < 0.05); HHb did not differ between trials. In IHG with arterial occlusion, BRJnitrate prolonged the time to fatigue (94.1 +/- 5.8 vs. 80.1 +/- 3.3 seconds; p < 0.01), with no effects on O2Hb decline (O2Hbslope: -0.226 +/- 0.015 vs. -0.230 +/- 0.026 MUMU s 1) and mVO2 (14.1 +/- 1.0 vs. 14.3 +/- 1.6 MUmol l-1 minute-1). CONCLUSION: Acute BRJ ingestion in moderately trained individuals (i) did not alter in vivo skeletal muscle microvascular reactivity (index of microvascular function at rest) and basal oxidative efficiency, (ii) increased muscle oxygenation during IHG (possibly via enhanced O2 delivery), and (iii) provided ergogenic benefits during sustained IHG with no effects on muscle oxidative efficiency. The ergogenic effects of BRJ appeared independent of its tissue perfusion benefits. PMID- 29425474 TI - Inhaled medication therapy for bronchiectasis: status quo and the next frontier. PMID- 29425475 TI - Anthropometry and Body Composition of Preterm Neonates in the Light of Metabolic Programming. AB - The improved survival of preterm infants has led to increased interest regarding their health as adults. In the context of metabolic programming, the connection between perinatal and early postnatal nutrition and growth with health in later life has brought to the fore the role of catch-up growth during the first months of preterm infants' lives and its association with body fat and obesity in childhood or puberty. A state-of-the art review was conducted in order to assess the way catch-up is evaluated, in terms of timing and rate. Adequate growth is of major importance for neurodevelopment; however, it may compete with adiposity or metabolic health. Studies based on body composition assessment have given conflicting results as regards the effect of early versus late and rapid versus slow catch-up growth on later health, mainly attributed to the lack of established criteria and definitions. Given that adequate early nutrition is crucial for the neurodevelopment of preterm infants, further studies are needed on the role of catch-up growth in long-term outcome, using generally accepted qualitative and quantitative criteria. PMID- 29425476 TI - Scottsdale Magnesium Study: Absorption, Cellular Uptake, and Clinical Effectiveness of a Timed-Release Magnesium Supplement in a Standard Adult Clinical Population. AB - OBJECTIVE: Suboptimal magnesium status is likely widespread in the United States and increasing evidence links it to many chronic diseases. Therapeutically addressing magnesium status can be challenging, as higher supplementation often leads to bowel intolerance. This study evaluated the absorption, cellular uptake, and clinical effectiveness of a timed-release formulation containing dimagnesium malate with vitamins B6, B12, and folate (MagSRTTM) in a standard clinical population. METHODS: A standard clinical population of 91 adults participated in a placebo-controlled study carried out at two clinics; 53 individuals received MagSRTTM, containing 500 mg dimagnesium malate and vitamins B6, B12, and folate, while the remaining individuals received a placebo. Baseline serum magnesium, red blood cell (RBC) magnesium, and magnesium status questionnaire scores were collected prior to trial initiation. Serum magnesium was measured 4 and 8 hours after participants ingested 2 supplemental tablets (250 mg magnesium) or 2 placebo tablets. After 30 days, RBC magnesium was evaluated and participants completed the magnesium status questionnaire. A subset of MagSRTTM participants (24) continued the trial for 90 days. Both RBC magnesium and the magnesium status questionnaire were evaluated at 90 days. RESULTS: More than 75% of trial participants presented with suboptimal serum and RBC magnesium status at baseline, while the magnesium status questionnaire predicted 100% of participants to have suboptimal magnesium status. MagSRTTM was well tolerated by 91% of magnesium intervention participants. RBC magnesium increased 6% and 30% over 30 and 90 days, respectively, suggesting magnesium absorption and uptake into red blood cells over time. Overall symptomatology, assessed through a magnesium status questionnaire, improved 28% over 30 days and 63% over 90 days. CONCLUSION: A standard adult clinical population presented with both qualitative and quantitative evidence of compromised magnesium status at the beginning of the trial. Supplementation with MagSRTTM, a timed-release dimagnesium malate supplement containing vitamins B6, B12, and folate, for at least 30 days significantly improved magnesium status symptoms and increased RBC magnesium with minimal gastrointestinal symptoms. PMID- 29425477 TI - Potential Cardioprotective Effects of Sumac Capsule in Patients With Hyperlipidemia: A Triple-Blind Randomized, Placebo-Controlled Crossover Trial. AB - OBJECTIVE: Alternative medicine and herbal drugs have been taken into account for managing cardiovascular risk factors. Sumac (Rhus coriaria L.) is rich in biologically active ingredients known to improve cardiovascular health. We investigated the effect of sumac on systolic (SBP) and diastolic (DBP) blood pressure, flow-mediated dilation (FMD), body mass index (BMI), and serum concentrations of lipids and fasting blood sugar (FBS) in participants with hyperlipidemia in a triple-blind randomized placebo- controlled crossover trial. METHODS: Thirty adults with dyslipidemia (mild to moderate elevation of plasma total cholesterol and/or triglycerides [TG; total cholesterol >= 6.0 mmol/L or TG >= 1.7 mmol/L and TG <= 5.0 mmol/L]) were assigned randomly to a sumac or a placebo group. Participants in the sumac group received sumac capsules (500 mg/twice daily) for the first 4 weeks, followed by 2 weeks' washout period; the patients were then switched to a 4-week interval and received placebo for 4 weeks in the second period. The placebo group received these treatments in reverse order. FMD, BMI, SBP, DBP, lipids, and FBS were measured at baseline and after each period. RESULTS: Differences between placebo group and sumac group (placebo sumac) were significantly decreased for BMI (0.21 +/- 0.075 kg/m2), SBP (1.87 +/- 0.83 mm Hg), DBP (1.32 +/- 0.46 mm Hg), and total cholesterol (14.42 +/- 4.95 mmol/L) and significantly increased for FMD (-0.23% +/- 0.065%). Plasma level of TG did not change significantly across the treatment. CONCLUSION: Sumac consumption may decrease cardiovascular risk factors in persons with mild to moderate hyperlipidemia. PMID- 29425478 TI - Postprandial Lipid Response to High-Saturated and High-Monounsaturated Fat Meals in Normal-Weight or Overweight Women. AB - PURPOSE: We evaluated postprandial response of the lipid metabolism markers after the intake of a high-saturated fat (HSM) or high-monounsaturated fat meal (HMM). METHODS: A randomized, controlled and acute intervention study included 63 women (age 26.9 +/- 6.1 years): 35 normal weight (NW) and 28 overweight (OW) (total body fat [TBF] 24.7 +/- 3.9% and 36.6 +/- 3.9%, respectively). After 12 hours of fasting, each subject was given one of the two test meals standardized, including 2 muffins and water (HSM, 42.1% of saturated fat acid, or HMM, 34.5% of monounsaturated fat acid). Plasma fatty acid profile and concentrations of apolipoproteins A1 and B100, complement C3, and triacylglycerols were analyzed during fasting and at 2, 3, and 5 postprandial hours. RESULTS: Among the markers studied, the triacylglycerol (TAG) and complement C3 were significantly higher in the OW group, compared to NW. The increment in the C3 concentration was higher after HSM intake, compared with HMM (iAUC = 4365.5 +/- 5477.4 vs. 1215.2 +/- 882.4; p = 0.006), with no differences between groups. After 5 hours postprandial, plasma oleic acid values remained high compared with the fasting value in the NW group, but not in the OW group (26.0 +/- 4.2 vs 23.7 +/- 3.9%; p < 0.001). Women with high percentage of total plasma saturated fatty acids (SFA) at the beginning of the intervention had higher incremental area under the curve (iAUC) for the palmitic, stearic, and total fatty acids (p < 0.005). Those women with a high percentage of monounsaturated fatty acids (MUFA) showed lower iAUC values for the same fatty acid profile (p < 0.005). CONCLUSION: This study demonstrated the effect of the HSM on postprandial increment of C3 concentration, suggesting another mechanism for saturated fat metabolism. The postprandial response to HSM appears to be the mediated by baseline lipid profile of the individuals, while the response to HMM was correlated to the weight status. PMID- 29425479 TI - Differential Risk of Hypertension Among Lean and Nonlean Rural Subjects in Relation to Decadal Changes in Anthropometry. AB - OBJECTIVE: Assessing risk of hypertension in relation to decadal changes in anthropometry among cohort of young rural Indian men. METHODS: Subjects (n = 140) were measured in 2005 and 2015 for blood pressure, body mass index (BMI), body fat (BF), waist circumference (WC), waist-to-hip ratio (WHR), and additionally for visceral fat (VF) at follow-up. RESULTS: Decadal changes showed significant (p < 0.001) increase in mean anthropometric measures and in prevalence of overall obesity (BMI >=25 kg/m2) from 3.6% to 37.1%; adiposity (BF >=25%) from 5.1% to 40.9%; and central obesity (WHR >=0.9) from 0.7% to 24.3%. Prevalence of hypertension increased (20.7% to 27.1%) but was not statistically significant. VF correlated significantly (p < 0.001) with decadal changes (Delta) in BMI, BF, WC, and WHR, and the correlations were stronger (r = 0.90, 0.78, 0.84, and 0.56, respectively) for lean (baseline BMI < median) subjects than nonlean (baseline BMI >=median) subjects (r = 0.68, 0.40, 0.61, and 0.43, respectively). Risk of hypertension was significant (odds ratio [OR] = 11.0, 95% confidence interval [CI]: 2.8-42.8) for subjects with higher DeltaBMI (>=4.7 kg/m2) compared with those with lower DeltaBMI (<4.7 kg/m2) among lean but was not significant among nonlean subjects. This was also true for change in other adiposity indicators, indicating greater vulnerability of lean subjects. Further, among lean subjects, ORs reduced considerably after adjusting for VF, whereas among nonlean subjects ORs continued to remain nonsignificant but showing independent significance for VF. CONCLUSIONS: For similar level of change in adiposity indicators, lean subjects were at greater risk of hypertension than nonlean subjects, probably due to higher VF deposition. PMID- 29425480 TI - Combined Administration of l-Carnitine and Ascorbic Acid Ameliorates Cisplatin Induced Nephrotoxicity in Rats. AB - OBJECTIVES: Cisplatin (CIS) is an effective antitumor drug. However, its clinical use is limited due to nephrotoxicity. l-Carnitine and vitamin C are both natural antioxidant that can be obtained from diets. This study investigated the effects of l-carnitine and/or vitamin C in rats against cisplatin-induced nephrotoxicity. METHODS: Twenty-five male Wistar rats were divided into 5 groups of 5 rats each. Group 1, normal control. Group 2, positive control, received cisplatin (10 mg/kg/day intraperitoneally [i.p.]) for 3 days. Groups 3, 4, and 5 received cisplatin for 3 days and thereafter l-carnitine (50 mg/kg/day), vitamin C (100 mg/kg/day), or their combination, respectively, for 28 days. At the end of the study, a biochemical study was carried out in which nephrotoxicity markers, electrolytes, hematological indices, oxidative stress biomarkers, and renal histopathological alterations were evaluated. RESULTS: CIS-treated rats developed significant polyuria, increase in the plasma levels of creatinine, urea, and inorganic phosphate (Pi), alteration in hematological parameters, and decrease in plasma levels of Na+, Cl-, K+, Ca2+, and Mg2+. Measurements of 24-hour urine output demonstrated markedly decreased creatinine and urea and increased Na+, Cl , K+, Ca2+, and Mg2+ levels in the CIS-treated group, whereas Pi levels were not changed. It also caused significantly decreased catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) levels in the rats' kidneys. Histopathological scores revealed renal tubular damage in CIS-treated rats. However, l-carnitine, vitamin C, or their combination significantly attenuated the alterations caused by CIS in the plasma and kidneys of the rats. CONCLUSION: l-Carnitine and vitamin C administration ameliorated CIS-induced nephrotoxicity due to their antioxidant and anti-inflammatory effects. PMID- 29425481 TI - Preliminary investigation of a videogame prototype for cigarette and marijuana prevention in adolescents. AB - BACKGROUND: Videogames are becoming increasingly popular to deliver health interventions; however, their role in the primary prevention of cigarette and marijuana use has not yet been evaluated. The purpose of this study was to conduct a preliminary test of the efficacy of a role-playing videogame prototype, smokeSCREEN, aimed at developing knowledge and behavioral skills associated with primary prevention of cigarette and marijuana use. The authors also explored participants' gameplay experience. METHODS: This study employed a 1-group pretest posttest design with 25 adolescent boys and girls aged 11 to 14 years (Mage = 11.56, SD = 0.77) who had never tried cigarettes or marijuana. Participants played four 1-hour gameplay sessions over a 2-week period. Assessments of knowledge, self-efficacy, attitudes, perceived norms, and intentions related to cigarette and marijuana prevention were collected at baseline and 2-week and 12 week follow-ups. Ratings of gameplay experience were collected after the 2 weeks of gameplay. One-way repeated-measures analyses of variance (ANOVAs) were conducted. RESULTS: Findings are (1) improvements in knowledge for both cigarette (Wilks' lambda = 0.62, F(2, 23) = 7.21, P = .004) and marijuana (Wilks' lambda = 0.67, F(2, 23) = 5.75, P = .009) use from pre- to post-gameplay that were characterized by large effects; and (2) nonsignificant trends in the expected direction emerged for changes in self-efficacy and perceived norms related to both cigarettes and marijuana that were characterized by medium-large effects. Overall, the players provided positive reports of their experience with the smokeSCREEN videogame prototype. CONCLUSIONS: These findings provide preliminary evidence that a videogame has the potential to influence key cognitive and motivational variables and can be an engaging means to deliver a cigarette and marijuana prevention intervention. PMID- 29425482 TI - To Bind or Not to Bind: Unravelling GPCR Polypharmacology. AB - Interaction of a single drug with multiple targets through "polypharmacology" is increasingly recognized as necessary for treatment of complex diseases, such as schizophrenia. G protein-coupled receptors (GPCRs) are major medicinal targets, and understanding the structural basis of both GPCR drug selectivity and promiscuity could provide novel avenues for drug development. PMID- 29425483 TI - Building a Stable Relationship: Ensuring Homeostasis among Cell Types within a Tissue. AB - Many processes controlling cell growth and death are well characterized for individual cell lineages, but how ensembles of different cell types in a tissue regulate collective size and composition remains unclear. In this issue of Cell, Zhou et al. employ experiments and theory to uncover design principles of tissue homeostasis arising from cross-talk between fibroblasts and macrophages. PMID- 29425484 TI - Sort Your Self Out! AB - Discrimination between viral and self-derived nucleic acid species is crucial in maintaining effective antiviral immunity whilst avoiding autoinflammation. Ahmad et al. and Chung et al. delineate the consequences of MDA5 gain of function and loss of ADAR1 activity, highlighting the blurring of the concept of self and non self when considering endogenous retroelements. PMID- 29425485 TI - A Subset of Cancer-Associated Fibroblasts Determines Therapy Resistance. AB - While functional heterogeneity of fibroblastic cells populating the tumor microenvironment is increasingly recognized, lack of definitive markers complicates elucidation of roles among ostensibly distinctive fibroblastic states. In this issue of Cell, Su et al. characterize a new pro-tumorigenic cancer-associated fibroblast subset mediating chemoresistance defined and driven by a novel signaling pathway. PMID- 29425486 TI - Brother's Keeper: Wild-Type Mutant K-Ras Dimers Limit Oncogenesis. AB - K-Ras is the undisputed champion of oncogenes, yet our ability to interfere with its oncogenic function is hampered by insufficient mechanistic understanding. In this issue of Cell, Ambrogio and colleagues connect the ability of K-Ras to dimerize to the ability of wild-type K-Ras to limit the oncogenic properties of the mutant. PMID- 29425487 TI - Custom-Made Oocytes to Clone Non-human Primates. AB - In this issue of Cell, Liu et al. (2018) report the birth of two healthy cloned macaque monkeys using fetal fibroblasts. By artificially enhancing the arsenal of epigenetic modifiers in the oocyte, the authors overcome the earliest roadblocks that take place during somatic cell nuclear transfer (SCNT). PMID- 29425488 TI - The Human Transcription Factors. AB - Transcription factors (TFs) recognize specific DNA sequences to control chromatin and transcription, forming a complex system that guides expression of the genome. Despite keen interest in understanding how TFs control gene expression, it remains challenging to determine how the precise genomic binding sites of TFs are specified and how TF binding ultimately relates to regulation of transcription. This review considers how TFs are identified and functionally characterized, principally through the lens of a catalog of over 1,600 likely human TFs and binding motifs for two-thirds of them. Major classes of human TFs differ markedly in their evolutionary trajectories and expression patterns, underscoring distinct functions. TFs likewise underlie many different aspects of human physiology, disease, and variation, highlighting the importance of continued effort to understand TF-mediated gene regulation. PMID- 29425489 TI - The Ancient Origins of Neural Substrates for Land Walking. AB - Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed ~420 million years ago. Leucoraja exhibits core features of tetrapod locomotor gaits, including left-right alternation and reciprocal extension flexion of the pelvic fins. Leucoraja also deploys a remarkably conserved Hox transcription factor-dependent program that is essential for selective innervation of fin/limb muscle. This network encodes peripheral connectivity modules that are distinct from those used in axial muscle-based swimming and has apparently been diminished in most modern fish. These findings indicate that the circuits that are essential for walking evolved through adaptation of a genetic regulatory network shared by all vertebrates with paired appendages. VIDEO ABSTRACT. PMID- 29425490 TI - Fast-Spiking Interneurons Supply Feedforward Control of Bursting, Calcium, and Plasticity for Efficient Learning. AB - Fast-spiking interneurons (FSIs) are a prominent class of forebrain GABAergic cells implicated in two seemingly independent network functions: gain control and network plasticity. Little is known, however, about how these roles interact. Here, we use a combination of cell-type-specific ablation, optogenetics, electrophysiology, imaging, and behavior to describe a unified mechanism by which striatal FSIs control burst firing, calcium influx, and synaptic plasticity in neighboring medium spiny projection neurons (MSNs). In vivo silencing of FSIs increased bursting, calcium transients, and AMPA/NMDA ratios in MSNs. In a motor sequence task, FSI silencing increased the frequency of calcium transients but reduced the specificity with which transients aligned to individual task events. Consistent with this, ablation of FSIs disrupted the acquisition of striatum dependent egocentric learning strategies. Together, our data support a model in which feedforward inhibition from FSIs temporally restricts MSN bursting and calcium-dependent synaptic plasticity to facilitate striatum-dependent sequence learning. PMID- 29425492 TI - Chromosome Translocation Inflates Bacillus Forespores and Impacts Cellular Morphology. AB - The means by which the physicochemical properties of different cellular components together determine bacterial cell shape remain poorly understood. Here, we investigate a programmed cell-shape change during Bacillus subtilis sporulation, when a rod-shaped vegetative cell is transformed to an ovoid spore. Asymmetric cell division generates a bigger mother cell and a smaller, hemispherical forespore. The septum traps the forespore chromosome, which is translocated to the forespore by SpoIIIE. Simultaneously, forespore size increases as it is reshaped into an ovoid. Using genetics, timelapse microscopy, cryo-electron tomography, and mathematical modeling, we demonstrate that forespore growth relies on membrane synthesis and SpoIIIE-mediated chromosome translocation, but not on peptidoglycan or protein synthesis. Our data suggest that the hydrated nucleoid swells and inflates the forespore, displacing ribosomes to the cell periphery, stretching septal peptidoglycan, and reshaping the forespore. Our results illustrate how simple biophysical interactions between core cellular components contribute to cellular morphology. PMID- 29425491 TI - TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue. AB - The noncanonical IKK family member TANK-binding kinase 1 (TBK1) is activated by pro-inflammatory cytokines, but its role in controlling metabolism remains unclear. Here, we report that the kinase uniquely controls energy metabolism. Tbk1 expression is increased in adipocytes of HFD-fed mice. Adipocyte-specific TBK1 knockout (ATKO) attenuates HFD-induced obesity by increasing energy expenditure; further studies show that TBK1 directly inhibits AMPK to repress respiration and increase energy storage. Conversely, activation of AMPK under catabolic conditions can increase TBK1 activity through phosphorylation, mediated by AMPK's downstream target ULK1. Surprisingly, ATKO also exaggerates adipose tissue inflammation and insulin resistance. TBK1 suppresses inflammation by phosphorylating and inducing the degradation of the IKK kinase NIK, thus attenuating NF-kappaB activity. Moreover, TBK1 mediates the negative impact of AMPK activity on NF-kappaB activation. These data implicate a unique role for TBK1 in mediating bidirectional crosstalk between energy sensing and inflammatory signaling pathways in both over- and undernutrition. PMID- 29425493 TI - Carnitine Palmitoyltransferase 1A Has a Lysine Succinyltransferase Activity. AB - Lysine succinylation was recently identified as a post-translational modification in cells. However, the molecular mechanism underlying lysine succinylation remains unclear. Here, we show that carnitine palmitoyltransferase 1A (CPT1A) has lysine succinyltransferase (LSTase) activity in vivo and in vitro. Using a stable isotope labeling by amino acid in cell culture (SILAC)-based proteomics approach, we found that 101 proteins were more succinylated in cells expressing wild-type (WT) CPT1A compared with vector control cells. One of the most heavily succinylated proteins in this analysis was enolase 1. We found that CPT1A WT succinylated enolase 1 and reduced enolase enzymatic activity in cells and in vitro. Importantly, mutation of CPT1A Gly710 (G710E) selectively inactivated carnitine palmitoyltransferase (CPTase) activity but not the LSTase activity that decreased enolase activity in cells and promoted cell proliferation under glutamine depletion. These findings suggest that CPT1A acts as an LSTase that can regulate enzymatic activity of a substrate protein and metabolism independent of its classical CPTase activity. PMID- 29425494 TI - Crosstalk between the RNA Methylation and Histone-Binding Activities of MePCE Regulates P-TEFb Activation on Chromatin. AB - RNAP II switching from the paused to the productive transcription elongation state is a pivotal regulatory step that requires specific phosphorylations catalyzed by the P-TEFb kinase. Nucleosolic P-TEFb activity is inhibited by its interaction with the ribonuclear protein complex built around the 7SK small nuclear RNA (7SK snRNP). MePCE is the RNA methyltransferase that methylates and stabilizes 7SK in the nucleosol. Here, we report that MePCE also binds chromatin through the histone H4 tail to serve as a P-TEFb activator at specific genes important for cellular identity. Notably, this histone binding abolishes MePCE's RNA methyltransferase activity toward 7SK, which explains why MePCE-bound P-TEFb on chromatin may not be associated with the full 7SK snRNP and is competent for RNAP II activation. Overall, our results suggest that crosstalk between the histone-binding and RNA methylation activities of MePCE regulates P-TEFb activation on chromatin in a 7SK- and Brd4-independent manner. PMID- 29425495 TI - highroad Is a Carboxypetidase Induced by Retinoids to Clear Mutant Rhodopsin-1 in Drosophila Retinitis Pigmentosa Models. AB - Rhodopsins require retinoid chromophores for their function. In vertebrates, retinoids also serve as signaling molecules, but whether these molecules similarly regulate gene expression in Drosophila remains unclear. Here, we report the identification of a retinoid-inducible gene in Drosophila, highroad, which is required for photoreceptors to clear folding-defective mutant Rhodopsin-1 proteins. Specifically, knockdown or genetic deletion of highroad blocks the degradation of folding-defective Rhodopsin-1 mutant, ninaEG69D. Moreover, loss of highroad accelerates the age-related retinal degeneration phenotype of ninaEG69D mutants. Elevated highroad transcript levels are detected in ninaEG69D flies, and interestingly, deprivation of retinoids in the fly diet blocks this effect. Consistently, mutations in the retinoid transporter, santa maria, impairs the induction of highroad in ninaEG69D flies. In cultured S2 cells, highroad expression is induced by retinoic acid treatment. These results indicate that cellular quality-control mechanisms against misfolded Rhodopsin-1 involve regulation of gene expression by retinoids. PMID- 29425496 TI - The Role of Ceramide Synthases in the Pathogenicity of Cryptococcus neoformans. AB - Cryptococcus neoformans (C. neoformans) is estimated to cause about 220,000 new cases every year in patients with AIDS, despite advances in antifungal treatments. C. neoformans possesses a remarkable ability to disseminate through an immunocompromised host, making treatment difficult. Here, we examine the mechanism of survival of C. neoformans under varying host conditions and find a role for ceramide synthase in C. neoformans virulence. This study also provides a detailed lipidomics resource for the fungal lipid research community in addition to discovering a potential target for antifungal therapy. PMID- 29425498 TI - Hybridization Kinetics Explains CRISPR-Cas Off-Targeting Rules. AB - Due to their specificity, efficiency, and ease of programming, CRISPR-associated nucleases are popular tools for genome editing. On the genomic scale, these nucleases still show considerable off-target activity though, posing a serious obstacle to the development of therapies. Off targeting is often minimized by choosing especially high-specificity guide sequences, based on algorithms that codify empirically determined off-targeting rules. A lack of mechanistic understanding of these rules has so far necessitated their ad hoc implementation, likely contributing to the limited precision of present algorithms. To understand the targeting rules, we kinetically model the physics of guide-target hybrid formation. Using only four parameters, our model elucidates the kinetic origin of the experimentally observed off-targeting rules, thereby rationalizing the results from both binding and cleavage assays. We favorably compare our model to published data from CRISPR-Cas9, CRISPR-Cpf1, CRISPR-Cascade, as well as the human Argonaute 2 system. PMID- 29425497 TI - Intrinsically Disordered Regions Can Contribute Promiscuous Interactions to RNP Granule Assembly. AB - Eukaryotic cells contain large RNA-protein assemblies referred to as RNP granules, whose assembly is promoted by both traditional protein interactions and intrinsically disordered protein domains. Using RNP granules as an example, we provide evidence for an assembly mechanism of large cellular structures wherein specific protein-protein or protein-RNA interactions act together with promiscuous interactions of intrinsically disordered regions (IDRs). This synergistic assembly mechanism illuminates RNP granule assembly and explains why many components of RNP granules, and other large dynamic assemblies, contain IDRs linked to specific protein-protein or protein-RNA interaction modules. We suggest assemblies based on combinations of specific interactions and promiscuous IDRs are common features of eukaryotic cells. PMID- 29425499 TI - BUB1 Is Essential for the Viability of Human Cells in which the Spindle Assembly Checkpoint Is Compromised. AB - The spindle assembly checkpoint (SAC) ensures faithful segregation of chromosomes. Although most mammalian cell types depend on the SAC for viability, we found that human HAP1 cells can grow SAC independently. We generated MAD1- and MAD2-deficient cells and mutagenized them to identify synthetic lethal interactions, revealing that chromosome congression factors become essential upon SAC deficiency. Besides expected hits, we also found that BUB1 becomes essential in SAC-deficient cells. We found that the BUB1 C terminus regulates alignment as well as recruitment of CENPF. Second, we found that BUBR1 was not essential in SAC-deficient HAP1 cells. We confirmed that BUBR1 does not regulate chromosome alignment in HAP1 cells and that BUB1 does not regulate chromosome alignment through BUBR1. Taken together, our data resolve some long-standing questions about the interplay between BUB1 and BUBR1 and their respective roles in the SAC and chromosome alignment. PMID- 29425500 TI - TRIP13 Functions in the Establishment of the Spindle Assembly Checkpoint by Replenishing O-MAD2. AB - The spindle assembly checkpoint (SAC) prevents premature segregation of chromosomes during mitosis. This process requires structural remodeling of MAD2 from O-MAD2 to C-MAD2 conformation. After the checkpoint is satisfied, C-MAD2 is reverted to O-MAD2 to allow anaphase-promoting complex/cyclosome (APC/C) to trigger anaphase. Recently, the AAA+-ATPase TRIP13 was shown to act in concert with p31comet to catalyze C- to O-MAD2. Paradoxically, although C-MAD2 is present in TRIP13-deficient cells, the SAC cannot be activated. Using a degron-mediated system to uncouple TRIP13 from O- and C-MAD2 equilibrium, we demonstrated that the loss of TRIP13 did not immediately abolish the SAC, but the resulting C-MAD2 only environment was insufficient to enable the SAC. These results favor a model in which MAD2-CDC20 interaction is coupled directly to the conversion of O- to C MAD2 instead of one that involves unliganded C-MAD2. TRIP13 replenishes the O MAD2 pool for activation by unattached kinetochores. PMID- 29425501 TI - Homeostatic Plasticity in the Hippocampus Facilitates Memory Extinction. AB - Correlated activity in the hippocampus drives synaptic plasticity that is necessary for the recruitment of neuronal ensembles underlying fear memory. Sustained neural activity, on the other hand, may trigger homeostatic adaptations. However, whether homeostatic plasticity affects memory function remains unknown. Here, we use optogenetics to induce cell autonomous homeostatic plasticity in CA1 pyramidal neurons and granule cells of the hippocampus. High frequency spike trains applied for 10 min decreased the number of excitatory spine synapses and increased the number of inhibitory shaft synapses. This activity stopped dendritic spine formation via L-type voltage-dependent calcium channel activity and protein synthesis. Applied selectively to the ensemble of granule cells encoding a contextual fear memory, the spike trains impaired memory recall and facilitated extinction. Our results indicate that homeostatic plasticity triggered by optogenetic neuronal firing alters the balance between excitation and inhibition in favor of memory extinction. PMID- 29425503 TI - Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility. AB - Recent proteome analyses have provided a comprehensive overview of various posttranslational modifications (PTMs); however, PTMs involving protein citrullination remain unclear. We performed a proteomic analysis of citrullinated proteins, and we identified more than 100 PAD4 (peptidyl arginine deiminase 4) substrates. Approximately one-fifth of the PAD4 substrates contained an RG/RGG motif, and PAD4 competitively inhibited the methylation of the RGG motif in FET proteins (FUS, EWS, and TAF15) and hnRNPA1, which are causative genes for ALS (amyotrophic lateral sclerosis). PAD4-mediated citrullination significantly inhibited the aggregation of FET proteins, a frequently observed feature in neurodegenerative diseases. FUS protein levels in arsenic-induced stress granules were significantly increased in Padi4-/- mouse embryonic fibroblasts (MEFs). Moreover, rs2240335 was associated with low expression of PADI4 in the brain and a high risk of ALS (p = 0.0381 and odds ratio of 1.072). Our findings suggest that PAD4-mediated RGG citrullination plays a key role in protein solubility and ALS pathogenesis. PMID- 29425502 TI - A Pixel-Encoder Retinal Ganglion Cell with Spatially Offset Excitatory and Inhibitory Receptive Fields. AB - The spike trains of retinal ganglion cells (RGCs) are the only source of visual information to the brain. Here, we genetically identify an RGC type in mice that functions as a pixel encoder and increases firing to light increments (PixON RGC). PixON-RGCs have medium-sized dendritic arbors and non-canonical center surround receptive fields. From their receptive field center, PixON-RGCs receive only excitatory input, which encodes contrast and spatial information linearly. From their receptive field surround, PixON-RGCs receive only inhibitory input, which is temporally matched to the excitatory center input. As a result, the firing rate of PixON-RGCs linearly encodes local image contrast. Spatially offset (i.e., truly lateral) inhibition of PixON-RGCs arises from spiking GABAergic amacrine cells. The receptive field organization of PixON-RGCs is independent of stimulus wavelength (i.e., achromatic). PixON-RGCs project predominantly to the dorsal lateral geniculate nucleus (dLGN) of the thalamus and likely contribute to visual perception. PMID- 29425504 TI - Functional CD169 on Macrophages Mediates Interaction with Dendritic Cells for CD8+ T Cell Cross-Priming. AB - Splenic CD169+ macrophages are located in the marginal zone to efficiently capture blood-borne pathogens. Here, we investigate the requirements for the induction of CD8+ T cell responses by antigens (Ags) bound by CD169+ macrophages. Upon Ag targeting to CD169+ macrophages, we show that BATF3-dependent CD8alpha+ dendritic cells (DCs) are crucial for DNGR-1-mediated cross-priming of CD8+ T cell responses. In addition, we demonstrate that CD169, a sialic acid binding lectin involved in cell-cell contact, preferentially binds to CD8alpha+ DCs and that Ag transfer to CD8alpha+ DCs and subsequent T cell activation is dependent on the sialic acid-binding capacity of CD169. Finally, functional CD169 mediates optimal CD8+ T cell responses to modified vaccinia Ankara virus infection. Together, these data indicate that the collaboration of CD169+ macrophages and CD8alpha+ DCs for the initiation of effective CD8+ T cell responses is facilitated by binding of CD169 to sialic acid containing ligands on CD8alpha+ DCs. PMID- 29425505 TI - IAPs Regulate Distinct Innate Immune Pathways to Co-ordinate the Response to Bacterial Peptidoglycans. AB - Inhibitors of apoptosis (IAPs) proteins are critical regulators of innate immune signaling pathways and therefore have potential as drug targets. X-linked IAP (XIAP) and cellular IAP1 and IAP2 (cIAP1 and cIAP2) are E3 ligases that have been shown to be required for signaling downstream of NOD2, an intracellular receptor for bacterial peptidoglycan. We used genetic and biochemical approaches to compare the responses of IAP-deficient mice and cells to NOD2 stimulation. In all cell types tested, XIAP is the only IAP required for signaling immediately downstream of NOD2, while cIAP1 and cIAP2 are dispensable for NOD2-induced nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) activation. However, mice lacking cIAP1 or TNFR1 have a blunted cytokine response to NOD2 stimulation. We conclude that cIAPs regulate NOD2-dependent autocrine TNF signaling in vivo and highlight the importance of physiological context in the interplay of innate immune signaling pathways. PMID- 29425507 TI - Supraphysiologic Administration of GDF11 Induces Cachexia in Part by Upregulating GDF15. AB - The age-related effects of GDF11 have been a subject of controversy. Here, we find that elevated GDF11 causes signs of cachexia in mice: reduced food intake, body weight, and muscle mass. GDF11 also elicited a significant elevation in plasma Activin A, previously shown to contribute to the loss of skeletal muscle. The effects of GDF11 on skeletal muscle could be reversed by administration of antibodies to the Activin type II receptors. In addition to the effects on muscle, GDF11 increased plasma GDF15, an anorectic agent. The anorexia, but not the muscle loss, could be reversed with a GDF15-neutralizing antibody. GDF15 upregulation is due to GDF11-induced recruitment of SMAD2/3 to the GDF15 promoter. Inhibition of GDF15 can restore appetite but cannot restore the GDF11 induced loss of muscle mass, which requires blockade of ActRII signaling. These findings are relevant for treatment of cachexia. PMID- 29425506 TI - Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions. AB - To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mitochondria. However, the signaling events that initiate aerobic glycolysis in T cells remain unclear. We show T cell activation rapidly induces glycolysis independent of transcription, translation, CD28, and Akt and not involving increased glucose uptake or activity of glycolytic enzymes. Rather, TCR signaling promotes activation of pyruvate dehydrogenase kinase 1 (PDHK1), inhibiting mitochondrial import of pyruvate and facilitating breakdown into lactate. Inhibition of PDHK1 reveals this switch is required acutely for cytokine synthesis but dispensable for cytotoxicity. Functionally, cytokine synthesis is modulated via lactate dehydrogenase, which represses cytokine mRNA translation when aerobic glycolysis is disengaged. Our data provide mechanistic insight to metabolic contribution to effector T cell function and suggest that T cell function may be finely tuned through modulation of glycolytic activity. PMID- 29425508 TI - beta-aminoisobutyric Acid, l-BAIBA, Is a Muscle-Derived Osteocyte Survival Factor. AB - Exercise has beneficial effects on metabolism and on tissues. The exercise induced muscle factor beta-aminoisobutyric acid (BAIBA) plays a critical role in the browning of white fat and in insulin resistance. Here we show another function for BAIBA, that of a bone-protective factor that prevents osteocyte cell death induced by reactive oxygen species (ROS). l-BAIBA was as or more protective than estrogen or N-acetyl cysteine, signaling through the Mas-Related G Protein Coupled Receptor Type D (MRGPRD) to prevent the breakdown of mitochondria due to ROS. BAIBA supplied in drinking water prevented bone loss and loss of muscle function in the murine hindlimb unloading model, a model of osteocyte apoptosis. The protective effect of BAIBA was lost with age, not due to loss of the muscle capacity to produce BAIBA but likely to reduced Mrgprd expression with aging. This has implications for understanding the attenuated effect of exercise on bone with aging. PMID- 29425509 TI - Polycomb Group Protein YY1 Is an Essential Regulator of Hematopoietic Stem Cell Quiescence. AB - Yin yang 1 (YY1) is a ubiquitous transcription factor and mammalian polycomb group protein (PcG) with important functions to regulate embryonic development, lineage differentiation, and cell proliferation. YY1 mediates stable PcG dependent transcriptional repression via recruitment of PcG proteins that catalyze histone modifications. Many questions remain unanswered regarding how cell- and tissue-specificity is achieved by PcG proteins. Here, we demonstrate that a conditional knockout of Yy1 in hematopoietic stem cells (HSCs) decreases long-term repopulating activity and ectopic YY1 expression expands HSCs. Although the YY1 PcG domain is required for Igkappa chain rearrangement in B cells, the YY1 mutant lacking the PcG domain retained the capacity to stimulate HSC self renewal. YY1 deficiency deregulated the genetic network governing HSC cell proliferation and impaired stem cell factor/c-Kit signaling, disrupting mechanisms conferring HSC quiescence. These results reveal a mechanism for how a ubiquitously expressed transcriptional repressor mediates lineage-specific functions to control adult hematopoiesis. PMID- 29425510 TI - Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2. AB - Transient receptor potential (TRP) channels are regulated by diverse stimuli comprising thermal, chemical, and mechanical modalities. They are also commonly regulated by phosphatidylinositol-4,5-bisphosphate (PIP2), with underlying mechanisms largely unknown. We here revealed an intramolecular interaction of the TRPP3 N and C termini (N-C) that is functionally essential. The interaction was mediated by aromatic Trp81 in pre-S1 domain and cationic Lys568 in TRP-like domain. Structure-function analyses revealed similar N-C interaction in TRPP2 as well as TRPM8/-V1/-C4 via highly conserved tryptophan and lysine/arginine residues. PIP2 bound to cationic residues in TRPP3, including K568, thereby disrupting the N-C interaction and negatively regulating TRPP3. PIP2 had similar negative effects on TRPP2. Interestingly, we found that PIP2 facilitates the N-C interaction in TRPM8/-V1, resulting in channel potentiation. The intramolecular N C interaction might represent a shared mechanism underlying the gating and PIP2 regulation of TRP channels. PMID- 29425511 TI - Quantitative and Statistical Study of the Dynamics of Clathrin-Dependent and Independent Endocytosis Reveal a Differential Role of EndophilinA2. AB - Eukaryotic cells internalize cargos specifically through clathrin-mediated endocytosis (CME) or clathrin-independent endocytosis (CIE). EndophilinA2 was shown as preferentially implicated in CIE, although initially involved in CME. Here, we investigated the native interplay of endophilinA2 and dynamin2 during CME as compared to CIE. We developed an unbiased integrative approach based on genome engineering, robust tracking methodology, and advanced analytics. We statistically identified CME and CIE subpopulations corresponding to abortive, active, and static endocytic events. Depletion of dynamin2 strongly affected active CME and CIE events, whereas the absence of endophilinA2 impacted only CIE. Accordingly, we demonstrated that endophilinA2 is needed for dynamin2 recruitment during CIE, but not in CME. Despite these differences, endophilinA2 and dynamin2 acted at the latest stage of endocytosis within a similar stoichiometry in both mechanisms. Thus, we propose a conserved function of dynamin2 and endophilinA2 in vesicle scission, but a differential regulation of their recruitment during CME and CIE. PMID- 29425512 TI - Deciphering Cell Lineage Specification during Male Sex Determination with Single Cell RNA Sequencing. AB - The gonad is a unique biological system for studying cell-fate decisions. However, major questions remain regarding the identity of somatic progenitor cells and the transcriptional events driving cell differentiation. Using time series single-cell RNA sequencing on XY mouse gonads during sex determination, we identified a single population of somatic progenitor cells prior to sex determination. A subset of these progenitors differentiates into Sertoli cells, a process characterized by a highly dynamic genetic program consisting of sequential waves of gene expression. Another subset of multipotent cells maintains their progenitor state but undergoes significant transcriptional changes restricting their competence toward a steroidogenic fate required for the differentiation of fetal Leydig cells. Our findings confirm the presence of a unique multipotent progenitor population in the gonadal primordium that gives rise to both supporting and interstitial lineages. These also provide the most granular analysis of the transcriptional events occurring during testicular cell fate commitment. PMID- 29425514 TI - High-Sensitivity Fluorometry to Resolve Ion Channel Conformational Dynamics. AB - Fluorescent labels offer the capability to follow conformational dynamics of membrane proteins, but signal detection in such recordings is inherently difficult to achieve in a cell membrane and lacks sufficient time resolution to follow physiologically relevant transitions. Here, we develop high-sensitivity patch-clamp fluorometry (hsPCF), a fluorescence-based approach that results in up to 10-fold increased signals and affords 50-fold faster fluorescence recordings than previous methods. The increased time resolution is paired with a very high versatility in terms of the choice of fluorescent dye, cell type, and protein of interest. We highlight this versatility by providing insight into the conformational dynamics of both ligand- and voltage-gated ion channels using fluorescent labels introduced in extracellular or transmembrane positions while changing either the extra- or intracellular solutions. Together, hsPCF will thus enable the future study of membrane-embedded proteins with sufficient temporal resolution to resolve conformational dynamics. PMID- 29425513 TI - Specific Labeling of Stem Cell Activity in Human Colorectal Organoids Using an ASCL2-Responsive Minigene. AB - Organoid technology provides the possibility of culturing patient-derived colon tissue and colorectal cancers (CRCs) while maintaining all functional and phenotypic characteristics. Labeling stem cells, especially in normal and benign tumor organoids of human colon, is challenging and therefore limits maximal exploitation of organoid libraries for human stem cell research. Here, we developed STAR (stem cell Ascl2 reporter), a minimal enhancer/promoter element that reports transcriptional activity of ASCL2, a master regulator of LGR5+ intestinal stem cells. Using lentiviral infection, STAR drives specific expression in stem cells of normal organoids and in multiple engineered and patient-derived CRC organoids of different genetic makeup. STAR reveals that differentiation hierarchies and the potential for cell fate plasticity are present at all stages of human CRC development. Organoid technology, in combination with the user-friendly nature of STAR, will facilitate basic research into human adult stem cell biology. PMID- 29425515 TI - Reprint of: Virus-Specific T Cells: Broadening Applicability. AB - Virus infection remains an appreciable cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although pharmacotherapy and/or antibody therapy may help prevent or treat viral disease, these drugs are expensive, toxic, and often ineffective due to primary or secondary resistance. Further, effective treatments are limited for many infections (eg, adenovirus, BK virus), which are increasingly detected after alternative donor transplants. These deficiencies in conventional therapeutics have increased interest in an immunotherapeutic approach to viral disorders, leading to adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs), which can rapidly reconstitute antiviral immunity post-transplantation without causing graft-versus-host disease. This review will explore how the VST field has improved outcomes for many patients with life-threatening viral infections after HSCT, and how to broaden applicability beyond the "patient-specific" products, as well as extending to other viral diseases even outside the context of HSCT. PMID- 29425517 TI - Reprint of: Emerging Therapeutics for the Control of Chronic Graft-versus-Host Disease. PMID- 29425516 TI - Reprint of: Building a Safer and Faster CAR: Seatbelts, Airbags, and CRISPR. AB - Therapeutic T cell engineering has recently garnered widespread interest because of the success of CD19 chimeric antigen receptor (CAR) therapy. CARs are synthetic receptors for antigen that redirect the specificity and reprogram the function of the T cells in which they are genetically introduced. CARs targeting CD19, a cell surface molecule found in most leukemias and lymphomas, have yielded high remission rates in patients with chemorefractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non Hodgkin lymphoma. The toxicities of this treatment include B cell aplasia, cytokine release syndrome (CRS), and neurotoxicity. Although reversible in most instances, these toxicities may require specific medical interventions, including transfer to intensive care to treat severe CRS. Guidelines for managing these toxicities are emerging. The recent report of a nonhuman primate model for CRS is poised to help advance the management of this syndrome. Finally, new engineering modalities, based on the use of targeted nucleases like CRISPR, may further enhance the efficacy and safety of CAR T cells. PMID- 29425519 TI - An Adverse Event Analysis: Inadvertent Exsanguination Following Left Ventricular Assist Device Implantation in a Child. AB - Neurologic deficit subsequent to cardiac surgery remains a cause of postoperative morbidity and mortality. Although myriad risk factors for postoperative cognitive decline have been identified, their individual influence remains undefined. Although less emphasis is now placed on the heart lung machine as the major source of postoperative cognitive decline, the conduct of cardiopulmonary bypass and, in particular, the management of the bypass circuit remain key to patient safety. We present a case of inadvertent intraoperative exsanguination of a patient following open heart surgery for implantation of a left ventricular assist device. The patient suffered significant neurologic damage. However, the nature of the patient's cerebral injury indicated thromboembolism as the likely cause, rather than hypoxic-ischemic injury caused by hypoperfusion. Subsequent investigation of the incident identified several possible sources and potential causes of embolization to the brain that could not rule out the exsanguination event as a contributing factor. PMID- 29425520 TI - Giessen Procedure as Comprehensive Stage II Palliation With Aortic Arch Reconstruction After Hybrid Bilateral Pulmonary Artery Banding and Ductal Stenting for Hypoplastic Left Heart Syndrome. AB - This article reviews our experience using hybrid stage I palliation in the neonatal period and subsequently with comprehensive stage II palliation for hypoplastic left heart syndrome. Between June 1998 and April 2017, 154 patients with the diagnosis of hypoplastic left heart syndrome and variants underwent a hybrid stage I palliation (bilateral pulmonary artery banding and ductal stenting). One hundred thirty-nine patients could be further univentricularly palliated. One hundred twenty-one patients underwent a comprehensive stage II operation with an operative mortality of 6.6%. The hybrid procedure provides reproducible results with reduced in-hospital, interstage, and long-term mortality and lower rates of aortic arch reinterventions. PMID- 29425521 TI - Identifiable Risk Factors and Miscalculations During Listing for Pediatric Heart Transplantation. AB - The objective of this study is to describe identifiable risk factors, complications, and pitfalls while listing pediatric patients for heart transplantation, which is the standard of care for end-stage heart disease in children. Since the introduction of cyclosporine in the 1980s, the management in pediatric heart transplantation has shown consistent improvement, mainly because of technological advances and the integration of multidisciplinary teams in the field. However, the complexity of this patient population makes medical providers vulnerable to complications as a result of undesirable mistakes. Transplant survival is impacted negatively when mistakes from health-care providers compound the high-risk status of the patient. The identification of multiple risk factors and undesirable miscalculations may help transplant teams make decisions before allocating organs, intervene or minimize morbidity, and provide the best quality of life to recipients. PMID- 29425522 TI - Direct Splanchnic Perfusion Safely Avoids Deep Hypothermia. AB - Deep hypothermia for the operative correction of congenital cardiac lesions protects hypoperfused organs, mostly because of its effect on lowering metabolic demand and oxygen requirement. Deleterious cerebral and extracranial side effects of deep hypothermia itself calls for a reexamination of the therapeutic value of hypothermia, and has led to the development of alternative perfusion strategies. Here we describe the potential advantages of milder hypothermia over deep hypothermia and our method of a practical and reproducible implementation of multisite perfusion under mild hypothermia (32 degrees C). PMID- 29425523 TI - Aortic Valvuloplasty or Rootplasty for Aortic Regurgitation. AB - At present, aortic valvuloplasty is considered an effective procedure for treatment of aortic regurgitation in pediatric patients. It has encouraging mid- and long-term results. The improved outcome is primarily related to better understanding of the functional anatomy of the normal valve and the different factors that alter it. It is also related to the realization that outcome after valvuloplasty is dependent on comprehensive repair of all of the involved components of the aortic root. Refinement in preoperative diagnosis has helped identify these abnormal components and focus the surgical approach on the needed reconstruction. Although the technical aspects of valvuloplasty are well defined, suboptimal long-term results still occur in some cases because the patch material used for valve repair can become fibrotic or calcified. This review summarizes the surgical approach to and the management of the different abnormal root components in pediatric patients with significant aortic valve regurgitation. PMID- 29425524 TI - Repair Techniques for Mitral Valve Insufficiency in Children. AB - Congenital mitral valve (MV) dysplasia is a relatively rare and highly complex cardiac disease. We sought to provide a comprehensive analysis of the current surgical techniques for treating mitral valve insufficiency and the results of mitral valve repair at our institution. Between 1972 and 2017, 104 consecutive patients underwent surgical repair of congenital MV dysplasia-insufficiency at our institution. Among these, 59 patients presented with MV insufficiency (or prevalent MV insufficiency) and were part of the study. There was 1 early (1.7%) and 1 late death (1.7%). Survival at 5, 10 and 20 years was 98%, 98% and 94%, respectively. Eight patients (14%) required MV replacement for residual significant MV insufficiency. Freedom from re-intervention for MV dysfunction at 5, 10 and 20 years were 89%, 84% and 79%, respectively. Surgical techniques for treating mitral valve insufficiency must be tailored for each patient with the main goal of achieving a proper valve function, rather than a "normal" anatomy. The mechanism underlying valve dysfunction in congenital mitral valve insufficiency is multifactorial and requires the application of a variety of surgical techniques in each case. PMID- 29425525 TI - Repair for Congenital Mitral Valve Stenosis. AB - We report the techniques and long-term outcome of mitral valve (MV) repair to correct congenital mitral stenosis in children. Between 1986 and 2014, 137 children (mean age 4.1 +/- 5.0, range 1 month-16.8 years) underwent repair of congenital mitral stenosis (CMS). In 48 patients, CMS is involved in Shone's anomaly. The typical congenital MS (type I) was seen in 56 patients. Hypoplastic MV (type II, n = 15) was associated with severe left ventricular outflow tract abnormalities and hypoplastic left ventricular cavity and muscle mass. Supravalvar ring (type III, n = 48) ranged from a thin membrane to a thick discrete fibrous ridge. Parachute MV (type IV, n = 10) have 2 leaflets and barely distinguishable commissures, but all chordae merged either into 1 major papillary muscle or asymmetric papillary muscles-1 dominant and the other minuscule. Hammock valve (type IV, n = 8) appeared dysplastic with shortened chordae directly inserted into the posterior left ventricular muscle mass. MV repair was performed using commissurotomy, chordal division, papillary muscle splitting and fenestration, and mitral ring resection, each applied according to the presenting morphology. During the 28-year follow-up period, 23 patients underwent repeat MV repair and 3 underwent MV replacement after failed attempts at repeat repair. At 1 and 15 years postoperatively, freedom from reoperation was 89.3 +/- 5.1% and 52.8 +/- 11.8%, and cumulative survival rates were 92.3 +/- 4.3% and 70.3 +/- 8.9, respectively. Mortality unrelated to repair accounted for 9 (20%) deaths. Long-term functional outcome of MV repair in children with CMS is satisfactory. Repeat repair or replacement may be deemed necessary during the course of follow up. PMID- 29425526 TI - Nikaidoh vs Reparation a l'Etage Ventriculaire vs Rastelli. AB - This review describes the different surgical options for transposition of the great arteries, ventricular septal defect (VSD), and left ventricular outflow tract obstruction. When the pulmonary valve can be used, an arterial switch operation with VSD closure and resection of pulmonary stenosis may be possible. This is not the scope of our review: we focus on the Rastelli, REV (Reparation a l'Etage Ventriculaire), and Nikaidoh techniques, and we also describe the "en bloc rotation" technique. Each of these procedures has a different history, and these techniques have not been used uniformly around the world. We describe the advantages and disadvantages of each technique together with their outcomes as reported in the literature. Some forms of transposition of the great arteries, VSD, and left ventricular outflow tract obstruction can only be corrected by the Nikaidoh operation, although this operation can be definitely contraindicated in other instances. Surgical eras and length of follow-up are not the same for all procedures, and there has been surgical bias in choosing 1 technique over another. This makes comparison between techniques difficult, although certain trends are observed. PMID- 29425527 TI - Approaches to Pulmonary Atresia With Major Aortopulmonary Collateral Arteries. AB - Pulmonary atresia with major aortopulmonary collateral arteries (MAPCAs) is one of the most challenging surgical conditions to manage-not only because of the technical complexity of the surgery but also in terms of defining the anatomy of the pulmonary vasculature, the timing of surgery, and decision making on staged vs complete repair. The importance of early definition of pulmonary blood supply is paramount, establishing which areas of the lung are supplied by MAPCAs alone and which have dual supply with the native system (noting that 20% of patients have absent intrapericardial native vessels). Early unifocalization (3-6 months) is ideal, with closure of the ventricular septal defect (VSD) performed if 15 or more out of 20 lung segments can be recruited. Leaving the ventricular septal defect open with a limiting right ventricle-pulmonary artery conduit can be a useful interim or even definitive circulation in patients with borderline vasculature. Rehabilitation of small native vessels with central shunts can be very effective, but best outcomes are achieved by a combination of unifocalization of MAPCAs together with the native vessels (if present). A variety of reconstructive techniques are necessary to be able to effect these complex repairs with careful choice of materials. Ideally, surgery can be completed through sternotomy alone, but separate thoracotomies may be necessary to control and access some MAPCAs. PMID- 29425528 TI - Comprehensive Management of Major Aortopulmonary Collaterals in the Repair of Tetralogy of Fallot. AB - The heterogenous anatomy of Tetralogy of Fallot with major aortopulmonary collateral arteries has engendered a similar degree of diversity in its management and, ultimately, outcome. We summarize our comprehensive treatment paradigm for this lesion evolved over 15 years of experience through 458 patients and the results obtained. An updated analysis of 307 patients treated primarily at our institution is included. A review of recent literature, comparison of management strategies, and discussion of ongoing controversies are provided. PMID- 29425529 TI - Surgical Approaches to Total Anomalous Pulmonary Venous Connection. AB - Total anomalous pulmonary venous connection (TAPVC) constitutes a spectrum of congenital lesions whereby the pulmonary veins remain connected to systemic venous vessels or aberrantly connect to the right atrium. Definitive management requires surgical intervention and, in patients with obstruction to pulmonary venous flow, urgent operation is required. Use of temporizing catheter-based interventions allow for optimization in hemodynamically unstable neonates. Overall, survival has significantly improved over the past decades through better perioperative management and evolution of surgical approaches to minimize post repair pulmonary vein stenosis, which persists as a major determinant of long term outcomes. PMID- 29425530 TI - Ventricular Assist Devices for Neonates and Infants. AB - Heart transplant waitlist survival in pediatric patients has been substantially improved since the introduction of pediatric-specific ventricular assist device. In neonates and infants, however, the waitlist mortality remains very high. The only long-term device currently approved for use in the United States is the Berlin Heart EXCOR, but this device has several important limitations because of the paracorporeal, pulsatile nature of the underlying technology. We reviewed Stanford ventricular assist experience on patients less than 1 year old since 2004. It shows overall 1-, 3-, and 5-year survival were 68%, 62%, and 49%, respectively. There are statistically significant differences in survival among cardiomyopathy group, end-stage congenital heart disease group and single ventricle group. In order to improve outcomes in this extremely high risk group, modifications were made to anticoagulation protocols, cannulation strategy in hypertrophic cardiomyopathy patients, and preferential use of continuous flow pumps in a single ventricle patients. The long-waited PumpKIN trial testing the Jarvik 2015 is about to start with the first human implant. PMID- 29425531 TI - Can we identify older people most vulnerable to living in cold homes during winter? AB - PURPOSE: Living in a cold home increases the risk of dying in winter, especially in older people. However, it is unclear which individual factors predict whether older people are living in cold homes. METHODS: Thousand four hundred two men aged 74-95 years from a U.K. population-based study reported difficulties in keeping warm during winter, answering four simple "yes/no" questions. Associations between individual's characteristics and each of the four self reported measures of cold homes were estimated using logistic regression models. Next, we investigated whether measures of cold homes predict mortality over the subsequent 2.1 years. RESULTS: Manual social class, difficulties making ends meet, and not being married were each associated (P < .05) with each of the four measures of cold homes (adjusted odds ratios ranged from 1.61 to 4.68). Social isolation, poor respiratory health, and grip strength were also associated with reports of cold homes. Hundred twenty-six men died; those who reported the presence of at least three measures cold homes had increased mortality (adjusted hazard ratios 2.85 [95% confidence interval, 1.11-7.30, P = .029]). CONCLUSIONS: Older people who find it hard to keep warm in winter, and have an elevated mortality, could be identified using a self-report questionnaire. PMID- 29425532 TI - Stigma as a barrier to health care utilization among female sex workers and men who have sex with men in Burkina Faso. AB - PURPOSE: The aim of this study is to examine the prevalence and correlates of perceived health care stigma among female sex workers (FSWs) and men who have sex with men (MSM), including other stigma types, suicidal ideation, and participation in social activities. METHODS: FSWs (N = 350) and MSM (N = 330) aged >=18 were recruited in Bobo-Dioulasso, Burkina Faso. Perceived health care stigma was defined as either ever being afraid of or avoiding health care services because someone might find out the participant has sex with men (for MSM) or sells sex (for FSW). Correlates of perceived health care stigma were examined using multivariable logistic regression. RESULTS: The prevalence of perceived health care stigma was 14.9% (52/350) and 24.5% (81/330) in FSWs and MSM, respectively. Among FSWs, experienced or social stigma, including verbal harassment (adjusted odds ratio [aOR] = 3.59, 95% confidence interval [CI] 1.48 8.71), feeling rejected by friends (aOR = 2.30, 95% CI 1.14-4.64), and feeling police refused to protect them (aOR = 2.58, 95% CI 1.27-5.25), was associated with perceived health care stigma. Among MSM, experiencing verbal harassment (aOR = 1.95, 95% CI 1.09-3.50) and feeling scared to walk in public (aOR = 2.93, 95% CI 1.47-5.86) were associated with perceived health care stigma. CONCLUSIONS: In these key populations, perceived health care stigma was prevalent and associated with experienced and social stigmas. To increase coverage of effective HIV services, interventions should incorporate approaches to comprehensively mitigate stigma. PMID- 29425533 TI - Erratum. PMID- 29425535 TI - [Percutaneous closure of the left atrial appendage: Eliminate the thromboembolic risk of atrial fibrillation?] PMID- 29425534 TI - Mechanical viability of a thermoplastic elastomer hydrogel as a soft tissue replacement material. AB - Hydrogels are a class of synthetic biomaterials composed of a polymer network that swells with water and as such they have both an elastic and viscous component making them ideal for soft tissue applications. This study characterizes the compressive, tensile, and shear properties of a thermoplastic elastomer (TPE) hydrogel and compares the results to published literature values for soft tissues such as articular cartilage, the knee meniscus, and intervertebral disc components. The results show the TPE hydrogel material is viscoelastic, strain rate dependent, has similar surface and bulk properties, displays minimal damping under dynamic load, and has tension-compression asymmetry. When compared to other soft tissues it has a comparable equilibrium compressive modulus of approximately 0.5MPa and shear modulus of 0.2MPa. With a tensile modulus of only 0.2MPa though, the TPE hydrogel is inferior in tension to most collagen based soft tissues. Additional steps may be necessary to reinforce the hydrogel system and increase tensile modulus depending on the desired soft tissue application. It can be concluded that this material could be a viable option for soft tissue replacements. PMID- 29425536 TI - Magnetic iodixanol - a novel contrast agent and its early characterization. AB - AIMS: Contrast-induced nephropathy is a commonly encountered problem in clinical practice. The purpose of the study was to design and develop a novel contrast agent, which could be used to prevent contrast-induced nephropathy in the future. METHODS: In total, 20-220nm magnetic nanoparticles were conjugated with iodixanol, and their radio-opacity and magnetic properties were assessed thereafter. Scanning electron microscopy pictures were acquired. Thereafter, the nanoparticles conjugate was tested in cell culture (HUVEC cells), and Quantibody(r) assay was studied after cell treatment in 1:5 dilutions for 48h, compared with control. RESULTS: The conjugate preparation had an adequate radio opacity. A 4mm magnetic bubble was attached to a bar magnet and the properties were studied. The magnetic bubble maintained its structural integrity in all angles including antigravity position. Scanning electron microscopy showed magnetic nanoparticles in all pictures and the particles are of 100-400nm agglomerates with primary particle sizes of roughly 20nm. 1:5 diluted particles had no effect on secretion of IL-1a, IL-1b, IL-4, IL-10, IL-13 and TNFa. Particles increased secretion of IL-8 from 24h and 48h. Secretion of IFNg was also increased when particles were added to the cells as early as 1h. Likewise, IL-6 was strongly secreted by HUVEC treated with particles from 24h incubation time. In contrast, the secretion of MCP-1 was slightly reduced on HUVEC treated with particles. CONCLUSION: There is potential for a novel iodixanol-magnetic nanoparticle conjugate to be used in cineradiography. Further investigations need to be performed to study its performance in vitro and in vivo. PMID- 29425537 TI - [Superior vena cava thrombosis or stricture secondary to implanted central venous access: Six cases of endovascular and direct surgical treatment in cancer patients]. AB - Superior vena cava (SVC) stenosis or thrombosis is a well-known complication of central venous catheterization for endocavitary treatments, hemodialysis, or chemotherapy. In cancer patients, these SVC lesions are often symptomatic due to intimal damage and chemotherapy toxicity. We report our experience with six patients treated between 2007 and 2012 via an endovascular approach (n=5) or a direct surgical approach (n=1). All patients had SVC syndrome with facial edema, headache and upper limb edema. In three cases, the catheter was in place when the clinical symptoms occurred. Duplex Doppler and computed tomography (CT) angiography identified the following lesions: isolated SVC stenosis (n=2); SVC stenosis with right Pirogoff confluence stenosis (n=1); SVC stenosis associated with left innominate vein thrombosis and right Pirogoff confluence stenosis (n=1); SVC thrombosis affecting azygos flow (n=2). In one patient, the thrombus extended into the right atrium. Five patients underwent endovascular repair via a right jugular approach (n=2) or a double jugular approach (n=3). Treatment involved: SVC angioplasty with stent (n=2); right Pirogoff angioplasty and SVC stent (n=1); kissing angioplasty of both innominate trunks with a SVC stent (n=1); and SVC angioplasty without stent because of an incomplete result with a residual lumen less than 8mm (n=1). One patient had a complete SVC occlusion with extension of thrombus into the right atrium. She was treated via a median sternotomy for open surgical control of both innominate trunks and lateral clamping of the right atrium. A long cavotomy prolonged on the right atrium allowed thrombo-intimectomy and pericardial patch angioplasty. Postoperative follow-up was uneventful in five cases. However, postoperative hemorrhage required pericardial drainage in one patient. The CT scan showed a good morphological aspect in five patients and an incomplete result in one case. Patients have been followed up annually with a duplex scan from two to six years. One patient had a restenosis at 7 months treated by a new angioplasty via a femoral approach. A new catheter was positioned via a cervical approach. Two patients died of metastatic diffusion at 8 and 32 months. The other four patients have remained asymptomatic, with a satisfactory duplex scan. In conclusion, VCS lesions after implanted central access for chemotherapy can often be treated endovascularly. Conventional surgery still has indications when lesions extend into the right atrium. PMID- 29425538 TI - [Etiological profile of secondary Raynaud's phenomenon in an internal medicine department. About 121 patients]. AB - INTRODUCTION: Raynaud's phenomenon is a reversible episodic vasospastic disorder triggered by cold or emotion. Two types of Raynaud's phenomenon were distinguished: Raynaud's disease and secondary Raynaud's phenomenon. The purpose of this study was to determine the etiologic profile of secondary Raynaud's phenomenon in an internal medicine department. METHODS: A descriptive retrospective study including patients with secondary Raynaud's phenomenon followed in a tertiary internal medicine department between 2000 and 2013. RESULTS: We included 121 patients. The sex ratio M/F was 0.16. The mean age at the onset of Raynaud's phenomenon was 41.7 years. The average age of patients at the time of the etiologic diagnosis was 47.3 years. The mean delay between Raynaud's phenomenon onset and the first consultation was 41.33 months. Raynaud's phenomenon involved hands in all cases and feet in 16.10% of cases with a typical form in most cases (41.4%). Complications (digital ulcers and scars) were noted in 32.23% of cases. Nail fold capillaroscopy showed scleroderma pattern in 49.52% of patients. Antinuclear antibodies were positive in 88.49% of patients. Interstitial lung disease was reported in 54.04% of cases. Connective tissue diseases were diagnosed in 86.77% of patients. Other secondary Raynaud's phenomenon causes were vasculitis (6.61%), atherosclerosis (1.65%) and medical or professional causes (1.65%). The most frequent one cause systemic sclerosis (n=61, 98%) followed by systemic lupus erythematosus (11.57%) and primary Sjogren syndrome (6.61%). CONCLUSION: In our study, the Raynaud's phenomenon was most frequently secondary to connective tissue diseases. This may be a selection bias because our department is a third-line unit where patients are often referred for systemic disease suspicion. PMID- 29425539 TI - [Quality standards for ultrasonographic assessment of peripheral vascular malformations and vascular tumors. Report of the french society for vascular medicine. 2018 Update]. AB - : The quality standards of the French Society of Vascular Medicine for the ultrasonographic assessment of vascular malformations are based on the two following requirements: (1) technical know-how: mastering the use of ultrasound devices and the method of examination; (2) medical know-how: ability to adapt the methods and scope of the examination to its clinical indication and purpose, and to rationally analyze and interpret its results. AIMS OF THE QUALITY STANDARDS: To describe an optimal method of examination in relation to the clinical question and hypothesis. To homogenize practice, methods, glossary, and reporting. To provide good practice reference points, and promote a quality process. ITEMS OF THE QUALITY STANDARDS: The 3 levels of examination; their clinical indications and goals. The reference standard examination (level 2), its variants according to clinical needs. The minimal content of the examination report; the letter to the referring physician (synthesis, conclusion and proposal for further investigation and/or therapeutic management). Commented glossary (anatomy, hemodynamics, semiology). Technical bases. Setting and use of ultrasound devices. Here, we discuss ultrasonography methods of using of ultrasonography for the assessment of peripheral vascular malformations and tumors (limbs, face, trunk). PMID- 29425540 TI - [When to ask for a skin biopsy in a patient with leg ulcer? Retrospective study of 143 consecutive biopsies]. AB - OBJECTIVE: A vascular cause is found in around 85% of leg ulcer patients, but non vascular causes are also observed. Their diagnosis is based on a set of clinical arguments and skin biopsy with histological analysis. The aim of this study was to analyze the results of these biopsies and to find common criteria for ulcers whose skin biopsies had led to the diagnosis of a non-vascular ulcer. MATERIAL AND METHOD: A retrospective study was carried out on the analysis of 143 skin biopsies of leg ulcers. The reasons for the biopsy were mainly atypical clinical signs and/or the lack of improvement in care after 6 months, as advocated by the French health authorities. RESULTS: The skin biopsies led to a diagnosis of non vascular ulcer in 4.9% of cases (7/143), including skin cancer (n=5, 3.5%), cutaneous leishmaniasis (n=1, 0.7%) and Pyoderma gangrenosum (n=1, 0.7%). The univariate statistical analysis revealed that an elevated rim and abnormal excessive granulation tissue were significantly more frequently found in these ulcers. All patients with a positive skin biopsy had associated vascular involvement. CONCLUSION: This study found a 5% rate of non-vascular causes of ulcers, mainly skin cancer. Elevated rims and abnormal excessive granulation tissue were the unusual features most commonly found in these ulcers. All patients whose skin biopsy revealed a non-vascular cause had associated vascular involvement. This information confirms the need to perform a skin biopsy, even in the presence of a vascular disease. PMID- 29425541 TI - [Spontaneous coronary artery dissection: An exceptional cause of acute coronary syndrome]. AB - Spontaneous coronary artery dissection (SCAD) is an uncommon cause of acute coronary syndrome (ACS) or sudden death, which typically affects young women. We reported two cases of black Africans patients, aged 56 and 52 years old, who presented to Abidjan Heart Institute for ACS. Coronary angiography showed spontaneous dissection of the right coronary artery in the first case, and dissection of the distal left anterior descending artery in the second. A conservative approach was preferred. Both patients received antiplatelet agents, beta-blockers, angiotensin converting enzyme inhibitors and statins, with a favorable in-hospital course. These cases highlight SCAD as a possible cause of ACS. Implementation of interventional cardiology in Sub-Saharan Africa will help identify this uncommon cause of ACS. PMID- 29425542 TI - [Spontaneous neonatal aortic thrombosis revealing protein S deficiency]. AB - Arterial thrombosis of the newborn is rare and associated with poor prognosis, often attributed to umbilical arterial catheterization. The aortic and spontaneous forms are exceptional. Its severity requires fast and effective treatment. Although therapeutic means are numerous, no consensus has been established to date although thrombolysis and heparin therapy appear to give good results depending on the site and extent of thrombosis. We report a case of extensive thrombosis of the abdominal aorta in a 5-day-old newborn, revealed by acute hypernatremic dehydration. Thrombosis was not related to umbilical catheterization. The diagnosis was confirmed by Doppler ultrasound with discovery during the etiologic assessment of an authentic protein S deficiency. This observation was the occasion for a review of the literature concerning the evolutionary and therapeutic clinical aspects of neonatal arterial thrombosis. PMID- 29425544 TI - Ranibizumab and digital ischemia. AB - : Case report of a patient with age-related macular degeneration whose digital ischemia can most plausibly be attributed to ranibizumab. PURPOSE: To report ranibizumab as the probable cause of digital ischemia in a patient treated for age-related macular degeneration. METHODS: Single-patient case report. RESULTS: An 83-year-old woman with an unremarkable medical history suffered acute ischemia in her left hand with necrosis of the distal phalange of the fifth finger after six intravitreal injections of ranibizumab. Her etiological work-up was negative. Her condition improved after endovascular revascularization and remained good at six months' follow-up after three months of dual antithrombotic therapy (low molecular weight heparin then rivaroxaban, both with aspirin) followed by rivaroxaban alone and four courses of intravenous iloprost. CONCLUSION: The increased incidence of peripheral arterial thromboembolic events in patients under ranibizumab treatment is slight but significant, with 0.8-5% of patients affected, most of which suffer strokes. These events seem to occur at a random time after ranibizumab treatment is initiated and no reliable marker has yet been identified. The most probable cause of digital ischemia in our patient was ranibizumab. PMID- 29425543 TI - [Digital ischemia revealing multiple myeloma]. AB - Digital ulcers generally arise in a context of microangiopathy-related focal ischemia. In women, connective tissue diseases are the main etiology, while in men the cause is often diffuse arterial disease, e.g. Leo-Buerger disease, or emboligenic heart disease. A paraneoplastic origin of digital necrosis due to ischemia is rarely reported. A 75-year-old man presented with cyanosis of the fingertips and toes that had begun one month earlier. The physical examination found pulp ulcers on the fingers and toes of both hands and feet. Two weeks later, necrotic damage developed distally, with no other associated symptoms. Blood tests were suggestive of Kahler disease; immunodeficiency disorders tests were negative; the cyroglobulin test was positive. Multiple-drug chemotherapy was followed by clinical improvement. Distal necrotic damage is a frequent inaugural symptom in vascular disease. If the common causal mechanisms (iatrogenic, occupational, toxic, atheromatous, emboligenic heart disease, or systemic disease) have been ruled out, it is important to search for a blood disorder or cancer as the cause of distal necrotic damage. PMID- 29425545 TI - Neural stem cells in health and disease. PMID- 29425546 TI - Prognostic impact of electrical storm in patients with implantable cardioverter defibrillators: Mechanistic and therapeutic considerations to reduce the risk of death. PMID- 29425547 TI - Microbiome and atrial fibrillation. PMID- 29425548 TI - Ejection fraction as related to basic components in the left and right ventricular volume domains. AB - BACKGROUND: Ejection fraction (EF) is commonly applied as a clinically relevant metric to assess ventricular function. The numerical value of EF depends on the interplay between end-systolic volume (ESV) and end-diastolic volume (EDV). Remarkably, the relative impact of the two constitutive components on EF received little attention. METHODS: Three patient groups not using beta-blockers were analyzed for a robust investigation into the relative contribution of ESV and EDV when assessing EF: cardiac patients (N=155) with left ventricular (LV) data obtained by biplane ventriculography, near-normals (N=276) by gated SPECT investigation, and an MRI-based post Fallot repair study including right ventricular (RV) data (N=124), besides LV. We compared various routes to evaluate EF via linear and several types of nonlinear regression with ESV as independent variable. Advanced statistics was applied to evaluate sex-specific differences. RESULTS: In all cases ESV emerges as the dominant component of EF, with less (P<0.0001) impact of EDV. The relationship for EF versus ESV is nonlinear (P<0.0001), and similar for both sexes. A linear approach may be inadequate and generate erroneous statistical outcomes when comparing subgroups of patients. CONCLUSIONS: Values for EF primarily depend on ESV, both for LV and RV. This relationship is essentially nonlinear, and similar for both sexes. A logarithmic approximation is convenient and often acceptable. However, application of linear regression for EF vs ESV may lead to incorrect conclusions, particularly when comparing males and females. PMID- 29425549 TI - Low relative muscle mass and left ventricular diastolic dysfunction in middle aged adults. AB - OBJECTIVES: The association between low skeletal muscle mass and left ventricular diastolic dysfunction (LVDD), a predictor of future heart failure, is largely unexplored. We investigated the relationship between relative muscle mass and LVDD. METHODS: We conducted a cross-sectional study in 67,106 Koreans who underwent an echocardiography as part of a comprehensive health examination between January 2012 and December 2014. Skeletal muscle mass index (SMI) [SMI (%)=total skeletal muscle mass (kg)/body weight (kg)*100] was estimated using a bioelectrical impedance analyzer. The presence of LVDD was determined using echocardiographic findings. RESULTS: In 67,106 participants, 19,232 subjects (28.7%) and 1553 subjects (2.3%) had LVDD and left ventricular (LV) hypertrophy, respectively. SMI was positively associated with E/A ratio and septal E', whereas E/E' ratio and LV mass index were negatively associated with SMI. Lower SMI was associated with increased presence of LVDD. In a multivariable-adjusted model controlling for potential confounders including physical activity, insulin resistance, and LV mass, the odds ratios for LVDD in SMI quartiles 1, 2, and 3 compared with quartile 4 were 2.11 (1.97-2.25), 1.79 (1.68-1.90), and 1.45 (1.36 1.55), respectively (P for trend<0.001). CONCLUSIONS: In a large sample of young and middle-aged Korean adults, low relative muscle mass was independently associated with increased risk of LVDD, indicating an independent role of skeletal muscle mass in the pathogenesis of LVDD. PMID- 29425551 TI - Does the mode of delivery in Cardiac Rehabilitation determine the extent of psychosocial health outcomes? AB - BACKGROUND: Cardiac Rehabilitation (CR) is a multicomponent tailored intervention aiming to reduce lifestyle risk factors and promote health in patients post cardiovascular disease. CR is delivered either as supervised or facilitated self delivered yet little evidence exists evaluating the association between mode of delivery and outcomes. METHODS: This observational study used data routinely collected from the National Audit of Cardiac Rehabilitation from April 2012-March 2016. The analysis compared the populations receiving supervised and facilitated self-delivered modes for differences in baseline demographics, four psychosocial health measures pre and post CR and changes in anxiety, depression and quality of life following the intervention. The analysis also modelled the relationship between mode and outcomes, accounting for covariates such as age, gender, duration and staffing. RESULTS: The study contained 120,927 patients (age 65, 26.5 female) with 82.2% supervised and 17.8% self-delivered. The analysis showed greater proportion of females, employed and older patients in the self-delivered group. Following CR, patients in both groups demonstrated positive changes which were of comparable size. The regression model showed no significant association between mode of delivery and outcome in all four psychosocial outcomes when accounting for covariates (p-value>0.0.5). CONCLUSIONS: Patients benefited from attending both modes of CR showing improved psychosocial health outcomes with 3 76% change from baseline. Over half of CR programmes in the UK do not provide self-delivered CR yet this mode is known to reach older patients, female and employed patients. Facilitated self-delivered CR should be offered and supported as a genuine option, alongside supervised CR, by clinical teams. PMID- 29425550 TI - Efficacy of intramyocardial injection of Algisyl-LVR for the treatment of ischemic heart failure in swine. AB - BACKGROUND: Progressive thinning and dilation of the LV due to ischemic heart failure (IHF) increases wall stress and myocardial oxygen consumption. Injectable biopolymers implanted in the myocardial wall have been used to increase wall thickness to reduce chamber volume, decrease wall stress, and improve cardiac function. We sought to evaluate the efficacy of a biopolymer (Algisyl-LVR) to prevent left ventricular (LV) remodeling in a swine model of IHF. METHODS: IHF was induced in 11 swine by occluding the marginal obtuse branches of the left circumflex artery. Eight weeks later, Algisyl-LVR was injected into the LV myocardial free wall in five of the 11 animals. Echocardiographic examinations were done every 2weeks for 16weeks. RESULTS: Within eight weeks of treatment, the ejection fraction increased from 30.5%+/-7.7% to 42.4%+/-3.5% (treated group) vs. 37.3%+/-3.8% to 34.3%+/-2.9% (control), p<0.01. Stroke volume increased from 18.5+/-9.3mL to 41.3+/-13.3mL (treated group) vs. 25.4+/-2.3mL to 31.4+/-5.3mL (control), p<0.05. Wall thickness in end-diastole of the infarcted region changed from 0.69+/-0.06cm to 0.81+/-0.13cm (treated group) vs. 0.73+/-0.09cm to 0.68+/ 0.11cm (control), p<0.05. Sphericity index remained almost unchanged after treatment, although differences were found at the end of the study between both groups (p<0.001). Average myofiber stress changed from 16.3+/-5.8kPa to 10.2+/ 4.0kPa (treated group) vs. 15.2+/-4.8kPa to 17.9+/-5.6kPa (control), p<0.05. CONCLUSIONS: Algisyl-LVR is an effective strategy that serves as a micro-LV assist device to reduce stress and hence prevent or reverse maladaptive cardiac remodeling caused by IHF in swine. PMID- 29425552 TI - Sex-related differences in chronic heart failure. AB - The prevalence of chronic heart failure (CHF) is steadily increasing. Both sexes are affected, with significant differences in etiology, epidemiology and clinical presentation, prognosis, comorbidities, and response to treatment. Women tend to develop CHF at a more advanced age, present more often with HF with preserved ejection fraction, are more symptomatic, and have a worse quality of life than men, but also a better prognosis. In women, CHF has more frequently a non ischemic etiology, and arterial hypertension and diabetes mellitus are leading comorbidities. Furthermore, many sex-related differences have been detected in the response to treatment, for example a greater prognostic benefit from angiotensin-receptor blockers in women, a higher incidence of complications after defibrillator implantation, and a greater response to cardiac resynchronization therapy. Furthermore, women are less likely to receive defibrillator therapy or heart transplantation. The significant underrepresentation of women in clinical trials limits our capacity to evaluate the extent of sex-related differences in CHF, although their characterization seems crucial in order to achieve the ultimate goal of a tailored therapy for this condition. PMID- 29425553 TI - Invasive treatment of NSTEMI patients in German Chest Pain Units - Evidence for a treatment paradox. AB - BACKGROUND: Patients with non ST-segment elevation myocardial infarction (NSTEMI) represent the largest fraction of patients with acute coronary syndrome in German Chest Pain units. Recent evidence on early vs. selective percutaneous coronary intervention (PCI) is ambiguous with respect to effects on mortality, myocardial infarction (MI) and recurrent angina. With the present study we sought to investigate the prognostic impact of PCI and its timing in German Chest Pain Unit (CPU) NSTEMI patients. METHODS AND RESULTS: Data from 1549 patients whose leading diagnosis was NSTEMI were retrieved from the German CPU registry for the interval between 3/2010 and 3/2014. Follow-up was available at median of 167days after discharge. The patients were grouped into a higher (Group A) and lower risk group (Group B) according to GRACE score and additional criteria on admission. Group A had higher Killip classes, higher BNP levels, reduced EF and significant more triple vessel disease (p<0.001). Surprisingly, patients in group A less frequently received early diagnostic catheterization and PCI. While conservative management did not affect prognosis in Group B, higher-risk CPU-NSTEMI patients without PCI had a significantly worse survival. CONCLUSIONS: The present results reveal a substantial treatment gap in higher-risk NSTEMI patients in German Chest Pain Units. This treatment paradox may worsen prognosis in patients who could derive the largest benefit from early revascularization. PMID- 29425554 TI - Reshaping the failing heart: One step forward in elucidating the role of biomaterials in preventing cardiac remodeling. PMID- 29425555 TI - Cardiac rehabilitation in real life. PMID- 29425556 TI - The need of a gender-corrected evidence based medicine. PMID- 29425557 TI - Low density lipoprotein interferes with intracellular signaling of monocytes resulting in impaired chemotaxis and enhanced chemokinesis. AB - BACKGROUND: Hypercholesterolemia (HC) is an important cardiovascular risk factor characterized by elevated low density lipoprotein-cholesterol (LDL-C) plasma levels. HC negatively affects monocyte function by reducing their chemotactic response towards different growth factors. We aimed to elucidate the molecular mechanisms by which LDL induces monocyte dysfunction. METHODS AND RESULTS: Human monocytes exposed to either native (nLDL) or oxidized LDL (oxLDL) in vitro showed reduced chemotactic responses towards vascular endothelial growth factor A (VEGFA) and monocyte chemotactic protein-1 (MCP-1), but displayed enhanced random migration (chemokinesis). Mechanistically, the exposure to LDL resulted in the activation of p38 mitogen-activated protein kinase (MAPK) and modulated MCP-1 and VEGFA-induced signaling in human monocytes. Furthermore, the aberrant p38 activation induced by oxLDL is due to the functional impairment of Dual Specificity Phosphatase-1 (DUSP-1). In the absence of LDL, the pharmacological inhibition of DUSP-1 alone was sufficient to recapitulate the accelerated chemokinetic and blunted chemotactic phenotype of monocytes. Finally, p38 MAPK inhibition in monocytes isolated from hyperlipidemic mice prevented the aberrant chemokinetic phenotype. CONCLUSIONS: Our data demonstrate that LDL induces monocyte chemokinesis of human monocytes by inducing mononuclear cell activation through the aberrant modulation of DUSP-1-p38/MAPK signaling axis. Moreover, our findings suggest that MCP-1/VEGFA-induced chemotaxis is reduced by LDL secondary to the impairment of ligand-induced signaling. These findings provide novel insight into hypercholesterolemia-associated vascular dysfunction and its potential involvement in the pathogenesis of atherosclerosis. PMID- 29425558 TI - Monocyte dysfunction induced by low density lipoprotein occurs via a DUSP-1/p38 MAPK signaling impairment. PMID- 29425559 TI - Percutaneous coronary interventions for non-ST elevation acute coronary syndromes - The two faces of inappropriateness. PMID- 29425560 TI - Right atrial function in patients with pulmonary hypertension: A study with two dimensional speckle-tracking echocardiography. AB - BACKGROUND: The role of right atrial (RA) dysfunction in patients with pulmonary hypertension (PH), as evaluated by two-dimensional speckle-tracking echocardiography (2D-STE) remains to be determined. METHODS: Sixty consecutive PH patients and 30 healthy volunteers were included. RA function was evaluated by 2D STE, and the following parameters were recorded: an average longitudinal strain (LS) curve that included LSpos during RA filling and LSneg representing RA active contraction (their summation is LStot), the phasic RA volumes, total RA emptying fraction, and the ratio of RA passive and active emptying to total emptying. The associations between these indices and the results of invasive pulmonary hemodynamics, cardiac structure and function, and NT-terminal pro brain natriuretic peptide (NT-proBNP) level were evaluated. RESULTS: LStot, total RA emptying fraction, LSpos, passive RA emptying fraction were significantly lower, while the contribution of active RA empting fraction/total RA emptying fraction was higher in PH patients than in controls. Among PH patients, LStot was negatively correlated with greater RA size, RA pressure, and pulmonary vascular resistance, but not pulmonary artery pressure, while LStot was also negatively associated with right ventricular enlargement and higher NT-proBNP. In receiver operator characteristic analysis, RA LStot was of optimal accuracy for prediction of WHO-function class >=III in PH patients. CONCLUSIONS: PH was associated with impaired reservoir and conduit function, but enhanced active contract function of RA, while RA LStot confers an optimal predictive effect of poor WHO-function class in PH patients. PMID- 29425562 TI - Right atrial function: A blind spot in a blind spot. PMID- 29425561 TI - Impact of peripheral artery disease on early and late outcomes of transcatheter aortic valve implantation in patients with severe aortic valve stenosis. AB - AIMS: Peripheral artery disease (PAD) is frequently present in patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis. This study assessed the impact of PAD on clinical outcome after TAVI. METHODS: A total of 115 patients who underwent TAVI were evaluated retrospectively. Patients were divided into PAD and non-PAD groups, with PAD defined as stenosis>=50% in lower extremity arteries. Immediate and late clinical outcomes were compared between the two groups. RESULTS: PAD was present in 31.3% (36/115) of the patients undergoing TAVI. Compared to the non-PAD group, the PAD group had higher Society of Thoracic Surgeons' (STS) risk scores (8.83%+/-6.20% vs 6.23%+/-4.15%, p=0.039) and more frequent diagnoses of diabetes (52.8% vs 30.4%, p=0.021) and multi-vessel coronary artery disease (55.6% vs 29.1%, p=0.007). The PAD group also had higher incidence of major vascular complication (11.1% vs 1.3%, p=0.033), 30-day mortality (13.9% vs 1.3%, p<0.001), and subsequent 1-year (30.6% vs 3.8%, p<0.001) and 2-year (47.2% vs. 10.1%, p<0.001) all-cause mortality. PAD was identified as an independent predictor of increased 1-year mortality (hazard ratio [HR] 8.65; 95% confidence interval [CI], 1.05 71.14, p=0.045) after TAVI along with high STS score (HR 11.18, 95% CI 1.36 92.04, p=0.025). CONCLUSIONS: Presence of PAD was significantly associated with increased rates of major vascular complications as well as immediate and late mortality in patients undergoing TAVI. Assessment of PAD before TAVI is essential to choose an access strategy and to predict clinical results. PMID- 29425563 TI - Peripheral artery disease and transcatheter aortic valve implantation: The tip of the atherosclerotic iceberg. PMID- 29425565 TI - Is it time to update standard cardiac rehabilitation programming? The evidence suggests we must go above and beyond. PMID- 29425564 TI - Effects of two behavioral cardiac rehabilitation interventions on physical activity: A randomized controlled trial. AB - BACKGROUND: Standard cardiac rehabilitation (CR) is insufficient to help patients achieve an active lifestyle. The effects of two advanced and extended behavioral CR interventions on physical activity (PA) and sedentary behavior (SB) were assessed. METHODS: In total, 731 patients with ACS were randomized to 1) 3months of standard CR (CR-only); 2) 3months of standard CR with three pedometer-based, face-to-face PA group counseling sessions followed by 9months of aftercare with three general lifestyle, face-to-face group counseling sessions (CR+F); or 3) 3months of standard CR, followed by 9months of aftercare with five to six general lifestyle, telephonic counseling sessions (CR+T). An accelerometer recorded PA and SB at randomization, 3months, 12months, and 18months. RESULTS: The CR+F group did not improve their moderate-to-vigorous intensity PA (MVPA) or SB time compared to CR-only (between-group difference=0.24% MVPA, P=0.349; and 0.39% SB, P=0.529). However, step count (between-group difference=513 steps/day, P=0.021) and time in prolonged MVPA (OR=2.14, P=0.054) improved at 3months as compared to CR-only. The improvement in prolonged MVPA was maintained at 18months (OR=1.91, P=0.033). The CR+T group did not improve PA or SB compared to CR-only. CONCLUSIONS: Adding three pedometer-based, face-to-face group PA counseling sessions to standard CR increased daily step count and time in prolonged MVPA. The latter persisted at 18months. A telephonic after-care program did not improve PA or SB. Although after-care should be optimized to improve long-term adherence, face-to-face group counseling with objective PA feedback should be added to standard CR. PMID- 29425566 TI - Functional outcome in contemporary children with total cavopulmonary connection - Health-related physical fitness, exercise capacity and health-related quality of life. AB - OBJECTIVE: Children and adolescents with an univentricular heart after total cavopulmonary connection (TCPC) have functional impairments. This study assesses health-related physical fitness (HRPF) and exercise capacity, as well as their relation to health-related quality of life (HRQoL) in patients with an univentricular heart after total-pulmonary connection (TCPC). PATIENTS AND METHODS: Between July 2014 and October 2016 a total of 78 children and adolescents with TCPC (12.0+/-3.2years, 21 female) performed a motor test including five tasks for strength and flexibility during their routine follow-up appointment. They also underwent a symptom limited cardio-pulmonary exercise test and filled in a HRQoL questionnaire (KINDL-R). Patients' data were compared to a recent sample of healthy children (n=1650, 12.6+/-2.4years, 49% female). RESULTS: Multivariable regressions corrected for sex, age and BMI showed that TCPC patients achieved 12.4 repetitions of curl-ups (p<0.001) and 2.6 push-ups (p=0.010) less than healthy counterparts. They had impairments in trunk (-8.5cm; p<0.001), shoulder (-7.5cm; p<0.001) and lower limb flexibility (-4.7cm; p<0.001). Peak oxygen uptake was reduced to 34.8+/-7.5ml/min/kg and 77.7% respectively, compared to peers (p<0.001). Ventilatory efficiency was also impaired (healthy: 27.5+/-2.9 vs. TCPC: 31.6+/-3.3; p<0.001). HRQoL did not differ significantly (p=0.233). CONCLUSIONS: Children and adolescents with TCPC still present impaired HRPF and exercise capacity whereas HRQoL is similar to healthy peers. Since low HRPF may yield to worse motor competence and exercise capacity, early screening for HRPF and early treatment, if indicated, is recommended. PMID- 29425567 TI - Should we prescribe physical activity in Fontan as a conventional therapy? PMID- 29425568 TI - Time-to-isolation guided titration of freeze duration in 3rd generation short-tip cryoballoon pulmonary vein isolation - Comparable clinical outcome and shorter procedure duration. AB - BACKGROUND: The optimal freeze duration in cryoballoon pulmonary vein isolation (PVI) is unknown. The 3rd generation cryoballoon facilitates observation of the time-to-isolation (TTI) and thereby enables individualized cryoenergy titration. To evaluate the efficacy of an individualized freeze duration we compared the clinical outcome of patients treated with a TTI-guided ablation protocol to the outcome of patients treated with a fixed ablation protocol. METHODS: We compared 100 patients treated with the 3rd generation cryoballoon applying a TTI-based protocol (TTI group) to 100 patients treated by a fixed freeze protocol (fixed group). In the fixed group a 240s freeze cycle was followed by a 240s bonus freeze after acute PV isolation. In the TTI group freeze duration was 180s if TTI was >=30s and reduced to only 120s, if TTI was <30s. In case of a TTI >60s a 180s bonus freeze was applied. RESULTS: Freedom from atrial arrhythmia recurrence off class I/III antiarrhythmic drugs after one year was not different between the TTI group (73.6%) and the fixed group (75.7%; p=0.75). Mean procedure duration was 85.8+/-27.3min in the TTI group compared to 115.7+/-27.1min in the fixed group (p<0.001). Mean fluoroscopy time was 17.5+/-6.6min in the TTI group and 22.5+/ 9.8min in the fixed group (p<0.001). CONCLUSIONS: TTI-guided cryoenergy titration leads to reduced procedure duration and fluoroscopy time and appears to be as effective as a fixed ablation strategy. A single 2-minute freeze seems to be sufficient in case of short TTI. PMID- 29425569 TI - Significant impact of electrical storm on mortality in patients with structural heart disease and an implantable cardiac defibrillator. AB - BACKGROUND: Electrical storm (E-Storm), defined as multiple episodes of ventricular arrhythmias within a short period of time, is an important clinical problem in patients with an implantable cardiac defibrillator (ICD) including cardiac resynchronization therapy devices capable of defibrillation. The detailed clinical aspects of E-Storm in large populations especially for non-ischemic dilated cardiomyopathy (DCM), however, remain unclear. OBJECTIVE: This study was performed to elucidate the detailed clinical aspects of E-Storm, such as its predictors and prevalence among patients with structural heart disease including DCM. METHODS: We analyzed the data of the Nippon Storm Study, which was a prospective observational study involving 1570 patients enrolled from 48 ICD centers. For the purpose of this study, we evaluated 1274 patients with structural heart disease, including 482 (38%) patients with ischemic heart disease (IHD) and 342 (27%) patients with DCM. RESULTS: During a median follow-up of 28months (interquartile range: 23 to 33months), E-Storm occurred in 84 (6.6%) patients. The incidence of E-Storm was not significantly different between patients with IHD and patients with DCM (log-rank p=0.52). Proportional hazard regression analyses showed that ICD implantation for secondary prevention of sudden cardiac death (p=0.0001) and QRS width (p=0.015) were the independent risk factors for E-storm. In a comparison between patients with and without E-Storm, survival curves after adjustment for clinical characteristics showed a significant difference in mortality. CONCLUSION: E-Storm was associated with subsequent mortality in patients with structural heart disease including DCM. PMID- 29425571 TI - Finding the right timing in cryoballoon ablation for pulmonary vein isolation. PMID- 29425570 TI - A potential relationship between gut microbes and atrial fibrillation: Trimethylamine N-oxide, a gut microbe-derived metabolite, facilitates the progression of atrial fibrillation. AB - BACKGROUND: Emerging evidence indicates gut microbes and their products could activate the autonomic nervous system (ANS), which plays important roles in the initiation and maintenance of atrial fibrillation (AF). Trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes, is associated with cardiovascular diseases. The present study aimed to investigate the role of TMAO in the progression of AF. METHODS: In part 1: TMAO or saline was locally injected into 4 major atrial ganglionated plexi (GP) to clarify its effect on cardiac ANS and AF inducibility in normal canines. In part 2: TMAO or saline was injected into 4 major atrial GP to test its effect on AF progression in a rapid atrial pacing (RAP)-induced AF model. RESULTS: In part 1: Local injection of TMAO significantly increased anterior right GP (ARGP) function and neural activity, shortened ERP values. In part 2, compared with the control group, 6-hour RAP significantly shortened the ERP, widened the ?WOV, enhanced the ARGP function and neural activity, increased the NGF and c-fos expression, and up-regulated the inflammatory cytokines. TMAO aggravated all of these changes by activating the proinflammatory p65 NF-kappaB signaling pathway. CONCLUSIONS: TMAO could increase the instability of atrial electrophysiology in normal canines and aggravate the acute electrical remodeling in a RAP-induced AF model by exacerbating autonomic remodeling. The increased inflammatory cytokines in the GP due to the activation of p65 NF-kappaB signaling may contribute to these effects. PMID- 29425572 TI - [In process]. PMID- 29425573 TI - Diurnal variation of default mode network in patients with restless legs syndrome. AB - OBJECTIVE: Restless legs syndrome (RLS) patients compared to controls have been found to have abnormal patterns in the default mode network (DMN) in the morning when symptom threshold is the highest and symptoms are least likely to occur. If these morning abnormalities in DMN are pertinent to disease expression, then similar or further detectable differences may be expected on a nighttime assessment when RLS symptom threshold is at its lowest. The purpose of this study was to elucidate the potential neural mechanisms underlying the circadian aspect of RLS symptom expression by assessing diurnal changes in DMN. METHODS: Fifteen drug-naive subjects with idiopathic RLS and 15 age- and gender-matched healthy subjects had fMRI scans in the morning and evening. The DMN patterns were compared both for differences between morning and evening and between RLS and controls. RESULTS: RLS patients compared to the healthy controls showed significant differences in morning and evening DMN. In particular, RLS patients showed consistent increased connectivity in the parietal lobule in both the morning and evening. In contrast, connectivity in the thalamus was increased in the morning and reduced in the evening. In addition, there were negative correlations between thalamic connectivity and the Korean versions of the international RLS scale and the quality-of-life subscore. CONCLUSIONS: The results indicated diurnal disturbances of the DMN in RLS subjects are consistent with both the circadian rhythm and severity of RLS. The circadian expression of RLS may relate to changes in arousal cortical-activation thresholds occurring with diurnal changes in the thalamic circuits of the DMN. PMID- 29425574 TI - Sleep in ambulatory patients with stable cirrhosis of the liver. AB - BACKGROUND: Questionnaires indicate that patients with liver disease have disturbed sleep. However, polysomnographic studies to quantify sleep architecture and sleep disorders in this population are lacking. The current study compared polysomnographic findings of two groups of patients with clinically stable but severe end-stage pathology of the liver and heart. METHODS: This was a prospective study of consecutive patients with end-stage liver disease or severe heart failure (HF). MEASUREMENTS AND RESULTS: Patients underwent full-night, attended polysomnography along with a number of laboratory tests. Polysomnograms were scored blindly. Compared to HF patients, patients with cirrhosis suffered from severe periodic limb movements during sleep (PLMS), with an index of 39/hour associated with excessive arousals. In patients with cirrhosis, serum iron and ferritin levels were either at the upper normal limit or elevated. There were significant correlations between severity of PLMS versus blood levels of bilirubin (r = 0.73, p = 0.004) and ammonia (r = 0.74, p = 0.017). CONCLUSIONS: This was the first polysomnographic study of patients with stable cirrhosis demonstrating severely disturbed sleep infrastructure and presence of excessive PLMS with arousals. The pathobiochemical mechanisms of these findings remain to be established. Independent of the mechanisms, these polysomnographic findings confirmed the subjective reports of poor sleep by patients with cirrhosis. Further, a subset of patients with cirrhosis acquired a syndrome similar to idiopathic Parkinson's disease, which per se was frequently associated with PLMS; the current results were consistent with this notion. Future studies are needed to determine if PLMS of cirrhosis is an early indication of incident Parkinsonian syndrome. PMID- 29425575 TI - Effect of a patient engagement tool on positive airway pressure adherence: analysis of a German healthcare provider database. AB - OBJECTIVE/BACKGROUND: This study investigated the addition of a real-time feedback patient engagement tool on positive airway pressure (PAP) adherence when added to a proactive telemedicine strategy. PATIENTS/METHODS: Data from a German healthcare provider (ResMed Healthcare Germany) were retrospectively analyzed. Patients who first started PAP therapy between 1 September 2009 and 30 April 2014, and were managed using telemedicine (AirViewTM; proactive care) or telemedicine + patient engagement tool (AirViewTM + myAirTM; patient engagement) were eligible. Patient demographics, therapy start date, sleep-disordered breathing indices, device usage hours, and therapy termination rate were obtained and compared between the two groups. RESULTS: The first 500 patients managed by telemedicine-guided care and a patient engagement tool were matched with 500 patients managed by telemedicine-guided care only. The proportion of nights with device usage >=4 h was 77 +/- 25% in the patient engagement group versus 63 +/- 32% in the proactive care group (p < 0.001). Therapy termination occurred less often in the patient engagement group (p < 0.001). The apnea-hypopnea index was similar in the two groups, but leak was significantly lower in the patient engagement versus proactive care group (2.7 +/- 4.0 vs 4.1 +/- 5.3 L/min; p < 0.001). CONCLUSIONS: Addition of a patient engagement tool to telemonitoring guided proactive care was associated with higher device usage and lower leak. This suggests that addition of an engagement tool may help improve PAP therapy adherence and reduce mask leak. PMID- 29425576 TI - Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. AB - BACKGROUND: Brain iron deficiency has been implicated in the pathophysiology of RLS, and current RLS treatment guidelines recommend iron treatment when peripheral iron levels are low. In order to assess the evidence on the oral and intravenous (IV) iron treatment of RLS and periodic limb movement disorder (PLMD) in adults and children, the International Restless Legs Syndrome Study Group (IRLSSG) formed a task force to review these studies and provide evidence-based and consensus guidelines for the iron treatment of RLS in adults, and RLS and PLMD in children. METHODS: A literature search was performed to identify papers appearing in MEDLINE from its inception to July 2016. The following inclusion criteria were used: human research on the treatment of RLS or periodic limb movements (PLM) with iron, sample size of at least five, and published in English. Two task force members independently evaluated each paper and classified the quality of evidence provided. RESULTS: A total of 299 papers were identified, of these 31 papers met the inclusion criteria. Four studies in adults were given a Class I rating (one for IV iron sucrose, and three for IV ferric carboxymaltose); only Class IV studies have evaluated iron treatment in children. Ferric carboxymaltose (1000 mg) is effective for treating moderate to severe RLS in those with serum ferritin <300 MUg/l and could be used as first-line treatment for RLS in adults. Oral iron (65 mg elemental iron) is possibly effective for treating RLS in those with serum ferritin <=75 MUg/l. There is insufficient evidence to make conclusions on the efficacy of oral iron or IV iron in children. CONCLUSIONS: Consensus recommendations based on clinical practice are presented, including when to use oral iron or IV iron, and recommendations on repeated iron treatments. New iron treatment algorithms, based on evidence and consensus opinion have been developed. PMID- 29425577 TI - Clinical significance of periodic limb movements during sleep: the HypnoLaus study. AB - OBJECTIVE: Periodic limb movements during sleep (PLMS) are prevalent in the general population, but their impact on sleep and association with cardiometabolic disorders are a matter of debate. METHODS: Data from 2162 participants (51.2% women, mean age 58.4 +/- 11.1 years) of the population-based HypnoLaus study (Lausanne, Switzerland) were collected. Subjective sleep complaints and habits were assessed using the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale (ESS). Participants underwent a full polysomnography (PSG) at home and were evaluated for the presence of hypertension, diabetes, and metabolic syndrome. RESULTS: Participants with a PLMS index (PLMSI) > 15/h (28.6% of the sample) had longer subjective sleep latency (18.6 +/- 17.2 vs. 16.1 +/- 14.3 min, p = 0.014) and duration (7.1 +/- 1.2 vs. 6.9 +/- 1.1 h, p < 0.001) than participants with PLMSI <= 15/h. At the PSG, they spent more time in stage N2 sleep (49.0 +/- 11.2 vs. 45.5 +/- 9.8%, p < 0.001), less in stage N3 (17.6 +/- 8.2 vs. 20.6 +/- 8.4%, p < 0.001) and in REM sleep (20.3 +/- 6.4 vs. 22.4 +/- 6.0%, p < 0.001), and exhibited longer REM latency (104.2 +/- 70.2 vs. 91.7 +/- 58.6 min, p < 0.001) and higher arousal index (26.5 +/- 12.3 vs. 19.2 +/- 9.7 n/h, p < 0.001). Participants with a PLMSI > 15/h had a lower ESS scores and higher prevalence of hypertension, diabetes, and metabolic syndrome. Multivariate analysis adjusting for confounding factors confirmed the independent association of PLMSI > 15/h with subjective sleep latency and duration, and with objective sleep structure disturbances. However, the associations with sleepiness and cardiovascular risk factors disappeared. CONCLUSIONS: In our large middle-age European population-based sample, PLMSI > 15/h was associated with subjective and objective sleep disturbances but not with sleepiness, hypertension, diabetes, or metabolic syndrome. PMID- 29425578 TI - Massage-based bedtime routine: impact on sleep and mood in infants and mothers. AB - Establishment of a consistent bedtime routine is often recommended to families with young children with sleep difficulties. However, there are limited studies assessing specific bedtime routines in the treatment of infant and toddler sleep disturbances. Thus, the purpose of this study was to examine the impact of a massage-based bedtime routine on infant sleep, maternal sleep, and maternal mood. A total of 123 mothers and their 3- to 18-month-old infant were randomly assigned to a routine (one-week baseline of usual bedtime routine, two-weeks intervention) or control group (three-weeks of their usual bedtime routine). All mothers completed the Brief Infant Sleep Questionnaire (BISQ) on a weekly basis and measures of maternal sleep and mood (eg, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Edinburgh Postnatal Depression Scale). This bedtime routine resulted in improvements in child and mother night wakings, maternal perceptions of child sleep and mood (ie, sleep problem, bedtime ease, and morning mood), and improvements in maternal sleep quality. No comparative changes were seen in the control group. Notably, other than number of night wakings for both the child and the mother, there were no changes in other sleep patterns including sleep onset latency, duration of night wakings, longest stretch of sleep, or sleep duration. This study supports recommending a massage-based routine in those families, with the codicil that improvements in maternal perceptions and maternal sleep will be noted, with few improvements in sleep itself other than night wakings. PMID- 29425579 TI - The impact of sleep disordered breathing on cardiovascular health in overweight children. AB - BACKGROUND: Up to 50% of overweight/obese children have obstructive sleep apnea (OSA) compared to up to 6% of normal weight children. We compared cardiovascular variables between normal weight and overweight/obese children with and without OSA, and controls. METHODS: Seventy-four referred children and 24 normal weight non-snoring controls (8-18 years) were recruited. Referred children were grouped according to their obstructive apnea hypopnea index (OAHI): OSA (>1 event/h) or primary snoring (PS <= 1 event/h) and whether they were normal weight (BMI z score <1.04) or overweight/obese (BMI z-score >= 1.04). Wake blood pressure (BP), heart rate (HR), and pulse transit time (PTT, an inverse continuous surrogate measure of blood pressure) during sleep were recorded. RESULTS: Wake BP was higher in the overweight/obese OSA group than in the control, normal weight PS, and overweight/obese PS groups (p < 0.05 for all). During sleep, BP, and HR were elevated in the overweight/obese OSA group compared to those in non-snoring controls (p < 0.05). More children who were overweight/obese had reduced BP and HR dipping from wake to sleep than normal weight children. The BMI z-score predicted HR and PTT when asleep and both age and BMI z-score predicted BP when awake. CONCLUSION: This study showed that BMI has both combined and independent effects on BP and HR in children with OSA. We have previously shown that treatment of OSA reduces BP and suggest that treatment of OSA in the growing number of overweight/obese children may improve cardiovascular outcomes. PMID- 29425580 TI - Japanese Sleep Questionnaire for Elementary Schoolers (JSQ-ES): validation and population-based score distribution. AB - OBJECTIVE: The Japanese Sleep Questionnaire for Elementary Schoolers (JSQ-ES) was developed to measure the sleep habits and disturbances of Japanese children. The current study aimed to present psychometric properties and describe the score distribution of the JSQ-ES. In addition, it examined correlations between the sleep and daytime behavior of school-aged children. METHOD: Guardians of 4369 elementary school children and 100 children diagnosed with sleep disorders in two clinics completed the JSQ-ES. RESULTS: Exploratory factor analysis and confirmatory factor analysis suggested a nine-factor structure. The JSQ-ES internal consistency was 0.876 and 0.907 for the community and clinical groups, respectively. Score distribution differences were observed between the two groups. A cut-off point of 80 was identified for the total JSQ-ES score. CONCLUSIONS: Exploratory factor analysis and confirmatory factor analysis suggested a nine-factor structure: (1) restless legs syndrome; (2) sleep disordered breathing; (3) morning symptoms; (4) nighttime awakenings; (5) insomnia; (6) excessive daytime sleepiness; (7) daytime behavior; (8) sleep habits; and (9) irregular/delayed sleep phase. The study verified that the JSQ-ES is a valid and reliable instrument with which to evaluate Japanese sleep habits using a large population-based sample. The JSQ-ES may be useful in both clinical and academic settings. PMID- 29425581 TI - Long sleep duration is associated with lower cognitive function among middle-age adults - the Doetinchem Cohort Study. AB - OBJECTIVES: In older adults, both short and long sleep duration are associated with lower cognitive function, suggesting an inverted U-shaped association between sleep duration and cognitive outcomes. This study examined whether sleep duration is associated with (changes in) cognitive function in a middle-aged population. METHODS: In the Doetinchem Cohort Study, the cognitive function of 2970 men and women aged 41-75 years at baseline (1995-2007) was examined 2-3 times, with 5-year time intervals. Global cognitive function and the domains memory, information processing speed, and cognitive flexibility were assessed. In multivariable linear regression models, (change in) self-reported sleep duration was studied in association with the level and change in cognitive function. In a subsample of the population (n = 2587), the association of sleep duration and feeling rested with cognitive function was studied. RESULTS: Sleep duration of 9 h and more was statistically significantly associated with lower global cognitive function (p < 0.01), memory (p = 0.02), and flexibility (p = 0.03), compared to a sleep duration of 7 or 8 h. Among adults feeling frequently not well rested, both short and long sleep duration were associated with a lower speed of cognitive function. An inverted U-shaped association between sleep duration and cognitive function was observed for speed, flexibility, and global cognitive function. Sleep duration was not associated with change in cognitive function. CONCLUSIONS: Middle-age adults with long sleep duration had a lower cognitive function. PMID- 29425582 TI - Identifying the best sleep measure to screen clinical insomnia in a psychiatric population. AB - BACKGROUND: Insomnia symptoms are highly prevalent among patients with psychiatric disorders, and this mandates the need to identify the best self administered sleep measure to screen for clinical insomnia among them. METHODS: A total of 400 psychiatric outpatients completed the Pittsburgh Sleep Quality Index, Insomnia Severity Index (ISI), Epworth Sleepiness Scale, Flinders Fatigue Scale, Functional Outcomes of Sleep Questionnaire, and Dysfunctional Beliefs and Attitudes about Sleep Scale in a cross-sectional study. The sensitivity, specificity, positive, and negative predictive values of these six sleep scales were assessed and compared in relation to both ICD-10 and DSM-5 insomnia disorder status established using the interviewer-administered Brief Insomnia Questionnaire. RESULTS: Receiver operator characteristic curves with the area under the curve (AUC) revealed the ISI to be the most accurate measure to discriminate cases and non-cases on both ICD-10 (AUC = 0.88, 95% CI = 0.84-0.92) and DSM-5 (AUC = 0.82, 95% CI = 0.78-0.86) criteria with "good" accuracy. The cut off scores of >=14 and >= 11 for the ISI provided optimal sensitivity and specificity for the detection of ICD-10 and DSM-5 insomnia, respectively. DISCUSSION: With the new calling from DSM-5 to treat sleep symptoms in the presence of a co-existing mental condition, early detection of psychiatric patients with clinically significantly insomnia using a simple but accurate self report sleep measure becomes important. Our study suggests that the ISI could be used as a potential screening tool for comorbid insomnia disorder in patients with mental disorders. PMID- 29425584 TI - The journal year in review. PMID- 29425583 TI - Prevalence of sleep-disordered breathing in Japanese medical students based on type-3 out-of-center sleep test. AB - BACKGROUND: Sleep-disordered breathing (SDB), especially obstructive sleep apnea disorder (OSA), is thought to mainly affect men over the age of 40. Following findings that Asian people are more likely to experience severe OSA, regardless of obesity, we investigated the prevalence of SDB and OSA in a larger sample and in more younger age groups than those described in previous reports. METHODS: Between 2011 and 2016, 487 medical students (358 males, mean age 24.8 +/- 1.9 years; 129 females: mean age 23.8 +/- 1.6 years) underwent an out-of-center sleep test using a type-3 portable monitor. The results were analyzed visually. RESULTS: The mean +/- standard deviation of the respiratory event index (REI: events/hour of monitoring) was 5.4 +/- 6.7 (6.7 +/- 7.5 in male participants, 2.6 +/- 2.1 in female participants). There were 170 participants (36.6%) with an REI>=5, including 158 male participants (46.9%) and 12 female participants (9.1%). SDB or undefined OSA with low REI (15 > REI>=5) was observed in 141 participants (30.4%), defined OSA with moderate REI (30 > REI>=15) in 19 participants (4.1%), and defined OSA with high REI (REI>=30) in 10 participants (2.2%). Among the male students, 129 had low REI (38.3%), 19 had moderate REI (5.6%), and 10 had high REI (3.0%). All female participants with OSA events (9.4%) had a low REI. CONCLUSIONS: The prevalence of OSA in Japanese young adults, especially males under 30 years old, is similar or even higher than that in older age groups described previously. Thus, an aggressive sleep study for SDB might be necessary for the younger generation in the Asian population. PMID- 29425585 TI - Molecular diversity analysis of Tetradium ruticarpum (WuZhuYu) in China based on inter-primer binding site (iPBS) markers and inter-simple sequence repeat (ISSR) markers. AB - "Wu zhu yu", which is obtained from the dried unripe fruits of Tetradium ruticarpum (A. Jussieu) T. G. Hartley, has been used as a traditional Chinese medicine for treatment of headaches, abdominal colic, and hypertension for thousands of years. The present study was designed to assess the molecular genetic diversity among 25 collected accessions of T. ruticarpum (Wu zhu yu in Chinese) from different areas of China, based on inter-primer binding site (iPBS) markers and inter-simple sequence repeat (ISSR) markers. Thirteen ISSR primers generated 151 amplification bands, of which 130 were polymorphic. Out of 165 bands that were amplified using 10 iPBS primers, 152 were polymorphic. The iPBS markers displayed a higher proportion of polymorphic loci (PPL = 92.5%) than the ISSR markers (PPL = 84.9%). The results showed that T. ruticarpum possessed high loci polymorphism and genetic differentiation occurred in this plant. The combined data of iPBS and ISSR markers scored on 25 accessions produced five clusters that approximately matched the geographic distribution of the species. The results indicated that both iPBS and ISSR markers were reliable and effective tools for analyzing the genetic diversity in T. ruticarpum. PMID- 29425586 TI - Cucurbitacin B suppresses metastasis mediated by reactive oxygen species (ROS) via focal adhesion kinase (FAK) in breast cancer MDA-MB-231 cells. AB - Metastasis is responsible for the majority of cancer-related deaths and prevention of metastasis remains a big challenge for cancer therapy. Cucurbitacin B (Cuc B) is a natural triterpenoid with potent anticancer activities while its effect on metastasis remains unclear. In the present study, the inhibitory effect and mechanisms of Cuc B on metastasis were investigated in MDA-MB-231 breast cancer cells. The cells were treated with or without Cuc B, and the cytotoxicity was determined by MTT assay. The effect of Cuc B on metastasis was evaluated with wound healing, transwell, and adhesion assays. Furthermore, the adhesion of cancer cells to endothelial cells was determined. The protein expression was determined by Western blotting. Cuc B (< 100 nmol.L-1) showed no obvious cytotoxicity to MDA-MB-231 cells, but significantly inhibited migration, invasion, and adhesion to Matrigel, fibronectin, type I collagen, and endothelial cells. Cuc B dramatically inhibited the phosphorylation of focal adhesion kinase (FAK) and paxillin in dose- and time-dependent manners. Furthermore, Cuc B induced intracellular reactive oxygen species (ROS) generation, which could be reduced by N-acetyl-l-cysteine (NAC). In addition, NAC pretreatment could reverse Cuc B-induced suppression of migration and adhesion, expression of FAK, but showed no effect on paxillin expression. In summary, Cuc B suppressed ROS dependent metastasis through FAK pathway in breast cancer MDA-MB-231 cells, demonstrating novel mechanisms for the anticancer effects of Cuc B. PMID- 29425587 TI - Reversal of multidrug resistance by icaritin in doxorubicin-resistant human osteosarcoma cells. AB - Multidrug resistance (MDR) is one of the major obstacles in cancer chemotherapy. Our previous study has shown that icariin could reverse MDR in MG-63 doxorubicin resistant (MG-63/DOX) cells. It is reported that icariin is usually metabolized to icariside II and icaritin. Herein, we investigated the effects of icariin, icariside II, and icaritin (ICT) on reversing MDR in MG-63/DOX cells. Among these compounds, ICT exhibited strongest effect and showed no obvious cytotoxicity effect on both MG-63 and MG-63/DOX cells ranging from 1 to 10 MUmol.L-1. Furthermore, ICT increased accumulation of rhodamine 123 and 6-carboxyfluorescein diacetate and enhanced DOX-induced apoptosis in MG-63/DOX cells in a dose dependent manner. Further studies demonstrated that ICT decreased the mRNA and protein levels of multidrug resistance protein 1 (MDR1) and multidrug resistance associated protein 1 (MRP1). We also verified that blockade of STAT3 phosphorylation was involved in the reversal effect of multidrug resistance in MG 63/DOX cells. Taken together, these results indicated that ICT may be a potential candidate in chemotherapy for osteosarcoma. PMID- 29425588 TI - Saponins isolated from Schizocapsa plantaginea inhibit human hepatocellular carcinoma cell growth in vivo and in vitro via mitogen-activated protein kinase signaling. AB - The underground cane of Schizocapsa plantaginea (Hance) has long been used by Chinese ethnic minority as a constituent of anti-cancer formulae. Saponins are abundant secondary metabolic products located in the underground cane of this plant. The potential therapeutic effects of total saponins isolated from Schizocapsa plantaginea (Hance) (SSPH) on human hepatocellular carcinoma (HCC) were tested in vitro in human liver cancer cell lines, SMMC-7721 and Bel-7404. Apoptosis and cell cycle arrest were determined using flow cytometry, caspase activation was determined by ELISA, and PARP, cleaved PARP, mitogen-activated protein kinase (MAPK) expression and phosphorylation were measured using Western blotting analysis. In vivo anti-HCC effects of SSPH were verified in nude mouse xenograft model. SSPH exerted markedly inhibitory effect on HCC cell proliferation in time- and concentration-dependent manner. Moreover, SSPH significantly induced apoptosis through caspase-dependent signaling and arrested cell cycle at G2/M phase. These anti-proliferation effects of SSPH were associated with up-regulated phosphorylation of extracellular signal-regulated kinase-1/2 (Erk1/2) and c-jun-NH2-kinase-1/2 (JNK1/2) and reduced phosphorylation of p38MAPK. Furthermore, inhibitors of ERK, UO126, and JNK, SP600125 inhibited the anti-proliferation effects by SSPH, suggesting that Erk and JNK were the effector molecules in SSPH induced anti-proliferative action. During in vivo experiments, SSPH was found to inhibit xenograft tumor growth in nude mice, with a similar mechanism in vitro. Our study confirmed that SSPH exerted antagonistic effects on human liver cancer cells both in vitro and in vivo. Molecular mechanisms underlying SSPH action might be closely associated with MAPK signaling pathways. These results indicated that SSPH has potential therapeutic effects on HCC. PMID- 29425589 TI - Puerarin attenuates angiotensin II-induced cardiac fibroblast proliferation via the promotion of catalase activity and the inhibition of hydrogen peroxide dependent Rac-1 activation. AB - The aims of the present study were to evaluate the effects of puerarin on angiotensin II-induced cardiac fibroblast proliferation and to explore the molecular mechanisms of action. Considering the role of H2O2 in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, we hypothesized that modulating catalase activity would be a potential target in regulating the redox sensitive pathways. Our results showed that the activation of Rac1 was dependent on the levels of intracellular H2O2. Puerarin blocked the phosphorylation of extracellular regulated protein kinases (ERK)1/2, abolished activator protein (AP)-1 binding activity, and eventually attenuated cardiac fibroblast proliferation through the inhibition of H2O2-dependent Rac1 activation. Further studies revealed that angiotensin II treatment resulted in decreased catalase protein expression and enzyme activity, which was disrupted by puerarin via the upregulation of catalase protein expression at the transcriptional level and the prolonged protein degradation. These findings indicated that the anti proliferation mechanism of puerarin was mainly through blocking angiontensin II triggered downregulation of catalase expression and H2O2-dependent Rac1 activation. PMID- 29425590 TI - Network pharmacology-based analysis of Chinese herbal Naodesheng formula for application to Alzheimer's disease. AB - Naodesheng (NDS) formula, which consists of Rhizoma Chuanxiong, Lobed Kudzuvine, Carthamus tinctorius, Radix Notoginseng, and Crataegus pinnatifida, is widely applied for the treatment of cardio/cerebrovascular ischemic diseases, ischemic stroke, and sequelae of cerebral hemorrhage, etc. At present, the studies on NDS formula for Alzheimer's disease (AD) only focus on single component of this prescription, and there is no report about the synergistic mechanism of the constituents in NDS formula for the potential treatment of dementia. Therefore, the present study aimed to predict the potential targets and uncover the mechanisms of NDS formula for the treatment of AD. Firstly, we collected the constituents in NDS formula and key targets toward AD. Then, drug-likeness, oral bioavailability, and blood-brain barrier permeability were evaluated to find drug like and lead-like constituents for treatment of central nervous system diseases. By combining the advantages of machine learning, molecular docking, and pharmacophore mapping, we attempted to predict the targets of constituents and find potential multi-target compounds from NDS formula. Finally, we built constituent-target network, constituent-target-target network and target biological pathway network to study the network pharmacology of the constituents in NDS formula. To the best of our knowledge, this represented the first to study the mechanism of NDS formula for potential efficacy for AD treatment by means of the virtual screening and network pharmacology methods. PMID- 29425591 TI - A pair of cyclopeptide epimers from the seeds of Celosia argentea. AB - Two cyclopeptides, celogentin L (1) and its epimer lyciumin A (2) were firstly isolated from Celosia argentea L.. The planar structures of the two compounds were fully determined by spectroscopic data, including 1D-, 2D-NMR, and HR ESI/MS. The absolute configurations of amino acid components were assigned via chiral-phase HPLC analyses after acid hydrolysis. Furthermore, the configuration of C-N linkage at the glycine Calpha was elucidated by extensive analyses of 2D NMR and comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Cytotoxicity of the two compounds against human alveolar epithelial A549, hepatocellular carcinoma HepG2, and cervical cancer Hela cell lines was assayed. Although both of them were inactive in these cells, the present findings add new facets for the chemistry of Celosia argentea. PMID- 29425592 TI - Improved stability and oral bioavailability of Ganneng dropping pills following transforming lignans of herpetospermum caudigerum into nanosuspensions. AB - The present study was designed to improve storage stability and oral bioavailability of Ganneng dropping pills (GNDP) by transforming lignans of Herpetospermum caudigerum (HL) composed of herpetrione (HPE) and herpetin (HPN) into nanosuspension (HL-NS), the main active ingredient of GNDP, HL-NS was prepared by high pressure homogenization and lyophilized to transform into solid nanoparticles (HL nanoparticles), and then the formulated HL nanoparticles were perfused into matrix to obtain NS-GNDP by melting method. For a period of 3 months, the content uniformity, storage stability and pharmacokinetics test in vivo of NS-GNDP were evaluated and compared with regular GNDP at room temperature. The results demonstrated that uniformity of dosage units of NS-GNDP was acceptable according to the criteria of Chinese Pharmacopoeia 2015J. Physical stability of NS-GNDP was investigated systemically using photon correlation spectroscopy (PCS), zeta potential measurement, and scanning electron microscopy (SEM). There was a slight increase in particles and PI of HL-NS re-dispersed from NS-GNDP after storage for 3 months, compared with new formulated NS-GNDP, which indicated a good redispersibility of the NS-GNDP containing HL-NS after storage. Besides, chemical stability of NS-GNDP was studied and the results revealed that HPE and HPN degradation was less when compared with that of GNDP, providing more than 99% of drug residue after storage for 3 months. In the dissolution test in vitro, NS-GNDP remarkably exhibited an increased dissolution velocity compared with GNDP and no distinct dissolution difference existed within 3 months. The pharmacokinetic study showed that HPE and HPN in NS-GNDP exhibited a significant increase in AUC0-t, Cmax and decrease in Tmax when compared with regular GNDP. These results indicated that NS-GNDP possessed superiority with improved storage stability and increased dissolution rate and oral bioavailability. PMID- 29425594 TI - Developing Capacity to Do Improvement Science Work. AB - Developing capacity to do improvement science starts with prioritizing quality improvement training in all health professions curricula so that a common knowledge base and understanding are created. Educational programs should include opportunities for colearning with patients, health professionals, and leaders. In this way, knowledge translation (also called implementation) is more effective and better coordinated when applied across organizations. Key factors that enable and drive behavior change are reviewed, as is the importance of influence and leadership. A comprehensive approach that accounts for these factors hardwires quality improvement into the health care systems and creates a culture that enables its ongoing development. PMID- 29425593 TI - Implementation Science in Perioperative Care. AB - There is a 17-year gap between the initial publication of scientific evidence and its uptake into widespread practice in health care. The field of implementation science (IS) emerged in the 1990s as an answer to this "evidence-to-practice gap." In this article, we present an overview of implementation science, focusing on the application of IS principles to perioperative care. We describe opportunities for additional training and discuss strategies for funding and publishing IS work. The objective is to demonstrate how IS can improve perioperative patient care, while highlighting perioperative IS studies and identifying areas in need of additional investigation. PMID- 29425595 TI - Diffusing Innovation and Best Practice in Health Care. AB - Diffusing innovation and best practices in healthcare are among the most challenging aspects of advancing patient safety and quality improvement. Recommendations from the Baldrige Foundation, Institute for Healthcare Improvement, and The Joint Commission provide guidance on the principles for successful diffusion. Perioperative leaders are encouraged to applying these principles to high priority areas such as handovers, enhanced recovery and patient blood management. Completing a successful pilot project can be exciting, however, effective diffusion is essential to achieving meaningful and lasting impact on the service line and health system. PMID- 29425596 TI - Human Factors Applied to Perioperative Process Improvement. AB - This article discusses some of the major theories of the science of human factors/ergonomics (HF/E) in relation to perioperative medicine, with a focus on safety and errors within these systems. The discussion begins with human limitations based in cognition, decision making, stress, and fatigue. Given these limitations, the importance of measuring human performance is discussed. Finally, using the HF/E perspective on safety, high-level recommendations are provided for increasing safety within the perioperative environment. PMID- 29425597 TI - Quality Improvement in Anesthesiology - Leveraging Data and Analytics to Optimize Outcomes. AB - Quality improvement is at the heart of practice of anesthesiology. Objective data are critical for any quality improvement initiative; when possible, a combination of process, outcome, and balancing metrics should be evaluated to gauge the value of an intervention. Quality improvement is an ongoing process; iterative reevaluation of data is required to maintain interventions, ensure continued effectiveness, and continually improve. Dashboards can facilitate rapid analysis of data and drive decision making. Large data sets can be useful to establish benchmarks and compare performance against other providers, practices, or institutions. Audit and feedback strategies are effective in facilitating positive change. PMID- 29425598 TI - Emergency Manuals: How Quality Improvement and Implementation Science Can Enable Better Perioperative Management During Crises. AB - How can teams manage critical events more effectively? There are commonly gaps in performance during perioperative crises, and emergency manuals are recently available tools that can improve team performance under stress, via multiple mechanisms. This article examines how the principles of implementation science and quality improvement were applied by multiple teams in the development, testing, and systematic implementations of emergency manuals in perioperative care. The core principles of implementation have relevance for future patient safety innovations perioperatively and beyond, and the concepts of emergency manuals and interprofessional teamwork are applicable for diverse fields throughout health care. PMID- 29425599 TI - Use of Simulation in Performance Improvement. AB - Human error and system failures continue to play a substantial role in preventable errors that lead to adverse patient outcomes or death. Many of these deaths are not the result of inadequate medical knowledge and skill, but occur because of problems involving communication and team management. Anesthesiologists pioneered the use of simulation for medical education in an effort to improve physician performance and patient safety. This article explores the use of simulation for performance improvement. Educational theories that underlie effective simulation programs are described as driving forces behind the advancement of simulation in performance improvement. PMID- 29425600 TI - Developing Multicenter Registries to Advance Quality Science. AB - There are several benefits to clinical registries as an information repository tool, ultimately lending itself to the acquisition of new knowledge. Registries have the unique advantage of garnering much data quickly and are, therefore, especially helpful for niche populations or low-prevalence diseases. They can be used to inform on the ideal structure, process, or outcome involving an identified population. The data can be used in many ways, for example, as an observational tool to reveal associations or as a basis for framing future research studies or quality improvement projects. PMID- 29425601 TI - Handovers in Perioperative Care. AB - Handovers around the time of surgery are common, yet complex and error prone. Interventions aimed at improving handovers have shown increased provider satisfaction and teamwork, improved efficiency, and improved communication and have been shown to reduce errors and improve clinical outcomes in some studies. Common recommendations in the literature include a standardized institutional process that allows flexibility among different units and settings, the completion of urgent tasks before information transfer, the presence of all members of the team for the duration of the handover, a structured conversation that uses a cognitive aid, and education in team skills and communication. PMID- 29425602 TI - Rethinking Clinical Workflow. AB - The concept of clinical workflow borrows from management and leadership principles outside of medicine. The only way to rethink clinical workflow is to understand the neuroscience principles that underlie attention and vigilance. With any implementation to improve practice, there are human factors that can promote or impede progress. Modulating the environment and working as a team to take care of patients is paramount. Clinicians must continually rethink clinical workflow, evaluate progress, and understand that other industries have something to offer. Then, novel approaches can be implemented to take the best care of patients. PMID- 29425605 TI - 2017 ESC/EACTS Guidelines for the Management of Valvular Heart Disease. PMID- 29425606 TI - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS). PMID- 29425609 TI - Comments on the 2017 ESC/EACTS Guidelines for the Management of Valvular Heart Disease. PMID- 29425611 TI - Foreword. PMID- 29425610 TI - Comments on the 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases. PMID- 29425612 TI - Morphologic and Other Forms of Heterogeneity in Small Cell Lung Cancer: What Can We Learn from Them? PMID- 29425613 TI - Erratum. PMID- 29425614 TI - C797S and T790M EGFR Mutations in Non-Small Cell Lung Cancer: In Trans or in Separate Clones? PMID- 29425615 TI - In Reply to Leone. PMID- 29425616 TI - Comments on "Treatment Strategies and Prognostic Factors of Limited-Stage Primary Small Cell Carcinoma of the Esophagus". PMID- 29425617 TI - Response to "Comments on Treatment Strategies and Prognostic Factors of Limited Stage Primary Small Cell Carcinoma of the Esophagus". PMID- 29425618 TI - Prognostic Value of Primary Tumor Volume Changes on Kilovoltage Onboard Cone Beam Computed Tomography during Definitive Chemoradiotherapy for stage III Non-Small Cell Lung Cancer: Methodological Issues. PMID- 29425619 TI - Response to the Letter to Editor re: Methodological Issues. PMID- 29425620 TI - Information sources of self-care strategies for persons living with HIV. AB - OBJECTIVES: A number of studies have been conducted to identify the self-care strategies that are used by persons living with chronic illnesses to manage their symptoms, but little work has been done to identify the primary information source for these self-care strategies. METHODS: We conducted an anonymous online survey with 1373 persons living with HIV to identify the self-care strategies they use to manage 28 commonly experienced symptoms. Following their report of their symptoms and self-care strategies, we asked an open-ended question to identify where the participant obtained the information. We applied iterative content analysis of the narrative data and multi-nominal regression to identify which demographic factors were significantly related to each information source category. RESULTS: Respondents reported a total of 8539 information sources for their self-care strategies categorized as follows: Common sense/Self-experience, Healthcare professional, Internet, Literature, Multiple Sources, Social Support, and TV ads. CONCLUSIONS: We found that respondents with no college education were significantly more likely to report the use of the Internet as the information source for their self-care strategies. On the other hand, males as compared to females were significantly less likely to use the Internet and significantly more likely to use TV ads. PMID- 29425621 TI - The influence of patient portals on users' decision making is insufficiently investigated: A systematic methodological review. AB - BACKGROUND: Patient portals are considered valuable conduits for supporting patients' self-management. However, it is unknown why they often fail to impact on health care processes and outcomes. This may be due to a scarcity of robust studies focusing on the steps that are required to induce improvement: users need to effectively interact with the portal (step 1) in order to receive information (step 2), which might influence their decision-making (step 3). We aimed to explore this potential knowledge gap by investigating to what extent each step has been investigated for patient portals, and explore the methodological approaches used. METHODS: We performed a systematic literature review using Coiera's information value chain as a guiding theoretical framework. We searched MEDLINE and Scopus by combining terms related to patient portals and evaluation methodologies. Two reviewers selected relevant papers through duplicate screening, and one extracted data from the included papers. RESULTS: We included 115 articles. The large majority (n = 104) evaluated aspects related to interaction with patient portals (step 1). Usage was most often assessed (n = 61), mainly by analysing system interaction data (n = 50), with most authors considering participants as active users if they logged in at least once. Overall usability (n = 57) was commonly assessed through non-validated questionnaires (n = 44). Step 2 (information received) was investigated in 58 studies, primarily by analysing interaction data to evaluate usage of specific system functionalities (n = 34). Eleven studies explicitly assessed the influence of patient portals on patients' and clinicians' decisions (step 3). CONCLUSIONS: Whereas interaction with patient portals has been extensively studied, their influence on users' decision-making remains under-investigated. Methodological approaches to evaluating usage and usability of portals showed room for improvement. To unlock the potential of patient portals, more (robust) research should focus on better understanding the complex process of how portals lead to improved health and care. PMID- 29425622 TI - Prevalence of computerized physician order entry systems-related medication prescription errors: A systematic review. AB - OBJECTIVE: The positive impact of computerized physician order entry (CPOE) systems on prescription safety must be considered in light of the persistence of certain types of medication-prescription errors. We performed a systematic review, based on the PRISMA statement, to analyze the prevalence of prescription errors related to the use of CPOE systems. MATERIALS AND METHODS: We searched MEDLINE, EMBASE, CENTRAL, DBLP, the International Clinical Trials Registry, the ISI Web of Science, and reference lists of relevant articles from March 1982 to August 2017. We included original peer-reviewed studies which quantitatively reported medication-prescription errors related to CPOE. We analyzed the prevalence of medication-prescription errors according to an adapted version of the National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) taxonomy and assessed the mechanisms responsible for each type of prescription error due to CPOE. RESULTS: Fourteen studies were included. The prevalence of CPOE systems-related medication errors relative to all prescription medication errors ranged from 6.1 to 77.7% (median = 26.1% [IQR:17.6-42,1]) and was less than 6.3% relative to the number of prescriptions reviewed. All studies reported "wrong dose" and "wrong drug" errors. The "wrong dose" error was the most frequently reported (from 7 to 67.4%, median = 31.5% [IQR:20.5-44.5]). We report the associated mechanism for each type of medication described (those due to CPOE or those occurring despite CPOE). DISCUSSION: We observed very heterogeneous results, probably due to the definition of error, the type of health information system used for the study, and the data collection method used. Each data collection method provides valuable and useful information concerning the prevalence and specific types of errors related to CPOE systems. CONCLUSIONS: The reporting of prescription errors should be continued because the weaknesses of CPOE systems are potential sources of error. Analysis of the mechanisms behind CPOE errors can reveal areas for improvement. PMID- 29425623 TI - Why hospitals adopt patient engagement functionalities at different speeds? A moderated trend analysis. AB - OBJECTIVE: To investigate acute care hospitals' adoption speed of patient engagement health information technology (HIT) functionalities from 2008 to 2013 and how this speed is contingent on environmental factors and hospital characteristics. METHODS: Data on non-government acute care hospitals located in the United States was obtained from merging three databases: the American Hospital Association's (AHA) annual survey information technology supplement, AHA annual survey, and the Area Health Resource File (AHRF). The variables obtained from these datasets were the amount of annually adopted patient engagement HIT functionalities and environmental and organizational characteristics. Environmental factors included were uncertainty, munificence, and complexity. Hospital characteristics included size, system membership, ownership, and teaching status. RESULTS: A regression analysis of 4176 hospital-year observations revealed a positive trend in the adoption of HIT functionalities for patient engagement (beta= 1.109, p < 0.05). Moreover, the study showed that large, system-affiliated, not-for-profit, teaching hospitals adopt patient engagement HIT functionalities at a faster speed than their counterparts. Environmental munificence and uncertainty were also associated with an accelerating speed of adoption. Environmental complexity however did not show a significant impact on the speed of adoption. DISCUSSION: From 2008 to 2013, there was a significant acceleration in the speed of adopting patient engagement HIT functionalities. Further efforts should be made to ensure proper adoption and consistent use by patients in order to reap the benefits of these IT investments. CONCLUSION: Hospitals adopted at least one HIT functionality for patient engagement per year. The adoption speed varied across hospitals, depending on both environmental and organizational factors. PMID- 29425624 TI - Internet and social media use for antibiotic-related information seeking: Findings from a survey among adult population in Italy. AB - BACKGROUND: The Internet represents an increasingly common source of health related information. Internet and Social Media can be used to promote a prudent use of antibiotics. OBJECTIVE: To establish the extent of Internet and Social Media use to search for antibiotic related information and the potential implications in health care among adult population in Italy. METHODS: This cross sectional study was conducted from March to May 2017, among a sample of parents of public school students. A 2-stage cluster sample design was planned. An informed consent form and a questionnaire were given to selected students to deliver to their parents. The questionnaire included questions on knowledge, attitudes, and behavior toward antibiotic use, and questions about Internet use to gather information about antibiotics. RESULTS: A total of 913 parents completed the questionnaire, with a 67.4% response rate; 22.1% did not know when it was appropriate to use antibiotics. 32.3% of parents reported self-medication with antibiotics. 73.4% of respondents used the Internet to search for information about antibiotic use. Among social networks users, 46.5% reported the use of these media to get information about antibiotics and 45% of instant messaging app users share information about antibiotics. The results of the multiple logistic regression analysis showed that Internet use to search for antibiotic-related information was higher among females, younger subjects, with a higher level of education, in those who reported self-medication with antibiotics and in those who needed additional information on side effects of antibiotics from the GP compared with those who did not need any additional information. Internet use was significantly less likely in participants with cardiovascular diseases and cancer compared with those without chronic conditions, and in those who reported to strongly agree/agree, or were uncertain about antibiotic use without a GP prescription, compared with those who reported to be disagree/strongly disagree. CONCLUSIONS: Internet and social media are widely used for antibiotic-related information seeking in the Italian population. Health organizations must consider social media within their communication strategy to promote the appropriate Web use for antibiotic-related information seeking in the general population, although more evidence is needed regarding the optimal mix of communication interventions. PMID- 29425625 TI - Information extraction from Italian medical reports: An ontology-driven approach. AB - OBJECTIVE: In this work, we propose an ontology-driven approach to identify events and their attributes from episodes of care included in medical reports written in Italian. For this language, shared resources for clinical information extraction are not easily accessible. MATERIALS AND METHODS: The corpus considered in this work includes 5432 non-annotated medical reports belonging to patients with rare arrhythmias. To guide the information extraction process, we built a domain-specific ontology that includes the events and the attributes to be extracted, with related regular expressions. The ontology and the annotation system were constructed on a development set, while the performance was evaluated on an independent test set. As a gold standard, we considered a manually curated hospital database named TRIAD, which stores most of the information written in reports. RESULTS: The proposed approach performs well on the considered Italian medical corpus, with a percentage of correct annotations above 90% for most considered clinical events. We also assessed the possibility to adapt the system to the analysis of another language (i.e., English), with promising results. DISCUSSION AND CONCLUSION: Our annotation system relies on a domain ontology to extract and link information in clinical text. We developed an ontology that can be easily enriched and translated, and the system performs well on the considered task. In the future, it could be successfully used to automatically populate the TRIAD database. PMID- 29425626 TI - Emergency information management needs and practices of older adults: A descriptive study. AB - OBJECTIVE: To better understand how older adults currently manage emergency information, the barriers and facilitators to planning and management of emergency information, as well as the potential role of information technology to facilitate emergency planning and management. INTRODUCTION: Older adults face a much higher risk of sudden illness/injury and are the age group with the largest percentages of emergent and urgent healthcare visits. Emergency information (health information needed in an emergency situation such as emergency contact information, diagnoses, and advance directives) needs to be maintained and easily accessible to ensure older adults get appropriate care and treatment consistent with their wishes in emergency situations. Current health information technologies rarely take into consideration the emergency information needs of older adults, their caregivers, and emergency responders. METHODS: As part of a larger study we performed in-depth interviews with 90 older adults living in a variety of residential settings (independent living, retirement communities, assisted living) regarding how they manage information about their health. Interview sessions included photos of important health information artifacts. Interviews were transcribed and coded. RESULTS: Analysis of in-depth interviews revealed that emergency information is a type of health information that older adults frequently manage. Participants differed in whether they practice emergency planning (e.g. the preparation and continued management of emergency information), and in whether they involve others in emergency information and emergency planning. Despite its importance, emergency information was often not up-to-date and not always kept in locations readily apparent to emergency responders. CONCLUSION: Emergency information, such as emergency contact information, diagnoses, and advance directives, is a type of health information that older adults manage. Considering emergency information in the design of health information technologies for older adults could address some of the barriers and support the facilitators to emergency planning and information management. PMID- 29425627 TI - Predicting post-stroke activities of daily living through a machine learning based approach on initiating rehabilitation. AB - OBJECTIVES: Prediction of activities of daily living (ADL) is crucial for optimized care of post-stroke patients. However, no suitably-validated and practical models are currently available in clinical practice. METHODS: Participants of a Post-acute Care-Cerebrovascular Diseases (PAC-CVD) program from a reference hospital in Taiwan between 2014 and 2016 were enrolled in this study. Based on 15 rehabilitation assessments, machine learning (ML) methods, namely logistic regression (LR), support vector machine (SVM), and random forest (RF), were used to predict the Barthel index (BI) status at discharge. Furthermore, SVM and linear regression were used to predict the actual BI scores at discharge. RESULTS: A total of 313 individuals (men: 208; women: 105) were enrolled in the study. All the classification models outperformed single assessments in predicting the BI statuses of the patients at discharge. The performance of the LR and RF algorithms was higher (area under ROC curve (AUC): 0.79) than that of SVM algorithm (AUC: 0.77). In addition, the mean absolute errors of both SVM and linear regression models in predicting the actual BI score at discharge were 9.86 and 9.95, respectively. CONCLUSIONS: The proposed ML-based method provides a promising and practical computer-assisted decision making tool for predicting ADL in clinical practice. PMID- 29425628 TI - High-priority and low-priority drug-drug interactions in different international electronic health record systems: A comparative study. AB - OBJECTIVES: To investigate whether alert warnings for high-priority and low priority drug-drug interactions (DDIs) were present in five international electronic health record (EHR) systems, to compare and contrast the severity level assigned to them, and to establish the proportion of alerts that were overridden. METHODS: We conducted a comparative, retrospective, multinational study using a convenience sample of 5 EHRs from the U.S., U.K., Republic of Korea and Belgium. RESULTS: Of the 15 previously defined, high-priority, class-based DDIs, alert warnings were found to exist for 11 in both the Korean and UK systems, 9 in the Belgian system, and all 15 in the two US systems. The specific combinations that were included in these class-based DDIs varied considerably in number, type and level of severity amongst systems. Alerts were only active for 8.4% (52/619) and 52.4% (111/212) of the specific drug-drug combinations contained in the Belgian and UK systems, respectively. Hard stops (not possible to override) existed in the US and UK systems only. The override rates for high priority alerts requiring provider action ranged from 56.7% to 83.3%. Of the 33 previously defined low-priority DDIs, active alerts existed only in the US systems, for three class-based DDIs. The majority were non-interruptive. CONCLUSIONS: Alert warnings existed for most of the high-priority DDIs in the different EHRs but overriding them was easy in most of the systems. In addition to validating the high- and low-priority DDIs, this study reported a lack of standardization in DDI levels across different international knowledge bases. PMID- 29425629 TI - WhatsApp Use In The Evaluation of Hematuria. AB - INTRODUCTION: The advancements in telemedicine provide the possibility to send photos of hematuria cases to professionals for further evaluation. We aimed to evaluate the inter-rater reliability of WhatsApp use in the evaluation of hematuria. MATERIALS AND METHODS: Between December 2014 and April 2016, 212 patients were evaluated prospectively for hematuria by 2 groups of urologists; Group A: in direct contact with patients for evaluation; Group B: "blind" urologist who had no access to the patients' data but received pictures via WhatsApp. Two photos of voided urine in a sterile container were taken and sent using WhatsApp. The opinions of Group A and B about the grade of hematuria were evaluated. Shapiro-Wilk test and Fleiss' kappa statistics were used for statistical analyses. RESULTS: The median age of patients was 71 (min 22, max 96). The Group A urologists were in accordance in 96.22% of cases. Group B urologists had common opinions in 99.5% (n = 203) and there was almost perfect agreement between 2 groups (lambda = 0.992). The number of common opinions among "blind" urologists is more than the number of common opinions among the consultants. When further classification is performed as serious and non-serious hematuria, the rate of misdiagnosing serious cases is approximately 6.5-7%. However, using WhatsApp, the urologists can differentiate normal urine and any form of hematuria with 100% accuracy. CONCLUSION: It is possible to evaluate hematuria remotely and also reduce unnecessary costs of services for hematuria of mild clinical significance by using telemedicine. WhatsApp can provide valuable aid to tertiary hospitals where the urologist is not always present as well as in rural areas. PMID- 29425630 TI - Research on gender differences in online health communities. AB - With the growing concern about health issues and the emergence of online communities based on user-generated content (UGC), more and more people are participating in online health communities (OHCs) to exchange opinions and health information. This paper aims to examine whether and how male and female users behave differently in OHCs. Using data from a leading diabetes community in China (Tianmijiayuan), we incorporate three different techniques: topic modeling analysis, sentiment analysis and friendship network analysis to investigate gender differences in chronic online health communities. The results indicated that (1) Male users' posting content was usually more professional and included more medical terms. Comparatively speaking, female users were more inclined to seek emotional support in the health communities. (2) Female users expressed more negative emotions than male users did, especially anxiety and sadness. (3) In addition, male users were more centered and influential in the friendship network than were women. Through these analyses, our research revealed the behavioral characteristics and needs for different gender users in online health communities. Gaining a deeper understanding of gender differences in OHCs can serve as guidance to better meet the information needs, emotional needs and relationship needs of male and female patients. PMID- 29425631 TI - Combining spatial information and optimization for locating emergency medical service stations: A case study for Lower Austria. AB - OBJECTIVES: Emergency medical services have been established in many countries all over the world. Good first care improves the outcome of patients in terms of hospital stay duration, chances of full recovery and of treatment costs. In this paper, we present an integrated approach combining spatial information and integer optimization for emergency medical service location planning. The research is motivated by a recent call for bids to restructure the location of emergency medical services in the Austrian federal state of Lower Austria by the local state government. METHODS: Our framework allows for constraints on the places where an emergency care physician is stationed, accounting for the fact that - for economical reasons - it might not be feasible to arbitrarily place emergency care physicians. We use maximum coverage linear programs to get accurate solutions for the problem instances (depending on the maximum allowed number of emergency care physicians and the constraints of their placement). We optimize for the maximum number of covered residents given certain parameters. The travelling distances are calculated by means of a digital road graph. Moreover we analyze the coverage of the day population as there are significant shifts in the number of persons present at daytime. For every problem instance we have calculated the ten best solutions and examined the variance among them. For the demand point aggregation we have used a cell grid. RESULTS: Using our method we can show that with less emergency care physicians more residents can be covered. This is highly applicable to low populated areas where the coverage becomes better. There is little variance from the best to the second best solution: There are only small changes (usually only one cell is shifted) between the best and the second best solution. The coverage of the day population - except for a few problem instances - is always better than the coverage of the residents (reflecting the fact that many residents commute to more densely populated areas). CONCLUSIONS: In our study, we show that our solutions provide better coverage of residents with fewer emergency care physicians than the current status quo. PMID- 29425632 TI - Electronic health record on the go: Device form factor and Fitts' law. AB - PURPOSE: With electronic health records (EHRs) becoming ubiquitous, computer use in exam rooms during patient-provider interactions is commonplace. Although computer use brings many benefits to providers, and patients generally rate computer-use as having a positive impact, the use of mobile devices could eliminate existing issues, for example allowing providers to enter or review records while face-to-face with patients. Using mobile devices increases flexibility of providers, but also creates challenges associated with the mobile device itself. For example, the form factor (i.e., display size) of the mobile device may affect provider performance, satisfaction and usability of the EHR. This study assessed the impact of the device form factor on usability of the EHR by measuring the most commonly used devices. This question relates to the applicability of Fitts' law, which does not predict differences in usability of devices varying in their form factor, assuming a linear scaling of the user interface. PROCEDURES: Health care providers participated in this study by performing common EHR related tasks using devices differing in their form factor. Each participant performed these tasks on each of the devices. Interaction with a desktop computer served as baseline. RESULTS: Usability and task load ratings for all mobile devices were significantly lower than for the desktop. Among the mobile devices, the iPad with its largest form factors performed best, where the iPhone performed the worst. The time to complete the tasks revealed that the mobile devices took more time to complete the tasks with the iPad requiring the least time among the mobile devices. Finally, in terms of error rates, all mobile devices had a significantly higher error rate than the desktop control. Again, the lowest error rate was observed with the devices that had the largest form factor. CONCLUSIONS: The results of this study suggest that the form factor of mobile devices is of critical importance for usability and task performance with none of the mobile devices performing as well as the desktop. In addition, it appears that Fitt's law requires some additional examination in the context of touch screen devices. Given these results, challenges associated with mobile access to the EHR exist that need to be addressed in the future. PMID- 29425633 TI - Electronic medical records as a replacement for prospective research data collection in postoperative pain and opioid response studies. AB - BACKGROUND AND AIM: Many clinical research studies claim to collect data that are also captured in the electronic medical record (EMR). We evaluate the potential for EMR data to replace prospective research data collection. METHODS: Using a dataset of 358 surgical patients enrolled in a prospective study, we examined the completeness and agreement of EMR and study entries for several variables, including the patient's stay in the post-operative care unit (PACU), surgical pain relief and pain medication side effects. RESULTS: For all variables with a completeness percentage, values were greater than 96%. For the adverse event variables, we found slight to substantial agreement (Cohen's kappa), ranging from 0.19 (nausea) to 0.48 (respiratory depression) to 0.73 (emesis). CONCLUSION: The potential to use EMR data as a replacement for prospective research data collection shows promise, but for now, should be evaluated on a variable-by variable basis. PMID- 29425634 TI - Quantifying medical student clinical experiences via an ICD Code Logging App. AB - OBJECTIVES: The logging of ICD Diagnostic, Procedure and Drug codes is one means of tracking the experience of medical students' clinical rotations. The goal is to create a web-based computer and mobile application to track the progress of trainees, monitor the effectiveness of their training locations and be a means of sampling public health status. MATERIALS AND METHODS: We have developed a web based app in which medical trainees make entries via a simple and quick interface optimized for both mobile devices and personal computers. For each patient interaction, users enter ICD diagnostic, procedure, and drug codes via a hierarchical or search entry interface, as well as patient demographics (age range and gender, but no personal identifiers), and free-text notes. Users and administrators can review and edit input via a series of output interfaces. The user interface and back-end database are provided via dual redundant failover Linux servers. RESULTS AND DISCUSSION: Students master the interface in ten minutes, and thereafter complete entries in less than one minute. Five hundred forty 3rd year VCOM students each averaged 100 entries in the first four week clinical rotation. Data accumulated in various Appalachian clinics and Central American medical mission trips has demonstrated the public health surveillance utility of the application. CONCLUSION: PC and mobile apps can be used to collect medical trainee experience in real time or near real-time, quickly, and efficiently. This system has collected 75,596 entries to date, less than 2% of trainees have needed assistance to become proficient, and medical school administrators are using the various summaries to evaluate students and compare different rotation sites. PMID- 29425635 TI - The state of knowledge on technologies and their use for fall detection: A scoping review. AB - BACKGROUND: Globally, populations are aging with increasing life spans. The normal aging process and the resulting disabilities increase fall risks. Falls are an important cause of injury, loss of independence and institutionalization. Technologies have been developed to detect falls and reduce their consequences but their use and impact on quality of life remain debatable. Reviews on fall detection technologies exist but are not extensive. A comprehensive literature review on the state of knowledge of fall detection technologies can inform research, practice, and user adoption. OBJECTIVES: To examine the extent and the diversity of current technologies for fall detection in older adults. METHODS: A scoping review design was used to search peer-reviewed literature on technologies to detect falls, published in English, French or Spanish since 2006. Data from the studies were analyzed descriptively. RESULTS: The literature search identified 3202 studies of which 118 were included for analysis. Ten types of technologies were identified ranging from wearable (e.g., inertial sensors) to ambient sensors (e.g., vision sensors). Their Technology Readiness Level was low (mean 4.54 SD 1.25; 95% CI [4.31, 4.77] out of a maximum of 9). Outcomes were typically evaluated on technological basis and in controlled environments. Few were evaluated in home settings or care units with older adults. Acceptability, implementation cost and barriers were seldom addressed. CONCLUSIONS: Further research should focus on increasing Technology Readiness Levels of fall detection technologies by testing them in real-life settings with older adults. PMID- 29425636 TI - Computerised decision support in physical activity interventions: A systematic literature review. AB - BACKGROUND: The benefits of regular physical activity for health and quality of life are unarguable. New information, sensing and communication technologies have the potential to play a critical role in computerised decision support and coaching for physical activity. OBJECTIVES: We provide a literature review of recent research in the development of physical activity interventions employing computerised decision support, their feasibility and effectiveness in healthy and diseased individuals, and map out challenges and future research directions. METHODS: We searched the bibliographic databases of PubMed and Scopus to identify physical activity interventions with computerised decision support utilised in a real-life context. Studies were synthesized according to the target user group, the technological format (e.g., web-based or mobile-based) and decision-support features of the intervention, the theoretical model for decision support in health behaviour change, the study design, the primary outcome, the number of participants and their engagement with the intervention, as well as the total follow-up duration. RESULTS: From the 24 studies included in the review, the highest percentage (n = 7, 29%) targeted sedentary healthy individuals followed by patients with prediabetes/diabetes (n = 4, 17%) or overweight individuals (n = 4, 17%). Most randomized controlled trials reported significantly positive effects of the interventions, i.e., increase in physical activity (n = 7, 100%) for 7 studies assessing physical activity measures, weight loss (n = 3, 75%) for 4 studies assessing diet, and reductions in glycosylated hemoglobin (n = 2, 66%) for 3 studies assessing glycose concentration. Accelerometers/pedometers were used in almost half of the studies (n = 11, 46%). Most adopted decision support features included personalised goal-setting (n = 16, 67%) and motivational feedback sent to the users (n = 15, 63%). Fewer adopted features were integration with electronic health records (n = 3, 13%) and alerts sent to caregivers (n = 4, 17%). Theoretical models of decision support in health behaviour to drive the development of the intervention were not reported in most studies (n = 14, 58%). CONCLUSIONS: Interventions employing computerised decision support have the potential to promote physical activity and result in health benefits for both diseased and healthy individuals, and help healthcare providers to monitor patients more closely. Objectively measured activity through sensing devices, integration with clinical systems used by healthcare providers and theoretical frameworks for health behaviour change need to be employed in a larger scale in future studies in order to realise the development of evidence-based computerised systems for physical activity monitoring and coaching. PMID- 29425637 TI - Population exacerbation incidence contains predictive information of acute exacerbations in patients with chronic obstructive pulmonary disease in telecare. AB - OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major global burden largely resulting from acute exacerbations. We investigated whether the incidences of patient and population exacerbations contain predictive information for continuous prediction of exacerbations in COPD patients. METHODS: Data analysis was performed using home measurements from 1225 patients included in the large-scale telehomecare trial TeleCare North, where data supported 84 exacerbations occurring in 57 patients. Twenty-nine predictors were extracted and validated in two prediction models based on logistic regression. One model without and one model with inclusion of patient and population exacerbation incidences as potential predictors. The predictors were then evaluated by discriminative abilities between periods with and without exacerbation. RESULTS: The optimal predictor combinations provided an average area under the receiver operation characteristics curve of 0.63 with exclusion; inclusion of the population exacerbation incidence provided a curve of 0.74 (p < 0.05). These results were based on a two-fold patient dependent cross-validation. DISCUSSION: The present study has presented how the population exacerbation incidence contains predictive information in the continuous prediction of exacerbations in COPD patients. A system capable of predicting acute exacerbations could potentially prevent some cases of COPD-related complications and increase the health-related quality of life among COPD patients in telecare. PMID- 29425638 TI - Mapping the Dutch SNOMED CT subset to Omaha System, NANDA International and International Classification of Functioning, Disability and Health. AB - BACKGROUND: Nurses register data in electronic health records, which can use various terminology and coding systems. The net result is that information cannot be exchanged and reused properly, for example when a patient is transferred from one care setting to another. A nursing subset of patient problems was therefore developed in the Netherlands, based on comparable and exchangeable terms that are used throughout the healthcare sector and elsewhere (semantic interoperability). The purpose of the current research is to develop a mapping between the subset of patient problems and three classifications in order to improve the exchangeability of data. Those classifications are the Omaha System, NANDA International, and ICF (the International Classification of Functioning, Disability and Health). METHOD: Descriptive research using a unidirectional mapping strategy. RESULTS: Some 30%-39% of the 119 SNOMED CT patient problems can be mapped one-to-one from the subset onto each separate classification. Between 6% and 8% have been mapped partially to a related term. This is considered to be a one-to-one mapping, although the meanings do not correspond fully. Additionally, 23%-51% of the patient problems could be mapped n-to-one, i.e. more specifically than the classification. Some loss of information will always occur in such exchanges. Between 1% and 4% of the patient problems from the subset are defined less specifically than the problems within the individual classifications. Finally, it turns out that 9%-32% of the terms from the subset of patient problems could not be mapped onto a classification, either because they did not occur in the classification or because they could not be mapped at a higher level. CONCLUSION: To promote the exchange of data, the subset of patient problems has been mapped onto three classifications. Loss of information occurs in most cases when the patient problems are transformed from the subset into a classification. This arises because the classifications are different in structure and in the degree of detail. Structural cooperation between suppliers, healthcare organisations and the experts involved is required in order to determine how the mapping should be used within the electronic health records, and whether it is usable in day-to-day practice. PMID- 29425640 TI - Prediction models to identify individuals at risk of metabolic syndrome who are unlikely to participate in a health intervention program. AB - OBJECTIVES: Since the launch of a nationwide general health check-up and instruction program in Japan in 2008, interest in strategies to improve implementation of the program based on predictive analytics has grown. We investigated the performance of prediction models developed to identify individuals classified as "requiring instruction" (high-risk) who were unlikely to participate in a health intervention program. METHODS: Data were obtained from one large health insurance union in Japan. The study population included individuals who underwent at least one general health check-up between 2008 and 2013 and were identified as "requiring instruction" in 2013. We developed three prediction models based on the gradient boosted trees (GBT), random forest (RF), and logistic regression (LR) algorithms using machine-learning techniques and compared the areas under the curve (AUC) of the developed models with those of two conventional methods The aim of the models was to identify at-risk individuals who were unlikely to participate in the instruction program in 2013 after being classified as requiring instruction at their general health check-up that year. RESULTS: At first we performed the analysis using data without multiple imputation. The AUC values for the GBT, RF, and LR prediction models and conventional methods: 1, and 2 were 0.893 (95%CI: 0.882-0.905), 0.889 (95%CI: 0.877-0.901), 0.885 (95%CI: 0.872-0.897), 0.784 (95%CI: 0.767-0.800), and 0.757 (95%CI: 0.741-0.773), respectively. Subsequently, we performed the analysis using data after multiple imputation. The AUC values for the GBT, RF, and LR prediction models and conventional methods: 1, and 2 were 0.894 (95%CI: 0.882-0.906), 0.889 (95%CI: 0.887-0.901), 0.885 (95%CI: 0.872-0.898), 0.784 (95%CI: 0.767-0.800), and 0.757 (95%CI: 0.741-0.773), respectively. In both analyses, the GBT model showed the highest AUC among that of other models, and statistically significant difference were found in comparison with the LR model, conventional method 1, and conventional method 2. CONCLUSION: The prediction models using machine-learning techniques outperformed existing conventional methods: for predicting participation in the instruction program among participants identified as "requiring instruction" (high-risk). PMID- 29425639 TI - Natural language processing of clinical notes for identification of critical limb ischemia. AB - BACKGROUND: Critical limb ischemia (CLI) is a complication of advanced peripheral artery disease (PAD) with diagnosis based on the presence of clinical signs and symptoms. However, automated identification of cases from electronic health records (EHRs) is challenging due to absence of a single definitive International Classification of Diseases (ICD-9 or ICD-10) code for CLI. METHODS AND RESULTS: In this study, we extend a previously validated natural language processing (NLP) algorithm for PAD identification to develop and validate a subphenotyping NLP algorithm (CLI-NLP) for identification of CLI cases from clinical notes. We compared performance of the CLI-NLP algorithm with CLI-related ICD-9 billing codes. The gold standard for validation was human abstraction of clinical notes from EHRs. Compared to billing codes the CLI-NLP algorithm had higher positive predictive value (PPV) (CLI-NLP 96%, billing codes 67%, p < 0.001), specificity (CLI-NLP 98%, billing codes 74%, p < 0.001) and F1-score (CLI-NLP 90%, billing codes 76%, p < 0.001). The sensitivity of these two methods was similar (CLI-NLP 84%; billing codes 88%; p < 0.12). CONCLUSIONS: The CLI-NLP algorithm for identification of CLI from narrative clinical notes in an EHR had excellent PPV and has potential for translation to patient care as it will enable automated identification of CLI cases for quality projects, clinical decision support tools and support a learning healthcare system. PMID- 29425641 TI - Cardioprotection of Sheng Mai Yin a classic formula on adriamycin induced myocardial injury in Wistar rats. AB - BACKGROUND: Sheng Mai Yin (SMY), a well-known Chinese herbal medicine, is widely used to treat cardiac diseases characterized by the deficiency of Qi and Yin syndrome in China. SMY-based treatment has been derived from Traditional Chinese Medicine (TCM), officially recorded in the Chinese Pharmacopoeia. PURPOSE: We aimed to clarify whether SMY attenuates myocardial injury induced by adriamycin in Wistar rats with chronic heart failure (CHF). METHODS: To quantify ginsenoside Rg1, ophiopogonin D, ophiopogonin D', schisandrin by HPLC. To establish CHF animal model, adriamycin was intraperitoneally injected in Wistar rats for 7 weeks at a dose of 2 mg/kg body weight. Overall, 180 rats were randomly assigned to six groups: control, CHF model, captopril (positive control), high dose (HSMY), medium dose (MSMY), and low dose (LSMY). Experimental rats were fed 0.625 mg/kg captopril and 90 mg/kg, 45 mg/kg, and 22.5 mg/kg SMY, respectively, over 7 weeks. The inflammatory cytokines TNF-alpha and IL-6 were measured using ELISA. Matrix metalloproteinases (MMPs) were identified using immunohistochemistry (IHC). Both IHC and RT-PCR were used for quantification of COL-IV expression levels in the heart tissues. Scanning electron microscopy (SEM) was used for the visualization of myocardium morphology. RESULTS: The concentration of ginsenoside Rg1, ophiopogonin D, ophiopogonin D' and schisandrin in SMY was found to be 25.63 +/- 3.42 mg, 11.00 +/- 1.17 mg, 7.02 +/- 0.51 mg, and 25.31 +/- 4.28 mg per gram of SMY, respectively. Compared with CHF model group, TNF-alpha levels were significantly lower (p < .01) in the four drug-administered groups. Moreover, except in the SYM low dose group, IL-6 levels in the other 3 drug-administered groups were also significantly reduced (p < .01). COL-IV expression was also significantly reduced on treatment with high SYM dose (p < .05). IHC results confirmed that SMY and captopril significantly reduced MMPs expression in the heart. CONCLUSION: SMY could control or slow CHF progression by suppressing pathological changes in the myocardium in CHF models. This could be attributed at least partly to the downregulation of IL-6 and TNF-alpha and inhibition of overexpression of MMPs and COL-IV, which significantly relieved the cardiac linked pathologies, decreased the risk of myocardial fibrosis, and inhibited cardiac remodeling. These findings suggested that SMY and captopril have similar efficacy for the treatment of adriamycin-induced myocardial injury. In addition, Chinese herbal preparation SMY may play a role in the treatment of cardiac diseases. PMID- 29425642 TI - Effect of dioscin on promoting liver regeneration via activating Notch1/Jagged1 signal pathway. AB - BACKGROUND: Development of novel candidates to promote liver regeneration is critical important after partial hepatectomy (PH). Dioscin, a natural product, shows potent effect on liver protection in our previous works. PURPOSE: This work aimed to investigate the effect and underlying mechanisms of dioscin on liver regeneration. METHODS: The promoting proliferation effects of dioscin on mouse hepatocytem AML12 cells, rat primary hepatocytes, rats and mice after 70% PH were evaluated. RESULTS: Dioscin significantly promoted proliferation of rat primary hepatocytes and AML12 cells through MTT, BrdU and PCNA staining assays. Meanwhile, dioscin rapidly recovered the liver to body weight ratios, declined ALT and AST levels, and relieved hepatocytes necrosis compared with 70% PH operation groups in rats and mice. Mechanistic test showed that dioscin significantly increased Notch1 and Jagged1 levels, and accelerated gamma secretase activity by up-regulating PS1 expression, leading to nuclear translocation of Notch1 intracellular domain (NICD1). Subsequently, the significant activation of Notch-dependent target genes (Hey1, Hes1, EGFR, VEGF), and cell-cycle regulatory proteins (CyclinD1, CyclinE1, CDK4 and CDK2) were all recognized. In addition, these results were further confirmed by Notch1 siRNA silencing and inhibition of gamma-secretase by DAPT (a well-characterized gamma secretase inhibitor) in vitro. CONCLUSIONS: Dioscin, as a novel efficient gamma secretase activator, NICD1 nucleus translocation promoter and cell cycle regulator, markedly activated Notch1/Jagged1 pathway to promote hepato proliferation. Our findings provide novel insights into dioscin as a natural product with facilitating liver regeneration after PH. PMID- 29425643 TI - Biological activity and chemical profile of Lavatera thuringiaca L. extracts obtained by different extraction approaches. AB - BACKGROUND: Lavatera thuringiaca L. is herbaceous perennial plant from Malvaceae family, which is known for its biological activity and richness in polyphenolic compounds. Despite this, the information regarding the biological activity and chemical profile is still insufficient. PURPOSE: Aim of this study was to investigate biological potential and chemical profile of Lavatera thuringiaca L., as well as influence of applied extraction technique on them. STUDY DESIGN AND METHODS: Two conventional and four non-conventional extraction techniques were applied in order to obtain extracts rich in bioactive compound. Extracts were further tested for total phenolics, flavonoids, condensed tannins, gallotannins and anthocyanins contents using spectrophotometric assays. Polyphenolic profile was established using HPLC-DAD analysis. Biological activity was investigated regarding antioxidant, cytotoxic and antibacterial activities. Four antioxidant assays were applied as well as three different cell lines for cytotoxic and fifteen bacterial strain for antibacterial activity. RESULTS AND CONCLUSION: Results showed that subcritical water extraction (SCW) dominated over the other extraction techniques, where SCW extract exhibited the highest biological activity. Study indicates that plant Lavatera thuringiaca L. may be used as a potential source of biologically compounds. PMID- 29425644 TI - Ligustilide attenuates vascular inflammation and activates Nrf2/HO-1 induction and, NO synthesis in HUVECs. AB - BACKGROUND: Ligustilide is a bioactive phthalide derivative isolated from Cnidii Rhizoma (Cnidium officinale, rhizome) and Angelicae Gigantis Radix (Angelica gigas Nakai, root) which are both medicinal herbs used to treat circulatory disorders. Vascular endothelium is a central spot in developing cardiovascular diseases and chronic vascular inflammation might result in atherosclerosis development. PURPOSE: We previously found out that a traditional herbal formula, Samul-Tang (Si-Wu-Tang, containing Cnidii Rhizoma and Angelicae Gigantis Radix), attenuated vascular inflammation in human umbilical vein endothelial cells (HUVECs). However, which compound was responsible for vascular protective action remained unclear. Here, we investigated vascular protective potential of an isolated single compound, (Z)-ligustilide. METHODS: MTT assay, western blotting, immunofluorescence, electrophoretic mobility shift assay was performed. BCECF-AM, CM-H2DCFDA, DAF-FM diacetate were used as a fluorescent indicator. RESULTS: Ligustilide suppressed HL-60 monocyte adhesion and CAMs (ICAM-1, VCAM-1, E selectin) expression in HUVECs. Ligustilide significantly inhibited TNF-alpha increased production of ROS and activated NF-kappaB signaling pathway. Also, ligustilide treated HUVECs exhibited significant HO-1 induction via Nrf2 nuclear translocation and endothelial NO synthesis. CONCLUSION: Present study demonstrates that ligustilde attenuates vascular inflammation and activate defense system of endothelial cell. Ligustilide is a bioactive compound which might prevent cardiovascular complications such as thrombosis or atherosclerosis. PMID- 29425645 TI - Repeated administration of Sailuotong, a fixed combination of Panax ginseng, Ginkgo biloba, and Crocus sativus extracts for vascular dementia, alters CYP450 activities in rats. AB - BACKGROUND: Sailuotong (SLT) is a standard Chinese preparation made from extracts of Panax ginseng (ginseng), Ginkgo biloba (ginkgo), and Crocus sativus (saffron). Preliminary clinical trials and animal experiments have demonstrated that SLT could improve cognition of vascular dementia (VD). PURPOSE: To avoid incident drug-drug interaction which is easily encountered in patients of VD, the potential influence of SLT on main drug-metabolic cytochromes P450 enzymes (CYP450) was investigated. METHOD: A "cocktail probes" approach was employed to evaluate the activities of CYP450. A rapid and selective analysis method was developed to examine 5 CYP probe drugs and their specific metabolites in plasma by using online SPE followed by a single LC-MS/MS run. After pretreatment for 2 weeks with SLT, ginseng, gingko, saffron or water (control), a cocktail solution containing caffeine, losartan, omeprazole, dextromethorphan and midazolam was given to rats orally. The plasma was obtained at different time intervals and then measured for the concentration of probes and their metabolites using developed SPE-LC-MS/MS method. Activity of five isozymes was estimated by comparing plasma pharmacokinetics of substrates and their metabolites (caffeine/paraxanthine for CYP1A2, losartan/E-3174 for CYP2C11, omeprazole/5 hydroxyl omeprazole for CYP2C6, dextromethorphan/dextrophan for CYP2D2 and midazolam/1-hydroxyl midazolam for CYP3A1/2) between control and drug treatment groups. RESULT: Compared with control group, repeated administration of SLT induced CYP1A2 by enhancing AUC paraxanthine / AUC caffeine to144%. The influence is attributed to its herbal component of ginseng to a large extent. Meanwhile, metabolic ability towards losartan was significantly elevated in SLT and gingko group by 31% and 25% respectively, indicating weak induction of CYP2C11 in rats. The analysis on probes of omeprazole and dextromethorphan showed a lack of influence on CYP 2C6 and CYP2D2 in all treated groups. In terms of CYP3A1/2, SLT decreased AUC ratio of 1-hydroxyl midazolam to midazolam by 39% and extended the half-life of midazolam apparently. Besides, significantly decreased systematic exposure of midazolam suggested the inhibition on metabolism of CYP3A1/2 is likely secondary to the interaction on absorption at intestinal level. The inhibition of SLT on CYP3A was likely attributed to ginseng and gingko cooperatively. CONCLUSION: Further observation on herb-drug interaction should be considered during clinical application of SLT. PMID- 29425647 TI - Predicting tyrosinase inhibition by 3D QSAR pharmacophore models and designing potential tyrosinase inhibitors from Traditional Chinese medicine database. AB - BACKGROUND: Tyrosinase plays a key role in the formation of skin melanin. The excessive accumulation of skin melanin will cause the serious aesthetic problems for human beings. HYPOTHESIS/PURPOSE: To find the potent tyrosinase inhibitors using computational simulation from TCM Database@Taiwan. STUDY DESIGN: Inhibitors of tyrosinase have been thought as potential drugs for the decrease of melanin synthesis in the process of pigmentation. To develop new tyrosinase inhibitors, we performed a virtual screening from Traditional Chinese medicine (TCM) and Druglike Databases using the best 3D QSAR pharmacophore model as a 3D search query. METHODS: A total of 109 compounds were obtained after filtering by Lipinski's rule of five. Finally, 148 compounds (22 from training set, 17 from test set, 109 from TCM and Druglike databases) were selected for further docking studies. De Novo Evolution designed the top 10 candidates from the docking results. RESULTS: Hypo1 was selected as the best quantitative pharmacophore model, because Hypo1 has characters of the highest cost difference (353.773), the lowest RMS (1.985), the lowest Error (121.440), and the best correlation coefficient (0.933). By the analysis of interaction amino acids in the top 10 hits including two controls, HIS42, HIS60, HIS204, HIS208, ARG209 and VAL218 are identified as the key binding site residues, ARG209 and VAL218 are the critical residues for the inhibitory activity of tyrosinase. This finding is consistent with the results from literatures. CONCLUSION: De Novo Evolution study suggested Tyrosinase_1*_Evo_4, Tyrosinase_23*_Evo_7, magnolone.cdx_15_Evo_4, compound_2.cdx_2_Evo_2, Compound_B_Evo_5, Compound_C_Evo_9, Compound_D_Evo_6 and malabaricone_C.cdx_3_Evo_10 as the potential tyrosinase inhibitor candidates. De Novo Evolution study also suggested compound_2.cdx_2_Evo_2 as the most potential tyrosinase inhibitor candidate. A total of ten novel leading compounds were identified to have the favorable interaction with tyrosinase by the docking analyses. PMID- 29425646 TI - Immunomodulatory, hemolytic and cytotoxic activity potentials of triterpenoid saponins from eight Cephalaria species. AB - BACKGROUND: Saponins isolated from a number of plants possess a broad spectrum of biological and pharmacological activities by using in vitro and in vivo bioassays. The recent investigations and findings in biological activity studies of saponins have mostly focused on immunomodulatory, hemolytic and cytotoxic properties. HYPOTHESIS/PURPOSE: Considering the great potential of saponins as bioactive agents, we investigated the cytotoxic, hemolytic and immunomodulatory activities of nineteen triterpenoid saponins from the aerial parts of eight Cephalaria species from Turkey. STUDY DESIGN: The isolated oleanane type saponins from Cephalaria species were tested for their hemolytic, cytotoxic and immunomodulatory activities through anin vitro cell based assay systems. METHODS: HeLa, A549, and a normal cell line HEK293 were used for testing cytotoxicity using MTT method. Immunomodulatory activity was performed in stimulated whole blood cells by PMA plus ionomycin. Hemolytic activity was assessed on human erythrocytes. RESULTS: Aristatoside C (3) and davisianoside B (16) displayed significant inhibitory effects on cancerous A549 and HeLa cells, and non cancerous HEK293 cells with IC50 values of 3.52 +/- 0.11, 35.69 +/- 0.50, 8.96 +/ 0.62 uM and 4.08 +/- 0.06, 11.74 +/- 0.82, 20.43 +/- 3.21 uM, respectively. Thirteen saponins out of the nineteen tested increased IL-1beta concentrations considerably, while six compounds changed IL-2 or IFN-gamma levels slightly. Almost all of the saponins showed noticeable hemolysis in human erythrocyte cells based on the sugar units. CONCLUSION: In this study, almost all saponins with oleanolic acid as aglycones exhibited significant hemolysis, monodesmosidic saponins with hederagenin as aglycone were the most active compounds against lung cancer cells with greater activity than standard commercial chemotherapy drug doxorubicin and some of the hederagenin type saponins induced remarkable IL-1beta secretion. PMID- 29425648 TI - Effect of rosmarinic acid on the arterial blood pressure in normotensive and hypertensive rats: Role of ACE. AB - BACKGROUND: In recent years, it has been demonstrated the inhibitory effect of some plant species on the angiotensin-converting enzyme and rosmarinic acid is a prominent constituent of these species. HYPOTHESIS/PURPOSE: This study was carried out to verify the effect of rosmarinic acid on blood pressure through inhibitory activity on angiotensin-converting enzyme in rats. STUDY DESIGN: The arterial hypertension was promoted using 2-kidneys 1-clip model in rats. The potential inhibitory rosmarinic acid effect on angiotensin-converting enzyme activity was compared with captopril actions by analyzing in vivo blood pressure dose-response curves to angiotensin I and bradykinin. The in vitro plasma angiotensin-converting enzyme activity was measured by fluorimetry using the substrate Abz-FRK(Dnp)P-OH substrate. In addition, dosages of nitrite/nitrate analysis were carried out. RESULTS: (1) rosmarinic acid caused systolic blood pressure dose-dependent decrease in hypertensive rats; (2) The angiotensin I dose response curves demonstrated that rosmarinic acid promotes minor changes in systolic blood pressure only in the hypertensive group; (3) The bradykinin dose response curves showed that both rosmarinic acid and captopril promoted a systolic blood pressure reduction, but only the captopril effect was significant; (4) The angiotensin-converting enzyme activity in rat lung tissue was inhibited by the rosmarinic acid in a dose dependent manner; (5) The analysis of nitrite/nitrate plasma concentrations showed no significant difference among the experimental groups. CONCLUSION: The rosmarinic acid is effective in reducing blood pressure, selectively, only in hypertensive animals. The rosmarinic acid (173uM) promoted almost a 98.96% reduction on angiotensin-converting enzyme activity. PMID- 29425649 TI - Plasma pharmacokinetics and cerebral nuclei distribution of major constituents of Psoraleae fructus in rats after oral administration. AB - BACKGROUND: The fruit of Psoralea corylifolia L., Psoraleae fructus (PF), is widely used in traditional Chinese medicine as a well-known herbal tonic. Previous studies have shown that PF and its major constituents may have potential values in the treatment of Parkinson and Alzheimer diseases, though their pharmacokinetics and brain distribution were largely unknown. PURPOSE: To develop a liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for simultaneous studies of the plasma pharmacokinetics and cerebral nuclei (including cerebellum, thalamus, brainstem, hippocampus, corpus striatum and cortex) distribution in rats of eleven known PF compounds following as psoralen, isopsoralen, psoralidin, bavachin, bavachinin, isobavachin, isobavachalcone, bavachalcone, neobavaisoflavone, corylifol A, and corylin. METHODS: Rats were orally administered via gavage at a single dose of PF extract at 1.2 g/kg. The eleven known PF compounds were extracted from rat plasma and cerebral nuclei at different time points, and then determined by the established LC-MS/MS method. Non-compartmental pharmacokinetic profiles were calculated, and the distribution in rat plasma and cerebral nuclei were compared. RESULTS: The results showed that all the tested compounds were quickly absorbed into rat plasma and distributed almost evenly to the cerebral nuclei. The distribution concentrations at different nuclei varied at one determined time point, but the overall trends were basically similar to the plasma concentration-time results. Psoralen and isopsoralen, the two highest coumarins contained in PF, displayed far higher plasma concentrations (AUC0->infinity, plasma~53,884~65,578 ng.h/ml) and central nervous system penetration (AUC0->infinity, brain nuclei ~44,659~65,823 ng.h/g) than the prenylflavonoids (other compounds except psoralidin, AUC0->infinity, plasma~69~324 ng.h/ml; AUC0->infinity, brain nuclei ~119~3662 ng.h/g). However, the total brain-to-plasma ratios of the prenylflavonoids were higher than the coumarins, suggesting the prenylflavonoids can more readily enter the brain than the coumarins. CONCLUSION: The established LC-MS/MS method is sensitive and specific for the simultaneous quantitation of the eleven PF compounds in rat plasma and cerebral nuclei. The results of plasma pharmacokinetics and cerebral nuclei distribution may reveal the possible substance basis for the CNS activities of PF, and highlight the application possibility of PF and its major constituents in the treatment of Parkinson and Alzheimer diseases. PMID- 29425650 TI - Antihypoxic activities of constituents from Arenaria kansuensis. AB - BACKGROUND: In previous investigation, we have identified antioxidative effects of water-soluble ethanolic extracts (named as AKE) from Arenaria kansuensis and inferred that these extracts or their constituents may also have antihypoxic activity. A. kansuensis has been widely used in traditional Tibetan medicine for altitude sickness (AS) and has been known as the herb of anti-inflammatory and hypoxia resistance for a long time. PURPOSE: The purpose of this study is to evaluate protective effects of AKE and its major constituents against hypoxia induced lethality in mice and RSC96 cells. STUDY DESIGN AND METHODS: Hypoxia induced lethality in mice was investigated by 3 experimental animal models of hypoxia. Meanwhile, we established a RSC96 cell model of hypoxia which applied to screen and assess the anti-hypoxic activity of compounds isolated from A. kansuensis. RESULTS: Results indicated that AKE dose-dependently prolonged survival time of hypoxia induced lethality in mice compared to vehicle group and exhibited significantly anti-hypoxic effect. AKE also enhanced the number of red blood cells (RBC) and the concentration of hemoglobin (HB). 8 compounds were bio guided separated and purified from AKE based on the animal model and cell model of hypoxia. Among which pyrocatechol (C16) and tricin 7-O-beta-d-glucopyranoside (C13) were confirmed to express better protective effects on cell damage induced by hypoxia, suggesting that these two compounds are major active constituents of AKE for anti-hypoxia. CONCLUSION: This study demonstrated that pyrocatechol and tricin 7-O-beta-d-glucopyranoside could be therapeutic candidates for treatment of AS. It is the first time to find the major active constituents of AKE for anti hypoxia. Meanwhile, a RSC96 cell model of hypoxia was established to screen anti hypoxic activity of compounds for the first time. PMID- 29425651 TI - Astragaloside VI and cycloastragenol-6-O-beta-D-glucoside promote wound healing in vitro and in vivo. AB - BACKGROUND: Astragalus genus includes most of the common, historical herbal medicines that have various applications in Asian countries. However, clinical data and mechanistic insights into their actions are still lacking. PURPOSE: In this study, we aimed to examine the effects of astragalosides on wound healing in vitro and in vivo, as well as the underlying mechanisms of these actions. METHODS: The wound healing activity of astragalosides was investigated in human HaCaT keratinocytes, human dermal fibroblast (HDF) cells, and murine models of wound healing. RESULTS: All eight astragalosides studied enhanced epidermal growth factor receptor (EGFR) activity in HaCaT cells. Among them, astragaloside VI (AS-VI) showed the strongest EGFR activation. Consistently, AS-VI and cycloastragenol-6-O-beta-D-glucoside (CMG), which is the major metabolite of astragalosides, enhanced extracellular signal-regulated kinase (ERK) activity in a concentration-dependent manner. In agreement, both compounds induced EGFR dependent cell proliferation and migration in HaCaT and HDF cells. In addition, we showed that AS-VI and CMG accelerated the healing of both sterile and infected wounds in vivo. These effects were associated with increased angiogenesis in the scar tissue. CONCLUSION: AS-VI and CMG increased the proliferation and migration of skin cells via activation of the EGFR/ERK signalling pathway, resulting in the improvement of wound healing in vitro and in vivo. These findings indicate the therapeutic potential of AS-VI and CMG to accelerate wound healing; additionally, they suggest the mechanistic basis of this activity. PMID- 29425652 TI - Oroxin A from Oroxylum indicum prevents the progression from prediabetes to diabetes in streptozotocin and high-fat diet induced mice. AB - BACKGROUND: Oroxylum indicum (L.) Kurz (Bignoniaceae) has been widely used for the treatment of respiratory infections and gastrointestinal disorders. Our previous study showed that an ethanol-water O. indicum seed extract (OISE), when combined with acarbose, reduced the risk of diabetes by 75% and effectively prevented the associated complications. Oroxin A, a major component of OISE, can activate PPARgamma and inhibit alpha-glucosidase and it represents a promising candidate for diabetes intervention. PURPOSE: The aim of this study is to investigate the effect of oroxin A from O. indicum on the progression of prediabetes to diabetes and the underlying mechanisms in streptozotocin and high fat-diet induced prediabetic mice. METHODS: Oroxin A was purified from OISE and its PPARgamma transcriptional activation was determined in vitro and in vivo. The prediabetic mice were established by high-fat diet and streptozotocin, which was followed by treatment with oroxin A. The effect of oroxin A was determined by analysis of the lipid profiles, oxidative stress, hepatic function and histology. The mechanism of oroxin A was also investigated. RESULTS: Oroxin A is a compound with low toxicity that has reduced the relative risk of progression from prediabetes to diabetes by 66.7% without inducing weight gain or hepatotoxicity. Oroxin A also improved the complications of prediabetes, such as lipid metabolism dysfunction and liver injury. Results of mechanism studies suggested that oroxin A is a partial PPARgamma agonist that can activate PPARgamma transcriptional activation in vitro and in vivo. Oroxin A also exhibited an inhibitory activity against alpha-glucosidase and an antioxidant capacity. CONCLUSION: Oroxin A prevents the progression from prediabetes to diabetes through a multi-pathway intervention mechanism. PMID- 29425653 TI - In vitro and in silico perspectives on biological and phytochemical profile of three halophyte species-A source of innovative phytopharmaceuticals from nature. AB - BACKGROUND: Halophytes are considered as valuable sources of traditional drugs in different countries. PURPOSE: The present study aimed to evaluate biological and chemical fingerprints of three halophytes (Arthrocnemum macrostachyum (Moric.) C, Koch, Halimione portulacoides (L.) Aellen and Salicornia europaea L.). MATERIALS AND METHODS: The antioxidant and enzymatic inhibitory potential (acetylcholinesterase, butyrylcholinesterase, alpha-amylase, alpha-glucosidase, and tyrosinase) were assessed. The total phenolic, flavonoid contents, and the chemical profiles were appraised using the ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Molecular docking was conducted to provide additional insights of molecular interactions of the enzymes/phytochemicals. RESULTS: Ethyl acetate extract was the most efficient extract, with A. macrostachyum being the most potent towards DPPH and ABTS radicals and phosphomolybdenum assay. Ethyl acetate extract of A. macrostachyum was also the best reducing agent (CUPRAC and FRAP assays). Methanol and ethyl acetate extract of A. macrostachyum, H. portulacoides, and S. europaea showed significant enzyme inhibition potential. Ethyl acetate extract of A. macrostachyum showed the highest total phenolic (29.54 +/- 0.78 mgGAEs/g extract) while the ethyl acetate extract of S. europaea was more abundant in flavonoids (18.26 +/- 0.11 mgREs/g extract). Phytochemical profiling allowed the identification of several components in the methanolic extracts (16 in A. macrostachyum, 14 in H. portulacoides, and 11 in S. europaea), with quinic acid, p-coumaric acid, and rhamnetin being most abundant. Docking studies revealed that the above compounds showed scores for the enzymes tested. CONCLUSION: The three halophytes studies could be considered as potential sources of biologically active compounds for novel phytopharmaceuticals development. PMID- 29425654 TI - Anti-inflammatory and anti-arthritic effects of the ethanolic extract of Aralia continentalis Kitag. in IL-1beta-stimulated human fibroblast-like synoviocytes and rodent models of polyarthritis and nociception. AB - BACKGROUND: Blocking the formation and invasive growth of pannus and its secretion of inflammatory cytokines and MMPs is important for treating rheumatoid arthritis. HYPOTHESIS/PURPOSE: Anti-arthritic activity of Aralia continentalis Kitag., an oriental herbal medicine, and the underlying mechanisms involved were investigated. STUDY DESIGN: Anti-inflammatory and anti-nocicpetive activities of the ethanolic extract (50% v/v) of Aralia continentalis Kitag. harvested from Imsil, Korea (ACI) were investigated in IL-1beta-stimulated human fibroblast-like synoviocyte (FLS) cells and rodent models of collagen-induced polyarthritis and carrageenan-induced acute paw pain. METHODS: In IL-1beta-stimulated FLS cells derived from rheumatoid arthritis patients, the anti-inflammatory activity of ACI was examined by analyzing the expression levels of inflammatory mediators such as TNF-alpha, IL-6, IL-8, MMP-1, MMP-3, MMP-13, PGE2, and COX-2 using ELISA and RT PCR analysis. The anti-arthritic activity of ACI was investigated by measuring body weight, squeaking score, paw volume, and arthritis index in collagen-induced polyarthritis mice. The anti-nociceptive activity of ACI was examined in the paw pressure test and Tail-flick latency test in rats. RESULTS: The ethanolic extract (50% v/v) of ACI reduced the levels of TNF-alpha, IL-6, IL-8, MMP-1, and MMP-13 secreted by IL-1beta-stimulated FLS cells, whereas MMP-3, COX-2, and PGE2 were not significantly affected. ACI inhibited the migration of NF-kappaB into the nucleus through the inhibition of ERK- and JNK-dependent MAP kinase pathways in IL-1beta-stimulated FLS cells. In collagen-induced polyarthritis mice, oral administration of ACI extract (200 mg/kg) significantly alleviated arthritic behaviors. Histological observations of arthritic mouse knees were consistent with their behaviors. The anti-arthritic and anti-inflammatory activities of 200 mg/kg ACI extract were comparable to those of 10 mg/kg prednisolone when administered to mice. However, ACI administration did not significantly affect carrageenan-induced hyperalgesia or thermal nociception in rats. CONCLUSION: These results suggest that the ethanolic extract of ACI have significant anti inflammatory and anti-arthritic effects in a rodent arthritis model and in IL 1beta-stimulated FLS cells. Thus, ACI may be a useful candidate for developing pharmaceuticals or dietary supplements for the treatment of inflammatory arthritis. PMID- 29425655 TI - Could essential oils enhance biopolymers performance for wound healing? A systematic review. AB - BACKGROUND: Millions of people in the world suffer from chronic wounds of different etiologies such as diabetic foot and leg ulcers, without solutions nowadays. Molecules obtained from plants offer an alternative to aid wound healing. Strong evidence about essential oils (EO) anti-inflammatory and antimicrobial properties is thoroughly described in literature and their chemical compositions are well characterized. More recently, EO effects in experimental wounds have begun to be analyzed. AIM: We aim to summarize the evidence of EO in experimental wounds, and the possibility of combining them with biopolymers commonly used in skin regeneration. METHODS: Electronic databases such as ScienceDirect, PubMed and Scopus were used to search scientific contributions until March 2017, using relevant keywords. In a first step, literature focusing on EO and/or mono- or sesqui-terpenoids effects in rodent wounds was identified and summarized. In all cases, chemical structures and EO composition were detailed, as well as references to in vitro activities previously determined, e.g. antibacterial, antioxidant or anti-inflammatory. In a second step, scientific literature devoted to combine EO and biopolymers with the focus set on wound healing innovations, was collected and analyzed. RESULTS: Treatments with EO from species of genders Lavandula, Croton, Blumea, Eucalyptus, Pinus, Cymbopogon, Eucalyptus, Cedrus, Abies, Rosmarinus, Origanum, Salvia and Plectranthus, have shown positive results in rodent wounds. All of these EO were mainly composed by monoterpenoids-thymol, 1,8-cineole, linalool-or monoterpenes, as limonene or pinenes. Experimental wounds in rodents have shown faster closure rate, better collagen deposition and/or enhanced fibroblasts proliferation. In blends with biopolymers, several EO combined with chitosan, alginate, gelatin or collagen, were processed to give active films or nanofibers, with antioxidant, anti-inflammatory or antimicrobial activities. Curiously, all of these works were carried out since 2010. CONCLUSIONS: There is significant evidence about the effectivity of EO as wound healers. The incorporation of EO into a polymer matrix that contributes to wound healing is still incipient. However, scientific based evidence of the EO incorporation in resorbable polymeric scaffolds was found and analyzed herein. In summary, EO-biopolymer dressings or scaffolds have become promising artifacts regarding wound treatments, especially in chronic wounds, where treating infection and inflammation are still important issues. PMID- 29425656 TI - In vivo schistosomicidal activity of 7-epiclusianone and its quantification in the plasma of healthy and Schistosoma mansoni infected mice using UPLC-MS/MS. AB - BACKGROUND: The tetraprenylated benzophenone 7-epiclusianone (7-epi) is a substance isolated from the fruits of Garcinia brasiliensis and in vitro studies have demonstrated that 7-epi is effective against Schistosoma mansoni adult worms. HYPOTHESIS/PURPOSE: Here we report the in vivo evaluation of 7-epi and its pharmacokinetic in healthy and Schistosoma mansoni infected mice. STUDY DESIGN AND METHODS: In this work, we assayed the schistosomicidal activity of 7-epi at the dose of 100 mg/kg and 300 mg/kg body weight/day in S. mansoni experimentally infected mice. Besides, two groups of animals were treated and a detailed analysis of plasma samples was performed by liquid chromatography coupled to mass spectrometry (LC-MS/MS). RESULTS: The worm burden showed a reduction in the infected mice after treatment with 300 mg/kg for five days (p < .05). And we found an increase of AUC0-infinity (20846 vs. 32438 ng.h/ml) and a decrease of total apparent clearance (0.006 vs. 0.004 l/h/kg) of 7- epi in the infected group compared to the healthy group. Consequently, the half-life increased (1.73 vs. 6.11 h) and Cmax was reduced (5427.5 vs. 3321.0 ng/ml) in the infected group compared to the healthy group. In addition, histopathological investigations were performed analysing liver samples from healthy and infected mice. CONCLUSION: The results showed significant schistosomicidal in vivo activity at 300 mg/kg. In addition, livers from S. mansoni infected mice showed a greater number of egg granulomas and the changes in the pharmacokinetic parameters in this group could be associated with the pathology of the murine experimental schistosomiasis. PMID- 29425657 TI - Urine metabolomics shows an induction of fatty acids metabolism in healthy adult volunteers after supplementation with green coffee (Coffea robusta L.) bean extract. AB - BACKGROUND AND OBJECTIVE: Green coffee bean extract is used as herbal medicine or supplement for weight reduction and obesity. The active constituents are considered caffeine and chlorogenic acid (CGA) derivatives. The mode of action of CGA is still unclear and can be related to peroxisome proliferator-activated receptor alpha (PPAR-alpha) and liver X receptor Ralpha (LXR-alpha). Metabolomics may be an innovative tool for the description and discovery of the multiple target nature of such phytocomplex. METHODS: 24 h urine samples were collected once a week from ten healthy adult volunteers consuming daily 400 mg of dry Green coffee bean extract (GCBE, 4.9% of chlorogenic acid) each day for 30 days (5 harvesting days, considering also the first day of supplementation). Urine samples were analyzed by LC-QTOF using both untargeted and targeted approaches. The latter was used to monitor two urinary markers of oxidative stress (allantoin, 8-OHdG). RESULTS: Metabolomics analysis (PLS-DA) revealed changes in urine composition before and during the treatment with GCBE. Markers related to treatment were metabolites related to polyphenol administration as hippuric acid, benzoic acid derivatives, dihydroferulic and dihydrosinapic acid sulphate, but also carnitine derivatives and dicarboxylic acids. On the other hand, no changes in the levels of allantoin and 8-OHdG were observed. CONCLUSION: This preliminary study showed the possible usefulness of metabolomics approach in the evaluation of GCBE consumption in healthy subjects. The observed changes in urinary composition can be related to the catabolism of GCBE constituents and to induced fatty acid metabolism, mainly related to carnitine derivatives. This latter result could be considered, at least in part, as a further proof of the mode of action of green coffee extract. PMID- 29425658 TI - Kinetics and metabolism of apocynin in the mouse brain assessed with positron emission tomography. AB - BACKGROUND: Apocynin is a constituent of the medicinal herb Picrorhiza kurroa. It is an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase. This compound shows potential anti-inflammatory and antioxidant effects and has been tested as a neuroprotectant in many animal models of brain disease. In such studies, understanding the brain kinetics of apocynin would be important for interpreting its in vivo efficacy; however, little has been reported on the kinetics of apocynin in the brain. PURPOSE: The purpose of this study is to investigate the kinetics and metabolism of apocynin in the brain of mice. STUDY DESIGN: The kinetics and metabolism of apocynin were examined using [11C]apocynin and positron-emission tomography (PET). METHODS: In vivo PET scanning was performed in mice for 20min after intraperitoneal administration of an apocynin solution containing [11C]apocynin. Metabolites in the brain were analyzed using high-performance liquid chromatography. The doses of apocynin used ranged from <1.5 ug/kg (tracer dose) to 100mg/kg. RESULTS: Brain radioactivity during the period of 0 to 20min after administration was negligible at the tracer dose and extremely low at the dose of 10mg/kg. Moderate radioactivity was observed in the brain a few minutes after administration at the doses of 25 and 50mg/kg and rapidly decreased thereafter. At a dose of 100mg/kg, [11C]apocynin resulted in a high uptake of radioactivity followed by a gradual washout. In contrast to the brain, a clear dose-dependent increase in radioactivity was not observed in the blood. The fraction of the unchanged form in the brain decreased with time, and the degree of the reduction depended on apocynin doses: apocynin was rapidly metabolized in the brain at lower doses, whereas it was slowly decomposed at higher doses. On the basis of these data, the maximum apocynin concentrations in the brain were calculated to be 10 uM (10mg/kg), 49 uM (25mg/kg), 150 uM (50mg/kg), and 380 uM (100mg/kg). A metabolite observed in the brain was found to be apocynin glucuronide but not diapocynin, an active metabolite. CONCLUSION: These results would be useful for an evaluation of the potential efficacy of apocynin as a neuroprotective agent. PMID- 29425659 TI - Seabuckthorn berry polysaccharide extracts protect against acetaminophen induced hepatotoxicity in mice via activating the Nrf-2/HO-1-SOD-2 signaling pathway. AB - BACKGROUND: Oxidative stress is concomitant with acetaminophen (APAP)-induced hepatotoxicity, which has been highlighted as therapeutic targets for such diseases. The berries of Seabuckthorn (Hippophae rhamnoides L.) have been traditionally used in Tibetan medicine for thousands of years. The effect of Seabuckthorn berry polysaccharide on drug- induced liver injury (DILI) has not yet been elucidated. PURPOSE: This study aims to investigate the protective effects and mechanisms of Seabuckthorn polysaccharide (SP) against APAP-induced hepatotoxicity. STUDY DESIGN: Sixty C57BL/6 mice were randomly divided into six groups (n = 10 per group), namely the control group (Ctrl), APAP-induced-liver injury group (APAP), NAC pretreated group (NAC), 100 mg/kg SP pretreated group (APAP/SP100), 200 mg/kg SP pretreated group (APAP/SP200) and 200 mg/kg SP pretreated group without APAP challenge (SP200). SP was given orally to mice for 30 consecutive days prior to APAP exposure (300 mg/kg). NAC (150 mg/kg) was administrated 1 h before APAP challenge. METHODS: ALT and AST were detected 16 h after APAP treatment; Hepatic expression of GSH, SOD, NO, iNOS and GSH-Px were examined. The expression of p-JNK, Bcl-2/Bax, p62, Keap-1 and SOD-2 was detected by Western blotting. The expression of Nrf-2 and its target genes HO-1, GCLC and NQO-1 were analyzed by RT-PCR and Western blotting. RESULTS: Pretreatment with SP led to decreased levels of ALT and AST in APAP mice, without affecting APAP metabolism. This was accompanied by diminished liver injuries, increased levels of GSH and GSH-Px, reduced NO and iNOS expression. SP increased the activity of SOD as well as SOD-2 expression in APAP mice. SP suppressed APAP-induced JNK phosphorylation and increased the ratio of Bcl-2/Bax. Furthermore, SP decreased the expression of Keap-1 and increased the nuclear expression of Nrf-2. The expression of Nrf-2 target gene HO-1 was increased by SP pretreatment in APAP mice. CONCLUSION: SP alleviates APAP-induced hepatotoxicity. The protective effects of SP are associated with the activation of the Nrf-2/HO-1-SOD-2 signaling pathway. PMID- 29425661 TI - Linguistic and Cultural Validation of Patient-Reported Outcomes Used in Clinical Trials. PMID- 29425662 TI - Penile Implant Satisfaction: Do We Really Know? PMID- 29425660 TI - Cranberry anthocyanin as an herbal medicine lowers plasma cholesterol by increasing excretion of fecal sterols. AB - BACKGROUND: Interest in using herbal medicines to treat the hypercholesterolemia is increasing. Cranberry extract could decrease plasma cholesterol, however, the active ingredients and the underlying mechanisms remain largely unknown. HYPOTHESIS: The present study was to test the hypothesis that cranberry anthocyanins (CrA) were at least one of the active ingredients responsible for the cholesterol-lowering activity of cranberry fruits via a mechanism of increasing fecal sterol excretion. METHODS: Forty-four hamsters were randomly divided into five groups and fed one of the five diets, namely a non-cholesterol control diet (NCD), a high-cholesterol control diet (HCD), a HCD diet supplemented with a low dose of 1% CrA (CL), a HCD diet supplemented with a high dose of 2% CrA (CH), and a HCD diet supplemented with 0.5% cholestyramine as a positive control drug (P-CTL), respectively, for six weeks. Plasma lipoprotein cholesterol was quantified using the enzymatic kits, while the gene expressions of transporters, enzymes and receptors involved in cholesterol absorption and metabolism were quantified using the quantitative RT-PCR. Fecal sterols were quantified using gas chromatography (GC). RESULTS: Plasma total cholesterol and aorta atherosclerotic plaque decreased dose-dependently with the increasing amounts of CrA added into diets. This was accompanied by a dose-dependent increase in excretion of both neutral and acidic sterols. CrA had no effect on the mRNA levels of intestinal Niemann-Pick C1 like 1 protein (NPC1L1), acyl CoA:cholesterol acyltransferase2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter 5 (ABCG5) as well as hepatic cholesterol-7alpha-hydroxylase (CYP7A1), 3-Hydroxy-3-methylglutaryl reductase (HMG-CoA-R), sterol regulatory element binding protein 2 (SREBP2), LDL receptor (LDL-R), and Liver X receptor alpha (LXRalpha). CONCLUSION: CrA as an herbal medicine could favorably modify the lipoprotein profile in hamsters fed a high cholesterol diet by enhancing excretion of fecal neutral and acidic sterols, most likely not mediated by interaction with genes of transporters, enzymes and proteins involved in cholesterol absorption and metabolism. PMID- 29425663 TI - Sexual Rehabilitation After Nerve-Sparing Radical Prostatectomy: Free-of-Charge Phosphodiesterase Type 5 Inhibitor Administration Improves Compliance to Treatment. AB - BACKGROUND: In December 2006, the region of Tuscany (Italy) authorized the free of-charge provision of phosphodiesterase type 5 inhibitors (PDE5I) for all patients with Tuscan citizenship who undergo nerve-sparing radical prostatectomy (NSRP). OBJECTIVE: To compare sexual rehabilitation outcomes in patients with low risk of erectile dysfunction and minimal comorbidities who received PDE5Is free of charge (PDE5I-F) with those who paid for PDE5Is (PDE5I-P) after bilateral NSRP. METHODS: We reviewed prospectively recorded clinical data of 2,368 patients with Tuscan (PDE5I-F) and non-Tuscan (PDE5I-P) citizenship treated with NSRP at 3 different institutions in Tuscany from 2008 to 2013. Inclusion criteria for the final analysis were open or robot-assisted bilateral NSRP; low risk of postoperative erectile dysfunction according to the Briganti risk stratification tool; no smoking and no drug and alcohol abuse; no cardiovascular risk factors; no major surgery before and after NSRP; no neoadjuvant or adjuvant treatment; and no biochemical relapse. Dropout was defined as an interruption longer than 40 days of the treatment protocol indicated in the inclusion criteria. Treatment compliance was defined as more than 90% consumption of the prescribed PDE5I. OUTCOMES: The Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) and the Italian version of the University of California-Los Angeles Prostate Cancer Index sexual function (UCLA-PCI-s) questionnaires were administered to assess patients' satisfaction with PDE5I treatment and sexual function. RESULTS: Overall, 648 patients in the PDE5I-F group and 182 in the PDE5I-P group met the inclusion criteria and were eligible for the study. Patients had comparable preoperative and surgical characteristics. The PDE5I-F group had a significantly higher early rehabilitation onset (P < .001), lower treatment dropout at 12, 24, and 36 months (P < .001 for all comparisons), and higher compliance to the treatment protocol at 6 and 12 months (P = .01 and P < .001, respectively). At multivariable analysis, the PDE5I-F protocol was an independent predictor of an EDITS score higher than 50 (hazard ratio = 1.54, P = .03) and a UCLA-PCI-s score higher than 50 (hazard ratio = 3.12, P = .01) after adjusting for the effects of several clinical features. CLINICAL IMPLICATIONS: The free-of-charge protocol has a significant impact on patients' satisfaction with PDE5I treatment. STRENGTHS AND LIMITATIONS: To our knowledge, this is the first study comparing free vs paid access to a sexual rehabilitation protocol. Major limitations are the observational nature of the study and the different population sizes of the 2 groups. CONCLUSIONS: In a selected cohort of patients after NSRP, free-of-charge access to a sexual rehabilitation protocol was significantly associated with higher early rehabilitation onset, major compliance to the protocol, minor treatment dropout, and higher satisfaction rate of patients. Siena G, Mari A, Canale A, et al. Sexual Rehabilitation After Nerve-Sparing Radical Prostatectomy: Free-of-Charge Phosphodiesterase Type 5 Inhibitor Administration Improves Compliance to Treatment. J Sex Med 2018;15:120-123. PMID- 29425664 TI - Topical Testosterone Therapy Adherence and Outcomes Among Men With Primary or Secondary Hypogonadism. AB - BACKGROUND: Men with primary or secondary hypogonadism (HG) prescribed testosterone therapy (TTh) who terminate treatment early might not obtain the benefit of symptom relief. AIM: To estimate adherence to topical TTh and to compare baseline characteristics and follow-up outcomes between adherent and non adherent patients in a population of commercially insured US men with primary or secondary HG. METHODS: A retrospective cohort of adult men with primary or secondary HG and initiating topical TTh from 2007 through 2014, with continuous coverage during 12-month baseline and follow-up periods, was identified from a large US health plan. Clinical conditions were assessed using International Classification of Diseases, 9th Revision, Clinical Modification codes. Adherence to initial topical TTh was defined as proportion of days covered of at least 80%. Characteristics and outcomes were compared across adherent and non-adherent patients. OUTCOMES: Adherence to topical TTh, occurrence of HG-related clinical outcomes, and total health care costs. RESULTS: We identified 3,184 topical TTh initiators (mean age = 49 years), of whom 17% (n = 538) were adherent at 12 months. Factors positively associated with adherence included prescribing by specialists, a lower prevalence of certain comorbidities at baseline, residence in the Northeast, and an earlier start year of the topical TTh prescription. Adherence to topical TTh was associated with lower odds of having HG-associated clinical conditions (composite measure) over 12-month follow-up. In the subset of patients with available laboratory results, adherent patients had greater increases in testosterone levels compared with non-adherent patients. Increased pharmacy costs for adherent patients were partly offset by decreases in medical costs. CLINICAL IMPLICATIONS: Adherence to topical testosterone is low but associated with positive outcomes, demonstrating the need for future efforts to focus on improving adherence in this population. STRENGTHS AND LIMITATIONS: Strengths of this study include the large number of analyzed patients and the routine care (rather than interventional trial) setting, which maximizes generalizability within the source population. Limitations are primarily a result of reliance on medical claims data, which lack clinical context and are subject to potential coding errors. Certain factors of potential importance for adherence, such as patient and provider preferences, were not available in the dataset. The study analyzed commercially insured US patients and our ability to generalize these results to the entire US population or other countries might be limited. CONCLUSION: Study findings provide further evidence for suboptimal topical TTh adherence among men treated for primary or secondary HG. Adherence is associated with greater improvement in total testosterone laboratory values and might be associated with a lower likelihood of having certain HG-related conditions. Grabner M, Hepp Z, Raval A, et al. Topical Testosterone Therapy Adherence and Outcomes Among Men With Primary or Secondary Hypogonadism. J Sex Med 2018;15:148-158. PMID- 29425665 TI - Newly Diagnosed Bipolar Disorder and the Subsequent Risk of Erectile Dysfunction: A Nationwide Cohort Study. AB - BACKGROUND: Although erectile dysfunction (ED) is a common problem in men with mental disorders, there are few reports in the literature on the relation between bipolar disorder (BD) and ED. AIMS: To establish the incidence rate of ED in men with BD and assess the risk of ED in patients with BD according to type of treatment offered or no active treatment with medication during the 1st year of onset. METHODS: We identified 5,150 men with newly diagnosed BD using Taiwan's National Health Insurance Research Database. 2 matched controls per case were selected using the propensity score and a greedy matching method to obtain a balanced control group. Multivariate Cox regression analysis was used to examine the independent risk factors for ED, including obesity and comorbidities. Hazard ratios (HRs) for ED risk were calculated for the different psychotropic therapy groups, including antidepressants, antipsychotics, and mood stabilizers. OUTCOME: HRs for ED risk were calculated for the different psychotropic therapy groups, including antidepressants, antipsychotics, and mood stabilizers. Patients with BD had a significantly higher HR for an ED diagnosis than controls. RESULTS: Patients with BD had a higher HR for an ED diagnosis than controls. Although some psychotropic medications can increase the risk of ED, patients with BD not actively treated with medication still showed a higher risk of ED than controls. CLINICAL IMPLICATIONS: Because ED might be more prevalent in patients with BD than in the general population, clinicians should assess erectile function when selecting appropriate treatment for patients with BD to minimize the risk of ED as an annoying side effect and improve treatment compliance. STRENGTHS AND LIMITATIONS: This is the first large-scale population-based study to explore the association between BD and ED. A particular strength of this study is its nationwide, population-based study design, which afforded substantial statistical power for detecting subtle differences between the 2 cohorts, thereby minimizing selection bias. There are some limitations to the present study. (i) Data on other potential risk factors is lacking. (ii) Patient compliance and dose effect between psychotropic medication and ED could not be established. (iii) We could not assess the relation between ED and the severity and phases of BD. CONCLUSION: This cohort study found a temporal association between BD and subsequent ED in a large national sample of men. Clinicians should consider the risk of ED when choosing treatment for patients with BD. Hou P-H, Mao FC, Chang G-R, et al. Newly Diagnosed Bipolar Disorder and the Subsequent Risk of Erectile Dysfunction: A Nationwide Cohort Study. J Sex Med 2018;15:183-191. PMID- 29425666 TI - Early Hormonal Treatment Affects Body Composition and Body Shape in Young Transgender Adolescents. AB - BACKGROUND: Transgender adolescents aspiring to have the body characteristics of the affirmed sex can receive hormonal treatment. However, it is unknown how body shape and composition develop during treatment and whether transgender persons obtain the desired body phenotype. AIM: To examine the change in body shape and composition from the start of treatment with gonadotropin-releasing hormone agonists (GnRHa) until 22 years of age and to compare these measurements at 22 years with those of age-matched peers. METHODS: 71 transwomen (birth-assigned boys) and 121 transmen (birth-assigned girls) who started treatment from 1998 through 2014 were included in this retrospective study. GnRHa treatment was started and cross-sex hormonal treatment was added at 16 years of age. Anthropometric and whole-body dual-energy x-ray absorptiometry data were retrieved from medical records. Linear mixed model regression was performed to examine changes over time. SD scores (SDS) were calculated to compare body shape and composition with those of age-matched peers. OUTCOMES: Change in waist-hip ratio (WHR), total body fat (TBF), and total lean body mass (LBM) during hormonal treatment. SDS of measures of body shape and composition compared with age matched peers at 22 years of age. RESULTS: In transwomen, TBF increased (+10%, 95% CI = 7-11) while total LBM (-10%, 95% CI = -11 to -7) and WHR (-0.04, 95% CI = -0.05 to -0.02) decreased. Compared with ciswomen, SDS at 22 years of age were +0.3 (95% CI = 0.0-0.5) for WHR, and 0.0 (95% CI = -0.2 to 0.3) for TBF. Compared with cismen, SDS were -1.0 (95% CI = -1.3 to -0.7) for WHR, and +2.2 (95% CI = 2.2-2.4) for TBF. In transmen, TBF decreased (-3%, 95% CI = -4 to -1), while LBM (+3%, 95% CI = 1-4) and WHR (+0.03, 95% CI = 0.01-0.04) increased. Compared with ciswomen, SDS at 22 years of age were +0.6 (95% CI = 0.4-0.8) for WHR, and -1.1 (95% CI = -1.4 to -0.9) for TBF. Compared with cismen, SDS were -0.5 (95% CI = 0.8 to -0.3) for WHR, and +1.8 (95% CI = 1.6-1.9) for TBF. CLINICAL IMPLICATIONS: Knowing body shape and composition outcomes at 22 years of age will help care providers in counseling transgender youth on expectations of attaining the desired body phenotype. STRENGTHS AND LIMITATIONS: This study presents the largest group of transgender adults to date who started treatment in their teens. Despite missing data, selection bias was not found. CONCLUSIONS: During treatment, WHR and body composition changed toward the affirmed sex. At 22 years of age, transwomen compared better to age-matched ciswomen than to cismen, whereas transmen were between reference values for ciswomen and cismen. Klaver M, de Mutsert R, Wiepjes CM, et al. Early Hormonal Treatment Affects Body Composition and Body Shape in Young Transgender Adolescents. J Sex Med 2018;15:251-260. PMID- 29425667 TI - Erratum. PMID- 29425668 TI - Erratum. PMID- 29425670 TI - Robustness of the Beckman Coulter Access TSH (3rd IS) assay. PMID- 29425671 TI - Cardiovascular stress-response adaptation: Conceptual basis, empirical findings, and implications for disease processes. AB - Cardiovascular reactivity to stress is an established marker of lifetime disease risk, with both elevated and blunted reactions empirically identified as being predictive of ill-health. However, in the relevant studies, traditional laboratory protocols do not account for patterns of response adaptation across time, patterns that may be particularly important in the prediction of future health outcomes. We outline the evidence suggesting that habituation to repeated or prolonged stress represents an informative and health-relevant aspect of the cardiovascular stress response. In this position paper, we outline what studies of cardiovascular adaptation have elucidated to date. Cardiovascular response habituation occurs for various types of stressor, is most pronounced after initial stress responses have subsided (making initial stress responses potentially misleading if scrutinized in isolation), emerges in both women and men, and is subject to individual differences. Such moderating factors fit within the biopsychosocial model, suggesting that CVR adaptation is etiologically relevant and potentially modifiable through intervention. However, as yet, there is no prospective evidence to confirm that patterns of adaptation predict adverse health, despite there being strong reasonable and logical grounds to suspect so. We suggest how existing studies may offer a means to fill this gap in prospective evidence, and outline four potential typologies in cardiovascular reactivity patterns that fit within and extend the classic reactivity hypothesis. PMID- 29425672 TI - An increase in estradiol facilitates the onset of paternal behavior in the dwarf hamster (Phodopus campbelli). AB - In the dwarf hamster (Phodopus campbelli), activational effects of testosterone (T) and estradiol (E2) in the regulation of paternal behavior have been repeatedly rejected because peripheral concentrations of E2 do not change across the reproductive cycle of males. Further, castration no affected paternal behavior despite that both T and E2 concentrations decreased significantly. However, the role of these hormones has not been evaluated in models of castration and hormonal replacement in virgin males. Here, we analysed the effects of E2 and T in paternal behavior in virgin male dwarf hamster (Phodopus campbelli). Thirty paternal (PAT) males were bilaterally castrated; of them, 10 were implanted with T, 10 with E2 and 10 males received no treatment. Other 10 PAT males underwent sham-castration. Seventeen aggressive (AGG) males were also bilaterally castrated; of these, 10 AGG received E2 replacement, 7 were not treated. Other 7 AGG males were submitted to sham-castration. Following treatments, paternal behavior tests were conducted again. T and E2 levels in plasma were quantified by radioimmunoassay (RIA). The results showed that the treatments did not affect the paternal behavior of males that were initially paternal. Neither castration nor sham-castration surgery affected the behavior of AGG males. However, when these males were treated with E2 and the concentrations of this hormone increase significantly they became paternal. Our data suggest that an increase in E2 levels shifted infanticidal behavior to paternal behavior in dwarf hamster. PMID- 29425674 TI - Predictive Variables for Failure in Administration of Intrapleural Tissue Plasminogen Activator/Deoxyribonuclease in Patients With Complicated Parapneumonic Effusions/Empyema. AB - BACKGROUND: Combined intrapleural therapy with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) has been shown to reduce the need for surgical intervention for complicated pleural effusion/empyema (CPE/empyema). For patients in whom tPA/DNase is likely to fail, however, receipt of this therapy may simply delay the inevitable. The goal of this study was to identify risk factors for failure of combined intrapleural therapy. METHODS: We performed a retrospective chart review of patients who received intrapleural tPA/DNase for the treatment of CPE/empyema. Clinical variables included demographic data, radiographic parameters at time of diagnosis, and results from pleural fluid analysis. We used gradient boosted trees-an ensemble machine learning technique, with hyperparameter tuning to mitigate overfitting-to rank the importance of 19 candidate clinical variables with respect to their ability to predict failure of tPA/DNase therapy. RESULTS: We identified 84 patients who received intrapleural tPA/DNase for the treatment of complicated pleural effusions/empyema over a 5 year period. Resolution of CPE/empyema with intrapleural tPA/DNase was achieved in two-thirds of the patients (n = 57). Of the 19 candidate predictors of tPA/DNase failure, the presence of pleural thickening was found to be the most important (48% relative importance), followed by the presence of an abscess or necrotizing pneumonia (24%), the pleural protein level (6%), and the presence of loculated effusion (4%). CONCLUSIONS: Our analysis found that the presence of pleural thickening and the presence of an abscess/necrotizing pneumonia helps to triage patients in whom combined intrapleural therapy is likely to fail. The results warrant further study and validation in a prospective multicenter study. PMID- 29425675 TI - Health Services Burden of Undiagnosed and Overdiagnosed COPD. AB - BACKGROUND: Misdiagnosis of COPD is common. The goal of this study was to quantify the health services burden of undiagnosed and overdiagnosed COPD in a real-world, North American population. METHODS: A population-based cohort study was conducted. Presence of COPD using spirometry was ascertained in randomly selected adults aged >= 40 years from Ontario, Canada, who participated in the Canadian Obstructive Lung Disease study. The presence of physician-diagnosed COPD was ascertained for the same subjects by using linked health administrative data. Participants were then categorized into four groups: correctly diagnosed, undiagnosed, overdiagnosed, and no COPD according to either criteria. Age- and sex-standardized rates of hospitalizations, ED visits, and ambulatory care visits in each group were determined and compared. RESULTS: Of 1,403 participants, 13.7% had undiagnosed COPD, 5.1% were overdiagnosed, and 3.7% had correctly diagnosed COPD. Subjects with overdiagnosed COPD had significantly higher rates of hospitalizations, ED visits, and ambulatory care visits, and subjects with moderate to severe undiagnosed COPD had higher rates of hospitalizations, than subjects in the non-COPD population. CONCLUSIONS: Undiagnosed and overdiagnosed COPD contribute to significant health care burden. Given that misdiagnosed COPD was fivefold more common than correctly diagnosed COPD, these findings point to a substantial misdiagnosis-associated burden of disease that might be prevented, at least in part, with a correct diagnosis. PMID- 29425673 TI - Structural stability of purified human CFTR is systematically improved by mutations in nucleotide binding domain 1. AB - The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is an ABC transporter containing two transmembrane domains forming a chloride ion channel, and two nucleotide binding domains (NBD1 and NBD2). CFTR has presented a formidable challenge to obtain monodisperse, biophysically stable protein. Here we report a comprehensive study comparing effects of single and multiple NBD1 mutations on stability of both the NBD1 domain alone and on purified full length human CFTR. Single mutations S492P, A534P, I539T acted additively, and when combined with M470V, S495P, and R555K cumulatively yielded an NBD1 with highly improved structural stability. Strategic combinations of these mutations strongly stabilized the domain to attain a calorimetric Tm > 70 degrees C. Replica exchange molecular dynamics simulations on the most stable 6SS-NBD1 variant implicated fluctuations, electrostatic interactions and side chain packing as potential contributors to improved stability. Progressive stabilization of NBD1 directly correlated with enhanced structural stability of full-length CFTR protein. Thermal unfolding of the stabilized CFTR mutants, monitored by changes in intrinsic fluorescence, demonstrated that Tm could be shifted as high as 67.4 degrees C in 6SS-CFTR, more than 20 degrees C higher than wild-type. H1402S, an NBD2 mutation, conferred CFTR with additional thermal stability, possibly by stabilizing an NBD-dimerized conformation. CFTR variants with NBD1-stabilizing mutations were expressed at the cell surface in mammalian cells, exhibited ATPase and channel activity, and retained these functions to higher temperatures. The capability to produce enzymatically active CFTR with improved structural stability amenable to biophysical and structural studies will advance mechanistic investigations and future cystic fibrosis drug development. PMID- 29425676 TI - Punicalagin, an active pomegranate component, is a new inhibitor of PDIA3 reductase activity. AB - BACKGROUND: Polyphenolic compounds isolated from pomegranate fruit possess several pharmacological activities including anti-inflammatory, hepatoprotective, antigenotoxic and anticoagulant activities. The present work focuses the attention on PDIA3 interaction with punicalagin and ellagic acid, the most predominant components of pomegranate extracts. PDIA3, a member of the protein disulfide isomerase family involved in several cellular functions, is associated with different human diseases and it has the potential to be a pharmacological target. METHODS: The interaction of polyphenols with PDIA3 purified protein was explored by fluorescence quenching and calorimetric techniques and their effect on PDIA3 activity was investigated. RESULTS: A higher affinity was observed for punicalagin which also strongly affects PDIA3 reductase activity in vitro as a non-competitive inhibitor. Isothermal titration calorimetry confirmed the high affinity of punicalagin for PDIA3. Considering the PDIA3 involvement in oxidative cellular stress response observed in neuroblastoma cells after treatment with hydrogen peroxide, a comparative study was conducted to evaluate the effect of punicalagin on wild type and PDIA3-silenced cells. Punicalagin increases the cell sensitivity to hydrogen peroxide in neuroblastoma cells, but this effect is drastically reduced in PDIA3-silenced cells treated in the same experimental conditions. CONCLUSIONS: Punicalagin binds PDIA3 and inhibits its redox activity. Comparative experiments conducted on unsilenced and PDIA3-silenced neuroblastoma cells suggest the potential of punicalagin to modulate PDIA3 reductase activity also in a biological model. GENERAL SIGNIFICANCE: Punicalagin can be used as a new PDIA3 inhibitor and this can provide information on the molecular mechanisms underlying the biological activities of PDIA3 and punicalagin. PMID- 29425677 TI - Coffee consumption and decreased all-cause mortality - What is the true estimate of effect? PMID- 29425678 TI - Mesenchymal stromal cell therapy for liver diseases. AB - The therapeutic potential of mesenchymal stromal cells (MSCs) in the treatment of liver fibrosis is predominantly based on their immunosuppressive properties, and their ability to secrete various trophic factors. This potential has been investigated in clinical and preclinical studies. Although the therapeutic mechanisms of MSC transplantation are still not fully characterised, accumulating evidence has revealed that various trophic factors secreted by MSCs play key therapeutic roles in regeneration by alleviating inflammation, apoptosis, and fibrosis as well as stimulating angiogenesis and tissue regeneration in damaged liver. In this review, we summarise the safety, efficacy, potential transplantation routes and therapeutic effects of MSCs in patients with liver fibrosis. We also discuss some of the key strategies to enhance the functionality of MSCs, which include sorting and/or priming with factors such as cytokines, as well as genetic engineering. PMID- 29425679 TI - Environmental Scan of Breastfeeding Resources in Canadian NICUs. AB - We conducted an environmental scan using a mixed methods approach to determine the types and frequencies of breastfeeding resources available to mothers of infants in Canadian NICUs. Through interviews with key informants from 29 Level 3 NICUs, we identified six categories of resources: breastfeeding-friendly layout, breastfeeding support personnel, breastfeeding education for mothers, breast pump related resources, coordination of postdischarge breastfeeding support, and breastfeeding-related policies. Findings from this national study indicate that a wide range of breastfeeding resources were reportedly available in Canadian Level 3 NICUs. NICU professionals are encouraged to connect with other units across Canada to facilitate the exchange of breastfeeding resources and best practices. PMID- 29425681 TI - Differences in the internalization of self-inactivating VSVG-pseudotyped murine leukemia virus-based vectors in human and murine cells. AB - Self-inactivating VSVG-pseudotyped murine leukemia virus (SIN-VSVG-MLV) has been widely used to generate stable cell lines and produce gene delivery vectors. Despite the broad cellular tropism of the VSVG-pseudotyped MLV, we observed differential viral transduction efficiency depending on the host cell type used. In order to determine the mechanism underlying these differences, we used a GFP expressing SIN-VSVG-MLV and analyzed the major steps of viral transduction in different cell lines including human epithelial, T-lymphocytes, monocytes and murine fibroblast cells. We observed the better transduction efficiency in HeLa cells, which was 20-fold higher than THP-1 and NIH/3T3 cells. To quantify viral internalization, we determined genomic RNA content by quantifying the early reverse transcription product. Genomic RNA and transduction levels were correlated with HeLa cells showing the higher amount of early RT product followed by tsA201 cells, while NIH/3T3, Jurkat and THP-1 had the lowest amounts. Similar results were observed when the late reverse transcription product was analyzed. Reverse transcription efficiency was 66-85% in HeLa cells and about 30% in tsA201, NIH/3T3, Jurkat and THP-1 cells. Viral integration, determined by Alu Nested-qPCR, was higher for HeLa and lowerst for Jurkat and THP-1 cells. Interestingly, we observed that viral entry was correlated with the cellular availability of clathrin-mediated endocytosis, which was higher in HeLa and tsA201 cells, potentially explaining the higher rates of SIN-VSVG-MLV transduction and early RT synthesis observed in these cell lines. In conclusion, the SIN-VSVG-MLV vector showed significantly different rates of infectivity depending on the host cell type, possibly due to differential rates of viral internalization. PMID- 29425682 TI - Crucial role of non-coding RNAs in disease. PMID- 29425680 TI - New Coxsackievirus 2Apro and 3Cpro protease antibodies for virus detection and discovery of pathogenic mechanisms. AB - Enteroviruses (EVs), such as the Coxsackie B-viruses (CVBs), are common human pathogens, which can cause severe diseases including meningitis, myocarditis and neonatal sepsis. EVs encode two proteases (2Apro and 3Cpro), which perform the proteolytic cleavage of the CVB polyprotein and also cleave host cell proteins to facilitate viral replication. The 2Apro cause direct damage to the infected heart and tools to investigate 2Apro and 3Cpro expression may contribute new knowledge on virus-induced pathologies. Here, we developed new antibodies to CVB-encoded 2Apro and 3Cpro; Two monoclonal 2Apro antibodies and one 3Cpro antibody were produced. Using cells infected with selected viruses belonging to the EV A, B and C species and immunocytochemistry, we demonstrate that the 3Cpro antibody detects all of the EV species B (EV-B) viruses tested and that the 2Apro antibody detects all EV-B viruses apart from Echovirus 9. We furthermore show that the new antibodies work in Western blotting, immunocyto- and immunohistochemistry, and flow cytometry to detect CVBs. Confocal microscopy demonstrated the expression kinetics of 2Apro and 3Cpro, and revealed a preferential cytosolic localization of the proteases in CVB3 infected cells. In summary, the new antibodies detect proteases that belong to EV species B in cells and tissue using multiple applications. PMID- 29425683 TI - Cynanbungeigenin C and D, a pair of novel epimers from Cynanchum bungei, suppress hedgehog pathway-dependent medulloblastoma by blocking signaling at the level of Gli. AB - Uncontrolled excessive activation of Hedgehog (Hh) signaling pathway is linked to a number of human malignant tumorigenesis. To obtain valuable Hh pathway inhibitors from natural product, in present study, a pair of novel epimers, Cynanbungeigenin C (CBC) and D (CBD) from the plant Cynanchum bungei Decne were chemically characterized by multiple spectroscopic data and chemical derivatization, and evaluated for their inhibition on Hh pathway. Mechanistically, CBC and CBD block Hh pathway signaling not through targeting Smo and Sufu, but at the level of Gli. In addition, both eipmers significantly suppress Hh pathway-dependent Ptch+/-; p53-/- medulloblastoma in vitro and in vivo. Furthermore, both CBC and CBD inhibited two Smo mutants induced Hh pathway activation, which suggested that they are potential compounds for the treatment of medulloblastoma with primary or acquired resistance to current Smo inhibitors. These results highlight the potential of CBC and CBD as effective lead compounds in the treatment of medulloblastoma and other Hh-dependent malignancy. PMID- 29425684 TI - Novel ex vivo ovarian cancer tissue explant assay for prediction of chemosensitivity and response to novel therapeutics. AB - The majority of ovarian cancer patients present with advanced disease and despite aggressive treatment, prognosis remains poor. Response to first-line carboplatin containing chemotherapy is usually good, however, recurrence rates and subsequent chemoresistance are very high and ultimately responsible for the fatal outcome of the disease. To improve treatment outcomes pre-clinical models that can predict individual patient response to 1st line chemotherapy and novel therapeutics are urgently required. In this study, we employed an ex vivo ovarian cancer tissue explant assay to assess response to carboplatin and an inhibitor of the extracellular matrix molecule, hyaluronan (4-methylubelliferone, 4-MU), shown to inhibit cancer metastasis. Cryopreserved ovarian cancer tissues were cultured on gelatine sponges for 48-120 h with increasing concentrations of carboplatin (0 400 MUM) or 4-MU (1 mM) alone or the combination of both drugs. Effects on apoptosis and proliferation were assessed by immunohistochemistry using antibodies to cleaved caspase 3 or Ki67, respectively. The ex vivo tissue explant assay maintained viable tumor cells in an intact tumor microenvironment similar to the in vivo situation over the 120 h culture period. Carboplatin treatment promoted apoptosis in chemosensitive (P = 0.0047) but not chemoresistant cancer tissues. The combination of 4-MU (1 mM) and carboplatin (100 MUM) significantly increased apoptosis (P = 0.0111) and reduced proliferation (P = 0.0064) in chemoresistant tissues. Overall, our results show that the ex vivo explant assay is a robust and cost effective model to assess chemosensitivity and the effect of novel therapeutics in ovarian cancer. PMID- 29425685 TI - Out of the darkness and into the light: New strategies for improving treatments for locally advanced non-small cell lung cancer. AB - The standard treatment for locally advanced non-small cell lung cancer (LA NSCLC) includes surgery, radiotherapy, chemotherapy, or some combination of these modalities. Many clinical trials have been conducted in attempts to intensify treatment for LA NSCLC, but with little improvement. A therapeutic plateau had been reached, with no major progress in extending survival for patients with this disease. However, several recent trials of newer targeted therapies and immunotherapies may shed new light on potential therapeutic breakthroughs. The potential benefits from new targeted therapies and immunotherapies in combination with other forms of therapy for LA NSCLC are sufficiently striking as to change current treatment paradigms. Trials of these agents are moving forward from patients with advanced disease to those with earlier stage disease, and from palliative intent to curative intent, which may well revolutionize treatment strategies that have been considered standard over the past several decades. Future studies are needed to explore the role of targeted therapies and immunotherapies in combination with existing therapies for earlier stage disease and for frontline treatment, either as concurrent or perhaps neoadjuvant or adjuvant approaches. PMID- 29425687 TI - ASC-J9(r) suppresses prostate cancer cell invasion via altering the sumoylation phosphorylation of STAT3. AB - The androgen-deprivation therapy (ADT) to either reduce the androgen biosynthesis (for example, Abiraterone) or to prevent binding of androgen to the androgen receptor (AR), for example using Casodex or Enzalutamide, which may result in .decrease of the prostate cancer (PCa) cell growth, yet may also increase the PCa cell invasion. In contrast, the recently identified AR degradation enhancer ASC J9(r) may function via degrading the AR protein to simultaneously suppress the PCa cell proliferation and invasion. The details of this unique mechanism, however, remain unclear. Here we found that ASC-J9(r) could suppress PCa cell invasion via inducing the sumoylation of STAT3, thereby inhibiting the STAT3 phosphorylation that led to suppress the EMT-SNAIL2 signals in both PCa DU145 and PC3 AR-negative cells. Mutation of lysine-679 on the sumoylation site of the STAT3 effectively blocked the ASC-J9(r)-suppressed PCa cell invasion in both in vitro cell lines and in vivo mouse models. These results suggest that in addition to degrading AR to suppress PCa cell proliferation, ASC-J9(r) can also function through an AR-independent mechanism via modulating the STAT3 sumoylation to alter the phospho-STAT3 status to suppress the PCa cell invasion. These dual functions of ASC-J9(r) to suppress PCa proliferation and invasion (via altering STAT3 sumoylation) may help us to develop a better anti-AR compound that may overcome the current antiandrogens' unwanted side-effect of increasing the metastasis to better suppress the castration-resistant PCa progression. PMID- 29425686 TI - Exosomal microRNAs (exomiRs): Small molecules with a big role in cancer. AB - Exosomes are secreted vesicles which can transmit molecular cargo between cells. Exosomal microRNAs (exomiRs) have drawn much attention in recent years because there is increasing evidence to suggest that loading of microRNAs into exosomes is not a random process. Preclinical studies have identified functional roles for exomiRs in influencing many hallmarks of cancer. Mechanisms underpinning their actions, such as exomiR receptors ("miRceptors"), are now becoming apparent. Even more exciting is the fact that exomiRs are highly suitable candidates for use as non-invasive biomarkers in an era of personalized cancer medicine. PMID- 29425688 TI - Osimertinib resistance in non-small cell lung cancer: Mechanisms and therapeutic strategies. AB - Given the successful identification of epidermal growth factor receptor EGFR T790M, the third-generation EGFR tyrosine kinase inhibitor (TKI), osimertinib (OSI, AZD9291), was developed to target EGFR T790M mutation. OSI was approved for the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation. However, the disease would progress after the patient received OSI treatment for approximately 10 months. Resistance mechanisms to OSI, such as additional mutation of EGFR and alternative kinase activation, were recently identified, and some novel therapeutic strategies were proposed to overcome OSI resistance. In this review, the resistance mechanisms and therapeutic strategies for OSI-resistant NSCLC were summarized to direct further use of OSI and aid in the development of novel drugs or strategies for OSI-resistant NSCLC. PMID- 29425689 TI - An easy-to-use liquid chromatography method with fluorescence detection for the simultaneous determination of five neuroactive amino acids in different regions of rat brain. AB - INTRODUCTION: To comprehend the normal function and pathological characteristics of certain neurological disorders it is important to evaluate the neuroactive amino acids levels in animal models. METHODS: This work describes a simple liquid chromatography-fluorescence detection (LC-FLD) method for the simultaneous determination of aspartic acid (Asp), glutamic acid (Glu), glutamine (Gln), taurine (Tau) and gamma-aminobutyric acid (GABA), using methyl-L-arginine as internal standard, in samples of rat brain tissue. The five target analytes (Asp, Glu, Gln, Tau and GABA) were determined in a single chromatographic run of less 11 min after a derivatization step with o-phthalaldehyde. The derivatives were separated on a reversed-phase C18 column and detected by fluorescence at excitation and emission wavelengths of 340 and 448 nm, respectively. RESULTS: The method was validated in accordance with international guidelines on bioanalytical methods validation and it presented limits of quantification in the range of 25 50 ng mL-1 and calibration curves with determination coefficients (r2) equal to or higher than 0.9920. In addition, the precision (coefficient variation, %) and accuracy (bias, %) of the method meet the established criteria, and the stability of the analytes at the sample handling and storage conditions was demonstrated. DISCUSSION: Unlike other similar bioanalytical assays, the current method was validated using diluted biological matrix, which is advantageous in order to ensure the derivatization process integrity. Moreover, this LC-FLD method was successfully applied for the determination of the compounds of interest in different rat brain tissue regions (frontal cortex, amygdala, hippocampus, cerebellum and striatum). Thus, this bioanalytical assay represents a useful tool to support multiple nonclinical studies in the field of neurosciences, requiring the quantitative profiling and pattern analysis of neuroactive amino acids. PMID- 29425691 TI - The intracellular region of silkworm cadherin-like protein is not necessary to mediate the toxicity of Bacillus thuringiensis Cry1Aa and Cry1Ab toxins. AB - The cadherin-like protein in lepidopteran insects, known as a receptor for Bacillus thuringiensis Cry1A toxins, is a single-pass membrane protein that can be divided into extracellular and intracellular regions. The extracellular region is important for toxin binding and oligomerization, whereas the role of the intracellular region during Cry1A intoxication is unclear. In the present study, we generated a deletion mutant of Bombyx mori cadherin-like protein (BtR175) that lacked the intracellular region to investigate its role in mediating Cry1A toxicity. Like wild-type BtR175, the mutant protein conferred susceptibility to Cry1Aa and Cry1Ab toxins in Sf9 cells, suggesting that the intracellular region is not required to mediate intoxication. The deletion mutant maintained another role of cadherin-like proteins; that it, synergistic activity with B. mori ABC transporter C2 (ABCC2) when mediating Cry1Aa and Cry1Ab toxicity. In addition, we evaluated the effects of reagents that have been reported to inhibit Cry1A toxicity (e.g., protein kinase A inhibitors, EDTA, and sucrose) on Cry1A toxicity in BtR175-expressing cells. Our results suggest that Cry1Aa-induced cell death in BtR175-expressing cells was not caused by signal transduction but by osmotic lysis. Overall, our data indicate that BtR175 mediates the toxicity of Cry1Aa and Cry1Ab toxins entirely via its extracellular region. They also indicate that the synergism between cadherin-like protein and ABCC2 occurs outside of cells or in the cell membrane. PMID- 29425692 TI - A rapidly acquired foraging-based working memory task, sensitive to hippocampal lesions, reveals age-dependent and age-independent behavioural changes in a mouse model of amyloid pathology. AB - Three experiments examined the ability of mice to forage efficiently for liquid rewards in pots located in an open field arena. Search behaviour was unconstrained other than by the walls of the arena. All mice acquired the task within 4 days of training, with one trial per day. Experiment 1 tested the hypothesis that hippocampal lesions would disrupt foraging behaviour using extramaze cues. Mice with hippocampal lesions showed normal latency to initiate foraging and to complete the task relative to sham-operated mice. However, lesioned mice showed increased perseverative responding (sensitization) to recently rewarded locations, increased total working memory errors and an increased propensity to search near previously rewarded locations. In Experiment 2, the extramaze cues were obscured and each pot was identified by a unique pattern. Under these conditions, mice with hippocampal lesions showed comparable working memory errors to control mice. However, lesioned mice continued to display increased perseverative responding and altered search strategies. Experiment 3 tested the hypothesis that age-related accumulation of amyloid would disrupt foraging behaviour in transgenic PDAPP mice expressing the V717F amyloid precursor protein (APP) mutation. Consistent with previous findings, PDAPP mice showed both age-dependent and age-independent behavioural changes. More specifically, 14-16 month-old PDAPP mice showed a deficit in perseverative responding and working memory errors. In contrast, changes in search behaviour, such as systematic circling, were present throughout development. The latter indicates that APP overexpression contributed to some features of the PDAPP behavioural phenotype, whereas working memory and flexible responding was sensitive to ageing and beta-amyloid burden. In conclusion, the present study provided novel insight into the role of the hippocampus and the effects of APP overexpression on memory and search behaviour in an open-field foraging task. PMID- 29425690 TI - Light-induced oxidant production by fluorescent proteins. AB - Oxidants play an important role in the cell and are involved in many redox processes. Oxidant concentrations are maintained through coordinated production and removal systems. The dysregulation of oxidant homeostasis is a hallmark of many disease pathologies. The local oxidant microdomain is crucial for the initiation of many redox signaling events; however, methods to control oxidant product are limited. Some fluorescent proteins, including GFP, TagRFP, KillerRed, miniSOG, and their derivatives, generate oxidants in response to light. These genetically-encoded photosensitizers produce singlet oxygen and superoxide upon illumination and offer spatial and temporal control over oxidant production. In this review, we will examine the photosensitization properties of fluorescent proteins and their application to redox biology. Emerging concepts of selective oxidant species production via photosensitization and the impact of light on biological systems are discussed. PMID- 29425693 TI - Clinical levofloxacin-resistant Streptococcus pneumoniae isolates in North Africa. PMID- 29425695 TI - Hyaluronan in the lymphatics: The key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking. AB - LYVE-1, a close relative of the leucocyte receptor, CD44, is the main receptor for hyaluronan (HA) in lymphatic vessel endothelium and a widely used marker for distinguishing between blood and lymphatic vessels. Enigmatic for many years because of its anomalous HA-binding characteristics, the function of LYVE-1 has just recently been identified as that of a lymphatic docking receptor for dendritic cells, selectively engaging with their surface HA glycocalyx to regulate entry to peripheral lymphatics and migration to downstream lymph nodes for immune activation. Furthermore, LYVE-1 mediates the trafficking of macrophages, and is also exploited by HA-encapsulated Group A streptococci for lymphatic invasion and host dissemination. Consistent with a role in lymphatic trafficking, the interaction of LYVE-1 with HA and its degradation products can also activate intracellular signalling pathways for endothelial junctional retraction and lymphatic endothelial proliferation. Here we outline the latest findings on the receptor in the context of its peculiar biochemical properties and speculate on how the interaction of LYVE-1 with different HA sizes and conformations might variably influence cell function as a consequence of avidity and receptor crosslinking. Finally, we evaluate evidence that LYVE-1 can also bind growth factors and associate with kinase-linked growth factor receptors and conclude on how the LYVE-1.HA axis may be exploited as a target to either block inflammation or tissue allograft rejection, or potentiate vaccine and drug delivery. PMID- 29425694 TI - Renal fibrosis: Primacy of the proximal tubule. AB - Tubulointerstitial fibrosis (TIF) is the hallmark of chronic kidney disease and best predictor of renal survival. Many different cell types contribute to TIF progression including tubular epithelial cells, myofibroblasts, endothelia, and inflammatory cells. Previously, most of the attention has centered on myofibroblasts given their central importance in extracellular matrix production. However, emerging data focuses on how the response of the proximal tubule, a specialized epithelial segment vulnerable to injury, plays a central role in TIF progression. Several proximal tubular responses such as de-differentiation, cell cycle changes, autophagy, and metabolic changes may be adaptive initially, but can lead to maladaptive responses that promote TIF both through autocrine and paracrine effects. This review discusses the current paradigm of TIF progression and the increasingly important role of the proximal tubule in promoting TIF both in tubulointerstitial and glomerular injuries. A better understanding and appreciation of the role of the proximal tubule in TIF has important implications for therapeutic strategies to halt chronic kidney disease progression. PMID- 29425697 TI - Descriptive Findings of the VA Polytrauma Rehabilitation Centers TBI Model Systems National Database. AB - OBJECTIVES: To present initial descriptive findings from the Veterans Affairs (VA) Polytrauma Rehabilitation Centers (PRC) Traumatic Brain Injury (TBI) Model Systems (MS) National Database. DESIGN: Prospective cohort study. SETTING: VA PRC TBIMS National Database. PARTICIPANTS: 712 service members and veterans with TBI who consented to participate between January 2010 and June 2015. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Demographics, preinjury characteristics, injury characteristics, rehabilitation course, functional outcomes, and discharge disposition by TBI severity level. RESULTS: The study cohort was predominantly male with moderate to severe TBI secondary to vehicular accident or blast injury. Sixty-five percent were active duty service members; one-third had been injured during deployment. One-third reported mental health treatment and/or alcohol use problems in the year predating the index TBI. The median number of days between injury and PRC admission was 42.5. Nearly 25% reported clinical levels of posttraumatic stress disorder; 75% reported mild to moderate neurobehavioral symptomatology. The median length of stay in the PRC was 36 days; those with severe TBI had the longest lengths of stay. Functional independence ratings improved from admission to discharge across all TBI severity levels. A majority were discharged to urban areas to reside with spouses or other residents in private residences or adult homes, with some variability by injury severity. CONCLUSIONS: The VA PRC TBIMS national database is a rich source of information on a unique group of individuals with TBI and promises to complement existing knowledge on TBI in the civilian population. PMID- 29425698 TI - Assessment of Sleep Quantity and Sleep Disturbances During Recovery From Sports Related Concussion in Youth Athletes. AB - OBJECTIVE: To determine the relation between sleep quantity and sleep disturbances on symptoms and neurocognitive ability during the acute phase (<7d) and after sports-related concussion (SRC; >21d). DESIGN: Prospective inception cohort study. SETTING: General community setting of regional middle and high schools. PARTICIPANTS: A sample (N=971) including youth athletes with SRC (n=528) and controls (n=443) (age, 10-18y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Athletes completed the Immediate Post-Concussion Assessment and Cognitive Testing battery. Partial correlation analyses and independent t tests were conducted to assess sleep quantity the night before testing. Multivariate analysis of covariance was used to assess sleep disturbances and their interaction with age. RESULTS: Less sleep quantity was correlated with greater report of cognitive (P=.001) and neuropsychological (P=.024) symptoms specific to prolonged recovery from SRC. Sleep disturbances significantly affect each migraine, cognitive, and neuropsychological symptoms (P<.001). A significant interaction was found between sleep disturbances and age (P=.04) at >21 days post SRC. CONCLUSIONS: Findings emphasize that the continued presence of low sleep quantity and sleep disturbances in youth athletes with SRC should be a specific indicator to health professionals that these athletes are at an increased risk of protracted recovery. Further research should identify additional factors that may interact with sleep to increase the risk of protracted recovery. PMID- 29425696 TI - The pericellular hyaluronan of articular chondrocytes. AB - The story of hyaluronan in articular cartilage, pericellular hyaluronan in particular, essentially is also the story of aggrecan. Without properly tethered aggrecan, the load bearing function of cartilage is compromised. The anchorage of aggrecan to the cell surface only occurs due to the binding of aggrecan to hyaluronan-with hyaluronan tethered either to a hyaluronan synthase or by multivalent binding to CD44. In this review, details of hyaluronan synthesis are discussed including how HAS2 production of hyaluronan is necessary for normal chondrocyte development and matrix assembly, how an abundance or deficit of pericellular hyaluronan alters chondrocyte metabolism, and whether hyaluronan size matters or changes with aging or disease. The biomechanical role and matrix assembly function of hyaluronan in addition to the functions of hyaluronidases are discussed. The turnover of hyaluronan is considered including mechanisms by which its turnover, at least in part, is mediated by endocytosis by chondrocytes and regulated by aggrecan degradation. Differences between turnover and clearance of newly synthesized hyaluronan and aggrecan versus the half-life of hyaluronan remaining within the inter-territorial matrix of cartilage are discussed. The release of neutral pH-acting hyaluronidase activity remains one unanswered question concerning the loss of cartilage hyaluronan in osteoarthritis. Signaling events driven by changes in hyaluronan-chondrocyte interactions may involve a chaperone function of CD44 with other receptors/cofactors as well as the changes in hyaluronan production functioning as a metabolic rheostat. PMID- 29425700 TI - Muscular Strength as a Predictor of All-Cause Mortality in an Apparently Healthy Population: A Systematic Review and Meta-Analysis of Data From Approximately 2 Million Men and Women. AB - OBJECTIVES: The aims of the present systematic review and meta-analysis were to determine the relationship between muscular strength and all-cause mortality risk and to examine the sex-specific impact of muscular strength on all-cause mortality in an apparently healthy population. DATA SOURCES: Two authors systematically searched MEDLINE, EMBASE and SPORTDiscus databases and conducted manual searching of reference lists of selected articles. STUDY SELECTION: Eligible cohort studies were those that examined the association of muscular strength with all-cause mortality in an apparently healthy population. The hazard ratio (HR) estimates with 95% confidence interval (CI) were pooled by using random effects meta-analysis models after assessing heterogeneity across studies. DATA EXTRACTION: Two authors independently extracted data. DATA SYNTHESIS: Thirty eight studies with 1,907,580 participants were included in the meta-analysis. The included studies had a total of 63,087 deaths. Higher levels of handgrip strength were associated with a reduced risk of all-cause mortality (HR=0.69; 95% CI, 0.64 0.74) compared with lower muscular strength, with a slightly stronger association in women (HR=0.60; 95% CI, 0.51-0.69) than men (HR=0.69; 95% CI, 0.62-0.77) (all P<.001). Also, adults with higher levels of muscular strength, as assessed by knee extension strength test, had a 14% lower risk of death (HR=0.86: 95% CI, 0.80-0.93; P<.001) compared with adults with lower muscular strength. CONCLUSIONS: Higher levels of upper- and lower-body muscular strength are associated with a lower risk of mortality in adult population, regardless of age and follow-up period. Muscular strength tests can be easily performed to identify people with lower muscular strength and, consequently, with an increased risk of mortality. PMID- 29425699 TI - Evaluating the Use of Medicare Part D in the Veteran Population With Spinal Cord Injury/Disorder. AB - OBJECTIVE: To examine the different sources of medications, the most common drug classes filled, and the characteristics associated with Medicare Part D pharmacy use in veterans with spinal cord injury/disorder (SCI/D). DESIGN: Retrospective, cross-sectional, observational study. SETTING: Outpatient clinics and pharmacies. PARTICIPANTS: Veterans (N=13,442) with SCI/D using Medicare or Veteran Affairs pharmacy benefits. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Characteristics and top 10 most common drug classes were examined in veterans who (1) used VA pharmacies only; (2) used both VA and Medicare Part D pharmacies; or (3) used Part D pharmacies only. Chi-square tests and multinomial logistic regression analyses were used to determine associations between various patient variables and source of medications. Patient level frequencies were used to determine the most common drug classes. RESULTS: A total of 13,442 veterans with SCI/D were analyzed in this study: 11,788 (87.7%) used VA pharmacies only, 1281 (9.5%) used both VA and Part D pharmacies, and 373 (2.8%) used Part D pharmacies only. Veterans older than 50 years were more likely to use Part D pharmacies, whereas those with traumatic injury, or secondary conditions, were less associated with the use of Part D pharmacies. Opioids were the most frequently filled drug class across all groups. Other frequently used drug classes included skeletal muscle relaxants, gastric medications, antidepressants (other category), anticonvulsants, and antilipemics. CONCLUSIONS: Approximately 12% of veterans with SCI/D are receiving medication outside the VA system. Polypharmacy in this population of veterans is relatively high, emphasizing the importance of health information exchange between systems for improved care for this medically complex population. PMID- 29425701 TI - Temporal map formation in appetitive second-order conditioning in rats. AB - Three experiments examined whether second-order conditioning resulted in the formation of a fully-featured temporal map, as proposed by the temporal coding hypothesis. Experiments 1 and 2 examined second-order conditioning with different first- and second-order relationships. Measures of the strength of second-order conditioning were mostly consistent with the temporal coding hypothesis; second order conditioning was best with arrangements in which CS2 occurred prior to the time that the US normally occurred during CS1-US presentations. However, there was no evidence of anticipatory timing during CS2 during second-order conditioning. A third experiment directly examined whether a fully-featured temporal map was formed during second-order conditioning by examining the acquisition of anticipatory timing in subsequent reinforced second-order trials. The results of Experiment 3 suggested that the effects obtained in Experiments 1 and 2 were due to learning of the temporal order and coincidence of events that resulted in the formation of an ordinal temporal map, but that precise durations were not encoded. PMID- 29425702 TI - Harmonising phenomics information for a better interoperability in the rare disease field. AB - HIPBI-RD (Harmonising phenomics information for a better interoperability in the rare disease field) is a three-year project which started in 2016 funded via the E-Rare 3 ERA-NET program. This project builds on three resources largely adopted by the rare disease (RD) community: Orphanet, its ontology ORDO (the Orphanet Rare Disease Ontology), HPO (the Human Phenotype Ontology) as well as PhenoTips software for the capture and sharing of structured phenotypic data for RD patients. Our project is further supported by resources developed by the European Bioinformatics Institute and the Garvan Institute. HIPBI-RD aims to provide the community with an integrated, RD-specific bioinformatics ecosystem that will harmonise the way phenomics information is stored in databases and patient files worldwide, and thereby contribute to interoperability. This ecosystem will consist of a suite of tools and ontologies, optimized to work together, and made available through commonly used software repositories. The project workplan follows three main objectives: The HIPBI-RD ecosystem will contribute to the interpretation of variants identified through exome and full genome sequencing by harmonising the way phenotypic information is collected, thus improving diagnostics and delineation of RD. The ultimate goal of HIPBI-RD is to provide a resource that will contribute to bridging genome-scale biology and a disease centered view on human pathobiology. Achievements in Year 1. PMID- 29425703 TI - Training and Validating a Portable Electronic Nose for Lung Cancer Screening. AB - INTRODUCTION: Profiling volatile organic compounds in exhaled breath enables the diagnosis of several types of cancer. In this study we investigated whether a portable point-of-care version of an electronic nose (e-nose) (Aeonose, [eNose Company, Zutphen, the Netherlands]) is able to discriminate between patients with lung cancer and healthy controls on the basis of their volatile organic compound pattern. METHODS: In this study, we used five e-nose devices to collect breath samples from patients with lung cancer and healthy controls. A total of 60 patients with lung cancer and 107 controls exhaled through an e-nose for 5 minutes. Patients were assigned either to a training group for building an artificial neural network model or to a blinded control group for validating this model. RESULTS: For differentiating patients with lung cancer from healthy controls, the results showed a diagnostic accuracy of 83% with a sensitivity of 83%, specificity of 84%, and area under the curve of 0.84. Results for the blinded group showed comparable results, with a sensitivity of 88%, specificity of 86%, and diagnostic accuracy of 86%. CONCLUSION: This feasibility study showed that this portable e-nose can properly differentiate between patients with lung cancer and healthy controls. This result could have important implications for future lung cancer screening. Further studies with larger cohorts, including also more participants with early-stage tumors, should be performed to increase the robustness of this noninvasive diagnostic tool and to determine its added value in the diagnostic chain for lung cancer. PMID- 29425704 TI - A Measured Solution: Klinefelter Syndrome. PMID- 29425705 TI - A Plethora of Pustules: Acute Generalized Exanthematous Pustulosis. PMID- 29425706 TI - Diabetic Cystopathy with Bilateral Hydronephrosis. PMID- 29425708 TI - Will Cardio-Virology Be the Next Cardio-Oncology? PMID- 29425707 TI - Dementia. AB - Dementia is any decline in cognition that is significant enough to interfere with independent, daily functioning. Dementia is best characterized as a syndrome rather than as one particular disease. The causes of dementia are myriad and include primary neurologic, neuropsychiatric, and medical conditions. It is common for multiple diseases to contribute to any one patient's dementia syndrome. Neurodegenerative dementias, like Alzheimer disease and dementia with Lewy bodies, are most common in the elderly, while traumatic brain injury and brain tumors are common causes in younger adults. While the recent decade has seen significant advancements in molecular neuroimaging, in understanding clinico pathologic correlation, and in the development of novel biomarkers, clinicians still await disease-modifying therapies for neurodegenerative dementias. Until then, clinicians from varied disciplines and medical specialties are well poised to alleviate suffering, aggressively treat contributing conditions, employ medications to improve cognitive, neuropsychiatric, and motor symptoms, promote evidence-based brain-healthy behaviors, and improve overall quality of life for patients and families. PMID- 29425709 TI - Intracranial rat glioma model for tumor resection and local treatment. AB - BACKGROUND: Although tumor resection is among the most important prognostic factors, high grade gliomas regrow in most cases. Also, resection of glial tumors in eloquent brain regions is not or only partially possible. Despite these severe restraints, however, only a few in-vivo models have been established to investigate tumor recurrence and local treatment. Here we characterize the intracranial BT4Ca rat glioma as a model for these aspects. NEW METHOD: BT4Ca cells were stereotaxically implanted into the frontal cortex of BDIX rats. Rats were than allocated to (1) a control group, which received no further treatment; (2) a catheter group, where a catheter was implanted for repeated microinjection of vehicle every 3rd day as catheter-control; (3) a resection group, where the tumor was microsurgically removed eight days after cell injection. Postoperatively, survival time, weight and general health condition were scored and the tumor size was histologically assessed. RESULTS: Injection of BT4Ca cells induced fast-growing tumors with a mean survival time of 16 days in the control and catheter groups. Resection significantly prolonged survival time whereby the tumor regrew in all rats. Tumor size was similar between all groups. COMPARISON WITH EXISTING METHOD(S): We here present a robust and reliable intracranial rat glioma model, which is suitable to simulate tumor recurrence after surgical resection and local treatment. Importantly, this model does not require advanced imaging or elaborate surgical techniques. CONCLUSIONS: The intracranial BT4Ca glioma model appears to be a feasible tool to investigate tumor recurrence after resection and to test local treatment. PMID- 29425710 TI - Seronegative alveolar echinococcosis in a patient with multiple myeloma. PMID- 29425711 TI - Scurvy as a mimicker of osteomyelitis in a child with autism spectrum disorder. AB - A case of scurvy in a 10-year-old boy with autism spectrum disorder is described. His clinical presentation was initially thought to be due to osteomyelitis, for which empirical antimicrobial therapy was initiated. Further invasive and ultimately unnecessary investigations were avoided when scurvy was considered in the context of a restricted diet and classic signs of vitamin C deficiency. Infectious diseases specialists should be aware of scurvy as an important mimicker of osteoarticular infections when involved in the care of patients at risk of nutritional deficiencies. PMID- 29425713 TI - The effect of oxidative stress induced by tert-butylhydroperoxide under distinct folic acid conditions: An in vitro study using cultured human trophoblast-derived cells. AB - Preeclampsia is a pregnancy disorder characterized by high maternal blood pressure, fetal growth restriction and intrauterine hypoxia. Folic acid is a vitamin required during pregnancy. In this work, we investigated the relationship between preeclampsia and the intake of distinct doses of folic acid during pregnancy. Considering that preeclampsia is associated with increased placental oxidative stress levels, we investigated the effect of oxidative stress induced by tert-butylhydroperoxide (TBH) in human trophoblast-derived cells cultured upon deficient/low, physiological and supra-physiological folic acid levels. The negative effect of TBH upon thiobarbituric acid reactive substances (TBARS), total, reduced and oxidized glutathione, cell viability, cell proliferation, culture growth and cell migration was more marked under folic acid excess. This study suggests more attention on the dose administered, and ultimately, on the overall folic acid levels during pregnancy, in the context of preeclampsia risk. PMID- 29425714 TI - Leucyl-tRNA synthetase is required for the myogenic differentiation of C2C12 myoblasts, but not for hypertrophy or metabolic alteration of myotubes. AB - Mammalian target of rapamycin (mTOR) signaling controls skeletal muscle cell differentiation, growth, and metabolism by sensing the intracellular energy status and nutrients. Recently, leucyl-tRNA synthetase (Lars) was identified as an intracellular sensor of leucine involved in the activation of mTOR signaling. However, there is still no evidence for the activation of mTOR signaling by Lars and its physiological roles in skeletal muscle cells. In this study, we determined the potential roles of Lars for the activation of mTOR signaling, skeletal muscle cell differentiation, hypertrophy, and metabolism using small interfering (si)-RNA knockdown. siRNA-mediated knockdown of Lars decreased phosphorylated p70 S6 kinase and inhibited the differentiation of C2C12 mouse myoblasts into myotubes, as evidenced by a decreased fusion index and decreased mRNA and protein expression levels of myogenic markers. Importantly, si-Lars decreased the level of Insulin-like growth factor 2 (Igf2) mRNA expression from the early stages of differentiation, indicating the possibility of an association between the mTOR-IGF2 axis and Lars. However, Lars knockdown did not decrease phosphorylated mTOR in differentiated myotubes, nor did it affect the hypertrophy of myotubes as evidenced by measuring their diameters and detecting the mRNA and protein expression of hypertrophy markers. Similarly, an extracellular flux analyzer showed that Lars knockdown did not affect the metabolism (glycolysis and mitochondrial respiration) of myotubes. These results demonstrate that Lars is required for skeletal muscle differentiation through the activation of mTOR signaling, but not for hypertrophy or metabolic alteration of myotubes. PMID- 29425712 TI - A utilitarian comparison of two alcohol use biomarkers with self-reported drinking history collected in antenatal clinics. AB - BACKGROUND: Alcohol use is reported accurately among pregnant women in some populations. METHODS: Self-reported alcohol use via the AUDIT and 90-day recall for 193 women from antenatal clinics was compared to biomarker results: phosphatidylethanol (PEth) from bloodspots and ethyl glucuronide (EtG) in fingernails. RESULTS: AUDIT was positive for 67.9% of respondents, and 65.3% directly reported drinking. Individual biomarkers detected less drinking (PEth = 57.0%, EtG = 38.9%) than self-report. But 64.8% had drinking-positive values (>8 ng) on one or both biomarkers, which was not significantly different from self report. Biomarkers indicated that 3.1% -6.8% of drinkers denied drinking. Combined biomarker sensitivity was 95% -80% and specificity 49% -76% for drinking in the previous 7-90 days. Combined biomarker results have their best yield (89.6%) and accuracy (78.8%) when measuring 90 day drinking. CONCLUSIONS: Women reported their alcohol use accurately, and the combined use of PEth and EtG is supported. PMID- 29425715 TI - Three-dimensional micro-scale strain mapping in living biological soft tissues. AB - : Non-invasive characterization of the mechanical micro-environment surrounding cells in biological tissues at multiple length scales is important for the understanding of the role of mechanics in regulating the biosynthesis and phenotype of cells. However, there is a lack of imaging methods that allow for characterization of the cell micro-environment in three-dimensional (3D) space. The aims of this study were (i) to develop a multi-photon laser microscopy protocol capable of imprinting 3D grid lines onto living tissue at a high spatial resolution, and (ii) to develop image processing software capable of analyzing the resulting microscopic images and performing high resolution 3D strain analyses. Using articular cartilage as the biological tissue of interest, we present a novel two-photon excitation imaging technique for measuring the internal 3D kinematics in intact cartilage at sub-micrometer resolution, spanning length scales from the tissue to the cell level. Using custom image processing software, we provide accurate and robust 3D micro-strain analysis that allows for detailed qualitative and quantitative assessment of the 3D tissue kinematics. This novel technique preserves tissue structural integrity post-scanning, therefore allowing for multiple strain measurements at different time points in the same specimen. The proposed technique is versatile and opens doors for experimental and theoretical investigations on the relationship between tissue deformation and cell biosynthesis. Studies of this nature may enhance our understanding of the mechanisms underlying cell mechano-transduction, and thus, adaptation and degeneration of soft connective tissues. STATEMENT OF SIGNIFICANCE: We presented a novel two-photon excitation imaging technique for measuring the internal 3D kinematics in intact cartilage at sub-micrometer resolution, spanning from tissue length scale to cellular length scale. Using a custom image processing software (lsmgridtrack), we provide accurate and robust micro-strain analysis that allowed for detailed qualitative and quantitative assessment of the 3D tissue kinematics. The approach presented here can also be applied to other biological tissues such as meniscus and annulus fibrosus, as well as tissue-engineered tissues for the characterization of their mechanical properties. This imaging technique opens doors for experimental and theoretical investigation on the relationship between tissue deformation and cell biosynthesis. Studies of this nature may enhance our understanding of the mechanisms underlying cell mechano-transduction, and thus, adaptation and degeneration of soft connective tissues. PMID- 29425716 TI - Biological connective tissues exhibit viscoelastic and poroelastic behavior at different frequency regimes: Application to tendon and skin biophysics. AB - : In this study, a poroviscoelastic finite element model (FEM) was developed and used in conjunction with an AFM-based wide-bandwidth nanorheology system to predict the frequency-dependent mechanical behavior of tendon and dermis subjected to compression via nanoindentation. The aim was to distinguish between loading rates that are dominated by either poroelasticity, viscoelasticity, or the superposition of these processes. Using spherical probe tips having different radii, the force and tip displacement were measured and the magnitude, E*, and phase angle, phi, of the dynamic complex modulus were evaluated for mouse supraspinatus tendon and mouse dermis. The peak frequencies of the phase angle were associated with the characteristic time constants of poroelastic and viscoelastic material behavior. The developed FE model could predict the separate poroelastic and viscoelastic responses of these soft tissues over a 4 decade frequency range, showing good agreement with experimental results. We observed that poroelasticity was the dominant energy dissipation mechanism for mouse dermis and supraspinatus tendon at higher indentation frequencies (102 to 104 Hz) whereas viscoelasticity was typically dominant at lower frequencies (<102 Hz). These findings show the underlying mechanical behavior of biological connective tissues and give insight into the role played by these different energy dissipation mechanisms in governing the function of these tissues at nanoscale. STATEMENT OF SIGNIFICANCE: Soft biological tissues exhibit complex, load- and time-dependent mechanical behavior. Evaluating their mechanical behavior requires sophisticated experimental tools and numerical models that can capture the fundamental mechanisms governing tissue function. Using an Atomic-force microscopy-based rheology system and finite element models, the roles of the two most dominant time-dependent mechanisms (poroelasticity and viscoelasticity) that govern the dynamic loading behavior of mouse skin and tendon have been investigated. FE models were able to predict and quantify the contribution of each mechanism to the overall dynamic response and confirming the presence of these two distinct mechanisms in the mechanical response. Overall, these results provide novel insight into the viscoelastic and poroelastic properties of mouse skin and tendon and promote better understanding of the underlying origins of each mechanism. PMID- 29425717 TI - Localized delivery of miRNAs targets cyclooxygenases and reduces flexor tendon adhesions. AB - : The formation of adhesions during healing of an injured tendon remains a difficult problem in clinical practice. Local anti-inflammation gene delivery provides high local gene concentration, reduces the inflammatory response of the injured tendon microenvironment, and decreases systemic side effects to enhance in vivo efficacy. In this study, we designed a novel local sustained gene delivery system by using cyclooxygenase (COX-1 and COX-2)-engineered miRNA plasmid/nanoparticles embedded in hyaluronic acid (HA) hydrogel to reduce flexor tendon adhesions. The local sustained gene delivery system significantly downregulates COX-1 and COX-2 expression in the tendon tissue and the surrounding subcutaneous tissue. More importantly, this plasmid/nanoparticle hydrogel system significantly reduced tissue adhesion formation. This approach offers an effective therapeutic strategy to reduce tendon adhesions by directly targeting the down-regulation of COX-1 and COX-2 expression within the microenvironment of the injured tendon. STATEMENT OF SIGNIFICANCE: A local sustained gene delivery system was developed to regulate the expression of targeted genes in the specific time and location for tendon adhesion treatment. The engineered miRNA plasmid/nanoparticles embedded in hyaluronic acid hydrogel were synthesized to downregulate the expression of cyclooxygenases in the tendon tissue during the early stage of tendon healing with inflammatory response. This plasmid/nanoparticle hydrogel system offers an effective therapeutic strategy to attenuate the formation of tendon adhesion through direct downregulation of COX-1 and COX-2 expression within the microenvironment of the injured tendon. PMID- 29425718 TI - Effect of strontium surface-functionalized implants on early and late osseointegration: A histological, spectrometric and tomographic evaluation. AB - : Numerous in vivo, in vitro and clinical studies report on beneficial effects of strontium with respect to increased bone growth. Based on this knowledge the aim of this study was to evaluate early and late osseointegration stages of functionalized titanium implants showing sustained release of strontium (Sr) and further investigate its potential systemic effect. Strontium functionalized (Ti Sr-O) and Grade 4 (Control) titanium implants were inserted in the femoral condyle of New Zealand White rabbits. The Ti-Sr-O coating was characterized using Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray Spectrometry (EDX) for structure, coating thickness and chemical composition. Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES) was used to evaluate released strontium in vitro while Atomic Absorption Spectrometry (AAS) was utilized to monitor serum levels of strontium and calcium. Additionally, histological and tomographic analysis of bone-to-implant contact (BIC%) and bone formation (BF%) was performed, following implantation periods of two or twelve weeks, respectively. Median values for BIC% for Ti-Sr-O revealed significant differences within the two- and twelve-week observation periods, while exceeding BF% was discovered especially after twelve weeks when performing the histological evaluation. The results from the micro-computed tomography (u-CT) showed no significant differences, when comparing the experimental groups. AAS measurements did not indicate a systemic effect by the local strontium release. Within the limitations of the study, it was shown that a Ti-Sr-O coating with sustained release characteristics of strontium, accelerates bone apposition and represents a potential potent surface modification for endosseous medical implant devices. STATEMENT OF SIGNIFICANCE: This study presents first data with respect to early and late in vivo response on a strontium functionalized titanium surface comprising a nanotopography manufactured by a magnetron sputtering process. We investigated different osseointegration stages of screw-shaped implants with dental implant geometries in a rabbit femur model observing beneficial effects of the functionalized surface on bone-to-implant contact and bone formation caused by tailored release of the bone anabolic strontium. Histomorphometrical data revealed that a functionalized titanium surface with controlled liberation of strontium accelerates osseointegration while spectrometry measurements did not indicate a potential systemic effect of this osteoinductive agent and could thus have impact on modifications of medical implant devices. PMID- 29425719 TI - Cell reprogramming by 3D bioprinting of human fibroblasts in polyurethane hydrogel for fabrication of neural-like constructs. AB - : 3D bioprinting is a technique which enables the direct printing of biodegradable materials with cells into 3D tissue. So far there is no cell reprogramming in situ performed with the 3D bioprinting process. Forkhead box D3 (FoxD3) is a transcription factor and neural crest marker, which was reported to reprogram human fibroblasts into neural crest stem-like cells. In this study, we synthesized a new biodegradable thermo-responsive waterborne polyurethane (PU) gel as a bioink. FoxD3 plasmids and human fibroblasts were co-extruded with the PU hydrogel through the syringe needle tip for cell reprogramming. The rheological properties of the PU hydrogel including the modulus, gelation time, and shear thinning were optimized for the transfection effect of FoxD3 in situ. The corresponding shear rate and shear stress were examined. Results showed that human fibroblasts could be reprogrammed into neural crest stem-like cells with high cell viability during the extrusion process under an average shear stress ~190 Pa. We further translated the method to the extrusion-based 3D bioprinting, and demonstrated that human fibroblasts co-printed with FoxD3 in the thermo responsive PU hydrogel could be reprogrammed and differentiated into a neural tissue like construct at 14 days after induction. The neural-like tissue construct produced by 3D bioprinting from human fibroblasts may be applied to personalized drug screening or neuroregeneration. STATEMENT OF SIGNIFICANCE: There is no study so far on cell reprogramming in situ with 3D bioprinting. In this manuscript, a new thermoresponsive polyurethane bioink was developed and employed to deliver FoxD3 plasmid into human fibroblasts by the extrusion-based bioprinting. When the polyurethane gel was extruded through the syringe tip, the shear stress generated may have caused the transient membrane permeability for transfection. The shear stress was optimized for transfection in situ by 3D bioprinting. We demonstrated that human fibroblasts could be reprogrammed into neural crest-like stem cells by 3D bioprinting with the gel, and the reprogrammed cells underwent neural differentiation in the printed structure after induction. The neural-like tissue engineering constructs fabricated by 3D bioprinting from human fibroblasts may be applied for neuroregeneration or further developed as mini-brain for basic research and drug screening. PMID- 29425720 TI - Nanoengineered injectable hydrogels for wound healing application. AB - : We report injectable nanoengineered hemostats for enhanced wound healing and tissue regeneration. The nanoengineered system consists of the natural polysaccharide, kappa-carrageenan (kappaCA), loaded with synthetic two dimensional (2D) nanosilicates. Nanoengineered hydrogels showed shear-thinning characteristics and can be injected for minimally invasive approaches. The injectable gels can be physically crosslinked in presence of monovalent ions to form mechanically strong hydrogels. By controlling the ratio between kappaCA and nanosilicates, compressive stiffness of crosslinked hydrogels can be modulated between 20 and 200 kPa. Despite high mechanical stiffness, nanocomposite hydrogels are highly porous with an interconnected network. The addition of nanosilicates to kappaCA increases protein adsorption on nanocomposite hydrogels that results in enhance cell adhesion and spreading, increase platelets binding and reduce blood clotting time. Moreover, due to presence of nanosilicates, a range of therapeutic biomacromolecules can be deliver in a sustain manner. The addition of nanosilicates significantly suppresses the release of entrap vascular endothelial growth factor (VEGF) and facilitate in vitro tissue regeneration and wound healing. Thus, this multifunctional nanocomposite hydrogel can be used as an injectable hemostat and an efficient vehicle for therapeutic delivery to facilitate tissue regeneration. STATEMENT OF SIGNIFICANCE: Hemorrhage is a leading cause of death in battlefield wounds, anastomosis hemorrhage and percutaneous intervention. Thus, there is a need for the development of novel bioactive materials to reduce the likelihood of hemorrhagic shock stemming from internal wounds. Here, we introduce an injectable hemostat from kappa-carrageenan and two-dimensional (2D) nanosilicates. Nanosilicates mechanically reinforce the hydrogels, provide enhanced physiological stability and accelerate the clotting time by two-fold. The sustained release of entrapped therapeutics due to presence of nanosilicates promotes enhanced wound healing. The multifunctional nanocomposite hydrogels could be used as an injectable hemostat for penetrating injury and percutaneous intervention during surgery. PMID- 29425721 TI - Using a Mobile Smartphone to Perform Laparoscopy. AB - Laparoscopy has gradually expanded its use in gynecologic surgery over the last 3 decades. In this report, a new laparoscopic setup is presented using a mobile smartphone that allows for a low-cost, portable laparoscopic viewing system. The setup was created with the coupling of a rigid 0-degree, 10-mm-diameter laparoscope via a commercially available adapter with a smartphone. The light source used was also a portable and rechargeable light-emitting diode cold light source. We completed 17 diagnostic laparoscopies for different pathologies such as ectopic pregnancy, ovarian torsion, a luteal hemorrhagic cyst, and disseminated ovarian cancer. Five operations were converted from diagnostic to operative laparoscopy. The diagnosis was right tubal pregnancy, salpingectomy was performed, and the new setup was used for the entire operation, allowing the surgeon to complete the surgery successfully. This is the first report of the application of mobile technology used to facilitate a laparoscopic operation. It is our intention that this experience coupled with future hardware improvements will lead to future studies to expand the use of mobile technology in the laparoscopic setting. PMID- 29425722 TI - Safe Veress Needle Intraperitoneal Placement and Safer Laparoscopic Entry. AB - STUDY OBJECTIVE: Fifty percent of laparoscopic bowel and vascular injuries occur at the time of entry. These serious complications can lead to significant morbidity and even mortality. This video demonstrates 3 techniques that have been developed to minimize the risk of these injuries during entry. DESIGN: Step-by step description of 3 techniques that can be used as a highly reliable and safe method of obtaining intraperitoneal entry during laparoscopy. MEASUREMENTS AND MAIN RESULTS: Caudal displacement of the umbilicus before insertion of the veress needle allows for a median displacement of 6 cm between the site of entry and the common iliac vessels. An entry pressure of less than 9 mm Hg is suggestive of successful intraperitoneal entry. The left upper quadrant should be used in specific cases instead of the umbilicus as the point of entry for the veress needle. The use of a visualized trocarless cannula instead of a conventional primary trocar for entry after insufflation allows for real-time recognition of injury and converts linear penetrating force to radial torque. CONCLUSION: These 3 techniques can help decrease the risk and improve intraoperative recognition of serious bowel and vascular injuries during laparoscopy. PMID- 29425723 TI - Alopecia areata is associated with impaired health-related quality of life: A survey of affected adults and children and their families. PMID- 29425725 TI - Thermal actuation in TRPV1: Role of embedded lipids and intracellular domains. AB - The transient response potential cation channel TRPV1 responds to high temperature, but many of the mechanisms driving its thermal actuation remain unclear. Its recently resolved structure has enabled a number of molecular dynamics (MD) studies focused on illuminating these mechanisms. We add to these efforts by performing the first all-atom MD simulations of its most recently resolved structure at different temperatures. While the complete, thermally induced transition of TRPV1 from its closed to open configuration remains elusive, our analysis of the hydrogen bonding networks, thermodynamics, hydration, and principal components of motion provide a wealth of information on the mechanisms which initiate or influence the thermal opening in TRPV1. In particular, we (i) support the previously proposed mechanism driving thermal actuation in the extracellular pore of TRPV1, (ii) present new hypotheses regarding the thermal actuation in the C-terminal and adjacent linker domains, and (iii) support and build upon the existing hypothesis regarding the role of the vanilloid binding pocket and lipids embedded therein. PMID- 29425724 TI - Skin cancer interventions across the cancer control continuum: A review of experimental evidence (1/1/2000-6/30/2015) and future research directions. AB - While the general efficacy of skin cancer interventions have been reviewed, employing the cancer control continuum would be useful to identify research gaps at specific cancer control points. We characterized the intervention evidence base for specific behavioral targets (e.g., tanning, sun protection, screening) and clinically related targets (e.g., sunburn, skin exams, cancers) at each point in the cancer control continuum. The review included articles published from 1/1/2000-6/30/15 that had an experimental design and targeted behavioral intervention in skin cancer (e.g., specific behaviors or clinically related targets). The search yielded 86 articles, including seven dissemination studies. Of the 79 non-dissemination studies, 57 exclusively targeted primary prevention behaviors, five exclusively targeted screening, 10 targeted both detection and prevention, and eight addressed cancer survivorship. Among prevention studies (n=67), 29 (43%) targeted children and 38 (57%) targeted adults. Of the 15 screening studies, nine targeted high-risk groups (e.g., men aged >=50 years) and six targeted the general population. Although research has focused on skin cancer prevention, empirically validated interventions are still needed for youth engaged in indoor tanning and for behavioral interventions to pursue change in clinically relevant targets. Research must also address detection among those at highest risk for skin cancer, amelioration of emotional distress attendant to diagnosis and treatment, and survivorship concerns. We discuss essential qualities and opportunities for intervention development and translational research to inform the field. PMID- 29425726 TI - Does poor fetal growth influence the extent of fetal exposure to maternal medications? AB - A large proportion of women are prescribed a medication during pregnancy, and the conditions requiring treatment with these medicines are often also associated with placental dysfunction and abnormal fetal growth. For the fetus, exposure to maternal illness or medications can alter fetal growth trajectory, which is a key indicator of fetal and postnatal wellbeing. There is a large amount of human and animal evidence highlighting the hormonal and/or metabolic changes that occur in both the mother and the fetus as a result of maternal illness or either excessive or restricted fetal growth. These changes can affect the expression of drug metabolising enzymes and drug transporters in the both the mother and her fetus, and may ultimately alter fetal drug exposure. This review aims to explore the complex and multidirectional interplay between maternal illness, fetal growth trajectory, maternal drug treatment, and fetal drug exposure. PMID- 29425727 TI - What are the chances that resveratrol will be the drug of tomorrow? PMID- 29425728 TI - Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer's disease. AB - Synaptic plasticity is a cellular process involved in learning and memory whose alteration in its two main forms (Long Term Depression (LTD) and Long Term Potentiation (LTP)), is observed in most brain pathologies, including neurodegenerative disorders such as Alzheimer's disease (AD). In humans, AD is associated at the cellular level with neuropathological lesions composed of extracellular deposits of beta-amyloid (Abeta) protein aggregates and intracellular neurofibrillary tangles, cellular loss, neuroinflammation and a general brain homeostasis dysregulation. Thus, a dramatic synaptic environment perturbation is observed in AD patients, involving changes in brain neuropeptides, cytokines, growth factors or chemokines concentration and diffusion. Studies performed in animal models demonstrate that these circulating peptides strongly affect synaptic functions and in particular synaptic plasticity. Besides this neuromodulatory action of circulating peptides, other synaptic plasticity regulation mechanisms such as metaplasticity are altered in AD animal models. Here, we will review new insights into the study of synaptic plasticity regulatory/modulatory mechanisms which could influence the process of synaptic plasticity in the context of AD with a particular attention to the role of metaplasticity and peptide dependent neuromodulation. PMID- 29425729 TI - The prognostic value of proton magnetic resonance spectroscopy in term newborns treated with therapeutic hypothermia following asphyxia. PMID- 29425730 TI - High and low nightly running behavior associates with nucleus accumbens N-Methyl d-aspartate receptor (NMDAR) NR1 subunit expression and NMDAR functional differences. AB - The extent to which N-Methyl-d-aspartate (NMDA) receptors facilitate the motivation to voluntarily wheel-run in rodents has yet to be determined. In so, we utilized female Wistar rats selectively bred to voluntarily run high (HVR) and low (LVR) nightly distances in order to examine if endogenous differences in nucleus accumbens (NAc) NMDA receptor expression and function underlies the propensity for high or low motivation to voluntarily wheel-run. 12-14 week old HVR and LVR females were used to examine: 1.) NAc mRNA and protein expression of NMDA subunits NR1, NR2A and NR2B; 2.) NMDA current responses in isolated medium spiny neurons (MSNs) and 3.) NMDA-evoked dopamine release in an ex vivo preparation of NAc punches. Expectedly, there was a large divergence in nightly running distance and time between HVR and LVR rats. We saw a significantly higher mRNA and protein expression of NR1 in HVR compared to LVR rats, while seeing no difference in the expression of NR2A or NR2B. There was a greater current response to a 500 ms application of 300 MUM of NMDA in medium-spiny neurons isolated from the NAc HVR compared to LVR animals. On average, NMDA-evoked punches (50 MUM of NMDA for 10 min) taken from HVR rats retained ~54% of the dopamine content compared to their bilateral non-evoked sides, while evoked punches from LVR animals showed no statistical decrease in dopamine content compared to their non-evoked sides. Collectively, these data suggest a potential link between NAc NR1 subunit expression as well as NMDA function and the predisposition for nightly voluntary running behavior in rats. In light of the epidemic rise in physical inactivity, these findings have the potential to explain a neuro-molecular mechanism that regulates the motivation to be physically active. PMID- 29425731 TI - Toxins as tools: Fingerprinting neuronal pharmacology. AB - Toxins have been used as tools for decades to study the structure and function of neuronal ion channels and receptors. The biological origin of these toxins varies from single cell organisms, including bacteria and algae, to complex multicellular organisms, including a wide variety of plants and venomous animals. Toxins are a structurally and functionally diverse group of compounds that often modulate neuronal function by interacting with an ion channel or receptor. Many of these toxins display high affinity and exquisite selectivity, making them valuable tools to probe the structure and function of neuronal ion channels and receptors. This review article provides an overview of the experimental techniques used to assess the effects that toxins have on neuronal function, as well as discussion on toxins that have been used as tools, with a focus on toxins that target voltage-gated and ligand-gated ion channels. PMID- 29425732 TI - Exploration of association rule mining for coding consistency and completeness assessment in inpatient administrative health data. AB - OBJECTIVE: Data quality assessment is a challenging facet for research using coded administrative health data. Current assessment approaches are time and resource intensive. We explored whether association rule mining (ARM) can be used to develop rules for assessing data quality. MATERIALS AND METHODS: We extracted 2013 and 2014 records from the hospital discharge abstract database (DAD) for patients between the ages of 55 and 65 from five acute care hospitals in Alberta, Canada. The ARM was conducted using the 2013 DAD to extract rules with support >=0.0019 and confidence >=0.5 using the bootstrap technique, and tested in the 2014 DAD. The rules were compared against the method of coding frequency and assessed for their ability to detect error introduced by two kinds of data manipulation: random permutation and random deletion. RESULTS: The association rules generally had clear clinical meanings. Comparing 2014 data to 2013 data (both original), there were 3 rules with a confidence difference >0.1, while coding frequency difference of codes in the right hand of rules was less than 0.004. After random permutation of 50% of codes in the 2014 data, average rule confidence dropped from 0.72 to 0.27 while coding frequency remained unchanged. Rule confidence decreased with the increase of coding deletion, as expected. Rule confidence was more sensitive to code deletion compared to coding frequency, with slope of change ranging from 1.7 to 184.9 with a median of 9.1. CONCLUSION: The ARM is a promising technique to assess data quality. It offers a systematic way to derive coding association rules hidden in data, and potentially provides a sensitive and efficient method of assessing data quality compared to standard methods. PMID- 29425733 TI - Polymicrobial anaerobic bacteremia due to Atopobium rimae and Parvimonas micra in a patient with cancer. AB - Atopobium rimae and Parvimonas micra are both Gram-positive anaerobes involved infrequently in human infections. We report a polymicrobial anaerobic bacteremia caused by these microorganisms. A 43-year-old woman receiving coadjuvant chemotherapy due to a retroperitoneal leiomiosarcoma presented with nausea, vomiting, abdominal pain and fever (38 degrees C). The two blood cultures resulted in isolation of A. rimae and P. micra, being identified at species level by matrix assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS) technology with high log scores. The microorganisms were susceptible to penicilllin, amoxicillin-clavulanate, piperacillin-tazobactam, clindamycin, metronidazole, imipenem, and moxifloxacin. Treatment with levofloxacin was started and subsequently it was changed to piperacillin/tazobactam plus metronidazole and completed for 10 days, but the patient died days later due to her underlying disease. PMID- 29425734 TI - In vitro and in vivo pharmacodynamics of three novel antileishmanial lead series. AB - OBJECTIVES: Three new chemical series (bicyclic nitroimidazoles, aminopyrazoles and oxaboroles) were selected by Drugs for Neglected Diseases initiative as potential new drug leads for leishmaniasis. Pharmacodynamics studies included both in vitro and in vivo efficacy, cross-resistance profiling against the current antileishmanial reference drugs and evaluation of their cidal activity potential. METHODS: Efficacy against the reference laboratory strains of Leishmania infantum (MHOM/MA(BE)/67/ITMAP263) and L. donovani (MHOM/ET/67/L82) was evaluated in vitro on intracellular amastigotes and in vivo in the early curative hamster model. Cidal activity was assessed over a period of 15 days in an in vitro 'time-to-kill' assay. Cross-resistance was assessed in vitro on a panel of L. infantum strains with different degrees of resistance to either antimony, miltefosine or paromomycin. RESULTS: All lead compounds showed potent and selective in vitro activity against the Leishmania strains tested and no cross-resistance could be demonstrated against any of the current antileishmanial drugs. Cidal activity was obtained in vitro for all series within 15 days of exposure with some differences noted between L. donovani and L. infantum. When evaluated in vivo, all lead compounds showed high efficacy and no adverse effects were observed. CONCLUSIONS: The new lead series were shown to have cidal pharmacodynamic activity. The absence of cross-resistance with any of the current antileishmanial drugs opens possibilities for combination treatment to reduce the likelihood of treatment failures and drug resistance. PMID- 29425735 TI - Revealing the interaction mode of the highly flexible Sorghum bicolor Hsp70/Hsp90 organizing protein (Hop): A conserved carboxylate clamp confers high affinity binding to Hsp90. AB - Proteostasis is dependent on the Hsp70/Hsp90 system (the two chaperones and their co-chaperones). Of these, Hop (Hsp70/Hsp90 organizing protein), also known as Sti1, forms an important scaffold to simultaneously binding to both Hsp70 and Hsp90. Hop/Sti1 has been implicated in several disease states, for instance cancer and transmissible spongiform encephalopathies. Therefore, human and yeast homologous have been better studied and information on plant homologous is still limited, even though plants are continuously exposed to environmental stress. Particularly important is the study of crops that are relevant for agriculture, such as Sorghum bicolor, a C4 grass that is among the five most important cereals and is considered as a bioenergy feedstock. To increase the knowledge on plant chaperones, the hop putative gene for Sorghum bicolor was cloned and the biophysical and structural characterization of the protein was done by cross linking coupled to mass spectroscopy, small angle X-ray scattering and structural modeling. Additionally, the binding to a peptide EEVD motif, which is present in both Hsp70 and Hsp90, was studied by isothermal titration calorimetry and hydrogen/deuterium exchange and the interaction pattern structurally modeled. The results indicate SbHop as a highly flexible, mainly alpha-helical monomer consisting of nine tetratricopeptide repeat domains, of which one confers high affinity binding to Hsp90 through a conserved carboxylate clamp. Moreover, the present insights into the conserved interactions formed between Hop and Hsp90 can help to design strategies for potential therapeutic approaches for the diseases in which Hop has been implicated. PMID- 29425736 TI - Targeted proteomics analyses of phosphorylation-dependent signalling networks. AB - Protein phosphorylation often regulates interactions between components of signalling networks. Its tight regulation by opposing actions of kinases and phosphatases contribute to making this modification key in controlling the dynamic architecture of phosphorylation-dependent networks. The introduction in cell signalling research of long-standing targeted proteomics approaches such as selected reaction monitoring (SRM) combined with the development of state-of-the art methods such as parallel reaction monitoring (PRM) and data-independent analysis (DIA), have allowed delineating temporal quantitative profiles of interactions networks. This review summarizes how targeted proteomics analyses have recently contributed to our comprehension of phosphorylation-dependent protein interaction networks and proposes how these could be applied to address clinical problems. BIOLOGICAL SIGNIFICANCE: Intracellular communication and information processing are performed by context-specific protein interaction networks that are often regulated by protein phosphorylation. Quantification of dynamic changes within these signalling networks is of critical importance to understand cell biology in normal and disease states, but remains challenging. Targeted proteomics approaches have contributed greatly to our understanding of these phosphorylation-dependent signalling networks. PMID- 29425737 TI - The lysine acetylome of the nematocidal bacterium Bacillus nematocida and impact of nematode on the acetylome. AB - : Bacillus nematocida B16 (B16) is a pathogenic bacterium that is nematotoxic to plant-parasitic nematodes. In this study, we performed a quantitative lysine acetylome analysis on B16 to understand the potential roles of protein lysine acetylation on this host-pathogen interaction. Altogether, we identified 529 acetylation sites in 349 proteins, quantified 411 sites in 288 proteins, determined that the acetylation levels of 18 sites were up-regulated and those of 19 sites were down-regulated during pathogenesis. The acetylated proteins mainly participated in metabolic processes, protein synthesis, and cell wall/membrane biogenesis. Moreover, these proteins are involved in more than twenty KEGG pathways. Eight peptide motifs of acetylated proteins were identified, five of which have been thus far found only in the B16 acetylome. Twenty-two acetylated proteins were found to be involved in the synthesis of nematode attractants, and two were found to be involved in the secretion of virulence factors. In addition, the acetylation levels of ten lysine sites were regulated significantly differently in the presence of nematodes. Our results reveal that lysine acetylation may play roles in regulating B16-nematode interaction. SIGNIFICANCE: B. nematocida B16 is a bio-control bacterium against nematodes. It lures nematodes to their death by a Trojan horse mechanism. But there is little understanding about the regulation of this "Trojan horse" like pathogenesis. Lysine acetylation was reported to regulate diverse cellular processes. Our results revealed that lysine acetylation played indeed roles in regulating the B16-nematodes interaction. Our data laid a foundation for studying the molecule mechanism of lysine acetylation in regulating this host-pathogen interaction. PMID- 29425738 TI - Investigation of blended learning video resources to teach health students clinical skills: An integrative review. AB - OBJECTIVES: The aim of this review is to inform future educational strategies by synthesising research related to blended learning resources using simulation videos to teach clinical skills for health students. DESIGN: An integrative review methodology was used to allow for the combination of diverse research methods to better understand the research topic. This review was guided by the framework described by Whittemore and Knafl (2005), DATA SOURCES: Systematic search of the following databases was conducted in consultation with a librarian using the following databases: SCOPUS, MEDLINE, COCHRANE, PsycINFO databases. Keywords and MeSH terms: clinical skills, nursing, health, student, blended learning, video, simulation and teaching. REVIEW METHODS: Data extracted from the studies included author, year, aims, design, sample, skill taught, outcome measures and findings. After screening the articles, extracting project data and completing summary tables, critical appraisal of the projects was completed using the Mixed Methods Appraisal Tool (MMAT). RESULTS: Ten articles met all the inclusion criteria and were included in this review. The MMAT scores varied from 50% to 100%. Thematic analysis was undertaken and we identified the following three themes: linking theory to practice, autonomy of learning and challenges of developing a blended learning model. Blended learning allowed for different student learning styles, repeated viewing, and enabled links between theory and practice. The video presentation needed to be realistic and culturally appropriate and this required both time and resources to create. CONCLUSIONS: A blended learning model, which incorporates video-assisted online resources, may be a useful tool to teach clinical skills to students of health including nursing. Blended learning not only increases students' knowledge and skills, but is often preferred by students due to its flexibility. PMID- 29425739 TI - [In process]. PMID- 29425740 TI - Comparison of flavonoids and isoflavonoids to inhibit rat and human 11beta hydroxysteroid dehydrogenase 1 and 2. AB - Many flavonoids and isoflavonoids have anti-diabetic effects in animal models. However, the mechanisms that are involved are generally unclear. Since 11beta hydroxysteroid dehydrogenases (HSD11Bs) play important roles in diabetes, we hypothesize that flavonoids and isoflavonoids may affect diabetes by targeting two isoforms of HSD11B differently. The inhibitory effects of flavonoids (apigenin and quercetin) and isoflavonoids [genistein and (+/-) equol] on rat and human HSD11B1 and HSD11B2 were analyzed. The potencies of inhibition on human HSD11B1 reductase was in the order of apigenin > quercetin > genistein > (+/-) equol, with IC50 values of 2.19, 5.36, 11.00, and over 100 MUM, respectively. Genistein also inhibited rat HSD11B1 reductase with IC50 value of 24.58 MUM, while other three chemicals showed no effects on the enzyme activity with IC50 values over 100 MUM. However, apigenin and (+/-) equol did not inhibit human HSD11B2 at concentrations as high as 100 MUM, while genistein and quercetin inhibited human HSD11B2 by 60% and 50% at 100 MUM, respectively. The effective flavonoids and isoflavonoids are noncompetitive inhibitors of HSD11B1 when steroid substrates were used. Docking analysis showed that they bound to the steroid-binding site of the human HSD11B1. These data indicate that apigenin is a selective inhibitor of human HSD11B1 of two HSD11B isoforms, which may be useful in managing symptoms of the metabolic syndrome. PMID- 29425741 TI - Patterns of care and outcomes of postoperative radiation for intracranial hemangiopericytoma in United States hospitals. AB - OBJECTIVE: Several small (<100 patients) studies have been suggestive of a survival benefit associated with postoperative radiation for intracranial hemangiopericytoma. Given the rarity of this disease, we sought to examine the patterns of care and outcomes of this tumor in the National Cancer Database (NCDB). PATIENTS AND METHODS: We accessed the NCDB to identify patients with intracranial hemangiopericytoma between 2004-2012. Patients were categorized by surgical status, postoperative radiation usage, and location (meningeal or brain parenchyma). Multivariable Cox regression was used to identify covariables associated with differences in survival. RESULTS: There were 588 patients included in this study, of which 323 (54.9%) received postoperative radiation. The median age at diagnosis was 51 years and the median follow up was 55.1 months. There were no differences in overall survival between the two groups. The 5-year overall survival was 77.1% for those receiving postoperative radiation and 83.8% for those who did not (p = .14). On subgroup analysis by tumor location there remained no significant differences between groups. For those with tumors in the brain parenchyma, the 5-year overall survival was 77.6% for postoperative radiation compared to 85.8% for no postoperative radiation (p = .08). For those with tumors identified as being meningeal in origin, the 5-year overall survival was 75.7% for those who received postoperative radiation compared to 81.6% for those who did not receive postoperative radiation (p = .86). On multivariable analysis, postoperative radiation was not associated with any differences on survival (HR 1.35. 95% CI 0.90-2.02, p = .15). CONCLUSIONS: More than 50% of patients with hemangiopericytoma received postoperative radiation but there was no survival benefit associated with this treatment. This is a hypothesis generating study and further studies are necessary to better determine how best to treat this rare disease. PMID- 29425742 TI - The analysis of the cerebral venous blood volume in cavernous sinus using 320 row multi-detector CT. AB - OBJECTIVES: Functional venous anatomy in the brain has been mostly understood from the morphological and embryological points of view and no published study has directly evaluated the blood flow volume of cerebral small veins. We developed a method to directly evaluate the relative blood volume in small venous channels using multi-detector computed tomography (CT) and applied it to evaluate the blood volume in each tributary of the cavernous sinus, which plays an important role in cerebral venous drainage. PATIENTS AND METHODS: Ten patients with small brain tumors who had normal venous anatomy were included in the present study. All of them underwent preoperative 320-row multi-detector CT. After injecting the contrast bolus, we measured the Hounsfield units (HUs) at 10 time point over 60 s in each tributary of the cavernous sinus. The gamma distribution fitting to each HU enabled us to obtain a time-density curve and determine the relative venous volume in each venous channel. RESULTS: In terms of blood volume, the superficial middle cerebral vein and inferior petrosal sinus were the largest inflow and outflow channels of the cavernous sinus and accounted for 36.1% and 24.7% of its inflow and outflow on average, respectively. The superior orbital vein did not contribute to the blood volume passing through the cavernous sinus in the current study. CONCLUSIONS: The present study allowed us to determine the relative blood volume in each tributary of the cavernous sinus, which was very useful to understand the physiological actual venous drainage pattern concerning the cavernous sinus in normal anatomy. PMID- 29425743 TI - Is MGMT promoter methylation to be considered in the decision making for recurrent surgery in glioblastoma patients? AB - OBJECTIVES: At present, there is no standard therapy approved for recurrent glioblastoma (rGB). In particular, the counselling of patients with an unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter GB remains a challenge. Our aim was to compare the overall survival (OS) and progression free survival (PFS) in patients treated surgically and non-surgically at the time of GB recurrence. This was evaluated with particular reference to the impact of recurrent surgery for patients with unmethylated MGMT promoter rGB. PATIENTS AND METHODS: The clinical and radiological data from 127 consecutive cases of rGB was retrospectively identified and evaluated. The PFS and OS from cohorts of surgically and non-surgically treated patients at time of GB recurrence were compared using Kaplan Meier estimations and Log-Rank tests. Multivariate Cox regression analysis included the major influencing variables (surgical resection, MGMT promoter methylation status, Karnofsky performance scale (KPS), age, eloquent tumor location) to analyze the survival benefit. Subgroup analysis of cases depending on the MGMT promoter methylation status was performed. RESULTS: Multiple Cox regression analysis revealed inferior OS (p = 0.029, OR = 1.731, CI 95% 1.059-2.829) of patients treated non-surgically (14 vs. 31 months). MGMT promoter methylation and age were related to longer OS (p < 0.001, OR 2.683, CI 95% 1.631-4.414 and p = 0.009, OR = 1.029, CI95% 1.007-0.052 respectively). Gross total resection (GTR) in comparison to subtotal resection (STR) lead to a median OS of 39 months vs. 22 months and a PFS of seven vs. four months respectively. In the subgroup of cases with unmethylated MGMT promoter rGB, those who underwent GTR survived significantly longer (OS: 31 months) than patients who underwent STR (OS: 15 months, p = 0.024). PFS was six vs. four months after GTR and STR respectively. CONCLUSION: Surgical management for recurrent glioblastoma appears to be a safe procedure which results in longer OS in comparison to non-surgical management. GTR may be of particular benefit to patients with unmethylated MGMT promoter rGB. PMID- 29425744 TI - LncRNA Uc.173 is a key molecule for the regulation of lead-induced renal tubular epithelial cell apoptosis. AB - Transcribed ultra-conserved region (T-UCR) transcripts are a novel class of long non-coding RNAs (lncRNAs) transcribed from ultra-conserved region which is highly conserved in human, rat, and mouse genome. LncRNA UC.173 has been found significantly down-regulated in lead-exposed population and lead-exposed animal mode, and had an inhibitory effect on lead-induced nerve cell apoptosis. We supposed that lncRNA UC.173 had an inhibitory effect on lead-induced renal tubular epithelial cell apoptosis. Thus, the aim of our study was to explore the function of lncRNA UC.173 in lead-exposed renal tubular epithelial cells. In our results, lead exposure inhibited renal tubular epithelial cells viability and promoted cell apoptosis and apoptosis-associated genes expression, but no effect on cell-cycle distribution. Lead exposure inhibited the expression of lncRNA UC.173 in renal tubular epithelial cells, and the inhibition effect was time dependent and concentration-dependent. Up-regulation of lncRNA UC.173 had no effect on renal tubular epithelial cell viability, cell cycle and apoptosis, but significantly rescued lead-induced inhibition of renal tubular epithelial cell viability and suppressed lead-induced cell apoptosis. In summary, our experiments suggest that lncRNA UC.173 is certainly involved in the regulation of lead induced renal tubular epithelial cell apoptosis, which may supply a new strategy to minimize lead-induced nephrotoxicity. PMID- 29425746 TI - miR-145 overexpression triggers alteration of the whole transcriptome and inhibits breast cancer development. AB - Cumulative evidence has associated microRNA (miRNA) with cancer development, and among those miRNAs, miR-145 has been identified as an anti-oncomiRNA. However, the comprehensive mechanisms of action of miR-145 in breast cancer development have not yet been fully elucidated. Herein, we performed next-generation sequencing to detect the expression profiles of the transcriptome and conducted cellular function experiments after miR-145 overexpression. The results verified the inhibitory effects of miR-145 on breast cancer cell proliferation, colony formation, migration and invasion. Sequencing data revealed that miR-145 triggered the alteration of the whole transcriptome and further led to regulation of the competing endogenous RNA (ceRNA) network. Our study also identified a list of 49 target mRNAs of miR-145 and specific non-coding RNAs, which could be utilized as potential breast cancer biomarkers. This study might serve as a significant platform for further research on miR-145 along with the ceRNA network in breast cancer. PMID- 29425745 TI - Tumor suppressive ZBTB4 inhibits cell growth by regulating cell cycle progression and apoptosis in Ewing sarcoma. AB - Increasing studies identify that zinc finger and BTB domain containing 4 (ZBTB4) functions as a tumor suppressor in human cancer. Underexpression of ZBTB4 is correlated with poor survival of breast cancer patients. However, the expression of ZBTB4 and its possible function remain unknown in Ewing sarcoma (ES). To clarify these issues, we investigated the expression difference between ES and normal tissues based on Gene Expression Omnibus (GEO) data from R2: Genomics Analysis and Visualization Platform (http://r2.amc.nl). GEO data (GSE68776) indicated that the expression of ZBTB4 in ES tissues was prominently lower compare to normal tissues. Our data further confirmed the underexpression of ZBTB4 in ES tissues. GEO data (GSE63157 and GSE17679) demonstrated that ZBTB4 underexpression predicted a obvious shorter overall survival and event-free survival of ES patients. Interestingly, the expression of ZBTB4 was inversely correlated with proliferation makers Ki-67 and proliferating cell nuclear antigen (PCNA) in ES tissues. In vitro, ZBTB4 overexpression inhibited cell proliferation, and induced cell cycle arrest at G1 phase and apoptosis in SK-ES-1 and RD-ES cells. Moreover, ZBTB4 restoration suppressed the tumor growth of ES in mice. An inversely correlation between ZBTB4 and Survivin expression was observed in ES tissues. ZBTB4 overexpression reduced Survivin abundance in ES cells. Notably, Survivin restoration reversed the regulatory effect of ZBTB4 on ES cell proliferation, cell cycle progression and apoptosis. To conclude, our data indicated that ZBTB4 exhibited a tumor suppressive role in ES possibly by reducing Survivin expression. ZBTB4/Survivin axis might serve as a therapeutic target for ES. PMID- 29425747 TI - Annona muricata Linn. leaf as a source of antioxidant compounds with in vitro antidiabetic and inhibitory potential against alpha-amylase, alpha-glucosidase, lipase, non-enzymatic glycation and lipid peroxidation. AB - Annona muricata leaves are used in traditional medicine to manage diabetes mellitus and its complications. The aim of this study was to evaluate the potential in vitro antidiabetic properties of Annona muricata leaf by identifying its main phytochemical constituents and characterizing the phenolic-enriched fractions for their in vitro antioxidant capacity and inhibitory activities against glycoside and lipid hydrolases, advanced glycation end-product formation and lipid peroxidation. Ethanol extract of A. muricata leaf was subjected to a liquid-liquid partitioning and its fractions were used in enzymatic assays to evaluate their inhibitory potential against alpha-amylase, alpha-glucosidase and lipase, as well as their antioxidant (DPPH, ORAC, FRAP and Fe2+-ascorbate-induced lipid peroxidation assays) and anti-glycation (BSA-fructose, BSA-methylglyoxal and arginine-methylglyoxal models) capacities. In addition, identification of the main bioactive compounds of A. muricata leaf by HPLC-ESI-MS/MS analysis was carried out. Ethyl acetate (EtOAc) and n-butanol (BuOH) fractions showed, respectively, antioxidant properties (ORAC 3964 +/- 53 and 2707 +/- 519 MUmol trolox eq g-1, FRAP 705 +/- 35 and 289 +/- 18 MUmol trolox eq g-1, and DPPH IC50 4.3 +/- 0.7 and 9.3 +/- 0.8 MUg mL-1) and capacity to reduce liver lipid peroxidation (p < .01). Also, EtOAc and BuOH, respectively, inhibited glycation in BSA-fructose (IC50 45.7 +/- 13.5 and 61.9 +/- 18.2 MUg mL-1), BSA methylglyoxal (IC50 166.1 +/- 21.6 and 413.2 +/- 49.5 MUg mL-1) and arginine methylglyoxal (IC50 437.9 +/- 89.0 and 1191.0 +/- 199.0 MUg mL-1) assays, alpha amylase (IC50 9.2 +/- 2.3 and 6.1 +/- 1.6 MUg mL-1), alpha-glucosidase (IC50 413.1 +/- 121.1 and 817.4 +/- 87.9 MUg mL-1) and lipase (IC50 74.2 +/- 30.1 and 120.3 +/- 50.5 MUg.mL-1), and presented lower cytotoxicity, when compared to the other fractions and crude extract. Various biomolecules known as potent antioxidants were identified in these fractions, such as chlorogenic and caffeic acids, procyanidins B2 and C1, (epi)catechin, quercetin, quercetin-hexosides and kaempferol. This study presents new biological activities not yet described for A. muricata, which contributes to the understanding of the potential effectiveness in the use of the A. muricata leaf, especially its polyphenols enriched fractions, for the management of diabetes mellitus and its complications. PMID- 29425748 TI - Ginsenoside Rb2 promotes glucose metabolism and attenuates fat accumulation via AKT-dependent mechanisms. AB - Ginsenosides, the major active constituents of ginseng, have been demonstrated possess anti-diabetic, anti-inflammatory effects. Ginsenoside Rb2 (Rb2) is the most abundant saponin in Panax ginseng, this study investigates the role of Rb2 in the anti-hyperglycemic mechanism of insulin-sensitive cell lines 3T3-L1 adipocytes as well as high fat diet-induced obesity mice. Glucose uptake of 3T3 L1 adipocytes was measured. The insulin signaling cascade, including insulin AKT, insulin receptor (IR) beta-subunit, IR substrate (IRS) -1, phosphatidylinositol 3 kinase (PI3K) were also examined. TNF-alpha-treated 3T3-L1 adipocytes were used as an insulin resistant model in which p-AKT, c-Jun NH2-terminal kinase (JNK), MAPK, and nuclear factor (NF) -kappaB signaling cascades were examined. As an in vivo study, C57BL/6J mice were fed with a high-fat diet for 9 weeks, with or without Rb2 supplementation. Then we investigated the effects of Rb2 on glycometabolism in these high fat diet-induced obesity mice. Our results demonstrate Rb2 increases glucose uptake in 3T3-L1 adipocytes, independent of insulin receptor beta-subunit (IRbeta) and principally through the insulin receptor substrate (IRS)-1-phosphatidylinositol 3-kinase (PI3K)-AKT/PKB pathway. Rb2 inhibited TNF-alpha-induced activation of MAPK and nuclear factor (NF)-kappaB signaling pathway as well as the expression of inflammatory factors. In high fat diet-induced obesity mice, Rb2 attenuated fat mass and regulated insulin resistance. In mouse adipose tissue, Rb2 phosphorylation of AKT was correlated with glycometabolism. Furthermore, Rb2 attenuates insulin resistance in 3T3-L1 adipocytes, reduces fat mass, and improves insulin sensitivity in high fat diet obesity mice. PMID- 29425749 TI - Development of a lateral flow recombinase polymerase assay for the diagnosis of Schistosoma mansoni infections. AB - Infection with Schistosoma mansoni causes intestinal schistosomiasis, a major health problem across Africa. The accurate diagnosis of intestinal schistosomiasis is vital to inform surveillance/control programs. Diagnosis mainly relies on microscopic detection of eggs in faecal samples but many factors affect sensitivity. Molecular diagnostics are sensitive and specific but application is limited as necessary infrastructure, financial resources and skilled personnel are often lacking in endemic settings. Recombinase Polymerase Amplification (RPA) is an isothermal DNA amplification/detection technology that is practical in nearly any setting. Here we developed a RPA lateral flow (LF) assay targeting the 28S rDNA region of S. mansoni. The 28S LF-RPA assay's lower limit of detection was 10pg DNA with the lower test parameters permitting sufficient amplification being 6 min and 25 degrees C. Optimal assay parameters were 40-45 degrees C and 10 min with an analytical sensitivity of 102 copies of DNA. Additionally the PCRD3 lateral flow detection cassettes proved more robust and sensitive compared to the Milenia HybriDetect strips. This 28S LF-RPA assay produces quick reproducible results that are easy to interpret, require little infrastructure and is a promising PON test for the field molecular diagnosis of intestinal schistosomiasis. PMID- 29425750 TI - The Influential Bony Factors and Vectors for Predicting Soft Tissue Responses After Orthognathic Surgery in Mandibular Prognathism. AB - PURPOSE: We sought to identify the hard tissue points and vectors that have the greatest effect on soft tissue movement after orthognathic surgery in patients with mandibular prognathism. PATIENTS AND METHODS: The present retrospective study involved patients who had undergone mandibular setback surgery with or without maxillary advancement. Multiple linear regression models were adapted to evaluate the association between the 8 hard tissue landmark (predictor variables) changes and 11 soft tissue responses (outcome variables) using the x and y coordinates assessed from superimposed pre- and postoperative 3-dimensional computed tomography images. RESULTS: A total of 50 patients (42 patients had undergone 2-jaw surgery; 8 patients had undergone 1-jaw surgery; mean age 23 +/- 4 years) were included in the present study. Our statistical models demonstrated that the horizontal hard tissue changes had a greater influence on the soft tissue responses than did the vertical changes, and these changes were more notable in the lower facial area (lower lip contour and chin profile) than the midfacial area (nasal profile, upper lip contour, upper lip length, and nasolabial angle). In the horizontal soft tissue response model, the soft tissue A point/A point ratio was 0.86:1 (95% confidence interval [CI] 0.674-1.049); the soft tissue B point/B point ratio was almost 1:1 (95% CI 0.919-1.071); and the soft tissue pogonion/pogonion ratio was 0.88:1 (95% CI 0.805-0.963). CONCLUSIONS: Horizontal or vertical bone tissue changes affected both the horizontal and vertical soft tissue changes in most areas. Our study demonstrated that the soft tissue response is not linear but a more complicated and dynamic reaction. PMID- 29425751 TI - Aggression Using a Knife or Other Sharp Instruments and Oral-Maxillofacial Trauma: Incidence, Risk Factors, and Epidemiologic Trends. AB - PURPOSE: The aim of the present study was to characterize the profile of victims of interpersonal physical violence (IPV) caused by a knife or other sharp instrument, identify the factors associated with maxillofacial trauma, and examine the incidence of maxillofacial trauma over time. PATIENTS AND METHODS: In a retrospective cohort study, we evaluated 569 medicolegal and social records of IPV victims by knife or other sharp instruments treated at a forensic medicine and dentistry center in Brazil during a 4-year consecutive period. The variables investigated were related to the sociodemographic characteristics of the victims, circumstances of the aggression, and trauma patterns. Descriptive and multivariate statistics through Poisson regression and trend analysis with the creation of polynomial regression models were used. RESULTS: The cumulative incidence of oral-maxillofacial trauma was 19.3%. The mean age of the victims was 31.29 +/- 13.82 years. Cases of trauma affecting more than one region of the face prevailed (45.5%). Based on the final Poisson regression model, unemployed people were more likely to exhibit maxillofacial trauma (relative risk [RR] 1.86; 95% confidence interval [CI] 1.03-3.35; P = .039). In addition, individuals were more likely to experience maxillofacial trauma on Wednesdays (RR 1.85; 95% CI 1.01 3.37; P = .045). The trend analysis revealed a significant increase in oral maxillofacial injuries over time (P < .05). CONCLUSIONS: The incidence of oral maxillofacial trauma was high, and the main factors associated with trauma were the victim's employment status and day of occurrence. Future studies will focus on assessing the effect of maxillofacial trauma on the quality of life and well being of violence victims. PMID- 29425752 TI - Management of Facial Pyoderma Gangrenosum Using Platelet-Rich Fibrin: A Technical Report. AB - This report describes a case of local pyoderma gangrenosum that was treated with short-term immunosuppressive therapy and the topical application of platelet-rich fibrin (PRF). Medical treatment included oral corticosteroid therapy and topical treatment with PRF in solid and liquid form. This therapy initially led to the reduction of the ulcer's size and an improvement in symptoms, until the ulcer was completely healed after a few weeks. A relapse was treated with only the application of PRF to the affected tissue with excellent recovery. The efficacy of PRF as a guide for wound healing is a result of the continuous release of growth factors involved in tissue repair mechanisms. PRF has proved to be suitable for the management of facial pyoderma gangrenosum while allowing a reduction in systemic corticosteroid therapy. The ease of preparation, low cost, and outpatient use make PRF an optimal scaffold for tissue healing processes. PMID- 29425753 TI - Effects of rhBMP-2/7 Heterodimer and RADA16 Hydrogel Scaffold on Bone Formation During Rabbit Mandibular Distraction. AB - PURPOSE: The effects of a recombinant human bone morphogenetic protein-2/7 (rhBMP 2/7) heterodimer and a RADA16 (Ac-RADARADARADARADA-CONH2) hydrogel scaffold on bone formation during distraction osteogenesis were evaluated. MATERIALS AND METHODS: Forty New Zealand white rabbits, which underwent mandibular lengthening, were randomly divided into 5 groups. One group served as the control group. The others received 2 MUg of rhBMP-2 homodimer, 2 MUg of rhBMP-2/7 heterodimer, 100 MUL of RADA16, or 100 MUL of RADA16 plus 2 MUg of rhBMP-2/7 heterodimer in the mandibular distraction gap at the beginning of distraction. Fluorine-18-labeled fluoride positron emission tomography was used to assess osteogenesis both after distraction and at the end of consolidation. Dual-energy x-ray absorptiometry (DEXA) examination and bone histologic findings were also evaluated. RESULTS: At the end of distraction, the radioactivity concentration in the distracted area was significantly greater in the RADA16 plus rhBMP-2/7 heterodimer group than in the other groups (P < .01). The differences among the other 4 groups were also statistically significant in the following order: rhBMP-2/7 heterodimer group greater than the rhBMP-2 homodimer group, which was greater than the RADA16 group (or control group; P < .05). However, the radioactivity concentration of the RADA16 group was slightly greater than that of the control group with a nonsignificant difference (P > .05). By the end of consolidation, the activity in the control group, RADA16 group, rhBMP-2 homodimer group, and rhBMP-2/7 heterodimer group had significantly diminished (P < .05). However, the activity in the RADA16 plus rhBMP-2/7 heterodimer group remained at the same level (P > .05). The DEXA results and bone histologic findings indicated that more callus regeneration was noted in the RADA16 plus rhBMP-2/7 heterodimer group than in any other group. CONCLUSIONS: The use of rhBMP-2/7 heterodimer and RADA16 hydrogel scaffold significantly promoted mandibular distraction osteogenesis. PMID- 29425754 TI - Does the Medical Comorbidity Profile of Obstructive Sleep Apnea Patients Treated With Maxillomandibular Advancement Differ From That of Obstructive Sleep Apnea Patients Managed Nonsurgically? AB - PURPOSE: Obstructive sleep apnea (OSA) patients with retrognathia and measurable anatomic airway determinants may represent a subset of OSA patients and have distinct comorbidity profiles. Our aim was to compare the medical comorbidities of OSA patients managed surgically with maxillomandibular advancement with those of nonsurgical patients. PATIENTS AND METHODS: In this cross-sectional retrospective study, patients for both cohorts were identified through the Massachusetts General Hospital oral and maxillofacial surgery data registry and the Massachusetts General Hospital Research Patient Data Registry. The inclusion criteria consisted of clinical records documenting body mass index (BMI), apnea hypopnea index, respiratory disturbance index, and/or oxygen nadir. The primary predictor variable was the treatment modality chosen: surgical (maxillomandibular advancement) or nonsurgical. Demographic information and OSA parameters were evaluated. The primary outcome variable was the number of documented comorbidities in each group. Two-sample t tests were used for continuous variables, whereas chi2 or Fisher exact tests were used for categorical variables. RESULTS: The nonsurgical cohort consisted of 71 patients (67.6% men), and the surgical cohort consisted of 51 patients (84.3% men). Comparison of descriptive characteristics showed that the nonsurgical cohort had a higher average age (49 +/- 9.4 years) than the surgical cohort (41 +/- 10.7 years, P < .001). In addition, a higher average BMI was present in the nonsurgical group (42.3 +/- 11.9 in nonsurgical group vs 29.7 +/- 5.5 in surgical group, P < .001). Polysomnogram parameters were comparable with the exception of a higher Epworth Sleepiness Scale score in the surgical cohort (15.5 +/- 5.30 in surgical group vs 9.90 +/- 6.80 in nonsurgical group, P = .005). The nonsurgical cohort had a higher total number of comorbidities (7 +/- 4 in nonsurgical group vs 4 +/- 3 in surgical group, P < .001). Hypertension, cardiovascular disease, hyperlipidemia, pulmonary hypertension, obstructive pulmonary disease, and type 2 diabetes mellitus had higher prevalences within the nonsurgical group. CONCLUSIONS: The results of this study suggest that nonsurgically managed OSA patients tend to have more complex medical comorbidity profiles than those managed surgically. Obesity (BMI >30) was more prevalent in the nonsurgical cohort, which may be contributory. The additive contribution of OSA needs to be further elucidated. PMID- 29425755 TI - Streptococcus anginosus Dental Implant-Related Osteomyelitis of the Jaws: An Insidious and Calamitous Entity. AB - PURPOSE: We analyzed the data from a series of patients with dental implant related suppurative osteomyelitis of the jaws (DIOMJ) due to Streptococcus anginosus. PATIENTS AND METHODS: The medical records of all patients seen for osteomyelitis of the jaws from 2011 to 2016 were reviewed. The primary outcome variable was Streptococcus anginosus DIOMJ. Other variables included age, gender, smoking habits, associated comorbidities, dental implant localization, type of osteomyelitis, delay between dental implant placement and DIOMJ, microbiologic examination and antibiogram, antibiotherapy, type of surgery, and final outcome. Cases from previous reports of DIOMJ were also analyzed for comparison. Finally, descriptive statistics were computed. RESULTS: A total of 26 patients had jaw osteomyelitis; in 6 patients (26%), jaw osteomyelitis had developed after dental implant placement. S. anginosus was found in 5 patients and Escherichia coli in 1. The osteomyelitis was located in the mandible and associated with a deep neck abscess in all cases. All the patients were women and were either smokers or had comorbidities affecting bone metabolism. In all 6 cases, the dental implants were removed, and several surgical debridement procedures (>=2) and prolonged antibiotherapy (average of 6 months) were needed. Of the 6 patients, 3 required a radical surgical reconstructive procedure with partial resection and bone grafting. CONCLUSIONS: The present study demonstrated that Streptococcus anginosus DIOMJ is a particularly aggressive form of osteomyelitis that has a propensity to develop in the mandible of women in their 60s who are either smokers or have comorbidities. PMID- 29425756 TI - Management of Bilateral Edentulous Mandible Fractures Through an Intraoral Approach Using CAD/CAM Technology: A Case Report. AB - The surgical management of edentulous mandible fractures presents unique challenges secondary to poor bone stock and the absence of dentition to assist with fracture reduction. In complex injury patterns, such as bilateral edentulous mandible fractures, an external approach is often necessary to achieve adequate reduction and adaptation of a load-bearing reconstruction plate. We report a case in which computer-assisted design/computer-assisted manufacturing (CAD/CAM) was applied as an adjunct for the acute management of bilateral edentulous mandible fractures in a 58-year-old man. CAD/CAM technology was used to fabricate a patient-specific reconstruction plate and a maxillomandibular splint, which facilitated the successful treatment of this complex injury through an intraoral approach. This case highlights the potential of CAD/CAM technology to improve operative efficiency and clinical outcomes in the acute management of complex edentulous mandible fractures. PMID- 29425757 TI - Clinical and Radiographic Performance of Rough Surfaced Implants Placed in the Atrophic Posterior Maxilla With Sinus Membrane Elevation Without Bone Grafting: A Prospective and Preliminary Study. AB - PURPOSE: The aim of the present prospective and preliminary study was to compare the clinical and radiographic outcomes of 2 types of rough surfaced implants after implant placement in the atrophic posterior maxilla with sinus membrane elevation without bone grafting using the crestal approach. PATIENTS AND METHODS: All clinical and radiographic records for 28 patients who had received 40 implants were included in the present study. The patients returned for radiographic and clinical examinations at 1, 3, and 6 months and every 6 months thereafter after implantation. Cone-beam computed tomography images were taken to evaluate the amount of bone gain in the maxillary sinus. Standardized periapical digital radiographs were taken to evaluate the changes in the crestal peri implant bone level and peri-implant fixture radiolucency. RESULTS: The Kaplan Meier survival estimates demonstrated a 100% probability of survival to 24 months. No significant differences were found in cervical bone loss (CBL) or residual bone height (RBH) between the TS III CA group and the TS III SA group during the 2-year follow-up period after implant placement. The CBL values according to gender, implant placement region, prosthesis type, and the time of implantation were not significantly different between the 2 groups. CONCLUSIONS: The results of the present preliminary study demonstrate that 2 types of rough surfaced implants placed in the atrophic posterior maxilla with sinus membrane elevation without a bone graft have good clinical and radiographic outcomes. PMID- 29425758 TI - Long-Term Effects of Distraction Osteogenesis of the Mandible. AB - PURPOSE: 1) To assess the fate of the permanent teeth in and adjacent to the regenerate in pediatric patients who underwent mandibular distraction osteogenesis (DO) and 2) to compare the postoperative growth of the distracted mandible with age- and gender-matched controls. PATIENTS AND METHODS: This was a retrospective cohort study of children who underwent mandibular DO during the primary or mixed dentition period and before completion of somatic growth (boys aged <=14 years and girls aged <=12 years) at Massachusetts General Hospital from 1996 to 2014. From the DO registry, patients were selected who had complete clinical and radiographic records and at least 1 year of follow-up. Patients with disorders of dental development (eg, ectodermal dysplasia) were excluded. Panoramic radiographs were used to assess changes in morphology, eruption, and orientation of the dentition. Standardized digital lateral cephalograms were used to assess the mandible (sella-nasion-B point, mandibular unit length, ramus height, body length) preoperatively, at the end of distraction, at 1 year after device removal, and at longest follow-up. RESULTS: A total of 118 patients of all ages in the registry underwent some form of DO during the study period. For assessment of the effects on dentition, 26 subjects, who had 36 osteotomies and distraction wounds, met the inclusion criteria. In this sample, 22 of 26 subjects (85%) had 52 adverse effects in 38 of 90 permanent teeth (42.2%) assessed. Cephalometric measurements indicated that there was net mandibular growth at longest follow-up, after a period of skeletal relapse from the end of distraction to 1 year after device removal; however, only 2 of 25 subjects (8%) regained a growth rate in the vector of DO that matched or exceeded normal age- and gender matched controls. CONCLUSIONS: DO commonly results in adverse effects on the dentition within and adjacent to the DO gap, with only a minority resolving over time. Net growth of the mandible occurs after DO but at a slower rate and lesser magnitude than that of age- and gender-matched controls. PMID- 29425759 TI - Expression of proteins upregulated in hepatocellular carcinoma in patients with alcoholic hepatitis (AH) compared to non-alcoholic steatohepatitis (NASH): An immunohistochemical analysis of candidate proteins. AB - Both non-alcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) can lead to cirrhosis and hepatocellular carcinoma. However, the rate of progression to cirrhosis and tumorigenesis in AH is greater than that in NASH. We asked whether there are differences between the two conditions in the expression levels of proteins involved in the pathogenesis of hepatocellular carcinoma. The proteins tested were presented at the 2017 American Association for the Study of Liver Diseases (AASLD) Liver Meeting as overexpressed in hepatocellular carcinoma: KLF4, SCL19A1, FANCG, HRH-1, DNMT1, DNMT3B, TNFR2, DUSP4, EGFR, Integrin alpha6, HDACII, PDE3A, BCL-XL, and MTCO2. The expression of these proteins was measured in liver biopsy sections from NASH and AH patients using immunohistochemical staining with fluorescent antibodies and then quantifying the fluorescence intensity morphometrically. In AH patients, levels of all tested proteins except HRH-1 were elevated compared to normal patients. In NASH patients, KLF4, SCL19A1, FANCG, HDACII, BCL-XL levels were increased compared to normal controls while HRH 1, DNMT1 and PDE3A levels were decreased. The relative expression of all proteins studied except BCL-XL was significantly higher in AH compared to NASH. In conclusion, proteins involved in hepatocellular cancer development are more highly expressed in AH compared to NASH and normal liver, which corresponds with the higher rate of tumorigenesis in AH patients compared to NASH patients. PMID- 29425760 TI - Agathisflavone, a flavonoid derived from Poincianella pyramidalis (Tul.), enhances neuronal population and protects against glutamate excitotoxicity. AB - Flavonoids are bioactive compounds that are known to be neuroprotective against glutamate-mediated excitotoxicity, one of the major causes of neurodegeneration. The mechanisms underlying these effects are unresolved, but recent evidence indicates flavonoids may modulate estrogen signaling, which can delay the onset and ameliorate the severity of neurodegenerative disorders. Furthermore, the roles played by glial cells in the neuroprotective effects of flavonoids are poorly understood. The aim of this study was to investigate the effects of the flavonoid agathisflavone (FAB) in primary neuron-glial co-cultures from postnatal rat cerebral cortex. Compared to controls, treatment with FAB significantly increased the number of neuronal progenitors and mature neurons, without increasing astrocytes or microglia. These pro-neuronal effects of FAB were suppressed by antagonists of estrogen receptors (ERalpha and ERbeta). In addition, treatment with FAB significantly reduced cell death induced by glutamate and this was associated with reduced expression levels of pro inflammatory (M1) microglial cytokines, including TNFalpha, IL1beta and IL6, which are associated with neurotoxicity, and increased expression of IL10 and Arginase 1, which are associated with anti-inflammatory (M2) neuroprotective microglia. We also observed that FAB increased neuroprotective trophic factors, such as BDNF, NGF, NT4 and GDNF. The neuroprotective effects of FAB were also associated with increased expression of glutamate regulatory proteins in astrocytes, namely glutamine synthetase (GS) and Excitatory Amino Acid Transporter 1 (EAAT1). These findings indicate that FAB acting via estrogen signaling stimulates production of neurons in vitro and enhances the neuroprotective properties of microglia and astrocytes to significantly ameliorate glutamate-mediated neurotoxicity. PMID- 29425762 TI - Surface area normalized dissolution to study differences in itraconazole copovidone solid dispersions prepared by spray-drying and hot melt extrusion. AB - Amorphous solid dispersions of itraconazole (ITZ) and copovidone (PVPVA 64) at 1:1 to 1:9 drug-polymer ratios were prepared using spray-drying (SD) and hot melt (HM) extrusion for comparative evaluation. Surface area normalized dissolution studies were carried out using a modified intrinsic dissolution rate (IDR) assembly and rate of release of drug as well as polymer were quantified using ultraviolet spectroscopy. The melt quenched amorphous form of ITZ provided an 18 fold dissolution advantage over the crystalline form. In general, dispersions prepared by either SD or HM showed similar dissolution profiles in terms of drug release. Both drug-controlled and polymer-controlled ITZ dissolution rates were observed, depending on the drug loading, where a switch from a drug-controlled to a polymer-controlled regime was observed when the drug loading was approximately 20% or lower. The impact of the spray drying solvent composition was studied and found to have a large effect on the drug release rate for dispersions containing a drug loading of 20%. Electron microscopy showed differences in surface morphology (scanning) and internal structure (transmission) in these dispersions as a function of solvent system. X-ray photoelectron spectroscopy (XPS) revealed differences in the surface composition of drug and polymer whereby poorly dissolving systems showed drug enrichment. This study provides insight into the complex interplay between formulation, processing and performance of amorphous solid dispersion systems. PMID- 29425761 TI - Dry-powder formulations of non-covalent protein complexes with linear or miktoarm copolymers for pulmonary delivery. AB - Pulmonary delivery of protein therapeutics has considerable clinical potential for treating both local and systemic diseases. However, poor protein conformational stability, immunogenicity and protein degradation by proteolytic enzymes in the lung are major challenges to overcome for the development of effective therapeutics. To address these, a family of structurally related copolymers comprising polyethylene glycol, mPEG2k, and poly(glutamic acid) with linear A-B (mPEG2k-lin-GA) and miktoarm A-B3 (mPEG2k-mik-(GA)3) macromolecular architectures was investigated as potential protein stabilisers. These copolymers form non-covalent nanocomplexes with a model protein (lysozyme) which can be formulated into dry powders by spray-drying using common aerosol excipients (mannitol, trehalose and leucine). Powder formulations with excellent aerodynamic properties (fine particle fraction of up to 68%) were obtained with particle size (D50) in the 2.5 um range, low moisture content (<5%), and high glass transitions temperatures, i.e. formulation attributes all suitable for inhalation application. In aqueous medium, dry powders rapidly disintegrated into the original polymer-protein nanocomplexes which provided protection towards proteolytic degradation. Taken together, the present study shows that dry powders based on (mPEG2k-polyGA)-protein nanocomplexes possess potentials as an inhalation delivery system. PMID- 29425763 TI - Buccal drug delivery technologies for patient-centred treatment of radiation induced xerostomia (dry mouth). AB - Radiotherapy is a life-saving treatment for head and neck cancers, but almost 100% of patients develop dry mouth (xerostomia) because of radiation-induced damage to their salivary glands. Patients with xerostomia suffer symptoms that severely affect their health as well as physical, social and emotional aspects of their life. The current management of xerostomia is the application of saliva substitutes or systemic delivery of saliva-stimulating cholinergic agents, including pilocarpine, cevimeline or bethanechol tablets. It is almost impossible for substitutes to replicate all the functional and sensory facets of natural saliva. Salivary stimulants are a better treatment option than saliva substitutes as the former induce the secretion of natural saliva from undamaged glands; typically, these are the minor salivary glands. However, patients taking cholinergic agents systemically experience pharmacology-related side effects including sweating, excessive lacrimation and gastrointestinal tract distresses. Local delivery direct to the buccal mucosa has the potential to provide rapid onset of drug action, i.e. activation of minor salivary glands within the buccal mucosa, while sparing systemic drug exposure and off-target effects. This critical review of the technologies for the local delivery of saliva-stimulating agents includes oral disintegrating tablets (ODTs), oral disintegrating films, medicated chewing gums and implantable drug delivery devices. Our analysis makes a strong case for the development of ODTs for the buccal delivery of cholinergic agents: these must be patient-friendly delivery platforms with variable loading capacities that release the drug rapidly in fluid volumes typical of residual saliva in xerostomia (0.05-0.1 mL). PMID- 29425764 TI - Comparison of two DSC-based methods to predict drug-polymer solubility. AB - The aim of the present study was to compare two DSC-based methods to predict drug polymer solubility (melting point depression method and recrystallization method) and propose a guideline for selecting the most suitable method based on physicochemical properties of both the drug and the polymer. Using the two methods, the solubilities of celecoxib, indomethacin, carbamazepine, and ritonavir in polyvinylpyrrolidone, hydroxypropyl methylcellulose, and Soluplus(r) were determined at elevated temperatures and extrapolated to room temperature using the Flory-Huggins model. For the melting point depression method, it was observed that a well-defined drug melting point was required in order to predict drug-polymer solubility, since the method is based on the depression of the melting point as a function of polymer content. In contrast to previous findings, it was possible to measure melting point depression up to 20 degrees C below the glass transition temperature (Tg) of the polymer for some systems. Nevertheless, in general it was possible to obtain solubility measurements at lower temperatures using polymers with a low Tg. Finally, for the recrystallization method it was found that the experimental composition dependence of the Tg must be differentiable for compositions ranging from 50 to 90% drug (w/w) so that one Tg corresponds to only one composition. Based on these findings, a guideline for selecting the most suitable thermal method to predict drug-polymer solubility based on the physicochemical properties of the drug and polymer is suggested in the form of a decision tree. PMID- 29425765 TI - Compressibility and tablet forming ability of bimodal granule mixtures: Experiments and DEM simulations. AB - Compressibility and tablet forming ability (compactibility) of bimodal mixtures of differently sized granules formed from microcrystalline cellulose were studied experimentally and numerically with the discrete element method (DEM). Compression data was analysed using the Kawakita equation. A multi-body contact law that accounts for contact dependence resulting from plastic incompressibility/geometric hardening was used in the DEM simulations. The experimental Kawakita a and 1/b parameters both depended non-monotonically on composition (weight fraction of large particles). For the a parameter, this dependence was explained by variations in the porosity of the initial granule beds; for the 1/b parameter, other factors were found to be of importance as well. The numerical results generally compared favourably with the experiments, demonstrating the usefulness of the DEM at high relative densities, provided that a suitable multi-particle contact model is used. For all mixtures, the tensile strength of the formed tablets increased with increasing applied pressure. The tensile strength generally decreased with increasing fraction of large particle, and this decrease was more rapid for large differences in particle size. A possible interpretation of these findings was proposed, in terms of differences in lateral support of small particles in the vicinity of large particles. PMID- 29425766 TI - Antidiabetic effects of SGLT2 inhibitor ipragliflozin in type 2 diabetic mice fed diets containing different carbohydrate contents. AB - AIMS: Daily intake of carbohydrates differs among individual patients with type 2 diabetes. Here, we investigated whether or not dietary carbohydrate content affects the efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin in type 2 diabetic mice. MAIN METHODS: Diabetic mice were fed a regular (50% kcal), high (75% kcal)-, or low (25% kcal)-carbohydrate diet. Ipragliflozin was orally administered once a day for 4 weeks. KEY FINDINGS: In all groups, mice exhibited characteristics of type 2 diabetes, including hyperglycemia, hyperinsulinemia, and obesity. Hyperglycemia was more severe in the high-carbohydrate diet group and milder in the low-carbohydrate diet group than in the regular diet group. In all diabetic mice, ipragliflozin significantly increased urinary glucose excretion and improved hyperglycemia, hyperinsulinemia, glucose tolerance, insulin resistance, obesity, and nephropathy. Although these antidiabetic effects of ipragliflozin were more marked in the high-carbohydrate diet group (which showed more severe hyperglycemia) than in the other two groups, no significant differences in effective dose or degree of response were observed among the three groups. SIGNIFICANCE: The antidiabetic effects of ipragliflozin were not greatly affected by dietary carbohydrate content, suggesting that ipragliflozin may have similar efficacy for patients with type 2 diabetes regardless of carbohydrate intake. PMID- 29425768 TI - Differences in dynamics of horizontal transmission of Tomato planta macho viroid and Potato spindle tuber viroid after pollination with viroid-infected pollen. AB - For viroids, pollen transmission is an important transmission pathway to progeny seeds and new hosts. In the current study, we found that Tomato planta macho viroid (TPMVd)-but not Potato spindle tuber viroid (PSTVd)-was horizontally transmitted by pollen from petunia plants. Using tissue-printing hybridization to track the changes in viroid distribution after pollination, we noted that TPMVd was present in petunia stigma, styles, and eventually ovaries, whereas PSTVd was detected in the stigma and upper style but not the ovary. These findings suggest that horizontal transmission of viroids depends on the infection of the lower style and ovary during the elongation of pollen tubes after pollination. Additionally, TPMVd was transmitted horizontally, leading to systematic infection, when we used TPMVd-infected petunia pollen to pollinate the flowers of healthy tomato plants. Fertilization typically does not occur after heterologous pollination and thus likely is not required to accomplish horizontal transmission of viroids. PMID- 29425769 TI - Combined use of nanocarriers and physical methods for percutaneous penetration enhancement. AB - Dermal and transdermal drug delivery (due to its non-invasiveness, avoidance of the first-pass metabolism, controlling the rate of drug input over a prolonged time, etc.) have gained significant acceptance. Several methods are employed to overcome the permeability barrier of the skin, improving drug penetration into/through skin. Among chemical penetration enhancement methods, nanocarriers have been extensively studied. When applied alone, nanocarriers mostly deliver drugs to skin and can be used to treat skin diseases. To achieve effective transdermal drug delivery, nanocarriers should be applied with physical methods, as they act synergistically in enhancing drug penetration. This review describes combined use of frequently used nanocarriers (liposomes, novel elastic vesicles, lipid-based and polymer-based nanoparticles and dendrimers) with the most efficient physical methods (microneedles, iontophoresis, ultrasound and electroporation) and demonstrates superiority of the combined use of nanocarriers and physical methods in drug penetration enhancement compared to their single use. PMID- 29425767 TI - Proteomic profiling of HIV-infected T-cells by SWATH mass spectrometry. AB - Viral pathogenesis results from changes in host cells due to virus usurpation of the host cell and the innate cellular responses to thwart infection. We measured global changes in protein expression and localization in HIV-1 infected T-cells using subcellular fractionation and the Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS) proteomic platform. Eight biological replicates were performed in two independent experimental series. In silico merging of both experiments identified 287 proteins with altered expression (p < .05) between control and infected cells- 172 in the cytoplasm, 84 in the membrane, and 31 in nuclei. 170 of the proteins are components of the NIH HIV interaction database. Multiple Reaction Monitoring and traditional immunoblotting validated the altered expression of several factors during infection. Numerous factors were found to affect HIV infection in gain- and loss-of-expression infection assays, including the intermediate filament vimentin which was found to be required for efficient infection. PMID- 29425770 TI - Scarring vs. functional healing: Matrix-based strategies to regulate tissue repair. AB - All vertebrates possess mechanisms to restore damaged tissues with outcomes ranging from regeneration to scarring. Unfortunately, the mammalian response to tissue injury most often culminates in scar formation. Accounting for nearly 45% of deaths in the developed world, fibrosis is a process that stands diametrically opposed to functional tissue regeneration. Strategies to improve wound healing outcomes therefore require methods to limit fibrosis. Wound healing is guided by precise spatiotemporal deposition and remodelling of the extracellular matrix (ECM). The ECM, comprising the non-cellular component of tissues, is a signalling depot that is differentially regulated in scarring and regenerative healing. This Review focuses on the importance of the native matrix components during mammalian wound healing alongside a comparison to scar-free healing and then presents an overview of matrix-based strategies that attempt to exploit the role of the ECM to improve wound healing outcomes. PMID- 29425771 TI - Early Outcomes with Fast-Track EVAR in Teaching and Nonteaching Hospitals. AB - BACKGROUND: The influence of hospital teaching status on fast-track endovascular aneurysm repair (EVAR) outcomes is unknown. This study explored the feasibility, safety, and effectiveness of a fast-track EVAR protocol at teaching and nonteaching hospitals. METHODS: Patients underwent a fast-track EVAR protocol composed of bilateral percutaneous access using a 14F stent graft, avoidance of general anesthesia and intensive care admission, and next-day discharge. Patients were followed up for 1 month post-treatment. Participating hospitals were categorized by teaching status (teaching versus nonteaching) and compared for perioperative and 30-day outcomes. RESULTS: Between October 2014 and May 2016, 250 patients were enrolled at 31 centers in the United States. The study included 186 patients treated among 21 teaching hospitals and 64 patients treated among 10 nonteaching hospitals. Fast-track EVAR protocol completion was higher at teaching hospitals (91% vs. 73%, P = 0.01). Intensive care admission was avoided in 99% of patients at teaching hospitals versus 84% at nonteaching hospitals (P < 0.001). The ability to complete all other fast-track EVAR elements was proportionally higher at teaching hospitals, but differences were not statistically different. In-hospital outcomes by teaching status were comparable overall. Median time to discharge was 25 and 26 hr, respectively. There were no reports of type III endoleak, abdominal aortic aneurysm rupture, or secondary intervention. Comparing teaching versus nonteaching hospitals, there were no differences in major adverse events (1% vs. 0%), type I endoleak (0% vs. 2%), limb occlusion (1% vs. 0%), all cause mortality (1% vs. 0%), and 30-day readmissions (1% vs. 3%). CONCLUSIONS: A fast-track EVAR protocol can be implemented with high success in well-selected patients at teaching and nonteaching hospitals. Health care resource utilization, perioperative data, and 30-day outcomes were excellent overall, with higher frequency of intensive care admission at nonteaching hospitals. PMID- 29425772 TI - Ultrastructure and function of the seminal vesicle of Bittacidae (Insecta: Mecoptera). AB - The fine structure of the seminal vesicle and reproductive accessory glands was investigated in Bittacidae of Mecoptera using light and transmission electron microscopy. The male reproductive system of Bittacidae mainly consists of a pair of testes, a pair of vasa deferentia, and an ejaculatory sac. The vas deferens is greatly expanded for its middle and medio-posterior parts to form a well developed seminal vesicle. The seminal vesicle is composed of layers of developed muscles and a mono-layered epithelium surrounding the small central lumen. The epithelium is rich in rough endoplasmic reticulum and mitochondria, and secretes vesicles and granules into the central lumen by merocrine mechanisms. A pair of elongate mesodermal accessory glands opens into the lateral side of the seminal vesicles. The accessory glands are similar to the seminal vesicle in structure, also consisting of layers of muscle fibres and a mono-layered elongated epithelium, the cells of which contain numerous cisterns of rough endoplasmic reticulum and mitochondria, and a few Golgi complexes. The epithelial cells of accessory glands extrude secretions via apocrine and merocrine processes. The seminal vesicles mainly serve the function of secretion rather than temporarily storing spermatozoa. The sperm instead are temporarily stored in the epididymis, the greatly coiled distal portion of the vas deferens. PMID- 29425773 TI - Cocaine- and Amphetamine-Regulated Transcript Peptide (CART) Alleviates MK-801 Induced Schizophrenic Dementia-Like Symptoms. AB - Exaggerated thoughts, diminished mood and impaired cognition are the hallmarks of the schizophrenia-like condition. These symptoms are attributed to the dysregulation of dopamine and glutamate signaling in the brain. Since cocaine- and amphetamine-regulated transcript peptide (CART) modulates actions of dopamine as well as glutamate, we tested the role of this peptide in MK-801-induced schizophrenic dementia-like condition. MK-801-treated rats were allowed to interact with conspecific juvenile and tested for short-term (30-min) and long term (24-h) social memory acquisition and recall. While MK-801 impaired the social interaction with a juvenile, the behavior was restored in CART [intracerebroventricular (icv) or intra-ventral tegmental area (VTA)] pre-treated animals. This action of CART was blocked by SCH23390 (dopamine D1 receptor antagonist) administered directly into the prefrontal cortex (PFC). Application of neuronal tracer Di-I in the PFC retrogradely labeled dopamine cells of the VTA, which in turn seem to receive CARTergic innervation. A significant increase in CARTimmunoreactivity was evidenced in the VTA, PFC and accumbens of the animals allowed to interact with a juvenile. However, MK-801 treatment attenuated the peptide expression and induced social memory deficits. The schizophrenic dementia-like symptoms following antagonism of glutamatergic receptors may be attributed to the reduced dopamine activity in the mesocortical system. We suggest that CART may, positively modulate the dopamine system to alleviate cognitive deficits associated with schizophrenia. PMID- 29425774 TI - A membrane-type surfactant protein D (SP-D) suppresses macrophage-mediated cytotoxicity in swine endothelial cells. AB - OBJECTIVE: Surfactant protein D (SP-D), which is secreted mainly in the lung, is an oligometric C type lectin that promotes phagocytosis by binding to carbohydrates on microbial surfaces. SP-D can also bind SIRPalpha, leading to a decrease in cytokine production by monocytes/macrophages. In the present study, we examined the possibility that SP-D suppresses macrophage-mediated xenogeneic cytotoxicity, by creating a membrane-type SP-D. METHODS: The cDNA for the carbohydrate recognition domain (CRD) of human SP-D was switched to that of a membrane-type protein, collectin placenta 1 (CL-P1), with a Flag-tag. The cDNA of CD47 was prepared as a control. The suppressive function of the membrane-type protein of the hybrid molecule, CL-SP-D, to monocytes/macrophages was then studied and the results compared with that for CD47. RESULTS: The expression of Flag-tagged CL-SP-D on the transfected SECs and the SIRPalpha on monocyte-like cells, THP-1 cells, was confirmed by FACS using anti-Flag Ab and anti-CD172a, respectively. The molecular size of the hybrid protein was next assessed by western blot. While significant cytotoxicity against SEC was induced in differentiated THP-1 cells, CL-SP-D significantly reduced THP-1-mediated cytotoxicity. In addition, phosphorylated SHP-1 was clearly detected in SEC/CL-SP D in western blots. Moreover, IL-10 production was upregulated and IL-1beta production was suppressed in the case of THP-1 and SEC/CL-SP-D, compared with naive SEC. Next, the cytotoxicity caused by the in vitro generated macrophage was assessed under the same conditions as were used for THP-1. CL-SP-D also showed the significant down-regulation on the macrophage. In addition, changes in IL-10 production by the macrophage confirmed the results. CONCLUSIONS: These findings indicate that the membrane-type SP-D serve as an effective therapeutic strategy for inhibiting macrophage-mediated xenograft rejection in xenotransplantation. PMID- 29425775 TI - Inhibitory effect of wild-type P53 gene transfer on graft coronary artery disease. AB - OBJECTIVE: The aim of the present study was to investigate the inhibitory effect of wild-type P53 gene transfer on graft coronary artery disease (GCAD) after heart transplantation and the underlying mechanisms. METHODS: A rat model of heterotopic heart transplantation was established using Wistar rats as donors and Sprague-Dawley (SD) rats as recipients. The donor hearts were collected and perfused, via the coronary artery, with 800 MUl of recombinant adenovirus carrying the P53 gene (Ad-P53). Thirty minutes later, heart transplant was performed. At 5 d after the transplant surgery, the expression of the exogenous P53 gene and protein in the coronary artery tissues of the donor hearts was examined. At 28 d after the transplant surgery, tissues were collected from the transplanted hearts. The degree of coronary artery stenosis was examined, and apoptosis of the coronary artery smooth muscle cells in the donor hearts was analysed. In addition, histological changes in the vital organs of the recipient rats and the levels of serum biochemical indicators in the rats were also examined. RESULTS: The exogenous gene was successfully transferred into donor heart tissues and the coronary artery and was highly expressed. At 28 d after the transplant surgery, the ratio of tunica intima thickness to tunica media thickness (I/M) and the ratio of wall thickness to the lumen diameter of the coronary artery were decreased in the Ad-P53 group compared to those in the Ad LacZ group and the control group (P < 0.05). A terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay revealed that the percentage of apoptotic coronary artery smooth muscle cells in the donor hearts was significantly increased in the Ad-P53 group compared to that in the Ad-LacZ group and the control group (P < 0.01). The wild-type P53 gene had no effect on the morphology and functions of the vital organs of the recipient rats. CONCLUSIONS: P53 gene transfer inhibits coronary artery intimal hyperplasia and reduces the degree of luminal stenosis in transplanted hearts. The inhibitory effect may be related to the wild-type P53 gene-induced apoptosis of vascular smooth muscle cells and inhibition of vascular smooth muscle cell proliferation. This approach is effective and safe and may have good prospects for clinical application. PMID- 29425776 TI - The effects of hemoglobin glutamer-200 and iNO on pulmonary vascular tone and arterial oxygenation in an experimental acute respiratory distress syndrome. AB - INTRODUCTION: Hemoglobin-based oxygen carriers (HBOC) have been developed as an alternative to blood transfusions. Their nitric-oxide-scavenging properties HBOC also induce vasoconstriction. In acute lung injury, an excess of nitric oxide results in a general vasodilation, reducing oxygenation by impairing the hypoxic pulmonary vasoconstriction. Inhaled nitric oxide (iNO) is used to correct the ventilation perfusion mismatch. We hypothesized that the additional use of HBOC might increase this effect. In a rodent model of ARDS we evaluated the combined effect of HBOC and iNO on vascular tone and gas exchange. METHODS: ARDS was induced in anaesthetized Wistar rats by saline lavage and aggressive ventilation. Two groups received either hydroxyethylstarch 10% (HES; n = 10) or the HBOC hemoglobin glutamer-200 (HBOC-200; n = 10) via a central venous infusion. Additionally, both groups received iNO. Monitoring of the right ventricular pressure (RVP) and mean arterial pressure (MAP) was performed with microtip transducers. Arterial oxygenation was measured via arterial blood gas analyses. RESULTS: Application of HBOC-200 led to a significant increase of MAP and RVP when compared to baseline and to the HES group. This effect was reversed by iNO. The application of HBOC and iNO had no effect on the arterial oxygenation over time. No difference in arterial oxygenation was found between the groups. CONCLUSION: Application of HBOC led to an increase of systemic and pulmonary vascular resistance in this animal model of ARDS. The increase in RVP was reversed by iNO. Pulmonary vasoconstriction by hemoglobin glutamer-200 in combination with iNO did not improve arterial oxygenation in ARDS. PMID- 29425777 TI - Easy-to-perform and cost-effective fabrication of continuous-flow reactors and their application for nanomaterials synthesis. AB - The translation of continuous-flow microreactor technology to the industrial environment has been limited by cost and complexity of the fabrication procedures and the requirement for specialised infrastructure. In the present study, we have developed a significantly more cost-effective and easy-to-perform fabrication method for the generation of optically transparent, continuous-flow reactors. The method combines 3D printing of master moulds with sealing of the PDMS channels' replica using a pressure-sensitive adhesive tape. Morphological characterisation of the 3D printed moulds was performed and reactors were fabricated with an approximately square-shaped cross-section of 1 mm2. Notably, they were tested for operation over a wide range of volumetric flow rates, up to 20 ml/min. Moreover, the fabrication time (i.e., from design to the finished product) was <1 day, at an average material cost of ~L5. The flow reactors have been applied to the production of both inorganic nanoparticles (silver nanospheres) and organic vesicular systems (liposomes), and their performance compared with reactors produced using more laborious fabrication methods. Numerical simulations were performed to characterise the transport of fluids and chemical species within the devices. The developed fabrication method is suitable for scaled-up fabrication of continuous-flow reactors, with potential for application in biotechnology and nanomedicine. PMID- 29425778 TI - Preface. PMID- 29425779 TI - Dynamics of cholera epidemics with impulsive vaccination and disinfection. AB - Waterborne diseases have a tremendous influence on human life. The contaminated drinking water causes water-borne disease like cholera. Pulse vaccination is an important and effective strategy for the elimination of infectious diseases. A waterborne disease like cholera can also be controlled by using impulse technique. In this paper, we have proposed a delayed SEIRB epidemic model with impulsive vaccination and disinfection. We have studied the pulse vaccination strategy and sanitation to control the cholera disease. The existence and stability of the disease-free and endemic periodic solution are investigated both analytically and numerically. It is shown that there exists an infection-free periodic solution, using the impulsive dynamical system defined by the stroboscopic map. It is observed that the infection-free periodic solution is globally attractive when the impulse period is less than some critical value. From the analysis of the model, we have obtained a sufficient condition for the permanence of the epidemic with pulse vaccination. The main highlight of this paper is to introduce impulse technique along with latent period into the SEIRB epidemic model to investigate the role of pulse vaccination and disinfection on the dynamics of the cholera epidemics. PMID- 29425780 TI - Risk of Pancreatic Cancer in Patients With Pancreatic Cysts and Family History of Pancreatic Cancer. AB - BACKGROUND & AIMS: A diagnosis of pancreatic cancer in a first-degree relative increases an individuals' risk of this cancer. However, it is not clear whether this cancer risk increases in individuals with pancreatic cystic lesions who have a first-degree relative with pancreatic cancer. The Fukuoka criteria are used to estimate risk of pancreatic cancer for patients with pancreatic cystic lesions: individuals with cysts with high risk or worrisome features (Fukuoka positive) have a higher risk of pancreatic cancer than individuals without these features (Fukuoka negative). We aimed to compare the risk of pancreatic cancer and surgery based on presence or absence of pancreatic cystic lesions and a first-degree relative with pancreatic cancer. METHODS: We performed a retrospective study of patients seen at the Mayo Clinic in Rochester, Minnesota, from January 1, 2000, through December 31, 2012. We identified individuals with: pancreatic cystic lesions and first-degree relative with pancreatic cancer (group 1, n = 269), individuals with pancreatic cystic lesions but no first-degree relative with pancreatic cancer (group 2, n = 1195), and individuals without pancreatic cystic lesions but with a first-degree relative with pancreatic cancer (group 3, n = 720). We compared, among groups, as well among patients with cysts classified according to Fukuoka criteria, proportions of individuals who developed pancreatic cancer or underwent pancreatic surgery within a 5-year period. RESULTS: A significantly higher proportion of individuals in group 1 developed pancreatic cancer during the 5-year period than in group 3 (6.64% vs 1.69%; P = .03); there was no significant difference between the percentage of individuals in group 1 vs group 2 who developed pancreatic cancer (6.64% vs 4.05%; P = .41). There was no significant difference in pancreatic cancer development among individuals with Fukuoka-positive cysts with vs without a family history of pancreatic cancer (P = .39). There was no significant difference in the proportion of patients in group 1 vs group 2 who underwent pancreatic surgery for their pancreatic cyst over the 5-year period (14.37% vs 11.80%; P = .59). Among patients with Fukuoka-negative cysts, a significantly higher proportion underwent surgery in group 1 than in group 2 (10.90% vs 5.90%; P = .03). However, among patients with Fukuoka-positive cysts, there was no difference in proportions of patients who underwent surgery between groups 1 and 2 (P = .66). CONCLUSIONS: In a retrospective study of patients with pancreatic cysts and/or cancer, we found that a family history of pancreatic cancer does not affect 5-year risk of pancreatic cancer in patients with pancreatic cystic lesions. Despite this, among patients with Fukuoka-negative cysts, a higher proportion of those with a family history of pancreatic cancer undergo surgery than patients without family history of pancreatic cancer. PMID- 29425782 TI - Carbohydrate Maldigestion and Malabsorption. PMID- 29425781 TI - Single Fluid-Filled Intragastric Balloon Safe and Effective for Inducing Weight Loss in a Real-World Population. AB - BACKGROUND & AIMS: The Orbera intragastric balloon (OIB) is a single fluid-filled intragastric balloon approved for the induction of weight loss and treatment of obesity. However, little is known about the effectiveness and safety of the OIB outside clinical trials, and since approval, the Food and Drug Administration has issued warnings to health care providers about risk of balloon hyperinflation requiring early removal, pancreatitis, and death. We analyzed data on patients who have received the OIB since its approval to determine its safety, effectiveness, and tolerance in real-world clinical settings. METHODS: We performed a postregulatory approval study of the safety and efficacy of the OIB, and factors associated with intolerance and response. We collected data from the Mayo Clinic's database of patient demographics, outcomes of OIB placement (weight loss, weight-related comorbidities), technical aspects of insertion and removal, and adverse events associated with the device and/or procedure, from 8 centers (3 academic, 5 private, 4 surgeons, and 4 gastroenterologists). Our final analysis comprised 321 patients (mean age, 48.1 +/- 11.9 y; 80% female; baseline body mass index, 37.6 +/- 6.9). Exploratory multivariable linear and logistic regression analyses were performed to identify predictors of success and early balloon removal. Primary effectiveness outcomes were percentage of total body weight lost at 3, 6, and 9 months. Primary and secondary safety outcomes were rates of early balloon removal, periprocedural complications, dehydration episodes requiring intravenous infusion, balloon migration, balloon deflation or hyperinflation, pancreatitis, or other complications. RESULTS: Four patients had contraindications for placement at the time of endoscopy. The balloon was safely removed in all instances with an early removal rate (before 6 months) in 16.7% of patients, at a median of 8 weeks after placement (range, 1-6 mo). Use of selective serotonin or serotonin-norepinephrine re-uptake inhibitors at the time of balloon placement was associated with increased odds of removal before 6 months (odds ratio, 3.92; 95% CI, 1.24-12.41). Total body weight lost at 3 months was 8.5% +/- 4.9% (n = 204), at 6 months was 11.8% +/- 7.5% (n = 199), and at 9 months was 13.3% +/- 10% (n = 47). At 6 months, total body weight losses of 5%, 10%, and 15% were achieved by 88%, 62%, and 31% of patients, respectively. Number of follow-up visits and weight loss at 3 months were associated with increased weight loss at 6 months (beta = 0.5 and 1.2, respectively) (P < .05). Mean levels of cholesterol, triglycerides, low-density lipoprotein, and hemoglobin A1c, as well as systolic and diastolic blood pressure, were significantly improved at 6 months after OIB placement (P < .05). CONCLUSIONS: In an analysis of a database of patients who received endoscopic placement of the OIB, we found it to be safe, effective at inducing weight loss, and to reduce obesity-related comorbidities in a real-world clinical population. Rates of early removal (before 8 weeks) did not differ significantly between clinical trials and the real-world population, but were affected by use of medications. PMID- 29425783 TI - Variceal Hemorrhage With White Nipple Sign Associated With Strangulated Umbilical Hernia in a Patient With Cirrhosis. PMID- 29425784 TI - The reach of human health risks associated with metals/metalloids in water and vegetables along a contaminated river catchment: South Africa and Mozambique. AB - BACKGROUND: Anthropogenic pollution was identified as an environmental problem of concern when, in 2008, dozens of crocodiles died in the Olifants River catchment near the border of South Africa and Mozambique. Given the close proximity of households to the river and their making use of river water, we aimed to determine to what extent water pollution has an impact on health of indigent communities in South Africa and Mozambique in the catchment area. METHODS: Water and vegetable samples were collected from the study areas. Biota samples were washed with double de-ionized Milli-Q water and freeze-dried. Heavy metal analyses in water and vegetables were done by means of Inductively Coupled Plasma Optical Emission Spectroscopy. Metal concentrations were applied in a human health risk assessment to estimate health risks. RESULTS: Mean concentrations of antimony, arsenic, cadmium, chromium, mercury, molybdenum, nickel and selenium in water samples from South Africa exceeded the World Health Organization guidelines for safe levels of intake. Only iron exceeded the recommended guidelines in water samples from Mozambique. Metals/metalloids were found in lower concentrations at Mozambique sites downstream of South African sites. In vegetables, uranium was between 10 and 20 times above safe guidelines in South Africa and between 3 and 6 times in Mozambique. Arsenic in water samples posed the highest cancer risk. CONCLUSIONS: Even with a reduction in the metal concentrations in river water from South Africa to Mozambique, the potential to cause adverse human health impacts from direct use of polluted river water is evident in both countries. PMID- 29425785 TI - Reflections of an Editor. PMID- 29425786 TI - Changes in Nutrition Labeling in 1970 vs 2018. PMID- 29425787 TI - Erratum. PMID- 29425788 TI - Trait mindfulness predicts the presence but not the magnitude of cortisol responses to acute stress. AB - BACKGROUND: Mindfulness, or the practice of observing present moment experiences with acceptance, is thought to improve health at least partially by limiting hypothalamic-pituitary-adrenal (HPA) axis over-responsiveness during episodes of acute stress. However, models of allostatic load suggest that HPA axis under responsiveness can also be detrimental to health, and the relationship between mindfulness and cortisol under-responsiveness has yet to be examined. The present study therefore aimed to address this knowledge gap, and to revisit the relationship between mindfulness and acute cortisol response magnitude while excluding (or statistically controlling for) individuals displaying HPA axis under-responsiveness. METHODS: Participants (124 healthy undergraduate students) were subjected to a stressful speech task, and completed a trait mindfulness questionnaire. Salivary cortisol was collected 0, +15, +25, +40, and +55 min post stressor onset. RESULTS: Greater trait mindfulness was associated with greater odds of displaying a cortisol response relative to none, but was unrelated to the magnitude of cortisol responses among those who displayed an acute response. CONCLUSIONS: In the present sample, trait mindfulness was associated with cortisol responses, but this was driven by the fact that subjects low in mindfulness were more likely to be non-responders. Contrasting the effects of mindfulness on the presence (i.e., present vs. absent) and the degree (i.e., magnitude) of acute stress responses may therefore be warranted in future research. PMID- 29425789 TI - Refining androstenedione and bisnorcholenaldehyde from mother liquor of phytosterol fermentation using macroporous resin column chromatography followed by crystallization. AB - Androstenedione is an androgen and intermediate in the biosynthesis of most adrenocortical, anabolic, sex and synthetic steroids, such as canrenone, eplerenone, norethindrone and spironolactone. Bisnorcholenaldehyde is an important intermediate in the synthesis of progesterone. This study established an androstenedione and bisnorcholenaldehyde separation method that used a macroporous adsorption resin and an ethanol-water mixture as eluent. The adsorption properties of 12 non-polar or weakly polar macroporous adsorption resins were compared, and three resins exhibited a high adsorption capacity and high desorption rate for both androstenedione and bisnorcholenaldehyde. The three resins were then compared using column chromatography, and one resin was selected and parameters (flow rate, resin size, ethanol concentration and volume) of chromatography were optimized to obtain high purity and recovery. Chromatography eluate was concentrated, dissolved in suitable solvent and crystallized at an optimal temperature to obtain a high purity of both androstenedione and bisnorcholenaldehyde from the same starting material. The levels of androstenedione and bisnorcholenaldehyde in the raw material were 39.78% and 19.15%, respectively. After preparative separation and enrichment by resin column chromatography and crystallization, the purity of androstenedione and bisnorcholenaldehyde was 94.3% and 98.6%, respectively, with their recovery yields of 66.8% and 57.9%, respectively. In addition, the resin maintained over 90% separation efficiency for 5 cycles of adsorption. These results indicated that the combination of macroporous resin chromatography followed by crystallization provide a simple, effective, environmentally friendly and low cost method for the simultaneous purification of androstenedione and bisnorcholenaldehyde. PMID- 29425790 TI - Low-dose computed tomography screening reduces lung cancer mortality. AB - Lung cancer causes an estimated 1.6 million deaths each year, being the leading cause of cancer-related deaths in the world. Late diagnosis and, in some cases, the high aggressiveness of the tumour result in low overall five-year survival rates of 12% among men and 7% among women. The cure is most likely in early-stage disease. The poor outcomes of treatment in lung cancer resulting from the fact that most cases are diagnosed in the advanced stage of the disease justify the implementation of an optimal lung cancer prevention in the form of smoking cessation and screening programmes that would offer a chance to detect early stages of the disease, while fitting within specific economic constraints. The National Lung Screening Trial (NLST) - the largest and most expensive randomised, clinical trial in the USA demonstrated a 20% mortality rate reduction in patients who had undergone chest low-dose computed tomography (LDCT) screening, as compared to patients screened with a conventional chest X-ray. Results of the NLST enabled the implementation of lung cancer screening programme among highrisk patients in the USA and parts of China. In 2017, recommendations of the European Society of Thoracic Surgeons also strongly recommend an implementation of a screening programme in the EU. Further studies of improved lung cancer risk assessment scores and of effective molecular markers should intensify in order to reduce all potential harms to the high-risk group and to increase cost effectiveness of the screening. PMID- 29425791 TI - Prescription drug use and misuse in a cohort of people who inject drugs (PWID) in Baltimore. AB - BACKGROUND: Prescription drug misuse and its consequences (e.g., overdose) are a major public health concern. While national focus has been on opioids, misuse of sedatives/tranquilizers also occurs. Here we describe the use, correlates, and sources of prescription drugs in a community-based cohort of people who inject drugs (PWID). METHODS: We included participants of the AIDS Linked to the IntraVenous Experience (ALIVE) study in follow-up in 2014. We defined prescription drug use as use of opioids or sedatives/tranquilizers considering both medical "prescribed by a doctor" and non-medical sources "obtained from the street/friend/relative." Correlates were evaluated separately for opioids and sedatives/tranquilizers using logistic regression and included socioeconomic factors, health conditions, substance use, and health care access. RESULTS: 823 predominantly African-American (90.6%) and male (66.3%) ALIVE participants with a median age of 55 were included. Prevalence of prescription opioid and sedative/tranquilizer use was 25.3% and 16.3% respectively. While the majority (70%) obtained prescription drugs exclusively through medical sources, the 30% who reported any non-medical source were also more likely to use other substances by injection and non-injection routes. PWID reporting prescription drug use (from medical and non-medical sources) were significantly more likely to report other substance use, mental health disorder, and recent contact with health care providers or detoxification facilities. CONCLUSIONS: Prescription drug use was highly prevalent among PWID. While it is difficult to distinguish medically indicated from non-medical use, high levels of prescription drug use in conjunction with other drugs and alcohol heightens the risk for drug overdose and other adverse consequences. PMID- 29425792 TI - Working memory moderates the association between perceived norms and heavy episodic drinking among college students. AB - Heavy episodic drinking (4+/5+ drinks/occasion for females/males) is highly prevalent among college students and is influenced by social factors. Among these social risk factors, perceived peer drinking norms have been shown to significantly predict heavy episodic drinking across a number of studies. However, there is little known about which students may be most and least susceptible to these influences or why individual differences may moderate the impact of norms on heavy drinking. Recent work has suggested self-control may be an important individual difference factor in this regard. Working memory (WM) is a central component of self-control that has been shown to buffer the effect of social influence variables. This study examined whether WM, as measured by memory span tasks, moderates the relationship between perceived drinking norms and alcohol use among college students reporting one or more past month drinking occasions (n = 98). Hierarchical linear regression analyses were used to examine whether WM significantly moderated the relationship between perceived norms and heavy drinking episodes (HDEs) as well as number of drinking days in the past month. Analyses revealed a significant WM x norms interaction for both drinking indices. Simple slopes analyses suggested a buffering effect of WM as higher perceived norms predicted more HDEs and drinking days at low (-1SD) and mean WM scores but not high (+1SD) WM. These results suggest WM serves as a protective factor for the influence of norms such that individuals high in WM may be more able to inhibit the impact of norms on alcohol use. PMID- 29425793 TI - Risky sexual behavior among cannabis users: The role of protective behavioral strategies. AB - Cannabis users tend to use condoms less often than cannabis abstainers, placing them at risk for sexually transmitted disease and unplanned pregnancies. This is especially problematic among college students, who experience such problems at especially high rates. Despite accumulating data indicating that cannabis users are less likely to use condoms, little research has identified potentially malleable cognitive vulnerability factors that may be related to condom use in this vulnerable population. Thus, the current study tested whether cannabis users believed others use condoms less often and/or whether they engaged in less condom related protective behavior strategies (PBS) than cannabis abstainers and whether cannabis use status was indirectly related to condom use via these vulnerability factors. Among 214 college students (64 past-month cannabis users), cannabis users engaged in less PBS (although cannabis use was unrelated to normative beliefs). Cannabis use status was indirectly related to condom use via PBS and cannabis use status was unrelated to condom use after controlling for PBS. Results highlight the importance of PBS use among cannabis users, a group at particular risk for risky sexual behaviors. PMID- 29425794 TI - Phosphorylation and SUMOylation of CRMP2 regulate the formation and maturation of dendritic spines. AB - The posttranslational modifications of CRMP2 play an important role in axon outgrowth, cell polarization and dendritic morphogenesis. However, whether CRMP2 and its posttranslational modifications are involved in dendritic spine development specifically is not completely clear. Here, we show that CRMP2 can promote the formation and maturation of dendritic spines in cultured hippocampal neurons. Overexpression of CRMP2 results in an increase in the density of spines especially the mushroom-shape spines. The amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) are both enhanced and the intensity of PSD95 is strengthened in the neurons with CRMP2 overexpression. Furthermore, dephosphorylation of CRMP2 at Thr514 and deSUMOylation at Lys374 can further promote the formation and maturation of dendritic spines, whereas, no cross-talk is found between these two posttranslational modifications in the regulation of dendritic spine formation and maturation. Taken together, our data support a model in which phosphorylation and SUMOylation modification of CRMP2 independently promote the formation and maturation of dendritic spines and participate in the process of dendritic spine plasticity. PMID- 29425795 TI - Postconditioning with repeated mild hypoxia protects neonatal hypoxia-ischemic rats against brain damage and promotes rehabilitation of brain function. AB - RATIONALE: Mild hypoxia conditioning induced by repeated episodes of transient ischemia is a clinically applicable method for protecting the brain against injury after hypoxia-ischemic brain damage. OBJECTIVE: To assess the effect of repeated mild hypoxia postconditioning on brain damage and long-term neural functional recovery after hypoxia-ischemic brain damage. METHODS AND RESULTS: Rats received different protocols of repeated mild hypoxia postconditioning. Seven-day-old rats with hypoxia ischemic brain damage (HIBD) from the left carotid ligation procedure plus 2 h hypoxic stress (8% O2 at 37 degrees C) were further receiving repeated mild hypoxia intermittently. The gross anatomy, functional analyses, hypoxia inducible factor 1 alpha (HIF-1a) expression, and neuronal apoptosis of the rat brains were subsequently examined. Compared to the HIBD group, rats postconditioned with mild hypoxia had elevated HIF-1a expression, more Nissl-stain positive cells in their brain tissue and their brains functioned better in behavioral analyses. The recovery of the brain function may be directly linked to the inhibitory effect of HIF-1alpha on neuronal apoptosis. Furthermore, there were significantly less neuronal apoptosis in the hippocampal CA1 region of the rats postconditioned with mild hypoxia, which might also be related to the higher HIF-1a expression and better brain performance. Overall, these results suggested that postconditioning of neonatal rats after HIBD with mild hypoxia increased HIF-1a expression, exerted a neuroprotective effect and promoted neural functional recovery. CONCLUSIONS: Repeated mild hypoxia postconditioning protects neonatal rats with HIBD against brain damage and improves neural functional recovery. Our results may have clinical implications for treating infants with HIBD. PMID- 29425796 TI - Doxycycline prevents and reverses schizophrenic-like behaviors induced by ketamine in mice via modulation of oxidative, nitrergic and cholinergic pathways. AB - The involvement of oxidative, nitrergic, cholinergic and inflammatory alterations have been reported to contribute to the pathophysiology of schizophrenia, a debilitating neuropsychiatric disorder. Our previous studies have shown that doxycycline (DOX), a notable member of tetracyclines with proven antioxidant and anti-inflammatory properties, attenuated psychotic-like behaviors induced by apomophine and ketamine (KET) in mice. This present study was designed to further evaluate in detail the ability of DOX and its combination with risperidone (RIS) to prevent and reverse KET-induced schizophrenic-like behaviors and the role of oxidative/nitrergic and cholinergic pathways in mice. In the prevention protocol, mice were treated orally with DOX (25, 50 or 100 mg/kg), RIS (0.5 mg/kg), DOX (50 mg/kg) in combination with RIS, or vehicle for 14 consecutive days. In addition, the animals received intraperitoneal injection of KET (20 mg/kg/day) from the 8th to the 14th day. In the reversal protocol, the animals received KET or vehicle for 14 days prior to DOX, RIS, DOX in-combination with RIS or vehicle treatments. Schizophrenic-like behaviors consisting of positive, negative and cognitive symptoms were evaluated using open field, social interaction, Y-maze and novel object recognition tests. Thereafter, the brain levels of biomarkers of oxidative stress, nitrite and acetylcholinesterase activity were determined. DOX given alone or in combination with RIS attenuated schizophrenic-like behaviors induced by chronic injection of KET in both preventive and reversal treatment protocols. DOX significantly increased glutathione, superoxide dismutase and catalase levels in the brain of chronic KET-treated mice. However, it decreased malonyladehyde, nitrite levels and acetylcholinesterase activity when given alone or in combination with RIS in both protocols. Taken together, these findings showed that doxycycline ameliorated schizophrenic-like behaviors induced by ketamine in both preventive and reversal treatment protocols in mice via inhibition of oxidative and nitrergic alterations, and acetylcholinesterase activity. Our data further suggests that adjunctive oral administration of doxycycline may augment the therapeutic efficacy of risperidone particularly for the treatment of negative and cognitive symptoms associated with schizophrenia. PMID- 29425797 TI - Antinociceptive effects of the endogenous cannabinoid peptide agonist VD hemopressin(beta) in mice. AB - Cannabinoids (CBs) play important roles in pain modulation. Recently, VD hemopressin(beta) [VD-Hpbeta], a 12-residue beta-hemoglobin-derived peptide, was reported to activate both CB1 and CB2 receptors in vitro. To further characterize in vivo actions of VD-Hpbeta, its antinociceptive activity and site(s) were evaluated in the mouse tail-flick test, and supraspinal antinociception of VD Hpbeta was further assessed in the writhing test. Our results demonstrated that supraspinal, intrathecal, subcutaneous and intraperitoneal administrations of VD Hpbeta produced analgesia in the tail-flick test. When given at the same levels, the CB1 antagonist AM251, rather than the CB2 antagonist AM630 diminished VD Hpbeta-induced antinociception. Furthermore, our results indicated that supraspinal, intrathecal or subcutaneous pretreatment with AM251 significantly inhibited VD-Hpbeta-induced systemic antinociception. In the writhing test, supraspinal VD-Hpbeta inhibited pain-related behaviors, which was partially prevented by AM251. Notably, supraspinal administration of VD-Hpbeta failed to affect motor function at the antinociceptive doses. These findings suggest that VD-Hpbeta induces CB1 receptor-mediated antinociception in tail-flick test in various routes of administration, and its systemic antinociception is mediated by both central and peripheral CB1 receptor. In addition, VD-Hpbeta produces analgesic activity in the writhing test, which is at least partially mediated by CB1 receptor. Therefore, our present animal models show a CB1 agonistic character of VD-Hpbeta, an endogenous cannabinoid peptide. PMID- 29425798 TI - The antioxidant status of coenzyme Q10 and vitamin E in children with type 1 diabetes. AB - OBJECTIVE: The purpose of this study was to evaluate the antioxidant status of plasma vitamin E and plasma and intracellular coenzyme Q10 in children with type 1 diabetes. METHOD: This case-control study was conducted on 72 children with type 1 diabetes and compared to 48 healthy children, who were age, sex, and ethnicity-matched. The diabetic children were divided according to their glycosylated hemoglobin (A1c %) into two groups: poor and good glycemic control groups. All children underwent full history taking, clinical examination, and laboratory measurement of complete blood count, A1c %, plasma cholesterol, triglycerides, and vitamin E levels and coenzyme Q10 levels in plasma, erythrocytes, and platelets. RESULTS: Children with poor glycemic control showed significantly higher plasma vitamin E, coenzyme Q10, triglycerides, low-density lipoproteins, waist circumference/height ratio, cholesterol levels, and lower high-density lipoproteins and platelet coenzyme Q10 redox status in comparison to those with good glycemic control and the control group (p<0.05). Plasma coenzyme Q10 showed a positive correlation with the duration of type 1 diabetes, triglycerides, cholesterol, vitamin E, and A1c %, and negative correlation with the age of the diabetic group (p<0.05). The platelet redox status showed a negative correlation with the A1c % levels (r=-0.31; p=0.022) and the duration of type 1 diabetes (r=-0.35, p=0.012). CONCLUSION: Patients with type 1 diabetes, especially poorly controlled, had elevation of plasma vitamin E and coenzyme Q10 levels and decreased platelet redox status of coenzyme Q10, which may be an indicator of increased oxidative stress. PMID- 29425799 TI - Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: A Clinical Pathophysiological Analysis. AB - PURPOSE: To derive novel insights into the pathophysiology of vancomycin-related hemorrhagic occlusive retinal vasculopathy (HORV) through a careful clinicopathologic correlation. METHODS: We retrospectively reviewed the clinical and pathologic course of 2 consecutive patients who developed HORV. The clinical history, multimodal imaging, ultrasound biomicroscopy (UBM), and intraoperative and histologic findings are reported. RESULTS: Both patients presented with decreased vision and eye pain within 1 week following otherwise uncomplicated cataract extraction and were diagnosed with HORV after endophthalmitis was ruled out. Both patients presented with significant ocular discomfort that progressively worsened, and both experienced a dismal visual outcome despite early aggressive medical and surgical therapy. One patient requested enucleation for a blind and painful eye. Upon histologic examination of this eye, the iris and ciliary body appeared to be infarcted with separation of the iris and ciliary epithelia from their adjacent stromal components. These findings were corroborated by UBM of the second patient. Histologic examination of the posterior segment demonstrated severe hemorrhagic necrosis of the neurosensory retina and an occlusive nonarteritic vasculopathy of the retina and choroid. The choroid was thickened by prominent nongranulomatous chronic inflammation accompanied by a glomeruloid proliferation of small vessels. The inflammatory infiltrate was almost exclusively confined to the choroid and consisted of predominantly T cells. There was conspicuous absence of inflammatory cells in the retina and no histologic evidence of leukocytoclastic vasculitis. CONCLUSIONS: HORV is a rare condition that can lead to profound vision loss. Significant ocular pain can be a presenting sign of HORV in cases with severe iris and ciliary body ischemia. Although it has been suggested that HORV is a form of leukocytoclastic retinal vasculitis, the histologic findings herein indicate that the pathophysiology is more complex. It is grounded in a necrotizing retinal vasculopathy in the absence of retinal vasculitis, chronic nongranulomatous choroiditis, and an unusual glomeruloid proliferation of endothelial cells in the choroid and elsewhere in the eye. PMID- 29425800 TI - Influence of the selective COX-2 inhibitor celecoxib on sex differences in blood pressure and albuminuria in spontaneously hypertensive rats. AB - We previously reported that female spontaneously hypertensive rats (SHR) have greater cyclooxygenase-2 (COX-2) expression in the renal medulla and enhanced urinary excretion of prostaglandin (PG) E2 (PGE2) metabolites compared to male SHR. Based on the role of COX-2-derived prostanoids in the regulation of cardiovascular health, the aim of the current study was to test the hypothesis that blood pressure (BP) in female SHR is more sensitive to COX-2 inhibition than in males. Seven week old male and female SHR were implanted with telemetry transmitters for continuous BP recording. After one week of baseline BP recording, male and female SHR were randomized to receive the selective COX-2 inhibitor celecoxib (10 mg/kg/day) or vehicle for six weeks (from 9 to 14 weeks of age). Female SHR had lower BP and albuminuria compared to male SHR as well as enhanced urinary excretion of PGE metabolite (PGEM), 6-keto PGF1alpha and thromboxane B2, indicators of PGE2, PGI2 and TXA2, respectively. Treatment with celecoxib did not significantly alter BP or albuminuria in either female or male SHR. Celecoxib did not change PGs metabolites excretion in male SHR; however, excretion levels of PGEM and 6-keto PGF1alpha were reduced in female SHR. COX-2 derived PG can also induce oxidative stress. Markers of oxidative stress (thiobarbituric acid reactive substances (TBARs) and H2O2 excretion) were lesser in female SHR versus male SHR. Celecoxib treatment did not significantly change markers of oxidative stress in female SHR, however, urinary TBARs excretion was significantly reduced in male SHR after 6 weeks of treatment with celecoxib. Therefore, although celecoxib treatment appears to have distinct effects on prostanoids levels in female SHR vs. males, it is unlikely that COX-2 contributes to established sex differences in BP in SHR. PMID- 29425801 TI - Analytical and clinical validation of an LC-MS/MS method to measure thiopurine S methyltransferase activity by quantifying d3-6-MMP. AB - BACKGROUND: Identification of patients with thiopurine S-methyltransferase (TPMT) deficiency prior to thiopurine drug therapy has become routine clinical practice worldwide. To measure TPMT activity, traditional radiochemical assays have been replaced by chromatographic methods. METHOD: Inspired by the increasing number of isotope labelled sources that may be of benefit for the TPMT assay, a new LC MS/MS method for TPMT activity was developed and validated. Isotope labelled d3-S adenosyl-l-methionine (d3-SAM) was selected for the enzymatic methylation of mercaptopurine during sample incubation; d3-6-methylmercaptopurine (d3-6-MMP) with d2-2, 8-hypoxanthine as the internal standard was quantified to ascertain individual TPMT activity. RESULTS: The validation of the analytical part of this method showed good linearity (coefficient of determination 0.9999 in the range of 1-500 ng/mL) with the intra-and inter-day impression CV% between 7.6% and 9.1% and 3.7% and 9.2%, respectively. Recovery ranged from 94.9% to 112.3%. The specificity of the enzymatic reaction was validated by using 108 clinical check samples. After compared with traditional radiochemical assay and genotype results, all homozygous and heterozygous deficiency clinical checks fitted into the nominal groups, inter-batch and intra-batch impression CV% were between 2.3% and 9.7%. CONCLUSION: With the inclusion of isotope labelled substrate, interfering non-enzymatic methylation no longer results in potential false assignment of abnormal patients. Furthermore, the method can be applied to patients who have already been prescribed thiopurine drugs. This new LC-MS/MS is therefore a favourable clinical routine application to test TPMT activity, as it shows excellent performance in identifying patients with TPMT deficiency. PMID- 29425802 TI - Health Changes in Low Income Men Transitioning from a State Funded Prostate Cancer Program to Comprehensive Insurance. AB - PURPOSE: We evaluated the effect of transitioning from a prostate cancer specific treatment program to comprehensive insurance under the ACA (Patient Protection and Affordable Care Act) on the physical, mental and prostate cancer related health of poor, previously uninsured men. MATERIALS AND METHODS: We assessed general and prostate cancer specific health related quality of life using the RAND SF-12v2TM (12-Item Short Form Survey, version 2) and the UCLA PCI (Prostate Cancer Index) at 3 time points in 24 men who transitioned to comprehensive insurance as the insured group relative to 39 who remained in the prostate cancer program as the control group. We used mixed effects models controlling for treatment and patient factors to measure health differences between the groups during the transition period. RESULTS: Demographics, prostate cancer treatment patterns, and mental, physical and general health were similar before transition in the control and insured groups. After transition men who gained insurance coverage reported significantly worse physical health than men who remained in the prostate cancer program (p = 0.0038). After adjustment in the mixed effects model physical health remained worse in men who gained insurance (p = 0.0036). Mental health and prostate cancer related quality of life did not differ with time between the groups. CONCLUSIONS: Compared to controls who remained in the state funded prostate cancer treatment program for poor, uninsured men, newly insured men reported worse physical health after transitioning to ACA coverage. Providers and policy makers may draw important lessons from understanding the mechanisms of this paradoxical worsening in physical health after gaining insurance. These results inform the development of disease specific models of care in the broader health insurance context. PMID- 29425803 TI - Exogenous vs. endogenous attention: Shifting the balance of fronto-parietal activity. AB - Despite behavioral and electrophysiological evidence for dissociations between endogenous (voluntary) and exogenous (reflexive) attention, fMRI results have yet to consistently and clearly differentiate neural activation patterns between these two types of attention. This study specifically aimed to determine whether activity in the dorsal fronto-parietal network differed between endogenous and exogenous conditions. Participants performed a visual discrimination task in endogenous and exogenous attention conditions while undergoing fMRI scanning. Analyses revealed robust and bilateral activation throughout the dorsal fronto parietal network for each condition, in line with many previous results. In order to investigate possible differences in the balance of neural activity within this network with greater sensitivity, a priori regions of interest (ROIs) were selected for analysis, centered on the frontal eye fields (FEF) and intraparietal sulcus (IPS) regions identified in previous studies. The results revealed a significant interaction between region, condition, and hemisphere. Specifically, in the left hemisphere, frontal areas were more active than parietal areas, but only during endogenous attention. Activity in the right hemisphere, in contrast, remained relatively consistent for these regions across conditions. Analysis of this activity over time indicates that this left-hemispheric regional imbalance is present within the FEF early, at 3-6.5 s post-stimulus presentation, whereas a regional imbalance in the exogenous condition is not evident until 6.5-8 s post stimulus presentation. Overall, our results provide new evidence that although the dorsal fronto-parietal network is indeed associated with both types of attentional orienting, regions of the network are differentially engaged over time and across hemispheres depending on the type of attention. PMID- 29425804 TI - Systematic survey of non-retroviral virus-like elements in eukaryotic genomes. AB - Endogenous viral elements (EVEs) are viral sequences that are endogenized in the host cell. Recently, several eukaryotic genomes have been shown to contain EVEs. To improve the understanding of EVEs in eukaryotes, we have developed a system for detecting EVE-like sequences in eukaryotes and conducted a large-scale nucleotide sequence similarity search using all available eukaryotic and viral genome assembly sequences (excluding those from retroviruses) stored in the National Center for Biotechnology Information genome database (as of August 14, 2017). We found that 3856 of 7007 viral genomes were similar to 4098 of 4102 eukaryotic genomes. For those EVE-like sequences, we constructed a database, Predicted Endogenous Viral Elements (pEVE, http://peve.med.u-tokai.ac.jp) which provides comprehensive search results summarized from an evolutionary viewpoint. A comparison of EVE-like sequences among closely related species may be useful to avoid false-positive hits. We believe that our search system and database will facilitate studies on EVEs. PMID- 29425805 TI - The discovery and comparative expression analysis of three distinct type I interferons in the perciform fish, meagre (Argyrosomus regius). AB - Type I interferons (IFN) play an important role in anti-viral responses. In teleost fish multiple genes exist, that are classified by group/subgroup. That multiple subgroups are present in Acanthopterygian fish has only become apparent recently, and 3 subgroups are now known to be expressed, including a new subgroup termed IFNh. However, the potential to express multiple IFN subgroups and their interplay is not well defined. Hence this study aims to clarify the situation and undertook the first in-depth analysis into the nature and expression of IFNc, IFNd and IFNh in the perciform fish, meagre. Constitutive expression was analysed initially during larval development and in adult tissues (gills, mid-gut, head kidney, spleen). During early ontogeny IFNc was the highest expressed IFN, and this was also the case in adult tissues with the exception of gills where IFNd was highest. However, comparison between tissues for individual isoforms showed that spleen had high transcript levels of all three IFNs, IFNd/IFNh were also highly expressed in gills. The expression of each sub-group was increased significantly in the four tissues following injection of poly I:C, however, this increase was only seen in the mid-gut for IFNh. Following in vitro stimulation with poly I:C again all three isoforms were upregulated, although with differences in kinetics and the cell source used. For example, early induction was seen for IFNc/IFNh in gill cells, IFNd/IFNh in splenocytes and all three isoforms in head kidney cells. Induction was sustained in splenocytes and head kidney cells, but in gut cells only a late induction was seen. These results demonstrate a complex pattern of regulation between the different IFN isoforms present in meagre and highlights potential sub-functionalisation of these IFN subgroups during perciform anti-viral responses. PMID- 29425806 TI - Hyperactivated m-calpain affects acquisition of doxorubicin resistance in breast cancer cells. AB - BACKGROUND: Doxorubicin is commonly using chemotherapeutic agents for breast cancer. However, doxorubicin has limitations in clinical use because of dose dependent cardiotoxicity and drug resistance. Despite of previously reported studies about mechanisms of doxorubicin resistance including overexpression of P gp and abnormal expression and mutation of topoisomerase IIalpha, resistance to this agent still abundantly occur and is regarded as a major obstacle to successful treatment. METHODS: We have established doxorubicin resistant T47D cells. Intracellular calcium and ROS levels and calpain activity were measured using fluorometric experiments. Cell viability assay, cell cycle analysis, immunofluorescence and western blot analysis were performed to evaluate m-calpain specific truncation of topoisomerase IIalpha and molecular mechanism in doxorubicin resistant cells. RESULTS: We observed that doxorubicin treatment increased intracellular calcium and ROS (Reactive Oxygen Species) in parental and doxorubicin resistant T47D cells. The increases in intracellular calcium and ROS were much greater in doxorubicin resistant T47D cells, which led to higher activity of calpains. Hyperactivated m-calpain, but not MU-calpain, specifically induced cleavage of topoisomerase IIalpha and accumulation of truncated topoisomerase IIalpha in the cytoplasm. The increase in cytoplasmic truncated topoisomerase IIalpha reduced the efficacy of doxorubicin. Doxorubicin resistant T47D cells, with hyperactivated m-calpain and truncated cytosolic topoisomerase IIalpha, obtained cross-resistance to other topoisomerase II-targeting drugs. CONCLUSION: Hyperactivated m-calpain induced cytoplasmic accumulation of truncated topoisomerase IIalpha in doxorubicin resistant T47D cells. GENERAL SIGNIFICANCE: These data provide a new mechanism of doxorubicin resistance and suggest a novel strategy for overcoming drug resistance in topoisomerase IIalpha targeting therapy. PMID- 29425807 TI - Inhibition of Echis carinatus venom by DNA, a promising therapeutic molecule for snakebite management. AB - BACKGROUND: E. carinatus bite is a serious threat to South-Asian countries including India, as it causes the highest number of deaths and debilitating sustained tissue necrosis at the bite site. One of our previous studies has demonstrated the strong interaction between DNA and E. carinatus venom. Therefore, in this study, the effect of DNA on E. carinatus venom has been examined. METHODS: Here we show that calf thymus DNA interact strongly with E. carinatus venom and inhibits its enzymatic and pharmacological activities such as proteolytic, hemolytic, hyaluronidase, L-amino acid oxidase, NETosis, hemorrhage, pro-coagulant, and lethality. Further, using immunoblots and immunofluorescence, the study demonstrates the inhibition of proteolytic cleavage of several surface receptors on PMNs, PBMCs, and platelets by the DNA. CONCLUSIONS: This study for the first time explored the efficient inhibition of enzymatic, pharmacological and lethal properties of E. carinatus venom by the naked DNA and demonstrates the possible therapeutic application of it during snakebite management. GENERAL SIGNIFICANCE: This study identifies naked DNA as an effective defense weapon that has got the therapeutic potential to inhibit the detrimental effects of E. carinatus bite. PMID- 29425808 TI - Metabolism of 2alpha-[2-(tetrazol-2-yl)ethyl]-1alpha,25-dihydroxyvitamin D3 by CYP24A1 and biological activity of its 24R-hydroxylated metabolite. AB - Our previous study revealed that the 2alpha-substituted vitamin D analog 2alpha [2-(tetrazol-2-yl)ethyl]-1alpha,25(OH)2D3 (AH-1) exhibited a higher osteocalcin promoter transactivation activity in human osteosarcoma cells and a greater effect on bone mineral density in a rat model of osteoporosis than 1alpha,25(OH)2D3 without increasing blood calcium concentration. Thus, we hypothesized that AH-1 could be a promising therapeutic agent for osteoporosis without any serious side effects. In this study, we compared the CYP24A1 dependent metabolism of AH-1 with that of 1alpha,25(OH)2D3. The resistance to CYP24A1-dependent metabolism could be an important property of vitamin D analogs in prolonging their biological effects. A kinetic analysis was performed using a membrane fraction prepared from recombinant E. coli expressing human CYP24A1. The kcat/Km (MUM-1 min-1) value for AH-1 was 31% of that for 1alpha,25(OH)2D3, suggesting that AH-1 is not as resistant to CYP24A1-dependent metabolism as the other C2-substituted vitamin D analogs such as eldecalcitol [2beta-hydroxypropoxy 1alpha,25(OH)2D3]. The major metabolite of AH-1 was the 24R-hydroxylated metabolite, which had high vitamin D receptor (VDR) binding affinity and high HL 60 cell differentiation activity similar to AH-1 itself. In contrast, 1alpha,25(OH)2D3 was metabolized by multistep monooxygenation reactions, which led to the loss of affinity for VDR. Thus, the greater therapeutic effects of AH 1 than those of 1alpha,25(OH)2D3 in in vivo studies using osteoporosis rat models may be due to 24R-hydroxy-AH-1 whose VDR affinity was 91% of that of AH-1. PMID- 29425809 TI - Tribute to Albert Sheffer, MD, and Sheldon Spector, MD. PMID- 29425810 TI - Authors' response. PMID- 29425811 TI - An in vitro study on the influence of viscosity and frequency of application of fluoride/tin solutions on the progression of erosion of bovine enamel. AB - OBJECTIVE: To evaluate the influence of the viscosity and frequency of application of solutions containing fluoride (F) and stannous chloride (SnCl2) on enamel erosion prevention. DESIGN: Bovine enamel specimens were randomly distributed into 12 groups (n = 10), according to the following study factors: solution (C: deionized water; F: 500 ppm F-; F + Sn: 500 ppm F- + 800 ppm Sn2+); viscosity (low and high); and frequency of application (once and twice a day). Specimens were submitted to an erosive cycling model, consisting of 5 min immersion in 0.3% citric acid, followed by 60 min exposure to a mineral solution. This procedure was repeated 4*/day, for 5 days. Treatment with the experimental solutions was performed for 2 min, 1*/day or 2*/day. Enamel surface loss (SL) was determined by optical profilometry. Data were analyzed by 3-way ANOVA and Tukey tests (alpha = 0.05). RESULTS: There were significant differences between the levels of the factor solution (p < .001), viscosity (p < .001) and in the interaction between solution and viscosity (p = .01). Regarding solution, the mean SL +/- standard deviation for the groups was F + Sn (4.90 +/- 1.12) < F (7.89 +/- 1.19) < C (14.20 +/- 1.69). High viscosity solutions demonstrated less SL than low viscosity; however, only when applied once a day (p < .001). Applying the solutions twice a day yielded lower SL than once a day, but only for the low viscosity solutions (p = .003). CONCLUSIONS: Under the conditions of this short term in vitro experiment, it could be concluded that increasing the viscosity of the oral rinse solutions reduced enamel loss by erosion; however, this effect was small and only observed when the solutions were applied once a day. PMID- 29425812 TI - Assessment of the Prosthetic Replacement of Ocular Surface Ecosystem (PROSE) scleral lens on visual acuity for corneal irregularity and ocular surface disease. AB - PURPOSE: To describe changes in visual acuity in patients fit with the Prosthetic Replacement of Ocular Surface Ecosystem (PROSE) with irregular corneas compared to those with ocular surface disease, as well as describe patient demographics and fitting indications for PROSE at an academic medical center. METHODS: A retrospective chart review from 2010 to 2016 on a total of 825 eyes from 493 patients fitted with a PROSE lens, and grouped by etiology, either irregular cornea/dystrophy or ocular surface disease and associated sub-etiologies. We compared best corrected visual acuity (BCVA) before and after PROSE fitting. RESULTS: The irregular cornea group (n = 262 eyes) included corneal scar (n = 57), dystrophy (n = 17), post-operative corneal irregularity (n = 70), and primary ectasia (n = 118). The OSD group included 563 eyes. For all etiologies combined, mean BCVA prior to PROSE fitting compared to after improved by 0.28 logMAR (p < .001). In the irregular cornea group, the mean BCVA improved by 0.46 logMAR (p < .001), while the improvement in BCVA for the OSD group was 0.20 logMAR (p < .001). All etiologies in the irregular cornea group demonstrated improvement in BCVA (p < .05) with the exception of post-PRK (n = 2). BCVA improvement was found for all sub-etiologies in the OSD subgroup (p < .05). CONCLUSIONS: PROSE treatment had a positive impact on visual acuity for a wide range of corneal irregularities and ocular surface disease, suggesting that PROSE lenses may offer improvements in visual acuity without risks inherent to surgery. PMID- 29425813 TI - Overexpression of a tomato carotenoid epsilon-hydroxylase gene (SlLUT1) improved the drought tolerance of transgenic tobacco. AB - Drought stress is a considerable environmental factor that restrains photosynthesis. Lutein, the most prolific carotenoid in plant photosynthetic tissues, plays vital roles in the light-harvesting complexes. However, its biological functions under abiotic stresses remain unclear. In our research, transgenic tobacco plants were utilized to investigate the function of the tomato chloroplast-targeted carotenoid epsilon-ring hydroxylase (SlLUT1) in drought stress tolerance. The analysis of SlLUT1-pro-LUC and qRT-PCR showed that drought stress induced SlLUT1 expression. Transgenic tobacco plants exhibit higher lutein content than wild-type (WT) tobacco. Under drought stress, transgenic plants overexpressing SlLUT1 showed better growth performance, higher chlorophyll and relative water contents and more intact chloroplast and PSII supercomplex structures than WT tobacco. The Fv/Fm, Pn, NPQ, and content of D1 protein in transgenic plants were higher than those in WT plants under drought stress. The accumulation of H2O2 and O2- decreased in transgenic tobacco plants. Moreover, transgenic plants exhibited lower MDA accumulation and REL. These results indicate that overexpression of SlLUT1 enhances tolerance to drought stress by maintaining photosynthesis and scavenging ROS in transgenic tobacco. PMID- 29425814 TI - Mg-dechelation of chlorophyll a by Stay-Green activates chlorophyll b degradation through expressing Non-Yellow Coloring 1 in Arabidopsis thaliana. AB - The first step in chlorophyll a degradation is the extraction of the central Mg. This reaction is catalyzed by Mg-dechelatase encoded by Stay-Green (SGR) in land plants. SGR extracts Mg from chlorophyll a but not from chlorophyll b, and chlorophyll b must be converted to chlorophyll a before degradation. The first reaction of the chlorophyll b to chlorophyll a conversion is catalyzed by chlorophyll b reductase. Non-Yellow Coloring 1 (NYC1) and NYC1 like (NOL) are isozymes of chlorophyll b reductase. When SGR was transiently overexpressed in Arabidopsis, both chlorophyll a and b were degraded, suggesting that the chlorophyll b to chlorophyll a conversion is activated by SGR overexpression. To examine the involvement of chlorophyll b reductases in SGR-induced chlorophyll b degradation, SGR was transiently overexpressed in nyc1, nol, and nyc1 nol double mutants by dexamethasone treatment. It was found that in the wild type and nol mutant, chlorophyll a and b were degraded and all the chlorophyll-binding proteins decreased. Meanwhile, in nyc1 and nyc1 nol mutants, chlorophyll b degradation was suppressed and the light-harvesting complex of photosystem II remained. The mRNA and protein levels of NYC1 increased after SGR overexpression in wild type plants. These results suggest that Mg-dechelation of chlorophyll a by SGR activates chlorophyll b degradation by inducing the expression of NYC1. This is an effective regulation of a metabolic pathway. PMID- 29425815 TI - Computer-aided insights into receptor-ligand interaction for novel 5 arylhydantoin derivatives as serotonin 5-HT7 receptor agents with antidepressant activity. AB - This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2 methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (1, MF-8), as part of the search for potent and selective serotonin 5-HT7 receptor (5-HT7R) agents. New hydantoin derivatives (4-19) were designed and synthesized. For 5 phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5 methylimidazolidine-2,4-dione (4), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT7R and selectivity over 5-HT1AR, dopamine D2R and alpha1-, alpha2-and beta-adrenoceptors. Selected compounds (5-8) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT7R in RBA, in particular seven compounds (4, 5, 7, 8 and 10 12,Ki <= 10 nM). Antidepressant-like activity in vivo for all tested compounds (5 8) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono-phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT7R affinity than the di phenyl ones. PMID- 29425816 TI - Recent updates for designing CCR5 antagonists as anti-retroviral agents. AB - The healthcare system faces various challenges in human immunodeficiency virus (HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a consequence of the evolutionary process. Despite the success of antiretroviral drugs like Zidovudine, Zalcitabine, Raltegravir WHO ranks HIV as one of the deadliest diseases with a mortality of one million lives in 2016. Thus, there emerges an urgency of developing a novel anti-retroviral agent that combat resistant HIV strains. The clinical development of ART from a single drug regimen to current triple drug combination is very slow. The progression in the structural biology of the viral envelope prompted the discovery of novel targets, which can be demonstrated a proficient approach for drug design of anti-retroviral agents. The current review enlightens the recent updates in the structural biology of the viral envelope and focuses on CCR5 as a validated target as well as ways to overcome CCR5 resistance. The article also throws light on the SAR studies and most prevalent mutations in the receptor for designing CCR5 antagonists that can combat HIV-1 infection. To conclude, the paper lists diversified scaffolds that are in pipeline by various pharmaceutical companies that could provide an aid for developing novel CCR5 antagonists. PMID- 29425817 TI - Design, synthesis and biological evaluation of novel bouchardatine analogs as potential inhibitors of adipogenesis/lipogenesis in 3T3-L1 adipocytes. AB - Inhibition of the differentiation of adipocytes and reduced lipid synthesis are efficacious approaches for treating obesity-related metabolic disorders. Bouchardatine (Bou) is a natural alkaloid that has been reported to moderately inhibit the differentiation of 3T3-L1 cells without inducing toxicity. To explore the importance of aldehyde group at 8a-position of Bou and optimize the activity, we synthesized 35 (31 novel) compounds by discarding or replacing aldehyde group with halogen and introducing different amine chains at 5-position of Bou. The lipid-lowering activity was evaluated using a cell-based screening system. The substitution of the group at the 8a-position of compounds was important for its lipid-lowering activity, and the SAR was discussed. The selective compound 6e showed a 93-fold increase in its lipid-lowering effect (EC50 = 0.24 MUM) compared with Bou (EC50 ~ 25 MUM). Further mechanistic studies revealed that compound 6e activated AMP-activated protein kinase (AMPK) pathway and inhibited MCE activity to block cell proliferation and induce cell cycle arrest at the early stage of differentiation, thus decreasing the expression of adipogenic factors and fatty acid synthesis-related proteins. PMID- 29425818 TI - DNA methylation of the Klf14 gene region in whole blood cells provides prediction for the chronic inflammation in the adipose tissue. AB - Kruppel-Like Factor 14 (KLF14) gene, which appears to be a master regulator of gene expression in the adipose tissue and have previously been associated with BMI and Type 2 diabetes (T2D) by large genome-wide association studies. In order to find predictive biomarkers for the development of T2D, it is necessary to take epigenomic changes affected by environmental factors into account. This study focuses on ageing and obesity, which are T2D risk factors, and examines epigenetic changes and inflammatory changes. We investigated DNA methylation changes in the Klf14 promoter region in different organs of mice for comparing aging and weight. We found that methylation levels of these sites were increased with aging and weight in the spleen, the adipose tissue, the kidney, the lung, the colon and the whole blood cells. In addition, in the spleen, the adipose tissue and the whole blood, these epigenetic changes were also significantly associated with inflammatory levels. Moreover, not only Klf14, but also expression levels of some downstream genes were decreased with methylation in the spleen, the adipose tissue and the whole blood cells. Taken together, our results suggest that methylation changes of Klf14 in those tissues may be associated with changes in gene expression and inflammation on the adipose tissue of obesity and T2D. In addition, the methylation changes in the whole blood cells may serve as a predictive epigenetic biomarker for the development of T2D. PMID- 29425819 TI - Functional characterization of lethal P-loop mutations in Tetrahymena outer arm dynein (Dyh3p). AB - Mutational analyses of axonemal dyneins are useful for elucidating the molecular mechanism of ciliary motility. This study demonstrates a mutation system for characterizing lethal P-loop mutations in Tetrahymena outer arm dynein (Dyh3p). The viable DYH3-knockout (vKO-DYH3) cells isolated in this study enabled the examination of lethal mutations in P-loops 1 and 2. The P1 mutant dynein localized in the oral apparatus and the proximal region of the cilia, and the P2 mutant dynein localized only in the oral apparatus. Both results are different from the localization of wild-type Dyh3p. In addition, a co-precipitation assay showed that the P1 and P2 mutant dyneins did not dissociate from microtubules in ATP plus vanadate or in no-ATP conditions, in contrast to wild-type Dyh3p. This mutation system is useful for further molecular studies of axonemal dyneins and ciliary motility. PMID- 29425820 TI - Quercetin restrains TGF-beta1-induced epithelial-mesenchymal transition by inhibiting Twist1 and regulating E-cadherin expression. AB - Emerging evidence has indicated that transforming growth factor-beta 1 (TGF beta1) induces the epithelial-mesenchymal transition (EMT) in cancer cells, thus promoting their motility and invasiveness. Quercetin, a member of the polyphenolic flavonoid family, has been reported to display anticancer activity against a broad range of cancer cell types. Indeed, numerous studies have shown the cancer preventive effects and molecular mechanisms of quercetin in vitro using diverse cell model systems. However, the potential effect of quercetin on EMT remains unclear. In this study, we identified a unique function of quercetin in inhibiting the EMT process induced by TGF-beta1. In particular, quercetin rescued the morphological changes and EMT-like phenotypes in TGF-beta1-activated SW480 cells, and this inhibition of TGF-beta1-induced EMT was mediated via the suppression of Twist1 expression. In addition, quercetin strongly suppressed TGF beta1-induced invasion of SW480 cells. Thus, quercetin may be considered a novel therapeutic agent for the treatment of patients with refractory cancer and for the prevention of the metastatic cascade initiated by EMT. PMID- 29425822 TI - Microfluidics for secretome analysis under enhanced endogenous signaling. AB - Cell secretome, the complex set of proteins that are secreted by the cells, is a fundamental mechanism of cell-cell communication both in vitro and in vivo. In vivo, the analysis of proteins secreted into body fluids can bring to the identification of biomarkers for important physiopathological conditions. However, due to the complexity of the protein content of body fluids, a better understanding of the secreted proteins by different cell types is highly desirable and can be performed in vitro for dissection. To this aim, microfluidic culture systems could be particularly relevant because of the accumulation of extrinsic endogenous signals at microliter scale, which better preserves the self regulation occurring in the small interstitial spaces in vivo. In this work, we perform a quantitative study to compare the secretome in microfluidics and in a standard well plate. Human foreskin fibroblasts are used as a case study. This work also represents an important technological advance in terms of feasibility of high-throughput quantitative protein analyses in microfluidics. PMID- 29425821 TI - MMP9 is involved in HO-1-mediated upregulation of apical junctional complex in Caco-2 cells under oxygen-glucose deprivation. AB - Ischemia reperfusion injury is a critical factor in the recovery process after intestine trauma and the functional restoration of intestinal reconstruction. This study was the first to explore the expression of apical junctional complex (AJC) induced by heme oxygenase-1 (HO-1) in Caco-2 cells in oxygen-glucose deprivation (OGD) models. Here we showed that HO-1 was upregulated after OGD. Notably, activation of HO-1 largely enhanced the expression of AJC proteins including Claudin-4, E-cadherin and beta-catenin in Caco-2 cells, but decreased the expression of matrix metalloproteinase 9 (MMP9). Knockdown of HO-1 attenuated the OGD-induced overexpression of AJC proteins but promoted the expression of MMP9. Interestingly, inhibition of MMP9 further enhanced AJC expression. These results suggest that HO-1 is involved in OGD-evoked upregulation of AJC proteins, which is partly mediated by MMP9 pathway. High expression of HO-1 may play an important role in the pathophysiological process of ischemia reperfusion injury and has potential clinical value for the treatment of intestine related diseases. PMID- 29425823 TI - The presence of the 1068 G>A variant of P2X7 receptors is associated to an increase in IL-1Ra levels, insulin secretion and pancreatic beta-cell function but not with glycemic control in type 2 diabetes patients. AB - It has been reported that an increased function of the P2X7 purinergic receptor is associated with an increase in both insulin sensitivity and secretion. Accordingly, we explored the possible effect of the 1068 G>A polymorphism of the gene P2RX7 on glucose homeostasis and the levels of the anti-inflammatory cytokine IL-1Ra in T2D patients. The presence of the 1068 G>A polymorphism in T2D patients (n = 100) and healthy subjects (n = 100) was determined by DNA sequencing, and serum levels of IL-1Ra were measured by ELISA. Pancreatic beta cell function, insulin resistance, blood glucose levels and glycated hemoglobin (HbA1c) were also analyzed. We detected a significant negative association between T2D and the 1068 G>A SNP (Odds ratio 0.3916, p = 0.0045). In addition, we observed that T2D patients bearing the 1068 G>A variant showed higher serum levels of IL-1Ra compared to both, patients with the GG genotype or healthy individuals (GG or G>A). Moreover, T2D patients bearing the 1068 G>A SNP showed increased insulin levels and a better pancreatic beta-cell function (p < 0.05 in both cases) compared to patients with the wild type genotype. However, the HbA1c levels, fasting glucose levels and the degree of insulin resistance were similar in T2D patients carrying or not the G>A SNP. Our results suggest that although the 1068 G>A polymorphism of the P2RX7 gene is associated with an increased beta cell function and IL-1Ra release in T2D patients, the glycemic control is not significantly affected by the presence of this SNP. PMID- 29425824 TI - Salt and drought stress and ABA responses related to bZIP genes from V. radiata and V. angularis. AB - Mung bean and adzuki bean are warm-season legumes widely cultivated in China. However, bean production in major producing regions is limited by biotic and abiotic stress, such as drought and salt stress. Basic leucine zipper (bZIP) genes play key roles in responses to various biotic and abiotic stresses. However, only several bZIP genes involved in drought and salt stress in legumes, especially Vigna radiata and Vigna angularis, have been identified. In this study, we identified 54 and 50 bZIP proteins from whole-genome sequences of V. radiata and V. angularis, respectively. First, we comprehensively surveyed the characteristics of all bZIP genes, including their gene structure, chromosome distribution and motif composition. Phylogenetic trees showed that VrbZIP and VabZIP proteins were divided into ten clades comprising nine known and one unknown subgroup. The results of the nucleotide substitution rate of the orthologous gene pairs showed that bZIP proteins have undergone strong purifying selection: V. radiata and V. angularis diverged 1.25 million years ago (mya) to 9.20 mya (average of 4.95 mya). We also found that many cis-acting regulatory elements (CAREs) involved in abiotic stress and plant hormone responses were detected in the putative promoter regions of the bZIP genes. Finally, using the quantitative real-time PCR (qRT-PCR) method, we performed expression profiling of the bZIP genes in response to drought, salt and abscisic acid (ABA). We identified several bZIP genes that may be involved in drought and salt responses. Generally, our results provided useful and rich resources of VrbZIP and VabZIP genes for the functional characterization and understanding of bZIP transcription factors (TFs) in warm-season legumes. In addition, our results revealed important and interesting data - a subset of VrbZIP and VabZIP gene expression profiles in response to drought, salt and ABA stress. These results provide gene expression evidence for the selection of candidate genes under drought and salt stress for future study. PMID- 29425825 TI - Molecular characterization and gene expression patterns of retinoid receptors, in normal and regenerating tissues of the sea cucumber, Holothuria glaberrima. AB - Retinoic acid receptors (RAR) and retinoid X receptors (RXR) are ligand-mediated transcription factors that synchronize intricate signaling networks in metazoans. Dimer formation between these two nuclear receptors mediates the recruitment of co-regulatory complexes coordinating the progression of signaling cascades during developmental and regenerative events. In the present study we identified and characterized the receptors for retinoic acid in the sea cucumber Holothuria glaberrima; a model system capable of regenerative organogenesis during adulthood. Molecular characterizations revealed the presence of three isoforms of RAR and two of RXR as a consequence of alternative splicing events. Various analyses including: primary structure sequencing, phylogenetic analysis, protein domain prediction, and multiple sequence alignment further confirmed their identity. Semiquantitative reverse transcription PCR analysis of each receptor isoform herein identified showed that the retinoid receptors are expressed in all tissues sampled: the mesenteries, respiratory trees, muscles, gonads, and the digestive tract. During regenerative organogenesis two of the receptors (RAR-L and RXR-T) showed differential expression in the posterior segment while RAR-S is differentially expressed in the anterior segment of the intestine. This work presents the first description of the components relaying the signaling for retinoic acid within this model system. PMID- 29425827 TI - Association of HLA-DPB1 polymorphisms with rheumatoid arthritis: A systemic review and meta-analysis. AB - BACKGROUND: The current reports on the association between HLA-DPB1 alleles and rheumatoid arthritis (RA) results were controversial. Thus, we conducted a meta analysis to assess whether DPB1 alleles are associated with increased risk of rheumatoid arthritis. METHODS: Systematic searches on PubMed, Embase, Elsevier, CNKI (China National Knowledge Infrastructure), Wanfang data and Cochrane Library prior to July 2017 were performed. The pooled odds ratios (ORs) and 95% confidence interval (95% CI) was used to assess the association between frequencies of DPB1 alleles and RA patients. RESULTS: Eight studies with 592 cases and 935 controls were included in this meta-analysis. Overall, the pooled ORs showed that frequencies of DPB1*0401 and *0601 were higher in the RA group compared with controls (*0401: OR: 1.586, 95%CI: 1.296-1.941, P<0.001; *0601: OR: 1.921, 95%CI: 1.142-3.229, P=0.014). Whereas, the frequencies of DPB1*0101, *0402 and *0501 were lower in the RA control than the controls (*0101: OR: 0.691, 95%CI: 0.481-0.993, P=0.046; *0402: OR: 0.707, 95%CI: 0.555-0.902, P=0.005; *0501: OR: 0.502, 95%CI: 0.329-0.767, P=0.001). No associations were observed for DPB1*0201, *0202, *0301 and *0901 (*0201: OR: 1.129, 95%CI: 0.882-1.446, P = 0.335; *0202: OR: 0.840, 95%CI: 0.940-1.441, P = 0.527; *0301: OR: 0.769, 95%CI: 0.577-1.026, P = 0.074; *0901: OR: 1.221, 95% CI: 0.541-2.755, P = 0.630). CONCLUSIONS: This meta-analysis demonstrates that high frequency expression of DPB1*0401 and *0601 are significantly associated with susceptibility to RA, it may be a risk factor for occurrence of RA. Low frequency expression of DPB1*0101, *0402 and *0501 may be negatively associated with RA, it may be a protective factor for occurrence of RA. PMID- 29425826 TI - Correlation of clinical and pathological staging and response to neoadjuvant therapy in resected pancreatic cancer. AB - BACKGROUND: Neoadjuvant therapy (NAT) has been increasingly employed to optimize outcomes in pancreatic cancer; however, little is known about its pathologic impact. METHODS: The National Cancer Data Base (2003-2011) was retrospectively reviewed for patients with pancreatic carcinoma who underwent initial surgery or NAT followed by resection. Response to NAT, determined by comparing clinical and pathologic stage, and survival were evaluated. RESULTS: 16,087 patients underwent initial pancreatectomy and 2307 patients received NAT. Clinical stage correlated poorly with pathological stage in patients who received initial surgery (kappa = 0.2865, p < 0.001). With NAT, 21.9% were downstaged, 47.9% had no stage change, and 30.3% progressed. In clinical stage II disease, patients downstaged with neoadjuvant chemotherapy or multimodality therapy demonstrated improved survival over patients who did not respond or who progressed (P = 0.0022, P = 0.0012, respectively). This benefit was not preserved in stage III disease (P = 0.7380, P = 0.0726, respectively). In multivariable analysis, downstage in disease was associated with a 19% lower hazard of mortality (HR 0.81, 95% CI: 0.7-0.92, P = 0.002). CONCLUSIONS: Clinical stage correlates poorly with pathological stage in resectable pancreatic cancer. The majority of patients do not experience a change in stage with NAT. Those with early stage disease, responsive to NAT, experience a survival benefit. PMID- 29425828 TI - Outcomes of renal transplant from donors with polycystic kidney disease. AB - INTRODUCTION: Kidneys from donors affected by autosomal-dominant polycystic kidney disease (ADPKD) are, in general, considered unsuitable for transplantation. However, some authors report cases of patients who received kidneys from a deceased ADPKD donor showing encouraging outcomes. Our aim is to provide our experience of a patient with end stage renal failure who received a deceased donor kidney from a 29-year-old who themselves had been diagnosed with ADPKD but well maintained renal function, and to provide a comprehensive review of all the published literature. METHODS: In addition to our case, a literature search (PubMed database, Embase, Cochrane Library) of articles published between 1980 and 2017 was performed. RESULTS: Sixteen cases were identified. Median donor age was 24 (range12-55) years old. Median recipient age was 46 (range 19-72) years old. Fifteen cases had a single kidney transplant and one case had a dual kidney transplant. 13/16 (81%) had immediate function, 2 patients (12.5%) had delayed graft function and one patient (6.25%) had primary non-function. Median graft follow up was 36 months (range 6-180). Median serum creatinine at last follow up was 124 MUmol/L (range75-442). Thirteen patients (81%) were still alive with a working renal transplant at last follow up. CONCLUSION: The published literature is encouraging and supports the use of polycystic kidneys from younger deceased donors. Therefore, we believe that if kidneys from ADPKD donors are offered, they should have a full assessment and be considered acceptable for renal donation to recipients who may have a life expectancy of 10 years or less and who are fully informed and have the capacity to consent to receiving a polycystic kidney. PMID- 29425829 TI - Assessment and optimization of liver volume before major hepatic resection: Current guidelines and a narrative review. AB - Post hepatectomy liver failure (PHLF) remains a significant cause of morbidity and mortality after major liver resection. Although the etiology of PHLF is multifactorial, an inadequate functional liver remnant (FLR) is felt to be the most important modifiable predictor of PHLF. Pre-operative evaluation of FLR function and volume is of paramount importance before proceeding with any major liver resection. Patients with inadequate or borderline FLR volume must be considered for volume optimization strategies such as portal vein embolization (PVE), two stage hepatectomy with portal vein ligation (PVL), Yttrium-90 radioembolization, and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). This paper provides an overview of assessing FLR volume and function, and discusses indications and outcomes of commonly used volume optimization strategies. PMID- 29425830 TI - Metal-chelating 3-hydroxypyrimidine-2,4-diones inhibit human cytomegalovirus pUL89 endonuclease activity and virus replication. AB - Human cytomegalovirus terminase complex cleaves the concatemeric genomic viral DNA into unit lengths during genome packaging and particle assembly. Terminase complex ATPase and endonuclease activity is provided by the viral protein pUL89. pUL89 is an attractive drug target because its activities are required for infectious virus production. A domain located in the C-terminus of pUL89 has an RNase H/integrase-like fold and endonuclease activity that can be inhibited by compounds featuring a chelating triad motif. Previously, we developed a novel ELISA approach to screen for pUL89 inhibitors. In this report, we used the ELISA to identify 3-hydroxypyrimidine-2,4-dione as a promising scaffold for pUL89 inhibitor development. Several potent pUL89 inhibitors yielded low micromolar IC50 values in the enzymatic assay and low micromolar EC50 values for inhibition of HCMV replication. Two representative compounds inhibitory effects depended upon metal ions and occurred late in virus replication consistent with pUL89 inhibitors in infected cells. PMID- 29425831 TI - GS-9620 inhibits enterovirus 71 replication mainly through the NF-kappaB and PI3K AKT signaling pathways. AB - Human enterovirus 71 (EV71) is the second most common cause of hand, foot, and mouth disease (HFMD), which can occur as a severe epidemic especially among children under 5-years old. New and improved treatment strategies to control EV71 infection are therefore urgently required. The heterocyclic compound GS-9620, a potent and selective agonist of Toll-like receptor 7 (TLR7), has been reported to activate plasmacytoid dendritic cells (pDCs), and suppress HBV as well as HIV replication. In this study, we indicated that GS-9620 also could inhibit EV71 replication in the mouse model of EV71 infection. With three-days treatment after EV71 infection, the levels of proinflammatory cytokines/chemokines, like IFN alpha, IFN-gamma and MCP-1, were sharply reduced in serum compared to those without treatment. Furthermore, GS-9620 activated TLR7 in the limb muscle cells, which stimulated the NF-kappaB and PI3K/AKT signaling pathways. When NF-kappaB or PI3K/AKT inhibitors were used, the antiviral effect of the GS-9620 was impacted. Overall, our data implied GS-9620 probably activates NF-kappaB and PI3K/AKT signaling pathways to clear the virus. PMID- 29425832 TI - Small activating RNA induced expression of VHL gene in renal cell carcinoma. AB - Recent studies have reported that chemically synthesized double-stranded RNAs (dsRNAs), also known as small activating RNA (saRNAs), can specifically induce gene expression by targeting promoter sequences by a mechanism termed RNA activation (RNAa). In the present study, we designed 4 candidate saRNAs targeting the Von Hippel-Lindau (VHL) gene promoter. Among these saRNAs, dsVHL-821 significantly inhibited cell growth by up-regulating VHL at both the mRNA and protein levels in renal cell carcinoma 769-P cells. Functional analysis showed that dsVHL-821 induced apoptosis by increasing p53, decreasing Bcl-xL, activating caspase 3/7 and poly-ADP-ribose polymerase in a dose-dependent manner. Chromatin immunoprecipitation analysis revealed that dsVHL-821 increased the enrichment of Ago2 and RNA polymerase II at the dsVHL-821 target site. In addition, Ago2 depletion significantly suppressed dsVHL-821-induced up-regulation of VHL gene expression and related effects. Single transfection of dsVHL-821 caused long lasting (14 days) VHL up-regulation. Furthermore, the activation of VHL by dsVHL 821 was accompanied by an increase in dimethylation of histone 3 at lysine 4 (H3K4me2) and acetylation of histone 4 (H4ac) and a decrease in dimethylation of histone 3 at lysine 9 (H3K9me2) and lysine 27 (H3K27me2) in the dsVHL-821 target region. Taken together, these results demonstrate that dsVHL-821, a novel saRNA for VHL, induces the expression of the VHL gene by epigenetic changes, leading to inhibition of cell growth and induction of apoptosis, and suggest that targeted activation of VHL by dsVHL-821 may be explored as a novel treatment of renal cell carcinoma. PMID- 29425833 TI - Over expressing miR-19b-1 suppress breast cancer growth by inhibiting tumor microenvironment induced angiogenesis. AB - Metastastic breast cancer, especially triple-negative (TN), is one of the most common causes of cancer related deaths in women. Recent years, tumor-associate vessel formation is considered as a more generally and effective target to patient with malignant cancer. Our previous studies indicated that miR-19b-1 controls the intrinsic angiogenic activity of human umbilical vein endothelial cells (HUVECs) in vitro. In this study, in silico analysis indicated VEZF1 that implicates in angiogenesis and triple-negative breast cancer progression might be the target of miR-19b-1. Further investigation showed that overexpressing miR-19b 1 in human triple-negative breast cancer cell line(MDA-MB-231) led to impaired angiogenic activity of HUVECs in vitro and in vivo. Additionally, miR-19b-1 upregulation inhibited the vessel imitation mediated by MDA-MB-231. Furthermore, enforced expression of miR-19b-1 in MDA-MB-231 has impact on HUVECs apoptosis and altered the mitochondrial membrane potential, which suggested the possible mechanism involved in interaction between breast cancer and endothelial cells. What's more, we found that miR-19b-1 stable overexpression in MDA-MB-231 caused tumor growth arresting entirely. Besides, our results suggested that miR-19b-1 could inhibit angiogenesis by possibly targeting VEGF receptor endocytosis signaling pathway. Taking together, our findings suggest an important role of miR 19b-1 in crosstalk between metastatic breast cancer and endothelial cells and provide us new insights for exploring miR-19b-1 and its multiple targets as promising therapeutic candidates to interfere breast cancer progression. PMID- 29425834 TI - Population pharmacokinetics/pharmacodynamics of linezolid in sepsis patients with and without continuous renal replacement therapy. AB - PURPOSE: The purpose of this study was to identify the optimum dosing regimen of linezolid in sepsis patients with and without renal dysfunction and sepsis patients on low-dose continuous renal replacement therapy (CRRT) using a pharmacokinetics/pharmacokinetics (PK/PD) approach. METHODS: Sepsis patients with and without renal dysfunction (creatinine clearance < 50 mL/min), and sepsis patients on low-dose CRRT (dose: 800 mL/h) were studied. The PK data were modeled using a two-compartment model, and then used for simulation. The target PK/PD was the 24-h area under the concentration-time curve to minimum inhibitory concentration ratio of >= 80. Dosing regimens were evaluated using cumulative fraction of response (CFR) and safety probability (trough level < 7 ug/mL) by Monte Carlo simulation. RESULTS: Twenty-seven patients, including 8 patients with preserved renal function, 9 patients with renal dysfunction, and 10 patients on CRRT, were studied. The proposed regimen to attain CFR >= 90% was 800 mg every 12 h (safety probability 82.4%) for patients with preserved renal function. By contrast, the target CFR was attained with a decreased regimen in patients with renal dysfunction and those on CRRT [600 mg every 24h (safety probability 68.6%) and 800 mg every 24h (42.1%)]. CONCLUSIONS: We identified different dosage strategies to achieve target linezolid concentrations according to renal function and use of CRRT in sepsis patients. Because of unassured safety probability in patients without preserved renal function, dosing regimens should be adjusted based on the therapeutic drug monitoring. PMID- 29425835 TI - The influence of internal and external tibial rotation offsets on knee joint and ligament biomechanics during simulated athletic tasks. AB - BACKGROUND: Following anterior cruciate ligament injury and subsequent reconstruction transverse plane tibiofemoral rotation becomes underconstrained and overconstrained, respectively. Conflicting reports exist on how rotations influence loading at the knee. This investigation aimed to determine the mechanical effects of internal and external tibial rotation offsets on knee kinematics and ligament strains during in vitro simulations of in vivo recorded kinematics. METHOD: A 6-degree-of-freedom robotic manipulator arm was used to articulate 11 cadaveric tibiofemoral joint specimens through simulations of four athletic tasks produced from in vivo recorded kinematics. These simulations were then repeated with 4 degrees tibial rotation offsets applied to the baseline joint orientation. FINDINGS: Rotational offsets had a significant effect on peak posterior force for female motion simulations (P < 0.01), peak lateral force for most simulated tasks (P < 0.01), and peak anterior force, internal torque, and flexion torque for sidestep cutting tasks (P <= 0.01). Rotational offsets did not exhibit statistically significant effects on peak anterior cruciate ligament strain (P > 0.05) or medial collateral ligament strain (P > 0.05) for any task. INTERPRETATION: Transverse plane rotational offsets comparable to those observed in anterior cruciate ligament deficient and reconstructed patients alter knee kinetics without significantly altering anterior cruciate ligament strain. As knee degeneration is attributed to abnormal knee loading profiles, altered transverse plane kinematics may contribute to this. However, altered transverse plane rotations likely play a limited role in anterior cruciate ligament injury risk as physiologic offsets failed to significantly influence anterior cruciate ligament strain during athletic tasks. PMID- 29425836 TI - The impact of a daily smartphone-based feedback system among women with gestational diabetes on compliance, glycemic control, satisfaction, and pregnancy outcome: a randomized controlled trial. AB - BACKGROUND: Patient compliance and tight glycemic control have been demonstrated to improve outcome in pregnancies complicated by gestational diabetes mellitus. The use of advanced technological tools, including smartphone-based platforms, to improve medical care and outcomes has been demonstrated in various fields of medicine, but only a few small studies were performed with gestational diabetes mellitus patients. OBJECTIVE: We aimed to study the impact of introducing a smartphone-based daily feedback and communication platform between gestational diabetes mellitus patients and their physicians, on patient compliance, glycemic control, pregnancy outcome, and patient satisfaction. STUDY DESIGN: This is a prospective, single-center, randomized controlled trial. Newly diagnosed gestational diabetes mellitus patients presenting to our multidisciplinary diabetes-in-pregnancy clinic were randomized to: (1) routine biweekly prenatal clinic care (control group); or (2) additional daily detailed feedback on their compliance and glycemic control from the clinic team via an application installed on their smartphone (smartphone group). The primary outcome was patient compliance defined as the actual blood glucose measurements/instructed measurements *100. The secondary outcomes included diabetes-control parameters, pregnancy, and neonatal outcomes. The study was adequately powered to detect a 20% difference in patient compliance, based on a preliminary phase that demonstrated 70% baseline compliance to glucose measurements. RESULTS: A total of 120 newly diagnosed gestational diabetes mellitus patients were analyzed. The 2 groups did not differ in terms of age, parity, education, body mass index, family history, maternal comorbidities, oral glucose tolerance test values, and hemoglobin A1C at randomization. The smartphone group demonstrated higher level of compliance (84 +/- 0.16% vs 66 +/- 0.28%, P < .001); lower mean blood glucose (105.1 +/- 8.6 mg/dL vs 112.6 +/- 7.4 mg/dL, P < .001); lower rates of off-target measurements both fasting (4.7 +/- 0.4% vs 8.4 +/- 0.6%, P < .001) and 1-hour postprandial (7.7 +/- 0.8% vs 14.3 +/- 0.8%, P < .001); and a lower rate of pregnancies requiring insulin treatment (13.3% vs 30.0%, P = .044). The rates of macrosomia, neonatal hypoglycemia, shoulder dystocia, and other delivery and neonatal complications did not differ between the groups. Patients in the smartphone group reported excellent satisfaction from the use of the application and from their overall prenatal care. CONCLUSION: Introduction of a smartphone based daily feedback and communication platform between gestational diabetes mellitus patients and the multidisciplinary diabetes-in-pregnancy clinic team improved patient compliance and glycemic control, and lowered the rate of insulin treatment. PMID- 29425837 TI - Robotic-assisted sacrocolpopexy: early postoperative outcomes after surgical reduction of enlarged genital hiatus. AB - BACKGROUND: Currently, the decision to perform a concurrent posterior repair/perineoplasty at the time of robotic-assisted sacrocolpopexy is not standardized. OBJECTIVE: We sought to compare anatomic failure after robotic assisted sacrocolpopexy among 3 groups of patients categorized by their preoperative and postoperative genital hiatus size. STUDY DESIGN: We performed a retrospective cohort study of women who underwent robotic-assisted sacrocolpopexy, from January 2013 through September 2016. We defined a wide genital hiatus as >=4 cm and a normal genital hiatus as <4 cm. We compared 3 groups: (1) wide preoperative and postoperative genital hiatus (persistently wide); (2) wide preoperative and normal postoperative genital hiatus (improved); and (3) normal preoperative and postoperative genital hiatus (stably normal). Our primary outcome was composite anatomic failure defined as either recurrent prolapse in any compartment past the hymen or retreatment for prolapse with either surgery or pessary. Our data were analyzed using 1-way analysis of variance and chi2 test. Logistic regression was performed to evaluate for independent risk factors for anatomic failure among the 3 groups. P < .05 was considered significant. RESULTS: Our study population consisted of 452 women with a mean age of 59.3 +/- 10.0 years and a mean body mass index of 27.8 +/- 5.3 kg/m2. Of the women with reported race, 394/447 (88.1%) were white. The genital hiatus groups were distributed as follows: 57 (12.6%) were persistently wide, 296 (65.5%) were improved, and 99 (21.9%) were stably normal. The stably normal group had less advanced preoperative prolapse (stage >=3) than the other groups (P < .01). A similar percentage of patients among groups had a concomitant posterior repair/perineoplasty (P = .09) with a total of 84 (18.6%) women undergoing this procedure. There was a statistically significant difference in overall composite anatomic failure among the groups (P = .03). There was an increase in failure in the persistently wide group (14.0%) compared to the improved group (5.7%, P = .04) and compared to the stably normal group (4.0%, P = .03). In a logistic regression model, controlling for number of vaginal deliveries and posterior repair/perineoplasty, there was a 5.3-fold increased odds of composite anatomic failure in the persistently wide group (adjusted odds ratio, 5.3; 95% confidence interval, 1.4-19.1; P = .01) compared to the stably normal group. In a subanalysis of failure by compartment, there was an increase in failure of the posterior compartment in the persistently wide group compared to the improved group (8.8% vs 2.0%, P < .01), but not the stably normal group (3.0%, P = .12). There was not a statistically significant difference in failure of the combined apical and anterior compartments among groups (P = .29). CONCLUSION: Surgical reduction of an enlarged preoperative genital hiatus decreases early composite anatomic failure, after robotic sacrocolpopexy, specifically related to the posterior compartment. Studies investigating the correlation of intraoperative measurement of genital hiatus to postoperative genital hiatus are needed to help clinicians determine who may benefit from a concomitant posterior repair/perineoplasty at the time of robotic-assisted sacrocolpopexy. PMID- 29425838 TI - Lost and found-advocacy during residency. PMID- 29425839 TI - A prospective study of the natural history of urinary incontinence in women. AB - BACKGROUND: Symptoms of urinary incontinence are commonly perceived to vary over time; yet, there is limited quantitative evidence regarding the natural history of urinary incontinence, especially over the long term. OBJECTIVE: We sought to delineate the course of urinary incontinence symptoms over time, using 2 large cohorts of middle-aged and older women, with data collected over 10 years. STUDY DESIGN: We studied 9376 women from the Nurses' Health Study, age 56-81 years at baseline, and 7491 women from the Nurses' Health Study II, age 39-56 years, with incident urinary incontinence in 2002 through 2003. Urinary incontinence severity was measured by the Sandvik severity index. We tracked persistence, progression, remission, and improvement of symptoms over 10 years. We also examined risk factors for urinary incontinence progression using logistic regression models. RESULTS: Among women age 39-56 years, 39% had slight, 45% had moderate, and 17% had severe urinary incontinence at onset. Among women age 56-81 years, 34% had slight, 45% had moderate, and 21% had severe urinary incontinence at onset. Across ages, most women reported persistence or progression of symptoms over follow-up; few (3-11%) reported remission. However, younger women and women with less severe urinary incontinence at onset were more likely to report remission or improvement of symptoms. We found that increasing age was associated with higher odds of progression only among older women (age 75-81 vs 56-60 years; odds ratio, 1.84; 95% confidence interval, 1.51-2.25). Among all women, higher body mass index was strongly associated with progression (younger women: odds ratio, 2.37; 95% confidence interval, 2.00-2.81; body mass index >=30 vs <25 kg/m2; older women: odds ratio, 1.93; 95% confidence interval, 1.62-2.22). Additionally, greater physical activity was associated with lower odds of progression to severe urinary incontinence (younger women: odds ratio, 0.86; 95% confidence interval, 0.71-1.03; highest vs lowest quartile of activity; older women: odds ratio, 0.68; 95% confidence interval, 0.59-0.80). CONCLUSION: Most women with incident urinary incontinence continued to experience symptoms over 10 years; few had complete remission. Identification of risk factors for urinary incontinence progression, such as body mass index and physical activity, could be important for reducing symptoms over time. PMID- 29425840 TI - Microwave assisted synthesis of doped carbon dots and their application as green and simple turn off-on fluorescent sensor for mercury (II) and iodide in environmental samples. AB - A novel, green, facile and dual turn-off/on sensor for detection of Hg2+ and I- was developed based on carbon dots. Carbon dots were synthesized from citric acid, urea, and thiourea by microwave-assisted method. The size of the carbon dots (CDs) was about 10 nm and the synthesized CDs showed a strong emission at 523 nm upon excitation at 416 nm. The fluorescence quantum yield was 19.2%. Mercury (II) quenched the fluorescence of carbon dots. This turn off sensor had linear response for Hg2+ over a concentration range from 0.1 to 20 uM with detection limit as low as 62 nM. The carbon dots/Hg2+ system was also used as a turn on sensor for detection of iodide. Linear concentration range for I- was 0.1 10 uM with detection limit as low as 72 nM. The proposed method showed good sensitivity and selectivity with respect to interference ions. Finally, this system was successfully used for the detection of Hg2+ and I- in tap, river and mineral waters and fish samples. PMID- 29425841 TI - Boron reduces aluminum-induced growth inhibition, oxidative damage and alterations in the cell wall components in the roots of trifoliate orange. AB - Aluminum (Al) toxicity is a major restriction for crops production on acidic soils. The primary symptom of aluminum toxicity is visible in the roots of plants. Recently, several studies reported the alleviation of Al toxicity by the application of Boron (B), however, the information how B alleviates Al toxicity is not well understood. Thus, we investigated the ameliorative response of B on Al-induced growth inhibition, oxidative damages, and variations in the cell wall components in trifoliate orange roots. The results indicated that plants under Al stress experienced a substantial decrement in root length and overall plant growth. The supply of B improved the root elongation by eliminating oxidative stress, membrane peroxidation, membrane leakage, and cell death produced under Al toxicity. Moreover, accumulation of Al on the cell wall and alteration in the cell wall components might be one of the causes resulting in the quick inhibition of root elongation under B-starvation circumstances by providing susceptible negative charges on pectin matrix for binding of Al. The results provide a useful understanding of the insight into mechanisms of B-induced mitigation of Al toxicity especially in the trifoliate orange that might be helpful in the production of crops on acidic soils. PMID- 29425842 TI - Influence of biochar aged in acidic soil on ecosystem engineers and two tropical agricultural plants. AB - Biochar amendment to soil is predicted globally as a means to enhance soil health. Alongside the beneficial result on soil nutrient availability and retention, biochar is presumed to increase soil macro / microbiota composition and improve plant growth. However, evidence for such an effect remains elusive in many tropical agricultural soils. The influence of biochar aged in soil was assessed on soil microbiota, macrobiota (Eudrilus eugeniae), seedling emergence and early plant growth of Oryza sativa and Solanum lycopersicum in tropical agricultural soil, over a 90 d biochar-soil contact time. Results showed negative impacts of increased loading of biochar on the survival and growth of E. eugeniae. LC50 and EC50 values ranged from 34.8% to 86.8% and 0.9-23.7% dry biochar kg-1 soil, over time. The growth of the exposed earthworms was strongly reduced (R2 = -0.866, p < 0.05). Biochar significantly increased microbiota abundance relative to the control soil (p < 0.001). However, fungal population was reduced by biochar addition. Biochar application threshold of 10% and 5% was observed for (O. sativa) and (S. lycopersicum), respectively. Furthermore, the addition of biochar to soil resulted in increased aboveground (shoot) biomass (p < 0.01). However, the data revealed that biochar did not increase the belowground (root) biomass of the plant species during the 90 d biochar-soil contact time. The shoot-to-root-biomass increase indicates a direct toxic influence of biochar on plant roots. This reveals that nutrient availability is not the only mechanism involved in biota-biochar interactions. Detailed studies on specific biota-plant responses to biochars between tropical, temperate and boreal environments are needed to resolve the large variations and mechanisms behind these effects. PMID- 29425843 TI - Analysis of digital gene expression profiling in the gonad of male silkworms (Bombyx mori) under fluoride stress. AB - Fluorine is an essential element, but excessive fluoride can cause serious effects on the respiratory, digestive, and reproductive systems. Fluorine has been suggested to cause reproductive toxicity in vertebrates, but its potential to reproductively affect invertebrates remains unknown. In the present study, the lepidopteran model insect Bombyx mori was used to assess the reproductive toxicity of NaF. The underlying molecular mechanisms were explored by RNA sequencing, and we investigated the testes transcriptomic profile of B. mori treated with NaF via a digital gene expression (DGE) analysis. Among 520 candidate genes, 297 and 223 were identified as significantly upregulated or downregulated, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out on all genes to determine their biological functions and associated processes. The results indicated that numerous differentially expressed genes are involved in the stress response, detoxification, antibacterial, transport, oxidative phosphorylation, and ribosome. The reliability of the data was confirmed by a quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The changed Glutathione S transferase (GST) activity and glutathione (GSH) content in the NaF-treated groups were increased and reduced respectively. This study reveals that using RNA sequencing for the transcriptome profiling of B. mori testes can lead to better comprehension of the male reproductive toxicity effects of NaF. Furthermore, we expect that these results will aid future molecular studies on the reproductive toxicity of NaF in other species. PMID- 29425844 TI - Transcriptional profiling analysis of Zearalenone-induced inhibition proliferation on mouse thymic epithelial cell line 1. AB - Zearalenone (ZEA) was a mycotoxin biosynthesized by a variety of Fusarium fungi via a polypeptide pathway. ZEA has significant toxic reaction on immune cells. Thymic epithelial cells (TECs) as a crucial constituent of thymic stroma can provide unique microenvironment for thymocyte maturation, but the mechanism of ZEA affecting the TECs is poorly understood. The basic data about gene expression differences for the ZEA on thymic epithelial cell line 1 (MTEC1) will help us to elucidate this mechanism. Here, cell viability and proliferation assay and transcriptome sequencing on MTEC1 treated with ZEA were performed. 4188 differentially expressed genes (DEGs) between ZEA treated and control groups were identified, confirmed and analyzed. Our results showed that 10-50MUg/ml ZEA significantly inhibited MTEC1 proliferation and arrested cell cycle at G2/M phase. Gene ontology and KEGG pathway analysis revealed that Chemokine, JAK-STAT and Toll-like receptor signaling pathway, were involved in the cell cycle pathway. 16 key genes involved in the cell cycle processes were validated and the results suggested that Mitotic catastrophe (MC) may take part in ZEA inhibition of METC1 cell proliferation. These data highlighted the importance of cell cycle pathway in MTEC1 treated with ZEA, and will contribute to get the molecular mechanisms of ZEA inhibition of MTEC1 cell proliferation. PMID- 29425845 TI - Health risk assessment and soil and plant heavy metal and bromine contents in field plots after ten years of organic and mineral fertilization. AB - Heavy metals and bromine (Br) derived from organic and industrialized fertilizers can be absorbed, transported and accumulated into parts of plants ingested by humans. This study aimed to evaluate in an experiment conducted under no-tillage for 10 years, totaling 14 applications of pig slurry manure (PS), pig deep-litter (PL), dairy slurry (DS) and mineral fertilizer (MF), the heavy metal and Br contents in soil and in whether the grains produced by corn (Zea mays L.) and wheat (Triticum aestivum L.) under these conditions could result in risk to human health. The total contents of As, Cd, Pb, Cr, Ni, Cu, Zn and Br were analyzed in samples of fertilizers, waste, soil, shoots and grains of corn and wheat. Afterwards, enrichment factor (EF), accumulation factor (AF), health risk index (HRI), target hazard quotient (THQ) and target cancer risk (TCR) were determined. Mineral fertilizer exhibited the highest As and Cr content, while the highest levels of Cu and Zn were found in animal waste. The contents of As, Cd, Cr, Cu, Ni, Pb and Zn in soil were below the limits established by environmental regulatory agencies. However, a significant enrichment factor was found for Cu in soil with a history of PL application. Furthermore, high Zn contents were found in shoots and grains of corn and wheat, especially when the plants were grown in soil with organic waste application. Applications of organic waste and mineral fertilizer provided high HRI and THQ for Br and Zn, posing risks to human health. The intake of corn and wheat fertilized with pig slurry manure, swine deep bed, liquid cattle manure and industrialized mineral fertilizer did not present TCR. PMID- 29425846 TI - A human endogenous protein exerts multi-role biomimetic chemistry in synthesis of paramagnetic gold nanostructures for tumor bimodal imaging. AB - Protein-mediated biomimetic nanoparticles because of simplicity of their synthesis, subdued nonspecific adsorption, improved pharmacokinetics, and biocompatibility have been receiving increasing attention recently. Nevertheless, only a handful of proteins have been developed for biomimetic synthesis. Worse still, most of them are constrained on single-function usages in chemistry. Exploring new functional proteins, especially those with multi-dentate moieties for multi-role biomimetic chemistry, still remains a substantial challenge. Here, we report on a human endogenous protein, glutathione S-transferase (GST), with favorable amino acid motifs, that has innate talents in incubating high quality gold nanoparticles without adding reducing agents at physiological temperature, and particularly can further anchor gadolinium ions without adding extra chelators. The resultant paramagnetic AuNPs@GSTGd exhibits highly crystallization and uniform size of ca. 10 nm. Compared with clinical contrast agents (Iopamidol, Magnevist), AuNPs@GSTGd shows better imaging performance (e.g. enhanced relaxivity and larger X-ray attenuation efficiency) with clear evidence from Monte Carlo simulation and in vitro experimental results. Further in vivo imaging demonstrates good tumor targeting and clearance of AuNPs@GSTGd without obvious systemic toxicity. Particularly, low immunogenicity of AuNPs@GSTGd is certified by immunological status evaluation of T cells after stimulated with them. This study for the first time demonstrates the manipulation of a human protein for multi-role biomimetic chemistry depending on its unique amino acid motifs and its incorporation into a synthetic agent for potentially addressing some critical issues in cancer nanotheranostics such as synthetic methodology, biocompatibility, function integration, targeting, and immunogenicity. PMID- 29425847 TI - "All-in-one" in vitro selection of collagen-binding vascular endothelial growth factor. AB - To enhance the therapeutic effect of growth factors, a powerful strategy is to direct their localization to damaged sites. To treat skin wounds and myocardial infarction, we selected vascular endothelial growth factor (VEGF) carrying binding affinity to collagen. A simple conjugation of a reported collagen-binding sequence and VEGF did not increase the collagen-binding affinity, indicating that the molecular interaction between the two proteins abolished collagen binding activity. Here, we present a new molecular evolution strategy, "all-in-one" in vitro selection, in which a collagen-binding VEGF (CB-VEGF) was directly identified from a random library consisting of random and VEGF sequences. As expected, the selected CB-VEGFs exhibited high binding affinity to collagen and maintained the same growth enhancement activity for endothelial cells as unmodified VEGF in solution. Furthermore, the selected CB-VEGF enhanced angiogenesis at skin wounds and infarcted myocardium. This study demonstrates that "all-in-one" in vitro selection is a novel strategy for the design of functional proteins for regenerative medicine. PMID- 29425849 TI - Farm dust reduces viral load in human bronchial epithelial cells by increasing barrier function and antiviral responses. PMID- 29425848 TI - Thiol-capped Bi nanoparticles as stable and all-in-one type theranostic nanoagents for tumor imaging and thermoradiotherapy. AB - Bismuth (Bi)-based semiconductors and composites have been well developed for cancer treatments due to their multimodal diagnostic and therapeutic functions, while the development of metallic Bi nanocrystals is rather hindered by the easy oxidation and unsatisfactory near-infrared photoabsorption. Herein, we prepared uniform Bi nanoparticles (~40 nm) capped with thiol ligands (Bi-SR) through the chemical reduction method and then surface-modified them with PEGylated phospholipids. The resulting Bi-SR-PEG has strong NIR absorbance and high photothermal conversion efficiency of 45.3%. Importantly, thiol ligands on the surface of Bi-SR-PEG can significantly prevent the metal Bi core from oxidation because of the strong chemisorption energy between sulfur and metal, thus maintaining the high stability and long-term near-infrared photoabsorption. More importantly, given the low toxicity, good blood compatibility and high X-ray attenuation coefficient, Bi-SR-PEG can passively accumulatein the tumor area through intravenous injection, endowing them with the simultaneous tumor CT imaging and thermoradiotherapy, and thereafter they can be metabolized and excreted from the mice body overtime. Therefore, the satisfying therapeutic effect of tumors can be achieved, undoubtedly verifying that Bi-SR-PEG can be used as a novel, stable and all-in-one type theranostic nanoagent for cancer treatment. PMID- 29425851 TI - Mechanistic aspects of epigenetic dysregulation in SLE. AB - Epigenetic events have been linked with disease expression in individuals genetically predisposed to the development of systemic lupus erythematosus (SLE), a severe systemic autoimmune/inflammatory disease. Altered DNA methylation and hydroxymethylation as well as histone modifications mediate changes in chromatin accessibility and gene expression in immune cells from SLE patients. Defective epigenetic control contributes to uncontrolled expression of inflammatory mediators, including cytokines and co-receptors, resulting in systemic inflammation and tissue damage. While the pathophysiological involvement of epigenetic changes in SLE has been accepted for some time, we only recently started to investigate and understand molecular events contributing to epigenetic dysregulation. Here, epigenetic alterations will be discussed with a focus on underling molecular events that may be target of preventative measures or future treatment strategies. PMID- 29425850 TI - Neuroprotective effect of Da Chuanxiong Formula against cognitive and motor deficits in a rat controlled cortical impact model of traumatic brain injury. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Da Chuanxiong Formula (DCXF) is one of the famous herb pairs that contains dried rhizomes of Ligusticum chuanxiong Hort. and Gastrodia elata Bl. in the mass ratio of 4:1. This classic representative traditional Chinese medicine has been widely used to treat brain diseases like headache and migraine caused by blood stasis and wind pathogen. However, the therapeutic effect of DCXF on traumatic brain injury (TBI) has not been reported yet. AIM OF STUDY: The present study was performed to investigate the neuroprotective effects of DCXF and its underlying mechanisms in the controlled cortical impact (CCI)-induced TBI rat model. MATERIALS AND METHODS: Male Sprague Dawley rats were divided into four groups: Sham, TBI control, 1X DCXF (520.6 mg/kg) and 5X DCXF (2603.0 mg/kg). Two treatment groups (1X and 5X DCXF) were intragastrically administered daily for 7 days before CCI-induced TBI and then DCXF treatments were continued post-TBI until the animal behavioral tests, including Morris water maze test, acceleration rotarod motor test and CatWalk quantitative gait analysis test, were done. The brain water content and blood brain barrier (BBB) integrity were measured by wet-dry weight method and Evans blue method, respectively. The number of neuron cells, neural stem cells (NSCs), GFAP positive cells (astrocyte) as well as Iba-1 positive cells (microglia) were determined by histology and immunohistochemistry. RESULTS: Treatment with DCXF significantly improved the learning ability and memory retention in Morris water maze test, and remarkably enhanced motor performances in acceleration rotarod motor test and catwalk quantitative gait analysis test after TBI. Moreover, DCXF treatment was able to reduce BBB permeability, brain edema, microglia and astrocyte activation, improve the proliferation of NSCs and decrease neurons loss in the brain with TBI. CONCLUSIONS: The present study demonstrated that DCXF treatment could decrease BBB leakage and brain edema, reduce neuron loss, microglia and astrocyte activation, and increase NSCs proliferation, which may contribute to the cognitive and motor protection of DCXF in the TBI rats. It is the first time to provide potentially underlying mechanisms of the neuroprotective effect of DCXF on TBI-induced brain damage and functional outcomes. PMID- 29425852 TI - Diminished antibody response to influenza vaccination is characterized by expansion of an age-associated B-cell population with low PAX5. AB - Individuals over the age of 65 comprise a substantial portion of the world population and become more susceptible to vaccine-preventable infections with age as vaccination response diminishes. The underlying reason for this impaired vaccine response in older individuals is not entirely clear. We evaluated potential differences in phenotypic and functional responses of B cells from healthy younger (22-45years) and older (64-95years) individuals that may associate with a diminished antibody response to influenza vaccination. We report that age is associated with expansion of atypical memory B cells (CD10-CD20+CD21 CD27-) and an age-associated B cell (ABC, CD21-T-bet+CD11c+) phenotype. Reduced expression of PAX5 was also seen in older individuals. Poor influenza-specific antibody production following vaccination was associated with low PAX5 expression and a distinct composition of the ABC compartment. Collectively, these findings demonstrate that the characteristics of the ABC populations of older individuals are associated with antibody production following influenza vaccination. PMID- 29425853 TI - Sandwich-type electrochemical immunoassay based on Co3O4@MnO2-thionine and pseudo ELISA method toward sensitive detection of alpha fetoprotein. AB - In this study, a sensitive sandwich-type electrochemical immunosensor was fabricated for the detection of alpha fetoprotein (AFP) based on Co3O4@MnO2 thionine (Co3O4@MnO2-Th) and the screen printing technique. Meanwhile, the pseudo enzyme-linked immunosorbent assay (pseudo-ELISA) method was applied in fabricating the immunosensor. Screen-printed carbon electrode (SPCE) was applied for achieving the detection of AFP. Simultaneously, the amino functionalized Co3O4@MnO2-Th was employed as secondary label and could greatly improve the electrochemical response signal, which was beneficial for detecting AFP. Differential pulse voltammetry (DPV) was applied for the detection of AFP and electrochemical impedance spectroscopy (EIS) confirmed the successful fabrication of the immunosensor. Under optimal conditions, the immunosensor exhibited a linear response toward AFP in the range of 0.001-100 ng/mL, with a low detection limit of 0.33 pg/mL. Simultaneously, the proposed immunosensor displayed acceptable selectivity, excellent stability and well reproducibility. Furthermore, this proposed strategy may open up new ideas and find many potential applications in the detection of other tumor markers. PMID- 29425855 TI - Continuous detection of entry of cell-penetrating peptide transportan 10 into single vesicles. AB - Entry of cell-penetrating peptides (CPPs) into living cells by translocating across plasma membranes is an important physiological phenomenon. To elucidate the mechanism of the translocation of CPPs across lipid bilayers, it is essential to reveal its elementary processes. For this purpose, here, we have developed a new method for the continuous, quantitative detection of the entry of CPPs into giant unilamellar vesicles (GUVs), where we investigate the interaction of fluorescent probe-labeled CPPs with single GUVs containing large unilamellar vesicles (LUVs) and fluorescent probes in their lumens using confocal microscopy. Using this method, we investigated the interaction of carboxyfluorescein (CF) labeled transportan 10 (CF-TP10) with single GUVs comprised of dioleoylphosphatidylglycerol (DOPG) and dioleoylphosphatidylcholine (DOPC) containing LUVs of the same membrane and Alexa Fluor 647 hydrazide (AF647) in their lumens. At low concentrations of CF-TP10, first the fluorescence intensity (FI) of the GUV membrane increased with time, and then after some lag time the FI of the GUV lumen due to CF-TP10 increased continuously with time without leakage of AF647. At higher concentrations of CF-TP10, after the FI of the GUV lumen due to CF-TP10 increased significantly, leakage of AF647 started. These results indicate that CF-TP10 entered the GUV lumen by translocating across the GUV membrane and then bound to the LUVs there without pore formation and that CF-TP10 concentration in the lumen increased with time. The rate of entry of CF-TP10 into GUV lumen increased with CF-TP10 concentration. We discussed the kinetics of entry of CF-TP10 into single GUVs. PMID- 29425854 TI - Genotype characteristic and phylogenetic analysis of hepatitis B virus in northeast-Iran. AB - Viral hepatitis is considered as a worldwide health problem and hepatitis B virus (HBV) infection is one of the major health concerns which are annually responsible for more than one million deaths. HBV can be classified into at least eight genotypes, A-H and four major subtypes. Predominant HBV genotype in Mediterranean and Middle East countries is genotype D, but there is a few studies have been performed on the HBV genotype in Iran. The genotype characteristic and phylogenetic analyses were determined in chronic HBV patients in the northeast of Iran. First, seventy-eight patients with chronic HBV infection were enrolled. Demographic features were reviewed and sera samples were collected. HBV genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and results were confirmed by sequencing. Finally, a phylogenetic tree was obtained using Geneious software. Sixty-two (79.48%) of patients were males (mean age: 36.82 years). Twelve out of 78 patients (15.4%) were hepatitis B envelope antigen (HBeAg)-reactive. There were no significant differences between the clinical and HBeAg-positive serological data and HBeAb positive individuals. RFLP DNA sequencing and phylogenetic analysis showed that genotype D was the only genotype which observed in Mashhad, northeast of Iran. This is the first report of HBV genotyping in Mashhad. The results revealed that genotype D was the only genotype detected in this area which was consistence with previous studies in the Middle East, Mediterranean countries, southwest and center of Iran. PMID- 29425856 TI - Gene detection and expression profiling of Neisseria meningitidis using NanoString nCounter platform. AB - Detection of bacterial gene transcripts in low density mucosal samples is challenging. We evaluated the NanoString nCounter system for transcript detection in Neisseria meningitidis (Nm) cultures. The method was sensitive, reproducible (R2 = 0.99) and demonstrated changes in gene expression. Studying Nm transcripts from pharyngeal samples may be feasible using this approach. PMID- 29425857 TI - A disposable immunosensor using ITO based electrode modified by a star-shaped polymer for analysis of tumor suppressor protein p53 in human serum. AB - Label-free immunosensor based on tetra armed star-shaped poly(glycidylmethacrylate) (StarPGMA) modified disposable ITO electrode was developed for detection of p53 protein, an important colorectal cancer biomarker. This disposable biosensor was fabricated by spin-coating technique using star shaped StarPGMA with epoxy side groups. After formation of a stable film with epoxy ends, anti-p53 antibodies were bound to these groups covalently. Stepwise modification of the electrode was followed by electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) studies. The electrochemical performance of the immunosensor was studied by EIS. Furthermore, the antibody and antigen coupling was monitored by single frequency impedance (SFI) technique. The immunosensor showed a low limit of detection (7 fg/mL) and a linear detection range between 0.02 pg/mL and 4 pg/mL. Additionally, atomic force microscopy (AFM) and scanning electron microscopy (SEM) were utilized for monitoring of immunosensor surface at different stages of fabrication. The antibody coupling on the electrode surface was proved by Fourier-transform infrared spectroscopy (FTIR) and Raman spectroscopy. Furthermore, the proposed immunosensor had good reproducibility and repeatability. PMID- 29425858 TI - An electrochemical immunosensor based on a 3D carbon system consisting of a suspended mesh and substrate-bound interdigitated array nanoelectrodes for sensitive cardiac biomarker detection. AB - We developed an electrochemical redox cycling-based immunosensor using a 3D carbon system consisting of a suspended mesh and substrate-bound interdigitated array (IDA) nanoelectrodes. The carbon structures were fabricated using a simple, cost-effective, and reproducible microfabrication technology known as carbon microelectromechanical systems (C-MEMS). We demonstrated that the 3D sub micrometer-sized mesh architecture and selective modification of the suspended mesh facilitated the efficient production of large quantities of electrochemical redox species. The electrochemically active surfaces and small size of IDA nanoelectrodes with a 1:1 aspect ratio exhibited high signal amplification resulting from efficient redox cycling of electrochemical species (PAP/PQI) by a factor of ~25. The proposed selective surface modification scheme facilitated efficient redox cycling and exhibited a linear detection range of 0.001-100 ng/mL for cardiac myoglobin (cMyo). The specific detection of cMyo was also achieved in the presence of other interfering species. Moreover, the proposed 3D carbon system-based immunosensor successfully detected as low as ~0.4 pg/mL cMyo in phosphate-buffered saline and human serum. PMID- 29425859 TI - Multiplex polymerase chain reaction assays for the detection of the zearalenone chemotype of Fusarium species in white and brown rice. AB - Early detection of the zearalenone (ZEA) chemotype of Fusarium species could be a precautionary measure for preventing ZEA contamination in rice. In this study, a multiplex polymerase chain reaction (mPCR) assay for detecting ZEA-producing fungi in rice was established using a set of four primers targeting the ZEA biosynthesis genes PKS3, PKS13, ZEB1, and ZEB2. Two mPCR approaches were used: one that amplified the DNA obtained from Fusarium isolates (conventional method) and another that directly amplified the target DNA from rice samples without time consuming DNA isolation (direct method). The two mPCR methods showed high sensitivity in detecting ZEA-producing species, with a detection limit of 1.25 pg/MUL of genomic DNA and 102 and 103 spores/g of white and brown rice, respectively. Both methods were specific for ZEA-producing species and gave four band patterns. The application of the two mPCR methods to 51 Fusarium isolates and 41 rice samples revealed that 31% (16 of 51) and 24% (10 of 41) of the samples were contaminated with ZEA-producing species, respectively. The mPCR results were further evaluated using high-performance liquid chromatography; in general, the two methods yielded similar results. These findings indicate that both mPCR methods are suitable for the detection of ZEA-producing Fusarium species in white and brown rice; however, the direct method yielded more rapid results. PMID- 29425860 TI - Efficacy of chlorine dioxide on Escherichia coli inactivation during pilot-scale fresh-cut lettuce processing. AB - Controlling water quality is critical in preventing cross-contamination during fresh produce washing. Process wash water (PWW) quality can be controlled by implementing chemical disinfection strategies. The aim of this study was to evaluate the pilot-scale efficacy of chlorine dioxide (ClO2) during processing on the reduction of Escherichia coli in the PWW and on processed fresh-cut 'Lollo Rossa' lettuce. The objective was to have a residual target concentration of either 5 or 3 mg/L ClO2 in the washing tank (3.5 m3) before and during 800 kg of lettuce processing (90 min). After 90 min., a nonpathogenic, non-Extended Spectrum Beta-Lactamase (ESBL) E. coli inoculum from an overnight culture broth (37 degrees C) was added to the tank resulting in an approximate final level of 106 CFU/mL. PWW and lettuce samples for microbiological and chemical analyses were taken before and after the input and supply halted. ClO2 concentrations quickly decreased after ClO2 input halted, yet a residual concentration of >=2.5 mg/L and >=2.1 mg/L ClO2, respectively for 5 and 3 mg/L pilots, was present 12 min after the supply halted. No detectable levels of E. coli (limit of detection 5 log) were determined in the water within 1 min after E. coli was added to the ClO2 containing wash water. Results demonstrated that ClO2 use at the semi commercial pilot scale was able to reduce the E. coli peak contamination in the PWW. After storage (5 days, 4 degrees C), background microbial communities (i.e., fluorescent Pseudomonads and total heterotrophic bacteria) grew out on lettuce. Overall, ClO2 decreased the potential for cross-contamination between batches compared to when no sanitizer was used. Chlorate levels of the lettuce sampled before entering the wash water ranged from 7.3-11.6 MUg/kg. The chlorate levels of the lettuce sampled after being washed in the ClO2 containing wash water, as well as after rinsing and centrifugation, ranged from 22.8-60.4 MUg/kg; chlorite levels ranged from 1.3-1.6 mg/kg, while perchlorate levels were below the limit of quantification (LOQ, <5 ng/g). In this study, we report the semi commercial pilot-scale evaluation of ClO2, for its ability to maintain the PWW quality and to prevent cross-contamination in the washing tank during fresh-cut lettuce processing. Furthermore, we provide quantitative values of ClO2 disinfection by-products chlorate and chlorite as well as of perchlorate from PWW and/or lettuce samples. PMID- 29425861 TI - Effect of 5,7-dimethoxyflavone on Bcrp1-mediated transport of sorafenib in vitro and in vivo in mice. AB - Tyrosine kinase inhibitors (TKI) are a novel and target-specific class of anticancer drugs. One drawback of TKI therapy is cancer resistance to TKI. An important TKI resistance mechanism is enhanced efflux of TKI by efflux transporters, such as Breast Cancer Resistance Protein (BCRP), in cancer cells. 5,7-Dimethoxyflavone (5,7-DMF) is a natural flavonoid which was recently reported to be a potent BCRP inhibitor. In the current study, the effect of 5,7-DMF on the disposition of sorafenib, a TKI which is a good substrate of BCRP, was investigated both in vitro in efflux transporter expressing cells and in vivo in mice. 5,7-DMF significantly inhibited Bcrp1-mediated sorafenib efflux in a concentration dependent manner in MDCK/Bcrp1 cells, with EC50 value of 8.78 MUM. The pharmacokinetics and tissue distribution of sorafenib (10 mg/kg) with and without co-administration of 75 mg/kg 5,7-DMF were determined. With 5,7-DMF, the AUC of sorafenib in plasma was 47,400 +/- 4790 ng.h/mL, which was significantly higher than 27,300 +/- 2650 ng.h/mL in sorafenib alone group. In addition, compared to sorafenib alone group, great increase in sorafenib AUC was observed in most tissues collected when sorafenib was given with 5,7-DMF. Our results indicated that 5,7-DMF may represent a novel and very promising chemosensitizing agent for BCRP-mediated anticancer drug resistance due to its low toxicity and potent BCRP inhibition. PMID- 29425862 TI - A reaction limited in vivo dissolution model for the study of drug absorption: Towards a new paradigm for the biopharmaceutic classification of drugs. AB - The aim of this work is to develop a gastrointestinal (GI) drug absorption model based on a reaction limited model of dissolution and consider its impact on the biopharmaceutic classification of drugs. Estimates for the fraction of dose absorbed as a function of dose, solubility, reaction/dissolution rate constant and the stoichiometry of drug-GI fluids reaction/dissolution were derived by numerical solution of the model equations. The undissolved drug dose and the reaction/dissolution rate constant drive the dissolution rate and determine the extent of absorption when high-constant drug permeability throughout the gastrointestinal tract is assumed. Dose is an important element of drug-GI fluids reaction/dissolution while solubility exclusively acts as an upper limit for drug concentrations in the lumen. The 3D plots of fraction of dose absorbed as a function of dose and reaction/dissolution rate constant for highly soluble and low soluble drugs for different "stoichiometries" (0.7, 1.0, 2.0) of the drug reaction/dissolution with the GI fluids revealed that high extent of absorption was found assuming high drug- reaction/dissolution rate constant and high drug solubility. The model equations were used to simulate in vivo supersaturation and precipitation phenomena. The model developed provides the theoretical basis for the interpretation of the extent of drug's absorption on the basis of the parameters associated with the drug-GI fluids reaction/dissolution. A new paradigm emerges for the biopharmaceutic classification of drugs, namely, a model independent biopharmaceutic classification scheme of four drug categories based on either the fulfillment or not of the current dissolution criteria and the high or low % drug metabolism. PMID- 29425863 TI - In situ observation of sol-gel transition of agarose aqueous solution by fluorescence measurement. AB - Sol-gel transition behavior of agarose aqueous solution was investigated by using rheology and fluorescence measurement. On heating, the storage modulus G' decreased gradually, then deviated abruptly at the temperature of about 65 degrees C, and finally decreased slowly again. For fluorescence measurement, the phase transition point kept almost at the temperature of 65 degrees C, which was consistent with that in rheology measurement. Upon compression, it was indicated that the fluorescence lifetime for the probe in the agarose aqueous solution showed a dramatic change in the vicinity of the phase transition point. T vs. P phase diagram of agarose aqueous solution was constructed, which showed that the melting point was an increasing function of pressure. Based on the phase diagram, the agarose gels were prepared by cooling under atmospheric pressure and the pressure of 300MPa, respectively. From the result of the recovered samples studied by optical rheometry, it was found that agarose gel prepared under high pressure had a higher elasticity and lower viscosity index, compared with that under atmospheric pressure. It could be speculated that such kinds of properties might be attributed to the smaller pore size during gelation under high pressure. PMID- 29425864 TI - Investigation of amyloid formation inhibition of chemically and biogenically from Citrus aurantium L. blossoms and Rose damascena oils of gold nanoparticles: Toxicity evaluation in rat pheochromocytoma PC12 cells. AB - Fibrillation inhibition effects of chemically and biogenically gold nanoparticles (GNPs) were investigated in vitro using human insulin as a model for fibrillation of protein. This inspection was followed using the Congo red assay, thioflavin T fluorescence measurements, transmission electron microscopy, and evaluation of cytotoxicity effects on rat pheochromocytoma PC12 cells. Biogenic GNPs were synthesized using oil extracts of Citrus aurantium L. blossoms and Rose damascena blossoms as reducing and concomitant agents. Congo red assay showed development of fibril formation of insulin at acidic media at 60 degrees C over a period of 48h. In these circumstances, transmission electron micrographs confirmed the progress of fibril state from globular chains to amyloid. However, the results of ThT fluorescence measurements indicated a concentration-dependent inhibiting effect of chemically synthesized GNPs on insulin fibrillation in vitro, simultaneously by conversion of the formed fibrils into amorphous aggregates. Furthermore, biogenic GNPs were found to more effectively inhibit the fibril formation, compared to chemically synthesized GNPs. Accordingly, just 0.05nmolL-1 of the biogenic GNPs showed similar inhibition property of chemically synthesized GNPs with a concentration of 10nmolL-1. Both types of GNPs diminished toxicity of insulin fibrils in rat pheochromocytoma PC12 cells viability. PMID- 29425865 TI - Characterization and long term antimicrobial activity of the nisin anchored cellulose films. AB - To obtain a safe and biodegradable material for food packaging, this study developed a facile and green process of anchoring nisin onto oxidized cellulose through a simple Schiff base reaction for long-term antimicrobial active food packaging. To the best of our knowledge, this is the first report of such a packaging. The grafting reaction between the amino groups of nisin and the aldehyde groups of oxidized cellulose films was successfully established to obtained a nisin anchored cellulose films (NC) membrane; the structure was characterized with Fourier transform infrared spectroscopy, scanning electron microscopy, and thermogravimetric analysis. The NCs membrane had an outstanding transparent property of above 90% transmittance through 300nm to 800nm; while, the barrier properties against oxygen remain excellent. The thermal stability of the NCs membrane remained excellent and enabled an easier degradation than the original cellulose membrane. The NCs membrane displayed good antimicrobial activity against Alicyclobacillus acidoterrestris DSM 3922T in a long-term way, thus demonstrating good potential as food packaging material. The obtained results are promising and confirm the development of NCs membranes as green materials for food packaging. PMID- 29425866 TI - Effect of real-world sounds on protein crystallization. AB - Protein crystallization is sensitive to the environment, while audible sound, as a physical and environmental factor during the entire process, is always ignored. We have previously reported that protein crystallization can be affected by a computer-generated monotonous sound with fixed frequency and amplitude. However, real-world sounds are not so simple but are complicated by parameters (frequency, amplitude, timbre, etc.) that vary over time. In this work, from three sound categories (music, speech, and environmental sound), we selected 26 different sounds and evaluated their effects on protein crystallization. The correlation between the sound parameters and the crystallization success rate was studied mathematically. The results showed that the real-world sounds, similar to the artificial monotonous sounds, could not only affect protein crystallization, but also improve crystal quality. Crystallization was dependent not only on the frequency, amplitude, volume, irradiation time, and overall energy of the sounds but also on their spectral characteristics. Based on these results, we suggest that intentionally applying environmental sound may be a simple and useful tool to promote protein crystallization. PMID- 29425867 TI - The effects of biological buffers TRIS, TAPS, TES on the stability of lysozyme. AB - To explore the mechanism of lysozyme stabilization in buffer system, we have investigated the interactions between lysozyme and the biological buffers (TRIS, TAPS, and TES) using spectroscopic techniques, including ultraviolet-visible (UV Vis), fluorescence, thermal fluorescence, dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR) and circular dichroism (CD) spectroscopy. From the series of spectroscopic studies, it is found that the native structure of the protein remains intact in the different concentrations (0.05, 0.1, 0.25, 0.5, and 1.0M) of the biological buffer aqueous solutions at pH7.0. Moreover, all these three investigated buffers are able to protect lysozyme against thermal denaturation, particularly in high concentration (1.0M) of the buffer aqueous solutions. PMID- 29425868 TI - l-Cysteine functionalized bagasse cellulose nanofibers for mercury(II) ions adsorption. AB - Presence of mercury ions in water, even in trace amounts, is a serious environmental hazard. Hence, there is imperative need to develop innovative and environmentally-friendly materials for their removal from wastewaters. In the present study, cellulose nanofibers (CNFs) extracted from bagasse was esterified with l-cysteine to yield thiol and amine functionalized green material (Cys-CNFs) for removal of Hg2+ ions. The Cys-CNFs were well characterized by SEM, TEM, FTIR, EDS and XRD and evaluated for selective removal of Hg2+ ions from the simulated wastewater. It was observed that Cys-CNFs adsorb Hg2+ ions even at a very low concentration of 1.0mg/L and it exhibited a maximum adsorption capacity of 116.822mgg-1. Kinetic analysis of the data revealed that pseudo-second order kinetics and Langmuir isotherm were followed for adsorption of Hg2+ ions. PMID- 29425869 TI - Fluorescence studies on the aggregation behaviors of collagen modified with NHS activated poly(gamma-glutamic acid). AB - The poly(gamma-glutamic acid)-NHS (gamma-PGA-NHS) esters were used to endow collagen with both of excellent water-solubility and thermal stability via cross linking reaction between gamma-PGA-NHS and collagen. In the present work, the effect of gamma-PGA-NHS on the aggregation of collagen molecules was studied by fluorescence techniques. The fluorescence emission spectra of pyrene in collagen solutions and the intrinsic fluorescence emission spectra of collagen suggested different effects of gamma-PGA-NHS on collagen molecules: inhibiting aggregation below critical aggregation concentration (CAC) and promoting aggregation above CAC. The two-dimensional (2D) fluorescence correlation spectra indicated that the intermolecular hydrogen bonding and cross-linking between gamma-PGA-NHS and collagen would influence the aggregation of collagen molecules. By the ultra sensitive differential scanning calorimeter (VP-DSC), it was found that the main denaturational transition temperature (Tm2) of modified collagen increased, while its calorimetric enthalpy changes (DeltaH2) decreased compared to those of native collagen, further indicating that the modification of gamma-PGA-NHS influenced the aggregation of collagen molecules. The study provide useful information for the utilizing and or the processing of water-soluble collagen in aqueous solution in the fields such as cosmetics, health care products, tissue engineering and biomedical materials, etc. PMID- 29425870 TI - Rational design toward developing a more efficient laccase: Catalytic efficiency and selectivity. AB - Laccases are multicopper oxidases that catalyze the oxidation of variety of substrates. The specificity and efficiency of laccases are clearly the important components leading to their remarkable uses. To develop an improved biocatalysts, site directed mutagenesis of laccase from Bacillus HR03 was carried out in the current study. Based on the ABTS-bound crystal structure of CotA from B. subtilis and alignment with closely related enzymes, T415 and T418 at the vicinity of the type 1 copper site were chosen and several mutants (T415I, T418I, T415G, T415G/T418I) were made. Kinetic parameters of the constructs were then determined using ABTS and SGZ as substrates. In comparison with the wild-type, catalytic efficiency toward ABTS was improved by 4 fold in T415I and 1.5 fold in T418I and T415G. T415I and T418I variants were identified to be almost 11 and 27 times more specific for ABTS than for SGZ compared with the wild type. T415I was also found to acquire enhanced thermal stability with the half-life of 60min at 80 degrees C. Secondary and tertiary structure of mutants were analyzed by CD and fluorescence spectroscopy. Our result illustrated that replacement of residues in the substrate-binding pocket would change the specificity and efficiency of variants. PMID- 29425871 TI - Biosynthesis of levan from sucrose using a thermostable levansucrase from Lactobacillus reuteri LTH5448. AB - Levan, a versatile fructan, possesses promising prospects for application in the food and pharmaceutical industries and in many other fields due to the superior physicochemical properties and physiological functions of this fructan. In this study, a thermostable levansucrase was identified from Lactobacillus reuteri LTH5448. This enzyme shared higher identity with reported inulosucrases than levansucrases but, unexpectedly, yielded a levan-type fructan. Structural analysis of the produced polysaccharide revealed that the glycosidic bonds were beta-(2, 6) linkages, and the average molecular weight was 3.924*107Da under optimized conditions. The optimal pH and temperature for levan formation were 6.0 and 35 degrees C, respectively. The total activity was enhanced to 135% in the presence of Ca2+. After optimizing the production of levan, 13U/g sucrose of levansucrase and 500g/L sucrose were utilized to obtain 183g/L levan after a 12-h reaction. PMID- 29425873 TI - Digestibility of sulfated polysaccharide from the brown seaweed Ascophyllum nodosum and its effect on the human gut microbiota in vitro. AB - Sulfated polysaccharides from marine algae exhibit various bioactivities with potential benefits for human health and well-being. In this study, the in vitro digestibility and fermentability of polysaccharides from the brown seaweed Ascophyllum nodosum (AnPs) were examined, and the effects of AnPs on gut microbiota were determined using high-throughput sequencing technology. Salivary amylase, artificial gastric juice, and intestinal juice had no effect on AnPs, but the molecular weight of AnPs and reducing sugar decreased significantly after fermentation by gut microbiota. AnPs significantly modulated the composition of the gut microbiota; in particular, they increased the relative abundance of Bacteroidetes and Firmicutes, suggesting the potential for AnPs to decrease the risk of obesity. Furthermore, the total SCFA content after fermentation increased significantly. These results suggest that AnPs have potential uses as functional food components to improve human gut health. PMID- 29425872 TI - Effects of different chemical modifications on the antioxidant activities of polysaccharides sequentially extracted from peony seed dreg. AB - Four types of sequentially extracted peony seed dreg polysaccharides (PSDPs) fractions were modified through sulfation, phosphorylation and carboxymethylation and studied for their in vitro antioxidant characteristics. The modified derivatives showed decreased sugar and protein content, while uronic acid content was elevated as compared to native (un-modified) polysaccharides. Further, modified derivatives shared the similar maximum absorption peaks indicating their homogeneous nature. The Fourier transform infrared (FTIR) spectra of sulfated, carboxymethylated and phosphorylated derivatives showed that hydroxyl groups were converted to OS, COO and POH bonds, respectively. The sulfated polysaccharides (S PSDPs) displayed the highest reducing ability [S-CASS (1.854)], DPPH radical scavenging ability [S-CASS (95.07%)] and ABTS radical scavenging activity [S-CASS (99.85%)]. The phosphorylated polysaccharides (P-PSDPs) exhibited maximum hydroxyl radical scavenging activity [P-DASS (92.61%)] and ferrous ion chelating ability (99.94% for all the fractions). The carboxymethylated polysaccharides (C PSDPs) maintained moderately stable antioxidant ability. Overall, the four different PSDPs modified by the same chemical method also resulted into different chemical composition, characteristic absorption peaks and antioxidant attributes. We conclude that the different modifications of the polysaccharide fractions had their own potential significance as new antioxidants for food industry and human health. PMID- 29425874 TI - Polysaccharides obtained from bamboo shoots (Chimonobambusa quadrangularis) processing by-products: New insight into ethanol precipitation and characterization. AB - Chimonobambusa quadrangularis polysaccharides (CPS) were extracted by ultrasonic assisted extraction from bamboo shoots (C. quadrangularis) processing by products. Three polysaccharide fractions, CPS70, CPS75 and CPS80, were obtained by precipitation at final ethanol concentrations of 70%, 75% and 80%, respectively. The physicochemical characterization and chemical antioxidant activities of the three polysaccharide fractions were compared on the basis of HPLC, FT-IR, XRD, TGA, and antioxidant measurements in vitro. The results suggested that ethanol concentrations used for precipitation of CPS can affect its physicochemical and associated functional properties, and antioxidant activities. Compared with CPS70 and CPS80, CPS75 had lower glucose content, higher total sugar content, and higher protein and uronic acid contents. The CPS70 and CPS80 were composed of Man, Rha, GlcA, Glc, Gal, Xyl and Ara, but none of them were found to contain GalA. In contrast, CPS75 consisted of Man, Rha, GlcA, GalA, Glc, Gal, Xyl and Ara. CPS75 had the lowest medium-high-molecular weight value (116.53-118.18kDa) and the highest medium-low-molecular-weight value (21.30-22.68kDa). Meanwhile, CPS75 exhibited better functional properties including the repose angle, swelling capacity (SC), water retention capacity (WRC), and oil retention capacity (ORC). Moreover, CPS75 possessed higher scavenging capacities on DPPH, hydroxyl and ABTS radicals, higher oxygen radical absorbance capacity (OARC), higher metal chelating activity, and more significant reducing power. According to the results above, a final ethanol concentration of 75% could be chose to precipitate polysaccharides from bamboo shoots (C. quadrangularis) processing by-products. In summary, it is strongly recommended that the ethanol concentration employed in precipitation of natural polysaccharides could be optimized in advance. PMID- 29425875 TI - Burn wound healing potential of a polysaccharide from Sanguisorba officinalis L. in mice. AB - Sanguisorba officinalis L. is widely used in China to treat various wounds, particularly burns. The present study was carried to evaluate the healing efficacy of a purified polysaccharide (SOP) from the roots of S. officinalis L. on burn wound models in mice. The results indicated that oral administration of SOP (50 and 200mg/kg) significantly stimulated wound contraction and reduced epithelialization time as compared to control group, which might be mediated by promoting collagen synthesis as evidenced by an increase of hydroxyproline content. Elevation of IL-1beta and VEGF content was also observed in mice following SOP treatment, which in turn facilitate epithelization and angiogenesis. Besides, histopathological examination of the wound tissues in the SOP-treated animals showed collagen deposition and epidermal formation. It may be concluded that the enhancement of burn wound healing by SOP might be due to promotional collagen synthesis and angiogenesis during skin wound repair as a result of the stimulation of hydroxyproline, IL-1beta and VEGF production. The excellent wound-healing activities of SOP provide a scientific rationale for the development of plant-based product in the management of wounds. PMID- 29425876 TI - Inhibitory effect of pyrogallol on alpha-glucosidase: Integrating docking simulations with inhibition kinetics. AB - In this study we conducted serial kinetic studies integrated with computational simulations to judge the inhibitory effect of pyrogallol on alpha-glucosidase, due to the association between this enzyme and the treatment of type 2 diabetes. As a result, we found that pyrogallol bound to the active site of alpha glucosidase, interacting with several key residues, such as ASP68, MET69, TYR71, PHE157, PHE158, PHE177, GLN181, HIS348, ASP349, ASP406, VAL407, ASP408, ARG439, and ARG443, which was predicted by performing a protein-ligand docking simulation. Subsequently, we evaluated the inhibitory effect of pyrogallol on alpha-glucosidase, and found that it induced a mixed type of inhibition in a reversible and quick-binding manner. The relevant kinetic parameters were evaluated to be: IC50=0.72+/-0.051mM; Ki=0.37+/-0.018mM. A tertiary conformational change was synchronized with pyrogallol inhibition and modulation of the shape of the active site was correspondingly observed. Our study provides insight into the functional inhibitory role of pyrogallol, which results from its triple-hydroxyl groups interacting with the active site of alpha-glucosidase. We suggest that compounds similar to pyrogallol (phenolic hydroxyl compounds) which target the key residues of the active site of alpha-glucosidase could be potential agents for alpha-glucosidase inhibition. PMID- 29425877 TI - Investigation of the structural, physicochemical properties, and aggregation behavior of lipopeptide biosurfactant produced by Acinetobacter junii B6. AB - In the present study the produced biosurfactant of Acinetobacter junii B6 (recently isolated from Iranian oil excavation site) were partially purified and identified by high performance thin layer chromatography (HPTLC), Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance (1H NMR). Elemental analysis of the biosurfactant by energy dispersive X-ray spectroscopy (EDS) revealed that the biosurfactant was anionic in nature. The physiochemical properties of the lipopeptide biosurfactant were evaluated by determination of its critical micelle concentration (CMC) and hydrophile lipophile balance (HLB). The produced biosurfactant decreased the surface tension of water to 36mNm-1 with the CMC of approximately 300mg/l. Furthermore, the solubility properties of the biosurfactant (dissolved in phosphate-buffer saline solution, pH7.4) were investigated by turbidity examination, dynamic light scattering (DLS) measurements, and transmission electron microscopy (TEM) inspection. It could be concluded that the biosurfactant showed the spherical shaped vesicles at a concentration higher than its CMC and the circular dichroism (CD) spectra showed that the secondary structure of the biosurfactant vesicles is dominated by the beta sheet. PMID- 29425878 TI - The klotho-related protein KLPH (lctl) has preferred expression in lens and is essential for expression of clic5 and normal lens suture formation. AB - KLPH/lctl belongs to the Klotho family of proteins. Expressed sequence tag analyses unexpectedly revealed that KLPH is highly expressed in the eye lens while northern blots showed that expression is much higher in the eye than in other tissues. In situ hybridization in mouse localized mRNA to the lens, particularly in the equatorial epithelium. Immunofluorescence detected KLPH in lens epithelial cells with highest levels in the germinative/differentiation zone. The gene for KLPH in mouse was deleted by homologous recombination. Littermate knockout (KO) and wild type (WT) mice were compared in a wide panel of pathology examinations and were all grossly normal, showing no systemic effects of the deletion. However, the lens, while superficially normal at young ages, had focusing defects and exhibited age-related cortical cataract by slit lamp examination. Whole-lens imaging showed that KO mice had disorganized lens sutures, forming a loose double-y or x instead of the tight y formation of WT. RNA-seq profiles for KO and WT littermates confirmed the absence of KLPH mRNA in KO lens and also showed complete absence of transcripts for Clic5, a protein associated with cilium/basal body related auditory defects in a mouse model. Immunofluorescence of lens epithelial flat mounts showed that Clic5 localized to cilia/centrosomes. Mice mutant for Clic5 (jitterbug) also had defective sutures. These results suggest that KLPH is required for lens-specific expression of Clic5 and that Clic5 has an important role in the machinery that controls lens fiber cell extension and organization. PMID- 29425879 TI - Retinal neuroinflammatory induced neuronal degeneration - Role of toll-like receptor-4 and relationship with gliosis. AB - The purpose of this study was to explore retina-intrinsic neuroinflammatory reactions, effects on neuronal survival, relationship with classic gliosis, and possible role of the toll-like receptor 4 (TLR4). To isolate the adult retina from the systemic immune system, a previously described large animal explant culture model was used in which full-thickness porcine retinal sheets can be kept in vitro for extended time periods. Explants were kept for 5 days in vitro (DIV) and were treated with either; lipopolysaccharide (LPS), a Toll-like receptor-4 (TLR4) inhibitor (CLI-095), LPS + CLI-095, or solvent vehicle throughout the culture period after which retinal sections were examined with hematoxylin and eosin staining and extensive immunohistochemistry. In addition, the culture medium of all explants was assayed for a panel of cytokines at 2 and 5DIV. Compared with in vivo controls, vehicle controls (CT) as well as CLI-095 explants displayed moderate reduction of total thickness and number of retinal neurons with upregulation of glial fibrillary acidic protein (GFAP) throughout the Muller cells. In contrast, LPS and LPS + CLI-095 treated counterparts showed extensive overall thinning with widespread neuronal degeneration but only minimal signs of classical Muller cell gliosis (limited upregulation of GFAP and no downregulation of glutamine synthetase (GS). These specimens also displayed a significantly increased expression of galectin-3 and TGF-beta activated kinase 1 (TAK1). Multiplex proteomic analysis of culture medium at 2DIV revealed elevated levels of IL-1beta, IL-6, IL-4 and IL-12 in LPS-treated explants compared to CLI-095 and CT counterparts. LPS stimulation of the isolated adult retina results in substantial neuronal cell death despite only minimal signs of gliosis indicating a retina-intrinsic neuroinflammatory response directly related to the degenerative process. This response is characterized by early upregulation of several inflammatory related cytokines with subsequent upregulation of Galectin 3, TLR4 and TAK1. Pharmacological block of TLR4 does not attenuate neuronal loss indicating that LPS induced retinal degeneration is mediated by TLR4 independent neuroinflammatory pathways. PMID- 29425880 TI - Protoporphyrinogen oxidase is involved in the fluorescence intensity of 5 aminolevulinic acid-mediated laser-based photodynamic endoscopic diagnosis for early gastric cancer. AB - BACKGROUND/AIM: Laser-based photodynamic endoscopic diagnosis (LPDED) is a type of endoscopic diagnosis that uses the fluorescence caused by the photochemical reaction that occurs when a fluorescent substance is irradiated by a light of a specific wavelength. Although 5-aminolevulinic acid (5-ALA) can detect early gastric cancer (EGC) during LPDED, there is an unresolved issue of the differences in fluorescence intensity among histopathological types of gastric cancer. Thus, the aim of the present study was to assess whether protoporphyrinogen oxidase (PPOX), involved in the activation of protoporphyrin IX, can affect the fluorescence intensity in EGC. METHODS: Thirty-three gastric tumor lesions in 30 patients were assessed by LPDED using a prototype endoscope equipped with a blue laser ray to cause excitation following oral 5-ALA administration. The tumors were then resected by endoscopic submucosal dissection or laparoscopic surgery. PPOX expression was examined immunohistochemically in the excised specimens. To explore the mechanisms of histopathological diversity in PPOX and coproporphyrinogen oxidase (CPOX) expression of EGC, immunohistochemical analysis was performed using 75 surgically resected specimens of diverse EGCs. RESULTS: Among the 33 lesions, 26 tumors were detectable by LPDED, whereas seven were undetectable. Between the LPDED-positive and negative groups, there was a significant difference in histopathology. The expression of PPOX was higher in tubular adenocarcinoma (tub) than in signet-ring cell carcinoma (sig). There were significant differences in PPOX and CPOX expression scores of the surgically resected specimens among tub, poorly differentiated adenocarcinoma (por), and sig. CONCLUSION: PPOX protein expression could be involved in the fluorescence intensity of LPDED in EGC, possibly reflecting histopathological features. PMID- 29425882 TI - Family Meetings in Inpatient Specialist Palliative Care: A Mechanism to Convey Empathy. AB - CONTEXT: Family meetings are increasingly used in palliative care, yet have little empirical evidence of their impact in inpatient settings. OBJECTIVES: To examine whether relatives report more empathy after a family meeting in a specialist palliative care inpatient ward. METHODS: Pre/post self-complete questionnaires measuring relational empathy and information needs were administered. Qualitative interviews were also conducted. Data were collected during nine months from one inpatient specialist palliative care unit. Participants from 52 family meetings completed pre/post questionnaires, and 13 relatives participated in an interview that was analyzed thematically. RESULTS: Families reported more empathy from staff after a family meeting (Wilcoxon test: n = 47; P > 0.001; Z score -4.17). Some families with relatives who do not speak with each other reported that meeting facilitators were unable to manage the pre existing dynamics. CONCLUSION: Family meetings improve reported empathy. It would be beneficial to have more specific preparation and planning by the clinical team for meetings with people who have a history of familial conflict, and those where the staff's agenda is around discharge planning. Published guidelines could be adapted to better support staff to run meetings where there are complex family dynamics. Adoption of family meetings in outpatient settings has the potential to improve perceptions of empathy with a larger patient group. PMID- 29425881 TI - Pediatric Oncology Providers' Perceptions of a Palliative Care Service: The Influence of Emotional Esteem and Emotional Labor. AB - CONTEXT: Pediatric palliative care consults for children with cancer often occur late in the course of disease and close to death, when earlier involvement would reduce suffering. The perceptions that pediatric oncology providers hold about the pediatric palliative care service (PPCS) may shape referral patterns. OBJECTIVES: To explore how pediatric oncology providers at one institution perceived the hospital's PPCS and the way these perceptions may influence the timing of consultation. METHODS: We conducted semistructured qualitative interviews with pediatric oncology providers at a large children's hospital. Interviews were audio-recorded, transcribed, and analyzed by two coders using a modified grounded theory approach. RESULTS: We interviewed 16 providers (10 physicians, one nurse practitioner, two social workers, two psychologists, and one child life specialist). Three core perceptions emerged: 1) the PPCS offers a diverse range of valuable contributions to the care of children with advancing cancer; 2) providers held favorable opinions about the PPCS owing to positive interactions with individual palliative care specialists deemed extraordinarily emotionally skilled; and 3) there is considerable emotional labor involved in calling a PPCS consult that serves as a barrier to early initiation. CONCLUSION: The pediatric oncology providers in our study held a highly favorable opinion about their institution's PPCS and agreed that early consultation is ideal. However, they also described that formally consulting PPCS is extremely difficult because of what the PPCS symbolizes to families and the emotional labor that the provider must manage in introducing them. Interventions to encourage the early initiation of palliative care in this population may benefit from a focus on the emotional experiences of providers. PMID- 29425883 TI - Foods with increased protein content: A qualitative study on European consumer preferences and perceptions. AB - Foods with increased protein content have rapidly become one of the fastest growing product categories targeting image- and health-focused consumers. However, it is not clear whether consumers really understand the difference between 'inherently rich in protein' and 'artificially increased protein'. This study used a qualitative focus group approach to investigate the consumer preferences and perceptions of foods with increased protein content among mixed age and older population in four European countries. In total fifty-two participants were involved in the study. Understanding of the concept of foods with 'increased protein' content was limited. Both older and mixed-age participants could not differentiate between natural sources of protein and foods with increased protein content, no matter whether foods with animal or plant proteins were mentioned. Older participants expressed more scepticism towards foods with increased protein content than mixed-age participants. The combination of protein type and food carrier closer to conventional foods received more acceptance among both older and mixed-age participants. Future use and acceptance of foods with increased protein content will depend on the extent to which consumer concerns about incorporating additional protein into a diet can be responded. PMID- 29425884 TI - Nanostructured Co-Mn containing perovskites for degradation of pollutants: Insight into the activity and stability. AB - The efficient oxidative removal of persistent organic components in wastewater relies on low-cost heterogeneous catalysts that offer high catalytic activity, stability, and recyclability. Here, we designed a series of nanostructured Co-Mn containing perovskite catalysts, LaCo1-xMnxO3+delta (LCM, x = 0, 0.3, 0.5, 0.7, and 1.0), with over-stoichiometric oxygen (delta > 0) to show superior catalytic activity for the degradation of a variety of persistent aqueous organic pollutants by activating peroxymonosulfate (PMS). The nature of LCM for catalysis was comprehensively investigated. A "volcano-shaped" correlation was observed between the catalytic activity and electron filling (eg) of Co in LCM. Among these compounds, LaCo0.5Mn0.5O3+delta (LCM55) exhibited an excellent activity with eg = 1.27. The high interstitial oxygen ion diffusion rate (DO2- = 1.58 +/- 0.01 * 10-13 cm2 s-1) of LCM55 also contributes to its catalytic activity. The enhanced stability of LCM55 can be ascribed to its stronger relative acidity (3.22). Moreover, an increased solution pH (pH >= 7) generated a faster organic degradation rate and a decrease in metal leaching (0.004 mM) for LCM55 perovskite, justifying it as a potential material for environmental remediation. PMID- 29425885 TI - Scoping the scope: endoscopic evaluation of endoscope working channels with a new high-resolution inspection endoscope (with video). AB - BACKGROUND AND AIMS: Outbreaks of transmission of infection related to endoscopy despite reported adherence to reprocessing guidelines warrant scrutiny of all potential contributing factors. Recent reports from ambulatory surgery centers indicated widespread significant occult damage within endoscope working channels, raising concerns regarding the potential detrimental impact of this damage on the adequacy of endoscope reprocessing. METHODS: We inspected working channels of all 68 endoscopes at our academic institution using a novel flexible inspection endoscope. Inspections were recorded and videos reviewed by 3 investigators to evaluate and rate channel damage and/or debris. Working channel rinsates were obtained from all endoscopes, and adenosine triphosphate (ATP) bioluminescence was measured. RESULTS: Overall endoscope working channel damage was rated as minimal and/or mild and was consistent with expected wear and tear (median 1.59 on our 5-point scale). Our predominant findings included superficial scratches (98.5%) and scratches with adherent peel (76.5%). No channel perforations, stains, or burns were detected. The extent of damage was not predicted by endoscope age. Minor punctate debris was common, and a few small drops of fluid were noted in 42.6% of endoscopes after reprocessing and drying. The presence of residual fluid predicted higher ATP bioluminescence values. The presence of visualized working channel damage or debris was not associated with elevated ATP bioluminescence values. CONCLUSION: The flexible inspection endoscope enables high-resolution imaging of endoscope working channels and offers endoscopy units an additional modality for endoscope surveillance, potentially complementing bacterial cultures and ATP values. Our study, conducted in a busy academic endoscopy unit, indicated predominately mild damage to endoscope working channels, which did not correlate with elevated ATP values. PMID- 29425886 TI - ERCP performed through previously placed duodenal stents: a multicenter retrospective study of outcomes and adverse events. AB - BACKGROUND AND AIMS: ERCP performed through previously placed enteral stents is an uncommon procedure without a significant amount of supporting literature and with a wide reported range of technical success. The purpose of this study was to evaluate and better define the technical feasibility and safety of performing ERCP through enteral stents in patients with combined malignant biliary and gastric outlet obstruction. METHODS: We conducted a multicenter, retrospective study on 71 patients with combined gastric outlet and biliary obstruction who underwent ERCP through a previously placed enteral stent at 2 tertiary care centers. Outcomes included but were not limited to technical success, clinical success, need for repeat ERCP, adverse events, and survival time. RESULTS: Overall technical success was achieved in 60 of 71 patients (85%), with technical success of 40 of 46 (87%) in type I obstructions (gastric outlet obstruction above the ampulla), 16 of 21 (76%) in type II obstructions (gastric outlet obstruction at the level of the ampulla), and 4 of 4 (100%) in type III obstructions (gastric outlet obstruction distal to the ampulla). In general, patients who achieved technical success also achieved clinical success. Adverse events occurred in 3 patients (3/71): 2 patients with acute cholangitis and 1 patient with perforation. Average survival time after the procedure was 4.6 months overall. CONCLUSIONS: ERCP performed through enteral stents is safe, with a high technical and clinical success rate, but may be more technically challenging in the setting of type II obstructions. This procedure could be considered first line in the unique setting that a patient requires ERCP through a previously placed enteral stent for malignant gastric outlet and biliary obstruction. PMID- 29425887 TI - Improved photosynthetic efficacy of maize (Zea mays) plants with arbuscular mycorrhizal fungi (AMF) under high temperature stress. AB - In this study, pot experiments were performed to investigate the effects of high temperature stress (44 degrees C) in maize plants colonized with and without arbuscular mycorrhizal fungi (AMF). Various parameters characterizing photosynthetic activity were measured in order to estimate the photosynthetic efficiency in maize plants. It was observed that density of active reaction centers of PSII, quantum efficiency of photosystem II (PSII), linear electron transport, excitation energy trapping, performance index, net photosynthesis rate increased in AMF (+) plants at 44 degrees C +/- 0.2 degrees C. Efficiency of primary photochemical reaction (represented as Fv/Fo) increased in AMF (+) plants as compared to AMF (-) plants. AMF seems to have protected water splitting complex followed by enhanced primary photochemistry of PSII under high temperature. Basic morphological parameters like leaf width, plant height and cob number increased in AMF (+) plants as compared to AMF (-) plants. AMF (+) plants grew faster than AMF (-) plants due to larger root systems. Chl content increased in AMF (+) plants as compared to AMF (-) maize plants. AMF hyphae likely increased Mg uptake which in turn increased the total chlorophyll content in AMF (+) maize plants. This subsequently led to a higher production in photosynthate and biomass. Thus AMF (+) plants have shown better photosynthesis performance as compared to AMF (-) maize plants under high temperature stress. PMID- 29425888 TI - Understanding the microbiome: Emerging biomarkers for exploiting the microbiota for personalized medicine against cancer. AB - The human body is a home to more than 1 trillion microbes with a diverse variety of commensal microbes that play a crucial role towards the health of the individual. These microbes occupy different habitats such as gut, skin, vagina, oral etc. Not only the types and abundance of microbes are different in different organs, but also these may differ in different individuals. The genome of these microbiota and their ecosystem constitute to form a microbiome. Factors such as diet, environment, host genetics etc. may be the reason behind the wide microbial diversity. A number of studies performed on human microbiome have revealed that microbiota present in healthy and diseased individuals are distinct. Altered microbiome is many a times the reason behind the overexpression of genes which may cause complex diseases including cancer. Manipulation of the human microbiome can be done by microbial supplements such as probiotics or synbiotics, diet or prebiotics and microbial suppression strategies using antibiotics. Recent advances in genome sequencing technologies and metagenomic analysis provide us the broader understanding of these commensal microbes and highlighting the distinctive features of microbiome during healthy and disease states. Molecular pathological epidemiology (MPE) studies have been very helpful in providing insights into the pathological process behind disease evolution and progression by determining the specific etiological factors. New emerging field of research targets the microbiome for therapeutic purposes by which personalized medicines can be made for treating various types of tumors. Screening programmes might be helpful in identifying patients who are at the verge of developing cancer and in delivering appropriate approaches according to individual risk modes so that disease could be prevented. PMID- 29425889 TI - Comparison of the effects of sodium phenobarbital in wild type and humanized constitutive androstane receptor (CAR)/pregnane X receptor (PXR) mice and in cultured mouse, rat and human hepatocytes. AB - Phenobarbital (PB), a constitutive androstane receptor (CAR) activator, produces liver tumours in rodents by a mitogenic mode of action involving CAR activation. In this study, the hepatic effects of sodium phenobarbital (NaPB) were compared in male C57BL/6J wild type (WT) mice and in humanized mice, where both the mouse CAR and pregnane X receptor (PXR) have been replaced by their human counterparts (hCAR/hPXR mice). Investigations were also performed in cultured male C57BL/6J and CD-1 mouse, male Sprague-Dawley rat and male and female human hepatocytes. The treatment of WT and hCAR/hPXR mice with 186-984 ppm NaPB in the diet for 7 days resulted in increased relative liver weight, hypertrophy and induction of cytochrome P450 (CYP) enzyme activities. Treatment with NaPB also produced dose dependent increases in hepatocyte replicative DNA synthesis (RDS), with the effect being more marked in WT than in hCAR/hPXR mice. While the treatment of cultured C57BL/6J and CD-1 mouse, Sprague-Dawley rat and human hepatocytes with 100 and/or 1000 MUM NaPB for 4 days induced CYP enzyme activities, increased RDS was only observed in mouse and rat hepatocytes. However, as a positive control, epidermal growth factor increased RDS in hepatocytes from all three species. In summary, although human hepatocytes are refractory to the mitogenic effects of NaPB, treatment with NaPB induced RDS in vivo in hCAR/hPXR mice, which is presumably due to the human CAR and PXR receptors operating in a mouse hepatocyte regulatory environment. As the response of the hCAR/hPXR mouse to the CAR activator NaPB differs markedly from that of human hepatocytes, the hCAR/hPXR mouse is thus not a suitable animal model for studies on the hepatic effects of nongenotoxic rodent CAR activators. PMID- 29425890 TI - Top Medical Education Studies of 2016: A Narrative Review. AB - Education, like clinical medicine, should be based on the most current evidence in the field. Unfortunately, medical educators can be overwhelmed by the sheer volume and range of resources for this literature. This article provides an overview of 15 articles from 2016 that the authors consider the top articles in the field of pediatric medical education. The 7 authors, all medical educators with combined leadership and expertise across the continuum of pediatric medical education, used an iterative 3-stage process to review more than 6339 abstracts published in 2016. This process was designed to identify a small subset of articles that were most relevant to educational practices and most applicable to pediatric medical education. In the first 2 stages, pairs of authors independently reviewed and scored abstracts in 13 medical education-related journals and reached consensus to identify the articles that best met these criteria. In the final stage, all articles were discussed using a group consensus model to select the final articles included in this review. This article presents summaries of the 15 articles that were selected. The results revealed a cluster of studies related to observed standardized clinical encounters, self-assessment, professionalism, clinical teaching, competencies/milestones, and graduate medical education management strategies. We provide suggestions on how medical educators can apply the findings to their own practice and educational settings. This narrative review offers a useful tool for educators interested in keeping informed about the most relevant and valuable information in the field. PMID- 29425891 TI - Promoting Resident Professional Development Using Scholarly Academies. AB - Promoting professional development is a challenging but vital component of residency training. We created resident academies (scholarly homes) that aimed to develop academic skills, enhance mentorship, and create a sense of community based on scholarly interest. PMID- 29425893 TI - The mechanisms behind decreased internalization of angiotensin II type 1 receptor. AB - The internalization of angiotensin II type 1 receptor (AT1R) plays an important role in maintaining cardiovascular homeostasis. Decreased receptor internalization is closely related to cardiovascular diseases induced by the abnormal activation of AT1R, such as hypertension. However, the mechanism behind reduced AT1R internalization is not fully understood. This review focuses on four parts of the receptor internalization process (the combination of agonists and receptors, receptor phosphorylation, endocytosis, and recycling) and summarizes the possible mechanisms by which AT1R internalization is reduced based on these four parts of the process. (1) The agonist has a large molecular weight or a stronger ability to hydrolyze phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5) P2), which can increase the consumption of PtdIns (4,5) P2. (2) AT1R phosphorylation is weakened because of an abnormal function of phosphorylated kinase or changes in phospho-barcoding and GPCR-beta-arrestin complex conformation. (3) The abnormal formation of vesicles or AT1R heterodimers with fewer endocytic receptors results in less AT1R endocytosis. (4) The enhanced activity and upregulated expression of small GTP-binding protein 4 (Rab4) and 11 (Rab11), which regulate receptor recycling, and phosphatidylinositol 3-kinase increase AT1R recycling. In addition, lower expression of AT1R-associated protein (ATRAP) or higher expression of AT1R-associated protein 1 (ARAP1) can reduce receptor internalization. PMID- 29425894 TI - Diabetic macroangiopathy: Pathogenetic insights and novel therapeutic approaches with focus on high glucose-mediated vascular damage. AB - Diabetic macroangiopathy - a specific form of accelerated atherosclerosis - is characterized by intra-plaque new vessel formation due to excessive/abnormal neovasculogenesis and angiogenesis, increased vascular permeability of the capillary vessels, and tissue edema, resulting in frequent atherosclerotic plaque hemorrhage and plaque rupture. Mechanisms that may explain the premature and rapidly progressive nature of atherosclerosis in diabetes are multiple, and to a large extent still unclear. However, mechanisms related to hyperglycemia certainly play an important role. These include a dysregulated vascular regeneration. In addition, oxidative and hyperosmolar stresses, as well as the activation of inflammatory pathways triggered by a dysregulated activation of membrane channel proteins aquaporins, have been recognized as key events. Here, we review recent knowledge of cellular and molecular pathways of macrovascular disease related to hyperglycemia in diabetes. We also here highlight how new insights into pathogenic mechanisms of vascular damage in diabetes may indicate new targets for prevention and treatment. PMID- 29425892 TI - LncRNAs in vascular biology and disease. AB - Accumulating studies indicate that long non-coding RNAs (lncRNAs) play important roles in the regulation of diverse biological processes involved in homeostatic control of the vessel wall in health and disease. However, our knowledge of the mechanisms by which lncRNAs control gene expression and cell signaling pathways is still nascent. Furthermore, only a handful of lncRNAs has been functionally evaluated in response to pathophysiological stimuli or in vascular disease states. For example, lncRNAs may regulate endothelial dysfunction by modulating endothelial cell proliferation (e.g. MALAT1, H19) or angiogenesis (e.g. MEG3, MANTIS). LncRNAs have also been implicated in modulating vascular smooth muscle cell (VSMC) phenotypes or vascular remodeling (e.g. ANRIL, SMILR, SENCR, MYOSLID). Finally, emerging studies have implicated lncRNAs in leukocytes activation (e.g. lincRNA-Cox2, linc00305, THRIL), macrophage polarization (e.g. GAS5), and cholesterol metabolism (e.g. LeXis). This review summarizes recent findings on the expression, mechanism, and function of lncRNAs implicated in a range of vascular disease states from mice to human subjects. An improved understanding of lncRNAs in vascular disease may provide new pathophysiological insights and opportunities for the generation of a new class of RNA-based biomarkers and therapeutic targets. PMID- 29425895 TI - Developing a model of midwifery mentorship for Uganda: The MOMENTUM project 2015 2017. AB - MOMENTUM was a 20 month midwifery twinning project between the Royal College of Midwives UK and the Ugandan Private Midwives Association. It ran from 2015-2017 and was funded by UK-Aid through THET. MOMENTUM aimed to develop a model of mentorship for Ugandan midwifery students. The project achieved its objectives. 41 Ugandan midwives were trained as mentors following a work-based learning curriculum. 142 student midwives from 8 midwifery schools received mentorship in 7 participating clinical sites. All sites showed measured improvement in the clinical learning environment. 7 UK midwives were twinned with Ugandan counterparts and engaged in peer-exchange visits and virtual support via smart phones. The model is context-specific and may not be replicable in other countries or professions. However it will inform midwifery education in the UK and elsewhere. PMID- 29425896 TI - Women's satisfaction with care at the birthplace in Austria: Evaluation of the Babies Born Better survey national dataset. AB - OBJECTIVE: to evaluate women's satisfaction with care at the birthplace in Austria and to provide reference data for cross-country comparisons within the international Babies Born Better project. DESIGN: a cross-sectional design was applied. The data were extracted from the Babies Born Better survey as a national sub-dataset that included all participants with Austria as the indicated country of residence. SETTING: an online survey targeting women who had given birth within the last five years and distributed primarily via social media. In addition to sociodemographic and closed-ended questions regarding pregnancy and the childbirth environment, the women's childbirth experiences and satisfaction with the birthplace were obtained with three open-ended questions regarding (i) best experience of care, (ii) required changes in care and (iii) honest description of the experienced care. PARTICIPANTS: five hundred thirty-nine women who had given birth in Austria within the last five years. MEASUREMENTS AND FINDINGS: based on the concepts of public health, salutogenesis and self efficacy, a deductive coding framework was developed and applied to analyse the qualitative data of the Babies Born Better survey. Regarding honest descriptions of the experienced care at the birthplace, 82% were positive, indicating that most of the respondents were mostly satisfied with the care experienced. More than 95% of the survey participants' positive experiences and more than 87% of their negative experiences with care could be assigned to the categories of the deductive coding framework. Whereas positive experiences mainly addressed care experienced at the individual level, negative experiences more frequently related to issues of the existing infrastructure, breastfeeding counselling or topics not covered by the coding framework. Evaluation of these unassigned responses revealed an emphasis on antenatal and puerperal care as well as insufficient reimbursements of expenses by health insurance funds and the desire for more midwifery-led care. KEY CONCLUSIONS: although the participating women were mostly satisfied with perinatal care in Austria, it appears that shortcomings particularly exist in antenatal and puerperal care and counselling. IMPLICATIONS FOR RESEARCH: the established coding framework that covered the vast majority of the women's responses to the open-ended questions might serve as a basis for cross-country comparisons within the international Babies Born Better project. PMID- 29425897 TI - The dynamics of human cognition: Increasing global integration coupled with decreasing segregation found using iEEG. AB - Cognitive processing requires the ability to flexibly integrate and process information across large brain networks. How do brain networks dynamically reorganize to allow broad communication between many different brain regions in order to integrate information? We record neural activity from 12 epileptic patients using intracranial EEG while performing three cognitive tasks. We assess how the functional connectivity between different brain areas changes to facilitate communication across them. At the topological level, this facilitation is characterized by measures of integration and segregation. Across all patients, we found significant increases in integration and decreases in segregation during cognitive processing, especially in the gamma band (50-90 Hz). We also found higher levels of global synchronization and functional connectivity during task execution, again particularly in the gamma band. More importantly, functional connectivity modulations were not caused by changes in the level of the underlying oscillations. Instead, these modulations were caused by a rearrangement of the mutual synchronization between the different nodes as proposed by the "Communication Through Coherence" Theory. PMID- 29425898 TI - The attributable risk of chronic obstructive pulmonary disease due to ambient fine particulate pollution among older adults. AB - BACKGROUND: The linkage between ambient fine particle pollution (PM2.5) and chronic obstructive pulmonary disease (COPD) and the attributable risk remained largely unknown. This study determined the cross-sectional association between ambient PM2.5 and prevalence of COPD among adults >=50 years of age. METHODS: We surveyed 29,290 participants aged 50 years and above in this study. The annual average concentrations of PM2.5 derived from satellite data were used as the exposure indicator. A mixed effect model was applied to determine the associations and the burden of COPD attributable to PM2.5. RESULTS: Among the participants, 1872 (6.39%) were classified as COPD cases. Our analysis observed a threshold concentration of 30 MUg/m3 in the PM2.5-COPD association, above which we found a linear positive exposure-response association between ambient PM2.5 and COPD. The odds ratio (OR) for each 10 MUg/m3 increase in ambient PM2.5 was 1.21(95% CI: 1.13, 1.30). Stratified analyses suggested that males, older subjects (65 years and older) and those with lower education attainment might be the vulnerable subpopulations. We further estimated that about 13.79% (95% CI: 7.82%, 21.62%) of the COPD cases could be attributable to PM2.5 levels higher than 30 MUg/m3 in the study population. CONCLUSION: Our analysis indicates that ambient PM2.5 exposure could increase the risk of COPD and accounts for a substantial fraction of COPD among the study population. PMID- 29425899 TI - Influence of exposure to perfluoroalkyl substances (PFASs) on the Korean general population: 10-year trend and health effects. AB - This study demonstrated the 10-year trend of 13 perfluoroalkyl substances (PFASs) serum levels among 786 adults living in Seoul, Korea. PFAS levels gradually increased from 2006 to 2013, decreasing thereafter. We found that PFAS levels were higher in male than in female participants and were positively correlated with age. PFASs were not significantly correlated with body mass index, although we observed positive correlations with total cholesterol, low-density lipoprotein cholesterol, and triglycerides and negative correlations with high-density lipoprotein cholesterol. Uric acid and free thyroxine (fT4) also showed positive correlations with major congeners while correlations between thyroid stimulating hormone and PFASs were inconsistent. We demonstrated significant correlations between fT4 and perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorodecanoic acid (PFDA). There were significant differences in PFHxS and perfluorododecanoic acid (PFDoDA) levels between participants with and without diabetes. Furthermore, principal component analysis suggested possible differences in disease manifestation based on the congener distribution of PFASs. This study is the first study of temporal trends of 13 PFAS congeners in serum samples obtained from the Korean general population; it is currently longest and largest scale study of this type. PMID- 29425900 TI - Fluoroquinolones and beta-lactam antibiotics and antibiotic resistance genes in autumn leachates of seven major municipal solid waste landfills in China. AB - Landfills are reservoirs of antibiotics, heavy metals, disinfectants and other emerging contaminants, and they are closely associated with the increasing prevalence of antibiotic-resistance genes (ARGs). In this study, two classes of clinical use antibiotics, i.e., fluoroquinolones (FQs) and beta-lactams (BLs), twelve subtypes of their parallel ARGs, and five mobile genetic elements (MGEs), were measured in municipal solid waste (MSW) landfill leachates from seven mega cities in China. The highest concentration of FQs was detected in Shanghai (48,326.67 ng/L), and the highest concentration of BLs was detected in Hangzhou (1304 ng/L). In landfill leachates in Suzhou, the total contents of targeted ARGs subtypes ((1.44 +/- 4.64) * 10-4 (ARGs/16S)) and MGEs (7.88 * 10-2 +/- 1.18 * 10 1 (ARGs/16S)) were the highest. The relative abundance of ARGs and MGEs was significantly correlated with the contents of As and Cr, and the presence of MGEs was highly correlated with the content of Cd (r = -0.438, p = 0.475). Linear regression analysis showed that MGEs are closely associated with the abundance of genes resistant to FQs and BLs. These results suggest that the occurrences of FQs and BLs ARGs in the landfills of China are substantially influenced by heavy metals and MGEs. Regional differences concerning the antibiotics and ARGs contents in leachates were observed across seven mega-cities, and FQs were significantly correlated with the local population level (p < 0.01). Further, the nitrogen input to the landfills contributes significantly to the elevated levels of target ARGs. PMID- 29425901 TI - Multicenter, multivendor phantom study to validate proton density fat fraction and T2* values calculated using vendor-provided 6-point DIXON methods. AB - PURPOSE: To evaluate the reproducibility of proton density fat fraction (PDFF) and T2* in a fat-water phantom on three different 3 T MRI systems using 6-point DIXON methods. METHODS: A phantom which included varying fat volume percentages (true fat fraction [FF]) was scanned by three 3 T MR machines, and PDFF and T2* were measured. RESULTS: The mean difference between true FF and PDFF was small in all vendors (-2.11% to 0.41%). However, the difference ratio for T2* values was large among vendors (1.79 to 3.36). CONCLUSIONS: True FF and PDFF were consistent across vendors; however, T2* varied greatly. PMID- 29425902 TI - Is there a 'pig cycle' in the labour supply of doctors? How training and immigration policies respond to physician shortages. AB - Many OECD countries are faced with the considerable challenge of a physician shortage. This paper investigates the strategies that OECD governments adopt and determines whether these policies effectively address these medical shortages. Due to the amount of time medical training requires, it takes longer for an expansion in medical school capacity to have an effect than the recruitment of foreign-trained physicians. Using data obtained from the OECD (2014) and Bhargava et al. (2011), we constructed a unique country-level panel dataset that includes annual data for 17 OECD countries on physician shortages, the number of medical school graduates and immigration and emigration rates from 1991 to 2004. By calculating panel fixed-effect estimates, we find that after a period of medical shortages, OECD governments produce more medical graduates in the long run but in the short term, they primarily recruit from abroad; however, at the same time, certain practising physicians choose to emigrate. Simulation results show the limits of recruiting only abroad in the long term but also highlight its appropriateness for the short term when there is a recurrent cycle of shortages/surpluses in the labour supply of physicians (pig cycle theory). PMID- 29425903 TI - Efficacy and Safety of 5-Day Challenge for the Evaluation of Nonsevere Amoxicillin Allergy in Children. AB - BACKGROUND: Penicillin allergy is the most frequent drug allergy, among which aminopenicillins are reputed for causing delayed rashes in children, particularly in the context of viral infections. Despite a negative allergy evaluation, a significant proportion of individuals continue to avoid penicillin antibiotics for fear of an allergic reaction. OBJECTIVE: To evaluate the safety and efficacy of a 5-day challenge to amoxicillin and the proportion of subsequent use of amoxicillin. METHODS: Pediatric patients with a history of a reaction to amoxicillin were prospectively recruited in the study. All patients were challenged, and those with negative immediate challenges underwent an ambulatory 5-day challenge to amoxicillin to rule out nonimmediate reactions. Patients were called 2 years after their initial allergy evaluation to assess subsequent amoxicillin use and tolerance. RESULTS: One hundred thirty children with a history of amoxicillin allergy underwent a graded drug provocation test (DPT) to amoxicillin. Three patients had a positive immediate challenge, 3 had a positive nonimmediate challenge, and 2 were equivocal. Of the 122 patients with a negative challenge, 114 (93.4%) were reached 2 years after their initial allergy evaluation: 75 had used antibiotics since, of which only 1 (1.3%) had refused to reuse amoxicillin because of fear of an allergic reaction. Finally, the 5-day DPT resulted in a 24.1% decrease in future penicillin avoidance compared with classical single-dose graded DPT performed for 1 day in a historical cohort (P < .0001). CONCLUSION: The 5-day challenge is a safe and effective way to rule out nonimmediate amoxicillin allergy, and it ensures better compliance with future penicillin use. PMID- 29425904 TI - Onset of Action of the Fixed Combination Intranasal Azelastine-Fluticasone Propionate in an Allergen Exposure Chamber. AB - BACKGROUND: A fixed-dose combination of intranasal azelastine hydrochloride and fluticasone propionate (MP-AzeFlu) is the most effective treatment of allergic rhinitis, but its onset of action requires further investigation. OBJECTIVE: To compare the onset of action of MP-AzeFlu with the free combination of oral loratadine (LORA) and intranasal fluticasone propionate (INFP). METHODS: In this single-center, randomized, placebo-controlled, double-blind, double-dummy, 3 period crossover trial, allergic rhinitis symptoms were induced in asymptomatic patients by ragweed pollen challenge in an allergen environmental exposure chamber. Patients received single-dose MP-AzeFlu, LORA/INFP, or placebo and were monitored for 4 hours. The primary outcome was onset of action measured by total nasal symptom score (TNSS). Secondary measures were total ocular symptom score (TOSS), total score of the 7 nasal and ocular symptoms (T7SS), and the global visual analog scale (VAS). RESULTS: The full analysis set included 82 patients, of which 78 completed all treatments. TNSS was significantly reduced versus placebo from 5 minutes for MP-AzeFlu and 150 minutes for LORA/INFP onward (both P < .05) till the end of assessment (0-4 hours). MP-AzeFlu reduced TNSS to a greater extent at each time point from 5 to 90 minutes (P < .05) and over the entire assessment interval (P <= .005) versus LORA/INFP or placebo. No statistically significant difference between LORA/INFP and placebo was observed over the assessment interval (P = .182). The onset of action of MP-AzeFlu assessed by TOSS, T7SS, and VAS was 10 minutes, 2 hours earlier than with LORA/INFP. CONCLUSION: MP-AzeFlu had a more rapid onset of action (5 minutes) and was more effective than LORA/INFP. PMID- 29425905 TI - The impact of ART initiation on household food security over time. AB - While evidence suggests that adequate nutrition contributes to the efficacy of ART, the potential causal impact of ART initiation on household food security has not been thoroughly examined. In this study, we present some of the first causal evidence of the impact of ART initiation on household food security. We employ a quasi-experimental design, regression discontinuity, over 5540 individuals from an ongoing population cohort study in KwaZulu-Natal, South Africa, by utilizing the CD4 count-based ART eligibility threshold to examine the impact of ART initiation on household food security. We find that ART initiation causes a significant increase in the probability of food insecurity in the first year, which diminishes to zero within three years of initiation. Within the first year, ART initiation was found to significantly increase the probabilities that (1) the surveyed adult had missed any food in the past month by 10.2 percentage points (coefficient = 0.102, 95%CI = [0.039, 0.166]); (2) any adult in the household had missed a meal in the past month by 15.2 percentage points (coefficient = 0.152, 95%CI = [0.073, 0.231]); and (3) any child in the household had missed a meal in the past month by 8.9 percentage points (coefficient = 0.0898, 95%CI = [0.0317, 0.148]). While we cannot definitively isolate the mechanistic pathways from ART to household food security, our results are consistent with ART affecting food security through household resource strain and patient appetite recovery. Several policies could mitigate the negative impact of ART on food security, in particular food parcels or food vouchers for ART patients in the first two years after treatment initiation. PMID- 29425907 TI - Visceral pain - Novel approaches for optogenetic control of spinal afferents. AB - Painful stimuli arising within visceral organs are detected by peripheral nerve endings of spinal afferents, whose cell bodies are located in dorsal root ganglia (DRG). Recent technical advances have made it possible to reliably expose and inject single DRG with neuronal tracers or viruses in vivo. This has facilitated, for the first time, unequivocal identification of different types of spinal afferent endings in visceral organs. These technical advances paved the way for a very exciting series of in vivo experiments where individual DRG are injected to facilitate opsin expression (e.g. Archaerhodopsin). Organ-specific expression of opsins in sensory neurons may be achieved by retrograde viral transduction. This means activity of target-specific populations of sensory neurons, within single DRG, can be modulated by optogenetic photo-stimulation. Using this approach we implanted micro light-emitting diodes (micro-LEDs) adjacent to DRG of interest, thereby allowing focal DRG-specific control of visceral and/or somatic afferents in conscious mice. This is vastly different from broad photo-illumination of peripheral nerve endings, which are dispersed over much larger surface areas across an entire visceral organ; and embedded deep within multiple anatomical layers. Focal DRG photo-stimulation also avoids the potential that wide-field illumination of the periphery could inadvertently activate other closely apposed organs, or co-activate different classes of axons in the same organ (e.g. enteric and spinal afferent endings in the gut). It is now possible to selectively control nociceptive and/or non-nociceptive pathways to specific visceral organs in vivo, using wireless optogenetics and micro-LEDs implanted adjacent to DRG, for targeted photo-stimulation. PMID- 29425906 TI - Effects of vagal neuromodulation on feeding behavior. AB - Implanted vagus nerve stimulation (VNS) for obesity was recently approved by the FDA. However, its efficacy and mechanisms of action remain unclear. Herein, we synthesize clinical and preclinical effects of VNS on feeding behavior and energy balance and discuss engineering considerations for understanding and improving the therapy. Clinical cervical VNS (<=30 Hz) to treat epilepsy or depression has produced mixed effects on weight loss as a side effect, albeit in uncontrolled, retrospective studies. Conversely, preclinical studies (cervical and subdiaphragmatic VNS) mostly report decreased food intake and either decreased weight gain or weight loss. More recent clinical studies report weight loss in response to kilohertz frequency VNS applied to the subdiaphragmatic vagi, albeit with a large placebo effect. Rather than eliciting neural activity, this therapy putatively blocks conduction in the vagus nerves. Overall, stimulation parameters lack systematic exploration, optimization, and justification based on target nerve fibers and therapeutic outcomes. The vagus nerve transduces, transmits, and integrates important neural (efferent and afferent), humoral, energetic, and inflammatory information between the gut and brain. Thus, improved understanding of the biophysics, electrophysiology, and (patho)physiology has the potential to advance VNS as an effective therapy for a wide range of diseases. PMID- 29425908 TI - Enteric glia: Diversity or plasticity? AB - Glial cells of the enteric nervous system correspond to a unique glial lineage distinct from other central and peripheral glia, and form a vast and abundant network spreading throughout all the layers of the gastrointestinal wall. Research over the last two decades has demonstrated that enteric glia regulates all major gastrointestinal functions via multiple bi-directional crosstalk with enteric neurons and other neighboring cell types. Recent studies propose that enteric glia represents a heterogeneous population associated with distinct localization within the gut wall, phenotype and activity. Compelling evidence also indicates that enteric glial cells are capable of plasticity leading to phenotypic changes whose pinnacle so far has been shown to be the generation of enteric neurons. While alterations of the glial network have been heavily incriminated in the development of gastrointestinal pathologies, enteric glial cells have also recently emerged as an active player in gut-brain signaling. Therefore, the development of tools and techniques to better appraise enteric glia heterogeneity and plasticity will undoubtedly unveil critical regulatory mechanisms implicated in gut health and disease, as well as disorders of the gut brain axis. PMID- 29425909 TI - EEG activity during the spatial span task in young men: Differences between short term and working memory. AB - Short-term memory and working memory are two closely-related concepts that involve the prefrontal and parietal areas. These two types of memory have been evaluated by means of the spatial span task in its forward and backward conditions, respectively. To determine possible neurofunctional differences between them, this study recorded electroencephalographic activity (EEG) in the frontopolar (Fp1, Fp2), dorsolateral (F3, F4), and parietal (P3 and P4) areas during performance of the forward and backward conditions of this task in young men. The backward condition (an indicator of working memory) was characterized by fewer correct answers, higher absolute power (AP) of the delta band in dorsolateral areas, and a lower correlation between frontopolar and dorsolateral regions in the fast bands (alpha, beta and gamma), mainly in the right hemisphere. The prefrontal EEG changes during backward performance may be associated with the higher attentional demands and inhibition processes required to invert the order of reproduction of a sequence. These data provide evidence that the forward and backward conditions of the spatial span task can be distinguished on the basis of neurofunctional activity and performance, and that each one is associated with a distinct pattern of electrical activity and synchronization between prefrontal areas. The higher AP of the delta band and lower correlation of the fast bands, particularly between right prefrontal areas during the backward condition of this visuospatial task, suggest greater participation by the right prefrontal areas in working memory. PMID- 29425910 TI - Neuroprotective effects of Tongxinluo on focal cerebral ischemia and reperfusion injury in rats associated with the activation of the MEK1/2/ERK1/2/p90RSK signaling pathway. AB - Ischemic stroke brings a huge family and social burden. Although the reperfusion of ischemic cerebral tissue is the most important way to rescue ischemic stroke, ischemia-reperfusion (I/R) injury further results in brain damage and even lead to death. Recent studies demonstrated that Tongxinluo (TXL) helps to protect the brain against focal cerebral I/R injury in rats by reducing neuronal apoptosis, and the MEK1/2/ERK1/2/90 ribosomal S6 kinase (p90RSK) pathway may be involved in this protective effect. Therefore, our present research was designed to identify the potential mechanisms involved. Adult male Sprague-Dawley rats (n = 108) were randomly divided into 4 groups: sham, cerebral ischemia and reperfusion (I/R), I/R plus TXL (TXL), and TXL plus U0126, a highly selective inhibitor of MEK 1 and MEK 2 (TXL + U0126). Brain edema was measured by T2-weighted magnetic resonance imaging (MRI). Pathological destruction of the blood brain barrier (BBB) ultrastructure was assessed by transmission electron microscopy, and proteins involved in the MEK1/2/ERK1/2/p90RSK pathway were detected by immunofluorescence and Western blotting. Our results indicated that TXL significantly improved neurological function, reduced brain edema, ameliorated the destruction of the BBB ultrastructure and markedly reduced neuronal injury. However, these benefits were diminished when the MEK1/2/ERK1/2/p90RSK pathway was inhibited by U0126. We also found that TXL upregulated the expression levels of p-MEK1/2, p-ERK1/2, p p90RSK and p-bad, which were all significantly reversed by U0126. Collectively, our data demonstrate that TXL provides neuroprotection against cerebral I/R injury and neuronal injury, and that these effects are mediated, in part, by activation of the MEK1/2/ERK1/2/p90RSK pathway. PMID- 29425912 TI - Participant experiences of clean intermittent self-catheterisation, urinary tract infections and antibiotic use on the ANTIC trial - A qualitative study. AB - BACKGROUND: Recurrent urinary tract infections are a commonly reported problem in people who use clean intermittent self-catheterisation. Yet there is a lack of knowledge regarding both the impact on people's lives, the use of prophylactic anti-biotics and perceptions of patients on their use. AIMS: To explore the views and experiences of adults who use clean intermittent self-catheterisation for long-term bladder conditions, with a focus on urinary tract infection experience and prophylactic antibiotic use. DESIGN: A qualitative descriptive study. METHODS: Twenty-six semi-structured qualitative interviews were conducted with individuals recruited from the ANTIC Trial (Antibiotic treatment for intermittent bladder catheterisation: A randomised controlled trial of once daily prophylaxis). Participants were intermittent self-catheter users aged 18 years or older. Interviews took place between August 2015 and January 2016. Transcript data were analysed thematically. FINDINGS: Three overarching topics were revealed with corresponding themes: the experiences of intermittent self-catheterisation and urinary tract infections (normalisation, perceived burden); attitudes towards antibiotics for urinary tract infection treatment (nonchalant attitudes, ambivalence towards antibiotic resistance); and experiences of low-dose prophylaxis antibiotics (habitual behaviour and supportive accountability). CONCLUSION: The emotional and practical burden of catheter use and urinary tract infection was considerable. Beliefs pertaining to antibiotic use were based on utility, gravity of need and perceived efficacy. These opinions were often influenced by clinician recommendations. PMID- 29425911 TI - Antenatal and neonatal antecedents of learning limitations in 10-year old children born extremely preterm. AB - BACKGROUND: Children born extremely preterm are at increased risk of learning limitations. AIM: To identify the antecedents of learning limitations of children born extremely preterm. STUDY DESIGN: Prospective observational study from birth to age 10 years. Variables entered into the multinomial logistic regression analyses were ordered temporally, with the earliest occurring predictors/covariates of each learning limitation risk entered first and not displaced by later occurring covariates. SUBJECTS: 874 children who were born before the 28th week of gestation. OUTCOME MEASURES: A reading limitation was defined as a score one or more standard deviations below the expected mean on the WIAT-III Word Reading and a mathematics limitation was defined as a similarly low score on the Numerical Operations component. RESULTS: 56 children had a "reading ONLY" limitation, 132 children had a "math ONLY" limitation and 89 children had "reading AND math" limitations. All risk profiles included an indicator of socioeconomic disadvantage (e.g., mother's "racial" identity and eligibility for government-provided health care insurance), an indicator of newborn's immaturity/vulnerability (e.g., high illness severity score, receipt of hydrocortisone, and/or ventilator-dependence at 36 weeks post-menstruation), and all but the math only limitation included an indicator of fetal growth restriction and inflammation (i.e., pregnancy urinary tract infection or late ventilator-dependence). CONCLUSIONS: The themes of socioeconomic disadvantage and immaturity/vulnerability characterize all three risk profiles, while the themes of fetal growth restriction and inflammation are characteristic of a reading limitation only, and the reading and math limitations entity. PMID- 29425913 TI - Retraction of publications in nursing and midwifery research: A systematic review. AB - BACKGROUND: Rates of manuscript retraction in academic journals are increasing. Papers are retracted because of scientific misconduct or serious error. To date there have been no studies that have examined rates of retraction in nursing and midwifery journals. DESIGN: A systematic review of Journal Citation Report listed nursing science journals. DATA SOURCES: The Medline database was searched systematically from January 1980 through July 2017, and www.retractionwatch.com was manually searched for relevant studies that met the inclusion criteria. REVIEW METHODS: Two researchers undertook title and abstract and full text screening. Data were extracted on the country of the corresponding author, journal title, impact factor, study design, year of retraction, number of citations after retraction, and reason for retraction. Journals retraction index was also calculated. RESULTS: Twenty-nine retracted papers published in nursing science journals were identified, the first in 2007. This represents 0.029% of all papers published in these journals since 2007. We observed a significant increase in the retraction rate of 0.44 per 10,000 publications per year (95% CI; 0.03-0.84, p = .037). There was a negative association between a journal's retraction index and impact factor with a significant reduction in retraction index of -0.57 for a one-point increase in impact factor (95% CI; -1.05 to -0.09, p = .022). Duplicate publication was the most common reason for retraction (n = 18, 58%). The mean number of citations manuscripts received after retraction was seven, the highest was 52. Most (n = 27, 93.1%) of the retracted papers are still available online (with a watermark indicating they are retracted). CONCLUSION: Compared to more established academic disciplines, rates of retraction in nursing and midwifery are low. Findings suggest that unsound research is not being identified and that the checks and balances incumbent in the scientific method are not working. In a clinical discipline, this is concerning and may indicate that research that should have been removed from the evidence base continues to influence nursing and midwifery care. PMID- 29425914 TI - Soil gross nitrogen transformations in responses to land use conversion in a subtropical karst region. AB - Gross nitrogen (N) transformations can provide important information for assessing indigenous soil N supply capacity and soil nitrate leaching potential. The current study aimed to assess the variation of gross N transformations in response to conversion of maize-soybean fields to sugarcane, mulberry, and forage grass fields in a subtropical karst region of southwest China. Mature forests were included for comparison. Gross rates of N mineralization (GNM) were highest in the forests, intermediate in the maize-soybean and forage grass fields, and lowest in the sugarcane and mulberry fields, suggesting capacity of indigenous soil N supply derived from organic N mineralization was lowered after conversion to sugarcane and mulberry fields. The relative high indigenous soil N supply capacity in the maize-soybean fields was obtained at the cost of soil organic N depletion. Gross nitrification (GN) rates were highest in the forests, intermediate in the forage grass fields and lowest in the other three agricultural land use types. The nitrate retention capacity (24.1 +/- 2.0% on average) was similar among the five land use types, implying that nitrate leaching potential was not changed after land use conversion. Microbial biomass N exerted significant direct effects on the rates of N mineralization, nitrification, ammonium immobilization and nitrate immobilization. Soil organic carbon, total N and exchangeable magnesium had significant indirect effects on these N transformation rates. Our findings suggest that forage grass cultivation instead of other agricultural land uses should be recommended from the perspective of increasing indigenous soil N supply while not depleting soil organic N pool. PMID- 29425915 TI - Toxicokinetic and toxicodynamic of depleted uranium in the zebrafish, Danio rerio. AB - This study investigated the accumulation pattern and biological effects (genotoxicity and histopathology) to adult zebrafish (male and female) exposed to a nominal waterborne concentration of 20 MUg L-1 of depleted uranium (DU) for 28 days followed by 27 days of depuration. Accumulation pattern showed that (i) DU accumulated in brain, (ii) levels in digestive tract were higher than those measured in gills and (iii) levels remained high in kidney, brain and ovary despite the 27 days of depuration period. Genotoxicity, assessed by comet assay, was significant not only during DU exposure, but also during depuration phase. Gonads, in particular the testes, were more sensitive than gills. The histology of gonads indicated severe biological damages in males. This study improved knowledge of ecotoxic profile of uranium, for which a large range of biological effects has already been demonstrated. PMID- 29425916 TI - Genetically defined fear-induced aggression: Focus on BDNF and its receptors. AB - Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro peptide, BDNF mRNA levels, as well as TrkB and p75NTR receptors mRNA and protein levels, were studied in the brain of rats, selectively bred for more than 85 generations for either the high level or the lack of fear-induced aggressive behavior. Furthermore, we have found that rats of aggressive strain demonstrated both high level of aggression toward humans and increased amplitude of acoustic startle response compared to rats selectively bred for the lack of fear-induced aggression. Significant increase in the BDNF mRNA, mature BDNF and proBDNF protein levels in the raphe nuclei (RN), hippocampus (Hc), nucleus accumbens (NAcc), amygdala, striatum and hypothalamus (Ht) of aggressive rats was revealed. The BDNF/proBDNF ratio was significantly reduced in the Hc and NAcc of highly aggressive rats suggesting prevalence of the proBDNF in these structures. In the Hc and frontal cortex (FC) of aggressive rats, the level of the full-length TrkB (TrkB-FL) receptor form was decreased, whereas the truncated TrkB (TrkB-T) protein level was increased in the RN, FC, substantia nigra and Ht. The TrkB FL/TrkB-T ratio was significantly decreased in highly aggressive rats suggesting TrkB-T is predominant in highly aggressive rats. The p75NTR expression was slightly changed in majority of studied brain structures of aggressive rats. The data indicate the BDNF system in the brain of aggressive and nonaggressive animals is extremely different at all levels, from transcription to reception, suggesting significant role of BDNF system in the development of highly aggressive phenotype. PMID- 29425917 TI - Incorporation of new neurons in the olfactory bulb after paced mating in the female rat. AB - One of the regions that constantly produces neurogenesis in the adult brain is the subventricular zone (SVZ), whose new cells migrate to the olfactory bulbs (OB). When the females regulate the copulatory events (paced mating) the number of new cells in the SVZ increases, as well as those observed in the OB 15 days later. However, no changes were observed in the number of cells 45 days after the females paced the sexual interaction. Constant sensory stimulation is an important promoter of cell survival in the OB circuit. Hence, we increased the number of mating sessions in this study to cover the period where stimulation of the new cells is critical for their incorporation into pre-existing circuits in the OB. Ovariectomized female Wistar rats, were injected with the mitotic marker 5-bromo-2'-deoxyuridine (BrdU, 100 mg/kg, per injection) before, at the end and one hour after mating. Sexual behavior was recorded for 1 h in 10 weekly sessions. After the last mating session, brain sections were processed to determine BrdU immunoreactivity. Our results indicate that females that paced the sexual interaction for 10 sessions had a higher number of cells in the glomerular layer (GL) of the accessory olfactory bulb (AOB) and a higher number of neurons in the granular layer (GrL) of the main olfactory bulb (MOB) in comparison to the control group. These results indicate that continued sexual interaction contributes to the integration of new cells and neurons, induced in the first sexual experience, into pre-exiting circuits of the OB. PMID- 29425918 TI - Age and HIV effects on resting state of the brain in relationship to neurocognitive functioning. AB - This study examined the effects of age and HIV infection on the resting state (RS) functional connectivity (FC) of the brain and cognitive functioning. The objective was to evaluate the moderating role of age and HIV on the relationship between RS-FC and cognition. To examine RS-FC we implemented the Independent Component Analysis (ICA) and Regional Homogeneity (ReHo). Neurocognition was evaluated with comprehensive battery of standardized neuropsychological tests. Age and HIV were entered as the independent variables. The independent effects of age, HIV, and interaction effects of age-HIV on RS-fMRI measures (ICA, ReHo) were tested in 108 participants (age M = 42). RS-FC indices that exhibited age-HIV interactions were entered into further analysis. Bivariate correlation analysis was performed between the retained RS-FC indices and T-scores of neurocognitive domains (Attention, Executive, Memory, Psychomotor, Semantic Skills). Multivariate regression modeling determined the impact of age and HIV on these relationships. We found that in the ICA measures, HIV-seropositivity was decreasing RS-FC in the left middle occipital gyrus (p < .001). Age-HIV interaction was observed in the left superior frontal gyrus (LSupFrontG), where FC was decreasing with age in HIV+ (p < .001) and increasing in HIV- (p = .031). ReHo indices did not reveal significant effects. HIV strengthened the relationship between RS-FC in LSupFrontG, Memory and Psychomotor Factor scores. Aging weakened those relationships only in control group. In sum, age-HIV interaction effects are prominent rather in remote than local RS-FC. Seroconversion strengthens relationships between intrinsic brain activity and neurocognition, but no acceleration with years of age was noted in HIV+ individuals. PMID- 29425919 TI - The Visible Burrow System: A behavioral paradigm to assess sociability and social withdrawal in BTBR and C57BL/6J mice strains. AB - Disrupted sociability and consequent social withdrawal are (early) symptoms of a wide variety of neuropsychiatric diseases, such as schizophrenia, autism spectrum disorders, depressive disorders and Alzheimer's disease. The paucity of objective measures to translationally assess social withdrawal characteristics has been an important limitation to study this behavioral phenotype, both in human and rodents. The aim of the present study was to investigate sociability and social withdrawal in rodents using an ethologically valid behavioral paradigm, the Visible Burrow System (VBS). The VBS mimics a natural environment, with male and female rodents housed together in an enclosure where a large open arena is connected to a continuously dark burrow system that includes 4 nest boxes. In this study, mixed-sex colonies of C57BL/6J and of BTBR mice have been investigated (n = 8 mice per colony). Results showed marked differences between the two strains, in terms of sociability as well as social withdrawal behaviors. In particular, BTBR mice performed less social behaviors and have a preference for non-social behaviors compared to C57BL/6J mice. Neurobiologically, the decreased sociability of BTBR was accompanied by reduced GABA and increased glutamate concentrations in brain prefrontal cortex (PFC) and amygdala regions. In conclusion, our study validated the use of the VBS as an ethologically relevant behavioral paradigm in group-housed mice to investigate individual sociability and social withdrawal features and their underlying neurobiology. This paradigm may provide new insights to develop new therapeutic treatments for behavioral dysfunctions that may be relevant across neuropsychiatric diseases. PMID- 29425921 TI - Coffee and Colorectal Cancer: Grounds for Prevention? PMID- 29425922 TI - Genetic Testing and Early Onset Colon Cancer. PMID- 29425920 TI - STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis. AB - BACKGROUND & AIMS: Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP. METHODS: We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow-derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI). RESULTS: STING signaling was activated in pancreata from mice with AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than mice given wild-type bone marrow. DNA from dying acinar cells activated STING signaling in macrophages, which was inhibited by addition of DNaseI. CONCLUSIONS: In mice with AP, STING senses acinar cell death (by detecting DNA from dying acinar cells) and activates a signaling pathway that promotes inflammation. Macrophages express STING and activate pancreatic inflammation in AP. PMID- 29425924 TI - Cellular Plasticity in the Stomach: Insights Into the Cellular Origin of Gastric Metaplasia. PMID- 29425925 TI - Virtual Endoscopy Based on 3-Dimensional Reconstruction of Histopathology Features of Endoscopic Resection Specimens. PMID- 29425923 TI - Effects of Training and Feedback on Accuracy of Predicting Rectosigmoid Neoplastic Lesions and Selection of Surveillance Intervals by Endoscopists Performing Optical Diagnosis of Diminutive Polyps. AB - BACKGROUND & AIMS: Real-time differentiation of diminutive polyps (1-5 mm) during endoscopy could replace histopathology analysis. According to guidelines, implementation of optical diagnosis into routine practice would require it to identify rectosigmoid neoplastic lesions with a negative predictive value (NPV) of more than 90%, using histologic findings as a reference, and agreement with histology-based surveillance intervals for more than 90% of cases. METHODS: We performed a prospective study with 39 endoscopists accredited to perform colonoscopies on participants with positive results from fecal immunochemical tests in the Bowel Cancer Screening Program at 13 centers in the Netherlands. Endoscopists were trained in optical diagnosis using a validated module (Workgroup serrAted polypS and Polyposis). After meeting predefined performance thresholds in the training program, the endoscopists started a 1-year program (continuation phase) in which they performed narrow band imaging analyses during colonoscopies of participants in the screening program and predicted histological findings with confidence levels. The endoscopists were randomly assigned to groups that received feedback or no feedback on the accuracy of their predictions. Primary outcome measures were endoscopists' abilities to identify rectosigmoid neoplastic lesions (using histology as a reference) with NPVs of 90% or more, and selecting surveillance intervals that agreed with those determined by histology for at least 90% of cases. RESULTS: Of 39 endoscopists initially trained, 27 (69%) completed the training program. During the continuation phase, these 27 endoscopists performed 3144 colonoscopies in which 4504 diminutive polyps were removed. The endoscopists identified neoplastic lesions with a pooled NPV of 90.8% (95% confidence interval 88.6-92.6); their proposed surveillance intervals agreed with those determined by histologic analysis for 95.4% of cases (95% confidence interval 94.0-96.6). Findings did not differ between the group that did vs did not receive feedback. Sixteen endoscopists (59%) identified rectosigmoid neoplastic lesions with NPVs greater than 90% and selected surveillance intervals in agreement with those determined from histology for more than 90% of patients. CONCLUSIONS: In a prospective study following a validated training module, we found that a selected group of endoscopists identified rectosigmoid neoplastic lesions with pooled NPVs greater than 90% and accurately selected surveillance intervals for more than 90% of patients over the course of 1 year. Providing regular interim feedback on the accuracy of neoplastic lesion prediction and surveillance interval selection did not lead to differences in those endpoints. Monitoring is suggested, as individual performance varied. ClinicalTrials.gov no: NCT02516748; Netherland Trial Register: NTR4635. PMID- 29425926 TI - Introducing Traditional Herbal Medicine into Conventional Health Care in Treating Ulcerative Colitis: Primum Non Nocere. PMID- 29425927 TI - A New Model of Alagille Syndrome With Broad Phenotypic Representation. PMID- 29425928 TI - How to Become a Physician Executive: From Fellowship to Leadership. PMID- 29425929 TI - Hepatitis B Reactivation With Hepatitis C Treatment: Bringing Some Clarity to the Black Box. PMID- 29425932 TI - Ablation of C/EBP homologous protein attenuates renal fibrosis after ureteral obstruction by reducing autophagy and microtubule disruption. AB - Fibrosis is an undesirable consequence of injury and a critical problem in many diseases. Recent studies have demonstrated an association of C/EBP homologous protein (CHOP) with fibrosis. We investigated the mechanism of CHOP in kidney fibrosis progression after unilateral ureteral obstruction (UUO) using Chop gene deleted (Chop-/-) mice and their wild-type littermates (Chop+/+). UUO-induced kidney fibrosis was reduced in the Chop-/- than Chop+/+ mice. After UUO, CHOP expression was detected in the cytosol and nucleus of distal tubule cells and collecting duct cells of the kidney. UUO formed the autophagosome and increased the expression of autophagy proteins, Beclin-1, LC3-I and II, and p62 in the kidneys. These UUO-induced changes were significantly reduced in Chop-/- mice. Furthermore, Chop gene deletion attenuated mitochondrial fragmentation with lower expression of Fis-1, a mitochondrial fission protein, but higher expression of Opa-1, a mitochondrial fusion protein, than that seen in the wild-type mice. UUO disrupted the microtubule, which is involved in autophagosome formation, and this disruption was milder in the Chop-/- than Chop+/+ mouse kidney, with less reduction of histone deacetylase 6 and alpha-tubulin acetyl transferase, which acetylates tubulin, a component of the microtubule. After UUO, apoptosis, a consequence of autophagy and mitochondrial damage, was reduced in the Chop-/- mouse kidney cells than in Chop+/+ mice. Thus, the ablation of Chop attenuates renal fibrosis, accompanied by reduced autophagy, mitochondrial fragmentation, microtubule disruption, and apoptosis. Overall, these results suggest that CHOP plays a critical role in the progression of kidney fibrosis, likely through regulation of autophagy and apoptosis. PMID- 29425931 TI - Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. AB - BACKGROUND & AIMS: Society guidelines differ in their recommendations for surveillance to detect early-stage hepatocellular carcinoma (HCC) in patients with cirrhosis. We compared the performance of surveillance imaging, with or without alpha fetoprotein (AFP), for early detection of HCC in patients with cirrhosis. METHODS: Two reviewers searched MEDLINE and SCOPUS from January 1990 through August 2016 to identify published sensitivity and specificity of surveillance strategies for overall and early detection of HCC. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. RESULTS: Thirty-two studies (comprising 13,367 patients) characterized sensitivity of imaging with or without AFP measurement for detection of HCC in patients with cirrhosis. Ultrasound detected any stage HCC with 84% sensitivity (95% confidence interval [CI] 76%-92%), but early-stage HCC with only 47% sensitivity (95% CI 33%-61%). In studies comparing ultrasound with vs without AFP measurement, ultrasound detected any stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (relative risk [RR] 0.88; 95% CI 0.83-0.93) and early-stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (RR 0.81; 95% CI 0.71-0.93). However, ultrasound alone detected HCC with a higher level of specificity than ultrasound plus AFP measurement (RR 1.08; 95% CI 1.05-1.09). Ultrasound with vs without AFP detected early-stage HCC with 63% sensitivity (95% CI 48%-75%) and 45% sensitivity (95% CI 30%-62%), respectively (P = .002). Only 4 studies evaluated computed tomography or magnetic resonance image-based surveillance, which detected HCC with 84% sensitivity (95% CI 70%-92%). CONCLUSIONS: We found ultrasound alone has a low sensitivity to detect early stage HCC in patients with cirrhosis. Addition of AFP to ultrasound significantly increases sensitivity of early HCC detection in clinical practice. PMID- 29425933 TI - Spatial variation and probabilistic risk assessment of exposure to fluoride in drinking water. AB - Assessing the health risks of exposure to fluoride in developing countries has been unclear. In this study, the concentration of fluoride and its spatial analysis in groundwater of 6 counties of Yazd province, Iran, were investigated. Health risk assessment of three age groups (children, teens and adults), sensitivity analysis and uncertainties of effective variables were carried out using Monte Carlo simulation. The results showed that 68.77% of the samples taken were within the standard range set by the WHO guidelines (0.5-1.5 mg/l). The mean (Standard division) of fluoride in Ardakan, Azezar, Mehriz, Meybod, Taft and Yazd were 0.83 (0.31), 0.73 (0.41), 0.56 (0.20), 0.91 (0.32), 0.60 (0.32) and 0.64 (0.25) respectively. Among the studied counties, Ashkezar has the highest dispersion in terms of high concentration of fluoride. The hazard quotient (HQ) value for all age groups except children was less than 1, indicated potential of non-cancer risk of exposure to fluoride for this group. The most important variable in calculating the HQ was the drinking water ingestion rate, concentration of fluoride and the fraction of skin in contact with water, so more focused on these parameters should be made for a more accurate health risk assessment. PMID- 29425934 TI - Simultaneous and fast separation of three chlorogenic acids and two flavonoids from bamboo leaves extracts using zirconia. AB - Phenolic acids and flavonoids in bamboo leaves are of great importance for their functional attributes, but they can hardly be separated simultaneously. In this study, zirconia was prepared and applied as a potential absorbent for simultaneous separation of these phenolic compounds. Three phenolic acids (neochlorogenic acid, chlorogenic acid and cryptochlorogenic acid) and two flavonoids (isoorientin and orientin) were isolated at the same time. The influence of bamboo leaves extraction conditions, zirconia calcination temperatures, desorption conditions and absorption/desorption dynamics on the separation were further investigated. When zirconia-400 (calcined at 400 degrees C) was treated with 70% ethanol extract of bamboo leaves for 40 min followed by desorption with 70% acetic acid solution for 60 min, the recovery of three chlorogenic acids and two flavonoids was about 65%. To conclude, the concise method developed here may provide a new way for simultaneous separation of phenolic acids and flavonoids from various plants. PMID- 29425935 TI - Molecular dynamics simulation studies suggests unconventional roles of non secretary laccases from enteropathogenic gut bacteria and Cryptococcus neoformans serotype D. AB - Laccase in Cryptococcus neoformans is covalently linked to the carbohydrate moiety of the cell wall, which allows it to get access to the different substrates for catalyzing their oxidation and therefore plays a vital role in the virulence. The laccase gene (3.0 kb) from C. neoformans serotype D was amplified, cloned and sequenced for protein modeling, docking and simulation studies. The three dimensional homology models of laccase protein from C. neoformans and other pathogenic gut bacteria were docked with selected biomolecules like prostaglandins (PG), membrane phospholipids, neurotransmitters (serotonin) using GOLD software. The GOLDscore values of laccase from C. neoformans docked with prostaglandinH2 (59.76), prostaglandinG2 (59.45), prostaglandinE2 (60.99), phosphatidylinositol (54.95), phosphatidylcholine (46.26), phosphatidylserine (55.26), arachidonic acid (53.08) and serotonin (46.22) were similar to the laccase from enteropathogenic bacteria but showed a better binding affinity as compared to that of the non-pathogenic bacteria (e.g. Bacillus safensis, Bacillus pumilus and Bacillus subtilis). The RMSD of MD simulation study done for 25 ns using laccase protein from C. neoformans complexed with phosphatidylcholine was found to be highly stable, followed by the laccase-PGE2 and laccase-serotonin complexes. Furthermore, the binding free energy results were found to support the docking and MD simulation results. The present study implies that few candidate ligands can be intermediate substrate in the catalysis of microbial laccases, which can further play some crucial role in the cell signaling and pathogenesis of enteropathogenic gut micro flora and C. neoformans. PMID- 29425936 TI - Oxidized low density lipoproteins: The bridge between atherosclerosis and autoimmunity. Possible implications in accelerated atherosclerosis and for immune intervention in autoimmune rheumatic disorders. AB - Atherosclerotic vasculopathy is a multifactorial process causing vessels damage and cardiovascular diseases, the leading causes of death worldwide. Atherosclerotic plaque is the asymptomatic primary, elementary, lesion of atherosclerotic vasculopathy. Accumulation of the oxidized low-density lipoprotein (oxLDL) at sub endothelial sites is now recognized as one of the major trigger events in plaque formation. The concomitant presence at the plaque site of cells belonging to either natural or adaptive immunity, the detection of autoantibodies to oxLDL, the cross-reactivity of oxLDL with anti-phospholipid antibodies, in addition to the clinical evidence of increased rates of cardiovascular events in several rheumatic diseases, has stimulated intensive research to define interconnections between the immune system and traditional risk factors at the molecular levels in order to explain accelerated atherosclerosis. Here, we critically review the results of previous and recent studies, which have disclosed molecules of both innate or adaptive immunity involved in atherosclerosis, focusing primarily on B cells and autoantibodies, where data are more consolidated. Particular attention has also been paid to molecules that may be predictive markers of atherosclerosis progression and can be potential targets for immune intervention to delay the atherosclerotic process. The latter include CD20 antigen, molecules involved in the BAFF-BAFF receptor axis, inflammatory molecules and modified LDL. The successful results of a recent randomized controlled clinical trial targeting inflammasome with anti IL1beta monoclonal antibody in non-autoimmune conditions, prove that specific immunotherapy can be a promising and effective strategy to control atherosclerosis in rheumatic diseases as well. PMID- 29425937 TI - IgE in lupus pathogenesis: Friends or foes? AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple immunological pathways. Recently, several studies have suggested an implication of Immunoglobulin E (IgE) in the pathophysiology of SLE. In the Lyn-/ and FcgammaIIB-/-.Yaa lupus mouse models, autoreactive IgE activate basophils, and promote a Th2 environment with, subsequently, production of autoantibodies by plasma cells. Autoreactive IgE has been also shown to play a role in the activation of human plasmacytoid dendritic cells (pDCs), in synergy with IgG, which results in an increase of interferon-alpha (IFN-alpha) production. In contrast, a protective effect of total non-autoreactive IgE has also been suggested, through a decreased ability of FcepsilonRI-triggered pDCs to secrete IFN-alpha. This review summarizes in a comprehensive manner the emerging recent literature in the field, and propose new concepts to reconcile the observations. PMID- 29425938 TI - Specific solubilization of impurities in culture media: Arg solution improves purification of pH-responsive tag CspB50 with Teriparatide. AB - Protein purification using non-chromatographic methods is a simple technique that avoids costly resin. Recently, a cell surface protein B (CspB) tag has been developed for a pH-responsive tag for protein purification by solid-liquid separation. Proteins fused with the CspB tag show reversible insolubilization at acidic pH that can be used in solid-liquid separation for protein purification. However, brown-color impurities from co-precipitation hamper further analysis of the target proteins. In this study, we investigated the effect of additives on the co-precipitation of CspB-tagged Teriparatide (CspB50TEV-Teriparatide) expressed in Corynebacterium glutamicum and associated impurities. Arginine (Arg) at 1.0 M was found to be the most effective additive for removing impurities, particularly carotenoids and nucleic acids. Furthermore, all impurities detected in the fluorescence and absorbance spectra were successfully removed by the repetition of precipitation-redissolution in the Arg solution. The precipitation yield of the CspB50TEV-Teriparatide did not change with the addition of Arg and the repetition of the precipitation-redissolution process. Collectively, our findings indicate that the specific desorption of pi-electron rich compounds by Arg may be useful in conjunction with the pH-responsive CspB tag for solid-liquid protein purification. PMID- 29425939 TI - To evaluate or not: Evaluability study of 40 interventions of Belgian development cooperation. AB - Due to an increasing importance of evaluations within development cooperation, it has become all the more important to analyse if initial conditions for quality and relevant evaluations are met. This article presents the findings from an evaluability study of 40 interventions of Belgian development cooperation. A study framework was developed focusing on three key dimensions (i.e. theoretical evaluability, practical evaluability and the evaluation context) and subdivided over the different OECD/DAC criteria. Drawing upon a combination of desk and field research, the study framework was subsequently applied on a set of 40 interventions in Benin, DRC, Rwanda and Belgium. Findings highlight that the context dimension scores remarkably better than the theoretical and practical evaluability in particular. The large majority of the interventions have the conditions in place to satisfactorily evaluate effectiveness and efficiency while the opposite holds for sustainability and impact in particular. These findings caution against commissioning of evaluations that ritually focus on all OECD/DAC criteria regardless of their readiness. It underscores the usefulness of a flexible 'portfolio' approach towards evaluations, in which a more systematic use of evaluability assessment from the start of interventions could play a role. PMID- 29425940 TI - Rehabilitation Course and Specification of Dysmetria of a Patient With Ataxia, Dysmetria, and Hemiparesis After a Stroke in the Corona Radiata: A Case Presentation. AB - : We present a case of a patient with ataxia, dysmetria, and hemiparesis after a stroke in the corona radiata. The patient had an excellent clinical course with near resolution of symptoms in 2 and a half weeks and returned back to work full duty and full time a couple of weeks later. We use videos of several neurologic tests to demonstrate and characterize the dysmetria. Interestingly, a key characteristic of the dysmetria appears to be different from that seen in patients with dysmetria arising from a cerebellar, thalamic, or pontine lesion. We propose a possible neurophysiologic mechanism-damage to and redundancy of part of the corticopontine portion of the cerebellar circuit located in the corona radiata-respectively responsible for this condition and recovery. We also discuss how a simple noninvasive study of patients with ataxia and dysmetria secondary to corona radiata, thalamic, pontine, and possibly other brain lesions may be helpful in elucidating the contribution of pontocerebellar fibers and other structures to motor control. LEVEL OF EVIDENCE: V. PMID- 29425941 TI - "These African stories": Life, labor, and dying in northern Zambia. AB - This paper analyzes the effects of antiretroviral therapy (ART) on the social worlds of people living with HIV and ART (PLHA) in rural northern Zambia. Studies have demonstrated high rates of ART adherence over a range of sites in southern Africa. Drawing on a year of ethnographic research conducted in Zambia's Mukungule chiefdom between 2006 and 2008, this study investigates expectations of this exemplary adherence, and experiences of treatment failure. Motivated by the life and AIDS-related death of a Mukungule resident, Grace, it moves beyond asking "what made initial cohorts of African PLHA exceptionally adherent?" to raise the pressing question of "what happens next?" Previous scholarship addressing this question has analyzed how PLHA navigate the competing moral and political economies of local kinship and social networks and global HIV/AIDS initiatives. Scholars have emphasized the afterlives of access and adherence, looking beyond survival to what "the good life" means for PLHA, and placing PLHA at the center of action and analysis. This paper flips that script, by focusing on the stories that Grace's death spurred Mukungule residents to share. It shows how attention to and analysis of stories told not just about, but by members of PLHA's kinship and social networks, are critical to developing a more robust understanding of exemplary adherence and treatment failure. Such understanding critically depends on paying more attention to how those living with and caring for PLHA (and especially their families) facilitate PLHA's pursuit of good and "normal" lives - not just while, but also through, pursuing their own. PMID- 29425942 TI - The impact of economic growth on environmental efficiency of the electricity sector: A hybrid window DEA methodology for the USA. AB - This paper estimates the efficiency of the power generation sector in the USA by using Window Data Envelopment Analysis (W-DEA). We integrate radial and non radial efficiency measurements in DEA using the hybrid measure while we extend the proposed model by considering good and undesirable outputs as separable and non separable. Then in the second stage, we perform parametric and non-parametric econometric techniques in order to model the relationship between the calculated environmental efficiencies and economic growth in attaining sustainability. Our empirical findings indicate a stable N-shape relationship between environmental efficiency and regional economic growth in the case of global and total pollutants but an inverted N-shape in the case of local pollutants. This implies that attention is required when considering local and global pollutants and the extracted environmental efficiency scores. A clear message to policy makers and government officials is that climate change which calls for economic, environmental and social concern should be analyzed according to its dispersion and regional dimension. PMID- 29425943 TI - Chlorinated insecticides (toxaphene and endrin) affect oxytocin, testosterone, oestradiol and prostaglandin secretion from ovarian and uterine cells as well as myometrial contractions in cow in vitro. AB - We examined the direct effects of toxaphene and endrin, chlorinated insecticides that are widespread in the environment, on myometrial contractions and on the secretion of hormones involved in regulating these contractions. Granulosa, luteal, endometrial and myometrial cells, and myometrial strips from non-pregnant cows were incubated with both insecticides at environmentally relevant doses. Toxaphene inhibited and endrin stimulated the secretion of testosterone and oestradiol from granulosa cells. Toxaphene also inhibited and endrin stimulated the expression of the mRNA encoding the precursor of oxytocin (OT), as well OT secretion in luteal cell cultures. Moreover, endrin increased OT secretion from granulosa cells. Neither insecticide exerted an effect on progesterone secretion from luteal cells. Only toxaphene decreased the secretion of prostaglandins (PGF2 and PGE2) from endometrial cells. Meanwhile, only endrin decreased basal myometrial contractions, which was accompanied by inhibition of PGF2 secretion from the myometrium. Both endrin and toxaphene also decreased the force of the OT stimulated myometrial contractions, whereas only toxaphene inhibited the stimulatory effect of OT on the force of myometrial contractions. In contrast to endrin, toxaphene decreased synthesis and secretion of one of the primary stimulators of myometrial contractions (OT) and indirectly inhibited OT signal reception in the myometrium by reducing E2 secretion. Both insecticides decreased OT-stimulated myometrial contractions; therefore, they may inhibit further transmission of the OT signal. Moreover, endrin inhibited basal myometrial contractions, potentially resulting from reduced PGF2 secretion from the myometrium. Our data indicate the potential of these insecticides to disturb the course of the oestrous cycle or fertilisation. PMID- 29425944 TI - Interactions of perfluorooctanoic acid and perfluorooctanesulfonic acid with serum albumins by native mass spectrometry, fluorescence and molecular docking. AB - The binding information of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) with bovine and human serum albumins was investigated and characterized in details by using a combination method of electrospray ionization mass spectrometry (ESI-MS), fluorescence, circular dichroism (CD) and molecular docking (MD). The ESI-MS analysis revealed that maximally eight PFOA or PFOS molecules could bind to serum albumins at high mole ratios of PFOA/PFOS. Association constants were measured by ESI-MS and suggested that PFOS had a better binding affinity than PFOA. PFOA and PFOS were likely to bind with serum albumins in more than one pocket. The CD data demonstrated that binding of PFOA and PFOS could change the conformation of serum albumins with decreasing alpha-helix content, which may affect the protein physiological function. The phenomenon of protein fluorescence quenching by the binding of PFOA and PFOS indicated that the hydrophobic pocket proximate to Trp 214 in human serum albumin might be one of the dominated binding sites. This assumption was further confirmed by MD simulation. Consistent to ESI-MS observation, MD results also displayed a stronger binding affinity of PFOS than PFOA according to the calculated binding free energy, which is probably ascribed to one more hydrogen bond formed in the PFOS-bound protein complexes. PMID- 29425946 TI - Evaluation of carbon aerogel-based solid-phase extraction sorbent for the analysis of sulfur mustard degradation products in environmental water samples. AB - In this study, SPE method using a carbon aerogel(CA)-based sorbent was developed and evaluated for the simultaneous extraction of sulfur mustard (HD) degradation products from environmental water samples. Applied CAs proved to be very promising materials for use as SPE sorbents, due to their high porosity, very low density and a large specific surface area. 10 degradation products of HD, both aliphatic and cyclic (thiodiglycol (TDG), TDG sulfoxide, TDG sulfone, 3,5-dithia 1,7-heptanediol, 3,6-dithia-1,8-octanediol, 1,4-thioxane, 1,3-dithiolane, 1,4 dithiane, 1,2,5-trithiepane, and 1,4,5-oxadithiepane) were extracted on a CA based SPE cartridge. The concentrations of target analytes in the eluate were determined by HPLC-DAD and CE-DAD. Several parameters affecting the extraction efficiency, including the kind and volume of the eluting solvent, sample loading flow rate, volume and ionic strength as well as the reusability of the cartridge, were investigated and optimized to achieve the best performance for the analytes. A series of quantitative parameters such as linear range, coefficient of determination, LOD, LOQ and precision were examined under the optimized conditions. High sensitivity (LODs 0.17-0.50 MUM) and high precision (intraday RSD = 2.0-7.7% and interday RSD = 2.7-9.9%) for all the analytes were achieved. The performance of the CA-based sorbent was compared with that of commonly used SPE sorbents. Applied for the analysis of spiked pore water samples collected from the Bornholm Basin, one of the largest chemical warfare dumping sites in the Baltic Sea, the proposed method allowed high SPE recoveries of all the analytes ranging from 83.5 to 99.7% to be obtained. PMID- 29425945 TI - Bamboo- and pig-derived biochars reduce leaching losses of dibutyl phthalate, cadmium, and lead from co-contaminated soils. AB - Biochar effect on the potential mobility of dibutyl phthalate (DBP), cadmium (Cd), and lead (Pb) in co-contaminated soils is not well investigated. A laboratory leaching study was conducted to evaluate the effect of biochars derived from bamboo (BB) and pig (PB) on the leachability of DBP, Cd, and Pb through soil columns packed with two soils with low or high organic carbon content (LOC; 0.35% C: HOC; 2.24% C) and spiked with DBP, Cd, and Pb. Application of PB to the LOC soil significantly (P < 0.05) reduced the leaching loss by up to 88% for DBP, 38% for Cd, and 71% for Pb, whereas its impact was insignificant in the HOC soil. The higher efficacy of PB in reducing the leaching of DBP, Cd, and Pb in the LOC soil than that of BB might be related to PB's higher specific surface area, surface alkalinity, pH, and mineral contents compared to those of BB. Co-contamination of Cd and Pb enhanced leaching of DBP in the LOC soil treated with PB, possibly by competition for the sorption sites. Leaching of DBP, Cd, and Pb were significantly (P < 0.05) higher in the LOC soil than in the HOC soil. This study revealed that the effectiveness of biochars was dependent on the soil organic carbon content. Application of PB to the LOC soil was effective in reducing the leaching risk of DBP, Cd, and Pb. PMID- 29425947 TI - Galleria mellonella larvae allow the discrimination of toxic and non-toxic chemicals. AB - The acute toxicities of 19 chemicals were assessed using G. mellonella larvae. The results obtained were compared against LD50 values derived from in vitro cytotoxicity tests and against in vivo acute oral LD50 values. In general, cell culture systems overestimated the toxicity of chemicals, especially low toxicity chemicals. In contrast, toxicity testing in G. mellonella larvae was found to be a reliable predictor for low toxicity chemicals. For the 9 chemicals tested which were assigned to Globally Harmonised System (GHS) category 5, the toxicity measured in G. mellonella larvae was consistent with their GHS categorisation but cytotoxicity measured in 3T3 or NHK cells predicted 4 out of 9 chemicals as having low toxicity. A more robust assessment of the likely toxicity of chemicals in mammals could be made by taking into account their toxicities in both cell cultures and in G. mellonella larvae. PMID- 29425948 TI - A model assessment of the potential of river water to induce the photochemical attenuation of pharmaceuticals downstream of a wastewater treatment plant (Guadiana River, Badajoz, Spain). AB - We predicted the possible direct and indirect phototransformation kinetics of carbamazepine (CBZ), ibuprofen (IBU) and diclofenac (DIC) in river water, based on data of water chemistry obtained for the Guadiana River near Badajoz (Southwestern Spain) during a year-round sampling campaign. The three compounds were chosen, (i) because they occurred at the outlet of the wastewater treatment plant (WWTP) in Badajoz, as well as in river water sampled 1 km downstream of the WWTP, and (ii) because their photochemical fate in surface waters is known well enough to be modelled. The predicted phototransformation kinetics would be negligible in winter and fastest in April-August, with comparable rate constants in April through August despite differences in sunlight irradiance. Favourable water chemistry would in fact offset the lower irradiance, and vice versa. Half life times of at least three weeks - one month are predicted for CBZ and IBU. Photodegradation may be an important attenuation pathway for biorecalcitrant CBZ, while IBU photochemistry is unlikely to be competitive with other processes including biodegradation. The predicted DIC photochemical half-life times of 7-10 days in April-August would be comparable with the biodegradation kinetics data reported in the literature. Photochemistry might not induce extensive phototransformation of xenobiotics in the Guadiana River under normal flow conditions, but it could become important in the case of low flow produced by water scarcity. PMID- 29425949 TI - Net acidity indicates the whole effluent toxicity of pH and dissolved metals in metalliferous saline waters. AB - Measurements of potential acidity in water are used to manage aquatic toxicity risks of discharge from acid sulfate soils or acid mine drainage. Net acidity calculated from pH, dissolved metals and alkalinity is a common measurement of potential acidity but the relevance of current risk thresholds to aquatic organisms are unclear. Aquatic toxicity testing was carried out using four halophytic organisms with water from four saline sources in southern Western Australia (3 acidic drains and one alkaline river; 39-40 g TDS/L) where acidity was varied by adjusting pH to 4.5-6.5. The test species were brine shrimps (Artemia salina), locally sourced ostracods (Platycypris baueri), microalgae (Dunaliella salina) and amphipods (Allorchestes compressa). Testing found the EC10 and IC10 of net acidity ranged from -7.8 to 10.5 mg CaCO3/L with no survival or growth of any species at >47 mg CaCO3/L. Reduced net acidity indicated reduced whole effluent toxicity more reliably than increased pH alone with organisms tolerating pH up to 1.1 units lower in the absence of dissolved metals. Variation in toxicity indicated by net acidity was mostly attributed to reduced concentrations of dissolved Al and Fe combined with higher pH and alkalinity and some changes in speciation of Al and Fe with pH. These results indicate that rapid in-field assessments of net acidity in acidic, Al dominated waters may be an indicator of potential acute and sub-chronic impacts on aquatic organisms. PMID- 29425950 TI - Changes in perceived centrality of anxious events following cognitive behavioral therapy for social anxiety disorder and panic disorder. AB - BACKGROUND AND OBJECTIVE: The purpose of the present study was to explore the association between reductions in symptoms of psychopathology and perceived centrality of negative autobiographical memories in participants with social anxiety disorder (SAD) or panic disorder (PD). METHODS: Thirty-nine individuals with SAD or PD recalled and rated four negative autobiographical memories before and after ten sessions of cognitive behavioral therapy (CBT) over a three-month period. Twenty-eight healthy controls did the same before and after a three-month period. RESULTS: As hypothesized, results showed a decrease in perceived centrality following CBT. This decrease in perceived centrality was larger, although at the trend level, for individuals who experienced reliable change on disorder-specific symptoms. LIMITATIONS: The correlational nature of the study prevents establishing the causal relationship between changes in perceived centrality and psychopathology, and future studies should explore such mechanisms. CONCLUSIONS: The present study adds to the emerging body of literature, investigating changes in centrality of event following psychotherapy. PMID- 29425951 TI - A novel approach to challenging OCD related beliefs using a mobile-app: An exploratory study. AB - BACKGROUND AND OBJECTIVES: According to cognitive models, obsessive compulsive symptoms result from catastrophic misinterpretations of commonly occurring intrusive experiences and the use of counterproductive strategies to manage them. Obsessive Compulsive Disorder (OCD) related beliefs such as inflated responsibility, importance of thoughts and perfectionism increases the likelihood of such misinterpretations. Consistent with a growing body of literature supporting the usefulness of mobile delivered technologies in fostering cognitive behavior change, the present study assessed the effectiveness of a novel cognitive training exercise designed to challenge OCD-related beliefs. This mobile app training exercise consists of users having to pull statements challenging OCD beliefs towards themselves (downwards) and to throw away (push upwards) contra-productive self-statements. METHODS: 36 third-year BA students started the trial. Twenty completed pre and post measures of OCD-beliefs, mood and OCD symptoms including relationship-obsessions. Participants were instructed to complete 3 min of daily training for a period of 15 days. RESULTS: No significant differences were found between completers and non-completers on demographic and most symptom related measures at Time 1. Repeated-measures MANOVA of the 20 completers showed a significant reduction on all OCD symptoms measures and on OCD-beliefs. No significant reduction was found in depression symptoms. Regression analysis showed change in levels of OCD-beliefs was associated with reduction in OCD symptoms at Time 2 over and above OCD symptoms at Time 1. LIMITATIONS: The study is an open trial with non-clinical participants. CONCLUSIONS: This mobile delivered training exercise may be useful for the reduction and relapse prevention of OCD-related beliefs and symptoms. PMID- 29425952 TI - Safety of Therapeutic Fever Induction in Cancer Patients Using Approved PAMP Drugs. AB - William Coley, between 1895 and 1936, treated hundreds of cancer patients using infusions of fever inducing bacerial extracts. Similar experiments were done by Klyuyeva and co-workers in the 1940ies in Russia using trypanosoma extracts. Many remissions and cures were reported. We have conjectured that pathogen associated molecular pattern substances (PAMP) are the molecular explanation for the beneficial treatments in both groups. We could show that a combination of PAMP can eradicate solid tumours in cancer mice if applied several times. Accordingly, we suggested to combine PAMP containing approved drugs to treat cancer patients using a protocol similar to the old fever induction regimen. In this retrospective phase-1 study we report on the fever induction capacity and safety of applications of bacterial extracts, combinations of bacterial extracts with approved drugs, and combinations of approved drugs in 131 mainly cancer patients. Adverse reactions were those which can be expected during a feverish infection and mild. Over 523 fever inductions, no severe adverse reaction was observed. PMID- 29425953 TI - Efficacy and Safety of Nimotuzumab Plus Radiotherapy With or Without Cisplatin Based Chemotherapy in an Elderly Patient Subgroup (Aged 60 and Older) With Nasopharyngeal Carcinoma. AB - OBJECTIVE: This study was conducted to assess the efficacy and safety of nimotuzumab combined with radiotherapy (RT) in elderly patients with nasopharyngeal carcinoma. MATERIALS AND METHODS: The clinical data of 75 nasopharyngeal carcinoma patients, who were initially treated with nimotuzumab combined with RT, were collected and retrospectively reviewed from December 2008 to April 2014. They were aged 60 to 81 years (median 64 years). The distribution of disease was stage II in 10 (13.3%), stage III in 33 (44.0%), and stage IV in 32 (42.7%). Among these patients, 59 cases received cisplatin-based chemotherapy. Survival outcomes and treatment toxicity were analyzed using IBM SPSS 19.0 software. RESULTS: With a median follow-up of 45 months (range, 13-78 months), the estimated 3-year local recurrence-free survival (LRFS), regional recurrence free survival (RRFS), distant metastasis-free survival (DMFS), progression failure-free survival (PFS), and overall survival (OS) rates were 95.6%, 95.5%, 98.6%, 89.7%, and 89.2%, respectively. In the subgroup, 3-year OS rate in the patients with concurrent chemotherapy was 90.5% and 77.4% in patients without concurrent chemotherapy (Log-Rank = 1.795, P = .180). Univariate analysis showed that T stage and clinical stage were correlated with OS. Multivariate analysis indicated that age, T stage and tumor response at the end of treatment were independent prognosticators. Nine patients experienced grade 3 to 4 acute mucositis and 26 patients experienced grade 3-4 leukocytopenia, with no cases of skin rash and infusion reaction. Twelve patients developed mild liver function damage. No serious gastrointestinal or renal toxicities were observed. CONCLUSION: The efficacy of combined nimotuzumab with RT in elderly NPC patients was encouraging and the toxicities were accepted. In addition, nimotuzumab provides a better option for elderly patients who cannot be tolerate chemotherapy. PMID- 29425954 TI - Slit pores preferred over cylindrical pores for high selectivity in biomolecular filtration. AB - Microelectromechanical systems (MEMS) have enabled the fabrication of silicon nanopore membranes (SNM) with uniform non-overlapping "slit shaped" pores. The application of SNM has been suggested for high selectivity of biomolecules in a variety of medical filtration applications. The aim of this study was to rigorously quantify the differences in sieving between slit pore SNM and more commonly modeled cylindrical pore membranes, including effects of the extended Derjaguin, Landau, Verwey, and Overbeek (XDLVO) interactions. Applying equations derived for SNM in previous work, we compare the partition coefficient of slit and cylindrical pore membranes while accounting for both steric and XDLVO interactions. Simple, steric approximations demonstrate that slit pore membranes exhibit significantly lower partition coefficients than cylindrical pore models. Incorporating XDLVO interactions results in an even more marked difference between slit pore and cylindrical pore membranes. These partition coefficients were used to evaluate changes in beta-2-microglobulin (B2M) selectivity. The data demonstrate that XDLVO interactions increase the selectivity advantage that slit pores possess over cylindrical pores, particularly for larger values of the acid base decay constant. Finally, the bovine serum albumin (BSA) to B2M selectivity ratio was investigated. The selectivity ratio appears larger in slit pores than cylindrical pores for all cases, indicating that slit pores are particularly well suited for hemofiltration applications. The results of this study have significant implications for the application of SNM in membrane processes where highly selective separation of biomolecules is desirable. PMID- 29425955 TI - Ionic liquids gels: Soft materials for environmental remediation. AB - HYPOTHESIS: Nanostructured sorbents and, in particular, supramolecular gels are emerging as efficient materials for the removal of toxic contaminants from water, like industrial dyes. It is also known that ionic liquids can dissolve significant amounts of dyes. Consequently, supramolecular ionic liquids gels could be highly efficient sorbents for dyes removal. This would also contribute to overcome the drawbacks associated with dye removal by liquid-liquid extraction with neat ionic liquids which would require large volumes of extractant and a more difficult separation of the phases. EXPERIMENTS: Herein we employed novel supramolecular ionic liquid gels based on diimidazolium salts bearing naturally occurring or biomass derived anions, to adsorb cationic and anionic dyes from wastewaters. We also carried out a detailed investigation of thermal, structural, morphological and rheological features of our gels to identify which of them are key in designing better sorbents for environmental remediation. FINDINGS: The most effective gels showed fast and thorough removal of cationic dyes like Rhodamine B. These gels could also be reused up to 20 times without any loss in removal efficiency. Overall, our ionic gels outperform most of gel-based sorbents systems so far reported in literature. PMID- 29425956 TI - Magnetic properties and photovoltaic applications of ZnO:Mn nanocrystals. AB - A simple and large-scale synthetic method of Mn doped ZnO (ZnO:Mn) was developed in this work. ZnO:Mn nanocrystals with hexagonal structure were prepared by thermal decomposition of zinc acetate and manganese acetate in the presence of oleylamine and oleic acid with different temperatures, ligand ratios, and Mn doping concentrations. The particle size (47-375 nm) and morphology (hexagonal nanopyramid, hexagonal nanodisk and irregular nanospheres) of ZnO:Mn nanocrystals can be controlled by the ratio of capping ligand, reaction temperature, reaction time and Mn doping concentration. The corresponding optical and magnetic properties were systemically studied and compared. All samples were found to be paramagnetic with antiferromagnetic (AFM) exchange interactions between the Mn moments in the ZnO lattice, which can be affected by the reaction conditions. The quantum dot sensitized solar cells (QDSSCs) were fabricated based on ZnO:Mn nanocrystals and CdS quantum dots, and the device performance affected by Mn doping concentration was also studied and compared. PMID- 29425957 TI - An assessment of polyurethane foam passive samplers for atmospheric metals compared with active samplers. AB - In this study, we conducted an assessment of polyurethane foam (PUF) passive sampling for metals combining active sampling. Remarkably, we found that the metals collected in the passive samples differed greatly from those collected in active samples. By composition, Cu and Ni accounted for significantly higher proportions in passive samples than in active samples, leading to significantly higher uptake rates of Cu and Ni. In assessing seasonal variation, metals in passive samples had higher concentrations in summer (excluding Heshan), which differed greatly from the pattern of active samples (winter > summer), indicating that the uptake rates of most metals were higher in summer than in winter. Overall, due to the stable passive uptake rates, we considered that PUF passive samplers can be applied to collect atmospheric metals. Additionally, we created a snapshot of the metal pollution in the Pearl River Delta using principal component analysis of PUF samples and their source apportionment. PMID- 29425958 TI - Difference in sensitivities of blood HDL cholesterol and LDL cholesterol levels to alcohol in middle-aged Japanese men. AB - Blood HDL cholesterol and LDL cholesterol levels are known to be higher and lower, respectively, in drinkers than in nondrinkers, and the beneficial effects of alcohol on cholesterol metabolism are thought to mainly explain the lower risk for ischemic heart disease in light-to-moderate drinkers than in nondrinkers. However, it remains unknown whether sensitivities of HDL and LDL cholesterol levels to alcohol are different or not. The subjects of this study were 21,572 middle-aged Japanese men, and they were divided into three tertile groups for blood HDL cholesterol levels. The relationships between habitual alcohol intake and LDL cholesterol levels were investigated in each tertile for HDL cholesterol. In all of the tertile groups for HDL cholesterol, mean LDL cholesterol levels were significantly lower in the drinking subgroups than in the nondrinking subgroup and tended to be lower with an increase of alcohol intake. In all of the tertile groups for HDL cholesterol, odds ratios for high LDL cholesterol of each drinking subgroup vs. the nondrinking subgroup were significantly lower than the reference level of 1.00, and also tended to be lower with an increase of alcohol intake. The odds ratios of each drinking subgroup tended to be lower in the 1st tertile group for HDL cholesterol than in the 3rd tertile group. Drinkers in the 1st tertile for HDL cholesterol are thought to have relatively low sensitivity of HDL cholesterol to alcohol, but clearly showed lower LDL cholesterol levels than those found in nondrinkers. Therefore, the sensitivity of LDL cholesterol level to alcohol is different from the sensitivity of HDL cholesterol level to alcohol. PMID- 29425960 TI - Quercetin decreases the activity of matrix metalloproteinase-2 and ameliorates vascular remodeling in renovascular hypertension. AB - BACKGROUND AND AIMS: Increased activity of matrix metalloproteinase (MMP)-2 is observed in aortas of different models of hypertension, and its activation is directly mediated by oxidative stress. As quercetin is an important flavonoid with significant antioxidant effects, the hypothesis here is that quercetin will reduce increased MMP-2 activity by decreasing oxidative stress in aortas of hypertensive rats and then ameliorate hypertension-induced vascular remodeling. METHODS: Male two-kidney one-clip (2K1C) hypertensive Wistar rats and controls were treated with quercetin (10 mg/kg/day) or its vehicle for three weeks by gavage. Rats were then analyzed at five weeks of hypertension. Systolic blood pressure (SBP) was determined by tail-cuff plethysmography. Aortas were used to determine MMP activity by in situ zymography and reactive oxygen species (ROS) levels by dihydroethidium. Western blot was performed to detect focal adhesion kinase (FAK) and phosphorylated-FAK levels. RESULTS: SBP was increased in 2K1C rats and only a borderline reduction in SBP was observed after treating 2K1C rats with quercetin. Cross-sectional area and the number of vascular smooth muscle cells were significantly increased in aortas of hypertensive rats, and quercetin reduced them. Quercetin reduced ROS levels in aortas of 2K1C rats and the increased activity of gelatinases in situ. However, quercetin did not affect the levels of tissue inhibitor of MMP (TIMP)-2 and did not interfere with FAK and p FAK levels in aortas of hypertensive rats. Furthermore, different concentrations of quercetin did not directly reduce the activity of human recombinant MMP-2 in vitro. CONCLUSIONS: Quercetin reduces hypertension-induced vascular remodeling, oxidative stress and MMP-2 activity in aortas. PMID- 29425959 TI - Imaging mass spectrometry of frontal white matter lipid changes in human alcoholics. AB - BACKGROUND: Chronic alcohol use disorders (AUD) are associated with white matter (WM) degeneration with altered myelin integrity. Matrix assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) enables high throughput analysis of myelin lipid biochemical histopathology to help characterize disease mechanisms. PURPOSE: This study utilized MALDI-IMS to investigate frontal lobe WM myelin lipid abnormalities in AUD. METHODS: Standardized cores of formalin-fixed WM from Brodmann Area 4 (BA4) and BA8/9 of 20 postmortem AUD and 19 control adult human brains were embedded in carboxymethyl-cellulose, cryo-sectioned (8 MUm), thaw-mounted onto indium tin oxide (ITO) -coated glass slides, and sublimed with 2,5-dihydroxybenzxoic acid (DHB) matrix. Lipids were imaged by MALDI-time of flight in the negative ionization mode. Data were visualized with FlexImaging software v4.0 and analyzed with ClinProTools v3.0. RESULTS: Principal component analysis (PCA) and data bar plots of MALDI-IMS data differentiated AUD from control WM. The dominant effect of AUD was to broadly reduce expression of sphingolipids (sulfatides and ceramides) and phospholipids. Data bar plots demonstrated overall similar responses to AUD in BA4 and BA8/9. However, differential regional effects of AUD on WM lipid profiles were manifested by non overlapping expression or discordant responses to AUD for a subset of lipid ions. CONCLUSIONS: Human AUD is associated with substantial inhibition of frontal lobe WM lipid expression with regional variability in these effects. MALDI-IMS can be used to characterize the nature of AUD-associated lipid biochemical abnormalities for correlation with lifetime exposures and WM degeneration, altered gene expression, and responses to abstinence or treatment. PMID- 29425961 TI - Risk of acute coronary syndrome and peripheral arterial disease in chronic liver disease and cirrhosis: A nationwide population-based study. AB - BACKGROUND & AIMS: Until now, no study has investigated the risks of acute coronary syndrome (ACS) and peripheral arterial disease (PAD) in cirrhosis. METHODS: In this study, 57,214 patients diagnosed with cirrhosis between 2000 and 2010 were identified from the Taiwan National Health Insurance claims data. Each patient was randomly selected and frequency-matched with an individual without cirrhosis by age, sex, and index year. RESULTS: The overall incidence rates of ACS and PAD were 2.81 and 2.97 per 1000 person-years, respectively, in the cirrhosis cohort. The cirrhosis cohort had a higher risk of ACS [adjusted subhazard ratio (aSHR) = 1.12, 95% confidence interval (CI) = 1.03-1.22] and PAD (aSHR = 1.11, 95% CI = 1.02-1.21). The risk of ACS was highest among members of the cirrhosis cohort with ascites (aSHR = 1.09, 95% CI = 1.11-1.19). CONCLUSIONS: Patients with chronic liver disease and cirrhosis have higher risks of ACS and PAD than those without chronic liver disease and cirrhosis. PMID- 29425962 TI - Identification of chronic myeloid leukemia patients treated with imatinib who are potentially eligible for treatment discontinuation by assessing real-life molecular responses on the international scale in a EUTOS-certified lab. AB - A retrospective study was performed to describe molecular responses (MR) on the international scale (IS) in patients with chronic myeloid leukemia (CML) treated with imatinib in routine clinical practice in Belgium and to identify patients potentially eligible for treatment discontinuation. The analysis included 116 patients with CML in chronic phase at treatment centers sending blood samples for molecular follow-up to a single EUTOS-certified laboratory. IS MR from the last patient visit between October 2014 and April 2015 were retrospectively collected. Most patients (93.1%) had an IS MR corresponding to an optimal response per European LeukemiaNet 2013 guidelines; 53.4% (62/116) of patients were in deep molecular responses >=MR4.5 at their last visit (mean treatment duration: 91.0 months) among whom 36.2% (42/116) had been receiving imatinib for >5.8 years and 26.7% (31/116) for >8 years (margins of error: 8.74% and 8.05%, respectively). These patients would likely have the highest chance of staying in treatment-free remission (TFR) upon discontinuation, based on published TFR trial data. Although our study only provides a snapshot in time of a patient's last MR reported, without precise information regarding MR duration, the study settings could nevertheless support the feasibility of attempting TFR outside clinical trials in the future. PMID- 29425963 TI - Sox9 knockout mice have improved recovery following stroke. AB - The partial recovery that can occur after a stroke has been attributed to structural and functional plasticity that compensate for damage and lost functions. This plasticity is thought to be limited in part by the presence of growth inhibitors in the central nervous system. Blocking or reducing signals from inhibitors of axonal sprouting such as Nogo and chondroitin sulfate proteoglycans (CSPGs) increases post-stroke axonal sprouting and improves recovery. We previously identified the transcription factor SOX9 as a key up regulator of CSPG production and demonstrated that conditional Sox9 ablation leads to increased axonal sprouting and improved recovery after spinal cord injury. In the present study we evaluate the effect of conditional Sox9 ablation in a transient middle cerebral artery occlusion (MCAO) model of stroke. We demonstrate that conditional Sox9 ablation leads to reduced CSPG levels, increased tissue sparing and improved post-stroke neurological recovery. Anterograde tract tracing studies demonstrate that in the Sox9 conditional knockout mice corticorubral and corticospinal projections from the contralateral, uninjured cortex increase projections to targets in the midbrain and spinal cord denervated by the injury. These results suggest that targeting SOX9 is a viable strategy to promote reparative axonal sprouting, neuroprotection and recovery after stroke. PMID- 29425964 TI - Alterations of L-type voltage dependent calcium channel alpha 1 subunit in the hippocampal CA3 region during and after pilocarpine-induced epilepsy. AB - Voltage-dependent calcium channels (VDCC) have been shown to regulate neuronal excitability and their antagonists have been used clinically for the control of seizures. While functional studies of VDCC in epileptogenesis in the CA1 area of hippocampus or the dentate gyrus have been done, few studies were carried out in the CA3 area. Given the bursting characteristics of the CA3 neurons, we speculated that VDCC in the CA3 area might play an important role in the epileptogenesis. In the present study in the mouse pilocarpine model of temporal lobe epilepsy, we investigated the alterations of alpha 1 subunits of L-type VDCC in the CA3 area of the hippocampus at different stages of epileptogenesis, i.e., acute stage from 10 min to 1 day during and after pilocapine-induced status epilepticus (SE), latent period at 1 week, and chronic stage with spontaneous recurrent seizures at 2 months after SE. We found that an immediate redistribution of alpha 1 subunits in the CA3 area occurred during SE which might be involved in the seizure occurrence indicated by the Racine score record. Alterations of alpha 1 subunits were also demonstrated in the latent period and chronic stage, which might be related to the epileptogenesis and occurrence of epilepsy. Cav1.3, but not Cav1.2, was expressed in reactive astrocytes of the CA3 area, indicating the involvement of Cav1.3 in the modulation of astrocytic Ca2+ homeostasis during epileptogenesis. PMID- 29425965 TI - The small heat shock proteins, especially HspB4 and HspB5 are promising protectants in neurodegenerative diseases. AB - Small heat shock proteins (sHsps) are a group of proteins with molecular mass between 12 and 43 kDa. Currently, 11 members of this family have been classified, namely HspB1 to HspB11. HspB1, HspB2, HspB5, HspB6, HspB7, and HspB8, which are expressed in brain have been observed to be related to the pathology of neurodegenerative diseases, including Parkinson's, Alzheimer's, Alexander's disease, multiple sclerosis, and human immunodeficiency virus-associated dementia. Specifically, sHsps interact with misfolding and damaging protein aggregates, like Glial fibrillary acidic protein in AxD, beta-amyloid peptides aggregates in Alzheimer's disease, Superoxide dismutase 1 in Amyotrophic lateral sclerosis and cytosine-adenine-guanine/polyglutamine (CAG/PolyQ) in Huntington's disease, Spinocerebellar ataxia type 3, Spinal-bulbar muscular atrophy, to reduce the toxicity or increase the clearance of these protein aggregates. The degree of HspB4 expression in brain is still debated. For neuroprotective mechanisms, sHsps attenuate mitochondrial dysfunctions, reduce accumulation of misfolded proteins, block oxidative/nitrosative stress, and minimize neuronal apoptosis and neuroinflammation, which are molecular mechanisms commonly accepted to mirror the progression and development of neurodegenerative diseases. The increasing incidence of the neurodegenerative diseases enhanced search for effective approaches to rescue neural tissue from degeneration with minimal side effects. sHsps have been found to exert neuroprotective functions. HspB5 has been emphasized to reduce the paralysis in a mouse model of experimental autoimmune encephalomyelitis, providing a therapeutic basis for the disease. In this review, we discuss the current understanding of the properties and the mechanisms of protection orchestrated by sHsps in the nervous system, highlighting the promising therapeutic role of sHsps in neurodegenerative diseases. PMID- 29425966 TI - Genotype assembly, biological activity and adaptation of spatially separated isolates of Spodoptera litura nucleopolyhedrovirus. AB - The cotton leafworm Spodoptera litura is a polyphagous insect. It has recently made a comeback as a primary insect pest of cotton in Pakistan due to reductions in pesticide use on the advent of genetically modified cotton, resistant to Helicoverpa armigera. Spodoptera litura nucleopolyhedrovirus (SpltNPV) infects S. litura and is recognized as a potential candidate to control this insect. Twenty two NPV isolates were collected from S. litura from different agro-ecological zones (with collection sites up to 600 km apart) and cropping systems in Pakistan to see whether there is spatial dispersal and adaptation of the virus and/or adaptation to crops. Therefore, the genetic make-up and biological activity of these isolates was measured. Among the SpltNPV isolates tested for speed of kill in 3rd instar larvae of S. litura, TAX1, SFD1, SFD2 and GRW1 were significantly faster killing isolates than other Pakistani isolates. Restriction fragment length analysis of the DNA showed that the Pakistan SpltNPV isolates are all variants of a single SpltNPV biotype. The isolates could be grouped into three genogroups (A-C). The speed of kill of genogroup A viruses was higher than in group C according to a Cox' proportional hazards analysis. Sequence analysis showed that the Pakistan SpltNPV isolates are more closely related to each other than to the SpltNPV type species G2 (Pang et al., 2001). This suggests a single introduction of SpltNPV into Pakistan. The SpltNPV-PAK isolates are distinct from Spodoptera littoralis nucleopolyhedrovirus. There was a strong correlation between geographic spread and the genetic variation of SpltNPV, and a marginally significant correlation between the latter and the cropping system. The faster killing isolates may be good candidates for biological control of S. litura in Pakistan. PMID- 29425967 TI - Combined use of the entomopathogenic fungus, Metarhizium brunneum, and the mosquito predator, Toxorhynchites brevipalpis, for control of mosquito larvae: Is this a risky biocontrol strategy? AB - Mosquitoes transmit several diseases, which are of global significance (malaria, dengue, yellow fever, Zika). The geographic range of mosquitoes is increasing due to climate change, tourism and trade. Both conidial and blastospore formulations of the entomopathogenic fungus, Metarhizium brunneum ARSEF 4556, are being investigated as mosquito larvicides. However, concerns have been raised over possible non-target impacts to arthropod mosquito predators such as larvae of Toxorhynchites brevipalpis which feed on larvae of mosquito vector species. Laboratory-based, small container bioassays showed, that T. bevipalpis larvae are susceptible to relatively high concentrations (i.e. >=107 spores ml-1) of inoculum with blastospores being significantly more virulent than conidia. At lower concentrations (e.g. <107 spores ml-1), it appears that M. brunneum complements T. brevipalpis resulting in higher control than if either agent was used alone. At a concentration of 105 spores ml-1, the LT50 of for conidia and blastospores alone was 5.64 days (95% CI: 4.79-6.49 days) and 3.89 days (95% CI: 3.53-4.25 days), respectively. In combination with T. brevipalpis, this was reduced to 3.15 days (95% CI: 2.82-3.48 days) and 2.82 days (95% CI: 2.55-3.08 days). Here, combined treatment with the fungus and predator was beneficial but weaker than additive. At 107 and 108 blastospores ml-1, mosquito larval mortality was mostly due to the fungal pathogen when the predator was combined with blastospores. However, with conidia, the effects of combined treatment were additive/synergistic at these high concentrations. Optimisation of fungal concentration and formulation will reduce: (1) risk to the predator and (2) application rates and costs of M. brunneum for control of mosquito larvae. PMID- 29425968 TI - Characterization of calcium signals in human induced pluripotent stem cell derived dentate gyrus neuronal progenitors and mature neurons, stably expressing an advanced calcium indicator protein. AB - Pluripotent stem cell derived human neuronal progenitor cells (hPSC-NPCs) and their mature neuronal cell culture derivatives may efficiently be used for central nervous system (CNS) drug screening, including the investigation of ligand-induced calcium signalization. We have established hippocampal NPC cultures derived from human induced PSCs, which were previously generated by non integrating Sendai virus reprogramming. Using established protocols these NPCs were differentiated into hippocampal dentate gyrus neurons. In order to study calcium signaling without the need of dye loading, we have stably expressed an advanced calcium indicator protein (GCaMP6fast) in the NPCs using the Sleeping Beauty transposon system. We observed no significant effects of the long-term GCaMP6 expression on NPC morphology, gene expression pattern or neural differentiation capacity. In order to compare the functional properties of GCaMP6 expressing neural cells and the corresponding parental cells loaded with calcium indicator dye Fluo-4, a detailed characterization of calcium signals was performed. We found that the calcium signals induced by ATP, glutamate, LPA, or proteases - were similar in these two systems. Moreover, the presence of the calcium indicator protein allowed for a sensitive, repeatable detection of changes in calcium signaling during the process of neurogenesis and neuronal maturation. PMID- 29425969 TI - Fast and robust segmentation of white blood cell images by self-supervised learning. AB - A fast and accurate white blood cell (WBC) segmentation remains a challenging task, as different WBCs vary significantly in color and shape due to cell type differences, staining technique variations and the adhesion between the WBC and red blood cells. In this paper, a self-supervised learning approach, consisting of unsupervised initial segmentation and supervised segmentation refinement, is presented. The first module extracts the overall foreground region from the cell image by K-means clustering, and then generates a coarse WBC region by touching cell splitting based on concavity analysis. The second module further uses the coarse segmentation result of the first module as automatic labels to actively train a support vector machine (SVM) classifier. Then, the trained SVM classifier is further used to classify each pixel of the image and achieve a more accurate segmentation result. To improve its segmentation accuracy, median color features representing the topological structure and a new weak edge enhancement operator (WEEO) handling fuzzy boundary are introduced. To further reduce its time cost, an efficient cluster sampling strategy is also proposed. We tested the proposed approach with two blood cell image datasets obtained under various imaging and staining conditions. The experiment results show that our approach has a superior performance of accuracy and time cost on both datasets. PMID- 29425970 TI - The therapeutic potential of cystathionine gamma-lyase in temporomandibular inflammation-induced orofacial hypernociception. AB - Hydrogen sulfide (H2S) is an endogenous neuromodulator produced mainly by the enzyme cystathionine gamma-lyase (CSE) in peripheral tissues. A pronociceptive role of endogenously produced H2S has been previously reported by our group in a model of orofacial inflammatory pain. Using the established persistent orofacial pain rat model induced by complete Freund's adjuvant (CFA) injection into temporomandibular joint (TMJ), we have now investigated the putative role of endogenous H2S modulating hypernociceptive responses. Additionally, plasmatic extravasation on TMJ was measured following different treatments by Evans blue dye quantification. Thus, rats were submitted to Von Frey and Formalin tests in orofacial region before and after pharmacological inhibition of the CSE-H2S system combined or not with CFA-induced TMJ inflammation. Pretreatment with CSE inhibitor, propargylglycine (PAG; 88.4 MUmol/kg) reduced temporomandibular inflammatory pain when injected locally as well as systemically. In particular, local PAG injection seems to be more effective for hypernociceptive responses in orofacial persistent inflammation since its action is evidenced in the majority analyzed periods of the inflammatory process compared to its systemic use. Moreover, local injection seems to act on temporomandibular vascular permeability, evidenced by decreased plasmatic extravasation induced by local PAG administration. Our data are consistent with the notion that the endogenous synthetized gas H2S modulates persistent orofacial pain responses revealing the pharmacological importance of the CSE inhibitor as a possible therapeutic target for their control. PMID- 29425971 TI - Competition stage influences perceived performance but does not affect rating of perceived exertion and salivary neuro-endocrine-immune markers in elite young basketball players. AB - This study examined the effects of competition stage on the salivary concentration of testosterone (T), cortisol (C), alpha-amylase (sAA), and IL 1beta cytokine, perceived performance (PP) and session rating of perceived exertion (session-RPE) in elite youth basketball players (age, 15.8 +/- 0.8 yrs.; stature, 190.9 +/- 7.9 cm; body mass, 90.0 +/- 16.9 kg) from two age-categories (U16; n = 7; U17; n = 7). Two winning playoff matches (FM; playing for the championship; 1 for each age-category) and two winning regular stage matches (RM; 1 for each age category, played against opponents ranked 2nd place), were assessed in the current study. Saliva samples were collected before and after each match and analyzed by ELISA; PP and session-RPE were assessed after each match. The results from the two-way ANOVA (condition; FM and RM) with repeated measures (pre-and post-matches) showed a significant effect for time (increase from pre-to-post matches) in T (F = 7.0, p < .001), C (F = 34.0, p < .001), and sAA (F = 25.0, p < .001), but not for IL-1beta (p > .05). No effect of condition or interaction (FM and RM) was observed on salivary markers. PP was higher for FM, compared to RM (effect size; ES = 0.85), despite no clear difference in session-RPE (ES = 0.22). A higher PP for FM might be associated with the fact that players were no longer concerned about issues linked to social dominance and status threats after FM, but they might be uncertain about their status after RM. Additionally, when playing against a high-level opponent, the players might perceive their opponent as a threat against status stability, regardless of the stage of the competition, which might explain the similar change in salivary neuro-endocrine-immune-related markers. PMID- 29425972 TI - A longitudinal analysis of salivary testosterone concentrations and competitiveness in elite and non-elite women athletes. AB - BACKGROUND: There is evidence linking women's testosterone (T) to competitive behaviours in sport and exercise. To advance this work, we examined the longitudinal relationships between salivary T (sal-T) and competitiveness in athletic women who differ in training status. METHODS: Elite (n = 9) and non elite (n = 21) women athletes were monitored on days 6-8 (follicular phase), 13 15 (ovulatory phase) and 20-22 (Luteal phase) of a menstrual cycle with two repeats. Salivary T levels were assessed before breakfast, followed by two questions (each rated on a 1-7 scale) on competitive desire and training motivation. Using a linear mixed model, we evaluated the menstrual phase and training status effects on each variable, before assessing the within-subject effects of sal-T on competitiveness. RESULTS: Salivary T concentrations were higher at ovulation (effect size [ES] difference = 0.2-1.4), relative to the follicular and luteal phases, with a more marked response among elite women (p < .01). The competitiveness ratings showed similar menstrual-phase variation (ES difference = 0.6-1.0 at ovulation). A positive effect of sal-T on competitiveness emerged in both groups (p < .001), but with different slope patterns (p < .015). Specifically, the elite sal-T relationships with desire to compete (standardized beta = 1.147, SE = 0.132) and training motivation (beta = 1.195, SE = 0.124) were stronger compared with non-elite women (beta = 0.631, SE = 0.114; beta = 0.778, SE = 0.114), respectively. CONCLUSIONS: Morning sal-T concentrations, competitive desire and training motivation all peaked around ovulation in women athletes. Notably, sal-T availability and its relationship with competitiveness was stronger among high-performing athletes. Our findings confirm menstrual fluctuations in T and competitiveness among naturally-cycling women, with population context as a moderating factor. PMID- 29425973 TI - Metabolic and cognitive improvement from switching to saccharin or water following chronic consumption by female rats of 10% sucrose solution. AB - High consumption of sugar-sweetened beverages (SSBs) is a risk factor for weight gain and metabolic disease. Whether this risk is reduced by switching to 'diet' beverages containing low-calorie sweeteners (LCS) is controversial. Two experiments modeled whether a switch from SSB to LCS beverages produced positive outcomes on behavioral and metabolic measures. Both experiments consisted of a Stage 1, in which adult female rats received unrestricted access to 10% sucrose solution in addition to chow and water for 4 (Experiment 1) or 8 weeks (Experiment 2). In Stage 2 rats were switched to either saccharin (Suc-Sacch) or water (Suc-Water) or remained on 10% sucrose (Suc-Suc) for a further 4 (Experiment 1) or 7 weeks (Experiment 2). Experiment 2 contained a fourth group that was maintained on water throughout (Water-Water). In both experiments energy intake and weight gain in Stage 2 was reduced for Suc-Sacch and Suc-Water groups relative to the Suc-Suc groups and at cull the Suc-Suc groups showed poorer insulin sensitivity and greater g/kg fat than Suc-Water and Suc-Sacch groups. In Experiment 2 short-term place recognition memory was impaired at the end of Stage 1 but recovered to a similar extent in the Suc-Water and Suc-Sacch groups; when the latter groups were compared with the Water-Water group, recovery was found to be essentially complete. A higher saccharin concentration in Experiment 2 than in Experiment 1 increased absolute amounts of saccharin ingested but intake solution volumes remained low. These results show that switching from sucrose to either water or saccharin produces equivalent improvements on both metabolic and cognitive measures. PMID- 29425974 TI - Propensity scores - A brief introduction for resuscitation researchers. AB - Propensity scores are commonly used in observational research. This article provides a brief introduction to propensity scores aimed for resuscitation researchers. We discuss the concept and calculation of the propensity score and how it can be used to adjust for confounding via regression adjustment, stratification, weighting or matching. The interpretation of these method is briefly discussed and the advantages and limitations of propensity scores are presented. Lastly, we provide some practical recommendations for the presentation of studies using propensity scores. PMID- 29425975 TI - "Resuscitation time bias"-A unique challenge for observational cardiac arrest research. AB - Observational studies are prone to a number of biases. One of these is immortal time bias. In this manuscript, we discuss immortal time bias as it pertains to post-cardiac arrest research and describes a related bias which we term "resuscitation time bias". This bias can occur when studying exposures during cardiac arrest. In this unique situation, an exposure is more likely to occur the longer the cardiac arrest continues. Since length of resuscitation is strongly associated with worse outcome, this will bias the results toward a harmful effect of the exposure. We discuss this bias and present methods to account for it. PMID- 29425976 TI - Non-invasive characterization of hemodynamics in adult out-of-hospital cardiac arrest patients soon after return of spontaneous circulation. AB - BACKGROUND: Little is known about hemodynamics in adult, out-of-hospital (OHCA) patients following return of spontaneous circulation (ROSC). A 1994 study when "high-dose epinephrine" use was common showed consistently elevated systemic vascular resistance (SVR) lasting >=6 h in 49 adult patients after return of spontaneous circulation (ROSC). STUDY AIM: To characterize hemodynamic abnormalities in adult OHCA patients soon after ROSC. Our hypothesis was that, unlike the consistently high SVR values reported when "high-dose" epinephrine was in common use, there would be a more heterogenous distribution of SVR values using current adrenergic therapy. METHODS: We included adult, OHCA patients transported by paramedics to the Emergency Department (ED) post-ROSC. Children, prisoners, pregnant women, and those with ongoing CPR or arrest due to traumatic injury were excluded. Hemodynamics were recorded non-invasively as soon as feasible after ED arrival but were not used to influence therapy, which was guided by clinical judgment of treating ED physicians. RESULTS: Hemodynamics were recorded on 30 patients 20 [16,25] minutes after ED arrival: 50% had a normal SVR, 30% had a high SVR, and 20% had a low SVR. There was no difference in survival to admission among groups, although there was a difference among groups in survival to discharge. Comparing the low SVR group vs the combined normal and high group revealed a trend for fewer 0/6 (0%) low vs. 10/24 (42%) normal or high SVR patients surviving to hospital discharge (p = .053). CONCLUSION: A heterogeneous range of hemodynamic states exist post-ROSC rather than consistent vasoconstriction. Adequately powered, randomized clinical trials will be needed to determine whether noninvasively-derived, hemodynamic-directed therapy can play a role in improving neurologically-intact survival following OHCA in adults. PMID- 29425977 TI - Survival after out-of-hospital cardiac arrest in nursing homes - A nationwide study. AB - BACKGROUND: Survival among nursing home residents who suffers out-of-hospital cardiac arrest (OHCA) is sparsely studied. Deployment of automated external defibrillators (AEDs) in nursing home facilities in Denmark is unknown. We examined 30-day survival following OHCA in nursing and private home residents. METHODS: This register-based, nationwide, follow-up study identified OHCA patients >=18 years of age with a resuscitation attempt in nursing homes and private homes using Danish Cardiac Arrest Register data from June 1, 2001 to December 31, 2014. The primary outcome measure was 30-day survival. Multiple logistic regression analyses were used to assess factors potentially associated with survival among nursing and private home residents separately. RESULTS: Of 26,999 OCHAs, 2516 (9.3%) occurred in nursing homes, and 24,483 (90.7%) in private homes. Nursing home residents were older (median 83 (Q1-Q3: 75-89) vs. 71 (Q1-Q3: 61-80) years), had more witnessed arrest (55.4% vs. 43.4%), received more bystander cardiopulmonary resuscitation (CPR) (49.7% vs. 35.3%), but less pre hospital defibrillation (15.1% vs. 29.8%). Registered AEDs increased in the period 2007-2014 from 1 to 211 in nursing homes vs. 1 to 488 in private homes. Average 30-day survival in nursing homes was 1.7% [95%CI: 1.2-2.2%] vs. 4.9% [95%CI: 4.6-5.2%] in private homes (P < 0.001). If bystanders witnessed the arrest, performed CPR, and pre-hospital defibrillation was performed, 30-day survival was 7.7% [95%CI: 3.5-11.9%] vs. 24.2% [95%CI: 22.5-25.9%] in nursing vs. private home residents. CONCLUSIONS: Average 30-day survival after OHCA was very low in nursing home residents, but those who received early resuscitative efforts had higher chance of survival. PMID- 29425978 TI - Intraventricular Epithelioid Glioblastoma: A Case Report. AB - BACKGROUND: Epithelioid glioblastoma, a high-grade, diffuse astrocytic tumor variant, comprises closely packed epithelioid cells and rhabdoid cells. This rare tumor usually develops in the cerebral cortex and diencephalon; however, in the case reported here, it was located intraventricularly. CASE DESCRIPTION: A 47 year-old woman was referred to our hospital with a right intraventricular mass that had rapidly increased in size. On discovery of the tumor 3 years earlier at the referring hospital, the mass was small, calcified, and attached to the periventricular parenchyma. Over the next 2 years, the mass grew slowly, as observed on periodic magnetic resonance imaging scans. Forty days before the referral, the patient experienced headache and nausea, and marked growth and intratumoral hemorrhage were visible on a computed tomography scan of the head. The tumor was partially removed via a superior parietal lobule corticotomy. Histopathological examination confirmed an isocitrate dehydrogenase-wild-type epithelioid glioblastoma with a BRAF V600E mutation, but the original slow growing lesion was no longer detected. Consequently, we assume that in this case, a low-grade glioma transformed into an aggressively malignant epithelioid glioblastoma. CONCLUSIONS: We present the first case of an intraventricular epithelioid glioblastoma that might have arisen from a low-grade glioma with calcification. We recommend including this tumor variant in the differential diagnosis of lateral ventricle tumors. PMID- 29425979 TI - Percutaneous Endoscopic Laminotomy with Flavectomy by Uniportal, Unilateral Approach for the Lumbar Canal or Lateral Recess Stenosis. AB - OBJECTIVE: To evaluate clinical feasibility and safety of percutaneous endoscopic decompression by a uniportal, unilateral approach for lumbar canal or lateral recess stenosis. METHODS: In this retrospective study, the procedure was performed with endoscopic instruments in the same way as conventional microscopic laminotomy and flavectomy. Clinical outcomes (visual analog scale, Oswestry Disability Index, modified MacNab criteria) were evaluated. Surgical outcomes, including operative time, hospital stay, and complications, were recorded. RESULTS: Decompression was performed in 213 patients (232 lumbar levels) for spinal canal or lateral recess stenosis (unilateral laminotomy, n = 80; bilateral laminotomy, n = 152). Mean follow-up period was 26.45 months. Mean visual analog scale for leg pain, and back pain and mean Oswestry Disability Index improved from 8.24%, 5.35%, and 67.8% at baseline to 1.93% (P < 0.001), 2.05% (P < 0.001), and 17.14% (P < 0.001) at final follow-up. Based on modified MacNab criteria, excellent or good results were obtained in 93.8% of patients. Average operative time was 105.3 +/- 56 minutes. In the late period of the learning curve, mean operative time was shortened by two thirds, and mean hospital stay was 2.45 days. There were 12 cases of transient postoperative dysesthesia, 3 cases of motor weakness, and 6 cases of dural tear. No patient had postoperative infection, hematoma, or need for revision surgery for incomplete decompression. CONCLUSIONS: Percutaneous endoscopic decompression by a uniportal, unilateral approach is a safe, clinically feasible, and effective surgical technique for treatment of lumbar stenosis. PMID- 29425980 TI - Dose-Dependent Effects of Statins for Patients with Aneurysmal Subarachnoid Hemorrhage: Meta-Regression Analysis. AB - OBJECTIVE: The study uses meta-regression analysis to quantify the dose-dependent effects of statin pharmacotherapy on vasospasm, delayed ischemic neurologic deficits (DIND), and mortality in aneurysmal subarachnoid hemorrhage. METHODS: Prospective, retrospective observational studies, and randomized controlled trials (RCTs) were retrieved by a systematic database search. Summary estimates were expressed as absolute risk (AR) for a given statin dose or control (placebo). Meta-regression using inverse variance weighting and robust variance estimation was performed to assess the effect of statin dose on transformed AR in a random effects model. Dose-dependence of predicted AR with 95% confidence interval (CI) was recovered by using Miller's Freeman-Tukey inverse. RESULTS: The database search and study selection criteria yielded 18 studies (2594 patients) for analysis. These included 12 RCTs, 4 retrospective observational studies, and 2 prospective observational studies. Twelve studies investigated simvastatin, whereas the remaining studies investigated atorvastatin, pravastatin, or pitavastatin, with simvastatin-equivalent doses ranging from 20 to 80 mg. Meta regression revealed dose-dependent reductions in Freeman-Tukey-transformed AR of vasospasm (slope coefficient -0.00404, 95% CI -0.00720 to -0.00087; P = 0.0321), DIND (slope coefficient -0.00316, 95% CI -0.00586 to -0.00047; P = 0.0392), and mortality (slope coefficient -0.00345, 95% CI -0.00623 to -0.00067; P = 0.0352). CONCLUSIONS: The present meta-regression provides weak evidence for dose dependent reductions in vasospasm, DIND and mortality associated with acute statin use after aneurysmal subarachnoid hemorrhage. However, the analysis was limited by substantial heterogeneity among individual studies. Greater dosing strategies are a potential consideration for future RCTs. PMID- 29425982 TI - Intracranial Aneurysm Is Associated with High Intracranial Artery Tortuosity. AB - BACKGROUND: Although intracranial aneurysms (IAs) are focal bulges of arterial walls, an uncharacterized predisposing factor that affects cerebral arteries may increase tortuosity of intracranial arteries in patients with IAs. METHODS: Subjects who underwent routine health examinations and magnetic resonance angiography at a university hospital health promotion center were enrolled. Age- and sex-matched control subjects were selected from among individuals who did not have IAs. Tortuosity of right and left middle cerebral arteries and basilar artery (BA) was measured. Distant factor [(arc/chord ratio * 100) - 100] was used to estimate tortuosity. Vascular risk factors and intracranial arterial tortuosities were compared between subjects with IAs and control subjects. Independent factors associated with intracranial artery tortuosity were also investigated. RESULTS: Of 18,954 (1.9%) subjects, 367 exhibited IAs. The prevalence of hypertension (P = 0.01) and current smoking (P = 0.01) were higher in subjects with IAs than in control subjects. The BA tortuosity was greater in subjects with IAs compared with control subjects (9.0 +/- 8.1 vs. 5.5 +/- 7.2; P < 0.001). In addition to hypertension, smoking, and absence of coronary artery disease, BA tortuosity (P < 0.001) was independently associated with presence of IAs. The presence of IA (P < 0.001) and absence of coronary artery disease (P = 0.002) were independently associated with high BA tortuosity. CONCLUSIONS: Patients with IAs exhibit a more tortuous BA. A predisposing factor weakening the cerebrovasculature in patients with IAs may exist and may manifest as high tortuosity of intracranial arteries. PMID- 29425981 TI - Spontaneous Cervical Spinal Epidural Hematoma Associated with Dabigatran. AB - BACKGROUND: While spontaneous spinal epidural hematomas are rare, 1 of the identified risk factors is vitamin K antagonist therapy. CASE DESCRIPTION: We present a case of a spontaneous spinal epidural hematoma occurring in a patient under treatment with dabigatran, a non-vitamin K oral anticoagulant. The initial hemiparesis symptom was misleading and was retrospectively identified as Brown Sequard syndrome. Immediate dabigatran antagonism with idarucizumab followed by posterior cervical laminectomy permitted a complete neurologic recovery at day 4. CONCLUSIONS: This is the first description of a spontaneous spinal epidural hematoma under non-vitamin K antagonist oral anticoagulant therapy that has been successfully antagonized and emphasizes the importance of specific antidote development. PMID- 29425983 TI - Primary Intracranial Angioleiomyomas as Rare, Nonmalignant, and Distinct Neoplastic Entities: A Series of 8 Cases and a Literature Review. AB - OBJECTIVE: Primary intracranial angioleiomyoma is a rare and distinct neoplasm. Only 29 cases have been reported previously, and we aimed to investigate the clinical and radiopathologic features of these lesions. METHODS: Medical records and radiographs of 8 patients (7 male and 1 female; mean age: 48.7 years) at our institution were reviewed retrospectively. Patient follow-up and a literature review were performed. RESULTS: The most common preoperative symptom was a visual defect (n = 2), followed by diplopia (n = 1) and abducens paralysis (n = 1). Three patients were asymptomatic. The parasellar area (particularly the cavernous sinus) was the predilection site (n = 4; 50.0%). Radiographically, all lesions were solid without cystic degeneration. All lesions appeared with T1 hypointensity and T2 hyperintensity, and they were gradually heterogeneously enhanced after the administration of gadolinium. Complete resection was achieved in 7 patients (87.5%) without recurrence after 26.8 months of follow-up. Mitosis was rarely observed, and the Ki-67 labeling index was less than 1%; pathologically, the cavernous type was the most common. CONCLUSIONS: Primary intracranial angioleiomyomas were prevalent in middle-aged men, and they usually involved the cavernous sinus and were frequently pathologically identified as the cavernous type. Preoperative symptoms varied depending on lesion location. The preoperative diagnosis of primary intracranial angioleiomyomas is difficult without pathology. Digital subtraction angiography and preoperative embolization are useful for differential diagnosis and surgery. Given the indolent biology of these tumors, a favorable outcome can be achieved using total resection without recurrence. A larger sample size with long-term follow-up is needed to verify our findings. PMID- 29425984 TI - Defining a Clopidogrel Response Cut-Off Value Using Light Transmission Aggregometry Before Pipeline Embolization of Unruptured Intracranial Aneurysms. AB - BACKGROUND: The choice of appropriate antiplatelet therapy before the Pipeline Embolization Device (PED) placement is usually guided by platelet function testing such as light transmission aggregometry (LTA). In this study, we aimed to define the optimal threshold LTA value for clopidogrel responsiveness to predict the risk of postprocedural thromboembolic complications and to help guide appropriate antiplatelet regimen. METHODS: A prospectively maintained database at an academic neurosurgical center in the United States was retrospectively analyzed from 2014 to 2017 to identify patients with unruptured intracranial aneurysms treated with the PED. Clinical and radiographic data were analyzed to identify thromboembolic complications in the context of platelet function testing performed by LTA. RESULTS: A total of 95 procedures were performed for PED placement to treat 110 unruptured intracranial aneurysms. Thromboembolic complications were encountered in 4 (4.2%) of these patients. After stratifying the complication rate based on the maximal extent of platelet aggregation after administration of an exogenous platelet agonist, a marked increase in thromboembolic events was observed in patients with LTA values greater than 50%. When LTA was dichotomized based on this value, patients with an LTA value less than 50% had a thromboembolic complication rate of 1.3% (1/80), compared with 20% (3/15) for those with LTA values >=50% (P = 0.001). CONCLUSIONS: We observed the greatest increase in the rate of thromboembolic complications with LTA values of >=50%. This can serve as an appropriate cut-off value for determining the clopidogrel response in patients undergoing endovascular treatment with the PED. PMID- 29425985 TI - Clinical Features and Treatment of Secondary Pituitary Abscess After Transsphenoidal Surgery: A Retrospective Study of 23 Cases. AB - OBJECTIVE: Pituitary abscess (PA) is a rare but serious intrasellar disorder with potentially high disability and mortality. Secondary PA after transsphenoidal surgery (TS) is extremely rare, and only a few case reports have been identified in the literature. This study explored the salient clinical manifestations and etiologies to determine appropriate treatment. METHODS: A retrospective review of 6832 consecutive patients who had undergone TS for pituitary diseases in Peking Union Medical College Hospital between 2003 and 2017 was performed. Demographics, previous medical and surgical history, clinical presentation, imaging features, and treatment details of 23 patients who had been diagnosed with secondary PA after TS among the cohort were reviewed. RESULTS: Among these patients, the original pituitary lesion before TS included Rathke's cleft cyst (8 patients, 34.8%), nonfunctioning pituitary adenoma (11 patients, 47.8%), and somatotropic adenoma (4 patients, 17.4%). The diameter of the original pituitary lesion ranged from 11 to 47 mm. About 52% of secondary PAs occurred within a half a year after surgery. Based on the history of TS, clinical presentation, biochemical testing, and typical imaging features, the preoperative diagnosis rate was as high as 78%. CONCLUSIONS: Although rare, secondary PA should be included in the differential diagnosis of intrasellar lesions after TS. Patients with an initial diagnosis of Rathke's cleft cyst or pituitary macroadenoma were more likely to have PA after TS. Adequate surgical drainage combined with microbiology-guided antibiotic therapy is the first choice for treatment. PMID- 29425986 TI - Is Edema a Matter of Concern After Laser Ablation of Epileptogenic Focus? AB - BACKGROUND: A stereotactically placed laser fiber can deliver thermal energy to an epileptogenic focus in the brain. This procedure is done under intraoperative (thermography) magnetic resonance imaging (MRI) guidance. Thermoablation can lead to edema in the surrounding area and can cause a secondary insult. In this report of 3 cases, we have quantified the edema produced after laser ablation by sequential MRI in the immediate postoperative period. CASE DESCRIPTIONS: Three patients with intractable epilepsy underwent a detailed neurologic and neuroradiologic workup to localize the site of epileptogenic foci. Two of the patients had mesial temporal lobe sclerosis, and the other patient had hypothalamic hamartoma. A laser fiber was placed stereotactically in the epileptogenic zone, and MRI-guided thermoablation was done. Postoperatively, T1 weighted and fluid-attenuated inversion recovery (FLAIR)-based volumetric MRI sequences were performed on postoperative days 1, 3, and 5 to quantify the edema. I-Plan software was used for volumetric analysis. Targeted volumes were 0.22, 4.2, and 3.5 mL, and lesions were 0.3, 6.5, and 6 mL, respectively. FLAIR hyperintensity was 2.3, 11.8, and 8.4 mL on the first postoperative day and 1.5, 12.6, and 6.3 mL on postoperative day 8. All patients remained seizure-free during the postoperative period. No complications were observed. CONCLUSIONS: Laser ablation of epileptic focus is safe. FLAIR hyperintensity in the postoperative period is 3-5 times the targeted volume. However, no significant increase occurs during the first 8 days, and thus steroids can be stopped within 5 days of surgery. PMID- 29425987 TI - Inferring causes during speech perception. AB - One of the central challenges in speech perception is the lack of invariance: talkers differ in how they map words onto the speech signal. Previous work has shown that one mechanism by which listeners overcome this variability is adaptation. However, talkers differ in how they pronounce words for a number of reasons, ranging from more permanent, characteristic factors such as having a foreign accent, to more temporary, incidental factors, such as speaking with a pen in the mouth. One challenge for listeners is that the true cause underlying atypical pronunciations is never directly known, and instead must be inferred from (often causally ambiguous) evidence. In three experiments, we investigate whether these inferences underlie speech perception, and how the speech perception system deals with uncertainty about competing causes for atypical pronunciations. We find that adaptation to atypical pronunciations is affected by whether the atypical pronunciations are seen as characteristic or incidental. Furthermore, we find that listeners are able to maintain information about previous causally ambiguous pronunciations that they experience, and use this previously experienced evidence to drive their adaptation after additional evidence has disambiguated the cause. Our findings revise previous proposals that causally ambiguous evidence is ignored during speech adaptation. PMID- 29425988 TI - Effects of metric hierarchy and rhyme predictability on word duration in The Cat in the Hat. AB - Word durations convey many types of linguistic information, including intrinsic lexical features like length and frequency and contextual features like syntactic and semantic structure. The current study was designed to investigate whether hierarchical metric structure and rhyme predictability account for durational variation over and above other features in productions of a rhyming, metrically regular children's book: The Cat in the Hat (Dr. Seuss, 1957). One-syllable word durations and inter-onset intervals were modeled as functions of segment number, lexical frequency, word class, syntactic structure, repetition, and font emphasis. Consistent with prior work, factors predicting longer word durations and inter-onset intervals included more phonemes, lower frequency, first mention, alignment with a syntactic boundary, and capitalization. A model parameter corresponding to metric grid height improved model fit of word durations and inter-onset intervals. Specifically, speakers realized five levels of metric hierarchy with inter-onset intervals such that interval duration increased linearly with increased height in the metric hierarchy. Conversely, speakers realized only three levels of metric hierarchy with word duration, demonstrating that they shortened the highly predictable rhyme resolutions. These results further understanding of the factors that affect spoken word duration, and demonstrate the myriad cues that children receive about linguistic structure from nursery rhymes. PMID- 29425989 TI - [Do pediatricians identify adverse drug reactions even when they do not report them?] AB - INTRODUCTION: Spontaneous notification depends on the ability of pediatricians to identify adverse drug reactions (ADRs) along with their habit of reporting these incidents. During the years 2008 and 2009, the frequency of reports of ADRs to the Electronic Program of Pharmacovigilance (SISFAR) in the Hospital Infantil of Mexico Federico Gomez (HIMFG) was low (0.44% and 0.20%, respectively). Because of the above, the ability of pediatricians from the Emergency Department (ED) to identify ADRs using the clinical chart review was evaluated in 2010 in this study. METHODS: A descriptive, observational, cross-sectional retrospective study was conducted in the ED from March 1 to August 31. ADRs were classified and quantified as "ADRs identified by pediatricians" when there was evidence in the clinical chart that pediatricians associated a clinical sign, symptom and laboratory value with an ADR. The numbers of notifications reported in SISFAR were quantified. Descriptive analysis was done using SPSS v.18. RESULTS: Considering patients who were admitted to the ED, the frequency of ADRs was 21.8%. The frequency of ADRs identified by physicians in clinical charts was 86%. The pharmacist detected 14% of ADRs. The frequency of ADRs reported by physicians was 6.1%. CONCLUSIONS: Although identification of ADRs in the clinical charts by pediatricians was high, it is possible that some ADRs were undetected. Because underreporting was very high, it is necessary to take actions to improve the reporting process. PMID- 29425990 TI - [Nutritional implications of elimination diets]. AB - BACKGROUND: The backbone of food allergy treatment is the restriction of causative foods. These interventions have shown that children who restrict the consumption of basic foods have a higher risk of malnutrition. The aim of the study was to identify the nutritional status of patients with elimination diet, characterizing their anthropometric indexes and identifying the percentage of patients in the group with true food allergies. METHODS: A cross-sectional study was carried out from January to October 2014 at the Hospital Infantil de Mexico Federico Gomez. Patients 1 to 11 years of age with a history of elimination of at least one of five foods (eggs, milk, wheat, corn, soybeans) for a minimum of 6 months were included. Full nutritional assessment was performed by comparing the anthropometric indexes to z score for age. Data analysis used descriptive statistics. Kruskal-Wallis and Spearman correlation were performed. RESULTS: The most frequent eliminated foods were milk, soy, eggs, corn, and wheat. Comparing the number of foods eliminated with different anthropometric indexes, with a greater amount of eliminated food, the z-score of weight/age (W/A), height/age (H/A) and weight/height (W/H) were lower and the most affected index was fat reserve. Only in 5% of children was food allergy confirmed. CONCLUSIONS: The study confirms the need for nutrition counseling for patients who have elimination diets and overdiagnosis of food allergy. PMID- 29425991 TI - [DRESS syndrome associated with carbamazepine]. AB - BACKGROUND: DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) is a serious adverse reaction to medication. It is usually defined by the triad of fever, rash and symptomatic or asymptomatic involvement of internal organs. Diagnostic criteria are suspected drug reaction, eosinophilia (>=1.5 x109/l and/or atypical lymphocytes in peripheral blood) and involvement of two or more internal organs (including the skin). The estimated incidence of this syndrome ranges from 1/1000 to 1/10,000 drug exposures and up to 30% mortality. CASE REPORT: We present a 14-year-old female with a history of complex partial seizures secondary to head trauma. She began treatment with carbamazepine. After 4 weeks she developed fever, generalized rash, adenopathy and multisystem involvement. Following paraclinical studies and evaluation by various specialists, DRESS Syndrome diagnosis was established. The patient was treated with carbamazepine suspension, steroids and gammaglobulin administration with good response and remission of symptoms. CONCLUSIONS: Immediate withdrawal of the causative drug and initiation of systemic corticosteroids is the mainstay in disease management. PMID- 29425992 TI - [Hepatopulmonary syndrome as a cause of hypoxemia in hepatic diseases in children]. AB - BACKGROUND: Hepatopulmonary syndrome is a rare complication characterized by liver disease associated with hypoxemia and intrapulmonary vascular dilatations. The prevalence reported in the few studies in children with cirrhosis is 3-8%. Although uncommon, it is important for physicians to recognize this condition because of its progressive course. CASE REPORT: We report the case of an 8-year old girl diagnosed with liver cirrhosis and portal hypertension with symptoms of dyspnea and cyanosis. On physical examination the patient was found malnourished with jaundice, telangiectasias in abdomen, severe clubbing, acrocyanosis, platypnea and orthodeoxia; arterial blood gas showed PaO2 of 59mmHg. Echocardiography with agitated saline test was positive and lung perfusion scan with albumin macroaggregates reported 15% right-to-left short circuit, thus demonstrating the existence of intrapulmonary shunt. Diagnosis of severe hepatopulmonary syndrome was made. Liver transplantation is recommended as the only effective treatment. CONCLUSIONS: In children with liver disease presenting dyspnea and hypoxemia and those enrolled in a liver transplant protocol, hepatopulmonary syndrome must be intentionally searched because the prognosis will depend on timely diagnosis. PMID- 29425993 TI - [Multicentric Castleman's disease characterized by polyclonal hyperimmunoglobulinemia and paraneoplastic pemphigus]. PMID- 29425994 TI - [Congenital hypothyroidism]. AB - Congenital hypothyroidism (CH) is a cause of preventable mental retardation; therefore, timely diagnosis and treatment by the primary care physician is very important. CH screening must be performed between the second and fifth days of life with capillary blood done with a heel prick and must be confirmed by measurement of thyroid hormones in venous blood. The most common cause of CH is thyroid dysgenesis, which may be identified by a thyroid scan carried out before initiating treatment. Treatment should be with levothyroxine (10-15MUg/kg/day) and should not be delayed or suspended during the first 3 years of life due to the deleterious effect on neurodevelopment in case of low thyroid hormones during this time. Preterm or sick infants or those with Down syndrome require special consideration. This article provides diagnostic and therapeutic algorithms for CH. PMID- 29425995 TI - [Depression among adolescents. A hidden problem for public health and clinical practice]. AB - Depression is an important public health problem that requires more and better attention. In the present work we review epidemiologic studies of depression among adolescents in Mexico and discuss strategies that may help in earlier identification and referral of potential cases for timely care. In summary, depressive symptoms are prevalent among adolescents and adults in Mexico as in many other countries, with a higher ratio of female cases. Young people experiencing the most challenging socio-urban situations have higher rates of depression. Even though depressive disorders are more prevalent among females, consequences may be even worse for males. The authors posit that, among males, stigma attached to depression might lead to attempts to hide depressive symptoms by masking them through high-risk behaviors (e.g., alcohol, drug use, and violence, among others). Women may have higher rates of suicide attempts, but the case-fatality rate of suicide attempts is higher among males. Despite of barriers and resource scarcity among healthcare and educational institutions, it is necessary to continue to develop alternatives that will lead to better attention of mental health issues among the youth, even when their mental health needs are not expressed directly or their chief complaints are in regard to "other" health issues. PMID- 29425996 TI - ? PMID- 29425997 TI - [From suspicion to certainty: adverse drug reactions in our children]. PMID- 29425998 TI - [Review of models for the analysis of ethical dilemmas]. AB - In pediatric medical practice it is common to encounter situations that represent a dilemma for health professionals. A dilemma occurs when ethical problems found in professional practice cause serious internal conflicts because they imply actions that contradict their colleagues, employees, or their own personal values and are classified as personal value conflicts, conflicts with other professionals, conflicts with clients and with organizations. A literature review allowed identifying different models to debate these types of dilemmas. The present work is a review of the search of scientific articles using databases such as Ebsco Host, ProQuest, Ovid, and InMex as well as metasearch tools such as metacrawler. The models found are as follows: Model of Anne Davis, Nijmegen method, Method of Diego Gracia, Integral method, Bochum Center Ethics model, Model of Brody and Payton, Model of Curtin and Flaherty, Model of Thompson and Thompson, SAD method, Model of Javier Morata, Model of Elaine Congress, IFSW model, Model of Loewenberg and Dolgoff, Ley Social Model, DOER method, Model of Brommer, Model of Corey and Callanan, Model of Pope and Vasquez, Model of Bush, Connell and Denney, Model of Ferrell, Gresham and Fraedrich, and Model of Hunt and Vitell. The key criteria shared in the different models are a) specifying the ethical dilemma, b) description of the facts, c) value definition, moral code and facts, decision making and d) identifying alternative solutions. In order to review the literature, some models are explained with the purpose of identifying and representing critical elements that clinical ethics committees could use in a practical manner in pediatric health institutions in Mexico. PMID- 29425999 TI - [Determination of 25(OH)D serum levels in children with systemic lupus erythematosus and juvenile idiopathic arthritis]. AB - BACKGROUND: It is well recognized that vitamin D has a direct effect in bone and muscle and has been associated as well with some rheumatologic diseases. Reports in children are scarce. The aim of this study was to determine the concentration level of 25(OH)D in a group of patients with systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) and compare them with healthy controls. METHODS: Vitamin D (25(OH)D) was measured with isotope-dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS), PTH with immunoradiometric assay (IRMA), calcium, phosphorus and alkaline phosphatase by colorimetric assay in 37 patients with SLE, 37 patients with JIA and 79 healthy controls. RESULTS: Mean 25(OH)D concentration levels were as follows: SLE 18.9+/-7.92ng/ml, JIA 21.97+/-5.55ng/ml and 23.6+/-3.07ng/ml in healthy controls. There was a significant difference between SLE patients vs. healthy controls (p <0.05); 29.7% of SLE patients, 35.1% of JIA patients and 31.6% of healthy controls had deficient levels of vitamin D. CONCLUSIONS: One third of the total sample of children in this study had deficient levels of vitamin D. Patients with SLE presented a significant difference compared with healthy controls. PMID- 29426000 TI - d-galactose induces premature senescence of lens epithelial cells by disturbing autophagy flux and mitochondrial functions. AB - Cataract is the leading cause of blindness with an estimated 16 million people affected worldwide. d-galactose (d-gal) is a reducing sugar that widely distributed in foodstuffs, and studies show that d-gal could promote cataract formation by damaging nature lens epithelial cells (LECs). However, the underlying mechanism is unclear. In our present study, d-gal resulted in premature senescence of LECs, which was confirmed by determining the beta galactosidase activity, cell proliferative potential and cell cycle distribution, though apoptosis of LECs was not observed. We also verified that d-gal induced the impairment of autophagy flux by measuring the expression of LC3II and P62. Meanwhile, we found that d-gal induced mitochondrial dysfunctions of LECs through increasing reactive oxygen species (ROS), reducing ATP synthesis and mitochondrial potential (MMP), enhancing the concentration of cytoplasm Ca2+ and permeability transition pore (mPTP) opening. Metformin, as a potential anti-aging agent, suppressed the senescence of LECs by restoring autophagy flux and mitochondria functions. Nevertheless, the antioxidant N-acetylcysteine (NAC) scavenged ROS significantly but was not efficient in preventing LECs from premature senescence. Our data suggests that restoring autophagy activity and improving mitochondrial functions may be a potential strategy for the prevention of LECs senescence-related cataract. PMID- 29426001 TI - Mobilization of human mesenchymal stem cells through different cytokines and growth factors after their immobilization by sulfur mustard. AB - INTRODUCTION: The chemical warfare agent sulfur mustard (SM), also known as mustard gas, was first used in World War I. Although prohibited by the chemical warfare convention, significant amounts of SM still exist and have still to be regarded as a threat for military personnel and civilians. After SM exposure, the most prominent clinical symptom is the development of extensive non-healing skin wounds. This chronic wound healing dysfunction is persisting over long time. Mesenchymal stem cells (MSC) are known to play an important role in wound healing. Moreover, it is also known that patients with chronic wound healing diseases have compromised mesenchymal stem cell functionality. Based on these observations and the known relationship between wound healing dysfunction and MSC function we investigated the impact of sulfur mustard on human MSC. MATERIAL & METHODS: Mesenchymal stem cells (MSC) were isolated from femoral heads of healthy donors. They were cultured for less than four passages. MSC were exposed towards different sulfur mustard concentrations. After exposure we analyzed the secretome and the migration capacity. The migration capacity under influence of SM was analyzed after treatment with various cytokines. RESULTS: SM exposure (even at very low concentrations) showed negative effects on the migration capability. Many cytokines that are necessary for MSC migration were secreted in a reduced manner. The reduced migratory capacity can be compensated in part by the addition of cytokines. Here especially IL-8 (e and m) and IL-6 significantly compensated the SM induced migration reduction. DISCUSSION: The effect of sulfur mustard on MSC might play an important role in the persistence of long-term adverse effects; here the reduced migration could particularly be important. The compensation of the SM-induced migration reduction by addition of cytokines could possibly solve this problem. Moreover, our current results will help to understand the relationship between alkylating agents and MSC and thus will also give guidance in the future perspective for the therapeutic use of MSC in patients suffering from sulfur mustard induced chronic skin wounds. PMID- 29426003 TI - Programmed necrosis in heart disease: Molecular mechanisms and clinical implications. AB - Programmed cell death plays an essential role in myocardial homeostasis and pathology. Three distinct forms of programmed cell death have been identified, namely apoptosis, necrosis, and autophagic cell death. Necrosis, previously known as an unregulated form of cell death, has been recognized as a highly regulated process now and attracted great attention over the past decade. Programmed necrosis mainly refers to necroptosis, pyroptosis, ferroptosis, and mitochondrial permeability transition (MPT)-dependent necrosis. Among them, role of necroptosis and MPT-dependent necrosis in the pathogenesis of heart disease, mainly including myocardial infarction (MI), ischemia/reperfusion (I/R), and heart failure is well defined now. Necroptosis is orchestrated by a complex of proteins involving receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). While MPT-dependent necrosis is another modality of necrosis characterized by MPT pore opening and cyclophilin-D (CypD)-dependent death signaling. Of note, the observed effects of necrostatin-1 (Nec-1, inhibitor of RIPK1) and cyclosporine A (CsA, inhibitor of CypD) on attenuating programmed necrosis and related cardiac injury further demonstrated the significant role of programmed necrosis in dictating cell demise and shed light on their further clinical application, along with other types of inhibitors targeting programmed necrosis. In this review, we summarized the recent progress on programmed necrosis in heart disease from molecular mechanisms to therapeutic strategies. PMID- 29426002 TI - Acrylamide-induced oxidative stress and inflammatory response are alleviated by N acetylcysteine in PC12 cells: Involvement of the crosstalk between Nrf2 and NF kappaB pathways regulated by MAPKs. AB - Acrylamide (ACR) is a classic neurotoxin in animals and humans. However, the mechanism underlying ACR neurotoxicity remains controversial, and effective prevention and treatment measures against this condition are scarce. This study focused on clarifying the crosstalk between the involved signaling pathways in ACR-induced oxidative stress and inflammatory response and investigating the protective effect of antioxidant N-acetylcysteine (NAC) against ACR in PC12 cells. Results revealed that ACR exposure led to oxidative stress characterized by significant increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels and glutathione (GSH) consumption. Inflammatory response was observed based on the dose-dependently increased levels of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6). NAC attenuated ACR-induced enhancement of MDA and ROS levels and TNF-alpha generation. In addition, ACR activated nuclear transcription factor E2-related factor 2 (Nrf2) and nuclear factor-kappaB (NF-kappaB) signaling pathways. Knockdown of Nrf2 by siRNA significantly blocked the increased NF-kappaB p65 protein expression in ACR-treated PC12 cells. Down-regulation of NF-kappaB by specific inhibitor BAY11-7082 similarly reduced ACR-induced increase in Nrf2 protein expression. NAC treatment increased Nrf2 expression and suppressed NF kappaB p65 expression to ameliorate oxidative stress and inflammatory response caused by ACR. Further results showed that mitogen-activated protein kinases (MAPKs) pathway was activated prior to the activation of Nrf2 and NF-kappaB pathways. Inhibition of MAPKs blocked Nrf2 and NF-kappaB pathways. Collectively, ACR activated Nrf2 and NF-kappaB pathways which were regulated by MAPKs. A crosstalk between Nrf2 and NF-kappaB pathways existed in ACR-induced cell damage. NAC protected against oxidative damage and inflammatory response induced by ACR by activating Nrf2 and inhibiting NF-kappaB pathways in PC12 cells. PMID- 29426004 TI - Cell membrane-coated nanocarriers: the emerging targeted delivery system for cancer theranostics. AB - Cancer is a leading cause of death worldwide. The use of nanocarriers (NCs) has generated significant interest to improve cancer therapy by targeted delivery. However, conventional NCs in general lack specificity and have poor biodistribution, resulting in low efficacy in cancer therapy. To circumvent this problem, there has been an increasing focus on cancer cell membrane-coated NCs (CCMCNCs), which can deliver therapeutics directly to tumor cells. CCMCNCs comprise active cancer cell surface adhesive molecules combined with other functional proteins, and offer extended blood circulation with robust cell specific targeting, ensuring enhanced intratumoral penetration and higher tumor specific accumulation of NCs. In this review, we discuss the preparation, homologous targeting mechanisms, and application of CCMCNCs in targeted cancer therapy. PMID- 29426006 TI - Effectiveness of an Ayurveda treatment approach in knee osteoarthritis - a randomized controlled trial. AB - OBJECTIVE: Ayurveda is commonly used in South Asia to treat knee osteoarthritis (OA). We aimed to evaluate the effectiveness of Ayurvedic treatment compared to conventional conservative care in patients with knee OA. METHOD: According to American College of Rheumatology (ACR) criteria knee OA patients were included in a multicenter randomized, controlled, open-label trial and treated in 2 hospital clinics and 2 private outpatient clinics in Germany. Participants received either a multi-modal Ayurvedic treatment or multi-modal conventional care with 15 treatments over 12 weeks respectively. Primary outcome was the change on the Western Ontario and McMaster University Osteoarthritis (WOMAC) Index after 12 weeks. Secondary outcomes included WOMAC subscales; the pain disability index and a pain experience scale, numeric rating scales for pain and sleep quality, quality-of-life and mood, rescue medication use, and safety issues. RESULTS: One hundred fifty-one participants (Ayurveda n = 77, conventional care n = 74) were included. Changes of the WOMAC Index from baseline to 12 weeks were more pronounced in the Ayurveda group (mean difference 61.0 [95%CI: 52.4;69.6]) than in the conventional group (32.0 [95%CI: 21.4;42.6]) resulting in a significant between-group difference (p < 0.001) and a clinically relevant effect size (Cohen's d 0.68 [95% CI:0.35;1.01]). Similar trends were observed for all secondary outcomes at week 12. Effects were sustained at follow-ups after 6 and 12 months. CONCLUSION: Results suggest that Ayurvedic treatment is beneficial in reducing knee OA symptoms. Further studies should be conducted to confirm the magnitude of the effect and to clarify the role of different treatment components and non-specific effects. REGISTRATION: at clinicaltrials.gov (NCT01225133; initial release 10/06/2010). PMID- 29426005 TI - Harmonising measures of knee and hip osteoarthritis in population-based cohort studies: an international study. AB - OBJECTIVE: Population-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses. METHOD: International OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI). RESULTS: OA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade >=2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question. CONCLUSION: This research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts. PMID- 29426007 TI - How do patients trade-off surgeon choice and waiting times for total joint replacement: a discrete choice experiment. AB - OBJECTIVE: Patients face significant waiting times for hip and knee total joint replacement (TJR) in publicly funded healthcare systems. We aimed to assess how surgeon selection and reputation affect patients' willingness to wait for TJR. DESIGN: We assessed patient preferences using a discrete choice experiment questionnaire with 12 choice scenarios administered to patients referred for TJR. Based on qualitative research, pre- and pilot-testing, we characterized each scenario by five attributes: surgeon reputation, surgeon selection, waiting time to surgeon visit (initial consultation), waiting time to surgery, and travel time to hospital. Preferences were assessed using hierarchical Bayes (HB) analysis and evaluated for goodness-of-fit. We conducted simulation analyses to understand how patients value surgeon reputation and surgeon selection in terms of willingness to wait for surgeon visit and surgery. RESULTS: Of 422 participants, 68% were referred for knee TJR. The most important attribute was surgeon reputation followed by waiting times, surgeon selection process and travel time. Patients appear willing to wait 10 months for a visit with an excellent reputation surgeon before switching to a good reputation surgeon. Patients in the highest pain category were willing to wait 7.3 months before accepting the next available surgeon, compared to 12 months for patients experiencing the least pain. CONCLUSIONS: Our findings confirm that patients value surgeon reputation in the context of wait times and surgeon selection. We suggest opportunities to reduce wait times by explicitly offering the next available surgeon to increase patient choice, and by reporting surgeon performance to reduce potential misinformation about reputation. PMID- 29426008 TI - Colchicine lack of effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): a randomized controlled trial. AB - OBJECTIVES: Uric acid may activate an innate immune response in osteoarthritis (OA), contributing to disease pathology and progression. We evaluated the effectiveness of colchicine on pain and function in symptomatic knee OA (KOA) and the underlying mechanism of action. METHODS: Colchicine effectiveness in symptoms and inflammation modification in knee osteoarthritis (COLKOA) was a double-blind, placebo-controlled, randomized trial comparing 16 weeks of treatment with 0.5 mg twice-daily oral colchicine to placebo for knee osteoarthritis (KOA). The primary endpoint was >=30% improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at week 16. Secondary endpoints included improvement in pain (0-10 Likert scales); WOMAC pain; patient global assessment (0-100); physical function; the OARSI-OMERACT response; quality of life; and change in serum, urine, synovial fluid (SF) biomarkers of cartilage metabolism and inflammation, and plasma/SF colchicine concentrations. RESULTS: Of 109 randomly assigned participants, 39% (95% confidence interval (CI) 27-52%) and 49% (95% CI 36-62%) in the colchicine and placebo arms respectively met the primary endpoint at study end (P = 0.284, odds ratio 0.66, 95% CI 0.31-1.41). No strong evidence of treatment differences was identified on clinical secondary endpoints. Treatment significantly reduced mean serum hs-CRP (P = 0.008) and SF CTXI (P = 0.002); treatment tended to reduce inflammatory markers (SF IL-6, IL8, TNFalpha, CD14 and IL-18), but these differences were not statistically significant. CONCLUSION: Colchicine (0.5 mg twice-daily orally) reduced inflammation and high bone turnover biomarkers known to be associated with OA severity and progression risk, but did not reduce KOA symptoms over a 16-week study period. A longer-term study to evaluate for slow-acting disease modifying effects is warranted. TRIAL REGISTRATION: The trial has been registered at clinicaltrials.gov as NCT02176460. Date of registration: June 26, 2014. PMID- 29426009 TI - Clinimetrics of ultrasound pathologies in osteoarthritis: systematic literature review and meta-analysis. AB - OBJECTIVE: The aims of this study were to systematically review clinimetrics of commonly assessed ultrasound pathologies in knee, hip and hand osteoarthritis (OA), and to conduct a meta-analysis for each clinimetric. METHODS: Medline, Embase, and Cochrane Library databases were searched from their inceptions to September 2016. According to the Outcome Measures in Rheumatology (OMERACT) Instrument Selection Algorithm, data extraction focused on ultrasound technical features and performance metrics. Methodological quality was assessed with modified 19-item Downs and Black score and 11-item Quality Appraisal of Diagnostic Reliability (QAREL) score. Separate meta-analyses were performed for clinimetrics: (1) inter-rater/intra-rater reliability; (2) construct validity; (3) criteria validity; and (4) internal/external responsiveness. Statistical Package for the Social Sciences (SPSS), Excel and Comprehensive Meta-analysis were used. RESULT: Our search identified 1126 records; of these, 100 were eligible, including a total of 8542 patients and 32,373 joints. The average Downs and Black score was 13.01, and average QAREL was 5.93. The stratified meta analysis was performed only for knee OA, which demonstrated moderate to substantial reliability [minimum kappa > 0.44(0.15,0.74), minimum intraclass correlation coefficient (ICC) > 0.82(0.73-0.89)], weak construct validity against pain (r = 0.12 to 0.27), function (r = 0.15 to 0.23), and blood biomarkers (r = 0.01 to 0.21), but weak to strong correlation with plain radiography (r = 0.13 to 0.60), strong association with Magnetic Resonance Imaging (MRI) [minimum r = 0.60(0.52,0.67)] and strong discrimination against symptomatic patients (OR = 3.08 to 7.46). There was strong criterion validity against cartilage histology [r = 0.66(-0.05,0.93)], and small to moderate internal [standardized mean difference(SMD) = 0.20 to 0.58] and external (r = 0.35 to 0.43) responsiveness to interventions. CONCLUSION: Ultrasound demonstrated strong criterion validity with cartilage histology, poor to strong correlation with patient findings and MRI, moderate reliability, and low responsiveness to interventions. PROSPERO REGISTRATION NO: CRD42016039954. PMID- 29426010 TI - Persisting CAM deformity is associated with early cartilage degeneration after Slipped Capital Femoral Epiphysis: 11-year follow-up including dGEMRIC. AB - OBJECTIVE: Slipped capital femoral epiphysis (SCFE) in adolescence is associated with increased risk of future osteoarthritis (OA). The purpose of this study was to study clinical and radiographic risk factors for early cartilage degeneration after SCFE. DESIGN: 22 patients (44 hips) (mean age 24 years, range 18-27) treated with in situ fixation (The Hansson hook-pin) for stable SCFE on average 11 years previously were investigated. Cartilage status was assessed with delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC). The alpha angle, reflecting femoroacetabular impingement (FAI), and the original slip angle were measured. Clinical outcome was assessed with the Copenhagen hip and groin outcome score (HAGOS) and clinical examination. RESULTS: The dGEMRIC index was lower in SCFE hips than unaffected hips 456 ms (CI 419-493) vs 521 ms (CI 476 567) (P = 0.03). The difference was larger (mean 21 ms) in anterior than posterior regions of the hip (P = 0.038). The alpha angle was higher in SCFE hips, 61.5 degrees (CI 53.9-69.1) vs 45.6 degrees (CI 43.6-47.6), (P < 0.001). The alpha angle, but not the original slip angle, correlated negatively with the dGEMRIC index (R = -0.40, P = 0.046). There was a positive correlation between HAGOS and the dGEMRIC-index (R = 0.41, P = 0.012). CONCLUSIONS: Early cartilage degeneration after SCFE seems related to persisting FAI in adulthood, rather than the initial slip severity. The correlation between dGEMRIC and HAGOS indicates a clinical relevance of the MRI findings. Our results suggest that FAI after SCFE should be evaluated already after physeal closure in order to predict and possibly prevent future OA development. PMID- 29426011 TI - The knee, osteoarthritis and biomarkers. PMID- 29426012 TI - MRI UTE-T2* profile characteristics correlate to walking mechanics and patient reported outcomes 2 years after ACL reconstruction. AB - OBJECTIVE: Quantitative magnetic resonance imaging (MRI) ultrashort echo time (UTE) T2* is sensitive to cartilage deep tissue matrix changes after anterior cruciate ligament reconstruction (ACLR). This study was performed to determine whether UTE-T2* profile analysis is a useful clinical metric for assessing cartilage matrix degeneration. This work tests the hypotheses that UTE-T2* depthwise rates of change (profile slopes) correlate with clinical outcome metrics of walking mechanics and patient reported outcomes (PRO) in patients 2 years after ACLR. DESIGN: Thirty-six patients 2 years after ACLR completed knee MRI, gait analysis, and PRO. UTE-T2* maps were generated from MRI images and depthwise UTE-T2* profiles were calculated for weight-bearing cartilage in the medial compartment. UTE-T2* profiles from 14 uninjured subjects provided reference values. UTE-T2* profile characteristics, including several different measures of profile slope, were tested for correlation to kinetic and kinematic measures of gait and also to PRO. RESULTS: Decreasing UTE-T2* profile slopes in ACLR knees moderately correlated with increasing knee adduction moments (r = 0.41, P < 0.015), greater external tibial rotation (r = 0.44, P = 0.007), and moderately negatively correlated with PRO (r = -0.36, P = 0.032). UTE-T2* profiles from both ACLR and contralateral knees of ACLR subjects differed from that of uninjured controls (P < 0.015). CONCLUSIONS: The results of this study suggest that decreasing UTE-T2* profile slopes reflect cartilage deep tissue collagen matrix disruption in a population at increased risk for knee osteoarthritis (OA). That UTE-T2* profiles were associated with mechanical and patient reported measures of clinical outcomes support further study into a potential mechanistic relationship between these factors and OA development. PMID- 29426013 TI - Celecoxib-mediated reduction of prostanoid release in Hoffa's fat pad from donors with cartilage pathology results in an attenuated inflammatory phenotype. AB - OBJECTIVE: The Hoffa's fat pad (HFP) is an intra-articular adipose tissue which is situated under and behind the patella. It contains immune cells next to adipocytes and secretes inflammatory factors during osteoarthritis (OA). In this study, we compared the release profile of prostanoids, which are involved in inflammation, of HFP from OA patients vs patients with a focal cartilage defect (CD) without evidence for OA on MRI and investigated the prostanoid modulatory anti-inflammatory action of celecoxib on HFP. DESIGN: Prostanoid release was analyzed in conditioned medium of HFP explant cultures from 17 osteoarthritic patients and 12 CD patients, in the presence or absence of celecoxib. Furthermore, gene expression of COX enzymes and expression of genes indicative of a pro-inflammatory or anti-inflammatory phenotype of HFP was analyzed. RESULTS: Prostanoid release by HFP from knee OA patients clustered in two subgroups with high and low prostanoid producers. HFP from high prostanoid producers released higher amounts of PGE2, PGF2alpha and PGD2 compared to HFP from CD patients. PGE2 release by OA HFP was positively associated with expression of genes known to be expressed by M1 macrophages, indicating a role for macrophages. Celecoxib modulated prostanoid release by HFP, and also modulated the inflammation ratio towards a more favorable anti-inflammatory M2 phenotype, most effectively in patients with higher prostanoid release profiles. CONCLUSION: In knee OA patients with inflamed HFP's, celecoxib may exert positive effects in the knee joint via decreasing the release of prostanoids produced by the HFP and by favorably modulating the anti-inflammatory marker expression in HFP. PMID- 29426015 TI - The factors related to self-other agreement/disagreement in nursing competence assessment: Comparative and correlational study. AB - BACKGROUND: While assessment made by nurses of themselves (self-assessment) and assessment made of them by others (other-assessment) provide unique and valuable information as to individual nurses' competence, the subjective nature of both assessments often causes a disagreement between them. This is problematic when educational interventions to foster nurses' competence are designed. However, the question of what factors contribute to the self-other disagreement in competence assessment has rarely been investigated in nursing. OBJECTIVES: The aims of this study were to compare competence assessments made by nurses with that by others, and to investigate what types of demographic variables of nurses and others, and which personality traits of nurses were associated with the self-other agreement/disagreement in the competence assessment. DESIGN: A cross-sectional survey design. SETTINGS: Three hospitals in Japan. PARTICIPANTS: A total of 1167 registered nurses, who were practising in these three hospitals, were invited to participate in the study. The inclusion criteria of the participants were as follows: 1) currently working in an inpatient department, and 2) directly involved in patient care. METHODS: The survey package included two sets of questionnaires: one for self-assessment and the other for other-assessment, each of which was accompanied by an ID number for matching. Collected data were analysed using a Wilcoxon signed-rank test to compare the scores on competence assessed by nurses and others, and using multiple regression to examine the relationships between the demographics, personality traits, and the degree of self-other disagreement. RESULTS: A total of 207 matched questionnaires were obtained. The results showed that the scores on the assessment made by others were statistically significantly higher than those made by nurses of themselves. Moreover, regression analysis suggested that the age of nurses (i.e., younger nurses) and that of others (i.e., older evaluators), and nurses' personality traits of conscientiousness and extraversion were statistically significantly related to the agreement in self-other competence assessment. CONCLUSIONS: Nurse managers need to understand which factors contribute to self-other disagreement in competence assessment, and to identify a way to precipitate mutual agreement between them. By doing so, both nurses and managers can comprehend nurses' own strengths and weaknesses, and can determine educational needs and goals regarding nurses' competence development. PMID- 29426016 TI - [In process]. PMID- 29426017 TI - Abnormal rsFC and GMV changes in parahippocampal and DLPFC for high Deja vu experienced subjects. AB - How deja vu works has long been a mystery, partially because of its characteristics of unpredictable occurrences and quick disappearances, which make it difficult to be explored. Previous studies have described the anatomical structures underlying deja vu in healthy subjects; however, the functional mechanism of deja vu remains unclear. Therefore, this study investigated the brain structural and functional components underlying deja vu by combining voxel based morphometry analysis (VBM) with resting-state functional connectivity (rsFC). The VBM analysis revealed that the anterior parahippocampal gyrus (PHG) had significantly less grey matter volume (GMV) in high deja vu group than low group, confirming previous studies. Further functional connectivity analysis revealed that the frequency of deja vu experiences was negatively correlated with the strength of the rsFC between anterior dorsal lateral prefrontal cortex (DLPFC) and anterior PHG but positively correlated with the strength of the rsFC between posterior DLPFC and posterior PHG. Moreover, the frequency of deja vu experiences was negatively correlated with the strength of the rsFC between the anterior and posterior regions of the PHG. These findings indicated that familiarity without recollection (PHG) and superior context monitoring (DLPFC) are critical for real-life deja vu experiences. PMID- 29426019 TI - Use of performance-enhancing (and image-enhancing) drugs: A growing problem in need of a solution. PMID- 29426018 TI - Regulatory identification of BPA as an endocrine disruptor: Context and methodology. AB - BPA is one of the most investigated substances for its endocrine disruptor (ED) properties and it is at the same time in the center of many ED-related controversies. The analysis on how BPA fits to the regulatory identification as an ED is a challenge in terms of methodology. It is also a great opportunity to test the regulatory framework with a uniquely data-rich substance and learn valuable lessons for future cases. From this extensive database, it was considered important to engage in a detailed analysis so as to provide specific and strong evidences of ED while reflecting accurately the complexity of the response as well the multiplicity of adverse effects. An appropriate delineation of the scope of the analysis was therefore critical. Four effects namely, alterations of estrous cyclicity, mammary gland development, brain development and memory function, and metabolism, were considered to provide solid evidence of ED-mediated effects of BPA. PMID- 29426014 TI - Network Analysis of UBE3A/E6AP-Associated Proteins Provides Connections to Several Distinct Cellular Processes. AB - Perturbations in activity and dosage of the UBE3A ubiquitin-ligase have been linked to Angelman syndrome and autism spectrum disorders. UBE3A was initially identified as the cellular protein hijacked by the human papillomavirus E6 protein to mediate the ubiquitylation of p53, a function critical to the oncogenic potential of these viruses. Although a number of substrates have been identified, the normal cellular functions and pathways affected by UBE3A are largely unknown. Previously, we showed that UBE3A associates with HERC2, NEURL4, and MAPK6/ERK3 in a high-molecular-weight complex of unknown function that we refer to as the HUN complex (HERC2, UBE3A, and NEURL4). In this study, the combination of two complementary proteomic approaches with a rigorous network analysis revealed cellular functions and pathways in which UBE3A and the HUN complex are involved. In addition to finding new UBE3A-associated proteins, such as MCM6, SUGT1, EIF3C, and ASPP2, network analysis revealed that UBE3A-associated proteins are connected to several fundamental cellular processes including translation, DNA replication, intracellular trafficking, and centrosome regulation. Our analysis suggests that UBE3A could be involved in the control and/or integration of these cellular processes, in some cases as a component of the HUN complex, and also provides evidence for crosstalk between the HUN complex and CAMKII interaction networks. This study contributes to a deeper understanding of the cellular functions of UBE3A and its potential role in pathways that may be affected in Angelman syndrome, UBE3A-associated autism spectrum disorders, and human papillomavirus-associated cancers. PMID- 29426020 TI - To Clip or Not to Clip? Can We Predict Which Patients with Functional Mitral Regurgitation Will Benefit From Transcatheter Mitral Valve Repair? PMID- 29426021 TI - A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2. AB - BACKGROUND: Variation in an individual's genetic status can impact the development of pancreatic ductal adenocarcinoma; however, the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss-of function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC. STUDY DESIGN: Germline DNA from patients who underwent resection for pancreatic ductal adenocarcinoma (n = 79) was sequenced for the IDO2 SNPs R248W and Y359Stop. Genotypes resulting in inactivation of IDO2 (Y325X homozygous, R248W homozygous) were labeled as homozygous, and the other genotypes were grouped as wild-type or heterozygous. Genotype distributions of each SNP were analyzed for Hardy-Weinberg deviation. A genotype frequency set from the 1000 Genomes Project (n = 99) was used as a genetic control for genotype distribution comparisons. RESULTS: A significant 2-fold increase in the overall prevalence of the Y359Stop homozygous genotype compared with the expected Hardy-Weinberg equilibrium was noted (p < 0.05). Familial pancreatic cancer was noted in 15 cases (19%) and comparison of the FPC cohort set to the genetic control set showed a 3-fold increase in Y359Stop homozygous rates (p = 0.054). Overall in our cohort, the homozygous genotype group was associated with increased risk of FPC (odds ratio 5.4; 95% CI 1.6 to 17.6; p < 0.01). Sex, age at diagnosis, and history of tobacco use were not found to be significantly associated with FPC. CONCLUSIONS: Our preliminary data suggest a strong association between the IDO2 inactivating Y359Stop SNP and an increased risk of FPC when compared with the control group. Future studies will evaluate the value of IDO2 genotyping as a prognostic, early detection marker for pancreatic ductal adenocarcinoma and a predictive marker for novel immune checkpoint therapies. PMID- 29426022 TI - Trends in injury morbidity in China, 1993-2013: A longitudinal analysis of population-based survey data. AB - Understanding long-term trends in injury morbidity is critical to prevention and intervention planning. The aim of this study was to assess long-term trends in injury morbidity rates in China from 1993 to 2013. Using data from the National Health Service Survey (NHSS), which is conducted every five years, crude and age standardized prevalence during the previous two weeks and hospitalization rates in the last 12 months with 95% confidence intervals (CI) were calculated. The Rao Scott Chi-square test examined injury morbidity differences across the five survey years by location (urban/rural), sex, age group, and household income. Percent changes in morbidity rate were approximated using logistic regressions. Sampling weights were applied to all analyses. In 2013, crude two-week injury prevalence in China was 0.46% (95% CI: 0.40%, 0.52%) and 12-month crude hospitalization rate was 0.70% (95% CI: 0.63%, 0.77%). Age-standardized injury prevalence increased 31.4% (95% CI: 7.6%, 60.6%) between 1993 and 2013 (29.4%, 95% CI: 6.7%, 56.9% from 1993-2003; 1.6%, 95% CI: -14.8%, 21.0% from 2003-2013), and age-standardized hospitalization rates rose 107.2% (95% CI: 75.1%, 145.2%) from 1993 to 2013 (-9.5%, 95% CI: -24.6%, 8.6% from 1993-2003 and 129.0%, 95% CI: 93.9%, 170.4% from 2003-2013). Subgroup analyses showed similar trends over time. The leading cause of injury was dislocation, sprain or strain for prevalence, and fractures for hospitalization. In conclusion, injury morbidity increased substantially from 1993 to 2013 in China. Inconsistent changes in two-week prevalence and 12-month hospitalization rate merit attention from researchers and policy-makers. PMID- 29426023 TI - Latent class analysis of factors that influence weekday and weekend single vehicle crash severities. AB - This paper investigates factors that influence the severity of single-vehicle crashes that happen on weekdays and weekends. Crash data from 2012 to 2016 for the State of Alabama was used for this study. Latent class logit models were developed as alternative to the frequently used random parameters models to account for unobserved heterogeneity across crash-severity observations. Exploration of the data revealed that a high proportion of severe injury injury crashes happened on weekends. The study examined whether single-vehicle crash contributing factors differ between weekdays and weekends. The model estimation results indicate a significant association of severe injury crashes to risk factors such as driver unemployment, driving with invalid license, no seatbelt use, fatigue, driving under influence, old age, and driving on county roads for both weekdays and weekends. Research findings show a strong link between human factors and the occurrence of severe injury single-vehicle crashes, as it has been observed that many of the factors associated with severe-injury outcome are driver behavior related. To illustrate the significance of the findings of this study, a third model using the combined data was developed to explore the merit of using sub-populations of the data for improved and detailed segmentation of the crash-severity factors. It has also been shown that generally, the factors that influence single-vehicle crash injury outcomes were not very different between weekdays and weekends. The findings of this study show the importance of investigating sub-populations of data to reveal complex relationships that should be understood as a necessary step in targeted countermeasure application. PMID- 29426025 TI - A cross sectional study of urinary phthalates, phenols and perchlorate on thyroid hormones in US adults using structural equation models (NHANES 2007-2008). AB - BACKGROUND: Biomonitoring data shows that people are exposed to phthalates, phenols and perchlorates. Many of these compounds are endocrine disrupting compounds that affect thyroid hormone levels. Yet the effect of these compounds on thyroid hormone levels are often evaluated individually rather than as a mixture. Our objective was to examine the association between 11 urinary endocrine disrupting compounds and thyroid hormones using structural equation models. METHODS: Using data from the National Health and Nutrition and Examination Survey 2007-2008, we fit a latent variable utilizing urinary measurements of 9 compounds in females (perchlorate, bisphenol A, benzophenone-3, mono-2ethyl5carboxypentyl phthalate, mono-n-butyl phthalate, mono-(3 carboxypropyl) phthalate, mono(2ethyl5hydroxyhexyl) phthalate, mono-benzyl phthalate, and mono-isobutyl phthalate) and 8 compounds in males (without benzophenone-3). The association of the latent variable with serum thyroid hormones (Total T3, Total T4, and Thyroid Stimulating Hormones) was assessed in females (N = 710) and males (N = 850) over the age of 12 controlling for age, race, and urinary creatinine. RESULTS: In males, urinary endocrine disrupting compound levels were negatively associated with thyroxine (beta: -0.19, 95% Confidence Interval (95% CI): -0.31, -0.05). In females, urinary endocrine disrupting compound levels were positively associated with triiodothyronine serum concentrations (beta: 0.09, 95% CI: -0.03, 0.21) however this association was not statistically significant. CONCLUSIONS: This cross-sectional analysis provides additional evidence that environmental exposure to phthalates and phenols is associated with endocrine-related processes. Furthermore, these results suggested sex-specific differences in exposure to endocrine disrupting mixtures, and the exposure-response between endocrine disrupting mixtures and thyroid hormone levels. Specifically, higher exposure to a mixture of endocrine disrupting compounds was associated with lower levels of total T4 in males but not in females. While a structural methodological framework was used to assess these complex relationships, the cross sectional nature of this analysis limits causal inference and further research is needed to determine the clinical significance of these findings. PMID- 29426024 TI - Mechanical properties of silicone based composites as a temperature insensitive ballistic backing material for quantifying back face deformation. AB - This paper describes a new witness material for quantifying the back face deformation (BFD) resulting from high rate impact of ballistic protective equipment. Accurate BFD quantification is critical for the assessment and certification of personal protective equipment, such as body armor and helmets, and ballistic evaluation. A common witness material is ballistic clay, specifically, Roma Plastilina No. 1 (RP1). RP1 must be heated to nearly 38 degrees C to pass calibration, and used within a limited time frame to remain in calibration. RP1 also exhibits lot-to-lot variability and is sensitive to time, temperature, and handling procedures, which limits the BFD accuracy and reproducibility. A new silicone composite backing material (SCBM) was developed and tested side-by-side with heated RP1 using quasi-static indentation and compression, low velocity impact, spherical projectile penetration, and both soft and hard armor ballistic BFD measurements to compare their response over a broad range of strain rates and temperatures. The results demonstrate that SCBM mimics the heated RP1 response at room temperature and exhibits minimal temperature sensitivity. With additional optimization of the composition and processing, SCBM could be a drop-in replacement for RP1 that is used at room temperature during BFD quantification with minimal changes to the current RP1 handling protocols and infrastructure. It is anticipated that removing the heating requirement, and temperature-dependence, associated with RP1 will reduce test variability, simplify testing logistics, and enhance test range productivity. PMID- 29426026 TI - Lung health in era of climate change and dust storms. AB - Dust storms are strong winds which lead to particle exposure over extensive areas. These storms influence air quality on both a local and global scale which lead to both short and long-term effects. The frequency of dust storms has been on the rise during the last decade. Forecasts suggest that their incidence will increase as a response to the effects of climate change and anthropogenic activities. Elderly people, young children, and individuals with chronic cardiopulmonary diseases are at the greatest risk for health effects of dust storms. A wide variety of infectious and non-infectious diseases have been associated with dust exposure. Influenza A virus, pulmonary coccidioidomycosis, bacterial pneumonia, and meningococcal meningitis are a few examples of dust related infectious diseases. Among non-infectious diseases, chronic obstructive pulmonary disease, asthma, sarcoidosis and pulmonary fibrosis have been associated with dust contact. Here, we review two molecular mechanisms of dust induced lung disease for asthma and sarcoidosis. We can also then further understand the mechanisms by which dust particles disturb airway epithelial and immune cells. PMID- 29426028 TI - Performance of low-cost monitors to assess household air pollution. AB - Exposure to household air pollution is a leading cause of morbidity and mortality globally. However, due to the lack of validated low-cost monitors with long lasting batteries in indoor environments, most epidemiologic studies use self reported data or short-term household air pollution assessments as proxies of long-term exposure. We evaluated the performance of three low-cost monitors measuring fine particulate matter (PM2.5) and carbon monoxide (CO) in a wood combustion experiment conducted in one household of Spain for 5 days (including the co-location of 2 units of HAPEX and 3 units of TZOA-R for PM2.5 and 3 units of EL-USB-CO for CO; a total of 40 unit-days). We used Spearman correlation (rho) and Concordance Correlation Coefficient (CCC) to assess accuracy of low-cost monitors versus equivalent research-grade devices. We also conducted a field study in India for 1 week (including HAPEX in 3 households and EL-USB-CO in 4 households; a total of 49 unit-days). Correlation and agreement at 5-min were moderate-high for one unit of HAPEX (rho = 0.73 / CCC = 0.59), for one unit of TZOA-R (rho = 0.89 / CCC = 0.62) and for three units of EL-USB-CO (rho = 0.82 0.89 / CCC = 0.66-0.91) in Spain, although the failure or malfunction rate among low-cost units was high in both settings (60% of unit-days in Spain and 43% in India). Low-cost monitors tested here are not yet ready to replace more established exposure assessment methods in long-term household air pollution epidemiologic studies. More field validation is needed to assess evolving sensors and monitors with application to health studies. PMID- 29426027 TI - Ozone, NO2 and PM10 are associated with the occurrence of multiple sclerosis relapses. Evidence from seasonal multi-pollutant analyses. AB - BACKGROUND: Triggers of multiple sclerosis (MS) relapses are essentially unknown. PM10 exposure has recently been associated with an increased risk of relapses. OBJECTIVES: We further explore the short-term associations between PM10, NO2, benzene (C6H6), O3, and CO exposures, and the odds of MS relapses' occurrence. METHODS: Using a case-crossover design, we studied 424 MS patients living in the Strasbourg area, France between 2000 and 2009 (1783 relapses in total). Control days were chosen to be +/- 35 days relative to the case (relapse) day. Exposure was modeled through ADMS-Urban software at the census block scale. We consider single-pollutant and multi-pollutant conditional logistic regression models coupled with a distributed-lag linear structure, stratified by season ("hot" vs. "cold"), and adjusted for meteorological parameters, pollen count, influenza-like epidemics, and holidays. RESULTS: The single-pollutant analyses indicated: 1) significant associations between MS relapse incidence and exposures to NO2, PM10, and O3, and 2) seasonality in these associations. For instance, an interquartile range increase in NO2 (lags 0-3) and PM10 exposure were associated with MS relapse incidence (OR = 1.08; 95%CI: [1.03-1.14] and OR = 1.06; 95%CI: [1.01 1.11], respectively) during the "cold" season (i.e., October-March). We also observed an association with O3 and MS relapse incidence during "hot" season (OR = 1.16; 95%CI: [1.07-1.25]). C6H6 and CO were not significantly related to MS relapse incidence. However, using multi-pollutant models, only O3 remained significantly associated with the odds of relapse triggering during "hot" season. CONCLUSION: We observed significant single-pollution associations between the occurrence of MS relapses and exposures to NO2, O3 and PM10, only O3 remained significantly associated with occurrence of MS relapses in the multi-pollutant model. PMID- 29426030 TI - An empirical assessment of adjustment disorder as proposed for ICD-11 in a general population sample of Israel. AB - BACKGROUND: A new diagnostic concept of Adjustment Disorder (AjD) was proposed for inclusion in the International Classification of Diseases, 11th version (ICD 11). However, the symptom structure of AjD is poorly understood. The aim of the present study was to investigate the dimensionality of AjD as a stress-response syndrome. METHODS: A general population sample of the Israeli population (N = 1003) completed the Adjustment Disorder - New Module 20 and the WHO-5 Wellbeing Scale. We compared seven alternative models of AjD using confirmatory factor analysis (CFA). A latent profile analysis (LPA) was performed to determine if subtypes of AjD were present. The performance of the unidimensional and multidimensional models of AjD were evaluated using regression analyses. RESULTS: CFA results supported a unidimensional model of AjD. The LPA identified three quantitatively distinct classes (low, medium, and high) with no evidence of any subtypes of AjD. The criterion validity of AjD was superior when treated as unidimensional. AjD was associated with lower levels of psychological wellbeing (beta = -.32, p < .001). CONCLUSIONS: Our results suggest that AjD is better conceptualised as a unidimensional construct. Future work should focus on a reduction of required symptoms in order to improve clinical utility and validity of the diagnosis. PMID- 29426029 TI - Endocrine disrupting chemicals in seminal plasma and couple fecundity. AB - Growing evidence supports the importance of men's exposure to non-persistent endocrine disruptors (EDCs) and couple fecundability, as measured by time-to pregnancy (TTP). This evolving literature contrasts with the largely equivocal findings reported for women's exposures and fecundity. While most evidence relies upon urinary concentrations, quantification of EDCs in seminal plasma may be more informative about potential toxicity arising within the testes. We analyzed 5 chemical classes of non-persistent EDCs in seminal plasma for 339 male partners of couples who were recruited prior to conception and who were followed daily until pregnant or after one year of trying. Benzophenones, bisphenols, parabens, and phthalate metabolites and phthalate diesters were measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) except for phthalate diesters, which were analyzed using gas chromatography-mass spectrometry. Cox regression with discrete-time was used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs) for each chemical to estimate the probability of pregnancy. While most EDCs were detected in seminal plasma, concentrations were lower than urinary concentrations previously analyzed for the cohort. None of the EDCs were significantly associated with fecundability even after covariate adjustment, though benzophenones consistently yielded FORs <1.0 (ranging from 0.72 to 0.91) in couple-adjusted models suggestive of diminished fecundity (longer TTP). The findings underscore that a range of EDCs can be quantified in seminal plasma, but the lower concentrations may require a large cohort for assessing couple fecundability, as well as the need to consider other fecundity outcomes such as semen quality. PMID- 29426031 TI - Quantitative design of emergency monitoring network for river chemical spills based on discrete entropy theory. AB - Field monitoring strategy is critical for disaster preparedness and watershed emergency environmental management. However, development of such is also highly challenging. Despite the efforts and progress thus far, no definitive guidelines or solutions are available worldwide for quantitatively designing a monitoring network in response to river chemical spill incidents, except general rules based on administrative divisions or arbitrary interpolation on routine monitoring sections. To address this gap, a novel framework for spatial-temporal network design was proposed in this study. The framework combines contaminant transport modelling with discrete entropy theory and spectral analysis. The water quality model was applied to forecast the spatio-temporal distribution of contaminant after spills and then corresponding information transfer indexes (ITIs) and Fourier approximation periodic functions were estimated as critical measures for setting sampling locations and times. The results indicate that the framework can produce scientific preparedness plans of emergency monitoring based on scenario analysis of spill risks as well as rapid design as soon as the incident happened but not prepared. The framework was applied to a hypothetical spill case based on tracer experiment and a real nitrobenzene spill incident case to demonstrate its suitability and effectiveness. The newly-designed temporal-spatial monitoring network captured major pollution information at relatively low costs. It showed obvious benefits for follow-up early-warning and treatment as well as for aftermath recovery and assessment. The underlying drivers of ITIs as well as the limitations and uncertainty of the approach were analyzed based on the case studies. Comparison with existing monitoring network design approaches, management implications, and generalized applicability were also discussed. PMID- 29426032 TI - Impacts of quaternary ammonium compounds on membrane bioreactor performance: Acute and chronic responses of microorganisms. AB - Quaternary ammonium compounds (QACs) are emerging contaminants with the extensive applications in a variety of fields. However, little is known about their potential impacts on activated sludge and performance of biological wastewater treatment processes. In this work, the effects of benzalkonium chloride (BAC, a kind of QACs) on acute and chronic responses of microorganisms and on MBR performance were systematically investigated. The results showed that a low concentration (0.5-2.0 mg BAC/g SS) caused no significant effects on activated sludge property. In contrast, an elevated concentration of BAC led to severer inhibition on activated sludge and key enzyme activity (e.g., dehydrogenase activity) in both short-term and long-term exposure, thus deteriorating the pollutant removal efficiency. Compared with the control MBR (R1) and the reactor with 0.5 mg/L BAC (R2), the removal efficiency of ammonia in R3 with 5.0 mg/L BAC at identical hydraulic retention time (4.3 h) and sludge retention time (30 d) was decreased, i.e., ammonium removal efficiency in R1~R3 was 95.4 +/- 6.1, 93.4 +/- 8.1 and 89.3 +/- 17.6%, respectively. Moreover, MBR tests showed that membrane fouling was aggravated in the presence of high-concentration BAC. Long term exposure to BAC reduced microbial community diversity and enriched the BAC resistant microbes. For instance, the abundance of Pseudomonas genus in R3 was increased from 0.02% to 14.9% with the increase of operation time. Microbial community structure was changed to resist the environmental stress induced by BAC during long-term exposure, thus decreasing the inhibition effects. PMID- 29426033 TI - Enhanced adsorption of ionizable antibiotics on activated carbon fiber under electrochemical assistance in continuous-flow modes. AB - Ionizable antibiotics have attracted serious concerns because of their variable dissociation forms and thereby rendering unique toxicity and microorganism resistance. Developing an efficient and environmentally friendly method for removing these micropollutants from environmental media remains very challenging. Here, electro-assisted adsorption onto activated carbon fiber in continuous-flow mode was used to remove three ionizable antibiotics, sulfadimethoxine (SDM), ciprofloxacin (CIP), and clarithromycin (CLA), from water. Benefiting from strengthened electrostatic interactions, the adsorption capacities for the target antibiotics (10 mg/L) in flow mode (70.9-202.2 mg/g) increased by ~5 times under a potential of 1.0 V (SDM) or -1.0 V (CIP and CLA) relative to those of open circuit (OC) adsorption. Meanwhile, effluent concentration decreased from >100 MUg/L to 9.6 MUg/L with removal efficiency increasing from 99.0% to 99.9%. Moreover, high recovery efficiency of ACF up to 96.35 +/- 0.65% was achieved by imposing a reverse potential (-1.0 V) relative to that used for SDM adsorption. In addition, trace levels of antibiotics (364-580 ng/L) in surface water could be removed effectively to achieve low effluent concentration (0.4-1.2 ng/L) and high removal efficiency (99.9%) upon treating up to ~1560 bed volumes (BVs), demonstrating the potential of electro-assisted adsorption for practical application in water treatment. PMID- 29426034 TI - Ozonation of municipal wastewater effluent containing metal sulfides and metal complexes: Kinetics and mechanisms. AB - Ozonation can be applied to mitigate the discharge of organic micropollutants from municipal wastewater treatment plants (WWTPs) to the aquatic environment. The toxicity of metals also present in WWTP effluents strongly depends on their speciation. Therefore, knowledge on the change of the metal speciation during ozonation of a WWTP effluent is essential to assess possible negative impacts. The kinetics and the stoichiometries of the reactions of ozone with three metal sulfides (ZnS, CuS and CdS) and metal-ethylenediaminetetraacetate (EDTA)/nitriloriacetic acid (NTA) complexes of Cu(II), Cd(II), Ni(II), Zn(II), Mg(II) and Pb(II) were investigated. With a stoichiometric factor of 2.6-3.9 moles of ozone per mole of sulfide and apparent second-order rate constants at pH 8 > 104 M-1 s-1, a complete oxidation of the sulfides and a concomitant release of the respective metals is expected during ozonation of a WWTP effluent for enhanced micropollutant abatement. The apparent second-order rate constants at pH 8 for the reactions of metal-EDTA complexes with ozone ranged from 42 M-1s-1 to 2.0 * 104 M-1s-1 and increased in the order Cd(II) < Cu(II) < Mg(II) < Ni(II) < Zn(II). Approximately 40% of Cd(II)-EDTA spiked to a WWTP effluent was oxidized at typical specific ozone doses of 0.5-0.7 gO3/gDOC. For the other metal-EDTA complexes a significantly higher fraction was oxidized. The bioavailable fraction determined by the diffusive-gradient thin films (DGT) method in the WWTP effluent increased during ozonation, due to the oxidative release of the metal ions. Algal toxicity (chlamynomodas reinhardtii) tests with CuS/CdS spiked WWTP effluent revealed a high tolerance toward Cu and Cd in the respective media. A toxic response was only observed at Cu concentrations above 10 MUM, which is above typical WWTP effluent concentrations. Biological post-treatment after ozonation generally reduced the bioavailability of the metals, which resulted in a lower toxicity. Therefore, the biological post-treatment serves as an additional barrier to protect the downstream ecology of receiving waters. PMID- 29426035 TI - Exploring the pathway from anxiety sensitivity intervention to suicide risk reduction: Chained mediation through anxiety and depressive symptoms. AB - BACKGROUND: The suicide rate in the Unites States continues to increase suggesting novel intervention strategies are needed. Anxiety sensitivity (AS), or a fear of anxiety-related sensations, is a suicide risk factor that can be ameliorated via a single-session, computerized intervention called the Cognitive Anxiety Sensitivity Treatment (CAST). Results from randomized controlled trials have demonstrated that reductions in suicidal ideation (SI) due to CAST were mediated by AS reductions. However, a more detailed analysis of the mechanisms of SI reduction due to AS interventions is needed to further our understanding of theoretical models of AS and suicide, and to refine AS treatments. METHODS: Participants (N = 74) with co-occurring anxiety pathology and SI were randomized to a single-session computerized treatment (CAST + cognitive bias modification) or a control intervention. Assessments were conducted immediately post treatment, and at 1 month and 4 month follow-ups. RESULTS: Chained mediation models revealed significant reductions in SI (month 4 follow-up) through AS (post-treatment) and subsequently anxiety symptoms (month 1 follow-up), but not depressive symptoms. There were no direct mediation effects through either AS or anxiety or depressive symptoms. LIMITATIONS: Limitations include self-report assessment of symptoms, a sample of only individuals with a diagnosed anxiety pathology, and exploratory nature of anxiety/depression dimension analyses. CONCLUSIONS: Results of the current study help clarify the mechanistic pathways of SI reduction due to an AS intervention, and suggest future work attempting to increase the efficacy of AS interventions should consider the potentially important role of downstream mechanisms that follow AS reduction. PMID- 29426036 TI - Internalizing and externalizing symptoms among Palestinian adolescents from Israel as consequences of their exposure to community violence: Are they moderated by their self-efficacy and collective efficacy? AB - This article presents the findings of a study that examined the rates and the consequences of exposure to community violence (ECV) as reflected in witnessing and experiencing such violence, among Palestinian adolescents from Israel. In particular, it examined the extent to which these adolescents exhibit high levels of internalizing and externalizing symptoms as consequences of such exposure, and the extent to which self-efficacy and collective efficacy moderate these consequences. A systematic random sample of 760 Palestinian adolescents in Israel (320 boys, and 440 girls) filled out a self-administered questionnaire. The results show that most of the adolescents had witnessed community violence during the last year and during lifetime, and more than one third had directly experienced such violence during their lifetime compared with 19.6% during the last year. Boys were exposed to community violence more often than girls. Moreover, participants' ECV predicted high levels of externalizing and internalizing symptoms. Hierarchical regression analysis revealed that collective efficacy moderated the correlation between experiencing community violence and internalizing symptoms, whereas self-efficacy moderated the correlation between witnessing community violence and externalizing symptoms. There is a need for providing support for youth from close adults as well as from formal and informal resources in the community before and after their ECV. PMID- 29426037 TI - Typologies of adverse childhood experiences and their relationship to incarceration in U.S. military veterans. AB - Numerous studies have reported that adverse childhood experiences (ACEs) are associated with negative psychosocial outcomes in adulthood, but no study has examined the different typologies of ACEs and the relationship of these with adult incarceration in military veterans. The current study used latent class analysis to examine the existence of different childhood maltreatment and household dysfunction typologies in a sample of U.S. military veterans identified through the National Epidemiological Survey on Alcohol and Related Conditions-III ((NESARC-III)). A total of 60.73% of veterans reported one or more ACEs. Four latent classes were identified and were named Low adversities, Moderate maltreatment with high household substance use, Severe maltreatment with moderate household dysfunction and Severe multi-type adversities. Relative to the Low adversities class, the three maltreatment/dysfunction classes had significantly elevated odds ratios (1.72-2.29) for adult incarceration, when controlling for sociodemographic characteristics and alcohol and drug use. The results point to the importance of examining childhood risk factors for incarceration and suggest that a certain sub-group of military personnel who are about to transition into the civilian life may need additional support to adjust and live successful lives. PMID- 29426038 TI - Effect of short-term training on fine motor control in trigeminally innervated versus spinally innervated muscles. AB - We hypothesized that the trigeminally innervated jaw muscles and spinally innervated hand muscles would differ in the force control and muscle activity when similar fine motor training tasks are performed. Sixteen healthy volunteers performed six series (with ten trials each) of an oral fine motor task (OFMT) and a hand fine motor task (HFMT), in random order. The task was to hold-and-break a test material (5 cm spaghetti pasta) placed on the force transducer between either their anterior teeth (OFMT) or the thumb and the index finger (HFMT). The hold and the break forces along with the electromyographic (EMG) activity of the left and right masseter (MAL and MAR), left anterior temporalis (TAL) and digastric (DIG) muscles during OFMT, and first dorsal interosseous (FDI) and abductor pollicis brevis (APB) during HFMT, were recorded. There was no significant difference in the relative change of holding force during the six subsequent series, neither for the OFMT (P = 0.39) nor for the HFMT (P = 0.10). The relative change of EMG activity of MAL (P = 0.01) and MAR (P = 0.02) during the hold phase decreased significantly during the six series of OFMT. Also the relative change of break force (P = 0.001) and the relative change of EMG activity of APB during the hold (P = 0.003) and break phases (P = 0.002) decreased significantly during the six series of HFMT. The results indicate functional differences between the jaw and hand muscles during a similar hold-and break task, with the most pronounced changes for the spinally innervated hand muscles. Overall, these findings indicate that training-related neuroplasticity cannot be extrapolated directly from the spinal to the trigeminal system and vice versa. PMID- 29426039 TI - Prohormones in the Early Diagnosis of Cardiac Syncope. AB - BACKGROUND: The early detection of cardiac syncope is challenging. We aimed to evaluate the diagnostic value of 4 novel prohormones, quantifying different neurohumoral pathways, possibly involved in the pathophysiological features of cardiac syncope: midregional-pro-A-type natriuretic peptide (MRproANP), C terminal proendothelin 1, copeptin, and midregional-proadrenomedullin. METHODS AND RESULTS: We prospectively enrolled unselected patients presenting with syncope to the emergency department (ED) in a diagnostic multicenter study. ED probability of cardiac syncope was quantified by the treating ED physician using a visual analogue scale. Prohormones were measured in a blinded manner. Two independent cardiologists adjudicated the final diagnosis on the basis of all clinical information, including 1-year follow-up. Among 689 patients, cardiac syncope was the adjudicated final diagnosis in 125 (18%). Plasma concentrations of MRproANP, C-terminal proendothelin 1, copeptin, and midregional proadrenomedullin were all significantly higher in patients with cardiac syncope compared with patients with other causes (P<0.001). The diagnostic accuracies for cardiac syncope, as quantified by the area under the curve, were 0.80 (95% confidence interval [CI], 0.76-0.84), 0.69 (95% CI, 0.64-0.74), 0.58 (95% CI, 0.52-0.63), and 0.68 (95% CI, 0.63-0.73), respectively. In conjunction with the ED probability (0.86; 95% CI, 0.82-0.90), MRproANP, but not the other prohormone, improved the area under the curve to 0.90 (95% CI, 0.87-0.93), which was significantly higher than for the ED probability alone (P=0.003). An algorithm to rule out cardiac syncope combining an MRproANP level of <77 pmol/L and an ED probability of <20% had a sensitivity and a negative predictive value of 99%. CONCLUSIONS: The use of MRproANP significantly improves the early detection of cardiac syncope among unselected patients presenting to the ED with syncope. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01548352. PMID- 29426040 TI - Neutrophils from Both Susceptible and Resistant Mice Efficiently Kill Opsonized Listeria monocytogenes. AB - Inbred mouse strains differ in their susceptibility to infection with the facultative intracellular bacterium Listeria monocytogenes, largely due to delayed or deficient innate immune responses. Previous antibody depletion studies suggested that neutrophils (polymorphonuclear leukocytes [PMN]) were particularly important for clearance in the liver, but the ability of PMN from susceptible and resistant mice to directly kill L. monocytogenes has not been examined. In this study, we showed that PMN infiltrated the livers of BALB/c/By/J (BALB/c) and C57BL/6 (B6) mice in similar numbers and that both cell types readily migrated toward leukotriene B4 in an in vitro chemotaxis assay. However, CFU burdens in the liver were significantly higher in BALB/c mice than in other strains, suggesting that PMN in the BALB/c liver might not be able to clear L. monocytogenes as efficiently as B6 PMN. Unprimed PMN harvested from either BALB/c or B6 bone marrow killed L. monocytogenes directly ex vivo, and pretreatment with autologous serum significantly enhanced killing efficiency for both. L. monocytogenes were internalized within 10 min and rapidly triggered intracellular production of reactive oxygen species in a dose-dependent manner. However, PMN from gp91phox-deficient mice also readily killed L. monocytogenes, which suggested that nonoxidative killing mechanisms may be sufficient for bacterial clearance. Together, these results indicate that there is not an intrinsic defect in the ability of PMN from susceptible BALB/c mice to kill L. monocytogenes and further suggest that if PMN function is impaired in BALB/c mice, it is likely due to locally produced modulating factors present in the liver during infection. PMID- 29426041 TI - Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis. AB - Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii, which has the capacity to infect all warm-blooded animals worldwide. Toxoplasmosis is a major cause of visual defects in the Colombian population; however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. This work evaluates the associations between polymorphisms in genes coding for the cytokines tumor necrosis factor alpha (TNF-alpha) (rs1799964, rs1800629, rs1799724, rs1800630, and rs361525), interleukin 1beta (IL-1beta) (rs16944, rs1143634, and rs1143627), IL-1alpha (rs1800587), gamma interferon (IFN-gamma) (rs2430561), and IL-10 (rs1800896 and rs1800871) and the presence of ocular toxoplasmosis (OT) in a sample of a Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the "dideoxynucleotide (ddNTP) primer extension" technique. Functional-effect predictions of single nucleotide polymorphisms (SNPs) were done by using FuncPred. A polymorphism in the IL-10 gene promoter (-1082G/A) was significantly more prevalent in OT patients than in controls (P = 1.93e-08; odds ratio [OR] = 5.27e+03; 95% confidence interval [CI] = 3.18 to 8.739; Bonferroni correction [BONF] = 3.48e 07). In contrast, haplotype "AG" of the IL-10 gene promoter polymorphisms (rs1800896 and rs1800871) was present at a lower frequency in OT patients (P = 7e 04; OR = 0.10; 95% CI = 0.03 to 0.35). The +874A/T polymorphism of IFN-gamma was associated with OT (P = 3.37e-05; OR = 4.2; 95% CI = 2.478 to 7.12; BONF = 6.07e 04). Haplotype "GAG" of the IL-1beta gene promoter polymorphisms (rs1143634, rs1143627, and rs16944) appeared to be significantly associated with OT (P = 0.0494). The IL-10, IFN-gamma, and IL-1beta polymorphisms influence the development of OT in the Colombian population. PMID- 29426042 TI - Natural and Vaccine-Induced Acquisition of Cross-Reactive IgG-Inhibiting ICAM-1 Specific Binding of a Plasmodium falciparum PfEMP1 Subtype Associated Specifically with Cerebral Malaria. AB - Cerebral malaria (CM) is a potentially deadly outcome of Plasmodium falciparum malaria that is precipitated by sequestration of infected erythrocytes (IEs) in the brain. The adhesion of IEs to brain endothelial cells is mediated by a subtype of parasite-encoded erythrocyte membrane protein 1 (PfEMP1) that facilitates dual binding to host intercellular adhesion molecule 1 (ICAM-1) and endothelial protein receptor C (EPCR). The PfEMP1 subtype is characterized by the presence of a particular motif (DBLbeta_motif) in the constituent ICAM-1-binding DBLbeta domain. The rate of natural acquisition of DBLbeta_motif-specific IgG antibodies and the ability to induce such antibodies by vaccination are unknown, and the aim of this study was to provide such data. We used an enzyme-linked immunosorbent assay (ELISA) to measure DBLbeta-specific IgG in plasma from Ghanaian children with malaria. The ability of human immune plasma and DBLbeta specific rat antisera to inhibit the interaction between ICAM-1 and DBLbeta was assessed using ELISA and in vitro assays of IE adhesion under flow. The acquisition of DBLbeta_motif-specific IgG coincided with age-specific susceptibility to CM. Broadly cross-reactive antibodies inhibiting the interaction between ICAM-1 and DBLbeta_motif domains were detectable in immune plasma and in sera of rats immunized with specific DBLbeta_motif antigens. Importantly, antibodies against the DBLbeta_motif inhibited ICAM-1-specific in vitro adhesion of erythrocytes infected by four of five P. falciparum isolates from cerebral malaria patients. We conclude that natural exposure to P. falciparum as well as immunization with specific DBLbeta_motif antigens can induce cross-reactive antibodies that inhibit the interaction between ICAM-1 and a broad range of DBLbeta_motif domains. These findings raise hope that a vaccine designed specifically to prevent CM is feasible. PMID- 29426043 TI - Nonspecific CD8+ T Cells and Dendritic Cells/Macrophages Participate in Formation of CD8+ T Cell-Mediated Clusters against Malaria Liver-Stage Infection. AB - CD8+ T cells are the major effector cells that protect against malaria liver stage infection, forming clusters around Plasmodium-infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8+ T cells in cluster formation and protective immunity. To this end, we used Plasmodium berghei ANKA expressing ovalbumin as well as CD8+ T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8+ T cells specific for an unrelated antigen, respectively. While antigen-specific CD8+ T cells were essential for cluster formation, both antigen-specific and nonspecific CD8+ T cells joined the clusters. However, nonspecific CD8+ T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8+ T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. In vivo imaging of the liver revealed that specific CD8+ T cells interact with CD11c+ cells around infected hepatocytes. The depletion of CD11c+ cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c+ dendritic cells and presumably macrophages in the formation of CD8+ T cell clusters around Plasmodium-infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8+ T cells, specific and unrelated activated CD8+ T cells join the clusters in a chemokine- and dendritic cell-dependent manner. Nonspecific CD8+ T cells seem to play a limited role in protective immunity against Plasmodium parasites. PMID- 29426046 TI - [Severe thoracic bleeding - 25 years after nephrectomy]. AB - We report a case of a 62 year old patient, who was hospitalised due to haemorrhagic shock. The cause was a rupture of the pulmonary artery due to metastasis of a renal cell carcinoma. This cause is now reported for the first time. The primary tumour (pT2,pN0,M0,R0) was resected 25 years ago. This case demonstrates that after curative nephrectomy pulmonary metastasis can occur, even after decades. This is why patients of this type need lifelong follow-up. PMID- 29426044 TI - Dysbiosis of Inferior Turbinate Microbiota Is Associated with High Total IgE Levels in Patients with Allergic Rhinitis. AB - Abnormalities in the human microbiota are associated with the etiology of allergic diseases. Although disease site-specific microbiota may be associated with disease pathophysiology, the role of the nasal microbiota is unclear. We sought to characterize the microbiota of the site of allergic rhinitis, the inferior turbinate, in subjects with allergic rhinitis (n = 20) and healthy controls (n = 12) and to examine the relationship of mucosal microbiota with disease occurrence, sensitized allergen number, and allergen-specific and total IgE levels. Microbial dysbiosis correlated significantly with total IgE levels representing combined allergic responses but not with disease occurrence, the number of sensitized allergens, or house dust mite allergen-specific IgE levels. Compared to the populations in individuals with low total IgE levels (group IgElow), low microbial biodiversity with a high relative abundance of Firmicutes phylum (Staphylococcus aureus) and a low relative abundance of Actinobacteria phylum (Propionibacterium acnes) was observed in individuals with high total serum IgE levels (group IgEhigh). Phylogeny-based microbial functional potential predicted by the 16S rRNA gene indicated an increase in signal transduction related genes and a decrease in energy metabolism-related genes in group IgEhigh as shown in the microbial features with atopic and/or inflammatory diseases. Thus, dysbiosis of the inferior turbinate mucosa microbiota, particularly an increase in S. aureus and a decrease in P. acnes, is linked to high total IgE levels in allergic rhinitis, suggesting that inferior turbinate microbiota may be affected by accumulated allergic responses against sensitized allergens and that site-specific microbial alterations play a potential role in disease pathophysiology. PMID- 29426045 TI - Smad nuclear interacting protein 1 (SNIP1) inhibits intestinal inflammation through regulation of epithelial barrier function. AB - Smad nuclear interacting protein 1 (SNIP1) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms involved are still largely unknown. Our results demonstrated that SNIP1 was markedly decreased in intestinal epithelial cells (IEC) from IBD patients compared with healthy controls. Impaired expression of SNIP1 caused a significant decrease of transepithelial electrical resistance but an increase of fluorescein isothiocyanate-dextran flux in Caco-2 monolayers, whereas overexpression of SNIP1 reversed such effects. Overexpression of SNIP1 also inhibited the activity of NF kappaB p65 and proinflammatory cytokine production (e.g., TNF-alpha, IL-1beta, and IL-8) by IEC. Importantly, supplementation of exogenous SNIP1 significantly ameliorated intestinal mucosal inflammation in experimental colitis, characterized by less-severe intestinal epithelial barrier damage and decreased proinflammatory cytokine production. Our data thus demonstrated a novel mechanism whereby SNIP1 regulates intestinal inflammation through modulating intestinal epithelial barrier function. Targeting SNIP1 may provide a therapeutic approach for the treatment of IBD. PMID- 29426047 TI - ? PMID- 29426048 TI - [Respiratory Insufficiency: State of the Art - Diagnosis and Therapy]. AB - The term "respiratory insufficiency" (RI) describes the inability of an organism to maintain the gas exchange between the ambient air and its peripheral organs. This causes a hypoxia and hypercapnia. The mechanisms that lead to RI are either an impaired gas exchange in the lung tissue or an alveolar hypoventilation caused by an insufficient ventilatory pump. Thus the RI is divided into a hypoxic or a hypercapnic RI. The diagnostic procedure for RI contains several examinations. One key aspect of the exploration is the identification of potential reversible and thus correctable reasons of the RI. The goal of the therapy is to maintain the oxygen supply for the peripheral organs and the elimination of CO2. It covers supportive and causal therapeutic interventions. Wherever possible, therapy should resolve the cause of the RI. The non-invasive ventilation (NIV) is the therapy of choice in severe cases of a hypercapnic RI. It relieves the exhausted respiratory muscles and improves respiratory situation. It can be used for hypoxic RI as well, but frequently invasive ventilation is required. If NIV is not able to improve the patient's condition, invasive ventilation (IV) is applied. PMID- 29426049 TI - [ARDS - An Update - Part 1: Epidemiology, Pathophysiology and Diagnosis]. AB - The Acute Respiratory Distress Syndrome (ARDS) is defined by hypoxemic respiratory failure caused by inflammatory response within the lung usually requiring invasive mechanical ventilation. Despite more than 50 years of research numerous issues regarding epidemiology, pathophysiology and diagnosis remain unclear until today: Due to rather unspecific clinical diagnostic criteria incidence of ARDS varies considerably in clinical trials with a range from 4 to 79 cases per 100 000 persons per year. Consequently, mortality is also highly variable from about 40 to 60% in severe ARDS. Pathophysiology is mainly characterized by granulocyte infiltration of the lung thereby inducing interstitial and intra-alveolar lung edema with surfactant depletion and atelectasis formation. However, it is unknown whether pulmonary and extrapulmonary causes and risk factors for ARDS are accompanied by different pathophysiologic processes due to primary endothelial and epithelial injury. Thus, possible benefits of corresponding biomarker panels for the differentiation of endothelial and epithelial lung injury are also speculative until today. Therefore, ARDS diagnosis is still based on clinical findings and radiological imaging. PMID- 29426050 TI - [ARDS - An Update - Part 2: Therapy and Outcome]. AB - The Acute Respiratory Distress Syndrome (ARDS) is defined by hypoxemic respiratory failure due to inflammatory response within the lung usually requiring invasive mechanical ventilation. Despite more than 50 years of scientific research numerous issues especially regarding mechanical ventilation as the most important treatment option remain unclear. Most important, adjustment of mechanical ventilation is challenging due to desirable beneficial effects on pulmonary gas exchange on the one hand and deleterious effects in terms of ventilator-associated lung injury on the other. Specifically, optimal settings of positive end-expiratory pressure and the role of spontaneous breathing activity are still controversial. Because no specific pharmacological therapy revealed beneficial effects until today, adjunctive treatment is actually limited to prone positioning and restrictive fluid balance. Long-term outcome of ARDS survivors is often affected by anxiety and mental health disorders. PMID- 29426051 TI - [Respiratory Failure: Innovations in Diagnostics and Therapy]. AB - Acute and chronic respiratory failures require immediate diagnosis and preferably individualized ventilation therapy. If possible, non-invasive ventilation should be considered to avoid complications of invasive mechanical ventilation. Especially in patients with ARDS and moderate to severe cases, non-invasive ventilation may not be suitable and should not be used uncritically.Invasive mechanical ventilation parameters should be adjusted individually. In the future, additional parameters such as transpulmonary pressure, monitoring of regional ventilation using electrical impedance tomography could help to individualize ventilator settings. Problems include the lack of wide distribution of these techniques and automatic tools for data analyses are missing.So for today the best thing is to implement the current evidence consequently. This includes lung protective ventilation with an adequate PEEP and a tidal volume between 6 and 8 ml/kg IBW and a limitation of peak pressure or driving pressure. According to this early mobilization and positioning including prone-position is important, same as a score-based sedation regime and an individualized volume therapy. PMID- 29426052 TI - [SSC International Guideline 2016 - Management of Sepsis and Septic Shock]. AB - The new guideline of the Surviving Sepsis Campaign was revised in 2016 and presented in 2017. Furthermore, "Sepsis-3" in 2016 completely changed the definition of Sepsis from inflammation plus infection to a "life-threatening organ dysfunction caused by a dysregulated host response". To cope with the great challenge to unite the new evidence of sepsis treatment with the new definition of sepsis, the guidelines have been completely reconstructed and comprehensively deal with new evidence. The guidelines discuss sepsis-specific treatment and provide recommendations on general measures of intensive care for sepsis. The article summarizes the most important recommendations and additionally discusses some crucial amendments. This is intended to encourage the reader to incorporate the new guideline into clinical practice, thus improving the prognosis of patients suffering from sepsis or septic shock. PMID- 29426053 TI - [Renal Replacement Therapy in Acute Kidney Injury - Indication and Implementation]. AB - Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with a worse short- and long-term outcome. The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines suggest to implement preventive strategies in high-risk patients. Definition and classification of acute kidney injury according to the KDIGO criteria are based on an increase in serum creatinine and/or a decrease in urinary output. Renal replacement therapy (RRT) is the only supportive measure in patients with severe AKI. The KDIGO guidelines recommend to initiate RRT immediately if an absolute indication exists. However, in the absence of absolute indication, there are no recommendations when to start RRT in AKI patients with a progressive decline of renal function. Continuous or intermittent techniques of renal replacement therapy may be used equally for treatment of acute kidney injury. In hemodynamically instable patients and patients with increased intracranial pressures continuous renal replacement therapy is recommended. Although weak evidence exists, regional citrate anticoagulation is suggested for patients receiving continuous renal replacement therapy and systemic heparin anticoagulation is suggested for patients receiving intermittent renal replacement therapy. The KDIGO guidelines recommend to deliver an effluent volume of 20 - 25 ml/kg/h for CRRT in AKI. PMID- 29426054 TI - Correction: How I do colonoscopy. PMID- 29426055 TI - The Manchester Triage System (MTS): a score for emergency management of patients with acute gastrointestinal bleeding. AB - BACKGROUND: Suspected gastrointestinal (GI) bleeding is a common initial diagnosis in emergency departments. Despite existing endoscopic scores to estimate the risk of GI bleeding, the primary clinical assessment of urgency can remain challenging. The 5-step Manchester Triage System (MTS) is a validated score that is often applied for the initial assessment of patients presenting in emergency departments. METHODS: All computer-based records of patients who were admitted between January 2014 and December 2014 to our emergency department in a tertiary referral hospital were analyzed retrospectively. The aim of our retrospective analysis was to determine if patient triage using the MTS is associated with rates of endoscopy and with presence of active GI bleeding. RESULTS: In summary, 5689 patients with a GI condition were treated at our emergency department. Two hundred eighty-four patients (4.9 %) presented with suspected GI bleeding, and 165 patients (58 %) received endoscopic diagnostic. Endoscopic intervention for hemostasis was needed in 34 patients (21 %). In patients who underwent emergency endoscopy, triage into MTS categories with higher urgency was associated with higher rates of endoscopic confirmation of suspected GI bleeding (79 % of patients with MTS priority levels 1 or 2, 53 % in level 3 patients, and 40 % in levels 4 or 5 patients; p = 0.024). CONCLUSIONS: The MTS is an established tool for triage in emergency departments and could have a potential to guide early clinical decision-making with regards to urgency of endoscopic evaluation in patients with suspected GI bleeding. PMID- 29426056 TI - G-EYE advanced colonoscopy for improved polyp detection rates - a randomized tandem pilot study with different endoscopists. AB - BACKGROUND AND AIMS: The most commonly missed polyps in colonoscopy are those located behind haustral folds. The G-EYE system is a standard colonoscope consisting of re-processable balloon at its distal tip. The G-EYE balloon improves the detection of polyps by straightening the haustral folds. In our back to-back tandem study, we aimed to determine whether and to what extent the G-EYE system could reduce adenoma miss rates in screening colonoscopy. METHODS: Patients referred to colonoscopy were randomized into 2 groups. Group A underwent a standard colonoscopy (SC) followed by balloon colonoscopy (BC), and Group B underwent BC followed by SC. In this randomized tandem study, the investigator's level of training and the endoscopists themselves were changed after each withdrawal. Each endoscopist was blinded to the results of the first withdrawal. RESULTS: Fifty-eight patients were enrolled and randomized into 2 groups with similar baseline characteristics. Nine patients were excluded from the study. Twenty-five patients underwent SC followed by BC while 24 underwent BC followed by SC. The adenoma miss rate for SC was 41 %, with an additional detection rate of 69 % for BC (ratio 1.69). The overall miss rate for polyps was 60 % for SC, with an additional detection rate of 150 % for BC (ratio 2.5). Experienced investigators who used BC were able to identify an additional 7 polyps while inexperienced investigators. CONCLUSIONS: Although our results could not clearly confirm that BC improves adenoma detection, the investigator's experience appears to be a major determinant of the adenoma detection rate. PMID- 29426057 TI - Inflammatory bowel disease and Clostridium difficile infection: contrasting views of international clinical professionals. AB - INTRODUCTION: In patients with inflammatory bowel disease (IBD), Clostridium difficile infection (CDI) is a risk factor for both morbidity and mortality. Currently, appropriate management is unclear. Guidance on best practice in the diagnosis and treatment of CDI in IBD patients is therefore needed. METHODS: A multidisciplinary group of clinicians involved in the treatment of patients with IBD and CDI developed 27 consensus statements. Respondents were asked to rate their agreement with each statement using a 4-point Likert scale. A modified Delphi methodology was used to review responses of 442 physicians from different specialties (including infectious disease specialists [n = 104], microbiologists [n = 95], and gastroenterologists [n = 73]). A threshold of 75 % agreement was predefined as consensus. RESULTS: Consensus was achieved for 17 of the 27 statements. Unprompted recognition of risk factors for CDI was low. Intensification of immunosuppressive therapy in the absence of clinical improvement was controversial. Clear definitions of treatment failure of antibiotic therapy in CDI and recurrence of CDI in IBD are needed. Respondents require further clarity regarding the place of fecal microbiota transplantation in CDI patients with IBD. Differences were observed between the perceptions of microbiologists and gastroenterologists, as well as between countries. CONCLUSIONS: Different perceptions both between specialties and geographical locations complicate the development of an internationally accepted algorithm for the diagnosis and treatment of CDI in patients with IBD. This study highlights the need for future studies in this area. PMID- 29426058 TI - The metabolism of flubendazole in human liver and cancer cell lines. AB - Flubendazole (FLU), a benzimidazole anthelmintic drug widely used in veterinary medicine, has been approved for the treatment of gut-residing nematodes in humans. In addition, FLU is now considered a promising anti-cancer agent. Despite this, information about biotransformation of this compound in human is lacking. Moreover, there is no information regarding whether cancer cells are able to metabolize FLU in order to deactivate it. For these reasons, the present study was designed to identify all metabolites of Phase I and Phase II of FLU in human liver and in various cancer cells using ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. Precision-cut human liver slices and 9 cell lines of different origin (breast, colon, oral cavity) were used as in vitro model systems. Our study showed that FLU with a reduced carbonyl group (FLUR) is the only FLU metabolite formed in the human liver. All human cancer cell lines were able to form FLUR. In addition, methylated FLUR was detected in breast cells MCF7 and intestinal SW480 cells. The accumulation of FLU and its reduction to FLUR markedly differed among cells. The extent of FLU reduction was in a good correlation with the detected expression level of carbonyl reductase 1. In most cases, FLU entered in a higher amount and was reduced to a lesser extent in proliferating (metastatic) cells than in differentiated (non-cancerous, non-metastatic) ones. These results support the promising potential of FLU in anti-cancer therapy. PMID- 29426060 TI - Discovery and Validation of Novel Protein Biomarkers in Ovarian Cancer Patient Urine. AB - PURPOSE: For the vast majority of ovarian cancer patients, optimal surgical debulking remains a key prognostic factor associated with improved survival. A standardized, biomarker-based test, to preoperatively discriminate benign from malignant disease and inform appropriate patient triage, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified. EXPERIMENTAL DESIGN: We conducted a pilot study consisting of 40 patient urine samples (20 from each group), using label-free quantitative (LFQ) mass spectrometry, to identify potential biomarker candidates in urine from individual ovarian cancer patients. To validate these changes, we used parallel reaction monitoring (PRM) to investigate their abundance in an independent validation cohort (n = 20) of patient urine samples. RESULTS: LFQ analyses identified 4394 proteins (17 027 peptides) in a discovery set of 20 urine samples. Twenty-three proteins were significantly elevated in the malignant patient group compared to patients with benign disease. Several proteins, including LYPD1, LYVE1, PTMA, and SCGB1A1 were confirmed to be enriched in the urine of ovarian cancer patients using PRM. We also identified the established ovarian cancer biomarkers WFDC2 (HE4) and mesothelin (MSLN), validating our approach. CONCLUSIONS AND CLINICAL RELEVANCE: This is the first application of a LFQ-PRM workflow to identify and validate ovarian cancer-specific biomarkers in patient urine samples. PMID- 29426059 TI - Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis. AB - OBJECTIVE: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies. METHODS: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA. RESULTS: As expected, the HLA region was strongly associated with RF positive polyarticular JIA (P = 5.51 * 10-31 ). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16-29 years than to that of RA patients with age at onset >=70 years. CONCLUSION: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies. PMID- 29426061 TI - Microbiome-based mechanisms hypothesized to initiate obesity-associated rheumatoid arthritis. AB - Worldwide, the growing obesity pandemic contributes to a range of chronic diseases. Recent epidemiological studies have suggested an association between obesity and the development of rheumatoid arthritis (RA), particularly among young women, whereby pro-inflammatory effects of adipokines provide one explanatory hypothesis. Yet, recent clinical and laboratory-based studies provide emerging evidence indicating microbiome involvement in RA initiation and development, including anti-citrullinated antibody formation and Th17 cell activation. Obesity and RA-associated microbiome alteration might provide a plausible link to address the impact of obesity to RA pathogenesis. The microbiome's influence on RA development - at mucosal as well as articular sites and relevant pathophysiological mechanisms regarding obesity's association with RA are presented herein to discuss this hypothesis and aid understanding of obesity's role in RA development. PMID- 29426062 TI - Prediction of designer drugs: Synthesis and spectroscopic analysis of synthetic cathinone analogs that may appear on the Swedish drug market. AB - The use of hyphenated analytical techniques in forensic drug screening enables simultaneous identification of a wide range of different compounds. However, the appearance of drug seizures containing new substances, mainly new psychoactive substances (NPS), is steadily increasing. These new and other already known substances often possess structural similarities and consequently they exhibit spectral data with slight differences. This situation has made the criteria that ensure indubitable identification of compounds increasingly important. In this work, 6 new synthetic cathinones that have not yet appeared in any Swedish drug seizures were synthesized. Their chemical structures were similar to those of already known cathinone analogs of which 42 were also included in the study. Hence, a total of 48 synthetic cathinones making up sets of homologous and regioisomeric compounds were used to challenge the capabilities of various analytical techniques commonly applied in forensic drug screening, ie, gas chromatography-mass spectrometry (GC-MS), gas chromatography-Fourier transform infrared spectroscopy (GC-FTIR), nuclear magnetic resonance (NMR), and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Special attention was paid to the capabilities of GC-MS and GC-FTIR to distinguish between the synthetic cathinones and the results showed that neither GC-MS nor GC FTIR alone can successfully differentiate between all synthetic cathinones. However, the 2 techniques proved to be complementary and their combined use is therefore beneficial. For example, the structural homologs were better differentiated by GC-MS, while GC-FTIR performed better for the regioisomers. Further, new spectroscopic data of the synthesized cathinone analogs is hereby presented for the forensic community. The synthetic work also showed that cathinone reference compounds can be produced in few reaction steps. PMID- 29426063 TI - Differential Imaging Features of Widening and Pseudo-Widening of the Sacroiliac Joints. PMID- 29426065 TI - A review of machine learning in obesity. AB - Rich sources of obesity-related data arising from sensors, smartphone apps, electronic medical health records and insurance data can bring new insights for understanding, preventing and treating obesity. For such large datasets, machine learning provides sophisticated and elegant tools to describe, classify and predict obesity-related risks and outcomes. Here, we review machine learning methods that predict and/or classify such as linear and logistic regression, artificial neural networks, deep learning and decision tree analysis. We also review methods that describe and characterize data such as cluster analysis, principal component analysis, network science and topological data analysis. We introduce each method with a high-level overview followed by examples of successful applications. The algorithms were then applied to National Health and Nutrition Examination Survey to demonstrate methodology, utility and outcomes. The strengths and limitations of each method were also evaluated. This summary of machine learning algorithms provides a unique overview of the state of data analysis applied specifically to obesity. PMID- 29426064 TI - Successful weight loss initiation and maintenance among adolescents with overweight and obesity: does age matter? AB - Treatments for adolescents with overweight/obesity demonstrate mixed success, which may be due to a lack of consideration for developmental changes during this period. Potential developmental differences in weight loss motivations, weight maintenance behaviours and the role of parents in these efforts were examined in a sample of successful adolescent weight losers. Participants enrolled in the Adolescent Weight Control Registry (n = 49) self-reported demographic information and weight history, reasons for weight loss and weight control, weight loss approach and weight maintenance strategies, and perceived parental involvement with weight loss. Associations between age at weight loss initiation and the aforementioned factors were examined using linear and generalized regressions, controlling for highest z-BMI and sex. Adolescents who were older (>=16 years) at their weight loss initiation were more likely to report losing weight on their own (37.5% vs. 75%, P = 0.01) and reported greater responsibility for their weight loss and weight loss maintenance (P < 0.001) compared to younger adolescents. Younger age at weight loss initiation was associated with greater parental involvement (P = 0.005), whereas older age was associated with greater adolescent responsibility for the decision to lose weight (P = 0.002), the weight loss approach (P = 0.007) and food choices (P < 0.001). Findings suggest the importance of considering developmental differences in responsibility for weight loss and maintenance among adolescents with overweight/obesity. PMID- 29426066 TI - Screening High-Resolution Computed Tomography of the Chest to Detect Interstitial Lung Disease in Systemic Sclerosis: A Global Survey of Rheumatologists. PMID- 29426067 TI - Reversal of Sepsis-Like Features of Neutrophils by Interleukin-1 Blockade in Patients With Systemic-Onset Juvenile Idiopathic Arthritis. AB - OBJECTIVE: Neutrophils are the most abundant innate immune cells in the blood, but little is known about their role in (acquired) chronic autoinflammatory diseases. This study was undertaken to investigate the role of neutrophils in systemic-onset juvenile idiopathic arthritis (JIA), a prototypical multifactorial autoinflammatory disease that is characterized by arthritis and severe systemic inflammation. METHODS: Fifty patients with systemic-onset JIA who were receiving treatment with recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) were analyzed at disease onset and during remission. RNA sequencing was performed on fluorescence-activated cell-sorted neutrophils from 3 patients with active systemic-onset JIA and 3 healthy controls. Expression of activation markers, apoptosis, production of reactive oxygen species (ROS), and degranulation of secretory vesicles from neutrophils were assessed by flow cytometry in serum samples from 17 patients with systemic-onset JIA and 15 healthy controls. RESULTS: Neutrophil counts were markedly increased at disease onset, and this correlated with the levels of inflammatory mediators. The neutrophil counts normalized within days after the initiation of rIL-1Ra therapy. RNA-sequencing analysis revealed a substantial up-regulation of inflammatory processes in neutrophils from patients with active systemic-onset JIA, significantly overlapping with the transcriptome of sepsis. Correspondingly, neutrophils from patients with active systemic-onset JIA displayed a primed phenotype that was characterized by increased ROS production, CD62L shedding, and secretory vesicle degranulation, which was reversed by rIL-1Ra treatment in patients who had achieved clinical remission. Patients with a short disease duration had high neutrophil counts, more immature neutrophils, and a complete response to rIL-1Ra, whereas patients with symptoms for >1 month had normal neutrophil counts and an unsatisfactory response to rIL-1Ra. In vitro, rIL-1Ra antagonized the priming effect of IL-1beta on neutrophils from healthy subjects. CONCLUSION: These results strongly support the notion that neutrophils play an important role in systemic-onset JIA, especially in the early inflammatory phase of the disease. The findings also demonstrate that neutrophil numbers and the inflammatory activity of systemic-onset JIA are both susceptible to IL-1 blockade. PMID- 29426068 TI - [In process]. PMID- 29426069 TI - [In process]. PMID- 29426070 TI - [In process]. PMID- 29426071 TI - [In process]. PMID- 29426072 TI - [In process]. PMID- 29426073 TI - [In process]. PMID- 29426074 TI - [In process]. PMID- 29426075 TI - [In process]. PMID- 29426076 TI - [In process]. PMID- 29426077 TI - [In process]. PMID- 29426078 TI - [In process]. PMID- 29426079 TI - [In process]. PMID- 29426080 TI - [In process]. PMID- 29426081 TI - [In process]. PMID- 29426082 TI - [In process]. PMID- 29426083 TI - [In process]. PMID- 29426084 TI - [In process]. PMID- 29426085 TI - [In process]. PMID- 29426086 TI - [Letter to the Editor]. PMID- 29426087 TI - [Reply]. PMID- 29426088 TI - [In process]. PMID- 29426089 TI - [In process]. PMID- 29426090 TI - [In process]. PMID- 29426091 TI - [In process]. PMID- 29426092 TI - [In process]. PMID- 29426093 TI - [In process]. PMID- 29426094 TI - [In process]. PMID- 29426095 TI - [In process]. PMID- 29426096 TI - [In process]. PMID- 29426097 TI - [In process]. PMID- 29426098 TI - [In process]. PMID- 29426099 TI - [In process]. PMID- 29426100 TI - [In process]. PMID- 29426102 TI - [In process]. PMID- 29426101 TI - [In process]. PMID- 29426103 TI - [Letter to the Editor]. PMID- 29426104 TI - [Reply]. PMID- 29426105 TI - [In process]. PMID- 29426106 TI - [In process]. PMID- 29426107 TI - [In process]. PMID- 29426108 TI - [In process]. PMID- 29426109 TI - [In process]. PMID- 29426110 TI - [In process]. PMID- 29426111 TI - [In process]. PMID- 29426112 TI - [In process]. PMID- 29426113 TI - [In process]. PMID- 29426114 TI - [In process]. PMID- 29426115 TI - [In process]. PMID- 29426116 TI - [In process]. PMID- 29426117 TI - [In process]. PMID- 29426118 TI - [In process]. PMID- 29426119 TI - Multistressor effects on river biofilms under global change conditions. AB - Freshwater ecosystems are confronted with multiple chemical, biological and physical stressors. Co-occurring stressors commonly result in additive responses, but non-additive interactions may also occur, hindering our predicting capacity. Despite growing interest in multiple stressor research, the response of freshwater communities to co-occurring chemical and climate change-related physical stressors remains largely unexplored. Here, we used a microcosm approach to evaluate the effect of the combined action of chemical and physical stressors on river biofilms. Results showed that additive responses dominated, whereas 14.5% of all responses were non-additive (75% antagonisms and 25% synergisms). Among these non-additive interactions, physical stressors dominated over chemicals and drove the overall responses. Overall, the occurrence of these non additive interactions, together with the dominance of the climate-change related physical stressors, might lead to unexpected responses as a result of climate change. PMID- 29426120 TI - Contaminants of emerging concern in the Hartbeespoort Dam catchment and the uMngeni River estuary 2016 pollution incident, South Africa. AB - A quantitative assessment of pollutants of emerging concern in the Hartbeespoort Dam catchment area was conducted using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to establish the occurrence, source and distribution of 15 environmental pollutants, including 10 pharmaceuticals, 1 pesticide and 4 steroid hormones. Seasonal sampling was conducted in the Hartbeespoort Lake using sub-surface grab sampling to determine the lake's ecological status and obtain data for establishment of progressive operational monitoring. The Jukskei River, which lies upstream of the Hartbeespoort Dam, was sampled in the winter season. Five year old carp (Cyprinus carpio) and catfish (Clarias gariepinus) were also sampled from the Hartbeespoort Dam to study bioaccumulation in biota as well as to estimate risk associated with fish consumption. In the Jukskei River, the main source of 11 emerging pollutants (EPs) was identified as raw sewage overflow, with the highest ?11 EP concentration of 593ngL-1 being recorded at the Midrand point and the lowest ?11 EP concentration of 164ngL-1 at the N14 site located 1km downstream of a large wastewater treatment plant. The Jukskei River was found to be the largest contributor of the emerging contaminants detected in the Hartbeespoort Dam. In the Hartbeespoort Dam EP concentrations were generally in the order efavirenz>nevirapine>carbamazepine>methocarbamol>bromacil>venlafaxine. Water and sediment were sampled from the uMngeni River estuary within 24h after large volumes of an assortment of pharmaceutical waste had been discovered to be washed into the river estuary after flash rainfall on 18 May 2016. Analytical results revealed high levels of some emerging pollutants in sediment samples, up to 81ngg-1 for nevirapine and 4ngg-1 for etilefrine HCL. This study shows that efavirenz, nevirapine, carbamazepine, methocarbamol, bromacil and venlafaxine are contaminants that require operational monitoring in South African urban waters. PMID- 29426121 TI - The impact of human activities and lifestyles on the interlinked microbiota and health of humans and of ecosystems. AB - Plants, animals and humans, are colonized by microorganisms (microbiota) and transiently exposed to countless others. The microbiota affects the development and function of essentially all organ systems, and contributes to adaptation and evolution, while protecting against pathogenic microorganisms and toxins. Genetics and lifestyle factors, including diet, antibiotics and other drugs, and exposure to the natural environment, affect the composition of the microbiota, which influences host health through modulation of interrelated physiological systems. These include immune system development and regulation, metabolic and endocrine pathways, brain function and epigenetic modification of the genome. Importantly, parental microbiotas have transgenerational impacts on the health of progeny. Humans, animals and plants share similar relationships with microbes. Research paradigms from humans and other mammals, amphibians, insects, planktonic crustaceans and plants demonstrate the influence of environmental microbial ecosystems on the microbiota and health of organisms, and indicate links between environmental and internal microbial diversity and good health. Therefore, overlapping compositions, and interconnected roles of microbes in human, animal and plant health should be considered within the broader context of terrestrial and aquatic microbial ecosystems that are challenged by the human lifestyle and by agricultural and industrial activities. Here, we propose research priorities and organizational, educational and administrative measures that will help to identify safe microbe-associated health-promoting modalities and practices. In the spirit of an expanding version of "One health" that includes environmental health and its relation to human cultures and habits (EcoHealth), we urge that the lifestyle-microbiota-human health nexus be taken into account in societal decision making. PMID- 29426122 TI - Analysis of stimulant drugs in the wastewater of five Nordic capitals. AB - Wastewater-based epidemiology is an efficient way to assess illicit drug use, complementing currently used methods retrieved from different data sources. The aim of this study is to compare stimulant drug use in five Nordic capital cities that include for the first time wastewater samples from Torshavn in the Faroe Islands. Currently there are no published reports that compare stimulant drug use in these Nordic capitals. All wastewater samples were analyzed using solid phase extraction and ultra-high performance liquid chromatography coupled to tandem mass spectrometry. The results were compared with data published by the European Monitoring Centre for Drugs and Drug Addiction based on illicit drugs in wastewater from over 50 European cities. Confirming previous reports, the results showed high amphetamine loads compared with other European countries. Very little apparent abuse of stimulant drugs was detected in Torshavn. Methamphetamine loads were the highest from Helsinki of the Nordic countries, indicating substantial fluctuations in the availability of the drug compared with previous studies. Methamphetamine loads from Oslo confirmed that the use continues to be high. Estimated cocaine use was found to be in the lower range compared with other cities in the southern and western part of Europe. Ecstasy and cocaine showed clear variations between weekdays and weekends, indicating recreational use. This study further demonstrates geographical trends in the stimulant drug market in five Nordic capitals, which enables a better comparison with other areas of the continent. PMID- 29426123 TI - Impervious area percentage predicated influence of rapid urbanization on macroinvertebrate communities in a southwest China river system. AB - Urban areas and their development depress water physicochemical properties, river habitats and aquatic biotic integrity worldwide. Benthic macroinvertebrates at 61 sites representing three types of river reach locations (upstream rural areas, intermediate and downstream of urban areas) on the Liangtan River, a rapidly urbanized river with untreated sewage discharge in southwest China, were examined to compare their community composition and diversity. Their relationships with environmental variables were also explored. The results indicate a significant reduction in sensitive EPT (Ephemeroptera, Plecoptera and Trichoptera) species, dominance by a few tolerant taxa (Oligochaeta and Chironomidae), a significant decline in biodiversity and dominance of collector-gatherers at intermediate and downstream urban sites compared with aquatic macroinvertebrates at rural sites. The community composition of urban sites were different from those of rural sites and were quite similar to those of downstream sites, but maintained a much higher Oligochaeta density. The species-environment relation was predominately explained by the percentage of impervious area (PIA) and farmland at the catchment scale. At the local scale chemical oxygen demand (COD) and pH-value explained this relationship. Six community indicators, including richness, the Shannon-Wiener index, EPT(%), collector-filterers(%), scrapers(%) and collector-gatherers(%), had exponential relationships with PIA. Density of macroinvertebrates, Oligochaeta density, Oligochaeta(%), predator(%) and shredder(%) exhibited stepped threshold response patterns with PIA. Pielou's index had an approximately negative linear relationship with PIA. For exponential pattern, a threshold value of PIA between 10.6% and 14.4% was found. For stepped threshold response pattern, the first threshold was between 11.2% and 13.8%, and the second threshold was 23.8%. Our study indicates particularly great influences of urbanization with untreated sewage on macroinvertebrates and river ecosystems. PIA also showed to be a good indicator of urbanization and an accurate predictor of urban impacts on river macroinvertebrate integrity. PMID- 29426124 TI - Spatial analysis of the risk to human health from exposure to arsenic contaminated groundwater: A kriging approach. AB - A long-term groundwater quality survey in northeastern Taiwan's Lanyang Plain has revealed obvious contamination of the groundwater in some areas, with measured As concentrations in excess of the acceptable level of 10MUg/L. Efforts for assessing the health risk associated with the intake of As through the drinking of contaminated groundwater are a necessary part of the important work of health risk management. However, the standard approach to assessing risks to human health does not adequately account for spatial heterogeneity in the measured As concentrations. Thus, this study applies two different kriging approaches to carry out a spatial analysis of the health risk associated with ingesting As through the drinking of groundwater in the Lanyang Plain. It is found that the indicator kriging (IK) approach, with occurrence probability threshold values of 0.4, 0.5 and 0.6 yields correct classification percentages of 75%, 68% and 61%, respectively, of unacceptable HQ zones. An HQ map prepared with the ordinary kriging (OK) approach shows a correct classification of unacceptable HQ zones of 80%. Considering that the OK approach does not require subjective selection of an occurrence probability threshold value as is the case with the IK approach and can yield a higher percentage of correct classification for unacceptable HQ zones, it is recommended as a more direct and reliable method for spatial analysis of human health risk due to arsenic exposure through the drinking of groundwater. The results show that the geographical distribution of unacceptable HQ zones is concentrated in the eastern part of the study area, which includes the high-population density townships. In other words, 34% of the people had access to groundwater where the HQ was >1. The results of this type of spatial health risk assessment can provide a basis for improving the decision-making process for health risk management. PMID- 29426125 TI - Biodegradation of the sulfonamide antibiotic sulfamethoxazole by sulfamethoxazole acclimatized cultures in microbial fuel cells. AB - Microbial fuel cells (MFCs) are known for their ability to enhance the removal rate of toxins while generating power. This research presents a performance assessment of MFCs for power generation and sulfamethoxazole (SMX) degradation using SMX acclimatized cultures. Experiments were performed in MFC batch mode using different SMX concentrations in synthetic wastewater. The experimental results showed that voltage generation was >400mV up to the SMX concentration of 0.20mM (at 400Omega external resistance). Control experiments supported the inference that biodegradation was the main process for SMX removal compared to sorption by SMX acclimatized cultures and that the process results in efficient removal of SMX in MFC mode. The specific removal rates of SMX in MFC with SMX acclimatized sludge were 0.67, 1.37, 3.43, 7.32, and 13.36MUm/h at initial SMX concentrations of 0.04, 0.08, 0.20, 0.39, and 0.79mM, respectively. Moreover, the MFC was able to remove >90% of the TOC from the wastewater up to SMX concentrations of 0.08mM. However, this TOC removal produces negative effects at higher SMX concentrations due to toxic intermediates. Microbial community analysis revealed large changes in bacterial communities at the phylum, class, and genus levels after SMX acclimatization and MFC operation. Thauera, a well known aromatic-degrading bacteria, was the most dominant genus present in post acclimatized conditions. In summary, this study showed that acclimatized sludge can play an important role in the biodegradation of SMX in MFCs. PMID- 29426126 TI - Recent developments of anthropogenic air pollutant emission inventories in Guangdong province, China. AB - Emission inventory (EI) requires continuous updating to improve its quality and reduce its uncertainty. In this study, recent developments on source classification, emission methods, emission factors and spatial-temporal surrogates in the Guangdong regional anthropogenic emission inventory are presented. The developments include: ~40 additional emission sources in a re classified source classification system, >50 improved spatial and temporal surrogates, 85% of local/domestic emission factors used, and updated estimation methods of on-road mobile, marine, and solvent use sources. The developments were updated to the recent 2012-based high resolution emission inventories, and their results were compared with previous 2006- and 2010-based emission inventories. The results indicated: (1) The total SO2, NOx, CO, PM10, PM2.5, BC, OC, VOCs and NH3 emissions in 2012 were 777.0kt, 1532.2kt, 7305.4kt, 1176.4kt, 480.9kt, 54.2kt, 79.9kt, 1255.1kt and 584.1kt, respectively, for Guangdong province, with higher emission densities observed in the central PRD region. (2) No great changes on source structures were found among three years, but their contributions varied. (3) SO2, PM10 and PM2.5 emissions showed downward trends, likely a result of strict control measures on power plant and industrial combustion sources. (4) NOx emission exhibited relatively stable levels in 2010 and 2012, but contributions from industrial, on-road and non-road mobile sources increased. (5) VOCs emissions showed an upward trend, mainly resulting from dramatically increased light-duty passenger car population and solvent use. (6) Spatial and temporal allocations were updated with constant improvements of spatial and temporal surrogates. (7) Uncertainty ranges of emission estimates were reduced, indicating that the 2012-based PRD regional EI are more reliable. The work shown in this study can be a reference example for other regions to continuously update their emission inventories. PMID- 29426127 TI - Disentangling multiple pressures on fish assemblages in large rivers. AB - European large rivers are exposed to multiple human pressures and maintained as waterways for inland navigation. However, little is known on the dominance and interactions of multiple pressures in large rivers and in particular inland navigation has been ignored in multi-pressure analyzes so far. We determined the response of ten fish population metrics (FPM, related to densities of diagnostic guilds and biodiversity) to 11 prevailing pressures including navigation intensity at 76 sites in eight European large rivers. Thereby, we aimed to derive indicative FPM for the most influential pressures that can serve for fish-based assessments. Pressures' influences, impacts and interactions were determined for each FPM using bootstrapped regression tree models. Increased flow velocity, navigation intensity and the loss of floodplains had the highest influences on guild densities and biodiversity. Interactions between navigation intensity and loss of floodplains and between navigation intensity and increased flow velocity were most frequent, each affecting 80% of the FPM. Further, increased sedimentation, channelization, organic siltation, the presence of artificial embankments and the presence of barriers had strong influences on at least one FPM. Thereby, each FPM was influenced by up to five pressures. However, some diagnostic FPM could be derived: Species richness, Shannon and Simpson Indices, the Fish Region Index and lithophilic and psammophilic guilds specifically indicate rhithralisation of the potamal region of large rivers. Lithophilic, phytophilic and psammophilic guilds indicate disturbance of shoreline habitats through both (i) wave action induced by passing vessels and (ii) hydromorphological degradation of the river channel that comes along with inland navigation. In European large rivers, inland navigation constitutes a highly influential pressure that adds on top of the prevailing hydromorphological degradation. Therefore, river management has to consider river hydromorphology and inland navigation to efficiently rehabilitate the potamal region of large rives. PMID- 29426128 TI - Intake estimates of dioxins and dioxin-like polychlorobiphenyls in the Italian general population from the 2013-2016 results of official monitoring plans in food. AB - The implementation of the European Union strategy for polychlorodibenzo-dioxins and -furans (PCDD/Fs), and dioxin-like polychlorobiphenyls (DL-PCBs) is determining a general reduction of their presence in the environment and in the food chain. The most important route for human exposure to these substances is food consumption and, as a consequence, a progressive decrease of their dietary intake has been observed in the last decades. In this context, it seemed worth updating the PCDD/F and DL-PCB intake estimation for the Italian population. A total of 2659 samples of food of animal and vegetable origin analyzed for PCDD/Fs and DL-PCBs in the period 2013-2016 by accredited official laboratories and the national food consumption database were considered for the dietary intake assessment in different age groups of the Italian general population The median cumulative intake estimates expressed as pg WHO-TEQ/kg body weight per day and computed with a deterministic and a probabilistic approach were 1.40-1.52 for children, 0.82-0.85 for adolescents, and 0.64-0.61 for adults, respectively. Such results confirm the decreasing trend of PCDD/F and DL-PCB dietary intake even though the Tolerable Daily Intake (TDI) value of 2 WHO-TEQ/kg body weight per day is exceeded at the 95th percentile for all age groups, with children as sensitive group. Most contributing food categories to the intake resulted fish, food of vegetable origin, and cheese. A sensitivity analysis was also performed to calculate the target contamination levels able to keep the dietary exposure below the TDI. Computed target levels fall between P50 and P97 of the occurrence distribution of the main food groups, meaning that most of the Italian food production can be considered safe. PMID- 29426129 TI - Multielement geochemistry identifies the spatial pattern of soil and sediment contamination in an urban parkland, Western Australia. AB - Urban environments are dynamic and highly heterogeneous, and multiple additions of potential contaminants are likely on timescales which are short relative to natural processes. The likely sources and location of soil or sediment contamination in urban environment should therefore be detectable using multielement geochemical composition combined with rigorously applied multivariate statistical techniques. Soil, wetland sediment, and street dust was sampled along intersecting transects in Robertson Park in metropolitan Perth, Western Australia. Samples were analysed for near-total concentrations of multiple elements (including Cd, Ce, Co, Cr, Cu, Fe, Gd, La, Mn, Nd, Ni, Pb, Y, and Zn), as well as pH, and electrical conductivity. Samples at some locations within Robertson Park had high concentrations of potentially toxic elements (Pb above Health Investigation Limits; As, Ba, Cu, Mn, Ni, Pb, V, and Zn above Ecological Investigation Limits). However, these concentrations carry low risk due to the main land use as recreational open space, the low proportion of samples exceeding guideline values, and a tendency for the highest concentrations to be located within the less accessible wetland basin. The different spatial distributions of different groups of contaminants was consistent with different inputs of contaminants related to changes in land use and technology over the history of the site. Multivariate statistical analyses reinforced the spatial information, with principal component analysis identifying geochemical associations of elements which were also spatially related. A multivariate linear discriminant model was able to discriminate samples into a-priori types, and could predict sample type with 84% accuracy based on multielement composition. The findings suggest substantial advantages of characterising a site using multielement and multivariate analyses, an approach which could benefit investigations of other sites of concern. PMID- 29426130 TI - Combining monitoring and modelling tools as a basis for city-scale concepts for a sustainable thermal management of urban groundwater resources. AB - Increasing anthropogenic impacts lead to elevated temperatures of the shallow subsurface, including the unsaturated and groundwater saturated zone, in many urban areas in comparison to unaffected natural thermal states. The "current thermal state" of four groundwater bodies in the urban area of Basel-City, Switzerland, was investigated by means of high-resolution multilevel temperature wells and numerical 3D groundwater flow and heat transport models. The calibrated and validated numerical groundwater flow and heat transport models allow evaluating and comparing groundwater and heat fluxes for the investigated groundwater bodies and defined cross-sections for differing urban districts, e.g. residential and industrial areas under development. We present the overall and the specific advective heat fluxes within two urban districts, which will be restructured in the near future. The management of groundwater resources in urban areas plays an important role not only for groundwater quantity but also for its quality, i.e. thermal subsurface and groundwater regimes. We demonstrate how monitoring and modelling tools can be the basis for a sustainable management of complex urban groundwater resources. Furthermore, we argue that such tools should be integrated in the thermal management of urban groundwater bodies. Such tools also allow integrating the potentially available energy of shallow subsurface resources into energetic management strategies on the urban scale. PMID- 29426131 TI - Coarse particle (PM10-2.5) source profiles for emissions from domestic cooking and industrial process in Central India. AB - To develop coarse particle (PM10-2.5, 2.5 to 10MUm) chemical source profiles, real-world source sampling from four domestic cooking and seven industrial processing facilities were carried out in "Raipur-Bhilai" of Central India. Collected samples were analysed for 32 chemical species including 21 elements (Al, As, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, Pb, S, Sb, Se, V, and Zn) by atomic absorption spectrophotometry (AAS), 8 water-soluble ions (Na+, K+, Mg2+, Ca2+, Cl-, F-, NO3-, and SO42-) by ion chromatography, ammonium (NH4+) by spectrophotometry, and carbonaceous fractions (OC and EC) by thermal/optical transmittance. The carbonaceous fractions were most abundant fraction in household fuel and municipal solid waste combustion emissions while elemental species were more abundant in industrial emissions. Most of the elemental species were enriched in PM2.5 (<2.5MUm) size fraction as compared to the PM10-2.5 fraction. Abundant Ca (13-28%) was found in steel-rolling mill (SRM) and cement production industry (CPI) emissions, with abundant Fe (14-32%) in ferro-manganese (FEMNI), steel production industry (SPI), and electric-arc welding emissions. High coefficients of divergence (COD) values (0.46 to 0.88) among the profiles indicate their differences. These region-specific source profiles are more relevant to source apportionment studies in India than profiles measured elsewhere. PMID- 29426132 TI - Life cycle analysis of a new modular greening system. AB - The construction and use of buildings represent about half of the extracted materials and energy consumption, and around one third of the water consumption and waste produced in the European Union. Therefore it is becoming more important to use sustainable materials that reduce the environmental impacts of construction, by conserving and using resources more efficiently. Green walls can be used as a sustainable strategy to reduce the environmental impact of buildings. The aim of this study is to evaluate the environmental impact of a new modular system for green roofs and green walls (Geogreen) which uses waste and sustainable materials in its composition. A life cycle analysis (LCA) is used to evaluate the long term environmental benefits of this system. The life cycle analysis (LCA) is carried according to ISO 14040/44 using GaBi software and CML 2001 impact category indicators. The adopted functional unit is the square meter of each material required to assemble the Geogreen system. This study also compares the environmental performance of the Geogreen system with other living wall systems and other cladding materials using data from the literature. This LCA study of the Geogreen system became relevant to identify a curing process with a major impact on GWP due to the energy consumed in this process. A change on this process allowed reducing 74% of the overall GWP. After this change it can be noticed that the Geogreen System presents one of the lowest environmental burden when compared to other construction systems. PMID- 29426133 TI - Characterization of brominated disinfection byproducts formed during chloramination of fulvic acid in the presence of bromide. AB - To date, study on the speciation of brominated disinfection byproducts (Br-DBPs), which have higher cytotoxicity and genotoxicity than their analogous chlorinated DBPs (Cl-DBPs), formed in chloramination is still limited. In this study, the previous unknown Br-DBPs formed during chloramination of artificial drinking water were explored with electrospray ionization ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS). In total, 193 formulae of one bromine containing Br-DBPs and 5 formulae of two bromine containing Br-DBPs were detected in the chloraminated artificial drinking water sample. Compared to Br-DBPs formed in chlorination, Br-DBPs formed in chloramination have relatively high O/C ratio for the same nominal molecular mass. More than 63% of the Br-DBPs formed during chloramination can be classified as aromatic molecules or polycyclic aromatic molecules, according to their modified aromaticity index (AImod). Further investigation on the change of precursor SRFA molecules during chloramination showed that SRFA molecules with high O/C ratio and low H/C ratio were more reactive and decreased significantly in relative abundance during chloramination. Precursor SRFA molecules with high degree of oxidation and high unsaturation were preferred to form Br-DBPs during chloramination. The results reported in this study provide valuable information on Br-DBPs formed during chloramination and may help us in minimizing DBPs during chloramination. PMID- 29426134 TI - Assessment of toxic metal contamination using a regional lithogenic geochemical background, Pampean area river basin, Argentina. AB - Contamination assessment in riverbed sediments depends on the accurate determination of the background values. The aim of this study is to assess the degree of contamination and to evaluate the most adequate background for the determination of anthropogenic contamination in Cd, Cr, Cu, Ni, Pb and Zn in bed sediments of the Pampean area river basin (Matanza-Riachuelo River and tributary streams), Argentina. The geo-accumulation index (Igeo) values were calculated using selected lithogenic backgrounds (loess, loessoid sediments and paleosoils), the metal concentrations in the residual fraction (F4) in riverbed sediments and a global average shale often applied in the estimation of toxic metal Igeo. The IgeoF4, IgeoLZB and most of the others Igeos, indicated that in land areas used mainly for agriculture and cattle grazing, the superficial sediments were uncontaminated with Cd, Cr, Cu and Zn, and slightly contaminated with Ni and Pb. Conversely, in those areas dedicated to urban and industrial use, the metal contamination was greater. Overall, the relatively significant anthropogenic contamination of Cr > Pb >= Cu > Zn > Ni > Cd in the Riachuelo River area was associated with metallurgic activities, tanning and industrial waste. The comparative analysis of different values suggested that Buenos Aires' "pristine" loess could be recommended to evaluate the Igeo index of riverbed sediments in the Pampean area. To enhance the use of the selected background, the normalized enrichment factor using Al. In this study case, the Igeo and the EF using LZB background display the same trend, showing the greatest degree of contamination, as would be expected, in Riachuelo samples (RIA 1 and RIA 2) located in the urban/industrial area. PMID- 29426135 TI - Phthalates and polycyclic aromatic hydrocarbons (PAHs) in the indoor settled carpet dust of mosques, health risk assessment for public. AB - A number of studies have reported the occurrence of phthalates and polycyclic aromatic hydrocarbons (PAHs) in indoor settled dust from different occupational and residential settings around the world but limited studies are available from public and religious places. In recent decades Kingdom of Saudi Arabia (KSA) has experienced tremendous industrial growth especially in the petroleum industries, and as result environmental issues related with such industries have also increased but scientific data is still scarce to understand the impact on public health. Therefore, the main objective of this study was to report the phthalates and PAHs profile in the settled dust collected from various mosques of Jeddah, an important part of people living in the region, and to evaluate the health risk associated with these chemicals via dust ingestion, inhalation and dermal contact for the general public who attend mosques for prayers. Phenanthrene (500-3000 ng/g), pyrene (40-1220 ng/g), and chrysene (95-4590 ng/g) were the major PAHs and ?12PAHs concentrations ranged from 2550 to 9150 ng/g. Whereas, DEHP ( coral tissue > skeleton > reef sediment > seawater. The bioaccumulation of these compounds was 2-times higher in ahermatypic than in hermatypic corals, among which significant variations were observed in both sites. In Kharg, Porites lutea had the highest mean concentration of ?30n-alkanes and ?40PAHs in soft tissue, whereas the lowest values were in Platygyra daedalea. A contrasting trend was documented for ?22PCBs and 20PCNs, with the highest level reported in soft tissue of P. daedalea and the lowest in P. lutea at Kharg. Compositional pattern of AHs and PAHs demonstrated the predominance of LMW-PAHs and n-alkanes. In skeleton and reef sediments, tetra, penta and tri-CBs were the most abundant PCBs congeners followed by di-CB > hexa-CB > hepta-CB > octa-CB,whiletri-CB > di-CB > tetra-CB > penta-CB > hexa-CB > hepta-CB > octa-CB was observed for soft tissue, zooxanthellae and seawater. The results of RAD test indicated significantly negative correlation between total concentration of these compounds with zooxanthellae density, the chlorophyll-a and C2 in corals at both reefs. This is the first report on levels, health assessment and source apportionments of POPs in zooxanthellae and a first step in the implementation of specific coral reef management measures. PMID- 29426137 TI - Spatial pattern and variations in the prevalence of congenital heart disease in children aged 4-18 years in the Qinghai-Tibetan Plateau. AB - PURPOSE: This study aimed to investigate the spatial distribution pattern of the prevalence of congenital heart disease (CHD) in children in Qinghai-Tibetan Plateau (QTP), a high-altitude region in China. METHODS: Epidemiological data from a survey on the prevalence of CHD in Qinghai Province including 288,066 children (4-18 years) were used in this study. The prevalence and distribution pattern of CHD was determined by sex, CHD subtype, and nationality and altitude. Spatial pattern analysis using Getis-Ord Gi* was used to identify the spatial distribution of CHD. Bayesian spatial binomial regression was performed to examine the relationship between the prevalence of CHD and environmental risk factors in the QTP. RESULTS: The prevalence of CHD showed a significant spatial clustering pattern. The Tibetan autonomous prefecture of Yushu (average altitude > 4000 m) and the Mongolian autonomous county of Henan (average altitude > 3600 m) in Huangnan had the highest prevalence of CHD. Univariate analysis showed that with ascending altitude, the total prevalence of CHD, that in girls and boys with CHD, and that of the subtypes PDA and ASD increasing accordingly. Thus, environmental factors greatly contributed to the prevalence of CHD. CONCLUSIONS: The prevalence of CHD shows significant spatial clustering pattern in the QTP. The CHD subtype prevalence clustering pattern has statistical regularity which would provide convenient clues of environmental risk factors. Our results may provide support to make strategies of CHD prevention, to reduce the incidence of CHD in high altitude regions of China. PMID- 29426139 TI - Influence of natural organic matter in porous media on fine particle transport. AB - Although extensive research has been conducted to understand the effects of dissolved organic matter (DOM) on fine particle transport, less attention has been paid to natural organic matter (NOM) in the transport medium (i.e., immobile rock and sediment grains). The objective of this study is to elucidate the roles of NOM in the transport medium in mediating particle transport. We conducted experimental and modelling study on the transport of nanoscale titanium dioxide (nTiO2) and illite colloid in columns packed with quartz sand under water saturated conditions. Peat moss was used as an example NOM and packed in some of the columns to investigate its influence on particle transport. Experimental results showed that NOM may either increase or decrease particle transport depending on the specific conditions. NOM in the transport medium was found to attract particles and reduce particle mobility when the energy barrier between particle and NOM is low or non-existent. NOM also adsorb to Fe and Al oxyhydroxides and promote the transport of negatively-charged particles at low pH. Partial dissolution of NOM releases DOM, and the DOM adsorbs to and increases the transport of positively-charged particles. Additionally, NOM changes pore water pH, which influences particle mobility by affecting the interaction energy between the particle and transport medium. Modelling results showed that the deposition sites provided by peat moss are very heterogeneous, and the NOM from peat moss may reduce particle deposition rate by adsorbing to the particle and/or transport medium. Findings from this study demonstrate that NOM in the transport medium not only changes property of the medium, but also may alter water chemistry. Therefore, the role of NOM in mediating particle transport is complicated and dependent on the property of the particle, NOM, and mineralogical composition of the medium. PMID- 29426138 TI - Nitrogen cycling in the soil-plant system along a series of coral islands affected by seabirds in the South China Sea. AB - The nitrogen (N) utilization strategy of plants has become a topic of interest within the field of phytoecology. However, few studies have considered N cycling on coral island ecosystems from the perspective of their evolution. The aim of this study was to test the impacts of biological transport by seabirds, on the sources and uses of N by plants, and pathways of N cycling in soil-plant ecosystems on coral islands. A series of eight coral islands were investigated, five of which were affected to a varying extent by seabirds. The total phosphorus (TP) concentration from avian sources and the delta15N values of total nitrogen (TN) and inorganic nitrogen (IN: NH4+-N, and NO3--N), delta18O of NO3--O, in soils were determined, as well as proxies in plant leaves of two dominant plant species, including TN, the carbon/nitrogen ratio (C/N), and delta13C and delta15N values. The results show that, with an increase of TP, the TN and IN content, and delta15N values in soils all increased. Plant C/N and delta15N values decreased and increased, respectively, as the soil N content increased. When the TN content of the soil was low, the delta15N value in plant leaves was similar to that in soil NO3-, but was much lower than that in soil NH4+. When the soil TN content was high, the delta15N values were similar. Both plants and soil were probably N limited prior to seabird colonization, with the N source on the barren coral islands originating primarily from atmospheric deposition. With seabird guano input and subsequent pedogenesis, the source of N switched to guano. Under these conditions, most of the N utilized by plants originated from NH4+, while nitrate is dominant for non-seabirds islands. Seabird activities have played a key role in the N dynamics of soil-plant ecosystems at coral islands. PMID- 29426140 TI - Influence of technical maintenance measures on ecological status of agricultural lowland rivers - Systematic review and implications for river management. AB - Intensification of agriculture and ongoing urban sprawl exacerbate pressures on rivers. Small rivers in agricultural landscapes are especially exposed to excessive technical actions implemented in order to allow for harvesting river water for irrigation, draining agricultural water and receiving sewage. Regular dredging and macrophyte removal strongly interfere with the global need for preserving river biodiversity that allows agricultural lowland rivers to remain refuges for a variety of species, and-accordingly-to keep water bodies resilient for the benefit of society. In order to provide a comprehensive look at the influence of agricultural lowland river management on the ecological status of these water bodies, we conducted a literature review and a meta-analysis. For the structured literature review we selected 203 papers reflecting on the response of aquatic ecosystems to dredging and macrophyte management actions. The database of scientific contributions developed for our study consists of papers written by the authors from 33 countries (first authorship) addressing dredging, macrophyte removal, status of fish and macroinvertebrates as well as the general ecological status of lowland agricultural rivers. We revealed that 96% of the analyzed papers indicated unilateral, negative responses of aquatic ecosystems, particularly macroinvertebrates, ichthyofauna and macrophyte composition, to maintenance measures. We revealed that studies conducted in the European Union on the ecological status of rivers appeared to significantly increase in quantity after the implementation of the Water Framework Directive. Finally, we concluded that day-to-day management of lowland agricultural rivers requires revision in terms of compliance with environmental conservation requirements and the recurrent implementation of technical measures for river maintenance. PMID- 29426141 TI - Biogeography and ecological processes affecting root-associated bacterial communities in soybean fields across China. AB - Root-associated bacteria have profound effects on plant health and productivity, but their biogeographic patterns across large spatial scales remain poorly understood. Here, we used high-throughput sequencing to compare the bacterial distributions in the bulk soil, rhizosphere, and endosphere across 51 soybean fields in China. Environmental variables were more important than spatial variables, and edaphic variables were more important than climatic variables, for governing bacterial community turnover in each soil-root compartment. Both bacterial richness and community turnover were significantly correlated with different environmental and spatial variables among the three compartments. Their different spatial autocorrelation ranges for bacteria suggested distinct bacterial biogeographic patterns were present. The distributions of nearest taxon index (NTI) showed that deterministic processes dominated local bacterial communities, while its importance decreased from the bulk soil to the endosphere. These results provide new insights into the assembly of root-associated bacterial communities at a continental scale. PMID- 29426142 TI - Impact of synoptic weather patterns on 24 h-average PM2.5 concentrations in the North China Plain during 2013-2017. AB - North China Plain area (NCP) is one of the most densely populated and heavily polluted regions in the world. In the last five years, frequently happened fine particulate matter (PM2.5) serious pollution events were one of the top environmental concerns in China. As PM2.5 concentrations are highly influenced by synoptic flow patterns and local meteorological conditions, a two-stage hierarchical clustering method based on dynamic principal component analysis (DPCA) and standard k-means clustering algorithm was employed to classify synoptic wind fields into 6 patterns over the NCP area using the data of 5 PM2.5 seasons (Sept. 15th-Apr. 15th) from 2013 to 2017. Among the six identified synoptic patterns, pattern of uniform pressure field (U) and that of zonal high pressure (ZH) accounted for 78.21%, 65.55%, 63.56%, 57.11%, 59.13% and 58.27% studied heavy smog pollution events in Beijing, Tianjin, Tangshan, Baoding, Shijiazhuang and Xingtai city. The two particular patterns were associated with uniform pressure field and sparsely latitudinal isobar in 850 hPa level, respectively. They were also characterized by high relative humidity, low temperature, low-speed northerly wind in Tianjin and Tangshan, and southerly wind in the other cities. Under the continuous control of pattern ZH, the values of 24 h-average PM2.5 were found to increase at a rate of 31.78 MUg/m3 per day. To evaluate the contribution of meteorological factors and precursors to PM2.5 levels, linear mixed-effects models (LMMs) were applied to establish relations among 24 h-average PM2.5 concentrations, concentrations of main precursors, local meteorological factors and synoptic patterns. Results show that the variations of precursors, local meteorological factors and synoptic flow patterns can explain 51.67%, 19.15% and 14.01% changes of the 24 h-average PM2.5 concentrations, respectively. This study illustrates that dense precursor emissions are still the main cause for heavy haze pollution events, although meteorological conditions play almost equal roles sometimes. PMID- 29426143 TI - Association of ultrafine particles with cardiopulmonary health among adult subjects in the urban areas of northern Taiwan. AB - The association between short-term exposure to particulate air pollution, especially fine particles, and cardiopulmonary health has been well-established in previous studies. However, previous findings regarding the effect of ultrafine particles (UFPs) on cardiopulmonary health are inconsistent. We repeatedly measured the mass concentrations of UFPs using a Micro-Orifice Uniform Deposit Impactor (MOUDI) in the apartments of 100 adult participants and collected the participants' health data from the pulmonary outpatient unit of Shuang-Ho Hospital to investigate the association between short-term exposure to UFPs and cardiopulmonary health using mixed-effects models from January 1, 2014 to August 31, 2017. We also collected ambient air pollution monitoring data from the Taiwan Environmental Protection Administration for data analysis. We observed that an interquartile range increase in the 24-hour mean UFPs (0.97 MUg/m3) was associated with a 6.3% [95% confidence interval (CI) = 2.9, 9.7], 5.6% (95% CI = 4.1, 7.1) and 8.5% (95% CI = 3.9, 13.1) increase in systolic blood pressure, diastolic blood pressure and high sensitivity-C-reactive protein, respectively. We also observed the association of particulate matter less than or equal to 2.5 MUm in diameter and nitrogen dioxide with increased blood pressure and ozone with decreased lung function. A negative trend between UFPs and forced expiratory volume in the first second was observed. We concluded that short-term exposure to UFPs was associated with cardiovascular health in adult subjects in the urban areas of northern Taiwan. PMID- 29426144 TI - Influence of environmental changes on the biogeochemistry of arsenic in a soil polluted by the destruction of chemical weapons: A mesocosm study. AB - Thermal destruction of chemical munitions from World War I led to the formation of a heavily contaminated residue that contains an unexpected mineral association in which a microbial As transformation has been observed. A mesocosm study was conducted to assess the impact of water saturation episodes and input of bioavailable organic matter (OM) on pollutant behavior in relation to biogeochemical parameters. Over a period of about eight (8) months, the contaminated soil was subjected to cycles of dry and wet periods corresponding to water table level variations. After the first four (4) months, fragmented litter from the nearby forest was placed on top of the soil. The mesocosm solid phase was sampled by three rounds of coring: at the beginning of the experiment, after four (4) months (before the addition of OM), and at the end of the experiment. Scanning electron microscopy coupled to energy dispersive X-ray spectroscopy observations showed that an amorphous phase, which was the primary carrier of As, Zn, and Cu, was unstable under water-saturated conditions and released a portion of the contaminants in solution. Precipitation of a lead arsenate chloride mineral, mimetite, in soils within the water saturated level caused the immobilization of As and Pb. Mimetite is a durable trap because of its large stability domain; however, this precipitation was limited by a low Pb concentration inducing that high amounts of As remained in solution. The addition of forest litter modified the quantities and qualities of soil OM. Microbial As transformation was affected by the addition of OM, which increased the concentration of both As(III)-oxidizing and As(V)-reducing microorganisms. The addition of OM negatively impacted the As(III) oxidizing rate, however As(III) oxidation was still the dominant reaction in accordance with the formation of arsenate-bearing minerals. PMID- 29426145 TI - Sunlight irradiation triggers changes in the fouling potentials of natural dissolved organic matter. AB - Sunlight-initiated photodegradation has a great impact on the composition and properties of natural dissolved organic matter (DOM) in aquatic environments, which potentially changes the behavior and roles of DOM in water treatment facilities. Here, we explored the effect of sunlight irradiation on membrane fouling behavior of two natural DOM (i.e., Aldrich humic acid (AHA) and Suwannee River DOM (SRNOM)), particularly in the presence of calcium ion (Ca(II)). Results showed that a long-term exposure (3 months) to sunlight during the summer led to decreases in the chromophores and molecular size of both DOM. The characterization by UV-vis spectral parameter DSlope350-400 (the slope of the log transformed absorbance spectra in the range of 350-400 nm) indicated that sunlight-exposed DOM had a weaker Ca(II)-binding ability than unirradiated DOM, which could be attributable to the photochemically induced loss of carboxyl and phenolic groups. Additionally, AHA was found to be more susceptible to sunlight irradiation and Ca(II) addition than SRNOM, likely due to its higher aromaticity. Crucially, dead-end ultrafiltration tests showed that sunlight exposure of both AHA and SRNOM can reduce their fouling potential in the absence of Ca(II) and the presence of low Ca(II) (0.4 mM). In contrast, the addition of higher Ca(II) concentrations (2 and 3.6 mM) led to an increase in their fouling propensities. Overall, sunlight exposure can greatly alter the fouling behavior of natural DOM. This study provides a nexus between the naturally occurring transformation of DOM and its behavior (i.e., membrane fouling) in water treatment facilities. PMID- 29426146 TI - Adsorption of tetracycline antibiotics from aqueous solutions on nanocomposite multi-walled carbon nanotube functionalized MIL-53(Fe) as new adsorbent. AB - Adsorption of tetracycline antibiotics from aqueous solutions by a multi-walled carbon nanotube (MWCNT) loaded iron metal-organic framework (MIL-53(Fe)) composite was studied. The adsorbent was characterized by environmental scanning electron microscope, energy dispersive X-ray spectroscopy, brunauer-emmett teller, thermogravimetric analysis, X-ray diffraction, fourier transform infrared spectrum, and X-ray photoelectron spectrum. The adsorption kinetics of tetracycline hydrochloride (TCN), oxytetracycline hydrochloride (OTC), and chlortetracycline hydrochloride (CTC) were all well fitted to the pseudo-second order equation as well as the adsorption isotherms could be well delineated via Langmuir equations. The main influencing factors such as pH and ionic strength were studied in detail. At initial pH of 7.0, maximum adsorption capacity of TCN, OTC and CTC on MWCNT/MIL-53(Fe) was 364.37, 325.59, 180.68 mg.g-1 at 25 degrees C, which was 1.25, 8.28 and 3.34 times than that of single MWCNT, respectively. The adsorption capacity of TCS for this adsorbent was in the order: TCN > OTC > CTC, which was determined by the adsorbate molecule magnitude. In addition, pi-pi adsorbate-adsorbent interactions played an important role during the adsorption process. The excellent reusability and great water stability indicated the potential application of this novel composite in the removal of TCS from aqueous solutions. PMID- 29426147 TI - Plant basket hydraulic structures (PBHS) as a new river restoration measure. AB - River restoration has become increasingly attractive worldwide as it provides considerable benefits to the environment as well as to the economy. This study focuses on changes of hydromorphological conditions in a small lowland river recorded during an experiment carried out in the Flinta River, central Poland. The proposed solution was a pilot project of the construction of vegetative sediment traps (plant basket hydraulic structures - PBHS). A set of three PBSH was installed in the riverbed in one row and a range of hydraulic parameters were recorded over a period of three years (six measurement sessions). Changes of sediment grain size were analysed, and the amount and size of plant debris in the plant barriers were recorded. Plant debris accumulation influencing flow hydrodynamics was detected as a result of the installation of vegetative sediment traps. Moreover, various hydromorphological processes in the river were initiated. Additional simulations based on the detected processes showed that the proposed plant basket hydraulic structures can improve the hydromorphological status of the river. PMID- 29426148 TI - The experimental observation, mechanism and kinetic studies on the reaction of hexachloro-1,3-butadiene initiated by typical atmospheric oxidants. AB - Hexachloro-1,3-butadiene (HCBD) is a persistent organic pollutant in the environment. When its samples were collected and observed, the levels of HCBD in its source and high mountains are higher than in urban cities, oil factories and countryside. The density functional theory is applied to the degradation mechanism of HCBD with Cl, NO3, HO2, OH and O3. Those reactions are optimized and calculated at two carbon sites of double bonds, and then the subsequent reactions of the OH-initiated intermediates with O2 and NO are taken as examples. Ozonization reactions of HCBD including the formation of primary and secondary ozonides are investigated. The Criegee intermediates created in the ozonization reactions can react with O2, SO2, NO2 and H2O. Reaction rate constants of the Cl, NO3, HO2, OH and O3 initiated reactions with HCBD are calculated within 200 to 400 K with the transition state theory method, and the rate constants of the Cl, NO3, HO2, OH and O3 at 298.15 K are 4.51 * 10-13, 1.32 * 10-20, 4.33 * 10-29, 6.33 * 10-16, 5.80 * 10-27 cm3 molecule-1 s-1, respectively. The reactions of OH and Cl radicals with HCBD are more important than those of NO3, HO2 and O3 according to the reaction rate branching ratio. Both the temperature and reaction rate could change with the height. PMID- 29426149 TI - Measuring spatio-temporal dynamics of impervious surface in Guangzhou, China, from 1988 to 2015, using time-series Landsat imagery. AB - This study evaluated the spatio-temporal change characteristics of urban development at different scales with time-series impervious surface fractions. Landsat-5 Thematic Mapper (TM) and Landsat-8 Operational Land Imager (OLI) images were used to extract impervious surface fractions using a modified linear spectral mixture analysis method in Guangzhou from 1988 to 2015. The results indicated that the impervious surface area has substantially increased, from 70.3 km2 in 1988 to 580.5 km2 in 2015. In 2015, the impervious surfaces were distributed almost throughout the whole region of the study area, except in the forest region. Next, impervious surface weighted mean centre (ISWMC) and the standard deviational ellipse (SDE) methods were used to systematically analyse the principle orientation, direction, spatio-temporal expansion trends, and the distribution differences of impervious surfaces at the whole and local region scales from 1988 to 2015. The spatio-temporal dynamics of ISWMC exhibited different expansion directions and intensities of impervious surfaces at the whole and local region scales. On a whole region scale, the principle expansion direction of impervious surfaces was northward. However, the expansion trend of impervious surfaces in the different districts was significantly different from other trends at the local region scale. The parameters of SDE were used to investigate the orientation and the clustering or dispersion degree of impervious surface at different scales. The results from SDE analysis indicated that the impervious surfaces exhibited uncertainty in the expansion direction at the whole region scale; in contrast, they had a distinct preferred orientation and expansion direction at the local region scale. The analysis revealed that urban expansion exhibited different change characteristics in various directions at the local region scale. In summary, the results at the local region scale can better reflect the change trajectory of spatio-temporal dynamics of urban development and its fine spatial structure than at the whole region scale. PMID- 29426150 TI - Probabilistic evaluation of the water footprint of a river basin: Accounting method and case study in the Segura River Basin, Spain. AB - In the current study a method for the probabilistic accounting of the water footprint (WF) at the river basin level has been proposed and developed. It is based upon the simulation of the anthropised water cycle and combines a hydrological model and a decision support system. The methodology was carried out in the Segura River Basin (SRB) in South-eastern Spain, and four historical scenarios were evaluated (1998-2010-2015-2027). The results indicate that the WF of the river basin reached 5581 Mm3/year on average in the base scenario, with a high variability. The green component (3231 Mm3/year), mainly generated by rainfed crops (62%), was responsible for the great variability of the WF. The blue WF (1201 Mm3/year) was broken down into surface water (56%), renewable groundwater (20%) and non-renewable groundwater (24%), and it showed the generalized overexploitation of aquifers. Regarding the grey component (1150 Mm3/year), the study reveals that wastewater, especially phosphates (90%), was the main culprit producing water pollution in surface water bodies. The temporal evolution of the four scenarios highlighted the successfulness of the water treatment plans developed in the river basin, with a sharp decrease in the grey WF, as well as the stability of the WF and its three components in the future. So, the accounting of the three components of the WF in a basin was integrated into the management of water resources, it being possible to predict their evolution, their spatial characterisation and even their assessment in probabilistic terms. Then, the WF was incorporated into the set of indicators that usually is used in water resources management and hydrological planning. PMID- 29426151 TI - A process-based framework for soil ecosystem services study and management. AB - Soil provides various indispensable ecosystem services for human society. Soil's complex structure and property makes the soil ecological processes complicated and brings about tough challenges for soil ecosystem services study. Most of the current frameworks on soil services focus exclusively on services per se, neglecting the links and underlying ecological mechanisms. This article put forward a framework on soil services by stressing the underlying soil mechanisms and processes, which includes: 1) analyzing soil natural capital stock based on soil structure and property, 2) disentangling the underlying complex links and soil processes, 3) soil services valuation based on field investigation and spatial explicit models, and 4) enacting soil management strategy based on soil services and their driving factors. By application of this framework, we assessed the soil services of sediment retention, water yield, and grain production in the Upper-reach Fenhe Watershed. Based on the ecosystem services and human driving factors, the whole watershed was clustered into five groups: 1) municipal area, 2) typical coal mining area, 3) traditional farming area, 4) unsustainable urbanizing area, and 5) ecological conservation area. Management strategies on soils were made according to the clustering based soil services and human activities. PMID- 29426152 TI - Determining factors for levels of volatile organic compounds measured in different microenvironments of a heavy traffic urban area. AB - The levels of BTEX (benzene, toluene, ethylbenzene and xylenes) in a congested urban area of Hanoi were characterized in a winter and a transitional period in 2015. Monitoring was conducted at two roads simultaneously with traffic flows and one ambient site together with meteorology. Hourly and bi-hourly BTEX samples collected using charcoal tubes were analyzed by GC-FID. BTEX levels in winter, 131 +/- 71 MUg/m3 in heavy traffic Truong Chinh (TC) road, 101 +/- 29 MUg/m3 in small residential Nguyen Ngoc Nai (NN) road, and 30 +/- 15 MUg/m3 in the ambient air site (AA, about 150 m from each road) were 1.3-2.1 times higher than the respective levels in the transitional period. Hourly benzene levels exceeded the Vietnam national standard more frequently at TC (45%) than at NN (32%) and least at AA (5%) out of 120-180 measurements, respectively. Roadside hourly levels well reflected the diurnal traffic flow pattern and higher BTEX levels were measured at TC than NN. The ambient site exhibited lower BTEX levels and different diurnal patterns, with more pronounced evening peaks than morning rush hour peaks. BTEX pollution rose showed a strong influence of wind to levels measured at AA. Species ratios (T/B and X/E) showed typical ranges for traffic emissions at roadsides. Ratios for AA and NN after midnight with no vehicles operating showed the aging effects with typical low X/E ratios. Multivariate analysis results suggested association of gasoline vehicles with BTEX at roadsides. Backward trajectory analysis indicated potential regional transport of long-lived benzene associated with continental airmass categories. BTEX at TC our study were 2-3 times lower for every species compared to those previously reported, showing results of fuel quality and vehicle technologies improvement. Health risks of people working at the roadside also reduced by about 3 times during the 10 years. PMID- 29426153 TI - Integrating the social, hydrological and ecological dimensions of freshwater health: The Freshwater Health Index. AB - Degradation of freshwater ecosystems and the services they provide is a primary cause of increasing water insecurity, raising the need for integrated solutions to freshwater management. While methods for characterizing the multi-faceted challenges of managing freshwater ecosystems abound, they tend to emphasize either social or ecological dimensions and fall short of being truly integrative. This paper suggests that management for sustainability of freshwater systems needs to consider the linkages between human water uses, freshwater ecosystems and governance. We present a conceptualization of freshwater resources as part of an integrated social-ecological system and propose a set of corresponding indicators to monitor freshwater ecosystem health and to highlight priorities for management. We demonstrate an application of this new framework -the Freshwater Health Index (FHI) - in the Dongjiang River Basin in southern China, where stakeholders are addressing multiple and conflicting freshwater demands. By combining empirical and modeled datasets with surveys to gauge stakeholders' preferences and elicit expert information about governance mechanisms, the FHI helps stakeholders understand the status of freshwater ecosystems in their basin, how ecosystems are being manipulated to enhance or decrease water-related services, and how well the existing water resource management regime is equipped to govern these dynamics over time. This framework helps to operationalize a truly integrated approach to water resource management by recognizing the interplay between governance, stakeholders, freshwater ecosystems and the services they provide. PMID- 29426154 TI - Biosynthesized iron oxide nanoparticles used for optimized removal of cadmium with response surface methodology. AB - To effectively reuse adsorbent in removal of Cd (II), magnetic modification was considered as an alternative. In this study, iron oxide nanoparticles (IONPs) synthesized from the extract of Excoecaria cochinchinensis Lour leaves were modified by low-temperature calcination, and used to remove Cd (II). Transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and magnetic properties analysis confirmed the successful synthesis of nanoscale magnetic FeOC composite. Response surface methodology (RSM) served to optimize the adsorption of Cd (II) by IONPs based on Box-Behnken design (BBD). According to the quadratic model, the effect of each factor on the removal of Cd (II) by IONPs was: pH > dosage > ionic strength > temperature. In percentage terms, 98.50% of Cd (II) (10 mg L-1) was removed when the pH, absorbent dosage, temperature and ionic strength conditions were 8.07, 2.5 g L-1, 45 degrees C, and 0.07 mol L-1, respectively. The adsorption of Cd (II) by IONPs is consistent with pseudo-second order kinetics and Langmuir adsorption isotherm models, indicating that the process of adsorption of Cd (II) by IONPs belongs to monolayer chemical adsorption. The COOH, -COH, Cpi electron and =FeOH may be the binding sites for Cd (II) on the surface of IONPs. Overall, IONPs can be used to remove Cd (II) effectively from aqueous solution in a wide range of conditions. PMID- 29426155 TI - Arsenic, cadmium and lead in fresh and processed tuna marketed in Galicia (NW Spain): Risk assessment of dietary exposure. AB - Currently, metal bioaccumulation in fish is increasing and is a cause of concern due to toxicity. Total arsenic, cadmium and lead concentrations in fresh and processed tuna (110 samples) marketed in Galicia (NW Spain) were determined by ICP-MS spectrometry. The average concentrations of As and Cd, 3.78 and 0.024 mg kg-1 w.w., respectively, in fresh tuna were statistically significantly higher than those in processed tuna (p < 0.001). The contents in processed tuna were 0.295-7.85 mg kg-1 for As and ND-0.045 mg kg-1 for Cd. The Pb content was negligible in both types of tuna. In canned tuna, decreasing As and Cd concentrations were observed in different preparation-packaging media: olive oil > natural > pickled sauce. Of the two species studied in canned tuna, Thunnus alalunga showed statistically significant higher levels both for As 1.28 mg kg-1 (p < 0.001) and Pb 0.013 mg kg-1 (p = 0.0496) than Thunnus albacares. No samples surpassed the limits set by the EU for Cd and Pb. The limit for As in fish has not been established, but the arsenic contents in fresh tuna reported here are important, as they are among the highest reported in the literature. Considering public health in children and adults with respect to the investigated metals, the estimated daily intakes (EDIs) did not exceed the tolerable intakes. No chronic systemic risk was found since all the target hazard quotients (THQs-TTHQs) were far below 1 (critical value), and the carcinogenic risk (CR) for As did not exceed the acceptable value of 10-5. Thus, tuna consumption in the Galician diet does not pose a risk for different population groups in terms of these studied metals/metalloids. PMID- 29426156 TI - Dynamic membrane for micro-particle removal in wastewater treatment: Performance and influencing factors. AB - Dynamic membranes (DMs) have been of great interest in recent years because they can reduce energy consumption and costs during wastewater treatment. Dynamic membranes are a promising technology for the removal of low-density, non degradable micro-particles, such as plastics, which are an increasingly prevalent wastewater contaminant. These micro-particles are not easily removed via conventional sedimentation and result in increased operation and maintenance costs in downstream unit processes. In this study, DMs were formed on a 90 MUm supporting mesh through filtration of a synthetic wastewater. The impact of influent flux (solid flux) and influent particle concentration on DM performance was investigated. The effluent turbidity was reduced to <1 NTU after 20 mins of filtration, verifying the effective removal of micro-particles by the DM. Transmembrane pressure (TMP) and total filtration resistance increased linearly with filtration time, and were highly correlated (R2 > 0.998). TMP ranged from 80 to 180 mm of water head, and total filtration resistance ranged from 2.89 * 10-9 m-1 to 6.52 * 10-9 m-1 during DM filtration. In general, an increase in influent flux and influent particle concentration corresponds with increasing TMP and filtration resistance, as well as a rapid reduction in effluent turbidity due to swift formation of a DM on the supporting mesh. PMID- 29426157 TI - Mercury in fish from Norwegian lakes: The complex influence of aqueous organic carbon. AB - Mercury (Hg) concentrations in water and biota are often positively correlated to organic matter (OM), typically measured as total or dissolved organic carbon (TOC/DOC). However, recent evidence suggests that higher OM concentrations inhibit bioaccumulation of Hg. Here, we test how TOC impacts the Hg accumulation in fish in a synoptic study of Methyl-Hg (MeHg) in water and total Hg (THg) in perch (Perca fluviatilis) in 34 boreal lakes in southern Norway. We found that aqueous MeHg (r2 = 0.49, p < 0.0001) and THg (r2 = 0.69, p < 0.0001), and fish THg (r2 = 0.26, p < 0.01) were all positively related with TOC. However, we found declining MeHg bioaccumulation factors (BAFMeHg) for fish with increasing TOC concentrations. The significant correlation between fish THg concentrations and aqueous TOC suggests that elevated fish Hg levels in boreal regions are associated with humic lakes. The declining BAFMeHg with increasing TOC suggest that increased OM promotes increased aqueous Hg concentrations, but lowers relative MeHg bioaccumulation. A mechanistic understanding of the response from OM on BAFMeHg might be found in the metal-complexation properties of OM, where OM complexation of metals reduces their bioavailability. Hence, suggesting that MeHg bioaccumulation becomes less effective at higher TOC, which is particularly relevant when assessing potential responses of fish Hg to predicted future changes in OM inputs to boreal ecosystems. Increased browning of waters may affect fish Hg in opposite directions: an increase of food web exposure to aqueous Hg, and reduced bioavailability of Hg species. However, the negative relationship between BAFMeHg and TOC is challenging to interpret, and carries a great deal of uncertainty, since this relationship may be driven by the underlying correlation between TOC and MeHg (i.e. spurious correlations). Our results suggest that the trade-off between Hg exposure and accumulation will have important implications for the effects of lake browning on Hg transport, bioavailability, and trophodynamics. PMID- 29426158 TI - First attempts to obtain a reference drift curve for traditional olive grove's plantations following ISO 22866. AB - The current standard for the field measurements of spray drift (ISO 22866) is the only official standard for drift measurements in field conditions for all type of crops, including bushes and trees. A series of field trials following all the requirements established in the standard were arranged in a traditional olive grove in Cordoba (south of Spain). The aims of the study were to evaluate the applicability of the current standard procedure to the particular conditions of traditional olive trees plantations, to evaluate the critical requirements for performing the tests and to obtain a specific drift curve for such as important and specific crop as olive trees in traditional plantations, considering the enormous area covered by this type of crop all around the world. Results showed that the field trials incur a very complex process due to the particular conditions of the crop and the very precise environmental requirements. Furthermore, the trials offered a very low level of repeatability as the drift values varied significantly from one spray application to the next, with the obtained results being closely related to the wind speed, even when considering the standard minimum value of 1 m.s-1. The collector's placement with respect to the position of the isolated trees was determined as being critical since this substantially modifies the ground deposit in the first 5 m. Even though, a new drift curve for olive trees in traditional plantation has been defined, giving an interesting tool for regulatory aspects. Conclusions indicated that a deep review of the official standard is needed to allow its application to the most relevant orchard/fruit crops. PMID- 29426159 TI - Analyzing and modelling the effect of long-term fertilizer management on crop yield and soil organic carbon in China. AB - This study analyzes the influence of various fertilizer management practices on crop yield and soil organic carbon (SOC) based on the long-term field observations and modelling. Data covering 11 years from 8 long-term field trials were included, representing a range of typical soil, climate, and agro-ecosystems in China. The process-based model EPIC (Environmental Policy Integrated Climate model) was used to simulate the response of crop yield and SOC to various fertilization regimes. The results showed that the yield and SOC under additional manure application treatment were the highest while the yield under control treatment was the lowest (30%-50% of NPK yield) at all sites. The SOC in northern sites appeared more dynamic than that in southern sites. The variance partitioning analysis (VPA) showed more variance of crop yield could be explained by the fertilization factor (42%), including synthetic nitrogen (N), phosphorus (P), potassium (K) fertilizers, and fertilizer NPK combined with manure. The interactive influence of soil (total N, P, K, and available N, P, K) and climate factors (mean annual temperature and precipitation) determine the largest part of the SOC variance (32%). EPIC performs well in simulating both the dynamics of crop yield (NRMSE = 32% and 31% for yield calibration and validation) and SOC (NRMSE = 13% and 19% for SOC calibration and validation) under diverse fertilization practices in China. EPIC can assist in predicting the impacts of different fertilization regimes on crop growth and soil carbon dynamics, and contribute to the optimization of fertilizer management for different areas in China. PMID- 29426161 TI - Public health co-benefits of greenhouse gas emissions reduction: A systematic review. AB - BACKGROUND AND OBJECTIVES: Public health co-benefits from curbing climate change can make greenhouse gas (GHG) mitigation strategies more attractive and increase their implementation. The purpose of this systematic review is to summarize the evidence of these health co-benefits to improve our understanding of the mitigation measures involved, potential mechanisms, and relevant uncertainties. METHODS: A comprehensive search for peer-reviewed studies published in English was conducted using the primary electronic databases. Reference lists from these articles were reviewed and manual searches were performed to supplement relevant studies. The identified records were screened based on inclusion criteria. We extracted data from the final retrieved papers using a pre-designed data extraction form and a quality assessment was conducted. The studies were heterogeneities, so meta-analysis was not possible and instead evidence was synthesized using narrative summaries. RESULTS: Thirty-six studies were identified. We identified GHG mitigation strategies in five domains - energy generation, transportation, food and agriculture, households, and industry and economy - which usually, although not always, bring co-benefits for public health. These health gains are likely to be multiplied by comprehensive measures that include more than one sectors. CONCLUSIONS: GHG mitigation strategies can bring about substantial and possibly cost-effective public health co-benefits. These findings are highly relevant to policy makers and other stakeholders since they point to the compounding value of taking concerted action against climate change and air pollution. PMID- 29426160 TI - Plankton dynamics across the freshwater, transitional and marine research sites of the LTER-Italy Network. Patterns, fluctuations, drivers. AB - A first synoptic and trans-domain overview of plankton dynamics was conducted across the aquatic sites belonging to the Italian Long-Term Ecological Research Network (LTER-Italy). Based on published studies, checked and complemented with unpublished information, we investigated phytoplankton and zooplankton annual dynamics and long-term changes across domains: from the large subalpine lakes to mountain lakes and artificial lakes, from lagoons to marine coastal ecosystems. This study permitted identifying common and unique environmental drivers and ecological functional processes controlling seasonal and long-term temporal course. The most relevant patterns of plankton seasonal succession were revealed, showing that the driving factors were nutrient availability, stratification regime, and freshwater inflow. Phytoplankton and mesozooplankton displayed a wide interannual variability at most sites. Unidirectional or linear long-term trends were rarely detected but all sites were impacted across the years by at least one, but in many case several major stressor(s): nutrient inputs, meteo-climatic variability at the local and regional scale, and direct human activities at specific sites. Different climatic and anthropic forcings frequently co-occurred, whereby the responses of plankton communities were the result of this environmental complexity. Overall, the LTER investigations are providing an unparalleled framework of knowledge to evaluate changes in the aquatic pelagic systems and management options. PMID- 29426162 TI - Soil nutrient variability and groundwater nitrate-N in agricultural fields. AB - Landscape may result in uneven nutrient loads within a field. The objective of this study was to determine the influence of landscape on soil carbon and nutrient levels, and on levels of nitrate-N in groundwater. Soil samples were collected in three fields, two transects each, 30 sites in each field. The soil morphology was characterized for the profile, and soil organic carbon and nutrient levels were determined for 0-0.15 and 0.15-0.3 m depths. Each field had wells installed at three of the sites. One field showed a wide range of landscape variability, and significant effects of curvature on soil carbon and nutrient levels. Another field showed no significant effect of slope or curvature on soil carbon and nutrient levels because the nutrient levels were quite variable, including high spikes. The third field had less variable landscape trends but still showed a few significant effects on soil carbon and nutrient levels. Nitrate-N levels remained high in two of the nine wells (20 to 50 mg L-1), suggesting that additions of nitrate-N at the concave or converging sites replaced any losses. Median nitrate-N levels at the other seven well sites were lower, ranging from 8 to 17 mg L-1. Influence of landscape on soil carbon and nutrients was more detectable when the landscape factors were highly variable without excessive variability in soil nutrient properties. PMID- 29426163 TI - Burning intensity and low light availability reduce resprouting ability and vigor of Buxus sempervirens L. after clearing. AB - Thinning and prescribed burning are two common operations for reducing fuel accumulation and decreasing the intensity and severity of wildfires. However, the resprouting response of understory species may reduce the effectiveness of fuel load treatments and thus negatively affect the cost-benefit ratio of these treatments. This study focuses on Buxus sempervirens, a slow-growing, multi stemmed tree species, frequently dominant in the understory of temperate European forests, which resprouts strongly after clearing or burning. The aim was to assess how light availability and burning influence resprouting ability (resprouting or not) and vigor (i.e. the growth of resprouts) after clearing B. sempervirens in thinned stands without slash removal (unburned) or with burning of slash residues (burned), two years after the treatments. All individuals studied resprouted shortly after clearing in unburned stands, whereas almost ca. 40% never resprouted in the burned stands. Fire intensity, measured at the base of 49 individuals, contributed to explaining the likelihood of mortality. The number of resprouts was directly influenced by the pre-treatment size of individuals, but this relationship was lower in burned stands. Fire intensity, recorded in 29 resprouted individuals, also influenced the number of resprouts. Post-treatment light availability, in addition to pre-treatment size, contributed to explaining the volume of the ten largest resprouts and the length of the largest resprout. No tradeoffs between the resprout number and the volume of the ten largest resprouts or the maximum resprout length were found. Our study suggests that burning after clearing reduces the resprouting ability of B. sempervirens. Moreover, avoiding affecting the canopy cover reduces its resprouting vigor and, consequently, increases the effectiveness of understory fuel load treatments. PMID- 29426164 TI - SCOPE model applied for rapeseed in Spain. AB - The integrated SCOPE (Soil, Canopy Observation, Photochemistry and Energy balance) model, coupling radiative transfer theory and biochemistry, was applied to a biodiesel crop grown in a Spanish agricultural area. Energy fluxes and CO2 exchange were simulated with this model for the period spanning January 2008 to October 2008. Results were compared to experimental measurements performed using eddy covariance and meteorological instrumentation. The reliability of the model was proven by simulating latent (LE) and sensible (H) heat fluxes, soil heat flux (G), and CO2 exchanges (NEE and GPP). LAI data used as input in the model were retrieved from the MODIS and MERIS sensors. SCOPE was able to reproduce similar seasonal trends to those measured for NEE, GPP and LE. When considering H, the modelled values were underestimated for the period covering July 2008 to mid September 2008. The modelled fluxes reproduced the observed seasonal evolution with determination coefficients of over 0.77 when LE and H were evaluated. The modelled results offered good agreement with observed data for NEE and GPP, regardless of whether LAI data belonged to MODIS or MERIS, showing slopes of 0.87 and 0.91 for NEE-MODIS and NEE-MERIS, and 0.91 and 0.94 for GPP-MODIS and GPP MERIS, respectively. Moreover, SCOPE was able to reproduce similar seasonal behaviours to those observed for the experimental carbon fluxes, clearly showing the CO2 sink/source behaviour for the whole period studied. PMID- 29426165 TI - CAP payments and agricultural GHG emissions in Italy. A farm-level assessment. AB - The Common Agricultural Policy (CAP) is an important external driver of European agricultural production. Nowadays and in its envisioned future structure post 2020, the CAP has among its major objectives tackling climate change, for what concerns both adaptation and mitigation strategies. However, little is known about the link between past CAP reforms and agricultural greenhouse gases (GHG) emissions. This paper investigates the possible role played by the Fischler Reform (FR) on the agricultural GHG emissions at the farm level. The FR represents a major CAP reform for which data availability allows an ex-post analysis about its actual impacts. The empirical analysis concerns a balanced panel of 6542 Italian Farm Accountancy Data Network observed over years the 2003 2007. Multinomial Logit models are estimated in sequence to express how the farm level production choices, and the respective emissions, vary over time also in response to CAP expenditure. Results suggest that CAP expenditure had a role in the evolution of the farm-level emissions, though the direction of this effect may differ across farms and deserves further investigation. PMID- 29426166 TI - Using moss and lichens in biomonitoring of heavy-metal contamination of forest areas in southern and north-eastern Poland. AB - In the years 2014-2016 biomonitoring studies were conducted in the forest areas of south and north-eastern Poland: the Karkonosze Mountains, the Beskidy Mountains, the Borecka Forest, the Knyszynska Forest and the Bialowieska Forest. This study used epigeic moss Pleurozium schreberi and epiphytic lichens Hypogymnia physodes. Samples were collected in spring, summer and autumn. Approximately 500 samples of moss and lichens were collected for the study. In the samples, Mn, Ni, Cu, Zn, Cd, Hg and Pb concentrations were determined. Based on the obtained results, the studied areas were ranked by extent of heavy-metal deposition: Beskidy > Karkonosze Mountains > forests of north-eastern Poland. Some seasonal changes in concentrations of metals accumulated in moss and lichens were also indicated. There was observed, i.a., an increase in Cd concentration at the beginning of the growing season, which may be related to low emissions during the heating season. Analysis of the surface distribution of deposition of metals in the studied areas showed a significant contribution of nearby territorial emissions and unidentified local emission sources. The contribution of distant emission to Zn, Hg and Pb deposition levels in the Karkonosze and Beskidy region was also indicated. PMID- 29426167 TI - Spatiotemporal analysis of bacterial biomass and activity to understand surface and groundwater interactions in a highly dynamic riverbank filtration system. AB - Characterization of surface water - groundwater interaction in riverbank filtration (RBF) systems is of decisive importance to drinking water utilities due to the increasing microbial and chemical contamination of surface waters. These interactions are commonly assessed by monitoring changes in chemical water quality, but this might not be indicative for microbial contamination. The hydrological dynamics of the infiltrating river can influence these interactions, but seasonal temperature fluctuations and the supply of oxygen and nutrients from the surface water can also play a role. In order to understand the interaction between surface water and groundwater in a highly dynamic RBF system of a large river, bacterial abundance, biomass and carbon production as well as standard chemical parameters were analyzed during a 20 month period under different hydrological conditions. In the investigated RBF system, groundwater table changes exhibited striking dynamics even though flow velocities were rather low under regular discharge conditions. Bacterial abundance, biomass, and bacterial carbon production decreased significantly from the river towards the drinking water abstraction well. The cell size distribution changed from a higher proportion of large cells in the river, towards a higher proportion of small cells in the groundwater. Although biomass and bacterial abundance were correlated to water temperatures and several other chemical parameters in the river, such correlations were not present in the groundwater. In contrast, the dynamics of the bacterial groundwater community was predominantly governed by the hydrogeological dynamics. Especially during flood events, large riverine bacteria infiltrated further into the aquifer compared to average discharge conditions. With such information at hand, drinking water utilities are able to improve their water abstraction strategies and react quicker to changing hydrological conditions in the RBF system. PMID- 29426168 TI - Carbon budget and greenhouse gas balance during the initial years after rice paddy conversion to vegetable cultivation. AB - Rice paddy conversion to vegetable production is a common agricultural practice driven by economic benefits and shifting diets. However, little is known on the initial effects of this land-use conversion on net ecosystem carbon budget (NECB) and greenhouse gas (GHG) balance. Annual NECB and emissions of CH4 and N2O were measured from a native double rice cropping system (Rice) and a vegetable field recently converted from rice paddy (Veg) under no nitrogen (N) fertilization (Rice-N0 and Veg-N0) and conventional N fertilization (Rice-N+ and Veg-N+) during the initial four years upon conversion in subtropical China. Land-use conversion from rice to vegetable cultivation led to substantial C losses (2.6 to 4.5 Mg C ha-1 yr-1), resulting from strongly reduced C input by 44-52% and increased soil organic matter mineralization by 46-59% relative to Rice. The magnitude of C losses from Veg was highest in the first year upon conversion, and showed a decreasing trend over time. N fertilization shifted rice paddy from a slight C source in Rice-N0 (-1.0 Mg C ha-1 yr-1) to a significant C sink in Rice-N+ (1.1 Mg C ha-1 yr-1) and alleviated the impact of land-use conversion on C loss via increased C input from higher crop productivity. Land-use conversion greatly increased the global warming potential (GWP) from Veg by 116-395% relative to Rice in the first year, primarily due to increased C losses and N2O emission outweighing the decreased CH4 emission. However, the GWP did not show obvious difference between Rice and Veg in the following years. N fertilization and land use conversion interactively increased GWP in the first year via increased N2O production. Concluding, NECB and GHG emissions in the first year after conversion are crucial and should be considered when evaluating the environmental consequences of land-use conversion. PMID- 29426169 TI - Spatial responses of antioxidative system to aluminum stress in roots of wheat (Triticum aestivum L.) plants. AB - Aluminum (Al) toxicity associated with acid soils represents one of the biggest limitations to crop production worldwide. The root apex of plants is the major perception site of Al toxicity. In Al stressed wheat primary roots, Al accumulation and loss of plasma membrane integrity were highest in the root apex (0-5mm), and decreased along the root axis (5-25mm). To further understand these responses in wheat, spatial profiles of antioxidant responses to Al along the 0 25mm root tip of two wheat genotypes differing in Al tolerance were analyzed. Under Al stress, the lowest root elongation was in the 0-5mm root tip, and more severe inhibition was observed in Al-sensitive genotype than Al-tolerant genotype. The highest increase of Al and hydrogen peroxide (H2O2) was in the 0 5mm zone, with the most pronounced increase of malondialdehyde content and Evans blue uptake after Al exposure, especially in Al-sensitive genotype. The activities of superoxides dismutase (SOD), ascrobate peroxidase (APX), catalase (CAT) and peroxidase (POD) and levels of antioxidants (ascorbic acid, reduced glutathione, dehydroascorbate, glutathione disulfide) were significantly increased along the root tip under Al stress, with the 0-5mm region again being the most active zone. In the same zone, the activities of CAT, APX and contents of antioxidants were higher in Al-tolerant genotype while SOD and POD activities were lower. Our results indicate that Al-induced changes in H2O2 production and antioxidative system in root tip are regulated in a spatially-specific manner, suggesting that this response may play an important role in wheat adaptation to Al toxicity. PMID- 29426170 TI - The formation of iron nanoparticles by Eucalyptus leaf extract and used to remove Cr(VI). AB - The advantages of green synthesized iron nanoparticles by plant extracts include simplicity, high efficiency and sustainability. However, there are limitations in our understanding of the formation of Fe NPs. In this report, the synthesized iron nanoparticles by eucalyptus leaf extract (Fe NPs) showed that Cr(VI) removal efficiency reached approximately 100% at volume ratio of leaf extract and iron(III) solution of 2:1 and pH 4. In addition, the morphology, surface and compositions of Fe NPs were characterized by various techniques. The diameter distribution of 95 +/- 5 nm with a capping layer was observed, containing polyphenols and aliphatic acids confirmed by FTIR and XRD. XPS indicated that Fe NPs contained iron oxides, as well as a layer covering on Fe NPs created by biomolecules from eucalyptus leaf extract. Furthermore, the biomolecules identified by GC-MS indicated that alcohol phenols and alkylaldehyde acted as reducing agents, while alcohol acids, alkanols, phytols, acetate and aromatic ketones acted as capping agents. It can be concluded that aldehydes, phenols and alcoholic compounds played dominant roles during the synthesis of Fe NPs. Finally, the mechanism for the formation of Fe NPs was proposed, including both that of Fe NPs and capped Fe NPs. PMID- 29426171 TI - Ecological-economic assessment of the effects of freshwater flow in the Florida Everglades on recreational fisheries. AB - This research develops an integrated methodology to determine the economic value to anglers of recreational fishery ecosystem services in Everglades National Park that could result from different water management scenarios. The study first used bio-hydrological models to link managed freshwater inflows to indicators of fishery productivity and ecosystem health, then link those models to anglers' willingness-to-pay for various attributes of the recreational fishing experience and monthly fishing effort. This approach allowed us to estimate the foregone economic benefits of failing to meet monthly freshwater delivery targets. The study found that the managed freshwater delivery to the Park had declined substantially over the years and had fallen short of management targets. This shortage in the flow resulted in the decline of biological productivity of recreational fisheries in downstream coastal areas. This decline had in turn contributed to reductions in the overall economic value of recreational ecosystem services enjoyed by anglers. The study estimated the annual value of lost recreational services at $68.81 million. The losses were greater in the months of dry season when the water shortage was higher and the number of anglers fishing also was higher than the levels in wet season. The study also developed conservative estimates of implicit price of water for recreation, which ranged from $11.88 per AF in November to $112.11 per AF in April. The annual average price was $41.54 per AF. Linking anglers' recreational preference directly to a decision variable such as water delivery is a powerful and effective way to make management decision. This methodology has relevant applications to water resource management, serving as useful decision-support metrics, as well as for policy and restoration scenario analysis. PMID- 29426172 TI - Use of agricultural by-products in the development of an agro-energy chain: A case study from the Umbria region. AB - Use of agricultural and livestock by-products for anaerobic digestion (AD), in total or partial substitution of the maize silage was evaluated from an environmental and economical point of view. The evaluation process included three methodological interdependent and consequential steps: the chemical stage at laboratory and plant level, the environmental and economic steps developing the Life Cycle Assessment and Life Cycle Costing jointly. The laboratory test showed that the two mixtures prepared with by-products, in partial (MIX A) and total (MIX B) substitution of maize silage, did not show differences in bio-methane production compared to a reference mixture with the 33% of maize silage. All mixtures tested at full-scale plant, showed the same performances, resulting in a similar energy production. Environmentally, MIX B increased greenhouse gas credits derived from the avoided production of mineral fertiliser for the energetic crops, resulting also in better economic performances. The break-even transport distances follow the positive environmental pattern result, in contrast to what was found for the break-even transport distances from the economic point of view. PMID- 29426173 TI - Association of phthalate exposures with urinary free cortisol and 8-hydroxy-2' deoxyguanosine in early childhood. AB - Several studies suggested potential links of phthalates to stress-related outcomes. However, limited evidence has been available for the relationships between phthalate metabolites and free cortisol and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in perinatal and postnatal environments. Therefore, we evaluated the relationships between phthalate metabolites and free cortisol and 8-OHdG in mother-child pairs. We repeatedly collected urine samples of 287 mother-child pairs from just before delivery to 15 months of age to measure the levels of four phthalate metabolites - mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2 ethyl-5-oxohexyl) phthalate (MEOHP), mono-isobutyl phthalate (MiBP), and mono-n butyl phthalate (MnBP) - and free cortisol and 8-OHdG. We used linear mixed effect models and generalized additive mixed models to estimate the relationship between the phthalate metabolites and free cortisol and 8-OHdG after adjusting for the child's gender, urine collection time, and maternal smoking status. The four phthalate metabolite levels were strongly correlated each other (all, p < .0001), and intra-class correlation for each metabolite in children ranged from 0.18 to 0.96. All four phthalate metabolites were positively associated with both free cortisol (MEHHP, beta = 0.18 and p < .0001; MEOHP, beta = 0.17 and p < .0001; MiBP, beta = 0.13 and p = .0001; MnBP, beta = 0.21 and p < .0001; and molar sum of metabolites, beta = 0.21 and p < .0001) and 8-OHdG (MEHHP, beta = 0.20 and p < .0001; MEOHP, beta = 0.18 and p < .0001; MiBP, beta = 0.23 and p < .0001; MnBP, beta = 0.28 and p < .0001; and molar sum of metabolites, beta = 0.29 and p < .0001) in childhood. Our findings suggest that phthalate exposures increase free cortisol and 8-OHdG levels in early childhood. PMID- 29426174 TI - Bioconcentration factor-based management of soil pesticide residues: Endosulfan uptake by carrot and potato plants. AB - Uptake characteristics of endosulfan (ED), including alpha-, beta-isomers and sulfate-metabolites, from the soils by carrot and potato plants were investigated to establish a method that may be used to calculate recommended permissible soil contaminant concentrations (Cs, permissible) at time of planting so that maximum residue level (MRL) standards are not exceeded. The residues of ED were analyzed in soils treated with ED at concentrations of either 2 or 10 mg kg soil-1 and in the plants (carrots and potatoes) grown in such soils for 60-90 d. Presence of plants increased ED dissipation rates in soils in patterns that were best fit to a double-exponential decay model (R2 of 0.84-0.99). The ED uptake extent varied with type of crop, ED isomer, plant growth duration, and plant compartments. However, ED concentrations in all edible parts of crops eventually exceeded their maximum residue limits. Total ED bioconcentration factor (BCF), the ratio of soil ED concentration at planting time to that in edible part of each crop at harvest day, was found to decrease with time due to decreasing soil ED concentration and increasing plant biomass in a pattern that followed a first order kinetic model. Using this model, the Cs, permissible values, specific to the soils used in this study, were calculated to be 0.32 and 0.19 mg kg soil-1 for carrots and potatoes, respectively. The results and methods developed in this study may be utilized as a prediction tool to ensure crop safety from pesticide residues. PMID- 29426175 TI - Modeling crop residue burning experiments to evaluate smoke emissions and plume transport. AB - Crop residue burning is a common land management practice that results in emissions of a variety of pollutants with negative health impacts. Modeling systems are used to estimate air quality impacts of crop residue burning to support retrospective regulatory assessments and also for forecasting purposes. Ground and airborne measurements from a recent field experiment in the Pacific Northwest focused on cropland residue burning was used to evaluate model performance in capturing surface and aloft impacts from the burning events. The Community Multiscale Air Quality (CMAQ) model was used to simulate multiple crop residue burns with 2 km grid spacing using field-specific information and also more general assumptions traditionally used to support National Emission Inventory based assessments. Field study specific information, which includes area burned, fuel consumption, and combustion completeness, resulted in increased biomass consumption by 123 tons (60% increase) on average compared to consumption estimated with default methods in the National Emission Inventory (NEI) process. Buoyancy heat flux, a key parameter for model predicted fire plume rise, estimated from fuel loading obtained from field measurements can be 30% to 200% more than when estimated using default field information. The increased buoyancy heat flux resulted in higher plume rise by 30% to 80%. This evaluation indicates that the regulatory air quality modeling system can replicate intensity and transport (horizontal and vertical) features for crop residue burning in this region when region-specific information is used to inform emissions and plume rise calculations. Further, previous vertical emissions allocation treatment of putting all cropland residue burning in the surface layer does not compare well with measured plume structure and these types of burns should be modeled more similarly to prescribed fires such that plume rise is based on an estimate of buoyancy. PMID- 29426176 TI - Estimation of PM10-bound manganese concentration near a ferromanganese alloy plant by atmospheric dispersion modelling. AB - Numerous studies have associated air manganese (Mn) exposure with negative health effects, primarily neurotoxic disorders. This work presents a description of the emission and dispersion of PM10-bound Mn from industrial sources in the Santander bay area, Northern Spain. A detailed day-specific emission estimation was made and assessed for the main Mn source, a manganese alloy production plant under 8 different scenarios. Dispersion analysis of PM10-bound Mn was performed using the CALPUFF model. The model was validated from an observation dataset including 101 daily samples from four sites located in the vicinities of the manganese alloy plant. Model results were in reasonable agreement with observations (r = 0.37; NMSE = 2.08; Fractional Bias = 0.44 and Modelled/Observed ratio = 1.57). Simulated and observed Mn concentrations in the study area were much higher than the guidelines proposed by the World Health Organization (WHO) and the U.S. Environmental Protection Agency (USEPA), highlighting the need to reduce the Mn concentrations in the area. Based on the analysis of the Mn source contribution from the ferromanganese alloy plant, some preventive and corrective measures are discussed at the end of the paper. This work shows that CALPUFF dispersion model can be used to predict PM10-bound Mn concentrations with reasonable accuracy in the vicinities of industrial facilities allowing the exposure assessment of the nearby population, which can be used in future epidemiological studies. PMID- 29426177 TI - Large variation in glyphosate mineralization in 21 different agricultural soils explained by soil properties. AB - Glyphosate and its main metabolite aminomethylphosphonic acid (AMPA) have frequently been detected in surface water and groundwaters. Since adequate glyphosate mineralization in soil may reduce its losses to environment, improved understanding of site specific factors underlying pesticide mineralization in soils is needed. The aim of this study was to investigate the relationship between soil properties and glyphosate mineralization. To establish a sound basis for resilient correlations, the study was conducted with a large number of 21 agricultural soils, differing in a variety of soil parameters, such as soil texture, soil organic matter content, pH, exchangeable ions etc. The mineralization experiments were carried out with 14C labelled glyphosate at a soil water tension of -15 kPa and at a soil density of 1.3 g cm-3 at 20 +/- 1 degrees C for an incubation period of 32 days. The results showed that the mineralization of glyphosate in different agricultural soils varied to a great extent, from 7 to 70% of the amount initially applied. Glyphosate mineralization started immediately after application, the highest mineralization rates were observed within the first 4 days in most of the 21 soils. Multiple regression analysis revealed exchangeable acidity (H+ and Al3+), exchangeable Ca2+ ions and ammonium lactate extractable K to be the key soil parameters governing glyphosate mineralization in the examined soils. A highly significant negative correlation between mineralized glyphosate and NaOH-extractable residues (NaOH-ER) in soils strongly suggests that NaOH-ER could be used as a simple and reliable parameter for evaluating the glyphosate mineralization capacity. The NaOH-ER were composed of glyphosate, unknown 14C-residues, and AMPA (12%-65%, 3%-34%, 0%-11% of applied 14C, respectively). Our results highlighted the influential role of soil exchangeable acidity, which should therefore be considered in pesticide risk assessments and management to limit efficiently the environmental transfers of glyphosate. PMID- 29426178 TI - Effect of nanohydroxyapatite on cadmium leaching and environmental risks under simulated acid rain. AB - Cadmium (Cd) contamination in soil is a global environmental pollution issue. Nanohydroxyapatite (NHAP) has been used in soil remediation to immobilize cadmium in contaminated soils. However, the effect of acid rain on the export of cadmium from topsoil and its behavior in deep soil and leachate is unclear. In this study, column experiments and development of parsimonious model were performed to estimate Cd leaching behavior from topsoil and environmental risk of groundwater after 0.5% NHAP remediation. Four leaching events were performed and total Cd, different fractions of Cd determined by sequential extraction procedure and pH were determined for each leaching. The results show that with the export of Cd in topsoil, the total Cd concentration in soil at different depths had the following vertical distributions: 0-5 cm > 5-10 cm > 10-15 cm > 15-20 cm. NHAP treatment increased the soil pH and decreased Cd leaching loss by 56.45% compared to the control, and the results fit the parabolic diffusion model. With sequential extraction it was observed that NHAP application increased the residual fraction of cadmium in soil. After leaching, there was a positive correlation between soil pH and Cd concentration with regards to the exchangeable, reducible, oxidizable and residual Cd fractions. The parabolic diffusion model showed that Cd contaminated soil with NHAP remediation is harmless to humans after sufficient remediation duration, whereas the resultant concentrations from the CK treatment could be toxic. The results indicate that nanohydroxyapatite could significantly reduce the bioavailability of cadmium and the environmental risk. However, the release of Ca and P from the dissolution of NHAP should be carefully studied as this will impact the mobilization of Cd or colloid Cd, and high leaching of P may result in P-induced eutrophication risk. PMID- 29426179 TI - Heavy mowing enhances the effects of heat waves on grassland carbon and water fluxes. AB - Heat waves (HWs) are a type of extreme weather event that is of growing concern in the scientific community. Yet field data based on sound experiment on the variation of ecosystem CO2 levels under HWs remain rare. Additionally, ecosystems react to HWs and the coupled human activities (such as grazing in grasslands) are unknown. Thus, a 3-year field experiment was conducted to simulate HWs in conjunction with different mowing intensities that mimicking grazing in a Stipa krylovii steppe on the Mongolian Plateau. HWs significantly decreased ecosystem exchange (NEE) of CO2, ecosystem respiration (Re) and gross ecosystem productivity (GEP) by 31%, 5% and 16%, respectively, over the three years. Continuous HWs over multiple years produced cumulative effects by reducing NEE at 20%, 34% and 40% in the first, second and third HW years, respectively. During three pre-defined three periods of HWs (during HW period, after HW period in the same year, and after HW period in the next year), variations in water use efficiency indicated that the grassland ecosystem exhibited a strategy for adapting to the continuous HWs to a certain extent, by adjusting community structure or increasing litter biomass. Finally, mowing increased the effects of HWs by extending the legacy effect, such that restoration of the grassland required a greater amount of time under the combination of HWs and mowing. PMID- 29426180 TI - Substrate degradation and nutrient enrichment structuring macroinvertebrate assemblages in agriculturally dominated Lake Chaohu Basins, China. AB - Rapid agricultural development has induced severe environmental problems to freshwater ecosystems. In this study, we aimed to examine the structure and environmental determinants of macroinvertebrate assemblages in an agriculture dominated Lake Chaohu Basin, China. A cluster analysis of the macroinvertebrate communities identified four groups of sites that were characterized by significantly different macroinvertebrate species. These four groups of sites had concentric spatial distribution patterns that followed the variation in the environmental conditions from the less anthropogenically disturbed headwaters towards the more anthropogenically disturbed lower reaches of the rivers and the Lake Chaohu. Moreover, taxa richness decreased from the headwaters towards the Lake Chaohu. The increasing practice of agriculture has reduced the abundances and richness of pollution sensitive species while opposite effects on pollution tolerant species. The study identified substrate heterogeneity and nutrient concentrations as the key environmental factors regulating the changes in the macroinvertebrate communities. We propose that particular attentions should be paid to reduce the nutrient enrichment and habitat degradation in the Lake Chaohu Basin and similar agriculture dominated basins. PMID- 29426181 TI - Modeling the effects of Irgarol 1051 on coral using lipidomic methodology for environmental monitoring and assessment. AB - Coral is commonly selected as a bioindicator of detecting a variety of adverse factors such as photosystem II herbicide Irgarol 1051, through measuring pan-type biomarkers. To improve the effectiveness of biomonitoring, omic technologies have recently been applied to model the systemic changes in an organism. Membrane lipids create a dynamic cell structure based on the physiological state, which offers a distinct lipid profile to specifically detect environmental threats and assess the associated health risk. To demonstrate the potential of a lipidomic methodology for biomonitoring, the glycerophosphocholine (GPC) profiles of the coral Seriatopora caliendrum were observed during 3 days of Irgarol (0.1-2.0 MUg/L) exposure. The lipid profile variations were modeled based on the Irgarol dose and the coral photoinhibition levels to develop an excellent quantitative model. The predominant changes correlated with the photoinhibition, decreasing the lyso-GPCs and GPCs with lower unsaturated chains and increasing GPCs with highly polyunsaturated chains, can be related to the consequence of blocking the photosynthetic electron flow based on the associated physiological roles. Other dose-specific lipid changes led to the partial exchange of PC(O-16:0/20:5) for PC(16,0/20:5) as a first-line response to counteract the membrane opening caused by Irgarol. Increased levels of the GPCs with 20:4 or 22:6 chains, which can promote mitochondrial functionality, confirmed an elevated respiration level in the coral exposed to Irgarol levels of >0.5 MUg/L. Notably, plasmanylcholines with 20:4 or 22:6 chains and phosphatidylcholines with 22:6 or 22:5 chains, which can alter their membrane material properties to mitigate organelle pre-swelling and swelling in different ways, formed in the coral exposed to the 0.5 and 2.0 MUg/L Irgarol levels. Such coral adaptations further predict the health risks associated with altered physiological conditions. In this study, the lipidomic methodology is demonstrated as a potential tool for environmental monitoring and assessment. PMID- 29426182 TI - Dissolved organic carbon fractionation accelerates glacier-melting: A case study in the northern Tibetan Plateau. AB - In glacierized regions, melting process has a significant effect on concentrations and light absorption characteristics of dissolved organic carbon (DOC), potentially resulting in variations of its radiative forcing, which is not yet relevant research at glacier region of the Tibetan Plateau (TP). In this study, DOC fractionation and its radiative forcing change during the melting process were investigated at Laohugou glacier No. 12 (LHG glacier) in western Qilian Mts., northern TP. DOC concentrations in fresh snow, snowpit and surface ice samples were 0.38 +/- 0.06, 0.22 +/- 0.11 and 0.60 +/- 0.21 mg L-1, respectively. Their mass absorption cross-section at 365 nm (MAC365) were 0.65 +/ 0.16, 4.71 +/- 3.68 and 1.44 +/- 0.52 m2 g-1, respectively. The MAC365 values of snowpit samples showed a significant negative correlation with DOC concentrations, indicating DOC with high MAC365 values were likely to be kept in snow during the melting process. Topsoil samples of LHG glacierized region likely contributed a lot to snowpit DOC with high MAC365 values due to their similar absorption spectra. Spatially, the DOC concentration of surface ice samples increased from terminus to the upper part of the glacier. Correspondingly, the MAC365 value showed decreased trend. In the freezing experiment on surface ice and topsoil samples, small part of DOC with high MAC365 value was also likely to enter first frozen solid phase. In addition, the radiative forcing caused by snowpit and surface ice DOC increased around 7.64 +/- 2.93 and 4.95 +/- 1.19 times relative to fresh snow DOC, indicating the snow/ice melting caused by increased light-absorbing DOC needs to be considered in the future research. PMID- 29426183 TI - Sediment grain-size characteristics and relevant correlations to the aeolian environment in China's eastern desert region. AB - To identify characteristics of aeolian activity and the aeolian environment in China's eastern desert region, this study collected surface sediment samples from the main desert and sandy lands in this region: the Hobq Desert and the Mu Us, Otindag, Horqin, and Hulunbuir sandy lands. We analyzed the grain-size characteristics and their relationships to three key environmental indicators: drift potential, the dune mobility index, and vegetation cover. The main sediment components are fine to medium sands, with poor (Hulunbuir) to moderate (all other areas) sorting, of unimodal to bimodal distribution. This suggests that improved sorting is accomplished by the loss of both relatively coarser and finer grains. Since 2000, China's eastern desert region has generally experienced low wind energy environmental conditions, resulting in decreased dune activity. In the Hobq Desert, however, the dry climate and sparse vegetation, in conjunction with the most widely distributed mobile dune area in the eastern desert region, have led to frequent and intense aeolian activity, including wind erosion, sand transport, and deposition, resulting in conditions for good sediment sorting. In the Mu Us, Otindag, and Horqin sandy lands, mosaic distribution has resulted from wind erosion-dominated and deposition-dominated aeolian environments. In the Hulunbuir Sandy Land, high precipitation, low temperatures, and steppe vegetation have resulted in well-developed soils; however, strong winds and flat terrain have created an aeolian environment dominated by wind erosion. PMID- 29426184 TI - Shift in the microbial community composition of surface water and sediment along an urban river. AB - Urban rivers represent a unique ecosystem in which pollution occurs regularly, leading to significantly altered of chemical and biological characteristics of the surface water and sediments. However, the impact of urbanization on the diversity and structure of the river microbial community has not been well documented. As a major tributary of the Yangtze River, the Jialing River flows through many cities. Here, a comprehensive analysis of the spatial microbial distribution in the surface water and sediments in the Nanchong section of Jialing River and its two urban branches was conducted using 16S rRNA gene-based Illumina MiSeq sequencing. The results revealed distinct differences in surface water bacterial composition along the river with a differential distribution of Proteobacteria, Cyanobacteria, Actinobacteria, Bacteroidetes and Acidobacteria (P < 0.05). The bacterial diversity in sediments was significantly higher than their corresponding water samples. Additionally, archaeal communities showed obvious spatial variability in the surface water. The construction of the hydropower station resulted in increased Cyanobacteria abundance in the upstream (32.2%) compared to its downstream (10.3%). Several taxonomic groups of potential fecal indicator bacteria, like Flavobacteria and Bacteroidia, showed an increasing trend in the urban water. PICRUSt metabolic inference analysis revealed a growing number of genes associated with xenobiotic metabolism and nitrogen metabolism in the urban water, indicating that urban discharges might act as the dominant selective force to alter the microbial communities. Redundancy analysis suggested that the microbial community structure was influenced by several environmental factors. TP (P < 0.01) and NO3- (P < 0.05), and metals (Zn, Fe) (P < 0.05) were the most significant drivers determining the microbial community composition in the urban river. These results highlight that river microbial communities exhibit spatial variation in urban areas due to the joint influence of chemical variables associated with sewage discharging and construction of hydropower stations. PMID- 29426185 TI - Polycyclic aromatic hydrocarbons (PAHs) associated with PM2.5 within boundary layer: Cloud/fog and regional transport. AB - A study of PM2.5-associated PAHs analysis at Mount Lushan (1165m) was conducted to investigate the distributions of PAHs in PM2.5 and influences of cloud/fog. The main purpose was to quantify the main emission sources of PAHs and estimate regional transport effects within the boundary layer. Mount Lushan is located between the boundary layer and troposphere, which is an ideal site for atmosphere transport investigation. The concentrations of PAHs in PM2.5 were analyzed with GC-MS. The results showed that the volume concentration was 6.98ng/m3 with a range from 1.47 to 25.17ng/m3 and PAHs mass were 160.24MUg/g (from 63.86 to 427.97MUg/g) during the sampling time at Mount Lushan. The dominant compounds are BbF, Pyr and BP. In terms of aromatic-ring PAHs distributions, 4-6-ring PAHs are predominant, indicating that the high-ring PAHs tend to contribute more than low ring PAHs in particulates. Due to frequent cloud/fog days at Mount Lushan, PAHs concentrations in the PM2.5 were determined before and after cloud/fog weather. The results demonstrated that the cloud/fog and rain conditions cause lower PAHs levels. Regression analysis was used for studying the relationship of PAHs distributions with meteorological conditions like temperature, humidity and wind. The results showed that the temperature and wind speed were inversely related with PAHs concentration but humidity had no significant relationship. Furthermore, backward trajectories and PCA combined with DR (diagnostic ratio analysis) were employed to identify the influences of regional transport and main emission sources. The results revealed that PAHs in PM2.5 were mainly affected by regional transport with the main emissions by mobile vehicle and steel industry, which contributed about 56.0% to the total PAHs in the area of Mount Lushan. In addition, backward trajectories revealed that the dominant air masses were from the northwest accounting for about one third of total PAHs. PMID- 29426186 TI - Inferring changes in soil organic matter in post-wildfire soil burn severity levels in a temperate climate. AB - Simple, rapid and reliable methods of assessing soil burn severity (SBS) are required in order to prioritize post-fire emergency stabilization actions. SBS proxies based on visual identification and changes in soil organic matter (SOM) content and quality can be related to other soil properties in order to determine the extent to which soil is perturbed following fire. This task is addressed in the present study by an approach involving the use of differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) to determine changes in SOM generated in soils subjected to different levels of SBS. Intact topsoil monoliths comprising the organic horizons and the surface mineral soil (alumic-humic umbrisols) were collected from a representative P. pinaster stand in NW Spain. The monoliths were experimentally burned in a combustion wind tunnel to simulate different fire conditions (fuel bed comprising forest pine litter and wood; air flow, 0.6 m s-1). Changes in OM properties in the soil organic layer and mineral soils samples (0-2 cm) at the different temperatures and SBS levels were identified. For both duff and mineral soil, the data revealed a temperature induced increase in aromatic compounds and a concomitant decrease of carbohydrates and alkyl products. However, for a given temperature, the degree of carbonization/aromatization was lower in the mineral soil than in the duff, possibly due to the different composition of the OM and to the different combustion conditions. The low degree of aromatization of the organic matter suggests that this soil component could undergo subsequent biological degradation. SOM content and thermal recalcitrance (measured as T50) discriminated the SBS levels. Use of visual identification of SBS levels in combination with DSC-TGA enables rapid evaluation of the spatial variability of the effects of fire on SOM properties. This information is useful to predict soil degradation process and implement emergency soil stabilization techniques. PMID- 29426187 TI - Refined source apportionment of coal combustion sources by using single particle mass spectrometry. AB - In this study, samples of three typical coal combustion source types, including Domestic bulk coal combustion (DBCC), Heat supply station (HSS), and Power plant (PP) were sampled and large sets of their mass spectra were obtained and analyzed by SPAMS during winter in a megacity in China. A primary goal of this study involves determining representative size-resolved single particle mass spectral signatures of three source types that can be used in source apportionment activities. Chemical types describe the majority of the particles of each source type were extracted by ART-2a algorithm with distinct size characteristics, and the corresponding tracer signals were identified. Mass spectral signatures from three source types were different from each other, and the tracer signals were effective in distinguishing different source types. A high size-resolution source apportionment method were proposed in this study through matching sources' mass spectral signatures to particle spectra in a twelve days ambient sampling to source apportion the particles. Contributions of three source types got different size characteristics, as HSS source got higher contribution in smaller sizes, But PP source got higher contributions as size increased. Source contributions were also quantified during two typical haze episodes, and results indicated that HSS source (for central-heating) and DBCC source (for domestic heating and cooking) may contribute evidently to pollution formation. PMID- 29426188 TI - Impacts of land-use on surface waters at the watershed scale in southeastern China: Insight from fluorescence excitation-emission matrix and PARAFAC. AB - In recent years, the Chinese government has strengthened its efforts in surface water protection and restoration through strict policies and heavy investments. A clear understanding of the impacts of land use on water quality is necessary in order to ensure an effective and efficient implementation of the ongoing surface water restoration program in China. To this end, four small watersheds (less than 5000 ha) in southeastern China, which have clear gradients in the intensities of agriculture (17.0-45.4%), forest (35.2-73.6%) and built-up area (3.3-8.5%), were investigated regarding the impacts of land use on water quality. In addition to the general water quality indices, characteristic components derived by fluorescence excitation-emission matrices (FEEMs) coupled with parallel factor analysis (PARAFAC) were employed to explore a more accurate association between land use and water quality. The results show that agricultural intensity has significant effects by elevating the concentrations of dissolved organic carbon (DOC, an approximate six-fold increase) and total phosphorous (TP, an approximate four-fold increase) in the surface waters. A total of five PARAFAC components representing terrestrial (three components) and protein-like (two components) substances were identified. The PARAFAC results indicate that land-use patterns affected the dissolved organic matter (DOM) in the aspects of both amount and composition. The intensity (R.U.) of the terrestrial components showed a strong correlation (r2 = 0.95, p = 0.01) with agricultural land percentage. Moreover, although the proportion of built-up area varies with a relatively small range, a protein-like component could predict its impact with excellent sensitivity (r2 = 0.94, p = 0.02), whereas the general water quality indices were incapable of predicting the impact due to their multiple sources. The results of this study demonstrate that the FEEMs-PARAFAC technique provides an inexpensive and effective tool for policy makers to overcome the insensitivity of general water quality indices, particularly for the restoration of watersheds with complex land use patterns. PMID- 29426189 TI - Sub-lethal doses of widespread nanoparticles promote antifungal activity in Pseudomonas protegens CHA0. AB - Nanoparticles are widely used as antimicrobial compounds. At sub-lethal concentrations, they may also stress microbes, potentially inducing antibiosis. Here we assess whether nanoparticles can serve as an enhancer of antibiosis in beneficial microbes. Several host-associated bacteria can suppress pathogens, providing therefore a first line of defense against diseases. In the present study, we assessed whether nanoparticles stimulate the antifungal activity of Pseudomonas protegens CHA0, a model plant-associated bacterium, against the ascomycete yeast Candida albicans. We synthesized and characterized four of the most common nanoparticles, namely Ag, SiO2, TiO2, and ZnO, with an average size of 25, 11, 25 and 35 nm, respectively. The dose-dependent effect of these nanoparticles on the growth of Pseudomonas protegens CHA0 was assessed. Ag, SiO2, TiO2, and ZnO nanoparticles inhibited the growth of Pseudomonas protegens by 100, 22, 15 and 15%, respectively at a concentration of 250 MUg/mL. We then selected sub-lethal dose (500 ng/mL) and assessed whether the same nanoparticles stimulated the production of antifungal compounds inhibiting C. albicans. Incubating the bacteria in the presence of nanoparticles led to a four-fold increase in antifungal activity. We finally show that nanoparticles induce the expression of the prn operon, responsible for the production of antifungal compound pyrrolnitrin, within hours after nanoparticle exposure. This study shows that nanoparticle application may be a valuable tool to stimulate the antifungal activity of fluorescent pseudomonads, potentially assisting the development of future sustainable disease control strategies. PMID- 29426190 TI - Sulfide alleviates cadmium toxicity in Arabidopsis plants by altering the chemical form and the subcellular distribution of cadmium. AB - Several sulfur compounds are thought to play important roles in the plant tolerance to cadmium (Cd), but the role of inorganic sulfide in Cd tolerance remains largely unknown. In this study, we found that Cd exposure increased the accumulation of soluble sulfide in Arabidopsis plants. When exogenous sulfide, in the form of NaHS, was foliarly applied, Cd-induced growth inhibition and oxidative stress were alleviated. In addition, although the foliar application of sulfide did not affect the total Cd levels, it significantly decreased the soluble Cd fractions in plants. Furthermore, foliar applications of sulfide decreased Cd distribution in the cytoplasm and organelles, but increased Cd retention in the cell wall, which is a less sensitive compartment. These results suggest that the Cd-induced accumulation of soluble sulfide alleviates Cd toxicity in plants by inactivating Cd and sequestering it into the cell wall. PMID- 29426191 TI - Higher health effects of ambient particles during the warm season: The role of infiltration factors. AB - A large number of studies have shown much higher health effects of particulate matter (PM) during the warm compared to the cold season. In this paper we present the results of an experimental study carried out in an unoccupied test apartment with the aim of understanding the reasons behind the seasonal variations of the health effects due to ambient PM2.5 exposure. Measurements included indoor and outdoor PM2.5 mass and chemical composition as well as particle size distribution of ultrafine particles. Monitoring campaigns were carried out during summer and winter following a ventilation protocol developed to replicate typical occupant behaviour according to a questionnaire-based survey. Our findings showed that seasonal variation of the relationship between ambient and indoor mass concentrations cannot entirely explain the apparent difference in PM toxicity between seasons and size distribution and chemical composition of particles were identified as other possible causes of changes in the apparent PM toxicity. A marked decrease of ultrafine particles (<100 nm) passing from outdoors to indoors was observed during winter; this resulted in higher indoor exposure to nanoparticles (<50 nm) during summer. With regards to the chemical composition, a pooled analysis showed infiltration factors of chemical species similar to that obtained for PM2.5 mass with values increasing from 0.73 during winter to 0.90 during summer and few deviations from the pooled estimates. In particular, significantly lower infiltration factors and sink effect were found for nitrates and ammonium during winter. In addition, a marked increase in the contribution of indoor and outdoor sulfates to the total mass was observed during summer. PMID- 29426192 TI - Spatial variation and sources of polycyclic aromatic hydrocarbons influenced by intensive land use in an urbanized river network of East China. AB - The concentrations and distribution of polycyclic aromatic hydrocarbons (PAHs) in urbanized river networks are strongly influenced by intensive land use, industrial activities and population density. The spatial variations and their influencing factors of 16 priority PAHs were investigated in surface water, suspended particulate matter (SPM) and sediments among areas under different intensive land uses (industrial areas, agricultural areas, inner city, suburban towns and island areas) in the Shanghai river network, East China. Source apportionment was carried out using isomer ratios of PAHs and Positive Matrix Factorization (PMF). Total concentrations of 16 PAHs ranged from 105.2 to 400.5 ng/L, 108.1 to 1058.8 ng/L and 104.4 to 19,480.0 ng/g in water, SPM and sediments, respectively. The concentrations of PAHs in SPM and sediments varied significantly among areas (p < 0.05), with the highest concentrations in inner city characterized by highly intensive land use and high population density. The PAH concentrations in sediments were positively correlated with those in SPM and were more strongly correlated with black carbon than with total organic carbon, indicating a stronger influence of prolonged anthropogenic contamination than the recent surface input in sediments. Biomass and coal combustion contributed strongly to total PAHs, followed by natural gas combustion in water and SPM, and vehicular emissions in sediments. Vehicular emissions were the strongest contributors in SPM and sediments of the inner city, indicating the strong influence of vehicular transportation to PAHs pollution in the urbanized river network. PMID- 29426193 TI - Sewage sludge used as organic manure in Moroccan sunflower culture: Effects on certain soil properties, growth and yield components. AB - The wastewater treatment and sludge production sectors in Morocco are recent. Considered as waste, no management strategy for sewage sludge (SS) has been implemented. Thus, its disposal definitely represents a major environmental problem since sludge is either incinerated, used as landfill or simply deposited near wastewater treatment plants. The objective of this study was to determine the effects of dehydrated SS on certain soil properties (pH, electrical conductivity (EC), Mineral nitrogen, available phosphate P2O5, and soluble potassium K2O), and also on growth and yield components of the sunflower (Helianthus annuus L.). An experiment was conducted using six treatment rates (0; 0 + NPK; 15; 30; 60 and 120 t ha-1). The results showed that soil pH was significantly affected by SS, becoming less alkaline compared to the control, while electrical conductivity increased significantly when the applied doses were above 30 t ha-1. Also, a significant enrichment in mineral N and available phosphorus was detected in amended soil. However, no differences were found between pots having received the mineral fertilization and the SS at 15 t ha-1. Stem height growth of the sunflower seedlings receiving SS increased significantly compared to the two controls. For both the aerial and root parts, significant increases in dry biomass accumulation were observed compared to the unamended plants. Net CO2 assimilation (An) increased, while stomatal conductance (gsw) and transpiration rates (Tr) decreased with increasing SS rates. SS application at 15 t ha-1 presented similar values of the yield components compared to plants fertilized chemically. However, grain yield (in quintals ha-1) was noted to be 2.4, 5 and 8 times higher in treatments receiving SS respectively at the rate of 30, 60 and 120 t ha-1. PMID- 29426194 TI - Assessment of occupational exposure to engineered nanomaterials in research laboratories using personal monitors. AB - Exposure assessment is a key stage in the risk assessment/management of engineered nanomaterials. Although different sampling strategies and instruments have been used to define the occupational exposure to nano-scale materials, currently there is no international consensus regarding measurement strategy, metrics and limit values. In fact, the assessment of individual exposure to engineered nanomaterials remains a critical issue despite recent innovative developments in personal monitors and samplers. Hence, we used several of these instruments to evaluate the workers' personal exposure in a large research laboratory where engineered nanomaterials are produced, handled, and characterized in order to provide input data for nanomaterial exposure assessment strategies and future epidemiological studies. The results obtained using personal monitors showed that the workplace concentrations of engineered nanomaterials (lung deposited surface area and particle number concentrations) were quite low in all the different workplaces monitored, with short spikes during the execution of some specific job tasks. The sampling strategy was been adopted on the basis of an Organisation for Economic Cooperation and Development (OECD) suggestion for a tiered approach and was found to be suitable for determining the individual exposure and for identifying possible sources of emission, even those with very low emission rates. The use of these instruments may lead to a significant improvement not only in the exposure assessment stage but, more generally, in the entire risk assessment and management process. PMID- 29426195 TI - Occurrence, distribution, and potential sources of antibiotics pollution in the water-sediment of the northern coastline of the Persian Gulf, Iran. AB - Occurrence and frequency of six most prescribed antibiotics (tetracycline, norfloxacin, azithromycin, anhydro erythromycin, cephalexin, and amoxicillin) were assessed in three wastewater treatment plants (WWTPs), and in water and sediments of the Persian Gulf at Bushehr coastline, Iran. The antibiotics concentration in the influent and effluent of septic tank (the hospital WWTP), activated sludge (the hospital WWTP), and stabilization pond (municipal WWTP) ranged between 7.89 and 149.63, 13.49-198.47, 6.55-16.37 ng/L, respectively. Conventional treatment resulted in incomplete removal of most of the studied antibiotics. Furthermore, the activated sludge was more effective in terms of antibiotic elimination compared to the stabilization pond or septic tank. The mean concentration of antibiotics ranged 1.21-51.50 ng/L in seawater and 1.40 25.32 ng/g in sediments during summer and winter. Norfloxacin was the dominant detected antibiotic in seawater, sediments, and influent of two hospital WWTPs. Seasonal comparisons showed significant differences for erythromycin and amoxicillin concentrations in seawater. Spatial variation indicated the role of physicochemical properties on distribution of antibiotics in seawater and sediments. The results emphasize the need to pay attention to antibiotic contamination in water and sediments of the Persian Gulf. PMID- 29426196 TI - Assessing clogging of laminated hydrophobic membrane during fecal sludge drying. AB - A new sanitation technology has been proposed in which a laminated hydrophobic membrane contains and enhances drying of fecal sludge in a toilet, with particular focus on application to urban regions of low-income countries. The proposed technology uses a laminated hydrophobic membrane liner as an integral component of container-based sanitation systems. The focus of this study is to quantitatively evaluate the laminate's clogging after repeated use, which will affect replacement interval and might limit the laminate's application in container-based toilets. The membrane of the laminated hydrophobic membrane used in this process is hydrophobic and only allows vapor transport. Drying of water vapor using the laminated hydrophobic membrane occurs due to moderate temperature or humidity gradients, while other constituents such as aqueous dissolved solutes of fecal sludge are retained. Controlled laboratory experiments evaluated repeated use of a laminated hydrophobic membrane for fecal sludge drying, with mild brushing/rinsing of the laminate between each application. Drying occurred at a constant rate as long as the fecal sludge moisture content exceeded 11.6 (g/g), below which water activity <1. Over five drying cycles, at a significance level of alpha = 0.05 the dimensionless drying rate in the constant-rate period was not reduced. While scanning electron microscopy and energy dispersive X-ray analyses of used laminated hydrophobic membrane showed deposition of fecal sludge on the inner fabric of the laminate, particulate accumulation was never sufficient to alter the fecal sludge drying rate. Experiments with only water indicated that the fecal sludge increased the effective diffusion length through the laminate by 10-30%. These data demonstrate that clogging of the laminated hydrophobic membrane is minor over five cycles of fecal sludge drying with mild rinsing between cycles, indicating that use of the laminate may be feasible in many field applications. PMID- 29426197 TI - Use of porous materials to remove oil contaminants from water. AB - The purpose of the research was to remove petroleum substances from water using porous materials. Birch bark, cork, glass wool and polyurethane foam were used for the study. The model solution was distilled water enriched with a mixture of petrol and diesel fuel in a volume ratio of 1:3. The model water used had 3 different concentrations of oil substances. The research included petroleum substances expressed as mineral oil index and aliphatic hydrocarbons, n-alkanes (from C7H16 to C38H78). The process of oil substances removal was carried out applying two methods: static and dynamic. Based on the research, it was found that materials the most effective in lowering the index of mineral oil and C7H16 C38H78 n-alkane concentrations were both birch bark and glass wool, both static and dynamic, while cork and polyurethane foam were less effective. In addition, concentration of C7H16-C38H78 n-alkanes was lowered in each measurement series to a greater extent than the mineral oil index. PMID- 29426198 TI - Modelling the effects of climate and land-use change on the hydrochemistry and ecology of the River Wye (Wales). AB - Interactions between climate change and land use change might have substantial effects on aquatic ecosystems, but are still poorly understood. Using the Welsh River Wye as a case study, we linked models of water quality (Integrated Catchment - INCA) and climate (GFDL - Geophysical Fluid Dynamics Laboratory and IPSL - Institut Pierre Simon Laplace) under greenhouse gas scenarios (RCP4.5 and RCP8.5) to drive a bespoke ecosystem model that simulated the responses of aquatic organisms. The potential effects of economic and social development were also investigated using scenarios from the EU MARS project (Managing Aquatic Ecosystems and Water Resources under Multiple Stress). Longitudinal position along the river mediated response to increasing anthropogenic pressures. Upland locations appeared particularly sensitive to nutrient enrichment or potential re acidification compared to lowland environments which are already eutrophic. These results can guide attempts to mitigate future impacts and reiterate the need for sensitive land management in upland, temperate environments which are likely to become increasingly important to water supply and biodiversity conservation as the effects of climate change intensify. PMID- 29426199 TI - A comparative assessment of decision trees algorithms for flash flood susceptibility modeling at Haraz watershed, northern Iran. AB - Floods are one of the most damaging natural hazards causing huge loss of property, infrastructure and lives. Prediction of occurrence of flash flood locations is very difficult due to sudden change in climatic condition and manmade factors. However, prior identification of flood susceptible areas can be done with the help of machine learning techniques for proper timely management of flood hazards. In this study, we tested four decision trees based machine learning models namely Logistic Model Trees (LMT), Reduced Error Pruning Trees (REPT), Naive Bayes Trees (NBT), and Alternating Decision Trees (ADT) for flash flood susceptibility mapping at the Haraz Watershed in the northern part of Iran. For this, a spatial database was constructed with 201 present and past flood locations and eleven flood-influencing factors namely ground slope, altitude, curvature, Stream Power Index (SPI), Topographic Wetness Index (TWI), land use, rainfall, river density, distance from river, lithology, and Normalized Difference Vegetation Index (NDVI). Statistical evaluation measures, the Receiver Operating Characteristic (ROC) curve, and Freidman and Wilcoxon signed-rank tests were used to validate and compare the prediction capability of the models. Results show that the ADT model has the highest prediction capability for flash flood susceptibility assessment, followed by the NBT, the LMT, and the REPT, respectively. These techniques have proven successful in quickly determining flood susceptible areas. PMID- 29426200 TI - Response of a multi-stressed Mediterranean river to future climate and socio economic scenarios. AB - Streams and rivers are among the most threatened ecosystems in Europe due to the combined effects of multiple pressures related to anthropogenic activities. Particularly in the Mediterranean region, changes in hydromorphology along with increased nutrient loadings are known to affect the ecological functions and ecosystem services of streams and rivers with the anticipated climate change being likely to further impair their functionality and structure. In this study, we investigated the combined effects of agricultural driven stressors on the ecology and delivered services of the Pinios river basin in Greece under three future world scenarios developed within the EU funded MARS project. Scenarios are based on combinations of Representative Concentration Pathways and Shared Socioeconomic Pathways and refer to early century (2030) and mid-century (2060) representing future climate worlds with particular socioeconomic characteristics. To assess the responses of ecological and ecosystem service indicators to the scenarios we first simulated hydrology and water quality in Pinios with a process based model. Simulated abiotic stressor parameters (predictors) were linked to two biotic indicators, the macroinvertebrate indicators ASPT and EPT, with empirical modelling based on boosted regression trees and general linear models. Our results showed that the techno world scenario driven by fast economic growth and intensive exploitation of energy resources had the largest impact on both the abiotic status (nutrient loads and concentrations in water) and the biotic indicators. In contrast, the predicted changes under the other two future worlds, consensus and fragmented, were more diverse and were mostly dictated by the projected climate. This work showed that the future scenarios, especially the mid century ones, had significant impact on both abiotic status and biotic responses underpinning the need for implementing catchment management practices able to mitigate the ecological threat on waters in the long-term. PMID- 29426201 TI - Effects of different fertilizers on methane emissions and methanogenic community structures in paddy rhizosphere soil. AB - Paddy soil accounts for 10% of global atmospheric methane (CH4) emissions. Many types of fertilizers may enhance CH4 emissions, especially organic fertilizer. The aim of this study was to explore the effects of different fertilizers on CH4 and methanogen patterns in paddy soil. This experiment involved four treatments: chemical fertilizer (CT), organic fertilizer (OT), mixed with chemical and organic fertilizer (MT), and no fertilizer (ctrl). The three fertilization treatments were applied with total nitrogen at the same rate of 300 kg N ha-1. Paddy CH4, soil physicochemical variables and methanogen communities were quantitatively analyzed. Rhizosphere soil mcrA and pmoA gene copy numbers were determined by qPCR. Methanogenic 16S rRNA genes were identified by MiSeq sequencing. The results indicated CH4 emissions were significantly higher in OT (145.31 kg ha-1) than MT (84.62 kg ha-1), CT (77.88 kg ha-1) or ctrl (32.19 kg ha 1). Soil organic acids were also increased by organic fertilization. CH4 effluxes were significantly and negatively related to mcrA and pmoA gene copy numbers, and positively related to mcrA/pmoA. Above all, hydrogenotrophic Methanocella and acetoclastic Methanosaeta were the predominant methanogenic communities; these communities were strictly associated with soil potassium, oxalate, acetate, and succinate. Application of organic fertilizer promoted the dominant acetoclastic methanogens, but suppressed the dominant hydrogenotrophic methanogens. The transformation in methanogenic community structure and enhanced availability of C substrates may explain the increased CH4 production in OT compared to other treatments. Compared to OT, MT may partially mitigate CH4 emissions while guaranteeing a high rice yield. On this basis, we recommend the local fertilization pattern should change from 300 N kg ha-1 of organic manure to the same level of mixed fertilization. Moreover, we suggest multiple combinations of mixed fertilization merit more investigation in the future. PMID- 29426202 TI - Estimating forest carbon fluxes using four different data-driven techniques based on long-term eddy covariance measurements: Model comparison and evaluation. AB - With the recent availability of large amounts of data from the global flux towers across different terrestrial ecosystems based on the eddy covariance technique, the use of data-driven techniques has been viable. In this study, two advanced techniques, namely adaptive neuro-fuzzy inference system (ANFIS) and extreme learning machine (ELM), were developed and investigated for their viability in estimating daily carbon fluxes at the ecosystem level. All the data used in this study were based upon the long-term chronosequence observations derived from the flux towers in eight forest ecosystems. Both ANFIS and ELM methods were further compared with the most widely used artificial neural network (ANN) and support vector machine (SVM) methods. Moreover, we also focused on probing into the effects of internal parameters on their corresponding approaches. Our estimates showed that most variation in each carbon flux could be effectively explained by the developed models at almost all the sites. Moreover, the forecasting accuracy of each method was strongly dependent upon their respective internal algorithms. The best training function for ANN model can be acquired through the trial and error procedure. The SVM model with the radial basis kernel function performed considerably better than the SVM models with the polynomial and sigmoid kernel functions. The hybrid ELM models achieved similar predictive accuracy for the three fluxes and were consistently superior to the original ELM models with different transfer functions. In most instances, both the subtractive clustering and fuzzy c-means algorithms for the ANFIS models outperformed the most popular grid partitioning algorithm. It was demonstrated that the newly proposed ELM and ANFIS models were able to produce comparable estimates to the ANN and SVM models for forecasting terrestrial carbon fluxes. PMID- 29426203 TI - Effects of atmospheric stability and urban morphology on daytime intra-urban temperature variability for Glasgow, UK. AB - This study investigates the joint effect of atmospheric conditions and urban morphology, expressed as the Sky View Factor (SVF), on intra-urban variability. The study has been carried out in Glasgow, UK, a shrinking city with a maritime temperate climate type, and findings could guide future climate adaptation plans in terms of morphology and services provided by the municipality to overcome thermal discomfort in outdoor settings. In this case, SVF has been used as an indicator of urban morphology. The modified Pasquill-Gifford-Turner (PGT) classification system was adopted for classifying the temperature monitoring periods according to atmospheric stability conditions. Thirty two locations were selected on the basis of SVF with a wide variety of urban shapes (narrow streets, neighbourhood green spaces, urban parks, street canyons and public squares) and compared to a reference weather station during a total of twenty three transects during late spring and summer in 2013. Maximum daytime intra-urban temperature differences were found to be strongly correlated with atmospheric stability classes. Furthermore, differences in air temperature are noticeable in urban canyons, with a direct correlation to the site's SVF (or sky openness) and with an inverse trend under open-air conditions. PMID- 29426204 TI - Implications of a valuation study for ecological and social indicators associated with Everglades restoration. AB - The Everglades of south Florida, although degraded, imparts vital ecosystem benefits, including contributions to high quality drinking water supplies and habitat for a number of threatened and endangered species. Restoration of the Everglades can improve the provision of these benefits but also may impose tradeoffs with competing societal demands. This study focuses on understanding public preferences for Everglades restoration and estimating the willingness to pay (WTP) values for restored ecosystem services (ES) through the implementation of a discrete choice experiment (DCE). We collected data from 2302 respondents from the general public from an online survey designed to elicit WTP values for selected ecological and social attributes associated with Everglades restoration scenarios. We compare the findings to results from earlier studies (Milon et al., 1999; Milon and Scrogin, 2005), which also estimated WTP values among Floridians for Everglades restoration. For some attributes, WTP for Everglades restoration appears to have slightly increased while for others WTP appears to have decreased. We estimated statewide aggregate WTP values for components of species population restoration up to $2B over 10 years. Several factors impeded a direct comparison of current and historical WTP values, including time elapsed, different samples and sampling methods- which may have implications for integrating ecosystem service valuation studies into water management decisions. PMID- 29426205 TI - Optical and molecular characterization of dissolved organic matter (DOM) in the Arctic ice core and the underlying seawater (Cambridge Bay, Canada): Implication for increased autochthonous DOM during ice melting. AB - Sea ice contains a large amount of dissolved organic matter (DOM), which can be released into the ocean once it melts. In this study, Arctic sea ice DOM was characterized for its optical (fluorescence) properties as well as the molecular sizes and composition via size exclusion chromatography and Fourier transformation ion cyclotron resonance mass spectrometry (FT-ICR MS). Ice cores were collected along with the underlying seawater samples in Cambridge Bay, an Arctic area experiencing seasonal ice formation. The ice core samples revealed a marked enrichment of dissolved organic carbon (DOC) compared to the seawater counterparts (up to 6.2 times greater). The accumulation can be attributed to in situ production by the autotrophic and heterotrophic communities. Fluorescence excitation emission matrices (EEMs) elaborated with parallel factor analysis (PARAFAC) evidenced the prevalence of protein-like substances in the ice cores, which likely results from in situ production followed by accumulation in the ice. Size exclusion chromatography further revealed the in situ production of all DOM size fractions, with the exception of the humic substance fraction. The majority of DOM in both the ice and seawater consists of low molecular weight compounds (<350 Da) probably derived by the microbial degradation/transformation of freshly produced DOM. Molecular characterization also supported the in situ production of DOM and highlighted the marked difference in molecular composition between sea ice and seawater. This study provides new insights into the possible role of sea ice DOM in the Arctic carbon cycle under climate change. PMID- 29426206 TI - First results on zooplankton community composition and contamination by some persistent organic pollutants in the Gulf of Tadjoura (Djibouti). AB - The Gulf of Tadjoura is located in the Horn of Africa and is widely recognized as an important site where the zooplanktivorous whale sharks seasonally aggregate from October to February. The surface zooplankton community (0-3m) was weekly sampled from November 2016 to February 2017 in two sites during the whale shark aggregation period. A total of 12 phyla were identified. Copepoda represented the most abundant and diverse group with 29 different genera, and contributed with an average of 82% of the mean zooplankton density of approximately 6600indm-3. During the sampling period, copepods were dominated numerically by Calanoida (3600indm-3), followed by Poicilostomatatoida (1300indm-3). Within the copepods, Paracalanidae, Calanidae, Oncaeidae and Miraciidae were the most common families. The temporal trend in zooplankton biomass at both stations revealed the highest peak in December (41.3+/-36.4mgm-3), and the lowest in February (6.6+/-3.3mgm-3). As no information is available on the occurrence of legacy contaminants use and release in this area, analysis revealed the consistent presence of both DDT and PCB residues in zooplankton samples in the Gulf of Tadjoura. Total PCB ranged from approximately 110 to 637ngg-1 d.w., while total DDT from 21 to 80ngg-1 d.w. The proportion of primary DDT in the total residue was higher than DDE and DDD, which strongly suggests that the area might actually be subjected to DDT inputs of the parent compound. PMID- 29426207 TI - Towards sustainable and multifunctional agriculture in farmland landscapes: Lessons from the integrative approach of a French LTSER platform. AB - Agriculture is currently facing unprecedented challenges: ensuring food, fiber and energy production in the face of global change, maintaining the economic performance of farmers and preserving natural resources such as biodiversity and associated key ecosystem services for sustainable agriculture. Addressing these challenges requires innovative landscape scale farming systems that account for changing economic and environmental targets. These novel agricultural systems need to be recognized, accepted and promoted by all stakeholders, including local residents, and supported by public policies. Agroecosystems should be considered as socio-ecological systems and alternative farming systems should be based on ecological principles while taking societal needs into account. This requires an in-depth knowledge of the multiple interactions between sociological and ecological dynamics. Long Term Socio-Ecological Research platforms (LTSER) are ideal for acquiring this knowledge as they (i) are not constrained by traditional disciplinary boundaries, (ii) operate at a large spatial scale involving all stakeholders, and (iii) use systemic approaches to investigate biodiversity and ecosystem services. This study presents the socio-ecological research strategy from the LTSER "Zone Atelier Plaine & Val de Sevre" (ZA PVS), a large study area where data has been sampled since 1994. Its global aim is to identify effective solutions for agricultural development and the conservation of biodiversity in farmlands. Three main objectives are targeted by the ZAPVS. The first objective is intensive monitoring of landscape features, the main taxa present and agricultural practices. The second objective is the experimental investigation, in real fields with local farmers, of important ecosystem functions and services, in relation to pesticide use, crop production and farming socio-economic value. The third aim is to involve stakeholders through participatory research, citizen science and the dissemination of scientific results. This paper underlines the relevance of LTSERs for addressing agricultural challenges, while acknowledging that there are some yet unsolved key challenges. PMID- 29426208 TI - Tannery mixed liquors from an ecotoxicological and mycological point of view: Risks vs potential biodegradation application. AB - Fungi are known to be present in the activated sludge of wastewater treatment plants (WWTP). Their study should be at the base of an overall vision of the plant effectiveness and of effluents sanitary impact. Moreover, it could be fundamental for the implementation of successful bioaugmentation strategies aimed at the removal of recalcitrant or toxic compounds. This is one of the first studies on the cultivable autochthonous mycoflora present in the mixed liquors of two WWTP treating either vegetable or chromium tannery effluents. All samples showed a risk associated with potential pathogens or toxigenic species and high ecotoxicity (Lepidium sativum and Raphidocelis subcapitata were the most sensitive organisms). Diverse fungal populations developed, depending on the origin of the samples (63% of the 102 identified taxa were sample-specific). The use of a fungistatic was determinant for the isolation and, thus, for the identification of sample-specific species with a lower growth rate. The incubation temperature also affected the mycoflora composition, even though at lower extent. A selective medium, consisting of agarised wastewater, allowed isolating fungi with a biodegradation potential. Pseudallescheria boydii/Scedosporium apiospermum species complex was ubiquitously dominant, indicating a possible role in the degradation of pollutants in both WWTP. Other species, i.e. Trichoderma spp., Trematosphaeria grisea, Geotrichum candidum, Lichtheimia corymbifera, Acremonium furcatum, Penicillium simplicissimum, Penicillium dangeardii, Fusarium solani, Scopulariopsis brevicaulis potentially could be involved in the degradation of specific pollutants of vegetable or chromium tannery wastewaters. However, several of these fungi are potential pathogens and their application, for an in situ treatment, must be carefully evaluated. PMID- 29426209 TI - Determination of hand soil loading, soil transfer, and particle size variations after hand-pressing and hand-mouthing activities. AB - Hand-pressing trials and hand-to-mouth soil transfer experiments were conducted to better understand soil loadings, soil transfer ratios for three mouthing activities, and variations in particle size distributions under various conditions. Results indicated that sand caused higher soil loadings on the hand than clay. When the moisture level of clay soil exceeded its liquid limit, soil loadings also increased. Greater pressing pressures also led to larger clay loadings. Clay with a moisture content close to its plastic limit caused the smallest soil loadings due to strong soil cohesion. Particle sizes of the transferred clay were larger than that of the original clay, indicating that hand pressing and the pressure exerted may have enhanced clay particles of larger sizes adhering onto the hand. Nevertheless, the sizes of most particles that adhered to the hand were still smaller than 150 MUm. Higher pressing pressures and greater moisture contents resulted in larger soil loadings on the hand, and transfer ratios became smaller. Transfer ratios from palm-licking with clay particles were smaller than those from finger-mouthing, which may have been due to finer particles that more readily adhered to the skin of the palm and that were transferred from the hand to the mouth with greater difficulty. PMID- 29426210 TI - Design and application of a web-based real-time personal PM2.5 exposure monitoring system. AB - Growing demand from public health research for conduct large-scale epidemiological studies to explore health effect of PM2.5 was well-documented. To address this need, we design a web-based real-time personal PM2.5 exposure monitoring system (RPPM2.5 system) which can help researcher to get big data of personal PM2.5 exposure with low-cost, low labor requirement, and low operating technical requirements. RPPM2.5 system can provide relative accurate real-time personal exposure data for individuals, researches, and decision maker. And this system has been used in a survey of PM2.5 personal exposure level conducted in 5 cities of China and has provided mass of valuable data for epidemiological research. PMID- 29426211 TI - Emissions of organic compounds from produced water ponds III: Mass-transfer coefficients, composition-emission correlations, and contributions to regional emissions. AB - A common method for treating the aqueous phase (produced water) brought to the surface along with oil and natural gas is to discharge it into surface impoundments, also known as produced water ponds. Here we analyze data on the concentration of organic compounds in the water and on the flux of the same compounds into the atmosphere. Flux data extending from about 5 * 10-2 to 10+3 mg m-2 h-1 are consistent with mass-transfer laws given by the WATER9 semi-empirical algorithm, although empirical data display a noise level of about one order of magnitude and predictions by WATER9 are biased high. The data suggest partitioning between hydrocarbons in aqueous solution and in suspension, especially at higher overall concentrations. Salinity of the produced water does not have a detectable effect on hydrocarbon fluxes. Recently impounded waters are stronger emitters of hydrocarbons, while emissions of older waters are dominated by CO2. This aging effect can be explained by assuming, first, poor vertical mixing in the ponds, and second, gradual oxidation of hydrocarbons to CO2. Our measurements account for about 25% of the produced water ponds in the Uinta Basin, Eastern Utah, and when extrapolated to all ponds in the basin, account for about 4% to 14% of all organic compound emissions by the oil and natural gas sector of the basin, depending on the emissions inventory, and about 13% and 58%, respectively, of emissions of aromatics and alcohols. PMID- 29426212 TI - Monetary valuation of salicylic acid, methylparaben and THCOOH in a Mediterranean coastal wetland through the shadow prices methodology. AB - The presence of pharmaceutical and personal care products and drugs of abuse (PPCPs) in wastewater treatment plants (WWTPs) indicates discharge of the effluent may not be suitable for the ecological balance of water ecosystems, such as wetlands. These PPCPs degrade water quality, considered as an ecosystem service (ES), provoking serious environmental impacts. Assessing the monetary value of PPCPs can be used as a proxy for environmental status of the ES of water quality (ESWQ). Considering PPCPs as non-desirable outputs of WWTPs, the shadow prices methodology has been implemented using directional distance function to measure the environmental avoided cost of removing salicylic acid (SA), methylparaben (MP), and THCOOH from WWTPs effluents discharged to Albufera Natural Park (Spain). The SA shows the highest shadow price (138.16 ?/MUg), followed by THCOOH (48.15 ?/MUg), and MP (30.66 ?/MUg). These values are interpreted as the environmental cost that would be avoided if SA, MP, and THCOOH were removed from WWTPs effluents. The non-parametric tests show that wastewater treatment technology, together with population equivalent (as a proxy of the size of urban areas) and seasonality are factors that influence shadow prices obtained. The approach used in this study highlights the use of PPCPs as status indicators of ESWQ quantified in monetary units. As a way to synthesize the essential concepts to implement the shadow prices approach, this study proposes a flow diagram to represent the relationship between all the factors involved in this work. The use of shadow prices methodology proves that removing SA, MP, and THCOOH is associated with a measurable improvement in the ESWQ of Albufera Natural Park. The findings of this study will be useful for plant managers in order to make decisions about the removal of PPCPs in WWTPs effluents. PMID- 29426213 TI - A conceptual model for the analysis of multi-stressors in linked groundwater surface water systems. AB - Groundwater and surface water are often closely coupled and are both under the influence of multiple stressors. Stressed groundwater systems may lead to a poor ecological status of surface waters but to date no conceptual framework to analyse linked multi-stressed groundwater - surface water systems has been developed. In this paper, a framework is proposed showing the effect of groundwater on surface waters in multiple stressed systems. This framework will be illustrated by applying it to four European catchments, the Odense, Denmark, the Regge and Dinkel, Netherlands, and the Thames, UK, and by assessing its utility in analysing the propagation or buffering of multi-stressors through groundwater to surface waters in these catchments. It is shown that groundwater affects surface water flow, nutrients and temperature, and can both propagate stressors towards surface waters and buffer the effect of stressors in space and time. The effect of groundwater on drivers and states depends on catchment characteristics, stressor combinations, scale and management practises. The proposed framework shows how groundwater in lowland catchments acts as a bridge between stressors and their effects within surface waters. It shows water managers how their management areas might be influenced by groundwater, and helps them to include this important, but often overlooked part of the water cycle in their basin management plans. The analysis of the study catchments also revealed a lack of data on the temperature of both groundwater and surface water, while it is an important parameter considering future climate warming. PMID- 29426214 TI - Effect of CO2 on NADH production of denitrifying microbes via inhibiting carbon source transport and its metabolism. AB - The potential effect of CO2 on environmental microbes has drawn much attention recently. As an important section of the nitrogen cycle, biological denitrification requires electron donor to reduce nitrogen oxide. Nicotinamide adenine dinucleotide (NADH), which is formed during carbon source metabolism, is a widely reported electron donor for denitrification. Here we studied the effect of CO2 on NADH production and carbon source utilization in the denitrifying microbe Paracoccus denitrificans. We observed that NADH level was decreased by 45.5% with the increase of CO2 concentration from 0 to 30,000ppm, which was attributed to the significantly decreased utilization of carbon source (i.e., acetate). Further study showed that CO2 inhibited carbon source utilization because of multiple negative influences: (1) suppressing the growth and viability of denitrifier cells, (2) weakening the driving force for carbon source transport by decreasing bacterial membrane potential, and (3) downregulating the expression of genes encoding key enzymes involved in intracellular carbon metabolism, such as citrate synthase, aconitate hydratase, isocitrate dehydrogenase, succinate dehydrogenase, and fumarate reductase. This study suggests that the inhibitory effect of CO2 on NADH production in denitrifiers might deteriorate the denitrification performance in an elevated CO2 climate scenario. PMID- 29426215 TI - Comparison of the sampling rates and partitioning behaviour of polar and non polar contaminants in the polar organic chemical integrative sampler and a monophasic mixed polymer sampler for application as an equilibrium passive sampler. AB - In this work, Oasis HLB(r) beads were embedded in a silicone matrix to make a single phase passive sampler with a higher affinity for polar and ionisable compounds than silicone alone. The applicability of this mixed polymer sampler (MPS) was investigated for 34 aquatic contaminants (log KOW -0.03 to 6.26) in batch experiments. The influence of flow was investigated by comparing uptake under static and stirred conditions. The sampler characteristics of the MPS was assessed in terms of sampling rates (RS) and sampler-water partition coefficients (KSW), and these were compared to those of the polar organic chemical integrative sampler (POCIS) as a reference kinetic passive sampler. The MPS was characterized as an equilibrium sampler for both polar and non-polar compounds, with faster uptake rates and a shorter time to reach equilibrium than the POCIS. Water flow rate impacted sampling rates by up to a factor of 12 when comparing static and stirred conditions. In addition, the relative accumulation of compounds in the polyethersulfone (PES) membranes versus the inner Oasis HLB sorbent was compared for the POCIS, and ranged from <1% to 83% depending on the analyte properties. This is indicative of a potentially significant lag-phase for less polar compounds within POCIS. The findings of this study can be used to quantitatively describe the partitioning and kinetic behaviour of MPS and POCIS for a range of aquatic organic contaminants for application in field sampling. PMID- 29426217 TI - The effect of ground borne vibrations from high speed train on overhead line equipment (OHLE) structure considering soil-structure interaction. AB - At present, railway infrastructure experiences harsh environments and aggressive loading conditions from increased traffic and load demands. Ground borne vibration has become one of these environmental challenges. Overhead line equipment (OHLE) provides electric power to the train and is, for one or two tracks, normally supported by cantilever masts. A cantilever mast, which is made of H-section steel, is slender and has a poor dynamic behaviour by nature. It can be seen from the literature that ground borne vibrations cause annoyance to people in surrounding areas especially in buildings. Nonetheless, mast structures, which are located nearest and alongside the railway track, have not been fully studied in terms of their dynamic behaviour. This paper presents the effects of ground borne vibrations generated by high speed trains on cantilever masts and contact wire located alongside railway tracks. Ground borne vibration velocities at various train speeds, from 100 km/h to 300 km/h, are considered based on the consideration of semi-empirical models for predicting low frequency vibration on ground. A three-dimensional mast structure with varying soil stiffness is made using a finite element model. The displacement measured is located at the end of cantilever mast which is the position of contact wire. The construction tolerance of contact stagger is used as an allowable movement of contact wire in transverse direction. The results show that the effect of vibration velocity from train on the transverse direction of mast structure is greater than that on the longitudinal direction. Moreover, the results obtained indicate that the ground bourn vibrations caused by high speed train are not strong enough to cause damage to the contact wire. The outcome of this study will help engineers improve the design standard of cantilever mast considering the effect of ground borne vibration as preliminary parameter for construction tolerances. PMID- 29426216 TI - Bioreactors for oil sands process-affected water (OSPW) treatment: A critical review. AB - Canada has the world's largest oil sands reservoirs. Surface mining and subsequent caustic hot water extraction of bitumen lead to an enormous quantity of tailings (volumetric ratio bitumen:water=9:1). Due to the zero-discharge approach and the persistency of the complex matrix, oil producers are storing oil sands tailings in vast ponds in Northern Alberta. Oil sands tailings are comprised of sand, clay and process-affected water (OSPW). OSPW contains an extremely complex matrix of organic contaminants (e.g., naphthenic acids (NAs), residual bitumen, and polycyclic aromatic hydrocarbons (PAHs)), which has proven to be toxic to a variety of aquatic species. Biodegradation, among a variety of examined methods, is believed to be one of the most cost effective and practical to treat OSPW. A number of studies have been published on the removal of oil sands related contaminants using biodegradation-based practices. This review focuses on the treatment of OSPW using various bioreactors, comparing bioreactor configurations, operating conditions, performance evaluation and microbial community dynamics. Effort is made to identify the governing biotic and abiotic factors in engineered biological systems receiving OSPW. Generally, biofilms and elevated suspended biomass are beneficial to the resilience and degradation performance of a bioreactor. The review therefore suggests that a hybridization of biofilms and membrane technology (to ensure higher suspended microbial biomass) is a more promising option to remove OSPW organic constituents. PMID- 29426218 TI - The effect of biochar feedstock, pyrolysis temperature, and application rate on the reduction of ammonia volatilisation from biochar-amended soil. AB - Ammonia (NH3) volatilisation is one of the most important causes of nitrogen (N) loss in soil-plant systems worldwide. Carbon-based amendments such as biochar have been shown to mitigate NH3 volatilisation in agricultural soils to various degrees. In this study, we investigated the influence of biochar feedstocks (poultry manure, green waste compost, and wheat straw), pyrolysis temperatures (250, 350, 450, 500 and 700 degrees C) and application rates (1 and 2%), on NH3 volatilisation from a calcareous soil. The 15 biochars were chemically characterized, and a laboratory incubation study was conducted to assess NH3 volatilisation from the soil over a period of four weeks. Furthermore, changes to the bacterial and fungal communities were assessed via sequencing of phylogenetic marker genes. The study showed that biochar feedstock sources, pyrolysis temperature, and application rates all affected NH3 volatilisation. Overall, low pyrolysis temperature biochars and higher biochar application rates achieved greater reductions in NH3 volatilisation. A feedstock related effect was also observed, with poultry manure biochar reducing NH3 volatilisation by an average of 53% in comparison to 38% and 35% reductions for biochar from green waste compost and wheat straw respectively. Results indicate that the biogeochemistry underlying biochar-mediated reduction in NH3 volatilisation is complex and caused by changes in soil pH, NH3 sorption and microbial community composition (especially ammonia oxidising guilds). PMID- 29426219 TI - Transgenerational acclimation to seawater acidification in the Manila clam Ruditapes philippinarum: Preferential uptake of metabolic carbon. PMID- 29426220 TI - Comprehensive assessment of drought risk in the arid region of Northwest China based on the global palmer drought severity index gridded data. AB - Droughts are extremely widespread natural disasters, which cause the most severe losses among natural disasters. The comprehensive drought risk in Northwest China (NWC) was evaluated based on the self-calibrating (SC) Palmer Drought Severity Index (PDSI) and copula method. The major conclusions are the following: (1) based on the rotated empirical orthogonal function (REOF), a significant consistency in the spatial distribution of the monthly averaged SC-PDSI was observed in NWC, especially in the subregions Inner Mongolia Plateau (IM), Hexi Corridor (HX), and Qiangtang Plateau (QT); (2) the largest frequency was obtained for slight drought and slight wet conditions, while extreme drought and extreme wet showed the lowest values; (3) with respect to the PDSI-th, the Clayton, Arch12, Arch12, Arch12, Arch12, and Frank played the major roles in the copula weight in the subregions IM, HX, Qinghai River Basin (QH), QT, North Xinjiang (NXJ), and South Xinjiang (SXJ), respectively. In terms of PDSI-pm, Arch12, Clayton, Gaussian, Arch12, Clayton, and Clayton dominated the weights of multi copula functions in the regions IM, HX, QH, QT, NXJ, and SXJ, respectively; and (4) the frequency and probability of droughts in each area differed. The least drought events occurred in the QT and the most emerged in the HX for SC-PDSI. PMID- 29426221 TI - Contrasting effects of biochar on phosphorus dynamics and bioavailability in different soil types. AB - We investigated how two different biochars (wood biochar - WBC and straw biochar SBC) affected P dynamics and bioavailability in five different soils differing in pH, C%, texture, Fe, Al, Ca, and Mg giving a range of soils with low (S1 and S2), intermediate (S4), and high (S3 and S5) P sorption capacities. Langmuir and Freundlich equations were fitted to the sorption data of soil and soil/biochar mixtures. P fertilizer applied to all treatments was fractioned into strongly sorbed P (qS), easily available sorbed P (qA) and solution P (c) by determining the anion exchange resin (AER)-extractable P in samples from the sorption experiment. A pot experiment was conducted to measure P uptake by maize grown in S1, S2 and S3 amended with WBC or SBC at two P fertilizer levels (0 or 70mgPkg 1). Only WBC could sorb P from solution partly due to a high content of calcite. SBC did not have any effect on P sorption isotherms, whereas WBC increased the P sorption in S1, S2, and S4, yet decreased P sorption in acidic soil S5. qS increased in S1, S2, and S4, and decreased in S5 in WBC treatments, whereas, qS decreased in SBC treatments in soils S2, S4, and S5. Accordingly, there was a significant interaction between soil type and biochar on maize growth and P uptake. Biochar had no effect in an alkaline soil (S3), whereas, WBC and SBC had positive effects on maize growth in slightly acidic soils S1 and S2, depending on the soil P status, however, the P uptake was lower in WBC compared to SBC treatments. Biochar and soil properties and the P status of the soil affect P bioavailability. The study provides useful information for optimizing the use of biochar in agricultural P management. PMID- 29426223 TI - Dry-wet cycles of kettle hole sediments leave a microbial and biogeochemical legacy. AB - Understanding interrelations between an environment's hydrological past and its current biogeochemistry is necessary for the assessment of biogeochemical and microbial responses to changing hydrological conditions. The question how previous dry-wet events determine the contemporary microbial and biogeochemical state is addressed in this study. Therefore, sediments exposed to the atmosphere of areas with a different hydrological past within one kettle hole, i.e. (1) the predominantly inundated pond center, (2) the pond margin frequently desiccated for longer periods and (3) an intermediate zone, were incubated with the same rewetting treatment. Physicochemical and textural characteristics were related to structural microbial parameters regarding carbon and nitrogen turnover, i.e. abundance of bacteria and fungi, denitrifiers (targeted by the nirK und nirS functional genes) and nitrate ammonifiers (targeted by the nrfA functional gene). Our study reveals that, in combination with varying sediment texture, the hydrological history creates distinct microbial habitats with defined boundary conditions within the kettle hole, mainly driven by redox conditions, pH and organic matter (OM) composition. OM mineralization, as indicated by CO2 outgassing, was most efficient in exposed sediments with a less stable hydrological past. The potential for nitrogen retention via nitrate ammonification was highest in the hydrologically rather stable pond center, counteracting nitrogen loss due to denitrification. Therefore, the degree of hydrological stability is an important factor leaving a microbial and biogeochemical legacy, which determines carbon and nitrogen losses from small lentic freshwater systems in the long term run. PMID- 29426224 TI - Shelf life extension as solution for environmental impact mitigation: A case study for bakery products. AB - Over the last years, increasing attention has been paid to environmental concerns related to food production and potential solutions to this issue. Among the different strategies being considered to reduce the impact food production has on the environment, only moderate has been paid to the extension of shelf life; a longer shelf life can reduce food losses as well as the economic and environmental impacts of the distribution logistics. The aim of this study is to assess the environmental performance of whole-wheat breadsticks with extended shelf lives and to evaluate whether the shelf-life extension is an effective mitigation solution from an environmental point of view. To this purpose, the life cycle assessment (LCA) approach was applied from a "cradle-to-grave" perspective. Rosmarinic acid was used as an antioxidant to extend the shelf life. To test the robustness of the results and to investigate the influence of the choices made in the modelling phase, a sensitivity and uncertainty analysis were carried out. The achieved results highlighted how, for 10 of the 12 evaluated impact categories, the shelf-life extension is a proper mitigation solution, and its effectiveness depends on the magnitude of product loss reduction that is achieved. The shelf-life extension doesn't allow for the reduction of environmental impact in the categories of human toxicity, cancer effects and freshwater eutrophication. PMID- 29426222 TI - GEMAS: CNS concentrations and C/N ratios in European agricultural soil. AB - A reliable overview of measured concentrations of TC, TN and TS, TOC/TN ratios, and their regional distribution patterns in agricultural soil at the continental scale and based on measured data has been missing - despite much previous work on local and the European scales. Detection and mapping of natural (ambient) background element concentrations and variability in Europe was the focus of this work. While total C and S data had been presented in the GEMAS atlas already, this work delivers more precise (lower limit of determination) and fully quantitative data, and for the first time high-quality TN data. Samples were collected from the uppermost 20cm of ploughed soil (Ap horizon) at 2108 sites with an even sampling density of one site per 2500km2 for one individual land-use class (agricultural) across Europe (33 countries). Laboratory-independent quality control from sampling to analysis guaranteed very good data reliability and accuracy. Total carbon concentrations ranged from 0.37 to 46.3wt% (median: 2.20wt%) and TOC from 0.40 to 46.0wt% (median: 1.80wt%). Total nitrogen ranged from 0.018 to 2.64wt% (median: 0.169wt%) and TS from 0.008 to 9.74wt% (median: 0.034wt%), all with large variations in most countries. The TOC/TN ratios ranged from 1.8 to 252 (median: 10.1), with the largest variation in Spain and the smallest in some eastern European countries. Distinct and repetitive patterns emerge at the European scale, reflecting mostly geogenic and longer-term climatic influence responsible for the spatial distribution of TC, TN and TS. Different processes become visible at the continental scale when examining TC, TN and TS concentrations in agricultural soil Europe-wide. This facilitates large-scale land-use management and allows specific areas (subregional to local) to be identified that may require more detailed research. PMID- 29426225 TI - High-Content Microfluidic Screening Platform Used To Identify sigma2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model. AB - The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently, we developed a single-copy model of amyloid precursor protein (SC_APP) induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons. Our previous work with this model suggests that small molecule ligands of the sigma 2 receptor (sigma2R), which was recently cloned and identified as transmembrane protein 97 (TMEM97), are neuroprotective. To determine structure-activity relationships for unexplored chemical space in our sigma2R/Tmem97 ligand collection, we developed an in vivo high-content screening (HCS) assay to identify potential drug leads. The HCS assay uses our recently developed large scale microfluidic immobilization chip and automated imaging platform. We discovered norbenzomorphans that reduced neurodegeneration in our C. elegans model, including two compounds that demonstrated significant neuroprotective activity at multiple doses. These findings provide further evidence that sigma2R/Tmem97-binding norbenzomorphans may represent a new drug class for treating neurodegenerative diseases. PMID- 29426226 TI - Shape of Nanoparticles as a Design Parameter to Improve Docetaxel Antitumor Efficacy. AB - It was reported that the shape of nanocarriers played an important role in achieving a better therapeutic effect. To optimize the morphology and enhance the antitumor efficacy, in this study based on the amphiphilic PAMAM- b-OEG codendrimer (POD), docetaxel-loaded spherical and flake-like nanoparticles (DTX nanospheres and nanosheets) were prepared via an antisolvent precipitation method with similar particle size, surface charge, stability, and release profiles. The feed weight ratio of DTX/POD and the branched structure of OEG dendron were suggested to influence the shapes of the self-assembled nanostructures. As expected, DTX nanospheres and nanosheets exhibited strong shape-dependent cellular internalization efficiency and antitumor activity. The clathrin-mediated endocytosis and macropincytosis-dependent endocytosis were proven to be the main uptake mechanism for DTX nanospheres, while it was clathrin-mediated endocytosis for DTX nanosheets. More importantly, DTX nanosheets presented obviously superior antitumor efficacy over nanospheres, the tumor inhibition rate was increased 2 fold in vitro and 1.3-fold in vivo. An approximately 2-fold increase in pharmacokinetic parameter (AUC, MRT, and T1/2) and tumor accumulation were observed in the DTX nanosheets group. These results suggested that the particle shape played a key role in influencing cellular uptake behavior, pharmacokinetics, biodistribution, and antitumor activity; the shape of drug loaded nanoparticles should be considered in the design of a new generation of nanoscale drug delivery systems for better therapeutic efficacy of anticancer drug. PMID- 29426227 TI - Bacterially driven cadmium sulfide precipitation on porous membranes: Toward platforms for photocatalytic applications. AB - The emerging field of biofabrication capitalizes on nature's ability to create materials with a wide range of well-defined physical and electronic properties. Particularly, there is a current push to utilize programmed, self-organization of living cells for material fabrication. However, much research is still necessary at the interface of synthetic biology and materials engineering to make biofabrication a viable technique to develop functional devices. Here, the authors exploit the ability of Escherichia coli to contribute to material fabrication by designing and optimizing growth platforms to direct inorganic nanoparticle (NP) synthesis, specifically cadmium sulfide (CdS) NPs, onto porous polycarbonate membranes. Additionally, current, nonbiological, chemical synthesis methods for CdS NPs are typically energy intensive and use high concentrations of hazardous cadmium precursors. Using biosynthesis methods through microorganisms could potentially alleviate these issues by precipitating NPs with less energy and lower concentrations of toxic precursors. The authors adopted extracellular precipitation strategies to form CdS NPs on the membranes as bacterial/membrane composites and characterized them by spectroscopic and imaging methods, including energy dispersive spectroscopy, and scanning and transmission electron microscopy. This method allowed us to control the localization of NP precipitation throughout the layered bacterial/membrane composite, by varying the timing of the cadmium precursor addition. Additionally, the authors demonstrated the photodegradation of methyl orange using the CdS functionalized porous membranes, thus confirming the photocatalytic properties of these composites for eventual translation to device development. If combined with the genetically programmed self-organization of cells, this approach promises to directly pattern CdS nanostructures on solid supports. PMID- 29426230 TI - Lifestyle and Dietary Factors and Prostate Cancer Risk: A Multicentre Case Control Study. AB - This study aims to explore the association between fruit and vegetable intake, high fat, body mass index (BMI) score, physical activity, and the occurrence of prostate cancer among Jordanian men. A case-control study was conducted in three large referral hospitals. The sample included 165 prostate cancer patients in the case group and 177 healthy participants in the control group. The results showed that smoking (odds ratio [OR] = 0.32; 95% confidence interval [CI] = [0.18, 0.57]), a history of prostate infection (OR = 0.21; 95% CI = [0.11, 0.38]), high fat intake (OR = 0.44; 95% CI = [0.23, 0.85]), and increased mean of BMI (OR = 1.08; 95% CI = [1.02, 1.13]) increased the likelihood of developing prostate cancer. Healthy diet and giving up smoking are recommended, as they may contribute to a reduction in the incidence of prostate cancer. More randomized clinical trials in this area are needed to strengthen the available evidence and reduce the effects of confounding variables. PMID- 29426231 TI - The impact of route of diagnosis on survival in patients with glioblastoma. AB - INTRODUCTION: The standard of care for glioblastoma is maximal debulking surgery followed by chemo-radiotherapy (CRT). Published data show worse outcomes for patients who present with GBM as an emergency. This study investigates prognostic factors in a cohort of GBM patients treated with postoperative CRT, and compares outcomes in patients who present via emergency pathways with those who present through outpatient clinics. METHODS: Patients with GBM operated on between 1 April 2010 and 5 October 2015 and then treated with postoperative CRT were included in the study. Data were collected from electronic patient records and radiotherapy planning systems. Survival data were censored on 22 March 2016. Univariate and multivariate analyses of prognostic factors were performed. RESULTS: 104 patients were studied; mean age 51.6 years (range 19 to 70 years). Median overall survival (OS) was 16.5 months, with 68.2% and 37.8% alive at 12 and 24 months respectively. On multivariate analysis, improved OS was associated with ECOG Performance Status of 0 (vs >=1; p = .012), patient age <60 years (vs >=60 years; p < .001), and surgical debulking or macroscopic complete resection (vs biopsy; p < .001). Patients who presented through emergency medical pathways had worse survival (p = .005). CONCLUSION: This study supports published data that initial presentation through emergency pathways is associated with worse outcomes in GBM, even in patients who remain fit enough to receive post-operative CRT. PMID- 29426243 TI - External Auditory Canal Dimensions, Age, and Cerumen Retention or Impaction in Persons With Down Syndrome. AB - OBJECTIVE: To investigate associations between age, external auditory canal (EAC) dimensions, and cerumen retention/impaction among persons with Down syndrome (DS). METHODS: This cross-sectional study evaluated EAC dimensions, cerumen retention/impaction, and middle ear status with pneumatoscopy after extraction in 130 persons with DS. Descriptive and inferential statistics correlated age, presence of impacted/retained cerumen, and EAC diameter. RESULTS: Of 260 ears in 67 males and 63 females with average age of 9.48 years, 72.3% (188) had EAC of <=4 mm. Those <=1 year were 4.97 times more likely to have cerumen problems than those >1 year (95% CI, 1.45-17.02, P = .011). The odds of having cerumen problems with an EAC diameter of <=4 mm were 3.31 times higher than with a diameter of 5 mm (95% CI, 1.46-7.50, P = .004), and odds of having cerumen impaction were as much as 6.19 times higher (95% CI, 2.38-16.08, P < .001). Male gender and low lying external ear were also associated with increased odds of cerumen problems. CONCLUSION: There is a high prevalence of cerumen retention/impaction in persons with DS compared to the general Philippine population and a higher prevalence rate for EAC stenosis than elsewhere. A canal diameter of 4 mm and below and age 1 year or less are associated with a significantly higher likelihood of cerumen retention/impaction. PMID- 29426237 TI - Targeted delivery of doxorubicin by CSA-binding nanoparticles for choriocarcinoma treatment. AB - Gestational trophoblastic neoplasia (GTN) can result from the over-proliferation of trophoblasts. Treatment of choriocarcinoma, the most aggressive GTN, currently requires high doses of systemic chemotherapeutic agents, which result in indiscriminate drug distribution and severe toxicity. To overcome these disadvantages and enhance the chemotherapeutic efficacy, chondroitin sulfate A (CSA)-binding nanoparticles were developed for the targeted delivery of doxorubicin (DOX) to choriocarcinoma cells using a synthetic CSA-binding peptide (CSA-BP), derived from malarial protein, which specifically binds to the CSA exclusively expressed in the placental trophoblast. CSA-BP-conjugated nanoparticles rapidly bonded to choriocarcinoma (JEG3) cells and were efficiently internalized into the lysosomes. Moreover, CSA-BP modification significantly increased the anti-cancer activity of the DOX-loaded nanoparticles in vitro. Intravenous injections of CSA-BP-conjugated nanoparticles loaded with indocyanine green (CSA-INPs) were rapidly localized to the tumor. The CSA-targeted nanoparticles loaded with DOX (CSA-DNPs) strongly inhibited primary tumor growth and, more importantly, significantly suppressed metastasis in vivo. Collectively, our results highlight the potential of the CSA-BP-decorated nanoparticles as an alternative targeted delivery system of chemotherapeutic agents for treating choriocarcinoma and for developing new GTN therapies based on drug targeting. PMID- 29426245 TI - Albumin coated cadmium nanoparticles as chemotherapeutic agent against MDA-MB 231 human breast cancer cell line. AB - With the aim of dedicating toxicity of cadmium nanoparticles (CdNPs) against invasive breast cancer, with minimum damage to surrounding healthy cells, CdNPs were coated with albumin nanocarrier by nanoprecipitation method and named CdNPs@BSA. The characterization was done by TEM image, DLS and UV-Vis, fluorescence, circular dichroism spectroscopy. The cytotoxic efficacy of the CdNPs@BSA against human breast cancer cells (MDA-MB 231 cells) was examined by MTT assay. Apoptosis, as the mechanism of cell death, was verified by inverted microscopy, fluorescent microscopy, gel electrophoresis and flow cytometry. The role of ROS generation in apoptosis was also studied. It was found that the resulted CdNPs@BSA (diameter of 88 nm and zeta potential of about -18.85 mV) was suitable for penetration in tumour micro vessels. In the form of CdNPs@BSA, the 77% of the secondary structure and almost all of the tertiary structure remain intact. Comparing to CdNPs, CdNPs@BSA could significantly suppress the MDA-MB 231 while they were less toxic on WBCs. Therefore, they could be a brilliant candidate to be used as a chemotherapeutic agent against invasive breast cancer cells. PMID- 29426244 TI - Ideal Characteristics of a Laser-Protected Endotracheal Tube: ABEA and AHNS Member Survey and Biomechanical Testing. AB - OBJECTIVES: To determine the characteristics of laser-protected endotracheal tubes (LPETs) valued by otolaryngologists performing transoral laser surgery in the head and neck and to measure LPET stiffness. METHODS: An online questionnaire was completed by American Broncho-Esophagological Association (ABEA) and American Head and Neck Society (AHNS) members. LPET distal end compliance was measured in a biomechanics laboratory. RESULTS: A total of 228 out of 2109 combined ABEA and AHNS members completed the survey. The following LPET characteristics, which were properties of the Medtronic Laser-Shield II tube (MLST), were highly valued: softness and flexibility, surface smoothness, and a tight-to-shaft balloon (all P < .01). Prior to industry-driven discontinuation of the MLST, 52% of surgeons (78% of fellowship-trained laryngologists [FTLs]) reported using it; afterward, 58% reported using the stainless steel, Mallinckrodt Laser-Flex tube (MLFT). Forty-six percent of all respondents (69% of FTLs) did not consider cost being a factor in LPET choice. Biomechanical testing revealed the distal end of the MLST to be 3.45 times more compliant than the MLFT ( P < .01). CONCLUSION: Members of the ABEA and AHNS, particularly FTLs, highly value distinguishing properties of the now discontinued MLST. Manufacturers should consider this in the design of new LPETs. PMID- 29426248 TI - Cholesterol and vitamin E-conjugated PEGylated polymeric micelles for efficient delivery and enhanced anticancer activity of curcumin: evaluation in 2D monolayers and 3D spheroids. AB - A newly synthesized PEGylated cholesterol/alpha-tocopheryl succinate (alpha-TOS) linked polymer (CV) was self-assembled and loaded with curcumin to form a micellar system (C-CVM). The tri-functionalized amphiphilic polymer was constituted of hydrophobic cholesterol and alpha-TOS connected to hydrophilic PEG via a lysine linker. The synthesized polymer and the micelles were characterized by 1H NMR, DLS, zeta potentiometer, TEM, CMC determination and hemolysis studies. CVM displayed low CMC value of 15 uM with extent of hemolysis as less than 4%. The stable C-CVM with optimum % drug loading (14.2 +/- 0.24) displayed Z average of 175.8 +/- 0.68 nm with PDI (0.248 +/- 0.075) and released curcumin in sustained manner in the in vitro drug release study. C-CVM demonstrated dose dependent cellular uptake and cytotoxicity in murine melanoma, B16F10 and human breast cancer, MDA-MB-231 cell lines. CV exhibited marked reversal of drug resistance as indicated by significantly higher retention of P-glycoprotein substrate, rhodamine-123 in the resistant B16F10 cell line compared to standard P glycoprotein inhibitor, verapamil. C-CVM demonstrated significantly higher spheroidal growth inhibition compared to C-PPM. The results provide strong evidence for CVM as promising drug delivery system and confirm the potential of C CVM as chemotherapy in cancer. PMID- 29426250 TI - alpha-Conotoxin ImI-modified polymeric micelles as potential nanocarriers for targeted docetaxel delivery to alpha7-nAChR overexpressed non-small cell lung cancer. AB - A micelle system modified with alpha-Conotoxin ImI (ImI), a potently antagonist for alpha7 nicotinic acetylcholine receptor (alpha7-nAChR) previously utilized for targeting breast cancer, was constructed. Its targeting efficiency and cytotoxicity against non-small cell lung cancer (NSCLC) highly expressing alpha7 nAChR was investigated. A549, a non-small cell lung cancer cell line, was selected as the cell model. The cellular uptake study showed that the optimal modification ratio of ImI on micelle surface was 5% and ImI-modification increased intracellular delivery efficiency to A549 cells via receptor-mediated endocytosis. Intracellular Ca2+ transient assay demonstrated that ImI modification led to enhanced molecular interaction between nanocarriers and A549 cells. The in vivo near-infrared fluorescence imaging further revealed that ImI modified micelles could facilitate the drug accumulation in tumor sites compared with non-modified micelles via alpha7-nAChR mediation. Moreover, docetaxel (DTX) was loaded in ImI-modified nanomedicines to evaluate its in vitro cytotoxicity. As a result, DTX-loaded ImI-PMs exhibited greater anti-proliferation effect on A549 cells compared with non-modified micelles. Generally, our study proved that ImI-modified micelles had targeting ability to NSCLC in addition to breast cancer and it may provide a promising strategy to deliver drugs to NSCLC overexpressing alpha7-nAChR. PMID- 29426251 TI - Risk Assessment in Habitual Offenders With Substance Use Problems: A Quasi Prospective Study of the Predictive Validity of the HKT-30. AB - The predictive validity of the Dutch risk assessment instrument HKT-30 was investigated with a quasi-prospective design in a sample of habitual offenders with a substance use disorder (SUD). The study is reported according to RAGEE guidelines. The HKT-30 is an extension of the HCR-20. Files of 89 patients were coded and recidivism data were requested from the Ministry of Justice. Total scale scores and scores of the Clinical and Future scales were significantly predictive of recidivism for 1 and 2 years of time at risk, respectively. In contrast to earlier studies into recidivism, the H-scale had no predictive value. Regression analysis showed that the Clinical and Future scales contributed to the explanation of variance in recidivism, but not independently from each other. The conclusion is that the HKT-30 is a useful instrument for discovering risk factors and predicting recidivism for the population of habitual offenders with an SUD. PMID- 29426252 TI - Evaluating the Implementation of a Collaborative Juvenile Reentry System in Oakland, California. AB - Traditional juvenile reentry systems often inadequately meet offenders' complex needs. Policymakers and researchers increasingly recognize the importance of a collaborative community- and development-based reentry system to improve recidivism, youth developmental outcomes, and public safety. Yet, system-level process evaluations of integrated reentry systems are scarce. California's Alameda County juvenile reentry system implemented evidence-based strategies and practices to better serve reentry youth. We report findings from a process evaluation, using data from 15 key stakeholder interviews, focus groups with community-based providers, a reentry system-wide stakeholder survey, site visit observations, and document reviews. We identified strengths, challenges, and lessons learned. System-level strengths included increased multidisciplinary assessments, interagency collaboration, and specialty courts. Challenges included differing agency agendas, limited family and youth engagement, and data sharing. We recommend future researchers and practitioners to further examine and implement integrated system-level processes and organizational change, informed by the ecological-developmental perspective, to help promote positive outcomes for reentry youth. PMID- 29426253 TI - Symptom Profile of Psychiatric Patients With Psychosis or Psychotic Mood Disorder in Prison. AB - There is evidence that psychiatric patients with psychotic or manic disorders who are incarcerated suffer from the same symptoms as psychiatric patients who are treated in the community. There are also indications that their symptoms might be more severe. The aim of this study was to examine the severity of psychotic and manic symptoms, as well as to collect information about the emotional functioning of patients admitted to a prison psychiatric ward. Incarcerated patients with a diagnosis of psychotic or a manic disorder were examined with the Brief Psychiatric Rating Scale-Expanded (BPRS-E). With the scores of 140 assessments, a symptom profile was created using the domains of the BPRS-E. This profile was compared with the clinical profile of three nonincarcerated patient groups described in literature with a diagnosis in the same spectrum. We found high scores on positive and manic psychotic symptoms and hostility, and low scores on guilt, depression, and negative symptoms. High scores on manic and psychotic symptoms are often accompanied by violent behavior. Low scores on guilt, depression, and negative symptoms could be indicative of externalizing coping skills. These characteristics could complicate treatment in the community and warrant further research along with clinical consideration. PMID- 29426258 TI - Validation of the self-assessment teamwork tool (SATT) in a cohort of nursing and medical students. AB - INTRODUCTION: Poor teamwork has been implicated in medical error and teamwork training has been shown to improve patient care. Simulation is an effective educational method for teamwork training. Post-simulation reflection aims to promote learning and we have previously developed a self-assessment teamwork tool (SATT) for health students to measure teamwork performance. This study aimed to evaluate the psychometric properties of a revised self-assessment teamwork tool. METHODS: The tool was tested in 257 medical and nursing students after their participation in one of several mass casualty simulations. RESULTS: Using exploratory and confirmatory factor analysis, the revised self-assessment teamwork tool was shown to have strong construct validity, high reliability, and the construct demonstrated invariance across groups (Medicine & Nursing). CONCLUSIONS: The modified SATT was shown to be a reliable and valid student self assessment tool. The SATT is a quick and practical method of guiding students' reflection on important teamwork skills. PMID- 29426257 TI - Lipid-based nanocarrier efficiently delivers highly water soluble drug across the blood-brain barrier into brain. AB - Delivering highly water soluble drugs across blood-brain barrier (BBB) is a crucial challenge for the formulation scientists. A successful therapeutic intervention by developing a suitable drug delivery system may revolutionize treatment across BBB. Efforts were given here to unravel the capability of a newly developed fatty acid combination (stearic acid:oleic acid:palmitic acid = 8.08:4.13:1) (ML) as fundamental component of nanocarrier to deliver highly water soluble zidovudine (AZT) as a model drug into brain across BBB. A comparison was made with an experimentally developed standard phospholipid-based nanocarrier containing AZT. Both the formulations had nanosize spherical unilamellar vesicular structure with highly negative zeta potential along with sustained drug release profiles. Gamma scintigraphic images showed both the radiolabeled formulations successfully crossed BBB, but longer retention in brain was observed for ML-based formulation (MGF) as compared to soya lecithin (SL)-based drug carrier (SYF). Plasma and brain pharmacokinetic data showed less clearance, prolonged residence time, more bioavailability and sustained release of AZT from MGF in rats compared to those data of the rats treated with SYF/AZT suspension. Thus, ML may be utilized to successfully develop drug nanocarrier to deliver drug into brain across BBB, in a sustained manner for a prolong period of time and may provide an effective therapeutic strategy for many diseases of brain. Further, many anti-HIV drugs cannot cross BBB sufficiently. Hence, the developed formulation may be a suitable option to carry those drugs into brain for better therapeutic management of HIV. PMID- 29426259 TI - Effect of Seasonal Change on Testicular Protein Expression in White Roman Geese. AB - The purpose of this study was to investigate the change in protein expression in the testes of ganders at various breeding stages. A total of nine 3-year-old male White Roman ganders were used. The blood and testis samples were collected at the nonbreeding, sexual reactivation, and breeding stages for sex hormone analysis and proteomic analysis, respectively. The testicular weight and serum testosterone observed for ganders at the breeding stage were higher than those for ganders at nonbreeding and sexual reactivation stages (P < 0.05). There were 124 protein spots differentially expressed in the testes of ganders at various reproductive stages. A total of 107 protein spots of 74 proteins was identified through mass spectrometry. Most of the differentially expressed proteins were responsible for the molecular functions of protein binding (24%) and catalytic activity (16%). A functional pathway analysis suggested that proteins involved in steroidogenesis, metabolism, and spermatogenesis pathways changed in the White Roman geese at various reproductive stages. In conclusion, ganders at various reproductive stages exhibited different levels of testosterone and protein expression in the testes. The varied levels of the proteins might be essential and unique key factors in seasonal reproduction in ganders. PMID- 29426260 TI - Gambling and its clinical correlates in university students. AB - OBJECTIVE: This study sought to examine the prevalence of gambling disorder (GD) in a university sample and its associated physical and mental health correlates. METHODS: A 156-item anonymous online survey was distributed via random email generation to a sample of 9449 university students. Current use of alcohol and drugs, psychological and physical status and academic performance were assessed, along with questionnaire-based measures of impulsivity and compulsivity. Positive screens for GD were based upon individuals meeting DSM-5 criteria. RESULTS: A total of 3421 participants (59.7% female) were included in the analysis. The overall prevalence of GD was 0.4%, while an additional 8.4% reported subsyndromal symptoms of GD. GD was significantly associated with past-year use of cocaine, heroin/opiate pain medications, sedatives, alcohol and tobacco. Those with GD were more likely to have generalized anxiety, PTSD and compulsive sexual behavior. Questionnaire-based measures revealed higher levels of both compulsivity and impulsivity associated with disordered gambling. CONCLUSIONS: Some level of gambling symptomatology is common in young adults and is associated with alcohol and drug use, as well as impulsive and compulsive behaviors. Clinicians should be aware of the presentation of problematic gambling and screen for it in primary care and mental health settings. PMID- 29426262 TI - The relationship between theory of mind and insight in obsessive-compulsive disorder. AB - BACKGROUND: It is known that obsessive-compulsive disorder (OCD) patients with poor insight display more severe neuropsychological impairments than other patients with OCD. There are limited studies of OCD and theory of mind (ToM). AIM: To investigate ToM skills in patients with OCD and the relationship between insight and ToM skills by comparing OCD patients with good and poor insight. METHODS: Eighty patients with OCD and 80 healthy controls completed the structured clinical interview for DSM-IV axis I disorders, the Yale Brown Obsessive-Compulsive Scale, the Beck Anxiety and Beck Depression Inventories, and the Brown Assessment of Beliefs Scale. To assess ToM skills, first- and second order false-belief tests, a hinting test, a faux pas test, a reading the mind in the eyes test, and a double-bluff test were administered. RESULTS: Patients with OCD had poorer ToM abilities than healthy controls. All ToM scores were significantly lower in the poor insight group than in the good insight group (p < .001). A significant negative correlation was found between the BABS-total scores and all the ToM test mean scores (p < .05). CONCLUSIONS: The finding of significantly lower ToM skills in OCD with poor insight than in OCD with good insight may contribute to the idea of OCD with poor insight being a subtype with different clinical and neuropsychological characteristics. PMID- 29426261 TI - Effect of blue dye guided lymph channel ligation on the surgical morbidity of groin lymphadenectomy for vulval cancer: a feasibility study. AB - Inguinal lymphadenectomy has significant morbidity. Blue dye-guided lymph channel ligation is an effective technique for resolving lymphocele. This was a feasibility study in a preventative setting. Patients with vulval cancer requiring bilateral inguinal lymphadenectomy were recruited. After lymphadenectomy, patent blue V dye was injected and the severed lymph channels leaking blue dye, on the randomly-designated side were ligated. The median age was 72.5 years and the median body mass index was 25. The median lymph node harvest was 18.5. There were no significant surgical procedural differences between the right and the left sides. There was no significant difference between the two arms in terms of the duration or the volume of drainage and post operative complications. All patients were alive at the follow-up period of 40.5 months. In this feasibility study, blue dye-guided lymph channel ligation did not significantly impact on post-operative outcomes. Impact statement What is already known on this subject? Lymph channel ligation with blue dye-guidance is an effective strategy for managing recalcitrant inguinal lymphocyst. This strategy was prospectively-studied in a small series of patients with non-gynaecological cancers. This particular study by Nakamura et al. ( 2011 ) revealed that such a strategy might be efficacious in reducing wound drain output. What do the results of this study add? Our study is the first study to assess this technique exclusively in vulval cancer. Blue dye-guided lymph channel ligation at the time of inguinal lymphadenectomy does not appear to reduce wound drainage. However, this study suggests that primary lymphocyst predominantly results from inflammatory exudates, whereas persistent secondary lymphocysts are likely to result from lymphorrhoea. What are the implications of these findings for clinical practice and/or further research? Future studies, which aim to reduce the morbidity of open inguinal lymphadenectomy, should employ a composite strategy to reduce inflammatory secretions. In addition, a biochemical and cytological analysis on lymphocysts at various time points should be performed to characterise the natural history of groin lymphocysts. PMID- 29426263 TI - Drug promotional activities in Nigeria: impact on the prescribing patterns and practices of medical practitioners and the implications. AB - OBJECTIVE: Pharmaceutical companies spend significant amount of resources on promotion influencing the prescribing behavior of physicians. Drug promotion can negatively impact on rational prescribing, which may adversely affect the quality of patient care. However, little is known about these activities in Nigeria as the most populous country in Africa. We therefore aimed to explore the nature of encounters between Nigerian physicians and pharmaceutical sales representatives (PSRs), and how these encounters influence prescribing habits. METHODS: Cross sectional questionnaire-based study conducted among practicing physicians working in tertiary hospitals in four regions of Nigeria. RESULTS: 176 questionnaires were completed. 154 respondents (87.5%) had medicines promoted to them in the previous three months, with most encounters taking place in outpatients' clinics (60.2%), clinical meetings (46%) and new medicine launches (17.6%). Information about potential adverse effects and drug interactions was provided in 41.5%, and 27.3% of cases, respectively. Food, in the form of lunch or dinner, was the most common form of incentive (70.5%) given to physicians during promotional activities. 61% of physicians felt motivated to prescribe the drug promoted to them, with the quality of information provided being the driving factor. Most physicians (64.8%) would agree to some form of regulation of the relationship between medical doctors and the pharmaceutical industry. CONCLUSION: Interaction between PSRs and physicians is a regular occurrence in Nigeria, influencing prescribing practices. Meals and cheap gifts were the most common items offered to physicians during their encounters with PSRs. The need for some form of regulation by professional organizations and the government was expressed by most respondents to address current concerns. PMID- 29426264 TI - Comparison between maternal and neonatal outcome of PPROM in the cases of amniotic fluid index (AFI) of more and less than 5 cm. AB - The study was performed on pregnant women with a gestational age of 26-32 weeks of pregnancy, who had been admitted to the hospital with a confirmed diagnosis of premature rupture of membranes. In all eligible women, ultrasounds were performed for the evaluation of amniotic fluid index. Then, the women were divided into two groups according to amniotic fluid index of >=5 cm and <5 cm. These women were followed and monitored up to delivery. The women of the two groups did not have significant difference between them according to age, gestational age at the time of ruptured membrane, body mass index, gravidity, parity, gestational age at delivery and route of delivery. Maternal morbidities including chorioamnionitis, placental abruption, uterine atony after delivery and retention of placenta did not show significant difference between the two groups. There was no significant difference between the two groups' amniotic fluid index <5 cm and amniotic fluid index >=5 cm, regarding neonatal morbidities, except for neonatal sepsis and neonatal death, which were higher in the amniotic fluid index <5 cm group [7(14.6%) versus 1(2.3%), p = .039, RR = 7.7 (95%CI 0.04-0.06) and 11(30.9%) versus 2(4.7%), p = .013, RR = 6.095 (95%CI = 1.26-29.31)]. In the subgroups of two categories of gestational ages of 260-296 and 300-346, neonatal morbidities were higher in the amniotic fluid index <5 cm group. The results suggest that amniotic fluid index <5 cm should be considered as a warning sign for predicting poor prognosis of pregnancy complicated by preterm premature rupture of membranes. Impact statement What is already known on this subject? In a retrospective study in 1993, the relationship between oligohydramnios (which was defined as the largest single packet of fluid less than 2 * 2 cm) at the time of hospital admission, and the outcome of mother, foetus and neonates in a gestational age of less than 35 weeks of pregnancy was evaluated. In the oligohydramnios group, chorioamnionitis and funistis were more common. Also, the mean gestational age at the time of delivery and neonatal weight was less than that of the normal amniotic fluid group. According to these results, it was concluded that a low amniotic fluid volume in the women with preterm premature rupture of membranes (PPROM) can be considered as a prognostic factor in the cases of conservative management of PPROM. In contrast, the other study, which was performed on a larger sample size (290 patients), could not show more cases of amnionitis in the cases of amniotic fluid index (AFI) of less than 5 cm; however, the latency period was shorter in comparison with AFI of more than 5 cm. What do the results of this study add? Chorioamnionitis, placental abruption and uterine atony after delivery, retention of placenta and route of delivery did not show a significant difference between the two groups. Respiratory distress syndrome (RDS), need of surfactant and intubation, intra ventricular haemorrhage (IVH) and duration of neonatal intensive care unit (NICU) admission did not show a significant difference between the two groups; however, the rate of neonatal sepsis and neonatal death were higher in the AFI <5 cm group. What are the implications of these findings for clinical practice and/or further research? The results suggest that AFI <5 cm should be considered as a warning sign for predicting poor prognosis of pregnancy complicated by PPROM. PMID- 29426265 TI - Molecular karyotyping in early miscarriages: potential for the routine use of cytogenetic microarrays. PMID- 29426266 TI - FEV1 reversibility for asthma diagnosis: a critical evaluation. PMID- 29426267 TI - Biomechanical Evaluations of Bed-to-Wheelchair Transfer: Gait Belt Versus Walking Belt. AB - Nursing personnel, particularly caregivers who frequently perform manual patient transfer tasks, are at risk for work-related musculoskeletal disorders (WMSDs). The purpose of this study was to perform biomechanical evaluations of bed-to wheelchair transfer using two low-cost assistive devices: walking belt and gait belt. Twenty-eight college students, serving as caregivers, transferred 14 students, serving as patients. "Caregiver" spinal loading and strength requirements at major joints were measured using a 3D Static Strength Prediction Model. "Caregiver"-perceived stresses were assessed using the Borg CR-10 Scale. "Patient" safety and comfort ratings were determined using Likert-type scales. The findings indicated that transferring "patients" using walking belts with a pulling technique produced significantly lower biomechanical stress than using gait belts. "Patients" also felt more comfortable and safer during walking belt transfers. It is recommended that health care facilities should consider use of walking belts in place of gait belts to transfer partially weight-bearing patients. PMID- 29426268 TI - 46,XX,der(9)t4;9)(q31.1;p24) as a novel genetic marker for spontaneous resolution of foetal pleural effusion. PMID- 29426269 TI - Identification of preterm birth in women with threatened preterm labour between 34 and 37 weeks of gestation. AB - The aim of this study was to assess whether serum markers would be useful as a new predictor of preterm birth in patients with spontaneous, late preterm labour. Patients diagnosed with late preterm labour were divided into preterm delivery (229 patients) and term delivery (178 patients) groups. The two groups were compared in terms of clinical characteristics and levels of serum markers (leukocyte subtypes, platelet, C-reactive protein [CRP], neutrophil to lymphocyte ratio [NLR] and platelet to lymphocyte ratio [PLR]), which were obtained at admission. The levels of leukocyte (p < .001), neutrophil (p < .001), CRP (p = .001), NLR (p < .001) and PLR (p = .003) were significantly higher, whereas lymphocytes (p = .012) were significantly lower in the preterm delivery group, compared to the term delivery group. On multivariate regression analysis, NLR positive was the most powerful predictive variable (OR = 1.41; 95%CI: 1.32-1.51; p = .005). NLR had the highest area under curve (0.711; 95%CI 0.662-0.760) in predicting preterm birth and a NLR >6.2 had the highest sensitivity (65.1%) and specificity (62.5%). High NLR at admission is an independent predictor of preterm birth in patients with spontaneous, late preterm labour. Impact statement What is already known on this subject: Preterm birth accounts for 5-12% of all births, and is a major factor associated with perinatal morbidity and mortality worldwide. However, more than 70% of preterm births occur at late preterm between 340/7 and 366/7 weeks of gestation. The central role of systemic and subclinical infections in preterm labour is well documented. Intrauterine infection leading to delivery can be measured by using a variety of laboratory parameters. What do the results of this study add: Neutrophil to lymphocyte ratio is an inexpensive, easily interpretable and promising haematologic parameter that is widely available. This study explored the association of high neutrophil to lymphocyte ratio with the risk of preterm birth in women with preterm labour between 34 and 37 weeks of gestation. What are the implications of these findings for clinical practice and/or further research: Neutrophil to lymphocyte ratio could be used in combination with existing markers to improve detection rates of preterm birth. Concomitant use of markers could be more powerful than measuring any of the individual markers alone. PMID- 29426270 TI - Evening primrose oil and labour, is it effective? A randomised clinical trial. AB - The purpose of the present study was to evaluate the effects of evening primrose oil (EvPO) on the duration of pregnancy and labour. The study was performed as a triple blind placebo controlled randomised clinical trial on nulliparous low-risk women with a certain gestational age of 40 weeks of pregnancy and a Bishop score of less than 4. In the case group (EvPO group), EvPO capsules were administered, 1000 mg, twice daily, for 7 days, and in the control group, placebo was administered similarly. The women of the two groups were followed up to delivery. In total, 80 women finished the study (40 in each group). The women of the two groups did not have significant differences according to age, BMI, Bishop Score at the beginning of the study, gestational age at entering the study, employment status and education level, the number of capsules used and duration of using medications. There was no significant difference between the two groups according to gestational age at delivery, need for induction or augmentation of labour, duration of different stages of labour, neonatal weight and Apgar scores, and the indications for hospital admission. Impact statement What is already known on this subject? Evening primrose oil has been used for the treatment of systemic disorders, which are accompanied with chronic inflammation such as atopic dermatitis, rheumatoid arthritis and psoriasis. Also, it has been proposed for some women's health conditions including breast pain (mastalgia), symptoms of premenstrual syndrome and menopausal symptoms, cervical ripening and induction or augmentation of labour. What do the results of this study add? Evening primrose oil does not have any impact on Bishop Score and the duration of different stages of labour. What are the implications of these findings for clinical practice and/or further research? According to the present study and the other performed studies, there is not enough evidence confirming effectiveness of Evening primrose oil for cervical ripening and duration of labour. It is suggested that pending further data its usage should be limited to experimental RCTs and its use in clinical practice should be prevented. Also, different routes of administration and different dosages should be investigated. PMID- 29426271 TI - Long-term results of atresiaplasty in patients with congenital aural atresia. AB - OBJECTIVES: To evaluate long-term benefits of atresiaplasty on hearing and the impact of surgery on quality of life (QoL) in congenital aural atresia (CAA) patients. METHODS: We evaluated the long-term hearing results, the impact of atresiaplasty on QoL, the meatal diameter of the operated ear canal, and the cumulative number of post-operative hospital visits in 14 CAA patients, on average, 12 years (range: 4-17 years) post-operatively. RESULTS: The mean preoperative pure tone average (PTA) was 61 dB HL. The postoperative short-term PTA was 36 dB HL and the long-term PTA was 51 dB HL. The mean total Glasgow Benefit Inventory (GBI) score was 16 (range: -11-39), showing the positive benefit of atresiaplasty on QoL. The mean postoperative diameter of the auditory meatus was 6 mm. The average number of hospital outpatient visits during the first postoperative year was 10. CONCLUSION: Surgery for CAA is a demanding operation with variable anatomical and hearing outcomes. Atresiaplasty operations should be centralized to hospitals with large numbers of such patients to ensure sufficient levels of surgical experience. Bone-anchored hearing devices or middle ear implants should be considered as a first-line option because they offer good hearing predictability. PMID- 29426272 TI - Influence of estrogen on individual exercise motivation and bone protection in ovariectomized rats. AB - Bone protection and metabolism are directly linked to estrogen levels, but exercise is also considered to have bone protective effects. Reduced estrogen levels lead to a variety of disorders, for example, bone loss and reduced movement drive. The objective of this study was to investigate the effects of estrogen on individual voluntary exercise motivation and bone protection. We investigated sham operated, ovariectomized, and ovariectomized with estrogen supplemented Wistar rats (20 weeks old) either with or without access to exercise wheels. We selected an experimental approach where we could monitor the individual exercise of group-housed rats with ad libitum access to a running wheel with the help of a subcutaneous chip. In vivo and ex vivo microcomputed tomography analyses of the tibia were performed at two-week intervals from week 0 to week 6. Furthermore, tibial trabecular structure was evaluated based on histomorphometric analyses. We observed a significant bone protective effect of E2. For exercise performance, a substantially high intra-group variability was observed, especially in the E2 group. We presume that dominant behavior occurs within the group-housed rats resulting in a hierarchical access to the running wheel and a high variability of distance run. Exercise did not prevent ovariectomy-induced bone loss. However, lack of estrogen within the ovariectomized rats led to a drastically reduced activity prevented by estrogen supplementation. Our findings are important for future studies working with group housed rats and exercise. The reason for the high intra-group variability in exercise needs to be investigated in future studies. PMID- 29426273 TI - Testosterone- and Cortisol-secreting Oncocytic Adrenocortical Adenoma in the Pediatric Age-group. AB - Oncocytic tumors are epithelial neoplasms that occur in various organs, including adrenal glands. Oncocytic adrenocortical adenomas and carcinomas are uncommon but well-known pathological entities in adults. However, generally oncocytic tumors, particularly in the adrenal glands, are very rare in the pediatric age-group. Most oncocytic adrenal tumors are not functional. We present a rare case of right sided, functional oncocytic adrenocortical adenoma in a 5-year-old boy, who presented with clinical manifestations of precocious puberty and Cushing syndrome. Laparoscopic adrenalectomy showed a well-defined mass weighing 8.4 g and measuring 3 cm in maximum dimension. Histological examination demonstrated no features suggestive of aggressive biological behavior. The patient showed no evidence of recurrent or metastatic disease and continued to have normal serum hormonal levels 28 months following the surgery. In this report, we discuss the clinicopathological characteristics of this rare pathological entity and briefly review the literature on functional oncocytic adrenal tumors in the pediatric population. PMID- 29426274 TI - FTL c.-168G>C Mutation in Hereditary Hyperferritinemia Cataract Syndrome: A New Italian Family. AB - We describe a new Italian family with 7 members affected by hereditary hyperferritinemia cataract syndrome (HHCS), an uncommon autosomal dominant disease caused by mutations of the iron-responsive element (IRE) of the ferritin light chain (FTL) gene determining its overexpression. The family diagnosis of HHCS took place after finding high ferritin levels in a 6-year-old girl. Seven members of the family had bilateral and symmetrical cataracts, normal iron, and hematological parameters except for high serum ferritin levels. About 160 families/unrelated cases with HHCS are known worldwide. This report documents a second Italian family, with a c.-168G>C mutation that is located in the highly conserved 3-nucleotide bulge structure of the FTL in the 5' untranslated region. This case shows how important the family history is in reaching a correct diagnosis and avoiding unnecessary and invasive analysis. HHCS should be considered in the differential diagnosis of childhood hyperferritinemia, especially in the presence of normal transferrin saturation. PMID- 29426275 TI - Primary Renal Hybrid Low-grade Fibromyxoid Sarcoma-Sclerosing Epithelioid Fibrosarcoma: An Unusual Pediatric Case With EWSR1-CREB3L1 Fusion. AB - Low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF) are rare tumors with distinct sets of morphological features, both characterized by MUC4 immunoreactivity. Tumors exhibiting features of both entities are considered hybrid LGFMS-SEF lesions. While the majority of LGFMS cases are characterized by FUS-CREB3L2 gene fusions, most cases of pure SEF show EWSR1 gene rearrangements. In the largest study of hybrid LGFMS-SEF tumors to date, all cases exhibited FUS rearrangements, a similar genetic profile to LGFMS. We herein describe the clinicopathological features and genetic findings of a case of primary renal hybrid LGFMS-SEF occurring in a 10-year-old child, with disseminated metastases. Fusion gene detection using a next-generation sequencing based anchored multiplex PCR technique (Archer FusionPlex Sarcoma Panel) was performed on both the primary renal tumor that showed the morphology of a LGFMS, and a cervical metastasis that showed the morphology of SEF. An EWSR1-CREB3L1 gene fusion occurring between exon 11 of EWSR1 and exon 6 of CREB3L1 was present in both the LGFMS and SEF components. This unusual case provides evidence that a subset of hybrid LGFMS-SEF harbor EWSR1-CREB3L1 gene fusions. In this case, these features were associated with an aggressive clinical course, with disease associated mortality occurring within 12 months of diagnosis. PMID- 29426276 TI - Rare MYC-amplified Neuroblastoma With Large Cell Histology. AB - Background Although MYCN (aka N-myc) amplification is reported in ~20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN amplification nor MYCN protein overexpression. Both of these tumors exhibited "large cell neuroblastoma" histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with "aberrant" desmin expression. Conclusions MYC-amplified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features. PMID- 29426277 TI - Phylogeography of Eomecon chionantha in subtropical China: the dual roles of the Nanling Mountains as a glacial refugium and a dispersal corridor. AB - BACKGROUND: Mountains have not only provided refuge for species, but also offered dispersal corridors during the Neogene and Quaternary global climate changes. Compared with a plethora of studies on the refuge role of China's mountain ranges, their dispersal corridor role has received little attention in plant phylogeographic studies. Using phylogeographic data of Eomecon chionantha Hance (Papaveraceae), this study explicitly tested whether the Nanling Mountains, which spans from west to east for more than 1000 km in subtropical China, could have functioned as a dispersal corridor during the late Quaternary in addition to a glacial refugium. RESULTS: Our analyses revealed a range-wide lack of phylogeographic structure in E. chionantha across three kinds of molecular markers [two chloroplast intergenic spacers, nuclear ribosomal internal transcribed spacer (nrITS), and six nuclear microsatellite loci]. Demographic inferences based on chloroplast and nrITS sequences indicated that E. chionantha could have experienced a strong postglacial range expansion between 6000 and 1000 years ago. Species distribution modelling showed that the Nanling Mountains and the eastern Yungui Plateau were the glacial refugia of E. chionantha. Reconstruction of dispersal corridors indicated that the Nanling Mountains also have acted as a corridor of population connectivity for E. chionantha during the late Quaternary. CONCLUSIONS: Our results suggest that the Nanling Mountains may acted dual roles as a dispersal corridor in east-west direction and as a glacial refugium in subtropical China during the late Quaternary. The population connectivity mediated by the mountain range and a strong postglacial range expansion are the most likely reasons for the lack of phylogeographic structure in E. chionantha. The hypothesis of dual roles of the mountain range presented here sheds new insights into the phylogeographic patterns of organisms in subtropical China. PMID- 29426278 TI - Cytochrome P450 family 4 subfamily F member 2 (CYP4F2) rs1558139, rs2108622 polymorphisms and susceptibility to several cardiovascular and cerebrovascular diseases. AB - BACKGROUND: Inconsistent conclusions have been reported for the genetic relationship between CYP4F2 (Cytochrome P450 Family 4 Subfamily F Member 2) polymorphisms and the susceptibility to cardiovascular and cerebrovascular diseases. METHODS: We performed a meta-analysis to assess the potential role of rs1558139 C/T and rs2108622 G/A polymorphisms of CYP4F2 in the risks of cardiovascular and cerebrovascular diseases. The retrieval of four databases, including PubMed, Web of Science (WOS), China National Knowledge Infrastructure (CNKI) and WANFANG DATA, was conducted. Mantel-Haenszel statistics for association test, Cochran's Q statistic, sensitivity analysis for heterogeneity assessment, and Begg's/Egger's tests for publication bias evaluation were performed under allele, homozygote, heterozygote, dominant, and recessive models, respectively. RESULTS: A total of 597 articles were initially obtained by database searching, and twenty eligible articles were finally included. For rs1558139, a decreased risk of cardiovascular and cerebrovascular diseases was observed in the overall meta-analysis and in "hypertension", "population-based" and "male" subgroups under models of T vs. C, CT vs. CC, and CT + TT vs. CC [all P values in association tests < 0.05, odds ratio (OR) < 1]. For rs2108622, a decreased coronary artery disease (CAD) risk was observed in the subgroup meta analysis based on disease type under all genetic models (all P values in association tests < 0.05, OR< 1). Begg's/Egger's tests excluded the potential publication bias, while sensitivity analysis data supported the stability of the above results. CONCLUSION: C/T genotype of CYP4AF2 rs1558139 may be linked to the decreased risk of hypertension in the male patients of Asian populations, while CYP4F2 rs2108622 is likely associated with reduced susceptibility to CAD. PMID- 29426280 TI - Blood oxygen level dependent magnetic resonance imaging for detecting pathological patterns in lupus nephritis patients: a preliminary study using a decision tree model. AB - BACKGROUND: Precise renal histopathological diagnosis will guide therapy strategy in patients with lupus nephritis. Blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) has been applicable noninvasive technique in renal disease. This current study was performed to explore whether BOLD MRI could contribute to diagnose renal pathological pattern. METHODS: Adult patients with lupus nephritis renal pathological diagnosis were recruited for this study. Renal biopsy tissues were assessed based on the lupus nephritis ISN/RPS 2003 classification. The Blood oxygen level dependent magnetic resonance imaging (BOLD MRI) was used to obtain functional magnetic resonance parameter, R2* values. Several functions of R2* values were calculated and used to construct algorithmic models for renal pathological patterns. In addition, the algorithmic models were compared as to their diagnostic capability. RESULTS: Both Histopathology and BOLD MRI were used to examine a total of twelve patients. Renal pathological patterns included five classes III (including 3 as class III + V) and seven classes IV (including 4 as class IV + V). Three algorithmic models, including decision tree, line discriminant, and logistic regression, were constructed to distinguish the renal pathological pattern of class III and class IV. The sensitivity of the decision tree model was better than that of the line discriminant model (71.87% vs 59.48%, P < 0.001) and inferior to that of the Logistic regression model (71.87% vs 78.71%, P < 0.001). The specificity of decision tree model was equivalent to that of the line discriminant model (63.87% vs 63.73%, P = 0.939) and higher than that of the logistic regression model (63.87% vs 38.0%, P < 0.001). The Area under the ROC curve (AUROCC) of the decision tree model was greater than that of the line discriminant model (0.765 vs 0.629, P < 0.001) and logistic regression model (0.765 vs 0.662, P < 0.001). CONCLUSIONS: BOLD MRI is a useful non-invasive imaging technique for the evaluation of lupus nephritis. Decision tree models constructed using functions of R2* values may facilitate the prediction of renal pathological patterns. PMID- 29426279 TI - Genomic analyses of the Chlamydia trachomatis core genome show an association between chromosomal genome, plasmid type and disease. AB - BACKGROUND: Chlamydia trachomatis (Ct) plasmid has been shown to encode genes essential for infection. We evaluated the population structure of Ct using whole genome sequence data (WGS). In particular, the relationship between the Ct genome, plasmid and disease was investigated. RESULTS: WGS data from 157 Ct isolates deposited in the Chlamydiales pubMLST database ( http://pubMLST.org/chlamydiales/ ) were annotated with 902 genes including the core and accessory genome. Plasmid associated genes were annotated and a plasmid MLST scheme was defined allowing plasmid sequence types to be determined. Plasmid allelic variation was investigated. Phylogenetic relationships were examined using the Genome Comparator tool available in pubMLST. Phylogenetic analyses identified four distinct Ct core genome clusters and six plasmid clusters, with a strong association between the chromosomal genotype and plasmid. This in turn was linked to ompA genovars and disease phenotype. Horizontal genetic transfer of plasmids was observed for three urogenital-associated isolates, which possessed plasmids more commonly found in isolates resulting from ocular infections. The pgp3 gene was identified as the most polymorphic plasmid gene and pgp4 was the most conserved. CONCLUSION: A strong association between chromosomal genome, plasmid type and disease was observed, consistent with previous studies. This suggests co-evolution of the Ct chromosome and their plasmids, but we confirmed that plasmid transfer can occur between isolates. These data provide a better understanding of the genetic diversity occurring across the Ct genome in association with the plasmid content. PMID- 29426281 TI - Primary percutaneous coronary intervention during ST elevation myocardial infarction in prosthetic valve endocarditis: a case report. AB - BACKGROUND: Infective endocarditis (IE) is still a condition with high mortality and morbidity, especially in the elderly, and in patients with prosthetic valves. The concept of "time-to-therapy" plays a key role for the prompt management of IE and related complications, and the currently available multimodality imaging may play a key role in this setting. Myocardial ischemia due to extrinsic coronary compression from an aortic abscess is an extremely rare condition where the optimal therapeutic strategy has not been defined yet. We present herein the first case of a patient with ST elevation myocardial infarction caused by an aortic root abscess treated with percutaneous stent implantation. CASE PRESENTATION: An 82-year-old woman with a history of atrial fibrillation, chronic renal failure, anemia and a bioprosthetic aortic valve replacement performed in 2014, was admitted to hospital with profound asthenia and a pyrexia of unknown origin. Because of high clinical suspicion of endocarditis, a trans-esophageal echocardiogram was performed. Empirical broad-spectrum antimicrobial therapy was initiated, followed by targeted treatment based on the results of blood cultures (Staphylococcus aureus). The echocardiogram did not show vegetations and the patient was managed conservatively. She suddenly deteriorated, due to an acute coronary syndrome (ACS) with anterior ST segment elevation. An urgent angiogram was performed, and extrinsic compression of the left coronary system, due to an aortic root abscess, was suspected. After discussion with the surgical team, percutaneous revascularization was attempted, aiming to restore satisfactory hemodynamics, in order to plan surgery. Unfortunately, the patient rapidly developed cardiogenic shock, with multi organ failure, and died in less than 24 h. CONCLUSIONS: Patients with fever, and significant risk factors for endocarditis, who develop ACS, need a prompt diagnostic work up, including trans esophageal echocardiography. At present, the specific timing of echocardiographic follow-up and surgical intervention is still a matter of debate, and our case aims to highlight the importance of this aspect in the management of endocarditis, in order to avoid severe complications that adversely affect patient prognosis. PMID- 29426282 TI - Correction to: Systematic reporting to improve the emergency medical response to major incidents: a pilot study. AB - ERRATUM: The original article [1] contains an error whereby all authors' names were mistakenly interchanged. The original article has now been corrected to present the authors' names correctly. PMID- 29426283 TI - The association between oxidative stress and endothelial dysfunction in early childhood patients with Kawasaki disease. AB - BACKGROUND: Oxidative stress has recently been shown to play an important role in the development of arteriosclerosis in patients with Kawasaki disease (KD); however, no study has investigated this association in early childhood patients with KD. In this study, we evaluated prospectively the association between the levels of oxidative stress and the endothelial function in early childhood patients with KD. METHODS: We compared the derivatives of reactive oxygen metabolites (ROM), flow-mediated dilatation (FMD), and biological characteristics in a population of 50 children: 10 patients with KD and coronary artery lesions (CAL) (group 1), 15 KD patients without CAL (group 2), and 25 healthy age- and sex-matched children (group 3). RESULTS: The median age of all KD children at study enrollment was 6.8 (IQR 4.4-8.2) years. ROM levels were significantly higher in group 1 (p < 0.001) and group 2 (p = 0.004) than in group 3. The %FMD of group 1 (p < 0.001) and group 2 (p = 0.026) was significantly lower than that of group 3. There was a significant negative correlation between ROM and %FMD (r = - 0.60, p < 0.001). A multiple linear regression analysis identified ln-ROM (standardized coefficient = - 0.403, p = 0.043) and total fever duration (standardized coefficient = - 0.413, p = 0.038) as significant determinants of %FMD in the patients with KD. CONCLUSIONS: Our study suggests that oxidative stress is strongly associated with endothelial dysfunction in early childhood patients with KD. Furthermore, we found that the longer the fever duration, the higher the risk of oxidative stress-induced endothelial dysfunction in these children. PMID- 29426284 TI - Identification of the WRKY gene family and functional analysis of two genes in Caragana intermedia. AB - BACKGROUND: WRKY transcription factors, one of the largest families of transcriptional regulators in plants, play important roles in plant development and various stress responses. The WRKYs of Caragana intermedia are still not well characterized, although many WRKYs have been identified in various plant species. RESULTS: We identified 53 CiWRKY genes from C. intermedia transcriptome data, 28 of which exhibited complete open reading frames (ORFs). These CiWRKYs were divided into three groups via phylogenetic analysis according to their WRKY domains and zinc finger motifs. Conserved domain analysis showed that the CiWRKY proteins contain a highly conserved WRKYGQK motif and two variant motifs (WRKYGKK and WKKYEEK). The subcellular localization of CiWRKY26 and CiWRKY28-1 indicated that these two proteins localized exclusively to nuclei, supporting their role as transcription factors. The expression patterns of the 28 CiWRKYs with complete ORFs were examined through quantitative real-time PCR (qRT-PCR) in various tissues and under different abiotic stresses (drought, cold, salt, high-pH and abscisic acid (ABA)). The results showed that each CiWRKY responded to at least one stress treatment. Furthermore, overexpression of CiWRKY75-1 and CiWRKY40-4 in Arabidopsis thaliana suppressed the drought stress tolerance of the plants and delayed leaf senescence, respectively. CONCLUSIONS: Fifty-three CiWRKY genes from the C. intermedia transcriptome were identified and divided into three groups via phylogenetic analysis. The expression patterns of the 28 CiWRKYs under different abiotic stresses suggested that each CiWRKY responded to at least one stress treatment. Overexpression of CiWRKY75-1 and CiWRKY40-4 suppressed the drought stress tolerance of Arabidopsis and delayed leaf senescence, respectively. These results provide a basis for the molecular mechanism through which CiWRKYs mediate stress tolerance. PMID- 29426285 TI - Transcriptome profiles in peripheral white blood cells at the time of artificial insemination discriminate beef heifers with different fertility potential. AB - BACKGROUND: Infertility is a longstanding limitation in livestock production with important economic impact for the cattle industry. Female reproductive traits are polygenic and lowly heritable in nature, thus selection for fertility is challenging. Beef cattle operations leverage estrous synchronization in combination with artificial insemination (AI) to breed heifers and benefit from an early and uniform calving season. A couple of weeks following AI, heifers are exposed to bulls for an opportunity to become pregnant by natural breeding (NB), but they may also not become pregnant during this time period. Focusing on beef heifers, in their first breeding season, we hypothesized that: a- at the time of AI, the transcriptome of peripheral white blood cells (PWBC) differs between heifers that become pregnant to AI and heifers that become pregnant late in the breeding season by NB or do not become pregnant during the breeding season; and b the ratio of transcript abundance between genes in PWBC classifies heifers according to pregnancy by AI, NB, or failure to become pregnant. RESULTS: We generated RNA-sequencing data from 23 heifers from two locations (A: six AI pregnant and five NB-pregnant; and B: six AI-pregnant and six non-pregnant). After filtering out lowly expressed genes, we quantified transcript abundance for 12,538 genes. The comparison of gene expression levels between AI-pregnant and NB pregnant heifers yielded 18 differentially expressed genes (DEGs) (ADAM20, ALDH5A1, ANG, BOLA-DQB, DMBT1, FCER1A, GSTM3, KIR3DL1, LOC107131247, LOC618633, LYZ, MNS1, P2RY12, PPP1R1B, SIGLEC14, TPPP, TTLL1, UGT8, eFDR<=0.02). The comparison of gene expression levels between AI-pregnant and non-pregnant heifers yielded six DEGs (ALAS2, CNKSR3, LOC522763, SAXO2, TAC3, TFF2, eFDR<=0.05). We calculated the ratio of expression levels between all gene pairs and assessed their potential to classify samples according to experimental groups. Considering all samples, relative expression from two gene pairs correctly classified 10 out of 12 AI-pregnant heifers (P = 0.0028) separately from the other 11 heifers (NB pregnant, or non-pregnant). CONCLUSION: The transcriptome profile in PWBC, at the time of AI, is associated with the fertility potential of beef heifers. Transcript levels of specific genes may be further explored as potential classifiers, and thus selection tools, of heifer fertility. PMID- 29426287 TI - Preoperative versus postoperative ultrasound-guided rectus sheath block for improving pain, sleep quality and cytokine levels in patients with open midline incisions undergoing transabdominal gynecological surgery: a randomized controlled trial. AB - BACKGROUND: Nerve block is usually performed before surgery because it inhibits reflection of the skin incision and reduces the amount of intraoperative anesthetic used. We hypothesized that performing rectus sheath block (RSB) after surgery would result in a longer duration of the analgesic effects and have a subtle influence on sleep time after surgery but that it would not decrease the perioperative cytokine levels of patients undergoing gynecological surgery. METHODS: A randomized, double-blinded, controlled trial was conducted from October 2015 to June 2016. Seventy-seven patients undergoing elective transabdominal gynecological surgery were randomly assigned to the following two groups: a general anesthesia group who received 0.5% ropivacaine hydrochloride RSB preoperatively and saline RSB postoperatively, and another group who received the opposite sequence. The objective of the trial was to evaluate the postoperative pain, sleep and changes in cytokine levels of patients during the postoperative 48 h. RESULTS: A total of 61 female patients (mean age: 50 years; range: 24-65 years) were included in the final study sample. There was no significant difference in the pain, consumption of oxycodone, or time to first administration of patient-controlled intravenous analgesia between the two groups. The postoperative sleep stages N2 and N3 were increased by 52.9 and 29.1 min per patient, respectively, in the preoperative RSB group compared with those in the postoperative group. The preoperative IL-6 concentration in the preoperative RSB group was lower than that in the same group at the end of surgery and 24 h postoperatively. CONCLUSIONS: We concluded that preoperative RSB might preserve postoperative sleep by inhibiting the increase of IL-6 without shortening the analgesia time compared with postoperative RSB in female patients undergoing elective midline incision transabdominal gynecological surgery. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02477098 , registered on 15 June 2015. PMID- 29426286 TI - Monitoring of argatroban and lepirudin anticoagulation in critically ill patients by conventional laboratory parameters and rotational thromboelastometry - a prospectively controlled randomized double-blind clinical trial. AB - BACKGROUND: Argatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). Although aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. However, in-vivo data is lacking for this patient population. Therefore, we studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients. METHODS: This study was part of the double-blind randomized trial "Argatroban versus Lepirudin in critically ill patients (ALicia)", which compared critically ill patients treated with argatroban or lepirudin. Following institutional review board approval and written informed consent, for this sub-study blood of 35 critically ill patients was analysed. Before as well as 12, 24, 48 and 72 h after initiation of argatroban or lepirudin infusion, blood was analysed for aPTT, aPTT ratios, thrombin time (TT), INTEM CT,INTEM CT ratios, EXTEM CT, EXTEM CT ratios and maximum clot firmness (MCF) and correlated with the corresponding plasma concentrations of the direct thrombin inhibitor. RESULTS: To reach a target aPTT of 1.5 to 2 times baseline, median [IQR] plasma concentrations of 0.35 [0.01-1.2] MUg/ml argatroban and 0.17 [0.1-0.32] MUg/ml lepirudin were required. For both drugs, there was no significant correlation between aPTT and aPTT ratios and plasma concentrations. INTEM CT, INTEM CT ratios, EXTEM CT, EXTEM CT ratios, TT and TT ratios correlated significantly with plasma concentrations of both drugs. Additionally, agreement between argatroban plasma levels and EXTEM CT and EXTEM CT ratios were superior to agreement between argatroban plasma levels and aPTT in the Bland Altman analysis. MCF remained unchanged during therapy with both drugs. CONCLUSION: In critically ill patients, TT and ROTEM parameters may provide better correlation to argatroban and lepirudin plasma concentrations than aPTT. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00798525 , registered on 25 Nov 2008. PMID- 29426288 TI - Clinical effectiveness of care managers in collaborative care for patients with depression in Swedish primary health care: a pragmatic cluster randomized controlled trial. AB - BACKGROUND: Depression is one of the leading causes of disability and affects 10 15% of the population. The majority of people with depressive symptoms seek care and are treated in primary care. Evidence internationally for high quality care supports collaborative care with a care manager. Our aim was to study clinical effectiveness of a care manager intervention in management of primary care patients with depression in Sweden. METHODS: In a pragmatic cluster randomized controlled trial 23 primary care centers (PCCs), urban and rural, included patients aged >= 18 years with a new (< 1 month) depression diagnosis. Intervention consisted of Care management including continuous contact between care manager and patient, a structured management plan, and behavioral activation, altogether around 6-7 contacts over 12 weeks. Control condition was care as usual (CAU). OUTCOME MEASURES: Depression symptoms (measured by Mongomery Asberg depression score-self (MADRS-S) and BDI-II), quality of life (QoL) (EQ 5D), return to work and sick leave, service satisfaction, and antidepressant medication. Data were analyzed with the intention-to-treat principle. RESULTS: One hundred ninety two patients with depression at PCCs with care managers were allocated to the intervention group, and 184 patients at control PCCs were allocated to the control group. Mean depression score measured by MADRS-S was 2.17 lower in the intervention vs. the control group (95% CI [0.56; 3.79], p = 0.009) at 3 months and 2.27 lower (95% CI [0.59; 3.95], p = 0.008) at 6 months; corresponding BDI-II scores were 1.96 lower (95% CI [- 0.19; 4.11], p = 0.07) in the intervention vs. control group at 6 months. Remission was significantly higher in the intervention group at 6 months (61% vs. 47%, p = 0.006). QoL showed a steeper increase in the intervention group at 3 months (p = 0.01). During the first 3 months, return to work was significantly higher in the intervention vs. the control group. Patients in the intervention group were more consistently on antidepressant medication than patients in the control group. CONCLUSIONS: Care managers for depression treatment have positive effects on depression course, return to work, remission frequency, antidepressant frequency, and quality of life compared to usual care and is valued by the patients. TRIAL REGISTRATION: Identifier: NCT02378272 . February 2, 2015. Retrospectively registered. PMID- 29426289 TI - FMLRC: Hybrid long read error correction using an FM-index. AB - BACKGROUND: Long read sequencing is changing the landscape of genomic research, especially de novo assembly. Despite the high error rate inherent to long read technologies, increased read lengths dramatically improve the continuity and accuracy of genome assemblies. However, the cost and throughput of these technologies limits their application to complex genomes. One solution is to decrease the cost and time to assemble novel genomes by leveraging "hybrid" assemblies that use long reads for scaffolding and short reads for accuracy. RESULTS: We describe a novel method leveraging a multi-string Burrows-Wheeler Transform with auxiliary FM-index to correct errors in long read sequences using a set of complementary short reads. We demonstrate that our method efficiently produces significantly more high quality corrected sequence than existing hybrid error-correction methods. We also show that our method produces more contiguous assemblies, in many cases, than existing state-of-the-art hybrid and long-read only de novo assembly methods. CONCLUSION: Our method accurately corrects long read sequence data using complementary short reads. We demonstrate higher total throughput of corrected long reads and a corresponding increase in contiguity of the resulting de novo assemblies. Improved throughput and computational efficiency than existing methods will help better economically utilize emerging long read sequencing technologies. PMID- 29426290 TI - Transcriptome profiling of two maize inbreds with distinct responses to Gibberella ear rot disease to identify candidate resistance genes. AB - BACKGROUND: Gibberella ear rot (GER) is one of the most economically important fungal diseases of maize in the temperate zone due to moldy grain contaminated with health threatening mycotoxins. To develop resistant genotypes and control the disease, understanding the host-pathogen interaction is essential. RESULTS: RNA-Seq-derived transcriptome profiles of fungal- and mock-inoculated developing kernel tissues of two maize inbred lines were used to identify differentially expressed transcripts and propose candidate genes mapping within GER resistance quantitative trait loci (QTL). A total of 1255 transcripts were significantly (P <= 0.05) up regulated due to fungal infection in both susceptible and resistant inbreds. A greater number of transcripts were up regulated in the former (1174) than the latter (497) and increased as the infection progressed from 1 to 2 days after inoculation. Focusing on differentially expressed genes located within QTL regions for GER resistance, we identified 81 genes involved in membrane transport, hormone regulation, cell wall modification, cell detoxification, and biosynthesis of pathogenesis related proteins and phytoalexins as candidate genes contributing to resistance. Applying droplet digital PCR, we validated the expression profiles of a subset of these candidate genes from QTL regions contributed by the resistant inbred on chromosomes 1, 2 and 9. CONCLUSION: By screening global gene expression profiles for differentially expressed genes mapping within resistance QTL regions, we have identified candidate genes for gibberella ear rot resistance on several maize chromosomes which could potentially lead to a better understanding of Fusarium resistance mechanisms. PMID- 29426291 TI - Paediatric pancreaticobiliary endoscopy: a 21-year experience from a tertiary hepatobiliary centre and systematic literature review. AB - BACKGROUND: In adults ERCP and endoscopic ultrasound (EUS) are standard methods of evaluating and treating many hepatopancreaticobiliary (HPB) conditions. HPB disease is being diagnosed with increasing frequency in children but information about role of ERCP and EUS and their outcomes in this population remain limited. Therefore the aims of this study were to describe the paediatric ERCP and EUS experience from a large tertiary referral HPB centre, and to systematically compare outcomes with those of other published series. METHODS: All patients <18 years undergoing an ERCP or EUS between January 1992-December 2014 were included. Indications for the procedure, rates of technical success, procedural adverse events and reinterventions were recorded in all cases. RESULTS: Ninety children underwent 111 procedures (87 ERCPs and 24 EUS). 53% (48) were female with a median age of 14 years (range: 3 months - 17 years). Procedures were performed under general anaesthesia (n = 48) or conscious sedation (n = 63). Common indications for ERCP included chronic or recurrent pancreatitis and biliary obstruction. Patients frequently had multiple comorbidities, with a median ASA grade of 2 (range 1-4). Therapeutic procedures performed included biliary or pancreatic sphincterotomy, common bile duct or pancreatic duct stone removal, biliary or pancreatic stent insertion, EUS-guided fine needle aspiration and endoscopic transmural drainage of pancreatic fluid collections. No adverse events were reported following ERCP but there was one complication requiring surgery following EUS guided cystenterostomy. CONCLUSION: ERCP and EUS in children and adolescents have high technical success rates and low rates of adverse events when performed in high volume HPB centres. PMID- 29426292 TI - Pre-treatment clinical features in central retinal vein occlusion that predict visual outcome following intravitreal ranibizumab. AB - BACKGROUND: Predicting how patients with central retinal vein occlusion (CRVO) will respond to intravitreal anti-VEGF is challenging. The purpose of this study was to identify pre-treatment clinical features in CRVO that predict visual acuity (VA) following intravitreal ranibizumab. METHODS: Medical records, fundus images and optical coherence tomography (OCT) scans of treatment naive patients with CRVO receiving PRN intravitreal ranibizumab were retrospectively reviewed. Early Treatment Diabetic Retinopathy Study (ETDRS) VA and central retinal thickness (CRT) were recorded at baseline, 3 and 12 months after starting therapy. Regression analysis was used to determine independent predictors of VA at 3 and 12 months follow-up. Possible predictors included baseline VA, age, presence of cotton wool spots (CWS), haemorrhages (few scattered or multiple deep), foveal detachment, CRT, time from presentation to treatment, number of injections given, presence of RAPD, and cause of CRVO. RESULTS: Data from 52 eyes of 50 patients receiving intravitreal ranibizumab treatment for CRVO were analyzed. The mean pre-treatment VA was 43.3 (SD 22.5) letters, which improved to 52.0 (SD 24.3) letters at 3 months, then dropped to 42.0 (SD 30.26) at 12 months. Baseline CRT reduced from 616.7 MUm (SD 272.4) to 346.0 MUm (SD 205.2) at 3 months and 304.0 MUm (SD 168.3) at 12 months. The following features were predictive of poorer VA after starting intravitreal ranibizumab: Poorer pretreatment VA (3-months, P = 0.010; 12-months, P = 0.006), increasing age (3 months, P = < 0.001; 12-months, P = 0.006), and presence of CWS (3-months, P < 0.001; 12-months, P = 0.045). CONCLUSION: Pre-treatment VA, older age, and presence of CWS are easily identifiable clinical features in the hospital setting which help predict visual outcome in patients with CRVO receiving intravitreal ranibizumab. PMID- 29426293 TI - Comparison of first-line chemotherapy regimens for ovarian carcinosarcoma: a single institution case series and review of the literature. AB - BACKGROUND: The optimal first-line chemotherapy for ovarian carcinosarcoma has not yet been determined. We therefore sought to determine the progression-free survival (PFS) and overall survival (OS) for patients with ovarian carcinosarcoma treated at our institution with different first-line chemotherapy regimens. METHODS: This single-institution, retrospective analysis included all patients with ovarian or primary peritoneal carcinosarcoma diagnosed from September 1996 to July 2017. Kaplan Meier analysis with a log-rank Mantel-Cox test was used to compare PFS and OS between treatment groups, and a p-value of < 0.05 was considered statistically significant. RESULTS: Thirty-one patients met inclusion criteria: two patients were stage IC, 5 were stage II, 21 were stage III, and 3 were stage IV. The median PFS and OS for all stages was 9.3 and 19.7 months respectively. Fifteen patients (48%) received carboplatin/paclitaxel as first therapy, 7 (23%) received ifosfamide/paclitaxel, 6 (19%) received a different regimen, and 3 (10%) did not receive chemotherapy. Patients treated with carboplatin/paclitaxel had a statistically significant longer PFS when compared to those receiving ifosfamide/paclitaxel (17.8 vs. 8.0 months, p = 0.025). OS was similar between all comparisons. CONCLUSIONS: In summary, in our cohort of ovarian carcinosarcoma patients, median PFS is longer in patients treated with carboplatin/paclitaxel compared to ifosfamide/paclitaxel. Overall survival was similar for all treatment groups, potentially due to subsequent treatment crossover. Given the rarity and aggressive nature of this tumor, further study into optimal first-line chemotherapy is warranted. PMID- 29426294 TI - Factors associated with breast cancer recurrences or mortality and dynamic prediction of death using history of cancer recurrences: the French E3N cohort. AB - BACKGROUND: In addition to tumor characteristics and lifestyle factors, cancer relapses are often related to the risk of death but have not been jointly studied. We investigate the prognostic factors of recurrent events and death after a diagnosis of breast cancer and predict individual deaths including a history of recurrences. METHODS: The E3N (Etude Epidemiologique aupres de Femmes de la Mutuelle Generale de l'Education Nationale) study is a prospective cohort study that was initiated in 1990 to investigate factors associated with the most common types of cancer. Overall survival and three types of recurrent events were considered: locoregional recurrence, metastasis, and second primary breast cancer. Recurrent events and death were analyzed using a joint frailty model. RESULTS: The analysis included 4926 women from the E3N cohort diagnosed with a first primary invasive breast cancer between June 1990 and June 2008; during the follow-up, 1334 cases had a recurrence (median time of follow-up is 7.2 years) and 469 women died. Cases with high grade, large tumor size, axillary nodal involvement, and negative estrogen and progesterone receptors had a higher risk of recurrence or death. Furthermore, smoking increased the risk of relapse. For cases with a medium risk profile in terms of tumor characteristics and lifestyle factors, the probability of dying between 5 and 10 years after diagnosis was 6, 20 and 36% for 0, 1 or 2 recurrences within the first 5 years after diagnosis, respectively. CONCLUSIONS: Our study showed the importance of considering baseline lifestyle characteristics and history of relapses to dynamically predict the risk of death in breast cancer cases. Medical experience coupled with an estimate of a patient's survival probability that considers all available information for this patient would enable physicians to make better informed decisions regarding their actions and thus improve clinical output. PMID- 29426295 TI - Preclinical evaluation and reverse phase protein Array-based profiling of PI3K and MEK inhibitors in endometrial carcinoma in vitro. AB - BACKGROUND: The phosphoinositide-3-kinase (PI3K) pathway is the most commonly activated pathway in cancers due to mutations at multiple nodes and loss of PTEN. Furthermore, in endometrial cancer (EC), PI3K and RAS/RAF/MEK/MAPK (RAS/MAPK herein) pathway mutations frequently co-exist. We examined the role of PI3K and RAS/MAPK pathway mutations in determining responsiveness to therapies targeted to these pathways in vitro in EC. METHODS: 13 EC cell lines were profiled for their PI3K pathway and KRAS mutational and PTEN protein status and treated with one MEK and two PI3K- targeted inhibitors alone and in combination. Expression and phosphorylation of 66 proteins were evaluated by Reverse-Phase-Protein-Array (RPPA) in 6 EC cell lines to identify signalling changes in these pathways in response to therapy. RESULTS: PTEN protein loss and the absence of any tested pathway mutations are dominant negative predictors of sensitivity to MEK inhibition. KRAS-mutated cells were most sensitive to MEK inhibition, but significantly more resistant to PI3K inhibition than KRAS-wild-type cell lines. Combinations of PI3K and MEK inhibitors showed synergy or additivity in all but two cell lines tested. Treatment of KRAS-mutated cells with PI3K inhibitors and treatment of PTEN-low cells with a MEK inhibitor were most likely to induce activation of MEK/MAPK and AKT, respectively, likely indicative of feedback-loop regulation. CONCLUSIONS: MEK inhibition may be a promising treatment modality, not just for ECs with mutated KRAS, but also for those with retained PTEN. Up regulation of MEK/MAPK signalling by PI3K inhibition, and up-regulation of AKT activation by MEK inhibition may serve as potential biomarkers of likely responsiveness to each inhibitor. PMID- 29426296 TI - Repeated intraocular crystallization of ganciclovir in one eye after bilateral intravitreal injections: a case report. AB - BACKGROUND: Cytomegalovirus (CMV) retinitis is an opportunistic infection that primarily affects immunocompromised individuals. Intravitreal ganciclovir injection monotherapy or in combination with systemic anti-CMV therapy are effective treatments for CMV retinitis. Crystallization of ganciclovir after intravitreal injection is extremely rare. Only two cases had been reported in literature. Crystallization in only one eye after bilateral injections had not been reported before. We hereby report a case of intraocular ganciclovir crystallization in one eye after bilateral intravitreal injections, and repeated crystallization in the same eye after repeated injections. CASE PRESENTATION: A 79-year-old patient had bilateral cytomegalovirus retinitis and received bilateral intravitreal ganciclovir injections of 2.5 mg in 0.05 ml sterile water. Fundus examination after injection showed formation of needle-shaped, golden yellow crystals in the vitreous of right eye but not in left eye. The crystals dissolved spontaneously. Repeated bilateral intravitreal ganciclovir injections 4 days later resulted in repeated crystallization of ganciclovir in right eye but not in left eye. The crystals dissolved spontaneously and completely after 5 minutes. Visual acuity remained unchanged and intraocular pressure was normal. CONCLUSIONS: Intraocular ganciclovir crystallization could occur after intravitreal injections. It is important to perform fundus examination after injection. The crystals may dissolve rapidly and vitrectomy may not be necessary. Our case suggested intraocular ganciclovir crystallization is an idiosyncratic phenomenon, subjects to distinctive intraocular environment which could be different between two eyes of the same patient. The susceptible intraocular environment could be persistent leading to repeated crystallization. PMID- 29426297 TI - Prevalence of Mouse Mammary Tumor Virus (MMTV)-like sequences in human breast cancer tissues and adjacent normal breast tissues in Saudi Arabia. AB - BACKGROUND: Breast cancer is considered the most common cancer in women worldwide and is the leading cause of cancer mortality. Sequences similar to Mouse Mammary Tumor Virus (MMTV) were detected in human breast cancer in several studies from different geographical areas. However, the role played by this virus in breast cancer tumorigenesis is not completely understood. These MMTV-like sequences were found to be associated with breast cancer of more malignant types. The aim of this study is to determine the prevalence of MMTV-like envelope gene (env) positivity in breast cancer and non-cancerous breast tissue from Saudi Arabia. METHODS: Detection of MMTV-like env proviral sequences was done using newly designed primers for conventional polymerase chain reaction (PCR). One hundred nighty four samples were collected from 103 females with breast cancer in addition to 51 control breast tissue obtained from individuals without cancer. We additionally investigated the association of proviral positivity with age of the patients, grade of breast cancer and presence of lymph node metastasis. The results were confirmed by sequencing. RESULTS: The prevalence of MMTV-like env proviral positivity was 8.7% (9/103). MMTV env proviral sequences were detected in 5.9% (6/101) of breast cancer tissues and 9.7% (9/93) of non-cancerous adjacent tissues obtained from the same patients. None of the 51 control sample showed positive result for the MMTV env gene. No significant association was found between detection of the virus and the age of the patient, grade of the cancer or presence of metastasis. CONCLUSION: We document the presence of low frequency of MMTV env provirus sequence among breast cancer patients from Saudi Arabia. Further studies are needed to explore the role of the MMTV in breast cancer. PMID- 29426298 TI - Albuminuria, serum creatinine, and estimated glomerular filtration rate as predictors of cardio-renal outcomes in patients with type 2 diabetes mellitus and kidney disease: a systematic literature review. AB - BACKGROUND: Albuminuria, elevated serum creatinine and low estimated glomerular filtration rate (eGFR) are pivotal indicators of kidney decline. Yet, it is uncertain if these and emerging biomarkers such as uric acid represent independent predictors of kidney disease progression or subsequent outcomes among individuals with type 2 diabetes mellitus (T2DM). This study systematically examined the available literature documenting the role of albuminuria, serum creatinine, eGFR, and uric acid in predicting kidney disease progression and cardio-renal outcomes in persons with T2DM. METHODS: Embase, MEDLINE, and Cochrane Central Trials Register and Database of Systematic Reviews were searched for relevant studies from January 2000 through May 2016. PubMed was searched from 2013 until May 2016 to retrieve studies not yet indexed in the other databases. Observational cohort or non-randomized longitudinal studies relevant to albuminuria, serum creatinine, eGFR, uric acid and their association with kidney disease progression, non-fatal cardiovascular events, and all-cause mortality as outcomes in persons with T2DM, were eligible for inclusion. Two reviewers screened citations to ensure studies met inclusion criteria. RESULTS: From 2249 citations screened, 81 studies were retained, of which 39 were omitted during the extraction phase (cross-sectional [n = 16]; no outcome/measure of interest [n = 13]; not T2DM specific [n = 7]; review article [n = 1]; editorial [n = 1]; not in English language [n = 1]). Of the remaining 42 longitudinal study publications, biomarker measurements were diverse, with seven different measures for eGFR and five different measures for albuminuria documented. Kidney disease progression differed substantially across 31 publications, with GFR loss (n = 9 [29.0%]) and doubling of serum creatinine (n = 5 [16.1%]) the most frequently reported outcome measures. Numerous publications presented risk estimates for albuminuria (n = 18), serum creatinine/eGFR (n = 13), or both combined (n = 6), with only one study reporting for uric acid. Most often, these biomarkers were associated with a greater risk of experiencing clinical outcomes. CONCLUSIONS: Despite the utility of albuminuria, serum creatinine, and eGFR as predictors of kidney disease progression, further efforts to harmonize biomarker measurements are needed given the disparate methodologies observed in this review. Such efforts would help better establish the clinical significance of these and other biomarkers of renal function and cardio-renal outcomes in persons with T2DM. PMID- 29426299 TI - The delirium and population health informatics cohort study protocol: ascertaining the determinants and outcomes from delirium in a whole population. AB - BACKGROUND: Delirium affects 25% of older inpatients and is associated with long term cognitive impairment and future dementia. However, no population studies have systematically ascertained cognitive function before, cognitive deficits during, and cognitive impairment after delirium. Therefore, there is a need to address the following question: does delirium, and its features (including severity, duration, and presumed aetiologies), predict long-term cognitive impairment, independent of cognitive impairment at baseline? METHODS: The Delirium and Population Health Informatics Cohort (DELPHIC) study is an observational population-based cohort study based in the London Borough of Camden. It is recruiting 2000 individuals aged >=70 years and prospectively following them for two years, including daily ascertainment of all inpatient episodes for delirium. Daily inpatient assessments include the Memorial Delirium Assessment Scale, the Observational Scale for Level of Arousal, and the Hierarchical Assessment of Balance and Mobility. Data on delirium aetiology is also collected. The primary outcome is the change in the modified Telephone Interview for Cognitive Status at two years. DISCUSSION: DELPHIC is the first population sample to assess older persons before, during and after hospitalisation. The cumulative incidence of delirium in the general population aged >=70 will be described. DELPHIC offers the opportunity to quantify the impact of delirium on cognitive and functional outcomes. Overall, DELPHIC will provide a real-time public health observatory whereby information from primary, secondary, intermediate and social care can be integrated to understand how acute illness is linked to health and social care outcomes. PMID- 29426300 TI - Effect of calcitriol on serum hepcidin in individuals with chronic kidney disease: a randomized controlled trial. AB - BACKGROUND: Anemia is highly prevalent in chronic kidney disease (CKD). Elevated hepcidin concentrations are an important mediator of disordered iron metabolism, a key mechanism underlying anemia of CKD. Vitamin D was recently shown to reduce serum hepcidin concentrations in healthy individuals. We examined whether treatment with calcitriol reduces serum hepcidin in individuals with CKD. METHODS: A total of 40 participants with stage 3 or 4 CKD (eGFR 15-60 ml/min/1.73m2) were randomized to receive either oral calcitriol 0.5 mcg daily or identically-matched placebo for 6 weeks. The primary outcome variable was change in serum hepcidin concentrations. Secondary outcomes variables included the change in iron parameters, calcium, phosphorus, intact parathyroid hormone and hemoglobin concentrations. Study samples were drawn at baseline, 3 days, 1 week, 4 weeks and 6 weeks after randomization. Repeated measures analysis was used to examine differences in outcome variables over time in the two groups. RESULTS: There were no significant differences in the baseline characteristics between the placebo and calcitriol arms. Over 6 weeks of follow-up there were no significant differences in the change in serum hepcidin, iron parameters, or hemoglobin between the two groups. Serum calcium and phosphorus significantly increased and PTH significantly decreased after 6 weeks in calcitriol group whereas these analytes did not change in the placebo group. CONCLUSION: Calcitriol did not reduce serum hepcidin concentrations among individuals with mild to moderate CKD. Future studies are needed to assess if nutritional forms of vitamin D affect hepcidin concentrations in CKD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01988116 . Registered: November 4, 2013. PMID- 29426301 TI - The COMT-polymorphism is not associated with the incidence of acute kidney injury after cardiac surgery - a prospective cohort study. AB - BACKGROUND: The Catechol-O-methyltransferase (COMT) represents the key enzyme in catecholamine degradation. Recent studies suggest that the COMT rs4680 polymorphism is associated with the response to endogenous and exogenous catecholamines. There are, however, conflicting data regarding the COMT Met/Met phenotype being associated with an increased risk of acute kidney injury (AKI) after cardiac surgery. The aim of the current study is to prospectively investigate the impact of the COMT rs4680 polymorphism on the incidence of AKI in patients undergoing cardiac surgery. METHODS: In this prospective single center cohort study consecutive patients hospitalized for elective cardiac surgery including cardiopulmonary-bypass (CPB) were screened for participation. Demographic clinical data, blood, urine and tissue samples were collected at predefined time points throughout the clinical stay. AKI was defined according to recent recommendations of the Kidney Disease Improving Global Outcome (KDIGO) group. Genetic analysis was performed after patient enrolment was completed. RESULTS: Between April and December 2014, 150 patients were recruited. The COMT genotypes were distributed as follows: Val/Met 48.7%, Met/Met 29.3%, Val/Val 21.3%. No significant differences were found for demography, comorbidities, or operative strategy according to the underlying COMT genotype. AKI occurred in 35 patients (23.5%) of the total cohort, and no differences were evident between the COMT genotypes (20.5% Met/Met, 24.7% Val/Met, 25.0% Val/Val, p = 0.66). There were also no differences in the post-operative period, including ICU or in hospital stay. CONCLUSIONS: We did not find statistically significant variations in the risk for postoperative AKI, length of ICU or in-hospital stay according to the underlying COMT genotype. PMID- 29426302 TI - The relationship of undernutrition/psychosocial factors and developmental outcomes of children in extreme poverty in Ethiopia. AB - BACKGROUND: Extreme poverty is severe deprivation of basic needs and services. Children living in extreme poverty may lack adequate parental care and face increased developmental and health risks. However, there is a paucity of literature on the combined influences of undernutrition and psychosocial factors (such as limited play materials, playground, playtime, interactions of children with their peers and mother-child interaction) on children's developmental outcomes. The main objective of this study was, therefore, to ascertain the association of developmental outcomes and psychosocial factors after controlling nutritional indices. METHODS: A community-based cross-sectional study design was used to compare the developmental outcomes of extremely poor children (N = 819: 420 girls and 399 boys) younger than 5 years versus age-matched reference children (N = 819: 414 girls and 405 boys) in South-West Ethiopia. Using Denver II-Jimma, development in personal-social, language, fine and gross motor skills were assessed, and social-emotional skills were evaluated using the Ages and Stages Questionnaires: Social-Emotional (ASQ: SE). Nutritional status was derived from the anthropometric method. Independent samples t-test was used to detect mean differences in developmental outcomes between extremely poor and reference children. Multiple linear regression analysis was employed to identify nutritional and psychosocial factors associated with the developmental scores of children in extreme poverty. RESULTS: Children in extreme poverty performed worse in all the developmental domains than the reference children. Among the 819 extremely poor children, 325 (39.7%) were stunted, 135 (16.5%) were underweight and 27 (3.3%) were wasted. The results also disclosed that stunting and underweightness were negatively associated with all the developmental skills. After taking into account the effects of stunting and being underweight on the developmental scores, it was observed that limited play activities, limited child to-child interactions and mother-child relationships were negatively related mainly to gross motor and language performances of children in extreme poverty. CONCLUSION: Undernutrition and psychosocial factors were negatively related to the developmental outcomes, independently, of children living in extreme poverty. Intervention, for these children, should integrate home-based play-assisted developmental stimulation and nutritional rehabilitation. PMID- 29426303 TI - A rare case of scleral buckle infection with Curvularia species. AB - BACKGROUND: Scleral buckling is an established modality of treating retinal detachment. Being an external implant the buckle may be prone to infections. We report such a case with a delayed presentation and a rare etiology. CASE PRESENTATION: A 45 year old male presented with redness, foreign body sensation and discharge for one month in his right eye. The patient had undergone a retinal detachment surgery elsewhere 14 years back without any visual gain. Right eye demonstrated no perception of light and the best corrected visual acuity in the left eye was 6/6, N6. On downgaze an exposed and anteriorly displaced scleral buckle was identified with black deposits and mucopurulent material overlying the buckle. Scleral buckle removal was done. On microbiological examination Curvularia species was identified. Successful treatment with antifungals was done. CONCLUSIONS: Scleral buckle infection with dematiaceous fungi is a rare occurrence. To the best of our knowledge this is the first case report describing a buckle infection caused by the curvularia species. PMID- 29426304 TI - Rationale, design, and methodology of a trial evaluating three models of care for HCV treatment among injection drug users on opioid agonist therapy. AB - BACKGROUND: People who inject drugs (PWID) constitute 60% of the approximately 5 million people in the U.S. infected with hepatitis C virus (HCV). Treatment of PWID is complex due to addiction, mental illness, poverty, homelessness, lack of positive social support, poor adherence-related skills, low motivation and knowledge, and poor access to and trust in the health care system. New direct acting antiviral medications are available for HCV with high cure rates and few side effects. The life expectancy and economic benefits of new HCV treatments will not be realized unless we determine optimal models of care for the majority of HCV-infected patients. The purpose of this study is to evaluate the effectiveness of directly observed therapy and group treatment compared with self administered individual treatment in a large, urban opioid agonist therapy clinic setting in the Bronx, New York. METHODS/DESIGN: In this randomized controlled trial 150 PWID with chronic HCV were recruited from opioid agonist treatment (OAT) clinics and randomized to one of three models of onsite HCV treatment in OAT: 1) modified directly observed therapy; 2) group treatment; or 3) control - self-administered individual treatment. Participants were age 18 or older, HCV genotype 1, English or Spanish speaking, treatment naive (or treatment experienced after 12/3/14), willing to receive HCV treatment onsite, receiving methadone or buprenorphine at the medication window at least once per week, and able to provide informed consent. Outcomes of interest include adherence (as measured by self-report and electronic blister packs), HCV treatment completion, sustained virologic response, drug resistance, and cost-effectiveness. DISCUSSION: This paper describes the design and rationale of a randomized controlled trial comparing three models of care for HCV therapy delivered in an opioid agonist treatment program. Our trial will be critical to rigorously identify models of care that result in high adherence and cure rates. Use of blister pack technology will help us determine the role of adherence in successful cure of HCV. Moreover, the trial methodology outlined here can serve as a template for the development of future programs and studies among HCV infected drug users receiving opioid agonist therapy, as well as the cost effectiveness of such programs. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov ( NCT01857245 ). Trial registration was obtained prospectively on May 20th, 2013. PMID- 29426305 TI - Adherence to guidelines for testing and treatment of children with pharyngitis: a retrospective study. AB - BACKGROUND: Group A streptococcus (GAS) is the most common bacterial etiology of pharyngitis but is difficult to distinguish clinically from viral pharyngitis. There are benefits to early antibacterial treatment of GAS pharyngitis, but administering antibiotics to children with viral pharyngitis is ineffective and costly. We evaluated adherence to guidelines that were developed to help clinicians distinguish between viral and GAS pharyngitis and guide management. METHODS: Retrospective cohort study of patients ages 3-18 who had a rapid streptococcal test and/or throat culture performed in an outpatient setting. We collected data on documentation of components of the McIsaac score and classified tests as indicated if the score was >=2. Based on McIsaac score and GAS test results, we determined whether each antibiotic course prescribed was indicated according to the Infectious Diseases Society of America guideline. RESULTS: Among 291 eligible children, 87 (30%) had all five components of the McIsaac score documented. There was sufficient data to classify the score as either < 2 or >=2 in 234 (80%); among these, 96% of tests were indicated. Twenty-nine patients (10%) were prescribed antibiotics. Eight (28%) of these prescriptions were not indicated according to guidelines. CONCLUSIONS: The majority of GAS tests in children with pharyngitis are indicated, although providers do not regularly document all elements of a validated pharyngitis scoring tool. Over one quarter of children prescribed antibiotics for pharyngitis did not require antibiotics according to guidelines. There remains a role for targeted antimicrobial stewardship education regarding pharyngitis management in pediatric outpatient settings. PMID- 29426307 TI - Rapid intravenous rehydration of children with acute gastroenteritis and dehydration: a systematic review and meta-analysis. AB - BACKGROUND: The World Health Organization (WHO) recommends rapid intravenous rehydration, using fluid volumes of 70-100mls/kg over 3-6 h, with some of the initial volume given rapidly as initial fluid boluses to treat hypovolaemic shock for children with acute gastroenteritis (AGE) and severe dehydration. The evidence supporting the safety and efficacy of rapid versus slower rehydration remains uncertain. METHODS: We conducted a systematic review of randomised controlled trials (RCTs) on 11th of May 2017 comparing different rates of intravenous fluid therapy in children with AGE and moderate or severe dehydration, using standard search terms. Two authors independently assessed trial quality and extracted data. Non-RCTs and non-English articles were excluded. The primary endpoint was mortality and secondary endpoints included adverse events (safety) and treatment efficacy. MAIN RESULTS: Of the 1390 studies initially identified, 18 were assessed for eligibility. Of these, 3 studies (n = 464) fulfilled a priori criteria for inclusion; most studied children with moderate dehydration and none were conducted in resource-poor settings. Volumes and rates of fluid replacement varied from 20 to 60 ml/kg given over 1-2 h (fast) versus 2-4 h (slow). There was substantial heterogeneity in methodology between the studies with only one adjudicated to be of high quality. There were no deaths in any study. Safety endpoints only identified oedema (n = 6) and dysnatraemia (n = 2). Pooled analysis showed no significant difference between the rapid and slow intravenous rehydration groups for the proportion of treatment failures (N = 468): pooled RR 1.30 (95% CI: 0.87, 1.93) and the readmission rates (N = 439): pooled RR 1.39 (95% CI: 0.68, 2.85). CONCLUSIONS: Despite wide implementation of WHO Plan C guideline for severe AGE, we found no clinical evaluation in resource limited settings, and only limited evaluation of the rate and volume of rehydration in other parts of the world. Recent concerns over aggressive fluid expansion warrants further research to inform guidelines on rates of intravenous rehydration therapy for severe AGE. PMID- 29426306 TI - Characteristics of people living in Italy after a cancer diagnosis in 2010 and projections to 2020. AB - BACKGROUND: Estimates of cancer prevalence are widely based on limited duration, often including patients living after a cancer diagnosis made in the previous 5 years and less frequently on complete prevalence (i.e., including all patients regardless of the time elapsed since diagnosis). This study aims to provide estimates of complete cancer prevalence in Italy by sex, age, and time since diagnosis for all cancers combined, and for selected cancer types. Projections were made up to 2020, overall and by time since diagnosis. METHODS: Data were from 27 Italian population-based cancer registries, covering 32% of the Italian population, able to provide at least 7 years of registration as of December 2009 and follow-up of vital status as of December 2013. The data were used to compute the limited-duration prevalence, in order to estimate the complete prevalence by means of the COMPREV software. RESULTS: In 2010, 2,637,975 persons were estimated to live in Italy after a cancer diagnosis, 1.2 million men and 1.4 million women, or 4.6% of the Italian population. A quarter of male prevalent cases had prostate cancer (n = 305,044), while 42% of prevalent women had breast cancer (n = 604,841). More than 1.5 million people (2.7% of Italians) were alive since 5 or more years after diagnosis and 20% since >=15 years. It is projected that, in 2020 in Italy, there will be 3.6 million prevalent cancer cases (+ 37% vs 2010). The largest 10-year increases are foreseen for prostate (+ 85%) and for thyroid cancers (+ 79%), and for long-term survivors diagnosed since 20 or more years (+ 45%). Among the population aged >=75 years, 22% will have had a previous cancer diagnosis. CONCLUSIONS: The number of persons living after a cancer diagnosis is estimated to rise of approximately 3% per year in Italy. The availability of detailed estimates and projections of the complete prevalence are intended to help the implementation of guidelines aimed to enhance the long-term follow-up of cancer survivors and to contribute their rehabilitation needs. PMID- 29426308 TI - Quality of social and emotional wellbeing services for families of young Indigenous children attending primary care centers; a cross sectional analysis. AB - BACKGROUND: The quality of social and emotional wellbeing services for Indigenous families of young children is not known, in many settings especially services provided by primary care centers. METHODS: Our primary objective was to assess delivery of social and emotional wellbeing services to the families of young (3 11 months) and older (12-59 months) Indigenous children attending primary care centers. Our secondary objective was to assess if delivery differed by geographic location. Two thousand four hundred sixty-six client files from 109 primary care centers across Australia from 2012 to 2014 were analysed using logistic regression and generalised estimating equations. RESULTS: The proportion of families receiving social and emotional wellbeing services ranged from 10.6% (102) (food security) to 74.7% (1216) (assessment of parent child interaction). Seventy one percent (71%, 126) of families received follow up care. Families of children aged 3-11 months (39.5%, 225) were more likely to receive social and emotional wellbeing services (advice about domestic environment, social support, housing condition, child stimulation) than families of children aged 12-59 months (30.0%, 487) (adjusted odds ratio [aOR] 1.68 95% CI 1.33 to 2.13). Remote area families (32.6%, 622) received similar services to rural (29.4%, 68) and urban families (44.0%, 22) (aOR 0.64 95% CI 0.29, 1.44). CONCLUSIONS: The families of young Indigenous children appear to receive priority for social and emotional wellbeing care in Australian primary care centers, however many Indigenous families are not receiving services. Improvement in resourcing and support of social and emotional wellbeing services in primary care centers is needed. PMID- 29426309 TI - Neighborhood-based PA and its environmental correlates: a GIS- and GPS based cross-sectional study in the Netherlands. AB - BACKGROUND: To improve our understanding of the neighborhood environment - physical activity (PA) relationship, it is of importance to assess associations between neighborhood environmental characteristics and neighborhood-based PA. METHODS: Participants' (N = 308; 45-65 years) light PA (LPA) and moderate vigorous PA (MVPA) within a 400, 800, and 1600 m buffer around adults' homes was measured using accelerometers and GPS-devices. Land use data in ArcGIS provided neighborhood characteristics for the same buffers. Multilevel linear regression models, adjusted for socio-demographic variables and attitude towards PA, were used to assess associations of objective neighborhood characteristics with neighborhood-based LPA and MVPA. RESULTS: LPA was positively associated with the proportions of roads (within a 400 m buffer), and negatively associated with the proportions of recreational areas (within an 800 m buffer), and the proportion of green space (within the 800 m and 1600 m buffers). Multiple characteristics of 400 m buffers were positively associated with MVPA, i.e. proportions of green space, blue space, residences, shops and foodservice industry, sports terrain, and public social-cultural facilities. Also, characteristics of larger buffers were positively associated with MVPA, i.e. the proportions of shops and foodservice industry, sports terrain, and blue space (within an 800 m buffer), and the proportion of public social-cultural facilities (within the 800 m and 1600 m buffers). CONCLUSIONS: Objective neighborhood characteristics of smaller as well as larger sized buffers were associated with neighborhood-based LPA and MVPA. Green and blue spaces seem to be of particular importance for PA in the smallest buffer, i.e. in the direct surrounding of adults' homes. PMID- 29426310 TI - Barriers to voluntary participation in sport for children: a systematic review. AB - BACKGROUND: Numerous studies have detailed the physical health benefits of children's participation in sport and a growing body of research also highlights the benefits for mental health. Children who participate in sport have also been shown to be advantaged academically. However, despite the benefits there is evidence that children are leading increasingly sedentary lifestyles and are at greater risk of chronic disease than those with active lifestyles. Sport provides an important means for children to achieve their recommended amount of daily physical activity. This systematic review asks 'what are those barriers to children's participation in sport?' METHODS: Literature searches were carried out in June 2015 using; EMBASE, Medline, CINAHL and SportDiscus using the search terms barrier*, stop*, prevent*, participat*, taking part, Sports/, sport*, "physical education", PE, child*, young person*, adolescen*. These were supplemented with hand searches. A total of 3434 records were identified of which 22 were suitable for inclusion in the review, two additional studies were identified from Google Scholar in November 2016. Both qualitative and quantitative studies were included. Study's included in the review assessed children up to 18 years of age. Study quality was assessed using Critical Appraisal Skills Programme (CASP) tools. RESULTS: Studies took place in the school environment (n = 14), sports club (n = 1), community setting (n = 8) and adolescent care setting (n = 1). Frequently reported barriers across quantitative studies were 'time' (n = 4), 'cost' (n = 3), 'opportunity/accessibility' (n = 3) and 'friends' (n = 2). Frequently reported barriers across qualitative studies were 'time' (n = 6), 'cost' (n = 5), 'not being good at sport' (n = 6) and 'fear of being judged/embarrassed' (n = 6). CONCLUSION: Policy makers, parents and teachers should all be aware that 'cost' and 'time' are key barriers to participation in sport. More local sports opportunities are needed where costs are reduced. Schools and local clubs could better work together to provide more affordable local opportunities to increase children's participation in sport. PMID- 29426311 TI - Avian malaria and bird humoral immune response. AB - BACKGROUND: Plasmodium parasites are known to impose fitness costs on their vertebrate hosts. Some of these costs are due to the activation of the immune response, which may divert resources away from self-maintenance. Plasmodium parasites may also immuno-deplete their hosts. Thus, infected individuals may be less able to mount an immune response to a new pathogen than uninfected ones. However, this has been poorly investigated. METHODS: The effect of Plasmodium infection on bird humoral immune response when encountering a novel antigen was tested. A laboratory experiment was conducted on canaries (Serinus canaria) experimentally infected with Plasmodium relictum (lineage SGS1) under controlled conditions. Birds were immune challenged with an intra-pectoral injection of a novel non-pathogenic antigen (keyhole limpet haemocyanin, KLH). One week later they were challenged again. The immune responses to the primary and to the secondary contacts were quantified as anti-KLH antibody production via enzyme linked immunosorbent assay (ELISA). RESULTS: There was no significant difference in antibody production between uninfected and Plasmodium infected birds at both primary and secondary contact. However, Plasmodium parasite intensity in the blood increased after the primary contact with the antigen. CONCLUSIONS: There was no effect of Plasmodium infection on the magnitude of the humoral immune response. However, there was a cost of mounting an immune response in infected individuals as parasitaemia increased after the immune challenge, suggesting a trade-off between current control of chronic Plasmodium infection and investment against a new immune challenge. PMID- 29426312 TI - Anterior cruciate ligament reconstruction with quadriceps tendon-patellar bone allograft: matched case control study. AB - BACKGROUND: Quadriceps tendon-patellar bone (QTPB) autograft is an excellent graft option with good clinical outcome. Use of QTPB autografts have increased because they minimize donor-site morbidity including anterior knee pain, while providing adequate mechanical strength. Although, there were many clinical results about allografts that used in anterior cruciate ligament (ACL) reconstruction, it have never been reported about the clinical outcome of ACL reconstruction with QTPB allograft. The purpose of this study is to evaluate the clinical outcome of ACL reconstruction with QTPB allograft and to compare with QTPB autograft. We hypothesized that ACL reconstruction with QTPB allograft had good functional outcomes and stability and no significant difference compared to the ACL reconstruction with QTPB autograft. METHODS: From February 2009 to January 2014, 213 cases who received ACL reconstruction with QTPB grafts were included. Forty-five patients who received ACL reconstruction with QTPB allograft were individually matched in age, sex, direction of the injured knee and body mass index (BMI) to a control group of 45 patients who received QTPB autograft. Clinical results were evaluated using International Knee Documentation Committee (IKDC) score, Lysholm score, Tegner scale, Knee injury and Osteoarthritis Outcome Score (KOOS) and ligament laxity. An average follow-up time was 31.2 months. RESULTS: The functional scores and ligament laxity improved from initial to the last visit in those with ACL reconstruction with QTPB allograft (p < 0.05). No significant statistical difference was found in clinical outcomes and complications including re-rupture between the QTPB allograft and autograft groups (p > 0.05). Laxity using anterior drawer test, Lachman test and KT-2000 showed no significant difference. No significant difference was found between the two groups in quadriceps peak extension torque, except at 60 degrees per second at 6 months. CONCLUSION: QTPB allograft achieved good clinical outcome with no difference compared with QTPB autograft. QTPB allograft for ACL reconstruction is promising alternative to selected and compliant patients. Long-term follow-up needs to further evaluate the clinical outcomes and complications including re rupture rate. PMID- 29426313 TI - Urban-rural disparities in health care utilization among Chinese adults from 1993 to 2011. AB - BACKGROUND: Despite economic growth and improved health outcomes over the past few decades, China still experiences striking urban-rural health inequalities. Urban and rural residents distinguished by the hukou system may experience profound disparities because of institutional effect. The aim of this study is to estimate trends in urban-rural disparities in self-care, outpatient care, and inpatient care utilization from a perspective of the hukou system. METHODS: Data were extracted from the seven latest waves of the China Health and Nutrition Survey (CHNS). We used the hukou system to distinguish between urban and rural residents. Chi-square tests were performed to examine urban-rural gaps in self care, outpatient care, and inpatient care utilization. Multinomial logistic regression was employed to confirm these disparities and to explore whether the urban-rural gaps have narrowed or widened from 1993 to 2011 once known determinants of utilization are taken into account according to Andersen/Aday's Health Behaviour Model. RESULTS: The urban-rural disparities were evident after controlling for confounding variables: urban adults were 3.24 (p < 0.05), 2.23 (p < 0.1), and 4.77 (p < 0.01) times more likely to choose self-care vs. no care, outpatient care vs. no care, and inpatient care vs. no care than their rural counterparts, respectively. The results showed upward trends in self-care, outpatient care, and inpatient care utilization from 2004 to 2011. The urban rural gaps in health care utilization gradually narrowed during the period of 1993-2011. The hukou distinctions of self-care, outpatient care, and inpatient care in 2011 were only 33.3%, 35.5%, and 9.6% of that in 1993, respectively. CONCLUSIONS: Although rural residents were underutilizing health care when compared to their urban counterparts, the significant decrements in urban-rural disparities reflect the positive effect of the on-going health system reform in China. To maintain an equitable distribution of health care utilization, policy makers need to be aware of challenges due to aging problems and health expenditure increment. PMID- 29426314 TI - Overcoming barriers to access and utilization of maternal, newborn and child health services in northern Nigeria: an evaluation of facility health committees. AB - BACKGROUND: Poor quality of health services and socio-cultural dynamics may severely limit utilization of health services. Facility health committees were established in several states in northern Nigeria to reduce these barriers. The committees were charged with mobilizing communities, improving quality of health services, and promoting utilization of maternal and child health services. This study assessed this intervention. METHODS: To obtain a comprehensive picture of facility health committees' influence on maternal and child health services, we selected 33 facilities in three states in northern Nigeria (Jigawa, Kaduna, Kano) where the intervention was active. For each of these facilities we interviewed committee members (n = 399), conducted focus group discussions with a subset of committee members (18 focus groups), interviewed facility health providers (two providers from each facility), and conducted client exit interviews (n = 501). RESULTS: Facility health committees appear to have a positive influence on quality of maternal and child health services in the selected facilities. Committee members, health providers, and facility clients all agree that the committees have a tangible positive effect. The most important roles of the committees are to mobilize the community and increase demand for maternal and child health services, in a region where demand is very low. Committee activities further improve health services in many ways, including advocacy, community facility coordination, fund raising, money donation, and problem mitigation. CONCLUSION: Facility health committees can be invaluable in contributing to improved demand for and access to quality maternal and child health services in health facilities in northern Nigeria. They provide strong linkages between community members and the health facilities, directly work to increase demand for services, and address supply-side challenges that often limit utilization of services in health facilities. The intervention can be improved by more broadly communicating committee activities in the community, and by incentivizing facility health committee members. PMID- 29426315 TI - Effects of smoke-free air law on acute myocardial infarction hospitalization in Indianapolis and Marion County, Indiana. AB - BACKGROUND: A comprehensive smoke-free air law was enacted on June 1, 2012 in most of Marion County, Indiana, including all of the City of Indianapolis. We evaluated changes in acute myocardial infarction (AMI) admission rates in Indianapolis and Marion County before compared to after the law. METHODS: We collected AMI admissions from five Marion County hospitals between May 2007 and December 2014. We used Poisson regression to evaluate the overall effects of the law on monthly AMI hospitalizations, adjusting for month, seasonality, meteorology, air pollution, and hospital utilization. We tested the interactions between the law and AMI risk factors on monthly AMI admission rates to identify subpopulations for which the effects might be stronger. RESULTS: Monthly AMI admissions declined 20% (95% CI 14-25%) in Marion County and 25% (95% CI 20-29%) in Indianapolis after the law was implemented. We observed decreases among never (21%, 95% CI 13-29%), former (28%, 95% CI 21-34%), and current smokers (26%, 95% CI 11-38%); Medicaid beneficiaries (19%, 95% CI 9-29%) and non-beneficiaries (26%, 95% CI 20-31%). We observed decreases among those with a history of diabetes (Yes: 22%, 95% CI 14-29%; No: 25%, 95% CI 18-31%), congestive heart failure (Yes: 23%, 95% CI 16-30%; No: 24%, 95% CI 17-31%), and hypertension (Yes: 23%, 95% CI 17-28%: No: 26%, 95% CI 15-36%). CONCLUSIONS: We observed decreases in AMI admissions comparable with previous studies. We identified subpopulations who benefitted from the law, such as former and current smokers, and those without comorbidities such as congestive heart failure and hypertension. PMID- 29426316 TI - Test-retest repeatability of child's respiratory symptoms and perceived indoor air quality - comparing self- and parent-administered questionnaires. AB - BACKGROUND: Questionnaires can be used to assess perceived indoor air quality and symptoms in schools. Questionnaires for primary school aged children have traditionally been parent-administered, but self-administered questionnaires would be easier to administer and may yield as good, if not better, information. Our aim was to compare the repeatability of self- and parent-administered indoor air questionnaires designed for primary school aged pupils. METHODS: Indoor air questionnaire with questions on child's symptoms and perceived indoor air quality in schools was sent to parents of pupils aged 7-12 years in two schools and again after two weeks. Slightly modified version of the questionnaire was administered to pupils aged 9-12 years in another two schools and repeated after a week. 351 (52%) parents and 319 pupils (86%) answered both the first and the second questionnaire. Test-retest repeatability was assessed with intra-class correlation (ICC) and Cohen's kappa coefficients (k). RESULTS: Test-retest repeatability was generally between 0.4-0.7 (ICC; k) in both self- and parent administered questionnaire. In majority of the questions on symptoms and perceived indoor air quality test-retest repeatability was at the same level or slightly better in self-administered compared to parent-administered questionnaire. Agreement of self- and parent administered questionnaires was generally < 0.4 (ICC; k) in reported symptoms and 0.4-0.6 (ICC; k) in perceived indoor air quality. CONCLUSIONS: Children aged 9-12 years can give as, or even more, repeatable information about their respiratory symptoms and perceived indoor air quality than their parents. Therefore, it may be possible to use self administered questionnaires in future studies also with children. PMID- 29426317 TI - Barriers and enablers to skin-to-skin contact at birth in healthy neonates - a qualitative study. AB - BACKGROUND: Skin to skin contact (SSC) at birth is the standard of care for newborns without risk factors. However, implementation of SSC at birth has been far from optimal. A qualitative study was undertaken to determine the barriers, enablers and potential solutions to implementation of SSC at birth in healthy newborn infants in a level III neonatal-care facility in Bangalore, India. METHODS: Consultants and residents/postgraduates (PG) from the departments of Obstetrics (n = 19) and Pediatrics (n = 14) and nurses (n = 8) in the labor room (LR) participated in the study. In depth interviews (IDI) and focus group discussions (FGD) were carried out with an interview guide and a moderators' guide containing inbuilt probes. Subjects of FGD were homogenous. All IDI and FGD were audio-taped, transcribed and analyzed using N VIVO version 9 (using free and tree nodes). Two authors separately coded the transcripts. Major and minor themes were identified. Rigor was ensured by triangulation and theoretical saturation. Informed consent and ethical approval was obtained. RESULTS: All subjects were aware of SSC at birth, some of its benefits and had practiced SSC. The major barriers identified were lack of personnel (nurses), time constraint, difficulty in deciding on eligibility for SSC, safety concerns, interference with clinical routines, and interdepartmental issues. Recall of an adverse event during SSC was also a major barrier. Furthermore, we found that most participants considered 1 h as impractical; and promoted 5-15 min SSC. Minor themes were gender bias of the newborn and cultural practices. The participants offered solutions such as assigning a helper exclusively for SSC, allowing a family member into the LR, continuing SSC after initial routines, antenatal counselling, constant reminders in the form of periodic sessions with audiovisual aids or posters in the obstetrics ward, training of new nurses and PG, and inclusion of SSC in medical and nursing curriculum. CONCLUSIONS: The major barriers to SSC at birth are lack of personnel, time constraint and safety concerns. Training, designated health personnel for SSC and teamwork are the key interventions likely to improve SSC at birth. PMID- 29426318 TI - Hospital discharge documentation of a designated clinician for follow-up care and 30-day outcomes in hip fracture and stroke patients discharged to sub-acute care. AB - BACKGROUND: Transitions to sub-acute care are regularly complicated by inadequate discharge communication, which is exacerbated by a lack of clarity regarding accountability for important follow-up care. Patients discharged to sub-acute care often have complex medical conditions and are at heightened risk for poor post-hospital outcomes, yet many do not see a provider until 30 days post discharge due to current standards in Medicare regulations. Lack of designation of a responsible clinician or clinic for follow-up care may adversely impact patient outcomes, but the magnitude of this potential impact has not been previously studied. METHODS: We examined the association of designating a responsible clinician/clinic for post-hospital follow-up care within the hospital discharge summary on risk for 30-day rehospitalization and/or death in stroke and hip fracture patients discharged to sub-acute care. This retrospective cohort study used Medicare Claims and Electronic Health Record data to identify non hospice Medicare beneficiaries with primary discharge diagnoses of stroke/ or hip fracture discharged from one of two urban hospitals to sub-acute care facilities during 2003-2008 (N = 1130). We evaluated the association of omission of the designation of a responsible clinician/clinic for follow-up care in the hospital discharge summary on the composite outcome of 30-day rehospitalization and/or death after adjusting for patient characteristics and utilization. We used multivariate logistic regression robust estimates clustered by discharging hospital. RESULTS: Patients whose discharge summaries omitted designation of a responsible clinician/clinic for follow-up care were significantly more likely to experience 30-day rehospitalization and/or death (OR: 1.51, 95% CI 1.07-2.12, P = 0.014). CONCLUSIONS: The current study found a strong relationship between the omission of a responsible clinician/clinic for follow-up care from the hospital discharge summary and the poor outcomes for patients transferred to sub-acute care. More research is needed to understand the role and impact of designating accountability for follow-up care needs on patient outcomes. PMID- 29426319 TI - Risk factors for neck pain among forklift truck operators: a retrospective cohort study. AB - BACKGROUND: No previous research has been performed into neck pain among forklift operators. This is a common complaint among these workers, who number around 150,000 in Sweden and six million in Europe. The aim of the study was to examine long-term exposure to unnatural neck positions among forklift operators as a risk factor for neck pain. METHODS: A retrospective cohort study was conducted of all eligible employees at a high-level warehouse. Forklift operators and office workers answered an 18-page questionnaire comprising questions about joint pain, work tasks, work postures and year of start for all items. By using person years in the exposed and less-exposed groups before start of neck pain we were able to calculate Incident Rate ratios for various exposures. RESULTS: Forty nine percent of the forklift operators reported having experienced neck pain compared to 30 % of office workers. Being a forklift operator was associated with an increased risk of neck pain (OR = 5.1, 95% CI 1.4-18.2). Holding the head in an unnatural position resulted in significantly increased risks for neck pain, irrespective of type of position. The risks for neck pain remained after taking other ergonomic exposures and psychosocial aspects into consideration. CONCLUSIONS: This is the first published study showing that forklift operators have an increased risk of neck pain. The results are therefore of significance for improving work schedules, the adjustment of work tasks for these workers and the design of the vehicles. PMID- 29426320 TI - Supporting play exploration and early developmental intervention versus usual care to enhance development outcomes during the transition from the neonatal intensive care unit to home: a pilot randomized controlled trial. AB - BACKGROUND: While therapy services may start in the Neonatal Intensive Care Unit (NICU) there is often a gap in therapy after discharge. Supporting Play Exploration and Early Development Intervention (SPEEDI) supports parents, helping them build capacity to provide developmentally supportive opportunities starting in the NICU and continuing at home. The purpose of this single blinded randomized pilot clinical trial was to evaluate the initial efficacy of SPEEDI to improve early reaching and exploratory problem solving behaviors. METHODS: Fourteen infants born very preterm or with neonatal brain injury were randomly assigned to SPEEDI or Usual Care. The SPEEDI group participated in 5 collaborative parent, therapist, and infant interventions sessions in the NICU (Phase 1) and 5 at home (Phase 2). Parents provided daily opportunities designed to support the infants emerging motor control and exploratory behaviors. Primary outcome measures were assessed at the end of the intervention, 1 and 3 months after the intervention ended. Reaching was assessed with the infant supported in an infant chair using four 30 s trials. The Early Problem Solving Indicator was used to evaluate the frequency of behaviors during standardized play based assessment. Effect sizes are including for secondary outcomes including the Test of Infant Motor Performance and Bayley Scales of Infant and Toddler Development. RESULTS: No group differences were found in the duration of toy contact. There was a significant group effect on (F1,8 = 4.04, p = 0.08) early exploratory problem solving behaviors with infants in the SPEEDI group demonstrating greater exploration with effect sizes of 1.3, 0.6, and 0.9 at the end of the intervention, 1 and 3 months post-intervention. CONCLUSIONS: While further research is needed, this initial efficacy study showed promising results for the ability of SPEEDI to impact early problem solving behaviors at the end of intervention and at least 3 months after the intervention is over. While reaching did not show group differences, a ceiling effect may have contributed to this finding. This single blinded pilot RCT was registered prior to subject enrollment on 5/27/14 at ClinicalTrials.Gov with number NCT02153736. PMID- 29426321 TI - Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade. AB - BACKGROUND: Autoinflammatory disorders are distinguished by seemingly random episodes of systemic hyperinflammation, driven in particular by IL-1. Recent pre clinical work has shown a key role for IL-1 in epilepsy in animal models, and therapies for autoinflammation including IL-1 blockade are proposed for refractory epilepsy. CASE PRESENTATION: Here, we report an adolescent female with signs of persistent systemic inflammation and epilepsy unresponsive to multiple anti-epileptic drugs (AED). She was diagnosed with generalized epilepsy with a normal brain MRI and an electroencephalogram (EEG) showing occasional generalized spike and slow wave discharges. Her diagnostic evaluation showed no signs of autoimmunity or genetic causes of epilepsy or periodic fever syndromes but persistently elevated serum inflammatory markers including S100 alarmin proteins. She experienced prompt clinical response to IL-1 blockade with first anakinra and then canakinumab, with near complete resolution of clinical seizures. Additionally, she displayed marked improvements in quality of life and social/academic functioning. Baseline gene expression studies on peripheral blood mononuclear cells (PBMC) from this patient showed significantly activated gene pathways suggesting systemic immune activation, including focal adhesion, platelet activation, and Rap1 signaling, which is an upstream regulator of IL 1beta production by the NLRP3 inflammasome. It also showed activation of genes that characterize inflammasome-mediated autoinflammatory disorders and no signs of interferon activation. This gene expression signature was largely extinguished after anakinra treatment. CONCLUSIONS: Together, these findings suggest that patients with epilepsy responsive to immune modulation may have distinct autoinflammatory features supporting IL-1 blockade. As such, IL-1 blockade may be highly efficacious adjunctive medication for certain refractory epilepsy syndromes. PMID- 29426322 TI - Whether vitamin D was associated with clinical outcome after IVF/ICSI: a systematic review and meta-analysis. AB - BACKGROUND: There exist contradictive views on whether the vitamin D has association with clinical outcome of in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). The present meta-analysis aim to establish whether vitamin D was associated with clinical outcomes of IVF/ICSI. METHODS: MEDLINE, Google Scholar and the Cochrane Library from database inception to March 2017 were searched. Clinical studies, which evaluated the association of vitamin D level and the clinical outcomes after IVF/ICSI, were included. The Main Outcome Measures were clinical pregnancy, ongoing pregnancy, and live birth. RESULTS: In the analysis of clinical pregnancy, 9 cohort studies were included. Of which, 2 studies and 3 studies were identified in analyzing ongoing pregnancy and live birth, respectively. Meta-analysis showed trends toward lower clinical pregnancy [RR 0.91, (95% CI 0.77-1.07)] and higher ongoing pregnancy [RR 1.06, (95% CI 0.95-1.19)] for women with deficient level of vitamin D. The probability of live birth for women with deficient level of vitamin D was significantly lower than cases with sufficient level of vitamin D [RR 0.74, (95% CI 0.58-0.90)]. CONCLUSIONS: Deficient vitamin D was associated with decreased probability of live birth after IVF/ICSI. So vitamin D should be supplied to women with deficient level vitamin D. PMID- 29426323 TI - Assessment of grief-related rumination: validation of the German version of the Utrecht Grief Rumination Scale (UGRS). AB - BACKGROUND: Bereavement can result in severe mental health problems, including persistent, severe and disabling grief symptoms, termed complicated grief. Grief rumination (i.e., repetitive thought about the causes and consequences of the loss) is a malleable cognitive risk-factor in adjustment to bereavement. The Utrecht Grief Rumination Scale (UGRS) was recently developed to assess grief rumination. The present study aimed to develop and validate a German version of the UGRS. METHODS: An online survey including measures of demographic and loss related variables, grief rumination (UGRS), depressive rumination (brooding and reflection), and symptoms of depression, anxiety, and complicated grief, was administered online among 159 persons (87% women) who had lost a first-degree relative in the past three years. UGRS item analyses, a confirmatory factor analysis and associations of grief rumination with brooding, reflection and symptom levels were performed. RESULTS: The internal consistency of the UGRS was good. The confirmatory factor analysis obtained a good fit for a model with five correlated grief rumination subscales. The UGRS contributed uniquely to the prediction of complicated grief symptoms even when controlling for symptoms of anxiety and depression, brooding, reflection, and demographic and loss-related variables. Discriminant validity of the UGRS was demonstrated by the fact that higher UGRS scores were found in participants with a higher likelihood of receiving a diagnosis of complicated grief (d > 1.60). CONCLUSION: The translated UGRS showed very good psychometric properties and the correlations with maladaptive ruminative styles and complicated grief symptoms demonstrated the clinical relevance of grief rumination. Limitations concerning generalisability of the results are discussed. PMID- 29426325 TI - A research utilisation framework for informing global health and development policies and programmes. AB - A shift in the culture and practice of health and development research is required to maximise the real-world use of evidence by non-academic or non research-oriented audiences. Many frameworks have been developed to guide and measure the research utilisation process, yet none have been widely applied. Some frameworks are simplified to an unrealistic linear representation while others are rendered overly complex and unusable in an attempt to capture all aspects of the research utilisation process. Additionally, many research utilisation frameworks have focused on the policy development process or within a clinical setting, with less application of the translation process at the programme level. In response to this gap - and drawing from over a decade of experience implementing research utilisation strategies - we developed a simple, four-phase framework to guide global health and development efforts that seek to apply evidence to policies and programmes. We present a detailed description of each phase in our framework, with examples of its relevance and application illustrated through our own case study experiences in global health. We believe the utility of this framework extends beyond the health sector and is relevant for maximising use of evidence to achieve the Sustainable Development Goals. PMID- 29426324 TI - Role of parental and environmental characteristics in toddlers' physical activity and screen time: Bayesian analysis of structural equation models. AB - BACKGROUND: Guided by the Socialization Model of Child Behavior (SMCB), this cross-sectional study examined direct and indirect associations of parental cognitions and behavior, the home and neighborhood environment, and toddlers' personal attributes with toddlers' physical activity and screen time. METHODS: Participants included 193 toddlers (1.6 +/- 0.2 years) from the Parents' Role in Establishing healthy Physical activity and Sedentary behavior habits (PREPS) project. Toddlers' screen time and personal attributes, physical activity- or screen time-specific parental cognitions and behaviors, and the home and neighborhood environment were measured via parental-report using the PREPS questionnaire. Accelerometry-measured physical activity was available in 123 toddlers. Bayesian estimation in structural equation modeling (SEM) using the Markov Chain Monte Carlo algorithm was performed to test an SMCB hypothesized model. Covariates included toddlers' age, sex, race/ethnicity, main type of childcare, and family household income. RESULTS: In the SMCB hypothesized screen time model, higher parental barrier self-efficacy for limiting toddlers' screen time was associated with higher parental screen time limiting practices (beta = 0.451), while higher parental negative outcome expectations for limiting toddlers' screen time was associated with lower parental screen time limiting practices (beta = - 0.147). In turn, higher parental screen time limiting practices was associated with lower screen time among toddlers (beta = - 0.179). Parental modeling of higher screen time was associated with higher screen time among toddlers directly (beta = 0.212) and indirectly through the home environment. Specifically, higher screen time among parents was associated with having at least one electronic device in toddlers' bedrooms (beta = 0.146) and, in turn, having electronics in the bedroom, compared to none, was associated with higher screen time among toddlers (beta = 0.250). Neighborhood safety was not associated with toddlers' screen time in the SEM analysis. No significant correlations were observed between the SMCB variables and toddlers' physical activity; thus, no further analyses were performed for physical activity. CONCLUSIONS: Parents and their interactions with the home environment may play an important role in shaping toddlers' screen time. Findings can inform family-based interventions aiming to minimize toddlers' screen time. Future research is needed to identify correlates of toddlers' physical activity. PMID- 29426326 TI - Remote photoplethysmography with constrained ICA using periodicity and chrominance constraints. AB - BACKGROUND: Remote photoplethysmography (rPPG) has been in the forefront recently for measuring cardiac pulse rates from live or recorded videos. It finds advantages in scenarios requiring remote monitoring, such as medicine and fitness, where contact based monitoring is limiting and cumbersome. The blood volume pulse, defined as the pulsative flow of arterial blood, gives rise to periodic changes in the skin color which are then quantified to estimate a temporal signal. This temporal signal can be analysed using various methods to extract the representative cardiac signal. METHODS: We present a novel method for measuring rPPG signals using constrained independent component analysis (cICA). We incorporate a priori information into the cICA algorithm to aid in the extraction of the most prominent rPPG signal. This a priori information is implemented using two constraints: first, based on periodicity using autocorrelation, and second, a chrominance-based constraint exploiting the physical characteristics of the skin. RESULTS AND CONCLUSION: Our method showed improved performances over traditional blind source separation methods like ICA and chrominance based methods with mean absolute errors of 0.62 beats per minute (BPM) and 3.14 BPM for the two datasets in our inhouse video database UBFC-RPPG, and 4.69 BPM for the public MMSE-HR dataset. Its performance was also better in comparison to other state of the art methods in terms of accuracy and robustness. Our UBFC-RPPG database is also made publicly available and is specifically aimed towards testing rPPG measurements. PMID- 29426327 TI - Porphyromonas gingivalis lipopolysaccharide induces cognitive dysfunction, mediated by neuronal inflammation via activation of the TLR4 signaling pathway in C57BL/6 mice. AB - BACKGROUND: Porphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS) is one of the major pathogenic factors of chronic periodontitis (CP). Few reports on the correlation between P. gingivalis-LPS and cognitive function exist. Thus, the present study aimed to investigate the effects of P. gingivalis-LPS on cognitive function and the associated underlying mechanism in C57BL/6 mice. METHODS: The C57BL/6 mice were injected with P. gingivalis-LPS (5 mg kg-1) either with or without Toll-like receptor 4 (TLR4) inhibitor (TAK-242, 5 mg kg-1). After 7 days, behavioral alterations were assessed with the open field test (OFT), Morris water maze (MWM) test, and passive avoidance test (PAT). The activation of astrocytes and microglia in the cerebral cortex and hippocampus of mice was observed by immunohistochemistry. The expression of inflammatory cytokines (TNF-alpha, IL 1beta, IL-6, and IL-8), TLRs (TLR2, TLR3, and TLR4), and CD14 and the activation of the NF-kappaB signaling pathway (IRAK1, p65, and p-p65) in the cerebral cortex of the mice were evaluated by RT-PCR, ELISA, and western blot. RESULTS: The OFT showed that P. gingivalis-LPS did not affect the initiative and activity of mice. Administration of P. gingivalis-LPS significantly impaired spatial learning and memory during the MWM test and attenuated the ability of passive avoidance learning during the PAT. Both astrocytes and microglia were activated in the cortex and hippocampus. The messenger RNA (mRNA) and protein expression of inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-8) was upregulated by P. gingivalis-LPS in the cortex. In addition, the TLR4/NF-kappaB signaling pathway was activated (TLR4, CD14, IRAK1, and p-p65). These effects were effectively alleviated by TAK-242. CONCLUSIONS: Administration of P. gingivalis LPS can lead to learning and memory impairment in C57BL/6 mice. This impairment is mediated by activation of the TLR4 signaling pathway. Our study suggests that P. gingivalis-LPS-induced neuroinflammation plays an important role in cognitive impairment. It also reveals that endotoxins of periodontal pathogens could represent a risk factor for cognitive disorders. PMID- 29426328 TI - Feasibility and acceptability of a beverage intervention for Hispanic adults: a protocol for a pilot randomized controlled trial. AB - BACKGROUND: In the U.S., Hispanics have among the highest rates of overweight and obesity when compared to other racial/ethnic groups placing them at a greater risk for obesity-related disease. Identifying intervention strategies to reduce caloric intake and/or improve cardiometabolic health in Hispanics is critical to reducing morbidity and mortality among this large and growing population. Evidence exists to support diet-specific behavioral interventions, including beverage modifications, in reducing obesity-related health risks. However, the acceptability and feasibility of a beverage intervention in obese Hispanic adults has not been robustly evaluated. METHODS: The objective of this pilot study is to assess the feasibility and acceptability of a randomized, controlled beverage intervention in 50 obese Hispanic adults ages 18-64 over 8-weeks. Eligible participants were obese (30-50.0 kg/m2), between the ages 18-64, self-identified as Hispanic, and were able to speak, read, and write in either English and/or Spanish. Study recruitment was completed August 2017. Upon the completion of baseline assessments, participants will be randomized to either Mediterranean lemonade, Green Tea, or flavored water control. After completing a 2-week washout period, participants will be asked to consume 32 oz. per day of study beverage for 6-weeks while avoiding all other sources of tea, lemonade, citrus, juice, and other sweetened beverages; water is permissible. Primary outcomes will be recruitment, retention, and acceptability of the intervention strategies. Our study will also evaluate participant-reported tolerance and as an exploratory aim, assess safety/toxicity-related to renal and/or liver function. Fasting blood samples will be collected at baseline and 8-weeks to assess the primary efficacy outcomes: total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). Secondary outcomes include fasting glucose, hemoglobin A1c (HbA1c), and high-sensitivity C-reactive protein (hs-CRP). DISCUSSION: This pilot study will provide important feasibility, safety, and early efficacy data necessary to design a larger, adequately-powered randomized controlled trial. TRIAL REGISTRATION: NCT02911753 ( ClinicalTrials.gov ). Registered September 19, 2016. Last updated November 1, 2017. PMID- 29426330 TI - Molecular evidence for relapse of an imported Plasmodium ovale wallikeri infection. AB - BACKGROUND: Malaria caused by Plasmodium ovale spp. has been neglected by and large from research and has received only little scientific attention during the past decades. Ovale malaria is considered to feature relapses by liver hypnozoites although scientific evidence for this paradigm is scarce. CASE PRESENTATION: Here, the case of a 16-year-old male, who presented with fevers to the outpatient department in Vienna, Austria, after travelling to Uganda and Papua New Guinea is described. Infection with Plasmodium malariae was diagnosed by microscopy and the patient was treated accordingly with a full course of supervised artemether-lumefantrine. He was discharged in good clinical condition with a negative blood smear. One month after initial diagnosis, he returned complaining of fever. Thick blood smear was positive again for malaria parasites, which were confirmed as P. ovale wallikeri by PCR. Retrospective analysis revealed the identical Plasmodium spp. in the initial blood samples. Molecular analysis of various gene loci (nuclear porbp2, 18S rRNA and potra genes) gave identical results providing further evidence for relapse by an identical parasite genotype. Consecutively, the patient was retreated with artemether-lumefantrine and received a regimen of primaquine according to WHO guidelines. CONCLUSION: Conclusive evidence for relapses with P. ovale spp. is rare. The presented case provides convincing confirmation for the relapse paradigm based on re-appearing parasitaemia following supervised treatment in a non-endemic region with a parasite strain of identical genotype. PMID- 29426329 TI - Efficacy comparison of transcervical video-assisted mediastinoscopic lymphadenectomy combined with left transthoracic esophagectomy versus right transthoracic esophagectomy for esophageal cancer treatment. AB - BACKGROUND: This study aimed to propose a new surgical strategy, i.e., the transcervical video-assisted mediastinoscopic lymphadenectomy (VAMLA) with esophagectomy via the left transthoracic approach for patients with esophageal cancer (EC), and to compare the outcomes with those of esophagectomy via the right thoracic approach. METHODS: From December 2014 to March 2016, 49 cases were enrolled in this non-randomized concurrent control study. Twenty-eight patients with EC who underwent transcervical VAMLA with esophagectomy via the left transthoracic approach were assigned into the study group, while 21 EC patients undergoing esophagectomy via the right transthoracic approach during the same period were enrolled into the control group. Operative outcomes including operative time, the numbers of removed lymph nodes, intraoperative blood loss, the length of hospital stay, and postoperative complications in both groups were evaluated and compared. RESULTS: There were no significant differences in the baseline profiles between the two groups, and all patients in the two groups successfully underwent the surgery. There was a significant difference between transcervical VAMLA with esophagectomy via the left thoracic approach and esophagectomy via the right thoracic approach with regard to the number of all dissected lymph nodes [(29.0 +/- 8.7) vs. (17.8 +/- 8.1), p < 0.05], dissected superior mediastinal lymph nodes [(11.2 +/- 5.0) vs. (3.7 +/- 2.9), p < 0.05], and dissected in the recurrent laryngeal nerve lymph nodes [(5.6 +/- 3.5) vs. (2.3 +/- 2.1), p < 0.05]. No significant differences were observed in the operative time, intraoperative blood loss, length of postoperative hospital stay, number of dissected abdominal lymph nodes, postoperative pulmonary complications (pneumonia and atelectasis), anastomotic fistula, chylothorax, and vocal cord paralysis (p > 0.05). CONCLUSION: Transcervical VAMLA combined with esophagectomy via the left thoracic approach appears technically feasible and safe and shows advantages in the number of dissected superior mediastinal lymph nodes, suggesting that it may serve as a new treatment option for patients with esophageal carcinoma. PMID- 29426331 TI - Body size perceptions and preferences favor overweight in adult Saharawi refugees. AB - BACKGROUND: Culture affects body image and body size perceptions from an early age and in many African countries, overweight has been associated with richness, health, strength, and fertility. The present study investigated body size perceptions and preferences in an African refugee population. METHODS: The cross sectional study was comprised of 180 and 175 randomly selected Saharawi women and men, respectively, between 18 and 80 years. Stunkard's body figure scale was used to identify self-perceived body size, desired body size and desired body size in the opposite gender. RESULTS: Approximately half of the participants had a correct self-perceived body size; among them 70% did not have a desire to have a smaller body size. Among women who preferred a body size corresponding to overweight in men, 77% also had a desired body size corresponding to overweight; compared to 43% for men. The youngest participants (18-25 years) were the least likely to overestimate their body size in comparison to the older participants (26-45 years and 46-80 years). CONCLUSION: We found an overall preference for an overweight body size, and a significant difference in body size perception associated with age. PMID- 29426332 TI - Active listing and more consultations in primary care are associated with reduced hospitalisation in a Swedish population. AB - BACKGROUND: Healthcare systems are complex networks where relationships affect outcomes. The importance of primary care increases while health care acknowledges multimorbidity, the impact of combinations of different diseases in one person. Active listing and consultations in primary care could be used as proxies of the relationships between patients and primary care. Our objective was to study hospitalisation as an outcome of primary care, exploring the associations with active listing, number of consultations in primary care and two groups of practices, while taking socioeconomic status and morbidity burden into account. METHODS: A cross-sectional study using zero-inflated negative binomial regression to estimate odds of any hospital admission and mean number of days hospitalised for the population over 15 years (N = 123,168) in the Swedish county of Blekinge during 2007. Explanatory factors were listed as active or passive in primary care, number of consultations in primary care and primary care practices grouped according to ownership. The models were adjusted for sex, age, disposable income, education level and multimorbidity level. RESULTS: Mean days hospitalised was 0.94 (95%CI 0.90-0.99) for actively listed and 1.32 (95%CI 1.24-1.40) for passively listed. For patients with 0-1 consultation in primary care mean days hospitalised was 1.21 (95%CI 1.13-1.29) compared to 0.77 (95%CI 0.66-0.87) days for patients with 6-7 consultations. Mean days hospitalised was 1.22 (95%CI 1.16 1.28) for listed in private primary care and 0.98 (95%CI 0.94-1.01) for listed in public primary care, with odds for hospital admission 0.51 (95%CI 0.39-0.63) for public primary care compared to private primary care. CONCLUSIONS: Active listing and more consultations in primary care are both associated with reduced mean days hospitalised, when adjusting for socioeconomic status and multimorbidity level. Different odds of any hospitalisation give a difference in mean days hospitalised associated with type of primary care practice. To promote well performing primary care to maintain good relationships with patients could reduce mean days hospitalised. PMID- 29426333 TI - Contraceptive use and pregnancy rates among women receiving antiretroviral therapy in Malawi: a retrospective cohort study. AB - BACKGROUND: In 2011, family planning (FP) services were integrated at Martin Preuss Centre (MPC), in urban Lilongwe, Malawi. To date, no previous study evaluated pregnancy rates among HIV-positive women after the integration of FP services into HIV care at the facility. In this study, we investigated whether integration of FP services into HIV clinical care led to increased use of contraceptives and decreased pregnancy rates. METHODS: This was a retrospective cohort analysis of HIV-positive women from 15 to 49 years of age who accessed antiretroviral therapy (ART) services at MPC. Ascertainment of FP needs, contraceptive methods and pregnancy status were done at ART initiation, and at each ART follow-up visit. Women were offered a wide range of contraceptive methods. Outcomes of interest were contraceptive use and rate of pregnancy. Incident pregnancy was ascertained through patient self-reports during clinic consultation. Trends of contraceptive use and pregnancy rates were analyzed using chi-square (chi2). RESULTS: A total of 10,472 women were included in the analysis and contributed 15,700 person-years of observation. Contraceptive use among all women receiving ART increased from 28% in 2012 to 62% in 2016 (p < 0.001). A total of 501 pregnancies occurred, including 13 multiple pregnancies, resulting in an overall pregnancy rates of 3.2 per 100 person-years. Rates of pregnancy decreased from 6.8 per 100 person-years in 2012 to 1.3 per 100 person-years in 2016 (p < 0.001). CONCLUSION: Integration of FP services into HIV care resulted in increased contraceptive use and, subsequently, decreased pregnancy rates in women receiving ART. HIV programs should consider offering FP services to women who are receiving ART. PMID- 29426334 TI - Modelling the cost differential between healthy and current diets: the New Zealand case study. AB - BACKGROUND: Evidence on whether healthy diets are more expensive than current diets is mixed due to lack of robust methodology. The aim of this study was to develop a novel methodology to model the cost differential between healthy and current diets and apply it in New Zealand. METHODS: Prices of common foods were collected from 15 supermarkets, 15 fruit/vegetable stores and from the Food Price Index. The distribution of the cost of two-weekly healthy and current household diets was modelled using a list of commonly consumed foods, a set of min and max quantity/serves constraints for each, and food group and nutrient intakes based on dietary guidelines (healthy diets) or nutrition survey data (current diets). The cost differential between healthy and current diets was modelled for several diet, prices and policy scenarios. Acceptability of resulting meal plans was validated. RESULTS: The average cost of healthy household diets was $27 more expensive than the average cost of current diets, but 25.8% of healthy diets were cheaper than the average cost of current diets. This cost differential could be reduced if fruits and vegetables became exempt from Goods and Services Tax. Healthy diets were cheaper with an allowance for discretionary foods and more expensive when including takeaway meals. For Maori and Pacific households, healthy diets were on average $40 and $60 cheaper than current diets due to large energy intakes. Discretionary foods and takeaway meals contributed 30-40% to the average cost of current diets. CONCLUSION: Healthy New Zealand diets were on average more expensive than current diets, but one-quarter of healthy diets were cheaper than the average cost of current diets. The impact of diet composition, types of prices and policies on the cost differential was substantial. The methodology can be used in other countries to monitor the cost differential between healthy and current household diets. PMID- 29426335 TI - Oral recombinant Lactobacillus vaccine targeting the intestinal microfold cells and dendritic cells for delivering the core neutralizing epitope of porcine epidemic diarrhea virus. AB - BACKGROUND: Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus (PEDV) has led to serious economic losses to the swine industry worldwide. In this study, an oral recombinant Lactobacillus casei vaccine against PEDV infection targeting the intestinal microfold (M) cells and dendritic cells (DCs) for delivering the core neutralizing epitope (COE) of PEDV spike protein was developed with M cell-targeting peptide (Col) and dendritic cell-targeting peptide (DCpep). The immunogenicity of the orally administered recombinant strains was evaluated. RESULTS: After immunization, significantly higher levels of anti-PEDV specific IgG antibodies with PEDV neutralizing activity in the sera and mucosal sIgA antibodies in the tractus genitalis, intestinal mucus, and stools were detected in mice orally administered with the recombinant strain pPG COE-Col-DCpep/L393, which expressed DCpep and Col targeting ligands fused with the PEDV COE antigen, compared to mice orally immunized with the recombinant strain pPG-COE/L393 without the DCpep and Col targeting ligands. Moreover, in response to restimulation with the PEDV COE antigen in vitro, a significant difference in splenocyte proliferation response and Th2-associated cytokine IL-4 level was observed in the group of mice orally immunized with pPG-COE-Col DCpep/L393 (p < 0.05) compared to the groups of mice that received pPG-COE Col/L393 and pPG-COE-DCpep/L393, respectively. CONCLUSIONS: The intestinal M cells- and DCs-targeting oral delivery of genetically engineered Lactobacillus expressing the COE antigen of PEDV can efficiently induce anti-PEDV mucosal, humoral, and cellular immune responses via oral administration, suggesting a promising vaccine strategy against PEDV infection. PMID- 29426336 TI - Salidroside provides neuroprotection by modulating microglial polarization after cerebral ischemia. AB - BACKGROUND: Following stroke, microglia can be driven to the "classically activated" pro-inflammatory (M1) phenotype and the "alternatively activated" anti inflammatory (M2) phenotype. Salidroside (SLDS) is known to inhibit inflammation and to possess protective effects in neurological diseases, but to date, the exact mechanisms involved in these processes after stroke have yet to be elucidated. The purpose of this study was to determine the effects of SLDS on neuroprotection and microglial polarization after stroke. METHODS: Male adult C57/BL6 mice were subjected to focal transient cerebral ischemia followed by intravenous SLDS injection. The optimal dose was determined by evaluation of cerebral infarct volume and neurological functions. RT-PCR and immunostaining were performed to assess microglial polarization. A transwell system and a direct contact coculture system were used to elucidate the effects of SLDS-induced microglial polarization on oligodendrocyte differentiation and neuronal survival. RESULTS: SLDS significantly reduced cerebral infarction and improved neurological function after cerebral ischemia. SLDS treatment reduced the expression of M1 microglia/macrophage markers and increased the expression of M2 microglia/macrophage markers after stroke and induced primary microglia from M1 phenotype to M2 phenotype. Furthermore, SLDS treatment enhanced microglial phagocytosis and suppressed microglial-derived inflammatory cytokine release. Cocultures of oligodendrocytes and SLDS-treated M1 microglia resulted in increased oligodendrocyte differentiation. Moreover, SLDS protected neurons against oxygen glucose deprivation by promoting microglial M2 polarization. CONCLUSIONS: These data demonstrate that SLDS protects against cerebral ischemia by modulating microglial polarization. An understanding of the mechanisms involved in SLDS-mediated microglial polarization may lead to new therapeutic opportunities after stroke. PMID- 29426338 TI - Arachidonic acid induces macrophage cell cycle arrest through the JNK signaling pathway. AB - BACKGROUND: Arachidonic acid (AA) has potent pro-apoptotic effects on cancer cells at a low concentration and on macrophages at a very high concentration. However, the effects of AA on the macrophage cell cycle and related signaling pathways have not been fully investigated. Herein we aim to observe the effect of AA on macrophages cell cycle. RESULTS: AA exposure reduced the viability and number of macrophages in a dose- and time-dependent manner. The reduction in RAW264.7 cell viability was not caused by apoptosis, as indicated by caspase-3 and activated caspase-3 detection. Further research illustrated that AA exposure induced RAW264.7 cell cycle arrested at S phase, and some cell cycle-regulated proteins were altered accordingly. Moreover, JNK signaling was stimulated by AA, and the stimulation was partially reversed by a JNK signaling inhibitor in accordance with cell cycle-related factors. In addition, nuclear and total Foxo1/3a and phosphorylated Foxo1/3a were elevated by AA in a dose- and time dependent manner, and this elevation was suppressed by the JNK signaling inhibitor. CONCLUSION: Our study demonstrated that AA inhibits macrophage viability by inducing S phase cell cycle arrest. The JNK signaling pathway and the downstream FoxO transcription factors are involved in AA-induced RAW264.7 cell cycle arrest. PMID- 29426337 TI - Non-coding RNAs and retroviruses. AB - Retroviruses can cause severe diseases such as cancer and acquired immunodeficiency syndrome. A unique feature in the life cycle of retroviruses is that their RNA genome is reverse transcribed into double-stranded DNA, which then integrates into the host genome to exploit the host machinery for their benefits. The metazoan genome encodes numerous non-coding RNAs (ncRNA), which act as key regulators in essential cellular processes such as antiviral response. The development of next-generation sequencing technology has greatly accelerated the detection of ncRNAs from viruses and their hosts. ncRNAs have been shown to play important roles in the retroviral life cycle and virus-host interactions. Here, we review recent advances in ncRNA studies with special focus on those have changed our understanding of retroviruses or provided novel strategies to treat retrovirus-related diseases. Many ncRNAs such as microRNAs (miRNAs) and long non coding RNAs (lncRNAs) are involved in the late phase of the retroviral life cycle. However, their roles in the early phase of viral replication merit further investigations. PMID- 29426339 TI - Telephone health services in the field of rare diseases: a qualitative interview study examining the needs of patients, relatives, and health care professionals in Germany. AB - BACKGROUND: Rare diseases are, by definition, very serious and chronic diseases with a high negative impact on quality of life. Approximately 350 million people worldwide live with rare diseases. The resulting high disease burden triggers health information search, but helpful, high-quality, and up-to-date information is often hard to find. Therefore, the improvement of health information provision has been integrated in many national plans for rare diseases, discussing the telephone as one access option. In this context, this study examines the need for a telephone service offering information for people affected by rare diseases, their relatives, and physicians. METHODS: In total, 107 individuals participated in a qualitative interview study conducted in Germany. Sixty-eight individuals suffering from a rare disease or related to somebody with rare diseases and 39 health care professionals took part. Individual interviews were conducted using a standardized semi-structured questionnaire. Interviews were analysed using the qualitative content analysis, triangulating patients, relatives, and health care professionals. The fulfilment of qualitative data processing standards has been controlled for. RESULTS: Out of 68 patients and relatives and 39 physicians, 52 and 18, respectively, advocated for the establishment of a rare diseases telephone service. Interviewees expected a helpline to include expert staffing, personal contact, good availability, low technical barriers, medical and psychosocial topics of counselling, guidance in reducing information chaos, and referrals. Health care professionals highlighted the importance of medical topics of counselling-in particular, differential diagnostics-and referrals. CONCLUSIONS: Therefore, the need for a national rare diseases helpline was confirmed in this study. Due to limited financial resources, existing offers should be adapted in a stepwise procedure in accordance with the identified attributes. PMID- 29426340 TI - PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validation metrics. AB - BACKGROUND: The programmed death receptor 1 (PD-1) protein is a cell-surface receptor on certain lymphocytes that, with its ligand programmed death ligand 1 (PD-L1), helps to down-regulate immune responses. Many cancer types express PD-L1 and evade immune recognition via the PD-1/PD-L1 interaction. Precision therapies targeting the PD-1/PD-L1 pathway have the potential to improve response and thereby offer a novel treatment avenue to some patients with cancer. However, this new therapeutic approach requires reliable methods for identifying patients whose cancers are particularly likely to respond. Therefore, we conducted a systematic literature review assessing evidence on test validation and scoring algorithms for PD-L1 immunohistochemistry (IHC) tests that might be used to select potentially responsive patients with bladder/urothelial cell, lung, gastric, or ovarian cancers for immunotherapy treatment. METHODS AND RESULTS: To identify evidence on commercially available PD-L1 IHC assays, we systematically searched MEDLINE and Embase for relevant studies published between January 2010 and September 2016 and appraised abstracts from recent oncology conferences (January 2013 to November 2016). Publications that met the predefined inclusion criteria were extracted and key trends summarized. In total, 26 eligible primary studies were identified, all of which reported on the test validation metrics associated with PD-L1 IHC tests in lung cancer, most using immunohistochemistry testing. There was significant heterogeneity among the available tests for PD-L1. Specifically, no definitive cutoff for PD-L1 positivity was identifiable, with more than one threshold being reported for most antibodies. Studies also differed as to whether they evaluated tumor cells only or tumor cells and tumor infiltrating immune cells. However, all of the tests developed and validated to support a therapeutic drug in the context of phase 2-3 clinical trials reported more than 90% inter-reader concordance. In contrast, other PD-L1 antibodies identified in the literature reported poorer concordance. CONCLUSIONS: Published validation metric data for PD-L1 tests are mainly focused on immunohistochemistry tests from studies in lung cancer. The variability in test cutoffs and standards for PD-L1 testing suggests that there is presently no standardized approach. This current variability may have implications for the uptake of precision treatments. PMID- 29426341 TI - Navigating the sustainability landscape: a systematic review of sustainability approaches in healthcare. AB - BACKGROUND: Improvement initiatives offer a valuable mechanism for delivering and testing innovations in healthcare settings. Many of these initiatives deliver meaningful and necessary changes to patient care and outcomes. However, many improvement initiatives fail to sustain to a point where their full benefits can be realised. This has led many researchers and healthcare practitioners to develop frameworks, models and tools to support and monitor sustainability. This work aimed to identify what approaches are available to assess and influence sustainability in healthcare and to describe the different perspectives, applications and constructs within these approaches to guide their future use. METHODS: A systematic review was carried out following PRISMA guidelines to identify publications that reported approaches to support or influence sustainability in healthcare. Eligibility criteria were defined through an iterative process in which two reviewers independently assessed 20% of articles to test the objectivity of the selection criteria. Data were extracted from the identified articles, and a template analysis was undertaken to identify and assess the sustainability constructs within each reported approach. RESULTS: The search strategy identified 1748 publications with 227 articles retrieved in full text for full documentary analysis. In total, 62 publications identifying a sustainability approach were included in this review (32 frameworks, 16 models, 8 tools, 4 strategies, 1 checklist and 1 process). Constructs across approaches were compared and 40 individual constructs for sustainability were found. Comparison across approaches demonstrated consistent constructs were seen regardless of proposed interventions, setting or level of application with 6 constructs included in 75% of the approaches. Although similarities were found, no approaches contained the same combination of the constructs nor did any single approach capture all identified constructs. From these results, a consolidated framework for sustainability constructs in healthcare was developed. CONCLUSIONS: Choosing a sustainability method can pose a challenge because of the diverse approaches reported in the literature. This review provides a valuable resource to researchers, healthcare professionals and improvement practitioners by providing a summary of available sustainability approaches and their characteristics. TRIAL REGISTRATION: This review was registered on the PROSPERO database: CRD42016040081 in June 2016. PMID- 29426342 TI - Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced esophageal squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to perform a dosimetric comparison between proton beam therapy (PBT) and photon radiation therapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were treated with PBT in our institution. In addition, we evaluated the correlation between toxicities and dosimetric parameters, especially the doses to normal lung or heart tissue, to clarify the clinical advantage of PBT over photon radiation therapy. METHODS: A total of 37 consecutive patients with Stage III thoracic ESCC who had received PBT with or without concurrent chemotherapy between October 2012 and December 2015 were evaluated in this study. The dose distributions of PBT were compared with those of dummy 3-dimensional conformal radiation therapy (3DCRT) and Intensity Modulated Radiation Therapy (IMRT), focusing especially on the doses to organs at risk, such as normal lung and heart tissue. RESULTS: Of the 37 patients, the data from 27 patients were analyzed. Among these 27 patients, four patients (15%) developed grade 2 pericardial effusion as a late toxicity. None of the patients developed grade 3 or worse acute or late pulmonary and cardiac toxicities. When the dosimetric parameters between PBT and planned 3DCRT were compared, all the PBT domestic variables for the lung dose except for lung V10 GyE and V15 GyE were significantly lower than those for the dummy 3DCRT plans, and the PBT domestic variables for the heart dose were also significantly lower than those for the dummy 3DCRT plans. When the PBT and IMRT plans were compared, all the PBT domestic variables for the doses to the lung and heart were significantly lower than those for the dummy IMRT plans. Regarding the correlation between the grades of toxicities and the dosimetric parameters, no significant correlation was seen between the occurrence of grade 2 pericardial effusion and the dose to the heart. CONCLUSIONS: When the dosimetric parameters of the dose distributions for the treatment of patients with locally advanced stage III ESCC were compared between PBT and 3DCRT or IMRT, PBT enabled a significant reduction in the dose to the lung and heart, compared with 3DCRT or IMRT. PMID- 29426343 TI - Differences in MWCNT- and SWCNT-induced DNA methylation alterations in association with the nuclear deposition. AB - BACKGROUND: Subtle DNA methylation alterations mediated by carbon nanotubes (CNTs) exposure might contribute to pathogenesis and disease susceptibility. It is known that both multi-walled carbon nanotubes (MWCNTs) and single-walled carbon nanotubes (SWCNTs) interact with nucleus. Such, nuclear-CNT interaction may affect the DNA methylation effects. In order to understand the epigenetic toxicity, in particular DNA methylation alterations, of SWCNTs and short MWCNTs, we performed global/genome-wide, gene-specific DNA methylation and RNA-expression analyses after exposing human bronchial epithelial cells (16HBE14o- cell line). In addition, the presence of CNTs on/in the cell nucleus was evaluated in a label free way using femtosecond pulsed laser microscopy. RESULTS: Generally, a higher number of SWCNTs, compared to MWCNTs, was deposited at both the cellular and nuclear level after exposure. Nonetheless, both CNT types were in physical contact with the nuclei. While particle type dependency was noticed for the identified genome-wide and gene-specific alterations, no global DNA methylation alteration on 5-methylcytosine (5-mC) sites was observed for both CNTs. After exposure to MWCNTs, 2398 genes were hypomethylated (at gene promoters), and after exposure to SWCNTs, 589 CpG sites (located on 501 genes) were either hypo- (N = 493 CpG sites) or hypermethylated (N = 96 CpG sites). Cells exposed to MWCNTs exhibited a better correlation between gene promoter methylation and gene expression alterations. Differentially methylated and expressed genes induced changes (MWCNTs > SWCNTs) at different cellular pathways, such as p53 signalling, DNA damage repair and cell cycle. On the other hand, SWCNT exposure showed hypermethylation on functionally important genes, such as SKI proto-oncogene (SKI), glutathione S-transferase pi 1 (GTSP1) and shroom family member 2 (SHROOM2) and neurofibromatosis type I (NF1), which the latter is both hypermethylated and downregulated. CONCLUSION: After exposure to both types of CNTs, epigenetic alterations may contribute to toxic or repair response. Moreover, our results suggest that the observed differences in the epigenetic response depend on particle type and differential CNT-nucleus interactions. PMID- 29426344 TI - Implementation strategies to improve cervical cancer prevention in sub-Saharan Africa: a systematic review. AB - BACKGROUND: Developed countries, such as the USA, have achieved significant decreases in cervical cancer burden since the introduction of Pap smear-based programs in the 1960s. Due to implementation barriers and limited resources, many countries in sub-Saharan Africa (SSA) have been unable to attain such reductions. The purpose of this review is to evaluate implementation strategies used to improve the uptake and sustainability of cervical cancer prevention programs in SSA. METHODS: A reviewer (LJ) independently searched PubMed, Ovid/MEDLINE, Scopus, and Web of Science databases for relevant articles with the following search limits: English language, peer reviewed, and published between 1996 and 2017. The 4575 search results were screened for eligibility (CJ, LJ) to identify original research that empirically evaluated or tested implementation strategies to improve cervical cancer prevention in SSA. Fifty-three articles met criteria for inclusion in the final review. AA, CJ, and LJ abstracted the included articles for implementation-related content and evaluated them for risk of bias according to study design with the National Heart, Lung, and Blood Institute's (NHLBI) Quality Assessment Tools. Results were reported according to PRISMA guidelines. RESULTS: The 53 included studies are well represented among all sub Saharan regions: South (n = 16, 30.2%), West (n = 16, 30.2%), East (n = 14, 26.4%), and Middle (n = 7, 13.2%). There are 34 cross-sectional studies (64.2%), 10 pre-posttests (18.9%), 8 randomized control trials (15.1%), and one nonrandomized control trial (1.9%). Most studies are "fair" quality (n = 22, 41.5%). Visual inspection with acetic acid (VIA) (n = 19, 35.8%) was used as the main prevention method more frequently than HPV DNA/mRNA testing (n = 15, 28.3%), Pap smear (n = 13, 24.5%), and HPV vaccine (n = 9, 17.0%). Effectiveness of strategies to improve program implementation was measured using implementation outcomes of penetration (n = 33, 62.3%), acceptability (n = 15, 28.3%), fidelity (n = 14, 26.4%), feasibility (n = 8, 15.1%), adoption (n = 6, 11.3%), sustainability (n = 2, 3.8%), and cost (n = 1, 1.9%). Education strategies (n = 38, 71.7%) were used most often but have shown limited effectiveness. CONCLUSION: This systematic review highlights the need to diversify strategies that are used to improve implementation for cervical cancer prevention programs. While education is important, implementation science literature reveals that education is not as effective in generating change. There is a need for additional organizational support to further incentivize and sustain improvements in implementation. PMID- 29426345 TI - From Kisiizi to Baltimore: cultivating knowledge brokers to support global innovation for community engagement in healthcare. AB - BACKGROUND: Reverse Innovation has been endorsed as a vehicle for promoting bidirectional learning and information flow between low- and middle-income countries and high-income countries, with the aim of tackling common unmet needs. One such need, which traverses international boundaries, is the development of strategies to initiate and sustain community engagement in health care delivery systems. OBJECTIVE: In this commentary, we discuss the Baltimore "Community-based Organizations Neighborhood Network: Enhancing Capacity Together" Study. This randomized controlled trial evaluated whether or not a community engagement strategy, developed to address patient safety in low- and middle-income countries throughout sub-Saharan Africa, could be successfully applied to create and implement strategies that would link community-based organizations to a local health care system in Baltimore, a city in the United States. Specifically, we explore the trial's activation of community knowledge brokers as the conduit through which community engagement, and innovation production, was achieved. Cultivating community knowledge brokers holds promise as a vehicle for advancing global innovation in the context of health care delivery systems. As such, further efforts to discern the ways in which they may promote the development and dissemination of innovations in health care systems is warranted. TRIAL REGISTRATION: Trial Registration Number: NCT02222909 . Trial Register Name: Reverse Innovation and Patient Engagement to Improve Quality of Care and Patient Outcomes (CONNECT). Date of Trial's Registration: August 22, 2014. PMID- 29426346 TI - Correction to: Implementing goals of care conversations with veterans in VA long term care setting: a mixed methods protocol. AB - CORRECTION: The authors would like to correct errors in the original article [1] that may have lead readers to misinterpret the scope, evidence base and target population of VHA Handbook 1004.03 "Life-Sustaining Treatment (LST) Decisions: Eliciting, Documenting, and Honoring Patients' Values, Goals, and Preferences". PMID- 29426347 TI - Attitudes of sperm, egg and embryo donors and recipients towards genetic information and screening of donors. AB - BACKGROUND: Gamete and embryo donors undergo genetic screening procedures in order to maximise the health of donor-conceived offspring. In the era of genomic medicine, expanded genetic screening may be offered to donors for the purpose of avoiding transmission of harmful genetic mutations. The objective of this study was to explore the attitudes of donors and recipients toward the expanded genetic screening of donors. METHODS: Qualitative interview study with thematic analysis, undertaken in a tertiary fertility centre. Semi-structured in-depth qualitative interviews were conducted with eleven recipients and nine donors from three different cohorts (sperm, egg and embryo donors/recipients). RESULTS: Donors and recipients acknowledged the importance of genetic information and were comfortable with the existing level of genetic screening of donors. Recipients recognised some potential benefits of expanded genetic screening of donors; however both recipients and donors were apprehensive about extended genomic technologies, with concerns about how this information would be used and the ethics of genetic selectivity. CONCLUSION: Participants in donor programs support some level of genetic screening of donors, but are wary of expanding genetic screening beyond current levels. PMID- 29426348 TI - Effect and safety of acupuncture for Hwa-byung, an anger syndrome: a study protocol of a randomized controlled pilot trial. AB - BACKGROUND: Hwa-byung (HB) is an anger syndrome caused by an inadequate release of accumulated anger that leads to somatic and psychiatric symptoms. As HB results from long-term inadequately treated negative emotions, its symptoms are complex, intractable and concomitant with other psychiatric disorders. Therefore, studies aiming to develop effective and safe treatment options for HB are needed. We plan to conduct a pilot study for a future, full-scale, randomized controlled trial (RCT) of an optimal acupuncture procedure using semi-individualized acupuncture points that consider participants' personal disposition and type of emotional stress. METHOD/DESIGN: This randomized, sham-controlled, participant- and assessor-blinded pilot trial aims to determine the study feasibility of acupuncture for HB and to explore its clinical effects and safety. This clinical trial will be conducted with two groups: one treated with real acupuncture and the other with sham acupuncture for 10 sessions over 4 weeks. The experimental group (EG) will receive semi-individualized acupuncture, whereas the control group (CG) will receive sham acupuncture, namely minimal acupuncture on non acupuncture points. The recruitment, compliance, and completion rate and clinical evaluations, including a Visual Analogue Scale (VAS), the Korean version of the Beck Depression Inventory (BDI), the short form of the Stress Response Inventory (SRI-short form) and the Instrument of the Oriental Medical Evaluation for HB (IOME-HB), will be assessed to evaluate feasibility and possible effects and safety. Four weeks after completing treatment, follow-up assessments will be performed. DISCUSSION: As this is a pilot study mainly aiming to investigate trial feasibility, the results of this study will be analyzed descriptively and interpreted for the study purposes. Cohen's d will be reported to determine the effect of acupuncture for HB and to enable comparisons with other treatment methods. This protocol is significant in that it provides optimal semi individualized acupuncture treatment. We expect this study to offer information about the feasibility of this treatment and data about the possible effects and safety. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), Republic of Korea: KCT0001732 . Registered on 14 December 2015. PMID- 29426349 TI - Neurofibroma involving obturator nerve mimicking an adnexal mass: a rare case report and PRISMA-driven systematic review. AB - BACKGROUND: Pelvic masses are a common gynecologic problem, and majority of them are diagnosed as ovarian tumors finally. Sometimes, it is hard to distinguish the origin of these pelvic masses. The following case is a solitary neurofibroma arising from the right-side obturator nerve, which was impressed as a right-side ovarian tumor initially. We reported this case, and also performed a PRISMA driven systematic review to summary the similar cases in the literature. This review includes image, molecular and pathological findings and outcome of neurofibroma. CASE PRESENTATION: A 33-year-old woman with a regular menstrual period denied any symptoms or signs. During her physical check-up, image examination revealed a right-side heterogeneous pelvic mass; it was suggestive of a complex of right-side ovarian tumor. A provisional diagnosis of retroperitoneal pelvic mass, probably a benign ovarian tumor, was made. Excision of the right side pelvic mass was performed. We sent the specimens for frozen pathology, which indicated neurofibroma and lipomatous tumor and that the possibility of liposarcoma cannot be excluded. A segment of the obturator nerve was attached to the tumor and was severed. A right-side obturator nerve tear during tumor excision was observed, and a neurosurgeon was consulted for obturator nerve grafting and repair. The patient complained of mild weakness and paresthesia affecting the right leg, and we consulted a rehabilitation doctor for neuron injury. The patient's recovery was uneventful, and she was discharged eight days after the drain was removed. Further rehabilitation treatment was arranged. CONCLUSION: A neurofibroma is an uncommon pelvic retroperitoneal tumor, and it can be misdiagnosed as an adnexal mass. To our knowledge, this is a rare case of a solitary neurofibroma arising from the obturator nerve. It usually does not have any neurological deficit. We present this case to demonstrate that pelvic neurofibroma can be mistaken for an adnexal mass. This fact should be borne in mind during the diagnosis process. PMID- 29426350 TI - Effect of gelatin-polysuccinat on cerebral oxygenation and microcirculation in a porcine haemorrhagic shock model. AB - BACKGROUND: During early treatment of haemorrhagic shock maintenance of cerebral and end-organ oxygen supply by fluid resuscitation is mandatory. Gelatin polysuccinat (GP) recently regained attention despite a still unclear risk profile and widely unknown effects on cerebral and peripheral microcirculation. This study investigates the effects of GP versus balanced electrolyte solution (BEL) with focus on cerebral regional oxygen saturation and peripheral microcirculation in a porcine haemorrhagic shock model. METHODS: After Animal Care Committee approval haemorrhagic shock was induced by arterial blood withdrawal in 27 anaesthetized pigs. Consequently, the animals received rapid fluid resuscitation by either GP or BEL to replace the removed amount of blood, or remained untreated (n = 3 * 9). Over two hours cerebral regional oxygen saturation by near-infrared spectroscopy and peripheral buccal microcirculation by combined white-light spectrometry and laser-Doppler flowmetry were recorded. Secondary parameters included extended haemodynamics, spirometry, haematological and blood gas parameters. RESULTS: Both fluid resuscitation regimes sufficiently stabilized the macro- and microcirculation in haemorrhagic shock with a more pronounced effect following GP infusion. GP administration led to a persisting, critical impairment of cerebral regional oxygen saturation through considerable haemodilution. Survival rates were 100% in both fluid resuscitation groups, but only 33% in the untreated control. CONCLUSION: Equal amounts of GP and BEL sufficiently stabilize systemic circulation and microcirculatory perfusion. Forced fluid resuscitation by GP should be applied with caution to prevent haemodilution-induced impairment of cerebral oxygen delivery. PMID- 29426352 TI - Clinical and histopathologic findings in dogs with the ultrasonographic appearance of gastric muscularis unorganized hyperechoic striations. AB - BACKGROUND: Ultrasonographic appearance of unorganized hyperechoic striations (UHS) has been observed in the canine gastric muscularis layer. The purpose of the study was to determine the prevalence, sonographic and postmortem histologic features, and to determine the clinical significance of canine gastric muscularis UHS. In the prospective study, 72 dogs were included. The presence of gastric muscularis UHS were reviewed to determine its distribution and location. In the retrospective study, 167 dogs that had both abdominal ultrasonography and necropsy were included. RESULTS: The prevalence of gastric muscularis UHS in dogs was 37.5% in the prospective and 5.4% in the retrospective studies respectively. The higher prevalence in prospective study was due to greater anticipation by the radiologists in search for gastric muscularis UHS. In the ventral gastric wall, the muscularis UHS were better defined when the gastric lumen was empty or non distended, and were mostly parallel with the serosa when the gastric wall was distended (with gas or fluid). Visualization of the dorsal gastric wall was often obscured by gas shadowing from luminal gas. Histopathology was performed on eight dogs with gastric muscularis UHS, three of which had fibrous tissue observed with Masson's trichrome stain. CONCLUSION: Presence of gastric muscularis UHS in dogs may have been attributable to presence of incomplete interfaces between the inner oblique, middle circular and outer longitudinal layers of the gastric tunica muscularis or due to presence of fibrous tissue within the gastric muscularis layer. The clinical significance of canine gastric muscularis UHS is uncertain. PMID- 29426351 TI - Poly-arginine R18 and R18D (D-enantiomer) peptides reduce infarct volume and improves behavioural outcomes following perinatal hypoxic-ischaemic encephalopathy in the P7 rat. AB - We examined the neuroprotective efficacy of the poly-arginine peptide R18 and its D-enantiomer R18D in a perinatal hypoxic-ischaemic (HI) model in P7 Sprague Dawley rats. R18 and R18D peptides were administered intraperitoneally at doses of 30, 100, 300 or 1000 nmol/kg immediately after HI (8% O2/92%N2 for 2.5 h). The previously characterised neuroprotective JNKI-1-TATD peptide at a dose of 1000 nmol/kg was used as a control. Infarct volume and behavioural outcomes were measured 48 h after HI. For the R18 and R18D doses examined, total infarct volume was reduced by 25.93% to 43.80% (P = 0.038 to < 0.001). By comparison, the JNKI-1 TATD reduced lesion volume by 25.27% (P = 0.073). Moreover, R18 and R18D treatment resulted in significant improvements in behavioural outcomes, while with JNKI-1-TATD there was a trend towards improvement. As an insight into the likely mechanism underlying the effects of R18, R18D and JNKI-1-TATD, the peptides were added to cortical neuronal cultures exposed to glutamic acid excitotoxicity, resulting in up to 89, 100 and 71% neuroprotection, respectively, and a dose dependent inhibition of neuronal calcium influx. The study further confirms the neuroprotective properties of poly-arginine peptides, and suggests a potential therapeutic role for R18 and R18D in the treatment of HIE. PMID- 29426353 TI - Precise genome-wide mapping of single nucleosomes and linkers in vivo. AB - We developed a chemical cleavage method that releases single nucleosome dyad containing fragments, allowing us to precisely map both single nucleosomes and linkers with high accuracy genome-wide in yeast. Our single nucleosome positioning data reveal that nucleosomes occupy preferred positions that differ by integral multiples of the DNA helical repeat. By comparing nucleosome dyad positioning maps to existing genomic and transcriptomic data, we evaluated the contributions of sequence, transcription, and histones H1 and H2A.Z in defining the chromatin landscape. We present a biophysical model that neglects DNA sequence and shows that steric occlusion suffices to explain the salient features of nucleosome positioning. PMID- 29426354 TI - Lentivirus-mediated expression of human secreted amyloid precursor protein-alpha prevents development of memory and plasticity deficits in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disease driven in large part by accumulated deposits in the brain of the amyloid precursor protein (APP) cleavage product amyloid-beta peptide (Abeta). However, AD is also characterised by reductions in secreted amyloid precursor protein-alpha (sAPPalpha), an alternative cleavage product of APP. In contrast to the neurotoxicity of accumulated Alphabeta, sAPPalpha has many neuroprotective and neurotrophic properties. Increasing sAPPalpha levels has the potential to serve as a therapeutic treatment that mitigates the effects of Abeta and rescue cognitive function. Here we tested the hypothesis that lentivirus-mediated expression of a human sAPPalpha construct in a mouse model of AD (APPswe/PS1dE9), begun before the onset of plaque pathology, could prevent later behavioural and electrophysiological deficits. Male mice were given bilateral intra-hippocampal injections at 4 months of age and tested 8-10 months later. Transgenic mice expressing sAPPalpha performed significantly better than untreated littermates in all aspects of the spatial water maze task. Expression of sAPPalpha also resulted in partial rescue of long-term potentiation (LTP), tested in vitro. These improvements occurred in the absence of changes in amyloid pathology. Supporting these findings on LTP, lentiviral-mediated expression of sAPPalpha for 3 months from 10 months of age, or acute sAPPalpha treatment in hippocampal slices from 18 to 20 months old transgenic mice, completely reversed the deficits in LTP. Together these findings suggest that sAPPalpha has wide potential to act as either a preventative or restorative therapeutic treatment in AD by mitigating the effects of Abeta toxicity and enhancing cognitive reserve. PMID- 29426355 TI - Role of postoperative radiotherapy in reducing ipsilateral recurrence in DCIS: an observational study of 1048 cases. AB - BACKGROUND: The objective of the present study was to evaluate the effectiveness of postoperative radiotherapy after breast conserving surgery (BCS) in DCIS in a large patient population treated in clinical practice. METHODS: Data were provided by the population-based Munich Cancer Registry. Between 1998 and 2014, 1048 female patients with diagnosis of DCIS and treated at two Breast Care Centres were included in this observational study. The effectiveness of postoperative radiotherapy and variables predicting the use of radiotherapy were retrospectively analysed. RESULTS: After adjusting for age, tumour characteristics and therapies, Cox regression analysis for local recurrence-free survival identified RT as an independent predictor for improved local control (HR: 0.579; 95%CI: 0.384-0.872, p = 0.008). Ten-year cumulative incidence of in breast recurrences was 20.0% following BCS, compared to 13.6% in patients receiving postoperative radiotherapy (p = 0.012). As an estimate for disease specific survival, 10-year relative survival was 105.4% for patients receiving postoperative radiotherapy and 101.6% without radiotherapy. On multivariate analysis, postoperative radiotherapy was not associated with improved overall survival (HR 0.526; 95%CI: 0.263-1.052, p = 0.069). Over time, a significant increase of RT was registered: while 1998 only 42.9% of patients received postoperative radiotherapy, the proportion rose to 91.2% in 2014. Women aged < 50 years (OR: 2.559, 95%CI: 1.416-4.625, p < 0.001) or with negative hormone receptor status (OR: 2.625, 95%CI: 1.458-4.728, p = 0.001) or receiving endocrine therapy (OR: 1.762, 95%CI: 1.060-2.927, p = 0.029) were more likely to receive postoperative radiotherapy after BCS. CONCLUSIONS: In conclusion, this study provides insights regarding the adoption and treatment pattern of postoperative RT following BCS for DCIS in a large cohort reflecting "real-life" clinical practice in this setting. Postoperative RT was found to be associated with a reduced risk of ipsilateral recurrence and no survival benefit compared to observation alone. PMID- 29426356 TI - The correlation between serum AMH and HOMA-IR among PCOS phenotypes. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) is known to be one of the most prevalent endocrine disorders affecting reproductive age women. One of the endocrine disorder is hyperinsulinemia, which corresponds with the severity of PCOS. However, the pathogenesis of PCOS is not fully understood, but one theory of anti-mullerian hormone (AMH) has been proposed as one of the factor related to the degree of severity of PCOS. However, there are no clear correlation between levels of AMH with the incidence of insulin resistance in PCOS patients especially in Indonesia. METHODS: This is a cross-sectional study involving reproductive age women aged 18-35 years. Subjects were recruited consecutively at Dr. Cipto Mangunkusumo General Hospital between 2011 until 2014. PCOS women diagnosed using 2003 Rotterdam criteria were categorized into four different PCOS phenotypes. Subsequently, serum level of AMH and HOMA-IR was measured and evaluated with correlation tests performed using SPSS 11.0 RESULTS: A total of 125 PCOS patients were included in a study conducted within a 3-year period. Phenotype 1 (anovulation, hyperandrogenism, and polycystic ovaries) shows the highest levels of AMH and HOMA-IR, which decreases in accordance to severity level (p < 0.005). The positive correlation between AMH and HOMA-IR persisted even after adjusting for BMI in multivariate analysis. CONCLUSIONS: There was a positive correlation between serum AMH and HOMA IR levels. Serum AMH and HOMA IR levels were significantly different across the four PCOS phenotypes; with the highest values were present with phenotype 1. PMID- 29426357 TI - 14, 15-EET induces breast cancer cell EMT and cisplatin resistance by up regulating integrin alphavbeta3 and activating FAK/PI3K/AKT signaling. AB - BACKGROUND: 14,15-epoxyeicosatrienoic acid (14,15-EET) is an important lipid signaling molecule involved in the regulation of tumor metastasis, however, the role and molecular mechanisms of 14,15-EET activity in breast cancer cell epithelial-mesenchymal transition (EMT) and drug resistance remain enigmatic. METHODS: The 14, 15-EET level in serum and in tumor or non-cancerous tissue from breast cancer patients was measured by ELISA. qRT-PCR and western blot analyses were used to examine expression of integrin alphavbeta3. The role of 14, 15-EET in breast cancer cell adhesion, invasion was explored by adhesion and Transwell assays. The role of 14, 15-EET in breast cancer cell cisplatin resistance in vitro was determined by MTT assay. Western blot was conducted to detect the protein expressions of EMT-related markers and FAK/PI3K/AKT signaling. Xenograft models in nude mice were established to explore the roles of 14, 15-EET in breast cancer cells EMT and cisplatin resistance in vivo. RESULTS: In the present study, we show that serum level of 14, 15-EET increases in breast cancer patients and 14, 15-EET level of tumor tissue is higher than that of non-cancerous tissue. Moreover, 14, 15-EET increases integrin alphavbeta3 expression, leading to FAK activation. 14, 15-EET induces breast cancer cell EMT via integrin alphavbeta3 and FAK/PI3K/AKT cascade activation in vitro. Furthermore, we find that 14, 15 EET induces breast cancer cells EMT and cisplatin resistance in vivo, alphavbeta3 integrin and the resulting FAK/PI3K/AKT signaling pathway are responsible for 14, 15-EET induced-breast cancer cells cisplatin resistance. CONCLUSIONS: Our findings suggest that inhibition of 14, 15-EET or inactivation of integrin alphavbeta3/FAK/PI3K/AKT pathway could serve as a novel approach to reverse EMT and cisplatin resistance in breast cancer cells. PMID- 29426358 TI - Optimizing the prescription isodose level in stereotactic volumetric-modulated arc radiotherapy of lung lesions as a potential for dose de-escalation. AB - BACKGROUND: To derive and exploit the optimal prescription isodose level (PIL) in inverse optimization of volumetric modulated arc radiotherapy (VMAT) as a potential approach to dose de-escalation in stereotactic body radiotherapy for non-small cell lung carcinomas (NSCLC). METHODS: For ten patients, inverse Monte Carlo dose optimization was performed to cover 95% PTV by varying prescription isodose lines (PIL) at 60 to 80% and reference 85%. Subsequently, these were re normalized to the median gross tumor volume dose (GTV-based prescription) to assess the impacts of PTV and normal tissue dose reduction. RESULTS: With PTV based prescription, GTV mean dose was much higher with the optimized PIL at 60% with significant reduction of normal lung receiving 30 to 10 Gy (V 30-10Gy ), and observable but insignificant dose reduction to spinal cord, esophagus, ribs, and others compared with 85% PIL. Mean doses to the normal lung between PTV and GTV was higher with 60-70% PIL than 85%. The dose gradient index was 5.0 +/- 1.1 and 6.1 +/- 1.4 for 60 and 85% PIL (p < 0.05), respectively. Compared with the reference 85% PIL plan using PTV-base prescription, significant decreases of all normal tissue doses were observed with 60% and 70% PIL by GTV-based prescription. Yet, the resulting biological effective (BED) mean doses of PTV remain sufficiently high, ranging 104.2 to 116.9 Gy alpha/beta = 10. CONCLUSIONS: Optimizing the PIL with VMAT has notable advantage of improving the dosimetric quality of lung SBRT and offers the potential of dose de-escalation for surrounding tissues while increasing the GTV dose simultaneously. The clinical implication of re-normalizing plans from PTV-prescription at 60-70% to the GTV median dose requires further investigations. PMID- 29426359 TI - Twenty weeks of isometric handgrip home training to lower blood pressure in hypertensive older adults: a study protocol for a randomized controlled trial. AB - BACKGROUND: Hypertension markedly increases the risk of cardiovascular diseases and overall mortality. Lifestyle modifications, such as increased levels of physical activity, are recommended as the first line of anti-hypertensive treatment. A recent systematic review showed that isometric handgrip (IHG) training was superior to traditional endurance and strength training in lowering resting systolic blood pressure (SBP). The average length of previous IHG training studies is approximately 7.5 weeks with the longest being 10 weeks. Therefore, presently it is unknown if it is possible to further lower blood pressure levels beyond the 10-week mark. Recently, we developed a novel method for monitoring handgrip intensity using a standard Nintendo Wii Board (Wii). The primary aim of this study is to explore the effects of a 20-week IHG home training facilitated by a Wii in hypertensive older adults (50 + years of age) on lowering SBP compared to usual care. Secondary aims are to explore if/when a leveling-off effect on SBP will occur during the 20-week intervention period in the training group and to explore adherence and potential harms related to the IHG home training. METHODS/DESIGN: Based on previous evidence, we calculated that 50 hypertensive (SBP between 140 and 179 mmHg), older adults (50 + years of age) are needed to achieve a power of 80% or more. Participants will be randomly assigned to either an intervention >group (IHG home training + hypertension guidelines on lifestyle changes) or to a control group (hypertension guidelines on lifestyle changes). Participants in the intervention group will perform IHG home training (30% of maximum grip strength for a total of 8 min per day per hand) three times a week for 20 weeks. Resting blood pressure and maximal handgrip strength will be obtained by a blinded outcome assessor in both groups at specific time points (baseline, follow-up at 5, 10, 15, and 20 weeks) throughout the study. DISCUSSION: This assessor-blinded, randomized controlled trial will explore the effect of a 20-week IHG home training intervention on resting blood pressure in hypertensive older adults. In addition, the trial will report adherence and potential harms related to the IHG home training. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03069443 . Registered on 3 March 2017. PMID- 29426360 TI - Not all false positive diagnoses are equal: On the prognostic implications of false-positive diagnoses made in breast MRI versus in mammography / digital tomosynthesis screening. AB - BACKGROUND: Breast magnetic resonance imaging (MRI) has been reported to frequently result in false-positive diagnoses, limiting its positive predictive value (PPV). However, for PPV calculation, all nonmalignant tissue changes are equally considered false-positive, although the respective prognostic importance, and thus patient management implications, of different pathologies may well differ. We investigated the pathology of false-positive diagnoses made by MRI compared with radiographic (digital mammography/tomosynthesis [DM/DBT]) screening. METHODS: We conducted an institutional review board-approved prospective analysis of 710 consecutive asymptomatic women at average risk for breast cancer who underwent vacuum biopsy with or without surgical biopsy for screen-detected DM/DBT (n = 344) or MRI (n = 366) findings. We compared the frequency of false-positive biopsies (given by PPV3), as well as the types of nonmalignant tissue changes that caused the respective false-positive biopsies. In an order of increasing relative risk of subsequent breast cancer, pathologies of false-positive biopsies were categorized as nonproliferative, simple proliferative, complex proliferative, or atypical proliferative (including lobular carcinoma in situ/lobular intraepithelial neoplasia). The Mann-Whitney U test was used to compare distributions. RESULTS: Histology yielded nonmalignant tissue in 202 of 366 biopsies done for positive MRI studies and 195 of 344 biopsies for positive DM/DBT studies, respectively, yielding a similar PPV3 percentages of 44.8% (164 of 202) and 43.3% (149 of 202) for both methods. However, the distribution of tissue types that caused false-positive diagnoses differed significantly (p < 0.0001). On the basis of MRI, high-risk atypical proliferative changes (40.1%; 81 of 202) were most common, followed by complex proliferative changes (23.8%; 48 of 202). In DM/DBT, low-risk, nonproliferative changes were the dominant reason for false-positive diagnoses (49.7%; 97 of 195), followed by simple proliferative changes (25.2%; 51 of 195). Low-risk nonproliferative changes resulted in false-positive diagnoses based on MRI as infrequently as did high-risk atypical proliferative changes based on DM/DBT (18.8% [38 of 202] vs. 18.0% [35 of 195]). The likelihood of a false-positive diagnosis including atypias was twice as high in women undergoing biopsy for MRI findings (81 of 202; 40%) as for those with DM/DBT findings (35 of 195; 18%). CONCLUSIONS: The prognostic importance, and thus the clinical implications, of false-positive diagnoses made on the basis of breast MRI vs. radiographic screening differed significantly, with a reversed prevalence of high- and low risk lesions. This should be taken into account when discussing the rate of false positive diagnoses (i.e., PPV levels of MRI vs. radiographic screening). Current benchmarks that rate the utility of breast cancer screening programs (i.e., cancer detection rates and PPVs) do not reflect these substantial biological differences and the different prognostic implications. PMID- 29426361 TI - Nursing home care educational intervention for family caregivers of older adults post stroke (SHARE): study protocol for a randomised trial. AB - BACKGROUND: Family caregivers of aged stroke survivors face challenging difficulties such as the lack of support and the knowledge and skills to practice home care. These aspects negatively influence the caregivers' burden and quality of life, the use of health services, and hospital readmissions of the stroke survivor. The aim of this research is to describe an educational intervention focused on family caregivers of stroke survivors for the development of home care in the south of Brazil. METHODS: A randomized clinical trial with 48 family caregivers of stroke survivors will be recruited and divided into two groups: 24 in the intervention group and 24 in the control group. The intervention will consist of the systematic follow-up by nurses who will perform three home visits over a period of 1 month. The control group will not receive the visits and will have the usual care guidelines of the health services. Primary outcomes: burden and quality of life of the caregiver. SECONDARY OUTCOMES: functional capacity and readmissions of the stroke survivors; the use of health services of the stroke survivors and their family caregivers. Outcomes will be measured 2 months after discharge. The project was approved in April 2016. DISCUSSION: This research offers information for conducting educational intervention with family caregivers of stroke survivors, presenting knowledge so that nurses can structure and plan the actions aimed at the education of the family caregiver. It is expected that the educational intervention will contribute to reducing caregiver burden and improving their quality of life, as well as avoiding readmissions and inadequate use of health services by stroke survivors. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02807012 . Registered on 3 June 2016. Name: Nursing Home Care Intervention Post Stroke (SHARE). PMID- 29426362 TI - Clinical effect of a dentifrice containing three kinds of bactericidal ingredients on periodontal disease: a pilot study in patients undergoing supportive periodontal therapy. AB - OBJECTIVE: This study aimed to evaluate clinically the effect of a novel dentifrice containing three kinds of bactericidal ingredients on periodontal disease. RESULTS: This was a single-arm, prospective clinical study that enrolled patients with periodontitis undergoing supportive periodontal therapy. Periodontal examination, microbiological testing of saliva samples, and evaluation of inflammatory markers (IL-1beta, IL-6, IL-8, TNF-alpha) in gingival crevicular fluid were performed. After 4 weeks of the use of test dentifrice, these parameters were re-evaluated. The use of dentifrice was also subjectively evaluated by clinicians and participants. Among 30 participants, there were significant improvements in the periodontal and microbiological parameters, and the level of interleukin-1beta in the gingival crevicular fluid, following the use of the test dentifrice. In clinicians' subjective evaluation of the overall usefulness of the dentifrice, 'mild' and 'moderate' improvement accounted for 83% of the total responses. In the participants' subjective evaluation, the majority indicated their experience of the use as favorable. Within the limitations of this study, it is suggested that the progression of periodontal disease during the supportive periodontal therapy can be prevented by the use of the test dentifrice. Trial registration UMIN Clinical Trials Registry (UMIN-CTR) 000023175. Date of formal registration: July 14, 2016 ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000026716 ). PMID- 29426363 TI - Effect of heat shock on hot water plumbing microbiota and Legionella pneumophila control. AB - BACKGROUND: Heat shock is a potential control strategy for Legionella pneumophila in hot water plumbing systems. However, it is not consistently effective, with little understanding of its influence on the broader plumbing microbiome. Here, we employed a lab-scale recirculating hot water plumbing rig to compare the pre- and post-"heat shock" (i.e., 40 -> 60 -> 40 degrees C) microbiota at distal taps. In addition, we used a second plumbing rig to represent a well-managed system at 60 degrees C and conducted a "control" sampling at 60 degrees C, subsequently reducing the temperature to 40 degrees C to observe the effects on Legionella and the microbiota under a simulated "thermal disruption" scenario. RESULTS: According to 16S rRNA gene amplicon sequencing, in the heat shock scenario, there was no significant difference or statistically significant, but small, difference in the microbial community composition at the distal taps pre- versus post-heat shock (both biofilm and water; weighted and unweighted UniFrac distance matrices). While heat shock did lead to decreased total bacteria numbers at distal taps, it did not measurably alter the richness or evenness of the microbiota. Quantitative PCR measurements demonstrated that L. pneumophila relative abundance at distal taps also was not significantly different at 2-month post-heat shock relative to the pre-heat shock condition, while relative abundance of Vermamoeba vermiformis, a known Legionella host, did increase. In the thermal disruption scenario, relative abundance of planktonic L. pneumophila (quantitative PCR data) increased to levels comparable to those observed in the heat shock scenario within 2 months of switching long-term operation at 60 to 40 degrees C. Overall, water use frequency and water heater temperature set point exhibited a stronger effect than one-time heat shock on the microbial composition and Legionella levels at distal taps. CONCLUSIONS: While heat shock may be effective for instantaneous Legionella control and reduction in total bacteria numbers, water heater temperature set point and water use frequency are more promising factors for long-term Legionella and microbial community control, illustrating the importance of maintaining consistent elevated temperatures in the system relative to short-term heat shock. PMID- 29426364 TI - RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1. AB - BACKGROUND: 40-50% of colorectal cancer (CRC) patients develop metastatic disease; the presence of metastasis hinders the effective treatment of cancer through surgery, chemotherapy and radiotherapy, which makes 5-year survival rate extremely low; therefore, studying CRC metastasis is crucial for disease therapy. In the present study, we investigated the role of rhomboid domain containing 1 (RHBDD1) in tumor metastasis of CRC. METHODS: The expression of RHBDD1 was analyzed in 539 colorectal tumor tissues for its correlation with lymphatic metastasis and distal metastasis. Transwell assay in vitro and pleural metastasis analysis in vivo were performed to determine the functions of RHBDD1 during CRC cells metastasis. RNA-seq analysis, TOP/FOP flash reporter assay, western blot and transwell assay were performed to investigate the underlying mechanism for the function of RHBDD1 on Wnt signaling pathway. Bioinformatics analysis was conducted to investigate epithelial-mesenchymal transition (EMT) and stemness in HCT-116 cells. Tissue microarray analysis, Q-PCR and western blot were performed to determine the correlation of RHBDD1 and Zinc Finger E-Box Binding Homeobox 1 (ZEB1). RESULTS: In this study, we found that RHBDD1 expression was positively correlated with lymphatic metastasis and distal metastasis in 539 colorectal tumor tissues. RHBDD1 expression can promote CRC cells metastasis in vitro and in vivo. RNA-Seq analysis showed that the Wnt signaling pathway played a key role in this metastatic regulation. RHBDD1 mainly regulated ser552 and ser675 phosphorylation of beta-catenin to activate the Wnt signaling pathway. Rescuing ser552 and ser675 phosphorylation of beta-catenin resulted in the recovery of signaling pathway activity, migration, and invasion in CRC cells. RHBDD1 promoted EMT and a stem-like phenotype of CRC cells. RHBDD1 regulated the Wnt/beta-catenin target gene ZEB1, a potent EMT activator, at the RNA and protein levels. Clinically, RHBDD1 expression was positively correlated with ZEB1 at the protein level in 71 colon tumor tissues. CONCLUSIONS: Our findings therefore indicated that RHBDD1 can promote CRC metastasis through the Wnt signaling pathway and ZEB1. RHBDD1 may become a new therapeutic target or clinical biomarker for metastatic CRC. PMID- 29426365 TI - Proteome-wide comparison between the amino acid composition of domains and linkers. AB - OBJECTIVE: Amino acid composition is a sequence feature that has been extensively used to characterize proteomes of many species and protein families. Yet the analysis of amino acid composition of protein domains and the linkers connecting them has received less attention. Here, we perform both a comprehensive full proteome amino acid composition analysis and a similar analysis focusing on domains and linkers, to uncover domain- or linker-specific differential amino acid usage patterns. RESULTS: The amino acid composition in the 38 proteomes studied showcase the greater variability found in archaea and bacteria species compared to eukaryotes. When focusing on domains and linkers, we describe the preferential use of polar residues in linkers and hydrophobic residues in domains. To let any user perform this analysis on a given domain (or set of them), we developed a dedicated R script called RACCOON, which can be easily used and can provide interesting insights into the compositional differences between a domain and its surrounding linkers. PMID- 29426366 TI - Children with oedema recover better than those with severe wasting in outpatient therapeutic program at Boloso Sore district, Southwest Ethiopia. AB - OBJECTIVES: Severely undernourished young children clinically present with a typical nutritional oedema or none-oedematous. However, research evidence is limited on how these types predict treatment outcomes in Ethiopia. This study was aimed to compare oedematous and none-oedematous children for their treatment outcomes in Boloso Sore district in Southwest Ethiopia. RESULTS: The overall recovery rate was 396 (68%). From oedematous children; 235 (79.9%) recovered, 18 (6.1%) transferred, 6 (2.0%) defaulted, 3 (1.0%) died, and 32 (11%) remained none respondents. The treatment outcomes among the none-oedematous children were 161 (55.9%), 12 (4.2%), 4 (1.4%), 3 (1.0%), and 108 (37.5%) in similar order. Treatment outcomes of severely undernourished children in the two arms were statistically different (Chi2 = 5.82, P < 0.016). Severely malnourished children with oedema were 2.3 times highly likely to recover as compared to those without it (adjusted hazard ratio = 2.3 at 95% confidence interval: 1.79, 2.82). We documented that oedematous children in the study area had a better likelihood of recovery as compared to those with severe wasting. We recommend targeted community outreach activities on severe acute malnutrition focusing on the types. PMID- 29426367 TI - PIP5K1alpha promotes myogenic differentiation via AKT activation and calcium release. AB - BACKGROUND: Skeletal muscle satellite cell-derived myoblasts are mainly responsible for postnatal muscle growth and injury-induced regeneration. Many intracellular signaling pathways are essential for myogenic differentiation, while a number of kinases are involved in this modulation process. Type I phosphatidylinositol 4-phosphate 5-kinase (PIP5KI) was identified as one of the key kinases involved in myogenic differentiation, but the underlying molecular mechanism is still unclear. METHODS: PIP5K1alpha was quantified by quantitative reverse transcriptase PCR and western blot assay. Expression levels of myogenin and myosin heavy chain, which showed significant downregulation in PIP5K1alpha siRNA-mediated knockdown cells in western blot analysis, were confirmed by immunostaining. Phosphatidylinositol 4,5-bisphosphate in PIP5K1alpha siRNA mediated knockdown cells was also measured by the PI(4,5)P2 Mass ELISA Kit. C2C12 cells were overexpressed with different forms of AKT, followed by western blot analysis on myogenin and myosin heavy chain, which reveals their function in myogenic differentiation. FLIPR assays are used to test the release of calcium in PIP5K1alpha siRNA-mediated knockdown cells after histamine or bradykinin treatment. Statistical significances between groups were determined by two-tailed Student's t test. RESULTS: Since PIP5K1alpha was the major form in skeletal muscle, knockdown of PIP5K1alpha consistently inhibited myogenic differentiation while overexpression of PIP5K1alpha promoted differentiation and rescued the inhibitory effect of the siRNA. PIP5K1alpha was found to be required for AKT activation and calcium release, both of which were important for skeletal muscle differentiation. CONCLUSIONS: Taken together, these results suggest that PIP5K1alpha is an important regulator in myoblast differentiation. PMID- 29426368 TI - Oxford Screening CSF and Respiratory samples ('OSCAR'): results of a pilot study to screen clinical samples from a diagnostic microbiology laboratory for viruses using Illumina next generation sequencing. AB - OBJECTIVES: There is increasing interest in the use of metagenomic (next generation sequencing, NGS) approaches for diagnosis of infection. We undertook a pilot study to screen samples submitted to a diagnostic microbiology laboratory in a UK teaching hospital using Illumina HiSeq. In the short-term, this small dataset provides insights into the virome of human respiratory and cerebrospinal fluid (CSF) samples. In the longer term, assimilating metagenomic data sets of this nature can inform optimization of laboratory and bioinformatic methods, and develop foundations for the interpretation of results in a clinical context. The project underpins a larger ongoing effort to develop NGS pipelines for diagnostic use. DATA DESCRIPTION: Our data comprise a complete metagenomic dataset from 20 independent samples (10 CSF and 10 respiratory) submitted to the clinical microbiology laboratory for a large UK teaching hospital (Oxford University Hospitals NHS Foundation Trust). Sequences have been uploaded to the European Nucleotide Archive and are also presented as Krona plots through which the data can be interactively visualized. In the longer term, further optimization is required to better define sensitivity and specificity of this approach to clinical samples. PMID- 29426369 TI - Cervico-shoulder dystonia following lateral medullary infarction: a case report and review of the literature. AB - BACKGROUND: Secondary cervical dystonia is induced by organic brain lesions involving the basal ganglia, thalamus, cerebellum, and brain stem. It is extremely rare to see cervical dystonia induced by a medullary lesion. CASE PRESENTATION: We report a case of an 86-year-old Japanese woman who developed cervical dystonia following lateral medullary infarction. She developed sudden onset left upper and lower extremity weakness, right-side numbness, and dysarthria. Brain magnetic resonance imaging revealed an acute ischemic lesion involving the left lateral and dorsal medullae. A few days after her stroke, she complained of a taut sensation in her left neck and body, and cervico-shoulder dystonia toward the contralateral side subsequently appeared. Within a few weeks, it disappeared spontaneously, but her hemiplegia remained residual. CONCLUSIONS: To date, to the best of our knowledge, there has been only one reported case of cervical dystonia associated with a single medullary lesion. It is interesting to note the similarities in the clinical characteristics of the previously reported case and our patient: the involvement of the dorsal and caudal parts of the medullary and associated ipsilateral hemiplegia. The present case may support the speculation that the lateral and caudal regions of the medulla may be the anatomical sites responsible for inducing cervical dystonia. PMID- 29426370 TI - Patient delay in seeking tuberculosis diagnosis and associated factors in Hadiya Zone, Southern Ethiopia. AB - OBJECTIVE: To assess patient delay in seeking tuberculosis diagnosis and associated factors in Hadiya Zone, Southern Ethiopia. RESULTS: The median patient delay in tuberculosis diagnosis in Hadiya Zone was found to be 30 days. Socioeconomic and perception related factors were identified as independent predictors for tuberculosis diagnosis delay. Socioeconomic characteristics like urban residence [OR 2.36; CI 1.64-3.40], religious views [OR 1.24; CI 1.73-7.0], low monthly income [OR 3.38; CI 2.01-5.66] were statistically significantly associated with patient delay in tuberculosis diagnosis. On the other hand, attitudinal determinants such as misconception about the time of TB treatment to be cured and lack of comfort with directly observed treatment short course service [OR 1.54; CI 1.02-2.30] were identified as independent predictors of patient delay in tuberculosis diagnosis. Thus, there is a need for more robust information dissemination strategy to ultimately change people's views that tuberculosis can only be cured when diagnosed and treated promptly. PMID- 29426371 TI - Transcriptomic response in Acropora muricata under acute temperature stress follows preconditioned seasonal temperature fluctuations. AB - OBJECTIVE: Global climate change has resulted in the decline of health and condition of various coral reefs worldwide. Here, we describe expression profiles of Acropora muricata collected during opposing seasons in Otsuki, Kochi, Japan to define the capacity of corals to cope with changing environmental conditions. Coral communities in Otsuki experience large temperature fluctuations between the winter (~ 16 degrees C) and summer (~ 27 degrees C). RESULTS: Coral nubbins that were collected in the summer showed no change in photochemical efficiency when exposed to thermal or cold stress, while winter samples showed a decrease in photochemical health when subjected to thermal stress. Under cold stress, corals that were collected in the summer showed an up-regulation of actin-related protein and serine/threonine protein kinase, while corals collected during the winter did not show any cellular stress. On the other hand, under thermal stress, the most notable change was the up-regulation of phosphoenolpyruvate carboxykinase in corals that were collected during the winter season. Our observations in the differential genes expressed under temperature-derived stress suggest that A. muricata from Kochi may maintain physiological resilience due to the frequently encountered environmental stress, and this may play a role in the coral's thermal tolerance. PMID- 29426373 TI - Silencing Artemis Enhances Colorectal Cancer Cell Sensitivity to DNA-damaging Agents. AB - Artemis is a key protein of NHEJ (non-homologous end-joining), which is the major pathway for the repair of IR-inducedDSBs in mammalian cells. However, it has not been largely investigated about the expression of Artemis in tumor and the influence of silencing Artemis on the tumor's sensitivity to radiation. In this study, we investigated how expression levels of Artemis may affect treatment outcome of radiotherapy and chemotherapy in colorectal cancer cells. Firstly, we found that the expression of Artemis is strong in some human rectal cancer samples, even can be higher than adjacent normal tissues using immunohistochemical staining. We then knocked down Artemis gene in human colorectal cancer cell line (RKO) using lentivirus-mediated siRNAs. As compared to the control RKO cells, the Artemis-knockdown cells showed significantly increased sensitivity to Bleomycin, Etoposide, Camptothecin, and IR. Induced by DNA damaging agents, delayed DNA repair kinetics was found by gamma-H2AX foci assay and a significantly increased cell apoptosis happened in the Artemis knockdown RKO cells through apoptosis detection methods and Western blot. We also found that the p53/p21 signaling pathway may be involved in the apoptosis process. Taken together, our study indicates that it is applicable to enhance colorectal cancer cell sensitivity to DNA-damaging agents by manipulating Artemis. Artemis can serve as a therapeutic target in rectal cancer therapy. PMID- 29426372 TI - Assessment of GeneXpert GxAlert platform for multi-drug resistant tuberculosis diagnosis and patients' linkage to care in Tanzania. AB - OBJECTIVE: The gap between patients diagnosed with multi-drug resistant tuberculosis (MDR-TB) and enrolment in treatment is one of the major challenges in tuberculosis control programmes. A 4-year (2013-2016) retrospective review of patients' clinical data and subsequent in-depth interviews with health providers were conducted to assess the effectiveness of the GeneXpert GxAlert platform for MDR-TB diagnosis and its impact on linkage of patients to care in Tanzania. RESULTS: A total of 782 new rifampicin resistant cases were notified, but only 242 (32.3%) were placed in an MDR-TB regimens. The remaining 540 (67.07%) patients were not on treatment, of which 103 patients had complete records on the GxAlert database. Of the 103 patients: 39 were judged as untraceable; 27 died before treatment; 12 were treated with first-line anti-TBs; 9 repeat tests did not show rifampicin resistance; 15 were not on treatment due to communication breakdown, and 1 patient was transferred outside the country. In-depth interviews with health providers suggested that the pre-treatment loss for the MDR-TB patients was primarily attributed to health system and patients themselves. We recommend strengthening the health system by developing and implementing well defined interventions to ensure all diagnosed MDR-TB patients are accurately reported and timely linked to treatment. PMID- 29426374 TI - Ectopic expression of miR-147 inhibits stem cell marker and epithelial mesenchymal transition (EMT)-related protein expression in colon cancer cells. AB - Colon cancer is one of the most common cancers in the world. Epithelial-to mesenchymal transition (EMT) is a crucial step in tumor progression and also involves in the acquisition of stem cell-like properties. Some miRNAs have been shown to function as either tumor suppressors or oncogenes in colon cancer. Here, we investigated the role of miR-147 in the regulation of stem cell-like traits of colon cancer cells. We observed that miR-147 was down-regulated in several colon cancer cell lines and overexpressed miR-147 decreased the expression of cancer stem cell (CSC) markers OCT4, SOX2 and NANOG in colon cancer cells (HCT116, SW480). Besides that, overexpressed miR-147 inhibited EMT by increasing the expression of epithelial markers Ecadherin and alpha-catenin while decreasing the expression of mesenchymal markers fibronectin and vimentin. Moreover, activation of EMT by TGF-beta1 treatment counteracted the inhibitive effect of miR-147 on the expression of CSC markers OCT4, SOX2 and NANOG significantly, supporting that overexpressed miR-147 inhibited stem cell-like traits by suppressing EMT in colon cancer. In addition, we found that overexpressed miR-147 down-regulated the expression of beta-Catenin, c-myc and Survivin which were related to Wnt/beta Catenin pathway. Moreover, treatment with Wnt/beta-Catenin pathway activator Licl in miR-147 mimic transfected cells attenuated the inhibitive effect of miR-147 mimic on EMT and stem cell-like traits of colon cancer cells, indicating that ectopic expression of miR-147 inhibited stem cell-like traits in colon cancer cells through suppressing EMT via the Wnt/beta-Catenin pathway. In summary, our present study highlighted the crucial role of miR-147 in the inhibition of stem cell-like traits of colon cancer cells and indicated that miR-147 could be a promising therapeutic target for colon cancer treatment. PMID- 29426375 TI - Triptolide Inhibits Proliferation and Migration of Human Neuroblastoma SH-SY5Y Cells by Upregulating MicroRNA-181a. AB - Neuroblastoma is the primary cause of cancer-related death for children 1 to 5 years of age. New therapeutic strategies and medicines are urgently needed. This study aimed to investigate the effects of triptolide (TPL), the major active component purified from Tripterygium wilfordii Hook F, on neuroblastoma SH-SY5Y cell proliferation, migration, and apoptosis, as well as underlying potential mechanisms. We found that TPL inhibited SH-SY5Y cell viability, proliferation, and migration, but induced cell apoptosis. The expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 after TPL treatment in SH-SY5Y cells was decreased. The expression of microRNA-181a (miR-181a) was upregulated after TPL treatment. Moreover, suppression of miR-181a reversed the effects of TPL on SH SY5Y cell proliferation, apoptosis, and migration. Overexpression of miR-181a enhanced the TPL-induced activation of p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor kappa light chain enhancer of activated B cells (NF kappaB) pathways. In conclusion, our research verified that TPL inhibited the proliferation and migration of human neuroblastoma SH-SY5Y cells by upregulating the expression of miR-181a. PMID- 29426376 TI - Silencing of NADPH oxidase 4 attenuates hypoxia resistance in neuroblastoma cells SHSY-5Y by inhibiting PI3K/Akt-dependent glycolysis. AB - Hypoxia-induced chemoresistance is a major obstacle in the development of effective cancer therapy. In our study, the reversal abilities of NADPH oxidase 4 (NOX4) silence on the hypoxia resistance and the potential mechanism were investigated. Our data showed that the expression of NOX4 was up-regulated in human neuroblastoma cells SHSY-5Y under hypoxia condition time-dependently. Knockdown of NOX4 expression by siRNA inhibited glycolysis induced by hypoxia through decreasing the expression of glycolysis related proteins (HIF-1alpha, LDHA, PDK1), decreasing glucose uptake, lactate production, ROS production while increasing mitochondria membrane potential. Moreover, NOX4 silence inhibited cell viability under hypoxia condition through suppressing cell proliferation and proliferation related proteins (Ki67, PCNA) compared with hypoxia 24h + siRNA NC group. Further, western blot experiments exhibited that NOX4 siRNA could down regulate the rate of p-Akt/Akt. Treatment with PI3K/Akt signaling activator IGF-I blocked while treatment with Akt inhibitor Perifosine enhanced the inhibitory effect of si-NOX4 on glycolysis and cell viability. In summary, knockdown of NOX4 had an ability of reversing hypoxia resistance, and the major mechanism is considered to be the inhibition of glycolysis and cell viability via PI3K/Akt signaling pathway. Therefore, NOX4 could be a novel target against hypoxia resistance in neuroblastoma. PMID- 29426378 TI - Using the New Postacute Care Quality Measures to Demonstrate the Value of Occupational Therapy. AB - As the health care system continues to evolve toward one based on quality not quantity, demonstrating the value of occupational therapy has never been more important. Providing high-quality services, achieving optimal outcomes, and identifying and promoting occupational therapy's distinct value are the responsibilities of all practitioners. In relation to the Improving Medicare Post Acute Care Transformation (IMPACT) Act of 2014, the Centers for Medicare and Medicaid Services (CMS) is implementing new functional items and related outcome performance measures across postacute care (PAC) settings. Practitioners can demonstrate the role and value of occupational therapy services through their participation in data collection and the interpretation of the resulting performance measures. In this column, we review the objectives of the IMPACT Act, introduce the new self-care and mobility items and outcome performance measures being implemented in PAC settings, and describe ways to use these new data to advocate for occupational therapy. We also discuss American Occupational Therapy Association initiatives to provide materials and guidance for occupational therapy practitioners to contribute to PAC data collection. PMID- 29426379 TI - Success in Adults With Probable Developmental Coordination Disorder Using Structural Equation Modeling. AB - OBJECTIVE: The aim of this study was to conduct a broad in-depth examination of the relationship between developmental coordination disorder (DCD) and use of executive strategies, daily life activities, emotional state, and internal factors attributed to success. METHOD: We used a large randomized cohort of young adults. Structural equation modeling was performed to test both the direct effects and the mediated effects of the independent variable (probable DCD) on dependent variables (executive functions, academic and nonacademic activities, emotional state, and attribution to success). RESULTS: Probable DCD had a direct and significant effect on all variables. Motor coordination impairments directly affected daily function in nonacademic and academic abilities and resulted in decreased use of executive strategies. Likewise, all the indirect effects hypothesized in the model were found to be significant. CONCLUSION: The model revealed the direct and indirect influences of probable DCD on a range of functions, with far-reaching clinical implications. PMID- 29426380 TI - Occupation-Based Coaching by Means of Telehealth for Families of Young Children With Autism Spectrum Disorder. AB - OBJECTIVE: We investigated the efficacy of Occupation-Based Coaching delivered via telehealth for families of young children with autism spectrum disorder (ASD). METHOD: Participants were 18 families of children with ASD ages 2-6 yr. We used descriptive statistics to understand intervention characteristics and paired sample t tests to examine changes in parent efficacy and child participation. RESULTS: Parents identified many areas of child adaptive behavior as intervention goals. Results showed that parent efficacy and various domains of child participation significantly increased postintervention (both ps < .05). Additionally, children showed significant gains in parent-identified goals. CONCLUSION: Occupation-Based Coaching delivered via telehealth appears to be an effective method of intervention to increase parent efficacy and child participation among families of children with ASD. Occupational therapists may consider how telehealth may be used to provide intervention to an increased number of families, in particular those in underserved areas. PMID- 29426381 TI - Interventions for Women With Substance Abuse Issues: A Scoping Review. AB - OBJECTIVE: The aim of this scoping review was to describe the characteristics and features of substance abuse interventions for women in North America and discuss the findings from an occupational perspective. METHOD: A scoping review was conducted to examine North American peer-reviewed literature published between 2001 and 2014. Four databases were searched using terms related to intervention, substance abuse, and women only. Descriptive statistics of categorical groupings were used to describe the data sources and characteristics and features of the interventions. RESULTS: Forty-two articles met the inclusion criteria, with the majority citing a harm-reduction approach and using multifaceted interventions with various targets for change. CONCLUSION: Substance abuse interventions for women are typically multifaceted and follow a harm-reduction philosophy. Further research into the efficacy of interventions that more specifically target occupation beyond substance use is needed. PMID- 29426382 TI - Impact of an Activity-Based Program on Health, Quality of Life, and Occupational Performance of Women Diagnosed With Cancer. AB - OBJECTIVE: We evaluated the impact of a 1-wk activity program on the health, quality of life (QOL), and occupational performance of community-living women diagnosed with cancer. METHOD: A one-group pretest-posttest repeated-measures design was used. Participants completed a functional health measure (36-Item Short Form Health Survey [SF-36]), a QOL measure (World Health Organization Quality of Life-Brief version [WHOQOL-BREF]), and an occupational performance and satisfaction measure (Canadian Occupational Performance Measure [COPM]) before and 6 wk after program completion. The COPM was also administered on Day 5. RESULTS: Paired t tests for the SF-36 and WHOQOL-BREF showed no significant differences, except for the WHOQOL-BREF's Social Relationships subscale (p < .008). Repeated-measures analyses of variance showed a significant difference in COPM performance and satisfaction scores (p < .001). CONCLUSION: The activity program effectively improved occupational performance and satisfaction and social relationships of community-living women diagnosed with cancer. PMID- 29426384 TI - Development of Internet-Based Tasks for the Executive Function Performance Test. AB - OBJECTIVE: The Executive Function Performance Test (EFPT) is a reliable and valid performance-based tool to assess executive functions (EFs). This study's objective was to develop and verify two Internet-based tasks for the EFPT. METHOD: A cross-sectional study assessed the alternate-form reliability of the Internet-based bill-paying and telephone-use tasks in healthy adults and people with subacute stroke (Study 1). It also sought to establish the tasks' criterion reliability for assessing EF deficits by correlating performance with that on the Trail Making Test in five groups: healthy young adults, healthy older adults, people with subacute stroke, people with chronic stroke, and young adults with attention deficit hyperactivity disorder (Study 2). RESULTS: The alternative-form reliability and initial construct validity for the Internet-based bill-paying task were verified. Criterion validity was established for both tasks. CONCLUSION: The Internet-based tasks are comparable to the original EFPT tasks and can be used for assessment of EF deficits. PMID- 29426385 TI - Development of an Item Pool Reflecting Cognitive Concerns Expressed by People With HIV. AB - OBJECTIVE: The overall aim of this study is to create an item pool reflecting the cognitive concerns expressed by people with HIV as a first step toward developing such a measure. METHOD: Semiqualitative interviews with 292 people with HIV were carried out. Their concerns were mapped to neurocognitive domains to identify concern content areas and were compared with existing cognitive questionnaires. A questionnaire was developed to estimate the prevalence and importance of the items. RESULTS: Sixty of 125 items were retained in the questionnaire based on ratings of their prevalence, importance, and clarity. Memory and behavioral and emotional concerns were the most common content areas (15 each); other domains were attention (7), executive function (6), language (5), and cognitive change (12). CONCLUSION: People living with HIV experience difficulties in all domains of cognition. By recognizing all domains, this new measure can help clinicians better understand areas of perceived cognitive difficulty and plan interventions accordingly. PMID- 29426383 TI - Therapy Caps and Variation in Cost of Outpatient Occupational Therapy by Provider, Insurance Status, and Geographic Region. AB - OBJECTIVE: This article describes the cost of occupational therapy by provider, insurance status, and geographic region and the number of visits allowed and out of-pocket costs under proposed therapy caps. METHOD: This retrospective, population-based study used Medicare Provider Utilization and Payment Data for occupational therapists billing in 2012 and 2013 (Ns = 3,662 and 3,820, respectively). We examined variations in outpatient occupational therapy services with descriptive statistics and the impact of therapy caps on occupational therapy visits and patient out-of-pocket costs. RESULTS: Differences in cost between occupational and physical therapists were minimal. The most frequently billed service was therapeutic exercises. Wisconsin had the most inflated outpatient costs in both years. Under the proposed therapy cap, patients could receive an evaluation plus 12-14 visits. DISCUSSIO: . Wide variation exists in potential patient out-of-pocket costs for occupational therapy services on the basis of insurance coverage and state. Patients without insurance pay a premium. PMID- 29426386 TI - Mirror Therapy and Task-Oriented Training for People With a Paretic Upper Extremity. AB - OBJECTIVE: This study investigates the effect of mirror therapy and task-oriented training on the paretic upper extremity function and occupational performance of people with stroke. METHOD: This study used a repeated-measures, case-series design in which 4 participants completed a 4-wk intervention consisting of mirror therapy and task-specific training. The intervention was conducted 2*/wk in the clinic and 4*/wk at home. RESULTS: All participants displayed clinically meaningful improvements in self-identified goals at the end of the intervention and at follow-up. Three participants showed clinically meaningful changes in motor function. Although only 1 participant improved in his reported amount of use, all participants showed clinically meaningful improvements in perceived movement quality at varying points of assessment. CONCLUSION: Mirror therapy, when used as priming for task-oriented training, can produce clinical improvements in upper extremity function and occupational performance in people with hemiparesis. PMID- 29426387 TI - Effectiveness of the Co-PID for Students With Moderate Intellectual Disability. AB - OBJECTIVE: We aimed to corroborate the effectiveness of the Collaborative Consultation for Participation of Students With Intellectual Disability (Co-PID), intended for enhancing participation in classroom-related activities. METHOD: The study took place in two special education schools and included students with moderate intellectual and developmental disabilities ages 7-20 yr. The schools were randomly assigned to intervention (Co-PID; n = 28 students, n = 4 teachers) and control (In-Service [IS]; n = 32 students, n = 7 teachers) groups. Participation was evaluated at pre- and posttest of an 8-mo intervention. RESULTS: The Co-PID improved students' ability to choose among provided options. Additionally, the Co-PID group achieved more goals (measured by goal attainment scaling) than the IS group in all participation areas, and their enhanced participation transferred to other school environments (as measured by the School Function Assessment). CONCLUSION: The Co-PID was found to be an effective program for enhancing classroom and school participation. PMID- 29426388 TI - Goal Attainment and Goal Adjustment of Older Adults During Person-Directed Cancer Rehabilitation. AB - OBJECTIVE: In this pilot study of a home-based occupational therapy intervention intended to reduce disability and improve quality of life, our objective was to identify rates of goal attainment and patterns of goal adjustment of participants. METHOD: Thirty older adults with cancer were randomized to the intervention arm, and 24 participants identified goals and completed the six session intervention. An exploratory content analysis of qualitative and quantitative session data was performed. RESULTS: Participants set 63 6-wk goals and attained 62% of them. Most of the goals addressed walking (28%), sedentary leisure (24%), exercising (16%), or instrumental activities of daily living (14%). When 6-wk goals were not attained (n = 24), there were 10 instances of goal disengagement and 14 instances of goal reengagement. CONCLUSION: Although most participants were able to meet their goals, many also changed their goals and priorities after reflection and attempts to resume or initiate meaningful activities. PMID- 29426389 TI - Occupational Therapy in Medicaid Home and Community-Based Services Waivers. AB - OBJECTIVE: Medicaid Home and Community-Based Services (HCBS) 1915(c) waivers are the largest provider of long-term services and supports for people with intellectual and developmental disabilities (IDDs). In this study, we explored how HCBS IDD waivers projected providing occupational therapy services in Fiscal Year (FY) 2015. METHOD: Medicaid HCBS IDD waivers across the nation gathered from the Centers for Medicare and Medicaid Services were qualitatively and quantitatively analyzed to determine how they projected providing occupational therapy services in terms of service expenditures and utilization. RESULTS: In FY 2015, $14.13 million of spending was projected for occupational therapy services of 7,500 participants. However, there was large heterogeneity across states and services in terms of total projected spending, spending per participant, and reimbursement rates. CONCLUSION: Comparisons across states strengthen the profession's ability to assert the value of its services. These findings can help identify best practices and can advocate for the refinement of state occupational therapy programs. PMID- 29426390 TI - Lighting as a Compensatory Strategy for Acquired Visual Deficits After Stroke: Two Case Reports. AB - OBJECTIVE: The objective of this article was to explore the effects of enhanced lighting on the function of people with an acquired visual deficit resulting from cerebrovascular accident (CVA) in an inpatient rehabilitation facility (IRF). METHOD: An ABAB design was used with two cases to assess how a short-term intervention involving lighting changes affected clients' grooming performance in an IRF. Analysis consisted of scores on the grooming section of the FIM(r), times for each grooming task, and light meter readings. RESULTS: Both participants demonstrated improvements in function as measured by the FIM and in time to complete grooming tasks with enhanced lighting. CONCLUSION: These results suggest that individualized lighting can lead to improved grooming function in clients with CVA. PMID- 29426391 TI - Use of the Wilmington Robotic Exoskeleton to Improve Upper Extremity Function in Patients With Duchenne Muscular Dystrophy. AB - Patients with Duchenne muscular dystrophy in their second decade of life present with decreased upper extremity strength and active range of motion (AROM) that limit activities of daily living (ADLs). We evaluated the ability of the Wilmington Robotic Exoskeleton (WREX) to improve AROM and independence with ADLs. A retrospective chart review of 9 patients who trialed the WREX was performed. Patients were classified on the basis of the Brooke Upper Extremity Scale. AROM, strength, and independence with ADLs were assessed before and after a WREX trial. Patients demonstrated increased shoulder flexion and abduction (25 degrees -100 degrees , median = 55 degrees ) and elbow flexion (10 degrees -110 degrees , median = 60 degrees ). Increased independence with self-feeding, item retrieval, use of phones and tablets, and facial grooming were noted. The WREX allowed for gravity-reduced movement via elastic bands to unweight the upper extremity, enabling increased upper extremity active movement that supported increased independence with ADLs. PMID- 29426392 TI - Effects of Lighting on Reading Speed as a Function of Letter Size. AB - OBJECTIVE: We sought to determine under what conditions brighter lighting improves reading performance. METHOD: Thirteen participants with typical sight and 9 participants with age-related macular degeneration (AMD) read sentences ranging from 0.0 to 1.3 logMAR under luminance levels ranging from 3.5 to 696 cd/m2. RESULTS: At the dimmest luminance level (3.5 cd/m2), reading speeds were slowest at the smaller letter sizes and reached an asymptote for larger sizes. When luminance was increased to 30 cd/m2, reading speed increased only for the smaller letter sizes. Additional lighting did not increase reading speeds for any letter size. Similar size-related effects of luminance were observed in participants with AMD. CONCLUSION: In some instances, performance on acuity limited tasks might be improved by brighter lighting. However, brighter lighting does not always improve reading; the magnitude of the effect depends on the text size and the relative changes in light level. PMID- 29426393 TI - Pilot Study Combining Electrical Stimulation and a Dynamic Hand Orthosis for Functional Recovery in Chronic Stroke. AB - OBJECTIVE: We investigated the effect of a combined neuromuscular electrical stimulation (ES) and dynamic hand orthosis (DHO) regimen with a group of people with chronic stroke to improve performance on specific daily tasks. METHOD: Four people with chronic stroke participated in an ES-DHO regimen using the affected upper extremity 5*/wk for 6 wk. Outcome measures included grip strength, range of motion (ROM), and analysis of muscle activation-deactivation during release of grasp through electromyography. Ability to perform specific daily living tasks was assessed using the Assessment of Motor and Process Skills (AMPS). RESULTS: Results suggested that improvements in strength, ROM, and grasp deactivation are possible with the combined ES-DHO regimen. All participants' AMPS motor scores improved. CONCLUSIONS: An ES-DHO regimen may improve motor skills needed for functional task performance in people with chronic stroke. Results should be interpreted cautiously because of the pilot nature of the study and the small sample size. PMID- 29426394 TI - Feasibility of a Manualized Occupation-Based Diabetes Management Intervention. AB - OBJECTIVE: We investigated the feasibility and acceptability of an occupational therapy intervention targeting diabetes management for underserved young adults. METHOD: Eight participants completed the intervention and a battery of assessments at baseline and after the intervention. At completion, the participants and occupational therapist were interviewed about their experiences with the study. Four categories of assessment questions were used to guide the study: process, resource, management, and scientific. RESULTS: Successes included recruitment; fulfillment of tasks by staff and partnering clinics; adequate space, financial support, and equipment; and meaningfulness of the intervention for participants. Challenges included scheduling participants for the intervention and follow-up focus groups and providing client centeredness and flexibility while reducing burden on the intervener. CONCLUSION: This feasibility study allowed us to make necessary revisions to our study protocol before implementing a larger pilot study. PMID- 29426395 TI - Research Opportunities in the Area of Adults With Alzheimer's Disease and Related Neurocognitive Disorders. AB - The American Occupational Therapy Association (AOTA) Evidence-Based Practice Project has developed a table summarizing the research opportunities for adults with Alzheimer's disease and related major neurocognitive disorders. The table provides an overview of the state of current available evidence on interventions within the scope of occupational therapy practice and is based on the systematic reviews from the AOTA Practice Guidelines Series. Researchers, clinicians, and students can use this information in developing innovative research to answer important questions within the occupational therapy field. PMID- 29426398 TI - Corrigendum to "Total parenteral nutrition for the very low birth weight infant" [Semin Fetal Neonatal Med 2017;22(1):2-7]. PMID- 29426399 TI - Induction of innate host responses characterized by production of interleukin (IL)-1beta and recruitment of macrophages to the respiratory tract of chickens following infection with infectious bronchitis virus (IBV). AB - Infectious bronchitis virus (IBV) infection is a major cause of economic losses to the poultry industry. Due to limitations in current control measures, alternative approaches, based on thorough understanding of the host responses are required. As one of the key component of the avian immune system, the innate immune system has a crucial role in limiting virus replication at the initial stage of the infection. As parts of the innate host response, macrophages and cytokines, such as interleukin (IL)-1beta, are critical components as shown in other host-virus infection models. Since information on the importance of macrophages and IL-1beta in IBV infection in chickens is limited, our objective was to determine the association of IL-1beta, originating from avian macrophages and IBV infection in the trachea and lung. Following experimental IBV infection in 6 days old chickens, we found increased production of IL-1beta and increased recruitment of macrophages in the respiratory tract. Towards the end of the study (5 and 7 days following the IBV infection), the recruited macrophages appear to be a significant source IL-1beta. However, only the recruitment of macrophages in the lung correlated with IBV genome loads in this tissue. In conclusion, the present study demonstrates that recruitment of macrophages and the production of IL-1beta originating from macrophages, as well as other sources, occur following IBV infection in the respiratory tract suggesting potential roles of these mediators in the host responses to IBV infection. However, further studies are warranted to elucidate whether macrophages and IL-1beta are the causes of reduced IBV genome loads in the respiratory tract and also to investigate whether immune mediators that were not measured in the current study were involved in reducing IBV genome load in the respiratory tract towards the end of the study. PMID- 29426400 TI - Role of the stress-associated chemicals norepinephrine, epinephrine and substance P in dispersal of Mannheimia haemolytica from biofilms. AB - Bovine respiratory disease (BRD) is a major problem for the cattle industry that is triggered by various environmental stressors, pathogens and host responses. Mannheimia hemolytica, an important bacterial component of BRD, are present within the nasopharayngeal region of normal calves as commensal biofilm communities. However, following stress there are changes in the nasopharyngeal microenvironment that triggers the transition of the commensal M. haemolytica into a pulmonary pathogen. The factors responsible for this transition in- vivo are unknown. In this study we developed an in-vitro biofilm model and investigated the effect of three stress- related compounds: norepinephrine (NE), epinephrine (E), and substance P (SP) on M. haemolytica biofilms. Biofilm formation was demonstrated for 3 bovine nasal isolates of M. haemolytica by growing them in basal culture media, basal media with additional glucose, and basal media with a reduced pH. Increased glucose enhanced biofilm biomass for 2/3 isolates, but acidic media did not increase biofilm biomass when compared to biofilm biomass in basal media. When the biofilm was exposed to NE, E and SP, there was a dispersal of the biofilm which was most effective with E, followed by NE, and SP being the least effective. Using high - throughput scanning electron microscopy and confocal-imaging we confirmed our experimental data that treatment with NE, E and SP cause dispersion of M.haemolytica from biofilms. PMID- 29426401 TI - Guinea pig infection with the intracellular pathogen Rhodococcus equi. AB - Rhodococcus equi is an opportunistic, intracellular pathogen that causes pyogranulomatous pneumonia in foals and immunocompromised people. Currently, there is no experimental model of R. equi pneumonia other than intra-bronchial experimental infection of foals with R. equi, which is labor-intensive and costly. This study's objective was to develop a guinea pig (GP) model of R. equi pneumonia that would facilitate development of novel approaches for controlling and preventing this disease. Guinea pigs were infected with either 101, 102, 103, or 104 colony forming units (CFUs) of a virulent strain of R. equi using a Madison aerosol chamber, or 106 or 107 CFUs of this strain intratracheally. Animals were monitored daily for clinical signs of pneumonia, and were euthanized and necropsied on days 1, 3, 7, or 35 post-infection (PI). Lung homogenates were plated onto selective agar to determine bacterial load. No clinical signs of disease were observed regardless of the inoculum dose or infection method. No bacteria were recovered from GPs euthanized at 35 days PI. Histology and immunostaining of T-cells, B-cells, and macrophages in lungs showed that inflammatory responses in infected GPs were similarly unremarkable irrespective of dose or route of infection. Guinea pigs appear to be resistant to pulmonary infection with virulent R. equi even at doses that reliably produce clinical pneumonia in foals. PMID- 29426402 TI - Duck hepatitis A virus structural proteins expressed in insect cells self assemble into virus-like particles with strong immunogenicity in ducklings. AB - Duck hepatitis A virus (DHAV), a non-enveloped ssRNA virus, can cause a highly contagious disease in young ducklings. The three capsid proteins of VP0, VP1 and VP3 are translated within a single large open reading frame (ORF) and hydrolyzed by protease 3CD. However, little is known on whether the recombinant viral structural proteins (VPs) expressed in insect cells could spontaneously assemble into virus-like particles (VLPs) and whether these VLPs could induce protective immunity in young ducklings. To address these issues, the structural polyprotein precursor gene P1 and the protease gene 3CD were amplified by PCR, and the recombinant proteins were expressed in insect cells using a baculovirus expression system for the characterization of their structures and immunogenicity. The recombinant proteins expressed in Sf9 cells were detected by indirect immunofluorescence assay and Western blot analysis. Electron microscopy showed that the recombinant proteins spontaneously assembled into VLPs in insect cells. Western blot analysis of the purified VLPs revealed that the VLPs were composed with the three structural proteins. In addition, vaccination with the VLPs induced high humoral immune response and provided strong protection. Therefore, our findings may provide a framework for development of new vaccines for the prevention of duck viral hepatitis. PMID- 29426403 TI - Putative virulence factors and clonal relationship of O174 Shiga toxin-producing Escherichia coli isolated from human, food and animal sources. AB - Shiga toxin-producing Escherichia coli (STEC) is th etiological agent of gastrointestinal diseases as haemorrhagic colitis and haemolytic-uraemic syndrome (HUS). Shiga toxin (Stx) is the main virulence factor. There are two types, Stx1 and Stx2, and several subtypes. Other virulence factors are involved in pathogenesis. While O157:H7 is the predominant serotype, at present non-O157 STEC strains are increasingly recognized as foodborne pathogens worldwide. In Argentina, STEC O174 stands out as an emerging pathogen and is one of the four most prevalent non-O157 STEC serogroups. The aim of this study was to characterize 41 O174:[H21, H28] STEC strains isolated from animals, food, and humans. Isolates were characterized by stx genotyping, adhesion factors (afaC, eae, iha, lpfO113, saa, and toxB), additional toxins (cdtV, ehxA, subA) and clonal relationship by pulsed-field gel electrophoresis (PFGE). Among 30 O174:H21 strains, the most prevalent stx subtype was stx2c (56.7%), and among 11 O174:H28 strains, the most prevalent was stx2a (90.9%). Regarding virulence factors, all strains were positive for afaC gene and negative for eae and toxB genes. In O174:H21, the frequency of additional factors was lpfO113 (96.6%), iha (83.3%), ehxA and saa (10%), and subA (3.3%), meanwhile in O174:H28 strains the frequency was iha and subA (100%), lpfO113 (90.9%), ehxA and saa (90.9%), and cdtV (9.09%). By Xbal-PFGE, 29 patterns were established with 64.01% similarity and three clusters were detected. Given the fact that the O174 serogroup is a local emergent, it is important to study the virulence profiles to understand its potential pathogenicity. PMID- 29426404 TI - Genomic investigation of Staphylococcus aureus isolates from bulk tank milk and dairy cows with clinical mastitis. AB - Staphylococcus aureus is one of the most common pathogens that cause mastitis in dairy cows. Various subtypes, virulence genes and mobile genetic elements have been associated with isolates from bulk tank milk and clinical mastitis. So far, no Danish cattle associated S. aureus isolates have been whole-genome sequenced and further analyzed. Thus, the main objective was to investigate the population structure and genomic content of isolates from bulk tank milk and clinical mastitis, using whole-genome sequencing. This may reveal the origin of strains that cause clinical mastitis. S. aureus isolates from bulk tank milk (n = 94) and clinical mastitis (n = 63) were collected from 91 and 24 different farms, respectively and whole-genome sequenced. The genomic content was analyzed and a phylogenetic tree based on single nucleotide polymorphisms was constructed. In general, the isolates from both bulk tank milk and clinical mastitis were of similar genetic background. This suggests that dairy cows are natural carriers of the S. aureus subtypes that cause clinical mastitis if the right conditions are present and that a broad range of subtypes cause mastitis. A phylogenetic cluster that mostly consisted of ST151 isolates carried three mobile genetic elements that were primarily found in this group. The prevalence of resistance genes was generally low. However, the first ST398 methicillin resistant S. aureus isolate from a Danish dairy cow with clinical mastitis was detected. PMID- 29426405 TI - Bta-miR-2411 attenuates bovine viral diarrhea virus replication via directly suppressing Pelota protein in Madin-Darby bovine kidney cells. AB - MicroRNAs (miRNAs) are endogenous ~22 nt noncoding RNAs that control the translation initiation and stability of target genes in a sequence-specific manner and, thus, play important regulatory roles in animals and plants. Homologs of Dom34, called Pelota or PELO, are broadly conserved in eukaryotes and archaea. Biochemical and genetic studies indicate that eukaryotic Dom34/Pelota plays an important role in cell division, differentiation of germline stem cells, and stem cell self-renewal by controlling the expression of specific genes at the translational level. Additionally, it is reported that Pelota is specifically required for high efficiency synthesis of proteins in numerous viruses. In earlier studies, we found the Bos taurus bta-miR-2411 (shortly miR-2411 herein) was significantly upregulated by more than 2.1 times in bovine viral diarrhea virus (BVDV) strain NADL-infected Madin-Darby bovine kidney (MDBK) cells after 8 h post-infection (pi) compared to normal MDBK cells without BVDV infection. Moreover, miR-2411 overexpression significantly reduced the BVDV E1 mRNA level and viral titer. Nevertheless, the mechanisms of miR-2411 attenuating on viral replication remain unclear. Here, we report that miR-2411 as a novel microRNA regulates BVDV NADL replication via directly targeting the Pelota gene in MDBK cells. We investigated whether the potential target sequences of miR-2411, located in the Pelota 3'UTR, and miR-2411 agomir transfection attenuated Pelota mRNA and protein levels. Indeed, upon miR-2411 overexpression, BVDV NADL replication was prevented. Importantly, BVDV NADL replication levels were reversed to normal levels as a result of the Pelota rescuing experiment even though miR-2411 was existent. Overall, we profiled the unique role of miR-2411 in regulating BVDV NADL replication and provided a novel strategy for generalized inhibition of viral infection. PMID- 29426406 TI - Seroprevalence of horses to Coxiella burnetii in an Q fever endemic area. AB - Coxiella burnetii can infect many animal species, but its circulation dynamics in and through horses is still unclear. This study evaluated horse exposure in an area known to be endemic for ruminants and humans. We assessed antibody prevalence in horse serum by ELISA, and screened by qPCR horse blood, ticks found on horses and dust from stables. Horse seroprevalence was 4% (n = 335, 37 stables) in 2015 and 12% (n = 294, 39 stables) in 2016. Of 199 horses sampled both years, 13 seroconverted, eight remained seropositive, and one seroreverted. Seropositive horses were located close to reported human cases, yet none displayed Q fever-compatible syndromes. Coxiella DNA was detected in almost 40% of collected ticks (n = 59/148 in 2015; n = 103/305 in 2016), occasionally in dust (n = 3/46 in 2015; n = 1/14 in 2016) but never in horse blood. Further studies should be implemented to evaluate if horses may be relevant indicators of zoonotic risk in urban and suburban endemic areas. PMID- 29426407 TI - Seroprevalence and risk factors for selected respiratory and reproductive tract pathogen exposure in European bison (Bison bonasus) in Poland. AB - After the complete extinction from the wild of European bison (Bison bonasus) at the beginning of the twentieth century, the worldwide species population was restored to approximately 5500 individuals, with the species however remaining endangered. Despite numerous studies on the ecology and genetics of European bison, the threats of infectious diseases have been largely unexamined. The aim of this study was to screen the exposure of the world's largest population of European bison to the pathogens, which may influence the condition and development of the endangered species. A total of 240 free-ranging and captive European bison from eight main Polish populations sampled were tested for the presence of specific antibodies against ten different viruses, bacteria or protozoan. The samples were collected from chemically immobilized, selectively culled or found dead animals. Based on serology, the exposure to bovine viral diarrhea virus (BVDV), bovine herpesvirus type 1 (BoHV-1), Mycoplasma and Brucella spp. was determined as rather accidental. Using gamma-interferon assay followed by Mycobacterium tuberculosis subs. caprae detection in tissues, diagnosis of bovine tuberculosis was made for 6 out of 78 (7.7%) bison from one captive herd. The highest seroprevalence was found for bovine adenovirus type 3 (BAdV-3) -60.2% and bovine parainfluenza type 3 (PIV-3) -34.0%, while the antibodies against bovine respiratory syncytial virus (BRSV), Toxoplasma gondii and Leptospira spp. were found in 10.4%, 10.4% and 8.7% of samples, respectively. In the multivariable statistical analysis using generalized linear mixed models (GLMMS), the risk factors for PIV-3 seropositivity included population type (free living/captive), age and health status (apparently healthy/eliminated due to the poor condition). Higher risk of BAdV-3 seropositive result was observed in free living female European bison. The high BAdV-3 and PIV-3 seroprevalences may suggest involvement of these pathogens in the most frequently observed respiratory disorders in European bison. Moreover, this is the first study demonstrating BAdV-3 exposure in the species. PMID- 29426408 TI - Potential for the cross-species transmission of swine torque teno viruses. AB - Torque teno viruses [TTVs] are negative sense, single-stranded, DNA viruses, which are distributed globally in several mammalian hosts such as humans, apes, sheep and swine in a species-specific manner. While the pathogenic potential of TTVs is under debate, recent experimental studies in gnotobiotic pigs indicate that swine TTVs, TTSuV1 in particular, can act as a primary or co-infecting pathogen. Hence, determining whether TTSuV1 can infect other mammals would eventually further our understanding of viral pathogenesis, especially in coinfections. In this study, we tested sera from horses, cattle, sheep, dogs and elk for the presence of TTSuV1 DNA using a panel of TTSuV1-specific primers, and assessed the extent of sero-conversion to TTSuV1 in the selected species. We found that TTSuV1 DNA was detected in 46.7% of equines, 70% of canine, 100% of bovine, 40% of ovine and 93.3% of elk samples. However, significant TTSuV1 specific antibody responses were detected only in the bovine, ovine and equine samples but not the canine or elk samples, indicating that these animals could support the replication of TTSuV1. This combined serological and molecular epidemiological profile of TTSuV1 infection in five different species indicates the host range of species-specific TTVs could be wider than initially believed. Further studies are required to understand the health risks to these animal species from TTSuV-1 infection. PMID- 29426409 TI - Porcine circovirus type 3 (PCV3) infection in grower pigs from a Thai farm suffering from porcine respiratory disease complex (PRDC). AB - Porcine circovirus type 3 (PCV3) is a newly emerging virus with unknown pathogenesis. The major objective of this study was to investigate the presence of PCV3 in pigs from a farm in Thailand suffering from porcine respiratory disease complex (PRDC). Initially, a Thai PCV3 strain (PCV3/Thailand/PB01/17) was identified from a pig originated from a farm with PRDC problem during grower period and whole genome analysis showed that the Thai PCV3 shared highest nucleotide identity of 99.60% with the South Korean strain PCV3/KU-1602. The presence of PCV3 infection in PRDC-affected pigs was then investigated in this farm. Serum samples from clinically healthy pigs and pigs showing PRDC-related clinical signs during 5-18 weeks were used in PCV3 detection by PCR. The results showed that the PRDC-affected pigs exhibited higher prevalence of PCV3 infection and higher PCV3 titers comparing with the clinically healthy pigs. These results confirmed the presence of PCV3 in a Thai farm with PRDC problem. The pathogenesis of PCV3 on PRDC should be clarified in further studies. PMID- 29426410 TI - Diversity of methicillin-resistant Staphylococcus aureus (MRSA) isolated from Austrian ruminants and New World camelids. AB - The aim of this study was to determine the prevalence, the antimicrobial resistance patterns and the genetic diversity of methicillin-resistant Staphylococcus aureus (MRSA) from Austrian ruminants and New World camelids that were treated at the University of Veterinary Medicine, Vienna. Between April 2014 and January 2017, 723 nasal swabs originating from ruminants and New World camelids were examined. MRSA isolates were characterized by mecA/mecA1/mecC PCRs and by DNA microarray analysis. They were genotyped by spa typing, dru typing, MLST and MLVA. Glycopolymer fingerprinting by FTIR spectroscopy was also performed. Antimicrobial susceptibility testing was conducted by agar disk diffusion. Twelve MRSA isolates were mecA-positive, whereas three were mecC positive. The MRSA isolates carried five different SCCmec elements, and belonged to three sequence types (ST45, ST130, ST398). The MRSA isolates displayed seven different resistance phenotypes. The present study describes for the first time mecC-carrying MRSA isolates originating from domesticated animals in Austria. More systematic studies are needed to unravel the role of ruminants and New World camelids as reservoirs for MRSA as a potential risk for zooanthropogenic transmission. PMID- 29426411 TI - Lack of association between Leptospira spp. serovars Hardjobovis and Pomona and pregnancy and mid-term abortion in New Zealand farmed red deer. AB - This paper investigates Leptospira borgpeterseni serovar Hardjobovis and L. interrogans serovar Pomona as potential causes of sub-optimum pregnancy rates and mid-term abortion in farmed red deer. Rising two-year-old (R2, n = 22,130) and mixed-age (MA, n = 36,223) hinds from 87 and 71 herds, respectively, throughout New Zealand were ultrasound scanned early in gestation (Scan-1) and a sub-sample re-scanned (Scan-2) 55-89 days later and mid-term daily abortion rate calculated. A sub-sample of sera from pregnant and non-pregnant hinds at both scans, both with (case herds) and without aborted hinds was tested for Leptospira using the microscopic agglutination test with titre cut-point >=1:48 as positive. At Scan 1, 44.3% of 661 and 4.6% of 647 hinds were sero-positive for Hardjobovis and Pomona, respectively. The geometric mean titre (GMT) for Pomona was higher in pregnant than non-pregnant MA hinds (p = 0.015) but not in R2 hinds. At Scan-2 in case herds, 40.3% of 2242 and 7.1% of 2243 hinds were sero-positive for Hardjobovis and Pomona, respectively. There was no association between Hardjobovis or Pomona serology and non-pregnancy (Scan-1) or mid-term abortion (Scan-2) at animal or herd level. In case herds, GMT was higher in non-aborted than aborted hinds for Hardjobovis (p = 0.018) in MA herds and for Pomona in R2 herds (p = 0.006). No uteri from hinds not pregnant or aborting at either scan, or not rearing a calf to weaning, and fetuses as available, were positive on PCR. Evidence is insufficient to confirm that Leptospira Hardjobovis and Pomona play a significant role in sup-optimum early pregnancy or mid-term abortion rates in deer. PMID- 29426413 TI - Comparative effectiveness research requires competitive effectiveness. PMID- 29426412 TI - New host species for Leptospira borgpetersenii and Leptospira interrogans serovar Copenhageni. AB - We investigated the presence of infection by Leptospira spp. in an assembly of Sigmodontinae rodents from the Parana Delta, Argentina. Rodents were captured in places with natural grassland, implanted forest, with and without raising cattle and in sites prone and not prone to flooding. The DNA was amplified from cultured isolates by PCR and Leptospira spp. strains were genotyped using Multiple - Locus Variable Number Tandem Repeat Analysis (MLVA). We isolated Leptospira interrogans serovar Copenhageni from Oligoryzomys nigripes, Leptospira borgpetersenii from Scapteromys aquaticus and Leptospira interrogans serovar Icterohaemorrhagiae from Akodon azarae. The zoonotic Leptospira isolated and genotyped from O. nigripes and S. aquaticus are the first reports from these species. The geographic range of these rodent species include, in addition to Argentina, the countries of Paraguay, Uruguay and Brazil, suggesting that these rodents might be involved in the transmission of spirochetes in other regions. Human and animal health care professionals should be alert to the potential occurrence of leptospirosis in areas where these rodent species are present. PMID- 29426414 TI - A critical assessment of transmethylation procedures for n-3 long-chain polyunsaturated fatty acid quantification of lipid classes. AB - Lipid transmethylation methods described in the literature are not always evaluated with care so to insure that the methods are effective, especially on food matrix or biological samples containing polyunsaturated fatty acid (PUFA). The aim of the present study was to select a method suitable for all lipid species rich in long chain n-3 PUFA. Three published methods were adapted and applied on individual lipid classes. Lipid (trans)methylation efficiency was characterized in terms of reaction yield and gas chromatography (GC) analysis. The acid-catalyzed method was unable to convert triglycerides and sterol esters, while the method using an incubation at a moderate temperature was ineffective on phospholipids and sterol esters. On the whole only the method using sodium methoxide and sulfuric acid was effective on lipid classes taken individually or in a complex medium. This study highlighted the use of an appropriate (trans)methylation method for insuring an accurate fatty acid composition. PMID- 29426415 TI - Alliinase and cysteine synthase transcription in developing garlic (Allium sativum L.) over time. AB - Garlic is a valuable source of healthy compounds, including secondary metabolites rich in sulphur such as cysteine sulphoxides (CSOs). Here, we present new qRT-PCR assays analysing the transcription of two genes encoding key enzymes in CSO biosynthetic pathways (cysteine synthase and alliinase) in developing garlic. We also identified a set of genes (ACT I, GAPDH, and TUB) to use as transcription normalisation controls. We showed that the (normalised) transcription of both enzymes was highest during sprouting and decreased significantly in fully developed leaves, which are the major CSO-producing organs. Transcriptional activity further declined at the end of the growing season. Different cultivars show similar sulphur metabolism gene expression when European garlics were compared to Chinese and American genotypes. The qRT-PCR assays presented are also suitable for investigating the effects of agricultural practices on CSO formation in garlic to satisfy consumer demands. PMID- 29426416 TI - Seasonal variations of iminosugars in mulberry leaves detected by hydrophilic interaction chromatography coupled with tandem mass spectrometry. AB - A rapid, sensitive, and validated method was developed for the simultaneous determination of four iminosugars, 1-deoxynojirimycin (DNJ), d-fagomine (FAG), 2 O-a-d-galactopyranosyl-DNJ (Gal-DNJ), and 4-O-beta-d-glucopyranosyl-fagomine (Glu FAG), in mulberry leaves. The method used hydrophilic interaction chromatography coupled with tandem mass spectrometry. Based on this method, the seasonal variations of iminosugars in the leaves of different mulberry species (Morus alba, Morus multicaulis Perr, Morus atropurpurea Roxb. and Morus wittiorum Hand Mazz.) collected in Guangzhou, China, during 10 consecutive months in 2013 were investigated. The results indicated that the maximum content of DNJ in the leaves of all four species occurred in summer (June or July). The highest FAG level was found in spring (April or May). The highest levels of Gal-DNJ and Glu-FAG were recorded in autumn (September or October). PMID- 29426417 TI - Production of galacto-oligosaccharides from whey permeate using beta galactosidase immobilized on functionalized glass beads. AB - The conversion of whey permeates to galacto-oligosaccharides (GOS) was studied by the enzymatic action of beta-galactosidase from Aspergillus oryzae in a continuous flow packed-bed reactor. A novel method of enzyme immobilization involving covalent immobilization of beta-galactosidase on 3-aminopropyl triethoxysilane(3-APTES)-modified glass beads was developed by the cross-linking method. The pH and temperature dependence of the enzymatic efficiency of the glass bead-immobilized enzyme was compared with that of the free enzyme. Increased pH and thermal stabilities were observed for the immobilized enzyme versus the free enzyme. The reusability of the enzyme immobilized packed-bed reactor was studied and only about 4.6% of GOS yield was lost after eight reuses. Repeated cycle reactions were also carried out to improve the formation of GOS. The results showed that the GOS formation increased and a maximum GOS yield of 39.3% with 56.4% lactose conversion was obtained after the 2nd cycle of passing. PMID- 29426418 TI - Antioxidative and anti-inflammatory pyranoids and isochromenyl analogues from Corbiculid bivalve clam, Villorita cyprinoides. AB - Bivalve black clam, Villorita cyprinoides is traditional seafood in Southwestern coast of Arabian Sea. In this study, bioactivity-guided purification of ethyl acetate:methanol extract of black clam was carried out. Two irregular meroterpenoids {tetrahydro-3-methoxy-5-((E)-8,12-dimethyloct-8-enyl)-pyran-2-one (1) and dihydro-5-(8-(9,12-dihydro-8-methyl-11-propyl-2H-pyran-8-yl)-ethyl)-furan 2(3H)-one (2)} and two hexahydro-isochromenyl-meroterpenoids (3-4) were identified. The structures were characterized by detailed spectroscopy and their antioxidant/anti-inflammatory potentials were evaluated. Compound 2 registered significantly greater 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging ability (IC50 <0.65 mg/mL) than other analogues (IC50 >=0.70 mg/mL). Ferrous ion (Fe2+) chelating ability was higher for 1-2 (IC50 ~0.84 mg/mL) than alpha tocopherol (IC50 0.89 mg/mL). The 5-lipoxygenase inhibitory potential of furano meroterpenoid analogue, 2 (IC50 0.76 mg/mL) was greater than other compounds (IC50 >0.90 mg/mL). An optimum hydrophobic-hydrophilic balance of furano meroterpenoid and lesser steric bulk manifested towards its greater bioactivities compared to other compounds. These anti-inflammatory and antioxidant leads could be used as potential functional food components. PMID- 29426419 TI - Effects of chitosan based coatings enriched with procyanidin by-product on quality of fresh blueberries during storage. AB - The aim of this work was to evaluate the efficacy of an innovative edible coating, based on chitosan from mushrooms enriched with procyanidins extracted from grape seeds, on fresh blueberry quality maintenance, (weight loss, pH, dry matter, colour, firmness and antioxidant activity) and microbial growth, during 14 days of storage at 4 degrees C. For weight loss, pH and dry matter no relevant differences were detected among the control and the differently coated samples at each considered storage time. Chitosan and chitosan + procyanidins coatings promoted a slight decrease of luminosity and an increase of blue hue colour of blueberry samples during the whole storage period. The use of coating promoted an increase in the antiradical activity that was the highest in blueberries coated with chitosan + procyanidins. Microbiological analysis results indicated that the chitosan-based coated samples had a significantly higher yeast and mould growth inhibition compared to the uncoated sample. PMID- 29426420 TI - Differential proteomic analysis to identify proteins associated with quality traits of frozen mud shrimp (Solenocera melantho) using an iTRAQ-based strategy. AB - An iTRAQ-based strategy was applied to investigate proteome changes in mud shrimp during long-term frozen storage under different conditions. A total of 226 proteins was identified as differential abundance proteins (DAPs) in mud shrimp from two frozen treatment groups (-20 degrees C and -40 degrees C) compared with the fresh control group. The proteome changes in mud shrimp muscle stored under -20 degrees C was much greater than that under -40 degrees C. Correlation analysis between DAPs and quality traits of mud shrimp muscle showed that 12 proteins were correlated closely with color (L*, a*, and b* value) and texture (hardness, elasticity, and chewiness). Bioinformatic analysis revealed that most of these proteins were involved in protein structure, metabolic enzymes, and protein turnover. Among them, several proteins might be potential protein markers for color, and some proteins are good candidate predictors for textural properties of mud shrimp muscle. PMID- 29426421 TI - Structural properties and prebiotic activities of fractionated lotus seed resistant starches. AB - The objective of this study was to fractionate lotus seed resistant starch (LRS3) and investigate their structural properties and prebiotic activities. Two main fractions of resistant starch precipitated gradually by ethanol at concentrations of 20% and 30% were named as LRS3-20% and LRS3-30%, respectively. The swelling power and solubility of LRS3-20% were smaller compared to LRS3-30%, and their moisture and resistant starch contents were not significantly different. LRS3-20% and LRS3-30% had molecular weights mainly of 2.0 * 104-4.0 * 104 and 1.0 * 104 2.0 * 104 g/mol. Layered strips and gully shapes were evident on the rough surfaces of LRS3-20%, while LRS3-30% displayed a relatively smooth surface. Both LRS3-20% and LRS3-30% had a B-type crystalline structure with LRS3-20% containing more ordered structures and double-helices. Furthermore, LRS3-20% displayed higher prebiotic activities against Bifidobacterium adolescentis and Lactobacillus acidophilus compared to LRS3-30% and high amylose maize starch. This effect was related to its rough surface and double helix structure. PMID- 29426423 TI - Improvement of curcuminoid bioaccessibility from turmeric by a nanostructured lipid carrier system. AB - Turmeric contains curcumin and its analogues, which show anticancer and antiinflammatory effects; however, curcuminoids are lipophilic and are poorly absorbed by the human body. Nanostructured lipid carriers for encapsulating whole turmeric powder were successfully produced by ultrasonication, and their physicochemical properties and stability in simulated gastric and intestinal media were evaluated. The turmeric nanostructured lipid carriers (TNLCs) exhibited a round shape, small diameter (282 +/- 7.19 nm), adequate zeta potential (-22.75 +/- 1.20 mV), and high encapsulation efficiency (93.3 +/- 0.01%). The TNLCs were able to protect the encapsulated curcuminoids under acidic gastric conditions, and effectively released 95 +/- 2.51% of the curcuminoids in the simulated intestinal medium, demonstrating their suitability for controlled release. The in vitro bioaccessibility of the encapsulated curcuminoids was 75 +/ 1.24%, representing more than a fourfold increase compared to that of free turmeric. Therefore, the proposed TNLCs are a promising delivery system for increasing the bioaccessibility of curcuminoids from turmeric. PMID- 29426422 TI - Improved collagen extraction from jellyfish (Acromitus hardenbergi) with increased physical-induced solubilization processes. AB - Efficiency and effectiveness of collagen extraction process contribute to huge impacts to the quality, supply and cost of the collagen produced. Jellyfish is a potential sustainable source of collagen where their applications are not limited by religious constraints and threats of transmittable diseases. The present study compared the extraction yield, physico-chemical properties and toxicology in vitro of collagens obtained by the conventional acid-assisted and pepsin-assisted extraction to an improved physical-aided extraction process. By increasing physical intervention, the production yield increased significantly compared to the conventional extraction processes (p < .05). Collagen extracted using the improved process was found to possess similar proximate and amino acids composition to those extracted using pepsin (p > .05) while retaining high molecular weight distributions and polypeptide profiles similar to those extracted using only acid. Moreover, they exhibited better appearance, instrumental colour and were found to be non-toxic in vitro and free of heavy metal contamination. PMID- 29426424 TI - Resistant starch and other dietary fiber components in tubers from a high-amylose potato. AB - Tubers from a genetically modified high-amylose line T-2012 and its parental potato cultivar Dinamo were analyzed for resistant starch (RS) and dietary fiber (DF) after cooking and cold storage. For uncooked potatoes, the high-amylose tubers (30% of dry matter, DM) had much lower RS than the parent tubers (56% of DM). However, after cooking, the high-amylose tubers gave more RS (13% of DM) than the parent (4% of DM), and the RS level increased further to about 20% of DM after 1 day of cold storage. The altered RS content was attributable to changes in amylose content, starch granule structure, and amylopectin structure induced by the genetic modification. The high-amylose tubers also contained more DF (10 14% of DM) than the parent (5-7% of DM). Furthermore, cell wall composition was indirectly affected by the genetic modification, giving more cellulose and less pectin in the high-amylose tubers than the parent. PMID- 29426426 TI - One-step sample preparation for convenient examination of volatile monoterpenes and phenolic compounds in peppermint leaves using deep eutectic solvents. AB - Deep eutectic solvents (DESs) were investigated as an extraction medium for one step sample preparation for chemical characterization of peppermint (Mentha piperita L.). Rather than applying discontinuous, time-consuming extraction methods to prepare two types of extracts, peppermint leaves were extracted efficiently into a DES, which was composed of choline chloride and d-(+)-glucose at a 5:2 molar ratio. The produced peppermint extracts contained volatile monoterpenes and phenolics at levels sufficient for direct chemical examination of peppermint leaves. The extracted monoterpenes in DES could be quantified via a newly developed method based on headspace solid-phase microextraction coupled to gas chromatography. The same extracts were also directly used to assess phenolics in terms of total phenolic content, total flavonoid content, and antioxidant activity. The proposed method allowed one-step sample preparation for extraction of volatile monoterpenes and phenolics of peppermint leaves and could be applied to various peppermint samples obtained from different origins. PMID- 29426425 TI - Nonconventional enzymatic method to determine free asparagine level in whole grain wheat. AB - A new enzymatic methodology is herein proposed to measure free asparagine content in wheat grains and to predict their potential for Maillard reaction products. Our model estimates the acrylamide levels generated during the industrial heat treatment of whole-grain wheat based on free asparagine and glucose measurements. We selected fifteen wheat varieties currently grown in Belgium as benchmark for the present study. While conventional chromatographic methods require a long and tedious multi-step sample preparation, the proposed method takes advantage of being simple and quick. Statistical analysis of free asparagine content indicates that selected wheat varieties can be classified into seven content levels from 0.0149% to 0.0216% of the dry matter. Based on our analysis, the varieties KWS Ozon, Benchmark and Pionier appears to be the most suitable for thermal processing (i.e. cooking applications). PMID- 29426427 TI - Transepithelial transport across Caco-2 cell monolayers of angiotensin converting enzyme (ACE) inhibitory peptides derived from simulated in vitro gastrointestinal digestion of cooked chicken muscles. AB - Korat-chicken breast and thigh were subjected to heating at 70, 100 or 121 degrees C for 30 min and simulated in vitro gastrointestinal digestion. At 70 or 100 degrees C heating, digests of breast possessed higher ACE inhibitory activity than those of thigh. The highest ACE inhibitory activity was found in the digest of breast cooked at 70 degrees C (B/H-70), whereas breast heated at 121 degrees C (B/H-121) exhibited the lowest. The 1-kDa permeate of the B/H-70 digest revealed higher permeability through colorectal adenocarcinoma monolayers and ACE inhibitory activity than did B/H-121. Among nine transported peptides, APP derived from myosin showed the highest ACE inhibition, with a non-competitive characteristic (Ki 0.93 MUM). Molecular docking showed that APP interacts with ACE via hydrogen bonds, electrostatic and van der Waals interactions. In conclusion, mild thermal treatment of chicken breast resulted in a higher amount of transported peptides, exerting higher ACE inhibitory activity, which could lead to potential health benefits. PMID- 29426428 TI - Discrimination of geographical origin of extra virgin olive oils using terahertz spectroscopy combined with chemometrics. AB - Discrimination of geographical origin of extra-virgin olive oils (EVOOs) is of great importance for legislation and consumers worldwide. The feasibility of a rapid discrimination of four different geographical origins of EVOOs with terahertz spectroscopy system was examined. Different chemometrics including least squares-support vector machines (LS-SVM), back propagation neural network (BPNN) and random forest (RF) combined with principal component analysis (PCA), genetic algorithm (GA) were compared to obtain the best discrimination model. The results demonstrated that there were apparent differences among the four different geographical origins of EVOOs in fatty acid compositions and the absorbance spectra, and an excellent classification (accuracy was 96.25% in prediction set) could be achieved using the LS-SVM method combine with GA. It can be concluded that THz spectroscopy together with chemometrics would be a promising technique to rapid discriminate the geographical origin of EVOOs with high efficiency. PMID- 29426429 TI - Effect of exogenous ATP on the postharvest properties and pectin degradation of mung bean sprouts (Vigna radiata). AB - The effects of exogenous ATP on the postharvest quality, browning and softening of mung bean (Vigna radiata) sprouts were evaluated. ATP treatment significantly alleviated the quality loss and browning events during the storage of 3 days. It also reduced the oxidant damage by inducing high activities of peroxidase (9.3 13.9%) and superoxide dismutase (8.8-10.3%) which scavenged the reactive oxygen species (ROS) effectively. Transcriptional results indicated that ATP treatment decreased VrPL1, VrPME and VrPG1 gene expression levels more than 2 folds at some time points. Furthermore, the atomic force microscope (AFM) images revealed that the pectin degradation was notably slowed by ATP treatment and the width and height of pectin backbone were better maintained (47.1% and 45.6% higher than control without ATP treatment). The cooperative effects of ROS scavenging and decreased expressions of pectin-related genes might contribute to the deferred pectin deterioration and firmness loss by ATP treatment. PMID- 29426431 TI - Practice patterns of Canadian ophthalmological society members in cataract surgery: 2017 survey. PMID- 29426430 TI - Impact of US Brown Swiss genetics on milk quality from low-input herds in Switzerland: Interactions with season. AB - This study investigated the effect of, and interactions between, US Brown Swiss (BS) genetics and season on milk yield, basic composition and fatty acid profiles, from cows on low-input farms in Switzerland. Milk samples (n = 1,976) were collected from 1,220 crossbreed cows with differing proportions of BS, Braunvieh and Original Braunvieh genetics on 40 farms during winter-housing and summer-grazing. Cows with more BS genetics produced more milk in winter but not in summer, possibly because of underfeeding potentially high-yielding cows on low input pasture-based diets. Cows with more Original Braunvieh genetics produced milk with more (i) nutritionally desirable eicosapentaenoic and docosapentaenoic acids, throughout the year, and (ii) vaccenic and alpha-linolenic acids, total omega-3 fatty acid concentrations and a higher omega-3/omega-6 ratio only during summer-grazing. This suggests that overall milk quality could be improved by re focussing breeding strategies on cows' ability to respond to local dietary environments and seasonal dietary changes. PMID- 29426432 TI - Rehabilitation of lost functional vision with the Argus II retinal prosthesis. AB - The Argus II retinal prosthesis is the first commercially available device for restoration of vision in patients with Retinitis Pigmentosa or with similar retinal pathology who still have minimal residual native vision. The technology is able to restore vision with production of artificial visual percepts which usually are given adequate useful interpretation by the visual system in most implanted patients. The technology usually produces visual perception at the level of shape identification or better in some cases enabling in many less dependence on vision substitution devices and skills. There is no consensus among vision rehabilitation practitioners on single methods for assessments, outcome measures and training, yet there is constant progress in these areas of concern. Hence the current vision rehabilitation practice related to the implantation of the Argus II retinal prosthesis is a work in progress with many learning opportunities for all involved. All agree that implementation of this technology in clinical practice requires the combined work of a multi-disciplinary team which includes a specialized surgical team as well as a specialized rehabilitation team in order to obtain optimal results. Our own experience is presented in this paper and indicates so far that the Argus II technology is beneficial to patients and that it could be successfully managed within the Canadian heath care system. PMID- 29426434 TI - Innovation in Ophthalmology. PMID- 29426433 TI - L'innovation. PMID- 29426435 TI - Sural nerve graft for neurotrophic keratitis: early results. AB - OBJECTIVE: To report our center's experience in treating neurotrophic keratitis (NK) through corneal neurotization using nerve transfers and sural nerve grafts in the adult population. DESIGN: Prospective observational case series, single center study. METHODS: Six consecutive patients (5 males and 1 female) with severe NK were evaluated. All patients had complete corneal anaesthesia in the neurotrophic eye. Three patients had unstable epithelial disease with recurrent breakdowns despite maximal medical and standard surgical management; three presented with dense scarring of their cornea. These patients were surgically treated using nerve transfers and sural nerve grafts for neurotization of the neurotrophic eye. Subjects were evaluated for corneal sensation, epithelial breakdown, and visual acuity. RESULTS: Mean participant age was 57 years (SD 19) with a mean denervation time before the procedure of 23 months (SD 20). Patients were followed up for a minimum of 6 months following the procedure, with a mean follow up time 12 months (SD 4.2). All patients had improved corneal sensation within half a year following the procedure. Five patients (83%) demonstrated improved visual acuity. Of these patients, three (50%) had improved visual acuity with no further surgical intervention. One patient underwent cataract extraction 13 months after neurotization and another underwent amniotic membrane grafting 17 months after neurotization. CONCLUSIONS: Our experience suggests that corneal neurotization using nerve transfers and sural nerve grafts for patients suffering from deteriorating neurotrophic keratitis is a safe procedure in adults. It successfully restored corneal sensation in all patients and improved visual acuity in most patients. PMID- 29426436 TI - Prospective case-control trial evaluating silicone gel for the treatment of direct brow lift scars. AB - OBJECTIVE: To evaluate the effectiveness of a topical silicone gel on scars in patients who had undergone bilateral direct brow lift surgery. DESIGN: A randomized double-blind clinical trial with a placebo applied to one scar and topical silicone gel (Dermatix Ultra; Valeant Pharmaceuticals, Laval, Que.) used on the other scar for 2 months. PARTICIPANTS: Twelve patients (for a total of 24 surgical scars evaluated) were included in the study. METHODS: This study was performed in 2 academic hospitals of the University of Montreal in Montreal, Que. (Maisonneuve-Rosemont Hospital and Notre-Dame Hospital). Inclusion criteria were all bilateral direct brow lift surgeries performed in our hospitals. Exclusion criteria included revision surgery, silicone or latex allergy, and wound infection. Each patient received 2 tubes (1 with silicone gel and 1 with placebo) and applied 1 tube to their right brow scar and the other tube to their left brow scar, following the preassigned instructions. The patient and surgeon were blinded to the nature of the substance that was applied to each scar. At each visit, pictures of both scars were taken, and a questionnaire titled "The Patient and Observer Scar Assessment Scale" was filled out by the patient and the surgeon. A grade ranging from 0 to 10 was given on the multiple criteria in the questionnaire, and the sum of these grades was subsequently used for the data analysis. A lower sum was interpreted as improved scarring. At the end of the study, an independent evaluator graded both scars based on pictures. Follow-up visits were held on day 7, week 6, month 3, and month 6 after surgery. A comparison of the experimental and placebo group was performed with nonparametric tests of Wilcoxon signed rank. RESULTS: A total of 24 scars of 12 patients were analyzed (based on 4 follow-up visits). General improvement of scars was reported by the patient, the surgeon, and based on pictures. No statistically significant difference was found between the group treated with silicone gel and the group treated with placebo. All tests had a p value >=0.08. CONCLUSIONS: We did not find a statistically significant difference between scars treated with silicone gel and scars treated with the placebo after direct brow lift surgery. PMID- 29426437 TI - Rehabilitation of reading skills in patients with age-related macular degeneration. AB - Reading is the most frequent clinical complaint and the primary goal for patients with macular degeneration seeking vision rehabilitation. The current prevalent methods for reading skills training across the globe are still magnification and basic scotoma awareness training. More recent studies showed that specific eccentric training, comprehension ability training, and specific oculomotor training are all beneficial to reading skills rehabilitation. In clinical practice, ophthalmologists should strive to implement reading skills methods that include assessment of cognitive skills, optimal eyewear, optimal reading material, PRL assessment, training of better oculomotor control, and efficient perceptual training. PMID- 29426438 TI - Role of methotrexate in thyroid-related orbitopathy. AB - OBJECTIVE: To report the experience of a tertiary care orbital service in treating severe active thyroid related orbitopathy with methotrexate (MTX) managed by the Ophthalmologist. DESIGN: Retrospective consecutive case series. PARTICIPANTS: Nineteen consecutive patients (5 males and 14 females) with severe active thyroid related orbitopathy. METHODS: Severe active thyroid orbitopathy patients with partial or no response to intravenous glucocorticoids were treated with MTX and observed for inflammatory scale reduction and treatment complications. RESULTS: Nineteen consecutive patients (5 males and 14 females) with severe active thyroid related orbitopathy were evaluated. Mean follow-up time was 1206 days (standard deviation (SD) 576). Months passed from beginning of TRO symptoms to initiation of MTX therapy showed a mean of 12 (SD 9). After the initiation of MTX 91% of eyes demonstrated a clinically significant improvement to a VISA inflammatory scale of <3 within a mean of 189 days (SD 119); A subset of patients (29%) demonstrated a rapid response, reaching a VISA inflammatory score of <3 within 90 days. One patient (5%) discontinued the medication secondary to an adverse event (elevated liver enzymes) which normalized after discontinuation of MTX. During the follow up period 12 patients (63%) have ended their MTX treatment due to TRO inactivity; One patient (8%) developed a recurrence of inflammation after discontinuing MTX which resolved with the re initiation of MTX treatment. Adjunctive treatments including glucocorticoids and/or external beam radiotherapy were administered to 21% of patients. CONCLUSION: Our experience suggests that methotrexate managed by an Ophthalmologist is a safe and effective treatment for severe active thyroid related orbitopathy. PMID- 29426439 TI - Characterization of serological markers of healed/healing arteritis and giant cell arteritis. AB - OBJECTIVE: Temporal artery biopsy (TAB) is the gold standard for confirming the diagnosis of giant cell arteritis (GCA) when positive. However, the clinical significance of healed/healing (HH) arterial injury on TAB is not well understood. The purpose of this study was to evaluate the clinical significance of this finding on TAB by determining its association with seromarkers typically predictive of GCA. DESIGN: Single-centre, retrospective, investigational cohort study. PARTICIPANTS: A total of 385 consecutive TABs for clinical suspicion of GCA between January 2009 and January 2016. METHODS: Elevations in erythrocyte sedimentation rate, C-reactive protein, and platelet count were compared between patients with negative TAB, GCA-positive TAB, and HH arterial injury using statistical trend testing. Odds ratios of seromarker elevations for HH arterial injury versus GCA were calculated. RESULTS: Seventy-six GCA-positive, 69 HH, and 240 negative TABs were identified. Mantel-Haenszel tests of trend indicated that platelets >400 000/uL (p < 0.01), erythrocyte sedimentation rate >=50 mm/hr (p < 0.01), and C-reactive protein >=24.5 mg/L (p < 0.01) occurred with intermediate frequency in the HH TAB group. The odds of HH TAB were 3.6 times greater (95% CI 1.5-8.5) with platelets >400 000/uL. CONCLUSION: HH arterial injury is a heterogenous group that requires treatment in the appropriate clinical setting. From our study, we found that the HH group is intermediate between GCA-positive and GCA-negative biopsy with respect to serology markers only. Thrombocytosis is an independent predictor of HH TAB. With further studies, this marker may be considered when making treatment decisions. Further studies are required to better understand this entity. PMID- 29426440 TI - Evaluation and surgical outcome of acquired nonaccommodative esotropia among older children. AB - OBJECTIVE: To describe the presentation, clinical evaluation, work-up, surgical management, and surgical outcomes in children older than 8 years with spontaneous, comitant, acquired nonaccommodative esotropia (ANAET). DESIGN: Retrospective chart review. PARTICIPANTS: Children who underwent bilateral medial rectus recession surgery for ANAET with initial esotropia onset later than 8 years of age. METHODS: The medical records of children older than 8 years presenting with ANAET from 2009 to 2015 were retrospectively reviewed. The clinical presentation, work-up, surgical intervention, preoperative and postoperative deviations, and surgical outcomes were recorded. RESULTS: A total of 7 healthy patients were identified. The average age of onset was 11.9 years. All patients presented with symptoms of diplopia with large-angle esotropia. Most patients had no preceding illness and presented with minimal refractive error. All 7 patients had unremarkable neurological and general pediatric evaluations without findings of acute intracranial pathology on neuroimaging. Bilateral medial recession surgery was performed for all 7 patients with resolution of diplopia and excellent stereopsis postoperatively. CONCLUSIONS: Diplopia is the most common presenting symptom among older children presenting with ANAET. Bilateral medial recession surgery achieved excellent postoperative results with resolution of diplopia and excellent stereopsis. PMID- 29426441 TI - Surgical outcomes and complications of sutured scleral fixated intraocular lenses in pediatric eyes. AB - OBJECTIVE: To study the outcome and complications of sutured scleral fixated intraocular lenses (SSFIOL) in children. DESIGN: Retrospective study. SUBJECTS: A total of 279 eyes of 230 children who underwent SSFIOL at <=18 years of age in a tertiary eye care centre in India. METHODS: Treatment-naive children having traumatic cataract or subluxated lens underwent a single-sitting lensectomy and pars plana vitrectomy (PPV), along with SSFIOL insertion. Children with aphakia underwent PPV with SSFIOL, and vitrectomized eyes underwent only SSFIOL implantation. Fixation of SSFIOL was done by the 4-point ab externo fixation technique using 10-0 prolene suture. MAIN OUTCOME MEASURES: Preoperative and postoperative visual acuity, as well as intraoperative and postoperative complications. RESULTS: The mean age at which SSFIOL was performed was 10.8 +/- 4.22 years. The most common indication of SSFIOL in our study was traumatic subluxation of lens (47.63%; n = 133 patients), followed by congenital subluxation in 38.7% (n = 108). Best-corrected visual acuity was maintained or improved from the preoperative visual acuity in 93.19% of eyes. The complications included choroidal detachment in 2.86% (n = 8), dispersed vitreous hemorrhage in 2.86% (n = 8), endophthalmitis in 0.72% (n = 2), raised intraocular pressure in 12.54% (n = 35), diplopia in 0.72% (n = 2), retinal detachment in 5.73% (n = 16), and dislocation of the SSFIOL in 4.6% (n = 13). The mean follow-up after SSFIOL implantation was 39.68 months. CONCLUSIONS: SSFIOLs are effective in correcting aphakia in children; long-term follow-up of these children is, however, necessary. PMID- 29426442 TI - Effect of femtosecond laser on efficiency of cataract surgery in public setting. AB - OBJECTIVE: To determine the time needed to perform a femtosecond laser-assisted cataract surgery (FLACS) and its effect on the efficiency of cataract surgery flow in a Canadian public health centre. DESIGN: Retrospective chart review. PARTICIPANTS: Patients who had cataract surgery performed in the first 3 months of femtosecond laser (FSL) technology use were compared with patients who had conventional phacoemulsification in the 3 months before FSL installation at Brandon Regional Health Centre (Brandon, Man.). METHODS: The primary outcome measure was the time needed to complete FLACS versus the time needed to complete conventional phacoemulsification. Secondary outcome measures were the time the patient spent in the operating room (time in and time out) and the number of cataract surgeries done per surgical day before and after FSL was implemented systemwide. RESULTS: There were 235 FSL cases and 199 conventional cases. Operating room time, total surgery time, and manual time were significantly longer in patients who underwent FLACS compared with patients who underwent conventional phacoemulsification (p < 0.001). Manual times and FSL suction times on the first day of implementing FLACS surgery were significantly longer than those on day 23 (p < 0.03), which suggests a learning curve effect. The number of cases per surgical day dropped by 28.6% in the first operative day and by 7.1% in the second and third operative days of FSL use, then reverted to pre-FSL levels. CONCLUSION: The addition of FLACS results in longer time per case than traditional cataract surgery. Although statistically significant, the results may not be indicative of practical differences. PMID- 29426443 TI - Choroidal thickness changes following cataract surgery using swept source optical coherence tomography. AB - OBJECTIVE: The aim of this study was to assess changes in subfoveal choroidal thickness (SFCT), measured using swept-source optical coherence tomography (SS OCT), after routine phacoemulsification cataract surgery. DESIGN: This is a prospective, interventional, controlled study that took place at Shahzad Eye Hospital, Karachi, Pakistan, between February 2015 and January 2016. PARTICIPANTS: One hundred and one patients who were undergoing routine cataract surgery were recruited. One eye per patient was included. The unoperated fellow eyes acted as controls. METHODS: Swept-source optical coherence tomography scans were performed preoperatively, 1 week postoperatively, and 1 month postoperatively. Two independent graders evaluated the scans to measure the SFCT. The SFCT was measured and recorded for OCT scans from each visit. The general linear model repeated analysis technique was used to assess data from the 3 different time intervals, and paired t tests were used to assess a statistically significant difference between mean preoperative and postoperative SFCT. Probability values of less than 0.05 were considered to be statistically significant. RESULTS: The mean preoperative SFCT in the study eye was 272.9 +/- 96.2; SFCT was 278.9 +/- 101.4 (p = 0.051) and 281.5 +/- 105.2 (p = 0.01) at week 1 and month 1, respectively. In the control eyes, the mean measurement of preoperative SFCT was 274.2 +/- 98.5; measurements were 273.8 +/- 100.7 (p = 0.875) and 277.9 +/- 103.1 (p = 0.063) at week 1 and month 1, respectively. CONCLUSIONS: There was a gradual increase in SFCT at 1 month after cataract removal in the study eyes. The effect was more pronounced in younger individuals and nondiabetic individuals. PMID- 29426444 TI - EyePrintPRO therapeutic scleral contact lens: indications and outcomes. AB - OBJECTIVE: To describe indications and outcomes of patients fitted with the EyePrintPRO therapeutic scleral lens. METHODS: A database search of patients fitted with the EyePrintPRO from 2014 to 2016. Fourteen eyes of 10 patients were reviewed retrospectively. Patient demographics, medical and ocular history, indications for fitting, duration of wear, symptoms, and best-corrected visual acuity (BCVA) were analyzed. RESULTS: Mean age at lens fitting was 49 years (range, 21-67 years). The average duration of wear was 12 months (range, 7-17 months). Indications for fitting included limbal stem cell deficiency, post photorefractive keratectomy (PRK) decentred ablation, pellucid marginal degeneration, Stevens-Johnson syndrome, keratoconus, dry eye, neurotrophic keratitis, exposure keratitis from facial nerve paralysis, and post-radial keratotomy (RK) symptoms. Mean BCVA was 20/36 (range, 20/20-20/200). After the fitting, mean BCVA was 20/21 (range 20/10-20/60, p = 0.001). Nine patients reported resolution of their blurry vision, and all reported improvement of dry eye, eye redness, and pain symptoms. Six of 7 previous lens wearers reported significantly greater comfort with EyePrintPRO wear and the ability to wear the lens throughout the day; only 2 experienced fogging and needed to clean the lens after 4-6 hours of wear. CONCLUSIONS: A variety of indications for the EyePrintPRO scleral lens exist, and patients experience resolution of major symptoms. The ophthalmologist should be aware that therapeutic scleral lenses, including the EyePrintPRO, exist for patients for whom there is no surgical intervention or who want to delay or obviate the need for surgery. PMID- 29426445 TI - Evaluating selective laser trabeculoplasty versus argon laser trabeculoplasty in pseudoexfoliation glaucoma patients. AB - OBJECTIVE: Laser trabeculoplasty effectively reduces intraocular pressure (IOP) in primary open angle glaucoma, with argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT) showing equivalent outcomes. However, it is unclear which laser modality is more effective in pseudoexfoliation (PXE) glaucoma. This study aims to compare the effectiveness of ALT and SLT in PXE glaucoma. DESIGN: Retrospective cohort study. METHODS: A chart review evaluating patients diagnosed with PXE glaucoma and treated with laser trabeculoplasty from 2005-2015. Patients with previous glaucoma surgery, other forms of secondary glaucoma, ocular surgery within six months of initial trabeculoplasty or lacking preoperative IOP measurements were excluded. Post-laser measurements were recorded until 24 months after initial intervention. Follow-up data was censored if the patient underwent a subsequent trabeculoplasty different from initial laser treatment. RESULTS: We included 84 patients in the ALT group and 123 in the SLT group. The mean (SD) baseline IOP values were 22.7 (+/-5.6) and 21.6 (+/-4.8) respectively (p = 0.11), while number of medications were 2.0 (+/-1.0) and 1.8 (+/-1.3) for ALT and SLT groups respectively (p = 0.36). The mean IOP reduction for the ALT group at 6, 12 and 24 months were 5.2 (+/-6.1), 5.4 (+/-6.9), and 4.9(+/-7.7) respectively. The corresponding values for the SLT group were 3.4 (+/ 5.2), 3.8 (+/-4.6), and 4.6 (+/-6.5). Comparison of both lasers at each time point revealed no significant differences (p > 0.05) in IOP reduction or reduction of glaucoma medication. CONCLUSIONS: Our study showed equivalent efficacy between ALT and SLT in patients with PXE glaucoma. PMID- 29426446 TI - Risk of obstructive sleep apnea in open-angle glaucoma versus controls using the STOP-Bang questionnaire. AB - OBJECTIVE: To compare the percentage of patients at risk for obstructive sleep apnea (OSA) in open-angle glaucoma (OAG) versus controls using the STOP-Bang questionnaire. METHODS: This study used a cross-sectional survey. Patients with OAG and controls completed the STOP-Bang questionnaire-a validated tool to identify patients at high risk for OSA. Patients were considered at risk if they scored 3 or more points or at high risk for moderate/severe OSA if they scored 5 or more out of the maximum 8 points. Demographic information, medical history, and previous diagnosis of OSA were recorded. Details regarding the patients' glaucoma were obtained from their medical records. RESULTS: A total of 437 patients with OAG and 441 controls were included. The mean STOP-Bang score was 3.01 +/- 1.3 for the glaucoma group and 3.03 +/- 1.4 for the control group (p = 0.92). There was no significant difference between the percentage of subjects considered at risk for OSA (62.7% OAG vs 59.4% controls, p = 0.37) or at high risk for moderate/severe OSA (12.6% OAG vs 16.5% controls, p = 0.1). Significantly more patients in the control group had a previous diagnosis of OSA (p = 0.01). More patients with OAG reported feeling tired compared with controls (p = 0.003). A risk/high risk for OSA was not associated with glaucoma severity, progression, intraocular pressure control, or glaucoma type. CONCLUSIONS: Our results indicate that a risk or high risk for moderate/severe OSA as measured by the STOP-Bang questionnaire is not correlated with the presence or absence of glaucoma (regardless of the type), glaucoma severity, glaucoma progression, or IOP control. PMID- 29426447 TI - Selective laser trabeculoplasty for primary open-angle glaucoma patients younger than 40 years. AB - OBJECTIVE: To evaluate the efficacy of selective laser trabeculoplasty (SLT) among patients with juvenile-onset primary open-angle glaucoma (JOAG). METHODS: Patients diagnosed with JOAG who were not controlled on medical therapy were offered a trial of SLT. The patients were followed up prospectively for 1, 3, 6, and 12 months postlaser to evaluate the efficacy of SLT as second-line therapy. Success was defined as an intraocular pressure (IOP) reduction of >=20% at 12 months without the need for further medication, laser, or surgery. Factors associated with success/failure, prelaser IOP, age, and angle dysgenesis on gonioscopy were analysed. RESULTS: The average prelaser IOP in these JOAG eyes (n = 30) was 25.3 +/- 6.5 mm Hg, which reduced to 17.3 +/- 5.8 mm Hg at 12 months (p = 0.01). All patients were of Indian ethnicity. Out of 30 eyes, at 12 months post SLT, 13 (43%) eyes had at least a 20% reduction in IOP. In the eyes that achieved success, the average reduction of IOP was 37.6%. There was no difference in the prelaser IOP between those with success (25.5 +/- 5.6 mm Hg) and those that failed (25.1 +/- 8 mm Hg; p = 0.8), nor was there a difference in the mean age between successful cases (34.4 +/- 9.4 years) and failures (31.6 +/- 8.9 years; p = 0.4). However, those without angle dysgenesis were 4 times (CI 1.1-15.2) more likely to succeed with SLT than those with angle dysgenesis (p = 0.03). CONCLUSIONS: A significant proportion of patients with JOAG can benefit from an IOP reduction after SLT. Those with gonioscopically normal-appearing angles are more likely to respond to SLT. PMID- 29426448 TI - The Toronto experience with the Argus II retinal prosthesis: new technology, new hope for patients. AB - Surgical restoration of vision with retinal prostheses is a new and developing technology currently available in a select group of countries, Canada among them. The Argus II retinal prosthesis is the first commercially available device for restoration of vision in patients with Retinitis Pigmentosa or with similar retinal pathology who still have minimal residual native vision. The surgery is complex and requires training however it is within the abilities of any experienced retina surgeon. Surgical experience builds up with each case and in our patients length of surgery constantly went down. Complications occurred however we experienced no catastrophic events. Most notable is that in our implanted cases the Argus II technology proved to be beneficial to most patients. In order to obtain optimal results with this surgical intervention it is absolutely required that the surgical work is complemented simultaneously with the work of a specialized rehabilitation team. A review of the technology, of our experience, comments and concerns is presented in this paper. PMID- 29426449 TI - Structural and functional degeneration of retinal nerves in sibling carriers of a Leber's hereditary optic neuropathy mutation. PMID- 29426450 TI - Implantation pearl cyst after uncomplicated clear cornea phacoemulsification mimicking an iris tumour. PMID- 29426451 TI - Photodynamic therapy for choroidal carcinoid metastasis. PMID- 29426452 TI - Choroidal metastasis arising from esophageal adenocarcinoma. PMID- 29426453 TI - Progressive optic nerve glioma: orbital biopsy technique using a surgical navigation system. PMID- 29426454 TI - Orbital metastatic small cell carcinoma of the pancreas with optic nerve compression. PMID- 29426455 TI - Bilateral simultaneous artificial iris implantation for post-traumatic aniridia: a case report. PMID- 29426456 TI - Management of positive dysphotopsia in a patient with prior refractive surgery. PMID- 29426457 TI - Transscleral fixation of a toric intraocular lens by a slipable suture technique. PMID- 29426458 TI - Deep anterior lamellar keratoplasty for an intrastromal epithelial corneal cyst: a case report. PMID- 29426459 TI - Clinical evaluation of a novel surgical technique (large cross incision) for conjunctival cysts. PMID- 29426460 TI - Case of Ab Interno Trabeculectomy in Juvenile Open-angle Glaucoma with 5-year Follow-up. PMID- 29426461 TI - A rare case of bilateral ocular neuromyotonia. PMID- 29426462 TI - Mydriasis due to Opcon-A: An indication to avoid pharmacologic testing for anisocoria. PMID- 29426463 TI - Added value of newer optical coherence tomography technologies in hyperphosphatemic familial tumoural calcinosis. PMID- 29426464 TI - A new multiplex PCR assay to distinguish among three cryptic Galba species, intermediate hosts of Fasciola hepatica. AB - A molecular tool described here allows in one step for specific discrimination among three cryptic freshwater snail species (genus Galba) involved in fasciolosis transmission, a worldwide infectious disease of humans and livestock. The multiplex PCR approach taken targets for each species a distinctive, known microsatellite locus which is amplified using specific primers designed to generate an amplicon of a distinctive size that can be readily separated from the amplicons of the other two species on an agarose gel. In this way, the three Galba species (G. cubensis, G. schirazensis, and G. truncatula) can be differentiated from one another, including even if DNA from all three were present in the same reaction. The accuracy of this new molecular tool was tested and validated by comparing multiplex PCR results with species identification based on sequences at mitochondrial and nuclear markers. This new method is accurate, inexpensive, simple, rapid, and can be adapted to handle large sample sizes. It will be helpful for monitoring invasion of Galba species and for developing strategies to limit the snail species involved in the emergence or re emergence of fasciolosis. PMID- 29426465 TI - Sensitivity and specificity of the FAMACHA(c) system in growing lambs. AB - The FAMACHA(c) system is used for targeted selective treatment (TST) of small ruminants for the control of haemonchosis. The aim of this study was to evaluate the sensitivity and specificity of this system in growing lambs. Between 2015 and 2016, lambs aged 60-210 days on two sheep farms were evaluated at 15-day intervals using the FAMACHA(c) system (F1-F5), with analysis of hematocrit (Ht), counting of eggs per gram of feces, and larval culture. The sensitivity and specificity of the system were calculated according to two criteria: criterion 1, lambs classified as F4 or F5 were considered anemic (positive test) and those classified as F1, F2, or F3 were considered not anemic (negative test); and criterion 2, lambs classified as F3, F4, or F5 were considered anemic (positive test) and those classified as F1 and F2 were considered not anemic (negative test). Three gold standard Ht cutoff values were used to diagnose anemia, i.e., <=22%, <=18%, and <=15%. In total, 1591 assessments were analyzed. The highest percentage of larvae in the fecal cultures was for Haemonchus spp., with an average of 78.5%. The sensitivity values found when F3 lambs were considered anemic were 13.9%, 30.8%, and 66.7%, respectively, for Ht cutoff values of <=22%, <=18%, and <=15%. When F3 lambs were excluded, the maximum sensitivity was 14.9% and the specificity was 100% for all degrees of anemia using criterion 1. The FAMACHA(c) system had low sensitivity in growing lambs and should not be used alone for control of haemonchosis in young animals. PMID- 29426466 TI - Combination deworming for the control of double-resistant cyathostomin parasites short and long term consequences. AB - Equine cyathostomin are pervasive gastrointestinal parasites with wide-spread resistance to the benzimidazole and tetrahydropyrimidine drug classes worldwide. Combination deworming has been proposed as a more sustainable parasite control strategy. Simulation studies have found combination deworming to be effective in controlling drug resistant ovine trichostrongylid parasites. One equine study demonstrated an additive effect of a combination of oxibendazole and pyrantel pamoate against cyathostomins. However, this is the only equine study evaluating combination therapy, and the effects of repeated combination treatments administered over time remain unknown. The purpose of this study was to observe the efficacy of repeated oxibendazole/pyrantel pamoate combination therapy administered over one year against a cyathostomin population with resistance to benzimidazole and pyrantel products. Fecal egg counts were determined for the entire herd (N = 21) at the day of anthelmintic treatment and at two-week intervals for eight weeks post treatment. Starting efficacies of oxibendazole (OBZ, 10 mg/kg) and pyrantel pamoate (PYR, 6.6 mg base/kg) were 66.7% and 63.3%, respectively. Hereafter, the herd was treated four times with an oxibendazole/pyrantel pamoate combination, eight weeks apart, followed by repeating the single active treatments before concluding the study. While the first combination treatment exhibited an additive effect of the two active ingredients, this efficacy was not sustained over the course of the study. Mean fecal egg count reduction (FECR) was significantly greater for the first combination treatment (76.6%) than the second (42.6%, p = 0.0454), third (41.6%, p = 0.0318), and fourth (40.7%, p = 0.0372) combination treatments. The final single active mean FECRs were 42.3% for oxibendazole, and 42.7% for pyrantel pamoate. These efficacies were not significantly different from the initial single active efficacies (OBZ, p = 0.4421; PYR, p = 0.8361). These results suggest that combination therapy against double resistant equine cyathostomin populations is not sustainable, when using actives with markedly decreased starting efficacies. PMID- 29426467 TI - Comparative diagnostics reveals PCR assays on skin scrapings is the most reliable method to detect Sarcoptes scabiei infestations. AB - Sarcoptic mange is a globally significant parasitic disease of humans and other animals, both domestic and wild. But clinical diagnosis of S. scabiei infestation, using the standard skin scraping followed by microscopy technique, remains highly variable (predominantly due to false-negatives), and a major challenge for human and animal welfare. Here, we utilised a unique sample set from bare-nosed wombats (Vombatus ursinus) to evaluate a variety of putatively useful diagnostic approaches for S. scabiei. Against the standard of skin scrapings followed by microscopy, we compared observational scoring of mange severity (often employed in field studies of wildlife), PCR on skin scrapings (recently proposed as an improvement for humans and other animals), and PCR on skin swabs (proposed a non-invasive method for humans and other animals). We find that observational scoring positively correlated with counts of S. scabiei from skin scrapings, particularly as mange severity increases, but underdiagnoses early mange. Species-specific PCR for S. scabiei on skin scrapings had enhanced capacity for mite detection relative to microscopy. Finally, the non-invasive sampling method of PCR on skin swab samples had a high congruence to skin scraping microscopy, however prospective false negatives as a consequence to sampling is concerning. To our knowledge, this is the first study to simultaneously assess this combination of methods for S. scabiei diagnosis. We conclude that PCR on skin scrapings as an advancement on traditional microscopy, and the other techniques (observational, skin swabs and microscopy) remain useful, but harbour greater false-negatives. Outcomes are transferrable to diagnosis of S. scabiei for other host species, including humans, particularly for crusted mange and potentially ordinary mange also. PMID- 29426468 TI - In vitro activity of natural and chemical products on sporulation of Eimeria species oocysts of chickens. AB - This study was designed to investigate the ability of two herbal extracts and different chemical substances to inhibit or disrupt sporulation of Eimeria species oocysts of the chickens. The two herbal extracts were Allium sativum (garlic) and Moringa olifiera while the chemical substances included commercial disinfectants and diclazuril. Field isolates of Eimeria oocysts were propagated in chickens to obtain a continuous source of oocysts. The collected unsporulated oocysts (105oocysts/5 ml) were dispensed into 5 cm Petri dish. Three replicates were used for each treatment. The treated oocysts were incubated for 48 h at 25 29 degrees C and 80% relative humidity. The results showed that herbal extracts, the commercial recommended dose of Dettol, TH4, Phenol, Virkon(r)S, and Diclazuril 20% have no effect on the sporulation. While Sodium hypochlorite showed a significant degree of sporulation inhibition reached to 49.67%. Moreover, 70% ethanol, and 10% formalin showed 100% sporulation inhibition. It was concluded that 70% ethanol and 10% formalin are the most effective methods to inhibit Eimeria species sporulation. PMID- 29426469 TI - Implications of zoonotic and vector-borne parasites to free-roaming cats in central Spain. AB - Cats are definitive hosts and reservoirs for several parasites, some of which are responsible for serious zoonotic diseases. We conducted a case-control study of data from a trap-neuter-return (TNR) programme (years 2014-2017) designed to examine the prevalence of zoonotic parasites in free-roaming cats living in urban areas of central Spain. In the animal population tested (n = 263), we detected a 29.2% prevalence of endoparasites, including high rates of cestodes (12.9%) and Toxocara cati (11.7%). While faecal samples showed no Toxoplasma gondii oocysts, the seroprevalence of T. gondii infection was 24.2%. Antibodies to Leishmania infantum were detected in 4.8% of the animals, though all skin and blood samples analyzed were PCR negative for this parasite. Ectoparasites (ticks and fleas) were found in 4.6% of the cat population, and 10.6% of the cats were detected with Otodectes cynotis. Finally, 6.3% and 7.9% cats tested positive for feline leukaemia virus and feline immunodeficiency virus, respectively. Our study provides useful information for animal-welfare and public-health, as the parasites detected can affect native wild animals through predation, competition and disease transmission. Our detection of zoonotic parasites such as L. infantum, T. gondii, T. cati, Giardia duodenalis and several ectoparasites prompts an urgent need for health control measures in stray cats. PMID- 29426470 TI - Feline leishmaniosis: Is the cat a small dog? AB - Leishmania infantum is a vector-borne zoonotic disease transmitted by phlebotomine sand flies and dogs are considered the main reservoir of the parasite. Feline leishmaniosis (FeL) caused by L. infantum is an emergent feline disease more and more frequently reported in endemic areas. This review summarizes current knowledge focusing similarities and differences with canine leishmaniosis (CanL). Cats are infected by the same Leishmania species than dogs but prevalence of the infection is lower and cases of disease are less frequently reported. Scarce information is available on adaptive immune response of cats naturally exposed to L. infantum infection and mechanisms responsible for susceptibility or resistance of feline hosts. However, about half of clinical cases of FeL are reported in cats with possible impaired immunocompetence. Coinfections or comorbidities are frequently detected in sick cats and they can contribute to a misrepresentation of clinical FeL albeit lesions associated with the presence of the parasite have been detected in skin, lymph nodes, spleen, bone marrow, liver, oral mucosa, stomach, large bowel, kidney, nasal exudate, lung, eye. As for dogs, skin or mucocutaneous lesions are the most common reason for veterinary consultation and finding on physical examination in cats with leishmaniosis. Molecular investigations of Leishmania DNA and anti- Leishmania antibody detection are largely used with the same methodologies for both CanL and FeL, however few information is available about their diagnostic performance in feline hosts. Treatment of cats with clinical FeL is still empirically based and off label by using the most common drugs prescribed to dogs. Life expectancy of cats with clinical FeL is usually good unless concurrent conditions or complications occur and prognosis does not seem significantly influenced by therapy or retroviral coinfection. According to current knowledge, cats can play a role as additional reservoir host of L. infantum and, in a " One Health " perspective, preventative measures should be taken. In conclusion, albeit feline infection and the associated cat disease caused by L. infantum is increasingly reported in endemic areas and have many similarities with CanL, consolidated evidence-based knowledge is not available and we cannot exclude that important differences between dogs and cats exist about transmission, immunopathogenesis and best practice for management and prevention. PMID- 29426471 TI - Neglected vector-borne zoonoses in Europe: Into the wild. AB - Wild vertebrates are involved in the transmission cycles of numerous pathogens. Additionally, they can affect the abundance of arthropod vectors. Urbanization, landscape and climate changes, and the adaptation of vectors and wildlife to human habitats represent complex and evolving scenarios, which affect the interface of vector, wildlife and human populations, frequently with a consequent increase in zoonotic risk. While considerable attention has focused on these interrelations with regard to certain major vector-borne pathogens such as Borrelia burgdorferi s.l. and tick-borne encephalitis virus, information regarding many other zoonotic pathogens is more dispersed. In this review, we discuss the possible role of wildlife in the maintenance and spread of some of these neglected zoonoses in Europe. We present case studies on the role of rodents in the cycles of Bartonella spp., of wild ungulates in the cycle of Babesia spp., and of various wildlife species in the life cycle of Leishmania infantum, Anaplasma phagocytophilum and Rickettsia spp. These examples highlight the usefulness of surveillance strategies focused on neglected zoonotic agents in wildlife as a source of valuable information for health professionals, nature managers and (local) decision-makers. These benefits could be further enhanced by increased collaboration between researchers and stakeholders across Europe and a more harmonised and coordinated approach for data collection. PMID- 29426473 TI - First report of Taenia ovis infection in Danish sheep (Ovis aries). AB - We report Taenia ovis infection in Danish sheep for the first time. In spring 2016, the metacestode stage of T. ovis was at slaughter observed in heart muscles, diaphragm and skeletal muscles from approx. a third of all sheep from one specific farm localised in South Jutland. The diagnosis was confirmed by molecular typing of the mitochondrial cytochrome c oxidase I (cox1) gene. Three newly imported dogs were suspected but the definitive host was unidentifiable. The finding is not regulated in the meat control procedures. However, infected meat is usually condemned due to aesthetic reasons causing economic losses. Thus, finding of T. ovis is of concern to sheep meat producers in the area, as the infection could have spread further on to other farms. PMID- 29426474 TI - Assessment of anthelmintic activity and bio-guided chemical analysis of Persea americana seed extracts. AB - The aim of this study was to characterize the extracts and fractions of Persea americana Mill. (Avocado) seeds and to determine the composition and the in vitro anthelmintic activity against third-stage larvae (L3) of Haemonchus contortus. The fresh (F) and dried (H) avocado seeds (PA) were subjected to extraction with hot water (W-PAF, W-PAH), ethanol (E-PAF, E-PAH) or methanol 70% (v/v), and partition with solvents of increasing polarity [n-hexane (H-PAF, H-PAH), chloroform (C-PAF, C-PAH), ethyl acetate (Ea-PAF, Ea-PAH), and n-butanol (B-PAF, B-PAH)], yielding a total of 14 extracts/fractions. After considering the yield, water solubility, and the preliminary results of the larval migration test (LMT), the E-PAF, E-PAH, H-PAF, and H-PAH were selected for further experiments. E-PAH presented an efficiency concentration of 50% (EC50) of 36 MUg/mL on the LMT. E PAH showed the greatest efficiency when its EC50 was compared to the other fractions (E-PAF = 147 MUg/mL; H-PAF = 801 MUg/mL; H-PAH = 77 MUg/mL). After that, the E-PAH was chemically characterized, considering its quantitative polyphenolic and flavonoid contents by colorimetric and chromatographic techniques. E-PAH presented 50, 38, and 24 mg/g of dry matter of total phenol, condensed tannins (CT), and flavonoid contents, respectively. Using high performance liquid chromatography (HPLC) analysis, E-PAH had shown to have epicatechin (4.7 MUg/mL), rutin (2.8 MUg/mL), and chlorogenic acid (1.4 MUg/mL) as its main constituents besides quercetin. These isolated compounds were evaluated using the LMT in order to relate the composition to the anthelmintic activity observed for E-PAH. Quercetin (EC50 = 7.8 MUg/mL) and epicatechin (EC50 = 10 MUg/mL) presented a higher efficiency than rutin (EC50 = 30 MUg/mL). Chlorogenic acid was also tested with the LMT but did not present a significant efficiency. According to the results, the phenolic composition of E-PAH and the EC50 values obtained for the isolated phenols, it can be suggested that, besides the CT content, the presence of epicatechin and rutin contributed to the larvicidal activity of E-PAH. In conclusion, avocado seeds may be used as a source of polyphenols with promising anthelmintic applications. PMID- 29426472 TI - Nuclear delivery of parasite Cdg2_FLc_0220 RNA transcript to epithelial cells during Cryptosporidium parvum infection modulates host gene transcription. AB - Intestinal infection by the zoonotic protozoan, Cryptosporidium parvum, causes significant alterations in the gene expression profile in host epithelial cells. The molecular mechanisms of how C. parvum may modulate host cell gene transcription and the pathological significance of such alterations are largely unclear. Previous studies demonstrate that a panel of parasite RNA transcripts are delivered into infected host cells and may modulate host gene transcription. Using in vitro models of intestinal cryptosporidiosis, in this study, we analyzed the impact of host delivery of C. parvum Cdg2_FLc_0220 RNA transcript on host gene expression profile. We found that alterations in host gene expression profile following C. parvum infection were partially associated with the nuclear delivery of Cdg2_FLc_0220. Specifically, we identified a total of 46 overlapping upregulated genes and 8 overlapping downregulated genes in infected cells and cells transfected with Full-Cdg2_FLc_0220. Trans-suppression of the DAZ interacting zinc finger protein 1 like (DZIP1L) gene, the top overlapping downregulated gene in host cells following C. parvum infection and cells transfected with Full-Cdg2_FLc_0220, was mediated by G9a, independent of PRDM1. Cdg2_FLc_0220-mediated trans-suppression of the DZIP1L gene was independent of H3K9 and H3K27 methylation. Data from this study provide additional evidence that delivery of C. parvum Cdg2_FLc_0220 RNA transcript in infected epithelial cells modulates the transcription of host genes, contributing to the alterations in the gene expression profile in host epithelial cells during C. parvum infection. PMID- 29426475 TI - Eulimdana clava (Nematoda: Filarioidea) infection in domestic pigeons (Columba livia domestica): Molecular characterization and pathological changes. AB - Filarial nematodes of the Eulimdana genus inhabit subcutaneous tissue of various avian species, mostly Charadriiforme birds. In domestic pigeons, E. clava is the only species recorded in the subcutaneous tissue in a number of isolated cases. In the present study, we discuss the morphology and histopathology of filarial nematodes recovered from subcutaneous tissue of domestic pigeons in Bosnia and Herzegovina. In total 110 pigeons were submitted to necropsy at the Department of Pathology of the Faculty of Veterinary Medicine in Sarajevo. At necropsy, in four pigeons (3.6%) numerous thread-like 0.9-2.1 cm long nematode parasites were observed in the subcutaneous tissue, peritracheal and periesophageal connective tissue. In one pigeon, the parasites were also found free in the body cavity around the heart and lungs. In addition, several 80-90 MUm long microfilariae were noted in the tissue cross-sections. No significant lesions were observed associated with adult parasites or microfilariae. Based on morphology, host species and localization detected parasites were identified as E. clava. Molecular analyses of the cox1 and 12S rRNA nucleotide sequences herein generated revealed the close genetic relationship to other filarioid nematodes. The importance of the nematodes in pigeons and the lack of sequences in genetic databases for comparison of avian filarial parasites are emphasized. PMID- 29426476 TI - Larval development of Aelurostrongylus abstrusus in experimentally infected Rumina decollata snails. AB - Aelurostrongylus abstrusus is a lungworm distributed worldwide that affects wild and domestic cats, causing bronchopneumonia of varying intensity. Snails serve as intermediate hosts. The aim of the present study was to assess the larval development of A. abstrusus in R. decollata snails and to investigate its potential as an intermediate host. For this purpose, first-stage larvae (L1) of A. abstrusus were obtained from the faeces of naturally infected cats. Doses of 500 L1/snail were given to 24 R. decollata snails, placed on the soil of the breeder chamber, and maintained under laboratory conditions. Three snails were killed at 8, 10, 12, 16, 22, 26, 45 and 55 days post-infection (dpi), and the muscular foot and visceral body were separately digested by an artificial digestion technique. The morphometric parameters of different larval stages were recorded. The mean number of larvae reaching the infective stage at the end of the study (L3) was 262 larvae/snail. The greatest development to L3 was recorded from days16 to 55 pi, during which the isolation was maximum. A. Abstrusus L3 were isolated from the viscera, but isolation from the snail foot was significantly higher. Our results showed for the first time the ability of A. Abstrusus larvae to develop in R. decollata, thus serving as a potential intermediate host. PMID- 29426477 TI - The effect on liveweight gain of using anthelmintics with incomplete efficacy against resistant Cooperia oncophora in cattle. AB - A replicated field trial was conducted to measure the effect on liveweight gain of failing to adequately control anthelmintic resistant populations of Cooperia oncophora and to determine whether populations, and hence production losses, increased with time. Eight mobs of 10 Friesian-Hereford calves were run on independent farmlets from January to December, over each of two years. All mobs were routinely treated with a pour-on formulation of eprinomectin every six weeks, which controlled parasites other than Cooperia. Four mobs also received six weekly treatments with an oral levamisole plus albendazole combination anthelmintic to control Cooperia. Liveweights, condition scores, faecal egg counts and larval numbers on pasture were measured throughout. In the first year animals treated with eprinomectin alone were 12.9 kg lighter in November than those treated with eprinomectin plus albendazole and levamisole, however, in the second year there was no difference between the treatment groups. The data, therefore, support the view that while C. oncophora is less pathogenic than other cattle parasite species it can still cause production losses when present in sufficient numbers. In the first year of the study, parasite load, as measured by faecal nematode egg count and larval numbers on herbage, tended to be higher and calf growth rates lower than in the second year. In both years, counts of infective larvae on herbage declined over winter-spring to be at low levels before mid-summer. This suggests that the carry-over of infection from one crop of calves to the next was relatively small and hence that the level of challenge to the young calves at the start of each year was largely due to the effectiveness of the quarantine treatments administered when the animals arrived on the trial site. Low survival of larvae on pasture between grazing seasons, resulting in small larval populations on pasture when drenching programmes start each summer, might help to explain the widespread development of anthelmintic resistance in this parasite under New Zealand grazing systems. PMID- 29426478 TI - Taenia solium from a community perspective: Preliminary costing data in the Katete and Sinda districts in Eastern Zambia. AB - The tapeworm Taenia solium is endemic in Zambia, however its socioeconomic cost is unknown. During a large-scale interventional study conducted in Zambia, baseline economic costs of human and porcine T. solium infections were measured. Questionnaire surveys were conducted within three neighbourhoods in Zambia's Eastern province in 2015 and 2016. A human health questionnaire, capturing costs of clinical symptoms commonly attributable to human cysticercosis and taeniasis, was conducted in randomly selected households (n = 267). All pig-keeping households were administered a pig socioeconomic questionnaire (n = 271) that captured pig demographic data, costs of pig-keeping, and economic losses from porcine cysticercosis. Of all respondents 62% had reportedly experienced at least one of the surveyed symptoms. Seizure-like episodes were reported by 12%, severe chronic headaches by 36%, and vision problems by 23% of respondents. These complaints resulted in 147 health care consultations and 17 hospitalizations in the five years preceding the study, and an estimated productivity loss of 608 working days per year. Of all pigs 69% were bought within villages. Nearly all adult pigs were sold to local traders, and tongue palpation for detection of cysticerci was commonly performed. Reportedly, 95% of pig owners could not sell tongue-positive pigs, while infected pigs fetched only 45% of the normal sale value. These preliminary costing data indicate that human and porcine T. solium infections substantially impact endemic areas of Eastern Zambia. A full socioeconomic burden assessment may enable improved T. solium management in sub Saharan Africa. PMID- 29426479 TI - Arthropod-borne pathogens of dogs and cats: From pathways and times of transmission to disease control. AB - Vector-borne pathogens have developed a close relationship with blood feeding arthropod ectoparasites (e.g., mosquitoes, ticks, phlebotomine sand flies, black flies, fleas, kissing bugs, lice) and exploited a huge variety of vector transmission routes. Therefore, the life cycles of these pathogens result in a long evolved balance with the respective arthropod biology, ecology and blood feeding habits, instrumentally to the infection of several animal species, including humans. Amongst the many parasite transmission modes, such as ingestion of the arthropod, with its faeces or secretions, blood feeding represents the main focus for this article, as it is a central event to the life of almost all arthropod vectors. The time frame in which pathogens are transmitted to any animal host is governed by a large number of biological variables related to the vector, the pathogen, the host and environmental factors. Scientific data available on transmission times for each pathogen are discussed relative to their impact for the success of vector-borne disease control strategies. Blocking pathogen transmission, and thus preventing the infection of dogs and cats, may be achievable by the use of chemical compounds if they are characterised by a fast onset of killing activity or repellence against arthropods. The fast speed of kill exerted by systemic isoxazoline, as well as the repellent effect of pyrethroids have renewed the interest of the scientific community and pharmaceutical companies towards reducing the burden of vector-borne diseases under field conditions. However, endosymbionts and vaccines targeting arthropods or pathogen antigens should be further investigated as alternative strategies towards the goal of achieving an effective integrated control of vector-borne diseases. PMID- 29426480 TI - Development of a direct PCR assay to detect Taenia multiceps eggs isolated from dog feces. AB - Taenia multiceps is a tapeworm that leads to the death of livestock, resulting in major economic losses worldwide. The adult stage of this parasite invades the small intestine of dogs and other canids. In the present study, we developed a direct PCR assay to detect T. multiceps eggs isolated from dog feces to help curb further outbreaks. The genomic DNA was rapidly released using a lysis buffer and the PCR reaction was developed to amplify a 433-bp fragment of the T. multiceps mitochondrial gene encoding NADH dehydrogenase subunit 5 (nad5) from eggs isolated from dog feces. The procedure could be completed within 3 h, including flotation. The sensitivity of the assay was determined by detecting DNA from defined numbers of eggs, and the specificity was determined by detecting DNA from other intestinal tapeworm and roundworm species that commonly infect dogs. In addition, 14 taeniid-positive fecal samples determined by the flotation technique were collected and further evaluated by the regular PCR and our direct PCR. The results showed that the direct PCR developed herein was sensitive enough to detect the DNA from as few as 10 T. multiceps eggs and that no cross-reactions with other tapeworm and roundworm were observed, suggesting its high sensitivity and specificity for T. multiceps detection. Moreover, 14 taeniid-positive samples were screened by the regular PCR and direct PCR, with detection rates of 78.6% and 85.7%, respectively. In conclusion, the direct PCR assay developed in the present study has high sensitivity and specificity to identify T. multiceps eggs isolated from dog feces and therefore could represent an invaluable tool to identify T. multiceps outbreaks and would contribute to future clinical applications. PMID- 29426481 TI - Albendazole nanocrystals in experimental alveolar echinococcosis: Enhanced chemoprophylactic and clinical efficacy in infected mice. AB - Human alveolar echinococcosis is caused by the fox tapeworm Echinococcus multilocularis and is usually fatal if left untreated. Medical treatment with albendazole (ABZ) remains an effective option. However, due to its low aqueous solubility, ABZ is poorly and erratically absorbed following oral administration resulting in low drug levels in plasma and liver distribution. Thus, there arises the need to find a simple, efficient and scalable method to produce new ABZ formulations with increased bioavailability. Bearing this in mind, ABZ nanocrystals (ABZ-NCs) appears to be a useful tool to achieve this goal. The aim of the current study was to investigate the chemoprophylactic and clinical efficacy of an ABZ-NC formulation on mice infected with E. multilocularis. In the chemoprophylactic efficacy study, mean weight of the cysts recovered from the ABZ NC group was 50% lower than that recorded from untreated mice, whereas the treatment with ABZ suspension did not show preventive effect. The viability of protoscoleces isolated from ABZ-NC treated mice was significantly lower than control groups. In the clinical efficacy studies, both ABZ formulations resulted in a reduction in the mean weight of the cysts obtained from mice, however only the treatment with the nanosuspension revealed significant differences (P < 0.05) compared to the control groups. Treatment with ABZ-NCs reduced the weight of the cysts by 77% and the viability of their protoscoleces to 34%. All these results coincided with the tissue damage determined at the ultrastructural level. The enhanced chemoprophylactic and clinical efficacy of ABZ-NCs observed in this study could be attributed to an increase in the oral bioavailability of the drug. In a next step, we will characterize the cyst concentration profile after the administration of ABZ-NCs in mice infected with E. multilocularis. PMID- 29426482 TI - Comparison of early detection of Fasciola hepatica in experimentally infected Merino sheep by real-time PCR, coproantigen ELISA and sedimentation. AB - Fasciolosis due to infection with Fasciola hepatica, Fasciola gigantica or their hybrids is a significant global cause of livestock production loss. Infection is commonly diagnosed by a labour-intensive sedimentation and faecal egg count (FEC), which has limited throughput and is only applicable after completion of the 8-12 week pre-patent period (PPP). A commercially-available ELISA for the detection of coprological antigen (coproELISA) enables detection prior to the completion of the PPP and is suitable for diagnosis of larger sample sizes, although the sensitivity reported under experimental infection settings can be difficult to replicate in the field, particularly in cattle. A recently-published real-time PCR workflow for the sensitive detection of Fasciola spp. DNA in faecal samples provides increased sample throughput, although the point at which this technique is first able to diagnose infection remains unknown. Other tools for the molecular diagnosis of fasciolosis, such as conventional PCR and loop mediated isothermal amplification (LAMP), have been shown to detect F. hepatica DNA as early as 1 week post infection (WPI). In this study, faecal samples were collected weekly from 10 experimentally-infected Merino lambs and subjected to diagnosis via traditional sedimentation, coproELISA and real-time PCR. Samples were first considered positive at 6-8 WPI by coproELISA, real-time PCR and sedimentation, respectively. At 9 WPI 100% of samples were positive by all three methods. To evaluate the capacity of the real-time PCR approach to detect infection prior to completion of the PPP, two methods of sample preparation were compared at 2 WPI: (i) 150 mg raw faecal samples and (ii) 3 g faecal starting volume prior to sedimentation and pelleting. Neither method of sample preparation yielded positive results at 2 WPI suggesting that DNA amplification by real-time PCR is associated with faecal egg load. PMID- 29426483 TI - In vitro growth inhibition of Theileria equi by bumped kinase inhibitors. AB - INTRODUCTION: Theileria equi, an etiologic agent of equine piroplasmosis, is a tick-transmitted hemoprotozoan of the phylum Apicomplexa. Recent outbreaks of piroplasmosis in the United States have renewed interest in safe and effective treatment options. Although imidocarb dipropionate (IMD) is the drug of choice for clearance of T. equi, adverse reactions and recently documented resistance support the need for alternative therapeutic strategies. The recently described bumped kinase inhibitors (BKIs) are a new class of compounds that could potentially be used as safe and effective alternatives to IMD. In an initial effort to evaluate this potential, herein we determined the T. equi growth inhibitory activity of 11 BKIs relative to that of IMD and the previously tested BKI 1294. Because some BKIs have known human ether-a-go-go related gene (hERG) channel activity, we also assessed the hERG activity of each compound with the goal to identify those with the highest potency against T. equi coupled with the lowest potential for cardiotoxicity. RESULTS: Six BKIs inhibited T. equi growth in vitro, including the previously evaluated BKI 1294 which was used as a positive control. All six compounds were significantly less potent (higher 50% effective concentration (EC50)) than IMD. Two of those compounds were more potent than BKI 1294 control but had similar hERG activity. Although the remaining three compounds had similar to lower potency than BKI 1294, hERG EC50 was higher for three of them (BKI 1735, BKI 1369 and BKI 1318). CONCLUSIONS: The BKI compounds evaluated in this study inhibited T. equi in vitro and had diverse hERG activity. Based on these considerations, three compounds would be suitable for further evaluation. While these results provide a foundation for future work, in vivo pharmacokinetic, pharmacodynamics, and safety studies are needed before BKI compounds can be recommended for clinical use in T. equi infected horses. PMID- 29426484 TI - The endoparasitism challenge in developing countries as goat raising develops from smallholder to commercial production systems: A study from Laos. AB - Progressing economic development in Southeast Asia has increased regional demand for goat meat, leading to expanding production by smallholders and recently, development of commercial farms. In Laos, an emerging export market for goats into Vietnam has led to increased goat numbers, with potential increases in risk of disease, particularly endoparasitism. A cross-sectional survey investigated the prevalence of gastrointestinal parasites in indigenous Kambing-Katjang goats on smallholder farms (n = 389) in 8 villages where no anthelmintic treatments were in use, providing comparisons with a case study of imported Boer crossbred goats (n = 45) on a commercial farm where intensive anthelmintic treatments were required to manage mortalities attributable to Haemonchosis. Clinical examinations, collection of faecal samples, and pathological examination on the commercial farm, accompanied collection of information on animal gender, age and body weight, with data analyses performed in Genstat. Faecal samples contained eggs of multiple endoparasitic species, with Strongyles spp. and coccidian oocysts of Eimeria spp. most prevalent. Significant associations between the presence of endoparasites and the farm type (smallholder versus commercial; p < 0.008 and 0.001) were observed, with the odds ratios of the commercial farm having Stronglyes spp. and Eimeria spp. of 1.3 (CI = 0.6-2.9) and 4.8 (CI = 2.5 9.1). Mortalities from endoparasitism were only recorded at the commercial farm, with the loss of 24 goats in the final 3 months of the dry season (Feb-April). This study identified a moderate prevalence of multiple endoparasitic species in smallholder goat farms that appeared well-tolerated, whereas in the developing commercial system, endoparasites posed significant risks to enterprise viability, even with use of anthelmintics. Further studies on endoparasite control are required if commercial tropical goat meat production is to prove sustainable and assist in addressing regional food security, plus provide a pathway to improve the livelihoods of Lao goat smallholders seeking to expand and intensify their enterprises. PMID- 29426485 TI - Untangling the overlap between frailty and low lean mass: Data from Toulouse frailty day hospital. AB - BACKGROUND: The decline in lean mass, observed in older people, has been frequently associated with frailty. This assumption has scarcely been assessed. This study explored the association between current proposed definitions of low lean mass and the Fried phenotype of frailty. METHODS: Cross-sectional study. Participants admitted to the Toulouse frailty day hospital, with an assessment of body composition, 70 years or older were included consecutively in the study. Low lean mass (LLM), was identified using five international operative definitions. To construct the definitions, muscle mass was assessed using Intelligent Dual Energy X-ray absorptiometry (I-DXA, LUNAR). Frailty was assessed using the Fried criteria. RESULTS: Data from 283 participants, mean age 82 years and 71% of women were analyzed. LLM was identified between 8.5% and 39.2% of the participants according to the different definitions. Frailty was identified in 46.6% of the sample. 9.1%-48.5% of the frail older people had LLM depending on the definition. The highest association between frailty and LLM was observed with the definition proposed by the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project [adjusted Odds Ratio 2.64; 95% confidence interval 1.5-4.8]. CONCLUSION: The decline in lean mass is a component of the frailty syndrome but not universally present. Indeed, LLM and frailty were associated and partly overlapped. Future research including longitudinal studies should exploit the added value of combining LLM and frailty measures in preventing disability and other negative health outcomes. PMID- 29426486 TI - Noodle based analytical devices for cost effective green chemical analysis. AB - Noodle based analytical devices are proposed for cost effective green chemical analysis. Two noodle based analytical platforms have been examined. Conditions for flow with laminar behaviors could be established. Detection may be via a webcam camera or a flatbed scanner. Acid-base reactions were chosen as a model study. The assays of acetic acid and sodium hydroxide were investigated. Apart from bromothymol blue, simple aqueous extract of butterfly pea flower was used as a natural reagent. Another model was the assay of copper (Cu2+) which was based on the redox reaction of copper (Cu2+) with iodide to produce tri-iodide forming brown/black product with starch which already exists in the noodle platform. Demonstration to apply the noodle platforms for real samples was made. PMID- 29426487 TI - A novel BODIPY-based fluorescent probe for selective detection of hydrogen sulfide in living cells and tissues. AB - Hydrogen sulfide (H2S) is a critical biological messenger in numerous physiological and pathophysiological processes. Small-molecule fluorescent probes combined with fluorescent microscopy have been developed for the sensitive detection of H2S. Here, we designed and synthesized a long-wavelength BODIPY based probe (TMSDNPOB) based on the thiolysis of dinitrophenyl ether according to photo-induced electron transfer theory and the results of computational calculation. 4,4-Difluoro-8-phenyl-1,5,7-trimethyl-3-(4-(2,4 dinitrophenoxy)styryl- 4-bora-3a,4a-diaza-s-indacene (TMSDNPOB) is nearly non fluorescent, but the reaction product (TMSHOB) emits strong red fluorescence at 592nm when excited at 574nm. The long wavelengths of the designed probe indicate low background interference from biological matrix and little photo damage on fluorescence imaging of H2S. With the advantages of the turn-on probe for H2S including high sensitivity, high selectivity, good biocompatibility and low toxicity, the probe has been used for imaging H2S in living cells and liver tissues. PMID- 29426488 TI - Magnetic Cu-MOFs embedded within graphene oxide nanocomposites for enhanced preconcentration of benzenoid-containing insecticides. AB - Hybrid magnetic nanocomposites based on Cu-MOFs, graphene oxide (GO), and Fe3O4 nanoparticles (NPs) were prepared via chemical bonding approach, which GO were used as platforms to load nanostructured Cu-MOFs and Fe3O4 NPs. The composite features both magnetic separation characteristics and high MOFs porosity, making it an excellent adsorbent for magnetic solid-phase extraction (MSPE). The as synthesized nanocomposites are characterized by XRD, TGA, SEM, TEM, nitrogen adsorption-desorption analysis and FT-IR spectroscopy. The composites are used in MSPE of six aromatic insecticides from various real samples prior to their quantification by HPLC. Amount of adsorbent, extraction times, extraction temperature, desorption times and oscillation rate are optimized. Under the optimal conditions, the method has a relative standard deviations (RSDs) of 1.9 2.7%, and good linearity (correlation coefficients higher than 0.9931). The low LOD and LOQ for six insecticides are found to be 0.30-1.58MUgL-1 and 1.0-5.2MUgL 1, respectively. The RSDs of within batch extraction are 1.6-9.5% and 3.9-12% for batch to batch extraction. The experimental results suggest that the nanocomposites have potential application for removal of hazardous pollutants from effluents. PMID- 29426489 TI - Two 3-hydroxyflavone derivatives as two-photon fluorescence turn-on chemosensors for cysteine and homocysteine in living cells. AB - Two 3-hydroxyflavone derivatives as one- and two-photon fluorescent chemosensors for cysteine (Cys) and homocysteine (Hcy) were synthesized. The recognition properties and mechanism of the chemosensors for Cys and Hcy were investigated systematically. The experiment results indicate that 3-hydroxyflavone compound 1 (6-bromo-2-(9-ethyl-9H-carbazol-3-yl)-3-hydroxy-chromen-4-one) after the addition of nickel ions exhibits good recognition properties for Cys and Hcy with fluorescence enhancement and 65nm absorption peak blue shift based on nickel displacement reaction mechanism. The detection limits (DL) with fluorescence as detected signal are 4.06 * 10-3uM (Cys, linear range of 10-80uM) and 5.8 * 10-3uM (Hcy, linear range of 10-100uM), respectively. But acrylate substituted 3 hydroxyflavone compound 2 (4-oxo-2-(4-diethylamino-phenyl)-4H-chromen-3-yl acrylate) can specially identify Cys with fluorescence turn-on (DL = 1.87 * 10 3uM, linear range of 4-22uM) based on Cys leading to acrylate hydrolysis mechanism and succedent excited-state intramolecular proton transfer process of 3 hydroxyflavone compound. Then Cys and Hcy biological thiols can be recognized at one time by these two 3-hydroxyflavone derivatives. The bioimaging experiment indicates that both the compounds can be successfully applied to the detection of Cys/Hcy in living cells and compound 2 also can be applied to bioimaging Cys in zebrafish by one- and two-photon fluorescence mode. Then these two compounds have a potential in the application of biological sample analysis. PMID- 29426490 TI - TATP isotope ratios as influenced by worldwide acetone variation. AB - Isotope ratio analysis has been shown to discriminate samples of forensic interest and to link many synthesized and natural materials to their precursors when traditional chemical and physical analyses cannot. Successful application of stable isotope analysis to chemicals of interest requires a background of likely variations in stable isotope ratios; often, this background population can be generated from analysis of possible precursors and the relationships of stable isotopes of precursor(s) to product(s), which may depend on synthesis techniques. Here we measured the carbon (13C/12C) and hydrogen (2H/1H) isotope ratios of the oft-illicitly manufactured explosive triacetone triperoxide, TATP, and one of its precursors, acetone. As acetone is the sole source of carbon and hydrogen to TATP, a survey of acetone from 12 countries was conducted to explore the breadth of 13C/12C and 2H/1H variation in the precursor, and therefore, its product. Carbon and hydrogen isotope ratios were measured using continuous flow isotope ratio mass spectrometry (IRMS) techniques. We observed greater ranges in both C and H isotope ratios of acetone than previously published; we also found that country-of-purchase was a large contributing factor to the observed variation, larger than acetone grade and brand. Following clandestine production methods, we observed that the stable isotope ratios of TATP retained the stable isotope signatures of acetone used in synthesis. We confirmed the robustness of TATP carbon isotope ratios to both recrystallization and time-dependent sublimation, important considerations when faced with the task of practical sampling of potential unexploded TATP from a crime scene. PMID- 29426491 TI - A novel electroanalytical approach to the measurement of B vitamins in food supplements based on screen-printed carbon sensors. AB - This paper describes the development of a novel electrochemical assay for the measurement of water-soluble vitamins in food and pharmaceutical products. The optimum conditions for the determination of vitamin B1 (thiamine), B2 (riboflavin) and B6 (pyridoxine) in phosphate buffer were established using cyclic voltammetry in conjunction with screen printed carbon electrodes (SPCEs). The optimum current response for all three vitamins was achieved in 0.1M phosphate buffer pH 11 using an initial potential of -1.0V. Using square wave voltammetry, the linear ranges for thiamine, riboflavin, and pyridoxine were found to be: 15-110ug/ml, 0.1-20ug/ml, and 2-80ug/ml respectively. The application of the method to a commercial food product yielded a recovery of 95.78% for riboflavin, with a coefficient of variation (CV) of 3.38% (n = 5). The method was also applied to a multi-vitamin supplement for the simultaneous determination of thiamine, riboflavin and pyridoxine. In both cases only simple dilution with buffer followed by centrifugation was required prior to analysis. The resulting square wave voltammetric signals were completely resolved with Ep values of -0.7V, +0.2V, and +0.6V respectively. The recoveries determined for the vitamin B complex in a commercial supplement product were found to be 110%, 114%, and 112% respectively (CV = 7.14%, 6.28%. 5.66% respectively, n = 5). PMID- 29426492 TI - A comprehensive methodology for the chiral separation of 40 tobacco alkaloids and their carcinogenic E/Z-(R,S)-tobacco-specific nitrosamine metabolites. AB - The predominant enantiomer of nicotine found in nature is (S)-nicotine and its pharmacology has been widely established. However, pharmacologic information concerning individual enantiomers of nicotine-related compounds is limited. Recently, a modified macrocyclic glycopeptide chiral selector was found to be highly stereoselective for most tobacco alkaloids and metabolites. This study examines the semi-synthetic and native known macrocyclic glycopeptides for chiral recognition, separation, and characterization of the largest group of nicotine related compounds ever reported (tobacco alkaloids, nicotine metabolites and derivatives, and tobacco-specific nitrosamines). The enantioseparation of nicotine is accomplished in less than 20s for example. All liquid chromatography separations are mass spectrometry compatible for the tobacco alkaloids, as well as their metabolites. Ring-closed, cyclized structures were identified and separated from their ring-open, straight chain equilibrium structures. Also, E/Z tobacco-specific nitrosamines and their enantiomers were directly separated. E/Z isomers also are known to have different physical and chemical properties and biological activities. This study provides optimal separation conditions for the analysis of nicotine-related isomers, which in the past have been reported to be ineffectively separated which can result in inaccurate results. The methodology of this study could be applied to cancer studies, and lead to more information about the role of these isomers in other diseases and as treatment for diseases. PMID- 29426493 TI - Rapid DNA detection based on self-replicating catalyzed hairpin assembly using nucleotide base analog pyrrolo-deoxycytidine as fluorophore. AB - A rapid signal amplified DNA detection method based on self-replicating catalyzed hairpin assembly (SRCHA) has been proposed. In this SRCHA system, two split target DNA sequences were respectively integrated into hairpin auxiliary probes H1 and H2. H2 was used as fluorescent probe which containing a fluorescent nucleotide base analog pyrrolo-deoxycytidine (P-dC) at the end of the stem. Target DNA can be circularly used in this SRCHA system to form the helix DNA H1 H2 complex, the structure change of H2 will move P-dC from hairpin stem to flexible ssDNA sticky end, leading to fluorescence increase due to the less stacking interaction. Meanwhile, the two spilt target DNA sequence was reunited and the target DNA replicate was obtained, which also can be circularly used as new activator to trigger additional CHA reaction and fluorescence signal was then rapidly and significantly enhanced. This SRCHA system has been successfully employed for DNA detection with picomolar within around 15min, and provides a potential technology for the real-time rapid bioanalysis. PMID- 29426494 TI - Disposable photoelectrochemical sensing strip for highly sensitive determination of perfluorooctane sulfonyl fluoride on functionalized screen-printed carbon electrode. AB - Owing to the lack of chromophores and ionizable functional groups, it is a significant challenge to determine perfluorooctane sulfonyl fluoride (PFOSF) by traditional high-performance liquid chromatography or liquid chromatography/mass spectrometry, especially at a low concentration. In this work a unique photoelectrochemical (PEC) sensing strip has been developed for the first time for the detection of PFOSF. The sensing strip is cost effective and disposable, whereby BiOI nanoflake arrays are fabricated on a home-made screen-printed electrode through a facile one-step in-situ electrodeposition process, and then the molecule tags (i.e., molecularly imprinted polymers) for PFOSF are subsequently grafted on the surface. Benefitting from a three-dimensional interconnected framework, the as-fabricated sensing strip has a rapid response to the interfacial steric hindrance effect between the sensing platform and the target analyte of PFOSF. The elaborated PEC sensor exhibits a outstanding linear response to a concentration of PFOSF ranging from 0.05 to 500.0 ppb and a detection limit down to 0.01 ppb (S/N = 3) Furthermore, our low-cost and highly sensitive sensor has been further explored to detect PFOSF in real water samples, showing satisfactory results. PMID- 29426496 TI - Comprehensive approach to the validation of the standard method for total reflection X-ray fluorescence analysis of water. AB - In this work, we present the validation of the chemical method for total reflection X-ray fluorescence (TXRF) analysis of water, proposed as a standard to the International Standard Organization. The complete experimental procedure to define the linear calibration range, elements sensitivities, limits of detection and quantification, precision and accuracy is presented for a commercial TXRF spectrometer equipped with Mo X-ray tube. Least squares linear regression, including all statistical tests is performed separately for each element of interest to extract sensitivities. Relative sensitivities with respect to Ga, as internal standard, are calculated. Accuracy and precision of the quantification procedure using Ga as internal standard is evaluated with reference water samples. A detailed discussion on the calibration procedure and the limitation of the use of this method for quantitative analysis of water is presented. PMID- 29426495 TI - Designing and facilely synthesizing a series of cobalt nitride (Co4N) nanocatalysts as non-enzymatic glucose sensors: A comparative study toward the influences of material structures on electrocatalytic activities. AB - Designing high-efficiency electrocatalysts for glucose concentration detection plays a pivotal role in developing various non-enzymatic glucose detection devices. Herein, we have successfully designed and synthesized various cobalt nitrides (Co4N) by using different weak bases (i.e. hexamethylenetetramine (HMT), urea, and ammonium hydroxide (AH)) through nitridation treatment in ammonia (NH3) atmosphere. Physical characterization results demonstrate that Co4N-NSs (nanosheets) with vast meso/macropores and large BET surface are successfully constructed once adding carbon paper and HMT into precursors. As the synergistic effect of metallic character of Co4N phase, excellent electroconductibility of pyrolytic carbon, and large surface area, Co4N-NSs surfaces can form more Co4+ active sites in electrochemical reaction processes. Meanwhile, the abundant meso/macroporous structures constructed in Co4N-NSs further promoted its mass transfer ability. Benefitting from the above mentioned advantages, Co4N-NSs therefore exhibit more excellent glucose oxidation ability than another three control samples (i.e. Co4N-HMT, Co4N-Urea and Co4N-AH). When used for glucose detection, the optimal Co4N-NSs display excellent detection parameters as well, such as: a wide linear range of 0.6-10.0mM, a large sensitivity of 1137.2uAcm-2mM 1 glucose, a low detection limit of 0.1uM, a small response time of 1.7s, good reproducibility and stability, and the excellent anti-interference to other electroactive molecules and Cl-. Upon utilized for measuring glucose concentrations in human blood serum samples, the detection results on Co4N-NSs are accurate and satisfying as well. This work opens a new possibility for boosting electrochemical catalysis abilities of Co4N samples by the structure design. PMID- 29426497 TI - Detection and scavenging of hydroxyl radical via D-phenylalanine hydroxylation in human fluids. AB - Hydroxyl radical (.OH) is highly reactive, and therefore very short-lived. Finding new means to accurately detect .OH, and testing the ability of known .OH scavengers to neutralize them in human biological fluids would leverage our ability to more effectively counter oxidative (.OH) stress-mediated damage in human diseases. To achieve this, we pursued the evaluation of secondary products resulting from .OH attack, using a detection system based on Fenton reaction mediated D-phenylalanine (D-Phe) hydroxylation. This reaction in turn generates o tyrosine (o-tyr), m-tyrosine (m-tyr) and p-tyrosine (p-tyr). Here, these isomers were separated by HPLC, equipped with fluorescence detectors due to the natural fluorescence of these hydrotyrosines. By extension, we found that, adding radical scavengers competed with D-Phe on .OH attack, thus allowing to determine the .OH quenching capacity of a given compound expressed as inhibition ratio percent (IR%). Using a kinetic approach, we then tested the .OH scavenging capacity (OHSC) of well-known antioxidant molecules. In a test tube, N,N'-dimethylthiourea (DMTU) was the most efficient scavenger as compared to Trolox and N-Acethyl-L cysteine, with NAC being the less effective. OHSC assay was then applied to biological fluid samples as seminal plasma, human serum from normal subjects and patients undergoing hemodialysis (HD), colostrum and human breast milk from mothers that received daily doses of 30g of chocolate (70% cocoa) during pregnancy. We found that a daily administration of dark chocolate during pregnancy almost doubled OHSC levels in breast milk (1.88 +/- 0.12 times, p < 0.01). Furthermore, HD treatment determined a significant reduction of serum OHSC concentration (54.63 +/- 2.82%, p < 0.001). Our results provide evidence that Fenton reaction-mediated D-Phe hydroxylation is a suitable method for routine and non-invasive evaluation of .OH detection and its scavenging in human biological fluids. PMID- 29426498 TI - Capillary zone electrophoresis method to assay tipranavir capsules and identification of oxidation product and organic impurity by quadrupole-time of flight mass spectrometry. AB - Tipranavir (TPV) is one of the most recently developed protease inhibitors (PI) and it is specially recommended for treatment-experienced patients who are resistant to other PI drugs. In this work, a simple and friendly environmental CZE stability-indicating method to assay TPV capsules was developed and two TPV organic impurities were identified by high resolution mass spectrometry (HRMS). The optimized analytical conditions were: background electrolyte composed of sodium borate 50mM, pH 9.0 and 5% of methanol; voltage + 28kV; hydrodynamic injection of 5s (100mbar), detection wavelength 240nm, at 25 degrees C. The separation was achieved in a fused silica capillary with 50um * 40cm (inner diameter * effective length), using furosemide as internal standard. All the validation parameters were met and the method was specific, even in the presence of degradation products and impurities. Oxidation was indicated as the main degradation pathway among those evaluated in this study (acidic, alkaline, thermal, photolytic and oxidative) and it showed a second order degradation kinetic, under the conditions used in this study. The main oxidation product and an organic impurity detected in the standard were characterized by Q-TOF, and both of them correspond to oxidation products of TPV. PMID- 29426499 TI - Electrochemical sensing using magnetic molecularly imprinted polymer particles previously captured by a magneto-sensor. AB - The determination of 1-chloro-2,4-dinitrobenzene (CDNB) was used as a proof-of concept to a simple analytical practical configuration applying magnetic molecularly imprinted particles (mag-MIPs). Mag-MIPs were captured from an emulsion by a home-made magneto-sensor (where a small magnet was entrapped by a graphite-epoxy composite) and then, this sensor, was transferred to the solution containing the analyte, where, after binding to the mag-MIPs, the analyte was directly analysed using differential pulse voltammetry (DPV) since the magneto sensor acted as the working electrode. After optimization, a detection limit of 6.0 MUmol L-1 with a RSD of 2.7% was achieved along with suitable recoveries and selectivity. This methodology offers a different approach for electroanalytical methodologies using mag-MIPs. PMID- 29426500 TI - Competitive fluorescent pseudo-immunoassay exploiting molecularly imprinted polymers for the detection of biogenic amines in fish matrix. AB - We developed a competitive fluorescent molecularly imprinted polymer (MIP) assay to detect biogenic amines in fish samples. MIPs synthesized by precipitation polymerization using histamine as template were used in a batch binding assay analogous to competitive fluoroimmunoassays. Introducing a complex sample matrix, such as fish extract, into the assay changes the environment and the binding conditions, therefore the importance of the sample preparation is extensively discussed. Several extraction and purification methods for fish were comprehensively studied, and an optimal clean-up procedure for fish samples using liquid-liquid extraction was developed. The feasibility of the competitive MIP assay was shown in the purified fish extract over a broad histamine range (1 - 430uM). The MIP had the highest affinity towards histamine, but recognized also the structurally similar biogenic amines tyramine and tryptamine, as well as spermine and spermidine, providing simultaneous analysis and assessment of the total amount of biogenic amines. PMID- 29426502 TI - A new tool for the evaluation of the analytical procedure: Green Analytical Procedure Index. AB - A new means for assessing analytical protocols relating to green analytical chemistry attributes has been developed. The new tool, called GAPI (Green Analytical Procedure Index), evaluates the green character of an entire analytical methodology, from sample collection to final determination, and was created using such tools as the National Environmental Methods Index (NEMI) or Analytical Eco-Scale to provide not only general but also qualitative information. In GAPI, a specific symbol with five pentagrams can be used to evaluate and quantify the environmental impact involved in each step of an analytical methodology, mainly from green through yellow to red depicting low, medium to high impact, respectively. The proposed tool was used to evaluate analytical procedures applied in the determination of biogenic amines in wine samples, and polycyclic aromatic hydrocarbon determination by EPA methods. GAPI tool not only provides an immediately perceptible perspective to the user/reader but also offers exhaustive information on evaluated procedures. PMID- 29426501 TI - Electrodialytic extraction of anionic pharmaceutical compounds from a single drop of whole blood using a supported liquid membrane. AB - A method to introduce target analytes to a chromatograph from a single drop of whole blood was investigated for minimally invasive monitoring of anionic pharmaceuticals. In this work, salicylate and loxoprofen were examined as organic anions. A micro ion extractor (MIE) has been developed for extraction of inorganic trace anions from whole blood, but this device is not suitable for extraction of pharmaceuticals. In the present study, we improved and optimized the MIE device for organic anion extraction. Various supported liquid membranes were evaluated for use as the ion transfer membrane, with each membrane placed between a droplet sample (donor) and an acceptor solution. A supported liquid membrane of porous polypropylene impregnated with 1-butanol was selected. In addition, the methods for electric field creation and electrode contact were examined to improve the characteristics of the MIE device. The current and extraction time were also optimized. With the optimized method, salicylate and loxoprofen were successfully extracted from a single drop of whole blood. Changes in the concentrations of these pharmaceuticals in blood over time were monitored after administration. As only 25MUL of whole blood was required for analysis, repeat measurements could be conducted to monitor changes in the concentrations. This MIE will be useful for monitoring pharmaceutical concentrations in blood. PMID- 29426503 TI - Aqueous biphasic systems formed by deep eutectic solvent and new-type salts for the high-performance extraction of pigments. AB - Deep eutectic solvent (DES) composed of polypropylene glycol 400 (PPG 400) and tetrabutylammonium bromide (TBAB) was combined with a series of new-type salts such as quaternary ammonium salts, amino acid and polyols to form Aqueous Biphasic Systems (ABSs). Phase-forming ability of the salts was investigated firstly. The results showed that polyols had a relatively weak power to produce phases within studied scopes. And the shorter of carbon chain length of salts, the easier to obtain phase-splitting. Then partitioning of three pigments in PPG 400/betaine-based ABSs was addressed to investigate the effect of pigments' hydrophobicity on extraction efficiency. It was found that an increase in hydrophobicity contributed to the migration of pigments in the DES-rich phase. On the other hand, with a decline in phase-forming ability of salts, the extraction efficiency of the whole systems started to go down gradually. Based on the results, selective separation experiment was conducted successfully in the PPG 400/betaine-based systems, including more than 93.00% Sudan III in the top phase and about 80.00% sunset yellow FCF/amaranth in the bottom phase. Additionally, ABSs constructed by DES/betaine for partitioning amaranth were further utilized to explore the performances of influence factors and back extraction. It can be concluded that after the optimization above 98.00% amaranth was transferred into the top phase. And 67.98% amaranth can be transferred into the bottom phase in back-extraction experiment. At last, dynamic light scattering (DLS) and transmission electron microscope (TEM) were applied to probe into extraction mechanism. The results demonstrated that hydrophobicity played an important role in the separation process of pigments. Through combining with new-type DES, this work was devoted to introducing plentiful salts as novel compositions of ABSs and providing an eco-friendly extraction way for partitioning pigments, which boosted development of ABSs in the monitoring food safety field. PMID- 29426504 TI - Combination of nano-material enrichment and dead-end filtration for uniform and rapid sample preparation in matrix-assisted laser desorption/ionization mass spectrometry. AB - Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is a fast analysis tool for the detection of a wide range of analytes. However, heterogeneous distribution of matrix/analyte cocrystal, variation in signal intensity and poor experimental reproducibility at different locations of the same spot means difficulty in quantitative analysis. In this work, carbon nanotubes (CNTs) were employed as adsorbent for analyte cum matrix on a conductive porous membrane as a novel mass target plate. The sample pretreatment step was achieved by enrichment and dead-end filtration and dried by a solid liquid separation. This approach enables the homogeneous distribution of analyte in the matrix, good shot-to-shot reproducibility in signals and quantitative detection of peptide and protein at different concentrations with correlation coefficient (R2) of 0.9920 and 0.9909, respectively. The simple preparation of sample in a short time, uniform distribution of analyte, easy quantitative detection, and high reproducibility makes this technique useful and may diversify the application of MALDI-MS for quantitative detection of a variety of proteins. PMID- 29426505 TI - An interferometric imaging biosensor using weighted spectrum analysis to confirm DNA monolayer films with attogram sensitivity. AB - Interferometric imaging biosensors are powerful and convenient tools for confirming the existence of DNA monolayer films on silicon microarray platforms. However, their accuracy and sensitivity need further improvement because DNA molecules contribute to an inconspicuous interferometric signal both in thickness and size. Such weaknesses result in poor performance of these biosensors for low DNA content analyses and point mutation tests. In this paper, an interferometric imaging biosensor with weighted spectrum analysis is presented to confirm DNA monolayer films. The interferometric signal of DNA molecules can be extracted and then quantitative detection results for DNA microarrays can be reconstructed. With the proposed strategy, the relative error of thickness detection was reduced from 88.94% to merely 4.15%. The mass sensitivity per unit area of the proposed biosensor reached 20 attograms (ag). Therefore, the sample consumption per unit area of the target DNA content was only 62.5 zeptomoles (zm), with the volume of 0.25 picolitres (pL). Compared with the fluorescence resonance energy transfer (FRET), the measurement veracity of the interferometric imaging biosensor with weighted spectrum analysis is free to the changes in spotting concentration and DNA length. The detection range was more than 1um. Moreover, single nucleotide mismatch could be pointed out combined with specific DNA ligation. A mutation experiment for lung cancer detection proved the high selectivity and accurate analysis capability of the presented biosensor. PMID- 29426506 TI - Development and application of molecularly imprinted polymer - Mn-doped ZnS quantum dot fluorescent optosensing for cocaine screening in oral fluid and serum. AB - A molecularly imprinted polymer - Mn-doped ZnS quantum dot-based fluorescence probe for cocaine abuse screening has been prepared and applied to complex samples such as serum and oral fluid. The fluorescent sensing material was prepared by anchoring a selective MIP for COC on the surface of polyethylene glycol (PEG) modified Mn-doped ZnS quantum dots (QDs). Simple and low cost methods have thus been optimized for assessing cocaine abuse in serum and oral fluid by monitoring fluorescence quenching when cocaine (COC) is present (optimized operating conditions with 1.5mL of 200mgL-1 MIP-coated QDs solution, pH 5.5, and 15min before fluorescence scanning). The matrix effect was found to be important when analyzing oral fluid and serum, and several strategies based on centrifugation for oral fluid and solid phase extraction (SPE) for serum were explored. Two analytical methods were developed for oral fluid. The first one (direct method) requires a centrifugation step (6 degrees C, 4000rpm, 20min) to avoid the matrix effect, and allows for cocaine determination by using an aqueous calibration (1:20 dilution). The second method was developed for oral fluid sampled by Salivette devices, and also requires a further centrifugation (6 degrees C, 4000rpm, 20min) of the recovered oral fluid. This method, however, requires the standard addition technique (1:20 dilution) because of the existence of the matrix effect. Regarding serum samples, a direct method (serum dilution) was not possible, and an SPE procedure was needed to avoid the matrix effect (use of aqueous calibration). The limits of detection and quantification when using the Salivette method were 0.035mgL-1and 0.117mgL-1, respectively; whereas, 0.015mgL-1 (LOD) and 0.050mgL-1 (LOQ) were obtained for serum. PMID- 29426507 TI - A rhodamine-based fluorescent probe for colorimetric and fluorescence lighting-up determination of toxic thiophenols in environmental water and living cells. AB - Thiophenols are a class of highly toxic environmental pollutant, hence it is very necessary to monitor thiophenols in environment and living cells with an efficient and reliable method. Herein, a novel fluorescent probe for thiophenols has been developed, which exhibited a colorimetric and fluorescence turn-on dual response towards thiophenols with good selectivity and fast response. The sensing mechanism for thiophenols was attributed to nucleophilic substitution reaction, which was confirmed by HPLC. The probe exhibited good recovery (from 90% to 107%) and low limit of detection for thiophenols (37nM) in industrial wastewater. Moreover, the probe has been successfully employed to visualize thiophenol in living cells. Therefore, the fluorescent probe has good capability for monitoring thiophenols in environmental samples and biological systems. PMID- 29426508 TI - A molecular beacon based on DNA-templated silver nanoclusters for the highly sensitive and selective multiplexed detection of virulence genes. AB - In this work, we develop a fluorescent molecular beacon based on the DNA templated silver nanoclusters (DNA-Ag NCs). The skillfully designed molecular beacon can be conveniently used for detection of diverse virulence genes as long as the corresponding recognition sequences are embedded. Importantly, the constructed detection system allows simultaneous detection of multiple nucleic acids, which is attributed to non-overlapping emission spectra of the as synthesized silver nanoclusters. Based on the target-induced fluorescence enhancement, three infectious disease-related genes HIV, H1N1, and H5N1 are detected, and the corresponding detection limits are 3.53, 0.12 and 3.95nM, respectively. This design allows specific, versatile and simultaneous detection of diverse targets with easy operation and low cost. PMID- 29426509 TI - Polydopamine-based functional composite particles for tumor cell targeting and dual-mode cellular imaging. AB - Particles which bear tumor cell targeting and multimode imaging capabilities are promising in tumor diagnosis and cancer therapy. A simple and versatile method to fabricate gold/polydopamine-Methylene Blue@Bovine Serum Albumin-glutaraldehyde Transferrin composite particles (Au/PDA-MB@BSA-GA-Tf NPs) for tumor cell targeting and fluorescence (FL) / surface-enhanced Raman scattering (SERS) dual modal imaging were reported in this work. Polydopamine (PDA) spheres played an important role in gold ion reduction, gold nanoparticle (Au NPs) binding and methylene blue (MB) adsorption, MB were employed as both fluorescence label and Raman reporter. In addition, glutaraldehyde (GA) crosslinked bovine serum albumin (BSA) in the outer layer of Au/PDA-MB nanoparticles can prevent MB from dissociation and leakage. The composite nanoparticles were further conjugated with transferrin (Tf) to target transferrin receptor (TfR)-overexpressed cancer cells. The targeting ability as well as the intracellular location of the probe was investigated through SERS mapping and fluorescence imaging. Their excellent biocompatibility was demonstrated by low cytotoxicity against breast cancer cell (4T1 cell). PMID- 29426511 TI - Speciation of inorganic arsenic(III) and arsenic(V) by a facile dual-cloud point extraction coupled with inductively plasma-optical emission spectrometry. AB - A simple and efficient method using dual-cloud point extraction (dual-CPE) coupled with inductively coupled plasma-optical emission spectrometry (ICP-OES) was developed for the speciation of inorganic arsenic [As(III) and As(V)]. In first step of dual-CPE, As(III) formed a hydrophobic complex with ammonium pyrrolidine dithiocarbamate (As-APDC), and was subsequently entrapped by the Triton X-114 surfactant-rich phase at pH 5.0, whereas As(V) remained in the bulk supernatant. The surfactant-rich phase containing the As(III)-APDC complex was treated with a 2.0molL-1 of nitric acid, and As(III) was back extracted into the aqueous phase at the second cloud point extraction stage before ICP-OES detection. The As(V) concentration was calculated by subtracting the concentration of As(III) from the total inorganic arsenic concentration after reducing As(V) to As(III) by thiourea. Different factors affecting the extraction of As(III) were investigated in detail. Under the optimum conditions, the detection limit for As(III) was 0.72ngmL-1 along with the relative standard deviation of 3.5% (C = 10.0ngmL-1, n = 5). The calibration curve was linear in the range of 2.0-50.0ngmL-1. This method was validated against the certified reference material (GSBZ 50004-88), and applied for the speciation of inorganic As(III) and As(V) in the spiked snow water sample. PMID- 29426510 TI - Fluorescence ELISA based on glucose oxidase-mediated fluorescence quenching of quantum dots for highly sensitive detection of Hepatitis B. AB - Herein, we present a novel sandwich fluorescence enzyme linked immunosorbent assay (ELISA) for highly sensitive detection of Hepatitis B virus surface antigen (HBsAg) based on glucose oxidase (GOx)-induced fluorescence quenching of mercaptopropionic acid-modified CdTe quantum dots (MPA-QDs). In this system, hydrogen peroxide (H2O2) sensitive MPA-QDs was used as a signal output, and glucose oxidase (GOx) was used as label which can generate H2O2 via catalytic oxidation of glucose. The proposed method showed dynamic linear detection of HBsAg both in the range of 47pgmL-1 ~ 380pgmL-1 and 0.75ngmL-1 ~ 12.12ngmL-1. The detection limit of the proposed fluorescence ELISA was 1.16pgmL-1, which was approximately 430-fold lower than that of horseradish peroxidase (HRP)-based conventional ELISA. The average recoveries for HBsAg-spiked serum samples ranged from 98.0% to 126.8% with the relative standard derivation below 10%, thus indicating acceptable precision and high reproducibility of the proposed fluorescence ELISA for HBsAg detection. Additionally, the developed method showed no false positive results analyzing 35 real HBsAg-negative serum samples, and exhibited excellent agreement (R2=0.9907) with a commercial time-resolved fluorescence immunoassay (TRFIA) kit for detecting 31 HBsAg-positive serum samples. In summary, the proposed method based on fluorescence quenching of H2O2 sensitive QDs is considerably to be an excellent biodetection platform with ultrahigh sensitivity, good accuracy and excellent reliability. PMID- 29426512 TI - Surface imprinted polymers based on amino-hyperbranched magnetic nanoparticles for selective extraction and detection of chlorogenic acid in Honeysuckle tea. AB - Novel water-compatible magnetic molecularly imprinted polymers were developed. The magnetic core was firstly grafted by methyl acrylate and ethanediamine to increase the number of amino groups, which could immobilize more templates and form high-density recognition sites. Dopamine was adopted as functional monomer and crosslinker to retighten templates and prepare hydrophilic polymers. The characterization, adsorption capability, selectivity, and reusability were investigated in detail. The limit of detection and quantification of the method were 0.01MUgmL-1 and 0.038MUgmL-1. The experimental results exhibited that the resultant nanomaterials had high crystallinity, satisfactory magnetic property, fast kinetics, favorable adsorption capacity, excellent specificity, and pleasing recovery after a mild elution. In addition, the recoveries of the proposed method at four spiked levels analysis were between 98.4% to 101.3%. The obtained imprinted nanoparticles were used as sorbents for selective separation and determination of chlorogenic acid in Honeysuckle tea. PMID- 29426513 TI - Thermo/pH dual-stimuli-responsive drug delivery for chemo-/photothermal therapy monitored by cell imaging. AB - A thermo/pH dual-stimuli-responsive drug delivery system (DDS) based on polymer coated mesoporous silica nanostructures (MSNs) is developed for facilitating chemotherapy and photothermal therapy. Thermo/pH-responsive polymer, poly((N isopropylacrylamide, NIPAM)-co-methacrylic acid, MA), is grafted onto MSNs by in situ polymerization, followed by loading a chemotherapeutic drug (doxorubicin hydrochloride, DOX) and a near-infrared-absorbing phototherapeutic agent (indocyanine green, ICG) to construct the intelligent drug delivery system, shortly as DOX-ICG-MSN@p(NIPAM-co-MA). At NIR irradiation, the photothermal conversion capability of ICG raises the temperature of the DDS and opens the gatekeeper by shrinkage of the copolymer p(NIPAM-co-MA), which triggers controlled release of DOX at an elevated temperature. On the other hand, drug release is also realized at pH 5.3, a characteristic pH value in cancer cell microenvironment, at which it not only causes the shrinkage of the pH-sensitive polymeric moiety of methacrylic acid in MSN@p(NIPAM-co-MA) but also deteriorates electrostatic interaction of DOX molecules in the mesoporous channel by protonation of silanols. In addition, ICG further ensures photothermal therapy (PTT) and photodynamic therapy (PDT). The cytotoxicity assay of HeLa cells shows obvious synergistic effect by demonstrating that the combined use of DOX and ICG is more effective in killing HeLa cells than free DOX and ICG. The endocytosis of the drug is monitored by cell imaging. PMID- 29426514 TI - Application of polyacrylonitrile nanofibers decorated with magnetic carbon dots as a resonance light scattering sensor to determine famotidine. AB - In this study, a novel resonance light scattering (RLS) sensor was synthesized using polyacrylonitrile nanofibers decorated with magnetic carbon dots (MCDs@NFs) nanocomposite and applied for famotidine (FMD) determination. The MCDs@NFs nanocomposite was synthesized by combining electrospinning and a simple one-step hydrothermal method. Different methods were applied in order to characterize the MCDs@NFs nanocomposite such as: scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), Transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD). Light scattering properties of the synthesized nanocomposite in the presence or absence of FMD have been selected as the detection signal considering the fact that FMD addition increases the RLS intensities of the system. Thus, the prepared nanocomposite was employed as a RLS sensor to detect FMD. A linear response was observed under the optimal conditions in range of 0.15-50.0MUmolL-1 with detection limit of 0.04MUmolL-1. The MCDs@NFs nanocomposite was effectively capable in determining FMD in real samples and the results were close to those results obtained by reversed-phase HPLC method (RP-HPLC). PMID- 29426515 TI - Preparation of core-shell structured magnetic covalent organic framework nanocomposites for magnetic solid-phase extraction of bisphenols from human serum sample. AB - Core-shell structured magnetic covalent organic framework (Fe3O4@COF) nanocomposites were synthesized via a facile approach at room temperature and explored as an absorbent for magnetic solid-phase extraction (MSPE) of bisphenols (BPs) from human serum sample. The as-prepared Fe3O4@COF nanocomposites with core shell structure possessed high specific surface area (181.36m2/g), uniform mesoporous size (~ 3.6nm), high saturation magnetization (42.7emu/g), and excellent thermal and chemical stability, rendering it as an ideal adsorbent with high adsorption efficiency and size selectivity. The experimental parameters influencing extraction efficiency, including adsorbent dosage, extraction time, pH and ion strength, desorption solvent and time, were investigated in detail. Taking these advantages together, a simple, fast, effective and sensitive method that MPSE followed by HPLC-MS, was proposed to detect five BPs, which exhibited good linearity (r > 0.9982) within the concentration ranges of 0.1-50MUg/L. Moreover, the low detection limits (1.0-78.1ng/L), signal-to-noise ratio (S/N = 3), the high enrichment factors (56-95 fold), and good recoveries (93.0-107.8%) with relative standard deviations (RSDs) less than 3.4% for inter-day and 6.9% for intra-day were achieved. The developed method was also successfully applied to the analysis of trace BPs in human serum sample, which demonstrated the most promising potential of the Fe3O4@COF nanocomposites as good adsorbent in sample pretreatment. PMID- 29426516 TI - A colorimetric sensor array based on sulfuric acid assisted KMnO4 fading for the detection and identification of pesticides. AB - Pesticides play a critical role in improving crop yield in modern agriculture, but their residues significantly harm the environment and human health. Herein, a novel and simple colorimetric sensor array built on sulfuric acid assisted KMnO4 fading strategy has been developed for pesticides detection and discrimination. This sensor array is facilely fabricated by KMnO4 and sulfuric acid through simply adjusting their concentrations and ratios. Hierarchical clustering analysis (HCA) demonstrates that the as-fabricated colorimetric sensor array has a high dimensionality, and shows excellent capability to recognize common kinds of pesticides from potential interferants. Semi-quantitative detection was achieved through combining HCA and corresponding fitting curves. Moreover, the proposed sensor array was successfully applied to detect pesticide residues (e.g. carbaryl) in real samples. The strategy described herein will not only "maximally" simplify the design and fabrication approach, but expand the application fields of colorimetric sensor array methodology towards weak-reactive analytes. PMID- 29426517 TI - Adsorption behavior of thorium on N,N,N',N'-tetraoctyldiglycolamide (TODGA) impregnated graphene aerogel. AB - As a kind of three-dimensional graphene architecture material with superhydrophobic, low density, high specific surface area and porosity, graphene aerogel (GA) can be used to immobilize extractant to constitute the solvent impregnated adsorbent. In this paper, the N,N,N',N'-tetraoctyldiglycolamide impregnated graphene aerogel ( GA-TODGA) was prepared to remove the thorium from aqueous solution. It is found that the adsorption of thorium on GA-TODGA is strongly dependent on the concentration of TODGA in GA and HNO3 in aqueous solution. Compared with other solvent impregnated adsorbents, the adsorption capacity of GA-TODGA is much higher due to the high immobilization capacity of GA for TODGA. Furthermore, the GA-TODGA also possesses excellent stability and reusability, ensuring the application potential of using GA-TODGA in large scale. PMID- 29426518 TI - A highly sensitive and selective detection of Cr(VI) and ascorbic acid based on nitrogen-doped carbon dots. AB - A highly sensitive and selective detection of hexavalent chromium (Cr(VI)) and ascorbic acid (AA) was proposed using nitrogen-doped carbon dots (N-CDs). In the absence of AA, the quantitative detection of Cr(VI) was realized through Cr(VI) acting as a quencher to quench the fluorescence of N-CDs by inner filter effect (IFE) and static quenching effect. Under the optimal conditions, the linear range for Cr(VI) detection was from 0.01 to 250MUM with a detection limit of 5nM (S/N = 3). In the presence of AA, the fluorescence intensity could be rapidly enhanced compared with the fluorescence of N-CDs/Cr(VI) system since Cr(VI) can be reduced into trivalent chromium (Cr(III)) by AA. And a wide linear range for AA detection was obtained from 1 to 750MUM. The detection limit was 0.3MUM (S/N = 3). More importantly, this method can be successfully applied to the detection of Cr(VI) in real water samples, and AA in vitamins C tablets and human serum sample. PMID- 29426519 TI - Electrochemical synthesis of silver nanoclusters on electrochemiluminescent resonance energy transfer amplification platform for Apo-A1 detection. AB - Herein, a novel electrochemiluminescence resonance energy transfer (ERET) strategy between in situ electrogenerated silver nanoclusters (AgNCs) as the donor and Ru(bpy)2(5-NH2-1,10-phen)Cl2 (Ru(II)) as the acceptor was reported, which was applied for the construction of a ultrasensitive immunosensor for the determination of apolipoprotein-A1 (Apo-A1). Notably, the Ag NCs were in suit electro-reducted on glassy carbon electrode (GCE) based on a simple, fast and controllable electrochemical technique, which acted as not only biocompatible ECL emitters, but also protein immobilization platform via Ag-N or Ag-S bond. Subsequently, the acceptor probe was constructed by modifying Ru(II) and secondary antibody on the nanocarriers of carboxyl-functionalized MWCNTs. Based on the sandwiched immunoassay method, the ECL signals declining at 449nm (Ag NCs) and the increasing at 650nm (Ru(II)) both reflect the amount of Apo-A1. By measuring the ratio of ECL650nm/ECL449nm, we could accurately quantify the concentration of Apo-A1 in range from 1.0pg/mL to 1.0ng/mL and limit of detection down to 0.33pg/mL, which opened up a new research direction for ultrasensitive ECL bioanalysis based metal NCs. PMID- 29426520 TI - Testing of nylon 6 nanofibers with different surface densities as sorbents for solid phase extraction and their selectivity comparison with commercial sorbent. AB - Nylon 6 nanofibers were tested for their ability to serve as a sorbent for solid phase extraction (SPE). The regular nanostructure providing a great sorption area and amidic functionality should lead to the assumption that nylon 6 nanofibers could be used as a novel sorbent with great potential for sample pre-treatment. However, due to the substantial differences between classical particle sorbents used for solid phase extraction and nanofibers, it is necessary to evaluate this novel approach. This article describes three types of laboratory fabricated nylon 6 nanofibers with different surface density (5.04gm-2, 3.90gm-2 and 0.75gm-2) and corresponding surface areas for solid phase extraction of several groups of compounds with different structural and physicochemical properties (parabens, steroids, flavonoids and pesticides). The nanofibers were created by needleless electrospinning. Extraction columns were manually packed in classic 1- or 3-mL plastic syringe cartridges with 26-30mg of nanofibers and the column bed was sealed with polypropylene frits. The SPE procedure followed a typical five-step protocol and the collected eluates were analyzed by HPLC with UV detection. Extraction recovery was used as a parameter to evaluate the behavior of the analytes within the SPE process. Under this set condition, the recovery of the SPE process ranged from 23.1% to 125.8%. SPE showed good repeatability (0.58 11.87% RSD) and inter-day reproducibility (3.86-9.79% RSD). The achieved results were compared with SPE using a classic particle sorbent column. Good mechanical and chemical stability of nanofibers was proved. Scanning electron microscope was used for the evaluation of morphological changes in nanostructure. Nylon 6 nanofibers proved being a cost-effective sorbent for repeated use in SPE. Nylon 6 nanofibers have great potential in miniaturized SPE enabling users to overcome troubles with high back-pressure. PMID- 29426521 TI - Superhydrophobic titania nanoparticles for fabrication of paper-based analytical devices: An example of heavy metals assays. AB - A new strategy has been introduced to successfully fabricate the hydrophobic barriers of PADs by using organofluorine-modified superhydrophobic TiO2 NPs. Superhydrophobic TiO2-140 NPs with high-photoactivity can be converted to hydrophilicity by self-degradation of surface organic moieties under full spectrum light irradiation. Superhydrophobic TiO2-RT NPs with low-photoactivity exhibits good hydrophobic stability under light irradiation. Thus, combining these features, the PADs have been designed and constructed by photo-induced fabrication of hydrophobic barriers on the surface of the paper. To demonstrate the effectiveness of the constructed PADs, colorimetric detections have been displayed for Fe3+ and Ni2+ ions. The synchronous multi-component detections based on the "multi-channel" PADs and the intuitive detections based on the "chemical-symbol-style" PADs are rapid and feasible. A detection range of Fe3+ and Ni2+ ions based on the "circle-array" PAD is applicable and reliable in 0.2 6.0 mM and 0.4-4.0 mM, respectively. Thus, these results make it to be believed that this new strategy provides an alternative way to effectively construct the PADs. PMID- 29426522 TI - Multifunctional Au NPs-polydopamine-polyvinylidene fluoride membrane chips as probe for enrichment and rapid detection of organic contaminants. AB - High-throughput and rapid detection of hazardous compounds in complicated samples is essential for the solution of environmental problems. We have prepared a "pH paper-like" chip which can rapidly "indicate" the occurrence of organic contaminants just through dipping the chip in water samples for short time followed by fast analysis with surface-assisted laser desorption/ionization time of-flight mass spectrometry (SALDI-TOF MS). The chips are composed of polyvinylidene fluoride membrane (PVDFM), polydopamine (PDA) film and Au nanoparticles (Au NPs), which are layer-by-layer assembled according to the adhesion, self-polymerization and reduction property of dopamine. In the Au NPs loaded polydopamine-polyvinylidene fluoride membrane (Au NPs-PDA-PVDFM) chips, PVDFM combined with PDA film are responsible for the enrichment of organic analyte through hydrophobic interactions and pi-pi stacking; Au NPs serve as effective SALDI matrix for the rapid detection of target analyte. After dipping into water solution for minutes, the Au-PDA-PVDFM chips with enriched organic analytes can be detected directly with SALDI-TOF MS. The good solid-phase extraction performance of the PDA-PVDFM components, remarkable matrix effect of the loaded AuNPs, and sensitivity of the SALDI-TOF MS technique ensure excellent sensitivity and reproducibility for the quantification of trace levels of organic contaminants in environmental water samples. PMID- 29426523 TI - An ultrasensitive and switch-on platform for aflatoxin B1 detection in peanut based on the fluorescence quenching of graphene oxide-gold nanocomposites. AB - Graphene oxide-gold nanocomposites (GO/AuNCs) were prepared and used as a novel fluorescence quenching platform for ultrasensitive detection of aflatoxin B1 (AFB1) coupled with hybridization chain reaction (HCR) amplification. In the designed system, two fluorophore labeled hairpin probes (HP1/HP2) were introduced, and the fluorescence signals of them were effectively quenched due to the adsorption on GO/AuNCs. Associate probe (AP) was used for the specific recognition of AFB1, and the stem-loop structure of it was opened. Meanwhile, the exposed section of AP was utilized as an initiator for the happen of HCR between HP1 and HP2, a strong fluorescence signal was obtained due to the formation of long nicked dsDNA duplex and desorbed of them from the surface of GO/AuNCs. Under the optimal conditions, GO/AuNCs displayed 94% of the quenching efficiency to the fluorescent probes, and a detection limit down to 0.03pg/mL was obtained for AFB1 detection. In particular, the assay exhibited excellent selectivity for the detection of AFB1 against other interfering agents that normally coexist with AFB1 in mildewed agriculture products. Moreover, the assay could realize the detection of AFB1 effectively in peanut samples. PMID- 29426524 TI - Adsorption studies of cadmium onto magnetic Fe3O4@FePO4 and its preconcentration with detection by electrothermal atomic absorption spectrometry. AB - Superparamagnetic Fe3O4@FePO4 nanoparticles with core shell structure were prepared by coating iron phosphate on the surface of Fe3O4 nanoparticles by liquid phase deposition method. The prepared materials were characterized by vibrating sample magnetometer, scanning electron microscopy, X-ray diffractometer, Fourier transform infrared spectrometer, nano Zetasizer, X-ray photoelectron spectroscopy and Raman spectrometer. These characterization methods were also used to describe the adsorption mechanism. The obtained composite material was used for the adsorption of a heavy metal element, cadmium. Its unique magnetic properties are favorable for rapid separation and preconcentration of trace cadmium from aqueous solutions. About 100% sorption was achieved at pH 7 for 1mL, 10MUgL-1 of cadmium. Batch adsorption experiments show that the adsorption fits Langmuir model, and a maximum adsorption capacity 13.51mgg-1 is derived for Cd(II). The retained Cd(II) could be readily recovered by 200MUL of HNO3 (0.01molL-1). The cadmium in the eluate is quantified with detection by electrothermal atomic absorption spectrometry (ETAAS). A sample volume of 2000MUL creates an enrichment factor of 10.3, along with a detection limit of 0.021ugL-1 (3sigma, n=7) and a RSD of 1.3% (0.1ugL-1, n=7) within a linear calibration range of 0.05-0.5ugL-1. The practical applicability of this procedure was validated by analyzing cadmium contents in a certified reference material (GBW08608) and two environmental water samples. PMID- 29426525 TI - An automated continuous homogeneous microextraction for the determination of selenium and arsenic by hydride generation atomic fluorescence spectrometry. AB - An automated continuous homogeneous microextraction approach based on a flow system has been developed and coupled with a hydride generation atomic fluorescence spectrometry system (HG-AFS). The developed approach was applied for the determination of trace arsenic and selenium in environmental water and liver samples. The nonanoic acid was investigated as a switchable hydrophilicity solvent (SHS) for homogeneous microextraction of As(III) and Se(IV) complexes with pyrrolidinedithiocarbamate (PDC). The procedure involved on-line mixing ammonium PDC (aqueous phase), sodium nonanoate (aqueous phase) and acid sample solution resulting in the formation of SHS (nonanoic acid) dispersed into the acid aqueous phase. By this continuous process, analytes complexes with PDC were formed and extracted into the fine SHS droplets followed by retention into a monolithic column packed with block of porous PTFE. Finally, the retained complexes were eluted with NaOH solution and delivered to the HG-AFS system. The limits of detection, calculated from a blank test based on 3sigma, were 0.01MUgL 1 for both analytes. PMID- 29426526 TI - Sensitive arsenic speciation by capillary electrophoresis using UV absorbance detection with on-line sample preconcentration techniques. AB - The World Health Organization (WHO) guideline states that the total arsenic concentration in drinking water must not exceed 10 ppb. However, arsenic toxicity varies significantly, with inorganic arsenic species being more toxic than organic species. Arsenic speciation is therefore important for evaluating the health risks from arsenic-contaminated drinking water. Capillary electrophoresis provides the necessary high performance separation to determine arsenic species in water, but its sensitivity with absorbance detection is far below than needed. Using a coated capillary, several on-line sample preconcentration techniques such as large volume sample stacking with an electroosmotic flow pump, field amplified sample injection (FASI), transient isotachophoresis (tITP), electrokinetic supercharging (EKS) combining FASI and tITP, and counter flow (CF)-EKS, were therefore investigated. With CF-EKS using phosphate and N-cyclohexyl-2 aminoethanesulfonate as leading and terminating electrolytes, respectively, standard samples of arsenite, arsenate, monomethylarsonic acid, and dimethylarsinic acid were preconcentrated from 6,300- to 45,000-fold. The limits of detection obtained with UV absorbance detection were 0.08-0.3 ppb As. For a spring water sample spiked with the four arsenic species, LODs of 2-9 ppb As were obtained, which are lower than the WHO guideline of 10 ppb total As. PMID- 29426527 TI - Quantitative and qualitative analysis of polycyclic aromatic hydrocarbons in urine samples using a non-separative method based on mass spectrometry. AB - In this work, a method for the quantitative and qualitative analysis of 11 polycyclic aromatic hydrocarbons (PAHs) in urine samples is reported. The method is based on the coupling of a programmed temperature vaporizer (PTV) with a quadrupole mass spectrometer (qMS), via a deactivated fused silica tubing. Before the PTV-qMS analysis, the samples were subjected to a liquid-liquid extraction (LLE). The method was rapid since no chromatographic separation was performed. The samples were introduced directly into the PTV, and the analytes were trapped in the Tenax-TA(r) packed liner while the solvent was purged. After that, all the compounds reached the mass spectrometer, obtaining the fingerprint of the analysed samples. Urine samples free of PAHs and the same samples spiked with the compounds were analysed. The resulting profile signals were used to quantify the analytes using multivariate calibration, and to classify the samples according to the presence or absence of the PAHs. In the latter task, non-supervised and supervised pattern recognition techniques were employed. The calibration models worked satisfactorily and errors lower or equal to 15% were obtained, in most cases, when an external validation set was analysed. Regarding the classification of the samples, most of the supervised pattern recognition techniques provided excellent results (100% success), where all of the samples were classified correctly. PMID- 29426528 TI - Vis-NIR spectrometric determination of Brix and sucrose in sugar production samples using kernel partial least squares with interval selection based on the successive projections algorithm. AB - This paper proposes a new variable selection method for nonlinear multivariate calibration, combining the Successive Projections Algorithm for interval selection (iSPA) with the Kernel Partial Least Squares (Kernel-PLS) modelling technique. The proposed iSPA-Kernel-PLS algorithm is employed in a case study involving a Vis-NIR spectrometric dataset with complex nonlinear features. The analytical problem consists of determining Brix and sucrose content in samples from a sugar production system, on the basis of transflectance spectra. As compared to full-spectrum Kernel-PLS, the iSPA-Kernel-PLS models involve a smaller number of variables and display statistically significant superiority in terms of accuracy and/or bias in the predictions. PMID- 29426529 TI - Potentiometric chemical sensors for the detection of paralytic shellfish toxins. AB - Potentiometric chemical sensors for the detection of paralytic shellfish toxins have been developed. Four toxins typically encountered in Portuguese waters, namely saxitoxin, decarbamoyl saxitoxin, gonyautoxin GTX5 and C1&C2, were selected for the study. A series of miniaturized sensors with solid inner contact and plasticized polyvinylchloride membranes containing ionophores, nine compositions in total, were prepared and their characteristics evaluated. Sensors displayed cross-sensitivity to four studied toxins, i.e. response to several toxins together with low selectivity. High selectivity towards paralytic shellfish toxins was observed in the presence of inorganic cations with selectivity coefficients ranging from 0.04 to 0.001 for Na+ and K+ and 3.6*10-4 to 3.4*10-5 for Ca2+. Detection limits were in the range from 0.25 to 0.9 MUmolL 1 for saxitoxin and decarbamoyl saxitoxin, and from 0.08 to 1.8 MUmolL-1 for GTX5 and C1&C2, which allows toxin detection at the concentration levels corresponding to the legal limits. Characteristics of the developed sensors allow their use in the electronic tongue multisensor system for simultaneous quantification of paralytic shellfish toxins. PMID- 29426530 TI - Flow injection spectrophotometric determination of V(V) involving on-line separation using a poly(vinylidene fluoride-co-hexafluoropropylene)-based polymer inclusion membrane. AB - A poly(vinylidene fluoride-co-hexafluoropropylene)-based polymer inclusion membrane (PIM) using Cyphos(r) IL 101 (i.e. trihexyl(tetradecyl)phosphonium chloride) as the carrier and 2-nitrophenyl octyl ether as a plasticizer in a mass ratio of 55/35/10 was employed for the on-line extractive separation of V(V) prior to its spectrophotometric determination in a flow injection analysis (FIA) system using xylenol orange as the colorimetric reagent. The selectivity of the membrane allowed the determination of V(V) in sulfate solutions in the presence of a variety of cations and anions. The interference of molybdenum(VI) was eliminated by off-line extraction using the same PIM. A univariate sequential optimization of the newly developed FIA system was conducted and under optimal conditions the system is characterized by a linear concentration range of 0.5 8.0mgL-1, detection limit of 0.08mgL-1 and sample throughput of 4h-1. The relative standard deviation at the 3mgL-1 level of V(V) was 2.9% based on 8 replicate determinations. The membrane was stable, which was reflected by the standard deviation value for determinations over three consecutive days (24 determinations of 3mgL-1 V(V)) of 3.6%. The newly developed FIA system was applied to the determination of V(V) in water and dietary supplements samples and a good agreement with inductively coupled plasma optical emission spectrometry was observed. PMID- 29426531 TI - A water-compatible magnetic molecularly imprinted polymer for the selective extraction of risperidone and 9-hydroxyrisperidone from human urine. AB - An accurate, rapid, and sensitive method for the determination of risperidone and 9-hydroxyrisperidone in urine samples was developed by combining water-compatible magnetic molecularly imprinted solid-phase extraction with high performance liquid chromatography. Several variables relating to the efficiency of magnetic solid phase extraction were optimized, including the amount of adsorbent, adsorption time, type of elution solvent, and desorption time. The analytical performance of this method was validated under the optimized conditions. The linearity for risperidone and 9-hydroxyrisperidone was obtained in the range 1 2000ngmL-1 with correlation coefficient >= 0.991. Limits of detection of risperidone and 9-hydroxyrisperidone are 0.21ngmL-1 and 0.24ngmL-1, respectively. Recoveries at three spike levels (10, 100, and 1000ngmL-1) ranged from 94.6% to 102.4% with relative standard deviations (%) <= 5.3. These results confirmed that this method can be successfully and facilely used to analyze the multi-residues of risperidone and 9-hydroxyrisperidone in urine samples with high efficiency and good sensitivity. PMID- 29426532 TI - A simple method for chromium speciation analysis in contaminated water using APDC and a pre-heated glass tube followed by HPLC-PDA. AB - In this study, a simple sample preparation method was developed for the determination of tri-and hexavalent chromium in water samples. It utilizes a pre heated customized glass tube (CGT), to supply the heat energy required for the reaction of Cr(III) with ammonium pyrrolidinedithiocarbamate (APDC). The products of the Cr complexes, tris(1-pyrrolidinecarbodithioato)chromium(III) and bis(1 pyrrolidinecarbodithioato)[1-pyrrolidinecarbodithio(thioperoxoato)]chromium(III) were chromatographed with Shimadzu LC-20AT and Zobax Eclipse C18 (150mm * 4.6mm, 5um) column using ACN: Water, (7:3, v/v) as the mobile phase. The concentration of Cr(III) ranged from 0.06mgL-1 to 0.09mgL-1 and that of Cr(VI) was between 0.02mgL-1 to 0.04mgL-1 in the samples. Percentage recoveries from spiked real samples were between 87% (tap water) to 110% (wastewater) for Cr(III) and 92% (pond water) to 117% (tap water) for Cr(VI). The limits of detection (LODs) were 0.0029mgL-1 and 0.0014mg/L-1 for Cr(III) Cr(VI) respectively. While the limits of quantitation (LOQs), were 0.0098mgL-1 and 0.0047mgL-1 for Cr(III) and Cr(VI) respectively. Method precision (RSD (%)) was 3.3% and 3.5% for Cr(III) and Cr(VI) respectively. The developed method was applied for the speciation analysis of chromium in drinking water, tap water, wastewater, river water, and pond water samples. Our findings proved the method is simple and inexpensive. The method was validated by the analysis of a certified reference material (CRM) SLRS-4. The percentage recovery and RSD(%) from the spiked CRM were 91% and 115% and 0.32% and 1.4% for Cr(III) and Cr(VI) respectively. PMID- 29426533 TI - A luminescent Lanthanide-free MOF nanohybrid for highly sensitive ratiometric temperature sensing in physiological range. AB - Luminescent MOF materials with tunable emissions and energy/charge transfer processes have been extensively explored as ratiometric temperature sensors. However, most of the ratiometric MOF thermometers reported thus far are based on the MOFs containing photoactive lanthanides, which are potentially facing cost issue and serious supply shortage. Here, we present a ratiometric luminescent thermometer based on a dual-emitting lanthanide-free MOF hybrid, which is developed by encapsulation of a fluorescent dye into a robust nanocrystalline zirconium-based MOF through a one-pot synthesis approach. The structure and morphology of the hybrid product was characterized by Powder X-ray diffraction (PXRD), N2 adsorption-desorption measurement and Scanning electron microscopy (SEM). The pore confinement effect well isolates the guest dye molecules and therefore suppresses the nonradiative energy transfer process between dye molecules. The incorporated dye emission is mainly sensitized by the organic linkers within MOF through fluorescence resonance energy transfer. The ratiometric luminescence of the MOF hybrid shows a significant response to temperature due to the thermal-related back energy transfer process from dye molecules and organic linkers, thus can be exploited for self-calibrated temperature sensing. The maximum thermometric sensitivity is 1.19% degrees C-1 in the physiological temperature range, which is among the highest for the ratiomtric MOF thermometers that operating in 25-45 degrees C. The temperature resolution is better than 0.1 degrees C over the entire operative range (20-60 degrees C). By integrating the advantages of excellent stability, nanoscale nature, and high sensitivity and precision in the physiological temperature range, this dye@MOF hybrid might have potential application in biomedical diagnosis. What' more, this work has expanded the possibility of non-lanthanide luminescent MOF materials for the development of ratiometric temperature sensors. PMID- 29426534 TI - Multiple-channel ultra-violet absorbance detector for two-dimensional chromatographic separations. AB - In recent years, much research has gone into developing online comprehensive two dimensional liquid chromatographic systems allowing for high peak capacities in comparable separation times to that of one-dimensional liquid chromatographic systems. However, the speed requirements in the second dimension (2nd-D) still remain one challenge for complex biological samples due to the current configuration of two column/two detector systems. Utilization of multiple 2nd-D columns can mitigate this challenge. To adapt this approach, we need a multiple channel detector. Here we develop a versatile multichannel ultraviolet (UV) light absorbance detector that is capable of simultaneously monitoring separations in 12 columns. The detector consists of a deuterium lighthouse, a flow cell assembly (a 13-channel flow cell fitted with a 13-photodiode-detection system), and a data acquisition and monitoring terminal. Through the use of a custom high optical quality furcated fiber to improve light transmission, precise machining of a flow cell to reduce background stray light through precision alignment, and sensitive electronic circuitry to reduce electronic noise through an active low pass filter, the background noise level is measured in the tens of uAU. We obtain a linear dynamic range of close to three orders of magnitude. Compared to a commercialized multichannel UV light absorbance detector like the Waters 2488 UV/Vis, our device provides an increase in channel detection while residing within the same noise region and linear range. PMID- 29426535 TI - Facile synthesis of a SnO2@rGO nanohybrid and optimization of its methane-sensing parameters. AB - Stannic oxide nanoparticles and various compositions of SnO2@rGO (reduced graphene oxide) nanohybrids were synthesized by a facile hydrothermal method and utilized as chemiresistive methane gas sensors. To characterize the synthesized nanohybrids, BET (Brunauer-Emmett-Teller), XRD, FESEM, TEM, FTIR, and Raman techniques were used. Sensing elements were tested using a U-tube flow chamber with temperature control. To obtain the best sensor performance, i.e., the highest signal and the fastest response and recovery times, the sensing element composition, operating temperature, and gas flow rate were optimized. The highest response (change in resistance) of 47.6% for 1000 +/- 5ppm methane was obtained with the SnO2@rGO1% nanohybrid at 150 degrees C and a flow rate of 160sccm; the response and recovery times were 61s and 5min, respectively. A sensing mechanism was suggested, based on the experiments. PMID- 29426536 TI - Synthesis of hierarchical Co3O4@NiO core-shell nanotubes with a synergistic catalytic activity for peroxidase mimicking and colorimetric detection of dopamine. AB - Fabrication of core-shell nanostructured catalyst is a promising way for tuning its catalytic performance due to the highly active interface and rich redox properties. In this work, hierarchical Co3O4@NiO core-shell nanotubes are fabricated by the deposition of NiO shells via a chemical bath treatment using electrospun Co-C composite nanofibers as templates, followed by a calcination process in air. The as-prepared Co3O4@NiO core-shell nanotubes exhibit a uniform and novel hollow structure with Co3O4 nanoparticles attached to the inner wall of NiO nanotubes and excellent catalytic activity toward the oxidation of 3,3',5,5' tetramethylbenzidine (TMB) in the presence of H2O2. Due to the synergistic effect, the peroxidase-like activity of the Co3O4@NiO core-shell nanotubes is much higher than that of individual Co3O4 and NiO components. Owing to the superior peroxidase-like activity, a simple and rapid colorimetric approach for the detection of dopamine with a detection limit of 1.21uM and excellent selectivity has been developed. It is anticipated that the prepared Co3O4@NiO core-shell nanotubes are promising materials applied for biomedical analysis and environmental monitoring. PMID- 29426537 TI - Rapid determination of hydrophilic phenols in olive oil by vortex-assisted reversed-phase dispersive liquid-liquid microextraction and screen-printed carbon electrodes. AB - A novel approach is presented to determine hydrophilic phenols in olive oil samples, employing vortex-assisted reversed-phase dispersive liquid-liquid microextraction (RP-DLLME) for sample preparation and screen-printed carbon electrodes for voltammetric analysis. The oxidation of oleuropein, hydroxytyrosol, caffeic acid, ferulic acid and tyrosol was investigated, being caffeic acid and tyrosol selected for quantification. A matrix-matching calibration using sunflower oil as analyte-free sample diluted with hexane was employed to compensate matrix effects. Samples were analyzed under optimized RP DLLME conditions, i.e., extractant phase, 1M HCl; extractant volume, 100uL; extraction time, 2min; centrifugation time, 10min; centrifugation speed, 4000rpm. The working range showed a good linearity between 0.075 and 2.5mgL-1 (r = 0.998, N = 7) for caffeic acid, and between 0.075 and 3mgL-1 (r = 0.999, N = 8) for tyrosol. The methodological limit of detection was empirically established at 0.022mgL-1 for both analytes, which is significantly lower than average contents found in olive oil samples. The repeatability was evaluated at two different spiking levels (i.e., 0.5mgL-1 and 2mgL-1) and coefficients of variation ranged from 8% to 11% (n = 5). The applicability of the proposed method was tested in olive oil samples of different quality (i.e., refined olive oil, virgin olive oil and extra virgin olive oil). Relative recoveries varied between 83% and 108% showing negligible matrix effects. Finally, fifteen samples were analyzed by the proposed method and a high correlation with the traditional Folin-Ciocalteu spectrophotometric method was obtained. Thereafter, the concentrations of the fifteen oil samples were employed as input variables in linear discriminant analysis in order to distinguish between olive oils of different quality. PMID- 29426539 TI - A combined Surface Enhanced Raman Spectroscopy (SERS)/UV-vis approach for the investigation of dye content in commercial felt tip pens inks. AB - The development of protocols for the protection of the large patrimony of works of art created by felt tip pen media since the 1950's requires detailed knowledge of the main dyes constituting commercial ink mixtures. In this work Surface Enhanced Raman Scattering (SERS) and UV-vis spectroscopy were used for the first time for the systematic identification of dye composition in commercial felt tip pens. A large selection of pens comprising six colors of five different brands was analyzed. Intense SERS spectra were obtained for all colors, allowing identification of main dye constituents. Poinceau 4R and Eosin dyes were found to be the main constituents of red and pink colors; Rhodamine and Tartrazine were found in orange and yellow colors; Erioglaucine was found in green and blue colors. UV-vis analysis of the same inks was used to support SERS findings but also to unequivocally assign some uncertain dye identifications, especially for yellow and orange colors. The spectral data of all felt tip pens collected through this work were assembled in a database format. The data obtained through this systematic investigation constitute the basis for the assembly of larger reference databases that ultimately will support the development of conservation protocols for the long term preservation of modern art collections. PMID- 29426538 TI - A selective volatilization method for determination of chloride and sulfate in calcium carbonate pharmaceutical raw material and commercial tablets. AB - In this work a feasible method for chloride and sulfate determination in calcium carbonate pharmaceutical raw material and commercial tablets by ion chromatography after microwave-induced combustion was developed. The analytes were released from matrix by combustion in closed system pressurized with oxygen. Starch as volatilization aid, 100mmolL-1 HNO3 as absorbing solution and 5min of microwave irradiation time were used. Recovery tests using standard solutions were performed for the accuracy evaluation. A mixture of calcium carbonate pharmaceutical raw material or commercial tablets, starch and a certified reference material was also used as a type of recovery test. Recoveries ranging from 88% to 103% were obtained in both spike tests. Limits of detection (Cl-: 40ugg-1 and SO42-: 140ugg-1) were up to eighteen times lower than the maximum limits established for the analytes by Brazilian, British, European and Indian Pharmacopoeias. The limit tests recommended by the European Pharmacopoeia for Cl- and SO42- in CaCO3 were carried out to compare the results. Chloride and SO42- concentrations in the samples analyzed by proposed method were in agreement with those results obtained using the tests recommended by the European Pharmacopoeia. However, the proposed method presents several advantages for the routine analysis when compared to pharmacopoeial methods, such as the quantitative simultaneous determination, high sample preparation throughput (up to eight samples per run in less than 30min), reduced volume of reagents and waste generation. Thus, the proposed method is indicated as an excellent alternative for Cl- and SO42- determination in CaCO3 pharmaceutical raw material and commercial tablets. PMID- 29426540 TI - Gas-diffusion-based passive sampler for ammonia monitoring in marine waters. AB - A novel passive sampler based on gas-diffusion across a hydrophobic membrane is described for the determination of the time-weighted average concentration of dissolved molecular ammonia in high ionic strength aquatic environments, such as sea, coastal and estuarine waters, for a period of 3 days. The passive sampler developed is cheap, easy-to-use, reusable, and has a dynamic concentration range of 2.0-12uM, which covers the water quality guideline trigger value of 11.4uM (160ugL-1 NH3-N) for high conservation value waters, making this a powerful new tool for water quality managers involved in long-term ammonia monitoring. The gas diffusion-based passive sampler was calibrated under laboratory conditions and deployed in a tank of seawater in the laboratory and at an estuarine site for proof of concept, and a good agreement between passive and spot sampling was achieved in both cases. PMID- 29426541 TI - The effect of loading carbon nanotubes onto chitosan films on electrochemical dopamine sensing in the presence of biological interference. AB - In vivo monitoring of the neurotransmitter dopamine can potentially improve the diagnosis of neurological disorders and elucidate their underlying biochemical mechanisms. While electrochemical sensors can detect unlabeled dopamine molecules, their sensing performance is dramatically reduced by electrochemical currents generated by other, interfering molecules (e.g., uric acid) in the biological environment. To overcome this caveat, the surface of the sensor is often modified with electrocatalytic materials, which are encapsulated inside a polymeric film; however, the effect of the encapsulating film on the sensing performance of the electrode has not been systematically studied. This study characterizes the effect of loading carbon nanotubes (CNTs) onto a chitosan film on the electrochemical sensing performance of dopamine in the presence of uric acid. Higher CNT loading increases the diffusion and electron transfer rate coefficients of the sensor and, in the presence of uric acid, provides better sensitivity (3.00uALumol-1 for 1.75% CNT loading, vs 0.01uALumol-1 for 1% loading) but a poorer limit-of-detection (2.00umolL-1vs 1.00, respectively), as reported here for the first time. These findings can help optimize the sensitivity and the limit-of-detection of electrochemical sensors in complex biofluids to enable an in vivo monitoring of dopamine and other redox-active molecules. PMID- 29426542 TI - Magnetic ferrite particles combined with electrothermal atomic absorption spectrometry for the speciation of low concentrations of arsenic. AB - Freshly in situ prepared ferrite particles were used for the micro-solid phase extraction of arsenic species. When the separation was carried out at pH 8, inorganic arsenic (As(III) + As(V)) and monomethylarsonic acid (MMA) were retained in the magnetic material. A second aliquot was treated with 2,3 dimercapto propanol, leading to the retention of As(V)+MMA, while a third aliquot was first treated with sodium thiosulphate, in which case only inorganic arsenic passed to the solid phase. In all cases, the solid residue collected by a magnet was suspended in a dilute nitric acid solution containing Triton X-100 and introduced into the electrothermal atomizer to obtain the analytical signal of arsenic. The use of palladium as a chemical modifier allowed calibration to be carried out with aqueous standards. The detection limit was 0.02ugL-1 arsenic for a 10mL sample volume. The procedure was applied to waters and herbal infusions, and its reliability was evaluated by analyzing eleven certified reference materials for which speciation data are provided. PMID- 29426543 TI - Silica nanoparticles coated by poly(acrylic acid) brushes via host-guest interactions for detecting DNA sequence of Hepatitis B virus. AB - Poly(acrylic acid) (PAA) brushes coated onto silica nanoparticles have been widely utilized in bioassays due to their abilities of providing favorable microenvironments and ensuring good biological activities for biomolecules. However, traditional PAA brushes are synthesized by reversible addition fragmentation chain transfer polymerization. Hence, it is generally difficult to control and characterize the molecular weight of the PAA brushes, which may depress the reproducibility and bring more uncertain results. Herein, atom transfer radical polymerization method is employed to synthesize beta cyclodextrin-cored PAA with uniform and controllable molecular weight. After loading on the surfaces of adamantane-functionalized silica nanoparticles via host-guest interactions, glucose oxidase and probe single strand DNA (ssDNA) are further immobilized on the as-prepared nanoparticles. Meanwhile, capture ssDNA is functionalized on amino modified magnetic beads. In the presence of ssDNA sequence of Hepatitis B Virus (HBV) containing completely matched sequence of both probe and capture ssDNA, a bioconjugate is formed and can be separated by an external magnet. The isolated glucose oxidase can further catalyze glucose into gluconic acid and H2O2, and then reduce HAuCl4 on Au seeds. By monitoring the absorption intensity change of the Au NPs at 530nm, the proposed biosensor with novel signal amplification probes can be used to detect DNA sequence of HBV with high sensitivity and selectivity in both buffer and serum samples. This developed strategy has presented a new way to construct silica nanoparticles coated by PAA brushes for the fields of clinical diagnosis and other life sciences. PMID- 29426544 TI - The synthesis of a smart streptavidin-functionalized poly(N-isopropylacrylamide) composite and its application in the separation and detection of virus nucleic acid. AB - A new kind of polymeric material (PNIPAAm-co-SA) was prepared by conjugating a thermosensitive polymer, Poly (N-isopropylacrylamide) (PNIPAAm) with streptavidin (SA). This smart prepared composite displayed a controllable conformation change between an expanded and a collapsed form, below or above its lower critical solution temperature (LCST). Differential scanning calorimetry (DSC) analysis demonstrated that the PNIPAAm-co-SA bioconjugate showed the same LCST as the original synthetic polymer, PNIPAAm, which was also 32 degrees C. Based on the specific interaction between SA and biotin, a higher capture efficiency of PNIPAAm-co-SA, which was almost 100% in PBS buffer solution and above 70% in serum was obtained, respectively. And the high affinity between PNIPAAm-co-SA and biotin was still maintained after three heating cycles. Subsequently, the variola virus (small pox, VV) oligonucleotide sequence was chosen as a model to demonstrate the sensitivity of the biosensor which was fabricated based on PNIPAAm-co-SA. The biosensor exhibited the ability to separate and enrich targets from complicated system with its phase transition ability, and high sensitivity toward VV-targets were achieved. Moreover, other types of targets such as proteins and cells, could be detected by changing the biotin-captures, which indicated the broad applicability of biosensors based on this smart polymer material. PMID- 29426545 TI - An electrochemical sensor based on copper-based metal-organic frameworks-graphene composites for determination of dihydroxybenzene isomers in water. AB - A highly and simply sensitive electrochemical sensor was presented for the simultaneous determination of hydroquinone (HQ) and catechol (CT) in the water based on copper centered metal-organic framework-graphene composites (Cu-MOF-GN) [Cu-MOF = Cu3(BTC)2 (BTC = 1, 3, 5-benzenetricarboxylicacid)] modified glassy carbon electrode (Cu-MOF-GN/GCE). The modification procedure was carried out through casting metal-organic framework-graphene oxide composites (Cu-MOF-GO) on the bare glassy carbon electrode and followed by the transformation of Cu-MOF-GO to Cu-MOF-GN by an electrochemical reduction. The electrochemical behavior of HQ and CT at Cu-MOF-GN/GCE was investigated by cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). Under the optimized conditions, the modified electrode had excellent electrocatalytic activity and high selectivity toward HQ and CT. The electrochemical sensor exhibited a linear response in the same range of 1.0 * 10-6 to 1.0 * 10-3M with the detection limits of 5.9 * 10-7M for HQ and 3.3 * 10-7M for CT (S/N = 3). Four samples of tap water spiked with different concentrations of HQ and CT were considered. The method has been applied to the analysis of these isomers in spiked tap water with recoveries from 99.0 ~ 102.9% and relative standard deviations (RSDs) for 5 successive measurements less than 5% were also acceptable. This method was successfully applied to detect target analytes in the real samples with satisfying results. The MOFs-based sensors in the field of electrochemical sensing held a great promise for routine sensing applications. PMID- 29426546 TI - A chemometric approach for characterization of serum transthyretin in familial amyloidotic polyneuropathy type I (FAP-I) by electrospray ionization-ion mobility mass spectrometry. AB - In this study, we describe a chemometric data analysis approach to assist in the interpretation of the complex datasets from the analysis of high-molecular mass oligomeric proteins by ion mobility mass spectrometry (IM-MS). The homotetrameric protein transthyretin (TTR) is involved in familial amyloidotic polyneuropathy type I (FAP-I). FAP-I is associated with a specific TTR mutant variant (TTR(Met30)) that can be easily detected analyzing the monomeric forms of the mutant protein. However, the mechanism of protein misfolding and aggregation onset, which could be triggered by structural changes in the native tetrameric protein, remains under investigation. Serum TTR from healthy controls and FAP-I patients was purified under non-denaturing conditions by conventional immunoprecipitation in solution and analyzed by IM-MS. IM-MS allowed separation and characterization of several tetrameric, trimeric and dimeric TTR gas ions due to their differential drift time. After an appropriate data pre-processing, multivariate curve resolution alternating least squares (MCR-ALS) was applied to the complex datasets. A group of seven independent components being characterized by their ion mobility profiles and mass spectra were resolved to explain the observed data variance in control and patient samples. Then, principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were considered for exploration and classification. Only four out of the seven resolved components were enough for an accurate differentiation. Furthermore, the specific TTR ions identified in the mass spectra of these components and the resolved ion mobility profiles provided a straightforward insight into the most relevant oligomeric TTR proteoforms for the disease. PMID- 29426548 TI - ? PMID- 29426547 TI - Upconversion particle@Fe3O4@molecularly imprinted polymer with controllable shell thickness as high-performance fluorescent probe for sensing quinolones. AB - Localized photo-polymerization was ingeniously applied to prepare a multifunctional molecularly imprinted polymer (MIP) fluorescent probe using the "layer-by-layer" assembly of MIP and Fe3O4 nanoparticles on NaYF4: Yb3+, Er3+ upconversion particles (MUCPs@MIP). Enrofloxacin was used as the template and chosen as the target molecular during the investigation of the adsorption property. This ternary probe has magnetic and broad-spectrum molecular recognition capability, fast response, and upconversion fluorescence. The results of the fluorescence quenching analysis showed good linear ranges of 1.03nmol/L to 0.28MUmol/L for enrofloxacin, 1.69nmol/L to 0.22MUmol/L for fleroxacin, 6.92nmol/L to 0.28MUmol/L for levofloxacin, 7.54nmol/L to 0.30MUmol/L for ciprofloxacin, and 3.90nmol/L to 0.25MUmol/L for enoxacin. This probe was further used to determine five quinolones in fish tissues and the recoveries ranging from 90.33% to 108.43% were obtained with relative standard deviation below 5.53%. This work offers a new and general strategy to synthesize a MUCPs@MIP upconversion fluorescence probe with magnetic and selective molecular recognition capability for rapid and accurate sensing of multiple chemical residues in the environment and agri-food products. PMID- 29426549 TI - ? PMID- 29426550 TI - [Prevention of psychosocial risks]. AB - The theme of psychosocial risks remains in the workplace. It is therefore essential that all members of a company are made aware of the terminology and specific prevention actions in this field. Distinguishing between the manifestations of these risks and their causes and consequences helps to improve prevention. PMID- 29426552 TI - [The nurse interview, a tool for detecting occupational stress]. AB - Nurses who work on general wards are on the frontline for detecting psychosocial risk factors during induction and support interviews. They supplement their diagnoses by exploring areas in which occupational stress may be expressed. PMID- 29426551 TI - [The meaning of nursing work, a fragile collective construction]. AB - The meaning of nursing work depends on many personal, social and structural aspects: choices, standards, expectations, resources, training, team, management and organisation. It is a fragile construction, which must be re-examined every day to ensure nurses are not over-committed and to avoid burnout. PMID- 29426553 TI - [Preventing suffering among nursing staff, a public health challenge]. AB - Being a caregiver means seeking to ensure the wellbeing of others. However, when these members of staff are not treated well by their employers, their health can be affected. In health care facilities, to prevent occupational stress, managers must provide opportunities for listening, exchanges and dialogue between different professionals, give employees the power to act and talk, and observe working conditions as well as their reorganisation. PMID- 29426554 TI - [Caring for those who care for us]. AB - The AAPML is a French association offering support for health professionals and private practice doctors suffering from stress via a helpline. It provides information and training for health professionals and takes into account their engagement in the workplace. PMID- 29426555 TI - [Role of the occupational health nurse]. AB - The missions of occupational health nurses are exclusively preventive, except in the event of emergency situations. They are involved in the prevention of occupational stress, the assessment of psychosocial risks and the improvement of quality of life at work. PMID- 29426556 TI - [Homo digitalis and occupational health]. AB - Although the digital transformation is widely viewed as a lever for productivity, it is now also seen, in public occupational health policies, as a factor for the potential increase in occupational risks. This digital transformation can also provide possible solutions enabling the homo digitalis to avoid these risks. PMID- 29426557 TI - [Patients taking an active role in their care in ambulatory knee replacement surgery]. AB - National recommendations encourage the development of ambulatory surgery. This form of treatment, reserved mainly for short procedures, can also be used for more complex operations such as a total knee replacement. The teams at Vitre general hospital share their experience and emphasise the need to ensure the compliance of patients and their family. PMID- 29426558 TI - [Prevention of psychological disorders after a road accident]. AB - A psychological intervention programme, set up within a trauma centre, revealed common factors contributing to the emotional upheaval felt by road accident victims. These factors are linked to the event itself, its medical management, the quality of family support and the patient's history. Early psychotherapy, the awareness of the nursing teams and the involvement of the families are the key elements ensuring coherent and effective prevention. PMID- 29426559 TI - [Health literacy and therapeutic education, converging objectives]. AB - As part of the support provided to people with chronic diseases, nurses contribute to therapeutic patient education. This approach, drawing in particular on health literacy, aims to give people the skills needed for greater autonomy. PMID- 29426560 TI - [Frostbites: cold-freezing injuries due to a biting cold]. AB - Frostbites are cold-freezing injuries of the extremities due to the exposure to temperatures below 0 degrees C. The risk, in the absence of treatment, is the amputation of frostbitten areas which become gangrenous. Victims of frostbite must be treated and evacuated urgently. Nurses play an active role in the secondary long-term treatment. PMID- 29426561 TI - ? PMID- 29426562 TI - A nurse-led cervical screening clinic in primary care. AB - Eliza is a practice nurse in a large general practice in England. She is trained in cancer screening and health promotion as well as chronic disease management. Today patients are consulting with her for their cervical smear test. PMID- 29426563 TI - ? PMID- 29426564 TI - ? PMID- 29426565 TI - ? PMID- 29426566 TI - Special section: Replication stress, a threat to the nuclear and mitochondrial genome. PMID- 29426567 TI - Differences in characteristics of raters who use the visual estimation method in hospitals based on their training experiences. AB - BACKGROUND & AIMS: Despite a clinical need, only a few studies have provided information concerning visual estimation training for raters to improve the validity of their evaluations. This study aims to describe the differences in the characteristics of raters who evaluated patients' dietary intake in hospitals using the visual estimation method based on their training experiences. METHODS: We collected data from three hospitals in Tokyo from August to September 2016. The participants were 199 nursing staff members, and they completed a self administered questionnaire on demographic data; working career; training in the visual estimation method; knowledge, attitude, and practice associated with nutritional care; and self-evaluation of method validity of and skills of visual estimation. We classified participants into two groups, experienced and inexperienced, based on whether they had received training. Square test, Mann Whitney U test, and univariable and multivariable logistic regression analysis were used to describe the differences between these two groups in terms of their characteristics; knowledge, attitude, and practice associated with nutritional care; and self-evaluation of method validity and tips used in the visual estimation method. RESULTS: Of the 158 staff members (79.4%) (118 nurses and 40 nursing assistants) who agreed to participate in the analysis, thirty-three participants (20.9%) were trained in the visual estimation method. Participants who had received training had better knowledge (2.70 +/- 0.81, score range was 1 5) than those who had not received any training (2.34 +/- 0.74, p = 0.03). Score of self-evaluation of method validity of the visual estimation method was higher in the experienced group (3.78 +/- 0.61, score range was 1-5) than the inexperienced group (3.40 +/- 0.66, p < 0.01). Mean total scores of using tips in the visual estimation method in the experienced and inexperienced groups were 19.6 +/- 1.76 and 17.9 +/- 2.28, respectively (score range was 6-24), differing significantly between the two groups (p < 0.01). Multivariable logistic regression revealed that participants who had been trained had adequate knowledge (OR: 2.78, 95% CI: 1.05-7.35) and frequently used tips in visual estimation (OR: 1.85, 95% CI: 1.26-2.73). CONCLUSION: Trained participants had more required knowledge and they used visual estimation tips more frequently than participants who had not been trained in the visual estimation method. This study provides new evidence for the importance of training clinical staff members to use the visual estimation method appropriately and makes suggestions to improve the validity of the visual estimation method. PMID- 29426568 TI - Complement links platelets to innate immunity. AB - The complement system is a versatile part of our immune system. Various intersection points of complement with other cells and molecules of the immune response are well described. Platelets are classically conceived as cells of hemostasis. In recent years, however, several functions of platelets "beyond thrombosis" were discovered. This review depicts the crosstalk of platelets with components of the immune system in the context of thrombo-inflammation. In particular, the various ways, in which platelets interact with the complement system, are illustrated. Platelets cannot only aggravate vascular inflammation and cardiovascular diseases, but they also contribute to organ remodeling and tissue homeostasis. Here, we portray the role of complement factors associated with platelet activation in tissue remodeling. Importantly, the clinical relevance of this platelet-complement crosstalk is addressed. A focus lies on thrombo-inflammatory disorders, other diseases with thrombo-embolic mechanisms or complications, but also autoimmune diseases. Finally, we draw attention to the growing body of evidence on the role of complement-platelet crosstalk in cardiovascular diseases. For future clinical, translational and basic science approaches, this crosstalk may prove a fruitful area of research in order to procure novel therapeutic and diagnostic targets in cardiovascular medicine and previously less addressed diseases featuring a platelet-complement axis. PMID- 29426569 TI - Individual learning plans foster self-directed learning skills and contribute to improved educational outcomes in the surgery clerkship. AB - BACKGROUND: The Individual Learning Plan (ILP) is a newly implemented curricular element designed to foster self-directed learning (SDL) skills among medical students during our surgery clerkship. Our aim was to determine the impact of ILPs on educational outcomes and acquisition of SDL skills. METHODS: Students were surveyed regarding the educational value of ILPs, their acquisition of SDL skills, and the impact of the surgery clerkship on fostering these skills. Mean scores for the NBME surgery subject exam (SSE) were compared before and after implementation of the ILP requirement. RESULTS: Students perceived the ILP requirement as having strong educational value. Mean scores for the SSE increased significantly in the year following ILP implementation (74.9 vs 76.6; p = .042; d = 0.21). Students reported successful acquisition and frequent utilization of SDL skills. CONCLUSIONS: SDL exercises, such as the ILP requirement, lead to improved education outcomes while fostering the acquisition of SDL skills. PMID- 29426570 TI - Transversus abdominis block (TAP) versus thoracic epidural analgesia: Do we have a winner? PMID- 29426571 TI - Likely, but uncertain. PMID- 29426572 TI - The incremental value of a geriatric assessment-derived three-item scale on estimating overall survival in older adults with cancer. AB - OBJECTIVE: A geriatric assessment (GA) assesses functional age of older patients with cancer and is a well-established tool predictive of toxicity and survival. The objective of this study was to investigate the prognostic value of individual GA items. MATERIALS AND METHODS: 546 patients with cancer >= 65 years completed GA from 2009 to 2014 and were followed for survival status for a median of 3.7 years. The GA consisted of function, nutrition, comorbidity, cognition, psychological state, and social activity/support domains. GA items with p < 0.05 in univariable analyses for overall survival (OS) were entered into multivariable stepwise selection procedure using a Cox proportional hazards model. A prognostic scale was constructed with significant GA items retained in the final model. RESULTS: Median age was 72 years, 49% had breast cancer, and 42% had stage 3-4 cancer. Three GA items were significant prognostic factors, independent of traditional factors (cancer type, stage, age, and Karnofsky Performance Status): (1) "limitation in walking several blocks", (2) "limitation in shopping", and (3) ">= 5% unintentional weight loss in 6 months". A three-item prognostic scale was constructed with these items. In comparison with score 0 (no positive items), hazard ratios for OS were 1.85 for score 1, 2.97 for score 2, and 8.67 for score 3. This translated to 2-year estimated survivals of 85%, 67%, 51% and 17% for scores of 0, 1, 2 and 3, respectively. CONCLUSIONS: This three-item scale was a strong independent predictor of survival. If externally validated, this could be a streamlined tool with broader applicability. PMID- 29426573 TI - Intolerance of uncertainty in youth with obsessive-compulsive disorder and generalized anxiety disorder: A transdiagnostic construct with implications for phenomenology and treatment. AB - Obsessive-compulsive disorder (OCD) and generalized anxiety disorder (GAD) are early-onset disorders with significant overlapping phenomenology, especially in young patients who, due to developmental stage, may have difficulty recognizing obsessions and worries as unrealistic or excessive. Shared phenomenology and high rates of comorbidity between OCD and GAD raise the possibility of common underlying processes, and recent work has focused on intolerance of uncertainty (IU) as a reasonable candidate. With an emphasis on the youth literature, we review the phenomenological overlap between OCD and GAD, how symptoms may relate to IU, and how IU may be measured. We review existing psychotherapeutic treatments and discuss how understanding the role of IU may assist in the development of novel psychotherapeutic strategies to improve treatment outcomes. Neuroimaging studies of IU in OCD and GAD are also discussed and suggestions for further research are offered. We conclude that, consistent with Research Domain Criteria (RDoC), IU represents a transdiagnostic construct with a demonstrable neural basis that could be targeted to improve existing treatments for these disorders. PMID- 29426574 TI - Short-term clinical outcome of orthosis alone vs combination of orthosis, nerve, and tendon gliding exercises and ultrasound therapy for treatment of carpal tunnel syndrome. AB - STUDY DESIGN: Prospective randomized study. INTRODUCTION: Carpal tunnel syndrome (CTS) has been described as the most common compression neuropathy. Many modalities exist for conservative treatment. Efficacy of each modality has been described in the literature. However, the effectiveness of combination of these modalities is not well established. The purpose of this study is to assess the short-term clinical outcome of conservative treatment for CTS comparing orthosis alone with combination of orthosis, nerve/tendon gliding exercises, and ultrasound therapy. METHODS: Forty-one patients who presented to Upper Limb Reconstructive and Microsurgery Clinic, University Malaya Medical Centre with CTS and positive electrodiagnostic study were recruited. Fifteen patients had bilateral CTS. Fifty-six wrists were equally randomized to orthosis alone and a combined therapy of orthosis, nerve/tendon gliding exercise, and ultrasound therapy. All patients were required to complete the Boston Carpal Tunnel Questionnaire during the first visit and 2 months after treatment. RESULTS: Both the orthosis and combined therapy groups showed a significant improvement in symptoms and function after treatment. The mean difference of symptoms in the orthosis group was 0.53; 95% confidence interval [CI]: 0.23-0.83 (P = .001) and in the combined therapy group was 0.48; 95% CI: 0.24-0.72 (P < .001). Mean difference of function in the orthosis group was 0.59; 95% CI: 0.28-0.91 (P = .001) and combined group was 0.69; 95% CI: 0.49-0.89 (P < .001). However, there was no significant difference in symptom severity and functional status scores between the groups. DISCUSSION: Our findings support other findings where orthosis and exercises improved symptom severity and functional status scores, however, there was no significant difference between orthosis alone and combined treatment. CONCLUSION: Patients who underwent conservative management for CTS showed improvement in symptoms and function. However, the combination of orthosis, nerve/tendon gliding exercises, and ultrasound therapy did not offer additional benefit compared to orthosis alone. PMID- 29426575 TI - Systematic review, and meta-analysis of steroid-sparing effect, of biologic agents in randomized, placebo-controlled phase 3 trials for systemic lupus erythematosus. AB - OBJECTIVES: To systematically review, and conduct a meta-analysis of steroid sparing effect in, phase 3 randomized, placebo-controlled trials of biologic therapies for systemic lupus erythematosus (SLE). METHODS: Studies were identified by searching Medline (via Pubmed), EMBASE, CINAHL and SCOPUS databases, the Cochrane library, and clinicaltrials.gov. Adult human studies published in English in the last ten years (until 18/04/2017) were included. A random-effects meta-analysis comparing a common corticosteroid-reduction endpoint in the trials of rituximab, belimumab, tabalumab and epratuzumab in SLE, was conducted. RESULTS: Twenty-eight studies were identified; nine were conducted in SLE, five in lupus nephritis and the remaining 14 were post hoc analyses of phase 3 trials in SLE. All therapies trialed targeted B-cells (rituximab (anti-CD20 monoclonal antibody (mAb)), belimumab (anti-BAFF mAb), tabalumab (anti-BAFF mAb), epratuzumab (anti-CD22 mAb), atacicept (TACI-Ig), ocrelizumab (anti-CD20 mAb)), except for abetimus sodium and abatacept (CTLA4-Ig). Only the three trials of belimumab met their primary endpoints, although benefit in secondary endpoints and reduction in serological activity was often seen in the other studies. Meta analysis showed that most therapies (belimumab, tabalumab, and epratuzumab) had a steroid-sparing effect, compared to placebo (pooled RR 1.36 (1.19, 1.56), I2 = 0, p < 0.67). Therapies were generally well tolerated; however, three studies were terminated prematurely due to serious side effects. CONCLUSIONS: With the exception of belimumab, none of the phase 3 trials of biologic therapy in SLE have met their primary endpoint. However, the significant steroid-sparing effect of these agents suggests that future trials may need to include steroid dose in a composite primary endpoint. PMID- 29426576 TI - Primary female epispadias: Perineal approach or Kelly repair? AB - OBJECTIVES: Primary female epispadias encompasses a spectrum of disease, presenting with a variable degree of incontinence. We hypothesized that although perineal urethrocervicoplasty can be a successful first-line procedure in patients with normal bladder, a more radical reconstruction was necessary to achieve continence in cases lying at the most severe end of the spectrum. Our aim was to assess the results of a surgical management using perineal approach in girls with normal bladder capacity, and Kelly radical soft-tissue mobilization (RSTM) in patients with inadequate bladder, based on the assumption that bladder capacity (BC) is a reliable marker of epispadias severity. STUDY DESIGN: Prospective inclusion of incontinent girls with female epispadias referred to a single institution. Patients with normal BC were treated with perineal urethrocervicoplasty (PUCP, group 1). Patients with small bladder underwent RSTM (group 2). Follow-up was at 1, 3, 6, and 12 months postoperatively, then annually, including physical examination, renal ultrasound at each visit, continence status, and estimation of functional/maximal BC. The main study outcome was continence status at the age of 5 years or later, if postoperative follow-up was >12 months. RESULTS: From 2006 to 2017, 16 consecutive children were prospectively included in this study, at a median age of 39 months (5-102 months). Seven girls were included in group 1 and underwent PUCP; at the last follow-up, five out of seven were dry by day (4/5 day and night), although three out of five required bladder-neck injection after perineal reconstruction due to stress incontinence. Two patients with persistent incontinence and absence of BC increase after PUCP subsequently underwent RSTM. Eleven patients with low BC (56% [10-94%] of expected BC) were included in group 2 (9 without prior surgery, 2 after PUCP failure). Among the eight evaluable patients, eight out of eight achieved diurnal continence, and 3/8 were fully continent. One girl with obstructive micturition required clean intermittent catheterization. DISCUSSION: The traditional approach of female epispadias based on staged reconstruction (urethroplasty followed by bladder-neck reconstruction) raised concerns regarding the risk of non-physiological obstructive micturition. The perineal approach was suggested as an alternative, with reported diurnal continence rates of 60-80%, but less than 50% of nocturnal continence, presumably in relation with limited bladder capacity. In cases selected within the most severe end of the epispadias spectrum, the Kelly RSTM seems to offer excellent continence rates. CONCLUSION: A tailored approach to female epispadias, based on perineal reconstruction in favorable cases, and radical soft-tissue mobilization in severe cases, seems to yield good continence outcomes in the long term. PMID- 29426577 TI - Common variants at somatostatin are significantly associated with hypertension incidence in smoking and drinking populations. AB - Somatostatin (SST) and growth hormone-releasing hormone (GHRH) are involved in the development of hypertension. This study aimed to evaluate whether SST and GHRH contribute to genetic susceptibility to hypertension. A case-control study consisting of 2012 hypertensive patients and 2210 matched control individuals was performed, and three tagging single-nucleotide polymorphisms were genotyped. The association of these single-nucleotide polymorphisms with hypertension and ischemic stroke was further evaluated among 4098 participants in a follow-up study. Hazard ratio (HR) and 95% confidence interval were estimated by Cox proportional hazards regression. The follow-up study indicated that in smoking population, variants at SST presented significant association with hypertension incidence; the adjusted HR of rs3755792 (GA + AA vs. GG) was 0.634 (P = .037), and the adjusted HR of rs7624906 (TC + CC vs. TT) was 1.803 (P = .005). In drinking population, rs3755792 at SST was associated with hypertension incidence, and the adjusted HR was 0.580 (P = .009). Moreover, rs6032470 at GHRH had a statistical association with ischemic stroke incidence in smoking population, and the adjusted HR of the additive model was 1.625 (P = .049). These results suggested that SST and GHRH harbor genetic susceptible loci with incident hypertension and ischemic stroke and that smoking and drinking might modify the genetic effect. PMID- 29426579 TI - Duration of Breastfeeding and Subsequent Adolescent Obesity: Effects of Maternal Behavior and Socioeconomic Status. AB - PURPOSE: Previous research has shown that longer duration of breastfeeding is associated with less risk of obesity in childhood and adolescence. However, although putative physiological mechanisms have been proposed, less work has focused on psychosocial or environmental factors, including socioeconomic status (SES) and stressful family environments. METHODS: The current study examined the role of observed maternal emotional behavior and SES (parental education) in the association between duration of breastfeeding and adolescent body mass index (BMI). One hundred fifteen mothers and adolescents participated in interaction tasks when adolescents were approximately 12 years of age. We measured adolescent BMI at approximately 15 years of age and, at one point over the course of the study, mothers retrospectively reported on duration of breastfeeding. RESULTS: Controlling for adolescent gender, age, physical activity, number of perinatal complications, SES, birth weight, and mother's depressive symptoms, longer duration of breastfeeding was associated with lower adolescent BMI (p = .019), and this association was moderated by the mother's observed behavior during interactions with her adolescent, such that greater frequency of dysphoric behavior was associated with a stronger association between breastfeeding and adolescent BMI (p = .002). Longer duration of breastfeeding mediated the association between higher family SES and lower adolescent BMI. CONCLUSIONS: This study is the first to show that observed parental behavior during adolescence may be an important moderator of the association between breastfeeding and obesity. The findings provide justification for future intervention research examining family environment factors in improving adolescent health. PMID- 29426578 TI - TGF-beta signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune arthropathy characterized by chronic articular inflammation. Methotrexate (MTX) remains the first-line therapy for RA and its anti-inflammatory effect is associated with the maintenance of high levels of extracellular adenosine (ADO). Nonetheless, up to 40% of RA patients are resistant to MTX treatment and this is linked to a reduction of CD39 expression, an ectoenzyme involved in the generation of extracellular ADO by ATP metabolism, on circulating regulatory T cells (Tregs). However, the mechanism mediating the reduction of CD39 expression on Tregs is unknown. Here we demonstrated that the impairment in TGF-beta signalling lead to the reduction of CD39 expression on Tregs that accounts for MTX resistance. TGF-beta increases CD39 expression on Tregs via the activation of TGFBRII/TGFBRI, SMAD2 and the transcription factor CREB, which is activated in a p38-dependent manner and induces CD39 expression by promoting ENTPD1 gene transcription. Importantly, unresponsive patients to MTX (UR-MTX) show reduced expression of TGFBR2 and CREB1 and decreased levels of p-SMAD2 and p-CREB in Tregs compared to MTX-responsive patients (R-MTX). Furthermore, RA patients carrying at least one mutant allele for rs1431131 (AT or AA) of the TGFBR2 gene are significantly (p = 0.0006) associated with UR-MTX. Therefore, we have uncovered a molecular mechanism for the reduced CD39 expression on Tregs, and revealed potential targets for therapeutic intervention for MTX resistance. PMID- 29426580 TI - Letter to the Editor. PMID- 29426581 TI - Point of care diagnostics for tuberculosis. AB - The goals of the End TB strategy, which aims to achieve a 90% reduction in tuberculosis (TB) incidence and a 95% reduction in TB mortality by 2035, will not be achieved without new tools to fight TB. These include improved point of care (POC) diagnostic tests that are meant to be delivered at the most decentralised levels of care where the patients make the initial contact with the health system, as well as within the community. These tests should be able to be performed on an easily accessible sample and provide results in a timely manner, allowing a quick treatment turnaround time of a few minutes or hours (in a single clinical encounter), hence avoiding patient loss-to-follow-up. There have been exciting developments in recent years, including the WHO endorsement of Xpert MTB/RIF, Xpert MTB/RIF Ultra, loop-mediated isothermal amplification (TB-LAMP) and lateral flow lipoarabinomannan (LAM). However, these tests have limitations that must be overcome before they can be optimally applied at the POC. Furthermore, worrying short- to medium-term gaps exist in the POC diagnostic test development pipeline. Thus, not only is better implementation of existing tools and algorithms needed, but new research is required to develop new POC tests that allow the TB community to truly make an impact and find the "missed TB cases". PMID- 29426582 TI - Frequency of Acute and Subacute Infarcts in a Population-Based Study. AB - OBJECTIVE: To determine the frequency of incidental acute or subacute cerebral infarction (CI) in a population-based study. PATIENTS AND METHODS: We identified 2095 participants aged 50 to 98 years in the population-based Mayo Clinic Study of Aging from October 23, 2009, to October 5, 2016, with a usable diffusion tensor imaging (DTI) sequence (total scans=3230). Acute and subacute infarcts were identified by neuroradiologists. For each participant, vascular risk factors, medications, clinical symptoms, and neurological examination near the time of the CI were abstracted from the medical record. The probable etiologic mechanism for the CI was determined. RESULTS: Nine CIs were identified with a frequency of 0.28% among individual magnetic resonance imaging (MRI) scans and 0.43% among unique individuals. Infarctions were detected in 0.097% of scans from participants younger than 70 years and in 0.36% of scans of those 70 years or older. Six CIs were acute, and 3 were subacute. Most participants with infarcts were men (78%), with a mean age of 76.9+/-6.74 years. All were asymptomatic at the time of CI detection. The probable mechanisms of CI were small vessel (n=6), cardioembolic (n=2), and cryptogenic (n=1). CONCLUSION: Acute and subacute cerebral infarcts occur as incidental findings in approximately 1 in 230 people aged 50 to 98 years, particularly in elderly men and those with vascular risk factors. As brain MRI becomes more widely used, incidentally detected acute or subacute infarcts will provide an opportunity to improve stroke prevention. PMID- 29426583 TI - [Use of new technologies by adolescents in the search for health information]. AB - OBJECTIVE: To describe Internet sources used by adolescents to consult health information and their sociodemographic characteristics, as well as to identify the variables that influence the choice of Internet site. DESIGN: Cross-sectional descriptive study. Survey adapted from the questionnaire validated by Rideout. PARTICIPANTS AND LOCATION: Adolescents aged 12-18 from 4schools in rural municipalities. RESULTS: The study included a total of 405 adolescents, of whom 51.6% were female, age 14.9 +/- 1.2 years. Most of them (87.25%) live with both parents, and 93.6% have computers at home, with 45.2% in their rooms, and a mean of 2.1 computers/home. The large majority (85.2%) have Internet at home, with 76.3% in their room. A total of 53.8% sought health information 0.71 +/- 0.91 h/week, seeking mainly information on: cancer (89.9%), addictions (67.7%), STIs and HIV (49.6%), pregnancies/contraception (21, 5%), mental illness (40%), heart disease and diabetes mellitus (53.6%), and eating disorders (39.3%). Google was chosen by 63.2%, and only 11.9% chose medical websites. Information was shared on social networks by 12.8% (70.3% Facebook). The information found led to a change of behaviour in 70.7%. Just over half (56.05%) preferred to use the Internet for: speed, 34.8%, privacy, 15.8%, reliability, 13.6%, and more information, 17.6%. CONCLUSIONS: Adolescents seek information mainly through Google, with no knowledge of systems that accredit content quality, but consider it useful and reliable, changing their behaviour patterns according to the information found. All this carries a risk in this age group with very sensitive characteristics. Therefore, we believe that we should continue along the line of designing other alternative communication channels adapted to their current reality. PMID- 29426584 TI - Non-invasive ventilation in children and adults in low- and low-middle income countries: A systematic review and meta-analysis. AB - PURPOSE: We systematically reviewed the effects of NIV for acute respiratory failure (ARF) in low- and low-middle income countries. MATERIALS AND METHODS: We searched MEDLINE, CENTRAL, and EMBASE (to January 2016) for observational studies and trials of NIV for ARF or in the peri-extubation period in adults and post neonatal children. We abstracted outcomes data and assessed quality. Meta analyses used random-effect models. RESULTS: Fifty-four studies (ten pediatric/n=1099; 44 adult/n=2904), mostly South Asian, were included. Common diagnoses were pneumonia and chronic obstructive pulmonary disease (COPD). Considering observational studies and the NIV arm of trials, NIV was associated with moderate risks of mortality (pooled risk 9.5%, 95% confidence interval (CI) 4.6-14.5% in children; 16.2% [11.2-21.2%] in adults); NIV failure (10.5% [4.6 16.5%] in children; 28.5% [22.4-34.6%] in adults); and intubation (5.3% [0.8 9.7%] in children; 28.8% [21.9-35.8%] in adults). The risk of mortality was greater (p=0.035) in adults with hypoxemic (25.7% [15.2-36.1%]) vs. hypercapneic (12.8% [7.0-18.6%]) ARF. NIV reduced mortality in COPD (relative risk [RR] 0.47 [0.27-0.79]) and in patients weaning from ventilation (RR 0.48 [0.28-0.80]). The pooled pneumothorax risk was 2.4% (0.8-3.9%) in children and 5.2% (1.0-9.4%) in adults. Meta-analyses had high heterogeneity. CONCLUSIONS: NIV for ARF in these settings appears to be effective. PMID- 29426585 TI - Location of the euryon in scaphocephalic vs. non-scaphocephalic controls: A novel assessment of cranial vault remodeling outcomes. AB - We describe a novel measurement of cranial morphology in pre- and post-operative scaphocephalic patients to complement the cephalic index. This will better describe restoration of normal skull and head shape, further defining the nuances of the corrected skull. In this retrospective comparative study the location of the euryon on the skull was statistically significantly different in preoperative scaphocephalic patients versus non-scaphocephalic controls. This difference was resolved with surgical cranial vault remodeling, indicating restoration of a normal skull profile. Additional measurements of the location of the euryon in relation to the forehead prominence, combined with validated cephalic index measurements, can further describe postoperative outcomes in scaphocephaly. More sensitive clinical measurements such as these can aid the craniofacial surgeon in assessing outcomes in cranial vault remodeling. Further, large-scale study is needed to determine if additional anterior skull metric points may be useful in documenting skull shape restoration. PMID- 29426586 TI - Safety of rAAV2/2-ND4 Gene Therapy for Leber Hereditary Optic Neuropathy. PMID- 29426588 TI - [Magnetic Resonance Imaging beyond the proton: what does oxygen-17 MRI have to offer?] PMID- 29426587 TI - Transcutaneous electrical nerve stimulation and interferential current demonstrate similar effects in relieving acute and chronic pain: a systematic review with meta-analysis. AB - BACKGROUND: Transcutaneous electrical nerve stimulation and interferential current have been widely used in clinical practice. However, a systematic review comparing their effects on pain relief has not yet been performed. OBJECTIVES: To investigate the effects of transcutaneous electrical nerve stimulation and interferential current on acute and chronic pain. METHODS: We use Pubmed, Embase, LILACS, PEDro and Cochrane Central Register of Controlled Trials as data sources. Two independent reviewers that selected studies according to inclusion criteria, extracted information of interest and verified the methodological quality of the studies made study selection. The studies were selected if transcutaneous electrical nerve stimulation and interferential current were used as treatment and they had pain as the main outcome, as evaluated by a visual analog scale. Secondary outcomes were the Western Ontario Macmaster and Rolland Morris Disability questionnaires, which were added after data extraction. RESULTS: Eight studies with a pooled sample of 825 patients were included. The methodological quality of the selected studies was moderate, with an average of six on a 0-10 scale (PEDro). In general, both transcutaneous electrical nerve stimulation and interferential current improved pain and functional outcomes without a statistical difference between them. CONCLUSION: Transcutaneous electrical nerve stimulation and interferential current have similar effects on pain outcome The low number of studies included in this meta-analysis indicates that new clinical trials are needed. PMID- 29426589 TI - Determination of the effective dose delivered by image guided radiotherapy in head & neck and breast treatments. AB - PURPOSE: Image guided radiotherapy (IGRT) improves patient positioning for treatment delivery at the cost of an additional dose. This work aimed to calculate the effective dose (as an indicator of dose) for head & neck (H&N) and breast IGRT treatments by implementing dose calculation models to determine the dose distributions. METHODS: The kV dose-models were created for the IGRT systems of Elekta Synergy (XVI) and Varian Clinac (OBI) linear accelerators within Philips Pinnacle TPS. Profiles and depth dose curves were measured in water. The models were validated in a CIRS thorax phantom. The IGRT dose distributions for five H&N and five breast patients were calculated. The effective dose was determined from the dose distributions following ICRP 103 recommendations. Moreover, time-saving approximations were studied in order to propose an alternative way of segmenting the tissues for a clinical implementation of the method. RESULTS AND CONCLUSION: The effective dose specifically associated with IGRT varied from 1 to 10mSv depending on the protocol. The kV dose-model allowed us to calculate the dose distributions from IGRT for different configurations and patients, and to determine effective dose for IGRT protocols. The clinical implementation of the method was found to reduce time and to introduce a small enough increase of uncertainty in the results to be clinically usable. PMID- 29426591 TI - Surveillance of British ticks: An overview of species records, host associations, and new records of Ixodes ricinus distribution. AB - Public Health England's passive Tick Surveillance Scheme (TSS) records the distribution, seasonality and host associations of ticks submitted from across the United Kingdom (UK), and helps to inform the UK government on emerging tick borne disease risks. Here we summarise data collected through surveillance during 2010-2016, and compare with previous TSS data from 2005 to 2009, particularly in relation to the primary Lyme borreliosis vector Ixodes ricinus. 4173 records were submitted, constituting >14,000 ticks; 97% were endemic tick records (13,833 ticks of 11 species), with an additional 97 records of imported ticks (438 ticks of 17 species). Tick submissions were mainly from veterinary professionals (n = 1954; 46.8%) and members of the public and amateur entomologists (n = 1600; 38.3%), as well as from academic institutions (n = 249; 6.0%), wildlife groups (n = 239; 5.7%) and health professionals (n = 131; 3.1%). The most commonly reported hosts of endemic ticks were dogs (n = 1593; 39.1% of all records), humans (n = 835; 20.5%) and cats (n = 569; 14%). New host associations were recorded for a number of tick species. Ixodes ricinus was the most frequently recorded endemic tick species (n = 2413; 59.2% of all records), followed by I. hexagonus (n = 1355; 33.2%), I. canisuga (n = 132; 3.2%) and I. frontalis (n = 56; 1.4%), with other species each making up <1% total records. 81% of I. ricinus recorded from humans were nymphs, whereas 93.4% of I. ricinus from companion animals were adults. Recent TSS records of I. ricinus in the UK add a considerable amount of new presence data for this species, particularly in the southern regions of England, and confirm that this species is widespread across the UK. The scheme remains a valuable method of collecting continuous national distribution data on ticks from a variety of host species. PMID- 29426592 TI - The Modified Arch Landing Areas Nomenclature (MALAN) Improves Prediction of Stent Graft Displacement Forces: Proof of Concept by Computational Fluid Dynamics Modelling. AB - OBJECTIVE: To assess whether the Modified Arch Landing Areas Nomenclature (MALAN), which merges Ishimaru's map with the Aortic Arch Classification, predicts the magnitude of displacement forces and their orientation in proximal landing zones for TEVAR. METHODS: Computational fluid dynamic (CFD) modelling was employed to prove the hypothesis. Healthy aorta CT angiography scans were selected based on aortic arch geometry to reflect Types I to III arches equally (each n = 5). CFDs were used to compute pulsatile displacement forces along the Ishimaru's landing zones in each aorta including their three dimensional orientation along the upward component and sideways component. Values were normalised to the corresponding aortic wall area to calculate equivalent surface traction (EST). RESULTS: In Types I and II arches, EST did not change across proximal landing zones (p = .297 and p = .054, respectively), whereas in Type III, EST increased towards more distal landing zones (p = .019). Comparison of EST between adjacent zones, however, showed that EST was greater in 3/II than in 2/II (p = .016), and in 3/III than in 2/III (p = .016). Notably, these differences were related to the upward component, that was four times greater in 3/II compared with 2/II (p < .001), and five times greater in 3/III compared with 2/III (p < .001). CONCLUSION: CFD modelling suggests that MALAN improves discrimination of expected displacement forces in proximal landing zones for TEVAR, which might influence clinical outcomes. The clinical relevance of the finding, however, remains to be validated in a dedicated post-operative outcome analysis of patients treated by TEVAR of the arch. PMID- 29426590 TI - Detection and molecular characterization of tick-borne pathogens infecting sheep and goats in Blue Nile and West Kordofan states in Sudan. AB - Tick-borne pathogens (TBPs) are common in livestock of sub-Saharan Africa. However, information regarding TBPs in sheep and goats in Sudan is limited. In this study, 178 blood samples of sheep and goats in Blue Nile and West Kordofan states were investigated for TBPs using PCR. Overall, 110 (61.8%) samples were found to be infected with at least one of the following pathogens: Anaplasma ovis, Theileria ovis, and Ehrlichia ruminantium. Babesia ovis and T. lestoquardi were not identified. A. ovis was the most prevalent pathogen (n = 107, 60.1%), followed by T. ovis (n = 23, 12.9%) and E. ruminantium (n = 1, 0.6%). The prevalence rates of A. ovis and T. ovis were significantly higher in sheep than in goats. Phylogenetic analysis of T. ovis 18S rRNA and A. ovis msp4, groEL, and 16S rRNA, revealed that the pathogens identified in this study are clustered together, indicating similar molecular characteristics. Additionally, phylogenetic analysis of E. ruminantium pCS20 revealed that E. ruminantium in this study belong to the West Africa group, and different to E. ruminantium previously identified in ticks from Sudan. We concluded that TBPs are highly prevalent in the study area and continuous monitoring of TBPs in sheep and goats in Sudan is highly required. PMID- 29426593 TI - Editor's Choice - An Updated Systematic Review and Meta-analysis of Outcomes Following Eversion vs. Conventional Carotid Endarterectomy in Randomised Controlled Trials and Observational Studies. AB - INTRODUCTION: A 2011 meta-analysis comparing eversion (eCEA) with conventional (cCEA) carotid endarterectomy in 16,251 patients concluded that eCEA was associated with lower rates of peri-operative stroke and late occlusion compared with cCEA. However, randomised controlled trials (RCTs) showed no difference in outcomes. Since then, the literature contains outcome data on 49,500 patients undergoing eCEA or cCEA. An updated meta-analysis was performed to establish whether eCEA confers significant benefit over cCEA. METHODS: This was a systematic review of PubMed/Medline, Embase, and Cochrane databases for RCTs and observational studies (OSs) comparing eCEA with cCEA. A sensitivity analysis was also performed using data from OSs with a Newcastle-Ottawa score >5. RESULTS: There were 25 eligible studies (5 RCTs, 20 OSs) involving 49,500 CEAs (16,249 eCEAs; 33,251 cCEAs). RCT data: Compared with cCEA, eCEA did not confer significant reductions in 30 day stroke, death, death/stroke, death/stroke/MI, or neck haematoma. However, eCEA was associated with reduced late restenosis (OR 0.40; p = .001). OS data: eCEA was associated with significant reductions in 30 day death (OR 0.46; p < .0001), stroke (OR 0.58; p < .0001), death/stroke (OR 0.52; p < .0001), death/stroke/MI (OR 0.50; p < .0001), and late restenosis (OR 0.49; p = .032) compared with cCEA. RCT and OS data combined: eCEA was associated with significant reductions in 30 day death (OR 0.55; p < .0001), stroke (OR 0.63; p = .004), death/stroke (OR 0.58; p < .0001), and late restenosis (OR 0.45; p = .004) compared with cCEA. eCEA vs. patched cCEA (RCT and OS data): There were no differences between the two procedures except for neck haematoma, where eCEA was better than patched cCEA. CONCLUSIONS: Using combined RCT and OS data, eCEA was superior to cCEA regarding peri-operative outcomes (stroke, death, death/stroke) and late restenosis, but was similar to patched CEA in both early and late outcomes. This updated meta-analysis suggests that early and late outcomes following cCEA are similar to eCEA, provided the arteriotomy is patched. PMID- 29426594 TI - The foundation: Mechanism, prediction, and falsification in Bayesian enactivism: Comment on "Answering Schrodinger's question: A free-energy formulation" by Maxwell James Desormeau Ramstead et al. PMID- 29426596 TI - Correction to Lancet Public Health 2018; 3: e64-71. PMID- 29426595 TI - The observability principle and beyond: Reply to comments on "Seeing mental states: An experimental strategy for measuring the observability of other minds" by Cristina Becchio et al. PMID- 29426597 TI - Determinants of tuberculosis trends in six Indigenous populations of the USA, Canada, and Greenland from 1960 to 2014: a population-based study. AB - BACKGROUND: Tuberculosis continues to disproportionately affect many Indigenous populations in the USA, Canada, and Greenland. We aimed to investigate whether population-based tuberculosis-specific interventions or changes in general health and socioeconomic indicators, or a combination of these factors, were associated with changes in tuberculosis incidence in these Indigenous populations. METHODS: For this population-based study we examined annual tuberculosis notification rates between 1960 and 2014 in six Indigenous populations of the USA, Canada, and Greenland (Inuit [Greenland], American Indian and Alaska Native [Alaska, USA], First Nations [Alberta, Canada], Cree of Eeyou Istchee [Quebec, Canada], Inuit of Nunavik [Quebec, Canada], and Inuit of Nunavut [Canada]), as well as the general population of Canada. We used mixed-model linear regression to estimate the association of these rates with population-wide interventions of bacillus Calmette-Guerin (BCG) vaccination of infants, radiographic screening, or testing and treatment for latent tuberculosis infection (LTBI), and with other health and socioeconomic indicators including life expectancy, infant mortality, diabetes, obesity, smoking, alcohol use, crowded housing, employment, education, and health expenditures. FINDINGS: Tuberculosis notification rates declined rapidly in all six Indigenous populations between 1960 and 1980, with continued decline in Indigenous populations in Alberta, Alaska, and Eeyou Istchee thereafter but recrudescence in Inuit populations of Nunavut, Nunavik, and Greenland. Annual percentage reductions in tuberculosis incidence were significantly associated with two tuberculosis control interventions, relative to no intervention, and after adjustment for infant mortality and smoking: BCG vaccination (-11%, 95% CI 6 to -17) and LTBI screening and treatment (-10%, -3 to -18). Adjusted associations were not significant for chest radiographic screening (-1%, 95% CI 7 to 5). Declining tuberculosis notification rates were significantly associated with increased life expectancy (-37.8 [95% CI -41.7 to -33.9] fewer cases per 100 000 for each 1-year increase) and decreased infant mortality (-9.0 [-9.5 to -8.6] fewer cases per 100 000 for each death averted per 1000 livebirths) in all six Indigenous populations, but no significant associations were observed for other health and socioeconomic indicators examined. INTERPRETATION: Population-based BCG vaccination of infants and LTBI screening and treatment were associated with significant decreases in tuberculosis notification rates in these Indigenous populations. These interventions should be reinforced in populations still affected by tuberculosis, while also addressing the persistent health and socioeconomic disparities. FUNDING: Public Health Department of the Cree Board of Health and Social Services of James Bay. PMID- 29426598 TI - A false economy: we cannot afford to be complacent when it comes to tuberculosis control. PMID- 29426599 TI - Erratum and comment: Envelope following responses in normal hearing and in tinnitus. PMID- 29426600 TI - The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice. AB - The endocochlear potential (EP) provides part of the electrochemical drive for sound-driven currents through cochlear hair cells. Intense noise exposure (110 dB SPL, 2 h) differentially affects the EP in three inbred mouse strains (C57BL/6 [B6], CBA/J [CBA], BALB/cJ [BALB]) (Ohlemiller and Gagnon, 2007, Hearing Research 224:34-50; Ohlemiller et al., 2011, JARO 12:45-58). At least for mice older than 3 mos, B6 mice are unaffected, CBA mice show temporary EP reduction, and BALB mice may show temporary or permanent EP reduction. EP reduction was well correlated with histological metrics for injury to stria vascularis and spiral ligament, and little evidence was found for holes or tears in the reticular lamina that might 'short out' the EP. Thus we suggested that the genes and processes that underlie the strain EP differences primarily impact cochlear lateral wall, not the organ of Corti. Our previous work did not test the range of noise exposure conditions over which strain differences apply. It therefore remained possible that the relation between exposure severity and acute EP reduction simply has a higher exposure threshold in B6 mice compared to CBA and BALB. We also did not test for age dependence. It is well established that young adult animals are especially vulnerable to noise-induced permanent threshold shifts (NIPTS). It is unknown, however, whether heightened vulnerability of the lateral wall contributes to this condition. The present study extends our previous work to multiple noise exposure levels and durations, and explicitly compares young adult (6-7 wks) and older mice (>4 mos). We find that the exposure level-versus-acute EP relation is dramatically strain-dependent, such that B6 mice widely diverge from both CBA and BALB. For all three strains, however, acute EP reduction is greater in young mice. Above 110 dB SPL, all mice exhibited rapid and severe EP reduction that is likely related to tearing of the reticular lamina. By contrast, EP-versus-noise duration examined at 104 dB suggested that different processes contribute to EP reduction in young and older mice. The average EP falls to a constant level after ~7.5 min in older mice, but progressively decreases with further exposure in young mice. Confocal microscopy of organ of Corti surface preparations stained for phalloidin and zonula occludens-1 (ZO-1) indicated this corresponds to rapid loss of outer hair cells (OHCs) and formation of both holes and tears in the reticular lamina of young mice. In addition, when animals exposed at 119 dB were allowed to recover for 1 mo, only young B6 mice showed collapse of the EP to <=5 mV. Confocal analysis suggested novel persistent loss of tight junctions in the lateral organ of Corti. This may allow paracellular leakage that permanently reduces the EP. From our other findings, we propose that noise-related lateral wall pathology in young CBA and BALB mice promotes hair cell loss and opening of the reticular lamina. The heightened vulnerability of young adult animals to noise exposure may in part reflect special sensitivity of the organ of Corti to acute lateral wall dysfunction at younger ages. This feature appears genetically modifiable. PMID- 29426601 TI - From quality markers to data mining and intelligence assessment: A smart quality evaluation strategy for traditional Chinese medicine based on quality markers. AB - BACKGROUND: The quality of traditional Chinese medicine (TCM) forms the foundation of its clinical efficacy. The standardization of TCM is the most important task of TCM modernization. In recent years, there has been great progress in the quality control of TCM. However, there are still many issues related to the current quality standards, and it is difficult to objectively evaluate and effectively control the quality of TCM. PURPOSE: To face these challenge, we summarized the current quality marker (Q-marker) research based on its characteristics and benefits, and proposed a reasonable and intelligentized quality evaluation strategy for the development and application of Q-markers. METHODS: Ultra-performance liquid chromatography-quadrupole/time-of-flight with partial least squares-discriminant analysis was suggested to screen the chemical markers from Chinese medicinal materials (CMM), and a bioactive-guided evaluation method was used to select the Q-markers. Near-infrared spectroscopy (NIRS), based on the distinctive wavenumber zones or points from the Q-markers, was developed for its determination. Then, artificial intelligence algorithms were used to clarify the complex relationship between the Q-markers and their integral functions. Internet and mobile communication technology helped us to perform remote analysis and determine the information feedback of test samples. CHAPTERS: The quality control research, evaluation, standard establishment and quality control of TCM must be based on the systematic analysis of Q-markers to study and describe the material basis of TCM efficacy, define the chemical markers in the plant body, and understand the process of herb drug acquisition, change and transmission laws affecting metabolism and exposure. Based on the advantages of chemometrics, new sensor technologies, including infrared spectroscopy, hyperspectral imaging, chemical imaging, electronic nose and electronic tongue, have become increasingly important in the quality evaluation of CMM. Inspired by the concept of Q-marker, the quantitation can be achieved with the help of artificial intelligence, and these subtle differences can be discovered, allowing the quantitative analysis by NIRS and providing a quick and easy detection method for CMM quality evaluations. CONCLUSION: The concept of Q-markers focused on unique CMM differences, dynamic changes and their transmission and traceability to establish an overall quality control and traceability system. Based on the basic attributes, an integration model and artificial intelligence research path was proposed, with the hope of providing new ideas and perspectives for the TCM quality management. PMID- 29426602 TI - Airway inflammation after epicutaneous sensitization of mice requires protease activity of low-dose allergen inhalation. PMID- 29426603 TI - Proximal Pole Scaphoid Nonunion Reconstruction With 1,2 Intercompartmental Supraretinacular Artery Vascularized Graft and Compression Screw Fixation. AB - PURPOSE: To review the incidence of union of patients with proximal pole scaphoid fracture nonunions treated using a 1,2 intercompartmental supraretinacular artery (1,2 ICSRA) vascularized graft and a small compression screw. METHODS: This is a retrospective case series of 12 patients. Calculations of the size of the proximal pole fragment relative to the total scaphoid were performed using posteroanterior view scaphoid radiographs with the wrist in ulnar deviation and flat on the cassette. Analyses were repeated 3 times per subject, and the average ratio of proximal pole fragment relative to the entire scaphoid was calculated. We reviewed medical records, radiographs, and computed tomography (CT) scans of these 12 patients. The CT scans that were performed after an average of 12 weeks were ultimately used to confirm union of the scaphoid fractures. One patient was unable to have a CT so was excluded from the final calculation. RESULTS: All 11 (100%) scaphoid fractures that were assessed by CT were found to be healed at the 12-week assessment point. The mean proximal pole fragment size was 18% (range, 7% 27%) of the entire scaphoid. CONCLUSIONS: The 1,2 ICSRA vascularized graft and compression screw was an effective treatment for patients with proximal pole scaphoid fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29426604 TI - Damage in a Distal Radius Fracture Model Treated With Locked Volar Plating After Simulated Postoperative Loading. AB - PURPOSE: "Damage" is an engineering term defining a period between a state of material perfection and the onset of crack initiation. Clinically, it is a loss of fixation due to microstructural breakdown, indirectly measured as a reduction of stiffness of the bone-implant construct, normalized by the cross-sectional area and length of the bone. The purpose of this study was to characterize damage in a cadaver model of extra-articular distal radius fracture with dorsal comminution treated using 2-column volar distal radius plates. METHODS: Ten matched distal radii were randomly divided into 2 groups: group I specimens were treated with a volar distal radius plate with an independent, 2-tiered scaffold design; group II specimens (contralateral limbs) were treated with a volar plate with a single-head design for enhanced ulnar buttressing. Specimens were cyclically loaded to simulate a 6-month postoperative load-bearing period. We report damage after a defined protocol of cyclical loading and load to failure simulating a fall on an outstretched hand. RESULTS: Group II specimens experienced more damage under cyclic loading conditions than group I specimens. Group I specimens were stiffer than group II specimens under load-to-failure conditions. Ultimate force at failure in group I and group II specimens was not different. Specimens failed by plate bending (group I, n = 6/10; group II, n = 2/10) and fracture of the lunate facet (group I, n = 4/10; group II, n = 8/10). CONCLUSIONS: Group I specimens had less screw cutout at the lunate facet than group II specimens under cyclic loading as indicated by lower damage measures and fewer facet fractures during load-to-failure testing. The overall strength of the construct is not affected by plate design. CLINICAL RELEVANCE: Microstructural damage or a loss of fixation due to an overly rigid volar plate design may cause malunion or nonunion of fracture fragments and lead to bone-implant instability. PMID- 29426605 TI - Diversity of circulating tumor cells in peripheral blood: Detection of heterogeneous BRAF mutations in a patient with advanced melanoma by single-cell analysis. PMID- 29426606 TI - Symptomatic and Functional Recovery From Major Depressive Disorder in the Ibadan Study of Ageing. AB - OBJECTIVES: Very little is known about the association between symptomatic and functional recovery from late-life major depressive disorder (MDD) in sub-Saharan Africa. We investigated factors associated with sustained symptomatic remission (SR) from MDD and the 5-year trajectory of post-MDD physical functioning. DESIGN: 5-year prospective study with three follow-up waves in 2007, 2008, and 2009. SETTING/PARTICIPANTS: Household multistage probability sample of 2,149 Nigerians who were aged 65 years or older. MEASUREMENTS: Activities of Daily Living (ADL) and MDD were assessed using the Kadz index and Composite International Diagnostic Interview, respectively. We studied those with current MDD (prevalent in 2003 2004 or incident in 2007), and who achieved SR in subsequent waves compared with a chronic/recurrent course (CR). RESULTS: Baseline demographic characteristics, health, and lifestyle factors were not associated with SR in logistic regression analyses. In mixed-effect linear regression models adjusting for age, sex, and socioeconomic status, ADL worsened in SR (beta = 1.0, 95% CI: 0.2, 1.8), but more so in CR (beta = 2.3, 95% CI: 1.6, 3.0). Poorer ADL at follow-up was predicted by age (beta = 2.9, 95% CI: 1.8, 4.0) and economic status (beta = 1.4, 95% CI: 0.3, 2.4). CONCLUSIONS: There was a deteriorating course of disability despite symptomatic recovery from late-life MDD in this sample. This finding has implications for policy and guidelines for the management of late-life depression and disability. PMID- 29426607 TI - A Systematic Review of Dementia-related Stigma Research: Can We Move the Stigma Dial? AB - Stigma negatively affects individuals with cognitive impairment and dementia. This literature review examined the past decade (January 2004 to December 2015) of world-wide research on dementia-related stigma. Using standard systematic review methodology, original research reports were identified and assessed for inclusion based on defined criteria. Initial database searches yielded 516 articles. After removing duplicates and articles that did not fit inclusion criteria (419), 97 articles were reviewed, yielding a final total of 51 publications, mainly originating in the United States and Europe. Studies were assessed for date, geographic region, sample description, methodology, and key findings. Reports were evaluated on 1) how stigmatizing attitudes may present in various subgroups, including in racial or ethnic minorities; 2) stigma assessment tools; and 3) prospective or experimental approaches to assess or manage stigma. Stigma impedes help-seeking and treatment, and occurs broadly and world wide. Stigmatizing attitudes appear worse among those with limited disease knowledge, those with little contact with people with dementia, in men, in younger individuals, and in the context of ethnicity and culture. In some cases, healthcare providers may have stigmatizing attitudes. In research studies, there does not appear to be consensus on how to best evaluate stigma, and there are few evidence-based stigma reduction approaches. Given the projected increase in persons with dementia globally, there is a critical need for research that better identifies and measures stigma and tests new approaches that can reduce stigmatizing attitudes. PMID- 29426608 TI - The effect of tranexamic acid on hidden bleeding in older intertrochanteric fracture patients treated with PFNA. AB - OBJECTIVE: To investigate the effect of tranexamic acid (TXA) on hidden bleeding in older intertrochanteric fracture patients treated with intramedullary nails. METHOD: Between January 2016 and January 2017, 100 cases of intertrochanteric fractures eligible for the study were treated with proximal femoral nail antirotation (PFNA) in our hospital. All patients were divided into two groups of 50 patients each: the TXA group and a blank control group. In the TXA group, all patients received TXA at a dose of 10 mg/kg-1 intravenously, 10 min preoperatively and 5 h postoperatively. The control group did not receive TXA. We recorded the volume of intraoperative blood loss and postoperative drainage, and the need for postoperative blood transfusion and transfusion volume for all patients. Blood routine examination was performed on the day of surgery and 2 days postoperatively. We calculated the total blood loss and hidden blood loss in the two groups separately according to the Gross equation. All patients underwent deep vein ultrasound of the lower limbs preoperatively and 1 week postoperatively to detect thrombosis. RESULTS: Compared with controls, patients in the TXA group had lower: overt bleeding (50.59 ml; p = .012), total blood loss (181.58 ml; p = .005), hidden blood loss (130.64 ml; p = .037), volume of blood transfusion (110.0 ml; p = .019), and 20% lower transfusion rate compared with the control group. Patients receiving short-nail fixation had significantly lower hidden blood loss compared with patients receiving long-nail fixation (p < .05). However, we found no statistically significant difference in the incidence of deep vein thrombosis in the lower limbs between the two groups (p = .938). CONCLUSION: TXA significantly reduced hidden blood loss in older intertrochanteric fracture patients treated with intramedullary nails without an increased risk of thrombosis in lower limb deep veins. PMID- 29426609 TI - Factors influencing survival following hip fracture among octogenarians and nonagenarians in the United States. AB - INTRODUCTION: Hip fractures account for a significant disease burden in the Unites States. With an aging population, this disease burden is expected to increase in the upcoming decades. MATERIALS AND METHODS: This represents a retrospective cohort study to assess mortality following hip fracture in the octogenarian and nonagenarian populations. Odds ratios for postoperative mortality were constructed using normalized patients from United States Social Security death tables. Kaplan Meier analysis and binary logistic regression were used to assess the impact of surgical delay and medical comorbidity (measured by the Carlson Comorbidity Index (CCI)) on postoperative mortality. RESULTS: 189 octogenarians and 95 nonagenarians were included. One-year mortality was nearly three times higher for both the octogenarians (OR: 3.1) and nonagenarians (OR: 3.14), and returned to that of the normal population 4 years post-op for octogenarians and 5 years post-op for nonagenarians. Higher preoperative medical comorbidity (CCI) was associated with higher post-op mortality for both octogenarians (log rank = 0.026) and nonagenarians (log rank = 0.034). A 48-h surgical delay resulted in significantly increased postoperative mortality among healthy patients (CCI of 0 or 1, OR: 18.1), but was protective for patients with significant medical comorbidity (CCI >= 3). Age, preoperative CCI, and 48-h surgical delay were all independent predictors of 1-year post-op mortality. CONCLUSIONS: Following hip fracture, there is a 3-fold increase in mortality for octogenarians and nonagenarians at 1 year post-op. A 48-h surgical delay significantly increased mortality for healthier patients but was protective against mortality for sicker patients. PMID- 29426610 TI - A new predicting model for syndesmotic injuries? PMID- 29426611 TI - Letter to the editor concerning "Risk factors for implant failure after fixation of proximal femoral fractures with fracture of the lateral femoral wall". PMID- 29426613 TI - Correction. PMID- 29426612 TI - Pharmacist prescriptive authority for smoking cessation medications in the United States. AB - OBJECTIVES: To characterize the status of state laws regarding the expansion of pharmacists' prescriptive authority for smoking cessation medications and to summarize frequently asked questions and answers that arose during the associated legislative debates. DATA SOURCES: Legislative language was reviewed and summarized for all states with expanded authority, and literature supporting the pharmacist's capacity for an expanded role in smoking cessation is described. SUMMARY: The core elements of autonomous tobacco cessation prescribing models for pharmacists vary across states. Of 7 states that currently have fully or partially delineated protocols, 4 states (Colorado, Idaho, Indiana, New Mexico) include all medications approved by the U.S. Food and Drug Administration for smoking cessation, and 3 (Arizona, California, Maine) include nicotine replacement therapy products only. The state protocol in Oregon is under development. Most states specify minimum cessation education requirements and define specific elements (e.g., patient screening, cessation intervention components, and documentation requirements) for the autonomous prescribing models. CONCLUSION: Through expanded authority and national efforts to advance the tobacco cessation knowledge and skills of pharmacy students and licensed pharmacists, the profession's role in tobacco cessation has evolved substantially in recent years. Eight states have created, or are in the process of creating, pathways for autonomous pharmacist prescriptive authority. States aiming to advance tobacco control strategies to help patients quit smoking might consider approaches like those undertaken in 8 states. PMID- 29426614 TI - Rethinking public mental health: learning from obesity. PMID- 29426617 TI - Databases for surgical health services research: Medicare claims. PMID- 29426616 TI - Emergency double-balloon enteroscopy for retrieval of an ingested dental-bridge, partially embedded within the wall of the jejunum. PMID- 29426615 TI - Low childhood high density lipoprotein cholesterol levels and subsequent risk for chronic inflammatory bowel disease. AB - BACKGROUND AND AIMS: Several genetic and environmental risk factors have been linked to chronic inflammatory bowel disease (IBD). The incidence of IBD has significantly increased in developed countries during last decades. The aim of the present study was to examine childhood risk factors for subsequent IBD diagnosis in a longitudinal cohort study of children and adolescents. METHODS: A Finnish study population consisting of 3551 children and adolescents originally evaluated as part of the Cardiovascular Risk in Young Finns study in 1980. At baseline, participant BMI, insulin, lipid, C-reactive protein and blood pressure levels, socioeconomic position, dietary habits, and physical activity, were evaluated. In addition, information was gathered on rural residency, severe infections, breast feeding, parental smoking and birth weight. Subsequent IBD diagnosis status was evaluated based on nationwide registries on hospitalisations and drug imbursement decisions. RESULTS: Altogether, 49 participants (1.4%) had IBD diagnosed during the 34 years of register follow-up, of which 31 had ulcerative colitis, 12 Crohn's disease and 6 undetermined colitis. In univariate analyses, significant correlations were observed between childhood HDL cholesterol (risk ratio (95% CI) for 1-SD change (0.58 (0.42-0.79)) and CRP concentrations (1.20 (1.01-1.43)) with IBD. The inverse association between HDL cholesterol and IBD remained significant (0.57 (0.39-0.82)) in a multivariable model including data on age, sex and CRP. In addition, a weighted genetic z-score of 71 single nucleotide polymorphisms associated with elevated HDL-cholesterol levels was significantly lower in IBD patients, P=0.01). CONCLUSION: Low childhood HDL-cholesterol levels are associated with subsequent IBD diagnosis. In addition, a genetic risk score associated with low HDL-cholesterol levels predict later IBD suggesting that HDL-cholesterol metabolism might have a role in the pathogenesis of IBD. PMID- 29426619 TI - Altmetrics: Beyond the Impact Factor. PMID- 29426618 TI - Thyroid lobectomy is not sufficient for T2 papillary thyroid cancers. AB - BACKGROUND: Histologic subtypes of papillary thyroid cancer affect prognosis. The objective of this study was to examine whether survival is affected by extent of surgery for conventional versus follicular-variant papillary thyroid cancer when stratified by tumor size. METHODS: Using the National Cancer Data Base, we evaluated 33,816 adults undergoing surgery for papillary thyroid cancer from 2004 to 2008 for 1.0-3.9 cm tumors and clinically negative lymph nodes. Conventional and follicular-variant papillary thyroid cancers were divided into separate groups. Cox regression models stratified by tumor size were used to determine if extent of surgery affected overall survival. RESULTS: A total of 30,981 patients had total thyroidectomy and 2,835 had thyroid lobectomy; 22,899 patients had conventional papillary thyroid cancer and 10,918 had follicular-variant papillary thyroid cancer. On unadjusted KM analysis, total thyroidectomy was associated with improved survival for conventional (P = 0.02) but not for follicular-variant papillary thyroid cancer patients (P = 0.42). For conventional papillary thyroid cancer, adjusted analysis showed total thyroidectomy was associated with improved survival for 2.0-3.9 cm tumors (P = 0.03) but not for 1.0-1.9 cm tumors (P = 0.16). For follicular-variant, lobectomy and total thyroidectomy had equivalent survival for 1.0-1.9 cm (P = 0.45) and 2.0-3.9 cm (P = 0.88) tumors. CONCLUSION: Tumor size, histologic subtype, and surgical therapy are important factors in papillary thyroid cancer survival. Total thyroidectomy was associated with improved survival in patients with 2.0-3.9 cm conventional papillary thyroid cancer, and should be considered for 2.0-3.9 cm papillary thyroid cancers when preoperative molecular analysis is not used to distinguish conventional from follicular-variant. PMID- 29426620 TI - Sensitive bowel syndrome better than irritable bowel syndrome. PMID- 29426621 TI - Update on the management of Helicobacter pylori infection. Position paper from the Catalan Society of Digestology. AB - More than 30 years after its discovery, Helicobacter pylori (H. pylori) infection remains the most common cause of gastric and duodenal diseases. H. pylori is the leading cause of chronic gastritis, peptic ulcer, gastric MALT lymphoma and gastric adenocarcinoma. Several consensuses have recently been published on the management of H. pylori infection. The general guidelines of the Spanish consensus, the Toronto Consensus and the Maastricht V Consensus of 2016 are similar but concrete recommendations can vary significantly. In addition, the recommendations of some of these consensuses are decidedly complex. This position paper from the Catalan Society of Digestology is an update of evidence-based recommendations on the management and treatment of H. pylori infection. The aim of this document is to review this information in order to make recommendations for routine clinical practice that are simple, specific and easily applied to our setting. PMID- 29426622 TI - Atypical hemolytic uremic syndrome: An unusual postoperative complication. AB - INTRODUCTION AND OBJECTIVES: Thrombotic thrombocytopenic purpura and atypical haemolytic uremic syndrome (aHUS) are acute, rare, life-threatening thrombotic microangiopathies that require swift management. We report a case of acute microangiopathic haemolytic anaemia (MAHA) presenting in perioperative setting. CLINICAL CASE: After hepatic pericystectomy for hydatid cyst, a 46-year-old female developed MAHA, thrombocytopenia and acute renal failure in the immediate postoperative period. "aHUS" was considered and immediate plasma exchange was initiated. Plasma exchange was performed for 2 weeks with remission of renal dysfunction. Further evaluation of genetic mutations and immunological causes for MAHA were sought. Mutations in complement factor H associated with factor H deficiency were identified, which are associated with increased risk of aHUS. CONCLUSION: MAHA is a rare postoperative condition, requiring rapid differential diagnosis and treatment. Anaesthetists should bear in mind aHUS as a possible cause of MAHA, especially concerning immediate care for these patients. PMID- 29426623 TI - Updated Guideline of the Canadian Pain Society for the pharmacological management of chronic neuropathic pain: Does it bring something new? PMID- 29426624 TI - Duodopa nasoduodenal tube at intrabronchial position. PMID- 29426625 TI - A thyrotropin-secreting pituitary adenoma treated with radiosurgery: Long-term outcomes. PMID- 29426626 TI - Antituberculosis Treatment in a Patient with Celiac Disease. PMID- 29426627 TI - [Interstitial lung diseases from autoimmune origins: A prognostic and diagnostic challenge for the clinician]. AB - Acute or subacute interstitial lung diseases from autoimmune origins are especially hard to diagnose but have to be detected promptly. We illustrate this necessity with three case reports. One case of paraneoplasic polymyositis, one case of interstitial lung disease caused by a connectivite and one case of interstitial lung disease related to an anti-synthetase syndrome. The subject is to alert the practitioners to the early search of extra pulmonary signs, autoantibodies analysis in the objective to set up quickly the right treatment. PMID- 29426628 TI - Design, synthesis, and biological evaluation of inhibitors of the NADPH oxidase, Nox4. AB - NADPH oxidases (Nox enzymes) are critical mediators of both physiologic and pathophysiologic processes. Nox enzymes catalyze NADPH-dependent generation of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. Until recently, Nox4 was proposed to be involved exclusively in normal physiologic functions. Compelling evidence, however, suggests that Nox4 plays a critical role in fibrosis, as well as a host of pathologies and diseases. These considerations led to a search for novel, small molecule inhibitors of this important enzyme. Ultimately, a series of novel tertiary sulfonylureas (23-25) was designed using pharmacophore modeling, synthesized, and evaluated for inhibition of Nox4 dependent signaling. PMID- 29426629 TI - Novel aromatic sulfonyl naphthalene-based boronates as 20S proteasome inhibitors. AB - A novel series of non-peptide proteasome inhibitors (PIs) that act on chymotrypsin-like (ChT-L) of the proteasome were developed. These PIs bearing 4 aromatic sulfonyl naphthalene-based scaffold and Leu-boronic moiety as covalent bonding group displayed far better activity than PI-8182 for inhibiting ChT-L in preliminary biological activity test. The results showed that 2a (IC50 = 6.942 MUM, MCF-7) and 2c (IC50 = 6.905 MUM, MCF-7) displayed higher anti-proliferative activities than Bortezomib (IC50 = 18.37 MUM, MCF-7) under our experimental conditions. Furthermore, in the microsomal stability assay, 2a demonstrated excellent metabolic stability profiles with 56% remaining after 40 min, as compared to Bortezomib of which approximately 30% was remaining. The compounds 2a, 2c emerged as promising lead compounds for the development of novel non peptide boronate PIs. PMID- 29426630 TI - Modifying hernia mesh design to improve device mechanical performance and promote tension-free repair. AB - PURPOSE: Approximately 348,000 ventral hernia repairs are performed annually in the United States and the incisional hernia recurrence rate is approximately 20% as a result of suture and mesh device failure. Device failure is related to changes at the suture/tissue interface that leads to acute or chronic suture pull through and surgical failure. To better manage mechanical tension, we propose a modified mesh design with extensions and demonstrate its mechanical superiority. METHODS: Comparative uniaxial static tensile testing was conducted on polypropylene suture and a modified mesh. Subsequently, a standard of care (SOC) mesh and modified mesh were evaluated using a tensometer in an acute hernia bench top model. RESULTS: Modified mesh breaking strength, extension knot breaking strength, extension disruption, and extension anchoring were superior to suture (p < .05). Modified mesh ultimate tensile strength of anchoring was superior to SOC mesh (p < .05). Various stitch patterns and modifications in device design significantly improved device tension-free performance far beyond clinically relevant benchmarks (p < .05). CONCLUSIONS: Testing demonstrates that the modified mesh outperforms SOC mesh and suture in all tested failure modes. SOC hernia mesh tears through tissue at stress levels below maximum physiologic stress, whereas, the modified hernia mesh is up to 200% stronger than SOC mesh at resisting suture tearing through tissue and maintains anchoring at stresses far beyond clinically relevant benchmarks. Modifying hernia mesh design significantly improves device mechanical performance and enhances tension-free repair. PMID- 29426631 TI - Outcomes of a novel thin-strut bioresorbable-polymer sirolimus-eluting stent in patients with chronic total occlusions: A multicenter registry. AB - BACKGROUND: We aimed to evaluate the mid-term outcomes of a novel thin-strut bioresorbable-polymer sirolimus-eluting stent (BP-SES) in chronic total occlusion (CTO) percutaneous coronary intervention (PCI), as compared with durable-polymer everolimus-eluting stents (EES). METHODS: We compiled a multicenter registry of patients undergoing CTO recanalization followed by BP-SES or EES implantation. The primary endpoint was the incidence of target-lesion failure (TLF, a composite of cardiac death, target-vessel myocardial infarction, and target-lesion revascularization) at one year. Propensity score matching (PSM) was used to adjust for case mix. RESULTS: Overall, 413 patients were included (BP-SES n = 242, EES n = 171). PSM resulted in 131 matched pairs, which represented the subject of the main analysis. Antegrade wire escalation was the most successful crossing technique (66% vs. 63%, p = 0.98) in both the BP-SES and EES groups, respectively. Procedural success rates were similar between groups (BP-SES 96% vs. EES 93%, p = 0.24). At one-year follow-up, there were no differences in the primary endpoint of TLF (5.7% vs. 8.3%, p = 0.44), and in cardiac death (0.9% vs. 2.8%, p = 0.32), target-vessel myocardial infarction (0.9% vs 1.9%, p = 0.57), target-lesion revascularization (3.7% vs 3.7%, p = 0.99), or stent thrombosis (0.9% vs. 1.9%, p = 0.57), in BP-SES vs. EES, respectively. CONCLUSIONS: Patients undergoing CTO PCI with BP-SES suffer a low rate of TLF at one-year follow-up, which is similar to that of subjects treated with durable-polymer EES. PMID- 29426632 TI - Comparison of thermodilution and indirect Fick cardiac outputs in pulmonary hypertension. AB - BACKGROUND: The accurate measurement of cardiac output (CO) is required in patients with pulmonary hypertension (PH).While both the thermodilution (TDCO) and indirect Fick (IFCO) methods are commonly used, there is little data comparing them in patients with PH. METHODS: We performed a retrospective analysis of patients evaluated at our center. All patients who had right heart catheterization (RHC) within 3 months of an echocardiogram, and CO assessment by both TDCO and IFCO methods were included. Bland-Altman analysis was used to assess agreement between the two methods. We further evaluated their agreement in each sex, and within tertiles of age, BMI and TR severity. We investigated the correlation between each method of CO and objective parameters of right ventricular function on echocardiography. RESULTS: In a cohort of 168 patients, the correlation between IFCO and TDCO was modest at (r = 0.61). On average, values for CO were lower with IFCO than with TDCO, by 0.62 L/min (95% CI -0.82, 0.40). This difference was greater for females: 0.86 L/min (95% CI -1.08, -0.63) and in the highest tertile of BMI: 0.97 L/min (95% CI -1.4, -0.55). Moderate and severe TR did not in general result in lower TDCO values. Echocardiographic parameters of right ventricular function were correlated more strongly with TDCO than with IFCO. CONCLUSION: In PH patients, IFCO was substantially lower than TDCO on average, suggesting that these two techniques cannot be used interchangeably. TDCO correlated more strongly with echocardiographic measures of RV function, suggesting that it may be preferred over IFCO. PMID- 29426633 TI - Patient-reported causes of heart failure in a large European sample. AB - BACKGROUND: Patients diagnosed with chronic diseases develop perceptions about their disease and its causes, which may influence health behavior and emotional well-being. This is the first study to examine patient-reported causes and their correlates in patients with heart failure. METHODS: European heart failure patients (N = 595) completed questionnaires, including the Brief Illness Perceptions Questionnaire. Using deductive thematic analysis, patient-reported causes were categorized into physical, natural, behavioral, psychosocial, supernatural and other. Clinical data were collected from medical records. RESULTS: Patients who did not report any cause (11%) were on average lower educated and participated less often in cardiac rehabilitation. The majority of the remaining patients reported physical causes (46%, mainly comorbidities), followed by behavioral (38%, mainly smoking), psychosocial (35%, mainly (work related) stress), and natural causes (32%, mainly heredity). There were socio demographic, clinical and psychological group differences between the various categories, and large discrepancies between prevalence of physical risk factors according to medical records and patient-reported causes; e.g. 58% had hypertension, while only 5% reported this as a cause. Multivariable analyses indicated trends towards associations between physical causes and poor health status (Odds ratio (OR) = 1.41, 95% confidence interval (95% CI) = 0.95-2.09, p = 0.09), psychosocial causes and psychological distress (OR = 1.54, 95% CI = 0.94 2.51, p = 0.09), and behavioral causes and a less threatening view of heart failure (OR = 0.64, 95% CI = 0.40-1.01, p = 0.06). CONCLUSION: European patients most frequently reported comorbidities, smoking, stress, and heredity as heart failure causes, but their causal understanding may be limited. There were trends towards associations between patient-reported causes and health status, psychological distress, and illness perceptions. PMID- 29426635 TI - Neoadjuvant therapy affects margins and margins affect all: perioperative and survival outcomes in resected pancreatic adenocarcinoma. AB - BACKGROUND: Resection margin status is an important prognostic factor in pancreatic cancer; however, the impact of positive resection margins in those who received neoadjuvant therapy remains unclear. The current study investigates the prognostic impact of resection margin status after neoadjuvant therapy and pancreaticoduodenectomy for patients with pancreatic adenocarcinoma. METHODS: Patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma between 2006 and 2013 were identified from the National Cancer Database. Multivariable logistic regression analysis was utilized to examine the predictive value of neoadjuvant therapy for resection margin status. Long-term outcomes were compared using a Cox proportional hazards model. RESULTS: 7917 patients were identified in total: 1077 (13.6%) and 6840 (86.4%) patients received neoadjuvant therapy and upfront surgery, respectively. Upfront surgery was independently predictive of a positive margin (25.7% vs. 17.7%; OR, 1.54) compared to neoadjuvant therapy. After receipt of neoadjuvant therapy, positive margins (median overall survival, 18.5 vs. 25.9 months; HR, 1.58) remained significantly associated with poor survival on multivariable analysis. DISCUSSION: While neoadjuvant therapy is associated with decreased R1/R2-resection rates after pancreaticoduodenectomy, the poor prognostic impact of positive margins is not abrogated by neoadjuvant therapy, stressing the need for complete tumor clearance and postoperative treatment even after neoadjuvant therapy. PMID- 29426636 TI - Phylogenetic relationships among endosymbiotic R-body producer: Bacteria providing their host the killer trait. AB - R-body producing bacterial endosymbionts of Paramecium spp. transform their hosts into "killer" paramecia and provide them a selective advantage. This killer trait is connected to the presence of R-bodies, which are peculiar, tightly coiled protein ribbons capable of rapid unrolling. Based mainly on those two characteristics the respective obligate intracellular bacteria have been comprised in the genus Caedibacter and additional traits such as host species, subcellular localization, and R-body dimensions and mode of unrolling were used for species discrimination. Previous studies applying the full-cycle rRNA approach demonstrated the polyphyly of this assemblage. Following this approach, we obtained new sequences and in situ hybridizations for five strains of Caedibacter taeniospiralis and four strains associated to Caedibacter varicaedens and Caedibacter caryophilus. Detailed phylogenetic reconstructions confirm the association of C. taeniospiralis to Fastidiosibacteraceae and to Holosporales in case of the others. Therefore, we critically revise the taxonomy of the latter group. The high 16S rRNA gene sequence similarity among the type strains of Caedibacter varicaedens and C. caryophilus indicate that they should be classified within a single species for which we propose Caedimonas varicaedens comb. nov. owing to the priority of Caedibacter varicaedens. Moreover, we propose to establish the new family Caedimonadaceae fam. nov. to encompass Caedimonas varicaedens, "Ca. Paracaedimonas acanthamoebae" comb. nov. and "Ca. Nucleicultrix amoebiphila" within the order Holosporales. PMID- 29426634 TI - Model-based directional analysis of cardiovascular variability identifies patients developing atrial fibrillation after coronary artery bypass grafting. AB - BACKGROUND: Postoperative atrial fibrillation (AF) might be favored by cardiovascular control impairment. We hypothesize that cardiovascular regulation indexes derived from directional model-based analysis of the spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) can identify subjects at risk to develop AF after coronary artery bypass graft (CABG) surgery. METHODS: Beat-to-beat HP and SAP series were derived from electrocardiogram (ECG) and invasive arterial pressure recorded for 5 min just before CABG surgery in conscious condition. The group comprised subjects who did develop AF (AF, n = 37, 71 +/- 8 years, 27 males) or did not (noAF, n = 92, 65 +/ 10 years, 85 males). From HP and SAP variabilities we computed classical time domain, spectral, cross-spectral and complexity indexes characterizing autonomic function and cardiac baroreflex control. Moreover, we performed model-based directional analysis assessing the gain and strength of the relations from SAP to HP along cardiac baroreflex feedback and from HP to SAP along the feedforward pathway while disambiguating the effect of respiration as estimated from respiratory-related ECG modulations. RESULTS: Classical HP and SAP variability indexes and baroreflex sensitivity could not separate AF from noAF individuals. Causality markers, and more specifically, the strength of the dynamical interactions from SAP to HP and vice versa, could distinguish the two groups: indeed, AFs have a lower degree of association from SAP to HP and vice versa. CONCLUSIONS: An impairment of the feedforward and feedback arms of the HP-SAP closed loop relation predisposes subjects undergoing CABG surgery to develop postoperative AF. PERSPECTIVES: Competency in medical knowledge: Atrial fibrillation (AF) is a frequent complication after coronary artery bypass graft (CABG) surgery lengthening hospitalization duration and increasing healthcare system costs. Translational outlook 1: CABG patients who developed AF had a less preserved cardiovascular interactions due to less active physiological control mechanisms as resulting from the lower degree of dependence of systolic arterial pressure on heart period and vice versa before CABG surgery. Translational outlook 2: Cardiovascular control markers improve stratification of the AF risk after CABG surgery above and beyond more traditional demographic and clinical indexes. PMID- 29426637 TI - Agrobacterium rosae sp. nov., isolated from galls on different agricultural crops. AB - The plant tumorigenic strain NCPPB 1650T isolated from Rosa*hybrida, and four nonpathogenic strains isolated from tumors on grapevine (strain 384), raspberry (strain 839) and blueberry (strains B20.3 and B25.3) were characterized by using polyphasic taxonomic methods. Based on 16S rRNA gene phylogeny, strains were clustered within the genus Agrobacterium. Furthermore, multilocus sequence analysis (MLSA) based on the partial sequences of atpD, recA and rpoB housekeeping genes indicated that five strains studied form a novel Agrobacterium species. Their closest relatives were Agrobacterium sp. R89-1, Agrobacterium rubi and Agrobacterium skierniewicense. Authenticity of the novel species was confirmed by average nucleotide identity (ANI) and in silico DNA-DNA hybridization (DDH) comparisons between strains NCPPB 1650T and B20.3, and their closest relatives, since obtained values were considerably below the proposed thresholds for the species delineation. Whole-genome-based phylogeny further supported distinctiveness of the novel species, that forms together with A. rubi, A. skierniewicense and Agrobacterium sp. R89-1 a well-delineated sub-clade of Agrobacterium spp. named "rubi". As for other species of the genus Agrobacterium, the major fatty acid of the strains studied was 18:1 w7c (73.42-78.12%). The five strains studied were phenotypically distinguishable from other species of the genus Agrobacterium. Overall, polyphasic characterization showed that the five strains studied represent a novel species of the genus Agrobacterium, for which the name Agrobacterium rosae sp. nov. is proposed. The type strain of A. rosae is NCPPB 1650T (=DSM 30203T=LMG 230T=CFBP 4470T=IAM 13558T=JCM 20915T). PMID- 29426638 TI - Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy. AB - For volumes up to 2 cm3 of the bladder and possibly up to 5 cm3 of the rectum, doses computed from the whole organ were good estimates of the doses in the wall in cervix brachytherapy, and there were no significant differences between patients treated with or without interstitial needles. PMID- 29426639 TI - Imbalance of dietary nutrients and the associated differentially expressed genes and pathways may play important roles in juvenile Kashin-Beck disease. AB - BACKGROUND: Kashin-Beck disease (KBD) is a childhood-onset endemic osteoarthropathy in China. Nutrients including trace elements may play active roles in the development of KBD. OBJECTIVE: This study aimed to estimate the nutrient intakes of children in endemic areas and to identify the imbalanced nutrients associated differentially expressed genes in the juvenile patients with KBD. METHODS: In this cross-sectional study, a consecutive 3 day 24 h semi quantitative dietary retrospect questionnaire was conducted to estimate the daily nutrient intakes of children using CDGSS 3.0 software. Gene profile analysis was employed to identify differentially expressed genes in peripheral blood mononuclear cells of children with KBD. GOC, CTD, KEGG, and REACTOME databases were used to establish the relationship between nutrients and nutrients associated differentially expressed genes and pathways. Statistical analyses were accomplished by SPSS 18.0 software. RESULTS: Daily Se intakes without supplementation of children were significantly lower in Se-supplemented (Se + ) KBD areas (29.3 ~ 29.6 mg/d) and non-endemic area (27.8 +/- 7.9 mg/d) compared to non-Se-supplemented (Se-) KBD area (32.9 +/- 7.9 mg/d, c2 = 20.24, P < .01). Children in Se+ KBD areas were suffering more serious insufficient intake of multiple nutrients, including vitamins-B2/-C/-E, Ca, Fe, Zn and I. Gene profile analysis combined with bioinformatics technique identified 34 nutrients associated differentially expressed genes and 10 significant pathways which are related to the pathological changes in juvenile KBD. CONCLUSIONS: Imbalance of dietary nutrients and nutrients-associated differentially expressed genes and pathways may play important roles in the development of juvenile KBD. PMID- 29426640 TI - Corrigendum to "Synthesis and characterization of new 1-hydroxy-2-pyridinethione derivatives: Their lead complexes and efficacy in the treatment of acute lead poisoning in rats" [J. Trace Elem. Med. Biol. 44 (December 2017) 209-217]. PMID- 29426641 TI - Exosomes with Highly Angiogenic Potential for Possible Use in Pulp Regeneration. AB - INTRODUCTION: Angiogenesis is critical for pulp regeneration. Exosomes, a key component of paracrine secretion, have emerged as important players in the modulation of angiogenesis. The role of dental pulp cell-derived exosomes (DPC Exos) in angiogenesis has rarely been reported. The proangiogenic properties of DPC-Exos in human umbilical vein endothelial cells (HUVECs) are investigated in the current study. METHODS: Exosomes were isolated from dental pulp cell (DPC) culture supernatants by ultracentrifugation and were characterized by transmission electron microscopy, Western blotting, and nanoparticle tracking analysis. Their roles in HUVEC proliferation, proangiogenic factor expression, and tube formation were examined in vitro. RESULTS: We isolated and characterized exosomes from DPCs and showed that DPC-Exos promoted HUVEC proliferation, proangiogenic factor expression, and tube formation. Furthermore, we found that p38 mitogen-activated protein kinase (MAPK) signaling inhibition enhances DPC Exos-induced tube formation. CONCLUSIONS: Taken together, these results suggest that DPC-Exos have vital roles in angiogenesis, and p38 MAPK signaling inhibition enhances tubular morphogenesis. PMID- 29426642 TI - Nuclear Magnetic Resonance Imaging in Endodontics: A Review. AB - INTRODUCTION: This review analyzes the increasing role of magnetic resonance imaging (MRI) in dentistry and its relevance in endodontics. Limits and new strategies to develop MRI protocols for endodontic purposes are reported and discussed. METHODS: Eligible studies were identified by searching the PubMed databases. Only original articles on dental structures, anatomy, and endodontics investigated by in vitro and in vivo MRI were included in this review. Original articles on MRI in dentistry not concerning anatomy and endodontics were excluded. RESULTS: All the consulted studies showed well-defined images of pathological conditions such as caries and microcracks. The enhanced contrast of pulp provided a high-quality reproduction of the tooth shape and root canal in vitro and in vivo. Assessment of periapical lesions is possible even without the use of contrast medium. CONCLUSIONS: MRI is a nonionizing technique characterized by high tissue contrast and high image resolution of soft tissues; it could be considered a valid and safe diagnostic investigation in endodontics because of its potential to identify pulp tissues, define root canal shape, and locate periapical lesions. PMID- 29426643 TI - Comparative Evaluation of Stress Distribution in Experimentally Designed Nickel titanium Rotary Files with Varying Cross Sections: A Finite Element Analysis. AB - INTRODUCTION: Single cross-sectional nickel-titanium (NiTi) rotary instruments during continuous rotations are subjected to constant and variable stresses depending on the canal anatomy. This study was intended to create 2 new experimental, theoretic single-file designs with combinations of triple U (TU), triangle (TR), and convex triangle (CT) cross sections and to compare their bending stresses in simulated root canals with a single cross-sectional instrument using finite element analysis. METHODS: A 3-dimensional model of the simulated root canal with 45 degrees curvature and NiTi files with 5 cross sectional designs were created using Pro/ENGINEER Wildfire 4.0 software (PTC Inc, Needham, MA) and ANSYS software (version 17; ANSYS, Inc, Canonsburg, PA) for finite element analysis. The NiTi files of 3 groups had single cross-sectional shapes of CT, TR, and TU designs, and 2 experimental groups had a CT, TR, and TU (CTU) design and a TU, TR, and CT (UTC) design. The file was rotated in simulated root canals to analyze the bending stress, and the von Mises stress value for every file was recorded in MPa. Statistical analysis was performed using the Kruskal-Wallis test and the Bonferroni-adjusted Mann-Whitney test for multiple pair-wise comparison with a P value <.05 (95 %). RESULTS: The maximum bending stress of the rotary file was observed in the apical third of the CT design, whereas comparatively less stress was recorded in the CTU design. The TU and TR designs showed a similar stress pattern at the curvature, whereas the UTC design showed greater stress in the apical and middle thirds of the file in curved canals. All the file designs showed a statistically significant difference. CONCLUSIONS: The CTU designed instruments showed the least bending stress on a 45 degrees angulated simulated root canal when compared with all the other tested designs. PMID- 29426644 TI - Targeted Endodontic Microsurgery: A Novel Approach to Anatomically Challenging Scenarios Using 3-dimensional-printed Guides and Trephine Burs-A Report of 3 Cases. AB - Endodontic microsurgery (EMS) techniques have increased success rates over traditional approaches. Despite surgical advances, anatomically challenging scenarios can preclude EMS in certain cases. The aim of this article was to introduce targeted EMS, which uses 3-dimensional-printed surgical guides (3DSGs) and trephine burs to achieve single-step osteotomy, root-end resection, and biopsy in complex cases. In each of 3 cases, a 3DSG with a trephine port was printed using computer-aided design/computer-aided manufacturing implant planning software. The osteotomy site, angulation, and depth of preparation were defined preoperatively to avoid sensitive anatomic structures. The 3DSG was inserted at the target site to achieve precise osteotomy and root-end resection during surgery. A hollow trephine rotated within the 3DSG port produced single-step osteotomy, root-end resection, and biopsy. Root-end preparation and fill were accomplished, and tissues were sutured in place. Targeted EMS potentiated successful surgical treatment in 3 anatomically challenging scenarios: (1) a palatal approach to the palatal root of a maxillary second molar, (2) a facial approach to a fused distofacial-palatal root of a maxillary first molar, and (3) a mandibular second premolar in close proximity to the mental foramen. Trephine burs guided by 3DSGs produce efficient targeted osteotomies with a predictable site, angulation, and depth of preparation. Apical surgery in challenging anatomic cases such as the palatal root of the maxillary second molar, fused molar roots, and root ends in approximation to the mental nerve are possible with targeted EMS. PMID- 29426645 TI - Novel Endodontic Disinfection Approach Using Catalytic Nanoparticles. AB - INTRODUCTION: The aim of this study was to test a new disinfection technology using biomimetic iron oxide nanoparticles (IO-NPs) with peroxidaselike activity to enhance antibacterial activity on root canal surfaces and in dentinal tubules. METHODS: The canal surfaces and dentinal tubules of single-rooted intact extracted teeth were infected by growing Enterococcus faecalis biofilms for 3 weeks. The samples were divided into 6 treatment groups: (1) phosphate-buffered saline (PBS) (negative control), (2) 3% hydrogen peroxide (H2O2) (test control), (3) IO-NPs (0.5 mg/mL) (test control), (4) IO-NPs (0.5 mg/mL) + 3% H2O2, (5) 3% sodium hypochlorite (positive control), and (6) 2% chlorhexidine (positive control). Environmental scanning electron microscopy coupled with energy dispersive spectroscopy was used to confirm IO-NPs binding to the canal surface after a single treatment. Specimens were labeled with fluorescent staining for live/dead cells, and confocal laser scanning microscopy was used for the quantification of dead bacteria relative to the negative control (PBS). RESULTS: Both biofilm formation and dentinal tubule infection were successfully recapitulated using the in vitro model. IO-NPs were capable of binding to the infected canal surfaces despite a single, short-term (5-minute) treatment. IO-NP activation of H2O2 killed significantly more E. faecalis present on the canal surfaces and at different depths of dentinal tubules when compared with all other experimental groups (P < .05-.0005). CONCLUSIONS: The results reveal the potential to exploit nanocatalysts with enzymelike activity as a potent alternative approach for the treatment of endodontic infections. PMID- 29426646 TI - Effect of 3 Bioceramic Materials on Stem Cells of the Apical Papilla Proliferation and Differentiation Using a Dentin Disk Model. AB - INTRODUCTION: There is a complex interaction between biomaterials placed as a coronal barrier with stem cells and dentin in regenerative procedures. In this study, the effect of Biodentine (BD; Septodont, Saint-Maurdes-Fosses, France), Endosequence BC Root Repair Material-Putty (ES; Brasseler, Savannah, GA), Endosequence BC Root Repair Material-Putty Fast set (ES-fast, Brasseler), and ProRoot (Dentsply Tulsa Dental Specialties, Johnson City, TN) mineral trioxide aggregate (MTA) on the viability and differentiation of stem cells of the apical papilla (SCAP) was evaluated using an ex vivo dentin disk model. METHODS: Standardized human dentin disks were treated using an established protocol. Disk lumens were filled with BD, ES, ES-fast, or MTA, and SCAP were cultured directly onto the samples. Cell viability was measured at 7 days, whereas differentiation into a mineralizing phenotype was evaluated by real-time reverse-transcription polymerase chain reaction and alizarin red staining at 21 days in culture. Results were analyzed using 1-way analysis of variance with the Bonferroni post hoc test or the Mann-Whitney U test (P <= .05). RESULTS: All materials promoted SCAP viability and proliferation with a greater response in the BD and ES groups. Also, a greater expression of alkaline phosphatase messenger RNA and dentin sialophosphoprotein was noted in the BD and ES groups, whereas MTA promoted a greater expression of the osteoblastic marker IBSP. Interestingly, no difference in alizarin red staining was observed with MTA, BD, or ES, which were significantly greater than ES-fast. CONCLUSIONS: These data suggest that BD and ES promoted greater survival and differentiation of SCAP and the increase of the odontoblastic marker DSPP, whereas MTA appeared to promote greater osteoblastic differentiation. Thus, BD and ES can be considered for regenerative and vital pulp therapies. PMID- 29426647 TI - Relationship between Root Apices and the Mandibular Canal: A Cone-beam Computed Tomographic Comparison of 3 Populations. AB - INTRODUCTION: This study aimed to investigate the difference in the location of the inferior alveolar nerve (IAN) in relation to the apices of mandibular molars in 3 different populations using cone-beam computed tomographic (CBCT) imaging and to assess the proportion of teeth in close proximity (a distance of 1 mm or less) to the IAN. METHODS: Random CBCT images (N = 1224, Israel = 408, South Korea = 416, and India = 400) were examined. The shortest distance to the mandibular canal was measured by imaging software. RESULTS: The mean distance was 4.81 +/- 2.15 mm. The mean distances for Israel, South Korea, and India were 4.60 +/- 2.37 mm, 5.45 +/- 2.13 mm, and 4.35 +/- 1.76 mm, respectively. The distance in samples obtained from South Korea was significantly larger than the distance in samples obtained from Israel and India (P < .05). Samples from Israel exhibited close proximity in 6.6% of samples versus 3% in samples from India and 0.7% of samples from South Korea, a statistically significant difference (P < .05). CONCLUSIONS: Although variation in tooth morphology in different populations was widely researched, the variation in the location of the IAN in relation to tooth apices of different populations was not addressed in the literature. Our study reveals that a difference in the distance of the apices to the IAN exists between populations as well as a difference in the proportion of teeth in close proximity to the IAN. PMID- 29426648 TI - Utility of Left Atrial Expansion Index and Stroke Volume in Management of Chronic Systolic Heart Failure. AB - BACKGROUND: Titration of evidence-based medications, important for treating heart failure (HF), is often underdosed by symptom-guided treatment. The aim of this study was to investigate, using echocardiographic parameters, stroke volume and left ventricular (LV) filling pressure to guide up-titration of medications, increasing prognostic benefits. METHODS: A total of 765 patients with chronic HF and severely reduced LV ejection fractions (<35%), referred from 2008 to 2016, were prospectively studied. Echocardiographic guidance was performed in 149 patients. LV filling pressure was assessed by left atrial expansion index, and stroke volume was estimated from diameter and time-velocity integral in the LV outflow tract. Up-titration of evidence-based medications and adjustment for side effects or worsening clinical conditions according to those parameters were performed. Propensity score matching was used to match pairs of patients with (n = 110) or without (n = 110) echocardiographic guidance. End points were 4-year frequencies of HF hospitalization and all-cause mortality. RESULTS: During a mean follow-up time of 4.1 years, rates of adverse events were 58 (52.7%) with no echocardiographic guidance and 36 (32.7%) with echocardiographic guidance (P < .0001). Echocardiography provided effective guidance to reduce prescribing frequency and dose of diuretics and to promote evidence-based medication prescription. It reduced HF rehospitalization and all-cause mortality. By multivariate analysis, prognostic improvement was associated with up-titration of medications with echocardiographic guidance. CONCLUSIONS: There was a statistically significant difference in long-term prognosis between propensity score-matched pairs of patients with chronic severe HF with and without echocardiographic guidance. These findings need further validation in large prospective clinical trials. PMID- 29426649 TI - Rest and Stress Longitudinal Systolic Left Ventricular Mechanics in Hypertrophic Cardiomyopathy: Implications for Prognostication. AB - BACKGROUND: Exercise intolerance is the most common symptom in hypertrophic cardiomyopathy (HCM). We examined whether inability to augment myocardial mechanics during exercise would influence functional performance and clinical outcomes in HCM. METHODS: Ninety-five HCM patients (32 nonobstructive, 32 labile obstructive, 31 obstructive) and 26 controls of similar age and gender distribution were recruited prospectively. They underwent rest and treadmill stress strain echocardiography, and 61 of them underwent magnetic resonance imaging. Mechanical reserve (MRES) was defined as percent change in systolic strain rate (SR) immediately postexercise. RESULTS: Global strain and SR were significantly lower in HCM patients at rest (strain: nonobstructive, -15.6 +/- 3.0; labile-obstructive, -15.9 +/- 3.0; obstructive, -13.8 +/- 2.9; control, 17.7% +/- 2.1%, P < .001; SR: nonobstructive, -0.92 +/- 0.20; labile-obstructive, -0.94 +/- 0.17; obstructive, -0.85 +/- 0.18; control, -1.04 +/- 0.14 s-1, P = .002); and immediately postexercise (strain: nonobstructive, -15.6 +/- 3.0; labile-obstructive, -17.6 +/- 3.6; obstructive, -15.6 +/- 3.6; control, -19.2 +/- 3.1%; P = .001; SR: nonobstructive, -1.41 +/- 0.37; labile-obstructive, -1.64 +/- 0.38; obstructive, -1.32 +/- 0.29; control, -1.82 +/- 0.29 s-1, P < .001). MRES was lower in nonobstructive and obstructive compared with labile-obstructive and controls (51% +/- 29%, 54% +/- 31%, 78% +/- 38%, 77% +/- 30%, P = .001, respectively). Postexercise SR and MRES were associated with exercise capacity (r = 0.47 and 0.42, P < .001 both, respectively). When adjusted for age, gender, body mass index, E/e', and resting peak instantaneous systolic gradient, postexercise SR best predicted exercise capacity (r = 0.74, P = .003). Postexercise SR was correlated with extent of late gadolinium enhancement (r = 0.34, P = .03). By Cox regression, exercise SR and MRES predicted ventricular tachycardia/ventricular fibrillation (VT/VF) even after adjustment for age, gender, family history of sudden cardiac death, septum >= 3 cm and abnormal blood pressure response (P = .04 and P = .046, respectively). CONCLUSIONS: Nonobstructive and obstructive patients have reduced MRES compared with labile obstructive and controls. Postexercise SR correlates with LGE and exercise capacity. Exercise SR and MRES predict VT/VF. PMID- 29426650 TI - The RIPASA score for the diagnosis of acute appendicitis: A comparison with the modified Alvarado score. AB - INTRODUCTION AND OBJECTIVES: Acute appendicitis is the first cause of surgical emergencies. It is still a difficult diagnosis to make, especially in young persons, the elderly, and in reproductive-age women, in whom a series of inflammatory conditions can have signs and symptoms similar to those of acute appendicitis. Different scoring systems have been created to increase diagnostic accuracy, and they are inexpensive, noninvasive, and easy to use and reproduce. The modified Alvarado score is probably the most widely used and accepted in emergency services worldwide. On the other hand, the RIPASA score was formulated in 2010 and has greater sensitivity and specificity. There are very few studies conducted in Mexico that compare the different scoring systems for appendicitis. The aim of our article was to compare the modified Alvarado score and the RIPASA score in the diagnosis of patients with abdominal pain and suspected acute appendicitis. MATERIAL AND METHODS: An observational, analytic, and prolective study was conducted within the time frame of July 2002 and February 2014 at the Hospital Universitario de Puebla. The questionnaires used for the evaluation process were applied to the patients suspected of having appendicitis. RESULTS: The RIPASA score with 8.5 as the optimal cutoff value: ROC curve (area .595), sensitivity (93.3%), specificity (8.3%), PPV (91.8%), NPV (10.1%). Modified Alvarado score with 6 as the optimal cutoff value: ROC curve (area .719), sensitivity (75%), specificity (41.6%), PPV (93.7%), NPV (12.5%). CONCLUSIONS: The RIPASA score showed no advantages over the modified Alvarado score when applied to patients presenting with suspected acute appendicitis. PMID- 29426652 TI - Considering the Setting. PMID- 29426651 TI - Advances in the Anesthetic Management of Transcatheter Aortic Valve Implantation. PMID- 29426653 TI - Postoperative Symptom Distress of Laparoscopic Cholecystectomy Ambulatory Surgery Patients. AB - PURPOSE: The purposes of this study were to (1) identify symptoms that cause postoperative distress in ambulatory surgery patients; (2) identify symptom management techniques that effectively reduce distress of laparoscopic cholecystectomy (LC) postoperative symptoms at home after ambulatory surgery; and (3) identify facilitators and barriers to self-management of postoperative symptoms. DESIGN: A qualitative descriptive study. METHODS: Two focus groups of ambulatory surgery patients who had experienced a laparoscopic cholecystectomy procedure and their caregivers were queried to elicit understanding of postoperative symptoms and symptom management techniques. FINDINGS: Themes identified included distressing symptoms and consequences of surgery, symptom management, and self-management facilitators and barriers. Pain was a major symptom after surgery and impacted mobility and sleep. Participants in our study wanted realistic information about symptoms and more specific information on symptom management. Caregivers were important to the success of symptom management but experienced their own stress. CONCLUSIONS: Perianesthesia nurses should focus not only on the immediate recovery, but also prepare patients and their caregivers for the more prolonged issues of recovery at home. PMID- 29426654 TI - A Culture of Civility: Positively Impacting Practice and Patient Safety. PMID- 29426655 TI - French mandatory vaccine policy. PMID- 29426656 TI - A rapid lateral flow immunoassay for serological diagnosis of pertussis. AB - Current serological diagnosis of pertussis is usually done by ELISA. However, the ELISAs are often central-laboratory based, require trained staff and have long turnaround times. A rapid point-of-care (POC) assay for pertussis serology would aid in both diagnosis and surveillance of the disease. While lateral flow immunoassays (LFIA) are simple to use and ideal for point-of-care diagnostics, they were limited to qualitative assays until recently. In this study, we developed a quantitative LFIA with fluorescent Eu-nanoparticle reporters for the detection of anti-pertussis toxin (PT) IgG. The assay was evaluated by testing 198 serum samples with varying anti-PT IgG levels and the result was compared to those obtained with standardized anti-PT IgG ELISA. At the diagnostic cutoff of 100 IU/mL in ELISA, the LFIA had a concordance of 92% with the ELISA, with a specificity of 96% [95% confidence interval (CI): 89-99%] and a sensitivity of 88% [CI: 77-94%]. The developed LFIA has a turnaround time of one hour and requires only a simple manipulation by the user and an instrument for the quantitative detection of the signal. We conclude that the LFIA is specific and sensitive for serological diagnosis of pertussis and is suitable for a POC test. PMID- 29426657 TI - MesVaccins.net: A global, multi-functional and integrated platform for information and communication on vaccination. PMID- 29426658 TI - Vaccination in immunocompromised host: Recommendations of Italian Primary Immunodeficiency Network Centers (IPINET). AB - Infectious complications are a major cause of morbidity and mortality in patients with primary or secondary immunodeficiency. Prevention of infectious diseases by vaccines is among the most effective healthcare measures mainly for these subjects. However immunocompromised people vary in their degree of immunosuppression and susceptibility to infection and, therefore, represent a heterogeneous population with regard to immunization. To date there is no well- established evidence for use of vaccines in immunodeficient patients, and indications are not clearly defined even in high-quality reviews and in most of the guidelines prepared to provide recommendations for the active vaccination of immunocompromised hosts. The aim of this document is to issue recommendations based on published literature and the collective experience of the Italian primary immunodeficiency centers, about how and when vaccines can be used in immunocompromised patients, in order to facilitate physician decisions and to ensure the best immune protection with the lowest risk to the health of the patient. PMID- 29426659 TI - Current status of cerebrospinal meningitis and impact of the 2015 meningococcal C vaccination in Kebbi, Northwest Nigeria. AB - INTRODUCTION: Following the significant reduction of Neisseria meningitidis A (NmA) in most parts of northern Nigeria, a new strain of Neisseria meningitidis C (NmC) emerged in 2013 causing outbreaks in the north and recently spreading to southern parts of the Nigeria. This study provides detailed epidemiological investigation in the last four years. METHODS: Analysis of confirmed and suspected cases of meningitis in Kebbi, Nigeria from 2014 to June 2017 detected through Integrated Disease Surveillance and Response. RESULTS: Of the 2776 cases, 1568 were males, and 1208 females. The median age of males and females was 10 and 11 years (Interquartile range of ages is 9 years) respectively. The attack rate (AR) per 100,000 in the state between 2014 and 2017 was 13.2, 46.7, 2.2 and 3.2 respectively. Case fatality rate (CFR) in 2014 was highest in the 4 years analysed at 13.8%. Binary logistic regression analysis suggests that the odds of confirmation of meningitis was 3.6 (Odds ratio, OR 3.60, 95% CI 1.58-8.2; p = 0.002) times as high in the age group 6-10 years and 2.4 times in the age group 11-19 years compared to the age group 0-5 years (OR 2.44, 95% CI 1.09-5.48; p = 0.03). An epidemic of NmC in 2015, led to a reactive vaccination campaign in selected wards in Aliero and Jega targeting age groups 1-29 years old, with a coverage of 72% and 51% respectively. In 2016-2017 Aliero and Jega local government areas (LGA) had no recorded deaths due to meningitis, a significant improvement over 2015 mortality rates (MR) per 100,000 of 33.4 and 12.2 respectively. CONCLUSION: The CFR in the state is still very high, suggesting the need for a more coordinated approach aimed at improving disease notification and early treatment. Vaccination in Aliero and Jega LGAs have demonstrated the usefulness of meningococcal C vaccine in reduction of morbidity and mortality. PMID- 29426661 TI - National immunization strategies targeting migrants in six European countries. AB - Over the last three years an unprecedented flow of migrants arrived in Europe. There is evidence that vaccine preventable diseases have caused outbreaks in migrant holding centres. These outbreaks can be favored by a combination of factors including low immunization coverage, bad conditions that migrants face during their exhausting journey and overcrowding within holding facilities. In 2017, we conducted an online survey in Croatia, Greece, Italy, Malta, Portugal and Slovenia to explore the national immunization strategies targeting irregular migrants, refugees and asylum seekers. All countries stated that a national regulation supporting vaccination offer to migrants is available. Croatia, Italy, Portugal and Slovenia offer to migrant children and adolescents all vaccinations included in the National Immunization Plan; Greece and Malta offer only certain vaccinations, including those against diphtheria-tetanus-pertussis, poliomyelitis and measles-mumps-rubella. Croatia, Italy, Malta and Portugal also extend the vaccination offer to adults. All countries deliver vaccinations in holding centres and/or community health services, no one delivers vaccinations at entry site. Operating procedures that guarantee the migrants' access to vaccination at the community level are available only in Portugal. Data on administered vaccines is available at the national level in four countries: individual data in Malta and Croatia, aggregated data in Greece and Portugal. Data on vaccination uptake among migrants is available at national level only in Malta. Concluding, although diversified, strategies for migrant vaccination are in place in all the surveyed countries and generally in line with WHO and ECDC indications. Development of procedures to keep track of migrants' immunization data across countries, development of strategies to facilitate and monitor migrants' access to vaccinations at the community level and collection of data on vaccination uptake among migrants should be promoted to meet existing gaps. PMID- 29426660 TI - PED subunit vaccine based on COE domain replacement of flagellin domain D3 improved specific humoral and mucosal immunity in mice. AB - Porcine epidemic diarrhea (PED) is an important re-emergent infectious disease and inflicts huge economic losses to the swine industry worldwide. To meet the pressing need of developing a safe and cost-efficient PED maternal vaccine, we generated three PED subunit vaccine candidates, using recombined Salmonella flagellin (rSF) as a mucosal molecular adjuvant. Domain D3 in rSF was replaced with COE domain of PEDV to generate rSF-COE-3D. COE fused to the flanking C'/N' terminal of rSF yielded rSF-COE-C and rSF-COE-N. As a result, rSF-COE-3D could significantly improve COE specific antibody production including serum IgG, serum IgA, mucosal IgA and PEDV neutralizing antibody. Furthermore, rSF-COE-3D elicited more CD3+CD8+ T cell and cytokine production of IFN-gamma and IL-4 in mouse splenocytes. In summary, our data showed that rSF-COE-3D could improve specific humoral and mucosal immunity in mice, thus suggesting that rSF-COE-3D could be applied as a novel efficient maternal PED vaccine. PMID- 29426662 TI - The impact of vaccination and patient characteristics on influenza vaccination uptake of elderly people: A discrete choice experiment. AB - OBJECTIVES: To improve information for patients and to facilitate a vaccination coverage that is in line with the EU and World Health Organization goals, we aimed to quantify how vaccination and patient characteristics impact on influenza vaccination uptake of elderly people. METHODS: An online discrete choice experiment (DCE) was conducted among 1261 representatives of the Dutch general population aged 60 years or older. In the DCE, we used influenza vaccination scenarios based on five vaccination characteristics: effectiveness, risk of severe side effects, risk of mild side effects, protection duration, and absorption time. A heteroscedastic multinomial logit model was used, taking scale and preference heterogeneity (based on 19 patient characteristics) into account. RESULTS: Vaccination and patient characteristics both contributed to explain influenza vaccination uptake. Assuming a base case respondent and a realistic vaccination scenario, the predicted uptake was 58%. One-way changes in vaccination characteristics and patient characteristics changed this uptake from 46% up to 61% and from 37% up to 95%, respectively. The strongest impact on vaccination uptake was whether the patient had been vaccinated last year, whether s/he had experienced vaccination side effects, and the patient's general attitude towards vaccination. CONCLUSIONS: Although vaccination characteristics proved to influence influenza vaccination uptake, certain patient characteristics had an even higher impact on influenza vaccination uptake. Policy makers and general practitioners can use these insights to improve their communication plans and information regarding influenza vaccination for individuals aged 60 years or older. For instance, physicians should focus more on patients who had experienced side effects due to vaccination in the past, and policy makers should tailor the standard information folder to patients who had been vaccinated last year and to patient who had not. PMID- 29426663 TI - Assessing the reactogenicity of Tdap vaccine administered during pregnancy and antibodies to Bordetella pertussis antigens in maternal and cord sera of Thai women. AB - INTRODUCTION: Pregnant Thai women have low antibody titers against B. pertussis antigens, which coincide with an increasing incidence of pertussis among Thai infants. Thus, there exists a potential benefit of a booster dose of tetanus- diphtheria-acellular pertussis (Tdap) vaccine administered during pregnancy. Here, we report the vaccine reactogenicity profile and birth outcomes in Tdap vaccinated pregnant women who have or have not had prior immunization with tetanus vaccine, and the IgG levels to B. pertussis antigens in maternal and cord sera at delivery. MATERIALS AND METHODS: Pregnant women (N = 370) aged 18-40 years were administered the Tdap vaccine (Boostrix(r), GlaxoSmithKline, Rixensart, Belgium) at 26-36 weeks gestation. Adverse events following vaccination were identified by follow-up telephone call and medical record review. IgG against pertussis toxin (anti-PT), filamentous hemagglutinin (anti FHA) and pertactin (anti-PRN) in both maternal and umbilical cord blood obtained at delivery were quantitatively evaluated using enzyme-linked immunosorbent assay (EUROIMMUN(r), Lubeck, Germany). RESULTS: There was no reported increase in the severity or duration of adverse events associated with the administration of an extra tetanus-containing vaccine within the previous five years (N = 181) or multiple doses of tetanus-containing vaccines during the current pregnancy (N = 98). Vaccination at least eight weeks prior to delivery resulted in high antibody titers to all B. pertussis antigens studied. CONCLUSIONS: The reactogenicity of Tdap vaccine administered during pregnancy was not affected by prior tetanus toxoid immunization. High transplacental antibody against B. pertussis antigens in the cord blood provides evidence of antibody transfer and should thus help to protect newborns from pertussis during early life. PMID- 29426664 TI - Inactivation of phoPQ genes attenuates Salmonella Gallinarum biovar Gallinarum to susceptible chickens. AB - Salmonella Gallinarum is a host-restrict pathogen that causes fowl typhoid, a severe systemic disease that is one of the major concerns to the poultry industry worldwide. When infecting the bird, SG makes use of evasion mechanisms to survive and to replicate within macrophages. In this context, phoPQ genes encode a two component regulatory system (PhoPQ) that regulates virulence genes responsible for adaptation of Salmonella spp. to antimicrobial factors such as low pH, antimicrobial peptides and deprivation of bivalent cations. The role of the mentioned genes to SG remains to be investigated. In the present study a phoPQ depleted SG strain (SG DeltaphoPQ) was constructed and its virulence assessed in twenty-day-old laying hens susceptible to fowl typhoid. SG DeltaphoPQ did cause neither clinical signs nor mortality in birds orally challenged, being non pathogenic. Furthermore, this strain was not recovered from livers or spleens. On the other hand, chickens challenged subcutaneously with the mutant strain had discreet to moderate pathological changes and also low bacterial counts in liver and spleen tissues. These findings show that SG DeltaphoPQ is attenuated to susceptible chickens and suggest that these genes are important during chicken infection by SG. PMID- 29426666 TI - The vagus nerve modulates BDNF expression and neurogenesis in the hippocampus. AB - Accumulating evidence suggests that certain gut microbiota have antidepressant like behavioural effects and that the microbiota can regulate neurogenesis and the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. The precise mechanisms underlying these effects are not yet clear. However, the vagus nerve is one of the primary bidirectional routes of communication between the gut and the brain and thus may represent a candidate mechanism. Yet, relatively little is known about the direct influence of vagus nerve activity on hippocampal function and plasticity. Thus, the aim of the present study was to determine whether constitutive vagus nerve activity contributes to the regulation of neurogenesis and BDNF mRNA expression in the hippocampus. To this end, we examined the impact of subdiaphragmatic vagotomy in adult mice on these parameters. We found that vagotomy decreased BDNF mRNA in all areas of the hippocampus. Vagotomy also reduced the proliferation and survival of newly born cells and decreased the number of immature neurons, particularly those with a more complex dendritic morphology. Taken together, these findings suggest that vagal nerve activity influences neurogenesis and BDNF mRNA expression in the adult hippocampus. PMID- 29426665 TI - Phenotypic, genetic and symbiotic characterization of Erythrina velutina rhizobia from Caatinga dry forest. AB - Erythrina velutina ("mulungu") is a legume tree from Caatinga that associates with rhizobia but the diversity and symbiotic ability of "mulungu" rhizobia are poorly understood. The aim of this study was to characterize "mulungu" rhizobia from Caatinga. Bacteria were obteined from Serra Talhada and Caruaru in Caatinga under natural regeneration. The bacteria were evaluated to the amplification of nifH and nodC and to metabolic characteristics. Ten selected bacteria identified by 16S rRNA sequences. They were tested in vitro to NaCl and temperature tolerance, auxin production and calcium phosphate solubilization. The symbiotic ability were assessed in an greenhouse experiment. A total of 32 bacteria were obtained and 17 amplified both symbiotic genes. The bacteria showed a high variable metabolic profile. Bradyrhizobium (6), Rhizobium (3) and Paraburkholderia (1) were identified, differing from their geographic origin. The isolates grew up to 45 degrees C to 0.51molL-1 of NaCl. Bacteria which produced more auxin in the medium with l-tryptophan and two Rhizobium and one Bradyrhizobium were phosphate solubilizers. All bacteria nodulated and ESA 90 (Rhizobium sp.) plus ESA 96 (Paraburkholderia sp.) were more efficient symbiotically. Diverse and efficient rhizobia inhabit the soils of Caatinga dry forests, with the bacterial differentiation by the sampling sites. PMID- 29426667 TI - [Latin american scientific production in the Anales de Pediatria journal]. PMID- 29426668 TI - [Growing teratoma syndrome]. PMID- 29426669 TI - [Attention deficit hyperactivity disorder as a risk factor in unintentional poisonings and injuries]. PMID- 29426670 TI - Simulation-based Transfusion Education for Medical Students. PMID- 29426671 TI - Decreased short-interval intracortical inhibition correlates with better pinch strength in patients with stroke and good motor recovery. AB - BACKGROUND: Deeper short-interval intracortical inhibition (SICI), a marker of GABAA activity, correlates with better motor performance in patients with moderate to severe hand impairments in the chronic phase after stroke. OBJECTIVES: We evaluated the correlation between SICI in the affected hemisphere and pinch force of the paretic hand in well-recovered patients. We also investigated the correlation between SICI and pinch force in controls. METHODS: Twenty-two subjects were included in the study. SICI was measured with a paired pulse paradigm. The correlation between lateral pinch strength and SICI was assessed with Spearman's rho. RESULTS: There was a significant correlation (rho = 0.69, p = 0.014) between SICI and pinch strength in patients, but not in controls. SICI was significantly deeper in patients with greater hand weakness. CONCLUSIONS: These preliminary findings suggest that decreased GABAA activity in M1AH correlates with better hand motor performance in well-recovered subjects with stroke in the chronic phase. PMID- 29426672 TI - Clinical scales: Tools for the diagnosis of unstable angina. PMID- 29426673 TI - Sex bias in mouse humoral immune response to influenza vaccine depends on the vaccine type. AB - The study explored influence of biological sex on development of humoral immune response to seasonal trivalent whole inactivated virus (WIV) and split virus (SV) influenza vaccines in outbred Swiss mouse model. To this end, mice of both sexes were immunized with WIV (WIV mice) and SV vaccines (SV mice) and examined for specific antibody response. Irrespective of sex, total IgG and neutralizing antibody responses to distinct virus strains were weaker in SV than in WIV mice. In WIV mice of both sexes, irrespective of strain specificity, IgG isotype response was dominated by IgG2a antibodies, while in SV mice nearly equal representation of IgG2a and IgG1 antibodies was found. The analyses of sex differences showed higher titers of H1N1-specific and both H1N1- and H3N2 specific total IgG and neutralizing antibodies in female WIV and SV mice, respectively. Additionally, sexual dimorphism in IgG subclass profile depended on vaccine type. Specifically, compared with males, in females WIV shifted IgG2a/IgG1 antibody ratio towards IgG2a isotype on the account of weaker IgG1 response, whereas in SV mice, irrespective of virus strain, IgG2a and IgG1 isotypes were equally represented in both sexes. These findings indicate the vaccine type-dependent sex bias in antibody response to inactivated influenza vaccines. PMID- 29426674 TI - Making sense of the latest evidence on electronic cigarettes. PMID- 29426675 TI - The use of cerebral imaging for investigating delirium aetiology. AB - BACKGROUND: This study aims to investigate the frequency and patterns of use of cerebral imaging in delirium and to describe pathological changes associated with delirium using computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: This retrospective observational study included patients with delirium admitted to a tertiary hospital (The Royal Melbourne Hospital, Australia) between January 2015 and August 2016. Data on cerebral imaging was collected and positive imaging findings were defined as: Acute or subacute infarct, haemorrhage, abscess, neoplasm, vasculitis, posterior reversible encephalopathy syndrome, encephalitis, acute demyelination, or fat embolism. RESULTS: There were 1653 (5% of 32,725) patients with delirium (median age 80 years, inter-quartile range 71 86, 54% male). Thirty-three percent (N = 538) had cerebral imaging (CT only: N = 457, MRI only: N = 10, both: N = 71). In 11% (N = 57) of patients, CT brain scans were positive. MRI brain was completed in 17 patients with a positive CT (17/57), changing the diagnosis in two cases. Fifty-four patients with negative CT scans also had MRI brain; 33% (N = 18) of these were positive. Younger patients were more likely to have MRI compared to CT brain scan. Patients admitted to a neurology unit were more likely to have cerebral imaging. CONCLUSION: Use of CT brain was common in delirium patients, with an 11% rate of positive findings. Fewer patients had MRI brain scans, which added diagnostic information in some cases. Future studies are needed to define the significance of cerebral imaging in delirium management and establish guidelines for its use. PMID- 29426676 TI - Predicting resistant etiology in hospitalized patients with blood cultures positive for Gram-negative bacilli. AB - OBJECTIVE: To develop a risk-scoring tool to predict multidrug-resistant (MDR) etiology in patients with bloodstream infections (BSI) caused by Gram-negative bacilli (GNB). METHODS: A prospective multicenter study analyzed patients with BSI hospitalized in 31 Internal Medicine wards in Italy from March 2012 to December 2012. Patients with BSI caused by MDR-GNB (non-susceptible to at least one agent in three antimicrobial categories) were compared to those with BSI due to susceptible GNB. A logistic regression to identify predictive factors of MDR GNB was performed and the odds ratio (OR) were calculated. A score to predict the risk of MDR was developed. RESULTS: Of 533 BSI episodes, 253 (47.5%) were caused by GNB. Among GNB-BSI, 122 (48.2%) were caused by MDR-GNB while 131 (51.8%) by non-MDR GNB. At multivariate analysis transfer from long-term care facility (OR 9.013, 95% CI 1.089-74.579, p = 0.041), hospitalization in the last 3 months (OR 2.882, 95% CI 1.580-5.259, p = 0.001), urinary catheter (OR 2.315, 95% CI 1.202 4.459, p = 0.012), antibiotic therapy in the last 3 months (OR 1.882, 95% CI 1.041-3.405, p = 0.036), age >= 75 years (OR 1.866, 95% CI 1.076-3.237, p = 0.026) were factors independently associated with MDR etiology. A score ranging from 0 to 10 was useful to recognize patients at lowest risk (0 points: Negative Likelihood Ratio 0.10) and those at highest risk (>6 points, Positive Likelihood Ratio 11.8) of GNB bacteremia due to a MDR strain. CONCLUSIONS: Specific predictors of MDR etiology are useful to calculate probabilities of MDR etiology among hospitalized patients with blood cultures positive for GNB. PMID- 29426677 TI - Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs. AB - OBJECTIVE: To compare the effects of alfaxalone and propofol, with and without acepromazine and butorphanol followed by doxapram, on laryngeal motion and quality of laryngeal examination in dogs. STUDY DESIGN: Randomized, crossover, blinded study. ANIMALS: Ten female Beagle dogs, aged 11-13 months and weighing 7.2-8.6 kg. METHODS: The dogs were administered four intravenous (IV) treatments: alfaxalone (ALF), alfaxalone+acepromazine and butorphanol (ALF-AB), propofol (PRO) and propofol+AB (PRO-AB). AB doses were standardized. Dogs were anesthetized 5 minutes later by administration of alfaxalone or propofol IV to effect. Arytenoid motion during maximal inspiration and expiration was captured on video before and after IV doxapram (0.25 mg kg-1). The change in rima glottidis surface area (RGSA) was calculated to measure arytenoid motion. An investigator blinded to the treatment scored laryngeal examination quality. RESULTS: A 20% increase in RGSA was the minimal arytenoid motion that was detectable. RGSA was significantly less in ALF before doxapram compared with all other treatments. A <20% increase in RGSA was measured in eight of 10 dogs in PRO and in all dogs in ALF before doxapram. After doxapram, RGSA was significantly increased for PRO and ALF; however, 20% of dogs in PRO and 50% of dogs in ALF still had <20% increase in RGSA. A <20% increase in RGSA was measured in five of 10 dogs in PRO-AB and ALF-AB before doxapram. All dogs in PRO-AB and ALF-AB with <20% increase in RGSA before doxapram had >=20% increase in RGSA after doxapram. Examination quality was significantly better in PRO-AB and ALF-AB. CONCLUSIONS AND CLINICAL RELEVANCE: The use of acepromazine and butorphanol improved the quality of laryngeal examination. Any negative impact on arytenoid motion caused by these premedications was overcome with doxapram. Using either propofol or alfaxalone alone is not recommended for the evaluation of arytenoid motion. PMID- 29426678 TI - Low Yield of Extensive Workup for Embolic Sources in Lacunar Stroke Patients. AB - OBJECTIVE: We aimed to evaluate the yield of extensive etiologic workup in lacunar stroke patients. BACKGROUND: As lacunar strokes are infrequently caused by thromboembolism, the clinical relevance of extensive workup for thromboembolic sources is questioned. METHODS: Among consecutive stroke admissions to a single center over 3 years, the 100 cases initially classified as lacunar stroke and a sample of 100 cases classified as non-lacunar ischemic strokes were studied. Review of brain imaging resulted in reclassification of 24 cases, and exclusion of 3 cases, producing a final cohort of 86 confirmed lacunar strokes and 111 confirmed non-lacunar strokes. In each of these cases, results of echocardiographic and vascular imaging studies were evaluated. RESULTS: Echocardiography was performed in 93% of both the lacunar stroke cases and non lacunar stroke cases. High-risk cardiac embolic sources were found less often in lacunar than in non-lacunar stroke cases (19% versus 34%). Findings potentially requiring anticoagulant therapy were found exclusively in the non-lacunar stroke patients. Vascular imaging studies (computed tomography angiography or magnetic resonance angiography) were also performed in similar proportions of lacunar and non-lacunar stroke cases (85% versus 84%). Cerebrovascular occlusions or high grade stenoses were frequent (62%) in non-lacunar stroke patients but less frequent (25%) in lacunar stroke patients. In the non-lacunar stroke patients, identified vascular lesions were very frequently in a vessel anatomically related to the infarction, but in lacunar stroke patients, this occurred in only 6 cases. CONCLUSIONS: Echocardiography and vascular imaging studies rarely disclose findings of etiologic relevance, or of likelihood to change management, in patients with lacunar strokes. PMID- 29426679 TI - Comments on "Short-Term Outcome of Spontaneous Intracerebral Hemorrhage in Algarve, Portugal: Retrospective Hospital-Based Study". PMID- 29426680 TI - Effects of Memantine on Nitric Oxide Production and Hydroxyl Radical Metabolism during Cerebral Ischemia and Reperfusion in Mice. AB - BACKGROUND: The purpose of this study was to investigate the effects of memantine on brain ischemia. Because we can measure nitric oxide (NO) production and hydroxyl radical metabolism continuously, we investigated the effect of memantine on NO production and hydroxyl radical metabolism in cerebral ischemia and reperfusion. METHODS: Memantine (25 umol/kg) was administered intraperitoneally to 6 C57BL/6 mice 30 minutes before ischemia. Seven additional mice received no injection (controls). NO production and hydroxyl radical metabolism were continuously monitored using bilateral striatal microdialysis in vivo. Hydroxyl radical formation was monitored using the salicylate trapping method. Forebrain ischemia was produced in all mice by occluding the common carotid artery bilaterally for 10 minutes. Levels of the NO metabolites nitrite (NO2-) and nitrate (NO3-) were determined using the Griess reaction. Survival rates of hippocampal CA1 neurons were calculated and 8-hydroxydeoxyguanosine (8-OHdG) immunopositive cells were counted to evaluate the oxidative stress in hippocampal CA1 neurons 72 hours after the start of reperfusion. RESULTS: The regional cerebral blood flow was significantly higher in the memantine group than in the control group after reperfusion. Furthermore, the level of 2,3-dihydroxybenzoic acid was significantly lower in the memantine group than in the control group during ischemia and reperfusion. Levels of NO2- and NO3- did not differ significantly between the 2 groups. Although survival rates in the CA1 did not differ significantly, there were fewer 8-OHdG-immunopositive cells in animals that had received memantine than in control animals. CONCLUSIONS: These data suggest that memantine exerts partially neuroprotective effects against cerebral ischemic injury. PMID- 29426682 TI - Retrospective view of primary Raynaud's phenomenon in childhood. AB - OBJECTIVES: Primary Raynaud's phenomenon (PRP) manifests as episodes of transient spasms of peripheral blood vessels. To elucidate the clinical clues and laboratory characteristics will facilitate the identification of PRP. METHODS: A retrospective data collection of clinical and laboratory characteristics of 58 children with PRP was performed between January 2007 and December 2016. RESULTS: A positive ANA test at lower titers <1:100 was detected in 24.1% of the patients. There was a significant relationship between presence of ANA positivity and migraine in female patients with PRP (p=0.01; p=0.020 respectively). The most common accompanying disorder was migraine which was detected in 37.9% of all patients with PRP. Hemoglobin and serum ferritin levels were significantly lower in PRP patients with migraine (p=0.045; p<0.05, respectively). Additionally, the mean platelet volume (MPV) measurements were significantly higher in patients with migraine compared to those without migraine (p=0.045; p<0.05 respectively). DISCUSSION: There is limited data concerning childhood PRP. For the first time we showed a high frequency of migraine in childhood PRP. Anemia and high MPV could be the underlying triggering factors of these two episodic diseases. PMID- 29426681 TI - Activities suggestion based on emotions in AAL environments. AB - The elderly population is increasing and the response of the society was to provide them with services directed to them to cope with their needs. One of the oldest solutions is the retirement home, providing housing and permanent assistance for the elderly. Furthermore, most of the retirement homes are inhabited by multiple elderly people, thus creating a community of people who are somewhat related in age and medical issues. The ambient assisted living (AAL) area tries to solve some of the elderly issues by producing technological products, some of them dedicated to elderly homes. One of the identified problem is that elderly people are sometimes discontent about the activities that consume most of their day promoted by the retirement home social workers. The work presented in this paper attempts to improve how these activities are scheduled taking into account the elderlies' emotional response to these activities. The aim is to maximize the group happiness by promoting the activities the group likes, minding if they are bored due to activities repetition. In this sense, this paper presents an extension of the Cognitive Life Assistant platform incorporating a social emotional model. The proposed system has been modelled as a free time activity manager which is in charge of suggesting activities to the social workers. PMID- 29426683 TI - Cardiothoracic MRI in the ICU: A 10-Year Experience. AB - RATIONALE AND OBJECTIVE: The objective of this study was to identify the feasibility and pitfalls of cardiothoracic magnetic resonance imaging (MRI) in intensive care unit (ICU) patients. MATERIALS AND METHODS: This retrospective study identified adult ICU patients scheduled for cardiothoracic MRIs during a 10 year study period. ICU patients scheduled for brain MRIs served as a comparison group. A chart review was performed to identify factors impacting a patient's ability to undergo an MRI. Differences between completed and canceled examinations for both cardiothoracic and brain MRIs were evaluated. For the cardiothoracic group, clinical indications and the diagnostic value of the study performed were also identified. RESULTS: A total of 143 cardiothoracic MRIs and 1011 brain MRIs were requested. Cardiothoracic MRI patients were less frequently completed (52% vs 62%), more frequently men (64% vs 43%), younger (55 vs 63 years), less likely mechanically ventilated (8% vs 29%), more likely to require intravenous contrast (83% vs 23%), and had longer examination times compared to brain MRI patients (64 vs 21 minutes). Successful completion of cardiothoracic MRI was associated with lower serum creatinine, higher glomerular filtration rate, and the absence of mechanical ventilation; significant differences were not seen with regard to gender and use of vasoactive agents. Cardiothoracic MRI results were diagnostic in 69% of examinations, most frequently when performed for myocardial disease (84%) and aortic disease (33%), and less frequently for viability (33%). CONCLUSIONS: In an ICU population, successful completion of cardiothoracic MRI is challenging but feasible in patients with intact renal function and the absence of mechanical ventilation. Examinations were most frequently diagnostic for myocardial and aortic disease indications. PMID- 29426684 TI - Fat Necrosis of the Breast: Magnetic Resonance Imaging Characteristics and Pathologic Correlation. AB - RATIONALE AND OBJECTIVES: This study aims to describe the magnetic resonance imaging (MRI) features of fat necrosis on magnetic resonance mammography, which may downstage a suspicious lesion to a merely benign finding. MATERIALS AND METHODS: This prospective study included 82 female patients (mean age 50 years) who were diagnosed to have suspicious lesions by mammography, ultrasonography or both. All patients underwent MRI including diffusion-weighted imaging and spectroscopy. Image postprocessing and analysis included signal intensity, enhancement characteristics, diffusion restriction, and spectroscopic analysis. All patients underwent histopathological analysis for confirmation. Sensitivity, specificity, positive predictive value (PPV), and negative (NPV) predictive value were calculated. RESULTS: To label a lesion as fat necrosis on MRI analysis, presence of fat signal in a lesion revealed sensitivity of 98.04%, specificity of 100%, PPV of 100%, and NPP of 96.88%, whereas nonenhancement of the lesion itself revealed sensitivity of 96.08%, specificity of 100%, PPV of 100%, and NPP of 93.94%. However, adding both the nonrestriction on diffusion analysis and the lack of tCholine at 3.22 ppm increased the sensitivity and specificity to 100%, as well as PPV of 100% for fat necrosis and hence a NPV for malignancy of 100%. CONCLUSIONS: MRI proved to be of value in differentiating fat necrosis from malignancy based on the molecular composition of fat necrosis, clearly depicted by MRI without the need for invasive confirmation by biopsy. PMID- 29426685 TI - Burnout: Job Resources and Job Demands Associated With Low Personal Accomplishment in United States Radiology Residents. AB - OBJECTIVE: We aimed to identify job resources and job demands associated with measures of personal accomplishment (PA) in radiology residents in the United States. MATERIALS AND METHODS: A 34-item online survey was administered between May and June 2017 to U.S. radiology residents and included the 8 Likert-type PA questions from the Maslach Burnout Inventory-Human Services Survey, 19 visual analog scale job demands-resources questions, and 7 demographic questions. Multiple linear regression was calculated to predict PA based on job demands resources. Effects of binomial demographic factors on PA scores were compared with independent-samples t tests. Effects of categorical demographic factors on PA scores were compared with one-way between-subjects analysis of variance tests. A linear regression was calculated to evaluate the relationship of age on PA scores. RESULTS: "The skills and knowledge that I am building are important and helpful to society" (P = 2 * 10-16), "I have good social support from my co residents" (P = 4 * 10-5), and "I regularly receive adequate constructive feedback" (P = 4 * 10-6) all positively correlated with PA. PA scores were significantly lower for individuals who were single vs those married or partnered (P = .01). CONCLUSIONS: Radiology residents score higher in the PA domain of burnout when they receive adequate constructive feedback, have good co-resident social support, and feel that the skills and knowledge they are building are important to society. Improving constructive feedback mechanisms, enabling resident-only social time, and supporting opportunities that reinforce the importance of their contributions may therefore improve radiology residents' sense of PA. PMID- 29426686 TI - Reinforcing the Importance and Feasibility of Implementing a Low-dose Protocol for CT-guided Biopsies. AB - RATIONALE AND OBJECTIVES: This study sought to more definitely illustrate the impact and feasibility of implementing a low-dose protocol for computed tomography (CT)-guided biopsies using size-specific dose estimates and multivariate analyses. MATERIALS AND METHODS: Fifty consecutive CT-guided lung and extrapulmonary biopsies were reviewed before and after implementation of a low-dose protocol (200 patients total, mean age 61 +/- 15 years, 128 women). Analyses of variance with Bonferroni correction were used to compare standard and low-dose protocols in terms of patient demographics, physician experience, target lesion size, total dose-length product, total acquisitions, size-specific dose estimate, signal-to-noise ratio, contrast-to-noise ratio, and lesion conspicuity ratings. All procedures were performed on the same 16-slice CT scanner. RESULTS: Voluntary protocol adherence was 100% (lung) and 89% (extrapulmonary). The low dose protocol achieved significantly lower total average dose-length product [(lung) 735.6 +/- 599.4 mGy * cm to 252.1 +/- 101.9 mGy * cm, P < .001; (extrapulmonary) 724.7 +/- 545.0 mGy * cm to 392.9 +/- 239.5 mGy * cm, P < .001] and size-specific dose estimate [(lung) 5.2 +/- 0.8 mGy * cm to 4.3 +/- 1.5 mGy, P < .001; (extrapulmonary) 10.1 +/- 6.7 mGy to 6.5 +/- 2.7 mGy, P < .001]. Only the change in protocol was independently associated with lower size-specific dose estimates when controlling for the other variables (P < .0001). This was achieved with no significant differences in signal-to-noise ratio, contrast-to-noise ratio, or lesion conspicuity. CONCLUSIONS: Implementation of a low-dose protocol for CT-guided biopsies resulted in 21% and 36% of size-specific dose estimate reduction for lung and extrapulmonary biopsies, respectively, with excellent adherence. Interventional and body radiologists should implement low dose CT guidance protocols aiming to improve patient safety. PMID- 29426687 TI - Coronary manifestations of Kawasaki Disease in computed tomography coronary angiography. AB - Coronary arteritis in Kawasaki disease can lead to serious complications such myocardial infarction and sudden death. The identification of coronary manifestations with a method that is minimally invasive and of low radiation exposure is therefore important in paediatric patients with Kawasaki disease. Coronary CT angiography can be an attractive alternative to invasive coronary angiography. This paper describes imaging techniques for coronary CT angiography in pediatric patients and demonstrates the spectrum of cardiovascular manifestations in patients with Kawasaki disease. PMID- 29426688 TI - Variation in Adolescent Idiopathic Scoliosis Surgery: Implications for Improving Healthcare Value. AB - OBJECTIVES: To investigate the variation in care and cost of spinal fusion for adolescent idiopathic scoliosis (AIS), and to identify opportunities for improving healthcare value. STUDY DESIGN: Retrospective cohort study from the Pediatric Health Information Systems database, including children 11-18 years of age with AIS who underwent spinal fusion surgery between 2004 and 2015. Multivariable regression was used to evaluate the relationships between hospital cost, patient outcomes, and resource use. RESULTS: There were 16 992 cases of AIS surgery identified. There was marked variation across hospitals in rates of intensive care unit admission (0.5%-99.2%), blood transfusions (0%-100%), surgical complications (1.8%-32.3%), and total hospital costs ($31 278-$90 379). Hospital cost was 32% higher at hospitals that most frequently admitted patients to the intensive care unit (P = .009), and 8% higher for each additional 25 operative cases per hospital (P = .003). Hospital duration of stay was shorter for patients admitted to hospitals with highest intensive care unit admission rates and higher surgical volumes. There was no association between cost and duration of stay, 30-day readmission, or surgical complications. The largest contribution to hospital charges was supplies (55%). Review of a single hospital's detailed cost accounting system also found supplies to be the greatest single contributor to cost, the majority of which were for spinal implants, accounting for 39% of total hospital costs. CONCLUSIONS: The greatest contribution to AIS surgery cost was supplies, the majority of which is likely attributed to spinal implant costs. Opportunities for improving healthcare value should focus on controlling costs of spinal instrumentation, and improving quality of care with standardized treatment protocols. PMID- 29426689 TI - Reply. PMID- 29426690 TI - Self-management and liver allograft rejection in adolescence and beyond. PMID- 29426691 TI - Toward consensus reporting of radiation-induced liver toxicity in the treatment of primary liver malignancies: Defining clinically relevant endpoints. AB - BACKGROUND: Our purpose was to define the most clinically relevant "nonclassic" radiation-induced liver disease (RILD) endpoints in cirrhotic patients receiving stereotactic body radiation therapy or proton beam therapy for primary liver cancer. METHODS AND MATERIALS: We retrospectively collected pretreatment, detailed toxicity (<=6 months posttreatment), and outcomes data from 48 patients. Deaths were examined for association with RILD. Univariate and multivariate Cox models defined significant predictors of overall survival (OS)/RILD-specific survival (RILD-SS). RESULTS: With median follow-up of 13 months, 23 patients (48%) had an increase in Child-Pugh (CP) score (>=2, 25%) and 3 (6%) had >=G3 transaminase elevation. Of 18 deaths, 6 were potentially ascribed to RILD. Univariate analysis showed that CP score increases of >=1 and >=2 and CP class change predicted OS, as did >=G3 aspartate transaminase (AST) elevation and >=1 Common Terminology Criteria for Adverse Events (CTCAE) AST toxicity grade change. On multivariate analysis, CP score increase of >=2 and >=1 CTCAE AST toxicity grade change were the strongest independent nonclassic RILD predictors of OS. For RILD-SS, CP score increases of >=2, >=grade 3 CTCAE alanine transaminase, and >=grade 2 bilirubin elevations were predictive. CONCLUSIONS: Increased CP score >=2 strongly predicts for both OS and RILD-SS and should be reported in future studies along with transaminase elevations, which are also predictive of outcomes. PMID- 29426692 TI - Pancreatic gross tumor volume contouring on computed tomography (CT) compared with magnetic resonance imaging (MRI): Results of an international contouring conference. AB - PURPOSE: Accurate identification of the gross tumor volume (GTV) in pancreatic adenocarcinoma is challenging. We sought to understand differences in GTV delineation using pancreatic computed tomography (CT) compared with magnetic resonance imaging (MRI). METHODS AND MATERIALS: Twelve attending radiation oncologists were convened for an international contouring symposium. All participants had a clinical and research interest in pancreatic adenocarcinoma. CT and MRI scans from 3 pancreatic cases were used for contouring. CT and MRI GTVs were analyzed and compared. Interobserver variability was compared using Dice's similarity coefficient (DSC), Hausdorff distances, and Jaccard indices. Mann-Whitney tests were used to check for significant differences. Consensus contours on CT and MRI scans and constructed count maps were used to visualize the agreement. Agreement regarding the optimal method to determine GTV definition using MRI was reached. RESULTS: Six contour sets (3 from CT and 3 from MRI) were obtained and compared for each observer, totaling 72 contour sets. The mean volume of contours on CT was significantly larger at 57.48 mL compared with a mean of 45.76 mL on MRI, P = .011. The standard deviation obtained from the CT contours was significantly larger than the standard deviation from the MRI contours (P = .027). The mean DSC was 0.73 for the CT and 0.72 for the MRI (P = .889). The conformity index measurement was similar for CT and MRI (P = .58). Count maps were created to highlight differences in the contours from CT and MRI. CONCLUSIONS: Using MRI as a primary image set to define a pancreatic adenocarcinoma GTV resulted in smaller contours compared with CT. No differences in DSC or the conformity index were seen between MRI and CT. A stepwise method is recommended as an approach to contour a pancreatic GTV using MRI. PMID- 29426693 TI - Clinical needs assessment for sexual health among cancer patients receiving pelvic radiation: Implications for development of a radiation oncology sexual health clinic. AB - BACKGROUND: Cancer patients treated with pelvic radiation therapy (RT) often experience sexual health-related side effects during and following treatment. A clinical needs assessment was used to evaluate sexual health needs and to determine how needs differed between patients receiving and who had completed RT. METHODS AND MATERIALS: A questionnaire was used to evaluate sexual health needs among patients treated with pelvic RT. All answers were rated using a 4-point Likert scale. Convenience sampling was used, and patients were stratified by whether they were on-treatment or in follow-up. Charts were reviewed for demographic, diagnostic, and treatment information. Pearson's chi2 test and logistic regression analysis were used to analyze the associations between sexual health-related topics and clinical variables. RESULTS: A total of 107 of 109 (98%) invited patients completed the questionnaire (46 females, 61 males; 52 undergoing RT, 54 completed RT). Most (75%) reported some degree of change in sexual health from the effects of cancer and/or treatment; 22% and 28% reported "quite a bit" or "very much" change, respectively. Sixty-nine percent reported that they experienced some degree of distress from sexual health changes (28% reported "very much" or "quite a bit" of distress). Seventy-six percent "agreed" or "strongly agreed" that they were interested in access to a multidisciplinary sexual health clinic (MSHC). Compared with patients currently receiving RT, patients in follow-up were significantly more likely to report worsening degrees of "change" (P = .008) and "distress" (P = .04) and to express interest in having access to an MSHC (P = .03). CONCLUSION: The majority of patients receiving pelvic RT reported a change in sexual health with associated distress, with more reports among those in follow-up. Patients undergoing pelvic RT expressed a high interest in attending a radiation oncology MSHC. Our findings emphasize the important role radiation oncologists can play in the quality of life of our patients. PMID- 29426694 TI - Non-Local Consciousness and the Anthropology of Dreams. PMID- 29426695 TI - Only <10% of Patients Selected for Radical Prostatectomy Reach the Competing Mortality Rate of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). AB - : In the Prostate Cancer Intervention Versus Observation Trial (PIVOT), surgery was not associated with lower mortality compared with observation. However, the high competing mortality rate of approximately 33% after 10 yr among the PIVOT study population has raised concerns on the generalizability of these results. We investigated 4282 patients who underwent radical prostatectomy at our institution between 1992 and 2010 to determine which subgroups harbored a competing (non prostate cancer) mortality risk comparable to that of PIVOT and tested several combinations of higher age and comorbidities ("worst case scenarios") to identify subgroups reaching or even superseding the competing mortality rate of the PIVOT population. The competing mortality rate of PIVOT was not reached till an age adjusted Charlson score of 5 or higher (corresponding to an age of 70-79 yr with diabetes with end-organ damage). Only 8.9% of patients belonged to this high-risk subgroup, and only small subgroups comprising 1-5% patients superseded the competing mortality rate among the PIVOT study population. This data underline that the results of PIVOT should be used with great caution to exclude candidates for radical prostatectomy with comorbidities from curative treatment. PATIENT SUMMARY: Only <10% of patients selected for radical prostatectomy reached the competing mortality rate of approximately 33% observed in the Prostate Cancer Intervention Versus Observation Trial (PIVOT). The results of PIVOT should be used with great caution to exclude patients with concomitant diseases who seem otherwise fit for radical prostatectomy from curative treatment. PMID- 29426696 TI - Prognostic impact of concomitant loss of PBRM1 and BAP1 protein expression in early stages of clear cell renal cell carcinoma. AB - PURPOSE: To evaluate the prognostic impact of immunohistochemical expression of BAP1 and PBRM1 in patients with early stage (pT1-pT2N0M0) clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: A total of 441 consecutive patients treated surgically for stages I and II (TNM-AJCC 2010) ccRCC between 1990 and 2016 were selected. All cases were reviewed for uniform reclassification and the most representative tumor areas were selected for the construction of a tissue microarray. Sixty-two patients had frozen tumoral tissue available in the tumor bank of our institution for quantitative real-time reverse transcriptase polymerase chain reaction analysis. RESULTS: Of the 441-immunostained ccRCC specimens, 91 (20.6%) and 107 (24.3%) showed negative-expression of PBRM1 and BAP1, respectively. Fifty-eight (13.2%) showed negative-expression of both markers (PBRM1-/BAP-). There was an association between both markers expression pattern and classical parameters, such as pT stage (P<0.001), tumor size (P<0.001), and tumor grade (P<0.001). Both independent PBRM1 and BAP1 negative expression were associated with lower rates of disease-specific survival and recurrence-free survival. When patients were grouped into presence of positive expression of one or both markers vs. PBRM1-/BAP1- patients, disease-specific survival and rates were 95.3% vs. 77.6%, respectively (P<0.001). PBRM1-/BAP1 group presented a higher risk of cancer specific death (hazard ratio = 2.722, P = 0.007) and disease recurrence (hazard ratio = 2.467, P = 0.004) in multivariate analysis. CONCLUSION: Patients with early stage tumors that present concomitant loss of both PBRM1 and BAP1 demonstrated worse survival rates and represent a relevant risk group for tumor recurrence and death. PMID- 29426697 TI - The prognostic value of basal DNA damage level in peripheral blood lymphocytes of patients affected by bladder cancer. AB - BACKGROUND: Bladder cancer (BC) is one of the most aggressive malignancies of the urinary tract, with the highest lifetime treatment costs per patient of all cancers, due to the high rate of recurrences requiring continuous surveillance. An early diagnosis is essential to improve survival of patients with BC. Noninvasive and sensitive molecular biomarkers are needed to improve current strategies for the detection and monitoring of BC. Previous studies suggested that elevated DNA damage levels and suboptimal nucleotide excision DNA repair (NER) may be associated with BC. METHODS: In the present study, we investigated basal DNA damage and DNA repair capacity in peripheral blood mononuclear cells (PBMCs) from 146 newly diagnosed patients with BC and 155 controls using a modified comet assay able to evaluate NER activity after challenging cells by benzo(a)pyrene diolepoxide (BPDE). RESULTS: We found an association between DNA damage levels in PBMCs of BC cases and patients' outcomes. Basal DNA damage at diagnosis was significantly increasing with tumor grades (trend test, P = 0.02) and risk classes (trend test, P = 0.02). The overall survival analysis showed that DNA damage in patients at BC diagnosis was significantly higher in subjects with a shorter survival time (hazard ratio = 3.7; 95% CI: 1.3-10.6; P = 0.02). CONCLUSIONS: Based on these data, we suggest that DNA damage levels measured in PBMCs of patients with BC may potentially represent a prognostic marker associated with poor survival; further validation is needed to better stratify patients with BC for clinical trials. PMID- 29426698 TI - External beam radiotherapy with or without androgen deprivation therapy in elderly patients with high metastatic risk prostate cancer. AB - OBJECTIVE: Several randomized controlled trials have documented significant overall survival benefit in high metastatic risk prostate cancer (PCa) patients treated with combination of androgen deprivation therapy (ADT) at radiotherapy (RT) relative to RT alone. Unfortunately, elderly patients are either not included or are underrepresented in these trials. In consequence, the survival benefit of combination of ADT at RT in the elderly warrants detailed reassessment, including its cost. METHODS: Between 1991 and 2009 within the Surveillance Epidemiology and End Results (SEER)-Medicare-linked database, we identified 3,692 patients aged 80 years or more with clinical T1-T2 PCa and WHO histological grade 3, or clinical T3-T4 PCa and any histological grade, treated with or without combination of ADT at RT. Competing risks analyses focused on cancer-specific mortality (CSM) and other-cause mortality, after accounting for confounders. All analyses were repeated in patients with no comorbidity and in most contemporary patients, treated between 2001 and 2009. Finally, we assessed median annual cost according to use of combination of ADT at RT, after adjusting for patient and tumor characteristics. RESULTS: In competing-risks multivariable analyses, no statistically significant difference was observed in CSM and other cause mortality between patients treated with or without combination of ADT at RT. Same results were recorded in subgroup analyses of patients with no comorbidity and in most contemporary patients. The median annual costs of $36,140 and of $47,510 were recorded, respectively in patients treated without and with ADT at RT. CONCLUSION: Our findings failed to confirm that combination of ADT at RT reduces CSM rates in high metastatic risk PCa patients aged 80 years or more. Moreover, combination of ADT at RT resulted in a significant cost increase, relative to RT alone. PMID- 29426699 TI - Perioperative lipid-enriched enteral nutrition versus standard care in patients undergoing elective colorectal surgery (SANICS II): a multicentre, double-blind, randomised controlled trial. AB - BACKGROUND: Postoperative ileus and anastomotic leakage severely impair recovery after colorectal resection. We investigated the effect of perioperative lipid enriched enteral nutrition versus standard care on the risk of postoperative ileus, anastomotic leakage, and other clinical outcomes. METHODS: We did an international, multicentre, double-blind, randomised, controlled trial of patients (>=18 years) undergoing elective colorectal surgery with primary anastomosis at six clinical centres in the Netherlands and Denmark. Patients were randomly assigned (1:1), stratified by location (colonic and rectal) and type of surgery (laparoscopic and open), via online randomisation software, with block sizes of six, to receive either continuous lipid-enriched enteral tube feeding from 3 h before until 6 h after surgery (intervention) or no perioperative nutrition (control). Surgeons, patients, and researchers were masked to treatment allocation for the entire study period. The primary outcome was postoperative ileus. Secondary outcomes included anastomotic leakage, pneumonia, preoperative gastric volumes, time to functional recovery, length of hospital stay, the need for additional interventions, intensive care unit admission, postoperative inflammatory response, and surgical complications. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175979, and trialregister.nl, number NTR4670. FINDINGS: Between July 28, 2014, and February 20, 2017, 280 patients were randomly assigned, 15 of whom were excluded after random allocation because they fulfilled one or more exclusion criteria. 265 patients received perioperative nutrition (n=132) or standard care (n=133) and were included in the analyses. A postoperative ileus occurred in 37 (28%) patients in the intervention group versus 29 (22%) in the control group (risk ratio [RR] 1.09, 95% CI 0.95-1.25; p=0.24). Anastomotic leakage occurred in 12 (9%) patients in the intervention group versus 11 (8%) in the control group (RR 1.01, 95% CI 0.94-1.09; p=0.81). Pneumonia occurred in ten (8%) patients in the intervention group versus three (2%) in the control group (RR 1.06, 95% CI 1.00 1.12; p=0.051). All other secondary outcomes were similar between groups (all p>0.05). INTERPRETATION: Perioperative lipid-enriched enteral nutrition in patients undergoing elective colorectal surgery has no advantage over standard care in terms of postoperative complications. FUNDING: Netherlands Organisation for Health Research and Development (ZonMW), Fonds NutsOhra, and Danone Research. PMID- 29426700 TI - When should feeding begin in patients undergoing colorectal surgery? PMID- 29426703 TI - Methodological update in Medicina Intensiva. AB - Research in the critically ill is complex by the heterogeneity of patients, the difficulties to achieve representative sample sizes and the number of variables simultaneously involved. However, the quantity and quality of records is high as well as the relevance of the variables used, such as survival. The methodological tools have evolved to offering new perspectives and analysis models that allow extracting relevant information from the data that accompanies the critically ill patient. The need for training in methodology and interpretation of results is an important challenge for the intensivists who wish to be updated on the research developments and clinical advances in Intensive Medicine. PMID- 29426702 TI - High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. AB - Individual reports suggest that the central nervous system (CNS) contains multiple immune cell types with diverse roles in tissue homeostasis, immune defense, and neurological diseases. It has been challenging to map leukocytes across the entire brain, and in particular in pathology, where phenotypic changes and influx of blood-derived cells prevent a clear distinction between reactive leukocyte populations. Here, we applied high-dimensional single-cell mass and fluorescence cytometry, in parallel with genetic fate mapping systems, to identify, locate, and characterize multiple distinct immune populations within the mammalian CNS. Using this approach, we revealed that microglia, several subsets of border-associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease-specific transformations in the immune microenvironment during aging and in models of Alzheimer's disease and multiple sclerosis. Together, these data and the described framework provide a resource for the study of disease mechanisms, potential biomarkers, and therapeutic targets in CNS disease. PMID- 29426701 TI - A Macrophage Colony-Stimulating-Factor-Producing gammadelta T Cell Subset Prevents Malarial Parasitemic Recurrence. AB - Despite evidence that gammadelta T cells play an important role during malaria, their precise role remains unclear. During murine malaria induced by Plasmodium chabaudi infection and in human P. falciparum infection, we found that gammadelta T cells expanded rapidly after resolution of acute parasitemia, in contrast to alphabeta T cells that expanded at the acute stage and then declined. Single-cell sequencing showed that TRAV15N-1 (Vdelta6.3) gammadelta T cells were clonally expanded in mice and had convergent complementarity-determining region 3 sequences. These gammadelta T cells expressed specific cytokines, M-CSF, CCL5, CCL3, which are known to act on myeloid cells, indicating that this gammadelta T cell subset might have distinct functions. Both gammadelta T cells and M-CSF were necessary for preventing parasitemic recurrence. These findings point to an M-CSF producing gammadelta T cell subset that fulfills a specialized protective role in the later stage of malaria infection when alphabeta T cells have declined. PMID- 29426704 TI - Handover in Intensive Care. AB - Handover is a frequent and complex task that also implies the transfer of the responsibility of the care. The deficiencies in this process are associated with important gaps in clinical safety and also in patient and professional dissatisfaction, as well as increasing health cost. Efforts to standardize this process have increased in recent years, appearing numerous mnemonic tools. Despite this, local are heterogeneous and the level of training in this area is low. The purpose of this review is to highlight the importance of IT while providing a methodological structure that favors effective IT in ICU, reducing the risk associated with this process. Specifically, this document refers to the handover that is established during shift changes or nursing shifts, during the transfer of patients to other diagnostic and therapeutic areas, and to discharge from the ICU. Emergency situations and the potential participation of patients and relatives are also considered. Formulas for measuring quality are finally proposed and potential improvements are mentioned especially in the field of training. PMID- 29426705 TI - Is a project needed to prevent urinary tract infection in patients admitted to spanish ICUs? AB - OBJECTIVE: To analyze epidemiological data of catheter-associated urinary tract infection (CAUTI) in critically ill patients admitted to Spanish ICUs in order to assess the need of implementing a nationwide intervention program to reduce these infections. DESIGN: Non-intervention retrospective annual period prevalence analysis. SETTING: Participating ICUs in the ENVIN-UCI multicenter registry between the years 2007-2016. PATIENTS: Critically ill patients admitted to the ICU with catheter-associated urinary tract infection (CAUTI). MAIN VARIABLES: Incidence rates per 1,000 catheter-days; urinary catheter utilization ratio; proportion of CAUTIs in relation to total health care-associated infections (HAIs). RESULTS: A total of 187,100 patients, 137,654 (73.6%) of whom had a urinary catheter in place during 1,215,673 days (84% of days of ICU stay) were included. In 4,539 (3.3%) patients with urinary catheter, 4,977 CAUTIs were diagnosed (3.6 episodes per 100 patients with urinary catheter). The CAUTI incidence rate showed a 19% decrease between 2007 and 2016 (4.69 to 3.8 episodes per 1,000 catheter-days), although a sustained urinary catheter utilization ratio was observed (0.84 [0.82-0.86]). The proportion of CAUTI increased from 23.3% to 31.9% of all HAIs controlled in the ICU. CONCLUSIONS: Although CAUTI rates have declined in recent years, these infections have become proportionally the first HAIs in the ICU. The urinary catheter utilization ratio remains high in Spanish ICUs. There is room for improvement, so that a CAUTI-ZERO project in our country could be useful. PMID- 29426706 TI - An update on bariatric tourism: time for a national registry? PMID- 29426707 TI - Comment on: Laparoscopic gastric bypass for the treatment of type 2 diabetes: a comparison of Roux-en-Y versus single anastomosis gastric bypass. PMID- 29426708 TI - New Perspectives in Equine Intestinal Parasitic Disease: Insights in Monitoring Helminth Infections. AB - Regular anthelmintic treatment has contributed to anthelmintic resistance in horse helminths. This mass anthelmintic treatment was originally developed owing to a lack of larvicidal drugs against Strongylus vulgaris. The high prevalence of anthelmintic resistance and shortening of strongyle egg reappearance period after avermectins/moxidectins requires epidemiologically appropriate and sustainable measures. Selective anthelmintic treatment is a much-needed deworming approach: More than 50% of adult horses manifest no strongyle egg excretion. In this article, selective anthelmintic treatment procedure is described, with the specific focus on the advantages of an evidence-based, medically appropriate, and sustainable treatment system that slows the development of anthelmintic resistance. PMID- 29426709 TI - Diagnosis and Treatment of Undifferentiated and Infectious Acute Diarrhea in the Adult Horse. AB - Acute, infectious, diarrhea in adult horses is a major cause of morbidity and is associated with numerous complications. Common causes include salmonellosis, clostridiosis, Coronavirus, and infection with Neorickettsia risticii (Potomac horse fever). Treatment is empirical and supportive until results of specific diagnostic tests are available. Supportive care is aimed at restoring hydration, correcting electrolyte imbalances, and limiting the systemic inflammatory response. The mainstays of therapy are intravenous fluid therapy, electrolyte supplementation where necessary, nonsteroidal anti-inflammatory agents, and nutritional support. Specific therapies include colloid oncotic support, antibiotics, hyperimmune plasma, polymyxin B, pentoxifylline, probiotics, binding agents, gastroprotectants, laminitis prevention, and coagulation prophylaxis. PMID- 29426710 TI - Diagnostics and Treatments in Chronic Diarrhea and Weight Loss in Horses. AB - Chronic diarrhea in the horse is defined as diarrhea present for more than several days with little if any improvement. The diagnosis and treatment of horses with chronic diarrhea usually present a great challenge to the clinician. There are many limitations to treatment of these patients given the limited numbers in which a final diagnosis can be achieved. The lack of knowledge of the alterations of horse microbiota during chronic diarrhea and the multiplicity of causes also make treatment challenging. A poor prognosis is often attached to chronic diarrhea, particularly in cases with neoplasia and inflammatory bowel disease. PMID- 29426711 TI - Enteral/Parenteral Nutrition in Foals and Adult Horses Practical Guidelines for the Practitioner. AB - Nutritional support is an important adjunct to medical therapy in the sick, injured, or debilitated equine patient. What is not clear is the optimal route, composition, or amounts of support. The enteral route should be chosen whenever possible to maximize the benefits to the gastrointestinal tract and the patient as a whole. Complete or partial parenteral nutrition is most useful as a bridge during recovery and transition to enteral feeding in the horse. The reader is encouraged to consider nutritional support whether enteral or parenteral in any anorexic, chronically debilitated, or sick equine patient. PMID- 29426712 TI - Getting Momentum: From Biocatalysis to Advanced Synthetic Biology. AB - Applied biocatalysis is driven by environmental and economic incentives for using enzymes in the synthesis of various pharmaceutical and industrially important chemicals. Protein engineering is used to tailor the properties of enzymes to catalyze desired chemical transformations, and some engineered enzymes now outperform the best chemocatalytic alternatives by orders of magnitude. Unfortunately, custom engineering of a robust biocatalyst is still a time consuming process, but an understanding of how enzyme function depends on amino acid sequence will speed up the process. This review demonstrates how recent advances in ultrahigh-throughput screening, mutational scanning, DNA synthesis, metagenomics, and machine learning will soon make it possible to model, predict, and manipulate the relationship between protein sequence and function, accelerating the tailor design of novel biocatalysts. PMID- 29426713 TI - Fast-Forwarding Genetic Gain. AB - 'Speed breeding' enables scientists to exploit gene bank accessions and mutant collections for an unparalleled rapid gene discovery and gene deployment. Combining speed breeding and other leading-edge plant breeding technologies with strategic global partnerships, has the potential to achieve the genetic gain targets required to deliver our future crops. PMID- 29426714 TI - Automated analysis and classification of melanocytic tumor on skin whole slide images. AB - This paper presents a computer-aided technique for automated analysis and classification of melanocytic tumor on skin whole slide biopsy images. The proposed technique consists of four main modules. First, skin epidermis and dermis regions are segmented by a multi-resolution framework. Next, epidermis analysis is performed, where a set of epidermis features reflecting nuclear morphologies and spatial distributions is computed. In parallel with epidermis analysis, dermis analysis is also performed, where dermal cell nuclei are segmented and a set of textural and cytological features are computed. Finally, the skin melanocytic image is classified into different categories such as melanoma, nevus or normal tissue by using a multi-class support vector machine (mSVM) with extracted epidermis and dermis features. Experimental results on 66 skin whole slide images indicate that the proposed technique achieves more than 95% classification accuracy, which suggests that the technique has the potential to be used for assisting pathologists on skin biopsy image analysis and classification. PMID- 29426715 TI - The first step of a long journey: Effect of induction regimen on prognosis among simultaneous heart-kidney transplant recipients. PMID- 29426716 TI - Utility of troponin assays for exclusion of acute cellular rejection after heart transplantation: A systematic review. AB - BACKGROUND: Acute cellular rejection (ACR) is a common complication in the first year after heart transplantation (HT). Routine surveillance for ACR is undertaken by endomyocardial biopsy (EMB). Measurement of cardiac troponins (cTn) in serum is an established diagnostic test of cardiac myocyte injury. This systematic review aimed to determine whether cTn measurement could be used to diagnose or exclude ACR. METHODS: PubMed, Google Scholar and the JHLT archive were searched for studies reporting the result of a cTn assay and a paired surveillance EMB. Significant ACR was defined as International Society for Heart and Lung Transplantataion (ISHLT) Grade >=3a/>=2R. Considerable heterogeneity between studies precluded quantitative meta-analysis. Individual study sensitivity and specificity data were examined and used to construct a pooled hierarchical summary receiver-operator characteristic (ROC) curve. RESULTS: Twelve studies including 993 patients and 3,803 EMBs, of which 3,729 were paired with cTn levels, had adequate data available for inclusion. The overall rate of significant ACR was 12%. There was wide variation in diagnostic performance. cTn assays demonstrated sensitivity of 8% to 100% and specificity of 13% to 88% for detection of ACR. The positive predictive value (PPV) was low but the negative predictive value (NPV) was relatively high (79% to 100%). High-sensitivity cTn assays had greater sensitivity and NPV than conventional cTn assays for detection of ACR (sensitivity: 82% to 100% vs 8% to 77%; NPV: 97% to 100% vs 81% to 95%, respectively). CONCLUSIONS: cTn assays do not have sufficient specificity to diagnose ACR in place of EMB. However, hs-cTn assays may have sufficient sensitivity and negative predictive value to exclude ACR and limit the need for surveillance EMB. Further research is required to assess this strategy. PMID- 29426717 TI - Dendritic core-shell silica spheres with large pore size for separation of biomolecules. AB - Monodispersed core-shell silica spheres with fibrous shell structure and tunable pore size were prepared by using a one-pot oil-water biphase method. The pore size could be tuned from 7 nm to 37 nm by using organic solvents with different polarities as oil phase. The spheres synthesized by using benzene as organic solvent had the maximum pore size of 37 nm and possessed a surface area of 61 m2 g-1. The obtained wide pore core-shell silica spheres were applied for rapidly separating small molecules, peptides, small proteins, and large proteins with molecular weight up to 200 kDa. Since the pore size of the core-shell silica spheres was sufficiently large for the free access of all the solutes, sharp and symmetric peaks were obtained. The separation performance was as high as 264,531 plates m-1 for fluorene. The great efficient separation demonstrates that the wide pore core-shell silica spheres have a great potential for rapid analysis of both small and large solutes with high performance liquid chromatography. PMID- 29426718 TI - Enantiomeric separations by capillary electrophoresis: Theoretical method to determine optimum chiral selector concentration. AB - A method to optimize the ligand concentration [S] in the background electrolyte of capillary electrophoresis separations is presented. It is based on the use of a model which predicts apparent electrophoretic mobilities as a function of ligand concentration (expressed as p[S] = -log[S]). This model is employed to compose the expression of a recently proposed criterion to qualify separations in electrophoresis. Two strategies to find the optimum p[S], leading to the best separation of all compounds, are explained: 1.- a graphical method using a windows map depicting the single separation criteria between all possible combination of compounds by pairs, and 2.- an analytical method where an extended multicriterion optimization function is composed and optimum p[S] is found by mathematical maximization. The procedure is applied to a hard-to-separate model system: enantiomeric separations of racemic mixtures. 2-Hydroxypropyl-beta cyclodextrin was chosen as a model ligand, and four pharmaceutical drugs as model analytes. In order to demonstrate the performance of the procedure, results of electrophoretic separations obtained at p[S] found as optimum are compared with separations obtained at p[S] values slightly higher and lower than the optimum. PMID- 29426719 TI - Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV associated Non-Hodgkin's Lymphoma (AMC-075). AB - INTRODUCTION: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). PATIENTS AND METHODS: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV+), 1 EBV+/HHV-8+ primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. RESULTS: The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%). CONCLUSION: VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL. PMID- 29426720 TI - Zero Tolerance for Sexual Harassment in Cardiology: Moving From #MeToo to #MeNeither. PMID- 29426721 TI - Waste-efficient materials procurement for construction projects: A structural equation modelling of critical success factors. AB - Albeit the understanding that construction waste is caused by activities ranging from all stages of project delivery process, research efforts have been concentrated on design and construction stages, while the possibility of reducing waste through materials procurement process is widely neglected. This study aims at exploring and confirming strategies for achieving waste-efficient materials procurement in construction activities. The study employs sequential exploratory mixed method approach as its methodological framework, using focus group discussion, statistical analysis and structural equation modelling. The study suggests that for materials procurement to enhance waste minimisation in construction projects, the procurement process would be characterised by four features. These include suppliers' commitment to low waste measures, low waste purchase management, effective materials delivery management and waste-efficient Bill of Quantity, all of which have significant impacts on waste minimisation. This implies that commitment of materials suppliers to such measures as take back scheme and flexibility in supplying small materials quantity, among others, are expected of materials procurement. While low waste purchase management stipulates the need for such measures as reduced packaging and consideration of pre assembled/pre-cut materials, efficient delivery management entails effective delivery and storage system as well as adequate protection of materials during the delivery process, among others. Waste-efficient specification and bill of quantity, on the other hand, requires accurate materials take-off and ordering of materials based on accurately prepared design documents and bill of quantity. Findings of this study could assist in understanding a set of measures that should be taken during materials procurement process, thereby corroborating waste management practices at other stages of project delivery process. PMID- 29426722 TI - Impact of heavy metals on hydrogen production from organic fraction of municipal solid waste using co-culture of Enterobacter aerogenes and E. Coli. AB - In the present study, the effect of heavy metals (lead, mercury, copper, and chromium) on the hydrogen production from the organic fraction of municipal solid waste (OFMSW) was investigated using co-culture of facultative anaerobes Enterobacter aerogenes and E. coli. Heavy metals were applied at concentration range of 0.5, 1, 2, 5, 10, 20, 50 and 100 mg/L. The results revealed that lead, mercury, and chromium negatively affected hydrogen production for the range of concentrations applied. Application of copper slightly enhanced hydrogen production at low concentration and resulted in the hydrogen yield of 36.0 mLH2/gCarboinitial with 10 mg/L copper supplementation as compared to 24.2 mLH2/gCarboinitial in control. However, the higher concentration of copper (>10 mg/L) declined hydrogen production. Hydrogen production inhibition potential of heavy metals can be arranged in the following increasing order: Cu2+ < Cr6+ < Pb2+ < Hg2+. COD removal rate and volatile fatty acid generation efficiencies were also significantly affected by heavy metal addition. Thus, the present study reveals that the presence of heavy metals in the feedstock is detrimental for the hydrogen production. Therefore, it is essential to remove the toxic heavy metals prior to anaerobic digestion. PMID- 29426723 TI - Topical therapy for refractory rhinosinusitis caused by methicillin-resistant Staphylococcus aureus: First report in a prospective series. AB - OBJECTIVE: The incidence of refractory chronic rhinosinusitis (CRS) associated with methicillin-resistant Staphylococcus aureus (MRSA) is rising and remains a therapeutic challenge. The goal of this study is to demonstrate the efficacy of a non-invasive topical therapy against MRSA in these patients. METHODS: Seventeen patients with refractory CRS caused by MRSA were treated with a topical therapy protocol. Treatment consisted of weekly endoscopic sinus debridement followed by intra-sinus installation of a hydroxyl-ethylcellulose gel that releases mometasone and a culture-directed antibiotic for a period of 6 weeks, along with daily nasal nebulization of mometasone with the same antibiotic and saline rinses. Clinical outcome was assessed using the Lund-Kennedy (LK) symptom and endoscopic appearance scores. Sinus mucosal tissue was homogenized and cultured, and microbial biofilm burden was assessed based on colony forming units (CFUs) counts. RESULTS: Rhinotopic therapy resulted in clearance of MRSA in 13 of 16 patients (81.2%). Treated patients also demonstrated significant improvement clinically as measured by the LK scores. In addition, a significant decrease in mucosal CFUs was observed post-therapy. CONCLUSION: Our findings demonstrate that topical therapy is an effective method for treating MRSA-associated refractory CRS. PMID- 29426724 TI - Factors affecting the outcome of adenoidectomy in children treated for chronic otitis media with effusion. AB - OBJECTIVE: The aim of this cohort was to determine potential risk factors, concerning the effectiveness of adenoidectomy in the treatment of chronic otitis media with effusion in children. METHODS: Ninety six children with chronic otitis media with effusion treated with adenoidectomy were enrolled in this study. A thorough medical history was taken, including family history of otologic disease, parental smoking habits and breast feeding history. Radiographic palatal airway size was measured preoperatively, whereas the presence of allergy was also investigated. All patients were, postoperatively, followed up for a period of two years, in three month intervals. Disease course was classified as "complete remission", "improvement" or "consistence", in every postoperative evaluation, according to strictly established criteria. RESULTS: Children's age proved to be a significant factor in the postoperative outcome of adenoidectomy, as a treatment of chronic otitis media with effusion, especially when comparing patients being over and under the fifth year of age. Also, the presence of allergy, family history of otologic disease and palatal airway size, all proved to influence postoperative outcome in a statistical significant way (p<0.05). On the other hand, child's sex, passive smoking, breast feeding and previous acute otitis media infections did not seem to alter the efficacy of adenoidectomy. CONCLUSION: Adenoidectomy remains a cornerstone in the treatment of chronic otitis media with effusion in children. Results document that young age, presence of allergy predisposition, otologic family history and small palatal airway can be important drawbacks and should be intensively sought for and taken into account, during treatment planning. PMID- 29426725 TI - Corrigendum to "Tailoring surface nanoroughness of electrospun scaffolds for skeletal tissue engineering" Acta Biomater. 59 (2017) 82-93. PMID- 29426726 TI - Jimmie C. Holland, M.D. PMID- 29426727 TI - Setting the stage for individualized therapy in hemophilia: What role can pharmacokinetics play? AB - Replacement therapy with clotting factor concentrates (CFC) is the mainstay of treatment in hemophilia. Its widespread application has led to a dramatic decrease in morbidity and mortality in patients, with concomitant improvement of quality of life. However, dosing is challenging and costs are high. This review discusses benefits and limitations of pharmacokinetic (PK)-guided dosing of replacement therapy as an alternative for current dosing regimens. Dosing of CFC is now primarily based on body weight and based on its in vivo recovery (IVR). Benefits of PK-guided dosing include individualization of treatment with better targeting, more flexible blood sampling, increased insight into association of coagulation factor levels and bleeding, and potential overall lowering of overall costs. Limitations include a slight burden for the patient, and availability of closely collaborating, experienced clinical pharmacologists. PMID- 29426728 TI - Outcomes of an Adolescent School-Based Health Initiative Needs Assessment. AB - Adolescent School-Based Health Initiatives (ASBHIs) are designed to increase adolescent access to medical homes and services that are not otherwise available without significant barriers. ASBHIs have been proven to increase access to care for school-aged adolescents with unique needs and limited access to these much needed medical services. For this descriptive study we conducted a needs assessment to understand and determine the needs and desires for a school-based health initiative in a middle school in the community. Survey topics included demographics, health care needs, and desired health resources. Most teachers (94%) and parents (83%) indicated that they would encourage their student/child to participate in an ASBHI program, and 57% of students reported that they would use an ASBHI program. Both parents (71%) and teachers (94%) indicated that student attendance would improve with an Adolescent School-Based Health Initiative. There is sufficient evidence for the need and utilization of an ASBHI program in this community. PMID- 29426729 TI - Parental Perspectives of the Impact of Epilepsy and Seizures on Siblings of Children with Epilepsy. AB - INTRODUCTION: To assess parental perspectives of the impact of epilepsy and seizures on siblings of children in the Seizures and Outcomes Study. METHODS: Parents completed surveys about their child with epilepsy, their own health and well-being, and the impact of epilepsy on unaffected siblings. RESULTS: The most common parental responses about the sibling were witnessing a seizure, protectiveness of the child with epilepsy, worry about seizures, belief that seizures cause pain, and pride toward the child with epilepsy. Embarrassment and keeping epilepsy a secret were rare. Parent reports supported that siblings that worried were more likely to have witnessed a seizure, feel sad or angry, think seizures cause pain, and have a parent with anxiety disorder. DISCUSSION: Some siblings of children with epilepsy are at risk for psychosocial problems. Primary and specialty care providers are well positioned to identify and monitor these children through evaluations and referrals as necessary. PMID- 29426731 TI - Corrections. PMID- 29426730 TI - The relationship between surrounding greenness in childhood and adolescence and depressive symptoms in adolescence and early adulthood. AB - PURPOSE: Exposure to nature, particularly vegetation (greenness), may be beneficial for mental health. We investigated whether higher surrounding greenness in early life was associated with subsequent reduced risk of depressive symptoms and whether this association was modified by age, sex, or population density. METHODS: Participants from the Growing Up Today Study were included if they reported on depressive symptoms between 1999 and 2013. Greenness exposure was characterized as the cumulative average normalized difference vegetation index value (1000 m resolution) from 1989 until 2 years before outcome assessment or age 18 based on geocoded addresses. We defined high depressive symptoms as the top 10% of scores on the McKnight Risk Factor Survey or the Center for Epidemiologic Studies of Depression scale, depending on the questionnaire. Data were analyzed using Cox proportional hazards model adjusted for socioeconomic status and other confounders. RESULTS: There was a 6% lower incidence of high depressive symptoms associated with an interquartile range increase in greenness (95% confidence interval, 11%-0%). This relationship was stronger in higher population density areas (>1000 people/mi2, 8% lower incidence, 95% confidence interval 15%-1%). CONCLUSIONS: Living in an area with greater surrounding greenness during childhood may be beneficial for mental health, particularly in more urban areas. PMID- 29426732 TI - Predictive value of Modic type II changes in the choice of surgical treatment of lumbar disc herniation. AB - OBJECTIVE: To evaluate the predictive value of Modic typeII changes on nuclear magnetic resonance (NMR) prior to intervention by discectomy for lumbar disc herniation in patients with radicular symptoms. MATERIAL AND METHOD: Retrospective descriptive study of 190 patients (58.2% men and 41.8% women) with a mean age of 43.5 years, treated between December 2005 and January 2013. They were divided into group 1, single disc herniation (n=85), and group 2, with disc herniation and changes Modic typeII (n=80). Variables studied: weight, height, handedness, level of injury, previous neurological deficit, postoperative complications, persistent pain and need for posterior lumbar fusion, with a mean of 67 months (group 1: 68.1; group 2: 66.8). RESULTS: In group 1 there were four hernia recurrences requiring revision surgery and six patients needed lumbar fusion. In group 2, four recurrences were also revised and eight cases requiring arthrodesis were observed. No statistically significant differences were found when comparing the occurrence of relapse (P=.903), the need for subsequent fusion (P=.572) or in the remaining variables. DISCUSSION: The data obtained and the characteristics of our study, we cannot say that Modic typeII changes were a predictive sign of the result of lumbar discectomy in our study population. PMID- 29426733 TI - Response to comment: Eustachian tube diameter: Is it associated with chronic otitis media development? PMID- 29426734 TI - Inclusion body myositis and human immunodeficiency virus type 1: A new case report and literature review. AB - Prevalence of muscle disease in human immunodeficiency virus (HIV) infection is less than 1% of patients with acquired immune deficiency syndrome. Sporadic inclusion body myositis (IBM) is observed in a few cases of patients infected by retroviruses such as HIV-1. A Caucasian man was diagnosed with HIV when he was 30 years old. The viral load was undetectable and CD4 cell count was 600/mm3 when the diagnosis of inclusion body myositis was confirmed. Histological findings were typical of IBM. The treatment consisted of immunoglobulin therapy for three years without effect. Twenty-two patients were found in the English and French literature. They are younger than those who suffer from IBM without HIV (median age = 47, range: 30 to 59), and they are mostly men with considerable serum creatine kinase (CK) elevation (median CK level = 1322 IU/L, range: 465 to 10270), most of them were treated with Zidovudine. PMID- 29426735 TI - Editorial Comment. PMID- 29426736 TI - Author Reply. PMID- 29426737 TI - [Demodex genus: colonizing parasites of healthy people or mites associated with ocular pathology?] AB - Demodex folliculorum and Demodex brevis are mites that are responsible for human demodicosis affecting skin and frequently linked to ocular diseasess. The aim of this work was to determine the association between Demodex sp. and eyelid and eyelash diseases and to establish the predisposing factors for acquiring this parasitic disease. Eyelashes from symptomatic and asymptomatic patients (n=72) between 9 and 82 years old were analyzed, where 53% were positive for Demodex sp., of which 66% manifested ocular symptoms and pathologies, blepharitis and dry eye being prevalent. Significant correlations between Demodex and patients over 60 years of age (p<0.001) and between Demodex sp. and dry eye patients / blepharitis (p<0.001) were observed. We consider that it is necessary to search for Demodex sp. especially in those patients suffering from dry eye and blepharitis and/or during immunosenescence in order to implement specific antiparasitic treatments. PMID- 29426738 TI - Long-term success of dental implants in patients with head and neck cancer after radiation therapy. AB - The purpose of this study was to analyze the long-term success and factors potentially influencing the success of dental implants placed in patients with head and neck cancer who underwent radiation therapy with a minimum total dose of 50Gy during the years 1995-2010. Thirty-five patients (169 dental implants) were included in this study. Data on demographic characteristics, tumour type, radiation therapy, implant sites, implant dimensions, and hyperbaric oxygen therapy (HBOT) were obtained from the medical records and analyzed. Implant survival was estimated using Kaplan-Meier survival curves. Seventy-nine dental implants were placed in the maxilla and 90 in the mandible. The mean follow-up after implant installation was 7.4 years (range 0.3-14.7 years). The overall 5 year survival rate for all implants was 92.9%. Sex (P<0.001) and the mode of radiation therapy delivery (P=0.005) had a statistically significant influence on implant survival. Age, time of implantation after irradiation, implant brand and dimensions, and HBOT had no statistically significant influence on implant survival. Osseointegrated dental implants can be used successfully in the oral rehabilitation of patients with head and neck cancer with a history of radiation therapy. Risk factors such as sex and the mode of radiation therapy delivery can affect implant survival. PMID- 29426739 TI - Patient satisfaction and oral health-related quality of life 10-15 years after orthodontic-surgical treatment of mandibular prognathism. AB - This study investigated 36 patients at 10-15 years after they had undergone mandibular setback surgery by intraoral vertical ramus osteotomy (IVRO) and subsequent intermaxillary fixation for 6 weeks. The patients completed a 37-item structured questionnaire to evaluate patient satisfaction and possible long-term effects of the treatment. Visual analogue scales were used to measure self perceived changes in seven items concerning oral function and appearance. Oral health-related quality of life was assessed using the Oral Impacts on Daily Performance (OIDP) index. The main reasons for seeking treatment were to improve chewing function and appearance. The treatment had resulted in significant improvements regarding chewing function, appearance, bullying, and self confidence in social settings (all P<0.05). All patients were either very satisfied (61%) or reasonably satisfied (39%) with the treatment result. The mean OIDP frequency score was 8.49 on a scale from 8 to 40. Seventy-four percent of the patients reported no oral impacts on quality of life. In conclusion, 10-15 years after combined orthodontic and IVRO surgical treatment of mandibular prognathism, the patients were satisfied, and oral health-related quality of life was reported to be good. PMID- 29426740 TI - [Evaluation of the feasibility of a program of adapted physical activity in day hospital of digestive oncology: From the point of view of patients]. AB - INTRODUCTION: Adapted physical activity (APA) is recognized as an effective supportive care for asthenia and quality of life in oncology. Before an APA program was organized, the feasibility of such a program was evaluated among the patients. METHODS: Descriptive, prospective, semi-qualitative, single-center study over a 3-month period in patients treated with ambulatory chemotherapy for digestive cancer. A self-questionnaire was offered to all patients to evaluate their practice and knowledge about APA. In ten patients, fatigue, anxiety and depression were assessed, before and after 9 weeks of hospital-based APA. The scores were compared by matched Student test. RESULTS: Of the 123 patients treated, 80 questionnaires (65%) were exploitable. Before the diagnosis of cancer, 40 patients (50%) were physically active, 20% after (n=16). The reasons for not practicing were: lack of interest/not the idea (42%), lack of time (34%), do not believe in profit (9%), too expensive (8%). Fifty-three patients (66%) were interested in the program. In 10 patients, the APA program significantly reduced the depression score (P=0.024) and a non-significant improvement in anxiety and fatigue. DISCUSSION: This study shows that patients treated with chemotherapy are unaware of the usefulness of APA and that medical information can improve adherence to such a program. The establishment of an intra-hospital APA program proved to be possible and relevant. PMID- 29426741 TI - Lower shoulder abduction during throwing motion may cause forceful internal impingement and decreased anterior stability. AB - BACKGROUND: Internal impingement and decreased anterior stability, which result from shoulder capsular loosening, are common shoulder pathologies in throwing athletes. The purpose of this study was to assess the effect of shoulder abduction angle on shoulder internal impingement and anterior shoulder stability during the simulated throwing motion. METHODS: Eight cadaveric shoulders were tested by simulating the late-cocking and acceleration phases of the throwing motion for intact and thrower's shoulder conditions. The maximal glenohumeral external rotation, anterior translation, location of the rotator cuff insertion with respect to the glenoid, length and site of internal impingement, and glenohumeral contact pressure were measured. All data were compared between shoulder abduction angles of 80 degrees , 90 degrees , and 100 degrees . RESULTS: Decreasing shoulder abduction in the simulated late-cocking phase shifted the humeral head posteriorly (P < .03) and superiorly (P < .001), decreasing the total internal impingement area between the greater tuberosity and glenoid (P = .04) and increasing the glenohumeral contact pressure during internal impingement (P = .02). In the simulated acceleration phase, anterior glenohumeral translation significantly increased as the shoulder abduction angle decreased (P < .001). CONCLUSION: Decreasing shoulder abduction significantly increased the contact pressure during internal impingement in the simulated late-cocking phase of the throwing motion. During the simulated acceleration phase of the throwing motion, anterior glenohumeral translation significantly increased as shoulder abduction decreased. PMID- 29426742 TI - Sequential 3-dimensional computed tomography analysis of implant position following total shoulder arthroplasty. AB - BACKGROUND: Detection of postoperative component position and implant shift following total shoulder arthroplasty (TSA) can be challenging using routine imaging. The purpose of this study was to evaluate glenoid component position over time using 3-dimensional computed tomography (CT) analysis with minimum 2 year follow-up. METHODS: Twenty patients underwent primary TSA with sequential CT scanning of the shoulder: a preoperative study, an immediate postoperative study within 2 weeks of surgery, and a postoperative study performed at minimum 2-year follow-up (CT3). Postoperative glenoid component position and central peg osteolysis were assessed across the immediate postoperative CT scan and CT3. Glenoids with evidence of component shift and/or grade 1 central peg osteolysis on CT3 were considered at risk of loosening. RESULTS: Of the patients, 7 (35%) showed evidence of glenoid components at risk of loosening on CT3, 6 with component shift (3 with increased inclination alone, 1 with increased retroversion alone, and 2 with both increased inclination and retroversion). Significantly more patients with glenoid component shift had grade 1 central peg osteolysis on CT3 compared with those without shift (83% vs 7%, P = .002). One clinical failure occurred, with the patient undergoing revision to reverse TSA for rotator cuff deficiency. CONCLUSIONS: Three-dimensional CT imaging analysis following TSA identified changes in glenoid component position over time, with inclination being the most common direction of shift and grade 1 central peg osteolysis commonly associated with shift. These findings raise concern for glenoids at risk of loosening, but further follow-up is needed to determine the long-term clinical impact of these findings. PMID- 29426743 TI - Bridging multimodal pain management provides 48-hour pain control in patients undergoing total shoulder replacement. AB - BACKGROUND: We report our experience with a bridging multimodal pain management program that provides comprehensive 48-hour pain control in patients undergoing total shoulder replacement (TSR). METHODS: The study included all patients undergoing unilateral TSR by 1 surgeon between May 2015 and April 2017. There were 62 patients (23 men, 39 women) with an average age of 68 years (range 38-92 years). Of these, 31 underwent standard nonconstrained TSR and 31 underwent reverse TSR. The bridging multimodal pain management protocol included scalene block regional anesthesia using 0.25% bupivacaine enhanced with 4 mg of dexamethasone, application of 20 mg of liposomal bupivacaine diluted with 40 mL of normal saline in the periarticular soft tissues at time of closure, scheduled 24 hours of intravenous acetaminophen and ketorolac, and immediate cryotherapy. Parameters measured included hospital length of stay, postoperative use of intravenous narcotics, and 30-day hospital readmission. RESULTS: The median length of stay was 1 day (range, 1-6; average, 1.5 days). Overall, 41 patients (66%) were discharged on postoperative day 1. Intravenous narcotics were required postoperatively in 22 patients (35.5%). There were no 30-day readmissions. CONCLUSION: This bridging multimodal pain management protocol resulted in a length of stay of 1 day for 66% of patients, even for higher-risk patients with American Society of Anesthesiologists Physical Status Classification III (63%). Of the 62 patients, 64% (n = 40) did not require postoperative intravenous narcotics. For properly selected patients, this program may be considered for performing TSR as an ambulatory procedure. PMID- 29426744 TI - Improving dose delivery by adding interstitial catheters to fixed geometry applicators in high-dose-rate brachytherapy for cervical cancer. AB - PURPOSE: Image-guided brachytherapy (IGBT) is an essential component of the treatment of locally advanced cervical cancer. Interstitial (IS) catheters are being increasingly used for bulkier tumors. We have retrospectively assessed the dosimetric impact of IS catheters. METHODS AND MATERIALS: All patients who received IGBT for cervical cancer between August 2014 and February 2017 were identified. Clinical and dosimetric data were collected. Patients were grouped into the intracavitary (IC) cohort or the IC and IS implant (IC/IS) cohort. Ten patients who had been treated with IS catheters (IC/IS plan) had their brachytherapy replanned without IS catheters (IC plan). The total D90% received by the high-risk clinical target volume (CTVHR) and the D2cm3 (minimum dose received by the most irradiated 2 cm3) to the bladder, bowel, sigmoid, and rectum were compared. RESULTS: Forty-two patients received IGBT in this period. Seventy four percent of patients were treated with IS catheters. Sixty-one percent of patients in the IC/IS cohort had CTVHR volumes >=30 cm3 at Fraction 1 compared to 18% in the IC cohort (p = 0.014). There was no difference in cumulative D90% to CTVHR between the IC/IS cohort and the IC cohort. The replanned brachytherapy showed that the cumulative CTVHRD90% was on average 5.8 Gy higher when IS catheters were used (mean CTVHRD90% 86.1 compared to 80.3 Gy, p < 0.001). The D2cm3 to the organs at risk was not significantly increased. CONCLUSIONS: IS catheters allow the dose to the CTVHR to be escalated significantly without increasing the dose to the bladder, bowel, sigmoid, and rectum in patients with bulky tumors. PMID- 29426745 TI - Single-institutional outcomes of adjuvant brachytherapy for Stage I endometrial cancer-Are outcomes consistent with randomized studies? AB - PURPOSE: Vaginal brachytherapy (VBT) alone has been shown to be a viable adjuvant treatment strategy for most patients with Stage I endometrioid endometrial cancer. We sought to examine our institutional data following practice pattern changes resulting from the publications of GOG-99 and PORTEC-2. METHODS AND MATERIALS: We retrospectively analyzed women who underwent adjuvant VBT after surgical staging for Stage 1 endometrioid endometrial cancer at our institution from 2007 to 2014. RESULTS: We identified 297 women. Median time to last followup or death was 52.3 months (interquartile range: 32.3-72.3 months). By International Federation of Gynecology and Obstetrics 2009 staging, 162 patients (54.5%) had Stage IA and 128 (43.1%) had Stage IB disease. Ninety-nine (33.3%) patients had Grade 1, 153 (51.5%) had Grade 2, and 45 (15.2%) had Grade 3 disease. According to GOG-249 and PORTEC-2 criteria, 167 (56.2%) and 127 (42.7%) patients were with high-intermediate-risk disease. Two women had Stage IB Grade 3 disease. The most common high-dose-rate-VBT regimen was 2100 cGy/three fractions to a depth of 5 mm. Four (two acute and two late) (1.3%) Grade 3 genitourinary toxicities were reported: three episodes of vaginal dehiscence (after second course of VBT, 2 months after completion of VBT, and 1 year after completion of VBT) and one episode of radiation necrosis. Twenty-one (7%) women recurred: three recurred in the vagina, two recurred in the pelvic lymph nodes, and 16 recurred distantly. CONCLUSIONS: Outcomes appear consistent with published randomized data in women with high-intermediate-risk endometrial cancer who are treated with brachytherapy alone. Recurrence and complication rates were minimal. PMID- 29426746 TI - Image-guided adaptive brachytherapy in primary vaginal cancers: A monocentric experience. AB - PURPOSE: Primary vaginal cancer is a rare disease for which treatment has been modeled based on cervical cancer. We report our experience in the use of image guided adaptive brachytherapy (IGABT) in this indication. METHODS AND MATERIALS: Patients treated for vaginal cancer with a combination of external beam radiation therapy and IGABT were identified through electronic search. The Groupe Europeen de Curietherapie-European Society for Radiotherapy and Oncology recommendations for cervical cancer have been extrapolated with the definition of two clinical target volumes (CTVs) corresponding to the residual disease after external beam radiation therapy (CTVBT), assessed from clinical and imaging findings, and the so-called CTVi, comprising the CTVBT with directional margins and at least the initial disease at diagnosis. RESULTS: Twenty-seven patients were identified. MRI was used for brachytherapy guidance in 82% of the cases. An interstitial component was used in 59% of the cases. The D90 CTVBT and D90 CTVi were 73.1 +/- 12.8 Gy and 66.6 +/- 6.7 Gy, respectively. After a median followup of 40.1 months, nine recurrences in 8 patients were observed of which four were local. Local relapses occurred within the CTVBT. Three-year local control and disease free rates were 82% and 65%, respectively. At 2 years, the Grade 2-4 gastrointestinal or urinary morbidity accrual rate was 9%. Twelve patients experienced late sexual morbidity, including three patients with Grade 3 stenosis. CONCLUSION: IGABT is feasible in vaginal cancer with promising outcomes. Harmonizing the definition of CTVs is required to allow comparisons between experiences and to perform multicenter studies. PMID- 29426747 TI - Comment on: "Comparison of new adiposity indices for the prediction of body fat in hospitalized patients". PMID- 29426748 TI - Trends in cardiovascular risk factor management in type 1 diabetes by sex. AB - AIMS: DCCT showed that intensive type 1 diabetes management reduces complication incidence but did not focus on other cardiovascular disease risk factors, whose control in type 1 diabetes has not been well-studied. We assessed trends in cardiovascular risk factors in type 1 diabetes and attainment of concurrent American Diabetes Association (ADA) guidelines/recommendations (for HbA1c, blood pressure, LDL cholesterol, triglycerides) for complication prevention. METHODS: Individuals with childhood-onset type 1 diabetes (n = 658; 49.4% women; baseline (1986-1988) median age 27 and duration 19 years) were followed biennially for up to 25 years, with surveys and/or examinations. RESULTS: At the latest recorded follow-up, achievement of concurrent ADA recommendations increased for HbA1c (from 9.7 to 25.6%, p < .0001); was unchanged for blood pressure (from 89.7% to 87.4%, p = .36); and decreased for LDL cholesterol (from 62.3 to 39.7%, p < .0001). Adoption of intensive insulin therapy (from 5.9 to 64.4%, p < .0001) and hypercholesterolemia (from 67.3 to 78.9%, p = .0006) also increased. Overall, the proportion meeting all four recommendations was essentially unaltered (from 6.8% to 7.6%) (p = .69). Results were similar by gender. CONCLUSIONS: Although the adoption of intensive insulin therapy and obtaining ADA HbA1c recommendations are increasing, overall cardiovascular risk factor compliance remains low and merits further intervention. PMID- 29426749 TI - Identifying criteria for diagnosis of post-traumatic pain and altered sensation of the maxillary and mandibular branches of the trigeminal nerve: a systematic review. AB - OBJECTIVE: The aim of the study was to systematically identify criteria used to diagnose patients with trigeminal nerve injury. STUDY DESIGN: A systematic review of the literature registered in the PROSPERO database. Inclusion criteria were patients diagnosed with nerve injury of the sensory divisions of the maxillary or mandibular branches of the trigeminal nerve, with reported tests and criteria used for diagnosis and persistent pain or unpleasant sensation associated with nerve injury. RESULTS: In total, 28 articles were included. Diagnostic tests included clinical neurosensory tests (89%), thermal quantitative sensory testing (QST; 25%), electromyography (7%), and patient interview (14%). Neuropathic pain was assessed by using the visual analogue scale (39%); patient use of neuropathic medication (7%); questionnaires, including McGill and PainDETECT (21%). Functional impact was assessed in 14% and psychological impact in 7% of articles. Methodology in performing clinical neurosensory tests, application of diagnostic terms and diagnostic grading of nerve injury was found to be inconsistent among the included articles, making direct comparison of results difficult. CONCLUSIONS: Recommendations for assessment and diagnosis of trigeminal nerve injury have been made based on the best available evidence from the review. There is an urgent requirement for a consensus in diagnostic criteria, criteria for assessment, and outcome reporting among stakeholder organizations to improve knowledge in this field. PMID- 29426750 TI - Smell loss is associated with severe and uncontrolled disease in children and adolescents with persistent allergic rhinitis. PMID- 29426752 TI - Increased Dose and Duration of Statin Use Is Associated with Decreased Asthma Related Emergency Department Visits and Hospitalizations. AB - BACKGROUND: Statins have pleiotropic anti-inflammatory and immunomodulatory effects, yet the effect of statin use on asthma-related emergency department (ED) visits and hospitalizations has remained unclear, especially in Asian populations. OBJECTIVE: We sought to examine the effect of statin therapy on asthma-related ED visits and/or hospitalizations. METHODS: A cohort study was conducted using data from Taiwan's National Health Insurance Research Database from 2001 to 2013. A total of 117,595 adult patients with asthma were included. The outcomes were defined as asthma-related ED visits and/or hospitalizations. Multiple Cox proportional hazards models were applied to determine the effect of statin use on asthma-related ED visits and/or hospitalizations. RESULTS: There were 3,417 asthma-related ED visits and/or hospitalizations among 117,595 subjects with asthma. Statin users were significantly less likely to experience asthma-related ED visits and/or hospitalizations (adjusted hazard ratio: 0.81; 95% confidence interval: 0.74-0.89) compared with nonstatin users. The risks of asthma-related ED visits and/or hospitalizations were decreased among those with a higher cumulative defined daily dose (DDD), greater average DDD, and longer cumulative-day users than the counterparts. CONCLUSIONS: Our study suggests that statin use is associated with the decreased risk of asthma-related ED visits and/or hospitalizations in patients with asthma. A dose-response effect of statin use is also observed in this study. Therefore, future randomized clinical trials would be warranted to further evaluate the association. PMID- 29426751 TI - The Dietary Inflammatory Index and Current Wheeze Among Children and Adults in the United States. AB - BACKGROUND: A proinflammatory diet may increase allergic airway inflammation by affecting innate and adaptive immune responses. OBJECTIVE: In this study, we examine the relation between the diet's inflammatory potential, measured by the Dietary Inflammatory Index (DII), and current asthma, current wheeze, and lung function in U.S. children and adults. METHODS: We analyzed data from 8,175 children (aged 6-17 years) and 22,294 adults (aged 18-79 years) who participated in the 2007-2012 National Health and Nutrition Examination Survey. The DII was calculated by nutrient intake based on 24-hour dietary recalls, and normalized as per 1,000 calories of food consumed to account for total energy intake. Multivariable regression models were used for the analysis of the DII and current asthma, current wheeze, and lung function measures. RESULTS: Higher DII (a proinflammatory diet) was associated with current wheeze among adults (eg, odds ratio [OR] for quartile 4 vs 1, OR = 1.41, 95% confidence interval [CI] = 1.17 1.70; Ptrend < .01) and among children with high fractional exhaled nitric oxide (a marker of eosinophilic airway inflammation; OR = 2.38, 95% CI = 1.13-5.02; Ptrend = .05). The DII also was associated with decreased forced expiratory volume in 1 second and forced vital capacity in adults without asthma or wheezing. The DII was not associated with lung function in children or current asthma in either age group. CONCLUSIONS: Our findings suggest that a proinflammatory diet, assessed by the DII, increases the odds of current wheeze in adults and children with allergic (atopic) wheeze. These results further support testing dietary interventions as part of the management of asthma. PMID- 29426753 TI - A favorable response to omalizumab in a patient with cheilitis granulomatosa. PMID- 29426754 TI - Chronic inducible urticarias in children. PMID- 29426756 TI - Uncertainty about the accuracy of extraoral bite-wing radiography for detecting proximal caries and marginal bone loss owing to study limitations. PMID- 29426755 TI - Immune modulation in a patient with Morquio syndrome treated with enzyme replacement therapy. PMID- 29426757 TI - Uncertainty about the relative effects of upright versus supine positions for inferior alveolar nerve block. PMID- 29426758 TI - Very low certainty in evidence suggesting benefits of nonpharmacologic interventions for reducing mental distress in adults undergoing dental treatment. PMID- 29426759 TI - Insufficient evidence available to reliably conclude how orthodontic treatment with lingual fixed appliances compares with orthodontic treatment with labial fixed appliances. PMID- 29426760 TI - [Erratum to "A 'fast track' to improve management of neovascular age related macular degeneration"]. PMID- 29426761 TI - Ocular manifestations of Zika virus: What we should know and what we should do. Response. PMID- 29426762 TI - [Phthiriasis palpebrarum in a 52-year-old woman]. PMID- 29426763 TI - [Toric lens implantation in cataract surgery: Automatic versus manual horizontal axis marking, analysis of 50 cases]. AB - SUBJECT: The main objective of our study is to evaluate the contribution of automated conjunctival recognition in the alignment of toric implants by comparing the automatic alignment optimized with CallistoTM to the manual marking of the horizontal axis. MATERIALS AND METHODS: We performed a prospective, descriptive, and monocentric study on patients undergoing cataract surgery with toric implantation (Asphina 709 Zeiss), operated by a surgeon with good experience in toricity, between September 2016 and March 2017. We analyzed the agreement between the manual marking of the 0 degrees -180 degrees axis versus the one automatically generated by the CallistoTM, as well as the alignment of the IOL and the refractive results at 1 month. RESULTS: We included 50 eyes of 26 patients. The corrected mean astigmatism was 1.9 D. The mean difference between the 2 axes was 4.7 degrees [0 degrees -12.3 degrees ]. Only 50 % of the preoperative manual markings were consistent with the automatic measurement (<5 degrees ). At one month, the average rotation recorded was 4.3 degrees [0 degrees -29 degrees ]. The alignment was identical for 70 % (n=35) of the IOL (<=5 degrees ). As for residual subjective astigmatism, it was on average 0.58 D. The mean visual acuity without correction was 8/10 and 55 % had 10/10 without correction. DISCUSSION: The refractive performance depends on the preoperative measurement, the correct alignment of the IOL and its stability in the bag. Our study shows the value of automatic conjunctival recognition in the determination of the axis of peroperative alignment, even in an experienced operator. This precision is essential for a good refractive result, especially since the residual astigmatism in case of misalignment will increase with the power of the implant. CONCLUSION: Our study shows excellent refractive results, whatever the initial astigmatism, using the automatic alignment. The precision of the toric implantation opens the way to the toric multifocal implantation under the best conditions. PMID- 29426764 TI - [Situs inversus of the optic disc with a "comet" appearance]. PMID- 29426765 TI - Women's perceptions of dense breast notifications in a Massachusetts safety net hospital: "So what is that supposed to mean?" AB - OBJECTIVE: Currently, 30 US states mandate that radiologists notify women when dense breast tissue is found on mammography. Little is understood about how notifications are perceived by recipients. This qualitative study sought to understand how dense breast notifications (DBNs) impact women's perceptions and their participation in follow-up care. METHODS: We assessed rates of DBN recall and conducted semi-structured telephone interviews with 30 English-speaking women ages 40 to 74 after receiving a DBN from a Massachusetts hospital. Content coding characterized women's recall of the notification content, perceptions of breast density, and planned or actual participation in follow-up care. RESULTS: Most women (81%) recalled receiving a DBN, but few could recall specific content. Women described struggling to understand the meaning of breast density and created their own explanatory models of dense breasts that differed from medical explanations. Many women planned to or did talk with their doctors about breast density as a result of receiving the notification. CONCLUSIONS: Women receiving DBNs have limited knowledge and many misperceptions about the implications of having dense breasts. PRACTICE IMPLICATIONS: Educational support is needed to promote informed decision- making about breast cancer screening that incorporates personal risk in the setting of dense breast legislation. PMID- 29426766 TI - Sequential analyses of actinides in large-size soil and sediment samples with total sample dissolution. AB - There is a growing demand for the determination of actinides in soil and sediment samples for environmental monitoring and tracing, radiological protection, and nuclear forensic reasons. A total sample dissolution method based on lithium metaborate fusion, followed by sequential column chromatography separation, was developed for simultaneous determination of Pu, Am and Cm isotopes in large-size environmental samples by alpha spectrometry and mass spectrometric techniques. The overall recoveries of both Pu and Am for the entire procedure were higher than 70% for large-size soil samples. The method was validated using 20 g of soil samples spiked with known amounts of 239Pu and 241Am as well as the certified reference materials IAEA-384 (Fangataufa Lagoon sediment) and IAEA-385 (Irish Sea sediment). All the measured results agreed very well with the expected values. PMID- 29426767 TI - Full-thickness rectal biopsy in children suspicious for Hirschsprung's disease is safe and yields a low number of insufficient biopsies. AB - INTRODUCTION: The diagnosis of Hirschsprung's disease (HD) relies on the histological demonstration of aganglionosis in the bowel wall. Biopsies may be obtained by rectal suction biopsy (RSB) or by transanal full-thickness excision biopsy (FTB). The objective of the present study was to evaluate the frequency of complications and inconclusive biopsies after FTB in children referred with suspicion of HD. The secondary objective was to calculate the frequency of proven aganglionosis. METHODS: A retrospective chart review was performed of all patients under the age of 16years who underwent transanal FTB during the time period of 2008-2014. RESULTS: A total of 555 patients were included in the review. Inconclusive biopsies were found at the primary biopsy in 35 patients (5.9%). Aganglionosis was found in 12% of the cases. The complication rate was 6.6% (39 patients), 85% of which were classified as a Clavien-Dindo I-II and 15% were classified as Clavien-Dindo III. CONCLUSIONS: In this retrospective evaluation of FTB for the diagnosis of HD, the frequency of inconclusive biopsies at primary attempt was low and the complication rate was relatively high. However, most were minor complications. LEVEL OF EVIDENCE: III. PMID- 29426768 TI - O6C-20-nor-salvinorin A is a stable and potent KOR agonist. AB - Salvinorin A (SalA) is a potent and selective agonist of the kappa-opioid receptor (KOR), but its instability has frustrated medicinal chemistry efforts. Treatment of SalA with weak bases like DBU leads to C8 epimerization with loss of receptor affinity and signaling potency. Here we show that replacement of C20 with H and replacement of O6 with CH2 stabilizes the SalA scaffold relative to its C8 epimer, so much so that epimerization is completely supressed. This new compound, O6C-20-nor-SalA, retains high potency for agonism of KOR. PMID- 29426769 TI - Synthesis and evaluation of bifunctional tetrahydroxamate chelators for labeling antibodies with 89Zr for imaging with positron emission tomography. AB - Two novel bifunctional tetrahydroxamate chelators 3 and 4 were synthesized and evaluated for labeling antibodies with 89Zr for positron emission tomography imaging. Compared to previously reported tetrahydroxamate chelators 1 and 2 with an iminodiacetamide backbone, 3 and 4 were based on an extended iminodipropionamide and dipropylenetriamine backbone, respectively. Trastuzumab conjugates of 3 and 4 were efficiently labeled with 89Zr (>95% radiochemical yield). The in vitro plasma stability of 89Zr-4-Trastuzumab and especially 89Zr-3 Trastuzumab was greatly improved over previously reported 89Zr-1-Trastuzumab and 89Zr-2-Trastuzumab, but their demetalation remained higher and faster than 89Zr deferoxamine (DFO)-Trastuzumab. These observations were confirmed by PET imaging and biodistribution in mice, with significant higher bone uptake for 89Zr-4 Trastuzumab, followed by 89Zr-3-Trastuzumab, and to a lesser extent for 89Zr-DFO Trastuzumab. Molecular modeling showed that 3 and 4 with an extended backbone could form eight-coordinate Zr-complexes as compared to only seven-coordinate Zr complexes of 1 and 2. Our data suggest further elongation of linker length between hydroxamate motifs of this class of chelators is needed to reach a better Zr-coordination configuration and improve in vivo stability. PMID- 29426770 TI - Diastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine beta amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation. AB - The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3 en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC50 = 15 nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Abeta40 levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease. PMID- 29426771 TI - Design, synthesis, anti-inflammatory activity and molecular docking of potential novel antipyrine and pyrazolone analogs as cyclooxygenase enzyme (COX) inhibitors. AB - As a part of a directed program for development of new active agents, novel heterocyclic derivatives with antipyrine and pyrazolone moieties -incorporated in have been designed and synthesized. Starting with 4-arylidene-3-methyl-1-phenyl 5-pyrazolone derivative 2a,b novel Mannich bases derivatives have been synthesized and biologically evaluated for their anti-inflammatory activity. Furthermore, the activity of such compounds has been tested interestingly as COX 1 and COX-2 inhibitors. Structure elucidation of the synthesized compounds was attained by the use of elemental analysis, IR, 1H NMR, 13C NMR, and Mass spectrometry techniques. Compounds 3b, 3d and 4b represent the high % inhibition values for both COX-1 and COX-2. On the other hand, compound 8 showed little selectivity against COX-2 while compound 10 showed good selectivity against COX-1 only. Structure activity relationship has been discussed and the results were confirmed by molecular docking calculations. PMID- 29426772 TI - Violacin A, a new chromanone produced by Streptomyces violaceoruber and its anti inflammatory activity. AB - A new chromanone derivative, named violacin A (1), was isolated from the fermentation broth of Streptomyces violaceoruber as a potential anti-inflammatory compound. The structure of violacin A was established using comprehensive NMR spectroscopic data analysis together with UV, IR, and MS data. The anti inflammatory effects and action mechanisms of violacin A were investigated in vitro. The results demonstrated that violacin A attenuated the production of NO, IL-1beta, IL-6, and TNF-alpha as well as inhibited the expression of iNOS in LPS induced RAW 264.7 cells. Additionally, Western blot and qRT-PCR results revealed that 1 down-regulated pro-inflammatory cytokines expression correlated with the suppression of NF-kappaB signaling pathway. PMID- 29426773 TI - An adult-onset case of chronic active Epstein-Barr virus infection with fulminant clinical course. AB - A 56-year-old Japanese male with chronic active Epstein-Barr virus (EBV) infection (CAEBV) who developed systemic gamma-delta T-cell lymphoproliferative disease (LPD) is reported. Although immune cooling therapy was effective, he died of sudden and severe hypoxia and anemia soon after the initiation of cytotoxic chemotherapy that had been previously recommended. There might remain a difficulty to control fulminant adult-onset CAEBV. Additionally, we describe three types of lymphoid cells that were observed in his peripheral blood: morphologically normal lymphocytes, large blastic cells and mature ones with rough granules. Morphological observation appeared to be useful to estimate clinical manifestations. Since CAEBV is extremely rare disease in adult population, it is important to accumulate clinical data to more understand the pathogenesis or to establish treatment strategy. PMID- 29426774 TI - Does ciprofloxacin prophylaxis during chemotherapy induce intestinal microflora resistance to ceftazidime in children with cancer? AB - To determine the susceptibility and minimal inhibitory concentrations (MIC) of ceftazidime, the commonly used empirical antibiotic in patients with febrile neutropenia, in Escherichia coli and Klebsiella pneumoniae isolated from the intestinal microflora of pediatric patients with cancer, who received ciprofloxacin prophylaxis during chemotherapy, children younger than 18 years with acute lymphoblastic leukemia or lymphoma scheduled to undergo chemotherapy were randomized to receive oral ciprofloxacin 20 mg/kg/day or placebo from the beginning of their chemotherapy. Rectal swab cultures were taken before (R0) and at 1 (R1), 2 (R2), and 3 (R3) weeks during the intervention. The antimicrobial susceptibilities and MICs of ceftazidime and ciprofloxacin were determined via the E test. Of the total 87 patients enrolled, 44 received ciprofloxacin and 43 placebo. A total of 350 isolates were obtained, 62, 49, 46 and 22 from the ciprofloxacin group and 68, 54, 38 and 11 from the placebo group at R0, R1, R2 and R3, respectively. The percentages of ceftazidime susceptibility did not show significantly greater decreases from R0 to R1-R3 in the ciprofloxacin group compared to the placebo group. The MIC50s of ceftazidime showed significantly greater increases after ciprofloxacin prophylaxis during R1-R3 compared to R0 in the intervention group compared to the placebo group (R0, 0.12 vs. 0.12; R1, 0.19 vs. 0.12; R2, 0.19 vs. 0.12 and R3, 0.38 vs. 0.09 MUg/mL, respectively). Due to the increasing MIC50 of ceftazidime over time after ciprofloxacin prophylaxis, the use of ceftazidime in patients who have previously had ciprofloxacin prophylaxis needs to be closely monitored. PMID- 29426776 TI - Therapeutic implications of the gastrointestinal microbiome. AB - Gut microbiome is an integral part of the metabolic machinery that contributes to normal host function. The advent of next generation sequencing technologies has allowed an in-depth investigation of the microbiome at various body sites including microbes which are challenging to culture. The same technologies have revealed the metabolic capacity of the microbiome, identified novel microbial products and suggested possible implications for human health. The gut microbiome has previously not been considered in aspects of human health such as response to medications, which may be metabolized to a varying extent by the microbiome, thereby, altering their efficacy and the incidence of adverse events. Recent data suggest that the gut microbiome is an important factor to consider while evaluating inter-individual responses to medications. The gut microbiome is also a rich source of novel therapeutics-pharmabiotics, which can be harnessed to modify host function or alter the gut microbial ecosystem. We will highlight these aspects of the microbiome in this review. PMID- 29426777 TI - Older people and emergency care - Current issues. PMID- 29426778 TI - Selection of the Best of 2017 in Implantable Defibrillators. PMID- 29426779 TI - Complete cytoreduction after five or more cycles of neo-adjuvant chemotherapy confers a survival benefit in advanced ovarian cancer. AB - OBJECTIVES: To assess the impact of 5 or more cycles of neoadjuvant chemotherapy (NACT) and cytoreductive outcomes on overall survival (OS) in patients undergoing interval debulking surgery (IDS) for advanced ovarian cancer. METHODS: A retrospective review of patients receiving NACT followed by IDS between 2007 and 2017. Patients were analysed according to number of NACT cycles received: group 1 consisted of patients receiving <=4 cycles and group 2 consisted of those receiving >=5 cycles. Outcomes were stratified by cytoreductive outcome, surgical complexity, stage and chemotherapy exposure. RESULTS: 231 patients in group 1 and 167 in group 2 were identified. In group 1, the OS for those achieving Complete (R0), Optimal<1 cm (R1) and Suboptimal (R2) was 51.1, 36.1, and 34.3 months respectively. Statistically significant differences in survival were seen in patients achieving R0vR2 (p < 0.019) but not in R0vR1 (p = 0.125) or R1vR2 (p = 0.358). In group 2, the OS for those achieving R0, R1 and R2 was 53.0, 24.7, and 22.1 months respectively. Statistically significant differences were seen between R0vR1 and R0vR2 (p < 0.00001) but not between R1vR2 (p = 0.917). No difference in OS was seen between groups 1 and 2. In patients achieving R1, there was a trend towards decreasing OS with increasing exposure to NACT from 36.1 (95%CI 32.0 40.2)months with 3 cycles to 24.3 (95%CI 14.4-34.2)months with >=6 cycles. CONCLUSIONS: Surgery with utilisation of cytoreductive procedures to achieve complete clearance should be offered to all patients even after >=5 cycles if R0 can be achieved. R1 cytoreduction has questionable value in those receiving <=4 cycles and no value in those receiving >=5 cycles. PMID- 29426780 TI - Conditional survival analysis for patients with intraductal papillary mucinous neoplasms (IPMNs) undergoing curative resection. AB - BACKGROUND: Conditional survival (CS) analysis represents a novel method that may provide more clinically relevant perspectives to cancer management compared to conventional survival analysis. The purpose of this study was to evaluate conditional survival for patients with intraductal papillary mucinous neoplasms (IPMNs) undergoing curative resection. METHODS: A retrospective search of the Surveillance Epidemiology and End Results (SEER) database was performed. Three year conditional survival (i.e. probability that a patient will survive an additional 3 years if they have already survived x years) was calculated using the formula 3-CS(x)=OS(x+3)/OS(x), where OS represents overall survival. RESULTS: Overall, 1303 patients were identified, with mean age of 65.2 +/- 12.2 years. 3 CS at 1, 3 and 5 years after diagnosis was 35.8%, 47.5% and 44.7%. Patients with stage III/IV disease demonstrated small differences in 3-CS at 1-3 years after diagnosis compared to patients with stage I/II disease (I/II: 35.1%-46.9%, III/IV: 22.1%-42.3%, d range 0.09-0.28), while their 3-CS was superior at 4-5 years after diagnosis (I/II: 41.5%-45.7%, III/IV: 57.9%-64.7%, d range 0.24 0.47). Differences in 3-CS based on tumor grade displayed a different pattern, with small differences at 1-3 years after diagnosis (well-differentiated (WD)/moderately-differentiated (MD): 34.6%-50%, poorly-differentiated (PD)/undifferentiated (UD): 23.2%-40%, d range 0.18-0.24), before becoming prominent at 4-5 years after diagnosis (WD/MD: 50%-51.7%, PD/UD: 24.1%-30%, d range 0.4-0.55). CONCLUSIONS: Conditional survival for patients with IPMNs undergoing resection improves over time, especially for patients with high-risk features. This information may be used to provide individualized approaches to surveillance and treatment. PMID- 29426782 TI - Role of endocrine therapy in weak estrogen/progesterone receptor expression in HER2 negative breast cancer. PMID- 29426783 TI - Reduced frontal activity during a verbal fluency test in fibromyalgia: A near infrared spectroscopy study. AB - Fibromyalgia (FM) is a complex disorder characterized by widespread chronic pain and associated sleep problems and cognitive dysfunction. However, only few studies focusing on cognitive dysfunction in FM are available so far. In the present study, we aimed to use near infrared spectroscopy (NIRS) to evaluate the brain function in FM patients subjected to a verbal fluency test (VFT). A total of 11 primary FM patients and 13 healthy individuals (HC) underwent NIRS while performing a VFT. The Fibromyalgia Impact Questionnaire (FIQ) was used to evaluate the symptom severity of FM and Beck Depression Inventory II (BDI) was used to evaluate the severities depression symptoms in study participants. Five regions of interests (ROIs) were defined: the frontal-, bilateral inferior frontal gyrus (IFG), and temporal regions. Brain activities of ROIs between the two groups were compared. In addition, we investigated the relationship between clinical symptoms and brain cortical activity in FM patients. Our results showed that there were no significant differences between HC and FM patients in age, sex, and BDI scores. We found significantly reduced brain activity over the frontal regions during a VFT in FM patients (p = .026). In addition, we found decreased frontal activity was associated with BDI scores (rho = -0.755, p = .007). Furthermore, there were no significant correlations between frontal activity and FIQ subscales. In conclusion, our study demonstrated a reduced frontal cortical activity during VFT in FM patients, and that NIRS could be a potential tool for evaluating brain function in FM patients in clinical settings. PMID- 29426784 TI - Breaking paradigms in severe epistaxis: the importance of looking for the S point. AB - INTRODUCTION: Since the introduction of nasal endoscopy into the field of Otorhinolaryngology, the treatment paradigm for cases of severe epistaxis has shifted toward early and precise identification of the bleeding site. Although severe epistaxis is usually considered to arise from posterior bleeding, an arterial vascular pedicle in the superior portion of the nasal septum, around the axilla projection of the middle turbinate, posterior to the septal body, frequently has been observed. That vascular pedicle was named the Stamm's S point. OBJECTIVE: The aim of this study was to describe the S-point and report cases of severe epistaxis originating from it. METHODS: A retrospective case series study was conducted. Nine patients with spontaneous severe epistaxis, where the S-point was identified as the source of bleeding, were treated between March 2016 and March 2017. RESULTS: Male predominance (77.8%) with age average of 59.3 years old were reported. Most cases presented comorbidities (88.9%) and were not taking acetylsalicylic acid (66.7%). A predominance of left sided involvement (55.6%) and anteroposterior bleeding being the principal initial presentation (77.8%) was seen. Six patients (66.7%) presented with hemoglobin levels below 10g/dL, and four (44.4%) required blood transfusion. Cauterization of S-point was performed in all patients, with complete resolution of bleeding. No patient experienced recurrence of severe epistaxis. CONCLUSION: The Stamm's S-point, a novel source of spontaneous severe epistaxis, is reported, and its cauterization was effective and safe. Otolaryngologists must actively seek this site of bleeding in cases of severe epistaxis. PMID- 29426786 TI - Effect of feldspathic porcelain layering on the marginal fit of zirconia and titanium complete-arch fixed implant-supported frameworks. AB - STATEMENT OF PROBLEM: Veneering with porcelain may adversely affect the marginal fit of long-span computer-aided design and computer-aided manufacturing (CAD-CAM) implant-supported fixed prostheses. Moreover, data regarding the precision of fit of CAD-CAM-fabricated implant-supported complete zirconia fixed dental prostheses (FDPs) before and after porcelain layering are limited. PURPOSE: The purpose of this in vitro study was to evaluate the effect of porcelain layering on the marginal fit of CAD-CAM-fabricated complete-arch implant-supported, screw retained FDPs with presintered zirconia frameworks compared with titanium. MATERIAL AND METHODS: An autopolymerizing acrylic resin-fixed complete denture framework prototype was fabricated on an edentulous typodont master model (all-on 4 concept; Nobel Biocare) with 2 straight in the anterior and 2 distally tilted internal-hexagon dental implants in the posterior with multiunit abutments bilaterally in canine and first molar locations. A 3-dimensional (3D) laser scanner (S600 ARTI; Zirkonzahn) was used to digitize the prototype and the master model by using scan bodies to generate a virtual 3D CAD framework. Five presintered zirconia (ICE Zirkon Translucent - 95H16; Zirkonzahn) and 5 titanium (Titan 5 - 95H14; Zirkonzahn) frameworks were fabricated using the CAM milling unit (M1 Wet Heavy Metal Milling Unit; Zirkonzahn).The 1-screw test was applied by fixing the frameworks at the location of the maxillary left first molar abutment, and an industrial computed tomography (CT) scanner (XT H 225 - Basic Configuration; Nikon) was used to scan the framework-model complex to evaluate the passive fit of the frameworks on the master model. The scanned data were transported in standard tessellation language (STL) from Volume Graphics analysis software to PolyWorks analysis software by using the maximum-fit algorithm to fit scanned planes in order to mimic the mating surfaces in the best way. 3D virtual assessment of the marginal fit was performed at the abutment-framework interface at the maxillary right canine (gap 3) and right first molar (gap 4) abutments without prosthetic screws. The facial or buccal aspects of the teeth on frameworks were layered with corresponding porcelain (Initial Dental Ceramic System; GC) and CT-scanned again using the same protocol. Marginal fit measurements were made for 4 groups: titanium (Ti) (control), porcelain-layered titanium (Ti-P) (control), zirconia (Zir), and porcelain-layered zirconia (Zir P). 3D discrepancy mean values were computed and calculated, and the results were analyzed with a repeated measures 3-way ANOVA using the maximum likelihood estimation method and Bonferroni adjustments for selected pairwise comparison t tests (alpha=.05). RESULTS: The 3D fit was measured at gap 3 and gap 4. Statistically significant differences in mean 3D discrepancies were observed between Zir-P (175 MUm) and Zir (89 MUm) and between Zir-P and Ti-P (71 MUm) (P<.001). CONCLUSIONS: Porcelain layering had a significant effect on the marginal fit of CAD-CAM-fabricated complete-arch implant-supported, screw retained FDPs with partially sintered zirconia frameworks. 3D marginal discrepancy mean values for all groups were within clinically acceptable limits (<120 MUm), except for the layered zirconia framework. PMID- 29426785 TI - Long-term prognostic impact of anticoagulation on patients with atrial fibrillation undergoing hemodialysis. AB - INTRODUCTION AND OBJECTIVES: Evidence for the efficacy and safety of oral anticoagulation with dicumarines in patients with atrial fibrillation (AF) on hemodialysis is controversial. The aim of our study is to evaluate the long-term prognostic implications of anticoagulation with dicumarines in a cohort of patients with non-valvular AF on a hemodialysis program due to end-stage renal disease. METHODS: Retrospective, observational study with consecutive inclusion of 74 patients with AF on hemodialysis. The inclusion period was from January 2005 to October 2016. The primary variables were all-cause mortality, non scheduled readmissions and bleeding during follow-up. RESULTS: Mean age was 75+/ 10 years; 66.2% were men and 43 patients (58.1%) received acenocoumarol. During a median follow-up of 2.40 years (IQR=0.88-4.15), acenocoumarol showed no survival benefit [HR=0.76, 95% CI (0.35-1.66), p=0.494]. However, anticoagulated patients were at increased risk of recurrent cardiovascular hospitalizations [IRR=3.94, 95% CI (1.06-14.69), p=0.041]. There was a trend towards an increase in repeated hospitalizations of ischemic cause in anticoagulated patients [IRR=5.80, 95% CI (0.86-39.0), p=0.071]. There was a statistical trend towards a higher risk of recurrent total bleeding in patients treated with acenocoumarol [IRR=4.43, 95% CI (0.94-20.81), p=0.059]. CONCLUSIONS: In this study, oral anticoagulation with acenocoumarol in patients with AF on hemodialysis did not increase survival. However, it was associated with an increased risk of hospitalizations of cardiovascular causes and a tendency to an increased risk of total bleeding. PMID- 29426787 TI - Direct object pronoun sentence processing in Spanish-English children with/without Specific Language Impairment and adults: A cross-modal priming study. AB - PURPOSE: This paper examines whether bilingual children with Specific Language Impairment (SLI) showed limited comprehension of Direct Object (DO) pronoun sentences and/or morphosyntactic priming compared to children with Typical Language Development (TLD) and adults. We analyzed the relation of these morphosyntactic processes to other psycholinguistic abilities, according to the MUC (Memory-Unification-Control) model. METHOD: Ten bilingual native Spanish speaking children with SLI (8;3-10;6) and 10 age-matched children with TLD (7;6 10;10) received a psycholinguistic evaluation in Spanish-English. The 20 children and 10 adults (19-34) performed an on-line cross-modal pronoun task. They listened to long distance animate DO pronoun sentences, and filler sentences without any pronoun. At the offset of the pronoun in each pronoun sentence, a picture of an animal for the antecedent (match condition), another animal for the second noun (mismatch), or an unrelated object (neutral) was displayed on the screen. In the filler sentences, a picture of an object that depicted the first noun, appeared at the offset of another later noun. Participants decided whether that pictured item was "alive"/"not alive" by pressing two keys on the computer keyboard. Immediately after, they answered an oral comprehension question about the DO pronoun sentence. RESULTS: Bilingual children with SLI showed significantly poorer comprehension of DO pronoun sentences than bilingual children with TLD. Pronoun sentence understanding in the overall children correlated significantly with oral sentence completion, expressive vocabulary abilities, auditory story comprehension, and the non-word repetition task, all in Spanish. Adults showed significantly the highest pronoun sentence comprehension, and the fastest animacy decisions across conditions; it was the only group showing a significant behavioral morphosyntactic priming effect. All groups exhibited high accuracy in the animacy decisions across conditions, although children with SLI showed lower accuracy and more variability. CONCLUSION: Bilingual Spanish-English children with SLI showed significant limitations in understanding long distance animate DO pronoun sentences. The deficits were also related to weak morphosyntactic, lexical, and/or phonological representations stored in their memory. These processes may be harder to combine in the unification process, and also to control for answering the comprehension questions. Clinical and educational implications are discussed. PMID- 29426781 TI - Mesothelioma and thymic tumors: Treatment challenges in (outside) a network setting. AB - The management of patients with mesothelioma and thymic malignancy requires continuous multidisciplinary expertise at any step of the disease. A dramatic improvement in our knowledge has occurred in the last few years, through the development of databases, translational research programs, and clinical trials. Access to innovative strategies represents a major challenge, as there is a lack of funding for clinical research in rare cancers and their rarity precludes the design of robust clinical trials that could lead to specific approval of drugs. In this context, patient-centered initiatives, such as the establishment of dedicated networks, are warranted. International societies, such as IMIG (International Mesothelioma Interest Group) and ITMIG (International Thymic Malignancy Interest Group) provide infrastructure for global collaboration, and there are many advantages to having strong regional groups working on the same issues. There may be regional differences in risk factors, susceptibility, management and outcomes. The ability to address questions both regionally as well as globally is ideal to develop a full understanding of mesothelioma and thymic malignancies. In Europe, through the integration of national networks with EURACAN, the collaboration with academic societies and international groups, the development of networks in thoracic oncology provides multiplex integration of clinical care and research, ultimately ensuring equal access to high quality care to all patients, with the opportunity of conducting high level clinical and translational research projects. PMID- 29426788 TI - Approach to a Patient with Diplopia in the Emergency Department. AB - BACKGROUND: Diplopia can be the result of benign or life-threatening etiologies. It is imperative for the emergency physician to be proficient at assessing diplopia and recognize when urgent referral or neuroimaging is required. OBJECTIVE: The first part of this review highlights a simple framework to arrive at the appropriate disposition of diplopic patients presenting to the emergency department (ED). The second part of this review provides more detail and further management strategies. DISCUSSION: ED strategies for assessment of diplopia are discussed. Management strategies, such as when to image, what modality of imaging to use, and urgency of referral, are discussed in detail. CONCLUSIONS: Unenhanced plain computed tomography (CT) of the head or orbits is largely not useful in the work-up of diplopia. Magnetic resonance imaging is preferred for ocular motor nerve palsies. Due to limited resources in the ED, patients with isolated fourth and sixth nerve palsies with the absence of other neurological signs on examination should be referred to Neurology or Ophthalmology for further work-up. All patients presenting with an acute isolated third nerve palsy should be imaged with CT and CT angiography of the brain to rule out a compressive aneurysm. Contrast-enhanced CT imaging of the brain and orbits would be indicated in suspected orbital apex syndrome or a retro-orbital mass, thyroid eye disease, or ocular trauma. CT and CT venogram should be considered in cases of suspected cavernous sinus thrombosis. In any patient over the age of 60 years presenting with recent (1 month) history of diplopia, inflammatory markers should be obtained to rule out giant cell arteritis. PMID- 29426789 TI - Management and treatment of gallbladder polyps. PMID- 29426790 TI - Metagenomic insights into the ecology and physiology of microbes in bioelectrochemical systems. AB - In bioelectrochemical systems (BESs), electrons are transferred between electrochemically active microbes (EAMs) and conductive materials, such as electrodes, via extracellular electron transfer (EET) pathways, and electrons thus transferred stimulate intracellular catabolic reactions. Catabolic and EET pathways have extensively been studied for several model EAMs, such as Shewanella oneidensis MR-1 and Geobacter sulfurreducens PCA, whereas it is also important to understand the ecophysiology of EAMs in naturally occurring microbiomes, such as those in anode biofilms in microbial fuel cells treating wastewater. Recent studies have exploited metagenomics and metatranscriptomics (meta-omics) approaches to characterize EAMs in BES-associated microbiomes. Here we review recent BES studies that used meta-omics approaches and show that these studies have discovered unexpected features of EAMs and deepened our understanding of functions and behaviors of microbes in BESs. It is desired that more studies will employ meta-omics approaches for advancing our knowledge on microbes in BESs. PMID- 29426791 TI - Collection, transport and general processing of clinical specimens in Microbiology laboratory. AB - The interpretation and the accuracy of the microbiological results still depend to a great extent on the quality of the samples and their processing within the Microbiology laboratory. The type of specimen, the appropriate time to obtain the sample, the way of sampling, the storage and transport are critical points in the diagnostic process. The availability of new laboratory techniques for unusual pathogens, makes necessary the review and update of all the steps involved in the processing of the samples. Nowadays, the laboratory automation and the availability of rapid techniques allow the precision and turn-around time necessary to help the clinicians in the decision making. In order to be efficient, it is very important to obtain clinical information to use the best diagnostic tools. PMID- 29426792 TI - Twelve-Year Follow-Up of Navigated Computer-Assisted Versus Conventional Total Knee Arthroplasty: A Prospective Randomized Comparative Trial. AB - BACKGROUND: Navigated computer-assisted total knee arthroplasty (TKA) was introduced to expedite long-term survival based on improved postoperative implantation accuracy. However, long-term outcome data after 10 years or more are rare, even available meta-analyses show controversial study results. METHODS: In a prospective randomized trial, 100 conventional TKAs (group CONV) were compared with 100 computer-assisted TKAs (group NAV) after a mean follow-up of 12 years postoperatively. A long-leg weight-bearing X-ray was performed for measuring mechanical axis of the limb, lateral distal femoral angle, and medial proximal tibial angle. Tibial slope, patella alpha angle, and radiolucent lines were also observed. Clinical investigation included evaluation of 4 different scores: Insall Knee Score, Western Ontario and MacMaster University Index score, Hospital for Special Surgery Knee Score, and visual analog scale. RESULTS: Based on a follow-up rate of at least 75%, no difference in TKA survival was found 12 years postoperatively: 91.5% in group CONV vs 98.2% in group NAV (P = .181). Since 5 year follow-up, no additional TKA revision had been performed in both groups. Group CONV showed a nonsignificant higher inaccuracy of neutral lower limb axis (1.8 degrees +/- 1.4 degrees ) compared to group NAV (1.6 degrees +/- 1.7 degrees , P = .700). All X-ray assessments were not significant different within both study groups (P >= .068). Clinical examination showed no differences in evaluations (P >= .204). All collected outcome score results were similar (P >= .222). CONCLUSION: Twelve years postoperatively, no differences were found in terms of long-term survival, implantation accuracy, clinical outcome or score results. PMID- 29426793 TI - [Widowhood, loneliness, and health in old age]. AB - INTRODUCTION: Elderly people are one of the most vulnerable groups in the population as regards loneliness, especially among those living alone. This paper aims to assess the impact of the feeling of loneliness on the elderly, taking into account that the loss of a spouse is the main reason that triggers this feeling. MATERIAL AND METHODS: Findings are presented from a qualitative study conducted in Spain. Data were gathered using a focus group approach (8 focus groups, differentiated by gender and place of residence). The data were analysed from a Grounded Theory perspective. RESULTS: Elderly people describe how they experience the feeling of loneliness after becoming widowed. The loss of the spouse brings an emotional vacuum that is impossible to be filled, especially at night. After long-lasting marriages, these older people are confronted with loneliness, both in the home and internally, which very often triggers depressive disorders. As regards health, 2 types of feelings were observed. On the one hand, there is helplessness for fear of accidents or unexpected illnesses when alone at home. On the other hand, they feel uncertainty about the future, as they wonder who will look after them in case of need. Both feelings contribute to activate loneliness. CONCLUSIONS: Our findings add to the available knowledge about the close relationship between loneliness, widowhood, and health in old age, and provide qualitative knowledge to supplement what we already know about that relationship through surveys and other quantitative techniques used in social research. PMID- 29426794 TI - Spanish National Hip Fracture Registry (SNHFR): a description of its objectives, methodology and implementation. AB - OBJECTIVE: To ascertain the current situation and clinical variability of the provision of care for Hip Fracture (HF) in Spain and the factors related to it by using a National Registry (NHFR) with high patient numbers and territorial representation NHFR, and to compare results on a national and international level and propose standards and criteria to improve healthcare quality. DESIGN: Continuous registry for at least three years of a representative sample of patients admitted to Spanish hospitals due to HF using the Minimum Common Dataset - international Fragility Fracture Network (FFN) MCD, adapted for Spanish. STUDY SCOPE AND SUBJECTS: all patients over the age of 74 years who are hospitalized with a diagnosis of a fragility HF at the participating hospitals distributed throughout the Spanish territory. Initially 48 hospitals are included, and we expect to incorporate the highest number of sites possible. RESULTS: It is expected to ascertain the current situation of provision of care for HF in Spain. Each hospital will be offered information regarding their results and their situation compared to the rest. The results from national hospitals will be compared to others included in the registry and to hospitals abroad, which use the same database. Variability will be studied, care standards will be established, and objectives will be proposed for the continuous improvement of the care process of this condition. PMID- 29426795 TI - Cholesterol granuloma of the maxilla. AB - Intra-osseous cholesterol granuloma (CG) is a rare and benign lesion. Very few cases of CG of the jaws have been described in the literature. CG of the jaws seems to be due to the accumulation of cholesterol of hematogenous origin in odontogenic cysts. We report on one case of CG of the maxilla treated by surgical enucleation in a 46-year-old man who presented an asymptomatic swelling of the maxilla. PMID- 29426796 TI - Road traffic deaths in Kashan region, Iran: An eight-year study (2006-2013). AB - PURPOSE: The aim of this study was to analyze the trend of road traffic fatalities in Kashan Region, Iran, in a period of eight years. METHODS: Through a cross-sectional study, all road traffic deaths classified under the V01V99 codes according to ICD-10 in Kashan region, central Iran, from March 2006 to March 2013 and population data were collected from the registration system of Kashan University of Medical Sciences. Years of lost life (YLL) and mortality rates were calculated regarding age, gender and year of the accident. Generalized linear model (GLM) with Poisson log-linear link was used to evaluate the effects of the mentioned variables on mortality rate. RESULTS: During the period of the study (8 years), 928 people (767 men) died due to road traffic injuries (RTIs). The total YLL was 20,818. The mortality rate due to RTIs has been declined constantly from 43.1 in March 2006 to 21.1 per 100,000 in March 2013. The highest mortality rate was found in the age group of over 60 years old and the lowest in the age group of 0-14 years old. Both mortality rate and YLL was greater in men than in women. Poisson regression showed that age, gender and year of the accidents had a significant effect on mortality rate (p < 0.001). CONCLUSION: Although there has been a constant decline of mortality rate in Kashan area within the study period, the value remains higher than the mean level of Eastern Mediterranean region and the global average, which is a notable fact for policymakers and authorities. PMID- 29426797 TI - Role of percutaneous cerclage wire in the management of subtrochanteric fractures treated with intramedullary nails. AB - PURPOSE: Cerclage wire application has emerged as a potential therapeutic adjunct to intramedullary nailing for subtrochanteric fractures. But its popularity is plagued by the concern of possible negative effect on fracture zone biology. This study was intended to analyze the clinico-radiological outcome and complications associated with cerclage wire application. METHODS: Retrospective analysis was performed on all the subtrochanteric fractures operated with intramedullary nailing between January 2012 and January 2016. After exclusion, 48 patients were available with an average follow-up of 20.8 months. Long oblique, spiral, spiral wedge or comminuted fracture configurations with butterfly fragments were particularly considered for cerclage wire application, which was employed by percutaneous cerclage passer in 21 patients. Assessment was done in terms of operation time, blood loss, quality of reduction, neck-shaft angle, follow-up redisplacement, union time, complications, and final functional evaluation by Merle d'Aubigne'-Postel score. RESULTS: Average operation time and blood loss were significantly higher in cerclage group (p < 0.05). However, cerclage use substantially improved quality of reduction in terms of maximum cortical displacement (p = 0.003) and fracture angulation (p = 0.045); anatomical reduction was achieved in 95.23% of cases as compared to 74.07% without cerclage. Union time was shorter, although not statistically different (p = 0.208), in cerclage group. Four patients in non-cerclage group developed non-union, 2 of them had nail breakage. No infection or any other implant related complications were reported with cerclage use. CONCLUSION: Minimally-invasive cerclage wire application has proved to be beneficial for anatomical reconstruction in difficult subtrochanteric fractures, whenever applicable, without any harmful effect on fracture biology. PMID- 29426799 TI - The quick sequential organ failure assessment (qSOFA) identifies septic patients in the out-of-hospital setting. AB - BACKGROUND: Recently a multispecialty, multinational task force convened to redefine the criteria for organ dysfunction, sepsis, severe sepsis, and septic shock. The study recommended the quick sequential organ failure assessment (qSOFA) score to identify sepsis patients. The qSOFA is felt to be the initial screen to prompt a more in-depth sepsis workup. This may be particularly true in resource-limited environments such as the prehospital arena. OBJECTIVES: The goal of this study was to identify whether emergency medical services (EMS) patients who met all three qSOFA criteria correlated with an emergency department (ED) identification of sepsis. METHODS: This was a retrospective chart review of adult patients>=18years of age, meeting qSOFA criteria and presenting to the emergency department between 1/01/2014 and 6/30/2016. Subjects were identified through an electronic query of the EMS record repository. RESULTS: 72 subjects were included in the final analysis. Subjects in the septic group tended to be older with a mean age of 72years vs 64years. There was no observed discrepancy relating to gender. 48 of the subjects (67%) were identified as septic and 24 (33%) were identified as non-septic after review of the ED chart. This yielded a positive predictive value of the prehospital qSOFA as 66.67% (95% CI 55.8-77.6). CONCLUSIONS: EMS patients with positive qSOFA screens were more likely to be septic upon disposition to the ED. PMID- 29426798 TI - Emergency coronary angioplasty with stenting using Cordis(r) diagnostic coronary catheters when there is difficulty in engaging guide catheters and bench evaluation of diagnostic and guide catheters. AB - INTRODUCTION AND AIMS: Difficulty in engaging with guide catheters is not uncommon in acute emergencies. We aimed to evaluate the use of Cordis(r) INFINITI diagnostic catheters to perform angioplasty in patients in whom the coronaries cannot be engaged using standard guide catheters. METHODS: In 34 cases of acute coronary syndrome, when difficulty in engagement with two standard guide catheters was encountered with reasonable manipulations, angioplasty was performed using diagnostic catheters. In total, 40 stents were placed by this technique. Pushability and trackability, distal tip flexion and three-point bending tests were performed to evaluate the performance of the guide and diagnostic catheters. RESULTS: Angioplasty was performed easily in a setting where it would have been very difficult to perform. Coronary dissection occurred in one patient, treated by a stent. The stent and dilatation balloons were easily passed through the diagnostic catheters. Pressure tracings were clearly preserved with certain stent delivery systems, and at angioplasty, although there was slightly reduced opacification of the respective artery, the coronary anatomy was sufficiently visualized to perform angioplasty. No periprocedural target lesion complications were seen in any cases. Pushability and trackability tests showed good force transmission along a tortuous path with diagnostic catheters, and balanced force-displacement curves from three-point bending tests and distal tip softness tests. CONCLUSION: Angioplasty with stenting can be performed safely through 6F Cordis(r) infiniti diagnostic catheters when difficulty in engaging guide catheters is encountered. PMID- 29426800 TI - Single-incision Eden-Lange procedure in trapezius muscle paralysis: A report of 11 cases. AB - OBJECTIVE: The aim of this study was to evaluate the outcome of single-incision Eden-Lange procedure in trapezius muscle paralysis. METHODS: The medical records of 11 patients (3 females and 8 males); mean age: 41 (25-59) years with trapezius muscle paralysis who underwent Eden-Lange procedure in our Center, between February 2009 and April 2013, were retrospectively analyzed. The clinical outcomes were evaluated with the American Shoulder and Elbow Surgeons Shoulder (ASES) score and visual analogue scale (VAS). RESULTS: The mean duration of symptoms before surgery was 10.18 months. The average duration of follow-up was 33.5 (24-48) months. The mean VAS score improved from 7.8 to 1.6 points (p < 0.05). The total ASES improved from 32.8 to 82.1 points (p < 0.05). The mean range of motion in forward elevation and abduction increased significantly from 121.80 to 154.40 (p < 0.05) and 80.00 to 148.18 degrees (p < 0.05), respectively. CONCLUSION: Single incision Eden-Lange procedure appears to be a safe and effective treatment option for the patients with trapezius muscle paralysis. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29426801 TI - Engineering strategies for enhancing C. vulgaris ESP-31 lipid production using effluents of coke-making wastewater. AB - Microalgae cultivation using wastewater is an approach for simultaneous wastewater treatment and biofuels/chemicals productions. In this study, three microalgae species Chorella vulgaris ESP-31, Chorella sorokiniana CY-1 and Scenedesmus sp. were cultivated using coke-making wastewater generated from a steel-making company. Of these, C.vulgaris ESP-31 had the best tolerance towards wastewater, with maximal biomass concentration of 2.82 g/l and lipid productivity of 32.3 mg/l/d. The highest biomass concentration 3.98 g/l and lipid productivity of 47.1 mg/l/d was obtained in 20% wastewater. Immobilization approach was applied to boost biomass growth and lipid production. Both maximal biomass growth (5.17 g/l) and lipid productivity (68.4 mg/l/d) was significantly enhanced with activated charcoal addition. Semi-batch cultivation resulted in stable biomass production and lipid productivity of 5.18 g/l and 77.3 mg/l/d, respectively. This study has revealed that C. vulgaris ESP-31 is a potential candidate for growth in coke making wastewater and biofuel production. PMID- 29426803 TI - Performance evaluation of delefilcon a water gradient daily disposable contact lenses in first-time contact lens wearers. AB - PURPOSE: To evaluate the tolerability of and subject and investigator satisfaction with delefilcon A (DAILIES TOTAL1(r)) daily disposable contact lenses in first-time contact lens wearers. METHODS: This European multicenter, open-label, single-arm, two-week trial enrolled first-time contact lens wearers and fitted them with delefilcon A contact lenses. Assessments were made at dispensing and at Weeks 1 and 2. Subject-reported outcomes included comfort, quality of vision, convenience, and intent to purchase, which were ranked by agreement responses. Investigator-reported outcomes included slit-lamp biomicroscopy findings and lens fit satisfaction. RESULTS: Ninety-two subjects were included in the per protocol dataset. Mean scores at Weeks 1 and 2 for subject-reported quality of vision and ocular comfort were significantly higher with delefilcon A contact lenses than with the subjects' habitual spectacles during the day, at the end of the day, and overall (all p <= 0.02). Ninety-one percent of subjects reported that their study lenses were more comfortable than expected, 98% agreed that they were convenient to use, and 92% were interested in purchasing the lenses (all p < 0.001). Investigators reported that study lenses had an acceptable fit in at least 97% of subjects. CONCLUSIONS: Practitioners can expect favorable outcomes when transitioning first-time contact lens wearers from spectacles to delefilcon A daily disposable contact lenses. PMID- 29426802 TI - Development of Mycoplasma pneumoniae biofilms in vitro and the limited role of motility. AB - Mycoplasma pneumoniae is a bacterial pathogen of humans that is a major causative agent of chronic respiratory disease. M. pneumoniae infections often recur even after successful treatment of symptoms with antibiotics, and resistance to antibiotics is increasing worldwide, with nearly complete resistance in some places. Although biofilms often contribute to chronicity and resistance, M. pneumoniae biofilms remain poorly characterized. Scanning electron microscopy revealed that cells of wild-type (WT) M. pneumoniae strain M129 biofilms, as well as mutants II-3 and II-3R, in vitro became increasingly rounded as the biofilm towers matured over 5 days. The role of gliding motility in biofilm formation was addressed by analyzing differences in biofilm architecture in non-motile mutant II-3R and hypermotile mutant prpC-and by using time-lapse microcinematography to measure flux of cells around biofilm towers. There were no major differences in biofilm architecture between WT and motility mutants, with perhaps a slight tendency for the prpC- cells to spread outside towers during early stages of biofilm formation. Consistent with an insignificant role of motility in biofilm development, flux of cells near towers, which was low, was dominated by exit of cells. Immunofluorescence microscopy revealed that motility-associated attachment organelle (AO) proteins exhibited no discernable changes in localization to foci over time, but immunoblotting identified a decrease in steady-state levels of protein P200, which is required for normal gliding speed, as the WT culture aged. Non-adherent strain II-3 and non-motile strain II-3R also exhibited a steady decrease in P200 steady-state levels, suggesting that the decrease in P200 levels was not a response to changes in gliding behavior during maturation. We conclude that M. pneumoniae cells undergo morphological changes as biofilms mature, motility plays no major role in biofilm development, and P200 loss might be related to maturation of cells. This study helps to characterize potential therapeutic targets for M. pneumoniae infections. PMID- 29426804 TI - ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Cell surface receptors and associated signaling pathways). AB - BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biologic therapies. AIMS: To review, from an infectious diseases perspective, the safety profile of therapies targeting cell surface receptors and associated signaling pathways among cancer patients and to suggest preventive recommendations. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Vascular endothelial growth factor (VEGF)-targeted agents (bevacizumab and aflibercept) are associated with a meaningful increase in the risk of infection, likely due to drug-induced neutropaenia, although no clear benefit is expected from the universal use of anti-infective prophylaxis. VEGF tyrosine kinase inhibitors (i.e. sorafenib or sunitinib) do not seem to significantly affect host's susceptibility to infection, and universal anti-infective prophylaxis is not recommended either. Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) induce neutropaenia and secondary skin and soft tissue infection in cases of severe papulopustular rash. Systemic antibiotics (doxycycline or minocycline) should be administered to prevent the latter complication, whereas no recommendation can be established on the benefit from antiviral, antifungal or anti-Pneumocystis prophylaxis. A lower risk of infection is reported for anti ErbB2/HER2 monoclonal antibodies (trastuzumab and pertuzumab) and ErbB receptor tyrosine kinase inhibitors (including dual-EGFR/ErbB2 inhibitors such as lapatinib or neratinib) compared to conventional chemotherapy, presumably as a result of the decreased occurrence of drug-induced neutropaenia. IMPLICATIONS: With the exception of VEGF-targeted agents, the overall risk of infection associated with the reviewed therapies seems to be low. PMID- 29426805 TI - Boveri's research at the Zoological Station Naples: Rediscovery of his original microscope slides at the University of Wurzburg. AB - Eric Davidson once wrote about Theodor Boveri: "From his own researches, and perhaps most important, his generalized interpretations, derive the paradigms that underlie modern inquiries into the genomic basis of embryogenesis" (Davidson, 1985). As luck would have it, the "primary data" of Boveri's experimental work, namely the microscope slides prepared by him and his wife Marcella during several stays at the Zoological Station in Naples (1901/02, 1911/12 and 1914), have survived at the University of Wurzburg. More than 600 slides exist and despite their age they are in a surprisingly good condition. The slides are labelled and dated in Boveri's handwriting and thus can be assigned to his published experimental work on sea urchin development. The results allowed Boveri to unravel the role of the cell nucleus and its chromosomes in development and inheritance. Here, I present an overview of the slides in the context of Boveri's work along with photographic images of selected specimens taken from the original slides. It is planned to examine the slides in more detail, take high resolution focal image series of significant specimens and make them online available. PMID- 29426806 TI - Neonatal epilepsies: Clinical management. AB - Whereas the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy, often linked to a pathogenic genetic variant. This defect may disrupt cortical development (e.g., lissencephaly, focal cortical dysplasia), lead to metabolic changes (e.g., pyridoxine-dependent epilepsy, sulfite oxidase deficiency) or lead to cortical dysfunction without metabolic or macroscopic structural changes (e.g., channelopathies, STXBP1). Historically, studies on treatment response and long-term consequences of neonatal seizures have lumped all etiologies together. However, etiology has been consistently shown to be the most important determinant of outcome. Here, we address the elements differentiating neonatal onset epilepsies from acute symptomatic seizures. We review some common neonatal onset epilepsies and emphasize how pathognomonic electro-clinical phenotypes such as the ones associated with KCNQ2 or KCNT1 gene mutation, when recognized early, can lead to targeted diagnostic testing and precision medicine treatment, enabling the possibility of improved outcome. PMID- 29426807 TI - Neonatal epilepsy genetics. AB - Neonatal epilepsy genetics is a rapidly expanding field with recent technological advances in genomics leading to an expanding list of genetic disorders associated with neonatal-onset epilepsy. The genetic causes of neonatal epilepsy can be grouped into the following categories: (i) malformations of cortical development, (ii) genetic-metabolic, (iii) genetic-vascular, (iv) genetic-syndromic, and (v) genetic-cellular. Clinically, epilepsy in the neonate shows phenotypic overlap with pathogenic variants in unrelated genes causing similar clinical presentation (locus heterogeneity) and variants in the same gene leading to a wide clinical spectrum ranging from benign familial neonatal seizures to more severe epileptic encephalopathies (variable expressivity). We suggest a diagnostic approach to obtaining a genetic diagnosis with emphasis on clinical features such as electro clinical phenotype and magnetic resonance imaging findings. Rapid identification of genetic disorders with targeted treatments should be a clinical priority. Achieving a genetic diagnosis can be challenging in a rapidly changing genetic landscape, but is increasingly possible. PMID- 29426808 TI - Response to: Studying the blood pressures of antegrade and retrograde internal mammary vessels: Do they really work as recipient vessels? Tomioka YK, Uda H, Yoshimura K, Sunaga A, Kamochi H, Sugawara Y. J Plast Reconstr Aesthet Surg. 2017 Oct;70(10):1391-1396. PMID- 29426809 TI - Current evidence on the role of smoking in plastic surgery elective procedures: A systematic review and meta-analysis. AB - BACKGROUND: Smoking is considered to be a significant risk factor for the development of postoperative complications after various surgical procedures, mainly by limiting oxygen delivery to tissues. Evidence on the collective impact of smoking in aesthetic procedure outcomes is scarce. The aim of this study is to evaluate the current evidence on the association between smoking and postoperative outcomes in patients who underwent common elective procedures in plastic surgery. METHODS: PubMed and Cochrane bibliographical databases were searched from January 1950 to October 2016 for studies reporting on patients who underwent facelift, abdominoplasty, breast reduction and breast reconstruction and for studies with included data on smoking history of treated patients. RESULTS: Fifty-three studies reporting on postoperative complications in tobacco users undergoing facelift, abdominoplasty, breast reduction and reconstruction were identified. Tobacco use is found to significantly increase the total number of postoperative complications as far as abdominoplasty (OR: 5.43; 95% CI = 2.92 10.10), breast reduction (OR: 2.36; 95% CI = 1.64-3.39) and breast reconstruction (OR: 1.91; 95% CI = 1.69-2.17) are concerned. Smoking history does not significantly affect total postoperative complications after facelift procedures (OR: 3.36; 95% CI = 0.92-12.30). CONCLUSIONS: Smoking predisposes to surgical site infections, delayed wound healing and skin necrosis in patients undergoing the most common aesthetic procedures in plastic surgery. More rigorous and detailed reporting on the history of tobacco use and surgical outcomes following plastic surgery procedures is needed to better quantify the impact of smoking on the overall postoperative care for this patient population. PMID- 29426810 TI - 'Abdominal reanimation' and massive flank hernias: Moving towards a more functional reconstruction. PMID- 29426811 TI - Intralesional cryotherapy versus excision with corticosteroid injections or brachytherapy for keloid treatment: Randomised controlled trials. AB - BACKGROUND: Keloids are a burden for patients due to physical, aesthetic and social consequences. Treatment remains a challenge due to therapy resistance and high recurrence rates. The main goals of treatment are to improve scar appearance and symptoms and patients' quality of life (QoL). METHODS: Two multicentre, randomised controlled open trials that compared 1) intralesional cryotherapy with excision and corticosteroid injections for primary keloids, and 2) intralesional cryotherapy with excision and brachytherapy for therapy resistant keloids. Primary outcome was scar appearance assessed with the Patient and Observer Scar Assessment Scale. Secondary outcomes were patient reported QoL (Skindex-29, SF 36, EQ-5D-5L), recurrence rates and scar volume reduction. For analysis, a linear mixed model was used. Power analysis indicated 33 patients in each group were needed. RESULTS: The trial was prematurely terminated after inclusion of 26 patients due to unexpectedly inferior outcomes after intralesional cryotherapy. For primary keloids no convincing difference between treatments was found, but surgery improved scar appearance while cryotherapy did not. For resistant keloids, excision followed by brachytherapy improved scar appearance (POSAS) and scar symptoms (itch and pain) significantly (p < 0.001, p < 0.001 and p = 0.006 respectively) while cryotherapy did not. Neither of the treatments caused indisputable improvements in QoL. CONCLUSIONS: Intralesional cryotherapy is inferior to keloid excision followed by brachytherapy for resistant keloids. In primary keloids, intralesional cryotherapy reduced keloid volume and, therefore, may be used in these patients and specific cases. Primary keloid group size was too small to draw valid conclusions, further research on the efficacy of intralesional cryotherapy for primary keloids is warranted. PMID- 29426812 TI - Toward Impactful Collaborations on Computing and Mental Health. AB - We describe an initiative to bring mental health researchers, computer scientists, human-computer interaction researchers, and other communities together to address the challenges of the global mental ill health epidemic. Two face-to-face events and one special issue of the Journal of Medical Internet Research were organized. The works presented in these events and publication reflect key state-of-the-art research in this interdisciplinary collaboration. We summarize the special issue articles and contextualize them to present a picture of the most recent research. In addition, we describe a series of collaborative activities held during the second symposium and where the community identified 5 challenges and their possible solutions. PMID- 29426813 TI - The Use of Communication Apps by Medical Staff in the Australian Health Care System: Survey Study on Prevalence and Use. AB - BACKGROUND: The use of communication apps on mobile phones offers an efficient, unobtrusive, and portable mode of communication for medical staff. The potential enhancements in patient care and education appear significant, with clinical details able to be shared quickly within multidisciplinary teams, supporting rapid integration of disparate information, and more efficient patient care. However, sharing patient data in this way also raises legal and ethical issues. No data is currently available demonstrating how widespread the use of these apps are, doctor's attitudes towards them, or what guides clinician choice of app. OBJECTIVE: The objective of this study was to quantify and qualify the use of communication apps among medical staff in clinical situations, their role in patient care, and knowledge and attitudes towards safety, key benefits, potential disadvantages, and policy implications. METHODS: Medical staff in hospitals across Victoria (Australia) were invited to participate in an anonymous 33 question survey. The survey collected data on respondent's demographics, their use of communication apps in clinical settings, attitudes towards communication apps, perceptions of data "safety," and why one communication app was chosen over others. RESULTS: Communication apps in Victorian hospitals are in widespread use from students to consultants, with WhatsApp being the primary app used. The median number of messages shared per day was 12, encompassing a range of patient information. All respondents viewed these apps positively in quickly communicating patient information in a clinical setting; however, all had concerns about the privacy implications arising from sharing patient information in this way. In total, 67% (60/90) considered patient data "moderately safe" on these apps, and 50% (46/90) were concerned the use of these apps was inconsistent with current legislation and policy. Apps were more likely to be used if they were fast, easy to use, had an easy login process, and were already in widespread use. CONCLUSIONS: Communication app use by medical personnel in Victorian hospitals is pervasive. These apps contribute to enhanced communication between medical staff, but their use raises compliance issues, most notably with Australian privacy legislation. Development of privacy-compliant apps such as MedX needs to prioritize a user-friendly interface and market the product as a privacy-compliant comparator to apps previously adapted to health care settings. PMID- 29426815 TI - Associations of Topics of Discussion on Twitter With Survey Measures of Attitudes, Knowledge, and Behaviors Related to Zika: Probabilistic Study in the United States. AB - BACKGROUND: Recent outbreaks of Zika virus around the world led to increased discussions about this issue on social media platforms such as Twitter. These discussions may provide useful information about attitudes, knowledge, and behaviors of the population regarding issues that are important for public policy. OBJECTIVE: We sought to identify the associations of the topics of discussions on Twitter and survey measures of Zika-related attitudes, knowledge, and behaviors, not solely based upon the volume of such discussions but by analyzing the content of conversations using probabilistic techniques. METHODS: Using probabilistic topic modeling with US county and week as the unit of analysis, we analyzed the content of Twitter online communications to identify topics related to the reported attitudes, knowledge, and behaviors captured in a national representative survey (N=33,193) of the US adult population over 33 weeks. RESULTS: Our analyses revealed topics related to "congress funding for Zika," "microcephaly," "Zika-related travel discussions," "insect repellent," "blood transfusion technology," and "Zika in Miami" were associated with our survey measures of attitudes, knowledge, and behaviors observed over the period of the study. CONCLUSIONS: Our results demonstrated that it is possible to uncover topics of discussions from Twitter communications that are associated with the Zika-related attitudes, knowledge, and behaviors of populations over time. Social media data can be used as a complementary source of information alongside traditional data sources to gauge the patterns of attitudes, knowledge, and behaviors in a population. PMID- 29426814 TI - Exploring the Specific Needs of Persons with Multiple Sclerosis for mHealth Solutions for Physical Activity: Mixed-Methods Study. AB - BACKGROUND: Multiple sclerosis (MS) is one of the world's most common neurologic disorders, with symptoms such as fatigue, cognitive problems, and issues with mobility. Evidence suggests that physical activity (PA) helps people with MS reduce fatigue and improve quality of life. The use of mobile technologies for health has grown in recent years with little involvement from relevant stakeholders. User-centered design (UCD) is a design philosophy with the goal of creating solutions specific to the needs and tasks of the intended users. UCD involves stakeholders early and often in the design process. In a preliminary study, we assessed the landscape of commercially available MS mobile health (mHealth) apps; to our knowledge, no study has explored what persons with MS and their formal care providers think of mHealth solutions for PA. OBJECTIVE: The aim of this study was to (1) explore MS-specific needs for MS mHealth solutions for PA, (2) detect perceived obstacles and facilitators for mHealth solutions from persons with MS and health care professionals, and (3) understand the motivational aspects behind adoption of mHealth solutions for MS. METHODS: A mixed-methods design study was conducted in Kliniken Valens, Switzerland, a clinic specializing in neurological rehabilitation. We explored persons with MS and health care professionals who work with them separately. The study had a qualitative part comprising focus groups and interviews, and a quantitative part with standardized tools such as satisfaction with life scale and electronic health (eHealth) literacy. RESULTS: A total of 12 persons with relapsing remitting MS and 12 health care professionals from different backgrounds participated in the study. Participants were well-educated with an even distribution between genders. Themes identified during analysis were MS-related barriers and facilitators, mHealth design considerations, and general motivational aspects. The insights generated were used to create MS personas for design purposes. Desired mHealth features were as follows: (1) activity tracking, (2) incentives for completing tasks and objectives, (3) customizable goal setting, (4) optional sociability, and (5) game-like attitude among others. Potential barriers to mHealth apps adoption were as follows: (1) rough on boarding experiences, (2) lack of clear use benefits, and (3) disruption of the health care provider-patient relationship. Potential facilitators were identified: (1) endorsements from experts, (2) playfulness, and (3) tailored to specific persons with MS needs. A total of 4 MS personas were developed to provide designers and computer scientists means to help in the creation of future mHealth solutions for MS. CONCLUSIONS: mHealth solutions for increasing PA in persons with MS hold promise. Allowing for realistic goal setting and positive feedback, while minimizing usability burdens, seems to be critical for the adoption of such apps. Fatigue management is especially important in this population; more attention should be brought to this area. PMID- 29426816 TI - Feasibility and Efficacy of a Parent-Focused, Text Message-Delivered Intervention to Reduce Sedentary Behavior in 2- to 4-Year-Old Children (Mini Movers): Pilot Randomized Controlled Trial. AB - BACKGROUND: Despite public health guidelines to limit sedentary behavior, many young children spend large amounts of time sedentary (eg, screen and sitting time) during waking hours. OBJECTIVE: The objective of this study was to test the feasibility and efficacy of a parent-focused, predominantly text message delivered intervention to support parents to reduce the amount of time their children spend in sedentary behavior. METHODS: Mini Movers was a pilot randomized controlled trial delivered to parents of 2- to 4-year-old children in Melbourne, Australia. Participants were recruited through playgroups, social media, and snowball sampling. Eligibility criteria were having an ambulatory child (2-4 years), English literacy, and smartphone ownership. Participants were randomized to intervention or wait-list control on a 1:1 ratio after baseline data collection. The 6-week intervention was predominantly delivered via text messages, using a Web-based bulk text message platform managed by the interventionist. Intervention strategies focused on increasing parental knowledge, building self-efficacy, setting goals, and providing reinforcement, and were underpinned by the Coventry, Aberdeen & London-Refined taxonomy of behavior change techniques and social cognitive theory. The primary outcome was intervention feasibility, measured by recruitment, retention, intervention delivery, and fidelity; process evaluation questionnaires; and qualitative interviews with a subsample of participants. Secondary outcomes were children's screen and restraint time (parent report), sitting time (parent report, activPAL), and potential mediators (parent report). Linear regression models were used to determine intervention effects on secondary outcomes, controlling for the child's sex and age and clustering by playgroup; effect sizes (Cohen's d) were calculated. RESULTS: A total of 57 participants (30 intervention; 27 wait-list control) were recruited, and retention was high (93%). Process evaluation results showed that the intervention was highly acceptable to parents. The majority of intervention components were reported to be useful and relevant. Compared with children in the control group, children in the intervention group had significantly less screen time postintervention (adjusted difference [95% CI]= 35.0 [-64.1 to -5.9] min/day; Cohen's d=0.82). All other measures of sedentary behavior were in the expected direction, with small to moderate effect sizes. CONCLUSIONS: Mini Movers was shown to be a feasible, acceptable, and efficacious pilot intervention for parents of young children, warranting a larger-scale randomized control trial. TRIAL REGISTRATION: Australian New Zealand Clinical Trials registry: ACTRN12616000628448; https://www.anzctr.org.au/ Trial/Registration/TrialReview.aspx?ACTRN=12616000628448p (Archived by WebCite at http://www.webcitation.org/ 6wZcA3cYM). PMID- 29426818 TI - Author Correction: Uncovering active precursors in colloidal quantum dot synthesis. AB - In the original version of this Article, Fig. 3 contained several errors in the chemical structures. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29426817 TI - The IAP family member BRUCE regulates autophagosome-lysosome fusion. AB - Autophagy has an important role in cellular homeostasis by degrading and recycling cytotoxic components. Ubiquitination is known to target cargoes for autophagy; however, key components of this pathway remain elusive. Here we performed an RNAi screen to uncover ubiquitin modifiers that are required for starvation-induced macroautophagy in mammalian cells. Our screen uncovered BRUCE/Apollon/Birc6, an IAP protein, as a new autophagy regulator. Depletion of BRUCE leads to defective fusion of autophagosomes and lysosomes. Mechanistically, BRUCE selectively interacts with two ATG8 members GABARAP and GABARAPL1, as well as with Syntaxin 17, which are all critical regulators of autophagosome-lysosome fusion. In addition, BRUCE colocalizes with LAMP2. Interestingly, a non-catalytic N-terminal BRUCE fragment that is sufficient to bind GABARAP/GABARAPL1 and Syntaxin 17, and to colocalize with LAMP2, rescues autolysosome formation in Bruce -/- cells. Thus, BRUCE promotes autolysosome formation independently of its ubiquitin-conjugating activity and is a regulator of both macroautophagy and apoptosis. PMID- 29426819 TI - Offenders become the victim in virtual reality: impact of changing perspective in domestic violence. AB - The role of empathy and perspective-taking in preventing aggressive behaviors has been highlighted in several theoretical models. In this study, we used immersive virtual reality to induce a full body ownership illusion that allows offenders to be in the body of a victim of domestic abuse. A group of male domestic violence offenders and a control group without a history of violence experienced a virtual scene of abuse in first-person perspective. During the virtual encounter, the participants' real bodies were replaced with a life-sized virtual female body that moved synchronously with their own real movements. Participants' emotion recognition skills were assessed before and after the virtual experience. Our results revealed that offenders have a significantly lower ability to recognize fear in female faces compared to controls, with a bias towards classifying fearful faces as happy. After being embodied in a female victim, offenders improved their ability to recognize fearful female faces and reduced their bias towards recognizing fearful faces as happy. For the first time, we demonstrate that changing the perspective of an aggressive population through immersive virtual reality can modify socio-perceptual processes such as emotion recognition, thought to underlie this specific form of aggressive behaviors. PMID- 29426820 TI - A Mathematical Model for Enzyme Clustering in Glucose Metabolism. AB - We have recently demonstrated that the rate-limiting enzymes in human glucose metabolism organize into cytoplasmic clusters to form a multienzyme complex, the glucosome, in at least three different sizes. Quantitative high-content imaging data support a hypothesis that the glucosome clusters regulate the direction of glucose flux between energy metabolism and building block biosynthesis in a cluster size-dependent manner. However, direct measurement of their functional contributions to cellular metabolism at subcellular levels has remained challenging. In this work, we develop a mathematical model using a system of ordinary differential equations, in which the association of the rate-limiting enzymes into multienzyme complexes is included as an essential element. We then demonstrate that our mathematical model provides a quantitative principle to simulate glucose flux at both subcellular and population levels in human cancer cells. Lastly, we use the model to simulate 2-deoxyglucose-mediated alteration of glucose flux in a population level based on subcellular high-content imaging data. Collectively, we introduce a new mathematical model for human glucose metabolism, which promotes our understanding of functional roles of differently sized multienzyme complexes in both single-cell and population levels. PMID- 29426821 TI - African ancestry of New World, Bemisia tabaci-whitefly species. AB - Bemisia tabaci whitefly species are some of the world's most devastating agricultural pests and plant-virus disease vectors. Elucidation of the phylogenetic relationships in the group is the basis for understanding their evolution, biogeography, gene-functions and development of novel control technologies. We report here the discovery of five new Sub-Saharan Africa (SSA) B. tabaci putative species, using the partial mitochondrial cytochrome oxidase 1 gene: SSA9, SSA10, SSA11, SSA12 and SSA13. Two of them, SSA10 and SSA11 clustered with the New World species and shared 84.8-86.5% sequence identities. SSA10 and SSA11 provide new evidence for a close evolutionary link between the Old and New World species. Re-analysis of the evolutionary history of B. tabaci species group indicates that the new African species (SSA10 and SSA11) diverged from the New World clade c. 25 million years ago. The new putative species enable us to: (i) re-evaluate current models of B. tabaci evolution, (ii) recognise increased diversity within this cryptic species group and (iii) re-estimate divergence dates in evolutionary time. PMID- 29426822 TI - Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide. AB - Current anti-hepatitis B virus (HBV) agents including interferons and nucleos(t)ide analogs efficiently suppress HBV infection. However, as it is difficult to eliminate HBV from chronically infected liver, alternative anti-HBV agents targeting a new molecule are urgently needed. In this study, we applied a chemical array to high throughput screening of small molecules that interacted with sodium taurocholate cotransporting polypeptide (NTCP), an entry receptor for HBV. From approximately 30,000 compounds, we identified 74 candidates for NTCP interactants, and five out of these were shown to inhibit HBV infection in cell culture. One of such compound, NPD8716, a coumarin derivative, interacted with NTCP and inhibited HBV infection without causing cytotoxicity. Consistent with its NTCP interaction capacity, this compound was shown to block viral attachment to host hepatocytes. NPD8716 also prevented the infection with hepatitis D virus, but not hepatitis C virus, in agreement with NPD8716 specifically inhibiting NTCP mediated infection. Analysis of derivative compounds showed that the anti-HBV activity of compounds was apparently correlated with the affinity to NTCP and the capacity to impair NTCP-mediated bile acid uptake. These results are the first to show that the chemical array technology represents a powerful platform to identify novel viral entry inhibitors. PMID- 29426823 TI - The Tanggula Mountains enhance population divergence in Carex moorcroftii: a dominant sedge on the Qinghai-Tibetan Plateau. AB - High-altitude mountains are often geographic barriers to gene flow and play important roles in shaping population divergence. The central Qinghai-Tibetan Plateau (QTP) stands the location of the Tanggula Mountains (TM). We use the TM as a case, using Carex moorcroftii, a dominant species on the QTP to test the effects of geographic barriers on plant population divergence. We sampled 18 C. moorcroftii populations along a north-south transect crossing the TM to investigate the correlations of genetic variation and morphological traits with climate variables. The results showed this species holds high genetic diversity (He = 0.58) and the surveyed populations can be genetically clustered into two groups: populations from the north face of TM, and the other from the south. Gene flow between populations within groups is higher than those between groups. The traits, number and mass of seeds, mass of root and infructescence significantly varied among populations. Mantel-tests detected a weak but significantly positive correlation between genetic and geographic (R2 = 0.107, p = 0.032) and climatic distance (R2 = 0.162, p = 0.005), indicating both isolation by distance and isolation by environment. These findings together suggest high-altitude mountains of TM interrupt habitat continuity, result in distinct climatic conditions on both sides, increasing population divergence of plant species. PMID- 29426824 TI - Plasma Abeta analysis using magnetically-labeled immunoassays and PET 18F florbetapir binding in non-demented patients with major depressive disorder. AB - An increased level of brain amyloid deposition and a decreased level of cerebral spinal fluid (CSF) Abeta42 are currently considered reliable biomarkers of Alzheimer's disease (AD); however, the usefulness of plasma Abeta levels are not well-established. This study investigated the relationships between plasma Abeta levels and cerebral amyloidosis in 36 non-demented patients with major depressive disorder (MDD). All participants underwent 18F-florbetapir PET imaging and provided a blood sample at the same time for immunomagnetic reduction assay to measure the plasma levels of Abeta40 and Abeta42. We found inverse associations of the plasma Abeta42 level and the Abeta42/Abeta40 ratio, and a positive association of the plasma Abeta40 level, with cerebral amyloid deposition in the precuneus, parietal and posterior cingulate cortex. Subgroup analyses in subjects with higher 18F-florbetapir uptake values or MDD with amnestic mild cognitive impairment revealed more pervasive relationships of plasma Abeta measures with 18F-florbetapir binding across the brain regions examined. The study suggested that regional brain amyloid deposition in terms of 18F-florbetapir PET uptake had weak-to-moderate associations with plasma Abeta42 and Abeta40 levels, and the Abeta42/Abeta40 ratio. Validation in a larger population of subjects of known cerebral amyloidosis status is needed. Careful interpretation of plasma data is warranted. PMID- 29426825 TI - Patterns of island change and persistence offer alternate adaptation pathways for atoll nations. AB - Sea-level rise and climatic change threaten the existence of atoll nations. Inundation and erosion are expected to render islands uninhabitable over the next century, forcing human migration. Here we present analysis of shoreline change in all 101 islands in the Pacific atoll nation of Tuvalu. Using remotely sensed data, change is analysed over the past four decades, a period when local sea level has risen at twice the global average (~3.90 +/- 0.4 mm.yr-1). Results highlight a net increase in land area in Tuvalu of 73.5 ha (2.9%), despite sea level rise, and land area increase in eight of nine atolls. Island change has lacked uniformity with 74% increasing and 27% decreasing in size. Results challenge perceptions of island loss, showing islands are dynamic features that will persist as sites for habitation over the next century, presenting alternate opportunities for adaptation that embrace the heterogeneity of island types and their dynamics. PMID- 29426827 TI - The Size Congruity Effect Vanishes in Grasping: Implications for the Processing of Numerical Information. AB - Judgments of the physical size in which a numeral is presented are often affected by the task-irrelevant attribute of its numerical magnitude, the Size Congruity Effect (SCE). The SCE is typically interpreted as a marker of the automatic activation of numerical magnitude. However, a growing literature shows that the SCE is not robust, a possible indication that numerical information is not always activated in an automatic fashion. In the present study, we tested the SCE via grasping by way of resolving the automaticity debate. We found results that challenge the robustness of the SCE and, consequently, the validity of the automaticity assumption. The SCE was absent when participants grasped the physically larger object of a pair of 3D wooden numerals. An SCE was still recorded when the participants perceptually indicated the general location of the larger object, but not when they grasped that object. These results highlight the importance of the sensory domain when considering the generality of a perceptual effect. PMID- 29426826 TI - Neurodynamics and connectivity during facial fear perception: The role of threat exposure and signal congruity. AB - Fearful faces convey threat cues whose meaning is contextualized by eye gaze: While averted gaze is congruent with facial fear (both signal avoidance), direct gaze (an approach signal) is incongruent with it. We have previously shown using fMRI that the amygdala is engaged more strongly by fear with averted gaze during brief exposures. However, the amygdala also responds more to fear with direct gaze during longer exposures. Here we examined previously unexplored brain oscillatory responses to characterize the neurodynamics and connectivity during brief (~250 ms) and longer (~883 ms) exposures of fearful faces with direct or averted eye gaze. We performed two experiments: one replicating the exposure time by gaze direction interaction in fMRI (N = 23), and another where we confirmed greater early phase locking to averted-gaze fear (congruent threat signal) with MEG (N = 60) in a network of face processing regions, regardless of exposure duration. Phase locking to direct-gaze fear (incongruent threat signal) then increased significantly for brief exposures at ~350 ms, and at ~700 ms for longer exposures. Our results characterize the stages of congruent and incongruent facial threat signal processing and show that stimulus exposure strongly affects the onset and duration of these stages. PMID- 29426828 TI - An Alfin-like gene from Atriplex hortensis enhances salt and drought tolerance and abscisic acid response in transgenic Arabidopsis. AB - Alfin-like (AL) is a small plant-specific gene family with prominent roles in root growth and abiotic stress response. Here, we aimed to identify novel stress tolerance AL genes from the stress-tolerant species Atriplex hortensis. Totally, we isolated four AhAL genes, all encoding nuclear-localized proteins with cis element-binding and transrepression activities. Constitutive expression of AhAL1 in Arabidopsis facilitated plants to survive under saline condition, while expressing anyone of the other three AhAL genes led to salt-hypersensitive response, indicating functional divergence of AhAL family. AhAL1 also conferred enhanced drought tolerance, as judged from enhanced survival, improved growth, decreased malonaldehyde (MDA) content and reduced water loss in AhAL1-expressing plants compared to WT. In addition, abscisic acid (ABA)-mediated stomatal closure and inhibition of seed germination and primary root elongation were enhanced in AhAL1-transgenic plants. Further analysis demonstrated that AhAL1 could bind to promoter regions of GRF7, DREB1C and several group-A PP2C genes and repress their expression. Correspondingly, the expression levels of positive stress regulator genes DREB1A, DREB2A and three ABFs were all increased in AhAL1-expressing plants. Based on these results, AhAL1 was identified as a novel candidate gene for improving abiotic stress tolerance of crop plants. PMID- 29426829 TI - Impaired thymopoiesis predicts for a high risk of severe infections after reduced intensity conditioning without anti-thymocyte globulin in double umbilical cord blood transplantation. AB - Umbilical cord blood stem cell transplantation (UCBT) is associated with retarded hematopoietic recovery and immune reconstitution and a high infection-related morbidity and mortality, especially after conditioning including anti-thymocyte globulin (ATG). However, data on immune recovery, incidence of infections, and outcome in double UCBT (dUCBT) recipients receiving an ATG-free reduced intensity conditioning (RIC) are lacking. In this study, recovery of lymphocyte subsets, thymopoiesis, and its association with severe infections and clinical outcome was assessed in a group of 55 recipients of a dUCBT ATG-free RIC regimen. T cell recovery was severely protracted in the majority of patients. However, T cell receptor excision circle TREC+ T cells were detectable in 62% of patients at 3 months post-transplantation. A total of 128 common toxicity criteria grade 3-4 infections were observed in the first year post-transplantation. Non-relapse mortality at 12 months post-transplant was 16%, of which 78% infectious mortality. One-year overall survival was 73%. Patients who failed to recover thymopoiesis at 3 months post-transplantation were at a 3.3-fold higher risk of subsequent severe grade 3-4 infections. PMID- 29426830 TI - Safety of live-attenuated measles-mumps-rubella and herpes zoster vaccination in multiple myeloma patients on maintenance lenalidomide or bortezomib after autologous hematopoietic cell transplantation. AB - Attenuated live virus vaccinations are generally recommended 24 months following hematopoietic cell transplantation (HCT) in patients not receiving immunosuppressive therapy. To date, there are no data regarding the safety of live-attenuated herpes zoster or measles-mumps-rubella (MMR) vaccinations in multiple myeloma patients on maintenance lenalidomide or bortezomib following autologous HCT. One hundred thirty-seven multiple myeloma patients on maintenance lenalidomide or bortezomib post-auto-HCT who received either MMR or herpes zoster vaccine were analyzed and any adverse events documented in the medical record in the 42 days following vaccination were recorded. Patients were vaccinated a median of 25 months (range, 18-62) post transplant. The most common post vaccination adverse event was upper respiratory tract infection (18/137 patients); no rash attributed to vaccine strains or other adverse outcomes potentially related to the vaccines were identified. MMR and herpes zoster vaccination were safe and well-tolerated in this cohort. PMID- 29426831 TI - Cardiovascular risk factors and subclinical organ damage after hematopoietic stem cell transplantation in pediatric age. AB - Advances in allogeneic hematopoietic stem cell transplantation (HSCT) in malignant and non-malignant diseases result in more long-term survivors, in whom cardiovascular (CV) disease is one leading non-cancer cause of death. This study aimed to evaluate risk factors and subclinical CV organ damage in survivors after HSCT in pediatric age. We enrolled 64 children in a cross-sectional approach 3.3 +/- 3.1 years after HSCT. Anthropometric data, laboratory values, office and 24-h ambulatory blood pressure monitoring (ABPM) were evaluated, showing a high prevalence of obesity, hypertension and dyslipidemia. CV organ damage was determined by non-invasive measurements of aortic pulse wave velocity (PWV), left ventricular mass index (LVMI), and carotid intima media thickness (IMT). Increased IMT and elevated PWV reflecting subclinical vascular damage were detected in 48% (IMT) and 6% (PWV) of our population. For IMT, physical activity had a positive impact and was worsened by time after HSCT. Our results show a surprisingly high rate of subclinical CV organ damage and classical risk factors. Therefore, diagnosis and management of well-known CV risk factors belong to clinical care after HSCT. PMID- 29426833 TI - Novel reversibly switchable fluorescent proteins for RESOLFT and STED nanoscopy engineered from the bacterial photoreceptor YtvA. AB - The reversibly switchable fluorescent proteins (RSFPs) commonly used for RESOLFT nanoscopy have been developed from fluorescent proteins of the GFP superfamily. These proteins are bright, but exhibit several drawbacks such as relatively large size, oxygen-dependence, sensitivity to low pH, and limited switching speed. Therefore, RSFPs from other origins with improved properties need to be explored. Here, we report the development of two RSFPs based on the LOV domain of the photoreceptor protein YtvA from Bacillus subtilis. LOV domains obtain their fluorescence by association with the abundant cellular cofactor flavin mononucleotide (FMN). Under illumination with blue and ultraviolet light, they undergo a photocycle, making these proteins inherently photoswitchable. Our first improved variant, rsLOV1, can be used for RESOLFT imaging, whereas rsLOV2 proved useful for STED nanoscopy of living cells with a resolution of down to 50 nm. In addition to their smaller size compared to GFP-related proteins (17 kDa instead of 27 kDa) and their usability at low pH, rsLOV1 and rsLOV2 exhibit faster switching kinetics, switching on and off 3 times faster than rsEGFP2, the fastest switching RSFP reported to date. Therefore, LOV-domain-based RSFPs have potential for applications where the switching speed of GFP-based proteins is limiting. PMID- 29426832 TI - Genome-wide tracking of dCas9-methyltransferase footprints. AB - In normal mammalian development cytosine methylation is essential and is directed to specific regions of the genome. Despite notable advances through mapping its genome-wide distribution, studying the direct contribution of DNA methylation to gene and genome regulation has been limited by the lack of tools for its precise manipulation. Thus, combining the targeting capability of the CRISPR-Cas9 system with an epigenetic modifier has attracted interest in the scientific community. In contrast to profiling the genome-wide cleavage of a nuclease competent Cas9, tracing the global activity of a dead Cas9 (dCas9) methyltransferase fusion protein is challenging within a highly methylated genome. Here, we report the generation and use of an engineered, methylation depleted but maintenance competent mouse ES cell line and find surprisingly ubiquitous nuclear activity of dCas9-methyltransferases. Subsequent experiments in human somatic cells refine these observations and point to an important difference between genetic and epigenetic editing tools that require unique experimental considerations. PMID- 29426834 TI - Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. AB - Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS. Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling. Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51 plex Luminex bead kit at baseline and 18 hours following exercise. Cardiac structure and exercise capacity were similar between groups. Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (kappa = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-beta, interferon-alpha and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls. PMID- 29426836 TI - Combinatorial hydrogels with biochemical gradients for screening 3D cellular microenvironments. AB - 3D microenvironmental parameters control cell behavior, but can be challenging to investigate over a wide range of conditions. Here, a combinatorial hydrogel platform is developed that uses light-mediated thiol-norbornene chemistry to encapsulate cells within hydrogels with biochemical gradients made by spatially varied light exposure. Specifically, mesenchymal stem cells are photoencapsulated in norbornene-modified hyaluronic acid hydrogels functionalized with gradients (0 5 mM) of peptides that mimic cell-cell or cell-matrix interactions, either as single or orthogonal gradients. Chondrogenesis varied spatially in these hydrogels based on the local biochemical formulation, as indicated by Sox9 and aggrecan expression levels. From 100 combinations investigated, discrete hydrogels are formulated and early gene expression and long-term cartilage specific matrix production are assayed and found to be consistent with screening predictions. This platform is a scalable, high-throughput technique that enables the screening of the effects of multiple biochemical signals on 3D cell behavior. PMID- 29426835 TI - Transcriptome analysis and prognosis of ALDH isoforms in human cancer. AB - Overexpression of ALDH is associated with cancer stem-like features and poor cancer prognosis. High ALDH activity has been observed in cancer stem-like cells. There are a total of 19 human ALDH isoforms, all of which are associated with reducing oxidative stress and protecting cells from damage. However, it is unknown whether all ALDHs are associated with poor cancer prognosis and which ones play a significant role in cancer progression. In this study, we used RNA sequencing data from The Cancer Genome Atlas (TCGA) to evaluate the differential expression of 19 ALDH isoforms in 5 common human cancers. The 19 ALDH genes were analyzed with an integrating meta-analysis of cancer prognosis. Genotyping and next-generation RNA sequencing for 30 pairwise samples of head and neck squamous cell carcinoma were performed and compared with the TCGA cohort. The analysis showed that each ALDH isoform had a specific differential expression pattern, most of which were related to prognosis in human cancer. A lower expression of ALDH2 in the tumor was observed, which was independent from the ALDH2 rs671 SNP variant and the expression of other mitochondria-associated protein coding genes. This study provides new insight into the association between ALDH expression and cancer prognosis. PMID- 29426837 TI - Association of CD14 rs2569190 polymorphism with mortality in shock septic patients who underwent major cardiac or abdominal surgery: A retrospective study. AB - The aim of this study was to investigate the relationship between the CD14 rs2569190 polymorphism and death related to septic shock in white European patients who underwent major cardiac or abdominal surgery. We carried out a retrospective study in 205 septic shock patients. The septic shock diagnosis was established by international consensus definitions. The outcome variable was the death within 28, 60 and 90 days after septic shock diagnosis. The CD14 rs2569190 polymorphism was analyzed by Agena Bioscience's MassARRAY platform. For the genetic association analysis with survival was selected a recessive inheritance model (GG vs. AA/AG). One hundred thirteen out of 205 patients (55.1%) died with a survival median of 39 days (95%CI = 30.6; 47.4). Patients with rs2569190 GG genotype had shorter survival probability than rs2569190 AA/AG genotype at 60 days (62.3% vs 50%; p = 0.035), and 90 days (62.3% vs 52.6%; p = 0.046). The rs2569190 GG genotype was associated with increased risk of septic shock-related death in the first 60 days (adjusted hazard ratio (aHR) = 1.67; p = 0.016) and 90 days (aHR = 1.64; p = 0.020) compared to rs2569190 AA/AG genotype. In conclusion, the presence of CD14 rs2569190 GG genotype was associated with death in shock septic patients who underwent major surgery. Further studies with bigger sample size are required to verify this relationship. PMID- 29426839 TI - Association of muscle mass and fat mass with insulin resistance and the prevalence of metabolic syndrome in Korean adults: a cross-sectional study. AB - Relationship of muscle mass and fat mass with insulin resistance and metabolic syndrome remains uncertain, especially among Asian population. We performed a cross-sectional study with 14,807 adult participants aged between 18 and 65 in the fourth and fifth Korea National Health and Nutrition Examination Survey with Dual Energy X-ray Absorptiometry (DEXA) data to investigate whether muscle mass and fat mass are associated with insulin resistance and metabolic syndrome. DEXA records were used to categorize the participants into four categories (low muscle/low fat, low muscle/high fat, high muscle/ low fat, and high muscle/high fat). Least square means and incidence rate ratios (IRR) were used to assess the associations of muscle mass and fat mass with insulin resistance and metabolic syndrome. After adjustment for potential confounders, high muscle/low fat was associated with significantly lower insulin resistance (P < 0.001) compared to low muscle/low fat. Low muscle/high fat (IRR: 1.90; 95% confidence interval [CI]:1.44-2.50, P < 0.001) and high muscle/high fat (IRR: 2.30; 95% CI:1.76-3.00, P < 0.001) were significantly associated with the prevalence of metabolic syndrome. Our study suggests that protective association of muscle mass with metabolic syndrome is attenuated by high fat mass in Korean adults. PMID- 29426840 TI - Spectroscopy of bulk and few-layer superconducting NbSe2 with van der Waals tunnel junctions. AB - Tunnel junctions, an established platform for high resolution spectroscopy of superconductors, require defect-free insulating barriers; however, oxides, the most common barrier, can only grow on a limited selection of materials. We show that van der Waals tunnel barriers, fabricated by exfoliation and transfer of layered semiconductors, sustain stable currents with strong suppression of sub gap tunneling. This allows us to measure the spectra of bulk (20 nm) and ultrathin (3- and 4-layer) NbSe2 devices at 70 mK. These exhibit two distinct superconducting gaps, the larger of which decreases monotonically with thickness and critical temperature. The spectra are analyzed using a two-band model incorporating depairing. In the bulk, the smaller gap exhibits strong depairing in in-plane magnetic fields, consistent with high out-of-plane Fermi velocity. In the few-layer devices, the large gap exhibits negligible depairing, consistent with out-of-plane spin locking due to Ising spin-orbit coupling. In the 3-layer device, the large gap persists beyond the Pauli limit. PMID- 29426838 TI - Gene-Specific Genetic Complementation between Brca1 and Cobra1 During Mouse Mammary Gland Development. AB - Germ-line mutations in breast cancer susceptibility gene, BRCA1, result in familial predisposition to breast and ovarian cancers. The BRCA1 protein has multiple functional domains that interact with a variety of proteins in multiple cellular processes. Understanding the biological consequences of BRCA1 interactions with its binding partners is important for elucidating its tissue specific tumor suppression function. The Cofactor of BRCA1 (COBRA1) is a BRCA1 binding protein that, as a component of negative elongation factor (NELF), regulates RNA polymerase II pausing during transcription elongation. We recently identified a genetic interaction between mouse Brca1 and Cobra1 that antagonistically regulates mammary gland development. However, it remains unclear which of the myriad functions of Brca1 are required for its genetic interaction with Cobra1. Here, we show that, unlike deletion of Brca1 exon 11, separation-of function mutations that abrogate either the E3 ligase activity of its RING domain or the phospho-recognition property of its BRCT domain are not sufficient to rescue the mammary developmental defects in Cobra1 knockout mice. Furthermore, deletion of mouse Palb2, another breast cancer susceptibility gene with functional similarities to BRCA1, does not rescue Cobra1 knockout-associated mammary defects. Thus, the Brca1/Cobra1 genetic interaction is both domain- and gene-specific in the context of mammary gland development. PMID- 29426842 TI - Molecular-channel driven actuator with considerations for multiple configurations and color switching. AB - The ability to achieve simultaneous intrinsic deformation with fast response in commercially available materials that can safely contact skin continues to be an unresolved challenge for artificial actuating materials. Rather than using a microporous structure, here we show an ambient-driven actuator that takes advantage of inherent nanoscale molecular channels within a commercial perfluorosulfonic acid ionomer (PFSA) film, fabricated by simple solution processing to realize a rapid response, self-adaptive, and exceptionally stable actuation. Selective patterning of PFSA films on an inert soft substrate (polyethylene terephthalate film) facilitates the formation of a range of different geometries, including a 2D (two-dimensional) roll or 3D (three dimensional) helical structure in response to vapor stimuli. Chemical modification of the surface allowed the development of a kirigami-inspired single layer actuator for personal humidity and heat management through macroscale geometric design features, to afford a bilayer stimuli-responsive actuator with multicolor switching capability. PMID- 29426841 TI - Altered DNA methylation indicates an oscillatory flow mediated epithelial-to mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve. AB - Disturbed flow has been suggested to contribute to aneurysm susceptibility in bicuspid aortic valve (BAV) patients. Lately, flow has emerged as an important modulator of DNA methylation. Hear we combined global methylation analysis with in vitro studies of flow-sensitive methylation to identify biological processes associated with BAV-aortopathy and the potential contribution of flow. Biopsies from non-dilated and dilated ascending aortas were collected from BAV (n = 21) and tricuspid aortic valve (TAV) patients (n = 23). DNA methylation and gene expression was measured in aortic intima-media tissue samples, and in EA.hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (+/-12 dynes/cm2) or laminar (12 dynes/cm2) flow. We show methylation changes related to epithelial-mesenchymal-transition (EMT) in the non-dilated BAV aorta, associated with oscillatory flow related to endocytosis. The results indicate that the flow-response in BAV ECs involves hypomethylation and increased expression of WNT/beta-catenin genes, as opposed to an angiogenic profile in TAV ECs. The EMT-signature was exasperated in dilated BAV aortas. Aberrant EMT in BAV aortic walls could contribute to increased aneurysm susceptibility, and may be due to disturbed flow-exposure. Perturbations during the spatiotemporally related embryonic development of ascending aorta and semilunar valves can however not be excluded. PMID- 29426843 TI - Josephson vortex loops in nanostructured Josephson junctions. AB - Linked and knotted vortex loops have recently received a revival of interest. Such three-dimensional topological entities have been observed in both classical- and super-fluids, as well as in optical systems. In superconductors, they remained obscure due to their instability against collapse - unless supported by inhomogeneous magnetic field. Here we reveal a new kind of vortex matter in superconductors - the Josephson vortex loops - formed and stabilized in planar junctions or layered superconductors as a result of nontrivial cutting and recombination of Josephson vortices around the barriers for their motion. Engineering latter barriers opens broad perspectives on loop manipulation and control of other possible knotted/linked/entangled vortex topologies in nanostructured superconductors. In the context of Josephson devices proposed to date, the high-frequency excitations of the Josephson loops can be utilized in future design of powerful emitters, tunable filters and waveguides of high frequency electromagnetic radiation, thereby pushing forward the much needed Terahertz technology. PMID- 29426844 TI - The impact of reconstructed soils following oil sands exploitation on aspen and its associated belowground microbiome. AB - The objective of this study was to investigate the impact of different soil covers used to reclaim decommissioned oil sands mining sites on the genetic diversity of aspen and their associated belowground microbiota. Aspen genotyping showed that trees mostly originated from sexual reproduction on sites reclaimed with soil covers made of upland forest floor-mineral mix (FFMM) and lowland peat mineral mix (PMM). In contrast, most individuals in mature and burned stands sampled as benchmarks for natural disturbances originated from vegetative reproduction. Nonetheless, aspen populations in the FFMM and PMM sites were not genetically different from those in mature and burned stands. DNA metabarcoding of bacteria and fungi in root and soil samples revealed that the diversity of the belowground microbiota associated with aspen and the relative abundance of putative symbiotic taxa in PMM were significantly lower than for FFMM and naturally disturbed sites. Despite similar aspen genetic diversity between FFMM and PMM sites, trees were not associated with the same belowground microbiota. Because the soil microbiome and more specifically the mycorrhizal communities are variable both in space and time, long-term monitoring is particularly important to better understand the ecological trajectory of these novel ecosystems. PMID- 29426845 TI - Short-term Effect of Ambient Ozone on Daily Emergency Room Visits in Beijing, China. AB - Little is known about the acute effects of ozone on morbidity risk in China. We conducted a time-series study to examine the association between ozone and daily emergency room visits (ERVs) in Beijing, China. We identified 7,088,309 ERVs between January 1, 2014 and December 31, 2015. A generalized additive model with Poisson regression incorporating penalized spline functions was employed to analyze ERVs in association with daily 8-h maximum ozone concentrations. An increase of 10 MUg/m3 of same-day ozone concentration was significantly associated with a 0.24% (95% CI, 0.21%-0.26%), 0.31% (95% CI, 0.27%-0.35%), and 0.43% (95% CI, 0.36%-0.50%) increase in daily ERVs for the whole study period, days when the daily 8-h maximum ozone met the Chinese Ambient Air Quality Standards (CAAQS) Grade II standard, and days that met the CAAQS Grade I standard, respectively. These results were robust when considering the potential confounding effects of PM2.5, PM10, NO2, SO2, and CO. In conclusion, our findings suggested significant effects of ozone exposure on daily ERVs in Beijing. Improving air quality with even lower ozone level than the current CAAQS could yield important public health. PMID- 29426846 TI - Contributions of Pavlovian incentive motivation to cue-potentiated feeding. AB - Cues signaling the availability of palatable food acquire the ability to potentiate food seeking and consumption. The current study employed a combination of behavioral, pharmacological, and analytical techniques to probe the role of Pavlovian incentive motivation in cue-potentiated feeding. We show that a cue paired with sucrose solution (CS+) can transfer its control over feeding to stimulate sucrose consumption at a new receptacle, and that this effect depends on activation of D1 dopamine receptors, which is known to modulate other forms of cue-motivated behavior but not taste palatability. Microstructural analyses of sucrose-licking behavior revealed that the CS+ tended to increase the frequency with which rats engaged in active bouts of licking behavior without having a reliable effect on the duration of those licking bouts, a measure that was instead associated with sucrose palatability. Furthermore, we found that individual differences in CS+ elicited increases in bout frequency were associated with total sucrose intake at test, supporting the view that this process was related to meaningful dysregulation of eating behavior. The current study, therefore, (1) demonstrates that a dopamine-dependent Pavlovian incentive motivational process can mediate cue-potentiated feeding, and (2) lays out an experimental and analytical approach for parsing this aspect of behavior. PMID- 29426847 TI - Compositional marker in vivo reveals intramyocellular lipid turnover during fasting-induced lipolysis. AB - Intramyocellular lipid (IMCL) is of particular metabolic interest, but despite many proton magnetic resonance spectroscopy (1H MRS) studies reporting IMCL content measured by the methylene (CH2) resonance signal, little is known about its composition. Here we validated IMCL CH3:CH2 ratio as a compositional marker using 1H MRS at short echo time, and investigated IMCL content and composition during a 28-hour fast in 24 healthy males. Increases in IMCL CH2 relative to the creatine and phosphocreatine resonance (Cr) at 3.0 ppm (an internal standard) correlated with circulating free fatty acid (FA) concentrations, supporting the concept of increased FA influx into IMCL. Significant decreases in IMCL CH3:CH2 ratio indicated a less unsaturated IMCL pool after fasting, and this compositional change related inversely to IMCL baseline composition, suggesting a selective efflux of unsaturated shorter-chain FA from the IMCL pool. This novel in vivo evidence reveals IMCL turnover during extended fasting, consistent with the concept of a flexible, responsive myocellular lipid store. There were also differences between soleus and tibialis anterior in basal IMCL composition and in response to fasting. We discuss the potential of this marker for providing insights into normal physiology and mechanisms of disease. PMID- 29426848 TI - Sleep endophenotypes of schizophrenia: slow waves and sleep spindles in unaffected first-degree relatives. AB - Sleep spindles and slow waves are the main brain oscillations occurring in non REM sleep. Several lines of evidence suggest that spindles are initiated within the thalamus, whereas slow waves are generated and modulated in the cortex. A decrease in sleep spindle activity has been described in Schizophrenia (SCZ), including chronic, early course, and early onset patients. In contrast, slow waves have been inconsistently found to be reduced in SCZ, possibly due to confounds like duration of illness and antipsychotic medication exposure. Nontheless, the implication of sleep spindles and slow waves in the neurobiology of SCZ and related disorders, including their heritability, remains largely unknown. Unaffected first-degree relatives (FDRs) share a similar genetic background and several neurophysiological and cognitive deficits with SCZ patients, and allow testing whether some of these measures are candidate endophenotypes. In this study, we performed sleep high-density EEG recordings to characterise the spatiotemporal features of sleep spindles and slow waves in FDRs of SCZ probands and healthy subjects (HS) with no family history of SCZ. We found a significant reduction of integrated spindle activity (ISAs) in FDRs relative to HS, whereas spindle density and spindle duration were not different between groups. FDRs also had decreased slow wave amplitude and slopes. Altogether, our results suggest that ISAs deficits might represent a candidate endophenotype for SCZ. Furthermore, given the slow wave deficits observed in FDRs, we propose that disrupted cortical synchronisation increases the risk for SCZ, but thalamic dysfunction is necessary for the disorder to fully develop. PMID- 29426849 TI - Early life exposure to ethinylestradiol enhances subsequent responses to environmental estrogens measured in a novel transgenic zebrafish. AB - Estrogen plays fundamental roles in a range of developmental processes and exposure to estrogen mimicking chemicals has been associated with various adverse health effects in both wildlife and human populations. Estrogenic chemicals are found commonly as mixtures in the environment and can have additive effects, however risk analysis is typically conducted for single-chemicals with little, or no, consideration given for an animal's exposure history. Here we developed a transgenic zebrafish with a photoconvertable fluorophore (Kaede, green to red on UV light exposure) in a skin pigment-free mutant element (ERE)-Kaede-Casper model and applied it to quantify tissue-specific fluorescence biosensor responses for combinations of estrogen exposures during early life using fluorescence microscopy and image analysis. We identify windows of tissue-specific sensitivity to ethinylestradiol (EE2) for exposure during early-life (0-5 dpf) and illustrate that exposure to estrogen (EE2) during 0-48 hpf enhances responsiveness (sensitivity) to different environmental estrogens (EE2, genistein and bisphenol A) for subsequent exposures during development. Our findings illustrate the importance of an organism's stage of development and estrogen exposure history for assessments on, and possible health risks associated with, estrogen exposure. PMID- 29426850 TI - Asymmetrical ligand-induced cross-regulation of chemokine (C-X-C motif) receptor 4 by alpha1-adrenergic receptors at the heteromeric receptor complex. AB - Recently, we reported that chemokine (C-X-C motif) receptor (CXCR)4 and atypical chemokine receptor 3 regulate alpha1-adrenergic receptors (alpha1-AR) through the formation of hetero-oligomeric complexes. Whether alpha1-ARs also regulate chemokine receptor function within such heteromeric receptor complexes is unknown. We observed that activation of alpha1b-AR within the alpha1b-AR:CXCR4 heteromeric complex leads to cross-recruitment of beta-arrestin2 to CXCR4, which could not be inhibited with AMD3100. Activation of CXCR4 did not cross-recruit beta-arrestin2 to alpha1b-AR. A peptide analogue of transmembrane domain 2 of CXCR4 interfered with alpha1b-AR:CXCR4 heteromerization and inhibited alpha1b-AR mediated beta-arrestin2 cross-recruitment. Phenylephrine (PE) induced internalization of CXCR4 in HEK293 cells co-expressing CXCR4 and alpha1b-AR and of endogenous CXCR4 in human vascular smooth muscle cells (hVSMC). The latter was detectable despite blockade of CXCR4 with the neutralizing antibody 12G5. hVSMC migrated towards CXCL12 and PE, but not towards a combination of CXCL12 and PE. PE inhibited CXCL12-induced chemotaxis of hVSMC (IC50: 77 +/- 30 nM). Phentolamine cross-inhibited CXCL12-induced chemotaxis of hVSMC, whereas AMD3100 did not cross-inhibit PE-induced chemotaxis. These data provide evidence for asymmetrical cross-regulation of CXCR4 by alpha1-adrenergic receptors within the heteromeric receptor complex. Our findings provide mechanistic insights into the function of alpha1-AR:CXCR4 heteromers and suggest alternative approaches to modulate CXCR4 in disease conditions. PMID- 29426852 TI - Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebo-controlled trial. PMID- 29426851 TI - Enantioselective [3+3] atroposelective annulation catalyzed by N-heterocyclic carbenes. AB - Axially chiral molecules are among the most valuable substrates in organic synthesis. They are typically used as chiral ligands or catalysts in asymmetric reactions. Recent progress for the construction of these chiral molecules is mainly focused on the transition-metal-catalyzed transformations. Here, we report the enantioselective NHC-catalyzed (NHC: N-heterocyclic carbenes) atroposelective annulation of cyclic 1,3-diones with ynals. In the presence of NHC precatalyst, base, Lewis acid and oxidant, a catalytic C-C bond formation occurs, providing axially chiral alpha-pyrone-aryls in moderate to good yields and with high enantioselectivities. Control experiments indicated that alkynyl acyl azoliums, acting as active intermediates, are employed to atroposelectively assemble chiral biaryls and such a methodology may be creatively applied to other useful NHC catalyzed asymmetric transformations. PMID- 29426853 TI - Performance of the Silverman Andersen Respiratory Severity Score in predicting PCO2 and respiratory support in newborns: a prospective cohort study. AB - OBJECTIVE: To determine if the Silverman Andersen respiratory severity score, which is assessed by physical exam, within 1 h of birth is associated with elevated carbon dioxide level and/or the need for increased respiratory support. STUDY DESIGN: Prospective cohort study including 140 neonates scored within 1 h of birth. We report respiratory scores and their association with carbon dioxide and respiratory support within 24 h. RESULTS: Carbon dioxide level correlated with respiratory score (n = 33, r = 0.35, p = 0.045). However, mean carbon dioxide for patients with score <5 vs. >=5 did not differ significantly (56 vs. 67, p = 0.095). Patients with respiratory scores >=5 had respiratory support increased within 24 h more often than those with scores <5 (79% vs. 28%, p < 0.001). CONCLUSION: The Silverman Andersen respiratory severity score may be valuable for predicting need for escalation of respiratory support and facilitate decision making for transfer in low-resource settings. PMID- 29426854 TI - Association between plasma cortisol and death or vasopressor refractory hypotension in preterm neonates: a prospective, cohort study. AB - OBJECTIVES: Temporal relation between adrenal insufficiency and hypotension is poorly understood. We examined the association between basal and post-stimulation cortisol and death or vasopressor refractory hypotension in preterm neonates. STUDY DESIGN: Prospective cohort study in <=30 weeks' and/or <1,250 g weight. Primary outcome-composite of death or vasopressor refractory hypotension by day 14 of life. Plasma cortisol levels were measured at 24-36 h (T1), 72-84 h (T2) and 10 days (T3), and post-stimulation cortisol at T1 and later at T2 and T3 if the adrenal response was inadequate earlier. RESULTS: Basal cortisol (ug/dl) at 24-36 h was significantly higher in the outcome group (37.2 +/- 21.1 vs. 22.04 +/ 14.6; mean difference (MD) (95% confidence interval (CI)): -15.1 (-23.6, -6.6); p = 0.005). High basal cortisol at 24-36 h (odds ratio (OR) (95% CI): 1.044 (1.009, 1.079); p = 0.01) and need for ventilation (OR (95% CI): 9.7 (1.2, 81.2); p = 0.04) independently increased the risk of death or vasopressor refractory hypotension. CONCLUSION: Preterm neonates who died or developed vasopressor refractory hypotension by day 14 had significantly elevated basal cortisol at 24 36 h of life. PMID- 29426855 TI - Quantum ensembles of quantum classifiers. AB - Quantum machine learning witnesses an increasing amount of quantum algorithms for data-driven decision making, a problem with potential applications ranging from automated image recognition to medical diagnosis. Many of those algorithms are implementations of quantum classifiers, or models for the classification of data inputs with a quantum computer. Following the success of collective decision making with ensembles in classical machine learning, this paper introduces the concept of quantum ensembles of quantum classifiers. Creating the ensemble corresponds to a state preparation routine, after which the quantum classifiers are evaluated in parallel and their combined decision is accessed by a single qubit measurement. This framework naturally allows for exponentially large ensembles in which - similar to Bayesian learning - the individual classifiers do not have to be trained. As an example, we analyse an exponentially large quantum ensemble in which each classifier is weighed according to its performance in classifying the training data, leading to new results for quantum as well as classical machine learning. PMID- 29426856 TI - Cellular imaging by targeted assembly of hot-spot SERS and photoacoustic nanoprobes using split-fluorescent protein scaffolds. AB - The in cellulo assembly of plasmonic nanomaterials into photo-responsive probes is of great interest for many bioimaging and nanophotonic applications but remains challenging with traditional nucleic acid scaffolds-based bottom-up methods. Here, we address this quandary using split-fluorescent protein (FP) fragments as molecular glue and switchable Raman reporters to assemble gold or silver plasmonic nanoparticles (NPs) into photonic clusters directly in live cells. When targeted to diffusing surface biomarkers in cancer cells, the NPs self-assemble into surface-enhanced Raman-scattering (SERS) nanoclusters having hot spots homogenously seeded by the reconstruction of full-length FPs. Within plasmonic hot spots, autocatalytic activation of the FP chromophore and near field amplification of its Raman fingerprints enable selective and sensitive SERS imaging of targeted cells. This FP-driven assembly of metal colloids also yields enhanced photoacoustic signals, allowing the hybrid FP/NP nanoclusters to serve as contrast agents for multimodal SERS and photoacoustic microscopy with single cell sensitivity. PMID- 29426857 TI - Next generation high throughput DNA damage detection platform for genotoxic compound screening. AB - Methods for quantifying DNA damage, as well as repair of that damage, in a high throughput format are lacking. Single cell gel electrophoresis (SCGE; comet assay) is a widely-used method due to its technical simplicity and sensitivity, but the standard comet assay has limitations in reproducibility and throughput. We have advanced the SCGE assay by creating a 96-well hardware platform coupled with dedicated data processing software (CometChip Platform). Based on the original cometchip approach, the CometChip Platform increases capacity ~200 times over the traditional slide-based SCGE protocol, with excellent reproducibility. We tested this platform in several applications, demonstrating a broad range of potential uses including the routine identification of DNA damaging agents, using a 74-compound library provided by the National Toxicology Program. Additionally, we demonstrated how this tool can be used to evaluate human populations by analysis of peripheral blood mononuclear cells to characterize susceptibility to genotoxic exposures, with implications for epidemiological studies. In summary, we demonstrated a high level of reproducibility and quantitative capacity for the CometChip Platform, making it suitable for high-throughput screening to identify and characterize genotoxic agents in large compound libraries, as well as for human epidemiological studies of genetic diversity relating to DNA damage and repair. PMID- 29426858 TI - Isolation and characterization of a minimal building block of polyubiquitin fibrils. AB - As a posttranslational modifier, polyubiquitin is involved in the regulation of diverse intracellular processes; however, it is also found in pathological protein aggregates associated with Alzheimer's disease and other neurodegenerative disorders. We previously observed that various types of polyubiquitin can form amyloid-like fibrils; however, the structural properties of these polyubiquitin fibrils have not been examined at an atomic level. Here we demonstrate that a soluble intermediate species can be extracted from disulfide conjugated diubiquitin fibrils after cleaving the disulfide bonds in the fibrils. This newly discovered molecule is structurally and physicochemically distinguishable from native ubiquitin. In addition, it is thermodynamically metastable, as demonstrated by real-time NMR measurements. Collectively, our results suggest that the fibril-derived molecule is a minimal building block of polyubiquitin fibrils that reflects their structural and physicochemical properties. PMID- 29426859 TI - Evoked and oscillatory EEG activity differentiates language discrimination in young monolingual and bilingual infants. AB - Language discrimination is one of the core differences between bilingual and monolingual language acquisition. Here, we investigate the earliest brain specialization induced by it. Following previous research, we hypothesize that bilingual native language discrimination is a complex process involving specific processing of the prosodic properties of the speech signal. We recorded the brain activity of monolingual and bilingual 4.5-month-old infants using EEG, while listening to their native/dominant language and two foreign languages. We defined two different windows of analysis to separate discrimination and identification effects. In the early window of analysis (150-280 ms) we measured the P200 component, and in the later window of analysis we measured Theta (400-1800 ms) and Gamma (300-2800 ms) oscillations. The results point in the direction of different language discrimination strategies for bilingual and monolingual infants. While only monolingual infants show early discrimination of their native language based on familiarity, bilinguals perform a later processing which is compatible with an increase in attention to the speech signal. This is the earliest evidence found for brain specialization induced by bilingualism. PMID- 29426860 TI - Optimization of the Synthesis of Superhydrophobic Carbon Nanomaterials by Chemical Vapor Deposition. AB - Demand is increasing for superhydrophobic materials in many applications, such as membrane distillation, separation and special coating technologies. In this study, we report a chemical vapor deposition (CVD) process to fabricate superhydrophobic carbon nanomaterials (CNM) on nickel (Ni)-doped powder activated carbon (PAC). The reaction temperature, reaction time and H2/C2H2 gas ratio were optimized to achieve the optimum contact angle (CA) and carbon yield (CY). For the highest CY (380%) and CA (177 degrees ), the optimal reaction temperatures were 702 degrees C and 687 degrees C, respectively. However, both the reaction time (40 min) and gas ratio (1.0) were found to have similar effects on CY and CA. Based on the Field emission scanning electron microscopy and transmission electron microscopy images, the CNM could be categorized into two main groups: a) carbon spheres (CS) free carbon nanofibers (CNFs) and b) CS mixed with CNFs, which were formed at 650 and 750 degrees C, respectively. Raman spectroscopy and thermogravimetric analysis also support this finding. The hydrophobicity of the CNM, expressed by the CA, follows the trend of CS-mixed CNFs (CA: 177 degrees ) > CS-free CNFs (CA: 167 degrees ) > PAC/Ni (CA: 65 degrees ). This paves the way for future applications of synthesized CNM to fabricate water-repellent industrial-grade technologies. PMID- 29426861 TI - Deficiency of a triterpene pathway results in humidity-sensitive genic male sterility in rice. AB - In flowering plants, the pollen coat protects the released male germ cells from desiccation and damage during pollination. However, we know little about the mechanism by which the chemical composition of the pollen coat prevents dehydration of pollen grains. Here we report that deficiency of a grass conserved triterpene synthase, OsOSC12/OsPTS1, in rice leads to failure of pollen coat formation. The mutant plants are male sterile at low relative humidity (RH < 60%), but fully male fertile at high relative humidity (>80%). The lack of three major fatty acids in the pollen coat results in rapid dehydration of pollen grains. We show that applying mixtures of linolenic acid and palmitic acid or stearic acid are able to prevent over-dehydration of mutant pollen grains. We propose that humidity-sensitive genic male sterility (HGMS) could be a desirable trait for hybrid breeding in rice, wheat, maize, and other crops. PMID- 29426862 TI - Author Correction: Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. AB - The original version of this Article contained an error in the spelling of the author James C. Mulloy, which was incorrectly given as James Mulloy. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29426863 TI - Identification of biochemical and cytotoxic markers in cocaine treated PC12 cells. AB - Cocaine is one of the powerful addictive drugs, widely abused in most Western countries. Because of high lipophilic nature, cocaine easily reaches various domains of the central nervous system (CNS) and triggers different levels of cellular toxicity. The aim of this investigation was to reproduce cocaine toxicity in differentiated PC12 cells through quantitative knowledge on biochemical and cytotoxicity markers. We differentiated the cells with 0.1 MUg/ml nerve growth factor (NGF) for 5 days, followed by treatment with cocaine for 48 h at in vivo and in vitro concentrations. Results indicated that cocaine at in vivo concentrations neither killed the cells nor altered the morphology, but decreased the mitochondrial membrane potential that paralleled with increased lactate and glutathione (GSH) levels. On the other hand, cocaine at in vitro concentrations damaged the neurites and caused cell death, which corresponded with increased reactive oxygen species (ROS) generation, plasma membrane damage, and GSH depletion with no detectable nitric oxide (NO) level. While direct understanding of cocaine and cell interaction under in vivo animal models is impeded due to high complexity, our present in vitro results assisted in understanding the onset of some key events of neurodegenerative diseases in cocaine treated neuronal cells. PMID- 29426864 TI - Comparative genomics reveals new single-nucleotide polymorphisms that can assist in identification of adherent-invasive Escherichia coli. AB - Adherent-invasive Escherichia coli (AIEC) have been involved in Crohn's disease (CD). Currently, AIEC are identified by time-consuming techniques based on in vitro infection of cell lines to determine their ability to adhere to and invade intestinal epithelial cells as well as to survive and replicate within macrophages. Our aim was to find signature sequences that can be used to identify the AIEC pathotype. Comparative genomics was performed between three E. coli strain pairs, each pair comprised one AIEC and one non-AIEC with identical pulsotype, sequence type and virulence gene carriage. Genetic differences were further analysed in 22 AIEC and 28 non-AIEC isolated from CD patients and controls. The strain pairs showed similar genome structures, and no gene was specific to AIEC. Three single nucleotide polymorphisms displayed different nucleotide distributions between AIEC and non-AIEC, and four correlated with increased adhesion and/or invasion indices. Here, we present a classification algorithm based on the identification of three allelic variants that can predict the AIEC phenotype with 84% accuracy. Our study corroborates the absence of an AIEC-specific genetic marker distributed across all AIEC strains. Nonetheless, point mutations putatively involved in the AIEC phenotype can be used for the molecular identification of the AIEC pathotype. PMID- 29426865 TI - The WDR11 complex facilitates the tethering of AP-1-derived vesicles. AB - Vesicluar transport of proteins from endosomes to the trans-Golgi network (TGN) is an essential cellular pathway, but much of its machinery is still unknown. A screen for genes involved in endosome-to-TGN trafficking produced two hits, the adaptor protein-1 (AP-1 complex), which facilitates vesicle budding, and WDR11. Here we demonstrate that WDR11 forms a stable complex with two other proteins, which localises to the TGN region and does not appear to be associated with AP-1, suggesting it may act downstream from budding. In a vesicle tethering assay, capture of vesicles by golgin-245 was substantially reduced in WDR11-knockout cells. Moreover, structured illumination microscopy and relocation assays indicate that the WDR11 complex is initially recruited onto vesicles rather than the TGN, where it may in turn recruit the golgin binding partner TBC1D23. We propose that the complex acts together with TBC1D23 to facilitate the golgin mediated capture of vesicles that were generated using AP-1. PMID- 29426866 TI - Flash-induced nanowelding of silver nanowire networks for transparent stretchable electrochromic devices. AB - Electrochromic devices (ECDs) are emerging as a novel technology for various applications like commercialized smart window glasses, and auto-dimming rear-view mirrors. Recently, the development of low-power, lightweight, flexible, and stretchable devices has been accelerated to meet the growing demand in the new wearable devices market. Silver nanowires (AgNWs) can become new primary transparent conducting electrode (TCE) materials to replace indium tin oxide (ITO) for ECDs. However, issues such as substrate adhesion, delamination, and higher resistance still exist with AgNWs. Herein, we report a high-performance stretchable flash-induced AgNW-network-based TCE on surface-treated polydimethylsiloxane (PDMS) substrates. A Xe flash light method was used to create nanowelded networks of AgNWs. Surface silane treatments increased the adhesion and durability of the films as well. Finally, ECDs were fabricated under the optimal conditions and examined under strained conditions to demonstrate the resistance and mechanical behaviours of the devices. Results showed a flexible and durable film maintaining a high level of conductivity and reversible resistance behaviour, beyond those currently achievable with standard ITO/PET flexible TCEs. PMID- 29426867 TI - Crystal structures of a bacterial dipeptidyl peptidase IV reveal a novel substrate recognition mechanism distinct from that of mammalian orthologues. AB - Dipeptidyl peptidase IV (DPP IV, DPP4, or DAP IV) preferentially cleaves substrate peptides with Pro or Ala at the P1 position. The substrate recognition mechanism has been fully elucidated for mammalian DPP IV by crystal structure analyses but not for bacterial orthologues. Here, we report the crystal structures of a bacterial DPP IV (PmDAP IV) in its free form and in complexes with two kinds of dipeptides as well as with a non-peptidyl inhibitor at 1.90 to 2.47 A resolution. Acyl-enzyme intermediates were observed for the dipeptide complexes of PmDAP IV, whereas tetrahedral intermediates were reported for the oligopeptide complexes of mammalian DPP IVs. This variation reflects the different structural environments of the active site Arg residues, which are involved in the recognition of a substrate carbonyl group, of mammalian and bacterial enzymes. A phylogenetic analysis revealed that PmDAP IV is a closer relative of dipeptidyl peptidases 8 and 9 (DPP8 and DPP9, DPP IV-family enzymes) than DPP IV. These results provide new insights into the substrate recognition mechanism of bacterial DAP IVs and may assist in the development of selective inhibitors for DAP IVs from pathogenic asaccharolytic bacteria, which utilise proteins or peptides as an energy source. PMID- 29426869 TI - Open-Label Placebo Treatment for Cancer-Related Fatigue: A Randomized-Controlled Clinical Trial. AB - The purpose of this 21-day assessor blinded, randomized-controlled trial was to compare an open-label placebo (OLP) to treatment as usual (TAU) for cancer survivors with fatigue. This was followed by an exploratory 21-day study in which TAU participants received OLPs while OLP participants in the main study were followed after discontinuing placebos. Cancer survivors (N = 74) who completed cancer treatment 6 months to 10 years prior to enrollment reporting at least moderate fatigue (i.e., >=4 on a 0-10 scale) were randomized to OLP or TAU. Those randomized to OLP took 2 placebo pills twice a day for 21 days. Compared to those randomized to TAU, OLP participants reported a 29% improvement in fatigue severity (average difference in the mean change scores (MD) 12.47, 95% CI 3.32, 21.61; P = 0.008), medium effect (d = 0.63), and a 39% improvement in fatigue disrupted quality of life (MD = 11.76, 95% CI 4.65, 18.86; P = 0.002), a large effect (d = 0.76). TAU participants who elected to try OLP for 21-days after the main study reported reductions in fatigue of a similar magnitude for fatigue severity and fatigue-disrupted quality of life (23% and 35%, respectively). OLP may reduce fatigue symptom severity and fatigue-related quality of life disruption in cancer survivors. PMID- 29426868 TI - Rice matrix metalloproteinase OsMMP1 plays pleiotropic roles in plant development and symplastic-apoplastic transport by modulating cellulose and callose depositions. AB - Matrix metalloproteinases (MMPs) are well-known proteolytic enzymes in animal systems and play roles in tissue differentiation, growth, and defence. Although a few plant MMPs have been reported, their exact functions in development and growth remain elusive. In this study, we characterized the promoter and coding sequence of OsMMP1, one of the putative MMP genes in rice (Oryza sativa). The OsMMP1 catalytic domain is structurally similar to human MMPs with respect to cofactor orientation as predicted by homology modeling. Bacterially expressed recombinant OsMMP1 showed protease activity with bovine serum albumin and gelatin as substrates. Analyses of transcript accumulation and promoter-reporter gene expression revealed that OsMMP1 is spatio-temporally expressed in vegetative and reproductive parts of plants. The plasma membrane-localized OsMMP1 protease affected plant development upon heterologous expression in tobacco and endogenous gene silencing in rice. Transgenic tobacco plants expressing OsMMP1 showed enhanced deposition of cellulose and callose, leading to impairment of symplastic and apoplastic translocations. Moreover, transgenic tobacco tissues exhibited tolerance to oxidative stress-inducing agent by confining the area of tissue death owing to callose lining. Collectively, these findings demonstrate the involvement of a plant MMP in growth, organ differentiation, and development in relation to cell wall modification. PMID- 29426871 TI - Robust water desalination membranes against degradation using high loads of carbon nanotubes. AB - Chlorine resistant reverse osmosis (RO) membranes were fabricated using a multi walled carbon nanotube-polyamide (MWCNT-PA) nanocomposite. The separation performance of these membranes after chlorine exposure (4800 ppm.h) remained unchanged (99.9%) but was drastically reduced to 82% in the absence of MWCNT. It was observed that the surface roughness of the membranes changed significantly by adding MWCNT. Moreover, membranes containing MWCNT fractions above 12.5 wt.% clearly improved degradation resistance against chlorine exposure, with an increase in water flux while maintaining salt rejection performance. Molecular dynamics and quantum chemical calculations were performed in order to understand the high chemical stability of the MWCNT-PA nanocomposite membranes, and revealed that high activation energies are required for the chlorination of PA. The results presented here confirm the unique potential of carbon nanomaterials embedded in polymeric composite membranes for efficient RO water desalination technologies. PMID- 29426870 TI - Leucine-rich repeat receptor-like gene screen reveals that Nicotiana RXEG1 regulates glycoside hydrolase 12 MAMP detection. AB - Activation of innate immunity by membrane-localized receptors is conserved across eukaryotes. Plant genomes contain hundreds of such receptor-like genes and those encoding proteins with an extracellular leucine-rich repeat (LRR) domain represent the largest family. Here, we develop a high-throughput approach to study LRR receptor-like genes on a genome-wide scale. In total, 257 tobacco rattle virus-based constructs are generated to target 386 of the 403 identified LRR receptor-like genes in Nicotiana benthamiana for silencing. Using this toolkit, we identify the LRR receptor-like protein Response to XEG1 (RXEG1) that specifically recognizes the glycoside hydrolase 12 protein XEG1. RXEG1 associates with XEG1 via the LRR domain in the apoplast and forms a complex with the LRR receptor-like kinases BAK1 and SOBIR1 to transduce the XEG1-induced defense signal. Thus, this genome-wide silencing assay is demonstrated to be an efficient toolkit to pinpoint new immune receptors, which will contribute to developing durable disease resistance. PMID- 29426872 TI - Morphological and molecular dissection of wild rices from eastern India suggests distinct speciation between O. rufipogon and O. nivara populations. AB - The inter relationships between the two progenitors is interesting as both wild relatives are known to be the great untapped gene reservoirs. The debate continues on granting a separate species status to Oryza nivara. The present study was conducted on populations of Oryza rufipogon and Oryza nivara from Eastern India employing morphological and molecular characteristics. The cluster analysis of the data on morphological traits could clearly classify the two wild forms into two separate discrete groups without any overlaps i.e. lack of intermediate forms, suggesting the non-sympatric existence of the wild forms. Amplification of hyper variable regions of the genome could reveal 144 alleles suggesting high genetic diversity values (average He = 0.566). Moreover, with 42.37% of uncommon alleles between the two wild relatives, the molecular variance analysis (AMOVA) could detect only 21% of total variation (p < 0.001) among them and rest 59% was within them. The population structure analysis clearly classified these two wild populations into two distinct sub-populations (K = 2) without any overlaps i.e. lack of intermediate forms, suggesting the non sympatric existence of the wild forms. Clear differentiation into two distinct groups indicates that O. rufipogon and O. nivara could be treated as two different species. PMID- 29426873 TI - Suppression of Staphylococcus aureus biofilm formation and virulence by a benzimidazole derivative, UM-C162. AB - Staphylococcus aureus is a major cause of nosocomial infections and secretes a diverse spectrum of virulence determinants as well as forms biofilm. The emergence of antibiotic-resistant S. aureus highlights the need for alternative forms of therapeutics other than conventional antibiotics. One route to meet this need is screening small molecule derivatives for potential anti-infective activity. Using a previously optimized C. elegans - S. aureus small molecule screen, we identified a benzimidazole derivative, UM-C162, which rescued nematodes from a S. aureus infection. UM-C162 prevented the formation of biofilm in a dose-dependent manner without interfering with bacterial viability. To examine the effect of UM-C162 on the expression of S. aureus virulence genes, a genome-wide transcriptome analysis was performed on UM-C162-treated pathogen. Our data indicated that the genes associated with biofilm formation, particularly those involved in bacterial attachment, were suppressed in UM-C162-treated bacteria. Additionally, a set of genes encoding vital S. aureus virulence factors were also down-regulated in the presence of UM-C162. Further biochemical analysis validated that UM-C162-mediated disruption of S. aureus hemolysins, proteases and clumping factors production. Collectively, our findings propose that UM-C162 is a promising compound that can be further developed as an anti-virulence agent to control S. aureus infections. PMID- 29426874 TI - Oxytocin curbs calorie intake via food-specific increases in the activity of brain areas that process reward and establish cognitive control. AB - The hypothalamic neurohormone oxytocin decreases food intake via largely unexplored mechanisms. We investigated the central nervous mediation of oxytocin's hypophagic effect in comparison to its impact on the processing of generalized rewards. Fifteen fasted normal-weight, young men received intranasal oxytocin (24 IU) or placebo before functional magnetic resonance imaging (fMRI) measurements of brain activity during exposure to food stimuli and a monetary incentive delay task (MID). Subsequently, ad-libitum breakfast intake was assessed. Oxytocin compared to placebo increased activity in the ventromedial prefrontal cortex, supplementary motor area, anterior cingulate, and ventrolateral prefrontal cortices in response to high- vs. low-calorie food images in the fasted state, and reduced calorie intake by 12%. During anticipation of monetary rewards, oxytocin compared to placebo augmented striatal, orbitofrontal and insular activity without altering MID performance. We conclude that during the anticipation of generalized rewards, oxytocin stimulates dopaminergic reward-processing circuits. In contrast, oxytocin restrains food intake by enhancing the activity of brain regions that exert cognitive control, while concomitantly increasing the activity of structures that process food reward value. This pattern points towards a specific role of oxytocin in the regulation of eating behaviour in humans that might be of relevance for potential clinical applications. PMID- 29426875 TI - Elavl3 is essential for the maintenance of Purkinje neuron axons. AB - Neuronal Elav-like (nElavl or neuronal Hu) proteins are RNA-binding proteins that regulate RNA stability and alternative splicing, which are associated with axonal and synaptic structures. nElavl proteins promote the differentiation and maturation of neurons via their regulation of RNA. The functions of nElavl in mature neurons are not fully understood, although Elavl3 is highly expressed in the adult brain. Furthermore, possible associations between nElavl genes and several neurodegenerative diseases have been reported. We investigated the relationship between nElavl functions and neuronal degeneration using Elavl3-/- mice. Elavl3-/- mice exhibited slowly progressive motor deficits leading to severe cerebellar ataxia, and axons of Elavl3-/- Purkinje cells were swollen (spheroid formation), followed by the disruption of synaptic formation of axonal terminals. Deficit in axonal transport and abnormalities in neuronal polarity was observed in Elavl3-/- Purkinje cells. These results suggest that nElavl proteins are crucial for the maintenance of axonal homeostasis in mature neurons. Moreover, Elavl3-/- mice are unique animal models that constantly develop slowly progressive axonal degeneration. Therefore, studies of Elavl3-/- mice will provide new insight regarding axonal degenerative processes. PMID- 29426876 TI - Challenging human locomotion: stability and modular organisation in unsteady conditions. AB - The need to move over uneven terrain is a daily challenge. In order to face unexpected perturbations due to changes in the morphology of the terrain, the central nervous system must flexibly modify its control strategies. We analysed the local dynamic stability and the modular organisation of muscle activation (muscle synergies) during walking and running on an even- and an uneven-surface treadmill. We hypothesized a reduced stability during uneven-surface locomotion and a reorganisation of the modular control. We found a decreased stability when switching from even- to uneven-surface locomotion (p < 0.001 in walking, p = 0.001 in running). Moreover, we observed a substantial modification of the time dependent muscle activation patterns (motor primitives) despite a general conservation of the time-independent coefficients (motor modules). The motor primitives were considerably wider in the uneven-surface condition. Specifically, the widening was significant in both the early (+40.5%, p < 0.001) and late swing (+7.7%, p = 0.040) phase in walking and in the weight acceptance (+13.6%, p = 0.006) and propulsion (+6.0%, p = 0.041) phase in running. This widening highlighted an increased motor output's robustness (i.e. ability to cope with errors) when dealing with the unexpected perturbations. Our results confirmed the hypothesis that humans adjust their motor control strategies' timing to deal with unsteady locomotion. PMID- 29426878 TI - Effect of genetic architecture on the prediction accuracy of quantitative traits in samples of unrelated individuals. AB - Predicting complex phenotypes from genomic data is a fundamental aim of animal and plant breeding, where we wish to predict genetic merits of selection candidates; and of human genetics, where we wish to predict disease risk. While genomic prediction models work well with populations of related individuals and high linkage disequilibrium (LD) (e.g., livestock), comparable models perform poorly for populations of unrelated individuals and low LD (e.g., humans). We hypothesized that low prediction accuracies in the latter situation may occur when the genetics architecture of the trait departs from the infinitesimal and additive architecture assumed by most prediction models. We used simulated data for 10,000 lines based on sequence data from a population of unrelated, inbred Drosophila melanogaster lines to evaluate this hypothesis. We show that, even in very simplified scenarios meant as a stress test of the commonly used Genomic Best Linear Unbiased Predictor (G-BLUP) method, using all common variants yields low prediction accuracy regardless of the trait genetic architecture. However, prediction accuracy increases when predictions are informed by the genetic architecture inferred from mapping the top variants affecting main effects and interactions in the training data, provided there is sufficient power for mapping. When the true genetic architecture is largely or partially due to epistatic interactions, the additive model may not perform well, while models that account explicitly for interactions generally increase prediction accuracy. Our results indicate that accounting for genetic architecture can improve prediction accuracy for quantitative traits. PMID- 29426877 TI - ZFP36L1 and ZFP36L2 inhibit cell proliferation in a cyclin D-dependent and p53 independent manner. AB - ZFP36 family members include ZFP36, ZFP36L1, and ZFP36L2, which belong to CCCH type zinc finger proteins with two tandem zinc finger (TZF) regions. Whether ZFP36L1 and ZFP36L2 have antiproliferative activities similar to that of ZFP36 is unclear. In this study, when ZFP36L1 or ZFP36L2 was overexpressed in T-REx-293 cells, cell proliferation was dramatically inhibited and the cell cycle was arrested at the G1 phase. The levels of cell-cycle-related proteins, including cyclin B, cyclin D, cyclin A, and p21, decreased; however, p53 increased in ZFP36L1-or ZFP36L2-overexpressing T-REx-293 cells. Forced expression of ZFP36L1 or ZFP36L2 also inhibited cell proliferation and cyclin D gene expression in three human colorectal cancer cell lines: HCT116 p53+/+, HCT116 p53-/-, and SW620 (mutated p53) cells. However, it increased p53 and p21 expression only in HCT116 p53+/+ cells. Knockdown of ZFP36L1 or ZFP36L2 increased cell proliferation and cyclin D expression; furthermore, the mutation of the TZF of ZFP36L1 or ZFP36L2 caused them to lose their antiproliferative ability, to the extent that they could not inhibit cyclin D expression in these three cell lines. The results indicated that ZFP36L1 and ZFP36L2 play a negative role in cell proliferation; the underlying mechanisms might be mediated through a cyclin D-dependent and p53 independent pathway. PMID- 29426880 TI - Three-dimensional structural dynamics of DNA origami Bennett linkages using individual-particle electron tomography. AB - Scaffolded DNA origami has proven to be a powerful and efficient technique to fabricate functional nanomachines by programming the folding of a single-stranded DNA template strand into three-dimensional (3D) nanostructures, designed to be precisely motion-controlled. Although two-dimensional (2D) imaging of DNA nanomachines using transmission electron microscopy and atomic force microscopy suggested these nanomachines are dynamic in 3D, geometric analysis based on 2D imaging was insufficient to uncover the exact motion in 3D. Here we use the individual-particle electron tomography method and reconstruct 129 density maps from 129 individual DNA origami Bennett linkage mechanisms at ~ 6-14 nm resolution. The statistical analyses of these conformations lead to understanding the 3D structural dynamics of Bennett linkage mechanisms. Moreover, our effort provides experimental verification of a theoretical kinematics model of DNA origami, which can be used as feedback to improve the design and control of motion via optimized DNA sequences and routing. PMID- 29426879 TI - Balancing selection at nonself recognition loci in the chestnut blight fungus, Cryphonectria parasitica, demonstrated by trans-species polymorphisms, positive selection, and even allele frequencies. AB - Balancing selection has been inferred in diverse organisms for nonself recognition genes, including those involved in immunity, mating compatibility, and vegetative incompatibility. Although selective forces maintaining polymorphisms are known for genes involved in immunity and mating, mechanisms of balancing selection for vegetative incompatibility genes in fungi are being debated. We hypothesized that allorecognition and its consequent inhibition of virus transmission contribute to the maintenance of polymorphisms in vegetative incompatibility loci (vic) in the chestnut blight fungus, Cryphonectria parasitica. Balancing selection was demonstrated at two loci, vic2 and vic6, by trans-species polymorphisms in C. parasitica, C. radicalis, and C. japonica and signatures of positive selection in gene sequences. In addition, more than half (31 of 54) of allele frequency estimates at six vic loci in nine field populations of C. parasitica from Asia and the eastern US were not significantly different from 0.5, as expected at equilibrium for two alleles per locus under balancing selection. At three vic loci, deviations from 0.5 were predicted based on the effects of heteroallelism on virus transmission. Twenty-five of 27 allele frequency estimates were greater than or equal to 0.5 for the allele that confers significantly stronger inhibition of virus transmission at three loci with asymmetric transmission. These results are consistent with the allorecognition hypothesis that vegetative incompatibility genes are under selection because of their role in reducing infection by viruses. PMID- 29426881 TI - Activated T follicular helper-like cells are released into blood after oral vaccination and correlate with vaccine specific mucosal B-cell memory. AB - T follicular helper (Tfh)-like cells with potent B-cell helping ability are mobilized into human circulation after parenteral vaccination and are generally held to reflect ongoing germinal center reactions. However, whether mucosal vaccination induces systemic Tfh responses and how such responses may relate to IgA production are unknown. We investigated the frequencies, phenotype and function of circulating Tfh-like CD4+CXCR5+ T cells (cTfh) in adults receiving an oral inactivated enterotoxigenic Escherichia coli vaccine. Subjects were classified as vaccine responders or weak/non-responders based on their intestine derived antibody-secreting cell (ASC) IgA responses to major vaccine antigens. Oral immunization induced significantly increased proportions of cTfh cells expressing the cTfh activation marker inducible costimulator (ICOS) in ASC responders, but not in weak/non-responders. Vaccination also enhanced the expression of IL-21, Th17 markers and integrin beta7 by activated cTfh cells, supporting functionality and gut homing potential. cTfh cells promoted total and vaccine specific IgA production from cocultured B cells. Magnitudes of cTfh responses assessed within a week after primary vaccinations correlated with memory intestine-derived vaccine specific IgA responses 1-2 years later. We conclude that activated ICOS+ Tfh-like cells are mobilized into blood after oral vaccination and may be used as biomarkers of vaccine specific mucosal memory in humans. PMID- 29426882 TI - Magnetic Nature of Light Transmission through a 5-nm Gap. AB - Slot antennas have been exploited as important building blocks of optical magnetism because their radiations are invoked by the magnetic fields along the axes, as vectorial Babinet principle predicts. However, optical magnetism of a few-nanometer-width slit, for which fascinating applications are found due to the colossal field enhancement but Babinet principle fails due to the nonnegligible thickness, has not been investigated. In this paper, we demonstrated that the magnetic field plays a dominant role in light transmission through a 5-nm slit on a 150-nm-thick gold film. The 5-nm slit was fabricated by atomic layer lithography, and the transmission was investigated for various incident angles by experiment and simulation at 785-nm wavelength. We found that, due to the deep subwavelength gap width, the transmission has the same incident angle dependence as the tangential magnetic field on the metal surface and this magnetic nature of a nanogap holds up to ~100-nm width. Our analysis establishes conditions for nanogap optical magnetism and suggests new possibilities in realizing magnetic field-driven optical nonlinearities. PMID- 29426883 TI - Visualizing catalyst heterogeneity by a multifrequential oscillating reaction. AB - It is well documented that different surface structures of catalytically active metals may exhibit different catalytic properties. This is typically examined by comparing the catalytic activities and/or selectivities of various well-defined smooth and stepped/kinked single crystal surfaces. Here we report the direct observation of the heterogeneity of active polycrystalline surfaces under reaction conditions, which is manifested by multifrequential oscillations during hydrogen oxidation over rhodium, imaged in situ by photoemission electron microscopy. Each specific surface structure, i.e. the crystallographically different um-sized domains of rhodium, exhibits an individual spiral pattern and oscillation frequency, despite the global diffusional coupling of the surface reaction. This reaction behavior is attributed to the ability of stepped surfaces of high-Miller-index domains to facilitate the formation of subsurface oxygen, serving as feedback mechanism of the observed oscillations. The current experimental findings, backed by microkinetic modeling, may open an alternative approach towards addressing the structure-sensitivity of heterogeneous surfaces. PMID- 29426884 TI - A lumenal interrupted helix in human sperm tail microtubules. AB - Eukaryotic flagella are complex cellular extensions involved in many human diseases gathered under the term ciliopathies. Currently, detailed insights on flagellar structure come mostly from studies on protists. Here, cryo-electron tomography (cryo-ET) was performed on intact human spermatozoon tails and showed a variable number of microtubules in the singlet region (inside the end-piece). Inside the microtubule plus end, a novel left-handed interrupted helix which extends several micrometers was discovered. This structure was named Tail Axoneme Intra-Lumenal Spiral (TAILS) and binds directly to 11 protofilaments on the internal microtubule wall, in a coaxial fashion with the surrounding microtubule lattice. It leaves a gap over the microtubule seam, which was directly visualized in both singlet and doublet microtubules. We speculate that TAILS may stabilize microtubules, enable rapid swimming or play a role in controlling the swimming direction of spermatozoa. PMID- 29426885 TI - Transitions from Ideal to Intermediate Cholesterol Levels may vary by Cholesterol Metric. AB - To examine the ability of total cholesterol (TC), a low-density lipoprotein cholesterol (LDL-C) proxy widely used in public health initiatives, to capture important population-level shifts away from ideal and intermediate LDL-C throughout adulthood. We estimated age (>=20 years)-, race/ethnic (Caucasian, African American, and Hispanic/Latino)-, and sex- specific net transition probabilities between ideal, intermediate, and poor TC and LDL-C using National Health and Nutrition Examination Survey (2007-2014; N = 13,584) and Hispanic Community Health Study/Study of Latinos (2008-2011; N = 15,612) data in 2016 and validated and calibrated novel Markov-type models designed for cross-sectional data. At age 20, >80% of participants had ideal TC, whereas the race/ethnic- and sex-specific prevalence of ideal LDL-C ranged from 39.2%-59.6%. Net transition estimates suggested that the largest one-year net shifts away from ideal and intermediate LDL-C occurred approximately two decades earlier than peak net population shifts away from ideal and intermediate TC. Public health and clinical initiatives focused on monitoring TC in middle-adulthood may miss important shifts away from ideal and intermediate LDL-C, potentially increasing the duration, perhaps by decades, that large segments of the population are exposed to suboptimal LDL-C. PMID- 29426886 TI - Monolayer PdSe2: A promising two-dimensional thermoelectric material. AB - Motivated by the recent experimental synthesis of two-dimensional semiconducting film PdSe2, we investigate the electronic and thermal transport properties of PdSe2 monolayer by using the density functional theory and semiclassical Boltzmann transport equation. The calculated results reveal anisotropic transport properties. Low lattice thermal conductivity about 3 Wm-1 K -1 (300K) along the x direction is obtained, and the dimensionless thermoelectric figure of merit can reach 1.1 along the x direction for p-type doping at room temperature, indicating the promising thermoelectric performance of monolayer PdSe2. PMID- 29426887 TI - Estimating dose-specific cell division and apoptosis rates from chemo-sensitivity experiments. AB - In-vitro chemo-sensitivity experiments are an essential step in the early stages of cancer therapy development, but existing data analysis methods suffer from problems with fitting, do not permit assessment of uncertainty, and can give misleading estimates of cell growth inhibition. We present an approach (bdChemo) based on a mechanistic model of cell division and death that permits rigorous statistical analyses of chemo-sensitivity experiment data by simultaneous estimation of cell division and apoptosis rates as functions of dose, without making strong assumptions about the shape of the dose-response curve. We demonstrate the utility of this method using a large-scale NCI-DREAM challenge dataset. We developed an R package "bdChemo" implementing this method, available at https://github.com/YiyiLiu1/bdChemo . PMID- 29426888 TI - Ice slurry ingestion reduces human brain temperature measured using non-invasive magnetic resonance spectroscopy. AB - We previously reported that ice slurry ingestion reduced forehead skin temperature, thereby potentially reducing brain temperature (Tbrain). Therefore, in the current study, we investigated the effect of ice slurry ingestion on Tbrain using proton magnetic resonance spectroscopy, which is a robust, non invasive method. Eight male participants ingested 7.5 g/kg of either a thermoneutral drink (37 degrees C; CON) or ice slurry (-1 degrees C; ICE) for about 5 min following a 15-min baseline period. Then, participants remained at rest for 30 min. As physiological indices, Tbrain, rectal temperature (Tre), mean skin temperature, nude body mass, and urine specific gravity were measured. Subjective thermal sensation (TS) and thermal comfort (TC) were measured before and after the experiment. Tbrain and Tre significantly reduced after ingestion of ICE compared with after ingestion of CON, and there was a significant correlation between Tbrain and Tre. The other physiological indices were not significantly different between beverage conditions. TS and TC were significantly lower with ICE than with CON (p < 0.05). These results indicate that ice slurry ingestion can cool the brain, as well as the body's core. PMID- 29426889 TI - SiO2 nanoparticles modulate the electrical activity of neuroendocrine cells without exerting genomic effects. AB - Engineered silica nanoparticles (NPs) have attracted increasing interest in several applications, and particularly in the field of nanomedicine, thanks to the high biocompatibility of this material. For their optimal and controlled use, the understanding of the mechanisms elicited by their interaction with the biological target is a prerequisite, especially when dealing with cells particularly vulnerable to environmental stimuli like neurons. Here we have combined different electrophysiological approaches (both at the single cell and at the population level) with a genomic screening in order to analyze, in GT1-7 neuroendocrine cells, the impact of SiO2 NPs (50 +/- 3 nm in diameter) on electrical activity and gene expression, providing a detailed analysis of the impact of a nanoparticle on neuronal excitability. We find that 20 ug mL-1 NPs induce depolarization of the membrane potential, with a modulation of the firing of action potentials. Recordings of electrical activity with multielectrode arrays provide further evidence that the NPs evoke a temporary increase in firing frequency, without affecting the functional behavior on a time scale of hours. Finally, NPs incubation up to 24 hours does not induce any change in gene expression. PMID- 29426890 TI - Guanosine monophosphate reductase 1 is a potential therapeutic target for Alzheimer's disease. AB - Alzheimer's disease (AD) is a severe neurodegenerative disorder for which identification of differentially expressed genes is one way to find new therapeutic targets. Here, we conducted analysis to identify age-independent, AD specific genes. We found that the MET, WIF1, and NPTX2 genes are downregulated in AD. WIF1 and MET are implicated in Wnt and MET signaling and regulate GSK3beta activity and are thus linked with AD. Importantly, we found that the GMPR gene exhibited a gradual increase in AD progression. A logistic model based on GMPR has good ability to classify AD cases. GMPR's product GMPR1 is in the AMPK and adenosine receptor pathways and is thus associated with Tau phosphorylation in AD. This allows GMPR1 to be a therapeutic target. Therefore, we screened five possible inhibitors to GMPR1 by docking GMPR1 with 1,174 approved drugs. Among them, lumacaftor is ideal. We then tested the effects of lumacaftor on AD model mice. After 20 days of oral administration, we observed that beta-Amyloid accumulation was slowed down, and phosphorylation of Tau was almost eliminated in the treated mice. We highlight the elevated expression level of GMPR in AD and propose a therapeutic strategy of inhibiting GMPR1 with lumacaftor. PMID- 29426891 TI - Laboratory evidence of dynamo amplification of magnetic fields in a turbulent plasma. AB - Magnetic fields are ubiquitous in the Universe. The energy density of these fields is typically comparable to the energy density of the fluid motions of the plasma in which they are embedded, making magnetic fields essential players in the dynamics of the luminous matter. The standard theoretical model for the origin of these strong magnetic fields is through the amplification of tiny seed fields via turbulent dynamo to the level consistent with current observations. However, experimental demonstration of the turbulent dynamo mechanism has remained elusive, since it requires plasma conditions that are extremely hard to re-create in terrestrial laboratories. Here we demonstrate, using laser-produced colliding plasma flows, that turbulence is indeed capable of rapidly amplifying seed fields to near equipartition with the turbulent fluid motions. These results support the notion that turbulent dynamo is a viable mechanism responsible for the observed present-day magnetization. PMID- 29426892 TI - Differential gene expression induced by anti-cancer agent plumbagin is mediated by androgen receptor in prostate cancer cells. AB - Treatment of mice harboring PTEN-P2 tumors in the prostate or on prostate tissue in vivo with 5-hydroxy-2-methyl-1,4-naphthoquinone, also known as plumbagin, results in tumor regression in castrated mice, but not in intact mice. This suggested that dihydrotestosterone (DHT) production in the testes may prevent cell death due to plumbagin treatment, but the underlying mechanism is not understood. We performed RNA-seq analysis on cells treated with combinations of plumbagin and DHT, and analyzed differential gene expression, to gain insight into the interactions between androgen and plumbgin. DHT and plumbagin synergize to alter the expression of many genes that are not differentially regulated by either single agent when used alone. These experiments revealed that, for many genes, increases in mRNAs caused by DHT are sharply down-regulated by plumbagin, and that many transcripts change in response to plumbagin in a DHT-dependent manner. This suggests that androgen receptor mediates some of the effects of plumbagin on gene expression. PMID- 29426893 TI - Thermal Conductivity of Graphene-hBN Superlattice Ribbons. AB - Superlattices are ideal model systems for the realization and understanding of coherent (wave-like) and incoherent (particle-like) phonon thermal transport. Single layer heterostructures of graphene and hexagonal boron nitride have been produced recently with sharp edges and controlled domain sizes. In this study we employ nonequilibrium molecular dynamics simulations to investigate the thermal conductivity of superlattice nanoribbons with equal-sized domains of graphene and hexagonal boron nitride. We analyze the dependence of the conductivity with the domain sizes, and with the total length of the ribbons. We determine that the thermal conductivity reaches a minimum value of 89 W m-1K-1 for ribbons with a superlattice period of 3.43 nm. The effective phonon mean free path is also determined and shows a minimum value of 32 nm for the same superlattice period. Our results also reveal that a crossover from coherent to incoherent phonon transport is present at room temperature for BNC nanoribbons, as the superlattice period becomes comparable to the phonon coherence length. Analyzing phonon populations relative to the smallest superlattice period, we attribute the minimum thermal conductivity to a reduction in the population of flexural phonons when the superlattice period equals 3.43 nm. The ability to manipulate thermal conductivity using superlattice-based two-dimensional materials, such as graphene hBN nanoribbons, opens up opportunities for application in future nanostructured thermoelectric devices. PMID- 29426894 TI - Site-specific N-glycosylation analysis of soluble Fcgamma receptor IIIb in human serum. AB - Fc-receptors for immunoglobulin G (FcgammaRs) mediate a variety of effector and regulatory mechanisms in the immune system. N-glycosylation of FcgammaRs critically affects their functions which is well exemplified by antibody dependent cell-mediated cytotoxicity (ADCC) and phagocytosis mediated by homologous FcgammaRIIIa and FcgammaRIIIb, respectively. Although several reports describe N-glycosylation profiles of recombinant FcgammaRIII glycoproteins, much remains unknown regarding their native glycoforms. Here we performed site specific N-glycosylation profiling of a soluble form of FcgammaRIIIb purified from human serum based on mass spectrometric analysis. Our data indicate a distinct and common tendency of the glycoforms exhibited at each N-glycosylation site between the native and the previously reported recombinant FcgammaRIII glycoproteins. Among the six N-glycosylation sites of serum soluble FcgammaRIIIb, Asn45 was shown to be exclusively occupied by high-mannose-type oligosaccharides, whereas the remaining sites were solely modified by the complex-type oligosaccharides with sialic acid and fucose residues. The results of our endogenous FcgammaRIII glycoform analyses are important for the optimization of therapeutic antibody efficacy. PMID- 29426895 TI - Author Correction: Genome expansion and lineage-specific genetic innovations in the forest pathogenic fungi Armillaria. AB - In the version of this Article originally published, it was incorrectly stated that "16,687 protein-coding genes were inferred for the most recent common ancestor (MRCA) of Armillaria"; the value was incorrect and it should have read "15,787". This has now been corrected. PMID- 29426896 TI - Minimising efficiency roll-off in high-brightness perovskite light-emitting diodes. AB - Efficiency roll-off is a major issue for most types of light-emitting diodes (LEDs), and its origins remain controversial. Here we present investigations of the efficiency roll-off in perovskite LEDs based on two-dimensional layered perovskites. By simultaneously measuring electroluminescence and photoluminescence on a working device, supported by transient photoluminescence decay measurements, we conclude that the efficiency roll-off in perovskite LEDs is mainly due to luminescence quenching which is likely caused by non-radiative Auger recombination. This detrimental effect can be suppressed by increasing the width of quantum wells, which can be easily realized in the layered perovskites by tuning the ratio of large and small organic cations in the precursor solution. This approach leads to the realization of a perovskite LED with a record external quantum efficiency of 12.7%, and the efficiency remains to be high, at approximately 10%, under a high current density of 500 mA cm-2. PMID- 29426898 TI - Publisher Correction: Mapping microscale wetting variations on biological and synthetic water-repellent surfaces. AB - The original version of this Article contained an error in Fig. 2b. The y-axis label in Fig. 2b was incorrectly labelled 'Snap-in force (MUN)'. In the correct version, the axis is labelled 'Snap-in force (nN)'. In the original version of this Article, the "Butterfly wings" section of the Methods incorrectly stated the name of the butterfly as 'Golden bird'. In the correct version, the name of the butterfly is 'Golden birdwing'. These have now been corrected in both the PDF and HTML versions of the article. PMID- 29426897 TI - A cleavage product of Polycystin-1 is a mitochondrial matrix protein that affects mitochondria morphology and function when heterologously expressed. AB - Recent studies have reported intrinsic metabolic reprogramming in Pkd1 knock-out cells, implicating dysregulated cellular metabolism in the pathogenesis of polycystic kidney disease. However, the exact nature of the metabolic changes and their underlying cause remains controversial. We show herein that Pkd1 k o /ko renal epithelial cells have impaired fatty acid utilization, abnormal mitochondrial morphology and function, and that mitochondria in kidneys of ADPKD patients have morphological alterations. We further show that a C-terminal cleavage product of polycystin-1 (CTT) translocates to the mitochondria matrix and that expression of CTT in Pkd1 ko/ko cells rescues some of the mitochondrial phenotypes. Using Drosophila to model in vivo effects, we find that transgenic expression of mouse CTT results in decreased viability and exercise endurance but increased CO2 production, consistent with altered mitochondrial function. Our results suggest that PC1 may play a direct role in regulating mitochondrial function and cellular metabolism and provide a framework to understand how impaired mitochondrial function could be linked to the regulation of tubular diameter in both physiological and pathological conditions. PMID- 29426899 TI - Far-UVC light: A new tool to control the spread of airborne-mediated microbial diseases. AB - Airborne-mediated microbial diseases such as influenza and tuberculosis represent major public health challenges. A direct approach to prevent airborne transmission is inactivation of airborne pathogens, and the airborne antimicrobial potential of UVC ultraviolet light has long been established; however, its widespread use in public settings is limited because conventional UVC light sources are both carcinogenic and cataractogenic. By contrast, we have previously shown that far-UVC light (207-222 nm) efficiently inactivates bacteria without harm to exposed mammalian skin. This is because, due to its strong absorbance in biological materials, far-UVC light cannot penetrate even the outer (non living) layers of human skin or eye; however, because bacteria and viruses are of micrometer or smaller dimensions, far-UVC can penetrate and inactivate them. We show for the first time that far-UVC efficiently inactivates airborne aerosolized viruses, with a very low dose of 2 mJ/cm2 of 222-nm light inactivating >95% of aerosolized H1N1 influenza virus. Continuous very low dose rate far-UVC light in indoor public locations is a promising, safe and inexpensive tool to reduce the spread of airborne-mediated microbial diseases. PMID- 29426900 TI - Extracellular cholesterol oxidase production by Streptomyces aegyptia, in vitro anticancer activities against rhabdomyosarcoma, breast cancer cell-lines and in vivo apoptosis. AB - In recent years, microbial cholesterol oxidases have gained great attention due to its widespread use in medical applications for serum cholesterol determination. Streptomyces aegyptia strain NEAE-102 exhibited high level of extracellular cholesterol oxidase production using a minimum medium containing cholesterol as the sole source of carbon. Fifteen variables were screened using Plackett-Burman design for the enhanced cholesterol oxidase production. The most significant variables affecting enzyme production were further optimized by using the face-centered central composite design. The statistical optimization resulted in an overall 4.97-fold increase (15.631 UmL-1) in cholesterol oxidase production in the optimized medium as compared with the unoptimized medium before applying Plackett Burman design (3.1 UmL-1). The purified cholesterol oxidase was evaluated for its in vitro anticancer activities against five human cancer cell lines. The selectivity index values on rhabdomyosarcoma and breast cancer cell lines were 3.26 and 2.56; respectively. The in vivo anticancer activity of cholesterol oxidase was evaluated against Ehrlich solid tumor model. Compared with control mice, tumors growth was significantly inhibited in the mice injected with cholesterol oxidase alone, doxorubicin alone and cholesterol oxidase/doxorubicin combination by 60.97%, 72.99% and 97.04%; respectively. These results demonstrated that cholesterol oxidase can be used as a promising natural anticancer drug. PMID- 29426901 TI - Rate-limiting steps in the dark-to-light transition of Photosystem II - revealed by chlorophyll-a fluorescence induction. AB - Photosystem II (PSII) catalyses the photoinduced oxygen evolution and, by producing reducing equivalents drives, in concert with PSI, the conversion of carbon dioxide to sugars. Our knowledge about the architecture of the reaction centre (RC) complex and the mechanisms of charge separation and stabilisation is well advanced. However, our understanding of the processes associated with the functioning of RC is incomplete: the photochemical activity of PSII is routinely monitored by chlorophyll-a fluorescence induction but the presently available data are not free of controversy. In this work, we examined the nature of gradual fluorescence rise of PSII elicited by trains of single-turnover saturating flashes (STSFs) in the presence of a PSII inhibitor, permitting only one stable charge separation. We show that a substantial part of the fluorescence rise originates from light-induced processes that occur after the stabilisation of charge separation, induced by the first STSF; the temperature-dependent relaxation characteristics suggest the involvement of conformational changes in the additional rise. In experiments using double flashes with variable waiting times (?tau) between them, we found that no rise could be induced with zero or short ?tau, the value of which depended on the temperature - revealing a previously unknown rate-limiting step in PSII. PMID- 29426902 TI - Evaluation of Serum CEA, CA19-9, CA72-4, CA125 and Ferritin as Diagnostic Markers and Factors of Clinical Parameters for Colorectal Cancer. AB - Blood-based protein biomarkers have recently shown as simpler diagnostic modalities for colorectal cancer, while their association with clinical pathological characteristics is largely unknown. In this study, we not only examined the sensitivity and reliability of single/multiple serum markers for diagnosis, but also assessed their connection with pathological parameters from a total of 279 colorectal cancer patients. Our study shown that glycoprotein carcinoembryonic antigen (CEA) owns the highest sensitivity among single marker in the order of CEA > cancer antigen 72-4 (CA72-4) > cancer antigen 19-9 9 (CA19 9) > ferritin > cancer antigen 125 (CA125), while the most sensitive combined markers for two to five were: CEA + CA72-4; CEA + CA72-4 + CA125; CEA + CA19-9 + CA72-4 + CA125; and CEA + CA19-9 + CA72-4 + CA125 + ferritin, respectively. We also demonstrated that patients who had positive preoperative serum CEA, CA19-9, or CA72-4 were more likely with lymph node invasion, positive CA125 were prone to have vascular invasion, and positive CEA or CA125 were correlated with perineural invasion. In addition, positive CA19-9, CA72-4, or CA125 was associated with poorly differentiated tumor, while CEA, CA19-9, CA72-4, CA125 levels were positively correlated with pathological tumor-node-metastasis stages. We here conclude that combined serum markers can be used to not only diagnose colorectal cancer, but also appraise the tumor status for guiding treatment, evaluation of curative effect, and prognosis of patients. PMID- 29426903 TI - Identifying source populations for the reintroduction of the Eurasian beaver, Castor fiber L. 1758, into Britain: evidence from ancient DNA. AB - Establishing true phylogenetic relationships between populations is a critical consideration when sourcing individuals for translocation. This presents huge difficulties with threatened and endangered species that have become extirpated from large areas of their former range. We utilise ancient DNA (aDNA) to reconstruct the phylogenetic relationships of a keystone species which has become extinct in Britain, the Eurasian beaver Castor fiber. We sequenced seventeen 492 bp partial tRNAPro and control region sequences from Late Pleistocene and Holocene age beavers and included these in network, demographic and genealogy analyses. The mode of postglacial population expansion from refugia was investigated by employing tests of neutrality and a pairwise mismatch distribution analysis. We found evidence of a pre-Late Glacial Maximum ancestor for the Western C. fiber clade which experienced a rapid demographic expansion during the terminal Pleistocene to early Holocene period. Ancient British beavers were found to originate from the Western phylogroup but showed no phylogenetic affinity to any one modern relict population over another. Instead, we find that they formed part of a large, continuous, pan-Western European clade that harbored little internal substructure. Our study highlights the utility of aDNA in reconstructing population histories of extirpated species which has real-world implications for conservation planning. PMID- 29426905 TI - Water mediated dielectric polarizability and electron charge transport properties of high resistance natural fibers. AB - Recent studies showed that silk and human hair fibers develop thermoelectric properties at optimal water, temperature and light conditions. The nature of charge carriers and the role of water in mediating charge conduction in these fibers is an unexplored issue. By studying four different classes of natural fibers, viz., silk cocoon, human hair, jute and corn silk, we uncover their common electrical transport properties and its dependence on water concentration and temperature. All these fibers uniformly exhibit nonlinear, hysteretic current - voltage characteristics, which scale with water concentration. The optimal electrical conductivity shows thermally activated hopping transport mechanism. Scanning tunneling microscope (STM) and dielectric measurements of silk cocoon fibers showed the electronic density of states and dielectric properties of the hydrated medium enhances with water concentration. Electron paramagnetic resonance (EPR) study reveals that the charge carriers in these membranes are electronic in nature. Our results are explained through the mechanism of hopping of a Polaron, which is an electron surrounded by positive charge fluctuations created by water molecules. The mechanism unravels the peculiar role water plays in mediating electrical activity in these membranes and also opens the possibility for exploring such charge transport mechanism in other biological membranes. PMID- 29426904 TI - TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing. AB - Intracellular nucleic acid sensors often undergo sophisticated modifications that are critical for the regulation of antimicrobial responses. Upon recognition of DNA, the cytosolic sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the second messenger cGAMP, which subsequently initiates downstream signaling to induce interferon-alphabeta (IFNalphabeta) production. Here we report that TRIM56 E3 ligase-induced monoubiquitination of cGAS is important for cytosolic DNA sensing and IFNalphabeta production to induce anti-DNA viral immunity. TRIM56 induces the Lys335 monoubiquitination of cGAS, resulting in a marked increase of its dimerization, DNA-binding activity, and cGAMP production. Consequently, TRIM56-deficient cells are defective in cGAS-mediated IFNalphabeta production upon herpes simplex virus-1 (HSV-1) infection. Furthermore, TRIM56-deficient mice show impaired IFNalphabeta production and high susceptibility to lethal HSV-1 infection but not to influenza A virus infection. This adds TRIM56 as a crucial component of the cytosolic DNA sensing pathway that induces anti-DNA viral innate immunity. PMID- 29426906 TI - Alps to Apennines zircon roller coaster along the Adria microplate margin. AB - We have traced the particle path of high-pressure metasedimentary rocks on Elba Island, Northern Apennines, with the help of a U-Pb-Hf detrital zircon study. One quarter of the analysed zircons are surprisingly young, 41-30 Ma, with a main age peak at ca. 32 Ma, indicating an unexpected early Oligocene maximum deposition age. These Oligocene ages with negative epsilonHf indicate a volcanic source region in the central-southern Alps. Though young by geological means, these zircons record an extraordinary geodynamic history. They originated in a volcanic arc, during the convergence/collision of the the Adria microplate with Europe from ca. 65 to 30 Ma. Thereafter, the Oligocene zircons travelled ca. 400 km southward along the Adria margin and the accretionary prism to present-day Tuscany, where they were subducted to depths of at least 40 km. Shortly thereafter, they were brought to the surface again in the wake of hinge roll back of the Apennine subduction zone and the resulting rapid extensional exhumation. Such a zircon roller coaster requires a microplate that has back-to-back subduction zones with opposing polarities on two sides. PMID- 29426907 TI - Identification of basic/helix-loop-helix transcription factors reveals candidate genes involved in anthocyanin biosynthesis from the strawberry white-flesh mutant. AB - As the second largest transcription factor family in plant, the basic helix-loop helix (bHLH) transcription factor family, characterized by the conserved bHLH domain, plays a central regulatory role in many biological process. However, the bHLH transcription factor family of strawberry has not been systematically identified, especially for the anthocyanin biosynthesis. Here, we identified a total of 113 bHLH transcription factors and described their chromosomal distribution and bioinformatics for the diploid woodland strawberry Fragaria vesca. In addition, transcription profiles of 113 orthologous bHLH genes from various tissues were analyzed for the cultivar 'Benihoppe', its white-flesh mutant 'Xiaobai', and the 'Snow Princess' from their fruit development to the ripening, as well as those under either the ABA or Eth treatment. Both the RT-PCR and qRT-PCR results show that seven selected FabHLH genes (FabHLH17, FabHLH25, FabHLH27, FabHLH29, FabHLH40, FabHLH80, FabHLH98) are responsive to the fruit anthocyanin biosynthesis and hormone signaling according to transcript profiles where three color modes are observed for strawberry's fruit skin and flesh. Further, prediction for the protein interaction network reveals that four bHLHs (FabHLH25, FabHLH29, FabHLH80, FabHLH98) are involved in the fruit anthocyanin biosynthesis and hormone signaling transduction. These bioinformatics and expression profiles provide a good basis for a further investigation of strawberry bHLH genes. PMID- 29426908 TI - Temozolomide-perillyl alcohol conjugate downregulates O6-methylguanin DNA methltransferase via inducing ubiquitination-dependent proteolysis in non-small cell lung cancer. AB - The DNA repair enzyme O6-methylguanin-DNA-methltransferase (MGMT) is able to remove products of alkylating agent such as O6-meG and emerges as a central determinant of cancer resistance to temozolomide (TMZ). Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel TMZ analog developed based on the conjugation of TMZ and POH, displayed strong anticancer potency in multiple cancer types, but seemed not to experience the chemoresistance even in cells with high MGMT expression unlike TMZ and other alkylating agents. In this study, we demonstrated TMZ-POH inhibited MGMT dependent on proteasomal pathway and this inhibition is a significant factor in its toxic effect in the non-small cell lung cancer (NSCLC) cells. PMID- 29426909 TI - Lifting the bandwidth limit of optical homodyne measurement with broadband parametric amplification. AB - Homodyne measurement is a corner-stone method of quantum optics that measures the quadratures of light-the quantum optical analog of the canonical position and momentum. Standard homodyne, however, suffers from a severe bandwidth limitation: while the bandwidth of optical states can span many THz, standard homodyne is inherently limited to the electronically accessible MHz-to-GHz range, leaving a dramatic gap between relevant optical phenomena and the measurement capability. We demonstrate a fully parallel optical homodyne measurement across an arbitrary optical bandwidth, effectively lifting this bandwidth limitation completely. Using optical parametric amplification, which amplifies one quadrature while attenuating the other, we measure quadrature squeezing of 1.7 dB simultaneously across 55 THz, using the pump as the only local oscillator. As opposed to standard homodyne, our measurement is robust to detection inefficiency, and was obtained with >50% detection loss. Broadband parametric homodyne opens a wide window for parallel processing of quantum information. PMID- 29426910 TI - Selective Tropism of Dengue Virus for Human Glycoprotein Ib. AB - Since the hemorrhage in severe dengue seems to be primarily related to the defect of the platelet, the possibility that dengue virus (DENV) is selectively tropic for one of its surface receptors was investigated. Flow cytometric data of DENV infected megakaryocytic cell line superficially expressing human glycoprotein Ib (CD42b) and glycoprotein IIb/IIIa (CD41 and CD41a) were analyzed by our custom written software in MATLAB. In two-dimensional analyses, intracellular DENV was detected in CD42b+, CD41+ and CD41a+ cells. In three-dimensional analyses, the DENV was exclusively detected in CD42b+ cells but not in CD42b- cells regardless of the other expressions. In single-cell virus-protein analyses, the amount of DENV was directly correlated with those of CD42b at the Pearson correlation coefficient of 0.9. Moreover, RT- PCR and apoptosis assays showed that DENV was able to replicate itself and release its new progeny from the infected CD42b+ cells and eventually killed those cells. These results provide evidence for the involvement of CD42b in DENV infection. PMID- 29426911 TI - Hypoxia induces pulmonary fibroblast proliferation through NFAT signaling. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and typically fatal lung disease with a very low survival rate. Excess accumulation of fibroblasts, myofibroblasts and extracellular matrix creates hypoxic conditions within the lungs, causing asphyxiation. Hypoxia is, therefore, one of the prominent features of IPF. However, there have been few studies concerning the effects of hypoxia on pulmonary fibroblasts. In this study, we investigated the molecular mechanisms of hypoxia-induced lung fibroblast proliferation. Hypoxia increased the proliferation of normal human pulmonary fibroblasts and IPF fibroblasts after exposure for 3-6 days. Cell cycle analysis demonstrated that hypoxia promoted the G1/S phase transition. Hypoxia downregulated cyclin D1 and A2 levels, while it upregulated cyclin E1 protein levels. However, hypoxia had no effect on the protein expression levels of cyclin-dependent kinase 2, 4, and 6. Chemical inhibition of hypoxia-inducible factor (HIF)-2 reduced hypoxia-induced fibroblast proliferation. Moreover, silencing of Nuclear Factor Activated T cell (NFAT) c2 attenuated the hypoxia-mediated fibroblasts proliferation. Hypoxia also induced the nuclear translocation of NFATc2, as determined by immunofluorescence staining. NFAT reporter assays showed that hypoxia-induced NFAT signaling activation is dependent on HIF-2, but not HIF-1. Furthermore, the inhibition or silencing of HIF-2, but not HIF-1, reduced the hypoxia-mediated NFATc2 nuclear translocation. Our studies suggest that hypoxia induces the proliferation of human pulmonary fibroblasts through NFAT signaling and HIF-2. PMID- 29426912 TI - A White Random Laser. AB - Random laser with intrinsically uncomplicated fabrication processes, high spectral radiance, angle-free emission, and conformal onto freeform surfaces is in principle ideal for a variety of applications, ranging from lighting to identification systems. In this work, a white random laser (White-RL) with high purity and high-stability is designed, fabricated, and demonstrated via the cost effective materials (e.g., organic laser dyes) and simple methods (e.g., all solution process and self-assembled structures). Notably, the wavelength, linewidth, and intensity of White-RL are nearly isotropic, nevertheless hard to be achieved in any conventional laser systems. Dynamically fine-tuning colour over a broad visible range is also feasible by on-chip integration of three free standing monochromatic laser films with selective pumping scheme and appropriate colour balance. With these schematics, White-RL shows great potential and high application values in high-brightness illumination, full-field imaging, full colour displays, visible-colour communications, and medical biosensing. PMID- 29426913 TI - A printable hydrogel microarray for drug screening avoids false positives associated with promiscuous aggregating inhibitors. AB - A significant problem in high-throughput drug screening is the disproportionate number of false hits associated with drug candidates that form colloidal aggregates. Such molecules, referred to as promiscuous inhibitors, nonspecifically inhibit multiple enzymes and are thus not useful as potential drugs. Here, we report a printable hydrogel-based drug-screening platform capable of non-ambiguously differentiating true enzyme inhibitors from promiscuous aggregating inhibitors, critical for accelerating the drug discovery process. The printed hydrogels can both immobilize as well as support the activity of entrapped enzymes against drying or treatment with a protease or chemical denaturant. Furthermore, the printed hydrogel can be applied in a high-throughput microarray-based screening platform (consistent with current practice) to rapidly ( <25 min) and inexpensively identify only clinically promising lead compounds with true inhibitory potential as well as to accurately quantify the dose response relationships of those inhibitors, all while using 95% less sample than required for a solution assay. PMID- 29426914 TI - Similarity of stream width distributions across headwater systems. AB - The morphology and abundance of streams control the rates of hydraulic and biogeochemical exchange between streams, groundwater, and the atmosphere. In large river systems, the relationship between river width and abundance is fractal, such that narrow rivers are proportionally more common than wider rivers. However, in headwater systems, where many biogeochemical reactions are most rapid, the relationship between stream width and abundance is unknown. To constrain this uncertainty, we surveyed stream hydromorphology (wetted width and length) in several headwater stream networks across North America and New Zealand. Here, we find a strikingly consistent lognormal statistical distribution of stream width, including a characteristic most abundant stream width of 32 +/- 7 cm independent of discharge or physiographic conditions. We propose a hydromorphic model that can be used to more accurately estimate the hydromorphology of streams, with significant impact on the understanding of the hydraulic, ecological, and biogeochemical functions of stream networks. PMID- 29426915 TI - Reference gene selection for RT-qPCR analysis in Harmonia axyridis, a global invasive lady beetle. AB - Harmonia axyridis is a voracious predator, a biological control agent, and one of the world most invasive insect species. The advent of next-generation sequencing platforms has propelled entomological research into the genomics and post genomics era. Real-time quantitative PCR (RT-qPCR), a primary tool for gene expression analysis, is a core technique governs the genomic research. The selection of internal reference genes, however, can significantly impact the interpretation of RT-qPCR results. The overall goal of this study is to identify the reference genes in the highly invasive H. axyridis. Our central hypothesis is that the suitable reference genes for RT-qPCR analysis can be selected from housekeeping genes. To test this hypothesis, the stability of nine housekeeping genes, including 18S, 28S, ACTB, ATP1A1, GAPDH, HSP70, HSP90, RP49, and ATP6V1A, were investigated under both biotic (developmental time, tissue and sex), and abiotic (temperature, photoperiod, in vivo RNAi) conditions. Gene expression profiles were analyzed by geNorm, Normfinder, BestKeeper, and the DeltaCt method. Our combined results recommend a specific set of reference genes for each experimental condition. With the recent influx of genomic information for H. axyridis, this study lays the foundation for an in-depth omics dissection of biological invasion in this emerging model. PMID- 29426916 TI - 2-Methoxyestradiol protects against pressure overload-induced left ventricular hypertrophy. AB - Numerous experimental studies have supported the evidence that 2-methoxyestradiol (2 ME) is a biologically active metabolite that mediates multiple effects on the cardiovascular system, largely independent of the estrogen receptor. 2 ME is a major cytochrome P450 1B1 (CYP1B1) metabolite and has been reported to have vasoprotective and anti-inflammatory actions. However, whether 2 ME would prevent cardiac hypertrophy induced by abdominal aortic constriction (AAC) has not been investigated yet. Therefore, the overall objectives of the present study were to elucidate the potential antihypertrophic effect of 2 ME and explore the mechanism(s) involved. Our results showed that 2 ME significantly inhibited AAC induced left ventricular hypertrophy using echocardiography. The antihypertrophic effect of 2 ME was associated with a significant inhibition of CYP1B1 and mid chain hydroxyeicosatetraenoic acids. Based on proteomics data, the protective effect of 2 ME is linked to the induction of antioxidant and anti-inflammatory proteins in addition to the modulation of proteins involved in myocardial energy metabolism. In vitro, 2 ME has shown a direct antihypertrophic effect through mitogen-activated protein kinases- and nuclear factor-kappaB-dependent mechanisms. The present work shows a strong evidence that 2 ME protects against left ventricular hypertrophy. Our data suggest the potential of repurposing 2 ME as a selective CYP1B1 inhibitor for the treatment of heart failure. PMID- 29426917 TI - Conformational states during vinculin unlocking differentially regulate focal adhesion properties. AB - Focal adhesions (FAs) are multi-protein complexes that connect the actin cytoskeleton to the extracellular matrix, via integrin receptors. The growth, stability and adhesive functionality of these structures are tightly regulated by mechanical stress, yet, despite the extensive characterization of the integrin adhesome, the detailed molecular mechanisms underlying FA mechanosensitivity are still unclear. Besides talin, another key candidate for regulating FA-associated mechanosensing, is vinculin, a prominent FA component, which possesses either closed ("auto-inhibited") or open ("active") conformation. A direct experimental demonstration, however, of the conformational transition between the two states is still absent. In this study, we combined multiple structural and biological approaches to probe the transition from the auto-inhibited to the active conformation, and determine its effects on FA structure and dynamics. We further show that the transition from a closed to an open conformation requires two sequential steps that can differentially regulate FA growth and stability. PMID- 29426918 TI - Caffeine Caused a Widespread Increase of Resting Brain Entropy. AB - Entropy is an important trait of brain function and high entropy indicates high information processing capacity. We recently demonstrated that brain entropy (BEN) is stable across time and differs between controls and patients with various brain disorders. The purpose of this study was to examine whether BEN is sensitive to pharmaceutical modulations with caffeine. Both cerebral blood flow (CBF) and resting fMRI were collected from sixty caffeine-naive healthy subjects before and after taking a 200 mg caffeine pill. Our data showed that caffeine reduced CBF in the whole brain but increased BEN across the cerebral cortex with the highest increase in lateral prefrontal cortex, the default mode network (DMN), visual cortex, and motor network, consistent with the beneficial effects of caffeine (such as vigilance and attention) on these areas. BEN increase was correlated to CBF reduction only in several regions (-0.5 < r < -0.4), indicating a neuronal nature for most of the observed BEN alterations. In summary, we showed the first evidence of BEN alterations due to caffeine ingestion, suggesting BEN as a biomarker sensitive to pharmaceutical brain function modulations. PMID- 29426920 TI - Verification of radiodynamic therapy by medical linear accelerator using a mouse melanoma tumor model. AB - Combined treatment with 5-aminolevulinic acid (5-ALA) and X-rays improves tumor suppression in vivo. This is because the accumulated protoporphyrin IX from 5-ALA enhances the generation of ROS by the X-ray irradiation. In the present study, a high-energy medical linear accelerator was used instead of a non-medical low energy X-ray irradiator, which had been previously used. Tumor-bearing mice implanted with B16-BL6 melanoma cells were treated with fractionated doses of irradiation (in total, 20 or 30 Gy), using two types of X-ray irradiator after 5 ALA administration. Suppression of tumor growth was enhanced with X-ray irradiation in combination with 5-ALA treatment compared with X-ray treatment alone, using both medical and non-medical X-ray irradiators. 5-ALA has been used clinically for photodynamic therapy. Thus, "radiodynamic therapy", using radiation from medical linacs as a physical driving force, rather than the light used in photodynamic therapy, may have potential clinical applications. PMID- 29426919 TI - Dietary supplementation with hybrid palm oil alters liver function in the common Marmoset. AB - Hybrid palm oil, which contains higher levels of oleic acid and lower saturated fatty acids in comparison with African palm oil, has been proposed to be somehow equivalent to extra virgin olive oil. However, the biological effects of its consumption are poorly described. Here we have explored the effects of its overconsumption on lipid metabolism in a non-human primate model, the common marmoset. Dietary supplementation of marmoset with hyperlipidic diet containing hybrid palm oil for 3 months did not modify plasma lipids levels, but increased glucose levels as compared to the supplementation with African palm oil. Liver volume was unexpectedly found to be more increased in marmosets consuming hybrid palm oil than in those consuming African palm oil. Hepatic total lipid content and circulating transaminases were dramatically increased in animals consuming hybrid palm oil, as well as an increased degree of fibrosis. Analysis of liver miRNAs showed a selective modulation of certain miRNAs by hybrid palm oil, some of which were predicted to target genes involved in cell adhesion molecules and peroxisomal pathways. Our data suggest that consumption of hybrid palm oil should be monitored carefully, as its overconsumption compared to that of African palm oil could involve important alterations to hepatic metabolism. PMID- 29426923 TI - Publisher Correction: Development of a genetically encodable FRET system using fluorescent RNA aptamers. AB - In the original version of this Article the last section of the Methods describing Fluorescence microscopy was inadvertently omitted during the production process. This has now been corrected in the PDF and HTML versions of the Article. PMID- 29426922 TI - Statistical modeling of RNA structure profiling experiments enables parsimonious reconstruction of structure landscapes. AB - RNA plays key regulatory roles in diverse cellular processes, where its functionality often derives from folding into and converting between structures. Many RNAs further rely on co-existence of alternative structures, which govern their response to cellular signals. However, characterizing heterogeneous landscapes is difficult, both experimentally and computationally. Recently, structure profiling experiments have emerged as powerful and affordable structure characterization methods, which improve computational structure prediction. To date, efforts have centered on predicting one optimal structure, with much less progress made on multiple-structure prediction. Here, we report a probabilistic modeling approach that predicts a parsimonious set of co-existing structures and estimates their abundances from structure profiling data. We demonstrate robust landscape reconstruction and quantitative insights into structural dynamics by analyzing numerous data sets. This work establishes a framework for data-directed characterization of structure landscapes to aid experimentalists in performing structure-function studies. PMID- 29426921 TI - The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. AB - The new edition of the 2016 World Health Organization (WHO) classification system for tumors of the hematopoietic and lymphoid tissues was published in September 2017. Under the category of myeloproliferative neoplasms (MPNs), the revised document includes seven subcategories: chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia-not otherwise specified and MPN, unclassifiable (MPN-U); of note, mastocytosis is no longer classified under the MPN category. In the current review, we focus on the diagnostic criteria for JAK2/CALR/MPL mutation-related MPNs: PV, ET, and PMF. In this regard, the 2016 changes were aimed at facilitating the distinction between masked PV and JAK2-mutated ET and between prefibrotic/early and overtly fibrotic PMF. In the current communication, we (i) provide practically useful resource tables and graphs on the new diagnostic criteria including outcome, (ii) elaborate on the rationale for the 2016 changes, (iii) discuss the complementary role of mutation screening, (iv) address ongoing controversies and propose solutions, (v) attend to the challenges of applying WHO criteria in routine clinical practice, and (vi) outline future directions from the perspectives of the clinical pathologist. PMID- 29426924 TI - A biopotential optrode array: operation principles and simulations. AB - We propose an optical electrode 'optrode' sensor array for biopotential measurements. The transduction mechanism is based on deformed helix ferroelectric liquid crystals which realign, altering the optrode's light reflectance properties, relative to applied potential fields of biological cells and tissue. A computational model of extracellular potential recording by the optrode including the electro-optical transduction mechanism is presented, using a combination of time-domain and frequency-domain finite element analysis. Simulations indicate that the device has appropriate temporal response to faithfully transduce neuronal spikes, and spatial resolution to capture impulse propagation along a single neuron. These simulations contribute to the development of multi-channel optrode arrays for spatio-temporal mapping of electric events in excitable biological tissue. PMID- 29426926 TI - Quantum Clique Gossiping. AB - This paper establishes a framework of quantum clique gossiping by introducing local clique operations to networks of interconnected qubits. Cliques are local structures in complex networks being complete subgraphs, which can be used to accelerate classical gossip algorithms. Based on cyclic permutations, clique gossiping leads to collective multi-party qubit interactions. We show that at reduced states, these cliques have the same acceleration effects as their roles in accelerating classical gossip algorithms. For randomized selection of cliques, such improved rate of convergence is precisely characterized. On the other hand, the rate of convergence at the coherent states of the overall quantum network is proven to be decided by the spectrum of a mean-square error evolution matrix. Remarkably, the use of larger quantum cliques does not necessarily increase the speed of the network density aggregation, suggesting quantum network dynamics is not entirely decided by its classical topology. PMID- 29426927 TI - Local temperatures predict breeding phenology but do not result in breeding synchrony among a community of resident cavity-nesting birds. AB - Weather and ecological factors are known to influence breeding phenology and thus individual fitness. We predicted concordance between weather conditions and annual variation in phenology within a community of eight resident, cavity nesting bird species over a 17-year period. We show that, although clutch initiation dates for six of our eight species are correlated with local daily maximum temperatures, this common driver does not produce a high degree of breeding synchrony due to species-specific responses to conditions during different periods of the preceding winter or spring. These "critical temperature periods" were positively associated with average lay date for each species, although the interval between critical periods and clutch initiation varied from 4-78 days. The ecological factors we examined (cavity availability and a food pulse) had an additional influence on timing in only one of our eight focal species. Our results have strong implications for understanding heterogeneous wildlife responses to climate change: divergent responses would be expected within communities where species respond to local conditions within different temporal windows, due to differing warming trends between winter and spring. Our system therefore indicates that climate change could alter relative breeding phenology among sympatric species in temperate ecosystems. PMID- 29426925 TI - Ageing potentiates diet-induced glucose intolerance, beta-cell failure and tissue inflammation through TLR4. AB - Ageing and obesity are two major risk factors for the development of type 2 diabetes (T2D). A chronic, low-grade, sterile inflammation contributes to insulin resistance and beta-cell failure. Toll-like receptor-4 (TLR4) is a major pro inflammatory pathway; its ligands as well as downstream signals are increased systemically in patients with T2D and at-risk individuals. In the present study we investigated the combined effects of high fat/high sucrose diet (HFD) feeding, ageing and TLR4-deficiency on tissue inflammation, insulin resistance and beta cell failure. In young mice, a short-term HFD resulted in a mildly impaired glucose tolerance and reduced insulin secretion, together with a beta-cell mass compensation. In older mice, HFD further deteriorated insulin secretion and induced a significantly impaired glucose tolerance and augmented tissue inflammation in adipose, liver and pancreatic islets, all of which was attenuated by TLR4 deficiency. Our results show that ageing exacerbates HFD-induced impairment of glucose homeostasis and pancreatic beta-cell function and survival, and deteriorates HFD-induced induction of mRNA expression of inflammatory cytokines and pro-inflammatory macrophage markers. TLR4-deficiency protects against these combined deleterious effects of a high fat diet and ageing through a reduced expression of inflammatory products in both insulin sensitive tissues and pancreatic islets. PMID- 29426928 TI - LAMB3 mediates metastatic tumor behavior in papillary thyroid cancer by regulating c-MET/Akt signals. AB - Laminin subunit beta-3 (LAMB3) encodes one of the three subunits of LM-332, a protein of the extracellular matrix secreted by cultured human keratinocytes. While LAMB3 is involved in the invasive and metastatic abilities of several tumor types, including those found in the colon, pancreas, lung, cervix, stomach, and prostate, its mechanism of action in thyroid cancer has not been investigated previously. Our results show that LAMB3 is up-regulated in papillary thyroid cancer, and that its suppression reduces cell migration/invasion via down regulation of epithelial-mesenchymal transition-associated proteins (N-cadherin, vimentin, slug) and inhibition of matrix metalloproteinase 9. LAMB3 suppression also significantly decreases Akt phosphorylation and inhibits the transcription of c-MET, reducing its activation. These results suggest that LAMB3 leads to tumor invasion via Akt activation induced by the HGF/c-MET axis in papillary thyroid cancer cells. Our findings reveal a novel mechanism of action for LAMB3 in papillary thyroid cancer cells. PMID- 29426929 TI - Selective PEGylation of Parylene-C/SiO2 Substrates for Improved Astrocyte Cell Patterning. AB - Controlling the spatial distribution of glia and neurons in in vitro culture offers the opportunity to study how cellular interactions contribute to large scale network behaviour. A recently developed approach to cell-patterning uses differential adsorption of animal-serum protein on parylene-C and SiO2 surfaces to enable patterning of neurons and glia. Serum, however, is typically poorly defined and generates reproducibility challenges. Alternative activation methods are highly desirable to enable patterning without relying on animal serum. We take advantage of the innate contrasting surface chemistries of parylene-C and SiO2 to enable selective bonding of polyethylene glycol SiO2 surfaces, i.e. PEGylation, rendering them almost completely repulsive to cell adhesion. As the reagents used in the PEGylation protocol are chemically defined, the reproducibility and batch-to-batch variability complications associated with the used of animal serum are avoided. We report that PEGylated parylene-C/SiO2 substrates achieve a contrast in astrocyte density of 65:1 whereas the standard serum-immersion protocol results in a contrast of 5.6:1. Furthermore, single-cell isolation was significantly improved on PEGylated substrates when astrocytes were grown on close-proximity parylene-C nodes, whereas isolation was limited on serum activated substrates due tolerance for cell adhesion on serum-adsorbed SiO2 surfaces. PMID- 29426930 TI - Low diet quality and the risk of stroke mortality: the multiethnic cohort study. AB - BACKGROUND/OBJECTIVES: Several diets, e.g., those low in fruits/vegetables, high in sodium, and red/processed meat, have been related to a higher stroke risk. We investigated stroke mortality associated with a priori diet-quality indices in the Multiethnic Cohort study. SUBJECTS/METHODS: Based on 172,043 observations including 3548 stroke deaths, we investigated the Healthy Eating Index-2010 (HEI 2010), the Alternative HEI-2010, the alternate Mediterranean diet score, and the Dietary Approaches to Stop Hypertension index in relation to stroke mortality. Using Cox regression, we estimated adjusted population attributable risks (PAR) and hazard ratios (HR) for tertiles of the indices while adjusting for relevant confounders. RESULTS: The associations between all diet-quality indices and stroke mortality were consistent in direction; a low-quality diet was associated with a greater risk of stroke death, but the HEI-2010 was the strongest predictor. The PAR for stroke death based on HEI-2010 was 7.9% (95%-CI: 3.7 12.2%), indicating the preventable percentage of deaths if the total population had the same diet quality as those in the highest tertile for this diet-quality index. The lowest as compared to the highest tertile of the HEI-2010 was associated with a 1.23-fold (95%-CI: 1.13-1.34) risk. The PARs for low and medium adherence to the indices were similar by sex and follow-up time, but varied by ethnicity, with the highest PAR in Whites (15.4%) and no association in Latinos. CONCLUSIONS: Findings for four diet-quality indices, in particular the HEI-2010, indicated that diet quality acts as an independent risk factor for stroke mortality. Promotion of a high diet quality could have a substantial impact on the prevention of stroke deaths. PMID- 29426931 TI - Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation. AB - Embryo implantation is central to pregnancy success. Our previous understanding is limited by studying this phenomenon primarily in two dimensions. Here we employ 3D visualization, revealing that epithelial evaginations that form implantation chambers (crypts) consistently arise with preexisting glands, suggesting direct access of glands to embryos within the chamber. While the lobular domains of the glands become more developed, the ductal regions continue to elongate and progressively stretch following implantation. Using diapausing mice and mice with deletion of the planar cell polarity gene Vangl2 in uterine epithelial cells, we show that dynamic changes in gland topography depend on implantation-competent blastocysts and planar cell polarity. By transferring blastocyst-size beads preloaded with HB-EGF in pseudopregnant mice, we found that HB-EGF is a trigger for the communication between embryos and glands. Glands directly connecting the crypt encasing the embryo during implantation are therefore fundamental to pregnancy success. PMID- 29426932 TI - Quantitative analysis of receptor-mediated uptake and pro-apoptotic activity of mistletoe lectin-1 by high content imaging. AB - Ribosome inactivating proteins (RIPs) are highly potent cytotoxins that have potential as anticancer therapeutics. Mistletoe lectin 1 (ML1) is a heterodimeric cytotoxic protein isolated from European Mistletoe and belongs to RIP class II. The aim of this project was to systematically study ML1 cell binding, endocytosis pathway(s), subcellular processing and apoptosis activation. For this purpose, state of the art cell imaging equipment and automated image analysis algorithms were used. ML1 displayed very fast binding to sugar residues on the membrane and energy-dependent uptake in CT26 cells. The co-staining with specific antibodies and uptake blocking experiments revealed involvement of both clathrin-dependent and -independent pathways in ML1 endocytosis. Co-localization studies demonstrated the toxin transport from early endocytic vesicles to Golgi network; a retrograde road to the endoplasmic reticulum. The pro-apoptotic and antiproliferative activity of ML1 were shown in time lapse movies and subsequently quantified. ML1 cytotoxicity was less affected in multidrug resistant tumor cell line 4T1 in contrast to commonly used chemotherapeutic drug (ML1 resistance index 6.9 vs 13.4 for doxorubicin; IC50: ML1 1.4 ng/ml vs doxorubicin 24000 ng/ml). This opens new opportunities for the use of ML1 as an alternative treatment in multidrug resistant cancers. PMID- 29426933 TI - A conserved R type Methionine Sulfoxide Reductase reverses oxidized GrpEL1/Mge1 to regulate Hsp70 chaperone cycle. AB - Cells across evolution employ reversible oxidative modification of methionine and cysteine amino acids within proteins to regulate responses to redox stress. Previously we have shown that mitochondrial localized methionine sulfoxide reductase (Mxr2) reversibly regulates oxidized yeast Mge1 (yMge1), a co-chaperone of Hsp70/Ssc1 to maintain protein homeostasis during oxidative stress. However, the specificity and the conservation of the reversible methionine oxidation mechanism in higher eukaryotes is debatable as human GrpEL1 (hGrpEL1) unlike its homolog yMge1 harbors two methionine residues and multiple cysteines besides the mammalian mitochondria hosting R and S types of Mxrs/Msrs. In this study, using yeast as a surrogate system, we show that hGRPEL1 and R type MSRs but not the S type MSRs complement the deletion of yeast MGE1 or MXR2 respectively. Our investigations show that R type Msrs interact selectively with oxidized hGrpEL1/yMge1 in an oxidative stress dependent manner, reduce the conserved hGrpEL1-Met146-SO and rescue the Hsp70 ATPase activity. In addition, a single point mutation in hGrpEL1-M146L rescues the slow growth phenotype of yeast MXR2 deletion under oxidative duress. Our study illustrates the evolutionarily conserved formation of specific Met-R-SO in hGrpEL1/yMge1 and the essential and canonical role of R type Msrs/Mxrs in mitochondrial redox mechanism. PMID- 29426934 TI - Involvement of orexin neurons in fasting- and central adenosine-induced hypothermia. AB - We examined whether orexin neurons might play a protective role against fasting- and adenosine-induced hypothermia. We first measured body temperature (BT) in orexin neuron-ablated (ORX-AB) mice and wild-type (WT) controls during 24 hours of fasting. As expected, the magnitude of BT drop and the length of time suffering from hypothermia were greater in ORX-AB mice than in WT mice. Orexin neurons were active just before onset of hypothermia and during the recovery period as revealed by calcium imaging in vivo using G-CaMP. We next examined adenosine-induced hypothermia via an intracerebroventricular administration of an adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA), which induced hypothermia in both ORX-AB and WT mice. The dose of CHA required to initiate a hypothermic response in ORX-AB mice was more than 10 times larger than the dose for WT mice. Once hypothermia was established, the recovery was seemingly slower in ORX-AB mice. Activation of orexin neurons during the recovery phase was confirmed by immunohistochemistry for c-Fos. We propose that orexin neurons play dual roles (enhancer in the induction phase and compensator during the recovery phase) in adenosine-induced hypothermia and a protective/compensatory role in fasting-induced hypothermia. PMID- 29426935 TI - Label-free Raman hyperspectral imaging analysis localizes the cyanogenic glucoside dhurrin to the cytoplasm in sorghum cells. AB - Localisation of metabolites in sorghum coleoptiles using Raman hyperspectral imaging analysis was compared in wild type plants and mutants that lack cyanogenic glucosides. This novel method allows high spatial resolution in situ localization by detecting functional groups associated with cyanogenic glucosides using vibrational spectroscopy. Raman hyperspectral imaging revealed that dhurrin was found mainly surrounding epidermal, cortical and vascular tissue, with the greatest amount in cortical tissue. Numerous "hotspots" demonstrated dhurrin to be located within both cell walls and cytoplasm adpressed towards the plasmamembrane and not in the vacuole as previously reported. The high concentration of dhurrin in the outer cortical and epidermal cell layers is consistent with its role in defence against herbivory. This demonstrates the ability of Raman hyperspectral imaging to locate cyanogenic glucosides in intact tissues, avoiding possible perturbations and imprecision that may accompany methods that rely on bulk tissue extraction methods, such as protoplast isolation. PMID- 29426936 TI - Genetic alterations driving metastatic colony formation are acquired outside of the primary tumour in melanoma. AB - Mouse models indicate that metastatic dissemination occurs extremely early; however, the timing in human cancers is unknown. We therefore determined the time point of metastatic seeding relative to tumour thickness and genomic alterations in melanoma. Here, we find that lymphatic dissemination occurs shortly after dermal invasion of the primary lesion at a median thickness of ~0.5 mm and that typical driver changes, including BRAF mutation and gained or lost regions comprising genes like MET or CDKNA2, are acquired within the lymph node at the time of colony formation. These changes define a colonisation signature that was linked to xenograft formation in immunodeficient mice and death from melanoma. Thus, melanoma cells leave primary tumours early and evolve at different sites in parallel. We propose a model of metastatic melanoma dormancy, evolution and colonisation that will inform direct monitoring of adjuvant therapy targets. PMID- 29426938 TI - Wavelength and pulse duration tunable ultrafast fiber laser mode-locked with carbon nanotubes. AB - Ultrafast lasers with tunable parameters in wavelength and time domains are the choice of light source for various applications such as spectroscopy and communication. Here, we report a wavelength and pulse-duration tunable mode locked Erbium doped fiber laser with single wall carbon nanotube-based saturable absorber. An intra-cavity tunable filter is employed to continuously tune the output wavelength for 34 nm (from 1525 nm to 1559 nm) and pulse duration from 545 fs to 6.1 ps, respectively. Our results provide a novel light source for various applications requiring variable wavelength or pulse duration. PMID- 29426937 TI - Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation. AB - Ultraconserved (uc) RNAs, a class of long non-coding RNAs (lncRNAs), are conserved across humans, mice, and rats, but the physiological significance and pathological role of ucRNAs is largely unknown. Here we show that uc.372 is upregulated in the livers of db/db mice, HFD-fed mice, and NAFLD patients. Gain of-function and loss-of-function studies indicate that uc.372 drives hepatic lipid accumulation in mice by promoting lipogenesis. We further demonstrate that uc.372 binds to pri-miR-195/pri-miR-4668 and suppresses maturation of miR-195/miR 4668 to regulate expression of genes related to lipid synthesis and uptake, including ACC, FAS, SCD1, and CD36. Finally, we identify that uc.372 is located downstream of the insulinoma-associated 2 (INSM2) gene that is transcriptionally activated by upstream transcription factor 1 (USF1). Our findings reveal a novel mechanism by which uc.372 drives hepatic steatosis through inhibition of miR 195/miR-4668 maturation to relieve miR-195/miR-4668-mediated suppression of functional target gene expression. PMID- 29426939 TI - SeagrassDB: An open-source transcriptomics landscape for phylogenetically profiled seagrasses and aquatic plants. AB - Seagrasses and aquatic plants are important clades of higher plants, significant for carbon sequestration and marine ecological restoration. They are valuable in the sense that they allow us to understand how plants have developed traits to adapt to high salinity and photosynthetically challenged environments. Here, we present a large-scale phylogenetically profiled transcriptomics repository covering seagrasses and aquatic plants. SeagrassDB encompasses a total of 1,052,262 unigenes with a minimum and maximum contig length of 8,831 bp and 16,705 bp respectively. SeagrassDB provides access to 34,455 transcription factors, 470,568 PFAM domains, 382,528 prosite models and 482,121 InterPro domains across 9 species. SeagrassDB allows for the comparative gene mining using BLAST-based approaches and subsequent unigenes sequence retrieval with associated features such as expression (FPKM values), gene ontologies, functional assignments, family level classification, Interpro domains, KEGG orthology (KO), transcription factors and prosite information. SeagrassDB is available to the scientific community for exploring the functional genic landscape of seagrass and aquatic plants at: http://115.146.91.129/index.php . PMID- 29426940 TI - Spatiotemporal regulation of liver development by the Wnt/beta-catenin pathway. AB - While the Wnt/beta-catenin pathway plays a critical role in the maintenance of the zonation of ammonia metabolizing enzymes in the adult liver, the mechanisms responsible for inducing zonation in the embryo are not well understood. Herein we address the spatiotemporal role of the Wnt/beta-catenin pathway in the development of zonation in embryonic mouse liver by conditional deletion of Apc and beta-catenin at different stages of mouse liver development. In normal development, the ammonia metabolising enzymes carbamoylphosphate synthetase I (CPSI) and Glutamine synthetase (GS) begin to be expressed in separate hepatoblasts from E13.5 and E15.5 respectively and gradually increase in number thereafter. Restriction of GS expression occurs at E18 and becomes increasingly limited to the terminal perivenous hepatocytes postnatally. Expression of nuclear beta-catenin coincides with the restriction of GS expression to the terminal perivenous hepatocytes. Conditional loss of Apc resulted in the expression of nuclear beta-catenin throughout the developing liver and increased number of cells expressing GS. Conversely, conditional loss of beta-catenin resulted in loss of GS expression. These data suggest that the Wnt pathway is critical to the development of zonation as well as maintaining the zonation in the adult liver. PMID- 29426941 TI - Microfluidic channel optimization to improve hydrodynamic dissociation of cell aggregates and tissue. AB - Maximizing the speed and efficiency at which single cells can be liberated from tissues would dramatically advance cell-based diagnostics and therapies. Conventional methods involve numerous manual processing steps and long enzymatic digestion times, yet are still inefficient. In previous work, we developed a microfluidic device with a network of branching channels to improve the dissociation of cell aggregates into single cells. However, this device was not tested on tissue specimens, and further development was limited by high cost and low feature resolution. In this work, we utilized a single layer, laser micro machined polyimide film as a rapid prototyping tool to optimize the design of our microfluidic channels to maximize dissociation efficiency. This resulted in a new design with smaller dimensions and a shark fin geometry, which increased recovery of single cells from cancer cell aggregates. We then tested device performance on mouse kidney tissue, and found that optimal results were obtained using two microfluidic devices in series, the larger original design followed by the new shark fin design as a final polishing step. We envision our microfluidic dissociation devices being used in research and clinical settings to generate single cells from various tissue specimens for diagnostic and therapeutic applications. PMID- 29426942 TI - Galectin-1 is required for the regulatory function of B cells. AB - Galectin-1 (Gal-1) is required for the development of B cells in the bone marrow (BM), however very little is known about the contribution of Gal-1 to the development of B cell regulatory function. Here, we report an important role for Gal-1 in the induction of B cells regulatory function. Mice deficient of Gal-1 (Gal-1-/-) showed significant loss of Transitional-2 (T2) B cells, previously reported to include IL-10+ regulatory B cells. Gal-1-/- B cells stimulated in vitro via CD40 molecules have impaired IL-10 and Tim-1 expression, the latter reported to be required for IL-10 production in regulatory B cells, and increased TNF-alpha expression compared to wild type (WT) B cells. Unlike their WT counterparts, T2 and T1 Gal-1-/- B cells did not suppress TNF-alpha expression by CD4+ T cells activated in vitro with allogenic DCs (allo-DCs), nor were they suppressive in vivo, being unable to delay MHC-class I mismatched skin allograft rejection following adoptive transfer. Moreover, T cells stimulated with allo-DCs show an increase in their survival when co-cultured with Gal-1-/- T2 and MZ B cells compared to WT T2 and MZ B cells. Collectively, these data suggest that Gal 1 contributes to the induction of B cells regulatory function. PMID- 29426943 TI - Giant rhyolite lava dome formation after 7.3 ka supereruption at Kikai caldera, SW Japan. AB - Kikai submarine caldera to the south of the Kyushu Island, SW Japan, collapsed at 7.3 ka during the latest supereruption (>500 km3 of magma) in the Japanese Archipelago. Multi functional research surveys of the T/S Fukae Maru in this caldera, including multi-beam echosounder mapping, remotely operated vehicle observation, multi-channel seismic reflection survey, and rock sampling by dredging and diving, provided lines of evidence for creation of a giant rhyolite lava dome (~32 km3) after the caldera collapse. This dome is still active as water column anomalies accompanied by bubbling from its surface are observed. Chemical characteristics of dome-forming rhyolites akin to those of presently active small volcanic cones are different from those of supereruption. The voluminous post-caldera activity is thus not caused simply by squeezing the remnant of syn-caldera magma but may tap a magma system that has evolved both chemically and physically since the 7.3-ka supereruption. PMID- 29426945 TI - Characterization of the complete mitogenome of Indian Mouse Deer, Moschiola indica (Artiodactyla: Tragulidae) and its evolutionary significance. AB - The mitochondrial genome of Indian mouse deer (Moschiola indica) was sequenced, assembled and characterized for the first time using 22 pairs of polymerase chain reaction (PCR) primers. The mitogenome of M. indica which is 16,444 bp in size was found very similar to most vertebrates in organisation that harbours 13 protein-coding genes, 22 transfer RNA, 2 ribosomal RNA and 1A + T-rich region. Its comparison with over 52 mitogenomes of the order Artiodactyla, showed a conserved nature of gene organisation, codon usage, gene orientation and evolutionary rates of proteins except that M. indica possesses an extra copy of trnF. The complete mitogenome and protein-coding genes of M. indica were found to be highly A + T biased. Rate of protein evolution was highest in atp8 and lowest in cox3. Further, a higher purifying selection pressure was found to be acting on family Tragulidae compared to Bovidae and Cervidae. The phylogenetic analysis of M. indica placed the Tragulidae as sister-group of all other ruminants, similar to previous analyses. Moschiola forms the sister-group to the other two tragulid genera Tragulus (from Asia) and Hyemoschus (from Africa), which is unexpected as usually the Asian species are thought to form a monophyletic group. PMID- 29426944 TI - Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy. AB - In this study, we upregulated insulin-like growth factor-1 (IGF1) expression specifically in skeletal muscle by engineering an enhancer into its non-coding regions and verified the expected phenotype in a mouse model. To select an appropriate site for introducing a skeletal muscle-specific myosin light chain (MLC) enhancer, three candidate sites that exhibited the least evolutionary conservation were chosen and validated in C2C12 single-cell colonies harbouring the MLC enhancer at each site. IGF1 was dramatically upregulated in only the site 2 single-cell colony series, and it exhibited functional activity leading to the formation of extra myotubes. Therefore, we chose site 2 to generate a genetically modified (GM) mouse model with the MLC enhancer incorporated by CRISPR/Cas9 technology. The GM mice exhibited dramatically elevated IGF1 levels, which stimulated downstream pathways in skeletal muscle. Female GM mice exhibited more conspicuous muscle hypertrophy than male GM mice. The GM mice possessed similar circulating IGF1 levels and tibia length as their WT littermates; they also did not exhibit heart abnormalities. Our findings demonstrate that genetically modifying a non-coding region is a feasible method to upregulate gene expression and obtain animals with desirable traits. PMID- 29426946 TI - Psychological morbidities and positive psychological outcomes in people with traumatic spinal cord injury in Mainland China. AB - STUDY DESIGN: Cross-sectional survey. OBJECTIVES: To explore the prevalences of three psychological morbidities (posttraumatic stress disorder, anxiety, and depression) and two positive psychological outcomes (resilience and posttraumatic growth) in people with spinal cord injury (SCI). To examine the relationships between the five aforementioned variables and to determine the predictors of the three psychological morbidities. SETTING: Shanghai Sunshine Rehabilitation Center, Mainland China. METHODS: Participants included 300 adults with SCI in one rehabilitation center in Shanghai. Standardized self-report measures were used. Sociodemographic, injury, and psychological variables were assessed. Descriptive analyses were used to calculate the prevalences of five psychological outcome variables. Pearson correlation analyses were conducted to examine the relationships between the five psychological variables and regression analyses were conducted to determine the predictors of posttraumatic stress disorder (PTSD), anxiety, and depression. RESULTS: Of the 300 respondents, 35%, 29%, and 27% exceeded the clinical cutoff score for PTSD, anxiety, and depression, respectively. About 32% reported good resilience, and 51% reported moderate to high levels of posttraumatic growth (PTG). Three psychological morbidities showed positive correlations between each other while significant negative relationships with the resilience and PTG. Hierarchical regressions indicated that both the extent of environmental barriers and resilience were the significant predictors of PTSD, anxiety, and depression. CONCLUSION: High prevalences of psychological morbidities were found in the SCI population in Mainland China. They should be identified and intervened early in the rehabilitation process. Some positive psychological techniques that focus on increasing resilience and promoting PTG would likely be beneficial for the SCI population. PMID- 29426947 TI - Additive manufacturing of 3D nano-architected metals. AB - Most existing methods for additive manufacturing (AM) of metals are inherently limited to ~20-50 MUm resolution, which makes them untenable for generating complex 3D-printed metallic structures with smaller features. We developed a lithography-based process to create complex 3D nano-architected metals with ~100 nm resolution. We first synthesize hybrid organic-inorganic materials that contain Ni clusters to produce a metal-rich photoresist, then use two-photon lithography to sculpt 3D polymer scaffolds, and pyrolyze them to volatilize the organics, which produces a >90 wt% Ni-containing architecture. We demonstrate nanolattices with octet geometries, 2 MUm unit cells and 300-400-nm diameter beams made of 20-nm grained nanocrystalline, nanoporous Ni. Nanomechanical experiments reveal their specific strength to be 2.1-7.2 MPa g-1 cm3, which is comparable to lattice architectures fabricated using existing metal AM processes. This work demonstrates an efficient pathway to 3D-print micro-architected and nano-architected metals with sub-micron resolution. PMID- 29426948 TI - Applying Data-driven Imaging Biomarker in Mammography for Breast Cancer Screening: Preliminary Study. AB - We assessed the feasibility of a data-driven imaging biomarker based on weakly supervised learning (DIB; an imaging biomarker derived from large-scale medical image data with deep learning technology) in mammography (DIB-MG). A total of 29,107 digital mammograms from five institutions (4,339 cancer cases and 24,768 normal cases) were included. After matching patients' age, breast density, and equipment, 1,238 and 1,238 cases were chosen as validation and test sets, respectively, and the remainder were used for training. The core algorithm of DIB MG is a deep convolutional neural network; a deep learning algorithm specialized for images. Each sample (case) is an exam composed of 4-view images (RCC, RMLO, LCC, and LMLO). For each case in a training set, the cancer probability inferred from DIB-MG is compared with the per-case ground-truth label. Then the model parameters in DIB-MG are updated based on the error between the prediction and the ground-truth. At the operating point (threshold) of 0.5, sensitivity was 75.6% and 76.1% when specificity was 90.2% and 88.5%, and AUC was 0.903 and 0.906 for the validation and test sets, respectively. This research showed the potential of DIB-MG as a screening tool for breast cancer. PMID- 29426949 TI - PP5 (PPP5C) is a phosphatase of Dvl2. AB - Dishevelled (Dvl) family proteins are key mediators of Wnt signalling and function in both canonical and noncanonical branches. Dvl2, the most studied Dvl protein, is extensively regulated by phosphorylation. Several kinases were found to be critical for Dvl2 localisation, stability control and functional segregation. For example, S143-phosphorylated Dvl2 was detected, together with CK1delta/epsilon, at the centrosome and basal body of primary cilia and plays pivotal roles during ciliogenesis. However, relatively less is known about Dvl dephosphorylation and the phosphatases involved. Here, we identified PP5 (PPP5C) as a phosphatase of Dvl2. PP5 interacts with and can directly dephosphorylate Dvl2. Knockdown of PP5 caused elevated Dvl2 phosphorylation both at the basal level and upon Wnt stimulation. In the Dvl2 protein, S143, the 10B5 cluster and other sites were dephosphorylated by PP5. Interestingly, comparison of PP5 with PP2A, another known Dvl2 phosphatase, revealed that PP5 and PP2A are not fully redundant in the regulation of Dvl2 phosphorylation status. In hTERT-RPE1 cells, PP5 was found at the basal body of cilia, where S143-phosphorylated Dvl2 also resides. Functional assays revealed modest effects on ciliogenesis after PP5 depletion or over-expression. Taken together, our results provided evidence to suggest PP5 as a new phosphatase for Dvl2. PMID- 29426950 TI - Drivers of spatio-temporal changes in paddy soil pH in Jiangxi Province, China from 1980 to 2010. AB - The spatio-temporal distribution soil pH is critical for understanding the productivity and long-term sustainability of our agri-ecosystem. This study quantified the spatio-temporal distribution of paddy soil pH in Jiangxi province, China, and the potential driver of the change between 1980 and 2010. Data from the Soil Survey Information of Jiangxi province (1980s) and Jiangxi Soil Testing and Fertilizer Recommendation study (2010s) were collected and categorized into six pH ranges from strongly-acidic to strongly-alkaline with unit pH differences. Changes were calculated from the maps developed using the Pedological Knowledge base for 1980s data (without geolocation) and geostatistical methods for the 2010s data (geolocated). An overall 0.6-unit decrease and a major shift of soil pH from weakly-acidic (54% -> 18%) to acidic (35% -> 74%) was observed over the province in a scattered fashion with concentration in the central part and the Poyang Lake area. About half of the area under paddy cultivation went through acidification by at least one pH unit and 7% by at least 2 pH units, while 40% of the area remained unchanged. Excessive fertilizer application and acid-rain intensity contributed to the acidification. Thus, a more knowledge-based and comprehensive fertilizer management should be adopted to make paddy production sustainable in the province. PMID- 29426951 TI - Small eukaryotic phytoplankton communities in tropical waters off Brazil are dominated by symbioses between Haptophyta and nitrogen-fixing cyanobacteria. AB - Symbioses between eukaryotic algae and nitrogen-fixing cyanobacteria have been recognized in recent years as a key source of new nitrogen in the oceans. We investigated the composition of the small photosynthetic eukaryote communities associated with nitrogen-fixing cyanobacteria in the Brazilian South Atlantic Bight using a combination of flow cytometry sorting and high throughput sequencing of two genes: the V4 region of 18S rRNA and nifH. Two distinct eukaryotic communities were often encountered, one dominated by the Mamiellophyceae Bathycoccus and Ostreococcus, and one dominated by a prymnesiophyte known to live in symbiosis with the UCYN-A1 nitrogen-fixing cyanobacterium. Among nifH sequences, those from UCYN-A1 were most abundant but three other UCYN-A clades (A2, A3, A4) were also found. Network analysis confirmed the relation between A1 and A2 clades and their hypothesized hosts and pointed out to the potential association between novel clade A4 with Braarudosphaera bigelowii, previously hypothesized to host A2. PMID- 29426952 TI - NanoSIMS and tissue autoradiography reveal symbiont carbon fixation and organic carbon transfer to giant ciliate host. AB - The giant colonial ciliate Zoothamnium niveum harbors a monolayer of the gammaproteobacteria Cand. Thiobios zoothamnicoli on its outer surface. Cultivation experiments revealed maximal growth and survival under steady flow of high oxygen and low sulfide concentrations. We aimed at directly demonstrating the sulfur-oxidizing, chemoautotrophic nature of the symbionts and at investigating putative carbon transfer from the symbiont to the ciliate host. We performed pulse-chase incubations with 14C- and 13C-labeled bicarbonate under varying environmental conditions. A combination of tissue autoradiography and nanoscale secondary ion mass spectrometry coupled with transmission electron microscopy was used to follow the fate of the radioactive and stable isotopes of carbon, respectively. We show that symbiont cells fix substantial amounts of inorganic carbon in the presence of sulfide, but also (to a lesser degree) in the absence of sulfide by utilizing internally stored sulfur. Isotope labeling patterns point to translocation of organic carbon to the host through both release of these compounds and digestion of symbiont cells. The latter mechanism is also supported by ultracytochemical detection of acid phosphatase in lysosomes and in food vacuoles of ciliate cells. Fluorescence in situ hybridization of freshly collected ciliates revealed that the vast majority of ingested microbial cells were ectosymbionts. PMID- 29426953 TI - Cerebral ischemia induces the aggregation of proteins linked to neurodegenerative diseases. AB - Protein aggregation critically affects cell viability in neurodegenerative diseases, but whether this also occurs in ischemic brain injury remains elusive. Prior studies report the post-ischemic aggregation of ubiquitin, small ubiquitin related modifier (SUMO) and ribosomes, however whether other proteins are also affected is unknown. Here we employed a proteomic approach to identify the insoluble, aggregated proteome after cerebral ischemia. Mice underwent transient middle cerebral artery occlusion or sham-surgery. After 1-hour reperfusion, prior to apparent brain injury, mice were sacrificed and detergent-insoluble proteins were obtained and identified by nanoLC-MS/MS. Naturally existing insoluble proteins were determined in sham controls and aggregated proteins after cerebral ischemia/reperfusion were identified. Selected aggregated proteins found by proteomics were biochemically verified and aggregation propensities were studied during ischemia with or without reperfusion. We found that ischemia/reperfusion induces the aggregation of RNA-binding and heat-shock proteins, ubiquitin, SUMO and other proteins involved in cell signalling. RNA-binding proteins constitute the largest group of aggregating proteins in ischemia. These include TDP43, FUS, hnRNPA1, PSF/SFPQ and p54/NONO, all of which have been linked to neurodegeneration associated with amyotrophic lateral sclerosis and frontotemporal dementia. The aggregation of neurodegeneration-related disease proteins in cerebral ischemia unveils a previously unappreciated molecular overlap between neurodegenerative diseases and ischemic stroke. PMID- 29426954 TI - 3D 7Li magnetic resonance imaging of brain lithium distribution in bipolar disorder. AB - Lithium is a major treatment for bipolar disorder and the likelihood of a favourable response may be determined by its distribution in the brain. Lithium can be directly detected by magnetic resonance (MR), but previous 7Li MR spectroscopy studies have demonstrated that this is challenging compared to conventional 1H MR imaging due to the MR properties of the lithium nucleus and its low concentration in brain tissue, as dictated by therapeutic dose. We have tested and implemented a highly efficient balanced steady-state free precession 7Li-MRI method to address these challenges and enable MRI of brain lithium in a short duration scan. We report a 3D 7Li-MRI acquisition with 25 mm isotropic resolution in an 8-min scan that demonstrates heterogeneity in lithium concentration within the brain in subjects with bipolar disorder. This represents the direct imaging of a pharmaceutical agent in its target organ and notably expands the repertoire of techniques available to investigate the effects of lithium in man. PMID- 29426955 TI - Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model. AB - Autoantibodies of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB) were considered pathognomonic for anti-NMDAR encephalitis. This view has been challenged by the age-dependent seroprevalence (up to >20%) of functional NMDAR1-AB of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. These findings question a merely encephalitogenic role of NMDAR1-AB. Here, we show that NMDAR1-AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons, and rhesus macaques, and are functional in the NMDAR1 internalization assay based on human IPSC-derived cortical neurons. The age dependence of seroprevalence is lost in nonhuman primates in captivity and in human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA class. Active immunization of ApoE-/- and ApoE+/+ mice against four peptides of the extracellular NMDAR1 domain or ovalbumin (control) leads to high circulating levels of specific AB. After 4 weeks, the endogenously formed NMDAR1-AB (IgG) induce psychosis-like symptoms upon MK-801 challenge in ApoE-/- mice, characterized by an open blood-brain barrier, but not in their ApoE+/+ littermates, which are indistinguishable from ovalbumin controls. Importantly, NMDAR1-AB do not induce any sign of inflammation in the brain. Immunohistochemical staining for microglial activation markers and T lymphocytes in the hippocampus yields comparable results in ApoE-/- and ApoE+/+ mice, irrespective of immunization against NMDAR1 or ovalbumin. These data suggest that NMDAR1-AB of the IgG class shape behavioral phenotypes upon access to the brain but do not cause brain inflammation on their own. PMID- 29426956 TI - Helping cancer patients quit smoking using brief advice based on risk communication: A randomized controlled trial. AB - This randomized controlled trial aimed to examine the effectiveness of a smoking cessation intervention using a risk communication approach. A total of 528 smoking cancer patients were randomly allocated either into an intervention group (n = 268) to receive brief advice based on risk communication by a nurse counselor or a control group (n = 260) to receive standard care. Subjects in both groups received a smoking cessation booklet. Patient follow-ups were at 1 week and at 1, 3, 6, 9 and 12 months. No significant differences were found in self reported point-prevalence 7-day abstinence between the intervention and control groups at 6 months (15.7% vs 16.5%; OR 0.94, 95% CI 0.59-1.50). The rate of at least 50% self-reported reduction of smoking at 6 months, was higher in the intervention group than in the control group (16.8% vs 12.3%; OR 1.43, 95% CI 0.88-2.35). The biochemically validated quit rate at the 6-month follow-up was higher in the intervention group than in the control group (5.2% vs 3.8%; OR 1.38, 95% CI 0.60-3.16). These data suggest that advice based on risk communication was not effective for quitting but improved the rate of smoking reduction among smoking cancer patients. PMID- 29426957 TI - MRI of pectoralis major tears: association between ancillary findings and tear severity. AB - OBJECTIVE: To evaluate the significance of biceps tendon (BT) displacement and peri-bicipital hematoma on MRI in subjects with pectoralis major (PM) tears. We hypothesized that these features might be associated with tear severity at surgery. MATERIALS AND METHODS: We retrospectively identified MRI cases with PM injury and reviewed clinical, imaging, and surgical records. MR images were reviewed independently by two musculoskeletal radiologists to determine anterior displacement of BT (BT-disp, in mm) and the presence of triangular-shaped peri bicipital hematoma. Data were compared with an age- and sex-matched control group and correlated with surgical reports grouped by tear severity. RESULTS: We identified 46 subjects with PM injury (43 men, 3 women; mean age 34 +/- 9 years), 26 of whom underwent surgical reconstruction, and 20 matched controls (P > 0.2). BT-disp was significantly higher in PM injury vs controls (P = 0.003), and in tendon vs myotendinous (MT) junction PM tears (P < 0.0001); however, MT junction tears vs controls were similar (P = 0.98). Higher BT-disp and presence of peri bicipital hematoma correlated significantly with surgical reports describing full thickness complete tears. BT-disp > 4.5 mm had 86% sensitivity and 75% specificity to detect the most severe tears on surgical reports, whereas the presence of peri-bicipital hematoma was the strongest predictor among both parameters. CONCLUSION: Anterior BT displacement and peri-bicipital hematoma are helpful indicators of full-thickness complete tears at the humeral insertion. PMID- 29426958 TI - Epiphyseal hyperplasia caused by an ectopic ossification center of the distal tibia: presentation of a pediatric case with 13 years of radiological surveillance. AB - Herein, we report the case of a 4-year-old boy, who presented with a cortical lytic lesion of his distal tibia. It was located eccentrically, measured 2 cm in its craniocaudal diameter, and was associated with a lamella-like soft-tissue mineralization that resembled a periosteal reaction. Thus, the lesion's radiographic features were initially suggestive of an aggressive disease. However, further imaging revealed the lesion to be of cartilaginous origin and to extend into the metaphysis, thus creating the aspect of hyperplastic epiphyseal cartilage. This cartilaginous hyperplasia was likely caused by an ectopic ossification center, although no similar cases have yet been reported. As radiology and clinics no longer indicated the imminent threat of a high-grade malignancy, we decided against a biopsy to avoid interfering with epiphyseal growth. However, because of the unprecedented nature of the given constellation, we closely monitored the lesion radiologically to rule out an untypical manifestation of a benign but potentially expanding lesion, in addition to a growth disturbance resulting from the lesion itself. However, further imaging indicated that mineralization and ossifications, which were already present at the lesion's initial presentation, increased over time, until the lesion fully disappeared after 13 years of clinical and radiological surveillance. This case is outstanding because of its singular morphology and the long-term follow-up that illustrates its self-limiting natural course. This report provides support in differential diagnosis to help discriminate potentially self-limiting conditions from other diseases that may require invasive diagnosis and/or therapy. PMID- 29426959 TI - Acute Effect of Inhaled Iloprost in Children with Pulmonary Arterial Hypertension Associated with Simple Congenital Heart Defects. AB - Inhaled prostacyclin analogue iloprost is currently utilized in adult patients with pulmonary arterial hypertension (PAH), but little information is available on its use in the pediatric population. This study evaluated the safety and acute haemodynamic effects of inhaled iloprost in children with PAH associated with congenital heart disease (CHD). Children with PAH-CHD who underwent cardiac catheterization and iloprost administration in our catheter laboratory between June 2007 and October 2015 were included. Iloprost was administered by atomization inhalation and changes in hemodynamic parameters were recorded. In total, 100 children with PAH-CHD were enrolled. Median age was 13 [1.5-18.0] years and 34% were male. A ventricular septal defect was present in 84%, a patent duct in 12%, a complete atrioventricular septal defect in 2%, and an isolated atrial septal defect in 2%. Pulmonary vascular resistance indexed (PVRI) was above 8 WU m2 in 96% and was above a third systemic (Rp/Rs > 0.33) in 97%. Iloprost was well tolerated in all patients. Following iloprost inhalation, mean pulmonary arterial pressure decreased from 78.4 +/- 9.2 to 72.8 +/- 10.8 mmHg (p < 0.01) and pulmonary-to-systemic blood flow ratio (Qp/Qs) increased from 1.12 +/ 0.48 to 1.37 +/- 0.63 (p < 0.01), with no change in cardiac index (Qs). PVRI decreased from 21.0 +/- 9.0 to 16.9 +/- 8.0 WU m2 (p < 0.01) following inhalation but 92% patients still had a PVRI > 8 WU m2 and 93% an Rp/Rs > 0.33. Acute inhalation of iloprost in children with PAH associated with CHD resulted in a significant improvement in hemodynamic parameters. Despite this, few patients achieve strict criteria of operability, underscoring the importance of early screening and timely repair of CHD. PMID- 29426960 TI - Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK-neurexin interaction. AB - Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia. The mutation M519T results in the replacement of an evolutionarily invariant methionine located in the PDZ signaling domain known to be critical for the CASK-neurexin interaction. CASKM519T is incapable of binding to neurexin, suggesting a critically important role for the CASK-neurexin interaction. The mutation G659D is in the SH3 (Src homology 3) domain of CASK, replacing a semi-conserved glycine with aspartate. We demonstrate that the CASKG659D mutation affects the CASK protein in two independent ways: (1) it increases the protein's propensity to aggregate; and (2) it disrupts the interface between CASK's PDZ (PSD95, Dlg, ZO-1) and SH3 domains, inhibiting the CASK-neurexin interaction despite residing outside of the domain deemed critical for neurexin interaction. Since heterozygosity of other aggregation-inducing mutations (e.g., CASKW919R) does not produce MICPCH, we suggest that the G659D mutation produces microcephaly by disrupting the CASK-neurexin interaction. Our results suggest that disruption of the CASK-neurexin interaction, not the CASK Tbr-1 interaction, produces microcephaly and cerebellar hypoplasia. These findings underscore the importance of functional validation for variant classification. PMID- 29426961 TI - Tissue microarray is suitable for scientific biomarkers studies in endometrial cancer. AB - The aim of this study was to define the concordance between tissue microarrays (TMAs) of different sizes and whole slide for 15 different antibodies in endometrial cancer and study the use of TMAs in preoperative endometrial samples. Cores of preoperative and hysterectomy specimens of 14 endometrial cancer and three atypical hyperplasia cases were collected in TMA blocks. Two 0.6-mm and two 2.0-mm cores were used from each sample. Different antibodies were tested in TMAs and compared with results of whole slides of hysterectomy. Tested antibodies were as follows: ER, PR, p53, Ki-67, MLH1, PMS2, MSH2, MSH6, ARID1A, stathmin, IMP3, L1CAM, PTEN, beta-catenin, and p16. Seventeen cases with four cores per paraffin block (both 0.6 and 2.0 mm in duplicate) and 15 different antibodies resulted in a total of 1020 cores for both preoperative and hysterectomy specimen. Overall, 2.0-mm cores were more assessable for evaluation than 0.6-mm cores (96.0 versus 79.5%, p < 0.01). For most antibodies, a substantial to good agreement between hysterectomy TMA and whole slide was present, with lowest agreement for p16 and stathmin and perfect agreement for mismatch repair proteins. Preoperative TMAs showed for most antibodies moderate to perfect agreement with hysterectomy TMAs. In conclusion, 2.0-mm cores are the preferred size for immunohistochemical studies in endometrial cancer. For all tested antibodies, TMAs are a good alternative for whole slide analysis in scientific studies with large patient cohorts, even in preoperative endometrial samples. However, caution is required for interpretation of TMA results of p16 and stathmin. PMID- 29426962 TI - Histopathological findings of pregnancy-induced hypertension: histopathology of early-onset type reflects two-stage disorder theory. AB - The placental tissues of pregnancy-induced hypertension (PIH) patients exhibit multiple infarctions, acute atherosis, distal villous hypoplasia, and increased syncytial knots. However, these findings are not observed in all cases of PIH; thus, the significance of these changes in PIH is still unclear. We studied the frequency of histopathological changes of placental tissue in the subgroups of PIH, such as mild and severe PIH and early-onset (< 34 weeks) and late-onset (>= 34 weeks) PIH. One hundred seven cases of PIH diagnosed at the Shinshu University Hospital, Matsumoto, Japan, between 2008 and 2014 were collected. PIH includes preeclampsia and gestational hypertension. The pathologic changes evaluated in the placenta were multiple infarctions, acute atherosis, distal villous hypoplasia, and increased syncytial knots. Placental tissues of patients with early-onset PIH demonstrated acute atherosis resulting from the incomplete remodeling of the spiral arteries and distal villous hypoplasia and increased syncytial knots reflecting placental hypoxia/ischemia much more frequently than those with late-onset PIH (all p < 0.001). The frequencies of multiple infarctions did not show a statistical difference between early-onset PIH and late-onset PIH. Moreover, there were no significant differences in the frequencies of histopathological features of placental tissue between mild PIH and severe PIH. Early-onset PIH exhibited histopathological changes of placental tissue consistent with the two-stage disorder theory more frequently than late onset PIH. These findings support the idea that early-onset PIH and late-onset PIH are distinct entities or different extremes of the PIH spectrum. PMID- 29426963 TI - Prostate-specific membrane antigen (PSMA) expression in breast cancer and its metastases. AB - The present study was undertaken to investigate the expression of prostate specific membrane antigen (PSMA) in normal breast tissues, in cancerous breast tissues and in distant metastases from patients with breast cancer. Immunohistochemical analysis was performed to determine PSMA expression and angiogenic activity using anti-PSMA mAb and anti-CD31 mAb respectively. Immunofluorescence staining was applied to confirm the exact co-localization of PSMA and CD31. We observed different patterns of PSMA expression between normal and cancerous tissues. Normal breast tissues showed PSMA expression only in normal glandular cells. However, primary breast tumors and distant metastases showed PSMA expression in tumor cells and in tumor-associated neovasculature. PSMA score group status in primary breast tumors was significantly associated with histologic type and tumor grade (p = 0.026 and p = 0.004 respectively). Distant metastases showed higher PSMA expression in tumor-associated neovasculature comparing with primary tumors. Moreover, brain tumor-associated neovasculture had significantly higher expression of PSMA comparing with bone tumor-associated neovasculture. The localized binding of PSMA mAb to the neovasculature endothelium was confirmed with the double Immunofluorescence staining. 68Ga-PSAM imaging of a patient with metastatic breast cancer showed strong tracer uptake in all known skeletal metastases. To the best of our knowledge, this study is the second one that has assessed PSMA expression in a large number of breast cancer patients. Our findings showed that PSMA is particularly expressed in tumor-associated neovasculature of breast tumors and its distant metastases, thus enhancing the evidence on the potential usefulness of PSMA as a therapeutic vascular target. PMID- 29426965 TI - Decisional Control Preferences in the Hispanic Population in the Bronx. AB - Hispanic Americans are among the fastest growing minority groups in the USA, and understanding their preferences for medical decision-making and information sharing is imperative to provide high quality end of life care. Studies exploring these decision control preferences (DCPs) are limited and found inconsistent results. (1) To measure DCPs of Hispanic patients in the Bronx. (2) To measure disclosure of information preferences of Hispanic patients in the Bronx. This is a cross-sectional survey. One hundred nineteen cancer patients who self identified as Hispanic and were waiting at the oncology clinic at Montefiore Medical Center Cancer Center. Proportions of patients endorsing DCPs and disclosure of information preferences are reported. The relationship between patient characteristics and DCPs was tested using chi-squared tests of homogeneity. The majority (63, 52.9%) preferred shared decision-making with their doctors, families or both, while 46 (38.7%) had an active decision-making style. A minority (9, 7.6%) had a passive decision-making style, deferring to their families, and only 1 (0.8%) deferring to the physician. No demographic characteristics significantly predicted DCPs. The majority of patients agreed or strongly agreed that they wanted to hear all of the information regarding their diagnosis (94%), treatment options (94%), treatment expectations (92%), and treatment risks and benefits (96%). These results confirm our hypothesis that most Hispanic patients prefer either an active or shared decision-making process rather than a passive decision-making process. Most patients prefer disclosure of diagnosis, prognosis, and plan. PMID- 29426964 TI - Incidental pulmonary embolism in suspected stroke patients undergoing carotid CT angiography. AB - PURPOSE: The purpose of this study was to investigate the prevalence of incidental pulmonary embolism (IPE) in suspected stroke patients receiving carotid computed tomography angiography (CTA) and its characteristics. MATERIALS AND METHODS: A total of 4873 cases receiving carotid CTA between January 2013 and December 2016 were retrospectively reassessed by one radiologist. Patients with previous or suspected PE were excluded. The remaining prior contrast-enhanced carotid CTA studies were regarded as a "potentially incidental" IPE when a filling defect was found in one or more pulmonary arteries and subjected to the other two thoracic radiologists independently for reviewing and assessing for characteristics of the IPE and the image quality of the PE. The differences were noted between inpatients and outpatients in prevalence of IPE. Characteristics of the patients with IPE were also studied in terms of gender, age, as well as clinical indication. RESULTS: The prevalence of IPE among these suspected stroke patients was 0.8% on carotid CT angiography, and 24 (96%) of all IPEs had not been previously diagnosed by the original reporting radiologists. Most of the IPEs were at the lobar or segmental levels, single and in right upper lobe of pulmonary arteries. In most of the cases, the reviewing radiologists judged the contrast bolus as good. The outpatient group had a lower percentage of patients with IPE when compared with the inpatient counterpart (p = 0.024). The prevalence of IPE in patients with suspected stroke was higher with the increasing of age (p = 0.013). CONCLUSIONS: IPE can occur in suspected stroke patients on carotid CT angiography, and most of them have been previously neglected in clinical practice. Radiologists should check the higher pulmonary arterial vasculature carefully on the contrast-enhanced carotid CTA scans. PMID- 29426966 TI - Multi-viral canaliculitis: case report and review of literature. AB - AIM: To report an atypical case of multiple viruses causing canaliculitis. METHODS: Case report of a young female presenting with atypical course of refractory unilateral canaliculitis with complete mid-bicanalicular obstructions. Canalicular scrapings were subjected to immunofluorescence techniques and polymerase chain reactions to identify the viruses. RESULTS: Investigations revealed a canaliculitis of multi-viral etiology; herpes simplex virus and varicella zoster virus. A canalicular curettage followed by topical acyclovir helped in the resolution of canaliculitis. CONCLUSION: An encounter with an atypical canaliculitis with negative bacteriology work up, suboptimal response to routine therapies, and mid-canalicular obstructions should alert the physician to investigate for viral etiology. PMID- 29426967 TI - Bleb-related infections and long-term follow-up after trabeculectomy. AB - PURPOSE: Bleb-related infections are serious complications after trabeculectomy. They can be limited to the bleb or disseminate and lead to endophthalmitis. We herein report on all bleb-related infections that have been diagnosed at the Eye Center of the University of Freiburg, Germany, since 1999. METHODS: We reviewed a total of 1816 consecutive trabeculectomies that were performed at our hospital between the years 1999 and 2014 (353 without and 1463 with intraoperative application of mitomycin C). All bleb-related infections that were diagnosed at our clinic during the same period were included in the analysis. We fitted a Cox proportional hazards model to characterize risk factors for bleb-related infections. RESULTS: We diagnosed a total of 19 bleb-related infections in this period. Three patients with bleb-related infections that came to our clinic had their trabeculectomy performed elsewhere. The overall percentage of bleb-related infections was 0.1% after 2 years (Kaplan-Meier estimate at median follow-up). Nine eyes suffered from only localized infection of the bleb. Seven eyes developed endophthalmitis. Four infections occurred during the first postoperative month. The median age on the day of diagnosis was 71 years; the median age at surgery was 69 years. In the Cox model, intraoperative application of mitomycin C and a fornix-based conjunctival flap were identified as significant risk factors (hazard ratio: 79.02, 4.69; p < 0.01, p < 0.01). The whole group showed a reduction of visual acuity in the median from logMAR 0.12 to 0.2. Eyes that suffered from endophthalmitis showed a loss from 0.3 to 0.96, while the localized infections had a reduction from 0.04 to 0.07. CONCLUSION: Bleb-related infections are a rare complication following trabeculectomy and can be localized on the bleb or can lead to endophthalmitis, thereby threatening visual acuity. The risks and benefits of mitomycin C-augmented trabeculectomies should be taken into consideration. PMID- 29426968 TI - Clinical experience with urgent tube shunt implantation through the ciliary sulcus in phakic eyes. AB - PURPOSE: To review the clinical course and outcomes of 3 phakic, ischemic, and inflamed eyes in which we performed urgent tube shunt implantation through the ciliary sulcus without lensectomy. METHODS: This is a retrospective interventional case series. Three eyes of 3 diabetic patients with uncontrolled severe neovascular glaucoma, shallow anterior chambers with closed angles and poor view to the posterior segment, where concomitant lensectomy was not recommended due to uncontrolled uveitis and ischemia, underwent tube shunt implantation through the ciliary sulcus. Main outcome measures were surgical complications, especially injury to the crystalline lens, and postoperative intraocular pressure (IOP). RESULTS: No surgical complications, including injury to the crystalline lens, have occurred. We used surgical modifications to allow sufficient visualization of the sulcus area to avoid injury to the crystalline lens during scleral tunneling and tube insertion through the ciliary sulcus. Postoperatively, the uveitis, ischemia, and vision have improved and IOP was controlled throughout follow-up. Cataract surgery with pupilloplasty was performed in one eye a year later with no complications and no interruption to IOP control. CONCLUSIONS: Based on our small and limited retrospective study, and under unusual circumstances, urgent tube shunt implantation through the ciliary sulcus may be considered in phakic eyes with severely uncontrolled IOP, shallow anterior chambers and poor view to the posterior segment, and when concomitant lensectomy is not recommended. We advise the use of appropriate surgical modifications by experienced glaucoma surgeons to prevent intraoperative complications. Further and larger studies are needed to evaluate the safety of this surgical option. PMID- 29426969 TI - The Impact of Financial Conflict of Interest on Surgical Research: An Observational Study of Published Manuscripts. AB - BACKGROUND: Substantial discrepancies exist between industry-reported and self reported conflicts of interest (COI). Although authors with relevant, self reported financial COI are more likely to write studies favorable to industry sponsors, it is unknown whether undisclosed COI have the same effect. We hypothesized that surgeons who fail to disclose COI are more likely to publish findings that are favorable to industry than surgeons with no COI. METHODS: PubMed was searched for articles in multiple surgical specialties. Financial COI reported by surgeons and industry were compared. COI were considered to be relevant if they were associated with the product(s) mentioned by an article. Primary outcome was favorability, which was defined as an impression favorable to the product(s) discussed by an article and was determined by 3 independent, blinded clinicians for each article. Primary analysis compared incomplete self disclosure to no COI. Ordered logistic multivariable regression modeling was used to assess factors associated with favorability. RESULTS: Overall, 337 articles were reviewed. There was a high rate of discordance in the reporting of COI (70.3%). When surgeons failed to disclose COI, their conclusions were significantly more likely to favor industry than surgeons without COI (RR 1.2, 95% CI 1.1-1.4, p < 0.001). On multivariable analysis, any COI (regardless of relevance, disclosure, or monetary amount) were significantly associated with favorability. CONCLUSIONS: Any financial COI (disclosed or undisclosed, relevant or not relevant) significantly influence whether studies report findings favorable to industry. More attention must be paid to improving research design, maximizing transparency in medical research, and insisting that surgeons disclose all COI, regardless of perceived relevance. PMID- 29426970 TI - Letter to the Editor: Functional Compromise Cohort Study (FCCS): Sarcopenia is a Strong Predictor of Mortality in the Intensive Care Unit. PMID- 29426971 TI - Laparoscopic Versus Open Right Posterior Sectionectomy for Hepatocellular Carcinoma in a High-Volume Center: A Propensity Score Matched Analysis. AB - BACKGROUND: While minimal invasive surgery is becoming popular in liver resection, right posterior sectionectomy (RPS) is still considered as a difficult procedure. We summarize the clinical data and investigate the feasibility of laparoscopic right posterior sectionectomy (LRPS) in hepatocellular carcinoma (HCC) by comparing its outcomes with those of open right posterior sectionectomy (ORPS). METHODS: We retrospectively reviewed 191 patients who underwent RPS for HCC during January 2009 to August 2016 at Samsung Medical Center. After 1:2 propensity score matching, 53 patients in LRPS group were matched to 97 patients in ORPS group. RESULTS: There was no statistical difference in preoperative data. While operation time was significantly longer in LRPS group (381.1 +/- 118.7 vs. 234.4 +/- 63.7 min, P < 0.001), transfusion rate (13.2 vs. 2.1%, P = 0.061) and complication rate (9.4 vs. 8.3%, P = 0.709) were not statistically different between groups. Clustered Cox proportional hazards regression analysis for matched paired data showed no difference in both disease-free survival (P = 0.607) and overall survival (P = 0.858). CONCLUSIONS: In HCC, LRPS can be performed safely compared to ORPS, regarding the operative outcome, patient recovery, and oncological outcomes. PMID- 29426972 TI - Depression Induced by Total Mastectomy, Breast Conserving Surgery and Breast Reconstruction: A Systematic Review and Meta-analysis. AB - BACKGROUND: To carry out a systematic review and meta-analysis of the literature to determine whether different type of surgery induces different depression occurrence in female breast cancer at mean time more than 1-year term postoperatively. METHODS: A systematic literature search of PubMed, Web of Science, EMBASE, OvidSP, EBSCO and PsycARTICLES was conducted. Observational clinical studies that compared the depression incidence in different surgery groups and presented empirical findings were selected. RESULTS: Sixteen studies met the inclusion criteria, including 5, 4, 2 and 5 studies compared depression between total mastectomy (TM) and breast conserving therapy (BCS), TM and breast reconstruction (BR), BCS and BR, or among all three groups (TM, BCS and BR), respectively. Only 1 of 5 studies, which subjected to multivariate analysis of depression in female breast cancer, reported a statistically significant effect of type of surgery on depression occurrence. Our meta-analysis showed no significant differences among the three types of surgery, with BCS patients versus TM patients (relative risk [RR] = 0.89, 95% confidence interval [CI] 0.78 1.01; P = 0.06), BR patients versus TM patients (RR = 0.87, 95% CI 0.71-1.06; P = 0.16) and BCS patients versus BR patients (RR = 1.10; 95% CI 0.89-1.35; P = 0.37), respectively. CONCLUSIONS: Our study showed that there were no statistically significant differences concerning the occurrence of depressive symptoms in breast cancer patients as a consequence of TM, BCS or BR at mean time more than 1-year term postoperatively. PMID- 29426973 TI - miR-148a-3p promotes rabbit preadipocyte differentiation by targeting PTEN. AB - Although emerging data support crucial roles for microRNAs (miRNAs) during adipogenesis, the detailed mechanisms remain largely unknown. In this study, it was shown that in rabbits, levels of miR-148a-3p not only increased in white adipose tissue during early stages of growth but also during in vitro cultured preadipocyte differentiation. Furthermore, overexpression of miR-148a-3p significantly upregulated the mRNA levels of PPARgamma, C/EBPalpha, and FABP4, as well as the protein levels of PPARgamma, as indicated by qPCR and western blotting analyses. Overexpression of miR-148a-3p also promoted intracellular triglyceride accumulation. In contrast, downregulation of miR-148a-3p inhibited the differentiation of rabbit preadipocytes. Next, based on target gene prediction and a luciferase reporter assay, we further demonstrated that miR-148a 3p directly targeted one of the 3' untranslated regions of PTEN. Finally, it was observed inhibition of PTEN by siRNA promoted rabbit preadipocyte differentiation. Taken together, our results suggested that miR-148a-3p could be involved in regulating rabbit preadipocyte differentiation through inhibiting expression of PTEN, which further highlighted the importance of miRNAs during adipogenesis. PMID- 29426974 TI - Infusion reactions associated with rituximab treatment for childhood-onset complicated nephrotic syndrome. AB - BACKGROUND: Infusion reaction (IR) is defined as an adverse event within 24 h after monoclonal antibody infusion. In non-Hodgkin lymphoma, IR incidence following rituximab treatment is high (77-80%), but there are no data in complicated nephrotic syndrome. METHODS: Records of rituximab infusions in patients with complicated nephrotic syndrome between February 2006 and December 2014 at the National Center for Child Health and Development were reviewed. Rituximab was administered at doses of 375 mg/m2. The severity of IR was evaluated using the Common Terminology Criteria for Adverse Events ver. 4.0. RESULTS: For 309 rituximab infusions in 159 patients (male, 110; median age, 12 years), IR was observed in 165 infusions (53.4%). Respiratory symptoms were most common (66% of all events). Ninety-five percent of the IR was observed within 3 h after rituximab infusion initiation. Sixty-eight percent of the events were classified as grade 1 and others classified as grade 2. Only 18% required medical intervention. CD20 cell count in patients with IR was significantly higher than in patients without IR. Incidence of IR was similar in subsequent rituximab treatment after B-cell recovery. Patients who experienced IR at first rituximab treatment were more likely to experience recurrent IR with subsequent treatments compared to those not having IR at initial treatment (odds ratio 3.64; p < 0.001). CONCLUSIONS: In patients with complicated nephrotic syndrome, respiratory symptoms were the major type of IR, mostly observed within 3 h of infusion. Incidence of IR was lower and its severity milder in patients with complicated nephrotic syndrome than those with lymphoma. PMID- 29426976 TI - Fabrication and Characterization of ZnO Nano-Clips by the Polyol-Mediated Process. AB - ZnO nano-clips with better monodispersion were prepared successfully using zinc acetate hydrate (Zn(OAc)2.nH2O) as Zn source and ethylene glycol (EG) as solvent by a simple solution-based route-polyol process. The effect of solution concentration on the formation of ZnO nano-clips has been investigated deeply. We first prove that the 0.01 M Zn(OAc)2.nH2O can react with EG without added water or alkaline, producing ZnO nano-clips with polycrystalline wurtzite structure at 170 degrees C. As-synthesized ZnO nano-clips contain a lot of aggregated nanocrystals (~ 5 to 15 nm) with high specific surface area of 88 m2/g. The shapes of ZnO nano-clips basically keep constant with improved crystallinity after annealing at 400-600 degrees C. The lower solution concentration and slight amount of H2O play a decisive role in ZnO nano-clip formation. When the solution concentration is <= 0.0125 M, the complexing and polymerization reactions between Zn(OAc)2.nH2O and EG predominate, mainly elaborating ZnO nano clips. When the solution concentration is >= 0.015 M, the alcoholysis and polycondensation reactions of Zn(OAc)2.nH2O and EG become dominant, leading to ZnO particle formation with spherical and elliptical shapes. The possible growth mechanism based on a competition between complexing and alcoholysis of Zn(OAc)2.nH2O and EG has been proposed. PMID- 29426975 TI - Study the influence of formulation process parameters on solubility and dissolution enhancement of efavirenz solid solutions prepared by hot-melt extrusion: a QbD methodology. AB - The current study investigates the dissolution rate performance of amorphous solid solutions of a poorly water-soluble drug, efavirenz (EFV), in amorphous Soluplus(r) (SOL) and Kollidon(r) VA 64 (KVA64) polymeric systems. For the purpose of the study, various formulations with varying drug loadings of 30, 50, and 70% w/w were developed via hot-melt extrusion processing and adopting a Box Behnken design of experiment (DoE) approach. The polymers were selected based on the Hansen solubility parameter calculation and the prediction of the possible drug-polymer miscibility. In DoE experiments, a Box-Behnken factorial design was conducted to evaluate the effect of independent variables such as Soluplus(r) ratio (A1), HME screw speed (A2), and processing temperature (A3), and Kollidon(r)VA64 ratio (B1), screw speed (B2), and processing temperature (B3) on responses such as solubility (X1 and Y1) and dissolution rate (X2 and Y2) for both ASS [EFV:SOL] and BSS [EFV:KVA64] systems. DSC and XRD data confirmed that bulk crystalline EFV transformed to amorphous form during the HME processing. Advanced chemical analyses conducted via 2D COSY NMR, FTIR chemical imaging, AFM analysis, and FTIR showed that EFV was homogenously dispersed in the respective polymer matrices. The maximum solubility and dissolution rate was observed in formulations containing 30% EFV with both SOL and KVA64 alone. This could be attributed to the maximum drug-polymer miscibility in the optimized formulations. The actual and predicted values of both responses were found precise and close to each other. PMID- 29426977 TI - Investigation of the phosphatidylserine binding properties of the lipid biosensor, Lactadherin C2 (LactC2), in different membrane environments. AB - Lipid biosensors are robust tools used in both in vitro and in vivo applications of lipid imaging and lipid detection. Lactadherin C2 (LactC2) was described in 2000 as being a potent and specific sensor for phosphatidylserine (PS) (Andersen et al. Biochemistry 39:6200-6206, 2000). PS is an anionic phospholipid enriched in the inner leaflet of the plasma membrane and has paramount roles in apoptosis, cells signaling, and autophagy. The myriad roles PS plays in membrane dynamics make monitoring PS levels and function an important endeavor. LactC2 has functioned as a tantamount PS biosensor namely in the field of cellular imaging. While PS specificity and high affinity of LactC2 for PS containing membranes has been well established, much less is known regarding LactC2 selectivity for subcellular pools of PS or PS within different membrane environments (e.g., in the presence of cholesterol). Thus, there has been a lack of studies that have compared LactC2 PS sensitivity based upon the acyl chain length and saturation or the presence of other host lipids such as cholesterol. Here, we use surface plasmon resonance as a label-free method to quantitatively assess the apparent binding affinity of LactC2 for membranes containing PS with different acyl chains, different fluidity, as well as representative lipid vesicle mimetics of cellular membranes. Results demonstrate that LactC2 is an unbiased sensor for PS, and can sensitively interact with membranes containing PS with different acyl chain saturation and interact with PS species in a cholesterol-independent manner. PMID- 29426979 TI - Role of ultrasound in detection of radiolucent foreign bodies in extremities. AB - Removal of foreign bodies from soft tissues in emergency is very challenging and becomes more problematic when it is radiolucent. Blind exploration is sometimes hazardous for patients especially when it is in proximity to a vessel or a nerve or an overlying tendon. The purpose of this study was to determine the accuracy of ultrasonography (USG) in detecting radiolucent soft tissue foreign bodies in the extremities. From January 2014 to January 2016, 120 patients with either a positive history or clinically suspected soft tissue foreign body and negative radiography were evaluated by USG with a high-frequency (13-6 MHz) linear-array transducer. The sonographic findings were used to guide surgical exploration. Out of 120 patients who underwent surgical exploration, USG was positive in 114 cases, and foreign body was retrieved in 108 cases, and among the six cases where USG was negative, foreign body was retrieved from one case. In one case with strong clinical suspicion of foreign body USG was falsely negative. Majority of foreign bodies were removed from foot (69 cases) and hands (26 cases), and rest of foreign bodies were removed from ankle (4 cases), wrist (3 cases), thigh (2 cases), leg (1 case), knee (2 cases), forearm (2 cases). Accuracy, sensitivity, and positive predictive value were determined as 94.16, 99.08, and 94.13%, respectively. The real-time high-frequency USG is a highly sensitive and accurate tool for detecting and removing radiolucent foreign bodies which cannot be visualized by routine radiography. PMID- 29426978 TI - Impact of intracranial artery calcification on cerebral hemodynamic changes. AB - PURPOSE: Intracranial artery calcification (IAC) has been demonstrated to be correlated with ischemic stroke, cognitive decline, and other vascular events by accumulating evidences from both Western and Asian populations. The proposed study aimed to investigate its potential mechanisms by evaluating the blood flow velocity and pulsatility index (PI) of cerebral arteries. METHODS: Consecutive ischemic stroke patients admitted to the Prince of Wales Hospital were recruited after excluding those with atrial fibrillation or poor temporal window. Quantitative measurements of IAC severity were assessed on brain CT scans. Transcranial Doppler (TCD) ultrasonography was performed to evaluate the blood flow velocity of the middle cerebral artery (MCA) and vertebral-basilar artery (VBA). RESULTS: In total, 318 patients were analyzed. Spearman's correlation analysis demonstrated both high MCA systolic flow velocity and high MCA PI were correlated with IAC Agatston score, p < 0.001 individually. Similar correlation was also found between IAC Agatston score and high VBA velocity/high VBA PI, p <= 0.001 individually. Multiple logistic regression analysis showed IAC Agatston score was an independent risk factor for high MCA velocity (OR 1.533; 95% CI 1.235-1.903), high VBA velocity (OR 1.964; 95% CI 1.381-2.794), and high VBA PI (OR 1.200; 95% CI 1.016-1.418), respectively. CONCLUSION: Heavier IAC might cause generalized artery flow velocity changes and increased pulsatility index, which may indicate high resistance within cerebrovasculature. PMID- 29426980 TI - Coupling relations underlying the production of speech articulator movements and their invariance to speech rate. AB - Since the seminal works of Bernstein (The coordination and regulation of movements. Pergamon Press, Oxford, 1967) several authors have supported the idea that, to produce a goal-oriented movement in general, and a movement of the organs responsible for the production of speech sounds in particular, individuals activate a set of coupling relations that coordinate the behavior of the elements of the motor system involved in the production of the target movement or sound. In order to characterize the configurations of the coupling relations underlying speech production articulator movements, we introduce an original method based on recurrence analysis. The method is validated through the analysis of simulated dynamical systems adapted to reproduce the features of speech gesture kinematics and it is applied to the analysis of speech articulator movements recorded in five German speakers during the production of labial and coronal plosive and fricative consonants at variable speech rates. We were able to show that the underlying coupling relations change systematically between labial and coronal consonants, but are not affected by speech rate, despite the presence of qualitative changes observed in the trajectory of the jaw at fast speech rate. PMID- 29426981 TI - Investigating the balance between goal-directed and habitual control in experimental and real-life settings. AB - Do people differ in their propensity to form habits? The current study related individual differences in habitual performance on the slips-of-action task to habit formation in real life. To this end, we developed a novel key-cover procedure that controls for the amount of repetition and motivation within a naturalistic setting. Participants received a key cover for the key to their home, which after several weeks was switched with a key cover that was previously attached to a dummy key. Participants recorded effort, time, attention, and mistakes in the key-selection process. Results were in line with established properties of habits, as attention decreased in the learning phase, yet effort, time, and mistakes increased after the key-cover switch. Performance on the slips of-action task correlated negatively with changes in attention in the real-life key-cover task. This negative correlation may reflect that flexible behavioral adjustment requires more attention in people with a relatively weak goal-directed system. PMID- 29426983 TI - [Perioperative management of patients facing long-term medication]. PMID- 29426982 TI - Characterization of bacterial composition and diversity in a long-term petroleum contaminated soil and isolation of high-efficiency alkane-degrading strains using an improved medium. AB - Bacterial community and diversity in a long-term petroleum-contaminated soil of an oilfield were characterized using 16S rRNA gene-based Illumina MiSeq high throughput sequencing. Results indicated that Proteobacteria (49.11%) and Actinobacteria (24.24%) were the most dominant phyla, and the most abundant genera were Pseudoxanthomonas (8.47%), Luteimonas (3.64%), Alkanindiges (9.76%), Acinetobacter (5.26%) and Agromyces (8.56%) in the soil. Meanwhile a series of cultivations were carried out for isolation of alkane degraders from petroleum contaminated soil with gellan gum and agar as gelling agents. And the isolates were classified by their 16S rRNA genes. Nine of the isolates including Enterobacter, Pseudomonas,Acinetobacter, Rhizobium, Bacillus, Sphingomonas, Paenibacillus, Variovorax and Rhodococcus showed strong biodegradability of alkane mixture (C9-C30) in a wide range of chain-length, which could be potentially applied in enhancement of bioremediation. PMID- 29426984 TI - Breast cancer subtype and survival by parity and time since last birth. AB - BACKGROUND: Pregnancy affects breast cancer risk but how it affects the subtype and prognosis remain controversial. We studied the effect of parity and time since last birth on breast cancer subtype and outcome. PATIENTS AND METHODS: We conducted a retrospective multivariate cohort study including all premenopausal women with early breast cancer aged <= 50 years (N = 1306) at diagnosis at the University Hospitals Leuven (Jan. 2000-Dec. 2009). Primary study endpoints were the breast cancer subtype, disease-free survival, and distant disease-free survival by parity and time since last birth. Statistical methods used were baseline-category logits models and Cox proportional hazard models. Multivariable models were used to correct for possible confounders. RESULTS: Breast cancer subtypes did not differ between nulliparous (N = 266) and parous women (N = 1040) but subtypes differed significantly in parous women by time since last birth (p < 0.001). Tumors within 5 years of last birth were proportionally more likely triple negative and HER-2 like, even when corrected for age at diagnosis. After a mean follow-up period of 10 years, parous women had a better disease-free survival compared to nulliparous women (HR 0.733; CI 0.560-0.961; p = 0.025, HR 0.738; CI 0.559-0.974; p = 0.032 before and after correction for known prognostic factors, respectively). In parous women, a longer time since last birth was correlated with a longer disease-free survival compared to patients with a recent pregnancy (HR 0.976; CI 0.957-0.996; p = 0.018). However, after correction, this association completely disappeared (HR 1.010; CI 0.982-1.040; p = 0.480). CONCLUSION: We observed a better disease-free survival for parous than nulliparous women. The influence of recent birth on disease-free survival is probably due to tumor and patient characteristics, as recent birth is associated with more aggressive subtypes. PMID- 29426986 TI - The PICKING technique for self-expanding nitinol stent expansion of an extremely calcified lesion in the femoropopliteal artery: the tail makes the difference. PMID- 29426985 TI - Cypripedin, a phenanthrenequinone from Dendrobium densiflorum, sensitizes non small cell lung cancer H460 cells to cisplatin-mediated apoptosis. AB - The life-threatening potential of lung cancer has increased over the years due to its acquisition of chemotherapeutic resistance, especially to cisplatin, a first line therapy. In response to this development, researchers have turned their attention to several compounds derived from natural origins, including cypripedin (CYP), a phenanthrenequinone substance extracted from Dendrobium densiflorum. The aim of the present study was to investigate the ability of CYP to induce apoptosis and enhance cisplatin-mediated death of human lung cancer NCI-H460 cells using cell viability and apoptosis assays. The induction of apoptosis by CYP was observed at a concentration of > 50 MUM with the appearance of morphological changes, including DNA condensation and chromatin fragmentation. Together with, CYP was able to activate caspase-3 and downregulate the anti apoptotic proteins Bcl-2 and Bcl-xL. Also, a non-cytotoxic dose of CYP synergistically potentiated the effect of cisplatin in non-small cell lung cancer line H460 cells, which clearly exhibited the apoptotic phenotype. Western blot analysis revealed that the underlying mechanism involved the downregulation of anti-apoptotic Bcl-xL, whereas the levels of other apoptotic regulatory proteins were not altered. This study provides interesting information on the potent effect of CYP as a chemotherapeutic sensitizer that could be further developed to improve the clinical outcomes of lung cancer patients. PMID- 29426987 TI - Coronary CT angiography in patients with atrial fibrillation: Standard-dose and low-dose imaging with a high-resolution whole-heart CT scanner. AB - OBJECTIVE: To compare image quality, observer confidence, radiation exposure in the standard-dose (SD-CCTA) and low-dose (LD-CCTA) protocols of coronary CT angiography (CCTA) in patients with atrial fibrillation (AF). MATERIAL AND METHODS: CCTA was performed in 303 patients using a CT scanner with 16-cm coverage (111 scans during sinus rhythm (SR); 192 during AF). LD-CCTA was used in 218 patients; SD-CCTA in 85 patients suspected of having coronary artery disease (CAD). Image quality and observer confidence were evaluated on 5-point scales. Radiation doses were recorded. RESULTS: Image quality was superior in the SD-CCTA compared to the LD-CCTA (SR 1.45+/-0.40; AF 1.72+/-0.46; vs. SR 1.83+/-0.48; AF 1.92+/-0.50; p < 0.001). Observers were more confident with SD-CCTA than with LD CCTA (SR 1.38+/-0.33; AF 1.61+/-0.43; vs. SR 1.70+/-0.45; AF 1.82+/-0.50; p < 0.001). Radiation doses in AF were significantly higher than in the SR (LD-CCTA, 1.68+/-0.71 mSv; SD-CCTA, 3.72+/-1.95 mSv; vs. LD-CCTA, 1.3 +/-0.52 mSv; SD-CCTA, 2.67+/-1.47 mSv; p < 0.001). CONCLUSION: Using a low-dose protocol in AF, radiation exposure can be decreased by 50 % at the expense of 20 % impaired image quality. A low-dose CCTA protocol can be considered in young patients, whereas the standard-dose protocol is recommended for older patients and those suspected of having CAD. KEY POINTS: * Whole-heart CT allows visualization of the coronary arteries in atrial fibrillation. * Low-dose CT decreases radiation exposure by 50%, image quality by 20%. * Standard-dose CT seems advantageous when concomitant coronary artery disease is suspected. PMID- 29426988 TI - RFA versus robotic partial nephrectomy for T1a renal cell carcinoma: a propensity score-matched comparison of mid-term outcome. AB - OBJECTIVE: To compare oncological and functional mid-term outcomes following robotic partial nephrectomy (RPN) and radiofrequency ablation (RFA) for treating T1a renal cell carcinoma (RCC) using propensity score-matching. METHODS: Between December 2008-April 2016, 63 patients from each treatment group were propensity score-matched for age, sex, American Society of Anesthesiologists score, tumour size, tumour laterality, tumour histology, R.E.N.A.L. nephrometry score and preoperative estimated glomerular filtration rate (eGFR). Post-treatment follow up periods for RPN and RFA ranged from 1-90 months (median, 24.6) and 1-65 months (21), respectively. Tumour location, percentage of eGFR preservation and 2-year recurrence-free survival rate were compared between groups. RESULTS: Exophytic and endophytic RCC occurred in 73.0 % (46/63) and 27.0 % (17/63) of the RPN group, and 52.4 % (33/63) and 47.6 % (30/63) of the RFA group, respectively (p=0.017). There was 91.7 % preservation of eGFR in the RPN group and 86.8 % in the RFA group (p=0.088). Two-year recurrence-free survival rate was 100 % in the RPN and 95.2 % in the RFA group (p=0.029). CONCLUSIONS: RPN provides a higher recurrence-free survival rate than RFA. However, RFA is a better treatment option for an endophytic or recurrent RCC that is difficult to treat with RPN. KEY POINTS: * RPN provides a higher recurrence-free survival rate than RFA. * Unlike RPN, repeat RFA is easy to perform for recurrent RCC. * Endophytic RCC could be better treated with RFA. PMID- 29426989 TI - Magnetic resonance post-contrast vascular hyperintensities at 3 T: a new highly sensitive sign of vascular occlusion in acute ischaemic stroke. AB - BACKGROUND: Magnetic resonance imaging (MRI) is the diagnostic cornerstone for precisely identifying acute ischaemic strokes and locating vascular occlusions, especially since mechanical thrombectomy has become a reference treatment. We observed that a post-contrast three-dimensional turbo-spin-echo T1-weighted sequence showed striking post-contrast vascular hyperintensities (PCVH) in ischaemic territories. We aimed to evaluate the prevalence and the meaning of this finding. METHODS: This retrospective single centre study included 130 consecutive patients admitted for acute ischaemic stroke with a 3-T MRI performed in the first 12 h of symptom onset from September 2014 through September 2016. Two neuroradiologists blinded to clinical data analysed the first MRI assessments. The association between PCVH and clinical, radiological and follow up findings was assessed, as well as inter- and intra-observer agreements. RESULTS: Of 130 patients, 105 (81%) had PCVH in the ischaemic territory. PCVH were associated with the presence of thrombus on susceptibility weighted imaging (p < 0.0001) and vascular occlusions on MR angiography (p < 0.0001). All patients with a visible thrombus had PCVH closely surrounding the clot. PCVH were associated with higher initial (p < 0.01) and follow-up (p < 0.01) National Institutes of Health Stroke Scale score, and higher mRS score (p < 0.05). Thrombectomy was the reference treatment for all patients with arterial occlusions. Inter- and intra-observer agreements for the detection of PCVH were excellent (kappa = 0.95 and kappa = 0.91, respectively). CONCLUSIONS: PCVH during acute strokes are a striking sensitive and reproducible tool for diagnosing and locating vascular occlusions. It may help triage patients who can benefit from thrombectomy. KEY POINTS: * Post-contrast vascular hyperintensities (PCVH) are a sensitive MR finding in acute stroke * PCVH are strongly associated with the presence and location of arterial occlusions * Inter- and intra-observer agreements for the detection of PCVH are excellent * PCVH are visible even in the case of significant motion artefacts * PCVH may help triage patients who can benefit from mechanical thrombectomy. PMID- 29426990 TI - What are the predictors of clinical success after percutaneous vertebroplasty for osteoporotic vertebral fractures? AB - OBJECTIVES: Osteoporotic vertebral fractures are responsible for acute pain and disability that may persist for more than 2 months. We wanted to identify predicting factors for mid-term outcome after vertebroplasty. METHODS: We included consecutive patients who underwent vertebroplasty for fragility fractures with persistent and intense pain between January 2014-June 2016. Outcome was assessed by an independent clinician after 1 month using a standardized questionnaire. Patients were classified as having either a favorable or a poor outcome. Presence of an intravertebral cleft and bone oedema mean signal intensity was assessed by an independent radiologist blinded to the clinical data. Pre-intervention clinical or radiological factors were analysed as predictors for outcome. RESULTS: In the 78 included patients (females 71%, age 75 +/- 8.3 years), 61.5% had a favourable outcome. When vertebroplasty was performed within 2 months after fracture, the outcome was favourable in 19 patients (39.6%) and poor in five (16.7%; estimate for favourable outcome: OR = 4.1, 95% CI 1.2 13.8, p = 0.021). Absence of intravertebral cleft on pre-intervention imaging was also a predictor of favourable outcome (OR = 3.7, 95% CI 1.2-11.8, p = 0.024). On pre-intervention MRI, vertebral body oedema intensity signal did not influence the outcome. CONCLUSIONS: In patients with persistent and intense pain after an osteoporotic vertebral fracture, early intervention and absence of intravertebral cleft were predictors of favourable outcome at 1 month after vertebroplasty. KEY POINTS: * Performing vertebroplasty within 2 months following a fragility fracture increases success rate. * Presence of an intravertebral cleft at baseline is a predictor of poor mid-term outcome. * A pre-intervention MRI should be performed to ascertain the indication of vertebroplasty. PMID- 29426991 TI - Post-contrast acute kidney injury - Part 1: Definition, clinical features, incidence, role of contrast medium and risk factors : Recommendations for updated ESUR Contrast Medium Safety Committee guidelines. AB - PURPOSE: The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) has updated its 2011 guidelines on the prevention of post-contrast acute kidney injury (PC-AKI). The results of the literature review and the recommendations based on it, which were used to prepare the new guidelines, are presented in two papers. AREAS COVERED IN PART 1: Topics reviewed include the terminology used, the best way to measure eGFR, the definition of PC AKI, and the risk factors for PC-AKI, including whether the risk with intravenous and intra-arterial contrast medium differs. KEY POINTS: * PC-AKI is the preferred term for renal function deterioration after contrast medium. * PC-AKI has many possible causes. * The risk of AKI caused by intravascular contrast medium has been overstated. * Important patient risk factors for PC-AKI are CKD and dehydration. PMID- 29426993 TI - Genotypic variability analysis of DENV-1 in Mexico reveals the presence of a novel Mexican lineage. AB - Here, we report for the first time the circulation of dengue virus type 1 (DENV 1) belonging to the lineage IV of genotype V (African American genotype) based on phylogenetic analysis of nucleotide sequences from 10 DENV-1-positive samples obtained in Mexico between 2012 and 2014. Our data revealed that the lineages III and IV of DENV-1 genotype V were found circulating during the same period, probably explaining the rise in the number of cases of severe dengue during that period. PMID- 29426992 TI - Determination of glomerular filtration rate (GFR) from fractional renal accumulation of iodinated contrast material: a convenient and rapid single-kidney CT-GFR technique. AB - OBJECTIVES: To develop a convenient and rapid single-kidney CT-GFR technique. METHODS: One hundred and twelve patients referred for multiphasic renal CT and 99mTc-DTPA renal dynamic imaging Gates-GFR measurement were prospectively included and randomly divided into two groups of 56 patients each: the training group and the validation group. On the basis of the nephrographic phase images, the fractional renal accumulation (FRA) was calculated and correlated with the Gates-GFR in the training group. From this correlation a formula was derived for single-kidney CT-GFR calculation, which was validated by a paired t test and linear regression analysis with the single-kidney Gates-GFR in the validation group. RESULTS: In the training group, the FRA (x-axis) correlated well (r = 0.95, p < 0.001) with single-kidney Gates-GFR (y-axis), producing a regression equation of y = 1665x + 1.5 for single-kidney CT-GFR calculation. In the validation group, the difference between the methods of single-kidney GFR measurements was 0.38 +/- 5.57 mL/min (p = 0.471); the regression line is identical to the diagonal (intercept = 0 and slope = 1) (p = 0.727 and p = 0.473, respectively), with a standard deviation of residuals of 5.56 mL/min. CONCLUSION: A convenient and rapid single-kidney CT-GFR technique was presented and validated in this investigation. KEY POINTS: * The new CT-GFR method takes about 2.5 min of patient time. * The CT-GFR method demonstrated identical results to the Gates-GFR method. * The CT-GFR method is based on the fractional renal accumulation of iodinated CM. * The CT-GFR method is achieved without additional radiation dose to the patient. PMID- 29426994 TI - Host-associated selection of a P3 mutant of zucchini yellow mosaic virus affects viral infectivity in watermelon. AB - In this study, we found that the infectivity of zucchini yellow mosaic virus (ZYMV) in watermelon lines H1 and K6 changed from partial to complete after propagation in the susceptible watermelon line ZXG637. When using cucumber infected with strain ZYMV-CH87 as an inoculum (named ZYMV-CH87C), the mean incidences of infection in lines H1 and K6 were 6% and 11%, respectively. However, when these lines were inoculated with ZXG637 infected with ZYMV-CH87C (named ZYMV-637), 100% of the plants became infected. Sequencing of ZYMV from these different inoculums revealed two nucleotide changes in the P3 cistron in ZYMV-637, which resulted in changes in the amino acids at positions 768 and 857 of the P3 protein, compared with the original strain ZYMV-CH87. We named this variant the M768I857-variant. The M768I857-variant was detected at low levels (3.9%) in ZYMV-CH87C. When ZYMV-CH87C was passaged with ZXG637, the M768I857 variant was selected by the host, and the original sequence was replaced entirely after two passages. These results may be explained by host-associated selection due to an unknown host-encoded factor. Using the M768I857-variant as an inoculum, 100% of the H1 and K6 plants showed systemic symptoms. These results suggest that (1) changing the individual amino acids at the end of the P3 N-terminus induces resistance-breaking, and (2) the P3 N-terminus may be involved in host recognition. PMID- 29426995 TI - Erratum to: Long-term changes in multimodal intensive tinnitus therapy. A 5-year follow-up. AB - Erratum to:HNO 2018 66 (Suppl):S34-S38 https://doi.org/10.1007/s00106-017-0463-4 Figure 1 was published incorrectly in the online version of this paper. The correct Figure is reproduced below. PMID- 29426996 TI - [Recurrent frontal swelling in a child]. PMID- 29426997 TI - Transcatheter heart valve for aortic valve implantation: republication of the article published in the Japanese Journal of Artificial Organs. AB - This review was created based on a translation of the Japanese review first reported in the Japanese Journal of Artificial Organs in 2015 (vol. 44, no. 3, pp. 136-140), with some modifications. PMID- 29426998 TI - Journal of Artificial Organs 2017: the year in review : Journal of Artificial Organs Editorial Committee. PMID- 29426999 TI - Addressing Moderate Interpersonal Hatred Before Addressing Forgiveness in Psychotherapy and Counseling: A Proposed Model. AB - This paper addresses the problem of pressure on a person to forgive that often makes forgiveness impossible or superficial. It proposes that clients who are unwilling or unable to forgive can still be encouraged to let go of interpersonal hatred because it is psychologically harmful to them. The issue of forgiving the person toward whom the hatred is directed can be treated more easily later, after the hatred has been removed or at least much reduced. The present theoretical approach distinguishes between anger and hatred; it provides a brief understanding of the origin of hatred from an object relations perspective with a focus on splitting. The emphasis is on moderate interpersonal hatred, since severe hatred raises special difficulties. The question of when a person has sufficient freedom to let go of moderate hatreds is addressed. This is followed by identifying reasons why people enjoy hatred, and how hatred provides some short-term psychological rewards. Finally, different psychological harms caused by hatred are identified. Overcoming interpersonal hatred by praying for those you hated is presented; the effect of such prayer on reducing splitting is especially noted. The conclusion is a descriptive summary of stages to be used in treating clients' hatreds before addressing forgiveness. PMID- 29427000 TI - Tardive Dyskinesia Associated with Atypical Antipsychotics: Prevalence, Mechanisms and Management Strategies. AB - All antipsychotics, including the atypical antipsychotics (AAPs), may cause tardive dyskinesia (TD), a potentially irreversible movement disorder, the pathophysiology of which is currently unknown. The prevention and treatment of TD remain major challenges for clinicians. We conducted a PubMed search to review the prevalence and etiology of and management strategies for TD associated with AAPs. TD prevalence rates varied substantially between studies, with an estimated prevalence of around 20% in patients using AAPs. The risk of TD is lower with AAPs than with typical antipsychotics (TAPs) but remains a problem because AAPs are increasingly being prescribed. Important risk factors associated with TD include the duration of antipsychotic use, age, and ethnicity other than Caucasian. Theories about the etiology of TD include supersensitivity of the dopamine receptors and oxidative stress, but other neurotransmitters and factors are probably involved. Studies concerning the management of TD have considerable methodological limitations. Thus, recommendations for the management of TD are based on a few trials and clinical experience, and no general guidelines for the management of TD can be established. The best management strategy remains prevention. Caution is required when prescribing antipsychotics, and regular screening is needed for early detection of TD. Other strategies may include reducing the AAP dosage, switching to clozapine, or administering vesicular monoamine transporter (VMAT)-2 inhibitors. In severe cases, local injections of botulinum toxin or deep brain stimulation may be considered. More clinical trials in larger samples are needed to gather valid information on the effect of interventions targeting TD. PMID- 29427001 TI - Association of benign prostatic hyperplasia and subsequent risk of bladder cancer: an Asian population cohort study. AB - OBJECTIVES: Few studies discussed the link between benign prostatic hyperplasia (BPH) and bladder cancer. We performed this cohort study to investigate whether there is an association between BPH and subsequent risk of bladder cancer. METHODS: We identified 35,092 study subjects including 17546 BPH patients and 17546 comparisons from the National Health Insurance database. The comparison cohort was frequency matched with age and index-year. We measured subsequent bladder cancer rates (per 1000 person-years) in two cohorts. Attributable risks (ARs) was calculated based on the bladder cancer rates in two cohorts. The hazard ratios (HRs) and 95% confidence intervals (CIs) for bladder cancer were estimated via Cox proportional hazard regression. RESULTS: BPH patients had a higher bladder cancer rate than comparisons (AR = 0.81 per 1000 person-years) and exhibited 4.69- and 4.11-fold increases in bladder cancer risk in the crude and adjusted Cox models, respectively (95% CIs = 4.15-6.99 and 2.70-6.26). The AR was highest in patients aged 65-74 years old (AR = 1.33). BPH patients with chronic kidney disease were at an elevated bladder cancer risk. Regarding the association between bladder cancer and transurethral prostatectomy (TURP), BPH patients who underwent TURP were at a higher risk of bladder cancer (AR = 1.69; HR = 6.17, 95% CI = 3.68-10.3) than those who did not (AR = 0.69; HR = 3.73, 95% CI = 2.43 5.74). CONCLUSIONS: In this study, BPH patients were found to have an increased risk of subsequent bladder cancer. Based on the limitations of retrospective nature, further studies are needed. PMID- 29427002 TI - Long-term oncological outcomes after robotic partial nephrectomy for renal cell carcinoma: a prospective multicentre study. AB - PURPOSE: This study aimed at reporting the long-term oncological outcomes of robotic partial nephrectomy (RPN) for renal cell carcinoma (RCC). METHODS: Data from all consecutive patients who underwent RAPN for RCC from July 2009 to January 2012 in three departments of urology were prospectively collected. Overall survival (OS), cancer-specific survival (CSS) and disease free-survival (DFS) were estimated using the Kaplan-Meier method. Prognostic factors associated with CSS were sought in univariate analysis. The log-rank test was used for categorical variables and the Cox model for continuous variables. RESULTS: 110 patients were included with a median follow-up of 64.4 months [95% CI = (61.0 66.7)]. Median age was 61 years (29-83) with 62.7% of men and 37.3% of women. Median RENAL score was 6 (4-10) with elective indications accounting for 95% of cases. Out of 27 patients (24.5%) who experienced peri-operative complication, 12 patients (10.9%) had a major complication (Clavien-Dindo grade >= 3). The TRIFECTA achievement rate was 52.7%. Three patients (2.7%) experienced local recurrence and seven patients (6.4%) progressed to a metastatic disease. 5-year OS, CSS, DFS were 94.9, 96.8, 86.4%, respectively. In univariate analysis, no pre/peri-operative characteristic was associated with DFS. No port-site metastasis was observed and there was one case of peritoneal carcinomatosis. CONCLUSION: In this multicenter series, long-term OS, DFS and CSS after RPN appeared comparable to large series of open partial nephrectomy, with no port site metastasis and one case of peritoneal carcinomatosis. PMID- 29427003 TI - Robotic surgery: new robots and finally some real competition! AB - PURPOSE: For the last 20 years, the predominant robot used in laparoscopic surgery has been Da Vinci by Intuitive Surgical. This monopoly situation has led to rising costs and relatively slow innovation. This article aims to discuss the two new robotic devices for laparoscopic surgery which have received regulatory approval for human use in different parts of the world. MATERIALS: A short description of the Senhance Surgical Robotic System and the REVO-I Robot Platform and their pros and cons compared to the Da Vinci system is presented. A discussion about the differences between the three robotic systems now in the market is presented, as well as a short review of the present state of robotic assistance in surgery and where we are headed. PMID- 29427004 TI - Immunohistochemically detected IDH1R132H mutation is rare and mostly heterogeneous in prostate cancer. AB - BACKGROUND: IDH1 mutations are oncogenic through induction of DNA damage and genome instability. They are of therapeutic interest because they confer increased sensitivity to radiation and cytotoxic therapy and hold potential for vaccination therapy. METHODS: In this study, we analyzed more than 17,000 primary prostate cancer tissues with a mutation-specific antibody for the IDH1R132H mutation. RESULTS: IDH1 mutation-specific staining was found in 42 of 15,531 (0.3%) interpretable cancers. IDH1 mutation was associated with higher preoperative PSA and Gleason grade (p < 0.05, each) but was unrelated to PSA recurrence. A comparison with other molecular tumor features available from earlier studies revealed that TMPRSS2-ERG fusion as well as deletion of PTEN, 5q21, 6q15, and 3p13 was less frequent in IDH1-mutated than in non-mutated cancer. Increased lethality of genetically instable, "aberration-rich" cancer cells in the presence of IDH1 mutations could possibly explain this observation. Heterogeneity analysis revealed a homogeneous mutation in only 1 of 16 IDH1 mutated cancers. This high degree of heterogeneity may profoundly limit therapeutic targeting of IDH1 mutations in prostate cancer. CONCLUSIONS: The data show that 0.3% of prostate cancers have an IDH1R132H mutation and that these are mostly heterogeneous. Once specific anti-IDH1 therapy becomes reality, only a very small group of prostate cancer patients may benefit from such a treatment. PMID- 29427005 TI - Multicenter evaluation of guideline adherence for pelvic lymph node dissection in patients undergoing open retropubic vs. laparoscopic or robot assisted radical prostatectomy according to the recent German S3 guideline on prostate cancer. AB - PURPOSE: Pelvic lymph node dissection (PLND) is recommended for patients with prostate cancer (PCa) and significant risk for nodal metastases. This study aimed to assess guideline adherence regarding PLND according to the German S3 guideline as example for a national but highly used guideline on prostate cancer and to compare the rate of complications different approaches for radical prostatectomy (RP). METHODS: Patients undergoing open (RRP), laparoscopic (LARP) or robot assisted (RARP) RP in six centers in Germany and Austria were included. The primary endpoint was the total number of removed lymph nodes (LN) between the different surgical approaches according to recent guideline recommendations. Secondary endpoints were the number of patients undergoing a sufficient PLND, defined as a removal of at least 10 LN and associated complication rates. RESULTS: 2634 patients undergoing RP were included (RRP: 66%, RARP/LARP: 34%). PLND was performed in 88% (RRP: 88.5%, RARP/LARP: 86.8%, p = 0.208). In intermediateor high risk PCa, PLND was performed in 97.2% (RRP: 97.7%, RARP/LARP: 96.2, p = 0.048). Of those, the mean number of LN was 19 (RRP: 19 vs. RARP/LARP: 17, p < 0.005) and sufficient PLND was observed in 84.6% of RRP compared to 77.2% of RARP/LARP (p < 0.005). Symptomatic lymphoceles requiring surgical treatment occurred more often in RRP than in RARP/LARP (4.0% vs. 1.6%, p = 0.001). CONCLUSIONS: The general guideline adherence regarding performing PNLD and the LN yield is high, regardless of the surgical approach. As expected, lymph node yield was higher when very experienced surgeons conducted the procedure. This should be considered in patients' counseling. PMID- 29427006 TI - Correlation Between Quorum Sensing Signal Molecules and Pseudomonas aeruginosa's Biofilm Development and Virulency. AB - Bacteria, when adhered to a substratum, can form biofilms. Nevertheless, many factors dictate biofilm formation and virulence factor production, including a response by the bacteria to their surroundings. This system is referred to as Quorum sensing (QS) also known as cell-cell communication. Pseudomonas aeruginosa is an infection causing agent in immune-compromised patients, it uses acyl homoserine lactone (AHL) to coordinate its QS systems. In this work, the connection between some members of AHL produced by P. aeruginosa PAO1 and its biofilm development and the production of virulence factor was investigated. It was discovered that N-butanoyl-homoserine lactone (C4-HSL) and N-hexanoyl-L homoserine lactone (C6-HSL) perform a more consequential and eminent function in the biofilm maturation and virulence factor production while N-(3-oxododecanoyl) L-homoserine lactone (3OC12-HSL) plays a role in biofilm initiation. Because QS has been reported to be required for biofilm development and pathogenesis of P. aeruginosa, the results of this work have great importance and significance for the design of strategies for the control and prevention of biofilms. PMID- 29427007 TI - Proteomic Analysis of Normal Expression Differences Exist in Bacillus Subtilis 168 Cultivation. AB - Biological science discovery often involves comparing conditions to a normal state, but little is known about "normal." Therefore, we used proteomic strategy to compare data from replicate samples of Bacillus subtilis 168 which were grown under identical condition. The results show that 294 differentially expressed proteins were annotated in 88 Gene Ontology functional groups and enriched in 13 KEGG pathways. We assume that normal expression differences are associated with adaptation to diverse environments. Moreover, five proteins (CotY, ThiG, SspA, SspB, and SspE) and their related genes were identified as having significantly different expressions at translational and transcriptional levels. Most of them are related to stress resistance and germination, indicating that normal expression differences can be regarded as a rapid response mechanism for survival. However, unstable protein expression may cause some fermentative problems that were observed in histidine and sulfur metabolism pathways. Our study facilitates dissection of the influence of biological variance on cultivation safety and stability. PMID- 29427008 TI - Oral health-related quality of life changes in children following dental treatment under general anaesthesia: a meta-analysis. AB - OBJECTIVE: To conduct a meta-analysis of studies that have employed the Early Childhood Oral Health Impact Scale (ECOHIS) and Child Oral Health-Related Quality of Life (COHRQoL) instruments, to evaluate the oral health-related quality of life (OHRQoL) changes in children following dental treatment under general anaesthesia (DGA). METHOD: A systematic search of 5 databases was conducted in accordance with the PRISMA guidelines. The inclusion criteria were use of ECOHIS and COHRQoL, pre-and post-operative assessments, patients aged between 0 and 16 years, no restrictions on the follow-up period and DGA. The primary outcome measure was changes in quality of life for both the children, which was based on mean difference (MD). Twenty-two articles were included in the meta-analysis. RESULTS: A favourable outcome in OHRQoL was identified in all studies. The combined MD for ECOHIS and COHRQoL were 1.62 [95% CI 1.52-1.71; P < 0.00001; I2 = 0%] and 0.86 [95% CI 0.74-0.99; P < 0.00001; I2 = 0%], respectively, both with no evidence of heterogeneity. CONCLUSION: There is evidence to support that the OHRQoL of children was improved, with large effect size, in the short-term following DGA. CLINICAL RELEVANCE: Dental treatment under GA significantly improved the OHRQoL of children. PMID- 29427010 TI - Feasibility of anterior screw fixation in children: a tomographic study. AB - PURPOSE: Morphology measures of the odontoid process in children under 12 years old were carried out to demonstrate the viability of anterior internal fixation in this population once their active profile may not be compatible with successful conservative treatment. METHODS: During a 6-month period, 36 tomographic examinations of the cervical spine region that provided visualization of the odontoid process were selected. Group 1 included children between 6 and 9 years of age, and group 2 contained children from 9 to 12 years of age. There were 23 (63.8%) male patients and 13 (36.2%) female patients. Patients diagnosed with a tumor, an infection, fracture non-union, or congenital malformation were excluded. Exams were ordered as part of a protocol applied to non-specific neck pain and pediatric trauma entries. The following parameters were analyzed: (1) screw attack angle, (2) height of the odontoid process, and (3) minimal transverse diameter of the odontoid process. RESULTS: In Groups 1 and 2, the average values of the screw attack angle were 55.9 degrees +/- 2.3 degrees and 54.8 degrees +/- 4.5 degrees , respectively; the average heights of the odontoid process were 26.58 +/- 3.28 and 29.48 +/- 3 mm, respectively, and the average minimal transverse diameter of the odontoid process were 6.57 +/- 1.08 and 6.23 +/- 0.88 mm, respectively. The minimal transverse diameter of the odontoid process was statistically higher in males than that in females, regardless of age (p = 0.007). CONCLUSION: In both groups, the minimal transverse diameter of the odontoid process allowed for the use of one 3.5-4.5 mm screw for anterior internal fixation. These slides can be retrieved under Electronic Supplementary Material. PMID- 29427009 TI - Anti-tubulin-alpha-1C autoantibody in systemic lupus erythematosus: a novel indicator of disease activity and vasculitis manifestations. AB - A variety of autoantibodies has been involved in the pathogenesis of systemic lupus erythematosus (SLE), some of which are well known and applied as disease biomarkers. This study aimed to determine the prevalence of a novel autoantibody, anti-tubulin-alpha-1C, in patients with SLE and investigate its clinical significance. Anti-tubulin-alpha-1C autoantibody levels were determined by enzyme linked immunosorbent assay (ELISA) in 128 SLE patients, 38 primary Sjogren's syndrome (pSS) patients, and 106 healthy controls (HCs).White blood cell (WBC) count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IgM, IgG, C3, C4, RF, ANA, dsDNA, Sm, AnuA, aCL, anti-SSA, and anti-SSB were measured by standard laboratory techniques. SLE Disease Activity Index (SLEDAI) was evaluated accordingly. Anti-tubulin-alpha-1C antibody levels were significantly increased in SLE patients. Elevated anti-tubulin-alpha-1C were correlated with higher levels of SLEDAI, increased titers of anti-Sm antibody, and decreased titers of anti-dsDNA antibody and significantly associated with cutaneous and mucosal vasculitis and milder renal involvement. Anti-tubulin-alpha-1C may become a novel biomarker indicative of active vasculitis in SLE and could be applied in future clinical practice. PMID- 29427011 TI - Self-learning computers for surgical planning and prediction of postoperative alignment. AB - PURPOSE: In past decades, the role of sagittal alignment has been widely demonstrated in the setting of spinal conditions. As several parameters can be affected, identifying the driver of the deformity is the cornerstone of a successful treatment approach. Despite the importance of restoring sagittal alignment for optimizing outcome, this task remains challenging. Self-learning computers and optimized algorithms are of great interest in spine surgery as in that they facilitate better planning and prediction of postoperative alignment. Nowadays, computer-assisted tools are part of surgeons' daily practice; however, the use of such tools remains to be time-consuming. METHODS: NARRATIVE REVIEW AND RESULTS: Computer-assisted methods for the prediction of postoperative alignment consist of a three step analysis: identification of anatomical landmark, definition of alignment objectives, and simulation of surgery. Recently, complex rules for the prediction of alignment have been proposed. Even though this kind of work leads to more personalized objectives, the number of parameters involved renders it difficult for clinical use, stressing the importance of developing computer-assisted tools. The evolution of our current technology, including machine learning and other types of advanced algorithms, will provide powerful tools that could be useful in improving surgical outcomes and alignment prediction. These tools can combine different types of advanced technologies, such as image recognition and shape modeling, and using this technique, computer assisted methods are able to predict spinal shape. The development of powerful computer-assisted methods involves the integration of several sources of information such as radiographic parameters (X-rays, MRI, CT scan, etc.), demographic information, and unusual non-osseous parameters (muscle quality, proprioception, gait analysis data). In using a larger set of data, these methods will aim to mimic what is actually done by spine surgeons, leading to real tailor made solutions. CONCLUSION: Integrating newer technology can change the current way of planning/simulating surgery. The use of powerful computer-assisted tools that are able to integrate several parameters and learn from experience can change the traditional way of selecting treatment pathways and counseling patients. However, there is still much work to be done to reach a desired level as noted in other orthopedic fields, such as hip surgery. Many of these tools already exist in non-medical fields and their adaptation to spine surgery is of considerable interest. PMID- 29427012 TI - [Blood pressure targets : The lower the better does not suit all]. AB - BACKGROUND: The systolic blood pressure intervention trial (SPRINT) published in 2015 has opened up new discussions on whether a lower blood pressure target as recommended by the current guidelines would be better for some patient groups. OBJECTIVES: To review patient groups in which lower blood pressure targets would not be better. MATERIALS AND METHODS: The results of SPRINT, its post-hoc and subgroup analyses, other studies and newer studies, as well as metaanalyses on the topic of blood pressure targets are reviewed and discussed. Studies with patients excluded from the SPRINT study were also analysed. The current international guidelines and recommendations of the Deutsche Hochdruckliga e. V. DHL(r) are included. RESULTS: Blood pressure monitoring methods differed considerably in the previously published studies. The low blood pressure value in SPRINT was mainly achieved due to the unusual method of blood pressure monitoring used and, as such, cannot be compared with blood pressure values in other studies. Based on current evidence, "the lower the better" should not be recommended in the following patient groups: older patients, in particular infirm older patients, patients with diabetes, patients without coronary heart disease or with low cardiovascular risk. CONCLUSIONS: When determining a blood pressure target, the method of blood pressure monitoring should be defined. A lower blood pressure target has been shown to be better in some well defined patient groups. However, adverse events due to antihypertensive medications should always be taken into account. Given the multiple exclusion criteria in trials and the results of many studies, "new" lower blood pressure targets could not be recommended in a large population of patients. PMID- 29427013 TI - Assessment of fluid responsiveness in spontaneously breathing patients: a systematic review of literature. AB - Patients who increase stoke volume or cardiac index more than 10 or 15% after a fluid challenge are usually considered fluid responders. Assessment of fluid responsiveness prior to volume expansion is critical to avoid fluid overload, which has been associated with poor outcomes. Maneuvers to assess fluid responsiveness are well established in mechanically ventilated patients; however, few studies evaluated maneuvers to predict fluid responsiveness in spontaneously breathing patients. Our objective was to perform a systematic review of literature addressing the available methods to assess fluid responsiveness in spontaneously breathing patients. Studies were identified through electronic literature search of PubMed from 01/08/2009 to 01/08/2016 by two independent authors. No restrictions on language were adopted. Quality of included studies was evaluated with Quality Assessment of Diagnostic Accuracy Studies tool. Our search strategy identified 537 studies, and 9 studies were added through manual search. Of those, 15 studies (12 intensive care unit patients; 1 emergency department patients; 1 intensive care unit and emergency department patients; 1 operating room) were included in this analysis. In total, 649 spontaneously breathing patients were assessed for fluid responsiveness. Of those, 340 (52%) were deemed fluid responsive. Pulse pressure variation during the Valsalva maneuver (?PPV) of 52% (AUC +/- SD: 0.98 +/- 0.03) and passive leg raising induced change in stroke volume (?SV-PLR) > 13% (AUC +/- SD: 0.96 +/- 0.03) showed the highest accuracy to predict fluid responsiveness in spontaneously breathing patients. Our systematic review indicates that regardless of the limitations of each maneuver, fluid responsiveness can be assessed in spontaneously breathing patients. Further well-designed studies, with adequate simple size and power, are necessary to confirm the real accuracy of the different methods used to assess fluid responsiveness in this population of patients. PMID- 29427014 TI - Breastfeeding Duration and the Theory of Planned Behavior and Breastfeeding Self Efficacy Framework: A Systematic Review of Observational Studies. AB - Introduction Numerous studies have shown that the constructs of the Theory of Reasoned Action (TRA), Theory of Planned Behavior (TPB) and Breastfeeding Self Efficacy (BSE) Framework can effectively identify relationships between maternal psychosocial factors and breastfeeding initiation. However, the ability of these theories to predict breastfeeding duration has not been adequately analyzed. The aim of the review was to examine the utility of the constructs of TRA/TPB and BSE to predict breastfeeding duration. Methods We conducted a literature search using Pubmed (1980-May 2015), Medline (1966-May 2015), CINAHL (1980-May 2015), EMBASE (1980-May 2015) and PsycINFO (1980-May 2015). We selected studies that were observational studies without randomization or blinding, using TRA, TPB or BSE as the framework for analysis. Only studies reporting on breastfeeding duration were included. Results Thirty studies were selected, which include four using TRA, 10 using TPB, 15 using BSE and one using a combination of TPB and BSE. Maternal intention and breastfeeding self-efficacy were found to be important predictors of breastfeeding duration. Inconsistent findings were found in assessing the relationship between maternal attitudes, subjective norms, perceived behavior control and breastfeeding duration. Discussion The inadequacy of these constructs in explaining breastfeeding duration indicates a need to further explore the role of maternal self-determination in breastfeeding behavior. PMID- 29427015 TI - Prenatal Maternal Depressive Symptoms Predict Early Infant Health Concerns. AB - INTRODUCTION: Recent research suggests that health disparities among low-SES and ethnic minority populations may originate from prenatal and early life exposures. Postpartum maternal depressive symptoms have been linked to poorer infant physical health, yet prenatal depressive symptoms not been thoroughly examined in relation to infant health. METHODS: In a prospective study of low-income Mexican American mothers and their infants, women (N = 322, median age 27.23, IQR = 22.01 32.54) completed surveys during pregnancy (median gestation 39.50, IQR = 38.71 40.14 weeks) and 12 weeks after birth. We investigated (1) if prenatal depressive symptoms predicted infant physical health concerns at 12 weeks of age, (2) whether these associations occurred above and beyond concurrent depressive symptoms, and (3) if birth weight, gestational age, and breastfeeding were mediators of prenatal depression predicting subsequent infant health. RESULTS: Higher prenatal depressive symptoms were associated with more infant physical health concerns at 12 weeks (p < .001), after accounting for 12-week maternal depressive symptoms, breastfeeding, gestational age, and birth weight. Twelve week maternal depressive symptoms were concurrently associated with more infant health concerns (p < .01). Birth weight, gestational age, and breastfeeding were not associated with maternal depression or infant health concerns. DISCUSSION: Results establish a link between prenatal depressive symptoms and an elevated risk of poor health evident shortly after birth. These findings underscore the importance of the prenatal period as a possible sensitive period for infants' health, and the need for effective interventions for depression during pregnancy to mitigate potentially teratogenic effects on the developing fetus and reduce risks for later health concerns. PMID- 29427016 TI - Media and Young Minds: Comparing State Screen Media Use Regulations for Children Under 24 Months of Age in Early Care and Education to a National Standard. AB - Introduction Excessive screen media use has been associated with a number of negative health outcomes in young children, including increased risk for obesity and comparatively lagging cognitive development. The purpose of this study was to assess state licensing regulations restricting screen media use for children under 24 months old in early care and education (ECE) and to compare regulations to a national standard. Methods We reviewed screen media use regulations for all US states for child care centers ("centers") and family child care homes ("homes") and compared these regulations to a national standard discouraging screen media use in children under 24 months of age. We assessed associations between state geographic region and year of last update with the presence of regulations consistent with the standard. In centers, 24 states had regulations limiting screen media use for children under 24 months of age and 19 states had regulations limiting screen media use in homes. Results More states in the South and fewer states in the Midwest had regulations limiting screen media use. The association between geographic region and regulations was not significant for centers (p = 0.06), but was for homes (p = 0.04). The year of last update (within the past 5 years versus older than 5 years) was not associated with regulations for centers (p = 0.18) or homes (p = 0.90). Discussion Many states lacked screen media use regulations for ECE. States should consider adding screen media use restrictions for children under 24 months based on current research data and current recommendations in future regulations updates. PMID- 29427017 TI - Measuring Sedentary Behavior During Pregnancy: Comparison Between Self-reported and Objective Measures. AB - Objectives To quantify and compare the sedentary time estimated by the Sedentary Behavior Questionnaire (SBQ) and the sedentary time objectively measured by a multi-sensor monitor (SWA) in pregnant women. Methods One hundred eighty-six participants answered the SBQ and wore the SWA at least 7 valid days. The concordance, correlation, agreement and relative activity levels between both measures of sedentary time were examined. Differences of sedentary time between weekday and weekend and between groups stratified by sociodemographic and clinical characteristic were evaluated by one-way analysis of variance. Results Pregnant women were sedentary the 64% of their waking hours. Television viewing is the most prevalent sedentary behavior. The concordance, correlation, and agreement between SBQ and SWA were weak, yet a significant correlation in weekday and average day sedentary time (r = 0.23 and 0.20, P = 0.001 and 0.008, respectively) was observed. A significant linear trend was found for increasing sedentary time between both methods using a relative activity levels analysis. Conclusions for Practice Pregnant women experience high amount of sedentary time, for approximately half of the day. The SBQ shows a low validity and agreement, but strong ability to rank individuals compared with SWA in pregnant women. PMID- 29427018 TI - Advancing Survival in Nigeria: A Pre-post Evaluation of an Integrated Maternal and Neonatal Health Program. AB - Introduction Nigeria contributes more obstetric, postpartum and neonatal deaths and stillbirths globally than any other country. The Clinton Health Access Initiative in partnership with the Nigerian Federal Ministry of Health and the state Governments of Kano, Katsina, and Kaduna implemented an integrated Maternal and Neonatal Health program from July 2014. Up to 90% women deliver at home in Northern Nigeria, where maternal mortality ratio and neonatal mortality rates (MMR and NMR) are high and severe challenges to improving survival exist. Methods Community-based leaders ("key informants") reported monthly vital events. Pre post comparisons of later (months 16-18) with conservative baseline (months 7-9) rates were used to assess change in MMR, NMR, perinatal mortality (PMR) and stillbirth. Two-tailed cross-tabulations and unadjusted and adjusted logistic regression analyses were conducted. Results Data on 147,455 births (144,641 livebirths and 4275 stillbirths) were analyzed. At endline (months 16-18), MMR declined 37% (OR 0.629, 95% CI 0.490-0.806, p <= 0.0003) vs. baseline 440/100,000 births (months 7-9). NMR declined 43% (OR 0.574, 95% CI 0.503-0.655, p < 0.0001 vs. baseline 15.2/1000 livebirths. Stillbirth rates declined 15% (OR 0.850, 95% CI 0.768-0.941, p = 0.0018) vs. baseline 21.1/1000 births. PMR declined 27% (OR 0.733, 95% CI 0.676-0.795, p < 0.0001) vs. baseline 36.0/1000 births. Adjusted results were similar. Discussion The findings are similar to the Cochrane Review effects of community-based interventions and indicate large survival improvements compared to much slower global and flat national trends. Key informant data have limitations, however, their limitations would have little effect on the results magnitude or significance. PMID- 29427019 TI - Gambling Disorder in Veterans: A Review of the Literature and Implications for Future Research. AB - To review the scientific literature examining gambling behavior in military veterans in order to summarize factors associated with gambling behavior in this population. Database searches were employed to identify articles specifically examining gambling behavior in military veterans. Cumulative search results identified 52 articles (1983-2017) examining gambling behavior in veteran populations. Articles generally fell into one or more of the following categories: prevalence, psychological profiles and psychiatric comorbidities, treatment evaluations, measurement, and genetic contributions to gambling disorder. Results from reviewed articles are presented and implications for future research discussed. Research to date has provided an excellent foundation to inform potential screening, intervention and research activities going forward. The authors suggest that a public health approach to future research endeavors would strengthen the evidence base regarding gambling in veteran populations and better inform strategies for screening, prevention and treatment. PMID- 29427020 TI - [Autoimmunity and glaucoma]. AB - In addition to the clinically most relevant risk factor for glaucoma, i.e., elevated intraocular pressure (IOP), there are other factors with high relevance for the disease. Changes in the autoimmune component of the immune system are of particular importance. Clinical studies have demonstrated alterations in different autoantibodies in glaucoma patients compared to healthy controls, some of which increase in abundance/have a raised titer, but also some which have a reduced titer. These changes have a distinct potential-not only as a tool for early glaucoma detection, but also as a therapeutic option due to the documented neuroprotective effects of some of these antibodies. Several antibodies displaying lower abundance in glaucoma patients, e.g., antibodies against 14-3-3 proteins, gamma-/alpha-synuclein, or also against glial fibrillary acidic protein (GFAP), show neuroprotective effects on retinal ganglion cells in vivo and in vitro. To assess the relevance of changes detected in the immune system of glaucoma patients, "-omics-based" analyses of different ocular tissues are of particular importance alongside cell culture studies. In this manner, not only samples derived from experimental studies but also samples derived from glaucoma patients in even very small amounts (e. g., tears, aqueous humor, serum, or post mortem retina) can be analyzed in detail in terms of protein and, in particular, antibody changes. Modern mass spectrometric proteomic characterization of relevant samples will deliver valuable information concerning the understanding of molecular disease mechanisms in the coming years, thus also improving diagnosis and treatment of glaucoma. PMID- 29427021 TI - Estimating the densities of benzene-derived explosives using atomic volumes. AB - The application of average atomic volumes to predict the crystal densities of benzene-derived energetic compounds of general formula C a H b N c O d is presented, along with the reliability of this method. The densities of 119 neutral nitrobenzenes, energetic salts, and cocrystals with diverse compositions were estimated and compared with experimental data. Of the 74 nitrobenzenes for which direct comparisons could be made, the % error in the estimated density was within 0-3% for 54 compounds, 3-5% for 12 compounds, and 5-8% for the remaining 8 compounds. Among 45 energetic salts and cocrystals, the % error in the estimated density was within 0-3% for 25 compounds, 3-5% for 13 compounds, and 5-7.4% for 7 compounds. The absolute error surpassed 0.05 g/cm3 for 27 of the 119 compounds (22%). The largest errors occurred for compounds containing fused rings and for compounds with three -NH2 or -OH groups. Overall, the present approach for estimating the densities of benzene-derived explosives with different functional groups was found to be reliable. Graphical abstract Application and reliability of average atom volume in the crystal density prediction of energetic compounds containing benzene ring. PMID- 29427022 TI - [Erratum to: Overactive bladder-which treatment when?] PMID- 29427023 TI - [Anogenital warts and HPV-associated precancers : Looking into the recently passed German S2k guideline]. AB - Anogenital warts are the most frequently sexually transmitted disease caused by viral infections worldwide. People's lifetime risk to suffer from this disease or HPV-associated precancers counts to more than 10%. The therapy and the recurrence rates of both disorders continue to be challenging in Germany because the coverage rate of the preventive HPV vaccination is still insufficient. This underlines the importance of a recently passed interdisciplinary German guideline on anogenital HPV lesions. This article summarizes the main aspects of the new guideline. Specialists should be consulted by children, pregnant women, individuals suffering from immunodeficiency and people frequently having relapses of HPV-associated diseases or having lesions being accessible only endoscopically. PMID- 29427024 TI - Comparison of the effects of linagliptin and voglibose on endothelial function in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, pilot study (EFFORT). AB - Endothelial dysfunction contributes to poor cardiovascular prognosis in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). The effect of dipeptidyl peptidase-4 inhibitors on endothelial function remains controversial. We sought to compare the effects of linagliptin and voglibose on endothelial function, as assessed by reactive hyperemia-peripheral arterial tonometry (RH-PAT). Sixteen patients with newly diagnosed T2DM and CAD were randomized 1:1 to linagliptin (5 mg, once-daily) or voglibose (0.9 mg, thrice daily). The RH-PAT and laboratory parameters, including 75 g oral glucose tolerance test, were measured at baseline and 3 months. Linagliptin increased serum levels of active glucagon-like peptide-1 and high-molecular-weight adiponectin. Age-, sex-, and baseline-adjusted changes in logarithmic RH-PAT index (LnRHI) after 3 months were significant between groups (linagliptin, 0.135 +/- 0.097; voglibose, - 0.124 +/- 0.091; P = 0.047). In the linagliptin group, change in LnRHI was positively correlated with change in high-density lipoprotein cholesterol and negatively correlated with changes in both urine albumin-to creatinine ratio and high-sensitivity C-reactive protein. Furthermore, linagliptin treatment for 3 months reduced serum levels of both glucose and insulin at 2 h, relative to voglibose, in the age-, sex-, and baseline-adjusted model. Linagliptin improved endothelial function relative to voglibose, accompanied by amelioration of glycemic, renal, and cardiometabolic parameters, in patients with newly diagnosed T2DM and CAD.Trial registration Unique Trial Number, UMIN 000029169 ( https://upload.umin.ac.jp/cgi-open bin/ctr_e/ctr_view.cgi?recptno=R000012442 ). PMID- 29427025 TI - Telemedicine in general neurology: use of audiovisual consultation for on call back-up service in an acute care hospital. AB - OBJECTIVE: While telemedicine is in expanding use in acute stroke care, little is known about its use in general neurology, especially in acute care. We sought to investigate the feasibility and possible effects of a telemedicine device within the neurological back-up service of an acute care hospital. METHODS: In a 450 bed academic teaching hospital an experienced neurologist (EN) is on call to support the junior doctor at the hospital. Support was possible whether by standard telephone advice (TA) or by audiovisual consultations (AVC). In AVC the expert used a mobile telemedicine device and so he could establish audiovisual contact from his home to the emergency room and examine newly admitted patients. Technical and patient details including timing and diagnosis were recorded. Video and audio quality as well as impact of AVC on diagnosis was rated by the EN. RESULTS: Out of about 1200 cases in off peak times, during the study period, 164 AVC including remote video examination were done (13.6%). Also 48 cases were documented by pure TA. Video quality was rated to a medium of 1.7, audio quality to 2.1. In 36 cases the audiovisual consultation was influenced by technical issues leading to cessation of AVC in 8 cases. Duration of teleconsultation was 17.3 min in AVC compared to 8.7 min for TA. The consultation diagnosis in AVC was confirmed in 74.4% of all cases compared to 57.7% in TA. AVC was rated as a valuable contribution to the diagnostic workup in 74.3% of all cases seen. In about 40% of all cases AVC was not possible due to technical or organizational reasons. CONCLUSIONS: Audiovisual consultation seems to be a feasible and useful support in routine neurology back-up service of an acute care hospital. Better mobility of devices and flexibility of service is needed to improve availability and quality of this valuable tool. PMID- 29427026 TI - Wearable sensors for clinical applications in epilepsy, Parkinson's disease, and stroke: a mixed-methods systematic review. AB - OBJECTIVES: Wearable technology is increasingly used to monitor neurological disorders. The purpose of this systematic review was to synthesize knowledge from quantitative and qualitative clinical researches using wearable sensors in epilepsy, Parkinson's disease (PD), and stroke. METHODS: A systematic literature search was conducted in PubMed and Scopus spanning from 1995 to January 2017. A synthesis of the main findings, reported adherence to wearables and missing data from quantitative studies, is provided. Clinimetric properties of measures derived from wearables in laboratory, free activities in hospital, and free living environment were also evaluated. Qualitative thematic synthesis was conducted to explore user experiences and acceptance of wearables. RESULTS: In total, 56 studies (50 reporting quantitative and 6 reporting qualitative data) were included for data extraction and synthesis. Among studies reporting quantitative data, 5 were in epilepsy, 21 PD, and 24 studies in stroke. In epilepsy, wearables are used to detect and differentiate seizures in hospital settings. In PD, the focus is on quantification of cardinal motor symptoms and medication-evoked adverse symptoms in both laboratory and free-living environment. In stroke upper extremity activity, walking and physical activity have been studied in laboratory and during free activities. Three analytic themes emerged from thematic synthesis of studies reporting qualitative data: acceptable integration in daily life, lack of confidence in technology, and the need to consider individualization. CONCLUSIONS: Wearables may provide information of clinical features of interest in epilepsy, PD and stroke, but knowledge regarding the clinical utility for supporting clinical decision making remains to be established. PMID- 29427027 TI - MR imaging features of cuboid fractures in children. AB - BACKGROUND: Cuboid fractures are rare, usually occult on initial radiographs and are often underdiagnosed. MRI is more sensitive than radiographs for detecting acute, non-displaced cuboid fractures in adults, but only case reports have described these findings in children. OBJECTIVE: To summarize the MR and clinical features of cuboid fractures and compare MR findings with initial and follow-up radiographs in a cohort of children. MATERIALS AND METHODS: A retrospective search for patients <18 years of age with cuboid fractures was performed during a 10-year period at a large tertiary children's hospital. Subjects with cuboid fractures reported on MRI and available clinical history were included. MR images were evaluated for fracture location, fracture morphology, percentage of marrow edema in the cuboid, subchondral disruption, and associated tendon or ligamentous injury. Initial and short-term follow-up radiographs were also reviewed when available. RESULTS: Nineteen children ages 18 months to 17 years (mean: 9.0 years, standard deviation: 4.1 years, 63% boys) were diagnosed with cuboid fractures by MRI. Most cases of cuboid fractures are related to acute trauma (63%) but can be seen as stress fractures (16%). Most fractures (17/19, 89%) were linear in configuration. Fractures were most commonly adjacent to the tarsometatarsal joint (10/19, 52%). The degree of marrow edema was variable. Ligamentous injury was seen in two patients and tendon pathology was seen in one, all adolescents. Initial radiographs (n=10) were negative in 9 cases (90%). All available follow-up radiographs (n=12, obtained 19-42 days after MRI) demonstrated sclerosis in the region of the fracture. CONCLUSION: MR-depicted cuboid fractures in children typically occur in isolation. The fractures were most commonly adjacent to the tarsometatarsal joint and linear in morphology. Initial radiographs were usually normal and follow-up radiographs depicted sclerosis at the site of fracture in all available cases. PMID- 29427029 TI - MRI Findings of Adult-Onset Orbital Xanthogranulomatous Disease : A Case Report. PMID- 29427028 TI - 2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT). AB - Imaging is crucial in the assessment of children with a primary hepatic malignancy. Since its inception in 1992, the PRETEXT (PRE-Treatment EXTent of tumor) system has become the primary method of risk stratification for hepatoblastoma and pediatric hepatocellular carcinoma in numerous cooperative group trials across the world. The PRETEXT system is made of two components: the PRETEXT group and the annotation factors. The PRETEXT group describes the extent of tumor within the liver while the annotation factors help to describe associated features such as vascular involvement (either portal vein or hepatic vein/inferior vena cava), extrahepatic disease, multifocality, tumor rupture and metastatic disease (to both the lungs and lymph nodes). This manuscript is written by members of the Children's Oncology Group (COG) in North America, the International Childhood Liver Tumors Strategy Group (SIOPEL) in Europe, and the Japanese Study Group for Pediatric Liver Tumor (JPLT; now part of the Japan Children's Cancer Group) and represents an international consensus update to the 2005 PRETEXT definitions. These definitions will be used in the forthcoming Trial to Pediatric Hepatic International Tumor Trial (PHITT). PMID- 29427030 TI - Sinonasal Neuroendocrine Neoplasms: Current Challenges and Advances in Diagnosis and Treatment, with a Focus on Olfactory Neuroblastoma. AB - Sinonasal tumors with neuroendocrine differentiation form a group of rare heterogeneous neoplasms of neuroectodermal and epithelial origin, consisting of olfactory neuroblastomas and neuroendocrine carcinomas. Because the natural history and biological behavior of this group of tumors vary, the morphological diagnosis coupled with grading/staging is important for prognostication, and the approach to treatment and rehabilitation is multidisciplinary. The identification of molecular abnormalities underlying these tumors is critical to the development of specific targeted therapies and the design of clinical trials. PMID- 29427031 TI - Unusual Multinucleated Giant Cell Reaction in a Tongue Squamous Cell Carcinoma: Histopathological and Immunohistochemical Features. AB - Multinucleated giant cell (MGC) reaction in oral squamous cell carcinoma (OSCC) usually represents a stromal foreign body reaction to keratin from neoplastic epithelial cells. We describe and illustrate by double immunohistochemistry a case of a tongue squamous cell carcinoma (SCC) in a 70-year-old female patient, with a copious MGC reaction not associated to keratin, showing a histopathological pattern not described before. The MGCs were directly associated with neoplastic cells, which are phagocytosed by the MGCs. Immunohistochemistry for CD68, AE1/AE3, CD163, CD11c, RANK, RANK-L, OPG were performed, as well as double staining for CD68 and AE1/AE3 to better illustrate the relationship between MGCs and neoplastic cells. The clinical and biological significance of this pattern of MGC reaction in OSCC needs to be better elucidated. PMID- 29427032 TI - Putting All the Pieces Together: Clinical, Macroscopic and Microscopic Characteristics of Subacute Thyroiditis. AB - Subacute thyroiditis (SAT) is a self-limiting inflammatory condition of the thyroid gland in which multinucleated giant cells constitute a key histological finding. SAT is generally a clinical diagnosis and consequently its histological features are rarely encountered by pathologist. Herein, we present a case that exemplifies the characteristic clinical and pathological features of this entity. In addition, we compare SAT to other thyroid disorders characterized by the presence of multinucleated giant cells. PMID- 29427033 TI - A Retrospective 20-Year Analysis of Proliferative Verrucous Leukoplakia and Its Progression to Malignancy and Association with High-risk Human Papillomavirus. AB - Proliferative verrucous leukoplakia (PVL) is defined as an aggressive, relentless and recalcitrant form of leukoplakia that has a high propensity for malignant transformation. The aim of this study was to evaluate the malignant potential of PVL and determine its possible association with high-risk human papillomavirus (HPV). Twenty cases with a clinical and biopsy proven diagnosis of PVL were collected from the University of Florida Oral Medicine clinic database. Immunohistochemistry was performed to evaluate the expression of p16INK4A and p53 genes in the PVL lesions. The lesions were also tested for high-risk HPV by DNA in-situ hybridization. The average age of the patients at the time of first biopsy was 62.7 years. Most patients had multiple sites of involvement, gingiva being the most common location. The lesions progressed to malignancy in approximately 50% of patients. The expression of p16INK4A gene was considered negative, with at least a 50-65% immunoreactivity observed in only three cases that progressed to malignancy. No expression of high-risk HPV was detected, whereas p53 staining was positive in less than 25% of the cells demonstrating gene expression. No definite association between PVL and high-risk HPV infection could be established. Due to the high transformation potential of PVL, early recognition with aggressive treatment, including multiple biopsies, and continued close clinical follow-up, remain the mainstay of favorable management of this condition. PMID- 29427034 TI - Effect of In Ovo Zinc Injection on the Embryonic Development and Epigenetics Related Indices of Zinc-Deprived Broiler Breeder Eggs. AB - The role of in ovo zinc (Zn) injection in improving the embryonic development in eggs from Zn-deficient hens, via epigenetic and antioxidant mechanisms, was examined. A completely randomized design involving a 1 (the non-injected control) + 1 (the injected control with sterilized water) + 2 (Zn source) * 2 (Zn level) factorial arrangement of treatments was used. The two injected Zn sources were inorganic Zn sulfate and organic Zn-lysine chelate with a moderate chelation strength, and the two injected Zn levels were 50 and 100 MUg Zn/egg. In ovo Zn injection decreased (P < 0.05) embryonic mortality, and increased (P < 0.05) hatchability and healthy chick ratio. In ovo Zn injection increased (P < 0.05) embryonic tibia Zn content, but had no effect (P > 0.05) on copper (Cu)- and Zn containing superoxide dismutase (CuZnSOD) activities and metallothionein IV (MT4) levels or their mRNA expression levels and malondialdehyde (MDA) levels in the embryonic liver. In ovo Zn injection had no effect (P > 0.05) on the global level of DNA methylation or DNA methylation and histone 3 lysine 9 (H3K9) acetylation levels of the MT4 promoter in the embryonic liver. However, the organic Zn had higher (P < 0.05) levels of DNA methylation and H3K9 acetylation than inorganic Zn. These data demonstrate that in ovo Zn injection improved the embryonic development, and the organic Zn was more effective than inorganic Zn in enhancing DNA methylation and H3K9 acetylation in the liver MT4 promoter, but the precise mechanisms require further investigations. PMID- 29427035 TI - Probiotics as a Complementary Therapy in the Model of Cadmium Chloride Toxicity: Crosstalk of beta-Catenin, BDNF, and StAR Signaling Pathways. AB - Cadmium chloride (CdCl2) is a ubiquitous environmental toxicant that causes a variety of disturbances in biological systems, including brain dysfunction and testicular tissue degeneration. On the other hand, it is supposed that beneficial properties of probiotic bacteria (Lactobacillus and Acidobacillus) are related to their capacity to adhere or bind different targets, thus leading to improved intestinal microbial balance and other benefits to the host. Bearing aforementioned in mind, the present study was undertaken to investigate the protective effect of probiotic supplementation against cadmium chloride-induced brain and testis toxicity in mice model. Animals received Lactobacillus and Acidobacillus either alone or added to folic acid for 1 week before CdCl2 intoxication in a dose of 20 mg/kg BW followed by probiotics (5 * 109) and/or folic acid (12 mg/kg) treatment for 3 weeks. The levels of malondialdehyde (MDA), butyrl choline esterase (BCHE), reduced glutathione (GSH), and total superoxide dismutase (SOD) activities were investigated. Finally, cadmium neurotoxicity was determined by estimating the gene expression of beta-catenin and brain-derived neurotrophic factor (BDNF), as well as estimating the alterations in testicular function by determining acid phosphatase level in addition to steroidogenic acute regulatory protein (StAR) and 17-hydroxy steroid dehydrogenase (17-beta HSD) gene expression. Based on our results, we can conclude that exposure of mice to cadmium chloride resulted in a significant elevation in MDA, BCHE levels accompanied with a significant reduction in GSH and SOD activities compared to the control value. CdCl2 also downregulated the gene expression of beta-catenin and BDNF, as well as acid phosphatase level, in addition to StAR and 17-beta HSD gene expression. These deviated parameters were significantly modulated in the co treated animals with probiotics compared with the cadmium-treated group. In conclusion, Lactobacillus and folic acid in a mixture with cadmium acted beneficially to an organism, increasing the cadmium excretion in feces, and consequently increasing beta-catenin and BDNF in brain tissue and StAR and 17 beta HSD in testis and improving their functions. Histoarchitecture analysis confirmed these results. PMID- 29427036 TI - Toxicological Effects of Mercury Chloride on Laying Performance, Egg Quality, Serum Biochemistry, and Histopathology of Liver and Kidney in Laying Hens. AB - The objective of this study was to determine the effects of mercury chloride (HgCl2) on laying performance, egg quality, hepatic and renal histopathology, and serum biochemical profiles in laying hens. A total of 768 Hy-line brown laying hens aged 40 weeks were randomly allocated to four groups (8 pens per group and 24 hens per pen). The concentrations of mercury (Hg) in four groups were 0.280, 3.325, 9.415, and 27.240 mg/kg. Results revealed that dietary Hg could significantly reduce laying performance (P < 0.05) and egg quality (P < 0.05) and was dose-dependently deposited in albumen, yolk, eggshell, and whole egg. Meanwhile, the thicknesses of palisade layer, mammillary layer, and total layer, and the percent of palisade layer were significantly decreased (P < 0.05), while the percent of mammillary layer was sharply increased (P < 0.05) in eggshell. In addition, with increasing dietary dosage of Hg, accumulation of Hg in viscera was significantly increased (P < 0.05), and histopathological damages in liver and kidney were more and more severe. Serum alanine aminotransferase, aspartate aminotransferase, and globulin were significantly increased (P < 0.05), while serum albumin and albumin to globulin ratio were significantly decreased (P < 0.05) in 27.240 mg/kg Hg group. Blood urea nitrogen, uric acid, and creatinine were significantly increased (P < 0.05) in 3.325, 9.415, and 27.240 mg/kg Hg groups. These results suggested that dietary HgCl2 could reduce laying performance and egg quality with hepatic and renal function disorders in laying hens. PMID- 29427037 TI - Effect of expanded bone marrow-derived osteoprogenitor cells seeded into polycaprolactone/tricalcium phosphate scaffolds in new bone regeneration of rabbit mandibular defects. AB - The purpose of this study was to assess and evaluate new bone formation in rabbit marginal mandibular defects using expanded bone marrow-derived osteoprogenitor cells seeded in three-dimensional scaffolds of polycaprolactone/tricalcium phosphate (PCL/TCP). Bone marrow was harvested from the rabbit ilium and rabbit bone marrow-derived osteoprogenitor cells were isolated and expanded in standard culture medium and osteogenic medium supplement. The cells were then seeded into the PCL/TCP scaffolds and the cell/scaffold constructions were implanted into prepared defects in rabbit mandibles. PCL/TCP scaffold alone and autogenous bone graft from the mandible were also implanted into the other prepared defects. The specimens were evaluated at 4 and 8 weeks after the implantation using clinical, radiographic, and histological techniques. The results of the experimental group demonstrated more newly formed bone on the surface and in the pores of the PCL/TCP scaffolds. In addition, the osteoblasts, osteocytes, and new bone trabeculae were identified throughout the defects that were implanted with the cell/scaffold constructions. The PCL/TCP alone group was filled mostly with fibrous cells particularly in the middle region with less bone formation. These results would suggest that the derived osteotoprogenitor cells have the potential to form bone tissue when seeded onto PCL/TCP scaffolds. PMID- 29427039 TI - Introducing laparoscopic total gastrectomy for gastric cancer in general practice: a retrospective cohort study based on a nationwide registry database in Japan. AB - BACKGROUND: Although laparoscopic total gastrectomy (LTG) is considered a technically demanding procedure with safety issues, it has been performed in several hospitals in Japan. Data from a nationwide web-based data entry system for surgical procedures (NCD) that started enrollment in 2011 are now available for analysis. METHODS: A retrospective cohort study was conducted using data from 32,144 patients who underwent total gastrectomy and were registered in the NCD database between January 2012 and December 2013. Mortality and morbidities were compared between patients who received LTG and those who underwent open total gastrectomy (OTG) in the propensity score-matched Stage I cohort and Stage II-IV cohort. RESULTS: There was no significant difference in mortality rate between LTG and OTG in both cohorts. Operating time was significantly longer in LTG while the blood loss was smaller. In the Stage I cohort, LTG, performed in 33.6% of the patients, was associated with significantly shorter hospital stay but significantly higher incidence of readmission, reoperation, and anastomotic leakage (5.4% vs. 3.6%, p < 0.01). In the Stage II-IV cohort, LTG was performed in only 8.8% of the patients and was associated with significantly higher incidence of leakage (5.7% vs. 3.6%, p < 0.02) although the hospital stay was shorter (15 days vs. 17 days, p < 0.001). CONCLUSION: LTG was more discreetly introduced than distal gastrectomy, but remained a technically demanding procedure as of 2013. This procedure should be performed only among the well trained and informed laparoscopic team. PMID- 29427038 TI - Efficacy and tolerability of ramucirumab monotherapy or in combination with paclitaxel in gastric cancer patients from the Expanded Access Program Cohort by the Korean Cancer Study Group (KCSG). AB - BACKGROUND: Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP). METHODS: Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen. RESULTS: Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS. CONCLUSION: In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group. PMID- 29427040 TI - Novel epigenetic markers for gastric cancer risk stratification in individuals after Helicobacter pylori eradication. AB - BACKGROUND: The risk stratification of healthy individuals after Helicobacter pylori eradication is an urgent issue. The assessment of aberrant DNA methylation accumulated in gastric tissues with normal appearance, which can reflect overall epigenomic damage, is a promising strategy. We aimed to establish novel epigenetic cancer risk markers for H. pylori-eradicated individuals. METHODS: Gastric mucosa was collected from eight healthy volunteers without H. pylori infection (G1), 75 healthy individuals with gastric atrophy (G2), and 94 gastric cancer patients (G3) after H. pylori eradication. Genome-wide analysis was conducted using Infinium 450 K and differentially methylated probes were screened using large difference and iEVORA-based methods. Bisulfite pyrosequencing was used for validation. RESULTS: Screening, using 8 G1, 12 G2, and 12 G3 samples, isolated 57 candidates unmethylated in G1 and differentially methylated in G3 compared with G2. Validation for nine candidate markers (FLT3, LINC00643, RPRM, JAM2, ELMO1, BHLHE22, RIMS1, GUSBP5, and ZNF3) in 63 G2 and 82 G3 samples showed that all of them had significantly higher methylation levels in G3 than in G2 (P < 0.0001). Their methylation levels were highly correlated, which indicated that they reflect overall epigenomic damage. The candidates had sufficient performance (AUC: 0.70-0. 80) and high odds ratios (5.43-23.41), some of which were superior to a previous marker, miR-124a-3. The methylation levels of our novel markers were not associated with gastric atrophy, gender, or age. CONCLUSIONS: Novel epigenetic markers for gastric cancer risk optimized for H. pylori-eradicated individuals were established. PMID- 29427041 TI - The validity of parental reports on motor skills performance level in preschool children: a comparison with a standardized motor test. AB - : Motor skills are interrelated with essential domains of childhood such as cognitive and social development. Thus, the evaluation of motor skills and the identification of atypical or delayed motor development is crucial in pediatric practice (e.g., during well-child visits). Parental reports on motor skills may serve as possible indicators to decide whether further assessment of a child is necessary or not. We compared parental reports on fundamental motor skills performance level (e.g., hopping, throwing), based on questions frequently asked in pediatric practice, with a standardized motor test in 389 children (46.5% girls/53.5% boys, M age = 3.8 years, SD = 0.5, range 3.0-5.0 years) from the Swiss Preschoolers' Health Study (SPLASHY). Motor skills were examined using the Zurich Neuromotor Assessment 3-5 (ZNA3-5), and parents filled in an online questionnaire on fundamental motor skills performance level. The results showed that the answers from the parental report correlated only weakly with the objectively assessed motor skills (r = .225, p < .001). CONCLUSION: Although a parental screening instrument for motor skills would be desirable, the parent's report used in this study was not a valid indicator for children's fundamental motor skills. Thus, we may recommend to objectively examine motor skills in clinical practice and not to exclusively rely on parental report. What is Known: * Early assessment of motor skills in preschool children is important because motor skills are essential for the engagement in social activities and the development of cognitive abilities. Atypical or delayed motor development can be an indicator for different developmental needs or disorders. * Pediatricians frequently ask parents about the motor competences of their child during well child visits. What is New: * The parental report on fundamental motor skills performance level used in this study was not a reliable indicator for describing motor development in the preschool age. * Standardized examinations of motor skills are required to validly assess motor development in preschoolers. PMID- 29427043 TI - Esophagography and gastroesophageal reflux disease: utilization and utility. PMID- 29427044 TI - Ultrasound-guided renal transplant biopsy: practical and pragmatic considerations. AB - Sonographically guided percutaneous core biopsy of renal allografts has been performed for decades, providing valuable information in monitoring the status of normally functioning renal transplants as well as investigating the cause of renal transplant dysfunction. This article reviews practical aspects of biopsy technique using the cortical tangential approach, with consideration of factors that may influence biopsy success, including selection of biopsy device. Clinically important complications from renal transplant biopsy are uncommon; the most recent experience for one institution is analyzed in the context of existing evidence regarding the frequency and timing of these major complications, to understand pragmatic implications for peri-procedural care. PMID- 29427045 TI - The "pelvic digit". PMID- 29427046 TI - Hepatobiliary phase liver MR imaging findings after Oxaliplatin-based chemotherapy in cancer patients. AB - OBJECTIVE: To describe Gd-EOB-DTPA-enhanced liver MR imaging findings in colon and rectal cancer patients who received Oxaliplatin. CONCLUSION: Spectrum of hepatobiliary phase imaging findings include diffuse heterogeneous dysfunction, macronodular and micronodular FNH-like lesions, and coexistence of periportal increased liver function with FNH-like lesions. Differentiation of these benign lesions from metastasis is crucial to avoid biopsy in patients with colorectal cancers and may allow better understanding of sinusoidal obstruction syndrome pathophysiology and regenerative response of liver. PMID- 29427042 TI - Amyotrophic Lateral Sclerosis Associated with Statin Use: A Disproportionality Analysis of the FDA's Adverse Event Reporting System. AB - INTRODUCTION: Apparent elevations in reporting of amyotrophic lateral sclerosis (ALS)-like conditions associated with statin use have been previously described from data obtained via US and European databases. OBJECTIVE: The aim of this study was to examine US FDA Adverse Event Reporting System (FAERS) data to compare reporting odds ratios (RORs) of ALS and ALS-like conditions between statins and other drugs, for each statin agent. METHODS: We assessed for disproportional rates of reported ALS and ALS-related conditions for each statin agent separately by using the ROR formula. FAERS data were analyzed through September 2015. RESULTS: RORs for ALS were elevated for all statins, with elevations possibly stronger for lipophilic statins. RORs ranged from 9.09 (6.57 12.6) and 16.2 (9.56-27.5) for rosuvastatin and pravastatin (hydrophilic) to 17.0 (14.1-20.4), 23.0 (18.3-29.1), and 107 (68.5-167) for atorvastatin, simvastatin, and lovastatin (lipophilic), respectively. For simvastatin, an ROR of 57.1 (39.5 82.7) was separately present for motor neuron disease. CONCLUSION: These findings extend previous evidence showing that significantly elevated ALS reporting extends to individual statin agents, and add to concerns about potential elevated occurrence of ALS-like conditions in association with statin usage. PMID- 29427047 TI - Are Personality Characteristics as Measured by the Temperament and Character Inventory (TCI) Associated with Obesity Treatment Outcomes? A Systematic Review. AB - PURPOSE OF REVIEW: Some personality traits seem to be associated with obesity, but there is little information available regarding their association with obesity treatment outcomes. The aim of this systematic review was therefore to assess the associations between personality traits-evaluated by means of the Temperament and Character Inventory (TCI)-and outcomes of obesity treatment, including attrition, weight loss, and weight loss maintenance. The PubMed database was searched, and studies were screened as per the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, and data were collated using a narrative approach. RECENT FINDINGS: Of the 886 articles retrieved, 9 studies assessing personality traits by means of the TCI in participants with obesity met the inclusion criteria and were reviewed. This approach revealed three main findings: (i) only one study found that attrition rate-during a 6-month behavioral weight loss program-is predicted by low reward dependence scores at baseline; (ii) two studies found that lower novelty-seeking and higher self-directedness scores at baseline positively predict short-term weight-loss magnitude; and (iii) four studies found that higher persistence and lower novelty-seeking scores at baseline predicted weight maintenance at 12 and 24 months. Novelty-seeking and self-directedness traits appear to be predictors of short-term weight loss (<= 6 months), and persistence and novelty-seeking traits may be related to long-term weight loss maintenance (>= 12 months), although great uncertainty still exists regarding predictors of attrition. PMID- 29427050 TI - Transcranial Magnetic Stimulation (TMS) in the Elderly. AB - PURPOSE OF REVIEW: This article aims to review select applications of Transcranial Magnetic Stimulation (TMS) that have significant relevance in geriatric psychiatry. RECENT FINDINGS: Small study sizes and parameter variability limit the generalizability of many TMS studies in geriatric patients. Additionally, geriatric patients have unique characteristics that can moderate the efficacy of TMS. Nonetheless, several promising experimental applications in addition to the FDA-approved indication for major depression have emerged. Cognitive impairment, neuropathic pain, and smoking cessation are experimental applications with special significance to the elderly. Cognitive impairment has been researched the most in this population and evidence thus far suggests that TMS has potential therapeutic benefit. There is also evidence to suggest benefit from TMS for neuropathic pain and smoking cessation in working age adults. TMS is consistently reported as a safe and well-tolerated treatment modality with no adverse cognitive side effects. TMS is a safe treatment modality that can be effective for certain applications in the elderly. Additional research that specifically includes older subjects is needed to replicate findings and to optimize treatment protocols for this population. PMID- 29427051 TI - The complex interplay between neutrophils and cancer. AB - Neutrophils are the most abundant type of white blood cell, and are an essential component of the innate immune system. They characteristically arrive rapidly at sites of infection and injury, and release a variety of cytokines and toxic molecules to eliminate pathogens and elicit an acute inflammatory response. Research into the function of neutrophils in cancer suggest they have divergent roles. Indeed, while most studies have found neutrophils to be associated with cancer progression, others have also documented anticancer effects. In this review, we describe the investigations into neutrophil populations that have been implicated in promoting tumor growth and metastasis as well those demonstrating antitumor functions. The collective research suggests a complex role for neutrophils in cancer biology, which raises the prospect of their targeting for the treatment of cancer. PMID- 29427049 TI - Favourable outcome in a child with symptomatic diagnosis of Glutaric aciduria type 1 despite vertical HIV infection and minor head trauma. AB - The first case of Glutaric aciduria Type 1(GA1) in an African child was reported in 2001. GA1 has a prevalence of 1:5000 in black South Africans. Although early diagnosis is essential for a favourable outcome, newborn screening is not routine in South Africa where an estimated 320,000 children have HIV infection. Neurodevelopmental delay and encephalopathy are complications of both HIV and GA1. In such a setting it is important to recognise that HIV and GA1 can occur simultaneously. We present an HIV-infected South African male child of Xhosa descent with macrocephaly who commenced combination antiretroviral therapy (ART) at 8 weeks of age in a clinical trial which included a neurodevelopmental sub study. He developed short-lived focal seizures at 16 months after minor head trauma. Neurological examination was normal. Neuroimaging showed temporal lobe atrophy, subtle hyperintense signal change in the globus pallidus, and focal haemosiderosis in the right Sylvian fissure region. As findings were not in keeping with HIV encephalopathy, a urine metabolic screen was undertaken which suggested GA1. Genetic testing confirmed Arg293Trp mutation. He began L-carnitine and a low protein diet as a restricted diet was not practicable. At 21 months he developed pulmonary tuberculosis, requiring 6 months treatment. He did not develop any neurologic motor symptoms. Serial neurodevelopmental and neuropsychological test scores until 9 years were similar to healthy neighbourhood controls, except for mild language delay at 31/2 years. Detection of GA1, probably facilitated through participation in a clinical trial, was pivotal for a favourable outcome. The concomitant use of ART and anti-tuberculous therapy in a child with GA1 appears safe. PMID- 29427052 TI - Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis. AB - Paragangliomas and pheochromocytomas are rare neuroendocrine tumors characterized by a large spectrum of hereditary predisposition. Based on gene expression profiling classification, they can be classically assigned to either a hypoxic/angiogenic cluster (cluster 1 including tumors with mutations in SDHx, VHL and FH genes) or a kinase-signaling cluster (cluster 2 consisting in tumors related to RET, NF1, TMEM127 and MAX genes mutations, as well as most of the sporadic tumors). The past 15 years have seen the emergence of an increasing number of genetically engineered and grafted models to investigate tumorigenesis and develop new therapeutic strategies. Among them, only cluster 2-related predisposed models have been successful but grafted models are however available to study cluster 1-related tumors. In this review, we present an overview of existing rodent models targeting predisposition genes involved or not in human pheochromocytoma/paraganglioma susceptibility and their contribution to the improvement of pheochromocytoma experimental research. PMID- 29427053 TI - Clinical utility of urine kidney injury molecule-1 (KIM-1) and gamma-glutamyl transferase (GGT) in the diagnosis of canine acute kidney injury. AB - The aim of the present study was to evaluate the sensitivity and specificity of urine KIM-1 and urine GGT for the detection of naturally-occurring AKI, compared to healthy control dogs, dogs with stable chronic kidney disease (CKD), and dogs with lower urinary tract disorders (LUTD). The study included AKI grade 1 (n = 21), AKI grade 2 to 5 (n = 11), stable CKD (n = 11), LUTD (n = 15), and healthy dogs (n = 37). Urine KIM-1 (ng/mg) and GGT (U/l) were normalized to urine creatinine (uCr). Statistically significant difference in KIM/uCr (p = 0.0007) and GGT/uCr (p < 0.0001) was found among the study groups. Area under the curve (AUC) for KIM-1/uCr and GGT/uCr as predictors of AKI was 0.81 and 0.91 respectively. Values of KIM-1/uCr of 0.73 ng/mg and of GGT/uCr of 54.33 showed the best combination of sensitivity and specificity (75% and 75.6%; 85.7% and 89.1% respectively). A significant positive correlation (p < 0.0001) between KIM 1/uCr and GGT/uCr was found. Both urine KIM-1/uCr and GGT/uCr seemed to be potentially good markers for the diagnosis of AKI. Dogs with AKI showed significantly higher levels of urine KIM-1/uCr and urine GGT/uCr, compared with healthy dogs. Caution should be used in the evaluation of elevated urine KIM 1/uCr and GGT/uCr in dogs with pre-existing CKD and/or LUTD. Urine KIM-1/uCr and GGT/uCr might have a significant clinical utility, as complementary test, particularly in diagnosis early, non-azotemic stages of AKI. PMID- 29427054 TI - Prevalence of Trauma in an Australian Inner City Mental Health Service Consumer Population. AB - This study examined the rates and types of trauma reported by consumers utilising an inner city mental health service in Sydney, Australia. The study also explored whether consumers felt that it had been helpful to be asked about their experience of trauma, whether they thought that these questions should be asked routinely and if they wanted to talk about these experiences. Ninety-one consumers from an inner city mental health service were assessed. Eighty-eight percent of the consumers assessed reported that they had experienced at least one traumatic event, while 79% reported having experienced two or more events. A majority of consumers identified that they thought it was helpful to be asked about trauma and that it should be part of an assessment. However, less than one third of these consumers surveyed wanted to talk about the trauma at the time of assessment. Concerns that clinicians may have in regards to addressing trauma in mental health assessment are not matched by consumers' expressed beliefs on the issue. PMID- 29427055 TI - Community Mental Health Providers' Beliefs About Addressing Weight Loss Among Youth Clients with Serious Emotional Disturbance and Overweight/Obesity: An Elicitation Study. AB - Youth with Serious Emotional Disturbance (SED) have high rates of overweight/obesity. Factors influencing mental health provider intentions to deliver weight-related advice are unclear. This study used qualitative methodology and Theory of Planned Behavior (TPB) constructs to examine these factors. Community mental health providers serving youth with SED were recruited via convenience sampling and an online provider list. Participants completed an open-ended TPB-based questionnaire online. Content analysis identified thematic beliefs. Twenty-one providers completed the questionnaire. Providers identified behavioral beliefs (e.g., client defensiveness), normative beliefs (e.g., medical professionals), and control beliefs (e.g., limited resources) that impact decisions to provide weight-related advice. Knowledge of factors that may influence providers' delivery of weight-related advice may lead to more effective healthy lifestyle programming for youth with SED. PMID- 29427056 TI - A Rare Case of Anal and Perianal Chemical Burn in a Child due to Potassium Permanganate Crystals. AB - Many chemicals used as medical treatments can cause chemical burns as an untoward side effect. One of such chemicals is potassium permanganate. It is a caustic chemical used as a disinfectant. The most common sites of burn by potassium permanganate are exposed sites like the face and hands. Chemical burns in the perianal and anal region are rare in clinical practice and even sparser in the pediatric age group. In this article, we report a case of perianal and anal chemical burn in an 18-month-old, male child, caused by potassium permanganate crystal applied wrongly for the treatment of pinworm infestation. As a chemical burn in this region can have serious complications, it is necessary to be vigilant when using such chemicals in these cases. Early and timely management in such cases leads to good outcomes. This is the first of such cases of chemical burn caused by potassium permanganate in the anal and perianal region. PMID- 29427057 TI - Effects of Probiotic Bacteria Bacillus on Growth Performance, Digestive Enzyme Activity, and Hematological Parameters of Asian Sea Bass, Lates calcarifer (Bloch). AB - This study was conducted to evaluate different doses of two species of Bacillus (Bacillus licheniformis and Bacillus subtilis), on growth parameters, chemical composition of fish, activity of liver, and digestive enzymes of Asian sea bass. During 8 weeks, juvenile Asian sea bass received diets supplemented with 1 * 103, 1 * 106, and 1 * 109 CFU g-1 probiotic in addition to a control diet without added microorganisms. At the end of the trial, growth indices (total weight, total length, specific growth rate, total weight gain, food conversion ratio, and condition factor), body composition (crude protein, crude lipid, ash, and dry matter), digestive enzymes (protease, lipase, and amylase), liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP)], immunologic indicators (lysozyme), and hematological parameters [hematocrit (Hct), hemoglobin (Hb), red blood cells (RBCs), white blood cells (WBCs)] were assessed. Asian sea bass receiving diets supplemented with probiotic Bacillus (Bacillus licheniformis and Bacillus subtilis) showed significantly better growth than those fed the basal diet (control). Regarding body composition, total protein levels and dry matter were higher and lipid levels were lower in fish fed the diet containing 1 * 106 CFU g-1 probiotic compared with the control group (P < 0.05). Digestive enzymes (protease, lipase, and amylase) and hematological parameters (RBC, WBC, and Hb) were all highest in fish fed diet supplemented with 1 * 106 CFU g-1 probiotic Bacillus. Also, liver enzymes (AST, ALT, ALP) were lower in fish fed diet supplemented with 1 * 106 CFU g-1 probiotic Bacillus. Being that supplementation of 1 * 106 CFU g-1 of Bacillus in the diet is the dose which delivers the best results. PMID- 29427058 TI - Characterization of Functional, Safety, and Probiotic Properties of Enterococcus faecalis AG5 Isolated From Wistar Rat, Demonstrating Adherence to HCT 116 Cells and Gastrointestinal Survivability. AB - Gut microbiota remains a prominent source for a diverse range of potential probiotics. In this context, the current study explored the rectal region of experimental Wistar rat for the isolation of potent probiotic. Sixteen lactic acid bacteria (LAB), from rectal swab of Wistar rats, were subjected to evaluation of probiotic properties. Among all, AG5 was found unique with consistent probiotic properties and was further identified as Enterococcus faecalis AG5 (NCBI accession number KT248537) using 16S rDNA sequencing, followed by BLAST analysis. Since the Enterococci strains inhibit various food-borne pathogens efficiently while proving itself as a safe probiotic candidate, the study further evaluated the safety of the strain AG5 using primer specific PCR amplification which revealed the existence of gene encoding gelE, asa1, efaA, ace, vanA, and vanB and negative for cylA, hyl, and esp respectively. SEM analysis confirmed the adherence ability of AG5 to HCT 116 cells. Adherence was found to be non-colonial and scattered manner. Furthermore, the strain demonstrated a significant survivability during simulated gastrointestinal transit. Taken together, the E. faecalis AG5 was found potential probiotic candidate with future implication in both food and health industry. PMID- 29427060 TI - Correction to: Cyber Victimization and Internalizing Difficulties: The Mediating Roles of Coping Self-Efficacy and Emotion Dysregulation. AB - The authors would like to note an error in the appendix, as items 13-16 are worded incorrectly in this paper. We apologise sincerely, this was a mistake made when formatting changes occurred. The stem of the question from the previous item was carried forward and not changed in the current item. PMID- 29427059 TI - ArthroPlanner: a surgical planning solution for acromioplasty. AB - PURPOSE: We present a computer-assisted planning solution "ArthroPlanner" for acromioplasty based on 3D anatomical models, computed tomography and joint kinematic simulations. METHODS: In addition to a standard static clinical evaluation (anamnesis, radiological examination), the software provides a dynamic assessment of the shoulder joint by computing in real time the joint kinematics from a database of activities of daily living. During motion, the precise bone resection (location and amount) is computed based on detected subacromial impingements, providing surgeons with precise information about the surgical procedure. Moreover, to improve the subjective reading of medical images, the software provides 3D measurement tools based on anatomical models assisting in the analysis of shoulder morphological features. RESULTS: We performed an in vivo assessment of the software in a prospective randomized clinical study conducted with 27 patients beneficiating from the planning solution and a control group of 31 patients without planning. Postoperatively, patient's pain decreased, and the shoulder range of motion and the functional outcomes improved significantly and the rotator cuff healing rate was good for both groups without intergroup differences. The amount of bone resected at surgery was comparable between the groups. The percentage of remaining impingement after surgery was in average reduced to 51% without groups difference. CONCLUSIONS: ArthroPlanner software includes all required materials (images data, 3D models, motion, morphological measurements, etc.) to improve orthopedists' performance in the surgical planning of acromioplasty. The solution offers a perfect analysis of the patient's anatomy and the ability to precisely analyze a dynamic mechanism to fully apprehend the patient's condition and to fulfill his/her expectations. The study however failed to detect any statistically significant difference in clinical outcomes and bone resection between the groups. Short-term clinical and radiological results were excellent in both groups. PMID- 29427061 TI - Deep coma does not always predict poor outcomes among patients with polytrauma. AB - PURPOSES: This study aimed to clarify the prognosis of polytrauma patients presenting to the emergency department (ED) with a Glasgow Coma Scale score (GCS) of 3. METHODS: A trauma registry system has been established at our institution since 2009. The current study reviewed patients in the registry who presented to the ED with a GCS of 3 from January 2011 to December 2015. Surviving and non surviving patients were compared to identify the prognostic factors of patient survival. The study also aimed to determine the factors contributing to patients who survived with a GCS > 13 at discharge. RESULTS: During the study period, 145 patients were enrolled in the study, 119 of whom (82.1%) did not survive the traumatic insult. Of the 26 survivors, 13 (9.0%) had a GCS of 14 or 15 at discharge. The multiple logistic regression revealed that a lack of bilateral dilated and fixed pupils (BFDP) (OR 5.967, 95% CI 1.780-19.997, p = 0.004) and a GCS > 3 after resuscitation (OR 6.875, 95% CI 2.135-22.138, p = 0.001) were independent prognostic factors of survival. Based on the multiple logistic regression, an age under 40 years (OR 16.405, 95% CI 1.520-177.066, p = 0.021) and a GCS > 3 after resuscitation (OR 12.100, 95% CI 1.058-138.352, p = 0.045) were independent prognostic factors of a GCS > 13 at discharge. CONCLUSION: Aggressive resuscitation still provided benefit to polytrauma patients presenting with a GCS of 3, especially those with a rapid response to the resuscitation. Young patients with a deep coma on arrival had a higher probability of functional recovery after resuscitation in the ED. PMID- 29427062 TI - Identification of new type I interferon-stimulated genes and investigation of their involvement in IFN-beta activation. AB - Virus infection induces the production of type I interferons (IFNs). IFNs bind to their heterodimeric receptors to initiate downstream cascade of signaling, leading to the up-regulation of interferon-stimulated genes (ISGs). ISGs play very important roles in innate immunity through a variety of mechanisms. Although hundreds of ISGs have been identified, it is commonly recognized that more ISGs await to be discovered. The aim of this study was to identify new ISGs and to probe their roles in regulating virus-induced type I IFN production. We used consensus interferon (Con-IFN), an artificial alpha IFN that was shown to be more potent than naturally existing type I IFN, to treat three human immune cell lines, CEM, U937 and Daudi cells. Microarray analysis was employed to identify those genes whose expressions were up-regulated. Six hundred and seventeen genes were up-regulated more than 3-fold. Out of these 617 genes, 138 were not previously reported as ISGs and thus were further pursued. Validation of these 138 genes using quantitative reverse transcription PCR (qRT-PCR) confirmed 91 genes. We screened 89 genes for those involved in Sendai virus (SeV)-induced IFN beta promoter activation, and PIM1 was identified as one whose expression inhibited SeV-mediated IFN-beta activation. We provide evidence indicating that PIM1 specifically inhibits RIG-I- and MDA5-mediated IFN-beta signaling. Our results expand the ISG library and identify PIM1 as an ISG that participates in the regulation of virus-induced type I interferon production. PMID- 29427064 TI - Diagnostic and prognostic value of amyloid PET textural and shape features: comparison with classical semi-quantitative rating in 760 patients from the ADNI 2 database. AB - We evaluated the performance of amyloid PET textural and shape features in discriminating normal and Alzheimer's disease (AD) subjects, and in predicting conversion to AD in subjects with mild cognitive impairment (MCI) or significant memory concern (SMC). Subjects from the Alzheimer's Disease Neuroimaging Initiative with available baseline 18F-florbetapir and T1-MRI scans were included. The cross-sectional cohort consisted of 181 controls and 148 AD subjects. The longitudinal cohort consisted of 431 SMC/MCI subjects, 85 of whom converted to AD during follow-up. PET images were normalized to MNI space and post-processed using in-house software. Relative retention indices (SUVr) were computed with respect to pontine, cerebellar, and composite reference regions. Several textural and shape features were extracted then combined using a support vector machine (SVM) to build a predictive model of AD conversion. Diagnostic and prognostic performance was evaluated using ROC analysis and survival analysis with the Cox proportional hazard model. The three SUVr and all the tested features effectively discriminated AD subjects in cross-sectional analysis (all p < 0.001). In longitudinal analysis, the variables with the highest prognostic value were composite SUVr (AUC 0.86; accuracy 81%), skewness (0.87; 83%), local minima (0.85; 79%), Geary's index (0.86; 81%), gradient norm maximal argument (0.83; 82%), and the SVM model (0.91; 86%). The adjusted hazard ratio for AD conversion was 5.5 for the SVM model, compared with 4.0, 2.6, and 3.8 for cerebellar, pontine and composite SUVr (all p < 0.001), indicating that appropriate amyloid textural and shape features predict conversion to AD with at least as good accuracy as classical SUVr. PMID- 29427063 TI - Functional brain abnormalities in major depressive disorder using the Hilbert Huang transform. AB - Major depressive disorder is a common disease worldwide, which is characterized by significant and persistent depression. Non-invasive accessory diagnosis of depression can be performed by resting-state functional magnetic resonance imaging (rs-fMRI). However, the fMRI signal may not satisfy linearity and stationarity. The Hilbert-Huang transform (HHT) is an adaptive time-frequency localization analysis method suitable for nonlinear and non-stationary signals. The objective of this study was to apply the HHT to rs-fMRI to find the abnormal brain areas of patients with depression. A total of 35 patients with depression and 37 healthy controls were subjected to rs-fMRI. The HHT was performed to extract the Hilbert-weighted mean frequency of the rs-fMRI signals, and multivariate receiver operating characteristic analysis was applied to find the abnormal brain regions with high sensitivity and specificity. We observed differences in Hilbert-weighted mean frequency between the patients and healthy controls mainly in the right hippocampus, right parahippocampal gyrus, left amygdala, and left and right caudate nucleus. Subsequently, the above-mentioned regions were included in the results obtained from the compared region homogeneity and the fractional amplitude of low frequency fluctuation method. We found brain regions with differences in the Hilbert-weighted mean frequency, and examined their sensitivity and specificity, which suggested a potential neuroimaging biomarker to distinguish between patients with depression and healthy controls. We further clarified the pathophysiological abnormality of these regions for the population with major depressive disorder. PMID- 29427066 TI - Ion-neutral Clustering of Bile Acids in Electrospray Ionization Across UPLC Flow Regimes. AB - Bile acid authentic standards were used as model compounds to quantitatively evaluate complex in-source phenomenon on a UPLC-ESI-TOF-MS operated in the negative mode. Three different diameter columns and a ceramic-based microfluidic separation device were utilized, allowing for detailed descriptions of bile acid behavior across a wide range of flow regimes and instantaneous concentrations. A custom processing algorithm based on correlation analysis was developed to group together all ion signals arising from a single compound; these grouped signals produce verified compound spectra for each bile acid at each on-column mass loading. Significant adduction was observed for all bile acids investigated under all flow regimes and across a wide range of bile acid concentrations. The distribution of bile acid containing clusters was found to depend on the specific bile acid species, solvent flow rate, and bile acid concentration. Relative abundancies of each cluster changed non-linearly with concentration. It was found that summing all MS level (low collisional energy) ions and ion-neutral adducts arising from a single compound improves linearity across the concentration range (0.125-5 ng on column) and increases the sensitivity of MS level quantification. The behavior of each cluster roughly follows simple equilibrium processes consistent with our understanding of electrospray ionization mechanisms and ion transport processes occurring in atmospheric pressure interfaces. Graphical Abstract ?. PMID- 29427065 TI - Rice tocopherol deficiency 1 encodes a homogentisate phytyltransferase essential for tocopherol biosynthesis and plant development in rice. AB - KEY MESSAGE: RTD1 encodes a homogentisate phytyltransferase catalyzing a key step in rice tocopherol biosynthesis, confers cold tolerance and regulates rice development by affecting the accumulation of DELLA protein SLENDER RICE1. Tocopherols are one of the most important lipid-soluble antioxidants having indispensable roles in living organisms. The physiological functions of tocopherols have been comprehensively characterized in animals and artificial membranes. However, genetic and molecular functions of tocopherols in plants are less understood. This study aimed to isolate a tocopherol-deficient mutant rtd1 in rice. The rtd1 mutant showed overall growth retardation throughout the growth period. Most of the agronomic traits were impaired in rtd1. Map-based cloning revealed that the RTD1 gene encoded a homogentisate phytyltransferase, a key enzyme catalyzing the committed step in tocopherol biosynthesis. RTD1 was preferentially expressed in green leafy tissues, and the protein was located in chloroplasts. Cold tolerance was found to be reduced in rtd1. The cold-related C repeat-binding factor (CBF)/dehydration-responsive element-binding protein 1 (DREB1) genes were significantly upregulated in rtd1 under natural growth conditions. Moreover, rtd1 exhibited a reduced response to gibberellin (GA).The transcript and protein levels of DELLA protein-coding gene SLENDER RICE 1 (SLR1) in rice was increased in rtd1. However, the GA content was not changed, suggesting a transcriptional, not posttranslational, regulation of SLR1. These findings implied that tocopherols play important roles in regulating rice growth and development. PMID- 29427067 TI - Individual biological sensitivity to environmental influences: testing the differential susceptibility properties of the 5HTTLPR polymorphism in relation to depressive symptoms and delinquency in two adolescent general samples. AB - The gene-environment interaction research field in psychiatry has traditionally been dominated by the diathesis-stress framework, where certain genotypes are assumed to confer increased risk for adverse outcomes in a stressful environment. In later years, theories of differential susceptibility, or biological sensitivity, suggest that candidate genes that interact with environmental events do not exclusively confer a risk for behavioural or psychiatric disorders but rather seem to alter the sensitivity to both positive and negative environmental influences. The present study investigates the susceptibility properties of the serotonin transporter-linked polymorphic region (5HTTLPR) in relation to depressive symptoms and delinquency in two separate adolescent community samples: n = 1457, collected in 2006; and n = 191, collected in 2001. Two-, three-, and four-way interactions between the 5HTTLPR, positive and negative family environment, and sex were found in relation to both depressive symptoms and delinquency. However, the susceptibility properties of the 5HTTLPR were distinctly less pronounced in relation to depressive symptoms. If the assumption that the 5HTTLPR induces differential susceptibility to both positive and negative environmental influences is correct, the previous failures to measure and control for positive environmental factors might be a possible explanation for former inconsistent findings within the research field. PMID- 29427069 TI - New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders. AB - Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R-N-(1,2-dihydroxypropyl) 2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ 11610 (3-30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder. PMID- 29427070 TI - Motivation Among Pre-intermediate Iranian Language Learners: From Explicit Knowledge Toward Implicit Syntactic Development. AB - The variable success in learning a second language (L2) may be best explained by varying degrees of motivation. This study investigated whether individual differences in appraisal dimensions of motivation explained explicit and implicit syntactic knowledge. Participants learned three syntactic structures under implicit and explicit training conditions. They also completed two motivation questionnaires before instruction. Syntactic development was assessed at early and late stages of acquisition. Results indicated superior performance on the tests of explicit knowledge, but a limited effect for the role of motivation in its development. However, with improvement in implicit knowledge at delayed testing, positive relationships emerged with several motivational dimensions. The results support L2 theoretical perspectives that posit different roles for explicit and implicit knowledge at early and late stages of L2 grammar, respectively. The findings also indicate that variation in learners' patterns of stimulus appraisals may contribute to variable success in the development of implicit knowledge. PMID- 29427068 TI - The brain as a "hyper-network": the key role of neural networks as main producers of the integrated brain actions especially via the "broadcasted" neuroconnectomics. AB - Investigations of brain complex integrative actions should consider beside neural networks, glial, extracellular molecular, and fluid channels networks. The present paper proposes that all these networks are assembled into the brain hyper network that has as fundamental components, the tetra-partite synapses, formed by neural, glial, and extracellular molecular networks. Furthermore, peri-synaptic astrocytic processes by modulating the perviousness of extracellular fluid channels control the signals impinging on the tetra-partite synapses. It has also been surmised that global signalling via astrocytes networks and highly pervasive signals, such as electromagnetic fields (EMFs), allow the appropriate integration of the various networks especially at crucial nodes level, the tetra-partite synapses. As a matter of fact, it has been shown that astrocytes can form gap junction-coupled syncytia allowing intercellular communication characterised by a rapid and possibly long-distance transfer of signals. As far as the EMFs are concerned, the concept of broadcasted neuroconnectomics (BNC) has been introduced to describe highly pervasive signals involved in resetting the information handling of brain networks at various miniaturisation levels. In other words, BNC creates, thanks to the EMFs, generated especially by neurons, different assemblages among the various networks forming the brain hyper-network. Thus, it is surmised that neuronal networks are the "core components" of the brain hyper network that has as special "nodes" the multi-facet tetra-partite synapses. Furthermore, it is suggested that investigations on the functional plasticity of multi-partite synapses in response to BNC can be the background for a new understanding and perhaps a new modelling of brain morpho-functional organisation and integrative actions. PMID- 29427071 TI - Response to 'Comment on ''Adjuvant Trastuzumab Therapy for Early HER2-Positive Breast Cancer in Iran: A Cost-Effectiveness and Scenario Analysis for an Optimal Treatment Strategy"'. PMID- 29427072 TI - Cost-Effectiveness Thresholds: the Past, the Present and the Future. AB - Cost-effectiveness (CE) thresholds are being discussed more frequently and there have been many new developments in this area; however, there is a lack of understanding about what thresholds mean and their implications. This paper provides an overview of the CE threshold literature. First, the meaning of a CE threshold and the key assumptions involved (perfect divisibility, marginal increments in budget, etc.) are highlighted using a hypothetical example, and the use of historic/heuristic estimates of the threshold is noted along with their limitations. Recent endeavours to estimate the empirical value of the thresholds, both from the supply side and the demand side, are then presented. The impact on CE thresholds of future directions for the field, such as thresholds across sectors and the incorporation of multiple criteria beyond quality-adjusted life years as a measure of 'value', are highlighted. Finally, a number of common issues and misconceptions associated with CE thresholds are addressed. PMID- 29427073 TI - Dissecting the biochemical architecture and morphological release pathways of the human platelet extracellular vesiculome. AB - Platelet extracellular vesicles (PEVs) have emerged as potential mediators in intercellular communication. PEVs exhibit several activities with pathophysiological importance and may serve as diagnostic biomarkers. Here, imaging and analytical techniques were employed to unveil morphological pathways of the release, structure, composition, and surface properties of PEVs derived from human platelets (PLTs) activated with the thrombin receptor activating peptide (TRAP). Based on extensive electron microscopy analysis, we propose four morphological pathways for PEVs release from TRAP-activated PLTs: (1) plasma membrane budding, (2) extrusion of multivesicular alpha-granules and cytoplasmic vacuoles, (3) plasma membrane blistering and (4) "pearling" of PLT pseudopodia. The PLT extracellular vesiculome encompasses ectosomes, exosomes, free mitochondria, mitochondria-containing vesicles, "podiasomes" and PLT "ghosts". Interestingly, a flow cytometry showed a population of TOM20+LC3+ PEVs, likely products of platelet mitophagy. We found that lipidomic and proteomic profiles were different between the small PEV (S-PEVs; mean diameter 103 nm) and the large vesicle (L-PEVs; mean diameter 350 nm) fractions separated by differential centrifugation. In addition, the majority of PEVs released by activated PLTs was composed of S-PEVs which have markedly higher thrombin generation activity per unit of PEV surface area compared to L-PEVs, and contribute approximately 60% of the PLT vesiculome procoagulant potency. PMID- 29427076 TI - Giant fish-killing water bug reveals ancient and dynamic venom evolution in Heteroptera. AB - True Bugs (Insecta: Heteroptera) produce venom or saliva with diverse bioactivities depending on their feeding strategies. However, little is known about the molecular evolution of the venom toxins underlying these biological activities. We examined venom of the giant fish-killing water bug Lethocerus distinctifemur (Insecta: Belostomatidae) using infrared spectroscopy, transcriptomics, and proteomics. We report 132 venom proteins including putative enzymes, cytolytic toxins, and antimicrobial peptides. Over 73% (96 proteins) showed homology to venom proteins from assassin bugs (Reduviidae), including 21% (28 proteins from seven families) not known from other sources. These data suggest that numerous protein families were recruited into venom and diversified rapidly following the switch from phytophagy to predation by ancestral heteropterans, and then were retained over > 200 my of evolution. In contrast, trophic switches to blood-feeding (e.g. in Triatominae and Cimicidae) or reversions to plant-feeding (e.g., in Pentatomomorpha) were accompanied by rapid changes in the composition of venom/saliva, including the loss of many protein families. PMID- 29427077 TI - Post-translational regulation of the maternal-to-zygotic transition. AB - The maternal-to-zygotic transition (MZT) is essential for the developmental control handed from maternal products to newly synthesized zygotic genome in the earliest stages of embryogenesis, including maternal component (mRNAs and proteins) degradation and zygotic genome activation (ZGA). Various protein post translational modifications have been identified during the MZT, such as phosphorylation, methylation and ubiquitination. Precise post-translational regulation mechanisms are essential for the timely transition of early embryonic development. In this review, we summarize recent progress regarding the molecular mechanisms underlying post-translational regulation of maternal component degradation and ZGA during the MZT and discuss some important issues in the field. PMID- 29427075 TI - Autophagy as a target for glucocorticoid-induced osteoporosis therapy. AB - Autophagy takes part in regulating the eukaryotic cells function and the progression of numerous diseases, but its clinical utility has not been fully developed yet. Recently, mounting evidences highlight an important correlation between autophagy and bone homeostasis, mediated by osteoclasts, osteocytes, bone marrow mesenchymal stem cells, and osteoblasts, and autophagy plays a vital role in the pathogenesis of glucocorticoid-induced osteoporosis (GIOP). The combinations of autophagy activators/inhibitors with anti-GIOP first-line drugs or some new autophagy-based manipulators, such as regulation of B cell lymphoma 2 family proteins and caspase-dependent clearance of autophagy-related gene proteins, are likely to be the promising approaches for GIOP clinical treatments. In view of the important role of autophagy in the pathogenesis of GIOP, here we review the potential mechanisms about the impacts of autophagy in GIOP and its association with GIOP therapy. PMID- 29427078 TI - Perspective: challenges and opportunities for the study of cardiolipin, a key player in bacterial cell structure and function. AB - Cardiolipin (CL) is a key player in bacterial cell biology. CL accumulates at the poles of rod-shaped cells; the polar localization and function of diverse bacterial proteins are CL-dependent. Cardiolipin (CL) is an unusual phospholipid comprised of a glycerol headgroup coupled with two phosphatidate moieties. CL rich membrane domains are often visualized with the fluorescent indicator 10-N nonyl-acridine orange (NAO). Recent data show that NAO can also indicate phosphatidylglycerol localization under different experimental conditions, in the absence of CL. The formation of CL-rich membrane domains at bacterial cell poles was predicted to occur spontaneously, by lipid microphase separation arising from the conical CL shape. New data reveal that membrane-anchored cardiolipin synthase A is targeted to the cytoplasmic membrane surface at bacterial cell poles. Thus, localized CL synthesis, interaction of CL with ClsA, and membrane curvature could all contribute to retention of CL at cell poles. These observations provide new insight regarding the mechanism for assembly of CL-rich membrane domains in prokaryotes and eukaryotes. PMID- 29427074 TI - Lipids in the cell: organisation regulates function. AB - Lipids are fundamental building blocks of all cells and play important roles in the pathogenesis of different diseases, including inflammation, autoimmune disease, cancer, and neurodegeneration. The lipid composition of different organelles can vary substantially from cell to cell, but increasing evidence demonstrates that lipids become organised specifically in each compartment, and this organisation is essential for regulating cell function. For example, lipid microdomains in the plasma membrane, known as lipid rafts, are platforms for concentrating protein receptors and can influence intra-cellular signalling. Lipid organisation is tightly regulated and can be observed across different model organisms, including bacteria, yeast, Drosophila, and Caenorhabditis elegans, suggesting that lipid organisation is evolutionarily conserved. In this review, we summarise the importance and function of specific lipid domains in main cellular organelles and discuss recent advances that investigate how these specific and highly regulated structures contribute to diverse biological processes. PMID- 29427079 TI - Dopamine and response selection: an Acute Phenylalanine/Tyrosine Depletion study. AB - The role of dopaminergic system in decision-making is well documented, and evidence suggests that it could play a significant role in response selection processes. The N-40 is a fronto-central event-related potential, generated by the supplementary motor areas (SMAs) and a physiological index of response selection processes. The aim of the present study was to determine whether infraclinical effects of dopamine depletion on response selection processes could be evidenced via alterations of the N-40. We obtained a dopamine depletion in healthy volunteers with the acute phenylalanine and tyrosine depletion (APTD) method which consists in decreasing the availability of dopamine precursors. Subjects realized a Simon task in the APTD condition and in the control condition. When the stimulus was presented on the same side as the required response, the stimulus-response association was congruent and when the stimulus was presented on the opposite side of the required response, the stimulus-response association was incongruent. The N-40 was smaller for congruent associations than for incongruent associations. Moreover, the N-40 was sensitive to the level of dopaminergic activity with a decrease in APTD condition compared to control condition. This modulation of the N-40 by dopaminergic level could not be explained by a global decrease of cerebral electrogenesis, since negativities and positivities indexing the recruitment of the primary motor cortex (anatomically adjacent to the SMA) were unaffected by APTD. The specific sensitivity of N-40 to ATPD supports the model of Keeler et al. (Neuroscience 282:156-175, 2014) according to which the dopaminergic system is involved in response selection. PMID- 29427080 TI - Amphetamine primes enhanced motivation toward uncertain choices in rats with genetic alcohol preference. AB - RATIONALE: Comorbidity with gambling disorder (GD) and alcohol use disorder (AUD) is well documented. OBJECTIVE: The purpose of our study was to examine the influence of genetic alcohol drinking tendency on reward-guided decision making behavior of rats and the impact of dopamine releaser D-amphetamine on this behavior. METHODS: In this study, Alko alcohol (AA) and Wistar rats went through long periods of operant lever pressing training where the task was to choose the profitable of two options. The lever choices were guided by different-sized sucrose rewards (one or three pellets), and the probability of gaining the larger reward was slowly changed to a level where choosing the smaller reward would be the most profitable in the long run. After training, rats were injected (s.c.) with dopamine releaser D-amphetamine (0.3, 1.0 mg/kg) to study the impact of rapid dopamine release on this learned decision making behavior. RESULTS: Administration of D-amphetamine promoted unprofitable decision making of AA rats more robustly when compared to Wistar rats. At the same time, D-amphetamine reduced lever pressing responses. Interestingly, we found that this reduction in lever pressing was significantly greater in Wistar rats than in AA rats and it was not linked to motivation to consume sucrose. CONCLUSIONS: Our results indicate that conditioning to the lever pressing in uncertain environments is more pronounced in AA than in Wistar rats and indicate that the reinforcing effects of a gambling-like environment act as a stronger conditioning factor for rats that exhibit a genetic tendency for high alcohol drinking. PMID- 29427082 TI - Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node. AB - A better understanding of antitumor immune responses is the key to advancing the field of cancer immunotherapy. Endogenous immunity in cancer patients, such as circulating anticancer antibodies or tumor-reactive B cells, has been historically yet incompletely described. Here, we demonstrate that tumor-draining (sentinel) lymph node (SN) is a rich source for tumor-reactive B cells that give rise to systemic IgG anticancer antibodies circulating in the bloodstream of breast cancer patients. Using a synergistic combination of high-throughput B-cell sequencing and quantitative immunoproteomics, we describe the prospective identification of tumor-reactive SN B cells (based on clonal frequency) and also demonstrate an unequivocal link between affinity-matured expanded B-cell clones in the SN and antitumor IgG in the blood. This technology could facilitate the discovery of antitumor antibody therapeutics and conceivably identify novel tumor antigens. Lastly, these findings highlight the unique and specialized niche the SN can fill in the advancement of cancer immunotherapy. PMID- 29427081 TI - Effects of tolcapone and bromocriptine on cognitive stability and flexibility. AB - RATIONALE: The prefrontal cortex (PFC) and basal ganglia (BG) have been associated with cognitive stability and cognitive flexibility, respectively. We hypothesized that increasing PFC dopamine tone by administering tolcapone (a catechol-O-methyltransferase (COMT) inhibitor) to human subjects should promote stability; conversely, increasing BG dopamine tone by administering bromocriptine (a D2 receptor agonist) should promote flexibility. OBJECTIVE: We assessed these hypotheses by administering tolcapone, bromocriptine, and a placebo to healthy subjects who performed a saccadic eye movement task requiring stability and flexibility. METHODS: We used a randomized, double-blind, within-subject design that was counterbalanced across drug administration sessions. In each session, subjects were cued to prepare for a pro-saccade (look towards a visual stimulus) or anti-saccade (look away) on every trial. On 60% of the trials, subjects were instructed to switch the response already in preparation. We hypothesized that flexibility would be required on switch trials, whereas stability would be required on non-switch trials. The primary measure of performance was efficiency (the percentage correct divided by reaction time for each trial type). RESULTS: Subjects were significantly less efficient across all trial types under tolcapone, and there were no significant effects of bromocriptine. After grouping subjects based on Val158Met COMT polymorphism, we found that Met/Met and Val/Met subjects (greater PFC dopamine) were less efficient compared to Val/Val subjects. CONCLUSIONS: Optimal behavior was based on obeying the environmental stimuli, and we found reduced efficiency with greater PFC dopamine tone. We suggest that greater PFC dopamine interfered with the ability to flexibly follow the environment. PMID- 29427083 TI - Fluoxetine Inhibits Natural Decay of Long-Term Memory via Akt/GSK-3beta Signaling. AB - Understanding the mechanisms underlying the natural decay of long-term memory can help us find means of extending the duration of long-term memory. However, the neurobiological processes involved in the decay of long-term memory are poorly understood. In the present study, we examined the effect of acute and chronic treatment of fluoxetine on natural decay of long-term memory and the possible mechanism. Late administration of fluoxetine prolonged the persistence of long term memory in mice, as demonstrated by object location recognition and Barnes maze tests. Fluoxetine altered Akt/glycogen synthase kinase-3beta (GSK 3beta)/beta-catenin signaling in the hippocampus. Late short- and long-term pharmacological inhibition of GSK-3beta mimicked the effect of fluoxetine on memory persistence. Pharmacological inhibition of Akt blocked the effect of fluoxetine on memory persistence. Finally, late infusion of fluoxetine increased hippocampal long-term potentiation (LTP) and pharmacological inhibition of GSK 3beta blocked the natural decline in LTP. These results demonstrate that GSK 3beta might be a key molecule in memory decay process, and fluoxetine extends the period of long-term memory maintenance via Akt/GSK-3beta signaling. PMID- 29427084 TI - Rosmarinic Acid Mitigates Mitochondrial Dysfunction and Spinal Glial Activation in Oxaliplatin-induced Peripheral Neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting complication which develops as a consequence of treatment with chemotherapeutic agents like oxaliplatin and is a mainstay of therapy for colorectal cancer. Ever since CIPN was identified, understanding its exact pathomechanisms remains a clinical challenge. The role of mitochondrial dysfunction and glial cell activation has surfaced in the etiology of CIPN. Rosmarinic acid (RA), a known mitoprotectant exerts neuroprotection against the oxidative stress and neuroinflammation in various disease conditions. Hence, in the present study, we investigated the effect using rosmarinic acid (25 and 50 mg/kg, po) in the experimental model of oxaliplatin-induced peripheral neuropathy (OIPN) in rats. Results showed that RA significantly (p < 0.001) prevented the functional deficits, reversed oxaliplatin induced mechanical allodynia and cold hyperalgesia in rats. It reduced the oxidative stress, improved the mitochondrial function, and prevented the oxaliplatin-induced loss of ATP levels. RA significantly (p < 0.01) inhibited the spinal glial cell activation and suppressed the expression of inflammatory markers. RA treatment also resulted in the activation of adenosine monophosphate activated protein kinase (AMPK) in the peripheral nerves and dorsal root ganglion (DRG) which also might have contributed to its neuroprotective actions. In vitro screening also revealed that RA did not compromise the anti-cancer activity of oxaliplatin in colon cancer cells (HT-29). Taken together, the above results demonstrate the therapeutic activity of RA against the oxaliplatin-induced mitochondrial dysfunction and neuroinflammation and thus, suggest its potential for the management of OIPN. Graphical Abstract Schematic representation of neuroprotective mechanisms of rosmarinic acid via AMPK activation in oxaliplatin evoked peripheral neuropathy. PMID- 29427085 TI - Regulatory Effects of Neuroinflammatory Responses Through Brain-Derived Neurotrophic Factor Signaling in Microglial Cells. AB - Inhibition of microglial over-activation is an important strategy to counter balance neurodegenerative progression. We previously demonstrated that the adenosine monophosphate-activated protein kinase (AMPK) may be a therapeutic target in mediating anti-neuroinflammatory responses in microglia. Brain-derived neurotrophic factor (BDNF) is one of the major neurotrophic factors produced by astrocytes to maintain the development and survival of neurons in the brain, and have recently been shown to modulate homeostasis of neuroinflammation. Therefore, the present study focused on BDNF-mediated neuroinflammatory responses and may provide an endogenous regulation of neuroinflammation. Among the tested neuroinflammation, epigallocatechin gallate (EGCG) and minocycline exerted BDNF upregulation to inhibit COX-2 and proinflammatory mediator expressions. Furthermore, both EGCG and minocycline upregulated BDNF expression in microglia through AMPK signaling. In addition, minocycline and EGCG also increased expressions of erythropoietin (EPO) and sonic hedgehog (Shh). In the endogenous modulation of neuroinflammation, astrocyte-conditioned medium (AgCM) also decreased the expression of COX-2 and upregulated BDNF expression in microglia. The anti-inflammatory effects of BDNF were mediated through EPO/Shh in microglia. Our results indicated that the BDNF-EPO-Shh novel-signaling pathway underlies the regulation of inflammatory responses and may be regarded as a potential therapeutic target in neurodegenerative diseases. This study also reveals a better understanding of an endogenous crosstalk between astrocytes and microglia to regulate anti-inflammatory actions, which could provide a novel strategy for the treatment of neuroinflammation and neurodegenerative diseases. PMID- 29427086 TI - Brain Metabolic DNA in Rat Cytoplasm. AB - Brain metabolic DNA (BMD) is not involved in cell division or DNA repair but is modulated by memory acquisition, sleep processing, and circadian oscillations. Using routine methods of subcellular fractionation, newly synthesized BMD from male rats is shown to be localized in crude nuclear, mitochondrial, and microsomal fractions and in two fractions of purified nuclei. Sub-fractionation of the mitochondrial fraction indicates the prevalent localization of BMD in free mitochondria and to a lesser degree in synaptosomes and myelin. Cesium density profiles of homogenate, subcellular fractions, and purified nuclei obtained after incorporation periods from 30 min to 4 h indicate that BMD synthesis takes place by reverse transcription in cytoplasmic organelles. Following the acquisition of the double-stranded structure, BMD is transferred to nuclei. Kinetic analyses lasting several weeks highlight the massive BMD turnover in subcellular fractions and purified nuclei and its dependence on age. Data are in agreement with the role of BMD as a temporary information store of cell responses of potential use in comparable forthcoming experiences. PMID- 29427087 TI - Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells. AB - Neuroinflammation is consistently found in many neurological disorders, but whether or not the inflammatory response independently affects neuronal network properties is poorly understood. Here, we report that intracerebroventricular injection of the prototypical inflammatory molecule lipopolysaccharide (LPS) in rats triggered a strong and long-lasting inflammatory response in hippocampal microglia associated with a concomitant upregulation of Toll-like receptor (TLR4) in pyramidal and hilar neurons. This, in turn, was associated with a significant reduction of the dendritic hyperpolarization-activated cyclic AMP-gated channel type 1 (HCN1) protein level while Kv4.2 channels were unaltered as assessed by western blot. Immunohistochemistry confirmed the HCN1 decrease in CA1 pyramidal neurons and showed that these changes were associated with a reduction of TRIP8b, an auxiliary subunit for HCN channels implicated in channel subcellular localization and trafficking. At the physiological level, this effect translated into a 50% decrease in HCN1-mediated currents (Ih) measured in the distal dendrites of hippocampal CA1 pyramidal cells. At the functional level, the band pass-filtering properties of dendrites in the theta frequency range (4-12 Hz) and their temporal summation properties were compromised. We conclude that neuroinflammation can independently trigger an acquired channelopathy in CA1 pyramidal cell dendrites that alters their integrative properties. By directly changing cellular function, this phenomenon may participate in the phenotypic expression of various brain diseases. PMID- 29427089 TI - XBP1 and PERK Have Distinct Roles in Abeta-Induced Pathology. AB - Endoplasmic reticulum (ER) stress triggers multiple cellular signals to restore cellular function or induce proapoptosis that is altered in the brains of patients with Alzheimer's disease (AD). However, the role of ER stress in beta amyloid (Abeta)-induced AD pathology remains elusive, and data obtained from different animal models and under different experimental conditions are sometimes controversial. The current study conducted in vivo genetic experiments to systematically examine the distinct role of each ER stress effector during disease progression. Our results indicated that inositol-requiring enzyme 1 was activated before protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation in Abeta42 transgenic flies. Proteasome activity played a key role in this sequential activation. Furthermore, our study separated learning deficits from early degeneration in Abeta-induced impairment by demonstrating that X-box binding protein 1 overexpression at an early stage reversed Abeta-induced early death without affecting learning performance in the Abeta42 transgenic flies. PERK activation was determined to only enhance Abeta-induced learning deficits. Moreover, proteasome overactivation was determined to delay PERK activation and improve learning deficits. Altogether, the findings of this study demonstrate the complex roles of ER stress during Abeta pathogenesis and the possibility of using different ER stress effectors as reporters to indicate the status of disease progression. PMID- 29427090 TI - Extracellular red Monascus pigment-mediated rapid one-step synthesis of silver nanoparticles and its application in biomedical and environment. AB - The development of a safe and eco-friendly method for metal nanoparticle synthesis has an increasing demand, due to emerging environmental and biological harms of hazardous chemicals used in existing nanosynthesis methods. The present investigation reports a rapid one-step, eco-friendly and green approach for the formation of nanosized silver particles (AgNPs) using extracellular non-toxic colored fungal metabolites (Monascus pigments-MPs). The formation of nanosized silver particles utilizing Monascus pigments was confirmed after exposure of reaction mixture to sunlight, by visually color change and further established by spectrophotometric analysis. The size, shape, and topography of synthesized MPs AgNPs were well-defined using different microscopic and spectroscopic techniques, i.e., FE-SEM, HR-TEM, and DLS. The average size of MPs-AgNPs was found to be 10 40 nm with a spherical shape which was highly stable and dispersed in the solution. HR-TEM and XRD confirmed crystalline nature of MPs-AgNPs. The biocidal potential of MPs-AgNPs was evaluated against three bacterial pathogens such as Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus and it was observed that the MPs-AgNPs significantly inhibited the growth of all three bacterial pathogens. The anti-biofilm activity of MPs-AgNPs was recorded against antibiotic-resistant P. aeruginosa. Besides, the colorimetric metal sensing using MPs-AgNPs was studied. Among the metals tested, the selective Hg2+-sensing potential at micromolar concentration was observed. In conclusion, this is the rapid one-step (within 12-15 min), environment-friendly method for synthesis of AgNPs and synthesized MPs-AgNPs could be used as a potential antibacterial agent against antibiotic-resistant bacterial pathogens. PMID- 29427088 TI - Effect of Resveratrol on Oxidative Stress and Mitochondrial Dysfunction in Immature Brain during Epileptogenesis. AB - The presence of oxidative stress in immature brain has been demonstrated during the acute phase of status epilepticus (SE). The knowledge regarding the long periods of survival after SE is not unequivocal, lacking direct evidence. To examine the presence and time profile of oxidative stress, its functional effect on mitochondria and the influence of an antioxidant treatment in immature rats during epileptogenesis, status epilepticus (SE) was induced in immature 12-day old rats by Li-pilocarpine and at selected periods of the epileptogenesis; rat pups were subjected to examinations. Hydroethidine method was employed for detection of superoxide anion (O2.-), 3-nitrotyrosine (3-NT), and 4 hydroxynonenal (4-HNE) for oxidative damage of mitochondrial proteins and complex I activity for mitochondrial function. Natural polyphenolic antioxidant resveratrol was given in two schemes: "acute treatment," i.p. administration 30 min before, 30 and 60 min after induction of SE and "full treatment" when applications continued once daily for seven consecutive days (25 mg/kg each dose). The obtained results clearly document that the period of epileptogenesis studied (up to 4 weeks) in immature brain is associated with the significant enhanced production of O2.-, the increased levels of 3-NT and 4-HNE and the persisting deficiency of complex I activity. Application of resveratrol either completely prevented or significantly reduced markers both of oxidative stress and mitochondrial dysfunction. The findings suggest that targeting oxidative stress in combination with current antiepileptic therapies may provide a benefit in the treatment of epilepsy. PMID- 29427091 TI - Current clinical and bacteriological profile of septic arthritis in young infants: a prospective study from a tertiary referral centre. AB - PURPOSE: The study was carried out to evaluate the clinical and bacteriological profile of SA in young infants (age <= 3 months) in a tertiary referral centre and to assess the risk factors and to document the changing trends in the epidemiology. METHODS: This was a prospective descriptive study on all young infants with SA. Clinical and perinatal history, examination, radiological and laboratory findings (blood count, ESR, CRP, blood and joint cultures) were studied. Emergency arthrotomy was done and antibiotics were administered in all patients. RESULT: Thirty young infants were included with a mean age of 22 +/- 13.6 days and with male-to-female ratio 1.5:1. Pseudoparalysis and pain were the most common presenting symptoms. Knee joint was most commonly involved followed by hip. Ultrasound of the joint (86%) and elevated CRP levels (97%) were found to be reliable diagnostic markers. Most common causative organism was methicillin resistant Staphylococcus aureus (43.3%) followed by Klebsiella pneumonia (23%). Sensitivity to empirical antibiotic regimen was lower (ceftriaxone 53%, amoxicillin 35%) when compared to higher antibiotics (gentamycin 88%, vancomycin 100%). Prematurity (57%), low birthweight (73%), anaemia (80%), previous history of hospitalisation (93%) and invasive procedures (90%) were found to be important risk factors. CONCLUSION: The disease has distinct regional variations, and the epidemiological and bacterial profile is constantly changing. There is a shift in causative organisms towards more resistant and gram-negative species. Prematurity, low birthweight and previous hospitalisation are the major predisposing factors. A better understanding of the varied presentations is necessary for an early diagnosis and treatment, which is the most important prognostic factor. PMID- 29427092 TI - Treatment of tibial nonunion with bone defect using a heterotopic ossification as autologous bone graft: literature overview and case report. AB - INTRODUCTION: Nonunion after open fracture of the lower leg is a frequent complication with a prevalence of up to 40%. In cases with major bone defects, revision of the osteosynthesis with bone grafting is commonly performed. Until today, there is no report on treatment of a tibial nonunion with transplantation of a heterotopic ossification. PRESENTATION OF CASE: We present a case of a 27 year-old male patient, who suffered from a paragliding accident with major injuries. An open fracture of the lower leg (Gustilo-Anderson IIIB) was initially treated with external fixation and vacuum-assisted closure, followed by reamed intramedullary nailing. The tibia resulted in a bone defect situation with nonunion. It was successfully treated with revision, fibular osteotomy and transplantation of a heterotopic ossification, harvested from the ipsilateral hip. CONCLUSION: In special cases, autologous transplantation of a mature heterotopic ossification is an attractive bone graft option in treating nonunion defects. PMID- 29427093 TI - Comparison between locked and unlocked intramedullary nails in intertrochanteric fractures. AB - BACKGROUND: Intertrochanteric fractures are of great interest worldwide and are the most frequently operated fractures. Intramedullary nailing is commonly used in the treatment of intertrochanteric fractures. The purpose of this study is to assess the necessity of using the distal blocking screw in 31-A1 and 31-A2 fractures, classified according to the Orthopaedic Trauma Association classification system (AO/OTA). METHODS: This is a prospective study of 143 consecutive patients (mean age 85.01 years, mean final follow-up 14.1 months) surgically treated with the same intramedullary nail. In 75 cases, the distal locking screw was not used. Parameters evaluated during follow-up were: blood loss, transfusion requirements, surgery duration, and fluoroscopy time. Harris Hip Score and Barthel Activity Daily Living were used for the clinical evaluation. Radiographic Union Score For Hip (RUSH score) and Tip apex distance (TAD) were measured for radiologic evaluation. RESULTS: The group treated without locking screw showed significantly shorter surgical duration time (31.9 vs. 47.2 min), a decrease in blood loss (variation Hb - 1.06 vs. - 1.97), and reduced X rays exposure time (25.4 vs. 31.6 s). No significant differences were observed in the postoperative period and in the radiographic and clinical scores. CONCLUSION: This study demonstrates that in intertrochanteric 31-A1 and 31-A2 stable fractures, the absence of distal locking screw does not compromise bone healing and prevents several clinical complications. PMID- 29427095 TI - Rifampicin-Induced Fever in a Patient with Brucellosis: A Case Report. AB - We present a 35-year-old female patient who was started on rifampicin (900 mg orally once daily) and trimethoprim/sulfamethoxazole (TMP/SMX) (160/800 mg orally twice daily) after being diagnosed with brucellosis. Following defervescence and improvement in her general condition, fever recurred on the 12th day of treatment. A re-challenge drug test lead to causality assessment and treatment was switched to a combination of streptomycin (1 g intramuscularly) for 10 days and TMP/SMX (160/800 mg orally twice daily) for 4 weeks. Our patient is doing well after 12 months of follow-up. PMID- 29427094 TI - Hemicorporectomy as a life-saving strategy for severe pelvic ring crush injury: a case report. AB - Hemicorporectomy is an ultra-radical surgery used only in extreme circumstances. Initially used for advanced pelvic neoplastic diseases and intractable pelvic infection, it may also be the only treatment option in patients with crushed pelvic trauma, in cases there are no reconstruction options. This procedure has a high mortality, and its success depends on the multidisciplinary approach, both in the initial phase and in the rehabilitation process. We present the case of a young patient with severe pelvic trauma that required a hemicorporectomy as the only treatment option and review of the literature. PMID- 29427096 TI - Clinical Features of Huntington's Disease. AB - Huntington's disease (HD) is the most common monogenic neurodegenerative disease and the commonest genetic dementia in the developed world. With autosomal dominant inheritance, typically mid-life onset, and unrelenting progressive motor, cognitive and psychiatric symptoms over 15-20 years, its impact on patients and their families is devastating. The causative genetic mutation is an expanded CAG trinucleotide repeat in the gene encoding the Huntingtin protein, which leads to a prolonged polyglutamine stretch at the N-terminus of the protein. Since the discovery of the gene over 20 years ago much progress has been made in HD research, and although there are currently no disease-modifying treatments available, there are a number of exciting potential therapeutic developments in the pipeline. In this chapter we discuss the epidemiology, genetics and pathogenesis of HD as well as the clinical presentation and management of HD, which is currently focused on symptomatic treatment. The principles of genetic testing for HD are also explained. Recent developments in therapeutics research, including gene silencing and targeted small molecule approaches are also discussed, as well as the search for HD biomarkers that will assist the validation of these potentially new treatments. PMID- 29427097 TI - Genetic Rodent Models of Huntington Disease. AB - The monogenic nature of Huntington disease (HD) has led to the development of a spectrum of useful genetically modified models. In particular, rodents have pioneered as the first HD model being generated and have since been the most widely used animal model for HD in both basic research and preclinical therapeutic studies. Based on the generation strategies, these rodent models can be classified into 3 major groups, the transgenic fragment models, the transgenic full-length models and the knock-in models. These models display a range of HD like characteristics which resemble the clinical symptoms of HD patients. Their applications in research are thus regarded as an invaluable approach to speeding up the unraveling of the underlying pathological mechanisms of HD and for finding a disease-modifying treatment for this devastating disease. In this chapter, the similarities and differences of the most commonly used rodent HD models and their relevance to human HD will be compared and discussed. This also serves to guide the selection of an appropriate rodent HD model according to the nature of investigation. PMID- 29427098 TI - Mitochondrial Dysfunction in Huntington's Disease. AB - Mitochondrial dysfunction has been described as an early pathological mechanism delineating the selective neurodegeneration that occurs in Huntington's disease (HD), a polyglutamine-expansion disorder that largely affects the striatum and the cerebral cortex. Over the years, mitochondria roles in eukaryotic cells (e.g. in neurons) have largely diverged from the classically attributed cell power source; indeed, mitochondria not only contribute for synthesis of several metabolites, but are also dynamic organelles that fragment and fuse to achieve a maximal bioenergetic performance, are transported along microtubules, regulate intracellular calcium homeostasis through the interaction with the endoplasmic reticulum, produce free radicals and participate in cell death processes. Indeed, most of these activities have been demonstrated to be affected in HD, potentially contributing for the neuronal dysfunction in pre-symptomatic stages. This chapter resumes some of the evidences that pose mitochondria as a main regulatory organelle in HD-affected neurons, uncovering some potentially therapeutic mitochondrial-based relevant targets. PMID- 29427099 TI - RNA Related Pathology in Huntington's Disease. AB - This chapter summarises research investigating the expression of huntingtin sense and anti-sense transcripts, the effect of the mutation on huntingtin processing as well as the more global effect of the mutation on the coding and non-coding transcriptomes. The huntingtin gene is ubiquitously expressed, although expression levels vary between tissues and cell types. A SNP that affects NF-KB binding in the huntingtin promoter modulates the expression level of huntingtin transcripts and is associated with the age of disease onset. Incomplete splicing between exon 1 and exon 2 has been shown to result in the expression of a small polyadenylated mRNA that encodes the highly pathogenic exon 1 huntingtin protein. This occurs in a CAG-repeat length dependent manner in all full-length mouse models of HD as well as HD patient post-mortem brains and fibroblasts. An antisense transcript to huntingtin is generated that contains a CUG repeat that is expanded in HD patients. In myotonic dystrophy, expanded CUG repeats form RNA foci in cell nuclei that bind specific proteins (e.g. MBL1). Short, pure CAG RNAs of approximately 21 nucleotides that have been processed by DICER can inhibit the translation of other CAG repeat containing mRNAs. The HD mutation affects the transcriptome at the level of mRNA expression, splicing and the expression of non coding RNAs. Finally, expanded repetitive stretched of nucleotides can lead to RAN translation, in which the ribosome translates from the expanded repeat in all possible reading frames, producing proteins with various poly-amino acid tracts. The extent to which these events contribute to HD pathogenesis is largely unknown. PMID- 29427100 TI - X-Linked Spinal and Bulbar Muscular Atrophy: From Clinical Genetic Features and Molecular Pathology to Mechanisms Underlying Disease Toxicity. AB - Spinal and Bulbar Muscular Atrophy (SBMA) is an inherited neuromuscular disorder caused by a CAG-polyglutamine (polyQ) repeat expansion in the androgen receptor (AR) gene. Unlike other polyQ diseases, where the function of the native causative protein is unknown, the biology of AR is well understood, and this knowledge has informed our understanding of how native AR function interfaces with polyQ-AR dysfunction. Furthermore, ligand-dependent activation of AR has been linked to SBMA disease pathogenesis, and has led to a thorough study of androgen-mediated effects on polyQ-AR stability, degradation, and post translational modifications, as well as their roles in the disease process. Transcriptional dysregulation, proteostasis dysfunction, and mitochondrial abnormalities are central to polyQ-AR neurotoxicity, most likely via a 'change-of function' mechanism. Intriguingly, recent work has demonstrated a principal role for skeletal muscle in SBMA disease pathogenesis, indicating that polyQ-AR toxicity initiates in skeletal muscle and results in secondary motor neuron demise. The existence of robust animal models for SBMA has permitted a variety of preclinical trials, driven by recent discoveries of altered cellular processes, and some of this preclinical work has led to human clinical trials. In this chapter, we review SBMA clinical features and disease biology, discuss our current understanding of the cellular and molecular basis of SBMA pathogenesis, and highlight ongoing efforts toward therapy development. PMID- 29427101 TI - Spinocerebellar Ataxia Type 1: Molecular Mechanisms of Neurodegeneration and Preclinical Studies. AB - Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, inherited disease that leads to degeneration of Purkinje cells of the cerebellum and culminates in death 10-30 years after disease onset. SCA1 is caused by a CAG repeat mutation in the ATXN1 gene, encoding the ATXN1 protein with an abnormally expanded polyglutamine tract. As neurodegeneration progresses, other brain regions become involved and contribute to cognitive deficits as well as problems with speech, swallowing, and control of breathing. The fundamental basis of pathology is an aberration in the normal function of Purkinje cells affecting regulation of gene transcription and RNA splicing. Glutamine-expanded ATXN1 is highly stable and more resistant to degradation. Moreover, phosphorylation at S776 in ATXN1 is a post-translational modification known to influence protein levels. SCA1 remains an untreatable disease managed only by palliative care. Preclinical studies are founded on the principle that mutant protein load is toxic and attenuating ATXN1 protein levels can alleviate disease. Two approaches being pursued are targeting gene expression or protein levels. Viral delivery of miRNAs harnesses the RNAi pathway to destroy ATXN1 mRNA. This approach shows promise in mouse models of disease. At the protein level, kinase inhibitors that block ATXN1-S776 phosphorylation may lead to therapeutic clearance of unphosphorylated ATXN1. PMID- 29427102 TI - Spinocerebellar [corrected] Ataxia Type 6: Molecular Mechanisms and Calcium Channel Genetics. AB - Spinocerebellar ataxia (SCA) type 6 is an autosomal dominant disease affecting cerebellar degeneration. Clinically, it is characterized by pure cerebellar dysfunction, slowly progressive unsteadiness of gait and stance, slurred speech, and abnormal eye movements with late onset. Pathological findings of SCA6 include a diffuse loss of Purkinje cells, predominantly in the cerebellar vermis. Genetically, SCA6 is caused by expansion of a trinucleotide CAG repeat in the last exon of longest isoform CACNA1A gene on chromosome 19p13.1-p13.2. Normal alleles have 4-18 repeats, while alleles causing disease contain 19-33 repeats. Due to presence of a novel internal ribosomal entry site (IRES) with the mRNA, CACNA1A encodes two structurally unrelated proteins with distinct functions within an overlapping open reading frame (ORF) of the same mRNA: (1) alpha1A subunit of P/Q-type voltage gated calcium channel; (2) alpha1ACT, a newly recognized transcription factor, with polyglutamine repeat at C-terminal end. Understanding the function of alpha1ACT in physiological and pathological conditions may elucidate the pathogenesis of SCA6. More importantly, the IRES, as the translational control element of alpha1ACT, provides a potential therapeutic target for the treatment of SCA6. PMID- 29427103 TI - Spinocerebellar Ataxia Type 2. AB - Spinocerebellar ataxia type 2 (SCA2) is autosomal dominantly inherited and caused by CAG repeat expansion in the ATXN2 gene. Because the CAG repeat expansion is localized to an encoded region of ATXN2, the result is an expanded polyglutamine (polyQ) tract in the ATXN2 protein. SCA2 is characterized by progressive ataxia, and slow saccades. No treatment for SCA2 exists. ATXN2 mutation causes gains of new or toxic functions for the ATXN2 protein, resulting in abnormally slow Purkinje cell (PC) firing frequency and ultimately PC loss. This chapter describes the characteristics of SCA2 patients briefly, and reviews ATXN2 molecular features and progress toward the identification of a treatment for SCA2. PMID- 29427104 TI - Molecular Mechanisms and Therapeutic Strategies in Spinocerebellar Ataxia Type 7. AB - Spinocerebellar Ataxia type 7 (SCA7, OMIM # 164500) is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive cerebellar ataxia and blindness. SCA7 is part of the large family of autosomal dominant cerebellar ataxias (ADCAs), and was estimated to account for 1-11.7% of ADCAs in diverse populations. The frequency of SCA7 is higher where local founder effects were observed as in Scandinavia, Korea, South Africa and Mexico. SCA7 is pathomechanistically related to the group of CAG/polyglutamine (polyQ) expansion disorders, which includes other SCAs (1-3, 6 and 17), Huntington's disease, spinal bulbar muscular atrophy and dentatorubro pallidoluysian atrophy. Two distinctive characteristics of SCA7 are the strong anticipation by which earlier onset and more severe symptoms are observed in successive generations of affected families, and the loss of visual acuity due to cone-rod dystrophy of the retina. The pathology is caused by an unstable CAG repeat expansion coding for a polyQ stretch in Ataxin-7 (ATXN7). PolyQ expansion in ATXN7 confers toxic properties and leads to selective neuronal degeneration in the cerebellum, the brain stem and the retina. Herein, we summarize the genetic, clinical and pathological features of SCA7 and review our current knowledge of pathomechanisms and preclinical studies. PMID- 29427105 TI - Spinocerebellar Ataxia Type 17 (SCA17). AB - In 1999, a polyglutamine expansion was identified in the transcription factor TATA-binding protein (TBP) in a patient with ataxia with negative family history. Subsequently, CAG/CAA repeat expansions in the TBP gene were identified in families with spinocerebellar ataxia (SCA), establishing this repeat expansion as the underlying mutation in SCA type 17 (SCA17). There are several characteristic differences between SCA17 and other polyglutamine diseases. First, SCA17 shows a complex and variable clinical phenotype, in some cases overlapping that of Huntington's disease. Second, compared to the other SCA subtypes caused by expanded trinucleotide repeats, anticipation in SCA17 kindreds is rare because of the characteristic structure of the TBP gene. And thirdly, SCA17 patients often have diagnostic problems that may arise from non-penetrance. Because the gap between normal and abnormal repeat numbers is very narrow, it is difficult to determine a cutoff value for pathologic CAG repeat number in SCA17. Herein, we review the clinical, genetic and pathologic features of SCA17. PMID- 29427106 TI - The Neuropathology of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease. AB - Spinocerebellar ataxia type 3 (SCA-3)/Machado-Joseph disease (MJD), the most common autosomal dominant ataxia, affects many regions of the brain and spinal cord. Similar to SCA-1, SCA-2, SCA-6, SCA-7, and SCA-17, the mutation consists of a pathogenic translated cytosine-adenine-guanine (CAG) trinucleotide repeat expansion. Almost invariably, the substantia nigra and the dentate nucleus of the cerebellum bear the brunt of the disease, and these lesions account for the Parkinsonian and ataxic phenotypes. Lesions of motor nuclei in the brain stem cause the complex disturbance of ocular motility and weakness of the tongue. Atrophy of the basis pontis is common, and polyglutamine-positive neuronal intranuclear inclusion bodies are most readily found in the pontine gray. Abnormalities of basal ganglia, thalamus, spinal cord, dorsal root ganglia, and sensory peripheral nerves are more variable. This report of the main neuropathological lesions is based on the study of 12 genetically confirmed autopsy cases of SCA-3/MJD. In the cerebellum, all layers of the cortex remain normal, but the dentate nucleus exhibits neuronal loss and a peculiar proliferation of synaptic terminals termed grumose regeneration. The clusters surrounding residual neuronal cell bodies and dendrites are interpreted as a response to loss of gamma-aminobutyric acid (GABA)-A-receptors and lack of gephyrin, a protein that accomplishes the proper positioning of GABA-A- and glycine receptors. At the spinal level, dorsal root ganglia reveal proliferation of satellite cells, active neuronal destruction, and residual nodules. The spinal cord shows total or subtotal loss of neurons in the dorsal nuclei, anterior horn cell atrophy, and variable long tract degeneration. While misfolding of ataxin-3 due to overly long polyglutamine stretches is a critical contributor to the pathogenesis of SCA-3/MJD, the great neuropathological complexity of the disorder remains largely unexplained. PMID- 29427107 TI - Origins and Spread of Machado-Joseph Disease Ancestral Mutations Events. AB - Machado-Joseph disease (MJD) is the most common autosomal dominant spinocerebellar ataxia reported worldwide, but it shows marked geographic differences in prevalence. The study of ancestral origins and spreading routes of MJD mutational events has contributed to explain such differences. During human evolution, at least two independent de novo MJD expansions occurred in distinct haplotype backgrounds: TTACAC and GTGGCA (named Joseph and Machado lineages). The most ancient Joseph lineage, probably of Asian origin, has been introduced recently in Europe, where founder effects are responsible for the high MJD prevalence, as occurs in the Portuguese/Azorean island of Flores and Northeastern mainland. The Machado lineage is geographically more restricted, with most known families in Portugal (island of Sao Miguel and along the Tagus valley). The hypothesis of other mutational origins has been raised, namely to explain the disease among Australian aborigines; however, a comprehensive haplotype study suggested the introduction of the Joseph lineage in that community via Asia. Also, additional SNP-based haplotypes (TTAGAC, TTGGAC and GTGCCA) were observed in other MJD families, but phylogenetic analysis with more polymorphic flanking markers did not point to independent mutational events, reinforcing the hypothesis of a very low mutation rate underlying this repeat expansion locus. PMID- 29427108 TI - Clinical Features of Machado-Joseph Disease. AB - Machado-Joseph disease (MJD) also known as Spinocerebellar ataxia type 3, is a hereditary neurodegenerative disease associated with severe clinical manifestations and premature death. Although rare, it is the most common autosomal dominant spinocerebellar ataxia worldwide and has a distinct geographic distribution, reaching peak prevalence in certain regions of Brazil, Portugal and China. Due to its clinical heterogeneity, it was initially described as several different entities and as had many designations over the last decades. An accurate diagnosis become possible in 1994, after the identification of the MJD1 gene. Among its wide clinical spectrum, progressive cerebellar ataxia is normally present. Other symptoms include pyramidal syndrome, peripheral neuropathy, oculomotor abnormalities, extrapyramidal signs and sleep disorders. On the basis of the presence/absence of important extra-pyramidal signs, and the presence/absence of peripheral signs, five clinical types have been defined. Neuroimaging studies like MRI, DTI and MRS, can be useful as they can characterize structural and functional differences in specific subgroups of patients with MJD. There is no effective treatment for MJD. Symptomatic therapies are used to relieve some of the clinical symptoms and physiotherapy is also helpful in improving quality of live. Several clinical trials have been carried out using different molecules like sulfamethoxazole-trimethoprim, varenicline and lithium carbonate, but the results of these trials were negative or showed little benefit. Future studies sufficiently powered and adequately designed are warranted. PMID- 29427109 TI - Polyglutamine-Independent Features in Ataxin-3 Aggregation and Pathogenesis of Machado-Joseph Disease. AB - The expansion of a trinucleotide (CAG) repeat, translated into a polyglutamine expanded sequence in the protein encoded by the MJD gene, was identified over 20 years ago as the causative mutation in a severe neurodegenerative disorder originally diagnosed in individuals of Portuguese ancestry. This incapacitating disease, called Machado-Joseph disease or spinocebellar ataxia type 3, is integrated into a larger group of neurodegenerative disorders-the polyglutamine expansion disorders-caused by extension of a CAG repeat in the coding sequence of otherwise unrelated genes. These diseases are generally linked with the appearance of intracellular inclusions , which despite having a controversial role in disease appearance and development represent a characteristic common fingerprint in all polyglutamine-related disorders. Although polyglutamine expansion is an obvious trigger for neuronal dysfunction, the role of the different domains of these complex proteins in the function and aggregation properties of the carrier proteins is being uncovered in recent studies. In this review the current knowledge about the structural and functional features of full length ataxin-3 protein will be discussed. The intrinsic conformational dynamics and interplay between the globular and intrinsically disordered regions of ataxin 3 will be highlighted, and a perspective picture of the role of known ataxin-3 post-translational modifications on regulating ataxin-3 aggregation and function will be drawn. PMID- 29427110 TI - Animal Models of Machado-Joseph Disease. AB - Animal models are an important tool to study the pathophysiology of Machado Joseph Disease (MJD). So far, animal models using simple organisms (like the round worm Caenorhabditis elegans or the fruit fly drosophila) but also mammalian models (mouse and even a non-human primate model) have been generated to study MJD. While simple organisms made an important contribution to the identification of pathophysiological mechanisms in MJD and were further used for modifier and screening purposes, mammalian models recapitulate major disease features of MJD in humans and are therefore a highly valuable tool for e.g. the validation of mechanisms or for pre-clinical validation of treatment approaches. Here we give an overview about the strategies which were used to model MJD and about the different models generated so far. We further highlight advantages of specific model organisms and describe the new findings which were made employing these animal models of MJD. PMID- 29427111 TI - Towards the Identification of Molecular Biomarkers of Spinocerebellar Ataxia Type 3 (SCA3)/Machado-Joseph Disease (MJD). AB - Whereas spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) remains an untreatable disorder, disease-modifying compounds have begun being tested in the context of clinical trials; their success is dependent on the sensitivity of the methods used to measure subtle therapeutic benefits. Thus, efforts are being made to propose a battery of potential outcome measures, including molecular biomarkers (MBs), which remain to be identified; MBs are particularly pertinent if SCA3 trials are expected to enroll preataxi c subjects. Recently, promising candidate MBs of SCA3 have emerged from gene expression studies. In this chapter we provide a synthesis of the cross-sectional and pilot longitudinal studies of blood-based transcriptional biomarkers conducted so far. Other alterations with potential to track the progression of SCA3, such as those involving mitochondrial DNA (mtDNA) are also referred. It is expected that a set of molecular biomarkers can be identified; these will be used in complementarity with clinical and imaging markers to fully track SCA3, from its preataxic phase to the disease stage. PMID- 29427112 TI - Planning Future Clinical Trials for Machado-Joseph Disease. AB - Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant multiple neurological systems degenerative disorder caused by a CAG repeat expansion at ATXN3 gene. Only a few treatments were evaluated in randomized clinical trials (RCT) in SCA3/MJD patients, with a lack of evidence for both disease-modifying and symptomatic therapies. The present chapter discuss in detail major methodological issues for planning future RCT for SCA3/MJD. There are several potential therapies for SCA3/MJD with encouraging preclinical results. Route of treatment, dosage titration and potential therapy biomarkers might differ among candidate drugs; however, the core study design and protocol will be mostly the same. RCT against placebo group is the best study design to test a disease-modifying therapy; the same cannot be stated for some symptomatic treatments. Main outcomes for future RCT are clinical scales: the Scale for the Assessment and Rating of ataxia (SARA) is currently the instrument of choice to prove efficacy of disease-modifying or symptomatic treatments against ataxia, the most important disease feature. Ataxia quantitative scales or its composite scores can be used as primary outcomes to provide preliminary evidence of efficacy in phase 2 RCT, due to a greater sensitivity to change. Details regarding eligibility criteria, randomization, sample size estimation, duration and type of analysis for both disease modifying and symptomatic treatment trials, were also discussed. Finally, a section anticipates the methodological issues for testing novel drugs when an effective treatment is already available. We conclude emphasizing four points, the first being the need of RCT for a number of different aims in the care of SCA3/MJD. Due to large sample sizes needed to warrant power, RCT for disease-modifying therapies should be multicenter enterprises. There is an urge need for surrogate markers validated for several drug classes. Finally, engagement of at risk or presymptomatic individuals in future trials will enable major advances on treatment research for SCA3/MJD. PMID- 29427113 TI - Molecular Mechanisms and Cellular Pathways Implicated in Machado-Joseph Disease Pathogenesis. AB - Machado-Joseph disease (MJD) is a dominantly inherited disorder originally described in people of Portuguese descent, and associated with the expansion of a CAG tract in the coding region of the causative gene MJD1/ATX3. The CAG repeats range from 10 to 51 in the normal population and from 55 to 87 in SCA3/MJD patients. MJD1 encodes ataxin-3, a protein whose physiological function has been linked to ubiquitin-mediated proteolysis. Despite the identification of the causative mutation, the pathogenic process leading to the neurodegeneration observed in the disease is not yet completely understood. In the past years, several studies identified different molecular mechanisms and cellular pathways as being impaired or deregulated in MJD. Autophagy, proteolysis or post translational modifications, among other processes, were implicated in MJD pathogenesis. From these studies it was possible to identify new targets for therapeutic intervention, which in some cases proved successful in models of disease. PMID- 29427114 TI - Pharmacological Therapies for Machado-Joseph Disease. AB - Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia type 3 (SCA3), is the most common autosomal dominant ataxia worldwide. MJD integrates a large group of disorders known as polyglutamine diseases (polyQ). To date, no effective treatment exists for MJD and other polyQ diseases. Nevertheless, researchers are making efforts to find treatment possibilities that modify the disease course or alleviate disease symptoms. Since neuroimaging studies in mutation carrying individuals suggest that in nervous system dysfunction begins many years before the onset of any detectable symptoms, the development of therapeutic interventions becomes of great importance, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset. Potential therapeutic targets for MJD and polyQ diseases can be divided into (i) those that are aimed at the polyQ proteins themselves, namely gene silencing, attempts to enhance mutant protein degradation or inhibition/prevention of aggregation; and (ii) those that intercept the toxic downstream effects of the polyQ proteins, such as mitochondrial dysfunction and oxidative stress, transcriptional abnormalities, UPS impairment, excitotoxicity, or activation of cell death. The existence of relevant animal models and the recent contributions towards the identification of putative molecular mechanisms underlying MJD are impacting on the development of new drugs. To date only a few preclinical trials were conducted, nevertheless some had very promising results and some candidate drugs are close to being tested in humans. Clinical trials for MJD are also very few to date and their results not very promising, mostly due to trial design constraints. Here, we provide an overview of the pharmacological therapeutic strategies for MJD studied in animal models and patients, and of their possible translation into the clinical practice. PMID- 29427115 TI - Gene Therapies for Polyglutamine Diseases. AB - Polyglutamine diseases are hereditary degenerative disorders of the nervous system that have remained, to this date, untreatable. Promisingly, investigation into their molecular etiology and the development of increasingly perfected tools have contributed to the design of novel strategies with therapeutic potential. Encouraging studies have explored gene therapy as a means to counteract cell demise and loss in this context. The current chapter addresses the two main focuses of research in the area: the characteristics of the systems used to deliver nucleic acids to cells and the molecular and cellular actions of the therapeutic agents. Vectors used in gene therapy have to satisfyingly reach the tissues and cell types of interest, while eliciting the lowest toxicity possible. Both viral and non-viral systems have been developed for the delivery of nucleic acids to the central nervous system, each with its respective advantages and shortcomings. Since each polyglutamine disease is caused by mutation of a single gene, many gene therapy strategies have tried to halt degeneration by silencing the corresponding protein products, usually recurring to RNA interference. The potential of small interfering RNAs, short hairpin RNAs and microRNAs has been investigated. Overexpression of protective genes has also been evaluated as a means of decreasing mutant protein toxicity and operate beneficial alterations. Recent gene editing tools promise yet other ways of interfering with the disease causing genes, at the most upstream points possible. Results obtained in both cell and animal models encourage further delving into this type of therapeutic strategies and support the future use of gene therapy in the treatment of polyglutamine diseases. PMID- 29427116 TI - Stem Cell-Based Therapies for Polyglutamine Diseases. AB - Polyglutamine (polyQ) diseases are a family of neurodegenerative disorders with very heterogeneous clinical presentations, although with common features such as progressive neuronal death. Thus, at the time of diagnosis patients might present an extensive and irreversible neuronal death demanding cell replacement or support provided by cell-based therapies. For this purpose stem cells, which include diverse populations ranging from embryonic stem cells (ESCs), to fetal stem cells, mesenchymal stromal cells (MSCs) or induced pluripotent stem cells (iPSCs) have remarkable potential to promote extensive brain regeneration and recovery in neurodegenerative disorders. This regenerative potential has been demonstrated in exciting pre and clinical assays. However, despite these promising results, several drawbacks are hampering their successful clinical implementation. Problems related to ethical issues, quality control of the cells used and the lack of reliable models for the efficacy assessment of human stem cells. In this chapter the main advantages and disadvantages of the available sources of stem cells as well as their efficacy and potential to improve disease outcomes are discussed. PMID- 29427117 TI - Delayed cerebral thrombosis complicating pneumococcal meningitis: an autopsy study. AB - BACKGROUND: Delayed cerebral thrombosis (DCT) is a devastating cerebrovascular complication in patients with excellent initial recovery of pneumococcal meningitis. The aetiology is unknown, but direct bacterial invasion, activation of coagulation or post-infectious immunoglobulin deposition has been suggested. METHODS: We studied histopathology of 4 patients with pneumococcal meningitis complicated by DCT. Results were compared with 8 patients who died of pneumococcal meningitis without DCT and 3 non-meningitis control cases. Furthermore, we evaluated vascular immunoglobulin depositions (IgA, IgG and IgM) and the presence of pneumococcal capsules by immunofluorescence. RESULTS: Patients who died after pneumococcal meningitis showed inflammation in the meninges and blood vessels with extensive infarction and thrombosis. We did not observe gross differences between DCT and non-DCT patients, except that 2 of 4 DCT patients had a basilar artery aneurysm compared to none of the non-DCT patients. We observed high density of IgM and IgG deposition in meningitis cases as compared to controls, but no difference between DCT and non-DCT patients. Immunofluorescence staining of pneumococci demonstrated the presence of bacterial capsules in the meninges of all meningitis patients, even 35 days after the initiation of antibiotic treatment. CONCLUSION: The aetiology of DCT complicating pneumococcal meningitis seems to be of multifactorial aetiology and includes vascular inflammation, thromboembolism of large arteries and infectious intracranial aneurysms. Pneumococcal cell wall components can be observed for weeks after pneumococcal meningitis and may be a source of resurging inflammation after the initial immunosuppression by dexamethasone. PMID- 29427118 TI - Associations Between Emotion Regulation and Social Impairment in Children and Adolescents with Autism Spectrum Disorder. AB - In typically-developing (TD) individuals, effective emotion regulation strategies have been associated with positive outcomes in various areas, including social functioning. Although impaired social functioning is a core criterion of Autism Spectrum Disorder (ASD), the role of emotion regulation ability in ASD has been largely ignored. This study investigated the association between emotion regulation and ASD symptomatology, with a specific emphasis on social impairment. We used parent-report questionnaires to assess the regulatory strategies and symptom severity of 145 youth with ASD. Results showed that: (1) more effective emotion regulation, defined by greater use of reappraisal, predicted less severe ASD symptomatology, and (2) greater use of reappraisal predicted less severe social impairment. Suppression was not predictive of general symptomatology or social functioning. PMID- 29427119 TI - The Co-occurrence of Gender Dysphoria and Autism Spectrum Disorder in Adults: An Analysis of Cross-Sectional and Clinical Chart Data. AB - Quantitative studies indicate an overrepresentation of ASD in individuals with GD. This study aims to determine the prevalence of autistic traits or ASD in adults with GD using two different data collection methods: (1) cross-sectional data using the social responsiveness scale-adults (SRS-A) and the autism quotient (AQ) (n = 63). (2) Clinical chart data (n = 532). Mean SRS-A scores were significantly higher compared to a norm population. Almost 5% of the patients with GD scored above the cut-off as measured by the AQ. In 32 patients (6%), a certain ASD diagnosis was found in the patient files, which is sixfold higher compared to the general population. Significantly more "birth assigned male" were affected compared to "birth assigned female". PMID- 29427120 TI - Challenges in Transition of Care for Pediatric Patients after Weight-Reduction Surgery: a Systematic Review and Recommendations for Comprehensive Care. AB - Obesity in pediatric patients is rising with nearly one third of children in the USA classified as overweight and up to 16-18% of the adolescent population obese with at least one comorbid condition. Consequently, bariatric procedures in this population have increased without consistent recommendations for follow-up and transition to adult providers. This review describes the known and potential long term consequences of bariatric surgery in pediatric patients, reviews the current literature on transitions of care for adolescent patients with chronic illnesses. Additionally, this review summarizes recommendations from the literature for developing a standardized program for transitioning care for post-bariatric surgical patients and offers useful tools and guidelines for doing so. PMID- 29427122 TI - Visual search for changes in scenes creates long-term, incidental memory traces. AB - Humans are very good at remembering large numbers of scenes over substantial periods of time. But how good are they at remembering changes to scenes? In this study, we tested scene memory and change detection two weeks after initial scene learning. In Experiments 1-3, scenes were learned incidentally during visual search for change. In Experiment 4, observers explicitly memorized scenes. At test, after two weeks observers were asked to discriminate old from new scenes, to recall a change that they had detected in the study phase, or to detect a newly introduced change in the memorization experiment. Next, they performed a change detection task, usually looking for the same change as in the study period. Scene recognition memory was found to be similar in all experiments, regardless of the study task. In Experiment 1, more difficult change detection produced better scene memory. Experiments 2 and 3 supported a "depth-of processing" account for the effects of initial search and change detection on incidental memory for scenes. Of most interest, change detection was faster during the test phase than during the study phase, even when the observer had no explicit memory of having found that change previously. This result was replicated in two of our three change detection experiments. We conclude that scenes can be encoded incidentally as well as explicitly and that changes in those scenes can leave measurable traces even if they are not explicitly recalled. PMID- 29427121 TI - Identification and functional characterisation of an allene oxide synthase from grapevine (Vitis vinifera L. Sauvignon blanc). AB - Jasmonic acid (JA) is known to be an important phytohormone that orchestrates plant defence mechanisms against a range of herbivores and pathogens. Studies have suggested allene oxide synthase (AOS; E.C 4.2.1.92), the first committed step in JA biosynthesis, is essential for JA biosynthesis, yet clear evidence of its role as a biosynthetic regulatory point is lacking, in the main due to conflicting results derived from transgenic studies. However other studies lend support to a biosynthetic regulatory role for AOS. These studies have suggested that certain amino acid substitutions can increase the biosynthetic capacity of the enzyme and consequently improve pathogen tolerance in plants. To explore the role of AOS in Grapevine we isolated and functionally characterised this enzyme for the first time from Vitis vinifera L. Sauvignon blanc. The cloned AOS consisted of a single 1563 bp open reading frame. Comparative sequence analysis showed that the cloned gene (VvAOS) was highly conserved compared to those from other species. Complementation of an Arabidopsis AOS null mutant (aos) with VvAOS recovered the male sterile mutant phenotype and confirmed its function. Transcript analysis showed that VvAOS was wound responsive in leaves and was detectable in most tissues, with the highest levels of transcript in the mesocarp (pulp) of mature berries. Sub-cellular localisation of the VvAOS protein indicated that VvAOS is associated with the chloroplast membrane. Unexpectedly high levels of VvAOS transcript in complemented aos lines did not lead to predicted increases in JA. We have functionally characterised the sole AOS from Grapevine. Patterns of transcript accumulation in grapevine suggest roles in growth, development as well as an important role for JA in fruit ripening. Expression of VvAOS in Arabidopsis suggest complex epigenetic interactions between transgenic and endogenous AOS alleles, providing a possible explanation for why transgenic studies of AOS have delivered conflicting data pointing to a questionable role of AOS as a key regulatory point in JA biosynthesis. PMID- 29427123 TI - Clinical utility of RT-PCR in assessing HER 2 gene expression versus traditional IHC and FISH in breast cancer patients. AB - BACKGROUND: IHC and FISH are used for categorizing HER 2 status in breast cancer at the protein and DNA level, respectively. HER 2 expression at the RNA level is quantitative, cheaper, easier to standardize and free from interobserver variation. METHODS: 115 consecutive patients were tested by IHC, FISH and RT-PCR (test cohort). Assuming FISH result to be the response variable, ROC curves for RT-PCR ratio were analyzed to label HER 2 negative, equivocal and positive cases as RT-PCR score 1, 2 and 3, respectively. Inter-relationships between RT-PCR, IHC and FISH were defined. 'Clinical benefit' of a test was defined as proportion of patients labeled unequivocally as HER 2 positive or negative. Population for 1 year was simulated constraint to previous reports of HER 2 positivity and IHC category distribution by a meta-analysis of previous studies that evaluated concordance between IHC and FISH to determine HER 2 status (simulation cohort). Four diagnostic pathways in the simulation cohort were defined-(1) initial IHC, followed by FISH (conventional pathway); (2) initial RT-PCR, followed by FISH; (3) initial IHC, followed by RT-PCR and then by FISH; (4) initial RT-PCR, followed by IHC and then by FISH. The clinical benefit of IHC and RT-PCR in the four pathways was analyzed and sensitivity analysis for incremental cost effectiveness ratio and cost-benefit comapring RT-PCR against IHC, both as first line tests and among those with IHC score 2 as a reflex second-line test was performed by the Monte Carlo technique. FINDINGS: 115 patients comprised the study population. While none with IHC score of 0 or 1 was FISH positive for HER 2, all cases with IHC score of 3 were FISH positive. 43 cases were assigned IHC score of 2. Thus, 72 patients benefited from the initial IHC testing [clinical benefit 62.6%], with the overall concordance between IHC and FISH being 100% for those with IHC score of 0, 1 and 3 (conclusive IHC categories). For RT-PCR with 100% concordance, 15.7% (115-97 = 18) patients would have benefited from RT-PCR testing if it was used as a first-line test. If RT-PCR would have been used as a second-line test among those with IHC score 2 (n = 43), then only 6 patients would have been assigned a conclusive RT-PCR category (category 1 or 3) translating to a clinical benefit of 14% (6/43) as a second-line test. As a second-line test it had 51% probability to prove more cost-effective than the conventional pathway, provided the cost of RT-PCR was 0.4 times the cost of IHC. Also in a three-step pathway, RT-PCR upfront would have 56% probability of higher cost-benefit provided the cost of RT-PCR was 0.1 times the cost of IHC. CONCLUSION: RT-PCR results were found to be suboptimal to IHC in terms of discriminative ability and clinical benefit; thus, it is unlikely to replace IHC as a first-line test in the near future. PMID- 29427124 TI - Neuroendocrine Pulmonary Tumors of Low, Intermediate and High Grade: Anatomopathological Diagnosis-Prognostic and Predictive Factors. AB - Neuroendocrine tumors (NETs) belong to a heterogeneous family of rare tumors with very broad and complex clinical behavior. Due to their heterogeneity, the lack of specific symptoms and the absence of sensitive methods for early detection, patients are usually diagnosed when the disease is in an advanced state for which curative treatments are scarce. In most cases, these few treatments try to prolong the survival of patients, maintaining the quality of life. The identification of biomarkers could help to improve early diagnosis and to choose the most suitable therapeutic strategy. This paper provides a review of the current histopathological diagnostic approaches for lung NET subtypes, including the predictive and prognostic factors, to help in the early diagnosis of this disease. PMID- 29427126 TI - Proximal versus distal metatarsal osteotomies for moderate to severe hallux valgus deformity: a systematic review and meta-analysis of clinical and radiological outcomes. AB - PURPOSE: The conventional surgical treatment of moderate to severe hallux valgus (HV) deformity includes proximal metatarsal osteotomies (PMOs). Recent evidence suggests that the extension of indications for distal metatarsal osteotomies (DMOs) may result in comparable outcomes. The purpose of this study was to compare the efficacy of proximal with that of distal metatarsal osteotomies for moderate to severe HV deformity. METHODS: We searched PubMed, Scopus, and CENTRAL up to 25 July 2017. We included studies comparing the results of proximal and distal metatarsal osteotomies for moderate to severe HV deformity. The primary outcomes included the assessment of the first intermetatarsal angle (IMA) and American Orthopaedic Foot and Ankle Society (AOFAS) scoring system. For the secondary outcomes, we considered the hallux valgus angle, sesamoid position, and participants' satisfaction. We also reported and analyzed complications. We evaluated all outcomes in the short-term (<= 1 year) and medium-term (> 1 and < 10 years). The quality assessment was performed using the Cochrane risk of bias and ROBINS-I tools for randomized and non-randomized studies, respectively. RESULTS: Data from 696 cases were considered in this review. For the assessment of the first IMA, there was a slight advantage in favour of the PMO group in the medium term (SMD was - 0.38, 95% CIs - 0.65 to - 0.12, p < 0.05, I2 = 21%). For the rest outcomes, we did not detect any significant differences between the intervention groups. CONCLUSIONS: For clinical and radiological outcomes, the quantitative synthesis demonstrated that there were no significant differences between PMO and DMO groups in the medium term. These findings were supported by data from non-randomized studies. For the reported complications, we did not detect any significant differences between the intervention groups. PMID- 29427125 TI - Survival, complications and functional outcomes of cemented megaprostheses for high-grade osteosarcoma around the knee. AB - PURPOSE: We initiated a retrospective study on the long-term survival of cemented endoprostheses for bone tumours around the knee to answer the following questions: (1) What was the survival of these patients? (2) What was the overall survival of cemented prostheses around the knee? (3) What types of failures were observed in these reconstructions? (4) Did the survival and complications vary according to the site of the implant? (5) What was the functional result after cemented prosthesis replacement around the knee? METHODS: From January 2006 to December 2013, 108 consecutive patients with an average age of 25 years, who had mature bone development as evidenced by imaging examinations, underwent 108 cemented endoprosthetic knee replacements for osteosarcoma resection. All patients received neoadjuvant chemotherapy using a multi-drug protocol consisting of high dose methotrexate (HDMTX), doxorubicin (ADM), cisplatin (DDP) and high dose ifosfamide (HDIFO). When extensor mechanism reconstruction was required, we ran nonabsorbable sutures through designated holes in the tibial component to fix detached hamstrings and the remaining ligaments in an imbricated fashion as well as reinforced the reconstruction with a medial gastrocnemius flap. Seventy-two (72/108, 66.7%) lesions were located in the distal femur and 36 (36/108, 33.3%) lesions at the proximal tibias. Nineteen patients were staged as IIA and 89 as IIB according to the Enneking staging system. The average follow-up was 53.3 months (range 12-125 months), with a minimum oncological follow-up of one year. Survival, prosthetic failure, complications and functional outcomes were recorded and reassessed at every visit after the primary operation. RESULTS: At the final follow-up, the oncologic results showed that 33 patients died from metastases, and local recurrence occurred in ten patients. The estimated overall five-year and eight-year survival rates were 71% (95% CI: 62.4-79.65%) and 67.2% (95% CI: 58-76.4%), respectively. In this study, a total of 51 complications occurred in 45 patients, and at the end of follow-up, 59 patients had prostheses in situ. The estimated overall five-year and eight-year implant survival rates were 77.7% (95% CI: 67.9-87.5%) and 54.5% (95% CI: 31.4-77.6%), respectively, when patients who died with their original prostheses were censored. In total, 21 (21/108, 19.4%) implants failed, five due to infections (5/21), eight due to aseptic loosening (8/21), four due to local recurrence (4/21), three due to structural failure (3/21) and one due to soft tissue failure (1/21). The average Musculoskeletal Tumor Society Score (MSTS) at the most recent follow-up was 22.9 (9-30) points on a 30-point scale, which indicated an excellent or good functional outcome. Analysis of the results based on implant site revealed a slight difference of the estimated five-year prosthesis survival between implants located in the distal femur and those located in the proximal tibia [86.1% (95% CI: 75.5-97%) versus 66.9% (95% CI: 49.8-83.9%); P = 0.09]. However, the functional outcomes and complication rates of prostheses located in the distal femur were both better than those located in the proximal tibia. CONCLUSIONS: With effective management strategies for complications, cemented endoprosthetic reconstruction of the proximal tibia and distal femur using an extensor mechanism reconstruction technique provides a reliable method of reconstruction following tumour resection around the knee. Level of Evidence Level IV, therapeutic study. PMID- 29427127 TI - From Dispensaries to Community Health Centers: Health Delivery Change Across the Twentieth Century. AB - This piece examines the historical forces and forebears that preceded, and helped shape, community health centers. Though the current iteration of community health centers date from the 1960s, their (deeper) roots go back to the earliest years of the twentieth century. They began life as largely urban phenomena, and rode the wave of the larger program of Progressive-era political and socioeconomic reforms. PMID- 29427128 TI - Community Health Advisors' Participation in a Dissemination and Implementation Study of an Evidence-Based Physical Activity and Healthy Eating Program in a Faith-Based Setting. AB - Community health advisors (CHAs) have been widely involved in health promotion, but few details on role expectations, retention, and evaluation have been reported. In a dissemination and implementation (D&I) study of an evidence-based healthy eating and physical activity program, 59 churches were randomized to an intervention (n = 39) or control (delayed intervention) (n = 20) condition. In a novel approach, CHAs worked with church committees rather than congregants by providing training (n = 59) and technical assistance (n = 54) to the committees to implement a program focused on structural and policy-level changes to support congregants' behavioral changes. CHA training comprised self-study via electronic training modules, in-person training, and telephone-based training. Evaluation methods were pilot test participants' and CHAs' ratings of their training; observers' ratings of CHAs' church training delivery; church committee members' ratings of the training experience, including CHAs' performance; and data from the TA database to assess CHAs' adherence to the protocol. The main challenge was the early dropout of one CHA and the reduced role of another. CHAs trained 142 intervention and 60 control church committee members in nine sessions; they covered 99% (intervention) and 90% (control) of training content, indicating high fidelity. Observers' scored CHAs' teaching and facilitation skills at 96.7% (intervention) and 80% (control) of the possible score. CHAs completed 92% of intervention and 93% of control TA calls. The great majority of church participants' comments regarding CHAs were positive. This study demonstrates that with training and support, CHAs demonstrate high levels of intervention fidelity, confidence, and competence. PMID- 29427129 TI - Trends in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma Incidence, Vermont 1999-2013. AB - This study examines trends in age-adjusted incidence rates of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) in comparison to oral cavity proper squamous cell carcinoma (OSCC) in the population of Vermont from 1999 to 2013. Data on cases of oral and pharynx cancers diagnosed in Vermont between 1999 and 2013 were obtained from the Vermont cancer registry. The age-adjusted incidence rates and annual percentage change of HPV-related OPSCC and OSCC were calculated using Joinpoint trend analysis. Four hundred and thirty-one cases of HPV-related OPSCC were diagnosed from 1999 to 2013. Males constituted 83% (P < 0.0001) of the cases and the 6th decade of life marked the highest incidence. The overall age-adjusted incidence rates for HPV-related OPSCC significantly increased (from 2.39 to 3.86 per 100,000, P < 0.0001). In males, it significantly increased (from 3.62 to 6.93 per 100,000, P < 0.0001), while in females it remained stable (from 1.18 to 1.02 per 100,000, P = 0.28) during 1999 2013. The average rate of HPV-related OPSCC significantly increased by 4.4% annually (P = 0.004). In males the average rate significantly increased by 5.3% annually (P = 0.001) and in females the rate increased by 0.37% annually (P = 0.87). In contrast, age-adjusted overall incidence rates for OSCC significantly decreased (from 3.99 to 3.35 per 100,000, P = 0.018). The overall rate of OSCC decreased by 0.96% annually (P = 0.37) and the highest incidence of cases was in the 7th decade of life. In conclusion, there was an increasing trend of HPV related OPSCC, specifically in males, and there appears to be a decreasing trend of OSCC in Vermont. PMID- 29427130 TI - Prevalence and Indicators of Household Smoking Bans Among American Indians. AB - More than 58 million nonsmokers in the U.S. encounter secondhand smoke that leads to tobacco-related diseases and deaths every year, making voluntary household smoking bans an important public health goal. American Indians/Alaska Natives are rarely included in research related to household smoking bans. Further, most studies dichotomize household smoking bans into complete bans versus partial/no bans, rendering it impossible to determine if partial and no bans are associated with different or similar risk factors. Using the 2014 Cherokee Nation American Indian Adult Tobacco Survey, our study sought to identify prevalence of household smoking bans, their extent, and their correlates in an American Indian population. This cross-sectional analysis used multinomial logistic regression to determine correlates of complete, partial, and no household smoking bans. Results indicated that approximately 84% of Cherokee households have a complete ban. Younger age, female gender, higher education, higher household income, respondent's nonsmoking status, good health, better awareness of harms related to secondhand smoke, visits with a healthcare provider within the past year, and children in the home were positively and significantly associated with complete household smoking bans. Additionally, there were notable differences between correlates related to partial bans and no bans. These results provide insight for the development of more appropriate interventions for American Indian households that do not have a complete household smoking ban. PMID- 29427131 TI - Eosinophilic Esophagitis Through the Flexible Endoscope and the Lens of a Photographer in the Amazon. AB - Eosinophilic esophagitis (EoE) is a disorder that has been identified recently, thus knowledge about it, its pathogenesis, and potential etiologies has spread in an era where the medical community and the public are receiving the information and discussing it as it appears in the medical literature. Because physiology, pathology, and pathophysiology are difficult to explain in layman terms, the author has used photographs taken in remote areas of the Amazon to create visual similes within a narrative that brings the scientific and medical concepts of the knowledge on EoE to a level that allows both medical and non-medical persons to grasp and discuss their significance. This set of photographs when presented to audiences has generated interest in the disorder as well as in the Amazon and its natural flora and fauna. The author hopes that this pictorial introduction sets the stage for the multiple novel topics reviewed and presented in this issue. PMID- 29427132 TI - Effects of Botanical Insecticides on Hymenopteran Parasitoids: a Meta-analysis Approach. AB - Botanical insecticides (BIs) are considered a valuable alternative for plant protection in sustainable agriculture. The use of both BIs and parasitoids are presumed to be mutually compatible pest management practices. However, there is controversy on this subject, as various studies have reported lethal and sublethal effects of BIs on hymenopteran parasitoids. To shed new light on this controversy, a meta-analytic approach of the effects of BIs on adult mortality, parasitism, and parasitoid emergence under laboratory conditions was performed. We show that BIs increased mortality, decreased parasitism, and decreased parasitoid emergence. Botanical insecticides derived from Nicotiana tabacum and Caceolaria andina were particulary lethal. Most of the parasitoid groups showed susceptibility to BIs, but the families Scelionidae and Ichneumonidae were not significantly affected. The negative effects of BIs were seen regardless of the type of exposure (topical, ingestion, or residual). In conclusion, this meta analysis showed that under laboratory conditions, exposure of hymenopteran parasitoids to BIs had significant negative effects on adult mortality, parasitism, and parasitoid emergence. PMID- 29427133 TI - Factors Influencing Mating Behavior and Success in the Red Palm Weevil, Rhynchophorus ferrugineus Olivier (Coleoptera: Dryophthoridae). AB - The effects of body size, age, feeding and mating status, conspecific volatiles from live adults, synthetic aggregation pheromone, and a pheromone synergist, ethyl acetate, on the mating behavior of red palm weevil, Rhynchophorus ferrugineus Olivier, were investigated. To evaluate these factors, variables such as mating latency, frequency and duration, and refractory period were assessed. While both, body size and age, influenced the mating behavior, the latter showed a stronger effect. The large males recorded frequent and longer matings, whereas the young males outperformed the old weevils in all the studied variables. The difference in body size or age of females showed a limited effect. After 72 h without food, the males showed a significant decline in mating frequency and duration, and refractory period. Mating status showed comparatively stronger effects on mating variables. In the case of females, mating status emerged as the most important factor affecting four out of five variables. The volatiles from the males, grouped males and females, and synthetic aggregation pheromone both alone and in combination with ethyl acetate triggered mating initiation, propelled mating frequency, prolonged total mating duration, and reduced the refractory period. However, the presence of females or ethyl acetate alone was a weak mating stimulator. PMID- 29427135 TI - Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model. AB - Amlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug-drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously. A novel physiologically-based pharmacokinetic (PBPK) model was developed for amlodipine, and the model was verified using published clinical PK and DDI data. The verified amlodipine PBPK model was linked to a pharmacodynamics model that describes changes in systolic blood pressure (SBP) during and after co administration with RTV. The magnitude and time course of RTV effects on amlodipine plasma exposures and SBP were evaluated, to provide guidance on dose adjustment of amlodipine during and after co-administration with RTV-containing regimens. Model simulations suggested that the increase in amlodipine's plasma exposure by RTV diminishes by approximately 80% within 5 days after the last dose of RTV. PBPK simulations suggested that resuming a full dose of amlodipine [5 mg once daily (QD)] immediately after RTV's last dose would decrease daily average SBP by a maximum of 3.3 mmHg, while continuing with the reduced dose (2.5 mg QD) for 5 days after the last dose of RTV would increase daily average SBP by a maximum of 5.8 mmHg. Based on these results, either approach of resuming amlodipine's full dose could be appropriate when combined with appropriate clinical monitoring. PMID- 29427136 TI - Molecular Alterations Associated with DNA Repair in Pancreatic Adenocarcinoma Are Associated with Sites of Recurrence. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with a rising incidence. Mutational analysis of PDAC has provided valuable information but has not yet dramatically changed the therapeutic landscape due to the number of variations detected in any one individual. The pattern of molecular alterations-gene mutations, variations in copy number, and changes in gene expression-has been described in the literature. The purpose of this study is to further investigate the molecular alterations in recurrent or metastatic PDAC based on the site of disease. METHODS: Molecular alterations in patients with recurrent or metastatic PDAC from 2007 to 2015 were analyzed. The most common molecular alterations found in PDAC tumors from the pancreas were compared to metastatic PDAC specimens from the liver, lung, peritoneum, and other locations. Means were compared with a two-tailed Student's t test or ANOVA as appropriate. Rates of molecular alterations among the different groups were compared with Pearson's chi2. RESULTS: Two thousand five hundred fifty-two patients with PDAC were identified in a retrospective database, and the 15 most common molecular alterations were utilized for analysis. The most common alterations among all patients were mutations in KRAS and PTEN (59 and 62%, respectively), with differences in prevalence by site of metastasis (p = 0.042 and p = 0.037, respectively). KRAS mutations were more commonly found in metastasis in the lung (72%) than in other sites (59%, p = 0.042). Low expression of ERCC1 was found in 49% of lung metastases from PDAC but only 15% in PDAC in the pancreas (p < 0.001). Five of the 8 molecular alterations significantly associated with site of metastatic disease were involved in DNA maintenance, repair, replication, or transcription (each p < 0.001). CONCLUSIONS: Aberrant expression or mutation in genes involved in DNA maintenance is found in association with specific sites of metastatic PDAC. Personalizing therapy for metastatic PDAC based on site of disease and their associated molecular alterations warrants further investigation. PMID- 29427134 TI - Acute kidney injury in major abdominal surgery: incidence, risk factors, pathogenesis and outcomes. AB - Acute kidney injury (AKI) is a common complication in patients undergoing major abdominal surgery. Various recent studies using modern standardized classifications for AKI reported a variable incidence of AKI after major abdominal surgery ranging from 3 to 35%. Several patient-related, procedure related factors and postoperative complications were identified as risk factors for AKI in this setting. AKI following major abdominal surgery has been shown to be associated with poor short- and long-term outcomes. Herein, we provide a contemporary and critical review of AKI after major abdominal surgery focusing on its incidence, risk factors, pathogeny and outcomes. PMID- 29427137 TI - Childhood peripheral facial palsy. AB - OBJECTIVE: The objectives of this study were to evaluate the demographic and clinical characteristics, causes, treatment patterns, outcome, and recurrence of childhood peripheral facial palsy. METHODS: We performed a retrospective study of 144 peripheral facial palsy patients, under 18 years old in a tertiary care pediatric hospital. Medical charts were reviewed to analyze the age, gender, side of facial nerve paralysis, family history, cause, grading by the House-Brackmann Facial Nerve Grading Scale (HBS), results of diagnostic tests, therapies, outcomes, and recurrence. RESULTS: Causes were as follows: 115 idiopathic (Bell's palsy) facial palsy (79.9%), 17 infections (11.8%) (9 otitis media, 4 varicella zoster virus (VZV) infection, 3 tooth abscess, and 1 group A beta-hemolytic streptococcus infection), 7 trauma (4.9%), 4 congenital-syndrome (2.8%), and 1 (0.7%) arterial hypertension. There was no difference in age, sex, family history, grading, or outcome between idiopathic and cause-defined facial palsy. At the end of the first year, our recovery rates were 98.3%. No significant difference in recovery outcome was detected between the patients who were treated with and without steroid treatment. Thirteen (9%) patients had recurrent attacks, and no differences in the outcomes of patients with recurrent facial palsy were observed. Recurrence time ranged from 6 months to 6 years. CONCLUSION: The results of this study indicate that both Bell's palsy and cause-defined facial palsy in children have a very good prognosis. Medical treatment based on corticosteroids is not certainly effective in improving outcomes in children. Recurrent attacks occurred in 6 years from the onset which leads to the conclusion that we should have a long-term follow-up of patients diagnosed with Bell's palsy. PMID- 29427138 TI - Correction to: Development of micro mechanical device having two-dimensional array of micro chambers for cell stretching. AB - The original article has been corrected. Instances of the character "MU" should be replaced by the term "micro". PMID- 29427140 TI - Quantifying Analysis of Uncertainty in Medical Reporting: Creation of User and Context-Specific Uncertainty Profiles. AB - While uncertainty is ubiquitous in medical practice, minimal work to date has been performed to analyze the cause and effect relationship between uncertainty and patient outcomes. In medical imaging practice, uncertainty in the radiology report has been well documented to be a source of clinician dissatisfaction. Before one can effectively create intervention strategies aimed at reducing uncertainty, it must first be better understood through context- and user specific analysis. One strategy for accomplishing this task is to characterize the source of uncertainty and create user-specific uncertainty profiles which take into account a number of provider-specific variables which may contribute to report uncertainty. The resulting data can in turn be used to create real-time report uncertainty metrics aimed at providing uncertainty analytics at the point of care, for the combined purposes of decision support, improved communication, and enhanced clinical/economic outcomes. PMID- 29427139 TI - Irrigation water quality and the threat it poses to crop production: evaluating the status of the Crocodile (West) and Marico catchments, South Africa. AB - Ensuring food security is becoming increasingly difficult due to limited freshwater resources. Low-quality irrigation water also poses a severe threat to crop yield and quality. The aim of this study was to evaluate the water quality associated with the Crocodile (West) and Marico catchments, which represent one of South Africa's most developed regions. Sources of irrigation water include the hypertrophic Hartbeespoort Dam, as well as the heavily impacted Crocodile (West) River. Analysis of historical irrigation water quality data (from January 2005 to December 2015) revealed that the Hartbeespoort and Crocodile (West) irrigation schemes were exposed to calcium sulfate enrichment, likely as a result of extensive mining activities in the Bushveld Igneous Complex. Also, significant differences in water quality parameters occurred between these irrigation schemes and the reference system (Marico-Bosveld Irrigation Scheme), while important salt (chloride and sodium) and nutrient (inorganic nitrogen and orthophosphate (as phosphorus)) concentrations exceeded threshold values provided by irrigation water quality guidelines. The Hartbeespoort and Crocodile (West) irrigation schemes also presented distinctive temporal (long-term and seasonal) patterns in water quality. Seasonal variation in pH levels at the Hartbeespoort Irrigation Scheme is likely caused by excessive algae growth and cyanobacteria blooms (Mycrocystis sp.), which also pose an important threat to human and animal health. Despite mitigation efforts by government and other stakeholders, some of South Africa's major irrigation schemes remain highly impacted as a result of water quality deterioration. PMID- 29427141 TI - ? PMID- 29427142 TI - ? PMID- 29427144 TI - Outcomes of synchronous and metachronous bilateral small renal masses (< 4 cm): a population-based cohort study. AB - OBJECTIVES: To report longitudinal outcomes of a population-based cohort of patients diagnosed with bilateral small renal masses from a period of over 11 years. PATIENTS AND METHODS: Consecutive patients diagnosed with bilateral small renal masses (synchronous or metachronous) of a defined geographical area were recorded in a large database (TUCAN database) between January 2005 and December 2016. Patients had a unique identifier number and followed during this period using an agreed upon protocol. Clinicopathological characteristics and outcomes of bilateral small renal masses on active surveillance were analysed and compared to propensity score-matched sporadic unilateral small renal masses. Data were analysed for renal mass growth rate, rate of intervention and development of metastatic disease and patient survival. RESULTS: A total of 1060 patients were diagnosed with renal cancer, of which bilateral small renal masses accounted for 70 (6.6%) cases. Synchronous SRMs were observed in 63 patients, whereas metachronous lesions were found in seven patients during the study period. Metachronous lesion mean time to appearance was 62 +/- 41 months (range 9-149 months). While most cases were sporadic, four were found to be hereditary. Growth rate of bilateral small renal masses did not differ from that of unilateral sporadic small renal masses. Similarly, there were no differences between the groups for rate of interventions and survival. CONCLUSIONS: Progression, rate of metastases and survival for patients diagnosed with bilateral small renal masses are similar to those diagnosed with unilateral disease. PMID- 29427143 TI - The Speed of Progression to Tobacco and Alcohol Dependence: A Twin Study. AB - We investigated the etiological role of genetic and environmental influences for two milestones of tobacco and alcohol use: age of initiation, and speed of progression to dependence (latency). Study participants included 1352 monozygotic and 1422 dizygotic twins (mean age at assessment = 24.31). Earlier ages of initiation significantly increased the likelihood of developing dependence, but were associated with longer dependence latencies for tobacco and alcohol. Latencies to dependence were heritable traits for tobacco (a2 = 0.63) and alcohol (a2 = 0.64). Genetic influences contributing to early age of initiation were associated with faster latencies to dependence but sometimes were counteracted by environmental factors, the extent to which depended on substance and, sometimes, sex. Our findings may have important implications for public policy and add to the literature by characterizing the genetic and environmental contributions to the speed of progression to tobacco and alcohol dependence. PMID- 29427145 TI - Effect of ultrasound on lactic acid production by Lactobacillus strains in date (Phoenix dactylifera var. Kabkab) syrup. AB - Date syrup is rich in fermentable sugars and may be used as a substrate for different microbial fermentations, including lactic acid fermentation processes. The beneficial effects of ultrasounds (US) on bioprocesses have been reported for several microorganisms, due to the enhancement of cell growth, as well as improvements in yields and productivities. Therefore, US treatments (30 kHz, 100 W, 10-30 min) were applied to two lactobacilli (Lactobacillus helveticus PTCC 1332 and Lactobacillus acidophilus PTCC 1643), during fermentation using date syrup as substrate. The effects on lactic acid fermentation were evaluated by analyzing cell growth (dry cell weight and viable cell count), substrate consumption (quantification of glucose and fructose), and product formation (quantification of lactic acid) over time. The effects of US were also evaluated on cell membrane permeability. Both lactobacilli were able to grow well on date syrup without the need for addition of further ingredients. The US effects were highly dependent on treatment duration: treatments of 10- and 20-min stimulated lactobacilli growth, while the treatment extension to 30 min negatively affected cell growth. Similarly, the 10- and 20-min treatments increased sugar consumption and lactic acid production, contrarily to the 30-min treatment. All US treatments increased cell membrane permeability, with a more pronounced effect at more extended treatments. The results of this work showed that application of appropriate US treatments could be a useful tool for stimulation of lactic acid production from date syrup, as well as for other fermentative processes that use date syrup as substrate. PMID- 29427146 TI - From the primitive streak to the somitic mesoderm: labeling the early stages of chick embryos using EGFP transfection. AB - Mesoderm is derived from the primitive streak. The rostral region of the primitive streak forms the somitic mesoderm. We have previously shown the developmental origin of each level of the somitic mesoderm using DiI fluorescence labeling of the primitive streak. We found that the more caudal segments were derived from the primitive streak during the later developmental stages. DiI labeled several pairs of somites and showed the distinct rostral boundary; however, the fluorescence gradually disappeared in the caudal region. This finding can be explained in two ways: the primitive streak at a specific developmental stage is primordial of only a certain number of pairs of somites, or the DiI fluorescent dye was gradually diluted within the primitive streak by cell division. Here, we traced the development of the primitive streak cells using enhanced green fluorescent protein (EGFP) transfection. We confirmed that, the later the EGFP transfection stage, the more caudal the somites labeled. Different from DiI labeling, EGFP transfection performed at any developmental stage labeled the entire somitic mesoderm from the anterior boundary to the tail bud in 4.5-day-old embryos. Furthermore, the secondary neural tube was also labeled, suggesting that not only the somite precursor cells but also the axial stem cells were labeled. PMID- 29427148 TI - Out-of-Pocket Household Expenditures on Medical Injections in Cambodia. AB - BACKGROUND: Cambodia has one of the highest rates of overall medical injection usage worldwide. Therapeutic injections, which are often unnecessary, contribute to the spread of blood-borne diseases. OBJECTIVE: This study describes injection practices and associated household expenditures in rural northwest Cambodia. METHODS: We assessed care-seeking patterns of surveyed adult family members who sought healthcare in the previous 30 days, including location of care, medical injection use, and out-of-pocket household expenditures for treatment. A regression model was used to explore the impact of injection use on out-of-pocket household expenditures. RESULTS: Among 480 households sampled, 298 included members who had been sick within the previous 30 days; a total of 342 episodes of care had been sought. Private providers accounted for over 66% (n = 226) of all episodes of care, with public and informal providers accounting for 20% (n = 69) and 14% (n = 47), respectively. Injections were administered in over 120 (35%) episodes of care, with 81% of injections administered by private providers. Patients who received injections incurred total out-of-pocket household expenditures that were, on average, 126,590 Cambodian Riel (KHR) (US$31.65) higher than those who did not receive injections (p < 0.01), equivalent to nearly half of the country's total annual health expenditure per capita. Receiving injections and perceived severity of illness were significantly associated with higher out-of-pocket household expenditures. CONCLUSION: This study found high levels of medical injection use, particularly among private healthcare providers, which was significantly associated with high healthcare expenditures. Reducing the number of medical injections would not only reduce disease transmission risk but also contribute to reduced healthcare costs and greater financial protection. PMID- 29427147 TI - Anatomical relation between the accessory process and pedicle in the lumbar vertebrae. AB - The pedicle screw is one of the most common medical devices used in spinal surgery. Although there are well-established insertion points based on anatomical landmarks, such as the mammillary process and the transverse process, morphological data on the relationship between the accessory process and the pedicle are still scarce. To clarify this relationship, we recruited 50 cases of hernia of lumbar intervertebral disc, diagnosed using three-dimensional computed tomography of the lumbar vertebrae. We identified the pedicle isthmus in a transverse plane parallel to the upper endplate and measured the angles and distances from the tip of the accessory process to the intersection points at the medial or lateral surface, or at the midpoint between the two intersection points. In a sagittal plane showing the pedicle isthmus, we measured the wedging angle of the vertebral body as well as the angle from the tip of accessory process to the posterior edge of the upper endplate of vertebral body, or to the lower end of the pedicle root. We found that from the tip of the accessory process passing through the pedicle isthmus, a line should be directed 20 (+/- 6.6) degrees medially in the transverse plane and 5 (+/- 4.3) degrees cranially in the sagittal plane. This distance from the tip of the accessory process to the isthmus was 1.5 (+/- 0.3) cm. Our study provides a new anatomical basis for the use of the accessory process as a landmark for insertion of the pedicle screw. PMID- 29427149 TI - Phase I trial of dasatinib, lenalidomide, and temozolomide in children with relapsed or refractory central nervous system tumors. AB - Single agent studies targeting the tumor microenvironment in central nervous system (CNS) tumors have largely been disappointing. Combination therapies targeting various pathways and cell types may be a more effective strategy. In this phase I study, we evaluated the combination of dasatinib, lenalidomide, and temozolomide in children with relapsed or refractory primary CNS tumors. Patients 1-21 years old with relapsed or refractory CNS tumors were eligible. Starting doses of dasatinib and lenalidomide were 65 mg/m2/dose twice daily and 55 mg/m2 once daily, respectively, while temozolomide was constant at 75 mg/m2 daily. The study followed a 3 + 3 phase I design, with a 4-week dose-limiting toxicity (DLT) evaluation period. Serial peripheral blood lymphocyte subsets were evaluated in consenting patients. Fifteen patients were enrolled and thirteen were DLT evaluable. DLTs occurred in 5 patients, including somnolence and confusion (1 patient), hypokalemia (1 patient) and thrombocytopenia (3 patients). The maximum tolerated dose for the combination was dasatinib 65 mg/m2 twice daily, lenalidomide 40 mg/m2 daily, and temozolomide 75 mg/m2 daily, for 21 days followed by 7 days rest in repeating 28-day cycles. Transient increases in natural killer effector cells and cytotoxic T-cells were seen after 1 week of treatment. One out of six response-evaluable patients showed a partial response. The combination was feasible and relatively well tolerated in this heavily pre treated population. The most common toxicities were hematologic. Preliminary evidence of clinical benefit was seen. PMID- 29427150 TI - Programmed death ligand 1 expression and tumor infiltrating lymphocytes in neurofibromatosis type 1 and 2 associated tumors. AB - Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been shown to be effective in treating patients with a variety of cancers. Biomarker studies have found positive associations between clinical response rates and PD-L1 expression on tumor cells, as well as the presence of tumor infiltrating lymphocytes (TILs). It is currently unknown whether tumors associated with neurofibromatosis types 1 and 2 (NF1 and NF2) express PD-L1. We performed immunohistochemistry for PD-L1 (clones SP142 and E1L3N), CD3, CD20, CD8, and CD68 in NF1-related tumors (ten dermal and six plexiform neurofibromas) and NF2-related tumors (ten meningiomas and ten schwannomas) using archival formalin-fixed paraffin-embedded tissues. Expression of PD-L1 was considered positive in cases with > 5% membranous staining of tumor cells, in accordance with previously published biomarker studies. PD-L1 expression in tumor cells (using the SP142 and E1L3N clones, respectively) was assessed as positive in plexiform neurofibromas (6/6 and 5/6) dermal neurofibromas (8/10 and 6/10), schwannomas (7/10 and 10/10), and meningiomas (4/10 and 2/10). Sparse to moderate presence of CD68, CD3, or CD8 positive TILs was found in 36 (100%) of tumor specimens. Our findings indicate that adaptive resistance to cell-mediated immunity may play a major role in the tumor immune microenvironment of NF1 and NF2-associated tumors. Expression of PD-L1 on tumor cells and the presence of TILs suggest that these tumors might be responsive to immunotherapy with immune checkpoint inhibitors, which should be explored in clinical trials for NF patients. PMID- 29427151 TI - Medulloblastoma with transitional features between Group 3 and Group 4 is associated with good prognosis. AB - Medulloblastoma, the most common malignant pediatric brain tumor, is a heterogeneous disease, with the existence of at least four molecular types: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4 tumors. The latter two groups, which can be identified by an application of multi-gene expression or methylation profiling, show sometimes ambiguous categorization and are still classified for diagnostic reason as non-SHH/non-WNT medulloblastomas in updated WHO 2016 classification. In order to better characterize non-SHH/non-WNT tumors, we applied the method based on the Nanostring nCounter Technology, using the 26 genes codeset in 68 uniformly treated medulloblastoma patients. This allowed for identification of tumors, which shared common Group 3 and Group 4 gene signatures. We recognized three transcriptional groups within non-WNT/non-SHH tumors: Group 3, Group 4 and the Intermediate 3/4 Group. Group 3, in line with previously published results, showed poor prognosis with survival rate < 40%, frequent metastases, large cell/anaplastic pathology and presence of tumors with MYCC amplification. This is in contrast to patients from the Intermediate 3/4 Group who showed the best survival rate (100%). Overall and progression free survival were better for this group than for Group 3 (p = 0.001, for both) and Group 4 (p = 0.064 and p = 0.066, respectively). Our work supports the view that within the non-WNT/non-SHH tumors different risk groups exist and that the current two groups classifier may be not sufficient for proper clinical categorization of individual patients. PMID- 29427152 TI - Solitary-fibrous tumor/hemangiopericytoma of the central nervous system: a population-based study. AB - The World Health Organization (WHO) classification of tumors of the central nervous system (CNS) was recently updated, restructuring solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) into one combined entity. This is the first population-based study to examine outcomes of SFT/HPC based on the new WHO guidelines. The Surveillance, Epidemiology, and End Results (SEER) database (1998 2013) was queried to examine age-adjusted incidence and prognostic factors associated with overall survival in 416 surgically resected cases. Age-adjusted incidence was calculated to be 3.77 per 10,000,000 and was rising. Median survival was 155 months, with 5- and 10-year survival rates of 78 and 61%, respectively. Younger age, Asian/Pacific Islander versus white race, benign histology, tumor location, gross-total resection (GTR), and GTR plus radiation (RT) versus subtotal resection were significantly associated with survival. In multivariable analysis, older age (HR = 1.038, p < 0.0001), infratentorial location (HR = 2.019, p = 0.038), GTR (HR = 0.313, p = 0.041), and GTR + RT (HR = 0.215, p = 0.008) were independent prognostic factors. In the HPC and borderline/malignant subgroups, GTR + RT was associated with significantly increased survival compared with GTR alone (HR = 0.537, p = 0.039 and HR = 0.525, p = 0.038). After eliminating patients that died within 3 months of diagnosis, GTR + RT was still associated with an incremental increase in survival (HR = 0.238, p = 0.031) over GTR alone (HR = 0.280, p = 0.054). GTR + RT may be optimal in the management CNS HPC and SFT/HPC tumors with borderline/malignant features. This study, in combination with existing literature, warrants further investigation of adjuvant radiation through a prospective clinical trial. PMID- 29427154 TI - Genital epidermal horn cyst (atheroma) after female genital mutilation WHO type III b. PMID- 29427153 TI - Effect of pH on the Transformation of a New Readymix Formulation of the Herbicides Bispyribac Sodium and Metamifop in Water. AB - A laboratory experiment was conducted to investigate the effect of pH on the persistence and the dissipation of the new readymix formulation of bispyribac sodium and metamifop. The experiment was conducted in water of three different pH viz. 4.0, 7.0 and 9.2. The spiking level of both the compounds in water was 1.0 and 2.0 ug/mL. The residues were extracted by a simple, quick and reliable method and quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS). The method was justified based on the recovery study, which was > 85%. The dissipation of both compounds followed first order kinetics. The half-life values ranged between 19.86-36.29 and 9.92-19.69 days for bispyribac sodium and metamifop, respectively. The pH of water has a prominent effect on degradation of both the compounds. The rate of dissipation of both the compounds was highest in water of acidic pH followed by neutral and alkaline pH. PMID- 29427155 TI - Spatial patterns of pollutants in water of metropolitan drain in Lahore, Pakistan, using multivariate statistical techniques. AB - The present study was conducted to investigate the pollutant load in surface water of the Sattukatla drain in Lahore, Pakistan. This drain is receiving high volumes of pollutants from industries and municipal sewage. To study the pollution status of this urban drain, different parameters such as pH, EC, TDS, BOD, NO3, PO4, COD, K, Mg, Ca, Ni, Fe, Co, Pb, Cu, Cd, and Zn were analyzed. These 17 parameters were monitored along the longitudinal gradient of drain consisting of 15 key sampling sites. The studied parameters were subjected to hierarchical cluster analysis (HCA) and factor analysis (FA). The HCA divided 15 sampling sites into three zones, i.e., low pollution, medium pollution, and high pollution. The PCA identified three major contributors, industrial followed by municipal sewage and agricultural sources. The trend of heavy metal levels was observed as Cu > Zn > Fe > Pb > Co > Ni > Cd. The results indicate levels of pollutants above the permissible limits described by NEQS, Pakistan for wastewater. There is an urgent need to address the issue and install treatment plants to reduce the pollution load on this urban drain in Lahore city. PMID- 29427156 TI - Monogenean parasites infect ornamental fish imported to Australia. AB - The ornamental fish trade provides a pathway for the global translocation of aquatic parasites. We examined a total of 1020 fish imported from Singapore, Malaysia, Thailand, or Sri Lanka to Australia (including freshwater and marine fish species) for monogenean ectoparasites. Fish were received following veterinary certification that they showed no clinical signs of pests and diseases from the exporting country and visual inspection at Australian border control. Australian import conditions require mandatory treatment for goldfish with parasiticides (e.g. trichlorfon, formaldehyde, sodium chloride) for the presence of gill flukes (Dactylogyrus vastator Nybelin, 1924 and Dactylogyrus extensus Mueller and Van Cleave, 1932) prior to export. Over 950 individual parasites were detected in five imported fish species, representing 14 monogenean species. Seven Dactylogyrus spp. including D. vastator and three Gyrodactylus spp. infected goldfish, Carassius auratus Linnaeus, 1758, from Malaysia, Singapore, and Thailand. Dactylogyrus ostraviensis Rehulka, 1988, infected rosy barb, Pethia conchonius Hamilton, 1822, from Singapore, Sri Lanka, and Thailand while two Trianchoratus spp. infected three spot gourami, Trichopodus trichopterus Pallas, 1970 and pearl gourami Trichopodus leerii Bleeker, 1852, from Sri Lanka. Urocleidoides reticulatus Mizelle & Price, 1964, infected guppy, Poecilia reticulata Peters, 1859, from Sri Lanka. The discovery of D. vastator in goldfish, as well as 13 other monogenean species, shows that pre-export health requirements, which include chemical treatment of goldfish, and inspection of all ornamental fish species did not prevent infection by monogeneans. Inspection prior to exportation and at border control must account for the highly cryptic nature of monogenean parasites and consider alternatives to current pre-export conditions and visual inspection at border control. PMID- 29427157 TI - Ultrastructural characterization of sensilla and microtrichia on the antenna of female Haematopota pandazisi (Diptera: Tabanidae). AB - The haematophagous females of the cleg fly Haematopota pandazisi (Krober) (Diptera: Tabanidae) are a common pest in areas inhabited by wild and domestic ungulates in southern Europe, North Africa and Anatolia. A morphological investigation by scanning electron microscopy (SEM) was carried out for the first time on the antennae of females of H. pandazisi, with special attention to the type and distribution of sensilla and microtrichia. The typical brachyceran antenna is divided into three regions: the scape, the pedicel and the flagellum, which is the longest of the three and is composed of four flagellomeres. The scape and pedicel are characterized by only one type of microtrichium and chaetic sensillum, whereas five types of microtrichia and sensilla were identified on the flagellum and classified according to shape and distribution. The sensilla are of the chaetic, clavate, basiconic, trichoid and coeloconic types; the latter with either a basiconic or grooved peg inside. The results obtained in this study were compared to those found in other species in the family Tabanidae and other Diptera, with special attention to haematophagous species. PMID- 29427158 TI - The Turning Point for Morphomechanical Remodeling During Complete Intestinal Obstruction in Rats Occurs After 12-24 h. AB - Intestinal obstruction prompts luminal dilation and wall remodeling proximal to the site of obstruction. Studies on temporal and spatial morphomechanical remodeling are needed for comprehending the pathophysiology of acute intestinal obstruction. The aim was to estimate the no-load and zero-stress morphomechanical properties in circumferential and longitudinal direction at 0, 6, 12, 24, 36, and 48 h after complete intestinal obstruction. Obstruction of the distal ileum was created surgically by placement of a polyethylene ring for up to 48 h in 30 rats. Sham and normal groups were also studied (n = 12). Five 6 cm-long intestinal segments proximal to the obstruction site were used for histological, morphometric and mechanical analysis at the designated times. Morphomechanical changes were huge but only subtle changes were observed between the 5 segments during the obstruction period. Due to dilation, the serosal length and mucosal length increased continuously from 6 to 48 h (p < 0.001). The wall area increased at 24 h and beyond (p < 0.001), demonstrating tissue growth. The opening and bending angle decreased to minimum values at 24 h where after the opening angle increased and the bending angle returned to pre-obstruction levels. For the residual stretch ratios and the position of the neutral axis the turning point was found after 24 h. Histologically, the thickness and area of most wall layers were quite stable for the first 12 h but with an increase at the 24 h time point that continued to the 48 h time point. The most pronounced change was found for the circumferential muscle layer (p < 0.05). Analysis of picrosirius red stained slides showed that submucosal type 3 collagen fraction increased significantly (p < 0.001), whereas the fraction of type 1 collagen decreased (p < 0.001). In conclusion, pronounced time-dependent morphomechanical remodeling was found. The obstructed intestine went from dilation remodeling to growth remodeling during the interval 12-24 h after creating the obstruction. PMID- 29427160 TI - Metformin-Associated Lactic Acidosis: A Case Report. AB - A 54-year-old woman with type 2 diabetes mellitus, hypertension, and peripheral vascular disease developed life-threatening lactic acidosis during treatment with metformin for type 2 diabetes. The woman received metformin at 1000 mg orally twice a day for type 2 diabetes. She presented to our emergency department with a 3-day history of severe watery diarrhea, nausea, and vomiting. Her grandson whom she cared for had gastroenteritis several days prior to the onset of her symptoms. She was confused and hypotensive with a blood pressure of 70/39 mmHg. Her initial laboratory findings were remarkable with an arterial blood gas pH 6.57, HCO[Formula: see text] 2 mEq/L, anion gap 30 mmol/L, and lactate 16.3 mmol/L. She was diagnosed with severe lactic acidosis. Metformin was discontinued. Upon arrival in the emergency department, she became unresponsive and experienced a pulseless electrical activity cardiac arrest. After resuscitation, her severe acidemia persisted despite aggressive intervention with volume resuscitation and vasopressors, leading to the initiation of renal replacement therapy. After multiple dialysis treatments, her severe acidemia resolved. Serum metformin concentration from presentation ultimately returned to 42 mcg/mL (therapeutic concentration: 1-2 mcg/mL). She was discharged from the hospital on day 15 without any neurologic complications. A Naranjo assessment score of 8 was obtained, indicating a probable relationship between the patient's lactic acidosis and her use of the suspect drug. PMID- 29427159 TI - Can anticancer chemotherapy promote the progression of brain metastases? AB - Brain metastases natural history from one primary tumor type might be accelerated or favored by using certain systemic chemotherapy. A great deal was described in mice and suggested in human with antiangiogenic drugs, but little is known about the metastatic progression generated by the perverse effect of anticancer drugs. A total of 413 patients who underwent treatment for brain metastasis (2013-2016) were included. The identification of all previous anticancer drugs received by patients from primary tumor diagnosis to brain metastases diagnosis was collated. The median value for the time of first appearance of brain metastasis in all patients was 13.1 months (SD 1.77). The values of brain metastasis-free survival (bMFS) for each primary cancer were: 50.9 months (SD 8.8) for breast, 28.5 months (SD 11.4) for digestive, 27.7 months (SD 18.3) for melanoma, 12.3 months (SD 8.3) for kidney, 1.5 months (SD 0.1) for lung and 26.9 months (SD 18.3) for others (p < 0.009). Through Cox multivariate proportional hazard model, we identified that the only independent factors associated with short bMFS were: lung primary tumor [odd ratio (OR) 0.234, CI 95% 0.16-0.42; p < 0.0001] and mitotic spindle inhibitor (taxanes) chemotherapy [OR 0.609, CI 95% 0.50-0.93; p < 0.001]. Contrariwise, breast primary tumor [odd ratio (OR) 2.372, CI 95% 1.29-4.3; p < 0.005] was an independent factor that proved a significantly longer bMFS. We suggest that anticancer drugs, especially taxane and its derivatives, could promote brain metastases, decreasing free survival. Mechanisms are discussed but still need to be determined. PMID- 29427161 TI - Safety of Pseudomonas chlororaphis as a gene source for genetically modified crops. AB - Genetically modified crops undergo extensive evaluation to characterize their food, feed and environmental safety prior to commercial introduction, using a well-established, science-based assessment framework. One component of the safety assessment includes an evaluation of each introduced trait, including its source organism, for potential adverse pathogenic, toxic and allergenic effects. Several Pseudomonas species have a history of safe use in agriculture and certain species represent a source of genes with insecticidal properties. The ipd072Aa gene from P. chlororaphis encodes the IPD072Aa protein, which confers protection against certain coleopteran pests when expressed in maize plants. P. chlororaphis is ubiquitous in the environment, lacks known toxic or allergenic properties, and has a history of safe use in agriculture and in food and feed crops. This information supports, in part, the safety assessment of potential traits, such as IPD072Aa, that are derived from this source organism. PMID- 29427162 TI - FGF-21 Elevated IL-10 Production to Correct LPS-Induced Inflammation. AB - Fibroblast growth factor 21 (FGF-21) has been previously judged as a major metabolic regulator. In this paper, we show that FGF-21 has a potential role in anti-inflammation and immunoregulation. In vivo, treatment with exogenous FGF-21 can alleviate LPS-induced inflammation. In vitro, FGF-21 inhibited LPS-induced IL 1beta expression in THP-1 cells. Furthermore, besides the NF-kappaB pathway, the mechanism of action of FGF-21 was observed to involve the elevation of IL-10 in the ERK1/2 pathway. This study clearly indicates that FGF21 can be used as an attractive target for the management of inflammatory disorders. This piece of research indicates that FGF-21 could have much value in the management of inflammatory disorders. PMID- 29427163 TI - Anti-Inflammatory Effects of Hypophyllanthin and Niranthin Through Downregulation of NF-kappaB/MAPKs/PI3K-Akt Signaling Pathways. AB - Hypophyllanthin (HYP) and niranthin (NIR) are major lignans in Phyllanthus spp. and have been shown to possess strong anti-inflammatory activity. In this study, we investigated the anti-inflammatory effects and the underlying molecular mechanisms of HYP and NIR in in vitro cellular model of LPS-induced U937 macrophages. The effects of HYP and NIR on the production of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) were measured by using ELISA, Western blot, and qRT PCR. The expressions of signaling molecules related to nuclear factor-kappa B (NF kappaB), mitogen-activated protein kinases (MAPKs), and phosphatidylinositol 3' kinase-Akt (PI3K-Akt) signaling pathways were examined. The role of NF-kappaB, MAPKs, and Akt signaling pathways was confirmed by using specific inhibitors (BAY 11-7082, U0126, SB202190, SP600125, and LY294002) mediated suppression of TNF alpha and COX-2 production. HYP and NIR significantly inhibited the protein and gene levels of COX-2 as well as the downstream signaling products of PGE2, TNF alpha, and IL-1beta. HYP and NIR also suppressed the inhibitors of kappa B (IkappaB), IkB kinases (Ikkalpha/beta), NF-kappaB phosphorylation, and IkappaB degradation. HYP suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 while NIR only suppressed JNK and ERK but did not have effect on p38. These results demonstrate that HYP and NIR downregulated COX-2, TNF-alpha, and IL-1beta gene expressions in U937 macrophages by interfering with the activation of NF-kappaB, MAPKs, and Akt. In conclusion, these lignans have potential to be developed as anti-inflammatory agents targeting the NF-kappaB, MAPK, and PI3K-Akt pathways. PMID- 29427164 TI - Plasma gelsolin level predicts acute kidney injury after cardiopulmonary bypass in infants and young children. AB - BACKGROUND: Acute kidney injury (AKI) after cardiopulmonary bypass (CPB) is a common complication especially in pediatric population. Plasma gelsolin (pGSN) is an anti-inflammatory factor through binding with actin and pro-inflammatory cytokines in circulation. Decrease in pGSN has been reported in some pathologic conditions. The purpose of the study was to determine the alterations of pGSN level in infants and young children after CPB and the role of pGSN as a predictor for the morbidity and severity of post-CPB AKI. METHODS: Sixty-seven infants and young children at age <= 3 years old undergoing CPB were prospectively enrolled. PGSN levels were measured during peri-operative period with enzyme-linked immuno sorbent assay and normalized with plasma total protein concentration. Other clinical characteristics of the patients were also recorded. RESULTS: In patients developing AKI, the normalized pGSN (pGSNN) levels significantly decreased at 6 h post-operation and remained low for 24 h post-operation as compared to the patients with non-AKI. PGSNN at 6 h post-operation combining with CPB time presents an excellent predictive value for AKI. CONCLUSIONS: Decreased pGSNN identifies post-CPB AKI in the patients <= 3 years old, and is associated with adverse clinical outcomes. The findings suggest that circulating GSN in post-CPB patients may have beneficial effects on diminishing inflammatory responses. PMID- 29427165 TI - Association of MTHFR gene polymorphisms with migraine in North Indian population. AB - Polymorphisms in MTHFR gene are mostly associated with increased levels of homocysteine in the absence of dietary folate and are a risk factor for complex neurovascular diseases like migraine. The aim of present case-control study was to determine the association between MTHFR gene polymorphisms (C667T; rs 1801133, A1298C; rs 1801131) with migraine susceptibility. In total, 100 patients with migraine (23with MA and 77 with MO) and age-sex matched 100 healthy controls were included in this study from OPD of ESIC Medical College & Hospital, Faridabad. Genotyping was done by PCR-RFLP method. Genotypic and allelic frequencies were compared by SPSS 24 version. Genotypic results indicated a non-significant increase in frequencies of CT and TT in C667T SNP in migraine patients with control (52 and 10% vs. 42 and 7%: p > 0.05), but CC genotype in A1298C was found to be a risk factor in migraine patients than controls (30 vs. 17% respectively: p < 0.05). On comparing migraine subclasses, migraine with aura (MA) and without aura (MO) with control groups, the present study suggests that in MTHFR polymorphisms, the prevalence of 677CT genotype and T allele in C667T SNP influences susceptibility to MA (p < 0.05) but not to MO. Meanwhile, CC genotype in A1298C SNP could be a risk factor for migraine patients without aura (p < 0.05). PMID- 29427166 TI - The epidemiology of Parkinson's disease in the Italian region Friuli Venezia Giulia: a population-based study with administrative data. AB - Parkinson's disease is known to pose a relevant burden to society in industrialized countries. However, not much research has been conducted on the epidemiology of this disease in Italy. Our aim was to estimate the incidence rate and prevalence of Parkinson's disease in the Italian Friuli Venezia Giulia region using administrative health-related databases. Five regional administrative databases (hospitalizations, exemptions from medical charges, drug prescriptions, nursing homes, and home visits) were individually linked with one another through an anonymous stochastic univocal key. Using a pre-defined algorithm, incident and prevalent cases of Parkinson's disease were identified for the year 2016. The estimated regional incidence rate was 0.28 new cases/1000 person-years; prevalence was 3.89/1000 inhabitants. Both increased with increasing age and were higher among males than among females. A considerable proportion of prevalent cases was admitted to the hospital or nursing home in 2016, whereas only a few received home visits by health professionals. The incidence and prevalence of the disease were considerable, especially in the older population, indicating the need to develop multidisciplinary models to care for patients living in the region. PMID- 29427168 TI - Diagnostic test accuracy of the Montreal Cognitive Assessment in the detection of post-stroke cognitive impairment under different stages and cutoffs: a systematic review and meta-analysis. AB - The purposes of this review were to give the optimal cutoffs of the Montreal Cognitive Assessment (MoCA) by comparing sensitivity and specificity under different cutoffs and compare the MoCA with other screening tools in post-stroke cognitive impairment (PSCI) determined by a neuropsychological evaluation. Articles were derived from a systematic search in PubMed, Web of science, Embase, and CINAHL and were assessed for internal validity by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The figure of risk of bias was made by Review Manager 5.3, and data of selected studies were synthesized by MetaDisc 1.4. Twelve diagnostic studies, involving 2130 patients, were included. The area under the curve (AUC) under cutoffs of 20v19, 21v20, and 26v25 are 0.90, 0.90, and 0.95, showing high predictive validity for PSCI screening within 1 month. When the sensitivity and specificity are equal important, the optimal cutoff is 20v19 (Youden Index = 0.58). Compared to the Mini-Mental State Examination (MMSE), the MoCA has higher sensitivity but lower specificity. The optimal cutoff differs in different stages of stroke. Both the MMSE and MoCA are appropriate screening tools for PSCI, and the use of these two tools should be in accordance with the aim of screening. The Addenbrooke's Cognitive Examination-Revised (ACE R) can act as a supplement for the MoCA. PMID- 29427169 TI - Multi-pollutant Modeling Through Examination of Susceptible Subpopulations Using Profile Regression. AB - PURPOSE OF REVIEW: The inter-correlated nature of exposure-based risk factors in environmental health studies makes it a challenge to determine their combined effect on health outcomes. As such, there has been much research of late regarding the development and utilization of methods in the field of multi pollutant modeling. However, much of this work has focused on issues related to variable selection in a regression context, with the goal of identifying which exposures are the "bad actors" most responsible for affecting the health outcome of interest. However, the question addressed by these approaches does not necessarily represent the only or most important questions of interest in a multi pollutant modeling context, where researchers may be interested in health effects from co-exposure patterns and in identifying subpopulations associated with patterns defined by different levels of constituent exposures. RECENT FINDINGS: One approach to analyzing multi-pollutant data is to use a method known as Bayesian profile regression, which aids in identifying susceptible subpopulations associated with exposure mixtures defined by different levels of each exposure. Identification of exposure-level patterns that correspond to a location may provide a starting point for policy-based exposure reduction. Also, in a spatial context, identification of locations with the most health-relevant exposure mixture profiles might provide further policy relevant information. In this brief report, we review and describe an approach that can be used to identify exposures in subpopulations or locations known as Bayesian profile regression. An example is provided in which we examine associations between air pollutants, an indicator of healthy food retailer availability, and indicators of poverty in Los Angeles County. A general tread suggesting that vulnerable individuals are more highly exposed and have limited access to healthy food retailers is observed, though the associations are complex and non-linear. PMID- 29427170 TI - Exploration into Uric and Cardiovascular Disease: Uric Acid Right for heArt Health (URRAH) Project, A Study Protocol for a Retrospective Observational Study. AB - The relevance of cardiovascular role played by levels of serum uric acid is dramatically growing, especially as cardiovascular risk factor potentially able to exert either a direct deleterious impact or a synergic effect with other cardiovascular risk factors. At the present time, it still remains undefined the threshold level of serum uric acid able to contribute to the cardiovascular risk. Indeed, the available epidemiological case studies are not homogeneous, and some preliminary data suggest that the so-called "cardiovascular threshold limit" may substantially differ from that identified as a cut-off able to trigger the acute gout attack. In such scenario, there is the necessity to clarify and quantify this threshold value, to insert it in the stratification of risk algorithm scores and, in turn, to adopt proper prevention and correction strategies. The clarification of the relationship between circulating levels of uric acid and cardio-nephro-metabolic disorders in a broad sample representative of general population is critical to identify the threshold value of serum uric acid better discriminating the increased risk associated with uric acid. The Uric acid Right for heArt Health (URRAH) project has been designed to define, as primary objective, the level of uricemia above which the independent risk of cardiovascular disease may increase in a significantly manner in a general Italian population. PMID- 29427172 TI - Up-regulation of Ca2+/CaMKII/CREB signaling in salicylate-induced tinnitus in rats. AB - The purpose of the study was to investigate the changes of Ca2+/calmodulin dependent protein kinases II (CaMKII)/cAMP response element-binding protein (CREB) signaling pathway in a rat tinnitus model. Eighteen Wistar rats were randomly divided into three groups: normal control (NC), normal saline (NS), and tinnitus model (TM) groups. Tinnitus model was induced by intraperitoneal injection of salicylate. The concentration of intracellular calcium level in auditory cortex cells was determined using Fura-2 acetoxymethyl ester (Fura-2 AM) method with fluorospectrophotometer. Expressions of calmodulin (CaM), N-methyl-D aspartate receptor 2B subunit (NR2B), calcium-calmodulin kinase II (CaMKII), and cAMP response element-binding protein (CREB) were detected with Western blot. Tinnitus model was successfully established by the intraperitoneal administration of salicylate in rats. Compared with rats in NC and NS groups, salicylate administration significantly elevated CaM, NR2B, phospho-CaMKII and phospho-CREB expression in auditory cortex from tinnitus model group (p < 0.05), and the free intracellular Ca2+ concentrations (p < 0.05). Our data reveal that salicylate administration causes tinnitus symptoms and elevates Ca2+/CaMKII/CREB signaling pathway in auditory cortex cells. Our study likely provides a new understanding of the development of tinnitus. PMID- 29427171 TI - CO2/bicarbonate modulates cone photoreceptor ROS-GC1 and restores its CORD6 linked catalytic activity. AB - This study with recombinant reconstituted system mimicking the cellular conditions of the native cones documents that photoreceptor ROS-GC1 is modulated by gaseous CO2. Mechanistically, CO2 is sensed by carbonic anhydrase (CAII), generates bicarbonate that, in turn, directly targets the core catalytic domain of ROS-GC1, and activates it to increased synthesis of cyclic GMP. This, then, functions as a second messenger for the cone phototransduction. The study demonstrates that, in contrast to the Ca2+-modulated phototransduction, the CO2 pathway is Ca2+-independent, yet is linked with it and synergizes it. It, through R787C mutation in the third heptad of the signal helix domain of ROS-GC1, affects cone-rod dystrophy, CORD6. CORD6 is caused firstly by lowered basal and GCAP1 dependent ROS-GC1 activity and secondly, by a shift in Ca2+ sensitivity of the ROS-GC1/GCAP1 complex that remains active in darkness. Remarkably, the first but not the second defect disappears with bicarbonate thus explaining the basis for CORD6 pathological severity. Because cones, but not rods, express CAII, the excessive synthesis of cyclic GMP would be most acute in cones. PMID- 29427173 TI - Guest editorial: advances in immunotherapy for hematological malignancies. PMID- 29427174 TI - Adverse Effects Associated with Clinical Applications of CAR Engineered T Cells. AB - Cancer has been ranked as the second leading cause of death in the United States. To reduce cancer mortality, immunotherapy is gaining momentum among other therapeutic modalities, due to its impressive results in clinical trials. The genetically engineered T cells expressing chimeric antigen receptors (CARs) are emerging as a new approach in cancer immunotherapy, with the most successful outcomes in the refractory/relapse hematologic malignancies. However, the widespread clinical applications are limited by adverse effects some of which are life-threatening. Strategies to reduce the chance of side effects as well as close monitoring, rapid diagnosis and proper treatment of side effects are necessary to take the most advantages of this valuable therapy. Here we review the reported toxicities associated with CAR engineered T cells, the strategies to ameliorate the toxicity, and further techniques and designs leading to a safer CAR T-cell therapy. PMID- 29427176 TI - Satisfaction with Subcutaneous Golimumab and its Auto-Injector among Rheumatoid Arthritis Patients with Inadequate Response to Adalimumab or Etanercept. AB - BACKGROUND: Patient perceptions of treatment success, including satisfaction/preference, may complement clinical efficacy assessments. OBJECTIVE: Our objective was to evaluate satisfaction with subcutaneous golimumab and its auto-injector in patients with rheumatoid arthritis (RA) and an inadequate adalimumab/etanercept response. METHODS: In the multicenter, assessor-blinded GO SAVE study, 433 patients with active RA (28-joint Disease Activity Score incorporating erythrocyte sedimentation rate [DAS28-ESR] >= 3.6 and six or more swollen and six or more tender joints) despite methotrexate and past adalimumab/etanercept treatment received open-label subcutaneous golimumab 50 mg every 4 weeks (q4w) through week 12. Week 16 responders (DAS28-ESR improvement from baseline > 1.2 and score <= 3.2) continued therapy through week 52; nonresponders were randomized (1:2) to double-blind subcutaneous golimumab 50 mg q4w or intravenous golimumab 2 mg/kg [weeks 16, 20, every 8 weeks (q8w)]. Patients rated satisfaction with their injection experience on a 5-point scale (1 = very dissatisfied; 5 = very satisfied) at screening, week 8 (all enrolled patients), and week 44 (for patients continuing open-label subcutaneous golimumab 50 mg q4w). Discomfort, pain, stinging, burning, and redness related to injection were assessed (none, mild, moderate, severe). RESULTS: Similar proportions of patients (N = 433) had most recently received adalimumab (50.3%) or etanercept (49.7%) prior to golimumab. Overall satisfaction (somewhat/very) with the golimumab injection experience was reported by 84.4% of patients at week 8 versus 63.4% of patients who were satisfied with prior adalimumab/etanercept. Patients receiving open-label subcutaneous golimumab through week 44 (N = 75) reported much less discomfort (60.9%), redness (60.9%), pain (59.4%), stinging (67.2%), and burning (65.6%) with the golimumab injection than with their previous tumor necrosis factor antagonist medication injection. CONCLUSION: Most patients with RA receiving golimumab following adalimumab/etanercept inadequate response were satisfied with their overall golimumab experience, including its auto-injector versus their previous injection device. CLINICAL TRIALS.GOV: NCT01004432; EudraCT 2009-010582-23. PMID- 29427177 TI - Trends in Diabetes Treatment and Monitoring among Medicare Beneficiaries. AB - BACKGROUND: Diabetes is a costly and common condition, but little is known about recent trends in diabetes management among Medicare beneficiaries. OBJECTIVE: To evaluate the use of diabetes medications and testing supplies among Medicare beneficiaries. DESIGN/SETTING: Retrospective cohort analysis of Medicare claims from 2007 to 2014. PARTICIPANTS: Traditional Medicare beneficiaries with a diagnosis of diabetes in the current or any prior year. MAIN MEASURES: We analyzed choices of first diabetes medication for those new to medication and patterns of adding medications. We also examined the use of testing supplies, use of statins and ACE inhibitors/angiotensin receptor blockers, and spending. KEY RESULTS: Diagnosed diabetes increased from 28.7% to 30.2% of beneficiaries from 2007 to 2014. The use of metformin as the most commonly prescribed first medication increased from 50.2% in 2007 to 70.2% in 2014, whereas long-acting sulfonylureas decreased from 16.6% to 8.2%. The use of thiazolidinediones fell considerably, while the use of new diabetes medication classes increased. Among patients prescribed insulin, long-acting insulin as the first choice increased substantially, from 38.9% to 56.8%, but short-acting or combination regimens remained common, particularly among older or sicker beneficiaries. Prescriptions of testing supplies for more than once-daily testing were also common. The mean total cost of diabetes medications per patient increased over the period due to the increasing use of high-cost drugs, particularly by those patients with costs above the 90th percentile of spending, although the median costs decreased for both medications and testing supplies. CONCLUSIONS: The use of metformin and long acting insulin have increased substantially among elderly Medicare patients with diabetes, but a substantial subgroup continues to receive costly and complex treatment regimens. PMID- 29427178 TI - The Effectiveness of Self-Management Interventions for Individuals with Low Health Literacy and/or Low Income: A Descriptive Systematic Review. AB - BACKGROUND: With the burden of chronic illness increasing globally, self management is a crucial strategy in reducing healthcare costs and increasing patient quality of life. Low income and low health literacy are both associated with poorer health outcomes and higher rates of chronic disease. Thus, self management represents an important healthcare strategy for these populations. The purpose of this study is to review self-management interventions in populations with low income or low health literacy and synthesize the efficacy of these interventions. METHODS: A systematic review of trials evaluating the efficacy of self-management interventions in populations with low income or low health literacy diagnosed with a chronic illness was conducted. Electronic databases were primarily searched to identify eligible studies. Data were extracted and efficacy summarized by self-management skills, outcomes, and content tailoring. RESULTS: 23 studies were reviewed, with ten reporting an overall positive effect on at least one primary outcome. Effective interventions most often included problem-solving as well as taking action and/or resource utilization. A wide range of health-related outcomes were considered, were efficacious empowerment and disease-specific quality of life were found to be significant. The efficacy of interventions did not seem to vary by duration, format, or mode of delivery or whether these included individuals with low health literacy and/or low income. Tailoring did not seem to impact on efficacy. DISCUSSION: Findings suggest that self-management interventions in populations with low income or low health literacy are most effective when three to four self-management skills are utilized, particularly when problem-solving is targeted. Healthcare providers and researchers can use these findings to develop education strategies and tools for populations with low income or low health literacy to improve chronic illness self-management. PMID- 29427179 TI - Evaluating the Quality of Patient Decision-Making Regarding Post-Acute Care. AB - BACKGROUND: Despite a national focus on post-acute care brought about by recent payment reforms, relatively little is known about how hospitalized older adults and their caregivers decide whether to go to a skilled nursing facility (SNF) after hospitalization. OBJECTIVE: We sought to understand to what extent hospitalized older adults and their caregivers are empowered to make a high quality decision about utilizing an SNF for post-acute care and what contextual or process elements led to satisfaction with the outcome of their decision once in SNF. DESIGN: Qualitative inquiry using the Ottawa Decision Support Framework (ODSF), a conceptual framework that describes key components of high-quality decision-making. PARTICIPANTS: Thirty-two previously community-dwelling older adults (>= 65 years old) and 22 caregivers interviewed at three different hospitals and three skilled nursing facilities. MAIN MEASURES: We used key components of the ODSF to identify elements of context and process that affected decision-making and to what extent the outcome was characteristic of a high quality decision: informed, values based, and not associated with regret or blame. KEY RESULTS: The most important contextual themes were the presence of active medical conditions in the hospital that made decision-making difficult, prior experiences with hospital readmission or SNF, relative level of caregiver support, and pressure to make a decision quickly for which participants felt unprepared. Patients described playing a passive role in the decision-making process and largely relying on recommendations from the medical team. Patients commonly expressed resignation and a perceived lack of choice or autonomy, leading to dissatisfaction with the outcome. CONCLUSIONS: Understanding and intervening to improve the quality of decision-making regarding post-acute care supports is essential for improving outcomes of hospitalized older adults. Our results suggest that simply providing information is not sufficient; rather, incorporating key contextual factors and improving the decision-making process for both patients and clinicians are also essential. PMID- 29427180 TI - Alleviation of Trigeminal Nociception Using p75 Neurotrophin Receptor Targeted Lentiviral Interference Therapy. AB - Acute and chronic trigeminal (TG) neuropathies are the cause of considerable distress, with limited treatments available at present. Nociceptive neurons enriched with the vanilloid type 1 receptor (VR1) partake in pain sensation and sensitization in the TG system. While VR1 blockers with anti-nociceptive potential are of substantial medical interest, their use remains limited due to poor selectivity and lack of cell-targeting capabilities. This study describes a methodology for the alleviation of nociception via targeted depletion of VR1 in TG sensory neurons in rats. In cultured TG ganglion neurons, VR1 expression was virtually abolished by lentiviral short hairpin RNA (LV-VR1). By decorating GFP encoding LV (LV-GFP) and LV-VR1 with IgG192 for targeting TG sensory neurons enriched with the p75 neurotrophin receptor (p75NTR), transduction of a reporter GFP and VR1 depletion was achieved after injection of targeted vectors into the whisker pad. In IgG192/LV-VR1-injected rats, the behavioral response to capsaicin exposure as well as Erk 1/2 phosphorylation and VR1 current activation by capsaicin were significantly reduced. This pioneering investigation, thus, provides a proof of principle for a means of attenuating TG nociception, revealing therapeutic potential. PMID- 29427182 TI - Neural mechanisms underlying subsequent memory for personal beliefs:An fMRI study. AB - Many fMRI studies have examined the neural mechanisms supporting emotional memory for stimuli that generate emotion rather automatically (e.g., a picture of a dangerous animal or of appetizing food). However, far fewer studies have examined how memory is influenced by emotion related to social and political issues (e.g., a proposal for large changes in taxation policy), which clearly vary across individuals. In order to investigate the neural substrates of affective and mnemonic processes associated with personal opinions, we employed an fMRI task wherein participants rated the intensity of agreement/disagreement to sociopolitical belief statements paired with neural face pictures. Following the rating phase, participants performed an associative recognition test in which they distinguished identical versus recombined face-statement pairs. The study yielded three main findings: behaviorally, the intensity of agreement ratings was linked to greater subjective emotional arousal as well as enhanced high confidence subsequent memory. Neurally, statements that elicited strong (vs. weak) agreement or disagreement were associated with greater activation of the amygdala. Finally, a subsequent memory analysis showed that the behavioral memory advantage for statements generating stronger ratings was dependent on the medial prefrontal cortex (mPFC). Together, these results both underscore consistencies in neural systems supporting emotional arousal and suggest a modulation of arousal-related encoding mechanisms when emotion is contingent on referencing personal beliefs. PMID- 29427183 TI - The potential role of clarithromycin addition to lenalidomide and dexamethasone therapy (BiRd) in multiple myeloma. PMID- 29427184 TI - Polyneuropathy and myopathy in beta-thalassemia major patients. AB - The thalassemias are the most common single gene disorder in the world. Nowadays, the average life expectancy of patients in developed countries has increased significantly, while, there was an increase of complications. We aimed to investigate peripheral neuropathy and myopathy in this patient group using a neurophysiological study. We performed nerve conduction studies and electromyography of upper and lower extremities on 36 beta-thalassemia major (beta-thal) patients. The electrophysiological findings were correlated with demographic data and laboratory parameters of the disease. Patients with beta thal present polyneuropathy or myopathy at (50%). Polyneuropathy was detected in (38.9%) and myopathy in (27.8%), while polyneuropathy and myopathy were present at (16.7%) with an overlap of the diseases in 1/3 of the patients. There was not a statistically significant correlation of polyneuropathy and myopathy with age, sex, splenectomy, nor with respect to laboratory parameters, hemoglobin, and ferritin. However, there was a statistically significant correlation of polyneuropathy and myopathy with iron overload, as recorded by the magnetic resonance imaging (MRI) of the heart and the liver. Our findings suggest that iron overload plays a key role in the pathogenesis of polyneuropathy and myopathy in beta-thal patients, and performing heart and liver MRI for the prediction of such lesions in an annual basis is warranted. PMID- 29427181 TI - Toxic alcohol diagnosis and management: an emergency medicine review. AB - Toxic alcohols are a group of substances containing a hydroxyl group not meant to be ingested. They are the cause of a significant number of accidental and non accidental exposures. Toxic alcohol poisoning can be associated with a significant degree of morbidity and mortality if not promptly recognized and treated. This review describes the clinical presentation and an approach to the recognition and management for toxic alcohol poisoning. Toxic alcohols classically refer to a group of alcohols not meant for ingestion. Methanol, ethylene glycol, and isopropyl alcohol are readily available in common hardware and household materials. Toxic alcohols are ingested for a variety of reasons including accidental exposures, intentional inebriation, homicide and suicide. The patient with an altered mental status or concerning history warrants consideration of this potentially deadly ingestion. Treatment considerations include alcohol dehydrogenase blockade and hemodialysis. Toxic alcohol poisoning can be an elusive diagnosis. This review evaluates toxic alcohol poisoning signs and symptoms and an approach to diagnosis and management. PMID- 29427185 TI - Geriatric nutritional risk index as a prognostic factor in patients with diffuse large B cell lymphoma. AB - The geriatric nutritional risk index (GNRI) is a simple and well-established nutritional assessment tool that is a significant prognostic factor for various cancers. However, the role of the GNRI in predicting clinical outcomes of diffuse large B cell lymphoma (DLBCL) patients has not been investigated. To address this issue, we retrospectively analyzed a total of 476 patients with newly diagnosed de novo DLBCL. We defined the best cutoff value of the GNRI as 96.8 using a receiver operating characteristic curve. Patients with a GNRI < 96.8 had significantly lower overall survival (OS) and progression-free survival (PFS) than those with a GNRI >= 96.8 (5-year OS, 61.2 vs. 84.4%, P < 0.001; 5-year PFS, 53.7 vs. 75.8%, P < 0.001). Multivariate analysis showed that performance status, Ann Arbor stage, serum lactate dehydrogenase, and GNRI were independent prognostic factors for OS. Among patients with high-intermediate and high-risk by National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI), the 5-year OS was significantly lower in patients with a GNRI < 96.8 than in those with a GNRI >= 96.8 (high-intermediate risk, 59.5 vs. 75.2%, P = 0.006; high risk, 37.4 vs. 64.9%, P = 0.033). In the present study, we demonstrated that the GNRI was an independent prognostic factor in DLBCL patients. The GNRI could identify a population of poor-risk patients among those with high-intermediate and high-risk by NCCN-IPI. PMID- 29427186 TI - Adult T cell leukemia/lymphoma with different pathological features in each tumor site. PMID- 29427187 TI - Acquired long QT syndrome during conditioning for allogeneic stem cell transplantation-are we aware of this side effect? PMID- 29427188 TI - Molecular characteristic of acute leukemias with t(16;21)/FUS-ERG. AB - T(16;21)(p11;q22)/FUS-ERG is a rare but recurrent translocation in acute leukemias and in some types of solid tumors. Due to multiple types of FUS-ERG transcripts, PCR-based minimal residual disease detection is impeded. In this study, we evaluated a cohort of pediatric patients with t(16;21)(p11;q22)/FUS-ERG and revealed fusion gene breakpoints. We implemented next-generation sequencing (NGS) on long PCR amplicons for the detection of fusion genes with unknown partners or DNA breakpoints. That allowed us to describe different fusion variants of FUS/ERG in different patients and to detect MRD on both RNA and DNA levels. We also found several accompanying mutations in epigenetic regulators (DNMT3A, ASXL1, BCOR) by targeted NGS approach in AML cases. These mutations preceded full transformation by t(16;21)(p11;q22)/FUS-ERG and allowed us to trace clonal evolution on all steps of therapy. As a casual observation, the ASXL1 mutation was found in the unrelated donor hematopoietic cells. PMID- 29427189 TI - Concurrent mucosa-associated lymphoid tissue lymphoma with diffuse large B-cell lymphoma transformation and Hodgkin lymphoma of the neck. PMID- 29427190 TI - Acidic Peptizing Agent Effect on Anatase-Rutile Ratio and Photocatalytic Performance of TiO2 Nanoparticles. AB - TiO2 nanoparticles were synthesized from titanium isopropoxide by a simple peptization method using sulfuric, nitric, and acetic acids. The effect of peptizing acid on physicochemical and photocatalytic properties of TiO2 powders was studied. The structural properties of synthesized TiO2 powders were analyzed by using XRD, TEM, N2-physisorption, Raman, DR UV-vis, FTIR, and X-ray photoelectron spectroscopy techniques. The characterization results showed that acetic acid peptization facilitated the formation of pure anatase phase after thermal treatment at 500 degrees C; in contrast, nitric acid peptization led to a major rutile phase formation (67%). Interestingly, the sample peptized using sulfuric acid yielded 95% anatase and 5% rutile phases. The photocatalytic activity of synthesized TiO2 nanoparticles was evaluated for degradation of selected organic dyes (crystal violet, methylene blue, and p-nitrophenol) in aqueous solution. The results confirmed that the TiO2 sample peptized using nitric acid (with rutile and anatase phases in 3:1 ratio) offered the highest activity for degradation of organic dyes, although, TiO2 samples peptized using sulfuric acid and acetic acid possessed smaller particle size, higher band gap energy, and high surface area. Interestingly, TiO2 sample peptized with nitric acid possessed relatively high theoretical photocurrent density (0.545 mAcm-2) and pore diameter (150 A), which are responsible for high electron-hole separation efficiency and diffusion and mass transportation of organic reactants during the photochemical degradation process. The superior activity of TiO2 sample peptized with nitric acid is due to the effective transfer of photogenerated electrons between rutile and anatase phases. PMID- 29427191 TI - Sequestered Alkaloid Defenses in the Dendrobatid Poison Frog Oophaga pumilio Provide Variable Protection from Microbial Pathogens. AB - Most amphibians produce their own defensive chemicals; however, poison frogs sequester their alkaloid-based defenses from dietary arthropods. Alkaloids function as a defense against predators, and certain types appear to inhibit microbial growth. Alkaloid defenses vary considerably among populations of poison frogs, reflecting geographic differences in availability of dietary arthropods. Consequently, environmentally driven differences in frog defenses may have significant implications regarding their protection against pathogens. While natural alkaloid mixtures in dendrobatid poison frogs have recently been shown to inhibit growth of non-pathogenic microbes, no studies have examined the effectiveness of alkaloids against microbes that infect these frogs. Herein, we examined how alkaloid defenses in the dendrobatid poison frog, Oophaga pumilio, affect growth of the known anuran pathogens Aeromonas hydrophila and Klebsiella pneumoniae. Frogs were collected from five locations throughout Costa Rica that are known to vary in their alkaloid profiles. Alkaloids were isolated from individual skins, and extracts were assayed against both pathogens. Microbe subcultures were inoculated with extracted alkaloids to create dose-response curves. Subsequent spectrophotometry and cell counting assays were used to assess growth inhibition. GC-MS was used to characterize and quantify alkaloids in frog extracts, and our results suggest that variation in alkaloid defenses lead to differences in inhibition of these pathogens. The present study provides the first evidence that alkaloid variation in a dendrobatid poison frog is associated with differences in inhibition of anuran pathogens, and offers further support that alkaloid defenses in poison frogs confer protection against both pathogens and predators. PMID- 29427192 TI - Community-acquired respiratory infections are common in patients with non-Hodgkin lymphoma and multiple myeloma. AB - PURPOSE: Available data suggest that respiratory infections are associated with increased morbidity and mortality in patients hospitalized due to acute leukemia and allogeneic stem cell transplantation (allo-SCT). However, the precise incidence, risk factors, and severity of respiratory infection, mainly community acquired, in patients with lymphoma and multiple myeloma (MM) are not fully determined. The current study aimed to investigate risk factors for respiratory infections and their clinical significance in patients with B cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) in the first year of diagnosis. METHODS: Data of consecutive patients diagnosed with NHL or MM and treated at the Rambam Hematology Inpatient and Outpatient Units between 01/2011 and 03/2012 were evaluated. Information regarding anticancer treatment, incidence and course of respiratory infections, and infection-related outcomes was analyzed. RESULTS: One hundred and sixty episodes of respiratory infections were recorded in 103 (49%) of 211 (73-MM, 138-NHL) patients; 126 (79%) episodes were community-acquired, 47 (29%) of them required hospitalization. In univariate analysis, age < 60 years, MM diagnosis, and autologous SCT increased the respiratory infection risk (P = 0.058, 0.038, and 0.001, respectively). Ninety episodes (56% of all respiratory episodes) were examined for viral pathogens. Viral infections were documented in 25/90 (28%) episodes, 21 (84%) of them were community-acquired, requiring hospitalization in 5 (24%) cases. Anti-flu vaccination was performed in 119 (56%) patients. Two of the six patients diagnosed with influenza were vaccinated. CONCLUSIONS: Respiratory infections, including viral ones, are common in NHL and MM. Most infections are community-acquired and have a favorable outcome. Rapid identification of viral pathogens allows avoiding antibiotic overuse in this patient population. PMID- 29427193 TI - Knowledge and perceptions of infertility in female cancer survivors and their parents. AB - PURPOSE: The purpose of this study was to assess knowledge and perceptions of infertility, reproductive concerns, quality of life, and emotional burden of fertility concerns in adolescent female cancer survivors and their parents. METHODS: A cross-sectional design was used to investigate reproductive knowledge and concerns among female childhood cancer survivors and their parents. The instruments administered at a single, routine visit were the 13-item knowledge instrument, Adolescent Fertility Values Clarification Tool (VCT), Impact of Event Scale (IES), and Pediatrics Quality of Life Assessment (PedsQL). The knowledge instrument was given to both patients and caregivers, while the PedsQL and VCT were given to only patients and IES only to caregivers. RESULTS: Twenty-six survivors and 23 parents completed evaluations. The mean age of survivors was 16. The mean knowledge instrument score for survivors was 9.5 (+/- 1.9) and 9.96 (+/- 1.7) for parents with a maximum possible score of 13. The VCT indicated almost all patients agreed or strongly agreed they would like more information on how their treatment may affect their fertility, with 84.6% identified wanting a baby in the future. The mean survivor PedsQL score was 67.7 (+/- 15.3). While parental IES scores as whole did not endorse symptoms of PTSD, 30% of our sample did fall within the range for PTSD. CONCLUSION: Although this population of women has above average knowledge scores, they still demonstrated a desire for more information on reproduction after cancer therapy. While PedsQL scores fell within a normal range, survivors report infertility would cause negative emotions. IMPLICATION FOR CANCER SURVIVORS: This information can be used refine educational programs within survivorship clinics to improve knowledge of post-treatment reproductive health. PMID- 29427195 TI - Key features and updates for origin 2018. AB - OriginLab's newest version update to Origin and OriginPro includes ease-of-use features, like Origin Central updates and creation of an App Center, as well as larger changes like the addition of Unicode characters, alteration to how user files are stored and visually searched, and user input formula in cells within worksheets. These features add additional value to an already powerful data analysis and plotting software package. PMID- 29427194 TI - The relationship between nutritional status and handgrip strength in adult cancer patients: a cross-sectional study. AB - PURPOSE: Malnutrition is a common complication in head, neck and lung cancer patients, particularly in cases of gastrointestinal system (GIS) cancer. Therefore, an assessment of malnutrition is crucial for early nutritional interventions. It was conducted as a cross-sectional study to evaluate nutritional status of adult cancer patients. METHODS: The nutritional status of 104 cancer patients (52 GIS and 52 non-GIS cancer cases) using a Patient Generated Subjective Global Assessment (PG-SGA), handgrip strength, certain anthropometric measurements and food consumption in and outside of the hospital were assessed. RESULTS: The percentages of malnutrition were 64.6 and 64.3% in the male patients with and without GIS cancer, respectively. They were 61.9 and 45.8% in the female patients with GIS and without GIS cancer, respectively. However, no significant difference was found between these two groups according to the malnutrition classification, PG-SGA score, handgrip strength and other anthropometric measurements (p > 0.05). The daily energy and protein intakes (per body weight) of the female patients in the hospital were significantly lower than those outside (p < 0.05). In addition, there was a positive moderate and significant relationship between the handgrip strength and lean body mass (r = 0.522, p = 0.000). A negative relationship was observed between the PG-SGA score and the handgrip strength (r = - 0.117, p = 0.071), but it was not statistically significant. CONCLUSIONS: Cancer patients could be provided with nutritional education, and arrangements could be made with hospital nutritional services in order to prevent malnutrition. PMID- 29427196 TI - Reduction of Health Care Costs and Improved Appropriateness of Incoming Test Orders: the Impact of Genetic Counselor Review in an Academic Genetic Testing Laboratory. AB - The goal of this study was to evaluate the impact of genetic counselor (GC) review of incoming test orders received in an academic diagnostic molecular genetics laboratory. The GC team measured the proportion of orders that could be modified to improve efficiency or sensitivity, tracked provider uptake of GC proposed testing changes, and calculated the health care dollar savings resulting from GC intervention. During this 6-month study, the GC team reviewed 2367 incoming test orders. Of these, 109 orders (4.6%) were flagged for review for potentially inefficient or inappropriate test ordering. These flagged orders corresponded to a total of 51 cases (1-5 orders for each patient), representing 54 individuals and including 3 sibling pairs. The GC team proposed a modification for each flagged case and the ordering providers approved the proposed change for 49 of 51 cases (96.08%). For the 49 modifications, the cost savings totaled $98,750.64, for an average of $2015.32 saved per modification. This study provides evidence of the significant contribution of genetic counselors in a laboratory setting and demonstrates the benefit of laboratories working with ordering providers to identify the best test for their patients. The review of test orders by a genetic counselor both improves genetic test ordering strategies and decreases the amount of health care dollars spent on genetic testing. PMID- 29427199 TI - Proceedings of the RAMI Section of OtoRhinoLaryngology Head and Neck Surgery (ORL HNS) Winter Meeting, Friday 8th December 2017, Education and Research Centre, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin 2. PMID- 29427198 TI - Can the synthetic C view images be used in isolation for diagnosing breast malignancy without reviewing the entire digital breast tomosynthesis data set? AB - AIMS AND OBJECTIVES: The aim of this study was to determine if the synthetic C view acquired at digital breast tomosynthesis (DBT) would give adequate information to confirm a malignancy and could obviate the need to review all the tomosynthesis image data set. METHODS: All patients with biopsy-proven breast cancer recalled from screening mammograms between May and September 2016 were included for review. For each patient, the screening 2D mammogram, the synthetic C view, and the DBT images were reviewed by three breast radiologists and each assigned a BIRADS code. Any discrepancies were reviewed and resolved by consensus. RESULTS: A total of 92 patients were diagnosed with breast cancer in this time period. Fourteen were excluded because they did not have DBT performed. Five women were recalled for evaluation of two lesions. In total, 83 lesions were assessed. In 27 cases, the BIRADS code remained unchanged in the three modalities. In 16 cases, the lesions appeared more concerning on C view and DBT that on the original mammogram but were not definitive for malignancy (BIRADS 4). In 29 cases, a BIRADS 5 code was assigned on C view and tomosynthesis but not on 2D. For 11 lesions, a BIRADS 5 code was assigned only on DBT. Four women had BIRADS 5 lesions seen on both the C view and DBT that were not seen on the screening 2D mammogram. One was multifocal. CONCLUSION: While the synthetic C view gives additional information when compared to a screening 2D mammogram, the full DBT tomosynthesis data set needs to be reviewed to diagnose a breast malignancy. PMID- 29427197 TI - The network structure of paranoia in the general population. AB - PURPOSE: Bebbington and colleagues' influential study on 'the structure of paranoia in the general population' used data from the British National Psychiatric Morbidity Survey and latent variable analysis methods. Network analysis is a relatively new approach in psychopathology research that considers mental disorders to be emergent phenomena from causal interactions among symptoms. This study re-analysed the British National Psychiatric Morbidity Survey data using network analysis to examine the network structure of paranoia in the general population. METHODS: We used a Graphical Least Absolute Shrinkage and Selection Operator (glasso) method that estimated an optimal network structure based on the Extended Bayesian Information Criterion. Network sub communities were identified by spinglass and EGA algorithms and centrality metrics were calculated per item and per sub-community. RESULTS: We replicated Bebbington's four component structure of paranoia, identifying 'interpersonal sensitivities', 'mistrust', 'ideas of reference' and 'ideas of persecution' as sub-communities in the network. In line with previous experimental findings, worry was the most central item in the network. However, 'mistrust' and 'ideas of reference' were the most central sub-communities. CONCLUSIONS: Rather than a strict hierarchy, we argue that the structure of paranoia is best thought of as a heterarchy, where the activation of high-centrality nodes and communities is most likely to lead to steady state paranoia. We also highlight the novel methodological approach used by this study: namely, using network analysis to re examine a population structure of psychopathology previously identified by latent variable approaches. PMID- 29427200 TI - A Reverse Judet approach to the scapula. AB - Fractures of the scapular body that extend to involve the neck and glenoid articular surface with a large gap pose a significant problem for surgical exposure. Several surgical approaches for scapula fixation have been described, but all give limited exposure to the entire scapular body, neck and articular surface. Here, we describe our 'Reverse Judet' technique, with cadaveric dissections and discuss a clinical case. We believe this approach gives a wide exposure of the infraspinous scapular body, neck and glenoid articular surface while keeping away from vital neural structures. PMID- 29427201 TI - Use of fully threaded cannulated screws decreases femoral neck shortening after fixation of femoral neck fractures. AB - BACKGROUND: Femoral neck fractures (FNF) are becoming increasingly common as population ages. Nondisplaced fractures are commonly treated by cancellous, parallel placed, partially threaded cannulated screws (PTS). This allows controlled fracture impaction. However, sliding implants can lead to femoral neck shortening (FNS) that has been shown to be correlated with reduced quality of life and impaired gait pattern. Recently, in our institution we have changed the fixation of FNF to fully threaded screws (FTS) with or without an additional partially threaded screw in order to minimize this phenomenon. The aim of this study was to compare the FNS in patients treated with FTS as compared with our historical controls treated with PTS. PATIENTS AND METHODS: Between 2014 and 2016, 38 patients with FNF were treated with FTS. Out of the 38, 24 were available for radiographic follow-up. 41 patients treated previously with PTS were available as a control group. Radiographic analysis was performed to assess the FNF in three vectors: Horizontal (X), Vertical (Y) and overall (Z) according to the neck-shaft angle. RESULTS: Time for admission to surgery was longer in the PTS group (p = 0.04). Patient demographics and major complication rates were similar in the two patient groups. Average FNS in the X axis was significantly smaller in the FTS group than in the PTS group (2.8 +/- 3.6 vs 7.6 +/- 4.2 mm, p < 0.01) as well as the Y axis (1.2 +/- 2.6 vs 4.9 +/- 4.2 mm, p < 0.01) and thus also decreased overall Z shortening (2.3 +/- 3.5 vs 6.23 +/- 4.5 mm, p < 0.01). There was a tendency towards a more valgus reduction in the PTS (137 degrees vs 134 degrees , p = 0.08). There was a significantly smaller number of FTS patients with moderate (5-10 mm) or severe (> 10 mm) FNS. Screw pull-out > 5 mm occurred in 17/41 patients in the PTS but none in the FTS group (p < 0.01). CONCLUSION: This study proves that use of FTS improves the radiographic results following FNF fixation using cannulated screws. PMID- 29427202 TI - Predictors of vasomotor symptoms among breast cancer survivors. AB - PURPOSE: Vasomotor symptoms (VMS) are a common side effect of breast cancer treatment, yet modifiable factors that may predict VMS among breast cancer survivors are unknown. METHODS: We estimated multivariable-adjusted odds ratios and 95% confidence intervals (aOR, 95% CI) for predictors of VMS among 3595 breast cancer survivors enrolled in the Life and Longevity after Cancer (LILAC) study, an ancillary study of the Women's Health Initiative (WHI). RESULTS: VMS post-diagnosis were reported by 790 (22.0%) participants. Risk of VMS after diagnosis was positively associated with prior chemotherapy (aOR 1.80, 95% CI 1.21-2.68) and adjuvant hormone therapy (aOR 2.73, 95% CI 2.08-3.58), postmenopausal hormone therapy use (aOR 1.67, 95% CI 1.30-2.13), prior VMS (aOR 2.20, 95% CI 1.73-2.80), bilateral oophorectomy (aOR 1.77, 95% CI 1.37-2.27), and baseline antidepressant use (aOR 1.49, 1.06-2.09). VMS post-diagnosis were less likely among younger women (aOR 0.94, 95% CI 0.93-0.96), women younger at menopause (aOR 0.98, 95% CI 0.97-1.00), women with more time since diagnosis (aOR 0.92, 95% CI 0.90-0.94), and diabetics (aOR 0.45, 95% CI 0.21-0.95). Metabolic syndrome was not associated with post-diagnosis VMS (aOR 0.76, 95% CI 0.45-1.28). CONCLUSIONS: VMS following breast cancer diagnosis was related to a number of modifiable factors, but was unrelated to metabolic syndrome. IMPLICATIONS FOR CANCER SURVIVORS: Identification of factors that predispose women to VMS following a breast cancer diagnosis may allow clinicians to recognize and address VMS in the subset of women who are most likely to experience such symptoms. PMID- 29427203 TI - Cardiovascular disease incidence in adolescent and young adult cancer survivors: a retrospective cohort study. AB - PURPOSE: Few population-based studies have focused on cardiovascular disease (CVD) risk in adolescent and young adult (AYA; 15-39 years) cancer survivors and none have considered whether CVD risk differs by sociodemographic factors. METHODS: Analyses focused on 79,176 AYA patients diagnosed with 14 first primary cancers in 1996-2012 and surviving > 2 years after diagnosis with follow-up through 2014. Data were obtained from the California Cancer Registry and State hospital discharge data. CVD included coronary artery disease, heart failure, and stroke. The cumulative incidence of developing CVD accounted for the competing risk of death. Multivariable Cox proportional hazards regression evaluated factors associated with CVD and the impact of CVD on mortality. RESULTS: Overall, 2249 (2.8%) patients developed CVD. Survivors of central nervous system cancer (7.3%), acute lymphoid leukemia (6.9%), acute myeloid leukemia (6.8%), and non Hodgkin lymphoma (4.1%) had the highest 10-year CVD incidence. In multivariable models, African-Americans (hazard ratio (HR) = 1.55, 95% confidence interval (CI) = 1.33-1.81; versus non-Hispanic Whites), those with public/no health insurance (HR = 1.78, 95% CI = 1.61-1.96; versus private) and those who resided in lower socioeconomic status neighborhoods had a higher CVD risk. These sociodemographic differences in CVD incidence were apparent across most cancer sites. The risk of death was increased by eightfold or higher among AYAs who developed CVD. CONCLUSION: While cancer therapies are known to increase the risk of CVD, this study additionally shows that CVD risk varies by sociodemographic factors. IMPLICATIONS FOR CANCER SURVIVORS: The identification and mitigation of CVD risk factors in these subgroups may improve long-term patient outcomes. PMID- 29427205 TI - Self-organization and information in biosystems: a case study. AB - Eigen's original molecular evolution equations are extended in two ways. (1) By an additional nonlinear autocatalytic term leading to new stability features, their dependence on the relative size of fitness parameters and on initial conditions is discussed in detail. (2) By adding noise terms that represent the spontaneous generation of molecules by mutations of substrate molecules, these terms are taken care of by both Langevin and Fokker-Planck equations. The steady state solution of the latter provides us with a potential landscape giving a bird's eye view on all stable states (attractors). Two different types of evolutionary processes are suggested: (a) in a fixed attractor landscape and (b) caused by a changed landscape caused by changed fitness parameters. This may be related to Gould's concept of punctuated equilibria. External signals in the form of additional molecules may generate a new initial state within a specific basin of attraction. The corresponding attractor is then reached by self-organization. This approach allows me to define pragmatic information as signals causing a specific reaction of the receiver and to use equations equivalent to (1) as model of (human) pattern recognition as substantiated by the synergetic computer. PMID- 29427204 TI - Reduced cooperativity of voltage-gated sodium channels in the hippocampal interneurons of an aged mouse model of Alzheimer's disease. AB - Beta amyloid (A[Formula: see text] ) associated with Alzheimer's disease (AD) leads to abnormal behavior in inhibitory neurons, resulting in hyperactive neuronal networks, epileptiform behavior, disrupted gamma rhythms, and aberrant synaptic plasticity. Previously, we used a dual modeling-experimental approach to explain several observations, including failure to reliably produce action potentials (APs), smaller AP amplitudes, higher resting membrane potential, and higher membrane depolarization in response to a range of stimuli in hippocampal inhibitory neurons from 12- to 16-month-old female AP Pswe/PSEN1DeltaE9 (APdE9) AD mice as compared to age-matched non-transgenic (NTG) mice. Our experimental results also showed that AP initiation in interneurons from APdE9 mice are significantly different from that of NTG mice. APs in interneurons from NTG mice are characterized by abrupt onset and an upstroke that is much steeper and occurs with larger variability as compared to cells from APdE9 mice. The phase plot (the rate of change of membrane potential versus the instantaneous membrane potential) of APs produced by interneurons from APdE9 mice shows a biphasic behavior, whereas that from NTG mice shows a monophasic behavior. Here we show that using the classic Hodgkin-Huxley (HH) formalism for the gating of voltage-gated sodium channels (VGSCs) in a single-compartment neuron, we cannot reproduce these features, and a model that takes into account a cooperative activation of VGSCs is needed. We also argue that considering a realistic multi-compartment neuron where the kinetics of VGSC is modeled by HH formalism, as done in the past, would not explain our observations when APs from both NTG and APdE9 mice are considered simultaneously. We further show that VGSCs in interneurons from APdE9 mice exhibit significantly lower cooperativity in their activation as compared to those from NTG mice. PMID- 29427206 TI - Neuromodulation in Inflammatory Skin Disease. AB - Inflammatory skin diseases are difficult to treat because of a lack of available treatment options for severe disease. However, recent advances have shown that vagus nerve stimulation can be used to decrease inflammation and reduce disease severity in rheumatoid arthritis and inflammatory bowel disease. Changes in cytokine profiles observed in these studies are similar to those seen with use of biologics in inflammatory skin disease, suggesting that they act along similar pathways to disrupt chronic inflammation and treat inflammatory disease. This commentary explores the existing evidence demonstrating the efficacy of neuromodulation in inflammatory disease, and outlines reasons why these findings could translate to the dermatology setting to treat inflammatory skin disease. PMID- 29427207 TI - Analysis of flood inundation in ungauged basins based on multi-source remote sensing data. AB - Floods are among the most expensive natural hazards experienced in many places of the world and can result in heavy losses of life and economic damages. The objective of this study is to analyze flood inundation in ungauged basins by performing near-real-time detection with flood extent and depth based on multi source remote sensing data. Via spatial distribution analysis of flood extent and depth in a time series, the inundation condition and the characteristics of flood disaster can be reflected. The results show that the multi-source remote sensing data can make up the lack of hydrological data in ungauged basins, which is helpful to reconstruct hydrological sequence; the combination of MODIS (moderate resolution imaging spectroradiometer) surface reflectance productions and the DFO (Dartmouth Flood Observatory) flood database can achieve the macro-dynamic monitoring of the flood inundation in ungauged basins, and then the differential technique of high-resolution optical and microwave images before and after floods can be used to calculate flood extent to reflect spatial changes of inundation; the monitoring algorithm for the flood depth combining RS and GIS is simple and easy and can quickly calculate the depth with a known flood extent that is obtained from remote sensing images in ungauged basins. Relevant results can provide effective help for the disaster relief work performed by government departments. PMID- 29427208 TI - Collaboration facilitates abstract category learning. AB - We examined the effects of collaboration (dyads vs. individuals) and category structure (coherent vs. incoherent) on learning and transfer. Working in dyads or individually, participants classified examples from either an abstract coherent category, the features of which are not fixed but relate in a meaningful way, or an incoherent category, the features of which do not relate meaningfully. All participants were then tested individually. We hypothesized that dyads would benefit more from classifying the coherent category structure because past work has shown that collaboration is more beneficial for tasks that build on shared prior knowledge and provide opportunities for explanation and abstraction. Results showed that dyads improved more than individuals during the classification task regardless of category coherence, but learning in a dyad improved inference-test performance only for participants who learned coherent categories. Although participants in the coherent categories performed better on a transfer test, there was no effect of collaboration. PMID- 29427209 TI - Long-term efficacy of ultrasound-guided low power microwave ablation for the treatment of primary papillary thyroid microcarcinoma: a 3-year follow-up study. AB - PURPOSE: To evaluate the safety and efficacy of ultrasound-guided low-power microwave ablation (MWA) for the treatment of papillary thyroid microcarcinoma (PTMC) with a 3-year follow-up. METHODS: A total of 21 nodules diagnosed as PTMC from the 15 patients were performed with MWA at a power of 20 W. The images of the nodules were recorded by ultrasound before MWA and 1, 3, 6, 12 months after MWA, and every 6 months thereafter, respectively. The volumes of the nodules were compared before MWA and at each follow-up point after MWA. The volume reduction rate (VRR) of nodules was also calculated. RESULTS: The mean volume of the nodules was 134.3 +/- 129.8 mm3 initially (the range was 7.4-423.8 mm3), which decreased significantly to 2.3 +/- 10.5 mm3 (the range was 0-48.1 mm3) of the ablation area (P = 0.000) at the follow-up point of 36 months with a mean VRR as 98.78 +/- 5.61% (the range was 74.28-100%). During the follow-up period (the range was 36-48 months), 20 of the 21 nodules were completely absorbed and no recurrent nodule was found. CONCLUSIONS: After a long-term follow-up of 3 years, the low power MWA showed a good safety and efficacy for the treatment of PTMC. In addition to surgery and active surveillance, MWA might be another alternative for patients with PTMC. PMID- 29427210 TI - A study of association of Oncotype DX recurrence score with DCE-MRI characteristics using multivariate machine learning models. AB - PURPOSE: To determine whether multivariate machine learning models of algorithmically assessed magnetic resonance imaging (MRI) features from breast cancer patients are associated with Oncotype DX (ODX) test recurrence scores. METHODS: A set of 261 female patients with invasive breast cancer, pre-operative dynamic contrast enhanced magnetic resonance (DCE-MR) images and available ODX score at our institution was identified. A computer algorithm extracted a comprehensive set of 529 features from the DCE-MR images of these patients. The set of patients was divided into a training set and a test set. Using the training set we developed two machine learning-based models to discriminate (1) high ODX scores from intermediate and low ODX scores, and (2) high and intermediate ODX scores from low ODX scores. The performance of these models was evaluated on the independent test set. RESULTS: High against low and intermediate ODX scores were predicted by the multivariate model with AUC 0.77 (95% CI 0.56 0.98, p < 0.003). Low against intermediate and high ODX score was predicted with AUC 0.51 (95% CI 0.41-0.61, p = 0.75). CONCLUSION: A moderate association between imaging and ODX score was identified. The evaluated models currently do not warrant replacement of ODX with imaging alone. PMID- 29427212 TI - Recontacting Patients with Updated Genetic Testing Recommendations for Medullary Thyroid Carcinoma and Pheochromocytoma or Paraganglioma. AB - BACKGROUND: No guidelines exist regarding physicians' duty to inform former patients about novel genetic tests that may be medically beneficial. Research on the feasibility and efficacy of disseminating information and patient opinions on this topic is limited. METHODS: Adult patients treated at our institution from 1950 to 2010 for medullary thyroid cancer, pheochromocytoma, or paraganglioma were included if their history suggested being at-risk for a hereditary syndrome but genetic risk assessment would be incomplete by current standards. A questionnaire assessing behaviors and attitudes was mailed 6 weeks after an information letter describing new genetic tests, benefits, and risks was mailed. RESULTS: Ninety-seven of 312 (31.1%) eligible patients with an identified mailing address returned the questionnaire. After receiving the letter, 29.2% patients discussed genetic testing with their doctor, 39.3% considered pursuing genetic testing, and 8.5% underwent testing. Nearly all respondents (97%) indicated that physicians should inform patients about new developments that may improve their or their family's health, and 71% thought patients shared this responsibility. Most patients understood the letter (84%) and were pleased it was sent (84%), although 11% found it upsetting. CONCLUSIONS: Patients believe it is important for physicians to inform them of potentially beneficial developments in genetic testing. However, physician-initiated letters to introduce new information appear inadequate alone in motivating patients to seek additional genetic counseling and testing. Further research is needed regarding optimal methods to notify former patients about new genetic tests and corresponding clinical and ethical implications. PMID- 29427211 TI - Treatment with 5-azacitidine delay growth of glioblastoma xenografts: a potential new treatment approach for glioblastomas. AB - PURPOSE: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults. The epigenetically active ribonucleoside analog 5-azacitidine is a new therapy option that changes tumor cell chromatin, which is frequently modified by methylation and deacetylation in malignant gliomas. METHODS: In vitro, we analyzed cell viability, cell apoptosis, and migration of human GBM cells. In vivo, we established subcutaneous and intracerebral GBM mouse models originating from U87MG, U373MG, and primary GBM cells as well as one patient-derived xenograft. Xenografts were treated with 5-azacitidine as well as valproic acid, bevacizumab, temozolomide, and phosphate buffered saline. The tumor sizes and Ki67 proliferation indices were determined. Glioma angiogenesis was examined immunohistochemically by expression analysis of endothelial cells (CD31) and pericytes (PDGFRbeta). RESULTS: In vitro, 5-azacitidine treatment significantly reduced human glioblastoma cell viability, increased cellular apoptosis, and reduced cellular migration. In vivo, 5-azacitidine significantly reduced growth in two intracerebral GBM models. Notably, this was also shown for a xenograft established from a patient surgery sample; whereas, epigenetically acting valproic acid did not show any growth reduction. Highly vascularized tumors responded to treatment, whereas low-vascularized xenografts showed no response. Furthermore, intracerebral glioblastomas treated with 5-azacitidine showed a clearly visible reduction of tumor angiogenesis and lower numbers of endothelial cells and tumor vessel pericytes. CONCLUSIONS: Our data show significant growth inhibition as well as antiangiogenic effects in intracerebral as well as patient derived GBM xenografts. This encourages to investigate in detail the multifactorial effects of 5-azacitidine on glioblastomas. PMID- 29427213 TI - Treatment Strategies in Octogenarians with Early-Stage, High-Risk Breast Cancer. AB - BACKGROUND: Octogenarians with early-stage breast cancer often have low-risk tumor biology. However, optimal treatment strategies for those with high-risk biology remain unclear. METHODS: We reviewed the records of women ages 80-89 years with biopsy-proven, Stage I-II invasive breast cancer who were referred for surgical evaluation from January 2001 through December 2010. High-risk was defined as human epidermal growth factor receptor-positive (HER2+), triple negative (TN), or histologic grade 3 disease. RESULTS: Among 178 patients, 40 (22%) were high-risk: 12 were grade 1-2 (10 HER2 + , 2 TN); 28 were grade 3 (7 HER2+, 6 TN, 15 estrogen receptor-positive (ER+)/HER2-). The high-risk group had larger tumors and more often had ductal histology and lymphovascular invasion than the low-risk group and was more likely to undergo mastectomy (18 vs. 5%, p = 0.02), radiotherapy (55 vs. 36%, p = 0.03), and chemotherapy (10 vs. 0%, p = 0.002). Endocrine therapy use was similar among ER+ patients in both groups. The four patients in the high-risk group given chemotherapy were HER2+ and received trastuzumab-based regimens, without any reported toxicities. At median follow-up of 67 months, 10% of the high-risk group had a recurrence (3 distant-only, 1 simultaneous locoregional and distant in a patient treated with mastectomy without radiotherapy). CONCLUSIONS: Tailored locoregional and systemic therapy resulted in low incidence of failure in these octogenarians with high-risk cancers with low morbidity. Modern adjuvant therapies should be considered for elderly women with high-risk cancers in the absence of significant comorbidities. PMID- 29427214 TI - Pharmacotherapy for Nocturia. AB - PURPOSE OF REVIEW: To assess current pharmacological principles used for treatment of nocturia/nocturnal polyuria. RECENT FINDINGS: The pathophysiology of nocturia is often multifactorial, but two main mechanisms have been identified, occurring alone or in combination: low functional bladder capacity and nocturnal polyuria. The multifactorial pathophysiology not only implies several possible targets for therapeutic intervention but also means that it is unlikely that one treatment modality including drugs will be successful in all patients. Drugs approved for the treatment of male LUTS and male and female OAB are known to be far more effective for treatment of the daytime symptoms than for nocturia. Several pharmacological principles have been tested with varying success. The treatment of choice should depend upon the main underlying cause, thus aiming primarily to increase bladder capacity by counteracting detrusor overactivity and/or reducing nocturnal polyuria. Using current available agents, effective, personalized treatment should be designed taking into account gender, co morbidities, and identified etiological factors. However, there is a medical need for new, approved drugs for treatments for patients with nocturia. PMID- 29427215 TI - Systematic review of quality of life in Turner syndrome. AB - PURPOSE: This study aimed to systematically review the available literature on "quality of life" (QoL) or "health-related quality of life" (HRQoL) in Turner syndrome (TS) patients and to analyze the relations among height, puberty, and the use of growth hormone (GH) and the QoL of TS patients. METHODS: An electronic bibliographic search was conducted through the PubMed, Embase, Bireme, Scopus, and Web of Science databases. The main terms were "Quality of Life" and "Turner syndrome." RESULTS: Among the databases, 559 articles were found; after the selection process, 13 studies were selected. A quality assessment was conducted, and all the studies were of high quality. Eight well-known QoL questionnaires were used, and the selected studies presented factors that may be related to the QoL of TS patients, such as height, puberty, and GH use. However, a more detailed understanding of which factors are associated with the QoL of TS patients is still needed, which may be due to the lack of specific QoL instruments involving important aspects related to TS. CONCLUSION: The QoL of TS patients appears to be compromised, but existing data regarding the relations among height, puberty, and GH and QoL are still controversial. Although these factors should be carefully considered in TS patients, it was not possible to determine whether they have a significant relation with the QoL of TS patients. PMID- 29427217 TI - First dutch experience of the accurate neo self-expanding supra-annular valve for valve-in-valve transcatheter aortic valve implantation. PMID- 29427216 TI - Measuring health-related quality of life in patients with advanced cancer: a systematic review of self-administered measurement instruments. AB - PURPOSE: Patient-reported outcome measures (PROMs) are becoming increasingly important in clinical practice. The implementation of PROMS in routine practice is challenging because information regarding psychometric quality of measurement instruments is fragmented and standardization is lacking. The aim of this study is to evaluate the quality of self-administered HRQoL measurement instruments for use in patients with advanced cancer in clinical practice. METHODS: A systematic literature search was performed in PubMed, Embase, PsycINFO, and CINAHL to identify studies concerning self-administered HRQoL measurement instruments in patients with advanced cancer between January 1990 and September 2016. Quality of the measurement instruments was assessed by predefined criteria derived from the COSMIN checklist. RESULTS: Sixty-nine articles relating to 39 measurement instruments met the inclusion criteria. Information regarding important measurement properties was often incomplete. None of the instruments performed sufficient on all measurement properties. Considering available information, the EORTC QLQ-C15-PAL appeared to have adequate psychometric properties, together with the EORTC QLQ-BM22. CONCLUSIONS: Many of the existing HRQoL measurement instruments have not yet been evaluated in an adequate manner. Validation of self administered HRQoL measurement instruments is an ongoing development and should be prioritized. This review contributes to improved clarity regarding the availability and quality of HRQoL measurement instruments for patients with advanced cancer and supports health care professionals in an adequate selection of suitable PROMs in clinical practice. PMID- 29427218 TI - Short- to mid-term outcomes of anatomic MCL reconstruction with Achilles tendon allograft after multiligament knee injury. AB - PURPOSE: Multiple techniques have been described in the literature for reconstruction of the medial collateral ligament. The purpose of this study is to describe functional outcome, range of motion, and knee stability following anatomic MCL reconstruction utilizing an Achilles tendon bone allograft after multiligament knee injury. METHODS: A comprehensive search of a single-hospital multiligament knee injury (MLKI) procedural database was conducted to identify all patients that underwent reconstruction of the MCL utilizing an Achilles tendon bone allograft and with 2-year clinical follow-up. Medical charts were retrospectively reviewed to determine each patient's knee dislocation (KD) grade, final range of motion, stability on clinical examination, and the incidence of complications and reoperations. KOOS, IKDC, and Marx scores were also collected. RESULTS: Thirty-two knees in 32 patients (21 males and 11 females) with a mean age of 30 years (range 15-51) were followed for an average of 40 months (range 28 87 months) following MCL reconstruction with Achilles tendon bone allograft. For patients with multiligament knee injuries, there were 14 KD-I (11 ACL/MCL; 3 MCL/PCL; 1 MCL/ACL/LCL; 1 MCL/PCL/LCL), 12 KD 3-M, and 3 KD-IV. One patient underwent isolated revision MCL reconstruction. At final follow-up, clinically significant valgus laxity was observed in only 1 patient (3%). All patients were able to achieve full extension of the knee and the average flexion was 121.1 +/- 19.6. The average IKDC score was 67.6 +/- 19.9 (range 27.7-98.9), the average KOOS score 77.1 +/- 16.8 (range 31-100). The average Marx score was 4.9 (range 0 16, SD 5.2). Thirty-one of 32 (96%) patients reported being satisfied with results of the surgery. Knee dislocation grades were significantly correlated with post-operative outcome measures. CONCLUSION: In a series utilizing a modified Marx Achilles tendon, MCL reconstruction in the setting of MLKI demonstrated satisfactory clinical and functional outcomes, as well as patient satisfaction at short- to mid-term follow-up. Furthermore, knee dislocation grades were demonstrated to correlate with post-operative IKDC, KOOS, and Marx scores. LEVEL OF EVIDENCE: Type IV. PMID- 29427219 TI - Penny-wise and pound-foolish. PMID- 29427221 TI - Use of Inhaled Corticosteroids and the Risk of Lung Cancer, the HUNT Study. AB - BACKGROUND: Inflammation plays a central role in chronic obstructive pulmonary disease and lung cancer carcinogenesis. Inhaled corticosteroids (ICS) reduce inflammation. This study has investigated whether ICS use is associated with a lower risk of lung cancer. MATERIALS AND METHODS: Data from the Nord-Trondelag Health Study (HUNT2 Survey, 1995-1997) were merged with The Cancer Registry of Norway and Norwegian Cause of Death Registry. From a total of 65,215 participants, those with chronic airway inflammation, defined by FEV1% < 70 and/or chronic cough and expectorate phlegm, were included (N = 4136). Of these, 3041 individuals reported regarding ICS use and were observed for a period of 12 years. Cox regression models were used to calculate the risk of lung cancer with a 95% confidence interval (CI) with sex, age, smoking pack years and FEV1% < 70 as known confounders. RESULTS: Among ICS users (N = 1095). we found a higher, but not significant, incidence of lung cancer N = 39 (3.6%), compared to non-users (N = 1946) with N = 65 (3.3%) cases. Age and smoking were associated with a higher risk, while sex and lung function were not. After adjusting for confounders, ICS use did not change the risk of lung cancer, hazard ratio (HR) 0.968, (95% CI, 0.608-1.540), and p value 0.890. CONCLUSION: ICS use is not associated with a reduced risk of lung cancer in our study population. PMID- 29427220 TI - Female adolescent elite handball players are more susceptible to shoulder problems than their male counterparts. AB - PURPOSE: Shoulder problems are frequent among senior elite handball players. The objective of this study was to assess the prevalence of shoulder problems among adolescent elite handball players and to investigate potential differences in gender, school grade, playing position and playing level. METHODS: During the 2014 and 2015 pre-season periods, 471 players (age 15-18 years, 54% female) completed a comprehensive baseline questionnaire regarding history of any shoulder pain and shoulder problems experienced during the past season. The players were monitored weekly for one competition season (September-April) regarding shoulder problems and the amount of match and training. Generalised linear models with a binomial link function were used to calculate a prevalence ratio (PR) with 95% confidence interval (CI) to compare the subgroups of players. RESULTS: In total, 110 players (23%) reported having substantial shoulder problems (defined as moderate/severe reduction in training volume, or moderate/severe reduction in performance, or complete inability to participate) at some point during the follow-up season, of which almost half reported complete inability to participate. Of those players reporting substantial problems, 43% (95% CI 39-48) did so for at least 3 consecutive weeks during the season. The prevalence was significantly higher in female players (PR 1.46, 95% 1.04-2.06) and in backcourt players (PR 1.58, 95% CI 1.08-2.32), but no differences were found for school grade (PR 1.21 95% CI 0.88-1.67) or playing level (PR 1.09 95% CI 0.76-1.56). CONCLUSIONS: The prevalence of substantial shoulder problems in adolescent elite handball players is high, especially among females, and this warrants further studies on risk factors for shoulder injury and the development of prevention strategies in handball players already before the age of 15. These findings also highlight the importance of introducing a clinical monitoring programme on a routine basis and improving the medical support, taking gender related aspects into consideration, at handball-profiled secondary schools. LEVEL OF EVIDENCE: II. PMID- 29427223 TI - Gastric Acid and Enteric Infections: Souring on the Use of PPIs. PMID- 29427222 TI - Long Noncoding RNA GAPLINC Promotes Cells Migration and Invasion in Colorectal Cancer Cell by Regulating miR-34a/c-MET Signal Pathway. AB - BACKGROUND: Gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC) has been detected in colorectal cancer (CRC) cells and reportedly performs many functions related to tumor proliferation and metastasis. Aim The present study aimed to comprehensively explore the biological functions of GAPLINC and their underlying mechanism in CRC cell. METHODS: The human cancer LncRNA PCR array was used to detect the differentially expressed long noncoding RNAs in human CRC samples. Real-time PCR, dual-luciferase assay, RNA pull-down assay, Transwell assay, and western blot analysis were performed to explore the molecular mechanism underlying GAPLINC functions related to migration and invasion of a human CRC cell line (HCT116). RESULTS: Compared to the non cancerous tissues, GAPLINC expression was obviously increased in CRC tissues. In HCT116, silencing of GAPLINC weakened cell migration and invasion, while overexpression of GAPLINC significantly promoted cell migration and invasion. Through dual-luciferase, RNA pull-down, and Transwell assays, we verified that miR-34a was the downstream molecule of GAPLINC and that miR-34a negatively regulated the migration and invasion of HCT116 cell. Furthermore, we found that GAPLINC positively regulated the miR-34a target gene c-MET in CRC tissues. CONCLUSIONS: Our findings revealed that GAPLINC was up-regulated in CRC tissues and was involved in the migration and invasion of CRC cells by regulating miR 34a/c-MET signaling pathway. PMID- 29427224 TI - Chemoprevention by Probiotics During 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis in Rats. AB - BACKGROUND: Probiotics are believed to have properties that lower the risk of colon cancer. However, the mechanisms by which they exert their beneficial effects are relatively unknown. AIM: To assess the impact of probiotics in preventing induction of colon carcinogenesis in rats. METHODS: The rats were divided into six groups viz., normal control, Lactobacillus plantarum (AdF10) treated, Lactobacillus rhamnosus GG (LGG)-treated, 1,2-dimethylhydrazine (DMH) treated, L. plantarum (AdF10) + DMH-treated and L. rhamnosus GG (LGG) + DMH treated. Both the probiotics were supplemented daily at a dose of 2 * 1010 cells per day. DMH at a dose of 30 mg/kg body weight was administered subcutaneously twice a week for the first 4 weeks and then once every week for a duration of 16 weeks. Glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and catalase as protein expression of genes involved in apoptosis were assessed during DMH-induced colon carcinogenesis in rats. RESULTS: DMH treatment decreased the activity of GSH, GPx, GST, SOD and catalase. However, AdF10 and LGG supplementation to DMH-treated rats significantly increased the activity of these enzymes. Further, DMH treatment revealed alterations in the protein expressions of various genes involved in the p53-mediated apoptotic pathway such as p53, p21, Bcl-2, Bax, caspase-9 and caspase-3, which, however, were shifted towards normal control levels upon simultaneous supplementation with probiotics. CONCLUSION: The present study suggests that probiotics can provide protection against oxidative stress and apoptotic-related protein disregulation during experimentally induced colon carcinogenesis. PMID- 29427226 TI - Mobile platform sampling for designing environmental sensor networks. AB - This paper proposes a method to design the deployment of sensor nodes in a new region where historical data is not available. A number of mobile platforms are simulated to build initial knowledge of the region. Further, an evolutionary algorithm is employed to find the optimum placement of a given number of sensor nodes that best represents the region of interest. PMID- 29427225 TI - Autophagy Strengthens Intestinal Mucosal Barrier by Attenuating Oxidative Stress in Severe Acute Pancreatitis. AB - BACKGROUND: Intestinal mucosal barrier dysfunction can be caused by severe acute pancreatitis (SAP). It is normally associated with changes to mucosal autophagy and oxidative stress. OBJECTIVE: The aim of this study was to investigate the correlation between autophagy and oxidative stress on the intestinal mucosal barrier of SAP rat model. METHODS: SAP was induced by retrograde injection of sodium taurocholate (5%) into the biliopancreatic duct. Bacterial translocation (BT) was detected by 16S rDNA sequencing analysis. Morphological alterations in the pancreas and gut were determined by hematoxylin-eosin staining. Oxidative stress status was determined by measuring the level of intestinal malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Western blot, RT-PCR, and immunofluorescent staining were preformed to analyze the expression of tight junction and autophagy proteins. RESULTS: According to the sequencing analysis, rats in SAP group were divided into BT (+) group (n = 9) and BT (-) group (n = 8). Pancreatic and intestinal injuries in SAP group were significantly higher than sham operation group. The content of MDA was clearly elevated, and SOD as well as GPx activities were decreased in BT (+) group as compared with BT (-) group. The expression of LC3II and Beclin1 in BT (-) group was higher than that observed in BT (+). In contrast, BT (+) group had a higher level of claudin 2 and a lower level of zonula occluden-1, occludin, and claudin-1. CONCLUSION: These results suggest that activated autophagy may attenuate intestinal mucosal barrier dysfunction by preventing and reducing the oxidative stress in SAP. PMID- 29427227 TI - Neoadjuvant Radiation Therapy in Locally Advanced Colon Cancer: a Cohort Analysis. AB - BACKGROUND: A paucity of data exists in the use of neoadjuvant chemoradiation therapy (NRT) for T4, non-metastatic colon cancer. This study was conducted to determine the effect of NRT on outcomes after resection for T4 colon cancer. METHODS: All patients with non-metastatic resected clinical T4 colon cancer from 2000 to 2012 at a tertiary care center were included. The cohort was divided into two groups-those that received NRT and those that did not (non-NRT). The primary outcomes were margin-negative resection and overall survival (OS). RESULTS: One hundred and thirty-one consecutive patients with non-metastatic clinical T4 colon cancer with a mean age of 65 years were included. NRT was used in 23 patients (17.4%). NRT group was noted to have non-statistically significant improvement in R0 resection rate (NRT 95.7% vs non-NRT 88.0%; p = 0.27) and local recurrence (NRT 4.3% vs non-NRT 15.7%; p = 0.15). There was a significant difference in T stage downstaging between the two groups (NRT 30.4% vs non-NRT 6.5%; p = 0.007). In a bivariate analysis, NRT was associated with improved 5-year OS (NRT 76.4% vs non-NRT 51.5%; p = 0.03). This relationship did not persist in a Cox proportional hazard analysis that included age and comorbidity (HR 2.19; 95% CI 0.87-5.52; p = 0.09). CONCLUSIONS: The use of NRT in locally advanced T4 colon cancer is safe and associated with increased downstaging. While there was a trend toward improvement in local recurrence and the ability to obtain margin-negative resections in the NRT group, this was not significant. Significantly improved overall survival was not observed in a multivariable analysis. PMID- 29427228 TI - The Influence of Screening on Outcomes of Clinically Locally Advanced Rectal Cancer. AB - BACKGROUND: Screening for colorectal cancer has resulted in declining incidence rates of both colon and rectal cancer and it may influence stage at presentation and improve survival. The aim of this study was to assess the impact of screening on patients diagnosed with locally advanced rectal cancer. METHODS: A retrospective analysis of a consecutive series of patients who underwent neoadjuvant therapy and had an R0-resection for clinical AJCC stage II or stage III disease. All patients received surgery at a single center between 2004 and 2015. Patients diagnosed through screening were compared to patients diagnosed through symptomatic presentation. RESULTS: Three hundred nine patients were included, of whom 43 (13.9%) were diagnosed through screening. Screened patients had more often a white ethnicity, while there were no other differences in baseline characteristics or median household income. Screened patients had a lower rate of disease recurrence in addition to a longer disease free survival and overall survival. CONCLUSIONS: Patients with locally advanced rectal cancer diagnosed through screening demonstrated more favorable short and long-term outcomes than patients diagnosed through symptoms. Findings of this study reinforce the need for screening programs in addition to the need for research regarding optimization of screening adherence. PMID- 29427229 TI - Diabetic Painful Neuropathy and Restless Legs Syndrome in Diabetes. AB - Restless legs syndrome (RLS) and diabetic painful neuropathy (DPN) are two distinct neurological conditions, which share many similarities. As RLS occurs frequently in persons with diabetes, the differential diagnosis and management of RLS and DPN may pose a clinical challenge. This communication describes the etiopathogenesis, clinical features, investigations, and treatment of both conditions. It highlights the similarities and differences between RLS and DPN, and helps the physician plan a rational clinical and therapeutic approach. PMID- 29427231 TI - Acceptability of Peer-Delivered HIV Testing and Counselling Among Men Who Have Sex with Men (MSM) and Transgender Women (TW) in Myanmar. AB - Men who have sex with men (MSM) and transgender women (TW) are a priority population for HIV prevention in Myanmar but report sub-optimal HIV testing frequency. Previous studies have shown that peer involvement in HIV testing can normalize stigmatized sexualities and reduce barriers to testing. We explored the acceptability of peer-delivered HIV testing among 425 undiagnosed MSM and TW in Yangon and Mandalay. An overwhelming majority of participants (86%) reported being 'comfortable/very comfortable' with peer-delivered HIV testing. Logistic regression identified reporting sexual identity as Apone [adjusted odds ratio (aOR) 3.8; 95% CI 1.2-11.7], recent HIV testing (aOR 3.1; 95% CI 1.4-6.5), reporting a high likelihood of HIV acquisition (aOR 3.6; 95% CI 1.7-7.6), and reporting >= 5 casual partners in the past 3 months (aOR 0.2; 95% CI 0.1-0.6) as associated with peer-delivered HIV testing acceptability. Given ongoing HIV vulnerability among MSM and TW in Myanmar, peer-delivered testing may offer prevention benefits by increasing testing rates and identifying undiagnosed infection earlier. PMID- 29427230 TI - Comparison of Self-report to Biomarkers of Recent HIV Infection: Findings from the START Trial. AB - Identifying individuals with recent HIV infection is critical to research related to viral reservoirs, outbreak investigations and intervention applications. A multi-assay algorithm (MAA) for recency of infection was used in conjunction with self-reported date of infection and documented date of diagnosis to estimate the number of participants recently infected in the Strategic Timing of AntiRetroviral Treatment (START) trial. We tested samples for three groups of participants from START using a MAA: (1) 167 individuals who reported being infected <= 6 months before randomization; (2) 771 individuals who did not know their date of infection but were diagnosed within 6 months before randomization; and (3) as controls for the MAA, 199 individuals diagnosed with HIV >= 2 years before randomization. Participants with low titer and avidity and a baseline viral load > 400 copies/mL were classified as recently infected. A significantly higher percentage of participants who self-reported being infected <= 6 months were classified as recently infected compared to participants diagnosed >= 2 years (65% [109/167] vs. 2.5% [5/199], p < 0.001). Among the 771 individuals who did not know their duration of infection at randomization, 206 (26.7%) were classified as recently infected. Among those diagnosed with HIV in the 6 months prior to enrollment, the 373 participants who reported recent infection (n = 167) or who had confirmed recent infection by the MAA (n = 206) differed significantly on a number of baseline characteristics from those who had an unknown date of infection and were not confirmed by the MAA (n = 565). Participants recently infected by self-report and/or MAA were younger, more likely to be Asian, less likely to be black, less likely to be heterosexual, more likely to be enrolled at sites in the U.S., Europe or Australia, and have higher HIV RNA levels. There was good agreement between self-report of recency of infection and the MAA. We estimate that 373 participants enrolled in START were infected within 6 months of randomization. Compared to those not recently infected, these participants were younger, had higher HIV RNA levels and were more likely to come from high income countries and from populations such as MSM with more regular HIV testing. PMID- 29427232 TI - Does Maternal HIV Disclosure Self-Efficacy Enhance Parent-Child Relationships and Child Adjustment? AB - Nondisclosure of maternal HIV status to young children can negatively impact child functioning; however, many mothers do not disclose due to lack of self efficacy for the disclosure process. This study examines demographic variations in disclosure self-efficacy, regardless of intention to disclose, and assesses the relationship between self-efficacy and child adjustment via the parent-child relationship among a sample of HIV+ mothers and their healthy children (N = 181 pairs). Mothers completed demographic and self-efficacy measures; children completed measures assessing the parent-child relationship and child adjustment (i.e., worry, self-concept, depression). Across demographics, few mothers reported confidence in disclosure. Results from covariance structural modeling showed mothers endorsing higher self-efficacy had children who reported better relationship quality, and, in turn, reported fewer adjustment difficulties; higher levels of disclosure self-efficacy also directly predicted fewer adjustment problems. Findings offer support for interventions aimed at providing mothers with skills to enhance confidence for disclosing their HIV status. PMID- 29427233 TI - An Online Risk Index for the Cross-Sectional Prediction of New HIV Chlamydia, and Gonorrhea Diagnoses Across U.S. Counties and Across Years. AB - The present study evaluated the potential use of Twitter data for providing risk indices of STIs. We developed online risk indices (ORIs) based on tweets to predict new HIV, gonorrhea, and chlamydia diagnoses, across U.S. counties and across 5 years. We analyzed over one hundred million tweets from 2009 to 2013 using open-vocabulary techniques and estimated the ORIs for a particular year by entering tweets from the same year into multiple semantic models (one for each year). The ORIs were moderately to strongly associated with the actual rates (.35 < rs < .68 for 93% of models), both nationwide and when applied to single states (California, Florida, and New York). Later models were slightly better than older ones at predicting gonorrhea and chlamydia, but not at predicting HIV. The proposed technique using free social media data provides signals of community health at a high temporal and spatial resolution. PMID- 29427234 TI - Uncarboxylated Osteocalcin Enhances Glucose Uptake Ex Vivo in Insulin-Stimulated Mouse Oxidative But Not Glycolytic Muscle. AB - Uncarboxylated osteocalcin (ucOC) stimulates muscle glucose uptake in mice EDL and soleus muscles. However, whether ucOC also exerts a similar effect in insulin stimulated muscles in a muscle type-specific manner is currently unclear. We aimed to test the hypothesis that, with insulin stimulation, ucOC per se has a greater effect on oxidative muscle compared with glycolytic muscle, and to explore the underlying mechanisms. Mouse (C57BL6, male 9-12 weeks) extensor digitorum longus (EDL) and soleus muscles were isolated and longitudinally split into halves. Muscle samples were treated with varying doses of recombinant ucOC (0, 0.3, 1, 3, 30 ng/ml), followed by insulin addition. Muscle glucose uptake, protein phosphorylation and total expression of protein kinase B (Akt), Akt substrate of 160 kDa (AS160), extracellular signal-regulated kinase isoform 2 (ERK2), and adenosine monophosphate-activated protein kinase subunit alpha (AMPKalpha) were assessed. ucOC treatment at 30 ng/ml enhanced muscle glucose uptake in insulin-stimulated soleus, a mainly oxidative muscle (17.5%, p < 0.05), but not in EDL-a mostly glycolytic muscle. In insulin-stimulated soleus only, ucOC treatment (3 and 30 ng/ml) increased phosphorylation of AS160 and ERK2, but not Akt or AMPKalpha. The ucOC-induced increase in ERK2 phosphorylation in soleus was not associated with the increase in glucose uptake or AS160 phosphorylation. ucOC enhances glucose uptake and AS160 phosphorylation in insulin-stimulated oxidative but not glycolytic muscle, via upstream mechanisms which appear to be independent of ERK or AMPK. PMID- 29427235 TI - Microbiota and Bone Health: The Gut-Musculoskeletal Axis. PMID- 29427236 TI - Retraction Note to: MIR221/MIR222-driven post-transcriptional regulation of P27KIP1 and P57KIP2 is crucial for high-glucose- and AGE-mediated vascular cell damage. AB - The authors are retracting this article [1]. Following publication, concerns were raised with respect to some of the western blots and the authors were asked to supply the original unmodified blots. PMID- 29427237 TI - Differential expression of Lp-PLA2 in obesity and type 2 diabetes and the influence of lipids. AB - AIMS/HYPOTHESIS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulatory macrophage-derived factor that increases with obesity and leads to a higher risk of cardiovascular disease (CVD). Despite this, its role in adipose tissue and the adipocyte is unknown. Therefore, the aims of this study were to clarify the expression of Lp-PLA2 in relation to different adipose tissue depots and type 2 diabetes, and ascertain whether markers of obesity and type 2 diabetes correlate with circulating Lp-PLA2. A final aim was to evaluate the effect of cholesterol on cellular Lp-PLA2 in an in vitro adipocyte model. METHODS: Analysis of anthropometric and biochemical variables from a cohort of lean (age 44.4 +/- 6.2 years; BMI 22.15 +/- 1.8 kg/m2, n = 23), overweight (age 45.4 +/- 12.3 years; BMI 26.99 +/- 1.5 kg/m2, n = 24), obese (age 49.0 +/- 9.1 years; BMI 33.74 +/- 3.3 kg/m2, n = 32) and type 2 diabetic women (age 53.0 +/- 6.13 years; BMI 35.08 +/- 8.6 kg/m2, n = 35), as part of an ethically approved study. Gene and protein expression of PLA2 and its isoforms were assessed in adipose tissue samples, with serum analysis undertaken to assess circulating Lp-PLA2 and its association with cardiometabolic risk markers. A human adipocyte cell model, Chub-S7, was used to address the intracellular change in Lp-PLA2 in adipocytes. RESULTS: Lp-PLA2 and calcium-independent PLA2 (iPLA2) isoforms were altered by adiposity, as shown by microarray analysis (p < 0.05). Type 2 diabetes status was also observed to significantly alter gene and protein levels of Lp-PLA2 in abdominal subcutaneous (AbdSc) (p < 0.01), but not omental, adipose tissue. Furthermore, multivariate stepwise regression analysis of circulating Lp-PLA2 and metabolic markers revealed that the greatest predictor of Lp-PLA2 in non-diabetic individuals was LDL-cholesterol (p = 0.004). Additionally, in people with type 2 diabetes, oxidised LDL (oxLDL), triacylglycerols and HDL-cholesterol appeared important predictors, accounting for 59.7% of the variance (p < 0.001). Subsequent in vitro studies determined human adipocytes to be a source of Lp-PLA2, as confirmed by mRNA expression, protein levels and immunochemistry. Further in vitro experiments revealed that treatment with LDL-cholesterol or oxLDL resulted in significant upregulation of Lp-PLA2, while inhibition of Lp-PLA2 reduced oxLDL production by 19.8% (p < 0.05). CONCLUSIONS/INTERPRETATION: Our study suggests adipose tissue and adipocytes are active sources of Lp-PLA2, with differential regulation by fat depot and metabolic state. Moreover, levels of circulating Lp-PLA2 appear to be influenced by unfavourable lipid profiles in type 2 diabetes, which may occur in part through regulation of LDL-cholesterol and oxLDL metabolism in adipocytes. PMID- 29427238 TI - Opinion paper: scientific, philosophical and legal consideration of doping in sports. AB - The term doping is generally used to indicate practices based on the use of performance-enhancing drugs (PEDs) or the abuse of medical therapies. Mostly analysed by doctors and officials, doping nevertheless also requires a philosophical consideration to avoid being simplistically portrayed as an isolated practice. To do this, we need to pay attention to the contradictions and paradoxes in the modern approach to doping in sport. In this context, doping is not only relevant to the health of an individual involved in the violation of World Anti-Doping Agency (WADA) criteria, but it actually represents a double edged phenomenon containing ethical and legal points of view. Several philosophical items affect the ethics of doping. While, indeed, through a deontological vision it is easy to morally condemn an athlete who takes the decision to turn to doping, the same condemnation becomes difficult when the practice of doping is compared with the strong social demand of winners in every field of life. This point must be considered to prevent doping from becoming accepted as a daily practice to excel at all costs and regarded not only as normal but as a necessity for those participating in sport at both an amateur and professional level. Furthermore, a complete discussion on doping has to consider not only the philosophy of performance-enhancing drug abuse, but also the widespread practice of an inappropriate and excessive intake of certain dietary supplements with the unique and obsessive purpose (similar to doping) of increasing physical or mental performance. Based on the above, the aim of this paper is to provide a critical opinion of the doping problem and its related practices and analyze possible solutions considering issues that go beyond the impact of doping on health and reflect on whether it is right or not that an athlete does all he can to improve his performance. PMID- 29427239 TI - Carbon Dioxide-Generating PLG Nanoparticles for Controlled Anti-Cancer Drug Delivery. AB - PURPOSE: Poly(D,L-lactide-co-glycolide) (PLG) nanoparticles containing doxorubicin and mineralized calcium carbonate were fabricated and their anti tumor efficacy was tested using a neuroblastoma-bearing mouse model. METHODS: PLG nanoparticles were prepared by a double emulsion (water-in-oil-in-water; W/O/W) method. Calcium carbonate was mineralized within the PLG nanoparticles during the emulsion process. Rabies virus glycoprotein (RVG) peptide was chemically introduced to the surface of the PLG nanoparticles as a targeting moiety against neuroblastoma. The cytotoxicity and cellular uptake characteristics of these nanoparticles were investigated in vitro. Moreover, their therapeutic efficacy was evaluated using a tumor-bearing mouse model. RESULTS: Mineralized calcium carbonate in PLG nanoparticles was ionized at acidic pH and generated carbon dioxide gas, which resultantly accelerated the release of doxorubicin from the nanoparticles. RVG peptide-modified, gas-generating PLG nanoparticles showed a significantly enhanced targeting ability to neuroblastoma and an increased therapeutic efficacy in vivo as compared with free doxorubicin. CONCLUSIONS: Targeting ligand-modified polymer nanoparticles containing both anti-cancer drug and mineralized calcium carbonate could be useful for cancer treatment. PMID- 29427240 TI - Bilateral deep brain stimulation of the subthalamic nucleus increases pointing error during memory-guided sequential reaching. AB - Deep brain stimulation of the subthalamic nucleus (STN DBS) significantly improves clinical motor symptoms, as well as intensive aspects of movement like velocity and amplitude in patients with Parkinson's disease (PD). However, the effects of bilateral STN DBS on integrative and coordinative aspects of motor control are equivocal. The aim of this study was to investigate the effects of bilateral STN DBS on integrative and coordinative aspects of movement using a memory-guided sequential reaching task. The primary outcomes were eye and finger velocity and end-point error. We expected that bilateral STN DBS would increase reaching velocity. More importantly, we hypothesized that bilateral STN DBS would increase eye and finger end-point error and this would not simply be the result of a speed accuracy trade-off. Ten patients with PD and bilaterally implanted subthalamic stimulators performed a memory-guided sequential reaching task under four stimulator conditions (DBS-OFF, DBS-LEFT, DBS-RIGHT, and DBS-BILATERAL) over 4 days. DBS-BILATERAL significantly increased eye velocity compared to DBS-OFF, DBS-LEFT, and DBS-RIGHT. It also increased finger velocity compared to DBS-OFF and DBS-RIGHT. DBS-BILATERAL did not change eye end-point error. The novel finding was that DBS-BILATERAL increased finger end-point error compared to DBS OFF, DBS-LEFT, and DBS-RIGHT even after adjusting for differences in velocity. We conclude that bilateral STN DBS may facilitate basal ganglia-cortical networks that underlie intensive aspects of movement like velocity, but it may disrupt selective basal ganglia-cortical networks that underlie certain integrative and coordinative aspects of movement such as spatial accuracy. PMID- 29427241 TI - Productivity of waterbirds in potentially impacted areas of Louisiana in 2011 following the Deepwater Horizon oil spill. AB - The Deepwater Horizon oil spill (2010) could have affected the behavior and productivity of birds nesting along the Gulf of Mexico. This research examined the productivity of several species of colonial waterbirds in 2011 in LA colonies that were classified according to the M252 peak SCAT shoreline map oiling designations (as of April 6 2011) within 2 km of each colony. Colonies were classified as no oil, little oil, or medium to heavy oil. Because of the uneven distribution of oil and variation in bird composition within colonies, not all species occurred in each of the three oiling classes in the LA colonies studied. I tested the following hypotheses: (1) there were no interspecific differences in nesting phenology, (2) there were no differences in the number of species per colony as a function of oiling, and (3) there were no differences in reproductive measures as a function of oiling. Nesting phenology differed among species, with brown pelicans (Pelecanus occidentalis), great egrets (Ardea alba), and tri colored herons (Egretta tricolor) nesting earlier than the other species. There were no significant differences in the number of species nesting in colonies as a function of oiling category. Along LA's shoreline, nests in colonies with a "no oil" category within 2 km of the colony had similar or lower maximum number of chicks/nest, than those from birds in colonies designated as light or moderate/heavy oiling. Average maximum chick sizes in nests in colonies designated as no oil were either similar to or smaller than chicks in nests in colonies designated as either category of oiled. The data suggest that in the year following the oil spill, there were no differences in reproductive success. Although long-term studies are essential to determine effects on population dynamics, the continued exposure of birds nesting along the Gulf of Mexico to acute and chronic oil sources make this a nearly impossible task. PMID- 29427242 TI - Sequence divergence between spelt and common wheat. AB - KEY MESSAGE: Sequence comparison between spelt and common wheat reveals that the former has huge potential in enriching the genetic variation of the latter. Genetic variation is the foundation of crop improvement. By comparing genome sequences of a Triticum spelta accession and one of its derived hexaploid lines with the sequences of the international reference genotype Chinese Spring, we detected variants more than tenfold higher than those present among common wheat (T. aestivum L) genotypes. Furthermore, different from the typical 'V-shaped' pattern of variant distribution often observed along wheat chromosomes, the sequence variation detected in this study was more evenly distributed along the 3B chromosome. This was also the case between T. spelta and the wild emmer genome. Genetic analysis showed that T. spelta and common wheat formed discrete groups. These results showed that, although it is believed that the spelt and common wheat are evolutionarily closely related and belong to the same species, a significant sequence divergence exists between them. Thus, the values of T. spelta in enriching the genetic variation of common wheat can be huge. PMID- 29427243 TI - Three-dimensional ultrastructure of osteocytes assessed by focused ion beam scanning electron microscopy (FIB-SEM). AB - The aim of this study is to demonstrate the application of focused ion beam scanning electron microscopy, FIB-SEM for revealing the three-dimensional features of osteocytic cytoplasmic processes in metaphyseal (immature) and diaphyseal (mature) trabeculae. Tibiae of eight-week-old male mice were fixed with aldehyde solution, and treated with block staining prior to FIB-SEM observation. While two-dimensional backscattered SEM images showed osteocytes' cytoplasmic processes in a fragmented fashion, three-dimensional reconstructions of FIB-SEM images demonstrated that osteocytes in primary metaphyseal trabeculae extended their cytoplasmic processes randomly, thus maintaining contact with neighboring osteocytes and osteoblasts. In contrast, diaphyseal osteocytes extended thin cytoplasmic processes from their cell bodies, which ran perpendicular to the bone surface. In addition, these osteocytes featured thick processes that branched into thinner, transverse cytoplasmic processes; at some point, however, these transverse processes bend at a right angle to run perpendicular to the bone surface. Osteoblasts also possessed thicker cytoplasmic processes that branched off as thinner processes, which then connected with cytoplasmic processes of neighboring osteocytes. Thus, FIB-SEM is a useful technology for visualizing the three-dimensional structures of osteocytes and their cytoplasmic processes. PMID- 29427244 TI - Anthelmintic efficacy of hydro-methanolic extracts of Larrea tridentata against larvae of Haemonchus contortus. AB - An in vitro study was conducted to determine the anthelminthic activity of hydro methanolic extracts of Larrea tridentata on sheathed and exsheathed larvae of Haemonchus contortus. Larvae of the parasite were incubated at 20-25 degrees C in hydro-methanolic extracts at concentrations of 12.5, 25, 50, 100, and 200 mg/mL for 24, 48, or 72 h. Ivermectin and water were the positive and negative controls, respectively. Total phenolic compounds of leaves of L. tridentata were 97.88 +/- 10.45 mg/g of dry matter. Other compounds detected in this shrub by HPLC-mass spectrometry were sesamin, galocatechin, peonidin 3-O rutinoside, methyl galangin, epigallocatechin 7-O-glucuronide, and epigalocatechin. Mortality rate of sheathed and exsheathed H. contortus was low (16-34%) with doses <= 100 mg/mL of the extracts. At 200 mg/ml, the hydro-methanolic extracts of L. tridentata killed 32.1 and 68.4% of sheathed and exsheathed larvae, respectively, regardless of incubation time. The effective concentration of the L. tridentata extract for 50% larvae mortality (EC50) after 24 h of incubation was 36 mg/mL (CI = 6-94). Microscopic observations revealed damage to the cuticle of this parasite exposed to extracts of L. tridentata. These in vitro results provided evidence that L. tridentata extracts possess anti-Haemonchus contortus properties, particularly during the exsheathed stage of this nematode. It would be necessary to assess the safety of this shrub in vivo and also to carry out in vivo efficacy studies. PMID- 29427245 TI - Energy balance in grazing Jersey cows in early lactation supplemented with peanut and sunflower oils. AB - In this study, we evaluated the effects of supplementation with peanut and sunflower oils on intake and digestibility, milk yield and composition, energy balance (EB), changes in weight and body condition score (BW and BCS), and blood metabolites of Jersey cows on pasture in early lactation. Twenty-four cows were distributed in a randomized block design where they received the following treatments: concentrate without oil (CON), concentrate plus 59.6 g/kg DM peanut oil (PEA), concentrate plus 59.6 g/kg DM sunflower oil (SUN), and concentrate plus 59.6 g/kg DM of a 1:1 mixture of peanut oil and sunflower oil (MIX). The data were analyzed at 30 and 60 days in milk (DIM). Oil supplementation did not affect total dry matter intake or forage intake. The treatment SUN reduced daily milk yield, 4% fat-corrected milk yield, and milk fat, while the other treatments generated similar results. The treatment SUN reduced the milk net energy and the use efficiency of the NEL for milk production and BW and BCS changes, and improved EB up to 60 DIM. On tropical pastures, supplementation with unsaturated oils for cows in early lactation does not result in better milk performance. The supplementation with sunflower oil improves the energy balance in early lactation. PMID- 29427246 TI - Effect of feeding oat and vetch forages on milk production and quality in smallholder dairy farms in Central Kenya. AB - Despite the significant livestock contribution to households' nutrition and incomes in many African smallholder farms, milk productivity remains low. Inadequate feeding is the main reason for the underperformance. To contribute towards addressing this, an on-farm feeding trial was undertaken in Ol-joro-Orok Central Kenya. A feed basket using oat (Avena sativa) cv Conway and vetch (Vicia villosa) was compared to farmers practice. Milk production (kg) and quality parameters, including butterfat, protein, lactose, and density, were monitored, and cost-benefit analysis (CBA) undertaken. Feeding both oat and vetch increased milk production by 21% (morning) and 18%, (evening), equivalent to 1.4 kg/day. Increases (%) in quality were butter fat (18.2), solid-non-fat (16.5), lactose (16.2), and protein (16.1). Concomitantly, the CBA returned positive results, supporting the hypothesis of economic advantage in using oat and vetch in milk production in the area, and possibly in other similar areas. PMID- 29427247 TI - Environmental Factors Associated with the Carriage of Bacterial Pathogens in Norway Rats. AB - Worldwide, Norway rats (Rattus norvegicus) carry a number of zoonotic pathogens. Many studies have identified rat-level risk factors for pathogen carriage. The objective of this study was to examine associations between abundance, microenvironmental and weather features and Clostridium difficile, antimicrobial resistant (AMR) Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA) carriage in urban rats. We assessed city blocks for rat abundance and 48 microenvironmental variables during a trap-removal study, then constructed 32 time-lagged temperature and precipitation variables and fitted multivariable logistic regression models. The odds of C. difficile positivity were significantly lower when mean maximum temperatures were high (>= 12.89 degrees C) approximately 3 months before rat capture. Alley pavement condition was significantly associated with AMR E. coli. Rats captured when precipitation was low (< 49.40 mm) in the 15 days before capture and those from blocks that contained food gardens and institutions had increased odds of testing positive for MRSA. Different factors were associated with each pathogen, which may reflect varying pathogen ecology including exposure and environmental survival. This study adds to the understanding of how the microenvironment and weather impacts the epidemiology and ecology of zoonotic pathogens in urban ecosystems, which may be useful for surveillance and control activities. PMID- 29427248 TI - Fabrication of 3-O-sn-Phosphatidyl-L-serine Anchored PLGA Nanoparticle Bearing Amphotericin B for Macrophage Targeting. AB - PURPOSE: To fabricate, characterize and evaluate 3-O-sn-Phosphatidyl-L-serine (PhoS) anchored PLGA nanoparticles for macrophage targeted therapeutic intervention of VL. MATERIALS AND METHODS: PLGA-AmpB NPs were prepared by well established nanoprecipitation method and decorated with Phos by thin film hydration method. Physico-chemical characterization of the formulation was done by Zetasizer nano ZS and atomic force microscopy. RESULTS: The optimized formulation (particle size, 157.3 +/- 4.64 nm; zeta potential, - 42.51 +/- 2.11 mV; encapsulation efficiency, ~98%) showed initial rapid release up to 8 h followed by sustained release until 72 h. PhoS generated 'eat-me' signal driven augmented macrophage uptake, significant increase in in-vitro (with ~82% parasite inhibition) and in-vivo antileishmanial activity with preferential accumulation in macrophage rich organs liver and spleen were found. Excellent hemo compatibility justified safety profile of developed formulation in comparison to commercial formulations. CONCLUSION: The developed PhoS-PLGA-AmpB NPs have improved efficacy, and necessary stability which promisingly put itself as a better alternative to available commercial formulations for optimized treatment of VL. PMID- 29427249 TI - Prefoldin, a jellyfish-like molecular chaperone: functional cooperation with a group II chaperonin and beyond. AB - Prefoldin is a hexameric molecular chaperone found in the cytosol of archaea and eukaryotes. Its hexameric complex is built from two related classes of subunits and has the appearance of a jellyfish: its body consists of a double beta-barrel assembly with six long tentacle-like coiled coils protruding from it. Using the tentacles, prefoldin captures an unfolded protein substrate and transfers it to a group II chaperonin. The prefoldin-group II chaperonin system is thought to be important for the folding of newly synthesized proteins and for their maintenance, or proteostasis, in the cytosol. Based on structural information of archaeal prefoldins, the mechanisms of substrate recognition and prefoldin chaperonin cooperation have been investigated. In contrast, the role and mechanism of eukaryotic PFDs remain unknown. Recent studies have shown that prefoldin plays an important role in proteostasis and is involved in various diseases. In this paper, we review a series of studies on the molecular mechanisms of archaeal prefoldins and introduce recent findings about eukaryotic prefoldin. PMID- 29427250 TI - Movement-Related Somatosensory Activity Is Altered in Patients with Multiple Sclerosis. AB - During active movement the somatosensory cortical responses are often attenuated. This attenuation is referred to as movement-related sensory gating. It is well known that patients with multiple sclerosis (MS) have sensory processing deficits, and recent work has also suggested that these patients display impaired motor control of the ankle musculature. The primary goal of the current study was to: (1) examine the movement-related somatosensory gating in patients with MS and demographically-matched controls, and (2) identify the relationship between the sensory gating and motor control of the ankle musculature. To this end, we used magnetoencephalography brain imaging to assess the neural responses to a tibial nerve electrical stimulation that was applied at rest (passive) and during an ankle plantarflexion motor task (active condition). All participants also completed an ankle isometric motor control task that was performed outside the scanner. Our results indicated that the controls, but not patients with MS, exhibited significantly reduced somatosensory responses during the active relative to passive conditions, and that patients with MS had stronger responses compared with controls during the active condition. Additionally, control of the ankle musculature was related to the extent of movement-related sensory attenuation, with poor motor control being associated with reduced gating. Overall, these results show that patients with MS do not attenuate the somatosensory cortical activity during motor actions, and that the inability to modulate somatosensory cortical activity is partially related to the poor ankle motor control seen in these patients. PMID- 29427251 TI - Heart-Brain Interactions in the MR Environment: Characterization of the Ballistocardiogram in EEG Signals Collected During Simultaneous fMRI. AB - The ballistocardiographic (BCG) artifact is linked to cardiac activity and occurs in electroencephalographic (EEG) recordings acquired inside the magnetic resonance (MR) environment. Its variability in terms of amplitude, waveform shape and spatial distribution over subject's scalp makes its attenuation a challenging task. In this study, we aimed to provide a detailed characterization of the BCG properties, including its temporal dependency on cardiac events and its spatio temporal dynamics. To this end, we used high-density EEG data acquired during simultaneous functional MR imaging in six healthy volunteers. First, we investigated the relationship between cardiac activity and BCG occurrences in the EEG recordings. We observed large variability in the delay between ECG and subsequent BCG events (ECG-BCG delay) across subjects and non-negligible epoch-by epoch variations at the single subject level. The inspection of spatial-temporal variations revealed a prominent non-stationarity of the BCG signal. We identified five main BCG waves, which were common across subjects. Principal component analysis revealed two spatially distinct patterns to explain most of the variance (85% in total). These components are possibly related to head rotation and pulse driven scalp expansion, respectively. Our results may inspire the development of novel, more effective methods for the removal of the BCG, capable of isolating and attenuating artifact occurrences while preserving true neuronal activity. PMID- 29427252 TI - Comparison of Measures of Adiposity and Cardiovascular Disease Risk Factors Among African American Adults: the Jackson Heart Study. AB - Obesity, particularly central adiposity, is a well-established risk factor for cardiovascular disease (CVD). Waist circumference (WC) is measured in numerous epidemiologic studies as a relatively simple indicator of central adiposity. However, recently, investigators have considered a measure that takes height into consideration, waist-to-height ratio (WHtR) as a more sensitive predictor of CVD. A limited number of studies have examined the association between various measures of central adiposity and obesity with CVD, but there is a dearth of information on this topic focused specifically on African American adults. Given the high rates of cardiovascular disease and metabolic risk factors in this population, it is important to develop validated, easy-to-measure indicators of CVD risk for clinical use. Data from 4758 African American adults participating in the baseline visit of the Jackson Heart Study with available risk factor data were examined, with three measures of body habitus (body mass index (BMI), WC, and WHtR) and five CVD risk factors (HDL and LDL cholesterol, triglycerides, diabetes, and hypertension), the latter also categorized into multiple (2+) risk factors present. C-statistics for waist circumference (WC), BMI, and WHtR were computed and compared for each model to assess their discriminant abilities. WHtR was a stronger correlate of HDL cholesterol, triglycerides, diabetes, hypertension, and multiple risk factors compared to BMI, and was a stronger correlate of HDL cholesterol when compared to WC. These data indicate that, for African American adults, WHtR may be more appropriate measure to identify those at elevated risk for CVD. PMID- 29427253 TI - Lack of connexin 40 decreases the calcium sensitivity of renin-secreting juxtaglomerular cells. AB - The so-called calcium paradoxon of renin describes the phenomenon that exocytosis of renin from juxtaglomerular cells of the kidney is stimulated by lowering of the extracellular calcium concentration. The yet poorly understood effect of extracellular calcium on renin secretion appears to depend on the function of the gap junction protein connexin 40 (Cx40) in renin-producing cells. This study aimed to elucidate the role of Cx40 for the calcium dependency of renin secretion in more detail by investigating if Cx40 function is really essential for the influence of extracellular calcium on renin secretion, if and how Cx40 affects intracellular calcium dynamics in renin-secreting cells and if Cx40-mediated gap junctional coupling of renin-secreting cells with the mesangial cell area is relevant for the influence of extracellular calcium on renin secretion. Renin secretion was studied in isolated perfused mouse kidneys. Calcium measurements were performed in renin-producing cells of microdissected glomeruli. The ultrastructure of renin-secreting cells was examined by electron microscopy. We found that Cx40 was not essential for stimulation of renin secretion by lowering of the extracellular calcium concentration. Instead, Cx40 increased the sensitivity of renin secretion response towards lowering of the extracellular calcium concentration. In line, the sensitivity and dynamics of intracellular calcium in response to lowering of extracellular calcium were dampened when renin secreting cells lacked Cx40. Disruption of gap junctional coupling of renin secreting cells by selective deletion of Cx40 from mesangial cells, however, did not change the stimulation of renin secretion by lowering of the extracellular calcium concentration. Deletion of Cx40 from renin cells but not from mesangial cells was associated with a shift of renin expression from perivascular cells of afferent arterioles to extraglomerular mesangial cells. Our findings suggest that Cx40 is not directly involved in the regulation of renin secretion by extracellular calcium. Instead, it appears that in renin-secreting cells of the kidney lacking Cx40, intracellular calcium dynamics and therefore also renin secretion are desensitized towards changes of extracellular calcium. Whether the dampened calcium response of renin-secreting cells lacking Cx40 function results from a direct involvement of Cx40 in intracellular calcium regulation or from the cell type shift of renin expression from perivascular to mesangial cells remains to be clarified. In any case, Cx40-mediated gap junctional coupling between renin and mesangial cells is not relevant for the calcium paradoxon of renin secretion. PMID- 29427254 TI - Letter to the Editor re: Increased Expression of Translocator Protein (TSPO) Marks Pro-inflammatory Microglia but Does Not Predict Neurodegeneration. PMID- 29427256 TI - Laparoscopic cholangiogram in biliary atresia: a refinement in the gallbladder hitch technique. AB - INTRODUCTION: The study describes a refinement in the gallbladder hitch stitch and assesses the value of the laparoscopic cholangiogram in children with suspected biliary atresia. METHODS: Twenty children with neonatal jaundice and no drainage as shown on the HIDA scan underwent a diagnostic laparoscopy through an umbilical 5 mm port. A 3 mm laparoscopic needle holder inserted through a 3.5 mm port to the left of the umbilicus was used to hitch the gallbladder to the abdominal wall. The stylet of a large bore 16F IV cannula then was used to penetrate the gallbladder to perform the laparoscopic cholangiogram. RESULTS: There was no need for conversion in all 20 children by this technique. Patent biliary anatomy was demonstrated in 11 children (11/20). These children had no further procedures. In 3 (3/20) children, the common bile duct was demonstrated, while the hepatic ducts were not. These children had a laparotomy for Kasai procedure after an open cholangiogram with a vascular bulldog clamp on the CBD confirmed the finding. Six (6/20) had no demonstrable patency; 3 had it confirmed when the abdomen was opened for the Kasai procedure; only those proceeding to Kasai portoenterostomy (3 hepatic duct atresia, 3 complete biliary atresias) had an epidural catheter placed by the anesthetist. The remaining 3 had no further procedure performed due to the advanced nodular liver with ascites and evidence of portal hypertension. CONCLUSION: The findings of laparoscopic cholangiogram were confirmed in all six children who underwent laparotomy for Kasai procedure. The laparoscopic cholangiogram using gallbladder hitch reliably demonstrates a patent biliary system (11/11) and was valuable in avoiding further invasive procedures in 70% (14/20) of babies. PMID- 29427255 TI - Genome-wide identification and expression profile analysis of the HOG gene family in Aspergillus oryzae. AB - The High osmolarity glycerol (HOG) gene family plays crucial roles in various developmental and physiological processes in fungi, such as the permeability of cell membrane, chlamydospore formation and stress signaling. Although the function of HOG genes has been investigated in Saccharomyces cerevisiae and some filamentous fungi, a comprehensive analysis of HOG gene family has not been performed in Aspergillus oryzae, a fungi mainly used for the production of soy sauce. In this study, we identified and corrected a total of 90 HOG genes from the A. oryzae genome. According to the phylogenetic relationship, they were divided into four discrete groups (Group A-D) comprising of 16, 24, 30 and 20 proteins, respectively. Six conserved motifs and exon-intron structures were examined among all HOG proteins to reveal the diversity of AoHOG genes. Based on transcriptome technology, the expression patterns of AoHOG genes across all developmental stages was identified, suggesting that the AoHOG gene family mainly functions in the logarithmic phase of development. The expression profiles of AoHOG genes under different concentrations of salt stress indicated that AoHOG genes are extensively involved in salt stress response, with possibly different mechanisms. The genome-wide identification, evolutionary, gene structures and expression analyses of AoHOG genes provide a comprehensive overview of this gene family as well as their potential involvements in development and stress responses. Our results will facilitate further research on HOG gene family regarding their physiological and biochemical functions. PMID- 29427258 TI - In reply: Postoperative pain and study design: the type of surgical procedure matters. PMID- 29427257 TI - Clinical and pathological features of patients with biliary atresia who survived for more than 5 years with native liver. AB - PURPOSE: The objective of this study was to determine the predictive index for prognosis in patients with biliary atresia (BA). METHODS: A total of 71 patients were divided into two groups. Group A included 39 postoperative BA patients who survived for more than 5 years with normal liver function and did not present cirrhosis, and group B included 32 patients who died from liver failure within 1 year after surgery. The clinical data of the two study groups were compared, and liver pathology was evaluated using a scoring system. RESULTS: The average age and weight were similar in the two groups (64.1 +/- 16.8 days vs. 60.7 +/- 19.3 days, p > 0.05; 4.9 +/- 0.9 kg vs. 4.7 +/- 0.8 kg, p > 0.05). There were no significant intergroup differences in preoperative total bilirubin (TB), direct bilirubin (DB), alanine transaminase, aspartate transaminase, and international normalized ratio. The preoperative levels of gamma-glutamyl transpeptidase (gamma GT) and albumin in group A were significantly higher than those in group B (gamma GT: 956.8 +/- 503.8 IU/L vs. 620.2 +/- 437.1 IU/L, p = 0.00; ALB: 40.8 +/- 2.5 g/L vs. 36.8 +/- 3.6 g/L, p = 0.04), whereas alkaline phosphatase was significantly lower in group A compared to group B (512.2 +/- 224.6 IU/L vs. 631.7 +/- 254.7 IU/L, p = 0.02). The postoperative TB and DB after 2 weeks of the Kasai procedure decreased significantly more in group A than in group B (TB: 53.9 vs. 21.4%, p = 0.00; DB: 51.0 vs. 22.7%, p = 0.00), whereas gamma-GT increased significantly less in group A than in group B (48.3 vs. 142.1%, p = 0.00). Cystic structures were observed at the porta hepatis on ultrasound in more patients from group A (28.2 vs. 3.2%, p < 0.00). There was no significant difference in the total pathological score between the two groups (p = 0.38) whereas the score of bile plugs was significantly higher in group A (0.95 vs. 0.38, p = 0.03). CONCLUSION: The cystic structures observed at the porta hepatis on ultrasound preoperatively and the rapid decrease in TB and DB within 2 weeks postoperatively predict good long-term prognosis, whereas a significant increase in gamma-GT with a lower preoperative level predicts poor long-term prognosis. The development of bile plugs may be an indicator of favorable prognosis. PMID- 29427259 TI - Intraoperative cerebral oximetry-based management for optimizing perioperative outcomes: a meta-analysis of randomized controlled trials. AB - PURPOSE: Although evidence from observational studies in a variety of clinical settings supports the utility of cerebral oximetry as a predictor of outcomes, prospective clinical trials thus far have reported conflicting results. This systematic review and meta-analysis was designed to evaluate the influence of management associated with intraoperative cerebral oximetry on postoperative outcomes. The primary outcome was postoperative cognitive dysfunction (POCD), with secondary outcomes that included postoperative delirium, length of intensive care unit (ICU) stay, and hospital length of stay (LOS). SOURCE: After searching the PubMed, EMBASE, Cochrane Library, Scopus, and Google Scholar databases, all randomized controlled trials (RCTs) assessing the impact of intraoperative cerebral oximetry-guided management on clinical outcomes following surgery were identified. PRINCIPAL FINDINGS: Fifteen RCTs comprising 2,057 patients (1,018 in the intervention group and 1,039 in control group) were included. Intraoperative management guided by the use of cerebral oximetry was associated with a reduction in the incidence of POCD (risk ratio [RR] 0.54; 95% confidence interval [CI], 0.33 to 0.90; P = 0.02; I2 = 85%) and a significantly shorter length of ICU stay (standardized mean difference [SMD], -0.21 hr; 95% CI, -0.37 to -0.05; P = 0.009; I2 = 48%). In addition, overall hospital LOS (SMD, -0.06 days; 95% CI, -0.18 to 0.06; P = 0.29; I2 = 0%) and incidence of postoperative delirium (RR, 0.69; 95% CI, 0.36 to 1.32; P = 0.27; I2 = 0%) were not impacted by the use of intraoperative cerebral oximetry. CONCLUSIONS: Intraoperative cerebral oximetry appears to be associated with a reduction in POCD, although this result should be interpreted with caution given the significant heterogeneity in the studies examined. Further large (ideally multicentre) RCTs are needed to clarify whether POCD can be favourably impacted by the use of cerebral oximetry-guided management. PMID- 29427261 TI - Simulative design in macroscale for prospective application to micro-catheters. AB - In this paper, a motion-transforming element is applied to the development of a new catheter device. The motion-transforming element structure allows a reduction of linear movement and converts linear movement to rotational movement. The simulative design of micro-catheters is based on a proposed structure called the Operating Mini Station (OMS). OMS is operated by movement of a motion transforming element. A new motion-transforming element is designed using multiple links that are connected by hinged joints based on an elastic design. The design of the links and the hinges are optimized for precise and reliable movement of the motion-transforming element. Because of the elastic design, it is possible to realize a catheter that allows various movements in small spaces like capillaries. PMID- 29427260 TI - Feasibility of analyzing DNA copy number variation in breast cancer tumor specimens from 1950 to 2010: how old is too old? AB - PURPOSE: The purpose of the study was to assess the feasibility of quantifying long-term trends in breast tumor DNA copy number variation (CNV) profiles. METHODS: We evaluated CNV profiles in formalin-fixed paraffin-embedded (FFPE) tumor specimens from 30 randomly selected Kaiser Permanente Northern California health plan women members diagnosed with breast cancer from 1950 to 2010. Assays were conducted for five cases per decade who had available tumor blocks and pathology reports. RESULTS: As compared to the tumors from the 1970s to 2000s, the older tumors dating back to the 1950s and 1960s were much more likely to (1) fail quality control, and (2) have fewer CNV events (average 23 and 31 vs. 58 to 69), fewer CNV genes (average 5.1 and 3.7k vs. 8.1 to 10.3k), shorter CNV length (average 2,440 and 3,300k vs. 5,740 to 9,280k), fewer high frequency Del genes (37 and 25% vs. 54 to 76%), and fewer high frequency high_Amp genes (20% vs. 56 to 73%). On average, assay interpretation took an extra 60 min/specimen for cases from the 1960s versus 20 min/specimen for the most recent tumors. CONCLUSIONS: Assays conducted in the mid-2010s for CNVs may be feasible for FFPE tumor specimens dating back to the 1980s, but less feasible for older specimens. PMID- 29427262 TI - Factor structure and clinical correlates of the 61-item Wender Utah Rating Scale (WURS). AB - The objective of this study was to assess the factor structure and clinical correlates of a 61-item version of the Wender Utah Rating Scale (WURS), a self report retrospective measure of childhood problems, experiences, and behavior used in ADHD assessment. Given the currently mostly widely used form of the WURS was derived via a criterion-keyed approach, the study aimed to use latent variable modeling of the 61-item WURS to potentially identify more and more homogeneous set of items reflecting current conceptualizations of ADHD symptoms. Exploratory structural equation modeling was used to generate factor scores which were then correlated with neuropsychological measures of intelligence and executive attention as well as a broad measure of personality and emotional functioning. Support for a modified five-factor model was found: ADHD, disruptive mood and behavior, negative affectivity, social confidence, and academic problems. The ADHD factor differed somewhat from the traditional 25-item WURS short form largely through weaker associations with several measures of personality and psychopathology. This study identified a factor more aligned with DSM-5 conceptualization of ADHD as well as measures of other types of childhood characteristics and symptoms which may prove useful for both research and clinical practice. PMID- 29427264 TI - Urban Renewal Mega Projects and Residents' Quality of Life: Evidence from Historical Religious Center of Mashhad Metropolis. AB - Urban decay is the process by which a historical city center, or an old part of a city, falls into decrepitude and faces serious problems. Urban management, therefore, implements renewal mega projects with the goal of physical and functional revitalization, retrieval of socioeconomic capacities, and improving of quality of life of residents. Ignoring the complexities of these large-scale interventions in the old and historical urban fabrics may lead to undesirable consequences, including an additional decline of quality of life. Thus, the present paper aims to assess the impact of renewal mega projects on residents' subjective quality of life, in the historical religious district of the holy city of Mashhad (Samen District). A combination of quantitative and qualitative methods of impact assessment, including questionnaires, semi-structured personal interviews, and direct observation, is used in this paper. The results yield that the Samen Renewal Project has significantly reduced the resident's subjective quality of life, due to its undesirable impacts on physical, socio-cultural, and economic environments. PMID- 29427263 TI - Park Use in Low-Income Urban Neighborhoods: Who Uses the Parks and Why? AB - We examined individual and environmental influences on park use among residents of two low-income predominantly African American neighborhoods to identify determinants of park use in lower-income urban neighborhoods. We analyzed data from interviews of 1003 individuals randomly selected from the neighborhoods, systematic observations of neighborhood parks, and police-recorded crime incidence within a .5-mi buffer around each park. Most participants (82.4%) had previously visited a neighborhood park, and nearly half (46.2%) had visited one in the past month. However, only 8.5% of participants were aware of their closest park. Compared with the parks closest to home, parks that participants reported visiting most were larger and had more amenities and features and fewer incivilities and reported crimes of a serious nature. Park use among residents of lower-income neighborhoods may be increased by offering more amenities and features and ensuring the presence of a well-appointed park within easy walking distance of residents' homes. PMID- 29427265 TI - Estimation of weight status and weight-loss efforts in Korean adults with non obesity considering metabolic syndrome. AB - PURPOSE: To examine whether metabolic syndrome (MetS) is related to estimation of weight status and weight-loss efforts in Korean adults with non-obesity. METHODS: In 4345 men and 6387 women in non-obese Koreans (age 49.2 +/- 16.7 years, BMI < 25 kg/m2) participating in the 2011-2013 Korean National Health and Nutrition Examination Survey, the presence/absence of MetS using the harmonized criteria, and weight perception and weight-loss efforts using questionnaires were assessed. Estimation of weight status was determined as underestimation, correct estimation, and overestimation based on differences between perceived weight categories and BMI-based categories. RESULTS: 15.7% in men and 12.6% in women with BMI < 25 kg/m2 had the MetS. After adjusting for sociodemographic factors, health-related behaviors, treatment of cardiovascular diseases and cardiovascular risk factors, and BMI-based categories, correct estimation and overestimation of weight status in men [odds ratio (95% CI), 1.58 (1.29-1.92); 2.82 (1.48-5.38)], and women [1.53 (1.26-1.86); 1.59 (1.09-2.31)] were positively associated with the presence of MetS compared to those with underestimation of weight status. After adjusting for weight estimation, sociodemographic factors, health-related behaviors, and treatment of cardiovascular diseases and cardiovascular risk factors, weight-loss efforts were positively associated with the presence of MetS [1.66 (1.33-2.08) in men, 1.31 (1.07-1.61) in women] in all subjects, and number of MetS components [1.28 (1.02-1.62) per 1 more component] in those with MetS. CONCLUSIONS: In non-obese individuals, correct estimation and overestimation of weight status may be more likely to identify individuals with MetS and concurrent MetS may increase weight-loss efforts regardless of weight estimation. LEVEL OF EVIDENCE: Level III, evidence obtained from a case-control observational study. PMID- 29427266 TI - Correction to: ACMT Position Statement: Addressing the Rising Cost of Prescription Antidotes. AB - This article contains a couple typographical errors in the table and in the formatting of references. The authors and the journal apologize for those errors and respectfully include a corrected table and corrected reference list here. PMID- 29427267 TI - Erratum to: Functional Analysis of Membrane Proteins Produced by Cell-Free Translation. PMID- 29427268 TI - Temporal trends in respiratory mortality and short-term effects of air pollutants in Shenyang, China. AB - Short-term exposures to air pollution are associated with acute effects on respiratory health. This study aimed to describe 10-year temporal trends in respiratory mortality in the urban areas of Shenyang, China, according to gender and age and estimate the effects of air pollution on respiratory diseases (ICD 10J00-J99) and lung cancer (ICD-10 C33-C34) using a case-crossover design. During the study period 2013-2015, the exposure-response relationship between ambient air pollutants and mortality data was fitted by a quasi-Poisson model. Age standardized mortality rates for a combined number of respiratory diseases and for lung cancer declined in Shenyang; however, death counts increased with aging. Deaths from respiratory diseases increased by 4.7% (95% CI, 0.00-9.9), and lung cancer mortality increased by 6.5% (95% CI, 1.2-12.0), both associated with a 10 MUg/m3 increase in exposure to particulate matter < 2.5 MUg in diameter (PM2.5). Moreover, males in Shenyang's urban areas were more susceptible to the acute effects of PM2.5 and SO2 exposure; people aged >= 65 years had a high susceptibility to ozone, and those aged < 65 years were more susceptible to other air pollutants. These results provided an updated estimate of the short-term effects of air pollution in Shenyang. Since population aging is also associated with increasing mortality from respiratory diseases and lung cancer, reinforcing air quality control measures and health-promoting behaviors is urgent and necessary in Shenyang. PMID- 29427269 TI - Preparation, characterization, and application of Ti/TiO2-NTs/Sb-SnO2 electrode in photo-electrochemical treatment of industrial effluents under mild conditions. AB - Ti/TiO2-NTs/Sb-SnO2 electrode was prepared by gradient pulsed electrodeposition, and its electrochemical properties were evaluated. The catalytic activity and reusability of the electrode were tested by electrochemical oxidation (EO) and photoelectrochemical oxidation (PEO) of organics present in textile industry wastewater (TWW) and coffee bean processing industry wastewater (CWW). COD removal of ~ 41% was achieved after 5-h electrolysis under a constant applied current density of 30 mA cm-2 for TWW and 50 mA cm-2 for CWW. Nearly 14 and 18% increment in COD removal was observed under PEO for TWW and CWW, respectively. The turbidity of TWW reduced from 15 to ~ 3 NTU and the turbidity of CWW reduced from 27 to ~ 3 NTU by both EO and PEO. The % COD removal observed after 5-h electrolysis remained consistent for 7 repeated cycles; however, the catalytic activity of the electrode reduced gradually. These results suggested that the Ti/TiO2-NTs/Sb-SnO2 can be a potential electrode for the treatment of industrial wastewater. PMID- 29427270 TI - Kinetic and isothermal adsorption-desorption of PAEs on biochars: effect of biomass feedstock, pyrolysis temperature, and mechanism implication of desorption hysteresis. AB - Biochar has the potential to sequester biomass carbon efficiently into land, simultaneously while improving soil fertility and crop production. Biochar has also attracted attention as a potential sorbent for good performance on adsorption and immobilization of many organic pollutants such as phthalic acid esters (PAEs), a typical plasticizer in plastic and presenting a current environmental issue. Due to lack of investigation on the kinetic and thermodynamic adsorption-desorption of PAEs on biochar, we systematically assessed adsorption-desorption for two typical PAEs, dimethyl phthalate (DMP) and diethyl phthalate (DEP), using biochar derived from peanut hull and wheat straw at different pyrolysis temperatures (450, 550, and 650 degrees C). The aromaticity and specific surface area of biochars increased with the pyrolysis temperature, whereas the total amount of surface functional groups decreased. The quasi-second-order kinetic model could better describe the adsorption of DMP/DEP, and the adsorption capacity of wheat straw biochars was higher than that of peanut hull biochars, owing to the O-bearing functional groups of organic matter on exposed minerals within the biochars. The thermodynamic analysis showed that DMP/DEP adsorption on biochar is physically spontaneous and endothermic. The isothermal desorption and thermodynamic index of irreversibility indicated that DMP/DEP is stably adsorbed. Sorption of PAEs on biochar and the mechanism of desorption hysteresis provide insights relevant not only to the mitigation of plasticizer mobility but also to inform on the effect of biochar amendment on geochemical behavior of organic pollutants in the water and soil. PMID- 29427272 TI - Energy crops on landfills: functional, environmental, and costs analysis of different landfill configurations. AB - The cultivation of energy crops on landfills represents an important challenge for the near future, as the possibility to use devalued sites for energy production is very attractive. In this study, four scenarios have been assessed and compared with respect to a reference case defined for northern Italy. The scenarios were defined taking into consideration current energy crops issues. In particular, the first three scenarios were based on energy maximisation, phytotreatment ability, and environmental impact, respectively. The fourth scenario was a combination of these characteristics emphasised by the previous scenarios. A multi-criteria analysis, based on economic, energetic, and environmental aspects, was performed. From the analysis, the best scenario resulted to be the fourth, with its ability to pursue several objectives simultaneously and obtain the best score relatively to both environmental and energetic criteria. On the contrary, the economic criterion emerges as weak, as all the considered scenarios showed some limits from this point of view. Important indications for future designs can be derived. The decrease of leachate production due to the presence of energy crops on the top cover, which enhances evapotranspiration, represents a favourable but critical aspect in the definition of the results. PMID- 29427271 TI - Screening cyhalothrin degradation strains from locust epiphytic bacteria and studying Paracoccus acridae SCU-M53 cyhalothrin degradation process. AB - All locust epiphytic bacteria were screened and a total of 62 epiphytic bacteria were obtained from samples of Acrida cinerea. Via phylogenetic analysis, the 62 epiphytic bacteria were allocated to 27 genera, 18 families, 13 orders, six classes, and four phylums. Then, cyhalothrin degradation experiments were conducted, and the 10 strains that degraded more than 30% cyhalothrin and Paracoccus acridae SCU-M53 showed the highest cyhalothrin degradation rate of 70.5%. Furthermore, Paracoccus acridae SCU-M53 was selected for optimal cyhalothrin biodegradation conditions via the response surface method (Design Expert). Under the optimum conditions (28 degrees C, 75 mg/L, and 180 rpm), the cyhalothrin degradation rate reached 79.84% after 2 days. This suggests the possibility that isolating biodegradation cyhalothrin strains from Acrida cinerea is feasible. PMID- 29427273 TI - Climate and environmental factors affecting the incidence of cutaneous leishmaniasis in Isfahan, Iran. AB - Cutaneous leishmaniasis (CL) is a vector-borne human disease caused by Leishmania, a parasite transmitted by sand flies. CL is endemic in the Isfahan Province, Iran. This study was designed to identify the climate and environmental factors associated with CL incidence in Isfahan Province. Data included incident cases of CL, climate, and environmental factors, which were collected across 23 districts of province from 2007 to 2015. Analyses were performed with generalized linear models (GLMs) to fit a function to the relationships between the response and predictors. We used negative binomial regression due to over-dispersed distribution of CL cases. The effects of all seven climate and environmental factors were found to be significant (all p < 0.01), and the model explained 40% of the deviance of CL incidence. There was a positive relation between mean temperature, relative humidity, and slope of area with disease incidence; however, negative association was demonstrated between maximum wind speed, rainfall, altitude, and vegetation cover with CL incidence. Cutaneous leishmaniasis continues to be a widespread challenge, especially in northwestern parts of Iran. Climate and environmental factors should be considered when selecting the most appropriate strategies for preventing and controlling CL. PMID- 29427274 TI - Genotoxicity of spent pot liner as determined with the zebrafish (Danio rerio) experimental model. AB - Spent pot liner (SPL) is a solid waste generated during the primary smelting of aluminum, and its toxicity is attributed to the presence of fluoride, cyanide, and aluminum salts, which can be leached into aquatic ecosystems. Since the effects of this waste on aquatic life forms have not yet been investigated, the objective of our study was to evaluate the toxicity of simulated leachates of SPL on zebrafish (Danio rerio). Animals were exposed to 0 (control), 0.32, 0.64, or 0.95 g L-1 of SPL for 24, 72, and 96 h, and genotoxicity was accessed through micronucleus and comet assays. All of the tested treatments induced DNA fragmentation, and the observed frequency of micronuclei and damaged nucleoids generally increased with increasing SPL concentration. The highest frequency of micronuclei (3.3 per 3000 erythrocytes) was detected after 96 h of exposure with 0.95 g L-1 SPL. In the comet assay, nucleoids classified with highest level of damage in relation to the control were observed principally after 24 and 96 h of exposure. The data obtained in this study confirm the genotoxicaction and mutagenic potential of SPL and indicate that open-air deposits of the waste material could represent a health risk to humans and ecosystems alike. PMID- 29427275 TI - Linear and non-linear impact of Internet usage and financial deepening on electricity consumption for Turkey: empirical evidence from asymmetric causality. AB - This study investigates the relationship between Internet usage, financial development, economic growth, capital and electricity consumption using quarterly data from 1993Q1 to 2014Q4. The integration order of the series is analysed using the structural break unit root test. The ARDL bounds test for cointegration in addition to the Bayer-Hanck (2013) combined cointegration test is applied to analyse the existence of cointegration among the variables. The study found strong evidence of a long-run relationship between the variables. The long-run results under the ARDL framework confirm the existence of an inverted U-shaped relationship between financial development and electricity consumption, not only in the long-run, but also in the short-run. The study also confirms the existence of a U-shaped relationship between Internet usage and electricity consumption; however, the effect is insignificant. Additionally, the influence of trade, capital and economic growth is examined in both the long run and short run (ARDL ECM). Finally, the results of asymmetric causality suggest a positive shock in electricity consumption that has a positive causal impact on Internet usage. The authors recommend that the Turkish Government should direct financial institutions to moderate the investment in the ICT sector by advancing credits at lower cost for purchasing energy-efficient technologies. In doing so, the Turkish Government can increase productivity in order to achieve sustainable growth, while simultaneously reducing emissions to improve environmental quality. PMID- 29427276 TI - Effect of biochar on growth and ion contents of bean plant under saline condition. AB - A pot experiment was conducted with three biochar ratios (non-biochar, 5, and 10% total pot mass) and three salinities (control, 6, and 12 dSm-1 sodium chloride) treatments. At the flowering stage, we harvested common bean (Phaseolus vulgaris L. cv. Derakhshan) plants and measured growth characteristics and nutrient contents. As an average, salt stress decreased shoot and root dry weight, leaf area, relative water content, chlorophyll fluorescence (Fv/Fm) and leaf chlorophyll content, however, increased root length, sodium (Na) content of root and shoot, Na uptake, and translocation of bean plants, compared to control. On the other hand, the growth and ion contents of bean were affected positively by use of biochar, but Na translocation was not changed. Addition of biochar improved content of chlorophylls a, b, and total, and potassium (K), calcium (Ca), and magnesium (Mg) contents, while, diminished Na content and uptakes. Moreover, in case of measured parameters, 10% biochar was more effective compared to 5%. Overall, biochar enhanced growth of a bean under saline condition, which may have contributed to the reduction of Na uptake and enhance of K, Ca, and Mg contents. PMID- 29427277 TI - Antibiotic residues in liquid manure from swine feedlot and their effects on nearby groundwater in regions of North China. AB - A survey was conducted in regions of North China to better understand the effect of antibiotic residue pollution from swine feedlots to nearby groundwater environment. A total of nine experimental sites located in the regions of Beijing, Hebei, and Tianjin were selected to analyze the presence of residues of 11 most commonly used antibiotics, including tetracyclines (TCs), fluoroquinolones (FQNs), sulfonamides (SAs), macrolides, and fenicols, by using liquid chromatography spectrometry. The three most common antibiotics were TCs, FQNs, and SAs, with mean concentrations of 416.4, 228.8, and 442.4 MUg L-1 in wastewater samples; 19.9, 11.8, and 0.3 MUg L-1 in groundwater samples from swine feedlots; and 29.7, 14.0, and 0 MUg L-1 in groundwater samples from villages. Ordination analysis revealed that the composition and distribution of antibiotics and antibiotic resistance genes (AGRs) were similar in groundwater samples from swine feedlots and villages. FQNs and TCs occurred along the path from wastewater to groundwater at high concentrations and showed correlations with ARGs, with a strong correlation between FQN resistance gene (qnrA) copy number. FQN concentration was also found (P < 0.01) in wastewater and groundwater in villages (P < 0.01). Therefore, antibiotics discharged from swine feedlots through wastewater could disseminate into surrounding groundwater environments together with ARG occurrence (i.e., qnrA, sulI, sulII, tetG, tetM, and tetO). Overall, this study suggests that the spread of veterinary antibiotics from swine feedlots to groundwater environments should be highly attended and controlled by restricting excess antibiotic usage or improving the technology of manure management. PMID- 29427278 TI - Complexation of sulfamethazine with Cd(II) and Pb(II): implication for co adsorption of SMT and Cd(II) on goethite. AB - This study quantified the complex stability constants of sulfamethazine (SMT) with cadmium (Cd2+) and lead (Pb2+) under different pH conditions. The UV-Vis spectrophotometer was used for acquiring the complexation data. Results showed that the complex stability constants of SMT with cadmium (Cd2+) and lead (Pb2+) increased as a function of the solution pH. In the investigated pH range, Cd2+ showed stronger complex affinity with SMT than Pb2+. It appeared that cation-pi interactions might dominate the complex between SMT with Pb2+ and Cd2+ at acid environment, and the covalent bonding might play a major role at neutral environment. Batch adsorption equilibrium experiment showed that the sorption capacity of Cd2+ on goethite increased from 3.83 to 7.64 mg/g along with the addition of 1 mg/L SMT, indicating SMT can impede the transportation of Cd. In general, this study worked out the complexation constants and clarified the complexation mechanism between SMT with lead and cadmium, while sorption experiment indicated that sorption of Cd onto goethite was enhanced with SMT. PMID- 29427279 TI - Identification of intermediates, acute toxicity removal, and kinetics investigation to the Ametryn treatment by direct photolysis (UV254), UV254/H2O2, Fenton, and photo-Fenton processes. AB - This paper reports the degradation of 10 mg L-1 Ametryn solution with different advanced oxidation processes and by ultraviolet (UV254) irradiation alone with the main objective of reducing acute toxicity and increase biodegradability. The investigated factors included Fe2+ and H2O2 concentrations. The effectiveness of the UV254 and UV254/H2O2 processes were investigated using a low-pressure mercury UV lamp (254 nm). Photo-Fenton process was explored using a blacklight blue lamp (BLB, lambda = 365 nm). The UV254 irradiation process achieved complete degradation of Ametryn solution after 60 min. The degradation time of Ametryn was greatly improved by the addition of H2O2. It is worth pointing out that a high rate of Ametryn removal was attained even at low concentrations of H2O2. The kinetic constant of the reaction between Ametryn and HO? for UV254/H2O2 was 3.53 * 108 L mol-1 s-1. The complete Ametryn degradation by the Fenton and photo Fenton processes was observed following 10 min of reaction for various combinations of Fe2+ and H2O2 under investigation. Working with the highest concentration (150 mg L-1 H2O2 and 10 mg L-1 Fe2+), around 30 and 70% of TOC removal were reached within 120 min of treatment by Fenton and photo-Fenton processes, respectively. Although it did not obtain complete mineralization, the intermediates formed in the degradation processes were hydroxylated and did not promote acute toxicity of Vibrio fischeri. Furthermore, a substantial improvement of biodegradability was obtained for all studied processes. PMID- 29427280 TI - Geniposide Increases Unfolded Protein Response-Mediating HRD1 Expression to Accelerate APP Degradation in Primary Cortical Neurons. AB - Altered proteostasis induced by amyloid peptide aggregation and hyperphosphorylation of tau protein, is a prominent feature of Alzheimer's disease, which highlights the occurrence of endoplasmic reticulum stress and triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis. In this study, we investigated the role of geniposide in the activation of UPR induced by high glucose in primary cortical neurons. We found that high glucose induced a significant activation of UPR, and geniposide enhanced the effect of high glucose on the phosphorylation of IRE1alpha, the most conserved UPR signaling branch. We observed that geniposide induced the expression of HRD1, an ubiquitin-ligase E3 in a time dependent manner, and amplified the expression of HRD1 induced by high glucose in primary cortical neurons. Suppression of IRE1alpha activity with STF 083010, an inhibitor of IRE1 phosphorylation, prevented the roles of geniposide on the expression of HRD1 and APP degradation in high glucose-treated cortical neurons. In addition, the results from RNA interfere on HRD1 revealed that HRD1 was involved in geniposide regulating APP degradation in cortical neurons. These data suggest that geniposide might be benefit to re-establish proteostasis by enhancing the UPR to decrease the load of APP in neurons challenged by high glucose. PMID- 29427281 TI - Idiopathic chylous ascites in a patient with HIV infection: response to total parenteral nutrition and octreotide therapy. AB - The authors describe a 47-year-old man infected with human immunodeficiency virus admitted for ascites and weight loss. Ascitic fluid analysis revealed chylous ascites (triglycerides 444 mg/dl) with negative microbiological tests. Neoplasia, cardiac disease and liver cirrhosis were excluded after an extensive diagnostic workout. Exploratory laparotomy with tissue sampling did not clarify ascites etiology. During hospital admission, patient status gradually deteriorated, severe malnutrition developed and ascites became refractory to diuretics. Total parenteral nutrition and octreotide therapy were started and maintained for 3 weeks with ascites resolution and no relapse after oral diet resumption. Chylous ascites is a rare entity with several causes that compromise intra-abdominal lymphatic drainage. This case illustrates the difficulty in establishing etiology in some patients and the effectiveness of total parenteral nutrition plus octreotide therapy in idiopathic chylous ascites in HIV-infected patients. PMID- 29427282 TI - Neonatal Exposure to Low-Dose (1.2%) Sevoflurane Increases Rats' Hippocampal Neurogenesis and Synaptic Plasticity in Later Life. AB - The increasing usage of general anesthetics on young children and infants has drawn extensive attention to the effects of these drugs on cognitive function later in life. Recent animal studies have revealed improvement in hippocampus dependent performance after lower concentrations of sevoflurane exposure. However, the long-term effects of low-dose sevoflurane on the developing brain remain elusive. On postnatal day (P) 7, rats were treated with 1.2% sevoflurane (1.2% sevo group), 2.4% sevoflurane (2.4% sevo group), and air control (C group) for 6 h. On P35-40, rats' hippocampus-dependent learning and memory was tested using the Morris water maze. Cognition-related and synapse-related proteins in the hippocampus were measured using Western blotting on P35. On the same day, neurogenesis and synapse ultrastructure were evaluated using immunofluorescence and transmission electron microscopy (TEM). On P35, the rats neonatally exposed to 1.2% sevoflurane showed better behavioral results than control rats, but not in the 2.4% sevo group. Exposure to 1.2% sevoflurane increased the number of 5' bromo-2-deoxyuridine (BrdU)-positive cells in the dentate gyrus and improved both synaptic number and ultrastructure in the hippocampus. The expression levels of BDNF, TrkB, postsynaptic density (PSD)-95, and synaptophysin in the hippocampus were also increased in the 1.2% sevo group. In contrast, no significant changes in neurogenesis or synaptic plasticity were observed between the C group and the 2.4% sevo group on P35. These results showed that exposure of the developing brain to a low concentration of sevoflurane for 6 h could promote spatial learning and memory function, along with increased hippocampal neurogenesis and synaptic plasticity, in later life. PMID- 29427283 TI - Naringenin Decreases alpha-Synuclein Expression and Neuroinflammation in MPTP Induced Parkinson's Disease Model in Mice. AB - The present study was designed to ascertain the role of naringenin (NGN), a citrus fruit flavanone, against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced alpha-synuclein (SYN) pathology and neuroinflammation in a mouse model. NGN was administered to C57BL/6J mice once a day for 5 consecutive days prior to the MPTP intoxication. On day 5, 40-50 min after the NGN or vehicle administration, MPTP was injected in two divided doses (2* 40 mg/kg, i.p. at 16 h apart). The animals were observed for motor functions 48 h after the first MPTP injection. The animals were then euthanized, the brains collected to analyze SYN pathology, cytokines, and oxidative stress levels in the substantia nigra region. The NGN significantly downregulated SYN and upregulated dopamine transporter (DAT) and tyrosine hydroxylase (TH) protein expressions. It also downregulated tumor necrosis factor-alpha (TNFalpha) and interleukin 1beta (IL1beta) mRNA expressions and improved superoxide dismutase levels. It also reduced glutathione levels when compared to vehicle-treated PD animals. The upregulation of TH corroborates to an increase in dopamine, DOPAC, and homovanillic acid turnover and motor functions with NGN treatment. To summarize, NGN, a dietary flavone, has the potential to counteract MPTP-induced dopaminergic degeneration by regulating SYN pathology, neuroinflammation, and oxidative stress. This warrants the investigation of NGN's potential effects in a genetic model of PD. PMID- 29427284 TI - A Single High Dose of Methamphetamine Reduces Monoamines and Impairs Egocentric and Allocentric Learning and Memory in Adult Male Rats. AB - Methamphetamine (MA) alters dopamine markers and cognitive function in heavy users. In rodents, there are MA dosing regimens that induce concordant effects using repeated administration at spaced intervals. These regimens are effective but complicate experiments designed to disentangle the effects of the drug on different brain regions in relation to their cognitive effects because of treatment spacing. In an effort to simplify the model, we tested whether a single dose of MA could induce the same monoamine and cognitive effects as multiple, spaced dosing without affecting survival. Adult male Sprague-Dawley rats were treated with 40 mg/kg MA subcutaneously once and tested starting 2 weeks later. MA-treated rats showed deficits in egocentric navigation in Cincinnati water maze, in spatial navigation in the Morris water maze, and in choosing a consistent problem-solving strategy in the Star water maze when given the option to show a preference. MA-treated rats had persistent dopamine and serotonin reductions in the neostriatum and nucleus accumbens, and serotonin reductions in the hippocampus of the same magnitude as in repetitive treatment models. The data demonstrate that a single dose recapitulates the neurocognitive and monoamine effects of multiple-dose regimens, thereby simplifying the model of MA-induced neurotoxicity. PMID- 29427286 TI - First Experience of Inserting a Metallic Mesh Stent (Uventa Stent) in Malignant Ureteral Obstruction in Iran. AB - Malignant ureteral obstruction is usually caused by an extrinsic compression including intra-abdominal cancers. One of the treatment modalities decompressing the obstruction is applying stent to open the ureter. Metallic Stent is an effective instrument which we used for the first time in Iran in our patient who had a metastatic colon cancerwith a single kidney and we used a Novel, Double Layered, Coated, Self-expandable Metallic Mesh Stent (Uventa Stent) to keep the ureter open. After six months of follow up with ureteroscopy, there was no obstruction any more. PMID- 29427287 TI - Determine the Relationship Between Abdominal Muscle Strength, Trunk Control and Urinary Incontinence in Children with Diplegic Cerebral Palsy. AB - PURPOSE: The aim of this study is to determine the relationship between abdominal muscle strength, trunk control and urinary incontinence in children with diplegic cerebral palsy. MATERIALS AND METHODS: The current study had a cross-sectional design using analytical study as well as an observational research model. Fifty children between the ages of 5 and 18 years who were diagnosed with diplegic clinical type of cerebral palsy were included in this study using improbable random sampling method. After patients' demographic information were obtained, Dysfunctional Voiding and Incontinence Symptoms Score Questionnaire (DVISS), Dysfunctional Voiding Symptom Score (DVSS), the manual muscle test of the muscles, Trunk ControlTest (TCT) and Trunk Control Measurement Scale (TCMS) were completed in order to evaluate trunk control. Also, Gross Motor Function Classification System (GMFCS) was performed in order to define the functional level. RESULTS: In this study, a highly correlated negative relationship was found between DVISS and DVSS scores with muscle abdominal strength, TCMS and TCT. In addition, a highly correlated positive relationship was found between both GMFCS and DVISS and GMFCS and DVSS. CONCLUSION: This is the first study that describes the effect of trunk control and muscle strength on urinary incontinence in children with diplegic cerebral palsy. This study showed that there is a correlation between trunk control, muscle strength and urinary incontinence. PMID- 29427285 TI - Effect of Tadalafil on Seizure Threshold and Activity of Antiepileptic Drugs in Three Acute Seizure Tests in Mice. AB - Tadalafil, a selective phosphodiesterase type 5 inhibitor, is a long-acting oral agent for the treatment of erectile dysfunction of multiple etiologies. Although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of tadalafil on seizure threshold as well as on the activity of some first and second-generation antiepileptic drugs in three acute seizure tests in mice. The obtained results showed that tadalafil, at the highest dose tested (20 mg/kg), significantly decreased the threshold for the first myoclonic twitch in the intravenous pentylenetetrazole (i.v. PTZ) seizure test. It did not affect the threshold for generalized clonic seizure and forelimb tonus in the i.v. PTZ, for tonic hindlimb extension in the maximal electroshock seizure threshold test, and for psychomotor seizure in the 6-Hz-induced seizure threshold test. Tadalafil did not alter the anticonvulsant activity of any of the studied antiepileptic drugs in electrically induced seizure tests. Interestingly, tadalafil potentiated the anticonvulsant activity of clonazepam and decreased the anticonvulsant activity of oxcarbazepine in the i.v. PTZ test. These interactions were pharmacodynamic in nature, as tadalafil did not alter clonazepam and oxcarbazepine concentrations both in serum and brain tissue. Furthermore, neither tadalafil alone nor its combinations with the studied antiepileptic drugs produced any significant impairment of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test), and long-term memory (assessed in the passive avoidance task). In conclusion, tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine. Further studies are warranted to evaluate the safety of tadalafil usage in patients with epilepsy. PMID- 29427288 TI - Handedness in gestural and manipulative actions in male hunter-gatherer Aka pygmies from Central African Republic. AB - OBJECTIVES: All human populations display a right-biased handedness. Nonetheless, if studies on western populations are plenty, investigations of traditional populations living at subsistence levels are rare. Yet, understanding the geographical variation of phenotypes of handedness is crucial for testing evolutionary hypotheses. We aimed to provide a preliminary investigation of factors affecting handedness in 25 Aka pygmies from Central African Republic when spontaneously gesturing or manipulating food/tools (Nactions = 593). MATERIALS AND METHODS: We recorded spontaneous behaviors and characterized individuals' hand preference using GLMM with descriptive variables as target position, task complexity (unimanual/bimanual), task nature (food/tool manipulation, gesture), and task physical/cognitive constraints (precision or power for manipulative actions and informative content for gestures). RESULTS: Individuals were lateralized to the right (93%, N = 15) when manipulating food/tools but not when gesturing. Hand preference was affected by target position but not by task complexity. While nonexplicitly informative gestures were more biased to the right compared to explicitly informative ones, no differences were found within food/tool manipulation (power or precision vs. none). DISCUSSION: Although we do not intend to assume generalizable results due to our reduced sample, our observations provide additional information on handedness in a contemporary traditional society. Especially, the study mainly evidenced considerable cultural effects in gestures while also supporting theories considering active tool manipulation as one of the overriding factor in human handedness evolution. PMID- 29427289 TI - Delay aversion in attention deficit/hyperactivity disorder is mediated by amygdala and prefrontal cortex hyper-activation. AB - BACKGROUND: Experimental research supports delay aversion as a motivational feature of attention deficit/hyperactivity disorder (ADHD). To investigate the neurobiology of delay aversion in ADHD, this study examined whether adolescents with ADHD display an unusually strong activation in affective brain regions in response to cues predicting forthcoming delay and whether these effects are (a) delay-dose dependent and (b) statistically mediate the association between ADHD and self-reported delay aversion. METHODS: Twenty-nine right-handed male adolescents with combined type ADHD and 32 typically developing controls (ages 10 18 years) performed a reaction time task in an MRI scanner. Pretarget cues indicated delay-related response consequences. One indicated that delay would follow the response irrespective of response speed (CERTAIN DELAY), a second that delay would only follow if the response was too slow (CONDITIONAL DELAY), and a third that no delay would follow the response whatever its speed (NO DELAY). Delay levels were 2, 6, or 14 s. Participants also rated their own delay aversion in everyday life. RESULTS: Individuals with ADHD rated themselves as more delay averse than controls. Significantly greater activation to CERTAIN DELAY cues relative to NO DELAY cues was found in participants with ADHD compared to controls (bilaterally) in amygdala, anterior insula, temporal pole, dorsolateral prefrontal cortex (DLPFC), and ventromedial prefrontal cortex. Amygdala and DLPFC activation strength were strongly and delay-dose dependently correlated with delay aversion ratings, and statistically mediated the relationship between ADHD status and delay aversion. CONCLUSIONS: When presented with cues predicting impending delay, adolescents with ADHD, relative to controls, displayed a delay related increase in activation in amygdala and DLPFC, regions known to be implicated in the processing of aversive events. Future studies should examine the specificity of these effects to delay aversion compared to aversive events in general. PMID- 29427290 TI - Disintegration of the agricultural by-product wheat bran under subcritical conditions. AB - BACKGROUND: The disintegration of destarched wheat bran in water and sulfuric acid (pH 3) under subcritical conditions (275-300 degrees C) and at short reaction times (1-4 min) was investigated. A cascade process comprising a stepwise separation of the liquid was applied to reduce the formation of undesired degradation products. RESULTS: The highest degree of biomass disintegration (67% dry mass solubilization) was achieved by application of a cascade process at 275 degrees C (pH 3). Regarding the dissolution of carbohydrates (monomeric and oligomeric form), the total glucose yields remained below 60%, while the total xylose and arabinose yields were about 76% and 67%. Approximately 74% of the protein and 95% of the mineral fraction could be extracted. The application of the cascade process enabled a substantially reduced formation of degradation products. CONCLUSION: When operating hydrothermally and subcritically in order to avoid some problematic aspects of a biorefinery, an extensive disintegration and monomerization of wheat bran and its constituents remains difficult even under the tested conditions (300 degrees C, pH 3). However, the applied cascade process proved to be useful to increase the yields and to substantially reduce the formation of undesired degradation products. Despite this fact, increased water consumption has to be conceded. (c) 2018 Society of Chemical Industry. PMID- 29427291 TI - Prognostic impact of tumour-stroma ratio in early-stage oral tongue cancers. AB - AIMS: Oral tongue squamous cell carcinoma (OTSCC) has a relatively poor outcome, and there is a need to identify better prognostic factors. Recently, tumour stroma ratio (TSR) has been associated with prognosis in several cancers. The aim of this multi-institutional study was to evaluate the prognostic value of TSR from original haematoxylin and eosin (HE)-stained tumour-resection slides in a series of early-stage (cT1-2N0) OTSCC patients. METHODS AND RESULTS: A TSR cutoff value of 50% was used to divide the patients into stroma-rich (>=50%) and stroma poor (<50%) groups. The relationships between TSR and clinicopathological characteristics of 311 early-stage OTSCC cases were analysed. The prognostic value of TSR in OTSCC was calculated separately and in combination with a previously published cancer cell budding and depth of invasion (BD) prognostic model. A total of 89 cases (28.6%) belonged to the stroma-rich group. In a multivariate analysis, the stroma-rich group had worse disease-free survival, with a hazard ratio (HR) of 1.81 [95% confidence interval (CI) 1.17-2.79, P = 0.008], and higher cancer-related mortality (HR 1.71, 95% CI 1.02-2.86, P = 0.03). The combination of the highest-risk parameter scores of TSR and the BD model showed significant correlations with recurrence rate (HR 3.42, 95% CI 1.71 6.82, P = 0.004) and cancer-related mortality (HR 11.63, 95% CI 3.83-35.31, P < 0.001). CONCLUSIONS: We conclude that TSR is a simple histopathological feature that is useful for prognostication of early-stage OTSCC, and suggest that TSR analyses in association with BD score could be included in routine clinical pathology reports for HE-stained slides. PMID- 29427292 TI - Intranasal oxytocin modulates neural functional connectivity during human social interaction. AB - Oxytocin (OT) modulates social behavior in primates and many other vertebrate species. Studies in non-primate animals have demonstrated that, in addition to influencing activity within individual brain areas, OT influences functional connectivity across networks of areas involved in social behavior. Previously, we used fMRI to image brain function in human subjects during a dyadic social interaction task following administration of either intranasal oxytocin (INOT) or placebo, and analyzed the data with a standard general linear model. Here, we conduct an extensive re-analysis of these data to explore how OT modulates functional connectivity across a neural network that animal studies implicate in social behavior. OT induced widespread increases in functional connectivity in response to positive social interactions among men and widespread decreases in functional connectivity in response to negative social interactions among women. Nucleus basalis of Meynert, an important regulator of selective attention and motivation with a particularly high density of OT receptors, had the largest number of OT-modulated connections. Regions known to receive mesolimbic dopamine projections such as the nucleus accumbens and lateral septum were also hubs for OT effects on functional connectivity. Our results suggest that the neural mechanism by which OT influences primate social cognition may include changes in patterns of activity across neural networks that regulate social behavior in other animals. PMID- 29427293 TI - Development of a nomogram for the estimation of long-term adherence to clozapine therapy using neutrophil fluorescence. AB - AIMS: Previously, we have reported an association between clozapine use and elevated FL3 neutrophil fluorescence, a flow-cytometric parameter for cell viability. Here, we developed and evaluated a pharmacokinetic-pharmacodynamic model relating FL3-fluorescence to clozapine exposure and derived a nomogram for estimation of long-term adherence. METHODS: Data from 27 patients initiating clozapine were analysed using nonlinear mixed effects modelling. A previously described pharmacokinetic model for clozapine was coupled to a FL3 fluorescence model. For this, an effect compartment with clozapine concentrations as input and a first order decay rate as output was linked with an Emax model to FL3 fluorescence. FL3-fluorescence was simulated for clozapine doses of 50, 150 and 400 mg daily (n = 10 000) to establish the nomogram. Finally, true simulated adherence (% of daily doses taken over 100 days) was compared to nomogram estimated adherence to evaluate the performance of the nomogram. RESULTS: The half-life of FL3-fluorescence was estimated at 228 h (coefficient of variation 35%). Median absolute prediction errors of the nomogram in case of fully random adherence for 50, 150 and 400 mg ranged from -0.193% to -0.525%. The nomogram performed slightly worse in case of nonrandom adherence (median prediction error up to 5.19%), but was still clinically acceptable. Compliance patterns containing longer drug holidays revealed that the nomogram adequately estimates compliance over approximately the last 3 weeks prior to FL3-measurement. CONCLUSION: Our nomogram could provide information regarding long-term adherence based on prescribed clozapine dose and FL3-fluorescence. Future studies should further explore the clinical value of this biomarker and nomogram. PMID- 29427294 TI - Simultaneous multislice refocusing via time optimal control. AB - PURPOSE: Joint design of minimum duration RF pulses and slice-selective gradient shapes for MRI via time optimal control with strict physical constraints, and its application to simultaneous multislice imaging. THEORY AND METHODS: The minimization of the pulse duration is cast as a time optimal control problem with inequality constraints describing the refocusing quality and physical constraints. It is solved with a bilevel method, where the pulse length is minimized in the upper level, and the constraints are satisfied in the lower level. To address the inherent nonconvexity of the optimization problem, the upper level is enhanced with new heuristics for finding a near global optimizer based on a second optimization problem. RESULTS: A large set of optimized examples shows an average temporal reduction of 87.1% for double diffusion and 74% for turbo spin echo pulses compared to power independent number of slices pulses. The optimized results are validated on a 3T scanner with phantom measurements. CONCLUSION: The presented design method computes minimum duration RF pulse and slice-selective gradient shapes subject to physical constraints. The shorter pulse duration can be used to decrease the effective echo time in existing echo-planar imaging or echo spacing in turbo spin echo sequences. PMID- 29427295 TI - Unveiling a hidden 31 P signal coresonating with extracellular inorganic phosphate by outer-volume-suppression and localized 31 P MRS in the human brain at 7T. AB - PURPOSE: The study was undertaken to demonstrate that there is more than 1 component in the extracellular Pi31 P signal ( Piex) acquired from human head using nonlocalized 31 P MRS. METHODS: Outer-volume-suppression (OVS) saturation and 1D/2D 31 P CSI were utilized to reveal the presence of an additional component in the Piex signal. RESULTS: 67% of the head extracellular Pi signal was attenuated upon OVS saturation of the peripheral meningeal tissues, likely reflecting elimination of the Pi signal in the meningeal fluids (the blood and CSF). Localized 1D/2D CSI data provided further support for this assignment. Upon correction for the meningeal contribution, the extracellular Pi concentration was 0.51 +/- 0.07 mM, whereas the intracellular Pi was 0.85 +/- 0.10 mM. The extracellular pH was measured as 7.32 +/- 0.04 when using OVS, as compared to 7.39 +/- 0.03 when measured without OVS (N = 7 subjects). CONCLUSION: The extracellular Pi signal acquired from the human head using nonlocalized 31 P MRS contains a significant component likely contributed by peripheral blood and CSF in meninges that must be removed in order to use this signal as an endogenous probe for measuring extracellular pH and other properties in the brain. PMID- 29427296 TI - Volumetric wireless coil based on periodically coupled split-loop resonators for clinical wrist imaging. AB - PURPOSE: Design and characterization of a new inductively driven wireless coil (WLC) for wrist imaging at 1.5 T with high homogeneity operating due to focusing the B1 field of a birdcage body coil. METHODS: The WLC design has been proposed based on a volumetric self-resonant periodic structure of inductively coupled split-loop resonators with structural capacitance. The WLC was optimized and studied regarding radiofrequency fields and interaction to the birdcage coil (BC) by electromagnetic simulations. The manufactured WLC was characterized by on bench measurements and in vivo and phantom study in comparison to a standard cable-connected receive-only coil. RESULTS: The WLC placed into BC gave the measured B1+ increase of the latter by 8.6 times for the same accepted power. The phantom and in vivo wrist imaging showed that the BC in receiving with the WLC inside reached equal or higher signal-to-noise ratio than the conventional clinical setup comprising the transmit-only BC and a commercial receive-only flex coil and created no artifacts. Simulations and on-bench measurements proved safety in terms of specific absorption rate and reflected transmit power. CONCLUSIONS: The results showed that the proposed WLC could be an alternative to standard cable-connected receive coils in clinical magnetic resonance imaging. As an example, with no cable connection, the WLC allowed wrist imaging on a 1.5 T clinical machine using a full-body BC for transmitting and receive with the desired signal-to-noise ratio, image quality, and safety. PMID- 29427297 TI - Fecal immunochemical test for predicting mucosal healing in ulcerative colitis patients: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Fecal immunochemical test (FIT) is a promising marker for assessment of inflammatory bowel disease activity. However, the utility of FIT for predicting mucosal healing (MH) of ulcerative colitis (UC) patients has yet to be clearly demonstrated. The objective of our study was to perform a diagnostic test accuracy test meta-analysis evaluating the diagnostic accuracy of FIT in predicting MH of UC patients. METHODS: We systematically searched the databases from inception to November 2017 that evaluated MH in UC. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. The extracted data were pooled using a summary receiver operating characteristic curve model. Random effects model was used to summarize the diagnostic odds ratio, sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio. RESULTS: Six studies comprising 625 UC patients were included in the meta-analysis. The pooled sensitivity and specificity values for predicting MH in UC were 0.77 (95% confidence interval [CI], 0.72-0.81) and 0.81 (95% CI, 0.76-0.85), respectively. The FIT level had a high rule-in value (positive likelihood ratio, 3.79; 95% CI, 2.85-5.03) and a moderate rule-out value (negative likelihood ratio, 0.26; 95% CI, 0.16-0.43) for predicting MH in UC. The results of the receiver operating characteristic curve analysis (area under the curve, 0.88; standard error of the mean, 0.02) and diagnostic odds ratio (18.08; 95% CI, 9.57-34.13) also revealed improved discrimination for identifying MH in UC with FIT concentration. CONCLUSION: Our meta-analysis has found that FIT is a simple, reliable non invasive marker for predicting MH in UC patients. PMID- 29427298 TI - Meningitis as a consequence of otitis media in a child referred from the newborn hearing screening programme: A missed opportunity. PMID- 29427299 TI - Herpes simplex virus type 2 IgG antibodies in sera of umbilical cord as a proxy for placental infection in asymptomatic pregnant women. AB - PROBLEM: Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent diseases worldwide and is mainly sexually transmitted. When infecting pregnant women, HSV-2 is able to infect the placenta, can reach the fetus, and may affect the fetal development. We sought to determine the prevalence of HSV-2 infection and reactivation in asymptomatic pregnant women, the correlation between IgG in the maternal circulation and cord blood, and the correlation between circulating IgG, placental, and newborn infection (blood cord). METHOD OF STUDY: Serum samples and placental tissues from pregnant women and umbilical cord blood samples from their newborns were collected. Anti-HSV-2 antibodies were identified by ELISA, and HSV-2 DNA was detected by nested PCR. RESULTS: The seropositivity of IgG in pregnant women was 29.7% and IgM was detected in 1 woman (0.5%). In the umbilical cord of newborns, 33.1% were IgG-positive and IgM was detected in 2 samples (1.5%). A positive correlation between HSV-2 IgG titers in serum from pregnant women and cord blood samples was found (r = .36, P = .001). A difference between the positive and negative placental groups (maternal side) was found in titers of IgG in sera of umbilical cord, which were significantly higher in the positive placental group (P = .004). CONCLUSION: We describe for the first time that newborns from mothers with HSV-2 placental infection have higher IgG titers in sera of umbilical cord, suggesting IgGs antibodies can be indicative of placental viral infection in asymptomatic women. PMID- 29427300 TI - The ecosystem services of animal microbiomes. AB - Microbiologists often evaluate microbial community dynamics by formulating functional hypotheses based on ecological processes. Indeed, many of the methods and terms currently used to describe animal microbiomes derive from ecology and evolutionary biology. As our understanding of the composition and functional dynamics of "the microbiome" grows, we increasingly refer to the host as an ecosystem within which microbial processes play out. Even so, an ecosystem service framework that extends to the context of the host has thus far been lacking. Here, we argue that ecosystem services are a useful framework with which to consider the value of microbes to their hosts. We discuss those "microbiome services" in the specific context of the mammalian gut, providing a context from which to develop new hypotheses and to evaluate microbial functions in future studies and novel systems. PMID- 29427301 TI - Prospective Validation and Refinement of a Decision Rule to Obtain Chest X-ray in Patients With Nontraumatic Chest Pain in the Emergency Department. AB - OBJECTIVES: The objective was to prospectively validate and refine previously published criteria to determine the potential utility of chest x-ray (CXR) in the evaluation and management of patients presenting to the emergency department (ED) with nontraumatic chest pain (CP). METHODS: A prospective observational study was performed of patients presenting to three EDs in the United States with a chief complaint of nontraumatic CP. Previously defined high-risk history and examination elements were combined into a refined decision rule and these elements were recorded for each patient by the ED physician. CXR results were reviewed and analyzed to determine the presence of clinically significant findings including pneumonia, pleural effusion, pneumothorax, congestive heart failure, or the presence of a new mass. Odds ratios for each history and examination element were analyzed as well as sensitivity, specificity, and negative predictive value (NPV) of the rule overall. RESULTS: A total of 1,111 patients were enrolled and 1,089 CXRs were analyzed. There were 70 (6.4%) patients with clinically relevant findings on CXR. The refined decision rule had a sensitivity of 92.9% (confidence interval [CI] = 83.4%-97.3%) and specificity of 30.4% (CI = 27.6%-33.4%) to predict clinically relevant findings on CXR, with a NPV of 98.4% (CI = 96.1%-99.4%). Five CXRs with clinically significant findings would have been missed by application of the refined rule (three pneumonias and two pleural effusions). Applying these criteria as a CXR decision rule to this population would have reduced CXR utilization by 28.9%. CONCLUSIONS: This study validates previous research suggesting a low clinical yield for CXR in the setting of nontraumatic CP in the ED. This refined clinical decision rule has a favorable sensitivity and NPV in a patient population with low incidence of disease. Further validation is needed prior to use in practice. PMID- 29427302 TI - Multiple roles of single-minded 2 in esophageal squamous cell carcinoma and its clinical implications. AB - Degree of histological differentiation is an important characteristic of cancers and may be associated with malignant potential. However, in squamous cell carcinomas, a key transcriptional factor regulating tumor differentiation is largely unknown. Chemoradiotherapy (CRT) is a standard treatment for locally advanced esophageal squamous cell carcinoma; however, the survival rate is still below 40%. From microarray data, single-minded 2 (SIM2) was overexpressed in the epithelial subtype. Here, we investigated the correlation between SIM2 expression and its clinical implication, and in vitro and in vivo functions of SIM2 in tumor differentiation and in CRT sensitivity. Although SIM2 was suppressed in cancerous tissues, SIM2-high ESCC showed a favorable prognosis in CRT. Transient SIM2 expression followed by 3D culture induced expression of differentiation markers and suppressed epithelial-mesenchymal transition- and basal-cell markers. Levels of PDPN-high tumor basal cells and of expression of genes for DNA repair and antioxidant enzymes were reduced in stable transfectants, and they showed high CDDP and H2 O2 sensitivities, and their xenografts showed a well-differentiated histology. Reduction of tumor basal cells was restored by knockdown of aryl hydrocarbon receptor nuclear translocator (ARNT) that interacted with SIM2. Together, SIM2 increases CRT sensitivity through tumor differentiation by cooperation with ARNT. PMID- 29427303 TI - Response to 'Preoperative geriatric assessment and tailored interventions in frail older patients with colorectal cancer: a randomized controlled trial'. PMID- 29427304 TI - Police and mental health responses to mental health crisis in the Waikato region of New Zealand. AB - New Zealand police report a high level of involvement with people in mental health crisis, something that has been reported in the international literature in recent decades. Involvement of police represents a coercive pathway to care and is likely to be associated with use of force. The aim of this study was to investigate the clinical, legal, and social characteristics of individuals subject to police response in the Waikato region of New Zealand. Data were also collected on characteristics of police response, including use of force, time of day, and disposition. Use of force, most commonly use of handcuffs, occurred in 78% of cases involving police. The study showed that Maori were overrepresented in police responses, but no more likely than Europeans to experience use of force. Almost half those subject to police response were not subsequently admitted to hospital, raising questions about the need for and nature of police response in these cases. Because mental health nurses are often part of police response, nurses need to take cognisance of their relationship with police and contribute to any initiatives that can reduce coercion in the pathway to care, and improve service users' experience in mental health crises. PMID- 29427305 TI - Comprehensive re-evaluation of historical von Willebrand disease diagnosis in association with whole blood platelet aggregation and function. AB - INTRODUCTION: Diagnosis of von Willebrand disease (VWD) is challenging, particularly for type 1. The current diagnostic guidelines emphasize simultaneous bleeding symptoms and von Willebrand factor (VWF) levels of <30-40 IU/dL. Historical diagnoses require updated evaluation. We assessed the accuracy of past VWD diagnoses in our comprehensive care center with the standardized bleeding score (BS) and central laboratory analysis, focusing on VWF-dependent platelet functions in whole blood. METHODS: Our study comprised 83 adults with prior VWD who were diagnosed a median of 20 years ago. We assessed BS, VWF antigen and activity (minimum of 3 measurements), FVIII, PFA-100(r) , and platelet aggregation via Multiplate(r) . Genetic testing was targeted to types 3, 2N, 2B, and equivocal cases. RESULTS: All 13/13 (100%) type 3 and 29/32 (90%) type 2, but only 10/38 (26%) of type 1 (overall 52/83 (63%)) patients met the current criteria for VWD. All confirmed cases had abnormal BS, impaired PFA-100(r) , and decreased or absent ristocetin-induced platelet aggregation (RIPA), except subtype 2B. VWF, FVIII, RIPA, and PFA correlated with BS including all study subjects. Ten of the 38 patients with previous type 1 had low VWF (35-50 IU/dL) and variable VWF-dependent platelet function. Altogether, 21/83 patients (25%) had repeatedly normal VWF:RCo (>50 IU/dL). CONCLUSION: von Willebrand disease is associated with impaired VWF-dependent whole blood platelet functions that match traditional VWF measurements. We detected normal VWF in 25% of historically diagnosed patients, mainly type 1 patients, implying that there is a need to systematically re-evaluate historical VWD diagnoses. PMID- 29427306 TI - Impaired fear extinction in serotonin transporter knockout rats is associated with increased 5-hydroxymethylcytosine in the amygdala. AB - AIMS: One potential risk factor for posttraumatic stress disorder (PTSD) involves the low activity (short; s) allelic variant of the serotonin transporter-linked polymorphic region (5-HTTLPR), possibly due to reduced prefrontal control over the amygdala. Evidence shows that DNA methylation/demethylation is crucial for fear extinction in these brain areas and is associated with neuronal activation marker c-Fos expression. We hypothesized that impaired fear extinction in serotonin transporter knockout (5-HTT-/- ) rats is related to changes in DNA (de) methylation and c-Fos expression in the prefrontal cortex (PFC) and/or amygdala. METHODS: 5-HTT-/- and 5-HTT+/+ rats were subjected to fear extinction. 2 hours after the extinction session, the overall levels of DNA methylation (5-mC), demethylation (5-hmC), and c-Fos in fear extinction and nonfear extinction rats were measured by immunohistochemistry. RESULTS: 5-HTT-/- rats displayed decreased fear extinction. This was associated with reduced c-Fos activity in the infralimbic PFC. In the central nucleus of the amygdala, c-Fos immunoreactivity was increased in the fear extinction group compared to the no-fear extinction group, regardless of genotype. 5-hmC levels were unaltered in the PFC, but reduced in the amygdala of nonextinction 5-HTT-/- rats compared to nonextinction wild-type rats, which caught up to wild-type levels during fear extinction. 5-mC levels were stable in central amygdala in both wild-type and 5-HTT-/- extinction rats. Finally, c-Fos and 5-mC levels were correlated with the prelimbic PFC, but not amygdala. CONCLUSIONS: In the amygdala, DNA demethylation, independent from c Fos activation, may contribute to individual differences in risk for PTSD, as conferred by the 5-HTTLPR s-allele. PMID- 29427308 TI - Shank3 mutations and HCN channelopathy: one size does not fit all. PMID- 29427307 TI - Healthy and sustainable diets for future generations. AB - Global food systems will face unprecedented challenges in the coming years. They will need to meet the nutritional needs of a growing population and feed an expanding demand for proteins. This is against a backdrop of increasing environmental challenges (water resources, climate change, soil health) and the need to improve farming livelihoods. Collaborative efforts by a variety of stakeholders are needed to ensure that future generations have access to healthy and sustainable diets. Food will play an increasingly important role in the global discourse on health. These topics were explored during Nestle's second international conference on 'Planting Seeds for the Future of Food: The Agriculture, Nutrition and Sustainability Nexus', which took place in July 2017. This article discusses some of the key issues from the perspective of three major stakeholder groups, namely farming/agriculture, the food industry and consumers. (c) 2018 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29427309 TI - The rice planthopper parasitoid Anagrus nilaparvatae is not at risk when feeding on honeydew derived from Bacillus thuringiensis (Bt) rice. AB - BACKGROUND: Honeydew is a sugar-rich excretion produced by sap-feeding Sternorrhyncha and is an important source of carbohydrates for natural enemies, especially for parasitoids. Honeydew derived from genetically modified (GM) crops can contain amounts of the transgene product. Thus, it is a possible route of exposure for natural enemies feeding on honeydew. In the present study, the potential effects of Nilaparvata lugens honeydew derived from Cry1C and Cry2A rice on different life-table parameters and parasitism dynamics of the egg parasitoid Anagrus nilaparvatae were evaluated under laboratory and field conditions. Furthermore, the Bacillus thuringiensis (Bt) levels and the sugar and amino acid composition of honeydew were analyzed. RESULTS: Results indicated that A. nilaparvatae was exposed to Bt proteins by feeding on N. lugens honeydew produced from Bt rice. However, honeydew derived from the tested Cry1C and Cry2A rice lines did not affect the development, longevity, emergence rate and fecundity of A. nilaparvatae. Also, the parasitism dynamics in the field remained unaffected. In addition, the sugar and amino acid composition of N. lugens honeydew was not significantly altered for the tested Bt rice lines compared with the parental non-Bt plant. CONCLUSION: The quality of honeydew derived from the tested Bt rice lines as a food resource for natural enemies was maintained. (c) 2018 Society of Chemical Industry. PMID- 29427310 TI - Psychological factors not strength deficits are associated with severity of gluteal tendinopathy: A cross-sectional study. AB - BACKGROUND: Gluteal tendinopathy is the most common lower limb tendinopathy presenting to general practice. It has a high prevalence amongst middle-aged women and impacts on daily activities, work participation and quality of life. The aim was to compare physical and psychological characteristics between subgroups of severity of pain and disability. METHODS: A multicentre cross sectional cohort of 204 participants (mean age 55 years, 82% female) who had a clinical diagnosis of gluteal tendinopathy with magnetic resonance imaging confirmation were assessed. A range of physical and psychosocial characteristics were recorded. Pain and disability were measured with the VISA-G questionnaire. A cluster analysis was used to identify mild, moderate and severe subgroups based on total VISA-G scores. Between-group differences were then evaluated with a MANCOVA, including sex and study site as covariates, followed by a Bonferroni post hoc test. Significance was set at 0.05. RESULTS: There were significantly higher pain catastrophizing and depression scores in the more severe subgroups. Lower pain self-efficacy scores were found in the severe group compared to the moderate and mild groups. Greater waist girth and body mass index (BMI), lower activity levels and poorer quality of life were reported in the severe group compared to the mild group. Hip abductor muscle strength and hip circumference did not differ between subgroups of severity. CONCLUSIONS: Individuals with severe gluteal tendinopathy present with psychological distress, poorer quality of life, greater BMI and waist girth. Given these features, the consideration of psychological factors in more severe patients may be important to optimize patient outcomes and reduce healthcare utilization. SIGNIFICANCE: Patients with severe gluteal tendinopathy exhibit greater psychological distress, poorer quality of life and greater waist girth and BMI when compared to less severe cases. This implies that clinicians ought to consider psychological factors in the management of more severe gluteal tendinopathy. PMID- 29427311 TI - Generalized accelerated recurrence time model for multivariate recurrent event data with missing event type. AB - Recurrent events data are frequently encountered in biomedical follow-up studies. The generalized accelerated recurrence time (GART) model (Sun et al., 2016), which formulates covariate effects on the time scale of the mean function of recurrent events (i.e., time to expected frequency), has arisen as a useful secondary analysis tool to provide meaningful physical interpretations. In this article, we investigate the GART model in a multivariate recurrent events setting, where subjects may experience multiple types of recurrent events and some event types may be missing. We propose methods for the GART model that utilize the inverse probability weighting technique or the estimating equation projection strategy to handle event types that are missing at random. The new methods do not require imposing any parametric model for the missing mechanism, and thus are robust; moreover, they enjoy easy and stable implementation. We establish the uniform consistency and weak convergence of the resulting estimators and develop appropriate inferential procedures. Extensive simulation studies and an application to a dataset from Cystic Fibrosis Foundation Patient Registry (CFFPR) illustrate the validity and practical utility of the proposed methods. PMID- 29427312 TI - Evaluation of surface and shallow depth dose reductions using a Superflab bolus during conventional and advanced external beam radiotherapy. AB - The purpose of this study was to evaluate a methodology to reduce scatter and leakage radiations to patients' surface and shallow depths during conventional and advanced external beam radiotherapy. Superflab boluses of different thicknesses were placed on top of a stack of solid water phantoms, and the bolus effect on surface and shallow depth doses for both open and intensity-modulated radiotherapy (IMRT) beams was evaluated using thermoluminescent dosimeters and ion chamber measurements. Contralateral breast dose reduction caused by the bolus was evaluated by delivering clinical postmastectomy radiotherapy (PMRT) plans to an anthropomorphic phantom. For the solid water phantom measurements, surface dose reduction caused by the Superflab bolus was achieved only in out-of-field area and on the incident side of the beam, and the dose reduction increased with bolus thickness. The dose reduction caused by the bolus was more significant at closer distances from the beam. Most of the dose reductions occurred in the first 2-cm depth and stopped at 4-cm depth. For clinical PMRT treatment plans, surface dose reductions using a 1-cm Superflab bolus were up to 31% and 62% for volumetric-modulated arc therapy and 4-field IMRT, respectively, but there was no dose reduction for Tomotherapy. A Superflab bolus can be used to reduce surface and shallow depth doses during external beam radiotherapy when it is placed out of the beam and on the incident side of the beam. Although we only validated this dose reduction strategy for PMRT treatments, it is applicable to any external beam radiotherapy and can potentially reduce patients' risk of developing radiation-induced side effects. PMID- 29427313 TI - A moderate financial incentive can increase effort, but not intelligence test performance in adult volunteers. AB - A positive correlation between self-reported test-taking motivation and intelligence test performance has been reported. Additionally, some financial incentive experimental evidence suggests that intelligence test performance can be improved, based on the provision of financial incentives. However, only a small percentage of the experimental research has been conducted with adults. Furthermore, virtually none of the intelligence experimental research has measured the impact of financial incentives on test-taking motivation. Consequently, we conducted an experiment with 99 adult volunteers who completed a battery of intelligence tests under two conditions: no financial incentive and financial incentive (counterbalanced). We also measured self-reported test-taking importance and effort at time 1 and time 2. The financial incentive was observed to impact test-taking effort statistically significantly. By contrast, no statistically significant effects were observed for the intelligence test performance scores. Finally, the intelligence test scores were found to correlate positively with both test-taking importance (rc = .28) and effort (rc = .37), although only effort correlated uniquely with intelligence (partial rc = .26). In conjunction with other empirical research, it is concluded that a financial incentive can increase test-taking effort. However, the potential effects on intelligence test performance in adult volunteers seem limited. PMID- 29427315 TI - An 8/15-channel Tx/Rx head neck RF coil combination with region-specific B1 + shimming for whole-brain MRI focused on the cerebellum at 7T. AB - PURPOSE: To design and evaluate an 8/15-channel transmit/receive (Tx/Rx) head neck RF coil combination with region-specific B1+ shimming for whole-brain MRI with focus on improved functional MRI of the cerebellum at 7 T. METHODS: An 8 channel transceiver RF head coil was combined with a 7-channel receive-only array. The noise parameters and acceleration capabilities of this 8Tx/15Rx coil setup were compared with a commercially available 1Tx/32Rx RF head coil. Region specific 8-channel B1+ shimming was applied when using the 8Tx/15Rx RF coil. To evaluate the capability for functional MRI of the cerebellum, temporal SNR and statistical nonparametric maps for finger-tapping experiments with 14 healthy subjects were derived by applying a variable slice thickness gradient-echo echo planar functional MRI sequence. RESULTS: The 8Tx/15Rx setup had a lower maximum noise correlation between channels, but higher average correlations compared with the 1Tx/32Rx coil. Both RF coils exhibited identical g-factors in the cerebellum with R = 3 acceleration. The enlarged FOV of the 8Tx/15Rx coil in combination with region-specific B1+ shimming increased homogeneity of the transmission field and temporal SNR in caudal cerebellar regions. Temporal SNR losses in cranial parts were reduced, resulting in more highly significant voxels in the caudally activated areas and identical patterns in the cranial cerebellar parts during a finger-tapping task. CONCLUSION: Compared with the 1Tx/32Rx RF coil, the presented 8Tx/15Rx RF coil combination successfully improves functional MRI of the human cerebellum at 7 T while maintaining whole-brain coverage. A clear temporal SNR gain in caudal cerebellar regions is shown. PMID- 29427314 TI - Analysis of the effect of seasonal administration on the efficacy of sitagliptin: Subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes Study. AB - AIMS/INTRODUCTION: Hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus fluctuate throughout the year. However, there are few studies that have evaluated the therapeutic effect of hypoglycemic agents while considering such fluctuations. In a multicenter study (Januvia Multicenter Prospective Trial in Type 2 Diabetes Study), pretreatment patients with type 2 diabetes mellitus were divided into seven groups and given sitagliptin for 1 year. The aim of the present study was to evaluate the differences in the therapeutic effect, and the efficacy of sitagliptin in patients with type 2 diabetes mellitus based on the month the administration of the drug began as a subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes Study. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus were divided into four groups according to the month of initiation of sitagliptin. Changes in HbA1c in each group were compared at 3 and 12 months after administration of sitagliptin. As a negative correlation has been reported between baseline HbA1c and the degree of change after administration of sitagliptin, an analysis using the residual error from the approximate line was carried out. RESULTS: In the analysis of the degree of change in HbA1c, patients in the group in which administration of sitagliptin was started between August and October had the lowest degree of improvement at 3 months after starting sitagliptin. However, there was no significant intergroup difference in improvement at 12 months after the start of sitagliptin. The same result was also obtained in residual analysis. CONCLUSIONS: The present study suggested that the season of administration of sitagliptin influenced the subsequent hypoglycemic effect even after analysis excluding the influence of HbA1c value at the start of treatment. This study provides possibility, showing that seasonal fluctuations have an effect on the efficacy of antidiabetic drugs. PMID- 29427316 TI - First report of COL7A1 mutations in two patients with recessive dystrophic epidermolysis bullosa from Peru. PMID- 29427317 TI - Overexpression of PGC-1alpha in aging muscle enhances a subset of young-like molecular patterns. AB - PGC-1alpha is a transcriptional co-activator known as the master regulator of mitochondrial biogenesis. Its control of metabolism has been suggested to exert critical influence in the aging process. We have aged mice overexpressing PGC 1alpha in skeletal muscle to determine whether the transcriptional changes reflected a pattern of expression observed in younger muscle. Analyses of muscle proteins showed that Pax7 and several autophagy markers were increased. In general, the steady-state levels of several muscle proteins resembled that of muscle from young mice. Age-related mtDNA deletion levels were not increased by the PGC-1alpha-associated increase in mitochondrial biogenesis. Accordingly, age related changes in the neuromuscular junction were minimized by PGC-1alpha overexpression. RNA-Seq showed that several genes overexpressed in the aged PGC 1alpha transgenic are expressed at higher levels in young when compared to aged skeletal muscle. As expected, there was increased expression of genes associated with energy metabolism but also of pathways associated with muscle integrity and regeneration. We also found that PGC-1alpha overexpression had a mild but significant effect on longevity. Taken together, overexpression of PGC-1alpha in aged muscle led to molecular changes that resemble the patterns observed in skeletal muscle from younger mice. PMID- 29427318 TI - Starch digestibility: past, present, and future. AB - In the last century, starch present in foods was considered to be completely digested. However, during the 1980s, studies on starch digestion started to show that besides digestible starch, which could be rapidly or slowly hydrolysed, there was a variable fraction that resisted hydrolysis by digestive enzymes. That fraction was named resistant starch (RS) and it encompasses those forms of starch that are not accessible to human digestive enzymes but can be fermented by the colonic microbiota, producing short-chain fatty acids. RS has been classified into five types, depending on the mechanism governing its resistance to enzymatic hydrolysis. Early research on RS was focused on the methods to determine its content in foods and its physiological effects, including fermentability in the large intestine. Later on, due to the interest of the food industry, methods to increase the RS content of isolated starches were developed. Nowadays, the influence of RS on the gut microbiota is a relevant research topic owing to its potential health-related benefits. This review summarizes over 30 years of investigation on starch digestibility, its relationship with human health, the methods to produce RS and its impact on the microbiome. (c) 2018 Society of Chemical Industry. PMID- 29427319 TI - Distinguishing myelofibrosis from polycythemia vera and essential thrombocythemia: The utility of enumerating circulating stem cells with aberrant hMICL expression by flow cytometry. AB - INTRODUCTION: Diagnosing BCR-ABL negative myeloproliferative neoplasms (MPN) may be challenging due to overlapping features and lack of robust discriminatory parameters, especially between essential thrombocythemia (ET) and prefibrotic myelofibrosis (MF). Circulating immature hematopoietic cells are variably present in polycythemia vera (PV), ET, and MF. The C-type lectin hMICL is aberrantly expressed on hematopoietic stem cells in the majority of acute myeloid leukemia patients. However, the hMICL expression in MPN, having varying propensity of leukemic transformation, is unsettled. We hypothesized that enumeration of immature cells by flow cytometry (FCM) could be a discriminatory tool in MPN diagnostics. METHODS: By FCM, we quantified circulating stem cells with aberrant hMICL expression in 39 MPN patients, 10 age-matched controls, and in leukapheresis products from 10 patients with lymphoproliferative neoplasms. The utility of the FCM assay for discriminating MPN entities was evaluated by applying ROC curve analysis. RESULTS: While hMICL was absent in control samples, MF patients had significantly more hMICL+ stem cells (median 15.2%) than PV and ET (0.0%, P = .001 and 0.0%, P = .002, respectively). By ROC curve analysis, the presence of hMICL+ stem cells (>0 cells) in peripheral blood reliably discriminates MF from ET and PV with a sensitivity of 80% and a specificity of 97%. CONCLUSION: Enumeration of circulating hMICL+ stem cells by FCM can discriminate between MPN phenotypes and holds potential for monitoring disease evolution. PMID- 29427320 TI - Demographic features of female urethra length. AB - AIMS: To determine cohort urethral length, identify epidemiological factors influencing the parameter and to establish the percentage of cases with clinically relevant outsized urethras. METHODS: Prospective cohort study conducted in two tertiary clinical centers between 2013 and 2017. Nine hundred and twenty seven consecutive adult, Caucasian females attending outpatients' clinics were included. The urethral length has been measured in pelvic floor ultrasound examination. The exclusion criteria were inadequate bladder filling (<200 mL; >400 mL), previous history of pelvic floor surgery, and no consent. RESULTS: Urethral length varied from 19 to 45 mm. The distribution of the examined parameter was normal. Obese patients had significantly longer urethras as compared to non-obese subjects. Number of vaginal deliveries was connected with shorter urethral length. The limitations of the study are: analysis only of Caucasian patients and subjects without previous pelvic floor surgeries. CONCLUSIONS: Differences in urethral length in the female population were demonstrated. Thirty percent of patients have atypical urethras that may be a risk factor for sling surgery failure. We therefore postulate introduction of urethral measurement before the procedure. PMID- 29427321 TI - Effects of sevoflurane preconditioning on microglia/macrophage dynamics and phagocytosis profile against cerebral ischemia in rats. AB - AIM: The effects of sevoflurane on microglia/macrophages, promoting or suppressing their activation, remains controversy. We aimed to determine whether sevoflurane preconditioning can protect brain via changing microglia/macrophage dynamics and phagocytosis profile after ischemia. METHODS: The impact of sevoflurane preconditioning was evaluated on microglia/macrophage migration, phagocytosis and proliferation altogether from day 1 to day 7 after transient middle cerebral arterial occlusion (tMCAO) in rats. RESULTS: Sevoflurane preconditioning was identified to accelerate microglia/macrophage migrating to and invasion in the ischemic core from day 1 to day 5 after damage. Significant accumulation of amoeboid and phagocytic microglia/macrophages was observed in sevoflurane group from day 3 to day 5 after ischemia injury. In addition, sevoflurane pretreatment also promoted the proliferation of microglia/macrophage (Iba1+ /Ki67+ ) dramatically in ischemic core on day 3 postinsult. CONCLUSIONS: Our current study has identified the impact of sevoflurane preconditioning on microglia/macrophage dynamics, including its migration, phagocytosis, and proliferation at early stage after brain ischemia and reperfusion. Sevoflurane might enhance microglia/macrophage activation and promote brain repair. These results could help to approach more relevant microglia/macrophage cell-based strategy for human stroke therapy. PMID- 29427322 TI - Comparison of risk factors and outcomes of daptomycin-susceptible and nonsusceptible vancomycin-resistant Enterococcus faecium infections in liver transplant recipients. AB - BACKGROUND: Vancomycin-resistant Enterococcus faecium (VRE) infections are common in liver transplant recipients (LTRs). Daptomycin (DAP) is an important treatment for such infections; however, DAP-nonsusceptible VRE (DNS-VRE) are increasingly frequent. The purpose of this study was to compare clinical characteristics and outcomes of LTRs with infections due to DNS-VRE and DAP-susceptible VRE (DS-VRE). METHODS: A single center, retrospective review of patients who underwent liver transplantation between January 1, 2010 and December 31, 2015 and developed infections due to DS-VRE or DNS-VRE post transplant was performed. Patients with DNS-VRE and DS-VRE infections were compared using univariate and logistic regression analysis. RESULTS: Fourteen LTRs developed DNS-VRE and 20 LTRs developed DS-VRE infection post-transplantation. No significant differences were observed in demographics, model for end-stage liver disease (MELD) scores, causes of end-stage liver disease, or rate of pre-transplant perirectal VRE colonization between groups. Bleeding complications and renal replacement therapy were more common in the DNS-VRE group than in the DS-VRE group. The duration of transplant hospitalization and post-transplant intensive care unit (ICU) admission was longer in the DNS-VRE group than in the DS-VRE group. The 30-day and 6-month mortality rate associated with DNS-VRE infection was similar to that associated with DS-VRE infection. CONCLUSIONS: Liver transplant recipients who develop DNS VRE infection have higher bleeding complications and longer, more complex hospitalizations compared to those who develop DS-VRE infection post transplantation; however, mortality at 30 days and 6 months is not significantly worse. Further study is needed to determine optimal strategies for the prevention and treatment of DNS-VRE infections in LTRs. PMID- 29427323 TI - Androgen receptor dampens tissue factor expression via nuclear factor-kappaB and early growth response protein 1. AB - : Essentials Androgen deprivation increases the rate of venous thromboembolism in prostate cancer patients. We characterized androgen receptor-mediated tissue factor regulation in prostate epithelial cells. Androgen receptor is dampening tissue factor expression in prostate epithelial cells. Androgen deprivation could enhance tissue factor expression and raise venous thromboembolism rates. SUMMARY: Background Prostate cancer is one of the leading causes of cancer death in men. Advanced prostate cancer is usually treated by androgen deprivation therapy (ADT), which is aimed at reducing circulating testosterone levels to reduce cancer growth. There is growing evidence that ADT can increase the rate of venous thromboembolism (VTE) in prostate cancer patients. The tissue factor (TF) gene is one of the most important mediators of coagulation and VTE, but, so far, there are limited data on androgen receptor (AR)-mediated TF gene expression. Objectives To characterize AR-mediated TF regulation in vitro and in vivo. Methods We used the androgen-dependent prostate cancer cell lines LNCaP and MyC CaP to test whether TF expression is regulated by AR. Furthermore, we cloned the TF gene promoter into a luciferase reporter vector to identify the transcription factor-binding sites that mediate TF regulation downstream of AR. Finally, we used castration experiments in mice to characterize AR-mediated TF regulation in vivo. Results TF is directly regulated by AR. In LNCaP cells, nuclear factor kappaB signaling and EGR1 mediate TF expression. By using castration experiments in mice, we could detect upregulation of TF and early growth response protein 1 mRNA and protein expression in prostate epithelial cells. Conclusion AR is crucial for dampening TF expression, which could be important for increased TF expression and TF-positive microvesicle release in androgen-deprived prostate cancer patients. PMID- 29427324 TI - Uptake and metabolism of the antidepressants sertraline, clomipramine, and trazodone in a garden cress (Lepidium sativum) model. AB - Environmental contamination with pharmaceuticals has received growing attention in recent years. Several studies describe the presence of traces of drugs in water bodies and soils and their impacts on nontarget organisms including plants. Due to these facts investigations of the uptake and metabolism of pharmaceuticals in organisms is an emerging research area. The present study demonstrates the analysis of three selected antidepressants (sertraline, clomipramine, and trazodone) as well as metabolites and transformation products in a cress model (Lepidium sativum). Cress was treated with tap water containing 10 mg/L of the parent drugs. Employing an analytical approach based on high performance liquid chromatography coupled with quadrupole time of flight or Orbitrap mass spectrometry in MS and MS2 modes, in total 14 substances were identified in the cress extracts. All three parent drugs were taken up by the cress and translocated from the roots to the leaves in specific patterns. In addition to this, eleven metabolite species were identified. They were generated by hydroxylation, demethylation, conjugation with amino acids, or combinations of these mechanisms. Finally, the inclusion of control cultures in the experimental setup allowed for a differentiation of "true" metabolites generated by the cress and transformation products generated by plant-independent mechanisms. PMID- 29427326 TI - Epiphytic bromeliads in a changing world: the effect of elevated CO2 and varying water supply on growth and nutrient relations. AB - Global climate change is likely to impact all plant life. Vascular epiphytes represent a life form that may be affected more than any other by possible changes in precipitation leading to water shortage, but negative effects of drought may be mitigated through increasing levels of atmospheric CO2 . We studied the response of three epiphytic Aechmea species to different CO2 and watering levels in a full-factorial climate chamber study over 100 days. All species use crassulacean acid metabolism (CAM). Response variables were relative growth rate (RGR), nocturnal acidification and foliar nutrient levels (N, P, K, Mg). Both elevated CO2 and increased water supply stimulated RGR, but the interaction of the two factors was not significant. Nocturnal acidification was not affected by these factors, indicating that the increase in growth in these CAM species was due to higher assimilation in the light. Mass-based foliar nutrient contents were consistently lower under elevated CO2 , but most differences disappeared when expressed on an area basis. Compared to previous studies with epiphytes, in which doubling of CO2 increased RGR, on average, by only 14%, these Aechmea species showed a relatively strong growth stimulation of up to +61%. Consistent with earlier findings with other bromeliads, elevated CO2 did not mitigate the effect of water shortage. PMID- 29427325 TI - Controlling T2 blurring in 3D RARE arterial spin labeling acquisition through optimal combination of variable flip angles and k-space filtering. AB - PURPOSE: To improve the SNR efficiency and reduce the T2 blurring of 3D rapid acquisition with relaxation enhancement stack-of-spiral arterial spin labeling imaging by using variable refocusing flip angles and k-space filtering. METHODS: An algorithm for determining the optimal combination of variable flip angles and filtering correction is proposed. The flip angles are designed using extended phase graph physical simulations in an analytical and global optimization framework, with an optional constraint on deposited power. Optimal designs for correcting to Hann and Fermi window functions were compared with conventional constant amplitude or variable flip angle only designs on 6 volunteers. RESULTS: With the Fermi window correction, the proposed optimal designs provided 39.8 and 27.3% higher SNR (P < .05) than conventional constant amplitude and variable flip angle designs. Even when power deposition was limited to 50% of the constant amplitude design, the proposed method outperformed the SNR (P < .05) of these 2 conventional approaches by 32.5 and 20.7%. The sharpness and the contrast between gray and white matter were improved with the k-space filtering correction for all of the flip angle designs. The improvements were moderate for the Hann window correction. CONCLUSION: This work demonstrates that variable flip angles can be derived as the output of an optimization problem. The combined design of variable flip angle and k-space filtering provided superior SNR to designs primarily emphasizing either approach singly. PMID- 29427327 TI - Systemic juvenile xanthogranuloma: a case report and brief review. PMID- 29427328 TI - Depletion of keratin 8/18 modulates oncogenic potential by governing multiple signaling pathways. AB - : Keratin 8/18, the predominant keratin pair of simple epithelia, is often aberrantly expressed in various squamous cell carcinomas (SCCs) including skin SCC. Its aberrant expression is correlated with increased invasiveness and poor prognosis of the same, although the underlying mechanism is still unclear. A previous report from our laboratory has shown K8-mediated regulation of alpha6beta4 integrin signaling and thereby tumorigenic potential of oral SCC derived cells. Another study on transgenic mouse model has shown that during skin carcinogenesis, K8 favors conversion of papillomas toward malignancy. In order to understand the role of K8 and allied mechanism in skin SCC, K8 was stably knocked down in a skin epidermoid carcinoma-derived A431 cells. K8 downregulation significantly reduced the tumorigenic potential of these cells. In agreement with our phenotypic data, differential quantitative proteomics followed by IPA analysis showed altered expression of many proteins associated with biological functions including 'Cancer', 'Cellular movement', 'Cell death and survival', and 'Cellular morphology'. Some of these proteins were TMS1, MARCKSL1, RanBP1, 14-3 3gamma, Rho-GDI2, etc. Furthermore, to our surprise, there was a significant reduction in K17 protein stability upon loss of K8, probably due to its caspase mediated degradation. This was supported by altered TMS1-NF-kappaB signaling, leading to increased apoptotic sensitivity of A431 cells which in turn affected 'Cell death and survival'. Moreover, MARCKSL1-Paxillin1-Rac axis was found to be deregulated bestowing a possible mechanism behind altered 'Cellular movement' pathway. Altogether our study unravels a much broader regulatory role of K8, governing multiple signaling pathways and consequently regulating oncogenic potential of skin SCC-derived cells. DATABASE: Proteome Xchange Consortium via PRIDE database (dataset identifier PXD007206). PMID- 29427329 TI - Honey adulteration detection: voltammetric e-tongue versus official methods for physicochemical parameter determination. AB - BACKGROUND: The aim of this study was to evaluate the usefulness of a voltammetric e-tongue (three electrodes: reference electrode (Ag/AgCl), counter electrode (glassy carbon electrode rod) and working electrode (Au, Ag, Pt and glass electrode)) for honey adulteration detection. For this purpose, 55 samples of authentic honey (acacia, honeydew, sunflower, Tilia and polyfloral) and 150 adulterated ones were analyzed. The adulteration was made using fructose, glucose, inverted sugar, hydrolyzed inulin syrup and malt wort at different percentages: 5%, 10%, 20%, 30%, 40% and 50%, respectively. The e-tongue has been compared with the physicochemical parameters (pH, free acidity, electrical conductivity (EC) and CIEL*a*b* parameters (L*, a* and b*)) in order to achieve a suitable method for the classification of authentic and adulterated honeys. RESULTS: The e-tongue and physicochemical parameters reached a 97.50% correct classification of the authentic and adulterated honeys. In the case of the adulterated honey samples, the e-tongue achieved 83.33% correct classifications whereas the physicochemical parameters only achieved 73.33%. CONCLUSION: The e tongue is a fast, easy and accurate method for honey adulteration detection which can be used in situ by beekeepers and provide useful information on EC and free acidity. (c) 2018 Society of Chemical Industry. PMID- 29427330 TI - GIAO-DFT calculation of 15 N NMR chemical shifts of Schiff bases: Accuracy factors and protonation effects. AB - 15 N NMR chemical shifts in the representative series of Schiff bases together with their protonated forms have been calculated at the density functional theory level in comparison with available experiment. A number of functionals and basis sets have been tested in terms of a better agreement with experiment. Complimentary to gas phase results, 2 solvation models, namely, a classical Tomasi's polarizable continuum model (PCM) and that in combination with an explicit inclusion of one molecule of solvent into calculation space to form supermolecule 1:1 (SM + PCM), were examined. Best results are achieved with PCM and SM + PCM models resulting in mean absolute errors of calculated 15 N NMR chemical shifts in the whole series of neutral and protonated Schiff bases of accordingly 5.2 and 5.8 ppm as compared with 15.2 ppm in gas phase for the range of about 200 ppm. Noticeable protonation effects (exceeding 100 ppm) in protonated Schiff bases are rationalized in terms of a general natural bond orbital approach. PMID- 29427331 TI - The role of the mucosa in modulation of evoked responses in the spinal cord injured rat bladder. AB - AIMS: Mounting evidence indicates that a variety of factors released from the urothelium or suburothelium can modulate smooth muscle activity. Although the relationship between the mucosa and smooth muscle has been investigated, little is known about the pathophysiologic changes in detrusor-mucosa interactions in neurogenic bladders. The goal of the study was to determine the impact of the mucosa on evoked responses in spinal cord injured (SCI) bladders. METHODS: Urinary bladders were obtained from 6wk SCI rats or age-matched uninjured controls. Ex vivo isometric tension studies were performed and muscarinic receptor expression was measured in bladder tissue with and without mucosa. RESULTS: The magnitude and area of nerve evoked responses in SCI tissue with mucosa was higher than without mucosa. The duration and decay time of nerve evoked responses were longer in SCI than control tissue irrespective of the mucosa. The level of the muscarinic M2 receptor was decreased in the mucosa of SCI bladders. CONCLUSIONS: Detrusor-mucosa interactions are substantially altered in the neurogenic bladder. After spinal cord injury, an excitatory modulation of smooth muscle contraction by the mucosa emerges, and could be targeted via intravesical treatment in the context of neurogenic bladder dysfunction. PMID- 29427333 TI - Bone loss at implants and teeth in the same inter-proximal unit: A radiographic study. AB - OBJECTIVE: This study was performed to determine whether the distance between an implant and a tooth present in an inter-proximal unit influenced the amount of marginal bone loss that occurred at the two facing (adjacent) surfaces. MATERIALS AND METHODS: One hundred and eighty patients with a total of 278 inter-proximal units were included. Radiographs of implants that also included adjacent (facing) natural tooth/teeth were digitalized, and various linear measurements were performed using a software program. The marginal bone level and the bone level change that had occurred during a mean of 5.8 years were assessed as well as distance between the implant and the adjacent tooth/teeth. RESULTS: The mean amount of additional marginal bone loss that took place during the observation period was about 0.4 mm at both implants and adjacent tooth surfaces. The horizontal distance between an implant and the facing tooth did not influence the amount of marginal bone loss that had occurred. In most inter-proximal units, more advanced bone loss (>1 mm, >2 mm) had ensued either at the implant or at the facing tooth surface. Advanced additional bone loss occurred at both the implant and the tooth in only about 3% of the examined subjects. CONCLUSION: Bone loss at implants and teeth appears to be a site-specific phenomenon and not dependent on the inter-proximal distance. PMID- 29427332 TI - Genetic relatedness of axial and radial diffusivity indices of cerebral white matter microstructure in late middle age. AB - Two basic neuroimaging-based characterizations of white matter tracts are the magnitude of water diffusion along the principal tract orientation (axial diffusivity, AD) and water diffusion perpendicular to the principal orientation (radial diffusivity, RD). It is generally accepted that decreases in AD reflect disorganization, damage, or loss of axons, whereas increases in RD are indicative of disruptions to the myelin sheath. Previous reports have detailed the heritability of individual AD and RD measures, but have not examined the extent to which the same or different genetic or environmental factors influence these two phenotypes (except for corpus callosum). We implemented bivariate twin analyses to examine the shared and independent genetic influences on AD and RD. In the Vietnam Era Twin Study of Aging, 393 men (mean age = 61.8 years, SD = 2.6) underwent diffusion-weighted magnetic resonance imaging. We derived fractional anisotropy (FA), mean diffusivity (MD), AD, and RD estimates for 11 major bilateral white matter tracts and the mid-hemispheric corpus callosum, forceps major, and forceps minor. Separately, AD and RD were each highly heritable. In about three-quarters of the tracts, genetic correlations between AD and RD were >.50 (median = .67) and showed both unique and common variance. Genetic variance of FA and MD were predominately explained by RD over AD. These findings are important for informing genetic association studies of axonal coherence/damage and myelination/demyelination. Thus, genetic studies would benefit from examining the shared and unique contributions of AD and RD. PMID- 29427334 TI - Effect of Irpex lacteus, Pleurotus ostreatus and Pleurotus cystidiosus pretreatment of corn stover on its improvement of the in vitro rumen fermentation. AB - BACKGROUND: The present work investigated changes in corn stover pretreated with different white rot fungi. Corn stover was inoculated with Irpex lacteus, Pleurotus ostreatus and Pleurotus cystidiosus prior to incubation under solid state fermentation conditions at 28 degrees C for 42 days. Changes in the chemical composition, in vitro rumen degradability, lignocellulolytic enzyme activity and multi-scale structure of the corn stover were analysed. RESULTS: Content of all lignocellulose components decreased to a certain extent after fungal pretreatment. The total gas production of sterilized corn stover treated with I. lacteus for 42 days increased from 200 to 289 mL g-1 organic matter. Moreover, the cellulase activity was highest at the later stage of I. lacteus pretreatment. Multi-scale structural analysis indicated that white rot fungal pretreatment, and in particular that of I. lacteus, increased and enlarged substrate porosity and caused changes in the structure of corn stover. CONCLUSION: Irpex lacteus pretreatment improved the nutritional value of corn stover as a ruminant feed by degrading both cellulose and acid-insoluble lignin as well as changing the structure of the cell walls. (c) 2018 Society of Chemical Industry. PMID- 29427335 TI - Adrenergic control mechanisms of heart rate: down to a T? PMID- 29427337 TI - Non-syndromic bilateral ulnar aplasia with humero-radial synostosis and oligo ectro-dactyly. AB - Congenital anomalies of the upper limbs are rare and etiologically heterogeneous. Herein, we report a male infant with non-syndromic bilateral Type Vb ulnar longitudinal dysplasia with radiohumeral synostosis (apparent humeral bifurcation), and bilateral oligo-ectro-syndactyly who was born following an uncomplicated pregnancy, with no maternal use of prescription or illicit medication. Array CGH (60,000 probes) and chromosomal breakage analysis (DEB) were normal. Similar appearances have been reported in children exposed to thalidomide or cocaine, but sporadic patients have also been reported without a prior history of exposure to known teratogens. PMID- 29427336 TI - Bayesian multivariate meta-analysis of multiple factors. AB - In medical sciences, a disease condition is typically associated with multiple risk and protective factors. Although many studies report results of multiple factors, nearly all meta-analyses separately synthesize the association between each factor and the disease condition of interest. The collected studies usually report different subsets of factors, and the results from separate analyses on multiple factors may not be comparable because each analysis may use different subpopulation. This may impact on selecting most important factors to design a multifactor intervention program. This article proposes a new concept, multivariate meta-analysis of multiple factors (MVMA-MF), to synthesize all available factors simultaneously. By borrowing information across factors, MVMA MF can improve statistical efficiency and reduce biases compared with separate analyses when factors were missing not at random. As within-study correlations between factors are commonly unavailable from published articles, we use a Bayesian hybrid model to perform MVMA-MF, which effectively accounts for both within- and between-study correlations. The performance of MVMA-MF and the conventional methods are compared using simulations and an application to a pterygium dataset consisting of 29 studies on 8 risk factors. PMID- 29427338 TI - Securing front-line T cell defense. PMID- 29427340 TI - Influence of the feed pipe position of an industrial scale two-phase decanter on extraction efficiency and chemical-sensory characteristics of virgin olive oil. AB - BACKGROUND: Nowadays, olive oil extraction is basically achieved by means of two phase decanters, which allow a reduction of water consumption and the leaching of phenolic compounds. Despite this, most of the working settings derive from studies carried out on three-phase decanters. Hence, the aim of the present study was to assess the influence of two-phase decanter feed pipe position (FP) on the extraction efficiency and chemical-sensory characteristics of virgin olive oil. Three different positions were considered: at 825 mm (FP1), 610 mm (FP2) and 520 mm (FP3) from the outlet of the oily phase. RESULTS: Position FP3 allowed the highest oil recovery (up to 10%), the lowest percentage of oil in the olive pomace and, in general, a regular trend in terms of oil extraction efficiency. However, the oily must that came out of the decanter was not completely clean in terms of residual content of solid sediment and water. The feeding position partially affected the profile of antioxidant compounds. CONCLUSION: In two-phase decanters, loading the olive paste close to the outlet of the oily phase is recommended to increase the extraction efficiency without jeopardizing the chemical-sensory characteristics of virgin olive oil. (c) 2018 Society of Chemical Industry. PMID- 29427339 TI - Stearate-to-palmitate ratio modulates endoplasmic reticulum stress and cell apoptosis in non-B non-C hepatoma cells. AB - The increased prevalence of hepatocellular carcinoma (HCC) without viral infection, namely, NHCC, is a major public health issue worldwide. NHCC is frequently derived from non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis, which exhibit dysregulated fatty acid (FA) metabolism. This raises the possibility that NHCC evolves intracellular machineries to adapt to dysregulated FA metabolism. We herein aim to identify NHCC-specifically altered FA and key molecules to achieve the adaptation. To analyze FA, imaging mass spectrometry (IMS) was performed on 15 HCC specimens. The composition of saturated FA (SFA) in NHCC was altered from that in typical HCC. The stearate-to palmitate ratio (SPR) was significantly increased in NHCC. Associated with the SPR increase, the ELOVL6 protein level was upregulated in NHCC. The knockdown of ELOVL6 reduced SPR, and enhanced endoplasmic reticulum stress, inducing apoptosis of Huh7 and HepG2 cells. In conclusion, NHCC appears to adapt to an FA-rich environment by modulating SPR through ELOVL6. PMID- 29427341 TI - Assessing ocular activity during performance of motor skills using electrooculography. AB - Eye-tracking research has revealed that, compared to novices, experts make longer ocular fixations on the target of an action when performing motor skills; that is, they have a longer quiet eye. Remarkably, the reason why a longer quiet eye aids movement has yet to be established. There is a need for interdisciplinary research and new measures to accelerate progress on the mechanistic understanding of the phenomenon. With the aim to provide researchers with new tools, we assessed the utility of electrooculography (EOG) to examine ocular activity while 10 experts and 10 novices putted golf balls. We measured quiet eye durations, distinguishing its pre- and postmovement initiation components, and developed a novel time-varying index of ocular activity, eye quietness, computed as the variability of the EOG in short time intervals: lower values correspond with greater quietness. Finally, we measured movement durations using a combination of infrared and sound sensors. Experts had longer postmovement initiation quiet eye compared to novices; however, total and premovement quiet eye durations did not differ between groups. Eye quietness was inversely correlated with quiet eye duration, and was greatest immediately after movement initiation. Importantly, movement duration correlated positively with postmovement initiation quiet eye and negatively with eye quietness shortly after movement initiation. This study demonstrates the utility of assessing ocular activity during performance of motor skills using EOG. Additionally, these findings provide evidence that expert novice differences in ocular activity may reflect differences in the kinematics (e.g., movement duration) of how experts and novices execute motor skills. PMID- 29427342 TI - Germination characteristics of Rhinanthus minor influence field emergence, competitiveness and potential use in restoration projects. AB - The facultative root hemi-parasite Rhinanthus minor is often used in grassland habitat restoration projects to regulate ecosystem structure and function. Its impact on community productivity and diversity as a function of resource supply, sward composition and management has been widely investigated. However, there is a lack of information about the possible influence of seed quality on the efficacy of the hemi-parasite. Ten seed lots from commercial sources were sown in the field and their germination characteristics were investigated in the laboratory. Seeds from four lots were also germinated and sown in pots alongside plants of two host species, Lotus corniculatus and Holcus lanatus. Plant establishment, height and flowering density were evaluated for the hemi-parasite, while plant biomass was measured for both R. minor and its host. Two aspects of seed quality influenced the field emergence of seed lots of R. minor, the radicle emergence (%) and the length of the lag period from the beginning of imbibition to germination (mean germination time), which indicates seed vigour. A longer lag period (lower vigour) was associated with higher levels of seedling mortality and lower plant vigour, in terms of plant height and biomass accumulation and was also reflected in the parasitic impact of the seed lots. Seed quality, specifically germination and vigour, can influence the establishment, survival, subsequent plant productivity and parasitic impact of R. minor in vegetation restoration projects. Seed quality is discussed as a key factor to consider when predicting the impact of the hemi-parasite on community productivity and diversity. This article is protected by copyright. All rights reserved. PMID- 29427343 TI - Editor's tribute: Dr. Robert Burke. PMID- 29427344 TI - Directional communication during movement execution interferes with tremor in Parkinson's disease. AB - BACKGROUND: Both the cerebello-thalamo-cortical circuit and the basal ganglia/cortical motor loop have been postulated to be generators of tremor in PD. The recent suggestion that the basal ganglia trigger tremor episodes and the cerebello-thalamo-cortical circuitry modulates tremor amplitude combines both competing hypotheses. However, the role of the STN in tremor generation and the impact of proprioceptive feedback on tremor suppression during voluntary movements have not been considered in this model yet. OBJECTIVES: The objective of this study was to evaluate the role of the STN and proprioceptive feedback in PD tremor generation during movement execution. METHODS: Local-field potentials of the STN as well as electromyographical and electroencephalographical rhythms were recorded in tremor-dominant and nontremor PD patients while performing voluntary movements of the contralateral hand during DBS surgery. Effective connectivity between these electrophysiological signals were analyzed and compared to electromyographical tremor activity. RESULTS: There was an intensified information flow between the STN and the muscle in the tremor frequencies (5-8 Hz) for tremor-dominant, in comparison to nontremor, patients. In both subtypes, active movement was associated with an increase of afferent interaction between the muscle and the cortex in the beta- and gamma-frequencies. The gamma-frequency (30-40 Hz) of this communication between muscle and cortex correlated inversely with electromyographical tremor activity. CONCLUSIONS: Our results indicate an involvement of the STN in propagation of tremor-related activity to the muscle. Furthermore, we provide evidence that increased proprioceptive information flow during voluntary movement interferes with central tremor generation. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29427346 TI - Simultaneous identification and quantification of bisphenol A and 12 bisphenol analogues in environmental samples using precolumn derivatization and ultra high performance liquid chromatography with tandem mass spectrometry. AB - A method for the identification and quantification of bisphenol A and 12 bisphenol analogues in river water and sediment samples combining liquid-liquid extraction, precolumn derivatization, and ultra high-performance liquid chromatography coupled with tandem mass spectrometry was developed and validated. Analytes were extracted from the river water sample using a liquid-liquid extraction method. Dansyl chloride was selected as a derivatization reagent. Derivatization reaction conditions affecting production of the dansyl derivatives were tested and optimized. All the derivatized target compounds were well separated and eluted in 10 min. Dansyl chloride labeled compounds were analyzed using a high-resolution mass spectrometer with electrospray ionization in the positive mode, and the results were confirmed and quantified in the parallel reaction monitoring mode. The method validation results showed a satisfactory level of sensitivity. Linearity was assessed using matrix-matched standard calibration, and good correlation coefficients were obtained. The limits of quantification for the analytes ranged from 0.005 to 0.02 ng/mL in river water and from 0.15 to 0.80 ng/g in sediment. Good reproducibility of the method in terms of intra- and interday precision was achieved, yielding relative standard deviations of less than 10.1 and 11.6%, respectively. Finally, this method was successfully applied to the analysis of real samples. PMID- 29427345 TI - Crosstalk of DNA double-strand break repair pathways in poly(ADP-ribose) polymerase inhibitor treatment of breast cancer susceptibility gene 1/2-mutated cancer. AB - Germline mutations in breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) significantly increase cancer risk in hereditary breast and ovarian cancer syndrome (HBOC). Both genes function in the homologous recombination (HR) pathway of the DNA double-strand break (DSB) repair process. Therefore, the DNA-repair defect characteristic of cancer cells brings about a therapeutic advantage for poly(ADP-ribose) polymerase (PARP) inhibitor-induced synthetic lethality. PARP inhibitor-based therapeutics initially cause cancer lethality but acquired resistance mechanisms have been found and need to be elucidated. In particular, it is essential to understand in detail the mechanism of DNA damage and repair to PARP inhibitor treatment. Further investigations have shown the roles of BRCA1/2 and its associations to other molecules in the DSB repair system. Notably, the repair pathway chosen in BRCA1-deficient cells could be entirely different from that in BRCA2-deficient cells after PARP inhibitor treatment. The present review describes synthetic lethality and acquired resistance mechanisms to PARP inhibitor through the DSB repair pathway and subsequent repair process. In addition, recent knowledge of resistance mechanisms is discussed. Our model should contribute to the development of novel therapeutic strategies. PMID- 29427347 TI - From Robinia pseudoacacia L. nectar to Acacia monofloral honey: biochemical changes and variation of biological properties. AB - BACKGROUND: Robinia pseudoacacia L. nectar and its derivative monofloral honey were systematically compared in this study, to understand how much the starting solution reflected the final product, after re-elaboration by Apis mellifera ligustica Spinola. RESULTS: Subjected to dehydration in the hive, nectar changed in its water and sugar content when transformed into honey, as physicochemical and gas chromatographic-mass spectrometric analyses revealed. Spectrophotometric measurements and characterization by high-performance liquid chromatography-diode array detection of 18 plant molecules demonstrated honey to be richer than nectar in secondary metabolites. For the first time, the hypothesis of the existence of a nectar redox cycle in R. pseudoacacia was reported, as previously described for Nicotiana sp., based on 1D-protein profiles, western blot analysis and detection of H2 O2 and ascorbate. The bioactivity of both matrices was also investigated. Antiradical in vitro tests showed that Acacia honey was more antioxidant than nectar, which was even able to induce oxidative stress directly in a eukaryotic cell system. Antimicrobial assays demonstrated that nectar was bacteriostatic, due to H2 O2 activity, whereas honey was even bactericidal. CONCLUSION: All these data support the ecological role of nectar and honey in nature: protection of the gynoecium from pathogens and preservation from degradative processes, respectively. (c) 2018 Society of Chemical Industry. PMID- 29427348 TI - The effect of tramadol on sneeze-induced urethral continence reflex through MU opioid receptors in the spinal cord in rats. AB - AIMS: We examined the efficacy of tramadol on the urethral reflex during sneezing, as well as the role of u-opioid receptors in the spinal cord, in rats. METHODS: Forty-one female Sprague-Dawley rats were used. The rats were divided into normal female rats and rats with vaginal distension (VD), which mimics stress urinary incontinence (SUI) in humans. Under urethane anesthesia, the sneeze-induced amplitude of urethral responses (AUR) and baseline pressure (BP) were examined after intravenous injection of tramadol using a microtransducer tipped catheter in both rat groups. The effect of intrathecal cyprodime, a selective u-opioid receptor antagonist, following intravenous tramadol injection was examined in normal rats. The tilt leak point pressure (tilt LPP) after intravenous tramadol injection was also evaluated in both groups. RESULTS: In normal rats, tramadol enhanced the AUR and BP by 33.2% and 19.5%, respectively. Tramadol also increased BP by 13.9% in rats with VD, but it did not change AUR. Intrathecal cyprodime alone did not change AUR, but it decreased BP. However, tramadol-provoked increments in AUR were blocked by intrathecal cyprodime, while BP was recovered to the level that it was before administration of cyprodime. Tramadol was associated with a significant elevation in tilt LPP: 24.8% and 19.5% in normal and VD rats, respectively. CONCLUSIONS: These findings suggest that tramadol effectively enhances the AUR at the spinal level and BP peripherally. Therefore, stimulation of the spinal u-opioid receptors may be useful for the treatment of SUI. PMID- 29427349 TI - Quantifying precision in cardiac diffusion tensor imaging with second-order motion-compensated convex optimized diffusion encoding. AB - PURPOSE: To quantify the precision of in vivo cardiac DTI (cDTI) acquired with a spin echo, first- and second-order motion-compensated (M1 M2 ), convex optimized diffusion encoding (CODE) sequence. METHODS: Free-breathing CODE-M1 M2 cDTI were acquired in healthy volunteers (N = 10) at midsystole and diastole with 10 repeated acquisitions per phase. 95% confidence intervals of uncertainty in reconstructed diffusion tensor eigenvectors ( E->1, E->2, E->3), mean diffusivity (MD), fractional anisotropy (FA), and tensor Mode were measured using a bootstrapping approach. Trends in observed tensor metric uncertainty were evaluated as a function of scan duration, image SNR, cardiac phase, and bulk motion artifacts. RESULTS: For midsystolic scans including 5 signal averages (scan time: ~5 min), the median myocardial 95% confidence intervals of uncertainties were: E->1: 15.5 +/- 1.2 degrees , E->2: 31.2 +/- 3.5 degrees , E >3: 21.8 +/- 3.1 degrees , MD: 0.38 +/- 0.02 * 10-3 mm2 /s, FA: 0.20 +/- 0.01, and Mode: 1.10 +/- 0.08. Uncertainty in all parameters increased for diastolic scans: E->1: 31.9 +/- 7.1 degrees , E->2: 59.6 +/- 6.8 degrees , E->3 : 40.5 +/- 6.4 degrees , MD: 0.52 +/- 0.09 * 10-3 mm2 /s, FA: 0.23 +/- 0.01, and Mode: 1.57 +/- 0.11. Diastolic cDTI also reported higher MD (MDDIA = 1.91 +/- 0.34 * 10-3 mm2 /s vs. MDSYS = 1.58 +/- 0.09 * 10-3 mm2 /s, P = 8 * 10-3 ) and lower FA values (FADIA = 0.32 +/- 0.06 vs. FASYS = 0.37 +/- 0.03, P = 0.03) . CONCLUSION: cDTI precision improved with increasing nondiffusion-weighted (b = 0) image SNR, but gains were minimal for SNR >= 25 (~10 averages). cDTI precision was also sensitive to intershot bulk motion artifacts, which led to better precision for midsystolic imaging. PMID- 29427350 TI - Characterization of anti-Mullerian hormone in a case of bovine male pseudohermaphroditism. AB - The current report aimed to characterize plasma anti-Mullerian hormone (AMH) in bovine male pseudohermaphroditism. The blood AMH concentration in a Japanese Black male pseudohermaphrodite calf was compared with pre- and post-pubertal male and female calves and castrated calves. The concentration in the case was higher than in post-pubertal males, castrated males, and pre- and post-pubertal female calves (p < .05), but similar to that in pre-pubertal male calves. After extraction of the testes, the concentration in the case dropped to a certain extent. The extracted testes expressed AMH, as detected by immunohistochemistry. This study is the first to show the characterization of AMH in a male pseudohermaphrodite calf. AMH levels in peripheral blood might be useful to diagnose male pseudohermaphroditism in cattle. PMID- 29427351 TI - Allergenicity of acrolein-treated shrimp tropomyosin evaluated using RBL-2H3 cell and mouse model. AB - BACKGROUND: Food processing effects can modify protein functional properties. However, protein was oxidized inevitably by lipid peroxidation during food processing. Acrolein, a primary by-product of lipid peroxidation, can modify the structural and functional properties of protein. The aim of the research was to analyze the effect of acrolein on allergenicity of TM, a major allergen in shrimp. RESULTS: The overall allergenic effects of acrolein-treated TM were evaluated using female BALB/c mice and a mediator-releasing RBL-2H3 cell line. Acrolein-treated TM significantly decreased TM-specific immunoglobulin E/G1 levels, and histamine and mMCP-1 release in mouse serum. Release of inflammatory mediators such as beta-hexosaminidase, histamine, cysteinyl leukotriene and prostaglandin D2 was clearly suppressed after acrolein treatment. CONCLUSION: These results indicate that acrolein-induced tropomyosin modification can decrease the allergenicity of TM. This reduction contributes to allergenic potential changes in shrimp during processing and preservation. (c) 2018 Society of Chemical Industry. PMID- 29427352 TI - A rare case of Epstein-Barr virus-associated hepatosplenic smooth muscle tumors after kidney transplantation. AB - A 27-year old caucasian male was diagnosed 2.7 years after kidney transplantation with Epstein-Barr virus (EBV)-associated smooth muscle tumors in liver and spleen. The reduction in immunosuppression and conversion from tacrolimus to sirolimus did not lead to a regression of the tumors. Additionally, the patient developed a cellular rejection of his renal allograft, which was successfully treated. A combined approach with stereotactic radiofrequency ablation (SRFA) and surgical resection was effective in the treatment of the tumors. PMID- 29427353 TI - Rapid reduction of extremely high kappa free light chains in a patient with myeloma cast nephropathy. AB - This report describes a patient with light chain myeloma and acute renal injury. Serum kappa free light chain (FLC) was extremely elevated, >33,000 mg/dL. Treatment with therapeutic plasma exchange (TPE) started day 2 for biopsy confirmed cast nephropathy. Bortezomib-containing chemotherapy was initiated on day 5, and hemodialysis for tumor lysis syndrome on day 7. TPE alone decreased kappa FLC >70% by day 5, indicating direct FLC removal was successful in this patient. A total of 25 TPE procedures were performed in a 31-day hospitalization. Hemodialysis was discontinued after 3 months, and the patient's renal function and kappa FLC remain stable. Although the use of TPE for FLC removal is controversial, recent evidence supports its use as adjuvant therapy for acute renal injury secondary to myeloma cast nephropathy. TPE can be effective for rapidly reducing FLC; however, several TPE procedures might be required to reduce the risk of hemodialysis dependency. PMID- 29427354 TI - Simple determination of some antidementia drugs in wastewater and human plasma samples by tandem dispersive liquid-liquid microextraction followed by high performance liquid chromatography. AB - In this work, a simple method, namely, tandem dispersive liquid-liquid microextraction, with a high sample clean-up is applied for the rapid determination of the antidementia drugs rivastigmine and donepezil in wastewater and human plasma samples. This method, which is based on two consecutive dispersive microextractions, is performed in 7 min. In the method, using a fast back-extraction step, the applicability of the dispersive microextraction methods in complicated matrixes is conveniently improved. This step can be performed in less than 2 min, and very simple tools are required for this purpose. To achieve the best extraction efficiency, optimization of the variables affecting the method was carried out. Under the optimized experimental conditions, the relative standard deviations for the method were in the range of 6.9-8.7%. The calibration curves were obtained in the range of 2-1100 ng/mL with good correlation coefficients, higher than 0.995, and the limits of detection ranged between 0.5 and 1.0 ng/mL. PMID- 29427355 TI - Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial. AB - OBJECTIVES: PALG CLL4 is the first, randomized, phase IIIb study with rituximab, cladribine, and cyclophosphamide (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients. METHODS: The induction treatment consisted of 6 RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm. RESULTS: In the intention-to-treat population, 97 patients completed the induction phase with an overall response rate (ORR) of 73.2% (CR 22.7%, PR 50.5%). Subsequently, 66 patients were randomized into the rituximab maintenance arm (n = 33) or the observational arm (n = 33). CR rates were 57.1% in the maintenance group vs 50% in the observational group. PFS was significantly longer in the rituximab maintenance vs the observational arm (P = .028). The multivariate Cox model indicated that del17p (P = .006) and elevated beta-2 microglobulin (P = .015) significantly increased the hazard ratio (HR) of progression, whereas the presence of CD38 (P = .013) significantly decreased it; maintenance therapy with rituximab (P < .0001) significantly decreased the HR of disease progression. CONCLUSIONS: The study confirmed the high efficacy and acceptable safety profile of induction therapy with RCC and maintenance therapy with rituximab in previously untreated patients with CLL. PMID- 29427357 TI - Validation of reaching in a virtual environment in typically developing children and children with mild unilateral cerebral palsy. AB - AIM: To compare three reaching movements made in two planes between a low-cost, game-based virtual reality and a matched physical environment in typically developing children and children with cerebral palsy (CP). To determine if differences in kinematics are related to sensory deficits. METHOD: An observational study in which 27 children (typically developing, n=17, mean age 13y, [SD] 2y 2mo, range 9y 3mo-17y 2mo; CP, n=10, mean age 13y 8mo, [SD] 1y 8mo, range 11y 1mo-17y 1mo, Manual Ability Classification System levels I-II) performed 15 trials of three gestures in each of a virtual reality and a matched physical environment. Upper-limb and trunk kinematics were recorded using an electromagnetic system (G4, Polhemus, six markers, 120Hz). RESULTS: Compared to the physical environment, movements in virtual reality made by typically developing children were slower (p=0.002), and involved less trunk flexion (p=0.002) and rotation (p=0.026). Children with CP had more curved trajectories (p=0.005) and used less trunk flexion (p=0.003) and rotation (p=0.005). Elbow and shoulder kinematics differed from 2.8% to 155.4% between environments in both groups. Between groups, there were small, clinically insignificant differences with only the vertical gesture being longer in typically developing children. Children with CP who had greater tactile impairment used more trunk displacement. INTERPRETATION: Clinicians and researchers need to be aware of differences in movement variables when setting goals or designing protocols for improving reaching in children with CP using low-cost, game-based virtual reality systems. WHAT THIS PAPER ADDS: Upper-limb kinematics differed in each group when reaching in physical versus virtual environments. There were small differences in movements made by children with mild unilateral cerebral palsy (CP) compared to typically developing children. Differences in reaching kinematics should be considered when goal setting using virtual reality interventions for children with mild unilateral CP. PMID- 29427356 TI - Epidemiology and outcomes of Clostridium difficile infection in allogeneic hematopoietic cell and lung transplant recipients. AB - BACKGROUND: Clostridium difficile infection (CDI) is a common complication of lung and allogeneic hematopoietic cell (HCT) transplant, but the epidemiology and outcomes of CDI after transplant are poorly described. METHODS: We performed a prospective, multicenter study of CDI within 365 days post-allogeneic HCT or lung transplantation. Data were collected via patient interviews and medical chart review. Participants were followed weekly in the 12 weeks post-transplant and while hospitalized and contacted monthly up to 18 months post-transplantation. RESULTS: Six sites participated in the study with 614 total participants; 4 enrolled allogeneic HCT (385 participants) and 5 enrolled lung transplant recipients (229 participants). One hundred and fifty CDI cases occurred within 1 year of transplantation; the incidence among lung transplant recipients was 13.1% and among allogeneic HCTs was 31.2%. Median time to CDI was significantly shorter among allogeneic HCT than lung transplant recipients (27 days vs 90 days; P = .037). CDI was associated with significantly higher mortality from 31 to 180 days post-index date among the allogeneic HCT recipients (Hazard ratio [HR] = 1.80; P = .007). There was a trend towards increased mortality among lung transplant recipients from 120 to 180 days post-index date (HR = 4.7, P = .09). CONCLUSIONS: The epidemiology and outcomes of CDI vary by transplant population; surveillance for CDI should continue beyond the immediate post-transplant period. PMID- 29427358 TI - MDM2 expression in the progression of Barrett's oesophagus. PMID- 29427359 TI - Xenotransplantation literature update, November/December 2017. PMID- 29427361 TI - The intersection between depth and the regulation of strategy use. PMID- 29427362 TI - Looking down the road: Future directions for research on depth and regulation of strategic processing. AB - PURPOSE: The primary goal of this commentary was to consider the future directions that researchers dealing with levels and regulation of strategies and with approaches to learning may wish to pursue in the years to come. PROCEDURE: In order to accomplish this goal, the first step was to look for any common ground shared by authors contributing to this Special Issue. That common ground represented a convergence of evidence for these programmes of research; in effect, where they intersect. Next, theoretical, methodological, and data analytic barriers that have long impeded progress within and across these research communities were identified. OUTCOME: Recommendations were offered that might serve to diminish or remove those existing barriers and, thus, open new avenues of inquiry. PMID- 29427363 TI - The relation between cognitive and metacognitive processing: Building bridges between the SRL, MDL, and SAL domains. AB - AIM: The main aim of this commentary was to connect the insights from the contributions of the special issue on the intersection between depth and the regulation of strategy use. The seven contributions in this special issue stem from three perspectives: self-regulated learning (SRL), model of domain learning (MDL), or the student approaches to learning (SAL). PROCEDURE: Prior to combining insights from different studies, the definition and operationalization of cognitive and metacognitive processing in the seven contributions is described. Subsequently, the grain size and statistical methods used in these contributions are discussed. This information allows us to - albeit cautiously - combine the results from the different studies regarding the relation between cognitive and metacognitive processing. CONCLUSION: Deep processing and self regulation/monitoring showed a strong correlation, regardless of the theoretical framework or data collection method chosen. The strength of the correlation between surface processing and metacognitive processing differed, however, between the studies. Pathways for future research on students' cognitive and metacognitive processing are suggested, at the methodological level as well as regarding the conceptualization of unregulated learning and surface processing. PMID- 29427364 TI - Crohn's disease associated strictures. AB - Crohn's disease (CD) is a chronic relapsing and remitting disease that can affect any segments of the gastrointestinal tract. More than 50% of patients with CD develop stricturing or penetrating complications within the first 10 years after diagnosis. Strictures can lead to intestinal obstruction, which is a common indication for surgery. Despite significant advances in the understanding of the pathogenesis of intestinal fibrostenosis, imaging and therapeutic armamentarium of CD, the risk of intestinal surgery remained significantly high. Endoscopic balloon dilation is a promising first-line alternative to surgery as it is less invasive and could preserve intestinal length. In this review, we will evaluate the literature on the mechanism of intestinal fibrosis, emerging imaging techniques, and management strategies for CD associated strictures. PMID- 29427365 TI - Neural and behavioral correlates of negative self-focused thought associated with depression. AB - A central feature of major depression (MDD) is heightened negative self-focused thought (negative-SFT). Neuroscientific research has identified abnormalities in a network of brain regions in MDD, including brain areas associated with SFT such as medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). To our knowledge no studies have investigated the behavioral and neural correlates of negative-SFT using a sentence completion task in a sample of individuals with varying depression histories and severities. We test the following hypotheses: (1) negative-SFT will be associated with depression; and (2) depression and negative-SFT will be related to resting-state functional connectivity (rsFC) for brain regions implicated in SFT. Seventy-nine women with varying depression histories and severities completed a sentence completion task and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Standard seed based voxelwise rsFC was conducted for self-network regions of interest: dorsomedial PFC (dmPFC) and pregenual ACC (pgACC). We performed linear regression analyses to examine the relationships among depression, negative-SFT, and rsFC for the dmPFC and pgACC. Greater negative-SFT was associated with depression history and severity. Greater negative-SFT predicted increased rsFC between dmPFC and pgACC seeds and dorsolateral prefrontal (dlPFC) and parietal regions; depression group was also associated with increased pgACC-dlPFC connectivity. These findings are consistent with previous literature reporting elevated negative-SFT thought in MDD. Our rs-fMRI results provide novel support linking negative-SFT with increased rsFC between self-network and frontoparietal network regions across different levels of depression. Broadly, these findings highlight a dimension of social-affective functioning that may underlie MDD and other psychiatric conditions. PMID- 29427366 TI - Simultaneous multislice acquisition without trajectory modification for hyperpolarized 13 C experiments. AB - PURPOSE: To investigate the feasibility of performing large FOV hyperpolarized 13 C metabolic imaging using simultaneous multislice excitation. METHODS: A spectral spatial multislice excitation pulse was constructed by cosine modulation and incorporated into a 13 C spiral imaging sequence. Phantom and in vivo pig experiments were performed to test the feasibility of simultaneous multislice data acquisition and image reconstruction. In vivo cardiac-gated images of hyperpolarized pyruvate, bicarbonate, and lactate were obtained at 1 * 1 * 1 cm3 resolution over a 48 * 48 * 24 cm3 FOV with 2-fold acceleration in the slice direction. Sensitivity encoding was used for image reconstruction with both autocalibrated and numerically calculated coil sensitivities. RESULTS: Simultaneous multislice images obtained with 2-fold acceleration were comparable to reference unaccelerated images. Retained SNR figures greater than 80% were achieved over the part of the image containing the heart. CONCLUSION: This method is anticipated to enable large FOV imaging studies using hyperpolarized 13 C substrates, with an aim toward whole-body exams that have to date been out of reach. PMID- 29427367 TI - Effects of Biorelevant Media Components on Dissolution Behaviour of 1,2,4 Thiadiazole Derivative Designed for Alzheimer's Disease Prevention. AB - In this study, dissolution behaviour of 1,2,4-thiadiazole derivative (1-[5-(3 chloro-phenylamino)-1,2,4-thiadiazol-3-yl]-propan-2-ol) displaying an anti Alzheimer activity was examined in biorelevant media such as Simulated Gastric Fluid (SGF, pH 1.2), Fasted State Simulated Gastric Fluid (FaSSGF, pH 1.6) and Fasted State Simulated Intestinal Fluid (FaSSIF, pH 6.5). It was found that solubility and dissolution rate of 1,2,4-thiadiazole derivative under consideration are not strongly dependent on pH, whereas these parameters are significantly affected by the buffer composition. Dissolution was found to be more effective in buffers composed of the surfactant micelles. It was demonstrated that considerable increase in solubility and dissolution rate in SGF is achieved through the interaction of 1,2,4-thiadiazole derivative with the micelles of sodium dodecyl sulfate. On the contrary, CMC of sodium taurochalate was shifted in the presence of 1,2,4-thiadiazole derivative, therefore, dissolution process is not so efficient in FaSSIF. Interactions occurring between 1,2,4-thiadiazole derivative and the components of biorelevant media were investigated in detail by means of UV/VIS spectroscopy, 1 H-NMR and phase solubility methods. PMID- 29427368 TI - ALT flares during nucleotide analogue therapy are associated with HBsAg loss in genotype A HBeAg-positive chronic hepatitis B. AB - BACKGROUND: Alanine aminotransferase (ALT) flares during NA therapy are uncommon but occur. Evaluation of ALT flares during nucleos(t)ide analogue (NA) therapy is important as new immunomodulatory therapies for hepatitis B virus (HBV) are developed. We evaluated the association between ALT flares and HBsAg loss during long-term therapy for genotype A CHB. METHODS: This analysis included genotype A subjects from a phase III study of tenofovir vs adefovir in HBeAg-positive HBV. ALT flare was defined as (i) a rise in ALT >2x ULN from normal ALT levels; or (ii) a rise in ALT >2x baseline ALT level. HBsAg response at week 384 was recorded as one of HBsAg loss vs HBsAg decline (>=1 log10 IU/mL decline) vs non response. The primary analysis evaluated the association between ALT flare and HBsAg response. RESULTS: 54 subjects were included. 23/54 (43%) subjects experienced an on-treatment ALT flare. 45% achieved an HBsAg reduction >=1 log10 IU/mL, and of these 67% achieved HBsAg loss at a median of 102 weeks [IQR: 64 156]. Flare was associated with HBsAg decline vs non-response (67% vs 23%, P = .002), and were more common in subjects who achieved HBsAg loss vs non-response (56% vs 23%), P = .049). There was a median delay of 56 weeks [IQR: 40-80] between a flare and HBsAg loss. CONCLUSION: In genotype A subjects undergoing long-term NA therapy, ALT flares predict for HBsAg response. The delay between ALT flare and HBsAg loss has implications for clinical trial design for early phase development of immunomodulatory strategies aiming for HBsAg loss. PMID- 29427369 TI - Pre-eclampsia affects procalcitonin production in placental tissue. AB - PROBLEM: Procalcitonin (PCT) is the prohormone of calcitonin which is usually released from neuroendocrine cells of the thyroid gland (parafollicular) and the lungs (K cells). PCT is synthesized by almost all cell types and tissues, including monocytes and parenchymal tissue, upon LPS stimulation. To date, there is no evidence for PCT expression in the placenta both in physiological and pathological conditions. METHOD: Circulating and placental PCT levels were analysed in pre-eclamptic (PE) and control patients. Placental cells and macrophages (PBDM), stimulated with PE sera, were analysed for PCT expression. The effect of anti-TNF-alpha antibody was analysed. RESULTS: Higher PCT levels were detected in PE sera and in PE placentae compared to healthy women. PE trophoblasts showed increased PCT expression compared to those isolated from healthy placentae. PE sera induced an upregulation of PCT production in macrophages and placental cells. The treatment of PBDM with PE sera in the presence of anti-TNF-alpha completely abrogated the effect induced by pathologic sera. CONCLUSION: Trophoblast cells are the main producer of PCT in PE placentae. TNF-alpha, in association with other circulating factors present in PE sera, upregulates PCT production in macrophages and normal placental cells, thus contributing to the observed increased in circulating PCT in PE sera. PMID- 29427370 TI - Weight Stigma Predicts Poorer Psychological Well-Being Through Internalized Weight Bias and Maladaptive Coping Responses. AB - OBJECTIVE: Weight-based stigmatization is associated with negative psychological and behavioral consequences, but individuals respond to stigma in different ways. The present study aimed to understand some of the factors that predict how one will cope with weight stigma and how different coping responses predict psychological well-being. METHODS: Across four samples, 1,391 individuals who identified as having overweight or obesity completed surveys assessing the frequency of weight stigma experiences, internalized weight bias, coping responses to weight stigma, and psychological distress. RESULTS: Frequency of weight stigma predicted greater internalized weight bias, which predicted more frequent use of maladaptive coping responses ("disengagement coping") and less frequent use of adaptive coping responses ("reappraisal coping"), in turn predicting more depression, anxiety, and stress symptoms. CONCLUSIONS: The more that individuals with overweight or obesity experience weight stigma and internalize weight bias, the more they report using maladaptive coping and the less they report using adaptive coping when dealing with weight stigma. Maladaptive coping is strongly associated with poorer psychological well-being. Thus, those who experience more frequent weight stigma may be more vulnerable to psychological distress because they appear to be at greater risk of employing maladaptive coping strategies. PMID- 29427371 TI - Cause or compensation?-Altered neuronal Ca2+ handling in Huntington's disease. AB - Huntington's disease (HD) is a hereditary neurodegenerative disorder of typically middle-aged onset for which there is no disease-modifying treatment. Caudate and putamen medium-sized spiny projection neurons (SPNs) most severely degenerate in HD. However, it is unclear why mutant huntingtin protein (mHTT) is preferentially toxic to these neurons or why symptoms manifest only relatively late in life. mHTT interacts with numerous neuronal proteins. Likewise, multiple SPN cellular processes have been described as altered in various HD models. Among these, altered neuronal Ca2+ influx and intracellular Ca2+ handling feature prominently and are addressed here. Specifically, we focus on extrasynaptic NMDA-type glutamate receptors, endoplasmic reticulum IP3 receptors, and mitochondria. As mHTT is expressed throughout development, compensatory processes will likely be mounted to mitigate any deleterious effects. Although some compensations can lessen mHTT's disruptive effects, others-such as upregulation of the ER-refilling store-operated Ca2+ channel response-contribute to pathogenesis. A causation based approach is therefore necessary to decipher the complex sequence of events linking mHTT to neurodegeneration, and to design rational therapeutic interventions. With this in mind, we highlight evidence, or lack thereof, that the above alterations in Ca2+ handling occur early in the disease process, clearly interact with mHTT, and show disease-modifying potential when reversed in animals. PMID- 29427372 TI - Cross-bridges in slow skeletal muscle: not only slow but also soft. PMID- 29427373 TI - Enhanced B-cell differentiation driven by advanced cirrhosis resulting in hyperglobulinemia. AB - BACKGROUND AND AIM: The mechanism underlying hyperglobulinemia in cirrhosis, a long appreciated phenomenon, has never been clearly understood. The aim of this study is to investigate the basis for changes in humoral immunity observed in cirrhosis. METHODS: We retrospectively reviewed our medical record to analyze serum immunoglobulin (Ig) levels in patients with liver disease. We also prospectively analyzed peripheral blood mononuclear cells and sera from liver disease patients. Peripheral blood mononuclear cell surface marker expressions were measured by flow cytometry and serum B-cell-activating factor was measured by enzyme-linked immunosorbent assay. Expression of specific gene expression in magnetically separated B cells was also analyzed by real-time polymerase chain reaction. RESULTS: In retrospective analysis, we found that advancing cirrhosis, irrespective of underlying etiology or hepatocellular carcinoma, resulted in progressively increasing levels of serum IgG and IgA. In prospective analysis using clinical samples, we demonstrated that advancing cirrhosis stage was associated with increased toll-like-receptor (TLR)9 expression in CD27+ B cell and serum B-cell-activating factor levels but decreased CD27+ memory B-cell frequency. The remaining CD27+ B cells in peripheral blood exhibited increased activation-induced cytidine deaminase mRNA expression. Finally, we also demonstrated isolated B cells from advanced cirrhosis were more reactive to TLR9 stimulation that drove antibody secreting cells differentiation leading to hyperimmunoglobulinemia in vitro. CONCLUSIONS: Enhanced TLR9-induced differentiation into antibody secreting cell may explain peripheral reductions of circulating CD27+ memory B cells as well as increased serum Ig levels in cirrhosis. PMID- 29427374 TI - Economic Analysis of Diagnostic Imaging in Pediatric Patients With Suspected Appendicitis. AB - OBJECTIVE: The use of computed tomography (CT) and ultrasound (US) in patients with acute abdominal pain has substantial variation across pediatric emergency departments (EDs). This study compares the cost of diagnosing and treating suspected appendicitis across a multicenter network of children's hospitals. METHODS: This study is a secondary analysis using deidentified data of a prospective, observational study of patients with suspected appendicitis at nine pediatric EDs. The study included patients 3 to 18 years old who presented to the ED with acute abdominal pain of <96 hours' duration. RESULTS: Our data set contained 2,300 cases across nine sites. There was an appendicitis rate of 31.8% and perforation rate of 25.7%. Sites correctly diagnosed appendicitis in over 95% of cases. The negative appendicitis rate ranged from 2.5% to 4.7% while the missed appendicitis rate ranged from 0.3% to 1.1% with no significant differences in these rates across site. Across sites, we found a strong positive correlation (0.95) between CT rate and total cost per case and a strong negative correlation (-0.71) between US rate and cost. The cost per case at US sites was 5.2% ($367) less than at CT sites (p < 0.001). Similarly, costs per case at mixed sites were 3.4% ($244) less than at CT sites (p < 0.001). Comparing costs among CT sites or among US sites, the cost per case generally increased as the images per case increased among both CT sites and US sites, but the costs were universally higher at CT sites. CONCLUSIONS: Our results provide support for US as the primary imaging modality for appendicitis. Sites that preferentially utilized US had lower costs per case than sites that primarily used CT. Imaging rates across sites varied due to practice patterns and resulted in a significant cost consequence without higher rates for negative appendectomies or missed appendicitis cases. PMID- 29427375 TI - Resistance development, stability, cross-resistance potential, biological fitness and biochemical mechanisms of spinetoram resistance in Thrips hawaiiensis (Thysanoptera: Thripidae). AB - BACKGROUND: Spinetoram, a new type of spinosyn with novel modes of action, has been used in effective thrips control programs, but resistance remains a threat. In the present study, a laboratory Thrips hawaiiensis population was subjected to spinetoram for resistance selection to investigate resistance development, stability, cross-resistance potential, biological fitness and underlying biochemical mechanisms. RESULTS: Resistance to spinetoram in T. hawaiiensis rapidly increased 103.56-fold (for 20 generations of selection with spinetoram) compared with a laboratory susceptible population, and the average realized heritability (h2 ) of resistance was calculated as 0.1317. Maintaining the resistant population for five generations without any further selection pressure resulted in a decline in the resistance ratio from 19.42- to 9.50-fold, suggesting that spinetoram resistance in T. hawaiiensis is unstable. Moreover, the spinetoram-resistant population exhibited a lack of cross-resistance to other classes of insecticides, and showed biological fitness costs. The results of synergism experiments using enzyme inhibitors and biochemical analyses revealed that metabolic mechanisms might not be responsible for the development of spinetoram resistance in T. hawaiiensis. CONCLUSION: The current study expands understanding of spinosyn resistance in thrips species, providing a basis for proposing better integrated pest management strageties for thrips control programs and defining the most appropriate tools for such resistance management. (c) 2018 Society of Chemical Industry. PMID- 29427377 TI - Development of an attract-and-infect system to control Rhynchophorus ferrugineus with the entomopathogenic fungus Beauveria bassiana. AB - BACKGROUND: A new Beauveria bassiana-based attract and infect device (AID) to control Rhynchophorus ferrugineus Olivier (Coleoptera: Curculionidae) was developed. The virulence and persistence of the fungal formulation used in the AID were evaluated in the laboratory. Semi-field and field trials were carried out to validate the results and establish the potential of this device as a control tool. RESULTS: In laboratory conditions, a 50% lethal time (LT50 ) of 4.33 days was obtained when adults (7-10 days old) were exposed to the inoculation tunnel (IT) containing 1 * 1010 conidia g-1 in an oil-based fungal formulation. This formulation maintained conidium viability at 50% for up to 2 months. Moreover, when adults were exposed to 2.5-month field-aged ITs, mortality still reached 50% 40 days after exposure. In addition, no differences were observed between ITs aged in early spring and those aged in summer, suggesting that the fungal formulation is not strongly affected by environmental factors in Mediterranean basin conditions. Semi-field assays showed that the device allowed an easy transit of weevils through the IT, which were effectively attracted and infected. Using the AIDs in 4-ha plot field trials, a reduction of >50% in the percentage of infested sentinel palms was obtained. CONCLUSION: Based on the results obtained in terms of the efficacy and persistence of this new AID in the field and its potential in reducing R. ferrugineus populations and palm infestation, this device could become a key tool for the management of R. ferrugineus. (c) 2018 Society of Chemical Industry. PMID- 29427376 TI - Longitudinal Increases in Adiposity Contribute to Worsening Adipokine Profile over Time in Mexican Americans. AB - OBJECTIVE: Limited studies have assessed the relationship between longitudinal changes in adiposity and changes in multiple adipokines over time. This study examined changes in BMI, total body fat, and trunk fat associated with changes in 16 circulating adipokines in Mexican Americans at risk for type 2 diabetes. METHODS: Participants included 1,213 individuals with cross-sectional data and a subset of 368 individuals with follow-up measures (mean 4.6 +/- 1.5 years from baseline). Joint multivariate associations between 3 adiposity measures and 16 adipokines were assessed by canonical correlation analysis. RESULTS: Longitudinal increases in adiposity were most strongly associated with increasing leptin, C reactive protein (CRP), and interleukin 1 receptor antagonist (IL-1Ra) and decreasing adiponectin and secreted frizzled protein 5 (SFRP5) over time. Participants with BMI >= 30 kg/m2 at baseline had greater increases in leptin, CRP, IL-1Ra, and interleukin 6 (IL-6) and greater decreases in adiponectin and SFRP5, associated with increasing adiposity over follow-up, than those with BMI < 30 kg/m2 . Associations between adiposity and adipokines were most accounted for by leptin; adjustment for leptin greatly reduced the magnitude of all associations between adiposity and remaining adipokines. CONCLUSIONS: Increasing adiposity contributes to a worsening imbalance of pro- and anti-inflammatory adipokines over time, in which leptin may have an important role as a key mediator of metabolic disease risk in Mexican Americans. PMID- 29427379 TI - Phase-correcting non-local means filtering for diffusion-weighted imaging of the spinal cord. AB - PURPOSE: DWI suffers from low SNR when compared to anatomical MRI. To maintain reasonable SNR at relatively high spatial resolution, multiple acquisitions must be averaged. However, subject motion or involuntary physiological motion during diffusion-sensitizing gradients cause phase offsets among acquisitions. When the motion is localized to a small region, these phase offsets become particularly problematic. Complex averaging of acquisitions lead to cancellations from these phase offsets, whereas magnitude averaging results in noise amplification. Here, we propose an improved reconstruction for multi-acquisition DWI that effectively corrects for phase offsets while reducing noise. THEORY AND METHODS: Each acquisition is processed with a refocusing reconstruction for global phase correction and a partial k-space reconstruction via projection-onto-convex-sets (POCS). The proposed reconstruction then embodies a new phase-correcting non local means (PC-NLM) filter. PC-NLM is performed on the complex-valued outputs of the POCS algorithm aggregated across acquisitions. The PC-NLM filter leverages the shared structure among multiple acquisitions to simultaneously alleviate nuisance factors including phase offsets and noise. RESULTS: Extensive simulations and in vivo DWI experiments of the cervical spinal cord are presented. The results demonstrate that the proposed reconstruction improves image quality by mitigating signal loss because of phase offsets and reducing noise. Importantly, these improvements are achieved while preserving the accuracy of apparent diffusion coefficient maps. CONCLUSION: An improved reconstruction incorporating a PC-NLM filter for multi-acquisition DWI is presented. This reconstruction can be particularly beneficial for high-resolution or high-b-value DWI acquisitions that suffer from low SNR and phase offsets from local motion. PMID- 29427378 TI - Dural recurrence among esthesioneuroblastoma patients presenting with intracranial extension. AB - OBJECTIVE: To quantify the rate of late intracranial recurrences among esthesioneuroblastoma patients treated with surgical resection and postoperative radiation. STUDY DESIGN: Retrospective review. METHODS: All patients receiving definitive-intent therapy for esthesioneuroblastoma between March 1995 and September 2015 were reviewed. Presenting disease extent was categorized based on radiologic, operative, and pathologic findings. Between-group survival differences were assessed using Kaplan-Meier method and log-rank test. Multivariate analyses were performed using Cox proportional hazards model. RESULTS: Of 38 patients initially treated at our institution, 53% (20 of 38) presented with intracranial extension. At a median follow-up of 90 months (range, 6-199), 37% (14 of 38) recurred; 5- and 8-year disease-free survival rates were 69% and 54%; and overall survival rates were 81% and 72%, respectively. Among these patients, the dura was the most commonly involved site of relapse (8), followed by local (6), regional (5), and distant extracranial (3) sites; and five patients had >= two categories of failure. Eight-year dural disease-free survival was 57% versus 90% (P = 0.017) and 0% versus 87% (P < 0.0001), with and without intracranial extension and subtotal resection, respectively. Of six patients treated at recurrence, five (83%) experienced dural-based failure such that, among all 44 patients, 13 (65%) of 20 recurrences involved the dura. After dural recurrence, the median survival time was 42 months (range, 12-125); salvage treatments were effective in rare cases of isolated low-volume recurrence. CONCLUSION: Esthesioneuroblastoma patients presenting with intracranial extension are at substantial and unique risk for long-term dural-based relapse. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2226-2233, 2018. PMID- 29427380 TI - How publication guidelines for clinical pharmacology trials may help to accelerate knowledge transfer. PMID- 29427381 TI - Feed and water deprivation has a negative but transient effect on the rumen kinetics of Bos indicus steers. AB - The effects on rumen kinetics after feed and water had been deprived for 72 hr were studied using four fistulated Bos indicus steers. The animals were assigned in a 2 * 4 crossover design with two treatments: feed and water ad libitum (control) and no feed and water for 72 hr (deprived) with four steers per treatment over two time periods. Feed and water deprivation caused decreases in the numbers of cellulolytic bacteria (1.4 vs. 0.4 cfu * 106 /ml; p = .001), live (23.7 vs. 0.8 * 109 /ml; p = .001), dead (12.7 vs. 0.5 * 109 /ml; p = .001) and total bacterial counts (36.4 vs. 1.4 * 109 /ml; p = .001) at day 0, compared with the control treatment. However, the deprived group had greater numbers of cellulolytic bacteria (2.7 vs. 50.1 cfu * 106 /ml; p = .001), live (18.3 vs. 42.2 * 109 /ml; p = .001), dead (6. 5 vs. 19.1 * 109 /ml; p = .001) and total bacterial counts (24.8 vs. 61.3 * 109 /ml; p = .001) from rumen fluid on day 4, compared with the control treatment. The numbers of protozoa in rumen fluid from the deprived group were less than (551.2 vs. 2.4 * 103 /ml; p = .001) the control group on day 0. However, the deprived treatment had fewer protozoa in rumen fluid than the control treatment on day 4 (p = .001) and day 9 (p = .001). Volatile fatty acids and in vitro gas production as functional measurements of rumen fluid followed the same trend as the bacterial and protozoa populations. These results indicate that feed and water deprivation would have a negative but transient effect on the rumen kinetics of Bos indicus steers. PMID- 29427382 TI - Feasibility of in vivo measurement of glucose metabolism in the mouse hypothalamus by 1 H-[13 C] MRS at 14.1T. AB - PURPOSE: Determine the feasibility of 1 H-[13 C] MRS in the mouse hypothalamus using a 14.1T magnet. METHODS: We optimized the design of a 1 H-[13 C] surface coil to maximize the signal-to-noise ratio of 1 H-[13 C] MRS in the mouse hypothalamus. With enhanced signal, 13 C accumulation in glucose metabolites was measured in a 8.7 uL voxel in the hypothalamus of 5 healthy mice during the continuous administration of [1,6-13 C2 ]glucose. RESULTS: Accumulation of 13 C label in glucose C6 and lactate C3 was visible in the hypothalamus 11 min after glucose administration. The 13 C fractional enrichment (FE) curves of lactate C3, glutamate and glutamine C4, glutamate+glutamine C3 and C2, GABA C2, C3, and C4, and aspartate C3 were measured with a time resolution of 11 min over 190 min. FE time-courses and metabolic pool sizes were averaged to fit a novel one compartment model of brain energy metabolism that incorporates the main features of the hypothalamus. CONCLUSION: Dynamic 1 H-[13 C] MRS is able to measure in vivo brain metabolism in small and deep areas of the mouse brain such as the hypothalamus, and it can be used to calculate metabolic fluxes, including glutamatergic and GABAergic metabolism as well as the contribution of metabolic sources other than glucose. PMID- 29427383 TI - Investigation of the chromatographic regulation properties of benzyl groups attached to bridging nitrogen atoms in a calixtriazine-bonded stationary phase. AB - Two reversed-phase/anion-exchange mixed-mode stationary phases for high performance liquid chromatography using calixtriazines as chromatographic ligands were investigated with Tanaka test solutes, monosubstituted benzenes, aromatic positional isomers, and inorganic anions. Calixtriazine as a chromatographic ligand has been reported previously, but the benzylated nitrogen-bridged calixtriazine-bonded silica gel reported in this study is new. The experimental data showed that the calixtriazine platform is a unique chromatographic selector because its multiple active sites are available for different solutes and its chromatographic selectivity could be tuned by introducing substituent on the bridging nitrogen atoms present in the calixtriazine matrix. The synergistic effects of aromatic rings, nitrogen atoms, benzyl groups, and tunable cavity in the host molecule influenced the separation selectivity by multiple retention mechanisms. Such hybrid stationary phases provide more versatility and have great potential in the analysis of complex samples. Moreover, the synthetic protocols presented herein may provide an alternative understanding on macrocyclic host guest chemistry, leading to new and selective separation media. PMID- 29427385 TI - Remotely Phototriggered, Transferrin-Targeted Polymeric Nanoparticles for the Treatment of Breast Cancer. AB - Triple-negative breast cancer (TNBC) has the worst prognosis among all subtypes of breast cancer. Currently, no targeted treatment has been approved for TNBC. The goal of this study was to design a remotely triggered, targeted therapy for TNBC using polymeric nanoparticles and light. Active targeting of TNBC was achieved by conjugating the nanoparticles to a peptide (hTf) that binds to the transferrin receptor, which is overexpressed in TNBC. Photodynamic therapy (PDT) was explored for TNBC treatment by remotely triggering benzoporphyrin derivative monoacid (BPD), a photosensitizer, using near-infrared light. In this study, we investigated the use of actively targeting polymeric nanoparticles for PDT against TNBC using in vitro imaging and cytotoxicity studies. Fluorescence imaging confirmed that the BPD-loaded nanoparticles showed greater fluorescence in TNBC cells compared to free BPD, but more importantly, actively targeted nanoparticles displayed stronger fluorescence compared to passively targeted nanoparticles. Moreover, fluorescence imaging following competition with empty targeted nanoparticles validated the specificity of the targeted nanoparticles for TNBC cells. The PDT killing results were in line with the fluorescence imaging results, where actively targeting nanoparticles exhibited the highest phototriggered cytotoxicity in TNBC cells, making them an attractive nanoplatform for TNBC treatment. PMID- 29427384 TI - LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice. AB - AIMS: Multiple evidence has indicated that myelin injury is common in Alzheimer's disease (AD). However, whether myelin injury is an early event in AD and the relationship between it and cognitive function is still elusive. METHODS: Spatial memory of 5XFAD mice was determined by Morris water maze at 1 and 3 months old. Meanwhile, the deposition of Abeta, the expression of myelin basic protein (MBP), LINGO-1, NgR, and myelin ultrastructure in many memory-associated brain regions were detected in one-month-old and three-month-old mice (before and after LINGO-1 antibody administration) using immunostaining, Western blot (WB), and transmission electron microscopy (TEM), respectively. RESULTS: No abnormal Abeta deposition was found in one-month-old 5XFAD mice. However, spatial memory deficits were proved in accordance with an obvious demyelination in memory associated brain regions in one-month-old mice and both deteriorated with age. Administration of LINGO-1 antibody could obviously restore the myelin impairments in CA1 and DG region and partially ameliorate spatial memory deficits. CONCLUSIONS: Our results demonstrated that myelin injury was an early event in 5XFAD mice even prior to emergence of deposition of Abeta. Intervention with the LINGO-1 antibody could attenuate impaired spatial memory deficits by remyelination, which suggested that myelin injury was involved in spatial memory deficits and remyelination may be a potential therapeutic strategy in early stage of AD or mild cognitive impairments. PMID- 29427387 TI - Design Principles for the Atomic and Electronic Structure of Halide Perovskite Photovoltaic Materials: Insights from Computation. AB - In the current decade, perovskite solar cell research has emerged as a remarkably active, promising, and rapidly developing field. Alongside breakthroughs in synthesis and device engineering, halide perovskite photovoltaic materials have been the subject of predictive and explanatory computational work. In this Minireview, we focus on a subset of this computation: density functional theory (DFT)-based work highlighting the ways in which the electronic structure and band gap of this class of materials can be tuned via changes in atomic structure. We distill this body of computational literature into a set of underlying design principles for the band gap engineering of these materials, and rationalize these principles from the viewpoint of band-edge orbital character. We hope that this perspective provides guidance and insight toward the rational design and continued improvement of perovskite photovoltaics. PMID- 29427386 TI - Diffusion MRI monitoring of specific structures in the irradiated rat brain. AB - PURPOSE: The analysis of biological and mesoscopic structures properties by diffusion MRI (dMRI) in brain after radiation therapy remains challenging. In our study, we described the consequences associated with an unwanted dose to healthy tissue, assessing radiation-induced brain alterations of living rats with dMRI compared to histopathology and behavioral assays. METHODS: The right primary motor cortex M1 of the rat brain was targeted by stereotactic radiosurgery with a mean radiation dose of 41 Gy. Multidirectional single b-value dMRI data of the whole brain were acquired with a 7T small-animal scanner before irradiation until 110 days post-irradiation. Diffusion tensor imaging metrics, such as fractional anisotropy (FA), mean diffusivity (MD), axial (AD), and radial diffusivity (RD) were compared to brain alterations detected by immunohistochemistry and motor performances measured by a behavioral test. RESULTS: Between days 90 and 110, radiation necrosis was observed into the white matter spreading into M1 . Results showed a reduction of FA in the corpus callosum and in the striatum, which was driven by an increase in RD from 90 to 110 days post-irradiation, whereas only RD increased in M1 . Values of RD and AD increased in the irradiated hippocampus, while FA remained constant. Moreover, an increased MD, AD and RD was observed in the hippocampus that was probably related to inflammation as well as reactive astrogliosis after 110 days post-irradiation. Finally, rats did not exhibit locomotor deficits. CONCLUSIONS: dMRI metrics can assess brain damage; the sensitivity of dMRI metrics depends on the brain region. PMID- 29427388 TI - Reviewing smokeless tobacco epidemiology, carcinogenesis, and cessation strategy for otolaryngologists. AB - OBJECTIVES/OBJECTIVES: We aimed to provide an otolaryngologist-targeted summary regarding the epidemiology, carcinogenesis, and cessation strategies for smokeless tobacco usage. STUDY DESIGN: Evidence-based literature review. METHODS: We reviewed the current evidence-based literature concerning trends in smokeless tobacco use, associations with neoplastic change, and therapeutic interventions to assist with sustained abstinence. In complement, we present an actual case of laryngeal squamous cell carcinoma in the setting of chronic tobacco-dentifrice usage in a lifelong nonsmoker. RESULTS: This report provides a synopsis of epidemiological data and evidence-based recommendations for general, pharmaceutical, and behavioral cessation strategies. CONCLUSIONS: Smokeless tobacco use continues to be prevalent among patients seen by otolaryngologists, particularly of various Indian and Southeast Asian descent. The data presented in this article will aid in the identification of at risk patients. The provided recommended cessation strategies will tool otolaryngologists for patient counseling and management, ultimately aimed at improving health outcomes. Laryngoscope, 128:2067-2071, 2018. PMID- 29427389 TI - In vivo self-gated 23 Na MRI at 7 T using an oval-shaped body resonator. AB - PURPOSE: This work faces three challenges of sodium (23 Na) torso MRI on the way to quantitative 23 Na MRI: Development of a 23 Na radiofrequency transmit and receive coil covering a large part of the human body in width and length for 23 Na MRI at 7 T; reduction of blurring due to respiration in free-breathing 23 Na MRI using a self-gating approach; and reduction of image noise using a compressed sensing reconstruction. METHODS: An oval-shaped birdcage resonator with a large field of view of (400 mm)3 and a homogeneous transmit and receive field distribution was designed, simulated, and implemented on a 7T MR system. In free breathing 3-dimensional radial 23 Na MRI (acquisition time ~ 30 minutes), retrospective respiratory self-gating was applied, which sorts the acquired projections into two respiratory states based on the intrinsic respiration dependent signal changes. Furthermore, a 3-dimensional dictionary-learning compressed-sensing reconstruction was applied. RESULTS: The developed body coil provided homogeneous radiofrequency excitation (flip angle error of 4.9% in central region of interest of 23 * 13 * 10 cm3 ) and homogeneous signal reception. The self-gating approach allowed for separation of the full data set into two subsets associated with different respiratory states (inhaled and exhaled), and thereby reduced blurring due to respiration in the separated images. Image noise was markedly reduced by the compressed-sensing algorithm. CONCLUSION: The presented body coil enables full body width 23 Na MRI with long z axis coverage at 7 T for the first time. Additionally, the retrospective respiratory self-gating performance is demonstrated for free-breathing lung and abdominal 23 Na MRI in 3 subjects. PMID- 29427390 TI - Prevention of acute radiodermatitis by photobiomodulation: A randomized, placebo controlled trial in breast cancer patients (TRANSDERMIS trial). AB - OBJECTIVE: Acute radiodermatitis (RD) is a distressing and painful skin reaction that occurs in 95% of the patients undergoing radiotherapy (RT). The aim of this study was to evaluate the effectiveness of photobiomodulation therapy (PBMT) in the prevention of acute RD in breast cancer (BC) patients undergoing RT. METHODS: This study was a randomized, placebo-controlled trial including 120 BC patients that underwent an identical RT regimen post-lumpectomy. Patients were randomly assigned to the laser therapy (LT) or placebo group, with 60 patients in each group. Laser or placebo treatments were applied 2 days a week, immediately after the RT session, starting at the first day of RT. PBMT was delivered using a class IV MLS(r) M6 laser that combines two synchronized laser diodes in the infrared range (808-905 nm) with a fixed energy density (4 J/cm2 ). Skin reactions were scored based on the criteria of the Radiation Therapy Oncology Group (RTOG) and the Radiation-Induced Skin Reaction Assessment Scale (RISRAS). The patients completed the Skindex-16 questionnaire to evaluate their quality of life. All the measurements were collected at the first day, at a RT dose of 40 Gray (Gy), and at the end of RT (total dose 66 Gy). RESULTS: At a RT dose of 40 Gy, there was no significant difference between the groups in the distribution of RTOG grades. However, at the end of RT the severity of the skin reactions significantly differed between the two groups (P = 0.004), with a larger percentage of patients experiencing RTOG grade 2 or higher (e.g., moist desquamation) in the placebo group (30% vs. 6.7%, for the placebo and laser group, resp.). The objective RISRAS score confirmed these results. In addition, the Skindex-16 and RISRAS subjective score demonstrated that the patients' quality of life was significantly better in the LT than in the control group. CONCLUSIONS: The results of this trial show that PBMT is an effective tool to prevent the development of grade 2 acute RD or higher in BC patients. In addition, it also reduces the patients' symptoms related to RD. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 29427391 TI - Noninvasive quantitative analysis of ceramide in skin of healthy Chinese population. AB - OBJECTIVE: The objective of this study was to make noninvasive quantitative analysis of ceramide (CER) in skin of healthy Chinese population by high performance liquid chromatography tandem mass spectrometry. METHODS: Seven healthy subjects were selected and the stratified skin samples were available using cyanoacrylate adhesion method. High performance liquid chromatography tandem mass spectrometry, use ceramide Subclass Standard C42H85NO3 Quantification of the 12 corresponding ceramide subclass in the epidermis on the 7 skin samples, which cannot get all the standard of ceramides subclass since the stratum corneum ceramide is complex and diverse. Data were collected and analyzed using full-flow lipid analysis software (LipidSearch). RESULTS: All the seven skin samples contained 12 subclasses of ceramide and the samples were quantitated with ceramide C42H85NO3 standard. The average contents were 33.63, 27.59, 108.57, 220.75, 149.20, 43.06, and 22.78 MUg/mL, respectively. CONCLUSION: Ceramide is an important lipid in the epidermis and is closely related to the skin barrier function. There are 12 subtypes of ceramide detected in the skin of Chinese healthy people, and there is a difference in the concentration between individuals. The difference may be associated with the skin barrier condition, and may also be related to the unavoidable error in the process of sampling, treatment, and detection. PMID- 29427392 TI - Determination of 16 antineoplastic drugs by capillary electrophoresis with UV detection: Applications in quality control. AB - Two capillary electrophoresis (CE) methods were developed for the analysis of 16 antineoplastic drugs contained in injectable pharmaceutical formulations. A capillary zone electrophoresis (CZE) method coupled to UV was developed with a background electrolyte (BGE) made of a 100 mM phosphate buffer at pH 2.5 containing 50% v/v of acetonitrile and dynamic coating of capillaries with Ceofix(r). This method allowed the analysis of doxorubicin, epirubicin, idarubicin, daunorubicin, irinotecan, topotecan, vincristine, vindesine, vinblastine, and vinorelbine in less than 8 min. A micellar electrokinetic chromatography (MEKC) method coupled to UV was also developed for the determination of methotrexate, pemetrexed, etoposide, etoposide phosphate, fludarabine phosphate, and 5-fluorouracil. A run time of 16 min was obtained with a BGE made of 50 mM borate buffer at pH 9.2 with 80 mM of sodium dodecyl sulfate (SDS) and 20% v/v of acetonitrile. For both methods, the applied voltage was 30 kV and the sample injection was performed in the hydrodynamic mode. All analyses were carried out in fused silica capillaries with an internal diameter of 50 MUm and a total length of 64.5 cm. Both methods were validated and trueness values between 99.4 and 101.3% were obtained with repeatability and intermediate precision values of 0.5-1.8% for all drugs. These methods were found appropriate for controlling injectable pharmaceutical formulations containing antineoplastic drugs and successfully applied in quality control. PMID- 29427393 TI - Dynamic 2D self-phase-map Nyquist ghost correction for simultaneous multi-slice echo planar imaging. AB - PURPOSE: To develop a reconstruction pipeline that intrinsically accounts for both simultaneous multislice echo planar imaging (SMS-EPI) reconstruction and dynamic slice-specific Nyquist ghosting correction in time-series data. METHODS: After 1D slice-group average phase correction, the separate polarity (i.e., even and odd echoes) SMS-EPI data were unaliased by slice GeneRalized Autocalibrating Partial Parallel Acquisition. Both the slice-unaliased even and odd echoes were jointly reconstructed using a model-based framework, extended for SMS-EPI reconstruction that estimates a 2D self-phase map, corrects dynamic slice specific phase errors, and combines data from all coils and echoes to obtain the final images. RESULTS: The percentage ghost-to-signal ratios (%GSRs) and its temporal variations for MB3Ry 2 with a field of view/4 shift in a human brain obtained by the proposed dynamic 2D and standard 1D phase corrections were 1.37 +/- 0.11 and 2.66 +/- 0.16, respectively. Even with a large regularization parameter lambda applied in the proposed reconstruction, the smoothing effect in fMRI activation maps was comparable to a very small Gaussian kernel size 1 * 1 * 1 mm3 . CONCLUSION: The proposed reconstruction pipeline reduced slice-specific phase errors in SMS-EPI, resulting in reduction of GSR. It is applicable for functional MRI studies because the smoothing effect caused by the regularization parameter selection can be minimal in a blood-oxygen-level-dependent activation map. PMID- 29427394 TI - A simplified regimen of targeted antifungal prophylaxis in liver transplant recipients: A single-center experience. AB - BACKGROUND: Invasive fungal infection (IFI) is a severe complication of liver transplantation burdened by high mortality. Guidelines recommend targeted rather than universal antifungal prophylaxis based on tiers of risk. METHODS: We aimed to evaluate IFI incidence, risk factors, and outcome after implementation of a simplified two-tiered targeted prophylaxis regimen based on a single broad spectrum antifungal drug (amphotericin B). Patients presenting 1 or more risk factors according to literature were administered prophylaxis. Prospectively collected data on all adult patients transplanted in Turin from January 2011 to December 2015 were reviewed. RESULTS: Patients re-transplanted before postoperative day 7 were considered once, yielding a study cohort of 581 cases. Prophylaxis was administered to 299 (51.4%) patients; adherence to protocol was 94.1%. Sixteen patients developed 18 IFIs for an overall rate of 2.8%. All IFI cases were in targeted prophylaxis group; none of the non-prophylaxis group developed IFI. Most cases (81.3%) presented within 30 days after transplantation during prophylaxis; predominant pathogens were molds (94.4%). Only 1 case of candidemia was observed. One-year mortality in IFI patients was 33.3% vs 6.4% in patients without IFI (P = .001); IFI attributable mortality was 6.3%. At multivariate analysis, significant risk factors for IFI were renal replacement therapy (OR = 8.1) and re-operation (OR = 5.2). CONCLUSIONS: The implementation of a simplified targeted prophylaxis regimen appeared to be safe and applicable and was associated with low IFI incidence and mortality. Association of IFI with re-operation and renal replacement therapy calls for further studies to identify optimal prophylaxis in this subset of patients. PMID- 29427395 TI - Minimum echo time PRESS-based proton observed carbon edited (POCE) MRS in rat brain using simultaneous editing and localization pulses. AB - PURPOSE: Indirect 13 C MRS by proton-observed carbon editing (POCE) is a powerful method to study brain metabolism. The sensitivity of POCE-MRS can be enhanced through the use of short TEs, which primarily minimizes homonuclear J-evolution related losses; previous POCE-MRS implementations use longer than optimal echo times due to sequence limitations, or short TE image selected in vivo spectroscopy-based multi-shot acquisitions for 3D localization. To that end, this paper presents a novel single-shot point resolved spectroscopy (PRESS)-localized POCE-MRS sequence that involves the application of simultaneous editing and localization pulses (SEAL)-PRESS, allowing the TE to be reduced to a theoretically optimal value of ~ 1/JHC . METHODS: The optimized SEAL-PRESS sequence was first evaluated in simulation and in phantom; next, the sequence was validated with dynamic in vivo POCE-MRS performed in a rat preparation during a 1,6-13 C2 -Glc infusion, and on a microwave fixed rat brain following a 2-hour [1,6-13 C2 ]-Glc infusion. POCE spectra from the SEAL-PRESS sequence were compared against a previously described 12.6-ms PRESS-POCE sequence utilizing a classical carbon editing scheme. RESULTS: The SEAL-PRESS sequence provides > 95% editing efficiency, optimal sensitivity, and localization for POCE MRS with an overall sequence TE of 8.1 ms. Signal amplitude of 13 C-labeled metabolites Glu H4, Gln-H4, Glx-H3, Glc-H6 +Glx-H2, and Asp-H2 were shown to be improved by >17% relative to a 12.6-ms PRESS-POCE sequence in vivo. CONCLUSION: We report for the first time, a single-shot PRESS-localized and edited 8.1-ms TE POCE-MRS sequence with optimal sensitivity, editing efficiency, and localization. PMID- 29427396 TI - Size-selective purification of hepatitis B virus-like particle in flow-through chromatography: Types of ion exchange adsorbent and grafted polymer architecture. AB - Hepatitis B virus-like particles expressed in Escherichia coli were purified using anion exchange adsorbents grafted with polymer poly(oligo(ethylene glycol) methacrylate) in flow-through chromatography mode. The virus-like particles were selectively excluded, while the relatively smaller sized host cell proteins were absorbed. The exclusion of virus-like particles was governed by the accessibility of binding sites (the size of adsorbents and the charge of grafted dextran chains) as well as the architecture (branch-chain length) of the grafted polymer. The branch-chain length of grafted polymer was altered by changing the type of monomers used. The larger adsorbent (90 MUm) had an approximately twofold increase in the flow-through recovery, as compared to the smaller adsorbent (30 MUm). Generally, polymer-grafted adsorbents improved the exclusion of the virus like particles. Overall, the middle branch-chain length polymer grafted on larger adsorbent showed optimal performance at 92% flow-through recovery with a purification factor of 1.53. A comparative study between the adsorbent with dextran grafts and the polymer-grafted adsorbent showed that a better exclusion of virus-like particles was achieved with the absorbent grafted with inert polymer. The grafted polymer was also shown to reduce strong interaction between binding sites and virus-like particles, which preserved the particles' structure. PMID- 29427397 TI - The effect of reminiscence therapy on quality of life, attitudes to ageing, and depressive symptoms in institutionalized elderly adults with cognitive impairment: A quasi-experimental study. AB - The aim of this study was to analyse the effect of group narrative reminiscence therapy on cognition, quality of life, attitudes towards ageing, and depressive symptoms in a group of older adults with cognitive impairment in institutional care. A quasi-experimental pretest/post-test control group design was employed. Interventions involving reminiscence therapy with a narrative approach were included in the care plan and implemented in groups of between five and ten respondents once a week for 8 weeks (total 59 participants). The members of the control group (n = 57) received standard care. A study questionnaire was designed to measure demographic characteristics, quality of life (WOHQOL-BREF, WHOQOL OLD), depressive symptoms (GDS), cognition (MMSE), and attitudes towards ageing (AAQ). Reminiscence therapy positively affected older adults' quality of life (mostly the areas of mental health and social participation), and also their attitudes to ageing and old age. It reduced symptoms of depression, but had no discernible effect on cognitive function. Reminiscence therapy can positively affect selected aspects of quality of life, attitudes towards old age, and symptoms of depression in the elderly in long-term healthcare facilities. Group reminiscence therapy can be used as a nursing intervention. PMID- 29427398 TI - Financial well-being of older Australians with multiple health conditions. AB - OBJECTIVE: Given recent rises in out-of-pocket health expenses, we examined the financial well-being of older Australians with multiple health conditions and disabilities. METHODS: The 2014 General Social Survey was used to measure the: (i) current financial position; (ii) propensity to experience financial difficulties; and (iii) types of behaviours older people with multiple health conditions engage in to improve financial resilience. RESULTS: Compared to older Australians with no health conditions, respondents with multiple health conditions had lower incomes and assets and a higher propensity to hold consumer debt (once controls were included). They were at a higher risk of cash flow difficulties, dissaving to meet day-to-day living expenses and exclusion from financial providers. However, the majority of people with multiple health conditions engaged in financially resilient behaviours. CONCLUSION: Many older Australians with multiple health conditions were in a financially precarious situation with implications for the ability to afford ongoing increases in out-of pocket health-care costs. PMID- 29427399 TI - The utility of bone marrow sampling in the diagnosis and staging of lymphoma in South Africa. AB - INTRODUCTION: The bone marrow biopsy (BMB) is a diagnostic and staging tool in lymphoma that remains practically useful and relevant in resource-constrained settings, despite restricted applications in international staging guidelines, which favour less invasive nuclear medicine techniques. METHODS: Retrospective laboratory data review of BMBs in adult lymphoma patients from 2005 to 2010 to determine subtypes, rates of bone marrow involvement (BMI), human immunodeficiency virus (HIV) seroprevalence and CD4 counts, trephine length and additional findings. RESULTS: A total of 1215 BMBs reported in lymphoma included 759 newly diagnosed patients, with BMI in 43.6% of non-Hodgkin lymphoma (NHL) overall, 28.9% of high-grade B subtypes and 35.7% of Hodgkin lymphoma (HL). HIV seroprevalence was 38.8%, 53.0% and 33.9% in the 3 respective groups. There was a statistical association between BMI and HIV seropositivity in Burkitt lymphoma and HL, and BMI and CD4 count in HIV-related HL. Over 10% (n = 79) of new lymphoma cases were diagnosed by BMB with ancillary tests. Occasional histological discordance and transformation were reported in NHL. Focal/unilateral BMI was uncommon. Bilateral BMB and biopsy length exceeding 26 mm did not improve BMI detection. CONCLUSION: In the South African public sector, high HIV prevalence leads to a different lymphoma pathology profile from the developed world. High BMI rates are encountered. Here, and in similar resource constrained settings, international lymphoma staging guidelines can be logistically challenging and unaffordable. BMB remains useful in the staging and diagnosis of lymphoma. Unilateral sampling with a processed trephine length of at least 26 mm is recommended. PMID- 29427400 TI - Pharmacokinetic Interaction between Faldaprevir and Cyclosporine or Tacrolimus in Healthy Volunteers: A Prospective, Open-Label, Fixed-Sequence, Crossover Study. AB - Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single-centre, open-label, fixed-sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co-administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co-administered with FDV was similar to CsA alone. However, the AUCtau,ss and Cmax,ss of FDV were increased by 23% and 41%, respectively, when FDV was co-administered with CsA. Exposure to TAC was slightly increased (AUC0-infinity increased by 27%, no change in Cmax ) when TAC was co-administered with FDV. In contrast, exposure to FDV co-administered with TAC was similar to FDV alone. No unexpected safety findings arose from the trial. The limitations of the study (use of single, low dose of TAC and CsA, and only healthy volunteers in the trial) are discussed. PMID- 29427401 TI - Ultrasound improving the physical stability of oil-in-water emulsions stabilized by almond proteins. AB - BACKGROUND: Vegetable proteins are increasingly used to stabilize oil-in-water (O/W) emulsions. However, emulsions are thermodynamically unstable. Recently, high-intensity ultrasound (US) has been used to enhance the stability of emulsions. For these reasons, and considering almond (Prunus dulcis L.) as a good source of high-quality proteins, the aim of this work was to investigate the effect of US treatment on the stability of pre-emulsification O/W emulsions coated with almond protein isolate (API). RESULTS: The influence of API concentration (0.25-2.0 g L-1 ), ion strength (0-500 mmol L-1 NaCl), and pH (3.0 7.0) on the stability of US-treated emulsions was evaluated. US treatment (200 600 W, 25 kHz, 15 min) led to a significant reduction in the particles size of droplets in emulsions, increased critical osmotic pressure and additional protein interfacial adsorption, and thus the formation of more stable emulsions. The more unfolded and random coil structures of the proteins were detected at higher US power, facilitating protein interfacial adsorption. Increasing API concentrations resulted in higher stability of US-treated emulsions against untreated counterparts. The US-treated emulsions were more resistant to salt than untreated samples. In the range from pH 3.0 to7.0, US treatment also enhanced the physical stability of emulsions compared with untreated emulsions. CONCLUSION: US technology could be applied to produce more stable O/W food emulsions stabilized by proteins. (c) 2018 Society of Chemical Industry. PMID- 29427402 TI - Retrospective multi-phase non-contrast-enhanced magnetic resonance angiography (ROMANCE MRA) for robust angiogram separation in the presence of cardiac arrhythmia. AB - PURPOSE: To develop a novel, retrospective multi-phase non-contrast-enhanced MRA (ROMANCE MRA) in a single acquisition for robust angiogram separation even in the presence of cardiac arrhythmia. METHODS: In the proposed ROMANCE MRA, data were continuously acquired over all cardiac phases using retrospective, multi-phase flow-sensitive single-slab 3D fast spin echo (FSE) with variable refocusing flip angles, while an external pulse oximeter was in sync with pulse repetitions in FSE to record real-time information on cardiac cycles. Data were then sorted into k-bin space using the real-time cardiac information. Angiograms were reconstructed directly from k-bin space by solving a constrained optimization problem with both subtraction-induced sparsity and low rank priors. Peripheral MRA was performed in normal volunteers with/without caffeine consumption and a volunteer with cardiac arrhythmia using conventional fresh blood imaging (FBI) and the proposed ROMANCE MRA for comparison. RESULTS: The proposed ROMANCE MRA shows superior performance in accurately delineating both major and small vessel branches with robust background suppression if compared with conventional FBI. Even in the presence of irregular heartbeats, the proposed method exhibits clear depiction of angiograms over conventional methods within clinically reasonable imaging time. CONCLUSION: We successfully demonstrated the feasibility of the proposed ROMANCE MRA in generating robust angiograms with background suppression. PMID- 29427403 TI - Preface. PMID- 29427405 TI - Robust SENSE reconstruction of simultaneous multislice EPI with low-rank enhanced coil sensitivity calibration and slice-dependent 2D Nyquist ghost correction. AB - PURPOSE: To improve simultaneous multislice (SMS) EPI by robust Nyquist ghost correction in both coil sensitivity calibration and SMS reconstruction. METHODS: To derive coil sensitivity and slice-dependent phase difference map between positive- and negative-echo images, single-band EPI reference data are fully sampled with EPI parameters matched to SMS acquisition. First, the reference data are organized into positive- and negative-echo virtual channels where missing data are estimated using low-rank-based simultaneous autocalibrating and k-space estimation (SAKE) at small matrix size. The resulting ghost-free positive- and negative-echo images are combined to generate coil sensitivity maps. Second, full matrix positive- and negative-echo images are SENSE reconstructed from the reference data. Their phase difference or error map is then calculated. Last, SMS EPI is reconstructed using phase error correction SENSE (PEC-SENSE) that incorporates phase error map into coil sensitivity maps for negative-echo data. The proposed method was evaluated using both experimental data from 7T systems and simulations. RESULTS: Virtual coil SAKE eliminated Nyquist ghosts in the single-band EPI, yielding high-quality coil sensitivity maps and phase error maps. The subsequent PEC-SENSE robustly reconstructed SMS EPI under various conditions, including presence of in-plane acceleration, with lesser artifacts and higher temporal SNR than slice-dependent 1D linear correction method. CONCLUSION: The proposed procedure of virtual coil SAKE calibration and PEC-SENSE reconstruction substantially reduces all ghost-related artifacts originating either directly from SMS EPI data or indirectly from EPI-based coil sensitivity maps. It is computationally efficient, and generally applicable to all SMS EPI based applications. PMID- 29427404 TI - Interleukin-8 mediates neutrophil-endothelial interactions in pig-to-human xenogeneic models. AB - BACKGROUND: Human neutrophils are sequestered by pig lung xenografts within minutes during ex vivo perfusion. This phenomenon is not prevented by pig genetic modifications that remove xeno-antigens or added human regulatory molecules intended to down-regulate activation of complement and coagulation pathways. This study investigated whether recipient and donor interleukin-8 (IL-8), a chemokine known to attract and activate neutrophils during inflammation, is elaborated in the context of xenogeneic injury, and whether human or pig IL-8 promote the adhesion of human neutrophils in in vitro xenograft models. METHODS: Plasma levels of pig, human or non-human primate (NHP) IL-8 from ex vivo pig lung perfusion experiments (n = 10) and in vivo pig-to-baboon lung transplantation in baboons (n = 22) were analysed by ELISA or Luminex. Human neutrophils stimulated with human or pig IL-8 were analysed for CD11b expression, CD18 activation, oxidative burst and adhesion to resting or TNF-activated endothelial cells (EC) evaluated under static and flow (Bioflux) conditions. For some experiments, human neutrophils were incubated with Reparixin (IL-8/CXCL8 receptor blocker) and then analysed as in the in vitro experiments mentioned above. RESULTS: Plasma levels of pig IL-8 (~6113 pg/mL) increased more than human (~1235 pg/mL) between one and four hours after initiation of ex vivo lung perfusion. However, pig IL-8 levels remained consistently low (<60 pg/mL) and NHP IL-8 plasma levels increased by ~2000 pg/mL after four hours in a pig-to-baboon lung xenotransplantation. In vitro, human neutrophils' CD11b expression, CD18 activation and oxidative burst all increased in a dose-dependent manner following exposure to either pig or human IL-8, which also were associated with increased adhesion to EC in both static and flow conditions. Reparixin inhibited human neutrophil activation by both pig and human IL-8 in a dose-dependent fashion. At 0.1 mg/mL, Reparixin inhibited the adhesion of IL-8-activated human neutrophils to pAECs by 84 +/- 2.5%. CONCLUSIONS: Pig IL-8 increased in an ex vivo model of pig-to-human lung xenotransplantation but is not detected in vivo, whereas human or NHP IL-8 is elevated to a similar degree in both models. Both pig and human IL-8 activate human neutrophils and increase their adhesion to pig aortic ECs, a process significantly inhibited by the addition of Reparixin to human neutrophils. This work implicates IL-8, whether of pig or human origin, as a possible factor mediating in lung xenograft inflammation and injury and supports the evaluation of therapeutic targeting of this pathway in the context of xenotransplantation. PMID- 29427406 TI - Risk factors for Clostridium difficile infection in intestinal transplant recipients during the first year post-transplant. AB - BACKGROUND: Clostridium difficile is the most common cause of healthcare associated infectious diarrhea. Risk factors for C. difficile infections (CDI) in intestinal transplant recipients (ITR) are not well-defined. The aim of our study was to assess specific risk factors for CDI in ITR. METHODS: This is a 1:3 case control study that included 29 ITR who developed CDI (cases) and 87 ITR without CDI (controls) observed during the first year post-transplantation. Wilcoxon rank sum and Fisher's exact tests were used to compare variables. Univariate and multivariable conditional logistic regressions analysis were performed to identify risk factors for CDI. RESULTS: The multivariable conditional logistic regression analysis showed that proton pump inhibitors (PPI) administration (odds ratio [OR] = 0.06; 95% confidence interval [CI]: 0.007-0.52; P = .01) was the only factor associated with lower rates of CDI. Outcomes for cases vs controls: rejection episodes 24.14% vs 20.69% (P = .7), graft loss 0% vs 2.3% (P = .99), and survival rate 1 year post-transplantation 79.3% (59.6-90.1%) vs 87.2% (78.1 92.7%) (P = .38). CONCLUSIONS: Proton pump inhibitor administration might be protective for CDI in ITR. Risks factors for CDI might be different in ITR compared to other populations; anatomical differences and medications administered in the post-transplantation period may affect intestinal microbiota. PMID- 29427407 TI - Genome-wide expression reveals multiple systemic effects associated with detection of anticoagulant poisons in bobcats (Lynx rufus). AB - Anticoagulant rodenticides (ARs) are indiscriminate toxicants that threaten nontarget predatory and scavenger species through secondary poisoning. Accumulating evidence suggests that AR exposure may have disruptive sublethal consequences on individuals that can affect fitness. We evaluated AR-related effects on genome-wide expression patterns in a population of bobcats in southern California. We identify differential expression of genes involved in xenobiotic metabolism, endoplasmic reticulum stress response, epithelial integrity and both adaptive and innate immune function. Further, we find that differential expression of immune-related genes may be attributable to AR-related effects on leucocyte differentiation. Collectively, our results provide an unprecedented understanding of the sublethal effects of AR exposure on a wild carnivore. These findings highlight potential detrimental effects of ARs on a wide variety of species worldwide that may consume poisoned rodents and indicate the need to investigate gene expression effects of other toxicants added to natural environments by humans. PMID- 29427408 TI - Feasibility and validity of frailty measurement in geriatric rehabilitation. AB - OBJECTIVES: The measurement of frailty using a Frailty Index (FI) has been criticised as too time-consuming for use in hospital settings. We aimed to assess the feasibility and characteristics of an FI derived from routinely collected data. METHODS: A total of 258 participants aged 65 and older were included in a single-centre prospective cohort study conducted in inpatient geriatric rehabilitation wards. The functional independence measure (FIMTM), medication count and comorbidities were coded as deficits. RESULTS: An FI could be derived in all participants. It was normally distributed with a mean (SD) of 0.42 (0.13) and reached a submaximal limit of 0.69. Adjusting for age and sex, the odds ratio of a poor outcome (death/discharge to higher care) was 1.38 (confidence interval 1.11-1.70) per unit (0.1) increase in FI. CONCLUSION: Derivation of an FI from routinely collected data is feasible in geriatric rehabilitation settings and is predictive of poor outcomes. PMID- 29427409 TI - Utilization of Antiepileptic Medicines in Swedish Children and Adolescents with Different Diagnoses. AB - This study aimed to investigate the utilization of antiepileptic drugs (AEDs) in children and adolescents with epilepsy and other diagnoses in a nationwide population between 2007 and 2014. Data on dispensed prescriptions of AEDs were collected from the Swedish Prescribed Drug Register and linked to diagnosis data from the National Patient Register covering all in- and outpatient consultations from Swedish hospitals. Children aged 0-17 years who had received at least one prescription for AEDs were selected. We calculated proportions of patients stratified by indication, sex and type of AED. A total of 18,131 patients (mean age 9.5 years, 50% boys) were initiated on AED treatment between January 2007 and December 2014. Epilepsy was the most frequent diagnosis (46%) recorded within the year prior to the first AED dispensing. Psychiatric and pain diagnoses were more common in girls (sex distribution 70/30 and 59/41, respectively). In epilepsy, the most frequently initiated AED was valproic acid in boys and lamotrigine in girls. Lamotrigine was the most frequently initiated drug in psychiatry, in both boys and girls. This nationwide study provides new knowledge on AED use in children and adolescents. The use of AEDs during the study period was mainly restricted to epilepsy, and the individual AEDs used seems to be in accordance with approved indications. However, the use of AED on non-epilepsy diagnoses, especially pain disorders, raises concerns. PMID- 29427410 TI - Chemical reactivation of fluorescein isothiocyanate immunofluorescence-labeled resin-embedded samples. AB - Resin embedding is widely used and facilitates microscopic imaging of biological tissues. In contrast, quenching of fluorescence during embedding process hinders the application of resin embedding for imaging of fluorescence-labeled samples. For samples expressing fluorescent proteins, it has been demonstrated that the weakened fluorescence could be recovered by reactivating the fluorophore with alkaline buffer. We extended this idea to immunofluorescence-labeling technology. We showed that the fluorescence of pH-sensitive fluorescein isothiocyanate (FITC) was quenched after resin embedding but reactivated after treating by alkaline buffer. We observed 138.5% fluorescence preservation ratio of reactivated state, sixfold compared with the quenched state in embedding resin, which indicated its application for fluorescence imaging of high signal-to-background ratio. Furthermore, we analyzed the chemical reactivation mechanism of FITC fluorophore. This work would show a way for high-resolution imaging of immunofluorescence labeled samples embedded in resin. PMID- 29427413 TI - TGF-beta1 Suppresses the Type I IFN Response and Induces Mitochondrial Dysfunction in Alveolar Macrophages. AB - TGF-beta1 is a pleiotropic cytokine with an established role in fibrosis; however, the immunosuppressive effects of TGF-beta1 are less characterized. Elevated levels of TGF-beta1 are found in patients with acute and chronic lung diseases, and the underlying disease processes are exacerbated by respiratory viral infections. The alveolar macrophage is the first line of cellular defense against respiratory viral infections, and its response to infections is dependent on environmental cues. Using the mouse alveolar macrophage line, MH-S, and human CD14+ monocyte-derived macrophages, we examined the effects of TGF-beta1 on the type I IFN antiviral response, macrophage polarization, and mitochondrial bioenergetics following a challenge with human respiratory syncytial virus (RSV). Our results showed that TGF-beta1 treatment of macrophages decreased the antiviral and proinflammatory response, and suppressed basal, maximal, spare mitochondrial respiration, and mitochondrial ATP production. Challenge with RSV following TGF-beta1 treatment further exacerbated mitochondrial dysfunction. The TGF-beta1 and TGF-beta1+RSV-treated macrophages had a higher frequency of apoptosis and diminished phagocytic capacity, potentially through mitochondrial stress. Disruption of TGF-beta1 signaling or rescue of mitochondrial respiration may be novel therapeutically targetable pathways to improve macrophage function and prevent secondary bacterial infections that complicate viral respiratory infections. PMID- 29427412 TI - Galectin-3 Interacts with the CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease. AB - Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in HPS-1 and HPS-4 patients. However, the mechanisms that underlie the exaggerated injury and fibroproliferative repair responses in HPS have not been adequately defined. In particular, although Galectin-3 (Gal-3) is dysregulated in HPS, its roles in the pathogenesis of HPS have not been adequately defined. In addition, although chitinase 3-like 1 (CHI3L1) and its receptors play major roles in the injury and repair responses in HPS, the ability of Gal-3 to interact with or alter the function of these moieties has not been evaluated. In this article, we demonstrate that Gal-3 accumulates in exaggerated quantities in bronchoalveolar lavage fluids, and traffics abnormally and accumulates intracellularly in lung fibroblasts and macrophages from bleomycin-treated pale ear, HPS-1-deficient mice. We also demonstrate that Gal-3 drives epithelial apoptosis when in the extracellular space, and stimulates cell proliferation and myofibroblast differentiation when accumulated in fibroblasts and M2-like differentiation when accumulated in macrophages. Biophysical and signaling evaluations also demonstrated that Gal-3 physically interacts with IL-13Ralpha2 and CHI3L1, and competes with TMEM219 for IL-13Ralpha2 binding. By doing so, Gal-3 diminishes the antiapoptotic effects of and the antiapoptotic signaling induced by CHI3L1 in epithelial cells while augmenting macrophage Wnt/beta-catenin signaling. Thus, Gal-3 contributes to the exaggerated injury and fibroproliferative repair responses in HPS by altering the antiapoptotic and fibroproliferative effects of CHI3L1 and its receptor complex in a tissue compartment-specific manner. PMID- 29427414 TI - Simultaneous Targeting of Multiple Hemagglutinins to APCs for Induction of Broad Immunity against Influenza. AB - There is a need for vaccines that can confer broad immunity against highly diverse pathogens, such as influenza. The efficacy of conventional influenza vaccines is dependent on accurate matching of vaccines to circulating strains, but slow and limited production capacities increase the probability of vaccine mismatches. In contrast, DNA vaccination allows for rapid production of vaccines encoding novel influenza Ags. The efficacy of DNA vaccination is greatly improved if the DNA-encoded vaccine proteins target APCs. In this study, we have used hemagglutinin (HA) genes from each of six group 1 influenza viruses (H5, H6, H8, H9, H11, and H13), and inserted these into a DNA vaccine format that induces delivery of the HA protein Ags to MHC class II molecules on APCs. Each of the targeted DNA vaccines induced high titers of strain-specific anti-HA Abs. Importantly, when the six HA vaccines were mixed and injected simultaneously, the strain-specific Ab titers were maintained. In addition, the vaccine mixture induced Abs that cross-reacted with strains not included in the vaccine mixture (H1) and could protect mice against a heterosubtypic challenge with the H1 viruses A/Puerto Rico/8/1934 (H1N1) and A/California/07/2009 (H1N1). The data suggest that vaccination with a mixture of HAs could be useful for induction of strain-specific immunity against strains represented in the mixture and, in addition, confer some degree of cross-protection against unrelated influenza strains. PMID- 29427416 TI - Correction: The Effect of Inhibitory Signals on the Priming of Drug Hapten Specific T Cells That Express Distinct Vbeta Receptors. PMID- 29427415 TI - CCR8 Expression Defines Tissue-Resident Memory T Cells in Human Skin. AB - Human skin harbors two major T cell compartments of equal size that are distinguished by expression of the chemokine receptor CCR8. In vitro studies have demonstrated that CCR8 expression is regulated by TCR engagement and the skin tissue microenvironment. To extend these observations, we examined the relationship between CCR8+ and CCR8- skin T cells in vivo. Phenotypic, functional, and transcriptomic analyses revealed that CCR8+ skin T cells bear all the hallmarks of resident memory T cells, including homeostatic proliferation in response to IL-7 and IL-15, surface expression of tissue localization (CD103) and retention (CD69) markers, low levels of inhibitory receptors (programmed cell death protein 1, Tim-3, LAG-3), and a lack of senescence markers (CD57, killer cell lectin-like receptor subfamily G member 1). In contrast, CCR8- skin T cells are heterogeneous and comprise variable numbers of exhausted (programmed cell death protein 1+), senescent (CD57+, killer cell lectin-like receptor subfamily G member 1+), and effector (T-bethi, Eomeshi) T cells. Importantly, conventional and high-throughput sequencing of expressed TCR beta-chain (TRB) gene rearrangements showed that these CCR8-defined populations are clonotypically distinct, suggesting unique ontogenies in response to separate antigenic challenges and/or stimulatory conditions. Moreover, CCR8+ and CCR8- skin T cells were phenotypically stable in vitro and displayed similar levels of telomere erosion, further supporting the likelihood of a nonlinear differentiation pathway. On the basis of these results, we propose that long-lived memory T cells in human skin can be defined by the expression of CCR8. PMID- 29427418 TI - High Mutation Frequency of the PIGA Gene in T Cells Results in Reconstitution of GPI Anchor-/CD52- T Cells That Can Give Early Immune Protection after Alemtuzumab Based T Cell-Depleted Allogeneic Stem Cell Transplantation. AB - Alemtuzumab (ALM) is used for T cell depletion in the context of allogeneic hematopoietic stem cell transplantation (alloSCT) to prevent acute graft-versus host disease and graft rejection. Following ALM-based T cell-depleted alloSCT, relatively rapid recovery of circulating T cells has been described, including T cells that lack membrane expression of the GPI-anchored ALM target Ag CD52. We show, in a cohort of 89 human recipients of an ALM-based T cell-depleted alloSCT graft, that early lymphocyte reconstitution always coincided with the presence of large populations of T cells lacking CD52 membrane expression. In contrast, loss of CD52 expression was not overt within B cells or NK cells. We show that loss of CD52 expression from the T cell membrane resulted from loss of GPI anchor expression caused by a highly polyclonal mutational landscape in the PIGA gene. This polyclonal mutational landscape in the PIGA gene was also found in CD52- T cells present at a low frequency in peripheral blood of healthy donors. Finally, we demonstrate that the GPI-/CD52- T cell populations that arise after ALM-based T cell-depleted alloSCT contain functional T cells directed against multiple viral targets that can play an important role in immune protection early after ALM-based T cell-depleted transplantation. PMID- 29427417 TI - TP53 Haploinsufficiency Rescues Emergency Granulopoiesis in FANCC-/- Mice. AB - Emergency (stress) granulopoiesis is an episodic process for the production of granulocytes in response to infectious challenge. We previously determined that Fanconi C, a component of the Fanconi DNA-repair pathway, is necessary for successful emergency granulopoiesis. Fanconi anemia results from mutation of any gene in this pathway and is characterized by bone marrow failure (BMF) in childhood and clonal progression in adolescence. Although murine Fanconi anemia models exhibit relatively normal steady-state hematopoiesis, FANCC-/- mice are unable to mount an emergency granulopoiesis response. Instead, these mice develop BMF and die during repeated unsuccessful emergency granulopoiesis attempts. In FANCC-/- mice, BMF is associated with extensive apoptosis of hematopoietic stem and progenitor cells through an undefined mechanism. In this study, we find that TP53 haploinsufficiency completely rescues emergency granulopoiesis in FANCC-/- mice and protects them from BMF during repeated emergency granulopoiesis episodes. Instead, such recurrent challenges accelerated clonal progression in FANCC-/-TP53+/- mice. In FANCC-/- mice, BMF during multiple emergency granulopoiesis attempts was associated with increased ataxia telangiectasia and Rad3-related protein (Atr) and p53 activation with each attempt. In contrast, we found progressive attenuation of expression and activity of Atr, and consequent p53 activation and apoptosis, in the bone marrow of FANCC-/-TP53+/- mice during this process. Therefore, activation of Atr-with consequent Fanconi-mediated DNA repair or p53-dependent apoptosis-is an essential component of emergency granulopoiesis and it protects the bone marrow from genotoxic stress during this process. PMID- 29427419 TI - Correction: Definition of the Nature and Hapten Threshold of the beta-Lactam Antigen Required for T Cell Activation In Vitro and in Patients. PMID- 29427420 TI - Activation and Regulation of Blood Vdelta2 T Cells Are Amplified by TREM-1+ during Active Pulmonary Tuberculosis. AB - Triggering receptor expressed on myeloid cells 1 (TREM-1) is a receptor mainly expressed on myeloid cells, and it plays an important role in modulating immune response against infectious agents. The function of TREM-1 on nonmyeloid cells such as Vdelta2 T cells has not been characterized, and their role in pulmonary tuberculosis (TB) remains unclear. To assess the expression of TREM-1 on blood Vdelta2 T cells from pulmonary TB patients and investigate its mechanism of induction, we exploited flow cytometry analysis to study the expression of TREM-1 on Vdelta2 T cells from active pulmonary TB patients and control subjects. In this study we demonstrate that TREM-1 (TREM-1+) is highly expressed on Vdelta2 T cells of patients with active pulmonary TB. Unlike TREM-1--expressing Vdelta2 T cells, TREM-1+-producing Vdelta2 T cells display APC-like phenotypes. Surprisingly, TREM-1+ signaling promotes the Ag-presenting capability of Vdelta2 T cells to induce the CD4+ T cell response. TREM-1+Vdelta2 T cells induced the proliferation and differentiation of naive CD4+ T cells, as well as the elimination of intracellular mycobacteria. We identified TREM-1+ (but not TREM-1 ) as an Ag-presentation amplifier on human blood Vdelta2 T cells, and data shed new light on the regulation of Vdelta2 T cells in the phase of innate and adaptive immune responses against Mycobacterium tuberculosis infection. Targeting TREM-1+Vdelta2 T cells may be a promising approach for TB therapy. PMID- 29427421 TI - Nitrogen Cycle Evaluation (NiCE) Chip for the Simultaneous Analysis of Multiple N Cycle Associated Genes. AB - Various microorganisms play key roles in the Nitrogen (N) cycle. Quantitative PCR (qPCR) and PCR-amplicon sequencing of the N cycle functional genes allow us to analyze the abundance and diversity of microbes responsible in the N transforming reactions in various environmental samples. However, analysis of multiple target genes can be cumbersome and expensive. PCR-independent analysis, such as metagenomics and metatranscriptomics, is useful but expensive especially when we analyze multiple samples and try to detect N cycle functional genes present at relatively low abundance. Here, we present the application of microfluidic qPCR chip technology to simultaneously quantify and prepare amplicon sequence libraries for multiple N cycle functional genes as well as taxon-specific 16S rRNA gene markers for many samples. This approach, named as N cycle evaluation (NiCE) chip, was evaluated by using DNA from pure and artificially mixed bacterial cultures and by comparing the results with those obtained by conventional qPCR and amplicon sequencing methods. Quantitative results obtained by the NiCE chip were comparable to those obtained by conventional qPCR. In addition, the NiCE chip was successfully applied to examine abundance and diversity of N cycle functional genes in wastewater samples. Although non specific amplification was detected on the NiCE chip, this could be overcome by optimizing the primer sequences in the future. As the NiCE chip can provide high throughput format to quantify and prepare sequence libraries for multiple N cycle functional genes, this tool should advance our ability to explore N cycling in various samples.Importance. We report a novel approach, namely Nitrogen Cycle Evaluation (NiCE) chip by using microfluidic qPCR chip technology. By sequencing the amplicons recovered from the NiCE chip, we can assess diversities of the N cycle functional genes. The NiCE chip technology is applicable to analyze the temporal dynamics of the N cycle gene transcriptions in wastewater treatment bioreactors. The NiCE chip can provide high-throughput format to quantify and prepare sequence libraries for multiple N cycle functional genes. While there is a room for future improvement, this tool should significantly advance our ability to explore the N cycle in various environmental samples. PMID- 29427422 TI - Relative Abundances of Candida albicans and Candida glabrata in In Vitro Coculture Biofilms Impact Biofilm Structure and Formation. AB - Candida is a member of the normal human microbiota and often resides on mucosal surfaces such as the oral cavity or the gastrointestinal tract. In addition to their commensality, Candida species can opportunistically become pathogenic if the host microbiota is disrupted or if the host immune system becomes compromised. An important factor for Candida pathogenesis is its ability to form biofilm communities. The two most medically important species-Candida albicans and Candida glabrata-are often coisolated from infection sites, suggesting the importance of Candida coculture biofilms. In this work, we report that biofilm formation of the coculture population depends on the relative ratio of starting cell concentrations of C. albicans and C. glabrata When using a starting ratio of C. albicans to C. glabrata of 1:3, ~6.5- and ~2.5-fold increases in biofilm biomass were observed relative to those of a C. albicans monoculture and a C. albicans/C. glabrata ratio of 1:1, respectively. Confocal microscopy analysis revealed the heterogeneity and complex structures composed of long C. albicans hyphae and C. glabrata cell clusters in the coculture biofilms, and reverse transcription-quantitative PCR (qRT-PCR) studies showed increases in the relative expression of the HWP1 and ALS3 adhesion genes in the C. albicans/C. glabrata 1:3 biofilm compared to that in the C. albicans monoculture biofilm. Additionally, only the 1:3 C. albicans/C. glabrata biofilm demonstrated an increased resistance to the antifungal drug caspofungin. Overall, the results suggest that interspecific interactions between these two fungal pathogens increase biofilm formation and virulence-related gene expression in a coculture composition dependent manner.IMPORTANCECandida albicans and Candida glabrata are often coisolated during infection, and the occurrence of coisolation increases with increasing inflammation, suggesting possible synergistic interactions between the two Candida species in pathogenesis. During the course of an infection, the prevalence of each Candida species may change over time due to differences in metabolism and in the resistance of each species to antifungal therapies. Therefore, it is necessary to understand the dynamics between C. albicans and C. glabrata in coculture to develop better therapeutic strategies against Candida infections. Existing in vitro work has focused on understanding how an equal-part culture of C. albicans and C. glabrata impacts biofilm formation and pathogenesis. What is not understood, and what is investigated in this work, is how the composition of Candida species in coculture impacts overall biofilm formation, virulence gene expression, and the therapeutic treatment of biofilms. PMID- 29427423 TI - Effects of Environmental and Management-Associated Factors on Prevalence and Diversity of Streptococcus suis in Clinically Healthy Pig Herds in China and the United Kingdom. AB - Streptococcus suis, a global zoonosis of pigs, shows regional differences in the prevalence of human-associated disease for Asian and non-Asian countries. The isolation rates and diversities of S. suis on tonsils of healthy slaughter pigs in China and the United Kingdom were studied for effects of geography, temperature, pig age, and farm type. Isolates underwent analysis of molecular serotype and multilocus sequence type and virulence-associated genotyping. Although we found no significant difference in positive isolation rates between Chinese and UK farms, the prevalences of serotypes previously associated with human disease were significantly greater in the Chinese collection (P = 0.003). A significant effect of temperature was found on the positive isolation rate of the Chinese samples and the prevalence of human disease-associated serotypes in the UK S. suis population (China, P = 0.004; United Kingdom, P = 0.024) and on the prevalence of isolates carrying key virulence genes in China (P = 0.044). Finally, we found marked diversity among S. suis isolates, with statistically significant temperature effects on detection of multiple strain types within individual pigs. This study highlighted the high carriage prevalence and diversity of S. suis among clinically healthy pig herds of China and the United Kingdom. The significant effect of temperature on prevalence of isolation, human disease-associated serotypes, and diversity carried by individual pigs may shed new light on geographic variations in human S. suis-associated disease.IMPORTANCEStreptococcus suis is a global zoonotic pathogen and also a normal colonizer mainly carried on the tonsil of pigs. Thus, it is important to study the effect of environmental and management-associated factors on the S. suis populations in clinically healthy pigs. In this research, we investigated the similarities and differences between the S. suis populations obtained from different pig ages, seasons, and farm management systems and discovered the relationship between high climatic temperature and the prevalence of S. suis. PMID- 29427424 TI - ResDE Two-Component Regulatory System Mediates Oxygen Limitation-Induced Biofilm Formation by Bacillus amyloliquefaciens SQR9. AB - Efficient biofilm formation and root colonization capabilities facilitate the ability of beneficial plant rhizobacteria to promote plant growth and antagonize soilborne pathogens. Biofilm formation by plant-beneficial Bacillus strains is triggered by environmental cues, including oxygen deficiency, but the pathways that sense these environmental signals and regulate biofilm formation have not been thoroughly elucidated. In this study, we showed that the ResDE two-component regulatory system in the plant growth-promoting rhizobacterium Bacillus amyloliquefaciens strain SQR9 senses the oxygen deficiency signal and regulates biofilm formation. ResE is activated by sensing the oxygen limitation-induced reduction of the NAD+/NADH pool through its PAS domain, stimulating its kinase activity, and resulting in the transfer of a phosphoryl group to ResD. The phosphorylated ResD directly binds to the promoter regions of the qoxABCD and ctaCDEF operons to improve the biosynthesis of terminal oxidases, which can interact with KinB to activate biofilm formation. These results not only revealed the novel regulatory function of the ResDE two-component system but also contributed to the understanding of the complicated regulatory network governing Bacillus biofilm formation. This research may help to enhance the root colonization and the plant-beneficial efficiency of SQR9 and other Bacillus rhizobacteria used in agriculture.IMPORTANCEBacillus spp. are widely used as bioinoculants for plant growth promotion and disease suppression. The exertion of their plant-beneficial functions is largely dependent on their root colonization, which is closely related to their biofilm formation capabilities. On the other hand, Bacillus is the model bacterium for biofilm study, and the process and molecular network of biofilm formation are well characterized (B. Mielich-Suss and D. Lopez, Environ Microbiol 17:555-565, 2015, https://doi.org/10.1111/1462 2920.12527; L. S. Cairns, L. Hobley, and N. R. Stanley-Wall, Mol Microbiol 93:587 598, 2014, https://doi.org/10.1111/mmi.12697; H. Vlamakis, C. Aguilar, R. Losick, and R. Kolter, Genes Dev 22:945-953, 2008, https://doi.org/10.1101/gad.1645008; S. S. Branda, A. Vik, L. Friedman, and R. Kolter, Trends Microbiol 13:20-26, 2005, https://doi.org/10.1016/j.tim.2004.11.006; C. Aguilar, H. Vlamakis, R. Losick, and R. Kolter, Curr Opin Microbiol 10:638-643, 2007, https://doi.org/10.1016/j.mib.2007.09.006; S. S. Branda, J. E. Gonzalez-Pastor, S. Ben-Yehuda, R. Losick, and R. Kolter, Proc Natl Acad Sci U S A 98:11621-11626, 2001, https://doi.org/10.1073/pnas.191384198). However, the identification and sensing of environmental signals triggering Bacillus biofilm formation need further research. Here, we report that the oxygen deficiency signal inducing Bacillus biofilm formation is sensed by the ResDE two-component regulatory system. Our results not only revealed the novel regulatory function of the ResDE two-component regulatory system but also identified the sensing system of a biofilm-triggering signal. This knowledge can help to enhance the biofilm formation and root colonization of plant-beneficial Bacillus strains and also provide new insights of bacterial biofilm formation regulation. PMID- 29427426 TI - Geographic and Host-Associated Variations in Bacterial Communities on the Floret Surfaces of Field-Grown Broccoli. AB - Fresh vegetables harbor diverse bacterial populations on their surfaces. However, information on this microbiota is limited to a few types of fresh vegetables, and little is known about how it varies with geography and host condition. Here, we analyzed bacterial communities on the floret surfaces of 66 field-grown broccoli collected from 22 farms in four farming regions of Jeju Island, South Korea, using 454 pyrosequencing of 16S rRNA amplicons, and we determined their relationships to farming region and host-associated factors. Geographic variations in bacterial community composition and diversity were observed among farming regions, which partly reflected their relative humidity and insolation. The most abundant phyla were Proteobacteria, followed by Actinobacteria, Firmicutes, and Bacteroidetes; core operational taxonomic units (OTUs) assigned to Pseudomonas, Acinetobacter, Oxalobacteraceae, Comamonadaceae, and Enterobacteriaceae contributed to the community differences. Bacterial community composition differed between immature and mature samples, with mature samples harboring higher bacterial diversity. In comparison with communities on other types of fresh vegetables and fruits, bacterial communities on broccoli florets were unique but more similar to those of ground vegetables than to those of tree fruits/vegetables. This study presents novel data on the variability of floret associated bacterial populations of field-grown broccoli relative to environmental and host-associated factors.IMPORTANCE Fresh vegetables harbor diverse and complex bacterial populations on their surfaces. These indigenous bacteria may play a role in human and crop health; however, the diversity and variability of bacterial communities on fresh vegetables require further study. A popular crop of leafy vegetables, broccoli, is of great agricultural and industrial importance. This study provides a detailed description of the bacterial community composition and diversity on the surfaces of broccoli florets. The variability of bacterial communities is associated with the geographic location of farming sites and is affected by host growth and health. The bacterial communities specific to broccoli were identified and showed greater similarity to those found on ground vegetables than to those found on tree fruits/vegetables. This study presents novel data on the impact of environmental and host-associated conditions on the variability of floret-associated bacterial populations present on field-grown broccoli. PMID- 29427425 TI - Dissociation between iron and heme biosynthesis is largely accountable for respiration defects of Shewanella oneidensis fur mutants. AB - Iron, a major protein cofactor, is essential for most organisms but can be toxic simultaneously. Iron homeostasis thus has to be effectively maintained under a range of iron regimes. This may be particularly true with Shewanella oneidensis, a representative of dissimilatory metal-reducing bacteria (DMRB) capable of respiring a variety of chemicals as electron acceptors (EAs), including iron ores. Although iron respiration and its regulation have been extensively studied in this bacterium, how iron homeostasis is maintained remains largely unknown. Here, we report that the loss of iron homeostasis master regulator Fur negatively affects respiration of all EAs tested. This defect appears mainly to be a result of reduced cytochrome c (cyt c) production, despite a decrease in expression of reductases that are under the direct control of Fur. We also show that S. oneidensis Fur interacts with canonical Fur-box motifs in F-F-x-R configuration rather than the palindromic motif proposed before. The fur mutant has lowered total iron and increased free iron contents. Under iron-rich conditions overproduction of major iron storage protein Bfr elevates total iron levels of the fur mutant over that of the wild-type but does not affect free iron levels. Intriguingly, such an operation only marginally improves cyt c production through affecting heme b biosynthesis. It is established that iron dictates heme b/cyt c biosynthesis in S. oneidensisfur+ strains, but the fur mutation annuls the dependence of heme b/cyt c biosynthesis on iron. Overall, our results suggest that Fur has a profound impact on iron homeostasis of S. oneidensis, through which many physiological processes, especially respiration, are transformed.Importance Iron reduction is a signature of S. oneidensis and this process relies on a large number of cyts c, which per se are iron-containing proteins. Thus, iron plays an essential and special role in iron respiration, but to date the iron metabolism and regulation of the bacterium remains largely unknown. In this study, we investigated impacts of Fur, the master regulator of iron homeostasis, on respiration. The loss of Fur causes a general defect in respiration, a result of impaired cyt c production rather than specific regulation. Additionally, the fur mutant is unresponsive to iron, resulting in imbalanced iron homeostasis and dissociation between iron and cyt c production. These findings provide important insights into the iron biology of DMRB. PMID- 29427427 TI - Effect of Laser Irradiation on Cell Function and Its Implications in Raman Spectroscopy. AB - Lasers are instrumental in advanced bioimaging and Raman spectroscopy. However, they are also well known for their destructive effects on living organisms, leading to concerns about the adverse effects of laser technologies. To implement Raman spectroscopy for cell analysis and manipulation, such as Raman-activated cell sorting, it is crucial to identify nondestructive conditions for living cells. Here, we evaluated quantitatively the effect of 532-nm laser irradiation on bacterial cell fate and growth at the single-cell level. Using a purpose-built microfluidic platform, we were able to quantify the growth characteristics, i.e., specific growth rates and lag times of individual cells, as well as the survival rate of a population in conjunction with Raman spectroscopy. Representative Gram negative and Gram-positive species show similar trends in response to a laser irradiation dose. Laser irradiation could compromise the physiological function of cells, and the degree of destruction is both dose and strain dependent, ranging from reduced cell growth to a complete loss of cell metabolic activity and finally to physical disintegration. Gram-positive bacterial cells are more susceptible than Gram-negative bacterial strains to irradiation-induced damage. By directly correlating Raman acquisition with single-cell growth characteristics, we provide evidence of nondestructive characteristics of Raman spectroscopy on individual bacterial cells. However, while strong Raman signals can be obtained without causing cell death, the variety of responses from different strains and from individual cells justifies careful evaluation of Raman acquisition conditions if cell viability is critical.IMPORTANCE In Raman spectroscopy, the use of powerful monochromatic light in laser-based systems facilitates the detection of inherently weak signals. This allows environmentally and clinically relevant microorganisms to be measured at the single-cell level. The significance of being able to perform Raman measurement is that, unlike label based fluorescence techniques, it provides a "fingerprint" that is specific to the identity and state of any (unlabeled) sample. Thus, it has emerged as a powerful method for studying living cells under physiological and environmental conditions. However, the laser's high power also has the potential to kill bacteria, which leads to concerns. The research presented here is a quantitative evaluation that provides a generic platform and methodology to evaluate the effects of laser irradiation on individual bacterial cells. Furthermore, it illustrates this by determining the conditions required to nondestructively measure the spectra of representative bacteria from several different groups. PMID- 29427428 TI - Mycotoxin Biosynthesis and Central Metabolism Are Two Interlinked Pathways in Fusarium graminearum, as Demonstrated by the Extensive Metabolic Changes Induced by Caffeic Acid Exposure. AB - Fusarium graminearum is a major plant pathogen that causes devastating diseases of cereals and produces type B trichothecene (TCTB) mycotoxins in infected grains. A comprehensive understanding of the molecular and biochemical mechanisms underlying the regulation of TCTB biosynthesis is required for improving strategies to control the TCTB contamination of crops and ensuring that these strategies do not favor the production of other toxic metabolites by F. graminearum Elucidation of the association of TCTB biosynthesis with other central and specialized processes was the focus of this study. Combined 1H nuclear magnetic resonance (1H NMR) and liquid chromatography-quadrupole time of flight-mass spectrometry (LC-QTOF-MS) analyses were used to compare the exo- and endometabolomes of F. graminearum grown under toxin-inducing and -repressing caffeic acid conditions. Ninety-five metabolites were putatively or unambiguously identified, including 26 primary and 69 specialized metabolites. Our data demonstrated that the inhibition of TCTB production induced by caffeic acid exposure was associated with significant changes in the secondary and primary metabolism of F. graminearum, although the fungal growth was not affected. The main metabolic changes were an increase in the accumulation of several polyketides, including toxic ones, alterations in the tricarboxylic organic acid cycle, and modifications in the metabolism of several amino acids and sugars. While these findings provide insights into the mechanisms that govern the inhibition of TCTB production by caffeic acid, they also demonstrate the interdependence between the biosynthetic pathway of TCTB and several primary and specialized metabolic pathways. These results provide further evidence of the multifaceted role of TCTB in the life cycle of F. graminearumIMPORTANCEFusarium graminearum is a major plant pathogen that causes devastating diseases of cereal crops and produces type B trichothecene (TCTB) mycotoxins in infected grains. The best way to restrict consumer exposure to TCTB is to limit their production before harvest, which requires increasing the knowledge on the mechanisms that regulate their biosynthesis. Using a metabolomics approach, we investigated the interconnection between the TCTB production pathway and several fungal metabolic pathways. We demonstrated that alteration in the TCTB biosynthetic pathway can have a significant impact on other metabolic pathways, including the biosynthesis of toxic polyketides, and vice versa. These findings open new avenues for identifying fungal targets for the design of molecules with antimycotoxin properties and therefore improving sustainable strategies to fight against diseases caused by F. graminearum Our data further demonstrate that analyses should consider all fungal toxic metabolites rather than the targeted family of mycotoxins when assessing the efficacy of control strategies. PMID- 29427429 TI - The Madness of Microbiome: Attempting To Find Consensus "Best Practice" for 16S Microbiome Studies. AB - The development and continuous improvement of high-throughput sequencing platforms have stimulated interest in the study of complex microbial communities. Currently, the most popular sequencing approach to study microbial community composition and dynamics is targeted 16S rRNA gene metabarcoding. To prepare samples for sequencing, there are a variety of processing steps, each with the potential to introduce bias at the data analysis stage. In this short review, key information from the literature pertaining to each processing step is described, and consequently, general recommendations for future 16S rRNA gene metabarcoding experiments are made. PMID- 29427430 TI - Multiple Environmental Factors Influence the Importance of the Phosphodiesterase DipA upon Pseudomonas aeruginosa Swarming. AB - Pseudomonas aeruginosa exhibits flagellum-mediated swimming in liquid and swarming on hydrated surfaces under diverse nutrient conditions. Prior studies have implicated a phosphodiesterase, DipA, in regulating these flagellum-mediated motilities, but collectively, the necessity for DipA was unclear. In this study, we find that the medium composition conditionally constrains the influence of DipA on flagellar motility. We show that DipA exhibits more influence on minimal medium supplemented with glutamate or glucose, where flagellar motility was negated for the dipA mutant. Conversely, a dipA-deficient mutant exhibits flagellar motility when growing with LB Lennox broth and minimal medium supplemented with Casamino Acids. Swarming under these rich medium conditions occurs under elevated levels of c-di-GMP. We also demonstrate that the influence of DipA upon swimming often differs from that upon swarming, and we conclude that a direct comparison of the motility phenotypes is generally valid only when characterizing motility assay results from the same medium composition. Our results are consistent with the explanation that DipA is one of several phosphodiesterases responding to the nutrient environment sensed by P. aeruginosa On minimal medium with glutamate or glucose, DipA is dominant; however, on rich medium, the necessity of DipA is fully negated.IMPORTANCE Motile and ubiquitous bacteria such as Pseudomonas aeruginosa can quickly colonize surfaces and form biofilms in numerous environments such as water distribution systems, soil, and the human lung. To effectively disrupt bacterial colonization, it is imperative to understand how bacteria regulate motility in these different growth environments. Here, we show that the phosphodiesterase DipA is not required for flagellar motility under all nutrient conditions. Thus, the maintenance of intracellular c-di-GMP levels to promote flagellar motility or biofilm development must be conditionally regulated by differing phosphodiesterases in variation with select nutrient cues. PMID- 29427431 TI - New Insights into the Function and Global Distribution of Polyethylene Terephthalate (PET)-Degrading Bacteria and Enzymes in Marine and Terrestrial Metagenomes. AB - Polyethylene terephthalate (PET) is one of the most important synthetic polymers used today. Unfortunately, the polymers accumulate in nature and to date no highly active enzymes are known that can degrade it at high velocity. Enzymes involved in PET degradation are mainly alpha- and beta-hydrolases, like cutinases and related enzymes (EC 3.1.1). Currently, only a small number of such enzymes are well characterized. In this work, a search algorithm was developed that identified 504 possible PET hydrolase candidate genes from various databases. A further global search that comprised more than 16 Gb of sequence information within 108 marine and 25 terrestrial metagenomes obtained from the Integrated Microbial Genome (IMG) database detected 349 putative PET hydrolases. Heterologous expression of four such candidate enzymes verified the function of these enzymes and confirmed the usefulness of the developed search algorithm. In this way, two novel and thermostable enzymes with high potential for downstream application were partially characterized. Clustering of 504 novel enzyme candidates based on amino acid similarities indicated that PET hydrolases mainly occur in the phyla of Actinobacteria, Proteobacteria, and Bacteroidetes Within the Proteobacteria, the Betaproteobacteria, Deltaproteobacteria, and Gammaproteobacteria were the main hosts. Remarkably enough, in the marine environment, bacteria affiliated with the phylum Bacteroidetes appear to be the main hosts of PET hydrolase genes, rather than Actinobacteria or Proteobacteria, as observed for the terrestrial metagenomes. Our data further imply that PET hydrolases are truly rare enzymes. The highest occurrence of 1.5 hits/Mb was observed in sequences from a sample site containing crude oil.IMPORTANCE Polyethylene terephthalate (PET) accumulates in our environment without significant microbial conversion. Although a few PET hydrolases are already known, it is still unknown how frequently they appear and with which main bacterial phyla they are affiliated. In this study, deep sequence mining of protein databases and metagenomes demonstrated that PET hydrolases indeed occur at very low frequencies in the environment. Furthermore, it was possible to link them to phyla that were previously not known to harbor such enzymes. This work contributes novel knowledge on the phylogenetic relationships, the recent evolution, and the global distribution of PET hydrolases. Finally, we describe the biochemical traits of four novel PET hydrolases. PMID- 29427432 TI - A Novel Dual-cre Motif Enables Two-Way Autoregulation of CcpA in Clostridium acetobutylicum. AB - The master regulator CcpA (catabolite control protein A) manages a large and complex regulatory network that is essential for cellular physiology and metabolism in Gram-positive bacteria. Although CcpA can affect the expression of target genes by binding to a cis-acting catabolite-responsive element (cre), whether and how the expression of CcpA is regulated remain poorly explored. Here, we report a novel dual-cre motif that is employed by the CcpA in Clostridium acetobutylicum, a typical solventogenic Clostridium species, for autoregulation. Two cre sites are involved in CcpA autoregulation, and they reside in the promoter and coding regions of CcpA. In this dual-cre motif, creP, in the promoter region, positively regulates ccpA transcription, whereas creORF, in the coding region, negatively regulates this transcription, thus enabling two-way autoregulation of CcpA. Although CcpA bound creP more strongly than creORFin vitro, the in vivo assay showed that creORF-based repression dominates CcpA autoregulation during the entire fermentation. Finally, a synonymous mutation of creORF was made within the coding region, achieving an increased intracellular CcpA expression and improved cellular performance. This study provides new insights into the regulatory role of CcpA in C. acetobutylicum and, moreover, contributes a new engineering strategy for this industrial strain.IMPORTANCE CcpA is known to be a key transcription factor in Gram-positive bacteria. However, it is still unclear whether and how the intracellular CcpA level is regulated, which may be essential for maintaining normal cell physiology and metabolism. We discovered here that CcpA employs a dual-cre motif to autoregulate, enabling dynamic control of its own expression level during the entire fermentation process. This finding answers the questions above and fills a void in our understanding of the regulatory network of CcpA. Interference in CcpA autoregulation leads to improved cellular performance, providing a new useful strategy in genetic engineering of C. acetobutylicum Since CcpA is widespread in Gram-positive bacteria, including pathogens, this dual-cre-based CcpA autoregulation would be valuable for increasing our understanding of CcpA-based global regulation in bacteria. PMID- 29427433 TI - Highly sensitive detection of mutations in CHO cell recombinant DNA using multi parallel single molecule real-time DNA sequencing. AB - High-fidelity replication of biologic-encoding recombinant DNA sequences by engineered mammalian cell cultures is an essential pre-requisite for the development of stable cell lines for the production of biotherapeutics. However, immortalized mammalian cells characteristically exhibit an increased point mutation frequency compared to mammalian cells in vivo, both across their genomes and at specific loci (hotspots). Thus unforeseen mutations in recombinant DNA sequences can arise and be maintained within producer cell populations. These may affect both the stability of recombinant gene expression and give rise to protein sequence variants with variable bioactivity and immunogenicity. Rigorous quantitative assessment of recombinant DNA integrity should therefore form part of the cell line development process and be an essential quality assurance metric for instances where synthetic/multi-component assemblies are utilized to engineer mammalian cells, such as the assessment of recombinant DNA fidelity or the mutability of single-site integration target loci. Based on Pacific Biosciences (Menlo Park, CA) single molecule real-time (SMRTTM) circular consensus sequencing (CCS) technology we developed a rDNA sequence analysis tool to process the multi parallel sequencing of ~40,000 single recombinant DNA molecules. After statistical filtering of raw sequencing data, we show that this analytical method is capable of detecting single point mutations in rDNA to a minimum single mutation frequency of 0.0042% (<1/24,000 bases). Using a stable CHO transfectant pool harboring a randomly integrated 5 kB plasmid construct encoding GFP we found that 28% of recombinant plasmid copies contained at least one low frequency (<0.3%) point mutation. These mutations were predominantly found in GC base pairs (85%) and that there was no positional bias in mutation across the plasmid sequence. There was no discernable difference between the mutation frequencies of coding and non-coding DNA. The putative ratio of non-synonymous and synonymous changes within the open reading frames (ORFs) in the plasmid sequence indicates that natural selection does not impact upon the prevalence of these mutations. Here we have demonstrated the abundance of mutations that fall outside of the reported range of detection of next generation sequencing (NGS) and second generation sequencing (SGS) platforms, providing a methodology capable of being utilized in cell line development platforms to identify the fidelity of recombinant genes throughout the production process. PMID- 29427434 TI - Differentiation of 3D-shape-controlled mouse neural stem cell to neural tissues in closed agarose microchambers. AB - This paper describes three-dimensional (3D) tissue shape control of mouse neural stem cell (mNSC) micro tissues by using closed agarose microchambers for effective differentiation induction of neurons in vitro. Our agarose microchambers, made by micromolding, can be sealed with an agarose sheet to form the mNSC tissues along the shape of microchambers. We constructed lane-shaped mNSC tissues with different width (~60-210 MUm) and thickness (~25-95 MUm) dimensions and induced differentiation to neurons with differentiation medium. We found that in thick tissues (thickness: >60 MUm), distribution of differentiated neurons was not uniform, whereas in thin tissues (thickness: ~30 MUm), differentiated neurons were uniformly distributed with high differentiation efficiency. Our system to construct in vitro 3D neural tissues having uniformly distributed neurons at high differentiation ratio, could become an effective tool for drug screening using 3D neural tissues and 3D mNSC tissues under differentiation induction. PMID- 29427435 TI - Anodic electro-fermentation: Anaerobic production of L-Lysine by recombinant Corynebacterium glutamicum. AB - Microbial electrochemical technologies (MET) are promising to drive metabolic processes for the production of chemicals of interest. They provide microorganisms with an electrode as an electron sink or an electron source to stabilize their redox and/or energy state. Here, we applied an anode as additional electron sink to enhance the anoxic metabolism of the industrial bacterium Corynebacterium glutamicum through an anodic electro-fermentation. In using ferricyanide as extracellular electron carrier, anaerobic growth was enabled and the feedback-deregulated mutant Corynebacterium glutamicum lysC further accumulated L-lysine. Under such oxidizing conditions we achieved L lysine titers of 2.9 mM at rates of 0.2 mmol/L/hr. That titer is comparable to recently reported L-lysine concentrations achieved by anaerobic production under reductive conditions (cathodic electro-fermentation). However unlike other studies, our oxidative conditions allowed anaerobic cell growth, indicating an improved cellular energy supply during anodic electro-fermentation. In that light, we propose anodic electro-fermentation as the right choice to support C. glutamicum stabilizing its redox and energy state and empower a stable anaerobic production of L-lysine. PMID- 29427436 TI - Highly metastatic K7M2 cell line: A novel murine model capable of in vivo imaging via luciferase vector transfection. AB - Osteosarcoma is rare and little improvement in survival rates has occurred in the last 25 years despite modern chemotherapeutic treatment. Bioluminescent cell lines for the modeling of osteosarcoma have shown success in tracking metastases in vivo, but commonly use adenoviral vectors to transfect the native cell line with bioluminescent reporters. The purpose of this study was to develop an orthotopic model for metastatic osteosarcoma capable of in vivo monitoring of metastatic and primary tumor burden in an immunocompetent mouse and compare that model to its wild type pathogenesis. K7M2 cells were transfected using a plasmid vector and were stable after 12 weeks. Thirty-four female BALB/c mice aged 4-5 weeks underwent orthotopic implantation of either wild type (n = 12) or transfected (n = 22) K7M2 cells in the proximal tibia. Mice were monitored for tumor growth and weekly In Vivo Imaging System (IVIS) imaging was performed to monitor for pulmonary metastasis. Although tumors developed sooner in the wild type group, no significant differences were seen compared to Transfected Group 1 in rate of inoculation, growth rates after first detection, metastatic rate, and time between inoculation and death. This study establishes a new murine model for metastatic osteosarcoma using the K7M2-wt cell line transfected with a non-viral plasmid luciferase vector. The benefits of this preclinical model include an intact immune system and orthotopically driven metastatic disease; this model appears comparable to its wild type counterpart. In the future, the model may be used to examine promising immunomodulatory therapies using bioluminescence in vivo. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 29427437 TI - Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: Impact on current therapeutic strategies. AB - The presence of resistance-associated substitutions (RASs) at NS5A region might compromise the efficacy of Direct Acting Antiviral agents (DAAs). HCV resistance at NS5A region is mainly focused on patients with hepatitis C virus (HCV) genotypes 1a (G1a) and 3 (G3) with other factors of poor treatment response (ie cirrhosis, prior treatment-exposure, or HCV-RNA >800 000 IU/mL). Herein, we evaluated in a cohort of HCV G1a and G3 infected patients the prevalence of RASs at domain I NS5A using population-based sequencing and the impact of RASs on the optimization of current therapeutic strategies. The RASs considered as clinically relevant were: M28A/G/T, Q30D/E/H/G/K/L/R, L31M/V/F, H58D, and Y93C/H/N/S for G1a and Y93H for G3. A total of 232 patients naive to NS5A inhibitors were included (166 G1a, 66 G3). The overall prevalence of NS5A RASs for G1a and G3 patients was low (5.5%) or null, respectively. A high proportion of patients harbored, at least, one factor of poor response (78.9% for G1a, and 75.8% for G3). Overall, the rates of patients harboring NS5A RASs in combination with any of the other factors were low and the vast majority of patients (G1a> 94% and G3 100%) could be treated with standard treatments of 12 weeks without ribavirin. In conclusion, testing NS5A RASs in specific HCV-infected populations (ie G1a & G3, cirrhosis, prior treatment experienced, HCV-RNA >800 000 IU/mL) might be useful to optimize current NS5A-based therapies avoiding ribavirin-related toxicities, and shortening treatment duration in the majority of patients. PMID- 29427438 TI - Nanoparticle-based approaches to immune tolerance for the treatment of autoimmune diseases. AB - Autoimmune diseases are caused by antigenically complex immune responses of the adaptive and innate immune system against specific cells, tissues or organs. Antigen-specific approaches for induction of immune tolerance in autoimmunity, based on the use of antigenic peptides or proteins, have failed to deliver the desired therapeutic results in clinical trials. These approaches, which are largely relying on triggering clonal anergy and/or deletion of defined autoreactive specificities, do not address the overwhelming antigenic, molecular, and cellular complexity of most autoimmune diseases, which involve various immune cells and ever-growing repertoires of antigenic epitopes on numerous self antigens. Advances in the field of regulatory T-cell (Treg) biology have suggested that Treg cells might be able to afford dominant tolerance provided they are properly activated and expanded in vivo. More recently, nanotechnology has introduced novel technical advances capable of modulating immune responses. Here, we review nanoparticle-based approaches designed to induce immune tolerance, ranging from approaches that primarily trigger clonal T-cell anergy or deletion to approaches that trigger Treg cell formation and expansion from autoreactive T-cell effectors. We will also highlight the therapeutic potential and positive outcomes in numerous experimental models of autoimmunity. PMID- 29427439 TI - Characteristics of genetic diseases in consanguineous populations in the genomic era: Lessons from Arab communities in North Israel. AB - The health outcome of consanguineous/endogamous unions is an increased risk of autosomal recessive disorders in their progeny. This manuscript is focused on consanguineous/endogamous populations living in North Israel. Molecular tools show that spouses' relatedness and hence their risks for congenital diseases among offspring are often greater than the risk calculated on the basis of reported pedigrees. Revealing founder mutations allow for effective genetic counseling, but also induce genetic screening of the whole community in case the mutations are found to be frequent. More complex genetic mechanisms, such as co inheritance of more than one condition, allelic and even locus heterogeneity, have been identified. These mechanisms make genetic counseling more challenging but with the advancement of molecular techniques, diseases can be better deciphered. Yet, the presence of multiple mutations responsible for genetic diseases in isolated populations, and occasionally locus heterogeneity of diseases, is an unexpected phenomenon that still needs mechanistic clarification. It seems probably that addressing genetic counseling challenges and estimations of risks for genetic morbidity in consanguineous/endogamous couples will be achieved by introducing high-throughput genetic technologies into daily practice. The genomic era has expanded dramatically the translation of research products to genetic counseling tools, and this tendency is expected to yield a stronger impact in a near future. PMID- 29427440 TI - Investigation of pumping mechanism for non-Newtonian blood flow with AC electrothermal forces in a microchannel by hybrid boundary element method and immersed boundary-lattice Boltzmann method. AB - Efficient pumping of blood flow in a microfluidic device is essential for rapid detection of bacterial bloodstream infections (BSI) using alternating current (AC) electrokinetics. Compared with AC electro-osmosis (ACEO) phenomenon, the advantage of AC electrothermal (ACET) mechanism is its capability of pumping biofluids with high electrical conductivities at a relatively high AC voltage frequency. In the current work, the microfluidic pumping of non-Newtonian blood flow using ACET forces is investigated in detail by modeling its multi-physics process with hybrid boundary element method (BEM) and immersed boundary-lattice Boltzmann method (IB-LBM). The Carreau-Yasuda model is used to simulate the realistic rheological behavior of blood flow. The ACET pumping efficiency of blood flow is studied in terms of different AC voltage magnitudes and frequencies, thermal boundary conditions of electrodes, electrode configurations, channel height, and the channel length per electrode pair. Besides, the effect of rheological behavior on the blood flow velocity is theoretically analyzed by comparing with the Newtonian fluid flow using scaling law analysis under the same physical conditions. The results indicate that the rheological behavior of blood flow and its frequency-dependent dielectric property make the pumping phenomenon of blood flow different from that of the common Newtonian aqueous solutions. It is also demonstrated that using a thermally insulated electrode could enhance the pumping efficiency dramatically. Besides, the results conclude that increasing the AC voltage magnitude is a more economical pumping approach than adding the number of electrodes with the same energy consumption when the Joule heating effect is acceptable. PMID- 29427441 TI - The utility of the ankle SPECT/CT scan to predict functional and clinical outcomes in supramalleolar osteotomy patients. AB - Combined single-photon emission computed tomography and conventional computed tomography (SPECT/CT) is a hybrid imaging modality that shows a combination of metabolic and structural information about the ankle, including arthritis. We hypothesize that uptake in specific locations within the ankle joint can be associated with both clinical outcomes and may help predict which patients will have a successful SMO. Eighty-five pre-operative SMO patients with varus (37), valgus (41), or neutral (7) alignment of the hindfoot were assessed using SPECT/CT. The level of activation on SPECT/CT scans was measured. Pre and Post operative functional scores were recorded. Patients with medial gutter activation had significantly worse (p < 0.05) AOFAS alignment (AOFAS-A) scores pre operatively. Patients with varus or valgus alignment did not have any difference in VAS pain scores, but those in valgus did have worse AOFAS-P (pain) scores. Those with cystic lesions had a worse FAOS score pre-operatively. Ten patients (12.5%) had a treatment failure. Pre or post-operative alignment did not correlate to a treatment failure. The only statistically significant (p = 0.036) poor prognostic indicator was a bipolar lesion. Pre-operative SPECT/CT evaluation of an ankle before a SMO can be used to clinically correlate patient-specific factors such as pain and function in the pre and post-operative period. We caution against performing a SMO in patients with bipolar activation on a pre operative SPECT-CT scan. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2015-2021, 2018. PMID- 29427442 TI - Nose resurfacing with free fasciocutaneous flaps in burns patients. AB - BACKGROUND: Nasal reconstruction after burn injury can be challenging due to limited availability of local flaps. We present our experience of free flap reconstruction for full-thickness nasal defect after severe facial burn injury. METHODS: Between August 1998 and September 2015, six patients underwent nasal reconstruction with seven free flaps after burn injury. Among them, flame burn occurred in two patients, chemical burn in two, explosive burn in one, and contact thermal burn in one patient. The percentage of total body surface area ranged from 4% to 48%, and the face and forehead were involved in all patients. Their clinical and photographic records were retrospectively reviewed to evaluate the aesthetic results. RESULTS: Four ulnar forearm flaps, one radial forearm flap, one anterolateral thigh flap, and one medial sural artery perforator flap were used for nasal reconstruction. The nasal framework was constructed simultaneously using costal cartilage or conchal cartilage. The facial artery and vein were typically used as recipient vessels. One case each of partial necrosis and infection were noted during the average follow-up of 59 months (range, 16-126 months). Patients had satisfactory aesthetic and functional outcomes after 4.5 times (range, 2-7 times) refinement operation. CONCLUSIONS: Free flap is an applicable alternative to restore nasal skin envelope, with rebuilding the nasal framework performed in the same stage after severe facial burn injury. Through thoughtful planning and sufficient refinement, satisfactory aesthetic, and functional results are achievable. PMID- 29427444 TI - Antibody response to hepatitis B vaccine in HIV-exposed infants in Malawi and correlation with HBV infection acquisition. AB - The aim of this study was to assess the immune response to HBV vaccine in HIV exposed infants and to correlate it to HBV infection acquisition. Protective anti HBs levels (>10 mIU/mL) were found in 54/58 (93.2%) infants at 6 months, 126/144 (87.5%) at 12 months and 141/176 (80.1%) children at 24 months. HBV infection (seven children were HBsAg + at Month 24) occurred also in the presence of levels above 10 mIU/mL. Our findings indicate limited impact of HIV exposure on anti-HBV immune response, but suggest that levels >10 mIU/mL may be required to confer protection in this context. PMID- 29427443 TI - Amino acid substitutions in the hepatitis C virus core region predict hepatocarcinogenesis following eradication of HCV RNA by all-oral direct-acting antiviral regimens. AB - Impact of substitution of aa70 in the core region (Core aa70) in HCV genotype 1b (HCV-1b) on hepatocarcinogenesis following eradication of HCV RNA by direct acting antiviral therapy is not clear. In a retrospective study, 533 patients with HCV-related chronic liver disease, with sustained virological response defined as negative HCV RNA at 12 weeks after cessation of direct-acting antiviral therapy, were examined to evaluate the relationship between Core aa70 substitution and hepatocarcinogenesis. Twelve patients developed hepatocellular carcinoma during the follow-up period. The cumulative hepatocarcinogenesis rates were 1.7% and 2.4% at the end of 1 and 2 years, respectively. Overall, multivariate analysis identified HCV subgroup (HCV-1b with Gln70(His70); P = 0.003) and age (>65 years; P = 0.049), as pretreatment predictors of hepatocarcinogenesis. In HCV-1b patients, multivariate analysis identified post treatment Wisteria floribunda agglutinin positive Mac-2 binding protein (>1.8 COI; P = 0.042) and HCV subgroup (HCV-1b with Gln70(His70); P = 0.071), as predictors of hepatocarcinogenesis, including post-treatment parameter. In conclusion, Core aa70 substitution in HCV-1b at the start of direct-acting antiviral therapy is an important predictor of hepatocarcinogenesis following eradication of HCV RNA. This study emphasizes the importance of detection of Core aa70 substitution before initiating antiviral therapy. PMID- 29427445 TI - Green Tea Polyphenols Modulate Colonic Microbiota Diversity and Lipid Metabolism in High-Fat Diet Treated HFA Mice. AB - : There is an increasing interest in the effect of dietary polyphenols on the intestinal microbiota and the possible associations between this effect and the development of obesity. However, limited information is available on how these polyphenols affect the gut microbiota and lipid metabolism. The co-action of a high-fat diet (HFD) and tea polyphenol (TP) on gut microbiota and lipid metabolism using a human flora-associated (HFA) C57BL/6J mice model is studied. TP reduced serum total cholesterol, triglyceride, low density lipoprotein, glucose (GLU) and insulin (INS) levels of HFD mice in a dose-dependent manner (P < 0.01). TP also significantly increased acetic acid and butyric acid levels in HFA mice. 16S rRNA V3 region Polymerase Chain Reaction-Denaturing Gradient Gel Electrophoresis (PCR-DGGE) profiles showed that HFD mice had significantly reduced microbial diversity. This reduction could be alleviated by TP, with a significant increase in the richness and diversity of colonic microbiota in the high-fat diet with 0.2% TP (TPM) and high-fat diet with 0.05% TP (TPL) groups (P < 0.05). 454 pyrosequencing analysis showed that the HFD group had a significant increase in the Bacteroidetes to Firmicutes (F/B) ratio (P < 0.001), which could effectively be reversed by TP. The results showed that the changes in composition and diversity of colonic microbiota by TP administration suppressed the host body weight and blood lipid increase in high-fat diet HFA mice. PRACTICAL APPLICATION: A high fat diet significantly impacted gut microbiota composition and lipid metabolism in human flora-associated mice, which were largely ameliorated by tea polyphenol (TP). Therefore, TPs may be effectively used in controlling or treating obesity, hyperlipidemia and other related metabolic diseases. PMID- 29427446 TI - Erratum to: Full Analytical Solution of the Bloch Equation When Using a Hyperbolic-Secant Driving Function (Magn Reson Med 2017;77:1630-1638). PMID- 29427447 TI - Going with the flow: contextual fine-tuning of vascular reactivity. PMID- 29427448 TI - Prevalence of human papillomavirus infection in women in Bulgaria: A 2017 update. AB - The distribution and prevalence of 33 high-, medium-, and low-risk HPV genotypes were surveyed in women aged between 15 and 54 years and with normal cytology in the biggest cities and regions in Bulgaria (viz., Sofia, Plovdiv, Varna, and Burgas) and in two smaller communities (viz., Pleven and Vidin). This survey was also intended to update previous data collected in 2012 and to assess the results of a national campaign to immunize all 12-year-old girls against HPV, which was also started in 2012. The GenoFlow HPV Array Test Kit was used to analyze HPV status in cervical samples collected in 2012-2016 from 5277 women who had visited 47 gynecological clinics across the study sites. HPV infection was confirmed in 1570 (29.8%). The most common infecting genotype was HPV-16, which was detected in 687 women (13%), followed by HPV-56 in 333 women (6.3%), HPV-33 in 209 cases (4%), and HPV-31 in 190 subjects (3.6%). This is the second study to assess the prevalence of HPV infection in larger Bulgarian cities including the capital and to draw attention to the unusually high proportion of specific infecting genotypes. PMID- 29427449 TI - Butyrated ManNAc analog improves protein expression in Chinese hamster ovary cells. AB - The chemical additive sodium butyrate (NaBu) has been applied in cell culture media as a direct and convenient method to increase the protein expression in Chinese hamster ovary (CHO) and other mammalian cells. In this study, we examined an alternative chemical additive, 1,3,4-O-Bu3 ManNAc, for its effect on recombinant protein production in CHO. Supplementation with 1,3,4-O-Bu3 ManNAc for two stable CHO cell lines, expressing human erythropoietin or IgG, enhanced protein expression for both products with negligible impact on cell growth, viability, glucose utilization, and lactate accumulation. In contrast, sodium butyrate treatment resulted in a ~20% decrease in maximal viable cell density and ~30% decrease in cell viability at the end of cell cultures compared to untreated or 1,3,4-O-Bu3 ManNAc treated CHO cell lines for both products. While NaBu treatment enhanced product yields more than the 1,3,4-O-Bu3 ManNAc treatment, the NaBu treated cells also exhibited higher levels of caspase 3 positive cells using microscopy analysis. Furthermore, the mRNA levels of four cell apoptosis genes (Cul2, BAK, BAX, and BCL2L11) were up-regulated more in sodium butyrate treated wild-type, erythropoietin, or IgG expressing CHO-K1 cell lines while most of the mRNA levels of apoptosis genes in 1,3,4-O-Bu3 ManNAc treated cell lines remained equal or increased only slightly compared to the levels in untreated CHO cell lines. Finally, lectin blot analysis revealed that the 1,3,4-O-Bu3 ManNAc-treated cells displayed higher relative sialylation levels on recombinant EPO, consistent with the effect of the ManNAc component of this additive, compared to control while NaBu treatment led to lower sialylation levels than control, or 1,3,4-O-Bu3 ManNAc-treatment. These findings demonstrate that 1,3,4-O-Bu3 ManNAc has fewer negative effects on cell cytotoxicity and apoptosis, perhaps as a result of a more deliberate uptake and release of the butyrate compounds, while simultaneously increasing the expression of multiple recombinant proteins, and improving the glycosylation characteristics when applied at comparable molarity levels to NaBu. Thus, 1,3,4-O-Bu3 ManNAc represents a highly promising media additive alternative in cell culture for improving protein yields without sacrificing cell mass and product quality in future bioproduction processes. PMID- 29427450 TI - Reconstruction of the plantar toe with a distal reverse instep sensory island flap. AB - BACKGROUND: Plantar toe ulcers are a challenging surgical problem. There are several methods for reconstruction, but no attention has been given to the preservation of sensation. This report proposes a method to provide protective sensation for the reconstructed area. PATIENTS AND METHODS: The ulcers of seven patients ranged from 2 * 3 to 7 * 3 cm with defects of the plantar first toe and distal metatarsus, including four burns, a trauma, a diabetic ulcer, and a neuropathy injury reconstructed with a distal reverse instep sensory island (DRISI) flap. The patients were 21-38 years old. The second metatarsus medial nerve was co-opted using the end-to-side method to the adjacent lateral nerve, then its proximal stump provided the donor nerve for the sensation of the flap. Patients were assessed in terms of protective sensory functions, including touch, pain, dermatomeric somatosensory-evoked potentials (SEP), thermal sensation and Semmes-Weinstein monofilament (SWM) light touch. RESULTS: The flaps ranged from 2 * 3 to 7 * 3 cm. All transferred flaps to the plantar first toe survived. No complications were observed at the donor and flap sites. Patients were followed up 8-24 months. Except for two cases, all nerves of the donor and flap sites exhibited protective sensation, including positive SEP responses between 44 and 50 ms and positive SWM responses <= 3.84. CONCLUSION: The DRISI flap can be used for the reconstruction of various plantar first toe defects with acceptable protective sensation. End-to-side neurorrhaphy provides a sensory nerve end to subsequent end to end co-optation to the flap nerve for protective sensation. PMID- 29427451 TI - Species-specific detection of Candida tropicalis using evolutionary conserved intein DNA sequences. AB - : Inteins (internal proteins) are self-splicing transportable genetic elements present in conserved regions of housekeeping genes. The study highlights the importance of intein as a potential diagnostic marker for species-specific identification of Candida tropicalis, a rapidly emerging opportunistic human pathogen. Initial steps of primer validation, sequence alignment, phylogenetic tree analysis, gel electrophoresis and real-time polymerase chain reaction (PCR) assays were performed to confirm the specificity of the designed primers. The primers were selective for C. tropicalis with 100% inclusivity and showed no cross-species or cross-genera matches. The established technique is a prototype for developing multifaceted PCR assays and for point-of-care testing in near future. SIGNIFICANCE AND IMPACT OF THE STUDY: Development of molecular markers for specific detection of microbial pathogens using real-time polymerase chain reaction (PCR) is an appealing and challenging technique. A real-time PCR is an emerging technology frequently used to detect the aetiologic agents. In recent times, designing species-specific primers for pathogen detection is gaining momentum. The method offers rapid, accurate and cost-effective strategy to identify the target, thus providing sufficient time to instigate appropriate chemotherapy. The study highlights the use of intein DNA sequence as molecular markers for species-specific identification of Candida tropicalis. The study also offers a prototype model for developing multifaceted PCR assays using intein DNA sequences, and provides a developmental starting point for point-of-care testing in near future. PMID- 29427452 TI - CXCR4-CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice. AB - Antibody-secreting cells (ASCs), including short-lived plasmablasts and long lived memory plasma cells (LLPCs), contribute to autoimmune pathology. ASCs, particularly LLPCs, refractory to conventional immunosuppressive drugs pose a major therapeutic challenge. Since stromal cells expressing C-X-C motif chemokine 12 (CXCL12) organize survival niches for LLPCs in the bone marrow, we investigated the effects of CXCL12 and its ligand CXCR4 (C-X-C chemokine receptor 4) on ASCs in lupus mice (NZB/W). Fewer adoptively transferred splenic ASCs were retrieved from the bone marrow of recipient immunodeficient Rag1-/- mice when the ASCs were pretreated with the CXCR4 blocker AMD3100. CXCR4 blockade also significantly reduced anti-OVA ASCs in the bone marrow after secondary immunization with OVA. In this study, AMD3100 efficiently depleted ASCs, including LLPCs. After two weeks, it decreased the total number of ASCs in the spleen and bone marrow by more than 60%. Combination with the proteasome inhibitor bortezomib significantly enhanced the depletion effect of AMD3100. Continuous long-term (five-month) CXCR4 blockade with AMD3100 after effective short-term LLPCs depletion kept the number of LLPCs in the bone marrow low, delayed proteinuria development and prolonged the survival of the mice. These findings identify the CXCR4-CXCL12 axis as a potential therapeutic target likely due to its importance for ASC homing and survival. PMID- 29427453 TI - Intrafamiliar clinical variability of circumferential skin creases Kunze type caused by a novel heterozygous mutation of N-terminal TUBB gene. AB - Circumferential skin creases Kunze type (CSC-KT; OMIM 156610, 616734) is a rare disorder characterized by folding of excess skin, which leads to ringed creases, known as Michelin Tire Baby Syndrome (MTBS). CSC-KT patients also exhibit facial dysmorphism, growth retardation, intellectual disability (ID) and multiple congenital malformations. Recently, 2 heterozygous mutations in TUBB gene and 4 mutations (both homozygous and heterozygous) in MAPRE2 gene were identified in 3 and 4 CSC-KT patients, respectively. In the 3 TUBB gene-related CSC-KT patients, all mutations fall in the N-terminal gene domain and were de novo. Mutations in the C-terminal of TUBB gene have been associated to microcephaly and structural brain malformation, in the absence of CSC-KT features. We report a 9-year-old boy with a diagnosis of CSC-KT based on MTBS, facial dysmorphism, microcephaly, severe ID, cortical atrophy and corpus callosum hypoplasia. Sanger sequencing identified a novel heterozygous c.218T>C (p.Met73Thr) mutation in the N-terminal of TUBB gene, that was inherited from the mother affected by isolated MTBS. This is the first report of inherited TUBB gene-related CSC-KT resulting from a novel heterozygous mutation in the N-terminal domain. Present data support the role of TUBB mutations in CSC-KT and definitely includes CSC-KT syndrome within the tubulinopathies. PMID- 29427456 TI - Transition in JLB Leadership: Letter from the new Editor-in-Chief. PMID- 29427454 TI - Proteomics in biomanufacturing control: Protein dynamics of CHO-K1 cells and conditioned media during apoptosis and necrosis. AB - Cell viability has a critical impact on product quantity and quality during the biomanufacturing of therapeutic proteins. An advanced understanding of changes in the cellular and conditioned media proteomes upon cell stress and death is therefore needed for improved bioprocess control. Here, a high pH/low pH reversed phase data independent 2D-LC-MSE discovery proteomics platform was applied to study the cellular and conditioned media proteomes of CHO-K1 apoptosis and necrosis models where cell death was induced by staurosporine exposure or aeration shear in a benchtop bioreactor, respectively. Functional classification of gene ontology terms related to molecular functions, biological processes, and cellular components revealed both cell death independent and specific features. In addition, label free quantitation using the Hi3 approach resulted in a comprehensive shortlist of 23 potential cell viability marker proteins with highest abundance and a significant increase in the conditioned media upon induction of cell death, including proteins related to cellular stress response, signal mediation, cytoskeletal organization, cell differentiation, cell interaction as well as metabolic and proteolytic enzymes which are interesting candidates for translating into targeted analysis platforms for monitoring bioprocessing response and increasing process control. PMID- 29427459 TI - Acute amnestic syndrome in isolated bilateral fornix stroke. AB - BACKGROUND AND PURPOSE: Acute onset of amnestic syndrome may represent a challenging diagnostic issue. In addition to non-vascular etiology, thalamic strokes or infarction involving several temporal lobe structures have been reported. METHODS: We describe three patients in whom an isolated bilateral anterior fornix infarction presented with an acute amnestic syndrome. Clinical presentation, differential diagnosis and magnetic resonance images are discussed for each patient and vascular anatomy of the involved brain regions is also considered. RESULTS: Bilateral anterior columns of the fornix showed cytotoxic edema and bilateral narrowing of anterior cerebral artery was demonstrated. CONCLUSIONS: We suggest that bilateral fornix infarction should always be considered in the diagnostic work-up of an amnestic syndrome with acute onset. PMID- 29427460 TI - Pro-apoptotic effects of micro-ribonucleic acid-365 on retinal neurons by targeting insulin-like growth factor-1 in diabetic rats: An in vivo and in vitro study. AB - AIMS/OBJECTIVE: The present study aimed to explore the effects of micro ribonucleic acid-365 (miR-365) on apoptosis of retinal neurons by targeting insulin-like growth factor-1 (IGF-1) in diabetes mellitus rats. MATERIALS AND METHODS: High glucose-induced retinal neurons were assigned into the blank (with no plasmid transfection), negative control (with plasmid transfection), anti-miR 365 (transfected miR-365 antagomir), transfected IGF-1 short hairpin RNA plasmid (sh-IGF-1) and transfected miR-365 antagomir and IGF-1 shRNA plasmid (anti-miR 365 + sh-IGF-1) groups. Proliferation and apoptosis of retinal neurons were detected by 5-ethynyl-2'-deoxyuridine assay and Hoechst 33342 staining, respectively. Expressions of miR-365, IGF-1, Bcl-2-associated X protein (Bax) and Bcl-2 were determined by reverse transcription quantitative polymerase chain reaction and western blotting. A control group contained 10 healthy rats. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used to evaluate apoptosis of retinal neurons in rats. RESULTS: In the anti-miR-365 group, the apoptosis rate and Bax expression were reduced in comparison with the negative control and blank groups, whereas the sh-IGF-1 and anti-miR-365 + sh-IGF 1 groups presented an opposite trend. Compared with the normal group, expressions of miR-365 and Bax were increased, and expressions of IGF-1 and Bcl-2 were decreased, with more apoptotic cells in diabetes mellitus rat models. The sh-IGF 1 group had lower Bax expression, and higher expressions of IGF-1 and Bcl-2 with fewer apoptotic cells. Additionally, Bax expression was upregulated, expressions of IGF-1 and Bcl-2 were downregulated, and apoptotic cells were higher in the anti-miR-365 + sh-IGF-1 groups than the anti-miR-365 group. CONCLUSION: The results of the present study suggest that suppressed miR-365 increases the IGF-1 expression, leading to anti-apoptotic effects on retinal neurons in diabetic rats. PMID- 29427462 TI - Is diffusion magnetic resonance imaging the future biomarker to measure therapeutic efficacy in multiple sclerosis? PMID- 29427461 TI - Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms-Clinical practice among Nordic specialists. AB - BACKGROUND: Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have higher risks of developing thromboembolisms compared to the general population. International guidelines on the management of MPNs therefore include recommendations concerning thromboembolism prophylaxis. In clinical practice, strict adherence to guidelines may be challenging and dependent on factors such as physician experience, outpatient clinic setting, and access to therapy; however, no data exist on physician adherence or patient compliance to thromboembolism prophylaxis in MPNs. OBJECTIVES: The Nordic Myeloproliferative Neoplasm Study Group (NMPN) performed a survey among Nordic hematology specialists with the aim of documenting the implementation of international recommendations in a region of Northern Europe with similar healthcare systems. RESULTS: The study showed that Nordic specialists managed their patients in accordance with international guidelines concerning medical intervention, but to a lesser degree regarding the management of additional cardiovascular risk factors. The survey also drew attention to the common clinical dilemma of combining antiaggregatory agents with vitamin K antagonists (VKA), or novel oral anticoagulants (NOAC), as well as phlebotomy limits in female polycythemia vera patients. CONCLUSIONS: The results of this study highlight the importance of considering all risk factors for thrombosis and an optimal collaboration with the primary healthcare sector. PMID- 29427463 TI - Salivary levels of angiopoietin-2 in infants with infantile haemangiomas treated with and without systemic propranolol. AB - Infantile haemangiomas (IHs) with functional or cosmetic concerns necessitate systemic treatment for which propranolol is the preferred treatment. However, the mechanism of action is unknown. Mouse models suggest the angiopoietin-2 (Ang2)/Tie-2 system is implicated. Ang2 can promote endothelial growth or induce apoptosis depending on the presence of vascular endothelial growth factor. This pilot study investigates the saliva Ang2 levels in infants with IH treated with and without systemic propranolol. Patients with clinically confirmed IHs were recruited from an academic paediatric dermatology centre. Treatment was based on clinical evaluation. Saliva samples were collected over 6 months. An enzyme linked immunosorbent assay determined Ang2 levels. Ang2 levels were detectable in 45% of samples. However, by the late time point, only 28% had detectable levels. There were no changes of Ang2 over time, and there were no differences in Ang2 levels between groups. However, Ang2 levels were correlated with baseline size and changes in size from baseline. Ang2 is detectable in saliva of affected infants, but does not decrease with propranolol treatment. However, Ang2 levels are positively correlated with size and changes in size. Thus, Ang2 is not the primary factor in the mechanism of propranolol resulting in IH reduction. PMID- 29427464 TI - The expression and function of galectins in skin physiology and pathology. AB - The galectin family comprises beta-galactoside-binding proteins widely expressed in many organisms. There are at least 16 family members, which can be classified into three groups based on their carbohydrate-recognition domains. Pleiotropic functions of different galectins in physiological and pathological processes through extracellular or intracellular actions have been revealed. In the skin, galectins are expressed in a variety of cells, including keratinocytes, melanocytes, fibroblasts, dendritic cells, lymphocytes, macrophages and endothelial cells. Expression of specific galectins is reported to affect cell status, such as activation or death, and regulate the interaction between different cell types or between cells and the extracellular matrix. In vitro cellular studies, in vivo animal studies and studies of human clinical material have revealed the pathophysiologic roles of galectins in the skin. The pathogenesis of diverse non-malignant skin disorders, such as atopic dermatitis, psoriasis, contact dermatitis and wound healing, as well as skin cancers, such as melanoma, squamous cell carcinoma, basal cell carcinoma and cutaneous haematologic malignancy can be regulated by different galectins. Revelation of biological roles of galectins in skin may pave the way to future development of galectin-based therapeutic strategies for skin diseases. PMID- 29427466 TI - The assessment of online health videos for surgery in Crohn's disease. AB - AIM: YouTubeTM is an open-access, nonpeer-reviewed video-hosting site and is used as a source of publicly available healthcare information. This study aimed to assess the thematic content of the most viewed videos relating to surgery and Crohn's disease and to explore the viewer interactions with these videos. METHOD: A search of YouTubeTM was carried out using one search string. The 50 most viewed videos were identified and categorized by source and content themes and assessed for viewer interactions. Video comments were used to describe the usefulness of the video content to viewers. RESULTS: The majority of videos were uploaded by patients (n = 21).The remainder were uploaded by individual healthcare professionals (n = 9), hospital/speciality associations (n = 18) and industry (n = 2). The median number of likes for patient videos was significantly higher than for hospital/speciality association videos (P < 0.001). Patient videos received more comments praising the video content (n = 27) and more comments asking for further information (n = 14). The median number of likes for 'experience of surgery' (P < 0.001) and 'experience of disease' (P = 0.0015) themed videos were significantly higher than for 'disease management' themed videos. CONCLUSION: Crohn's disease patients use YouTubeTM as a surgical information source. The content of patient-sourced videos focused on surgical and disease experience, suggesting that these themes are important to patients. Current patient developed videos provide limited information, as reflected by viewers requesting further information. Storytelling patient-centred videos combined with clinical evidence may be a good model for future videos. PMID- 29427467 TI - Ferroelectric Liquid Crystals: Synthesis and Thermal Behavior of Optically Active, Three-Ring Schiff Bases and Salicylaldimines. AB - The chiral ferroelectric smectic C (SmC*) phase, characterized by a helical superstructure, has been well exploited in developing high-resolution microdisplays that have been effectively employed in the fabrication of a wide varieties of portable devices. Although, an overwhelming number of optically active (chiral) liquid crystals (LCs) exhibiting a SmC* phase have been designed and synthesized, the search for new systems continues so as to realize mesogens capable of meeting technical necessities and specifications for their end-use. In continuation of our research work in this direction, herein we report the design, synthesis, and thermal behavior of twenty new optically active, three-ring calamitic LCs belonging to four series. The first two series comprise five pairs of enantiomeric Schiff bases whereas the other two series are composed of five pairs of enantiomeric salicylaldimines. In each pair of optical isomers, the configuration of a chiral center in one stereoisomer is opposite to that of the analogous center in the other isomer as they are derived from (3 S)-3,7 dimethyloctyloxy and (3 R)-3,7-dimethyloctyloxy tails. To probe the structure property correlations in each series, the length of the n-alkoxy tail situated at the other end of the mesogens has been varied from n-octyloxy to n-dodecyloxy. The measurement of optical activity of these chiral mesogens was carried out by recording their specific rotations. As expected, enantiomers rotate plane polarized light in the opposite direction but by the same magnitude. The thermal behavior of the compounds was established by using a combination of optical polarizing microscopy, differential scanning calorimetry, and powder X-ray diffraction. These complementary techniques demonstrate the existence of the expected, thermodynamically stable, chiral smectic C (SmC*) LC phase besides blue phase I/II (BPI or BPII) and chiral nematic (N*) phase. However, as noted in our previous analogous study, the vast majority of the Schiff bases show an additional metastable, unfamiliar smectic (SmX) phase just below the SmC* phase. Notably, the SmC* phase persists over the temperature range ~80-115 degrees C. Two mesogens chosen each from Schiff bases and salicylaldimines were investigated for their electrical switching behavior. The study reveals the ferroelectric switching characteristics of the SmC* phase featuring the spontaneous polarization (PS ) in the range 69-96 nC cm-2 . The helical twist sense of the SmC* phase as well as the N* phase formed by a pair of enantiomeric Schiff bases and salicylaldimines has been established with the help of circular dichroism (CD) spectroscopic technique. As expected, the SmC* and the N* phase of a pair of enantiomers showed mirror image CD signals. Most importantly, the reversal of helical handedness from left to right and vice versa has been evidenced during the N* to SmC* phase transition, implying that the screw sense of the helical array of the N* phase and the SmC* phase of an enantiomer is opposite. PMID- 29427465 TI - Mangifera indica L. extract (Vimang(r)) reduces plasma and liver cholesterol and leucocyte oxidative stress in hypercholesterolemic LDL receptor deficient mice. AB - Cardiovascular diseases are major causes of death worldwide. Beyond the classical cholesterol risk factor, other conditions such as oxidative stress are well documented to promote atherosclerosis. The Mangifera indica L. extract (Vimang(r)) was reported to present antioxidant and hypocholesterolemic properties. Thus, here we evaluate the effects of Vimang treatment on risk factors of the atherosclerosis prone model of familial hypercholesterolemia, the LDL receptor knockout mice. Mice were treated with Vimang during 2 weeks and were fed a cholesterol-enriched diet during the second week. The Vimang treated mice presented significantly reduced levels of plasma (15%) and liver (20%) cholesterol, increased plasma total antioxidant capacity (10%) and decreased reactive oxygen species (ROS) production by spleen mononuclear cells (50%), P < 0.05 for all. In spite of these benefits, the average size of aortic atherosclerotic lesions stablished in this short experimental period did not change significantly in Vimang treated mice. Therefore, in this study we demonstrated that Vimang has protective effects on systemic and tissue-specific risk factors, but it is not sufficient to promote a reduction in the initial steps of atherosclerosis development. In addition, we disclosed a new antioxidant target of Vimang, the spleen mononuclear cells that might be relevant for more advanced stages of atherosclerosis. PMID- 29427468 TI - Proteomic analysis of ametryn toxicity in zebrafish embryos. AB - Ametrym (AMT) is the most widely used herbicide and frequently detected in the aquatic environment. AMT also represent a potential health risk to aquatic organisms and animals, including humans. However, little data are available on their toxicity to zebrafish (Danio rerio). The aim of the present study was to evaluate the toxicological effects of AMT exposure on zebrafish embryos. In the acute toxicity test, 6 hpf embryos were exposed to various concentrations of AMT for 24 or 48 h. The results indicated that AMT induced malformation in larvae. To investigate the toxicological mechanism on the protein expression level. A proteomic approach was employed to investigate the proteome alterations of zebra fish embryos exposed to 20 mg/L AMT for 48 h. Among 2925 unique proteins identified, 298 differential proteins (> or <1.3-fold, P < 0.05) were detected in the treated embryos as compared to the corresponding proteins in the untreated embryos. Gene ontology analysis showed that these up-regulated proteins were most involved in glycolysis, lipid transport, protein polymerization, and nucleotide binding, and the down-regulated proteins were related to microtubule-based process, protein polymerization, oxygen transport. Moreover, KEGG pathway analysis indicated that tight junction, ribosome, and oxidative phosphorylation were inhibited in the treated embryos. These findings provide new insight into the mechanisms of toxicity induced by AMT. PMID- 29427469 TI - Analysis of pancreatic volume in acute-onset, slowly-progressive and fulminant type 1 diabetes in a Japanese population. AB - AIMS/INTRODUCTION: A decrease in the size of the pancreas is observed in islet autoantibody-positive non-diabetic donors and acute-onset type 1 diabetes irrespective of the diabetes duration. Little is known, however, about the relationship between the size of the pancreas and type 1 diabetes subtypes, including fulminant type 1 diabetes. MATERIALS AND METHODS: We examined the pancreatic volume (PV) in 44 adult patients with type 1 diabetes (16 acute-onset type 1 diabetes, 18 slowly progressive type 1 diabetes and 10 fulminant type 1 diabetes) and 39 age- and body mass index-matched non-diabetic controls. PV was measured by computed tomography. The ability to secrete insulin was assessed by stimulated C-peptide after intravenous glucagon administration. RESULTS: PV was significantly correlated with bodyweight in both control participants and type 1 diabetes patients. The PV index (PVI; PV/bodyweight) was decreased by 39% in type 1 diabetes compared with that in controls. PVI was significantly decreased in acute-onset type 1 diabetes patients and slowly progressive type 1 diabetes patients (both P < 0.0001), but not in fulminant type 1 diabetes patients (P = 0.10), compared with control participants. In cases patients with recent-onset type 1 diabetes (0-7 days post-diagnosis), PVI was significantly decreased in acute-onset type 1 diabetes patients (n = 8, P = 0.0005), but not in fulminant type 1 diabetes patients (n = 7, P = 0.44), compared with controls. PVI showed no correlations with the diabetes duration, C-peptide levels, glycated hemoglobin, glutamic acid decarboxylase autoantibody levels, serum amylase or daily total insulin dose in type 1 diabetes subtypes. CONCLUSIONS: The present results show that patients with acute-onset type 1 diabetes and slowly progressive type 1 diabetes have small pancreases irrespective of the diabetes duration or C-peptide levels. In contrast to earlier findings on acute-onset type 1 diabetes, we found no reduction of PVI at the onset of fulminant type 1 diabetes. PMID- 29427470 TI - Metal-Organic Frameworks for High Charge-Discharge Rates in Lithium-Sulfur Batteries. AB - We report a new method to promote the conductivities of metal-organic frameworks (MOFs) by 5 to 7 magnitudes, thus their potential in electrochemical applications can be fully revealed. This method combines the polarity and porosity advantages of MOFs with the conductive feature of conductive polymers, in this case, polypyrrole (ppy), to construct ppy-MOF compartments for the confinement of sulfur in Li-S batteries. The performances of these ppy-S-in-MOF electrodes exceed those of their MOF and ppy counterparts, especially at high charge discharge rates. For the first time, the critical role of ion diffusion to the high rate performance was elucidated by comparing ppy-MOF compartments with different pore geometries. The ppy-S-in-PCN-224 electrode with cross-linked pores and tunnels stood out, with a high capacity of 670 and 440 mAh g-1 at 10.0 C after 200 and 1000 cycles, respectively, representing a new benchmark for long cycle performance at high rate in Li-S batteries. PMID- 29427471 TI - Modified microassay for the isolation of antimicrobial-producing, spore-forming and nonspore-forming bacteria. AB - AIMS: To develop a microassay method to detect antimicrobials produced by spore forming bacteria, thus speeding up the discovery of new antimicrobials. METHODS AND RESULTS: Environmental isolates were grown in 96-well plates, to allow production of antimicrobial agents, then treated with lysozyme and heated sequentially. Lysozyme heat treatment inhibited or prevented spore-to-cell transformation, thus eliminating interference from spore outgrowth while detecting antimicrobials by indicator bacteria. Supplementation of the indicator strain medium with 2,3,5-triphenyltetrazolium chloride, as a vital stain, made it easy to rapidly differentiate between antimicrobial-deficient (indicator growth) and antimicrobial-containing (no growth) wells. The method was used to rapidly screen 657 bacteria isolated from eight soil samples. Results revealed 46 Bacillus sp. producing antimicrobials against Listeria sp., and a Bacillus sp. producing antimicrobial(s) against Escherichia coli. CONCLUSIONS: A microassay method was successfully developed and implemented to screen and detect antimicrobial agents from spore-forming, in addition to nonspore-forming, bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Antimicrobials are needed to combat antibiotic- and preservative-resistant bacteria. Spore-forming bacteria are prolific producers of antimicrobials. This assay will speed the discovery of antimicrobials from spore-forming bacteria; these new antimicrobials are urgently needed in food and medicinal applications. PMID- 29427472 TI - Impact of serum carbohydrate antigen 19-9 level on prognosis and prediction of lymph node metastasis in patients with intrahepatic cholangiocarcinoma. AB - BACKGROUND AND AIM: Lymph node metastasis is an important prognostic factor for intrahepatic cholangiocarcinoma (ICC), but accurate preoperative diagnosis is difficult. The aim of this study was to measure the concentration of serum carbohydrate antigen 19-9 (s-CA19-9) as a preoperative predictor of lymph node metastasis. METHODS: In our department, curative-intent hepatectomy for ICC has been performed only once the absence of metastases in para-aortic lymph nodes (PALN) has been confirmed from intraoperative frozen-section pathological examinations. The present study included 13 non-resected ICC patients with PALN metastasis (PALN group) and 44 resected ICC patients without PALN metastasis (non PALN group). S-CA19-9 was examined to evaluate predictive performance for PALN metastasis and regional lymph node metastasis (pN1) from analysis of the receiver operating characteristic curve. In the non-PALN group, univariate and multivariate analyses for survival were performed on clinicopathological variables. RESULTS: From receiver operating characteristic curve analysis, s-CA19 9 showed good diagnostic accuracy for PALN metastasis (68%; cut-off, 200 U/mL) and pN1 (77%; cut-off, 100 U/mL). In univariate analysis, age (<65 years), s-CA19 9 (>=100 U/mL), portal vein resection, pN1, and positive resection margin (R1) were all identified as significant negative prognostic factors. Five-year survival rates of patients with high s-CA19-9 and pN1 were 6.9% and 7.3%, respectively. In multivariate analysis, high s-CA19-9 and R1 represented independent predictors of poor prognosis. CONCLUSIONS: Preoperative s-CA19-9 appears useful as a biomarker in patients with ICC, for predicting not only lymph node metastasis but also prognosis after surgical resection with curative intent. PMID- 29427473 TI - Antimicrobial and cytotoxic activity of silver nanoparticles synthesized from two haloalkaliphilic actinobacterial strains alone and in combination with antibiotics. AB - AIMS: Presently, the effective antimicrobial agents have been limited by the emergence of microbial strains with multidrug resistance and biofilm formation potential. In the present study, we report remarkable antimicrobial activity of silver nanoparticles (AgNPs) synthesized from Streptomyces calidiresistens IF11 and IF17 strains, including inhibition of biofilm formation and synergistic effect of AgNPs and antibiotics against selected bacteria and yeasts. Cytotoxic effect of AgNPs on mammalian cell lines was also evaluated. METHODS AND RESULTS: Analysis of biosynthesized AgNPs by Fourier Transform Infrared Spectroscopy and transmission electron microscopy revealed their spherical shape, small size in the range of 5-50 and 5-20 nm, respectively, as well as the presence of capping agents. Study of antimicrobial activity of AgNPs against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Candida albicans and Malassezia furfur evaluated by minimum inhibitory concentration (MIC) and minimum biocidal concentration (MBC) assays revealed that MICs of AgNPs from IF11 and IF17 strains against bacteria and yeasts were found to be in the range of 16-128 and 8-256 MUg ml-1 , while MBCs were in the range of 48-192 and 32-256 MUg ml-1 respectively. AgNPs inhibited biofilm formation of microbial strains, which was tested by using crystal violet stain. The highest synergistic effect determined by fractional inhibitory index of AgNPs with antibiotic (kanamycin or tetracycline) was found against Staph. aureus; while in case of yeasts, M. furfur showed highest sensitivity to AgNPs-ketoconazole combination (FIC = 0.12). The cytotoxic activity of AgNPs towards HeLa and 3T3 cell lines was studied by MTT assay. The IC50 of AgNPs estimated against mouse fibroblasts was found to be 8.3 and 28.3 MUg ml-1 and, against HeLa cell line, 28.5 and 53.8 MUg ml-1 respectively. CONCLUSIONS: It can be concluded that AgNPs synthesized from S. calidiresistens IF11 and IF17 strains have potential as an effective antimicrobial and cytotoxic agent, especially when used in combination with antibiotics/antifungal agents. SIGNIFICANCE AND IMPACT OF THE STUDY: This study indicates potential application of biogenic silver nanoparticles as an antimicrobial agent in nanomedicine. PMID- 29427474 TI - Chemical Composition and Antimicrobial Activity of Ageratina deltoidea. AB - The chemical study of Ageratina deltoidea afforded grandiflorenic acid (1), ent kaurenoic acid (2), and eight benzylbenzoates (3 - 10), two of them, 3,5 dimethoxybenzyl 2,3,6-trimethoxybenzoate (5) and 4-(beta-d-glucopyranosyloxy)-3 hydroxybenzyl 2,6-dimethoxybenzoate (9), described for the first time. In addition, the new sesquiterpene lactone deltoidin C (13), together with the known 11 and 12, the phenolic compounds: ayanin, 2,6-dimethoxybenzoic acid, methyl 3,4 dihydroxycinnamate, chlorogenic acid, and 3,5-dicaffeoylquinic acid were also isolated. The structures of these compounds were determined by spectroscopic methods and chemical reactions. The antibacterial and antifungal activities of compounds 1 - 12 were evaluated on Staphylococcus aureus, Escherichia coli, and Candida albicans. Deltoidin A (11) was the most active antibacterial agent (MIC 16.0 MUg ml-1 ) against E. coli, and the ent-kaurenoid derivatives (1 - 2) showed activity (MIC 31.0 MUg ml-1 ) against S. aureus. PMID- 29427475 TI - Application of an 8% capsaicin patch normalizes epidermal TRPV1 expression but not the decreased intraepidermal nerve fibre density in patients with brachioradial pruritus. AB - BACKGROUND: Topical capsaicin shows efficacy in the treatment of brachioradial pruritus (BRP); however, its mechanisms of action remain unclear. OBJECTIVE: The effect of capsaicin on the epidermis (i.e. peripheral expression of non-neuronal sensory receptors on keratinocytes, morphological changes in innervation) is still unknown. We aimed to investigate the effect of topical capsaicin on keratinocyte expression of TRP channels and on the intraepidermal nerve fibre density (IENFD) in patients with BRP. METHODS: Thirty-one patients with BRP received an 8% capsaicin patch. Biopsies in lesional and non-lesional skin were taken to assess epidermal morphology, keratinocyte expression of TRP channels and IENFD before and 3 weeks after treatment. RESULTS: Treatment with the capsaicin patch led to a significant decrease in itch and paresthetic symptoms (P < 0.05). Keratinocyte morphology is unaltered after capsaicin therapy. Reduced keratinocyte expression of TRPV1 in lesional skin (P = 0.009; n = 9) normalized 3 weeks after treatment (P = 0.016; n = 10), but not the IENFD, which remained reduced in lesional epidermis. CONCLUSION: The normalization of the decreased TRPV1 expression may account for the effectiveness of topical capsaicin, which does not reconstitute the reduced IENFD, arguing for a role of epidermal TRPV1 in the maintenance of BRP. PMID- 29427476 TI - The Accuracy and Prognostic Value of Point-of-care Ultrasound for Nephrolithiasis in the Emergency Department: A Systematic Review and Meta-analysis. AB - INTRODUCTION: Point-of-care ultrasound (POCUS) has been suggested as an initial investigation in the management of renal colic. Our objectives were: 1) to determine the accuracy of POCUS for the diagnosis of nephrolithiasis and 2) to assess its prognostic value in the management of renal colic. METHODS: The review protocol was registered to the PROSPERO database (CRD42016035331). An electronic database search of MEDLINE, Embase, and PubMed was conducted utilizing subject headings, keywords, and synonyms that address our research question. Bibliographies of included studies and narrative reviews were manually examined. Studies of adult emergency department patients with renal colic symptoms were included. Any degree of hydronephrosis was considered a positive POCUS finding. Accepted criterion standards were computed tomography evidence of renal stone or hydronephrosis, direct stone visualization, or surgical findings. Screening of abstracts, quality assessment with the QUADAS-2 instrument, and data extraction were performed by two reviewers, with discrepancies resolved by consensus with a third reviewer. Test performance was assessed by pooled sensitivity and specificity, calculated likelihood ratios, and a summary receiver operator curve (SROC). The secondary objective of prognostic value was reported as a narrative summary. RESULTS: The electronic search yielded 627 unique titles. After relevance screening, 26 papers underwent full-text review, and nine articles met all inclusion criteria. Of these, five high-quality studies (N = 1,773) were included in the meta-analysis for diagnostic accuracy and the remaining yielded data on prognostic value. The pooled results for sensitivity and specificity were 70.2% (95% confidence interval [CI] = 67.1%-73.2%) and 75.4% (95% CI = 72.5% 78.2%), respectively. The calculated positive and negative likelihood ratios were 2.85 and 0.39. The SROC generated did not show evidence of a threshold effect. Two of the studies in the meta-analysis found that the finding of moderate or greater hydronephrosis yielded a specificity of 94.4% (95% CI = 92.7%-95.8%). Four studies examining prognostic value noted a higher likelihood of a large stone when positive POCUS findings were present. The largest randomized trial showed lower cumulative radiation exposure and no increase in adverse events in those who received POCUS investigation as the initial renal colic investigation. CONCLUSION: Point-of-care ultrasound has modest diagnostic accuracy for diagnosing nephrolithiasis. The finding of moderate or severe hydronephrosis is highly specific for the presence of any stone, and the presence of any hydronephrosis is suggestive of a larger (>5 mm) stone in those presenting with renal colic. PMID- 29427477 TI - Cryptotanshinone reduces psoriatic epidermal hyperplasia via inhibiting the activation of STAT3. AB - The discovery of new therapeutic drugs with the efficacious and safe ability to prevent epidermal hyperplasia is extremely urgent for psoriasis. Cryptotanshinone (CTS), an active component isolated from the root of Salvia miltiorrhiza Bunge, has been reported to have antibacterial and antitumor effects. However, its effects on psoriasis have not been reported. Here, we investigated the therapeutic effects of CTS on imiquimod (IMQ)-induced psoriatic-like skin model and explored the underlying mechanisms. Our results revealed that CTS effectively alleviates IMQ-induced epidermal hyperplasia. In vitro studies also indicated that CTS potently inhibits the growth of keratinocytes. We further found that STAT3, a transcription factor for the cell growth, is the key mediator of CTS on the proliferation of keratinocytes. Taken together, our findings indicated that the curative effects of CTS on psoriasis are accomplished mainly through modulating STAT3, which providing evidences to develop CTS as a potential therapeutic agent for patients with psoriasis. PMID- 29427478 TI - From Ruling Out to Ruling In: Putting POCUS in Focus. PMID- 29427479 TI - Towards HBV curative therapies. AB - Tremendous progress has been made over the last 2 decades to discover and develop approaches to control hepatitis B virus (HBV) infections and to prevent the development of hepatocellular carcinoma using various interferons and small molecules as antiviral agents. However, none of these agents have significant impact on eliminating HBV from infected cells. Currently the emphasis is on silencing or eliminating cccDNA, which could lead to a cure for HBV. Various approaches are being developed including the development of capsid effectors, CRISPR/Cas9, TALENS, siRNA, entry and secretion inhibitors, as well as immunological approaches. It is very likely that a combination of these modalities will need to be employed to successfully eliminate HBV or prevent virus rebound on discontinuation of therapy. In the next 5 years clinical data will emerge which will provide insight on the safety and feasibility of these approaches and if they can be applied to eradicate HBV infections globally. In this review, we summarize current treatments and we highlight and examine recent therapeutic strategies that are currently being evaluated at the preclinical and clinical stage. PMID- 29427480 TI - Why not to stop antiviral treatment in patients with chronic hepatitis B. AB - Treatment of chronic hepatitis B with entecavir or tenofovir leads to viral suppression in almost all patients. However, prolonged or lifelong treatment is necessary. At present, there is no consensus among the three major guidelines for the treatment of chronic hepatitis B on whether or not to stop antiviral treatment. One of the main reasons for this controversy is that virological relapse has been well documented in patients with chronic hepatitis B who stop treatment. Relapse rate is particularly high in patients who are HBeAg-negative when treatment begins, with reported relapse rates of up to 70% 36 months after treatment discontinuation. Moreover, hepatic decompensation, jaundice and death have been described in patients with cirrhosis after treatment discontinuation. The main reason for stopping antiviral treatment is related to cost, however there is no robust evidence to support treatment discontinuation in most patients. PMID- 29427481 TI - Treatment of hepatitis C: Results in real life. AB - Direct-acting antivirals (DAAs) have transformed traditional treatment options for hepatitis C virus (HCV) infection. DAA combinations have been shown to be highly effective in reducing the burden of chronic HCV infection in clinical trials and have been recommended by the European Association for the Study of the Liver (EASL) treatment guidelines. This review examines the results of second generation DAA combinations in real-life clinical practice in patients with genotypes 1-3 and in those co-infected with HIV (real-world data in genotypes 4-6 are rare). Second generation DAAs (sofosbuvir plus daclatasvir, sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, sofosbuvir plus velpatasvir, glecaprevir plus pibrentasvir, grazoprevir plus elbasvir) have very high SVR rates and good safety profiles, higher resistance barriers and are more convenient. Real-world data in all 3 genotypes generally support the EASL guidelines and high overall sustained virological response rates are reported with recommended regimens. However, real-world data are only available for sofosbuvir plus daclatasvir, sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir. Furthermore, because of the existing level of evidence, it is difficult to define optimal regimens based on real-world data (ie, treatment duration, when to include ribavirin and options for patients with cirrhosis). The real-life challenges of managing HIV-coinfected patients are also discussed showing the additional burden of avoiding drug-drug interactions between DAAs and antiretrovirals. PMID- 29427482 TI - How to improve access to therapy in hepatitis B patients. AB - Despite the availability of a preventive vaccine and active antiviral treatments that stop disease progression and reduce the risk of hepatocellular carcinoma, hepatitis B is still a major public health problem. Only an estimated 10% of the 257 million people living with HBV have been diagnosed and as few as 1% are being adequately treated. Barriers to diagnosis and treatment include: (i) limited awareness and lack of knowledge about HBV infection and HBV-related diseases; (ii) under-diagnosis with insufficient screening and referral to care; (iii) limited treatment due to drug availability, costs, reimbursement policies and the need for long-term or life-long therapy. These barriers and the actions needed to improve access to treatment are strongly influenced by the prevalence of infection and affect middle-high vs low-middle income countries differently, where most HBV carriers are found. In high-prevalence regions and low-to middle income countries, the main challenges are availability and cost while in low prevalence regions and middle-to high-income countries low screening rates, public awareness, social stigma and discrimination play an important role. Overcoming these challenges on a global scale is a complex clinical and public health challenge and multilateral commitment from pharmaceutical companies, governments, funders and the research community is lacking. The new WHO 2016 Global Health Sector Strategy on viral hepatitis targets testing and treatment, suggesting that important but strong actions are needed from advocacy groups, scientific societies and funding agencies to foster awareness and access to cure. PMID- 29427483 TI - How to improve long-term outcome after liver transplantation? AB - The outcome of liver transplantation has markedly improved in the last 3 decades. Although early post-transplantation outcomes have improved over time, this is not true of the long-term outcome. The majority of late deaths are not related to graft dysfunction, and with the advent of new antiviral agents, recurrence of hepatitis B and hepatitis C after transplantation may no longer represent a source of graft loss and patient's death in the long term. The complications of metabolic syndrome may represent an increasing source of morbidity and mortality after transplantation. This study discusses these modifiable factors associated with late mortality to improve the long-term results of transplantation. PMID- 29427484 TI - Treatment of hepatitis C virus infection with direct-acting antiviral agents: 100% cure? AB - Around 71 million people are chronically infected with HCV worldwide. HCV antiviral drug development has been remarkable. The availability of pangenotypic direct-acting antivirals with excellent efficacy and good tolerability profiles offer a unique opportunity to achieve HCV elimination worldwide. IFN-free DAA combinations can now cure HCV in more than 95% of patients with HCV infection after 8-12 weeks of treatment. Programmes to eliminate HCV must include increased screening (risk-based and universal), linkage to care, as well as increased access to treatment worldwide. In this paper, we will review the available data on recently approved direct-acting antiviral agents, with sustained virological response that reaches almost 100%. PMID- 29427485 TI - Treatment of hepatitis C: the use of the new pangenotypic direct-acting antivirals in "special populations". AB - BACKGROUND & AIMS: The recommended combination of pangenotypic direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) associates the co formulation of 2 or 3 second-generation DAAs. In the so-called "special populations" defined as patients with chronic kidney disease (CKD), HCV/HIV co infection, HCV/HBV co-infection and an unsuccessful previous DAA regimen, these combinations have a high antiviral potency (sustained virologic response (SVR) > 95%), fair tolerance and a reduced pill burden. METHODS: We have taken into account the scientific evidence on the treatment of "special populations", in particular from the RUBY 1-2 trials, EXPEDITION 2-4 study, C-WORTHY trial, ASTRAL 5, POLARIS 1-4 studies, MAGELLAN 1 and REVENGE study. RESULTS: CKD and HCV/HIV co infection are not predictors of a non-viral response. The glecaprevir/pibentrasvir (Maviret) combination appears to be the first-line therapy for CKD patients while the sofosbuvir/vlpatasvir/voxaliprevir (Sovesi) combination is the first-line option for DAAs failures. Both are effective in patients with HIV-or HBV-HCV co-infection and should be chosen according to the potential drug-drug interaction profile. CONCLUSIONS: The notion of "special populations" is no longer pertinent with pangenotypic DAAs combinations. International guidelines recommend treating all infected patients and the next challenge is not the therapeutic choice, but to improve the limitations for screening and access to care in HCV infection. PMID- 29427486 TI - Management of patients with non-alcoholic steatohepatitis (NASH) in real life. AB - Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is a prevalent condition that is associated with the development of cirrhosis and hepatocellular carcinoma and with no approved treatment options except for lifestyle changes. Guidelines have been drafted for the management of NAFLD patients in this setting. Because of the lack of real-life cohort data, we will focus on practice surveys on the management of patients with NAFLD/NASH, which included primary care practitioners, gastroenterologists/hepatologists and other specialists from various countries. Practice patterns have been collected from interviews with practitioners or reviews of patient's files. This review discusses the screening, diagnosis and therapeutic management of NAFLD/NASH patients in real life practice, as well as adherence to guidelines. PMID- 29427487 TI - The impact of treatment of hepatitis C with DAAs on the occurrence of HCC. AB - Hepatitis C virus infection is a major cause of chronic hepatitis resulting in cirrhosis and hepatocellular carcinoma (HCC). The recent introduction of direct acting antivirals (DAA), results in sustained virological response (SVR) rates of >90% in treated patients whatever the stage of liver fibrosis with an excellent safety profile. This major advancement has allowed treatment of a larger number of patients, some with more advanced liver dysfunction and a higher risk of HCC. An SVR is associated with a reduced risk of hepatic decompensation, the need for liver transplantation and both liver-related and overall mortality. This high rate of SVR has raised hopes that there would be a significant reduction in the incidence of HCC. However, the impact of DAA-based regimens on the occurrence of HCC in patients with cirrhosis, and in particular the recurrence of HCC following successful curative treatment is controversial. Published studies suggest that DAA does not increase the risk of de novo HCC following SVR. A more controversial topic is the effect of a DAA-based SVR on the recurrence of HCC following curative treatment of early HCC. Well-designed studies with robust comparisons are needed to determine the effect of DAA on the recurrence of HCC. At present, patients with HCV cirrhosis who have undergone resection or ablation for HCC should not be dissuaded from receiving DAA therapy to prevent the progression of liver disease. Monitoring for HCC with liver imaging and AFP should be performed twice a year indefinitely post-SVR in patients with HCV cirrhosis. PMID- 29427488 TI - Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: What we need in the future. AB - The estimated prevalence of non-alcoholic fatty liver disease (NAFLD) worldwide is approximately 25%. However, the real prevalence of NAFLD and the associated disorders is unknown mainly because reliable and applicable diagnostic tests are lacking. This is further complicated by the lack of consensus on the terminology of different entities such as NAFLD or nonalcoholic steatohepatitis (NASH). Although assessing fatty infiltration in the liver is simple by ultrasound, the gold standard for the assessment of fibrosis, the only marker of progression towards more severe liver disease is still liver biopsy. Although other non invasive tests have been proposed, they must still be validated in large series. Because NAFL/NAFLD/NASH and related metabolic diseases represent an economic burden, finding an inexpensive method to diagnose and stage fatty liver is a priority. A translational approach with the use of cell and/or animal models could help to reach this goal. PMID- 29427489 TI - Stopping long-term treatment with nucleos(t)ide analogues is a favourable option for selected patients with HBeAg-negative chronic hepatitis B. AB - The immune response against the infection is impaired in patients with chronic hepatitis B, and although HBV DNA can effectively be suppressed by nucleos(t)ide analogues (NA), durable immune control is only established in a minority of patients. This especially applies in HBeAg-negative patients who usually must receive lifelong NA treatment. Calculated withdrawal of NA leads to a relapse of HBV DNA in most patients. There is evidence that this sudden exposure of viral antigens can trigger immune control in some patients which may result in HBsAg loss or a form of immune control, then sustained low HBV DNA levels and normal alanine aminotransferase (ALT). In the first prospective randomized trial investigating tenofovir treatment cessation in HBeAg-negative patients, most patients did not need retreatment after NA cessation, although all patients showed a transient relapse in HBV DNA. HBsAg loss was identified in almost 20% nearly 3 years after stopping NA. Further confirmation of these findings is needed in larger randomized trials and patients who are most likely to benefit from finite therapy must be identified to individualize NA stopping strategies. However, these results suggest that in patients without risk factors such as cirrhosis or other severe conditions, NA treatment may be stopped, as long as adequate safety rules for retreatment are followed. PMID- 29427490 TI - How to control highly endemic hepatitis B in Asia. AB - Chronic hepatitis B virus (HBV) infection is an enormous economic and social burden. Asian countries such as Vietnam, Mongolia, Laos, China, the Philippines, South Korea, Singapore and Cambodia have high or high-intermediate HBsAg prevalence. Most of the chronic HBV carriers in this region acquire their infection during early childhood or through mother-to-child transmission (MTCT). Asia has been highly successful in controlling HBV in the last 2 decades. For example, China has adopted a comprehensive strategy to control HBV and has offered universal HBV vaccination to infants since 1992. With increasing coverage and a timely birth dose of the HBV vaccine, the prevalence of HBsAg in that general population decreased from 9.75% in 1992 to 7.18% in 2006. The prevalence of HBsAg in the population <30 years old decreased from 10.1% in 1992 to 2.6% in 2014. In addition, passive and active immunization has been increased and has successfully interrupted MTCT in recent years. Recent studies in China show that maternal antiviral therapy in the late trimesters of pregnancy could further reduce MTCT in mothers with a high viral load. First-line treatments such as entecavir and tenofovir as well as pegylated interferon alpha are recommended in Chinese guidelines and are on the Basic Medical Insurance reimbursement list. Increased awareness, access to and affordability of antiviral therapy will reduce HBV-related morbidity and mortality. The combined efforts of the government, the medical community, industry, civil society and the public should eliminate hepatitis B as a public threat by 2030. PMID- 29427491 TI - Managing hepatitis C in patients with the complications of cirrhosis. AB - Direct acting antivirals (DAA) have revolutionized the treatment of hepatitis C virus (HCV). Sustained virological response rates of nearly 100% have become common in the general population. However, physicians face the growing problem of managing HCV in patients with the complications of cirrhosis, eg hepatic decompensation or hepatocellular carcinoma (HCC). Safety and efficacy remain a clinical challenge in these difficult-to-treat patients. This review focuses on the current state of knowledge and treatment regimens in patients with decompensated cirrhosis as well as the potential risk of the development of HCC following DAA therapy. PMID- 29427492 TI - Future therapy for non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease is a leading cause of chronic liver disease and can lead to cirrhosis, hepatocellular cancer and end stage liver disease. It is also associated with increased cardiovascular and cancer related morbidity and mortality. The pathogenesis of non-alcoholic fatty liver disease includes metabolic stress to the liver associated with insulin resistance with downstream cell stress from reactive oxygen species and unfolded protein response with activation of inflammatory and fibrotic pathways. There are currently no approved therapies for non-alcoholic fatty liver disease. This review summarizes ongoing efforts to establish the treatment of non-alcoholic steatohepatitis the progressive form of non-alcoholic fatty liver disease. Therapies are currently directed towards improving the metabolic status of the liver, cell stress, apoptosis, inflammation or fibrosis. Several agents are now in pivotal trials and it is expected that the first therapies will be approved in 2-3 years. PMID- 29427493 TI - The next wave of hepatitis C virus: The epidemic of intravenous drug use. AB - The epidemic of hepatitis C virus (HCV) began in the 1960s when transmission was primarily the result of blood transfusions. By 1990, when HCV was identified and a serologic test for screening donated blood was implemented, 123 million persons had already become infected worldwide and HCV was the most common cause of cirrhosis, hepatocellular carcinoma and the most common indication for liver transplantation. Approximately 75% of persons with HCV are "baby boomers" born between the years 1945 and 1965. The number of new cases of HCV declined precipitously between 1990 and 2005. The next wave of HCV began in 2005, and transmission is primarily the result of an epidemic of intravenous drug use. New cases of HCV have increased three-fold between 2005 and 2015. Approximately 50% of persons who inject drugs (PWID) have been exposed to HCV, and 25% of these persons are under the age of 25 years. The treatment of chronic HCV in PWID has two goals; treating HCV and preventing the patient from returning to drug use and becoming reinfected. Highly effective oral antiviral agents are now available and can cure HCV in virtually all patients. Treatment can be highly effective in PWID with sustained virologic response rates similar to that observed in a non-drug using population. Preventing the patient from returning to drug use and becoming reinfected with HCV is more difficult and will require that the medical and social problems associated with intravenous drug use be addressed and resolved. PMID- 29427494 TI - Diagnosis of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Non invasive tests are enough. AB - Non-alcoholic fatty liver disease is a major cause of liver disease worldwide and the most common liver disorder in Western countries, affecting around 25% of the general population. Fibrosis is the major long-term histological prognostic criteria of this disease. Liver biopsy cannot be realistically performed in such a huge population and, moreover, has well-known limitations (invasiveness, rare but potentially life-threatening complications and sampling variability). Over the past decade, there has been a growing interest in alternative novel strategies for the non-invasive evaluation of fibrosis. These tests rely on two different but complementary approaches: either measuring the levels of serum biomarkers, or liver stiffness, using ultrasound-based elastography techniques. In non-alcoholic fatty liver disease patients, transient elastography, FIB-4 and the non-alcoholic fatty liver disease fibrosis score are the best validated tests, with summary area under the ROC curve values for diagnosing severe fibrosis-cirrhosis of 0.88, 0.84 and 0.84 respectively. They can also identify the subgroup of non-alcoholic fatty liver disease patients at high risk of developing liver-related complications and death. As a result, non-invasive tests are now widely used in routine clinical practice and included in national and international guidelines. The next step is the use of non-invasive tests as first line tools for screening non-alcoholic fatty liver disease in the general population to identify patients who should be referred to specialized centres. PMID- 29427495 TI - Hepatitis B: Who and when to treat? AB - As current treatment options almost never achieve eradication of hepatitis B virus (HBV), the most realistic goal for HBV treatment is persistent inhibition of viral replication and ALT normalization. Thus, the decision to start treatment should be based on careful patient selection and individualized decisions. Treatment is generally indicated in chronic hepatitis B patients with HBV DNA >2000 IU/mL, elevated ALT and/or at least moderate histological lesions, while all patients with cirrhosis and detectable HBV DNA should be treated. Patients with HBV DNA >20 000 IU/mL and ALT >2xULN (upper limit of normal), HBV DNA >2000 IU/mL and liver stiffness >9 or >12 kPa in case of normal or <=5xULN, HBV DNA >2000 IU/mL and a family history of cirrhosis and/or HCC as well as HBeAg positive patients with HBV DNA >20 000 IU/mL and over 30 years old can begin treatment whatever the liver histology. Moreover, patients with HBV DNA >2000 IU/mL and at least moderate histological lesions can begin treatment whatever the ALT levels. Prophylactic treatment is indicated in HBV-related liver transplantation patients to prevent recurrence, in the last trimester of pregnancy in women with high viraemia to prevent vertical transmission and in patients receiving immunosuppression/chemotherapy to prevent the reactivation of HBV. Treatment is also indicated in patients with co-infections, extrahepatic manifestations and severe acute hepatitis B, or healthcare workers with viraemia. These treatment indications can only change if HBV eradication or at least HBsAg clearance can be achieved in the future in a significant proportion of patients. PMID- 29427496 TI - Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening. AB - CLDs represent an important, and certainly underestimated, global public health problem. CLDs are highly prevalent and silent, related to different, sometimes associated causes. The distribution of the causes of these diseases is slowly changing, and within the next decade, the proportion of virus-induced CLDs will certainly decrease significantly while the proportion of NASH will increase. There is an urgent need for effective global actions including education, prevention and early diagnosis to manage and treat CLDs, thus preventing cirrhosis-related morbidity and mortality. Our role is to increase the awareness of the public, healthcare professionals and public health authorities to encourage active policies for early management that will decrease the short- and long-term public health burden of these diseases. Because necroinflammation is the key mechanism in the progression of CLDs, it should be detected early. Thus, large-scale screening for CLDs is needed. ALT levels are an easy and inexpensive marker of liver necroinflammation and could be the first-line tool in this process. PMID- 29427497 TI - Diagnosis of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Why liver biopsy is essential. AB - The pattern of non-alcoholic fatty liver disease is complex with an association of several lesions, each of them related to different pathophysiological mechanisms. Despite the progress in non-invasive tools, liver biopsy remains the only diagnostic procedure that can reliably assess these various patterns, their related severity and associations. The most important difficulties of liver biopsy can be avoided if this procedure is performed by an experienced hepatologist and read by a liver pathologist. However, for obvious reasons, biopsy should be restricted to selected patients, especially in the context of clinical trials. Indeed, liver biopsy is considered mandatory by regulatory authorities as a surrogate to assess drug efficacy in Phase 3 clinical trials. In addition to the clinical diagnosis, liver biopsy can be used to score the various histological patterns of disease (NASH-CRN, SAF scores) and accurately assess the extent of fibrosis, both of which are useful when follow-up biopsies are performed. When treatment becomes available in the near future, liver biopsy could remain useful for choosing the most suitable therapeutic option based on the main predominant histological features (activity, steatosis, fibrosis). PMID- 29427498 TI - Treatment of hepatitis B: Is there still a role for interferon? AB - The treatment of chronic hepatitis B (CHB) patients is based on monotherapy with pegylated-interferon (Peg-IFN) or with one of the three most potent nucleot(s)ide analogues (NUCs) with the best resistance profiles, i.e. entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Long-term NUCs treatment can achieve virological suppression in almost all patients. However, this requires lifelong therapy, is costly and the rate of hepatitis B surface antigen (HBsAg) seroclearance is low. A one-year course of Peg-IFN has the advantage of providing immune-mediated control of the hepatitis B virus (HBV) infection, the possibility of achieving a sustained off-treatment response in nearly 30% of the patients and ultimately, HBsAg loss in approximately 30%-50% of the latter patients during long-term off treatment follow-up. However, the major limitations to the extensive use of this treatment are the need for parenteral therapy and clinical and laboratory monitoring, the side-effects profile and contraindications in certain patients and the limited effectiveness in a large proportion of patients. Nevertheless, the cost-effectiveness of Peg-IFN can be significantly increased by careful patient selection based upon baseline alanine aminotransferase (ALT), HBV DNA levels, viral genotype, host genetic variants and especially by applying early on-treatment stopping rules based upon HBsAg kinetics. Recently, because of the different mechanisms of action of Peg-IFN and NUCs, the strategy of "adding-on" or "switching to" Peg-IFN in patients being treated with NUCs to accelerate the decline in HBsAg and enhance HBsAg seroclearance rates, has provided interesting results. PMID- 29427499 TI - Is global elimination of HCV realistic? AB - The elimination of hepatitis C virus (HCV) has been made possible through the availability of new antiviral drugs which may now be administered to all patients with HCV infection, even those with decompensated cirrhosis. The goal of the World Health Organization (WHO) is to reduce the incidence of chronic hepatitis infection from the current 6-10 million to 0.9 million cases of chronic infections by 2030, and annual deaths from 1.4 million to fewer than 0.5 million. Achieving these targets will require full implementation of epidemiological knowledge of HCV infection, screening and testing practices and strategies to link HCV patients to care. This review will focus on the current state of knowledge in the epidemiology of HCV and what can be done to increase patient awareness and reduce the barriers to treatment. Furthermore, we will discuss the role of HCV clearance on the control of HCV-related outcomes. PMID- 29427501 TI - Infections complicating cirrhosis. AB - Patients with cirrhosis have a high risk of bacterial infections. Bacterial infections induce systemic inflammation that may lead to organ failure and acute on-chronic liver failure (ACLF) resulting in a high risk of short term mortality. The early diagnosis and treatment of bacterial infections is essential to improve the patient's prognosis. However, in recent years, the spread of multidrug resistant (MDR) bacterial infections has reduced the efficacy of commonly used antibiotics such as third generation cephalosporins. In patients at high risk of MDR bacteria, such as those with nosocomial infections, the early administration of broad spectrum antibiotics has been shown to improve the prognosis. However, early de-escalation of antibiotics is recommended to reduce a further increase in antibiotic resistance. Strategies to prevent acute kidney injury and other organ failures should be implemented. Although prophylaxis of bacterial infections with antibiotics improves the prognosis in selected patients, their use should be limited to patients at high risk of developing infections. In this article, we review the pathogenesis and management of bacterial infections in patients with cirrhosis. PMID- 29427500 TI - Long-term safety and efficacy of nucleo(t)side analogue therapy in hepatitis B. AB - Long-term treatment of chronic hepatitis B (CHB) with nucleos(t)ide analogues is often necessary to achieve durable viral suppression. Therefore, current guidelines recommend the most potent drugs with optimal resistance profiles. Entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line monotherapies for CHB. All of these drugs are highly effective in suppressing viral replication but with slightly different safety profiles. This review provides an overview of the long-term efficacy and safety data that have become available over the 10 years since ETV and TDF were first approved for the treatment of chronic hepatitis, and recent data on TAF in patients with CHB. PMID- 29427502 TI - Evidence of sinks and sources in the phospholipase C-activated PIP2 cycle. AB - In many eukaryotic signalling cascades, receptor-mediated phospholipase C (PLC) activity triggers phosphatidylinositol-4,5-bisphosphate (PIP2 ) hydrolysis, leading to information transfer. Coupled with PLC activation is a sequence of reactions spread across multiple compartments which resynthesize PIP2 , a process essential for supporting sustained PLC signalling. The biochemical strategies coordinating these reactions and, in particular, whether this is a closed cycle with no net addition or loss of metabolites, are poorly understood. Using mathematical models, we find that most closed PIP2 cycles cannot explain experimentally observed changes in key metabolic intermediates in particular mutants. Thus, we propose that the PIP2 cycle likely includes at least one metabolic source and one sink whose net activity results in the experimentally observed regulation of this key signalling pathway. PMID- 29427503 TI - 36-Item Short Form Survey (SF-36) Versus Gait Speed As Predictor of Preclinical Mobility Disability in Older Women: The Women's Health Initiative. AB - OBJECTIVES: To compare the value of clinically measured gait speed with that of the self-reported Medical Outcomes Study 36-item Short-Form Survey Physical Function Index (SF-36 PF) in predicting future preclinical mobility disability (PCMD) in older women. DESIGN: Prospective cohort study. SETTING: Forty clinical centers in the United States. PARTICIPANTS: Women aged 65 to 79 enrolled in the Women's Health Initiative Clinical Trials with gait speed and SF-36 assessed at baseline (1993-1998) and follow-up Years 1, 3, and 6 (N = 3,587). MEASUREMENTS: Women were categorized as nondecliners or decliners based on changes (from baseline to Year 1) in gait speed and SF-36 PF scores. Logistic regression models were used to estimate incident PCMD (gait speed <1.0 m/s) at Years 3 and 6. Area under the receiver operating characteristic curve (AUC) was used to compare the predictive value of SF-36 PF with that of measured gait speed. RESULTS: Slower baseline gait speed and lower SF-36 PF scores were associated with higher adjusted odds of PCMD at Years 3 and 6 (all P < .001). For gait speed, decliners were 2.59 times as likely to have developed PCMD as nondecliners by Year 3 and 2.35 times as likely by Year 6. Likewise, for SF-36, decliners were 1.42 times as likely to have developed PCMD by Year 3 and 1.49 times as likely by Year 6. Baseline gait speed (AUC = 0.713) was nonsignificantly better than SF-36 (AUC = 0.705) at predicting PCMD over 6 years (P = .21); including measures at a second time point significantly improved model discrimination for predicting PCMD (all P < .001). CONCLUSION: Gait speed identified PCMD risk in older women better than the SF-36 PF did, although the results may be limited given that gait speed served as a predictor and to define the PCMD outcome. Nonetheless, monitoring trajectories of change in mobility are better predictors of future mobility disability than single measures. PMID- 29427505 TI - Does the Association of Comorbidity with 1-Year Mortality After Hip Fracture Differ According to Gender? The Norwegian Epidemiologic Osteoporosis Studies (NOREPOS). AB - BACKGROUND/OBJECTIVES: Excess mortality after hip fracture is higher in men than in women. The objective was to study whether comorbidity differs in men and women with hip fracture and to what degree differences in comorbidity according to gender may explain the higher excess mortality in men. DESIGN: Population-based matched cohort covering the population aged 50 and older in Norway. SETTING: Specialist healthcare (individuals with hip fracture) and general population (controls). PARTICIPANTS: All individuals with hip fracture aged 50 and older from 2005 to 2008 (n = 32,175) and individuals without hip fracture matched 3:1 to those with hip fracture on gender, age, and county of residence (n = 96,410). MEASUREMENTS: Comorbid diagnoses were recorded during the hospital stay. Relative and absolute excess 1-year mortality in individuals with hip fracture according to gender and Charlson Comorbidity Index (CCI) were investigated using Cox regression and linear regression, respectively. RESULTS: Despite lower age (mean 78.7 vs 81.7), men had higher comorbidity than women. Compared with controls, women (hazard ratio (HR) = 6.5, 95% confidence interval (CI) = 6.2-6.9) and men (HR = 7.8, 95% CI = 7.3-8.3) with a CCI of 2 or greater were more likely to die. Women with a CCI of 2 or greater had an estimated 1-year risk of dying of 44%, and controls had an 11% risk; men with a CCI of 2 or greater had an estimated risk of dying of 53%, and controls had a 12% risk. Men were twice as likely as women to die within 1 year (HR = 2.0, 95% CI = 1.9-2.1). When adjusting for comorbidity, the difference was only slightly smaller (HR = 1.8, 95% CI = 1.7 1.8). CONCLUSION: Men had greater comorbidity than women, but this did not explain the difference according to gender in excess mortality after hip fracture. Men who fracture a hip are an especially vulnerable subpopulation, even when there is no apparent comorbidity, and warrant special attention in follow-up and care. PMID- 29427504 TI - Chronic Physical Conditions, Multimorbidity, and Mild Cognitive Impairment in Low and Middle-Income Countries. AB - OBJECTIVES: To assess the association between chronic physical conditions and multimorbidity and mild cognitive impairment (MCI) in low- and middle-income countries (LMICs). DESIGN: Nationally representative, cross-sectional, community based study. SETTING: Six countries that participated in the World Health Organization Study on Global Ageing and Adult Health. PARTICIPANTS: Individuals aged 50 and older (N=32,715; mean age 62.1 +/- 15.6; 51.7% female). MEASUREMENTS: The definition of MCI was based on the recommendations of the National Institute on Ageing and Alzheimer's Association. Ten chronic conditions were assessed (angina pectoris, arthritis, asthma, cataract, chronic lung disease, diabetes mellitus, edentulism, hearing problems, hypertension, stroke). Multivariable logistic regression analysis was conducted to assess the association between chronic physical conditions, multimorbidity (>=2 chronic conditions), and MCI. RESULTS: The prevalence of multimorbidity was 49.8% (95% confidence interval (CI)=48.1-51.5%) and of MCI was 15.3% (95% CI=14.4-16.3%). After adjustment for potential confounders, edentulism (odds ratio (OR)=1.24), arthritis (OR=1.24), chronic lung disease (OR=1.29), cataract (OR=1.33), stroke (OR=1.94), hearing problems (OR=2.27), and multimorbidity (OR=1.40) were significantly associated with MCI. There was a gradual increase in the likelihood of MCI (1 condition: OR=1.21, 95% CI=1.03-1.42; >=4 conditions: OR=2.07, 95% CI=1.70-2.52). CONCLUSION: These results highlight the need to investigate the underlying mechanisms linking chronic conditions and MCI and whether prevention or treatment of chronic conditions or multimorbidity can reduce the onset of cognitive decline and subsequent dementia, especially in LMICs. PMID- 29427506 TI - Anatomical characterization of PDF-tri neurons and peptidergic neurons associated with eclosion behavior in Drosophila. AB - The peptidergic Pigment-dispersing factor (PDF)-Tri neurons are a group of non clock neurons that appear transiently around the time of adult ecdysis (=eclosion) in the fruit fly Drosophila melanogaster. This specific developmental pattern points to a function of these neurons in eclosion or other processes that are active around pupal-adult transition. As a first step to understand the role of these neurons, we here characterize the anatomy of the PDF-Tri neurons. In addition, we describe a further set of peptidergic neurons that have been associated with eclosion behavior, eclosion hormone (EH), and crustacean cardioactive peptide (CCAP) neurons, to single cell level in the pharate adult brain. PDF-Tri neurons as well as CCAP neurons co-express a classical transmitter indicated by the occurrence of small clear vesicles in addition to dense-core vesicles containing the peptides. In the tritocerebrum, gnathal ganglion and the superior protocerebrum PDF-Tri neurites contain peptidergic varicosities and both pre- and postsynaptic sites, suggesting that the PDF-Tri neurons represent modulatory rather than pure interneurons that connect the subesophageal zone with the superior protocerebrum. The extensive overlap of PDF-Tri arborizations with neurites of CCAP- and EH-expressing neurons in distinct brain regions provides anatomical evidence for a possible function of the PDF-Tri neurons in eclosion behavior. PMID- 29427508 TI - The correlation between menopausal complaints and personality traits. AB - PURPOSE: Aim is to investigate the correlation between personality traits of menopausal women and their menopausal complaints. DESIGN AND METHODS: This cross sectional and correlation study was conducted with 400 menopausal Turkish women. FINDINGS: A positive correlation was determined between extroversion/introversion scores of Cervantes Personality Scale (CPS) and somatic and urogenital subscale scores of Menopause Rating Scale (MRS), and between emotional instability/neuroticism scores of CPS and all subscale scores of MRS. PRACTICE IMPLICATIONS: Considering the effect of personality traits on menopausal symptoms, affected groups can be identified in advance and menopausal complaints can be reduced by increasing support. PMID- 29427509 TI - Managing High-Cost Healthcare Users: The International Search for Effective Evidence-Supported Strategies. AB - High-cost healthcare users (HCUs) are a small proportion of the population who use a disproportionate amount of healthcare resources. Although the phenomenon occurs across the entire age spectrum, older adults represent the majority of HCUs. HCUs have drawn increasing attention internationally from clinicians, health policy-makers, and government administrators. Many experts have suggested that the short- and long-term sustainability of the healthcare system is threatened unless current approaches to the care and healthcare costs of this population are modified. Complex case management and care coordination models are being implemented internationally to address HCUs despite a lack of strong evidence to support their effectiveness in improving clinical outcomes or savings in costs of care. We review what is known about HCUs and the available evidence for the effectiveness of interventions designed to manage their high and costly healthcare use. PMID- 29427507 TI - Epigenetic modifications-insight into oligodendrocyte lineage progression, regeneration, and disease. AB - Myelination by oligodendrocytes in the central nervous system permits high fidelity saltatory conduction from neuronal cell bodies to axon terminals. Dysmyelinating and demyelinating disorders impair normal nervous system functions. Consequently, an understanding of oligodendrocyte differentiation that moves beyond the genetic code into the field of epigenetics is essential. Chromatin reprogramming is critical for steering stage-specific differentiation processes during oligodendrocyte development. Fine temporal control of chromatin remodeling through ATP-dependent chromatin remodelers and sequential histone modifiers shapes a chromatin regulatory landscape conducive to oligodendrocyte fate specification, lineage differentiation, and maintenance of cell identity. In this Review, we will focus on the biological functions of ATP-dependent chromatin remodelers and histone deacetylases in myelinating oligodendrocyte development and implications for myelin regeneration in neurodegenerative diseases. PMID- 29427510 TI - The supportive care needs of individuals recovering from first episode psychosis: A scoping review. AB - BACKGROUND: First episode psychosis (FEP) can be a traumatic experience that may alter an individual's ability to meet their own needs. The Supportive Care Needs Framework (SCNF) could complement the recovery-oriented, person-centred approach that is the current foundation of mental health care. AIM: To identify the supportive care needs (SCNs) of individuals recovering from a FEP. METHODS: A scoping review of the literature was undertaken. Review questions were developed, and relevant studies were identified through database and hand searches of peer reviewed journal articles. Data from selected articles were tabulated, and contextual meaning was given to the data through a process of collating, summarizing, and reporting. RESULTS: A total of 14 peer-reviewed journal articles met inclusion criteria. SCNs were identified at different stages of recovery, ranging from initial treatment to 7 years postdiagnosis. Emotional, informational, practical, psychological, and social needs were identified in over half of the included articles, while needs in the physical and spiritual domains were identified in less than five. CONCLUSIONS: Unmet needs in each of the seven domains of need of the SCNF were identified in this population. There are a number of gaps in the literature relating to the specific needs of this population and the timing for which individuals may require more supportive care in their recovery journey. PMID- 29427511 TI - Cardiorespiratory fitness not sedentary time or physical activity is associated with cardiometabolic risk in active older adults. AB - Sedentary time (ST) and moderate-to-vigorous physical activity (MVPA) are associated with cardiometabolic health. Cardiorespiratory fitness (CRF) is also implicated but often overlooked in health recommendations. This study assessed the relationships between ST, MVPA, CRF, and cardiometabolic health in highly active older individuals. 125 healthy amateur cyclists aged 55 to 79 years had their ST and MVPA levels assessed by actigraphy over a 7-day period. CRF was assessed using a maximal effort cycle ergometry test to determine VO2max with results normalized to both body mass and fat-free mass measured by DXA. Markers of cardiometabolic risk (blood glucose, triglycerides, cholesterol, HDL, LDL, Insulin, HOMA IR, blood pressure, and body fat) were assessed and used to determine cumulative cardiometabolic risk. Multiple linear regression was used to assess ST, MVPA, and CRF associations with cardiometabolic health with the relationship between activity levels and CRF determined. CRF was associated with training volume (P = .003), but not ST or MVPA. A high CRF was associated with lower cumulative cardiometabolic risk, body fat percentage, triglyceride, and HDL levels (P < .05 in all cases). MVPA was negatively associated with body fat percentage, while ST was not associated with any marker of cardiometabolic risk when adjusting for activity levels. An association between CRF and cardiometabolic risk even in a group of older individuals with high fitness levels highlights the importance that CRF may have in maintaining health. PMID- 29427512 TI - The use of brexpiprazole amongst individuals with insufficient outcomes with aripiprazole or bupropion: A case series. AB - PURPOSE: We sought to characterize the clinical experience of outpatients treated with brexpiprazole after achieving suboptimal outcomes with aripiprazole or bupropion as determined by the treating psychiatric provider. DESIGN AND METHODS: Case series; inefficacy, intolerability, or other unsatisfactory outcome to previous trial with aripiprazole or bupropion. FINDINGS: The majority of individuals in our sample exhibited tolerability of brexpiprazole. In addition, reduction in mean PHQ-9 scores was observed with brexpiprazole treatment. IMPLICATIONS: The results of our preliminary analysis suggest that a subpopulation of adults who have insufficient outcomes on aripiprazole or bupropion due to intolerability, inefficacy or other unsatisfactory outcome may benefit by switching to brexpiprazole treatment. Larger randomized controlled trials are needed, as well as sophisticated network analysis to further understand efficacy and tolerability differences between atypical antipsychotics. PMID- 29427513 TI - Effectiveness of super brain yoga for children with hyperactivity disorder. AB - PURPOSE: This study aimed at determining the effectiveness of super brain yoga for children with hyperactivity disorder. DESIGN AND METHOD: This quasiexperimental and interventional research was conducted on 80 school-age children through a pretest-posttest design. RESULTS: Results showed that there was a significant difference between the means of severity of hyperactivity disorder before (75.1) and after the intervention (63.5) (p < .001). PRACTICE IMPLICATIONS: Practicing super brain yoga reduced the symptoms of hyperactivity disorder among the school-age children. PMID- 29427515 TI - Injury, repair, inflammation and metaplasia in the stomach. AB - The development of intestinal-type gastric cancer is preceded by the emergence of metaplastic cell lineages in the gastric mucosa. In particular, intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) have been associated with the pathological progression to intestinal-type gastric cancer. The development of SPEM represents a physiological response to damage that recruits reparative cells to sites of mucosal injury. Metaplastic cell lineages are characterized by mucus secretion, adding a protective barrier to the epithelium. Increasing evidence indicates that the influence of alarmins and cytokines is required to initiate the process of metaplasia development. In particular, IL-33 derived from epithelial cells stimulates IL-13 production by specialized innate immune cells to induce chief cell transdifferentiation into SPEM following the loss of parietal cells from the corpus of the stomach. While SPEM represents a physiological healing response to acute injury, persistent injury and chronic inflammation can perpetuate a recurring pattern of reprogramming and metaplasia that is a risk factor for gastric cancer development. The transdifferentiation of zymogen secreting cells into mucous cell metaplasia may represent both a general repair mechanism in response to mucosal injury in many epithelia as well as a common pre-neoplastic pathway associated with chronic injury and inflammation. PMID- 29427516 TI - Mechanisms of CD8+ T cell-mediated suppression of HIV/SIV replication. AB - In this article, we summarize the role of CD8+ T cells during natural and antiretroviral therapy (ART)-treated HIV and SIV infections, discuss the mechanisms responsible for their suppressive activity, and review the rationale for CD8+ T cell-based HIV cure strategies. Evidence suggests that CD8+ T cells are involved in the control of virus replication during HIV and SIV infections. During early HIV infection, the cytolytic activity of CD8+ T cells is responsible for control of viremia. However, it has been proposed that CD8+ T cells also use non-cytolytic mechanisms to control SIV infection. More recently, CD8+ T cells were shown to be required to fully suppress virus production in ART-treated SIV infected macaques, suggesting that CD8+ T cells are involved in the control of virus transcription in latently infected cells that persist under ART. A better understanding of the complex antiviral activities of CD8+ T cells during HIV/SIV infection will pave the way for immune interventions aimed at harnessing these functions to target the HIV reservoir. PMID- 29427514 TI - Pseudomonas pseudoalcaligenes KF707 grown with biphenyl expresses a cytochrome caa3 oxidase that uses cytochrome c4 as electron donor. AB - Combining peroxidase activity-based heme staining (TMBZ/SDS/PAGE) with mass spectrometry analyses (Nano LC-MS/MS) of protein extracts from wild-type and appropriate mutants, we provide evidence that the polychlorinated biphenyl degrader Pseudomonas pseudoalcaligenes KF707 primarily expresses a caa3 -type cytochrome c oxidase (caa3 -Cox) using cytochrome (cyt) c4 as an electron donor in cells grown with biphenyl versus glucose as the sole carbon source. Homology modeling of KF707 caa3 -Cox using the three-dimensional structure of that from Thermus thermophilus highlights multiple similarities and differences between the proton channels in subunit I of the aa3 - and caa3 -Cox of Paracoccus and Thermus spp., respectively. To our knowledge, this is the first report demonstrating the presence of a caa3 -Cox using cyt c4 as an electron donor in a Pseudomonas species. PMID- 29427517 TI - Structural and functional characterization of the Curli adaptor protein CsgF. AB - Curli are functional amyloids that form a major part of the biofilm produced by many enterobacteriaceae. A multiprotein system around the outer membrane protein CsgG is in charge of the export and controlled propagation of the main Curli subunits, CsgA and CsgB. CsgF is essential for the linkage of the main amyloid forming proteins to the cell surface. Here, we present a profound biochemical and biophysical characterization of recombinant CsgF, highlighted by a solution NMR structure of CsgF in the presence of dihexanoylphosphocholine micelles. Interestingly, CsgF contains large unstructured domains and does not show a globular fold. The data presented shed new light on the molecular mechanism of Curli amyloid surface attachment. PMID- 29427518 TI - Multi-omics approach to elucidate the gut microbiota activity: Metaproteomics and metagenomics connection. AB - Over the last few years, the application of high-throughput meta-omics methods has provided great progress in improving the knowledge of the gut ecosystem and linking its biodiversity to host health conditions, offering complementary support to classical microbiology. Gut microbiota plays a crucial role in relevant diseases such as obesity or cardiovascular disease (CVD), and its regulation is closely influenced by several factors, such as dietary composition. In fact, polyphenol-rich diets are the most palatable treatment to prevent hypertension associated with CVD, although the polyphenol-microbiota interactions have not been completely elucidated. For this reason, the aim of this study was to evaluate microbiota effect in obese rats supplemented by hesperidin, after being fed with cafeteria or standard diet, using a multi meta-omics approaches combining strategy of metagenomics and metaproteomics analysis. We reported that cafeteria diet induces obesity, resulting in changes in the microbiota composition, which are related to functional alterations at proteome level. In addition, hesperidin supplementation alters microbiota diversity and also proteins involved in important metabolic pathways. Overall, going deeper into strategies to integrate omics sciences is necessary to understand the complex relationships between the host, gut microbiota, and diet. PMID- 29427519 TI - Quality of Hospice Care at Home Versus in an Assisted Living Facility or Nursing Home. AB - OBJECTIVES: To describe differences in perceived quality of hospice care for individuals living at home or in a nursing home (NH) or assisted living facility (ALF) through analysis of after-death surveys of family members. DESIGN: Retrospective cohort study using hospice medical record data and Family Evaluation of Hospice Care (FEHC) survey data. SETTING: Large, national hospice provider. PARTICIPANTS: Individuals who died while receiving routine hospice care and family caregivers who completed after-death quality-of-care surveys. MEASUREMENTS: Survey results for 7,510 individuals were analyzed using analysis of variance and chi-square tests. Logistic regression was used to assess relationship between location of care and overall service quality. RESULTS: The overall survey response rate was 27%; 34.5% of families of individuals in ALFs in hospice, 27.4% of those at home, and 22.9% of those in NHs returned the survey (P < .001). Differences in return rate according to primary diagnosis were significant, although differences were not large. Most (84.3%) respondents reported that hospice referral had occurred at the right time, and 63.4% rated service quality as excellent. Hospice care in the NH was less likely to be perceived as excellent. CONCLUSION: There were significant differences in characteristics of individuals whose family members did and did not return surveys, which has implications for use of after-death surveys to evaluate hospice quality. Lower perceived quality of hospice care in NHs may be related to general dissatisfaction with receiving care in this setting. Survey results have the potential to set priorities for quality improvement, choice of provider, and potentially reimbursement. Underlying causes of differences of perceived quality in different settings of care should be examined. PMID- 29427521 TI - Neglected sexual needs: A qualitative study in Iranian patients with severe mental illness. AB - BACKGROUND: This paper has attempted to explore views of patients with severe mental illness and their care providers about sharing sexual problems with care providers in these patients within the context of Iran. METHOD: A total of 17 in depth semi-structured interviews were conducted in one of the psychiatric hospital in Tehran: 4 with patients, 2 with patient's family, and 11 with health providers who had been employed for 5 years in psychiatric wards at least. All participants were selected by purposive sampling. Using conventional qualitative content analysis data reduction was done. FINDINGS: A total of 89 codes about the reasons for lack of communication between clinician and patients, about sexuality were extracted. These are classified in two categories. The first is "Clinicians avoidance from addressing sexual issues" and second is "Patients avoidance from expressing their sexual problems." CONCLUSION: Despite having sexual needs, severe mental illnesses patients do not disclose it due to poor communication between clinician and patients, about sexuality. So, physician had to be pioneer in communicating with them. Therefore, to enhance clinicians' sexual knowledge and effective communication skills with patients, especially those with severe mental illnesses, training is completely necessary. PMID- 29427520 TI - Comprehensive review of genetic factors contributing to head and neck squamous cell carcinoma development in low-risk, nontraditional patients. AB - BACKGROUND: The past 2 decades have seen an increased incidence of head and neck squamous cell carcinoma (HNSCC) in a nontraditional, low-risk patient population (ie, <=45 years of age, no substance use history), owing to a combination of human papillomavirus (HPV) infection and individual genetic variation. METHODS: Articles positing genetic variants as contributing factors in HNSCC incidence in low-risk, nontraditional patients were identified using a PubMed search, reviewed in detail, and concisely summarized herein. RESULTS: Recent data suggest that common polymorphisms in DNA repair enzymes, cell-cycle control proteins, apoptotic pathway members, and Fanconi anemia-associated genes likely modulate susceptibility to HNSCC development in low-risk, nontraditional patients. CONCLUSION: At present, there is a lack of robust, comprehensive data on genetic drivers of oncogenesis in low-risk patients and a clear need for further research on genetic alterations underlying the rising incidence of HNSCC in low-risk, nontraditional patients. PMID- 29427522 TI - Glucosensing capacity of rainbow trout telencephalon. AB - To assess the hypothesis of glucosensing systems present in fish telencephalon, we first demonstrated in rainbow trout, by in situ hybridisation, the presence of glucokinase (GK). Then, we assessed the response of glucosensing markers in rainbow trout telencephalon 6 hours after i.c.v. treatment with glucose or 2 deoxyglucose (inducing glucoprivation). We evaluated the response of parameters related to the mechanisms dependent on GK, liver X receptor (LXR), mitochondrial activity, sweet taste receptor and sodium-glucose linked transporter 1 (SGLT-1). We also assessed mRNA abundance of neuropeptides involved in the metabolic control of food intake (agouti-related protein, neuropeptide Y, pro opiomelanocortin, and cocaine- and amphetamine-related transcript), as well as the abundance and phosphorylation status of proteins possibly involved in linking glucosensing with neuropeptide expression, such as protein kinase B (AkT), AMP activated protein kinase (AMPK), mechanistic target of rapamycin and cAMP response element-binding protein (CREB). The responses obtained support the presence in the telencephalon of a glucosensing mechanism based on GK and maybe one based on LXR, although they do not support the presence of mechanisms dependent on mitochondrial activity and SGLT-1. The mechanism based on sweet taste receptor responded to glucose but in a converse way to that characterised previously in the hypothalamus. In general, systems responded only to glucose but not to glucoprivation. Neuropeptides did not respond to glucose or glucoprivation. By contrast, the presence of glucose activates Akt and inhibits AMPK, CREB and forkhead box01. This is the first study in any vertebrate species in which the response to glucose of putative glucosensing mechanisms is demonstrated in the telencephalon. Their role might relate to processes other than homeostatic control of food intake, such as the hedonic and reward system. PMID- 29427523 TI - Meropenem and Vaborbactam: Stepping up the Battle against Carbapenem-resistant Enterobacteriaceae. AB - Vaborbactam (VAB; formerly RPX7009) is a novel beta-lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against Ambler class A and C beta-lactamases. It has been co-formulated with meropenem to restore its activity against Klebsiella pneumoniae carbapenemases (KPC). VAB does not inhibit class B or D carbapenemases, nor does it improve the activity of meropenem against multidrug-resistant nonfermenting gram-negative bacilli, notably Acinetobacter spp. and Pseudomonas aeruginosa. The purpose of this article is to review existing data pertaining to the biochemistry, mechanism of action, pharmacokinetics/pharmacodynamics, in vitro activity, and current progress in clinical trials of meropenem and VAB (MV). Phase 1 studies have demonstrated single and multiple doses of VAB up to 2000 mg, alone or in combination with meropenem 2000 mg administered as a prolonged infusion over 3 hours, are well tolerated with an adverse effect profile similar to that of meropenem monotherapy. The available data suggest preexisting resistance among KPC-producing isolates is rare. Strains with elevated MICs have been characterized by multiple resistance determinants including porin defects, increased drug efflux, and increased blaKPC expression. It remains uncertain whether multifactorial resistance will emerge during MV treatment and with more widespread use. Early data are positive for complicated urinary tract infections and MV compared with best available therapy in patients with serious carbapenem resistant Enterobacteriaciae (CRE) infections. As clinicians contemplate how to incorporate MV into CRE treatment strategies, it will be important to track and understand resistance, discern the role, if any, of combination therapy in enhancing efficacy and/or preserving activity, and define the specific therapeutic niche of MV among the expanding anti-CRE armamentarium. PMID- 29427524 TI - Differentiating corporal punishment from physical abuse in the prediction of lifetime aggression. AB - Corporal punishment and parental physical abuse often co-occur during upbringing, making it difficult to differentiate their selective impacts on psychological functioning. Associations between corporal punishment and a number of lifetime aggression indicators were examined in this study after efforts to control the potential influence of various forms of co-occurring maltreatment (parental physical abuse, childhood sexual abuse, sibling abuse, peer bullying, and observed parental violence). College students (N = 1,136) provided retrospective self-reports regarding their history of aggression and levels of exposure to childhood corporal punishment and maltreatment experiences. Analyses focused on three hypotheses: 1) The odds of experiencing childhood physical abuse would be higher among respondents reporting frequent corporal punishment during upbringing; 2) Corporal punishment scores would predict the criterion aggression indices after control of variance associated with childhood maltreatment; 3) Aggression scores would be higher among respondents classified in the moderate and elevated corporal punishment risk groups. Strong support was found for the first hypothesis since the odds of childhood physical abuse recollections were higher (OR = 65.3) among respondents who experienced frequent (>60 total disciplinary acts) corporal punishment during upbringing. Partial support was found for the second and third hypotheses. Dimensional and categorical corporal punishment scores were associated significantly with half of the criterion measures. These findings support efforts to dissuade reliance on corporal punishment to manage child behavior. PMID- 29427525 TI - Frailty Versus Stopping Elderly Accidents, Deaths and Injuries Initiative Fall Risk Score: Ability to Predict Future Falls. AB - OBJECTIVES: To compare the ability of frailty status to predict fall risk with that of community fall risk screening tools. DESIGN: Analysis of cross-sectional and longitudinal data from NHATS. SETTING: National Health and Aging Trend Study (NHATS) 2011-2015. PARTICIPANTS: Individuals aged 65 and older (N = 7,392). MEASUREMENTS: Fall risk was defined according to the Stopping Elderly Accidents, Deaths and Injuries (STEADI) initiative. Frailty was defined as exhaustion, weight loss, low activity, slow gait speed, and weak grip strength. Robust was defined as meeting 0 criteria, prefrailty as 1 or 2 criteria, and frailty as 3 or more criteria. Falls were self-reported and ascertained using NHATS subsequent rounds (2012-2015). We compared the ability of frailty to predict future falls with that of STEADI score, adjusting for age, race, sex, education, comorbidities, hearing and vision impairment, and disability. RESULTS: Of the 7,392 participants (58.5% female), there 3,545 (48.0%) were classified as being at low risk of falling, 2,966 (40.1%) as being at moderate risk, and 881 (11.9%) as being at high risk. The adjusted risk of falling over the 4 subsequent years was 2.5 times as great for the moderate-risk group (hazard ratio (HR) = 2.50, 95% confidence interval (CI) = 2.16-2.89) and almost 4 times as great (HR = 3.79, 95% CI = 2.76-5.21) for the high-risk group as for the low-risk group. Risk of falling was greater for those who were prefrail (HR = 1.34, 95% CI 1.16-1.55) and frail (HR = 1.20, 95% CI = 0.94-1.54) than for those who were robust. CONCLUSION: STEADI score is a strong predictor of future falls. Addition of frailty status does not improve the ability of the STEADI measure to predict future falls. PMID- 29427527 TI - UBC-Nepal expedition: The use of oral antioxidants does not alter cerebrovascular function at sea level or high altitude. AB - NEW FINDINGS: What is the central question of the study? Does the use of antioxidants alter cerebrovascular function and blood flow at sea level (344 m) and/or high altitude (5050 m)? What is the main finding and its importance? This is the first study to investigate whether antioxidant administration alters cerebrovascular regulation and blood flow in response to hypercapnia, acute hypoxia and chronic hypoxia in healthy humans. We demonstrate that an acute dose of antioxidants does not alter cerebrovascular function and blood flow at sea level (344 m) or after 12 days at high altitude (5050 m). ABSTRACT: Hypoxia is associated with an increase in systemic and cerebral formation of free radicals and associated reactants that may be linked to impaired cerebral vascular function and neurological sequelae. To what extent oral antioxidant prophylaxis impacts cerebrovascular function in humans throughout the course of acclimatization to the hypoxia of terrestrial high altitude has not been examined. Thus, the purpose of the present study was to examine the influence of orally ingested antioxidants at clinically relevant doses (vitamins C and E and alpha-lipoic acid) on cerebrovascular regulation at sea level (344 m; n = 12; female n = 2 participants) and at high altitude (5050 m; n = 9; female n = 2) in a randomized, placebo-controlled and double-blinded crossover design. Hypercapnic and hypoxic cerebrovascular reactivity tests of the internal carotid artery (ICA) were conducted at sea level, and global and regional cerebral blood flow (CBF; i.e. ICA and vertebral artery) were assessed 10-12 days after arrival at 5050 m. At sea level, acute administration of antioxidants did not alter cerebral hypoxic cerebrovascular reactivity (pre versus post: 1.5 +/- 0.7 versus 1.2 +/- 0.8%?CBF/ %?SpO2; P = 0.96) or cerebral hypercapnic cerebrovascular reactivity (pre versus post: 5.7 +/- 2.0 versus 5.8 +/- 1.9%?CBF/?mmHg; P = 0.33). Furthermore, global CBF (P = 0.43) and cerebral vascular conductance (ICA P = 0.08; vertebral artery P = 0.32) were unaltered at 5050 m after antioxidant administration. In conclusion, these data show that an oral antioxidant cocktail known to attenuate systemic oxidative stress failed to alter cerebrovascular function at sea level and CBF during acclimatization to high altitude. PMID- 29427526 TI - NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy. AB - The advent of large scale genomic sequencing technologies significantly improved the molecular classification of acute megakaryoblastic leukaemia (AMKL). AMKL represents a subset (~10%) of high fatality pediatric acute myeloid leukemia (AML). Recurrent and mutually exclusive chimeric gene fusions associated with pediatric AMKL are found in 60%-70% of cases and include RBM15-MKL1, CBFA2T3 GLIS2, NUP98-KDM5A and MLL rearrangements. In addition, another 4% of AMKL harbor NUP98 rearrangements (NUP98r), with yet undetermined fusion partners. We report a novel NUP98-BPTF fusion in an infant presenting with primary refractory AMKL. In this NUP98r, the C-terminal chromatin recognition modules of BPTF, a core subunit of the NURF (nucleosome remodeling factor) ATP-dependent chromatin-remodeling complex, are fused to the N-terminal moiety of NUP98, creating an in frame NUP98 BPTF fusion, with structural homology to NUP98-KDM5A. The leukemic blasts expressed two NUP98-BPTF splicing variants, containing one or two tandemly spaced PHD chromatin reader domains. Our study also identified an unreported wild type BPTF splicing variant encoding for 2 PHD domains, detected both in normal cord blood CD34+ cells and in leukemic blasts, as with the fly BPTF homolog, Nurf301. Disease course was marked by rapid progression and primary chemoresistance, with ultimately significant tumor burden reduction following treatment with a clofarabine containing regimen. In sum, we report 2 novel NUP98-BPTF fusion isoforms that contribute to refine the NUP98r subgroup of pediatric AMKL. Multicenter clinical trials are critically required to determine the frequency of this fusion in AMKL patients and explore innovative treatment strategies for a disease still plagued with poor outcomes. PMID- 29427528 TI - Cross-talk between sphingosine-1-phosphate and EGFR signaling pathways enhances human glioblastoma cell invasiveness. AB - We show that glioblastoma multiform (GBM) cells overexpressing the constitutively active form of the epidermal growth factor receptor [epidermal growth factor receptor variant III (EGFRvIII) and U87MG human GBM cell line overexpressing EGFRvIII (EGFR+) cells] possess greater invasive properties and have higher levels of extracellular sphingosine-1-phosphate (S1P) and increased sphingosine kinase-1 (SK1) activity than the empty vector-expressing cells. Notably, the inhibition of SK1 or S1P receptors decreases the invasiveness of EGFR+ cells. Moreover, EGFR and MEK1 inhibitors reduce both SK1 activation and cell invasion, suggesting that the enhanced invasiveness observed in the EGFR+ cells depends on the increased S1P secretion, downstream of the EGFRvIII-ERK-SK1-S1P pathway. Altogether, the results of the present study indicate that, in GBM cells, EGFRvIII is connected with the S1P signaling pathway to enhance cell invasiveness and tumor progression. PMID- 29427529 TI - Efficient bioconversion of oleuropein from olive leaf extract to antioxidant hydroxytyrosol by enzymatic hydrolysis and high-temperature degradation. AB - Hydroxytyrosol (HT), a powerful antioxidant, clears free radicals and exhibits many biological activities. Because contents of HT are low in natural sources, bioconversion of oleuropein (OLE) to HT is of increasing interest. A biotechnological process was investigated to produce HT from OLE presented in olive leaf extract. Enzymatic hydrolysis using two cellulases with high beta glucosidase activity, Novozymes CTec2 and commercial cellulase KDN (Qingdao, People's Republic of China) was carried out at 50 degrees C for 12 H followed by raising the temperature to 90 degrees C for chemical hydrolysis. After 48 H of hydrolysis, an OLE degradation rate of 100% and a HT yield of 86-88% were achieved. These cellulases degrade OLE and release a glucose molecule. Chemical hydrolysis at a high temperature promotes the cleavage of ester bond and the formation of HT. This process has a promising alternative for production of HT comparing with acid hydrolysis which not only causes significant pollution to the environment but also makes difficult to the subsequent separation. PMID- 29427531 TI - Osseointegration of 3D printed microalloyed CoCr implants-Addition of 0.04% Zr to CoCr does not alter bone material properties. AB - Electron beam melting (EBM) is a three-dimensional (3D) printing technique for the production of metal structures where complex geometries with interconnected porosities can be built. Incorporation of as little as 0.04% Zr into the CoCr alloy can significantly improve the biomechanical anchorage of constructs fabricated by EBM. Here we investigate bone material properties, including microstructure and composition, adjacent to 3D printed CoCr implants with and without addition of 0.04% Zr, after 8 weeks of healing in the rabbit femur. In low amounts, zirconium addition does not alter the microstructure and extracellular matrix composition of bone formed adjacent to the surface of EBM manufactured implants. Bone ingrowth into surface irregularities of 3D printed CoCr and CoCr + Zr implants is seen. Extensive remodeling is also evident. Osteocytes attach directly on to the implant surface. The interfacial tissue at CoCr and CoCr + Zr has similar mineral crystallinity, apatite-to-collagen ratio, carbonate-to-phosphate ratio, Ca/P ratio, bone-implant contact, percentage porosity, and osteocyte density (N.Ot/B.Ar). Compared to the native bone, the mineral crystallinity of the interfacial tissue was lower while N.Ot/B.Ar was higher for both CoCr and CoCr + Zr. Overall, the results indicate that bone tissue adjacent to CoCr and CoCr + Zr implants is highly mature and exhibits comparable healing kinetics. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1655-1663, 2018. PMID- 29427530 TI - Comparing side chain packing in soluble proteins, protein-protein interfaces, and transmembrane proteins. AB - We compare side chain prediction and packing of core and non-core regions of soluble proteins, protein-protein interfaces, and transmembrane proteins. We first identified or created comparable databases of high-resolution crystal structures of these 3 protein classes. We show that the solvent-inaccessible cores of the 3 classes of proteins are equally densely packed. As a result, the side chains of core residues at protein-protein interfaces and in the membrane exposed regions of transmembrane proteins can be predicted by the hard-sphere plus stereochemical constraint model with the same high prediction accuracies (>90%) as core residues in soluble proteins. We also find that for all 3 classes of proteins, as one moves away from the solvent-inaccessible core, the packing fraction decreases as the solvent accessibility increases. However, the side chain predictability remains high (80% within 30 degrees ) up to a relative solvent accessibility, rSASA?0.3, for all 3 protein classes. Our results show that ~40% of the interface regions in protein complexes are "core", that is, densely packed with side chain conformations that can be accurately predicted using the hard-sphere model. We propose packing fraction as a metric that can be used to distinguish real protein-protein interactions from designed, non-binding, decoys. Our results also show that cores of membrane proteins are the same as cores of soluble proteins. Thus, the computational methods we are developing for the analysis of the effect of hydrophobic core mutations in soluble proteins will be equally applicable to analyses of mutations in membrane proteins. PMID- 29427532 TI - A pilot study of high-dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation. AB - : Research has shown that a subset of the autism spectrum disorder (ASD) population presents with immune dysregulation. To explore this topic further, we investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD. In this study, participants were recruited based on a diagnosis of autistic disorder, Asperger's disorder, or pervasive developmental disorder not otherwise specified. Participants also showed evidence of immune dysfunction based on abnormal levels of specific biomarkers, including CD40 ligand (CD154), lymphocyte stimulation, and T or B cell dysfunction. Of 17 screened patients, 14 completed the trial and received IVIG treatment (1 g/kg dose) for ten 21-day treatment cycles. The primary endpoint was disease improvement assessed using standardized cognitive and behavioral tests (Children's Communication Checklist [CCC-2], Social Responsiveness Scale [SRS], Aberrant Behavior Checklist [ABC], Clinical Global Impressions-Severity [CGI-S] and -Improvement [CGI-I], Autism Diagnostic Observation Schedule [ADOS], and Peabody Picture Vocabulary Test [PPVT]). Secondary endpoints included experimental biomarkers such as CD154, toll-like receptor-4, memory B cells, FOXP3, and lymphocyte stimulation. Significant improvements from baseline to study endpoint were observed in several subscales of the CCC-2, SRS, CGI-I, CGI S, and ADOS, including Associated Maladaptive Behaviors (P <= .043), Reciprocal Social Interaction (P = .015), Communication (P < .001), and Stereotyped Behaviors and Repetitive Interests (P <= .013). Statistically significant reductions were also seen in numerous secondary outcomes of immunological biomarkers indicative of neuroinflammation. IVIG was well tolerated; no subjects withdrew due to an adverse event, and clinical data showed no evidence of thromboembolic events. Autism Res 2018, 11: 421-433. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Since research has demonstrated a link between autism spectrum disorder (ASD) and immune dysfunction, this study investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD. Fourteen patients received IVIG treatment and were assessed using standardized cognitive and behavioral tests. Following treatment with IVIG, significant improvement was observed across several subscales of the clinical tests and significant reductions were seen in the markers of neuroinflammation. These data suggest that inflammatory etiologies may play a role in select cases of autism, and IVIG treatment may exert a positive impact on behaviors and markers of inflammation in ASD. PMID- 29427533 TI - Utilization of a biomedical device (VeinViewer(r) ) to assist with peripheral intravenous catheter (PIV) insertion for pediatric nurses. AB - PURPOSE: Vascular access in pediatric patients can be challenging even with the currently available technological resources. This nurse-driven research study explored time, cost, and resources for intravenous access to determine if a biomedical device, VeinViewer(r) Vision, would facilitate improvements in pediatric access. In addition, this study looked at nurse perceptions of skills and confidence around intravenous insertion and if the use of the VeinViewer(r) impacted these perceptions. Literature examining pediatric intravenous access success rates compared with nurse perceived skills and confidence is lacking. DESIGN: Nonblinded randomized control trial of pediatric nurses working in an acute care hospital setting. METHODS: A preliminary needs assessment solicited feedback from nurses regarding their practice, perceived skills, and confidence with placing peripheral intravenous catheters (PIVs). Due to the results of the preliminary needs assessment, a research study was designed and 40 nurses were recruited to participate. The nurses were randomized into either a VeinViewer(r) or standard practice group. Nurse participants placed intravenous catheters on hospitalized pediatric patients using established procedures while tracking data for the study. RESULTS: Needs assessment showed a majority of nurses felt a biomedical device would be helpful in building their intravenous insertion skills and their confidence. The study results did not demonstrate any clinically significant differences between VeinViewer(r) use and standard practice for intravenous catheter insertion in pediatric patients for success of placement, number of attempts, or overall cost. In addition, no difference was noted between nurses in either group on perceived skills or confidence with insertion of PIVs. PRACTICE IMPLICATIONS: The ongoing need for resources focused on building nurse skills and confidence for PIV insertion was highlighted and organizations should continue to direct efforts toward developing skills and competency for staff that are responsible for pediatric vascular access. This study illustrates the importance of data-driven decision-making for expensive hospital-funded equipment purchases. This nursing led research study highlights how perceptions do not always align with outcomes. The lessons gleaned from this study may aid in decision-making around pediatric intravenous access practice. PMID- 29427534 TI - Gold nano-decorated aligned polyurethane nanofibers for enhancement of neurite outgrowth and elongation. AB - Neurite outgrowth and elongation of neural cells is the most important subject that is considered in nerve tissue engineering. In this regard, aligned nanofibers have taken much attention in terms of providing guidance for newly outgrown neurites. The main objective of this study was to fabricate aligned polyurethane nanofibers by electrospinning process and decorate them with gold nanoparticles to further investigate the synergistic effects of nanotopography, biological nerve growth factor (NGF) and electrical stimulations on neurite outgrowth and elongation of pheochromocytoma (PC-12) model cells. In this regard, smooth and uniform aligned polyurethane nanofibers with the average diameter of 519 +/- 56 nm were fabricated and decorated with the gold nanoparticles with the average diameter of ~50 nm. PC-12 cells were cultured on the various nanofiber surfaces inside the bio-mimetic bioreactor system and exposed either to NGF alone or combination of NGF and electrical stimulation. It was found that 50 ng/mL NGF concentration is an optimal value for the stimulation of neurite outgrowth. After 4 days of culture under 100 mV, 10 ms electrical stimulation in 1 h/day period it was found that the gold nanoparticle decorated aligned polyurethane nanofibers increased the neurite outgrowth and elongation more with the combinational NGF and electrical stimulation. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1604-1613, 2018. PMID- 29427535 TI - Endogenous biological factors modulated by substrate stiffness regulate endothelial differentiation of mesenchymal stem cells. AB - During the process of tissue regeneration facilitated by stem cells, physical properties of a scaffold affect behavior and activities of the cell. To enhance differentiation of human mesenchymal stem cells (MSCs) into endothelial-like cells (ELCs), we used electrospun fibrous substrates with different stiffness to enhance the differentiation. A simple method of annealing with different lengths of treatment time was employed to modulate stiffness of electrospun fibrous substrates without changing their chemistry. We seeded MSCs on substrates with different stiffness to study how stiffness of a culture substrate affects differentiation of MSCs into ELCs. Results of RT-PCR and western blotting revealed that stiffer substrates with the average surface modulus of 7.82 MPa induced differentiated MSCs to express more VEGF, CD31, and vWF mRNA transcripts and proteins than softer ones with that of 3.8 or 1.44 MPa. We also found that the production of macrophage migration inhibitory factor (MIF) in ELCs was increased with substrate stiffness. After silencing MIF mRNA, MSCs during differentiation showed lower expression levels of VEGF, CD31, and vWF than control cells whereas VEGF-silenced and control cells expressed comparable levels of MIF, indicating that MIF is an upstream molecule regulating VEGF in the mechanism. Our findings provide new insight into how stiffness of a culture substrate regulates differentiation of MSCs into ELCs. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1595-1603, 2018. PMID- 29427536 TI - Impaired Gas Exchange: Prognostic Clinical Indicators of Short-Term Survival in Children with Acute Respiratory Infection. AB - PURPOSE: To establish prognostic indicators of survival for impaired gas exchange (IGE) (00030). METHODS: Secondary analysis of data from an open prospective cohort developed with a group of 136 children with acute respiratory infection (ARI). FINDINGS: On Day 1, IGE (00030) was present in 42.6% of the sample. New cases arose until the last day of evaluation. With regards to defining characteristics, only hypoxemia and abnormal skin color were associated with a higher risk of developing diagnosis. CONCLUSIONS: Children with ARI who exhibit hypoxemia and abnormal skin color had a worse prognosis for IGE (00030). IMPLICATIONS FOR NURSE PRACTICE: Nurses can use the research findings as a predictive marker of the evolution of the patient's health status. PMID- 29427537 TI - Focus on histological abnormalities of intrahepatic vasculature in chronic viral hepatitis. AB - BACKGROUND & AIMS: The histological intrahepatic microvasculature lesions have not been deeply investigated outside the setting of portal hypertension. The aim of this study was to analyse the type and the prevalence of microvasculature abnormalities and their correlation with inflammatory activity, fibrosis stage and tissue markers of fibrogenesis, angiogenesis and oxidative DNA damage in liver biopsies obtained from patients with chronic viral hepatitis. METHODS: Seventy-four liver biopsies from untreated patients affected by hepatitis B (22 cases) and C (52 cases) were included. The presence of microvascular changes was correlated with (i) the severity of the activity and fibrosis; (ii) immunohistochemical markers of angiogenesis (CD34) and hepatic stellate cells activation (alpha-smooth muscle actin); (iii) a tissue marker of oxidative damage (8-OHdG adducts). RESULTS: Sixty-five out of 74 biopsies (87.8%) showed vascular lesions. Portal angiomatosis was the most prevalent (62.2%) and it was associated with, on 1 side, the fibrosis stage at both univariate (P < .0001) and multivariate analysis (P = .01, OR = 9.4 [1.6-54]) and, on the other, with angiogenesis (P = .05) and hepatic stellate cells activation (P = .002). Interestingly, 36/46 cases with portal angiomatosis were at early/intermediate fibrosis stage. The hepatic stellate cells activation was also associated with the presence of aberrant periportal vessels (P = .01). CONCLUSIONS: The histological alterations of intrahepatic microvasculature, usually seen in cirrhosis and portal hypertension, occur in chronic viral hepatitis even at early/intermediate fibrosis stages. Their correlation with angiogenesis and fibrogenesis supports a possible involvement in disease progression. PMID- 29427538 TI - The impact on the family of the co-existing conditions of children with autism spectrum disorder. AB - : We aimed to investigate whether the impact on families of children with Autism Spectrum Disorder (ASD) is associated with the number and/or type of emotional and behavioral co-existing conditions that parents/carers of children with ASD reported as occurring frequently. In addition, we examined whether there was a greater impact on families if their child was male, had lower levels of language, had more severe autism symptomatology, and whether impact was associated with the number and/or type of co-existing conditions. Families were recruited from large UK research databases. 420 parents/carers of children aged 3 years 2 months to 18 years 8 months completed the revised Impact on Family (IoF) Scale and reported on the frequency/rate of their child's co-existing conditions. Parents/carers reported higher mean IoF scores if their child: had a greater number of frequent co-existing conditions; had sleep problems; was only able to communicate physically; and had more severe autism symptomatology. The development and implementation of targeted treatment and management approaches are needed to reduce the impact of co-existing conditions on family life. Autism Res 2018, 11: 776-787. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism Spectrum Disorder (ASD) is commonly associated with emotional and/or behavior conditions that affect family life. Parents/carers of children with ASD who: (a) reported a greater number of frequent co-existing conditions, (b) had sleep problems, (c) were only able to communicate physically, and (d) had more severe symptoms characteristic of autism, reported a greater burden/strain on the family. Treatment approaches to target co-existing conditions alongside characteristics of ASD are needed to reduce their impact on family life. PMID- 29427539 TI - Cholesterol Absorption and Synthesis in Vegetarians and Omnivores. AB - SCOPE: Vegetarian diets are considered health-promoting; however, a plasma cholesterol lowering effect is not always observed. We investigate the link between vegetarian-diet-induced alterations in cholesterol metabolism. METHODS AND RESULTS: We study male and female omnivores, lacto-ovo vegetarians, lacto vegetarians, and vegans. Cholesterol intake, absorption, and fecal sterol excretion are measured as well as plasma concentrations of cholesterol and noncholesterol sterols. These serve as markers for cholesterol absorption, synthesis, and catabolism. The biliary cholesterol secretion rate is estimated. Flux data are related to body weight. Individual vegetarian diet groups are statistically compared to the omnivore group. Lacto vegetarians absorb 44% less dietary cholesterol, synthesized 22% more cholesterol, and show no differences in plasma total and LDL cholesterol. Vegan subjects absorb 90% less dietary cholesterol, synthesized 35% more cholesterol, and have a similar plasma total cholesterol, but a 13% lower plasma LDL cholesterol. No diet-related differences in biliary cholesterol secretion and absorption are observed. Total cholesterol absorption is lower only in vegans. Total cholesterol input is similar under all vegetarian diets. CONCLUSIONS: Unaltered biliary cholesterol secretion and higher cholesterol synthesis blunt the lowered dietary cholesterol intake in vegetarians. LDL cholesterol is significantly lower only in vegans. PMID- 29427540 TI - Novel standardized massive bone defect model in rats employing an internal eight hole stainless steel plate for bone tissue engineering. AB - Massive bone defects are a challenge in orthopaedic research. Defective regeneration leads to bone atrophy, non-union of bone, and physical morbidity. Large animals are important models, however, production costs are high, nursing is complex, and evaluation methods are limited. A suitable laboratory animal model is required to explore the underlying molecular mechanism and cellular process of bone tissue engineering. We designed a stainless steel plate with 8 holes; the middle 2 holes were used as a guide to create a standardized critical size defect in the femur of anaesthetized rats. The plate was fixed to the bone using 6 screws, serving as an inner fixed bracket to secure a tricalcium phosphate implant seeded with green fluorescent protein-positive rat bone marrow mesenchymal stem cells within the defect. In some animals, we also grafted a vessel bundle into the lateral side of the implant, to promote vascularized bone tissue engineering. X-ray, microcomputed tomography, and histological analyses demonstrated the stainless steel plate resulted in a stable large segmental defect model in the rat femur. Vascularization significantly increased bone formation and implant degradation. Moreover, survival and expansion of green fluorescent protein-positive seeded cells could be clearly monitored in vivo at 1, 4, and 8 weeks postoperation via fluorescent microscopy. This standardized large segmental defect model in a small animal may help to advance the study of bone tissue engineering. Furthermore, availability of antibodies and genetically modified rats could help to dissect the precise cellular and molecular mechanisms of bone repair. PMID- 29427541 TI - Asymmetric, nano-textured surfaces influence neuron viability and polarity. AB - Three dimensional, nanostructured surfaces have attracted considerable attention in biomedical research since they have proven to represent a powerful platform to influence cell fate. In particular, nanorods and nanopillars possess great potential for the control of cell adhesion and differentiation, gene and biomolecule delivery, optical and electrical stimulation and recording, as well as cell patterning. Here, we investigate the influence of asymmetric poly(dichloro-p-xylene) (PPX) columnar films on the adhesion and maturation of cortical neurons. We show that nanostructured films with dense, inclined polymer columns can support viable primary neuronal culture. The cell-nanostructure interface is characterized showing a minimal cell penetration but strong adhesion on the surface. Moreover, we quantify the influence of the nano-textured surface on the neural development (soma size, neuritogenesis, and polarity) in comparison to a planar PPX sample. We demonstrate that the nanostructures facilitates an enhancement in neurite branching as well as elongation of axons and growth cones. Furthermore, we show for the first time that the asymmetric orientation of polymeric nanocolumns strongly influences the initiation direction of the axon formation. These results evidence that 3D nano-topographies can significantly change neural development and can be used to engineer axon elongation. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1634-1645, 2018. PMID- 29427542 TI - School dysfunction in youth with autistic spectrum disorder in Taiwan: The effect of subtype and ADHD. AB - : School dysfunction is observed in youths with autism spectrum disorder (ASD), but the factors moderating their school dysfunction have not been well explored. This study investigated school functions in youths with ASD in Taiwan, stratified by personal characteristics including demographics, ASD subtypes, intelligence profiles, and the presence of attention-deficit hyperactivity disorder (ADHD). We recruited 160 youths (aged 6-18 years, 87.5% boys) with a clinical diagnosis of ASD and 160 age and gender-matched typically developing (TD) youths. Their parents received a semi-structured psychiatric interview for their ASD and ADHD diagnoses and reported their school functions. Youths with ASD were further grouped into low-functioning autism (LFA, ASD with intellectual disability and developmental language delay, n = 44), high-functioning autism (HFA, ASD with no intellectual disability, n = 55) and Asperger's syndrome (AS, ASD with neither language delay nor intellectual disability, n = 61). Compared to TD, ASD had worse school functions in the domains of academic performance, attitude toward schoolwork, social interaction, and behavioral problems except for no academic differences from TD in HFA and ASD without ADHD. Subgroup analysis revealed that HFA and AS had better academic performance but showed worse attitude toward school than LFA. Comorbidity of ADHD negatively impacted all domains of school functions. Besides autistic and ADHD symptoms, oppositional symptoms, lower intelligence, older age, and female gender in youths also predicted school dysfunction. Although youths with ASD have school dysfunction in several domains, this study specifically addresses the role of intelligence and comorbid ADHD on their school dysfunction. Autism Res 2018, 11: 857-869. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Impaired school functions varied in ASD youths with different characteristics. Youths with autism spectrum disorder (ASD) encounter varying levels and domains of impaired performance at schools, such as lower academic performance, negative attitude toward school work, fewer reciprocal friendships, and more behavioral problems. Our results indicate that ASD youths without intellectual disability had better academic performance, but worse attitude toward school than those with intellectual disability. Co-occurrence with ADHD is associated with school dysfunction. In summary, intelligence and comorbid ADHD influences several domains of school functions. PMID- 29427543 TI - FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells. AB - F-box and WD repeat domain-containing 7 (FBW7) is a SCF-type E3 ubiquitin ligase targeting a multitude of oncoproteins for degradation. Acting as one of the most important tumor suppressors, it is frequently inactivated in various tumors. In this study we aimed to evaluate the relationship of FBW7 with glioma pathology and prognosis, and examine its effect in glioma malignancies and temozolomide (TMZ)-based therapy. Clinical tissues and TCGA database analysis revealed that FBW7 expression was correlated inversely with glioma histology and positively with patient survival time. Lentivirus transfection-induced FBW7 overexpression significantly suppressed proliferation, invasion and migration of U251 and U373 cells, whereas knockdown of FBW7 by targeted shRNA promoted proliferation, invasion and migration of glioma cells. Most importantly, the expression level of FBW7 was found to affect the 50% inhibitory concentration (IC50) of U251 and the TMZ-resistant variant. Combining TMZ with FBW7 overexpression notably increased the cytotoxicity compared to TMZ treatment alone, which was conversely attenuated by FBW7 knockdown. Moreover, flow cytometry (FC) analysis showed overexpression of FBW7, TMZ or the combination-increased proportion of G2/M arrest and the apoptotic rate, whereas FBW7 inhibition reduced G2/M arrest and apoptosis in U251 cells. Finally, mechanistic study found that FBW7 overexpression downregulated Aurora B, Mcl1 and Notch1 levels in a time-dependent pattern and this expressional suppression was independent of TMZ. These findings collectively demonstrate the critical role of FBW7 as a prognostic factor and a potential target to overcome chemoresistance of glioblastoma. PMID- 29427545 TI - Evaluation of decellularized xenogenic porcine auricular cartilage as a novel biocompatible filler. AB - Fillers are products that fill the space in soft tissues of the human body and actively used in the various medical fields. Unfortunately, most of the cost effective commercially available fillers are synthetic and have limitations in terms of their biocompatibility. Here, we evaluated the possible application of decellularized xenogenic cartilage as a long-lasting material for soft tissue augmentation and compared it with two commercially available fillers Artesense (polymethylmethacrylate microspheres) and Radiesse (calcium hydroxyapatite [CaHa]). To do so, porcine auricular cartilage was harvested, followed by freezing and grinding of the tissue into flakes. Then, we used 1% Triton X-100 to decellularize the flakes. We then, respectively, injected 0.1 cc of each material (decellularized xenogenic cartilage, Radiesse, and Artesense) into the subcutaneous layer at three different sites per subject in 12 Sprague-Dawley rats, and evaluated the inflammatory cell infiltration and foreign body reactions of each. Our data indicate that the infiltration of giant cells in the injection area was significantly lower in the decellularized xenogenic cartilage injection group than that in the Radiesse and Artesense injection groups. Further, we observed some neutrophil infiltration in the xenogenic cartilage and Artesense injection groups at 1 month, but these levels were much lower at 3 months (comparable to the Radiesse injection group). Thus, decellularized xenogenic cartilage may have a distinct advantage in terms of biocompatibility compared with other commercial injectable long-lasting fillers, making it one of the most feasible, natural, and cost effective materials in the market. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2708-2715, 2018. PMID- 29427544 TI - Pediatric nurses' perceived knowledge and beliefs of evidence-based practice in the care of children and adolescents with moderate-to-severe traumatic brain injury. AB - PURPOSE: Pediatric nurses play a significant role in all phases of traumatic brain injury (TBI) recovery, particularly during the hospital stay. Although evidence-based nursing practice is known to improve patient outcomes, limited research exists on nurses' evidence-based perceived knowledge and beliefs specific to TBI care. As nurses' perceived knowledge and beliefs are known to guide their practice behaviors, this assessment is important to overall TBI outcomes. The purpose of this study was to evaluate pediatric nurses' evidence based perceived knowledge and beliefs in providing care for children and adolescents with moderate-to-severe TBI. DESIGN AND METHODS: Data for this study were obtained from a larger parent study on nurses' perceptions of caring for patients of all ages with moderate-to-severe TBI. The parent study was an exploratory, cross-sectional electronic survey of registered nurses across all hospital departments within a large Midwestern health system. Only data specific to pediatric nurses (n = 330) were analyzed for this study. Descriptive statistics and latent class analysis (LCA) were performed. RESULTS: Pediatric nurses, on average, were 38.79 years, female (90.37%), had over a decade of nursing experience (13.55 years), and practiced as a staff nurse (80.07%) on an inpatient unit (45.51%). Findings indicated pediatric nurses reported overall low levels of evidence-based perceived knowledge and had inaccurate beliefs about caring for patients with TBI. LCA indicated two distinct homogenous subgroups specific to evidence-based perceived knowledge: low (41%) and high (59%). Nurses in the low evidence-based perceived knowledge group were younger, had less nursing experience, worked primarily on an inpatient unit, and cared for patients with TBI at a higher frequency compared to high evidence-based perceived knowledge nurses. Additionally, there were significant differences in beliefs about sex-based patient differences after TBI and the role of nurses in caring for patients with TBI based on level of evidence-based perceived knowledge. PRACTICE IMPLICATIONS: Assessing nurses' perceived knowledge and beliefs of evidence-based practice is a foundational step toward implementing evidence-based care for patients with moderate-to-severe TBI. Implications of these findings indicate the need to provide additional education to increase pediatric nurses' perceived knowledge and ensure accurate beliefs about evidence-based TBI care. PMID- 29427546 TI - Special interests and subjective wellbeing in autistic adults. AB - : Special interests form part of the core features of autism. However, to date there has been limited research focusing on the role of special interests in the lives of autistic adults. This study surveyed autistic adults on their special interest topics, intensity, and motivation. It also assessed the relationship between special interests and a range of quality of life measures including subjective wellbeing and domain specific life satisfaction. About two thirds of the sample reported having a special interest, with relatively more males reporting a special interest than females. Special interest topics included computers, autism, music, nature and gardening. Most autistic adults engaged in more than one special interest, highlighting that these interests may not be as narrow as previously described. There were no differences in subjective wellbeing between autistic adults with and without special interests. However, for autistic adults who did have special interests, motivation for engaging in special interests was associated with increased subjective wellbeing. This indicates that motivation may play an important role in our understanding of special interests in autism. Special interests had a positive impact on autistic adults and were associated with higher subjective wellbeing and satisfaction across specific life domains including social contact and leisure. However, a very high intensity of engagement with special interests was negatively related to wellbeing. Combined, these findings have important implications for the role of special interests in the lives of autistic adults. Autism Res 2018, 11: 766-775. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autistic adults reported having special interests in a range of topics, including computers, music, autism, nature and gardening. Special interests were associated with a number of positive outcomes for autistic adults. They were also related to subjective wellbeing and satisfaction across specific life domains including social contact and leisure. Very high intensity of engagement with special interests was related to lower levels of wellbeing. This highlights the important role that special interests play in the lives of autistic adults. PMID- 29427547 TI - The importance of detecting anti-DFS70 in routine clinical practice: comparison of different care settings. AB - BACKGROUND: Screening for antinuclear antibodies by indirect immunofluorescence (ANA-IIF) is essential in the diagnostic workup of ANA-associated autoimmune rheumatic diseases (AARDs). However, also healthy individuals may test positive, making the interpretation challenging. Recent reports suggest that dense fine speckled 70 antibodies (anti-DFS70) may facilitate this challenge. Here, we investigate their clinical importance based on data from four Belgian laboratories (one primary, two secondary and one tertiary care). METHODS: At least one specific DFS70 assay (DFS70 IgG ELISA or lineblot [Euroimmun, full length antigen] and/or DFS70 IgG CLIA [Inova Diagnostics, truncated antigen]) was performed on four consecutive cohorts of homogeneous-like ANA-IIF samples (n=697). Co-occurrence with AARD-specific ANA and clinical information were documented in the anti-DFS70-positive samples. RESULTS: Using a combination of solid phase techniques, we found between 7.6% and 26% anti-DFS70 in the different cohorts. Focusing on anti-DFS70 CLIA-positive samples without co-occurrence of AARD-specific ANA, we observed a trend towards lower frequency in tertiary (8% [p=0.0786]) and secondary care (12% [p=0.1275] and 6% [p<0.001]) compared to primary care (21%). Moreover, in this specific subpopulation, AARD was less frequent (0%-50% compared to 6%-77% in the total anti-DFS70-positive group). CONCLUSIONS: Anti-DFS70 prevalence depends on the applied assay and care setting. Our data suggest that, for an ANA-IIF-positive patient, it is rather the absence of AARD-associated ANA and clinical symptoms that contribute to the exclusion of AARD than the presence of anti-DFS70. Nevertheless, isolated anti-DFS70 helps to clarify positive ANA-IIF results, especially if pretest probability for AARD is low. PMID- 29427548 TI - Multicenter validation study for the certification of a CFTR gene scanning method using next generation sequencing technology. AB - BACKGROUND: Many European laboratories offer molecular genetic analysis of the CFTR gene using a wide range of methods to identify mutations causative of cystic fibrosis (CF) and CFTR-related disorders (CFTR-RDs). Next-generation sequencing (NGS) strategies are widely used in diagnostic practice, and CE marking is now required for most in vitro diagnostic (IVD) tests in Europe. The aim of this multicenter study, which involved three European laboratories specialized in CF molecular analysis, was to evaluate the performance of Multiplicom's CFTR MASTR Dx kit to obtain CE-IVD certification. METHODS: A total of 164 samples, previously analyzed with well-established "reference" methods for the molecular diagnosis of the CFTR gene, were selected and re-sequenced using the Illumina MiSeq benchtop NGS platform. Sequencing data were analyzed using two different bioinformatic pipelines. Annotated variants were then compared to the previously obtained reference data. RESULTS AND CONCLUSIONS: The analytical sensitivity, specificity and accuracy rates of the Multiplicom CFTR MASTR assay exceeded 99%. Because different types of CFTR mutations can be detected in a single workflow, the CFTR MASTR assay simplifies the overall process and is consequently well suited for routine diagnostics. PMID- 29427549 TI - Linking type 2 diabetes and gynecological cancer: an introductory overview. AB - Type 2 diabetes (T2D) is a chronic disease with a growing prevalence and a leading cause of death in many countries. Several epidemiological studies observed an association between T2D and increased risk of many types of cancer, such as gynecologic neoplasms (endometrial, cervical, ovarian and vulvar cancer). Insulin resistance, chronic inflammation and high free ovarian steroid hormones are considered the possible mechanisms behind this complex relationship. A higher risk of endometrial cancer was observed in T2D, even though this association largely attenuated after adjusting for obesity. A clear relationship between the incidence of cervical cancer (CC) and T2D has still not be determined; however T2D might have an impact on prognosis in patients with CC. To date, studies on the association between T2D and ovarian cancer (OC) are limited. The effect of pre-existing diabetes on cancer-specific mortality has been evaluated in several studies, with less clear results. Other epidemiological and experimental studies focused on the potential role of diabetes medications, mainly metformin, in cancer development in women. The correct understanding of the link between T2D and gynecologic cancer risk and mortality is currently imperative to possibly modify screening and diagnostic-therapeutic protocols in the future. PMID- 29427550 TI - Clinically relevant discrepancies between different rheumatoid factor assays. PMID- 29427551 TI - Quantitative urine test strip reading for leukocyte esterase and hemoglobin peroxidase. AB - BACKGROUND: Recently, urine test strip readers have become available for automated test strip analysis. We explored the possibilities of the Sysmex UC 3500 automated urine chemistry analyzer based on complementary metal oxide semiconductor (CMOS) sensor technology with regard to accuracy of leukocyte esterase and hemoglobin peroxidase results. We studied the influence of possible confounders on these measurements. METHODS: Reflectance data of leukocyte esterase and hemoglobin peroxidase were measured using CMOS technology on the Sysmex UC-3500 automated urine chemistry analyzer. Analytical performance (imprecision, LOQ) as well as the correlation with white blood cell (WBC) and red blood cell (RBC) counts (Sysmex UF-5000) were studied. Furthermore, the influence of urinary dilution, haptoglobin, pH and ascorbic acid as confounders was determined. RESULTS: Within- and between-run imprecision (reflectance signal) ranged from 1.1% to 3.6% and 0.9% to 4.2% for peroxidase and 0.4% to 2.5% and 0.4% to 3.3% for leukocyte esterase. Good agreement was obtained between the UF 5000 for RBCs and peroxidase reflectance (r=0.843) and for WBCs and leukocyte esterase (r=0.821). Specific esterase activity decreased for WBC counts exceeding 100 cells/MUL. Haptoglobin influenced the peroxidase activity, whereas leukocyte esterase and peroxidase activities showed a pH optimum between 5.0 and 6.5. A sigmoidal correlation was observed between urinary osmolality and peroxidase activity. CONCLUSIONS: CMOS technology allows to obtain high quality test strip results for assessing WBC and RBC in urine. Quantitative peroxidase and leukocyte esterase are complementary with flow cytometry and have an added value in urinalysis, which may form a basis for expert system development. PMID- 29427552 TI - Quality and future of clinical laboratories: the Vico's whole cyclical theory of the recurring cycles. AB - In the last few decades, laboratory medicine has undergone monumental changes, and laboratory technology, which has made enormous advances, now has new clinical applications thanks to the identification of a growing number of biomarkers and risk factors conducive to the promotion of predictive and preventive interventions that have enhanced the role of laboratory medicine in health care delivering. However, the paradigm shift in the past 50 years has led to a gap between laboratory and clinic, with an increased risk of inappropriateness in test request and interpretation, as well as the consolidation of analytical work in focused factories and megastructurers oriented only toward achieving greater volumes, decreasing cost per test and generating a vision of laboratory services as simple commodities. A careful historical revision of the changing models for delivering laboratory services in the United States leads to the prediction that there are several reasons for counteracting the vision of clinical laboratory as a commodity, and restoring the true nature of laboratory services as an integral part of the diagnosis and therapy process. The present study, which reports on internal and external drivers for change, proposes an integrated vision of quality in laboratory medicine. PMID- 29427553 TI - Carboxylesterase 1 genes: systematic review and evaluation of existing genotyping procedures. AB - The carboxylesterase 1 gene (CES1) encodes a hydrolase that metabolizes commonly used drugs. The CES1-related pseudogene, carboxylesterase 1 pseudogene 1 (CES1P1), has been implicated in gene exchange with CES1 and in the formation of hybrid genes including the carboxylesterase 1A2 gene (CES1A2). Hence, the CES1 region is complex. Using in silico PCR and alignment, we assessed the specificity of PCR-assisted procedures for genotyping CES1, CES1A2 and CES1P1 in studies identified in PubMed. We identified 33 such studies and excluded those that were not the first to use a procedure or lacked sequence information. After this 17 studies remained. Ten of these used haplotype-specific amplification, restriction enzyme treatment or amplicon sequencing, and included five that were predicted to lack specificity. All procedures for genotyping of single nucleotide polymorphisms in eight studies lacked specificity. One of these studies also used amplicon sequencing, thus being present in the group above. Some primers and their intended targets were mismatched. We provide experimental evidence that one of the procedures lacked specificity. Additionally, a complex pattern of segmental duplications in the CES1 region was revealed. In conclusion, many procedures for CES1, CES1A2 and CES1P1 genotyping appear to lack specificity. Knowledge about the segmental duplications may improve the typing of these genes. PMID- 29427554 TI - Sporadic pediatric papillary thyroid carcinoma harboring the ETV6/NTRK3 fusion oncogene in a 7-year-old Japanese girl: a case report and review of literature. AB - BACKGROUND: There have been great concerns about pediatric thyroid cancers after the accident at the Fukushima Daiichi Nuclear Power Plant in 2011. CASE PRESENTATION: We report a case of a 7-year-old Japanese girl with sporadic papillary thyroid carcinoma (PTC) harboring an ETV6/NTRK3 rearrangement. The patient presented with tumors in both lobes and underwent thyroidectomy followed by radioactive iodine (RAI) ablation. Histopathology showed a classic type of PTC with cervical lymph node metastasis. CONCLUSIONS: Genetic evaluation showed ETV6/NTRK3 fusion but no BRAF mutations or RET/PTC rearrangements. RET/PTC rearrangement and BRAF mutations often contribute to the pathogenesis of PTC; however, rearrangements of NTRK genes are relatively rare in pediatric PTC. Although NTRK rearrangement has been shown to often present unique pathological types and infiltrative architectures in the western population, such findings were not observed in this patient. Thus, the present case of classic PTC with ETV6/NTRK3 rearrangement highlights the disparate collection of clinic pathological features compared to the trend in the western population. We therefore emphasize the need to further accumulate clinical as well as genetic data in pediatric PTCs. PMID- 29427555 TI - Therapeutic adherence in patients with systemic lupus erythematosus: a cross sectional study. AB - INTRODUCTION: The aim of the research was the study of the adherence to treatment in patients with systemic lupus erythematosus. METHODS: Cross-sectional study including 132 consecutive patients with systemic lupus erythematosus (SLICC, 2012 classification criteria). We collected clinical and socio-demographic data, socio economic status; we assessed SLEDAI-2k disease activity, and estimated the adherence to treatment by Morisky questionnaire. RESULTS: Our results demonstrated that low adherence to treatment in patients with systemic lupus erythematosus was in only 11.36% of patients, while 43.18% and 45.46% of the patients were scored as moderate and high adherence, respectively. A moderate/high adherence to treatment was associated to a high level of education (r = -0.51, p < 0.05, 95% CI = -0.25 to -0.66), low disease activity (r = 0.38, p < 0.05, 95% CI = 0.25 to 0.53) and low indices of physician global assessment (r = -0.31, p<0.05, 95% CI = -0.23 to -0.71). The sub-analysis of the adherence to each drug demonstrated that the highest adherence was to treatment with glucocorticosteroids - 92.85%, followed by hydroxychloroquine and aspirin - 92.15% and 89.79%, respectively. CONCLUSION: In our cohort, the adherence to treatment was high in 45.46%, moderate in 43.18% and low in only 11.36% cases. High adherence to treatment was associated to low disease activity. The adherence was positively influenced by the age at the onset of the disease and a high educational level. PMID- 29427556 TI - Correlation between neutrophil-to-lymphocyte ratio and severity scores in septic patients upon hospital admission. A series of 50 patients. AB - INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) as calculated from the white cell differential blood count is a marker that has been used as a prognostic index when assessing patients suffering from several clinical syndromes, including sepsis. The aim of this study was to evaluate the relationship between NLR and the commonly used severity scores of sepsis SOFA, APACHE II and SAPS II in a population of emergency admitted adult patients with sepsis in a tertiary center. METHODS: A prospective observational study was conducted in the Emergency Department of the University Hospital of Patras, Greece, based on data extracted from 50 patients consecutively enrolled, suffering from sepsis of multiple origin. The study period was from May 01, 2017 until June 30, 2017. The NLR was calculated from the total white blood cell (WBC) count values measured from a peripheral venous blood specimen drawn on admission. C-reactive protein (CRP) was also measured. The sepsis severity prognostic scores APACHE II, SAPS II and SOFA were calculated for each patient. RESULTS: NLR was positively correlated with the sepsis severity prognostic scores on admission (SOFA, rs = 0.497, p < 0.001; APACHE II, rs = 0.411, p = 0.003; SAPS II, rs = 0.445, p = 0.001). Total WBC was also significantly correlated with the scores (SOFA, rs = 0.342, p = 0.015; APACHE II, rs = 0.384, p = 0.006; SAPS II, rs = 0.287, p = 0.043). Serum CRP did not show any significant correlation either to NLR or to the sepsis severity scores on admission. CONCLUSIONS: NLR is an easily calculated, cost-efficient index that could be used as a tool for clinicians when assessing sepsis patients in the Emergency Department. Although NLR measurement is simple, and rapidly available, future and larger prospective studies are warranted to confirm its definite value as a prognostic index in sepsis patients. PMID- 29427557 TI - Motor unit number index: Guidelines for recording signals and their analysis. AB - INTRODUCTION: This study proposes guidelines for motor unit number index (MUNIX) recording and analysis. METHODS: MUNIX was measured in control participants and in patients with amyotrophic lateral sclerosis. Changes in MUNIX values due to E1 electrode position, number of surface electromyography interference pattern (SIP) epochs, SIP epoch duration, force of contraction, and outlier data points were investigated. RESULTS: MUNIX depends on optimized compound muscle action potential (CMAP) amplitude. Individual muscles showed variations when the number of epochs was low or when the SIP duration was short. Longer SIP duration allowed better recognition of artifacts. MUNIX results were affected by SIP values at all force levels but was more affected when SIP area was low. DISCUSSION: We recommend changing the E1 electrode position to maximize CMAP amplitude. Twenty or more SIP signals of 500-ms duration should be recorded by using force levels ranging from slight to maximum. Traces should be reviewed to identify and exclude signals with tremor or solitary spikes. Muscle Nerve 58: 374-380, 2018. PMID- 29427558 TI - The ABC of adaptive immunity in liver cancer. PMID- 29427559 TI - Gradient-based optimization with B-splines on sparse grids for solving forward dynamics simulations of three-dimensional, continuum-mechanical musculoskeletal system models. AB - Investigating the interplay between muscular activity and motion is the basis to improve our understanding of healthy or diseased musculoskeletal systems. To be able to analyze the musculoskeletal systems, computational models are used. Albeit some severe modeling assumptions, almost all existing musculoskeletal system simulations appeal to multibody simulation frameworks. Although continuum mechanical musculoskeletal system models can compensate for some of these limitations, they are essentially not considered because of their computational complexity and cost. The proposed framework is the first activation-driven musculoskeletal system model, in which the exerted skeletal muscle forces are computed using 3-dimensional, continuum-mechanical skeletal muscle models and in which muscle activations are determined based on a constraint optimization problem. Numerical feasibility is achieved by computing sparse grid surrogates with hierarchical B-splines, and adaptive sparse grid refinement further reduces the computational effort. The choice of B-splines allows the use of all existing gradient-based optimization techniques without further numerical approximation. This paper demonstrates that the resulting surrogates have low relative errors (less than 0.76%) and can be used within forward simulations that are subject to constraint optimization. To demonstrate this, we set up several different test scenarios in which an upper limb model consisting of the elbow joint, the biceps and triceps brachii, and an external load is subjected to different optimization criteria. Even though this novel method has only been demonstrated for a 2-muscle system, it can easily be extended to musculoskeletal systems with 3 or more muscles. PMID- 29427560 TI - Enteral Nutrition: Options for Short-Term Access. AB - The preferred method of nutrition support in the presence of a functional gastrointestinal tract is enteral nutrition (EN). Many factors contribute to the selection process for the type of enteral access device to be used. Short-term enteral access tubes are placed into the nares or, sometimes, orally, usually at bedside. The short-term access provides a means to meet patient nutrient needs and can provide a chance to assess tolerance of the tube feedings if more permanent long-term placement is determined to be required. Access for nutrition support does not come without a risk; it can be challenging, requiring an individualized approach for each patient. The selection type and access location can greatly impact the success of EN. The most advantageous tube choice must be determined carefully, taking into account the multiple considerations reviewed in this paper. PMID- 29427561 TI - Cerebellar herniation demonstrated by the occipitum-dens line: Ultrasonography assessment of normal fetuses, fetuses with myelomeningocele, and fetuses that underwent antenatal myelomeningocele surgery. AB - OBJECTIVE: To establish a method to quantify the position of the cerebellum by ultrasonography in normal fetuses, fetuses with myelomeningocele (MMC), and fetuses that underwent in utero MMC repair. METHODS: Reference points identifiable on ultrasound were established. The basilar portion of the occipital bone and upper portion of the odontoid process were considered as the external and internal limits, respectively, of the level zero of a line that was designated the occipitum-dens line (ODL). Eighty-three normal fetuses were assessed 1 occasion (cross-sectional study) in addition to 25 fetuses with MMC and 25 fetuses that underwent in utero MMC repair. The groups were compared using analysis of variance or the Kruskal-Wallis test. The intraclass correlation coefficient (ICC) was used to determine intra- and interobserver reproducibility. RESULTS: The analysis of ODL indicated that all normal fetuses had the cerebellar tonsil above level zero at a mean distance of 2.8 +/- 1.1 mm (P = 0.125). The fetuses with MMC had the cerebellar tonsil below level zero, except in 2 cases of myelocystocele. All the fetuses that underwent in utero MMC repair exhibited regression of the cerebellar herniation (0.5 mm per week, P < 0.005). Herniation increased gradually (1.0 mm per week, P < 0.005) in fetuses that did not undergo MMC repair. ICC indicated good intra- and interobserver reproducibility (0.996 and 0.983, respectively). CONCLUSION: The reference points for ODL may be used to assess cerebellar height. ODL allowed the demonstration of the regression of cerebellar herniation in fetuses that underwent in utero MMC repair. PMID- 29427562 TI - Liver paired exchange: Can the liver emulate the kidney? AB - Kidney paired exchange (KPE) constitutes 12% of all living donor kidney transplantations (LDKTs) in the United States. The success of KPE programs has prompted many in the liver transplant community to consider the possibility of liver paired exchange (LPE). Though the idea seems promising, the application has been limited to a handful of centers in Asia. In this article, we consider the indications, logistical issues, and ethics for establishing a LPE program in the United States with reference to the principles and advances developed from experience with KPE. Liver Transplantation 24 677-686 2018 AASLD. PMID- 29427563 TI - Promoting delayed umbilical cord clamping: an educational intervention in a rural hospital. PMID- 29427564 TI - On "Variation in Cesarean Birth Rates by Labor and Delivery Nurses". PMID- 29427565 TI - Intensified training increases salivary free light chains in trained cyclists: Indication that training volume increases oral inflammation. AB - Periods of short-term intensified training (IT) are often used by athletes during training cycles over the season and undergoing phases of increased physical stress may impact upon the immune system. This study investigated the effects of a period of IT on free light chains (FLCs) in saliva - an emerging immune biomarker of oral inflammation - and matched serum samples in well-trained athletes. It also examined if IT influences basal FLC levels and FLC flux during acute exercise. Highly trained male cyclists (n = 10) underwent a 9-day period of IT; before and after IT participants performed a 1 h time trial (TT) on a cycle ergometer, with blood and saliva samples collected pre- and post-exercise. FLCs were assessed in serum and saliva, and IgG, IgA, IgM and creatinine were also measured in serum. Weekly training volume increased by 143% (95% CI 114-172%), p < 0.001, during IT compared with pre-trial baseline training. Following IT, the cyclists demonstrated higher salivary FLC levels. Both salivary lambda FLC concentrations (p < 0.05, eta2 = 0.384) and secretion rates, and kappa FLC concentrations and secretion rates increased after IT. Salivary FLCs concentration and secretion rates decreased in response to the TT following IT (p < 0.05, eta2 = 0.387-0.428), but not in response to the TT prior to IT. No significant effects of IT on serum FLCs were observed. There were no significant changes in serum FLCs in response to the TT, before or after the IT period, nor did IT impact upon other serological responses to the TT. In conclusion, IT increased basal salivary FLC parameters and amplified decreases in salivary FLCs in response to acute exercise. Increases in salivary FLC concentration likely reflects alterations to oral inflammation during times of heavy training, and we show for the first time that FLCs may have utility as a marker of exercise stress and oral health status. PMID- 29427566 TI - Does the phycotoxin Okadaic acid cause oxidative stress damages and histological alterations to seabream (Sparus aurata)? AB - Okadaic Acid (OA) is a marine toxin responsible for DSP (Diarrheic Shellfish Poisoning) in humans produced by dinoflagellate. The genotoxic and cytotoxic effects of OA have been well reported in mammalian experimental animals and in vitro cultured cells. However, there are no available investigations regarding the involvement of the oxidative stress pathways in OA toxicity, especially on aquatic animals such as fish. In this context, we aimed in the present work to demonstrate whether OA (7.5 MUg/ml) induces oxidative stress and histopathological damages in the fish species Sparus aurata under short term exposure (2 h, 4 h and 24 h). To this end, we have assessed lipid peroxidation and anti-oxidative stress response in liver tissue, and finally ultrastructural changes were investigated in hepatic and gills tissues. Our results clearly showed that OA induced significant enhancement in all tested parameters in a time dependent manner and seems to be a strong inducer of oxidative stress in aquatic animals. The data of the present study indicate also that histology is a successful tool to reveal OA impact on liver and gill tissues of Sparus aurata since the animal showed vascular dilation and hepatocellular membrane disintegration in liver and hypertrophy in secondary lamellae and necrotic aspect in the primary lamellae in gill tissue. PMID- 29427567 TI - The biosynthesis of 15N-labeled microcystins and the comparative MS/MS fragmentation of natural abundance and their 15N-labeled congeners using LC MS/MS. AB - The global need for accurate and sensitive quantitation of microcystins (MCs) persists as incidents of cyanobacterial harmful algal blooms continue to rise and recent research reveals an underestimation of the human health implications of these toxins. An optimal approach for their accurate quantitation relies on the availability of stable isotope-labeled MC standards for use in stable isotope dilution analysis (SIDA) strategies involving liquid chromatography tandem mass spectrometry (LC-MS/MS). Due to the dearth of isotopically labeled MCs, ten different 15N-enriched MCs were biosynthesized from producing cultures and fully characterized. This involved the comparative MS/MS fragmentation of natural abundance or unlabeled metabolites with their 15N-labeled congeners for improved confidence in product ion annotation. These results revealed a series of incorrect annotations described previously in the literature. In this manuscript, the biosynthesis of labeled microcystin is detailed, and their complete analytical characterization for prospective use in targeted SIDA applications, such as routine water testing is described. PMID- 29427568 TI - Aging and nutrition induce tissue-specific changes on global DNA methylation status in rats. AB - A number of epigenetic studies have demonstrated that DNA methylation patterns exhibit a tissue specificity, but not much has been done to highlight the extent of this phenomenon. Moreover, it is unknown how external factors modulate the plasticity of the tissue specific epigenetic profile. We examined global DNA methylation profiles in tissues from rats of different age, fed with standard or low-calorie diet, and evaluated their association with aging and nutrition. Tissue-specific variations occur during aging with hyper-methylation taking place in all tissues except for liver. The expression of enzymes involved in methylation reactions (DNMTs and TETs) was consistent with the methylation patterns. Nutrition affects global DNA methylation status throughout lifespan. Interestingly, the differences among different tissues are magnified in 96 weeks old rats fed with low calorie diet. Moreover, the low-calorie diet appears to affect the offspring's epigenetic status more strongly if administered during the maternal pre-gestational period than the gestational and lactation time. Therefore, we propose that changes in the global DNA methylation status may represent an epigenetic mechanism by which age and nutrition intersect each other and, in turn, influence the aging plasticity. PMID- 29427569 TI - Re: Brown et al.: Percutaneous Vesicoscopic Approach for Retrograde Ureteroscopy Following Cohen Cross-trigonal Ureteral Reimplantation (Urology 2018;111:186 188). PMID- 29427570 TI - Long-term Outcome of Pars Plana Vitrectomy and Sutured Scleral-Fixated Posterior Chamber Intraocular Lens Implantation or Repositioning. AB - PURPOSE: To assess the long-term stability of sutured scleral-fixated posterior chamber intraocular lenses (PCIOLs) performed in combination with pars plana vitrectomy. DESIGN: Retrospective, consecutive, interventional case series. METHODS: Retrospective single-surgeon study of 118 eyes of 111 patients seen at Retina Consultants of Hawaii, who underwent sutured scleral fixation of at least 1 haptic of a posterior chamber intraocular lens with 10-0 polypropylene combined with a pars plana vitrectomy. The fixation knot-tying technique required 2 separate 10-0 polypropylene sutures tied into 1 combined knot-1 suture closed the fixation sclerotomy and created the scleral fixation, and 1 suture looped together around the haptic of the PCIOL, securing the haptic to the scleral fixation site. The primary outcomes were position of the PCIOL at last follow-up, dislocation of either 1 or both haptics of the PCIOL, and breakage of the 10-0 polypropylene fixation suture. RESULTS: PCIOLs remained well stabilized and positioned at last follow-up in 116 of 118 eyes (98.3%), with a mean follow-up of 6.0 years. The maximum stable follow-up with 2 intact fixation sutures was 24.75 years. There were 4 cases of redislocation (3.4%), but 2 cases were owing to unstable residual capsular support. There was 1 case of suture breakage in 214 fixation sutures (0.47%) and 1 case of haptic breakage. CONCLUSIONS: Scleral fixation sutures with 10-0 polypropylene provide excellent long-term fixation of PCIOLs, with a less than 0.5% incidence of suture breakage and documented suture stability for up to 24+ years. PMID- 29427571 TI - Feature-based information filtering in visual working memory is impaired in Parkinson's disease. AB - Increasing attention has been given to working memory (WM) impairment in Parkinson's disease (PD) patients. Previous studies revealed that the space orientated feature-based filtering (target and distractors in distinct locations) was impaired in PD patients. However, the object-orientated feature-based filtering (target and distractor information pertaining to one object) ability in PD patients remains unclear. In this study, we examined the object-orientated feature-based filtering ability of 14 PD patients and 14 healthy controls in a change detection task under EEG monitoring. Participants were asked to remember the colors of two different objects while ignoring their shapes. Critically, the irrelevant feature could be changed in the probe. A failure in complete feature based filtering would lead to an "irrelevant-change distracting effect," where the change of the irrelevant feature would impair the performance of the target feature, and lead to an enhanced anterior N2. We found that the distracting effect was larger in PD patients than in the control group in terms of d'; however, the N2 amplitude evoked by the irrelevant change was smaller in PD patients than in the control group. These results suggested that the object orientated feature-based filtering ability was impaired in PD, which might derive from the deficit of their executive control. PMID- 29427572 TI - EEG measures of brain activity reveal that smoking-related images capture the attention of smokers outside of awareness. AB - The capture of attention by substance-related stimuli in dependent users is a major factor in the maintenance and/or cessation of substance use. The present study examined the automaticity of this process in smokers, as well as the effects of craving. Event-related potential (ERP) measures of spatial-attention allocation (N2pc) and extended target processing (SPCN) were isolated during an object-substitution masking (OSM) task that disrupted the perceptual visibility of smoking-related and office-related targets. Each participant completed two experimental sessions: one in which they were deprived of nicotine for a period of several hours prior to the session (craving), and one before which they were allowed to smoke (non-craving). Results were consistent with an account of automatic attentional capture by smoking-related images outside of awareness, with masked trials yielding a selective enhancement of the attention-sensitive N2pc in response to these images, but in the absence of a corresponding behavioral enhancement on those trials. Finally, the manipulation of craving appeared to increase the overall task demand, yielding an enhancement of the SPCN component across target type and masking conditions. Together, these results suggest that smoking-related visual stimuli in the environment can capture the attention of smokers outside of awareness, in what seems to be an automatic process. PMID- 29427573 TI - Cryoprotective role of organic Zn and Cu supplementation in goats (Capra hircus) diet. AB - The current study focused on cryopreservation and assessment of characters of post-thaw semen of indigenous Osmanabadi bucks maintained with standard diet, supplemented with different concentrations of organic zinc (Zn), copper (Cu) or in combination, for a period of 180 days. The different doses of organic Zn and Cu were fed per kg DM basis, Zn groups (low: Zn20, medium: Zn40 and high: Zn60), Cu groups: (low: Cu12.5, medium: Cu25 and high: Cu37.5) and combination of Zn + Cu groups (low: Zn20 + Cu12.5, medium: Zn40 + Cu25 and high: Zn60 + Cu37.5) respectively. The control group bucks were maintained mainly on the basal diet without any additional mineral supplementation. Two hundred and forty (240) semen samples were collected from 40 bucks aged 11 months, through electro ejaculator method, processed and analysed for sperm quality parameters both at pre freeze and post-thaw stage. The semen samples were diluted in Tris egg yolk extender, cooled and equilibrated for 4 h at 5 degrees C, cryopreserved using programmable freezer (PLANER Kryo 360-1.7) and stored at -196 degrees C. The organic trace minerals (Zn, Cu and Zn + Cu) protected the spermatozoa against the cryoinjury and maintained higher post-thaw semen parameters except in high Zn group. Additional feeding of organic Cu and Zn to bucks had a protective role and resulted in higher sperm liveability, plasma membrane and acrosome integrities, motility and velocity and reduced oxidative stress in supplemented goats (P < 0.05). PMID- 29427574 TI - New product identification in the sterol metabolism by an industrial strain Mycobacterium neoaurum NRRL B-3805. AB - Mycobacterium neoaurum NRRL B-3805 metabolizes sterols to produce androst-4-en 3,17-dione (AD) as the main product, and androsta-1,4-dien-3,17-dione, 9alpha hydroxy androst-4-en-3,17-dione and 22-hydroxy-23,24-bisnorchol-4-en-3-one have been identified as by-products. In this study, a new by-product was isolated from the metabolites of sterols and identified as methyl 3-oxo-23,24-bisnorchol-4-en 22-oate (BNC methyl ester), which was proposed to be produced via the esterification of BNC catalyzed by an O-methyltransferase using S-adenosyl-l methionine as the methyl group donor. These results might open a new dimension for improvement of the efficiency of microbial AD production by eliminating this by-product via genetic manipulation of the strain. PMID- 29427575 TI - Rhythm Perception and Production Abilities and Their Relationship to Gait After Stroke. AB - OBJECTIVES: To assess rhythm abilities, to describe their relation to clinical presentation, and to determine if rhythm production independently contributes to temporal gait asymmetry (TGA) poststroke. DESIGN: Cross-sectional. SETTING: Large urban rehabilitation hospital and university. PARTICIPANTS: Individuals (N=60) with subacute and chronic stroke (n=39) and data for healthy adults extracted from a preexisting database (n=21). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Stroke group: National Institutes of Health Stroke Scale (NIHSS), Chedoke-McMaster Stroke Assessment (CMSA) leg and foot scales, Montreal Cognitive Assessment (MoCA), rhythm perception and production (Beat Alignment Test [BAT]), and spatiotemporal gait parameters were assessed. TGA was quantified with the swing time symmetry ratio. Healthy group: age and beat perception scores assessed by the BAT. Rhythm perception of the stroke group and healthy adults was compared with analysis of variance. Spearman correlations quantified the relation between rhythm perception and production abilities and clinical measures. Multiple linear regression assessed the contribution of rhythm production along with motor impairment and time poststroke to TGA. RESULTS: Rhythm perception in the stroke group was worse than healthy adults (F1,56=17.5, P=.0001) Within the stroke group, rhythm perception was significantly correlated with CMSA leg (Spearman rho=.33, P=.04), and foot (Spearman rho=.49, P=.002) scores but not NIHSS or MoCA scores. The model for TGA was significant (F3,35=12.8, P<.0001) with CMSA leg scores, time poststroke, and asynchrony of rhythm production explaining 52% of the variance. CONCLUSIONS: Rhythm perception is impaired after stroke, and temporal gait asymmetry relates to impairments in producing rhythmic movement. These results may have implications for the use of auditory rhythmic stimuli to cue motor responses poststroke. Future work will explore brain responses to rhythm processing poststroke. PMID- 29427576 TI - Clinical and Safety Outcomes of Long-Term Azithromycin Therapy in Severe COPD Beyond the First Year of Treatment. AB - BACKGROUND: Exacerbations of COPD (ECOPD) are a major cause of mortality and morbidity. Continuous cyclic azithromycin (CC-A) reduces the exacerbation rate, but it is unknown whether it remains effective and safe beyond the first year. METHODS: This study was a retrospective analysis of patients with severe COPD (Global Initiative for Chronic Obstructive Lung Disease grade D) with >= 4 moderate to severe ECOPD who received CC-A (500 mg three times per week) as add on therapy. Patients treated over 24 months were considered long-term continuous cyclic azithromycin (LT-CC-A) users, and ECOPD, hospitalizations, and length of hospital stays during the first, second, and third years were compared with the previous 12 months. Microbiologic monitoring, assessment of macrolide resistance, and analysis of side effects were maintained throughout the study period. RESULTS: A total of 109 patients with severe COPD treated with CC-A (39 for >= 24 months) comprised the LT-CC-A group (35.8%). This group presented average reductions in ECOPD from baseline of 56.2% at 12 months, 70% at 24 months, and 41% at 36 months, paralleled by respective reductions in hospitalizations of 62.6%, 75.8%, and 39.8%. ECOPD due to common microorganisms fell by 12.5% and 17.3% at 12 and 24 months of LT-CC-A, respectively, with a 50% increase in macrolide resistance. Pseudomonas aeruginosa ECOPD rose by 7.2% and 13.1% at these two time points. CC-A therapy was well tolerated with few side effects: digestive disorders in the short term (7.1%) and hearing loss in the long term (5.1%). CONCLUSIONS: LT-CC-A therapy over a 24- to 36-month period in patients with COPD (Global Initiative for Chronic Obstructive Lung Disease grade D) achieved sustained reductions in ECOPD and hospitalizations of > 50% with few adverse events, although macrolide resistance increased. PMID- 29427577 TI - Perception of facial expressions of emotion in migraine. AB - Both lower-level perceptual changes and especially higher-level cognitive alterations in individuals with migraine are poorly understood. Here, we behaviorally and electrophysiologically investigated the perception of emotional facial expressions in migraine. Young female individuals with migraine and healthy controls watching neutral faces gradually shifting to either happy, fearful, or angry expressions were asked to classify the facial expressions as quickly and accurately as possible by pressing a corresponding button, and to keep looking at the face until the last frame disappeared. Migraine individuals, compared to healthy controls, had a reduced habituation in the N170 time interval towards a gradually emerging emotional expression. The early P1, the early posterior negativity (EPN), and the late positive potential (LPP) amplitudes were not statistically different between groups and among expressions. The mean reaction time for recognizing an expression did not differ between groups and it was not at a cost of more incorrect responses. Interestingly, the amplitude of the early posterior negativity correlated negatively with the time interval since the last attack. It is concluded that young female individuals with migraine, compared to healthy controls, do not show a biased emotional facial processing toward positive or negative expressions. PMID- 29427578 TI - Hippocampal subfield volume changes in subtypes of attention deficit hyperactivity disorder. AB - OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) is accompanied by reduction of total hippocampal volume. However, disorder-related fine-grained structural alterations of hippocampal subfields remain unclear. METHOD: Here we compared hippocampal subfield volumes in a large sample of patients with ADHD and healthy controls. We used T1-weighted structural 3-Tesla MRI images of 880 individuals (7-21 years old) from the ADHD-200 database. The images were acquired from 553 healthy individuals and 327 children and adolescents with combined (N = 196) and inattentive (N = 131) ADHD subtypes. Hippocampal subfields were segmented into the cornu amonis regions (CA1, CA2/3, CA4), fimbria, hippocampal fissure, presubiculum, subiculum, hippocampal tail, parasubiculum, granule cell layers of the dentate gyrus, molecular layer within the subiculum and the CA fields, and the hippocampal-amygdala transition area using an automatic algorithm available in Freesurfer 6.0. RESULTS: We found a significant reduction of total hippocampal volume in the combined ADHD group compared to healthy controls. This reduction was due to the atrophy of CA1, CA4, molecular layer, granule cell layers of the dentate gyrus, presubiculum, subiculum, and hippocampal tail. These differences were exclusively driven by the corresponding brain volume reduction in the combined ADHD-subtype, while hippocampal volumes in inattentive ADHD showed no reliable differences relative to controls. Finally, there were negative correlations between the reduced hippocampal subfields and behavioral ADHD indices. CONCLUSION: The present results point to a clear dissociation between inattentive and combined subtypes of ADHD. Therefore, hippocampal subfields may contribute towards understanding the pathophysiology of ADHD. PMID- 29427580 TI - Lost in Inflammation: The Functional Conversion of Regulatory T Cells in Acute Hepatitis A Virus Infection. PMID- 29427579 TI - Protective effects of yangonin from an edible botanical Kava against lithocholic acid-induced cholestasis and hepatotoxicity. AB - Accumulation of toxic bile acids in liver could cause cholestasis and liver injury. The purpose of the current study is to evaluate the hepatoprotective effect of yangonin, a product isolated from an edible botanical Kava against lithocholic acid (LCA)-induced cholestasis, and further to elucidate the involvement of farnesoid X receptor (FXR) in the anticholestatic effect using in vivo and in vitro experiments. The cholestatic liver injury model was established by intraperitoneal injections of LCA in C57BL/6 mice. Serum biomarkers and H&E staining were used to identify the amelioration of cholestasis after yangonin treatment. Mice hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying yangonin hepatoprotection. The results indicated that yangonin promoted bile acid efflux and reduced hepatic uptake via an induction in FXR-target genes Bsep, Mrp2 expression and an inhibition in Ntcp, all of which are responsible for bile acid transport. Furthermore, yangonin reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1, which are involved in bile acid synthesis and metabolism. In addition, yangonin suppressed liver inflammation through repressing inflammation-related gene NF-kappaB, TNF-alpha and IL-1beta. In vitro evidences showed that the changes in transporters and enzymes induced by yangonin were abrogated when FXR was silenced. In conclusions, yangonin produces protective effect against LCA-induced hepatotoxity and cholestasis due to FXR mediated regulation. Yangonin may be an effective approach for the prevention against cholestatic liver diseases. PMID- 29427581 TI - Returning to (Electronic) Health Records That Guide and Teach. PMID- 29427582 TI - Increased plasma nesfatin-1 levels may be associated with corticosterone, IL-6, and CRP levels in patients with major depressive disorder. AB - OBJECTIVES: The aim of the present study was to evaluate the plasma nesfatin-1, corticosterone, and inflammatory cytokine (IL-6, CRP, and TNF-alpha) concentrations cross-sectionally in patients with major depressive disorder. METHODS: Subjects in the patient group were randomly selected from the Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. Healthy control subjects were matched in terms of weight and body mass index. The Hamilton Depression Rating Scale (HAM-D) was used to evaluate both groups. ELISAs were used for the measurement of plasma nesfatin-1, corticosterone, IL-6, CRP, and TNF-alpha levels. RESULTS: The HAM-D scores and average nesfatin-1, corticosterone, IL-6, and CRP levels were significantly higher in patients with major depressive disorder than those in the control group. Positive correlation was found between nesfatin-1 and corticosterone (r = 0.305, P = 0.007), IL-6 (r = 0.333, P = 0.003), and CRP (r = 0.244, P = 0.034) concentrations. CONCLUSIONS: Increased plasma nesfatin-1 levels may be associated with corticosterone, IL-6, and CRP levels in patients with major depressive disorder. PMID- 29427583 TI - A gut feeling: Microbiome-brain-immune interactions modulate social and affective behaviors. AB - The expression of a wide range of social and affective behaviors, including aggression and investigation, as well as anxiety- and depressive-like behaviors, involves interactions among many different physiological systems, including the neuroendocrine and immune systems. Recent work suggests that the gut microbiome may also play a critical role in modulating behavior and likely functions as an important integrator across physiological systems. Microbes within the gut may communicate with the brain via both neural and humoral pathways, providing numerous avenues of research in the area of the gut-brain axis. We are now just beginning to understand the intricate relationships among the brain, microbiome, and immune system and how they work in concert to influence behavior. The effects of different forms of experience (e.g., changes in diet, immune challenge, and psychological stress) on the brain, gut microbiome, and the immune system have often been studied independently. Though because these systems do not work in isolation, it is essential to shift our focus to the connections among them as we move forward in our investigations of the gut-brain axis, the shaping of behavioral phenotypes, and the possible clinical implications of these interactions. This review summarizes the recent progress the field has made in understanding the important role the gut microbiome plays in the modulation of social and affective behaviors, as well as some of the intricate mechanisms by which the microbiome may be communicating with the brain and immune system. PMID- 29427584 TI - Discordance between Ureteroscopic Biopsy and Final Pathology for Upper Tract Urothelial Carcinoma. AB - PURPOSE: We evaluated the discordance between ureteroscopic biopsy and surgical pathology findings for grading and staging upper tract urothelial carcinoma. We also sought to establish preoperative predictors of aggressive tumors. MATERIALS AND METHODS: We retrospectively reviewed the records of 314 patients who underwent ureteroscopic biopsy followed by surgical management of upper tract urothelial carcinoma from 2000 to 2016 at a total of 3 institutions. Our primary outcomes were muscle invasive (pT2 or greater) disease at surgical pathology and upgrading of clinical low grade tumors to pathological high grade. RESULTS: At biopsy 61% of the patients had clinical high grade tumors and 21% had subepithelial connective tissue invasion (cT1+). On final pathology 79% of the patients had pathological high grade tumors and 45% had stage pT2 or greater. On multivariate analysis advanced patient age, clinical high grade and cT1+ were independently associated with pT2 or greater. The combined presence of clinical high grade and cT1+ had 86% positive predictive value for muscle invasion while the combined absence of clinical high grade and cT1+ had 80% negative predictive value. The likelihood of missing invasion on biopsy in patients with muscle invasive disease was increased when biopsy fragments were limited to 1 mm or less. Of clinical low grade cases on biopsy 51% were upgraded at surgery. The presence of positive urine cytology was associated with an increased risk of upgrading but this was not statistically significant. CONCLUSIONS: Clinical high grade, cT1+ on biopsy and advanced patient age are independent risk factors for muscle invasive upper tract urothelial carcinoma. There is a significant risk of upgrading in patients with clinical low grade tumors on biopsy, especially when urine cytology is positive. The predictive value of biopsy can likely be improved by more extensive ureteroscopic sampling. PMID- 29427585 TI - Vildagliptin Significantly Increases the Risk of Bullous Pemphigoid: A Finnish Nationwide Registry Study. PMID- 29427587 TI - Highly Sensitive Virome Capture Sequencing Technique VirCapSeq-VERT Identifies Partial Noncoding Sequences but no Active Viral Infection in Cutaneous T-Cell Lymphoma. PMID- 29427586 TI - Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase. AB - Tyrosinase is the rate-limiting enzyme of melanin production and, accordingly, is the most prominent target for inhibiting hyperpigmentation. Numerous tyrosinase inhibitors have been identified, but most of those lack clinical efficacy because they were identified using mushroom tyrosinase as the target. Therefore, we used recombinant human tyrosinase to screen a library of 50,000 compounds and compared the active screening hits with well-known whitening ingredients. Hydroquinone and its derivative arbutin only weakly inhibited human tyrosinase with a half-maximal inhibitory concentration (IC50) in the millimolar range, and kojic acid showed a weak efficacy (IC50 > 500 MUmol/L). The most potent inhibitors of human tyrosinase identified in this screen were resorcinyl-thiazole derivatives, especially the newly identified Thiamidol (Beiersdorf AG, Hamburg, Germany) (isobutylamido thiazolyl resorcinol), which had an IC50 of 1.1 MUmol/L. In contrast, Thiamidol only weakly inhibited mushroom tyrosinase (IC50 = 108 MUmol/L). In melanocyte cultures, Thiamidol strongly but reversibly inhibited melanin production (IC50 = 0.9 MUmol/L), whereas hydroquinone irreversibly inhibited melanogenesis (IC50 = 16.3 MUmol/L). Clinically, Thiamidol visibly reduced the appearance of age spots within 4 weeks, and after 12 weeks some age spots were indistinguishable from the normal adjacent skin. The full potential of Thiamidol to reduce hyperpigmentation of human skin needs to be explored in future studies. PMID- 29427588 TI - Hyperpolarization by N-(3-oxododecanoyl)-l-homoserine-lactone, a quorum sensing molecule, in rat thymic lymphocytes. AB - To study the adverse effects of N-(3-oxododecanoyl)-l-homoserine-lactone (ODHL), a quorum sensing molecule, on mammalian host cells, its effect on membrane potential was examined in rat thymic lymphocytes using flow cytometric techniques with a voltage-sensitive fluorescent probe. As 3-300 MUM ODHL elicited hyperpolarization, it is likely that it increases membrane K+ permeability because hyperpolarization is directly linked to changing K+ gradient across membranes, but not Na+ and Cl- gradients. ODHL did not increase intracellular Ca2+ concentration. ODHL also produced a response in the presence of an intracellular Zn2+ chelator. Thus, it is unlikely that intracellular Ca2+ and Zn2+ are attributed to the response. Quinine, a non-specific K+ channel blocker, greatly reduced hyperpolarization. However, because charybdotoxin, tetraethylammonium chloride, 4-aminopyridine, and glibenclamide did not affect it, it is pharmacologically hypothesized that Ca2+-activated K+ channels, voltage gated K+ channels, and ATP-sensitive K+ channels are not involved in ODHL-induced hyperpolarization. Although the K+ channels responsible for ODHL-induced hyperpolarization have not been identified, it is suggested that ODHL can elicit hyperpolarization in mammalian host cells, disturbing cellular functions. PMID- 29427590 TI - Antioxidant potentials of nanoceria synthesized by solution plasma process and its biocompatibility study. AB - Nanoceria were synthesized by discharging plasma at 800 V with a frequency of 30 kHz for 0-25 min using a pulsed unipolar power supply into solutions containing 1 or 2 mM of Ce(NO3)2. UV-Vis spectroscopy showed a characteristic absorbance maxima at 304-320 nm for the nanoceria with increase in the intensity of the peaks as the concentration of Ce(NO3)2 increased. The peaks exhibited transition red shift due to nanoceria formation. High resolution transmission electron microscopy revealed that spherical nanoparticles with an average size of 7.0 +/- 0.2 nm were formed by discharging plasma for 15 min. The nanoceria showed excellent pH dependent antioxidant properties in hydroxyl and superoxide anion radical scavenging assays. Effect of the nanoceria on cell viability in vitro and inhibition of reactive oxygen species (ROS) by the nanoceria were examined using HeLa cell lines. As the results, no toxic effect was found up to 1600 MUg mL-1 of nanoceria and they had an effective antioxidant property. Therefore, the nanoceria synthesized by one-step solution plasma process without employing hazardous chemicals have potential for utilization as antioxidant biomaterials and sustained release in the stream to scavenge ROS in the modern medicine. PMID- 29427589 TI - Limonene: Aroma of innovation in health and disease. AB - Natural products obtained in dietary components may aid the prevention and treatment of a variety of diseases. Reports in the scientific literature have demonstrated that the consumption of terpenes is a successful alternative in the treatment of several diseases, triggering beneficial biological effects in clinical and preclinical studies. The monoterpene limonene is largely used in alimentary items, cleaning products, and it is one of the most frequent fragrances used in cosmetics formulation. The therapeutic effects of limonene have been extensively studied, proving anti-inflammatory, antioxidant, antinociceptive, anticancer, antidiabetic, antihyperalgesic, antiviral, and gastroprotective effects, among other beneficial effects in health. In this review, we collected, presented, and analyzed evidence from the scientific literature regarding the usage of limonene and its activities and underlying mechanisms involved in combating diseases. The highlighting of limonene applications could develop a useful targeting of innovative research in this field as well as the development of a limonene-based phytomedicine which could be used in a variety of conditions of health and disease. PMID- 29427592 TI - Establishment of engineered cell-based assays mediating LAG3 and PD1 immune suppression enables potency measurement of blocking antibodies and assessment of signal transduction. AB - LAG3 is an important regulator of T cell homeostasis and studies in mouse tumor models have demonstrated that simultaneously antagonizing LAG3 and PD1 can augment tumor-specific T cell responses and induce tumor rejection. The combined use of LAG3 antagonist antibodies with established anti-PD1 therapies is currently being evaluated in human clinical trials. A functional assay for human LAG3 was developed by co-culture of a Jurkat T-cell lymphoma line overexpressing LAG3 with a Raji B-cell lymphoma line in the presence of staphylococcal enterotoxins. Reversal of LAG3 repression was measured as an increase in IL-2 production or NFAT activation in response to treatment with MK-4280, an anti human LAG3 antagonist antibody. Changes in cytokines, chemokines, and other mRNA transcripts were in agreement with published in vitro and in vivo models for LAG3 biology which highlights the physiological relevance of the Jurkat functional assay. Additional engineering of PD1 and PDL1 components into the LAG3 assay resulted in a bi-functional assay that is capable of inducing a 10-fold response to individual antibodies blocking either PD1 or LAG3. Importantly, when MK-4280 and pembrolizumab were combined to block both pathways, a synergistic 50-fold increase in response was observed. PMID- 29427591 TI - Steroid regulation: An overlooked aspect of tolerance and chronic rejection in kidney transplantation. AB - Steroid conversion (HSD11B1, HSD11B2, H6PD) and receptor genes (NR3C1, NR3C2) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n = 14) were used as reference. The anti-inflammatory glucocorticoid receptor (NR3C1) and the cortisol activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene (NR3C2) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene expression signatures of both, tolerance and CR, alongside known tolerance associated genes, revealing a key role of steroid regulation and response in kidney transplantation. PMID- 29427593 TI - Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol. AB - Aldose reductase (ALR2) is a key enzyme involved in diabetic complications and the search for new aldose reductase inhibitors (ARIs) is currently very important. The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications. Non-psychotropic phytocannabinoids exert multiple pharmacological effects with therapeutic potential in many diseases such as inflammation, cancer, diabetes. Here, we have investigated the inhibitory effects of extracts and their fractions from two Cannabis sativa L. chemotypes with high content of cannabidiol (CBD)/cannabidiolic acid (CBDA) and cannabigerol (CBG)/cannabigerolic acid (CBGA), respectively, on human recombinant and pig kidney aldose reductase activity in vitro. A molecular docking study was performed to evaluate the interaction of these cannabinoids with the active site of ALR2 compared to known ARIs. The extracts showed significant dose-dependent aldose reductase inhibitory activity (>70%) and higher than fractions. The inhibitory activity of the fractions was greater for acidic cannabinoid-rich fractions. Comparative molecular docking results have shown a higher stability of the ALR2-cannabinoid acids complex than the other inhibitors. The extracts of Cannabis with high content of non-psychotropic cannabinoids CBD/CBDA or CBG/CBGA significantly inhibit aldose reductase activity. These results may have some relevance for the possible use of C. sativa chemotypes based preparations as aldose reductase inhibitors. PMID- 29427594 TI - Isoprenylated flavonoids from Morus nigra and their PPAR gamma agonistic activities. AB - A novel dihydroflavonol unprecedentedly with a prenyl group at C-2, nigragenon A (1), four new sanggenon-type flavonones, nigragenons B-E (2-5), along with six known isoprenylated flavonoids (6-11) were isolated from the twigs of Morus nigra. Their structures were elucidated through extensive analysis of spectroscopic data. Interestingly, compound 1 was the first reported biogenetic precursor of sanggenon-type flavanones and the biogenetic pathway from 1 to sanggenol F was proposed. The PPAR gamma agonistic activity was investigated in HEK293 cells using dual luciferase reporter assay. Compounds 2, 4, 7, and 9 showed obvious agonistic activities on PPAR gamma, and compound 2 was a potential PPAR gamma partial agonist. Moreover, the preliminary structure-activity relationships for the tested compounds were discussed. PMID- 29427595 TI - Effects of palmatine on rats with comorbidity of diabetic neuropathic pain and depression. AB - Diabetic neuropathic pain (DNP) is one of the common complications of diabetes. Depression (DP) is also one of the common complications of diabetes. P2X7 receptors play an important role in the transmission of nociceptive signal and are associated with depressive illness. In the study, the hyperalgesia, allodynia and depressive behaviours of rats with comorbidity of DNP and DP were confirmed by the thermal withdrawal latency (TWL) test, mechanical withdrawal threshold (MWT) test, sucrose preference test (SPT), immobility time of forced swimming test (IMFST) and open-field test (OFT). The change in expression of the P2X7 receptor of the hippocampus was observed through RT-PCR, qPCR, Western blotting and immunohistochemical staining methods The results showed that palmatine treatment can alleviate the hyperalgesia, allodynia and depressive behaviours of rats with comorbidity of DNP and DP. Meanwhile, the expression of P2X7 receptors, GFAP, TNF-alpha and IL-1beta in the hippocampus of the rats with comorbidity of DNP and DP was significantly increased compared with the control rats, and palmatine treatment could decrease the expression. Furthermore, the enhanced phosphorylation of ERK1/2 in the hippocampus of rats with DNP and DP was decreased noticeably by palmatine treatment. The results of this study suggest that palmatine can alleviate the comorbidity of DNP and DP by inhibiting the expression of P2X7 receptors in the hippocampus, and its action may be related to suppression of the phosphorylation of ERK1/2 and the release of TNF-alpha and IL 1beta in the hippocampus. PMID- 29427596 TI - Structural and functional modeling of viral protein 5 of Infectious Bursal Disease Virus. AB - Infectious Bursal Disease (IBD) is an acute, highly contagious and immunosuppressive disease of young chicken. The causative virus (IBDV) is a bi segmented, double-stranded RNA virus. The virus encodes five major proteins, viral protein (VP) 1-5. VPs 1-3 have been characterized crystallographically. Albeit a rise in the number of studies reporting successful heterologous expression of VP5 in recent times, challenging the notion that rapid death of host cells overexpressing VP5 disallows obtaining sufficiently pure preparations of the protein for crystallographic studies, the structure of VP5 remains unknown and its function controversial. Our study describes the first 3D model of IBD VP5 obtained through an elaborate computational workflow. Based on the results of the study, IBD VP5 can be predicted to be a structural analog of the leucine-rich repeat (LRR) family of proteins. Functional implications arising from structural similarity of VP5 with host Toll-like receptor (Tlr) 3 also satisfy the previously reported opposing roles of the protein in first abolishing and later inducing host-cell apoptosis. PMID- 29427597 TI - Insights into the homo-oligomerization properties of N-terminal coiled-coil domain of Ebola virus VP35 protein. AB - The multifunctional Ebola virus (EBOV) VP35 protein is a key determinant of virulence. VP35 is essential for EBOV replication, is a component of the viral RNA polymerase and participates in nucleocapsid formation. Furthermore, VP35 contributes to EBOV evasion of the host innate immune response by suppressing RNA silencing and blocking RIG-I like receptors' pathways that lead to type I interferon (IFN) production. VP35 homo-oligomerization has been reported to be critical for its replicative function and to increase its IFN-antagonism properties. Moreover, homo-oligomerization is mediated by a predicted coiled-coil (CC) domain located within its N-terminal region. Here we report the homo oligomerization profile of full-length recombinant EBOV VP35 (rVP35) assessed by size-exclusion chromatography and native polyacrylamide gel electrophoresis. Based on our biochemical results and in agreement with previous experimental observations, we have built an in silico 3D model of the so-far structurally unsolved EBOV VP35 CC domain and performed self-assembly homo-oligomerization simulations by means of molecular dynamics. Our model advances the understanding of how VP35 may associate in different homo-oligomeric species, a crucial process for EBOV replication and pathogenicity. PMID- 29427598 TI - Calcineurin knockout mice show a selective loss of small spines. AB - Calcineurin is required for long-term depression and activity-dependent spine shrinkage, and calcineurin mutations have been identified in patients with schizophrenia. Moreover, mice with conditional knockout of calcineurin B (CNB-KO) exhibit behavioral abnormalities suggestive of schizophrenia. Changes in the dendritic spines of these mice, however, have not been investigated. We therefore examined the dendritic spines of CNB-KO mice, and observed a significant reduction in small spines and an increase in large spines in the prefrontal and visual cortices. The effect of CNB-KO on the spine sizes was relatively moderate, possibly due to the presence of spontaneous fluctuations (dynamics) in the dendritic spines themselves. Thus, CNB-KO mice showed a spine phenotype similar to those recently reported in patients with schizophrenia. PMID- 29427599 TI - Differential proteome of haemocyte subpopulations responded to white spot syndrome virus infection in Chinese shrimp Fenneropenaeus chinensis. AB - In our previous study, the differentially expressed proteins have been identified by proteomic analysis in total haemocytes of shrimp (Fenneropenaeus chinensis) after white spot syndrome virus (WSSV) infection. To further investigate the differential response of haemocyte subpopulations to WSSV infection, granulocytes and hyalinocytes were separated from healthy and WSSV-infected shrimp by immunomagnetic bead (IMB) method, respectively. Then two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) were used to analyze the differentially expressed proteins in haemocyte subpopulations between healthy and WSSV-infected shrimp. The results of flow cytometry (FCM) showed that about 98% of granulocytes and about 96% of hyalinocytes in purity were obtained. Quantitative intensity analysis revealed that 26 protein spots in granulocytes and 24 spots in hyalinocytes were significantly changed post WSSV infection. Among them, 24 proteins in granulocytes and 23 proteins in hyalinocytes were identified by MS analysis, which could be divided into eight categories according to Gene Ontology. The identification of prophenoloxidase (proPO), proPO 2 and peroxiredoxin in WSSV-infected granulocytes was consistent with the facts that the proPO-activating system and peroxiredoxin were mainly existed in granulocytes. The phagocytosis of hyalinocytes seemed to be enhanced during the infection, because several proteins that involved in phagocytosis, including clathrin heavy chain, ADP ribosylation factor 4 and Alpha2 macroglobulin were up regulated in hyalinocytes upon WSSV infection. Our results also reflected the vital biological significance of calcium ion binding proteins in granulocytes and ATPase/GTPase in hyalinocytes during WSSV infection. The data in this study verified the roles of granulocytes and hyalinocytes involved in WSSV infection, and differentially expressed proteins identified in granulocytes and hyalinocytes had a close correlation with their function characteristics. PMID- 29427600 TI - The first report of siglec-3/CD33 gene in a teleost (rock bream, Oplegnathus fasciatus): An analysis of its spatial expression during stimulation to red seabream iridovirus (RSIV) and two bacterial pathogens. AB - Siglec-3/CD33 is a myeloid-specific inhibitory receptor that is expressed on cells of the immune system, where it is believed to play a regulatory role, modulating the inflammatory and immune responses. We characterized CD33 (RbCD33) in rock bream which is a transmembrane protein with two IG-like domains and a cytoplasmic tail. It has a deduced amino acid sequence of 390 residues and has tyrosine-based signaling motifs in the cytoplasmic tail. The RbCD33 mRNA was highly expressed in peripheral blood leukocytes and was also detected in the muscle, spleen, skin, head kidney, gills, trunk kidney, heart, stomach, brain, intestine and liver by quantitative real-time PCR. A temporal variation in expression of RbCD33 was observed in different tissues after stimulating with E. tarda, S. iniae and red seabream iridovirus (RSIV). In the head kidney tissue, E. tarda and S. iniae induced RbCD33, while a down regulation was observed with RSIV. In addition, in spleen tissue, S. iniae caused a very high induction of RbCD33 in comparison with an E. tarda and RSIV challenge. In the liver and gill tissues, all three pathogens induced a high expression of RbCD33. The expression pattern in various tissues and its high induction after pathogen stimulation suggests that RbCD33 plays an important role in initiating the immune response via the inhibition of signal transduction of the myeloid lineage cells. PMID- 29427601 TI - Impact of a systematic alert for antimicrobial treatment durations exceeding seven days in a university hospital. PMID- 29427602 TI - High heart rate reactors display greater decreases in tear SIgA concentration following a novel acute stressor. AB - : Tear secretory immunoglobulin-A (SIgA) is a putative biomarker of common-cold risk with potential utility in non-invasive diagnostics. As SIgA secretion at the ocular surface is under strong autonomic control, we investigated the relationship between HR reactivity and tear SIgA responses to novel experiential stress. Thirty-two healthy participants undertook a 60 s zip-line ride to evoke acute stress and a seated-rest control trial in a randomised-crossover design. We recorded heart rate (HR) continuously and collected unstimulated tear samples 5 min pre-, 2 min post- and 20 min post-stress/control. Stress increased HR and state anxiety whereas tear SIgA concentration decreased 44% post-stress vs. CONTROL: Higher peak HR values during stress uniquely explained 21% of the variance in tear SIgA reactivity to stress (p < 0.01); high HR reactors displayed greater decreases in tear SIgA concentration. We conclude that physiological arousal increases immune reactivity to acute stress and highlight tear SIgA as a minimally-invasive, physiologically relevant biomarker of immune reactivity. PMID- 29427603 TI - Long-Acting Octreotide Reduces the Recurrence of Gastrointestinal Bleeding in Patients With a Continuous-Flow Left Ventricular Assist Device. AB - BACKGROUND: Recurrent gastrointestinal bleeding is one of the most significant adverse events in patients with left ventricular assist devices (LVADs). METHODS: We enrolled LVAD patients who had received an intramuscular injection of 20 mg octreotide every 4 weeks as secondary prevention for recurrent gastrointestinal bleeding despite conventional medical therapies and repeated transfusions. The frequency of gastrointestinal bleeding and other associated clinical outcomes before and during octreotide therapy were compared. RESULTS: Thirty LVAD patients (66.4 +/- 8.8 years old, 16 men [53%]) received octreotide therapy for 498.8 +/- 356.0 days without any octreotide-associated adverse events. The frequency of gastrointestinal bleeding was decreased significantly during octreotide therapy (from 3.4 +/- 3.1 to 0.7 +/- 1.3 events/year; P < .001), accompanied by significant reductions in red blood cell and flesh frozen plasma transfusions, days in hospital, and need for endoscopic procedures (P < .05 for all). CONCLUSIONS: Octreotide therapy reduced the frequency of recurrent gastrointestinal bleeding and may be considered for secondary prevention. PMID- 29427604 TI - Developmental immunotoxicity is not associated with the consumption of transgenic Bt rice TT51 in rats. AB - TT51 is a transgenic strain of Bt rice generated by fusing a synthetic CryAb/Ac gene into MingHui rice. In this study, rats from F0, F1, and F2 generations were fed a diet with 60% TT51 rice, MingHui rice, or nominal-origin rice. The study focused on developmental immunotoxicity in F1 and F2 offspring after long-term consumption of TT51. A wide range of immunological parameters was monitored in this two-generation study on reproductive toxicity. The experiments were performed on F1 and F2 offspring at postnatal days 21 and 42. No adverse clinical effects were observed in any of the experimental groups. In addition, histopathology observations and immunotoxicity tests, including hematological indicators, spleen lymphocyte subsets, natural killer cell activity, lymphoproliferative response, and plaque-forming cell assay, revealed no significant difference between the groups. These results indicated that developmental immunotoxicity was not associated with a diet of transgenic Bt rice TT51, compared to the parental MingHui rice. PMID- 29427606 TI - Recommending flavanols and procyanidins for cardiovascular health: Revisited. AB - The last 8 years have seen significant developments in our understanding of dietary flavanols and procyanidins in the context of human health and nutrition. During the same time, recognition of the importance of nutrition in primary disease prevention and health maintenance has increased. In addition, the concept of dietary bioactives (food constituents that although not essential to human life and procreation, may nevertheless play an important role in disease risk reduction, primary disease prevention, and healthy aging) has been created and developed. Applying assessment criteria specific to health maintenance and primary disease prevention, we aimed at broadly evaluating and discussing currently available data on flavanols and procyanidins, with an eye towards potentially advancing the future development of dietary guidelines and public health recommendations. Novel insights and advancements as well as current gaps and shortcomings in our understanding are identified and discussed. While centered on flavanols and procyanidins, the outcomes of this review may also have broader relevance for the further development of the concept of bioactives, and any future framework for the assessment of their role in human health and nutrition. PMID- 29427605 TI - A mathematical framework for yield (vs. rate) optimization in constraint-based modeling and applications in metabolic engineering. AB - BACKGROUND: The optimization of metabolic rates (as linear objective functions) represents the methodical core of flux-balance analysis techniques which have become a standard tool for the study of genome-scale metabolic models. Besides (growth and synthesis) rates, metabolic yields are key parameters for the characterization of biochemical transformation processes, especially in the context of biotechnological applications. However, yields are ratios of rates, and hence the optimization of yields (as nonlinear objective functions) under arbitrary linear constraints is not possible with current flux-balance analysis techniques. Despite the fundamental importance of yields in constraint-based modeling, a comprehensive mathematical framework for yield optimization is still missing. RESULTS: We present a mathematical theory that allows one to systematically compute and analyze yield-optimal solutions of metabolic models under arbitrary linear constraints. In particular, we formulate yield optimization as a linear-fractional program. For practical computations, we transform the linear-fractional yield optimization problem to a (higher dimensional) linear problem. Its solutions determine the solutions of the original problem and can be used to predict yield-optimal flux distributions in genome-scale metabolic models. For the theoretical analysis, we consider the linear-fractional problem directly. Most importantly, we show that the yield optimal solution set (like the rate-optimal solution set) is determined by (yield optimal) elementary flux vectors of the underlying metabolic model. However, yield- and rate-optimal solutions may differ from each other, and hence optimal (biomass or product) yields are not necessarily obtained at solutions with optimal (growth or synthesis) rates. Moreover, we discuss phase planes/production envelopes and yield spaces, in particular, we prove that yield spaces are convex and provide algorithms for their computation. We illustrate our findings by a small example and demonstrate their relevance for metabolic engineering with realistic models of E. coli. CONCLUSIONS: We develop a comprehensive mathematical framework for yield optimization in metabolic models. Our theory is particularly useful for the study and rational modification of cell factories designed under given yield and/or rate requirements. PMID- 29427607 TI - Validating a probe from GhSERK1 gene for selection of cotton genotypes with somatic embryogenic capacity. AB - Substantial progress is being reported in the techniques for plant transformation, but successful regeneration of some genotypes remains a challenging step in the attempts to transform some recalcitrant species. GhSERK1 gene is involved on embryo formation, and its overexpression enhances the embryogenic competence. In this study we validate a short GhSERK1 probe in order to identify embryogenic cotton genotypes using RT-qPCR and blotting assays. Cotton genotypes with contrasting somatic embryogenic capacity were tested using in vitro procedures. High expression of transcripts was found in embryogenic genotypes, and the results were confirmed by the RT-PCR-blotting using a non radioactive probe. The regeneration ability was confirmed in embryogenic genotypes. We confirmed that GhSERK1 can be used as marker for estimating the somatic embryogenesis ability of cotton plants. PMID- 29427608 TI - Comparison between male and female rats in a model of self-administration of a chocolate-flavored beverage: Behavioral and neurochemical studies. AB - The existence of sex differences was studied in a rat model of operant self administration of a chocolate-flavored beverage (CFB), which possesses strong reinforcing properties and is avidly consumed by rats. Whether these differences occurred concomitantly to changes in extracellular dopamine in the dialysate obtained from the nucleus accumbens, was assessed by intracerebral microdialysis. Male, ovariectomized and intact female rats showed similar self-administration profiles, with minor differences in both acquisition and maintenance phases. Intact females self-administered larger amounts of CFB, when expressed per body weight, than males and ovariectomized females, in spite of similar values of lever-responding, latency to the first lever-response and consumption efficiency (a measure of rat's licking effectiveness) in males, ovariectomized and intact females and no difference in breakpoint value and number of lever-responses emerged when males, ovariectomized and intact females were exposed to a progressive ratio schedule of reinforcement. Intracerebral microdialysis revealed a slight but significant increase in dopamine activity in the shell of the nucleus accumbens of male rats when compared to intact female rats during CFB self-administration. The above differences may be caused by the hormonal (mainly estradiol) fluctuations that occur during the estrus cycle in intact females. Accordingly, in intact females CFB self-administration and dopamine activity were found to fluctuate across the estrus cycle, with lower parameters of CFB self administration and lower dopamine activity in the Proestrus and Estrus phases vs. the Metestrus and Diestrus phases of the cycle. PMID- 29427609 TI - Tartrazine induced neurobiochemical alterations in rat brain sub-regions. AB - Tartrazine is a synthetic lemon yellow azo dye primarily used as a food coloring. The present study aimed to screen the neurobiochemical effects of Tartrazine in Wistar rats after administering the Acceptable Daily Intake (ADI) level. Tartrazine (7.5 mg/kg b.w.) was administered to 21 day old weanling rats through oral gavage once daily for 40 consecutive days. On 41st day, the animals were sacrificed and brain sub regions namely, frontal cortex, corpus striatum, hippocampus and cerebellum were used to determine activities of anti-oxidant enzymes viz. Superoxide Dismutase (SOD), Catalase (CAT), Glutathione-Stransferase (GST), Glutathione Reductase (GR) and Glutathione Peroxidase (GPx) and levels of lipid peroxides using Thio-barbituric Acid Reactive Substance (TBARS) assay. Our investigation showed a significant decrease in SOD and CAT activity, whereas there occurred a decline in GST and GR activity with an increase in GPx activity to counteract the oxidative damage caused by significantly increased levels of lipid peroxides. The possible mechanism of this oxidative damage might be attributed to the production of sulphanilc acid as a metabolite in azofission of tartrazine. It may be concluded that the ADI levels of food azo dyes adversely affect and alter biochemical markers of brain tissue and cause oxidative damage. PMID- 29427610 TI - 2,4-Di-tert-butylphenol, a potential HDAC6 inhibitor, induces senescence and mitotic catastrophe in human gastric adenocarcinoma AGS cells. AB - The natural product 2,4-di-tert-butylphenol (DTBP) has a wide spectrum of biological functions, including anticancer activities, although the underlying mechanisms are poorly understood. Here, we found that DTBP induces senescence in human gastric adenocarcinoma AGS cells as evidenced by upregulation of p21 and Rb and increased beta-galactosidase activity. DTBP also induces mitotic catastrophe and generates multinucleated cells, which is accompanied by an increase in the proportion of polymerized tubulin, possibly caused by inhibition of HDAC6 enzyme activity. In silico docking analysis showed that DTBP docked at the entrance of the ligand-binding pocket of the HDAC6 enzyme. Accordingly, DTBP represents a promising lead structure for the development of HDAC6 inhibitors, with an improvement in specificity conferred by modification of the cap group. We propose for the first time that the underlying mechanism of the anticancer activity of DTBP is attributed to inhibition of HDAC6 activity. PMID- 29427612 TI - Comparison of quantitative T2 and ADC mapping in the assessment of 3 nitropropionic acid-induced neurotoxicity in rats. AB - To assess the relative performance of MRI T2 relaxation and ADC mapping as potential biomarkers of neurotoxicity, a model of 3-nitropropionic acid (NP) induced neurodegeneration in rats was employed. Male Sprague-Dawley rats received NP (N = 20, 16-20 mg/kg, ip or sc) or saline (N = 6, 2 ml/kg, ip) daily for 3 days. MRI was performed using a 7 T system employing quantitative T2 and ADC mapping based on spin echo pulse sequence. All maps were skull stripped and co registered and the changes were quantified using baseline subtraction and anatomical segmentation. Following the in vivo portion of the study, rat brains were histologically examined. Four NP-treated rats were considered responders based on their MRI and histology data. T2 values always increased in the presence of toxicity, while ADC changes were bidirectional, decreasing in some lesion areas and increasing in others. In contrast to T2 in some cases, ADC did not change. The effect sizes of T2 and ADC signals suggestive of neurotoxicity were 2.64 and 1.66, respectively, and the variability of averaged T2 values among anatomical regions was consistently lower than that for ADC. The histopathology data confirmed the presence of neurotoxicity, however, a more detailed assessment of the correlation of MRI with histology is needed. T2 mapping provides more sensitive and specific information than ADC about changes in the rat brain thought to be associated with neurotoxicity due to a higher signal-to-noise ratio, better resolution, and unidirectional changes, and presents a better opportunity for biomarker development. PMID- 29427611 TI - Imaging pathological activities of human brain tissue in organotypic culture. AB - BACKGROUND: Insights into human brain diseases may emerge from tissue obtained after operations on patients. However techniques requiring transduction of transgenes carried by viral vectors cannot be applied to acute human tissue. NEW METHOD: We show that organotypic culture techniques can be used to maintain tissue from patients with three different neurological syndromes for several weeks in vitro. Optimized viral vector techniques and promoters for transgene expression are described. RESULTS: Region-specific differences in neuronal form, firing pattern and organization as well as pathological activities were maintained over 40-50 days in culture. Both adeno-associated virus and lentivirus based vectors were persistently expressed from ~10 days after application, providing 30-40 days to exploit genetically expressed constructs. Different promoters, including hSyn, e/hSyn, CMV and CaMKII, provided cell-type specific transgene expression. The Ca probe GCaMP let us explore epileptogenic synchrony and a FRET-based probe was used to follow activity of the kinase mTORC1. COMPARISON WITH EXISTING METHODS: The use of a defined culture medium, with low concentrations of amino acids and no growth factors, permitted organotypic culture of tissue from humans aged 3-62 years. Epileptic activity was maintained and excitability changed relatively little until ~6 weeks in culture. CONCLUSIONS: Characteristic morphology and region-specific neuronal activities are maintained in organotypic culture of tissue from patients diagnosed with mesial temporal lobe epilepsy, cortical dysplasia and cortical glioblastoma. Viral vector techniques permit expression of probes for long-term measurements of multi-cellular activity and intra-cellular signaling. PMID- 29427613 TI - Microglial activation and vascular responses that are associated with early thalamic neurodegeneration resulting from thiamine deficiency. AB - Thiamine/vitamin B1 deficiency can lead to behavioral changes and neurotoxicity in humans. This may due in part to vascular damage, neuroinflammation and neuronal degeneration in the diencephalon, which is seen in animal models of pyrithiamine-enhanced thiamine deficiency. However, the time course of the progression of these changes in the animal models has been poorly characterized. Therefore, in this study, the progression of: 1) activated microglial association with vasculature; 2) neurodegeneration; and 3) any vascular leakage in the forebrain during the progress of thiamine deficiency were determined. A thiamine deficient diet along with 0.25 mg/kg/d of pyrithiamine was used as the mouse model. Vasculature was identified with Cd31 and microglia with Cd11b and Iba1 immunoreactivity. Neurodegeneration was determined by FJc labeling. The first sign of activated microglia within the thalamic nuclei were detected after 8 d of thiamine deficiency, and by 9 d activated microglia associated primarily with vasculature were clearly present but only in thalamus. At the 8 d time point neurodegeneration was not present in thalamus. However at 9 d, the first signs of neurodegeneration (FJc + neurons) were seen in most animals. Over 80% of the microglia were activated at 10 d but almost exclusively in the thalamus and the number of degenerating neurons was less than 10% of the activated microglia. At 10 d, there were sporadic minor changes in IgG presence in thalamus indicating minor vascular leakage. Dizocilpine (0.2-0.4 mg/kg) or phenobarbital (10-20 mg/kg) was administered to groups of mice from day 8 through day 10 to block neurodegeneration but neither did. In summary, activated microglia start to surround vasculature 1-2 d prior to the start of neurodegeneration. This response may be a means of controlling or repairing vascular damage and leakage. Glutamate excitotoxicity and vascular leakage likely only play a minor role in the early neurodegeneration resulting from thiamine deficiency. However, failure of dysfunctional vasculature endothelium to supply sufficient nutrients to neurons could be contributing to the neurodegeneration. PMID- 29427614 TI - Gene expression and activity of digestive enzymes of Daphnia pulex in response to food quality differences. AB - Food quality is an important factor influencing organisms' well-being. In freshwater ecosystems, food quality has been studied extensively for the keystone herbivore genus Daphnia, as they form the critical trophic link between primary producers and higher order consumers such as fish. For Daphnia, the edible fraction of phytoplankton in lakes (consisting mostly of unicellular algae and cyanobacteria) is extraordinarily diverse. To be able to digest different food particles, Daphnia possess a set of digestive enzymes that metabolize carbohydrates, lipids and proteins. Recent studies have found a connection between gene expression and activity of single digestive enzyme types of Daphnia, i.e. lipases and proteases, and transcriptome studies have shown that a variety of genes coding for gut enzymes are differentially expressed in response to different food algae. However, never before has a set of digestive enzymes been studied simultaneously both on the gene expression and the enzyme activity level in Daphnia. Here, we investigated several digestive enzymes of Daphnia pulex in a comparison between a high-quality (green algal) and a low-quality (cyanobacterial) diet. Diet significantly affected the expression of all investigated digestive enzyme genes and enzyme activity was altered between treatments. Furthermore, we found that gene expression and enzyme activity were significantly correlated in cellulase, triacylglycerol lipase and beta glucosidase when switched from high to low-quality food. We conclude that one of the factors causing the often observed low biomass and energy transfer efficiency from cyanobacteria to Daphnia is probably the switch to a cost-effective overall increase of gene expression and activity of digestive enzymes of this herbivore. PMID- 29427615 TI - Clinical Features of Ground Glass Opacity-Dominant Lung Cancer Exceeding 3.0 cm in the Whole Tumor Size. AB - BACKGROUND: Ground glass opacity (GGO)-dominant lung adenocarcinoma sized 3.0 cm or less in the whole tumor size is widely known to have an excellent prognosis and is regarded as early lung cancer. However, the characteristics and prognosis of lung cancer showing GGO exceeding 3.0 cm remains unclear. METHODS: From 2002 through 2012, we reviewed 3,735 lung cancers that underwent complete resection at our institution. We identified 160 lung cancers (4.3%) showing GGO exceeding 3.0 cm on thin-section computed tomography and divided them into three types by the consolidation/tumor ratio (CTR) using cutoff values of 0.25 and 0.5. We compared the characteristics and prognosis among these types. RESULTS: Type A (CTR, 0 to <=0.25), type B (CTR, >0.25 to <=0.5), and type C (CTR, >0.5 to <1.0) were found in 16 (10%), 37 (23%), and 107 lesions (67%), respectively. No lymph node metastasis was found in types A and B. Recurrence was not observed in types A and B. The 5-year overall survival and disease-free survival rates were both 100% in type A, both 97.2% in type B, and 88.4% and 66.7% in type C, respectively. Patients with type C had a significantly worse prognosis than those with the other types with respect to overall survival and disease-free survival. CONCLUSIONS: A patient with GGO-dominant lung cancer exceeding 3.0 cm can be considered to be in a group of patients with nodal-negative disease and an excellent prognosis. PMID- 29427616 TI - Complex Tracheocarinal Reconstructions Using Extrathoracic Muscle Flaps as Airway Substitutes. AB - BACKGROUND: Extrathoracic muscle flaps can be used as airway substitutes for the closure of complex bronchopleural or tracheoesophageal fistulas or in the context of tracheocarinal reconstructions after resection for centrally localized tumors in order to alleviate excess anastomotic tension. METHODS: Evaluation of all patients undergoing tracheocarinal reconstructions with extrathoracic muscle flap patches as airway substitutes in our institution from 1996 to 2016. RESULTS: A total of 73 patients underwent tracheocarinal reconstructions using extrathoracic muscle flap patches as airway substitutes for the closure of bronchopleural fistulas (n = 17) and complex tracheoesophageal fistulas (n = 7), or in the context of airway reconstructions after carinal resections in combination with pneumonectomy/sleeve lobectomy for centrally localized lung tumors (n = 36) and noncircumferential tracheal resections for tracheal disease processes (n = 14). The size of airway defects replaced by muscle patches ranged from 2 * 2 to 8 * 4 cm and was at most 40% of the airway circumference. The postoperative 90-day mortality was 8.2% and was only observed after right-sided pneumonectomy. Complications at the airway reconstruction site occurred in 8 patients (10%): 4 airway dehiscence (5%) with uneventful healing after reoperation (n = 2) or temporary stenting (n = 2) and 4 airway stenosis (5%) that required repeated bronchoscopy and stenting. Overall, 63 of 67 surviving patients (94%) revealed intact airways without further bronchoscopic interventions or tracheal appliance during follow-up. CONCLUSIONS: Extrathoracic muscle flaps used as airway substitutes are an interesting and sometimes life-saving option to close difficult tracheocarinal airway defects or to reduce anastomotic tension in the context of complex tracheocarinal surgeries. PMID- 29427617 TI - Single- Versus Multicenter Surgeons' Risk-Adjusted Coronary Artery Bypass Graft Procedural Outcomes. AB - BACKGROUND: Since 2010, 460+ hospital mergers have occurred in the United States, rerouting historical coronary artery bypass graft (CABG) referral patterns. The goals of this study were: (1) to compare risk-adjusted CABG outcomes between single-center versus multicenter surgeons; and (2) for multicenter surgeons, to evaluate the risk-adjusted outcomes between their home (primary) versus satellite (secondary) hospitals. METHODS: Using The Society of Thoracic Surgeons Adult Cardiac Surgery Database, nonemergent, first-time CABG procedures (n = 543,403) performed in the US between 2011 and 2014 were extracted across 1,120 centers and for 2,676 surgeons. Surgeons were classified as multicenter if they performed operations at two separate hospitals for >= 2 consecutive quarters; their home hospital was identified as their highest volume center. Observed-to-expected outcome ratios were reported using approved multivariable risk models for 30-day operative mortality and major morbidity. RESULTS: Of 2,676 cardiac surgeons, 668 (25.0%) operated at multiple centers. The observed-to-expected mortality ratios were 1.06 (95% confidence interval [CI], 1.01 to 1.12) and 0.97 (95% CI, 0.94 to 1.00) for multi- and single-center surgeons (p < 0.001). For multicenter surgeons, the observed-to-expected mortality ratios were 1.17 (95% CI, 1.09 to 1.27) versus 1.01 (95% CI, 0.96 to 1.07), p < 0.001, for their satellite versus home facilities, respectively. CONCLUSIONS: Single-center surgeons performing CABG had lower risk-adjusted outcome rates compared with multicenter surgeons, who performed better at their home versus satellite hospitals. To improve future quality of care, surgeons, health care networks, and health policy makers should now more closely scrutinize their single versus multicenter performance. PMID- 29427618 TI - Factors Influencing Team Behaviors in Surgery: A Qualitative Study to Inform Teamwork Interventions. AB - BACKGROUND: Surgical excellence demands teamwork. Poor team behaviors negatively affect team performance and are associated with adverse events and worse outcomes. Interventions to improve surgical teamwork focusing on frontline team members' nontechnical skills have proliferated but shown mixed results. Literature on teamwork in organizations suggests that team behaviors are also contingent on psychosocial, cultural, and organizational factors. This study examined factors influencing surgical team behaviors to inform more contextually sensitive and effective approaches to optimizing surgical teamwork. METHODS: This qualitative study of cardiac surgical teams in a large United States teaching hospital included 34 semistructured interviews. Thematic network analysis was used to examine perceptions of ideal teamwork and factors influencing team behaviors in the operating room. RESULTS: Perceptions of ideal teamwork were largely shared, but team members held discrepant views of which team and leadership behaviors enhanced or undermined teamwork. Other factors affecting team behaviors were related to the local organizational culture, including management of staff behavior, variable case demands, and team members' technical competence, and fitness of organizational structures and processes to support teamwork. These factors affected perceptions of what constituted optimal interpersonal and team behaviors in the operating room. CONCLUSIONS: Team behaviors are contextually contingent and organizationally determined, and beliefs about optimal behaviors are not necessarily shared. Interventions to optimize surgical teamwork require establishing consensus regarding best practice, ability to adapt as circumstances require, and organizational commitment to addressing contextual factors that affect teams. PMID- 29427619 TI - The Association of Aortic Valve Pathology With Renal Resistive Index as a Kidney Injury Biomarker. AB - BACKGROUND: Acute kidney injury (AKI) is a common serious complication after cardiac surgery. Doppler-determined renal resistive index (RRI) is a promising early AKI biomarker in this population. However, the relationship between aortic valve pathology (insufficiency and/or stenosis) and RRI is unknown. This study aimed to investigate RRI variability related to aortic valve pathology. METHODS: In a retrospective review of cardiac surgery patients, RRI and aortic valve pathology were assessed prior to cardiopulmonary bypass using transesophageal echocardiography. Aortic valve status was categorized into four subgroups: normal (insufficiency and stenosis, none/trace/mild), insufficiency (insufficiency, moderate/severe; stenosis, none/trace/mild), combined insufficiency/stenosis (insufficiency and stenosis, moderate/severe), or stenosis (insufficiency, none/trace/mild; stenosis, moderate/severe). RRI and time-matched hemodynamic and Doppler measurements were compared among subgroups. RESULTS: Of 175 patients, 60 had aortic valve pathology (16 insufficiency, 18 insufficiency/stenosis, 26 stenosis). Compared with the normal subgroup, patients with aortic insufficiency had lower diastolic blood pressure and trough renal Doppler velocities, and higher RRI (0.77 versus 0.69; p < 0.001); patients with combined insufficiency/stenosis also had higher RRI (0.72 versus 0.69, p = 0.042). CONCLUSIONS: Patients with aortic insufficiency and combined insufficiency/stenosis had higher median RRI values compared with normal patients. For these individuals, diastolic flow differences related to aortic insufficiency may explain why their presurgery RRI values often exceeded postoperative thresholds typically associated with AKI. Strategies to account for the potentially confounding effects of aortic insufficiency on renal flow patterns, independent of renal injury, may add to the value of RRI as an early AKI biomarker. PMID- 29427620 TI - Arterioplasty in Takayasu's Arteritis With Left Main Coronary Artery Involvement. AB - Here we report a case of a 24-year-old woman diagnosed with Takayasu's arteritis with left main coronary artery involvement in which we performed the arterioplasty of the left main coronary artery using a glutaraldehyde-fixed autologous pericardial patch. Ten years of follow-up demonstrated the satisfactory patency of the ostium of the left main coronary artery. PMID- 29427621 TI - Brg1 promotes liver fibrosis via activation of hepatic stellate cells. AB - Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by the persistent deposition of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Brg1, the core subunit of the SWI/SNF chromatin remodeling complex, has been proved to associated with nonalcoholic steatohepatitis which may progress to cirrhosis. Herein, we determined whether Brg1 regulates liver fibrosis and examined its mechanism by focusing on HSCs activation. In this study, we demonstrate that Brg1 is elevated in human and mouse fibrotic liver tissues and Brg1 mediate the profibrotic response in activated HSCs. Our data indicate that Brg1 regulates the activation of HSCs through TGFbeta/Smad signal pathway. Moreover, Brg1 deficiency mice displayed decreased HSCs activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. In addition, Brg1 expression is positively correlated with liver fibrosis in cirrhotic patients and may be a prognostic factor in HCC. Collectively, we demonstrate that Brg1 promotes liver fibrosis by activating HSCs and may represent a potential target for anti-fibrotic therapies. PMID- 29427622 TI - Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non canonical Wnt signaling. AB - Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is present in both intracellular and extracellular compartments. Although AGR2 is overexpressed in various human cancers and reported to promote aggressive tumor features, little is known regarding AGR2's extracellular functions during tumorigenesis. Here, we demonstrate that secreted AGR2 promotes cell migration and metastasis of colorectal cancer (CRC) in vitro and in vivo. Mechanistically, secreted AGR2 elevated Wnt11 expression, triggering non-canonical Wnt signaling: the Ca2+/Calmodulin-dependent protein kinase II (CaMKII) and c-jun amino-terminal kinase (JNK) pathways. Knockdown of Wnt11 or pretreatment with CaMKII and JNK inhibitors reversed the secreted AGR2's migration-promoting effect. Further studies revealed that AGR2 antagonized canonical Wnt/beta-catenin signaling via activating CaMKII. Collectively, our study uncovers a critical role of Wnt11 mediated non-canonical Wnt signaling (CaMKII and JNK pathways) in secreted AGR2's promoted migration of CRC cells. These results raise the possibility that secreted AGR2 may be a potential therapeutic target towards inhibiting CRC metastasis. PMID- 29427623 TI - Paracrine signaling by VEGF-C promotes non-small cell lung cancer cell metastasis via recruitment of tumor-associated macrophages. AB - High expression of tumoral vascular endothelial growth factor C (VEGF-C) is correlated with clinical non-small cell lung cancer (NSCLC) metastasis and patient survival. Nevertheless, the comprehensive mechanisms accounting for VEGF C-mediated cancer progression remain largely unclear. The present study found that VEGF-C expression was upregulated in various NSCLC cell lines. By utilizing transwell migration assay, we found that both recombinant VEGF-C protein and overexpression of VEGF-C in NSCLC cells (A549 and H441 cell lines) could efficiently enhance RAW264.7 cell (murine macrophages) migration. However, recombinant VEGF-C treatment had no effects on both CD206 (an M2 macrophage marker) expression and M1/M2 cytokine profiles of macrophages. Furthermore, additional treatment of recombinant Flt-4/Fc, the specific VEGFR-3 inhibitor or the specific VEGFR-2 inhibitor significantly suppressed macrophage migration compared with A549-CM (conditioned medium) or H441-CM alone group, confirming that NSCLC cells-derived VEGF-C is sufficient to promote macrophage migration. Interestingly, VEGF-C could stimulate the Src/p38 signaling via VEGFR-2/3 axis in macrophages, and inhibition of Src/p38 signaling obviously reversed the enhancement effect of VEGF-C on macrophage migration. Finally, the functional importance of macrophage infiltration induced by tumoral VEGF-C in promoting metastasis was established in a mouse model. In conclusion, our results highlight a novel function of tumoral VEGF-C that paracrinely induces macrophage recruitment, and resultantly promotes NSCLC cell metastasis. Therefore, VEGF C/VEGFR-2/3 axis may be a promising microenvironmental target against progression of NSCLC. PMID- 29427625 TI - Extracellular vesicles: A new therapeutic strategy for joint conditions. AB - Extracellular vesicles (EVs) are attracting increasing interest since they might represent a more convenient therapeutic tool with respect to their cells of origin. In the last years much time and effort have been expended to determine the biological properties of EVs from mesenchymal stem cells (MSCs) and other sources. The immunoregulatory, anti-inflammatory and regenerative properties of MSC EVs have been demonstrated in in vitro studies and animal models of rheumatoid arthritis or osteoarthritis. This cell-free approach has been proposed as a possible better alternative to MSC therapy in autoimmune conditions and tissue regeneration. In addition, EVs show great potential as biomarkers of disease or delivery systems for active molecules. The standardization of isolation and characterization methods is a key step for the development of EV research. A better understanding of EV mechanisms of action and efficacy is required to establish the potential therapeutic applications of this new approach in joint conditions. PMID- 29427626 TI - Leptin induces SIRT1 expression through activation of NF-E2-related factor 2: Implications for obesity-associated colon carcinogenesis. AB - Leptin, a representative adipokine secreted from the white adipose tissue, is considered as a potential linker between obesity and cancer. SIRT1 is an NAD+ dependent histone/protein deacetylase speculated to function as an oncogene. In the present study, we found that leptin signaling-defective ob/ob and db/db mice had lower colonic expression of SIRT1 compared with leptin signaling-intact C57BL/6J mice, implying that leptin signaling is crucial for SIRT1 expression in vivo. Moreover, leptin induced up-regulation of SIRT1 in human colon cancer (HCT 116) cells. Leptin stimulated migration and invasion of cultured HCT-116 cells and tumor growth in the xenograft assay, and these effects were abrogated by a SIRT1 inhibitor sirtinol, suggesting that SIRT1 plays a role in leptin-induced colon carcinogenesis. Leptin-induced SIRT1 expression was regulated by the redox sensitive transcription factor NF-E2-related factor 2 (Nrf2). Leptin stimulated nuclear accumulation of Nrf2 as well as its binding to the antioxidant response elements located in the SIRT1 promoter. Moreover, siRNA knockdown of Nrf2 abrogated the leptin-induced SIRT1 expression. Notably, SIRT1 was significantly reduced in colon tissues of Nrf2-null mice, lending further support to Nrf2 dependent SIRT1 expression. Expression of leptin, Nrf2 and SIRT1 was coordinately increased in human colon tumor tissues. In conclusion, leptin might play a role in colon carcinogenesis by inducing Nrf2-dependent SIRT1 overexpression. PMID- 29427624 TI - Adenosine metabolism, immunity and joint health. AB - The purine nucleoside adenosine is a present in most body fluids where it regulates a wide variety of physiologic and pharmacologic processes. Adenosine mediates its effects through activating 4 G protein-coupled receptors expressed on the cell membrane: A1, A2A, A2B, and A3. The adenosine receptors are widely distributed in the body, and tissues with high expression include immune tissues, cartilage, bone, heart, and brain. Here we review the source and metabolism of adenosine and the role of adenosine in regulating immunity and cartilage biology. PMID- 29427627 TI - Anti-inflammatory actions of Caesalpinin M2 in experimental colitis as a selective glucocoricoid receptor modulator. AB - Although repression of inflammatory gene expression makes glucocorticoids (GCs) powerful anti-inflammatory agents, side effects limit usage and drive the search for improved glucocorticoid receptor (GR) ligands. It has been postulated that the anti-inflammatory effects of GCs are primarily mediated by GR's activity in transrepressing major inflammation pathways such as NF-kappaB pathway, whereas their side effects are mostly mediated by GR's transactivation. In this study, we found that Caesalpinin M2 (C-M2), a cassane furanoditerpene isolated from a Chinese medical plant, exerts an anti-inflammatory potential both in vitro and in vivo. C-M2 inhibited the expression of proinflammatory cytokine IL-1beta and IL-6 in LPS-activated bone marrow-derived macrophages. Meanwhile, C-M2 treatment attenuated DSS-induced experimental acute colitis in mice and did not cause side effects, such as spleen involution, like dexamethasone treatment. Molecular docking and cellular thermal shift assay demonstrated that C-M2 could bind to GR in the ligand binding site. We showed that C-M2 mediates gene-inhibitory effects by activating GR. More importantly, C-M2 failed to induce GR binding to glucocorticoid response element-dependent genes and in turn activate their transcription. But it did repress NF-kappaB-dependent transcription by facilitating the interaction between GR and p65. Taken together, this non steroidal compound of plant origin may exert anti-inflammatory actions as a selective GR modulator and might hold great potential for therapeutic use in inflammatory diseases. PMID- 29427628 TI - Protection of therapeutic antibodies from visible light induced degradation: Use safe light in manufacturing and storage. AB - As macromolecules, biologics are susceptible to light exposure, which induces oxidation of multiple amino acid residues including tryptophan, tyrosine, phenylalanine, cysteine and methionine. Pertaining to safety, efficacy and potency, light-induced oxidation of biologics has been widely studied and necessary precautions need to be taken during biologics manufacturing process, drug substance and products handling and storage. Proteins will degrade to varying extents depending on the protein properties, degradation pathways, formulation compositions and type of light source. In addition to UV light, which has been widely known to degrade proteins, visible light from indoor fluorescent lighting also can mediate protein degradation. In this report, we examine and identify wavelengths in the visual spectrum (400-700 nm) that can cause monoclonal antibody and histidine buffer degradation. Installation of safe lights which exclude the identified damaging wavelengths from visible spectra in manufacturing and storage areas can provide a balance between lighting requirement for human operators and their safety and conservation of product quality. PMID- 29427629 TI - Screening therapeutics according to their uptake across the blood-brain barrier: A high throughput method based on immobilized artificial membrane liquid chromatography-diode-array-detection coupled to electrospray-time-of-flight mass spectrometry. AB - The Blood-Brain Barrier (BBB) plays an essential role in protecting the brain tissues against possible injurious substances. In the present work, 79 neutral, basic, acidic and amphoteric structurally unrelated analytes were considered and their chromatographic retention coefficients on immobilized artificial membrane (IAM) stationary phase were determined employing a mass spectrometry (MS) compatible buffer based on ammonium acetate. Their BBB passage predictive strength was evaluated and the statistical models based on IAM indexes and in silico physico-chemical descriptors showed solid statistics (r2 (n - 1) = 0.78). The predictive strength of the indexes achieved by the MS-compatible method was comparable to that achieved by employing the more "biomimetic" Dulbecco's phosphate buffered saline, even if some differences in the elution order were observed. The method was transferred to the MS, employing a diode-array-detection coupled to an electrospray ionization source and a time-of-flight analyzer. This setup allowed the simultaneous analysis of up to eight analytes, yielding a remarkable acceleration of the analysis time. PMID- 29427630 TI - Lactobacillus crispatus represses vaginolysin expression by BV associated Gardnerella vaginalis and reduces cell cytotoxicity. AB - Using a chemically-defined medium simulating genital tract secretions, we have shown that pre-adhering Lactobacillus crispatus to Hela epithelial cells reduced cytotoxicity caused by Gardnerella vaginalis. This effect was associated to the expression of vaginolysin and was specific to L. crispatus interference, as other vaginal facultative anaerobes had no protective effect. PMID- 29427631 TI - Urofecal steroid profiles of captive Blue-fronted parrots (Amazona aestiva) with different reproductive outcomes. AB - Despite Psitaciformes (parrots) being the third largest nonpasserine order (398 species), it currently ranks second in number of threatened species (28%) according to the Internatinal Union for Conservation of Nature (IUCN) criteria. Since most of the literature concerning reproductive endocrinology in avian species derives from domestic and song birds, it is puzzling that advances in reproductive science for the Psitaciformes order lags far behind, in spite of the growing threats against them. In order to expand our knowledge of Neotropical parrots (Psittacidae), we examined annual changes in urofecal sex steroid metabolites of Blue-fronted amazon pairs (Amazona aestiva) exhibiting successful (nestlings) and unsuccessful breeding (infertile or no eggs). Urofecal samples were collected over a year from eight breeding pairs housed under the same environmental and management conditions. Fecal androgen and progestagen concentrations were determined in males and females, respectively, by enzyme immunoassays previously validated for this species. All eggs were registered between late winter and mid-spring, and egg-laying intervals varied between females (range: 1-8 days; average 3.60 +/- 0.51 days). Similar profiles of urofecal progestagens were observed in reproductively successful females and females producing infertile eggs, with progestagen peaks preceding egg laying events (1.77 +/- 0.50 days). In contrast, non-laying females had no rises in progestagens during the year. Successful and unsuccessful males did not displayed distinct annual patterns of androgen production, and apart from the peaks during the breeding season, more than half of the individuals intriguingly presented significant increases from late summer to early autumn, a period without reproductive activity. Finally, we noticed that samples with progestagen levels exceeding 40 ng/g had very high probability (>97.5%) to be from females in pre laying or laying phases, suggesting a feasible application of this characteristic to noninvasively discriminate the reproductive status in amazon females with an accuracy and sensitivity of 94.55% and 58.13%, respectively. Our findings confirmed that urofecal progestagens and androgens are good indicators of the gonadal condition in Blue-fronted amazons, but there is still much to be done for their extensive use in artificial insemination or selection of the most suitable breeding birds for the season. PMID- 29427632 TI - Seasonal variation of cell proliferation and apoptosis in the efferent ductules and epididymis of the Neotropical bat Artibeus lituratus (Chiroptera, Phyllostomidae). AB - The balance between cell proliferation and apoptosis is important for maintenance of male fertility, being influenced by a variety of stimuli including androgens and estrogens. However, studies concerning regulation of these processes along the male reproductive tract under physiological conditions are scarce. Therefore, in this study, we investigated the profile of cell proliferation and apoptosis in the efferent ductules and epididymis of the Neotropical bat Artibeus lituratus, a seasonal breeder that presents natural variation in components of the androgen and estrogen responsive systems along the circannual cycle. Low rates of cell proliferation and apoptosis were found in the efferent ductules and epididymis of A. lituratus during the reproductive period, as few epithelial cells were positive for MCM7 (proliferation marker) and cleaved caspase-3 or TUNEL (apoptosis markers). In contrast, during the regressive period, the rate of both proliferating and apoptotic cells was significantly higher in the epithelium lining the efferent ductules as well as throughout the epididymis. The increased proliferative activity at this phase was positively correlated with the expression of estrogen receptor alpha (ERalpha), whereas the variation in apoptosis appears to be unrelated to the local expression of androgen and estrogen receptors. Together, these data suggest that cell proliferation and apoptosis are differentially modulated in the efferent ductules and epididymis of A. lituratus during the annual reproductive cycle, and support the hypothesis that ERalpha may be important in preparing the male reproductive tract for sexual recrudescence. PMID- 29427633 TI - Estimation of energetic condition in wild baboons using fecal thyroid hormone determination. AB - Understanding how environmental and social factors affect reproduction through variation in energetic condition remains understudied in wild animals, in large part because accurately and repeatedly measuring energetic condition in the wild is a challenge. Thyroid hormones (THs), such as triiodothyronine (T3) and thyroxine (T4), have a key role in mitigating metabolic responses to energy intake and expenditure, and therefore are considered important biomarkers of an animal's energetic condition. Recent method development has shown that T3 and T4 metabolites can be measured in feces, but studies measuring THs in wild populations remain rare. Here we measured fecal T3 metabolites (mT3) in baboons, and tested whether the conditions of collection and storage used for steroid hormones could also be used for mT3; we focused on mT3 as it is the biologically active form of TH and because fecal T4 metabolites (mT4) were below detection levels in our samples. We also tested if mT3 could be determined in freeze-dried samples stored for long periods of time, and if these concentrations reflected expected biological variations across seasons and reproductive states. Our results show that mT3 can be measured with accuracy and precision in baboon feces. The conditions of collection and storage we use for steroid hormones are appropriate for mT3 determination. In addition, mT3 concentrations can be determined in samples stored at -20 degrees C for up to 9 years, and are not predicted by the amount of time in storage. As expected, wild female baboons have lower mT3 concentrations during the dry season. Interestingly, mT3 concentrations are lower in pregnant and lactating females, possibly reflecting an energy sparing mechanism. Retroactive determination of mT3 concentration in stored, freeze-dried feces opens the door to novel studies on the role of energetic condition on fitness in wild animals. PMID- 29427634 TI - Mucuna pruriens (L.) DC chemo sensitize human breast cancer cells via downregulation of prolactin-mediated JAK2/STAT5A signaling. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer. AIM OF THE STUDY: We aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease. We also investigated chemo-sensitizing effect of MP on hyperprolactinemia-mediated cisplatin resistance. MATERIALS AND METHODS: Methanolic seed extract of MP were prepared and analysed using HPLC. Effect of LD and MP on the cellular viability of breast cancer cells (T47D, MCF-7, MDA-MB-468 and MDA-MB-231) were evaluated using MTT assay. Further, effect of LD and MP on colony forming potential, DNA damage, cell cycle distribution and apoptosis was determined using agar/agarose method, comet assay and annexin and PI method followed by FACS analysis. To reveal the molecular mechanism involved in the anti-cancer activity of MP, transcriptional and translational level analysis of the key proteins involved in the PRL-mediated signaling, was performed using RT-PCR and western blot analysis. The effect of MP extract on PRL-mediated signaling was validated using dopaminergic agonist bromocriptine. MP extract and cisplatin was given in different combination with appropriate controls to check their effect on chemo resistivity of breast cancer cells. RESULTS: Our results demonstrated that MP seed extract has the potential to inhibit cellular proliferation of PRL expressing T47D and MCF-7 breast cancer cells via induction of DNA damage, G1 phase of cell cycle arrest and apoptosis more effectively as compare to LD. Further, MP-mediated anti-cancerous effect was associated with the downregulation of PRL expression, further suppressing the JAK2/STAT5A/Cyclin D1 signaling pathway which has been validated using dopaminergic agonist bromocriptine. Cancer related hyperprolactinemia confers cisplatin resistance, we observed that MP via PRL inhibition, enhances cisplatin efficacy after their combinatorial treatment in breast cancer cells. CONCLUSIONS: Collectively, our study suggests that MP could be recommended as dietary supplement along with the chemotherapeutic agents against breast cancer. PMID- 29427635 TI - A Vibrio owensii strain as the causative agent of AHPND in cultured shrimp, Litopenaeus vannamei. AB - The causative agent of shrimp AHPND was identified as specific Vibrio parahaemolyticus strains, which harbor a virulent plasmid that contains the toxic genes pirA and B (pirAB). Herein, a Vibrio bacterium was isolated from shrimp in Shanghai. This bacterium was identified as Vibrio owensii using 16S rRNA gene phylogeny, whole genome sequencing and comparative analysis. The V. owensii cells are rod-shape (1.86 +/- 0.15 um) with a single polar flagellum (4 um). In addition, V. owensii form mauve colonies with jagged edges on CHROMagar plates. The pirAB genes on the plasmid revealed 100% sequence similarity to that of AHPND V. parahaemolyticus, and the encoded proteins were detected in the culture media. Subculture of V. owensii showed that the pirAB genes are unstable, and their loss rate is approximately 22% and reaches a dynamic equilibrium after the fifth generation. Upon immersion bioassay, the cumulative mortality of V. owensii (pirAB+)-infected shrimp was up to 100% within 4 days, and typical AHPND clinical signs were observed. Approximately 105 CFU/hepatopancreas of V. owensii cells were observed in the pirAB+-infected shrimp based on both culture-dependent and independent assay. Our results indicate that the expression of pirAB in the V. owensii strain is responsible for AHPND. PMID- 29427636 TI - Microbial control of phytophagous invertebrate pests in South Africa: Current status and future prospects. AB - Invertebrate pests pose a significant threat to food security on the African continent. In response, South Africa has become one of the largest importers of chemical pesticides in sub-Saharan Africa, with several hundred active ingredients registered. To address the over-reliance on such chemicals, the South African Department of Agriculture, Forestry and Fisheries (DAFF) has eliminated or restricted several pesticides since the late 1970s. The recent launch of the South African National Bio-Economy Strategy and establishment of the South African Bioproducts Organisation (SABO), together with new guidelines for registration of biopesticides in 2015, also support this endeavour. Concurrently, entomopathogen-related research and bioproduct development has increased over the past decade. Currently, 31 products (seven manufactured locally) are registered under the Fertilizers, Farm Feeds, Agricultural Remedies and Stock Remedies Act 36 of 1947. Commercially important microbes include Beauveria bassiana (Cordycipitaceae), Metarhizium anisopliae (Clavicipitaceae), Cydia pomonella granulovirus, Cryptophlebia leucotreta granulovirus, Helicoverpa armigera nucleopolyhedrovirus (Baculoviridae) and Bacillus thuringiensis subsp. kurstaki and B. thuringiensis subsp. aizawai (Bacillaceae). Both parasitic and entomopathogenic nematodes (EPNs) show potential for development as bioinsecticides with one commercial EPN product, based on Heterorhabditis bacteriophora (Heterorhabditidae), registered under the Act. Rapid scientific progression, supported by a favourable legislative environment, should facilitate further advances in microbial control of phytophagous invertebrate pests in South Africa. PMID- 29427637 TI - CEACAM1 resists hypoxia-induced inhibition of tube formation of human dermal lymphatic endothelial cells. AB - Tube formation is one of the fundamental events required by angiogenesis and lymphangiogenesis. To date, there is little knowledge on the effects of hypoxia on tube formation of human dermal lymphatic endothelial cells (HDLECs). In this study, we found that tube formation of HDLECs was inhibited under hypoxic condition with decreased expressions of VEGF-D, CEACAM1 and Prox1 genes. However, hypoxia-induced inhibition of tube formation of HDLECs was reversed by conditional media from hypoxic tumor cells. After knockdown of CEACAM1 by siRNA transfection, tube formation of HDLECs was increased with elevated Prox1 expression, suggesting that CEACAM1 downregulates Prox1 and plays an inhibitory role in tube formation of HDLECs. Since the expressions of CEACAM1 and Prox1 were both decreased by hypoxia, there are additional mechanisms downregulating Prox1 expressions during hypoxia-inhibited tube formation of HDLECs. PMID- 29427638 TI - FtsEX-CwlO regulates biofilm formation by a plant-beneficial rhizobacterium Bacillus velezensis SQR9. AB - Bacillus velezensis strain SQR9 is a well-investigated rhizobacterium with an outstanding ability to colonize roots, enhance plant growth and suppress soil borne diseases. The recognition that biofilm formation by plant-beneficial bacteria is crucial for their root colonization and function has resulted in increased interest in understanding molecular mechanisms related to biofilm formation. Here, we report that the gene ftsE, encoding the ATP-binding protein of an FtsEX ABC transporter, is required for efficient SQR9 biofilm formation. FtsEX has been reported to regulate the atolysin CwlO. We provided evidence that FtsEX-CwlO was involved in the regulation of SQR9 biofilm formation; however, this effect has little to do with CwlO autolysin activity. We propose that regulation of biofilm formation by CwlO was exerted through the spo0A pathway, since transcription of spo0A cascade genes was altered and their downstream extracellular matrix genes were downregulated in SQR9 ftsE/cwlO deletion mutants. CwlO was also shown to interact physically with KinB/KinD. CwlO may therefore interact with KinB/KinD to interfere with the spo0A pathway. This study revealed that FtsEX-CwlO plays a previously undiscovered regulatory role in biofilm formation by SQR9 that may enhance root colonization and plant-beneficial functions of SQR9 and other beneficial rhizobacteria as well. PMID- 29427639 TI - Genotyping-by-sequencing performance in selected livestock species. AB - Application of next generation sequencing for large scale genotyping in livestock is limited by high costs and challenging data analysis process. However, available restriction enzyme-based enrichment techniques like e.g. genotyping-by sequencing (GBS) are promising tools allowing reduction of financial outlies by a high sample multiplexing and narrowing down the sequenced genome areas to the randomly distributed read tags. In this study, we tested the performance of standard, PstI endonuclease-adapted GBS protocol for population genetics in cattle, horse and sheep with application of different, including low-depth sequencing setups. It was found that the detected SNPs display desirable polymorphism parameters and are evenly scattered across the whole genome including gene coding regions. It was also shown that the SNPs can be successfully applied in population genetics, revealing the genetic differentiation of the studied breeds. The GBS approach represents a cost effective alternative to existing genotyping methods which may find adoption in various research applications. PMID- 29427640 TI - Biphasic activation of complement and fibrinolysis during the human nasal allergic response. PMID- 29427641 TI - GITR cosignal in ILC2s controls allergic lung inflammation. PMID- 29427643 TI - New mechanism underlying IL-31-induced atopic dermatitis. AB - BACKGROUND: TH2 cell-released IL-31 is a critical mediator in patients with atopic dermatitis (AD), a prevalent and debilitating chronic skin disorder. Brain derived natriuretic peptide (BNP) has been described as a central itch mediator. The importance of BNP in peripheral (skin-derived) itch and its functional link to IL-31 within the neuroimmune axis of the skin is unknown. OBJECTIVE: We sought to investigate the function of BNP in the peripheral sensory system and skin in IL-31-induced itch and neuroepidermal communication in patients with AD. METHODS: Ca2+ imaging, immunohistochemistry, quantitative real-time PCR, RNA sequencing, knockdown, cytokine/phosphokinase arrays, enzyme immune assay, and pharmacologic inhibition were performed to examine the cellular basis of the IL-31-stimulated, BNP-related itch signaling in dorsal root ganglionic neurons (DRGs) and skin cells, transgenic AD-like mouse models, and human skin of patients with AD and healthy subjects. RESULTS: In human DRGs we confirmed expression and co occurrence of oncostatin M receptor beta subunit and IL-31 receptor A in a small subset of the neuronal population. Furthermore, IL-31 activated approximately 50% of endothelin-1-responsive neurons, and half of the latter also responded to histamine. In murine DRGs IL-31 upregulated Nppb and induced soluble N ethylmaleimide-sensitive factor activating protein receptor-dependent BNP release. In Grhl3PAR2/+ mice house dust mite-induced severe AD-like dermatitis was associated with Nppb upregulation. Lesional IL-31 transgenic mice also exhibited increased Nppb transcripts in DRGs and the skin; accordingly, skin BNP receptor levels were increased. Importantly, expression of BNP and its receptor were increased in the skin of patients with AD. In human skin cells BNP stimulated a proinflammatory and itch-promoting phenotype. CONCLUSION: For the first time, our findings show that BNP is implicated in AD and that IL-31 regulates BNP in both DRGs and the skin. IL-31 enhances BNP release and synthesis and orchestrates cytokine and chemokine release from skin cells, thereby coordinating the signaling pathways involved in itch. Inhibiting peripheral BNP function might be a novel therapeutic strategy for AD and pruritic conditions. PMID- 29427642 TI - Germline gain-of-function myeloid differentiation primary response gene-88 (MYD88) mutation in a child with severe arthritis. PMID- 29427644 TI - Severe asthma is associated with metabolic syndrome in Brazilian adolescents. PMID- 29427646 TI - Epigenetic deregulation in chronic lymphocytic leukemia: Clinical and biological impact. AB - Deregulated transcriptional control caused by aberrant DNA methylation and/or histone modifications is a hallmark of cancer cells. In chronic lymphocytic leukemia (CLL), the most common adult leukemia, the epigenetic 'landscape' has added a new layer of complexity to our understanding of this clinically and biologically heterogeneous disease. Early studies identified aberrant DNA methylation, often based on single gene promoter analysis with both biological and clinical impact. Subsequent genome-wide profiling studies revealed differential DNA methylation between CLLs and controls and in prognostics subgroups of the disease. From these studies, it became apparent that DNA methylation in regions outside of promoters, such as enhancers, is important for the regulation of coding genes as well as for the regulation of non-coding RNAs. Although DNA methylation profiles are reportedly stable over time and in relation to therapy, a higher epigenetic heterogeneity or 'burden' is seen in more aggressive CLL subgroups, albeit as non-recurrent 'passenger' events. More recently, DNA methylation profiles in CLL analyzed in relation to differentiating normal B-cell populations revealed that the majority of the CLL epigenome reflects the epigenomes present in the cell of origin and that only a small fraction of the epigenetic alterations represents truly CLL-specific changes. Furthermore, CLL patients can be grouped into at least three clinically relevant epigenetic subgroups, potentially originating from different cells at various stages of differentiation and associated with distinct outcomes. In this review, we summarize the current understanding of the DNA methylome in CLL, the role of histone modifying enzymes, highlight insights derived from animal models and attempts made to target epigenetic regulators in CLL along with the future directions of this rapidly advancing field. PMID- 29427645 TI - Forkhead box O proteins: Crucial regulators of cancer EMT. AB - The epithelial-mesenchymal transition (EMT) is an acknowledged cellular transition process in which epithelial cells acquire mesenchymal-like properties that endow cancer cells with increased migratory and invasive behavior. Forkhead box O (FOXO) proteins have been shown to orchestrate multiple EMT-associated pathways and EMT-related transcription factors (EMT-TFs), thereby modulating the EMT process. The focus of the current review is to evaluate the latest research progress regarding the roles of FOXO proteins in cancer EMT. First, a brief overview of the EMT process in cancer and a general background on the FOXO family are provided. Next, we present the interactions between FOXO proteins and multiple EMT-associated pathways during malignancy development. Finally, we propose several novel potential directions for future research. Collectively, the information compiled herein should serve as a comprehensive repository of information on this topic and should aid in the design of additional studies and the future development of FOXO proteins as therapeutic targets. PMID- 29427647 TI - Complete sequence of the tumor-inducing plasmid pTiChry5 from the hypervirulent Agrobacterium tumefaciens strain Chry5. AB - Agrobacterium tumefaciens strain Chry5 is hypervirulent on many plants including soybean that are poorly transformed by other A. tumefaciens strains. Therefore, it is considered as a preferred vector for genetic transformation of plants. Here we report the complete nucleotide sequence of its chrysopine-type Ti-plasmid pTiChry5. It is comprised of 197,268 bp with an overall GC content of 54.5%. Two T-DNA regions are present and 219 putative protein-coding sequences could be identified in pTiChry5. Roughly one half of the plasmid is highly similar to the agropine-type Ti plasmid pTiBo542, including the virulence genes with an identical virG gene, which is responsible for the supervirulence caused by pTiBo542. The remaining part of pTiChry5 is less related to that of pTiBo542 and embraces the trb operon of conjugation genes, genes involved in the catabolism of Amadori opines and the gene for chrysopine synthase, which replaces the gene for agropine synthase in pTiBo542. With the exception of an insertion of IS869, these Ti plasmids differ completely in the set of transposable elements present, reflecting a different evolutionary history from a common ancestor. PMID- 29427648 TI - Stretchable, anti-bacterial hydrogel activated by large mechanical deformation. AB - Hydrogels have been used extensively to deliver functional molecular cargos in response to external mechanical force. However, the intrinsic brittleness of gels restricts the applicable range of strain to 0.1, thus limiting the range of molecular release rate that may be controlled. Also, uncontrollable molecular diffusion, which is especially prominent in small molecules, reduces the role of mechanical stimulus on the release rate. As such, we hypothesized that these challenges would be resolved by combining cyclodextrin, which may form guest-host complexes with small molecular cargos, with a stretchable hydrogel system. We examined this hypothesis by synthesizing cyclodextrin acrylate and incorporating it into a polyacrylamide gel that can be stretched by 100% of its original length. In the absence of external stretching, hydrogels containing cyclodextrin acrylate with a degree of acryloyl group substitution (DSA) of 2.3 presented a lower molecular release rate than hydrogels without cyclodextrin acrylate. More interestingly, the polyacrylamide-cyclodextrin hydrogel system displayed an increased molecular release rate corresponding to the degree of stretching, particularly in the gels containing cyclodextrin acrylate with a DSA of 2.3. As such, this stretchable gel loaded with quinine was used to inhibit the growth of E. coli in lysogeny broth only when the gel was stretched. We believe the results of this study would be valuable for improving the quality of controlled molecular delivery and subsequent efficacy of molecular cargos. PMID- 29427649 TI - Rat strain differences in peritoneal immune cell response to selected gut microbiota: A crossroad between tolerance and autoimmunity? AB - AIMS: Some gut commensals can be protective, whereas others are implicated as necessary for development of inflammatory/autoimmune diseases. Peritoneal immune cells may play an important role in promoting autoimmunity in response to gut microbiota. This study investigated the phenotype and the function of peritoneal immune cells in the autoimmunity-resistant Albino Oxford (AO), and the autoimmunity-prone Dark Agouti (DA) rat strains upon stimulation with their own colonic E. coli or Enterococcus. MAIN METHODS: Rats were intraperitoneally injected with their own E. coli or Enterococcus. Peritoneal cells isolated two days later were tested for nitric oxide (NO) and cytokine production, and for arginase and myeloperoxidase (MPO) activity. The phenotype of cells was determined using flow cytometry. KEY FINDINGS: While the Enterococcus injection did not affect the composition of peritoneal cells in AO rats, the E. coli treatment increased the percentages of activated CD11bintHIS48hi neutrophils, and decreased the proportion of resident (CD11bhiHIS48int/low, CD163 + CD86+) and anti-inflammatory CD68 + CD206+ macrophages. E. coli increased the production of NO and urea, but preserved their ratio in cells from AO rats. Conversely, both E. coli and Enterococcus diminished the proportion of resident and anti-inflammatory macrophages, increased the proportion of activated neutrophils, and induced inflammatory polarization of peritoneal cells in DA rats. However, injection of E. coli maintained the ratio of typical CD11bintHIS48int neutrophils in DA rats, which correlated with the sustained MPO activity. SIGNIFICANCE: The rat strain differences in peritoneal cell response to own commensal microbiota may contribute to differential susceptibility to inflammatory/autoimmune diseases. PMID- 29427651 TI - Chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in basolateral amygdala neurons that project to prelimbic cortex. AB - Drug addiction is a brain disorder characterized by chronic, compulsive use of drugs. Previous studies have found a number of chronic morphine-induced changes in the brain at molecular levels. A study from our lab showed that chronic morphine-induced increase in the expression of presynaptic D1 receptors in basolateral amygdala (BLA) neurons played an important role in environmental cue induced retrieval of morphine withdrawal memory. However, the downstream neurocircuitry of chronic morphine-induced increase presynaptic D1 receptors in the BLA remains to be elucidated. Using retrogradely labelling technique combined with whole-cell patch-clamp methods, our results showed that (1) chronic morphine sensitized the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that projected to the prelimbic cortex (PrL), but had no influence on that in BLA neurons that projected to the nucleus accumbens (NAc) or the CA1 of the hippocampus; (2) chronic morphine sensitized the effect of D1 receptor agonist on action potential firing in BLA neurons that projected to the PrL, but without affecting the intrinsic excitability and the sensitivity of postsynaptic glutamate receptors to glutamate in BLA neurons that projected to the PrL. These results suggest that chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that project to PrL and induces a sensitization of the effect of D1 receptor agonist on action potential firing in BLA neurons that project to the PrL. PMID- 29427652 TI - Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans. AB - Psychedelics comprise drugs come from various pharmacological classes including 5 HT2A agonists, indirect 5-HT agonists, e.g., MDMA, NMDA antagonists and kappa opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e., no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e., schedules 2-5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e., drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates (CDER/FDA, 2017). We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. PMID- 29427650 TI - Abeta pathology downregulates brain mGluR5 density in a mouse model of Alzheimer. AB - The aim of the present study was to evaluate functional changes of mGluR5 expression in advanced Alzheimer's disease (AD) using positron emission tomography (PET) with an mGluR5 specific radiotracer ([18F]FPEB) in 5xFAD AD model. Subsequently, in the same animal, mGluR5 expression was quantified by immunoassay techniques. The non-displaceable binding potential values for mGluR5 was estimated by the Logan's graphical analysis. Brain PET imaging revealed that radioactivities in the hippocampus and the striatum were significantly lower in 5xFAD mice compared to control animals. Binding values were also significantly lowered in 5xFAD mice. This decline was validated by immunoblotting of protein isolates from brain tissues, as the mean band density for 5xFAD mice had a lower mGluR5 intensity than for wild type mice. These results indicated that mGluR5 levels in 5xFAD mice were down regulated in the limbic system. PMID- 29427653 TI - Advancing Neuroscience Research in Africa: Invertebrate Species to the Rescue. AB - Neuroscience research and training in many African countries are difficult due to funding and infrastructure deficit. This has resulted in few neuroscientists within Africa. However, invertebrates such as Drosophila and Caenorhabditis elegans could provide the perfect answer to these difficulties. These organisms are cheap, easy to handle and offer a comparable advantage over vertebrates in neuroscience research modeling because they have a simple nervous system and exhibit well-defined behaviors. Studies using invertebrates have helped to understand neurosciences and the complexes associated with it. If Africa wants to catch up with the rest of the world in neuroscience research, it needs to employ this innovative cost-effective approach in its research. To improve invertebrate neuroscience within the Africa continent, the authors advocated the establishment of invertebrate research centers either at regional or national level across Africa. Finally, there is also a need to provide public funding to consolidate the gains that have been made by not-for-profit international organizations over the years. PMID- 29427654 TI - Motor Sequence Learning in the Brain: The Long and Short of It. AB - Motor sequence learning involves predictive processing that results in the anticipation of each component of a sequence of actions. In smooth pursuit, this predictive processing is required to decrease tracking errors between the eye and the stimulus. Current models for motor sequence learning suggest parallel mechanisms in the brain for acquiring sequences of differing complexity. We examined this model by comparing shorter versus longer sequences of pursuit eye movements during fMRI. In this way we were able to identify overlapping and distinct brain areas involved in simple versus more complex oculomotor learning. Participants revealed predictive pursuit eye movements from the second presentation of the stimulus in both short and long sequences. Brain imaging results indicated activation of parallel brain areas for the different sequence lengths that consisted of the Inferior Occipital Gyrus and the Cingulate as areas in common. In addition, distinct activation was found in more working memory related brain regions for the shorter sequences (e.g. the middle frontal cortex and dorsolateral prefrontal cortex), and higher activation in the frontal eye fields, supplementary motor cortex and motor cortex for the longer sequences, independent on the number of repetitions. These findings provide new evidence that there are parallel brain areas that involve working memory circuitry for short sequences, and more motoric areas when the sequence is longer and more cognitively demanding. Additionally, our findings are the first to show that the parallel brain regions involved in sequence learning in pursuit are independent of the number of repetitions, but contingent on sequence complexity. PMID- 29427655 TI - Nicotinic Acetylcholine Receptors are Associated with Ketamine-induced Neuronal Apoptosis in the Developing Rat Retina. AB - Early synchronized spontaneous network activity is a hallmark of the brain growth spurt period, during which general anesthetics cause widespread neuronal apoptosis and subsequent cognitive dysfunction. However, the relationship of such activity to anesthetic-induced neuronal apoptosis remains to be determined. In this study, we utilized patch-clamp electrophysiological recording, immunohistochemistry, and TUNEL assays to investigate the potential roles of spontaneous network activity in ketamine-induced neuronal apoptosis during early development. All experiments were performed using acutely dissected whole-mount Sprague-Dawley rat retinas (0-14 postnatal days [P0-P14]). Ketamine reversibly blocked spontaneous network activity in the rat retina from P0 to P9 and irreversibly blocked such activity from P10 to P12. The peak of physiological and ketamine-induced neuronal apoptosis mainly occurred from P7 to P9. Blockade of nicotinic acetylcholine receptors (nAChRs) also induced reversible inhibition of spontaneous network activity from P0 to P7 and extensive neuronal apoptosis in the P7 rat retina, while activation of nAChRs or increases in endogenous ACh levels attenuated ketamine-induced apoptotic responses. Furthermore, blockade of alpha7-nAChR and beta2-nAChR subtypes induced neuronal apoptosis in the developing retina, while activation of the alpha7-nAChR subtype attenuated ketamine-induced apoptotic responses. These results demonstrate that ketamine may inhibit early synchronized spontaneous network activity by blocking nAChRs, and that such inhibition may contribute to ketamine-induced neuronal apoptosis in the developing rat retina. PMID- 29427656 TI - Gut Microbiota, Inflammation, and Probiotics on Neural Development in Autism Spectrum Disorder. AB - Recent evidence implicates immune alterations and gut microbiota dysbiosis in at least some subpopulations of individuals with autism spectrum disorder (ASD). Immune and gut alterations in ASD have mostly been studied separately, and the reviews and theoretical models up to now have mainly considered the immune system as one of the routes for gut-brain communication. We take a different perspective and consider possible common mechanisms of action for the gut microbiota and inflammation on the neural basis of ASD. We propose these to be their effects on ASD-susceptibility genes, neurodevelopment, and intestinal and blood-brain barrier integrity. We then use these common mechanisms to offer pathways for potentially beneficial effects of early-life probiotics on the neural development in ASD. This new perspective yields a conceptual framework for creating effective preventions for mothers at risk of giving birth to children with ASD. Such a framework may also inform effective interventions targeting these common mechanisms of action, which may be shared in many ASD cases regardless of their different etiological profiles. Probiotics may be one example of such preventions and interventions. Finally, the common mechanisms offered by this perspective can be useful in the search of comprehensive theories that can account for the complete neurobiological and behavioral symptoms of ASD. PMID- 29427657 TI - The Evolving Dialogue of Microglia and Neurons in Alzheimer's Disease: Microglia as Necessary Transducers of Pathology. AB - The understanding of the contribution of microglial cells to the onset and/or progression chronic neurodegenerative diseases is key to identify disease modifying therapies, given the strong neuroimmune component of these disorders. In this review, we dissect the different pathways by which microglia can affect, directly or indirectly, neuronal function and dysfunction associated with diseases like Alzheimer's. We here present the rationale for proposing a model to explain the contribution of microglia to the pathophysiology of Alzheimer's disease, defining microglial cells as necessary transducers of pathology and ideal targets for intervention. PMID- 29427658 TI - Puerarin protects against heart failure induced by pressure overload through mitigation of ferroptosis. AB - Heart failure (HF) is the end stage of cardiovascular disease and is characterized by the loss of myocytes caused by cell death. Puerarin has been found to improve HF clinically, and animal study findings have confirmed its anti cell-death properties. However, the underlying mechanisms remain unclear, especially with respect to the impact on ferroptosis, a newly defined mechanism of iron-dependent non-apoptotic cell death in HF. Here, ferroptosis-like cell death was observed in erastin- or isoprenaline (ISO)-treated H9c2 myocytes in vitro and in rats with aortic banding inducing HF, characterized by reduced cell viability with increased lipid peroxidation and labile iron pool. Interestingly, the increased iron overload and lipid peroxidation observed in either rats with HF or H9c2 cells incubated with ISO were significantly blocked by puerarin administration. These results provide compelling evidence that puerarin plays a role in inhibiting myocyte loss during HF, partly through ferroptosis mitigation, suggesting a new mechanism of puerarin as a potential therapy for HF. PMID- 29427659 TI - Construction of EMSC-islet co-localizing composites for xenogeneic porcine islet transplantation. AB - Pancreatic islet transplantation is an ultimate solution for treating patients with type 1 diabetes (T1D). The pig is an ideal donor of islets for replacing scarce human islets. Besides immunological hurdles, non-immunological hurdles including fragmentation and delayed engraftment of porcine islets need solutions to succeed in porcine islet xenotransplantation. In this study, we suggest a simple but effective modality, a cell/islet co-localizing composite, to overcome these challenges. Endothelial-like mesenchymal stem cells (EMSCs), differentiated from bone-marrow derived mouse mesenchymal stem cells (MSCs), and MSCs evenly coated the surface of porcine islets (>85%) through optimized culture conditions. Both MSCs and EMSCs significantly reduced the fragmentation of porcine islets and increased the islet masses, designated as islet equivalents (IEQs). In fibrin in vitro and in vivo angiogenesis analysis, constructed EMSC-islet composites showed higher angiogenic potentials than naked islets, MSC-islet composites, or human endothelial cell-islet composites. This novel delivery method of porcine islets may have beneficial effects on the engraftment of transplanted islets by prevention of fragmentation and enhancement of revascularization. PMID- 29427660 TI - Structural features and kinetic characterization of alanine racemase from Bacillus pseudofirmus OF4. AB - Alanine racemase (Alr) is a pyridoxal-5'-phosphate-dependent (PLP) enzyme that catalyzes a reversible racemization between the enantiomers of alanine. d-Alanine is an indispensable constituent in the biosynthesis of bacterial cell-wall peptidoglycan, and its inhibition is lethal to prokaryotes, which makes it an attractive target for designing antibacterial drugs. In this study, the molecular structure of alanine racemase from Bacillus pseudofirmus OF4 (DadXOF4) was determined by X-ray crystallography to a resolution of 1.8 A. The comparison of DadXOF4 with alanine racemases from other bacteria demonstrated a conserved overall fold. Enzyme kinetics analysis showed that the conserved residues at the substrate entryway and the salt bridge at the dimer interface are critical for enzyme activity. These structural and biochemical findings provide a template for future structure-based drug-development efforts targeting alanine racemases. PMID- 29427661 TI - miR-199a-5p inhibits the progression of papillary thyroid carcinoma by targeting SNAI1. AB - BACKGROUND: Increasing evidence has emphasized the important roles of differentially expressed miRNAs in papillary thyroid cancer (PTC) development. miR-199a-5p was previously documented to be downregulated in PTCs compared with normal thyroids. However, the role of miR-199a-5p in the progression of PTC and the underlying mechanism remain to be further addressed. METHODS: miR-199a-5p and snail family zinc finger 1 (SNAI1) mRNA expressions in PTC tissues and cells were detected by qRT-PCR. The effects of miR-199a-5p and SNAI1 on cell migration, invasion and epithelial-mesenchymal transition (EMT) were evaluated by cell migration and invasion assays, and western blot, respectively. The relationship between miR-199a-5p and SNAI1 was investigated by luciferase reporter assay and western blot. Xenograft tumor assay was performed to verify the role of miR-199a 5p and molecular mechanism in PTC. RESULTS: miR-199a-5p expression was significantly downregulated and SNAI1 was markedly upregulated in PTC tissues and cells. miR-199a-5p overexpression and SNAI1 knockdown suppressed the progression of PTC cells in vitro, as evidenced by the reduced cell migration, invasion and EMT. Of note, SNAI1 was identified as a target of miR-199a-5p and miR-199a-5p suppressed SNAI1 expression in PTC cells. Xenograft tumor assay proved that miR 199a-5p overexpression suppressed tumor growth in PTC in vivo by downregulating SNAI1. CONCLUSION: miR-199a-5p inhibited the progression of PTC by downregulating SNAI1, offering new insight into the molecular mechanism underlying PTC progression. PMID- 29427662 TI - TINCR facilitates non-small cell lung cancer progression through BRAF-activated MAPK pathway. AB - Long non-coding RNAs are critically involved in oncogenesis in various cancer types. Here we reported a novel lncRNA signature correlated with progression of non-small cell lung cancer (NSCLC). In particular, we identified elevated expression of terminal differentiation-induced noncoding RNA (TINCR) in human NSCLC samples, which were associated with enhanced migration, viability in NSCLC cells in vitro. Higher TINCR level was also correlated with poor survival. Furthermore, TINCR increased xenograft tumor growth in vivo mouse models. Mechanistic study demonstrated that TINCR can interact with BRAF to facilitate its kinase activity, thereby leading to activation of oncogenic mitogen-activated protein kinase (MAPK) pathway. These results suggested that TINCR upregulation may signal through the MAPK pathway to promote NSCLC tumorigenesis. Therefore, TINCR may serve as a potential prognostic marker and therapeutic target for NSCLC patients. PMID- 29427663 TI - Intracellular formyl peptide receptor regulates naive CD4 T cell migration. AB - We found that formyl peptide receptor (FPR) 1 and FPR3 were expressed intracellularly and/or the nucleus of naive CD4 T cell. Activation of naive CD4 T cells with synthetic intracellular agonists dTAT-WKYMVm and CTP-WKYMVm for FPR members stimulated CD4 T cell migration via pertussis toxin-sensitive manner. Knockdown of FPR1, but not knockdown of FPR3, blocked dTAT-WKYMVm-induced naive CD4 T cell migration. Stimulation of naive CD4 T cells with dTAT-WKYMVm elicited the activation of ERK, p38 MAPK, and Akt. Activation of CD4 T cells with anti-CD3 and anti-CD28 antibodies caused surface expression of FPR1 and FPR3, but not FPR2. CD4 T cells isolated from sepsis patients expressed the three members of FPR family on their cell surface. Taken together, our results suggest that intracellular FPR in naive CD4 T cells and surface FPRs in activated CD4 T cells might regulate immune responses by regulating CD4 T cell activity. PMID- 29427664 TI - pH-dependent Ca+2 oscillations prevent untimely acrosome reaction in human sperm. AB - During transit through the female reproductive tract, sperm encounter metabolites and environmental conditions that modulate various processes leading to fertilization. Intracellular Ca2+ dynamics regulate the acrosome reaction (AR), which involves exocytosis of the acrosomal granule, a prerequisite for successful fertilization. We explored the ability of progesterone, prostanglandin-E1, and GABA to induce Ca2+ mobilization and AR in single human spermatozoa capacitated under external pH (pHe) conditions found in different regions of the female reproductive tract (pHe 6.5, 7.4 and 8.0). The highest percentage of AR induction, regardless of the inducer, occurred when sperm were capacitated at pHe 7.4. Interestingly, at pHe 6.5 a high percentage of cells exhibit Ca2+ oscillations, which prevent AR. These oscillations involve extracellular and intracellular Ca2+ channels. Pharmacological inhibition of Ca2+ oscillations restores the ability of spermatozoa to undergo the AR when exposed to progesterone, even if capacitated at pHe 6.5. PMID- 29427665 TI - Biosynthetic machinery for C25,C25-diether archaeal lipids from the hyperthermophilic archaeon Aeropyrum pernix. AB - Archaea that thrive in harsh environments usually produce membrane lipids with specific structures such as bipolar tetraether lipids. Only a few genera of archaea, which are hyperthermophiles or halophiles, are known to utilize diether lipids with extended, C25 isoprenoid hydrocarbon chains. In the present study, we identify two prenyltransferases and a prenyl reductase responsible for the biosynthesis of C25,C25-diether lipids in the hyperthermophilic archaeon Aeropyrum pernix. These enzymes are more specific to C25 isoprenoid chains than to C20 chains, which are used for the biosynthesis of ordinary C20,C20-diether archaeal lipids. The recombinant expression of these enzymes with two known archaeal enzymes allows the production of C25,C25-diether archaeal lipids in the cells of Escherichia coli. PMID- 29427666 TI - Quantitative monitoring of two simultaneously binding species using Label Enhanced surface plasmon resonance. AB - Surface plasmon resonance (SPR) is a well-established method for biomolecular interaction studies. SPR monitors the binding of molecules to a solid surface, embodied as refractive index changes close to the surface. One limitation of conventional SPR is the universal nature of the detection that results in an inability to qualitatively discriminate between different binding species. Furthermore, it is impossible to directly discriminate two species simultaneously binding to different sites on a protein, which limits the utility of SPR, for example, in the study of allosteric binders or bi-specific molecules. It is also impossible in principle to discriminate protein conformation changes from actual binding events. Here we demonstrate how Label-Enhanced SPR can be utilized to discriminate and quantitatively monitor the simultaneous binding of two different species - one dye-labeled and one unlabeled - on a standard, single-wavelength SPR instrument. This new technique increases the versatility of SPR technology by opening up application areas where the usefulness of the approach has previously been limited. PMID- 29427667 TI - O-GlcNAcylation modulates PKA-CREB signaling in a manner specific to PKA catalytic subunit isoforms. AB - O-GlcNAcylation is a post-translational modification of proteins. Protein kinase A (PKA)-cAMP response element binding protein (CREB) signaling plays critical roles in multiple biological processes. Isoforms alpha and beta of PKA catalytic subunit (PKAc) and CREB are modified by O-GlcNAcylation. In the present study, we determined the role of O-GlcNAcylation in PKAc isoform-specific CREB signaling. We found that up-regulation of O-GlcNAcylation enhanced CREB phosphorylation, but suppressed CREB expression in exogenous PKAc isoform-unspecific manner. PKAc isoforms affected exogenous expression of OGT or OGA and protein O-GlcNAcylation differently. Up-regulation of O-GlcNAcylation did not significantly affect net PKAcalpha-CREB signaling, but enhanced PKAcbeta-CREB signaling. The role of O GlcNAcylation in PKA-CREB signaling was desensitized by insulin treatment. This study suggests a role of O-GlcNAcylation in PKA-CREB signaling by affecting phosphorylation of CREB in a PKAc isoform-specific manner. PMID- 29427668 TI - Neurokinin B and serum albumin limit copper binding to mammalian gonadotropin releasing hormone. AB - Gonadotropin releasing hormone (GnRH) triggers secretion of luteinizing hormone and follicle stimulating hormone from gonadotropic cells in the anterior pituitary gland. GnRH is able to bind copper, and both in vitro and in vivo studies have suggested that the copper-GnRH complex is more potent at triggering gonadotropin release than GnRH alone. However, it remains unclear whether copper GnRH is the active species in vivo. To explore this we have estimated the GnRH copper affinity and have examined whether GnRH remains copper-bound in the presence of serum albumin and the neuropeptide neurokinin B, both copper-binding proteins that GnRH will encounter in vivo. We show that GnRH has a copper dissociation constant of ~0.9 * 10-9 M, however serum albumin and neurokinin B can extract metal from the copper-GnRH complex. It is therefore unlikely that a copper-GnRH complex will survive transit through the pituitary portal circulation and that any effect of copper must occur outside the bloodstream in the absence of neurokinin B. PMID- 29427669 TI - High KIF2A expression promotes proliferation, migration and predicts poor prognosis in lung adenocarcinoma. AB - The Kinesin family member 2a (KIF2A), that belongs to the Kinesin-13 microtubule depolymerases, plays an important role in cancer cell proliferation, migration and apoptosis in various types of cancer such as gastric cancer, breast cancer, and squamous cell carcinoma of the oral tongue, but, its role and mechanism in lung adenocarcinoma (LUAD) is largely unknown. The present study reported that KIF2A was overexpressed in LUAD tissues as compared with adjacent normal tissues. KIF2A was closely correlated with TNM stage and lymph node metastasis (P < 0.01), whereas, no similar relationships between KIF2A and age, gender, smoking and differentiation. Multivariate analysis indicated that hyperexpression of KIF2A in LUAD was an independent risk factor for worse overall survival in LUAD patients (HR: 3.135, 95%CI: 1.331-7.112, p < 0.05). In vitro, KIF2A knockdown markedly reduced LUAD cell A549 migration and could regulate epithelial-mesenchymal transition. Furthermore, silencing KIF2A inhibited cell proliferation and induced apoptosis in lung adenocarcinoma(LUAD) cells. In conclusion, KIF2A may serve as a valuable prognostic indicator and promising therapeutic target of LUAD. PMID- 29427670 TI - Development of a TaqMan-based real-time RT-PCR assay for the detection of SADS CoV associated with severe diarrhea disease in pigs. AB - Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel coronavirus which was first reported in southern China in 2017. It can cause severe diarrhea disease in pigs. In order to detect this new emerging virus rapidly and reliably, a TaqMan-based real-time RT-PCR assay was established in this study. Specific primers and probe were designed and synthesized based on the conserved region within the N gene of the viral genome. Results showed that the lowest limit of detection was 3.0 * 101 copies/MUL. This approach was specific for SADS-CoV, and there were no cross-reaction observed against other 15 swine viruses. It was 10 times more sensitive than the conventional PCR and gave higher SADS-CoV positive detection rate (70.69%, 123/174) than the conventional PCR (51.15%, 89/174) from clinical samples. These data indicated that the TaqMan-based real-time RT-PCR assay established here was an effective method with high sensitivity, specificity and reproducibility for faster and more accurate detection and quantification of SADS-CoV. PMID- 29427671 TI - Prospective associations between toddler televiewing and subsequent lifestyle habits in adolescence. AB - BACKGROUND: Watching television is a common pastime for very young children. High exposure may negatively influence physical and mental health outcomes. Not much is known about how early exposure relates to lifestyle choices in adolescence. OBJECTIVE: To estimate how toddler televiewing is subsequently associated with lifestyle indicators at adolescence. METHODS: Participants are 986 girls and 999 boys from the Quebec Longitudinal Study of Child Development birth cohort (Canada). Child self-reports lifestyle habits at age 13 that were linearly regressed on parent-reported televiewing at age 2 while adjusting for potential confounders. RESULTS: Every 1 h 13 m increase in daily televiewing was prospectively associated with a 8.2% increased risk of unhealthy eating habits (unstandardized b = 0.05; 95% CI, 0.02 to 0.07), 10.1% decrease in eating breakfast on weekdays (unstandardized b = -0.06; 95% CI, -0.09 to -0.04), 13.3% increase in BMI (unstandardized b = 0.38; 95% CI, 0.26 to 0.50), 4.7% decrease in student engagement (unstandardized b = -0.07; 95% CI, -0.14 to -0.004), and 5.8% increase in concurrent screen time (unstandardized b = 0.06; 95% CI, 0.02 to 0.11). Post hoc simulations of noncompliance with AAP recommendations support their implementation. CONCLUSIONS: Excessive toddlerhood televiewing was prospectively associated with less optimal health and self-invested behavioral dispositions. Lifestyle habits not only affect metabolic risk but may also influence personal success outcomes. These independent relationships, observed more than a decade later, suggest a need for better parental awareness of the way children invest their limited waking hours could affect their long-term life course trajectories. PMID- 29427672 TI - The short-term impact of economic uncertainty on motor vehicle collisions. AB - Stress and anxiety lead to attention loss and sleep deprivation and may reduce driving performance, increasing the risk of motor vehicle collision. We used evidence from a natural experiment to examine whether daily changes in economic uncertainty, potentially leading to attention or sleep loss, are associated with collisions in Great Britain. Daily data from the economic policy uncertainty index, derived from analysis of daily UK newspapers, were linked to the daily number of motor vehicle collisions in Great Britain over the period 2005-2015, obtained from the Department for Transport. Exploiting daily variations in economic uncertainty, we used a GARCH approach to model daily rates of motor vehicle collisions as a function of economic uncertainty, controlling for month and day of the week, monthly unemployment rates and weekly unleaded petrol prices. A spike in the daily economic uncertainty index was associated with an immediate increase in the number of motor vehicle collisions. Results were robust to various sensitivity analyses. Overall, daily increases in economic uncertainty are associated with short-term spikes in motor vehicle collisions. Preventive and traffic control measures may need to increase during periods of economic uncertainty. PMID- 29427673 TI - Improvements in health-related quality of life among smokers who quit after hospitalization. AB - Few rigorous longitudinal assessments have examined health-related quality of life (HRQoL) changes after smoking cessation, especially among recently hospitalized smokers. We compared the change in HRQoL between those who did or did not quit smoking 6 months after hospital discharge. Participants were 1357 smokers recruited for a cessation trial between 2012 and 2014 while hospitalized at two hospitals in Massachusetts and one in Pennsylvania. Cessation was defined as biochemically confirmed 7-day point prevalence abstinence at 6 months or as self-reported continuous abstinence at 1, 3, or 6 months post discharge. HRQoL measures included a single-item global health measure (SF1); the Patient Health Questionnaire for Depression and Anxiety (PHQ-4) screening tool for psychological distress; and the EQ-5D-5L health utilities measure. Multivariable models controlled for age, sex, race, education, insurance, study site, study arm, discharge diagnoses, and baseline HRQoL. Improvements in HRQoL were evident in the first month after discharge among those achieving abstinence compared to continuing smokers. At 6 months post-discharge, those with biochemically confirmed cessation were 30% more likely to report at least good health by the SF1 (aRR 95% CI 1.14-1.45), 19% less likely to screen positive for psychological distress (aRR, 95% CI 0.68-0.93), and had EQ-5D-5L health utility scores 0.05 points (95% CI 0.02-0.08) higher than continuing smokers. Results were similar when assessed as a function of self-reported cessation. Hospital-initiated smoking cessation is associated with rapid statistically and clinically significant improvements in a range of HRQoL measures, providing an additional tool clinicians and health systems could use to encourage smoking cessation. PMID- 29427674 TI - Phage display antibodies against ectromelia virus that neutralize variola virus: Selection and implementation for p35 neutralizing epitope mapping. AB - In this study, five phage display antibodies (pdAbs) against ectromelia virus (ECTV) were selected from vaccinia virus (VACV)-immune phage-display library of human single chain variable fragments (scFv). ELISA demonstrated that selected pdAbs could recognize ECTV, VACV, and cowpox virus (CPXV). Atomic force microscopy visualized binding of the pdAbs to VACV. Three of the selected pdAbs neutralized variola virus (VARV) in the plaque reduction neutralization test. Western blot analysis of ECTV, VARV, VACV, and CPXV proteins indicated that neutralizing pdAbs bound orthopoxvirus 35 kDa proteins, which are encoded by the open reading frames orthologous to the ORF H3L in VACV. The fully human antibody fh1A was constructed on the base of the VH and VL domains of pdAb, which demonstrated a dose-dependent inhibition of plaque formation after infection with VARV, VACV, and CPXV. To determine the p35 region responsible for binding to neutralizing pdAbs, a panel of truncated p35 proteins was designed and expressed in Escherichia coli cells, and a minimal p35 fragment recognized by selected neutralizing pdAbs was identified. In addition, peptide phage-display combinatorial libraries were applied to localize the epitope. The obtained data indicated that the epitope responsible for recognition by the neutralizing pdAbs is discontinuous and amino acid residues located within two p35 regions, 15-19 aa and 232-237 aa, are involved in binding with neutralizing anti-p35 antibodies. PMID- 29427675 TI - Relevance of non-synonymous thymidine kinase mutations for antiviral resistance of recombinant herpes simplex virus type 2 strains. AB - Therapy or prophylaxis of herpes simplex virus type 2 (HSV-2) infections with the nucleoside analog aciclovir (ACV) can lead to the emergence of drug-resistant HSV 2 strains, particularly in immunocompromised patients. In this context, multiple amino acid (aa) changes can accumulate in the ACV-converting viral thymidine kinase (TK) which hampers sequence-based diagnostics significantly. In this study, the so far unknown or still doubted relevance of several individual aa changes for drug resistance in HSV-2 was clarified. For this purpose, ten recombinant fluorescent HSV-2 strains differing in the respective aa within their TK were constructed using the bacterial artificial chromosome (BAC) pHSV2(MS)Lox. Similar TK expression levels and similar replication behavior patterns were demonstrated for the mutants as compared to the unmodified BAC-derived HSV-2 strain. Subsequently, the resulting strains were tested for their susceptibility to ACV as well as penciclovir (PCV) in parallel to a modified cytopathic effect (CPE) inhibition assay and by determining the relative fluorescence intensity (quantified using units, RFU) as a measure for the viral replication capacity. While aa changes Y53N and R221H conferred ACV resistance with cross-resistance to PCV, the aa changes G25A, G39E, T131M, Y133F, G150D, A157T, R248W, and L342W maintained a susceptible phenotype against both antivirals. The CPE inhibition assay and the measurement of relative fluorescence intensity yielded comparable results for the phenotypic testing of recombinant viruses. The latter test showed some technical advantages. In conclusion, the significance of single aa changes in HSV-2 TK on ACV/PCV resistance was clarified by the construction and phenotypic testing of recombinant viral strains. This was facilitated by the fluorescence based method. PMID- 29427676 TI - In vitro susceptibility to ST-246 and Cidofovir corroborates the phylogenetic separation of Brazilian Vaccinia virus into two clades. AB - The Orthopoxvirus (OPV) genus of the Poxviridae family contains several human pathogens, including Vaccinia virus (VACV), which have been implicating in outbreaks of a zoonotic disease called Bovine Vaccinia in Brazil. So far, no approved treatment exists for OPV infections, but ST-246 and Cidofovir (CDV) are now in clinical development. Therefore, the objective of this work was to evaluate the susceptibility of five strains of Brazilian VACV (Br-VACV) to ST-246 and Cidofovir. The susceptibility of these strains to both drugs was evaluated by plaque reduction assay, extracellular virus's quantification in the presence of ST-246 and one-step growth curve in cells treated with CDV. Besides that, the ORFs F13L and E9L were sequenced for searching of polymorphisms associated with drug resistance. The effective concentration of 50% (EC50) from both drugs varies significantly for different strains (from 0.0054 to 0.051 MUM for ST-246 and from 27.14 to 61.23 MUM for CDV). ST-246 strongly inhibits the production of extracellular virus for all isolates in concentrations as low as 0.1 MUM and it was observed a relevant decrease of progeny production for all Br-VACV after CDV treatment. Sequencing of the F13L and E9L ORFs showed that Br-VACV do not present the polymorphism(s) associated with resistance to ST-246 and CDV. Taken together, our results showed that ST-246 and CDV are effective against diverse, wild VACV strains and that the susceptibility of Br-VACV to these drugs mirrored the phylogenetic split of these isolates into two groups. Thus, both ST-246 and CDV are of great interest as compounds to treat individuals during Bovine Vaccinia outbreaks in Brazil. PMID- 29427677 TI - Development of graft copolymer of carboxymethylcellulose and N-vinylcaprolactam towards strong antioxidant and antibacterial polymeric materials. AB - The present paper reports graft copolymerization of N-vinylcaprolactam (NVCL) onto carboxymethylcellulose (CMC) using tert-butyl hydroperoxide (TBHP) initiator in N2 atmosphere. The grafting was found to be highest when concentrations of CMC, NVCL and TBHP were 6.25*10-2gdm-3, 10*10-3moldm-3 and 20*10-5moldm-3 respectively. The graft copolymer (CMC-g-PNVCL-1) was characterized by FTIR, 1HNMR, SEM, AFM, XRD and TGA analysis. The antioxidant activity of the graft copolymer was found to be higher (3.81%) than CMC and slightly less (5.47%) than the standard one (butylated hydroxytoluene, BHT). The hydroxyl radical scavenging activity of graft copolymer was found to be slightly less (13.69%) than CMC and more (44.20%) than the BHT. The hydrogen peroxide scavenging activity of graft copolymer was observed to be less (20.42%) than CMC and 53.34% less than BHT. The superoxide scavenging activity of graft copolymer was greater than the both. Compared to CMC the graft copolymer has shown greater antibacterial activity against S. aureus, Proteus vulgaris and S. typhi bacteria and less against Klebsiellapneumonia and Salmonella typhimurium. PMID- 29427678 TI - Poly(I:C) enhanced anti-cervical cancer immunities induced by dendritic cells derived exosomes. AB - Dendritic cell (DC)-derived exosomes (Dexo) has been confirmed to be able to induce the specific anti-tumor immune response ex vivo and in vivo. Here, the aim of this study was to evaluate the application of the antigen-pulsed Dexo as a new vaccination platform in immunotherapy for cervical cancer. The immunogenic profile of the different Dexo was assessed by the cell proliferation, cytokines secretion and effector functions of CD8+ T cells and the splenocytes from Dexo vaccinated mice. Furthermore, the anti-tumor immunity elicited by Dexo was further compared in cervical cancer-bearing mice. Dexo from DCs loaded with E749 57 peptide could efficiently induce the cytotoxic activity of CD8+ T cells on TC 1 tumor cells ex vivo, the proliferation and IFN-gamma excretion of CD8+ T cells. Moreover, Dexo vaccine promoted the immune responses of vaccinated mice splenocytes induced by antigen E7 in vitro restimulation. Of note, poly(I:C) was significantly more potent inducer of the antigen-loaded Dexo mediated protective immunity responses for cervical cancer and further evidenced by that Dexo(E7+pIC) markedly inhibited the tumor growth and improved the survival rate of the tumor bearing mice. We provided evidence that poly(I:C) dramatically increased the potent antitumoral immunity induced by antigen-pulsed Dexo for ameliorating cervical cancer. PMID- 29427679 TI - Met117 oxidation leads to enhanced flexibility of cardiovascular biomarker- lipoprotein- associated phospholipase A2 and reduced substrate binding affinity with platelet-activating factor. AB - Human Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an important biomarker for cardiovascular diseases and a therapeutically important drug target against Atherosclerosis. It has the ability to hydrolyze various oxidized low density lipoproteins (LDL) and generates potent pro-inflammatory signaling molecules. Both physiological and non-physiological oxidants have been reported to inhibit Lp-PLA2 activity. The mechanism of the enzyme inhibition due to oxidation of surface exposed Met117 at the structural level is not clearly understood. In the present work, molecular dynamics (MD) simulation and Essential dynamics (ED) has been used in tandem with molecular docking approach to understand the structural alteration in Lp-PLA2 upon Met117 oxidation. Further, the binding of substrate, Platelet-activating factor (PAF) with the wild type and oxidized form have also been investigated. Our results showed that Met117 oxidation caused enhanced flexibility and decreased compactness in oxidized state. PAF binding interaction with oxidized protein was mediated only through hydrophobic interactions. MD simulation studies revealed that the oxidized protein failed to firmly bind PAF. Our present findings will help understand the mechanism of Lp-PLA2 inhibition under oxidative stress. PMID- 29427680 TI - Characterization of a recombinant d-allulose 3-epimerase from Agrobacterium sp. ATCC 31749 and identification of an important interfacial residue. AB - d-Allulose 3-epimerase (DAEase) catalyzes the epimerization between d-fructose and d-allulose. We had PCR-cloned and overexpressed the gene encoding Agrobacterium sp. ATCC 31749 DAEase (AsDAEase) in Escherichia coli. A high yield of active AsDAEase, 35,300U/L or 1350U/g of wet cells, was acquired with isopropyl beta-d-1-thiogalactopyranoside induction at 20 degrees C for 20h. Although only six residues including residue 234 located in tetrameric interface are different between AsDAEase and A. tumefaciens DAEase (AtDAEase), the specific activity of purified AsDAEase is much larger than that of AtDAEase. The optimal pHs and optimal temperatures of the purified recombinant AsDAEase are 7.5-8.0 and 55-60 degrees C, respectively. The half-life of the enzyme is 267min at 55 degrees C in the presence of 0.1mM Co2+, and the equilibrium ratio between d allulose and d-fructose is 30:70 at 55 degrees C. Besides characterizing AsDAEase, mutation N234D was constructed to assess its influence on activity. The specific activity of the purified N234D AsDAEase is only 25.5% of wild-type's activity, suggesting residue N234 is an important interfacial residue which substantially affects enzyme activity. The high specific activity and high expression yield of AsDAEase suggest its prospect to be applied in d-allulose production. PMID- 29427681 TI - In vitro activities of kappa-carrageenan isolated from red marine alga Hypnea musciformis: Antimicrobial, anticancer and neuroprotective potential. AB - This study assessed the antioxidant, antimicrobial, anticancer and neuroprotective activities of the kappa(k)-carrageenan isolated from the red alga Hypnea musciformis (Hm-SP). The chemical spectrum of the k-carrageenan from Hm-SP was confirmed by Fourier transform infrared (FT-IR) spectroscopy. Hm-SP revealed an antibacterial and antifungal action against Staphylococcus aureus and Candida albicans, respectively. Hm-SP did not promoted cytotoxic effects against Human breast cancer (MCF-7) and Human neuroblastoma (SH-SY5Y) cell-lines. However, it was observed a significant reduction of the cellular proliferation capacity in these cancer cells in presence of the Hm-SP. Furthermore, Hm-SP showed neuroprotective activity in 6-hydroxydopamine-induced neurotoxicity on SH-SY5Y cells by modulation of the mitochondria transmembrane potential and reducing Caspase 3 activity. In addition, Hm-SP demonstrates low antioxidant potential and did not induce significant cytotoxic effects or changes in the cell proliferation on Balb/c 3T3 mouse fibroblast cell-line. In summary, our data suggest that Hm-SP shows antimicrobial, anticancer and neuprotective activities. PMID- 29427682 TI - Effect of two seaweed polysaccharides on intestinal microbiota in mice evaluated by illumina PE250 sequencing. AB - Effect of polysaccharides from two seaweeds, Porphyra haitanensis and Ulva prolifera, on intestinal microbiota in mice was evaluated by illumina PE250 sequencing. Analysis showed significant structural changes in fecal microbiota among the three sample groups. There were significant differences in the composition of fecal microbiota among the three groups at phylum and genus levels. At the phylum level, the most predominant phylum was Bacteroidetes contributing 58.76%, 73.39%, 75.38% and 64.40% of the fecal microbiota in K, Z, H and D groups respectively, followed by Firmicutes, contributing 37.61%, 23.99%, 21.87% and 30.82% respectively. Many genera were significantly higher in the Z and H group than in the K group, including Prevotellaceae UCG-001 (p<0.05) and Rikenellaceae RC9 (p<0.01). In conclusion, our results suggest that polysaccharide type and glycoside may contribute to shaping mice gut microbiota. PMID- 29427683 TI - Interaction of proteins with lemon-juice/glutathione-derived carbon nanodot: Interplay of induced-aggregation and co-solubilization. AB - The accumulation of protein aggregates (tau) causes Alzheimer's disease (AD), Parkinson's disease (PD), and a range of neurodegenerative diseases. To develop a less toxic and bio-derived nanomaterials for inhibition of protein-aggregation, carbon nanodot has been used for this study. Nanodot have generated huge interest in biomedical applications owing to unique emission property and good biocompatibility. A carbon nanodot is synthesized from a natural resource-lemon juice and glutathione. The synthesized nanodot possesses excitation-independent emission and nano-sheet like with high graphitic content. Interaction of protein with CND is monitored by intrinsic fluorescence (trp residues), FT-IR and circular dichroism spectroscopy. Whereas it solubilizes the protein aggregates at its higher concentration. Both induced-aggregation and co-solubilization are sequence-independent and dictated by nanodot. The study may shed light on the role of glutathione in glutathione-dependent glyoxalase system toward defence against glycation product. PMID- 29427684 TI - Fabrication of micropatterned alginate-gelatin and k-carrageenan hydrogels of defined shapes using simple wax mould method as a platform for stem cell/induced Pluripotent Stem Cells (iPSC) culture. AB - Micropatterning techniques involve soft lithography, which is laborious, expensive and restricted to a narrow spectrum of biomaterials. In this work we report, first time employment of patterned wax moulds for generation of micropatterned alginate-gelatin and kappa-carrageenan (kappa-CRG) hydrogel systems by a novel, simple and cost effective method. We generated and characterized uniform and reproducible micropatterned hydrogels of varying sizes and shapes such as square projections, square grooves, and circular grids and crisscrossed hillocks. The rheological analysis showed that kappa-carrageenan hydrogels had higher gel strength when compared to alginate-gelatin hydrogels. Human Mesenchymal stem cells (hMSCs) and Human Induced Pluripotent Stem Cells (hiPSCs) were found to be cytocompatible with these hydrogels. This micropatterned hydrogel system may have potential application in tissue engineering and also in understanding the basic biology behind the stem cell/iPSC fate. PMID- 29427685 TI - Carbapenemase detection using the beta-CARBA test: Influence of test conditions on performance and comparison with the RAPIDEC CarbaNP assay. PMID- 29427686 TI - Laboratory diagnosis of urinary tract infections: Towards a BILULU consensus guideline. AB - Urinary tract infections (UTI) are very common throughout life and account for the majority of the workload in the clinical microbiology laboratory. Clear instructions for the interpretation of urine cultures by the laboratory technicians are indispensable to obtain standardized, reliable, and clinically useful results. In literature, there is often a lack of evidence-based practice in processing urinary samples in the laboratory. In this consensus document, the BILULU Study Group presents a practical approach for the implementation of existing guidelines for the culture of urine in the microbiology laboratory and offers answers for issues where no clear solution is available in the guidelines. PMID- 29427687 TI - Rapid detection of carbapenemase-producing Acinetobacter baumannii and carbapenem resistant Enterobacteriaceae using a bioluminescence-based phenotypic method. AB - Accurate detection of carbapenem-resistant Enterobacteriaceae (CRE) and carbapenemase-producing carbapenem-resistant Acinetobacter spp. (CP-CRA) constitutes a major challenge in laboratory diagnostics. We developed a bioluminescence-based carbapenem susceptibility detection assay (BCDA) which allows identification of CRE (carbapenemase-producing-CRE (CP-CRE) as well as non carbapenemase-producing-CRE (non-CP-CRE) and CP-CRA in 2.5 h from culture media. This laboratory method was evaluated with CP-CRE and CP-CRA isolates producing different beta-lactamases of different Ambler classes (A, n = 16; B, n = 25; D, n = 67) and 22 non-CP-CRE. The results were correlated with those obtained by BD PhoenixTM and genotypic analysis results. The performance of BCDA on 123 validated CRE (except C. freundii isolates) and CP-CPA isolates revealed that 122 of 123 isolates were identified correctly. Only one OXA-48-producing Klebsiella pneumoniae was falsely classified. Among 45 meropenem susceptible Enterobacteriaceae (except C. freundii isolates) and meropenem susceptible Acinetobacter spp. strains tested, 44 were confirmed as susceptible by our BCDA. Overall, our BCDA had a sensitivity of 99% and a specificity of 98% and is a rapid and accurate assay which distinguished CRE/CP-CRA from meropenem susceptible Enterobacteriaceae and Acinetobacter spp. PMID- 29427688 TI - Asset-Based Community Development as a Strategy for Developing Local Global Health Curricula. AB - BACKGROUND: A significant and growing proportion of US children have immigrant parents, an issue of increasing importance to pediatricians. Training globally minded pediatric residents to address health inequities related to globalization is an important reason to expand educational strategies around local global health (LGH). METHODS: We developed a curriculum in the pediatric global health residency track at the University of Wisconsin in an effort to address gaps in LGH education and to increase resident knowledge about local health disparities for global community members. This curriculum was founded in asset-based community development (ABCD), a strategy used in advocacy training but not reported in global health education. RESULTS: The initial curriculum outputs have provided the foundation for a longitudinal LGH curriculum and a community academic partnership. Supported by a community partnership grant, this partnership is focused on establishing a community-based postpartum support group for local Latinos, with an emphasis on building capacity in the Latino community. CONCLUSIONS: Aspects of this curriculum can serve other programs looking to develop LGH curricula rooted in building local partnerships and capacity using an ABCD model. PMID- 29427689 TI - Food insecurity, diet quality and body mass index of women participating in the Supplemental Nutrition Assistance Program: The role of intrapersonal, home environment, community and social factors. AB - Obesity is a public health problem that disproportionately affects low-income populations. Moreover, participation in Supplemental Nutrition Assistance Program (SNAP) has been associated with obesity among low-income women. The goal of this study was to determine the impact of intrapersonal, home environment, community and social factors on diet quality and body mass index (BMI) of low-income women participating in SNAP. This study also aimed to examine the role of these factors in mediating the relationship between food insecurity and diet quality, and BMI. A total of 152 women receiving SNAP benefits were recruited from low-income neighborhood centers and housing communities, and administered a demographics questionnaire, the United States adult food security scale, food frequency questionnaire, and multi-dimensional home environment scale (MHES). They also were measured for height and weight to calculate BMI. The Dietary Guidelines Adherence Index 2015 was used to measure diet quality. Regression analyses were conducted to determine the MHES subscales that were significant predictors of diet quality and BMI. The Preacher and Hayes mediation model was used to evaluate the mediation of the relationship between food insecurity and diet quality, and BMI by the MHES. Emotional eating resistance and favorable social eating behaviors were positively associated with diet quality; whereas emotional eating resistance, lower availability of unhealthy food at home, neighborhood safety and favorable social eating behaviors were inversely associated with BMI in women participating in SNAP. The MHES significantly mediated the relationship between food insecurity and BMI. These results emphasize the importance of intrapersonal, home environment, community and social factors in mediating the relationship between food insecurity and BMI in low-income women. PMID- 29427690 TI - The buffer effect of body compassion on the association between shame and body and eating difficulties. AB - Body compassion is a new construct which incorporates two multidimensional concepts: body image and self-compassion. Self-compassion has been revealed as a protective mechanism against body image and eating-related-related disturbances, including eating disorders. However, the study of this compassionate competence specifically focused on the domain of the body is still largely unexplored. This study aims to test whether body compassion moderate the impact of external shame on body image shame and disordered eating, in a sample of 354 women from the Portuguese general population. Correlation analyses showed that body compassion was negatively associated with experiences of shame and disordered eating. Path analysis results demonstrated the existence of a moderator effect of body compassion on the relationship between general feelings of shame and both body image shame and related behaviours, and disordered eating symptomatology. In fact, results suggested that body compassion buffered the impact of general feelings of shame on these psychopathological indices, with the tested model accounting for 46% and 39% of the variance of body image shame and disordered eating, respectively. This study contributes to a better understanding of the role of body compassion in body image and eating difficulties. Body compassion seems to be an important protector of these difficulties in women by buffering the effects of general shame on body image shame and related body concealment behaviours, as well as disordered eating. The findings from this study thus appear to offer important research and clinical implications, supporting the relevance of promoting body compassion in prevention and treatment programs for body image difficulties and disordered eating. PMID- 29427691 TI - Subjective satiety and plasma PYY concentration after wholemeal pasta. AB - Dietary fiber and whole grain foods may contribute to the regulation of appetite; however, evidence has produced inconclusive findings. The objective was to evaluate the effects of an experimental wholemeal pasta on appetite ratings, plasma concentrations of gastrointestinal hormones involved in appetite control, and postprandial glucose/insulin responses in healthy adults. Fourteen healthy adults (7M/7F), mean age 30+/-2 yrs (mean+/-SEM), participated in a randomized, controlled, crossover trial. Participants consumed on two different days, at one week interval, 117g of wholemeal pasta or 100g of refined wheat pasta (control pasta), similar in energy and macronutrient composition except for fiber amount, which was higher in wholemeal pasta (11 vs 3 g). Appetite ratings, glucose/insulin/lipid and gastrointestinal hormone responses were measured at fasting and for 4-h after the ingestion of the pasta tests, after which self reported energy intake for 8-h was evaluated. After the wholemeal pasta, the desire to eat and the sensation of hunger were lower (-16%, p=0.04 and -23%, p=0.004, respectively) and satiety was higher (+13%; p=0.08) compared with the control pasta; no effect on self-reported energy intake at subsequent meal was observed. After wholemeal pasta, glucose, triglyceride increased and GLP-1 responses were not different compared to control pasta but insulin response at 30 min (p<0.05) and ghrelin at 60 min (p=0.03) were lower and PYY levels higher (AUC=+44%, p=0.001). The appetite rating changes correlated with PYY plasma levels (p<0.03). In conclusion, consumption of whole grain instead of refined wheat pasta contributed to appetite control but did not seem to influence acute energy balance. Appetite ratings were associated with modifications in PYY hormone concentrations. PMID- 29427692 TI - Eating with eyes - Comparing eye movements and food choices between overweight and lean individuals in a real-life buffet setting. AB - Researchers have long sought to pinpoint factors underpinning individual differences in eating behaviour. Emerging data from eye-tracking studies have suggested that attentional biases to food exist among individuals and food types. However, such studies have thus far relied on food images and computerised tasks, limiting real-world implications. The present study tested 32 healthy male participants (16 being overweight) for attentional biases in an ad libitum buffet setting, using wearable eye-trackers. The eye-tracking analyses suggested that sugar content moderated visual fixation biases (p < 0.05), whereas BMI exerted significant effects on pupil diameter (p < 0.05). In addition, findings from the study revealed tripartite relationships between eye-tracking, self-reported liking, and ad libitum intake. Although visual fixation in the "view" condition was correlated with liking for high-calorie food, further analyses showed that this measure was not a strong predictor of food selection. Instead, visual fixation during the selection task could be the key predictor for selection of savoury food. In contrast, neither eye-tracking nor self-reported measures could adequately predict selection of desserts, implicating distinct decision-making processes for different types of food. Due to the small sample size, findings from this study should be replicated in future research. Overall, this study highlights the importance of realistic experimental settings in eye-tracking studies for understanding eating behaviour. PMID- 29427693 TI - A process and outcome evaluation of an in-class vegetable promotion program. AB - OBJECTIVE: Nutrition interventions that target both fruits and vegetables are effective in increasing fruit consumption, but have been limited in their ability to improve vegetable intake. To address the low proportion of children meeting vegetable intake guidelines, approaches specifically targeting vegetables are needed. This paper reports on a mixed-method analysis of a 10-week vegetable promotion pilot project that aimed to increase vegetable intake as part of the existing Crunch&Sip in-class fruit and vegetable break program. DESIGN: The intervention was designed to promote vegetable consumption through the implementation of vegetable-focused resources, including curriculum resources and parent education materials. Teachers completed pre- and end-of-intervention surveys. Process measures related to the use of resources and teachers' perceptions of barriers to implementation. The outcome evaluation included measures of children's vegetable consumption during Crunch&Sip breaks and teachers' attitudes and confidence relating to educating students about the benefits of consuming vegetables. SUBJECTS: Twenty-one Western Australian primary schools already participating in the Crunch&Sip program participated in the pilot intervention and evaluation. Coverage included 35 primary school teachers representing 818 students aged 4-11 years. RESULTS: The proportion of children bringing vegetables for Crunch&Sip more than doubled over the 10-week intervention (21% vs 46%; p < 0.001). Improvements were observed in teachers' perceived knowledge about the nutritional benefits of vegetables (p = 0.001) and confidence to educate students about the benefits of vegetable consumption (p = 0.028). CONCLUSIONS: Preferentially promoting vegetable consumption as part of an existing school-based nutrition program may be an effective strategy to increase children's vegetable intake. PMID- 29427694 TI - Pregnancy outcomes in women with an early diagnosis of gestational diabetes mellitus. AB - AIM: To examine pregnancy outcomes in women with gestational diabetes mellitus (GDM) based on the timing of diagnosis. METHOD: We compared demographics, blood sugars and outcomes between women diagnosed before (n = 167) or after 24 weeks' gestation (n = 1202) in a single hospital between 2009 and 2012. Because early screening is risk-based we used propensity score modelling and conditional logistic regression to account for systematic differences. RESULTS: Women diagnosed with GDM before 24 weeks were more likely to be obese and they were less likely to have excess gestational weight gain (35 vs. 45%, p = 0.04). Early diagnosis was associated with more frequent therapy including glyburide (65 vs. 56%, p < 0.001) and insulin (19 vs 6%, p < 0.001). After propensity score modelling and accounting for covariates, early diagnosis was associated with an increased risk for macrosomia (OR 2, 95% 1-4.15, p = 0.0498). Early diagnosis was not associated with other adverse outcomes. In a subgroup analysis comparing women treated with glyburide prior to 24 weeks compared to those diagnosed after 24 weeks, early diagnosis in women treated with glyburide was associated with an increased risk for macrosomia (OR 2.3, 95% CI 1.1-5.4, P = 0.04). CONCLUSION: Women diagnosed with GDM before 24 weeks have unique features, are at risk for adverse outcomes, and require targeted approaches to therapy. PMID- 29427696 TI - Skin complications of insulin injections: A case presentation and a possible explanation of hypoglycaemia. AB - We are willing to report the case of a woman with type 2 diabetes treated with insulin, 4 shots a day, referring to us for 2 very large pigmented abdominal lipo hypertrophy (LH) areas due to incorrect injection technique. The ultrasound examination showed the presence offluidwithin both LH lesions. Fluid examination showed insulin concentrations 13 times higher thancirculating ones. A12-month longstructured training on correct injection techniques normalized metabolic control and took rid of all sudden severe hypoglycemic episodes and the wide glycemic variability. In fact, both LH areas disappeared became softer and slightly smaller and got fluid-free. This is the first case documenting the presence of sort of an insulin reservoir within LH lesions and fluid reabsorption can explain the disappearance of hypoglycemic episodes and the improvement of glycemic control. PMID- 29427695 TI - Food insecurity is associated with high risk glycemic control and higher health care utilization among youth and young adults with type 1 diabetes. AB - AIMS: Household food insecurity (FI), i.e., limited availability of nutritionally adequate foods, is associated with poor glycemic control among adults with type 2 diabetes. We evaluated the association of FI among youth and young adults (YYA) with type 1 diabetes to inform recent clinical recommendations from the American Diabetes Association for providers to screen all patients with diabetes for FI. METHODS: Using data from the Washington and South Carolina SEARCH for Diabetes in Youth Study sites, we conducted an observational, cross-sectional evaluation of associations between FI and glycemic control, hospitalizations, and emergency department (ED) visits among YYA with type 1 diabetes. FI was assessed using the Household Food Security Survey Module, which queries conditions and behaviors typical of households unable to meet basic food needs. Participants' HbA1c were measured from blood drawn at the research visit; socio-demographics and medical history were collected by survey. RESULTS: The prevalence of FI was 19.5%. In adjusted logistic regression analysis, YYAs from food-insecure households had 2.37 higher odds (95% CI: 1.10, 5.09) of high risk glycemic control, i.e., HbA1c >9.0%, vs. peers from food-secure households. In adjusted binomial regression analysis for ED visits, YYAs from food-insecure households had an adjusted prevalence rate that was 2.95 times (95% CI [1.17, 7.45]) as great as those from food secure households. CONCLUSIONS: FI was associated with high risk glycemic control and more ED visits. Targeted efforts should be developed and tested to alleviate FI among YYA with type 1 diabetes. PMID- 29427697 TI - Barriers and strategies for oral medication adherence among children and adolescents with Type 2 diabetes. AB - AIMS: Examine barriers for taking glucose-lowering oral medications, associated baseline characteristics, strategies used, and the adherence impact in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: We studied youth prescribed oral diabetes medications over two years (N = 611, 583, and 525 at 6, 12, and 24 months). Clinicians documented barriers (e.g. forgetting, routines, other concerns) in the subsample that reported missed doses (N = 423 [69.2%], 422 [72.4%], and 414 [78.9%] at 6, 12, and 24 months, respectively). Adherence strategies were also assessed (e.g. family, schedule, reminder device) using standard questions. Logistic regression was used to analyze associations with medication adherence. RESULTS: Those missing doses were not different from the total sample (61.5% female, 13.9 +/- 2.0 years, >80% racial/ethnic minorities). No baseline demographic or clinical predictors of barriers to medication adherence were identified. Among those for whom barriers were assessed, "forgetting" with no reason named (39.3%) and disruptions to mealtime, sleep, and schedule (21.9%) accounted for the largest proportion of responses. Family support was the primary adherence strategy identified by most youth (>=50%), followed by pairing the medication regimen with daily routines (>40%); the latter strategy was associated with significantly higher adherence rates (p = 0.009). CONCLUSIONS: Family supported medication adherence was common in this mid-adolescent cohort, but self-management strategies were also in evidence. Findings are similar to those reported among youth with other serious chronic diseases. Prospective studies of multi-component family support and self management interventions for improving medication adherence are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT00081328. PMID- 29427698 TI - Correlations of the glycemic variability with oxidative stress and erythrocytes membrane stability in patients with type 1 diabetes under intensive treatment. AB - OBJECTIVES: This study aimed to evaluate the correlations of glycemic variability with erythrocyte membrane stability parameters and oxidative stress markers in patients with type 1 diabetes mellitus (T1DM) under intensive treatment. MATERIAL AND METHODS: 90 patients with T1DM and under intensive treatment of the disease were evaluated in relation to anthropometric indices, records of glycemic averages and parameters of glycemic variability, biochemical dosages (glucose, uric acid, lipidogram, glycated hemoglobin, microalbuminuria, creatinine and iron) reticulocyte count, erythrocyte membrane stability parameters and oxidative stress markers (thiobarbituric acid reactive substances, TBARS, and glutathione reductase, GR). RESULTS: Indicators of glycemic variability in the short and long term showed correlations with parameters of membrane stability and markers of oxidative stress (GR). In addition, the comparison of these same parameters between the subgroups consisting of quartiles of GV or glycemic control also showed significant differences. CONCLUSION: In the T1DM patients studied here, glycemic variability showed correlations with oxidative stress and erythrocyte membrane stability variables. This corroborates the hypothesis that glycemic fluctuations interfere with lipid peroxidation and cell membrane behavior, emphasizing its participation in mechanisms related to the development of chronic complications of diabetes. PMID- 29427699 TI - Metabolic risk factors in Korean adolescents with severe obesity: Results from the Korea National Health and Nutrition Examination Surveys (K-NHANES) 2007-2014. AB - AIMS: To investigate the metabolic risk factors according to the degree of obesity in Korean adolescents. METHODS: Among 7197 subjects aged 10-18 years who participated in the 2007-2014 K-NHANES, 1326 adolescents (M = 744, F = 582) with age and sex specific body mass index (BMI) >=85th percentile were included. These adolescents with obesity were classified as: overweight, obesity, severe obesity, and extreme severe obesity. For assessing central obesity, the subjects were further-classified as: normal waist obese, abdominal obesity I, abdominal obesity II and abdominal obesity III. RESULTS: The prevalence of overweight, obesity, severe obesity and extreme severe obesity were 5.6%, 6.2%, 5.9% and 0.9% in Korean adolescents. With increasing levels of obese category, the incidence of metabolic risk factors such as HDL-C < 40 mg/dL or <50 mg/dL in girls older than 16 years-old (20.2%, 18.5%, 34.4%, 43.6%, P < .0001), TG >= 150 mg/dL (15.3%, 16.7%, 26.5%, 30.9%, P < .003), HbA1C >= 5.8% (12.8%, 13.5%, 21.9%, 42.2%, P < .006), SBP >= 130 mg/dL (3.5%, 6.4%, 8.1%, 19.5%, P < .003) significantly increased. With increasing levels of central obese category, the incidence of metabolic risk factors such as HDL-C < 40 mg/dL or <50 mg/dL in girls older than 16 years-old (20.2%, 26.2%, 37.9%, 35.7%, P < .0007), TG >= 150 mg/dL (16.1%, 21.2%, 25.8%, 29.8%, P < .004), glucose >= 100 mg/dL (7.7%, 7.3%, 11.7%, 17.4%, P < .009) and SBP >= 130 mg/dL (5.1%, 7.1%, 3.0%, 13.9%, P < .002) significantly increased. CONCLUSION: Adolescents with severe obesity have more metabolic risk factors compared to adolescents with less severe degree of obesity. PMID- 29427700 TI - New arguments for beneficial effects of alpha-lipoic acid on the cardiovascular system in the course of type 2 diabetes. AB - PURPOSE: Alpha-lipoic acid (ALA), widely known as an antioxidant, modifies also serum levels of angiogenic factors in type 2 diabetic patients. These pharmacological activities may influence the status of the cardiovascular system. Taking into consideration that diabetes is related to the increased cardiovascular risk we investigated several effects of ALA on angiogenic factors in the myocardium and in the aortal wall using a rat model of type 2 diabetes. METHODS: Diabetes was induced in Wistar rats by a fat-rich diet and by intraperitoneal injection of a small dose of streptozotocin (30 mg/kg). Animals were divided into 3 groups: ALA-treated type 2 diabetes rat model, placebo treated type 2 diabetes rat model and placebo-treated non-diabetic rats. ALA was administered orally once a day, 20 mg/kg, for 8 consecutive weeks. mRNA VEGF, VEGF-R1 and VEGF-R2 expression was measured in the myocardium and the aortal wall, simultaneously with circulating VEGF and circulating endothelial cells (cEC) and endothelial progenitor cells (cEPC). RESULTS: ALA induced pro angiogenic effect in the myocardium of rats with diabetes increasing mRNA VEGF expression and decreasing mRNA VEGFR-1 expression, while in the aortal wall ALA increased mRNA VEGFR-2 and VEGFR-1 expression. cVEGF in the ALA-treated group was higher comparing to both control groups. It was revealed that cEC percentage in the ALA-treated group was decreased with no effect on the percentage of cEPC. CONCLUSIONS: In summary, the current data provide novel findings about potential beneficial effects of ALA on angiogenic factors in the cardiovascular system, especially on myocardium, in the course of type 2 diabetes. PMID- 29427701 TI - Statins differentially modulate microRNAs expression in peripheral cells of hyperlipidemic subjects: A pilot study. AB - AIM: Although statins are considered a cornerstone for the treatment of high cholesterol levels due to their powerful cholesterol-lowering effects, response to drug administration is still one of the main pitfalls of statin treatment. So far, the reasons underlying this undesired outcome are still poorly understood, but recently, various studies have suggested that miRNAs may be involved. Therefore, we aimed at evaluating the effect of short-term low-dose treatment with 2 statins on miRNAs expression in patients with hypercholesterolemia. METHODS: A total of 40 hypercholesterolemic (HC) subjects following 1 month of atorvastatin (10 mg/day; n = 20) or simvastatin (10 mg/day; n = 20) were included. Multiple available boinformatic algorithms (TargetScan, miRanda, DianaLab, MicroCosm and PicTar) were employed to select miRNAs regulating genes involved in cholesterol metabolism and statin response. Differential miRNAs expression was determined in peripheral cells using the miScript(r) miRNA PCR Array platform. Pathways involving differentially expressed miRNAs were explored using the Ingenuity Pathway Analysis software. RESULTS: Atorvastatin repressed miR-29a-3p, miR-29b-3p, miR-300, miR-33a-5p, miR-33b-5p and miR-454-3p in HC subjects. On the contrary, simvastatin did not show any effect on miRNAs expression. Network analysis indicated that atorvastatin-modulated miRNAs regulate key cholesterol genes (ABCA1, HMGCR, INSIG1, LDLR, LPL, SCAP and SREBF1). Further subgroups analyses showed that miR-106b-5p, miR-17-3p and miR 590-5p were repressed in HC subjects within the lower quartile of atorvastatin response (lower LDL-C reduction), while the expression of miR-106b-5p, miR-17-3p and miR-183-5p was higher in the upper quartile of simvastatin response (higher LDL-C reduction) (p < 0.05). CONCLUSION: We show that a miRNAs-mediated epigenetic mechanism is differentially affected by statins therapy in vivo, which could be implicated in the variable response to these drugs. Further studies are necessary to disclose their particular role in the cholesterol-reduction response to statins. PMID- 29427702 TI - High brain distribution of a new central nervous system drug candidate despite its P-glycoprotein-mediated efflux at the mouse blood-brain barrier. AB - Efficacy of drugs aimed at treating central nervous system (CNS) disorders rely partly on their ability to cross the cerebral endothelium, also called the blood brain barrier (BBB), which constitutes the main interface modulating exchanges of compounds between the brain and blood. In this work, we used both, conventional pharmacokinetics (PK) approach and in situ brain perfusion technique to study the blood and brain PK of PKRinh, an inhibitor of the double-stranded RNA-dependent protein kinase (PKR) activation, in mice. PKRinh showed a supra dose-proportional blood exposure that was not observed in the brain, and a brain to blood AUC ratio of unbound drug smaller than 1 at all tested doses. These data suggested the implication of an active efflux at the BBB. Using in situ brain perfusion technique, we showed that PKRinh has a very high brain uptake clearance which saturates with increasing concentrations. Fitting the data to a Michaelis-Menten equation revealed that PKRinh transport through the BBB is composed of a passive unsaturable flux and an active saturable protein-mediated efflux with a km of ? 3 MUM. We were able to show that the ATP-binding cassette (ABC) transporter P-gp (Abcb1), but not Bcrp (Abcg2), was involved in the brain to blood efflux of PKRinh. At the circulating PKRinh concentrations of this study, the P-gp was not saturated, in accordance with the linear brain PKRinh PK. Finally, PKRinh had high brain uptake clearance (14 MUl/g/s) despite it is a good P-gp substrate (P gp Efflux ratio ? 3.6), and reached similar values than the cerebral blood flow reference, diazepam, in P-gp saturation conditions. With its very unique brain transport properties, PKRinh improves our knowledge about P-gp-mediated efflux across the BBB for the development of new CNS directed drugs. PMID- 29427703 TI - Safety and clinical efficacy of tenvermectin, a novel antiparasitic 16-membered macrocyclic lactone antibiotics. AB - Tenvermectin (TVM) is a novel 16-membered macrocyclic lactone antibiotics, which contains component TVM A and TVM B. However there is not any report on safety and clinical efficacy of TVM for developing as a potential drug. In order to understand the part of safety and clinical efficacy of TVM, we conducted the acute toxicity test, the standard bacterial reverse mutation (Ames) test and the clinical deworming test. In the acute toxicity studies, TVM, TVM A and ivermectin (IVM) were administrated once by oral gavage to mice and rats. Results showed that the oral LD50 values of TVM, TVM A and IVM in mice were 74.41, 106.95 and 53.06 mg/kg respectively. The oral LD50 values of TVM and TVM A in rats were determined to be 164.22 and 749.34 mg/kg respectively. TVM and IVM are moderately toxic substances, meanwhile the TVM A belongs to low toxic compounds, implying that the acute toxicity is highly related to the length of side chain of TVM at position C25. In the Ames test, results showed that TVM did not induce mutagenicity in Salmonella typhimurium TA97a, TA98, TA100, TA102 and TA1535 with and without metabolic activation system, speculating that the mutagenicity is probably not related to the side chain at position C25 of 16-membered macrocyclic lactone antibiotics. In the efficacy trail of TVM against swine nematodes, growing pigs natural infection of Ascaris suum and Trichuris suis were treated with a single subcutaneous injection 0.3 mg/kg b.w.. Results showed that TVM and IVM had excellent effect in expelling Ascaris suum, and TVM had potential efficacy against Trichuris suis, however IVM had no effect on Trichuris suis. This study suggests that the side chain of TVM at position C25 may have important biological functions, which is one of the key sites of the studies on structure activity relationship of 16-membered macrocyclic lactone compounds. TVM is a new compound exhibited some advantages worthy of developing. PMID- 29427704 TI - Finding Makhubu: A morphological forensic facial comparison. AB - June 16, 1976, marks the Soweto Youth Student Uprising in South Africa. A harrowing image capturing police brutality from that day comprises of 18-year-old Mbuyisa Makhubu carrying a dying 12-year-old Hector Peterson. This circulated international press and contributed to world pressure against the apartheid government. This elevated Makhubu's profile with the national security police and forced him to flee to Botswana, then Nigeria, before disappearing in 1978. In 1988, Victor Vinnetou illegally entered Canada and was later arrested on immigration charges in 2004. Evasive of his true identity, the Canadian Border Services Agency and Makhubu's family believe Vinnetou is Makhubu, linking them by a characteristic moon-shaped birthmark on his left chest. A performed DNA test however, was inconclusive. Following the continued 40-year mystery, Eye Witness News in 2016 requested further investigation. Using a limited series of portrait images, a forensic facial comparison (FFC) was conducted utilising South African Police Service (SAPS) protocols and Facial Identification Scientific Working Group (FISWG) guidelines. The images provided, presented a substantial time-lapse and generally low resolution, while being taken from irregular angles and distances, with different subject poses, orientations and environments. This enforced the use of a morphological analysis; a primary method of FFC that develops conclusions based on subjective observations. The results were fundamentally inconclusive, but multiple similarities and valid explanations for visible differences were identified. To enhance the investigation, visual evidence of the moon-shaped birthmark and further DNA analysis is required. PMID- 29427705 TI - Dismantling the justice silos: Flowcharting the role and expertise of forensic science, forensic medicine and allied health in adult sexual assault investigations. AB - Forensic science is increasingly used to help exonerate the innocent and establishing links between individuals and criminal activities. With increased reliance on scientific services provided by multi-disciplinary (police, medicine, law, forensic science), and multi-organisational in the private and government sectors (health, justice, legal, police) practitioners, the potential for miscommunication resulting unjust outcomes increases. The importance of identifying effective multi-organisational information sharing is to prevent the 'justice silo effect'; where practitioners from different organisations operate in isolation with minimal or no interaction. This paper presents the findings from the second part of the Interfaces Project, an Australia-wide study designed to assess the extent of the justice silos. We interviewed 121 police, forensic scientists, lawyers, judges, coroners, pathologists and forensic physicians. The first paper published in 2013 presented two key findings: first investigative meetings were rare in adult sexual assault cases; second many medical practitioners were semi-invisible in case decision-making with this low level of visibility being due to lawyers, forensic scientists or police not being aware of the role/expertise medical practitioners offer. These findings led to the development of a flowchart model for adult sexual assault that highlights the range of agencies and practitioners typically involved in sexual assault. The rationale for the flowchart is to produce a visual representation of a typical sexual assault investigative process highlighting where and who plays a role in order to minimise the risk of justice silos. This is the second paper in a series of two. PMID- 29427706 TI - In vitro assessment of chemotherapy-induced neuronal toxicity. AB - Neurotoxicity is a major concern during drug development, and together with liver and cardio-toxicity, it is one of the main causes of clinical drug attrition. Current pre-clinical models may not sufficiently identify and predict the risk for central or peripheral nervous system toxicity. One such example is clinically dose-limiting neuropathic effects after the administration of chemotherapeutic agents. Thus, the need to establish novel in vitro tools to evaluate the risk of neurotoxicities, such as neuropathy, remains unmet in drug discovery. Though in vitro studies have been conducted using primary and immortalized cell lines, some limitations include the utility for higher throughput methodologies, method reproducibility, and species extrapolation. As a novel alternative, human induced pluripotent stem cell (iPSC)-derived neurons appear promising for testing new drug candidates. These iPSC-derived neurons are readily available and can be manipulated as required. Here, we describe a novel approach to assess neurotoxicity caused by different classes of chemotherapeutics using kinetic monitoring of neurite dynamic changes and apoptosis in human iPSC-neurons. These studies show promising changes in neurite dynamics in response to clinical inducers of neuropathy, as well as the ability to rank-order and gather mechanistic insight into class-specific compound induced neurotoxicity. This platform can be utilized in early drug development, as part of a weight of evidence approach, to screen drug candidates, and potentially reduce clinical attrition due to neurotoxicity. PMID- 29427707 TI - Assessment of endocrine disruption and oxidative potential of bisphenol-A, triclosan, nonylphenol, diethylhexyl phthalate, galaxolide, and carbamazepine, common contaminants of municipal biosolids. AB - The use of biosolids as a soil conditioner and fertiliser is hindered by the limited knowledge on the risks of micro-contaminants they contain. This study investigated the binding of six organic contaminants commonly found in biosolids, to the estrogen (ER), androgen (AR), aryl hydrocarbon (AhR), and transthyretin (TTR) receptors and their redox activity. Triclosan (TCS), bisphenol-A (BPA), and technical nonylphenol (TNP) had affinity for the TTR with relative potencies of 0.3, 0.03, and 0.076 respectively. Further, binding to TTR was the only toxicological response observed for carbamazepine, which induced sub-maximal response and relative potency of 0.0017. Estrogenic activity was induced by BPA, galaxolide (HHCB), diethylhexyl phthalate (DEHP) and TNP with BPA having the strongest potency of 5.1 * 10-6 relative to estradiol. Only BPA showed androgenic activity but it was not quantifiable. BPA also showed anti-androgenic activity along with TCS, HHCB, and TNP in the order of TNP > HHCB > TCS ~ BPA (relative potencies 0.126, 0.042, 0.032, 0.03). No compounds exhibited anti-estrogenic or AhR activity, or were redox-active in the dithiothreitol assay. The results highlight the multiple modes of action through which these compounds may impact exposed organisms, and the concentrations at which effects may occur. This allows assessment of the likelihood of effects being observed at environmental concentrations, and the potential contribution of these compounds. PMID- 29427708 TI - Tribromophenol affects the metabolism, proliferation, migration and multidrug resistance transporters activity of murine melanoma cells B16F1. AB - Murine melanoma cells B16F1 were exposed to the flame retardant and wood preservative chemical 2,4,6-tribromophenol (TBP) during 24 and 48 h, at the concentrations found in human diet. TBP-exposed cells had increased MTT and Alamar blue(r) metabolism and ABCB5 mRNA levels (qPCR), but the cells had decreased proliferation (crystal violet assay), migration (scratch assay), and drug-effux transporters activity (rhodamine B efflux assay). Exposure to TBP did not affect the cell viability (neutral red and annexin V-PI assays), colony formation (colony number, clonogenic assay), and the levels of reactive oxygen species (DCF probe) or P53 mRNA (qPCR). The tested TBP concentrations had low toxicity to melanoma cells B16F1. However, dual effect on metastatic profile and chemoresistance suggests that the increase of ABCB5 positively modulates the cell chemoresistance, but decreases cell migration and proliferation. These findings may be explored in cancer therapy. PMID- 29427709 TI - Synthesis of silver nanoparticles from Phenerochaete chrysosporium (MTCC-787) and their antibacterial activity against human pathogenic bacteria. AB - The present study elucidates an eco-friendly method for synthesizing silver nanoparticles using Phenerochaete chrysosporium (MTCC-787), its bactericidal and cytotoxic effect were studied. The formation of nanoparticles was evidenced by color change and UV-Vis spectroscopy. Atomic Force Microscope and Transmission electron microscope, showed spherical and oval shapes particles in the sizes ranging between 34 and 90 nm. The biosynthesised silver nanoparticles showed significant antibacterial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus and Staphylococcus epidermidis at a high dose. Further, the nanoparticles observed to be non-toxic at 12.5 MUg/ml towards fibroblast cells. PMID- 29427710 TI - Pathophysiology of peste des petits ruminants in sheep (Dorper & Kajli) and goats (Boer & Beetal). AB - Peste des petits ruminants (PPR), an economically important viral transboundary disease of small ruminants is not only prevalent in Pakistan but also in other countries where people rely on agriculture and animal products. The present study was aimed at describing the pathology and antigen localization in natural PPR infections in local (Kajli sheep; Beetal goats) as well as imported small ruminant breeds (Dorper sheep; Australian Boer goat). Morbidity and mortality rates were significantly (P < 0.001) higher in indigenous Kajli sheep (75.37 and 32.80%) and Beetal goats (81.10 and 37.24%) as compared to Dorper sheep (6.99 and 1.48%) and Australian Boer goat (5.01 and 2.23%). Affected animals exhibited high fever, severe diarrhea, abdominal pain, respiratory distress and nodular lesions on lips and nostrils. Thick mucous discharge was oozing out from nostrils. On necropsy, lungs were congested and pneumonic, with nodular and cystic appearance. Intestines were hemorrhagic with zebra stripping. Characteristic histopathological lesions of PPR were noted in intestines, lymphoid organs and lungs. In GI tract, stunting and blunting of villi, necrotic enteritis, and infiltration of mononuclear cells in duodenum, jejunum and ileum. Small intestines exhibited diffuse edema of the submucosa along with proliferation of fibrocytes leading to thickened submucosa which has not been reported previously. Lymphoid organs showed partial to complete destruction of lymphoid follicles. Lesions of the respiratory tract included depictive of bronchopneumonia, severe congestion of trachea and apical lobe of lungs with deposition of fibrinous materials. Histopathological lesions of respiratory tract were severe and characteristic of broncho-interstitial pneumonia, bronchopneumonia, interstitial pneumonia and fibrinous pneumonia. The alveoli were filled with edematous fluid mixed with fibrinous exudate, numerous alveolar macrophages, mononuclear cells along with thickened interalveolar septa and presence of intranuclear eosinophilic inclusion bodies. One-Step RT-PCR using NP3 and NP4 primers confirmed a PPR virus of 352 bp size in spleen, lungs and mesenteric and brachial lymph node samples. It was concluded that morbidity and mortality due to PPR were significantly higher in indigenous breeds of sheep and goat as compared to imported sheep and goat breeds. PPR has rendered various lesions in GI and respiratory tract which are characteristic in nature for the diagnosis of the disease under field condition. PMID- 29427711 TI - Complete genome sequence and pathogenicity of fowl adenovirus serotype 4 involved in hydropericardium syndrome in Southwest China. AB - Since 2015, an emerging infectious disease of inclusion body hepatitis and hydropericardium syndrome (IBH-HPS) has been occurred in China, which caused economic loss in poultry farming. In this study, we isolated four fowl adenovirus strains from flocks with an outbreak of HPS. The complete nucleotide sequence of SC-Neijiang was determined and its pathogenicity was evaluated. Phylogenetic analysis based on hexon gene revealed that all the isolates belonged to fowl adenovirus serotype 4. The full genome sequence of SC-Neijiang has a size of 43,719 bp, with 54.85% G + C content. Compared with JSJ13, 11-amino-acid deletion at the ORF29 was appeared on SC-Neijiang. In infectious experiments, 80% (16/20) birds died in intramuscular route and lesions characteristic for Hydropericardium Syndrome (HPS), while 5% (1/20) birds died in nasal route. The viral DNA was further detected by real-time PCR in several chicken organs. The highest titers were recorded in all the organs at day 5 post-infection. To our knowledge, this is first report on the prevalence of fowl adenovirus in Southwest China. This research elucidated the characteristics of genome sequence and pathogenicity of Chinese FAdV-4 strain and provided theoretical support for the prevention and control of the disease. PMID- 29427712 TI - Optimal pcr primers for rapid and accurate detection of Aspergillus flavus isolates. AB - Aspergillus flavus is among the most devastating opportunistic pathogens of several food crops including rice, due to its high production of carcinogenic aflatoxins. The presence of these organisms in economically important rice strip farming is a serious food safety concern. Several polymerase chain reaction (PCR) primers have been designed to detect this species; however, a comparative assessment of their accuracy has not been conducted. This study aims to identify the optimal diagnostic PCR primers for the identification of A. flavus, among widely available primers. We isolated 122 A. flavus native isolates from randomly collected rice strips (N = 300). We identified 109 isolates to the genus level using universal fungal PCR primer pairs. Nine pairs of primers were examined for their PCR diagnostic specificity on the 109 isolates. FLA PCR was found to be the optimal PCR primer pair for specific identification of the native isolates, over aflP(1), aflM, aflA, aflD, aflP(3), aflP(2), and aflR. The PEP primer pair was found to be the most unsuitable for A. flavus identification. In conclusion, the present study indicates the powerful specificity of the FLA PCR primer over other commonly available diagnostic primers for accurate, rapid, and large-scale identification of A. flavus native isolates. This study provides the first simple, practical comparative guide to PCR-based screening of A. flavus infection in rice strips. PMID- 29427713 TI - Structure determination of protein-ligand complexes by NMR in solution. AB - In this paper, we discuss methods for determining structures of protein-ligand complexes by NMR in solution. Our discussion is based on small ligands (<2 kDa) as for example drugs, metabolites or oligo-peptides, but most of the considerations also apply to more general cases. In NMR in solution, the kinetics of association and dissociation of the complex - the exchange rate - determines the optimal sample preparation and the NMR experimental approach. Additionally, depending on the part of the complex that will be studied (only the bound ligand, the protein, the protein-ligand interface or the entire protein-ligand complex structure), different types of NMR experiments are needed. Therefore, the choice of a combination of the appropriate experiment and a suitable sample preparation in terms of ligand to protein ratios are discussed in detail. Also, considerations for practically preparing samples of protein-ligand complexes and carrying out experiments including trouble shooting are described. For structure determination, the scope of this paper is limited to NOE-based methods and some of the most recent approaches will be covered. PMID- 29427714 TI - Peroxiredoxin-3 attenuates traumatic neuronal injury through preservation of mitochondrial function. AB - Peroxiredoxins (PRDXs) are a highly conserved family of thiol peroxidases that scavenge peroxides in cells. PRDX3 is one member of PRDXs localized in the mitochondria, and has been shown to be involved in antioxidant defense and redox signaling. In this study, we investigated the role of PRDX3 in neuronal trauma using a traumatic neuronal injury (TNI) model in primary cultured cortical neurons. We found that TNI significantly decreased the expression of PRDX3 at both mRNA and protein levels. Overexpression of PRDX3 by lentivirus (LV-PRDX3) transfection attenuated lactate dehydrogenase (LDH) release and neuronal apoptosis after TNI. The results of immunostaining showed that LV-PRDX3 transfection markedly reduced TNI-induced intracellular ROS production, protein radical formation and lipid peroxidation. In addition, overexpression of PRDX3 preserved mitochondrial membrane potential (MMP) levels and ATP generation, and inhibited mitochondrial cytochrome c release in TNI-injured neurons. The results of polymerase chain reaction (PCR) showed that PRDX3 overexpression also increased mitochondrial DNA (mtDNA) content and upregulated the expression of mitochondrial biogenesis-related factors. Taken together, our data demonstrate that PRDX3 protects against TNI insult by preserving mitochondrial function and mitochondrial biogenesis, and may have potential therapeutic value for traumatic brain injury (TBI). PMID- 29427715 TI - Two I84 family protease inhibitors from Chinese razor clams Sinonovacula constricta expressed in response to environmental challenges. AB - Protease inhibitors play critical roles in numerous biological processes including host defense in all multicellular organisms. Eighty three evolutionary families of protease inhibitors are currently accommodated in the MEROPS database and the I84 family currently consists of 3 novel serine protease inhibitors from the eastern oyster Crassostrea virginica. In this study, we identified 2 new I84 family members from the Chinese razor clam Sinonovacula constricta, scSI-1 and scSI-2, using cDNA cloning and sequencing. The scSI-1 cDNA consisted of 494 bp with a 282 bp ORF encoding a 93-amino acid polypeptide that was predicted to have a 19-amino acid signal peptide and a 74-residue mature protein with a calculated molecular mass of 8248.5 Da. The scSI-2 cDNA was 490 bp long with a 273 bp ORF encoding a 90-amino acid polypeptide that was predicted to have an 18-amino acid signal peptide and a 72-residue nature protein with a calculated molecular mass of 7528.4 Da. ScSI-1 and scSI-2 shared high sequence similarity with the 3 known members of I84 family and both expressed primarily in the clam digestive glands. Protease inhibitory activity in the clam plasma also exhibited the signature kinetic characteristics of the I84 members from the oyster. In addition, levels of scSI-1 and scSI-2 gene expression in digestive glands and the protease inhibitory activity in plasma elevated significantly in clams challenged by bacterial injections and Vibrio harveyi was more effective than Staphylococcus epidermidis in inducing the gene expression and plasma protease inhibitory activity. Moreover, drastic changes of salinity and temperature also caused significant changes in the gene expression and plasma activity. These results indicated that scSI-1 and scSI-2 represented 2 new members of the I84 family and they likely play a role in clam host defense against infections and in reactions against physiochemical stressors. PMID- 29427716 TI - Comparative proteomic analysis of hepatopancreas in Macrobrachium rosenbergii responded to Poly (I:C). AB - Gel-enhanced liquid chromatography coupled with tandem mass spectrometry (GeLC MS/MS) was used to analyze the proteome of Macrobrachium rosenbergii hepatopancreas responded to Poly (I:C). GeLC-MS/MS analysis identified 515 differentially-expressed proteins with >=1.5 and <= -0.5 log2 fold change. Of these, 195 differentially-expressed proteins were significantly matched to known proteins in the database, of which 102 proteins were up-regulated and 93 proteins were down-regulated. These proteins were classified into 21 categories, i.e. metabolic process, oxidative stress response, signaling, transcription, translation, cell cycle, transport, etc. Several immune factors were up-regulated upon Poly (I:C) injection. Protein-protein interaction network analysis of these immune factors identified three major protein clusters including RNAi, stress responses, and Toll pathway-proPO system, implying that Poly (I:C) activates immune responses in prawn through several mechanisms. PMID- 29427717 TI - Molecular characterization of thioredoxin-like protein 1 (TXNL1) from big-belly seahorse Hippocampus abdominalis in response to immune stimulation. AB - Thioredoxin is a highly conserved protein found in both prokaryotes and eukaryotes. Reactive oxygen species (ROS) are produced in response to metabolic processes, radiation, metal oxidation, and pathological infections. High levels of ROS lead to cell death via autophagy. However, thioredoxin acts as an active regulatory enzyme in response to excessive ROS. Here, we performed in-silico analysis, immune challenge experiments, and functional assays of seahorse thioredoxin-like protein 1 (ShTXNL1). Evolutionary identification showed that ShTXNL1 protein belongs to the thioredoxin superfamily comprising 289 amino acids. It possesses an N-terminal active thioredoxin domain and C-terminal proteasome-interacting thioredoxin domain (PITH) of ShTXNL1 which is a component of 26S proteasome and binds to the matrix or cell. Pairwise alignment results showed 99.0% identity and 99.7% similarity with the sequence of Hippocampus species. Conserved thiol-disulfide cysteine residue containing Cys-X-X-Cys motif may be found in the first few amino acids in the second beta sheet starting from the N-terminus. This motif can be discovered in ShTXNL1 as 14CRPC17 and comprised two N-linked glycosylation sites at 72NISA75 and 139NESD142. According to the quantitative real-time polymerase chain reaction analysis from healthy seahorses, highest ShTXNL1 mRNA expression was observed in muscle, followed by ovary, brain, gill, and blood tissues. Moreover, significant temporal expression of ShTXNL1 was observed in gill and blood tissues after bacterial stimuli. Thus, the ShTXNL1 gene may be identified as an immunologically important gene in seahorse. PMID- 29427718 TI - Identification and functional characterization of unfolded protein response transcription factor ATF6 gene in kuruma shrimp Marsupenaeus japonicus. AB - Activating transcription factor 6 (ATF6) pathway is the key branch of unfolded protein response (UPR). In this study, a homolog of ATFalpha from Marsupenaeus japonicus (MjATF6) was identified using genome sequencing and characterized, so as to investigate the role of ATF6 pathway in anti-viral immunity of M. japonicus. The cDNA of MjATF6 obtained was 1008 bp in length, with an open reading frame (ORF) of 849bp, which had encoded a putative of 283 amino acid proteins. Results of qRT-PCR showed that MjATF6 was distributed in all the six tested tissues, with the higher expression level being seen in hemocytes and hepatopancreas. Furthermore, MjATF6 expression would be up-regulated from 1 day to 7 day under white spot syndrome virus (WSSV) challenge. In comparison, RNA interference-induced MjATF6 knockdown had resulted in a lower 7-day cumulative mortality of M. japonicus in the presence of WSSV infection. Additionally, our results also revealed that less VP28 mRNA was extracted from hemocytes or hepatopancreas of MjATF6 knockdown shrimp than that from the control. Taken together, these results have confirmed that ATF6 pathway is vital for WSSV replication, and that UPR in M. japonicus may facilitate WSSV infection. PMID- 29427719 TI - Antibacterial activity of hemocyanin from red swamp crayfish (Procambarus clarkii). AB - Hemocyanins (HMC): the copper-containing respiratory proteins present in invertebrate hemolymph, which plays many essential roles in the immune system. Currently, little is known about the HMC domains of Procambarus clarkii (P. clarkii) and their function in antimicrobial immune response. In this present study, we comparatively studied the expression pattern of native PcHMC with the three recombinant proteins of variable domains of crayfish hemocyanin (PcHMC-N, N terminal domain of hemocyanin; PcHMC-T, tyrosinase domain of hemocyanin; PcHMC-C, C-terminal domain of hemocyanin). The results showed that three purified recombinant proteins had a strong binding to various bacteria and lipopolysaccharides that further highly agglutinated. The HMCs recombinant proteins showed strong antibacterial activity against V. parahaemolyticus and S. aureus by bacterial growth inhibition, phenoloxidase (PO) and phagocytosis assays. Specifically, rPcHMC1-T and rPcHMC1-C inhibited both the bacteria efficiently, rPcHMC1-T was highly upregulated the PO activity than the other recombinant proteins. Whereas, recombinant proteins pretreated crayfish hemocytes participated in phagocytosis activity, rPcHMC1-N and rPcHMC1-C proteins had a profound effect than the rPcHMC1-T on S. aureus and V. parahaemolyticus phagocytosis. The crayfish hemocyanin domains clearly exhibited antibacterial and phagocytic activities against both the bacteria, suggesting that its variable domains of hemocyanin have the different function on specific pathogen during the assault of pathogens. PMID- 29427720 TI - Construction of a Vibrio alginolyticus hopPmaJ (hop) mutant and evaluation of its potential as a live attenuated vaccine in orange-spotted grouper (Epinephelus coioides). AB - Vibrio alginolyticus, a bacterial pathogen in fish and humans, expresses a type III secretion system (T3SS) that is critical for pathogen virulence and disease development. However, little is known about the associated effectors (T3SEs) and their physiological role. In this study, the T3SE gene hopPmaJ (hop) was cloned from V. alginolyticus wild-type strain HY9901 and the mutant strain HY9901Deltahop was constructed by the in-frame deletion method. The results showed that the deduced amino acid sequence of V. alginolyticus HopPmaJ shared 78 98% homology with other Vibrio spp. In addition, the HY9901Deltahop mutant showed an attenuated swarming phenotype and a 2600-fold decrease in the virulence to grouper. However, the HY9901Deltahop mutant showed no difference in morphology, growth, biofilm formation and ECPase activity. Finally, grouper vaccinated via intraperitoneal (IP) injection with HY9901Deltahop induced a high antibody titer with a relative percent survival (RPS) value of 84% after challenging with the wild-type HY9901. Real-time PCR assays showed that vaccination with HY9901Deltahop enhanced the expression of immune-related genes, including MHC Ialpha, MHC-IIalpha, IgM, and IL-1beta after vaccination, indicating that it is able to induce humoral and cell-mediated immune response in grouper. These results demonstrate that the HY9901Deltahop mutant could be used as an effective live vaccine to combat V. alginolyticus in grouper. PMID- 29427721 TI - The effects singular or combined administration of fermentable fiber and probiotic on mucosal immune parameters, digestive enzyme activity, gut microbiota and growth performance of Caspian white fish (Rutilus frisii kutum) fingerlings. AB - The aim of the present study was to investigate the effects of single or combined administration of dietary fermentable fiber (Vitacel(r)) and probiotic PrimaLac(r) on mucosal immune parameters, digestive enzyme activity, gut microbiota and growth performance of Caspian white fish (Rutilus frisii kutum) fingerlings. Fish were transferred to laboratory, acclimatized for two weeks and then fish (0.56 +/- 0.026 g) were allocated into 12 tanks (30 fish per tank). Triplicate groups were fed a basal diet (Control) or basal diet supplemented with fermentable fiber [Vitacel(r)] (FF), probiotic [PrimaLac(r)] (P) and combined fermentable fiber and probiotic (FF + P). At the end of feeding trial, growth performance and feed utilization parameters were significantly (P < 0.05) improved in FF, P and FF + P treatments compared control group. Evaluation of digestive enzyme activity revealed significant (P < 0.05) increase of lipase activity in fish fed supplemented diet. However, amylase, protease and alkaline phosphatase were significantly higher (P < 0.05) only in P and FF + P treatments. Furthermore, total autochthonous intestinal microbiota and autochthonous LAB levels significantly increased in fish fed supplemented diet (P < 0.05). Also, inclusion of FF, P and FF + P in Caspian white fish diet remarkably increased skin mucus immune parameters compared control group (P < 0.05). These results indicate that singular or combined administration of FF and P can be considered as a beneficial dietary supplement for early stages of Caspian white fish (Rutilus fresii kutumn) culture. PMID- 29427722 TI - Effect of Argemone mexicana active principles on inhibiting viral multiplication and stimulating immune system in Pacific white leg shrimp Litopenaeus vannamei against white spot syndrome virus. AB - Argemone mexicana called as Mexican prickly poppy is a species of poppy found in Mexico and now widely naturalized in many parts of the world with broad range of bioactivities including anthelmintic, cures lepsory, skin-diseases, inflammations and bilious fevers. Plant parts of A. mexicana were serially extracted with hexane, ethyl acetate, methanol and performed antiviral and immunostimulant screening against WSSV and Vibrio harveyi respectively. The control groups succumbed to death 100% within three days, whereas the mortality was significantly (P < 0.5) reduced to 17.43 and 7.11 in the ethyl acetate extracts of stem and root treated shrimp group respectively. The same trend was reflected in the immunostimulant screening also. Different diets were prepared by the concentrations of 100 (AD-1), 200 (AD-2), 300 (AD-3) and 400 (AD-4) mg kg-1 using A. mexicana stem and root ethyl acetate extracts and fed to Pacific white leg shrimp Litopenaeus vannamei weighed about 9.0 +/- 0.5 g for 30 days. The control groups fed with the normal diets devoid of A. mexicana extracts. The antiviral screening results revealed that, the ethyl acetate extract of the stem and root were effectively suppressed the WSSV and it reflected in the lowest cumulative mortality of treated shrimps. After termination of feeding trials, group of shrimps from control and each experimental group were challenged with virulent WSSV by intramuscular (IM) injection and studied cumulative mortality, molecular diagnosis by quantitative real time PCR (qRT-PCR), biochemical, haematological and immunological parameters. Control group succumbed to 100% death within four days, whereas the survival was significantly (P < 0.001) increased to 30, 45, 75 and 79% in AD1, AD-2, AD-4 and AD-5 diets fed shrimp groups respectively. qRT PCR results with positive correlation analysis revealed that, the WSSV copies were gradually decreased when increasing the A. mexicana extracts in the diets. The highest concentrations (300 and 400 mg g-1) of A. mexicana extracts in the diets helped to reduce the protein level significantly (P < 0.05) after WSSV challenge. The diets AD-3 and AD-4 also helped to decrease the coagulation time of maximum 64-67% from control groups and maintained the normal level of total haemocyte, oxyhaemocyanin level after WSSV challenge. The proPO level was significantly increased (Column: F = 35.93; P <= 0.001 and Row: F = 37.14; P <= 0.001) in the AD1-AD-4 diet fed groups from the control diet fed groups. The lowest intra-agar lysozyme activity of 1.63 mm found in control diet fed group and the activity were significantly (P < 0.05) increased to 4.86, 7.89, 9.12 and 10.45 mm of zone of inhibition respectively in AD1 to AD4 diet fed groups. PMID- 29427723 TI - Intra-articular injection of mesenchymal stem cells in treating knee osteoarthritis: a systematic review of animal studies. AB - PURPOSE: Mesenchymal stem cells (MSCs) injection has emerged as a novel treatment for knee osteoarthritis (KOA) but with inconsistent results in the experimental studies. Thus, the purpose of the present study is to evaluate the preclinical animal studies of MSCs injection for KOA and to determine the evidence for a role for MSCs in further clinical trials. METHODS: A systematic search of KOA animal studies published through Aug 2017 was conducted using the PubMed, Embase and Web of science. Criteria for eligibility were animal studies assessing the therapeutic effects of MSCs intra-articular injection to animals with KOA. The methodological quality of included studies was assessed by the SYRCLE tool for assessing risk of bias in animal intervention studies. Descriptive synthesis was performed. Evidence quality was evaluated based on the Confidence in the Evidence from Reviews of Qualitative research (CERQual) tool. RESULTS: Twenty-three KOA animal studies were eligible for inclusion. According to the SYRCLE's tool, all included studies had high risk of bias. Between-study heterogeneity was substantial. The included studies varied in terms of species, modeling methods, MSCs origin, treatment timing, injections frequency, transplantation type and dose of MSCs. The following outcomes, gross morphology, histological analysis, immunohistochemical analysis, radiological evaluation or behavior analysis, were reported in the primary studies. For all outcomes, the evidence quality was low or very low. CONCLUSIONS: We do not have absolute confidence to recommend use MSCs injection for KOA clinical trials. Based on the internal and external validity of current animal studies, high quality experimental studies and efforts for effective translation from preclinical studies to clinical trials are still required. PMID- 29427725 TI - Knee extensor strength gains mediate symptom improvement in knee osteoarthritis: secondary analysis of a randomised controlled trial. AB - OBJECTIVE: To determine if an increase in knee extensor strength mediates the effect of a 12-week knee extensor strength training program on pain and physical function improvement in people with knee osteoarthritis (OA). DESIGN: Secondary analysis from a randomised controlled trial comparing the effects of a 12-week knee extensor strengthening exercise program to a control group with no intervention. METHODS: Data from participants with complete data (n = 97) enrolled in a previous clinical trial were analysed. Baseline and 12-week follow up assessments included peak isometric knee extensor strength, pain and physical function. Peak knee extensor strength (Nm/kg) was assessed on an isokinetic dynamometer and subscales of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index were used to assess pain and physical function. Twelve-week change in pain and physical function were regressed separately, on 12 week change in knee extensor strength and group allocation. Covariates included baseline pain or physical function as appropriate, and baseline knee extensor strength, age, sex and knee alignment (stratification variable). RESULTS: Improved knee extensor strength mediated the effect of the strengthening program on both pain relief (mediated effect size = 0.69, 95% confidence intervals (CI) 0.05-1.33, P = 0.03), and improved physical function (mediated effect size = 1.86, 95% CI 0.08-3.64, P = 0.04), at 12 weeks. CONCLUSIONS: Increased knee extensor strength partially mediates the effect of a knee extensor strength training program on pain and physical function improvement in people with knee OA. PMID- 29427724 TI - Relation of meniscus pathology to prevalence and worsening of patellofemoral joint osteoarthritis: the Multicenter Osteoarthritis Study. AB - OBJECTIVE: To determine the relationship of meniscal damage to magnetic resonance imaging (MRI) features of compartment-specific patellofemoral joint (PFJ) osteoarthritis (OA) at baseline and 2 years later. METHOD: Individuals from a prospective cohort of individuals aged 50-79 with or at risk of knee OA were included. At the 60-month and 84-month study visit, Whole-Organ MRI Score (WORMS) was used to assess meniscal tears and extrusions as well as cartilage damage and bone marrow lesions (BMLs) in the medial and lateral patella and trochlea. Worsening of structural features was defined as any increase in WORMS score from 60 to 84 months. Logistic regression was used to determine the cross-sectional and longitudinal relation of meniscus damage to features of compartment-specific PFJ OA. RESULTS: Relative to knees without lateral meniscal pathology at baseline, those with grades 3-4 lateral meniscal tear and extrusion had greater risk of worsening of cartilage damage in the lateral PFJ 2 years later (Risk ratio: 1.7 [95% CI: 1.1-2.7) and (1.7 [1.2-2.5]), respectively. Relative to those without medial meniscal pathology at baseline, those with grades 1-2 (0.6 [0.4 0.9]) and 3-4 (0.7 [0.5-1.0]) medial meniscal tears had lower risk of worsening of BMLs in the medial PFJ 2 years later. CONCLUSION: Meniscal tear and extrusion are associated with increased risk of medial and lateral PFJ OA and more severe meniscal pathology is associated with worsening of PFJ OA 2 years later. Lateral meniscal pathology appears to be more detrimental to the lateral PFJ. PMID- 29427726 TI - Role development in midwifery education: A place for simulation. AB - OBJECTIVE: simulation-based learning is increasingly seen as an effective strategy to develop student nurse-midwives into effective healthcare team members. A gap exists concerning the use of simulation to promote role transition/development of the student midwife. The purpose of this paper is to describe an evolving simulation curriculum aimed at role development of the student midwife as well as technical skills training. SETTING: the University of New Mexico, College of Nursing and the Interprofessional Healthcare Simulation Center. PARTICIPANTS: this program involves students enrolled in the Masters in Nursing Program, Midwifery Concentration and students enrolled in the pre licensure Bachelor of Science in Nursing program. FINDINGS: simulation allows for an opportunity to focus on communication skills with other team members, practicing the importance of clear delegation of responsibilities in high-stress situations. CONCLUSIONS: the value of practicing the necessary communication skills, as well as the opportunity to engage in simulated delegation of tasks, is an important aspect of midwifery role development. PMID- 29427728 TI - Intra-arterial idarubicin_lipiodol without embolisation in hepatocellular carcinoma: The LIDA-B phase I trial. AB - BACKGROUND & AIMS: Idarubicin shows high cytotoxicity against hepatocellular carcinoma (HCC) cells, a high hepatic extraction ratio, and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolisation) was conducted in patients with cirrhotic HCC to estimate the maximum-tolerated dose (MTD) and to assess the safety, efficacy, and pharmacokinetics of the drug, and the health-related quality of life achieved by patients. METHODS: Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. RESULTS: A group of 15 patients were enrolled, including one patient at 10 mg, four patients at 15 mg, seven patients at 20 mg, and three patients at 25 mg. Only two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20 and 25 mg, respectively. The calculated MTD of idarubicin was 20 mg. The most frequent grade >=3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) based on modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4 months [95% confidence limit (CI) 3.0-14.6 months] and median overall survival was 20.6 months (95% CI 5.7-28.7 months). Pharmacokinetic analysis of idarubicin showed that the mean Cmax of idarubicin after intra arterial injection of the idarubicin-lipiodol emulsion is approximately half the Cmax after intravenous administration. Health-related quality of life results confirmed the good safety results associated with use of the drug. CONCLUSIONS: The MTD of idarubicin was 20 mg after two chemolipiodolisation sessions. Encouraging safety results, and patient responses and survival were observed. A phase II trial has been scheduled. LAY SUMMARY: There is a need for transarterial regimens that improve the responses and survival of patients with unresectable HCC. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation was well tolerated and gave promising efficacy in terms of tumour control and patient survival. PMID- 29427727 TI - Eight-year survival in chronic hepatitis B patients under long-term entecavir or tenofovir therapy is similar to the general population. AB - BACKGROUND & AIMS: The effects of long-term antiviral therapy on survival have not been adequately assessed in chronic hepatitis B (CHB). In this 10-centre, ongoing cohort study, we evaluated the probability of survival and factors affecting survival in Caucasian CHB patients who received long-term entecavir/tenofovir therapy. METHODS: We included 1,951 adult Caucasians with CHB, with or without compensated cirrhosis and without hepatocellular carcinoma (HCC) at baseline, who received entecavir/tenofovir for >=12 months (median, six years). Kaplan-Meier estimates of cumulative survival over time were obtained. Standardized mortality ratios (SMRs) were calculated by comparing death rates with those in the Human Mortality Database. RESULTS: The one-, five-, and eight year cumulative probabilities were 99.7, 95.9, and 94.1% for overall survival, 99.9, 98.3, and 97.4% for liver-related survival, and 99.9, 97.8, and 95.8% for transplantation-free liver-related survival, respectively. Overall mortality was independently associated with older age and HCC development, liver-related mortality was associated with HCC development only, and transplantation-free liver-related mortality was independently associated with HCC development and lower platelet levels at baseline. Baseline cirrhosis was not independently associated with any type of mortality. Compared with the general population, in all CHB patients mortality was not significantly different (SMR 0.82), whereas it was lower in patients without HCC regardless of baseline cirrhosis (SMR 0.58) and was higher in patients who developed HCC (SMR 3.09). CONCLUSION: Caucasian patients with CHB and compensated liver disease who receive long-term entecavir/tenofovir therapy have excellent overall and liver-related eight-year survival, which is similar to that of the general population. HCC is the main factor affecting their overall mortality, and is the only factor affecting their liver-related mortality. LAY SUMMARY: Caucasian patients with chronic hepatitis B with or without compensated cirrhosis who receive long-term entecavir or tenofovir therapy have excellent overall eight-year survival, which is similar to that of the general population. Hepatocellular carcinoma is the main factor affecting their overall mortality, and is the only factor affecting liver-related mortality in this setting. PMID- 29427730 TI - Reply to: "Coffee consumption and decreased all-cause mortality - What is the true estimate of effect?" PMID- 29427729 TI - Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. AB - BACKGROUND & AIMS: Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs). METHODS: Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade >=3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens. RESULTS: In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1-49) weeks and median number of immunotherapy injections was two (range, 1-36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5-1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction. CONCLUSIONS: Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration. LAY SUMMARY: Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment. PMID- 29427731 TI - A Hard Nut to Crack: Bouveret's Syndrome. PMID- 29427733 TI - Extraesophageal Symptoms and Diseases Attributed to GERD: Where is the Pendulum Swinging Now? AB - The purpose of this review is to outline the recent developments in the field of extraesophageal reflux disease and provide clinically relevant recommendations. The recommendations outlined in this review are based on expert opinion and on relevant publications from PubMed and EMbase. The Clinical Practice Updates Committee of the American Gastroenterological Association proposes the following recommendations: Best Practice Advice 1: The role of a gastroenterologist in patients referred for evaluation of suspected extra esophageal symptom is to assess for gastroesophageal etiologies that could contribute to the presenting symptoms. Best Practice Advice 2: Non-GI evaluations by ENT, pulmonary and/or allergy are essential and often should be performed initially in most patients as the cause of the extraesophageal symptom is commonly multifactorial or not esophageal in origin. Best Practice Advice 3: Empiric therapy with aggressive acid suppression for 6-8 weeks with special focus on response of the extraesophageal symptoms can help in assessing association between reflux and extraesophageal symptoms. Best Practice Advice 4: No single testing methodology exists to definitively identify reflux as the etiology for the suspected extra esophageal symptoms. Best Practice Advice 5: Constellation of patient presentation, diagnostic test results and response to therapy should be employed in the determination of reflux as a possible etiology in extra esophageal symptoms. Best Practice Advice 6: Testing may need to be off or on proton pump inhibitor (PPI) therapy depending on patients' presenting demographics and symptoms in assessing the likelihood of abnormal gastroesophageal reflux. A. On therapy testing may be considered in those with high probability of baseline reflux (those with previous esophagitis, Barrett's esophagus or abnormal pH). B. Off therapy testing may be considered in those with low probability of baseline reflux with the goal of identifying moderate to severe reflux at baseline. Best Practice Advice 7: Lack of response to aggressive acid suppressive therapy combined with normal pH testing off therapy or impedance-pH testing on therapy significantly reduces the likelihood that reflux is a contributing etiology in presenting extraesophageal symptoms. Best Practice Advice 8: Surgical fundoplication is discouraged in those with extra esophageal reflux symptoms unresponsive to aggressive PPI therapy. Best Practice Advice 9: Fundoplication should only be considered in those with a mechanical defect (e.g., hiatal hernia), moderate to severe reflux at baseline off PPI therapy who have continued reflux despite PPI therapy and have failed more conservative non-GI treatments. PMID- 29427732 TI - Risk of Oral and Upper Gastrointestinal Cancers in Persons With Positive Results From a Fecal Immunochemical Test in a Colorectal Cancer Screening Program. AB - BACKGROUND & AIMS: European guidelines recommend screening for colorectal cancer (CRC) using the fecal immunochemical test (FIT), with follow-up colonoscopies for individuals with positive test results. However, more than half of participants with positive results from the FIT are not found to have advanced neoplasia in the colonoscopy examination. Fecal occult blood might also come from the upper gastrointestinal (GI) tract, so perhaps we should consider esophagogastroduodenoscopy (EGD), to detect upper GI cancers. We aimed to determine how many individuals are found to have oral or upper GI cancers (oral cavity, throat, esophageal, gastric, or small bowel cancer) within 3 years after a positive or negative result from a FIT in a CRC screening program. METHODS: We performed a retrospective analysis of data from a pilot study of 3 rounds of biennial FIT-based screening for CRC in 2 regions in the west of the Netherlands, from 2006 through October 2012. Participants who developed oral or upper GI cancers were identified through linkage with the National Cancer Registry. We classified these cancers into 3 groups: those that developed in individuals with a positive result from a FIT but negative findings from colonoscopy (no advanced neoplasia), those that developed in individuals with a positive result from a FIT and a positive finding from colonoscopy (advanced neoplasia), and those that developed in individuals with negative results from a FIT. We compared oral and upper GI cancer incidence among groups. RESULTS: Among 16,165 screening participants, linkage identified 52 persons who developed an oral or upper GI cancer within 3 years after a FIT. We found no significant difference in incidence values between individuals with a positive vs a negative FIT result: 8 cancers developed in individuals with a positive result from a FIT (0.37%; 95% CI, 0.19-0.76) and 44 developed in individuals with a negative result from a FIT (0.31%; 95% CI, 0.23-0.42) (P = .65). Of the 8 individuals with a positive result from a FIT and an oral or upper GI cancer, 6 were diagnosed after negative findings from colonoscopy and 2 after positive findings from colonoscopy. We found that only 0.14% of all persons with a positive result from a FIT were diagnosed with a gastric or esophageal cancer within 3 years. CONCLUSION: In a study of individuals in the Netherlands undergoing screening for CRC by FIT, we found fewer than 1% of patients with a positive result from the FIT to receive a diagnosis of upper GI cancers within 3 years. Routine EGD investigation of individuals with positive results from a FIT and negative findings from colonoscopy is therefore not recommended. TrialRegister.nl, Number: NTR5385. PMID- 29427734 TI - Increased Waitlist Mortality and Lower Rate for Liver Transplantation in Hispanic Patients With Primary Biliary Cholangitis. AB - BACKGROUND & AIMS: Data on the differences in ethnicity and race among patients with primary biliary cholangitis (PBC) awaiting liver transplantation (LT) are limited. We evaluated liver transplant waitlist trends and outcomes based on ethnicity and race in patients with PBC in the United States. METHODS: Using the United Network for Organ Sharing (UNOS) registry, we collected data on patients with PBC on the liver transplant waitlist, and performed analysis with a focus on ethnicity and race-based variations clinical manifestations, waitlist mortality and LT rates from 2000 to 2014. Outcomes were adjusted for demographics, complications of portal hypertension, and Model for End-stage Liver Disease score at time of waitlist registration. RESULTS: Although the number of white PBC waitlist registrants and additions decreased from 2000 to 2014, there were no significant changes in the number of Hispanic PBC waitlist registrants and additions each year. The proportion of Hispanic patients with PBC on the liver transplant waitlist increased from 10.7% in 2000 to 19.3% in 2014. Hispanics had the highest percentage of waitlist deaths (20.8%) of any ethnicity or race evaluated. After adjusting for demographic and clinical characteristics, Hispanic patients with PBC had the lowest overall rate for undergoing LT (adjusted hazard ratio, 0.71; 95% CI, 0. 60-0.83; P < .001) and a significantly higher risk of death while on the waitlist, compared to whites (adjusted hazard ratio, 1.41; 95% CI, 1.15-1.74; P < .001). Furthermore, Hispanic patients with PBC had the highest proportion of waitlist removals due to clinical deterioration. CONCLUSIONS: In an analysis of data from UNOS registry focusing on outcomes, we observed differences in rates of LT and liver transplant waitlist mortality of Hispanic patients compared with white patients with PBC. Further studies are needed to improve our understanding of ethnicity and race-based differences in progression of PBC. PMID- 29427735 TI - A New Marker for Severity of Alcoholic Hepatitis. PMID- 29427736 TI - Functional analysis of a type 2C protein phosphatase gene from Ammopiptanthus mongolicus. AB - In Arabidopsis and certain other plant species, the type 2C protein phosphatases (PP2Cs) of the clade A class have been demonstrated to act as negative regulators in ABA-induced stress responses, such as stomatal closure. The present study reports the identification of a PP2C ortholog from the ancient desert shrub Ammopiptanthus mongolicus (Maxim.) Cheng f. (AmPP2C), which is functionally conserved over its counterparts reported from other plant species. AmPP2C was primarily expressed in leaves, with strong transcriptional accumulation being observed in the guard cells. The expression of AmPP2C was induced in response to PEG or ABA treatments, implying the potential involvement in ABA-induced stress responses. The GFP-tagging observation revealed that AmPP2C was predominantly localized to the nuclei and partly to the cytoplasm. Furthermore, BiFC assays demonstrated an interaction between AmPP2C and the typical protein kinase SnRK2.6 (AmOST1). Overexpression of AmPP2C in Arabidopsis significantly overcame the inhibition of seed germination by ABA. The transgenic Arabidopsis lines exhibited larger stomatal apertures and significantly reduced sensitivity to ABA-induced stomatal closure, which subsequently led to greater water loss and decreased biomass under PEG-simulated drought stress treatments. Under limited nitrogen or potassium supplements, plants overexpressing AmPP2C obtained a superior capability of nitrogen (N) and potassium (K) acquisition in the green parts. Therefore, the impairment of ABA-induced stomatal closure rendered by the function of PP2C helped to identify a potential survival strategy in plants suffering persistent drought stress via the maintenance of the necessary mineral nutrient acquisition driven by transpirational solute flow. PMID- 29427737 TI - MicroRNA-139-5p affects cisplatin sensitivity in human nasopharyngeal carcinoma cells by regulating the epithelial-to-mesenchymal transition. AB - Nasopharyngeal carcinoma (NPC) is a head and neck cancer associated with poor prognosis. Many studies have shown that the epithelial-to-mesenchymal transition (EMT) is important in cancer progression, metastasis, and chemotherapy resistance and that microRNAs (miRNAs) play a key role in chemotherapy resistance associated with EMT. The miRNA miR-139-5p is downregulated in many human cancers and is closely related to tumor progression. The aim of this study was to investigate the ability of miR-139-5p to influence the cisplatin resistance, apoptosis, invasion and migration in NPC cells through the regulation of the EMT. We investigated these processes in parental HNE1 and cisplatin-resistant HNE1/DDP cells transfected with miR-139-5p inhibitors and mimics, respectively. Our results suggest that the upregulation of miR-139-5p expression inhibits proliferation, invasion, migration and EMT in human NPC cells. In addition, we found that miR-139-5p expression levels and DDP-induced apoptosis positively correlate in NPC cells. In conclusion, our results demonstrate that miR-139-5p can regulate the migration, invasion and DDP resistance in human NPC by modulating the EMT. The regulation of miR-139-5p levels might be a new approach to reverse EMT and DDP resistance and counteract metastasis and chemotherapy resistance in human NPC. PMID- 29427738 TI - Reversal of drug-induced gingival overgrowth by UV-mediated apoptosis of gingival fibroblasts - an in vitro study. AB - Gingival overgrowth (GO) is an undesirable result of certain drugs like Cyclosporine A (CsA). Histopathology of GO shows hyperplasia of gingival epithelium, expansion of connective tissue with increased collagen, or a combination. Factors such as age, gender, oral hygiene, duration, and dosage also influence onset and severity of GO. One of the mechanisms behind uncontrolled cell proliferation in drug-induced GO is inhibition of apoptotic pathways, with a consequent effect on normal cell turnover. Our objective was to determine if UV photo-treatment would activate apoptosis in the gingival fibroblast component. Human gingival fibroblast cells (HGF-1) were exposed to 200ng/ml or 400ng/ml CsA and maintained for 3, 6, and 9 days, followed by UV radiation for 2, 5, or 10min (N=6). Naive (no CsA or UV), negative (UV, no CsA), and positive controls (CsA, no UV) were designated. Prior to UV treatment, growth media was replaced with 1M PBS to prevent absorption of UV radiation by serum proteins, and cells were incubated in growth media for 24h post-UV before processing for TUNEL assay, cell proliferation assays, or immunofluorescence. Data showed a temporal increase in proliferation of HGF-1 cells under the influence of CsA. The 200ng/ml dose was more effective in causing over-proliferation. UV treatment for 10min resulted in significant reduction in cell numbers, as evidenced by counts and proliferation assays. Our study is a first step to further evaluate UV-mediated apoptosis as a mechanism to control certain forms of GO. PMID- 29427739 TI - Predictors of Late Palliative Care Referral in Children With Cancer. AB - CONTEXT: Early integration of palliative care (PC) in the management of children with high-risk cancer is widely endorsed by patients, families, clinicians, and national organizations. However, optimal timing for PC consultation is not standardized, and variables that influence timing of PC integration for children with cancer remain unknown. OBJECTIVES: To investigate associations between demographic, disease, treatment, and end-of-life attributes and timing of PC consultation for children with high-risk cancer enrolled on a PC service. METHODS: A comprehensive standardized tool was used to abstract data from the medical records of 321 patients treated at a large academic pediatric cancer center, who died between 2011 and 2015. RESULTS: Gender, race, ethnicity, enrollment on a Phase I protocol, number of high-acuity hospitalizations, and receipt of cardiopulmonary resuscitation were not associated with timing of PC involvement. Patients with hematologic malignancy, those who received cancer directed therapy during the last month of life, and those with advance directives documented one week or less before death had higher odds of late PC referral (malignancy: odds ratio [OR] 3.24, P = 0.001; therapy: OR 4.65, P < 0.001; directive: OR 4.81, P < 0.0001). Patients who received hospice services had lower odds of late PC referral <30 days before death (OR 0.31, P < 0.001). CONCLUSION: Hematologic malignancy, cancer-directed therapy at the end of life, and delayed documentation of advance directives are associated with late PC involvement in children who died of cancer. Identification of these variables affords opportunities to study targeted interventions to enhance access to earlier PC resources and services for children with high-risk cancer and their families. PMID- 29427740 TI - NK-18, a promising antimicrobial peptide: anti-multidrug resistant leukemia cells and LPS neutralizing properties. AB - With the increase of multidrug resistance, novel anti-leukemia agents with diverse mechanisms of action are required to address this challenge. NK-18, the core region of mammalian derived protein NK-lysin, effectively inhibited the viability of both multidrug resistant and sensitive leukemia cell lines. Meanwhile, this proliferation inhibition effect was not distinct between sensitive and multidrug resistant leukemia cell line. NK-18 showed selectivity between non-tumorigenic and tumorigenic cells. It preferentially bound to tumor cells whose outer leaflet with high phosphatidylserine content. NK-18 acted on the multidrug resistant leukemia cell line by a rapid pore formation on the cell membrane, it is not easy for K562/ADM cells developing resistance against NK-18. Furthermore, NK-18 could neutralize lipopolysaccharides by electrostatic attraction and reduce NO production. These research data demonstrated NK-18 possesses great advantage in the multidrug resistant leukemia treatment compared with conventional chemotherapies and it could be a potential candidate for further research. PMID- 29427741 TI - Pharmacokinetic and Pharmacodynamic Markers of Mycophenolic Acid Associated with Effective Prophylaxis for Acute Graft-Versus-Host Disease and Neutrophil Engraftment in Cord Blood Transplant Patients. AB - Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to prevent acute graft-versus-host disease (aGVHD) in patients receiving hematopoietic stem cell transplantation (HSCT). However, optimal doses of MMF and target MPA concentrations in HSCT patients have not been defined. In this study, relationships between pharmacokinetic or pharmacodynamic markers of MPA and successful aGVHD prevention and neutrophil engraftment were evaluated to inform individualized MPA treatments in HSCT patients. We recruited 35 patients undergoing cord blood transplantation (CBT) who were treated with MMF. Area under the concentration-time curves from 0 to 24 hours (AUC0-24) for free MPA and MPA acyl glucuronide (AcMPAG) at 1 week after the start of MMF treatments were significantly higher in patients with gastrointestinal (GI) aGVHD at stage >=I than those at stage 0. Patients with faster neutrophil engraftment had higher free MPA AUC0-24 at 1 week after the start of MMF treatments compared with those with slower neutrophil engraftment. Inosine-5'-monophosphate dehydrogenase activity in peripheral blood mononuclear cells and single nucleotide polymorphisms in genes that were previously associated with MPA pharmacokinetics and pharmacodynamics were not an independent predictor for the clinical outcomes. Receiver-operating characteristic model analyses showed that cutoff values of AUC0-24 for successful GI aGVHD prevention were .689 and 15.6 ug?hour?mL-1 for free MPA and AcMPAG, respectively. In addition, the cut-off value of free MPA AUC0-24 for neutrophil engraftment by day 25 was .405 ug?hour?mL-1. In conclusion, free MPA AUC0-24 may be a better predictor of the prevention of GI aGVHD and neutrophil engraftment compared with that of total MPA in patients receiving CBT. Hence, monitoring of the free MPA AUC0-24 between .405 and .689 ug?hour?mL-1 could be considered informative of individualized MPA treatments in CBT patients. PMID- 29427743 TI - The role of latency reversal agents in the cure of HIV: A review of current data. AB - The definitive cure for human immunodeficiency virus type-1 (HIV) infection is represented by the eradication of the virus from the patient's body. To reach this result, cells that are infected but do not produce the virus must become recognizable to be killed by the immune system. For this purpose, drugs defined "latency reverting agents" (LRA) that reactivate viral production are under investigation. A few clinical studies have been performed in HIV-infected patients treated with LRA and combined antiretroviral therapy (cART). The strategy is thus to combine cART and LRA to reactivate the virus and unmask latently infected cells that, because of cART, cannot produce a fully competent form of the virus. Unmasked cells can present viral antigens to the immune system, that ultimately recognizes and kills such latently infected cells. This review reports and discusses recent studies that have been published on this topic. PMID- 29427742 TI - Modulation of dendritic cell by pathogen antigens: Where do we stand? AB - Dendritic cells (DCs) are essential players in the activation of T cells and in the development of adaptive immune response towards invading pathogens. Upon antigen (Ag) recognition of Pathogen Associated Molecular Patterns (PAMPs) by their receptors (PRRs), DCs are activated and acquire an inflammatory profile. DCs have the ability to direct the profile of helper T (Th) cells towards Th1, Th2, Th17, Th9 and regulatory (Treg) cells. Each subset of Th cells presents a unique gene expression signature and is endowed with the ability to conduct or suppress effector cells in inflammation. Pathogens target DCs during infection. Many studies demonstrated that antigens and molecules derived from pathogens have the ability to dampen DC maturation and activation, leading these cells to a permissive state or tolerogenic profile (tolDCs). Although tolDCs may represent a hindrance in infection control, they could be positively used to modulate inflammatory disorders, such as autoimmune diseases. In this review, we focus on discussing findings that use pathogen-antigen modulated DCs and tolDCs in prophylactics and therapeutics approaches for vaccination against infectious diseases or inflammatory disorders. PMID- 29427744 TI - Towards the scale up of tissue engineered intervertebral discs for clinical application. AB - : Replacement of the intervertebral disc with a viable, tissue-engineered construct that mimics native tissue structure and function is an attractive alternative to fusion or mechanical arthroplasty for the treatment of disc pathology. While a number of engineered discs have been developed, the average size of these constructs remains a fraction of the size of human intervertebral discs. In this study, we fabricated medium (3 mm height * 10 mm diameter) and large (6 mm height * 20 mm diameter) sized disc-like angle ply structures (DAPS), encompassing size scales from the rabbit lumbar spine to the human cervical spine. Maturation of these engineered discs was evaluated over 15 weeks in culture by quantifying cell viability and metabolic activity, construct biochemical content, MRI T2 values, and mechanical properties. To assess the performance of the DAPS in the in vivo space, pre-cultured DAPS were implanted subcutaneously in athymic rats for 5 weeks. Our findings show that both sized DAPS matured functionally and compositionally during in vitro culture, as evidenced by increases in mechanical properties and biochemical content over time, yet large DAPS under-performed compared to medium DAPS. Subcutaneous implantation resulted in reductions in NP cell viability and GAG content at both size scales, with little effect on AF biochemistry or metabolic activity. These findings demonstrate that engineered discs at large size scales will mature during in vitro culture, however, future work will need to address the challenges of reduced cell viability and heterogeneous matrix distribution throughout the construct. STATEMENT OF SIGNIFICANCE: This work establishes, for the first time, tissue-engineered intervertebral discs for total disc replacement at large, clinically relevant length scales. Clinical translation of tissue-engineered discs will offer an alternative to mechanical disc arthroplasty and fusion procedures, and may contribute to a paradigm shift in the clinical care for patients with disc pathology and associated axial spine and neurogenic extremity pain. PMID- 29427747 TI - Nimodipine attenuates the parkinsonian neurotoxin, MPTP-induced changes in the calcium binding proteins, calpain and calbindin. AB - We have recently demonstrated neuroprotective abilities of nimodipine, an L-type voltage dependent calcium channel (VDCC) blocker in cellular and animal models of Parkinson's disease (PD). To understand the calcium regulatory mechanisms in the disease pathogenesis, the present study examined calcium regulatory proteins calbindin and calpain mRNA and protein levels employing quantitative PCR and western blot in 1-methyl-4-phenyl pyridinium ion (MPP+)-treated SH-SY5Y cell lines and in the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). mRNA and protein levels of calbindin were lower, while that of calpain were higher in MPP+-treated SH-SY5Y cells and MPTP-treated mouse striatum as compared to their respective controls. Nimodipine pretreatment significantly attenuated these effects in the parkinsonian neurotoxin-treated SH SY5Y cell line and in the mouse striatum. The activities of the apoptotic mediator, caspase-3 and calpain were increased in the neurotoxin-treated groups as compared to their respective controls, which was ameliorated by nimodipine pretreatment. These results suggest that parkinsonian neurotoxin-mediated dopaminergic neuronal death might involve defects in calcium regulatory proteins that control intracellular calcium homeostasis, and these could be corrected by inhibiting L-type VDCC activity. These findings support the notion that hypertensive patients who are on long-term intake of dihydropyridine have reduced risk for PD. PMID- 29427745 TI - Enhanced tendon-to-bone repair through adhesive films. AB - : Tendon-to-bone surgical repairs have unacceptably high failure rates, possibly due to their inability to recreate the load transfer mechanisms of the native enthesis. Instead of distributing load across a wide attachment footprint area, surgical repairs concentrate shear stress on a small number of suture anchor points. This motivates development of technologies that distribute shear stresses away from suture anchors and across the enthesis footprint. Here, we present predictions and proof-of-concept experiments showing that mechanically-optimized adhesive films can mimic the natural load transfer mechanisms of the healthy attachment and increase the load tolerance of a repair. Mechanical optimization, based upon a shear lag model corroborated by a finite element analysis, revealed that adhesives with relatively high strength and low stiffness can, theoretically, strengthen tendon-to-bone repairs by over 10-fold. Lap shear testing using tendon and bone planks validated the mechanical models for a range of adhesive stiffnesses and strengths. Ex vivo human supraspinatus repairs of cadaveric tissues using multipartite adhesives showed substantial increase in strength. Results suggest that adhesive-enhanced repair can improve repair strength, and motivate a search for optimal adhesives. STATEMENT OF SIGNIFICANCE: Current surgical techniques for tendon-to-bone repair have unacceptably high failure rates, indicating that the initial repair strength is insufficient to prevent gapping or rupture. In the rotator cuff, repair techniques apply compression over the repair interface to achieve contact healing between tendon and bone, but transfer almost all force in shear across only a few points where sutures puncture the tendon. Therefore, we evaluated the ability of an adhesive film, implanted between tendon and bone, to enhance repair strength and minimize the likelihood of rupture. Mechanical models demonstrated that optimally designed adhesives would improve repair strength by over 10-fold. Experiments using idealized and clinically-relevant repairs validated these models. This work demonstrates an opportunity to dramatically improve tendon-to-bone repair strength using adhesive films with appropriate material properties. PMID- 29427746 TI - Nanomedicine: An effective tool in cancer therapy. AB - Various types of nanoparticles (NPs) have been used in delivering anticancer drugs to the site of action. This area has become more attractive in recent years due to optimal size and negligible undesirable side effects caused by the NPs. The focus of this review is to explore various types of NPs and their surface/chemical modifications as well as attachment of targeting ligands for tuning their properties in order to facilitate targeted delivery to the cancer sites in a rate-controlled manner. Heme compatibility, biodistribution, longer circulation time, hydrophilic lipophilic balance for high bioavailability, prevention of drug degradation and leakage are important in transporting drugs to the targeted cancer sites. The review discusses advantages of polymeric, magnetic, gold, and mesoporous silica NPs in delivering chemotherapeutic agents over the conventional dosage formulations along with their shortcomings/risks and possible solutions/alternatives. PMID- 29427748 TI - The non-thyroidal illness syndrome is associated with postoperative surgical site infections in enterocutaneous fistulae. AB - BACKGROUND: Non-thyroidal illness syndrome (NTIS) is common in critically ill patients and associated with adverse outcomes. Many enterocutaneous fistula (ECF) patients still suffer NTIS prior to definitive surgery. This study was designed to explore the association between preoperative NTIS and postoperative outcomes in ECF patients. METHODS: A total of 264 ECF patients who underwent definitive surgery from April 2014 to November 2016 were studied. Thyroid hormones were tested for each patient before surgery, and the patients were divided into two groups (NTIS group and euthyroid group) according to the presence of NTIS. Demographics, surgery-related data, and complications during the first 30 days after surgery were recorded and analyzed. RESULTS: Among ECF patients accepted for definitive surgery, the prevalence of NTIS was 31.4% (83/264). The most common presentation of NTIS was a single low free triiodothyronine (FT3) 28.0% (74/264), followed by low FT3 combined with low thyrotropin (TSH) 1.9% (5/264), and low free thyroxine (FT4) combined with low TSH 1.5% (4/264). Compared to the euthyroid group, more patients with NTIS had multiple ECF, received more than three months of enteral nutrition pre-operatively, and developed surgical site infections (SSI). FT3 levels correlated with risk of SSI. Receiver operating characteristic curve (ROC) analysis revealed the diagnostic effectiveness of FT3, suggesting that the optimal cut-off value was 3.5 pmol/L. Area under the curve, sensitivity and specificity were 0.75, 72.6% and 68.7%, respectively. CONCLUSIONS: ECF patients with NTIS before definitive surgery appear to have a greater risk for poor outcomes. The benefit of thyroid hormone replacement therapy or delaying definitive surgery deserves further study. PMID- 29427749 TI - Long-term functional and oncological results after sphincter-saving resection for rectal cancer - Cohort study. AB - PURPOSE: The treatment of rectal cancer could be complex and the long term complications have the potential to greatly impact the quality of life. The aim of this study was to evaluate the long term functional and oncological results after sphincter-saving resection for rectal cancer. METHODS: Between January 2005 and December 2013, a total of 187 rectal resections with total mesorectal excision (TME) for cancer were performed. The data of 72 (38.5%) patients were available for analysis. Long-term follow-up was used to analyze the oncologic and functional results. Standardized questionnaires were used to determine fecal incontinence and urinary function. Relevant clinical variables were evaluated using univariate and multivariate analyses. RESULTS: The overall survival rate was 71% and the distribution of the International Union against Cancer (UICC) stages was 48.6% stage 1, 18% stage 2, and 33.3% stage 3. In univariate analysis, neoadjuvant radiotherapy (P < 0.01), rectal pouch (P < 0.01) and hand-sewn anastomosis (P = 0.02) was found to adversely affect fecal continence. On multivariate analysis fecal incontinence was significantly correlated with neoadjuvant radiochemotherapy (P < 0.05) and low rectal resection (P < 0.01). Urinary function was not statistically significant affected by preoperative treatment (P = 0.48) or surgical procedure (P = 0.45). CONCLUSION: Tumor location, surgical technique and neoadjuvant treatment had an impact on long term oncologic and functional results after sphincter-saving resection for rectal cancer. Urinary dysfunction occurs less frequently than anal disorders. These results highlight the importance of functional evaluation before and after rectal cancer resection in daily clinical practice and the necessity to tailor treatment to each patient. PMID- 29427750 TI - Is dynamic locking plate(Targon FN) a better choice for treating of intracapsular hip fracture? A meta-analysis. AB - PURPOSE: The aim of this study was to assess the outcomes of dynamic locking plate (Targon FN) and other alternative implant (cannulated cancellous screws or sliding hip screw) for treating of intracapsular hip fracture. METHODS: Relevant clinical trials on the dynamic locking plate and alternative implant treatment for intracapsular hip fracture were retrieved through searching the databases, PubMed, Embase and the Cochrane Central Register of Controlled Trials up to August 2017. Studies that investigated the comparing effectiveness or complications between both groups and provided sufficient data of interest were included in this meta-analysis. RESULTS: Four studies involving 385 intracapsular hip fractures were included. The differences in nonunion [odds ratio (OR) 0.16,95% confidence interval (CI) 0.05-0.49], revision (OR 0.56, 95%CI 0.32-0.96) and replacement rate (OR 0.26, 95%CI 0.10-0.69) were statistically significant between dynamic locking plate and alternative implant group. There was no statistically significant difference in osteonecrosis (OR1.73, 95%CI0.59-5.02), cut-out (OR0.89,95%CI0.23-3.46)and non orthopaedics complication rate (OR0.73, 95% CI 0.38-1.41). CONCLUSIONS: The available evidence indicate that dynamic locking plate offers a superior outcome in comparison with alternative implants and reduces the nonunion, revision and replacement rates for treating intracapsular hip fractures, but does not affect the osteonecrosis, cutout and non-orthopadeics complication rate. Decisions should be made in accordance with specific conditions for clinical application. PMID- 29427751 TI - A novel technique for estimating component sizes in total knee arthroplasty. AB - INTRODUCTION: Intra-operative assessment of total knee arthroplasty (TKA) components is performed with manufacturer specific jigs. Pre-operative templating, patient specific knee cutting blocks and computer-assisted surgeries have also been used to improve alignment and sizing; although the literature shows marginal improvement in functional scores. We propose pre-operative shoe size as a simple measurement tool for estimating the component sizes required for TKA. We investigate the relationship between TKA implant sizes, height, body weight and shoe size. METHODS: Retrospective single centre cohort study of all patients undergoing primary knee arthroplasty over a four-month period (August November 2015) was conducted. Standard data items recorded during routine admission. The spearman's rank correlation was used to assess the relationship between variables. RESULTS: One hundred and six patients were included in the final analysis. The mean age of the study group was 67.3 +/- 10.1 years (Range 44 90.) There were 42 male patients and 64 female patients. Statistically significant correlations were observed between: Shoe size and femoral component (rho = 0.589, p < 0.05); shoe size and tibial component (rho = 0.718, p < 0.05); shoe size and height (rho = 0.692, p < 0.05); height and femoral component (rho = 0.626, p < 0.05); height and tibial component (rho = 0.674, p < 0.05). CONCLUSION: We have demonstrated positive correlation between shoe and TKR component sizes. This relationship allows surgeons to estimate prosthesis size in the pre-operative setting. PMID- 29427752 TI - Diagnosis and treatment efficacy of digital subtraction angiography and transcatheter arterial embolization in post-pancreatectomy hemorrhage: A single center retrospective cohort study. AB - BACKGROUND: To evaluate the diagnostic and treatment efficacy of digital subtraction angiography (DSA), transcatheter arterial embolization (TAE) in post pancreatectomy hemorrhage (PPH). MATERIALS AND METHODS: This is a single-center retrospective cohort study. Clinicopathological data of 23 patients with PPH from August 2009 to November 2016 were collected. We observed (1) DSA procedures and hemorrhagic sites (2) TAE: successful rate and complications (3) Follow-up. RESULTS: (1) 30 procedures of DSA were conducted in 23 patients, 20 (66.7%) procedures of contrast medium extravasation were observed. Among 20 procedures of positive DSA, hemorrhagic site located 5 times in gastroduodenal artery,4 times in common hepatic artery, 3 times in superior mesenteric artery, 3 times in splenic artery, 1 time in left gastric artery, right gastric artery, left hepatic artery, right hepatic artery and inferior mesenteric artery respectively. (2) Besides 4 failure procedures of TAE managed by surgery, 16 procedures of TAE were conducted, with 14 successful hemostasis. 2 procedures of post-TAE re-hemorrhage were managed by surgery. In 9 patients with 10 procedures of negative DSA, 9 had conservative treatment and 1 was managed by surgery. (3) 6 patients died because of the metastasis, median survival time was 7.5 months. CONCLUSIONS: DSA is minimal invasive in the diagnosis of PPH, and TAE is safe and effective for patients with positive DSA. PMID- 29427753 TI - Impact of stress on aged immune system compartments: Overview from fundamental to clinical data. AB - Life expectancy is continuously increasing due to major progress in preventing, delaying or curing various pathologies normally encountered in old age. However, both scientific and medical advances are still required to understand underlying cause of the disparate comorbidities occurrence with aging. In one hand, aging profoundly impairs the immune system; it is characterized by many changes in haematopoiesis, adaptive and innate systems, associated with pro-inflammatory environment. In another hand, stressful events (acute or chronic) can also impact the immune system through the secretion of hormones, which are also altered with aging. The field of psychoneuroimmunology is now providing evidences that in acute medical conditions, elderly people are not equal in their responses to stressors depending on many extrinsic and intrinsic factors. These parameters could interfere with elderly's ability to mount an effective immune response. The objective of this review is to provide an overview of the literature (from fundamental to clinical observations) to draw a parallel between immune dysregulation caused by stress or by aging. Understanding this entanglement could enable us to target fundamental age-related pathways and thus open new avenues in improving both lifespan and health span. PMID- 29427754 TI - Withanolide A extends the lifespan in human EGFR-driven cancerous Caenorhabditis elegans. AB - The conserved EGFR pathway is linked with multiple cancers in humans including breast, ovarian, and lung carcinoma. Withanolide A, one of the major withanolidal active compounds isolated from the Withania somnifera, extends lifespan and ameliorates stress resistance in wild-type C. elegans by targeting the Insulin/IGF-1 signaling pathway. Up-regulation of IGF1 can transactivate EGFR which inturn reduces longevity and promotes tumor development in an organism. We examined the effects of Withanolide A on the lifespan of a human EGFR-driven C. elegans transgenic model exhibiting the multivulva (Muv) phenotype. The results showed that WA extends the lifespan of both wild human EGFR-driven C. elegans model (human wild-type tyrosine kinase) as well as models bearing single (L858R), and double mutations (T790M-L858R). The lifespan extension observed in these transgenic strains was 20.35, 24.21 and 21.27%, respectively. Moreover, the reduced fat levels were noticed in both wild-type N2 worms and transgenic strains. These observations support the heathspan promoting effect of WA as lipid rich diet has been reported to promote tumor development. In view of the fact that most of the well known FDA approved drugs such as gefitinib fail to inhibit the EGFR-associated cancers because of these mutations, the present findings show the potential of Withanolide A as a foreseen future nutraceutical to improve the average survival of cancer patients. PMID- 29427755 TI - High fat diet treatment impairs hippocampal long-term potentiation without alterations of the core neuropathological features of Alzheimer disease. AB - Type 2 diabetes (T2DM) and obesity might increase the risk for AD by 2-fold. Different attempts to model the effect of diet-induced diabetes on AD pathology in transgenic animal models, resulted in opposite conclusions. Here, we used a novel knock-in mouse model for AD, which, differently from other models, does not overexpress any proteins. Long-term high fat diet treatment triggers a reduction in hippocampal N-acetyl-aspartate/myo-inositol metabolites ratio and impairs long term potentiation in hippocampal acute slices. Interestingly, these alterations do not correlate with changes in the core neuropathological features of AD, i.e. amyloidosis and Tau hyperphosphorylation. The data suggest that AD phenotypes associated with high fat diet treatment seen in other models for AD might be exacerbated because of the overexpressing systems used to study the effects of familial AD mutations. Our work supports the increasing insight that knock-in mice might be more relevant models to study the link between metabolic disorders and AD. PMID- 29427756 TI - CRISPR/CAS9 ablation of individual miRNAs from a miRNA family reveals their individual efficacies for regulating cardiac differentiation. AB - Although it is well understood that genetic mutations, chromosomal abnormalities, and epigenetic miscues can cause congenital birth defects, many defects are still labeled idiopathic, meaning their origin is not yet understood. microRNAs are quickly entering the causal fray of developmental defects. miRNAs use a 7-8 base pair seed sequence to target a corresponding sequence on one or multiple mRNAs resulting in rapid down-regulation of translation. miRNAs can also control protein 'amounts' in cells. As a result if miRNAs are over or under expressed during development protein homeostasis can be compromised resulting in defects in the development of organ systems. Here, we show that during differentiation of embryonic stem cells, individual miRNAs that reside in the miRNA17 family (composed of 14 miRNAs) do not share the same function even though they have the same seed sequence. The advent of CRISPR/CAS9 technology has not only yielded a true observation of individual miRNA function, it has also reconnected advanced molecular biology approaches to classical cell biology approaches such as gene rescue. We show that miRNA106a and to a lesser extent miR17 and 93 target the cardiac suppressor gene Fog2, which specifically suppress Gata-4 and Coup-TF2. However, when each miRNA is knocked out, we find that their targeting efficacies for Fog2 differ resulting in varying degrees of cardiac differentiation. PMID- 29427757 TI - Evaluation of the extent of adaptation to sample size in clinical trials for cardiovascular and CNS diseases. AB - A planned adaptation to sample size in an ongoing trial aims at providing an opportunity to modify design assumptions made at the trial planning stage. Reassessment of sample size in an ongoing trial may be performed in a non comparative or a comparative fashion, either with or without use of external data that surface. We review the completed new drug applications (NDAs) and biologic license applications (BLAs) submitted since 2000 to cardio-renal, neurology and psychiatry drug products divisions of Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Interestingly, it was found that the maximal sample size increase across the identified confirmatory clinical trials was less than 2-fold the originally planned sample size. Additionally, as a result of sample size increase, precision in treatment effect estimation was often improved for the primary endpoint and the key secondary endpoints. PMID- 29427759 TI - Quantitative analysis of core fucosylation of serum proteins in liver diseases by LC-MS-MRM. AB - Aberrant core fucosylation of proteins has been linked to liver diseases. In this study, we carried out multiple reaction monitoring (MRM) quantification of core fucosylated N-glycopeptides of serum proteins partially deglycosylated by a combination of endoglycosidases (endoF1, endoF2, and endoF3). To minimize variability associated with the preparatory steps, the analysis was performed without enrichment of glycopeptides or fractionation of serum besides the nanoRP chromatography. Specifically, we quantified core fucosylation of 22 N glycopeptides derived from 17 proteins together with protein abundance of these glycoproteins in a cohort of 45 participants (15 disease-free control, 15 fibrosis and 15 cirrhosis patients) using a multiplex nanoUPLC-MS-MRM workflow. We find increased core fucosylation of 5 glycopeptides at the stage of liver fibrosis (i.e., N630 of serotransferrin, N107 of alpha-1-antitrypsin, N253 of plasma protease C1 inhibitor, N397 of ceruloplasmin, and N86 of vitronectin), increase of additional 6 glycopeptides at the stage of cirrhosis (i.e., N138 and N762 of ceruloplasmin, N354 of clusterin, N187 of hemopexin, N71 of immunoglobulin J chain, and N127 of lumican), while the degree of core fucosylation of 10 glycopeptides did not change. Interestingly, although we observe an increase in the core fucosylation at N86 of vitronectin in liver fibrosis, core fucosylation decreases on the N169 glycopeptide of the same protein. Our results demonstrate that the changes in core fucosylation are protein and site specific during the progression of fibrotic liver disease and independent of the changes in the quantity of N-glycoproteins. It is expected that the fully optimized multiplex LC-MS-MRM assay of core fucosylated glycopeptides will be useful for the serologic assessment of the fibrosis of liver. BIOLOGICAL SIGNIFICANCE: We have quantified the difference in core fucosylation among three comparison groups (healthy control, fibrosis and cirrhosis patients) using a sensitive and selective LC-MS-MRM method. Despite an overall increase in core fucosylation of many of the glycoproteins that we examined, core fucosylation changed in a protein- and site-specific manner. Moreover, increased and decreased fucosylation was observed on different N glycopeptides of the same protein. Altered core fucosylation of N-glycopeptides might be used as an alternative serologic assay for the evaluation of fibrotic liver disease. PMID- 29427758 TI - Screen for Slit/Robo signaling in trunk neural cells reveals new players. AB - Slits ligands and their Robo receptors are involved in quite disparate cell signaling pathways that include axon guidance, cell proliferation, cell motility and angiogenesis. Neural crest cells emerge by delamination from neural cells in the dorsal neural tube, and give rise to various components of the peripheral nervous system in vertebrates. It is well established that these cells change from a non-migratory to a highly migratory state allowing them to reach distant regions before they differentiate. However, but the mechanism controlling this delamination and subsequent migration are still not fully understood. The repulsive Slit ligand family members, have been classified also as true tumor suppressor molecules. The present study explored in further detail what possible Slit/Robo signals are at play in the trunk neural cells and neural crest cells by carrying out a microarray after Slit2 gain of function in trunk neural tubes. We found that in addition to molecules known to be downstream of Slit/Robo signaling, there were a large set of molecules known to be important in maintaining cells in non-motile, epithelia phenotype. Furthermore, we found new molecules previously not associated with Slit/Robo signaling: cell proliferation markers, Ankyrins and RAB intracellular transporters. Our findings suggest that neural crest cells use and array of different Slit/Robo pathways during their transformation from non-motile to highly motile cells. PMID- 29427760 TI - Interaction proteomics by using in-cell NMR spectroscopy. AB - : A synopsis of in-cell NMR spectroscopic approaches to study interaction proteomics in prokaryotic and eukaryotic cells is presented. We describe the use of in-cell NMR spectroscopy to resolve high resolution protein structures, discuss methodologies for determining and analyzing high and low affinity protein target structural interactions, including intrinsically disordered proteins, and detail important functional interactions that result from these interactions. SIGNIFICANCE: The ultimate goal of structural and biochemical research is to understand how macromolecular interactions give rise to and regulate biological activity in living cells. The challenge is formidable due to the complexity that arises not only from the number of proteins (genes) expressed by the organism, but also from the combinatorial interactions between them. Despite ongoing efforts to decipher the complex nature of protein interactions, new methods for structurally characterizing protein complexes are needed to fully understand molecular networks. With the onset of in-cell NMR spectroscopy, molecular structures and interactions can be studied under physiological conditions shedding light on the structural underpinning of biological activity. PMID- 29427761 TI - Status of Helicobacter pylori cag pathogenicity island (cagPAI) integrity and significance of its individual genes. AB - : One of the most important virulence factors of H. pylori is the intact cagPAI. The aim of the present study is to investigate cagPAI intactness among Bulgarian H. pylori isolates, its associations with clinical outcomes and vacA alleles, and to evaluate the significance of individual cagPAI genes. MATERIAL AND METHODS: Totally, 156 isolates from 156 patients with endoscopic findings for duodenal or gastric ulcer (33 subjects), non-ulcer disease (121) and other diseases, such as Crohn's disease and hepatitis (2) were tested. Polymerase chain reaction (PCR) was used to detect 14 essential cagPAI genes, including cagA, as well as vacA s, i and m alleles. RESULTS: CagA positive were 81.4% of all H. pylori isolates. Intact cagPAI was found in 64.1% of the all isolates, 16.7% and 19.2% showed complete and partial cagPAI absence, respectively. The prevalence of all cagPAI genes and intact cagPAI was significantly higher in isolates from ulcer patients compared with those from non-ulcer patients (p = 0.001). The most frequently missing genes among the isolates with partially deleted cagPAIs were cagE or/and cagY (28 of 30 isolates). Overall prevalence of vacA s1a allele was 80.1% and that of vacA i1 was 64.1%. The vacA s1a, m1 and i1 alleles were more prevalent in H. pylori isolates from ulcer patients (p = 0.03, p = 0.009, and p = 0.0003, respectively) and were associated with isolates with intact cagPAI. CONCLUSIONS: In Bulgaria the prevalence of intact cagPAI was high. cagE or/and cagY absence was the most important predictor of cagPAI status. PMID- 29427762 TI - Phylogenetic analysis of porcine circovirus type 3 and porcine circovirus type 2 in China detected by duplex nanoparticle-assisted PCR. AB - Porcine circovirus 2 causes different clinical syndromes resulting in a significant economic loss in the pork industry and PCV3 infection was mainly distributed in the pig herds exhibiting PDNS and reproductive failure symptoms and was widely prevalent in the swine population in several states of the USA. Subsequently, PCV3 was also detected in the Chinese pig herds in Hubei and Shandong Provinces, etc. In a screening of 265 clinical samples from Beijing, Zhejiang, Guangdong and Hebei in China for PCV2, PCV3 and co-infection of PCV2 and PCV3, 14.2%, 16.6% and 6.8% of the samples tested positive, respectively. Under novel and optimized nano-dPCR reaction conditions, two specific fragments of 528 bp (PCV2) and 251 bp (PCV3) were amplified, respectively. No fragments were amplified when other porcine viruses were used as template. In this study, three PCV2 and three PCV3 isolates were evaluated by phylogenetic and alignment analysis and the results revealed that the PCV2 and PCV3 isolates appear new nucleotide substitutions and PCV3 isolates from China still included branch of porcine circovirus in USA. PMID- 29427763 TI - Global distribution of NA1 genotype of respiratory syncytial virus and its evolutionary dynamics assessed from the past 11 years. AB - Respiratory syncytial virus (RSV) is a potent pathogen having global distribution. The main purpose of this study was to gain an insight into distribution pattern of the NA1 genotype of group A RSV across the globe together with its evolutionary dynamics. We focused on the second hypervariable region of the G protein gene and used the same for Phylogenetic, Bayesian and Network analyses. Eighteen percent of the samples collected from 500 symptomatic pediatric patients with acute respiratory tract infection (ARI) were found to be positive for RSV during 2011-15 from New Delhi, India. Of these, group B RSV was predominant and clustered into two different genotypes (BA and SAB4). Similarly, group A viruses clustered into two genotypes (NA1 and ON1). The data set from the group A viruses included 543 sequences from 23 different countries including 67 strains from India. The local evolutionary dynamics suggested consistent virus population of NA1 genotype in India during 2009 to 2014. The molecular clock analysis suggested that most recent common ancestor of group A and NA1 genotype have emerged in during the years 1953 and 2000, respectively. The global evolutionary rates of group A viruses and NA1 genotype were estimated to be 3.49 * 10-3 (95% HPD, 2.90-4.17 * 10-3) and 3.56 * 10-3 (95% HPD, 2.91 * 10-3-4.18 * 10-3) substitution/site/year, respectively. Analysis of the NA1 genotype of group A RSV reported during 11 years i.e. from 2004 to 2014 showed its dominance in 21 different countries across the globe reflecting its evolutionary dynamics. The Network analysis showed highly intricate but an inconsistent pattern of haplotypes of NA1 genotype circulating in the world. Present study seems to be first comprehensive attempt on global distribution and evolution of NA1 genotype augmenting the optimism towards the vaccine development. PMID- 29427764 TI - Identification and characterization of plasmid-mediated quinolone resistance determinants in Enterobacteriaceae isolated from healthy poultry in Brazil. AB - The expression of plasmid-mediated quinolone resistance (PMQR) genes confers low level quinolone and fluoroquinolones resistance alone. However, the association to chromosomal resistance mechanisms determines an expressively higher resistance in Enterobacteriaceae. These mechanisms are horizontally disseminated within plasmids and have contributed to the emergence of bacteria with reduced susceptibility or resistant to therapies worldwide. The epidemiological characterization of PMQR dissemination is highly relevant in the scientific and medical context, to investigate the dissemination within enterobacteria, from different populations, including humans and food-producing animals. In the present study, 200 Enterobacteriaceae isolates were harvested from poultry with cloacal swabs and identified as Escherichia coli (90.5%), Escherichia fergusonii (5.5%), Klebsiella oxytoca (2.5%) and Klebsiella pneumoniae (1.5%). Among isolates evaluated, 46 (23%) harboured PMQR genes including qnrB (43/200), qnrS (2/200) and aac(6')-Ib-cr (1/200). All isolates carrying PMQR genes showed multidrug-resistance phenotype. The 36 E. coli isolates showed 18 different PFGE types. All E. fergusonii isolates showed the same PFGE type. The two Klebsiella oxytoca belonged to two different PFGE types. The phylogenetic groups A, B1, and D were found among the E. coli harboring PMQR genes. Based on the phylogenetic analysis and PFGE, the population structure of E. coli isolates was diverse, even within the same farm. All isolates carrying qnrB and qnrS genes also harboured ColE-like plasmids. The Southern blot hybridization using the S1-PFGE revealed that the qnrB genes were located on low molecular weight plasmids, smaller than 10Kb. Resistance plasmids were sequenced and showed 100% identity with plasmid pPAB19-3. The association of PMQR genes with mobile genetic elements, such as transferable plasmids, favours the selection and dissemination of (fluoro) quinolones resistant bacteria among food-producing animals, and may play an important role in the current increased prevalence of resistant bacteria in different environments reported worldwide. PMID- 29427765 TI - Comparative genome analysis reveals a complex population structure of Legionella pneumophila subspecies. AB - The majority of Legionnaires' disease (LD) cases are caused by Legionella pneumophila, a genetically heterogeneous species composed of at least 17 serogroups. Previously, it was demonstrated that L. pneumophila consists of three subspecies: pneumophila, fraseri and pascullei. During an LD outbreak investigation in 2012, we detected that representatives of both subspecies fraseri and pascullei colonized the same water system and that the outbreak causing strain was a new member of the least represented subspecies pascullei. We used partial sequence based typing consensus patterns to mine an international database for additional representatives of fraseri and pascullei subspecies. As a result, we identified 46 sequence types (STs) belonging to subspecies fraseri and two STs belonging to subspecies pascullei. Moreover, a recent retrospective whole genome sequencing analysis of isolates from New York State LD clusters revealed the presence of a fourth L. pneumophila subspecies that we have termed raphaeli. This subspecies consists of 15 STs. Comparative analysis was conducted using the genomes of multiple members of all four L. pneumophila subspecies. Whereas each subspecies forms a distinct phylogenetic clade within the L. pneumophila species, they share more average nucleotide identity with each other than with other Legionella species. Unique genes for each subspecies were identified and could be used for rapid subspecies detection. Improved taxonomic classification of L. pneumophila strains may help identify environmental niches and virulence attributes associated with these genetically distinct subspecies. PMID- 29427766 TI - Content analysis of advertisements related to oral health in children: a systematic review and meta-analysis. AB - OBJECTIVES: The evidence about the content of TV advertisements broadcast during children's viewing times with an emphasis on the number of food advertisements and the number of cariogenic food advertisements was systematically reviewed and meta-analyzed. STUDY DESIGN: A systematic review and meta-analysis. METHODS: Articles published up until October 2017 in PubMed, Scopus, Embase, Web of Science, Cochrane Library, and Persian databases such as Magiran, IranDoc, and Iranmedex with the keywords that were related to advertising and oral health in children were searched and screened by two reviewers independently, and the outcomes of interest were extracted. Meta-analysis was performed using the Comprehensive Meta-Analysis, version 2.0. RESULTS: A total of 480 titles were retrieved and reduced to 256 eligible studies after deletion of duplicates, and finally, after closer assessment of titles and abstracts, five articles were selected for systematic review and meta-analysis. Of the included studies, three were conducted in the UK, one in India, and one in Greece. About 38.0% (95% confidence interval: 19.6-60.6, P = 0.296) of advertisements were related to food and also about 70.6% (95% confidence interval: 53.7-83.3, P < 0.019) of food advertisements were related to cariogenic foods. CONCLUSIONS: Food advertising during children's programs is dominated by food items that are potentially harmful to oral health. Moreover, the advertisements shifted toward food items that appeared healthy but contain a large amount of hidden sugar. PMID- 29427767 TI - An assessment of the relationship of physical activity, obesity, and chronic diseases/conditions between active/obese and sedentary/ normal weight American women in a national sample. AB - OBJECTIVE: Obesity and physical inactivity are associated with increased rates of chronic diseases and conditions. However, the 'fit but fat' theory posits that cardiopulmonary fitness (or physical activity) can mitigate risks to health associated with obesity. The purpose of this study was to compare chronic diseases and conditions of highly active/obese women with inactive/normal weight women. STUDY DESIGN: This was a cross-sectional study of the 2015 Behavioral Risk Factor Surveillance System data. METHODS: Weighted descriptive statistics were performed to describe the demographic characteristics of the two groups. We calculated odds ratios and adjusted odds ratios for chronic diseases and conditions comparing highly active/obese women with inactive/normal weight women. RESULTS: Highly active/obese women were more likely to report risk factors (hypertension, high cholesterol, and diabetes) for coronary heart disease (CHD) and cardiovascular disease (CVD) than inactive/normal weight women; however, they did not have increased rates of CVD, CHD, or heart attack and had decreased risk for stroke. Highly active/obese women had increased risk for asthma, arthritis, and depression, but not for cancer, kidney disease, or chronic obstructive pulmonary disease. CONCLUSIONS: Highly active/obese women appear to be staving off the actual development of CHD and CVD; however, further research is needed to understand the long-term health benefits of physical activity among obese women. PMID- 29427768 TI - Cost savings through implementation of an integrated home-based record: a case study in Vietnam. AB - OBJECTIVES: In Vietnam, there are three major home-based records (HBRs) for maternal and child health (MCH) that have been already nationally scaled up, i.e., Maternal and Child Health Handbook (MCH Handbook), Child Vaccination Handbook, and Child Growth Monitoring Chart. The MCH Handbook covers all the essential recording items that are included in the other two. This overlapping of recording items between the HBRs is likely to result in inefficient use of both financial and human resources. This study is aimed at estimating the magnitude of cost savings that are expected to be realized through implementing exclusively the MCH Handbook by terminating the other two. STUDY DESIGN: Secondary data collection and analyses on HBR production and distribution costs and health workers' opportunity costs. METHODS: Through multiplying the unit costs by their respective quantity multipliers, recurrent costs of operations of three HBRs were estimated. Moreover, magnitude of cost savings likely to be realized was estimated, by calculating recurrent costs overlapping between the three HBRs. RESULTS: It was estimated that implementing exclusively the MCH Handbook would lead to cost savings of United States dollar 3.01 million per annum. The amount estimated is minimum cost savings because only recurrent cost elements (HBR production and distribution costs and health workers' opportunity costs) were incorporated into the estimation. Further indirect cost savings could be expected through reductions in health expenditures, as the use of the MCH Handbook would contribute to prevention of maternal and child illnesses by increasing antenatal care visits and breastfeeding practices. CONCLUSION: To avoid wasting financial and human resources, the MCH Handbook should be exclusively implemented by abolishing the other two HBRs. This study is globally an initial attempt to estimate cost savings to be realized through avoiding overlapping operations between multiple HBRs for MCH. PMID- 29427770 TI - Impact of SLC22A1 and CYP3A5 genotypes on imatinib response in chronic myeloid leukemia: A systematic review and meta-analysis. AB - Contrasting results have been reported on the role of rs628031 and rs683369 polymorphisms of SLC22A1 and rs776746 of CYP3A5 on imatinib treatment response in patients with chronic myeloid leukemia (CML). In the present study, we conducted a systematic review and meta-analysis of published studies to estimate the impact of the above-mentioned gene variants on major molecular response (MMR) or complete cytogenetic response (CCyR) in imatinib-treated CML patients. We performed a comprehensive search through PubMed, Web of Knowledge, and Cochrane databases up to September 2017. The pooled analyses showed association between carriers of SLC22A1 rs628031A allele (GA + AA vs GG, OR: 0.58, 95% CI: 0.38-0.88, P = 0.011) or rs683369G allele (CG + GG vs CC, OR: 0.64, 95% CI: 0.42-0.96, P = 0.032) and a lower MMR rate. The combined analyses also revealed a correlation between the dominant (GG + AG vs AA, OR: 2.43, 95%CI: 1.12-5.27, P = 0.024) or the allelic model (G vs A, OR: 1.72, 95% CI: 1.09-2.72, P = 0.020) of CYP3A5 rs776746 with higher CCyR rates. The subsequent sensitivity analysis confirmed the statistical significance of CYP3A5 rs776746 among Asian CML patients (dominant model OR: 3.90; 95%CI: 2.47-6.14, P < 0.001; allelic model OR: 2.08; 95% CI: 1.47-2.95, P < 0.001). In conclusion, the present meta-analysis supports the association of SLC22A1 and CYP3A5 genotypes with clinical imatinib response rates of CML patients, nevertheless further large studies, particularly in Caucasians, are still warranted to provide conclusive evidences. PMID- 29427769 TI - Ideal Cardiovascular Health in the southern cone of Latin America. AB - OBJECTIVE: The American Heart Association developed the concept of 'Ideal Cardiovascular Health', which is based on the presence of ideal levels across seven health factors. The goal of this study is to assess the prevalence of Ideal Cardiovascular Health in the Southern Cone of Latin America. STUDY DESIGN: We conducted a cross-sectional analysis as part of CESCAS I cohort. METHODS: This report included 5458 participants aged between 35 and 75 years who were selected using stratified multistage probability sampling in Argentina, Chile and Uruguay. Interviews included demographic information, the International Physical Activity Questionnaire, and a food frequency questionnaire on dietary habits. Participants were classified as current, former or non-smokers. Weight, height and blood pressure were measured by trained personnel, and fasting cholesterol and glucose plasma levels were measured. RESULTS: Only 0.1% (95% confidence interval [CI]: 0.0-0.2) met the seven criteria that define the Ideal Cardiovascular Health. The least prevalent healthy behaviour was having a healthy diet: 0.5% (95% CI: 0.3 0.7), while the least prevalent health factor was having blood pressure < 120/80 mmHg: 23.6% (95% CI: 22.1-25.0). CONCLUSIONS: The prevalence of Ideal Cardiovascular Health is very low in a representative sample of population from the Southern Cone of Latin America, and the levels of healthy lifestyle behaviours are even lower than ideal biochemical parameters. These results highlight the challenge of developing strategies to improve the levels of Ideal Cardiovascular Health at primary prevention levels. PMID- 29427771 TI - Neuregulin 1/ErbB signalling modulates hippocampal mGluRI-dependent LTD and object recognition memory. AB - The neurotrophic factors neuregulins (NRGs) and their receptors, ErbB tyrosine kinases, regulate neurotransmission, synaptic plasticity and cognitive functions and their alterations have been associated to different neuropsychiatric disorders. Group 1 metabotropic glutamate receptors (mGluRI)-dependent mechanisms are also altered in animal models of neuropsychiatric diseases, especially mGluRI induced glutamatergic long-term depression (mGluRI-LTD), a form of synaptic plasticity critically involved in learning and memory. Despite this evidence, a potential link between NRGs/ErbB signalling and mGluRI-LTD has never been considered. Here, we aimed to test the hypothesis that NRGs/ErbB signalling regulates mGluRI functions in the hippocampus, thus controlling CA1 pyramidal neurons excitability and synaptic plasticity as well as mGluRI-dependent behaviors. We investigated the functional interaction between NRG1/ErbB signalling and mGluRI in hippocampal CA1 pyramidal neurons, by analyzing the effect of a pharmacological modulation of NRG1/ErbB signalling on the excitation of pyramidal neurons and on the LTD at CA3-CA1 synapses induced by an mGluRI agonist. Furthermore, we verified the involvement of ErbB signalling in mGluRI dependent learning processes, by evaluating the consequence of an intrahippocampal in vivo injection of a pan-ErbB inhibitor in the object recognition test in mice, a learning task dependent on hippocampal mGluRI. We found that NRG1 potentiates mGluRI-dependent functions on pyramidal neurons excitability and synaptic plasticity at CA3-CA1 synapses. Further, endogenous ErbB signalling per se regulates, through mGluRI, neuronal excitability and LTD in CA1 pyramidal neurons, since ErbB inhibition reduces mGluRI-induced neuronal excitation and mGluRI-LTD. In vivo intrahippocampal injection of the ErbB inhibitor, PD158780, impairs mGluRI-LTD at CA3-CA1 synapses and affects the exploratory behavior in the object recognition test. Thus, our results identify a key role for NRG1/ErbB signalling in the regulation of hippocampal mGluRI dependent synaptic and cognitive functions, whose alteration might contribute to the pathogenesis of different brain diseases. PMID- 29427772 TI - Circulating angiopoietin-2 and its soluble receptor Tie-2 concentrations are related to inflammatory markers in the general population. AB - BACKGROUND: The Angiopoietin/Tie (Tyrosine kinase with Ig and EGF homology domains) signaling axis has crucial influences on angiogenesis and the vasculature's reorganization. Moreover, angiopoietin-2 (Ang2) is discussed as a biomarker for diseases' severity and development. Previous studies reported increased Ang2 levels in patients with inflammatory diseases and associations of Ang2 with inflammation markers in relatively small samples. We aimed to assess the relation of Ang2 and Tie2 with inflammation markers in the general population. METHODS AND RESULTS: Data of 6624 participants of the population based Study of Health in Pomerania (SHIP-1) and the independent SHIP-Trend were used. Ang2, Tie2 and inflammatory biomarkers, including fibrinogen, high sensitive C-reactive protein (hsCRP) and white blood cell count (WBC), were measured. Adjusted analysis of variance (ANOVA) and linear/logistic regression models were performed in the entire sample and in individuals free of hypertension and diabetes. ANOVA [adjusted means of the 1st vs. 4th Ang2 quartile: fibrinogen 3.0 vs. 3.2 g/l; hsCRP 1.2 vs. 1.6 mg/l; WBC 5.9 vs. 6.6 Gpt/l] and regression models adjusted for potential confounders revealed positive relations of Ang2 with all considered inflammation markers. These associations persisted after the exclusion of individuals with hypertension and diabetes. In contrast, Tie2 showed no clear association pattern with the investigated inflammatory markers even if a trend toward a positive relation with fibrinogen became apparent. CONCLUSION: Ang2 was positively associated with fibrinogen, hsCRP and WBC in a large population-based setting. These findings partly agree with previous results, largely obtained in clinical samples. Ang2 has diverse postulated effects on inflammation processes, like increase of vascular leakage or influences on the adhesion of leukocytes to the vessel wall. The proinflammatory character of these effects is similar to these of fibrinogen which conforms to our findings of relations between the markers. However, further research is needed to elucidate possible functional mechanisms. PMID- 29427774 TI - The Anatomy of a Tweet: Social Media in Surgical Practice. AB - The use of social media by surgeons is not only encouraged, but should be seen as an obligation to patients and colleagues to help disseminate important information. In a rapidly expanding digital revolution, engagement in social media allows surgeons to network with the community and leverage content to a wide audience while owning their online presence. PMID- 29427773 TI - Tissue-engineered Vascular Grafts in Children With Congenital Heart Disease: Intermediate Term Follow-up. AB - Tissue engineering holds great promise for the advancement of cardiovascular surgery as well as other medical fields. Tissue-engineered vascular grafts have the ability to grow and remodel and could therefore make great advances for pediatric cardiovascular surgery. In 2001, we began a human clinical trial evaluating these grafts in patients with a univentricular physiology. Herein, we report the long-term results of patients who underwent implantation of tissue engineered vascular grafts as extracardiac total cavopulmonary conduits. Tissue engineered vascular grafts seeded with autologous bone marrow mononuclear cells were implanted in 25 patients with univentricular physiology. The graft is composed of a woven fabric of poly-l-lactide acid or polyglycolic acid and a 50:50 poly (l-lactic-co-epsilon-caprolactone) copolymer. Patients were followed up with postoperatively in a multidisciplinary clinic. Median patient age at operation was 5.5 years and the mean follow-up period was 11.1 years. There was no graft-related mortality during the follow-up period. There was also no evidence of aneurysmal formation, graft rupture, graft infection, or calcification. Seven (28%) patients had asymptomatic graft stenosis and underwent successful balloon angioplasty. Stenosis is the primary complication of the tissue-engineered vascular graft. Avoidance of anticoagulation therapy would improve patients' quality of life. Tissue-engineered vascular grafts have feasibility in pediatric cardiovascular surgery. PMID- 29427775 TI - Survival of mature mouse olfactory sensory neurons labeled genetically perinatally. AB - The main olfactory epithelium (MOE) of an adult mouse harbors a few million mature olfactory sensory neurons (OSNs), which are traditionally defined as mature by their expression of the olfactory marker protein (OMP). Mature OSNs differentiate in situ from stem cells at the base of the MOE. The consensus view is that mature OSNs have a defined lifespan and then undergo programmed cell death, and that the adult MOE maintains homeostasis by generating new mature OSNs from stem cells. But there is also evidence for mature OSNs that are long-lived. Thus far modern genetic tools have not been applied to quantify survival of a population of OSNs that are mature at a given point in time. Here, a genetic strategy was developed to label irreversibly OMP-expressing OSNs in mice. A gene targeted OMP-CreERT2 strain was generated in which mature OSNs express an enzymatically inactive version of the Cre recombinase. The fusion protein CreERT2 becomes transiently active when exposed to tamoxifen, and in the presence of a Cre reporter in the genome such as tdRFP, CreERT2-expressing cells become irreversibly labeled. A cohort of mice was generated with the same day of birth by in vitro fertilization and embryo transfer, and injected tamoxifen in their mothers at E18.5 of gestation. I counted RFP immunoreactive cells in the MOE and vomeronasal organ of 36 tamoxifen-exposed OMP-CreERT2 * tdRFP mice from 7 age groups: postnatal day (PD)1.5, PD3.5, PD6.5, 3 weeks, 9 weeks, 6 months, and 12 months. Approximately 7.8% of perinatally labeled cells remain at 12 months, confirming that some mature OSNs are indeed long-lived. The survival curve of the population of perinatally labeled MOE cells can be modeled with a mean half-life of 26 days for the population as a whole, excluding the long-lived cells. PMID- 29427776 TI - Beta estradiol and norepinephrine treatment of differentiated SH-SY5Y cells enhances tau phosphorylation at (Ser396) and (Ser262) via AMPK but not mTOR signaling pathway. AB - Hyperphosphorylation of tau is one of the main hallmarks for Alzheimer's disease (AD) and many other tauopathies. Norepinephrine (NE), a stress-related hormone and 17-beta-estradiol (E2) thought to influence tau phosphorylation (p-tau) and AD pathology. The controversy around the impact of NE and E2 requires further clarification. Moreover, the combination effect of physiological and psychological stress and estrogen alteration during menopause, which affect p tau, has not been addressed. Exposure to E2 is believed to reduce NE release, however, the link between these two hormones and AD at cellular level was also remained unknown. Here, we examined whether NE and E2 treatment of differentiated SH-SY5Y cells affected tau phosphorylation. The involvement of adenosine monophosphate kinase protein kinase (AMPK) and target of Rapamycin (mTOR) as the possible mechanisms, underlying this effect was also investigated. Subsequent to SH-SY5Y differentiation to mature neurons, we treated the cells with NE, E2 and NE plus E2 in presence and absence of Compound C and Rapamycin. Cell viability was not affected by our treatment while our Western blot and immunofluorescent findings showed that exposure to NE and E2 separately, and in combination enhanced p-tau (Ser396) and (Ser262)/tau but not (Ser202/Thr205)/tau. Blocking AMPK by Compound C reduced p-tau (Ser396) and (Ser262), while GSK-3beta and PP2A activities were remained unchanged. We also found that blocking mTOR by Rapamycin did not change increased p-tau (Ser396) and (Ser262) due to NE + E2 treatment. Collectively, our results suggested that tau hyperphosphorylation due to exposure to NE/E2 was mediated by AMPK, the main energy regulator of cells during stress with no significant involvement of mTOR, GSK-3beta and PP2A. PMID- 29427777 TI - Unweaving a taxon tangle: Comments on De Silva et al. (2017). PMID- 29427778 TI - Getting the Ploceidae tree right. PMID- 29427779 TI - Successful Laparoscopic Treatment of Chylous Ascites after Pelvic Lymphadenectomy: A Case Report and Peanut Oil Application. AB - A 23-year-old female patient with refractory chylous ascites was successfully treated with laparoscopic ligation of the ruptured lymphatic vessel. The young patient developed abdominal distention after right-side pelvic lymph node dissection for dysgerminoma of the right ovary. Conservative managements failed to control the symptoms. Laparoscopic surgery was performed after oral administration of peanut oil, revealing the presence of a whitish fluid in the abdominal cavity. The responsible lesion of the chylous ascites was detected in the right obturator fossa and ligated with the HEM-O-LOK System (Kangji Medical Instrument Co., Ltd., Hangzhou City, Zhejiang Province, China). The patient experienced an uneventful recovery and has been completely free of symptoms for 1 year. Laparoscopic surgery should be considered as a treatment of choice for intractable chylous ascites, and peanut oil could be used before surgery as an effective way to facilitate detection of the leakage during surgery. PMID- 29427780 TI - Transvaginal Natural Orifice Transluminal Endoscopic Surgery as a Rescue for Total Vaginal Hysterectomy. AB - BACKGROUND: Transvaginal surgery is the most minimally invasive surgery for a gynecologic procedure but can be challenging for many to perform as evidenced by its declining rate. Vaginal removal of the adnexal structures can be difficult because of poor visualization. Factors such as abnormal pathology, incidental finding of early-stage endometriosis or adhesions from previous cesarean section or surgery, and obesity may further complicate the procedure. Transvaginal natural orifice transluminal endoscopic surgery (NOTES) may be performed during vaginal surgery using basic laparoscopic single-site skills as a "rescue" procedure for the complete removal of the adnexae. This allows the surgeon to complete the procedure vaginally without requiring conversion or addition of abdominal incisions. The combination of total vaginal hysterectomy (TVH) with NOTES as a "rescue" procedure may be a useful tool for gynecologic surgeons for removal of the adnexae and performance of other pelvic procedures. STUDY OBJECTIVE: To demonstrate various common pelvic procedures that can be performed by transvaginal NOTES after completion of TVH. DESIGN: Variety demonstrations of the transvaginal NOTES technique as a "rescure" for total vaginal hysterectomy with narrated video footage (Canadian Task Force classification III). SETTING: Academic tertiary care hospital. PATIENTS: Patients with various surgeries including prophylactic bilateral salpingectomy, salpingo-oophorectomy, adhesiolysis, and incidental finding of superficial endometriosis resection. This video is exempt from institutional review board review at our institution. INTERVENTIONS: Transvaginal NOTES adnexal surgery and other procedures using basic laparoscopic single-site surgical skills. MEASUREMENTS AND MAIN RESULTS: Salpingectomy, oophorectomy, lysis of adhesions, and resection of endometriosis can be performed using NOTES at the time of vaginal hysterectomy. CONCLUSION: NOTES allows the surgeon to survey the pelvis for pathology and to complete other pelvic procedures transvaginally during TVH with no additional abdominal incisions. Transvaginal NOTES can be considered a "rescue" approach and can be a helpful tool for the pelvic surgeon. PMID- 29427781 TI - Retroperitoneal Laparoscopic Para-Aortic Lymphadenectomy in Para-Aortic Staging of Locally Advanced Cervical Cancer. AB - STUDY OBJECTIVE: To review/learn a surgical technique not very well-known by gynecologic oncologists. DESIGN: Level of evidence III. SETTING: A review of a surgical technique with emphasis on the para-aortic sentinel lymph nodes using indocyanine green. INTERVENTION: The film features the following steps to perform the procedure: 1. Creating a retroperitoneal window. 2. What to do if the peritoneum is torn. 3. Finding the psoas muscle, right ureter, and common iliac artery. Dissecting the right common iliac artery caudally to the bifurcation of the external iliac artery and internal iliac artery and cranially to the inferior mesenteric artery, the ovarian arteries, and the left renal vein. 4. A view of all of the nodes with fluorescence when indocyanine green is injected into the cervix. At present, the sentinel lymph nodes are not the standard of care for locally advanced cervical cancer. If the nodes are metastatic at this stage, all the para-aortic area will undergo radiation therapy. 5. Dissecting the inferior vena cava from the intersection with the right uterer to the right and left renal veins. 6. Performing the lateroaortic, preaortic, and precaval lymphadenectomy. 7. A final view with all of the elements (i.e., bifurcation of the common iliac artery, the left renal vein, and both ureters). 8. In the final part of the video, we open the peritoneal window to decrease the incidence of lymphoceles. CONCLUSION: The real novelty of this video is how the para-aortic area nodes are seen when green indocyanine is injected into the cervix. This video shows a simplified technique of retroperitoneal para-aortic lymphadenectomy using an advanced bipolar sealant. Some tips and tricks to facilitate the procedure are emphasized, especially in cases of accidental peritoneal tears. To decrease the incidence of lymphoceles before completing the surgery, the peritoneal window should be opened. This surgical technique is especially useful in endometrial cancer for staging the para-aortic area in obese patients and in advanced cervical cancer to determine the field of radiotherapy. PMID- 29427782 TI - Transcriptional and splicing dysregulation in the prefrontal cortex in valproic acid rat model of autism. AB - Gene-environmental interaction could be the major cause of autism. The aim of the current study is to detect the effects of valproic acid on gene expression profiles and alternatively spliced genes in the prefrontal cortex in rat models of autism. Female rats received a single intraperitoneal injection of 600 mg/kg valproic acid at day 12.5 post-conception, and controls were injected with saline. Only male offspring were employed in the current study. RNA sequencing was used to investigate transcriptome in the prefrontal cortex of VPA-exposed rats. There were 3228 differently expressed genes and 637 alternative spliced genes, in VPA rats compared to controls. Pathways enrichment among the differently expressed genes and alternatively spliced genes were associated with neurological diseases and neural system development. The results implied VPA affected transcriptional and splicing events genome-wide and the transcriptional and splicing events may be associated with the autistic behaviors of VPA rats. PMID- 29427783 TI - Gout drugs use and risk of cancer: A case-control study. AB - OBJECTIVE: Firm conclusion about whether short and long-term gout medications use has an impact on cancer risk remain inconclusive. The aim of this study was to investigate the association between gout drugs use and risk of cancer. METHODS: We conducted a retrospective longitudinal population-based case-control study in Taiwan. Cases were identified all patients who were aged 20years or above, and had a first time diagnosis of cancers for the period between 2001 and 2011. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated by using conditional logistic regression. RESULTS: We examined 601,733 cases and 2,406,932 matched controls. The adjusted odd ratio for any gout drugs use and overall cancer risk was 1.007 (95% CI: 0.994-1.020). There was a significant risk of leukemia (AOR: 1.34, 95% CI: 1.20-1.50), endometrial cancer (AOR: 1.33, 95% CI: 1.12-1.57), non-Hodgkin's (AOR: 1.24, 95% CI: 1.13-1.35), female breast cancer (AOR: 1.21, 95% CI: 1.13-1.29), cervical cancer (AOR: 1.21, 95% CI: 1.07 1.37). However, no association was observed in male group (AOR: 0.97, 95% CI: 0.95-0.98) but female showed a significantly increased risk of cancer at any site (AOR: 1.107, 95% CI: 1.08-1.13). CONCLUSION: In summary, our results suggest that gout drugs increase risk of the most common cancers, particularly in leukemia, non-Hodgkin's, endometrial, breast and cervical cancer. PMID- 29427784 TI - Evaluation of the treatment with resveratrol-loaded nanoparticles in intestinal injury model caused by ischemia and reperfusion. AB - The gastrointestinal tract is extremely sensitive to ischemia and reperfusion (I/R). Studies have reported that resveratrol (RSV) is able to combat damage caused by intestinal I/R. Because of its effectiveness in increasing the permanence and bioavailability of resveratrol in the intestinal epithelium, we investigated whether the effect of resveratrol-loaded in poly(anhydride) nanoparticles reduce oxidative stress and promote myenteric neuroprotection in the ileum of rats subjected to I/R. Physicochemical evaluations were performed on nanoparticles. The animals were divided into nine groups (n = 6/group) and treated every 48 h. Treatments with resveratrol (7 mg/kg of body weight) were applied 5 days before surgery and continued for 7 days after surgery (reperfusion period). The superior mesenteric artery was occluded to cause I/R injury. Oxidative stress, myeloperoxidase, nitrite, aspartate aminotransferase, alanine aminotransferase, immunolabeling of myenteric neurons and glial cells, and gastrointestinal transit was evaluated. Both nanoparticle formulations presented negative charge with homogeneous distribution, and the payload, showed an encapsulation efficiency of 60%. Resveratrol administered in free form prevented alterations that were caused by I/R. The results of the groups treated with RSV loaded nanoparticles presented similar results to the group treated with free resveratrol. Treatment with empty nanoparticles showed that poly(anhydride) is not an ideal nanocarrier for application in in vivo models of intestinal I/R injury, because of hepatotoxicity that may be caused by epithelial barrier dysfunction that triggers the translocation of nanoparticles. PMID- 29427785 TI - Mitochondrial dysfunction induced by leflunomide and its active metabolite. AB - Leflunomide, an anti-inflammatory drug used for the treatment of rheumatoid arthritis, has been marked with a black box warning regarding an increased risk of liver injury. The active metabolite of leflunomide, A771726, which also carries a boxed warning about potential hepatotoxicity, has been marketed as teriflunomide for the treatment of relapsing multiple sclerosis. Thus far, however, the mechanism of liver injury associated with the two drugs has remained elusive. In this study, cytotoxicity assays showed that ATP depletion and subsequent LDH release were induced in a time- and concentration-dependent manner by leflunomide in HepG2 cells, and to a lesser extent, by A77 1726. The decline of cellular ATP levels caused by leflunomide was dramatically exacerbated when galactose was substituted for glucose as the sugar source, indicating a potential mitochondrial liability of leflunomide. By measuring the activities of immuno captured mitochondrial oxidative phosphorylation (OXPHOS) complexes, we found that leflunomide and A77 1726 preferentially targeted complex V (F1FO ATP synthase), with IC50 values of 35.0 and 63.7 MUM, respectively. Bongkrekic acid, a mitochondrial permeability transition pore blocker that targets adenine nucleotide translocase, profoundly attenuated mitochondrial membrane depolarization, ATP depletion, and LDH leakage induced by leflunomide and A77 1726. Substantial alterations of mitochondrial function at the transcript level were observed in leflunomide-treated HepG2 cells, whereas the effects of A77 1726 on the cellular transcriptome were much less profound. Our results suggest that mitochondrial dysfunction may be implicated in the hepatotoxicity associated with leflunomide and A77 1726, with the former exhibiting higher toxicity potency. PMID- 29427786 TI - CLARITY-BPA: Effects of chronic bisphenol A exposure on the immune system: Part 2 - Characterization of lymphoproliferative and immune effector responses by splenic leukocytes. AB - Bisphenol A (BPA) is commonly used in the manufacturing of a wide range of consumer products, including polycarbonate plastics, epoxy resin that lines beverage and food cans, and some dental sealants. Consumption of food and beverages containing BPA represents the primary route of human BPA exposure, which is virtually ubiquitous. An increasing number of studies have evaluated the effects of BPA on immune responses in laboratory animals that have reported a variety of effects some of which have been contradictory. To address the divergent findings surrounding BPA exposure, a comprehensive chronic treatment study of BPA was conducted in Sprague-Dawley rats, termed the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA). As a participant in the CLARITY-BPA project, our studies evaluated the effects of BPA on a broad range of immune function endpoints using spleen cells isolated from BPA or vehicle treated rats. This comprehensive assessment included measurements of lymphoproliferation in response to mitogenic stimuli, immunoglobulin production by B cells, and cellular activation of T cells, NK cells, monocytes, granulocytes, macrophages and dendritic cells. In total, 630 different measurements in BPA treated rats were performed of which 35 measurements were statistically different from vehicle controls. The most substantive alteration associated with BPA treatment was the augmentation of lymphoproliferation in response to pokeweed mitogen stimulations in 1 year old male rats, which was also observed in the reference estrogen ethinyl estradiol treated groups. With the exception of the aforementioned, the statistically significant changes associated with BPA treatment were mostly sporadic and not dose-dependent with only one out of five BPA dose groups showing a statistical difference. In addition, the observed BPA-associated alterations were mostly moderate in magnitude and showed no persistent trend over the one-year time period. Based on these findings, we conclude that the observed BPA-mediated changes observed in this study are unlikely to alter immune competence in adult rats. PMID- 29427787 TI - ZNF462 and KLF12 are disrupted by a de novo translocation in a patient with syndromic intellectual disability and autism spectrum disorder. AB - We describe a patient with a de novo balanced translocation 46,XY,t(9; 13)(q31.2; q22.1) and autism spectrum disorder, intellectual disability, a metopic craniosynostosis, a corpus callosum dysgenesis and dysmorphic facial features, most notably ptosis. Breakpoint mapping was performed by means of targeted locus amplification (TLA) and sequencing, because conventional breakpoint mapping by means of fluorescent in situ hybridization and long-range PCR was hampered by a complex submicroscopic rearrangement. The translocation breakpoints directly affected the genes KLF12 (chromosome 13) and ZNF462 (chromosome 9). The latter gene was disrupted by multiple breakpoints, resulting in the loss of three fragments and a rearrangement of the remaining fragments. Therefore, haploinsufficiency of ZNF462 was assumed. Loss-of-function variants in ZNF462 have recently been published by Weiss et al. (2017) in a series of eight patients from six independent families delineating the ZNF462-associated phenotype. The latter closely matches with the clinical features of the current translocation patient. Besides, no direct evidence for an association of KLF12 to the phenotypic features was found. Therefore, we conclude that the phenotype of the current patient is mainly caused by the disruption of ZNF462. We present clinical data from birth to adulthood and data on the cognitive and behavioral profile of the current patient which may add to a more precise counseling and surveillance of development in young children with ZNF462 mutations. In addition, the current case illustrates that TLA is an efficient method for determining complex chromosomal breakpoints. PMID- 29427788 TI - Split hand-foot malformation and a novel WNT10B mutation. AB - We report an Indian girl with split-hand/foot malformation (SHFM), sparse hair, and interrupted eyebrows, who carries a novel homozygous deletion c.695_697delACA in WNT10B. The variant is deduced to cause an in-frame deletion of Asn residue 232 (p.Asn232del). According to the protein model, this single amino acid deletion at the critical position in the protein structure is likely to severely affect the protein structure and function. This deletion is likely to lead decreased lifetime and make it unable to bind to its receptors and other ligands. The patient and all family members had normal bone density and they were not obese like some of the patients with WNT10B variants. Here we report a patient with SHFM6 who carried a novel WNT10B mutation. Sparse hair and interrupted eyebrows may be associated findings of SHFM6. PMID- 29427790 TI - Activation of Nrf2 by Ginsenoside Rh3 protects retinal pigment epithelium cells and retinal ganglion cells from UV. AB - Excessive Ultra-violet (UV) radiation shall induce damages to resident retinal pigment epithelium (RPE) cells (RPEs) and retinal ganglion cells (RGCs). Here we tested the potential activity of Ginsenoside Rh3 ("Rh3") against the process. In cultured human RPEs and RGCs, pretreatment with Rh3 inhibited UV-induced reactive oxygen species (ROS) production and following apoptotic/non-apoptotic cell death. Rh3 treatment in retinal cells induced nuclear-factor-E2-related factor 2 (Nrf2) activation, which was evidenced by Nrf2 protein stabilization and its nuclear translocation, along with transcription of antioxidant responsive element (ARE) dependent genes (HO1, NOQ1 and GCLC). Nrf2 knockdown by targeted-shRNA almost abolished Rh3-induced retinal cell protection against UV. Further studies found that Rh3 induced microRNA-141 ("miR-141") expression, causing downregulation of its targeted gene Keap1 in RPEs and RGCs. On the other hand, Rh3-induced Nrf2 activation and retinal cell protection were largely attenuated by the miR-141's inhibitor, antagomiR-141. In vivo, intravitreal injection of Rh3 inhibited retinal dysfunction by light damage in mice. Rh3 intravitreal injection also induced miR-141 expression, Keap1 downregulation and Nrf2 activation in mouse retinas. We conclude that Rh3 protects retinal cells from UV via activating Nrf2 signaling. PMID- 29427789 TI - Bone tissue aging affects mineralization of cement lines. AB - Cement lines are known as thin peripheral boundaries of the osteons. With a thickness below 5 MUm their composition of inorganic and organic compounds has been a matter of debate. Here, we hypothesized that cement lines become hypermineralized and their degree of mineralization is not constant but related to the tissue age of the osteon. Therefore, we analyzed the calcium content of osteons and their corresponding cement lines in a range of different tissue ages reflected by osteonal mineralization levels in femoral cortical bone of both postmenopausal women with osteoporosis and bisphosphonate-treated cases. Quantitative backscattered electron imaging (qBEI) showed that cement lines are hypermineralized entities with consistently higher calcium content than their corresponding osteons (mean calcium content: 29.46 +/- 0.80 vs. 26.62 +/- 1.11 wt%; p < 0.001). Micro-Raman spectroscopy complemented the qBEI data by showing a significantly higher phosphate/amide I ratio in the cement lines compared to the osteonal bone (8.78 +/- 0.66 vs. 6.33 +/- 0.58, p < 0.001), which was both due to an increased phosphate peak and a reduced amide I peak in cement lines. A clear positive correlation of cement line mineralization and the mineralization of the osteon was observed (r = 0.839, p = 0.003). However, the magnitude of the difference between cement line and osteonal calcium content decreased with increased osteonal calcium content (r = -0.709, p < 0.001), suggesting diverging mineralization dynamics in these osseous entities. The number of mineralized osteocyte lacunae per osteon bone area correlated positively with both osteonal and cement line calcium content (p < 0.01). The degree of mineralization of cement lines may represent another tissue-age related phenomenon, given that it strongly relates to the osteonal mineralization level. Understanding of the cement lines' mineralization and their changes in aging and disease states is important for predicting crack propagation pathways and fracture resistance mechanisms in human cortical bone. PMID- 29427791 TI - CYP2J2-derived EETs attenuated ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis. AB - Chronic excessive drinking leads to myocardial contractile dysfunction and dilated cardiomyopathy, where ethanol toxicity plays an essential role. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the cardiovascular system, but their role in alcoholic cardiomyopathy is elusive. This study was designed to evaluate the effects and mechanisms of CYP2J2 gene delivery on ethanol-induced myocardial dysfunction with focus on autophagy and apoptosis. C57BL/6 J mice were challenged with a 4% Lieber-DeCarli ethanol liquid diet for 8 weeks, before which rAAV9-CYP2J2 was injected via the tail vein. Cardiac function was assessed using echocardiography, hemodynamic measurement, and cardiac histology. The results showed that chronic ethanol intake led to cardiac dilation, contractile dysfunction, cardiomyocyte hypertrophy, oxidative stress, and cardiomyocyte apoptosis, while CYP2J2 overexpression ameliorated these effects. Additionally, chronic ethanol consumption triggered myocardial autophagosome formation, but impaired autophagic flux via disrupting autophagosome-lysosome fusion, as evidenced by increased LC3 II/I, Beclin-1 and SQSTM1 levels, but reduced LAMP-2 expression. Interestingly, rAAV9-CYP2J2 treatment exerted cardioprotection via restoring autophagic flux in the alcoholic myocardium. Similarly, exogenous 11,12-EET addition significantly restored ethanol-induced neonatal rat cardiomyocyte autophagic flux impairment and inhibited apoptosis, both of which were mediated by AMPK/mTOR signaling pathway in vitro. In conclusion, our data suggest that CYP2J2-derived EETs attenuate ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis. PMID- 29427792 TI - S-glutathionylation exerts opposing roles in the regulation of STAT1 and STAT3 signaling in reactive microglia. AB - STAT1 and STAT3 are two transcription factors involved in a lot of cellular functions such as immune response, proliferation, apoptosis, and cell survival. A number of literature evidences described a yin-yang relationship between activation of STAT1 and STAT3 in neurodegenerative disorders where STAT1 exerts a pro-apoptotic effect whereas STAT3 shows neuroprotective properties through the inhibition of apoptosis. Although the role of oxidative-stress in the pathogenesis of neurodegeneration is clearly described, its influence in the regulation of these pathways is poorly understood. Herein, we demonstrate that H2O2 rapidly induces phosphorylation of STAT1 whereas it is not able to influence phosphorylation of STAT3 in mouse microglia BV2 cells. The analysis of the molecular mechanism of STATs signaling reveals that H2O2 induces S glutathionylation of both STAT1 and STAT3. The same post-translational event exerts an opposing role in the regulation of STAT1 and STAT3 signaling. These data not only confirm redox sensibility of STAT3 signaling but also reveal for the first time that STAT1 is susceptible to redox regulation. A deep study of the molecular mechanism of STAT1 redox regulation, identifies Cys324 and Cys492 as the main targets of S-glutathionylation and confirms that S-glutathionylation does not impair JAK2 mediated STAT1 tyrosine phosphorylation. These results demonstrate that both phosphorylation and glutathionylation contribute to activation of STAT1 during oxidative stress and underline that the same post translation event exerts an opposing role in the regulation of STAT1 and STAT3 signaling in microglia cells. PMID- 29427793 TI - Peroxynitrite enhances self-renewal, proliferation and neuronal differentiation of neural stem/progenitor cells through activating HIF-1alpha and Wnt/beta catenin signaling pathway. AB - Hypoxic/ischemic stimulation could mediate growth and differentiation of neural stem/progenitor cells (NSCs) into mature neurons but its underlying mechanisms are largely unclear. Peroxynitrite formation is considered as a crucial pathological process contributing to cerebral ischemia-reperfusion injury. In the present study, we tested the hypothesis that peroxynitrite at low concentration could function as redox signaling to promote the growth of NSCs under hypoxic/ischemic conditions. Increased NSCs proliferation was accompanied by peroxynitrite production in the rat brains with 1 h of ischemia plus 7 days of reperfusion in vivo. Cell sorting experiments revealed that endogenous peroxynitrite level affected the capacity of proliferation and self-renewal in NSCs in vitro. Hypoxia stimulated peroxynitrite production and promoted NSCs self renewal, proliferation and neuronal differentiation whereas treatments of peroxynitrite decomposition catalysts (PDCs, FeTMPyP and FeTPPS) blocked the changes in NSCs self-renewal, proliferation and neuronal differentiation. Exogenous peroxynitrite treatment revealed similar effects to promote NSCs proliferation, self-renewal and neuronal differentiation. Furthermore, the neurogenesis-promoting effects of peroxynitrite were partly through activating HIF-1alpha correlated with enhanced Wnt/beta-catenin signaling pathway. In conclusion, peroxynitrite could be a cellular redox signaling for promoting NSCs proliferation, self-renewal and neuronal differentiation and peroxynitrite production could contribute to neurogenesis in ischemic/hypoxic NSCs. PMID- 29427795 TI - Cellular senescence: Immunosurveillance and future immunotherapy. AB - In response to persistent DNA damage, induction into cell senescence promotes an immunogenic program which facilitates immune clearance of these damaged cells. Under physiological conditions, senescent cells can activate both innate and adaptive immune responses, functioning to maintain tissue homeostasis. In addition, emerging findings suggest that programmed induction of cell senescence may be important for regulating reproductive processes, partly facilitated by immune clearance. However, likely owing to ageing of the immune system, a failure to eliminate senescent cells can contribute to their persistence in tissues, leading to the development and progression of age-related diseases. Such immune failure may in part be due to activation of the senescence program in immune cells, leading to their dysfunction. Furthermore, senescent cells under certain biological contexts have been shown to instead promote immune suppression, a response that may reflect differences between an acute verses chronic senescent phenotype. In this review, we provide an overview of the research to date concerning senescence immunosurviellance, including a focused discussion on the mechanisms by which macrophages may recognise senescent cells. Senescence immunotherapy strategies as an alternative to senolytics for the removal of senescent cells will also be discussed. PMID- 29427794 TI - Concerted redox modulation by sulforaphane alleviates diabetes and cardiometabolic syndrome. AB - Diabetes and cardiometabolic disorders such as hypertension and obesity are major risk factors for the development of cardiovascular disease, with a wealth of evidence suggesting that oxidative stress is linked to the initiation and pathogenesis of these disease processes. With yearly increases in the global incidence of cardiovascular diseases (CVD) and diabetes, numerous studies have focused on characterizing whether upregulating antioxidant defenses through exogenous antioxidants (e.g. vitamin E, vitamin C) or activation of endogenous defenses (e.g. the Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant defense pathway) may be of benefit. The dietary isothiocyanate sulforaphane (SFN) is currently the subject of several clinical trials for a variety of disease states, including the evaluation of its therapeutic potential to ameliorate diabetic and cardiometabolic complications. SFN is a well characterized and potent Nrf2 inducer, however recent studies suggest its protective actions may be in part mediated by its modulation of various pro-inflammatory (e.g. Nuclear factor-kappa B (NFkappaB)) and metabolic (e.g. Peroxisome Proliferator-Activator Receptor Gamma (PPARgamma)) signaling pathways. The focus of this review is to provide a detailed analysis of the known mechanisms by which SFN modulates Nrf2, NFkappaB and PPARgamma signaling and crosstalk and to provide a critical evaluation of the evidence linking these transcriptional pathways with diabetic and cardiometabolic complications and SFN mediated cytoprotection. To allow comparison between rodent and human studies, we discuss the published bioavailability of SFN metabolites achieved in rodents and man in the context of Nrf2, NFkappaB and PPARgamma signaling. Furthermore, we provide an update on the functional outcomes and implicated signaling pathways reported in recent clinical trials with SFN in Type 2 diabetic patients. PMID- 29427796 TI - The influence of different illumination parameters on protoporphyrin IX induced cell death in squamous cell carcinoma cells. AB - BACKGROUND: Topical photodynamic therapy (PDT) is a highly effective therapy especially for extended cancerized fields of the skin. Whenever extended fields are treated pain management is advisable. Light source mediated pain management can be performed by reducing fluence rates, as long as this does not compromise efficacy. METHODS: Two squamous cell carcinoma cell lines (A431 and SCC-13) were subjected to in vitro PDT using two different ALA concentrations and synthesis intervals and protoporphyrin IX (PpIX) synthesis was assessed. Two total light doses (6 J/cm2 and 37 J/cm2) were applied at three different fluence rates and cell viability was measured using the MTS-test. RESULTS: Both cell lines synthetized PpIX at different kinetics. A431 cells produced a maximum 28.6 nmol/l PpIX, while SCC-13 reached only a production of 8.7 nmol/l. Illumination reduced cell viability depending on PpIX content and light dose. When a lower light dose (6 J/cm2) was applied, only the combination with the highest PpIX content was effective in A431 cells and no effect could be detected in SCC-13 cells. With a light dose of 37 J/cm2, lower PpIX amounts became effective in A431 and cell death could be induced in SCC-13 cells. Light fluence rate had no differential effect in this setup. CONCLUSIONS: In both, A431 and SCC-13 cells, total light dose is a key factor for photodynamic efficacy. Additionally, our results hint towards a threshold concentration of PpIX upon which a drastic loss of viability occurs. Light fluence rate in the analyzed range is not a limiting factor of photodynamic cytotoxicity. This may allow for the clinical implementation of low fluence rate protocols for pain management without compromising efficacy. PMID- 29427797 TI - Severe lower limb cellulitis: defining the epidemiology and risk factors for primary episodes in a population-based case-control study. AB - OBJECTIVE: To describe the epidemiology and risk factors for primary episodes of severe lower leg cellulitis (LLC). METHODS: This was a longitudinal cohort study using state-wide data linkage of adults presenting to Western Australian (WA) hospitals with a first ever LLC from January 2002 to December 2013. The study aimed at determining risk factors, medical records from the index patient, together with comparable data from controls matched by age, sex, postcode, and month of admission. RESULTS: During the period, 36 276 patients presented with their first episode of LLC. The incidence increased by 4.7% per annum, reaching 204.8 (95% CI 198.6-211.1) per 100 000 population by December 2013. Analysis of 29 062 case-control pairs showed several conditions with lower limb pathology were independently associated with LLC, including varicose veins (AOR 2.95, 95% CI 2.50-3.48, p < 0.001), lymphoedema (AOR 2.65, 95% CI 1.71-4.10, p < 0.001), tinea pedis (AOR 3.05, 95% CI 1.45-6.42, p 0.003), and saphenous vein harvest during coronary artery bypass grafting (AOR 1.74, 95% CI 1.32-2.30, p < 0.001). Also associated with LLC was obesity (AOR 2.05, 95% CI 1.82-2.31, p < 0.001), renal disease (AOR 1.28, 95% CI 1.14-1.44, p < 0.001), rheumatologic conditions (AOR 2.12, 95% CI 1.72-2.60, p < 0.001), hemiplegia/paraplegia (AOR 1.31, 95% CI 1.13-1.52, p < 0.001), and liver disease (AOR 1.77, 95% CI 1.51-2.06, p < 0.001). CONCLUSIONS: LLC presents a major burden to the health sector and is increasing with an ageing population. Given the high rates of recurrence, long-term morbidity, and economic impact, efforts to reduce primary episodes should be incorporated into the infectious diseases and healthy ageing research agenda. PMID- 29427798 TI - Evidence for multiple sylvatic transmission cycles during the 2016-2017 yellow fever virus outbreak, Brazil. AB - OBJECTIVES: Since December 2016, Brazil has experienced an unusually large outbreak of yellow fever (YF). Whether urban transmission may contribute to the extent of the outbreak is unclear. The objective of this study was to characterize YF virus (YFV) genomes and to identify spatial patterns to determine the distribution and origin of YF cases in Minas Gerais, Espirito Santo and Rio de Janeiro, the most affected Brazilian states during the current YFV outbreak. METHODS: We characterized near-complete YFV genomes from 14 human cases and two nonhuman primates (NHP), sampled from February to April 2017, retrieved epidemiologic data of cases and used a geographic information system to investigate the geospatial spread of YFV. RESULTS: All YFV strains were closely related. On the basis of signature mutations, we identified two cocirculating YFV clusters. One was restricted to the hinterland of Espirito Santo state, and another formed a coastal cluster encompassing several hundred kilometers. Both clusters comprised strains from humans living in rural areas and NHP. Another NHP lineage clustered in a basal relationship. No signs of adaptation of YFV strains to human hosts were detected. CONCLUSIONS: Our data suggest sylvatic transmission during the current outbreak. Additionally, cocirculation of two distinct YFV clades occurring in humans and NHP suggests the existence of multiple sylvatic transmission cycles. Increased detection of YFV might be facilitated by raised awareness for arbovirus-mediated disease after Zika and chikungunya virus outbreaks. Further surveillance is required, as reemergence of YFV from NHPs might continue and facilitate the appearance of urban transmission cycles. PMID- 29427799 TI - Epidemiology and risk factors for recurrent severe lower limb cellulitis: a longitudinal cohort study. AB - OBJECTIVE: To describe the epidemiology and risk factors for recurrence of severe lower leg cellulitis (LLC). METHODS: A longitudinal cohort study using state-wide data of adults presenting with recurrent LLC following a primary episode occurring between January 2002 and December 2013. The incidence of recurrent LLC was estimated using the cumulative incidence function, accounting for mortality. Independent risk factors for recurrence were identified using Fine-Gray sub distribution and Cox proportional hazards models. RESULTS: Of 36 276 patients presenting with their first episode of LLC, 4598 had at least one recurrence during the follow-up period. The cumulative incidence of first, second, and third recurrences at 12 months since previous infection was 6.3% (95% CI 6.0-6.5), 17.2% (95% CI 16.1-18.4), and 29.4% (95% CI 26.8-31.9), respectively, and at 5 years was 13.9% (95% CI 13.5-14.3), 35.9% (95% CI 34.2-37.5), and 52.9% (95% CI 49.5-56.2), respectively. The length of hospitalization increased from 3 days for the primary episode to 4 and 5 days for first and all subsequent recurrences, respectively. Independent risk factors for recurrent LLC included age, ethnicity (Indigenous Australian), local factors relating to lower leg pathology, conditions that commonly result in peripheral oedema, and systemic conditions that may be associated with increased leg size. CONCLUSIONS: LLC recurrences are frequent, and each episode increases the likelihood of subsequent recurrence and length of hospitalization. These data provide context and scope to develop workable and effective strategies to prevent secondary episodes for all cases of primary LLC. PMID- 29427800 TI - New insights into transmission of Clostridium difficile infection-narrative review. AB - BACKGROUND: Traditionally, Clostridium difficile has been considered a typical healthcare-associated pathogen-that is, one transmitted within healthcare facilities and thus prevented by implementation of standard infection control measures. Recently this concept has been challenged by studies suggesting a relevant role for community acquisition of C. difficile. AIMS: To discusses the current literature, compiled during the last decade, reporting on sources of acquisition of C. difficile and subsequent transmission. SOURCES: The databases PubMed, Medline, Embase and the Cochrane Database were searched for articles published from 1 January 2007 to 30 June 2017 reporting on possible transmission pathways of C. difficile and/or suggesting a source of acquisition of C. difficile. All study types reporting on adult populations were considered; case reports and series were excluded. The PRISMA guidelines for the reporting of systematic reviews were followed. CONTENT: Among 24 original articles included, 63% report on transmission of C. difficile in healthcare settings and 37% investigate sources and transmission of C. difficile in the community. Contact with symptomatic carriers (53.3%), the hospital environment (40.0%) and asymptomatic carriers (20%) were the most commonly reported transmission pathways within healthcare settings. The leading sources for acquisition of C. difficile in the community include direct contact with symptomatic and asymptomatic carriers in the community, including infants (30%) and residents of long-term non acute care facilities (30%), followed by contact with contaminated environments in outpatient care settings (20%) and exposure to livestock or livestock farms (20%). IMPLICATIONS: In healthcare settings, future control efforts may need to focus on extending cleaning and disinfection procedures beyond the immediate surroundings of symptomatic carriers. Potential targets to prevent acquisition of C. difficile in the community include household settings, long-term care facilities and outpatient settings, while the role of livestock in entertaining transmission requires further investigation. PMID- 29427801 TI - ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Introduction). AB - BACKGROUND: The field of new biological agents is increasing exponentially over the past years, thus making prevention and management of associated infectious complications a challenge for nonspecialized clinicians. AIMS: The present consensus document is an initiative of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) aimed at analysing, from an infectious diseases perspective, the safety of targeted and biological therapies. SOURCES: Computer based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: The document is structured in sections according to the targeted site of action of each drug class: proinflammatory cytokines; interleukins, immunoglobulins and other soluble immune mediators; cell surface receptors and associated signaling pathways; intracellular signaling pathways; lymphoma and leukaemia cells surface antigens; and other targeted therapies. A common outline is followed for each agent: summary of mechanism of action, approved indications and common off-label uses; expected impact on the host's susceptibility to infection; available clinical evidence (i.e. pivotal clinical trials, postmarketing studies, case series and case reports); and suggested prevention and risk minimization strategies. The methodologic and practical difficulties of assessing the specific risk posed by a given agent are also discussed. IMPLICATIONS: This ESGICH consensus document constitutes not only a comprehensive overview of the molecular rationale and clinical experience on the risk of infection associated with approved targeted therapies but also an attempt to propose a series of recommendations with the purpose of guiding physicians from different disciplines into this emerging framework. PMID- 29427802 TI - Invasive aspergillosis with pulmonary and central nervous system involvement during ibrutinib therapy for relapsed chronic lymphocytic leukaemia: case report. PMID- 29427803 TI - Chlamydia trachomatis genotypes A and B from urogenital specimens of patients in Spain: molecular characterization. AB - OBJECTIVES: Chlamydia trachomatis ompA genotypes A and B, primarily associated with trachoma, were unexpectedly detected in urogenital samples of patients in Spain, a trachoma-free country. In this study, we aimed to explain this finding using analysis of organotropism-related genes and a multilocus sequence typing (MLST) technique. METHODS: C. trachomatis genotypes A or B were detected in 8/930 (0.9%) infection episodes between 2006 and 2012. In these strains, organotropism related genes (polymorphic membrane protein gene H, tryptophan synthase gene A, CTA0934, and cytotoxin) were studied. Further, the strains were analysed by MLST, using a polymerase chain reaction that amplifies five highly variable genomic loci (hctB, CT058, CT144, CT172, and pbpB). Amplicons were sequenced and phylogenetic analysis was conducted. RESULTS: Seven strains were detected in the eight infection episodes (in one patient, an identical strain being found in two episodes). Analysis of organotropism-related genes showed that these strains shared genetic features characteristic of genitotropic genotypes but not of trachoma strains. Three strains of genotype A showed a unique and new MLST sequence type (ST551, allele profile 8-8-2-27-69). The four strains of genotype B belonged to ST138. CONCLUSIONS: C. trachomatis ompA genotypes A and B associated with trachoma, but detected sporadically in urogenital samples in trachoma-free countries, may be the result of recombination between strains adapted to trachoma and strains adapted to sexual transmission. PMID- 29427805 TI - Comparison of antipseudomonal beta-lactams for febrile neutropenia empiric therapy: systematic review and network meta-analysis: authors' reply. PMID- 29427806 TI - Seminal plasma and sperm proteome of ring-tailed coatis (Nasua nasua, Linnaeus, 1766). AB - Ring-tailed coati is listed as a species of least concern in the International Union for Conservation of Nature (IUCN) Red List, however, there has been a sharp decline in their population. The present study was conducted to evaluate the major proteins of both seminal plasma and sperm in ring-tailed coatis. Semen sample was collected from three adult coatis and evaluated for their morphological characteristics. Further, the sample was centrifuged to separate spermatozoa from seminal plasma, and then stored in liquid nitrogen. The seminal plasma and sperm proteins were subjected to one-dimensional (1-D) sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and identified by mass spectrometry. Gene ontology and protein networks were analyzed using bioinformatics tools. Based on sperm concentration and average protein content of the semen, the concentration of protein/spermatozoon was found to be 104.69 +/- 44.43 MUg. The analysis of SDS-PAGE gels showed 20.3 +/- 3.1 and 17 +/- 2 protein bands/lane for seminal plasma and sperm, respectively. In-gel protein digestion and peptide analysis by mass spectrometry revealed 238 and 246 proteins in the seminal plasma and sperm, respectively. The gene ontology analysis revealed that the proteins of seminal plasma mainly participated in cellular (35%) and regulatory (21%) processes. According to their cellular localization, seminal plasma proteins were categorized as structural (18%), extracellular (17%), and nuclear (14%) proteins with molecular functions, such as catalytic activity (43%) and binding (43%). The sperm proteins were also involved in cellular (38%) and regulatory (23%) processes, and mainly categorized as extracellular (17%), nuclear (13%), and cytoplasmic (10%) proteins. The major molecular functions of the sperm proteins were catalytic activity (44%) and binding (42%). These results indicated that the seminal plasma of ring-tailed coati has an array of proteins that can potentially modulate several sperm functions, from sperm protection to oocyte binding. However, further studies are necessary to interpret the roles of these major seminal plasma proteins in coatis. PMID- 29427804 TI - ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Immune checkpoint inhibitors, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors). AB - BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies. AIMS: To review, from an infectious diseases perspective, the safety profile of immune checkpoint inhibitors, LFA-3-targeted agents, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors, and to suggest preventive recommendations. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death (PD) 1/PD-1 ligand 1 (PD-L1)-targeted agents do not appear to intrinsically increase the risk of infection but can induce immune-related adverse effects requiring additional immunosuppression. Although CD4+ T-cell lymphopenia is associated with alefacept, no opportunistic infections have been observed. Progressive multifocal leukoencephalopathy (PML) may occur during therapy with natalizumab (anti-alpha4 integrin monoclonal antibody (mAb)) and efalizumab (anti-CD11a mAb), but no cases have been reported to date with vedolizumab (anti-alpha4beta7 mAb). In patients at high risk for PML (positive anti-JC polyomavirus serology with serum antibody index >1.5 and duration of therapy >=48 months), the benefit-risk ratio of continuing natalizumab should be carefully considered. Fingolimod induces profound peripheral blood lymphopenia and increases the risk of varicella zoster virus (VZV) infection. Prophylaxis with (val)acyclovir and VZV vaccination should be considered. Proteasome inhibitors also increase the risk of VZV infection, and antiviral prophylaxis with (val)acyclovir is recommended. Anti-Pneumocystis prophylaxis may be considered in myeloma multiple patients with additional risk factors (i.e. high-dose corticosteroids). IMPLICATIONS: Clinicians should be aware of the risk of immune-related adverse effects and PML in patients receiving immune checkpoint and cell adhesion inhibitors respectively. PMID- 29427807 TI - Isolation and culture of chicken growing follicles in 2- and 3-dimensional models. AB - The isolation and culture of ovarian follicles is essential for the studies of follicular development and function. In contrast to the relative ease of culture for mammalian follicles, developing in vitro cultures of high viability for the much larger avian follicles has always proven to be more challenging. In this study, the growing follicles from domestic hens (Gallus domesticus) were isolated using enzymatic and mechanical methods and then investigated for the optimized conditions for culture. Assessments of viability and hormonal responsiveness were also considered. A larger percentage of healthy follicles was achieved by mechanical separation than enzymatic dissociation (83% vs. 55% by collagenase I or 63% by trypsin), despite a lower recovery yield for the former (126 vs. 275 by collagenase I or 261 by trypsin) from each ovary. All of the mechanically isolated follicles (800 MUm) survived when cultured in the 3-dimensional (3D) system for 7 days whereas only 93% of the follicles survived in the 2-dimensional (2D) group. Follicles cultured in the 3D system also had a higher cell proliferation rates but lower apoptotic rates as assessed by BrdU incorporation and TUNEL assays. Ultrastructural examination showed that the granulosa cells in the 3D group were organized tightly with adjacent layers in contrast to the loose attachment in the 2D system group. After treatment with follicle-stimulating hormone in the 3D culture for 3 days, the mechanically isolated follicles (800 MUm) displayed elevated mRNA expression of steroidogenic enzymes, cytokines and cell cycle-regulating proteins. The 3D culture model established in this study thus provides a useful tool for in vitro culture using growing follicles in a large diameter to study the mechanisms of growing follicle development in the avian species. PMID- 29427808 TI - Adaptive optical microscopy for neurobiology. AB - With the ability to correct for the aberrations introduced by biological specimens, adaptive optics-a method originally developed for astronomical telescopes-has been applied to optical microscopy to recover diffraction-limited imaging performance deep within living tissue. In particular, this technology has been used to improve image quality and provide a more accurate characterization of both structure and function of neurons in a variety of living organisms. Among its many highlights, adaptive optical microscopy has made it possible to image large volumes with diffraction-limited resolution in zebrafish larval brains, to resolve dendritic spines over 600MUm deep in the mouse brain, and to more accurately characterize the orientation tuning properties of thalamic boutons in the primary visual cortex of awake mice. PMID- 29427809 TI - Evaluation of the potential agricultural use of biostimulated sewage sludge using mammalian cell culture assays. AB - Among the bioremediation processes, biostimulation is an effective methodology for the decontamination of organic waste by the addition of agents that stimulate the indigenous microbiota development. Rice hull is a biostimulating agent that promotes the aeration of edaphic systems and stimulates the aerobiotic activity of soil microorganisms. The present study aimed to evaluate the efficacy of the bioremediation and biostimulation processes in reducing the toxicity of sewage sludge (SS) and to evaluate its possible application in agriculture using cytotoxic and genotoxic assays in human hepatoma cells (HepG2). SS of domestic origin was tested as both the pure product (PSS) and mixed with soil (S) and with a stimulating agent, such as rice hull (RH), in different proportions (SS + S and SS + S + RH); we also examined different remediation periods (3 months - T1 and 6 months - T2). For the PSS sample, a significant induction of micronucleus (MN) in T2 was observed with nuclear buds in all of the periods assessed, and we observed the presence of more than one alteration per cell (MN and nuclear bud) in T1 and T2. The PSS sample caused genotoxic effects in the HepG2 cells even after being bioremediated. For the samples containing soil and/or rice hull, no toxic effects were observed in the test system used. Therefore, the addition of SS to agricultural soils should be conducted with caution, and it is important that the SS undergoes a remediation process, such as bioremediation and biostimulation treatments. PMID- 29427810 TI - Developmental toxicity and neurotoxicity of synthetic organic insecticides in zebrafish (Danio rerio): A comparative study of deltamethrin, acephate, and thiamethoxam. AB - Synthetic organic insecticides, including pyrethroids, organophosphates, neonicotinoids and other types, have the potential to alter the ecosystems and many are harmful to humans. This study examines the developmental toxicity and neurotoxicity of three synthetic organic insecticides, including deltamethrin (DM), acephate (AP), and thiamethoxam (TM), using embryo-larval stages of zebrafish (Danio rerio). Results showed that DM exposure led to embryo development delay and a significant increase in embryo mortality at 24 and 48 h post-fertilization (hpf). DM and AP decreased embryo chorion surface tension at 24 hpf, along with the increase in hatching rate at 72 hpf. Moreover, DM caused ntl, shh, and krox20 misexpression in a dose-dependent manner with morphological deformities of shorter body length, smaller eyes, and larger head-body angles at 10 MUg/L. TM did not show significant developmental toxicity. Furthermore, results of larval rest/wake assay indicated that DM (>0.1 MUg/L) and AP (0.1 mg/L) increased activity behavior with different patterns. Interestingly, as an insect-specific pesticide, TM still could alter locomotor activity in zebrafish larvae at concentrations as low as 0.1 mg/L. Our results indicate that different types of synthetic organic insecticides could create different toxicity outcomes in zebrafish embryos and larvae. PMID- 29427811 TI - New cytokines and TLR pathway signaling molecules in Chinese rare minnow (Gobiocypris rarus): Molecular characterization, basal expression, and their response to chlorpyrifos. AB - In this study, the cDNA fragments of cytokines (il-8) and toll-like receptor (TLR) pathway signaling molecules (myd88, irak-1, irf5, and irf7) in the Chinese rare minnow were cloned and exhibited a high amino-acid sequence identity compared to other cyprinid fish orthologs. The mRNA expressions of these genes in the different tissues (liver, brain, spleen, kidney, and skin) were observed. The highest expression levels of myd88, irak-1, and irf5 were detected in the spleen, whereas il-8 and irf7 were detected in the kidney and liver respectively. The mRNA expression of irak-1, irf5, and irf7 in the liver from 0.1 MUg/L and 0.5 MUg/L CPF treatments were significantly increased on day 7 (p < 0.05), whereas the levels of only irak-1 and irf7 were markedly increased on day 28 (p < 0.05). Moreover, the mRNA expression of il-8 in the spleen following 0.5 MUg/L CPF treatments was significantly decreased on day 7 (p < 0.05), whereas significantly decrease were observed in the levels of irf7 in the spleen at 2.5 MUg/L CPF on days 7 and 28 (p < 0.05). The 0.1 MUg/L and 0.5 MUg/L of CPF significantly induced the levels of irak-1 and myd88 in the spleen after 28 d exposure (p < 0.05). Therefore, the high induction of cytokines and TLR pathway signaling molecules demonstrated that Chinese rare minnow was immune-compromised exposed to CPF. Moreover, our finding indicated that these immune-related genes could be feasible to screen for substances hazardous to the immune system of fish. PMID- 29427812 TI - Chronic pain and its association with obesity among older adults in China. AB - OBJECTIVES: There is a paucity of epidemiological data on chronic pain and obesity among older adults. This study attempted to present the characterization of chronic pain and its association with obesity among the Chinese elderly. METHODS: A cross-sectional survey was undertaken among 6524 elderly individuals aged >=60 years in China. Chronic pain was identified by self-reports based on the definition from the International Association for the Study of Pain (IASP). Body Mass Index (BMI) was measured to assess obesity. Binary logistic regression analysis was performed to explore the association between obesity and chronic pain. RESULTS: The prevalence of chronic pain was 49.8%. The legs/feet (25.5%), back (23.2%), and neck/shoulder (14.6%) were the most salient locations for chronic pain. Compared with normal weight, subjects with overweight (OR = 1.234, 95%CI = 1.100-1.384) and obesity (OR = 1.715, 95%CI = 1.418-2.073) were considerably more likely to have chronic pain after adjusting for covariates (p < .05). Age was not significantly associated with chronic pain (p > .05). Further analyses revealed that the associations between chronic pain and obesity were restricted to the legs/feet and back. CONCLUSION: Chronic pain is common among older adults in China. Understanding the role of obesity in chronic pain is important for preventing and treating chronic pain. PMID- 29427813 TI - Life After the Neurosurgical Ward in Sub-Saharan Africa: Neurosurgical Treatment and Outpatient Outcomes in Uganda. AB - BACKGROUND: In the past decade, neurosurgery in Uganda experienced increasing surgical volume and a new residency training program. Although research has examined surgical capacity, minimal data exist on the patient population treated by neurosurgery and their eventual outcomes in sub-Saharan Africa. METHODS: Patients admitted to Mulago National Referral Hospital neurosurgical ward over 2 years (2014 and 2015) were documented in a prospective database. In total, 1167 were discharged with documented phone numbers and thus eligible for follow-up. Phone surveys were developed and conducted in the participant's language to assess mortality, neurologic outcomes, and follow-up health care. RESULTS: During the study period, 2032 patients were admitted to the neurosurgical ward, 80% for traumatic brain injury. A total of 7.8% received surgical intervention. The in hospital mortality rate was 18%. A total of 870 patients were reached for phone follow-up, a 75% response rate, and 30-day and 1-year mortality were 4% and 8%, respectively. Almost one-half of patients had not had subsequent health care after the initial encounter. Most patients had Glasgow Outcome Scale-Extended scores consistent with good recovery and mild disability, with patients experiencing trauma faring best and patients with tumor faring worst. A total of 85% felt they returned to baseline work performance, and 76% of guardians felt that children returned to baseline school performance. CONCLUSIONS: The neurosurgical service provided health care to a large proportion of nonoperative patients. Phone surveys captured data on patients in whom nearly one-half would be lost to subsequent health care. Although mortality during initial hospitalization was high, more than 90% of those discharged survived at 1-year follow up, and the vast majority returned to work and school. PMID- 29427814 TI - Management and Survival of Adult Patients with Pilocytic Astrocytoma in the National Cancer Database. AB - BACKGROUND: Adult pilocytic astrocytomas (PAs) are relatively rare central nervous system (CNS) tumors with a favorable prognosis. We sought to investigate existing clinical management strategies and overall survival (OS) as a function of various clinical characteristics in a cohort of adult patients with PA. METHODS: The study cohort comprised all patients age >18 years diagnosed with a CNS PA diagnosed between 2004 and 2014 and included in the National Cancer Database. Clinical and treatment-related characteristics were recorded and analyzed for associations with OS following diagnosis using univariate and multivariate analyses. RESULTS: A total of 3057 adult patients, with a median age of 32 years, met the inclusion criteria. At diagnosis, 1138 patients (41%) had cerebral tumors, 832 (30%) had cerebellar tumors, 252 (9%) had tumors of the spinal cord, and 534 (19%) had tumors of unspecified location. More than three quarters (77%) of the patients underwent surgery alone as local therapy, with the remainder split among surgery plus radiation (11.9%), radiation alone (4.5%), and biopsy alone (6.9%). On multivariate analysis, factors associated with inferior OS included older age (hazard ratio [HR], 1.05; P < 0.001), lower income (P < 0.001), higher Charlson/Deyo score (P = 0.023), larger tumor size (P = 0.023), and radiation therapy technique (P < 0.001; HR, 3.37 for external beam radiation therapy [EBRT]). CONCLUSIONS: Our data provide large-scale prognostic information from a contemporary cohort of patients with PA, confirming that age, median income, Charlson/Deyo Score, and tumor size have significant effects on OS. Although resection status, tumor size, and location likely bias against EBRT, novel therapeutics are clearly needed in patients with tumors not amenable to resection or radiosurgery. PMID- 29427815 TI - Traumatic Lateral Spondyloptosis: Case Series. AB - OBJECTIVE: To apprise readers about this rare but severest form of traumatic spine injury and its surgical management. BACKGROUND: Complete fracture dislocation and subluxation (>100%) of 1 vertebral body in the coronal or sagittal plane with respect to the adjacent vertebra is defined as spondyloptosis. In coronal spondyloptosis the subluxated vertebral bodies lie beside each other, and the condition is lateraloptosis. Patients with lateraloptosis present unique surgical challenges because reduction and achieving realignment of spinal column require meticulous planning and execution. METHODS: A retrospective analysis of patients admitted with lateraloptosis over a 4-year period (2013-2016) was done. Lateraloptosis was defined on computed tomography as complete subluxation of the spinal column with more than 50% of adjacent vertebral bodies lying directly lateral to each other. RESULTS: Five men, ranging from 18 to 50 years (mean, 35.2 years) old were included in the study. Three patients had thoracic spine lateraloptosis, and in 2 the injury was at the thoracolumbar junction. All patients underwent single-stage posterior surgical reduction and fixation. Intraoperatively, cord transection was seen in 3 patients, and dural tear with cerebrospinal fluid leak was seen in 1 patient. The mean follow-up period was 14 months (range, 1-36 months), during which 1 patient died of complications arising from bedsores. All patients remained at American Spinal Injury Association grade A neurologically. CONCLUSION: Lateraloptosis is difficult to treat, and the aim of surgery is to stabilize the spine. Rehabilitation remains the most crucial factor, but the scarcity of proper rehabilitation centers results in high mortality and morbidity. PMID- 29427816 TI - Digital Footprint of Neurological Surgeons. AB - BACKGROUND: Patients are increasingly turning to online resources to inquire about individual physicians and to gather health information. However, little research exists studying the online presence of neurosurgeons across the country. This study aimed to characterize these online profiles and assess the scope of neurosurgeons' digital identities. METHODS: Medicare-participating neurologic surgeons from the United States and Puerto Rico were identified using the Centers for Medicare and Medicaid Services (CMS) Physician Comparable Downloadable File. Each physician was characterized by his or her medical education, graduation year, city of practice, gender, and affiliation with an academic institution. Using a Google-based custom search tool, the top 10 search results for each physician were extracted and categorized as 1 of the following: 1) physician, hospital, or healthcare system controlled, 2) third-party or government controlled, 3) social media-based, 4) primary journal article, or 5) other. RESULTS: Among the physicians within the CMS database, 4751 self-identified as being neurosurgeons, yielding a total of 45,875 uniform resource locator search results pertinent to these physicians. Of the 4751 neurosurgeons, 2317 (48.8%) and 2434 (51.2%) were classified as academic and nonacademic neurosurgeons, respectively. At least 1 search result was obtained for every physician. Hospital, healthcare system, or physician-controlled websites (18,206; 39.7%) and third-party websites (17,122; 37.3%) were the 2 most commonly observed domain types. Websites belonging to social media platforms accounted for 4843 (10.6%) search results, and websites belonging to peer-reviewed academic journals accounted for 1888 (4.1%) search results. The frequency with which a third-party domain appeared as the first search result was higher for nonacademic neurosurgeons than for academic neurosurgeons. CONCLUSIONS: In general, neurosurgeons lacked a controllable online presence within their first page of Google Search results. Third-party physician rating websites constituted about half of the search results, and a relative lack of social media websites was apparent. Still, numerous opportunities exist for neurosurgeons to address this disparity. PMID- 29427817 TI - National Trends for Reoperation in Older Patients with Glioblastoma. AB - BACKGROUND: Despite multimodal therapies extending patient survival, glioblastoma (GBM) recurrence is all but a certainty. To date, there are few single-center studies of reoperations. Our study aimed to assess GBM reoperation trends nationally in older patients, with emphasis on outcomes. METHODS: The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was searched to identify patients 66 years and older with GBM from 1997 to 2010. The primary outcome was survival after diagnosis. Kaplan-Meier curves and multivariate analysis with proportional hazard ratios were used. RESULTS: Three thousand nine hundred sixty-three patients with recurrent GBM who initially received a surgical resection were identified (mean age = 74.7 years). Four hundred ninety-six (12%) of the patients with recurrent GBM underwent at least one reoperation at an average of 7.2 months after the initial diagnosis. Reoperation increased survival in patients compared with those who did not have surgical resection (12 vs. 5 months; P < 0.0001; hazard ratio [HR] = 0.666). Within the reoperated cohort, gross total resection improved median survival over subtotal resection (HR = 0.779). Two or more reoperations upon GBM recurrence improved survival to 17 months (P = 0.002). The overall complication rate was 21.7% in the initial resection-only group, versus 20.4% in the 1-reoperation group and 25.3% in the 2 reoperation group. CONCLUSIONS: Although definitive conclusions cannot be made given the lack of granularity, our national database study supports gross total resection as the initial treatment of choice, followed by reoperation at the time of recurrence, if tolerated, even in older patients. PMID- 29427818 TI - Mutation-linked, excessively tight interaction between the calmodulin binding domain and the C-terminal domain of the cardiac ryanodine receptor as a novel cause of catecholaminergic polymorphic ventricular tachycardia. AB - BACKGROUND: Ryanodine receptor (RyR2) is known to be a causal gene of catecholaminergic polymorphic ventricular tachycardia (CPVT), an important inherited disease. Some of the human CPVT-associated mutations have been found in a domain (4026-4172) that has EF hand motifs, the so-called calmodulin (CaM)-like domain (CaMLD). OBJECTIVE: The purpose of this study was to investigate the underlying mechanism by which CPVT is induced by a mutation at CaMLD. METHODS: A new N4103K/+ knock-in (KI) mice model was generated. RESULTS: Sustained ventricular tachycardia was frequently observed after infusion of caffeine plus epinephrine in KI mice. Endogenous CaM bound to RyR2 decreased even at baseline in isolated KI cardiomyocytes. Ca2+ spark frequency (CaSpF) was much higher in KI cells than in wild-type cells. Addition of GSH-CaM (higher affinity CaM to RyR2) significantly decreased CaSpF. In response to isoproterenol, spontaneous Ca2+ transient (SCaT) was frequently observed in intact KI cells. Incorporation of GSH CaM into intact KI cells using a protein delivery kit decreased SCaT significantly. An assay using a quartz crystal microbalance technique revealed that mutated CaMLD peptide showed higher binding affinity to CaM binding domain (CaMBD) peptide. CONCLUSION: In the N4103K mutant, CaM binding affinity to RyR2 was significantly reduced regardless of beta-adrenergic stimulation. We found that this was caused by an abnormally tight interaction between CaMBD and mutated CaM-like domain (N4103K-CaMBD). Thus, CaMBD-CaMLD interaction may be a novel therapeutic target for treatment of lethal arrhythmia. PMID- 29427819 TI - Significance of T-wave inversion triggered by spontaneous atrial premature beats in patients with long QT syndrome. AB - BACKGROUND: In patients with the long QT syndrome (LQTS), a sudden increase in heart rate can cause T-wave alternans (TWA) with beat-to-beat alternating polarity of T wave. We hypothesized that LQTS patients at high risk for torsades de pointes (TdP) may exhibit momentary atrial or sinoatrial premature beat induced T-wave inversion (APB-TWI). OBJECTIVE: The purpose of this study was to assess the association of APB-TWI with TdP history and with microvolt TWA. METHODS: Twenty-four-hour continuous 12-lead electrocardiograms (ECGs) were recorded in 18 healthy subjects and 39 consecutive patients with LQTS types 1 (n = 21), 2 (n = 4), 3 (n = 4), and unidentified (n = 10). Peak TWA was determined by the modified moving average method. RESULTS: The 39 LQTS patients were divided into 2 groups: 10 LQTS patients with TdP history (TdP group) and 29 without (non TdP group). None of the healthy subjects showed APB-TWI, whereas 38.5% of the LQTS patients (15/39) exhibited APB-TWI. The incidences of APB-TWI and TWA >=42 MUV were significantly higher in the TdP group than in the non-TdP group (APB TWI: 80% vs 24.1%, P = .006; TWA >=42 MUV: 100% vs 65.5%, P = .04). APB-TWI was inferior in sensitivity for an association with TdP history to TWA >=42 MUV (80% vs 100%) but superior in specificity (75.9% vs 51.7%). Patients with APB-TWI exhibited significantly higher TWA values than those without [median (interquartile range) 73 (55-106.5) vs 48 (37.5-71.8) MUV, P = .02]. CONCLUSION: APB-TWI is an easily measurable ECG pattern and is strongly associated with TdP history as well as TWA >=42 MUV in LQTS patients. APB-TWI and TWA may share pathophysiological mechanisms. PMID- 29427820 TI - Techniques for successful early retrieval of the Micra transcatheter pacing system: A worldwide experience. AB - BACKGROUND: Experience with retrieval of the Micra transcatheter pacing system (TPS) is limited because of its relatively newer technology. Although abandonment of the TPS at end of life is recommended, certain situations such as endovascular infection or device embolization warrant retrieval. OBJECTIVE: The purpose of this study was to report the worldwide experience with successful retrieval of the Micra TPS. METHODS: A list of all successful retrievals of the currently available leadless pacemakers (LPs) was obtained from the manufacturer of Micra TPS. Pertinent details of retrieval, such as indication, days postimplantation, equipment used, complications, and postretrieval management, were obtained from the database collected by the manufacturer. Other procedural details were obtained directly from the operators at each participating site. RESULTS: Data from the manufacturer consisted of 40 successful retrievals of the Micra TPS. Operators for 29 retrievals (73%) provided the consent and procedural details. Of the 29 retrievals, 11 patients underwent retrieval during the initial procedure (immediate retrieval); the other 18 patients underwent retrieval during a separate procedure (delayed retrieval). Median duration before delayed retrieval was 46 days (range 1-95 days). The most common reason for immediate retrieval was elevated pacing threshold after tether removal. The most common reasons for delayed retrieval included elevated pacing threshold at follow-up, endovascular infection, and need for transvenous device. Mean procedure duration was 63.11 +/- 56 minutes. All retrievals involved snaring via a Micra TPS delivery catheter or steerable sheath. No serious complications occurred during the reported retrievals. CONCLUSION: Early retrieval of the Micra TPS is feasible and safe. PMID- 29427821 TI - Image-based criteria to identify the presence of epicardial arrhythmogenic substrate in patients with transmural myocardial infarction. AB - BACKGROUND: Patients with transmural myocardial infarction (MI) who undergo endocardial-only substrate ablation are at increased risk for ventricular tachycardia recurrence. Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) can be used to assess infarct transmurality (IT). However, the degree of IT associated with an epicardial arrhythmogenic substrate (AS) has not been determined. OBJECTIVE: The purpose of this study was to determine the degree of IT observed by LGE-CMR and multidetector computed tomography (MDCT) that predicts the presence of epicardial AS. METHODS: The study included 38 post-MI patients. Ten patients with a subendocardial infarction underwent endocardial-only mapping, and 28 with a classic transmural MI (C-TMI), defined as hyperenhancement >=75% of myocardial wall thickness (WT), underwent endo-epicardial mapping. LGE-CMR/MDCT data were registered to high-density endocardial or epicardial maps to be analyzed for the presence of AS. RESULTS: Of the 28 post-MI patients with C-TMI, 18 had epicardial AS (64%) and 10 (36%) did not. An epicardial scar area >=14 cm2 on LGE-CMR identified patients with epicardial AS (sensitivity 1, specificity 1). Mean WT in the epicardial scar area in these patients was lower than in patients without epicardial AS (3.14 +/- 1.16 mm vs 5.54 +/- 1.78 mm; P = .008). A mean WT cutoff value <=3.59 mm identified patients with epicardial AS (sensitivity 0.91, specificity 0.93). CONCLUSION: An epicardial scar area >=14 cm2 on LGE-CMR and mean CT-WT <=3.59 mm predict epicardial AS in post-MI patients. PMID- 29427822 TI - Large-vessel involvement and aortic dilation in giant-cell arteritis. A multicenter study of 549 patients. AB - OBJECTIVES: Large-vessel involvement (LVI) can occur in giant-cell arteritis (GCA) and may represent a distinct disease subgroup with a higher risk for aortic dilation. This study aimed to better characterize the presentation and evolution of LVI in patients with GCA. PATIENTS AND METHODS: A retrospective multicenter study enrolled 248 GCA patients with LVI and 301 GCA patients without LVI on imaging. Factors associated with aortic dilation were identified in a multivariable model. RESULTS: The patients with LVI were younger (p<0.0001), more likely to be women (p=0.01), and showed fewer cephalic symptoms (p<0.0001) and polymyalgia rheumatica (p=0.001) but more extracranial vascular symptoms (p=0.05) than the patients without LVI. Glucocorticoids (GC) management did not differ between the two groups, but the GC discontinuation rate was lower in the patients with LVI (p=0.0003). Repeated aortic imaging procedures were performed at 19months [range: 5-162months] and 17months [range: 6-168months] after diagnosis in 154 patients with LVI and 123 patients without LVI, respectively, of whom 21% and 7%, respectively, presented new aortic dilations (p=0.0008). In the patients with LVI, aortic dilation occurred on an aorta segment shown to be inflammatory on previous imaging in 94% of patients. In the multivariate analysis, LVI was the strongest predictor of aortic dilation (hazard ratio: 3.16 [range: 1.34-7.48], p=0.009). CONCLUSIONS: LVI represents a distinct disease pattern of GCA with an increased risk of aortic dilation. Control of the aortic morphology during follow up is required. PMID- 29427824 TI - Comment on the article entitled "Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome" (Autoimmunity Reviews 16 (2017) 1036-1043). PMID- 29427825 TI - Beyond APECED: An update on the role of the autoimmune regulator gene (AIRE) in physiology and disease. AB - The autoimmune regulator gene (AIRE) is a transcription factor expressed both in the thymus, by medullary thymic epithelial cells, and in secondary lymphoid organs. AIRE controls the local transcription of organ- specific proteins typically expressed in peripheral tissues, thus allowing the negative selection of self- reactive T cells. The crucial role played by AIRE in central immune tolerance emerged in the studies on the pathogenesis of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy, a rare inherited polyendocrine/autoimmune disease. Thereafter, several studies found evidences indicating that AIRE impairment might be pathogenically involved in several autoimmune diseases and in tumorigenesis. In this review, we focus on recent advances relative to AIRE's effect on T cell development in physiology and disease. In particular, we address the following issues: 1) AIRE function and mTECs biology, 2) the impact of AIRE gene mutations in autoimmune diseases, and 3) the role of AIRE gene in anti-tumor immune response. PMID- 29427823 TI - Contribution of diagnostic tests for the etiological assessment of uveitis, data from the ULISSE study (Uveitis: Clinical and medicoeconomic evaluation of a standardized strategy of the etiological diagnosis). AB - PURPOSE: ULISSE is the only study that prospectively assessed the efficiency of a standardized strategy, compared to an open strategy for the etiologic diagnosis of uveitis. Our aim was to evaluate the diagnostic yield of the tests prescribed in the ULISSE study to clarify their relevance. METHODS: ULISSE is a non inferiority, prospective, multicenter and cluster randomized study. The standardized strategy is a two-steps strategy: in the first step, common standard tests were performed, and in the second step, tests were guided by the clinical and anatomic type of uveitis. We reported the relevance of the diagnostic tests used in the standardized strategy, as well as the profitability of the tests that were prescribed to more than twenty patients in each group. Based on diagnostic criteria, either an ophthalmologist, or an internist, established the profitability of a test by considering whether the test lead to a diagnosis or not. RESULTS: Among the 676 patients included (standardized 303; open 373), a diagnosis was made for 152 (50.4%) in the standardized group and 203 (54.4%) in the open group. The most common entities were HLA-B27 associated uveitis (22%), spondyloarthritis (11%), sarcoidosis (18%), tuberculosis (10.7%) and herpes virus infections (8.5%). Among the first step's systematic tests, tuberculin skin test was the most contributive investigation (17.1%), followed by chest X-ray (8.4%), C reactive protein and ESR (6.6% and 5.1%), complete blood count (2.2%) and VDRL (2.0%). The second step's most often contributive tests were: HLA B27 (56.3%), chest-CT (30.3%) and angiotensin converting enzyme (ACE) (16.5%). HLA B27 and ACE were significantly more contributive in the standardized group than in the open group. Immunological tests were never contributive. Among the free investigations, or among the investigations guided by clinical or paraclinical findings, the most often contributive tests were: Quantiferon(r) (24%), electrophoresis of serum protein (7.8%) and sacroiliac imagery (46.4%). Intracellular serologies (1.7%), serum calcium (2.1%) and hepatic tests (3.3%) were exceptionally contributive. Among the third intention tests, labial salivary gland biopsies were contributive in 17.9% of cases, but the profitability of other invasive investigations (anterior chamber tap, vitrectomy, bronchoscopy and lumbar puncture) or specialized imagery (18F-FDG PET, Brain MRI) could not be determined since these test were rarely performed. CONCLUSION: Only a few diagnostic tests are useful for the etiological assessment of uveitis. They are often cheap, simple, more often guided by the clinical findings, and lead to an etiological diagnosis in most patients. On the other hand, some tests are never or exceptionally contributive, such as immunological tests or intracellular serologies. Further studies are required to evaluate the profitability of third intention imagery and invasive investigations. PMID- 29427826 TI - Tocilizumab and refractory Takayasu disease: Four case reports and systematic review. AB - BACKGROUND: Relapses upon corticosteroids tapering and immunosuppressive agents are frequent in Takayasu arteritis (TA). Interleukin-6 is highly involved in physiopathology of TA. Many reports showed efficacy of tocilizumab (TCZ) in refractory TA cases. We report four cases and an updated literature review on the TCZ efficacy and safety in patients with TA. METHODS: Patients with TA defined by ACR 1990 criteria were included. Clinical, biological and imaging data were retrospectively reported. Disease activity was analyzed before TCZ and during the follow-up. Medline database was searched for systematic literature review. RESULTS: One hundred and five patients (median age 28years [22-38]) were included, mostly refractory cases (76 patients, 72%). Median TCZ duration was 12months [6-20]. Among 105 patients, 90 patients (85.7%) had an initial clinical response within three months [3-6] and 43/66 patients (65.2%) had a radiological improvement. Only seven patients (9%) showed relapse on therapy. Corticosteroid dose reduction was obtained in 75/83 patients (90.4%). Relapse after TCZ discontinuation was observed in six patients (46%), with a median time of five months [2-9]. Twenty-four side-effects were noted in 18 patients (18%), with TCZ interruption in seven cases (7%): 10 infections, five cytopenia, six hepatitis, one pancreatitis, one cutaneous rash and one breast cancer. CONCLUSIONS: This review confirms that TCZ is safe and effective in refractory cases of TA and TCZ is a corticosteroid-sparing therapy in patients with or without previous TNFalpha blockers therapy. However relapses after TCZ discontinuation are frequent. PMID- 29427827 TI - Nailfold capillaroscopy in systemic lupus erythematosus: A systematic review and critical appraisal. AB - Nailfold capillaroscopy is an easy, non-invasive technique to assess microvascular involvement in rheumatic diseases. Multiple studies describe capillaroscopic changes in systemic lupus erythematosus (SLE), including a wide range of non-specific findings. On behalf of the European League Against Rheumatism (EULAR) study group on microcirculation in rheumatic diseases, a systematic review was done to obtain all original research studies (in English) in which SLE patients had capillaroscopy. Forty such studies are identified. This article firstly provides a resume of the results of these studies according to capillaroscopic parameters (density, dimensions, morphology, haemorrhages), semi quantitative assessment and qualitative assessment of capillaroscopy in SLE patients. Secondly, the correlations between capillaroscopic parameters in SLE patients and clinical and laboratory parameters (including auto-immune parameters) are outlined. The following capillaroscopic parameters are found to be significantly more prevalent in SLE patients compared to healthy controls: tortuous capillaries, abnormal morphology and haemorrhages. Hairpin-shaped capillaries are significantly less prevalent than in healthy persons. The semi quantitatively determined nailfold capillaroscopic score (NFC score) in SLE patients is also higher than in healthy controls. Several correlations between clinical and laboratory parameters and capillaroscopic parameters are identified in the review. Disease activity is correlated with NFC score in seven studies, with abnormal morphology (i.e. "meandering") in one study and with haemorrhages in one study. Frequent attacks of Raynaud's phenomenon (RP) and gangrene are significantly correlated with dilated capillaries. In two studies a possible correlation between anti-SSA antibodies and lower density of capillaries is withheld. About other immune parameters conflicting results are found. In one study a significant negative correlation is found between 24-hour proteinuria and abnormal morphology (i.e. "meandering"). For the first time, an overview of the nailfold capillaroscopic changes that have been described in SLE and their correlations with clinical and laboratory findings is given. Further large-scale research on the identification of capillaroscopic changes in SLE and their correlations with standardised clinical and laboratory parameters, is ongoing at the EULAR study group on microcirculation in rheumatic diseases. PMID- 29427828 TI - An alcohol withdrawal test battery measuring multiple behavioral symptoms in mice. AB - Despite acceptance that risk for alcohol-use disorder (AUD) has a large genetic component, the identification of genes underlying various components of risk for AUD has been hampered in humans, in part by the heterogeneity of expression of the phenotype. One aspect of AUD is physical dependence. Alcohol withdrawal is a serious consequence of alcohol dependence with multiple symptoms, many of which are seen in multiple species, and can be experienced over a wide-ranging time course. In the present three studies, we developed a battery of withdrawal tests in mice, examining behavioral symptoms from multiple domains that could be measured over time. To permit eventual use of the battery in different strains of mice, we used male and female mice of a genetically heterogeneous stock developed from intercrossing eight inbred strains. Withdrawal symptoms were assessed using commonly used tests after administration of ethanol in vapor for 72 continuous hours. We found significant effects of ethanol withdrawal versus air-breathing controls on nearly all symptoms, spanning 4 days following ethanol vapor inhalation. Withdrawal produced hypothermia, greater neurohyperexcitability (seizures and tremor), anxiety-like behaviors using an apparatus (such as reduced transitions between light and dark compartments), anhedonia (reduced sucrose preference), Straub tail, backward walking, and reductions in activity; however, there were no changes in thermal pain sensitivity, hyper-reactivity to handling, or anxiety-like emergence behaviors in other apparatus. Using these data, we constructed a refined battery of withdrawal tests. Individual differences in severity of withdrawal among different tests were weakly correlated at best. This battery should be useful for identifying genetic influences on particular withdrawal behaviors, which should reflect the influences of different constellations of genes. PMID- 29427829 TI - Alcohol-naive USVs distinguish male HAD-1 from LAD-1 rat strains. AB - Ultrasonic vocalizations (USVs) are mediated through specific dopaminergic and cholinergic neural pathways and serve as real-time measures of positive and negative emotional status in rodents. Although most USV studies focus primarily on USV counts, each USV possesses a number of characteristics shown to reflect activity in the associated neurotransmitter system. In the present study, we recorded spontaneously emitted USVs from alcohol-naive high alcohol drinking (HAD 1) and low alcohol drinking (LAD-1) rats. Using our recently developed WAAVES algorithm, we quantified four acoustic characteristics (mean frequency, duration, power, and bandwidth) from each 22-28 kHz and 50-55 kHz frequency-modulated (FM) USV. This rich USV representation allowed us to apply advanced statistical techniques to identify the USV acoustic characteristics that distinguished HAD-1 from LAD-1 rats. Linear mixed models (LMM) examined the predictability of each USV characteristic in isolation and linear discriminant analysis (LDA), and binomial logistic regression examined the predictability of linear combinations of the USV characteristics as a group. Results revealed significant differences in acoustic characteristics between HAD-1 and LAD-1 rats in both 22-28 kHz and 50 55 kHz FM USVs. In other words, these rats selectively bred for high- and low alcohol consumption can be identified as HAD-1 or LAD-1 rats with high classification accuracy (approximately 92-100%) exclusively based on their emitted 22-28 kHz and 50-55 kHz FM USV acoustic characteristics. In addition, acoustic characteristics of 22-28 kHz and 50-55 kHz FM USVs emitted by alcohol naive HAD-1 and LAD-1 rats significantly correlate with their future alcohol consumption. Our current findings provide novel evidence that USV acoustic characteristics can be used to discriminate between alcohol-naive HAD-1 and LAD-1 rats, and may serve as biomarkers in rodents with a predisposition for, or against, excessive alcohol intake. PMID- 29427830 TI - Characterization of AHR2 and CYP1A expression in Atlantic sturgeon and shortnose sturgeon treated with coplanar PCBs and TCDD. AB - Atlantic sturgeon and shortnose sturgeon co-occur in many estuaries along the Atlantic Coast of North America. Both species are protected under the U.S. Endangered Species Act and internationally on the IUCN Red list and by CITES. Early life-stages of both sturgeons may be exposed to persistent aromatic hydrocarbon contaminants such as PCBs and PCDD/Fs which are at high levels in the sediments of impacted spawning rivers. Our objective was to compare the PCBs and TCDD sensitivities of both species with those of other fishes and to determine if environmental concentrations of these contaminants approach those that induce toxicity to their young life-stages under controlled laboratory conditions. Because our previous studies suggested that young life-stages of North American sturgeons are among the more sensitive of fishes to coplanar PCB and TCDD-induced toxicities, we were interested in identifying the molecular bases of this vulnerability. It is known that activation of the aryl hydrocarbon receptor 2 (AHR2) in fishes mediates most toxicities to these contaminants and transcriptional activation of xenobiotic metabolizing enzymes such as cytochrome P4501A (CYP1A). Previous studies demonstrated that structural and functional variations in AHRs are the bases for differing sensitivities of several vertebrate taxa to aromatic hydrocarbons. Therefore, in this study we characterized AHR2 and its expression in both sturgeons as an initial step in understanding the mechanistic bases of their sensitivities to these contaminants. We also used CYP1A expression as an endpoint to develop Toxicity Equivalency Factors (TEFs) for these sturgeons. We found that critical amino acid residues in the ligand binding domain of AHR2 in both sturgeons were identical to those of the aromatic hydrocarbon-sensitive white sturgeon, and differed from the less sensitive lake sturgeon. AHR2 expression was induced by TCDD (up to 6-fold) and by three of four tested coplanar PCB congeners (3-5-fold) in Atlantic sturgeon, but less so in shortnose sturgeon. We found that expression of AHR2 and CYP1A mRNA significantly covaried after exposure to TCDD and PCB77, PCB81, PCB126, but not PCB169 in both sturgeons. We also determined TEFs for the four coplanar PCBs in shortnose sturgeon based on comparison of CYP1A mRNA expression across all doses. Surprisingly, the TEFs for all four coplanar PCBs in shortnose sturgeon were much higher (6.4-162 times) than previously adopted for fishes by the WHO. PMID- 29427831 TI - Australian nursing students' knowledge and attitudes towards pressure injury prevention: A cross-sectional study. AB - AIM: The aim of this study was to assess student nurses' knowledge of and attitudes towards pressure injury prevention evidence-based guidelines. BACKGROUND: Pressure injuries are a substantial problem in many healthcare settings causing major harm to patients, and generating major economic costs for health service providers. Nurses have a crucial role in the prevention of pressure injuries across all health care settings. DESIGN: A multi-centered, cross-sectional study was conducted using a paper-based questionnaire with undergraduate nursing students enrolled in seven universities with campuses across five Australian states (Queensland, New South Wales, Western Australia, Victoria and Tasmania). METHODS: Data were collected from nursing students using two validated instruments (Pressure Ulcer Knowledge Assessment Instrument and Attitude Toward Pressure Ulcer Prevention Instrument), to measure students' pressure injury prevention knowledge and attitudes. RESULTS: Students reported relatively low pressure injury prevention knowledge scores (51%), and high attitude scores (78%). Critical issues in this study were nursing students' lack of knowledge about preventative strategies to reduce the amount and duration of pressure/shear, and lower confidence in their capability to prevent pressure injury. Level of education and exposure to working in a greater number of different clinical units were significantly related to pressure injury prevention knowledge and attitude scores. CONCLUSION: The study findings highlight the need to implement a comprehensive approach to increasing Australian nursing students' pressure injury prevention and management knowledge, as well as ensuring that these students have adequate experiences in clinical units, with a high focus on pressure injury prevention to raise their personal capability. PMID- 29427832 TI - Violence towards Emergency Nurses. The Italian National Survey 2016: A qualitative study. AB - INTRODUCTION: Physical and verbal aggression against health professionals, particularly nurses, is globally serious and widespread, with the most vulnerable being nurses working in the Accident and Emergency Department. Most international research into this issue focused on quantifying aggression, describing its nature, identifying perpetrators, stratifying risk and implementing preventive or mitigating interventions. Few studies investigated the nurses' subjective perceptions. As part of the 2016 Italian National Survey on Violence against Accident and Emergency Nurses, our research team collected qualitative data to explore their perceptions of Workplace Violence. METHODS: From 19th July 2016 to 19th March 2017 we distributed online a 39-item validated questionnaire to 15,618 Emergency Nurses working in 668 Italian National Health Service Accident and Emergency Departments in all 20 Italian Regions. Answers were analysed using van Kaan's method. RESULTS: 1100 Emergency Nurses responded to the survey and 265 replied to our focus question. There were 144 Females, 119 Males, 2 not stated, average age 42 +/- 9 years, average work experience 18 +/- 9 years, average Accident and Emergency Department experience 11 +/- 8 years. Four major themes emerged: the nurses' perception of physical and verbal aggression, precipitating factors, consequences, and solutions. DISCUSSION: These themes confirmed previous findings and showed that Italian nursing staff's perceptions of physical and verbal aggression is the same as emergency nurses working worldwide. CONCLUSION: How Italian Accident and Emergency nurses perceive Workplace Violence adds to our knowledge of the issue and contributes to finding shared solutions. PMID- 29427833 TI - Neurodevelopmental outcomes in newborns with neonatal seizures caused by rotavirus-associated leukoencephalopathy. AB - PURPOSE: Rotavirus infection has recently been reported to be associated with seizures accompanied by leukoencephalopathy in newborns. We aimed to determine long-term outcomes and prognostic factors in newborns with neonatal seizures caused by rotavirus-associated leukoencephalopathy. METHODS: We retrospectively reviewed the records and brain magnetic resonance (MR) images of 32 patients who fulfilled the following criteria: (1) neonatal seizures, (2) distinctive symmetric cerebral white matter lesions on diffusion-weighted MR images (DWI), (3) rotavirus infection, (4) absence of a specific etiology of seizures, except for the aforementioned DWI lesions, and (5) Korean Bayley Scales of Infant Development II (K-BSID-II) assessment after 12 months of age. RESULTS: The mean age at seizure onset was 4.7 +/- 0.8 days. The median age of the patients at the time of K-BSID-II assessment was 22 months. Fourteen patients (43.8%) showed normal or accelerated performance in the mental and motor scales, while 18 patients (56.2%) had delayed performance in the mental and/or motor scales. Seven patients (21.9%) had significantly delayed performances on the mental and/or motor scales. The percentage of volume of diffusion-restricted lesions based on total brain volume was significantly negatively correlated with the mental developmental index (MDI) score (r = -0.507, p = .003), but not with the psychomotor developmental index (PDI) score (r = -0.324, p = .071). CONCLUSIONS: Rotavirus-associated leukoencephalopathy in newborns around 5 days of age can cause adverse neurodevelopmental outcomes with a wide range of severity. The extent of white matter lesion on initial DWI can predict neurocognitive outcome. PMID- 29427834 TI - Safety of antiepileptic drugs in children and young people: A prospective cohort study. AB - PURPOSE: This study aims to describe the incidence of adverse drug reactions (ADRs) in children receiving antiepileptic drugs (AEDs) and compare ADRs to the individual drugs when given as monotherapy. METHOD: Paediatric patients (<=18 years old) were enrolled for this prospective observational study over a 6-month period, between September 2015 and March 2016. Adverse reactions to antiepileptic drugs (AEDs) were elicited at the time of enrolment and after 3 months using the Paediatric Epilepsy Side Effects Questionnaire. RESULTS: A total of 1139 suspected ADRs were reported in 124 participants. Eighteen different AEDs were prescribed. Sixty-six children (53%) were receiving AED monotherapy at the time of recruitment; 34/66 (52%) of whom received new generation AEDs. Levetiracetam was the most frequently prescribed AED (62/124, 50%). When only children receiving AED monotherapy were considered, fatigue, drowsiness, weight gain, dizziness were less likely with levetiracetam (p < .01). Slow thinking and decreased concentration were less likely with levetiracetam or carbamazepine than valproic acid (p < .05). Five patients (four on polytherapy) discontinued AED treatment due to ADRs and 2 had a dose reduction. CONCLUSIONS: Levetiracetam and carbamazepine were better tolerated than sodium valproate. PMID- 29427835 TI - Phenytoin-related ataxia in patients with epilepsy: clinical and radiological characteristics. AB - PURPOSE: Phenytoin is an effective anticonvulsant for focal epilepsy. Its use can be associated with long-term adverse effects including cerebellar ataxia. Whilst phenytoin is toxic to Purkinje cells in vitro; the clinical and radiological phenotype and mechanism of cerebellar degeneration in vivo remain unclear. We describe the prevalence, clinical and radiological characteristics of phenytoin related ataxia. METHODS: Patients with epilepsy receiving treatment with phenytoin were recruited from the Epilepsy clinics at Royal Hallamshire Hospital, Sheffield, UK. Neurological examination was performed on all patients after recruitment. Patients were categorised into those with and without ataxia. We determined the severity of ataxia clinically (SARA score) and the pattern of cerebellar involvement by neuroimaging (MRI volumetry and MR spectroscopy). RESULTS: Forty-seven patients were recruited. Median duration of epilepsy was 24 years, median duration of phenytoin treatment was 15 years and current median phenytoin daily dose was 325 mg. Fifty-five percent of patients complained of poor balance. Clinical evidence of ataxia was seen in 40% patients. Gait, stance and heel-shin slide were the predominant features of cerebellar dysfunction. MRI demonstrated structural, volumetric and functional deficits of the cerebellum. Only one patient with ataxia had phenytoin levels above the normal range. CONCLUSIONS: Cerebellar ataxia is present in 40% of patients with epilepsy and chronic exposure to phenytoin. Patients on long-term phenytoin have reduced cerebellar volume even if they have no clinical evidence of ataxia. Evidence of structural deficits on imaging suggests a predilection for vermian involvement. PMID- 29427836 TI - DNM1 encephalopathy - atypical phenotype with hypomyelination due to a novel de novo variant in the DNM1 gene. PMID- 29427837 TI - A Deep Hidden Diversity of Dictyostelia. AB - Dictyostelia is a monophyletic group of transiently multicellular (sorocarpic) amoebae, whose study is currently limited to laboratory culture. This tends to favour faster growing species with robust sorocarps, while species with smaller more delicate sorocarps constitute most of the group's taxonomic breadth. The number of known species is also small (~150) given Dictyostelia's molecular depth and apparent antiquity (>600 myr). Nonetheless, dictyostelid sequences are rarely recovered in culture independent sampling (ciPCR) surveys. We developed ciPCR primers to specifically target dictyostelid small subunit (SSU or 18S) rDNA and tested them on total DNAs extracted from a wide range of soils from five continents. The resulting clone libraries show mostly dictyostelid sequences (~90%), and phylogenetic analyses of these sequences indicate novel lineages in all four dictyostelid families and most genera. This is especially true for the species-rich Heterostelium and Dictyosteliaceae but also the less species-rich Raperosteliaceae. However, the most novel deep branches are found in two very species-poor taxa, including the deepest branch yet seen in the highly divergent Cavenderiaceae. These results confirm a deep hidden diversity of Dictyostelia, potentially including novel morphologies and developmental schemes. The primers and protocols presented here should also enable more comprehensive studies of dictyostelid ecology. PMID- 29427838 TI - A Re-investigation of Sarcinochrysis marina (Sarcinochrysidales, Pelagophyceae) from its Type Locality and the Descriptions of Arachnochrysis, Pelagospilus, Sargassococcus and Sungminbooa genera nov. AB - Systematists increasingly use molecular markers to identify species; however, most microalgae were described before gene sequencing and type specimens were often ink drawings. Cryptic speciation and biogeographic isolation are other potential problems when anchoring an old species name with a modern gene sequence. Therefore when biological type material is absent, the best approach is to recollect the alga from the type locality and sequence genes. Sarcinochrysis marina, described in 1930 by Geitler from the Canary Islands, Spain, is the oldest Pelagophyceae genus. Geitler used two cultures in his study, but these cultures no longer exist. We re-isolated S. marina from the type locality near Las Palmas, Gran Canaria. Furthermore, we included additional Pelagophyceae strains that were isolated from natural habitats for this study or were obtained from culture collections. We produced 85 sequences, representing the nuclear encoded SSU rRNA and the plastid-encoded rbcL, psaA, psaB, psbA, and psbC genes. The sequences were used to infer maximum likelihood phylogenetic trees. We anchored the name Sarcinochrysis marina using the Las Palmas isolate, and we described four new genera (Arachnochrysis, Pelagospilus, Sargassococcus, Sungminbooa) and nine new species in the Sarcinochrysidales. We also described a new family, Chrysocystaceae, based upon molecular phylogenetic analyses. PMID- 29427839 TI - Single-cell RNA sequencing reveals metallothionein heterogeneity during hESC differentiation to definitive endoderm. AB - Differentiation of human pluripotent stem cells towards definitive endoderm (DE) is the critical first step for generating cells comprising organs such as the gut, liver, pancreas and lung. This in-vitro differentiation process generates a heterogeneous population with a proportion of cells failing to differentiate properly and maintaining expression of pluripotency factors such as Oct4. RNA sequencing of single cells collected at four time points during a 4-day DE differentiation identified high expression of metallothionein genes in the residual Oct4-positive cells that failed to differentiate to DE. Using X-ray fluorescence microscopy and multi-isotope mass spectrometry, we discovered that high intracellular zinc level corresponds with persistent Oct4 expression and failure to differentiate. This study improves our understanding of the cellular heterogeneity during in-vitro directed differentiation and provides a valuable resource to improve DE differentiation efficiency. PMID- 29427840 TI - Generation of patient-specific induced pluripotent stem cells from Leber's hereditary optic neuropathy. AB - Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease caused by homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. In this report, we generated an induced pluripotent stem cell (iPSCs) line, TVGH-iPSC-010-09, from the peripheral blood mononuclear cells of a female patient with Leber's hereditary optic neuropathy (LHON) by using the Sendai-virus delivery system. The resulting iPSCs retained the disease causing mitochondrial DNA mutation, expressed pluripotent markers and could differentiate into the three germ layers. We believe LHON patient-specific iPSCs provide a powerful in vitro model for evaluating the pathological phenotypes of the disease. PMID- 29427841 TI - A novel type of activation function in artificial neural networks: Trained activation function. AB - Determining optimal activation function in artificial neural networks is an important issue because it is directly linked with obtained success rates. But, unfortunately, there is not any way to determine them analytically, optimal activation function is generally determined by trials or tuning. This paper addresses, a simpler and a more effective approach to determine optimal activation function. In this approach, which can be called as trained activation function, an activation function was trained for each particular neuron by linear regression. This training process was done based on the training dataset, which consists the sums of inputs of each neuron in the hidden layer and desired outputs. By this way, a different activation function was generated for each neuron in the hidden layer. This approach was employed in random weight artificial neural network (RWN) and validated by 50 benchmark datasets. Achieved success rates by RWN that used trained activation functions were higher than obtained success rates by RWN that used traditional activation functions. Obtained results showed that proposed approach is a successful, simple and an effective way to determine optimal activation function instead of trials or tuning in both randomized single and multilayer ANNs. PMID- 29427842 TI - Deep neural network for traffic sign recognition systems: An analysis of spatial transformers and stochastic optimisation methods. AB - This paper presents a Deep Learning approach for traffic sign recognition systems. Several classification experiments are conducted over publicly available traffic sign datasets from Germany and Belgium using a Deep Neural Network which comprises Convolutional layers and Spatial Transformer Networks. Such trials are built to measure the impact of diverse factors with the end goal of designing a Convolutional Neural Network that can improve the state-of-the-art of traffic sign classification task. First, different adaptive and non-adaptive stochastic gradient descent optimisation algorithms such as SGD, SGD-Nesterov, RMSprop and Adam are evaluated. Subsequently, multiple combinations of Spatial Transformer Networks placed at distinct positions within the main neural network are analysed. The recognition rate of the proposed Convolutional Neural Network reports an accuracy of 99.71% in the German Traffic Sign Recognition Benchmark, outperforming previous state-of-the-art methods and also being more efficient in terms of memory requirements. PMID- 29427843 TI - Design of nonlinear optimal control for chaotic synchronization of coupled stochastic neural networks via Hamilton-Jacobi-Bellman equation. AB - This paper presents a new theoretical design of nonlinear optimal control on achieving chaotic synchronization for coupled stochastic neural networks. To obtain an optimal control law, the proposed approach is developed rigorously by using Hamilton-Jacobi-Bellman (HJB) equation, Lyapunov technique, and inverse optimality, and hence guarantees that the chaotic drive network synchronizes with the chaotic response network influenced by uncertain noise signals. Furthermore, the paper provides four numerical examples to demonstrate the effectiveness of the proposed approach. PMID- 29427845 TI - Duloxetine loaded-microemulsion system to improve behavioral activities by upregulating serotonin and norepinephrine in brain for the treatment of depression. AB - Duloxetine is a well-known antidepressant molecule which is used in the treatment of depression but due to poor solubility it suffers with the drawback of low oral bioavailability. The objective of present work was to formulate and characterize duloxetine loaded microemulsion to enhance the oral bioavailability. Prepared microemulsion was studied for droplet size, zeta potential, refractive index, polydispersity index (PDI), percentage transmittance, viscosity and in vitro release study. Optimized microemulsion (D1) showed spherical droplets with mean diameter of 35.40 +/- 3.11 nm, PDI of 0.170 and zeta potential values of -25.8 mV. Formulation showed good transmittance (greater than 99%), viscosity (0.205 Pa s) and refractive index (1.43 +/- 0.01). Increased duloxetine release was obtained with microemulsion in comparison to drug suspension. Behavioral tests like mobility test, tail suspension test and forced swimming test performed in depressed and treated rats with duloxetine microemulsion significantly improved the behavioral activities in comparison to duloxetine suspension. Pharmacokinetic studies showed that microemulsion exhibited 1.8 times increment in bioavailability in comparison to duloxetine suspension. PMID- 29427844 TI - Seasonality of cerebrospinal fluid monoamine metabolite concentrations and their associations with meteorological variables in humans. AB - Seasonal variations in neurotransmitter parameters have been previously reported in humans. However, these studies have involved small sample sizes and have not examined possible relationships with meteorological variables. We compared cerebrospinal fluid (CSF) concentrations of the major monoamine neurotransmitter metabolites (5-HIAA, HVA, and MHPG) in 188 healthy controls (80 men, 108 women) in relationship to age, sex, BMI, and available meteorological variables. All subjects had a lumbar puncture (LP) performed at 9 a.m. after overnight stay. Meteorological data for the day prior to LP were obtained from the National Climatic Association and included the photoperiod, percent sunshine, temperature (max, min, mean), barometric pressure, relative humidity, amount of precipitation and sky cover. Results revealed differences across seasons and cross-seasons for CSF 5-HIAA (p <= .05), with post-hoc differences emerging between spring versus summer and fall and between x-spring and x-summer (p <= .05). Differences were also found across seasons for CSF HVA (p <= .05) with post-hoc differences between spring versus fall. CSF 5-HIAA was significantly inversely correlated with maximum (r = -.28, p <= .02), minimum (r = -.24, p <= .04), and mean temperature (r = -.28, p <= .02) in men. In women, 5-HIAA (r = -.22, p <= .02) and HVA (r = -.28, p <= .003) were significantly correlated with relative humidity. These data confirm previous findings of variations in serotonin and dopamine metabolites across the year and highlight possible underlying mechanisms involving meteorological changes, which may result in alterations in neurophysiology and behavior. PMID- 29427846 TI - Cooperation makes two less-creative individuals turn into a highly-creative pair. AB - This study aimed to investigate which type of group (e.g., consisting of less creative or highly-creative individuals) would perform better in solving creativity problems, and explore the underlying inter-brain neural correlates between team members. A preliminary test (an alternative-uses task) was performed to rank individuals' level of creativity, and divide participants into three types of dyads: high-high (two highly-creative individuals), low-low (two less creative individuals), and high-low (one highly-creative and one less-creative individual). Dyads were then asked to solve a realistic presented problem (RPP; a typical creativity problem) during which a functional near-infrared spectroscopy (fNIRS)-based hyperscanning device was used to record the variation of interpersonal brain synchronization (IBS). Results revealed that less-creative individuals, while working together, would perform as well as highly-creative individuals. The low-low dyads showed higher levels of cooperation behaviour than the other two types of dyads. The fNIRS results revealed increased IBS only for low-low dyads at PFC (prefrontal cortex) and rTPJ (right temporal-parietal junction) brain regions during RPP task performance. In the rDLPFC (right dorsolateral prefrontal cortex), the IBS in the low-low dyads was stronger than that of high-high and high-low dyads. In the rTPJ, the IBS in the low-low dyads was only stronger than that of the high-low dyads. Besides, the IBS at rDLPFC and rTPJ regions in the low-low dyads was positively correlated with their cooperation behaviour and group creative performance. These findings indicated when two less-creative individuals worked on a creativity problem together, they tended to cooperate with each other (indicated by both behaviour index and increased IBS at rDLPFC and rTPJ), which benefited their creative performance. PMID- 29427847 TI - Computationally optimized ECoG stimulation with local safety constraints. AB - Direct stimulation of the cortical surface is used clinically for cortical mapping and modulation of local activity. Future applications of cortical modulation and brain-computer interfaces may also use cortical stimulation methods. One common method to deliver current is through electrocorticography (ECoG) stimulation in which a dense array of electrodes are placed subdurally or epidurally to stimulate the cortex. However, proximity to cortical tissue limits the amount of current that can be delivered safely. It may be desirable to deliver higher current to a specific local region of interest (ROI) while limiting current to other local areas more stringently than is guaranteed by global safety limits. Two commonly used global safety constraints bound the total injected current and individual electrode currents. However, these two sets of constraints may not be sufficient to prevent high current density locally (hot spots). In this work, we propose an efficient approach that prevents current density hot-spots in the entire brain while optimizing ECoG stimulus patterns for targeted stimulation. Specifically, we maximize the current along a particular desired directional field in the ROI while respecting three safety constraints: one on the total injected current, one on individual electrode currents, and the third on the local current density magnitude in the brain. This third set of constraints creates a computational barrier due to the huge number of constraints needed to bound the current density at every point in the entire brain. We overcome this barrier by adopting an efficient two-step approach. In the first step, the proposed method identifies the safe brain region, which cannot contain any hot-spots solely based on the global bounds on total injected current and individual electrode currents. In the second step, the proposed algorithm iteratively adjusts the stimulus pattern to arrive at a solution that exhibits no hot-spots in the remaining brain. We report on simulations on a realistic finite element (FE) head model with five anatomical ROIs and two desired directional fields. We also report on the effect of ROI depth and desired directional field on the focality of the stimulation. Finally, we provide an analysis of optimization runtime as a function of different safety and modeling parameters. Our results suggest that optimized stimulus patterns tend to differ from those used in clinical practice. PMID- 29427849 TI - Luminance-polarity distribution across the symmetry axis affects the electrophysiological response to symmetry. AB - Electrophysiological studies of symmetry have found a difference wave termed the Sustained Posterior Negativity (SPN) related to the presence of symmetry. Yet the extent to which the SPN is modulated by luminance-polarity and colour content is unknown. Here we examine how luminance-polarity distribution across the symmetry axis, grouping by luminance polarity, and the number of colours in the stimuli, modulate the SPN. Stimuli were dot patterns arranged either symmetrically or quasi-randomly. There were several arrangements: 'segregated'-symmetric dots were of one polarity and randomly-positioned dots were of the other; 'unsegregated' symmetric dots were of both polarities in equal proportions; 'anti-symmetric' dots were of opposite polarity across the symmetry axis; 'polarity-grouped anti symmetric'-this is the same as anti-symmetric but with half the pattern of one polarity and the other half of opposite polarity; multi-colour symmetric patterns made of two, three to four colours. We found that the SPN is: (i) reduced by the amount of position-symmetry, (ii) sensitive to luminance-polarity mismatch across the symmetry axis, and (iii) not modulated by the number of colours in the stimuli. Our results show that the sustained nature of the SPN coincides with the late onset of a topographic microstate sensitive to symmetry. These findings emphasise the importance of not only position symmetry, but also luminance polarity matching across the symmetry axis. PMID- 29427850 TI - Integration of visual and non-visual self-motion cues during voluntary head movements in the human brain. AB - Our phenomenological experience of the stable world is maintained by continuous integration of visual self-motion with extra-retinal signals. However, due to conventional constraints of fMRI acquisition in humans, neural responses to visuo vestibular integration have only been studied using artificial stimuli, in the absence of voluntary head-motion. We here circumvented these limitations and let participants to move their heads during scanning. The slow dynamics of the BOLD signal allowed us to acquire neural signal related to head motion after the observer's head was stabilized by inflatable aircushions. Visual stimuli were presented on head-fixed display goggles and updated in real time as a function of head-motion that was tracked using an external camera. Two conditions simulated forward translation of the participant. During physical head rotation, the congruent condition simulated a stable world, whereas the incongruent condition added arbitrary lateral motion. Importantly, both conditions were precisely matched in visual properties and head-rotation. By comparing congruent with incongruent conditions we found evidence consistent with the multi-modal integration of visual cues with head motion into a coherent "stable world" percept in the parietal operculum and in an anterior part of parieto-insular cortex (aPIC). In the visual motion network, human regions MST, a dorsal part of VIP, the cingulate sulcus visual area (CSv) and a region in precuneus (Pc) showed differential responses to the same contrast. The results demonstrate for the first time neural multimodal interactions between precisely matched congruent versus incongruent visual and non-visual cues during physical head-movement in the human brain. The methodological approach opens the path to a new class of fMRI studies with unprecedented temporal and spatial control over visuo vestibular stimulation. PMID- 29427848 TI - Targeting alpha-band oscillations in a cortical model with amplitude-modulated high-frequency transcranial electric stimulation. AB - Non-invasive brain stimulation to target specific network activity patterns, e.g. transcranial alternating current stimulation (tACS), has become an essential tool to understand the causal role of neuronal oscillations in cognition and behavior. However, conventional sinusoidal tACS limits the ability to record neuronal activity during stimulation and lacks spatial focality. One particularly promising new tACS stimulation paradigm uses amplitude-modulated (AM) high frequency waveforms (AM-tACS) with a slow signal envelope that may overcome the limitations. Moreover. AM-tACS using high-frequency carrier signals is more tolerable than conventional tACS, e.g. in terms of skin irritation and occurrence of phosphenes, when applied at the same current intensities (e.g. 1-2 mA). Yet, the fundamental mechanism of neuronal target-engagement by AM-tACS waveforms has remained unknown. We used a computational model of cortex to investigate how AM tACS modulates endogenous oscillations and compared the target engagement mechanism to the case of conventional (unmodulated) low-frequency tACS. Analysis of stimulation amplitude and frequency indicated that cortical oscillations were phase-locked to the envelope of the AM stimulation signal, which thus exhibits the same target engagement mechanism as conventional (unmodulated) low frequency tACS. However, in the computational model substantially higher current intensities were needed for AM-tACS than for low-frequency (unmodulated) tACS waveforms to achieve pronounced phase synchronization. Our analysis of the carrier frequency suggests that there might be a trade-off between the use of high-frequency carriers and the stimulation amplitude required for successful entrainment. Together, our computational simulations support the use of slow envelope high frequency carrier AM waveforms as a tool for noninvasive modulation of brain oscillations. More empirical data will be needed to identify the optimal stimulation parameters and to evaluate tolerability and safety of both, AM- and conventional tACS. PMID- 29427851 TI - The effect of grazing system intensification on the growth and meat quality of beef cattle in the Brazilian Atlantic Forest biome. AB - This study was carried out to evaluate the effects of four levels of intensification of grazing systems: 1) degraded pasture - DP; 2) irrigated pasture with high stocking rate - IHS; 3) dryland pasture with high stocking rate - DHS; 4) dryland pasture with moderate stocking rate - DMS; on growth, muscle development and meat quality of Nellore steers (271+/-2.2kg of live body weight - BW; 15months old) during two consecutive periods (17 and 15months). The final BW, the average daily BW gain, the hot carcass weight and the dress percentage were greater (P<0.0001), and the ribeye area tended to be greater (P=0.085), in the intensified systems compared to the degraded system. Animals in all systems presented similar back fat. Muscle development increased with the intensification of the grazing systems and meat quality was not affected. PMID- 29427852 TI - Effects of aging/freezing sequence and freezing rate on meat quality and oxidative stability of pork loins. AB - The aim of this study was to evaluate the effect of aging/freezing sequence and freezing rate on quality attributes and oxidative stability of frozen/thawed pork loins (M. longissimus lumborum, n = 6). Six treatments were prepared by combining 3 aging/freezing sequences (FT, freezing/thawing only; AFT, aging prior to freezing/thawing; and FTA, freezing/thawing and aging) with 2 freezing rates (slow- and fast-freezing). The lowest purge/thaw loss and drip loss were found for AFT, in which fast-freezing reduced total exudate loss (P < 0.05). Aging combination (AFT/FTA) decreased shear force of frozen/thawed pork loins, and FTA with slow-freezing caused the lowest shear force (P < 0.05). However, aging combination regardless of the sequence accelerated discoloration and lipid/protein oxidation during display (P < 0.05). This study suggests that aging prior to freezing coupled with fast-freezing could be an effective way to minimize quality defects of frozen/thawed only meat, particularly water-holding capacity and tenderness. PMID- 29427853 TI - Effect of long term chilled (up to 5 weeks) then frozen (up to 12 months) storage at two different sub-zero holding temperatures on beef: 3. Protein structure degradation and a marker of protein oxidation. AB - Different chilled (~0.1 degrees C for up to 5 weeks) then frozen storage (up to 12 months) combinations and two frozen storage holding temperatures (-12 degrees C and -18 degrees C) effects on beef M. longissimus lumborum (LL) protein structure degradation and a marker of protein oxidation were tested. Particle size (PS) analysis and protein solubility results found storage combination effects on protein degradation to be significant (P < 0.05), although the influence of frozen holding temperatures was negligible. LL carbonyl, and nitrate and nitrite content responses were variable and yet broadly reflected an increased incidence of protein oxidation across increasing chilled storage and ensuing frozen storage periods - this aspect meriting future exploration. Total myoglobin content and the estimated myoglobin redox fractions (metmyoglobin, deoxymyoglobin, and oxymyoglobin) were also subject to storage treatment. These findings demonstrate the capacity for beef storage selection (chilled-then frozen) to manage compositional protein changes and its implications on sensory quality traits across comparative 'long term' durations. PMID- 29427854 TI - Decreased resistance of sublethally injured Escherichia coli O157:H7 to salt, mild heat, nisin and acids induced by high pressure carbon dioxide. AB - Resistance of sublethally injured cells (SICs) of Escherichia coli O157:H7 induced by high pressure carbon dioxide (HPCD) to salt, low temperature, mild heat, nisin, acids and low pHs was investigated in this study. The SICs of E. coli were obtained following HPCD at 5 MPa and 25 degrees C for 40-60 min or 5 MPa and 45 degrees C for 20 min. The untreated cells could survive normally while the HPCD-treated cells showed 2.87 log10 cycles' reduction on tryptic soy agar (TSA) with 3% NaCl. The counts of the untreated cells were not significantly changed during 5 h incubation at 4 degrees C or 40 min incubation at 45 degrees C, and the HPCD-treated cells were also not affected by 5 h incubation at 4 degrees C but showed 1.75 log10 cycles' reduction at 45 degrees C for 40 min. The antimicrobial nisin caused an extra 0.25-1.0 log10 cycles' reduction of the HPCD-treated cells while the untreated cells was not inactivated by nisin. Except for oxalic acid (OA), citric acid (CA), malic acid (MA), tartaric acid (TA), lactic acid (LA), acetic acid (AA) and hydrochloric acid (HCl) did not inactivate the untreated cells, but all these seven acids caused a 0.74-1.53 log10 cycles' reduction of HPCD-treated cells. These results indicated that HPCD-induced SICs had a decreased resistance to salt, mild heat, nisin and acids. Moreover, the recovery test was used to investigate the sensitivity of the SICs to different pHs. Results showed that the SICs could not recover below or equal to pH 4.0. These promising results would open up the possibility of exploring the combination of other technologies (eg. mild heat, nisin and acids) with HPCD as hurdle approaches to inactivate target pathogens in foods. PMID- 29427855 TI - Fungal synthesis of chiral phosphonic synthetic platform - Scope and limitations of the method. AB - Chiral hydroxyphosphonates due to their wide range of biological properties are industrially important chemicals. Chemical synthesis of their optical isomers is expensive, time consuming and not friendly to the environment, so biotransformations are under consideration. Among others, these compounds act as enzymes inhibitors. This makes the bioconversions of phosphonates, especially scaling experiments, hard to perform. Biocatalysis is one of the methods that can be applied in synthesis of optically pure compounds. To increase the efficiency of the process with whole cell biocatalysts, it is essential to ensure optimal reaction conditions that minimize cellular stress and can enhance the metabolic activity of cells. The present investigation focuses on the scaling up of the kinetic resolution of racemic mixture of 2-butyryloxy-2-(ethoxy-P phenylphosphinyl)acetic acid, applying free and immobilized form of the fungal biocatalysts and two operation systems: shake flask and recirculated fixed-bed batch reactor. Protocols of effective mycelium immobilization on polyurethane foams were set for T. purpurogenus IAFB 2512, F. oxysporum, P. commune. The best results of biotransformation were obtained with the immobilized P. commune in the column recirculated fixed-bed batch reactor. The conversion reaches 56% (maximal for the kinetic process) and the enantiomeric enrichment of the isomers mixture ranges between 82 and 93% (93% for ester of RP,R conformation). All biocatalysts exhibit SP-preference toward tested compound, what is essential because of importance of the phosphorus atom chirality for its biological activity. PMID- 29427856 TI - New anticancer drug candidates sulfonamides as selective hCA IX or hCA XII inhibitors. AB - In this study, new 4-[3-(aryl)-5-substitutedphenyl-4,5-dihydro-1H-pyrazole-1 yl]benzensulfonamides (19-36) were synthesized and evaluated their cytotoxic/anticancer and CA inhibitory effects. According to results obtained, the compounds 34 (4-[5-(2,3,4-trimethoxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H pyrazole-1-yl] benzensulfonamide, Potency-Selectivity Expression (PSE) = 141) and 36 (4-[5-(3,4,5-trimethoxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1 yl]benzensulfonamide, PSE = 54.5) were found the leader anticancer compounds with the highest PSE values. In CA inhibitory studies, the compounds 36 and 24 (4-[5 (3,4,5-trimethoxyphenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1 yl]benzensulfonamide) were found the leader CA inhibitors depending on selectivity ratios. The compound 36 was a selective inhibitor of hCA XII isoenzyme (hCA I/hCA XII = 1250 and hCA II/hCA XII = 224) while the compound 24 was a selective inhibitor of hCA IX isoenzyme (hCA I/hCA IX = 161 and hCA II/hCA IX = 177). The compounds 24, 34, and 36 can be considered to develop new anticancer drug candidates. PMID- 29427857 TI - Alkynyl and beta-ketophosphonates: Selective and potent butyrylcholinesterase inhibitors. AB - A series of thirty-three alkynyl and beta-ketophosphonates were evaluated for their in vitro acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitory activities using Ellman's spectrophotometric method. None of the examined compounds inhibited AChE activity at tested concentrations while twenty-nine of them showed significant and selective inhibition of BChE with IC50 values between 38.60 uM and 0.04 uM. In addition, structure-activity relationships were discussed. The most effective inhibitors were the dibutyl o-methoxyphenyl alkynylphosphonate 3dc and dibutyl o-methoxyphenyl beta-ketophosphonate 4dc. Activities of most potent compounds were also compared with a commercial organophosphorus compound. These results could inspire the design of new inhibitors with stronger activity against BChE. PMID- 29427858 TI - Spatiotemporal and kinematic characteristics of gait initiation across a wide speed range. AB - BACKGROUND: Gait initiation can be performed at a range of speeds. Those with disability tend to use a slower speed compared to those without disability. In assessing the spatiotemporal and kinematic characteristics of gait initiation it is therefore important to consider the effects of speed on outcomes. RESEARCH QUESTION: What is the effect of speed of performance on spatiotemporal and kinematic characteristics of gait initiation? METHODS: Spatiotemporal and kinematic characteristics were measured across a wide range of speeds from very slow to very fast (normalised initiating leg (swing or SW limb) step speed 0.1 0.5) for 20 health adults (10 men/10 women, 22-44 years) using three-dimensional motion analysis of the first two steps of gait. RESULTS: Mixed linear modelling of 295 walking trials indicated differences between individuals, sexes and strong non-linear relationships between normalised initiating leg step speed and cadence and step lengths (R2 > 0.5). Particular characteristics of joint kinematics (maxima and minima for both initiating (SW) and contralateral limb (stance or ST limb)) demonstrated significant non-linear (squared, cubic and power law) changes with speed. Moderate to strong relationships were identified for sagittal plane pelvis, hip and knee kinematics as well as hip adduction (0.3 < R2 < 0.7). SIGNIFICANCE: Gait initiation spatiotemporal and kinematic characteristics were quantified across the maximum range of speeds achievable, providing comprehensive characterisation of changes with speed. Significant, non-linear changes with speed were identified, suggesting different strategies are employed to modify speed at low and high speeds. The highlighted changes with speed illustrate the importance of taking speed into account when comparing outcomes between healthy adults and those with pathology. PMID- 29427859 TI - Preliminary concurrent validity of the Fitbit-Zip and ActiGraph activity monitors for measuring steps in people with polymyalgia rheumatica. AB - BACKGROUND: Activity monitors provide objective measurements of physical activity, however, the accuracy of these devices in people with polymyalgia rheumatica (PMR) is unknown. Therefore, this study aimed to obtain preliminary evidence of the accuracy of two activity monitors and explore if clinical and gait-related factors altered device accuracy in people with PMR. METHODS: The ActiGraph with low frequency extension (+LFE) and standard (-LFE) algorithms, Fitbit-Zip (waist) and Fitbit-Zip (shirt) were concurrently tested using a two minute walk test (2MWT) and stairs test in 27 people with PMR currently treated with prednisolone. To determine accuracy, activity monitor step-count was compared to a gold-standard step-count (GSSC; calculated from video recording) using Bland-Altman plots. RESULTS: The Fitbit-Zip (waist) achieved closest agreement to the GSSC for the 2MWT (mean bias (95%CI): 10 (-3, 23); 95%LOA: -55, 74). The ActiGraph (+LFE) achieved closest agreement to the GSSC for the stairs test (mean bias (95%CI): 0 (-1, 1); 95%LOA: -5, 5). The ActiGraph (-LFE) performed poorly in both tests. All devices demonstrated reduced accuracy in participants with lower gait velocity, reduced stride length, longer double-limb support phase and greater self-reported functional impairment. CONCLUSION: Our preliminary results suggest that in controlled conditions, the Fitbit-Zip fairly accurately measures step-count during walking in people with PMR receiving treatment. However, device error was greater than data published in healthy people. The ActiGraph may not be recommended without activation of the LFE. We identified clinical and gait-related factors associated with higher levels of functional impairment that reduced device accuracy. Further work is required to evaluate the validity of the activity monitors in field conditions. PMID- 29427860 TI - Health care expenditures of overweight and obese U.S. adults with intellectual and developmental disabilities. AB - BACKGROUND: U.S. adults with intellectual and developmental disabilities (IDD) have poorer health status and greater risks for being overweight and obese, which are major drivers of health care expenditures in the general population. Health care expenditures and IDD have not been studied using nationally representative samples, and the impact of overweight and obesity have not been examined. AIM: Using nationally representative data, we aimed to compare the health care expenditures of not-overweight, overweight and obese U.S. adults with IDD, and calculate model-adjusted expenditures. METHODS AND PROCEDURES: Pooled data from the 2002-2011 Medical Expenditure Panel Survey linked to National Health Interview Survey (n = 1224) were analyzed. Two-part model regressions were conducted, with covariates being year of survey, age, sex, race/ethnicity, household income status, geographical region, urban/rural, marital status, insurance coverage, perceived health status, and perceived mental health status. OUTCOMES AND RESULTS: Overall, obese adults with intellectual and developmental disabilities had higher expenditures than their non-obese peers. Being obese was associated with an estimated additional $2516 in mean expenditures and $1200 in median expenditures compared with the reference group, who were neither overweight nor obese. CONCLUSIONS AND IMPLICATIONS: Obesity is an important predictor of higher health care costs among community-living adults with IDD Finding effective strategies and interventions to address obesity in this population has great financial and policy significance. PMID- 29427861 TI - Removal of aqueous Cr(VI) by a magnetic biochar derived from Melia azedarach wood. AB - Magnetic biochar (MMABC) prepared from Melia azedarach wood was used for aqueous Cr(VI) removal. MMABC was a mesoporous material with SBET 5.219 m2/g and superparamagnetic magnetization 17.3 emu/g contributed by the contained Fe3O4. The MMABC showed higher removal efficiency (99.8%) than biochar under conditions of dosage 5 g/L, pH = 3.0, and Cr(VI) concentration 10 mg/L. The saturation magnetization (16.1emg/g) of MMABC still remained after adsorption. According to FTIR and Raman results, the benzene-ring adjacent carbonyl did not showed obvious positive effects on Cr(VI) removal. A potential mechanism and corresponding apparent kinetic model indicated the Cr(VI) removal process by MMABC followed adsorption-reduction-adsorption steps. Cr(VI) was firstly adsorbed on surface and subsequently reduced to Cr(III), which was further adsorbed on MMABC surface. Langmuir isotherm (with maximal adsorption capacity of 25.27 mg/g) and pseudo second-order kinetic model were suitable for adsorption step. PMID- 29427862 TI - Using a tubular photosynthetic microbial fuel cell to treat anaerobically digested effluent from kitchen waste: Mechanisms of organics and ammonium removal. AB - Anaerobically digested effluent from kitchen waste (ADE-KW) was used herein as the substrate of a tubular photosynthetic microbial fuel cell (PMFC) for power production, and also, after being diluted, as a medium for cultivation of algae in the cathodic chamber. Adding 3 mg/L phosphorus to the catholyte could efficiently enhance the algal growth and the PMFC performance. About 0.94 g/L algal biomass and 0.57 kWh/m3-ADE-KW bioelectricity were obtained from the PMFC. Soluble microbial byproduct-like material and aromatic proteins were the dominant organics in the ADE-KW, which were readily degradable in the system. About 79% of the 1550 mg/L ammonium in the anolyte transferred to the catholyte through the cation exchange membrane. The ammonium was removed mainly as electron acceptors at the cathode after being oxidized by oxygen, whereas algal assimilation only account for about 14.6% of the overall nitrogen. PMID- 29427863 TI - The influence of the filtration membrane air-cathode biofilm on wastewater treatment. AB - The aim of this work was to evaluate the influence of FMA biofilm on nutrient removal through the filtration membrane air-cathode (FMA) replacement test. The result showed that the biofilm accounted for only 29.9% of the COD removal, while 82.9% of the TN removal can be due to the contribution of the FMA biofilm. The microbial community analysis showed that most of the primary genus in the FMA biofilm were TN removal related bacteria. This quantitative determination of the FMA biofilm influence on COD and TN removal would promote the further optimization of the MFC reactor with FMA for higher wastewater treatment efficiency. PMID- 29427864 TI - Seneca Valley Virus 3Cpro abrogates the IRF3- and IRF7-mediated innate immune response by degrading IRF3 and IRF7. AB - Seneca Valley Virus (SVV) is a newly emerged virus belonging to the family Picornaviridae. Basic knowledge of the immunological response to SVV is limited. To date, one study has demonstrated that SVV 3Cpro mediates the cleavage of host MAVS, TRIF, and TANK at specific sites and consequently escapes the host's antiviral innate immunity. In this study, we show that SVV 3Cpro reduces IRF3 and IRF7 protein expression level and phosphorylation. SVV infection also reduces expression of IRF3 and IRF7 protein. The degradation of IRF3 and IRF7 is dependent on the 3Cpro protease activity. We also identify interactions between 3Cpro and IRF3 and IRF7 in PK-15 cells. A detailed analysis revealed that the degradation of IRF3 and IRF7 blocks the transcription of IFN-beta, IFN-alpha1, IFN-alpha4, and ISG54. Together, our results demonstrate a novel mechanism developed by SVV 3Cpro to allow the virus to escape the host's intrinsic innate immune system. PMID- 29427866 TI - Laterality recognition of images, motor performance, and aspects related to pain in participants with and without wrist/hand disorders: An observational cross sectional study. AB - OBJECTIVE: Musculoskeletal disorders are associated with altered sensory, proprioceptive and cognitive processes. Sensory processes affect the internal cortical representation of the body in space, the body schema, which in turn influences motor control. The purpose of this study was to determine if participants with wrist/hand disorders had impaired performance on a task associated with the body schema, the Left/Right Judgement Task (LRJT) and secondly how LRJT performance, motor performance, disability, pain and related aspects are associated. METHODS: Fifteen healthy control participants and 15 participants with hand/wrist pain were asked to determine the laterality of images of hands. Measures of motor performance (Purdue Pegboard test), self reported disability (Australian Canadian Hand Index), and pain related aspects (pain intensity, symptom duration, pain interference and affective distress) were recorded. RESULTS: Participants with wrist/hand pain scored lower on all segments of the Purdue Pegboard test. There were differences in LRJT performance between groups for both Accuracy (p = 0.03) and Reaction Time (RT) (p < 0.01). There was no correlation between RT and Accuracy with pain intensity, pain duration, and disability. Both motor performance (r = 0.58-0.64) and LRJT performance Accuracy (r = 0.59) and RT (r = -0.56) were correlated with affective distress. A significant correlation was observed between RT and motor performance in healthy control participants (r = -0.56, p = 0.03) but not in participants with wrist/hand pain (r = -0.26, p = 0.44). CONCLUSIONS: LRJT and motor performance was correlated with affective distress in participants with wrist/hand pain suggestive of complex interactions between cognitive-affective processes and sensorimotor integration. PMID- 29427865 TI - Expression of the cervical carcinoma expressed PCNA regulatory (CCEPR) long noncoding RNA is driven by the human papillomavirus E6 protein and modulates cell proliferation independent of PCNA. AB - Modulation of expression of noncoding RNAs is an important aspect of the oncogenic activities of high-risk human papillomavirus (HPV) E6 and E7 proteins. While HPV E6/E7-mediated alterations of microRNAs (miRNAs) has been studied in detail there are fewer reports on HPV-mediated dysregulation of long noncoding RNAs (lncRNAs). The cervical carcinoma expressed PCNA regulatory (CCEPR) lncRNA is highly expressed in cervical cancers and expression correlates with tumor size and patient outcome. We report that CCEPR is a nuclear lncRNA and that HPV16 E6 oncogene expression causes increased CCEPR expression through a mechanism that is not directly dependent on TP53 inactivation. CCEPR depletion in cervical carcinoma cell lines reduces viability, while overexpression enhances viability. In contrast to what was published and inspired its designation, there is no evidence for PCNA mRNA stabilization, and hence CCEPR likely functions through a different mechanism. PMID- 29427867 TI - Neck muscle vibration produces diverse responses in balance and gait speed between individuals with and without neck pain. AB - BACKGROUND: Neck muscle vibration can influence cervical proprioception and sensorimotor function. It is hypothesized to affect motor performance differently in persons with and without neck pain. STUDY DESIGN: Cross-sectional study. OBJECTIVE: To clarify the extent to which vibration-induced motor responses of neck muscles affect static standing balance and gait speed in persons with and without neck pain. METHODS: Thirty participants with chronic neck pain and 30 healthy controls were recruited. Balance and gait were measured before and after 30 s of suboccipital neck muscle vibration. Balance was measured in a confortable stance with eyes closed using a swaymeter and gait using the timed 10 m walk test. RESULTS: At baseline, neck pain participants had greater postural sway, particularly in the anterior-posterior direction and slower gait speed than healthy controls (p < 0.001). Immediately after vibration, neck pain participants displayed decreased postural sway, and increased gait speed (p < 0.001). Healthy controls had increased postural sway and decreased gait speed (p < 0.001). CONCLUSION: Neck muscle vibration improved standing balance and gait speed in participants with neck pain but reduced performance in healthy controls. The study supports the importance of cervical proprioceptive information in postural control. Use of vibration could be considered neck pain patients' rehabilitation. PMID- 29427868 TI - Acquired factor V deficiency in a patient with myeloma and amyloidosis. AB - INTRODUCTION: We describe our experience with managing an unusual case of acquired Factor V deficiency (aFVd) in a myeloma patient with demonstrated amyloidosis. METHODS: Following diagnosis, records of previous investigations were sought. Specific clotting factors and inhibitors were tested. The clinical progress and treatment response measured by serial factor V levels and coagulation parameters was then prospectively tracked. RESULTS: A 57 year-old woman presented with spontaneous right knee haemarthrosis in association with bilateral symmetrical polyneuropathy and proteinuria. Coagulation screen showed prolongation of both PT (18.6 s, normal range [9.9-11.4 s]) and aPTT (41.4 s, normal range [25.7-32.9 s]), which were both fully correctable following a mixing study. Liver function, fibrinogen, clotting factor II/VIII/X assays and disseminated intravascular coagulopathy screen was normal. FV level was reduced (19%, normal range [70-170%]). Inhibitor titer was undetectable. Congenital FVd was excluded as her previous coagulation screen was normal. Bone marrow investigation performed for suspected underlying plasma cell dyscrasia showed 60% neoplastic plasma cells. Congo red staining was positive for amyloid within vascular walls of the marrow trephine. She was diagnosed with light chain myeloma and aFVd. She received Bortezomib/Cyclophosphamide/Dexamethasone (VCD) chemotherapy. After one cycle of VCD, serum kappa free light chain (SFLC) was reduced from 6951 mg/L to 3354 mg/L with serial measurements of FV levels showing increment to 76% and normalization of PT/aPTT. CONCLUSION: Plasma cell dyscrasia with amyloidosis should be sought as a cause for aFVD, in particular one where bleeding manifestation is profound even with the absence of demonstrable inhibitors. PMID- 29427869 TI - Performance of four diagnostic approaches to depression in adults with cancer. AB - OBJECTIVE: The potentially confounding influence of somatic symptoms in identifying depression in medically ill patients has long been of concern, resulting in several proposed alternative diagnostic approaches. These approaches have been compared in the cancer setting, but the strengths and weaknesses of the alternative approaches have rarely been examined. The purpose of the current study was to examine the performance of four approaches to depression assessment among ambulatory cancer patients. METHOD: Outpatients were recruited from a large cancer center (N = 611). Participants had to be 40 years or older, English speaking, and have a cancer diagnosis. All participants completed a sociodemographic questionnaire and a modified Patient Health Questionnaire-9 with additional items targeting the Endicott and Cavanaugh substitutive criteria. RESULTS: Depression prevalence varied significantly by diagnostic approach, with the inclusive approach identifying the largest proportion as depressed (9.3%, n = 57), followed by the Endicott-substitutive (6.2%, n = 38), exclusive (4.6%, n = 28), and Cavanaugh-substitutive approach (1.8%, n = 11). Somatic items were significantly elevated across all four approaches. CONCLUSIONS: The inclusive approach that retains use of somatic symptoms is appropriate when screening cancer patients for depression. The fact that somatic symptoms were more prevalent across approaches suggests that they may not inflate the prevalence of depression as much as some have feared. Rather, somatic items may explain variance in depressive symptoms beyond that explained by the presence of cancer and its treatment. Additionally, the Endicott items appeared useful for capturing depressive symptoms that are not included in the existing DSM criteria, and may have a place in clinical and research settings. PMID- 29427871 TI - Reproduction in the freshwater crustacean Asellus aquaticus along a gradient of radionuclide contamination at Chernobyl. AB - Nuclear accidents such as Chernobyl and Fukushima have led to contamination of the environment that will persist for many years. The consequences of chronic low dose radiation exposure for non-human organisms inhabiting contaminated environments remain unclear. In radioecology, crustaceans are important model organisms for the development of environmental radioprotection. Previous laboratory studies have demonstrated deleterious effects of radiation exposure on crustacean reproduction. However, no studies have documented the effects of chronic radiation exposure on the reproduction of natural crustacean populations. Based on data from laboratory exposures, we hypothesised that populations of the freshwater isopod Asellus aquaticus exposed to radiation for thirty years at Chernobyl would display reduced reproductive output and altered timing of reproduction. To test this hypothesis, A. aquaticus was collected from six lakes at Chernobyl over two years with total dose rates ranging from 0.06-27.1MUGy/h. No significant differences in the fecundity, mass of broods or proportion of reproducing female A. aquaticus were recorded. Significant differences in the body mass of gravid females were recorded suggesting different timings of reproduction, however this was not related to radiation contamination. No significant effect of a range of environmental parameters on A. aquaticus reproduction was recorded. Our data suggests current dose rates at Chernobyl are not causing discernible effects on the reproductive output of A. aquaticus. This study is the first to assess the effects of chronic low-dose radiation exposure on the reproductive output of an aquatic invertebrate at Chernobyl. These findings are consistent with proposed radiological protection benchmarks for the maintenance of wildlife populations and will assist in management of environments impacted by radiation. PMID- 29427870 TI - The use of prescription medication in 239 patients with multiple functional somatic syndromes. AB - OBJECTIVE: To describe the use of prescription drugs and their association with patient characteristics in patients with multiple functional somatic syndromes (FSS) focusing on drugs generally recommended and not recommended in FSS treatment. METHOD: Using data from a national prescription registry, we describe the drug use during a two-year period for 239 trial participants. Using regression models, we analyse the associations of patient characteristics with the patterns of use of antidepressants, anticonvulsants, opioids and sedatives. RESULTS: The use of prescription drugs was highly heterogeneous. Antidepressants were used at least temporarily by 34% (88/239), anticonvulsants by 7% (16/239), opioids by 26% (61/239) and sedatives by 20% (47/239) of the patients. Severe impairment due to multiple FSS was associated with use of opioids or sedatives (OR 6.49 (95% CI 2.68-15.68; p < 0.001)) but also with use of antidepressants or anticonvulsants (OR 3.42 (95% CI 1.35-8.65; p = 0.009)). Poor self-reported physical health, additional physical comorbidities and low socioeconomic status were associated with use of opioids or sedatives only. CONCLUSION: Antidepressants and anticonvulsants were modestly used. Opioids and sedatives were especially used by the severely affected patients. Balancing treatment expectations and enhancing patients' understanding of FSS may direct treatments towards more generally recommended drugs. PMID- 29427872 TI - Integrating novel (thermophilic aerobic membrane reactor-TAMR) and conventional (conventional activated sludge-CAS) biological processes for the treatment of high strength aqueous wastes. AB - A combination of thermophilic aerobic membrane reactor (TAMR) and conventional activated sludge (CAS) was studied by means of two pilot plants at semi industrial scale in order to simulate the new configuration adopted in a full scale facility for the treatment of high strength aqueous wastes. Aqueous wastes with high contents of organic pollutants were treated by means of the TAMR technology, progressively increasing the organic load (3-12 kgCOD m-3 d-1). A mixture of municipal wastewater and thermophilic permeate was fed to the CAS plant. The main results are the following: achievement of a high COD removal yield by both the TAMR (78%) and the CAS (85%) plants; ammonification of the organic nitrogen under thermophilic conditions and subsequent mesophilic nitrification; capacity of the downstream mesophilic process to complete the degradation of the organic matter partially obtained by the TAMR process and precipitation of phosphorus as vivianite and carbonatehydroxylapatite in the TAMR plant. PMID- 29427873 TI - Marsilea spp.-A novel source of lignocellulosic biomass: Effect of solubilized lignin on anaerobic biodegradability and cost of energy products. AB - The present study concerns the liquefying potential of an unusual source of lignocellulosic biomass (Marsilea spp., water clover, an aquatic fern) during combinative pretreatment. The focus was on how the pretreatment affects the biodegradability, methane production, and profitability of thermochemical dispersion disintegration (TCDD) based on liquefaction and soluble lignin. The TCDD process was effective at 12,000 rpm and 11 min under the optimized thermochemical conditions (80 degrees C and pH 11). The results from biodegradability tests imply that 30% liquefaction was sufficient to achieve enhanced biodegradability of about 0.280 g-COD/g-COD. When biodegradability was >30% inhibition was observed (0.267 and 0.264 g-COD/g-COD at 35-40% liquefaction) due to higher soluble lignin release (4.53-4.95 g/L). Scalable studies revealed that achievement of 30% liquefaction was beneficial in terms of the energy and cost benefit ratios (0.956 and 1.02), when compared to other choices. PMID- 29427874 TI - Effect of nutrients on the growth and physiological features of newly isolated Haematococcus pluvialis TMU1. AB - The vegetative growth of Haematococcus pluvialis TMU1 was studied under batchwise cultivation in three common media, namely BBM, BG11, and 3NBBM. The BBM provided the best condition for the algal growth. It was further studied at different levels of nitrate and phosphate as macronutrients as well as iron and boron as trace elements. The dose-response of the algal growth to these macro/micronutrients was modeled with Monod/hormetic-type kinetics. Applying the modified BBM with 3-fold higher phosphate led to the highest cell density and up to 86% increase in the growth rate. At an inoculum size of 2 * 105 cells mL-1, the algal growth rate in BBM containing either 0.185 mM boron or 0.046 mM iron was higher than the medium containing half or twice ion levels. These optimal concentrations depend on inoculum size, so that changes from the optima increased the level of peroxide signaling molecules and induced defense pathways. PMID- 29427875 TI - Co-pyrolysis behavior of microalgae biomass and low-quality coal: Products distributions, char-surface morphology, and synergistic effects. AB - In this work, the distributions and releasing properties of the primary volatile products during co-pyrolysis of low-rank coal and green algae (GA) has been studied using fixed-bed reactor with online mass spectrometry. Surface morphology of the char was described quantitatively by SEM combined with fractal theory. Different forms of synergistic effects existed from both the yields of products and composition of the main gaseous products. Positive synergistic effects from tar yield were observed under 25% of GA from 600 to 850 degrees C, indicating GA promoted the formation of tar. Opposite synergistic effects on the content of H2 and CO were gained when the mass ratio of GA was 50%. The fractal dimensions of co-pyrolysis char were less than the calculated values except under 650 degrees C, which meant the GA promoted the homogeneity of char surface. This work could provide essential data for proper operation parameters selecting for co pyrolysis. PMID- 29427876 TI - A comparative study of biomass integrated gasification combined cycle power systems: Performance analysis. AB - The Biomass Integrated Gasification Combined Cycle (BIGCC) power system is believed to potentially be a highly efficient way to utilize biomass to generate power. However, there is no comparative study of BIGCC systems that examines all the latest improvements for gasification agents, gas turbine combustion methods, and CO2 Capture and Storage options. This study examines the impact of recent advancements on BIGCC performance through exergy analysis using Aspen Plus. Results show that the exergy efficiency of these systems is ranged from 22.3% to 37.1%. Furthermore, exergy analysis indicates that the gas turbine with external combustion has relatively high exergy efficiency, and Selexol CO2 removal method has low exergy destruction. Moreover, the sensitivity analysis shows that the system exergy efficiency is more sensitive to the initial temperature and pressure ratio of the gas turbine, whereas has a relatively weak dependence on the initial temperature and initial pressure of the steam turbine. PMID- 29427877 TI - The origins of infants' fairness concerns and links to prosocial behavior. AB - Concerns about fairness are central to mature moral judgments. We review research regarding the origins of a sensitivity to distributive fairness, and how it relates to early sharing. Infants' sensitivity to fairness appears to be commensurate with that of school-age children: infants notice violations to fairness norms and evaluate individuals based on their fair or unfair behavior. However, it may differ in other ways: there is no evidence that infants punish unfair individuals. Sharing behavior plays a role in both the developmental emergence of, and subsequent individual differences in, infants' fairness concerns. These results motivate novel questions, such whether infants can entertain other models of fairness, whether infants' socio-moral concerns hang together, and the relationship early fairness sensitivities and later fair behavior. PMID- 29427879 TI - Association between phthalate exposure and lower lung function in an urban elderly population: A repeated-measures longitudinal study. AB - BACKGROUND: Lung function is a major predictor of morbidity and mortality. Only a few studies have explored the association between phthalate exposure and lung function. OBJECTIVE: To evaluate the association between phthalate exposure and lung function in the elderly. METHODS: A total of 3 repeated-measures surveys were conducted in 559 elderly individuals aged >=60 years in Seoul, Korea, at 1 year intervals (2012-2015). During each survey, urinary mono-(2-ethyl-5 hydrohexyl) phthalate (MEHHP) (geometric mean, 15.68 MUg/L), mono-(2-ethyl-5 oxohexyl) phthalate (MEOHP) (11.97 MUg/L), and mono-n-butyl phthalate (MnBP) (2.09 MUg/L) levels were measured; moreover, lung function tests and a structured questionnaire interview were performed. We constructed linear mixed models to assess the association between urinary phthalate metabolite levels and lung function. RESULTS: A doubling of creatinine-adjusted urinary phthalate metabolite levels was inversely associated with forced expiratory volume in 1 s (L) (beta = 0.01, 95% confidence interval [CI]: -0.02, 0.004 for MEHHP; beta = -0.02, 95% CI: -0.03, -0.01 for MEOHP; beta = -0.01, 95% CI: -0.03, -0.003 for MnBP) and forced vital capacity (L) (beta = -0.02, 95% CI: -0.03, -0.001 for MEHHP; beta = -0.02, 95% CI: -0.03, -0.004 for MEOHP; beta = -0.02, 95% CI: -0.03, -0.001 for MnBP). A doubling of creatinine-adjusted MnBP levels was associated with increased rates of annual decline in forced vital capacity (L/year) (beta = -0.01, 95% CI: -0.02, -0.001). CONCLUSIONS: Urinary phthalate metabolite levels were associated with lower lung function and an increased rate of decline in lung function in an elderly population. PMID- 29427878 TI - Traffic related air pollution and development and persistence of asthma and low lung function. AB - BACKGROUND AND AIMS: Traffic Related Air Pollution (TRAP) exposure is known to exacerbate existing respiratory diseases. We investigated longer term effects of TRAP exposure for individuals with or without existing asthma, and with or without lower lung function. METHODS: Associations between TRAP exposure and asthma (n = 689) and lung function (n = 599) were investigated in the prospective Tasmanian Longitudinal Health Study (TAHS). TRAP exposure at age 45 years was measured using two methods based on residential address: mean annual NO2 exposure; and distance to nearest major road. Adjusted multinomial logistic regression was used to model the association between exposure to TRAP at 45 years and changes in asthma and lung function, using three follow ups of TAHS (45, 50 and 53 years). RESULTS: For those who never had asthma by 45, living <200 m from a major road was associated with increased odds of new asthma that persisted from 50 to 53 years (adjusted Odds Ratio [aOR] 5.20; 95% CI 1.07, 25.4). Asthmatic participants at 45 had an increased risk of persistent asthma up to 53 years if they were living <200 m from a major road, compared with asthmatic participants living >200 m from a major road (aOR = 5.21; 95% CI 1.54, 17.6). CONCLUSION: For middle aged adults, living <200 m for a major road (a marker of TRAP exposure) influences both the development and persistence of asthma. These findings have public health implications for asthma prevention strategies in primary and secondary settings. PMID- 29427880 TI - Selective and rapid determination of tadalafil and finasteride using solid phase extraction by high performance liquid chromatography and tandem mass spectrometry. AB - Highly selective and fast liquid chromatography-tandem mass spectrometric (LC MS/MS) method was developed and validated for simultaneous determination of tadalafil (TDL) and finasteride (FNS) in human plasma. The method was successfully applied for analysis of TDL and FNS samples in clinical study. The method was validated as per USFDA (United States Food and Drug Administration), EMA (European Medicines Agency), and ANVISA (Agencia Nacional de Vigilancia Sanitaria-Brazil) bio analytical method validation guidelines. Glyburide (GLB) was used as common internal standard (ISTD) for both analytes. The selected multiple reaction monitoring (MRM) transitions for mass spectrometric analysis were m/z 390.2/268.2, m/z 373.3/305.4 and m/z 494.2/369.1 for TDL, FNS and ISTD respectively. The extraction of analytes and ISTD was accomplished by a simple solid phase extraction (SPE) procedure. Rapid analysis time was achieved on Zorbax Eclipse C18 column (50 * 4.6 mm, 5 MUm). The calibration ranges for TDL and FNS were 5-800 ng/ml and 0.2-30 ng/ml respectively. The results of precision and accuracy, linearity, recovery and matrix effect of the method are acceptable. The accuracy was in the range of 92.9%-106.4% and method precision was also good; %CV was less than 8.1%. PMID- 29427881 TI - Rapid identification of limonoids from Cipadessa baccifera and Xylocarpus granatum using ESI-Q-ToF-MS/MS and their structure-fragmentation study. AB - Limonoids found to be chemotaxonomic markers from the plants of the Meliaceae and Rutaceae families. In the present study, rapid identification of limonoids from Cipadessa baccifera and Xylocarpus granatum were achieved using fast and simple electrospray ionization quadruple time-of-flight mass spectrometry (ESI-Q-ToF MS/MS) in positive-ion mode. Although the structures of these compounds were found to be similar, Collision Induced Dissociation (CID) mass spectrometric analysis of these protonated/sodiated molecules indicated different fragmentation patterns by which the structures were confirmed. The fragment ions were formed due to the loss of neutral components like H2O, CO2, methanol, as well as McLafferty rearrangement and Retro-ene reaction. Furthermore, MS/MS spectra revealed different fragmentation pathways for different classes of limonoids which further aided dereplication. PMID- 29427883 TI - Development of a molecularly imprinted polymer tailored on disposable screen printed electrodes for dual detection of EGFR and VEGF using nano-liposomal amplification strategy. AB - This work demonstrates the development of a gold screen-printed electrode (Au SPE)-based biosensor modified with a molecularly imprinted polymer and amplified using antibody-conjugated nano-liposomes. The developed biosensor was utilized for dual determination of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) as cancer biomarkers. To prepare this biosensor, Au-SPE was modified with 3,3'-dithiodipropionic acid di(N-hydroxysuccinimide ester) via self-assembly method and then the target proteins (EGFR and VEGF) were covalently attached to the modified SPE. To synthesize the molecularly imprinted polymer, monomers of acrylamide and N,N'-methylenebis(acrylamide) were polymerized around the EGFR and VEGF templates, and to characterize the prepared biosensor, electrochemical impedance spectroscopy was used for analyses of surface changes in the engineered electrodes. To produce reliable electrochemical signals, nano-liposomes which were loaded with Cd(II) and Cu(II) cations and decorated with antibodies specific for EGFR and VEGF were used as an efficient tool for detection of target biomarkers. In the analysis step, potentiometric striping analysis (PSA), as an electrochemical technique, was utilized for sensitive determination of these cations. The limits of detection (LODs) of EGFR and VEGF analyses were found to be 0.01 and 0.005 pg mL-1 with the linear dynamic ranges (LDRs) of 0.05-50000 and 0.01-7000 pg mL-1, respectively. Moreover, the proposed biosensor was successfully used for sensitive, reproducible, and specific detection of EGFR and VEGF in real samples. Due to the SPE nature of the developed biosensor, we envision that this sensing tool has capability of being integrated with lab-on-a-chip (LOC), microfluidics, and micro total analysis systems. PMID- 29427882 TI - Enzymatic fuel cells with an oxygen resistant variant of pyranose-2-oxidase as anode biocatalyst. AB - In enzymatic fuel cells (EnFCs), hydrogen peroxide formation is one of the main problems when enzymes, such as, glucose oxidase (GOx) is used due to the conversion of oxygen to hydrogen peroxide in the catalytic reaction. To address this problem, we here report the first demonstration of an EnFC using a variant of pyranose-2-oxidase (P2O-T169G) which has been shown to have low activity towards oxygen. A simple and biocompatible immobilisation approach incorporating multi-walled-carbon nanotubes within ferrocene (Fc)-Nafion film was implemented to construct EnFCs. Successful immobilisation of the enzymes was demonstrated showing 3.2 and 1.7-fold higher current than when P2O-T169G and GOx were used in solution, respectively. P2O-T169G showed 25% higher power output (maximum power density value of 8.45 +/- 1.6 MUW cm-2) and better stability than GOx in aerated glucose solutions. P2O-T169G maintained > 70% of its initial current whereas GOx lost activity > 90% during the first hour of 12 h operation at 0.15 V (vs Ag/Ag+). A different fuel cell configuration using gas-diffusion cathode and carbon paper electrodes were used to improve the power output of the fuel cell to 29.8 +/- 6.1 uW cm-2. This study suggests that P2O-T169G with low oxygen activity could be a promising anode biocatalyst for EnFC applications. PMID- 29427884 TI - Signal-on electrochemiluminescence biosensor for microRNA-319a detection based on two-stage isothermal strand-displacement polymerase reaction. AB - MicroRNAs play crucial role in regulating gene expression in organism, thus it is very necessary to exploit an efficient method for the sensitive and specific detection of microRNA. Herein, a signal-on electrochemiluminescence biosensor was fabricated for microRNA-319a detection based on two-stage isothermal strand displacement polymerase reaction (ISDPR). In the presence of target microRNA, amounts of trigger DNA could be generated by the first ISDPR. Then, the trigger DNA and the primer hybridized simultaneously with the hairpin probe to open the stem of the probe, and then the ECL signal will be emitted. In the presence of phi29 DNA polymerase and dNTPs, the trigger DNA could be displaced to initiate a new cycle which was the second ISDPR. Due to the two-stage amplification, this method presented excellent detection sensitivity with a low detection limit of 0.14 fM. Moreover, the applicability of the developed method was demonstrated by detecting the change of microRNA-319a content in the leaves of rice seedlings after the rice seeds were incubated with chemical mutagen of ethyl methanesulfonate. PMID- 29427885 TI - A nonenzymatic DNA nanomachine for biomolecular detection by target recycling of hairpin DNA cascade amplification. AB - Synthetic enzyme-free DNA nanomachine performs quasi-mechanical movements in response to external intervention, suggesting the promise of constructing sensitive and specific biosensors. Herein, a smart DNA nanomachine biosensor for biomolecule (such as nucleic acid, thrombin and adenosine) detection is developed by target-assisted enzyme-free hairpin DNA cascade amplifier. The whole DNA nanomachine system is constructed on gold nanoparticle which decorated with hundreds of locked hairpin substrate strands serving as DNA tracks, and the DNA nanomachine could be activated by target molecule toehold-mediated exchange on gold nanoparticle surface, resulted in the fluorescence recovery of fluorophore. The process is repeated so that each copy of the target can open multiplex fluorophore-labeled hairpin substrate strands, resulted in amplification of the fluorescence signal. Compared with the conventional biosensors of catalytic hairpin assembly (CHA) without substrate in solution, the DNA nanomachine could generate 2-3 orders of magnitude higher fluorescence signal. Furthermore, the DNA nanomachine could be used for nucleic acid, thrombin and adenosine highly sensitive specific detection based on isothermal, and homogeneous hairpin DNA cascade signal amplification in both buffer and a complicated biomatrix, and this kind of DNA nanomachine could be efficiently applied in the field of biomedical analysis. PMID- 29427886 TI - Understanding the exfoliation and dispersion of MoS2 nanosheets in pure water. AB - Exfoliation and dispersion of two dimensional (2D) transition metal dichacogenides (TMDCs) such as MoS2 in water are highly demanded. In this paper, we exfoliate MoS2 nanosheets in pure water via ultrasonication and attempt to understand the exfoliation process and the dispersion behavior of hydrophobic MoS2. Cavitation-induced exfoliation leads to thinning and fragmentation of MoS2 flakes. Formation of mesoporous MoS2 sheets suggests that the exfoliation initiates from the basal planes. As for the dispersion of MoS2 nanosheets in water, we find that higher centrifugation rate and thus smaller lateral size, results in improved stability. This can be attributed to the enhanced edge effects. Fragmentation of MoS2 flakes generates many edges, to which hydrophilic and ionizable groups are attached. Herein, the edge effects include two aspects. On the one hand, edge-attached polar and hydrophilic groups promote interactions of MoS2 nanosheets with water molecules and result in better wettability, which can be explained by the hemi-wicking model. On the other hand, dissociation of these groups makes MoS2 sheets negatively charged. It is found that edge charge dominates. As the flake size reduces, attractive van der Waals force and hydrophobic force can be overcome by electrostatic repulsions, which prevent MoS2 nanosheets from aggregation. This study opens a new vista on exfoliating and dispersing hydrophobic 2D nanomaterials in water. PMID- 29427887 TI - Non-contact AFM measurement of the Hamaker constants of solids: Calibrating cantilever geometries. AB - HYPOTHESIS: Surface effects arising from roughness and deformation can negatively affect the results of AFM contact experiments. Using the non-contact portion of an AFM deflection curve is therefore desirable for estimating the Hamaker constant, A, of a solid material. A previously validated non-contact quasi dynamic method for estimating A is revisited, in which the cantilever tip is now always represented by an "effective sphere". In addition to simplifying this previous method, accurate estimates of A can still be obtained even though precise knowledge of the nanoscale geometric features of the cantilever tip are no longer required. EXPERIMENTS: The tip's "effective" radius of curvature, Reff, is determined from a "calibration" step, in which the tip's deflection at first contact with the surface is measured for a substrate with a known Hamaker constant. After Reff is known for a given tip, estimates of A for other surfaces of interest are then determined. FINDINGS: An experimental study was conducted to validate the new method and the obtained results are in good agreement with predictions from the Lifshitz approximation, when available. Since Reff accounts for all geometric uncertainties of the tip through a single fitted parameter, no visual fitting of the tip shape was required. PMID- 29427888 TI - Red mud carbonation using carbon dioxide: Effects of carbonate and calcium ions on goethite surface properties and settling. AB - Carbonation using CO2 appears as an attractive solution for disposing of red mud suspensions, an aluminum industry hazardous waste since it also offers an option for CO2 sequestration. Here we report the novel findings that CO32- together with Ca2+ can significantly affect the surface properties and settling of goethite, a major component of red mud. Specifically, their effects on the goethite surface chemistry, colloidal interaction forces and settling in alkaline solutions are investigated. The surface potential becomes more negative by the formation of carbonate inner-sphere complexes on goethite surface. It is consistent with the strong repulsion, decreased particle size and settling velocity with increased carbonate concentrations as measured by atomic force microscopy, particle size analysis, and particle settling. Adding Ca2+ that forms outer-sphere complexes with pre-adsorbed carbonate changes goethite surface charge negligibly. Changing repulsion to the attraction between goethite surfaces by increasing calcium dosage indicates the surface bridging, in accordance with the increased settling velocity. The adverse effect of carbonate on goethite flocculation is probably due to its specific chemisorption and competition with flocculants. By forming outer-sphere complexes together with the flocculant-calcium bridging effect, calcium ions can eliminate the negative influence of carbonate and improve the flocculation of goethite particles. These findings contribute to a better understanding of goethite particle interaction with salt ions and flocculants in controlling the particle behavior in the handling processes, including the red mud carbonation. PMID- 29427889 TI - Functional analysis of StDWF4 gene in response to salt stress in potato. AB - The DWARF4 (DWF4) gene encodes a C-22 hydroxylase which is pivotal for brassinosteroids (BRs) biosynthesis. In this research, aimed to understand the molecular mechanism of DWF4 on regulation of potatoes tolerance to salt stress, DWF4 was cloned from potato, named as StDWF4. Its 1476 bp open reading frame encodes a protein of 491 amino acids. The StDWF4-overexpressing (OE) and interference-expressing (RNAi) transgenic potato plants were acquired using Agrobacterium-mediated transformation, respectively. Tissue specific analysis using Quantitative real-time polymerase chain reaction (qRT-PCR) demonstrated that the StDWF4 gene expressed in the leaves, stems and roots of the transgenic and un-transgenic (NT) plants, with specially increased (StDWF4-OE)/reduced (StDWF4-RNAi) expression in the roots. The content of malondialdehyde (MDA) in StDWF4-OE potato plants was lower than that of NT, and proline content was higher than that of NT. MDA and proline content in StDWF4-OE and NT under salt-stress was significantly higher than that of the control and was increased at different sampling times. The content of soluble protein, soluble sugar and the activities of superoxide dismutase (SOD), peroxidase (POD) and ascorbate peroxidase (APX) was higher in the StDWF4-OE plantlets at varied salt treatment time than in the NT potatoes. Reduction of H2O2 content in the StDWF4-OE plants was observed. All above plant physiology indicators in the StDWF4-RNAi potatoes showed opposite variation trends. The results proved that the overexpressing of StDWF4 in potato plantlets can enhance the salt resistance by alleviating the negative effects of salt-stress. However, its interference expression in potato plants depresses the salt resistance. The results lay the groundwork for intensive study of BRs regulation in potato growth and development, and will help us to reveal the molecular mechanisms of how the BRs signaling regulate potato salt tolerance. PMID- 29427890 TI - Short-term salt stress in Brassica rapa seedlings causes alterations in auxin metabolism. AB - Salinity is one of major abiotic stresses affecting Brassica crop production. Here we present investigations into the physiological, biochemical, and hormonal components of the short-term salinity stress response in Chinese cabbage seedlings, with particular emphasis on the biosynthesis and metabolism of auxin indole-3-acetic acid (IAA). Upon salinity treatments (50-200 mM NaCl) IAA level was elevated in a dose dependent manner reaching 1.6-fold increase at the most severe salt treatment in comparison to the control. IAA precursor profiling suggested that salinity activated the indole-3-acetamide and indole-3 acetaldoxime biosynthetic pathways while suppressing the indole-3-pyruvic acid pathway. Levels of the IAA catabolites 2-oxoindole-3-acetic acid and indole-3 acetic acid-aspartate increased 1.7- and 2.0-fold, respectively, under the most severe treatment, in parallel with those of IAA. Conversely, levels of the ester conjugate indole-3-acetyl-1-O-beta-d-glucose and its catabolite 2-oxoindole-3 acetyl-1-O-beta-d-glucose decreased 2.5- and 7.0-fold, respectively. The concentrations of stress hormones including jasmonic acid and jasmonoyl isoleucine (JA and JA-Ile), salicylic acid (SA) and abscisic acid (ABA) confirmed the stress induced by salt treatment: levels of JA and JA-Ile increased strongly under the mildest treatment, ABA only increased under the most severe treatment, and SA levels decreased dose-dependently. These hormonal changes were related to the observed changes in biochemical stress markers upon salt treatments: reductions in seedling fresh weight and root growth, decreased photosynthesis rate, increased levels of reactive oxygen species, and elevated proline content and the Na+/K+ ratio. Correlations among auxin profile and biochemical stress markers were discussed based on Pearson's coefficients and principal component analysis (PCA). PMID- 29427891 TI - Overexpression of Fagopyrum tataricum FtbHLH2 enhances tolerance to cold stress in transgenic Arabidopsis. AB - bHLH transcription factors play important roles in the abiotic stress response in plants, but their characteristics and functions in Tartary buckwheat (Fagopyrum tataricum), a traditional coarse cereal with a strong stress tolerance, haven't been sufficiently studied. Here, we found that the expression of a bHLH gene, FtbHLH2, was induced significantly by cold treatments in Tartary buckwheat seedlings. Subcellular localization indicated that FtbHLH2 localized in nucleus. Its overexpression in Arabidopsis increased tolerance to cold. The Arabidopsis plants overexpressing FtbHLH2 displayed higher root length and photosynthetic efficiency, and had lower malondialdehyde (MDA) and reactive oxygen species (ROS) after cold treatment compared to wild type (WT) plants. Meanwhile, the expression levels of some stress-related genes in transgenic plants were remarkably higher than that in wild type under normal and/or stress conditions. Furthermore, transgenic Arabidopsis lines with the FtbHLH2 promoter had higher GUS activity after cold stress. On the whole, the results suggest that FtbHLH2 may play a positive regulatory in cold stress of Tartary buckwheat. PMID- 29427892 TI - How health behaviors link romantic relationship dysfunction and physical health across 20 years for middle-aged and older adults. AB - RATIONALE: There has been substantial research linking marital quality to physical health outcomes; however, the mechanisms linking marital quality and physical health have been studied less extensively, especially with longitudinal data. Of the hypothesized mechanisms, only psychological distress (anxiety/depression) and physiological mechanisms (inflammation) have been tested and confirmed. Health behaviors such as diet, exercise, smoking, drinking, and sleeping have not previously been examined as mechanisms linking marital quality and physical health. OBJECTIVE: The present study tests how the emotional influence of the marital relationship is linked to subsequent health outcomes through behavioral mechanisms. A biopsychosocial theoretical model, the Biobehavioral Family Model (BBFM), is used to hypothesize the mediating paths between marital dysfunction and physical health. METHOD: The study hypotheses are tested with publicly accessible survey data, Midlife in the United States (MIDUS). We examined married or cohabiting participants (N = 5023) across the three time points of MIDUS, or 20 years. Specifically, we tested whether five health behaviors at Time 2 (smoking, alcohol, sleep, food to cope, and physical activity) function as mechanisms linking marital dysfunction (Time 1) to subsequent physical health (Time 3). We tested each health behavior as a mechanism in a series of mediating Structural Equation Models. RESULTS: Two health behaviors were significant mechanisms (food to cope and physical activity), while three were not (smoking, alcohol, and sleep). CONCLUSION: Diet and exercise are mechanisms linking marital dysfunction and health across 20 years because they may be linked to the emotional influence and not functional influence of the marriage context. According to the BBFM, diet and exercise may be part of the mediating construct of the model (i.e., biobehavioral reactivity), which explains how emotional stress from a marriage may produce declines in physical health over time. Implications for biopsychosocial healthcare interventions are discussed. PMID- 29427893 TI - Ghana's community-based primary health care: Why women and children are 'disadvantaged' by its implementation. AB - Policy analysis on why women and children in low- and middle-income settings are still disadvantaged by access to appropriate care despite Primary Health Care (PHC) programmes implementation is limited. Drawing on the street-level bureaucracy theory, we explored how and why frontline providers (FLP) actions on their own and in interaction with health system factors shape Ghana's community based PHC implementation to the disadvantage of women and children accessing and using health services. This was a qualitative study conducted in 4 communities drawn from rural and urban districts of the Upper West region. Data were collected from 8 focus group discussions with community informants, 73 in-depth interviews with clients, 13 in-depth interviews with district health managers and FLP, and observations. Data were recorded, transcribed and coded deductively and inductively for themes with the aid of Nvivo 11 software. Findings showed that apart from FLP frequent lateness to, and absenteeism from work, that affected care seeking for children, their exercise of discretionary power in determining children who deserve care over others had ripple effects: families experienced financial hardships in seeking alternative care for children, and avoided that by managing symptoms with care provided in non-traditional spaces. FLP adverse behaviours were driven by weak implementation structures embedded in the district health systems. Basic obstetric facilities such as labour room, infusion stand, and beds for deliveries, detention and palpation were lacking prompting FLP to cope by conducting deliveries using a patchwork of improvised delivery methods which worked out to encourage unassisted home deliveries. Perceived poor conditions of service weakened FLP commitment to quality maternal and child care delivery. Findings suggest the need for strategies to induce behaviour change in FLP, strengthen district administrative structures, and improve on the supply chain and logistics system to address gaps in CHPS maternal and child care delivery. PMID- 29427894 TI - Clinical characteristics associated with the intracranial dissemination of gliomas. AB - OBJECTIVES: Glioma is the most common malignant tumor of the brain and the intracranial dissemination of gliomas is the late stage of the development of the tumor. However, there is little research in literature on the occurrence of intracranial dissemination of gliomas. In order to provide a reference for clinical work, we carried out this study on intracranial dissemination of glioma. PATIENTS AND METHODS: A total of 629 patients with gliomas received tumor resection by the same surgeon from August 2010 to September 2015 were included in this study. The authors performed a retrospective review of the patients and the information regarding clinical features, histopathological results, molecular pathologic results and clinical outcomes was collected and analyzed. RESULTS: In this retrospective study, we found that the intracranial dissemination phenomenon occurred in 53 patients (8.43%). We analyzed the clinical characteristics of patients and found that the age at diagnosis (P = 0.011), WHO grade of the tumor (P < 0.001), and involvement of the corpus callosum (P = 0.010) were associated with the occurrence of dissemination. The higher grade of the tumor, the more prone to disseminate. Deletion of 1p/19q had no significant correlation with the intracranial dissemination. MMP9, Ki-67, and EGFR were highly expressed in tumor cells that caused dissemination, and the level of Ki-67 expression had significance in statistics (P < 0.01). CONCLUSION: In our study, older age (>40 years), high pathological grade, invasion of the corpus callosum and high levels of Ki-67 expression were risk factors associated with the intracranial dissemination of gliomas. PMID- 29427895 TI - Resolving conflicts with friends: Adolescents' strategies and reasons behind these strategies. AB - The study examined adolescents' strategies for managing hypothetical conflicts with the same-sex best friend and their reasons behind these strategies. The sample included 905 14-year-old Estonian adolescents. The findings indicated that negotiation was the most frequently suggested strategy by adolescents. At the same time, adolescents' strategies and reasons strongly depended on the source of conflict. Coercive strategies and self-oriented reasons were more common in case of severe conflicts that could damage interpersonal relatedness or pose a threat to the attainment of autonomy. Girls reported having conflicts more frequently and suggested more negotiation than boys in all conflict situations. Sex differences did, however, occur only in adolescents' strategies. Boys' and girls' reasons behind their strategies were similar. Implications will be discussed. PMID- 29427896 TI - Velocimetric ultrasound thermometry applied to myocardium protection monitoring. AB - Tissue temperature control during cardiac surgery is crucial for myocardial protection. To preserve the tissue, a hypothermic cardioplegia is applied in order to decrease the heart temperature down to around 10 degrees C. The monitoring of the thermal evolution of the myocardium is then of importance to minimize deleterious effects on the heart. The present work aims at evaluating the potential of an ultrasonic velocimetric thermometry on the monitoring of in vitro tissues heating. An indentation process is first proposed to identify the experimental linear relationship linking, in myocardia, the speed of the ultrasonic longitudinal wave to the tissue temperature. An extension of this method based on the echo-tracking principle is then proposed to approach surgical conditions. Temperature changes are measured by monitoring the induced time delays of backscattered ultrasonic echoes. These results are compared to T-type thermocouple reference measurements. They are then discussed in terms of measurement precision and in situ applications. PMID- 29427897 TI - Spatial aggregation of holistically-nested convolutional neural networks for automated pancreas localization and segmentation. AB - Accurate and automatic organ segmentation from 3D radiological scans is an important yet challenging problem for medical image analysis. Specifically, as a small, soft, and flexible abdominal organ, the pancreas demonstrates very high inter-patient anatomical variability in both its shape and volume. This inhibits traditional automated segmentation methods from achieving high accuracies, especially compared to the performance obtained for other organs, such as the liver, heart or kidneys. To fill this gap, we present an automated system from 3D computed tomography (CT) volumes that is based on a two-stage cascaded approach pancreas localization and pancreas segmentation. For the first step, we localize the pancreas from the entire 3D CT scan, providing a reliable bounding box for the more refined segmentation step. We introduce a fully deep-learning approach, based on an efficient application of holistically-nested convolutional networks (HNNs) on the three orthogonal axial, sagittal, and coronal views. The resulting HNN per-pixel probability maps are then fused using pooling to reliably produce a 3D bounding box of the pancreas that maximizes the recall. We show that our introduced localizer compares favorably to both a conventional non-deep-learning method and a recent hybrid approach based on spatial aggregation of superpixels using random forest classification. The second, segmentation, phase operates within the computed bounding box and integrates semantic mid-level cues of deeply learned organ interior and boundary maps, obtained by two additional and separate realizations of HNNs. By integrating these two mid-level cues, our method is capable of generating boundary-preserving pixel-wise class label maps that result in the final pancreas segmentation. Quantitative evaluation is performed on a publicly available dataset of 82 patient CT scans using 4-fold cross-validation (CV). We achieve a (mean +/- std. dev.) Dice similarity coefficient (DSC) of 81.27 +/- 6.27% in validation, which significantly outperforms both a previous state-of-the art method and a preliminary version of this work that report DSCs of 71.80 +/- 10.70% and 78.01 +/- 8.20%, respectively, using the same dataset. PMID- 29427898 TI - Psychological interventions for anxiety in adult primary care patients: A review and recommendations for future research. AB - Anxiety symptoms are prevalent in primary care, yet treatment rates are low. The integration of behavioral health providers into primary care via the Primary Care Behavioral Health (PCBH) model offers a promising way to improve treatment options by adding a team member with the necessary skillset to deliver evidence based psychological interventions for anxiety. We conducted a narrative review of psychological interventions for anxiety applied within adult primary care settings (k = 44) to update the literature and evaluate the fit of existing interventions with the PCBH model. The majority of studies were randomized controlled trials (RCTs; 70.5%). Most interventions utilized cognitive-behavioral therapy (68.2%) and were delivered individually, face-to-face (52.3%). Overall, 65.9% of interventions (58.6% of RCTs, 91.7% of pre-post) were effective in reducing anxiety symptoms, and 83.3% maintained the gains at follow-up. Although it is encouraging that most interventions significantly reduced anxiety, their longer formats (i.e., number and duration of sessions) and narrow symptom targets make translation into practice difficult. Methodological limitations of the research included homogenous samples, failure to report key procedural details, pre-post designs, and restrictive eligibility criteria. We offer recommendations to guide future research to improve the likelihood of successful translation of anxiety interventions into clinical practice. PMID- 29427899 TI - Shared reality as collective closure. AB - We draw on the theory of lay epistemics to understand how universal processes of knowledge formation drive the emergence, and determine the consequences of shared reality in groups. In particular, we highlight the role in these processes of the need for cognitive closure and credible epistemic authorities. Whereas the former construct explains why people seek a shared reality, the latter clarifies who the reality is shared with. In this connection, we review relevant bodies of empirical evidence that bear on the epistemic underpinnings of shared reality phenomena. PMID- 29427900 TI - Ideological asymmetries in conformity, desire for shared reality, and the spread of misinformation. AB - Ideological belief systems arise from epistemic, existential, and relational motives to reduce uncertainty, threat, and social discord. According to system justification theory, however, some ideologies-such as those that are conservative, religious, and legitimizing of the status quo-are especially appealing to people whose epistemic, existential, and relational motives are chronically or temporarily heightened. In this article, we focus on relational motivation, describing evidence that conservatives are more likely than liberals to: prioritize values of conformity and tradition; possess a strong desire to share reality with like-minded others; perceive within-group consensus when making political and non-political judgments; be influenced by implicit relational cues and sources who are perceived as similar to them; and maintain homogenous social networks and favor an 'echo chamber' environment that is conducive to the spread of misinformation. PMID- 29427901 TI - Existential isolation and I-sharing: Interpersonal and intergroup implications. AB - I-sharing, or believing one has the same in-the-moment experience as another person, constitutes a specific way in which people may share reality. I-sharing research underscores its significance for interpersonal and intergroup outcomes. I-sharing fosters liking for people who differ from us in objective and sometimes important ways, and counteracts robust tendencies to favor ingroup members and dehumanize outgroup members. Research and theory indicate that existential isolation-feeling alone in one's experience-explains the potency of I-sharing, insofar as people with high levels of existential isolation are especially drawn to those with whom they have reason to believe they I-share. Recent findings are reviewed, followed by a discussion of the clinical implications of the work. PMID- 29427902 TI - Processes and pathways mediating the experience of social anxiety and negative rumination. AB - Negative rumination in social anxiety disorder (SAD) occurs in anticipation of a social event (pre-event rumination) and in its aftermath (post-event rumination). Both are proposed to be key maintaining factors of the vicious cycle of social anxiety. Despite this, there is a dearth of research investigating the processes that mediate the relationship between social anxiety and pre-event rumination and uncertainty regarding the cognitive and attentional processes that mediate the relationship between social anxiety and post-event rumination. To investigate this further, the current study utilised a clinical sample of participants with SAD to determine the hypothesised mediators of a social anxiety and pre-event model (N = 239) and a social anxiety and post-event rumination model (N = 216). Results from path analyses were broadly consistent with cognitive models of SAD that posit several interrelated processes mediate the relationship between social anxiety and pre- and post-event rumination. Results also indicated slightly different processes showed stronger prediction of pre-event rumination (i.e., biased performance appraisals) and post-event rumination (i.e., negative attentional focus). Treatment recommendations that aim to address the maladaptive role of negative rumination in social anxiety are made in keeping with the inter connected and dynamic role played by cognitive and attentional processes in heightening social anxiety. PMID- 29427903 TI - The gut microbiota as a novel regulator of cardiovascular function and disease. AB - The gut microbiome has emerged as a critical regulator of human physiology. Deleterious changes to the composition or number of gut bacteria, commonly referred to as gut dysbiosis, has been linked to the development and progression of numerous diet-related diseases, including cardiovascular disease (CVD). Most CVD risk factors, including aging, obesity, certain dietary patterns, and a sedentary lifestyle, have been shown to induce gut dysbiosis. Dysbiosis is associated with intestinal inflammation and reduced integrity of the gut barrier, which in turn increases circulating levels of bacterial structural components and microbial metabolites that may facilitate the development of CVD. The aim of the current review is to summarize the available data regarding the role of the gut microbiome in regulating CVD function and disease processes. Particular emphasis is placed on nutrition-related alterations in the microbiome, as well as the underlying cellular mechanisms by which the microbiome may alter CVD risk. PMID- 29427904 TI - Lack of association between aryl hydrocarbon receptor gene Arg554Lys polymorphism and male infertility risk: A systematic review and meta-analysis. AB - OBJECTIVES: The association between aryl hydrocarbon receptor gene (AhR) polymorphism and male infertility risk remains conflicting. We conducted a meta analysis to examine the AhR Arg554Lys polymorphism in relation to the susceptibility to male infertility. STUDY DESIGN: Studies concerning the association between AHR polymorphism and male infertility were searched and related information were extracted from the included studies. The STATA 12.0 software was used to perform a meta-analysis. Pooled odd ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to estimate the association. RESULTS: Six case-control studies with 1234 cases and 1755 controls were included after literature research and data collection. Overall, the results indicated there was no association between the AhR Arg554Lys polymorphism and male infertility risk (G versus A, OR (95%CI) = 0.958 (0.710-1.291); GG vs AA, OR (95%CI) = 0.874 (0.702-1.088); GA versus AA, OR (95%CI) = 0.911(0.477-1.740); GG + GA vs AA, OR (95%CI) = 0.891 (0.468-1.696); GG versus GA + AA, OR (95%CI) = 1.049(0.896-1.229)). Subgroup analysis by study population revealed there was no association between AhR Arg554Lys polymorphism and susceptibility to male infertility in Asian population (G versus A, OR (95%CI) = 1.099 (0.940-1.286); GG vs AA, OR (95%CI) = 0.982 (0.781-1.235); GA versus AA, OR (95%CI) = 1.220 (0.726 2.052); GG + GA vs AA, OR (95%CI) = 1.221 (0.740-1.982); GG versus GA + AA, OR (95%CI) = 1.087 (0.919-1.286)). CONCLUSIONS: The association between AHR Arg55Lys polymorphism and male infertility risk was not confirmed in our meta-analysis. However, the results should be interpreted with caution and further studies are required. PMID- 29427905 TI - GC-MS determination of phthalate esters in human urine: A potential biomarker for phthalate bio-monitoring. AB - Six phthalic acid esters (PAEs) in human urine sampled randomly from three districts (Erode, Thanjavur, and Perambalur) in Tamil Nadu State and a Union Territory (Pondicherry) in India were quantified. We determined gender-wise, age wise and location-wise distribution of PAEs and measured estrogenic activity of urine by molecular docking. Bis(2-ethylhexyl) phthalate (DEHP) was the predominant phthalic acid ester found and had a recovery of 104.5% (ultrasonic extraction at 15 min). Gender-wise (pregnant women: 185 ng/mL, children: 156 ng/mL, female: 151 ng/mL, and male: 138 ng/mL), age-wise (1-20 y: 157 ng/mL, 21 40 y: 156 ng/mL, and >40 y: 146 ng/mL), location-wise (urban: 154 ng/mL, and rural: 151 ng/mL), and region-wise (Erode district: 185 ng/mL, Thanjavur district: 155 ng/mL, Perambalur district: 117 ng/mL, and Pondicherry: 135 ng/mL) differences with total mean of Sigma6 PAEs were found. The molecular docking study showed a high negative binding energy of PAEs with microbial receptors. Based on the results we conclude that urine could be used as an ideal biomarker to understand PAEs exposure in humans. PMID- 29427906 TI - Synthesis and biological evaluation of novel quinazoline-4-piperidinesulfamide derivatives as inhibitors of NPP1. AB - The ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) was recently shown to promote mineralization of the aortic valve, hence, its inhibition represents a significant target. A quinazoline-4-piperidine sulfamide compound (QPS1) has been described as a specific and non-competitive inhibitor of NPP1. We report herein the synthesis and in vitro inhibition studies of novel quinazoline-4-piperidine sulfamide analogues using QPS1 as the lead compound. Of the 26 derivatives prepared, four compounds were found to have Ki < 105 nM against human NPP1. PMID- 29427907 TI - Human coronavirus circulation in the United States 2014-2017. AB - BACKGROUND: Human coronaviruses (HCoVs) -OC43, -229E, -NL63 and -HKU1 cause upper and lower respiratory tract infections. HCoVs are globally distributed and the predominant species may vary by region or year. Prior studies have shown seasonal patterns of HCoV species and annual variation in species prevalence but national circulation patterns in the US have not yet been described. OBJECTIVES: To describe circulation patterns of HCoVs -OC43, -229E, -NL63 and -HKU1 in the US. STUDY DESIGN: We reviewed real-time reverse transcription polymerase chain reaction (rRT-PCR) test results for HCoV-OC43, -229E, -NL63 and -HKU1 reported to The National Respiratory and Enteric Virus Surveillance System (NREVSS) by U.S. laboratories from July 2014-June 2017. We calculated the total number of tests and percent positive by week. For a subset of HCoV positive submissions with age and sex of the patient available, we tested for differences in age and sex across the four HCoV species using Chi Square and Kruskal Wallace tests. RESULTS: 117 laboratories reported 854,575 HCoV tests; 2.2% were positive for HCoV-OC43, 1.0% for HCoV-NL63, 0.8% for HCoV-229E, and 0.6% for HCoV-HKU1. The percentage of positive tests peaked during December - March each year. No significant differences in sex were seen across species, although a significant difference in age distribution was noted. CONCLUSIONS: Common HCoVs may have annual peaks of circulation in winter months in the US, and individual HCoVs may show variable circulation from year to year. Different HCoV species may be detected more frequently in different age groups. Further years of data are needed to better understand patterns of activity for HCoVs. PMID- 29427908 TI - Kinetics of viral load and cytokines in severe fever with thrombocytopenia syndrome. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China, Japan, and Korea, which is characterized by high fever, thrombocytopenia, and high mortality. It is hypothesized that a cytokine storm plays an important role in the pathophysiology of SFTS. However, limited data have been published on the detailed kinetics of the viral load and cytokine profiles throughout the course of this disease. OBJECTIVES: We investigated the patterns of changes in cytokines and viral load in SFTS patients. STUDY DESIGN: During the admission period of patients, RNA was extracted from plasma and quantified by reverse transcription polymerase chain reaction. In addition, cytokine bead arrays were performed for the 18 cytokines and chemokines selected for testing. RESULTS: The median time from admission to the negative conversion of SFTS viremia was 17.0 days. When censored patients were found to be negative for viral load at discharge, the median duration of viral shedding was 13.0 days (95% CI, 5.4-20.6). Interferon (IFN)-alpha, interleukin (IL)-10, and IFN-gamma induced protein (IP)-10 concentrations significantly increased in the early course of disease and then decreased during the hospital stay. However, the concentrations of tumor necrosis factor-alpha, IL-1beta, IL-12p40, IL-13, IL-17A, Regulated on Activation and Normally T-cell Expressed and Secreted (RANTES), and vascular endothelial growth factor (VEGF) increased during the late course of disease. Initial IP-10 levels during hospital days 1-4 were the most significantly correlated with initial viral load (r = 0.88, P < .01). CONCLUSION: SFTS viremia persisted until weeks 2-3 and was highly correlated with initial plasma IP-10 levels. In addition, IFN-alpha, IL-10, and IP-10 were associated with the initial cytokine storm in SFTS. PMID- 29427909 TI - Allosteric inhibition abrogates dysregulated LFA-1 activation: Structural insight into mechanisms of diminished immunologic disease. AB - Lymphocyte Function Associated antigen-1(LFA-1) has been implicated severely in the pathophysiology of inflammatory and autoimmune diseases. Its active and inactive conformations correlate with its diseased and non-diseased state respectively. This is determined by its degree of affinity for its intrinsic ligand (ICAM) at the active site and accompanying synergistic coordination at the alpha7 helix. This potentiates the role of inhibitors in disrupting this interaction allosterically. Herein, we present a first account of the structural dynamics which characterizes the inhibitory effect of a novel LFA-1 antagonist, Lifitegrast (SAR1118), upon binding to the I-domain allosteric site (IDAS) using molecular dynamics simulation. Findings from this study revealed that the inhibitor stabilized the closed conformation and reversed the open conformation to a low ICAM-affinity state (closed) as evidenced by the upward movement of the alpha7 helix and corresponding transitions at the active site. This in both cases favors the formation of the non-disease inactive form. Upon allosteric modulation, the inhibitor significantly restored protein stability, enhanced compactness and decreased residual fluctuation as crucial to its potency in the amelioration of immunological and inflammatory diseases which agrees with experimental studies. These findings could therefore serve as the basis for the exploration of the allosteric domain and its active site affinity modulation to aid the design of more specific and selective inhibitors. PMID- 29427910 TI - Morningness-Eveningness questionnaire in bipolar disorder. AB - The Morningness-Eveningness Questionnaire (MEQ) is among the most commonly used scales to measure chronotype. We aimed to evaluate psychometric properties and clinical correlates of MEQ in bipolar disorder. Patients with a clinical diagnosis of bipolar disorder (n = 53) answered questionnaires for chronotype (MEQ), mood (Quick Inventory of Depressive Symptoms-16, Altman Self-Rating Mania Scale), insomnia (Athens Insomnia Scale, AIS), and sleepiness (Epworth Sleepiness Scale). Mood was evaluated using Montgomery-Asberg Depression Rating Scale and Young Mania Rating Scale. The MEQ showed high internal consistency with Cronbach's alpha of .85. Lower MEQ scores (eveningness) correlated with insomnia (AIS) (r = -.34, p = .013). The estimate for eveningness (13/53, 24.5%) in our study was higher than in comparable studies in the general population. Patients on lithium exhibited a higher mean MEQ score (56.0 on lithium vs 46.9 with no lithium, p = .007), whereas this score was lower for patients on an antidepressant (46.0 on antidepressants vs 52.6 with no antidepressants, p = .023). We conclude that the MEQ score is psychometrically reliable. However, future studies should further evaluate the association of medication with chronotype. Validation of categorical cut-offs for MEQ in a larger sample of bipolar patients is needed to increase clinical utility. PMID- 29427911 TI - Comparing characteristics of suicide attempters with suicidal ideation and those without suicidal ideation treated in the emergency departments of general hospitals in China. AB - Suicide attempts are more frequent than suicides, and suicidal ideation has been identified as an important precursor of both attempted and completed suicide. In this study, we compare the characteristics of suicide attempters with suicidal ideation and suicide attempters without suicidal ideation who were treated in the emergency departments of general hospitals in China. We identified 166 people as having suicidal ideation and 73 people who did not have suicidal ideation. The suicide attempters with suicidal ideation were more likely to be more depressed, older, have a lower score on life quality, female, divorced and unemployed, report having religious beliefs, have a suicide attempt history and a psychiatric diagnosis, and intend to reduce pain as motives. However, the suicide attempters without suicidal ideation were more likely to have a more self-rescue ideation and were more impulsive, and to threaten or intend revenge on others as motives. Multivariate logistic regression analysis identified the following independent predictors of suicidal ideation in the suicide attempters: a higher score on Hamilton Depression Rating Scale, religious beliefs, non-impulsive suicide attempts, and a psychiatric diagnosis. The results indicate the importance of developing different interventions for the two groups to prevent future suicide in China. PMID- 29427912 TI - Adjunctive therapy with statins in schizophrenia patients: A meta-analysis and implications. AB - There are some conflicting results regarding the benefit of adjunctive therapy with statins for severity of negative symptoms in schizophrenia. This study aimed to verify whether statins use for adjunctive therapy was indeed beneficial to improve psychiatric symptoms in schizophrenia. The data were from CENTRAL, PubMed, Embase and MEDLINE. The Boolean search term used for the electronic database search was (statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR mevastatin OR pitavastatin OR pravastatin OR rosuvastatin OR cerivastatin) and (schizophrenia OR schizoaffective disorder OR psychosis). Inclusion criteria were the following: RCTs, the adult schizophrenia patients, received antipsychotics plus statins or placebo, and the PANSS or SANS scores. Exclusion criteria were as follows: no data reported and multiple reports of the same study. A meta-analysis was used to compare psychiatric symptoms in schizophrenia patients with or without statins adjunctive therapy. The 6 RCTs included in the analysis represented 339 participants (169 in treatment group versus 170 in placebo group). A test for overall effect demonstrated that the PANSS positive scale and negative scale significantly reduced in participants receiving compliant with statins. Our meta-analyses first clarified that adjunctive therapy with statins could improve psychiatric symptoms, either negative symptoms or positive symptoms. PMID- 29427913 TI - L-carnosine as an add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: A double-blind, randomized placebo-controlled trial. AB - Since l-carnosine has shown effectiveness in improvement of cognition in patients with schizophrenia, this 8-week, randomized, double-blind, placebo-controlled pilot study was conducted. Sixty-three patients with chronic schizophrenia, who were clinically stable on a stable dose of risperidone, entered the study. The patients were randomly assigned to l-carnosine (2 gr/day in two divided doses) or placebo for eight weeks. The patients were assessed using the positive and negative syndrome scale (PANSS), extrapyramidal symptom rating scale (ESRS), and Hamilton depression rating scale (HDRS) during the study course. Sixty patients completed the trial. L-carnosine resulted in greater improvement of negative scores as well as total PANSS scores but not positive subscale scores compared to placebo. HDRS scores and its changes did not differ between the two groups. Both groups demonstrated a constant ESRS score during the trial course. Frequency of other side effects was not significantly different between the two groups. In a multiple regression analysis model (controlled for positive, general psychopathology, depressive and extrapyramidal symptoms, as well as other variables), the treatment group significantly predicted changes in primary negative symptoms. In conclusion, l-carnosine add-on therapy can safely and effectively reduce the primary negative symptoms of patients with schizophrenia. PMID- 29427914 TI - Charge dynamics in aluminum oxide thin film studied by ultrafast scanning electron microscopy. AB - The excitation dynamics of defects in insulators plays a central role in a variety of fields from Electronics and Photonics to Quantum computing. We report here a time-resolved measurement of electron dynamics in 100 nm film of aluminum oxide on silicon by Ultrafast Scanning Electron Microscopy (USEM). In our pump probe setup, an UV femtosecond laser excitation pulse and a delayed picosecond electron probe pulse are spatially overlapped on the sample, triggering Secondary Electrons (SE) emission to the detector. The zero of the pump-probe delay and the time resolution were determined by measuring the dynamics of laser-induced SE contrast on silicon. We observed fast dynamics with components ranging from tens of picoseconds to few nanoseconds, that fits within the timescales typical of the UV color center evolution. The surface sensitivity of SE detection gives to the USEM the potential of applying pump-probe investigations to charge dynamics at surfaces and interfaces of current nano-devices. The present work demonstrates this approach on large gap insulator surfaces. PMID- 29427915 TI - Cigarette cues capture attention of smokers and never-smokers, but for different reasons. AB - BACKGROUND: While the notion that smokers reliably show higher reactivity to cigarette-related versus neutral cues is both theoretically and empirically supported, it is unclear why never-smokers also show enhanced brain responses to cigarette-related cues. METHODS: Using a repetitive picture viewing paradigm, in which responses evoked by affective cues are more resistant to habituation, we assessed the effects of stimulus repetition on event-related potentials (ERPs) evoked by pleasant, unpleasant, cigarette-related, and neutral images in 34 smokers (SMO) and 34 never-smokers (NEV). We examined the early posterior negativity (EPN) and the late positive potential (LPP), two ERP components which are sensitive to a picture's motivational qualities. RESULTS: Before stimulus repetition, pleasant, unpleasant, and cigarette-related cues produced greater EPN and LPP amplitudes than neutral cues in all subjects. During stimulus repetition, both components were similarly modulated by emotional arousal, such that pleasant, unpleasant, and cigarette-related cues evoked greater EPN and LPP amplitude, relative to neutral. Smoking status did not modulate these effects. While there were no group differences in self-reported stimulus ratings of valence for pleasant, unpleasant, or neutral stimuli, NEV rated cigarette-related cues as unpleasant. We observed a moderate, negative correlation between LPP amplitude and self-reported valence ratings of cigarette-related cues among NEV. CONCLUSIONS: These data suggest that cigarette-related cues capture attentional resources of both SMO and NEV, but for different reasons. For SMO, cigarette related cues have acquired motivational significance through repeated associations with nicotine delivery, whereas for NEV, cigarette-related cues are perceived as unpleasant. PMID- 29427916 TI - Substitutability of nicotine alone and an electronic cigarette liquid using a concurrent choice assay in rats: A behavioral economic analysis. AB - BACKGROUND: For the Food and Drug Administration to effectively regulate tobacco products, the contribution of non-nicotine tobacco constituents to the abuse liability of tobacco must be well understood. Our previous work compared the abuse liability of electronic cigarette refill liquids (EC liquids) and nicotine (Nic) alone when each was available in isolation and found no difference in abuse liability (i.e., demand elasticity). Another, and potentially more sensitive measure, would be to examine abuse liability in a choice context, which also provides a better model of the tobacco marketplace. METHODS: Demand elasticity for Nic alone and an EC liquid were measured when only one formulation was available (alone-price demand) and when both formulations were concurrently available (own-price demand), allowing an assessment of the degree to which each formulation served as a substitute (cross-price demand) when available at a low fixed-price. RESULTS: Own-price demand for both formulations were more elastic compared to alone-price demand, indicating that availability of a substitute increased demand elasticity. During concurrent access, consumption of the fixed price formulation increased as the unit-price of the other formulation increased. The rate of increase was similar between formulations, indicating that they served as symmetrical substitutes. CONCLUSION: The cross-price model reliably quantified the substitutability of both nicotine formulations and indicated that the direct CNS effects of non-nicotine constituents in EC liquid did not alter its abuse liability compared to Nic. These data highlight the sensitivity of this model and its potential utility for examining the relative abuse liability and substitutability of tobacco products. PMID- 29427918 TI - Recognition method of construction conflict based on driver's eye movement. AB - Drivers eye movement data in simulated construction conflicts at different speeds were collected and analyzed to find the relationship between the drivers' eye movement and the construction conflict. On the basis of the relationship between the drivers' eye movement and the construction conflict, the peak point of wavelet processed pupil diameter, the first point on the left side of the peak point and the first blink point after the peak point are selected as key points for locating construction conflict periods. On the basis of the key points and the GSA, a construction conflict recognition method so called the CCFRM is proposed. And the construction conflict recognition speed and location accuracy of the CCFRM are verified. The good performance of the CCFRM verified the feasibility of proposed key points in construction conflict recognition. PMID- 29427917 TI - HIV treatment optimism and crystal methamphetamine use and initiation among HIV negative men who have sex with men in Vancouver, Canada: A longitudinal analysis. AB - BACKGROUND: Treatment as Prevention (TasP) leading to increased HIV treatment optimism among men who have sex with men (MSM) has been previously associated with behavioural risk compensation, though not yet via crystal methamphetamine (CM) use. Among HIV-negative MSM in a TasP environment, this study aimed to investigate the prevalence of recent CM use over time, examine the association between HIV treatment optimism and CM use and initiation, and identify correlates of recent CM use and predictors of CM initiation. METHODS: Using data from a prospective behavioural cohort study of sexually active MSM in the Vancouver area, we used multi-level generalized mixed effect models to evaluate temporal trends in CM use, univariable and multivariable logistic regression to identify covariates of recent CM use, and univariable and multivariable survival analysis to identify predictors of CM initiation. RESULTS: Of 497 HIV-negative cohort participants, 10.3% reported any recent CM use at enrollment. From 2012-2016, there were no statistically significant temporal trends in overall CM use or with routes of administration. In multivariable logistic regression analyses, HIV treatment optimism was not associated with recent CM use (not retained in final model) or CM initiation (aHR = 1.06, 95% CI:0.98-1.15). Significant correlates of CM use include recent gamma-hydroxybutyrate (GHB) and ecstasy use, and having received/given drugs for sex. CONCLUSIONS: Among HIV-negative MSM in Vancouver, HIV treatment optimism does not appear to be independently associated with CM use or initiation of use, though use of CM was both prevalent and stable over time. PMID- 29427919 TI - The building blocks of successful translation of proteomics to the clinic. AB - Recently, the first two multiplexed tests using selective reaction monitoring (SRM-MS) mass spectrometry have entered clinical practice. Despite different areas of indication, risk stratification in lung cancer and preterm birth, they share multiple steps in their development strategies. Here we review these strategies and their implications for successful translation of biomarkers to clinical practice. We believe that the identification of blood protein panels for the identification of disease phenotypes is now a reproducible and standard (albeit complex) process. PMID- 29427920 TI - Accuracy of the Demirjian and Willems methods of age estimation in a Black Southern African population. AB - The accuracies of the original Demirjian, modified Demirjian and Willems dental age estimation methods were compared for a Black Southern African population to determine their usefulness for forensic and anthropological purposes. Data were collected using a community-based prospective study design. Panoramic radiographs of seven left mandibular teeth from 540 children aged 5-15.99 years were scored using the three methods. Obtained estimates were compared to the chronological ages and mean absolute errors were calculated. The original Demirjian method significantly overestimated ages (males 0.85 years, female 1.0 years; mean absolute errors of 1.1 years for both sexes), as did the modified Demirjian method (males 0.90 years, females 1.21 years; mean absolute errors of males 1.1 years, females 1.4 years). The Willems method was the most accurate for Black Southern Africans, with the lowest significant mean difference (males 0.2 years, females 0.3 years) between dental and chronological age, with the least mean absolute errors (males 0.70 years, females 0.68 years). PMID- 29427921 TI - Development and validation of PediaTracTM: A web-based tool to track developing infants. AB - OBJECTIVE: PediaTracTM, a 363-item web-based tool to track infant development, administered in modules of ~40-items per sampling period, newborn (NB), 2--, 4--, 6--, 9-- and 12--months was validated. Caregivers answered demographic, medical, and environmental questions, and questions covering the sensorimotor, feeding/eating, sleep, speech/language, cognition, social-emotional, and attachment domains. METHODS: Expert Panel Reviews and Cognitive Interviews (CI) were conducted to validate the item bank. Classical Test Theory (CTT) and Item Response Theory (IRT) methods were employed to examine the dimensionality and psychometric properties of PediaTrac with pooled longitudinal and cross-sectional cohorts (N = 132). RESULTS: Intraclass correlation coefficients (ICC) for the Expert Panel Review revealed moderate agreement at 6 -months and good reliability at other sampling periods. ICC estimates for CI revealed moderate reliability regarding clarity of the items at NB and 4 months, good reliability at 2--, 9-- and 12--months and excellent reliability at 6 -months. CTT revealed good coefficient alpha estimates (alpha >= 0.77 for five of the six ages) for the Social-Emotional/Communication, Attachment (alpha >= 0.89 for all ages), and Sensorimotor (alpha >= 0.75 at 6-months) domains, revealing the need for better targeting of sensorimotor items. IRT modeling revealed good reliability (r = 0.85 0.95) for three distinct domains (Feeding/Eating, Social-Emotional/Communication and Attachment) and four subdomains (Feeding Breast/Formula, Feeding Solid Food, Social-Emotional Information Processing, Communication/Cognition). Convergent and discriminant construct validity were demonstrated between our IRT-modeled domains and constructs derived from existing developmental, behavioral and caregiver measures. Our Attachment domain was significantly correlated with existing measures at the NB and 2-month periods, while the Social-Emotional/Communication domain was highly correlated with similar constructs at the 6-, 9- and 12-month periods. CONCLUSION: PediaTrac has potential for producing novel and effective estimates of infant development via the Sensorimotor, Feeding/Eating, Social Emotional/Communication and Attachment domains. PMID- 29427922 TI - Psychotomimetic-like behavioral effects of memantine in the mouse. AB - A single administration of mice with memantine (1-amino-3,5-dimethyladamantane), a glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, induced stereotyped behaviors in dose- and time-dependent manners. The predominant behavioral component of the stereotypy was a continuous, exaggerated sniffing which was accompanied by persistent locomotion. In contrast, a psychostimulant methamphetamine (METH) predominantly induced a stereotyped biting and other forms of intense stationary stereotypical behaviors. Memantine-induced stereotyped sniffing was attenuated by pretreatment with haloperidol, a dopamine D2 receptor antagonist, in a dose-dependent manner. The memantine-induced stereotyped sniffing was also attenuated by pretreatment with betahistine (2-[2 (methylamino)ethyl]pyridine), an agent which increases histamine turnover and releases histamine in the brain. These observations suggest that memantine might induce stereotypies through neuronal mechanisms that are somewhat different from those of METH, but still overlap to a certain extent, since memantine-induced stereotypies can be attenuated by the mechanisms that also suppress METH-induced stereotypy. Importantly, these data suggests that the effects of memantine may be more limited to the ventral striatum including nucleus accumbens than those of METH, which is associated with dorsal striatal stimulation at high doses. In this respect memantine may also have pharmacological properties such as compartmentation (i.e. brain distribution) and neuronal mechanisms different from those of other NMDA receptor antagonists, such as ketamine, which may have important implications for therapeutic uses of these drugs. PMID- 29427923 TI - HG30, a tetrahydroanthraquinone compound isolated from the roots of Prismatomeris connate, induces apoptosis in human non-small cell lung cancer cells. AB - HG30, a tetrahydroanthraquinone compound isolated from the roots of Prismatomeris connate, was previously shown to inhibit the proliferation of A549 cells. The aim of this study was to evaluate the antitumor activity of HG30 in two non-small cell lung cancer cell lines, A549 and H1299, and to explore potential underlying mechanisms. In cell viability and colony formation assays, HG30 treatment suppressed the proliferation and number of colonies formed by A549 and H1299 cells. Western blot analysis further demonstrated that induction of apoptosis by HG30 in A549 and H1299 cells involves both caspase-dependent apoptosis pathways, including mitochondria- and death receptor-mediated pathways, and an apoptosis inducing factor (AIF) -associated caspase-independent apoptosis pathway. Specifically, HG30 treatment affected Bcl-2 family proteins and inhibitor of apoptosis protein (IAP) family proteins by down-regulating of Mcl-1, survivin and XIAP and up-regulation of Bid, and Bim. PMID- 29427924 TI - Highly sensitive electrochemical assay for Nosema bombycis gene DNA PTP1 via conformational switch of DNA nanostructures regulated by H+ from LAMP. AB - The portable and rapid detection of biomolecules via pH meters to monitor the concentration of hydrogen ions (H+) from biological reactions (e.g. loop-mediated isothermal amplification, LAMP) has attracted research interest. However, this assay strategy suffered from inherent drawback of low sensitivity, resulting in great limitations in practical applications. Herein, a novel electrochemical biosensor was constructed for highly sensitive detection of Nosema bombycis gene DNA (PTP1) through transducing chemical stimuli H+ from PTP1-based LAMP into electrochemical output signal of electroactive ferrocene (Fc). With use of target PTP1 as the template, the H+ from LAMP induced the conformational switch of pH responsive DNA nanostructures (DNA NSs, Fc-Sp@Ts) that was assembled by the hybridization of Fc-labeled signal probe (Fc-Sp) with DNA-based receptor (Ts). Due to the folding of Ts into stable triplex structure at decreased pH, the configuration change of Fc-Sp@Ts led to the releasing of Fc-Sp, which was subsequently immobilized in the electrode interface through the hybridization with the capture probe modified with -SH (SH-Cp), generating amplified electrochemical signal from Fc. The developed biosensor for PTP1 exhibited a reliable linear range of 1 fg uL-1 to 50 ng uL-1 with the limit of detection of 0.31 fg uL-1. Thus, by the regulation of H+ from LAMP reaction on DNA NSs allostery, this novel and simple transduction scheme would be interesting and promising to open up a novel analytical route for sensitive monitoring of different target DNAs in related disease diagnosis. PMID- 29427925 TI - Ultrasmall mesoporous organosilica nanoparticles: Morphology modulations and redox-responsive biodegradability for tumor-specific drug delivery. AB - Beyond mesoporous silica nanoparticles (MSNs), mesoporous organosilica nanoparticles (MONs) have been becoming an even more attractive alternative to the traditional organic or inorganic nanomaterials in biomedical applications, especially for drug delivery, due to its high surface area, stable physicochemical properties, low toxicity, high biocompatibility, and particularly the devisable features decided by the incorporated organic fragments. However, it is still challenging to fabricate uniform ultrasmall MONs with tunable composition, morphology and fine biodegradability. Herein, we report, on the large-scale fabrication of monodispersed and molecularly organic-inorganic hybrid MONs with framework-incorporated physiologically active thioether bonds, controllable nanostructure, composition and morphology, which provides the material foundation for exploring the versatile biomedical applications of organosilica nanosystems. The hybrid MONs of less than 50 nm in particle size exhibit the unique reduction-responsive biodegradation behavior, and the biodegradation rate is significantly higher than that of traditional mesoporous silica nanoparticles with pure inorganic SiOSi framework. The reductive microenvironment-triggered biodegradation of MONs induces the concurrent reduction-responsive anticancer drug releasing from MONs, enabling tumor-specific drug delivery. Importantly, these biocompatible and biodegradable MONs exhibit significantly improved drug-delivery efficiency and enhanced tumor-suppressing effect for combating cancer. Based on the facile and large-scale fabrication of MONs with controllable key structure/composition/morphology parameters, unique tumor microenvironment-responsive biodegradation behavior and high performance for drug delivery, the MONs therefore show more promising potentials for clinical translation as compared to traditional MSNs. PMID- 29427926 TI - Cyclic cRGDfk peptide and Chlorin e6 functionalized silk fibroin nanoparticles for targeted drug delivery and photodynamic therapy. AB - Regenerated silk fibroin (SF) is a natural biomacromolecule with excellent biocompatible and biodegradable properties. In this study, cyclic pentapeptide cRGDfk and Chlorin e6 (Ce6) were conjugated to SF polypeptides, and genipin was used to prepare 5-fluorouracil (5-FU) doped SF-based nanoparticles (NPs). The photodynamic therapy (PDT) potential and active targeting properties were systematically investigated in alphavbeta3 integrin receptor over-expressed MGC 803 cells in vitro. The results revealed that treatment with the multifunctional SF-based NPs and PDT, high level of reactive oxygen species (ROS) and cell death can be induced in MGC-803 cells. Combine with PDT, the in vivo antitumor effect of the SF-based NPs was evaluated in gastric cancer xenograft mice model. The results demonstrated that the SF-based NPs had ideal active tumor targeting property and the tumor burden can be reduced noticeably. Furthermore, the organs of mice in SF NPs treatment groups did not show obvious toxicity, demonstrating good biocompatibility and security profiles of SF NPs in vivo. Overall, our results suggest that the SF-based NPs are promising drug delivery carriers, together with PDT, the multimodality therapy could be potential regimen in future clinical cancer treatment. PMID- 29427927 TI - Using Chitosan/CHPATC as coagulant to remove color and turbidity of industrial wastewater: Optimization through RSM design. AB - One of the most important solid-liquid separation processes is coagulation and flocculation that is extensively used in the primary treatment of industrial wastewater. The biopolymers, because of biodegradable properties and low cost have been used as coagulants. In this study, chitosan as a natural coagulant of choice, was modified by (3-chloro 2-hydroxypropyl)trimethylammonium chloride and was used to remove the color and turbidity of industrial wastewater. To evaluate the effect of pH, settling time, the initial turbidity of wastewater, the amount of coagulant, and the concentration of dye (Melanoidin) were chosen to study their effects on removal of wastewater color and turbidity. The experiments were done in a batch system by using a jar test. To achieve the optimum conditions for the removal of color and turbidity, the response surface methodology (RSM) experimental design method was used. The results obtained from experiments showed that the optimum conditions for the removal of color were as: pH = 3, concentration of dye = 1000 mg/L, settling time = 78.93 min, and dose of coagulant = 3 g/L. The maximum color removal in these conditions was predicted 82.78% by the RSM model. The optimal conditions for the removal of turbidity of the waste water were as: pH = 5.66, initial turbidity = 60 NTU, settling time = 105 min, and amount of coagulant = 3 g/L. The maximum turbidity removal in these circumstances was predicted 94.19% by the model. The experimental results obtained in optimum conditions for removal of color and turbidity were 76.20% and 90.14%, respectively, indicating the high accuracy of the prediction model. PMID- 29427928 TI - Facile synthesis of hierarchical nickel (III) oxide nanostructure: A synergistic remediating action towards water contaminants. AB - Heavy metal ion removal from consumable water is an indispensable need to maintain healthy life. Therefore cost effective and highly efficient sorbents are strongly needed to pose threat to real water pollution. Nanomaterials are widely used to maintain clean aqueous system in a very cost effective way with high removal efficiency. In this present work, pure coral like Ni2O3 nanostructures were prescribed for Cr(VI) remediation which were prepared by two step synthesis procedure at room temperature. The single hierarchical morphology as confirmed from HRTEM (size~200 nm) were subjected to toxic Cr(VI) ion removal experiments. They were found to remove ~65% Cr(VI) ions that was higher than that of pure Ni2O3 nanoparticles of comparable size. The enhanced properties were explained on the basis of the defect states present within the nanostructure, investigated by positron annihilation lifetime spectroscopy (PALS). It was found that the hierarchical nanostructure had more number of di-vacancies and vacancy-clusters as compared to the particles. On performing isotherm fitting, it was found that the coral like morphology had a high heterogeneity factor that aided to a high adsorption rate when compared to the pure Ni2O3 nanoparticles (which had a homogenous surface). The synthesized nanostructure was severely toxic to bacterial community having minimum inhibitory concentration (MIC) of ~300 MUg/L. Also the nanostructure exhibited dual functionality towards Cr(VI) and bacteria contaminated water at 200 MUg/ml. The maximum Cr(VI) removal efficiency for this dual system is found to be 39% whereas antibacterial activity was turned out to be 30% which was extensively higher than that of toxic Cr(VI) ions. A plausible mechanism for the dual functionality was also predicted. PMID- 29427929 TI - Electrochemical removal and recovery of iron from groundwater using non-corrosive electrodes. AB - Iron contamination in groundwater has attracted much attention from environmentalists and government agencies because it can cause many problems in human life and in industrial and agricultural activities when groundwater is directly used without any treatment. This study aims to investigate the electrochemical oxidation of Fe(II) to Fe(III) and recovery of insoluble Fe(III) using non-corrosive graphite electrode which serves as a controllable, low-cost, low maintenance and virtually unlimited electron acceptor for Fe(II) oxidation. The lab-scale results indicated that Fe(II) removal up to 100% was obtained at an applied voltage higher than 2 V. The Fe(II) removal efficiency was linearly increased with the increase of potential supply in the range of 1-4 V in the salinity 0.5%. The Fe(II) removal rate could no longer be enhanced at the applied potential higher than 8 V in the condition without salinity. The results from SEM EDS and XRD revealed that Fe was recovered as FeOOH by conventional filtration with a recovery efficiency of 82.7-92.1%. The electrochemical Fe(II) removal might be an alternative for the conventional method of the in situ Fe removal from groundwater. Besides, the recovered FeOOH can be used as a raw material for environmental remediation and pigment industry. PMID- 29427931 TI - Viscoelastic properties of multi-layered cellularized vascular tissues fabricated from collagen gel. AB - Since collagen is one of the major extracellular matrix components in vascular tissues, its use for vascular tissue engineering has several advantages. However, collagen extraction and processing for tissue engineering application alters its structure. As a result, collagen-based vascular constructs show poor mechanical properties compared to native tissues. In this work, multi-layer (single, double, and triple) vascular tissue constructs were engineered from porcine smooth muscle cells (PSMCs) entrapped in collagen gel by concentrically and sequentially layering after compaction of the previous layer(s). The engineered tissues were matured for either 14 or 21 days to allow the collagen gel to remodel before viscoelasticity, compliance, histological, and protein expression studies were conducted. While there was no significant difference upon addition of the different layers on the elastic modulus (p > .05), the viscous modulus of the single layer construct was significantly lower than the double and triple layer constructs (p < .05). Increasing the number of layers of the cellularized collagen construct increased the wall thickness and the viscous modulus of the construct. Furthermore, the cellularized single-layer construct had a relatively high compliance, but the double and triple layer constructs had compliance values comparable to both engineered vessels and native vessels. PSMCs were uniformly distributed throughout the cross-section and expressed the anticipated marker proteins smooth muscle-alpha actin, calponin, and smooth muscle myosin heavy chain. Taken together, this study demonstrated the viscoelastic responsiveness of multi-layer collagen-gel based vascular tissues. PMID- 29427930 TI - Diagnosis of drowning by summation of sodium, potassium, and chloride ion levels in sphenoidal sinus fluid: Differentiating between freshwater and seawater drowning and its application to brackish water and bathtub deaths. AB - Analysis of ions in sphenoidal fluid can be a useful index for the diagnosis of drowning. We evaluated the reference ranges of non-drowning cases using statistical methods and three indices: sodium ion (Na+), summation of sodium and potassium ions (SUMNa+K), and summation of sodium, potassium and chloride ions (SUMNa+K+Cl). The reference ranges were 96<=Na+<152, 139<=SUMNa+K<179, 243<=SUMNa+K+Cl<311(mEq/L), respectively. Victim indices outside of the reference ranges indicate that the victim probably inspired water with higher or lower ion concentrations than those of body fluid in sphenoidal sinuses. Compared to the SUMNa+K+Cl index, the Na+ and SUMNa+K indices could distinguish among seawater drowning, freshwater drowning, and non-drowning. In drowning cases, sphenoidal fluid volume and time since death were not correlated, which suggests that water does not enter the sphenoidal sinuses after death and there is a different process for water accumulation in drowning and non-drowning cases. In bathtub cases, this method was not valid for the estimation of inspired water. Although it is necessary to observe the classical signs of drowning, this method is suitable for the estimation of drowning, especially in cases where pleural fluid or diatom tests are not available. PMID- 29427932 TI - A simple model for constant storage modulus of poly (lactic acid)/poly (ethylene oxide)/carbon nanotubes nanocomposites at low frequencies assuming the properties of interphase regions and networks. AB - The networks of nanoparticles in nanocomposites cause solid-like behavior demonstrating a constant storage modulus at low frequencies. This study examines the storage modulus of poly (lactic acid)/poly (ethylene oxide)/carbon nanotubes (CNT) nanocomposites. The experimental data of the storage modulus in the plateau regions are obtained by a frequency sweep test. In addition, a simple model is developed to predict the constant storage modulus assuming the properties of the interphase regions and the CNT networks. The model calculations are compared with the experimental results, and the parametric analyses are applied to validate the predictability of the developed model. The calculations properly agree with the experimental data at all polymer and CNT concentrations. Moreover, all parameters acceptably modulate the constant storage modulus. The percentage of the networked CNT, the modulus of networks, and the thickness and modulus of the interphase regions directly govern the storage modulus of nanocomposites. The outputs reveal the important roles of the interphase properties in the storage modulus. PMID- 29427933 TI - Influence of suture size on the frictional performance of surgical suture evaluated by a penetration friction measurement approach. AB - The frictional performances of surgical sutures have been found to play a vital role in their functionality. The purpose of this paper is to understand the frictional performance of multifilament surgical sutures interacting with skin substitute, by means of a penetration friction apparatus (PFA). The influence of the size of the surgical suture was investigated. The relationship between the friction force and normal force was considered, in order to evaluate the friction performance of a surgical suture penetrating a skin substitute. The friction force was measured by PFA. The normal force applied to the surgical suture was estimated based on a Hertzian contact model, a finite element model (FEM), and a uniaxial deformation model (UDM). The results indicated that the penetration friction force increased as the size of the multifilament surgical suture increased. In addition, when the normal force was predicted by UDM, it was found that the ratio between the friction force and normal force decreased as the normal force increased. A comparison of the results suggested that the UDM was appropriate in predicting the frictional behavior of surgical suturing. PMID- 29427935 TI - Molecular dynamics investigation of the mechanical behavior of multi-layered graphyne and its family under tensile loading. AB - This paper aims to study the mechanical properties of the multi-layered graphyne and other members of the graphyne family under the uniaxial tensile loading. For this purpose, molecular dynamics simulations are used. The effects of the size and number of layers on the fracture and elastic properties are studied. It is shown that Young's modulus of the zigzag multi-layered graphyne is slightly larger than armchair one. Comparing the stress-strain curves of the multi-layered graphynes with different number of layers, it is observed that the fracture stress and strain of the nanosheets are inversely related to the number of layers. Investigating the influence of the number of acetylene linkage in the structure of the graphyne-n family on their mechanical properties, it is shown increasing the number of triple bonds leads to weakening the fracture stress and Young's modulus of the nanosheet. PMID- 29427934 TI - Assessment of nanoscopic dynamic mechanical properties and B-C-N triad effect on MWCNT/h-BNNP nanofillers reinforced HDPE hybrid composite using oscillatory nanoindentation: An insight into medical applications. AB - A thrust on improvement of different properties of polymer has taken a contemporary route with advent of nanofillers. Although several nanofillers are existent; MultiWalled Carbon Nanotubes- (MWCNTs) and h-Boron Nitride nanoplatelets-(h-BNNPs) unique combination of 1D and 2D dimensional geometry aids an advantage of B-C-N triad elemental effects on properties of tested samples. The current study aims to investigate the effects of MWCNT and h-BNNP reinforcement in High Density Polyethylene (HDPE) for high load bearing areas of medical applications requiring both elastic and viscous behavior. The results were analyzed keeping a view of its application in areas like HDPE based fracture fixation plates, acetabular cups and others. The composite and hybrid samples with different loadings were prepared after surface modification of nanofillers by mechanical mixing and molding technique. The dynamic nano-mechanical properties like storage modulus, loss modulus and tan delta were assessed for each sample during frequency swept from 10 to 220 Hz. The viscoelastic properties like hc/hm, H/E, elastic-plastic deformation were investigated and evaluated. At a frequency of 10 Hz, the storage and loss modulus of 0.1 CNT increased by 37.56% and decreased by 23.52% respectively on comparison with pure HDPE. This infers a good elastic as well as viscous behavior. Overall elastic behavior of 0.1 CNT was confirmed from tan delta evaluation. The interaction between B-C-N elemental triad had significant effect on creep strength, visco-damping property (hc/hm and H/E), elastic plastic displacement and pile-up and sink-in behavior. Highest creep strength and visco-damping property was exhibited by 0.25 CNT/0.15 BNNP hybrid. The elastic-plastic displacement of hybrid composite was noted as least, which decreased by 30% on comparison with pure HDPE. It can be inferred that presence of 1D-MWCNT and 2D-h-BNNP had significant effect on important dynamic viscoelastic and creep properties of HDPE based hybrid composites. PMID- 29427936 TI - Eurecon: Equidistant uniform rigid-body ensemble constructor. AB - Conformational ensembles comprise one of the fundamental concepts in statistical bioinformatics and appear in a variety of applications, e.g. molecular docking, virtual screening, searching for pharmacophores, etc. High-throughput applications require billions of conformations to be considered, thus, one often uses the rigid-body representation of molecules or its fragments to cope with the computational cost. Of particular interest is generation of the near-native conformational ensembles, which consist of conformations structurally close to the biologically relevant ones. One possible way to compose such ensembles is to control the root mean square deviation (RMSD) between the original and the generated conformations. To the best of our knowledge there is no computational approach that guarantees that all the generated conformations have the desired RMSD with respect to the reference structure. In this study we presented a fast algorithm for the construction of rigid-body conformational ensembles, which possess two main properties: (i) each generated conformation has a fixed RMSD with respect to the original conformation, (ii) generated conformations are distributed uniformly over the sphere of axes corresponding to the rigid-body motions. The algorithm is very efficient, it does not require any standard RMSD computation between the conformations and has the O(N + M) complexity to generate the required rigid-body transforms, where N is the number of atoms in the system, and M is the size of the conformational ensemble. Eurecon is applicable to an arbitrary atomic system, thus, it could be used for molecular systems of various size and type. We demonstrated Eurecon application by generating near-native conformational ensembles for a ligand placed inside a binding site, a protein dimer embedded into a membrane, and a ribosomal complex. We implemented the developed algorithm in C++ and called it Eurecon, which stands for Equidistant Uniform Rigid-body Ensemble CONstructor. A user-friendly interface allows to define the desired RMSD value, the relative amplitudes for rotation and translation motions by means of the partition parameter, and the set of axes corresponding to the rigid-body motions. Eurecon is available as the SAMSON Element (https://samson-connect.net). PMID- 29427937 TI - Synthesis and characterization of stabilized oxygen-releasing CaO2 nanoparticles for bioremediation. AB - Bioremediation is one of the general methods to treat pollutants in soil, sediment, and groundwater. However, the low concentration and restricted dispersion of dissolved oxygen (DO) in these areas have limited the efficiency of remediation especially for microorganisms that require oxygen to grow. Calcium peroxide (CaO2) is one of the oxygen-releasing compounds and has been applied to magnify the remediation efficacy of polluting areas. In this study, CaO2 nanoparticles (NPs) were synthesized and evaluated by wet chemistry methods as well as dry and wet grinding processes. The characteristics of CaO2 particles and NPs were analyzed and compared by dynamic light scattering, transmission electron microscopy, scanning electron microscopy, and X-ray powder diffraction. Our results showed that wet-grinded CaO2 NPs had an average particle size of around 110 nm and were more stable compared to other particles from aggregation and sedimentation tests. In addition, we also observed that CaO2 NPs had better DO characteristics and patterns; these NPs generated higher DO levels than their non grinded form. Accordingly, our results suggested that wet-grinding CaO2 particles to nanoscale could benefit their usage in bioremediation. PMID- 29427938 TI - Comparison of the common spatial interpolation methods used to analyze potentially toxic elements surrounding mining regions. AB - The appropriate spatial interpolation methods must be selected to analyze the spatial distributions of Potentially Toxic Elements (PTEs), which is a precondition for evaluating PTE pollution. The accuracy and effect of different spatial interpolation methods, which include inverse distance weighting interpolation (IDW) (power = 1, 2, 3), radial basis function interpolation (RBF) (basis function: thin-plate spline (TPS), spline with tension (ST), completely regularized spline (CRS), multiquadric (MQ) and inverse multiquadric (IMQ)) and ordinary kriging interpolation (OK) (semivariogram model: spherical, exponential, gaussian and linear), were compared using 166 unevenly distributed soil PTE samples (As, Pb, Cu and Zn) in the Suxian District, Chenzhou City, Hunan Province as the study subject. The reasons for the accuracy differences of the interpolation methods and the uncertainties of the interpolation results are discussed, then several suggestions for improving the interpolation accuracy are proposed, and the direction of pollution control is determined. The results of this study are as follows: (i) RBF-ST and OK (exponential) are the optimal interpolation methods for As and Cu, and the optimal interpolation method for Pb and Zn is RBF-IMQ. (ii) The interpolation uncertainty is positively correlated with the PTE concentration, and higher uncertainties are primarily distributed around mines, which is related to the strong spatial variability of PTE concentrations caused by human interference. (iii) The interpolation accuracy can be improved by increasing the sample size around the mines, introducing auxiliary variables in the case of incomplete sampling and adopting the partition prediction method. (iv) It is necessary to strengthen the prevention and control of As and Pb pollution, particularly in the central and northern areas. The results of this study can provide an effective reference for the optimization of interpolation methods and parameters for unevenly distributed soil PTE data in mining areas. PMID- 29427939 TI - Identifying social factors that undermine support for nature-based coastal management. AB - Human use and degradation of coastal ecosystems is at an all-time high. Thus, a current challenge for environmental management and research is moving beyond ecological definitions of success and integrating socioeconomic factors. Projects and studies with this aim, however, have focused primarily on monetary valuations of ecosystem functions, overlooking the behaviors and psycho-social motivations of environmental management. Using a nature-based salt marsh restoration project on Martha's Vineyard, Massachusetts, we assess the role of human attitudes and preferences in evaluating social success for ecosystem management. We use structural equation modeling to compare the strengths of social variables in predicting restoration project support, and find public understanding to be a more important predictor than personal values. Our results show that even among stakeholders with strong pro-environmental values, a weak understanding of the management initiative can undermine support. We also find that project support does not necessarily translate to the prioritization of similar management strategies. Instead, when individuals consider overall management priorities, differences arise between particular resource user-groups. This suggests that strong public support for individual initiatives can misconstrue complexities in stakeholder preferences that emerge in more comprehensive management considerations. Future investigations of the psycho-social components of management solutions should address the potentially tiered nature of human preferences, as well as whether public perceptions of management effectiveness act as an additional context-dependency of social viability. PMID- 29427940 TI - Isolation and identification of the native population bacteria for bioremediation of high levels of arsenic from water resources. AB - Health of millions of people is threatened by the risk of drinking arsenic contaminated water worldwide. Arsenic naturally conflicts with the concept of life, but recent studies showed that some microorganisms use toxic minerals as the source of energy. Hence, the researchers should consider the development of cost-effective and highly productive procedures to remove arsenic. The current study was conducted on a native bacterial population of Seyed-Jalaleddin Spring Kurdistan, Iran. Accordingly, the arsenic amount in water samples was measured >500 MUg/L by the two field and in vitro methods. Water samples were transferred to laboratory and cultured on chemically defined medium (CDM) with arsenic salts. A total of 14 native arsenic-resistant bacterial strains were isolated and after providing pure culture and performing biochemical tests, the isolates were identified using polymerase chain reaction (PCR) and 16s rRNA genomic sequencing. The potential of bacterial strains for the biotransformation of arsenic was assessed by the qualitative assessment of AgNO3 method and efficiency of arsenic speciation was determined for the first time by silver diethyldithiocarbamate (SDDC) method with an error of less than 5%. Among the isolated strains, only strain As-11 and strain As-12 showed arsenic transformation characteristics and were registered in NCBI database by the access numbers KY119262 and KY119261, respectively. Results of the current study indicated that strain As-11 had the potential of biotransformation of As(V) to As(III) and vice versa with the efficiency of 78% and 48%, respectively. On the other hand, strain As-12 had the potential for biotransformation of As(V) to As(III) and vice versa with the efficiency of 28% and 45%, respectively. PMID- 29427941 TI - Chemical and biological assessment of Cd-polluted sediment for land use: The effect of stabilization using chitosan-coated zeolite. AB - Disposal of dredged sediment contaminated with heavy metals on site or in landfills inevitably causes leaching of metals that generate new environmental problems. In this study, we investigated the effectiveness of stabilizing heavy metal Cd in sediment taken from Dongting Lake, China, using a chitosan-coated zeolite, and assessed the feasibility of reusing the stabilized sediment in river bank soil based on chemical and biological analyses. Results showed that the addition of chitosan-coated zeolite significantly reduced acid-exchangeable Cd by 8% in the dredged sediment and 7% in a sediment-soil mixture. Cadmium leachability was greatly reduced in the amended sediment or sediment-soil mixture. Toxicity bioassay using Eisenia fetida showed the mortality rate of worms reduced by 16% in sediment-soil mixture with a Cd concentration of 550 mg/kg and by 17% under a Cd concentration of 250 mg/kg, both with the addition of modified zeolite. Moreover, assimilation of Cd in the earthworms was decreased by a maximum of 36 mg/kg in the sediment-soil mixture with zeolite amendment. These results indicate that the reuse of Cd-contaminated sediment following chitosan coated zeolite modification is a feasible option for treating the dredged sediment, and could thus benefit both aquatic and terrestrial systems. PMID- 29427942 TI - Ethanol content in different gasohol blend spills influences the decision-making on remediation technologies. AB - Gasohol blend spills with variable ethanol content exert different electron acceptor demands in groundwater and the distinct dynamics undergone by these blends underscores the need for field-based information to aid decision-making on suitable remediation technologies for each gasohol blend spill. In this study, a comparison of two gasohol releases (E10 (10:90 ethanol and gasoline, v/v) and E25 (25:75 ethanol and gasoline, v/v) under monitored natural attenuation (MNA) and nitrate biostimulation, respectively) was conducted to assess the most effective remediation strategy for each gasohol release. Microbial communities were assessed to support geochemical data as well as to enable the characterization of important population shifts that evolve during biodegradation processes in E25 and E10 field experiments. Results revealed that natural attenuation processes sufficiently supported ethanol and BTEX compounds biodegradation in E10 release, due to the lower biochemical oxygen demand they exert relative to E25 blend. In E25 release, nitrate reduction was largely responsible for BTEX and ethanol biodegradation, as intended. First-order decay constants demonstrated that ethanol degradation rates were similar (p < 0.05) for both remediation technologies (2.05 +/- 0.15 and 2.22 +/- 0.23, for E25 and E10, respectively) whilst BTEX compounds exhibited different degradation rates (p > 0.05) that were higher for the experiment under MNA (0.33 +/- 0.06 and 0.43 +/- 0.03, for E25 and E10, respectively). Therefore, ethanol content in different gasohol blends can influence the decision-making on the most suitable remediation technology, as MNA processes can be applied for the remediation of gasohol blends with lower ethanol content (i.e., 10% v/v), once the aquifer geochemical conditions provide a sufficient electron acceptor pool. To the best of our knowledge, this is the first field study to monitor two long-term gasohol releases over various time scales in order to assess feasible remediation technologies for each scenario. PMID- 29427943 TI - Introducing nursing practice to student nurses: How can we promote care compassion and empathy. AB - To the population nursing and caring are synonymous. Empathy and using therapeutic relationships are ways that nurses can utilise care and compassion in their practice. However health care delivery needs to be led by evidence and one way to ensure evidence-based care is delivered compassionately and with empathy is to utilise the principles of nursing therapeutics. Nursing therapeutics allows a nurse to understand how care should be delivered as well as why. This discussion paper explores the use of therapeutic relationship building, nursing therapeutics and compassionate nursing and how neophyte student nurses can be introduced into these concepts during their first practice exposure. Using clinical case-studies, role-play and reflective discussion, student nurses explore and re-evaluate assumptions, to apprise and consider their beliefs and their impulse to care. Educational dialogue encourages a connection with the patient, to the person and their humanity. The implementation of this approach is facilitated by the use of newly devised learning resources which have been formulated to frame the encounter and to enable the student to look at their interaction and develop their therapeutic approach. PMID- 29427944 TI - Antimicrobial coatings on polyethylene terephthalate based on curcumin/cyclodextrin complex embedded in a multilayer polyelectrolyte architecture. AB - Bacterial contamination is a growing concern worldwide. The aim of this work was to develop an antimicrobial coating based on curcumin-cyclodextrin inclusion complex and using polyethylene terephthalate (PET) film as a support matrix. After a pre-treatment aimed to provide sufficient electric charge to the PET surface, it was electrostatically coated with repeated multilayers comprising alternately deposited positively-charged poly-l-lysine (PLL) and negatively charged poly-l-glutamic acid (PLGA) and carboxymethyl-beta-cyclodextrin (CMBCD). The coatings had an architecture (PLL-PLGA)6-(PLL-PLGA-PLL-CMBCD)n, with the number of repeated multilayers n varying from 5 to 20. The CMBCD molecules were either covalently cross-linked using carbodiimide crosslinker chemistry or left unbound. The surface morphology, structure and elemental composition of the coatings were analysed by scanning electron microscopy and energy dispersive x ray spectroscopy. To impart antimicrobial properties to the coatings they were loaded with a natural phenolic compound curcumin forming inclusion complexes with beta-cyclodextrin. The non-cross-linked coatings showed bactericidal activity towards Escherichia coli in the dark, and this activity was further enhanced upon illumination with white light. Curcumin was released from the non-cross-linked coatings into an aqueous medium in the form of cyclodextrin inclusion complex. After the cross-linking, the coating lost its dark antimicrobial activity but retained the photodynamic properties. Stabilized cross-linked curcumin-loaded coatings can serve a basis for developing photoactivated antimicrobial surfaces controlling bacterial contamination and spread. PMID- 29427945 TI - Bioactive calcium phosphate silicate ceramic surface-modified PLGA for tendon-to bone healing. AB - Due to the dissimilar features between the tendon and bone, tendon to bone healing is the most challenging problems in sports medicine. In the present work, a novel bioactive calcium phosphate silicate ceramic (CPS) was coated on the surface of PLGA films using electron beam evaporation (EBE) technique to prepare a tailorable composite film with layered chemical composition similar to tendon bone interface. The physicochemical behaviors of the CPS-PLGA composite films were characterized and the cytocompatibility were also investigated. It was found that the CPS-modified samples exhibited a significantly improved hydrophilicity and a more negative zeta potential. Cell culture results showed that the CPS modified samples were beneficial to the attachment and proliferation of rBMSCs and NIH3T3 cells. CPS-modified samples also showed an improved osteogenic activity. The results suggested that CPS-modified PLGA films have great potentials for tendon-bone healing. PMID- 29427946 TI - Bioreducible amino acid-derived polymeric nanoparticles for delivery of functional proteins. AB - We report the preparation of protein encapsulated amino acid derived redox responsive nanoparticles (NPs) as effective nanocarriers for intracellular delivery of proteins. More specifically, acryloyl derivatives of lysine, ornithine, cystine and cystamine, were employed as monomers and disulfide crosslinkers for non-covalent encapsulation of model protein bovine serum albumin (BSA) and were interfacially crosslinked via free radical polymerization to form redox-responsive protein NPs. Notably, prepared NPs exhibited high protein loading content between 37 and 45%, averaged ~400 nm in hydrodynamic size and possessed a mean surface charge of -15 mV. Furthermore, blank polymeric NPs displayed exceptional cytocompatibility with cell viability exceeding 92% at concentrations as high as 4 mg/mL, while redox-responsive protein NPs displayed glutathione (GSH)-dependent BSA release behavior in vitro. Additionally, cellular uptake studies confirmed that protein NPs entered MDA-MA-231 cells predominantly via the endocytic pathway. Upon cellular internalization, redox-responsive NPs delivered protein into cytosol of cells within 60 min demonstrating intrinsic endosomolytic characteristics and efficient protein release under cytoplasmic high GSH conditions. Most importantly, insulin analog-loaded NPs significantly increased glucose consumption in HepG2 cultures confirming protein stability and retention of protein function. Cumulatively, our approach presents a simple yet effective strategy for intracellular delivery of biologically active proteins for various biomedical applications. PMID- 29427948 TI - An attitude of gratitude: The effects of body-focused gratitude on weight bias internalization and body image. AB - Internalized weight bias and body dissatisfaction are associated with a number of negative psychological and physical health outcomes. The current study examined the effectiveness of body-focused gratitude, through a short writing exercise, as a strategy to reduce internalized weight bias and improve body image. Young adults (Mage = 22.71, SD = 2.08, 51.2% female) were randomly assigned to either a body gratitude condition (n = 185) or a control condition (n = 184). Results indicated that participants in the gratitude condition reported significantly lower weight bias internalization and significantly more favorable appearance evaluation and greater body satisfaction when compared to the control condition. These effects were in the small range (ds = 0.27-0.33), and neither gender nor BMI moderated these effects. These findings provide preliminary support for body focused gratitude writing exercises as an effective individual-level strategy for both reducing internalized weight bias and improving body image. PMID- 29427947 TI - Analysis of ribosomal RNA stability in dead cells of wine yeast by quantitative PCR. AB - During wine production, some yeasts enter a Viable But Not Culturable (VBNC) state, which may influence the quality and stability of the final wine through remnant metabolic activity or by resuscitation. Culture-independent techniques are used for obtaining an accurate estimation of the number of live cells, and quantitative PCR could be the most accurate technique. As a marker of cell viability, rRNA was evaluated by analyzing its stability in dead cells. The species-specific stability of rRNA was tested in Saccharomyces cerevisiae, as well as in three species of non-Saccharomyces yeast (Hanseniaspora uvarum, Torulaspora delbrueckii and Starmerella bacillaris). High temperature and antimicrobial dimethyl dicarbonate (DMDC) treatments were efficient in lysing the yeast cells. rRNA gene and rRNA (as cDNA) were analyzed over 48 h after cell lysis by quantitative PCR. The results confirmed the stability of rRNA for 48 h after the cell lysis treatments. To sum up, rRNA may not be a good marker of cell viability in the wine yeasts that were tested. PMID- 29427949 TI - Evaluation of a national data set for insights into sources, composition, and concentrations of per- and polyfluoroalkyl substances (PFASs) in U.S. drinking water. AB - The United States Environmental Protection Agency (USEPA) completed nationwide screening of six perfluoroalkyl substances in U.S. drinking water from 2013 to 2015 under the Third Unregulated Contaminant Monitoring Rule (UCMR3). UCMR3 efforts yielded a dataset of 36,139 samples containing analytical results from >5000 public water systems (PWSs). This study used UCMR3 data to investigate three aspects of per- and polyfluoroalkyl substances (PFASs) in drinking water: the occurrence of PFAS and co-contaminant mixtures, trends in PFAS detections relative to PWS characteristics and potential release types, and temporal trends in PFAS occurrence. This was achieved through bivariate and multivariate analyses including categorical analysis, concentration ratios, and hierarchical cluster analysis. Approximately 50% of samples with PFAS detections contained >=2 PFASs, and 72% of detections occurred in groundwater. Large PWSs (>10,000 customers) were 5.6 times more likely than small PWSs (<=10,000 customers) to exhibit PFAS detections; however, when detected, median total PFAS concentrations were higher in small PWSs (0.12 MUg/L) than in large (0.053 MUg/L). Bivariate and multivariate analyses of PFAS composition suggested PWSs reflect impacts due to firefighting foam use and WWTP effluent as compared to other source types for which data were available. Mann-Kendall analysis of quarterly total PFAS detection rates indicated an increasing trend over time (p = 0.03). UCMR3 data provide a foundation for tiered design of targeted sampling and analysis plans to address remaining knowledge gaps in the sources, composition, and concentrations of PFASs in U.S. drinking water. PMID- 29427950 TI - Polyaniline/beta-MnO2 nanocomposites as cathode electrocatalyst for oxygen reduction reaction in microbial fuel cells. AB - An efficient and inexpensive catalyst for oxygen reduction reaction (ORR), polyaniline (PANI) and beta-MnO2 nanocomposites (PANI/beta-MnO2), was developed for air-cathode microbial fuel cells (MFCs). The PANI/beta-MnO2, beta-MnO2, PANI and beta-MnO2 mixture modified graphite felt electrodes were fabricated as air cathodes in double-chambered MFCs and their cell performances were compared. At a dosage of 6 mg cm-2, the maximum power densities of MFCs with PANI/beta-MnO2, beta-MnO2, PANI and beta-MnO2 mixture cathodes reached 248, 183 and 204 mW m-2, respectively, while the cathode resistances were 38.4, 45.5 and 42.3 Omega, respectively, according to impedance analysis. Weak interaction existed between the rod-like beta-MnO2 and surficial growth granular PANI, this together with the larger specific surface area and PANI electric conducting nature enhanced the electrochemical activity for ORR and improved the power generation. The PANI/beta MnO2 nanocomposites are a promising cathode catalyst for practical application of MFCs. PMID- 29427951 TI - Recovery of ammonium from aqueous solutions using ZSM-5. AB - The demand of reactive nitrogen (N), such as ammonium (NH4+) and nitrate (NO3-), continues to increase for fertilizer applications as the population grows, but the Haber Bosch (HB) process currently employed for industrial N fixation is challenged by low efficiency and high energy consumption. Here we report on the investigation of ZSM-5 as a superior sorbent for the recovery of ammonium from aqueous solutions. Fast capture and release of ammonium (NH4+) have been achieved with >90% overall efficiency of recovery using synthetic solutions of NH4Cl and NaCl, respectively. The ZSM-5 sorbent has also been found to be recyclable and sustain high recovery efficiencies after multiple capture-release cycles. The capture of N has been further studied systematically in dependence of the dose of sorbent and reaction temperature, based on which the mechanism, thermodynamics and kinetics of ion exchange are discussed. Compared to other ion-exchange materials, the ZSM-5 sorbent exhibits superior selectivity for capturing ammonium in the presence of competing cations (NH4+ " Ca2+ > Mg2+ > K+ > Na+) and demonstrates high efficiency of ammonium recovery from real wastewater streams. PMID- 29427952 TI - Survey of 218 organic contaminants in groundwater derived from the world's largest untreated wastewater irrigation system: Mezquital Valley, Mexico. AB - The Mezquital Valley system is the world's oldest and largest example with regard to use of untreated wastewater for agricultural irrigation. Because of the artificial high recharge associated with the Mezquital Valley aquifers, groundwater is extracted for human consumption, and there are plans to use this groundwater as a water resource for Mexico City. Thus, this study analyzed 218 organic micro-contaminants in wastewater, springs, and groundwater from Mezquital Valley. Five volatile organic compounds (VOCs) and nine semi-volatile organic compounds (SVOCs) were detected in the wastewater used for irrigation. Only two SVOCs [bis-2-(ethylhexyl) phthalate and dibutyl phthalate] were detected in all the wastewater canals and groundwater sources, whereas no VOCs were detected in groundwater and springs. Of the 118 pharmaceutically active compounds (PhACs) and 7 reproductive hormones measured, 65 PhACs and 3 hormones were detected in the wastewater. Of these, metformin, caffeine, and acetaminophen account for almost sixty percent of the total PhACs in wastewater. Nevertheless, 23 PhACs were detected in groundwater sources, where the majority of these compounds have low detection frequencies. The PhACs sulfamethoxazole, N,N-diethyl-meta-toluamide, carbamazepine, and benzoylecgonine (primary cocaine metabolite) were frequently detected in groundwater, suggesting that although the soils act as a filter adsorbing and degrading the majority of the organic pollutant content in wastewater, these PhACs still reach the aquifer. Therefore, the presence of these PhACs, together with the high levels of the endocrine disruptor bis-2 (ethylhexyl) phthalate, indicate that water sources derived from the recharge of the studied aquifers may pose a risk to consumer health. PMID- 29427953 TI - Genotoxic and carcinogenic effects of non-ionizing electromagnetic fields. AB - New technologies in electronics and communications are continually emerging. An increasing use of these electronic devices such as mobile phone, computer, wireless fidelity connectors or cellular towers is raising questions concerning whether they have an adverse effect on the body. Exposure to electromagnetic fields (EMF) is frequently suggested to have adverse health effects on humans and other organisms. This idea has been reported in many studies. In contrast, the therapeutic effects of EMF on different organs have also been reported. Research findings are inconsistent. This has given rise to very profound discrepancies. The duration and frequency of mobile phone calls and the association observed with various health effects has raised serious concerns due to the frequency with which these devices are used and the way they are held close to the head. The present review assesses the results of in vitro, in vivo, experimental, and epidemiological studies. The purpose of the study is to assess data concerning the carcinogenic and genotoxic effects of non-ionizing EMF. The major genotoxic and carcinogenic effects of EMF, divided into subsections as low frequency effects and radiofrequency effects, were reviewed. The inconsistent results between similar studies and the same research groups have made it very difficult to make any comprehensive interpretation. However, evaluation of current studies suggests that EMF may represent a serious source of concern and may be hazardous to living organisms. PMID- 29427954 TI - Modulation of oxidative phosphorylation (OXPHOS) by radiation- induced biophotons. AB - Radiation-induced biophotons are an electromagnetic form of bystander signalling. In human cells, biophoton signalling is capable of eliciting effects in non irradiated bystander cells. However, the mechanisms by which the biophotons interact and act upon the bystander cells are not clearly understood. Mitochondrial energy production and ROS are known to be involved but the precise interactions are not known. To address this question, we have investigated the effect of biophoton emission upon the function of the complexes of oxidative phosphorylation (OXPHOS). The exposure of bystander HCT116 p53 +/+ cells to biophoton signals emitted from beta-irradiated HCT116 p53 +/+ cells induced significant modifications in the activity of Complex I (NADH dehydrogenase or NADH:ubiquinone oxidoreductase) such that the activity was severely diminished compared to non-irradiated controls. The enzymatic assay showed that the efficiency of NADH oxidation to NAD+ was severely compromised. It is suspected that this impairment may be linked to the photoabsorption of biophotons in the blue wavelength range (492-455 nm). The photobiomodulation to Complex I was suspected to contribute greatly to the inefficiency of ATP synthase function since it resulted in a lower quantity of H+ ions to be available for use in the process of chemiosmosis. Other reactions of the ETC were not significantly impacted. Overall, these results provide evidence for a link between biophoton emission and biomodulation of the mitochondrial ATP synthesis process. However, there are many aspects of biological modulation by radiation-induced biophotons which will require further elucidation. PMID- 29427955 TI - Allostatic load is associated with psychotic symptoms and decreases with antipsychotic treatment in patients with schizophrenia and first-episode psychosis. AB - Current pathophysiological models of schizophrenia suggest that stress contributes to the etiology and trajectory of the disorder. We investigated if allostatic load (AL), an integrative index of neuroendocrine, immune and metabolic dysregulation in response to chronic stress, is elevated in patients with schizophrenia (SCZ) and first-episode psychosis (FEP) and related to psychotic symptoms and social and occupational functioning. Additionally, we assessed the temporal dynamics of AL in response to treatment with second generation antipsychotics. AL, psychotic symptoms and psychosocial functioning were assessed in a longitudinal design in patients with SCZ (n = 28), FEP (n = 28), and healthy controls (n = 53) at baseline and 6 and 12 weeks after commencement of antipsychotic therapy. AL at baseline was higher in patients with SCZ and FEP relative to controls, but not different between patients with SCZ and FEP. Adjusting for age and smoking, we found that positive symptoms were positively correlated with AL and psychosocial functioning was negatively correlated with AL at trend level. Linear mixed model analysis demonstrated that AL decreased after treatment was commenced in patients with SCZ and FEP between the baseline assessment and the 6 and 12-week follow-up. AL was not predictive of treatment response or symptomatic remission. Our data provide evidence for cumulative physiological dysregulation in patients with SCZ and FEP that is linked to the experience of current positive psychotic symptoms. AL could be a useful tool to monitor biological signatures related to chronic stress and unhealthy behaviors in schizophrenia. PMID- 29427956 TI - Experimental evidences of 95 mTc production in a nuclear reactor. AB - 95 mTc has been identified as by-product in some solutions of 99 mTc obtained by irradiation of molybdenum trioxide in a reactor neutron flux. The characterization was carried out using both measurements by gamma spectrometry and half-life determination. The possible ways that lead to the 95 mTc production in a nuclear reactor are discussed. PMID- 29427957 TI - Exploratory analysis for the identification of false banknotes using portable X ray Fluorescence spectrometer. AB - The aim of this study was to verify if a portable X-ray fluorescence (pXRF) spectrometer can recognize the security features in banknotes that are reproducible by counterfeiters. Peruvian Nuevo Sol banknotes were studied: 4 genuine and 3 fake ones, in 11 points of analysis for each one, at all 77 data set. The correlation analysis of spectra among original notes was 1.0, and there was no correlation with fake banknotes. pXRF prove that two security features were reproducible for counterfeiters. PMID- 29427958 TI - Synthesis and luminescence studies of Tb-doped MgO-MgAl2O4-Mg2SiO4 ceramic for use in radiation dosimetry. AB - In the present work, MgO ceramic samples with different terbium concentrations were produced and the Thermoluminescence (TL) and Optically Stimulated Luminescence (OSL) properties analyzed and discussed, aiming the use in radiation dosimetry. The samples were produced using MgO, Mg(NO3)2.6H2O, Al2O3, SiO2 and Tb(NO3)3.6H2O precursors in stoichiometric concentrations with five different terbium concentrations between 0.1 and 0.5 mol% and after, heat-treated at high temperature ~1500 degrees C. X-ray diffraction measurements on samples showed the formation of MgO as principal phase, and others in low concentration due to MgAl2O4, Mg2SiO4 and Tb4O7 phases. The TL glow curve of samples showed an intense and well-defined peak having the maximum at ~210 degrees C and other less intense at ~350 degrees C. The sample with 0.1 mol% of terbium concentration presented highest luminescence peak when compared to the other samples. The relationship between 210 degrees C TL peak intensity and dose was linear to doses between 1 and 20 Gy and the minimum detectable dose obtained by interpolation taking into account three times the standard deviation of the zero dose reading, was ~40 MUGy. A fading of ~20% during the first 5 hours after irradiation of 210 degrees C peak was observed. TL emission spectra showed strong emission lines due to Tb3+ ion. The OSL signal presented a linear behavior to doses between 1 and 10 Gy using 532 nm wavelength stimulation. PMID- 29427959 TI - O(t-alpha)-synchronization and Mittag-Leffler synchronization for the fractional order memristive neural networks with delays and discontinuous neuron activations. AB - This paper investigates O(t-alpha)-synchronization and adaptive Mittag-Leffler synchronization for the fractional-order memristive neural networks with delays and discontinuous neuron activations. Firstly, based on the framework of Filippov solution and differential inclusion theory, using a Razumikhin-type method, some sufficient conditions ensuring the global O(t-alpha)-synchronization of considered networks are established via a linear-type discontinuous control. Next, a new fractional differential inequality is established and two new discontinuous adaptive controller is designed to achieve Mittag-Leffler synchronization between the drive system and the response systems using this inequality. Finally, two numerical simulations are given to show the effectiveness of the theoretical results. Our approach and theoretical results have a leading significance in the design of synchronized fractional-order memristive neural networks circuits involving discontinuous activations and time varying delays. PMID- 29427960 TI - Performance and genome-centric metagenomics of thermophilic single and two-stage anaerobic digesters treating cheese wastes. AB - The present research is the first comprehensive study regarding the thermophilic anaerobic degradation of cheese wastewater, which combines the evaluation of different reactor configurations (i.e. single and two-stage continuous stirred tank reactors) on the process efficiency and the in-depth characterization of the microbial community structure using genome-centric metagenomics. Both reactor configurations showed acidification problems under the tested organic loading rates (OLRs) of 3.6 and 2.4 g COD/L-reactor day and the hydraulic retention time (HRT) of 15 days. However, the two-stage design reached a methane yield equal to 95% of the theoretical value, in contrast with the single stage configuration, which reached a maximum of 33% of the theoretical methane yield. The metagenomic analysis identified 22 new population genomes and revealed that the microbial compositions between the two configurations were remarkably different, demonstrating a higher methanogenic biodiversity in the two-stage configuration. In fact, the acidogenic reactor of the serial configuration was almost solely composed by the lactose degrader Bifidobacterium crudilactis UC0001. The predictive functional analyses of the main population genomes highlighted specific metabolic pathways responsible for the AD process and the mechanisms of main intermediates production. Particularly, the acetate accumulation experienced by the single stage configuration was mainly correlated to the low abundant syntrophic acetate oxidizer Tepidanaerobacter acetatoxydans UC0018 and to the absence of aceticlastic methanogens. PMID- 29427961 TI - Long-term nitrogen behavior under treated wastewater infiltration basins in a soil-aquifer treatment (SAT) system. AB - The long term behavior of total nitrogen and its components was investigated in a soil aquifer treatment system of the Dan Region Reclamation Project (Shafdan), Tel-Aviv, Israel. Use is made of the previous 40 years' secondary data for the main nitrogen components (ammonium, nitrate and organic nitrogen) in recharged effluent and observation wells located inside an infiltration basin. The wells were drilled to 106 and 67 m, both in a similar position within the basin. The transport characteristics of each nitrogen component were evaluated based on chloride travel-time, calculated by a cross-correlation between its concentration in the recharge effluent and the observation wells. Changes in the source of recharge effluent, wastewater treatment technology and recharge regime were found to be the main factors affecting turnover in total nitrogen and its components. During aerobic operation of the infiltration basins, most organic nitrogen and ammonium will be converted to nitrate. Total nitrogen removal in the upper part of the aquifer was found to be 47-63% by denitrification and absorption, and overall removal, including the lower part of the aquifer, was 49-83%. To maintain the aerobic operation of the infiltration fields, the total nitrogen load should remain below 10 mg/L. Above this limit, ammonium and organic nitrogen will be displaced into the aquifer. PMID- 29427962 TI - Complex pollution of antibiotic resistance genes due to beta-lactam and aminoglycoside use in aquaculture farming. AB - The prevalence of antibiotic resistance in the modern world has raised global concerns for public health. Establishing relationships between antibiotic use and antibiotic resistance genes (ARGs) is essential to understanding the dissemination and accumulation of ARGs in a human-impacted environment. In this study, ARG profiles in the sediments from a bullfrog farm, where penicillin and amoxicillin (beta-lactams) and gentamicin (aminoglycoside) were used for prophylactic purposes, were analyzed using metagenomic approaches. Analysis of both extracellular and intracellular DNA (eDNA and iDNA) demonstrated that use of the above-mentioned antibiotics led to complex pollution of ARGs not only related to beta-lactams and aminoglycoside but also to sulfonamides, tetracyclines, and macrolides. Most of the ARGs in the sediments from the bullfrog farm were likely carried by plasmids. A significant correlation was observed between the total abundance of ARG-related plasmids and that of plasmid-carrying ARGs. Approximately 85% of the plasmids likely present in the sediment from the bullfrog farm possessed at least 3 ARG subtypes, which conferred the resistance of bacterial hosts to different antibiotic categories. Our results suggest that antibiotics could lead to complex pollution of ARGs unrelated to those administered due to the concurrence of ARGs in the plasmids. PMID- 29427963 TI - On the derivation of a simple dynamic model of anaerobic digestion including the evolution of hydrogen. AB - Hydrogen has been found to be an important intermediate during anaerobic digestion (AD) and a key variable for process monitoring as it gives valuable information about the stability of the reactor. However, simple dynamic models describing the evolution of hydrogen are not commonplace. In this work, such a dynamic model is derived using a systematic data driven-approach, which consists of a principal component analysis to deduce the dimension of the minimal reaction subspace explaining the data, followed by an identification of the kinetic parameters in the least-squares sense. The procedure requires the availability of informative data sets. When the available data does not fulfill this condition, the model can still be built from simulated data, obtained using a detailed model such as ADM1. This dynamic model could be exploited in monitoring and control applications after a re-identification of the parameters using actual process data. As an example, the model is used in the framework of a control strategy, and is also fitted to experimental data from raw industrial wine processing wastewater. PMID- 29427964 TI - Fate of perfluoroalkyl substances within a small stream food web affected by sewage effluent. AB - The fate of fourteen target perfluoroalkyl substances (PFASs) are described within a small stream affected by a sewage treatment plant (STP) effluent. Concentrations of target PFASs in samples of water, benthic macroinvertebrates and brown trout (Salmo trutta) are presented. Two hundred brown trout individuals originating from clean sites within the same stream were tagged and stocked into an experimental site affected by the STP's effluent. As a passive sampling approach, polar organic chemical integrative samplers (POCIS) were deployed in the water to reveal the water-macroinvertebrates-fish biotransformation processes of PFASs. Bioconcentration/bioaccumulation of target compounds was monitored one, three, and six months after stocking. Twelve of the fourteen target PFASs were found in concentration above the LOQ in at least one of the studied matrices. The compound pattern varied significantly between both the studied species and water samples. Concerning the accumulation of PFASs in fish, the highest concentrations were found in the liver of individuals sampled after three months of exposure. These concentrations rapidly decreased after six months although the water concentrations were slightly increasing during experiment. PMID- 29427965 TI - Decision support toolkit for integrated analysis and design of reclaimed water infrastructure. AB - Planning of water reuse systems is a complex endeavor. We have developed a software toolkit, IRIPT (Integrated Urban Reclaimed Water Infrastructure Planning Toolkit) that facilitates planning and design of reclaimed water infrastructure for both centralized and hybrid configurations that incorporate satellite treatment plants (STPs). The toolkit includes a Pipeline Designer (PRODOT) that optimizes routing and sizing of pipelines for wastewater capture and reclaimed water distribution, a Selector (SelWTP) that assembles and optimizes wastewater treatment trains, and a Calculator (CalcBenefit) that estimates fees, revenues, and subsidies of alternative designs. For hybrid configurations, a Locator (LocSTP) optimizes siting of STPs and associated wastewater diversions by identifying manhole locations where the flowrates are sufficient to ensure that wastewater extracted and treated at an adjacent STP can generate the revenue needed to pay for treatment and delivery to customers. Practical local constraints are also applied to screen and identify STP locations. Once suitable sites are selected, System Integrator (ToolIntegrator) identifies a set of centralized and hybrid configurations that: (1) maximize reclaimed water supply, (2) maximize reclaimed water supply while also ensuring a financial benefit for the system, and (3) maximize the net financial benefit for the system. The resulting configurations are then evaluated by an Analyst (SANNA) that uses monetary and non-monetary criteria, with weights assigned to appropriate metrics by a decision-maker, to identify a preferred configuration. To illustrate the structure, assumptions, and use of IRIPT, we apply it to a case study for the city of Golden, CO. The criteria weightings provided by a local decision-maker lead to a preference for a centralized configuration in this case. The Golden case study demonstrates that IRIPT can efficiently analyze centralized and hybrid water reuse configurations and rank them according to decision-makers' preferences. PMID- 29427966 TI - Do higher cut-off values for tuberculin skin test increase the specificity and diagnostic agreement with interferon gamma release assays in immunocompromised Bacillus Calmette-Guerin vaccinated patients? AB - PURPOSE: Immunocompromised patients with latent tuberculosis infection (LTBI) are at high risk of progression to active tuberculosis. Detection and treatment of LTBI in this group of patients are very important to control active tuberculosis. Tuberculin skin test (TST) and interferon gamma release assays (IGRAs) are two methods for detection of LTBI. Diagnostic agreement between two tests are poor especially in Bacillus Calmette-Guerin (BCG) vaccinated immunocompromised patients. In this study, we tried to figure out if the use of a higher cut-off for TST increases diagnostic agreement with IGRAs and TST specificity and or not. MATERIALS/METHODS: In this retrospective study, BCG vaccinated solid organ transplantation (SOT) candidates and patients scheduled for anti-tumor necrosis factor-alpha (anti- TNFalpha) treatment patients who underwent both TST and IGRAs between 2011 and 2017 were enrolled in the study. Diagnostic agreement between the two tests was assessed for 5, 10, 15mm cut-off values for all participants, SOT candidates and anti- TNFalpha treatment subgroups separately. RESULTS: Fifty female and 55 male total 105 patients were included. In the anti- TNFalpha treatment group 92.8% of the patients were receiving at least one immunosuppressive drug. For all participants kappa (kappa) values were 0.303, 0.370, 0.321 respectively for 5, 10 and 15mm cut-offs. For SOT candidates kappa values were 0.488, 0.422, 0.288 respectively. For anti- TNFalpha treatment group kappa values were 0.235, 0.332, 0.275 respectively. CONCLUSIONS: In BCG vaccinated immunocompromised patients, the agreement between TST and QFT-GIT was poor regardless of cut-off value. And increasing the cut-off does not improve agreement. PMID- 29427967 TI - Pleiotropic effects of hypoglycemic agents: implications in asthma and COPD. AB - Diabetes mellitus (DM) is a complex multifactorial disease due to the interaction between environmental noxae and genetic predisposition. Furthermore, an increased association between DM, especially Type 2 diabetes mellitus (T2DM), and the onset of pulmonary function impairment with a bronchial hyperresponsiveness has been documented. DM is a risk factor for accelerated decline in FEV1 and the development of asthma and COPD. The increased blood glucose concentrations along with higher levels of oxidative stress and inflammation can influence the pulmonary function and, since hypoglycemic drugs can act on these different defects we can hypothesize their direct effect on obstructive pulmonary diseases. Metformin, a biguanide, is the molecule having several evidences of its action on asthma and COPD in patients with T2DM. In this population, Metformin can ameliorate pulmonary outcomes reducing high glucose concentrations, inflammation through the activation of the AMP-activated protein kinase, leading to the decreased production of pro-inflammatory cytokines and blunting allergic eosinophilic airway inflammation. There are evidences of Pioglitazone role on asthma, since the activation of PPARgamma Pioglitazone might inhibit the synthesis and release of pro-inflammatory cytokines. Indeed, Pioglitazone can improve symptoms associated with asthma reducing episodes of exacerbation and oral steroid prescription. Finally, randomized clinical trials using hypoglycemic agents on patients with asthma and COPD with and without DM should be proposed as well as the implementation of a new formulation of hypoglycemic agents to make it possible to administer it via aerosol. PMID- 29427968 TI - Incidence of malignant lymphoma in adolescents and young adults in the 58 counties of California with varying synthetic turf field density. AB - BACKGROUND: Case reports of cancer among soccer players raised concerns that the crumb rubber infill in synthetic turf fields may cause malignant lymphoma. One prior epidemiologic study on the topic found no association. METHODS: An ecologic evaluation of county-level incidence of lymphomas by race/ethnicity and socioeconomic status for the state of California with data obtained from the National Cancer Institute Surveillance, Epidemiology, and End Results Program. Synthetic turf field density by county was obtained from the Synthetic Turf Council. During 2000-2013, 7214 14- to 30-year-old Californians were diagnosed with malignant lymphoma. RESULTS: Annual lymphoma county incidence trends were not associated with the county-level synthetic turf field density. None of 20 sub analyses by race/ethnicity, sex and county median household income indicated a correlation of lymphoma incidence with synthetic turf field density. In California, there was no evidence at the county-level that synthetic turf fields are associated with an increased incidence of lymphoma in adolescents and young adults. CONCLUSION: Our findings in the state with the greatest number of such fields and a large, diverse patient population are consistent with those of a prior study observing no association between individual-level exposures to turf fields and cancer incidence. Avoidance of synthetic turf fields for fear of increased cancer risk is not warranted. PMID- 29427969 TI - Optimization of Pb(II) ions adsorption on nanohydroxyapatite adsorbents by applying Taguchi method. AB - This paper presents an optimization approach for the removal of lead ions (Pb+2) by nano-hydroxyapatite powder form adsorbents that were produced from bovine bone by mechanical activation method. The Taguchi method was implemented for designing the experiments by considering four controllable factors including (1) ball milling time (A), (2) the initial concentration of lead ions (B), (3) initial pH of the solution (C); and (4) the adsorbent dosage (D), each factor at four different levels. According to the ANOVA analysis results, the removal efficiency of the lead ions was predominantly influenced by the adsorbent dosage (38.2%) and the initial lead ions concentration (23.64%), whereas the effect of initial pH of the solution was ignorable and the ball milling time had a mild contribution of 14.79%. The total optimum adsorptive lead ions removal of 100% was achieved by optimization process at operating conditions of Co = 180 mg L- 1, ball milling time = 2 h, pH = 3, and adsorbent dosage = 0.15 g. The Langmuir isotherm model fitted to the equilibrium results with good accuracy and a maximum sorption capacity of 200 mg g-1 was predicted by the model for the hydroxyapatite adsorbent ball milled for 2 h. PMID- 29427970 TI - Removal of antiretroviral drugs stavudine and zidovudine in water under UV254 and UV254/H2O2 processes: Quantum yields, kinetics and ecotoxicology assessment. AB - The concentration of antiretroviral drugs in wastewater treatment plants (WWTP) effluents and surface waters of many countries has increased significantly due to their widespread use for HIV treatment. In this study, the removal of stavudine and zidovudine under UV254 photolysis or UV254/H2O2 was investigated in a microcapillary film (MCF) photoreactor, using minimal water samples quantities. The UV254 quantum yield of zidovudine, (2.357 +/- 0.0589).10-2 mol ein-1 (pH 4.0 8.0), was 28-fold higher that the yield of stavudine (8.34 +/- 0.334).10-4 mol ein-1 (pH 6.0-8.0). The second-order rate constant kOH,iof reaction of hydroxyl radical with the antiretrovirals (UV254/H2O2 process) were determined by kinetics modeling: (9.98 +/- 0.68).108 M-1 s-1 (pH 4.0-8.0) for zidovudine and (2.03 +/- 0.18).109 M-1 s-1 (pH 6.0-8.0) for stavudine. A battery of ecotoxicological tests (i.e. inhibition growth, bioluminescence, mutagenic and genotoxic activity) using bacteria (Aliivibrio fischeri, Salmonella typhimurium), crustacean (Daphnia magna) and algae (Raphidocelis subcapitata) revealed a marked influence of the UV dose on the ecotoxicological activity. The UV254/H2O2 treatment process reduced the ecotoxicological risk associated to direct photolysis of the antiretrovirals aqueous solutions, but required significantly higher UV254 doses (>=2000 mJ cm-2) in comparison to common water UV disinfection processes. PMID- 29427971 TI - The impact of radiocesium input forms on its extractability in Fukushima forest soils. AB - The effects of 137Cs deposit forms on its ageing in soil have not yet been reported. Soluble and Solid 137Cs input forms were mixed with the mineral soils collected under Fukushima's coniferous and broadleaf forests, incubated under controlled laboratory, and examined the evolution of 137Cs availability over time. Results show that the extracted 137Cs fraction with water was less than 1% for the soluble input form and below detection limit for the solid input forms. Likewise, with an acetate reagent, the extracted 137Cs fraction ranged from 46 to 56% for the soluble input and from 2 to 15% for the solid input, implying that the nature of the 137Cs contamination strongly influences its extractability and mobility in soil. Although the degradation of organic materials was apparent, its impact on the 137Cs extractability was found to be weak. Nevertheless, more Ac available 137Cs was obtained from broadleaf organic material mixes than the coniferous counterparts, suggesting that the lignified nature of latter tend to retain more 137Cs. When extrapolated to a field context, more available 137Cs fraction may be expected from wet-derived contaminated forest soils than contaminated via solid-derived inputs. Such information could be helpful for radioecological management schemes in contaminated forest environments. PMID- 29427972 TI - Three years of exposure to lead and elevated CO2 affects lead accumulation and leaf defenses in Robinia pseudoacacia L. seedlings. AB - Few studies have explored the long-term effects of elevated atmospheric CO2 combined with lead (Pb) contamination on plants. The objective of this study was to examine the effects of 3 years of elevated CO2 (700 +/- 23 MUmol mol-1) on Pb accumulation and plant defenses in leaves of Robinia pseudoacacia L. seedlings in exposed to Pb (500 mg kg-1 soil). Elevated CO2 increased Pb accumulation in leaves and Pb removal rate in soils. In plants exposed to Pb stress, total chlorophyll and carotenoid contents in leaves were lower under elevated CO2 than under ambient CO2, but seedling height and width increased under elevated CO2 relative to ambient CO2. Elevated CO2 significantly (p < .01) stimulated malondialdehyde content in leaves under Pb exposure. Superoxide dismutase and catalase activity increased significantly (p < .01), peroxidase activity decreased significantly (p < .01), and glutathione, cystine, and phytochelatin contents increased under elevated CO2 + Pb relative to Pb alone. Elevated CO2 stimulated the production of soluble sugars, proline, flavonoids, saponins, and phenolics in plants exposed to Pb stress. Ove rall, long-term elevation of CO2 increased Pb-induced oxidative damage in seedlings, but enhanced the phytoextraction of Pb from contaminated soils. PMID- 29427973 TI - Synthesis of hollow lantern-like Eu(III)-doped g-C3N4 with enhanced visible light photocatalytic perfomance for organic degradation. AB - A series of hollow structure lantern-like Eu(III)-doped g-C3N4 (xEu-CN, x = 1, 2, 3) was firstly synthesized by heating a mixture of melamine, HNO3 and Eu2O3 at 500 degrees C for 2 h. The phase, morphology and optical properties of the serial xEu-CN samples were characterized by different techniques, including TEM, XRD, FT-IR, SEM, XPS, BET, UV-vis, PL, photocurrent, and EIS. The results indicated that Eu doping extraordinarily enhanced the photocatalytic activity of pure g-C3N4, and the 2Eu-CN exhibited the highest photocatalytic performance with a 98% (82%) degradation rate for RhB (TC), 6.03 (1.71)-fold of pure g-C3N4(CN). The higher photocatalytic efficiency is ascribed to the synergy effect of Eu(III) and the hollow structures, which led to a larger surface specific area, bandgap narrowing, enhanced light harvesting ability and efficient charge separation. PMID- 29427974 TI - Time of day is not associated with increased rates of mortality in emergency surgery: An analysis of 49,196 surgical procedures. AB - STUDY OBJECTIVE: There is a lack of large, multi-institutional studies analyzing the association of timing of emergency surgery with death occurring either intraoperatively or in the recovery room setting. The primary objective of this study was to determine if time of day for emergency surgeries was associated with mortality. DESIGN: Retrospective analysis. SETTING: U.S. healthcare facilities. PATIENTS: Adult patients undergoing emergency surgery and general anesthesia. INTERVENTIONS: No intervention. MEASUREMENTS: Utilizing the National Anesthesia Clinical Outcomes Registry database, all emergency non-cardiac, non-obstetric surgeries undergoing general anesthesia occurring between 2010 and 2015 in the United States were identified. We performed mixed effects logistic regression to determine the effect of time of day with mortality occurring during the intraoperative and immediate postoperative period. MAIN RESULTS: There were 46,196 cases that were eligible for this analysis, in which 24,247 and 21,949 occurred during day and after-hours shifts, respectively. The overall morality rate was 0.28%. Mortality rates were 0.17% and 0.41% in the day and after-hour shifts, respectively. There was no statistically significant association of time of day with mortality (odds ratio 1.31, 95% CI 0.90-1.92, p = 0.16). American Society of Anesthesiologists physical status classification, age, and operative body part were all associated with mortality. CONCLUSIONS: Although, theoretically, health care providers working after-hour shifts may be impacted by sleep deprivation and/or limited resources, we found that time of day was not associated with increased risk of mortality during the intraoperative and immediate postoperative period in emergency surgery. PMID- 29427975 TI - Continuous quadratus lumborum type 2 block: Good analgesia alternative for complex iliac and acetabulum fracture. PMID- 29427976 TI - Predictive ecotoxicity of MoA 1 of organic chemicals using in silico approaches. AB - Persistent organic products are compounds used for various purposes, such as personal care products, surfactants, colorants, industrial additives, food, pesticides and pharmaceuticals. These substances are constantly introduced into the environment and many of these pollutants are difficult to degrade. Toxic compounds classified as MoA 1 (Mode of Action 1) are low toxicity compounds that comprise nonreactive chemicals. In silico methods such as Quantitative Structure Activity Relationships (QSARs) have been used to develop important models for prediction in several areas of science, as well as aquatic toxicity studies. The aim of the present study was to build a QSAR model-based set of theoretical Volsurf molecular descriptors using the fish acute toxicity values of compounds defined as MoA 1 to identify the molecular properties related to this mechanism. The selected Partial Least Squares (PLS) results based on the values of cross validation coefficients of determination (Qcv2) show the following values: Qcv2 = 0.793, coefficient of determination (R2) = 0.823, explained variance in external prediction (Qext2) = 0.87. From the selected descriptors, not only the hydrophobicity is related to the toxicity as already mentioned in previously published studies but other physicochemical properties combined contribute to the activity of these compounds. The symmetric distribution of the hydrophobic moieties in the structure of the compounds as well as the shape, as branched chains, are important features that are related to the toxicity. This information from the model can be useful in predicting so as to minimize the toxicity of organic compounds. PMID- 29427977 TI - Salinity stress accelerates the effect of cadmium toxicity on soil N dynamics and cycling: Does joint effect of these stresses matter? AB - The objective of this study was to determine responses of soil nitrogen (N) transformation, microbial biomass N, and urease activity to the combined effect of cadmium (Cd) toxicity (0 and 30 mg kg-1) and NaCl stress (0, 7.5 and 15 dS m 1) in a clay loam soil unamended (0%) or amended with alfalfa residues (1%, w/w). Cd, NaCl, and alfalfa residues were added to the soil, and the mixtures were incubated for 90 days under standard laboratory conditions (25 +/- 1 degrees C and 70% of water holding capacity [WHC]). The results showed that salinity increased soil Cd availability and toxicity and subsequently decreased soil microbial N transformations (i.e., potential ammonification and nitrification as well as net N mineralization), arginine ammonification and nitrification rates, microbial biomass N, and urease activity. The adverse effects of salinity on soil microbial properties were greater in Cd-polluted than unpolluted soils, at high than low salinity levels, but were lower in residue-amended than unamended soils. These effects were mainly attributed to the increased Cd availability under saline conditions or the decreased Cd availability with residue addition. All the measured soil microbial attributes showed a negative correlation with the available Cd content in the soil. The interaction or combined effects of Cd and NaCl on soil microbial attributes were mostly synergistic in residue-unamended soils but antagonistic in residue-amended soils. The addition of organic residues to Cd-polluted soils may moderate salinity effect, and thus could stimulate the activity of ammonifiers and nitrifiers, as well as urease. PMID- 29427978 TI - Spatial and temporal impacts of the Skjervoy harbour diesel spill on native population of blue mussels: A sub-Arctic case study. AB - This work was designed to investigate biological impacts on blue mussels (Mytilus edulis spp) after being exposed to diesel spill. On December 2013, an 180,000 litre accidental acute diesel spill was reported in a small harbour of northern Norway (Skjervoy). In order to assess the biological effects on the wild population of blue mussels, bivalves were collected at three different locations: at the oil-spill spot, at the other side of the harbour (opposite the oil-spill area), and in an uncontaminated site. Body burden and seawater samples were collected from a few days up to five months after the diesel spill. Biomarkers of oxidative stress and immunological effects were assessed in the blue mussels digestive glands. Our findings reported significant modulation of GST (detoxification), SOD (antioxidant response) and MDA (lipid peroxidation) in bivalves exposed to diesel with a similar response at two and five months after the spill. Laccase-type enzyme also highlighted an important aspect in terms of biomarker response of the immune function. Overall, our study demonstrated that some biomarkers returned to basal levels a few months after the diesel spill. Consequently, it highlighted the usefulness of normalised tools and guidelines for biomonitoring strategies after a diesel spill. PMID- 29427979 TI - Evolving Concepts in Asthma. PMID- 29427980 TI - Epidemiology of Asthma and Influence of Ethnicity. AB - Asthma is a heterogeneous disorder with a complex etiology. Prevalence rates for asthma have been increasing in many countries over the past few decades. While it is unclear why this increase is occurring, the variation reported in asthma prevalence and severity associated with ethnicity offers some insight into the determinants of asthma. In this chapter, we discuss the data linking asthma to ethnicity and some of the factors that may explain this association. These include socioeconomic status, environmental exposures, the host microbiome, and genetics. A better understanding of these processes may inform future mechanistic studies and identify modifiable risk factors for targeted health care interventions. PMID- 29427981 TI - Environmental Causes of Asthma. AB - Environmental factors which cause asthma are those that induce airway inflammation with eosinophils (more common) or neutrophils along with airway hyperresponsiveness (AHR). The most common of these (indeed the most common cause of asthma) are IgE-mediated inhalant allergen exposures. Allergen-induced AHR and inflammation are both associated with the allergen-induced late asthmatic response (LAR). Although allergens were previously recognized only as causes of symptoms and bronchoconstriction in asthmatics, we now appreciate them as causes of the fundamental pathophysiologic features of asthma. Low-molecular-weight chemical sensitizers, causes of occupational asthma, also cause asthma in a manner analogous to allergen. Acute irritant-induced asthma (reactive airways dysfunction syndrome) following a very heavy irritant exposure and chronic irritant-induced asthma following repeated high exposures can also induce persistent or permanent changes (inflammation and AHR) consistent with asthma. Textile dust exposure produces a different form of airway disease (byssinosis) which is less frequently observed currently. Environmental exposure to tobacco smoke facilitates the development of asthma in children. Personal smoking and environmental air pollution have an inconsistent and likely generally small effect in causing asthma. PMID- 29427982 TI - Exercise and Asthma. AB - Transient airway narrowing can occur during or following exercise, a phenomenon called exercise-induced bronchoconstriction (EIB). The main mechanism of EIB is considered to be airway dehydration, resulting from increased ventilation during exercise. In asthma, such water loss causes an increase in airway fluid osmolarity, inducing airway smooth muscle contraction following the release of mediators from airway inflammatory cells. Asthmatics frequently experience EIB, but it may also be observed in others not reporting asthma symptoms, particularly elite endurance athletes. Individuals with asthma often refrain from performing physical exercise because they fear troublesome respiratory symptoms. However, in addition to its well-known cardiovascular and metabolic benefits, physical training has been shown to be beneficial for asthmatic adults and children in improving asthma control and asthma-related quality of life. Exercise training also reduces the risk of asthma exacerbations, improves exercise capacity, and decreases frequency and severity of EIB. To minimize the risk of EIB, asthma must be well controlled, and specific pharmacological and nonpharmacological preventative measures can be taken. Counterintuitively, in high-level athletes, the development of asthma, airway hyperresponsiveness, and EIB can be promoted by intense training over many years following exposure to environmental conditions, such as cold air, pollutants, and allergens. As for nonathletes, athletes must have optimal asthma control and apply preventative measures against EIB, taking into account antidoping regulations for asthma medications. A better understanding of the impact of exercise on asthma should improve the overall care of asthmatic patients. PMID- 29427983 TI - Management of Asthma during Pregnancy: Optimizing Outcomes and Minimizing Risk. AB - Pregnancy may be complicated by new onset or preexisting asthma. This article reviews diagnosis and management of asthma in the pregnant patient. Special attention is paid to the challenges in diagnosis and management of this condition during pregnancy. Asthma is one of the most common potentially serious medical problems to complicate pregnancy, and asthma may adversely affect both maternal quality of life and perinatal outcomes. Asthma may adversely affect both maternal quality of life and, perinatal outcomes. Pregnant asthmatics have been shown to be at an increased risk of adverse perinatal outcomes. Optimal management of asthma during pregnancy is thus important for both mother and baby. This article provides an update on the available literature regarding the safety of commonly used asthma medications during pregnancy. PMID- 29427984 TI - Controlling the Risk Domain in Pediatric Asthma through Personalized Care. AB - Strategies to control the risk domain of NHLBI EPR-3 (National Heart, Lung, and Blood Institute Expert Panel Report-3) asthma guidelines, which includes exacerbations requiring systemic corticosteroids, reduction in lung growth, and progressive loss of lung function, and treatment-related adverse effects, are evolving in children and adolescents. Increasing evidence demonstrates that children and adolescents with asthma are at risk of a reduction in lung growth, leading to lower lung function and potentially chronic obstructive pulmonary disease as adults. Readily available clinical biomarkers for atopy, including aeroallergen testing, total serum IgE, blood eosinophilia, and spirometry, are being utilized to phenotype difficult-to-treat pediatric patients, to assess risk for seasonal exacerbations, and to predict response to controller therapies. The Composite Asthma Severity Index is a novel, freely available scoring system to define asthma control, incorporating NHLBI EPR-3 risk and impairment domains. As new asthma controller therapies, such as tiotropium, are introduced for pediatric use, the safety of established controller therapies including inhaled corticosteroid and long-acting beta-agonist are being reexamined. Macrolide antibiotics may be an oral corticosteroid sparing alternative for the treatment of severe respiratory tract infection in preschool-aged children. Seasonally directed courses of omalizumab may provide an alternative approach to prevent fall asthma exacerbations in children. Combining these pharmaceuticals and biomarker-directed therapies provide potential new options and personalized approaches to gain asthma control in pediatric patients failing current management. PMID- 29427985 TI - Respiratory Viruses and Asthma. AB - Asthma remains the most prevalent chronic respiratory disorder, affecting people of all ages. The relationship between respiratory virus infection and asthma has long been recognized, though remains incompletely understood. In this article, we will address key issues around this relationship. These will include the crucial role virus infection plays in early life, as a potential risk factor for the development of asthma and lung disease. We will assess the impact that virus infection has on those with established asthma as a trigger for acute disease and how this may influence asthma throughout life. Finally, we will explore the complex interaction that occurs between the airway and the immune responses that make those with asthma so susceptible to the effects of virus infection. PMID- 29427986 TI - Airway Inflammation and Inflammatory Biomarkers. AB - Severe asthma is a complex disease consisting of different endotypes with different inflammatory and clinicopathological characteristics due to the heterogeneity of immune responses and smooth muscle dysfunction. There is an unmet clinical need to develop and to validate biomarkers that can differentiate between the asthma endotypes and guide clinical management, particularly since the availability of biologicals directed against T2 cytokines. The presence of a "Th2 endotype" is currently assessed in clinical practice using markers, such as eosinophil count in sputum or blood, fraction of exhaled nitric oxide, and immunoglobulin E. Individually or in combination, they may help to identify, for example, if the dominant effector protein is interleukin (IL) 5, IL13, or IgE. There is no reliable marker of a "non-Th2 endotype" although sputum neutrophil may provide some indication. The unbiased systems biology approach to severe asthma endotyping which integrates omics signatures and clinical data using large cohort studies may provide more comprehensive information than simple cellular measurements. Novel imaging techniques, such as hyperpolarized noble gas magnetic resonance imaging and computed tomography parametric response maps and metabolomics profiling in breath and other body fluids are also being evaluated as potential biomarkers to guide therapy and to assess prognosis. PMID- 29427987 TI - Advances and Evolving Concepts in Allergic Asthma. AB - Allergic asthma is a heterogeneous disorder that defies a unanimously acceptable definition, but is generally recognized through its highly characteristic clinical expression of dyspnea and cough accompanied by clinical data that document reversible or exaggerated airway constriction and obstruction. The generally rising prevalence of asthma in highly industrialized societies despite significant therapeutic advances suggests that the fundamental cause(s) of asthma remain poorly understood. Detailed analyses of both the indoor (built) and outdoor environments continue to support the concept that not only inhaled particulates, especially carbon-based particulate pollution, pollens, and fungal elements, but also many noxious gases and chemicals, especially biologically derived byproducts such as proteinases, are essential to asthma pathogenesis. Phthalates, another common class of chemical pollutant found in the built environment, are emerging as potentially important mediators or attenuators of asthma. Other biological products such as endotoxin have also been confirmed to be protective in both the indoor and outdoor contexts. Proasthmatic factors are believed to activate, and in some instances initiate, pathologic inflammatory cascades through complex interactions with pattern recognition receptors (PRRs) expressed on many cell types, but especially airway epithelial cells. PRRs initiate the release of proallergic cytokines such as interleukin (IL)-33, IL-25, and others that coordinate activation of innate lymphoid cells type 2 (ILC2), T helper type 2 cells, and immunoglobulin E-secreting B cells that together promote additional inflammation and the major airway remodeling events (airway hyperresponsiveness, mucus hypersecretion) that promote airway obstruction. Proteinases, with airway fungi and viruses being potentially important sources, are emerging as critically important initiators of these inflammatory cascades in part through their effects on clotting factors such as fibrinogen. Recent clinical trials have demonstrated that targeting inflammatory pathways orchestrated through IL-4, IL-5, IL-13, and the prostaglandin receptor CRTH2 is potentially highly effective in adult asthma. PMID- 29427988 TI - Emerging Concepts in Evidence-Based Asthma Management. AB - Asthma management is in an intriguing phase, with acceptance of asthma as a heterogeneous condition with different phenotypes and underlying mechanisms and the potential for personalized asthma care, in parallel with increasing evidence about the population-level impact of basic strategies to increase access to medicines and improve inhaler technique and adherence. These changes have been facilitated by a more comprehensive view of evidence, including both randomized controlled trials with high internal validity and pragmatic and observational studies with high generalizability to patients in clinical practice. Evolving concepts of asthma control have led to new approaches to asthma assessment, recognizing the potential for discordance between symptom control and risk of exacerbations. A re-evaluation of evidence has also led to substantial changes in initial treatment of asthma, with the focus moving away from bronchodilator-only treatment, toward early use of inhaled corticosteroids and novel strategies for mild asthma. Sputum-guided treatment, where available, is successful in patients with moderate-severe asthma, but exhaled nitric oxide has not yet satisfied initial assumptions about its utility for biomarker-guided treatment. New interventions are emerging to improve adherence with asthma controller medications. A re-evaluation of evidence about written asthma action plans has led to encouragement of a rapid increase in controller dose, rather than relying on bronchodilator treatment and oral corticosteroids. Finally, new models of asthma care are emerging, utilizing the skills of allied health professionals and recognizing the potential role of telehealth. PMID- 29427989 TI - Diagnosis and Management of Severe Asthma. AB - Severe therapy-resistant asthma has been defined as "asthma which requires treatment with high dose inhaled corticosteroids (ICSs) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy". Patients who usually present with 'difficult-to-treat asthma' should first be assessed to determine whether he/she has asthma with the exclusion of other diagnoses and if so, whether the asthma can be classified as severe therapy-resistant. This necessitates an assessment of adherence to medications, confounding factors, and comorbidities. Increasingly, management of severe therapy-resistant asthma will be helped by the determination of phenotypes to optimize responses to existing and new therapies. Severe asthma patients are usually on a combination of high dose ICS and long acting beta-agonist (LABA) and, in addition, are often on a maintenance dose of oral corticosteroids. Phenotyping can be informed by measuring blood eosinophil counts and the level of nitric oxide in exhaled breath, and the use of sputum granulocytic counts. Severe allergic asthma and severe eosinophilic asthma are two defined phenotypes for which there are efficacious targeted biologic therapies currently available, namely anti-immunoglobulin E (IgE) and anti interleukin (IL)-5 antibodies, respectively. Further progress will be realized with the definition of noneosinophilic or non-T2 phenotypes. It will be important for patients with severe asthma to be ultimately investigated and managed in specialized severe asthma centers. PMID- 29427990 TI - Biologic Therapy and Asthma. AB - Although airway inflammation is an intrinsic and key feature of asthma, this response varies in its intensity and translation to clinical characteristics and responsiveness to treatment. The observations that clinical heterogeneity is an important aspect of asthma and a feature that likely dictates and determines responses to treatment in severe asthma, patient responsiveness to medication is incomplete, and risks for exacerbation are increased. The development of biologics, which target selected and specific components of inflammation, has been a promising advance to achieve asthma control in patients with severe disease. This article reviews the current biologics available and under development and how their use has affected asthma and which subpopulations appear to benefit the greatest. PMID- 29427991 TI - Reliability of core needle biopsy as a second-line procedure in thyroid nodules with an indeterminate fine-needle aspiration report: a systematic review and meta analysis. AB - PURPOSE: This study was undertaken to summarize the published data and to provide more robust estimates regarding the issue of core needle biopsy (CNB) for discriminating thyroid nodules with indeterminate fine-needle aspiration (FNA) results. METHODS: The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The sources comprised studies published through November 2017. Original articles that investigated CNB in indeterminate thyroid lesions were searched. A random-effects model was used for statistical pooling of the data. The I2 index was used to quantify the heterogeneity among the studies. The Egger test was carried out to evaluate the possible presence of significant publication bias. Quality assessment of the studies was performed according to QUADAS-2. RESULTS: A total of 205 articles were retrieved, seven were initially selected, and the data of five papers were ultimately pooled in a meta-analysis. The overall cancer rate was 34%. The rate of cancers correctly diagnosed by CNB was 83% (95% confidence interval [CI], 76 to 89), with neither heterogeneity (I2=25%) nor publication bias (Egger test, P=0.918). The rate of benign nodules correctly assessed by CNB was 84% (95% CI, 65 to 97), with significant heterogeneity (I2=93.4%) and publication bias (Egger test, P=0.016). CONCLUSION: Evidence was found that CNB can correctly diagnose the majority of nodules previously read as indeterminate on FNA. PMID- 29427992 TI - Apple, condom, and cocaine - body stuffing in prison: a case report. AB - BACKGROUND: Drug dealers and drug users resort to body stuffing to hastily conceal illicit drugs by ingesting their drug packets. This practice represents a medical challenge because rupture of the often insecure packaging can be toxic and even lethal. In an emergency setting, official guidelines are needed to help the medical team decide on the proper treatment. A preliminary observation period is generally accepted but its duration varies from hours to eventual packet expulsion. CASE PRESENTATION: This case involves a 20-year-old white man in detention who claimed to have ingested one cocaine packet wrapped in plastic food wrap and a condom in anticipation of an impending cell search. He reached out to medical professionals on day 4 after having unsuccessfully tried several methods to expel the drug packet, including swallowing olive oil, natural laxatives, liters of water, and 12 carved apple chunks. An initial computed tomography scan confirmed multiple packet-sized images throughout his stomach and bowel. After 24 hours of observation and normal bowel movements without expelling any packets, a subsequent scan found only one air-lined packet afloat in the gastric content. Due to the prolonged retention of the package there was an increased risk of rupture. The packet was eventually removed by laparoscopic gastrotomy. CONCLUSIONS: This case report illustrates that observation time needs to be adapted to each individual case of body stuffing. Proof of complete drug package evacuation ensures secure patient discharge. Body stuffers should be routinely asked for a detailed history, including how the drug is wrapped, and whether or not they ingested other substances to help expel the packets. The history enables the accurate interpretation of imaging. Repeated imaging can help follow the progress of packets if not all have been expelled during the observation period. Drug packets should be surgically removed in case of prolonged retention. To ensure the best possible outcomes, patients should have access to high-quality, private, and confidential medical care, which is equal to that offered to the general population. This is paramount to earning trust and collaboration from people in detention who resort to body stuffing. PMID- 29427993 TI - Clinical benefit of improved Prehospital stroke scales to detect stroke patients with large vessel occlusions: results from a conditional probabilistic model. AB - BACKGROUND: Clinical scales to detect large vessel occlusion (LVO) may help to determine the optimal transport destination for patients with suspected acute ischemic stroke (AIS). The clinical benefit associated with improved diagnostic accuracy of these scales has not been quantified. METHODS: We used a previously reported conditional model to estimate the probability of good outcome (modified Rankin scale sore <=2) for patients with AIS and unknown vessel status occurring in regions with greater proximity to a primary than to a comprehensive stroke center. Optimal rapid arterial occlusion evaluation (RACE) scale cutoff scores were calculated based on time-dependent effect-size estimates from recent randomized controlled trials. Probabilities of good outcome were compared between a triage strategy based on these cutoffs and a strategy based on a hypothetical perfect LVO detection tool with 100% diagnostic accuracy. RESULTS: In our model, the additional benefit of a perfect LVO detection tool as compared to optimal transport-time dependent RACE cutoff scores ranges from 0 to 5%. It is largest for patients with medium stroke symptom severity (RACE score 5) and in geographic environments with longer transfer time between the primary and comprehensive stroke center. CONCLUSION: Based on a probabilistic conditional model, the results of our simulation indicate that more accurate prehospital clinical LVO detections scales may be associated with only modest improvements in the expected probability of good outcome for patients with suspected acute ischemic stroke and unknown vessel status. PMID- 29427994 TI - Distinct genetic alteration profiles of acute myeloid leukemia between Caucasian and Eastern Asian population. AB - Racial and ethnic disparities in malignancies attract extensive attention. To investigate whether there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population, data from several prospective AML trials were retrospectively analyzed in this study. We found that there were more patients with core binding factor (CBF) leukemia in Eastern Asian cohorts and there were different CBF leukemia constitutions between them. The ratios of CBF leukemia are 27.7, 22.1, 21.1, and 23.4%, respectively, in our (ChiCTR-TRC 10001202), another Chinese, Korean, and Japanese Eastern Asian cohorts, which are significantly higher than those in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003 (15.5, 12.5, 9.3, 10.2, and 12%, respectively). And CBFbeta-MYH11 occurred more prevalently in HOVON/SAKK AML- 42 and ECOG1900 trials (50.0 and 54.3% of CBF leukemia, respectively) than in Chinese and Japanese trials (20.1 and 20.8%, respectively). The proportion of FLT3-ITD mutation is 11.2% in our cohort, which is lower than that in MRC AML15 and UK NCRI AML17 (24.6 and 17.9%, respectively). Even after excluding the age bias, there are still different incidence rates of mutation between Caucasian and Eastern Asian population. These data suggest that there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population. PMID- 29427996 TI - Respiratory syncytial virus prolifically infects N2a neuronal cells, leading to TLR4 and nucleolin protein modulations and RSV F protein co-localization with TLR4 and nucleolin. AB - BACKGROUND: Respiratory syncytial virus (RSV) infects the central nervous system, resulting in neurological symptoms. However, the precise underlying pathogenic mechanisms have not been elucidated. In the present study, the infectivity of RSV on N2a neuronal cells and the possible roles of Toll-like receptor 4 (TLR4) and nucleolin (C23) during RSV infection were investigated. METHODS: We compared two experimental groups (infected and non-infected) and monitored the RSV viral titers in the culture supernatant by a viral plaque assay. We also inspected the morphology of the nucleus in infected N2a cells. We measured the level of RSV F protein and studied its co-localization with TLR4 and nucleolin using immunofluorescence assays and laser confocal microscopy. The potential interaction of RSV F protein with TLR4 and nucleolin was examined by coimmunoprecipitation. The expression changes of TLR4, nucleolin, TLR3 and TLR7 proteins in N2a cells and IL-6 and TNF-alpha in the culture supernatant were investigated by Western Blot analysis and ELISA assay. Changes in neuronal cell apoptosis status was examined by flow cytometry. RESULTS: The results demonstrated prolific RSV infection of N2a cells, which triggered a decrease of NeuN protein expression, coinciding with an increase of nuclear lesions, F protein expression, RSV viral titers, and late apoptotic levels of N2a cells. RSV infection induced co-localization of RSV F protein with TLR4 and nucleolin, which could potentially lead to a direct interaction. Furthermore, it was found that TLR4 and nucleolin levels increased early after infection and decreased subsequently, whereas TLR3 and TLR7 expression increased throughout RSV infection. CONCLUSION: The RSV Long strain can prolifically infect N2a neuronal cells, modulating the expression of TLR4 and nucleolin, as well as TLR3, TLR7 and their downstream inflammatory factors, and inducing the co-localization of the RSV F protein with TLR4 and nucleolin. PMID- 29427995 TI - Severe thrombocytopaenia in patients with vivax malaria compared to falciparum malaria: a systematic review and meta-analysis. AB - BACKGROUND: Plasmodium vivax is the most geographically widespread species among human malaria parasites. Immunopathological studies have shown that platelets are an important component of the host innate immune response against malaria infections. The objectives of this study were to quantify thrombocytopaenia in P. vivax malaria patients and to determine the associated risks of severe thrombocytopaenia in patients with vivax malaria compared to patients with P. falciparum malaria. MAIN BODY: A systematic review and meta-analysis of the available literature on thrombocytopaenia in P. vivax malaria patients was undertaken. Relevant studies in health-related electronic databases were identified and reviewed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Fifty-eight observational studies (n = 29 664) were included in the current review. Severe thrombocytopaenia (< 50 000/mm3) to very severe thrombocytopaenia (< 20 000/mm3) was observed in 10.1% of patients with P. vivax infection. A meta-analysis of 11 observational studies showed an equal risk of developing severe/very severe thrombocytopaenia between the patients with P. vivax malaria and those with P. falciparum malaria (OR: 1.98, 95% CI: 0.92-4.25). This indicates that thrombocytopaenia is as equally a common manifestation in P. vivax and P. falciparum malaria patients. One study showed a higher risk of developing very severe thrombocytopaenia in children with severe P. vivax malaria than with severe P. falciparum malaria (OR: 2.80, 95% CI: 1.48 5.29). However, a pooled analysis of two studies showed an equal risk among adult severe cases (OR: 1.19, 95% CI: 0.51-2.77). This indicates that the risk of developing thrombocytopaenia in P. vivax malaria can vary with immune status in both children and adults. One study reported higher levels of urea and serum bilirubin in patients with P. vivax malaria and severe thrombocytopaenia compared with patients mild thrombocytopaenia or no thrombocytopaenia, (P < 0.001 in all comparisons). A pooled analysis of two other studies showed a similar proportion of bleeding episodes with thrombocytopaenia in severe P. vivax patients and severe P. falciparum patients (P = 0.09). This implied that both P. vivax and P. falciparum infections could present with bleeding episodes, if there had been a change in platelet counts in the infected patients. A pooled analysis of another two studies showed an equal risk of mortality with severe thrombocytopaenia in both P. vivax and P. falciparum malaria patients (OR: 1.16, 95% CI: 0.30-4.60). However, due to the low number of studies with small sample sizes within the subset of studies that provided clinically relevant information, our confidence in the estimates is limited. CONCLUSION: The current review has provided some evidence of the clinical relevance of severe thrombocytopaenia in P. vivax malaria. To substantiate these findings, there is a need for well designed, large scale, prospective studies among patients infected with P. vivax. These should include patients from different countries and epidemiological settings with various age and gender groups represented. PMID- 29427997 TI - Impact of the International Nosocomial Infection Control Consortium (INICC)'s Multidimensional Approach on Rates of Central Line-Associated Bloodstream Infection in 14 Intensive Care Units in 11 Hospitals of 5 Cities in Argentina. AB - OBJECTIVE To analyze the impact of the International Nosocomial Infection Control Consortium (INICC) Multidimensional Approach (IMA) and the INICC Surveillance Online System (ISOS) on central line-associated bloodstream infection (CLABSI) rates in 14 intensive care units (ICUs) in Argentina from January 2014 to April 2017. DESIGN This prospective, pre-post surveillance study of 3,940 ICU patients was conducted in 11 hospitals in 5 cities in Argentina. During our baseline evaluation, we performed outcome and process surveillance of CLABSI applying Centers for Disease Control and Prevention/National Health Safety Network (CDC/NHSN) definitions. During the intervention, we implemented the IMA through ISOS: (1) a bundle of infection prevention practice interventions, (2) education, (3) outcome surveillance, (4) process surveillance, (5) feedback on CLABSI rates and consequences, and (6) performance feedback of process surveillance. Bivariate and multivariate regression analyses were performed using a logistic regression model to estimate the effect of the intervention on the CLABSI rate. RESULTS During the baseline period, 5,118 CL days and 49 CLABSIs were recorded, for a rate of 9.6 CLABSIs per 1,000 central-line (CL) days. During the intervention, 15,659 CL days and 68 CLABSIs were recorded, for a rate of 4.1 CLABSIs per 1,000 CL days. The CLABSI rate was reduced by 57% (incidence density rate: 0.43; 95% confidence interval, 0.34-0.6; P<.001). CONCLUSIONS Implementing IMA through ISOS was associated with a significant reduction in the CLABSI rate in ICUs in Argentina. Infect Control Hosp Epidemiol 2018;39:445-451. PMID- 29427998 TI - EFFECTS OF INTERPERSONAL TRUST AMONG USERS OF ONLINE HEALTH COMMUNITIES ON PATIENT TRUST IN AND SATISFACTION WITH THEIR PHYSICIAN. AB - OBJECTIVES: Online Health Communities (OHCs) are increasingly being used by patients in the Web 2.0 era. Today's patients have instant access to a great deal of medical information and contacts. Despite the considerable development of OHCs, little is known regarding the impact on the patient-physician relationship. This research aims at filling this gap and examines how interpersonal trust on peer-to-peer OHCs influences two key relational variables, namely patient trust in the physician and patient satisfaction with the physician. It also investigates their influences on the patient's attitude toward the physician. METHODS: Drawing on both the relational and medical literatures, we propose a research model that brings out the relationships between interpersonal trust in OHCs, and patients' trust, satisfaction and attitude toward the physician. We then conduct a quantitative survey of 512 OHC users in France, using structural equation modeling to test our hypotheses. RESULTS: Our findings indicate that interpersonal trust in OHCs exerts a positive influence on both patients' trust in and satisfaction with their physician. It also highlights that these two relational variables have a positive influence on patient attitude toward the physician. Our findings also indicate that patient trust influences patient satisfaction with the physician. CONCLUSIONS: This research highlights the importance of OHCs, which can be seen as valuable instruments for enhancing patient-physician relationships. It shows that healthcare managers should seek to enhance interpersonal trust among OHC users, because this trust has a positive influence on patient satisfaction with, trust in and attitude toward the physician. PMID- 29427999 TI - Dissemination of Staphylococcus epidermidis ST22 With Stable, High-Level Resistance to Linezolid and Tedizolid in the Greek-Turkish Region (2008-2016). PMID- 29428000 TI - Clinical Significance of Low Colony-Count Urine Cultures Among Hospitalized Inpatients. PMID- 29428001 TI - An extremely rare clinical entity: congenitally corrected transposition with situs inversus and single coronary artery presented with complete atrioventricular block in a young man. AB - Congenitally corrected transposition of the great arteries is a rare form of CHD. Situs inversus is a much less common variant of a congenitally corrected transposition of the great arteries. In rare cases, transposition events may be accompanied by various cardiac anomalies. However, situs inversus patients with congenitally corrected transposition, single coronary artery anomaly, and atrioventricular block together have not been reported previously. This combination of abnormalities is presented as a first in the literature. PMID- 29428002 TI - Physician Perceptions Regarding Antimicrobial Use in End-of-Life Care. AB - BACKGROUND The decision to utilize antimicrobials in end-of-life situations is complex. Understanding the reasons why physicians prescribe antimicrobials in this patient population is important for informing the design of antimicrobial stewardship interventions. METHODS A 51-item survey containing both closed and open-ended questions on end-of-life antimicrobial use was administered to physicians affiliated with the University of Pennsylvania and Children's Hospital of Philadelphia from January through April 2017. A mixed-methods approach was used to analyze responses. RESULTS Of 637 physicians surveyed, 283 responses (44.4%) were received. Most (86.2%) physicians believed that respecting a patient's wish to continue antimicrobials was important. Approximately half of physicians (49.8%) believed that antimicrobial use at the end of life contributes to resistance. A higher proportion of pediatricians would often or always continue antimicrobial treatment for active infections and for hospice patients whose death was imminent compared to adult physicians (P<.001). Analysis of free text responses revealed additional reasons why physicians may continue antimicrobials at end of life, including meeting family expectations, wanting to avoid the perception of "giving up," uncertainty about prognosis, and reducing patient pain or discomfort. CONCLUSIONS Physician decision making concerning antimicrobial use in patients at the end of life is multifactorial. Clinicians may overweigh the benefits of antimicrobial therapy in end-of-life situations and view the importance of adhering to stewardship policies differently. Pediatric and adult clinicians have different approaches to this patient population. Better understanding of the complex decision making that occurs in the end-of-life patient population can help guide antimicrobial stewardship policies and improve patient care. Infect Control Hosp Epidemiol 2018;39:383-390. PMID- 29428003 TI - How Does a Photocatalytic Antimicrobial Coating Affect Environmental Bioburden in Hospitals? AB - BACKGROUND The healthcare environment is recognized as a source for healthcare acquired infection. Because cleaning practices are often erratic and always intermittent, we hypothesize that continuously antimicrobial surfaces offer superior control of surface bioburden. OBJECTIVE To evaluate the impact of a photocatalytic antimicrobial coating at near-patient, high-touch sites in a hospital ward. SETTING The study took place in 2 acute-care wards in a large acute-care hospital. METHODS A titanium dioxide-based photocatalytic coating was sprayed onto 6 surfaces in a 4-bed bay in a ward and compared under normal illumination against the same surfaces in an untreated ward: right and left bed rails, bed control, bedside locker, overbed table, and bed footboard. Using standardized methods, the overall microbial burden and presence of an indicator pathogen (Staphylococcus aureus) were assessed biweekly for 12 weeks. RESULTS Treated surfaces demonstrated significantly lower microbial burden than control sites, and the difference increased between treated and untreated surfaces during the study. Hygiene failures (>2.5 colony-forming units [CFU]/cm2) increased 2.6% per day for control surfaces (odds ratio [OR], 1.026; 95% confidence interval [CI], 1.009-1.043; P=.003) but declined 2.5% per day for treated surfaces (OR, 0.95; 95% CI, 0.925-0.977; P<.001). We detected no significant difference between coated and control surfaces regarding S. aureus contamination. CONCLUSION Photocatalytic coatings reduced the bioburden of high-risk surfaces in the healthcare environment. Treated surfaces became steadily cleaner, while untreated surfaces accumulated bioburden. This evaluation encourages a larger-scale investigation to ascertain whether the observed environmental amelioration has an effect on healthcare-acquired infection. Infect Control Hosp Epidemiol 2018;39:398-404. PMID- 29428004 TI - Moderation of prior exposure to trauma on the inverse relationship between callous-unemotional traits and amygdala responses to fearful expressions: an exploratory study. AB - BACKGROUND: Previous work has shown that amygdala responsiveness to fearful expressions is inversely related to level of callous-unemotional (CU) traits (i.e. reduced guilt and empathy) in youth with conduct problems. However, some research has suggested that the relationship between pathophysiology and CU traits may be different in those youth with significant prior trauma exposure. METHODS: In experiment 1, 72 youth with varying levels of disruptive behavior and trauma exposure performed a gender discrimination task while viewing morphed fear expressions (0, 50, 100, 150 fear) and Blood Oxygenation Level Dependent responses were recorded. In experiment 2, 66 of these youth performed the Social Goals Task, which measures self-reports of the importance of specific social goals to the participant in provoking social situations. RESULTS: In experiment 1, a significant CU traits-by-trauma exposure interaction was observed within right amygdala; fear intensity-modulated amygdala responses negatively predicted CU traits for those youth with low levels of trauma but positively predicted CU traits for those with high levels of trauma. In experiment 2, a bootstrapped model revealed that the indirect effect of fear intensity amygdala response on social goal importance through CU traits is moderated by prior trauma exposure. CONCLUSIONS: This study, while exploratory, indicates that the pathophysiology associated with CU traits differs in youth as a function of prior trauma exposure. These data suggest that prior trauma exposure should be considered when evaluating potential interventions for youth with high CU traits. PMID- 29428005 TI - Effects of branched-chain volatile fatty acids on lactation performance and mRNA expression of genes related to fatty acid synthesis in mammary gland of dairy cows. AB - Branched-chain volatile fatty acids (BCVFA) supplements could promote lactation performance and milk quality by improving ruminal fermentation and milk fatty acid synthesis. This study was conducted to evaluate the effects of BCVFA supplementation on milk performance, ruminal fermentation, nutrient digestibility and mRNA expression of genes related to fatty acid synthesis in mammary gland of dairy cows. A total of 36 multiparous Chinese Holstein cows averaging 606+/-4.7 kg of BW, 65+/-5.2 day in milk (DIM) with daily milk production of 30.6+/-0.72 kg were assigned to one of four groups blocked by lactation number, milk yield and DIM. The treatments were control, low-BCVFA (LBCVFA), medium-BCVFA (MBCVFA) and high-BCVFA (HBCVFA) with 0, 30, 60 and 90 g BCVFA per cow per day, respectively. Experimental periods were 105 days with 15 days of adaptation and 90 days of data collection. Dry matter (DM) intake tended to increase, but BW changes were similar among treatments. Yields of actual milk, 4% fat corrected milk, milk fat and true protein linearly increased, but feed conversion ratio (FCR) linearly decreased with increasing BCVFA supplementation. Milk fat content linearly increased, but true protein content tended to increase. Contents of C4:0, C6:0, C8:0, C10:0, C12:0, C14:0 and C15:0 fatty acids in milk fat linearly increased, whereas other fatty acids were not affected with increasing BCVFA supplementation. Ruminal pH, ammonia N concentration and propionate molar proportion linearly decreased, but total VFA production and molar proportions of acetate and butyrate linearly increased with increasing BCVFA supplementation. Consequently, acetate to propionate ratios linearly increased. Digestibilities of DM, organic matter, CP, NDF and ADF also linearly increased. In addition, mRNA expressions of peroxisome proliferator-activated receptor gamma, sterol regulatory element-binding factor 1 and fatty acid-binding protein 3 linearly increased, mRNA expressions of acetyl-coenzyme A carboxylase-alpha, fatty acid synthase and stearoyl-CoA desaturase quadratically increased. However, lipoprotein lipase mRNA expression was not affected by treatments. The results indicated that lactation performance and milk fat synthesis increased with BCVFA supplementation by improving ruminal fermentation, nutrient digestibility and mRNA expressions of genes related to milk fat synthesis. PMID- 29428006 TI - Reliability and validity of food portion size estimation from images using manual flexible digital virtual meshes. AB - OBJECTIVE: The eButton takes frontal images at 4s intervals throughout the day. A three-dimensional manually administered wire mesh procedure has been developed to quantify portion sizes from the two-dimensional images. The present paper reports a test of the inter-rater reliability and validity of use of the wire mesh procedure. DESIGN: Seventeen foods of diverse shapes and sizes served on plates, bowls and cups were selected to rigorously test the portion assessment procedure. A dietitian not involved in inter-rater reliability assessment used standard cups to independently measure the quantities of foods to generate the 'true' value for a total of seventy-five 'served' and seventy-five smaller 'left' images with diverse portion sizes. SETTING: The images appeared on the computer to which the digital wire meshes were applied. SUBJECTS: Two dietitians and three engineers independently estimated portion size of the larger ('served') and smaller ('left') images for the same foods. RESULTS: The engineers had higher reliability and validity than the dietitians. The dietitians had lower reliabilities and validities for the smaller more irregular images, but the engineers did not, suggesting training could overcome this limitation. The lower reliabilities and validities for foods served in bowls, compared with plates, suggest difficulties with the curved nature of the bowls. CONCLUSIONS: The wire mesh procedure is an important step forward in quantifying portion size, which has been subject to substantial self-report error. Improved training procedures are needed to overcome the identified problems. PMID- 29428007 TI - Controversies Regarding the Diagnosis and Management of Ductal Carcinoma In Situ. AB - Ductal carcinoma in situ (DCIS) is a premalignant condition, whose incidence is increasing in the current era of widespread screening mammography. While eminently treatable, there are innumerable controversies that surround this disease in terms of its diagnosis and treatment. We discuss these issues and review the data to date regarding this condition which affects roughly 20 per cent of all patients presenting with breast cancer. PMID- 29428011 TI - Rene Geronimo Favaloro (1923-2000): A Man Who Struggled with Matters of the Heart. AB - Rene Geronimo Favaloro prided himself on being a "simple country doctor." Born in La Plata, Argentina, Dr. Favaloro had an interest in Argentina's sociopolitical and healthcare systems beginning at a young age. He began his medical education at La Universidad Nacional de La Plata, graduating in 1949 with plans to continue his medical education in the field of surgery; however, in 1950, Dr. Favaloro temporarily resigned from his position as a surgeon to work as a country doctor in a small province of La Pampa, Argentina. It was during this time that Dr. Favaloro became acutely aware of the overwhelmingly poor state of the healthcare system in Argentina. In 1962, Dr. Favaloro redirected his focus back to his surgical interests and moved to the United States to work at the Cleveland Clinic, where he discovered the use of the saphenous vein graft for revascularization of the coronary arteries. Despite a productive medical career in the United States, Dr. Favaloro eventually brought his work back to Argentina, where his heart had always remained. Throughout the incredible milestones of his life, Dr. Rene Geronimo Favaloro consistently remained a humble, gracious, and simple country doctor. PMID- 29428014 TI - Comparison of Risk-Adjusted Outcomes in Medicare Open versus Laparoscopic Cholecystectomy. AB - More than 90 per cent of cholecystectomies are performed laparoscopically and this has resulted in concern that surgeons will not have sufficient experience to perform open procedures when clinical circumstances require it. We reviewed the open cholecystectomies (OCs) of Medicare patients from 2010 to 2012 in hospitals with 20 or more cases, created risk-adjusted models for adverse outcomes which were evaluated for 90-days after discharge, and compared the hospital-level outcomes with laparoscopic cholecystectomy performed in the same hospitals for the same period of time. Results demonstrated that inpatient deaths, inpatient prolonged length-of-stay outliers, 90-day postdischarge deaths without readmission, and 90-day readmissions were statistically the same with an overall adverse outcome rate of 21.6 per cent in OC versus 20.9 per cent in laparoscopic cholecystectomy. Conversion of laparoscopic to open procedures was not associated with increased adverse outcomes. Laparoscopic cholecystectomy provides patients with many advantages, but when clinical circumstances are necessary, OC continues to be performed with the same overall adverse outcome rates, and the conversion process is not associated with poorer results in this high-risk population of patients. PMID- 29428017 TI - Long-Term Functional Outcomes after Traumatic Thoracic and Lumbar Spine Fractures. AB - The incidence of thoracolumbar spine fractures in blunt trauma is 4 to 5 per cent. These fractures may lead to neurologic injury, chronic back pain, and disability. Most studies from United States trauma centers focus on neurologic sequelae and/or compare treatment modalities. However, most patients with spine fractures do not have a neurologic deficit. Our primary objective was to determine the long-term outcome of traumatic thoracolumbar spine fractures, specifically addressing quality of life, chronic pain, and employment using a validated patient outcome survey. A chart review of 138 adult blunt trauma patients who sustained a thoracolumbar spine fracture and were admitted to our Level I trauma center from 2008 to 2013 was performed. A phone interview based on the Short-Form 12(r), a general health survey, was then conducted. Of the 134 patients who met the inclusion criteria, 46 (34%) completed the survey. The average Short-Form 12(r) scores were 51.0 for the physical health component score and 52.9 for the mental health component score. These did not differ significantly from the national norm. Furthermore, 83 per cent (38) of the survey respondents returned to work full-time at the same level as before their injury. Majority of the patients (76%) said they did not have pain two to seven years after injury. Despite a commonly held belief that back injury leads to chronic pain and disability, after sustaining a thoracic or lumbar fracture, patients are generally able to return to work and have a comparable quality of life to the general population. This knowledge may be useful in counseling patients regarding expectations for recovery from trauma. PMID- 29428021 TI - Results after Definitive Surgical Treatment in Patients with Enteroatmospheric Fistula. AB - As enteroatmospheric fistulas (EAF) lack healthy overlying tissue, spontaneous healing is very unlikely. Our aim was to identify risk factors for recurrence and mortality after definitive surgical treatment for EAF. Sixty-two consecutive patients with a diagnosis of EAF were submitted to definitive surgical repair (fistula resection and primary anastomosis) during a 6-year period. Several patient, disease, and operative variables were assessed as risk factors associated to our endpoints: recurrence and mortality. All patients were followed up until hospital discharge or death. Univariate and multivariate analysis were performed. There were 24 females and 38 males with a median age of 53 years (interquartile ranges 43-63). EAF recurred in 23 patients. Univariate analysis identified several risk factors for recurrence which included performing more than one anastomosis (20 vs 52%, P = 0.013), failure of achieving total abdominal closure (16 vs 47%, P = 0.025), intraoperative hemorrhage >400 cc (28 vs 65%, P = 0.007), presence of multiple fistulas (25 vs 61%, P = 0.008), and preoperative C reactive protein >0.5 mg/dL (54 vs 82%, P = 0.029). The latter two remained significant after multivariate analysis. Final EAF closure was attained in 47 patients (76%) and 8 more (13%) had a low-output (<50 mL/day) enterocutaneous fistula. Timing of surgery was not related to fistula recurrence. Eight patients died (13%), and fistula recurrence was the only risk factor found related to mortality both through univariate (26 vs 5%, P = 0.043) and after multivariate analysis. EAF management represents a rather challenging problem. Timing for surgical treatment is controversial and is based mostly on patient status and surgeon's criteria. Recurrence is associated to EAF characteristics and an inflammatory state; it was also the only factor associated to mortality. PMID- 29428024 TI - Effect of Systemic Triphenylphosphonium on Organ Function and Oxidative Stress. AB - Conditions of systemic stress can lead to increased reactive oxygen species production, mitochondrial dysfunction, systemic inflammation, and multiorgan dysfunction. Triphenylphosphonium (TPP+) is a lipophilic cation used to target therapeutics to mitochondria. We sought to determine the effects of TPP+ on mitochondrial integrity. Male rats were anesthetized and TPP+ (5 mg/kg) or vehicle (saline) was administered intravenously 30-minutes after anesthesia initiation and intraperitoneally (20 mg/kg) 60-minutes later. Rats were exsanguinated 2-hours postinjection. Cardiac, pulmonary, hepatic, splenic, and renal tissues were analyzed for inflammation, lipid peroxidation, endogenous antioxidant activity, cytokine expression, and mitochondrial function. In vitro modeling was performed using freshly isolated hepatocytes subjected to 8-hours hypoxia/30-minutes reoxygenation in the absence or presence of TPP+. TPP+ increased lipid peroxidation in the liver, lung, and kidney as well as antioxidant activity in the liver, kidney, and spleen. Conversely, antioxidant activity decreased in the lung with TPP+. In addition, TPP+ altered hepatic inflammatory mediators. In vitro, TPP+ attenuated oxygen consumption and, when combined with hypoxic injury, depolarized mitochondrial membranes in hepatocytes. TPP+ induces systemic responses associated with oxidative stress and worsening pathologies in animals. Caution should be exercised when employing TPP+ for therapeutics. PMID- 29428027 TI - Does Vasopressin Exacerbate Cerebral Edema in Patients with Severe Traumatic Brain Injury? AB - : Arginine vasopressin (AVP) is often used as an alternative pressor to catecholamines (CATs). However, unlike CATs, AVP is a powerful antidiuretic that could promote edema. We tested the hypothesis that AVP promoted cerebral edema and/or increased requirements for osmotherapy, relative to those who received CATs, for cerebral perfusion pressure (CPP) management after traumatic brain injury (TBI). This is a retrospective review of 286 consecutive TBI patients with intracranial pressure monitoring at a single institution from September 2008 to January 2015. Cerebral edema was quantitated using CT attenuation in prespecified areas of gray and white matter. RESULTS: To maintain CPP >60 mm Hg, 205 patients required no vasopressors, 41 received a single CAT, 12 received AVP, and 28 required both. Those who required no pressors were generally less injured; required less hyperosmolar therapy and less total fluid; and had lower plasma Na, lower intracranial pressure, less edema, and lower mortality (all P < 0.05). Edema; daily mean, minimum, and maximum Na levels; and mortality were similar with AVP versus CATs, but the daily requirement of mannitol and 3 per cent NaCl were reduced by 45 and 35 per cent (both P < 0.05). In patients with TBI who required CPP therapy, AVP reduced the requirements for hyperosmolar therapy and did not delay resolution or increase cerebral edema compared with CATs. PMID- 29428028 TI - Chronic Obstructive Pulmonary Disease Exacerbations Are Influenced by Gastroesophageal Reflux Disease. AB - Gastroesophageal reflux disease (GERD) is associated with different pulmonary diseases, including chronic obstructive pulmonary disease (COPD). Whether GERD is contributory to COPD severity remains unclear. This study aims to evaluate the contribution of GERD to the clinical manifestation of COPD based on ventilatory parameters and yearly clinical exacerbations. We studied 48 patients (56% females, age 66 years) with COPD. All patients underwent high-resolution manometry and esophageal pH monitoring. The patients were separated into two groups according to the presence of GERD. GERD was present in 21 (44%) patients. GERD + and GERD - groups did not differ in regard to gender, age, and body mass index. Pulmonary parameters were not different in the absence or presence of GERD. The number of yearly exacerbations was higher in patients GERD+. The severity of GERD (as measured by DeMeester score) correlated with the number of exacerbations. Our results show the following: 1) GERD does not influence pulmonary parameters and 2) GERD is associated with a higher number of annual clinical exacerbations. We believe GERD must be objectively tested in patients with COPD because the prevalence of GERD in these patients is underestimated when only symptoms are considered. GERD treatment might decrease the frequency of episodes of exacerbation. PMID- 29428029 TI - The Hand-Assisted Laparoscopic Approach to Resection of Pancreatic Mucinous Cystic Neoplasms: An Underused Technique? AB - Pancreatic mucinous cystic neoplasms (MCNs) are rare tumors typically of the distal pancreas that harbor malignant potential. Although resection is recommended, data are limited on optimal operative approaches to distal pancreatectomy for MCN. MCN resections (2000-2014; eight institutions) were included. Outcomes of minimally invasive and open MCN resections were compared. A total of 289 patients underwent distal pancreatectomy for MCN: 136(47%) minimally invasive and 153(53%) open. Minimally invasive procedures were associated with smaller MCN size (3.9 vs 6.8 cm; P = 0.001), lower operative blood loss (192 vs 392 mL; P = 0.001), and shorter hospital stay(5 vs 7 days; P = 0.001) compared with open. Despite higher American Society of Anesthesiologists class, hand assisted (n = 46) had similar advantages as laparoscopic/robotic (n = 76). When comparing hand-assisted to open, although MCN size was slightly smaller (4.1 vs 6.8 cm; P = 0.001), specimen length, operative time, and nodal yield were identical. Similar to laparoscopic/robotic, hand-assisted had lower operative blood loss (161 vs 392 mL; P = 0.001) and shorter hospital stay (5 vs 7 days; P = 0.03) compared with open, without increased complications. Hand-assisted laparoscopic technique is a useful approach for MCN resection because specimen length, lymph node yield, operative time, and complication profiles are similar to open procedures, but it still offers the advantages of a minimally invasive approach. Hand-assisted laparoscopy should be considered as an alternative to open technique or as a successive step before converting from total laparoscopic to open distal pancreatectomy for MCN. PMID- 29428030 TI - Longer Time Intervals from Diagnosis to Surgical Treatment in Breast Cancer: Associated Factors and Survival Impact. AB - : Time interval (TI) from breast cancer diagnosis to definitive surgery is increasing, but the impact on outcomes is not well understood. TI longer than 30 days is associated with a greater chance of delay of chemotherapy, which may impact survival. We sought to identify factors associated with longer TI and the influence on outcome measures. METHODS: We examined TI for stage 0-III breast cancer patients treated between 2006 and 2015 at a university-based cancer center. Univariate and multivariate analyses were used to study factors associated with TI <30, 30 to 60, and >60 days. Kaplan-Meier plots were used to examine the effect of different TI on overall survival, disease-specific survival, and recurrence-free survival. RESULTS: 1589 patients were included with a median follow-up of 47 months. Median TI was 32 days. Median TI increased in patients from 2011 to 2015 compared with those from 2006 to 2010 (35 vs 30 days, P < 0.001). On multivariate analysis, mastectomy (with or without reconstruction), MRI use, and increasing age were independent predictors of TI >30 days . There were no significant differences in overall survival, disease specific survival, or recurrence-free survival. There was no association between TI >30 days and a subsequent delay >60 days to adjuvant chemotherapy (OR 1.04, 95% CI 0.72-1.52). CONCLUSIONS: TI has increased in the last five years. Patient characteristics, tumor biology, and stage do not influence TI, whereas age, mastectomy, and MRI use were all associated with longer TI. Longer TI does not appear to significantly delay adjuvant chemotherapy or influence short-term outcomes. PMID- 29428031 TI - Academic versus Clinical Productivity of Cardiac Surgeons in the State of New York: Who Publishes More and Who Operates More. AB - We investigated whether/how cardiac surgeons can be productive both academically and clinically. Using online resources (New York State Adult Cardiac Surgery database, SCOPUS), we collected individual clinical volumes (operations performed/year), academic metrics (ongoing publications, role as author), practice setting, and seniority for all cardiac surgeons in the State of New York from 1994 to 2011. Over time, individual clinical volumes decreased (median operations/year: 193 in 1995 vs 126 in 2010; P < 0.001), whereas academic productivity remained unchanged (median publications/year: 0.7 vs 0.3; P = 0.55). There was no correlation (Spearman's correlation coefficient: -0.061; P = 0.08) between the number of new publications and operations/year for the whole population. More operations/year (median: 155 vs 144; P = 0.03) were performed by surgeons without versus with publications during that same year. Who published more worked at hospitals with higher clinical volumes (Spearman's correlation coefficient: 0.16; P < 0.001) and was more likely affiliated with thoracic surgery fellowship programs (median publications/year: 1.7 for affiliated vs 0 for nonaffiliated surgeons; P < 0.001). Cardiac surgeons could be classified into four categories: ~40 per cent clinically busy, but not publishing at all; ~45 per cent operating less, but publishing a little; ~15 per cent clinically very productive (operating as much as the nonpublishers) and publishing a lot; and ~1 per cent operating the least, but publishing the most. PMID- 29428032 TI - Carbohydrate Antigen 19-9 Increases the Predictive Efficiency of alpha Fetoprotein for Prognosis of Resected Hepatocellular Carcinoma. AB - Serum alpha-fetoprotein (AFP) is a classical biomarker for both diagnosis and prognosis of hepatocellular carcinoma (HCC). However, its predictive efficiency for prognosis remains unsatisfactory. This study explores whether integrating AFP and carbohydrate antigen (CA) 19-9/carcinoembryonic antigen (CEA) increase its prognostic efficiency in HCC. A total of 67 HCC patients with complete record of AFP, CA19-9, and CEA, who underwent radical hepatectomy, were included. The sole and combined evaluations for prognostic significance of the three markers were performed. In the first, it was found by one-factor analysis that AFP was a univariate prognostic indicator for disease-free survival, but not overall survival, whereas CEA and CA19-9 were not statistically significant, although the latter was of marginally predictive significance for disease-free survival. Subsequently, it was revealed that combined evaluation of AFP and CA19-9, rather than AFP and CEA, distinguished overall and disease-free survival more effectively, compared with single ones. However, this combination was not significant in multivariate Cox regression analysis, thus needing further validation, especially in large-scale prospective investigations. The addition of vascular invasion to AFP/CA19-9 combination might provide enhanced predictive power for disease-free survival. Collectively, these results preliminarily suggest that CA19-9 increases the predictive efficiency of AFP for prognosis of HCC after resection. PMID- 29428033 TI - Definitive Wound Closure Techniques in Fournier's Gangrene. AB - Necrotizing soft tissue infection of the perineum, or Fournier's gangrene (FG), is a morbid and mortal diagnosis. Despite the severity of FG, the optimal definitive wound closure strategy is unknown, as are long-term wound outcomes. A retrospective review was performed over a 3-year period at a single trauma center. Patients were managed according to our institutional approach focusing on primary wound closure and secondary intention healing in residual wounds. Overall 168 patients were included. Complete primary wound closure was accomplished in 39.9 per cent of patients. Patients undergoing primary wound closure were primarily male (89.6 vs 64.4%, P < 0.001), had lower mean sequential organ failure assessment (SOFA) scores (1.70 +/- 2.30 vs 2.98 +/- 3.36, P = 0.004), more often had perineum-limited FG (67.2 vs 42.6%, P = 0.003), and required fewer debridements (2.40 vs 2.79, P = 0.02). On logistic regression, predictors of primary closure included gender (odds ratio 4.643, 95% confidence interval 1.885 11.437, P = 0.001) and SOFA score (odds ratio 0.834, 95% confidence interval 0.727-0.957, P = 0.01). Wound healing rates increased over time, to an 82.1 per cent wound healing rate without further intervention at greater than six months of follow-up. Wounds healed with secondary intention ranged from 70 to 9520 cm3 and primary closure ranged from 126 to 6912 cm3, whereas wounds requiring skin grafts ranged from 405 to 16,170 cm3. Complete primary wound closure is often achievable in FG patients. Using this standardized approach to FG wound management, even large wounds and wounds undergoing secondary intention healing will often close with long-term wound care and do not require flap creation or early skin grafting. PMID- 29428034 TI - Impact of Trauma-Certified Registered Nurse Anesthetists Team on Intra-Operative Resuscitation and Postoperative Outcomes of Trauma Patients. AB - A Trauma Certified Registered Nurse Anesthetists Team (TCT) was created and trained to provide trauma-focused anesthesia and resuscitation. The purpose of this study was to examine patient outcomes after implementation of TCT. We conducted retrospective analyses of trauma patients managed with surgical intervention from March to December 2015. During the first five months, patients managed before the development of TCT were grouped No-TCT, patients managed after were grouped TCT. To assess outcomes, we used hospital and intensive care unit length of stay, ventilator days, and a validated 10-point intraoperative Apgar score (IOAS). IOAS is calculated using the estimated blood loss, lowest heart rate, and lowest mean arterial pressure during surgery. Higher IOAS are associated with significantly decreased complications and mortality after surgery. We used t test and nonparametric tests for analyses. Fifty two patients were included (mean age 39 years, 75% male; 46.2% managed with TCT). Patients in the No-TCT group had significantly lower use of vasopressors (0.019), lower mean IOAS (P = 0.02), and spent more days on ventilator (P = 0.005) than patients in the TCT. These results suggest that trauma centers should take into consideration implementation of TCT to improve intraoperative and overall outcomes. PMID- 29428035 TI - The State of Prophylactic Mesh Augmentation. AB - Prophylactic mesh augmentation (PMA) is the implantation of mesh during closure of an index laparotomy to decrease a patient's risk for developing incisional hernia (IH). The current body of evidence lacks refined guidelines for patient selection, mesh placement, and material choice. The purpose of this study is to summarize the literature and identify areas of research needed to foster responsible and appropriate use of PMA as an emerging technique. We conducted a comprehensive review of Scopus, Cochrane, PubMed, and clinicaltrials.gov for articles and trials related to using PMA for IH risk reduction. We further supplemented our review by including select papers on patient-reported outcomes, cost utility, risk modeling, surgical techniques, and available materials highly relevant to PMA. Five-hundred-fifty-one unique articles and 357 trials were reviewed. Multiple studies note a significant decrease in IH incidence with PMA compared with primary suture-only-based closure. No multicenter randomized control trial has been conducted in the United States, and only two such trials are currently active worldwide. Evidence exists supporting the use of PMA, with practical cost utility and models for selecting high-risk patients, but standard PMA guidelines are lacking. Although Europe has progressed with this technique, widespread adoption of PMA requires large-scale pragmatic randomized control trial research, strong evidence-based guidelines, current procedural terminology coding, and resolution of several barriers. PMID- 29428036 TI - Span-1 and CA19-9 as Predictors of Early Recurrence and Lymph Node Metastasis for Patients with Invasive Pancreatic Cancer after Pancreatectomy. AB - Because pancreatic cancer is a disease with a dismal prognosis due to the high rate of early recurrence even after curative surgery, selecting the most effective treatment in an individual requires preoperative assessment of the tumor characteristics, including the potential for early recurrence. The study cohort included 84 patients undergoing surgical resection of pancreatic cancer. Univariate and multivariate analyses were conducted to identify the risk factors for early recurrence within six months after curative resection. Early recurrence was associated with a platelet-lymphocyte ratio >=0.23 (P = 0.04), carbohydrate antigen 19-9 (CA19-9) >=200 (P = 0.01), and S-pancreas-1 antigen (Span-1) >=37 (P = 0.0004) by univariate analysis. Multivariate analysis identified CA19-9 >=200 and Span-1 >=37 as independent risk factors for early recurrence. Patients with both risk factors had a significantly higher rate of lymph node metastasis than those with no or one risk factor. Span-1 >= 37 and CA19-9 >= 200 are independent risk factors for early recurrence in patients who underwent surgical resection, and the combination of Span-1 >=37 and CA19-9 >=200 is a useful indicator of lymph node metastasis. PMID- 29428037 TI - The Vicious Cycle of Motorcycle Rally Casualties: A Single Center's Experience. PMID- 29428038 TI - Incisional Hernia in the United States: Trends in Hospital Encounters and Corresponding Healthcare Charges. AB - Incisional hernia (IH) is a challenging, potentially morbid condition. This study evaluates recent trends in hospital encounters associated with IH care in the United States. Using Nationwide Inpatient Sample databases from 2007 to 2011, annual estimates of IH-related hospital discharges, charges, and serious adverse events were identified. Significance in observed trends was tested using regression modeling. From 2007 to 2011, there were 583,054 hospital discharges associated with a diagnosis of IH. 81.1 per cent had a concurrent procedure for IH repair. The average discharge included a female patient (63.2%), 59.8 years of age, with either Medicare (45.3%) or Private insurance (38.3%) as the anticipated primary payer. Comparing 2007 to 2011, significant increases in IH discharges (12%; 2007 = 109,702 vs 2011 = 123,034, P = 0.009) and IH repairs (10%; 2007 = 90,588 vs 2011 = 99,622, P < 0.001) were observed. This was accompanied by a 37 per cent increase in hospital charges (2007 = $44,587 vs 2011 = $60,968, P < 0.001), resulting in a total healthcare bill of $7.3 billion in 2011. Significant trends toward greater patient age (2007 = 59.7 years vs 2011 = 60.2 years, P < 0.001), higher comorbidity index (2007 = 3.0 vs 2011 = 3.5, P < 0.001), and increased frequency of serious adverse events (2007 = 13.5% vs 2011 = 17.7%, P < 0.001) were noted. Further work is needed to identify interventions to mitigate the risk of IH development. PMID- 29428039 TI - Rationale for Mastectomy after Neoadjuvant Chemotherapy. AB - Neoadjuvant chemotherapy (NAC) reduces tumor size, facilitating the use of breast conservation surgery (BCS). However, mastectomy remains the surgical outcome for certain women. The goal of this study was to determine the rationale for mastectomy after NAC, particularly in women eligible for BCS. Retrospective data were reviewed on patients who received NAC between February 2006 and August 2010 at our institution. Demographics and tumor characteristics were compared between patients who received BCS and mastectomy after NAC. Of 149 patients meeting inclusion criteria, 102 (68%) underwent BCS and 47 (32%) underwent mastectomy. Patient preference was the most common rationale for mastectomy (n = 19; 40%), followed by extent of disease (n = 13; 28%), presence of a breast cancer susceptibility gene (BRCA) mutation (n = 9; 19%), persistent positive margins (n = 5; 11%), and wound complications (n = 1; 2%). Of the 47 patients who underwent mastectomy, 37 (79%) were eligible for BCS after NAC. Larger pathologic tumor size (2.05 vs 1.25 cm, P = 0.04) and lobular histology [invasive lobular carcinomas, n = 12/17 (70%) vs invasive ductal carcinomas, n = 36/133 (27%); P < 0.01] were associated with increased rate of mastectomy. After NAC, patient preference, extent of disease, and the presence of a BRCA mutation account for the vast majority of mastectomies. Interestingly, most of these patients were shown to be candidates for breast conservation. This highlights the importance of educating patients about their surgical choice and the lack of evidence, showing a benefit to more extensive surgery. PMID- 29428040 TI - Evaluation of the Safety and Efficacy of Percutaneous Transhepatic Gallbladder Drainage Combined with Laparoscopic Cholecystectomy for Treating Acute Complicated Cholecystitis. AB - The rate of acute cholecystitis in patients with severe underlying diseases is currently increasing. Several studies have reported percutaneous transhepatic gallbladder drainage (PTGBD) combined with laparoscopic cholecystectomy (LC) as a safe and reliable therapeutic option in such patients. This study aimed to elucidate the optimal time interval between PTGBD and LC. In total, 65 patients with acute complicated cholecystitis from our hospital were divided into two groups, short-term LC (sLC) and postponed LC (pLC) group according to whether the procedure was performed within 5 days of gallbladder drainage or after 5 days, respectively. The complications after PTGBD, rate of conversion to open surgery, and complications and mortality after LC were compared between the groups. The sLC group showed significantly lesser operating time, blood loss, postoperative peritoneal drainage time, postoperative oral intake time, and complications compared to the pLC group (P < 0.05). Other factors such as the length of hospital stay (LOS), conversion to open cholecystectomy, and mortality were not statistically significant between the groups. Combined treatment with PTGBC and sLC showed superior outcomes compared to PTGBC and pLC for acute cholecystitis in severely ill patients, thus constituting a feasible and secure treatment option in specialized centers. PMID- 29428041 TI - The Sonographic Subcentimeter Malignant Thyroid Nodule: What Does It Stand for? AB - Thyroid cancer management has moved to less extensive surgery in lesions with favorable criteria. Our study evaluated if the sonographic (US) size of thyroid nodules is a reliable criterion to determine the extent of surgery in patients with papillary thyroid carcinoma (PTC). A retrospective study was performed to evaluate thyroid nodules measuring <10 mm in the preop sonogram with a permanent pathology of PTC. Patients were subdivided into two groups based on the US size: A (1-5 mm) and B (6-10 mm). Statistical correlations were made for the presence of the following unfavorable criteria: multifocality, capsular invasion, angio/lymphatic invasion, extrathyroidal invasion, and presence of metastases. A total of 1901 thyroidectomies were performed: 722 (38%) for PTC. 182 (25%) patients met the inclusion criteria. There were 30 patients in Group A (1-5 mm) and 152 patients in Group B (6-10 mm). Five (17%) patients in Group A and 53 (35%) patients in Group B presented unfavorable criteria (P < 0.005). Malignant thyroid nodules with the US size of <5 mm can in theory be candidates for partial thyroidectomy, but 17 per cent of them might still need further surgical intervention. Lesions with the US size of 6 to 10 mm still have a moderate risk of presenting unfavorable pathological criteria. PMID- 29428042 TI - Extremity Vascular Injury Management: Good Outcomes Using Selective Referral to Vascular Surgeons. AB - Revascularization after extremity vascular injury has long been considered an important skill among trauma surgeons. Increasingly, some trauma surgeons defer vascular repair in response to training or practice patterns. This study was designed to document results of extremity revascularization surgery to evaluate trauma surgeon outcomes and judicious referral of more complex injuries to vascular surgeons (VAS). The trauma registry of an urban level I trauma center was used to identify all patients from 2003 to 2013 who underwent an early (<24 hours) procedure for urgent management of acute injury to extremity vessels. Patients were managed by trauma (TRA) versus VAS based on the practice pattern of the on-call trauma surgeon. Injury and outcome variables were recorded. Of 115 patients, 84 patients were revascularized by trauma and 31 vascular surgeries. There was no difference in complication rates or frequency of any type of complication associated with repairs performed by VAS or TRA. There were similar rates between the two groups for patients with multiple injuries, such as venous, bone or tendon, and nerve injury to the affected extremity. One VAS patient and two TRA patients developed compartment syndrome. In appropriately selected patients, trauma surgeons achieve good outcomes after revascularization of injured extremities. PMID- 29428043 TI - Trauma Surgeons Save Lives-Scribes Save Trauma Surgeons! AB - With the advent of the electronic medical record, the documentation burden of the trauma surgeon has become overwhelming. To help, our trauma division added scribes to the rounding team. We hypothesized that scribe utilization would improve our documentation efficiency and offer a financial benefit to the institution. A review of trauma surgeon documentation and billing was performed at a Level I trauma center over two time periods: January to May 2014 (no scribes) and January to May 2015 (scribes). The number of notes written by trauma surgeons was obtained, as were documentation charges. Documentation efficiency was determined by noting both the hour of the day in which inpatient progress notes were written and the number of notes written after patient discharge. In the 2014 period, a total of 9726 notes were written by trauma attendings. In the 2015 period, 10,933 were written. Despite having 407 fewer trauma patient-days in the 2015 period, the group wrote 343 notes/week versus 298 notes/week (P = 0.008). More inpatient progress notes were written earlier in the working day and fewer were written in the evening. Fewer notes were written after patient discharge (12.7 vs 8.4%). A total of 1,664 hours of scribe time were used over the 5-month period, generating an expense of $32,787. The additional notes generated by scribes resulted in $191,394 in charges. Conservatively, assuming a 20 per cent charge reimbursement, the cost of the scribes was covered. The addition of scribes to the daily trauma rounding team improved note efficiency and increased charge capture at our center. PMID- 29428044 TI - Feasibility of Prophylactic Pancreatojejunostomy in Possible High-Risk Patients for Prevention of Pancreatic Fistula during Enucleation or Limited Pancreatic Resection. AB - The aim of this study was to assess the feasibility of prophylactic pancreatojejunostomy after enucleation or limited pancreatic resection regarding the risk of postoperative pancreatic fistula (PF). We retrospectively reviewed the medical records of 32 patients who underwent enucleation or limited pancreatic resection and compared the clinical parameters between patients with (n = 10) and without (n = 22) prophylactic pancreatojejunostomy. Prophylactic pancreatojejunostomy was performed in patients with a possible high risk ofPF. No operation-related mortality occurred. Operation time was significantly longer (P < 0.01) and blood loss significantly greater (P < 0.01) in patients with pancreatojejunostomy. Overall complications were more frequent (P = 0.02) and postoperative hospital stay was significantly longer (P = 0.02) in patients with pancreatojejunostomy. However, other assessed factors including the prevalence of postoperative PF did not differ between groups. In conclusion, prophylactic pancreatojejunostomy is feasible, and its efficacy in preventing PF after enucleation or limited pancreatic resection in high-risk patients will require further study. PMID- 29428045 TI - Genetic Testing for Hereditary Breast Cancer: The Decision to Decline. AB - Genetic testing is important for comprehensive cancer care. Commercial analysis of the BRCA1/2 genes has been available since 1996, and testing for hereditary breast and ovarian cancer syndrome is well established. The National Comprehensive Cancer Network (NCCN) guidelines identify individuals for whom BRCA1/2 analysis is appropriate and define management recommendations for mutation carriers. Despite recommendations, not all who meet NCCN criteria undergo genetic testing. We assess the frequency that individuals meeting NCCN criteria decline BRCA1/2 analysis, as well as factors that affect the decision making process. A retrospective chart review was performed from September 2013 through August 2014 of individuals who received genetic counseling at the Levine Cancer Institute. A total of 1082 individuals identified through the retrospective chart review met NCCN criteria for BRCA1/2 analysis. Of these, 267 (24.7%) did not pursue genetic testing. Of the Nontested cohort, 59 (22.1%) were disinterested in testing and 108 (40.4%) were advised to gather additional genetic or medical information about their relatives before testing. The remaining 100 (37.5%) individuals were insured and desired to undergo genetic testing but were prohibited by the expense. Eighty five of these 100 patients were responsible for the total cost of the test, whereas the remaining 15 faced a prohibitive copay expense. Financial concerns are a major deterrent to the pursuit of BRCA1/2 analysis among those who meet NCNN criteria, especially in patients diagnosed with breast or ovarian cancer. These findings highlight the need to address financial concerns for genetic testing in this high-risk population. PMID- 29428047 TI - Loss of hamster Leydig cells during regression after exposure to a short photoperiod. AB - The aim of the present study was to evaluate the changes that occur in hamster Leydig cells during regression. Animals were divided into control, mild regression (MR), strong regression (SR) and total regression (TR) groups. Leydig cells were characterised by light and electron microscopy. Terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) and proliferating cell nuclear antigen (PCNA) antibodies were used to detect apoptosis and proliferation respectively. Three types of Leydig cells (A, B and C) could be differentiated. Type A cells were small in size compared with Leydig cells from animals exposed to a long photoperiod, which was a result of a decreased cytoplasm and nucleus. Type B cells were even smaller than Type A cells in regression groups. Type C exhibited cytoplasm vacuolisation. The percentage of Type C cells from the control group was much lower than in the MR, SR and TR groups. (P<0.05). In the SR and TR groups, there was a significant decrease in the percentage of Type B cells compared with the control and MR groups (P<0.05). The total number of Leydig cells decreased during testicular regression (P<0.05). The total number of Type A and B cells was significantly lower in the MR, SR and TR groups compared with the control group (P<0.05). There were no significant differences in the proliferation and apoptosis index in the groups studied. The findings of the present study indicate that there are three types of Leydig cells (A, B and C) in all hamsters studied and that regression causes an increase in the number of Type C cells, so that the reduction in the number Leydig cells during the phases of regression studied must be the result of necrosis and/or necroptosis. PMID- 29428046 TI - The Bethesda Classification for Thyroid Fine Needle Aspiration: A Predictor or an Alarmist? AB - Thyroid malignancies comprise only 2 per cent of all cancers. Yet the incidence of thyroid cancers has been increasing faster than other malignancies, likely due to increased screening and surveillance of thyroid nodules. The Bethesda system represents the preferred method of evaluating thyroid nodules for malignancy using fine needle aspiration (FNA). Many thyroidectomies are performed for small, asymptomatic nodules found on ultrasound. These small papillary cancers (<0.5 cm) are termed microcarcinomas and represent a more indolent natural history causing some to name them "occult papillary tumors." The objective is to assess the relationship between the Bethesda classification and pathologic stage of thyroid cancer with attention to T1a lesions. A single institution, retrospective study of thyroidectomy patients who had a preoperative FNA and a final pathology of thyroid malignancy were performed. The distribution of stage relative to Bethesda classification was significantly different than expected (P = 0.00382). The low risk Bethesda II, (odds ratio;OR 9.15, 2.7931-29.97, P = 0.0003) and the intermediate group, Bethesda III, (OR 3.48, 1.4436-8.4124, P = 0.0055) had a statistically significant higher incidence of T1a. The Bethesda classification for thyroid FNA falls short in the accuracy of intermediate stage malignancies. Patients whose FNA were Bethesda II or III had a higher likelihood of indolent T1a disease. PMID- 29428048 TI - A new look into hypertrophic cardiomyopathy based on clinical evidence. PMID- 29428049 TI - How to predict futility: The holy grail of transcatheter aortic valve implantation. PMID- 29428050 TI - Erratum to "Heart transplantation for Chagas cardiomyopathy" (Rev. Port. Cardiol. 2017;36(11):871.e1-871.e4). PMID- 29428051 TI - Agreement and observer variability. PMID- 29428052 TI - HEART Score and Stress Test Emergency Department Bayesian Decision Scheme: Results from the Acute Care Diagnostic Collaboration. AB - BACKGROUND: Accurate identification of patients at risk of major adverse cardiac events (MACE) places a substantial burden on emergency physicians (EPs). Bayesian nomogram for risk stratification in low- to intermediate-risk cardiovascular patients has not been investigated previously. OBJECTIVE: The objective of this study was to develop a comparative diagnostic model using Bayesian statistics for exercise treadmill test (ETT) and stress echocardiogram (ECHO) to calculate post test diagnostic risk of MACE using HEART (history, electrocardiogram, age, risk factors, and troponin) risk score as predictor of pretest probability. METHODS: Stratification was made by applying HEART scores for the prediction of MACE. Likelihood ratios (LR) were calculated using pooled sensitivity and specificity of ETT and ECHO from the American College of Cardiology Foundation/American Heart Association systematic review. Post-test probabilities were obtained after inserting HEART score and LR into Bayesian nomogram. Analysis of variance was used to assess statistical association. RESULTS: Positive LR (LR+) for ETT was 4.56 and negative LR (LR-) was 0.27; for ECHO, LR+ 5.65 and LR- 0.15. Bayesian statistical modeling post-test probabilities for LR+ and low HEART risk yielded a post-test probability for ETT of 7.75% and 9.09% for ECHO; intermediate risk gave 47.62% and 52.63%, respectively. For LR-, low HEART risk post-test probability for ETT was 0.46% and for ECHO 0.26%; intermediate risk probabilities were 4.48% and 2.49%, respectively. LR- was statistically significant in ruling out MACE with ECHO (p < 0.001), but no significant differences were seen for LR+ (p = 0.64). CONCLUSIONS: This Bayesian analysis demonstrated slight superiority of stress ECHO over ETT in low- and intermediate-risk patients in ruling out MACE. PMID- 29428053 TI - Early Goal-Directed Therapy is Standard Therapy for Septic Shock. PMID- 29428054 TI - Reply. PMID- 29428055 TI - Recommendations for Treatment with Neuraminidase Inhibitors in Emergency Department Patients Infected with Influenza Virus. PMID- 29428056 TI - Response to: Recommendations for Treatment with Neuraminidase Inhibitors in Emergency Department Patients Infected with Influenza Virus. PMID- 29428057 TI - The Impact of Hospital and Patient Factors on the Emergency Department Decision to Admit. AB - BACKGROUND: Substantial variation exists in rates of emergency department (ED) admission. We examine this variation after accounting for local and community characteristics. OBJECTIVES: Elucidate the factors that contribute to admission variation that are amenable to intervention with the goal of reducing variation and health care costs. METHODS: We conducted a retrospective cross-sectional study of 1,412,340 patient encounters across 18 sites from 2012-2013. We calculated the adjusted hospital-level admission rates using multivariate logistic regression. We adjusted for patient, provider, hospital, and community factors to compare admission rate variation and determine the influence of these characteristics on admission rates. RESULTS: The average adjusted admission rate was 22.9%, ranging from 16.1% (95% confidence interval [CI] 11.5-22%) to 32% (95% CI 26.0-38.8). There were higher odds of hospital admission with advancing age, male sex (odds ratio [OR] 1.20, 95% CI 1.91-1.21), and patients seen by a physician vs. mid-level provider (OR 2.26, 95% CI 2.23-2.30). There were increased odds of admission with rising ED volume, at academic institutions (OR 2.23, 95% CI 2.20-2.26) and at for-profit hospitals (OR 1.15, 95% CI 1.12-1.18). Admission rates were lower in communities with a higher per capita income, a higher rate of uninsured patients, and in more urban hospitals. In communities with the most primary providers, there were lower odds of admission (OR 0.60, 95% CI 0.57-0.68). CONCLUSION: Variation in hospital-level admission rates is associated with a number of local and community characteristics. However, the presence of persistent variation after adjustment suggests there are other unmeasured variables that also affect admission rates that deserve further study, particularly in an era of cost containment. PMID- 29428058 TI - Notes on Trauma-Related Thyroid Storm in the Emergency Department. PMID- 29428059 TI - Absorption of orally administered ultrafine drug particles. PMID- 29428060 TI - Smart blood pressure holter. AB - BACKGROUND AND OBJECTIVE: In this study, a wireless blood pressure holter that can be used with smart mobile devices was developed. The developed blood pressure holter consists of two parts, which are a smart mobile device and a cuff. The smart mobile device is used as a recording, control and display device through a developed interface, while the cuff was designed to take measurements from the arm. METHODS: Resistor-Capacitor (RC) and digital filters were used on the cuff that communicates with the smart mobile device via Bluetooth. The blood pressure was estimated using the Simple Hill Climbing Algorithm (HCA). It is possible to measure instantaneous or programmable blood pressure and heart rate values at certain intervals using this holter. RESULTS: The test was conducted with 30 individuals at different ages with the guidance of a specialist health personnel. The results showed that an accuracy at 93.89% and 91.95% rates could be obtained for systolic and diastolic pressure values, respectively, when compared with those obtained using a traditional sphygmomanometer. The accuracy level for the heart rate was measured as 97.66%. Furthermore, this device was tested day and night in the holter mode in terms of working time, the continuity of the Bluetooth connection and the reliability of the measurement results. CONCLUSIONS: The test results were evaluated separately in terms of measurement accuracy, working time, the continuity of the Bluetooth connection and the reliability of the measurement results. The measurement accuracy for systolic, diastolic blood pressure and heart rate values was obtained as 93.89%, 91.95% and 97.66%, respectively. The maximum number of measurements which can be conducted with four 1000 mA alkaline batteries at 20 min intervals was found approximately 79 (little more than 24 h). In addition, it was determined that the continuity of the Bluetooth connection and the reliability of the measurement results were automatically achieved through the features in the interface developed for the smart mobile device. These different evaluations showed that the smart blood pressure holter can meet the requirements of a classical holter device. PMID- 29428061 TI - Classification of cancer cells using computational analysis of dynamic morphology. AB - BACKGROUND AND OBJECTIVE: Detection of metastatic tumor cells is important for early diagnosis and staging of cancer. However, such cells are exceedingly difficult to detect from blood or biopsy samples at the disease onset. It is reported that cancer cells, and especially metastatic tumor cells, show very distinctive morphological behavior compared to their healthy counterparts on aptamer functionalized substrates. The ability to quickly analyze the data and quantify the cell morphology for an instant real-time feedback can certainly contribute to early cancer diagnosis. A supervised machine learning approach is presented for identification and classification of cancer cell gestures for early diagnosis. METHODS: We quantified the morphologically distinct behavior of metastatic cells and their healthy counterparts captured on aptamer functionalized glass substrates from time-lapse optical micrographs. As a proof of concept, the morphologies of human glioblastoma (hGBM) and astrocyte cells were used. The cells were captured and imaged with an optical microscope. Multiple feature vectors were extracted to quantify and differentiate the complex physical gestures of cancerous and non-cancerous cells. Three different classifier models, Support Vector Machine (SVM), Random Forest Tree (RFT), and Naive Bayes Classifier (NBC) were trained with the known dataset using machine learning algorithms. The performances of the classifiers were compared for accuracy, precision, and recall measurements using five-fold cross-validation technique. RESULTS: All the classifier models detected the cancer cells with an average accuracy of at least 82%. The NBC performed the best among the three classifiers in terms of Precision (0.91), Recall (0.9), and F1-score (0.89) for the existing dataset. CONCLUSIONS: This paper presents a standalone system built on machine learning techniques for cancer screening based on cell gestures. The system offers rapid, efficient, and novel identification of hGBM brain tumor cells and can be extended to define single cell analysis metrics for many other types of tumor cells. PMID- 29428062 TI - BRAD: Software for BRain Activity Detection from hemodynamic response. AB - BACKGROUND AND OBJECTIVE: Precise estimation of neuronal activity from neuroimaging data is one of the central challenges of the application of noninvasive neuroimaging methods. One of the widely used methods for studying brain activity is functional magnetic resonance imaging, which is a neuroimaging procedure that measures brain activity based on the blood oxygenation level dependent effect. The blood oxygenation level dependent signal can be modeled as a linear convolution of a hemodynamic response function with an input signal corresponding to the neuronal activity. Estimating such input signals is a complicated problem. METHODS: We present a software tool for estimation of brain neuronal activity, which uses a combination of Wiener filtering with deconvolution methods, including the least absolute shrinkage and selection operator, the ordinary least squares method, and the Dantzig selector. The latter two are equipped with both established selection criteria (Akaike and Bayesian information criterion) as well as newly developed mixture criteria for selection of activations. RESULTS: The software tool was tested on two types of data: measurements during basic visual experiments and during complex naturalistic audiovisual stimulation (watching a movie segment). During testing the software showed reasonable results, with the mixture criteria performing well for temporally extended activations. CONCLUSIONS: The presented software tool can be used for estimation, visualization, and analysis of brain neuronal activity from functional magnetic resonance imaging blood oxygenation level dependent measurements. The implemented methods provide valid results not only in the sparse activity scenario studied previously but also for temporally extended activations. PMID- 29428063 TI - Integrated model of insulin and glucose kinetics describing both hepatic glucose and pancreatic insulin regulation. AB - BACKGROUND AND OBJECTIVES: Modeling of glucose kinetics has to a large extent been based on models with plasma insulin as a known forcing function. Furthermore, population-based statistical methods for parameter estimation in these models have mainly addressed random inter-individual variations and not intra-individual variations in the parameters. Here we present an integrated whole-body model of glucose and insulin kinetics which extends the well-known two compartment glucose minimal model. The population-based estimation technique allow for quantification of both random inter- and intra-individual variation in selected parameters using simultaneous data series on glucose and insulin. METHODS: We extend the two-compartment glucose model into a whole-body model for both glucose and insulin using a simple model for the pancreas compartment which includes feedback of glucose on both insulin secretion and formation of insulin in pancreas. The model has 15 unknown parameters of which 8 have been selected for both intra- and inter-individual variations. The statistical technique for parameter estimation is based on first order conditional estimation. RESULTS: The model has been evaluated on two datasets: Study group 1 includes 13 healthy subjects with 3-5 repeated IVGTT series of simultaneous plasma glucose and insulin measurements and Study group 2 includes 26 obese patients (3 subgroups: 10 type 2 diabetes (T2D), 7 impaired glucose tolerance (IGT) and 9 normal glucose tolerance (NGT)) with a single IVGTT series. In general the estimated population parameters compares well with reported values in similar studies. Overall the model fits the data series well and the random variation in the 8 selected parameters can account for both intra- and inter-individual variations in the data series. Simulation studies perform reasonable in response to either a slow glucose infusion or a staircase experiment with increasing glucose infusion. Furthermore, the parameters related to the pancreas compartment add useful interpretations in relation to discrimination between populations with varying degree of glucose intolerance. CONCLUSIONS: We report a new and improved whole body model of glucose and insulin kinetics which performs robustly under differing conditions and adds useful interpretations in relation to glucose intolerance. PMID- 29428064 TI - Automatic hemolysis identification on aligned dual-lighting images of cultured blood agar plates. AB - BACKGROUND AND OBJECTIVE: The recent introduction of Full Laboratory Automation systems in clinical microbiology opens to the availability of streams of high definition images representing bacteria culturing plates. This creates new opportunities to support diagnostic decisions through image analysis and interpretation solutions, with an expected high impact on the efficiency of the laboratory workflow and related quality implications. Starting from images acquired under different illumination settings (top-light and back-light), the objective of this work is to design and evaluate a method for the detection and classification of diagnostically relevant hemolysis effects associated with specific bacteria growing on blood agar plates. The presence of hemolysis is an important factor to assess the virulence of pathogens, and is a fundamental sign of the presence of certain types of bacteria. METHODS: We introduce a two-stage approach. Firstly, the implementation of a highly accurate alignment of same plate image scans, acquired using top-light and back-light illumination, enables the joint spatially coherent exploitation of the available data. Secondly, from each segmented portion of the image containing at least one bacterial colony, specifically designed image features are extracted to feed a SVM classification system, allowing detection and discrimination among different types of hemolysis. RESULTS: The fine alignment solution aligns more than 98.1% images with a residual error of less than 0.13 mm. The hemolysis classification block achieves a 88.3% precision with a recall of 98.6%. CONCLUSIONS: The results collected from different clinical scenarios (urinary infections and throat swab screening) together with accurate error analysis demonstrate the suitability of our system for robust hemolysis detection and classification, which remains feasible even in challenging conditions (low contrast or illumination changes). PMID- 29428065 TI - eCTG: an automatic procedure to extract digital cardiotocographic signals from digital images. AB - BACKGROUND AND OBJECTIVE: Cardiotocography (CTG), consisting in the simultaneous recording of fetal heart rate (FHR) and maternal uterine contractions (UC), is a popular clinical test to assess fetal health status. Typically, CTG machines provide paper reports that are visually interpreted by clinicians. Consequently, visual CTG interpretation depends on clinician's experience and has a poor reproducibility. The lack of databases containing digital CTG signals has limited number and importance of retrospective studies finalized to set up procedures for automatic CTG analysis that could contrast visual CTG interpretation subjectivity. In order to help overcoming this problem, this study proposes an electronic procedure, termed eCTG, to extract digital CTG signals from digital CTG images, possibly obtainable by scanning paper CTG reports. METHODS: eCTG was specifically designed to extract digital CTG signals from digital CTG images. It includes four main steps: pre-processing, Otsu's global thresholding, signal extraction and signal calibration. Its validation was performed by means of the "CTU-UHB Intrapartum Cardiotocography Database" by Physionet, that contains digital signals of 552 CTG recordings. Using MATLAB, each signal was plotted and saved as a digital image that was then submitted to eCTG. Digital CTG signals extracted by eCTG were eventually compared to corresponding signals directly available in the database. Comparison occurred in terms of signal similarity (evaluated by the correlation coefficient rho, and the mean signal error MSE) and clinical features (including FHR baseline and variability; number, amplitude and duration of tachycardia, bradycardia, acceleration and deceleration episodes; number of early, variable, late and prolonged decelerations; and UC number, amplitude, duration and period). RESULTS: The value of rho between eCTG and reference signals was 0.85 (P < 10-560) for FHR and 0.97 (P < 10-560) for UC. On average, MSE value was 0.00 for both FHR and UC. No CTG feature was found significantly different when measured in eCTG vs. reference signals. CONCLUSIONS: eCTG procedure is a promising useful tool to accurately extract digital FHR and UC signals from digital CTG images. PMID- 29428066 TI - Utility of bispectrum in the screening of pediatric sleep apnea-hypopnea syndrome using oximetry recordings. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to assess the utility of bispectrum-based oximetry approaches as a complementary tool to traditional techniques in the screening of pediatric sleep apnea-hypopnea syndrome (SAHS). METHODS: 298 blood oxygen saturation (SpO2) signals from children ranging 0-13 years of age were recorded during overnight polysomnography (PSG). These recordings were divided into three severity groups according to the PSG-derived apnea hypopnea index (AHI): AHI < 5 events per hour (e/h), 5 <= AHI < 10 e/h, AHI >= 10 e/h. For each pediatric subject, anthropometric variables, 3% oxygen desaturation index (ODI3) and spectral features from power spectral density (PSD) and bispectrum were obtained. Then, the fast correlation-based filter (FCBF) was applied to select a subset of relevant features that may be complementary, excluding those that are redundant. The selected features fed a multiclass multi layer perceptron (MLP) neural network to build a model to estimate the SAHS severity degrees. RESULTS: An optimum subset with features from all the proposed methodological approaches was obtained: variables from bispectrum, as well as PSD, ODI3, Age, and Sex. In the 3-class classification task, the MLP model trained with these features achieved an accuracy of 76.0% and a Cohen's kappa of 0.56 in an independent test set. Additionally, high accuracies were reached using the AHI cutoffs for diagnosis of moderate (AHI = 5 e/h) and severe (AHI = 10 e/h) SAHS: 81.3% and 85.3%, respectively. These results outperformed the diagnostic ability of a MLP model built without using bispectral features. CONCLUSIONS: Our results suggest that bispectrum provides additional information to anthropometric variables, ODI3 and PSD regarding characterization of changes in the SpO2 signal caused by respiratory events. Thus, oximetry bispectrum can be a useful tool to provide complementary information for screening of moderate-to-severe pediatric SAHS. PMID- 29428067 TI - Passive magnetic-based localization for precise untethered medical instrument tracking. AB - BACKGROUND AND OBJECTIVE: Motion tracking and navigation systems are paramount for both safety and efficacy in a variety of surgical insertions, interventions and procedures. Among the state-of-art tracking technology, passive magnetic tracking using permanent magnets or passive magnetic sources for localization is an effective technology to provide untethered medical instrument tracking without cumbersome wires needed for signal or power transmission. Motivated by practical needs in two medical insertion procedures: Nasogastric intubation and Ventriculostomy, we propose a unified method based on passive magnetic-field localization, for enhanced efficacy and safety. METHODS: Traditional approaches to passive magnetic tracking involve solving the inverse localization problem. Limited by the idealistic magnetic field dipole model and computationally intense nonlinear optimization algorithm, the overall accuracy and computational cost are greatly compromised. The method introduced here features direct localization with artificial neural network (ANN) models that bypasses the need to resolve the inverse problem and is adaptable for a variety of real-time localization and tracking applications. RESULTS: The efficiency of the two methods, the inverse optimization method and the direct ANN method are experimentally evaluated by comparing the estimated position of reference trajectories for typical nasogastric and ventriculostomy insertion paths performed by a dexterous robotic arm which provides ground truth measurement. It was found that within the region of interest (ROI), the direct ANN technique could significantly improve the localization accuracy, with an average experimental localization error of less than 2 mm, while that of the traditional inverse optimization method using a dipole-based mathematical model at greater than 5 mm. Ex-vivo experiments were performed to validate the localization methods in clinical settings. CONCLUSIONS: While the proposed method for passive magnetic tracking requires a procedure specific pre-procedural calibration, it is able to provide real-time tracking with high accuracy, robustness and diversity. It could be the missing piece to the puzzle to bring passive magnetic tracking technology into practice, therefore leading to untethered medical instrument tracking. PMID- 29428069 TI - Enhancement and restoration of non-uniform illuminated Fundus Image of Retina obtained through thin layer of cataract. AB - BACKGROUND AND OBJECTIVES: Retinal fundus images are extensively used in manually or without human intervention to identify and analyze various diseases. Due to the comprehensive imaging arrangement, there is a large radiance, reflectance and contrast inconsistency within and across images. METHOD: A novel method is proposed based on the cataract physical model to reduce the generated blurriness of the fundus image at the time of image acquisition through the thin layer of cataract by the fundus camera. After the blurriness reduction the method is proposed the enhancement procedure of the images with an objective on contrast perfection with no preamble of artifacts. Due to the uneven distribution of thickness of the cataract, the cataract surroundings are first predicted in the domain of frequency. Second, the resultant image of first step enhanced by the intensity histogram equalization in the adapted Hue Saturation Intensity (HSI) color image space such as the gamut problem can be avoided. The concluding image with suitable color and disparity is acquired by using the proposed max-min color correction approach. RESULTS: The result indicates that not only the proposed method can more effectively enhanced the non-uniform image of retina obtain through thin layer of cataract, but also the resulting image show appropriate brightness and saturation and maintain complete color space information. The projected enhancement method has been tested on the openly available datasets and the result evaluated with the standard used image enhancement algorithms and the cataract removal method. Results show noticeable development over existing methods. CONCLUSIONS: Cataract often prevents the clinician from objectively evaluating fundus feature. Cataract also affect subjective test. Enhancement and restoration of non-uniform illuminated Fundus Image of Retina obtained through thin layer of Cataract has shown here to be potentially beneficial. PMID- 29428068 TI - The prevalence and usage of mobile health applications among mental health patients in Saudi Arabia. AB - BACKGROUND: Mobile health (mHealth) applications provide new methods of engagement with patients and can help patients manage their mental health condition. OBJECTIVE: The main objective of this study is to explore the prevalence of the use of mobile health applications for mental health patients in Saudi Arabia. METHODS: A total of 376 participants with depression and/or anxiety completed an online survey distributed by social networks which asked questions relating to mobile phone ownership, uses of health applications, and utilization patterns to track mental health related issues. RESULTS: Approximately, 46% of the participants reported running one or two healthcare related applications on their mobile phones. In all age groups, 64% of the participants used their mobile phones to access information related to their own health. Also, 64% of the participants expressed interest in using their own mobile phones to track and follow the progression of their depression and/or anxiety. CONCLUSIONS: Developing mobile health applications for Saudi mental health patients is needed since it can offer opportunities for patients, researchers, caregivers, and legislators to work together to improve the state of mental health care in Saudi Arabia. PMID- 29428070 TI - Max-margin weight learning for medical knowledge network. AB - BACKGROUND AND OBJECTIVE: The application of medical knowledge strongly affects the performance of intelligent diagnosis, and method of learning the weights of medical knowledge plays a substantial role in probabilistic graphical models (PGMs). The purpose of this study is to investigate a discriminative weight learning method based on a medical knowledge network (MKN). METHODS: We propose a training model called the maximum margin medical knowledge network (M3KN), which is strictly derived for calculating the weight of medical knowledge. Using the definition of a reasonable margin, the weight learning can be transformed into a margin optimization problem. To solve the optimization problem, we adopt a sequential minimal optimization (SMO) algorithm and the clique property of a Markov network. Ultimately, M3KN not only incorporates the inference ability of PGMs but also deals with high-dimensional logic knowledge. RESULTS: The experimental results indicate that M3KN obtains a higher F-measure score than the maximum likelihood learning algorithm of MKN for both Chinese Electronic Medical Records (CEMRs) and Blood Examination Records (BERs). Furthermore, the proposed approach is obviously superior to some classical machine learning algorithms for medical diagnosis. To adequately manifest the importance of domain knowledge, we numerically verify that the diagnostic accuracy of M3KN is gradually improved as the number of learned CEMRs increase, which contain important medical knowledge. CONCLUSIONS: Our experimental results show that the proposed method performs reliably for learning the weights of medical knowledge. M3KN outperforms other existing methods by achieving an F-measure of 0.731 for CEMRs and 0.4538 for BERs. This further illustrates that M3KN can facilitate the investigations of intelligent healthcare. PMID- 29428071 TI - Detection of mass regions in mammograms by bilateral analysis adapted to breast density using similarity indexes and convolutional neural networks. AB - BACKGROUND AND OBJECTIVE: The processing of medical image is an important tool to assist in minimizing the degree of uncertainty of the specialist, while providing specialists with an additional source of detect and diagnosis information. Breast cancer is the most common type of cancer that affects the female population around the world. It is also the most deadly type of cancer among women. It is the second most common type of cancer among all others. The most common examination to diagnose breast cancer early is mammography. In the last decades, computational techniques have been developed with the purpose of automatically detecting structures that maybe associated with tumors in mammography examination. This work presents a computational methodology to automatically detection of mass regions in mammography by using a convolutional neural network. METHODS: The materials used in this work is the DDSM database. The method proposed consists of two phases: training phase and test phase. The training phase has 2 main steps: (1) create a model to classify breast tissue into dense and non-dense (2) create a model to classify regions of breast into mass and non mass. The test phase has 7 step: (1) preprocessing; (2) registration; (3) segmentation; (4) first reduction of false positives; (5) preprocessing of regions segmented; (6) density tissue classification (7) second reduction of false positives where regions will be classified into mass and non-mass. RESULTS: The proposed method achieved 95.6% of accuracy in classify non-dense breasts tissue and 97,72% accuracy in classify dense breasts. To detect regions of mass in non-dense breast, the method achieved a sensitivity value of 91.5%, and specificity value of 90.7%, with 91% accuracy. To detect regions in dense breasts, our method achieved 90.4% of sensitivity and 96.4% of specificity, with accuracy of 94.8%. CONCLUSIONS: According to the results achieved by CNN, we demonstrate the feasibility of using convolutional neural networks on medical image processing techniques for classification of breast tissue and mass detection. PMID- 29428072 TI - Taxonomy of multi-focal nematode image stacks by a CNN based image fusion approach. AB - BACKGROUND AND OBJECTIVE: In the biomedical field, digital multi-focal images are very important for documentation and communication of specimen data, because the morphological information for a transparent specimen can be captured in form of a stack of high-quality images. Given biomedical image stacks containing multi focal images, how to efficiently extract effective features from all layers to classify the image stacks is still an open question. METHODS: We present to use a deep convolutional neural network (CNN) image fusion based multilinear approach for the taxonomy of multi-focal image stacks. A deep CNN based image fusion technique is used to combine relevant information of multi-focal images within a given image stack into a single image, which is more informative and complete than any single image in the given stack. Besides, multi-focal images within a stack are fused along 3 orthogonal directions, and multiple features extracted from the fused images along different directions are combined by canonical correlation analysis (CCA). Because multi-focal image stacks represent the effect of different factors - texture, shape, different instances within the same class and different classes of objects, we embed the deep CNN based image fusion method within a multilinear framework to propose an image fusion based multilinear classifier. RESULTS: The experimental results on nematode multi-focal image stacks demonstrated that the deep CNN image fusion based multilinear classifier can reach a higher classification rate (95.7%) than that by the previous multilinear based approach (88.7%), even we only use the texture feature instead of the combination of texture and shape features as in the previous work. CONCLUSIONS: The proposed deep CNN image fusion based multilinear approach shows great potential in building an automated nematode taxonomy system for nematologists. It is effective to classify multi-focal image stacks. PMID- 29428073 TI - PFIM 4.0, an extended R program for design evaluation and optimization in nonlinear mixed-effect models. AB - BACKGROUND AND OBJECTIVE: Nonlinear mixed-effect models (NLMEMs) are increasingly used for the analysis of longitudinal studies during drug development. When designing these studies, the expected Fisher information matrix (FIM) can be used instead of performing time-consuming clinical trial simulations. The function PFIM is the first tool for design evaluation and optimization that has been developed in R. In this article, we present an extended version, PFIM 4.0, which includes several new features. METHODS: Compared with version 3.0, PFIM 4.0 includes a more complete pharmacokinetic/pharmacodynamic library of models and accommodates models including additional random effects for inter-occasion variability as well as discrete covariates. A new input method has been added to specify user-defined models through an R function. Optimization can be performed assuming some fixed parameters or some fixed sampling times. New outputs have been added regarding the FIM such as eigenvalues, conditional numbers, and the option of saving the matrix obtained after evaluation or optimization. Previously obtained results, which are summarized in a FIM, can be taken into account in evaluation or optimization of one-group protocols. This feature enables the use of PFIM for adaptive designs. The Bayesian individual FIM has been implemented, taking into account a priori distribution of random effects. Designs for maximum a posteriori Bayesian estimation of individual parameters can now be evaluated or optimized and the predicted shrinkage is also reported. It is also possible to visualize the graphs of the model and the sensitivity functions without performing evaluation or optimization. RESULTS: The usefulness of these approaches and the simplicity of use of PFIM 4.0 are illustrated by two examples: (i) an example of designing a population pharmacokinetic study accounting for previous results, which highlights the advantage of adaptive designs; (ii) an example of Bayesian individual design optimization for a pharmacodynamic study, showing that the Bayesian individual FIM can be a useful tool in therapeutic drug monitoring, allowing efficient prediction of estimation precision and shrinkage for individual parameters. CONCLUSION: PFIM 4.0 is a useful tool for design evaluation and optimization of longitudinal studies in pharmacometrics and is freely available at http://www.pfim.biostat.fr. PMID- 29428074 TI - Machine learning techniques for breast cancer computer aided diagnosis using different image modalities: A systematic review. AB - BACKGROUND AND OBJECTIVE: The high incidence of breast cancer in women has increased significantly in the recent years. Physician experience of diagnosing and detecting breast cancer can be assisted by using some computerized features extraction and classification algorithms. This paper presents the conduction and results of a systematic review (SR) that aims to investigate the state of the art regarding the computer aided diagnosis/detection (CAD) systems for breast cancer. METHODS: The SR was conducted using a comprehensive selection of scientific databases as reference sources, allowing access to diverse publications in the field. The scientific databases used are Springer Link (SL), Science Direct (SD), IEEE Xplore Digital Library, and PubMed. Inclusion and exclusion criteria were defined and applied to each retrieved work to select those of interest. From 320 studies retrieved, 154 studies were included. However, the scope of this research is limited to scientific and academic works and excludes commercial interests. RESULTS: This survey provides a general analysis of the current status of CAD systems according to the used image modalities and the machine learning based classifiers. Potential research studies have been discussed to create a more objective and efficient CAD systems. PMID- 29428075 TI - Automatic liver detection and standardised uptake value evaluation in whole-body Positron Emission Tomography/Computed Tomography scans. AB - BACKGROUND AND OBJECTIVE: Standardised Uptake Value (SUV), in clinical research and practice, is a marker of tumour avidity in Positron Emission Tomography/Computed Tomography (PET/CT). Since many technical, physical and physiological factors affect the SUV absolute measurement, the liver uptake is often used as reference value both in quantitative and semi-quantitative evaluation. The purpose of this investigation was to automatically detect the liver position in whole-body PET/CT scans and extract its average SUV value. METHODS: We developed an algorithm, called LIver DEtection Algorithm (LIDEA), that analyses PET/CT scans, and under the assumption that the liver is a large homogeneous volume near the centre of mass of the patient, finds its position and automatically places a region of interest (ROI) in the liver, which is used to calculate the average SUV. The algorithm was validated on a population of 630 PET/CT scans coming from more than 60 different scanners. The SUV was also calculated by manually placing a large ROI in the liver. RESULTS: LIDEA identified the liver with a 97.3% sensitivity with PET/CT images only and reached a 98.9% correct detection rate when using the co-registered CT scan to avoid liver misidentification in the right lung. The average liver SUV obtained with LIDEA was successfully validated against its manual assessment, with no systematic difference (0.11 +/- 0.36 SUV units) and a R2=0.89 correlation coefficient. CONCLUSIONS: LIDEA proved to be a reliable tool to automatically identify and extract the average SUV of the liver in oncological whole-body PET/CT scans. PMID- 29428076 TI - An automated blastomere identification method for the evaluation of day 2 embryos during IVF/ICSI treatments. AB - PURPOSE: Evaluation of human embryos is one of the most important challenges in vitro fertilization (IVF) programs. The morphology and the morphokinetic parameters of the early cleaving embryo are of critical clinical importance. This stage spans the first 48 h post-fertilization, in which the embryo is dividing in smaller blastomeres at specific time-points. The morphology, in combination with the symmetry of the blastomeres seems to be powerful features with strong prognostic value for embryo evaluation. To date, the identification of these features is based on human inspection in timed intervals, at best using camera systems that simply work as surveillance systems without any precise alerting and decision support mechanisms. The purpose of the study presented in this paper was to develop a computer vision technique to automatically detect and identify the most suitable cleaving embryos (preferably at day 2 post-fertilization) for embryo transfer (ET) during IVF/ICSI treatments. METHODS AND RESULTS: To this end, texture and geometrical features were used to localize and analyze the whole cleaving embryo in 2D grayscale images captured during in vitro embryo formation. Because of the ellipsoidal nature of blastomeres, the contour of each blastomere was modeled with an optimal fitting ellipse while the mean eccentricity of all ellipses is computed. The mean eccentricity in combination with the number of blastomeres forms the feature space on which the final criterion for the embryo evaluation was based. CONCLUSIONS: Experimental results with low quality 2D grayscale images demonstrated the effectiveness of the proposed technique and provided evidence of a novel automated approach for predicting embryo quality. PMID- 29428077 TI - Health status monitoring for ICU patients based on locally weighted principal component analysis. AB - BACKGROUND AND OBJECTIVES: Intelligent status monitoring for critically ill patients can help medical stuff quickly discover and assess the changes of disease and then make appropriate treatment strategy. However, general-type monitoring model now widely used is difficult to adapt the changes of intensive care unit (ICU) patients' status due to its fixed pattern, and a more robust, efficient and fast monitoring model should be developed to the individual. METHODS: A data-driven learning approach combining locally weighted projection regression (LWPR) and principal component analysis (PCA) is firstly proposed and applied to monitor the nonlinear process of patients' health status in ICU. LWPR is used to approximate the complex nonlinear process with local linear models, in which PCA could be further applied to status monitoring, and finally a global weighted statistic will be acquired for detecting the possible abnormalities. Moreover, some improved versions are developed, such as LWPR-MPCA and LWPR-JPCA, which also have superior performance. RESULTS: Eighteen subjects were selected from the Physiobank's Multi-parameter Intelligent Monitoring for Intensive Care II (MIMIC II) database, and two vital signs of each subject were chosen for online monitoring. The proposed method was compared with several existing methods including traditional PCA, Partial least squares (PLS), just in time learning combined with modified PCA (L-PCA), and Kernel PCA (KPCA). The experimental results demonstrated that the mean fault detection rate (FDR) of PCA can be improved by 41.7% after adding LWPR. The mean FDR of LWPR-MPCA was increased by 8.3%, compared with the latest reported method L-PCA. Meanwhile, LWPR spent less training time than others, especially KPCA. CONCLUSIONS: LWPR is first introduced into ICU patients monitoring and achieves the best monitoring performance including adaptability to changes in patient status, sensitivity for abnormality detection as well as its fast learning speed and low computational complexity. The algorithm is an excellent approach to establishing a personalized model for patients, which is the mainstream direction of modern medicine in the following development, as well as improving the global monitoring performance. PMID- 29428078 TI - A case-oriented web-based training system for breast cancer diagnosis. AB - BACKGROUND AND OBJECTIVE: Breast cancer is still considered as the most common form of cancer as well as the leading causes of cancer deaths among women all over the world. We aim to provide a web-based breast ultrasound database for online training inexperienced radiologists and giving computer-assisted diagnostic information for detection and classification of the breast tumor. METHODS: We introduce a web database which stores breast ultrasound images from breast cancer patients as well as their diagnostic information. A web-based training system using a feature scoring scheme based on Breast Imaging Reporting and Data System (BI-RADS) US lexicon was designed. A computer-aided diagnosis (CAD) subsystem was developed to assist the radiologists to make scores on the BI RADS features for an input case. The training system possesses 1669 scored cases, where 412 cases are benign and 1257 cases are malignant. It was tested by 31 users including 12 interns, 11 junior radiologists, and 8 experienced senior radiologists. RESULTS: This online training system automatically creates case based exercises to train and guide the newly employed or resident radiologists for the diagnosis of breast cancer using breast ultrasound images based on the BI RADS. After the trainings, the interns and junior radiologists show significant improvement in the diagnosis of the breast tumor with ultrasound imaging (p-value < .05); meanwhile the senior radiologists show little improvement (p-value > .05). CONCLUSIONS: The online training system can improve the capabilities of early-career radiologists in distinguishing between the benign and malignant lesions and reduce the misdiagnosis of breast cancer in a quick, convenient and effective manner. PMID- 29428079 TI - Joint segmentation of bones and muscles using an intensity and histogram-based energy minimization approach. AB - BACKGROUND AND OBJECTIVES: The segmentation of muscle and bone structures in CT is of interest to physicians and surgeons for surgical planning, disease diagnosis and/or the analysis of fractures or bone/muscle densities. Recently, the issue has been addressed in many research works. However, most studies have focused on only one of the two tissues and on the segmentation of one particular bone or muscle. This work addresses the segmentation of muscle and bone structures in 3D CT volumes. METHODS: The proposed bone and muscle segmentation algorithm is based on a three-label convex relaxation approach. The main novelty is that the proposed energy function to be minimized includes distance to histogram models of bone and muscle structures combined with gray-level information. RESULTS: 27 CT volumes corresponding to different sections from 20 different patients were manually segmented and used as ground-truth for training and evaluation purposes. Different metrics (Dice index, Jaccard index, Sensitivity, Specificity, Positive Predictive Value, accuracy and computational cost) were computed and compared with those used in some state-of-the art algorithms. The proposed algorithm outperformed the other methods, obtaining a Dice coefficient of 0.88 +/- 0.14, a Jaccard index of 0.80 +/- 0.19, a Sensitivity of 0.94 +/- 0.15 and a Specificity of 0.95 +/- 0.04 for bone segmentation, and 0.78 +/- 0.12, 0.65 +/- 0.16, 0.94 +/- 0.04 and 0.95 +/- 0.04 for muscle tissue. CONCLUSIONS: A fast, generalized method has been presented for segmenting muscle and bone structures in 3D CT volumes using a multilabel continuous convex relaxation approach. The results obtained show that the proposed algorithm outperforms some state-of-the art methods. The algorithm will help physicians and surgeons in surgical planning, disease diagnosis and/or the analysis of fractures or bone/muscle densities. PMID- 29428080 TI - Reliability of a clinical 3D freehand ultrasound technique: Analyses on healthy and pathological muscles. AB - BACKGROUND AND OBJECTIVE: 3D freehand Ultrasonography is a medical imaging technique that can be used to measure muscle and tendon morphological and structural properties, including volume, lengths and echo-intensity. These properties are clinically relevant in neurological disorders such as spastic cerebral palsy to monitor disease progression and evaluate the effect of treatment. This study presents a methodology for extracting these parameters along with a clinical reliability analysis for the data acquisition and processing. METHODS: The medial gastrocnemius muscles and Achilles tendon of 10 typically developing children and 10 children with spastic cerebral palsy were assessed. An open-source in-house software library developed in Python (Py3DFreeHandUS) was used to reconstruct, into one 3D data set, the data simultaneously acquired from an US machine and a motion tracking system. US images were manually segmented and linearly interpolated by means of a new simplified approach which involved sequentially decreasing the total number of images used for muscle border segmentation from 100% to 5%. Acquisition and processing reliability was defined based on repeated measures from different data processers and from different data acquirers, respectively. RESULTS: When only 10% of the US images were outlined, there was an average underestimation of muscle volume of 1.1% and 1.6% with respect the computation of all the available images, for the typically developing and spastic cerebral palsy groups, respectively. For both groups, the reliability was higher for data processing than for data acquisition. High inter-class correlation coefficient values were found for processing and acquisition reliability, with worst case values of 0.89 and 0.61, respectively. The standard error of measurement, expressed as a percentage of the average volumes, was smaller than 2.6 ml (4.8%) in all cases. CONCLUSIONS: The present analysis demonstrates the effectiveness of applying 3D freehand ultrasonography in a clinical setting for analysing healthy and pathological paediatric muscle. PMID- 29428081 TI - Machine learning based cancer detection using various image modalities. PMID- 29428082 TI - CD14 gene polymorphisms associated with increased risk of bovine tuberculosis in Chinese Holstein cows. AB - Cluster differentiation antigen 14 (CD14) is an important pattern recognition receptor protein in innate immunity. The aim of this study was to identify and assess the association of single-nucleotide polymorphisms (SNPs) in the CD14 gene with susceptibility to bovine tuberculosis (BTB) in Chinese Holstein cows. DNA samples from 517 Chinese Holstein cows (257 tuberculosis positive cases and 259 healthy controls) were collected from dairy farms in China. SNPs in the entire CD14 gene, including exonic regions, intronic regions and close to the 5'- and 3' terminal untranslated regions, were detected by PCR, followed by direct sequencing. Five SNPs (-5C/T, 613G/A, 1023G/A, 1306G/A and 1326G/T) were found in the CD14 gene region. Significantly increased BTB susceptibility was evident in T allele carriers of -5C/T (P<0.001; odds ratio, OR 2.02; 95% confidence interval, CI 1.57-2.77), G allele carriers of 613G/A (P<0.001; OR 2.17, 95% CI 1.50-3.08) and TG haplotype carriers of both SNPs (P<0.001; OR 3.14, 95% CI 1.24-4.50). These results suggest that -5C/T and 613G/A are risk factors for BTB in Chinese Holstein cattle and might be used as candidate genetic markers in breeding cows with natural resistance to BTB. PMID- 29428084 TI - Corrigendum to: "Directional asymmetry of facial and limb traits in horses and ponies" [Vet. J. 198 (2013) e46-51]. PMID- 29428083 TI - Comparison of central corneal thickness in dogs measured by ultrasound pachymetry and ultrasound biomicroscopy. AB - Ultrasound pachymetry (UP) is currently the most common technique used to evaluate central corneal thickness (CCT). New devices which allow assessment of CCT without corneal contact have been compared, but there are discrepancies among instruments. The aim of this study was to compare CCT measurements obtained by UP and ultrasound biomicroscopy (UBM) in 28 eyes of 14 healthy Beagles dogs. Mean CCT+/-standard deviation (SD) were 552+/-63MUm for UP and 551+/-55MUm for UBM. UBM showed both a fixed and proportional bias when compared to ultrasound pachymetry, but this was not considered to be clinically important. Measured CCT did not differ between UP and UBM (P=0.796). The intra-class correlation coefficient indicated a strong agreement between methods (0.990). The CCT measurements between left (548+/-61MUm) and right (555+/-59MUm) eyes did not differ (P=0.760). Male dogs had higher CCT measurements than female dogs (P=0.038). PMID- 29428085 TI - Evaluation of genes associated with human myxomatous mitral valve disease in dogs with familial myxomatous mitral valve degeneration. AB - Myxomatous mitral valve disease (MMVD) is the most common heart disease in the dog. It is believed to be heritable in Cavalier King Charles spaniels (CKCS) and Dachshunds. Myxomatous mitral valve disease is a familial disease in human beings as well and genetic mutations have been associated with its development. We hypothesized that a genetic mutation associated with the development of the human form of MMVD was associated with the development of canine MMVD. DNA was isolated from blood samples from 10 CKCS and 10 Dachshunds diagnosed with MMVD, and whole genome sequences from each animal were obtained. Variant calling from whole genome sequencing data was performed using a standardized bioinformatics pipeline for all samples. After filtering, the canine genes orthologous to the human genes known to be associated with MMVD were identified and variants were assessed for likely pathogenic implications. No variant was found in any of the genes evaluated that was present in least eight of 10 affected CKCS or Dachshunds. Although mitral valve disease in the CKCS and Dachshund is a familial disease, we did not identify genetic cause in the genes responsible for the human disease in the dogs studied here. PMID- 29428086 TI - Similar transmissibility of the Italian H7N1 highly pathogenic avian influenza virus and its low pathogenic avian influenza virus predecessor. AB - The transmissibility of the H7N1 highly pathogenic avian influenza virus (HPAIV), which caused a large epidemic in commercial poultry in Italy in 1999-2000, was studied in chickens and compared with that of the low pathogenic precursor virus (LPAIV). Group transmission experiments using the HPAIV were executed to estimate the infectious period (IP), the transmission parameter (beta) and the basic reproduction number (R0). These estimates were then compared with those reported for the LPAIV. The estimated beta and R0 were similar for both viruses, whilst the IP of the LPAIV was longer than that of the HPAIV. These findings indicate that transmissibility from chicken-to-chicken alone does not appear to confer an advantage for this LPAIV to evolve to a HPAIV. PMID- 29428087 TI - Evaluation of two-dimensional ultrasonography and computed tomography in the mapping and measuring of canine urinary bladder tumors. AB - Determining the dimensions of transitional cell carcinomas (TCCs) of the urinary bladder in dogs is important in assessing tumor progression and the response to treatment. The primary aim of this study was to evaluate the reliability of a standardized two-dimensional (2-D) ultrasound (US) protocol performed by a single experienced operator. Secondary aims were to compare World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, and to compare measurements by two operators following these guidelines. These were evaluated by inter-operator and intra-operator reliability using the concordance correlation coefficient (CCC) and Cohen's kappa statistics, which demonstrated substantial to better agreement by an experienced operator using either set of guidelines. It was demonstrated that 2-D US provides a reliable means to determine the dimensions of urinary bladder TCC when an experienced operator used a standardized protocol. In a subset of dogs, urinary bladder distension was varied, which resulted in differences in measurement with 2-D US and computed tomography. PMID- 29428088 TI - Comparison of efficacy of oral and parenteral cobalamin supplementation in normalising low cobalamin concentrations in dogs: A randomised controlled study. AB - The aim of this study was to compare the efficacies of parenteral and oral cobalamin supplementation protocols in dogs with chronic enteropathies and low cobalamin concentrations. It was hypothesised that both treatments would increase serum cobalamin concentrations significantly. Fifty-three dogs with chronic enteropathies and serum cobalamin concentrations<285ng/L (reference interval 244 959ng/L) were enrolled. Dogs were randomised to treatment with either daily oral cobalamin tablets (0.25-1.0mg cyanocobalamin daily according to body weight) or parenteral cobalamin (0.4-1.2mg hydroxycobalamin according to body weight). Serum cobalamin concentrations were analysed 28+/-5days and 90+/-15days after initiation of supplementation. After 28 days, all dogs had serum cobalamin concentrations within the reference interval or above. In the parenteral group (n=26), median (range) cobalamin concentrations were 228 (150-285) ng/L at inclusion, 2107 (725-10,009) ng/L after 28days and 877 (188-1267) ng/L after 90 days. In the oral group (n=27), median (range) serum cobalamin concentrations were 245 (150-285) ng/L at inclusion, 975 (564-2385) ng/L after 28days and 1244 (738-4999) ng/L after 90 days. In both groups, there were significant differences in serum cobalamin concentrations between baseline and 28 days, and between 28days and 90days (P<0.001). In conclusion, both parenteral and oral cobalamin supplementation effectively increase serum cobalamin concentrations in dogs with chronic enteropathies and low cobalamin concentrations. PMID- 29428089 TI - Plasma indoxyl sulfate concentration predicts progression of chronic kidney disease in dogs and cats. AB - Indoxyl sulfate is a protein-bound uremic toxin that increases as the severity of impaired renal function increases in humans, laboratory animals, dogs and cats. An elevation of indoxyl sulfate is related to prognosis among people with chronic kidney disease. However, whether indoxyl sulfate is able to predict the progression of chronic kidney disease in dogs and cats has not been previously studied. In the present study, 58 cats and 36 dogs with chronic kidney disease were enrolled. Plasma indoxyl sulfate was measured by high performance liquid chromatography. Renal progression was defined as an increase by one International Renal Interest Society (IRIS) stage and/or a rise in serum creatinine concentration of 0.5mg/dL during the same stage within a 3-month period. Compared with the non-progression groups, across different stages of renal failure, the baseline plasma indoxyl sulfate concentration was increased in the renal progression group (P<0.05), especially for IRIS stages 2 and 3 animals. The area under the receiver operator characteristic curves of indoxyl sulfate, when predicting renal progression, was above 0.75 for both dogs and cats. Indoxyl sulfate concentrations were also correlated with the increase of blood urea nitrogen, serum creatinine, and phosphate and the decrease of hematocrit among cats; while in dogs, concentrations were only correlated with the increase of phosphate concentrations. Indoxyl sulfate served as a biomarker of progression risk in dogs and cats with chronic kidney disease. PMID- 29428090 TI - Post-partum concentrations of serum progesterone, oestradiol and prolactin in Arabian mares demonstrating normal maternal behaviour and Arabian mares demonstrating foal rejection behaviour. AB - The aim of this prospective study was to investigate possible endocrine components to foal rejection behaviour in post-partum Arabian mares. Arabian mares were divided into two groups based on their maternal behaviour: (1) mares with normal post-parturient behaviour (8 mares); and (2) mares that demonstrated foal-rejecting behaviour post-partum (15 mares). Most mares were visited and sampled twice, in the first and third days post-partum. Serum samples were used for measurement of progesterone, oestradiol and prolactin concentrations. There were no statistically significant differences in oestradiol, progesterone or prolactin concentrations between the groups. In the rejecting mares, there was a statistically significant decrease in the progesterone (mean+/-standard deviation, SD, 3.14+/-6.2ng/dL on day 1 and 0.49+/-0.18ng/dL on day 3) and prolactin (mean+/-SD 216.2+/-325.4ng/mL on day 1 and 145.2+/-311.4ng/mL on day 3) concentrations between days 1 and 3, while the oestradiol concentration did not change significantly. In the non-rejecting mares, progesterone concentrations decreased significantly (mean+/-SD 0.8+/-0.23ng/dL on day 1 and 0.43+/-0.22 on day 3) while the oestradiol and prolactin concentrations did not change significantly. The oestradiol to progesterone ratio was significantly higher in non-rejecting mares on day 1 (mean+/-SD 114.8+/-140.2 on day 1 and 143.4+/-72.6 on day 3) and this ratio increased significantly from days 1 to 3 in the rejecting mares (mean+/-SD 47.3+/-21.1 on day 1 and 122.1+/-123.7 on day 3). PMID- 29428091 TI - Sensitivity and specificity of an in-clinic point-of-care PCR test for the diagnosis of canine leishmaniasis. AB - Canine leishmaniasis is an important infectious disease worldwide. Although commonly used, antibody tests are often falsely negative, and in such cases direct detection of the pathogen, such as PCR, is necessary. However, PCR is only performed in specialized laboratories and not available in all localities. The aim of this study was to compare the sensitivity and specificity of an in-clinic point-of-care (ICPOC) PCR for the diagnosis of canine Leishmania spp. infection to those of a well characterized reference real-time PCR. In this study, 515 samples from 251 dogs (201 EDTA blood samples, 244 conjunctival swabs, 19 lymph node aspirates, and 51 bone marrow aspirates) were collected prospectively and analysed for the presence of Leishmania DNA using an ICPOC test. The results were compared to those of a reference real-time PCR for identification of Leishmania kinetoplast minicircle DNA. Sensitivity and specificity with 95% confidence interval (CI 95%) were determined. Specificity was 100% for all samples examined. Sensitivity was 57.1% (CI 95%, 34.0-78.2) in bone marrow aspirates, 58.8% (CI 95%, 32.9-81.6) in lymph node aspirates, 46.9% (CI 95%, 32.5-61.7) in conjunctival swabs, and 10.0% (CI 95%, 3.3-21.8) in blood. The ICPOC PCR was easy to perform and was reliable in the case of positive test results. A negative result, however, did not exclude infection and therefore requires further diagnostics. PMID- 29428092 TI - Detection of specific bacterial agents by quantitative PCR assays in the bronchoalveolar lavage fluid of dogs with eosinophilic bronchopneumopathy vs. dogs with chronic bronchitis and healthy dogs. AB - In humans, Mycoplasma pneumoniae and Bordetella pertussis infections are suggested to trigger or exacerbate asthma. Whether Mycoplasma or Bordetella are associated with chronic inflammatory bronchial diseases in dogs has not been investigated. The aim of this study was to assess detection rates of Mycoplasma canis (M. canis), M. cynos and Bordetella bronchiseptica (Bb), in dogs with eosinophilic bronchopneumopathy (EBP) and chronic bronchitis (CB), compared with healthy dogs. Specific quantitative PCR (qPCR) analysis for M. canis, M. cynos and Bb were retrospectively performed on bronchoalveolar lavage fluid (BALF) collected from 24 dogs with EBP, 21 dogs with CB and 15 healthy dogs. Possible associations between qPCR results and age, BALF cytology or clinical severity scores (CSS) in dogs with EBP were investigated. There was no difference in M. canis, M. cynos and Bb detection rates in dogs with EBP (n=6, n=2 and n=6, respectively) and dogs with CB (n=2, n=2 and n=2, respectively) compared with control dogs (n=4, n=2 and n=2, respectively). In dogs with EBP, the proportion that were qPCR-positive for Bb was higher in dogs with higher CSS (P=0.014) and BALF from Bb-positive dogs had higher percentage of neutrophils (P<0.001). Among dogs that were qPCR-positive for Bb, moderate to high loads were only detected in dogs with EBP. M. canis and M. cynos detection was not associated with EBP or CB; higher Bb loads were only present in dogs with EBP and high CSS. A possible cause and effect relationship between Bb infection or load and EBP remains unclear and requires further investigation. PMID- 29428093 TI - New viruses associated with canine gastroenteritis. AB - A number of novel viruses have been associated with canine gastroenteritis in recent years, from viral families as diverse as Caliciviridae and Picornaviridae to Parvoviridae and Circoviridae. The ability of many of these viruses to cause disease is uncertain, but epidemiological studies are continually adding to our knowledge of these potential pathogens. This review presents a summary of the latest research and current understanding of novel viruses associated with canine gastroenteritis. PMID- 29428094 TI - Automated computation of femoral angles in dogs from three-dimensional computed tomography reconstructions: Comparison with manual techniques. AB - The aim of this ex vivo study was to test a novel three-dimensional (3D) automated computer-aided design (CAD) method (aCAD) for the computation of femoral angles in dogs from 3D reconstructions of computed tomography (CT) images. The repeatability and reproducibility of three manual radiography, manual CT reconstructions and the aCAD method for the measurement of three femoral angles were evaluated: (1) anatomical lateral distal femoral angle (aLDFA); (2) femoral neck angle (FNA); and (3) femoral torsion angle (FTA). Femoral angles of 22 femurs obtained from 16 cadavers were measured by three blinded observers. Measurements were repeated three times by each observer for each diagnostic technique. Femoral angle measurements were analysed using a mixed effects linear model for repeated measures to determine the levels of intra-observer agreement (repeatability) and inter-observer agreement (reproducibility). Repeatability and reproducibility of measurements using the aCAD method were excellent (intra-class coefficients, ICCs>=0.98) for all three angles assessed. Manual radiography and CT exhibited excellent agreement for the aLDFA measurement (ICCs>=0.90). However, FNA repeatability and reproducibility were poor (ICCs<0.8), whereas FTA measurement showed slightly higher ICCs values, except for the radiographic reproducibility, which was poor (ICCs<0.8). The computation of the 3D aCAD method provided the highest repeatability and reproducibility among the tested methodologies. PMID- 29428095 TI - Effects of pre-analytical variables on flow cytometric diagnosis of canine lymphoma: A retrospective study (2009-2015). AB - Flow cytometry (FC) is increasingly being used for immunophenotyping and staging of canine lymphoma. The aim of this retrospective study was to assess pre analytical variables that might influence the diagnostic utility of FC of lymph node (LN) fine needle aspirate (FNA) specimens from dogs with lymphoproliferative diseases. The study included 987 cases with LN FNA specimens sent for immunophenotyping that were submitted to a diagnostic laboratory in Italy from 2009 to 2015. Cases were grouped into 'diagnostic' and 'non-diagnostic'. Pre analytical factors analysed by univariate and multivariate analyses were animal related factors (breed, age, sex, size), operator-related factors (year, season, shipping method, submitting veterinarian) and sample-related factors (type of sample material, cellular concentration, cytological smears, artefacts). The submitting veterinarian, sample material, sample cellularity and artefacts affected the likelihood of having a diagnostic sample. The availability of specimens from different sites and of cytological smears increased the odds of obtaining a diagnostic result. Major artefacts affecting diagnostic utility included poor cellularity and the presence of dead cells. Flow cytometry on LN FNA samples yielded conclusive results in more than 90% of cases with adequate sample quality and sampling conditions. PMID- 29428096 TI - Rodent analgesia: Assessment and therapeutics. AB - Current use of analgesics to control procedure-related pain in laboratory rodents is unacceptably low. Almost all currently available analgesics were developed in small rodents, prior to use in man, so that safety and efficacy data in laboratory assays are available. Greater use of analgesics would be encouraged by critical evaluation of the potential interactions of these compounds with the outcomes of specific research studies. As in other species, effective post procedural analgesia requires reliable 'cage-side' methods of assessing pain. Recent advances in pain assessment should lead to both more extensive and more effective use of analgesics in these species. PMID- 29428097 TI - An online health survey of Dogue de Bordeaux owners and breeders with special emphasis on cardiac disease. AB - A questionnaire-based study was undertaken to assess health problems affecting the Dogue de Bordeaux breed of dog and, in particular, the potential impact of cardiac disease. An online survey tool was used to design a questionnaire for Dogue de Bordeaux owners and breeders. After 1year of response time, information was collected on 278 dogs owned by 215 individuals, mostly based in the United Kingdom. Of the 278 dogs, veterinary attention had been sought for chronic skin disease in 63 (22.7%), lameness in 43 (15.5%), gastrointestinal signs in 37 (13.3%) and neoplasia in 28 (10.1%). Cardiac disease was reported in 13/278 dogs (4.7%). At the time of completion of the survey, 55 (19.8%) dogs were dead, 17 (31%) of which were reported to have died suddenly and unexpectedly. Respondents expressed interest in a formal cardiac health screening scheme in the Dogue de Bordeaux breed, but would be reluctant to volunteer for such a scheme if information on disease detected during screening was open access. The incidence of sudden unexpected death was high; although there was no corroboration that the sudden deaths were related to cardiac disease, a possible connection should be explored further. PMID- 29428098 TI - Pathophysiological consequences of obstructive jaundice and perioperative management. AB - BACKGROUND: Obstructive jaundice is a common problem in daily clinical practice. Understanding completely the pathophysiological changes in obstructive jaundice remains a challenge for planning current and future management. DATA SOURCES: A PubMed was searched for relevant articles published up to August 2016. The effect of obstructive jaundice on proinflammatory cytokines, coagulation status, hemodynamics and organ functions were evaluated. RESULTS: The effects of obstructive jaundice included biliary tree, the hepatic cell and liver function as well as systemic complications. The lack of bile in the gut, the disruption of the intestinal mucosal barrier, the increased absorption of endotoxin and the subsequent endotoxemia cause proinflammatory cytokine production (TNF-alpha, IL 6). Bilirubin induces systemic inflammatory response syndrome which may lead to multiple organ dysfunction syndrome. The principal clinical manifestations include hemodynamic instability and acute renal failure, cardiovascular suppression, immune compromise, coagulation disorders, nutritional impairment, and wound healing defect. The proper management includes full replacement of water and electrolyte deficiency, prophylactic antibiotics, lactulose, vitamin K and fresh frozen plasma, albumin and dopamine. The preoperative biliary drainage has not been indicated in overall, but only in a few selected cases. CONCLUSION: The perioperative management is an essential measure in improving the outcome after the appropriate surgical operation in jaundiced patients especially those with malignancy. PMID- 29428099 TI - Strategies for pancreatic anastomosis after pancreaticoduodenectomy: What really matters? AB - BACKGROUND: The postoperative pancreatic fistula rate remains approximately 10 20% even in institutions treating a high-volume of pancreatic cases. The best strategy to restore the continuity between the pancreatic remnant and the digestive tract is still in debate. DATA SOURCES: Studies were identified by searching PubMed for studies published between January 1934 (when pancreaticogastrostomy was technically feasible) and December 2016. The following search terms were used: "duct-to-mucosa", "invagination", "pancreaticojejunostomy", "pancreaticogastrostomy," and "pancreaticoduodenectomy". The search was limited to English publications. RESULTS: Many technical methods have been developed and optimized to restore pancreaticoenteric continuity, including pancreaticojejunostomy, pancreaticogastrostomy, and stented drainage of the pancreatic duct, among other modifications. Researchers have also attempted to decrease the postoperative pancreatic fistula after pancreaticoduodenectomy by using fibrin glue and somatostatin analogues. However, no significant decrease in postoperative pancreatic fistula has been observed in most of these studies, and only an external pancreatic duct stent has been found to decrease the leakage rate of pancreatic anastomosis after pancreaticojejunostomy. CONCLUSION: Pancreatic surgeons should choose a suitable technique according to the characteristics of individual cases. PMID- 29428100 TI - Clinical analysis of liver transplantation in autoimmune liver diseases. AB - BACKGROUND: Autoimmune liver diseases (ALDs) consist of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), IgG4-associated cholangitis and overlap syndromes. Patients with these diseases may gradually progress to end-stage liver diseases and need liver transplantation. The present study aimed to explore the prognosis of patients with ALDs after liver transplantation. METHODS: The clinical data of 80 patients with ALD (24 cases of AIH, 35 of PBC, 15 of PSC and 6 of AIH-PBC overlap syndromes) who underwent liver transplantation in Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2004 to September 2016 were collected retrospectively. The causes of death were analyzed and the postoperative cumulative survival rate was estimated by the Kaplan-Meier method. Recurrence and other complications were also analyzed. RESULTS: Of the 80 patients, 18 were males and 62 were females. The average age was 50.5 years and the average Model for End-stage Liver Disease (MELD) score was 14.1. After a median follow-up of 19.8 months, 8 patients died. The 1-, 3- and 5-year cumulative survival rates were all 89.0%. Three cases of recurrent ALDs were diagnosed (3.8%) but they were not totally consistent with primary diseases. Biliary tract complication occurred in 10 patients (12.5%). The new onset of tumor was observed in 1 patient (1.3%). De novo HBV/CMV/EBV infection was found in 3, 8 and 3 patients, respectively. CONCLUSION: Liver transplantation is an effective and safe treatment for end-stage ALD. PMID- 29428101 TI - Optimized postconditioning algorithm protects liver graft after liver transplantation in rats. AB - BACKGROUND: Ischemia reperfusion injury (IRI) causes postoperative complications and influences the outcome of the patients undergoing liver surgery and transplantation. Postconditioning (PostC) is a known manual conditioning to decrease the hepatic IRI. Here we aimed to optimize the applicable PostC protocols and investigate the potential protective mechanism. METHODS: Thirty Sprague-Dawley rats were randomly divided into 3 groups: the sham group (n = 5), standard orthotopic liver transplantation group (OLT, n = 5), PostC group (OLT followed by clamping and re-opening the portal vein for different time intervals, n = 20). PostC group was then subdivided into 4 groups according to the different time intervals: (10 s * 3, 10 s * 6, 30 s * 3, 60 s * 3, n = 5 in each subgroup). Liver function, histopathology, malondialdehyde (MDA), myeloperoxidase (MPO), expressions of p-Akt and endoplasmic reticulum stress (ERS) related genes were evaluated. RESULTS: Compared to the OLT group, the grafts subjected to PostC algorithm (without significant prolonging the total ischemic time) especially with short stimulus and more cycles (10 s * 6) showed significant alleviation of morphological damage and graft function. Besides, the production of reactive oxidative agents (MDA) and neutrophil infiltration (MPO) were significantly depressed by PostC algorithm. Most of ERS related genes were down-regulated by PostC (10 s * 6), especially ATF4, Casp12, hspa4, ATF6 and ELF2, while p-Akt was up-regulated. CONCLUSIONS: PostC algorithm, especially 10 s * 6 algorithm, showed to be effective against rat liver graft IRI. These protective effects may be associated with its antioxidant, inhibition of ERS and activation of p-Akt expression of reperfusion injury salvage kinase pathway. PMID- 29428102 TI - Liver trauma: What current management? AB - BACKGROUND: The liver is the most commonly damaged organ in abdominal trauma. The management of liver trauma has experienced many changes over the last two decades. Currently there is a trend toward a non-operative treatment warranted by the successful pediatric experience and better results recorded in many trauma centers worldwide. This study aimed to evaluate outcomes of operative and non operative management of liver trauma in our institution over the last five years. METHODS: The patients with a diagnosis of blunt or penetrating liver injuries, admitted and managed in our hospital from January 2012 to December 2016 were retrospectively studied. The patients were divided into 2 groups, operated and non-operated groups, according to the initial management considered appropriate at the time of patient admission. Clinical features and outcomes were analyzed. RESULTS: The study involved 83 patients, with a mean age of 33 years and a marked male predominance (85.5%). The most common type of lesions was blunt trauma and the main cause was road traffic accidents. Sixty-eight liver injuries (81.9%) were of low severity (grades I, II, III), while 15 (18.1%) were of high severity (grade IV or greater). Fifty-six patients (67.5%) had multiple injuries. Surgical treatment was performed in 26 (31.3%) patients. Non-operative management was undertaken in 57 cases (68.7%). The morbidity and mortality rates were clearly lower in non-operative patients compared to those in the operated group. CONCLUSIONS: Careful non-operative management is an adequate therapeutic strategy for the patients suffering from liver trauma with stable hemodynamics. Patients with complex hepatic trauma and especially those with other organ injuries continue to have significantly higher mortality. PMID- 29428103 TI - Risk factors and metabolic abnormality of patients with non-alcoholic fatty liver disease: Either non-obese or obese Chinese population. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) occurs not only in obese individuals but also in non-obese ones. The aim of this study was to focus on the association between NAFLD and metabolic events in a non-obese or obese Chinese population. METHODS: Data collected from subjects registered at Taichung Veterans General Hospital from January to December 2009 were analyzed. The exclusion criteria were alcoholics, chronic hepatitis B or C. Patients included in analyses were assigned to four groups according to sonography of their liver (normal or NAFLD), and body mass index (BMI) levels (non-obese if BMI < 25 kg/m2 or obese if BMI >= 25 kg/m2). RESULTS: There were 745, 208, 770 and 285 patients enrolled in four groups labeled non-obese normal liver (group A), non-obese NAFLD (group B), obese normal liver (group C) and obese NAFLD (group D), respectively. The highest ratio of metabolic syndrome existed in the group B (26.9%), followed by group A (11.7%), group D (10.9%) and finally the group C (5.2%). The positive association with NAFLD in non-obese individuals was significant in triglyceride (OR = 1.01; 95% CI: 1.01-1.02) and glucose (OR = 1.02; 95% CI: 1.01-1.03), while the positive association with NAFLD in obese subjects was only significant in triglyceride (OR = 1.01; 95% CI: 1.01-1.02). The positive association was most significant in all cases (adjusted OR = 2.41; 95% CI: 1.78-3.24), especially in non-obese individuals (OR = 2.81; 95% CI: 1.92-4.12). CONCLUSIONS: Non-obese NAFLD subjects displayed a higher proportion of metabolic abnormality. Hyperlipidemia and hyperglycemia had the most positive strength association with NAFLD. PMID- 29428104 TI - Management of occluded self-expanding biliary metal stents in malignant biliary disease. AB - BACKGROUND: Occlusion of self-expanding metal stents (SEMS) in malignant biliary obstruction occurs in up to 40% of patients. This study aimed to compare the different techniques to resolve stent occlusion in our collective of patients. METHODS: Patients with malignant biliary obstruction and occlusion of biliary metal stent at a tertiary referral endoscopic center were retrospectively identified between April 1, 1994 and May 31, 2014. The clinical records were further analyzed regarding the characteristics of patients, malignant strictures, SEMS, management strategies, stent patency, subsequent interventions, survival time and case charges. RESULTS: A total of 108 patients with biliary metal stent occlusion were identified. Seventy-nine of these patients were eligible for further analysis. Favored management was plastic stent insertion in 73.4% patients. Second SEMS were inserted in 12.7% patients. Percutaneous transhepatic biliary drainage and mechanical cleansing were conducted in a minority of patients. Further analysis showed no statistically significant difference in median overall secondary stent patency (88 vs. 143 days, P = 0.069), median survival time (95 vs. 192 days, P = 0.116), median subsequent intervention rate (53.4% vs. 40.0%, P = 0.501) and median case charge (?5145 vs. ?3473, P = 0.803) for the treatment with a second metal stent insertion compared to plastic stent insertion. In patients with survival time of more than three months, significantly more patients treated with plastic stents needed re-interventions than patients treated with second SEMS (93.3% vs. 57.1%, P = 0.037). CONCLUSIONS: In malignant biliary strictures, both plastic and metal stent insertions are feasible strategies for the treatment of occluded SEMS. Our data suggest that in palliative biliary stenting, patients especially those with longer expected survival might benefit from second SEMS insertion. Careful patient selection is important to ensure a proper decision for either management strategy. PMID- 29428105 TI - Risk factor analysis of post-ERCP cholangitis: A single-center experience. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) may have complications. Our study aimed to investigate the risk factors and prevention of post-ERCP cholangitis. METHODS: We retrospectively analyzed 4234 cases undergone ERCP in the Affiliated Drum Tower Hospital of Nanjing University Medical School from January 2008 to December 2013. Patient-related factors and procedure-related factors were analyzed to find the risk factors of post-ERCP cholangitis. The time point of post-ERCP cholangitis was also analyzed. Univariate and multivariate analyses were performed to define the independent risk factors of post-ERCP cholangitis. RESULTS: The success rate of ERCP was 96.8% (4099/4234). The overall complication rate was 9.4% (399/4234). Post-ERCP cholangitis occurred in 102 cases (2.4%, 102/4234). The most dangerous time of post-ERCP cholangitis was from 24 h-48 h after ERCP (45.1%, 46/102). Univariate analysis revealed that age, hypertension, diabetes, previous ERCP history, biliary stent insertion, pancreatography, endoscopic sphincterotomy, balloon dilation and hilar obstruction were risk factors of post-ERCP cholangitis (P < 0.05). Multivariate analysis indicated that age, previous ERCP history and hilar obstruction were independent risk factors (P < 0.05). While endoscopic stone extraction was the potential protective factor. CONCLUSIONS: Many risk factors are involved in post ERCP cholangitis. Among them, old age, previous ERCP history and hilar obstruction were independently related to this post-ERCP complication. PMID- 29428107 TI - Evaluation of the 8th AJCC staging system for pathologically versus clinically staged pancreatic adenocarcinoma: A time to revisit a dogma? AB - BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic exocrine adenocarcinoma has been released. The current study seeks to assess the 7th and 8th editions among patients registered within the surveillance, epidemiology and end results (SEER) database. METHODS: SEER database (2010-2013) has been accessed through SEER*Stat program and AJCC 8th edition stages were reconstructed utilizing the collaborative stage descriptions. Kaplan-Meier analysis of overall survival and pancreatic cancer specific survival analyses (according to both 7th and 8th editions and according to whether pathological or clinical staging were conducted) has been performed. Multivariate analysis of factors affecting pancreatic cancer-specific survival was also conducted through a Cox proportional hazard model. RESULTS: A total of 18 948 patients with pancreatic adenocarcinoma were identified in the period from 2010-2013. Pancreatic cancer-specific survival among pathologically staged patients and according to the 8th edition showed significant differences for all pair wise comparisons among different stages (P < 0.0001) except for the comparison between stage IA and stage IB (P = 0.307) and the comparison between stage IB and stage IIA (P = 0.116). Moreover, P value for stage IA vs IIA was 0.014; while pancreatic cancer-specific survival according to the 7th edition among pathologically staged patients showed significant differences for all pair wise comparisons among different stages (P < 0.0001) except for the comparison between IA and IB (P = 0.072), the comparison between stage IIA and stage IIB (P = 0.065), the comparison between stage IIA and stage III (P = 0.059) and the comparison between IIB and III (P = 0.595). Among clinically staged patients (i.e. those who did not undergo initial radical surgery), the prognostic performance of both 7th and 8th stages for both overall survival and pancreatic cancer-specific survival was limited. CONCLUSION: There is clearly a need to have two staging systems for pancreatic adenocarcinoma: pathological and clinical staging systems. PMID- 29428106 TI - Efficacy of octreotide in the prevention of complications after pancreaticoduodenectomy in patients with soft pancreas and non-dilated pancreatic duct: A prospective randomized trial. AB - BACKGROUND: The efficacy of octreotide to prevent postoperative pancreatic fistula (POPF) of pancreaticoduodenectomy (PD) is still controversial. This study aimed to evaluate the effect of postoperative use of octreotide on the outcomes after PD. METHODS: This is a prospective randomized controlled trial for postoperative use of octreotide in patients undergoing PD. Patients with soft pancreas and pancreatic duct < 3 mm were randomized to 2 groups. Group I did not receive postoperative octreotide. Group II received postoperative octreotide. The primary end of the study is to compare the rate of POPF. RESULTS: A total of 104 patients were included in the study and were divided into two randomized groups. There were no significant difference in overall complications and its severity. POPF occurred in 11 patients (21.2%) in group I and 10 (19.2%) in group II, without statistical significance (P = 0.807). Also, there was no significant differences between both groups regarding the incidence of biliary leakage (P = 0.083), delayed gastric emptying (P = 0.472), and early postoperative mortality (P = 0.727). CONCLUSIONS: Octreotide did not reduce postoperative morbidities, reoperation and mortality rate. Also, it did not affect the incidence of POPF and its clinically relevant variants. PMID- 29428108 TI - Diagnostic yield of EUS-FNA of small (<=15 mm) solid pancreatic lesions using a 25-gauge needle. AB - BACKGROUND: Early detection of small solid pancreatic lesions is increasingly common. To date, few and contradictory data have been published about the relationship between lesion size and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) diagnostic yield. The aim of this study was to assess the relation between the size of solid pancreatic lesions and the diagnostic yield of EUS-FNA using a 25-gauge needle in a center without available rapid on-site evaluation. METHODS: In the retrospective cohort study, we selected patients who underwent EUS-FNA for solid pancreatic lesions with a 25-gauge needle from October 2014 to October 2015. Patients were divided into three groups (<=15 mm, 16-25 mm and >25 mm), and the outcomes were compared. RESULTS: We analyzed 163 patients. Overall adequacy, sensitivity, specificity and accuracy were 85.2%, 81.8%, 93.7%, and 80.4%, respectively. When stratified by size, the sensitivity and accuracy correlated with size (P = 0.016 and P = 0.042, respectively). Multivariate analysis showed that lesion size was the only independent factor (P = 0.019, OR = 4.76) affecting accuracy. The role of size as an independent factor affecting accuracy was confirmed in a separate multivariate analysis, where size was included in the model as a covariate (P = 0.018, OR = 1.08). CONCLUSION: Our study demonstrates that, in the absence of rapid on-site evaluation, mass size affects the accuracy of EUS-FNA of solid pancreatic lesions. PMID- 29428109 TI - CA19-9 level determines therapeutic modality in pancreatic cancer patients with para-aortic lymph node metastasis. AB - BACKGROUND: In general, para-aortic lymph node (LN16) metastasis has been considered as a contraindication for pancreatic resection. However, some pancreatic cancer patients with LN16 metastasis have been reported to survive for longer than expected after pancreatectomy. The purpose of this study was to determine whether pancreatic cancer patients with LN16 metastasis might benefit from surgery. METHODS: We retrospectively reviewed 201 consecutive patients with invasive pancreatic ductal adenocarcinoma who underwent surgery at Osaka National Hospital between April 2003 and December 2012. These patients included 22 patients with LN16 metastasis who underwent an extended lymphadenectomy and 25 patients who underwent a palliative surgical biliary and gastric bypass. The clinicopathological data and outcomes were evaluated using univariate and multivariate analyses. RESULTS: The overall survival of the patients with LN16 metastasis was poorer than that of the LN16-negative patients (P = 0.0014). An overall survival analysis of the LN16-positive patients stratified according to the preoperative CA19-9 level showed a significant difference between patients with a low preoperative CA19-9 level (<=360 U/mL) and those with a high preoperative CA19-9 level (>360 U/mL) (P = 0.0301). No significant difference in overall survival of patients was observed between those with LN16 positivity and those who underwent bypass surgery. However, the overall survival of the LN16 positive patients with a CA19-9 level <=360 U/mL (n = 11) was significantly higher than that of those who underwent bypass surgery (P = 0.0452). CONCLUSION: Surgical resection and extended lymphadenectomy remains an option for pancreatic cancer patients with LN16-positivity whose CA19-9 level is <=360 U/mL. PMID- 29428110 TI - Pancreatic parenchymal injection of ethanol and octreotide to induce focal pancreatic fibrosis in rats: Strategies to eliminate postoperative pancreatic fistula. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) is more likely to occur in a soft pancreas compared to a hard pancreas in which fibrosis has progressed. There is almost no leakage at the anastomosis site or cut surface of a hard pancreas. The aim of this study was to induce localized fibrosis at the cut surface of the pancreas in a rat model. METHODS: Thirty-six rats were divided into three groups (group S: normal saline group; group E: ethanol group; and group O: octreotide group). Each rat was directly injected with a particular compound at the duodenal lobe of the pancreatic parenchyma. Each group was divided into three subgroups according to the time of post-injection sacrifice (1, 2, or 4 weeks). The hardness, suture holding capacity (SHC), and histological fibrosis grade of each pancreas were measured. RESULTS: The hardness, SHC, and fibrosis grade of groups E and O were increased at week 1, with greater increases in group E (all P < 0.001). In a subgroup comparison, the hardness, SHC, and fibrosis grade of group E tended to decrease gradually over time, with no regular pattern evident in group O. A comparison between the injected site (duodenal lobe) and non-injected site (splenic lobe) of the pancreas revealed increases in the three parameters of group E only in the duodenal lobe, with increases in group O at both the duodenal and splenic lobes. CONCLUSIONS: Parenchymal injection of ethanol and octreotide increased pancreatic fibrosis. Unlike octreotide, ethanol provoked localized fibrosis that was maintained over time. It is expected that ethanol injection could eliminate POPF during pancreatic surgery. PMID- 29428111 TI - Asia's first combined liver transplant and aortic valve replacement. PMID- 29428112 TI - Complete resection of the hepatic veins: The role of right inferior vein. PMID- 29428113 TI - Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: A meta-analysis. AB - BACKGROUND: Minimal hepatic encephalopathy (MHE) is an early and reversible form of hepatic encephalopathy. The documentations on the treatment with probiotics are inconsistent. The present meta-analysis was to verify the role of probiotics in the treatment of cirrhotic patients with MHE. DATA SOURCES: Seven electronic databases were searched for relevant randomized controlled trials (RCTs) published until July 2015. The effects of probiotics on serum ammonia, endotoxin, and MHE were evaluated. RESULTS: A total of 14 RCTs (combined n = 1132) were included in the meta-analysis. When probiotics were compared to placebo or no treatment, probiotics were more likely to reduce values in the number connection test (NCT; week 4: MD = -30.25, 95% CI: -49.85 to -10.66), improve MHE (week 4: OR = 0.18, 95% CI: 0.07 to 0.47; week 12: OR = 0.15, 95% CI: 0.07 to 0.32), and prevent overt HE progression (week 4: OR = 0.22, 95% CI: 0.07 to 0.67) in patients with liver cirrhosis. When probiotics was compared to lactulose, probiotics tended to reduce serum ammonia levels (week 4: MD = -0.33 umol/L, 95% CI: -5.39 to 4.74; week 8: MD = 6.22 umol/L, 95% CI: -24.04 to 36.48), decrease NCT (week 8: MD = 3.93, 95% CI: -0.72 to 8.58), improve MHE (week 4: OR = 0.93, 95% CI: 0.45 to 1.91; week 12: OR = 0.73, 95% CI: 0.35 to 1.51) and prevent the development of overt HE (week 4: OR = 0.96, 95% CI: 0.17 to 5.44; week 12: OR = 2.7, 95% CI: 0.50 to 14.64) in patients with liver cirrhosis. However, lactulose appears to be more effective in reducing NCT values as compared to probiotics (week 4: MD = 6.7, 95% CI: 0.58 to 12.82). CONCLUSION: Probiotics can decrease serum ammonia and endotoxin levels, improve MHE, and prevent overt HE development in patients with liver cirrhosis. PMID- 29428114 TI - Effects of terlipressin versus splenectomy on liver regeneration after partial hepatectomy in rats: What we know so far? PMID- 29428115 TI - How can We Contribute? PMID- 29428117 TI - Editorial Comment on "Factors Related to Psychoactive Substance use in an Educational Institution in Jamundi Valle, Colombia". PMID- 29428116 TI - Clinical and Demographic Variables Associated Coping and the Burden of Caregivers of Schizophrenia Patients. AB - OBJECTIVE: To analyse of the relationship between burden of illness and coping strategies and the demographic variables of caregivers, and the demographic and clinical variables of people diagnosed with schizophrenia. METHODS: Multicentre correlational cross-sectional study including 70 people diagnosed with schizophrenia, or a schizoaffective disorder, and 70 primary informal caregivers. They were evaluated using Zarit Caregiver Burden Inventory, Family Coping Strategies Questionnaire, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and the brief Disability Assessment Scale. RESULTS: Burden of illness positively associated with patient impairment in occupational and social functioning, and negatively with education level. Avoidance, coercion and positive communication were positively associated with impairment in occupational and social functioning of patients. Social interest and friendships showed a positive association with the education level of caregivers. Spiritual assistance negatively correlated with impairment in social functioning and patient age, and resignation was negatively associated with length of the disorder and patient education level. CONCLUSIONS: Burden and dysfunctional coping strategies, such as avoidance and coercion, are associated with functional impairment of the patient. These findings suggest the need to provide support to caregivers, adjusted to the functional level of the patient, in order to prevent burden of care. PMID- 29428118 TI - Meaning of Depressive Syndrome for General Practice Physicians in a Colombian Region. AB - OBJECTIVE: To determine the perception that some general clinical practitioners have about depressive syndrome in a region of Colombia. METHODOLOGY: The qualitative approach was established as a basis for this study using grounded theory for the description, analysis, and interpretation of data collected in 20 semi-structured interviews aimed at general medical practitioners who had treated patients with depressive syndrome in their clinical practice. RESULTS: Throughout the interviews, some essential elements are highlighted such as: "seeing beyond a body," where the interest of the physician is reflected by individualising each patient case because regardless of having the same disease, knowing that not all can be addressed or treated equally. "From insignificant to terrifying" shows that the network of experiences, experiences, emotions, and desires that make up part of the physician, are reflected in the compassion that he has for patient with depression, a situation that makes him confront as a human being before the suffering of others. In contrast appears the "my hands are tied" with a health system that prevents proper care of these patients, and generates problems for the treating physician. CONCLUSIONS: The malleable and unfinished scenario where the physicians interact with the depressive syndrome, allows them to understand their humanity while reflecting on the possibilities, limitations, meanings, attitudes and actions that they have about this disorder that is reflected in the ability of general physicians to diagnose and treat depression that is not necessarily associated with age or experience in practice. However, errors in care can be reduced with sufficient knowledge and an appropriate approach to mental illness. PMID- 29428119 TI - Influence of Habits on Depression in the Peruvian Medical Student: Study in Seven Administrative Regions. AB - OBJECTIVE: To determine the influence of habits on depression in medical students from 7 Peruvian Regions. METHODS: Analytical cross-sectional study of a secondary data analysis. The diagnosis of depression was obtained according to the Zung test result, with any level of this condition being considered positive. This was also compared with other social and educational variables that were important according to previous literature. RESULTS: Of the 1922 respondents, 54.5% (1047) were female. The median age was 20 [interquartile range, 18-22] years, and 13.5% (259) had some degree of depression according to the Zung scale. In the multivariate analysis, the frequency of depression increased with the hours of study per day (RPA=1.03; 95%CI; 1.01-1.04; P<.001) and the student work (RPA=1.98; 95%CI; 1.21-3.23; P=.006). On the other hand, decreased the frequency of depression decreased on having similar meal schedules (RPA=0.59; 95%CI; 0.38 0.93; P=.022), and having a fixed place in which to get food (RPA=0.66; 95%CI; 0.46-0.96; P=.030), adjusted for the year of college entrance. CONCLUSIONS: Some stressors predisposed to depression were found (the work and studying more hours a day). On the other hand, to have order in their daily routine decreased this condition (having a set place and times for meals). PMID- 29428120 TI - Persistent Delirium in Elderly patients Three Months After Hospital Discharge from a University Clinic. AB - OBJECTIVE: The purpose of the study was to determine the prevalence and characteristics of patients with persistent delirium (PD) at three months after hospital discharge. METHODOLOGY: Longitudinal descriptive study to assess the prevalence and characteristics of in-patients aged 65 years and older in the Clinica Universitaria Bolivariana who met DSM-5 criteria for delirium at admission, at discharge, and at a 3-month follow up assessment. Socio-demographic features were determined, and CGI-S and DRS-R98 scales used. RESULTS: A total of 30 patients were evaluated between April and October 2013, but 6 did not fulfil the inclusion criteria. The study included 24 patients, with 9 (37.5%) dying during hospitalisation. Of the 15 surviving patients, five (20.8% of the total sample) had their delirium resolved at discharge, and ten (41.6% of the sample) continued with symptoms. These established the PD group, of whom five of them (20.8%) had full PD, and the other five (20.8%) sub-syndromal PD (SSPD). At the final assessment, only two patients (8.3%) continued with full PD, and another two (8.3%) with SSPD. Among the PD group, 30% had a full delirium at admission (prevalence), and 70% developed full delirium during hospitalization (incidence). CONCLUSIONS: A significant number of patients did not recover from delirium at leaving hospital, and remained symptomatic three months after discharge. The study findings suggest a course of gradual improvement of delirium, with a persistence of symptoms over time in 40% of the patients, which would have implications for the clinical practice. PMID- 29428121 TI - Evaluation and Socio-occupational Intervention in Bipolar and Schizophrenic Patients within a Multimodal Intervention Program- PRISMA. AB - BACKGROUND: Functional improvement in bipolar and schizophrenic patients is one of the main aims of treatment. Nevertheless, there is no evidence about the effect of socio-occupational intervention within a multimodal intervention (MI) programme. OBJECTIVE: To describe the socio-occupational profile and to evaluate the functional effect of a MI in bipolar I and schizophrenic patients. METHODS: A prospective, longitudinal, therapeutic-comparative study was performed including 302 subjects (104 schizophrenic and 198 Bipolar Disorder I [BDI] patients), who were randomised into two groups, multimodal (psychiatry, psychology, medicine, occupational therapy, neuropsychology, and family therapy), or traditional intervention (psychiatry and medicine only). Several scales were applied to assess assertiveness, free time management, social abilities, general anxiety, self-care and performance in home, work and community tasks. RESULTS: After performing the longitudinal analysis, it was shown that the multimodal intervention was more effective than traditional intervention in general anxiety scores (P=.026) and development in home tasks (P=.03) in schizophrenic patients. No statistical differences were found in bipolar patients. The other variables showed improvement, however, their effect was similar in both intervention groups. CONCLUSIONS: Our study identified functional improvement in home tasks in schizophrenic patients after receiving multimodal intervention. Other variables also showed improvement for both interventions groups. Future studies, applying longer rehabilitation programs and other ecological strategies should be performed to identify the most effective interventions. PMID- 29428122 TI - Depressive Disorder, Anxiety Disorder and Chronic Pain: Multiple Manifestations of a Common Clinical and Pathophysiological Core. AB - INTRODUCTION: A high proportion of depressive disorders are accompanied by anxious manifestations, just as depression and anxiety often present with many painful manifestations, or conversely, painful manifestations cause or worsen depressive and anxious expressions. There is increasingly more evidence of the pathophysiological, and neurophysiological and technical imaging similarity of pain and depression. METHODS: Narrative review of the pathophysiological and clinical aspects of depression and chronic pain comorbidity. Research articles are included that emphasise the most relevant elements related to understanding the pathophysiology of both manifestations. RESULTS: The pathological origin, physiology and clinical approach to these disorders have been more clearly established with the latest advances in biochemical and cellular techniques, as well as the advent of imaging technologies. This information is systematised with comprehensive images and clinical pictures. CONCLUSIONS: The recognition that the polymorphism of inflammation-related genes generates susceptibility to depressive manifestations and may modify the response to antidepressant treatments establishes that the inflammatory response is not only an aetiopathogenic component of pain, but also of stress and depression. Likewise, the similarity in approach with images corroborates not only the structural, but the functional and pathophysiological analogy between depression and chronic pain. Knowledge of depression-anxiety-chronic pain comorbidity is essential in the search for effective therapeutic interventions. PMID- 29428123 TI - Innovations, Reviews and Proposals on the DSM-5: the Case of Sexual Dysfunctions, Gender Dysphoria and Paraphilic Disorders. AB - Human behaviours have different meanings according to the historical moment and context. In this article sexual behaviours are taken as a category in order to analyse how psychiatric nosology is structured, as manifested in texts such as the DSM-5. The development of these diagnostic manuals are tools that are far from being free of subjectivities and interference of elements of power, expressed in the way health, illness, mental health, and mental disorders, are assumed; in short, the normal and pathological. Each new diagnosis, or even its elimination, and the recomposing of the different diagnostic criteria, especially in the field of sexual behaviour, present visions of how individual and collective human life is conceived, as well as an expression of accurate attempts to control human sexualities through the medicalisation of behaviour, coupled with moral, religious, and even legal considerations. Categories such as gender dysphoria, paraphilia or paraphilic disorders are examples of how the limits intended to establish a biomedical perspective are also incomplete and imprecise. These violate individual and social construction of sexualities and the conception of mental health, showing persistent difficulties and controversies that are evident in the way psychiatric classifications are made. PMID- 29428124 TI - Bipolar Disorder and Heart Transplantation: A Case Report. AB - INTRODUCTION: Bipolar disorder is a chronic and recurrent mood disease that includes symptoms that fluctuate from euphoria to depression. As a mood disorder, itis one of the main contraindications for transplantation procedures. The case is presented of a patient with bipolar disorder who had a heart transplant after a cardiac arrest. Heart transplantation is the treatment of choice in patients with heart failure and arrhythmias that do not respond to conventional treatment. METHODS: Case report and narrative review of literature. CASE REPORT: A 34-year old woman with bipolar disorder diagnosed when she was 13, treated with lithium and aripiprazole. She required a heart transplant as the only therapeutic option, after presenting with ventricular tachycardia refractory to conventional treatment. The patient did not suffer an emotional decompensation with the removal of the lithium and aripiprazole that were associated with prolonged QTc interval, and remained eurhythmic throughout the process. DISCUSSION: Heart transplantation can be performed safely and successfully in patients with bipolar disorder, when suitably followed-up by a liaison psychiatry group. CONCLUSIONS: Bipolar disorder should not be considered as an absolute contraindication for heart transplantation. PMID- 29428126 TI - [1868: A landmark year in French dermatology]. PMID- 29428127 TI - Dyslipidemia, steatohepatitis and atherogenesis in lipodystrophic apoE deficient mice with Seipin deletion. AB - SEIPIN is an integral membrane protein located in the endoplasmic reticulum, regulating adipocytes differentiation and lipolysis. Deficiency of Seipin in mice causes severe general lipodystrophy, accompanied by insulin resistance, postprandial hypertriglyceridemia and steatohepatitis. In atherosclerosis-prone Ldlr null (Ldlr-/-) mice, lipodystrophy caused by Seipin deletion even led to severe hypercholesteremia and accelerated atherogenesis, when challenged with an atherogenic diet. However, whether the phenotypes observed in Seipin-/-Ldlr-/- mice were a common consequence due to lipodystrophy, rather than genetic background restricted or diet dependent, was unknown. Herein we explored the lipodystrophy-related dyslipidemia, steatohepatitis and atherogenesis in another atherosclerosis-prone murine model, apolipoprotein E null (apoE-/-) mice. Besides, we also compared phenotypes between sexes in apoE-/- mice with Seipin deletion (Seipin-/-apoE-/-). We found that compared with apoE-/- controls, Seipin /-apoE-/- mice also developed severe general lipodystrophy with hyperlipidemia, steatohepatitis and increased atherogenesis. Although the severity of adipose loss in female and male Seipin-/-apoE-/- mice were similar, hyperlipidemia, steatohepatitis and atherosclerosis were less severe in females than in males. Therefore, we demonstrated that lipodystrophy-related metabolic disorders, caused by Seipin deletion, were independent of genetic background and experimental diet, as seen in Ldlr-/- and apoE-/- mice. However, gender factor affected the disease progression, with females more resistant to developing lipodystrophy-related metabolic consequences. PMID- 29428130 TI - Longevity of Cardiovascular Implantable Electronic Devices. AB - Battery depletion is the most common reason for device reoperation, which is associated with significant patient morbidity and mortality. This article describes the history of pacing and defibrillation power supplies and the factors that determine the longevity of pacing and defibrillator generators with a special emphasis on factors that can be adjusted or controlled by the implanting and following physician. Optimization of longevity is attained through device selection; shock minimization; avoidance of prolonged radiofrequency telemetry; selection of higher impedance vectors; avoidance of long pulse duration when possible; and avoidance of unnecessary feature activation, such as continuous electrogram storage. PMID- 29428128 TI - Role of Forkhead Box O (FOXO) transcription factor in aging and diseases. AB - Fork head box O (FOXO) transcription factor is a key player in an evolutionarily conserved pathway. The mammalian FOXO family consists of FOXO1, 3, 4 and 6, are highly similar in their structure, function and regulation. To maintain optimum body function, the organisms have developed complex mechanisms for homeostasis. Importantly, it is well known that when these mechanisms dysregulate it results in the development of age-related disease. FOXO proteins are involved in a diverse cellular function and also have clinical significance including cell cycle arrest, cell differentiation, tumour suppression, DNA repair, longevity, diabetic complications, immunity, wound healing, regulation of metabolism and thus treatment of several types of diseases. By the combinations of post translational modifications FOXO's serve as a 'molecular code' to sense external stimuli and recruit it as to specific regions of the genome and provide an integrated cellular response to changing physiological conditions. Akt/Protein kinase B a signaling pathway as a main regulator of FOXO to perform a diverse function in organisms. The present review summarizes the molecular and clinical aspects of FOXO transcription factor. And also elaborate the interaction of FOXO with the nucleosome remodelling complex to target genes, which is essential to cellular homeostasis. PMID- 29428131 TI - Use of the Wearable Cardioverter Defibrillator as a Bridge to Implantable Cardioverter Defibrillator. AB - The wearable cardioverter defibrillator has been shown to be effective in terminating ventricular arrhythmias in patients at risk for sudden cardiac death. There are numerous scenarios in which implant of a permanent implantable cardioverter defibrillator is temporarily contraindicated or not advisable and a wearable cardioverter defibrillator may be beneficial. There are no prospective randomized studies published that provide conclusive guidance toward the use of the wearable cardioverter defibrillator, and thus, patient management needs to be individualized based on the available data. PMID- 29428132 TI - Implantable Loop Recorders for Cryptogenic Stroke (Plus Real-World Atrial Fibrillation Detection Rate with Implantable Loop Recorders). AB - Cryptogenic stroke (CS) represents 10%-40% of ischemic strokes and is associated with significant morbidity and mortality and high risk of recurrence. Undetected atrial fibrillation is an important consideration in these patients. Tools for electrocardiographic monitoring range from 12-lead electrocardiogram to implantable loop recorders (ILRs). ILRs have become an important tool for long term electrocardiogram monitoring in CS patients. Advancements in ILR technology are needed to ensure more robust connectivity and to help triage incoming data. An unresolved issue is what duration of AF indicates that the CS patient is at high risk for recurrent stroke and thus would benefit from initiation of anticoagulation. PMID- 29428133 TI - Implantable Cardioverter Defibrillator Implantation with or Without Defibrillation Testing. AB - Defibrillation testing (DFT) during implantable cardioverter-defibrillator (ICD) implantation is still considered standard of care in some, but in increasingly fewer centers. The goal is to ensure that the device system functions as intended by testing in the controlled laboratory setting. Although safe, complications can occur and DFT is associated with an increased procedural time and cost. DFT is useful in assessing device function when programming changes or patient characteristics raise concerns regarding ICD efficacy. DFT remains standard of practice following implantation of subcutaneous ICDs and other specific circumstances. Implanting physicians should remain familiar with the process of DFT and situations where it is useful for individual patients. PMID- 29428134 TI - Lead Management and Lead Extraction. AB - Management of patients with cardiac implantable electronic devices (CIEDs) has become complex given the complications that can occur with implanted lead systems. Clinical problems such as infection, lead failure, and occluded vessels create situations that demand intervention to remove leads. Due to adhesions that occur in the venous system and at the endomyocardial attachment site, simple traction to remove a lead is often not sufficient. Infection is a mandatory reason to remove the entire CIED system. Tools and techniques are now available that enable a skilled operator to extract leads with a great deal of efficacy and safety. PMID- 29428135 TI - When Is It Safe Not to Reimplant an Implantable Cardioverter Defibrillator at the Time of Battery Depletion? AB - The implantable cardioverter defibrillator (ICD) is a life-saving therapy in various patient populations. Although data on the outcomes of initial ICD implants are abundant, data on ICD replacements, especially in patients with improved left ventricular (LV) function, are scarce. Therefore, it is not known when it is safe to not replace an ICD that has reached the end of battery life. This article reviews data on patients with primary prevention ICDs who have improvement in left ventricular ejection fraction during follow-up and provides some guidance, based on the available evidence, related to circumstances when replacement of an ICD may be forgone. PMID- 29428136 TI - Important Parameters for Implantable Cardioverter Defibrillator Selection. AB - The efficacy of implantable cardioverter defibrillators in reducing the risk of sudden cardiac death has been well established by several clinical trials. Several factors relating to device characteristics, patient attributes, and comorbidities should be considered when selecting the appropriate implantable cardioverter defibrillators for each patient. This review examines some of these issues. PMID- 29428137 TI - Management of Device Infections. AB - The rate of cardiac implantable electronic device (CIED) infection has increased disproportionately to the rate of implantation. Expanded indications for CIED implantation combined with a sicker patient population contribute to this increased rate. Device-related infections are most commonly due to perioperative contamination, and infection risk increases in conjunction with procedural complexity. Early pocket re-exploration and upgrade procedures confer a higher infectious risk. Confirmed CIED infection requires prompt removal of the CIED system combined with antimicrobial therapy. Understanding the risks of CIED infection and using preventive measures are critical. It is hoped that emerging technologies will mitigate CIED infection rates. PMID- 29428138 TI - Venous System Interventions for Device Implantation. AB - Subclavian obstruction is common after lead implantation and the need to add or replace a lead is increasing. Subclavian venoplasty (SV) is a safe and effective option for venous occlusion. Peripheral venography overestimates the severity of the obstruction. A wire can usually be advanced into the central circulation for SV. Compared with dilators, SV improves the quality of venous access, providing unrestricted catheter manipulation for His bundle pacing and left ventricular lead implantation. SV preserves venous access and reduces lead burden. SV can easily be added to the implanting physicians lead management options. PMID- 29428139 TI - Leadless Pacemakers: State of the Art and Future Perspectives. AB - Leadless pacemaker therapy is a new technology that aims at avoiding lead- and pocket-related complications of conventional transvenous and epicardial pacing. To date, 2 self-contained leadless pacemakers for right ventricular pacing have been clinically available: the Nanostim Leadless Pacemaker System and the Micra Transcatheter Pacing System. Additionally, a new multicomponent leadless pacemaker for endocardial left ventricular pacing has been proposed as an alternative choice for cardiac resynchronization therapy. In this review, we describe the state of the art of leadless pacing and compare the currently available devices with traditional transvenous leadless pacemakers. PMID- 29428140 TI - Right Ventricular Pacing and Cardiac Resynchronization Devices. AB - Long-term right ventricular pacing is associated with electrical and mechanical dyssynchrony and ultimately development of pacing-induced cardiomyopathy (PICM) in a subset of patients. Patients with a high degree of pacing burden and reduced left ventricular (LV) function prior to pacemaker implantation are at the greatest risk for developing PICM. Cardiac resynchronization therapy (CRT) has an established role in the treatment of patients with LV systolic heart failure and intraventricular delay and has been used to successfully treat PICM. This review evaluates predictors for PICM, as well as highlights the role for CRT in prevention and treatment in high risk patients. PMID- 29428141 TI - Remote Monitoring for Chronic Disease Management: Atrial Fibrillation and Heart Failure. AB - This review aims to cover the latest evidence of remote monitoring of cardiac implantable electronic devices for the management of atrial fibrillation and heart failure. Remote monitoring is useful for early detection for device detected atrial fibrillation, which increases the risk of thromboembolic events. Early anticoagulation based on remote monitoring potentially reduces the risk of stroke, but optimal alert setting needs to be clarified. Multiparameter monitoring with automatic transmission is useful for heart failure management. Improved adherence to remote monitoring and an optimal algorithm for transmitted alerts and their management are warranted in the management of heart failure. PMID- 29428142 TI - Should Single-Coil Implantable Cardioverter Defibrillator Leads Be Used in all Patients? AB - The historical preference for dual-coil implantable cardioverter defibrillator leads stems from high defibrillation thresholds associated with old device platforms. The high safety margins generated by contemporary devices have rendered the modest difference in defibrillation efficacy between single- and dual-coil leads clinically insignificant. Cohort data demonstrating worse lead extraction outcomes and higher all-cause mortality have brought the incremental utility of an superior vena cava coil into question. This article summarizes the current literature and re-evaluates the utility of dual-coil leads in the context of modern device technology. PMID- 29428143 TI - Causes and Prevention of Inappropriate Implantable Cardioverter-Defibrillator Shocks. AB - Use of implantable cardioverter-defibrillators as a primary prevention therapy has been shown to reduce mortality in patients after cardiac arrest and also with left ventricular systolic dysfunction. Yet, inappropriate shocks are variably reported and associated with a reduction in quality of life. Inappropriate shocks are the result of environmental causes leading to electromagnetic interference and inappropriate sensing of external noise, device-related causes from inappropriate sensing of physiologic or pathologic signals, and supraventricular arrhythmias. Strategies to reduce inappropriate shocks include aggressive treatment of supraventricular tachycardia, changes in device programming including prolonged detection time, programming antitachycardic pacing and using discriminator algorithms, and cardiac rehabilitation. PMID- 29428144 TI - When is Device-Detected Atrial Fibrillation Actionable? AB - Device-detected atrial high-rate episodes (AHREs) are frequently encountered in patients with no history of atrial fibrillation (AF) and represent a challenge for clinicians because patients with device-only documented AF have not been included in clinical trials of anticoagulants and other AF therapies. For patients with known history of AF, wireless continuous rhythm monitoring and rapidly acting oral anticoagulants offer the possibility of tailored anticoagulation in response to AHREs, with studies ongoing to evaluate the safety of this approach. This article provides an overview of current evidence on device detected AHREs and evolving areas of investigation. PMID- 29428145 TI - His Bundle Pacing: Is It Ready for Prime Time? AB - Long-term right ventricular apical pacing has been associated with detrimental effects, including an increased risk for heart failure, atrial fibrillation, and death. Most of these adverse effects result from ventricular dyssynchrony related to perturbed ventricular depolarization. In addition, biventricular pacing has limited benefits in patients with non-left bundle branch block and severely reduced ejection fraction. Consequently, alternative pacing strategies that mimic natural physiology are desired. Recently, permanent His bundle pacing has emerged as a true physiologic form of ventricular pacing that has been shown to be safe and feasible in clinical practice. PMID- 29428146 TI - Management of Perioperative Anticoagulation for Device Implantation. AB - Periprocedural management of anticoagulation for cardiac device implantation has evolved over the past 20 years. The traditional paradigm of vitamin K antagonist interruption with heparin bridging has now been shown to be less safe than continuation of vitamin K antagonists at therapeutic levels. Dual antiplatelet therapy during device implantation poses substantial risk but is often necessary. The safest dosing strategy for newer direct oral anticoagulants is still not clear. PMID- 29428147 TI - Cardiac Implantable Electronic Devices. PMID- 29428148 TI - Contemporary Review of the Cardiovascular Implantable Electronic Devices with Future Directions. PMID- 29428150 TI - Equal to or better than: The application of statistical non-inferiority to fatigue risk management. AB - In December 2014, the Federal Aviation Administration (FAA) completed a major revision of the rules and regulations governing flight and duty time in commercial aviation (Federal Aviation Regulation (FAR) Part 117). Scientists were included in the revision process and provided insights into sleep, sleep loss, the circadian rhythm, and their effects on performance that were incorporated into the new rule. If a planned flight was non-compliant with the regulation, for example if it exceeded flight and duty time limits, it could only be flown under an FAA-approved Fatigue Risk Management System (FRMS) as meeting an Alternative Method of Compliance (AMOC). One method that a flight could qualify as an AMOC is if it could be demonstrated empirically that it was as safe as or safer than a similar flight, designated the Safety Standard Operation (SSO), that was compliant with the regulation. In the present paper, we demonstrate the FRMS process using a comparison between a non-compliant AMOC flight from the US west coast to Australia and a compliant SSO flight from the US west coast to Taiwan. The AMOC was non-compliant because it exceeded the flight time limits in the prescriptive rule. Once a data collection exemption was granted by the FAA, both the outbound and inbound AMOC and SSO routes were studied on four Safety Performance Indicators (SPIs). The SPIs studied were inflight sleep, cognitive performance, self-reported fatigue, and self-reported sleepiness. These measures were made at top of descent (TOD), a critical phase of flight. The study was designed as a paired comparison. Forty volunteer pilots studied flew both the AMOC and the SSO flights for a total of 80 studied flights. Using statistical non inferiority applied to the AMOC and SSO SPIs, we demonstrated, as required by the new rule, that the US-Australia AMOC flight was "as safe as, or safer than" the US-Taiwan SSO flight. In the context of FRMS, statistical non-inferiority is a concept and technique of great utility, straightforward in application, producing clear visual representations of the findings, and providing a direct answer to the question posed by the regulation - is the AMOC flight "as safe as, or safer than" the SSO. PMID- 29428151 TI - Evaluation and proposal of novel resectability criteria for pancreatic cancer established by the Japan Pancreas Society. PMID- 29428152 TI - Assessing burn care in Brazil: An epidemiologic, cross-sectional, nationwide study. AB - BACKGROUND: The aim of this study was to describe the national epidemiology of burns in Brazil and evaluate regional access to care by defining the contribution of out-of-hospital mortality to total burn deaths. METHODS: We reviewed admissions data for Brazil's single-payer, free-at-point-of-care, public-sector provider and national death registry data abstracted from DATASUS for 2008-2014. Admissions, in-hospital mortality, hospital reimbursement, and total deaths from the death registry were assessed for records coded under ICD-10 codes corresponding to flame, scald, contact, and electrical burns. RESULTS: A total of 17,264 burn deaths occurred between 2008-2014 (mean annual 2,466 [SD 202]). Of all burns deaths 79.1% occurred out of hospital, with marked regional differences in the proportion of out-of-hospital deaths (P < 0.001), the greatest being in the North region. The mean annual number of admissions >24 hours was 18,551 (SD 1,504) with the greatest prevalence of flame burns overall (43.98%) and scalds prevailing in < 5 years (57.8%). Regional differences were found in per-capita admissions (P < 0.001) with the greatest number in the Central-West region. A mean of $1,022 (SD $94) US dollars was reimbursed per burn admission. CONCLUSION: Given that nearly 80% of burns mortalities occurred out of hospital, prevention of burns alongside interventions improving prehospital and access to care have potential for the greatest impact. PMID- 29428153 TI - Chronic renal disease in spain: prevalence and related factors in persons with diabetes mellitus older than 64 years. AB - INTRODUCTION: Type 2 diabetes mellitus and chronic kidney disease (CKD) are conditions which have a high prevalence in individuals >= 65 years of age and represent a major public health problem. OBJECTIVES: To determine the prevalence of CKD, its categories and its relationship with various demographic and clinical factors in elderly patients with type 2 diabetes mellitus in Spain. METHODS: Observational, cross-sectional, multicenter, Spanish epidemiological study. Patients with known type 2 diabetes mellitus, age >= 65 years of age treated in Primary Care were included. We collected demographic, anthropometric and analytical variables from the previous 12 months, including the albumin-to creatinine ratio and estimated glomerular filtration rate to evaluate renal function. RESULTS: The prevalence of CKD was 37.2% (95% CI, 34.1-40.3%), renal failure was 29.7% (95% CI, 26.8-32.6%) and increased albuminuria was 20.6% (95% CI, 17.3-23.9%), moderately increased albuminuria was 17.8% (95% CI, 14.7-20.9%) and severely increased albuminuria was 2.8% (95% CI, 1.4-4.2%). In turn, the prevalence of CKD categories were: G1 1.3% (95% CI, 0.6-2%), G2 6.2% (95% CI, 4.6 7.8%), G3a 17.2% (95% CI, 14.8-19.6%), G3b 9.8% (95% CI, 7.9-11.7%), G4 2% (95% CI, 1.1-2.9%) and G5 0.7% (95% CI, 0.2-1.2%). In the multivariate analysis, after adjusting for the remaining variables, CKD was associated with elderly age (OR 5.13, 95% CI, 3.15-8.35), high comorbidity (OR 3.36. 95% CI, 2.2-5.12) and presence of antihypertensive treatment (OR 2.43. 95% CI, 1.48-4.02). CONCLUSIONS: CKD is frequent in the diabetic population >= 65 years of age and is associated with elderly age, high comorbidity and with treated hypertension. No relationship has been found with gender and time in years since onset of diabetes. PMID- 29428154 TI - Neonatal Infection in Children With Cerebral Palsy: A Registry-Based Cohort Study. AB - BACKGROUND: The goal of this study was to explore the association between neonatal infection and outcomes in children with cerebral palsy. METHODS: We conducted a retrospective cohort study using the Canadian CP Registry. Neonatal infection was defined as meeting one of the following criteria: (1) septicemia, (2) septic shock, or (3) administration of antibiotics for >=10 days. Phenotypic profiles of children with cerebral palsy with and without an antecedent neonatal infection were compared. Subgroup analysis was performed, stratified by gestational age (term versus preterm). RESULTS: Of the 1229 registry participants, 505 (41.1%) were preterm, and 192 (15.6%) met the criteria for neonatal infection with 29% of preterm children having a neonatal infection compared with 6.5% in term-born children. Children with prior neonatal infection were more likely to have a white matter injury (odds ratio 2.2, 95% confidence interval 1.5 to 3.2), spastic diplegic neurological subtype (odds ratio 1.6, 95% confidence interval 1.1 to 2.3), and sensorineural auditory impairment (odds ratio 2.1, 95% confidence interval 1.4 to 3.3). Among preterm children, neonatal infection was not associated with a difference in phenotypic profile. Term-born children with neonatal infection were more likely to have spastic triplegia or quadriplegia (odds ratio 2.4, 95% confidence interval 1.3 to 4.3), concomitant white matter and cortical injury (odds ratio 4.1, 95% confidence interval 1.6 to 10.3), and more severe gross motor ability (Gross Motor Function Classification System IV to V) (odds ratio 2.6, 95% confidence interval 1.4 to 4.8) compared with preterm children. CONCLUSIONS: Findings suggest a role of systemic infection on the developing brain in term-born infants, and the possibility to develop targeted therapeutic and preventive strategies to reduce cerebral palsy morbidity. PMID- 29428155 TI - Statin medications are associated with decreased risk of sepsis and anastomotic leaks after rectal resections. AB - BACKGROUND: This study was designed to determine the effect of statins on colorectal postoperative complications related to sepsis. Previous studies have reported conflicting results. METHODS: This is a retrospective propensity score analysis of postoperative outcomes from a large regional database of patients who underwent elective colorectal resection from June 2012-July 2015. RESULTS: 7285 patients met inclusion criteria: 34.5% received statins. Propensity score matching revealed that patients taking statins had reduced risk of sepsis (3.75% vs 5.32%, p = .03). Subgroup analysis revealed that this difference was driven by patients undergoing rectal resections. Among the rectal resection group, anastomotic leaks were more common in the non-statins group (4.1% vs. 1.3%, p = .01). There was no significant difference between those taking statins and those not on statin medications with respect to composite SSI or 30-day mortality. CONCLUSIONS: Statin medications are associated with decreased risk of sepsis after colorectal surgery and anastomotic leaks after rectal resection. Future studies should focus on medication type, dosage, and duration to confirm these results and identify patient populations that would benefit most from statin therapy. PMID- 29428156 TI - Midwest Surgical Association 2017 Presidential Address. PMID- 29428157 TI - Retraction notice to "High-concentration supplemental perioperative oxygen and surgical site infection following elective colorectal surgery for rectal cancer: A prospective, randomized, double-blind, controlled, single-site trial" [Am J Surg 208 (2014) 719-726]. PMID- 29428158 TI - Editorial commentary: Heart failure with preserved ejection fraction-Clinical syndrome with incomplete understanding. PMID- 29428159 TI - Cerebral protection devices during transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) in patients with aortic valve stenosis is associated with an improvement of clinical outcomes, quality of life, and self-sufficiency. The most feared TAVI-related complication is the occurrence of stroke. In order to reduce peri-procedural cerebral embolizations, diverse cerebral protection devices have been developed. These devices work though deflection or filtering of emboli, and are in different stages of testing. Silent cerebral infarctions identified by diffusion-weighted magnetic resonance imaging (DW-MRI) are used as surrogate primary outcomes, but the clinical significance is still unclear. This review provides a synopsis of the diverse cerebral protection devices and summarizes the current evidence on their efficacy during TAVI. PMID- 29428160 TI - Editorial commentary: The lower the LDL the better but how and how much? PMID- 29428161 TI - Potentialities of the internal mammary arteries and refractory angina. PMID- 29428162 TI - Trends in Active and Assisted Living - Open hardware architecture, Human Data Interpretation, intervention and assistance. PMID- 29428163 TI - From neutral to zwitterionic poly(alpha-amino acid) nonfouling surfaces: Effects of helical conformation and anchoring orientation. AB - The development of high-performance nonfouling polymer surfaces for implantable medical devices and therapeutic nanomaterials is of great importance. Elaborating the relationship of polymer structural characteristics and the resulted surface properties can offer useful guidance toward ideal biointerfaces. In this work, we investigate the effects of the helical conformation and anchoring orientation of poly(alpha-amino acid)s (PalphaAAs) to produce advanced nonfouling surfaces. By using the neutral poly(gamma-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)esteryl glutamates) (P(EG3Glu)s) as a model system, the adsorption kinetics are monitored by ex-situ variable angle spectroscopic ellipsometry and in-situ quartz crystal microbalance with dissipation. It is found that the polymers adopting a rigid rod like alpha-helical conformation can self-assemble more rapidly to produce denser adlayers, and generate significantly improved nonfouling surfaces compared to those flexible polymer analogues including the widely used antifouling polymer PEG. Moreover, the surface properties can be further enhanced by using the antiparallel orientated helical P(EG3Glu)s. Most importantly, the insights gained from the P(EG3Glu) model system are successfully applied to the generation of ultra-low-fouling surfaces using zwitterionic PalphaAAs brushes, underscoring the generality of the approach. Particularly, the surface based on the antiparallel aligned zwitterionic helical PalphaAAs exhibits ~98-99% reduction of human serum adsorption relative to the bare gold, and gives almost no adhesion of mouse platelet. Taken together, this work depicts an extremely simple yet highly effective approach to manipulate surface properties for numerous applications in biomaterial interfaces, diagnostics, and biosensors. PMID- 29428164 TI - Collaborative action will generate better outcomes. PMID- 29428165 TI - Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study. AB - BACKGROUND: Gene expression patterns can be used as prognostic biomarkers in various types of cancers. We aimed to identify a gene expression pattern for individual distant metastatic risk assessment in patients with locoregionally advanced nasopharyngeal carcinoma. METHODS: In this multicentre, retrospective, cohort analysis, we included 937 patients with locoregionally advanced nasopharyngeal carcinoma from three Chinese hospitals: the Sun Yat-sen University Cancer Center (Guangzhou, China), the Affiliated Hospital of Guilin Medical University (Guilin, China), and the First People's Hospital of Foshan (Foshan, China). Using microarray analysis, we profiled mRNA gene expression between 24 paired locoregionally advanced nasopharyngeal carcinoma tumours from patients at Sun Yat-sen University Cancer Center with or without distant metastasis after radical treatment. Differentially expressed genes were examined using digital expression profiling in a training cohort (Guangzhou training cohort; n=410) to build a gene classifier using a penalised regression model. We validated the prognostic accuracy of this gene classifier in an internal validation cohort (Guangzhou internal validation cohort, n=204) and two external independent cohorts (Guilin cohort, n=165; Foshan cohort, n=158). The primary endpoint was distant metastasis-free survival. Secondary endpoints were disease-free survival and overall survival. FINDINGS: We identified 137 differentially expressed genes between metastatic and non-metastatic locoregionally advanced nasopharyngeal carcinoma tissues. A distant metastasis gene signature for locoregionally advanced nasopharyngeal carcinoma (DMGN) that consisted of 13 genes was generated to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter distant metastasis-free survival (hazard ratio [HR] 4.93, 95% CI 2.99-8.16; p<0.0001), disease-free survival (HR 3.51, 2.43-5.07; p<0.0001), and overall survival (HR 3.22, 2.18-4.76; p<0.0001) than patients with low-risk scores. The prognostic accuracy of DMGN was validated in the internal and external cohorts. Furthermore, among patients with low-risk scores in the combined training and internal cohorts, concurrent chemotherapy improved distant metastasis-free survival compared with those patients who did not receive concurrent chemotherapy (HR 0.40, 95% CI 0.19-0.83; p=0.011), whereas patients with high-risk scores did not benefit from concurrent chemotherapy (HR 1.03, 0.71-1.50; p=0.876). This was also validated in the two external cohorts combined. We developed a nomogram based on the DMGN and other variables that predicted an individual's risk of distant metastasis, which was strengthened by adding Epstein-Barr virus DNA status. INTERPRETATION: The DMGN is a reliable prognostic tool for distant metastasis in patients with locoregionally advanced nasopharyngeal carcinoma and might be able to predict which patients benefit from concurrent chemotherapy. It has the potential to guide treatment decisions for patients at different risk of distant metastasis. FUNDING: The National Natural Science Foundation of China, the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, the Natural Science Foundation of Guang Dong Province, the National Key Research and Development Program of China, the Innovation Team Development Plan of the Ministry of Education, the Health & Medical Collaborative Innovation Project of Guangzhou City, China, and the Program of Introducing Talents of Discipline to Universities. PMID- 29428166 TI - Direct healthcare cost of schizophrenia - European overview. AB - PURPOSE: To provide an overview on the magnitude of the impact of schizophrenia on the healthcare system in Europe and to gain a better understanding on the most important factors influencing the variation of costs. METHODS: Studies reporting costs and healthcare utilization among patients with schizophrenia were searched in MEDLINE (via Scopus), EMBASE (via Scopus) and Cochrane Database of Systematic Reviews on 19th January 2017. RESULTS: Twenty-three studies, from the 1075 references initially identified, were included in this review. The annual cost per patient ranged from ?533 in Ukraine to ?13,704 in the Netherlands. Notably drug costs contributed to less than 25% of the direct healthcare cost per patient in every country, which might be explained by similar pharmaceutical prices among countries due to the reference pricing system applied in Europe. Inpatient costs were the largest component of health service costs in the majority of the countries. Despite methodological heterogeneity across studies, four major themes could be identified (age, severity of symptoms, continuation of treatment/persistence, hospitalization) that have substantial impact on the costs of schizophrenia. CONCLUSIONS: Schizophrenia represents a substantial cost for the healthcare system in Europe driven by the high cost per patient. Substantial savings could potentially be achieved by increasing investment in the following areas: (1) reducing the number of hospitalizations e.g. by increasing the efficiency of outpatient care; (2) working out interventions targeted at specific symptoms; (3) improving patient persistence and adherence in antipsychotic therapy. PMID- 29428167 TI - Local Texture Anisotropy as an Estimate of Muscle Quality in Ultrasound Imaging. AB - This study introduces local pattern texture anisotropy as a novel parameter to differentiate healthy and disordered muscle and to gauge the severity of muscle impairments based on B-mode ultrasound images. Preliminary human results are also presented. A local pattern texture anisotropy index (TAI) was computed in one region of interest in the short head of the biceps brachii. The effects of gain settings and box sizes required for TAI computation were investigated. Between day reliability was studied in patients with sporadic inclusion body myositis (n = 26). The ability of the TAI to discriminate dystrophic from healthy muscle was evaluated in patients with Duchenne muscular dystrophy and healthy controls (n = 16). TAI values were compared with a gray-scale index (GSI). TAI values were less influenced by gain settings than were GSI values. TAI had lower between-day variability (typical error = 2.3%) compared with GSI (typical error = 2.3% vs. 8.3%, respectively). Patients with Duchenne muscular dystrophy had lower TAIs than controls (0.76 +/- 0.06 vs. 0.87 +/- 0.03, respectively, p <0.05). At 40% gain, TAI values correlated with percentage predicted elbow flexor strength in inclusion body myositis (R = 0.63, p <0.001). The TAI may be a promising addition to other texture-based approaches for quantitative muscle ultrasound imaging. PMID- 29428168 TI - Pulmonary Capillary Hemorrhage Induced by Different Imaging Modes of Diagnostic Ultrasound. AB - The induction of pulmonary capillary hemorrhage (PCH) is a well-established non thermal biological effect of pulsed ultrasound in animal models. Typically, research has been done using laboratory pulsed ultrasound systems with a fixed beam and, recently, by B-mode diagnostic ultrasound. In this study, a GE Vivid 7 Dimension ultrasound machine with 10 L linear array probe was used at 6.6 MHz to explore the relative PCH efficacy of B-mode imaging, M-mode (fixed beam), color angio mode Doppler imaging and pulsed Doppler mode (fixed beam). Anesthetized rats were scanned in a warmed water bath, and thresholds were determined by scanning at different power steps, 2 dB apart, in different groups of six rats. Exposures were performed for 5 min, except for a 15-s M-mode group. Peak rarefactional pressure amplitude thresholds were 1.5 MPa for B-mode and 1.1 MPa for angio Doppler mode. For the non-scanned modes, thresholds were 1.1 MPa for M mode and 0.6 MPa for pulsed Doppler mode with its relatively high duty cycle (7.7 * 10-3 vs. 0.27 * 10-3 for M-mode). Reducing the duration of M-mode to 15 s (from 300 s) did not significantly reduce PCH (area, volume or depth) for some power settings, but the threshold was increased to 1.4 MPa. Pulmonary sonographers should be aware of this unique adverse bio-effect of diagnostic ultrasound and should consider reduced on-screen mechanical index settings for potentially vulnerable patients. PMID- 29428169 TI - Effectiveness of a combination denture-cleaning method versus a mechanical method: comparison of denture cleanliness, patient satisfaction, and oral health related quality of life. AB - PURPOSE: Effective denture plaque control is necessary in elderly individuals to prevent oral and systemic diseases. However, comparative studies of denture cleaning methods are limited, especially those investigating patient satisfaction. The present study aimed to evaluate effectiveness of a mechanical denture cleaning method versus a combination of mechanical and chemical methods in terms of denture cleanliness, patient satisfaction, and oral health-related quality of life (OHRQoL). METHODS: Thirty edentulous participants were allocated to one of two groups: mechanical or combination method. The mechanical method group was instructed to brush dentures after each meal for 2min using tap water and a denture brush, and to soak them in saline solution while sleeping. The combination method group was instructed to brush dentures the same way, but to soak them in denture cleansers while sleeping. Both groups cleaned their dentures according to the respective method for 3 weeks. Denture cleanliness, patient satisfaction, and OHRQoL were examined. RESULTS: There were significant differences in adenosine triphosphate bioluminescence (p=0.00003), staining (p=0.003), and Candida albicans (C. albicans) abundance in upper complete dentures (p=0.002) between methods. There were no significant differences in oral mucosa C. albicans abundance, participant satisfaction, ease of cleaning, comfort, esthetics, or Oral Health Impact Profile for edentulous patients (Japanese version) scores between methods. CONCLUSIONS: A combination of mechanical and chemical denture cleaning methods was more effective at cleaning dentures than the mechanical method alone. Even if denture cleaning improves denture hygiene, it may not increase patient satisfaction or OHRQoL. PMID- 29428170 TI - Fitness and retentive force of cobalt-chromium alloy clasps fabricated with repeated laser sintering and milling. AB - PURPOSE: With computer-aided design and computer-aided manufacturing (CAD/CAM), the study was conducted to create a removable partial denture (RPD) framework using repeated laser sintering rather than milling and casting techniques. This study experimentally evaluated the CAM clasp and compared it to a conventional cast clasp. METHODS: After the tooth die was scanned, an Akers clasp was designed using CAD with and without 50MUm of digital relief on the occlusal surface of the tooth die. Cobalt-chromium (Co-Cr) alloy clasps were fabricated using repeated laser sintering (RLS) and milling as one process simultaneously (hybrid manufacturing; HM). The surface roughness of the rest region, gap distances between clasp and tooth die, initial retentive forces, and changes of retentive forces up to 10,000 insertion/removal cycles were measured before and after heat treatment. The HM clasp was compared to the cast clasp and the clasp made by repeated laser sintering only without a milling process. RESULTS: The HM clasp surface was smoother than those of cast and RLS clasps. With the digital relief, the fitness accuracy of the HM clasp improved. The retentive forces of the HM clasps with relief and after heat treatment were significantly greater than for the cast clasp. HM clasps demonstrated a constant or slight decrease of retention up to 10,000 cycles. CONCLUSIONS: HM clasp exhibited better fitness accuracy and retentive forces. The possibility of clinically using HM clasps as well as conventional cast clasps can be suggested. PMID- 29428171 TI - Human-cell-derived organoids as a new ex vivo model for drug assays in oncology. AB - In oncology, a 2D in vitro model of cancer cell lines is still widely used for large-scale drug screening. However, most promising candidates firstly identified by in vitro analysis tend to fail during the next steps of drug development. The generation of an ex vivo approach termed 'organoid' is emerging as a promising preclinical model to mimic human tumors more accurately. In this review, we focus on human-derived organoid use for anticancer drug screening. We describe the development of this new in vitro model, its use for anticancer agent assays and the advantages compared with the currently used 2D models. Finally, we discuss organoid limitations in the common use of this technology during preclinical studies. PMID- 29428172 TI - Social influences on health-related behaviour clustering during adulthood in two British birth cohort studies. AB - Building upon evidence linking socio-economic position (SEP) in childhood and adulthood with health-related behaviours (HRB) in adulthood, we examined how pre adolescent SEP predicted membership of three HRB clusters: "Risky", "Moderate Smokers" and "Mainstream" (the latter pattern consisting of more beneficial HRBs), that were detected in our previous work. Data were taken from two British cohorts (born in 1958 and 1970) in pre-adolescence (age 11 and 10, respectively) and adulthood (age 33 and 34). SEP constructs in pre-adolescence and adulthood were derived through Confirmatory Factor Analysis. Conceptualised paths from pre adolescent SEP to HRB cluster membership via adult SEP in our path models were tested for statistical significance separately by gender and cohort. Adult SEP mediated the path between pre-adolescent SEP and adult HRB clusters. More disadvantaged SEP in pre-adolescence predicted more disadvantaged SEP in adulthood which was associated with membership of the "Risky" and "Moderate Smokers" clusters compared to the "Mainstream" cluster. For example, large positive indirect effects between pre-adolescent SEP and adult HRB via adult SEP were present (coefficient 1958 Women = 0.39; 1970 Women = 0.36, 1958 Men = 0.51; 1970 Men = 0.39; p < 0.01) when comparing "Risky" and "Mainstream" cluster membership. Amongst men we found a small significant direct association (p < 0.001) between pre-adolescent SEP and HRB cluster membership. Our findings suggest that associations between adult SEP and HRBs are not likely to be pre determined by earlier social circumstances, providing optimism for interventions relevant to reducing social gradients in HRBs. Observing consistent findings across the cohorts implies the social patterning of adult lifestyles may persist across time. PMID- 29428173 TI - Medical diagnoses of heat wave-related hospital admissions in older adults. AB - Heat waves have been associated with adverse human health effects, including higher rates of all-cause and cardiovascular mortality, and these health effects may be exacerbated under continued climate change. However, specific causes of hospitalizations associated with heat waves have not been characterized on a national scale. We systematically estimated the risks of cause-specific hospitalizations during heat waves in a national cohort of 23.7 million Medicare enrollees residing in 1943 U.S. counties during 1999-2010. Heat waves were defined as >=2 consecutive days exceeding the county's 99th percentile of daily temperatures, and were matched to non-heat wave periods by county and week. We considered 50 outcomes from broad disease groups previously associated with heat wave-related hospitalizations, and estimated cause-specific relative risks (RRs) of hospital admissions on heat wave days. We identified 11 diagnoses with a higher admission risk on heat wave days, with heat stroke and sunstroke having the highest risk (RR = 22.5, [95% CI 14.9-34.2]). Other diseases with elevated risks included fluid and electrolyte disorders [(Hyperosmolality RR = 1.4, [95% CI 1.1-1.3]; Hypoosmolaltiy RR = 1.2, [95% CI 1.1-1.3])] and acute kidney failure (RR = 1.1, [95% CI 1.1-1.2]). These risks tended to be higher under more severe heat wave events. In addition, risks were higher among adults in the oldest (>=85) category (reference: 65-74) for volume depletion and heat exhaustion. Several causes of hospitalization identified are preventable, and public health interventions, including early warning systems and plans targeting risk factors for these illnesses, could reduce adverse effects of heat in the present and under climate change. PMID- 29428174 TI - Mid-term function and remodeling potential of tissue engineered tricuspid valve: Histology and biomechanics. AB - OBJECTIVE: Tricuspid valve reconstruction using a small intestinal submucosal porcine extracellular matrix (ECM) tube graft is hypothesized to be durable for six months and show signs of recellularization and growth potential. The purpose was to histologically and biomechanically test ECM valves before and after six months of implantation in pigs for comparison with native valves. METHODS: Ten 60 kg pigs were included, which survived tricuspid valve tube graft insertion. Anterior and septal tricuspid leaflets were explanted from all animals surviving more than one month and examined histologically (n = 9). Endothelialization, collagen content, mineralization, neovascularization, burst strength and tensile strength were determined for native valves (n = 5), ECM before implantation (n = 5), and ECM after six months (n = 5). RESULTS: Collagen density was significantly larger in ECM at implantation (baseline) compared to native leaflet tissue (0.3 +/- 0.02 mg/mm3 vs. 0.1 +/- 0.03 mg/mm3, p < .0001), but collagen density decreased and reached native leaflet collagen content, six months after ECM implantation (native vs. ECM valve at six months: 0.1 +/- 0.03 mg/mm3 vs. 0.2 +/- 0.05 mg/mm3, p = .8). Histologically, ECM valves showed endothelialization, host cell infiltration and structural collagen organization together with elastin generation after six months, indicating tissue remodeling and -engineering together with gradual development of a close-to-native leaflet structure without foreign body response. CONCLUSIONS: ECM tricuspid tube grafts were stronger than native leaflet tissue. Histologically, the acellular ECM tube grafts showed evidence of constructive tissue remodeling with endothelialization and connective tissue organization. These findings support the concept of tissue engineering and recellularization, which are prerequisites for growth. PMID- 29428175 TI - Beyond the Channel: Metabotropic Signaling by Nicotinic Receptors. AB - The alpha7 nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel (LGIC) that plays an important role in cellular calcium signaling and contributes to several neurological diseases. Agonist binding to the alpha7 nAChR induces fast channel activation followed by inactivation and prolonged desensitization while triggering long-lasting calcium signaling. These activities foster neurotransmitter release, synaptic plasticity, and somatodendritic regulation in the brain. We discuss here the ability of alpha7 nAChRs to operate in ionotropic (alpha7i) and metabotropic (alpha7m) modes, leading to calcium-induced calcium release (CICR) and G protein-associated inositol trisphosphate (IP3)-induced calcium release (IICR), respectively. Metabotropic activity extends the spatial and temporal aspects of calcium signaling by the alpha7 channel beyond its ionotropic limits, persisting into the desensitized state. Delineation of the ionotropic and metabotropic properties of the alpha7 nAChR will provide definitive indicators of moment-to-moment receptor functional status that will, in turn, spearhead new drug development. PMID- 29428176 TI - The impact of immunization programs on 10 vaccine preventable diseases in Italy: 1900-2015. AB - BACKGROUND: Vaccination has determined a dramatic decline in morbidity and mortality from infectious diseases over the last century. However, low perceived risk of the infectious threat and increased concern about vaccines' safety led to a reduction in vaccine coverage, with increased risk of disease outbreaks. METHODS: Annual surveillance data of nationally communicable infectious diseases in Italy between 1900 and 2015 were used to derive trends in morbidity and mortality rates before and after vaccine introduction, focusing particularly on the effect of vaccination programs. Autoregressive integrated moving average models were applied to ten vaccine-preventable diseases: diphtheria, tetanus, poliomyelitis, hepatitis B, pertussis, measles, mumps, rubella, chickenpox, and invasive meningococcal disease. Results of these models referring to data before the immunization programs were projected on the vaccination period to estimate expected cases. The difference between observed and projected cases provided estimates of cases avoided by vaccination. RESULTS: The temporal trend for each disease started with high incidence rates, followed by a period of persisting reduction. After vaccine introduction, and particularly after the recommendation for universal use among children, the current rates were much lower than those forecasted without vaccination, both in the whole population and among the 0-to-4 year olds, which is, generally, the most susceptible age class. Assuming that the difference between incidence rates before and after vaccination programs was attributable only to vaccine, more than 4 million cases were prevented, and nearly 35% of them among children in the early years of life. Diphtheria was the disease with the highest number of prevented cases, followed by mumps, chickenpox and measles. CONCLUSIONS: Universal vaccination programs represent the most effective prevention tool against infectious diseases, having a major impact on human health. Health authorities should make any effort to strengthen public confidence in vaccines, highlighting scientific evidence of vaccination benefits. PMID- 29428179 TI - The diagnosis of mucinous lesions in endometrial samplings by gynaecological pathologists: an analysis of diagnostic reproducibility. AB - The purpose of this study is to assess the reproducibility among gynaecological pathologists in their diagnosis of mucinous alterations in endometrial sampling specimens. Twenty-six cases were independently reviewed by four experienced gynaecological pathologists from four academic medical centres. Pathologists were asked to classify each case into one of four groups, including three World Health Organization (WHO)-recognised categories: (1) mucinous metaplasia; (2) atypical mucinous glandular proliferation; (3) carcinoma; and (4) 'other' (absence of a true mucinous alteration and/or an alteration of non-endometrial origin). The overall reproducibility was 'fair' (kappa = 0.39). In an analytical scenario that established three clinically significant groups ('benign/non-neoplastic', 'atypical', and 'carcinoma') by redistributing all group 4 responses, the resultant kappa improved to 0.51 (moderate reproducibility). In another analysis with only two categories-'benign/non-neoplastic' versus 'atypical/carcinoma' reproducibility was similarly moderate (kappa = 0.46). However, with one exception, all cases that were ultimately diagnosed as carcinoma in a follow-up hysterectomy specimen, were classified as atypical or carcinoma in the preceding sampling. For 11 cases that were classified as either 'carcinoma' or 'atypical' by all observers, there was moderate reproducibility (kappa = 0.53) in making that distinction, and none of a wide array of morphological features were found to significantly distinguish between these two categories. For five cases that all observers classified as either mucinous metaplasia or benign endocervix, reproducibility was substantial (kappa = 0.67). In summary, gynaecological pathologists show moderate reproducibility in categorising mucinous alterations in endometrial sampling specimens as benign, atypical, or carcinomatous. They accurately classify as at least 'atypical' those cases that are ultimately diagnosed as carcinoma in the subsequent resection. Our findings suggest that there are indeed some mucinous alterations which have features that do not allow for reproducible assignment by pathologists into the WHO-recognised categories. In this subset of cases, there may be a need for better-defined diagnostic criteria and/or extra-morphological diagnostic tools. PMID- 29428178 TI - Evaluation on the persistence of anti-HPV immune responses to the quadrivalent HPV vaccine in Chinese females and males: Up to 3.5 years of follow-up. AB - BACKGROUND: This was an extension study of a randomized, double-blind, placebo controlled immunogenicity and safety study of the quadrivalent human papillomavirus (qHPV) (HPV 6, 11, 16, and 18) vaccine conducted in Chinese female subjects aged 9-45 years and male subjects aged 9-15 years. To investigate the persistence of anti-HPV 6, -11, -16, and -18 responses among Chinese subjects, subjects enrolled in the base study were followed up at around month 42 (approximately 3.5 years after vaccination). METHODS: Among 600 subjects enrolled in the base study, a total of 468 subjects consented for participation in the extension study. Anti-HPV 6, -11, -16, and -18 antibodies were detected by the competitive Luminex immunoassay (cLIA) and total IgG Luminex immunoassay (IgG LIA). RESULTS: Among the female subjects who received the qHPV vaccine, the proportions of subjects remained seropositive were high with both the cLIA and IgG LIA for HPV type 6, 11, and 16 through approximately 42 months following the first dose vaccination. For HPV 18, the seropositivity rate remained high as 82.0% with the IgG LIA, while it decreased to 53.6% with the cLIA, which was similar to the findings observed in other studies. The seropositivity rates remained high at month 42 for all qHPV types with both the cLIA and IgG LIA among the male subjects. CONCLUSIONS: Administration of a 3-dose regimen of qHPV vaccine induces durable anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 responses among Chinese subjects for at least 3.5 years after vaccination. ClinicalTrials.gov registry:NCT01427777. PMID- 29428177 TI - Caregiver and adolescent factors associated with delayed completion of the three dose human papillomavirus vaccination series. AB - BACKGROUND: Delayed completion of human papillomavirus vaccination (4vHPV) series is common. We sought to identify factors associated with delay. METHODS: This substudy was part of a large prospective, multi-site study recruiting 9-17 year old girls at the time of their third 4vHPV dose to assess immunogenicity associated with prolonged dosing intervals. At participating sites, parents/legal guardians (caregivers) of all enrolled girls (9-17 years old) and enrolled girls aged 14-17 years were approached for participation. Caregivers completed a questionnaire measuring adolescent and caregiver sociodemographic characteristics, caregiver attitudes and beliefs about on-schedule HPV vaccination and HPV vaccine safety, adolescent's health behaviors, barriers to accessing health care, provider office vaccination practices and a Rapid Estimate of Adult Literacy in Medicine (REALM). Participating girls completed a separate questionnaire measuring their attitudes and beliefs about on-schedule HPV vaccination and HPV vaccine safety. Delay was defined as receiving the third 4vHPV dose >12 months after the first. Bivariate, multinomial logistic regression and multivariate logistic regression analyses were used to identify factors predicting delayed completion. RESULTS: Questionnaires were completed by 482 caregivers and 386 adolescents; 422 caregivers completed a REALM. Delayed 4vHPV dosing occurred in most adolescents (67%). In multivariate analyses, predictors of delayed completion included caregiver demographic factors (self-reported black vs. white race and high school or less education vs. college or more) and an interaction between caregiver's inability to get an immunization appointment as soon as needed and adolescent's type of insurance. CONCLUSIONS: Caregiver's race and educational level, accessibility of immunization appointments, and adolescent's insurance type were found to be related to delays in completion of 4vHPV, but caregiver or adolescent attitudes and beliefs about on-schedule HPV vaccination or HPV vaccine safety were not. Therefore, interventions to improve adherence to recommended vaccination schedules could benefit from a focus on improving access to immunizations. ClinicalTrials.gov (NCT01030562). PMID- 29428180 TI - International collaborative donor project. AB - The International Donor Collaborative Project (PCID) research group was created in 1996 in Spain with the aim of promoting research in the field of organ donation and transplantation, led by Spanish surgeons. During this period they have developed the questionnaires of the PCID, both the attitude towards cadaver and live donation, which are the most used questionnaires in publications in indexed journals. They have been the driving group of stratified studies representative of the populations under study, and of the performance of multivariate statistical analyzes in the field of psycho-social research in organ donation and transplantation. The main contributions of the group focus on the analysis of health center professionals and emerging migrant groups. In recent years, studies have been extended to the United States, Latin America (mainly Mexico) and Europe. PMID- 29428181 TI - Why Is This Auntminnie a Diagnostic Conundrum?: A Knowledge-Based Approach to Balo's Concentric Sclerosis From Reports of 3 Cases and Pooled Data From 68 Other Patients in the Literature. AB - INTRODUCTION: We came across 3 cases of Balo's concentric sclerosis (BCS). The first of these patients presented to an outside hospital and was transferred to our institution due to complications resulting from a biopsy. The other 2 patients, despite having a characteristic imaging appearance and despite insistence on our part on the diagnosis of BCS, underwent a surgical procedure, which could have been prevented. This led us to review the available literature on BCS. MATERIAL AND METHODS: A total of 68 patients diagnosed with BCS between 1995 and 2015 were studied and the data collected for the clinical presentation and course, imaging, spinal fluid analysis, treatment, and clinical and imaging outcome. CONCLUSIONS: A 25% surgery rate (biopsy or resection) was found in the study. We concluded that this relatively high surgery rate in this auntminnie nonsurgical disease is multifactorial; and includes factors like nonfamiliarity with the disease, anxiety on the part of patients and physicians, due to a sometimes rapidly deteriorating clinical picture; and resemblance of the disease with other entities such as tumor and infection. However, characteristic imaging appearance combined with acute or subacute presentation and dramatic improvement in clinical status after high-dose steroid chemotherapy; are highly suggestive of the disease, and can prevent unnecessary surgery. PMID- 29428182 TI - Online Interactive Case-Based Instruction in Prostate Magnetic Resonance Imaging Interpretation Using Prostate Imaging and Reporting Data System Version 2: Effect for Novice Readers. AB - PURPOSE: To assess the effect on reader performance of an interactive case-based online tutorial for prostate magnetic resonance imaging (MRI) interpretation using Prostate Imaging and Reporting Data System (PI-RADS). METHODS: An educational website was developed incorporating scrollable multiparametric prostate MRI examinations with annotated solutions based on PI-RADS version 2. Three second-year radiology residents evaluated a separate set of 60 prostate MRI examinations both before and after review of the online case material, identifying and scoring dominant lesions. These 60 examinations included 30 benign cases and 30 cases with a dominant lesion demonstrating Gleason score >=3 + 4 tumor on fusion-targeted biopsy. The readers' pooled performance was compared between the 2 sessions using logistic regression and Wilcoxon signed rank tests. RESULTS: All readers completed the online material within four-hours. Review of the online material significantly improved sensitivity (from 57.8%-73.3%, P = 0.003) and negative predictive value (from 69.2%-78.2%, P = 0.049), but not specificity (from 70.0%-67.8%, P = 0.692) or positive predictive value (from 59.6%-64.7%, P = 0.389). Reader confidence (1-10 scale; 10 = maximal confidence) also improved significantly (from 5.6 +/- 2.7 to 6.3 +/- 2.6, P = 0.026). However, accuracy of assigned PI-RADS scores did not improve significantly (from 45.5%-53.3%, P = 0.149). CONCLUSION: An online interactive case-based website in prostate MRI interpretation improved novice readers' sensitivity and negative predictive value for tumor detection, as well as readers' confidence. This online material may serve as a resource complementing existing traditional methods of instruction by providing a more flexible educational experience among a larger volume of learners. However, further more targeted educational initiatives regarding the proper application of PI-RADS remain warranted. PMID- 29428184 TI - Macrolide resistance in yaws. PMID- 29428183 TI - Re-emergence of yaws after single mass azithromycin treatment followed by targeted treatment: a longitudinal study. AB - BACKGROUND: Yaws is a substantial cause of chronic disfiguring ulcers in children in at least 14 countries in the tropics. WHO's newly adopted strategy for yaws eradication uses a single round of mass azithromycin treatment followed by targeted treatment programmes, and data from pilot studies have shown a short term significant reduction of yaws. We assessed the long-term efficacy of the WHO strategy for yaws eradication. METHODS: Between April 15, 2013, and Oct 24, 2016, we did a longitudinal study on a Papua New Guinea island (Lihir; 16 092 population) in which yaws was endemic. In the initial study, the participants were followed for 12 months; in this extended follow-up study, clinical, serological, and PCR surveys were continued every 6 months for 42 months. We used genotyping and travel history to identify importation events. Active yaws confirmed by PCR specific for Treponema pallidum was the primary outcome indicator. The study is registered with ClinicalTrials.gov, number NCT01955252. FINDINGS: Mass azithromycin treatment (coverage rate of 84%) followed by targeted treatment programmes reduced the prevalence of active yaws from 1.8% to a minimum of 0.1% at 18 months (difference from baseline -1.7%, 95% CI, -1.9 to -1.4; p<0.0001), but the infection began to re-emerge after 24 months with a significant increase to 0.4% at 42 months (difference from 18 months 0.3%, 95% CI 0.1 to 0.4; p<0.0001). At each timepoint after baseline, more than 70% of the total community burden of yaws was found in individuals who had not had the mass treatment or as new infections in non-travelling residents. At months 36 and 42, five cases of active yaws, all from the same village, showed clinical failure following azithromycin treatment, with PCR-detected mutations in the 23S ribosomal RNA genes conferring resistance to azithromycin. A sustained decrease in the prevalence of high-titre latent yaws from 13.7% to <1.5% in asymptomatic children aged 1-5 years old and of genetic diversity of yaws strains from 0.139 to less than 0.046 between months 24 and 42 indicated a reduction in transmission of infection. INTERPRETATION: The implementation of the WHO strategy did not, in the long-term, achieve elimination in a high-endemic community mainly due to the individuals who were absent at the time of mass treatment in whom yaws reactivated; repeated mass treatment might be necessary to eliminate yaws. To our knowledge, this is the first report of the emergence of azithromycin-resistant T p pertenue and spread within one village. Communities' surveillance should be strengthened to detect any possible treatment failure and biological markers of resistance. FUNDING: ISDIN laboratories, Newcrest Mining Limited, and US Public Health Service National Institutes of Health. PMID- 29428185 TI - Lack of correlation between left ventricular outflow tract velocity time integral and stroke volume index in mechanically ventilated patients. AB - OBJECTIVE: To assess the correlation between left ventricular outflow tract velocity time integral (LVOT VTI) and stroke volume index (SVI) calculated by thermodilution methods in ventilated critically ill patients. DESIGN: A prospective, descriptive, multicenter study was performed. SETTING: Five intensive care units from university hospitals. PATIENTS: Patients older than 17 years needing mechanical ventilation and invasive hemodynamic monitoring were included. INTERVENTIONS: LVOT VTI was measured by pulsatile Doppler echocardiography. Calculations of SVI were performed through a floating pulmonary artery catheter (PAC) or a Pulse index Contour Cardiac Output (PiCCO(r)) thermodilution methods. MAIN VARIABLES: The relation between LVOT VTI and SVI was tested by linear regression analysis. RESULTS: One hundred and fifty-six paired measurements were compared. Mean LVOT VTI was 20.83+/-4.86cm and mean SVI was 41.55+/-9.55mL/m2. Pearson correlation index for these variables was r=0.644, p<0.001; ICC was 0.52 (CI 95% 0.4-0.63). When maximum LVOT VTI was correlated with SVI, Pearson correlation index was r=0.62, p<0.001. Correlation worsened for extreme values, especially for those with higher LVOT VTI. CONCLUSIONS: LVOT VTI could be a complementary hemodynamic evaluation in selected patients, but does not eliminate the need for invasive monitoring at the present time. The weak correlation between LVOT VTI and invasive monitoring deserves additional assessment to identify the factors affecting this disagreement. PMID- 29428186 TI - Laminin peptide YIGSR enhances epidermal development of skin equivalents. AB - Since the use of animal experimentation is restricted with regard to cosmetic materials, alternative in vitro models such as skin equivalents (SEs) are needed. Laminin is one of the major non-collagenous glycoproteins. The pentapeptide YIGSR (Tyr-Ile-Gly-Ser-Arg) is a functional motif of laminin that binds to the laminin receptor. In the present study, we examined whether YIGSR could improve the reconstruction of SEs. YIGSR has no effects on monolayer cell proliferation of CCD25-Sk fibroblasts or HaCaT keratinocytes. Interestingly, YIGSR decreased TGF beta1 levels, although it promoted type Iota collagen synthesis in CCD25-Sk cells. In HaCaT cells, YIGSR decreased the expression of involucrin and loricrin, which are differentiation markers. Furthermore, YIGSR increased levels of proliferating cell nuclear antigen (PCNA), p63, and integrin alpha6, and decreased involucrin in SE models. In addition, two models containing YIGSR (mixed with dermal equivalents or added into media) did not show any differences in expression levels of PCNA, p63, integrin alpha6, and involucrin. Therefore, YIGSR is a useful agent for reconstruction of SEs, independent of its method of application. These results indicate that YIGSR stimulates epidermal proliferation and basement membrane formation while inhibiting keratinocyte differentiation of SEs. Taken together, these results indicate that YIGSR promotes the reconstruction of SEs, potentially via decreased TGF-beta1 levels and consequent inhibition of epidermal differentiation. PMID- 29428187 TI - Left main true bifurcation PCI: In the aftermath of DKCRUSH V trial: The case for modifying Medina terminology to include complexity of LMCA anatomy. PMID- 29428188 TI - "I'm Not a Spiritual Person." How Hope Might Facilitate Conversations About Spirituality Among Teens and Young Adults With Cancer. AB - CONTEXT: Supporting patients' spiritual needs is central to palliative care. Adolescents and young adults (AYAs) may be developing their spiritual identities; it is unclear how to navigate conversations concerning their spiritual needs. OBJECTIVES: To 1) describe spiritual narratives among AYAs based on their self identification as religious, spiritual, both, or neither and 2) identify language to support AYAs' spiritual needs in keeping with their self-identities. METHODS: In this mixed-methods, prospective, longitudinal cohort study, AYAs (14-25 years old) with newly diagnosed cancer self-reported their "religiousness" and "spirituality." One-on-one, semistructured interviews were conducted at three time points (within 60 days of diagnosis, six to 12 months, and 12-18 months later) and included queries about spirituality, God/prayer, meaning from illness, and evolving self-identity. Post hoc directed content analysis informed a framework for approaching religious/spiritual discussions. RESULTS: Seventeen AYAs (mean age 17.1 years, SD = 2.7, 47% male) participated in 44 interviews. Of n = 16 with concurrent survey responses, five (31%) self-identified as both "religious and spiritual," five (31%) as "spiritual, not religious," one (6%) as "religious, not spiritual," and five (31%) as neither. Those who endorsed religiousness tended to cite faith as a source of strength, whereas many who declined this self-identity explicitly questioned their preexisting beliefs. Regardless of self-identified "religiousness" or "spirituality," most participants endorsed quests for meaning, purpose, and/or legacy, and all included constructs of hope in their narratives. CONCLUSION: AYA self-identities evolve during the illness experience. When words such as "religion" and "spirituality" do not fit, explicitly exploring hopes, worries, meaning, and changing life perspectives may be a promising alternative. PMID- 29428189 TI - Training in Global Palliative Care Within Palliative Medicine Specialist Training Programs: A Moral Imperative. PMID- 29428190 TI - [Dermato-urology: Male genital lesions urologist should know]. AB - : This article aimed to gather male genital dermatoses that may lead to consult a urologist, except pre-neoplastic or neoplastic lesion. METHOD: This review is based on a research on Pubmed and EM-consult database, in English and in French, using the following key terms "male genital dermatoses", "male genital lesions", "balanitis", "balanoposthitis", "dermatoses des organes genitaux externes masculines", "lesions des organes genitaux externes de l'homme", "balanoposthites". RESULTS: It highlights normal morphological aspects, acute balanoposthitis (nonspecific, infectious, allergic, irritative and traumatic), common skin disease localized to male genital and male genital specific dermatoses. CONCLUSION: Any suspicious, fixed, must lead to a skin biopsy. PMID- 29428191 TI - [The biological rationale for immunotherapy in cancer]. AB - INTRODUCTION: Immunotherapy aims to promote the immune system's activity against malignant cells by stimulating the response to several tumor antigens. STATE OF THE ART: Immunosurveillance may adjust the immunogenicity of tumors. To be effective, immunity must induce the specific activation of CD4+ and CD8+ T lymphocytes, as well as activation of innate immunity. Activator and inhibitory costimulatory molecules regulate T lymphocyte activation at immunity checkpoints such as PD-1/PD-L1 and CTLA-4. Adaptive immune resistance confers tumour resistance to immunosurveillance through these immune checkpoints. PERSPECTIVES: Approaches involving the combination of several immunotherapies with each other or with chemotherapy and radiotherapy and antibodies against other molecules of costimulation are under development. The development of biomarkers, which can select a targeted population and predict therapeutic response, represents a major challenge. Tumour high-throughput sequencing could refine "immunoscore". Intratumoral T cell receptor seems to represent a promising biomarker. CONCLUSIONS: Numerous challenges still remain in developing research approaches for the development of immunotherapies. PMID- 29428192 TI - Expanding access to primary healthcare for women through a microfinance institution: A case study from rural Guatemala. AB - The utilization of existing social networks is increasingly being recognized as a powerful strategy for delivering healthcare services to underserved populations in low- and middle-income countries. In Guatemala, multiple barriers prevent access to healthcare services for rural and indigenous populations, and strategies for delivering healthcare in more efficient ways are needed. The case study we describe here is a unique collaboration between a microfinance institution (Friendship Bridge) and a primary care organization (Wuqu' Kawoq | Maya Health Alliance) to scale up healthcare through an existing lending borrowing social network. The program provides primary care services to female clients of Friendship Bridge in rural areas of Guatemala, with nurses working as frontline primary care providers, providing door-to-door healthcare services. Over the first 22 months of the project, we have reached over 3500 of Friendship Bridge's clients, with overall high acceptance of services. All clinical documentation and program monitoring and evaluation are done through audit trails within an electronical medical record system, which improves efficiency and lowers the associated time and resources costs. We utilize quality improvement methodologies to aid in decision making and programmatic adjustments scale up. These strategies have allowed us to expand services rapidly under challenging geographic and logistical constraints, while concurrently iteratively improving staff training and supervision, clinical care, and client engagement processes. PMID- 29428193 TI - Interactions between RNAP III transcription machinery and tRNA processing factors. AB - Eukaryotes have at least three nuclear RNA polymerases to carry out transcription. While RNA polymerases I and II are responsible for ribosomal RNA transcription and messenger RNA transcription, respectively, RNA Polymerase III transcribes approximately up to 300 nt long noncoding RNAs, including tRNA. For all three RNAPs, the nascent transcripts generated undergo extensive post transcriptional processing. Transcription of mRNAs by RNAP II and their processing are coupled with the aid of the C-terminal domain of the RNAP II. RNAP I transcription and the processing of its transcripts are co-localized to the nucleolus and to some extent, rRNA processing occurs co-transcriptionally. Here, I review the current evidence for the interaction between tRNA processing factors and RNA polymerase III. These interactions include the moonlighting functions of tRNA processing factors in RNAP III transcription and the indirect effect of tRNA transcription levels on tRNA modification machinery. PMID- 29428194 TI - Malignant transformation of Taiwanese patients with oral leukoplakia: A nationwide population-based retrospective cohort study. AB - BACKGROUND/PURPOSE: Oral leukoplakia (OL) is one of the clinically diagnosed oral potentially malignant disorders (OPMDs) with an increased risk of oral cancer development. In this study, we investigated the malignant transformation of OL in Taiwanese population. METHODS: A retrospective cohort study was analyzed from Taiwan's National Health Insurance Research Database. A comparison cohort was randomly frequency-matched with the OL cohort according to age, sex, and index year. Oral submucous fibrosis (OSF) and oral lichen planus (OLP) were further stratified to evaluate the possible synergistic effects for OL-associated malignant transformation. RESULTS: In this cohort, 102 (5.374%) of 1898 OL patients were observed to transform into oral cancer. The malignant transformation rate was 26.40-fold in the OL cohort than in the comparison cohort after adjustment (95% confidence intervals 18.46-37.77). To further stratify with OSF and OLP, OL with OSF (58.38; 95% confidence intervals 34.61-98.50) and OL with OLP (36.88; 95% confidence intervals 8.90-152.78) had higher risk of malignant transformation rate than OL alone (27.01; 95% confidence intervals 18.91-38.59). The Kaplan-Meier plot revealed the free of malignant transformation rate was significant over the 13 years follow-up period (log-rank test, p < 0.001). CONCLUSION: OL patients exhibited a significantly higher risk of malignant transformation than those without OL. In addition, both OSF and OLP could enhance malignant transformation in patients with OL. However, further studies are required to identify the histopathological and clinical parameters in the pathogenesis of malignant transformation among OPMDs. PMID- 29428195 TI - Ambulance traffic accidents in Taiwan. AB - BACKGROUND/PURPOSE: Ambulance traffic accidents (ATAs) are the leading cause of occupation-related fatalities among emergency medical service (EMS) personnel. We aim to use the Taiwan national surveillance system to analyze the characteristics of ATAs and to assist EMS directors in developing policies governing ambulance operations. METHODS: A retrospective, cross-sectional and largely descriptive study was conducted using Taiwan national traffic accidents surveillance data from January 1, 2011 to October 31, 2016. RESULTS: Among the 1,627,217 traffic accidents during the study period, 715 ATAs caused 8 deaths within 24 h and 1844 injured patients. On average, there was one ATA for every 8598 ambulance runs. Compared to overall traffic accidents, ATAs were 1.7 times more likely to result in death and 1.9 times more likely to have injured patients. Among the 715 ATAs, 8 (1.1%) ATAs were fatal and 707 (98.9%) were nonfatal. All 8 fatalities were associated with motorcycles. The urban areas were significantly higher than the rural areas in the annual number of ATAs (14.2 +/- 7.3 [7.0-26.7] versus 3.1 +/- 1.9 [0.5-8.4], p = 0.013), the number of ATA-associated fatalities per year (0.2 +/- 0.2 [0.0-0.7] versus 0.1 +/- 0.1 [0.0-0.2], p = 0.022), and the annual number of injured patients (who needed urgent hospital visits) in ATAs (19.4 +/- 7.3 [10.5-30.9] versus 5.2 +/- 3.8 [0.9-15.3], p < 0.001). CONCLUSION: The ATA associated fatality rate in Taiwan was high, and all fatalities were associated with motorcycles. ATAs in a highly motorcycle-populated area may require further investigation. An ambulance traffic accident reporting system should be built to provide EMS policy guidance for ATA reduction and outcome improvements. PMID- 29428196 TI - Evaluation of cellular immunogenicity of recombinant cytochrome p450 cyp141 protein of Mycobacterium tuberculosis in human and mouse model. AB - Mycobacterium tuberculosis (Mtb) is still considered one of the unsolved problems for the World Health Organization Identifying and selecting an immunogenic antigen capable of generating specific immune responses is generally the goal of all studies being carried out in to designing new vaccines. Accordingly, the present study was conducted to evaluate the immunogenicity of a M. tuberculosis recombinant protein which exist in the regions of the bacterium genome and may be an immunogenic protein. Immunogenicity of purified proteins was measured by PBMC and mouse spleen lymphocytes culturing methods using ELISA after an appropriate amount of time of incubation with Recombinant cytochrome P450 CYP141 protein. Cellular immune responses were determined and compared by measuring IFN-gamma and IL4 in human, and mouse groups. The results revealed a high level of IFN-gamma in PPD + individuals and the mice immunized with protein and adjuvant. Recombinant cytochrome P450 CYP141 protein proved capable of generating an immune response in mice and people with a history of previous encounters with Mycobacterium tuberculosis bacteria. It, could be considered a tuberculosis vaccine candidate in order to induce a specific effective immune response in both mice and humans. PMID- 29428197 TI - Therapeutic Impact of Statins on the Lipid Profile and Cardiovascular Risk in Patients With Systemic Lupus Erythematosus: Systematic Review of the Literature and a Meta-analysis. AB - BACKGROUND: There is strong evidence of a rise in cardiovascular risk in patients suffering from autoimmune diseases, especially in those with Sistemic Lupus Erythematosus. Until now, there are a few trials that assess the potencial benefit of statins on the incidence of cardiovascular events and on lipid profile of patients with SLE. This evidence has not been synthesized and assessed altogether. METHODS: We performed a search in databases of literature published until August of 2016 (Embase, MEDLINE, Cochrane Library, SciELO, Clinical Evidence, DynaMed, Cochrane Central Register of Controlled Trials, LILACS), identifying controlled clinical trials that could estimate the impact of statins on mortality, cardiovascular events, C-reactive protein and lipid profile in patients with Systemic Lupus Erythematosus. The quality of the information available was assessed with a meta-analysis, using a random effects model, employing the RevMan 5.3 software. RESULTS: 6 trials and 412 patients were included in the analysis. The use of statins in patients with SLE was found to significantly reduce the levels of serum total cholesterol (mean difference [MD] 31,4 mg/dL; CI 95% -43,0; -19,9), and serum low density cholesterol (MD -31,4 mg/dL; IC 95% -43,0; -19,9), but had no impact on levels of serum triglycerides (MD 4 mg/dL; IC 95% 2,49; 6,21) and C-reactive protein (MD -0,78; IC 95% -1,43; 0,13). No evidence was found about the impact on the risk of mortality or cardiovascular events. CONCLUSION: Statins have a significant effect on the levels of serum total cholesterol, LDL cholesterol and C-reactive protein, however, more randomized controlled trials with long-term follow-up are necessary to assess the impact on mortality and cardiovascular risk. PMID- 29428198 TI - Sex-specific associations of serum uric acid with metabolic syndrome in Chinese rural population: The RuralDiab study. AB - BACKGROUND: We explored the association between serum uric acid (SUA) and metabolic syndrome (MetS) in Chinese rural adults. METHODS: A total of 16,577 subjects (6354 men and 10,223 women) were from the RuralDiab study. SUA concentration was measured by the enzymatic colorimetric method. A meta-analysis including 12 eligible studies focused on SUA and MetS was preformed to confirm the findings of the cross-sectional study. RESULTS: After adjustment for age, educational level, and other covariates, the odds ratio (ORs) for MetS increased smoothly with the increasing SUA concentration in both sexes (P for no-linear trend > 0.05). The adjusted ORs of MetS comparing the fourth and firstly quartiles were 3.11 [95% CI: 2.58-3.74] in men and 3.64 [95% CI: 3.22-4.11] in women (Ptrend < 0.001). In continuous analysis, each 1 mg/dl increment in SUA concentration was significantly associated with a 41% increased risk of MetS in men and 62% in women. The meta-analysis validated the positive association between SUA and MetS (pooled OR: Men, 1.80 [95% CI: 1.57-2.07]; Women, 2.46 [95% CI: 1.95-3.12]). CONCLUSION: SUA concentration was positively with the prevalence of MetS in Chinese rural population, and more studies are needed to explore the mechanisms of the relationship. WHAT IS ALREADY KNOWN ON THIS TOPIC?: Previous studies have explored the association between serum uric acid and metabolic syndrome, but evidence on the strength and consistency of the association remains uncertain and limited, especially in rural population. In addition, the epidemiological research and meta-analysis on the association have not been reported. WHAT DOES THIS STUDY ADD?: The results of this study showed that serum uric acid was significantly associated with metabolic syndrome and its components in Chinese rural population. Furthermore, the findings demonstrated that the significant associations varied across sex. In addition, the results of epidemiological research were similar with the meta-analysis, which demonstrates the credible of the results of the epidemiology research. PMID- 29428199 TI - Elevated soluble ST2 concentration may involve in the progression of atrial fibrillation. AB - BACKGROUND: The aim of this study is to investigate the value of soluble suppression of tumorigenicity 2 (sST2) in Atrial fibrillation (AF) patients' risk prediction. METHODS: Healthy people (n = 60) and AF patients (n = 194) were consecutively enrolled into this project. RESULTS: In the health group, the mean age was 54 y (55% males). Serum median concentration of sST2 in healthy individuals was 17.04 ng/ml. In the AF patients group, the mean age was 61 years, and 64% were males. Median sST2 value was 21.69 ng/ml. According to subgroup analysis, median sST2 value of paroxysmal and persistent AF patients was 19.82 ng/ml and 24.15 ng/ml, respectively. Emergency AF patients showed much higher median sST2 concentration than AF outpatients (41.59 ng/ml vs. 20.53 ng/ml, p < 0.01). By multiple linear regression analysis adjusted for age and sex, heart failure (HF) and BNP strongly associated with sST2 concentration. After healthy people and AF patients with HF excluded, whether emergency visit or not become a patent predictor of sST2 concentration (n = 172). CONCLUSION: sST2 is probably an objective biomarker that can predict AF patients' risk of emergency admission or HF. Elevated sST2 concentration may involve in the progression of AF. PMID- 29428200 TI - ER stress-mediated autophagic cell death induction through methylated beta cyclodextrins-threaded acid-labile polyrotaxanes. AB - Autophagy plays a pivotal role in the development and prevention of numerous diseases, and the induction of autophagy is regarded as a potential therapeutic approach for intractable diseases. In this study, the induction of autophagy by methylated beta-cyclodextrins (Me-beta-CDs)-threaded acid-labile polyrotaxane (Me PRX) that can release the threaded Me-beta-CDs in response to acidic pH in lysosomes was investigated. We hypothesized that the Me-beta-CDs released from the Me-PRX interact with the membrane of organelles and cause autophagy. The Me PRX preferentially accumulated in endoplasmic reticulum (ER) and caused ER stress, which was confirmed by gene expression analysis and the expression of an ER stress-marker protein. Accompanying the ER stress, cells treated with Me-PRX showed autophagy, which was not observed in cells treated with non-labile Me-PRX, other chemically modified PRXs, or free Me-beta-CD. Furthermore, the Me-PRX treatment induced autophagic cell death and caused cell death even in apoptosis resistant cells. Overall, this study demonstrates that the acid-labile Me-PRX induces ER stress-mediated autophagic cell death, and the Me-PRX would be a promising candidate to induce effective cell death in apoptosis-resistant malignant tumors. PMID- 29428201 TI - The use of gold nanorods as a new vaccine platform against schistosomiasis. AB - Schistosomiasis is an important parasitic disease affecting >207 million people in 76 countries around the world and causing approximately 250,000 deaths per year. At present, the main strategy adopted for the control of schistosomiasis is the use of safe chemotherapy, such as praziquantel. However, the high rates of reinfection after treatment restrict the use of this treatment approach and assume the need for other forms of control such as vaccination. Sm29 is a protein that is localized in the Schistosoma mansoni tegument of adult worms and schistosomula and is considered a powerful vaccine candidate. Because of the chemical, physical and immunological characteristics of nanoparticles, nanocarriers have received increasing attention. In the field of nanotechnology, gold nanorods are considered potential vaccine carriers. In this study, we bound S. mansoni rSm29 protein to gold nanorods either directly or by cysteamine functionalization. When the worm burden was evaluated, the AuNRs-NH2-rSm29 group of immunized mice showed the best protection level (34%). Following AuNRs-NH2 rSm29 immunization, we observed a Th1 immunological response in mice with higher production of IFN-gamma, mainly by CD4+ and CD8+ T cells. Furthermore, AuNRs-NH2 rSm29 could activate dendritic cells in vitro, enhancing MHCII and MHCI expression and the production of IL-1beta in a NLRP3-, ASC- and Caspase-1 dependent manner. In summary, our findings support the use of nanorods as an immunization strategy in vaccine development against infectious diseases. PMID- 29428202 TI - PET-SUV Max and Upstaging of Lung Cancer. AB - BACKGROUND: Lung cancers managed surgically with curative intent are sometimes upstaged postoperatively. The potential contributions from surgical waiting time and primary tumour 18F-FDG avidity on positron emission tomography (PET)/computed tomography (CT) are unknown. METHODS: We reviewed the records of 153 Royal Adelaide Hospital surgical patients with primary lung cancers from 2013 to 2016 who had preoperative staging combining CT, 18F-FDG PET/CT and biopsy. Subjects were divided into two cohorts: postoperative Tumour, Node, Metastases (TNM) upstaged (US) and not upstaged (UN). The parameters of standardised uptake value (SUV max), pre-scan blood glucose level (BGL), the time interval between staging and surgery were analysed using a two-tailed Mann-Whitney U test. RESULTS: Subjects were aged 31 to 85 years; 75 were male. Ninety-three had adenocarcinoma (AC), 42 had squamous cell carcinoma (SCC). Sixty-four were upstaged after surgery, 40 AC and 18 SCC. For AC, US SUV max was significantly higher (mean US 6.4 (SD 4.6) vs. UN 4.6 (SD 3.4), p=0.03) but not time to surgery (mean US 55 (SEM 7.1) vs. UN 71 (SEM 14.8) days p=0.74). Upstaged were mainly T (imaging and histopathology discordance) and N (unexpected mediastinal or hilar nodal metastases). For SCC, US vs. UN SUV max (mean US 12.0 (SD 5.6) vs. UN 9.4 (SD 5.6), p=0.08) and time to surgery (mean US 48 (SEM 5.3) vs. UN 47 (SEM 5.0) days p=0.66) were not significantly different. Standardised uptake value max and surgical waiting time were not analysed for other tumour types due to small numbers. Pre-PET BGL US vs. UN was not significantly different for all (p=0.52), AC (p=0.32) and SCC (p=0.37) subjects, thus not a confounding factor. CONCLUSIONS: For lung cancers assigned to curative surgery, high primary tumour SUV max of AC but not SCC may predict surgical upstaging with implications for 18F-FDG PET/CT nodal assessments. Surgical waiting time appears not to be a predictor for both tumour types. PMID- 29428204 TI - Transmission disequilibrium of rs4809957 in type 2 diabetes mellitus families and its association with vitamin D deficiency: A family-based case-control study. AB - AIMS: Association between T2DM and vitamin D was found in many epidemiologic reports. And 24-hydroxylase encoded by CYP24A1 is the very enzyme that degrades the active vitamin D metabolite. We aimed to investigate the association between rs4809957 in CYP24A1 and T2DM, as well as vitamin D level. METHODS: A total of 419 pedigrees containing 1556 participants were included. T2DM diagnosis, 25(OH)D measurement and genotyping of rs4809957 were conducted for all the individual. Then association between rs4809957 and T2DM, as well as 25(OH)D level, was investigated by family-based association test (FBAT) and 1:1 matched case-control study. RESULTS: The FBAT results revealed that there was transmission disequilibrium for allele G in T2DM families by both additive model (Z = 2.183, P = 0.029049) and recessive model (Z = 2.236, P = 0.025347). Allele G was also associated with 25(OH)D level in both additive model (Z = 2.549, P = 0.010811) and dominant model (Z = 2.012, P = 0.044187). On the other hand, results of case control study suggested that vitamin D deficiency was a risk factor for T2DM (OR 1.987; 95%CI 1.331-2.964; P = 0.001). Further stratified analysis revealed that vitamin D deficiency increased T2DM risk in women (OR 2.347; 95%CI 1.373-4.012; P = 0.002), instead of men (OR 1.600; 95%CI 0.874-2.931; P = 0.127). In addition, T2DM patients with GG and AG genotypes were more susceptible to vitamin D deficiency than the control (P = 0.006 and P = 0.038, respectively). CONCLUSION: There was transmission disequilibrium for allele G of rs4809957 in T2DM families, which was linked to vitamin D deficiency. PMID- 29428203 TI - Outcomes of Obese and Morbidly Obese Patients Undergoing Percutaneous Coronary Intervention. AB - BACKGROUND: The risks of percutaneous coronary intervention (PCI) in obese and particularly morbidly obese patients remain uncertain. METHODS: 1082 consecutive patients were categorised as non-obese (NO, body mass index (BMI) <30kg/m2, n=688), obese (O, BMI 30-40kg/m2, n=354) or morbidly obese (MO, BMI >=40kg/m2, n=40). Demographic and procedural information was collated. Monte Carlo simulations modelled radiation dosimetric data. RESULTS: Obese and morbidly obese patients were younger (p=0.016), more frequently female (p=0.036), more frequently diabetic (p<0.0001), with better renal function (p<0.0001), and prior PCI (p=0.01). There was no difference in major adverse cardiovascular or cerebrovascular events (MACCE) (NO=1.2%, O=0.8%, MO=2.5%, p=NS), acute kidney injury, bleeding, length of stay, 30-day readmission or 30-day mortality. Obese and morbidly obese patients received increased contrast (NO=180 [150-230]mL, O=190 [160-250]mL, MO=200 [165-225]mL, p=0.016), dose area product (NO=75.56 [50.61-113.69]Gycm2, O=116.4 [76.11-157.82]Gycm2, MO=125.62 [92.22-158.81]Gycm2, p<0.0001), entrance air kerma (NO=1439.42 [977.0-2075.5]mGy, O=2111.63 [1492.0 3011.0]mGy, MO=2376.0 [1700.0-3234.42]mGy, p<0.0001), and peak skin dose (NO=1439.42 [977.0-2075.5], O=2111.63 [1492.0-3011.0], MO=2376.0 [1700.0 3234.42], p<0.0001). Effective radiation dose increased in obese patients (NO=20.9+/-14.9mSv, O=27.4+/-17.1mSv, MO=24.1+/-12.6mSv, p<0.0001 for NO vs O, p=0.449 for NO vs MO). CONCLUSIONS: Percutaneous coronary intervention can be performed in obese and morbidly obese patients without elevated risk for most clinical outcomes. However, radiation increases above levels that could cause both transient and late effects. Strategies should be pursued to minimise radiation dose. PMID- 29428205 TI - Biosimilars: Concepts and controversies. AB - Biosimilars are copies of reference biological drugs, developed as the patents for original biologicals expire. They are thus developed to replicate an original biological medicine just a generics are intended to replicate a chemically synthesized medicine; however, there are important technical and regulatory differences between the two. Unlike chemical drugs, molecular identity cannot generally be established for any two biological drugs. Accordingly, their pharmacological properties cannot be assumed to be the same. This is due to the complexity of the production of biologicals and to the presence of minor natural variations in the molecular structure (collectively known as microheterogeneity). Further, biological production yields slightly different versions of the drug over time, particularly when changes are introduced in the production process. In this case the prechange and postchange versions of the biological are analyzed in what is called a comparability exercise. The comparable versions thus validated are considered not to have any significant differences at the clinical level. Likewise, biosimilars are not identical copies but comparable versions of the original biological drug, also validated through a comparability exercise, although of a much broader scope. Although current knowledge about biosimilars has increased significantly, they still arise a number of controversies and misconceptions, particularly regarding issues like extrapolation of indications, immunogenicity and substitution. This review deals with concepts and controversies in the biosimilar field. PMID- 29428206 TI - Proprotein Convertase Subtilisin-Kexin type-9 (PCSK9) and triglyceride-rich lipoprotein metabolism: Facts and gaps. AB - After more than a decade of intense investigation, Pro-protein Convertase Subtilisin-Kexin type 9 (PCSK9) remains a hot topic of research both at experimental and clinical level. Interestingly PCSK9 is expressed in different tissues suggesting the existence of additional function(s) beyond the modulation of the Low-Density Lipoprotein (LDL) receptor in the liver. Emerging data suggest that PCSK9 might play a role in the modulation of triglyceride-rich lipoprotein (TGRL) metabolism, mainly Very Low-Density Lipoproteins (VLDL) and their remnants. In vitro, PCSK9 affects TGRLs production by intestinal cells as well as the catabolism of LDL receptor homologous and non-homologous targets such as VLDL receptor, CD36 and ApoE2R. However, the in vivo relevance of these findings is still debated. This review aims at critically discussing the role of PCSK9 on TGRLs metabolism with a major focus on the impact of its genetic and pharmacological modulation on circulating lipids and lipoproteins beyond LDL. PMID- 29428207 TI - Genome sequence of Streptomyces gilvigriseus MUSC 26T isolated from mangrove forest. AB - Streptomycetes remain as one of the important sources for bioactive products. Isolated from the mangrove forest, Streptomyces gilvigriseus MUSC 26T was previously characterised as a novel streptomycete. The high quality draft genome of MUSC 26T contained 5,213,277bp with G+C content of 73.0%. Through genome mining, several gene clusters associated with secondary metabolites production were revealed in the genome of MUSC 26T. These findings call for further investigations into the potential exploitation of the strain for production of pharmaceutically important compounds. PMID- 29428208 TI - Gender differences in tobacco use among U.S. Special Olympics athletes. AB - BACKGROUND: The rise in women's tobacco use and subsequent health complications has generated an increase in gender-related tobacco use research. However, no research has examined gender's influence on tobacco use among people with intellectual and developmental disabilities (IDD). OBJECTIVE: To examine 1) tobacco use prevalence rates among men and women with IDD, and 2) correlates of tobacco use among men and women with IDD. METHODS: This study examined gender differences in tobacco use among a sample of 3587 adult U.S. Special Olympics athletes who participated in health screenings from 2007 to 2014. The athletes were aged 18-89 (M = 32.86); 55.8% were male. Prevalence rates were calculated for men and women, and logistic regression analyses were conducted to examine tobacco use's association with age, blood pressure, body mass index, family member tobacco use, and daily fruit and vegetable consumption for each gender. RESULTS: Women's tobacco use prevalence was 4.1%, and men's was 9.4%. The only variable significantly associated with women's tobacco use was family member use, while men's tobacco use was associated with age, systolic blood pressure, family member tobacco use, and fruit and vegetable consumption. CONCLUSION: Results shed light on possible courses of action for reducing tobacco use among women and men with IDD. Further research is needed to develop effective prevention and intervention approaches appropriate for people with IDD. PMID- 29428209 TI - The structurally similar TRFH domain of TRF1 and TRF2 dimers shows distinct behaviour towards TIN2. AB - The telomere repeat binding-factor 1 and 2 (TRF1 and TRF2) proteins of the shelterin complex bind to duplex telomeric DNA as homodimers, and the homodimerization is mediated by their TRFH (TRF-homology) domains. We performed molecular dynamic (MD) simulations of the dimer forms of TRF1TRFH and TRF2TRFH in the presence/absence of the TIN2TBM (TIN2, TRF-interacting nuclear protein 2, TBM, TRF-binding motif) peptide. The MD results suggest that TIN2TBM is necessary to ensure the stability of TRF1TRFH homodimer but not the TRF2TRFH homodimer. In TRF1-TIN2-TRF2 complex, the peptide enhances the protein-protein interactions to yield a stable heterodimer. Both monomers in TRF1TRFH homodimer interact almost equally with the peptide, whereas in TRF2TRFH homodimer, monomer TRF2TRFH(M1) exhibits more dominant interactions than the TRF2TRFH(M2). The common residues of TRF1/2TRFH(M1) that form interactions with TIN2TBM in all peptide-bound systems originate from the H3 (helix) and L3 (loop) regions. Additionally, in the homodimer systems, residues of TRF1/2TRFH(M2) also interact with the peptide. The residue pair E71-K213 is responsible for different conformations of TRF1TRFH homodimers; specifically, this residue pair enhances the protein-peptide/protein interactions in peptide-bound/unbound systems, respectively. TRF1TRFH and TRF2TRFH proteins have a conserved but different interface responsible for the protein-protein/peptide interactions that exist in the corresponding dimers. PMID- 29428210 TI - Semiautomatic Assessment of the Terminal Ileum and Colon in Patients with Crohn Disease Using MRI (the VIGOR++ Project). AB - RATIONALE AND OBJECTIVES: The objective of this study was to develop and validate a predictive magnetic resonance imaging (MRI) activity score for ileocolonic Crohn disease activity based on both subjective and semiautomatic MRI features. MATERIALS AND METHODS: An MRI activity score (the "virtual gastrointestinal tract [VIGOR]" score) was developed from 27 validated magnetic resonance enterography datasets, including subjective radiologist observation of mural T2 signal and semiautomatic measurements of bowel wall thickness, excess volume, and dynamic contrast enhancement (initial slope of increase). A second subjective score was developed based on only radiologist observations. For validation, two observers applied both scores and three existing scores to a prospective dataset of 106 patients (59 women, median age 33) with known Crohn disease, using the endoscopic Crohn's Disease Endoscopic Index of Severity (CDEIS) as a reference standard. RESULTS: The VIGOR score (17.1 * initial slope of increase + 0.2 * excess volume + 2.3 * mural T2) and other activity scores all had comparable correlation to the CDEIS scores (observer 1: r = 0.58 and 0.59, and observer 2: r = 0.34-0.40 and 0.43-0.51, respectively). The VIGOR score, however, improved interobserver agreement compared to the other activity scores (intraclass correlation coefficient = 0.81 vs 0.44-0.59). A diagnostic accuracy of 80%-81% was seen for the VIGOR score, similar to the other scores. CONCLUSIONS: The VIGOR score achieves comparable accuracy to conventional MRI activity scores, but with significantly improved reproducibility, favoring its use for disease monitoring and therapy evaluation. PMID- 29428211 TI - An MRI-based Radiomics Classifier for Preoperative Prediction of Ki-67 Status in Breast Cancer. AB - RATIONALE AND OBJECTIVES: This study aims to investigate the value of a magnetic resonance imaging-based radiomics classifier for preoperatively predicting the Ki 67 status in patients with breast cancer. MATERIALS AND METHODS: We chronologically divided 318 patients with clinicopathologically confirmed breast cancer into a training dataset (n = 200) and a validation dataset (n = 118). Radiomics features were extracted from T2-weighted (T2W) and contrast-enhanced T1 weighted (T1+C) images of breast cancer. Radiomics feature selection and radiomics classifiers were generated using the least absolute shrinkage and selection operator regression analysis method. The correlation between the radiomics classifiers and the Ki-67 status in patients with breast cancer was explored. The predictive performances of the radiomics classifiers for the Ki-67 status were evaluated with receiver operating characteristic curves in the training dataset and validated in the validation dataset. RESULTS: Through the radiomics feature selection, 16 and 14 features based on T2W and T1+C images, respectively, were selected to constitute the radiomics classifiers. The radiomics classifier based on T2W images was significantly correlated with the Ki 67 status in both the training and the validation datasets (both P < .0001). The radiomics classifier based on T1+C images was significantly correlated with the Ki-67 status in the training dataset (P < .0001) but not in the validation dataset (P = .083). The T2W image-based radiomics classifier exhibited good discrimination for Ki-67 status, with areas under the receiver operating characteristic curves of 0.762 (95% confidence interval: 0.685, 0.838) and 0.740 (95% confidence interval: 0.645, 0.836) in the training and validation datasets, respectively. CONCLUSIONS: The T2W image-based radiomics classifier was a significant predictor of Ki-67 status in patients with breast cancer. Thus, it may serve as a noninvasive approach to facilitate the preoperative prediction of Ki-67 status in clinical practice. PMID- 29428212 TI - Computed Tomography Window Blending: Feasibility in Thoracic Trauma. AB - RATIONALE AND OBJECTIVES: This study aims to demonstrate the feasibility of processing computed tomography (CT) images with a custom window blending algorithm that combines soft-tissue, bone, and lung window settings into a single image; to compare the time for interpretation of chest CT for thoracic trauma with window blending and conventional window settings; and to assess diagnostic performance of both techniques. MATERIALS AND METHODS: Adobe Photoshop was scripted to process axial DICOM images from retrospective contrast-enhanced chest CTs performed for trauma with a window-blending algorithm. Two emergency radiologists independently interpreted the axial images from 103 chest CTs with both blended and conventional windows. Interpretation time and diagnostic performance were compared with Wilcoxon signed-rank test and McNemar test, respectively. Agreement with Nexus CT Chest injury severity was assessed with the weighted kappa statistic. RESULTS: A total of 13,295 images were processed without error. Interpretation was faster with window blending, resulting in a 20.3% time saving (P < .001), with no difference in diagnostic performance, within the power of the study to detect a difference in sensitivity of 5% as determined by post hoc power analysis. The sensitivity of the window-blended cases was 82.7%, compared to 81.6% for conventional windows. The specificity of the window-blended cases was 93.1%, compared to 90.5% for conventional windows. All injuries of major clinical significance (per Nexus CT Chest criteria) were correctly identified in all reading sessions, and all negative cases were correctly classified. All readers demonstrated near-perfect agreement with injury severity classification with both window settings. CONCLUSIONS: In this pilot study utilizing retrospective data, window blending allows faster preliminary interpretation of axial chest CT performed for trauma, with no significant difference in diagnostic performance compared to conventional window settings. Future studies would be required to assess the utility of window blending in clinical practice. PMID- 29428213 TI - Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs. AB - Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We translated this model to the Gottingen minipig by administering lactacystin into the medial forebrain bundle (MFB). Minipigs underwent positron emission tomography (PET) imaging with (+)-alpha-[11C]dihydrotetrabenazine ([11C]DTBZ), a marker of vesicular monoamine transporter 2 availability, at baseline and three weeks after the unilateral administration of 100 MUg lactacystin into the MFB. Compared to their baseline values, minipigs injected with lactacystin showed on average a 36% decrease in ipsilateral striatal binding potential corresponding to impaired presynaptic dopamine terminals. Behaviourally, minipigs displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs. In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies with translatability to human PD. PMID- 29428214 TI - The effects of bilateral, continuous, and chronic Deep Brain Stimulation of the medial forebrain bundle in a rodent model of depression. AB - BACKGROUND: Clinical trials of supra-lateral medial forebrain bundle (MFB) Deep Brain Stimulation (DBS) in treatment resistant major depressive patients have shown rapid and long-term benefits. OBJECTIVE/HYPOTHESIS: The study used Flinders Sensitive Line (FSL) rats with previously identified depressive-like phenotype to assess the range of behavior modification achieved by MFB DBS. METHODS: Male FSL and wild-type Sprague-Dawley rats as Controls were tested on mood/anxiety/exploration, cognitive and motor behaviors. The animals were implanted with bipolar stimulation electrodes in the MFB, and recovery was followed by 10 days of bilateral, chronic and continuous stimulation. RESULTS: Weight dynamics was assessed continuously and indicated similar growth rates although the FSL rats weighed approximately 20-25% less. MFB DBS had no impact on ultrasound calls emitted and the FSL rats continued to vocalize significantly less in the positive affect frequency compared to controls. Similarly, stimulation did not influence the FSL's exploration level (Elevated Plus Maze), nor locomotion (Open Field), although it reduced their freezing behavior (Open Field). Importantly, MFB DBS improved cognitive performance (Double-H) compared to Controls by reducing the time required and the number of errors committed to complete a spatial task. CONCLUSION: MFB DBS in the FSL animals selectively affected certain types of behaviors. Exploration and vocalization remained unaltered, but cognitive performance such as speed and precision of memory recall improved compared to unstimulated and stimulated controls. Future studies should focus on the mechanisms of action of MFB DBS, and in particular on the role of dopamine in the stimulation-dependent phenotype changes. PMID- 29428215 TI - Spinal PKC activation - Induced neuronal HMGB1 translocation contributes to hyperalgesia in a bone cancer pain model in rats. AB - Bone cancer pain (BCP) remains a serious complication of malignancy, which is an intractable clinical problem due to the gap in knowledge of its underlying mechanisms. Recent studies have demonstrated that the major involvement of neuroinflammation, particularly high-mobility group box 1 (HMGB1), which was identified as a late mediator of inflammation, in a number of pain conditions. However, the underlying mechanisms and functions of HMGB1 release in spinal cord, and its contributions to the development of BCP as well, are poorly understood. In the present study, we examined the theory that PKC activation lead to nuclear translocation and cytosolic HMGB1 secretion, which subsequently induces spinal neuro inflammatory responses (cytokine release) causing hyperalgesia. Our results showed that PKC activation and HMGB1 release in spinal neurons as well as mechanical allodynia in BCP rats, were all attenuated by intrathecal administration of the PKC inhibitor Go6983 and aggravated by its activator PMA. Intrathecal administration of anti-HMGB1 antibody also alleviated hypersensitivity caused by BCP. Meanwhile, phospho-PKC and cellular HMGB1 were found co-localized in neurons, but not in microglia and astrocytes, of the spinal dorsal horns of tumor-bearing rats. Additionally, we found that HMGB1 translocation from nuclei to cytoplasm may be the consequence of PKC translocation into the nuclei, which occurred 9 days after tumor inoculation. Total p-HMGB1 as well as nuclear and cytoplasmic HMGB1 expression levels were tested in response to broad-spectrum PKC inhibitor Go6983 or activator PMA in BCP rats. Together, these findings suggest that bone cancer related hyperalgesia is driven by PKC induced phosphorylation of HMGB1, which results in its translocation from the nucleus, and releasing from the cytosol of the dorsal horn, and the activation of spinal pro-inflammatory mediators. PMID- 29428216 TI - Corrigendum to "Elucidating the weak protein-protein interaction mechanisms behind the liquid-liquid phase separation of a mAb solution by different types of additives" [Eur. J. Pharm. Biopharm. 120 (2017) 1-8]. PMID- 29428217 TI - Oxidative stress, caspase-3 activation and cleavage of ROCK-1 play an essential role in MeHg-induced cell death in primary astroglial cells. AB - Methylmercury is a toxic environmental contaminant that elicits significant toxicity in humans. The central nervous system is the primary target of toxicity, and is particularly vulnerable during development. Rho-associated protein kinase 1 (ROCK-1) is a major downstream effector of the small GTPase RhoA and a direct substrate of caspase-3. The activation of ROCK-1 is necessary for membrane blebbing during apoptosis. In this work, we examined whether MeHg could affect the RhoA/ROCK-1 signaling pathway in primary cultures of mouse astrocytes. Exposure of cells with 10 MUM MeHg decreased cellular viability after 24 h of incubation. This reduction in viability was preceded by a significant increase in intracellular and mitochondrial reactive oxygen species levels, as well as a reduced NAD+/NADH ratio. MeHg also induced an increase in mitochondrial-dependent caspase-9 and caspase-3, while the levels of RhoA protein expression were reduced or unchanged. We further found that MeHg induced ROCK-1 cleavage/activation and promoted LIMK1 and MYPT1 phosphorylation, both of which are the best characterized ROCK-1 downstream targets. Inhibiting ROCK-1 and caspases activation attenuated the MeHg-induced cell death. Collectively, these findings are the first to show that astrocytes exposed to MeHg showed increased cleavage/activation of ROCK-1, which was independent of the small GTPase RhoA. PMID- 29428218 TI - Yoga in the Third Trimester May Reduce Labor Pain, Duration of Labor, and Risk of Cesarean Section. PMID- 29428219 TI - Capillary liquid chromatography-ion trap-mass spectrometry methodology for the simultaneous quantification of four angiotensin-converting enzyme-inhibitory peptides in Prunus seed hydrolysates. AB - Prunus genus fruit seeds are sources of highly angiotensin-I-converting enzyme (ACE)-inhibitory peptides. The presence of peptides IYSPH, IYTPH, IFSPR, and VAIP seems to be related to this activity but no previous work has demonstrated the direct relationship between the concentration of these peptides and the antihypertensive activity of hydrolysates. This work describes the development of a method for the quantification of these peptides in Prunus seeds hydrolysates based on capillary liquid chromatography-IT-MS/MS. The analytical characteristics of the method were evaluated through the study of the linearity, LOD, LOQ, presence of matrix interferences, precision, and recovery. The developed methodology was applied to the determination of the four peptides in seed hydrolysates from different Prunus genus fruits: peaches (7 varieties), plums (2 varieties), nectarines (3 varieties), apricots (2 varieties), cherry, and paraguayo. Peaches and plums seed hydrolysates yielded the highest concentrations of these peptides while paraguayo one showed the lowest concentrations. A high correlation between peptides concentrations was demonstrated suggesting that the four peptides could be released from the same seed proteins. PMID- 29428220 TI - On the effects of glasses on the SAR in human head resulting from wireless eyewear devices at phone call state. AB - This paper evaluates the effects of glasses on the specific absorption rates (SAR) in the human head resulting from wireless eyewear device at phone call state. We mainly concentrate on the SAR in the eyes since their sensitivity to electromagnetic fields (EMF). We find wearing glasses obviously alters the distribution and magnitude of the SAR. The maximal SAR in the ocular tissues with glasses is even 6 times more than that without glasses. Wearing glasses also induce the new hotspot in the eyes which may cause the biggest SAR increment in the ocular tissues. Moreover, calculated results indicate that the maximal SAR is sensitive to the size of glasses and radiation frequency. Because of this, we believe wearing glasses may possibly increase the risk of health hazard to eyes of wireless eyewear device user. These calculated results could be a valuable reference for the glasses designer to reduce the SAR in the eyes. PMID- 29428221 TI - The inflammatory microenvironment that promotes gastrointestinal cancer development and invasion. AB - Accumulating evidence has indicated that the inflammatory response is important for tumor promotion. However, the mechanisms underlying the induction of the inflammatory response in cancer tissues and how it promotes tumorigenesis remain poorly understood. We constructed several mouse models that develop inflammation associated gastric and intestinal tumors and examined the in vivo mechanisms of tumorigenesis. Of note, the activation of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway and Toll-like receptor (TLR)/MyD88 signaling cooperatively induced the generation of an inflammatory microenvironment, which is required for early-stage tumorigenesis. The inflammatory response in the stroma induces TNF alpha signaling in tumor cells, and the NOX1/ROS signaling pathway is activated downstream. In addition, the inflammatory pathway induces the expression of TLR2 in tumor epithelial cells. Both the NOX1/ROS and TLR2 pathways in tumor cells contribute to the acquisition and maintenance of stemness, which is an important tumor-promoting mechanism stimulated by inflammation. We also found that inflammation promotes malignant processes, like submucosal invasion, of TGF-beta signaling-suppressed tumor cells through the activation of MMP2 protease. Moreover, we showed that mutant p53 induces innate immune and inflammatory signaling in the tumor stroma by a gain-of-function mechanism of mutant p53, which may explain the "cancer-induced inflammation" mechanism. These results indicate that the regulation of the inflammatory microenvironment via the inhibition of the COX-2/PGE2 and TLR/MyD88 pathways in combination will be an effective preventive or therapeutic strategy against gastrointestinal cancer development and malignant progression, especially those carrying p53 gain-of function mutations. PMID- 29428222 TI - Cost-utility analysis in orthopaedic trauma; what pays? A systematic review. AB - BACKGROUND: As healthcare systems come under ever-increasing pressure to provide more care with fewer resources, emphasis is being placed on value-based systems that maximise quality and minimize cost. The aim of this study was to determine which interventions in fracture care have been demonstrated to be cost effective. METHODS: A systemic review of cost-utility studies on the management of fractures from 1976 to 2015 was carried out using a search of the Cost-Effectiveness Analysis Registry, National Health Service Economic Evaluation Database (NHS EED) and MEDLINE. RESULTS: 20 studies were included with 15 (75%) studies assessing interventions in lower limb trauma and 8 (25%) studies assessing interventions in upper limb trauma. 50% of studies used a decision tree model and 50% used collected data alongside a randomised clinical trial. Interventions which were shown to be cost effective in lower limb trauma were total hip replacement in displaced femoral neck fractures, the SHS in stable (A1 and A2) fractures and IM nailing for unstable (A3) fractures, salvage treatment for grade IIIB and IIIC open tibial fractures and operative treatment of ankle and calcaneal fractures. For systems-based strategies, there is evidence demonstrating cost effectiveness to treating hip fractures in high volume centres and to having resources in place to facilitate fractures being treated within 48 h of injury. In upper limb trauma there was evidence showing operative treatment of displaced proximal humerus fractures to be neither clinically nor cost effective. There was evidence supporting the operative treatment of non-displaced scaphoid fractures. Overall the quality of the studies was poor with only 50% (10) of studies able to make a treatment recommendation. Reasons for this included poor quality primary source data and poor reporting methodological practices. CONCLUSION: Certain aspects of fracture management have been shown to be cost effective. However, there is a paucity of evidence in this area and further research is required so that value based interventions are chosen by healthcare providers engaged in orthopaedic trauma care. PMID- 29428223 TI - Angiotensin 1-7 ameliorates 6-hydroxydopamine lesions in hemiparkinsonian rats through activation of MAS receptor/PI3K/Akt/BDNF pathway and inhibition of angiotensin II type-1 receptor/NF-kappaB axis. AB - MAS receptor (MASR), expressed in several brain areas, conferred neuroprotection against neurodegenerative disorders when activated by angiotensin (Ang) 1-7; however, its role in Parkinson's disease (PD) remains elusive. Intra-striatal post-administration of Ang1-7, using a 6-hydroxydopamine (OHDA) PD model, improved motor performance and muscle coordination. On the molecular level, Ang1 7 upregulated the striatal expression of MASR and caused upsurge in its downstream targets (p-PI3K/p-Akt/p-CREB/BDNF) to phosphorylate TrKB, which in a positive feedback upregulates MASR. Moreover, Ang1-7 increased substantia nigral tyrosine hydroxylase (TH) expression and striatal dopamine (DA) content to indicate the preservation of the dopaminergic neuronal signal. This effect extended to inhibit the striatal expression of Ang II type-1 receptor (AT-1R) to hold the neurodegenerative effect and to boost Ang1-7 anti inflammatory/antioxidant effects by abating NADPH oxidase, along with lipid peroxidation. Indeed, Ang1-7 was able to decrease p-MAPK p38/NF-kappaB p65 to level the inflammatory and oxidative stress events off. The Ang1-7-mediated activation of MASR cue and the suppression of the AT-1R cascade were partially reversed by the intrastartial injection of A-779, a MASR antagonist. The current data suggests a novel therapeutic potential for the Ang1-7 against neurotoxicity associated motor impairment related to PD. The anti-parkinsonian effect of Ang1 7, is in part, mediated by its binding to MASR and the initiation of PI3K/Akt/CREB/BDNF/TrKB cue to increase DA synthesis, besides the downregulation/inhibition of AT-1R/MAPK p38/NF-kappaB p65/NADPH oxidase pathway. PMID- 29428224 TI - Measuring quality of care in consultation liaison psychiatry: Outcomes from two Canadian hospitals. PMID- 29428225 TI - Of enzyme use in cost-effective high solid simultaneous saccharification and fermentation processes. AB - Enzyme cost is considered to be one of the most significant factors defining the final product price in lignocellulose hydrolysis and fermentation. Enzyme immobilization and recycling can be a tool to decrease costs. However, high solid loading is a key factor towards high product titers, and recovery of immobilized enzymes from this thick liquid is often overlooked. This paper aims to evaluate the economic feasibility of immobilized enzymes in simultaneous saccharification and fermentation (SSF) of lignocellulose biomass in general, as well as the recuperation of magnetic immobilized enzymes (m-CLEAs) during high solid loading in simultaneous saccharification, detoxification and fermentation processes (SSDF) of lignocellulose biomass. Enzyme prices were obtained from general cost estimations by Klein-Marcuschamer et al. [Klein-Marcuschamer et al. (2012) Biotechnol. Bioeng. 109, 1083-1087]. During enzyme cost analysis, the influence of inoculum recirculation as well as a shortened fermentation time was explored. Both resulted in 15% decrease of final enzyme product price. Enzyme recuperation was investigated experimentally and 99.5 m/m% of m-CLEAs was recovered from liquid medium in one step, while 88 m/m% could still be recycled from a thick liquid with high solid concentrations (SSF fermentation broth). A mathematical model was constructed to calculate the cost of immobilized and free enzyme utilization and showed that, with current process efficiencies and commercial enzyme prices, the cost reduction obtained by enzyme immobilization can reach around 60% compared to free enzyme utilization, while lower enzyme prices will result in a lower percentage of immobilization related savings, but overall enzyme costs will decrease significantly. These results are applied in a case study, estimating the viability of shifting from sugar to lignocellulose substrate for a 100 t lactic acid fermentation batch. It was concluded that it will only be economically feasible if the enzymes are produced at the most optimistic variable cost and either the activity of the immobilized catalyst or the recovery efficiency is further increased. PMID- 29428226 TI - Intravenous plus inhaled versus intravenous colistin monotherapy for lower respiratory tract infections: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate whether intravenous plus inhaled combination (IV/INHCC) compared to intravenous monotherapy (IVCM) was associated with patient outcomes and identify factors influencing study outcomes. METHODS: PubMed and Scopus were searched till November 2016. Studies were included if they evaluated adult patients with lower respiratory tract infections due to MDR/XDR Gram-negative bacteria and reported comparative mortality data (adjusted and unadjusted) for patients receiving IV/INHCC versus IVCM. Random effects meta-analyses were performed. RESULTS: Thirteen studies (11 retrospective, 2 prospective) were included. The overall quality of data was low to very low and characterized by the lack of adjusted data. The majority of the studies were designed to evaluate the outcome of the meta-analysis. Both IV and inhaled colistin were administered at variable doses. There was no difference in mortality between IV/INHCC and IVCM when all studies were combined (13 studies, 1115 patients, risk ratio 0.94, 95% confidence interval 0.81-1.08). Only the analysis that included studies with low dose IV colistin showed significant difference in favor of IV/INHCC versus IVCM (0.65, 0.45-0.94). CONCLUSIONS: Overall, low quality data suggest that IV/INHCC did not lower mortality in patients with MDR Gram negative infections unless low IV colistin dose was administered. PMID- 29428227 TI - Seroepidemiology of enterovirus D68 infection in infants and children in Jiangsu, China. PMID- 29428228 TI - Incidence and costs of herpes zoster and postherpetic neuralgia in German adults aged >=50 years: A prospective study. AB - OBJECTIVES: Herpes zoster (HZ) mainly affects elderly people and immunocompromised individuals. HZ is usually characterized by a unilateral painful skin rash. Its most common complication, postherpetic neuralgia (PHN), may cause chronic debilitating pain. This study aimed to estimate the HZ incidence in individuals aged >=50 years in Germany, the proportion of PHN and the economic burden. METHODS: From 2010 to 2014, HZ patients were recruited when consulting physicians in physician networks covering about 157,000 persons aged >=50 years. PHN was defined as "worst pain" rated >=3 on the zoster brief pain inventory persisting or appearing over 90 days after rash onset. Costs were calculated based on medical resource utilization and lost working time. RESULTS: HZ incidence was estimated as 6.7/1000 person-years, increasing with age to 9.4/1000 in >=80 year-olds. Among 513 HZ patients enrolled, the proportion of PHN was 11.9%, rising with age to 14.3% in HZ patients >=80 years. Estimated total cost per HZ patient was ?156 from the healthcare system perspective and ?311 from the societal perspective. CONCLUSIONS: The study confirmed previous findings that HZ causes a substantial clinical and economic burden in older German adults. It also confirmed the age-related increasing risk of HZ and PHN. PMID- 29428229 TI - Emerging insights into the role of matrix metalloproteases as therapeutic targets in fibrosis. AB - Fibrosis is the extensive accumulation and buildup of extracellular matrix components, especially fibrillar collagens, during wound healing in response to tissue injury. During all individual stages of fibrosis ECM proteases, mainly matrix metalloproteinases, have diverse roles. The functional role of MMPs and their endogenous inhibitors are differentiated among their family members, and according to the different stages of fibrosis. MMPs levels are elevated in several inflammatory and non-inflammatory fibrotic tissues contributing to the development, progression or resolution of the disease, whereas in other tissues their expression levels can be diminished or be stable to the baseline. The biological roles of MMPs during fibrosis are not fully resolved, but they seem to differ according the specific member of the family, the affected tissue and the stage of the fibrotic response. Remarkably, some members of the family exhibit profibrotic actions while other function as antifibrotic molecules. Diverse animal models indicate that MMPs are contributing in processes related to immunity, tissue repair and ECM turnover, providing significant impact on mechanisms related to fibrosis. For that purpose, these proteases are considered as pharmacological targets and new biological drugs have been developed in order to treat fibrosis. PMID- 29428230 TI - Fibrotic scarring following lesions to the central nervous system. AB - Following lesions to the central nervous system, scar tissue forms at the lesion site. Injury often severs axons and scar tissue is thought to block axonal regeneration, resulting in permanent functional deficits. While scar-forming astrocytes have been extensively studied, much less attention has been given to the fibrotic, non-glial component of the scar. We here review recent progress in understanding fibrotic scar formation following different lesions to the brain and spinal cord. We specifically highlight recent evidence for pericyte-derived fibrotic scar tissue formation, discussing the origin, recruitment, function and therapeutic relevance of fibrotic scarring. PMID- 29428231 TI - BCL9 Upregulation in Adrenocortical Carcinoma: A Novel Wnt/beta-Catenin Activating Event Driving Adrenocortical Malignancy. AB - BACKGROUND: B-Cell CLL/Lymphoma 9 (BCL9) is a recently described oncogene that promotes tumorigenesis via activation of the Wnt/beta-Catenin signaling cascade. Though constitutively active Wnt/beta-Catenin signaling is a molecular hallmark of adrenocortical carcinoma (ACC), a potential role for BCL9 to promote Wnt/beta Catenin pathway dysregulation in adrenocortical tumorigenesis remains to be elucidated. STUDY DESIGN: This study involved a retrospective analysis at a tertiary academic referral center of 27 patients with adrenocortical tumors, including in vitro investigation of BCL9. The Wnt signaling pathway polymerase chain reaction (PCR) array analysis queried comparative mRNA expression profiles of canonical Wnt pathway components including BCL9. Real-time quantitative PCR determined BCL9 mRNA expression levels in tumor samples. Expression levels of BCL9 mRNA were evaluated for correlation with tumor characteristics. RNA interference (RNAi) gene silencing was performed in ACC cell lines SW-13 and NCI H295R to test the role of BCL9 on clonal cell growth. RESULTS: Expression levels of the BCL9 gene were found to be significantly elevated in ACC compared with normal adrenal tissue (p < 0.05). Furthermore, a significant correlation was observed between BCL9 mRNA levels and the malignant status of adrenocortical tumors (p < 0.05). RNAi gene silencing of BCL9 inhibited clonal cell growth of SW 13 cells (p < 0.05), but not NCI-H295R cells, which carry a constitutively active beta-Catenin mutation. CONCLUSIONS: The gene BCL9 is overexpressed in malignant adrenocortical tumors and promotes clonal ACC cell growth. These findings suggest that BCL9 overexpression may serve as an alternative driver of constitutive Wnt/beta-Catenin activation in ACC and could represent a potential molecular and diagnostic marker of tumor malignancy. PMID- 29428232 TI - Evaluating the Effect of Margin Consensus Guideline Publication on Operative Patterns and Financial Impact of Breast Cancer Operation. AB - BACKGROUND: This study sought to evaluate re-excision rates, patient satisfaction with their breasts, and healthcare costs before and after publication of 2014 Society of Surgical Oncology/American Society of Radiation Oncology consensus guideline on margins for breast conserving operation with whole-breast irradiation for stage I and II breast cancer at an academic institution. STUDY DESIGN: Patients with stage I and II invasive carcinomas who underwent partial mastectomy were divided into 2 groups based on whether they were treated before (PRE) or after (POST) guideline publication in March 2014. Groups were compared with respect to re-excision rates, conversion to mastectomy, specimen volumes, mean cost per patient of surgical care, and prospectively collected patient post procedure quality of life. RESULTS: A total of 237 patients who underwent partial mastectomy were examined (n = 126 in the PRE group and n = 111 in the POST group). Patients in the POST group were less likely to require re-excision (9% POST vs 37% PRE; p < 0.001) and were less likely to undergo conversion to mastectomy (5% POST vs 14% PRE; p = 0.02). After consensus guideline publication, mean operative cost per patient decreased ($4,874 POST vs $5,772 PRE; p < 0.001), and patients had improved breast quality of life scores (77 out of 100 POST vs 61 out of 100 PRE; p = 0.03). On multivariable analysis, publication of the consensus statement was an independent predictor of decreased re-excision rates (odds ratio 0.17; 95% CI 0.08 to 0.38; p < 0.001) and operative cost per patient (odds ratio 0.14; 95% CI 0.78 to 0.30; p < 0.001). CONCLUSIONS: Widespread implementation of the consensus guideline on margins for breast conserving operation will likely lead to the intended improvements in operative and financial outcomes, as well as patient satisfaction with breast conserving operation. PMID- 29428233 TI - Reducing Early Readmissions after Ventral Hernia Repair with the Americas Hernia Society Quality Collaborative. AB - BACKGROUND: Early readmission after ventral hernia repair (VHR) can hinder patient recovery and increase resource use. The objective of this study was to evaluate the effectiveness of the Americas Hernia Society Quality Collaborative Early Readmission Reduction Initiative in reducing early readmissions after VHR. STUDY DESIGN: Risk factors for early readmission and best practices of surgeons with the lowest readmission rates after VHR were determined through collaborative learning. Two interventions for reducing early readmissions were developed: a structured questionnaire administered to patients within 1 week after discharge from the hospital or an early clinic visit after discharge and before a regularly scheduled postoperative visit. Multivariable logistic regression was used to evaluate the impact of these interventions on early readmission. RESULTS: Use of the questionnaire and early clinic visit was tracked in 3,007 patients. Of these, 343 received the questionnaire (2.6% readmission rate), 761 had an early clinic visit after discharge (3.0% readmission rate), 138 had both (4.3% readmission rate), and 1,765 patients received neither (5.9% readmission rate). After controlling for factors associated with early readmissions, administration of the questionnaire (odds ratio 0.42; 95% CI 0.21 to 0.84; p < 0.05) or having an early clinic visit (odds ratio 0.48; 95% CI 0.30 to 0.76; p < 0.05) were both associated with reduced odds for readmission. CONCLUSIONS: The Americas Hernia Society Quality Collaborative Early Readmission Reduction Initiative successfully reduced readmissions after VHR using a structured questionnaire or early clinic visit implemented after discharge and before routine 30-day postoperative follow up. PMID- 29428234 TI - Same-Day Discharge after Laparoscopic Roux-en-Y Gastric Bypass: An Analysis of the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program Database. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) has been performed with successful discharge on postoperative day 1 (POD1). There are limited studies on same-day discharge after LRYGB. The objective of this study was to examine the frequency and outcomes of same-day discharge after LRYGB. STUDY DESIGN: The 2015 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database was analyzed for adult patients who underwent elective LRYGB cases with same-day vs POD1 discharge. Open and revisional cases were excluded. Multivariate analysis was performed to compare risk-adjusted 30-day mortality, overall morbidity, readmission, and reoperation. RESULTS: There were 354 (0.9%) patients who were discharged on the same day as surgery after LRYGB. After exclusion criteria, 319 patients with same-day discharge and 9,402 patients with POD1 discharge were examined. For same-day vs POD1 discharge groups, mean ages were 45.0 and 44.5 years, respectively, and mean BMIs were 47.3 kg/m2 and 45.9 kg/m2, respectively. The unadjusted mortality rate was significantly higher for same-day compared with POD1 discharge (0.94% vs. 0.05%, respectively; p = 0.0017). Compared with POD1 discharge, same-day discharge had higher overall morbidity (3.76% vs 1.54%; adjusted odds ratio [AOR] 2.41; p = 0.0216), but no statistically significant differences for readmissions (3.45% vs. 3.66%; AOR 0.85; p = 0.9999) or reoperations (1.88% vs. 0.89%; AOR 2.33; p = 0.2428). CONCLUSIONS: Same-day discharge after LRYGB is associated with increased morbidity and mortality compared with POD1 discharge. The practice of same-day discharge after LRYGB should be considered experimental until further studies confirm which patient characteristics will ensure safe same-day discharge. PMID- 29428235 TI - Sequence- and structure-based computational analyses of Gram-negative tripartite efflux pumps in the context of bacterial membranes. AB - Gram-negative multidrug resistance currently presents a serious threat to public health with infections effectively rendered untreatable. Multiple molecular mechanisms exist that cause antibiotic resistance and in addition, the last three decades have seen slowing rates of new drug development. In this review, we summarize the use of various computational techniques for investigating the mechanisms of multidrug resistance mediated by Gram-negative tripartite efflux pumps and membranes. Recent work in our lab combines data-driven sequence and structure analyses to study the interactions and dynamics of these bacterial components. Computational studies can complement experimental methodologies for gaining crucial insights into combatting multidrug resistance. PMID- 29428236 TI - Liver fibrosis marker, 7S domain of collagen type IV, in patients with pre capillary pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension (PH) causes right ventricular dysfunction and central venous congestion, and may lead to congestive hepatopathy. The serum 7S domain of collagen type IV (P4NP 7S) is an established marker of liver fibrosis in chronic liver disease. We aimed to determine whether P4NP 7S is related to hemodynamic parameters, and assessed the potential values of P4NP 7S to predict mortality. METHODS: Consecutive 76 pre-capillary PH patients were divided into tertiles based on their serum P4NP 7S levels. We compared right-heart catheterization, echocardiographic findings, and mortality among the tertiles, and compared P4NP 7S with other known biomarkers of mortality. RESULTS: Cardiac index, mean pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular fractional area change did not differ among the three groups. In contrast, compared to 1st and 2nd tertiles, the 3rd tertile had higher levels of right atrial pressure, right atrial area, and right ventricular area (P<0.05, respectively). In the Kaplan-Meier analysis, mortality progressively increased from the 1st to 2nd and 3rd tertiles (log-rank, P=0.002). In the Cox proportional hazard analysis, P4NP 7S was a predictor of mortality. ROC analysis demonstrated that a P4NP 7S concentration of 4.75ng/ml predicted mortality (AUC 0.85, 95% CI 0.75-0.94; P<0.001), and that the prognostic value of P4NP 7S was comparable or superior to that of other biomarkers (total bilirubin, creatinine, uric acid, C reactive protein, B-type natriuretic peptide, and troponin I). CONCLUSIONS: Serum P4NP 7S is associated with higher central venous pressure, right-sided volume overload, and mortality in PH patients. PMID- 29428237 TI - Could persistency of current of injury forecast successful active-fixation pacing lead implantation? AB - BACKGROUND: Presence of adequate current of injury (COI) was recognized as a sign of favorable pacemaker lead outcome. Little is known regarding the value of its dynamic behavior. We sought to test whether persistency of COI could predict active-fixation pacing lead performance. METHODS: COI was monitored up to 10min after right ventricular (RV) pacing electrode fixation. COI persistency was defined as the percentage of COI magnitude relative to its initial measurement. An unacceptable pacing threshold (>=1.0V in acute evaluation or >=2.0V over 2 year follow-up) with or without lead dislodgement was considered as lead failure. RESULTS: Lead implantation was attempted for 217 times in 174 patients (age 66.3+/-7.8years, 78 female). Acute lead failures occurred 43 times. Independent predictors of acute lead failure were RV enlargement (odds ratio [OR] 1.23, 95% confidential interval [CI] 1.11-2.04, P=0.033), absence of COI (OR 3.13, 95%CI 2.08-9.09, P=0.027), and COI persistency at 5min (OR 0.32, 95%CI 0.20-0.69, P=0.001) and 10min (OR 0.41, 95%CI 0.13-0.77, P=0.001). The optimal cutoffs were COI5min persistency >=50% (sensitivity 81.4%; specificity 81.9%) and COI10min persistency >=20% (sensitivity 86%; specificity 88.6%). There were 12 lead failures during 24.0+/-6.4months of follow-up. Patients with COI5min persistency >=50% had higher event-free survival compared to those with COI5min persistency <50% (hazard ratio 3.54, 95% CI 1.04-12.06, P=0.043). CONCLUSIONS: COI persistency appears to be a valuable indicator for both acute and long-term outcome of active-fixation pacemaker leads. A precipitous decline in COI may require more attention to make sure of the lead performance. PMID- 29428238 TI - From in-clinic to fully remote follow-up model for pacemaker patients: A four year experience. PMID- 29428239 TI - Childhood socioeconomic status and lifetime health behaviors: The Young Finns Study. AB - BACKGROUND: Differences in health behaviors partly explain the socioeconomic gap in cardiovascular health. We prospectively examined the association between childhood socioeconomic status (SES) and lifestyle factors in adulthood, and the difference of lifestyle factors according to childhood SES in multiple time points from childhood to adulthood. METHODS AND RESULTS: The sample comprised 3453 participants aged 3-18 years at baseline (1980) from the longitudinal Young Finns Study. The participants were followed up for 31 years (N = 1675-1930). SES in childhood was characterized as reported annual family income and classified on an 8-point scale. Diet, smoking, alcohol intake and physical activity were used as adult and life course lifestyle factors. Higher childhood SES predicted a healthier diet in adulthood in terms of lower consumption of meat (beta +/- SE 3.6 +/- 0.99,p < 0.001), higher consumption of fish (1.1 +/- 0.5, p = 0.04) and higher diet score (0.14 +/- 0.044, p = 0.01). Childhood SES was also directly associated with physical activity index (0.059 +/- 0.023, p = 0.009) and inversely with the risk of being a smoker (RR 0.90 95%CI 0.85-0.95, p < 0.001) and the amount of pack years (-0.47 +/- 0.18, p = 0.01). Life course level of smoking was significantly higher and physical activity index lower among those below the median childhood SES when compared with those above the median SES. CONCLUSIONS: These results show that childhood SES associates with several lifestyle factors 31 years later in adulthood. Therefore, attention could be paid to lifestyle behaviors of children of low SES families to promote cardiovascular health. PMID- 29428240 TI - Anti-inflammatory activity and gastroprotective effect of Hertia cheirifolia L. roots extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hertia cheirifolia L. is used traditionally to treat rheumatic pains and known as a medicinal plant having several pharmaceutical and biological activities. The present study evaluated in vivo the anti-inflammatory and gastroprotective effects of the methanolic extract from H. cheirifolia L. MATERIALS AND METHODS: Reverse phase high-performance liquid chromatography (RP-HPLC) was performed to identify various chemical components of the plant extract. Anti-inflammatory and gastroprotective activities were assessed on carrageenan-induced paw edema and HCl/ethanol-induced gastric lesions in rats, respectively. RESULTS: (RP-HPLC) analysis indicated that coumarin is the abundant component in the extract (53.80%). Intraperitoneal administration of the methanolic extract at different doses showed interesting activities in rats in a dose-dependent manner. At 100 mg/kg, this extract showed the highest acute anti inflammatory activity and an important inhibition of gastric lesions with inhibition percentage of 79.41% and 88.53%, respectively. CONCLUSION: Altogether, the results of this study reveal the anti-inflammatory and gastroprotective effects of H. cheirifolia extract and promote the traditional use of this plant in the treatment of different pain and inflammatory diseases. PMID- 29428241 TI - Ethnomedical uses and pharmacological activities of most prevalent species of genus Piper in Panama: A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Piperaceae is the fifth largest family of plants in Panama. This review focuses on the ethnomedical uses of the most prevalent Panamanian species and biological activities of their extracts and/or constituents both in Panama and worldwide. Many species have a plethora of ethnomedical uses such as antibacterial, antifungal, anti-inflammatory, anticancer, antidiabetic, anti-Helicobacter pylori, antiulcer, antiprotozoal, estrogenic, insecticidal, local anesthetic, diuretic, and for women's health conditions. AIM OF THE REVIEW: The aim of this review is to compile all ethnomedical uses of most prevalent species of Piper in Panama, and their extracts or phytoconstituents worldwide, through a complete literature search, so that it may allow selection of potential unexplored Piper species for future research and development of phytotherapeuticals for important ailments. METHODOLOGY: This review conducted a thorough search in books and databases such as Google Scholar, PubMed, Sci-Finder, Scopus, ACS publications, Science Direct, and Reaxys (Elsevier), until October of 2017. The information provided in this review is based on peer-reviewed papers only in English. The key words used to search were: "Piper", "Piperaceae", "Panama", "Pharmacological activity", "Chemistry," "Toxicity," and "Clinical studies". Scientific names of the plants were validated through www.tropicos.org. Potential full-texts of eligible papers, irrespective of database, were identified. Study selection and data extraction were conducted by one author (AIS) and confirmed by others (MPG, ADA). The extracted data were summarized in tabular form and a narrative description was used to provide a summary of updated information. RESULTS: The ethnomedical uses of most prevalent 23 Panamanian species of Piper both in Panama as well in the world are provided. Of these species only Piper arboreum, Piper auritum, Piper cordulatum, Piper hispidum, Piper dariense, Piper multiplinervium and Piper umbellatum have ethnomedical uses in Panama. Some of the uses are by native Amerindians of Panama. These include ailments such as liver pains, common colds, skin infections, insecticidal, as a bath to alleviate colds, snakebites, different types of pains, skin ailments, wound healing, rheumatism, women's health, antipyretic, and anti-inflammatory. Other Panamanian species are widely used in many countries of the world. Of all the Piper species, P. aduncum has the most ethnomedical uses. Panamanian uses are different from the ones in other countries. A total of 61 compounds present in Piper species reported in this review have shown a variety of biological activities in vitro. These compounds belong to different chemical types, such as chromenes, amides, alkaloids, benzopyrans, benzoates, essential oils, pyrrolidines, flavokaines, chalcones, methylenedioxy propiophenones, cinnamates, monoterpenes, sesquiterpenes, phenols, among others. From this review it is evident that extracts and pure compounds isolated from Piper species have shown a wide array of mainly in vitro activity and some ethnomedical uses may be correlated with their activities reported. CONCLUSIONS: Plants of this genus have provided bioactive species, both from crude extracts and pure compounds thus substantiating their efficacy in traditional medicine. In vivo and toxicological studies are still limited, but the results of different activities of Piper reported point out the great potential of these species for obtaining bioactive principles that may be useful in treating diseases. However, a thorough investigation of Piper species relating to chemistry, in vivo pharmacological activities, with emphasis on their mechanism of action, safety and efficacy and toxicity is warranted. PMID- 29428243 TI - Allergic myocardial infarction (Kounis syndrome) after cefuroxime with side-chain cross-reactivity. PMID- 29428242 TI - Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bu Shen Yi Sui capsule (BSYSC), based on traditional Chinese formula Liu Wei Di Huang pill, is effective for the treatment of multiple sclerosis (MS) in clinical experience and trials. Our previous studies confirmed that BSYSC had the neuroprotective effect in MS and its animal model, experimental autoimmune encephalomyelitis (EAE); however, its mechanism of action was not clear. Thus, the effect of BSYSC on remyelination and the underlying mechanisms were investigated in the EAE mice. MATERIALS AND METHODS: The EAE model was established by injecting subcutaneously myelin oligodendrocyte protein (MOG) 35-55 in mice. Mice were treated with BSYSC (3.02 g/kg) or vehicle daily by oral gavage for 40 days. The body weight and clinical score of mice were evaluated. Brain was observed by magnetic resonance imaging. The inflammation infiltrate of brain and spinal cord was determined by hematoxylin-eosin staining, while the structure of myelin sheath was visualized by transmission electron microscopy on days 23 and 40 post immunization (dpi), respectively. The protein and mRNA levels of platelets-derived growth factor receptor (PDGFR) alpha and 2', 3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) were measured by immunohistochemistry, western blot and quantitative real-time polymerase chain reaction. The protein expressions of semaphorins (Sema) 3A, Neuropilin (NRP) - 1, leukemia inhibitory factor (LIF), LIF receptor (LIFR) and Nkx6.2 were further investigated by western blot. RESULTS: BSYSC treatment improved the body weight and clinical score of EAE mice, alleviated inflammatory infiltration and nerve fiber injuries. It also protected the ultrastructural integrity of myelin sheath. BSYSC significantly increased expressions of PDGFRalpha and CNPase in mice with EAE on 40 dpi. Furthermore, BSYSC treatment increased the expressions of LIF, LIFR and Nkx6.2 and reduced Sema3A and NRP-1 in EAE mice on 40 dpi. CONCLUSIONS: The data demonstrated that BSYSC exhibited the neuroprotective effect against EAE by promoting oligodendrocyte progenitor cells (OPCs) proliferation and differentiation, thus facilitating remyelination. Sema3A/NRP-1, LIF/LIFR and Nkx6.2 are likely contributed to the effects of BSYSC on OPCs. PMID- 29428244 TI - Delivery of high-quality pediatric spirometry in rural communities: A novel use for telemedicine. PMID- 29428245 TI - Sick Leave After Surgery for Thumb Carpometacarpal Osteoarthritis: A Population Based Study. AB - PURPOSE: Patients undergoing surgery for thumb carpometacarpal (CMC1) osteoarthritis often require sick leave owing to postoperative immobilization, pain, and decreased function. Our goal was to evaluate the amount of sick leave after surgery for 2 common CMC1 arthroplasty procedures. METHODS: Using registry data from the Skane region of southern Sweden, cross-linked with employment data showing person-specific sick leave, 2 cohorts of CMC1 surgical patients, between ages 40 and 59 years, were examined. These comprised all persons undergoing soft tissue arthroplasty and prosthetic implant arthroplasty from 2004 to 2012 identified using International Classification of Diseases, 10th Revision, and surgical codes. These subjects were analyzed against an age- and sex-matched reference population cohort. RESULTS: Surgical cohorts of 326 and 169 subjects undergoing soft tissue and prosthetic CMC1 arthroplasty, respectively, were compared with reference populations of 1,110 and 574 persons. Surgical subjects had a pronounced increase in sick leave in the first 2 months after surgery, followed by diminishing days of leave over time. Mean sick leave time after soft tissue arthroplasty was 202 days in women and 170 days in men. Following prosthetic arthroplasty, mean sick leave was 177 days in women and 188 in men. When we excluded those with documented sick leave in the month before surgery (owing to preoperative CMC1 disability or other medical issues), the mean postoperative sick leave decreased to 137 days in women and 125 days in men after soft tissue arthroplasty compared with 109 and 94 days in women and men after prosthetic implant arthroplasty, and this difference was significant. There were no differences in the length of sick leave between sexes and no correlation with age. CONCLUSIONS: Soft tissue arthroplasty and implant arthroplasty for patients with CMC1 osteoarthritis are both associated with substantial sick leave time, indicating the impact of surgery on return to work. There were no differences in sick leave by sex or age. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 29428246 TI - Measurement of Carpal Alignment Indices Using 3-Dimensional Computed Tomography. AB - PURPOSE: This study aimed to establish normal values for wrist carpal alignment measured by 3-dimensional computed tomography (CT) and to show the inter- and intraobserver reliability of this measurement compared with simple radiography. METHODS: The study utilized 3-dimensional CT and simple radiography of wrist joints in 30 asymptomatic volunteers. The wrist position was standardized using a custom-designed positioning device. Three independent observers measured carpal alignment parameters including distal radius articular angle, radiolunate angle, radioscaphoid angle, radiocapitate angle, radius-third metacarpal angle, scapholunate angle, lunocapitate angle, and lunate-third metacarpal angle. RESULTS: Based on 3-dimensional CT measurement, the mean values of these parameters were: 12.9 degrees +/- 1.8 degrees for the distal radius articular angle; 1.2 degrees +/- 3.8 degrees for the radiolunate angle; 54.2 degrees +/- 5.6 degrees for the radioscaphoid angle; 1.9 degrees +/- 2.2 degrees for the radiocapitate angle; -1.0 degrees +/- 2.5 degrees for the radius-third metacarpal angle; 52.9 degrees +/- 6.9 degrees for the scapholunate angle; 0.7 degrees +/- 4.1 degrees for the lunocapitate angle; -2.3 degrees +/- 4.6 degrees for the lunate-third metacarpal angle. All parameters showed high inter- and intraobserver reliability in the 2 modalities. CONCLUSIONS: The normal values and ranges for carpal alignment angles were evaluated by using 3-dimensional CT. We could obtain high reliability in 3-dimensional CT as well as plain radiograph for the measurement of carpal alignment. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 29428247 TI - Trithorax Group Proteins Act Together with a Polycomb Group Protein to Maintain Chromatin Integrity for Epigenetic Silencing during Seed Germination in Arabidopsis. AB - Polycomb group (PcG) and trithorax group (trxG) proteins have been shown to act antagonistically to epigenetically regulate gene expression in eukaryotes. The trxG proteins counteract PcG-mediated floral repression in Arabidopsis, but their roles in other developmental processes are poorly understood. We investigated the interactions between the trxG genes, ARABIDOPSIS HOMOLOG OF TRITHORAX1 (ATX1) and ULTRAPETALA1 (ULT1), and the PcG gene EMBRYONIC FLOWER 1 (EMF1) during early development. Unexpectedly, we found that mutations in the trxG genes failed to rescue the early-flowering phenotype of emf1 mutants. Instead, emf1 atx1 ult1 seedlings showed a novel swollen root phenotype and massive deregulation of gene expression. Greater ectopic expression of seed master regulatory genes in emf1 atx1 ult1 triple than in emf1 single mutants indicates that PcG and trxG factors together repress seed gene expression after germination. Furthermore, we found that the widespread gene derepression is associated with reduced levels of H3K27me3, an epigenetic repressive mark of gene expression, and with globally altered chromatin organization. EMF1, ATX1, and ULT1 are able to bind the chromatin of seed genes and ULT1 can physically interact with ATX1 and EMF1, suggesting that the trxG and EMF1 proteins directly associate at target gene loci for EMF1-mediated gene silencing. Thus, while ATX1, ULT1, and EMF1 interact antagonistically to regulate flowering, they work together to maintain chromatin integrity and prevent precocious seed gene expression after germination. PMID- 29428248 TI - Transgenic expression of plant-specific insert of potato aspartic proteases (StAP PSI) confers enhanced resistance to Botrytis cinerea in Arabidopsis thaliana. AB - The plant-specific insert of Solanum tuberosum aspartic proteases (StAP-PSI) has high structural similarity with NK-lysin and granulysin, two saposin-like proteins (SAPLIPs) with antimicrobial activity. Recombinant StAP-PSI and some SAPLIPs show antimicrobial activity against pathogens that affect human and plants. In this work, we transformed Arabidopsis thaliana plants with StAP-PSI encoding sequence with its corresponding signal peptide under the control of the cauliflower mosaic virus (CaMV) 35S promoter. Results obtained show that StAP-PSI significantly enhances Arabidopsis resistance against Botrytis cinerea infection. StAP-PSI is secreted into the leaf apoplast and acts directly against pathogens; thereby complementing plant innate immune responses. Data obtained from real-time PCR assays show that the constitutive expression of StAP-PSI induces the expression of genes that regulate jasmonic acid signalling pathway, such as PDF1.2, in response to infection due to necrotrophic pathogens. On the other hand, according to the data described for other antimicrobial peptides, the presence of the StAP-PSI protein in the apoplast of A. thaliana leaves is responsible for the expression of salicylic acid-associated genes, such as PR-1, irrespective of infection with B. cinerea. These results indicate that the increased resistance demonstrated by A. thaliana plants that constitutively express StAP-PSI owing to B. cinerea infection compared to the wild-type plants is a consequence of two factors, i.e., the antifungal activity of StAP-PSI and the overexpression of A. thaliana defense genes induced by the constitutive expression of StAP-PSI. We suggest that the use of this protein would help in minimizing the ecological and health risks that arise from the use of pesticides. We suggest that the use of this protein would help in minimizing the ecological and health risks that arise from the spreading of resistance of agriculturally important pathogens. PMID- 29428249 TI - Computed Tomography Perfusion Aids in the Prognostication of Comatose Postcardiac Arrest Patients. AB - Early assessment of the potential for neurologic recovery in comatose cardiac arrest patients (CCAP) has been a challenge despite significant evolution in management and imaging techniques. The purpose of study was to determine if the use of computed tomography perfusion (CTP) in CCAPs is feasible and if this technique can predict the likelihood that CCAPs will have a devastating outcome at hospital discharge. We prospectively enrolled 10 newly admitted comatose adults who had an out-of-hospital cardiac arrest and were treated with standard therapeutic hypothermia protocols. Patients underwent CTP of the head within 6 hours after finishing therapeutic hypothermia treatment. The imaging findings were compared with the results of a clinical assessment, as well as the modified Rankin Scale (mRS) score at hospital discharge. Sensitivity, specificity, and positive and negative predictive values for CTP were calculated to predict clinical outcome. Eight patients had an mRS score of >=5, and 2 patients had an mRS score of <=2 at hospital discharge. CTP predicted a good clinical outcome in both patients with an mRS score of <=2. The area under the curve (AUC) for plain computed tomography of the head, computerized tomography angiogram 4-point scale, computerized tomography angiogram 7-point scale, CTP of the whole brain, and CTP of the brainstem for predicting the results of the immediate clinical assessment were 0.76, 0.83, 0.67, 0.83, and 1.0, respectively. The AUCs for predicting outcome at discharge were 0.69, 0.63, 0.56, 0.63, 0.63, and 0.69, respectively. In conclusion, our pilot study showed that CTP is feasible and had a very high AUC for predicting the results of immediate clinical assessment in CCAP. PMID- 29428250 TI - Does Seed Migration Increase the Risk of Second Malignancies in Prostate Cancer Patients Treated With Iodine-125 Loose Seeds Brachytherapy? AB - PURPOSE: To evaluate the risk of second malignancies after migration of seeds (MS) in prostate cancer patients treated with 125I loose seeds brachytherapy. METHODS AND MATERIALS: Data from 2802 prostate cancer patients treated with 125I loose seeds brachytherapy in 3 Canadian centers were reviewed. After seeds implant, all patients underwent postimplant pelvic radiography and computed tomography scan for postimplant dosimetry. These images were used to assess whether seed migration occurred. The incidence of second malignancies was determined through the review of patient charts. The 7- and 10-year cumulative incidences of second malignancies and their 95% confidence intervals (CIs) were calculated. Fine and Gray competing risk regression analysis was used to assess the factors associated with the development of second malignancies. RESULTS: Mean age and median follow-up were 63.5 years and 74 (range, 12-246) months, respectively. Migration of seeds occurred in 263 of 2802 patients (9.4%). Second malignancy occurred in 87 patients (3.1%) for the entire cohort and was not different between patients who experienced MS (9, 3.4%) and those who did not (78, 3.1%) (P = .755). The 7-year cumulative incidence rates of second malignancies were 2.95% (95% CI 1.20%-6.00%) (with MS) versus 2.82% (2.10%-3.70%) (without MS) (P = .756). The corresponding values at 10 years were 6.16% (2.20% 12.3%) versus 4.51% (3.20%-5.50%) (P = .570). Migration of seeds did not seem to be a significant predictive factor for second malignancies development (adjusted hazard ratio 1.27 [95% CI 0.63-2.55]; P = .510). In both models, only advanced age was significantly associated with second malignancies development. CONCLUSIONS: These results did not show an increased risk of second malignancies associated with MS after 125I loose seeds brachytherapy for prostate cancer patients. Longer follow-up and more events are required to better correlate MS and second malignancies. PMID- 29428251 TI - Adaptive Boost Target Definition in High-Risk Head and Neck Cancer Based on Multi imaging Risk Biomarkers. AB - PURPOSE: Positron emission tomography with 18F-deoxyglucose (FDG), dynamic contrast-enhanced magnetic resonance imaging (MRI), and diffusion-weighted MRI each identify unique risk factors for treatment outcomes in head and neck cancer (HNC). Clinical trials in HNC largely rely on a single imaging modality to define targets for boosting. This study aimed to investigate the spatial correspondence of FDG uptake, perfusion, and the apparent diffusion coefficient (ADC) in HNC and their response to chemoradiation therapy (CRT) and to determine the implications of this overlap or lack thereof for adaptive boosting. METHODS AND MATERIALS: Forty patients with HNC enrolled in a clinical trial underwent FDG positron emission tomography-computed tomography before CRT and underwent dynamic contrast enhanced and diffusion-weighted MRI scans before and during CRT. The gross tumor volume (GTV) of the primary tumor was contoured on post-gadolinium T1-weighted images. Tumor subvolumes with high FDG uptake, low blood volume (BV), and low ADC were created by using previously established thresholds. Spatial correspondences between subvolumes were analyzed using the Dice coefficient, and those between each pair of image parameters at voxel level were analyzed by Spearman rank correlation coefficients. RESULTS: Prior to CRT, the median subvolumes of high FDG, low BV, and low ADC relative to the primary GTV were 20%, 21%, and 45%, respectively. Spearman correlation coefficients between BV and ADC varied from 0.47 to 0.22; between BV and FDG, from -0.08 to 0.59; and between ADC and FDG, from -0.68 to 0.25. Dice coefficients between subvolumes of FDG and BV, FDG and ADC, and BV and ADC were 10%, 46%, and 15%, respectively. The union of the 3 parameters was 64% of the GTV. The union of the subvolumes of BV and ADC was 56% of the GTV before CRT but was reduced significantly by 57% after 10 fractions of radiation therapy. CONCLUSIONS: High FDG uptake, low BV, and low ADC as imaging risk biomarkers of HNC identify largely distinct tumor characteristics. A single imaging modality may not define the boosting target adequately. PMID- 29428253 TI - May good clinical communication contribute to pain reduction? PMID- 29428252 TI - Delirium during the first evaluation of children aged five to 14 years admitted to a paediatric critical care unit. AB - OBJECTIVES: To describe the prevalence and characteristics of delirium during the initial evaluation of critically ill patients aged 5-14 years. METHOD/DESIGN: This is a cross-sectional descriptive study in a critical care unit. For six months, all patients were evaluated within the first 24-72 hours or when sedation permitted the use of the paediatric confusion assessment method for the intensive care unit (PCAM-ICU) and the Delirium Rating Scale-Revised-98 items #7 and #8 to determine motor type. We report the characteristics of PCAM-ICU delirium (at least three of the required items scored positive) and of subthreshold score cases (two positive items). RESULTS: Of 77 admissions, 15 (19.5%) had delirium, and 11 (14.2%) were subthreshold. A total of 53.3% of delirium and 45.5% of subthreshold cases were hypoactive. The prevalence of delirium and subthreshold PCAM-ICU was 83.3% and 16.7% in mechanically ventilated children. The most frequent combination of PCAM-ICU alterations in subthreshold cases was acute onset-fluctuation with altered alertness. The main nursing diagnoses were related to reduced cellular respiration. CONCLUSIONS: Delirium is common in critically ill children. It is necessary to assess whether certain nursing diagnoses imply an increase in delirium. Longitudinal studies of subthreshold PCAM-ICU cases are needed to understand their importance better. PMID- 29428254 TI - Animal models to study the impact of nutrition on the immune system of the transition cow. AB - The immune system is particularly challenged in transition cows as marked physiological changes occur in this period which are driven by late gestation, partus and onset of lactation. As a consequence, the metabolic and nutritional state of the cow also changes significantly with possible implications for the plasticity and flexibility of the immune system. In order to understand how the balance between metabolism, nutritional status and the immune system is maintained under challenging conditions, such as an infection, various animal models can be used which specifically manipulate the nutritional status through various feeding and management strategies. Such models aim at exploring the immunological response to a challenge under largely varying nutritional and metabolic states. As energy balance (EB) is strongly associated both with the metabolic state and with the immunoreactivity of the cows the manipulation of the EB by either influencing energy intake or energy excretion with milk, or by both, offers model opportunities for studying EB effects on the immune system. For example, assigning cows with a higher body condition score (BCS) at least 6 weeks prior to calving to an energy-dense diet exceeding the energy requirement in combination with a decelerated increase in the concentrate feed proportion post partum was shown to be effective in inducing a ketotic metabolic state under ad libitum feeding conditions. Compared to an adequately managed control group this model allows studying immune responses in the transit period and in dependence on dietary interventions. PMID- 29428255 TI - How to facilitate laparoscopy in obese oncologic patients - 10 steps towards successful surgery. PMID- 29428256 TI - [Usefulness of the Gram stain in urethral exudates in the Primary Care Unit]. PMID- 29428257 TI - [Association diabetes between sociodemographic variables, hypertension, hypercholesterolemia and periodontal disease]. PMID- 29428258 TI - The first clinical implementation of real-time image-guided adaptive radiotherapy using a standard linear accelerator. AB - PURPOSE: Until now, real-time image guided adaptive radiation therapy (IGART) has been the domain of dedicated cancer radiotherapy systems. The purpose of this study was to clinically implement and investigate real-time IGART using a standard linear accelerator. MATERIALS/METHODS: We developed and implemented two real-time technologies for standard linear accelerators: (1) Kilovoltage Intrafraction Monitoring (KIM) that finds the target and (2) multileaf collimator (MLC) tracking that aligns the radiation beam to the target. Eight prostate SABR patients were treated with this real-time IGART technology. The feasibility, geometric accuracy and the dosimetric fidelity were measured. RESULTS: Thirty nine out of forty fractions with real-time IGART were successful (95% confidence interval 87-100%). The geometric accuracy of the KIM system was -0.1 +/- 0.4, 0.2 +/- 0.2 and -0.1 +/- 0.6 mm in the LR, SI and AP directions, respectively. The dose reconstruction showed that real-time IGART more closely reproduced the planned dose than that without IGART. For the largest motion fraction, with real time IGART 100% of the CTV received the prescribed dose; without real-time IGART only 95% of the CTV would have received the prescribed dose. CONCLUSION: The clinical implementation of real-time image-guided adaptive radiotherapy on a standard linear accelerator using KIM and MLC tracking is feasible. This achievement paves the way for real-time IGART to be a mainstream treatment option. PMID- 29428259 TI - The influence of tissue composition uncertainty on dose distributions in brachytherapy. AB - BACKGROUND AND PURPOSE: Model-based dose calculation algorithms (MBDCAs) have evolved from serving as a research tool into clinical practice in brachytherapy. This study investigates primary sources of tissue elemental compositions used as input to MBDCAs and the impact of their variability on MBDCA-based dosimetry. MATERIALS AND METHODS: Relevant studies were retrieved through PubMed. Minimum dose delivered to 90% of the target (D90), minimum dose delivered to the hottest specified volume for organs at risk (OAR) and mass energy-absorption coefficients (MUen/rho) generated by using EGSnrc "g" user-code were compared to assess the impact of compositional variability. RESULTS: Elemental composition for hydrogen, carbon, oxygen and nitrogen are derived from the gross contents of fats, proteins and carbohydrates for any given tissue, the compositions of which are taken from literature dating back to 1940-1950. Heavier elements are derived from studies performed in the 1950-1960. Variability in elemental composition impacts greatly D90 for target tissues and doses to OAR for brachytherapy with low energy sources and less for 192Ir-based brachytherapy. Discrepancies in MUen/rho are also indicative of dose differences. CONCLUSIONS: Updated elemental compositions are needed to optimize MBDCA-based dosimetry. Until then, tissue compositions based on gross simplifications in early studies will dominate the uncertainties in tissue heterogeneity. PMID- 29428261 TI - [Opinion of professionals related to geriatrics and gerontology on chronicity strategies]. PMID- 29428260 TI - Radiocesium migration in the litter layer of different forest types in Fukushima, Japan. AB - Cesium-137 (137Cs) migration in the litter layer consists of various processes, such as input via throughfall, output via litter decomposition, and input from deeper layers via soil organism activity. We conducted litter bag experiments over 2 years (December 2014-November 2016) to quantify the inputs and outputs of 137Cs in the litter layer in a Japanese cedar plantation (Cryptomeria japonica) and a mixed broadleaf forest dominated by Quercus serrata located 40 km northwest of the Fukushima Dai-ichi Nuclear Power Plant. The experiments included four conditions, combining contaminated and non-contaminated litter and deeper layer material, and the inputs and outputs were estimated from the combination of 137Cs increases and decreases in the litter layer under each condition. The 137Cs dynamics differed between the two forests. In the C. japonica forest, some 137Cs input via throughfall remained in the litter layer, and downward 137Cs flux passed through the litter layer was 0.42 (/year).Upward flux of 137Cs from the deeper layer was very restricted, < 0.017 (/year). In the broadleaf forest, migration of 137Cs in throughfall into deeper layers was restricted, downward 137Cs flux was less than 0.003 (/year).Upward input of 137Cs from the deeper layer was prominent, 0.037 (/year). 137Cs output via litter decomposition was observed in both forests. The flux in the C. japonica forest was slower than that in the broadleaf forest, 0.12 and 0.15 (/year), respectively. PMID- 29428262 TI - Intracranial hemorrhage as initial manifestation of plasma cell myeloma: A case report. AB - This is the case of a previously healthy 48 year-old male whom presented with mild confusion, low-grade headache, and left sided weakness. Computed tomography of the head revealed a large acute right frontal lobe intracranial hemorrhage (ICH) and intraventricular extension, with normal vascular imaging. Initial laboratory testing was inconsequential. The patient required emergent evacuation, with pathology revealing only elements of a hematoma. Further laboratory testing and bone marrow biopsy results confirmed the diagnosis of plasma cell myeloma. Other systemic signs/symptoms of this disease were notably absent. This report provides the first description of an ICH as the presenting manifestation of plasma cell myeloma (PCM; multiple myeloma). PMID- 29428263 TI - Evidence based diagnosis and management of chronic subdural hematoma: A review of the literature. AB - Chronic subdural hematomas are encapsulated blood collections within the dural border cells with characteristic outer "neomembranes". Affected patients are more often male and typically above the age of 70. Imaging shows crescentic layering of fluid in the subdural space on a non-contrast computed tomography (CT) scan, best appreciated on sagittal or coronal reformats. Initial medical management involves reversing anticoagulant/antiplatelet therapies, and often initiation of anti-epileptic drugs (AEDs). Operative interventions, such as twist-drill craniostomy (TDC), burr-hole craniostomy (BHC), and craniotomy are indicated if imaging implies compression (maximum fluid collection thickness >1 cm) or the patient is symptomatic. The effectiveness of various surgical techniques remains poorly characterized, with sparse level 1 evidence, variable outcome measures, and various surgical techniques. Postoperatively, subdural drains can decrease recurrence and sequential compression devices can decrease embolic complications, while measures such as early mobilization and re-initiation of anticoagulation need further study. Non-operative management, including steroid therapy, etizolam, tranexamic acid, and angiotensin converting enzyme inhibitors (ACEI) also remain poorly studied. Recurrent hemorrhages are a major complication affecting around 10-20% of patients, and therefore close follow-up is essential. PMID- 29428264 TI - Images in Neuroscience: Calvarial hyperostosis associated with multiple intracranial tumours. PMID- 29428265 TI - First-line management of chronic subdural hematoma with the subdural evacuating port system: Institutional experience and predictors of outcomes. AB - Chronic subdural hematoma (cSDH) is a common condition that disproportionately affects older patients. Given the greater risks of general anesthesia in this population, interest has turned towards less invasive surgical approaches such as the subdural evacuating port system (SEPS; Medtronic, Inc., Minneapolis, MN). There is a relative dearth of information about the outcomes following this procedure. Here, we present our institution's experience with SEPS and analyze factors associated with the outcomes. Using a prospectively maintained institutional database, we retrospectively identified all patients who presented with cSDH and received first line therapy with SEPS. Pre- and post-operative clinical and radiographic data was obtained from the electronic health record. Outcomes included success or failure, Modified Rankin Scale (mRS) at discharge, length of stay (LOS), and discharge disposition. A total of 126 patients met the inclusion criteria (36 females and 90 males; mean age of 71.6 years). None of the pre-procedural clinical or radiographic variables were associated with the likelihood of a successful outcome. Increasing age was associated with non routine hospital discharge (p = 0.003), and lower presenting GCS was associated with longer hospital stay (p = 0.005). Greater thickness of the cSDH was associated with a lower likelihood of having a favorable outcome (mRS >= 3; p = 0.003). SEPS is an effective first-line therapy for cSDH. Variables previously reported to limit the effectiveness of the technique (presence of septations, mixed density collections) were not associated with treatment failure. PMID- 29428266 TI - Duraplasty using amniotic membrane versus temporal muscle fascia: A clinical comparative study. AB - In the field of neurosurgery, often the dura mater cannot be sutured, and consequently, it requires a duraplasty procedure using a dural fascial graft. Since 1890, various materials have been researched as dura mater substitutes. Amniotic membrane, for example, is suitable as a dural graft material and has been used in neurosurgery since 2012. However, there has been little research on human patient's dural healing after the use of amniotic membrane in their duraplasty procedure. To address this gap, a clinical experimental study was undertaken to evaluate the human dural healing of 16 patients who had undergone duraplasty in decompressive craniectomy surgery at Dr. Soetomo General Hospital, Surabaya. The amniotic membrane allograft, was sutured to cover the dural defect for eight randomly chosen patients (Group I). The fascial autograft from the temporal muscle had been applied for eight other patients (Group II). Between 10 and 20 weeks after surgery, the patients underwent cranioplasty and dural healing evaluation by cerebrospinal fluid (CSF) leakage testing through the edge of the dural defect. The fibrocyte infiltration around the edge of the dural defect was examined histologically. Statistical analysis, using an independent t-test, was performed with a confidence interval of 95%. The results of the clinical and histological analysis suggest that an amniotic membrane graft was able to provide watertight dural closure and adequate fibrocyte infiltration comparable with that provided by temporalis muscle fascia. This study shows that using an amniotic membrane in neurosurgery has a potential advantage over an alternative dural healing. PMID- 29428267 TI - Disseminated cerebral toxoplasmosis in a patient with chronic lymphocytic leukemia. AB - Infections are one of the most common causes of mortality in immunocompromised patients. In patients diagnosed with hematologic malignancies, treatment with stem cell transplants (SCT) or T-cell suppressing chemotherapy increases the risk of central nervous system (CNS) infections, of which toxoplasmosis is the most common. We report the case of a 63 year-old woman with chronic lymphocytic leukemia (CLL) that presented with gait instability and visual changes. Intracranial lesions were noted on initial neuro-imaging. A rapid decline in the patient's mental status warranted an urgent biopsy of the lesions that revealed tachyzoites consistent with toxoplasmosis. In the presence of diffuse brain lesions that lack a metastatic pattern or contrast enhancement, a common approach is to perform biopsy only after a battery of non-invasive testing. This diagnostic delay may take several days, exposing the patient to a rapidly fatal infection. This report illustrates the utility of early brain biopsy in high-risk patients with hematologic malignancies and CNS lesions. PMID- 29428268 TI - Web of the carotid artery: An under-recognized cause of ischemic stroke. AB - Ischemic stroke has rarely been reported in association with a web of the carotid artery. We describe here an additional case of ischemic stroke caused by a carotid web in a young healthy woman. Detection of this vascular abnormality required the use of CT angiography and cerebral digital subtraction angiography. Although there is little evidence regarding the optimal management of this condition, under medical treatment with dual antiplatelet therapy our patient remained free of recurrent stroke events. This case report study illustrates that the web of the carotid artery is an uncommon cause of stroke which should always be considered and ruled out, especially in young patients with otherwise cryptogenic stroke. Clinicians should be aware of this condition, which represents a diagnostic and therapeutic challenge. PMID- 29428269 TI - Comparison of craniotomy and decompressive craniectomy in large supratentorial intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is devastating disease with high mortality and morbidity rates. Most ICH is evacuated by either craniotomy (CR) or decompressive craniectomy (DC) although optimal treatment has not been established yet. The objective of this study was to compare clinical outcomes of spontaneous ICH patients between CR and DC groups and determine clinical factors affecting clinical prognosis. We retrospectively analyzed our single-center experience with large supratentorial ICH. From January 2011 to December 2016, 286 consecutive supratentorial large ICH patients underwent surgery in our institute. We compared CR group and DC group with regard to age, sex, GCS score, hematoma volume, midline shift, ICH score, and time from ictus to surgery. Statistical analysis was done using the t-test or x2 test, and odds ratio was calculated. During study period, CR was performed in 139 patients while DC was performed in 125 patients. There were no significant difference in 30-day mortality between the CR group and the DC group (13.7% vs 15.2%, p = 0.729). However, 12-month functional survival was 46.0% in the CR group, which was significantly (p = 0.014) higher than that (32.0%) of the DC group. In conclusion, the 30-day mortality of CR group was not inferior to that of the DC group while its 12-month functional survival was superior to that of the DC group. This suggests better functional outcome might be obtained for selected large ICH patients with CR than with DC. PMID- 29428270 TI - [Ten years of human papillomavirus vaccination. From dermatology to oncology via infectology]. AB - Human papillomavirus (HPV) was first identified in dermatology, and it was subsequently demonstrated that is was required for the development of uterine cervical cancer and other tumours, after a persistent infection by any of its oncogenic genotypes. Ten years ago, the most common infections and cancers associated with HPV could be prevented by immunisation with 2vaccines, one bivalent, and another tetravalent, and having just marketed a nonavalent one. During the period 2007-2008, the HPV vaccine was included in the Autonomous Communities vaccination calendar, and it is the second vaccine, after that of Hepatitis B, that prevents cancer. In these 10 years that these vaccines have been available the knowledge has progressed and there have been significant advances in vaccination strategies, as well as in the indications and recommendations. These include, lowering the age in the vaccination schedule, prescribing of 2doses at 9 years and at 13-14 years, systematic vaccination of the male in some countries, immunisation of the woman after adolescence, implementation of vaccination programmes in developed countries, prevention of other cancers, recommendations for vaccinations for populations at high risk of HPV infection, scientific evidence on the impact and effectiveness of vaccination, and confirmation of the safety of these vaccines, with more than 270 million doses administered, as has already been observed in clinical trials. The role of health professionals is essential to achieve and maintain high vaccine coverage. PMID- 29428271 TI - Congenital Absence of Skin on Scalp. PMID- 29428272 TI - Neonatal Parotitis. PMID- 29428273 TI - High Sustained Antibody Titers in Patients with Classic Infantile Pompe Disease Following Immunomodulation at Start of Enzyme Replacement Therapy. AB - OBJECTIVE: To evaluate whether immunomodulation at start of enzyme replacement therapy induces immune tolerance to recombinant human acid alpha-glucosidase (rhGAA) in patients with classic infantile Pompe disease. STUDY DESIGN: Three patients (1 cross reactive immunologic material negative, 2 cross reactive immunologic material positive) were treated with 4 weekly doses of rituximab, weekly methotrexate, and monthly intravenous immunoglobulin and enzyme replacement therapy at 40 mg/kg/week. Antibody titers were measured using enzyme linked immunosorbent assay. Neutralizing effects on rhGAA activity and cellular uptake were determined and combined with pharmacokinetic analysis. Clinical efficacy was evaluated by (ventilator-free) survival, reduction in left ventricular mass index, and improvement of motor function. RESULTS: Immunomodulation induced B cell depletion that was accompanied by absence of antibody formation in all 3 patients. Upon cessation of rituximab treatment, all 3 patients showed B cell recovery, which was accompanied by formation of very high sustained antibody titers in 2 patients. Neutralizing effects on infused rhGAA were low to mild/moderate. All patients were alive at study end, learned to walk, and showed (near) normalization of left ventricular mass index. CONCLUSIONS: Immunomodulation as recommended in the literature prevented formation of rhGAA antibodies only during B cell depletion but failed to induce immune tolerance in 2 out of 3 patients. PMID- 29428274 TI - Computational Models of Laryngeal Aerodynamics: Potentials and Numerical Costs. AB - Human phonation is based on the interaction between tracheal airflow and laryngeal dynamics. This fluid-structure interaction is based on the energy exchange between airflow and vocal folds. Major challenges in analyzing the phonatory process in-vivo are the small dimensions and the poor accessibility of the region of interest. For improved analysis of the phonatory process, numerical simulations of the airflow and the vocal fold dynamics have been suggested. Even though most of the models reproduced the phonatory process fairly well, development of comprehensive larynx models is still a subject of research. In the context of clinical application, physiological accuracy and computational model efficiency are of great interest. In this study, a simple numerical larynx model is introduced that incorporates the laryngeal fluid flow. It is based on a synthetic experimental model with silicone vocal folds. The degree of realism was successively increased in separate computational models and each model was simulated for 10 oscillation cycles. Results show that relevant features of the laryngeal flow field, such as glottal jet deflection, develop even when applying rather simple static models with oscillating flow rates. Including further phonatory components such as vocal fold motion, mucosal wave propagation, and ventricular folds, the simulations show phonatory key features like intraglottal flow separation and increased flow rate in presence of ventricular folds. The simulation time on 100 CPU cores ranged between 25 and 290 hours, currently restricting clinical application of these models. Nevertheless, results show high potential of numerical simulations for better understanding of phonatory process. PMID- 29428275 TI - Familial cases of progressive myoclonic epilepsy caused by maternal somatic mosaicism of a recurrent KCNC1 p.Arg320His mutation. AB - PURPOSE: A recurrent de novo mutation in KCNC1 (c.959G > A, p.Arg320His) has been identified recently as one of the important genetic causes of progress myoclonic epilepsy (PME). The clinical phenotype resulting from this mutation has been named as myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK). This finding carries important clinical implications in that autosomal dominant inheritance and de novo occurrence need to be considered when conducting genetic tests in patients with PME. We present two familial cases of MEAK in siblings with a recurrent p.Arg320His mutation in KCNC1. METHOD: Whole exome sequencing and subsequent Sanger sequencing were performed for the cases and their parents. RESULTS: A recurrent p.Arg320His mutation in KCNC1 was identified in the two brothers who showed characteristic features of MEAK: near normal early development, onset of myoclonus around 10 years of age, infrequent generalized tonic-clonic seizures, relatively mild cognitive impairment, and generalized epileptiform discharges. Interestingly, the asymptomatic mother was suspected as being mosaic for this mutation. This finding could lead to misleading inheritance patterns and make genetic diagnosis of PME more complicated. CONCLUSIONS: Our familial MEAK cases show that consideration of parental mosaicism in addition to meticulous phenotyping is needed when conducting KCNC1 genetic testing. PMID- 29428276 TI - A random version of principal component analysis in data clustering. AB - Principal component analysis (PCA) is a widespread technique for data analysis that relies on the covariance/correlation matrix of the analyzed data. However, to properly work with high-dimensional data sets, PCA poses severe mathematical constraints on the minimum number of different replicates, or samples, that must be included in the analysis. Generally, improper sampling is due to a small number of data respect to the number of the degrees of freedom that characterize the ensemble. In the field of life sciences it is often important to have an algorithm that can accept poorly dimensioned data sets, including degenerated ones. Here a new random projection algorithm is proposed, in which a random symmetric matrix surrogates the covariance/correlation matrix of PCA, while maintaining the data clustering capacity. We demonstrate that what is important for clustering efficiency of PCA is not the exact form of the covariance/correlation matrix, but simply its symmetry. PMID- 29428277 TI - Genetic Counseling Overview for the Obstetrician-Gynecologist. AB - This article outlines a framework for the process of genetic counseling in the primary obstetric and gynecologic setting. Specifics regarding risk assessment, family history evaluation, genetic testing, and pretest and posttest counseling are discussed. Additionally, the article provides strategies for counseling patients effectively and addresses when a referral for additional genetic counseling by a specialized genetics provider should be considered. PMID- 29428278 TI - Expanded Carrier Screening. AB - Prenatal carrier screening has expanded to include a larger number of genes and variants offered to all couples considering or with an ongoing pregnancy. Panethnic screening for cystic fibrosis and spinal muscular atrophy and screening for a limited number of conditions based on ethnicity are recommended by the American College of Obstetricians and Gynecologists. Residual risk calculations have become an obsolete part of posttest counseling when expanded carrier screening (ECS) is selected. The Perception of Uncertainties in Genome Sequencing scale offers a useful understanding of the pretest and posttest counseling concerns that should be considered as part of ECS implementation. PMID- 29428279 TI - Preimplantation Genetic Screening and Preimplantation Genetic Diagnosis. AB - Preimplantation genetic testing encompasses preimplantation genetic screening (PGS) and preimplantation genetic diagnosis (PGD). PGS improves success rates of in vitro fertilization by ensuring the transfer of euploid embryos that have a higher chance of implantation and resulting in a live birth. PGD enables the identification of embryos with specific disease-causing mutations and transfer of unaffected embryos. The development of whole genome amplification and genomic tools, including single nucleotide polymorphism microarrays, comparative genomic hybridization microarrays, and next-generation sequencing, has led to faster, more accurate diagnoses that translate to improved pregnancy and live birth rates. PMID- 29428280 TI - Key Ethical Issues in Prenatal Genetics: An Overview. AB - The clinical integration of prenatal genetic technologies raises a series of important medical and ethical considerations for patients, families, health care providers, health care systems, and society. It is critical to recognize, understand, and address these issues in conjunction with the continued development of new prenatal genetic screens and tests. This article discusses some of the lead ethical issues as a starting point to further understanding their ramifications on patients, families, communities, and health care providers. PMID- 29428281 TI - Cell-Free DNA Screening for Aneuploidy and Microdeletion Syndromes. AB - Cell-free DNA (cfDNA) screening for the common aneuploidies is an accurate noninvasive screen for the common autosomal and sex chromosome aneuploidies. However, cfDNA screening should not be considered a diagnostic test, and the positive predictive value should be used in counseling women with a positive test regarding the option for diagnostic testing. Compared with traditional screening, cfDNA may not detect as many chromosomal abnormalities of importance. Furthermore, due to the low prevalence of recurrent copy number variants, the clinical utility in screening for microdeletions and duplications is uncertain and is not recommended for the general obstetric population. PMID- 29428282 TI - The Status of Genetic Screening in Recurrent Pregnancy Loss. AB - Recurrent pregnancy loss is often idiopathic, but numerical and structural chromosomal abnormalities constitute an important cause. Numerical chromosomal abnormalities in the conceptus are primarily due to meiotic nondisjunction; the rate and complexity of embryonic aneuploidy are driven by female age. Structural chromosomal abnormalities (balanced translocations or inversions) can lead to unbalanced gametes depending on specific recombination and segregation patterns during meiosis. The attendant reproductive risk depends on the type of rearrangement and its parental origin. Current methods for analysis of products of conception include cytogenetics, array comparative genomic hybridization, and single nucleotide polymorphism microarray; each platform has advantages and disadvantages. PMID- 29428283 TI - Hereditary Cancers in Gynecology: What Physicians Should Know About Genetic Testing, Screening, and Risk Reduction. AB - Obstetrician gynecologists play a critical role in the identification of women who may carry a germline mutation placing them at an increased lifetime risk of gynecologic and nongynecologic cancers. Given this, all gynecologists must have a basic understanding of the most common hereditary cancer syndromes, the associated cancer risks, and possible risk-reducing interventions to play a proactive role in the care of these women. This article presents general guidelines and potential tools for identification of high-risk patients, reviews the current literature regarding genetic mutations associated with gynecologic malignancies, and proposes screening and risk-reduction options for high-risk patients. PMID- 29428284 TI - Cell-Free DNA: Screening for Single-Gene Disorders and Determination of Fetal Rhesus D Genotype. AB - The use of cell-free DNA (cfDNA) for screening and diagnosis of single-gene disorders is an evolving technology, and its application at this time is limited. Invasive testing is currently recommended for the diagnosis of single-gene disorders. The limitations of cfDNA technology are most notable in clinical settings involving X-linked and autosomal recessive conditions, in part because maternal mutant alleles greatly outnumber those of fetal origin. Examples of single-gene disorders for which cfDNA has been used include skeletal dyplasias, cystic fibrosis, congenital adrenal hyperplasia, beta-thalassemia, and muscular dystrophies. PMID- 29428285 TI - Screening for Aneuploidy in Multiple Gestations: The Challenges and Options. AB - As the incidence of multiple gestations increases, the need for effective aneuploidy screening grows. There are unique challenges associated with aneuploidy screening in twins, and the data supporting its use are limited. This article summarizes the risk of aneuploidy for twin gestations and the available screening methods, including nuchal translucency, first-trimester and second trimester serum screening, and cell-free DNA screening. PMID- 29428286 TI - The Use of Chromosomal Microarray Analysis in Prenatal Diagnosis. AB - Chromosomal microarray analysis (CMA) identifies microdeletions and duplications undetected on karyotype analysis. Copy number variants (CNVs) occur in 1% to 1.7% of all pregnancies, with clinical implications. All women undergoing invasive testing for routine indications should be offered microarray. Clinically significant CNVs are seen in approximately 6% of pregnancies with ultrasound anomalies, making CMAs the current standard of cytogenomic analysis. Clinicians should be familiar with different technologies and laboratory reporting practices. Pretest counseling is imperative and, when CMA results are abnormal, posttest counseling should be in-depth and conducted by a genetic counselor or clinical geneticist. PMID- 29428288 TI - Ethnicity-Based Carrier Screening. AB - Ethnicity-based carrier screening for single-gene disorders is an integral part of preconception and prenatal care. The role of ethnicity-based carrier screening has expanded over time with advancing technology. Patients and providers should understand the benefits and limitations of their screening options and engage in appropriate pretest and posttest counseling. The future management of single-gene disorders is changing and a time may be approaching when ethnicity-based carrier screening will be replaced with expanded carrier screening. PMID- 29428289 TI - Update on Reproductive Genetics: What an Obstetrician-Gynecologist Needs to Know. PMID- 29428287 TI - Whole Exome Sequencing: Applications in Prenatal Genetics. AB - Prenatal whole exome sequencing (WES) has the potential to increase the ability to provide more diagnostic capabilities in fetuses with sonographic abnormalities, which would then improve the ability to counsel families. It is also often the first step in improving the path toward informed diagnosis and treatment, which is especially important in the era of advancing in utero fetal therapy. This article discusses the current literature regarding prenatal WES, clinical indications for WES, challenges with interpretation/counseling (variants of unknown significance), research priorities, ethical issues, and potential future advances. PMID- 29428290 TI - Reproductive Genetics. PMID- 29428291 TI - A systematic review of precipitating physical and psychological traumatic events in the development of fibromyalgia. AB - The role of physical and psychological trauma precipitating fibromyalgia is often encountered by physicians, yet a proper systematical review of this association is lacking. Literature searches identified 51 studies which examined the association of fibromyalgia with a preceding traumatic event of physical or emotional nature. The overall quality of evidence of studies included, as assessed by the GRADE criteria, was low, however the majority of studies described a significant association between prior physically traumatic events and the onset of chronic widespread pain or fibromyalgia. Elevated rates of psychological trauma in fibromyalgia patients were demonstrated across the literature and several studies indicate a mediating effect of post-traumatic stress disorder. Potential biological mechanisms for conversion of traumatic events into a chronic pain syndrome, such as fibromyalgia, are discussed. PMID- 29428292 TI - Reliability of Foot Posture Index individual and total scores for adults and older adults. AB - BACKGROUND: Previous studies have suggested that the Foot Posture Index (FPI-6) is valid and reliable to evaluate foot posture of adults and children. However, studies with adults had some important limitations. In addition, it is not clear if FPI-6 is reliable for older adults. Variations in foot structure, such as edema, bone callosity and bunions, are more frequent in older adults, which may compromise FPI-6 reliability for this population. OBJECTIVES: To investigate test retest and inter-rater reliability of FPI-6 total and individual scores for the assessment of foot posture of adults and older adults. METHODS: Twenty-one adults and 19 older adults participated in this study. The examiners performed FPI-6 on two days of data collection. We used Cohen Weighted Kappa and Intraclass Correlation Coefficient for categorical and continuous variables, respectively. RESULTS: For adults, FPI-6 scores demonstrated test-retest reliability varying from fair to substantial and inter-rater reliability varying from fair to almost perfect. For older adults, FPI-6 scores demonstrated test-retest reliability varying from not reliable to moderate and inter-rater reliability varying from fair to almost perfect. The examiners demonstrated more than 80% of agreement in all FPI-6 scores for adults and older adults. CONCLUSIONS: The relatively low reliability in light of this high level of agreement suggest that the current version of FPI-6 can be a useful tool to assess foot posture for adults and should be further examined. On the other hand, FPI-6 should be cautiously used for older adults. PMID- 29428294 TI - Role of light and the circadian clock in the rhythmic oscillation of intraocular pressure: Studies in VPAC2 receptor and PACAP deficient mice. AB - The intraocular pressure of mice displays a daily rhythmicity being highest during the dark period. The present study was performed to elucidate the role of the circadian clock and light in the diurnal and the circadian variations in intraocular pressure in mice, by using animals with disrupted clock function (VPAC2 receptor knockout mice) or impaired light information to the clock (PACAP knockout mice). In wildtype mice, intraocular pressure measured under light/dark conditions showed a statistically significant 24 h sinusoidal rhythm with nadir during the light phase and peak during the dark phase. After transfer of the wildtype mice into constant darkness, the intraocular pressure increased, but the rhythmic changes in intraocular pressure continued with a pattern identical to that obtained during the light/dark cycle. The intraocular pressure in VPAC2 receptor deficient mice during light/dark conditions also showed a sinusoidal pattern with significant changes as a function of a 24 h cycle. However, transfer of the VPAC2 receptor knockout mice into constant darkness completely abolished the rhythmic changes in intraocular pressure. The intraocular pressure in PACAP deficient mice oscillated significantly during both 24 h light and darkness and during constant darkness. During LD conditions, the amplitude of PACAP deficient was significantly lower compared to wildtype mice, resulting in higher daytime and lower nighttime values. In conclusion, by studying the VPAC2 receptor knockout mouse which lacks circadian control and the PACAP knockout mouse which displays impaired light signaling, we provided evidence that the daily intraocular pressure rhythms are primarily generated by the circadian master clock and to a lesser extent by environmental light and darkness. PMID- 29428293 TI - Impact of spine alignment on the rotator cuff in long-term wheelchair users. AB - BACKGROUND: We investigated the impact of poor seated posture on the prevalence of rotator cuff tears (RCTs) among wheelchair-dependent individuals with long standing paraplegia. METHODS: The study included 319 patients. Lateral radiographs of the spine were collected from a database and analyzed to assess the global spinopelvic alignment (SPA). Magnetic resonance images of both shoulders were obtained to detect the presence of cuff tears. Patients were divided into 2 groups: Group RCT-I included all patients with cuff tears (right, left, or bilateral), whereas group RCT-II consisted exclusively of patients with bilateral cuff tears. We used the classification systems developed by Kendall et al and Roussouly et al to assess the sagittal spine alignment and SPA, respectively. Univariate and multivariate analyses were performed. To fit both models (groups RCT-I and RCT-II) to the data, the 4 spine curves according to Roussouly et al were subdivided into 2 groups: Group SPA-I included both type 1 and type 2, whereas group SPA-II included both type 3 and type 4. RESULTS: Magnetic resonance images showed a cuff tear in 192 patients (60.19%) (group RCT I). Among those, 37 patients (11.60%) had tears in both shoulders (group RCT-II). In group RCT-I, 70.31% of the patients had a kyphotic-lordotic posture. The kyphotic-lordotic posture, a longer duration, and a more rostral neurologic level of injury were highly associated with cuff tear prevalence. In group RCT-II, the multivariate analysis showed that only the duration of spinal cord injury was significantly associated with RCTs. CONCLUSION: Thoracic hyperkyphosis was associated with a markedly high rate of RCTs. The data from this study may provide support for developing preventive strategies. PMID- 29428295 TI - Dracorhodin perchlorate regulates fibroblast proliferation to promote rat's wound healing. AB - In recent years, plant-derived extracts are increasing interest from researchers worldwide due to good efficacy and lower side effects. Among the different plant extracts, Dracorhodin perchlorate (DP) is originated from Dragon's blood which has long been used as a natural medicine with various pharmacological activities. In the present study, we have explored the potential regulation of DP on fibroblast proliferation which promotes wound healing both in vitro and in vivo. DP at treatment of 12-24 h significantly induced fibroblast proliferation which is associated with increasing level of phosphorylated-extracellular signal regulated kinase (ERK). Moreover, if ERK is halted with siRNA, DP cannot induce fibroblast proliferation. In vivo, DP ointment treatment at low- (2.5 MUg/mL), medium- (5 MUg/mL) and high-(10 MUg/mL) doses, rat wounds healed more rapidly compared with the control group. After DP treatment for 7 days, Serpin family H member 1 (SERPINH1) staining confirmed enhanced fibroblast proliferation in the wound tissue. Finally, phosphorylated-ERK in the wound tissue remarkably increased with DP ointment treatment. Therefore, DP may be developed into a potential lead compounds for the treatment of wounds in clinical trials in the near future. PMID- 29428296 TI - Childhood adversities and cognitive deficits in first-episode psychosis. PMID- 29428297 TI - Improving drug policy: The potential of broader democratic participation. AB - Policies concerned with illicit drugs vex governments. While the 'evidence-based policy' paradigm argues that governments should be informed by 'what works', in practice policy makers rarely operate this way. Moreover the evidence-based policy paradigm fails to account for democratic participatory processes, particularly how community members and people who use drugs might be included. The aim of this paper is to explore the political science thinking about democratic participation and the potential afforded in 'deliberative democracy' approaches, such as Citizens Juries and other mini-publics for improved drug policy processes. Deliberative democracy, through its focus on inclusion, equality and reasoned discussion, shows potential for drug policy reform and shifts the focus from reliance on and privileging of experts and scientific evidence. But the very nature of this kind of 'deliberation' may delimit participation, notably through its insistence on authorised modes of communication. Other forms of participation beyond reasoned deliberation aligned with the ontological view that participatory processes themselves are constitutive of subject positions and policy problems, may generate opportunities for considering how the deleterious effects of authorised modes of communication might be overcome. PMID- 29428298 TI - The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL/6J Mice. AB - Improved delivery of adeno-associated virus (AAV) vectors to the CNS will greatly enhance their clinical utility. Selection of AAV9 variants in a mouse model led to the isolation of a capsid called PHP.B, which resulted in remarkable transduction of the CNS following intravenous infusion. However, we now show here that this enhanced CNS tropism is restricted to the model in which it was selected, i.e., a Cre transgenic mouse in a C57BL/6J background, and was not found in nonhuman primates or the other commonly used mouse strain BALB/cJ. We also report the potential for serious acute toxicity in NHP after systemic administration of high dose of AAV. PMID- 29428299 TI - G6PC mRNA Therapy Positively Regulates Fasting Blood Glucose and Decreases Liver Abnormalities in a Mouse Model of Glycogen Storage Disease 1a. AB - Glycogen storage disease type Ia (GSD1a) is an inherited metabolic disorder caused by the deficiency of glucose-6-phosphatase (G6Pase). GSD1a is associated with life-threatening hypoglycemia and long-term liver and renal complications. We examined the efficacy of mRNA-encoding human G6Pase in a liver-specific G6Pase /- mouse model (L-G6PC-/-) that exhibits the same hepatic biomarkers associated with GSD1a patients, such as fasting hypoglycemia, and elevated levels of hepatic glucose-6-phosphate (G6P), glycogen, and triglycerides. We show that a single systemic injection of wild-type or native human G6PC mRNA results in significant improvements in fasting blood glucose levels for up to 7 days post-dose. These changes were associated with significant reductions in liver mass, hepatic G6P, glycogen, and triglycerides. In addition, an engineered protein variant of human G6Pase, designed for increased duration of expression, showed superior efficacy to the wild-type sequence by maintaining improved fasting blood glucose levels and reductions in liver mass for up to 12 days post-dose. Our results demonstrate for the first time the effectiveness of mRNA therapy as a potential treatment in reversing the hepatic abnormalities associated with GSD1a. PMID- 29428300 TI - A case of postanaesthetic recurarization because of residual atracurium in the intravenous fluid line in a dog. PMID- 29428301 TI - An emergency airway management system to improve fresh gas delivery in a dog undergoing tracheal resection. PMID- 29428302 TI - Anaesthetic induction with alfaxalone in the ball python (Python regius): dose response and effect of injection site. AB - OBJECTIVE: To characterise the minimum dose of intramuscular alfaxalone required to facilitate intubation for mechanical ventilation, and to investigate the impact of cranial versus caudal injection on anaesthetic depth. STUDY DESIGN: Randomised crossover study. ANIMALS: Six healthy juvenile ball pythons (Python regius). METHODS: Three dosages (10, 20 and 30 mg kg-1) of alfaxalone were administered to each python in a caudal location with a minimum 2 weeks washout. Induction and recovery were monitored by assessing muscle tone, righting reflex, response to a noxious stimulus and the ability to intubate. A subsequent experiment assessed the influence of injection site by comparing administration of 20 mg kg-1 alfaxalone in a cranial location (1 cm cranial to the heart) with the caudal site. Respiration rate was monitored throughout, and when intubation was possible, snakes were mechanically ventilated. RESULTS: Regardless of dose and injection site, maximum effect was reached within 10.0 +/- 2.7 minutes. When administered at the caudal injection site, intubation was only successful after a dosage of 30 mg kg-1, which is higher than in previous reports for other reptiles. However, intubation was possible in all cases after 7.2 +/- 1.6 minutes upon cranial administration of 20 mg kg-1, and anaesthetic duration was significantly lengthened (p < 0.001). Both 30 mg kg-1 at the caudal site and 20 mg kg-1 at the cranial site led to apnoea approximately 10 minutes post injection, at which time the snakes were intubated and mechanically ventilated. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone provided rapid, smooth induction when administered intramuscularly to pythons, and may serve as a useful induction agent prior to provision of volatile anaesthetics. The same dosage injected in the cranial site led to deeper anaesthesia than when injected caudally, suggesting that shunting to the liver and first-pass metabolism of alfaxalone occur when injected caudally, via the renal portal system. PMID- 29428303 TI - Myoclonus and hypersensitivity of the tail following intrathecal administration of morphine and bupivacaine in a cat. PMID- 29428304 TI - Suitability of biomarkers of biological effects (BOBEs) for assessing the likelihood of reducing the tobacco related disease risk by new and innovative tobacco products: A literature review. AB - The health risk of tobacco smoking can best be avoided or reduced by not taking up or quitting the habit. The use of new and innovative tobacco (NTPs, e.g. electronic cigarettes) can either be an aid for smoking cessation or, for those who are not able or willing to quit, an alternative for smoking conventional tobacco products. Before the use of an NTP can be regarded as an effective approach in tobacco harm reduction (THR), the implicated risk has to be evaluated by suitable toxicological methods such as the analysis of the chemical composition as well as assessment of detrimental effects in animal and in vitro studies. In human (clinical) studies, the NTP-related exposure to toxicants and early biological effects can be assessed by the determination of suitable biomarkers. In this review, the suitability of established and newly developed biomarkers of biological effect (BOBEs) for the indicated purpose is evaluated according to five criteria, including the association to diseases, reported difference in BOBE levels between smokers and non-smokers, dose-response relationships, reversibility and kinetics after smoking cessation. Furthermore, the effect size and the resulting sample size required in clinical studies were estimated and considered in the BOBE evaluation process. It is concluded that the rating process presented is useful for selecting BOBEs suitable for risk evaluation of NTPs in clinical and other human studies. PMID- 29428305 TI - High-molecular-weight adiponectin is inversely associated with sympathetic activity in polycystic ovary syndrome. AB - OBJECTIVE: To examine the role of high-molecular-weight (HMW) adiponectin and its relationship to sympathetic activity in women with polycystic ovary syndrome (PCOS). DESIGN: Cross sectional study using biobanked samples. SETTING: Not applicable. PATIENT(S): Premenopausal women with PCOS (n = 46, Rotterdam diagnostic criteria) and without PCOS (n = 22). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): High-molecular-weight adiponectin levels with secondary outcomes of sympathetic activity and leptin levels. RESULT(S): The high-molecular weight adiponectin level was lower in women with PCOS (median 2.2 [interquartile range (IQR)2.3] MUg/mL) than in controls (median 3 [IQR2.5] MUg/mL) (age and BMI adjusted), and it correlated inversely with the values measured for homeostatic model of assessment of insulin resistance (HOMA-IR), fasting insulin, triglycerides, and free androgen index and positively with sex hormone-binding globulin (SHBG) and high-density lipoprotein cholesterol in all participants and in the PCOS group. In the PCOS group, sympathetic activity (burst frequency) was statistically significantly higher than in controls (median 26 [IQR11] vs. median 22 [IQR14], respectively) and correlated inversely with HMW adiponectin (r = 0.230). The leptin levels were similar between the women with PCOS and controls and did not statistically significantly correlate with HMW adiponectin or sympathetic activity. On multiple regression analysis, burst frequency and SHBG explained 40% of the HMW adiponectin variability (B = -0.7; 95% CI -1.2 to -0.2; and B = 0.01; 95% CI 0.004-0.01) in PCOS. CONCLUSION(S): Alongside insulin resistance, increased sympathetic activity is associated with and may modulate HMW adiponectin levels in women with PCOS. PMID- 29428306 TI - Cumulus cell transcriptome profiling is not predictive of live birth after in vitro fertilization: a paired analysis of euploid sibling blastocysts. AB - OBJECTIVE: To compare the transcriptome of cumulus cells associated with a euploid embryo that resulted in live birth with that of a sibling euploid embryo without sustained implantation. DESIGN: Paired analysis. SETTING: Academic institution. PATIENT(S): Couples undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection with preimplantation genetic screening with female age <=42 years and normal ovarian reserve. INTERVENTION(S): Transcriptome profiling of cumulus cells from sibling oocytes for correlation with live birth after euploid blastocyst transfer. Embryos were individually cultured to facilitate association with clinical outcomes. The cumulus cell transcriptome from the embryo resulting in live birth was compared with that of its sibling embryo without sustained implantation to investigate potential biomarkers that may aid in embryo selection. MAIN OUTCOME MEASURE(S): Differential gene expression in cumulus cells associated with a euploid embryo resulting in live birth and its sibling euploid embryo without sustained implantation using next-generation RNA sequencing (RNAseq). RESULT(S): Cumulus cell RNAseq of 34 samples (from 17 patients) generated an average of 10.4 +/- 4 * 106 reads per sample. A total of 132 differentially expressed genes between sibling embryos that resulted in a live birth and those that did not were identified (P<.05). However, after correcting for multiple testing none of the genes remained significantly differentially expressed (false discovery rate <.05). CONCLUSION(S): The RNAseq profiles were similar between cumulus cells associated with a euploid embryo resulting in live birth and its sibling embryo that did not sustain implantation. The cumulus cell transcriptome is not predictive of live birth within an individual patient's cohort of euploid embryos. PMID- 29428307 TI - Oocyte vitrification versus ovarian cortex transplantation in fertility preservation for adult women undergoing gonadotoxic treatments: a prospective cohort study. AB - OBJECTIVE: To compare the efficacy of oocyte vitrification (OV) with that of ovarian cortex cryopreservation and transplantation (OCT) in women undergoing gonadotoxic treatments. DESIGN: Prospective observational cohort study. SETTING: Not applicable. PATIENT(S): Candidates for chemo-/radiotherapy who joined our fertility preservation (FP) program were included in this study between 2005 and 2015. One cohort included 1,024 patients undergoing OV; the other cohort included 800 patients undergoing OCT. INTERVENTION(S): OV using the cryotop device and OCT using a slow freezing protocol. MAIN OUTCOME MEASURE(S): Live-birth rate (LBR) and clinical pregnancy rate (CPR). RESULT(S): Basal antimullerian hormone levels of the patients revealed no differences in ovarian reserve before FP (OV, 11.6 pM [5.4-24.7]; OCT, 11.8 pM [6.4-21.9]). In the OV cohort, 49 patients used the vitrified oocytes after a mean storage time of 3.9 years. In the OCT cohort, 44 sought pregnancy after a mean storage time of 5.5 years. A trend toward higher CPR and LBR (per patient) was observed in the OV group (risk ratio [RRCPR], 1.31 [95% confidence interval, 0.90-1.92]; RRLBR 1.39 [95% confidence interval, 0.95 2.03]), although differences were not statistically significant. In the OCT group, 46.7% of pregnancies occurred spontaneously and no pregnancy was achieved when the tissue was harvested beyond the age of 36 years. All patients except three undergoing OCT resumed or improved endocrine ovarian function. CONCLUSION(S): Although we observed a trend toward higher LBR after OV, OCT is a very effective method to preserve fertility, allows for natural pregnancy, and restores ovarian function. In clinical scenarios where OV is not feasible, OCT remains the FP technique of choice and should no longer be considered experimental. PMID- 29428308 TI - Differential rate in decline in ovarian reserve markers in women with polycystic ovary syndrome compared with control subjects: results of a longitudinal study. AB - OBJECTIVE: To estimate rates of ovarian aging in polycystic ovary syndrome (PCOS) subjects versus a community control population. DESIGN: Longitudinal. SETTING: Tertiary academic center. SUBJECT(S): PCOS subjects diagnosed according to the 2004 Rotterdam criteria were systematically enrolled in a PCOS cohort study. The comparison control subjects were from the Ovarian Aging study, a prospective longitudinal study of ovarian aging in healthy women with regular menstrual cycles. INTERVENTION(S): Clinical data collection over two study visits. MAIN OUTCOME MEASURE(S): Antral follicle count (AFC), ovarian volume (OV), and antimullerian hormone level (AMH). RESULT(S): PCOS subjects were found to have higher baseline values for all ovarian reserve markers compared with control subjects. Univariate models indicated that, compared with control subjects, PCOS patients experienced significantly faster rates of decline for both AFC and AMH. Change in OV did not differ significantly. To account for potential confounder effects, multiple analysis of covariance models were evaluated for the best fit, considering age, body mass index, and baseline ovarian reserve markers. Adjusted models demonstrated that PCOS patients do not experience a significant difference in AFC decline compared with control subjects, but they do experience a faster rate of decline in AMH (P<.01) and slower rate of decline in OV (P<.01). CONCLUSION(S): Ovarian aging in PCOS is characterized by a more rapid decline in AMH and a slower decline in OV compared with control subjects. PMID- 29428309 TI - Mycoplasma genitalium can modulate the local immune response in patients with endometriosis. AB - OBJECTIVE: To detect Mollicutes in women with endometriosis and healthy peritoneal tissues and evaluate the participation of these bacteria in the immune response during endometriosis. DESIGN: Cross-sectional study. SETTING: University hospitals. PATIENT (S): Women with endometriosis (n = 73) and without endometriosis (n = 31). INTERVENTION(S): Endocervical swabs, peritoneal fluid, and biopsied lesions of endometriosis of women with endometriosis (study group) and healthy peritoneal tissues (control group) were collected during surgery. Clinical characteristics were registered before surgery. MAIN OUTCOME MEASURE(S): We determined the infectious agents with the use of quantitative polymerase chain reaction (PCR). The cytokine secretion profile was determined with the use of Luminex. The expression of immune response related genes was determined with the use of a PCR array kit. RESULT(S): All target microorganisms were detected at least once in the swab samples analyzed. It was possible to observe higher diversity of microorganisms in the samples of swab and peritoneal fluid in the study group compared with the control. Ureaplasma parvum was associated with the severity of the symptom dyspareunia. Mycoplasma genitalium was associated with higher production of interferon-gamma and interleukin-1beta. Genes of inflammatory response activation and antigen presentation were up-regulated in biopsied tissue of women with endometriosis. In women with endometriosis, peritoneal fluid cells showed a down-regulation of genes associated with the inflammatory response. This down-regulation profile was higher in presence of M. genitalium. CONCLUSION(S): Mycoplasma genitalium may play a key role in the immune tolerance process and, especially, the aggravation of this profile. More studies are needed to understand this immune tolerance profile of bacterial infections. PMID- 29428310 TI - Assessing access to assisted reproductive services for serodiscordant couples with human immunodeficiency virus infection. AB - OBJECTIVE: To understand the barriers that serodiscordant couples with human immunodeficiency virus (HIV) face in accessing services for risk reduction and infertility using assisted reproductive technology (ART). DESIGN: Two-arm cross sectional telephone "secret shopper" study. SETTING: Infertility clinics designated by the Society for Assisted Reproductive Technology (SART), 140 from 15 American states with the highest prevalence of heterosexual HIV-infected men. PATIENT(S): Clinical and nonclinical staff at SART-registered clinics. INTERVENTION(S): Standardized telephone calls to SART-registered clinics by investigators in the roles of physician and patient callers. MAIN OUTCOME MEASURE(S): Availability and difference in services offered to callers and the rate of referral if the clinic did not provide these services. RESULT(S): Of the 140 sampled SART clinics across 15 states, callers in both patient and physician roles spoke to a staff member at greater than 90% of targeted clinics (127 clinics total). Of the physician callers 63% were told that the clinic could offer services, as compared to 40% of patient callers. Of the 55 clinics that were unable to provide services to the patient caller, 51% referred to other clinics with confidence that they could offer these services; 67% of clinics would provide services for both prevention and infertility purposes. CONCLUSION(S): Risk reduction services for HIV were more available at the sampled fertility clinics than previously reported in the literature. However, the responses depended on the person calling. The clinics demonstrated low rates of concordance with the American Society for Reproductive Medicine's guidelines, which endorse referral of patients to other facilities from sites unable to offer services. PMID- 29428311 TI - Impact of cancer treatment on risk of infertility and diminished ovarian reserve in women with polycystic ovary syndrome. AB - OBJECTIVE: To compare markers of fertility and ovarian reserve between cancer survivors and cancer-free women with and without polycystic ovary syndrome (PCOS). DESIGN: Furthering Understanding of Cancer, Health, and Survivorship in Adult (FUCHSIA) Women's Study-a population-based cohort study. SETTING: Not applicable. PATIENT(S): Female cancer survivors (n = 1,090) aged 22-45 years, diagnosed between ages 20 and 35 years, and at least 2 years after diagnosis; 369 participated in a clinic visit. Three hundred seventy-four reproductive-aged women without cancer also completed a clinic visit. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Infertility, time to first pregnancy after cancer diagnosis, and measures of ovarian reserve (antimullerian hormone [AMH] and antral follicle count [AFC]). RESULTS: Seventy-eight cancer survivors (7.2%) reported a PCOS diagnosis, with 41 receiving gonadotoxic treatment. Survivors with PCOS exposed to gonadotoxic treatment (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.2 4.5) and unexposed (OR 3.4, 95% CI 1.7-6.9) were more likely to report infertility than unexposed survivors without PCOS and were more likely to have fewer children than desired (exposed: OR 2.1, 95% CI 1.0-4.2; unexposed: OR 3.0, 95% CI 1.4-6.8). After adjusting for age, comparison women with PCOS had the highest markers of ovarian reserve (AMH: 2.43 ng/mL, 95% CI 1.22-4.82 ng/mL; AFC: 20.7, 95% CI 15.3-27.8), and cancer survivors without PCOS treated with gonadotoxic agents had the lowest levels (AMH: 0.19 ng/mL, 95% CI 0.14-0.26 ng/mL; AFC: 7.4, 95% CI 6.4-8.5). CONCLUSION(S): Despite having higher AMH and AFC on average after cancer treatment, cancer survivors with PCOS were less likely to meet their reproductive goals compared with survivors without PCOS. PMID- 29428312 TI - Reproductive and metabolic determinants of granulosa cell dysfunction in normal weight women with polycystic ovary syndrome. AB - OBJECTIVE: To determine the degree to which E2 hyperresponsiveness to FSH and antimullerian hormone (AMH) overproduction in normal-weight women with polycystic ovary syndrome (PCOS) correlate with increased antral follicle number (AFN), hyperandrogenism, and/or metabolic dysfunction. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): Seven normal-weight women with PCOS (1990 National Institutes of Health criteria) ages 20-34 years and 13 age- and body mass index- (BMI-; 18.5-25 kg/m2) matched normoandrogenic ovulatory women were studied. INTERVENTION(S): All women underwent basal serum hormone and metabolic measurements, FSH stimulation testing with transvaginal ovarian sonography, frequently sampled IV glucose tolerance testing, and whole-body dual energy x-ray absorptiometry. MAIN OUTCOME MEASURE(S): Serum hormone/metabolite levels, 24-hour serum E2 response to 150 IU recombinant human (rh) FSH infusion, AFN, insulin sensitivity, and body mass measurements. RESULT(S): Serum E2 responsiveness to rhFSH and AMH levels were greater in women with PCOS than in BMI- and age-matched control women, as were serum androgen levels, AFN, and abdominal fat mass. In all women combined, serum E2 responsiveness to rhFSH was associated with AFN. Serum AMH levels, however, positively correlated with AFN but remained positively correlated with serum LH and free T levels and negatively correlated with total body fat and percent body fat, adjusting for AFN. CONCLUSION(S): In normal-weight women with PCOS, serum E2 hyperresponsiveness to rhFSH represents increased AFN, while elevated serum AMH levels reflect opposing effects of stimulatory reproductive (hyperandrogenism and increased AFN) versus inhibitory metabolic (body fat) factors. Given the small number of subjects reported, additional follow-up studies are required to confirm these data. PMID- 29428313 TI - Clinical outcomes in carriers of complex chromosomal rearrangements: a retrospective analysis of comprehensive chromosome screening results in seven cases. AB - OBJECTIVE: To evaluate the clinical outcomes in carriers of complex chromosomal rearrangements (CCRs). DESIGN: Case series. SETTING: An institute for reproductive and stem cell engineering. PATIENT(S): Seven couples with CCRs. INTERVENTION(S): Assisted reproduction with preimplantation genetic diagnosis (PGD). MAIN OUTCOME MEASURE(S): PGD results, embryo rating, pregnancy outcomes. RESULT(S): In cases 1, 2, 3, 4, 5, and 6, each woman underwent one cycle of PGD. Case 7 underwent two PGD cycles. We obtained 51 blastocysts from seven couples with CCR, of which 47 were eligible for biopsy; only 3 (5.9%) were normal/balanced, and 2 (3.9%) conceptions resulted. One healthy baby girl was born (the other was not yet born at the time of publication). Karyotyping revealed that the healthy baby girl was 46,XX. Although the patient with both a balanced translocation and a CCR (case 7) had 12 embryos available for biopsy, all were chromosomally unbalanced. It is interesting that 22 (57.9%) of the total 38 blastocysts were of high quality for type A CCRs, and 2 (15.4%) of the total 13 blastocysts were of high quality for type B CCR at day 6 after fertilization. CONCLUSION(S): The chances of identifying normal/balanced blastocysts in patients with CCR are <6%; the chances of a pregnancy are <4%. Greater complexity CCRs result in fewer transplantable embryos. Moreover, CCRs of greater complexity have a lower rate of high quality blastocysts than CCRs of less complexity. PMID- 29428314 TI - Gestational carrier in assisted reproductive technology. AB - OBJECTIVE: To compare clinical outcomes of in vitro fertilization (IVF) cycles with the use of gestational carriers (GCs) with non-GC IVF cycles. DESIGN: Retrospective cohort study of assisted reproductive technology (ART) cycles performed with (24,269) and without (1,313,452) the use of a GC. SETTING: ART centers. PATIENT(S): Infertile patients seeking IVF with or without use of a GC. INTERVENTIONS(S): Autologous and donor oocyte cycles, fresh and cryopreserved embryo transfer cycles. MAIN OUTCOME MEASURE(S): Live birth rate (LBR), twin and high-order multiple birth rates. RESULT(S): Approximately 2% of embryo transfers used a GC. Per embryo transfer, GCs had greater pregnancy rate and LBR across all IVF types compared with non-GC cycles in crude models and models adjusted a priori for potential confounders. For women with uterine-factor infertility, embryo transfer with the use of a GC resulted in a higher odds of live birth for autologous fresh embryos and for cryopreserved embryos compared with patients with non-uterine-factor infertility diagnoses. CONCLUSION(S): GC benefits LBRs for some patients seeking ART. The highest LBRs occurred when the indication for GC was uterine-factor infertility. PMID- 29428315 TI - Association of testosterone and antimullerian hormone with time to pregnancy and pregnancy loss in fecund women attempting pregnancy. AB - OBJECTIVE: To examine whether higher T and/or antimullerian hormone (AMH) was associated with anovulation, time to pregnancy (TTP), or pregnancy loss risk among healthy, fecund women without diagnosed polycystic ovary syndrome. DESIGN: Prospective cohort study conducted as a secondary analysis from the Effects of Aspirin in Gestation and Reproduction randomized trial. SETTING: University medical centers. PATIENT(S): A total of 1,198 healthy, eumenorrheic women aged 18 40 years attempting spontaneous pregnancy with one to two prior pregnancy losses were included. Women were categorized by baseline antimullerian hormone (AMH), as a surrogate marker of antral follicle count, and T concentrations; the highest quartile for each was "high," and below the top quartile (i.e., lower 75% of values) was "norm," forming four groups: norm T/norm AMH (n = 742), norm T/high AMH (n = 156), high T/norm AMH (n = 157), and high T/high AMH (n = 143). INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Anovulation, pregnancy incidence, TTP, and pregnancy loss incidence. RESULT(S): Women with high T/high AMH had a greater anovulation risk (risk ratio 1.58, 95% confidence interval 1.13 2.22) compared with women with norm T/norm AMH, but with imprecise differences in incidence of pregnancy, TTP, or pregnancy loss. CONCLUSION(S): Women with higher T and AMH had more frequent anovulatory cycles but with marginal impacts on TTP or pregnancy loss. A continuum of mild inefficiency in reproductive function may be related to higher T and AMH, including in fecund women with normal menstrual cycles and no clinical diagnosis of polycystic ovary syndrome, but with unclear effects on fecundability and pregnancy loss. CLINICAL TRIAL REGISTRATION NUMBER: NCT00467363. PMID- 29428316 TI - Variability induced by the MR imager in dynamic contrast-enhanced imaging of the prostate. AB - PURPOSE: To evaluate the variability induced by the imager in discriminating high grade (Gleason>=7) prostate cancers (HGC) using dynamic contrast-enhanced MRI. MATERIAL AND METHODS: We retrospectively selected 3T MRIs with temporal resolution<10 seconds and comprising T1 mapping from a prospective radiologic pathologic database of patients treated by prostatectomy. Ktrans, Kep, Ve and Vp were calculated for each lesion seen on MRI using the Weinmann arterial input function (AIF) and three patient-specific AIFs measured in the right and left iliac arteries in pixels in the center of the lumen (psAIF-ST) or manually selected by two independent readers (psAIF-R1 and psAIF-R2). RESULTS: A total of 43 patients (mean age, 63.6+/-4.9 [SD]; range: 48-72 years) with 100 lesions on MRI (55 HGC) were selected. MRIs were performed on imager A (22 patients, 49 lesions) or B (21 patients, 51 lesions) from two different manufacturers. Using the Weinmann AIF, Kep (P=0.005), Ve (P=0.04) and Vp (P=0.01) significantly discriminated HCG. After adjusting on tissue classes, the imager significantly influenced the values of Kep (P=0.049) and Ve (P=0.007). Using patient-specific AIFs, Vp with psAIF-ST (P=0.008) and psAIF-R2 (P=0.04), and Kep with psAIF-R1 (P=0.03) significantly discriminated HGC. After adjusting on tissue classes, types of patient-specific AIF and side of measurement, the imager significantly influenced the values of Ktrans (P=0.0002), Ve (P=0.0072) and Vp (P=0.0003). For all AIFs, the diagnostic value of pharmacokinetic parameters remained unchanged after adjustment on the imager, with stable odds ratios. CONCLUSION: The imager induced variability in the absolute values of pharmacokinetic parameters but did not change their diagnostic performance. PMID- 29428317 TI - Don't worry, be happy with intravenous norepinephrine. PMID- 29428318 TI - Medial and lateral laxity in knees with advanced medial osteoarthritis. AB - OBJECTIVE: An increase in coronal laxity is recognized as a risk factor for progression of knee osteoarthritis (OA). The purpose of this study was to evaluate coronal laxity, which was defined as the angular motion from the neutral, unloaded (baseline) position to the loaded position, in patients with advanced medial knee OA. METHOD: Preoperative coronal laxity was assessed using radiographs in patients with medial knee OA undergoing total knee arthroplasty by applying a force of 150 N with an arthrometer. A consecutive series of 211 knees with OA and 40 normal control knees were examined. A knee with OA was defined as clinically "balanced" when the difference between medial and lateral laxity was 3 degrees or less. Values are expressed as median [25th, 75th percentile]. RESULTS: The laxity was 4 degrees [3, 5] from the baseline on the medial side and 3 degrees [2, 4] on the lateral side. The distribution of medial and lateral laxity indicated that 90% (189/211) of patients fell within 3 degrees . The equivalence test showed that the medial and lateral laxity was similar, with an equivalence margin of 3 degrees (P < 0.001). In the control knees, the laxity was 3 degrees [2, 4] from the baseline on the medial side and 2 degrees [2, 4] on the lateral side. The differences between the knees with advanced OA and the controls were significant (P = 0.005, medial; P = 0.006, lateral). CONCLUSION: This study showed that a clinically balanced knee was maintained even in patients with advanced medial knee OA. PMID- 29428319 TI - Characterization and functional correlation of multiple imaging modalities with focal choroidal excavation. AB - BACKGROUND: To investigate the clinical manifestations and imaging features of near-infrared autofluorescence (NIA), infrared reflectance (IR), fundus autofluorescence (FAF), indocyanine green angiography (ICGA) and fluorescein angiography (FAG) in the detection of patients with focal choroidal excavation (FCE) identified by cross-sectional spectral-domain optical coherence tomography (SD-OCT). METHODS: This retrospective cross-sectional study included 12 eyes of 10 Taiwanese patients with FCE diagnosed by SD-OCT. The areas and depths of FCE in serial cross-sectional and en-face OCT were compared in different imaging modalities. NIA, IR, FAF, ICGA and FAG images were obtained. Best corrected visual acuity, subjective distortion area in the Amsler grid and history of maculopathies were also recorded. RESULTS: In areas where the choroid started to excavate as shown in SD-OCT, hypo-autofluorescence in NIA was noted. The area of hypo-fluorescence in NIA of all the FCE lesions showed good correlation with the size. The area of FCE was associated with complications such as choroidal neovascularization and central serous chorioretinopathy (p = 0.014, d.f = 1) and the volume (NIA area * Depth measured by SD-OCT * 1/3) was associated with subjective distortion strongly (p = 0.051, Spearman's correlation = 0.600). CONCLUSION: Among all image modalities, NIA was the most sensitive tool in area measurement of FCE and peripheral lesion detection. Also, the volume of FCE was associated with subjective distortion and the area was related to complications. Recording the area and volume of FCE could play an important role in monitoring complications. PMID- 29428320 TI - Minimally traumatic stapes surgery for otosclerosis: Risk reduction of post operative vertigo. AB - BACKGROUND: The author (Dr. Shiao) modified traditional stapes surgery (TSS) specifically for patients with otosclerosis. The proposed technique, referred to as minimally traumatic stapes surgery (MTSS), reduces the risk of subjective discomfort (i.e. vertigo and tinnitus) following surgery. This paper compares the effectiveness of MTSS with that of TSS. METHODS: The medical records of patients with otosclerosis after stapes surgery (TSS or MTSS) were analyzed. Outcome variables included post-operative vertigo, tinnitus, and hearing success. Multivariate logistic regression analysis was used to determine the correlation between surgical technique and outcome variables. RESULTS: TSS was performed in 23 otosclerosis ears and MTSS was performed in 33 otosclerosis ears. The risk of post-operative vertigo was significantly lower among patients that underwent MTSS (27%) than among those that underwent TSS (83%, p < 0.001). No differences in the incidence of tinnitus were observed between the two groups. Post-operative audiometric outcomes were also equivalent between the two groups. However, multivariate logistic regression analysis revealed a correlation between post operative vertigo and surgical technique (p < 0.001). CONCLUSION: MTSS involves a lower risk of vertigo than does TSS. MTSS helps to prevent damage to the footplate, thereby reducing the risk of footplate floating. Therefore, MTSS provides a means to overcome some of the limitations associated with the narrow surgical field in Asian patients. PMID- 29428321 TI - Cement augmentation in the proximal femur to prevent stem subsidence in revision hip arthroplasty with Paprosky type II/IIIa defects. AB - BACKGROUND: Subsidence remains a common complication after revision hip arthroplasty which may lead to prolonged weight-bearing restrictions, leg-length discrepancies or considerable loss of function. We evaluated the effectiveness of cement augmentation in the proximal femoral metaphysis during a revision of femoral components to prevent post-operative stem subsidence. METHODS: Forty patients were enrolled. Follow-up averaged 67.7 months (range: 24-149). Twenty seven patients had a Paprosky type II defect and 13 had a type IIIa defect. All revision hip arthroplasty used a cementless, cylindrical, non-modular cobalt chromium stem. The defect in the metaphysis was filled with antibiotic-loaded bone cement. Thirteen patients who had undergone stem revision only was allowed to walk immediately without weight-bearing restrictions. Twenty-seven patients who had undergone revision total hip arthroplasty was allowed partial weight bearing within 6 weeks after surgery in the consideration of acetabular reconstruction. RESULTS: Three patients (7.5%) had post-surgery stem subsidences of three mm, five mm, and 10 mm, respectively, at three, one, and 14 months. There were no acute surgical site infections. There were three femoral stem failures: two delayed infections and one periprosthetic Vancouver B2 fracture. Both five- and 10-year survivorships of the femoral implant were 90.1%. CONCLUSION: An adequate length of the scratch-fit segment and diaphyseal ingrowth remain of paramount importance when revising femoral components. To fill metaphyseal bone defects with antibiotic-loaded bone cement may be an alternative method in dealing with proximal femoral bone loss during a femoral revision. PMID- 29428322 TI - Study of the profile of behavioral problems and quality of life indexes in a pediatric cohort of monosymptomatic enuresis. AB - OBJECTIVE: To evaluate and correlate, before and after the therapeutic intervention, the behavioral problem scores evaluated by the CBCL/6-18 questionnaire and the quality of life indexes evaluated by the PedsQLTM 4.0 in patients with monosymptomatic nocturnal enuresis. METHOD: After the initial evaluation and completion of the CBCL/6-18 questionnaire, a multidisciplinary evaluation and completion of the PedsQLTM 4.0 questionnaire was performed. Of the initially evaluated 140 children and adolescents aged 6-16 years, 58 were excluded due to non-monosymptomatic enuresis or associated comorbidities. Of the initially included 82 patients, who were randomized to three treatment groups, 59 completed the CBCL/6-18 and PedsQLTM 4.0 questionnaires at the end of the treatment and were included in this study. The alpha error was set at 5% for ruling out the null hypothesis. RESULTS: Of the total of 59 participants, 45.8% responded with total success, 23.7% were partially successful, 23.7% did not reach the improvement criteria, and 6.8% gave up the treatment. There was a significant increase in quality of life indexes and a reduction of post intervention behavioral problem scores, in the three proposed modalities, in patients who had a total or partial response to treatment. There was no correlation between higher scores of pre-treatment behavior problems and therapeutic failure. CONCLUSIONS: Only the participants who successfully responded to interventions showed improvement in quality of life and behavioral problems, which indicates that enuresis is a primary problem that has a negative impact on these parameters. The authors suggest that it is possible to achieve success in the treatment of monosymptomatic enuresis, even in patients with high pre-intervention behavioral problem scores. PMID- 29428323 TI - Cigarette craving and stressful social interactions: The roles of state and trait social anxiety and smoking to cope. AB - BACKGROUND: Previous research indicates that social anxiety (SA) is a risk factor for the maintenance and relapse of smoking behaviors. However, little is known about the mechanisms underlying this relationship. The current study tested the effects of state and trait levels of SA as well as smoking to cope with symptoms of SA on craving during a social stressor task in abstinent conditions. METHODS: Participants (n = 60) were daily smokers, aged 18-30. Participants attended two sessions: a baseline session and a second session, wherein they engaged in a social stressor task while deprived from nicotine for 24 h. Subjective ratings of cigarette craving and state levels of SA were assessed six times throughout the task. Data were analyzed via multilevel modeling. RESULTS: Both trait SA and some forms of smoking to cope with symptoms of SA were more likely to predict increased craving during times of high, relative to low, social stress. Further, individuals with higher state SA, greater smoking to cope behaviors, and those who experience greater relief of social distress by smoking experienced greater craving throughout the task. These effects remained after controlling for nicotine dependence, withdrawal symptoms, depression, and other symptoms of anxiety and stress. Smoking to cope with symptoms of SA did not moderate the relationship between state SA and craving. CONCLUSIONS: Smokers high in SA (state and trait) and smoking to cope with symptoms of SA may be at risk for continued smoking and relapse because of the intensity of cravings they experience during stressful social situations. PMID- 29428324 TI - Pre- and postnatal tobacco and cannabis exposure and child behavior problems: Bidirectional associations, joint effects, and sex differences. AB - AIMS: We examined prospective associations between pre-and-postnatal tobacco and cannabis exposure on child behavior problems from 2 to 3 years of child age, sex differences in these associations, and bidirectional associations between maternal postnatal substance use and child behavior problems across time. METHODS: The sample consisted of 247 primarily young, unmarried, low-income, minority mothers and their children (97 prenatally exposed to tobacco and cannabis, 81 exposed to tobacco only, and 69 non-exposed). Mothers were assessed during each trimester of pregnancy, at 2, 9, 16 months, 2 and 3 years of child age. RESULTS: Bivariate results indicated significant differences mainly for girls. Girls in the prenatal tobacco exposure group had higher internalizing problems compared to the other two groups, and higher attention and sleep problems at 3 years compared to the control group. Higher number of cigarettes per day during pregnancy was significantly associated with higher anxiety/depression and higher attention problems at 3 years, and the associations were stronger for girls compared to boys. In model testing controlling for prenatal exposure, results indicated bidirectional associations between behavior problems at 2 years and maternal postnatal cannabis use, such that higher cannabis use across the infant toddler period predicted higher behavior problems at 2 years, which in turn predicted higher cannabis use a year later. CONCLUSIONS: Results add to the literature on joint effects of tobacco and cannabis, highlight the importance of considering bidirectional associations between maternal substance use and child behavior problems, and indicate generally stronger prenatal tobacco exposure effects for girls. PMID- 29428325 TI - Regional cerebral blood flow predictors of relapse and resilience in substance use recovery: A coordinate-based meta-analysis of human neuroimaging studies. AB - BACKGROUND: Predicting relapse vulnerability can inform level-of-care and personalized substance use treatment. Few reliable predictors of relapse risk have been identified from traditional clinical, psychosocial, and demographic variables. However, recent neuroimaging findings highlight the potential prognostic import of brain-based signals, indexing the degree to which neural systems have been perturbed by addiction. These proposed "neuromarkers" forecast the likelihood, severity, and timing of relapse but the reliability and generalizability of such effects remains to be established. METHODS: Activation likelihood estimation was used to conduct a preliminary quantitative, coordinate based meta-analysis of the addiction neuroprediction literature; specifically, studies wherein baseline measures of regional cerebral blood flow were prospectively associated with substance use treatment outcomes. Consensus patterns of activation associated with relapse vulnerability (greater activation predicts poorer outcomes) versus resilience (greater activation predicts improved outcomes) were specifically investigated. RESULTS: Twenty-four eligible studies yielded 134 foci, representing 923 subjects. Consensus activation was identified in right putamen and claustrum (p < .05, cluster-corrected) in relation to positive and negative treatment outcomes - likely reflecting variability in measurement context (e.g., task, sample characteristics) across datasets. A single cluster in rostral-ventral anterior cingulate cortex (rACC) was associated with relapse resilience, specifically (p < .05, cluster-corrected); no significant vulnerability-related clusters were identified. CONCLUSIONS: Right putamen activation has been associated with relapse vulnerability and resilience, while increased baseline rACC activation has been consistently associated with improved treatment outcomes. Methodological heterogeneity within the existing literature, however, limits firm conclusions and future work will be necessary to confirm and clarify these results. PMID- 29428326 TI - A Modified Definition for Obstructive Sleep Apnea in Home Sleep Apnea Testing after Stroke or Transient Ischemic Attack. AB - BACKGROUND: Home sleep apnea testing (HSAT) underestimates obstructive sleep apnea (OSA) severity. Overnight oxygen desaturation has been shown to be a strong predictor of incident stroke, and may be helpful in determining which patients with lower apnea-hypopnea indices (AHIs) should be offered treatment. OBJECTIVES: To examine whether a modified definition for OSA that uses oxygen desaturation (i.e., AHI 5-14.9 per hour and lowest O2 desaturation <=88%), as compared to an AHI >= 15 per hour, would impact: (1) changes in Epworth Sleepiness Scale scores post-continuous positive airway pressure (CPAP) initiation; (2) CPAP compliance rates; and (3) the accuracy of automated versus manual scoring of HSAT. METHODS: One hundred and six patients with a prior stroke or transient ischemic attack (TIA) underwent HSAT. Epworth Sleepiness Scale and CPAP compliance were measured at baseline and 3-6 months. RESULTS: Median age was 67.5 years, 57.5% male, and 76.4% presented with stroke. Fifty-nine patients were diagnosed with OSA; of these 54.2% met criteria for the "modified definition" for OSA (AHI 5-14.9 per hour with oxygen desaturation) and 45.8% met criteria for the "classic definition" for OSA (AHI >=15). The modified (versus classic) definition had: (1) a greater decrease in ESS (P = .05) post-CPAP initiation; (2) comparable CPAP compliance rates; and (3) comparable automatically versus manually scored AHIs (Spearman's rho = .96, Cohen's Kappa >= .75 for both definitions, P < .001). CONCLUSIONS: Using a modified definition of OSA that uses a lower AHI cutoff and includes an oxygen desaturation cutoff in the setting of HSAT for stroke or transient ischemic attack (TIA) patients may improve daytime sleepiness post-CPAP initiation, while not significantly affecting CPAP compliance rates nor the accuracy of automated scoring. PMID- 29428327 TI - The Effect of Being Found with Stroke Symptoms on Predictors of Hospital Arrival. AB - BACKGROUND: Studies examining predictors of delay in hospital arrival after stroke symptom onset have not accounted for patients who are found with their symptoms and cannot seek help independently. Our objective is to show that inclusion of patients who are "found down" in studies of prehospital delay biases the estimated association of sociodemographic and clinical variables with time of hospital arrival. METHODS: We performed a retrospective analysis of sociodemographic and clinical characteristics of patients with acute ischemic stroke presenting to a tertiary care hospital in the Bronx, New York. RESULTS: Compared with all other patients with acute ischemic stroke (N = 1784), patients who were found down (N = 120) were more likely to be older (75 +/- 13 years versus 68 +/- 14 years, P < .0001), female (68% versus 53%, P = .003), Caucasian race (P < .001), have higher socioeconomic status (P = .001), more severe stroke deficits (P < .0001), use emergency medical services (P < .001), and arrive to the hospital more than 3 hours after symptom onset (P < .001). Inclusion of patients who were found down in a model predicting delay in hospital arrival decreased the strength of the association between the predictors and the outcome. CONCLUSIONS: Being found with stroke symptoms confounds the association of sociodemographic and clinical variables with time of hospital arrival. Studies of predictors of prehospital delay should therefore exclude patients who are found down. PMID- 29428328 TI - Mean Platelet Volume Is Associated with Early Neurological Deterioration in Patients with Branch Atheromatous Disease: Involvement of Platelet Activation. AB - BACKGROUND: The most attentive clinical problem in patients with branch atheromatous disease (BAD) is early neurological deterioration (END). Although the platelet activation (PA) is involved in pathogenesis, the relationship between PA and END has remained unclear. We investigated clinical data including mean platelet volume (MPV, fL) as a marker for PA to identify clinically useful biomarkers for END. METHODS: A total of 64 patients with BAD were investigated retrospectively, and divided into 2 groups based on whether neurologic symptoms deteriorated or not: BAD with and without END (END and non-END). The END was defined as patients with point increase of 1 or greater in the National Institutes of Health Stroke Scale (NIHSS); non-END was defined as those without such increase. Clinical features such as NIHSS, modified Rankin scale (mRS), laboratory data including MPV, lesion size (LS, mm) on admission, and treatments were compared between the 2 groups. RESULTS: Of 64 patients, 17 cases had an END. The median values of NIHSS, mRS, MPV, and LS on admission were significantly greater in END than in non-END (P < .05, respectively). There was no correlation of MPV with NIHSS, mRS and LS, respectively. The median values of MPV were significantly higher in END than in non-END and control (P < .05, respectively). A receiver operating characteristic curve indicated a value of 10.1 as cutoff level for MPV to discriminate between END and non-END. CONCLUSIONS: High MPV values on admission may be an independent biomarker for END. Physicians should pay more careful attention to END in BAD showing MPV values higher than 10.1 on admission. PMID- 29428329 TI - Three-Year Clinical Results of Carotid Artery Stenting in Treating Patients with Contralateral Carotid Artery Occlusion. AB - BACKGROUND: Patients presenting a carotid stenosis and contralateral carotid occlusion (CCO) have been historically considered at high risk of carotid surgical treatment, and there are few data regarding short-term recovery after stenting therapy in patients with CCO. The aim of this study is to evaluate the short-term recovery and safety of stenting for patients with CCO and different subgroup population. METHODS: We retrospectively reviewed the records of consecutive patients with CCO who were treated with stenting endovascular methods between 2008 and 2014. The postoperative outcomes were analyzed according to age, ischemic symptom, cerebral infarction history, and collateral situation subgroups, respectively. RESULTS: Fifty-eight consecutive patients with CCO were treated and 49 (84.5%) completed a 3-year follow-up. There were significant higher stroke, myocardial infarction, or death events in the aged (>=75 years old) group and poor collateral group (P = .007 and .0024, respectively). There was no difference in the 3-year primary endpoint incidence between the cerebral ischemia symptom subgroups and cerebral infarction history subgroups. Event-free survival, aged group, and poor collateral group were lower (P = .007 and P = .0024, respectively). CONCLUSIONS: Carotid artery stenting (CAS) for patients with common carotid artery is a safe and effective therapy. Factors such as age 75 years or older and poor collateral are associated with a higher 3-year rate of postprocedural stroke, myocardial infarction and death, and lower event-free survival in patients with CCO treated by CAS. Meanwhile, our data do not show a significant impact of cerebral ischemic symptom and cerebral infarction history on clinical outcome of patients with CCO undergoing CAS. PMID- 29428330 TI - Predictors of craving and substance use among patients with alcohol, tobacco, cannabis or opiate addictions: Commonalities and specificities across substances. AB - INTRODUCTION: Craving has been proposed as a major contributor to addiction relapse and the influence of mood on craving and substance use has been extensively documented. However, information is lacking concerning the extent to which the magnitude of these effects may vary according to different types of substances. The aim of the present study was to compare the prospective links between emotions, craving and substance use in four groups of patients beginning treatment for alcohol, tobacco, cannabis, or opiate addiction. METHODS: Ecological Momentary Assessment (EMA) was used over a two-week period. Data were analyzed using hierarchical linear modeling (HLM). RESULTS: 159 participants were recruited (67.3% male; M = 36.7 years). The average response rate to the EMA assessments was 83.1%. The findings confirmed the strong predictive role of craving intensity on substance use reported at the next assessment of the day among the alcohol (gamma = 0.224; p = .018), tobacco (gamma = 0.133; p = .013) and cannabis groups (gamma = 0.266; p = .019), but not for opiates (gamma = 0.098; p = .142). Craving intensity was itself predicted by greater anxious mood (gamma = 0.108; p = 0,029) and event negativity (gamma = 0.107; p = .003) among tobacco patients, lower sad mood among cannabis patients (gamma = -0.248; p = 0,002), and lower event negativity among opiate patients (gamma = -0.201; p = .002). CONCLUSION: While these results support the benefit of targeting craving in addiction treatment regardless of substance type, the substance-specific emotional risk factors for craving identified in this study may provide important insights for the development of personalized treatment strategies. PMID- 29428331 TI - Field-based method for evaluating the annual maximum specific conductivity tolerated by freshwater invertebrates. AB - Most water quality criteria are based on laboratory toxicity tests and usually include chronic and acute magnitudes. Field-based criteria are typically based on long-term or continuous exposures, so they are chronic. Biological responses of quantified, short-term aqueous exposures are seldom documented in the field. However, acute values may be derived by estimating an upper limit using temporal variance and chronic values. This method estimates an upper limit from the variance of pollutant measurements from stream locations that attain the chronic criterion. The formula for deriving a 90th centile of a standard normal distribution is used to identify the upper limit, a criterion maximum exposure concentration (CMEC). The calculated CMEC is interpreted as a maximum exposure that 95% of organisms may tolerate if the chronic exposure is not exceeded. The methods of deriving chronic and acute criteria are illustrated with specific conductivity in a mountainous area in the eastern United States. The biological relevance of the CMEC was assessed using the maximum annual exposure during the life cycle of the most salt-intolerant genera. The method using the chronic criterion and the variance of water chemistry data is practical, whereas frequently collecting and analyzing paired biological and chemical samples at numerous sites is impractical and may give misleading results due to lags in biological response. This method can be used anywhere with sufficient data to estimate the temporal variability and may be applicable for field-based criteria other than the specific conductivity criteria illustrated here. PMID- 29428332 TI - Development and exploration of the gratitude model of body appreciation in women. AB - Although researchers and clinicians recognize the importance of positive body image for women's well-being, development of theoretical frameworks for understanding positive body image has not kept pace with research documenting its many benefits. The present study proposed and tested a comprehensive model linking gratitude, contingent self-worth, social comparison, body appreciation, and intuitive eating. Path analysis indicated that this model fit the data for a sample of college and online community women (N = 263). Gratitude was indirectly linked to body appreciation via lower investment in self-worth based on appearance and others' approval, and via lower engagement in eating and body comparison. Gratitude had a strong direct effect on body appreciation, and body appreciation accounted for a large portion (88%) of gratitude's relationship with intuitive eating. These results provide strong preliminary support for the model, revealing that gratitude, which can be improved via intervention, plays a key role in body appreciation. PMID- 29428333 TI - The fit beauty ideal: A healthy alternative to thinness or a wolf in sheep's clothing? AB - Anecdotal testimony suggests the 'fit' female body ideal is 'healthier' than the thin ideal, because it simultaneously focuses on muscularity. However, statistical investigation into the outcomes associated with fit ideal internalisation is absent. Moderation analyses were used to investigate whether concurrent muscular internalisation mitigated the relationship between thin internalisation and; negative affect, body dissatisfaction, bulimic symptoms, and dieting. Further analyses were used to investigate whether concurrent thin internalisation amplified the relationship between muscular internalisation, compulsive exercise, and supplement use. No significant interaction was found on any of the outcome variables. Thus, the results suggest that incorporating muscularity into an ideal of thinness does not mitigate the detrimental eating and affective outcomes commonly associated with pursuing thinness. Equally, incorporating an ideal of thinness into one of muscularity does not appear to alter the detrimental behavioural outcomes commonly associated with pursuing muscularity. Such findings do not suggest fit internalisation is healthy for women. PMID- 29428335 TI - The Duodenum harbors a Broad Untapped Therapeutic Potential. PMID- 29428336 TI - Genetic variations of MTHFR gene and their association with preterm birth in Korean women. AB - BACKGROUND AND OBJECTIVE: The MTHFR gene encodes the methylenetetrahydrofolate reductase known to be involved in the homocysteine-methionine pathway. It has been reported that the deficiency of MTHFR activity may cause hyperhomocysteinemia which results in adverse pregnancy outcomes. Previous studies reported a correlation between the MTHFR gene polymorphisms (677 T/C and 1298 A/C) and lower MTHFR activity and its association with preterm birth in various populations. Since these results were conflicting, we analyzed the genetic association of MTHFR gene 677 T/C and 1298 A/C polymorphisms with preterm birth in Korean women. MATERIALS AND METHODS: The subjects for case-control study were collected a total of 226 Korean women (98 preterm-birth patients and 128 controls). Genotype frequency differences between the case and the control were assessed using chi-square tests. Mann-Whitney t-test was used to estimate the effects of 1298 A/C genotype on clinicopathological characteristics (systolic blood pressure, diastolic blood pressure, birth weight, and gestational age at delivery) in preterm-birth patients. RESULTS: Our results showed that the MTHFR 677 C/T polymorphism was significantly associated with preterm-birth patients in the analysis of genotype frequency (P=0.044) and the over-dominant model (OR=0.54; 95% CI, 0.320-0.920; P=0.023). The recessive model showed a marginal trend toward significance (OR=0.47; 95% CI, 0.220-1.010; P=0.046). The 1298 A/C polymorphism was also associated with reduced preterm-birth risk in the recessive model (P=0.032). In the correlation analysis, the 1298 C allele was significantly associated with increasing of gestational age at delivery in preterm-birth patients (P=0.034). CONCLUSIONS: Our findings suggested that the MTHFR gene 677 C/T and 1298 A/C polymorphisms might have protective effects for preterm birth in the Korean women. PMID- 29428337 TI - Relationship between diabetes mellitus and heart rate variability in community dwelling elders. AB - BACKGROUND AND OBJECTIVE: Diabetes mellitus is one of the most common non communicable diseases (NCDs) and may influence the autonomic nervous system. This study aims to analyze the autonomic control, through heart rate variability (HRV), from community-dwelling elders with (DM+) and without diabetes mellitus (DM-). MATERIALS AND METHODS: This cross-sectional study, in which 205 elders (>= 60 years old), from the urban area of Aiquara municipality gave their written consent to participate. HRV data was collected through a Polar RS800CX monitor with a 5-min initial record at rest, followed by the command to quickly stand up. RESULTS: The mean age was 71 years (SD, 7.32). The population was mostly made up of women 121 (59%), with low or no schooling 123 (60%), and low income 166 (81%). HRV analysis in a frequency domain showed no difference when comparing the two groups of DM+ and DM-. Henceforth in a time domain, the rMSSD showed a median value of 16.09 (interquartile range, 9.91-30.68); pNN50 median of 0.79 (interquartile range, 0.00-6.62), with a statistical significance between the group of DM+ and DM-. CONCLUSIONS: There is a difference between the studied groups principally in what concerns the time domain, which reflects the parasympathetic activity, suggesting that elders with diabetes mellitus may have a worse parasympathetic control. PMID- 29428338 TI - Extracorporeal Membrane Oxygenation Support During Pregnancy in Pulmonary Veno occlusive Disease. PMID- 29428334 TI - Biotechnology Challenges to In Vitro Maturation of Hepatic Stem Cells. AB - The incidence of liver disease is increasing globally. The only curative therapy for severe end-stage liver disease, liver transplantation, is limited by the shortage of organ donors. In vitro models of liver physiology have been developed and new technologies and approaches are progressing rapidly. Stem cells might be used as a source of liver tissue for development of models, therapies, and tissue engineering applications. However, we have been unable to generate and maintain stable and mature adult liver cells ex vivo. We review factors that promote hepatocyte differentiation and maturation, including growth factors, transcription factors, microRNAs, small molecules, and the microenvironment. We discuss how the hepatic circulation, microbiome, and nutrition affect liver function, and the criteria for considering cells derived from stem cells to be fully mature hepatocytes. We explain the challenges to cell transplantation and consider future technologies for use in hepatic stem cell maturation, including 3 dimensional biofabrication and genome modification. PMID- 29428339 TI - WITHDRAWN: Sickle cell disease; An overview of systemic and oral effects. PMID- 29428340 TI - Long-term outcomes of craniofacial implants for the restoration of facial defects. AB - The aim of this study was to evaluate the long-term survival of craniofacial implants and prostheses and to identify factors associated with failure in a cohort of patients. A 25-year retrospective analysis was conducted at Royal Melbourne Hospital. Data included demographic characteristics, age, site and cause of the deformity, and number and survival of implants. Odds ratios were calculated and event-to-time Kaplan-Meier analyses performed. One hundred and ten patients were included (341 implants); their mean age was 46.2 years. The overall implant survival rate was 79.5% (mean follow-up 10.6 years). Temporal implants had the highest success rate (97.0%), followed by nasal implants (87.5%) and orbital implants (63.3%); differences were statistically significant (P<0.0001 and P=0.033, respectively). Kaplan-Meier analyses to determine long-term implant and prosthesis survival found temporal implants had the highest prosthetic (P<0.0001) and implant survival (P<0.0001). Patients with congenital deformities demonstrated the highest success rate. Radiotherapy was found to increase the risk of implant failure (P=0.02). Craniofacial implant-retained prostheses are a reliable and effective option for the restoration of facial defects, with good long-term success rates. Orbital implants and those placed post oncological surgery have a higher failure rate. PMID- 29428341 TI - A method for characterizing essential tremor from the shoulder to the wrist. AB - BACKGROUND: Despite the pervasive and devastating effect of Essential Tremor (ET), the distribution of ET throughout the upper limb is unknown. We developed a method for characterizing the distribution of ET and performed a preliminary characterization in a small number of subjects with ET. METHODS: Using orientation sensors and inverse kinematics, we measured tremor in each of the seven major degrees of freedom (DOF) from the shoulder to the wrist while ten patients with mild ET assumed 16 different postures. We described the tremor in each DOF in terms of power spectral density measures and investigated how tremor varied between DOF, postures, gravitational torques, and repetitions. FINDINGS: Our method successfully resulted in tremor measures in each DOF, allowing one to compare tremor between DOF and determine the distribution of tremor throughout the upper limb, including how the distribution changes with posture. In our small number of subjects, we found that the amount of power in the frequency band associated with ET (4-12Hz) was lowest in the shoulder and greatest in the wrist. Similarly, the existence and amplitude of peaks in this band increased from proximal to distal. Although the amount of tremor differed significantly between postures, we did not find any clear patterns with changes in posture or gravitational torque. INTERPRETATION: This method can be used to characterize the distribution of tremor throughout the upper limb. Our preliminary characterization suggests that the amount of tremor increases in a proximal distal manner. PMID- 29428342 TI - Same But Different: FIM Summary Scores May Mask Variability in Physical Functioning Profiles. AB - OBJECTIVE: To examine how similar summary scores of physical functioning using the FIM can represent different patient clinical profiles. DESIGN: Retrospective cohort study. SETTING: Inpatient rehabilitation facilities. PARTICIPANTS: Medicare fee-for-service beneficiaries (N=765,441) discharged from inpatient rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We used patients' scores on items of the FIM to quantify their level of independence on both self-care and mobility domains. We then identified patients as requiring "no physical assistance" at discharge from inpatient rehabilitation by using a rule and score-based approach. RESULTS: In those patients with FIM self-care and mobility summary scores suggesting no physical assistance needed, we found that physical assistance was in fact needed frequently in bathroom-related activities (eg, continence, toilet and tub transfers, hygiene, clothes management) and with stairs. It was not uncommon for actual performance to be lower than what may be suggested by a summary score of those domains. CONCLUSIONS: Further research is needed to create clinically meaningful descriptions of summary scores from combined performances on individual items of physical functioning. PMID- 29428343 TI - Aerobic Stimulus Induced by Virtual Reality Games in Stroke Survivors. AB - OBJECTIVE: To evaluate whether virtual reality games (VRGs) in stroke survivors produce significant and reproducible heart rate and oxygen consumption (Vo2) responses during their execution, corresponding to an intensity between the anaerobic threshold (AT) and the respiratory compensation point (RCP). DESIGN: Single-subject, repeated-measure design. SETTING: Stroke survivors registered from a rehabilitation program. PARTICIPANTS: Chronic hemiparetic stroke survivors (N=12; 10 men; mean age +/- SD, 58+/-12y) rated at 3 or 4 in the Functional Ambulation Categories. INTERVENTIONS: Participants underwent, in a random order, 2 identical sessions of VRGs (console Xbox 360 + Kinect) and 1 control session (38min watching a movie). The VRG sessions were composed of 4 sets of VRGs (3min of tennis, 1min for changing the game, and 4min of boxing) interspaced with 2 minutes of rest. MAIN OUTCOME MEASURES: Heart rate and Vo2 were measured during the experimental sessions and compared with heart rate and Vo2 obtained at AT and RCP assessed during a maximal cardiopulmonary exercise test. RESULTS: Heart rate and Vo2 during VRGs had good reproducibility (intraclass correlation coefficients, >=.91 and >=.85, respectively; coefficients of variation, <=6.7% and <=13.7%, respectively). Heart rate during VRGs was similar to AT and significantly lower than RCP (P<=.05), while Vo2 was significantly lower than AT and RCP (P<.05). CONCLUSIONS: An acute session of VRGs composed of tennis and boxing games using the console XBox 360 + Kinect promotes reproducible responses of heart rate and Vo2 that corresponded, respectively, to AT and below AT, characterizing a low-intensity aerobic stimulus. PMID- 29428344 TI - Effects of Timing and Intensity of Neurorehabilitation on Functional Outcome After Traumatic Brain Injury: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To systematically review evidence on the effects of timing and intensity of neurorehabilitation on the functional recovery of patients with moderate to severe traumatic brain injury (TBI) and aggregate the available evidence using meta-analytic methods. DATA SOURCES: PubMed, Embase, PsycINFO, and Cochrane Database. STUDY SELECTION: Electronic databases were searched for prospective controlled clinical trials assessing the effect of timing or intensity of multidisciplinary neurorehabilitation programs on functional outcome of patients with moderate or severe TBI. A total of 5961 unique records were screened for relevance, of which 58 full-text articles were assessed for eligibility by 2 independent authors. Eleven articles were included for systematic review and meta-analysis. DATA EXTRACTION: Two independent authors performed data extraction and risk of bias analysis using the Cochrane Collaboration tool. Discrepancies between authors were resolved by consensus. DATA SYNTHESIS: Systematic review of a total of 6 randomized controlled trials, 1 quasi-randomized trial, and 4 controlled trials revealed consistent evidence for a beneficial effect of early onset neurorehabilitation in the trauma center and intensive neurorehabilitation in the rehabilitation facility on functional outcome compared with usual care. Meta-analytic quantification revealed a large sized positive effect for early onset rehabilitation programs (d=1.02; P<.001; 95% confidence interval [CI], 0.56-1.47) and a medium-sized positive effect for intensive neurorehabilitation programs (d=.67; P<.001; 95% CI, .38-.97) compared with usual care. These effects were replicated based solely on studies with a low overall risk of bias. CONCLUSIONS: The available evidence indicates that early onset neurorehabilitation in the trauma center and more intensive neurorehabilitation in the rehabilitation facility promote functional recovery of patients with moderate to severe TBI compared with usual care. These findings support the integration of early onset and more intensive neurorehabilitation in the chain of care for patients with TBI. PMID- 29428345 TI - Self-Regulatory Strategies as Correlates of Physical Activity Behavior in Persons With Multiple Sclerosis. AB - OBJECTIVE: To examine self-regulation strategies as correlates of physical activity in persons with multiple sclerosis (MS). DESIGN: Cross-sectional, or survey, study. SETTING: University-based research laboratory. PARTICIPANTS: Convenience sample of persons with MS (N=68). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Exercise Self-Efficacy Scale (EXSE), 12-item Physical Activity Self-Regulation Scale (PASR-12), and Godin Leisure-Time Exercise Questionnaire (GLTEQ). RESULTS: Correlation analyses indicated that GLTEQ scores were positively and significantly associated with overall self-regulation (r=.43), self-monitoring (r=.45), goal-setting (r=.27), reinforcement (r=.30), time management (r=.41), and relapse prevention (r=.53) PASR-12 scores. Regression analyses indicated that relapse prevention (B=5.01; SE B=1.74; beta=.51) and self monitoring (B=3.65; SE B=1.71; beta=.33) were unique predictors of physical activity behavior, and relapse prevention demonstrated a significant association with physical activity behavior that was accounted for by EXSE. CONCLUSIONS: Our results indicate that self-regulatory strategies, particularly relapse prevention, may be important correlates of physical activity behavior that can inform the design of future behavioral interventions in MS. PMID- 29428346 TI - Improvement on the Coma Recovery Scale-Revised During the First Four Weeks of Hospital Stay Predicts Outcome at Discharge in Intensive Rehabilitation After Severe Brain Injury. AB - OBJECTIVES: To evaluate the prognostic utility of serial assessment on the Coma Recovery Scale-Revised (CRS-R) during the first 4 weeks of intensive rehabilitation in patients surviving a severe brain injury. DESIGN: Prospective cohort study. SETTING: An intensive rehabilitation unit. PARTICIPANTS: Patients (N=110) consecutively admitted to the intensive rehabilitation unit. Inclusion criteria were (1) a diagnosis of unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS) caused by an acquired brain injury, and (2) aged >18 years. INTERVENTIONS: All patients underwent clinical evaluations using the Italian version of the CRS-R during the first month of hospital stay. MAIN OUTCOME MEASURES: Behavioral classification on the CRS-R and the score on the Glasgow Outcome Scale (GOS) at final discharge. Patients transitioning from UWS to MCS or emergence from MCS (E-MCS), and from MCS to E-MCS were classified as patients with improved responsiveness (IR). RESULTS: After a mean +/- SD hospital stay of 5.3+/-2.7 months, 59 of 110 patients (53.6%) achieved IR. In the multivariable analysis, a higher CRS-R score change at week 4 (odds ratio =1.99; 95% confidence interval [CI], 1.49-2.66; P<.001) was the only significant predictor of IR at discharge. Fifty-three patients (48.2%) were classified as severely impaired at discharge (GOS=3). In the multivariable analysis, higher GOS scores were related to a higher CRS-R score at admission (B=.051; 95% CI, .027 .074; P<.001), a higher CRS-R score change at week 4 (B=.087; 95% CI, .064-.110; P<.001), and an absence of severe infections (B=-.477; 95% CI, -.778 to -.176; P=.002). CONCLUSIONS: An improvement on the total CRS-R score and on different subscales across the first 4 weeks of inpatient rehabilitation discriminates patients who will have a better outcome at discharge, providing information for rehabilitation planning and for communication with patients and their caregivers. PMID- 29428347 TI - Optimizing the Management of Spasticity in People With Spinal Cord Damage: A Clinical Care Pathway for Assessment and Treatment Decision Making From the Ability Network, an International Initiative. AB - The recognition, evaluation, and management of disabling spasticity in persons with spinal cord damage (SCD) is a challenge for health care professionals, institutions, health systems, and patients. To guide the assessment and management of disabling spasticity in individuals with SCD, the Ability Network, an international panel of clinical experts, developed a clinical care pathway. The aim of this pathway is to facilitate treatment decisions that take into account the effect of disabling spasticity on health status, individual preferences and treatment goals, tolerance for adverse events, and burden on caregivers. The pathway emphasizes a patient-centered, individualized approach and the need for interdisciplinary coordination of care, patient involvement in goal setting, and the use of assessment and outcome measures that lend themselves to practical application in the clinic. The clinical care pathway is intended for use by health care professionals who provide care for persons with SCD and disabling spasticity in various settings. Barriers to optimal spasticity management in these people are also discussed. There is an urgent need for the clinical community to clarify and overcome barriers (knowledge-based, organizational, health system) to optimizing the management of spasticity in people with SCD. PMID- 29428348 TI - Creation and Initial Validation of the International Dysphagia Diet Standardisation Initiative Functional Diet Scale. AB - OBJECTIVE: To assess consensual validity, interrater reliability, and criterion validity of the International Dysphagia Diet Standardisation Initiative Functional Diet Scale, a new functional outcome scale intended to capture the severity of oropharyngeal dysphagia, as represented by the degree of diet texture restriction recommended for the patient. DESIGN: Participants assigned International Dysphagia Diet Standardisation Initiative Functional Diet Scale scores to 16 clinical cases. Consensual validity was measured against reference scores determined by an author reference panel. Interrater reliability was measured overall and across quartile subsets of the dataset. Criterion validity was evaluated versus Functional Oral Intake Scale (FOIS) scores assigned by survey respondents to the same case scenarios. Feedback was requested regarding ease and likelihood of use. SETTING: Web-based survey. PARTICIPANTS: Respondents (N=170) from 29 countries. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Consensual validity (percent agreement and Kendall tau), criterion validity (Spearman rank correlation), and interrater reliability (Kendall concordance and intraclass coefficients). RESULTS: The International Dysphagia Diet Standardisation Initiative Functional Diet Scale showed strong consensual validity, criterion validity, and interrater reliability. Scenarios involving liquid-only diets, transition from nonoral feeding, or trial diet advances in therapy showed the poorest consensus, indicating a need for clear instructions on how to score these situations. The International Dysphagia Diet Standardisation Initiative Functional Diet Scale showed greater sensitivity than the FOIS to specific changes in diet. Most (>70%) respondents indicated enthusiasm for implementing the International Dysphagia Diet Standardisation Initiative Functional Diet Scale. CONCLUSIONS: This initial validation study suggests that the International Dysphagia Diet Standardisation Initiative Functional Diet Scale has strong consensual and criterion validity and can be used reliably by clinicians to capture diet texture restriction and progression in people with dysphagia. PMID- 29428349 TI - CLARITY-BPA: Effects of chronic Bisphenol A exposure on the immune system: Part 1 - Quantification of the relative number and proportion of leukocyte populations in the spleen and thymus. AB - Bisphenol A (BPA) is extensively used in manufacturing of a broad range of consumer products worldwide. Due to its widespread use, human exposure to BPA is virtually ubiquitous. Broad human exposure coupled with a large scientific literature describing estrogenic activity of BPA in animals has raised public health concerns. To comprehensively evaluate the health effects of BPA exposure, a chronic toxicity study using a wide-range of BPA doses (2.5-25000 MUg/kg bw/day) was conducted jointly by the NTP, thirteen NIEHS-supported grantees, and the FDA, which is called the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA). As a participant in the CLARITY-BPA project, the objective of the current study was to evaluate the effects of chronic BPA exposure in Sprague-Dawley rats on the relative number and proportion of defined leukocyte populations in the spleen and the thymus. Toward this end, lymphoid tissues from a total of 641 rats were assayed after being continuously dosed with BPA or controls for up to one year. To comprehensively evaluate the effects of BPA on leukocyte compositions, extensive endpoints that cover major populations of leukocytes were assessed, including B cells, T cells, NK cells, granulocytes, monocytes, macrophages and dendritic cells. In total, of the 530 measurements in BPA-treated rats, 10 measurements were statistically different from vehicle controls and were mainly associated with either the macrophage or dendritic cell populations. Most, if not all, of these alterations were found to be transient with no persistent trend over the one-year time period. In addition, the observed BPA-associated alterations were mostly moderate in magnitude and not dose dependent. Due to the aforementioned, it is unlikely that the observed BPA mediated changes alone would adversely affect immune competence. PMID- 29428351 TI - Theory of mind in remitted bipolar disorder: Younger patients struggle in tasks of higher ecological validity. AB - BACKGROUND: To date, research concerning Theory of Mind (ToM) in remitted bipolar disorder (rBD) has yielded inconclusive results. This may be a result of methodological shortcomings and the failure to consider relevant third variables. Furthermore, studies using ecologically valid stimuli are rare. This study examines ToM in rBD patients, using ecologically valid stimuli. Additionally, the effects of sad mood induction (MI) as well as of age and gender are considered. METHODS: The sample comprises N = 44 rBD patients (rBDPs) and N = 40 healthy controls (HCs). ToM decoding is assessed using the Cambridge Mindreading Face Voice-Battery (CAM) and ToM reasoning using the Movie for the Assessment of Social Cognition (MASC). Both tasks were divided into two parts to conduct one part with and one without MI. RESULTS: While across the whole sample there was no evidence that rBDPs and HCs differed in ToM decoding or reasoning, in the younger subsample (age < 45) rBDPs performed worse than HCs in ToM decoding. While MI negatively influenced reasoning in both groups, gender had no effect. LIMITATIONS: Most patients in this study had a high level of social functioning, limiting the generalizability of the results. CONCLUSION: As important social steps have to be undertaken before middle-age, the decoding deficits in younger rBDPs might be of particular importance not only for social functioning but also for the course of illness. Furthermore, this age-related deficit may explain the inconclusive findings that have been reported so far. PMID- 29428350 TI - The Pivotal Role of Ethylene in Plant Growth. AB - Being continuously exposed to variable environmental conditions, plants produce phytohormones to react quickly and specifically to these changes. The phytohormone ethylene is produced in response to multiple stresses. While the role of ethylene in defense responses to pathogens is widely recognized, recent studies in arabidopsis and crop species highlight an emerging key role for ethylene in the regulation of organ growth and yield under abiotic stress. Molecular connections between ethylene and growth-regulatory pathways have been uncovered, and altering the expression of ethylene response factors (ERFs) provides a new strategy for targeted ethylene-response engineering. Crops with optimized ethylene responses show improved growth in the field, opening new windows for future crop improvement. This review focuses on how ethylene regulates shoot growth, with an emphasis on leaves. PMID- 29428352 TI - The influence of the anesthesia-to-stimulation time interval on seizure quality parameters in electroconvulsive therapy. AB - BACKGROUND: Electroconvulsive therapy (ECT) continues to be the most efficacious treatment for severe depression and other life-threatening acute psychiatric conditions. Treatment efficacy is dependent upon the induced seizure quality, which may be influenced by a range of treatment related factors. Recently, the time interval from anesthesia to the electrical stimulation (ASTI) has been suggested to be an important determinant of seizure quality. METHODS: We measured ASTI in 73 ECT sessions given to 22 individual patients, and analyzed its influence on five seizure quality parameters (EEG seizure time, power, coherence, postictal suppression, and peak heart rate). RESULTS: Longer ASTI was significantly associated with higher peak heart rate during the seizure (p = .003). After adjustment for confounders, the association continued to be significant, even after Bonferroni correction for multiple comparisons (p = .005). ASTI was not significantly associated with other seizure parameters. LIMITATIONS: The relatively low number of sessions may lead to false negative findings. The study did not include clinical outcomes. CONCLUSIONS: Longer ASTI is associated with higher peak heart rate; a phenomenon which is thought to reflect better seizure propagation to subcortical areas of the brain. The finding indicates that delay of stimulation after anesthesia could be a simple way of improving seizure quality and thereby the clinical effect of ECT. PMID- 29428353 TI - Structural characteristics of the online social networks of maltreated youth and offline sexual risk behavior. AB - Maltreated youth are at risk for exposure to online sexual content and high-risk sexual behavior, yet characteristics of their online social networks have not been examined as a potential source of vulnerability. The aims of the current study were: 1) to test indicators of size (number of friends) and fragmentation (number of connections between friends) of maltreated young adults' online networks as predictors of intentional and unintentional exposure to sexual content and offline high-risk sexual behavior and 2) to test maltreatment as a moderator of these associations. Participants were selected from a longitudinal study on the effects of child maltreatment (n = 152; Mean age 21.84 years). Data downloaded from Facebook were used to calculate network variables of size (number of friends), density (connections between friends), average degree (average number of connections for each friend), and percent isolates (those not connected to others in the network). Self-reports of intentional and unintentional exposure to online sexual content and offline high-risk sexual behavior were the outcome variables. Multiple-group path modeling showed that only for the maltreated group having a higher percent of isolates in the network predicted intentional exposure to online sexual content and offline high-risk sexual behavior. An implication of this finding is that the composition of the Facebook network may be used as a risk indicator for individuals with child-welfare documented maltreatment experiences. PMID- 29428354 TI - Uncommon Filaggrin Variants Are Associated with Persistent Atopic Dermatitis in African Americans. AB - Atopic dermatitis (AD) is a common illness that has been associated with filaggrin gene (FLG) loss of function (LoF) variation. In African Americans, a group that commonly has AD and has not been well studied, FLG LoF variation is rarely found. Our objective was to use massively parallel sequencing to evaluate FLG LoF variation in children of African ancestry to evaluate the association between FLG LoF variation and AD and AD persistence. We studied 262 African American children with AD. Nine unique FLG exon 3 LoF variants were identified for an overall minor variant frequency of 6.30% (95% confidence interval [CI] = 4.37-8.73). The most common variants were p.R501X (1.72%, 95% CI = 0.79-3.24), p.S3316X (1.34%, 95% CI = 0.54-2.73), and p.R826X (0.95%, 95% CI = 0.31-2.2). Over an average follow-up period of 96.4 (95% CI = 92.0-100.8) months, African American children with FLG LoF were less likely to be symptom free (odds ratio = 0.36, 95% CI = 0.14-0.89, P = 0.027) compared with a FLG wild-type child. In contrast to previous reports, uncommon FLG LoF variants in African American children exist and are associated with AD and more persistent AD. In contrast to Europeans, no FLG LoF variants predominate in African American children. Properly determining FLG LoF status requires advanced sequencing techniques. PMID- 29428356 TI - Classification of the Clinical Images for Benign and Malignant Cutaneous Tumors Using a Deep Learning Algorithm. AB - We tested the use of a deep learning algorithm to classify the clinical images of 12 skin diseases-basal cell carcinoma, squamous cell carcinoma, intraepithelial carcinoma, actinic keratosis, seborrheic keratosis, malignant melanoma, melanocytic nevus, lentigo, pyogenic granuloma, hemangioma, dermatofibroma, and wart. The convolutional neural network (Microsoft ResNet-152 model; Microsoft Research Asia, Beijing, China) was fine-tuned with images from the training portion of the Asan dataset, MED-NODE dataset, and atlas site images (19,398 images in total). The trained model was validated with the testing portion of the Asan, Hallym and Edinburgh datasets. With the Asan dataset, the area under the curve for the diagnosis of basal cell carcinoma, squamous cell carcinoma, intraepithelial carcinoma, and melanoma was 0.96 +/- 0.01, 0.83 +/- 0.01, 0.82 +/ 0.02, and 0.96 +/- 0.00, respectively. With the Edinburgh dataset, the area under the curve for the corresponding diseases was 0.90 +/- 0.01, 0.91 +/- 0.01, 0.83 +/- 0.01, and 0.88 +/- 0.01, respectively. With the Hallym dataset, the sensitivity for basal cell carcinoma diagnosis was 87.1% +/- 6.0%. The tested algorithm performance with 480 Asan and Edinburgh images was comparable to that of 16 dermatologists. To improve the performance of convolutional neural network, additional images with a broader range of ages and ethnicities should be collected. PMID- 29428357 TI - Transcatheter Aortic Valve Replacement With TandemHeart Support in a Patient With Cardiogenic Shock. PMID- 29428355 TI - Dissecting Wnt Signaling for Melanocyte Regulation during Wound Healing. AB - Abnormal pigmentation is commonly seen in the wound scar. Despite advancements in the research of wound healing, little is known about the repopulation of melanocytes in the healed skin. Previous studies have shown the capacity of melanocyte stem cells in the hair follicle to contribute skin epidermal melanocytes after injury in mice and humans. Here, we focused on the Wnt pathway, known to be a vital regulator of melanocyte stem cells in efforts to better understand the regulation of follicle-derived epidermal melanocytes during wound healing. We showed that transgenic expression of Wnt inhibitor Dkk1 in melanocytes reduced epidermal melanocytes in the wound scar. Conversely, forced activation of Wnt signaling by genetically stabilizing beta-catenin in melanocytes increases epidermal melanocytes. Furthermore, we show that deletion of Wntless (Wls), a gene required for Wnt ligand secretion, within epithelial cells results in failure in activating Wnt signaling in adjacent epidermal melanocytes. These results show the essential function of extrinsic Wnt ligands in initiating Wnt signaling in follicle-derived epidermal melanocytes during wound healing. Collectively, our results suggest the potential for Wnt signal regulation to promote melanocyte regeneration and provide a potential molecular window to promote proper melanocyte regeneration after wounding and in conditions such as vitiligo. PMID- 29428358 TI - Central Veno-Arterial Extracorporeal Membrane Oxygenation (C-VA-ECMO) After Cardiothoracic Surgery: A Single-Center Experience. AB - OBJECTIVES: Central veno-arterial extracorporeal membrane oxygenation (C-VA-ECMO) provides temporary cardiorespiratory support for patients in heart failure who cannot be weaned from cardiopulmonary bypass successfully. Outcomes are influenced by the reversibility of the initial insult and complications of the technique. METHODS: The authors reviewed their single-center experience over the last 8 years to inform future practice. The study included all patients supported with C-VA-ECMO after cardiothoracic surgery between January 2008 and July 2016. The authors identified mortality risk factors using logistic regression analysis and chi-square tests. RESULTS: One hundred and one patients were supported with C VA-ECMO during the studied period. Weaning from ECMO was successful in 57.4% of patients, whereas 7.9% were bridged to veno-venous ECMO, 2% to peripheral veno arterial ECMO, and 2% to biventricular ventricular assist devices. In-hospital and 1-year survival for all patients was 33.7% and 27.7%, respectively. Survival was considerably higher in transplantation patients (n = 11), at 63.6% and 54.5%, respectively. Risk factors linked to in-hospital mortality were age older than 70 years, lactate level greater than 4 mmol/L after 48 hours, and hepatic and kidney failure during ECMO support. CONCLUSIONS: Overall one-third of patients in the cohort who the authors believe would otherwise have died from postcardiotomy cardiogenic shock survived because C-VA-ECMO was commenced after cardiac surgery. Survival is greater in transplantation patients necessitating this form of support during or immediately after surgery. PMID- 29428359 TI - LAParoscopic simulator for pediatric ureteral reimplantation (LAP-SPUR) following the Lich-Gregoir technique. AB - OBJECTIVE: Acquiring surgical skills requires regular practice. Medical evidence supports that these skills can be learned outside the operating room (OR). The aim of the current study was to describe the first laparoscopic simulator for ureteral reimplantation (LAP-SPUR) following Lich- Gregoir technique. MATERIALS AND METHODS: LAP-SPUR was manufactured using reusable and disposable materials. The technique can be summarized in the following five steps: (1) a transperitoneal approach; (2) extra-vesical ureteral dissection; (3) detrusor division until exposing the mucosa; (4) reimplanting ureter into the new tunnel; and (5) reapproximation and suturing of the detrusor. LAP-SPUR was evaluated through a survey answered by urologists and surgeons. A 5-point Likert scale was employed for most items and the medians test was chosen to compare the response among physicians according to the number of laparoscopic surgical procedures performed per week (<=2 versus >2) and the experience in ureteral reimplantation of the respondent as a dichotomous variable (0 versus >=1 repairs). RESULTS: Thirty-four surveys were answered. The simulator was reported to: have a very high level of realism by the experts; be a reproducible procedure with similar anatomical structures and working space to pediatric patients by the non-experts; be extremely useful, easy and ergonomic for laparoscopic training outside the OR; be lightweight and portable for straightforward transportation; be inexpensive; and be reusable and have low maintenance requirements. It was found to provide a secure environment for trainees, to enhance cognitive knowledge acquisitions, and to increase technical performance. Only tissue handling was non-significant when groups were compared. CONCLUSION: Augmenting surgical dexterity using LAP-SPUR offered great promise because maneuvers could be rehearsed over and over until they were mastered. Of the urologists and surgeons who were evaluated, 100% reported lack of training at their institutions; therefore, all of them would definitely benefit by practicing with LAP-SPUR to enhance technical skill acquirement. Further development and validation are still needed to assess its true benefits. PMID- 29428360 TI - Adolescent testicular microlithiasis: A case-based, multinational survey of clinical management practices. AB - INTRODUCTION: Testicular microlithiasis (TM) is a condition characterized by calcium deposits within the testis, usually detected incidentally during ultrasonography of the scrotum. TM has been associated with the presence of, and possibly the development of, testicular malignancy. Our aim was to document international clinical management practices for TM and to analyze what factors and perception of risk influence conservative versus active management and follow up. METHODS: European Society for Paediatric Urology (ESPU) and Society for Pediatric Urology (SPU) members were invited to complete an online case-based survey of clinical management practices of TM. Eight cases had a single variable changed each time (classic versus limited TM, unilateral versus bilateral, prior cryptorchidism versus no cryptorchidism) to ascertain the provider's perception of risk. The respondents completed multiple choice questions on initial management, follow-up plan, length and interval of follow-up. Multivariate logistic regression was performed to determine factors associated with decisions on management and follow-up. RESULTS: There were 265 respondents to the survey from 35 countries (Table). Median time in practice was 13 years. Factors that were significantly associated with more aggressive initial management (more than counseling on self-examination) included: not yet in independent practice, low volume TM cases per year, those practicing pediatric and adult urology, classic appearance of TM and cryptorchidism. Factors that were significantly associated with urologist follow-up and active investigation included: European practitioners, low TM case volume per year, those practicing both pediatric urology and pediatric surgery, classic TM appearance and a case history of cryptorchidism. Interval and length of follow-up was wide-ranging, with most respondents favoring annual follow-up. CONCLUSION: Management of TM varies and a mix of surgeon and case factors significantly influences management strategies. This baseline understanding of the lack of systematic management suggests the need for the development of consensus guidelines and prospective study. PMID- 29428361 TI - Ethical issues in research: Human and animal experimentation. PMID- 29428362 TI - Changes in antimicrobial resistance and demographics of UTIs in pediatric patients in a single institution over a 6-year period. AB - PURPOSE: To determine changes in antimicrobial resistance and demographics of UTIs in pediatric patients in a single institution over a 6-year period. MATERIALS AND METHODS: The current study examined outpatient urinary isolates from patients aged <18 years. A retrospective cross-sectional analysis of bacteria isolated from children with UTI was performed between 2009 and 2014. The most common bacterial pathogens were determined in the following four age groups: <2 years; 2-5 years; 6-12 years; and 13-17 years. The study analyzed the prevalence and antibiotic resistance patterns for the six most common uropathogens: Escherichia coli, Proteus, Klebsiella, Enterobacter, Pseudomonas and Enterococcus (Summary table). The antibiotic resistance pattern for UTI during 2009-2014 was also examined. RESULTS: A total of 6515 urinary cultures was examined. The majority of these isolates were from female patients (66.8%). E. coli was the most common uropathogen overall, but the prevalence of E. coli was higher among females (79.5%) than males (54.9%). The biggest percentage of isolates in males was from children aged <2 years (46.1%). Conversely, the majority of isolates in females were from children aged >6 years (46.8%). Results of antimicrobial resistance for E. coli were the highest for ampicillin (70%) and lowest for meropenem (0.19%). Comparing the hospital network data from 2009 to 2014, E. coli resistance increased for ampicillin (from 47.1% to 89%), trimethoprim-sulfamethoxazole (TMP-SMX) (from 44.8% to 56%) and nitrofurantoin (from 5.3% to 15.1%). In contrast, cephalosporins have maintained low antibiotic resistance. CONCLUSION: UTI in females was nearly twice as common than in males. E. coli remained the most common pediatric uropathogen. Although widely used in other tract infections, ampicillin was a poor empiric choice for pediatric UTIs. Cephalosporins were appropriate alternatives given their low resistance rates. A successful empirical treatment protocol should be based on local epidemiology and susceptibility rates. PMID- 29428363 TI - Psychometric properties of the INICO-FEAPS scale in a Danish sample with autism spectrum disorders. AB - BACKGROUND: There is a need to evaluate subjective perspectives of outcomes, such as quality of life (QoL), in individuals with autism spectrum disorders (ASD), but to date, there is no specific instrument available to assess this population. While the INICO-FEAPS scale is customized for studying QoL in adolescents and adults with intellectual and/or developmental disabilities, this scale has not been previously evaluated in an ASD population. AIMS: To examine the usability of the INICO-FEAPS scale in a Danish population of adolescents and adults with ASD. METHODS: In a nationwide survey, 875 adolescents and adults with ASD and 1573 parents completed the INICO-FEAPS scale. Internal consistency was evaluated through several indices. Confirmatory factor analysis (CFA) was conducted to investigate the fit of the model with eight correlated first-order factors, and convergent validity was explored comparing the results of different QoL measures through correlation analysis. RESULTS: Internal consistency was adequate for the indices applied, and the CFA model tested indicated an acceptable fit to the data. Generally, comparisons of results of different QoL measures resulted in moderate to high correlations. CONCLUSION: Overall, it was concluded that due to the psychometric properties found, the INICO-FEAPS scale is applicable for use in ASD populations. PMID- 29428365 TI - The mechanisms linking obesity to colon cancer: An overview. AB - Obesity, characterised as a chronic low-grade inflammation is a crucial risk factor for colon cancer. The expansion of the adipose tissue is related to elevated triglyceride and low-density lipoprotein (LDL) levels and hyperinsulinemia, which all are presumed mediators of the tumour development. Obesity is also believed to support carcinogenesis by activating the insulin/IGF 1 pathway. Moreover, obesity increases the level of proinflammatory cytokines (e.g. TNF-alpha, IL-1, and IL-6) and has a significant impact on selected adipokines. This paper briefly outlines the latest evidence of the linkage between the obesity and colon cancer and discusses its possible implication for the improvement of anticancer prevention and treatment strategies connected with nutrition. PMID- 29428367 TI - Re: Prevalence and Prognosis of Low-volume, Oligorecurrent, Hormone-sensitive Prostate Cancer Amenable to Lesion Ablative Therapy. PMID- 29428366 TI - Electrochemical integrated paper-based immunosensor modified with multi-walled carbon nanotubes nanocomposites for point-of-care testing of 17beta-estradiol. AB - 17beta-estradiol (17beta-E2) plays a critical role in regulating reproduction in human, there is therefore an urgent need to detect it sensitively and precisely in a cost-effective and easy method. In this paper, a label-free integrated microfluidic paper-based analytical device was developed for highly sensitive electrochemical detection of 17beta-E2. The microfluidic channel of the paper based sensor was fabricated with wax printing and the three electrodes, including working, counter and reference electrode were screen-printed. Multi-walled carbon nanotubes (MWCNTs)/ thionine (THI)/ gold nanoparticles (AuNPs) Nano composites were synthesized and coated on screen-printed working electrode (SPWE) for the immobilization of anti-E2. In this electro-chemical system of paper-based immunoassay, THI molecules serving as an electrochemical mediator while MWCNTs and AuNPs, due to their excellent electrical conductivities, could accelerate electron transfer for the signal amplification. Experimental results revealed that the immunoassay is able to detect 17beta-E2 as low as 10 pg mL-1, with a linear range from 0.01 to 100 ng mL-1. This microfluidic paper-based immunosensor would provide a new platform for low cost, sensitive, specific, and point-of-care diagnosis of 17beta-E2. PMID- 29428368 TI - Leaders Growing Leaders: Designing a Tier-Based Leadership Program for Surgeons. AB - BACKGROUND: Leadership has emerged as a crucial component of professional development for physicians in academic medicine. Most leadership skills can be learned and therefore best practices of delivering leadership development are in high demand. For practicing surgeons, specific strategies to teach leadership have been lacking. OBJECTIVE: The purpose of this paper is to describe the structure of a tier-based leadership development program called Leaders Growing Leaders, to identify the major curricular components to each tier including measures and outcomes, and to share lessons learned for those who may want to begin a similar leadership development program. PMID- 29428369 TI - Radiotherapeutic factors affecting the incidence of developing hypothyroidism after radiotherapy for head and neck squamous cell cancer. AB - PURPOSE: The purpose of this study is to determine radiotherapy (RT) dose volumetric threshold of radiation-induced hypothyroidism (HT) in head and neck squamous cell carcinoma (HNSCC) patients. PATIENTS AND METHODS: The diagnosis of HT in 78 HNSCC patients treated with RT was based on a thyroid stimulating hormone (TSH) level greater than the maximum value of laboratory range. In all patients, dose-volumetric parameters were analyzed according to their relation to development of HT, and thyroid volumes spared from doses >=10, 20, 30, 40 and 50 Gy (V10, V20, V30, V40 and V50) were analyzed from the dose volume histograms (DVHs). RESULTS: Median follow-up duration was 31 months. At the end of study, 33 patients (42.3%) developed HT and the cumulative incidence of HT was 24.6%, 36.5% and 42.3% at one, two and three years, respectively. V30 of 42.1% (P = 0.005) was defined as dose-volumetric threshold of radiation-induced HT in HNSCC patients. Our analysis showed that V30 separates patients into low- and high-risk groups; the incidence of radiation-induced HT in the group with V30 < 42.1% and V30 >= 42.1% was 29.4% and 71.4%, respectively (P = 0.002). CONCLUSIONS: The V30 may predict risk of developing HT after RT for HNSCC patients. V30 of 42.1%, defined as dose-volumetric threshold of radiation-induced HT, can be useful in treatment planning of HNSCC patients. PMID- 29428364 TI - Metaplasticity at the addicted tetrapartite synapse: A common denominator of drug induced adaptations and potential treatment target for addiction. AB - In light of the current worldwide addiction epidemic, the need for successful therapies is more urgent than ever. Although we made substantial progress in our basic understanding of addiction, reliable therapies are lacking. Since 40-60% of patients treated for substance use disorder return to active substance use within a year following treatment discharge, alleviating the vulnerability to relapse is regarded as the most promising avenue for addiction therapy. Preclinical addiction research often focuses on maladaptive synaptic plasticity within the reward pathway. However, drug induced neuroadaptations do not only lead to a strengthening of distinct drug associated cues and drug conditioned behaviors, but also seem to increase plasticity thresholds for environmental stimuli that are not associated with the drug. This form of higher order plasticity, or synaptic metaplasticity, is not expressed as a change in the efficacy of synaptic transmission but as a change in the direction or degree of plasticity induced by a distinct stimulation pattern. Experimental addiction research has demonstrated metaplasticity after exposure to multiple classes of addictive drugs. In this review we will focus on the concept of synaptic metaplasticity in the context of preclinical addiction research. We will take a closer look at the tetrapartite glutamatergic synapse and outline forms of metaplasticity that have been described at the addicted synapse. Finally we will discuss the different potential avenues for pharmacotherapies that target glutamatergic synaptic plasticity and metaplasticity. Here we will argue that aberrant metaplasticity renders the reward seeking circuitry more rigid and hence less able to adapt to changing environmental contingencies. An understanding of the molecular mechanisms that underlie this metaplasticity is crucial for the development of new strategies for addiction therapy. The correction of drug-induced metaplasticity could be used to support behavioral and pharmacotherapies for the treatment of addiction. PMID- 29428370 TI - Reinforcing the utility of chick embryo model to in vivo evaluate engraftment of human leukemic stem cells. AB - BACKGROUND AND OBJECTIVE: Development of appropriate translational in vivo models is a prerequisite for personalized management of leukemic patients. Indeed, several immunodeficient mice models were developed for leukemias with main limitations due to their high cost, demanding management, and elongated assessment intervals. In this report, we aimed at evaluating the engraftment of CD34+ cells, isolated from an acute myeloid leukemia (AML) patient, in naturally immunodeficient chick embryo model. METHODS AND RESULTS: Mononuclear cells or immunomagnetic sorted CD34+ cells were injected into chick embryo chorioallantoic membrane (CAM) veins. Seven days post-injection, human CD34 transcript was detected by reverse transcription polymerase chain reaction (RT-PCR) in blood, bone marrow (BM), spleen and liver from embryos injected with human leukemic cells. Interestingly, an amplicon of the same length has been detected in both BM and spleen from PBS injected embryos, although analysis via bioinformatics tools revealed no matches in chicken; neither in transcriptome nor in genome databases. Importantly, splenomegaly and hepatic lesions were observed in some CD34+ cells injected embryos. CONCLUSION: Collectively, our data confirm the engraftment of primary human CD34+ leukemic cells in chick embryo liver, but other experiments are required to verify engraftment in BM and spleen, and to confirm the identity of a putative CD34 orthologous transcript in these two organs. PMID- 29428371 TI - Survival outcome of intermediate risk neuroblastoma at Children Cancer Hospital Egypt. AB - AIM: The study aims to evaluate survival outcome in newly diagnosed pediatric intermediate risk neuroblastoma patients treated at the Children Cancer Hospital Egypt and their relation to various clinical and pathological factors. METHODS: The study included stage 3 patients <1.5 years, children 1.5 years or older with stage 3 disease and favorable histopathological features, infants (<1 year) with International Neuroblastoma Staging System (INSS) stage 4 disease, stage 4 children 1-1.5 years with favorable biology, and infants stage 4 s (with unfavorable biologic features). Patients received systemic chemotherapy, in the form of etoposide and carboplatin alternating with cyclophosphamide, doxorubicin and vincristine, administered at 3-week intervals, with a total of 6 or 8 cycles guided by reaching objective overall response (complete/very good partial/partial response). RESULTS: The study included 136 patients, 67 males and 69 females. 101 patients had abdominal primary tumors, 28 had mediastinal masss and 7 with masses in the neck; 68% were stage 3 and the remaining (n = 44) had metastatic disease. The three-year overall survival (OS) and event-free survival (EFS) estimates were 94% +/- 2% and 90.9% +/- 2.5%, respectively. OS and EFS by gender, age, pathology and INPC were all statistically not significantly different. Moreover, OS for patients having surgery versus no surgery (inoperable residual only) was statistically significant (98.4% +/- 1.6% & 88.7% +/- 5.3%, respectively, p = .034). CONCLUSION: A very high rate of survival is currently achievable in patients with intermediate risk neuroblastoma by chemotherapy or chemotherapy and surgery. In addition to response, our plan is to adopt biologically-based treatment to reduce treatment-induced complications among survivors. PMID- 29428372 TI - Comparative study on the analgesic effect of acute ipsilateral shoulder pain after open thoracotomy between preoperative ultrasound guided suprascapular nerve block (SNB) and intraoperative phrenic nerve infiltration (PNI) in cancer lung patients. AB - INTRODUCTION: Acute ipsilateral shoulder pain (ISP) is a common complaint in patients after thoracotomy. The incidence ranges from 21% to 97%. Unfortunately, clinical studies did not put enough focus on ISP post thoracic surgery. AIM OF THE WORK: This study was designed to compare the effectiveness of suprascapular nerve block (SNB) and phrenic nerve infiltration (PNI) for controlling ISP. PATIENTS AND METHODS: One hundred and thirty-five lung cancer patients (135) scheduled for open-lung surgery were randomly allocated into three equal groups; control group: received thoracic epidural with general anesthesia, suprascapular group: (SNB) one hour before the operation with 10 ml bupivacaine plus thoracic epidural with general anesthesia and phrenic nerve group: (PNI) was performed by the operating surgeon with 10 ml bupivacaine plus thoracic epidural with general anesthesia. The visual analogue score (VAS) of ISP, rescue of ketorolac for break through shoulder pain, peak expiratory flow rate (PEFR) and arterial blood gases were measured every 6 h postoperatively for 48 h. RESULTS: The VAS, rescue doses of ketorolc and PEFR were significantly lower in the phrenic nerve group (P-value <0.05). There was no statistically significant difference between the three groups postoperatively as regards arterial blood gases (P-value >0.05). CONCLUSION: PNI is more effective than SNB for ISP. PMID- 29428374 TI - Forehead reduction and orbital contouring in facial feminisation surgery for transgender females. AB - Forehead reduction and orbital contouring form a considerable component of the procedures available to feminise the face in transgender females. In this paper I shall discuss the history and development of techniques to reduce bossing of the forehead and contour the orbits, and describe their classification, assessment, surgical approach, and complications. PMID- 29428373 TI - First-line paclitaxel and cisplatin used sequentially or in combination in metastatic breast cancer: A phase II randomized study. AB - INTRODUCTION: Breast cancer (BC) is the commonest cancer among females worldwide. Some patients present initially at advanced stages and more than 50% of them will develop metastasis (MBC) at some point. Compared to single agents, combination chemotherapy produces higher response rates (RR), longer progression-free survival (PFS) than single agents. This is associated with remarkably higher toxicities. At the same time, overall survival (OS) is comparable. This study aimed to compare safety and efficacy of combination and sequential chemotherapy. PATIENTS AND METHODS: Forty-six MBC patients were randomized to receive 6 cycles of the combination of paclitaxel (175 mg/m2) and cisplatin (70 mg/m2) (combination PC) or paclitaxel for 3 cycles followed by cisplatin for 3 cycles (sequential PC). Endpoints were RR, PFS, OS and safety. RESULTS: Both combination and sequential PC produced similar RR (52% in both arms) and disease control rates (78.3% vs. 73.9%, p = .652). Responses were faster in the combination arm. Median PFS was 8.2 months in the combination compared to 5.0 months in the sequential arm (p = .064). The median OS was 16.5 and 18.8 months in the combination and sequential arms, respectively (p = .866). The combination was more toxic than sequential PC. Grade 3 toxicities were higher with combination PC than to sequential PC (48% vs. 4.3%; p < .001). CONCLUSION: Sequential agent chemotherapy may provide similar response rate and overall survival to combination chemotherapy with much lower toxicities. The former can be considered the standard practice in most instances. PMID- 29428375 TI - Use of ultrasound-activated resorbable sheets and pins in the management of fractures of the condylar neck of the mandible: a case series. AB - The need to treat fractures of the mandibular condyle remains controversial, but when the decision to operate has been made, then multiple forms of fixation are advocated. Traditionally, metal plates and screws have been used, but this is thought to have several disadvantages, particularly in the growing skeleton. Resorbable fixation for maxillofacial fractures has not gained widespread acceptance because of technical difficulties with the materials and concern about inflammatory reactions during their resorption. Because not all patients have typical fracture patterns that fit the size and shape of metal plates, mouldable resorbable fixation materials can be useful, and ultrasound-activated resorbable sheets and pins have the necessary stability to fix fractures of the condylar neck. We present a series of patients in whom ultrasound-activated resorbable sheets and pins were used to fix condylar fractures in which the fracture pattern did not permit the use of stable metal fixation, or the age of the patient in our opinion precluded the use of metal fixation. There were no perioperative complications and no problems related to the stability of the fixation. Minor swelling relating to the resorption of the material in one case did not require any management. PMID- 29428376 TI - Amplified detection of streptomycin using aptamer-conjugated palladium nanoparticles decorated on chitosan-carbon nanotube. AB - A streptomycin-specific aptamer was used as a receptor molecule for ultrasensitive quantitation of streptomycin. The glassy carbon (GC) electrode was modified with palladium nanoparticles decorated on chitosan-carbon nanotube (PdNPs/CNT/Chi) and aminated aptamer against streptomycin. Modification of the sensing interface was characterized by scanning electron microscopy (SEM), energy dispersive X-ray (EDS), wavelength-dispersive X-ray spectroscopy (WDX), cyclic voltammetry (CVs), and electrochemical impedance spectroscopy (EIS). The methodologies applied for designing the proposed biosensor are based on target induced conformational changes of streptomycin-specific aptamer, leading to detectable signal change. Sensing experiments were performed in the streptomycin concentration range from 0.1 to 1500 nM in order to evaluate the sensor response as a function of streptomycin concentration. Based on the results, the charge transfer resistance (Rct) values increased proportionally to enhanced streptomycin content. The limit of detection was found to be as low as 18 pM. The superior selectivity and affinity of aptamer/PdNPs/CNT/Chi modified electrode for streptomycin recognition made it favorable for versatile applications such as streptomycin analysis in real samples. PMID- 29428377 TI - PD-1/PD-L1 inhibitor screening of caffeoylquinic acid compounds using surface plasmon resonance spectroscopy. AB - Following the FDA approval of three monoclonal antibodies of PD-1/PD-L1, this pathway has become a promising target for cancer treatment. Currently small molecule inhibitors have not been extensively investigated, and appropriate screening methods for such inhibitors are urgently required. In this study, surface plasmon resonance (SPR) technology was used to evaluate the affinity and competitive inhibition of nine caffeoylquinic acid compounds (CQAs) against PD 1/PD-L1. As a result, four small molecules including 1-CQA, 3-CQA, 4-CQA and 5 CQA were determined as PD-1/PD-L1 inhibitors. This study provided an efficient method for screening small-molecule inhibitors targeting PD-1/PD-L1 pathway. PMID- 29428378 TI - A convenient method of attaching fluorescent dyes on single-walled carbon nanotubes pre-wrapped with DNA molecules. AB - We demonstrated the attachment of different kinds of dyes, Uranine, Rhodamime 800 (R800), and Indocyanine green (ICG), to single-walled carbon nanotubes pre wrapped with single-stranded DNAs (ssDNA-SWCNTs). A new but simple method was employed, in which a dye solution was added to ssDNA-SWCNTs that had been prepared beforehand in the conventional way. Resulting conjugates of dyes, DNA, and SWCNTs were precisely evaluated by ultraviolet to near-infrared fluorescence/absorbance spectrometry and atomic force microscopy. In particular, simultaneous measurements of fluorescence and absorbance spectroscopy enabled us to find differences in the behaviors of the dyes on SWCNT surfaces. As a result, the fluorescence/absorbance spectra of dyes showed significant changes upon adsorption on SWCNTs. The fluorescence/absorbance peaks of Uranine, R800, and ICG were quenched by 41.3/2.8%, 72.3/48.9%, and 88.3/45.0%, respectively, in the presence of 11.5 MUg/mL SWCNTs. We concluded firstly that by pre-wrapping SWCNTs with ssDNA, stable hybrids with these components were obtained even if the dyes used were relatively hydrophobic and secondly that Uranine retained light absorption on the surface of SWCNT while R800 and ICG did not. PMID- 29428379 TI - Corrigendum to 'Continuous Femoral Nerve Block in Total Knee Arthroplasty: Immediate and Two-Year Outcomes' [J Arthroplasty 24 (2009) 204-209]. PMID- 29428380 TI - Corrigendum to "Three Year RSA Evaluation of Vitamin E Diffused Highly Cross linked Polyethylene Liners and Cup Stability". [The Journal of Arthroplasty 30/7 (2015) 1260-1264]. PMID- 29428381 TI - Genetic diversity of toxigenic Vibrio cholerae O1 from Sabah, Malaysia 2015. AB - BACKGROUND: Cholera is an important health problem in Sabah, a Malaysian state in northern Borneo; however, Vibrio cholerae in Sabah have never been characterized. Since 2002, serogroup O1 strains having the traits of both classical and El Tor biotype, designated as atypical El Tor biotype, have been increasingly reported as the cause of cholera worldwide. These variants are believed to produce clinically more severe disease like classical strains. PURPOSE: The purpose of this study is to investigate the genetic diversity of V.cholerae in Sabah and whether V.cholerae in Sabah belong to atypical El Tor biotype. METHODS: ERIC-PCR, a DNA fingerprinting method for bacterial pathogens based on the enterobacterial repetitive intergenic consensus sequence, was used to study the genetic diversity of 65 clinical V.cholerae O1 isolates from 3 districts (Kudat, Beluran, Sandakan) in Sabah and one environmental isolate from coastal sea water in Kudat district. In addition, we studied the biotype-specific genetic traits in these isolates to establish their biotype. RESULTS: Different fingerprint patterns were seen in isolates from these three districts but one of the patterns was seen in more than one district. Clinical isolates and environmental isolate have different patterns. In addition, Sabah isolates harbor genetic traits specific to both classical biotype (ctxB-1, rstRCla) and El Tor biotype (rstRET, rstC, tcpAET, rtxC, VC2346). CONCLUSION: This study revealed that V.cholerae in Sabah were genetically diverse and were atypical El Tor strains. Fingerprint patterns of these isolates will be useful in tracing the origin of this pathogen in the future. PMID- 29428382 TI - InVitro Evaluation of Optimal Inhalation Flow Patterns for Commercial Dry Powder Inhalers and Pressurized Metered Dose Inhalers With Human Inhalation Flow Pattern Simulator. AB - This study aimed at developing a novel analytical method to identify optimal inhalation flow patterns for commercial dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs). As typical commercial DPI and pMDI, Pulmicort(r) Turbuhaler(r), and Sultanol(r) Inhaler were evaluated by an in vitro inhalation performance testing system with a flow pattern simulator. An 8-stage Andersen cascade impactor (ACI) or twin stage liquid impinger (TSLI) was applied to determine the inhalation performance. The peak flow rate (PFR) of the inhalation flow pattern was set from 15 to 80 L/min in reference to our previous study. From TSLI test results, a higher PFR improved the inhalation performance of the DPI, while the performance of the pMDI was less affected by the PFR. Conversely, from ACI test results, the pMDI performance decreased with a higher PFR, while the DPI followed a similar pattern as in the TSLI test results, because ACI is a finer aerodynamic classification apparatus than TSLI. These results suggested that our in vitro system using a human inhalation flow pattern simulator successfully detected different optimal inhalation patterns between DPI and pMDI. That is, the higher PFR is better for Pulmicort(r) Turbuhaler(r) (DPI). Conversely, lower PFR is desirable for Sultanol(r) Inhaler (pMDI). PMID- 29428383 TI - Preparation, characterization and antioxidant activity of polysaccharide from spent Lentinus edodes substrate. AB - This study explored the potential of spent Lentinus edodes substrate, a by product of mushroom industries causing environmental pollution, serving as materials to produce antioxidant polysaccharide. The extraction process of spent Lentinus edodes substrate polysaccharide (SLSP) was optimized and the effects of drying methods on chemical composition, morphological property and antioxidant activity were investigated. Results showed that freeze-dried SLSP (SLSP-F) exhibited the best quality in terms of the polysaccharide yield (13.00%) and antioxidant activity. The EC50 values of SLSP-F on DPPH, ABTS and superoxide anion radicals was 0.051mg/mL, 0.379mg/mL, 0.719mg/mL, respectively, which was significantly lower than that of freeze-dried Lentinus edodes polysaccharide (LP F). After purification by Sephadex G-150, the purified SLSP-F (PSP) has a molecular weight of 16.77kDa. Compared with LP-F, PSP has more reducing sugars and uronic acids in chemical composition and higher contents of xylose, glucose and galactose in monosaccharide composition. FT-IR and NMR spectroscopy analysis revealed that PSP has both alpha and beta glycosidic bonds and massive acetyl groups, which is different from LP-F mainly composed of 1, 3 linked alpha-D-Manp residue with some acetyl groups. The findings provided a reliable approach for the development of antioxidant polysaccharide from spent Lentinus edodes substrate. PMID- 29428384 TI - Effects of different ultrasound power on physicochemical property and functional performance of chicken actomyosin. AB - The aim of present study was to investigate the effect of different ultrasound power on physicochemical property and functional performance of chicken actomyosin (CAM). The treated CAM had the lowest particle size and the highest absolute zeta potential at 150 W. The conformation changes of treated CAM exhibited the reduction in alpha-helix as well as the improvement of fluorescence intensity. Ultrasound power at 150 W could significantly increase protein hydrophobicity and reactive SH groups compared to the others (P < 0.05). The disappearance of specific peaks and lower endothermic peaks implied that the treated CAM became thermally instable. The microstructure of CAM revealed small and homogeneous sub-bunches treated by 100-150 W. Furthermore, the solubility and emulsion property of CAM was significantly increased at 150 W (P < 0.05). These results demonstrated that ultrasound treatment at the power of 100-150 W may be an appropriate range to modify CAM for enhancing its functional properties. PMID- 29428385 TI - Cognitive-enhancing effect of polysaccharides from Flammulina velutipes on Alzheimer's disease by compatibilizing with ginsenosides. AB - This study was performed to evaluate the cognitive-enhancing effect Flammulina velutipes polysaccharides (FVP) by compatibilizing with ginsenosides on D galactose-induced Alzheimer's disease (AD) rats. Results of the Morris water maze test suggested that the cognitive ability of AD rats was significantly elevated after combined treatment with FVP and ginsenosides. Moreover, the anti-oxidant effect was also elevated as reflected by the increased levels of superoxide dismutase, catalase, and glutathione peroxidase and decreased levels of malondialdehyde in the combination group. Terminal deoxynucleotidyl transferase mediated dUTP biotin nick-end labeling (TUNEL), immunohistochemistry, and Western blot analysis showed that the TUNEL apoptosis cell rate, Bax, cytochrome C, caspase-3, caspase-9, and apoptosis-inducing factor expression levels were obviously decreased, and the Bcl-2 expression levels were obviously increased in the hippocampi of rats treated with FVP and ginsenosides. The results suggested that the beneficial effect of FVP against AD can be significantly elevated by compatibilizing with ginsenosides. These findings provide scientific evidence supporting the use of FVP as a safe and effective drug to prevent and treat AD. PMID- 29428386 TI - Extraction condition optimization and effects of drying methods on physicochemical properties and antioxidant activities of polysaccharides from comfrey (Symphytum officinale L.) root. AB - This study was designed to investigate the extraction conditions of polysaccharides from comfrey (Symphytum officinale L.) root (CRPs) using response surface methodology (RSM). The effects of three variables including liquid-solid ratio, extraction time and extraction temperature on the extraction yield of CRPs were taken into consideration. Moreover, the effects of drying methods including hot air drying (HD), vacuum drying (VD) and freeze drying (FD) on the physicochemical properties and antioxidant activities of CRPs were evaluated. The optimal conditions to extract the polysaccharides were as follows: liquid-solid ratio (15mL/g), extraction time (74min), and extraction temperature (95 degrees C), allowed a maximum polysaccharides yield of 22.87%. Different drying methods had significant effects on the physicochemical properties of CRPs such as the chemical composition (contents of total polysaccharides and uronic acid), relative viscosity, solubility and molecular weight. CRPs drying with FD method showed stronger reducing power and radical scavenging capacities against DPPH and ABTS radicals compared with CRPs drying with HD and VD methods. Therefore, freeze drying served as a good method for keeping the antioxidant activities of polysaccharides from comfrey root. PMID- 29428387 TI - Characterization of a new oligoalginate lyase from marine bacterium Vibrio sp. AB - A new oligoalginate lyase encoding gene, designed oal17A, was cloned from marine bacterium Vibrio sp. W13, and then expressed in Escherichia coli. The recombinant Oal17A was purified by NTA-Ni resin with maximal activity at 30 degrees C and pH7.0. Oal17A exhibited broad substrate specificity, and preferred to degrade alginate than polyM or polyG into monosaccharide acid. The specific activity of Oal17A toward alginate, polyM and polyG was 21.14U/mg, 12.31U/mg and 7.43U/mg, respectively. With features of high-level expression and broad substrate specificity, Oal17A would be a potential tool for alginate monomer production process of alginate utilizing for biofuels and bioethanol production. PMID- 29428388 TI - Type II flavohemoglobin of Mycobacterium smegmatis oxidizes d-lactate and mediate electron transfer. AB - Two distantly related flavohemoglobins (FHbs), MsFHbI and MsFHbII, having crucial differences in their heme and reductase domains, co-exist in Mycobacterium smegmatis. Function of MsFHbI is associated with nitric-oxide detoxification but physiological relevance of MsFHbII remains unknown. This study unravels some unique spectral and functional characteristics of MsFHbII. Unlike conventional type I FHbs, MsFHbII lacks nitric-oxide dioxygenase and NADH oxidase activities but utilizes d-lactate as an electron donor to mediate electron transfer. MsFHbII carries a d-lactate dehydrogenase type FAD binding motif in its reductase domain and oxidizes d-lactate in a FAD dependent manner to reduce the heme iron, suggesting that the globin is acting as an electron acceptor. Importantly, expression of MsFHbII in Escherichia coli imparted protection under oxidative stress, suggesting its important role in stress management of its host. Since M. smegmatis lacks the gene encoding for d-lactate dehydrogenase and d-lactate is produced during aerobic metabolism and also as a by-product of lipid peroxidation, the ability of MsFHbII to metabolize d-lactate may provide it a unique ability to balance the oxidative stress generated due to accumulation of d lactate in the cell and at the same time sequester electrons and pass it to the respiratory apparatus. PMID- 29428389 TI - Allergenicity reduction of bovine milk beta-lactoglobulin by proteolytic activity of lactococcus lactis BMC12C and BMC19H isolated from Iranian dairy products. AB - Nowadays health benefits of bioactive food constituents, known as probiotic microorganisms, are a growing awareness. Cow's milk is a nutritious food containing probiotic bacteria. However, milk allergenicity is one of the most common food allergies. The milk protein, beta-lactoglobulin (BLG), is in about 80% of all main cases of milk allergies for children and infants. With the aim of screening proteolytic strains of lactic acid bacteria to evaluate their potential for the reduction of allergenicity of the major bovine milk proteins, we isolated new proteolytic strains of cocci lactic acid bacteria from traditional Iranian dairy products. The proteases produced by these strains had strong proteolytic activity against BLG. Proteolysis of BLG, observed after sodium dodecyl sulfate PAGE, was confirmed by the analysis of the peptide profiles by reversed-phase HPLC. The two isolates were submitted to 16S rDNA sequencing and identified as Lactcoccus lactis subsp. cremoris and Lactcoccus lactis subsp. hordniea. The competitive ELISA experiments confirmed that these isolates, with high proteolytic activity, reduce significantly the allergenicity of BLG. Accordingly, these isolates can reduce the immunoreactivity of bovine milk proteins, which can be helpful for the production of low-allergic dairy products. PMID- 29428390 TI - Iminodiacetic acid modified kenaf fiber for waste water treatment. AB - In the present study, iminodiacetic acid (IDA)-modified kenaf fiber, K-IDA formed by the chemical modification of plant kenaf biomass was tested for its efficacy as a sorbent material towards the purification of waste water. The K-IDA fiber was first characterized by the instrumental techniques like Fourier transform infrared (FTIR) analysis, elemental analysis (CHNSO), and scanning electron microscopy (SEM). On testing for the biosorption, we found that the K-IDA has an increment in the adsorption of Cu2+ ions as compared against the untreated fiber. The Cu2+ ions adsorption onto K-IDA fits very well with the Langmuir model and the adsorption maximum achieved to be 91.74mg/g. Further, the adsorption kinetics observed to be pseudo second-order kinetics model and the Cu2+ ions adsorption is a spontaneous endothermic process. The desorption study indicates a highest percentage of Cu2+ of 97.59% from K-IDA under 1M HCl solution against H2SO4 (72.59%) and HNO3 (68.66%). The reusability study indicates that the efficiency did not change much until the 4th cycle and also providing enough evidence for the engagement of our biodegradable K-IDA fiber towards the removal of Cu2+ ions in real-time waste water samples obtained from the electroplating and wood treatment industries. PMID- 29428391 TI - Evolution of IgE responses to multiple allergen components throughout childhood. AB - BACKGROUND: There is a paucity of information about longitudinal patterns of IgE responses to allergenic proteins (components) from multiple sources. OBJECTIVES: This study sought to investigate temporal patterns of component-specific IgE responses from infancy to adolescence, and their relationship with allergic diseases. METHODS: In a population-based birth cohort, we measured IgE to 112 components at 6 follow-ups during childhood. We used a Bayesian method to discover cross-sectional sensitization patterns and their longitudinal trajectories, and we related these patterns to asthma and rhinitis in adolescence. RESULTS: We identified 1 sensitization cluster at age 1, 3 at age 3, 4 at ages 5 and 8, 5 at age 11, and 6 at age 16 years. "Broad" cluster was the only cluster present at every follow-up, comprising components from multiple sources. "Dust mite" cluster formed at age 3 years and remained unchanged to adolescence. At age 3 years, a single-component "Grass" cluster emerged, which at age 5 years absorbed additional grass components and Fel d 1 to form the "Grass/cat" cluster. Two new clusters formed at age 11 years: "Cat" cluster and "PR-10/profilin" (which divided at age 16 years into "PR-10" and "Profilin"). The strongest contemporaneous associate of asthma at age 16 years was sensitization to dust mite cluster (odds ratio: 2.6; 95% CI: 1.2-6.1; P < .05), but the strongest early life predictor of subsequent asthma was sensitization to grass/cat cluster (odds ratio: 3.5; 95% CI: 1.6-7.4; P < .01). CONCLUSIONS: We describe the architecture of the evolution of IgE responses to multiple allergen components throughout childhood, which may facilitate development of better diagnostic and prognostic biomarkers for allergic diseases. PMID- 29428392 TI - Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation. AB - BACKGROUND: Eosinophils play a central role in propagation of allergic diseases, including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia, but the question of whether alterations in apoptotic cell clearance by phagocytes contributes directly to resolution of allergic airway inflammation remains unexplored. OBJECTIVES: In this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo to establish whether apoptotic cell clearance directly affects the resolution of allergic airway inflammation. METHODS: Alveolar and bone marrow macrophages were used to study Mer-mediated phagocytosis of apoptotic eosinophils. Allergic airway inflammation resolution was modeled in mice by using ovalbumin. Fluorescently labeled apoptotic cells were administered intratracheally or eosinophil apoptosis was driven by administration of dexamethasone to determine apoptotic cell clearance in vivo. RESULTS: Inhibition or absence of Mer impaired phagocytosis of apoptotic human and mouse eosinophils by macrophages. Mer-deficient mice showed delayed resolution of ovalbumin-induced allergic airway inflammation, together with increased airway responsiveness to aerosolized methacholine, increased bronchoalveolar lavage fluid protein levels, altered cytokine production, and an excess of uncleared dying eosinophils after dexamethasone treatment. Alveolar macrophage phagocytosis was significantly Mer dependent, with the absence of Mer attenuating apoptotic cell clearance in vivo to enhance inflammation in response to apoptotic cells. CONCLUSIONS: We demonstrate that Mer-mediated apoptotic cell clearance by phagocytes contributes to resolution of allergic airway inflammation, suggesting that augmenting apoptotic cell clearance is a potential therapeutic strategy for treating allergic airway inflammation. PMID- 29428393 TI - Reactivity to interpersonal stress in patients with eating disorders: A systematic review and meta-analysis of studies using an experimental paradigm. AB - Reactivity to interpersonal stress in patients with eating disorders: A systematic review and meta-analysis of studies using an experimental paradigm. NEUROSCI BIOBEHAV REV XXX-XXX, 2018.- Social difficulties have been implicated in the development and maintenance of eating disorder symptoms. The aim of this work was to conduct a systematic review and meta-analysis of experimental studies testing patientso reactivity to interpersonal stress, compared to healthy controls. Thirty-four studies were included. Meta-analyses were conducted on 16 studies and on following outcomes: attention bias and interference to threatening faces, cortisol, heart rate and negative affect before and after exposure to interpersonal stress. Patients showed heightened attention bias and interference to threatening faces. Lower heart rate after exposure to interpersonal stress and greater negative affect before and after interpersonal stress were observed in the clinical group compared to controls. Surprisingly, only a small minority of studies included measures of abnormal eating behaviour and attitudes. This seems a missed opportunity for testing the causal and maintaining role that abnormalities in interpersonal stress response play in eating disorders. Nonetheless, findings corroborate the hypothesis that patients' response to interpersonal stress differs from that of healthy controls. PMID- 29428394 TI - The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. AB - Psychostimulants, including amphetamines and methylphenidate, are first-line pharmacotherapies for individuals with attention-deficit/hyperactivity disorder (ADHD). This review aims to educate physicians regarding differences in pharmacology and mechanisms of action between amphetamine and methylphenidate, thus enhancing physician understanding of psychostimulants and their use in managing individuals with ADHD who may have comorbid psychiatric conditions. A systematic literature review of PubMed was conducted in April 2017, focusing on cellular- and brain system-level effects of amphetamine and methylphenidate. The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity, which impacts executive and attentional function. Amphetamine actions include dopamine and norepinephrine transporter inhibition, vesicular monoamine transporter 2 (VMAT-2) inhibition, and monoamine oxidase activity inhibition. Methylphenidate actions include dopamine and norepinephrine transporter inhibition, agonist activity at the serotonin type 1A receptor, and redistribution of the VMAT-2. There is also evidence for interactions with glutamate and opioid systems. Clinical implications of these actions in individuals with ADHD with comorbid depression, anxiety, substance use disorder, and sleep disturbances are discussed. PMID- 29428395 TI - Progesterone induces relaxation of human umbilical cord vascular smooth muscle cells through mPRalpha (PAQR7). AB - Progesterone effects on vascular smooth muscle cell (VSMC) relaxation and the mechanism were investigated in cultured human umbilical vein VSMCs. Membrane progesterone receptors mPRalpha, mPRbeta, and mPRgamma were highly expressed in VSMCs, whereas nuclear progesterone receptor (nPR) had low expression. Progesterone (20 nM) and 02-0 (mPR-selective agonist), but not R5020 (nPR agonist), induced muscle relaxation in both a VSMC collagen gel disk contraction assay and an endothelium-denuded human umbilical artery ring tension assay. Progesterone and 02-0 increased ERK and Akt phosphorylation and decreased cAMP levels. These effects were blocked by preincubation with pertussis toxin. Progestin-induced muscle relaxation was blocked by pretreatment with mPRalpha, but not nPR, siRNAs, and by co-treatment with 8-Br-cAMP, AZD6244 (MAP kinase inhibitor), and wortmannin (PI3K inhibitor). Progestins reduced myosin light chain phosphorylation which was blocked with AZD6244 and wortmannin. These results demonstrate progesterone directly relaxes human VSMCs through mPRalpha/Gi and MAP kinase/ERK-, Akt/PI3K-, and cAMP-dependent pathways. PMID- 29428396 TI - Concerns related to ED-mediated effects of Bisphenol A and their regulatory consideration. AB - The extensive database on BPA provides strong evidence of its adverse effects on reproductive, neurobehavioural, metabolic functions and mammary gland. Disruption of estrogenic pathway is central in the mediation of these effects although other modes of action may be involved. BPA has a weak affinity for ERalpha/beta but interaction with extranuclearly located pathways activated by estrogens such as ERRgamma and GPER reveals how BPA can act at low doses. The effects are observed later in life after developmental exposure and are associated with pathologies of major societal concern in terms of severity, incidence, impact on quality of life, burden on public health system. The complexity of the dose response raise uncertainties on the possibility to establish safe levels and the scope of ED mediated effects of BPA may be wider. These concerns fulfill the requirements for ED identification under REACH regulation. PMID- 29428398 TI - Real-time quantitative isothermal detection of Ostreid herpesvirus-1 DNA in Scapharca subcrenata using recombinase polymerase amplification. AB - Ostreid herpesvirus-1 (OsHV-1) is a well-known pathogen associated with high mortality rates in hatchery-reared larvae and juveniles of different bivalve species worldwide. Early, rapid and accurate diagnosis plays a fundamental role in disease prevention and control in aquaculture. Recombinase polymerase amplification (RPA) is a novel isothermal amplification method, which can amplify detectable amount of DNA at 37 degrees C-39 degrees C within 20 min. In the present study, two sets of specific primers and probes were designed for the real time quantitative RPA (qRPA) detection of OsHV-1 DNA. The sensitivity and specificity of detection were evaluated by comparison with quantitative polymerase chain reaction (qPCR). The detection limit for qRPA assays was shown to be 5 copies DNA/reaction for the primer set ORF95, which was lower than the 100 copies required for the qPCR test. The optimal reaction temperature and time were 37 degrees C for 20 min, making this approach faster than qPCR. This is the first study to apply qPCR and qRPA methods to detect OsHV-1 in Scapharca subcrenata. The percentage of viral load sample detected by the two methods was 22% and the correlation of the two virus quantitative results was 0.8. Therefore, qRPA assays is sensitive, fast, and high-temperature independent relative to qPCR and is suitable for critical clinical diagnostics use and rapid field analysis in resource-limited settings. PMID- 29428397 TI - Pyk2 deficiency potentiates osteoblast differentiation and mineralizing activity in response to estrogen or raloxifene. AB - Bone remodeling is controlled by the actions of bone-degrading osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affects bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in post-menopausal women. Although investigations of the effects of estrogen on osteoclast activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate and reduced osteoclast activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition we found that Pyk2-KO OBs cultured in the presence of either 17beta-estradiol (E2) or raloxifene, a SERM used for the treatment of post menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) activity and mineralization. We examined the possible mechanism of action and found that Pyk2 deletion promotes the proteasome-mediated degradation of estrogen receptor alpha (ERalpha), but not estrogen receptor beta (ERbeta). As a consequence, E2 signaling via ERbeta was enhanced in Pyk2-KO OBs. In addition, we found that Pyk2 deletion and E2 stimulation had an additive effect on ERK phosphorylation, which is known to stimulate cell differentiation and survival. Our findings suggest that in the absence of Pyk2, estrogen exerts an osteogenic effect on OBs through altered ERalpha and ERbeta signaling. Thus, targeting Pyk2, in combination with estrogen or raloxifene, may be a novel strategy for the prevention and/or treatment of bone loss diseases. PMID- 29428399 TI - Comparison of cobas HCV GT against Versant HCV Genotype 2.0 (LiPA) with confirmation by Sanger sequencing. AB - BACKGROUND: Correct identification of infecting hepatitis C virus (HCV) genotype is helpful for targeted antiviral therapy. OBJECTIVES: Here, we compared the HCV genotyping performance of the cobas HCV GT assay against the Versant HCV Genotype 2.0 (LiPA) assay, using 97 archived serum samples. STUDY DESIGN: In the event of discrepant or indeterminate results produced by either assay, the core and NS5B regions were sequenced. RESULTS: Of the 97 samples tested by the cobas, 25 (26%) were deemed indeterminate. Sequencing analyses confirmed 21 (84%) of the 25 samples as genotype 6 viruses with either subtype 6m, 6n, 6v, 6xa, or unknown subtype. Of the 97 samples tested by the LiPA, thirteen (13%) were deemed indeterminate. Seven (7%) were assigned with genotype 1, with unavailable/inconclusive results from the core region of the LiPA. Notably, the 7 samples were later found to be either genotype 3 or 6 by sequencing analyses. Moreover, 1 sample by the LiPA was assigned as genotypes 4 (cobas: indeterminate) but were later found to be genotype 3 by sequencing analyses, highlighting its limitation in assigning the correct genotype. CONCLUSIONS: The cobas showed similar or slightly higher accuracy (100%; 95% CI 94-100%) compared to the LiPA (99%; 95% CI 92-100%). Twenty-six percent of the 97 samples tested by the cobas had indeterminate results, mainly due to its limitation in identifying genotype 6 other than subtypes 6a and 6b. This presents a significant assay limitation in Southeast Asia, where genotype 6 infection is highly prevalent. PMID- 29428400 TI - Development and validation of a foot-and-mouth disease virus SAT serotype specific 3ABC assay to differentiate infected from vaccinated animals. AB - The effective control of foot-and-mouth disease (FMD) requires sensitive, specific and rapid diagnostic tools. However, the control and eradication of FMD in Africa is complicated by, among other factors, the existence of five of the seven FMD virus (FMDV) serotypes, including the SAT-serotypes 1, 2 and 3 that are genetically and antigenically the most variable FMDV serotypes. A key diagnostic assay to enable a country to re-gain its FMD-free status and for FMD surveillance, is the 3ABC or the non-structural protein (NSP) enzyme-linked immunosorbent assay (ELISA). Although many kits are available to detect 3ABC antibodies, none has been developed specifically for the variable SAT serotypes. This study designed a SAT-specific NSP ELISA and determined whether this assay could better detect NSP-specific antibodies from FMDV SAT-infected livestock. The assay's performance was compared to validated NSP assays (PrioCheck(r)-NSP and IZSLER-NSP), using panels of field and experimental sera, vaccinated and/or infected with FMDV SAT1, SAT2 or SAT3. The sensitivity () of the SAT-NSP was estimated as 76% (70%, 81%) whereas the specificity was 96% (95%, 98%) at a 95% confidence interval. The sensitivity and specificity were comparable to the commercial NSP assays, PrioCheck(r)-NSP (82% and 99%, respectively) and IZSLER NSP (78% and 98%, respectively). Good correlations were observed for all three assays. PMID- 29428402 TI - MSF challenges pneumococcal vaccine patent in India. PMID- 29428401 TI - Exposure to an obesogenic diet during adolescence leads to abnormal maturation of neural and behavioral substrates underpinning fear and anxiety. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) and obesity are highly prevalent in adolescents. Emerging findings from our laboratory and others are consistent with the novel hypothesis that obese individuals may be predisposed to developing PTSD. Given that aberrant fear responses are pivotal in the pathogenesis of PTSD, the objective of this study was to determine the impact of an obesogenic Western-like high-fat diet (WD) on neural substrates associated with fear. METHODS: Adolescent Lewis rats (n = 72) were fed with either the experimental WD (41.4% kcal from fat) or the control diet. The fear-potentiated startle paradigm was used to determine sustained and phasic fear responses. Diffusion tensor imaging metrics and T2 relaxation times were used to determine the structural integrity of the fear circuitry including the medial prefrontal cortex (mPFC) and the basolateral complex of the amygdala (BLA). RESULTS: The rats that consumed the WD exhibited attenuated fear learning and fear extinction. These behavioral impairments were associated with oversaturation of the fear circuitry and astrogliosis. The BLA T2 relaxation times were significantly decreased in the WD rats relative to the controls. We found elevated fractional anisotropy in the mPFC of the rats that consumed the WD. We show that consumption of a WD may lead to long-lasting damage to components of the fear circuitry. CONCLUSIONS: Our findings demonstrate that consumption of an obesogenic diet during adolescence has a profound impact in the maturation of the fear neurocircuitry. The implications of this research are significant as they identify potential biomarkers of risk for psychopathology in the growing obese population. PMID- 29428403 TI - The Sonic Hedgehog signaling pathway regulates inferior alveolar nerve regeneration. AB - Activation of Shh signaling is known to be observed following injury of the peripheral nerves such as the sciatic nerve. However, the precise role of Shh signaling during peripheral nerve regeneration is not fully understood. The inferior alveolar nerve (IAN) is most commonly injured during oral surgery. Unlike the sciatic nerve, the IAN is isolated from other craniofacial tissues, as it resides in a long bony canal within the mandible. The IAN is thus an excellent experimental model for investigating peripheral nerve regeneration. In this study, the role of Shh signaling in peripheral nerve regeneration was investigated using the mouse IAN transection model. During regeneration, Shh signaling was activated within the entire distal region of the IAN and proximal stumps. Inhibition of Shh signaling by cyclopamine application at the transection site led to abnormal axon growth in random directions, a reduced number of macrophages, and an increase in myelin debris within the distal region. Shh signaling is thus involved in peripheral nerve regeneration via the regulation of myelin degradation. PMID- 29428404 TI - Drug Holiday in Metastatic Renal-Cell Carcinoma Patients Treated With Vascular Endothelial Growth Factor Receptor Inhibitors. AB - INTRODUCTION: Tyrosine kinase inhibitor (TKI) therapy in metastatic renal-cell carcinoma (mRCC) is noncurative and may be associated with significant toxicities. Some patients may receive treatment breaks as a result of TKI-related adverse effects or planned drug holidays. PATIENTS AND METHODS: In this retrospective study, mRCC patients who underwent drug holidays during TKI therapy at 2 different institutions were analyzed. A drug holiday was defined as a period of drug cessation for >= 3 months for reasons other than progressive disease. RESULTS: Of the 112 patients, the median duration of the first drug holiday for the overall cohort was 16.8 months (95% confidence interval, 12.5-26.4), and 40 patients (36%) remain on the first drug holiday. Overall, patients received a median of 2 lines of treatment. Complete response before the initial drug holiday (n = 14) was associated with a longer surveillance period (P = .0004). The observed median survival of this cohort was 71.7 months (range, 1.3 to 93+ months). CONCLUSION: Some selected mRCC patients with a favorable response to TKIs may be eligible for drug holidays. The cohort evaluated in this retrospective study represents a highly selected group of patients with indolent disease biology. PMID- 29428405 TI - From Bereavement to Grief to Cognitive Decline: A Call for Novel Treatment and Prevention Approaches. PMID- 29428406 TI - Palliating Severe Refractory Neuropsychiatric Symptoms of Dementia: Is There a Role for Electroconvulsive Therapy? PMID- 29428407 TI - Subclinical haemorrhage in non-functional adenomas. AB - AIM: The prevalence and risk factors of subclinical haemorrhage on non-functional adenomas (NFA) remain controversial. The primary aim of our study was to assess the incidence of subclinical haemorrhage (SH) and the secondary objectives were to evaluate the risk factors of SH and the impact of SH on pituitary function at diagnosis. PATIENTS AND METHODS: This retrospective transversal analysis included 95 patients between January 2012 and December 2014. The patients included in this series were all adults (>18 years of age), who presented a non-functional adenoma confirmed by an endocrinological evaluation and on dedicated MRI pituitary imaging. Sixty-four patients were eligible for this study. Subclinical haemorrhage was defined by the presence of haemorrhage within pituitary adenoma confirmed by pituitary MRI with no clinical symptoms. A senior neuroradiologist blinded to the diagnosis reviewed all MRI. The population was prospectively divided into two groups based on MRI results (SH group vs. group control) to determine risk factors. RESULTS: SH was diagnosed in 22 patients (34.38%). No risk factors (age, sex, tumor size, chronic hypertension, diabetes mellitus, malignant disease, the use of anticoagulation or antithrombotic medication or Cabergoline treatment) were involved as regards the SH. At the diagnosis, pituitary deficiency was statistically significantly more frequent in the SH group (45.45%) than in the control group (19.04%) (P=0.04). CONCLUSION: The SH within NFA was observed in 34.38% of cases without an association of risk factors. PMID- 29428408 TI - Evaluating the diagnostic accuracy of the Xpert MTB/RIF assay on bronchoalveolar lavage fluid: A retrospective study. AB - OBJECTIVE: Limited data on the diagnostic accuracy of the Xpert MTB/RIF assay using bronchoalveolar lavage fluid from patients with suspected pulmonary tuberculosis (PTB) have been reported in China. Therefore, a retrospective study was designed to evaluate the diagnostic accuracy of this assay. METHODS: Clinical, radiological, and microbiological characteristics of 238 patients with suspected PTB were reviewed retrospectively. The sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of active PTB were calculated for the Xpert MTB/RIF assay using TB culture or final diagnosis based on clinical and radiological evaluation as the reference standard. RESULTS: The sensitivity and specificity of the Xpert MTB/RIF assay were 84.5% and 98.9%, respectively, and those for smear microscopy were 36.2% and 100%, respectively, when compared to the culture method. However, compared with the sensitivity and specificity of final diagnosis based on clinical and radiological evaluation, the sensitivity and specificity of the assay were 72.9% and 98.7%, respectively, which were significantly higher than those for smear microscopy. CONCLUSIONS: The Xpert MTB/RIF assay on bronchoalveolar lavage fluid could serve as an additional rapid diagnostic tool for PTB in a high TB-burden country and improve the time to TB treatment initiation in patients with PTB. PMID- 29428409 TI - Transplant tourism and invasive fungal infection. AB - BACKGROUND: Deceased and live-related renal transplants (RTXs) are approved procedures that are performed widely throughout the world. In certain regions, commercial RTX has become popular, driven by financial greed. METHODS: This retrospective, descriptive study was performed at the Royal Hospital from 2013 to 2015. Data were collected from the national kidney transplant registry of Oman. All transplant cases retrieved were divided into two groups: live-related RTX performed in Oman and commercial-unrelated RTX performed abroad. These groups were then divided again into those with and without evidence of fungal infection, either in the wound or renal graft. RESULTS: A total of 198 RTX patients were identified, of whom 162 (81.8%) had undergone a commercial RTX that was done abroad. Invasive fungal infections (IFIs) were diagnosed in 8% of patients who had undergone a commercial RTX; of these patients, 76.9% underwent a nephrectomy and 23.1% continued with a functioning graft. None of the patients with RTXs performed at the Royal Hospital contracted an IFI. The most common fungal isolates were Aspergillus species (including Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, and Aspergillus nigricans), followed by Zygomycetes. However, there was no evidence of fungal infection including Aspergillus outside the graft site. Computed tomography (CT) findings showed infarction of the graft, renal artery thrombosis, aneurysmal dilatation of the external iliac artery, fungal ball, or just the presence of a perigraft collection. Of the total patients with IFIs, 23.1% died due to septic shock and 53.8% were alive and on hemodialysis. The remaining 23.1% who did not undergo nephrectomy demonstrated acceptable graft function. CONCLUSIONS: This is the largest single-center study on commercial RTX reporting the highest number of patients with IFI acquired over a relatively short period of time. Aspergillus spp were the main culprit fungi, with no Candida spp being isolated. A high index of suspicion might be the most reasonable means to reduce the possible very poor outcomes. Improving legal transplant programs and strengthening the associated laws could prevent commercial transplant tourism. PMID- 29428410 TI - Fragment-growing guided design of Keap1-Nrf2 protein-protein interaction inhibitors for targeting myocarditis. AB - Small-molecule inhibitors that block the Keap1-Nrf2 protein-protein interactions are being intensely pursued as a new therapeutic strategy for oxidative stress related diseases, such as cancer, diabetes, Alzheimer's disease, arteriosclerosis, inflammation and myocarditis. However, there are not enough studies on antioxidant treatments using small molecules in myocarditis. We herein provided a series of novel hydronaphthoquinones as the Keap1-Nrf2 interaction inhibitors targeting LPS-induced myocarditis both in vitro and in vivo. These compounds were designed through an in-silico fragment growing approach based on our previous reported compound, S47 (1). The new compounds were predicted to form additional hydrogen bonds with the S363 residue, leading to higher inhibitory activity. Among these new derivatives, compounds S01 and S05 emerged as inhibitors with significant biochemical potency, as determined by fluorescent anisotropy assay and confirmed by surface plasmon resonance (SPR) and differential scanning fluorimetry (DSF) assays. These inhibitors can dose dependently protect the H9c2 cardiac cells against LPS-induced injury (100% at 2 MUM and 4 MUM) and effectively prolong survival or save the life of LPS-injured mice. Mechanistic studies showed that these inhibitors could release Nrf2 in H9c2 cells and LPS-inflammatory mouse models and translocate into the nucleus in a dose-response manner, which significantly increased the downstream genes (HO-1, NQO-1) and the pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6), while ROS production dramatically decreased. Their protective effects and the mechanism of action were further confirmed by siNrf2 transfected experiment. Collectively, the novel hydronaphthoquinones can be used as promising lead compounds for the study of Keap1-Nrf2 protein-protein interactions and further anti-myocarditis drug development. PMID- 29428411 TI - A sensor-based wrist pulse signal processing and lung cancer recognition. AB - Pulse diagnosis is an efficient method in traditional Chinese medicine for detecting the health status of a person in a non-invasive and convenient way. Jin's pulse diagnosis (JPD) is a very efficient recent development that is gradually recognized and well validated by the medical community in recent years. However, no acceptable results have been achieved for lung cancer recognition in the field of biomedical signal processing using JPD. More so, there is no standard JPD pulse feature defined with respect to pulse signals. Our work is designed mainly for care giving service conveniently at home to the people having lung cancer by proposing a novel wrist pulse signal processing method, having an insight from JPD. We developed an iterative slide window (ISW) algorithm to segment the de-noised signal into single periods. We analyzed the characteristics of the segmented pulse waveform and for the first time summarized 26 features to classify the pulse waveforms of healthy individuals and lung cancer patients using a cubic support vector machine (CSVM). The result achieved by the proposed method is found to be 78.13% accurate. PMID- 29428412 TI - Update on Family-Based Interventions to Prevent Children and Adolescents Using Tobacco. PMID- 29428413 TI - Treating Neonatal Abstinence Syndrome in a Rural Hospital: Lessons Learned. AB - OBJECTIVE: Our level 1 nursery and pediatric unit in a rural hospital adopted a family-centered, symptom-based oral morphine weaning protocol for neonatal abstinence syndrome (NAS) in 2009. Length of stay (LOS), treatment duration (TD), and hospital charges for infants treated for NAS were then compared to published data in neonatal intensive care units (NICUs) nationwide. METHODS: The electronic medical records of infants born January 1, 2011, to April 1, 2017, whose discharge diagnosis included an ICD-9 or ICD-10 code for NAS or prenatal drug exposure were paired with maternal electronic medical record and reviewed. TD was calculated by subtracting the last day morphine was provided from the day it was started, and LOS was calculated by subtracting the discharge date from the date of birth. Infant characteristics, maximum Finnegan score, breastfeeding, discharge disposition, maternal demographics, prenatal use of drugs or medications, and toxicology results were abstracted. Predictors of TD and LOS were analyzed, and hospital charges were enumerated. RESULTS: Chart review identified 167 infants with prenatal drug exposure, 33 of whom were treated for NAS. Median TD for infants with NAS was 18 days (range, 9-37 days) compared to 15 days (range, 9-25 days) in NICUs. Median LOS for infants treated for NAS was 22 days (range, 12-41 days) compared to 20 days (range, 12-32 days) in NICUs, but hospital charges were less. Maternal prenatal use of cocaine (P = .016) predicted LOS. CONCLUSIONS: Family-centered NAS treatment in a rural hospital lasted 2 to 3 days longer than in NICUs, largely as a result of social issues; however, hospital charges were less. PMID- 29428414 TI - Design of Adjacent Transcriptional Regions to Tune Gene Expression and Facilitate Circuit Construction. AB - Polycistronic architecture is common for synthetic gene circuits, however, it remains unknown how expression of one gene is affected by the presence of other genes/noncoding regions in the operon, termed adjacent transcriptional regions (ATR). Here, we constructed synthetic operons with a reporter gene flanked by different ATRs, and we found that ATRs with high GC content, small size, and low folding energy lead to high gene expression. Based on these results, we built a model of gene expression and generated a metric that takes into account ATRs. We used the metric to design and construct logic gates with low basal expression and high sensitivity and nonlinearity. Furthermore, we rationally designed synthetic 5'ATRs with different GC content and sizes to tune protein expression levels over a 300-fold range and used these to build synthetic toggle switches with varying basal expression and degrees of bistability. Our comprehensive model and gene expression metric could facilitate the future engineering of more complex synthetic gene circuits. PMID- 29428415 TI - Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies. AB - Identifying reliable drug response biomarkers is a significant challenge in cancer research. We present computational analysis of resistance (CARE), a computational method focused on targeted therapies, to infer genome-wide transcriptomic signatures of drug efficacy from cell line compound screens. CARE outputs genome-scale scores to measure how the drug target gene interacts with other genes to affect the inhibitor efficacy in the compound screens. Such statistical interactions between drug targets and other genes were not considered in previous studies but are critical in identifying predictive biomarkers. When evaluated using transcriptome data from clinical studies, CARE can predict the therapy outcome better than signatures from other computational methods and genomics experiments. Moreover, the CARE signatures for the PLX4720 BRAF inhibitor are associated with an anti-programmed death 1 clinical response, suggesting a common efficacy signature between a targeted therapy and immunotherapy. When searching for genes related to lapatinib resistance, CARE identified PRKD3 as the top candidate. PRKD3 inhibition, by both small interfering RNA and compounds, significantly sensitized breast cancer cells to lapatinib. Thus, CARE should enable large-scale inference of response biomarkers and drug combinations for targeted therapies using compound screen data. PMID- 29428417 TI - Juicebox.js Provides a Cloud-Based Visualization System for Hi-C Data. AB - Contact mapping experiments such as Hi-C explore how genomes fold in 3D. Here, we introduce Juicebox.js, a cloud-based web application for exploring the resulting datasets. Like the original Juicebox application, Juicebox.js allows users to zoom in and out of such datasets using an interface similar to Google Earth. Juicebox.js also has many features designed to facilitate data reproducibility and sharing. Furthermore, Juicebox.js encodes the exact state of the browser in a shareable URL. Creating a public browser for a new Hi-C dataset does not require coding and can be accomplished in under a minute. The web app also makes it possible to create interactive figures online that can complement or replace ordinary journal figures. When combined with Juicer, this makes the entire process of data analysis transparent, insofar as every step from raw reads to published figure is publicly available as open source code. PMID- 29428416 TI - GeneGini: Assessment via the Gini Coefficient of Reference "Housekeeping" Genes and Diverse Human Transporter Expression Profiles. AB - The expression levels of SLC or ABC membrane transporter transcripts typically differ 100- to 10,000-fold between different tissues. The Gini coefficient characterizes such inequalities and here is used to describe the distribution of the expression of each transporter among different human tissues and cell lines. Many transporters exhibit extremely high Gini coefficients even for common substrates, indicating considerable specialization consistent with divergent evolution. The expression profiles of SLC transporters in different cell lines behave similarly, although Gini coefficients for ABC transporters tend to be larger in cell lines than in tissues, implying selection. Transporter genes are significantly more heterogeneously expressed than the members of most non transporter gene classes. Transcripts with the stablest expression have a low Gini index and often differ significantly from the "housekeeping" genes commonly used for normalization in transcriptomics/qPCR studies. PCBP1 has a low Gini coefficient, is reasonably expressed, and is an excellent novel reference gene. The approach, referred to as GeneGini, provides rapid and simple characterization of expression-profile distributions and improved normalization of genome-wide expression-profiling data. PMID- 29428418 TI - Results of surgical treatment of acromioclavicular dislocations type III using modified Weaver Dunn technique. AB - OBJECTIVE: To evaluate the clinical and radiological results of the surgical treatment of type III acromioclavicular dislocations using the Weaver-Dunn technique in the delayed phase. MATERIAL AND METHOD: A non-randomised controlled retrospective observational study of 38 patients operated between January 2006 and December 2014. We excluded 10 patients due to death or non-localisation. We collected demographic data, time to intervention, complications, analysing the Visual Analog Scale, DASH and Oxford Shoulder Score and the updated radiological result. RESULTS: mean age of patients with right-dominant shoulder affected in 71% of cases predominantly by non-level falls was 35. 70% of the cases had subjective perception of both recovery of strength and disappearance of deformity. Full radiological reduction was observed in 95% of the cases with the appearance of mild osteoarthritis in 44% and moderate osteoarthritis in 5.6%. The results of the DASH presented values of 12,939 (+/-16,851) and the OSS of 42,736 (+/-7,794), indicating satisfactory articular function. DISCUSSION: The data from this study shows similar results to previous studies regarding subjective recovery of strength, maintenance of anatomical reduction, functional test results and efficacy of the Weaver-Dunn technique. CONCLUSIONS: The modified Weaver-Dunn technique provided good clinical and radiological results with patient reincorporation to their usual activities and maintenance over time. PMID- 29428419 TI - Resolution of giant biliary collection by spontaneous colon fistulization. AB - The treatment of bile collections is divided into: expectant attitude with radiological monitoring of the size and characteristics of the collection, percutaneous drainage guided by imaging tests (US/CT), endoscopic drainage depending on location and accessibility and surgical treatment. The clinical case of a man undergoing a scheduled hepatectomy was observerd, who presented a large asymptomatic subcapsular collection suggestive of bilioma, with progressive increase in size, spontaneously presenting a decrease until its resolution by fistulization to the hepatic angle of the colon confirmed by Radiological findings. The spontaneously formation of biliary fistulas to the colon is due to the extrinsic pressure of the collection on the intestinal wall with necrosis of the contact zone, being its presentation and radiological documentation exceptional. PMID- 29428420 TI - Diagnosis and treatment of male patients with lower urinary tract symptoms in Spain - The MERCURY Study. Do urologists follow the recommendations of the European guidelines? AB - OBJECTIVES: To explore the management of lower urinary tract symptoms (LUTS) in men in Spain and assess the compliance with recommendations established in the European Association of Urology (EAU) guidelines. MATERIAL AND METHODS: MERCURY was an epidemiological and cross-sectional study which involved 227 Urology Units across Spain assessing adult male patients with mixed LUTS and persisting storage symptoms. Sociodemographic, clinical and resource use data for the 6 months prior to study inclusion were collected. Additionally, through a theoretical clinical case, clinicians described their attitude toward the diagnostic and therapeutic management of males with mixed LUTS and persisting storage symptoms during the first and second visits. Answer options given to clinicians about LUTS management were aligned with those recommended by EAU guidelines. RESULT: 610 patients included in the study were evaluated. 87.7% of them consumed some health resource mainly due to: urologist visits (79.7%), PSA determination (76.6%) and treatment with alpha-blockers (37.5%) and alpha-blockers plus antimuscarinics (37.2%). According to the theoretical clinical case, urologists preference toward diagnostic tools and pharmacological treatment in first visit were mainly PSA determination (97.7%), digital rectal examination (91.4%) and treatment with alphablockers as monotherapy (56.6%), whereas in the second visit uroflowmetry (48.9%), voiding diary (40.3%) and treatment with alpha-blockers plus antimuscarinics (70.6%) were mainly preferred. CONCLUSIONS: Urologists attitude toward management of male patients with mixed LUTS and persisting storage symptoms is aligned with that recommended in the EAU guidelines. PMID- 29428421 TI - Prognostic Factors of Surgical Complications and Overall Survival of Patients with Metastatic Spinal Tumor. AB - OBJECTIVE: Oncologic treatments increase the incidence of spinal metastases. Surgical treatment of spinal metastases results in a high complication rate, which must set against the expected benefits. The aim of this article was to study the effect of several prognostic factors on surgical complications and survival time using an extended database of patients with spinal metastases. METHODS: This retrospective study comprised 337 patients with spinal metastases who were surgically treated between 2008 and 2015. Demographic and clinical features, oncologic histories, surgical interventions, and end results were collected. Descriptive statistical methods were used to analyze the cohort of patients. Kaplan-Meier formula and log-rank test were used to examine overall survival times. RESULTS: Median overall survival time was 222 days (range, 175 274 days). Age, preoperative motor disorders, preoperative Frankel grade categories, Karnofsky performance scale, type of primary tumor, and presence of internal metastasis had a significant negative effect on overall survival. Complications such as bleeding or need for intensive care could be predicted preoperatively based on preoperative performance status, type of primary tumor, affected vertebral levels, and type of surgical interventions. CONCLUSIONS: Spinal metastatic disease is a challenging surgical problem. If the exact prognostic factors are known preoperatively, surgical outcome and overall survival can be predicted more precisely. Our results could provide a basis for a future multicenter prospective study to determine the best treatment protocol for patients with spinal metastases. PMID- 29428422 TI - Yeasts from skin colonization are able to cross the acellular dermal matrix. AB - In recent decades, the prognosis for burn patients has improved considerably with the development of specialized care. The acellular dermal matrix (ADM) is a totally artificial acellular device that functions to control water loss, prevent penetration by bacteria and allow migration of endothelial cells and fibroblasts from patient tissues. However, little is known about its effectiveness against yeasts. The present study evaluated the capacity of colonization and migration of some human commensal yeasts. Three clinical isolates from skin scales, identified as Candida parapsilosis, Candida glabrata and Rhodotorula mucilaginosa, were used. Their ability to cross the ADM was evaluated. After three days, all isolates had crossed the ADM. C. parapsilosis showed the lowest growth, while R. mucilaginosa showed intermediate and C. glabrata the highest growth. In the plates incubated for seven days, the growth of C. parapsilosis and C. glabrata increased by 1 log over the third day. All isolates have the capacity to colonize and migrate through the matrix, increasing the potential risk to burn patients, who can develop severe and even fatal infections by invasive fungi. PMID- 29428423 TI - New potential bacterial antagonists for the biocontrol of fire blight disease (Erwinia amylovora) in Morocco. AB - The effectiveness of antagonistic bacteria to control Erwinia amylovora was evaluated under in vitro and field conditions. Among 61 bacteria isolated from soil and flowers of fire blight host plants of different Moroccan areas, 20 bacterial isolates showed higher antagonistic activity against the pathogen during agar-diffusion-test, attached blossoms assay and in a bioassay on immature pear fruits. Effective isolates were identified by using biochemical tests and 16 S rRNA genes sequencing. These isolates were grouped into the following genera: Alcaligenes (ACBC1), Pantoea (ACBC2, ACBP1, and ACBP2), Serratia (HC4), Brevibacterium (SF3, SF4, SF7, and SF15), Pseudomonas (SP9), and Bacillus (CPa12, CPa2, HF6, JB2, LMR2, SF14, SF16, SP10, SP13, and SP18). Furthermore, isolates were reported in the NCBI nucleotide sequence database (Genbank) under the accession numbers from KY357285 to KY357304. A 2-year field trials consisted of spray treatments with different bacterial antagonists was conducted on the susceptible apple cultivars 'Gala', 'Golden Parsi' and 'Golden Smoothee'. Their efficacies were evaluated 15 days post-inoculation on detached blossoms and were ranged from 54.6 to 95.0% for 11 strains, most of them were slightly better or better than that obtained with commercial bacterial strains P10c (66%) and QST713 (63%). In field trials, the most effective were P. agglomerans ACBP2, B. amyloliquefaciens LMR2, B. halotolerans (SF3 and SF4), and B. mojarvensis SF16. In addition, effective bacterial isolates did not show the pathogenicity signs towards plant tissue and are, therefore, considered as potential candidates to be integrated in actives ingredients of microbial formulation for the effective control of Fire Blight. PMID- 29428424 TI - Parvovirus B19 and in situ immune response in eczema and psoriasis skin lesions of patients from the Brazilian Amazon region. AB - Parvovirus B19 (PVB19) is a virus found in the skin that causes asymptomatic infections and can exist in the host for long periods to time. The virus induces a local inflammatory response and is associated with the development of arthritis and other autoimmunes diseases. Parvovirus B19 DNA was investigated by PCR in the skin of 20 patients with psoriasis and 20 patients with eczema. Additionally, immunohistochemistry was used to characterize the expression of cytokines in these lesions. The sociodemographic variables were similar in the two groups studied. Psoriasis vulgaris was the most common clinical type in men (50%) and women (80%) (p = 0.0106). Comorbidities were observed in most patients with psoriasis (75%), with an OR of 14 (p = 0.0068). Another important finding was the high prevalence (50%) of psychiatric disorders in patients with psoriasis (OR = 16, p = 0.0218). Only two patients (10%) with psoriasis were positive for PVB19. Comparison of cytokine expression showed the same cytokine profile in the two groups (p > 0.05). However, expression of TNF-alpha tended to be higher in psoriasis patients. There was no significant positivity for PVB19 in the two groups studied. Immunohistochemistry showed higher expression of TNF-alpha in psoriasis lesions compared to the eczema group. PMID- 29428425 TI - Physical relation and mechanism of ultrasonic bactericidal activity on pathogenic E. coli with WPI. AB - OBJECTIVE: This study aimed to investigate the physical relation and mechanism of bactericidal activity on pathogenic E. coli by ultrasonic field with whey protein isolate (WPI). METHODS: Ultrasound treatment was performed under the conditions of intensity at 65 W/cm2, pulse duty ratio at 0.5 for 0-15 min with WPI concentration ranged from 0 to 10%. Viscosity, granularity, surface hydrophobicity, free radical scavenging activity, and thermal denaturation were assessed by rotational viscometer, Malvern Mastersizer 2000 particle size analyzer, fluorescent probe ANS method, DPPH method, and differential scanning calorimetry, respectively. RESULTS: The thermal denaturation of WPI was not altered by ultrasound field, but the viscosity of WPI was increased upon 10 min treatment. Additionally, its ability to scavenge free radicals and hydrophobicity were increased. The result also showed that the bacteria viability was improved by WPI during ultrasound treatment. However, the WPI protection was decreased by the prolonged treatment. CONCLUSION: Ultrasound treatment resulted in the increasing of the viscosity, free radicals scavenging activity and hydrophobicity of WPI which led to reduced bactericidal activity on E. coil, while WPI protection was disintegrated by prolonged treatment. PMID- 29428426 TI - First-line treatment of Helicobacter pylori in Lebanon: Comparison of bismuth containing quadruple therapy versus 14-days sequential therapy. AB - Helicobacter Pylori (H. Pylori) is the most common cause of peptic ulcer disease (PUD) and represents a strong risk factor for gastric cancer. Treatment of H. Pylori is, therefore, a persistent need to avoid serious medical complications. Resistance to antibiotics remains to be the major challenge for H. Pylori eradication. In this study, we determined the prevalence of H. pylori infection and evaluated H. pylori eradication efficacy of bismuth-containing quadruple therapy (Pylera) versus 14-days sequential therapy in treatment naive-Lebanese patients. 1030 patients, showing symptoms of peptic ulcer (PU) and gastritis, underwent 14C-Urea Breath Test and esophagogastroduodenoscopy to examine H. Pylori infection and gastrointestinal disorders. Among the H. Pylori-positive patients 60 individuals were randomly selected, separated into two groups (each consisting of 30 patients) and treated with either bismuth-containing quadruple therapy or 14-days sequential therapy. We show that of the 1050 patients tested: 46.2% were H. pylori-positive, 55% had gastritis, 46.2% had both gastritis and H. pylori infection, 8.8% had gastritis but no H. pylori infection, 44.9% had neither gastritis nor H. pylori infection. Following the 14-days sequential therapy, the eradication rate was significantly higher than that obtained upon using bismuth-containing quadruple therapy [80% (24/30) versus 50% (15/30), chi2 = 5.93, P = 0.015]. In conclusion, we determined H. pylori and gastritis prevalence among Lebanese PU-patients and showed that 14-days sequential therapy is more efficient than bismuth-containing quadruple therapy in terms of H. Pylori eradication. PMID- 29428427 TI - Horizontal transfer of class 1 integrons from uropathogenic Escherichia coli to E. coli K12. AB - Class 1 integrons are genetic elements that carry a variable set of antibiotic resistance genes, being frequently found in clinical Gram-negative isolates. It is generally assumed that they easily spread horizontally among bacteria, thus contributing to the appearance of multidrug resistant clones. However, there are few experimental studies on the lateral transfer of these elements performed with bacterial collections that had been gathered following an epidemiological design. In this work, a collection with these characteristics, comprising uropathogenic Escherichia coli (UPEC) isolates bearing class 1 integrons, was employed to study the horizontal transfer of the integron to an E. coli K12 strain by means of conjugation and transduction experiments. Donor and resultant strains were characterized for their antibiotic resistances, presence of sul1, sul2 and sul3 genes, integron cassette arrays, plasmid replicons and tra region. Conjugation assays were carried out using 45 UPEC isolates as integron donors and transconjugants were obtained in 18 cases (40%). P1-transduction experiments only added the integron transfer from a single donor isolate. Thus, a collection of E. coli K12 strains carrying the class 1 integron from 19 UPEC isolates was generated. In all cases, the integron was co-transferred with at least one low copy-number plasmid, generally of the F replicon type. Several variables were searched for that could be related to the ability to horizontally transfer the integron. Although no strict correlation was observed, the phylogenetic background of the donor strain and the presence of the sul2 gene appeared as candidates to influence the process. Therefore, there appears that besides being carried by mobile genetic elements, class 1 integrons may be influenced by other factors to accomplish their horizontal transfer, a topic that requires further studies. PMID- 29428428 TI - Eosinophilic granulomatosis with polyangiitis: A case report. PMID- 29428429 TI - Design of an electrostatic phase shifting device for biological transmission electron microscopy. AB - I suggest an electrostatic phase plate designed to broaden the contrast transfer function of a transmission electron microscope operated close to Scherzer defocus primarily in the low resolution direction. At higher defocus the low frequency behavior is equal to that close to Scherzer defocus, but CTF-correction becomes necessary to extend image interpretation to higher resolution. One simple realization of the phase plate consists of two ring shaped electrodes symmetrically surrounding the central beam. Since no physical components come into contact with the central beam and charge on the electrodes is controlled by an external voltage supply, problems with uncontrolled charging are expected to be reduced. PMID- 29428430 TI - Theory of the spatial resolution of (scanning) transmission electron microscopy in liquid water or ice layers. AB - The sample dependent spatial resolution was calculated for transmission electron microscopy (TEM) and scanning TEM (STEM) of objects (e.g., nanoparticles, proteins) embedded in a layer of liquid water or amorphous ice. The theoretical model includes elastic- and inelastic scattering, beam broadening, and chromatic aberration. Different contrast mechanisms were evaluated as function of the electron dose, the detection angle, and the sample configuration. It was found that the spatial resolution scales with the electron dose to the -1/4th power. Gold- and carbon nanoparticles were examined in the middle of water layers ranging from 0.01--10 um thickness representing relevant classes of experiments in both materials science and biology. The optimal microscope settings differ between experimental configurations. STEM performs the best for gold nanoparticles for all layer thicknesses, while carbon is best imaged with phase contrast TEM for thin layers but bright field STEM is preferred for thicker layers. The resolution was also calculated for a water layer enclosed between thin membranes. The influence of chromatic aberration correction for TEM was examined as well. The theory is broadly applicable to other types of materials and sample configurations. PMID- 29428431 TI - Energy-weighted dynamical scattering simulations of electron diffraction modalities in the scanning electron microscope. AB - Transmission Kikuchi diffraction (TKD) has been gaining momentum as a high resolution alternative to electron back-scattered diffraction (EBSD), adding to the existing electron diffraction modalities in the scanning electron microscope (SEM). The image simulation of any of these measurement techniques requires an energy dependent diffraction model for which, in turn, knowledge of electron energies and diffraction distances distributions is required. We identify the sample-detector geometry and the effect of inelastic events on the diffracting electron beam as the important factors to be considered when predicting these distributions. However, tractable models taking into account inelastic scattering explicitly are lacking. In this study, we expand the Monte Carlo (MC) energy weighting dynamical simulations models used for EBSD [1] and ECP [2] to the TKD case. We show that the foil thickness in TKD can be used as a means of energy filtering and compare band sharpness in the different modalities. The current model is shown to correctly predict TKD patterns and, through the dictionary indexing approach, to produce higher quality indexed TKD maps than conventional Hough transform approach, especially close to grain boundaries. PMID- 29428433 TI - Coupled generative adversarial stacked Auto-encoder: CoGASA. AB - Coupled Generative Adversarial Network (CoGAN) was recently introduced in order to model a joint distribution of a multi modal dataset. The CoGAN model lacks the capability to handle noisy data as well as it is computationally expensive and inefficient for practical applications such as cross-domain image transformation. In this paper, we propose a new method, named the Coupled Generative Adversarial Stacked Auto-encoder (CoGASA), to directly transfer data from one domain to another domain with robustness to noise in the input data as well to as reduce the computation time. We evaluate the proposed model using MNIST and the Large scale CelebFaces Attributes (CelebA) datasets, and the results demonstrate a highly competitive performance. Our proposed models can easily transfer images into the target domain with minimal effort. PMID- 29428432 TI - Supporting doctors as healthcare quality and safety advocates: Recommendations from the Association of Surgeons in Training (ASiT). AB - BACKGROUND: As front-line healthcare staff, doctors in surgical training occupy a unique organisational space rotating through hospitals and services in which they witness first hand both good and bad practice. This puts trainees in a clear position to identify and raise patient safety issues, and to contribute to discussions regarding quality and safety improvement. However, there are a number of real and perceived barriers to trainees doing so. These include concerns about the impact on training assessments and career progression, and uncertainty about the appropriate route. METHODS: Paper-based survey of delegates attending the Association of Surgeons in Training (ASiT) conference (response rate 73%; 479/652). RESULTS: 288 (60%) of trainees reported previous concerns over practices and behaviour of colleagues that might pose risks to patient care including concerns over poor performance (n = 243; 84%), bullying (n = 45; 16%), alcohol and drug abuse (n = 15; 5%) and mental health problems (n = 8; 3%). However, 53% (n = 153) did not escalate these concerns. 178 (37%) of trainees also reported concerns over hospital policies, protocols or systems that might pose a risk to patient care, with 46% (n = 82) not escalating such concerns. Respondents highlighted fear of personal vilification or reprisal (n = 224; 47%), fear of impact on career (n = 206; 43%) and a lack of confidence in the process (n = 170; 36%) as barriers to whistleblowing. More senior trainees were significantly more likely to raise concerns than more junior grades (p < 0.0001). CONCLUSION: These results highlight worrying issues around reporting concerns, with trainees often "silent witnesses" to poor performance in healthcare. Adverse events must provide opportunities for learning to improve future outcomes. Herein, ASiT proposes 14 recommendations to improve protection for trainees in raising patient safety concerns. These include the creation of a positive workplace culture, promoting the active involvement of trainees in quality improvement discussions, with clear mechanisms for trainees to raise concerns. PMID- 29428434 TI - Impact of Body Mass Index on Heart Failure by Race/Ethnicity From the Get With The Guidelines-Heart Failure (GWTG-HF) Registry. AB - OBJECTIVES: This study sought to evaluate the influence of race/ethnicity on the relationship between body mass index (BMI) and mortality in heart failure with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF) patients. BACKGROUND: Prior studies demonstrated an "obesity paradox" among overweight and obese patients, where they have a better HF prognosis than normal weight patients. Less is known about the relationship between BMI and mortality among diverse patients with HF, particularly given disparities in obesity and HF prevalence. METHODS: The authors used Get With The Guidelines-Heart Failure data to assess the relationship between BMI and in-hospital mortality by using logistic regression modeling. The authors assessed 30-day and 1-year rates of all cause mortality following discharge by using Cox regression modeling. RESULTS: A total of 39,647 patients with HF were included (32,434 [81.8%] white subjects; 3,809 [9.6%] black subjects; 1,928 [4.9%] Hispanic subjects; 544 [1.4%] Asian subjects; and 932 [2.3%] other subjects); 59.7% of subjects had HFpEF, and 30.7% were obese. More black and Hispanic patients had Class I or higher obesity (BMI >=30 kg/m2) than whites, Asians, or other racial/ethnic groups (p < 0.0001). Among subjects with HFpEF, higher BMI was associated with lower 30-day mortality, up to 30 kg/m2 with a small risk increase above 30 kg/m2 (BMI: 30 vs. 18.5 kg/m2), hazard ratio (HR) of 0.63 (95% confidence interval [CI]: 0.54 to 0.73). A modest relationship was observed in HFrEF subjects (BMI: 30 vs. 18.5 kg/m2; HR: 0.73; 95% CI: 0.60 to 0.89), with no risk increase above 30 kg/m2. There were no significant interactions between BMI and race or ethnicity related to 30-day mortality (p > 0.05). CONCLUSIONS: This work is one of the first suggesting the obesity paradox for 30-day mortality exists at all BMI levels in HFrEF but not in patients with HFpEF. Higher BMI was associated with lower 30-day mortality across racial/ethnic groups in a manner inconsistent with the J-shaped relationship noted for coronary artery disease. The differential slope of obesity and mortality among HFpEF and patients with HFrEF potentially suggests differing mechanistic factors, requiring further exploration. PMID- 29428435 TI - Body Mass Index and Heart Failure Mortality: More Is Less? PMID- 29428436 TI - Sense and Sensibility of the Use of NT-proBNP for Eligibility in Clinical Trials. PMID- 29428437 TI - Obesity and Prognosis in Pediatric Dilated Cardiomyopathy: No Paradox or Adverse Effects. PMID- 29428438 TI - No Obesity Paradox in Pediatric Patients With Dilated Cardiomyopathy. AB - OBJECTIVES: This study aimed to examine the role of nutrition in pediatric dilated cardiomyopathy (DCM). BACKGROUND: In adults with DCM, malnutrition is associated with mortality, whereas obesity is associated with survival. METHODS: The National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry was used to identify patients with DCM and categorized by anthropometric measurements: malnourished (MN) (body mass index [BMI] <5% for age >=2 years or weight-for-length <5% for <2 years), obesity (BMI >95% for age >=2 years or weight-for-length >95% for <2 years), or normal bodyweight (NB). Of 904 patients with DCM, 23.7% (n = 214) were MN, 13.3% (n=120) were obese, and 63.1% (n=570) were NB. RESULTS: Obese patients were older (9.0 vs. 5.7 years for NB; p < 0.001) and more likely to have a family history of DCM (36.1% vs. 23.5% for NB; p = 0.023). MN patients were younger (2.7 years vs. 5.7 years for NB; p < 0.001) and more likely to have heart failure (79.9% vs. 69.7% for NB; p = 0.012), cardiac dimension z-scores >2, and higher ventricular mass compared with NB. In multivariable analysis, MN was associated with increased risk of death (hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.66 to 3.65; p < 0.001); whereas obesity was not (HR: 1.49; 95% CI: 0.72 to 3.08). Competing outcomes analysis demonstrated increased risk of mortality for MN compared with NB (p = 0.03), but no difference in transplant rate (p = 0.159). CONCLUSIONS: Malnutrition is associated with increased mortality and other unfavorable echocardiographic and clinical outcomes compared with those of NB. The same effect of obesity on survival was not observed. Further studies are needed investigating the long-term impact of abnormal anthropometric measurements on outcomes in pediatric DCM. (Pediatric Cardiomyopathy Registry; NCT00005391). PMID- 29428439 TI - Utilizing NT-proBNP for Eligibility and Enrichment in Trials in HFpEF, HFmrEF, and HFrEF. AB - OBJECTIVES: The purpose of this study was to assess the association between N terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiovascular (CV) versus non-CV events and between NT-proBNP and potential treatment effects in heart failure (HF) with preserved, mid-range, and reduced ejection fraction (HFpEF, HFmrEF, and HFrEF, respectively) and clinically relevant subgroups. BACKGROUND: Optimizing patient eligibility criteria in HF trials requires biomarkers that enrich for CV but not for non-CV events and select patients most likely to respond to the tested intervention. METHODS: In the Swedish HF registry population stratified by EF category, we used Kaplan-Meier curves to estimate unadjusted CV and non-CV risks (mortality or hospitalization); Poisson regressions to calculate crude event rates of CV and non-CV events according to NT-proBNP levels; and Cox regressions to calculate the adjusted hazard ratios for HF therapies according to NT-proBNP <= or > median. RESULTS: In a cohort of 15,849 patients (23% HFpEF, 21% HFmrEF, 56% HFrEF), median NT-proBNP was 2,037, 2,192, and 3,141 pg/ml, respectively. With increasing NT-proBNP, CV event rates increased more steeply than non-CV rates (range 20 to 160 and 30 to 100 per 100 patient-years in HFpEF; 20 to 130 and 20 to 100 in HFmrEF; and 20 to 110 and 20 to 50 in HFrEF, respectively). The CV-to-non-CV ratio increased with increasing NT-proBNP in HFpEF and HFrEF, but only in the lower range in HFmrEF. The association between treatments (e.g., angiotensin-converting enzyme-inhibitor, angiotensin II receptor blockers, and beta-blockers) and outcomes was consistent in NT-proBNP <= and > median. CONCLUSIONS: In HF trial design in different EF categories, NT-proBNP may be a useful tool for eligibility and enrichment for CV events, but its role in predicting a potential treatment response remains unclear. PMID- 29428441 TI - The role of external quality assessment in the verification of in vitro medical diagnostics in the traceability era. AB - Once an in-vitro diagnostic (IVD) measuring system has been marketed and introduced into daily practice, the possible sources of degradation of its performance are numerous. It is therefore essential to put in place a continuous post-market surveillance of the quality of performance of the IVD system and of the laboratories that perform measurements in clinical setting. The participation to external quality assessment (EQA) schemes that meet specific metrological criteria is central to the evaluation of performance of clinical laboratories in terms of standardization and clinical suitability of their measurements. In addition to the use of commutable materials, in this type of EQA it is necessary to assign values (and uncertainty) to them with reference procedures and to define and apply clinically permissible analytical performance specifications to substantiate the suitability of laboratory measurements in the clinical setting. Unfortunately, there are still few permanent EQA programs fully covering these requirements because some practical constraints, including technical and economic aspects, which limit their introduction. It is, however, clear that these issues should be quickly overcome, since EQA schemes are in a unique position to add substantial value to the practice of laboratory medicine, by identifying analytes that need improved harmonization and by stimulating and sustaining standardization initiatives that are needed to support clinical practice. Importantly, this will definitively help those manufacturers that produce superior products to demonstrate the superiority of those products and oblige end users (and consequently industry) to abandon assays with demonstrated insufficient quality. PMID- 29428443 TI - ? PMID- 29428444 TI - ? PMID- 29428445 TI - [Depression and suicidal thoughts associated with finasteride]. PMID- 29428440 TI - Melatonin: A Cutaneous Perspective on its Production, Metabolism, and Functions. AB - Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. Although melatonin is best known to regulate circadian rhythmicity and lower vertebrate skin pigmentation, the full spectrum of functional activities of this free radical-scavenging molecule, which also induces/promotes complex antioxidative and DNA repair systems, includes immunomodulatory, thermoregulatory, and antitumor properties. Because this plethora of functional melatonin properties still awaits to be fully appreciated by dermatologists, the current review synthesizes the main features that render melatonin a promising candidate for the management of several dermatoses associated with substantial oxidative damage. We also review why melatonin promises to be useful in skin cancer prevention, skin photo- and radioprotection, and as an inducer of repair mechanisms that facilitate the recovery of human skin from environmental damage. The fact that human skin and hair follicles not only express functional melatonin receptors but also engage in substantial, extrapineal melatonin synthesis further encourages one to systematically explore how the skin's melatonin system can be therapeutically targeted in future clinical dermatology and enrolled for preventive medicine strategies. PMID- 29428446 TI - ? PMID- 29428448 TI - Pulmonary Langerhans cell histiocytosis, acute myeloid leukemia, and myelofibrosis in a large family and review of the literature. AB - BACKGROUND: There is mounting evidence that Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are hematopoietic neoplasms that arise from the same myeloid precursor cell. In addition, studies suggest a relationship between LCH and primary idiopathic myelofibrosis (MF). Furthermore familial LCH, AML, and MF have each been reported. METHODS: We examined more than 750 pedigrees of familial hematologic malignancies for evidence of familial LCH, AML, and/or MF and identified one family with all three neoplasms, which is presented here. FINDINGS: In four generations of this large family there are five cases of AML in three generations, two cases of LCH in two generations and three cases of MF in two generations. Anticipation of -18 and -6 years was present in the patients with MF, and -8 years in the patients with LCH. Anticipation was also identified between one AML patient pair in generations III and IV (-18 years) and three patients with AML in generations II, III, and IV (-5 years and -10 years). INTERPRETATION: This is the first report of familial LCH, AML, and MF in one family. The pedigree suggests a common basis for these entities, which is further suggested by the presence of anticipation in the pedigree. PMID- 29428447 TI - Prognostic significance of SOX2, SOX3, SOX11, SOX14 and SOX18 gene expression in adult de novo acute myeloid leukemia. AB - Aberrant expression of different SOX (SRY-related high mobility group (HMG) box) genes has been observed in number of tumors but, little is known about their expression patterns in hematological malignancies, especially in acute myeloid leukemia (AML). In this study we investigated SOX2, SOX3, SOX11, SOX14 and SOX18 gene expression in 50 de novo adult AML patients and correlated our findings with known clinical and molecular prognostic markers of the disease. We have found that these genes are overexpressed in 10-22% of patients and preliminary findings suggest that high expression level of these genes may have prognostic significance in AML patients. This is the first study focused on examining the expression level of SOX2, SOX3, SOX11, SOX14 and SOX18 genes in AML patients. Although this is a relatively limited study, initial findings indicate the need for further investigation of these genes, their potential roles in leukemia pathogenesis as well as prognosis in AML patients. PMID- 29428449 TI - PD-1 /PD-L1 checkpoint in hematological malignancies. AB - Programmed cell death protein 1 (PD-1), is a cell surface receptor with an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. PD-1/PDL1 axis represents a checkpoint to control immune responses and it is often used as a mechanism of immune escaping by cancers and infectious diseases. Many data demonstrate its important role in solid tumors and report emerging evidences in lymphoproliferative disorders. In this review, we summarized the available data on the role of PD-1/PD-L1 checkpoint in lymphoproliferative diseases and the therapeutics use of monoclonal blocking antibodies. PMID- 29428450 TI - Physicians working under the influence of alcohol: An analysis of past disciplinary proceedings and their outcomes. AB - INTRODUCTION: The intoxicated person may cause harm to others, often requiring expert evaluation for the determination of guilt. The primary aim of this study was to determine the mechanisms of mistakes that led 17 doctors accused of working under the influence of alcohol to face malpractice. We also wanted to clarify what were the legal, professional, and financial consequences - depending on specific patient outcomes. METHOD: We based analysis on the review and meta analysis of the past forensic evaluation reports of institution-run forensics programs. Furthermore, we apply thematic analysis using combination of grounded theory and Pierre Bourdieu's theoretical framework. RESULTS: During the 2010-2016 timeframe, the regional forensic service opinionated on 17 physicians (3F, 14M) subjected to disciplinary action due to providing treatment under the influence of alcohol. In total, there were 157 patients potentially affected by malpractice - out of those, four were harmed; only one qualified for compensation. In the remaining 153 patients - only 11 persons reported having had awareness about the doctors' intoxication and apparent inability to perform the job, yet they agreed to receive care. Overall, in over 90% of patients, the physician did not harm anyone to a degree threatening patient's life. The supporting staff did not report experiencing distress either. The results of a blood test for the presence of alcohol were available for only four cases. Therefore, it was impossible to analyze the correlation between intoxication level and performance in providing care. All in all, in our analysis - less than 10% of 157 patients' care were compromised by provider's intoxication, either due to a mistake in diagnosis, medical procedure, or lacking communication skills. CONCLUSION: For physicians, working under the influence of alcohol is an uncommon phenomenon, but when it occurs - patients are at risk for receiving poor treatment. Presented analysis indicates that patients - just as much as supporting staff - frequently agree to receive supervision and care from a drunk doctor, despite possible harm. Therefore, it is evident that patients as much as supporting staff fear retaliation, leading to underreporting of these cases. PMID- 29428451 TI - Comparison of the applicability of Demirjian and Willems methods for dental age estimation in children from the Thrace region, Turkey. AB - OBJECTIVES: Dental age (DA) estimation is frequently used in the fields of orthodontics, paediatric dentistry and forensic science. DA estimation methods use radiology, and are reliable and non-destructive according to the literature. The Demirjian method is currently the most frequently used method, but recently, the Willems method was reported to have given results that were more accurate for some regions. The aim of this study was to detect and compare the accuracy of DA estimation methods for children and adolescents from the Thrace region, Turkey. The mean difference between the chronological age (CA) and the DA was selected as the primary outcome measure, and the difference range according to sex and age group was selected as the secondary outcome. MATERIALS AND METHODS: Panoramic radiographs (n=766) from a Thrace region population (380 males and 386 females) ranging in age from 6 to 14.99 years old were evaluated. DA was calculated using both the Demirjian and the Willems methods. RESULTS: The mean CA of the subjects was 11.39+/-2.34 years (males=11.08+/-2.42 years and females=11.70+/-2.23 years). The mean difference values between the CA and the DA (CA-DA) using the Demirjian method and the Willems method were -0.87 and -0.17 for females, respectively, and -1.04 and -0.40 for males, respectively. For the different age groups, the differences between the CA and the DA calculated using the Demirjian method (CA DA) ranged from -0.53 to -1.46 years for males and from -0.19 to -1.20 years for females, while the mean differences between the CA and the DA calculated by the Willems method (CA-DA) ranged from -0.19 to -0.50 years for males and from 0.20 to -0.49 years for females. CONCLUSION: The results suggest that the Willems method produced more accurate results for almost all age groups of both sexes, and it is better suited for children from the Thrace region of Turkey, than the Demirjian method. PMID- 29428452 TI - Association between Dietary Glycemic Index and Knee Osteoarthritis: The Korean National Health and Nutrition Examination Survey 2010-2012. AB - BACKGROUND: Obesity and metabolic abnormalities are important risk factors for knee osteoarthritis (KOA). Recent epidemiologic studies have found that a high glycemic index (GI) and glycemic load (GL) diet are associated with a higher risk for metabolic complications and cardiovascular mortality. OBJECTIVE: We aimed to examine the association between dietary GI, dietary GL, and KOA among Korean adults. DESIGN: This was a cross-sectional study that analyzed data obtained from the Korean National Health and Nutrition Examination Survey 2010-2012. PARTICIPANTS/SETTING: A total of 9,203 participants (5,275 women) aged >=50 years were included. MAIN OUTCOME MEASURES: KOA was defined as the presence of radiographic features of Kellgren-Lawrence grade >=2. Chronic knee pain was defined as the presence of knee pain for more than 30 days during the past 3 months. Dietary information was collected using a single 24-hour recall method. STATISTICAL ANALYSES PERFORMED: The association between the quintiles of dietary GI and dietary GL and knee conditions was analyzed using a multinomial logistic regression analysis adjusting for age, physical activity, obesity, hypertension and diabetes, serum low-density lipoprotein, and total energy intake. RESULTS: Among the women, the association between dietary GI and symptomatic KOA was: quintile 1: 1.00 (reference); quintile 2: 1.29 (95% CI 0.87 to 1.92); quintile 3: 1.59 (95% CI 1.11 to 2.28); quintile 4: 1.74 (95% CI 1.21 to 2.51); and quintile 5: 1.77 (95% CI 1.20 to 2.60) (P=0.001). Chronic knee pain without KOA was associated with dietary GI; however, this association was not linear across quintiles. There was no significant association between dietary GI and asymptomatic KOA. Among the men, no significant association was found between dietary GI and any knee conditions. There was no significant association between dietary GL and KOA in both men and women. CONCLUSIONS: There was a significant positive association between dietary GI and symptomatic KOA in women. PMID- 29428453 TI - US Military Dietetic Internship and Graduate Program: Retrospective Analysis of Selection Criteria and Student Success. AB - BACKGROUND: The US Military-Baylor Graduate Program in Nutrition (GPN) has a 10% 7-year attrition rate representing wasted military resources. Evidence-based selection criteria for dietetics masters of science (MS) programs do not exist, nor does descriptive information of successful students. OBJECTIVE: Identify GPN student characteristics predicting program success in the didactic and internship phases. DESIGN: Retrospective study using demographic, academic, and nonacademic data extracted from existing files. PARTICIPANTS AND SETTING: There were 72 GPN students enrolled from 2006 to 2013 in San Antonio, TX. MAIN OUTCOME MEASURES: Categorization by optimal performance (no course grade <3.0, no internship rotation delays, first attempt pass registered dietitian nutritionist examination) and GPN completion. RESULTS: The average GPN student was female (65%), in the US Army (94%), and single (64%), with a mean age of 26 years. Mean Quantitative, Verbal Reasoning, and Analytical Writing Graduate Record Examination (GRE) scores were 149, 153, and 4.2 points, respectively. Odds of GPN failure increased 1.3 times with each year increase in age at GPN program start (95% CI=1.089 to 1.612; P=0.005). Odds of attaining optimal performance decreased 4.5 times with each additional year increase between GRE completion and GPN start (95% CI=1.623 to 16.236; P=0.005) and 0.157 times with each grade point average point decrease in Biochemistry (95% CI=0.49 to 0.430; P=0.002). CONCLUSIONS: Modification of selection criteria based on time between GRE and GPN start and undergraduate Biochemistry grades could improve GPN success. However, identification and mitigation of potential student weaknesses is a more realistic approach to promote student success. Intentional development of students with optimal characteristics will strengthen the dietetics profession during the transition to an MS degree requirement. PMID- 29428454 TI - Choroidal Microvasculature Dropout Is Associated With Parafoveal Visual Field Defects in Glaucoma. AB - PURPOSE: To determine whether the frequency of parafoveal visual field (VF) damage differs according to the presence of choroidal microvasculature dropout (CMvD) in open-angle glaucoma (OAG) and to assess correlations between the angular circumference of CMvD and the severity of VF defects. DESIGN: Retrospective case-control study. METHODS: This study enrolled 88 eyes of 88 consecutive OAG patients (44 with CMvD and 44 without CMvD matched for age [<=5 years], axial length [<=1 mm], and the severity of VF loss [<=1 dB]). Angular circumference of CMvD was determined from choroidal layer images obtained from optical coherence tomography angiography. Demographic and ocular characteristics, including the presence of parafoveal VF defects and VF mean sensitivity (MS), were compared between OAG eyes with CMvD and those without. Logistic regression analyses were performed to derive the clinical factors associated with parafoveal VF defects. The relationships between CMvD angular circumference and global/regional VF defect severity were assessed. RESULTS: Parafoveal VF defects were observed in 96% (42/44) of eyes with CMvD but only in 39% (17/44) of eyes without CMvD. OAG eyes with CMvD showed significantly lower superior parafoveal VF MS compared to those without. A significant association was found between parafoveal VF defects and CMvD in OAG eyes, and CMvD angular circumference was significantly correlated with the severity of VF defects. CONCLUSIONS: The involvement of parafoveal VF defects was significantly associated with the presence of CMvD. Among eyes with CMvD, CMvD angular circumference had significant correlations with the severity of VF defects. PMID- 29428455 TI - Ophthalmic Findings of Rosai-Dorfman Disease. AB - PURPOSE: To describe the ophthalmic, pathologic, and BRAF V600E mutation status of Rosai-Dorfman disease (RDD). DESIGN: Retrospective case series. METHODS: A retrospective review of all cases of RDD seen at Mayo Clinic from 1992 to 2016 identified patients with ophthalmic manifestations (n = 8). Immunostain for BRAF and molecular studies for BRAF V600E mutation were performed on cases with tissue available. RESULTS: Of 76 patients with RDD, 15 had eye examinations; of those, 8 (5 female and 3 male) had ophthalmic manifestations. In RDD patients with ophthalmic manifestations compared to RDD patients without ophthalmic manifestations, the respective median (range) age in years was 42 (15-70) and 56 (32-79) (P = .13) and median (range) logMAR visual acuity was 0.048 (0.000-1.824) and 0.000 (-0.124 to 0.301) (P = .19). Of the 8 patients with ophthalmic manifestations, 4 had ocular involvement and 4 had orbital masses. Patients with ocular involvement had multiorgan disease including tracheal, aortic, renal, skeletal, and soft tissue lesions (n = 4). Patients with orbital masses had no systemic involvement (n = 2), skeletal involvement only (n = 1), or multiorgan disease (n = 1). BRAF immunostaining and molecular studies were negative in all available specimens (n = 6). CONCLUSIONS: In this series of patients with ophthalmic manifestations of RDD, those with ocular involvement had multiorgan disease while those with orbital masses had more limited systemic disease. Patients with ophthalmic manifestations tended to be younger and have worse visual acuity. Additionally, ophthalmic RDD does not seem to be associated with BRAF mutation. PMID- 29428456 TI - Precise Measurement of Retinal Vascular Bed Area and Density on Ultra-wide Fluorescein Angiography in Normal Subjects. AB - PURPOSE: To characterize and quantify the total retinal vascular bed area (RVBA) and vascular density (VD) in normal eyes using stereographically corrected ultra wide-field (UWF) fluorescein angiography (FA). DESIGN: Cross-sectional study. METHODS: Fifty-nine eyes of 31 normal subjects with no evidence of ocular disease underwent FA using the Optos 200Tx (Optos plc, Dunfermline, United Kingdom). Central and peripheral-steered FA images were montaged and stereographically projected. The early-phase FA was used to extract the retinal vasculature as a binary mask. Two independent, masked reading center-certified graders delineated the peripheral edge of the total retinal area (TRA) on a middle-phase frame. The RVBA and TRA were computed automatically in mm2 using software provided by the manufacturer. The VD was calculated by dividing RVBA by TRA. RESULTS: The mean RVBA was 42.3 +/- 14.8 mm2 for the entire retina, with no difference between male and female subjects (P = .439) or between right and left eyes (P = .407). The mean VD was 4.3% +/- 1.4% for the entire retina, with no difference based on sex (P = .629) or laterality (P = .426). A negative correlation was observed between age and both RVBA and VD (RVBA: R = -0.6, P < .001; VD: R = -0.52, P < .001). Pairwise comparisons showed that subjects aged >65 years had smaller RVBA and VD than those younger than 50 years for the entire retina and in all quadrants. CONCLUSIONS: RVBA and VD can be extracted from UWF FA images using automated processing techniques and may provide a reliable alternative to measures such as nonperfusion area. PMID- 29428457 TI - Molecular diversity and conjugal transferability of class 2 integrons among Escherichia coli isolates from food, animal and human sources. AB - Integrons are genetic platforms able to excise, integrate and express antibiotic resistance gene cassettes (GCs). Here we investigated the complete genetic organisation, genetic environment, location and conjugative transferability of a collection of class 2 integrons carried by Escherichia coli strains from different sources (poultry/pork meat, animals and humans). PCR cartography was conducted to determine the genetic arrangement of the integrons, their physical linkage to Tn7 and chromosomal insertion at the attTn7 site. Clonal relatedness of specific isolates was determined by MLST and DO-PCR. Transferability of class 2 integrons was tested by conjugation. The resulting transconjugants were characterised by antimicrobial resistance genotyping, S1-PFGE and replicon typing. Although a limited diversity of GCs was shown, a high percentage of novel structures was identified owing to the integration of insertion sequence (IS) elements at different sites (IS3/IS4/IS5/IS21 families). Insertion of IS10 in the attI2 site of a class 2 integron, between Pc2B and Pc2C promoters, was likely mediated by a site-specific transposition event. Chromosomal insertion of integrons at attTn7 was confirmed in 80% of the isolates. Conjugation experiments demonstrated that 29% of class 2 integrons could be mobilised to E. coli CHS26, demonstrating that they can be located in conjugative/mobilisable elements at a low frequency. Reported structures evidence how class 2 integrons have evolved by the activity of integron integrases and the invasion of ISs. Since most of them are chromosomally located, dispersion is predominantly vertical, although conjugation events also contribute to the spread of class 2 integrons among bacterial communities. PMID- 29428458 TI - Routine angiographic follow-up versus clinical follow-up in patients with diabetes following percutaneous coronary intervention with drug-eluting stents in Korean population. AB - AIMS: The usefulness of routine angiographic follow-up (RAF) and clinical follow up (CF) after percutaneous coronary intervention (PCI) in patients with diabetes is not well understood. We compare 3-year clinical outcomes of RAF and CF in diabetic patients underwent PCI with drug-eluting stents (DES). METHODS: A total of 843 patients with diabetes who underwent PCI with DES were enrolled. RAF was performed at 6-9 months after PCI (n = 426). Rest of patients were medically managed and clinically followed (n = 417); symptom-driven events were captured. After propensity score matched analysis, 2 propensity-matched groups (262 pairs, n = 524, C-statistic = 0.750) were generated. The primary endpoint was major adverse cardiac events (MACE), the composite of total death, non-fatal myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), non-target vessel revascularization (Non-TVR). RESULTS: During the 3-year follow-up period, the cumulative incidence of target lesion revascularization [TLR: hazard ratio (HR), 4.07; 95% confidence interval (CI), 1.18-9.34; p = 0.001], target vessel revascularization (TVR: HR, 4.02; 95% CI, 1.93-8.40; p < 0.001), non-TVR (HR, 4.92; 95% CI, 1.68-14.4; p = 0.004) and major adverse cardiac events (MACE: HR, 2.53; 95% CI, 1.60-4.01, p < 0.001) were significantly higher in the RAF group. However, the incidence of total death, non fatal MI were similar between the two groups. CONCLUSIONS: RAF following index PCI with DES in patients with diabetes was associated with increased incidence of revascularization and MACE without changes of death or re-infarction rates and increased TLR and TVR rates in both first- and second-generation DES. PMID- 29428459 TI - Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy. AB - BACKGROUND: The PIVOT trial examined whether patients with suppressed viral load on combination antiretroviral therapy could be safely switched long-term to ritonavir-boosted protease inhibitor (PI) monotherapy. The main trial publication reported that only one of 296 patients allocated to PI monotherapy experienced a loss of drug options due to protease mutations (identified by local Sanger sequencing resistance tests) likely selected by study drug. OBJECTIVES: To assess if we had missed low frequency mutations, using a more sensitive methodology. STUDY DESIGN: We performed next generation sequencing (NGS) on all available frozen plasma samples with VL >1000 copies/ml from patients who were randomised to PI monotherapy. Assays were performed at Public Health England laboratories using a previously described method. Median coverage depth was 76,000 and the threshold for detection of minority variants was 2%. Drug susceptibility was predicted using the Stanford HIVdb algorithm. RESULTS: 17 of 26 potential samples, all from different patients, were identified and successfully tested. The median viral load was 6780 copies/ml and the median time since randomisation was 43 weeks. NGS revealed previously unidentified minority variant protease mutations (G73D, I54T, L89V) in three samples, at frequencies ranging between 2% and 10%. None of these mutations predicted intermediate or high level resistance, the trial primary outcome. DISCUSSION: This report adds to the body of evidence that ritonavir-boosted PI monotherapy, when used as a switch strategy with prompt detection of viral load rebound and early re-introduction of combination therapy, rarely leads to the development of clinically important protease resistance mutations. PMID- 29428460 TI - Severe hantavirus disease in children. AB - BACKGROUND: Very recently, a novel European hantavirus, Sochi virus, has been discovered which causes severe courses of hantavirus disease with a case fatality rate of about 15 percent. OBJECTIVES: We aimed to study to which extent and with which clinical severity children were affected by Sochi virus infection. STUDY DESIGN: Sochi virus infection of patients was confirmed by molecular, serological, and epizoonotic studies. Clinical and laboratory parameters were analyzed for the age group of up to 15 years (n = 6) in comparison to all older patients (n = 56). RESULTS: 9.7 percent of patients with hantavirus disease studied (6/62) were up to 15 years old. The children showed moderate to severe clinical courses similarly to the situation in adults. CONCLUSIONS: While children are in general considered to be less affected by hantavirus infections than adults, in case of highly pathogenic hantaviruses, such as Sochi virus, frequency of clinical cases as well as their clinical course are comparable between children and adults. Therefore, hantavirus disease, particularly in regions endemic to highly pathogenic hantaviruses, should be considered in cases of unclear fever and kidney/pulmonary failure in children. PMID- 29428461 TI - Going Green and Cold: Biosurfactants from Low-Temperature Environments to Biotechnology Applications. AB - Approximately 80% of the Earth's biosphere is cold, at an average temperature of 5 degrees C, and is populated by a diversity of microorganisms that are a precious source of molecules with high biotechnological potential. Biosurfactants from cold-adapted organisms can interact with multiple physical phases - water, ice, hydrophobic compounds, and gases - at low and freezing temperatures and be used in sustainable (green) and low-energy-impact (cold) products and processes. We review the biodiversity of microbial biosurfactants produced in cold habitats and provide a perspective on the most promising future applications in environmental and industrial technologies. Finally, we encourage exploring the cryosphere for novel types of biosurfactants via both culture screening and functional metagenomics. PMID- 29428462 TI - CRISPR-Based Antibacterials: Transforming Bacterial Defense into Offense: (Trends in Biotechnology 36, 127-130, 2018). PMID- 29428463 TI - Cardiac repolarization evolves differently during the course of benign and disabling multiple sclerosis. AB - BACKGROUND: Cardiac repolarization is modulated by the autonomic nervous system. Even though multiple sclerosis associates with prolonged cardiac repolarization the physiology responsible for the phenomenon remains unknown. OBJECTIVE: To study in longitudinal setting whether the patients with confirmed benign and disabling outcome of relapsing-remitting multiple sclerosis (RRMS) differ in regard to changes of cardiac repolarization. METHODS: Total of 43 patients, 26% with benign (EDSS <=2 at least 10y after onset symptom) and 74% with disabling (EDSS >2 at least 10y after onset symptom) RRMS, having 12-lead electrocardiogram (ECG) recorded at the time of onset symptom (ECG1) and for follow-up (ECG2), were studied. Heart rate (HR) corrected QT intervals (QTc) reflecting cardiac repolarization were assessed. RESULTS: The time interval between ECG1 and ECG2 showed no statistical difference between benign (7.8 +/- 4.8y) and disabling (10.2 +/- 5.6y; p = .211) RRMS. Patients with benign and disabling RRMS showed similar values of HR (66+/-9 bpm vs 73 +/- 15 bpm; p=.146) and QTc (403 +/- 13 ms vs 408 +/- 19 ms; p = .450) at the time of ECG1. However, at the time of ECG2, HR was higher (79 +/- 14 bpm vs 65 +/- 10 bpm; p = .004) and QTc was longer (420 +/- 24 ms vs 400 +/- 15 ms; p = .012) in patients with disabling than benign RRMS. Correspondingly, HR increased (p = .063) and QTc prolonged (p = .014) during the disease course only in patients with disabling RRMS. CONCLUSIONS: Deterioration of cardiac autonomic regulation during the disease course associates with disabling but not with benign RRMS. Our findings suggest that assessment of cardiac autonomic regulation should be included in the evaluation of RRMS disease course. In addition, patients with disabling RRMS might be prone to unfavorable cardiovascular outcome also due to deterioration of autonomic nervous system. PMID- 29428464 TI - Why do people search Wikipedia for information on multiple sclerosis? AB - BACKGROUND: Wikipedia is a frequently-accessed online source of health-related information. In this study we evaluated the number of views of the Italian Wikipedia articles related to multiple sclerosis (MS) and its treatment. METHODS: Using Pageviews Analysis we assessed the total views, and mean monthly and daily views of the Italian Wikipedia articles on MS and its treatments from 1 January 2015 to 31 October 2017. We compared the views of the article on MS with those for Alzheimer's disease, epilepsy, migraine and stroke, and adjusted results for crude disease prevalence. RESULTS: The total views of the Italian Wikipedia article on MS was 929,983 (mean monthly views: 33,214; mean daily views: 1089). The adjusted views for the Italian Wikipedia article on MS were higher than those for the other neurological disorders. The normalized views for the MS article were 16, 7, 145 and 11 times higher than those of the articles on Alzheimer's disease, epilepsy, migraine and stroke, respectively. Peaks were temporally related to famous people with MS talking about their disease in talk shows on television or to news on novel treatments for MS. CONCLUSION: Wikipedia searches do not reliably reflect its actual epidemiology. Celebrities with MS acting as testimonials might effectively increase public knowledge on MS. PMID- 29428465 TI - Survival Rate of Short-Stem Hip Prostheses: A Comparative Analysis of Clinical Studies and National Arthroplasty Registers. AB - BACKGROUND: The primary aim was to evaluate the outcome of short-stem hip prostheses in terms of overall revision rates. Data were taken from published literature and national arthroplasty registers. The second study aim was to evaluate a potentially superior outcome of dependent compared to independent clinical studies. METHODS: All clinical studies on short-stem hip prostheses between 2006 and 2016 were reviewed and evaluated with a special interest on revision rates. Revision rate was calculated as "revision per 100 component years." Short stems were divided into femoral neck retaining (NR), neck sparing (NS), and neck harming (NH) prostheses. Published literature was further classified into dependent and independent studies, and data were compared to the Australian National Arthroplasty Register. RESULTS: Fifty-two studies with 56 cohorts met the inclusion criteria and were therefore included in our study. All clinical studies showed a median revision rate of 4.8% after 10 years. NS and NH stems performed equally, whereas neck retaining prostheses were significantly inferior. Independent showed higher revision rates compared to dependent data without being statistically significant. The Australian register revealed a revision rate of 6.6% after one decade. CONCLUSION: Similar low revision rates for NS and NH short-stem prostheses were found in the included data. Dependent studies seem not to be biased with regard to the longevity of short-stem hip replacement. Longer follow-up periods in clinical studies and more detailed information in arthroplasty registers would be desirable for future studies. PMID- 29428466 TI - Irrigation and Debridement for Early Periprosthetic Knee Infection: Is It Effective? AB - BACKGROUND: Irrigation and debridement (I&D) is performed for early management of periprosthetic joint infection (PJI) following total knee arthroplasty (TKA). Symptom reporting is a subjective measure and may miss direct management of PJI. Utilizing an objective time interval from index procedure to I&D may better inform treatment decisions. METHODS: From 2009 to 2017, retrospective review was performed of 55 knee PJI cases at our institution. All patients underwent polyethylene liner exchange and I&D for PJI. Patients were stratified by time from index procedure to I&D (<=2 weeks, >2 weeks). Success was defined as eradication of infection and resolution of presenting symptoms. Failed cases required subsequent procedures due to infection. RESULTS: Average follow-up time after index TKA was 2.5 years. Among patients with I&D within 2 weeks of index TXA, 14 patients (82%) were successfully treated while 3 (18%) had infection recurrence. These outcomes were significantly improved compared to patients with I&D after 2 weeks: 19 (50%) successes and 19 (50%) failures (P = .024). Staphylococcal species were the most frequent pathogen in patients treated before and after 2 weeks of index TKA (39% and 50%, respectively). Outcomes were pathogen-independent in PJIs treated before or after 2 weeks of index TKA (P = .206 and .594, respectively). CONCLUSION: Our results demonstrate that patients with early PJI managed with I&D and liner exchange within 2 weeks of index TKA had higher rates of treatment success when compared to those with I&D beyond 2 weeks. These findings suggest that time from index TKA to I&D is an objective and reliable indicator of treatment success when considering I&D in acute onset knee PJI. PMID- 29428467 TI - Impaction Force Influences Taper-Trunnion Stability in Total Hip Arthroplasty. AB - BACKGROUND: This study investigated the influence of femoral head impaction force, number of head strikes, the energy sequence of head strikes, and head offset on the strength of the taper-trunnion junction. METHODS: Thirty titanium alloy trunnions were mated with 36-mm zero-offset cobalt-chromium femoral heads of corresponding taper angle. A drop tower impacted the head with 2.5J or 8.25J, resulting in 6 kN or 14 kN impaction force, respectively, in a single strike or combinations of 6 kN + 14 kN or 14 kN + 14 kN. In addition, ten 36-mm heads with 5 and +5 offset were impacted with sequential 14 kN + 14 kN strikes. Heads were subsequently disassembled using a screw-driven mechanical testing frame, and peak distraction force was recorded. RESULTS: Femoral head pull-off force was 45% the strike force, and heads struck with a single 14 kN impact showed a pull-off force twice that of the 6 kN group. Two head strikes with the same force did not improve pull-off force for either 6 kN (P = .90) or 14 kN (P = .90). If the forces of the 2 impactions varied, but either impact measured 14 kN, a 51% higher pull-off force was found compared to impactions of either 6 kN or 6 kN + 6 kN. Femoral head offset did not significantly change the pull-off force among -5, 0, and +5 heads (P = .37). CONCLUSION: Femoral head impaction force influenced femoral head trunnion-taper stability, whereas offset did not affect pull-off force. Multiple head strikes did not add additional stability, as long as a single strike achieved 14 kN force at the mallet-head impactor interface. Insufficient impaction force may lead to inadequate engagement of the trunnion taper junction. PMID- 29428468 TI - The effect of levetiracetam on rat bone mineral density, bone structure and biochemical markers of bone metabolism. AB - Some data suggest that exposure to levetiracetam (LEV) might be associated with a risk for bone health in the model of orchidectomized rats. The aim of this study was to investigate if there is any significant risk of LEV for bone health in the model of gonadally intact animals. Wistar rats were divided into a control group and a test group, 8 rats in each group. The control rats received standard laboratory diet (SLD) while rats in the test group were fed SLD enriched with LEV for 12 weeks. Dual energy X-ray absorptiometry was used to measure BMD of the whole body, femur and lumbar vertebrae. The concentrations of bone markers were examined in bone homogenate. Both femurs and tibiae were used for biomechanical testing. We found in the LEV group significantly decreased absolute and relative values of adipose tissue, higher whole-body BMD, higher right tibia cortical thickness, and a significantly increased concentration of Bone Alkaline Phosphatase (BALP) and cross-linked C-telopeptide of type I collagen (CTX-I) compared with the control group. The results suggest that the long-term administration of LEV in the model of gonadally intact rats does not have a negative effect on bone. Significant increase in BMD and cortical thickness of the right tibia may indicate even a positive influence on the properties of bone. Further studies will be necessary in animals and humans to confirm these findings. PMID- 29428469 TI - Treatment with escitalopram modulates cardiovascular function in rats. AB - Considering depression is three times more common in cardiac patients compared to the normal population and selective serotonin reuptake inhibitors (SSRI) as drug of choice for treating patients with cardiovascular disease and depression, our work aims to evaluate the cardiovascular effects of treatment for 21 days with escitalopram (5 mg/kg/day, ip) in rats. The treatment caused an increase in mean arterial pressure concomitant with a decrease in heart rate. Concerning heart rate variability, there was a significant reduction in the sympathetic component and an elevation of the parasympathetic component, indicating that escitalopram caused an autonomic imbalance with parasympathetic predominance. In addition, we observed a decrease in both low and very low frequency power in blood pressure variability. The cardiac autonomic blockade indicated an increase in parasympathetic modulation to the heart with escitalopram chronic treatment. However, no change was observed on baroreflex activity. On the other hand, there was a decrease in pressure response during acute restraint stress with no changes in the tachycardia response. These findings showed that despite the escitalopram be a relatively safe drug it can cause tonic effects on cardiovascular function as well as during aversive situations. PMID- 29428470 TI - DSP-6952, a novel 5-HT4 receptor partial agonist, inhibits visceral hypersensitivity and ameliorates gastrointestinal dysfunction in experimental animals. AB - The pharmacological profile of DSP-6952, a novel 5-HT4 receptor partial agonist, was investigated to evaluate the potential use for GI disorders, and to compare its effects in some GI dysfunction models with those of clinically efficacious prokinetic agents. DSP-6952 enhanced gastric motility and caused colonic giant migrating contractions (GMCs) associated with defecation in conscious dogs, having ED50 value for inducing GMCs of 1.56 mg/kg. DSP-6952 (3-10 mg/kg, i.g.) significantly enhanced colonic transit rate in guinea pigs; this enhancement was antagonized by SB-207266, a selective 5-HT4 receptor antagonist. DSP-6952 (1-10 mg/kg, p.o.) rapidly increased fecal wet weight without increasing fluid content in mice. Sennoside (30-100 mg/kg, p.o.) also increased fecal wet weight; however, it significantly increased fluid content with diarrhea. DSP-6952 dose-dependently improved clonidine- and morphine-induced delay in whole-gut transit in mice (ED50= 0.429 mg/kg and 0.310 mg/kg, respectively), which represented atonic and spastic constipation models, respectively. In viscerally hypersensitive rats treated with acetic acid, DSP-6952 (10 mg/kg, i.p., 30 mg/kg, p.o., 30 mg/kg, i.c.) and tegaserod (1 mg/kg, i.p.), but not prucalopride (10 mg/kg, i.p.), significantly inhibited the increase in colorectal distension-induced visceromotor response; these findings suggest that DSP-6952 and tegaserod inhibit visceral hypersensitivity in rats. It was concluded that DSP-6952, a novel and orally available 5-HT4 receptor agonist, induced colonic GMCs, enhanced colonic transit, increased defecation without inducing diarrhea, improved drug-induced delay in whole-gut transit, and inhibited visceral hypersensitivity in experimental animals. Therefore, DSP-6952 is expected to become a useful drug for treatment of IBS-C and chronic constipation. PMID- 29428471 TI - Efficacy of constant long-term delivery of YM-58483 for the treatment of rheumatoid arthritis. AB - The aim of this study was to investigate the efficacy and safety of YM-58483, a small molecular antagonist of Ca2+ release-activated Ca2+ (CRAC) channels, for the treatment of rheumatoid arthritis (RA), in vivo and ex vivo. YM-58483 was continuously injected subcutaneously in a collagen-induced arthritis (CIA) mouS.E.M.odel using an implanted osmotic pump. The severity of CIA was evaluated using the following parameters: body weight, hind paw volume, clinical score, histological analysis, cytokine levels, Ca2+ influx, and specific IgG production. The efficacy of long-term application of YM-58483 was also verified ex vivo in RA patient-derived peripheral blood monocytes. Assessment of the clinical severity of CIA, cytokine profile in serum and joint protein extracts, and specific IgG production showed that continuous application of YM-58483 suppressed synovial inflammation by inhibiting immune cell activity. Chemical screening and hepatography indicated that long-term subcutaneous delivery of YM-58483 was safer than oral administration for systemic application. Moreover, constant preincubation with YM-58483 at an IC50 of 0.1-1 nM altered proinflammatory cytokine production ex vivo in peripheral T cells derived from RA patients. Our findings suggest that continuous long-term application of appropriate CRAC inhibitors such as YM-58483 is a potential therapeutic strategy for global immunosuppression in RA. PMID- 29428472 TI - A novel harmine derivative, N-(4-(hydroxycarbamoyl)benzyl)-1-(4- methoxyphenyl) 9H-pyrido[3,4-b]indole-3-carboxamide (HBC), as histone deacetylase inhibitor: in vitro antiproliferation, apoptosis induction, cell cycle arrest, and antimetastatic effects. AB - This study aims to design and synthesize a novel harmine derivative N-(4 (hydroxycarbamoyl) benzyl)-1-(4-methoxyphenyl)-9H-pyrido [3,4-b]indole-3 carboxamide (HBC) as histone deacetylase (HDAC) inhibitor, and evaluate its antitumor activities and anti-metastasis mechanism. HBC not only exerted significant ant-proliferation activity against five human cancer cell lines, especially for HepG2 cell with an IC50 value of 2.21 MUM, which is nearly three fold lower than SAHA (IC50 = 6.26 uM), but also showed selective HDAC1/6 inhibitory effects in vitro. However, HBC had little effect on normal hepatic cells LO2. Furthermore, HBC simultaneously increased the acetylation of histone H3, H4, and alpha-tubulin, induced hypochromism by electrostatical interaction with CT-DNA, triggered more significant cancer cell apoptosis and cell cycle arrest at G2/M than SAHA by inhibition of both CDK1 and cyclin B in a concentration dependent manner. In addition, scratch and invasion assay showed that HBC also dose-dependently suppressed migration and invasion capacities of highly metastatic HCC HepG2 cells through down-regulated the expression of tumor metastasis related proteins MMP-2 and MMP-9, significantly better than SAHA. Finally, HBC showed low acute toxicity to mice and significant growth inhibition of the hepatoma tumor in vivo. These results demonstrate that novel harmine-based HDAC inhibitor HBC not only exhibited selective HDAC1/6 inhibitory activity and significant in vitro and in vivo antitumor activity, but also possessed DNA binding effect, apoptosis induction, cell cycle arrest effects, and potent anti metastasis mechanisms, which may hold great promise as therapeutic agent targeting HDAC1/6 for the intervention of human cancers. PMID- 29428473 TI - Urinary dysfunction after rectal cancer surgery: Results from a randomized trial comparing mesorectal excision with and without lateral lymph node dissection for clinical stage II or III lower rectal cancer (Japan Clinical Oncology Group Study, JCOG0212). AB - BACKGROUND: Postoperative urinary dysfunction is a major complication of rectal cancer surgery. A randomized controlled trial (JCOG0212) concluded that the noninferiority of mesorectal excision alone to mesorectal excision with lateral lymph node dissection was not confirmed in terms of relapse-free survival. METHODS: Eligibility criteria included histologically proven clinical stage II/III rectal cancer, a main lesion located in the rectum with the lower margin below the peritoneal reflection, and the absence of lateral lymph node enlargement. After confirming R0 resection by mesorectal excision, patients were randomized intraoperatively. The residual urine volume was measured three times. Urinary dysfunction was defined as >=50 mL residual urine occurring at least once or no measurement of residual urinary volume. This trial was registered with the UMIN Clinical Trials Registry, number C000000034. RESULTS: In the mesorectal excision alone and the mesorectal excision with lateral lymph node dissection groups, the incidence of early urinary dysfunction were 58% and 59%, respectively. A tumor location in the lower rectum (vs. upper rectum) and a blood loss of >=500 mL (vs. <500 mL) were associated with an increased risk of early urinary dysfunction. However, only blood loss was independently predictive of early urinary dysfunction (relative risk, 1.25 [95% CI: 1.10-1.55], p = .04). CONCLUSIONS: Mesorectal excision with lateral lymph node dissection is not associated with a significant increase in the incidence of urinary dysfunction. Urinary dysfunction is associated with tumor location and blood loss. PMID- 29428474 TI - Low skeletal muscle mass outperforms the Charlson Comorbidity Index in risk prediction in patients undergoing pancreatic resections. AB - INTRODUCTION: Low skeletal muscle mass is a known predictor of morbidity and mortality in patients undergoing major pancreatic surgeries. We sought to combine low skeletal muscle mass with established risk predictors to improve their prognostic capacity for postoperative outcome and morbidity. METHODS: As established parameters to predict preoperative mortality risk for patients, the ASA classification and the Charlson Comorbidity Index (CCI) were used. The Hounsfield Units Average Calculation (HUAC) was measured to define low skeletal muscle mass in 424 patients undergoing pancreatic resections for malignancies. Patients in the lowest sex-adjusted quartile for HUAC were defined as having low skeletal muscle mass (muscle wasting). Multivariable Cox regression analysis was utilized to identify preoperative risk factors associated with postoperative morbidity. RESULTS: Median patient age was 63 years (19-87), 47.9% patients were male, and half the cohort had multiple comorbidities (Charlson Comorbidity Index [CCI]>6, 63.2%), 30-day mortality was 5.8% (n = 25). Median HUAC was 19.78 HU (IQR: 15.94-23.54) with 145 patients (34.2%) having low skeletal muscle mass. Preoperative frailty defined by low skeletal muscle mass was associated with an increased risk for postoperative complications (OR 1.55, CI 95% 0.98-2.45, p = 0.014), and a higher 30-day mortality (HR 5.17, CI 95% 1.57-16.69, p = 0.004). With an AUC of 0.85 HUAC showed the highest predictability for 30-day mortality (CI 95% 0.78-0.91, p = 0.0001). Patients with CCI >=6 and low skeletal muscle mass defined by the HUAC had a 9.78 higher risk of dying in the immediate postoperative phase (HR 9.78, CI 95% 2.98-12.2, p = 0.0001). CONCLUSION: Low skeletal muscle mass predicts postoperative mortality and complications best and it should be incorporated to conventional risk scores to identify high risk patients. PMID- 29428475 TI - Peritoneal metastases invading the seminal vesicles: Radiologic appearance and outcome of treatment. AB - BACKGROUND: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) may be of greatest benefit if all visible evidence of disease is resected. In some male patients the peritoneal metastases within the pelvis are invasive into the seminal vesicles and complete cytoreduction requires resection of these structures. PATIENTS AND METHODS: From a prospective database of colorectal and appendiceal cancer patients who had CT evidence of seminal vesicle involvement and then had cytoreduction including resection of the seminal vesicles were reviewed. Their clinical features were tabulated. RESULTS: Five patients were identified between ages 52 and 60. Three of 5 were appendiceal mucinous neoplasms and 4 of 5 had complete cytoreduction. Two of the patients are long-term survivors of 120 and 28 months. All patients are impotent and reported no return of sexual function over time. All five patients report normal micturition. CONCLUSIONS: Resection of the seminal vesicles in a patient with invasion of these structures by peritoneal metastases is possible and should be considered in selected patients. This resection causes impotence but normal urination is to be expected. PMID- 29428476 TI - Escherichia coli ST1421 harbouring the hybrid extended-spectrum beta-lactamase CTX-M-64 from a German patient. PMID- 29428477 TI - Next-generation strategies for understanding and influencing source-sink relations in crop plants. AB - Whether plants are source or sink limited, that is, whether carbon assimilation or rather assimilate usage is ultimately responsible for crop yield, has been the subject of intense debate over several decades. Here we provide a short review of this debate before focusing on the use of transgenic intervention as a means to influence yield by modifying either source or sink function (or both). Given the relatively low success rates of strategies targeting single genes we highlight the success of multi-target transformations. The emergence of whole plant models and the potential impact that these will have in aiding yield improvement strategies are then discussed. We end by providing our perspective for next generation strategies for improving crop plants by means of manipulating their source-sink relations. PMID- 29428478 TI - Cancer molecular markers: A guide to cancer detection and management. AB - Cancer is generally caused by the molecular alterations which lead to specific mutations. Advances in molecular biology have provided an impetus to the study of cancers with valuable prognostic and predictive significance. Over the hindsight various attempts have been undertaken by scientists worldwide, in the management of cancer; where, we have witnessed a number of molecular markers which allow the early detection of cancers and lead to a decrease in its mortality rate. Recent advances in oncology have led to the discovery of cancer markers that has allowed early detection and targeted therapy of tumors. In this context, current review provides a detail outlook on various molecular markers for diagnosis, prognosis and management of therapeutic response in cancer patients. PMID- 29428479 TI - Immuno-oncology-101: overview of major concepts and translational perspectives. AB - Cancer immunotherapy is demonstrating impressive clinical benefit in different malignancies and clinical oncologists are increasingly turning their attention to immune-oncology. It is now well recognized that innate and adaptive immune cells infiltrating tumors are associated with clinical outcomes and responses to treatments, and can be harnessed to patients' benefit. Considerable advances have also been made in understanding how cancers escape from immune attack. Targeting of immunological escape processes regulated by the expression of immune checkpoint receptors and ligands and the down-modulation of tumor antigen presentation is the basis of immuno-oncology treatments. Despite recent achievements, there remain a number of unresolved issues in order to successfully implement cancer immunotherapy in many cancers. Importantly, clinical biomarkers are still needed for better optimization of emerging combination immunotherapies and better treatment tailoring. In this review, we summarize the function of innate and adaptive immune cells in anti-tumor immunity and the general mechanisms exploited by tumor cells to escape and inhibit immune responses as well as therapeutic strategies developed to overcome these mechanisms and discuss emerging biomarkers in immuno-oncology. PMID- 29428480 TI - Patient positioning for robot-assisted laparoscopic benign gynecologic surgery: A review. AB - Robotic surgical platforms are now in widespread use in the practice of gynecology all over the world. The introduction of robotic surgery has required some modifications of patient positioning when compared to standard laparoscopic surgery. Optimal patient positioning is likely to be the most essential step of robotic surgery as it provides the technical feasibility to have adequate access to the pelvic structures for performing the surgery. It is prudent to pay attention to preventing patient shifting in Trendelenburg position because of tendency of sliding down toward the direction of the head. Inappropriate patient positioning is associated with inadequate exposure of the operative field as well as detrimental complications that may lead to long-term side effects. These issues can be reduced with use of proper or strategic positioning technique. The purpose of this review is to highlight important points to properly position patient for robot-assisted laparoscopic benign gynecologic surgery and protect patient from position-related injuries. PMID- 29428481 TI - Synthesis and conformational analysis of d-gluco-pyranosyl-(6,6')-d-gluco pyranuronate, a model compound for the inter-glycan 6,6'-ester linkage. AB - The synthesis of a 6,6'-ester linked disaccharide analog model compound was achieved in five steps from d-glucose and featured a key oxidative esterification transformation. The synthesized d-gluco-pyranosyl-(6,6')-d-gluco-pyranuronate was characterized in D2O using NMR spectroscopy. Using the experimental data together with molecular dynamics simulations (TIP3P, water), a model of the compound's conformational behavior was established. The effect of the 6,6'-ester linkage on the solution phase structure was compared to that of the previously reported 6,6' ether linkage in a disaccharide analog. Based on the established models, the ester linkage was found to have a profound effect on the overall shape of the molecule. PMID- 29428482 TI - New insight in crosslinking degree determination for crosslinked starch. AB - The crosslinked starch has been studied for many years, but it is difficult to characterize degree of substitution on crosslinking of the very high and low crosslinked starches. The available approaches (including viscosity, settling volume, and P content) all have their limitations, i.e., not applicable in a large scope, pollution problem, and can not reflect the internal structure change. Here in this paper starch-iodine (St-I) method was proposed as a new approach to characterize the crosslinking degree. In this investigation, three starches of A, B, and C crystalline pattern with different amount (from very low to very high, 0.01, 0.05, 0.1, 0.5, 1, 5, 10%) of crosslinking reagent added were studied. This method is based on the mechanism that crosslinking reaction take place between amylose/amylopectin, amylopectin/amylopectin, whereas the amylose dose not crosslink one another. After crosslinked to amylopectin, the result amylose-amylopectin complex can be considered as a new amylopectin. Results showed that the St-I method can characterize all the crosslinked starches of the three starches, at low reagent level (0.01-0.1%), the amylose was found to decrease rapidly, this can also replace the viscosity method, whereas at high reagent level (1-10%), although the significant differences can still be observed, the effect was not so obvious as it for the lower crosslinked starches, here we firstly applied dose efficiency to characterize this phenomenon, which was informative and helpful in determining this modification process. PMID- 29428483 TI - Ab-initio and experimental study of pentose sugar dehydration mechanism in the gas phase. AB - In this work pentose sugar (D-xylose, D-ribose and D-arabinose) gas phase dehydration reaction was investigated by means of mass spectrometric techniques and theoretical calculations. The ionic species derived from the dehydration reaction of protonated D-ribose and D-arabinose were structurally characterized by their fragmentation patterns and the relative dehydration energies measured by energy resolved CAD mass spectra. The results were compared with those recently obtained for D-xylose in the same mass spectrometric experimental conditions. Dehydration of C1-OH protonated sugars was theoretically investigated at the CCSD(T)/cc-pVTZ//M11/6-311++G(2d,2p) level of theory. Protonated pentoses are not stable and promptly lose a water molecule giving rise to the dehydrated ions at m/z 133. D-xylose, D-ribose and D-arabinose dehydration follows a common reaction pathway with ionic intermediates and transition states characterized by similar structures. Slightly different dehydration energies were experimentally measured and the relative trend was theoretically confirmed. The overall dehydration activation energy follows the order arabinose < ribose < xylose. Gas-phase pentose sugar dehydration leads to the formation of protonated 2-furaldehyde as final product. Based on the experimental and theoretical evidence a new mechanistic hypothesis starting from C1-OH protonation was proposed. PMID- 29428484 TI - Pre-transplant Screening for Non-HLA Antibodies: Who should be Tested? AB - Retrospective studies of angiotensin II type 1 receptor antibodies (AT1R-Ab) and anti-endothelial cell antibodies (AECA) have linked these antibodies to allograft injury. Because rising healthcare costs dictate judicious use of laboratory testing, we sought to define characteristics of kidney transplant recipients who may benefit from screening for non-HLA antibodies. Kidney recipients transplanted between 2011 and 2016 at Johns Hopkins, were evaluated for AT1R-Ab and AECA. Pre transplant antibody levels were compared to clinical and biopsy indications of graft dysfunction. Biopsies were graded using the Banff' 2009-2013 criteria. AT1R Ab and AECA were detected using ELISA and endothelial cell crossmatches, respectively. AT1R-Ab levels were higher in patients who were positive for AECAs. Re-transplanted patients (p < 0.0001), males (p = 0.008) and those with FSGS (p = 0.04) and younger (p = 0.04) at time of transplantation were more likely to be positive for AT1R-Ab prior to transplantation. Recipients who were positive for AT1R-Ab prior to transplantation had increases in serum creatinine within 3 months post-transplantation (p < 0.0001) and developed abnormal biopsies earlier than did AT1R-Ab negative patients (126 days versus 368 days respectively; p = 0.02). Defining a clinical protocol to identify and preemptively treat patients at risk for acute rejection with detectable non-HLA antibodies is an important objective for the transplant community. PMID- 29428485 TI - Polymorphisms in P2X4R and CAMKK2 may affect TNFalpha production: Implications for a role in HIV-associated sensory neuropathy. AB - Polymorphisms in P2X4R and CAMKK2 associate with susceptibility to HIV-associated sensory neuropathy (HIV-SN) - a condition likely mediated by TNFalpha. As single nucleotide polymorphisms (SNPs) and haplotypes of CAMKK2, and a neighbouring gene P2X4R, mark susceptibility to HIV-SN in South Africans living with HIV, we examined the relationship between P2X4R and CAMKK2 genotypes and TNFalpha production. Peripheral blood mononuclear cells from 129 healthy donors were stimulated with killed Escherichia coli, and concentrations of soluble TNFalpha were assessed. Their DNA was genotyped for 22 SNPs in P2X4R and CAMKK2. Three SNPs within P2X4R and two SNPs within CAMKK2 influenced concentrations of TNFalpha, but these SNP did not associate with risk for HIV-SN. This incongruence may reflect differences in P2X4R haplotypes present in Africans and Europeans. However some CAMKK2 haplotypes were found in both populations, so CAMKK2 polymorphisms may impact upon HIV-SN via effects of the protein on pathways other than TNFalpha. PMID- 29428486 TI - Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: Results of a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. AB - BACKGROUND: In this study, we intend to assess the safety and tolerability of intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in patients with rheumatoid arthritis (RA) and to determine the preliminary clinical efficacy data in this population. The trial registration numbers are as follows: Royan Institute Ethics Committee: AC/91/1133; NCT01873625. METHODS: This single-center, randomized, triple-blind, placebo controlled phase 1/2 clinical trial randomized RA patients with knee involvement to receive either an intra-articular knee implantation of 40 million autologous bone marrow-derived MSCs per joint or normal saline (placebo). Patients were followed up for 12 months to assess therapy outcomes. RESULTS: A total of 30 patients, 15 in the MSC group and 15 in the placebo group, enrolled in this study. There were no adverse effects reported after MSC administration or during follow-up. Patients who received MSCs had superior findings according to the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analogue scale (VAS), time to jelling and pain-free walking distance. However, this improvement could not be significantly sustained beyond 12 months. The MSC group exhibited improved standing time (P = 0.01). In addition, the MSCs appeared to contribute to reductions in methotrexate and prednisolone use. CONCLUSION: Intra-articular knee implantation of MSCs appeared to be safe and well tolerated. In addition, we observed a trend toward clinical efficacy. These results, in our opinion, have justified the need for further investigations over an extended assessment period with larger numbers of RA patients who have knee involvement. PMID- 29428487 TI - Development and clinimetric evaluation of the mouth impairment and disability assessment (MIDA). AB - INTRODUCTION: Burns of the face and mouth region have a profound impact on function. Currently the outcome measure that is most commonly used in the burn care literature is horizontal and vertical opening. Impairment-based outcomes such as this do not capture the functional implications of these injuries in spite of the devastating impact they can have on burn survivor's lives. PURPOSE OF THE STUDY: To generate an assessment that evaluates the impairments, activity limitations, and participation restrictions associated with mouth injuries and prospectively collect data to examine the clinimetric properties. METHODS: A multistep assessment development process was undertaken including a comprehensive literature search and review, burn care expert and burn survivor interviews, generation of a preliminary version and field-testing, modifications based on field testing and updated literature review, and further field testing with data collection of 23 burn survivors. Clinimetric properties were examined by evaluating: whether there was a ceiling or floor effect, the internal consistency, construct validity, and responsiveness. RESULTS: The mouth impairment and disability assessment (MIDA) has a 28 item self-report portion, divided into four subscales, completed by the patient and an impairment-based section completed by the burn therapist. Two items demonstrated a ceiling effect, one was removed the other retained. There was strong and statistically significant (p<0.0001) correlation of the symptoms subscale as well as vertical opening with the functional activities subscale of the MIDA. The functional activities subscale demonstrated good internal consistency and the symptoms subscale was adequate. Re-evaluation approximately seven and a half months after the baseline evaluation demonstrated a statistically significant change with time and treatment. CONCLUSIONS: The MIDA now offers clinicians the ability to assess mouth impairment and disability of burn survivors who have sustained burn injuries to their face and mouth region. PMID- 29428488 TI - A thymosin repeated protein1 reduces white spot syndrome virus replication in red claw crayfish Cherax quadricarinatus. AB - The beta-thymosins are a group of structurally related, highly conserved intracellular small peptides in vertebrates with various biological functions, including cytoskeletal remodeling, neuronal development, cell migration, cell survival, tissue repair and inhibition of inflammation. In contrast to vertebrates, the function of beta-thymosin is not fully understood in crustaceans. Previously, we found that a thymosin-repeated protein1 (CqTRP1) gene was up-regulated after white spot syndrome virus (WSSV) challenge in hematopoietic tissue (Hpt) cells from the red claw crayfish Cherax quadricarinatus. To further identify the effect of CqTRP1 on WSSV infection, a full length cDNA sequence of beta-thymosin homologue was cloned and analyzed from red claw crayfish followed by functional study. The CqTRP1 cDNA contains an open reading frame of 387 nucleotides encoding a protein of 129 amino acids with a putative molecular mass of 14.3 kDa. The amino acid sequence showed high identity with other beta-thymosins and contained three characteristic thymosin beta actin binding motifs, suggesting that CqTRP1 was a member of the beta-thymosin family. Tissue distribution analysis revealed a ubiquitous presence of CqTRP1 in all the examined tissues with the highest expression in hemocytes, Hpt and gonad at the transcriptional level. Interestingly, the gene silencing of endogenous CqTRP1 by RNAi enhanced the WSSV replication in Hpt cells. Meanwhile, the WSSV replication was significantly reduced in the Hpt cell cultures if overloaded with a recombinant CqTRP1. Taken together, these data clearly indicated that CqTRP1 was likely to be associated with the anti-WSSV response in a crustacean C. quadricarinatus, which provides new strategy against white spot disease in crustacean aquaculture. PMID- 29428489 TI - Broad-spectrum antiviral functions of duck interferon-induced protein with tetratricopeptide repeats (AvIFIT). AB - Mammalian interferon-induced proteins with tetratricopeptide repeats (IFITs) play important roles in many cellular processes and host innate immune response to viruses. However, the functions of IFIT proteins in birds are largely unknown. Here, we first describe that the only one avian IFIT protein is orthologous to ancestor of mammalian IFITs. We find that the predicted structure of duck AvIFIT protein is similar to that of human IFIT5. We also find that duck AvIFIT protein shows antiviral activity to a broad range of specific RNA and DNA viruses like mammalian IFIT proteins. Further analysis indicates that overexpression of duck AvIFIT protein in DF1 cells leads to a remarkable accumulation of cells at G1/S transition associated with growth arrest and may promote apoptosis. Moreover, duck AvIFIT binds to nucleoprotein (NP) of H5N1 influenza virus and upregulates the expression of genes involving the IFN pathway in DF1 cells. In summary, our findings support that duck AvIFIT protein plays critical role in host immune response to viruses, at least H5N1 virus, through affecting function of viral NP protein, magnifying the IFN signaling and arresting cell growth. PMID- 29428490 TI - Invertebrate host responses to microsporidia infections. AB - Microsporidia are a group of fungi-like intracellular and unicellular parasites, which infect nearly all animals. As "master parasites", over 1400 microsporidian species have been described to date. Microsporidia infections in economical invertebrates (e.g., silkworm, shrimp) cause huge financial losses, while other microsporidia infections in daphnia, nematode, locust, honeybee and mosquito play important roles in the regulation of their population size. Research investigating invertebrate host responses following microsporidia infections has yielded numerous interesting results, especially pertaining to the innate immune response to these pathogens. In this review, we comparatively summarize the invertebrate host responses to various microsporidia infections. We discuss numerous critical events in host responses including ubiquitin-mediated resistance, production of reactive oxygen species, melanization and innate immune pathways, and the increased basic metabolism and the accumulation of juvenile hormone in infected hosts. Recent studies progressing our understanding of microsporidia infection are also highlighted. Collectively, these advances shed more light on general rules of invertebrate host immune responses and pathogenesis mechanisms of microsporidia, and concurrently offer valuable clues for further research on the crosstalk between hosts and intracellular pathogens. PMID- 29428491 TI - Knowledge and preventive behaviors towards tick-borne diseases in Delaware. AB - Delaware is among the top 10 states in the United States with the highest incidence for Lyme disease. The Delaware Division of Public Health (DPH) therefore has been working diligently to prevent and control tick-borne diseases through a variety of interventions including awareness campaigns and educational programs. To assess if tick-borne disease related information is reaching Delawareans through these programs, DPH in collaboration with Delaware State University administered an anonymous survey to 1755 participants in all three of Delaware counties during May 2017. The questionnaire assessed individuals' general knowledge about tick-borne diseases and performance of selected tick borne disease prevention methods Overall, participants' knowledge of tick-borne diseases was poor; only 38.4% of respondents stated that ticks were problematic in Delaware and only 12.7% of respondents "strongly agreed" that Lyme disease is a problem in Delaware. A little over half of the respondents (51.6%) indicated having seen advertisements/infomercials/flyers for protection from ticks or the disease agents spread by ticks; the most common places for viewing these advertisements were doctor's offices and through social media. The reported frequency of performing preventive behaviors was variable and disparities were observed by age, race, gender and county of residence. Existing public health communication efforts on tick-borne diseases in Delaware do not appear to be having the desired effect. This study provides important baseline information to rethink communication channels for education and more effectively guide future tick-borne disease awareness campaigns. PMID- 29428492 TI - The gray scale value of ear tissues undergoing volume-rendering high-resolution cone-beam computed tomography. AB - OBJECTIVE: When the thresholds for VR reconstruction from multi-slice CT images are changed, problems develop when assessing pathologies in the absence of standardized thresholds. The advantages of CBCT include lower radiation exposure compared with other techniques and better visualization of small ear structures. However, a disadvantage is that the scanner provides unstandardized gray scale values, thus not CT numbers (Hounsfield units, HU). METHODS: We analyzed 88 sets of volume data obtained from temporal bones. The gray scale values were measured in aerated areas (two sites), along the ossicular chain (four sites) and in a bone area (one site) in the external and middle ears, and in soft tissue areas (five sites) and bone areas (two sites) in the inner ear. RESULTS: The standard male and female gray scale values were 2448-2970 and 2585-3091 for the aerated areas, 3248-4945 and 3359-5223 for the ossicular chains, 3368-4109 and 3371-4147 for soft tissues, and 4790-5776 and 5044-5959 for bone, respectively. Sex significantly affected the values (p<0.05). Significant differences between aerated areas and ossicular chains, and between soft tissues and bone, were evident (all p<0.0001). CONCLUSION: Volume-rendering (VR) images obtained by cone beam computed tomography (CBCT) can be standardized simply by using fixed thresholds. PMID- 29428493 TI - A questionnaire to assess olfactory rehabilitation for laryngectomized patients (Provox voice prosthesis users) in Japan. AB - OBJECTIVE: We used a questionnaire to investigate olfactory function and the present state of olfactory rehabilitation for laryngectomized patients in Japan. METHODS: This study was conducted using a questionnaire survey. We mailed questionnaires to 190 members of a Japanese laryngectomized patient group (the nonprofit organization YOUSAY-KAI). The survey queried the following items: (1) basic information (age, sex, alaryngeal speech method, etc.); (2) questions about olfactory rehabilitation, such as the individual's experience of olfactory rehabilitation, the number of days from laryngectomy to the start of olfactory rehabilitation, and the location of rehabilitation (i.e., hospital or patient association); (3) free comments; and (4) the self-administered Odor Questionnaire (SAOQ). RESULTS: We received 121/190 questionnaires by the submission deadline. Of these, 105 questionnaires were valid. All 105 responders used the Provox voice prosthesis as the alaryngeal speech method. Only 4.7% (5/105) of the patients received olfactory rehabilitation in hospitals. Many comments in the free comment column included demands for olfactory rehabilitation such as "I want to know where we can have olfactory rehabilitation" and "I want to have rehabilitation if olfaction recovers." The SAOQ score was significantly higher in the rehabilitation group (mean, 42.5%) compared to the nonrehabilitation group (mean, 22.1%) (p<0.05). There was no correlation between the SAOQ score and the number of days from laryngectomy to the start of rehabilitation (r=0.08, p=0.76). CONCLUSION: Patient demand for olfactory rehabilitation is strong, but this therapy is not widely offered to laryngectomized patients in Japan. Notably, the SAOQ scores showed that olfactory rehabilitation may have an effect, even if it is initiated after laryngectomy. We believe that when patients choose voice prosthesis for speech, their olfaction deteriorates unless they undergo olfactory rehabilitation separately from speech rehabilitation. It is therefore necessary to administer olfactory rehabilitation for laryngectomized patients who have never received olfactory rehabilitation, as well as for patients scheduled to undergo laryngectomy. PMID- 29428494 TI - Survival in patients with submandibular gland carcinoma - Results of a multi institutional retrospective study. AB - OBJECTIVE: Clinical studies demonstrating the prognostic factors in submandibular gland carcinoma are limited because the tumor is relatively rare. The aim of this study was to identify clinical outcomes and prognostic factors in submandibular gland carcinoma. METHODS: The study included 65 patients with submandibular gland carcinoma who underwent initial surgical treatment at the Kyoto University and its affiliated hospitals. RESULTS: The 3-year overall survival (OS), disease specific survival, locoregional control (LRC), and no distant metastasis (NDM) rates were 74.2%, 74.2%, 90.0%, and 64.8%, respectively. In the current follow-up study, 16 patients died of the disease, 5 patients were alive with recurrence, 43 patients were alive without disease, and 1 patient died of unrelated disease without recurrence. All patients who died of the disease had developed distant metastasis. Based on univariate analysis, tumor grade (high grade) and lymph node metastases (>=N2) were significant prognostic factors for OS and LRC. It also revealed tumor grade (high grade), T classification (>=T3), and lymph node metastases (>=N2) were significant for distant metastasis. Multivariate analysis showed the following significant prognostic factors: lymph node metastases (>=N2) for OS, LRC, and NDM, and high tumor grade for NDM. CONCLUSION: Our study suggested death of submandibular gland carcinoma occurred mainly due to distant metastasis. The significant predictors of distant metastasis were lymph node metastases (>=N2) and tumor grade (high grade). PMID- 29428495 TI - Site-specific aftercare completion criteria for sustainable landfilling in the Netherlands: Geochemical modelling and sensitivity analysis. AB - A novel, regulatory accepted approach is developed that enables competent authorities to decide whether landfill aftercare can be reduced or terminated. Our previous paper (Brand et al., Waste Management 2016, 56, 255-261, https://doi.org//10.1016/j.wasman.2016.07.038) outlines the general approach, that consists of a 10-year treatment phase (e.g., aeration, leachate recirculation), in combination with site-specific Environmental Protection Criteria (EPC) for contaminant concentrations in the landfill leachate after treatment. The current paper presents the unique modelling approach by which the site-specific EPC are derived. The modelling approach is based on the use of mechanistic multi-surface geochemical models covering the main sorption processes in soils underneath the landfills, and is composed of widely-accepted surface complexation models in combination with published "generic" parameter sets. This approach enables the consideration of the main site-specific soil properties that influence the attenuation of emitted contaminants. In addition, the sensitivity of the EPC is shown for variation of the main physicochemical-assumptions and policy-based decisions. Site-specific soil properties have been found to substantially determine the EPC and include soil-pH, dissolved organic matter, and iron-(hydr)oxide content. Apart from the sorption capacity of the local soil, EPC also depend strongly on the assumed dilution with local groundwater in the saturated zone. An important policy-related decision that influences the calculated EPC is the assessment period during which the groundwater is protected. The transparent setup of the approach using geochemical modelling, the explicit consideration of site-specific properties and the achieved regulatory acceptance may also stimulate application to landfills in other countries. PMID- 29428496 TI - Artificial intelligence in internal medicine: Between science and pseudoscience. PMID- 29428497 TI - Pleural effusions in acute decompensated heart failure: Prevalence and prognostic implications. AB - BACKGROUND: The incidence of pleural effusions (PEs) in acute decompensated heart failure (ADHF) is not well established. We aimed to determine their prevalence, clinical characteristics and prognostic implications. METHODS: Retrospective review of 3245 consecutive patients with ADHF from the Spanish RICA Registry. The clinical characteristics of those with or without PEs on chest radiographs were compared and a predictive PE model was generated. RESULTS: Patient's median age was 80 years and 60% had a left ventricular ejection fraction (LVEF) >50%. PEs were seen in 46% of the cases, and their distribution was as follows: 58% bilateral, 27% right-sided and 14% left-sided. Male gender (OR 2.18; 95%CI 1.23 3.87), serum amino-terminal fraction of the pro-brain natriuretic peptide (NT-pro BNP) levels >3500 pg/ml (OR 2.2; 95%CI 1.25-3.77), estimated systolic pulmonary artery pressure (sPAP) >55 mm Hg by echocardiography (OR 2.05; 95%CI 1.12-3.75), and serum prealbumin <15 mg/l (OR 1.96; 95%CI 1.08-3.52) were associated with PE development in a multivariate analysis. Serum NT-proBNP >8000 pg/ml, and systolic arterial pressure <110 mm Hg, but not PEs, independently predicted overall 1-year mortality. CONCLUSIONS: PEs are present on chest radiographs in nearly half of ADHF patients. They are mainly bilateral or right-sided and predominate in males with elevated sPAP on echocardiography and high serum levels of NT-proBNP. PEs do not independently predict 1-year mortality. PMID- 29428498 TI - The role of gut microbiota in Clostridium difficile infection. AB - Clostridium difficile infection has emerged as a major health problem. Because it is a spore-forming microorganism, C. difficile is difficult to eradicate and recurrences of the infection are frequent. The strong association of CDI with prior use of antibiotics led to the recognition that disturbances in the gut microbiota apparently plays a central role in CDI. Except for antibiotics, several other risk factors for CDI have been recognised, such as advanced age and use of proton pump inhibitors. The common characteristic of these factors is that they are associated with changes in the composition of gut microbiota. Data from human studies have shown that the presence of C. difficile, either as a colonizer or as a pathogen, is associated with reduced microbiota diversity. C. difficile infection per se seems to be associated with changes in the representation of specific microbial populations (e.g. taxa) which either may act protectively against C. difficile colonization of the gut or may increase susceptibility for C. difficile infection. Therapeutic gut microbiota manipulation can be achieved by faecal microbiota transplantation, which is highly effective for the treatment of CDI. PMID- 29428499 TI - Atomistic-level study of the interactions between hIAPP protofibrils and membranes: Influence of pH and lipid composition. AB - The pathology of type 2 diabetes mellitus is associated with the aggregation of human islet amyloid polypeptide (hIAPP) and aggregation-mediated membrane disruption. The interactions of hIAPP aggregates with lipid membrane, as well as the effects of pH and lipid composition at the atomic level, remain elusive. Herein, using molecular dynamics simulations, we investigate the interactions of hIAPP protofibrillar oligomers with lipids, and the membrane perturbation that they induce, when they are partially inserted in an anionic dipalmitoyl phosphatidylglycerol (DPPG) membrane or a mixed dipalmitoyl-phosphatidylcholine (DPPC)/DPPG (7:3) lipid bilayer under acidic/neutral pH conditions. We observed that the tilt angles and insertion depths of the hIAPP protofibril are strongly correlated with the pH and lipid composition. At neutral pH, the tilt angle and insertion depth of hIAPP protofibrils at a DPPG bilayer reach ~52 degrees and ~1.62 nm with respect to the membrane surface, while they become ~77 degrees and ~1.75 nm at a mixed DPPC/DPPG membrane. The calculated tilt angle of hIAPP at DPPG membrane is consistent with a recent chiral sum frequency generation spectroscopic study. The acidic pH induces a smaller tilt angle of ~40 degrees and a shallower insertion depth (~1.24 nm) of hIAPP at the DPPG membrane surface, mainly due to protonation of His18 near the turn region. These differences mainly result from a combination of distinct electrostatic, van der Waals, hydrogen bonding and salt-bridge interactions between hIAPP and lipid bilayers. The hIAPP membrane interaction energy analysis reveals that besides charged residues K1, R11 and H18, aromatic residues Phe15 and Phe23 also exhibit strong interactions with lipid bilayers, revealing the crucial role of aromatic residues in stabilizing the membrane-bound hIAPP protofibrils. hIAPP-membrane interactions disturb the lipid ordering and the local bilayer thickness around the peptides. Our results provide atomic-level information of membrane interaction of hIAPP protofibrils, revealing pH-dependent and membrane-modulated hIAPP aggregation at the early stage. PMID- 29428500 TI - Electrostatic and hydrophobic interactions of lipid-associated alpha-synuclein: The role of a water-limited interfaces in amyloid fibrillation. AB - Human alpha-synuclein (alphaSyn) is an intrinsically disordered protein (IDP) whose biological and pathological functions in brain neuronal cells have not yet been fully elucidated. alphaSyn intrinsically participates in aiding neurotransmitter trafficking through alphaSyn the association with lipid membranes. However, lipid-associated states of alphaSyn also induce amyloid self assembly that is linked to the pathogenesis of various synucleinopathies. These contradicting actions arise from the limited water content near lipid-water interfaces that controls alphaSyn electrostatic and hydrophobic interactions. Thus, understanding the molecular interactions between alphaSyn and lipid membranes in the presence of water molecules is critical in elucidating the pivotal role of lipid-associated alphaSyn in amyloid self-assembly. In this review, we describe how the membrane interface controls electrostatic and hydrophobic interactions of lipid-associated alphaSyn. Moreover, membrane amyloid self-assembly of alphaSyn will be further discussed with regards to the structural dynamics of lipid-associated alphaSyn and water molecules near the interface. PMID- 29428501 TI - Insulin-eukaryotic model membrane interaction: Mechanistic insight of insulin fibrillation and membrane disruption. AB - Injection of exogenous insulin in the subcutaneous mass has been a proven therapy for type II diabetes. However, chronic administration of insulin often develops local amyloidosis at the injection site, pathologically known as "Insulin Ball". This reduces the insulin bioavailability and exacerbates the disease pathology. Thus, the molecular interaction between insulin and the recipient's membrane surface plays a co-operative role in accelerating the amyloidosis. This interaction, however, is different from the molecular interaction of insulin with the native membranous environment of the pancreatic beta-cells. The differential membrane mediated interaction that directly affects the aggregation kinetics of insulin remains elusive yet intriguing to understand the mechanism of pathological development. In this study we have characterized the interactions of insulin at different states with model eukaryotic membranes using high and low resolution spectroscopic techniques in combination with microscopic investigation. Our results show that insulin amyloid intermediates are capable of interacting with model membranes with variable functional affinity towards the different compositions. Fluorescence correlation spectroscopy confirms the aggregation states of insulin in presence of the eukaryotic model membranes while solid-state NMR spectroscopy in conjugation with differential scanning calorimetry elucidates the molecular interaction of insulin intermediates with the lipid head groups along with the acyl chains. Additionally, dye leakage assays support the eukaryotic model membrane disruption by insulin intermediates, similar to hIAPP and Abeta40, as previously reported. Thus, the present study establishes the distinct mode of interactions of insulin amyloid with pancreatic beta-cell and general mammalian cell mimicking membranes. PMID- 29428502 TI - Protein 4.1N is required for the formation of the lateral membrane domain in human bronchial epithelial cells. AB - The membrane skeleton forms a scaffold on the cytoplasmic side of the plasma membrane. The erythrocyte membrane represents an archetype of such structural organization. It has been documented that a similar membrane skeleton also exits in the Golgi complex. It has been previously shown that betaII spectrin and ankyrin G are localized at the lateral membrane of human bronchial epithelial cells. Here we show that protein 4.1N is also located at the lateral membrane where it associates E-cadherin, beta-catenin and betaII spectrin. Importantly, depletion of 4.1N by RNAi in human bronchial epithelial cells resulted in decreased height of lateral membrane, which was reversed following re-expression of mouse 4.1N. Furthermore, although the initial phase of lateral membrane biogenesis proceeded normally in 4.1N-depleted cells, the final height of the lateral membrane of 4.1N-depleted cells was shorter compared to that of control cells. Our findings together with previous findings imply that 4.1N, betaII spectrin and ankyrin G are structural components of the lateral membrane skeleton and that this skeleton plays an essential role in the assembly of a fully functional lateral membrane. PMID- 29428503 TI - The Athletic Skills Track: Age- and gender-related normative values of a motor skills test for 4- to 12-year-old children. AB - OBJECTIVES: The aim of the presented study is to provide age- and gender-related normative values and MQ values for a motor skills test, the Athletic Skills Track, among 4- to 12-year-old children. DESIGN: Cross-sectional. METHODS: In 2016, a total of 7977 Dutch children, 4036 boys (mean age 8.6 years, SD 2.1) and 3941 girls (mean age 8.6 years, SD 2.1), performed an age-related version of the Athletic Skills Track (AST). The AST is a track consisting of 5-7 fundamental movement skill tasks that should be completed as fast as possible. The children performed the test during a regular physical education (PE) lesson under the supervision of their own PE teacher. For each version of the AST (AST-1: n=917; AST-2: n=3947; AST-3: n=3213) age- and gender-related reference centiles were derived from the gathered data using the Lambda, Mu, Sigma (LMS) method. RESULTS: All children completed the AST within 60s (mean 29.6s, SD 7.7). An independent samples t-test showed that boys were significantly faster in completing the track than girls, except for the 4-year-old boys. Therefore, age- and gender-related reference centiles were derived. The reference curves demonstrate an almost linear decrease in time to complete AST-1 and AST-2 with increasing age. CONCLUSIONS: The present study provides age- and gender-related normative values and MQ values for the AST among 4- to 12-year-old Dutch children. With these normative values PE teachers can interpret children's performance on the AST. PMID- 29428504 TI - Examining the association of injury with the Functional Movement Screen and Landing Error Scoring System in military recruits undergoing 16 weeks of introductory fitness training. AB - OBJECTIVES: To examine the association of injury with the Functional Movement Screen (FMS) and Landing Error Scoring System (LESS) in military recruits undergoing an intensive 16-week training block. DESIGN: Prospective cohort study. METHODS: One hundred and thirty-two entry-level male soldiers (18-25years) were tested using the FMS and LESS. The participants underwent an intensive 16-week training program with injury data recorded daily. Chi-squared statistics were used to examine associations between injury risk and (1) poor LESS scores, (2) any score of 1 on the FMS and (3) composite FMS score of <=14. RESULTS: A composite FMS score of <=14 was not a significant predictor of injury. LESS scores of >5 and having a score of 1 on any FMS test were significantly associated with injury. LESS scores had greater relative risk, sensitivity and specificity (2.2 (95% CI=1.48-3.34); 71% and 87% respectively) than scores of 1 on the FMS (relative risk=1.32 (95% CI=1.0-1.7); sensitivity=50% and specificity=76%). CONCLUSIONS: There was no association between composite FMS score and injury but LESS scores and scores of 1 in the FMS test were significantly associated with injury in varying degrees. LESS scores had a much better association with injury than both any scores of 1 on the FMS and a combination of LESS scores and scores of 1 on the FMS. Furthermore, the LESS provides comparable information related to injury risk as other well-established markers associated with injury such as age, muscular strength and previous injury. PMID- 29428505 TI - Optimising training adaptations and performance in military environment. AB - OBJECTIVES: Worldwide decreases in physical fitness and increases in body fat among youth have set challenges for armed forces to recruit physically capable soldiers. Therefore, knowledge of optimizing physical adaptation and performance through physical training is vital. In addition, maintaining or improving physical performance among professional soldiers in various military environments is crucial for overall military readiness. The present review focuses on the effects of military training on physical performance by searching for optimal methods to do it. DESIGN AND METHODS: Review article based on selected literature searches using the main keywords 'physical performance' and 'training' and 'military' from MEDLINE and SportDiscus(r) engines. Additional selected references were included that encompassed the same words but were not found in the present search. RESULTS: Military training mainly consists of prolonged physical activities and training performed at low-intensities, which may interfere with optimal muscle strength and considering development of maximal strength, power, and aerobic capacity. Combined endurance and strength training seems to be a superior training method to improve overall physical performance of soldiers. CONCLUSIONS: The present study demonstrated that military training needs a greater variation in training stimulus to induce more effective training adaptations, especially, when considering the development of maximal or explosive strength and maximal aerobic capacity. Training programs should be well periodised so that total training load increases progressively but also includes sufficient recovery periods. In addition, some individualized programming is required to avoid unnecessary injuries and overloading because the differences in initial physical fitness of soldiers can be very high. PMID- 29428506 TI - 8-year retrospective analysis of intravenous arginine therapy for acute metabolic strokes in pediatric mitochondrial disease. AB - BACKGROUND: Intravenous (IV) arginine has been reported to ameliorate acute metabolic stroke symptoms in adult patients with Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes (MELAS) syndrome, where its therapeutic benefit is postulated to result from arginine acting as a nitric oxide donor to reverse vasospasm. Further, reduced plasma arginine may occur in mitochondrial disease since the biosynthesis of arginine's precursor, citrulline, requires ATP. Metabolic strokes occur across a wide array of primary mitochondrial diseases having diverse molecular etiologies that are likely to share similar pathophysiologic mechanisms. Therefore, IV arginine has been increasingly used for the acute clinical treatment of metabolic stroke across a broad mitochondrial disease population. METHODS: We performed retrospective analysis of a large cohort of subjects who were under 18 years of age at IRB #08 6177 study enrollment and had molecularly-confirmed primary mitochondrial disease (n = 71, excluding the common MELAS m.3243A>G mutation). 9 unrelated subjects in this cohort received acute arginine IV treatment for one or more stroke-like episodes (n = 17 total episodes) between 2009 and 2016 at the Children's Hospital of Philadelphia. Retrospectively reviewed data included subject genotype, clinical symptoms, age, arginine dosing, neuroimaging (if performed), prophylactic therapies, and adverse events. RESULTS: Genetic etiologies of subjects who presented with acute metabolic strokes included 4 mitochondrial DNA (mtDNA) pathogenic point mutations, 1 mtDNA deletion, and 4 nuclear gene disorders. Subject age ranged from 19 months to 23 years at the time of any metabolic stroke episode (median, 8 years). 3 subjects had recurrent stroke episodes. 70% of subjects were on prophylactic arginine or citrulline therapy at the time of a stroke-like episode. IV arginine was initiated on initial presentation in 65% of cases. IV arginine was given for 1-7 days (median, 1 day). A positive clinical response to IV arginine occurred in 47% of stroke-like episodes; an additional 6% of episodes showed clinical benefit from multiple simultaneous treatments that included arginine, confounding sole interpretation of arginine effect. All IV arginine-responsive stroke-like episodes (n = 8) received treatment immediately on presentation (p = .003). Interestingly, the presence of unilateral symptoms strongly predicted arginine response (p = .02, Chi-Square); however, almost all of these cases immediately received IV arginine, confounding interpretation of causality direction. Suggestive trends toward increased IV arginine response were seen in subjects with mtDNA relative to nDNA mutations and in older pediatric subjects, although statistical significance was not reached possibly due to small sample size. No adverse events, including hypotensive episodes, from IV arginine therapy were reported. CONCLUSIONS: Single center retrospective analysis suggests that IV arginine therapy yields significant therapeutic benefit with little risk in pediatric mitochondrial disease stroke subjects across a wide range of genetic etiologies beyond classical MELAS. Acute hemiplegic stroke, in particular, was highly responsive to IV arginine treatment. Prospective studies with consistent arginine dosing, and pre- and post-neuroimaging, will further inform the clinical utility of IV arginine therapy for acute metabolic stroke in pediatric mitochondrial disease. PMID- 29428507 TI - Brain MRI abnormalities resembling Unidentified Bright Objects in a patient with Phelan-McDermid syndrome. PMID- 29428508 TI - The molecular tweezer CLR01 inhibits Ebola and Zika virus infection. AB - Ebola (EBOV) and Zika viruses (ZIKV) are responsible for recent global health threats. As no preventive vaccines or antiviral drugs against these two re emerging pathogens are available, we evaluated whether the molecular tweezer CLR01 may inhibit EBOV and ZIKV infection. This small molecule has previously been shown to inactivate HIV-1 and herpes viruses through a selective interaction with lipid-raft-rich regions in the viral envelope, which results in membrane disruption and loss of infectivity. We found that CLR01 indeed blocked infection of EBOV and ZIKV in a dose-dependent manner. The tweezer inhibited infection of epidemic ZIKV strains in cells derived from the anogenital tract and the central nervous system, and remained antivirally active in the presence of semen, saliva, urine and cerebrospinal fluid. Our findings show that CLR01 is a broad-spectrum inhibitor of enveloped viruses with prospects as a preventative microbicide or antiviral agent. PMID- 29428509 TI - Evolution of Hypolimnas butterflies (Nymphalidae): Out-of-Africa origin and Wolbachia-mediated introgression. AB - Hypolimnas butterflies (Nymphalidae), commonly known as eggflies, are a popular model system for studying a wide range of ecological questions including mimicry, polymorphism, wing pattern evolution, and Wolbachia-host interactions. The lack of a time-calibrated phylogeny for this group has precluded understanding its evolutionary history. We reconstruct a species-level phylogeny using a nine gene dataset and estimate species divergence times. Based on the resulting tree, we investigate the taxon's historical biogeography, examine the evolution of host plant preferences, and test the hypothesis that the endosymbiotic bacterium Wolbachia mediates gene transfer between species. Our analyses indicate that the species are grouped within three strongly supported, deeply divergent clades. However, relationships among these three clades are uncertain. In addition, many Hypolimnas species are not monophyletic or monophyletic with weak support, suggesting widespread incomplete lineage sorting and/or introgression. Biogeographic analysis strongly indicates that the genus diverged from its ancestor in Africa and subsequently dispersed to Asia; the strength of this result is not affected by topological uncertainties. While the larvae of African species feed almost exclusively on Urticaceae, larvae of species found further east often feed on several additional families. Interestingly, we found an identical mitochondrial haplotype in two Hypolimnas species, H. bolina and H. alimena, and a strong association between this mitotype and the Wolbachia strain wBol1a. Future investigations should explore the plausibility of Wolbachia mediated introgression between species. PMID- 29428510 TI - Spiny trapdoor spiders (Euoplos) of eastern Australia: Broadly sympatric clades are differentiated by burrow architecture and male morphology. AB - Spiders of the infraorder Mygalomorphae are fast becoming model organisms for the study of biogeography and speciation. However, these spiders can be difficult to study in the absence of fundamental life history information. In particular, their cryptic nature hinders comprehensive sampling, and linking males with conspecific females can be challenging. Recently discovered differences in burrow entrance architecture and male morphology indicated that these challenges may have impeded our understanding of the trapdoor spider genus Euoplos in Australia's eastern mesic zone. We investigated the evolutionary significance of these discoveries using a multi-locus phylogenetic approach. Our results revealed the existence of a second, previously undocumented, lineage of Euoplos in the eastern mesic zone. This new lineage occurs in sympatry with a lineage previously known from the region, and the two are consistently divergent in their burrow entrance architecture and male morphology, revealing the suitability of these characters for use in phylogenetic studies. Divergent burrow entrance architecture and observed differences in microhabitat preferences are suggested to facilitate sympatry and syntopy between the lineages. Finally, by investigating male morphology and plotting it onto the phylogeny, we revealed that the majority of Euoplos species remain undescribed, and that males of an unnamed species from the newly discovered lineage had historically been linked, erroneously, to a described species from the opposite lineage. This paper clarifies the evolutionary relationships underlying life history diversity in the Euoplos of eastern Australia, and provides a foundation for urgently needed taxonomic revision of this genus. PMID- 29428511 TI - Species identification of polygonati rhizoma in China by both morphological and molecular marker methods. AB - Morphological markers as well as two types of molecular markers, inter-sample sequence repeat (ISSR) and start codon targeted (SCoT) are suitable for species identification of the polygonati rhizoma germplasms. In this paper, we adopted these methods for the identification of rhizomes collected from 47 areas in China. Based on their morphological characters, the collected germplasms were classified into two populations, one with alternate leaf arrangement and the other with verticillate leaf arrangement, and they were comprised of five species and fourteen subgroups. Of the five species identified: Polygonatum kingianum, P. cirrhifolium, P. alternicirrhosum, and P. sibiricum belonged to one cluster, and P. cyrtonema belonged to a different cluster. According to the analysis of both ISSR and SCoT markers, all germplasms with greater genetic similarity were classified into one group. Especially, P. sibiricum and P. cirrhifolium, which shared ~80% similarity, were clustered together, whereas the germplasms identified as P. kingianum with ~86% similarity formed a separate clade. P. kingianum showed a much greater genetic similarity with P. cyrtonema than with P. sibiricum. The multidimensional scaling analysis further verified the accuracy and reliability of the molecular marker-based results. Thus, both morphological and molecular methods should be combined for the differentiation of germplasms such as those of polygonati rhizoma. PMID- 29428512 TI - The oxytocin receptor gene polymorphism -rs237902- is associated with the severity of autism spectrum disorder: A pilot study. AB - INTRODUCTION: Previous studies showed the association of Autism Spectrum Disorder (ASD) and oxytocin receptor (OXTR) gene. We aimed to explore the OXTR gene single nucleotide polymorphisms (SNPs) across the ASD severity categories based on DSM 5. METHOD: The whole encoding regions of the human OXTR gene were sequenced to identify the SNPs in 100 Turkish children with ASD. Genotypes of detected SNPs were also compared with the Childhood Autism Rating Scale (CARS) scores. RESULTS: Disease severity of the patients carrying GA and AA genotypes (GA/AA) of rs237902 were found more severe compared to those carrying GG genotype (chi2 = 6.456, df = 2, p = .040). This finding was more powerful in boys (chi2 = 9.288, df = 2, p = .010). Similarly, GA/AA genotypes of rs237902 were found associated with higher CARS scores in boys (U = 650.5, r = 0.24, p = .021). CONCLUSION: Significant relationship between the ASD severity categories of DSM-5 and rs237902 was shown for the first time. PMID- 29428513 TI - Phosphorylation of P27 by AKT is required for inhibition of cell cycle progression in cholangiocarcinoma. AB - BACKGROUND AND OBJECTIVE: P27 is a putative tumor suppressor when located in the nucleus and AKT is an inhibitor of P27 which promotes growth of cholangiocarcinoma. We hypothesized that AKT-dependent phosphorylation at the P27 nuclear localization sequence T157 leads to nuclear export of P27, and thus loss of its tumor suppressive function. This study investigated whether loss of cell cycle regulation in cholangiocarcinoma due to subcellular localization of P27. METHODS: Human cholangiocarcinoma cells were transfected with AKT. P27 was tagged with yellow fluorescence protein. Cell cycle progression was determined by flow cytometry. Migration and invasion of was measured by transwell assay. RESULTS: Overexpression of wildtype P27 or P27-T157A in Mz-ChA-1 cells resulted in G1 arrest; expression of myr-AKT caused translocation of P27-YFP and endogenous P27 from the nucleus to the cytoplasm, leading to inhibition of P27-dependent G1 arrest; the AKT inhibitor and expression of dnAKT increased P27-YFP accumulation in the nucleus and promoted G1 arrest. In contrast, cells expressing YFP-P27 T157A or P27-YFP accumulated only in the nucleus. Co-expression of myr-AKT failed to induce P27-YFP translocation to the cytoplasm or inhibit G1 arrest. Overexpression of P27-T157A significantly increased migration and invasion. CONCLUSIONS: Cholangiocarcinoma growth is associated with nuclear export of P27 that is due to AKT-mediated phosphorylation of P27 at T157. PMID- 29428514 TI - Target and non-target response of Swietenia Mahagoni Jacq. chemical constituents against tobacco cutworm Spodoptera litura Fab. and earthworm, Eudrilus eugeniae Kinb. AB - Toxicological screening of Swietenia mahagoni Jacq. (Meliaceae, West Indies Mahogany) against the lepidopteran pest Spodoptera litura was examined. Phytochemical screening through GC-MS analysis revealed nine peaks with prominent peak area % in Bis (2-ethylhexyl) phthalate (31.5%) was observed. The larvae exposed to discriminating dosage of 100 ppm deliver significant mortality rate compare to other treatment concentrations. The lethal concentrations (LC50 and LC90) was observed at the dosage of 31.04 and 86.82 ppm respectively. Sub-lethal concentrations (30 ppm) showed higher larval and pupal durations. However, pupal weight and mean fecundity rate reduced significantly. Similarly, the adult longevity reduced significantly in dose dependent manner. Midgut histology studies showed that the methanolic extracts significantly disturbs the gut epithelial layer, lumen and brush border membrane compare to the control. The soil assay on a non-target beneficial organism, the soil indicator earthworm Eudrilus eugeniae, with extracts from S. mahagoni (200 mg/kg) showed no toxicity compared to Monocrotophos at the dosage of 10 ppm/kg. Current results suggest that this bio-rational plant product from S. mahagoni displays a significant effect to reduce lepidopteran pests with low toxicity to other beneficial species. PMID- 29428515 TI - Sorption and bioaccumulation behavior of multi-class hydrophobic organic contaminants in a tropical marine food web. AB - While numerous studies have demonstrated the environmental behavior of legacy persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), information regarding sorption and bioaccumulation potential of other widely used organic chemicals such as halogenated flame retardants (HFRs) is limited. This study involved a comprehensive field investigation of multi-class hydrophobic organic contaminants (HOCs) in environmental media and fish in Singapore Strait, an important tropical maritime strait in Southeast Asia. In total, 90 HOCs were analyzed, including HFRs, synthetic musks, PCBs, OCPs, as well as triclosan and methyl triclosan. The results show that the organic carbon normalized sediment-seawater distribution ratios (CSED/CWD) of the studied compounds are comparable to the organic carbon water partition coefficients (KOC), over a log KOC range of approximately 4-11. The observed species-specific bioaccumulation factors (BAFs), biota-sediment accumulation factors (BSAFs), organism-environment media fugacity ratios (fFISH/fWD and fFISH/fSED) and trophic magnification factors (TMFs) indicate that legacy POPs and PBDE 47 show bioaccumulation behavior in this tropical marine ecosystem, while triclosan, tonalide, dodecachlorodimethanodibenzocyclooctane stereoisomers (DDC-COs), and hexabromocyclododecanes (HBCDDs) do not. Methyl triclosan and galaxolide exhibit moderate biomagnification. Tetrabromobisphenol A (TBBPA) and 1,2-bis (2,4,6-tribromophenoxy)ethane (BTBPE) were detected in environmental media but not in any of the organisms, suggesting low bioaccumulation potential of these flame retardants. The apparently low bioaccumulation potential of the studied HFRs and synthetic musks is likely because of metabolic transformation and/or reduced bioavailability due to the hydrophobic nature of these compounds. PMID- 29428516 TI - Potential of dissimilatory nitrate reduction pathways in polycyclic aromatic hydrocarbon degradation. AB - This study investigates the potential of an indigenous estuarine microbial consortium to degrade two polycyclic aromatic hydrocarbons (PAHs), naphthalene and fluoranthene, under nitrate-reducing conditions. Two physicochemically diverse sediment samples from the Lima Estuary (Portugal) were spiked individually with 25 mg L-1 of each PAH in laboratory designed microcosms. Sediments without PAHs and autoclaved sediments spiked with PAHs were run in parallel. Destructive sampling at the beginning and after 3, 6, 12, 30 and 63 weeks incubation was performed. Naphthalene and fluoranthene levels decreased over time with distinct degradation dynamics varying with sediment type. Next generation sequencing (NGS) of 16 S rRNA gene amplicons revealed that the sediment type and incubation time were the main drivers influencing the microbial community structure rather than the impact of PAH amendments. Predicted microbial functional analyses revealed clear shifts and interrelationships between genes involved in anaerobic and aerobic degradation of PAHs and in the dissimilatory nitrate-reducing pathways (denitrification and dissimilatory nitrate reduction to ammonium - DNRA). These findings reinforced by clear biogeochemical denitrification signals (NO3- consumption, and NH4+ increased during the incubation period), suggest that naphthalene and fluoranthene degradation may be coupled with denitrification and DNRA metabolism. The results of this study contribute to the understanding of the dissimilatory nitrate-reducing pathways and help uncover their involvement in degradation of PAHs, which will be crucial for directing remediation strategies of PAH-contaminated anoxic sediments. PMID- 29428517 TI - Heterogeneous electro-Fenton as plausible technology for the degradation of imidazolinium-based ionic liquids. AB - Conventional water treatments are generally inadequate for degradation of emerging pollutants such as ionic liquids (ILs). The use of heterogeneous electro Fenton (HEF) has attracted great interest, due to its ability to efficiently oxidize a wide range of organic pollutants operating in cycles or in continuous mode. In this study, the removal of a complex IL from the imidazolinium family (1,3-Bis(2,4,6-trimethylphenyl)imidazolinium chloride), by means of HEF using iron alginate spheres as catalyst has been investigated, resulting in significant TOC decay after 6 h. The optimization of the key process parameters (current, IL concentration and catalyst dosage) has been performed using a Box-Behnken experimental design and achieving 76.98% of TOC abatement in 2 h of treatment. Current proved to be a crucial parameter and high catalyst dosage is required to achieve the maximum removal. In addition, an insight about the availability of iron into the reactor and the evolution of several intermediates has been carried out by employing differential pulse voltammetry on screen-printed carbon electrodes. The evolution of the different voltammetric peaks confirmed the influence of iron release, and the generation of several iron complexes has permitted the comprehension of the degradation pathway, which has been validated by chromatographic techniques. PMID- 29428518 TI - EFEMP2 Mediates GALNT14-Dependent Breast Cancer Cell Invasion. AB - N-Acetylgalactosaminyltransferase-14 (GALNT14) is a member of acetylgalactosaminyltransferases family. We have shown that GALNT14 could promote breast cancer cell invasion. However, the underlying molecular mechanism is unclear. Here, using yeast two hybrid, we find that EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) interacts with GALNT14. Both in vitro and in vivo binding assays show that EFEMP2 is associated with GALNT14. Moreover, we find that GALNT14 mediates glycosylation of EFEMP2. EFEMP2 significantly increased the invasion ability of breast cancer cells including MCF-7 and MBA-MD 231 cells, and this phenomenon is suppressed by knockdown expression of GALNT14. In addition, the GALNT14-dependent O-glycosylation of EFEMP-2 regulates the stability of EFEMP-2 protein in breast cancer cells. Taken together, our results demonstrate a novel molecular mechanism underlying breast cancer invasion. PMID- 29428519 TI - In Response. PMID- 29428520 TI - Stress and Symptoms of Depression in Fathers of Infants Admitted to the NICU. AB - OBJECTIVE: To describe perceived stress and symptoms of depression in fathers of infants admitted to the NICU through 2 months after discharge and to explore associations between fathers' childhood and current relationships with their own parents and their stress and symptoms of depression. DESIGN: Observational, longitudinal. SETTING: Tertiary care center in northeastern United States. PARTICIPANTS: English-speaking fathers of newborns admitted to the NICU. METHODS: Fathers completed the Parental Stress Scale and the Edinburgh Postnatal Depression Scale (EPDS) at infants' NICU admissions (Time [T] 1), 3 weeks (T2), discharge (T3), and 2 months after discharge (T4). RESULTS: A total of 146 fathers were enrolled between March 2013 and February 2016. Infants' mean gestational age at birth was 31.9 weeks, and 88% remained in the NICU for 3 weeks or longer. We found that 12% of fathers reported high stress levels at T1, 8% at T3, and 13% at T4. Overall EPDS scores improved over time (p < .001). From T1 to T4, the proportion of fathers with distress/minor symptoms of depression decreased from 41% to 10% and with symptoms of major depression from 16% to 2%. Statistically significant positive associations were found between fathers' EPDS scores and the quality of relationships with their fathers (at T1, T2, and T3) and with their mothers (across all time points). CONCLUSION: From admission to 2 months after discharge, stress and symptoms of depression persisted for some fathers of infants admitted to the NICU. Evidence-based strategies to support fathers during and after their infants' NICU hospitalizations need to be further developed, implemented, and evaluated. PMID- 29428521 TI - What's New at JOGNN? PMID- 29428522 TI - Evaluation of the fit of zirconia copings fabricated by direct and indirect digital scanning procedures. AB - STATEMENT OF PROBLEM: Intraoral scanners are effective for direct digital scans when dental restorations are fabricated using computer-aided design and computer aided manufacturing (CAD-CAM); however, if the abutment tooth cannot be dried completely or the prepared margin is placed subgingivally, accurate digital images cannot always be guaranteed. PURPOSE: The purpose of this in vitro study was to compare the internal and marginal discrepancies of zirconia copings fabricated directly using an intraoral scanner with those fabricated indirectly with impression scanning. MATERIAL AND METHODS: Forty-five resin dies fabricated with a 3-dimensional (3D) printer were divided into 3 groups: direct scanning (DS), impression scanning (IMP), and lost-wax casting (LW). For the DS group, a resin die was scanned with an intraoral scanner (Trios; 3Shape), whereas for the IMP group, impressions made with polyether were scanned with a cast scanner (D700; 3Shape). The zirconia copings were fabricated in the same way in the DS and IMP groups. For the LW group, impressions were made in the same way as in the IMP group, and Ni-Cr alloy copings were fabricated using LW. The marginal and internal discrepancies of the copings were measured by cementing them onto resin dies, embedding them in acrylic resin, and sectioning them in a buccolingual direction. The cement layer was measured, and the Kruskal-Wallis test was used to detect significant differences (alpha=.05). A nonparametric Friedman test was also performed to compare the measurements of each group by location (alpha=.05). RESULTS: The mean marginal discrepancies in the DS, IMP, and LW groups were 18.1 +/-9.8, 23.2 +/-17.2, and 32.3 +/-18.6 MUm (mean +/-standard deviation), respectively. The mean internal discrepancies of the DS, IMP, and LW groups in the axial area were 38.0 +/-9.1, 47.0 +/-16.3, and 36.5 +/-15.8 MUm, and those in the occlusal area were 36.7 +/-16.9, 33.4 +/-21.6, and 44.5 +/-31.9 MUm, respectively. No statistically significant differences were found in marginal or internal discrepancies among groups (P>.05). CONCLUSIONS: Within the limitations of this study, the zirconia copings fabricated with CAD-CAM using different digitization methods and Ni-Cr copings fabricated using the lost-wax technique and casting produced clinically acceptable marginal and internal discrepancies. No significant differences were found among the DS, IMP, and LW groups. PMID- 29428523 TI - The Janus-like Face of IL-4Ralpha in Macrophages during Liver Fibrosis. PMID- 29428526 TI - New branched amino acids for high affinity dendrimeric DC-SIGN ligands. AB - A branched amino acid was synthesized from methyl glucopyranoside; this amino acid presents three amino groups protected by Fmoc and one acid group and can be used in classic peptide synthesis. In parallel, similar azido terminated blocks were synthesized. Successive coupling reaction and deprotection afforded dendrimers with up to 27 azido functional groups. As an example of application, d mannose and l-fucose residues were linked through CuAAC coupling and resulting glycodendrimers were evaluated in their interaction with DC-SIGN using SPR competition assay. PMID- 29428525 TI - Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors. AB - The Liver X receptors (LXRs) are members of the nuclear receptor family, that play fundamental roles in cholesterol transport, lipid metabolism and modulation of inflammatory responses. In recent years, the synthetic steroid N,N-dimethyl 3beta-hydroxycholenamide (DMHCA) arised as a promising LXR ligand. This compound was able to dissociate certain beneficial LXRs effects from those undesirable ones involved in triglyceride metabolism. Here, we synthetized a series of DMHCA analogues with different modifications in the steroidal nucleus involving the A/B ring fusion, that generate changes in the overall conformation of the steroid. The LXRalpha and LXRbeta activity of these analogues was evaluated by using a luciferase reporter assay in BHK21 cells. Compounds were tested in both the agonist and antagonist modes. Results indicated that the agonist/antagonist profile is dependent on the steroid configuration at the A/B ring junction. Notably, in contrast to DMHCA, the amide derived from lithocholic acid (2) with an A/B cis configuration and its 6,19-epoxy analogue 4 behaved as LXRalpha selective agonists, while the 2,19-epoxy analogues with an A/B trans configuration were antagonists of both isoforms. The binding mode of the analogues to both LXR isoforms was assessed by using 50 ns molecular dynamics (MD) simulations. Results revealed conformational differences between LXRalpha- and LXRbeta-ligand complexes, mainly in the hydrogen bonding network that involves the C-3 hydroxyl. Overall, these results indicate that the synthetized DMHCA analogues could be interesting candidates for a therapeutic modulation of the LXRs. PMID- 29428524 TI - The New Age of -omics in Urothelial Cancer - Re-wording Its Diagnosis and Treatment. AB - Unmet needs in urothelial cancer management represent an important challenge in our effort to improve long-term overall and disease-free survival rates with no significant compromise in quality of life. Radical cystectomy with pelvic lymph node dissection is the standard for the management of muscle-invasive, non metastatic cancers. In spite of a 90% local disease control, up to 50% of patients ultimately die of distant metastasis. Bladder preservation using chemo radiation is an acceptable alternative, but optimal patient selection remains elusive. Recent research is focused on the employment of tailored-made strategies in urothelial cancer exploiting the potential of theranostics in patient selection for specific therapies. Herein, we review the current knowledge on molecular theranostics in urothelial cancer and we suggest that this is the time to move toward imaging theranostics, if tailored-made disease management and patient stratification is envisaged. PMID- 29428527 TI - Discovery of chromenes as inhibitors of macrophage migration inhibitory factor. AB - Macrophage migration inhibitory factor (MIF) is an essential signaling cytokine with a key role in the immune system. Binding of MIF to its molecular targets such as, among others, the cluster of differentiation 74 (CD74) receptor plays a key role in inflammatory diseases and cancer. Therefore, the identification of MIF binding compounds gained importance in drug discovery. In this study, we aimed to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tautomerase enzyme activity. Inspired by the known chromen-4-one inhibitor Orita-13, a focused collection of compounds with a chromene scaffold was screened for MIF binding. The library was synthesized using versatile cyanoacetamide chemistry to provide diversely substituted chromenes. The screening provided inhibitors with IC50's in the low micromolar range. Kinetic evaluation suggested that the inhibitors were reversible and did not bind in the binding pocket of the substrate. Thus, we discovered novel inhibitors of the MIF tautomerase activity, which may ultimately support the development of novel therapeutic agents against diseases in which MIF is involved. PMID- 29428528 TI - Photosynthesis and nitrogen uptake of the giant kelp Macrocystis pyrifera (Ochrophyta) grown close to salmon farms. AB - Finfish aquaculture is an activity that has experienced an explosive global development, but presents several environmental risks, such as high nitrogen outputs with potential eutrophication consequences. Therefore, the integration of seaweed aquaculture with the aim of decreasing nitrogen emissions associated with intensive salmon farming has been proposed as a bioremediation solution. Ecophysiological knowledge about seaweeds cultured close to farming cages is, however, still rudimentary. We experimentally studied the growth and physiological responses of Macrocystis pyrifera (Linnaeus) C. Agardh in a suspended culture system near a commercial salmon farm at three culture depths in order to understand its productivity performance. The results showed maximum growth responses at intermediate depths (3 m) as opposed to near the surface (1 m) or at a deeper culture level (6 m). At 6 m depth, light limitations were detected, whereas the sporophytes growing at 1 m depth responded to high irradiances, especially in late spring and summer, where they were more intensely exposed to decay of photosynthesis than individuals from other depths. Accordingly, photosynthetic pigment concentrations (chlorophyll a and c, and fucoxonthin) were higher during low-light seasons (winter and early spring) but decreased during the summer. On the other hand, although both nitrogen uptake and Nitrate Reductase (NR) activity varied seasonally, increasing significantly in spring and summer, these variables were not affected by culture depth. Therefore, the optimal culture depth of M. pyrifera near salmon farms appears to be a physiological integration between nitrogen supply and demand, which is modulated by plant acclimation to the seasonal change in light and temperature. The results allow to discuss about the environmental constrains of M. pyrifera in an ecophysiological context to improve the understanding of its aquaculture, and to contribute relevant information on the use of this species in bioremediation. PMID- 29428529 TI - Sensitivity to ocean acidification differs between populations of the Sydney rock oyster: Role of filtration and ion-regulatory capacities. AB - Understanding mechanisms of intraspecific variation in resilience to environmental drivers is key to predict species' adaptive potential. Recent studies show a higher CO2 resilience of Sydney rock oysters selectively bred for increased growth and disease resistance ('selected oysters') compared to the wild population. We tested whether the higher resilience of selected oysters correlates with an increased ability to compensate for CO2-induced acid-base disturbances. After 7 weeks of exposure to elevated seawater PCO2 (1100 MUatm), wild oysters had a lower extracellular pH (pHe = 7.54 +/- 0.02 (control) vs. 7.40 +/- 0.03 (elevated PCO2)) and increased hemolymph PCO2 whereas extracellular acid base status of selected oysters remained unaffected. However, differing pHe values between oyster types were not linked to altered metabolic costs of major ion regulators (Na+/K+-ATPase, H+-ATPase and Na+/H+-exchanger) in gill and mantle tissues. Our findings suggest that selected oysters possess an increased systemic capacity to eliminate metabolic CO2, possibly through higher and energetically more efficient filtration rates and associated gas exchange. Thus, effective filtration and CO2 resilience might be positively correlated traits in oysters. PMID- 29428531 TI - Vitrification of one-cell mouse embryos in cryotubes. AB - Preventing intracellular ice formation is essential to cryopreserve cells. Prevention can be achieved by converting cell water into a non-crystalline glass, that is, to vitrify. The prevailing belief is that to achieve vitrification, cells must be suspended in a solution containing a high concentration of glass inducing solutes and cooled rapidly. In this study, we vitrified 1-cell mouse embryos and examined the effect of the cooling rate, the warming rate, and the concentration of cryoprotectant on cell survival. Embryos were vitrified in cryotubes. The vitrification solutions used were EFS20, EFS30, and EFS40, which contained ethylene glycol (20, 30 and 40% v/v, respectively), Ficoll (24%, 21%, and 18% w/v, respectively) and sucrose (0.4 0.35, and 0.3 M, respectively). A 5 MUl EFS solution suspended with 1-cell embryos was placed in a cryotube. After 2 min in an EFS solution at 23 degrees C, embryos were vitrified by direct immersion into liquid nitrogen. The sample was warmed at 34 degrees C/min, 4,600 degrees C/min and 6,600 degrees C/min. With EFS40, the survival was low regardless of the warming rate. With EFS30 and EFS20, survival was also low when the warming rate was low, but increased with higher warming rates, likely due to prevention of intracellular ice formation. When 1-cell embryos were vitrified with EFS20 and warmed rapidly, almost all of the embryos developed to blastocysts in vitro. Moreover, when vitrified 1-cell embryos were transferred to recipients at the 2-cell stage, 43% of them developed to term. In conclusion, we developed a vitrification method for 1-cell mouse embryos by rapid warming using cryotubes. PMID- 29428530 TI - Rotenone exerts developmental neurotoxicity in a human brain spheroid model. AB - Growing concern suggests that some chemicals exert (developmental) neurotoxicity (DNT and NT) and are linked to the increase in incidence of autism, attention deficit and hyperactivity disorders. The high cost of routine tests for DNT and NT assessment make it difficult to test the high numbers of existing chemicals. Thus, more cost effective neurodevelopmental models are needed. The use of induced pluripotent stem cells (iPSC) in combination with the emerging human 3D tissue culture platforms, present a novel tool to predict and study human toxicity. By combining these technologies, we generated multicellular brain spheroids (BrainSpheres) from human iPSC. The model has previously shown to be reproducible and recapitulates several neurodevelopmental features. Our results indicate, rotenone's toxic potency varies depending on the differentiation status of the cells, showing higher reactive oxygen species (ROS) and higher mitochondrial dysfunction during early than later differentiation stages. Immuno fluorescence morphology analysis after rotenone exposure indicated dopaminergic neuron selective toxicity at non-cytotoxic concentrations (1 MUM), while astrocytes and other neuronal cell types were affected at (general) cytotoxic concentrations (25 MUM). Omics analysis showed changes in key pathways necessary for brain development, indicating rotenone as a developmental neurotoxicant and show a possible link between previously shown effects on neurite outgrowth and presently observed effects on Ca2+ reabsorption, synaptogenesis and PPAR pathway disruption. In conclusion, our BrainSpheres model has shown to be a reproducible and novel tool to study neurotoxicity and developmental neurotoxicity. Results presented here support the idea that rotenone can potentially be a developmental neurotoxicant. PMID- 29428532 TI - Severe Pulmonary Embolism was Secondary to Cement Inferior Vena Cava Embolism after Percutaneous Vertebroplasty. AB - Cement pulmonary embolism (cPE) and inferior vena cava embolism (cIE) are rare but potentially life-threatening complications of percutaneous vertebroplasty (PVP). Most cPE and cIE occurred simultaneously. In this case, a 65-year-old woman complained of dyspnea after PVP for 4 days. Patient's symptom and image tests manifest that the cPE was secondary to cIE. Although cIE was found at the first day after PVP, the local surgeons treat the patient with a regular anticoagulant without another more effective therapeutic measure. Eventually, the long cement inferior vena cava embolus was broken and result in left pulmonary embolism via the systemic circulation. She was admitted to our hospital and performed with embolectomy surgery by cardiopulmonary bypass and discharged after 7 days. We report this case to show that cIE embolism is still underestimated by some spine surgeons in China, and cIE may be developed to severe cPE during conservation management with anticoagulation. PMID- 29428533 TI - Greater Compliance within Instruction for Use for Concomitant Iliac Aneurysms and Adverse Aneurysm Characteristics-Initial Experience with the Nellix Endovascular Aneurysm Sealing System at a Single Institution. AB - BACKGROUND: The Nellix was introduced to Asia in 2014. Data in Asians have been sparse. Two balloon-expandable stents, each surrounded by a polymer-filled endobag, are deployed in parallel to obliterate and seal the aneurysm. This paradigm shift to treating abdominal aortic aneurysms confers advantages for certain adverse aneurysm morphology that is outside the instruction-for-use (IFU) for standard endovascular aneurysm repair (EVAR) devices. We examine outcomes of 15 Asian patients with concomitant infrarenal aortic and iliac artery aneurysms treated with the Nellix at our institution. METHOD: Between July 2014 and August 2016, 15 male patients underwent elective EVAS at a single tertiary center by the same team of vascular surgeons and interventional radiologists. Patient demographics, clinical presentations, aneurysm morphology, perioperative complications, and follow-up imaging according to the standardized protocol were studied. Preoperative CT images were analyzed using validated automatic 3 dimensional sizing software EndoSize. RESULT: The novel stent-graft deployment proves consistent and achieved a 100% technical success. Eleven patients (70%) complied within specified Nellix IFU, as compared to 20% if standard endovascular aneurysm repair (EVAR) IFU was applied. The difference is due to the presence of concurrent common iliac aneurysms (n = 5), short neck length (n = 3), and angulated necks (n = 3). Adjunct procedures included 3 open access endarterectomy with embolectomy, 1 coil embolization of internal iliac artery, 1 bilateral renal artery chimneys, and 1 proximal stent deployment. There was no conversion to open surgery. Average operative time was 133 min. Median length of stay was 4 days. Thirty-day mortality was 0%. Perioperative morbidity included exacerbation of pre existing renal impairment (n = 6), peripheral vascular disease (n = 3), and postimplantation syndrome (n = 5). One endoleak (7%) and 2 instances of stent migration (14%) were detected. There was no complication of aneurysm or endobag rupture, limb thromboses, or fracture. CONCLUSIONS: Early data in our center are encouraging and highlight high procedural success with minimal complications despite challenging patient anatomy. PMID- 29428534 TI - Midterm Results of Endovascular Treatment for Iliac Vein Compression Syndrome from a Single Center. AB - BACKGROUND: The efficacy of endovascular interventional treatment for iliac vein compression syndrome (IVCS) is not well studied. The purpose of our study was to investigate the clinical outcome of endovascular interventional treatment for IVCS. METHODS: Data of 68 patients with IVCS, who underwent interventional treatment in our hospital, were analyzed retrospectively. Among these patients, 46 had lower extremity varicose veins. Sixty-five patients underwent stent implantation, and 3 patients underwent simple balloon angioplasty. Fourteen patients had post-thrombotic syndrome (PTS) and 11 patients had acute deep venous thrombosis (DVT). Among these 14 patients with PTS, 12 underwent stent implantation and 2 underwent iliac venous simple balloon angioplasty. On the other hand, 9 of the 11 patients with DVT underwent catheter-directed thrombolysis (CDT) and then stent implantation. Of the remaining 2 patients, one underwent Angiojet Rheolytic thrombectomy (ART) before CDT and the other underwent CDT with simple balloon angioplasty. The stenosis rate of iliac vein and the circumference differences between the affected limb and healthy one were measured before and after operation. These patients were followed up with duplex ultrasound postoperatively. RESULTS: A total of 75 stents were placed in 65 patients. The diameter and the length of stent were 6 to 14 mm (mean 12.5 +/- 2.0 mm) and 40 to 260 mm (mean 82.5 +/- 36.9 mm), respectively. CDT with/without ART was performed, using urokinase and/or alteplase, after inferior vena cava filtration in all of 11 patients with DVT, without the recurrence of pulmonary embolism. The difference in iliac venous stenosis was statistically significant ([91.2% +/- 8.4%] [70.0% ~ 100.0%] vs. 3.9% +/- 13.0% [0 ~ 70.0%], P < 0.01). The patency rates at 1-, 3-, 6- months, 1 year, and 2 years were 98.5%, 95.6%, 94.1%, 92.4%, and 90.7%, respectively. Four patients (5.9%) suffered from minor bleeding at puncture point and were successfully treated with compression. However, 1 (1.5%) patient underwent stent implantation of right iliac vein that became complicated due to migration of stent to the right ventricle which was successfully arrested by Amplatz Goose Neck Snare Kit. The incidence of PTS was 10.3% (7/68) during the follow-up at 1 to 24 (mean 18.2 +/- 7.7) months. CONCLUSIONS: Interventional therapy for patients of IVCS is safe and effective. Satisfactory outcomes were obtained for stent placement for IVCS. PMID- 29428535 TI - Diabetic Foot Limb Salvage-A Series of 809 Attempts and Predictors for Endovascular Limb Salvage Failure. AB - BACKGROUND: To review patient characteristics and outcomes of in-patient diabetic foot limb salvage and identify risk factors predicting for endovascular limb salvage failure. METHODS: Retrospective study of limb salvage attempts in 809 patients between August 2013 and July 2015. RESULTS: Sixty-eight percent of our study population were male with mean age at 65 years and 73% presented with Rutherford grade 6 critical limb ischemia, with the remaining 27% Rutherford grade 5. Eighty-one percent had toe pressures of less than 50 mm Hg, 64% had infrainguinal trans-Atlantic inter-society consensus (TASC II) C or D lesions while 78% had infrapopliteal TASC II C or D lesions. Seven hundred seventy-seven patients (96%) underwent endovascular-first approach limb salvage, with 95% requiring infrapopliteal angioplasty, with 84% of them requiring 2-vessel or 3 vessel revascularization. Thirty-two patients (4%) underwent surgical bypass limb salvage, with 63% performed as salvage procedures for failed angioplasties. The mean in-patient stay was 12.3 days within the endovascular group and 31.1 days within the bypass group (P < 0.01). One-year limb salvage was successful in 88% of endovascular group, as compared with 72% in bypass group (P = 0.01). Overall 1 year survival was 93% within the endovascular group and 88% within the bypass group (P = 0.27). The mean in-patient cost was SGD$5,518 within the endovascular group and SGD$15,141 within the bypass group (P < 0.01). Multivariate analysis showed that independent predictors for failure of endovascular limb salvage include end-stage renal failure (ESRF) (odds ratio [OR] 2.04, P = 0.01), toe pressures <50 mm Hg (OR 2.15, P = 0.01), infrainguinal TASC II patterns C or D (OR 1.99, P = 0.03), and indirect angiosome revascularization (OR 2.03, P = 0.02). CONCLUSIONS: Within our study population of Asian ethnicity, most in patient diabetic foot peripheral arterial disease presented with Rutherford grade 6 disease, with mostly TASC II C or D lesions and required infrapopliteal revascularization. As most patients had multiple comorbidities and were poor surgical candidates, the majority underwent endovascular-first approach revascularization. Independent predictors of endovascular limb salvage failure include ESRF, toe pressures <50 mm Hg, infrainguinal TASC II patterns C or D, and indirect angiosome revascularization. PMID- 29428536 TI - Prospective Comparison of Effect of Ligation and Foam Sclerotherapy with Foam Sclerotherapy Alone for Varicose Veins. AB - BACKGROUND: To compare the efficacy of ligation after foam sclerotherapy (FSL) with foam sclerotherapy (FS) alone for patients with varicose veins prospectively. METHODS: Ninety-four patients with varicose veins underwent foam sclerothrapy alone and 88 patients with varicose veins received FSL. Patients were followed up at 1, 3, 6, and 12 months after treatment. The postoperative complications were documented prospectively. RESULTS: In comparison with patients who underwent FSL, patients treated with FS only had higher incidence of phlebitis within 4 weeks (14.9% vs. 1.1%, P = 0.002) and at 6 months (10.6% vs. 0, P = 0.002) after treatment and had higher incidence of tenderness or discomfort (9.8% vs. 0, P = 0.003) and recanalization rate (8.5% vs. 1.1%, P = 0.007) at 6 months after treatment. All patients in both groups had no deep vein thrombosis and pulmonary embolism. CONCLUSIONS: Patients treated with FSL have less postoperative complications than those with foam sclerotheray alone. FSL is an alternative procedure for management of patients with varicose veins. Also, a randomized prospective study is required to observe the long-term outcomes of the FSL. PMID- 29428538 TI - Carotid Access for Endovascular Repair of Aortic Pathology: A Systematic Review. AB - BACKGROUND: Endovascular repair is now preferred to open access for the management of aortic diseases. This is typically performed via the femoral artery; however, not all patients are eligible for this. This systematic review summarizes the current evidence for utilizing the carotid artery as an alternative access route. METHODS: A systematic review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines using 4 electronic databases. RESULTS: The search found 11 case reports representing 12 patients eligible for analysis (mean age 64.5 years). This included 3 thoracic aneurysms, 3 abdominal aneurysms, 4 penetrating ulcers, 1 endoleak, and 1 pseudoaneurysm. An open procedure was contraindicated in 83% (10/12) due to the poor physiological fitness of the patient. In 75% (9/12) of cases, traditional endovascular access was contraindicated by severe iliac disease. The remainder were contraindicated because of an existing ligated aortic stump (1/12, 8.3%) or technical difficulty with graft deployment via the femoral artery (2/12, 16.7%). There was 1 death, with the 30-day mortality 8.3%. The same patient suffered the only spinal ischemia before death (8.3%). There were no cases of stroke (0%), with one case of transient ischemic attack (8.3%). CONCLUSIONS: Although there is a relative paucity of literature, this study demonstrates when traditional endovascular access is impossible and an open procedure contraindicated, carotid artery access for endovascular repair of aortic pathology is a viable alternative with good 30-day survival and low rates of neurological sequelae. PMID- 29428537 TI - Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Are Effective Predictors of Prognosis in Patients with Acute Mesenteric Arterial Embolism and Thrombosis. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be valuable prognostic markers for a variety of pathological conditions including solid tumors, sepsis, and others. However, the prognostic values of the NLR and PLR in patients with acute mesenteric arterial embolism (AMAE) and acute mesenteric arterial thrombosis (AMAT) have not been elucidated. The aim of this study was to determine the predictive value of the NLR and PLR for poor prognosis in patients with AMAE and AMAT. METHODS: A total of 137 patients with AMAE (n = 77) or AMAT (n = 60) were divided into a poor outcome group (cases of intestinal necrosis or death) and a better outcome group (cases without intestinal necrosis who survived successfully), according to prognosis. Neutrophil, platelet, and lymphocyte counts were recorded before pharmacotherapy or surgery. The NLR and PLR were calculated, and logistic regression analysis was performed to test their prognostic values. RESULTS: The cutoff values for NLR and PLR were 11.05 and 156.26, respectively. The PLR was linearly associated with the NLR (R = 0.769, P < 0.001). NLR (odds ratio [OR] = 6.835, 95% confidence interval [CI] = 2.282-20.469, P = 0.001), PLR (OR = 4.871, 95% CI = 1.627-14.587, P = 0.005), and coronary heart disease (OR = 3.388, 95% CI = 1.156-9.929, P = 0.026) were found to be independent prognostic factors for the patients. CONCLUSIONS: NLR >= 11.05, PLR >= 156.26, and coronary heart disease were shown to be risk factors for poor prognosis in patients with AMAE and AMAT. According to these factors, patients can be divided into 3 prognostic groups: good, NLR < 11.05 with PLR < 156.26; moderate, NLR < 11.05 with PLR >= 156.26 or NLR >= 11.05 with PLR < 156.26; and poor, NLR >= 11.05 with PLR >= 156.26. PMID- 29428539 TI - Vascular Trauma in Children-Review from a Major Paediatric Center. AB - BACKGROUND: Traumatic noniatrogenic vascular injuries in children are rare and rarely discussed in literature. Pediatric vascular injuries pose a set of challenges mainly because of continued growth and development in a child or adolescent. The purpose of the study is to characterize management strategies and outcomes in these cases. METHODS: This is a single-center retrospective review of patients less than age 18 years (pediatric age) with acute, noniatrogenic traumatic vascular injuries between January 2009 and December 2015. Patient's demographics, injury characteristics, surgical management, complications, and follow-up were analyzed. RESULTS: From 2009 to 2015, 3277 children with traumatic injuries were treated, of which 21 (0.6%) had 23 significant vascular injuries: 17 arterial and 6 venous injuries. The majority were males (n = 16), and the median age was 14 years (range 1 to 16 years). Penetrating injuries were the predominant mechanism (n = 21), mainly by glass (n = 13). At presentation, 4 patients were hemodynamically unstable, 3 of them in hypovolemic shock. All patients were managed operatively. Operations for arterial injuries included 5 primary arterial repairs, 4 repairs using vein grafts and 8 ligations. The following adjunct procedures were necessary: one 4-compartment leg fasciotomy due to associated soft tissue trauma, 8 tendon repairs, and 11 nerve repairs. Operations for venous injuries included 4 ligations and 2 primary repairs. There were no intraoperative or postoperative deaths, major complications, or limb loss. The median length of stay in the hospital was 6 days (range: 2-23 days). The median time of follow-up was 52 months (range: 20-94 months). Ten patients did not have any sequelae, and 11 patients reported impaired mobility and/or decreased sensation, which was transitory in most cases and related to associated neurological or muscle tendon injuries. All reconstructions remained patent over the course of follow-up. No limb asymmetry was observed. CONCLUSIONS: Noniatrogenic pediatric vascular trauma is uncommon. Penetrating mechanism is more common than blunt and extremities are more frequently affected. Overall complications come from associated injuries to tendons and nerves. PMID- 29428540 TI - In vitro assessment of the interactions of dopamine beta-hydroxylase inhibitors with human P-glycoprotein and Breast Cancer Resistance Protein. AB - Inhibition of the biosynthesis of noradrenaline is a currently explored strategy for the treatment of hypertension, congestive heart failure and pulmonary arterial hypertension. While some dopamine beta-hydroxylase (DBH) inhibitors cross the blood-brain barrier (BBB) and cause central as well as peripheral effects (nepicastat), others have limited access to the brain (etamicastat, zamicastat). In this context, peripheral selectivity is clinically advantageous, in order to prevent alterations of noradrenaline levels in the CNS and the occurrence of adverse central effects. A limited brain exposure results from the combination of several factors, such as a reduced passive permeability or affinity for efflux transporters, but efflux liabilities may also lead to unwanted drug-drug interactions (DDIs) in the presence of co-administered substrates or inhibitors. Thus, the purpose of the study herein presented was to explore the interaction of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), the two major efflux transporters of the BBB that hamper the entry of several drugs to the brain, with the DBH inhibitors, etamicastat, nepicastat and zamicastat. Madin-Darby canine kidney cells (MDCK II) and transfected lines with human MDR1 (MDCK-MDR1) and ABCG2 (MDCK-BCRP) genes were used as a BBB surrogate model. P-gp and BCRP substrates and/or inhibitors were identified through intracellular accumulation and bidirectional permeability assays. The obtained data revealed that zamicastat is a concentration-dependent dual P-gp and BCRP inhibitor with IC50 values of 73.8 +/- 7.2 MUM and 17.0 +/- 2.7 MUM, while etamicastat and nepicastat inhibited BCRP to greater extent than P gp, with IC50 values of 47.7 +/- 1.8 MUM and 59.2 +/- 9.4 MUM, respectively. Additionally, etamicastat was identified as P-gp and BCRP dual substrate, as demonstrated by net flux ratios of 5.84 and 3.87 and decreased >50% by verapamil and Ko143. Conversely, nepicastat revealed to be a P-gp-only substrate, with a net flux ratio of 2.01, reduced to 0.92 in the presence of verapamil. Furthermore, nepicastat displayed a consistently higher apparent permeability (>8.49 * 10-6 cm s-1) than etamicastat (<0.58 * 10-6 cm s-1). The identification of etamicastat as a dual efflux substrate suggests that P-gp and BCRP may be partially responsible for the limited central exposure of this compound, in association with its low passive permeability. Moreover, the weak efflux inhibitory potencies of etamicastat and nepicastat revealed a low DDI risk, while the dual P-gp/BCRP inhibition of zamicastat could be studied in the future with synergically effluxed compounds, for which BBB penetration is severely impaired. PMID- 29428541 TI - Jelly containing composite based on alpha-glucosyl stevia and polyvinylpyrrolidone: Improved dissolution property of curcumin. AB - Curcumin (CUR) solutions prepared with alpha-glucosyl stevia (Stevia-G) and polyvinylpyrrolidone K-30 (PVP) by evaporation method showed 11,000-fold higher solubility compared to CUR alone. Tri-component formulations of CUR/Stevia-G/PVP in aqueous solution showed improved CUR stability for precipitation-triggering conditions of CUR, such as aqueous dilution and temperature changes. Fluorescence study with CUR and pyrene indicated that Stevia-G/PVP mixed solutions produce a more hydrophilic microenvironment around their molecules with increasing PVP concentration compared to Stevia-G solution alone. These results suggested the composite formation associated with the adsorption of the aggregated structure of Stevia-G onto PVP molecules. Jelly formulations were prepared with kappa carrageenan, and jelly formulations containing nanocomposites formed by CUR/Stevia-G/PVP obviously enhanced the dissolution properties of CUR compared to CUR powder. This result indicated that the composite formed by CUR/Stevia-G/PVP could be maintained even after the preparation of jelly and release into a dissolution media. Production of jelly formulations using Stevia-G and PVP are a promising way to improve the dissolution properties of CUR. PMID- 29428542 TI - Quantification of microwave-induced amorphization of celecoxib in PVP tablets using transmission Raman spectroscopy. AB - In this study, the influence of drug load on the microwave-induced amorphization of celecoxib (CCX) in polyvinylpyrrolidone (PVP) tablets was investigated using quantitative transmission Raman spectroscopy. A design of experiments (DoE) setup was applied for developing the quantitative model using two factors: drug load (10, 30, and 50% w/w) and amorphous fraction (0, 25, 50, 75 and 100%). The data was modeled using partial least-squares (PLS) regression and resulted in a robust model with a root mean-square error of prediction of 2.5%. The PLS model was used to study the amorphization kinetics of CCX-PVP tablets with different drug content (10, 20, 30, 40 and 50% w/w). For this purpose, transition Raman spectra were collected in 60 s intervals over a total microwave time of 10 min with an energy input of 1000 W. Using the quantitative model it was possible to measure the amorphous fraction of the tablets and follow the amorphization as a function of microwaving time. The relative amorphous fraction of CCX increased with increasing microwaving time and decreasing drug load, hence 90 +/- 7% of the drug was amorphized in the tablets with 10% drug load whereas only 31 +/- 7% of the drug was amorphized in the 50% CCX tablets. It is suggested that the degree of amorphization depends on drug loading. The likelihood of drug particles being in direct contact with the polymer PVP is a requirement for the dissolution of the drug into the polymer upon microwaving, and this is reduced with increasing drug load. This was further supported by polarized light microscopy that revealed evidence of crystalline particles and clusters in all the microwaved tablets. PMID- 29428543 TI - Synergistic strategies of predominant toxins in snake venoms. AB - Synergism is a significant phenomenon present in snake venoms that may be an evolving strategy to potentiate toxicities. Synergism exists between different toxins or toxin complexes in various snake venoms, with phospholipaseA2s (PLA2s) (toxins or subunits) the main enablers. The predominant toxins, snake venom PLA2s, metalloproteases (SVMPs), serine proteases (SVSPs) and three-finger toxins (3FTxs), play essential roles in synergistic processes. The hypothetical mechanisms of synergistic effect can be generalized under the effects of amplification and chaperoning. The Toxicity Score is among the few quantitative methods to assess synergism. Selection of toxins involved in synergistically enhanced toxicity as the targets are important for development of novel antivenoms or inhibitors. PMID- 29428544 TI - Development and evaluation of a capacity building program in gender-relevant tobacco control research: A Brazilian experience. AB - INTRODUCTION: There is an increased need for capacity building of researchers and professionals in low- and middle-income countries with evidence-based approaches across the tobacco control continuum, particularly with regard to gender-relevant strategies. We describe the development, implementation, and evaluation of a Career Development and Research Training Program (CDRTP) in tobacco control. METHODS: The CDRTP is organized into two modules: Module I is open to the public and provides an overview of tobacco control; Module II, consists of a one-year program with multi-mode sessions toward the development of a pilot research project. Activities are implemented through co-learning to facilitate cross fertilization of knowledge, collaborations, and team science. RESULTS: Between 2010 and 2015, 255 individuals participated in Module I with 57 applying for Module II's selective process. Out of these, 35 were selected, 29 completed the program (83%), 21 submitted pilot research projects that have undergone review, and 16 were approved for funding. Pre- and post-tests among the 29 participants who completed the training indicated improvement in scholars' perceived knowledge and skills on all of the components. CONCLUSION: In addition to attracting researchers and professionals who have not been working in tobacco control, the capacity building program has promoted knowledge, skills, and confidence among participants to pursue gender-relevant tobacco control research. PMID- 29428545 TI - The Montreal Children's Hospital Feeding Scale: Relationships with parental report of child eating behaviours and observed feeding interactions. AB - : Feeding problems are common, with implications for nutrition, growth and family stress, placing burden on primary care services. The Montreal Children's Hospital Feeding Scale (MCHFS) is a quick and reliable measure of feeding problems for clinical settings, but there is little examination of its relationship to commonly used research measures of parental feeding practice, child eating behaviour and observations of parent-infant interaction at mealtimes. We examined the relationships between the MCHFS, demographics and early feeding history, weight across the first year, parental report of feeding practices and child eating behaviours, and observations of maternal-infant feeding interaction at 1 year. The MCHFS, Comprehensive Feeding Practices Questionnaire (CFPQ) and Child Eating Behaviour Questionnaire (CEBQ) were completed by 69 mothers when their infants were 1-year-old (37 male, 32 female). Infant weight was measured at 1 week, 1 month, 6 months and 1 year. Mothers were observed feeding their infants at 1 year. The MCHFS was reliable (Cronbach's alpha = .90) and showed significant overlap with other measures of feeding and eating. Potential feeding problems were identified in 10 of the children (14%) reflecting similar rates in other community samples. Higher MCHFS scores were associated with lower birthweight and weight across the first year, greater satiety responsiveness, fussiness and slowness in eating, lower enjoyment of food and food responsiveness, and less observed infant food acceptance. Parents of infants with more feeding problems reported less encouragement of balance and variety in their children's diets. CONCLUSION: MCHFS showed good criterion validity with other parental report measures of eating and observations of mealtime interactions. MCHFS may be a useful tool for researching feeding problems in community samples. PMID- 29428546 TI - (Not) Eating for the environment: The impact of restaurant menu design on vegetarian food choice. AB - Previous research has shown that restaurant menu design can influence food choices. However, it remains unknown whether such contextual effects on food selection are dependent on people's past behavior. In the present study, we focused on vegetarian food choices, given their important implications for the environment, and investigated whether the influence of different restaurant menus on the likelihood of selecting a vegetarian dish is moderated by the number of days on which people reported eating only vegetarian food during the previous week. In an online scenario, participants were randomly assigned to four different restaurant menu conditions-control (all dishes presented in the same manner), recommendation (vegetarian dish presented as chef's recommendation), descriptive (more appealing description of vegetarian dish), and vegetarian (vegetarian dishes placed in a separate section)-and ordered a dish for dinner. The results showed that the recommendation and descriptive menus increased the likelihood of vegetarian dish choices for infrequent eaters of vegetarian foods, whereas these effects tended to reverse for those who ate vegetarian meals more often. The vegetarian menu had no impact on the infrequent vegetarian eaters' choice but backfired for the frequent vegetarian eaters and made them less likely to order a vegetarian dish. These findings indicate that people's past behavior is an important determinant of the impact of nudging on food choices, and that achieving sustainable eating may require more personalized interventions. PMID- 29428547 TI - Evaluation of 4 molecular assays as part of a 2-step algorithm for the detection of Clostridium difficile in stool specimens. AB - Detection of Clostridium difficile infection is important for clinical laboratories, owing to debilitating disease, severe outcomes, patient awareness, and public reporting of hospital data. This study evaluated the performance of 4 nucleic acid amplification test (NAAT) assays as part of a 2-step algorithm that involves reflexive NAAT following enzyme immunoassay (EIA) testing that is indeterminate for glutamate dehydrogenase (GDH) antigen and toxin A/B (GDH+/toxin or GDH-/toxin+). A total of 500 stool specimens from consecutive patients were tested by each of the 5 methods and also evaluated as part of a 2-step algorithm. A specimen was considered positive for presence of C. difficile if it tested positive by 3 of 4 molecular methods or toxigenic culture. The sensitivity and specificity of the GDH-EIA method were each 93%. The toxin EIA had only 48% sensitivity, but it had 99% specificity. Sensitivity and specificity of 2-step algorithmic testing ranged from 88% to 93% and 99% to 100%, respectively, offering similar performance to stand-alone NAAT testing. PMID- 29428548 TI - The impact from the aftermath of chronic stress on hippocampal structure and function: Is there a recovery? AB - Chronic stress results in functional and structural changes to the brain and especially the hippocampus. Decades of research have provided insights into the mechanisms by which chronic stress impairs hippocampal-mediated cognition and the corresponding reduction of hippocampal CA3 apical dendritic complexity. Yet, when chronic stress ends and time passes, which we refer to as a "post-stress rest period," hippocampal-mediated spatial memory deficits begin to improve and CA3 apical dendritic arbors increase in complexity. The processes by which the hippocampus improves from a chronically stressed state are not simply the reversal of the mechanisms that produced spatial memory deficits and CA3 apical dendritic retraction. This review will discuss our current understanding of how a chronically stressed hippocampus improves after a post-stress rest period. Untangling the mechanisms that allow for this post-stress plasticity is a critical next step in understanding how to promote resilience in the face of stressors. PMID- 29428549 TI - Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation. AB - Bruce McEwen's discovery of receptors for corticosterone in the rat hippocampus introduced higher brain circuits in the neuroendocrinology of stress. Subsequently, these receptors were identified as mineralocorticoid receptors (MRs) that are involved in appraisal processes, choice of coping style, encoding and retrieval. The MR-mediated actions on cognition are complemented by slower actions via glucocorticoid receptors (GRs) on contextualization, rationalization and memory storage of the experience. These sequential phases in cognitive performance depend on synaptic metaplasticity that is regulated by coordinate MR- and GR activation. The receptor activation includes recruitment of coregulators and transcription factors as determinants of context-dependent specificity in steroid action; they can be modulated by genetic variation and (early) experience. Interestingly, inflammatory responses to damage seem to be governed by a similarly balanced MR:GR-mediated action as the initiating, terminating and priming mechanisms involved in stress-adaptation. We conclude with five questions challenging the MR:GR balance hypothesis. PMID- 29428550 TI - A New Model to Predict Benign Histology in Residual Retroperitoneal Masses After Chemotherapy in Nonseminoma. AB - BACKGROUND: Postchemotherapy retroperitoneal lymph node dissection (pcRPLND) is indicated in testicular cancer patients with normalised or plateaued serum tumour markers and residual retroperitoneal lesions >1cm. Challenges remain in predicting postchemotherapy residual mass (pcRM) histology, which may lead to unnecessary surgery. OBJECTIVE: To develop an accurate model to predict pcRM histology in patients with nonseminomatous germ cell tumours (NSGCTs). DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of 335 patients undergoing pcRPLND for metastatic NSGCTs to develop a model to predict benign histology in retroperitoneal pcRM. Our model was compared with others and externally validated. INTERVENTION: Chemotherapy and pcRPLND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable logistic regression to evaluate the presence of benign histology, and fractional polynomials to allow for a nonlinear association between continuous variables and the outcome. The final Princess Margaret model (PMM) was selected based on the number of variables used, reliability, and discriminative capacity to predict benign pcRM. RESULTS AND LIMITATIONS: PMM included the presence of teratoma in the orchiectomy, prechemotherapy alpha-fetoprotein, prechemotherapy mass size, and change in mass size during chemotherapy. Model specificity was 99.3%. Compared with Vergouwe et al's model, PMM had significantly better accuracy (C statistic 0.843 vs 0.783). PMM appropriately identified a larger number of patients for whom pcRPLND can safely be avoided (13.9% vs 0%). Validated in external cohorts, the model retained high discrimination (C statistic 0.88 and 0.80). Larger and prospective studies are needed to further validate this model. CONCLUSIONS: Our clinical model, externally validated, showed improved discriminative ability in predicting pcRM histology when compared with other models. The higher accuracy and reduced number of variables make this a novel and appealing model to use for patient counselling and treatment strategies. PATIENT SUMMARY: Princess Margaret model accurately predicted postchemotherapy benign histology. These results might have clinical impact by avoiding unnecessary retroperitoneal lymph node dissection and consequently changing the paradigm of advanced testicular cancer treatment. PMID- 29428552 TI - High bone mineral density in sickle cell disease: Prevalence and characteristics. AB - BACKGROUND: Osteosclerosis (OSC) is a rarely studied complication of sickle cell disease (SCD). The objective of our study was to determine the prevalence and characteristics of high bone mineral density (BMD) and its radiological features in adult SCD patients. METHODS: This prospective observational study was conducted from May 2007 to May 2016 in consecutive patients with steady-state SCD at two university hospitals. The BMD of the lumbar spine (L1-L4) and right femoral neck was determined by dual energy X-ray absorptiometry. Clinical, laboratory and radiographic data were recorded. High BMD was defined as a BMD Z score of at least +2.5 standard deviations at the lumbar spine or hip. The characteristics of the patients with high BMD were compared to those of individuals with low or middle BMD, using multivariate ordinal logistic regression. RESULTS: 135 patients (86 women and 49 men) with a median age of 27 (IQR 23-33) years were included. High BMD was diagnosed in 20 (15%) patients with a median age of 33.5 (IQR 28-45) years. The SCD genotypes of these patients were SS in 11, SC in 5, S/beta+ in 3, and S/beta0 in 1. High BMD patients more frequently harbored the S/beta SCD genotype (21% vs 5% in non-high BMD patients; p=0.047) and were older (p=0.0007). Compared to patients with low or middle BMD, after adjustment for age and SCD genotype, high BMD patients had a higher prevalence of avascular necrosis history (p=0.009), higher BMI (p=0.007), and lower serum resorption marker CTX (p=0.04), bilirubin (p=0.02) and parathyroid hormone levels (p=0.02). There were no differences between groups regarding fracture history, H-shaped vertebrae or other biological variables. CONCLUSION: High-BMD values is a common manifestation in SCD patients, especially in those with the S/beta-thalassemia genotypes. The prevalence of high-BMD in SCD is associated with older age, suggesting that it will be more common in the future because the life span of patients with SCD is increasing thanks to significant progress in SCD treatment. PMID- 29428551 TI - Detection of Bladder Cancer in Urine Sediments by a Novel Multicolor Fluorescence In Situ Hybridization (Quartet) Test. AB - BACKGROUND: Bladder cancer is among the common human malignancies that show a heavy mutational load and copy number variations of numerous chromosomes, which makes them a target for diagnostic explorations. OBJECTIVE: We aimed to design a multicolor fluorescence in situ hybridization (FISH) test referred to as the quartet test for the detection of bladder cancer in urine. DESIGN, SETTING, AND PARTICIPANTS: We performed genome-wide copy number variation analysis on cohorts from the University of Texas MD Anderson Cancer Center (n=40) and The Cancer Genome Atlas (n=129), and identified the most frequently amplified chromosomal regions. These data were used to select four of the amplified regions to design a multicolor FISH test, referred to as the quartet test. Assay validation was performed on urine samples from 98 patients with bladder cancer: 56 with low grade papillary, 42 with high-grade invasive disease, and 48 benign controls. INTERVENTION: The quartet test can be used in clinical practice for noninvasive detection of bladder cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We initially analyzed samples using a fraction of abnormal cell scores and then by the quantitative score, which included not only the proportion of cells with abnormal copy numbers, but also the proportion of cells with numbers of altered copies and degree of amplification. We used receiver operator characteristic (ROC) curves to identify cutoff values for the scores at which performances of sensitivity and specificity were maximized. RESULTS AND LIMITATIONS: The copy number status assessed by probes detected in voided urine reflected the amplification status of the primary tumor. An ROC curve summarizing the proportion of assayed cells with any abnormal copy numbers gave specificity of 93.8% and sensitivity of 78.6% using the proportion of cells with abnormal copy numbers. The quantitative score giving extra weight to cells with multiple simultaneous amplifications provided 95.8% specificity and 76.8% sensitivity. Both percentage of abnormal cells and quantitative scores were highly effective for assessing the grade of the tumor. The full spectrum of potential clinical applications was not explored in the current study, and further validation studies are needed. CONCLUSIONS: The quartet test shows promising specificity and sensitivity results, but it requires validation on a larger multi-institutional cohort of samples. PATIENT SUMMARY: The quartet test can be used for noninvasive detection of bladder cancer in voided urine. It can also be used to assess the grade of the tumor and tumor recurrence as well as post-treatment effects. PMID- 29428553 TI - Radiocarpal dislocations and fracture-dislocations: Injury types and long-term outcomes. AB - INTRODUCTION: Radiocarpal dislocation (RCD) and fracture-dislocations (RCFD) are severe but rare injuries for which the treatment and outcomes are not well defined. The aim of this retrospective study was to describe the prevalence of the various injury types and their long-term outcomes. PATIENTS AND METHODS: Between 1992 and 2014, 41 patients with RCFD were seen at our institution. According to the Dumontier classification, there were 4 cases of type 1 and 37 cases of type 2. Thirteen patients were reviewed again after a mean follow-up of 168 months (20-260). RESULTS: Among these 41 patients, 6 required secondary wrist fusion. At the latest follow-up evaluation, flexion-extension amplitude was 100 degrees (25 degrees -152 degrees ), grip strength was 86% of the contralateral side (10kgf-112kgf), the mean VAS for pain was 1.3 (0-5), the mean QuickDASH was 23 (0-59) and the mean PWRE was 27 (0-75). Six patients developed osteoarthritis in the radiocarpal and midcarpal joints. DISCUSSION: For cases of RCD, when reduction and stabilization have been confirmed by a dorsal approach, there is no reason to perform volar capsule and ligament suturing. For cases of RCFD, after anatomical reduction, radiostyloid pinning can be performed and an open surgical approach is not always required. Radiolunate fusion is a good solution for treating secondary instability. CONCLUSION: The good functional outcomes and absence of osteoarthritis can be attributed to the effective reduction and radiocarpal stabilization, along with the absence of radial and intracarpal marginal fractures. LEVEL OF EVIDENCE: IV, retrospective. PMID- 29428554 TI - Does scientific creativity be promoted by francophones? Manifesto from the "New World". PMID- 29428555 TI - The inflammatory molecule sphingosine-1-phosphate is not effective to evoke or sensitize cough in naive guinea pigs. AB - Sphingosine-1-phosphate (S1P) is an inflammatory mediator increased in the tissue in the number of inflammatory conditions. Preliminary data indicate that the vagal afferent neurons express several S1P receptors including S1PR2-3. We therefore evaluated the hypothesis that S1P induces cough and/or enhances the cough evoked by other tussive stimuli (TRPA1 and TRPV1 activators) in naive guinea pigs. Inhalation of S1P in the concentrations of 0.1 mM and 1 mM did not evoke cough. Preinhalation and continuing inhalation of S1P (1 mM) during citric acid (0.2 M) challenge did not enhance citric acid-induced cough. Preinhalation of S1P and continuing inhalation during AITC (3 mM) challenge also did not enhance AITC-induced cough. We conclude that S1P was not efficient to evoke cough in awake naive guinea pigs. S1P was also not effective to sensitize the cough evoked by stimulation of TRPV1 and TRPA1 receptors. Nonetheless it cannot be excluded that S1P influences cough in the context of inflamed airways when the cough-mediating nerves undergo sensory neuroplasticity. PMID- 29428556 TI - Effect of hypercapnia on self-sustained muscle activity. AB - The aim of the present study was to determine the effect of hypercapnia on motor neuromuscular activity of the human triceps surae muscle. Nine subjects participated in trials in a normal breathing condition and a CO2 rebreathing condition. In both conditions, in order to provoke self-sustained muscle activity, percutaneous electrical train stimulation was applied to the tibial nerve while each subject lay on a bed. Self-sustained muscle activity, which is an indirect observation of plateau potentials in spinal motoneurons, was measured for 30 s after the train stimulation by using surface electromyography. The sustained muscle activity was increased by CO2 rebreathing (P < 0.05). This finding suggests that motor neuromuscular activity may be linked to the respiratory system that is activated during hypercapnia. PMID- 29428557 TI - A complete structural characterization of the desferrioxamine E biosynthetic pathway from the fire blight pathogen Erwinia amylovora. AB - The Gram-negative bacterium Erwinia amylovora is the etiological agent of fire blight, a devastating disease which affects Rosaceae such as apple, pear and quince. The siderophore desferrioxamine E plays an important role in bacterial pathogenesis by scavenging iron from the host. DfoJ, DfoA and DfoC are the enzymes responsible for desferrioxamine production starting from lysine. We have determined the crystal structures of each enzyme in the desferrioxamine E pathway and demonstrate that the biosynthesis involves the concerted action of DfoJ, followed by DfoA and lastly DfoC. These data provide the first crystal structures of a Group II pyridoxal-dependent lysine decarboxylase, a cadaverine monooxygenase and a desferrioxamine synthetase. DfoJ is a homodimer made up of three domains. Each monomer contributes to the completion of the active site, which is positioned at the dimer interface. DfoA is the first structure of a cadaverine monooxygenase. It forms homotetramers whose subunits are built by two domains: one for FAD and one for NADP+ binding, the latter of which is formed by two subdomains. We propose a model for substrate binding and the role of residues 43-47 as gate keepers for FAD binding and the role of Arg97 in cofactors turnover. DfoC is the first structure of a desferrioxamine synthetase and the first of a multi-enzyme siderophore synthetase coupling an acyltransferase domain with a Non-Ribosomal Peptide Synthetase (NRPS)-Independent Siderophore domain (NIS). PMID- 29428558 TI - Structure and electrochemistry of proteins harboring iron-sulfur clusters of different nuclearities. Part II. [4Fe-4S] and [3Fe-4S] iron-sulfur proteins. AB - In the context of the plethora of proteins harboring iron-sulfur clusters we have already reviewed structure/electrochemistry of metalloproteins expressing single types of iron-sulfur clusters (namely: {Fe(Cys)4}, {[Fe2S2](Cys)4}, {[Fe2S2](Cys)3(X)} (X = Asp, Arg, His), {[Fe2S2](Cys)2(His)2}, {[Fe3S4](Cys)3}, {[Fe4S4](Cys)4} and {[Fe4S4](SgammaCys)3(nonthiolate ligand)} cores) and their synthetic analogs. More recently we are focussing on structure/electrochemistry of metalloproteins harboring iron-sulfur centres of different nuclearities. Having started such a subject with proteins harboring [4Fe-4S] and [2Fe-2S] clusters, we now depict the state of art of proteins containing [4Fe-4S] and [3Fe 4S] clusters. PMID- 29428559 TI - Elevated IL-27 in patients with acute coronary syndrome is associated with adverse ventricular remodeling and increased risk of recurrent myocardial infarction and cardiovascular death. AB - BACKGROUND AND AIMS: IL-27 is an immunoregulatory cytokine belonging to the IL 6/IL-12 family that was found to be elevated in acute coronary syndrome (ACS) patients. We investigated whether IL-27 is related to post-ischemic cardiac remodeling and long-term prognosis in this patient group. METHODS: We included 524 ACS patients, defined as acute myocardial infarction (AMI) or unstable angina (UA). A subgroup of 107 patients donated blood samples 6 weeks after the index event, and underwent a follow-up echocardiographical examination at 1 year. We measured plasma levels of IL-27, high sensitivity troponin T (hsTNT), C-reactive protein (hsCRP) and cystatin C at baseline and in the 6-week samples. The median follow-up period of the cohort was 2.2 years. RESULTS: The incidence of the combined end-point of AMI and cardiovascular death was higher in patients with plasma IL-27 within the top two tertiles both at baseline and after 6 weeks. After correction for cardiovascular risk factors, medication, hsTNT, hsCRP, and eGFR, patients with baseline IL-27 levels within the highest tertile had a significantly elevated risk for the combined end-point compared with the lowest tertile (hazard ratio 2.70, 95% CI 1.06-6.90, p = .038). Additionally, higher baseline IL-27 levels were associated with deleterious left ventricular remodeling and deterioration of systolic and diastolic function during the first year of follow-up. CONCLUSIONS: Elevated IL-27 at the time of an ACS is independently related to impaired cardiac function and worse long-term prognosis. Our data warrants further mechanistic studies to elucidate the involvement of IL 27 in cardiac repair and remodeling after ACS. PMID- 29428560 TI - Enabling personalized implant and controllable biosystem development through 3D printing. AB - The impact of additive manufacturing in our lives has been increasing constantly. One of the frontiers in this change is the medical devices. 3D printing technologies not only enable the personalization of implantable devices with respect to patient-specific anatomy, pathology and biomechanical properties but they also provide new opportunities in related areas such as surgical education, minimally invasive diagnosis, medical research and disease models. In this review, we cover the recent clinical applications of 3D printing with a particular focus on implantable devices. The current technical bottlenecks in 3D printing in view of the needs in clinical applications are explained and recent advances to overcome these challenges are presented. 3D printing with cells (bioprinting); an exciting subfield of 3D printing, is covered in the context of tissue engineering and regenerative medicine and current developments in bioinks are discussed. Also emerging applications of bioprinting beyond health, such as biorobotics and soft robotics, are introduced. As the technical challenges related to printing rate, precision and cost are steadily being solved, it can be envisioned that 3D printers will become common on-site instruments in medical practice with the possibility of custom-made, on-demand implants and, eventually, tissue engineered organs with active parts developed with biorobotics techniques. PMID- 29428561 TI - Marine algal carbohydrates as carbon sources for the production of biochemicals and biomaterials. AB - The high content of lipids in microalgae (>60% w/w in some species) and of carbohydrates in seaweed (up to 75%) have promoted intensive research towards valorisation of algal components for the production of biofuels. However, the exploitation of the carbohydrate fraction to produce a range of chemicals and chemical intermediates with established markets is still limited. These include organic acids (e.g. succinic and lactic acid), alcohols other than bioethanol (e.g. butanol), and biomaterials (e.g. polyhydroxyalkanoates). This review highlights current and potential applications of the marine algal carbohydrate fractions as major C-source for microbial production of biomaterials and building blocks. PMID- 29428563 TI - Acoustic streaming induced by two orthogonal ultrasound standing waves in a microfluidic channel. AB - A mathematical model is derived for acoustic streaming in a microfluidic channel confined between a solid wall and a rigid reflector. Acoustic streaming is produced by two orthogonal ultrasound standing waves of the same frequency that are created by two pairs of counter-propagating leaky surface waves induced in the solid wall. The magnitudes and phases of the standing waves are assumed to be different. Full analytical solutions are found for the equations of acoustic streaming. The obtained solutions are used in numerical simulations to reveal the structure of the acoustic streaming. It is shown that the interaction of two standing waves leads to the appearance of a cross term in the equations of acoustic streaming. If the phase lag between the standing waves is nonzero, the cross term brings about circular vortices with rotation axes perpendicular to the solid wall of the channel. The vortices make fluid particles rotate and move alternately up and down between the solid wall and the reflector. The obtained results are of immediate interest for acoustomicrofluidic applications such as the ultrasonic micromixing of fluids and the manipulation of microparticles. PMID- 29428562 TI - Notum attenuates Wnt/beta-catenin signaling to promote tracheal cartilage patterning. AB - Tracheobronchomalacia (TBM) is a common congenital disorder in which the cartilaginous rings of the trachea are weakened or missing. Despite the high prevalence and clinical issues associated with TBM, the etiology is largely unknown. Our previous studies demonstrated that Wntless (Wls) and its associated Wnt pathways are critical for patterning of the upper airways. Deletion of Wls in respiratory endoderm caused TBM and ectopic trachealis muscle. To understand mechanisms by which Wls mediates tracheal patterning, we performed RNA sequencing in prechondrogenic tracheal tissue of Wlsf/f;ShhCre/wt embryos. Chondrogenic Bmp4, and Sox9 were decreased, while expression of myogenic genes was increased. We identified Notum, a deacylase that inactivates Wnt ligands, as a target of Wls induced Wnt signaling. Notum's mesenchymal ventral expression in prechondrogenic trachea overlaps with expression of Axin2, a Wnt/beta-catenin target and inhibitor. Notum is induced by Wnt/beta-catenin in developing trachea. Deletion of Notum activated mesenchymal Wnt/beta-catenin and caused tracheal mispatterning of trachealis muscle and cartilage as well as tracheal stenosis. Notum is required for tracheal morphogenesis, influencing mesenchymal condensations critical for patterning of tracheal cartilage and muscle. We propose that Notum influences mesenchymal cell differentiation by generating a barrier for Wnt ligands produced and secreted by airway epithelial cells to attenuate Wnt signaling. PMID- 29428564 TI - Comparative assessment of toxicity of ZnO and amine-functionalized ZnO nanorods toward Daphnia magna in acute and chronic multigenerational tests. AB - Zinc oxide nanomaterials (ZnO NM) have been used in a large number of applications due to their interesting physicochemical properties. However, the increasing use of ZnO NM has led to concerns regarding their environmental impacts. In this study, the acute and chronic toxicity of ZnO nanorods (NR) bare (ZnONR) and amine-functionalized (ZnONR@AF) toward the freshwater microcrustacean Daphnia magna was evaluated. The ZnO NR were characterized by transmission electron microscopy (TEM), X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and the zeta potential and hydrodynamic diameter (HD). The acute EC50(48h) values for D. magna revealed that the ZnONR@AF were more toxic than the ZnONR. The generation of reactive oxygen species (ROS) was observed in both NM. Regarding the chronic toxicity, the ZnONR@AF were again found to be more toxic than the ZnONR toward D. magna. An effect on longevity was observed for ZnONR, while ZnONR@AF affected the reproduction, growth and longevity. In the multigenerational recovery test, we observed that maternal exposure can affect the offspring even when these organisms are not directly exposed to the ZnO NR. PMID- 29428565 TI - Steroid pulse therapy in patients with encephalopathy associated with severe fever with thrombocytopenia syndrome. AB - Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). Clinical symptoms of SFTS often involve encephalopathy and other central neurological symptoms, particularly in seriously ill patients; however, pathogenesis of encephalopathy by SFTSV is largely unknown. Herein, we present case reports of three patients with SFTS, complicated by encephalopathy, admitted to Tokushima University hospital: one patient was a 63-year-old man, while the other two were 83- and 86-year-old women. All of them developed disturbance of consciousness around the 7th day post onset of fever. After methylprednisolone pulse therapy of 500 mg/day, all of them recovered without any neurological sequelae. SFTSV genome was not detected in the cerebrospinal fluid of 2 out of the 3 patients that were available for examination. In these patients, disturbance of consciousness seemed to be an indirect effect of the cytokine storm triggered by SFTSV infection. We propose that short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy during early phase of SFTSV infection. PMID- 29428566 TI - Trends and patterns of national antimicrobial consumption in Japan from 2004 to 2016. AB - Frequent use of broad-spectrum antimicrobial classes has been reported in Japan; however, little is known about the long-term trend of national antimicrobial consumption, and that of individual agents. This study analyzed the national sales data of systemic antimicrobials from 2004 to 2016, derived from the IMS Japan Pharmaceutical Market database, to assess the consumption patterns of antimicrobial classes and agents in Japan. The number of defined daily doses per 1000 inhabitants per day (DID) was calculated for each antimicrobial agent. During the last 13 years, total antimicrobial consumption fluctuated by only 5% around the average of 14.41 DID. In 2016, the most used class was macrolides (32%), followed by cephalosporins (28%) and fluoroquinolones (19%). Oral agents comprised a large proportion (93%) of antimicrobial consumption. The most used agent, clarithromycin, accounted for 25% of all oral compounds used in 2016. The consumption of oral agents with high bioavailability, such as fluoroquinolones, amoxicillin, and sulfamethoxazole/trimethoprim increased, whereas that of cephalosporins decreased. In 2016, ceftriaxone was the most consumed parenteral agent, followed by cefazolin. The consumption of parenteral agents increased after 2009 when high-dose regimens of piperacillin/tazobactam, meropenem, and ampicillin/sulbactam were approved by the health insurance system. National antimicrobial consumption has been stable over the last 13 years. Moreover, shifts in the use of agents with high bioavailability and those approved for high dose regimens were observed. However, the increased use of broad-spectrum agents is worrisome. A multifaceted approach is required to reduce overall antimicrobial consumption. PMID- 29428567 TI - Clinical features of fatal severe fever with thrombocytopenia syndrome that is complicated by invasive pulmonary aspergillosis. AB - INTRODUCTION: Severe fever with thrombocytopenia syndrome (SFTS) has been prevalent in parts of Asia during recent years. However, SFTS with invasive pulmonary aspergillosis (IPA) is rare, and it is important to understand its clinical features. MATERIALS AND METHODS: Total four cases of SFTS with IPA are reviewed and detailing the disease progression, treatment options, and prognosis were summarized and analyzed. RESULTS: The patients with SFTS-associated IPA first presented with fever, gastrointestinal symptoms, thrombocytopenia, leukopenia, and multiple organ failure. After 1-2 weeks, the patients developed mild polypnea and wheezing rales, and quickly developed dyspnea and respiratory failure. Tracheal intubation was usually performed, but did not relieve the intractable airway spasm and pulmonary ventilation failure. Bronchoscopy confirmed that the antifungal treatment was ineffective and the aspergillosis had worsened. All patients died of type 2 respiratory failure caused by continued airway obstruction and spasticity. CONCLUSIONS: Given the high mortality rate in this series, there is a need for increased awareness of SFTS-associated IPA. Additional examinations should be performed in these cases, and early-stage antifungal treatment with organ support may be helpful. PMID- 29428568 TI - Are amine-only-containing products sporicidal? PMID- 29428569 TI - A continuum of mineralization from human renal pyramid to stones on stems. AB - : The development of new modalities for kidney stone prevention rests upon understanding the progression of mineralization within the renal pyramid. The progression from small foci of mineralized volumes within the renal pyramid to larger interstitial plaques that ultimately lead into clinically detectable calcium-based stones on calcium phosphate stems will be presented through correlative microscopy approach. High resolution X-ray computed tomography (micro XCT), electron microscopy, and energy dispersive X-ray (EDX) compositional analyses of interstitial plaques, stems, and attached stones were performed. Increase in mineral density progressed with mineralization severity, with the highest mineral densities detected within mature Randall's plaque and stems to which kidney stones were attached. EDX analyses revealed variable elemental composition within interstitial plaque, stems, and stones. Micro-XCT reconstructions of stones with stems enabled visualization of unoccluded tubules within stems, with average tubule diameters corresponding to thin limbs of Henle, blood vessels, and collecting ducts. Correlative microscopy confirmed that the progression of mineralization leading to calcium-based nephrolithiasis occurs through a continuum involving four anatomically and structurally distinct biomineralization regions: 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall's plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones. STATEMENT OF SIGNIFICANCE: Nephrolithiasis is a common condition affecting nearly 1 in 11 Americans. The most common type of stone, calcium oxalate is known to form on a calcium phosphate deposit on the renal papilla known as Randall's plaque. Novel imaging techniques have identified distinct regions of biomineralization not just at the tip, but throughout the renal papilla. The classic understanding of Randall's plaque formation is reformulated using correlative imaging techniques. This study establishes a stepwise progression of anatomically-specific biomineralization events including, 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall's plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones, and provides insights into the need for plausible site-specific therapeutic intervention. PMID- 29428570 TI - New research directions for areca nut/betel quid and oral submucous fibrosis for holistic prevention and treatment. PMID- 29428571 TI - Integrative expression quantitative trait locus-based analysis of colorectal cancer identified a functional polymorphism regulating SLC22A5 expression. AB - Multiple single nucleotide polymorphisms (SNPs) have been found to be highly correlated with colorectal cancer (CRC) risk. However, the variants identified thus far only explain a small part of the cases, suggesting the existence of many uncharacterised genetic determinants. In this study, using the multilevel 'omics' data provided in The Cancer Genome Atlas, we systematically performed expression quantitative trait locus (eQTL) analysis for CRC and identified nine SNPs with significant effects on mRNA expression (correlation |r| > 0.3 and FDR < 0.01). Then we conducted a two-stage case-control study consisting of 1528 cases and 1528 controls to examine the associations between candidate SNPs and CRC risk. We found that rs27437 in SLC22A5 was significantly correlated with CRC risk in both stages and the combined study (additive model, OR = 1.31, 95%CI = 1.17-1.47, P = 1.97 * 10-6). eQTL analysis showed that rs27437 GG and GA genotypes were associated with lower expression of SLC22A5 compared with the AA genotype. Dual luciferase reporter assays confirmed that the G risk allele could decrease the expression of luciferase. SLC22A5 was significantly decreased in CRC tumour tissues compared with adjacent normal tissues, indicating that SLC22A5 may play important roles in CRC, and rs27437 in SLC22A5 might serve as a novel biomarker for early detection and prevention of CRC. PMID- 29428573 TI - From the other side: The patient perspective on cancer clinical trials. AB - This article provides the patient perspective on cancer clinical trials. PMID- 29428574 TI - Can sex ratios at birth be used in the assessment of public health, and in the identification of causes of selected pathologies? AB - This paper will consist of two parts. In the first, further support is given to the proposal that offspring sex ratios (proportions male) may usefully be regarded as indicators of public health. In the second, it is shown that sex ratios may help in the identification of the causes and effects of several pathologies that seriously impinge on public health viz. autism, testicular cancer, hepatitis B and toxoplasmosis. PMID- 29428575 TI - S-Adenosylmethionine attenuates bile duct early warm ischemia reperfusion injury after rat liver transplantation. AB - Warm ischemia reperfusion injury (IRI) plays a key role in biliary complication, which is a substantial vulnerability of liver transplantation. The early pathophysiological changes of IRI are characterized by an excessive inflammatory response. S-Adenosylmethionine (SAM) is an important metabolic intermediate that modulates inflammatory reactions; however, its role in bile duct warm IRI is not known. In this study, male rats were treated with or without SAM (170 MUmol/kg body weight) after orthotopic autologous liver transplantation. The histopathological observations showed that bile duct injury in the IRI group was more serious than in the SAM group. The alanine aminotransferase (ALT), alkaline phosphatase (ALP) and direct bilirubin (DBIL) levels in the serum of the IRI group were significantly increased compared to the SAM group (P < .05). Simultaneously, SAM effectively improved the survival of the transplant recipients. Furthermore, the H2O2 and malondialdehyde (MDA) of the IRI group were much higher compared to the SAM group (P < .05). The GSH/GSSG ratio in the SAM group was significantly increased by SAM treatment compared to the IRI group (P < .05). SAM administration significantly inhibited macrophage infiltration in liver and bile duct tissues, down-regulated TNF-alpha levels and up-regulated IL-10 expression in bile duct tissues compared to the IRI group (P < .05). The number of apoptotic biliary epithelial cells and caspase-3-positive cells in IRI rat livers were much higher compared to those in SAM-treated rats at 24 h after liver transplantation (P < .05). These data suggested that SAM protected bile ducts against warm IRI by suppressing oxidative stress, inflammatory reactions and apoptosis of biliary epithelial cells after liver transplantation.alpha. PMID- 29428576 TI - Ganglioside GM1 protects against high altitude cerebral edema in rats by suppressing the oxidative stress and inflammatory response via the PI3K/AKT-Nrf2 pathway. AB - High altitude cerebral edema (HACE) is a severe type of acute mountain sickness (AMS) that occurs in response to a high altitude hypobaric hypoxic (HH) environment. GM1 monosialoganglioside can alleviate brain injury under adverse conditions including amyloid-beta-peptide, ischemia and trauma. However, its role in HACE-induced brain damage remains poorly elucidated. In this study, GM1 supplementation dose-dependently attenuated increase in rat brain water content (BWC) induced by hypobaric chamber (7600 m) exposurefor 24 h. Compared with the HH-treated group, rats injected with GM1 exhibited less brain vascular leakage, lower aquaporin-4 and higher occludin expression, but they also showed increase in Na+/K+-ATPase pump activities. Importantly, HH-incurred consciousness impairment and coordination loss also were ameliorated following GM1 administration. Furthermore, the increased oxidative stress and decrease in anti oxidant stress system under the HH condition were also reversely abrogated by GM1 treatment via suppressing accumulation of ROS, MDA and elevating the levels of SOD and GSH. Simultaneously, GM1 administration also counteracted the enhanced inflammation in HH-exposed rats by muting pro-inflammatory cytokines IL-1beta, TNF-alpha, and IL-6 levels in serum and brain tissues. Subsequently, GM1 potentiated the activation of the PI3K/AKT-Nrf2 pathway. Cessation of this pathway by LY294002 reversed GM1-mediated inhibitory effects on oxidative stress and inflammation, and ultimately abrogated the protective role of GM1 in abating brain edema, cognitive and motor dysfunction. Overall, GM1 may afford a protective intervention in HACE by suppressing oxidative stress and inflammatory response via activating the PI3K/AKT-Nrf2 pathway, implying a promising agent for the treatment of HACE. PMID- 29428572 TI - Metabolic control and complications in Italian people with diabetes treated with continuous subcutaneous insulin infusion. AB - BACKGROUND AND AIM: The objective of this cross-sectional study was to evaluate the degree of glycaemic control and the frequency of diabetic complications in Italian people with diabetes who were treated with continuous subcutaneous insulin infusion (CSII). METHODS AND RESULTS: Questionnaires investigating the organisation of diabetes care centres, individuals' clinical and metabolic features and pump technology and its management were sent to adult and paediatric diabetes centres that use CSII for treatment in Italy. Information on standard clinical variables, demographic data and acute and chronic diabetic complications was derived from local clinical management systems. The sample consisted of 6623 people with diabetes, which was obtained from 93 centres. Of them, 98.8% had type 1 diabetes mellitus, 57.2% were female, 64% used a conventional insulin pump and 36% used a sensor-augmented insulin pump. The median glycated haemoglobin (HbA1c) level was 60 mmol/mol (7.6%). The HbA1c target (i.e. <58 mmol/mol for age <18 years and <53 mmol/mol for age >18 years) was achieved in 43.4% of paediatric and 23% of adult participants. Factors such as advanced pump functions, higher rate of sensor use, pregnancy in the year before the study and longer duration of diabetes were associated with lower HbA1c levels. The most common chronic complications occurring in diabetes were retinopathy, microalbuminuria and hypertension. In the year before the study, 5% of participants reported >=1 episode of severe hypoglycaemic (SH) episodes (SH) and 2.6% reported >=1 episode of ketoacidosis. CONCLUSIONS: Advanced personal skills and use of sensor-based pump are associated with better metabolic control outcomes in Italian people with diabetes who were treated with CSII. The reduction in SH episodes confirms the positive effect of CSII on hypoglycaemia. CLINICAL TRIAL REGISTRATION NUMBER: NCT 02620917 (ClinicalTrials.gov). PMID- 29428578 TI - Treatment practices of households and antibiotic dispensing in medicine outlets in developing countries: The case of Ghana. AB - INTRODUCTION: Antibiotic resistance, associated with inappropriate drug use, is a global public health threat. The pharmaceutical sectors in developing countries are poorly regulated leading to antibiotic sales and use without a prescription. The study documents the treatment of acute illnesses in households and the antibiotic dispensing practices of medicine sales outlets in Eastern region, Ghana. METHOD: Twice-weekly illness recall visits were made to 12 households in three rural communities over eight consecutive weeks. Detailed fieldnotes were taken and analysed using a thematic approach. Quantitative counts of health events and treatment were also conducted. Dispensing practices were systematically observed and documented in three rural and three urban medicine outlets for analysis. RESULT: Fever, abdominal, and respiratory symptoms were the most common causes of ill-health in the 12 households. Most (65%) medicine-use events involved self-treatment with pharmaceuticals; 40% of medicine-use events involved antibiotics, often without a prescription. Although the number of antibiotic transactions without prescription in rural medicine outlets (n = 139, 27.4%) was statistically significantly more than in urban pharmacies (n = 140, 13.5%); z = 6.7, p < .0001), the volume of antibiotics sold in pharmacies was higher. Penicillins were the most commonly dispensed antibiotics constituting 30% of antibiotic sales in urban medicine outlets and 46% in rural ones. The lack of controls in the dispensing of antibiotics, community knowledge and use of antibiotics in ways inconsistent with biomedical recommendations, poverty and perceived barriers to formal healthcare were factors that influenced the inappropriate use of antibiotics. CONCLUSION: Self-medication, including antibiotic self-prescription, constitutes an integral part of healthcare in the study settings and the qualitative data provides a contextual understanding of over-the-counter antibiotic acquisition and use. Inappropriate antibiotic use is apparent in the study settings. Stricter regulation of the pharmaceutical sector, training of dispensers and evidence-based treatment guidelines, and public education are potential interventions. PMID- 29428577 TI - Qualitative analysis of governance trends after health system reforms in Latin America: lessons from Mexico. AB - OBJECTIVE: Health policies in Latin America are centered on the democratization of health. Since 2003, during the last generation of reforms, health systems in this region have promoted governance strategies for better agreements between governments, institutions, and civil society. In this context, we develop an evaluative research to identify trends and evidence of governance after health care reforms in six regions of Mexico. METHODS: Evaluative research was developed with a retrospective design based on qualitative analysis. Primary data were obtained from 189 semi-structured interviews with purposively selected health care professionals and key informants. Secondary data were extracted from a selection of 95 official documents on results of the reform project at the national level, national health policies, and lines of action for good governance. Data processing and analysis were performed using ATLAS.ti and PolicyMaker. RESULTS: A list of main strengths and weaknesses is presented as evidence of health system governance. Accountability at the federal level remains prescriptive; in the regions, a system of accountability and transparency in the allocation of resources and in terms of health democratization strategies is still absent. CONCLUSION: Social protection and decentralization schemes are strategies that have allowed for improvements with a proactive role of users and civil society. Regarding challenges, there are still low levels of governance and difficulties in the effective conduct of programs and reform strategies together with a lack of precision in the rules and roles of the different actors of the health system. PMID- 29428579 TI - Brain activations supporting linking of action phases in a sequential manual task. AB - Most everyday manual tasks, like grabbing a cup of coffee to drink, are comprised of a sequence of action phases. Efficient phase transitions, or linking, are achieved using a predictive control policy where motor commands for the next phase are specified and released in anticipation of sensory confirmation of goal completion of the current phase. If there is a discrepancy between predicted and actual sensory feedback about goal completion, corrective actions are employed to complete the current action phase before proceeding to the next. However, we lack understanding about brain activations supporting such predictive linking and corrective actions in manual tasks. In this study, during 3-T MRI-scanning, sixteen participants (5 males, 11 females; mean age 27.3 years, range 23-37) performed a sequential manual task, with or without the possibility for predictive linking. We found that predictive linking of action phases was associated with increased activation in a network that included right-sided fronto-parietal areas related to visuospatial attention, eye movements and motor planning, left-sided parietal areas related to implicit timing and shifts of motor attention, occipital regions bilaterally reflecting visual processing related to the attended next target, and finally, the anterior midcingulate cortex involved in continuous performance monitoring. Corrective actions were associated with increased activation in the left dorsolateral prefrontal cortex involved in reestablishing executive control over previously automatized behavior. PMID- 29428580 TI - Are you thinking what I'm thinking? Synchronization of resting fMRI time-series across subjects. AB - We describe BrainSync, an orthogonal transform that allows direct comparison of resting fMRI (rfMRI) time-series across subjects. For this purpose, we exploit the geometry of the rfMRI signal space to propose a novel orthogonal transformation that synchronizes rfMRI time-series across sessions and subjects. When synchronized, rfMRI signals become approximately equal at homologous locations across subjects. The method is based on the observation that rfMRI data exhibit similar connectivity patterns across subjects, as reflected in the pairwise correlations between different brain regions. We show that if the data for two subjects have similar correlation patterns then their time courses can be approximately synchronized by an orthogonal transformation. This transform is unique, invertible, efficient to compute, and preserves the connectivity structure of the original data for all subjects. Analogously to image registration, where we spatially align structural brain images, this temporal synchronization of brain signals across a population, or within-subject across sessions, facilitates cross-sectional and longitudinal studies of rfMRI data. The utility of the BrainSync transform is illustrated through demonstrative simulations and applications including quantification of rfMRI variability across subjects and sessions, cortical functional parcellation across a population, timing recovery in task fMRI data, comparison of task and resting state data, and an application to complex naturalistic stimuli for annotation prediction. PMID- 29428581 TI - Temporal recalibration of motor and visual potentials in lag adaptation in voluntary movement. AB - Adaptively recalibrating motor-sensory asynchrony is critical for animals to perceive self-produced action consequences. It is controversial whether motor- or sensory-related neural circuits recalibrate this asynchrony. By combining magnetoencephalography (MEG) and functional MRI (fMRI), we investigate the temporal changes in brain activities caused by repeated exposure to a 150-ms delay inserted between a button-press action and a subsequent flash. We found that readiness potentials significantly shift later in the motor system, especially in parietal regions (average: 219.9 ms), while visually evoked potentials significantly shift earlier in occipital regions (average: 49.7 ms) in the delay condition compared to the no-delay condition. Moreover, the shift in readiness potentials, but not in visually evoked potentials, was significantly correlated with the psychophysical measure of motor-sensory adaptation. These results suggest that although both motor and sensory processes contribute to the recalibration, the motor process plays the major role, given the magnitudes of shift and the correlation with the psychophysical measure. PMID- 29428582 TI - Predicting suicidal ideation in primary care: An approach to identify easily assessable key variables. AB - OBJECTIVE: To obtain predictors of suicidal ideation, which can also be used for an indirect assessment of suicidal ideation (SI). To create a classifier for SI based on variables of the Patient Health Questionnaire (PHQ) and sociodemographic variables, and to obtain an upper bound on the best possible performance of a predictor based on those variables. METHODS: From a consecutive sample of 9025 primary care patients, 6805 eligible patients (60% female; mean age = 51.5 years) participated. Advanced methods of machine learning were used to derive the prediction equation. Various classifiers were applied and the area under the curve (AUC) was computed as a performance measure. RESULTS: Classifiers based on methods of machine learning outperformed ordinary regression methods and achieved AUCs around 0.87. The key variables in the prediction equation comprised four items - namely feelings of depression/hopelessness, low self-esteem, worrying, and severe sleep disturbances. The generalized anxiety disorder scale (GAD-7) and the somatic symptom subscale (PHQ-15) did not enhance prediction substantially. CONCLUSIONS: In predicting suicidal ideation researchers should refrain from using ordinary regression tools. The relevant information is primarily captured by the depression subscale and should be incorporated in a nonlinear model. For clinical practice, a classification tree using only four items of the whole PHQ may be advocated. PMID- 29428583 TI - Independent risk factors for the development of incontinence-associated dermatitis (category 2) in critically ill patients with fecal incontinence: A cross-sectional observational study in 48 ICU units. AB - BACKGROUND: Critically ill patients suffering from fecal incontinence have a major risk of developing incontinence-associated dermatitis (IAD). The presence of moisture and digestive enzymes (lipase, protease) negatively influences skin barrier function. Additional risk factors will make some patients even more vulnerable than others. In order to provide (cost) effective prevention, this specific patient population should be identified timely. OBJECTIVES: To identify independent risk factors for the development of IAD category 2 (skin loss) in critically ill patients with fecal incontinence. DESIGN: A cross-sectional observational study. SETTING AND PARTICIPANTS: The study was performed in 48 ICU wards from 27 Belgian hospitals. Patients of 18 years or older, with fecal incontinence at the moment of data collection, were eligible to participate. Patients with persistent skin redness due to incontinence (IAD category 1) were excluded. METHODS: Potential risk factors were carefully determined based on literature and expert consultations. Data were collected over a period of eight months by trained researchers using patient records and observation of skin care practices. At the time a patient was included in the study, all relevant data from the past six days, or since admission at the ICU, were recorded. Simultaneously, direct skin observations were performed and high definition photographs were ratified by an expert IAD researcher. A multiple binary logistic regression model was composed to identify independent risk factors. Variables with P < .25 in single binary logistic regression analyses were added to the multiple model using a forward procedure. A cut-off value of P < .1 was established to retain variables in the final model. Nagelkerke's R2 and Hosmer Lemeshow statistic were calculated as measures of model fit. RESULTS: The sample comprised of 206 patients, of which 95 presented with IAD category 2, and 111 were free of IAD. Seven independent risk factors were identified: liquid stool [odds ratio (OR) 4.69; 95% confidence interval (CI) 2.28-9.62], diabetes (OR 2.89; 95% CI 1.34-6.27), age (OR 1.05; 95% CI 1.02-1.08), smoking (OR 2.67; 95% CI 1.21-5.91), non-use of diapers (OR 2.97; 95% CI 1.39-6.33), fever (OR 2.60; 95% CI 1.23-5.53), and low oxygen saturation (OR 2.15; 95% CI 1.03-4.48). Nagelkerke's R2 was 0.377. The Hosmer-Lemeshow statistic indicated no significant difference between the observed and expected values (p = .301). CONCLUSIONS: Liquid stool, diabetes, age, smoking, non-use of diapers, fever, and low oxygen saturation were independently associated with IAD category 2 in critically ill patients with fecal incontinence. PMID- 29428584 TI - The preliminary association study of ADIPOQ, RBP4, and BCMO1 variants with polycystic ovary syndrome and with biochemical characteristics in a cohort of Polish women. AB - PURPOSE: We aimed to elucidate the frequency of the SNPs in the ADIPOQ, RBP4 and BCMO1genes in a population of Caucasian Polish women with polycystic ovary syndrome (PCOS), and to evaluate the possible associations between these variants and the susceptibility to PCOS. Additionally, the relationship of these polymorphisms to a clinical phenotype of this syndrome, and the concentrations of adipokines, were determined. MATERIALS/METHODS: Clinical and biochemical profiles, DNA isolation and genotyping, and adipokine assays were performed in 294 PCOS women and 78 controls. RESULTS: In a cohort of Polish women, for the genotype distribution and allele frequencies (minor allele frequency - MAF) proved that only the SNP rs1501299 in the gene ADIPOQ (P = 0.0010, OR = 0.41, 95% C.I.:0.24-0.70) and rs7501331 in the gene BCMO1 (P = 0.0106, OR = 0.24, 95% C.I.:0.21-0.71), are significantly associated (the latter marginally significant) with the decrease of the risk of the disease. Also for this SNPs there were significant differences in the genotypic frequencies in the study population. There was a link between rs12934922 of BCMO1 gen and serum concentration of RBP4 (P = 0.034) and adiponectin (P = 0.038) in the study group but not in the control group. The elevated mean serum concentration of cholesterol (P = 0.020) and LDL cholesterol (P = 0.005) was observed for GG rs1501299 genotype and triglycerides (P = 0.028) for TT rs2241766 genotype. CONCLUSIONS: The results of the present study revealed that the genes variants RBP4 is not associated with PCO. It seems that rs1501299 of ADIPOQ gene influences the occurrence of PCO and lipids profile in those patients. PMID- 29428585 TI - Distally based anteromedial thigh flaps pedicled on the rectus femoris branch of the lateral circumflex femoral artery for reconstruction of soft-tissue defect of the knee. AB - BACKGROUND: Anteromedial thigh flaps are far less clinically appealing than their anterolateral counterparts, and are occasionally considered as an alternative to the anterolateral thigh flap. Herein, we report the study of soft-tissue defects reconstruction in the knee using a distally based anteromedial thigh flap pedicled on the rectus femoris branch of the descending branch of the lateral circumflex femoral artery. PATIENTS AND METHODS: Between July 2008 and September 2016, a distally based anteromedial thigh flap was used to reconstruct soft tissue defects of the knee in 5 patients (3 males, 2 females; age range at surgery 4-55 years old). The perforating vessels supplying anteromedial thigh were derived from the rectus femoris branch of the lateral circumflex femoral artery. The rectus femoris branch shared a common trunk with the descending branches of the lateral circumflex femoral artery. Defect etiologies included malignant neoplasms in 2 cases and post-burn scar contracture in the remaining 3 cases. RESULTS: The average flap size was 19.6 * 9.2 cm (range: 15-24 * 6-12 cm). There was no flap loss. Postoperative muscle weakness occurred in one case. The average follow-up time was 17.8 months (range: 5-36 months). No recurrence of tumor or scar contracture was noted. CONCLUSIONS: Distally based anteromedial thigh flaps pedicled on the rectus femoris branch of the descending branch of the lateral circumflex femoral artery may serve as an alternative option to the distally based anterolateral thigh flap for soft-tissue defect reconstruction of the knee. PMID- 29428586 TI - The pedicled internal pudendal artery perforator (PIPAP) flap for ischial pressure sore reconstruction: Technique and long-term outcome of a cohort study. AB - BACKGROUND: The ischial region is the site most affected by pressure sores and has the highest recurrence and complication rates compared to other affected sites. We developed a practical and safe pedicled flap for reconstruction of ischial pressure sores based on the rich available perforators from the internal pudendal artery and the surplus of skin at the infragluteal fold. METHODS: A retrospective cohort study was conducted in all patients who underwent ischial pressure ulcer reconstruction using the PIPAP flap between March 2010 and March 2017. The skin flap was designed along the gluteal fold. The skin perforators of the pudendal artery were marked with a Doppler probe in the medial region of the gluteal fold. Surgery was performed in the jackknife position, and flaps were elevated in the suprafascial plane. Patients were assessed for minor (requiring no additional surgery) and major complications (requiring additional surgery). RESULTS: Twenty-seven patients (34 flaps) were identified. The median follow-up period was 38 months (IQR 37). Primary closure of the donor-site was achieved in all procedures, only one flap required muscle flap transposition in order to fill the dead space. The mean operating time was 60 +/- 21 minutes. In six flaps (9%) wound healing problems were noted that did not require an additional operative procedure. Among the nine flaps (27%) that required a second procedure, 3 (9%) were necessary due to recurrent ulcers. CONCLUSIONS: The PIPAP flap is a safe and reliable alternative for ischial pressure sore reconstruction, certainly when compared to available techniques. Moreover, it has significant advantages over other techniques including minimal donor-site morbidity, preservation of posterior thigh skin, buttock-line integrity and reliable vascularity. PMID- 29428587 TI - Letter to the editor: Predictors of internal mammary vessel diameter: A computed tomographic angiography-assisted anatomic analysis. PMID- 29428588 TI - Corrigendum to "Development of an Italian RM Y-STR haplotype database: Results of the 2013 GEFI collaborative exercise" [Forensic. Sci. Int. Genet. 15 (2015) 56 63]. PMID- 29428589 TI - Infectious pathogens meet point-of-care diagnostics. AB - The field of point-of-care (POC) diagnostics provides the rapid diagnosis of infectious diseases which is essential and critical for improving the general public health in resource-limited settings. POC platforms offer many advantages for detection of various pathogens including portability, automation, speed, cost, and efficiency. In this review, we provide an overview of the recent trends for POC diagnostics of infectious diseases with focus on portable platforms. We review here the present status of POC platforms, emphasizing in period of the past three years, then extrapolate their advance into the future applications for diagnosis of infectious pathogens. PMID- 29428590 TI - Quantitative and ultrasensitive detection of multiplex cardiac biomarkers in lateral flow assay with core-shell SERS nanotags. AB - Rapid and sensitive quantification of multiplex proteins in a wide concentration range is challenging in high throughput analysis. Herein, we proposed a lateral flow assay (LFA) based on core-shell surface enhanced Raman scattering (SERS) nanotags for multiplex and quantitative detection of cardiac biomarkers for the early diagnosis of acute myocardial infarction (AMI). In practice, Raman dyes (RDs) were embedded into the interior-gap of silver core and gold shell nanoparticles (NPs) to form SERS nanotags as labels instead of gold colloids and three test lines were employed in the strip for the detection of three cardiac biomarkers, Myo, cTnI, and CK-MB, respectively. Due to the amplified signal of the SERS nanotags and the high surface area to volume ratio (SVR) of porous nitrocellulose (NC) membrane, ultrasensitive quantification of protein markers with wide linear dynamic range (LDR) was realized, which is crucial for the quick detection of multiplex biomarkers in the same sample without pretreatments at bedsides. This method makes it possible for LFA in point of care testing (POCT) to be comparable with chemiluminescence immunoassay (CLIA) used in labs. PMID- 29428591 TI - Blue-light photoelectrochemical sensor based on nickel tetra-amined phthalocyanine-graphene oxide covalent compound for ultrasensitive detection of erythromycin. AB - In this study, we developed a novel photoelectrochemical (PEC) sensor for the highly sensitive detection of erythromycin by functionalising graphene oxide (GO) with nickel tetra-amined phthalocyanine (NiTAPc) through covalent bonding, which resulted in the formation of NiTAPc-Gr. The fabricated sensor showed a higher PEC efficiency under blue light, exhibiting a peak wavelength of 456 nm, as compared to that of the monomer. Further, the NiTAPc-Gr/indium tin oxide (ITO) sensor exhibited a photocurrent that was 50-fold higher than that for a GO/ITO sensor under the same conditions. Under optimal conditions, the NiTAPc-Gr PEC sensor showed a linear response for erythromycin concentrations ranging from 0.40 to 120.00 MUmol L-1, with the minimum limit for detection being 0.08 MUmol L-1. Thus, the NiTAPc-Gr sensor exhibited superior performance and excellent PEC characteristics, high stability, and good reproducibility with respect to the sensing of erythromycin. Moreover, it is convenient to use, fast, small, and cheap to produce. Hence, it should find wide use in the analysis of erythromycin in real-world applications. PMID- 29428592 TI - Broad-specificity photoelectrochemical immunoassay for the simultaneous detection of ochratoxin A, ochratoxin B and ochratoxin C. AB - A broad-specific photoelectrochemical (PEC) immunosensor was developed for the simultaneous detection of ochratoxin A, ochratoxin B and ochratoxin C (OTA, OTB, OTC) by using the direct growth of CdS nanorods on FTO as the photoelectrode and Au nanoflowers-modified glass carbon electrode (GCE) as the bioelectrode. The bioelectrode was used to capture antigens and then associate corresponding antibodies, followed by using SiO2@Cu2+ nanocomposites to conjugate the secondary antibody (Ab2) and a DNA strand as the initiator. After the hybridization chain reaction (HCR) and the addition of hemin, numerous DNAzymes (G-quadruplex/hemin) were produced. Due to the similar enzymatic property with horseradish peroxidase (HRP), G-quadruplex/hemin can accelerate the oxidation of 4-chloro-1-naphthol (4 CN) with H2O2 to yield the biocatalytic precipitation (BCP) on the bioelectrode. Then, the bioelectrode was further treated with moderate acid and thus Cu2+ was released, which can decrease the photocurrent of the photoelectrode by the formation of CuS. Due to the advantages of surface effect of Au nanoflowers, DNA amplification and high photoelectrocatalytic activity, the proposed broad specificity PEC immunosensor can detect OTA, OTB and OTC with a detection limit of 0.02, 0.04 and 0.03 pg/mL, respectively. In addition, the acceptable stability and selectivity suggest its possible application in the detection of OTA, OTB and OTC in water samples. PMID- 29428593 TI - In silico study toward the identification of new and safe potential inhibitors of photosynthetic electron transport. AB - To address the rising global demand for food, it is necessary to search for new herbicides that can control resistant weeds. We performed a 2D-quantitative structure-activity relationship (QSAR) study to predict compounds with photosynthesis-inhibitory activity. A data set of 44 compounds (quinolines and naphthalenes), which are described as photosynthetic electron transport (PET) inhibitors, was used. The obtained model was approved in internal and external validation tests. 2D Similarity-based virtual screening was performed and 64 compounds were selected from the ZINC database. By using the VEGA QSAR software, 48 compounds were shown to have potential toxic effects (mutagenicity and carcinogenicity). Therefore, the model was also tested using a set of 16 molecules obtained by a similarity search of the ZINC database. Six compounds showed good predicted inhibition of PET. The obtained model shows potential utility in the design of new PET inhibitors, and the hit compounds found by virtual screening are novel bicyclic scaffolds of this class. PMID- 29428594 TI - Predictive value of oxygenation index for outcomes in left-sided congenital diaphragmatic hernia. AB - BACKGROUND & OBJECTIVES: Congenital Diaphragmatic Hernia (CDH) is associated with significant morbidity and mortality. This study compares the efficacy of the highest oxygenation index in the first 48 h (HiOI) versus current prenatal indices to predict survival and morbidity. METHODS: Medical records of 50 prenatally diagnosed, isolated, left-sided CDH patients treated from January 2011 to April 2016 were reviewed. Data abstracted included HiOI, lung to head ratio (LHR), observed to expected total fetal lung volume (O/E TFLV), percent liver herniation (%LH), 6 month survival, respiratory support at discharge, ventilator days and length of stay. Data were analyzed using parametric and nonparametric tests and regression analyses as appropriate. RESULTS: HiOI was associated with significantly increased LOS (p<0.001), respiratory support at discharge (p<0.001), greater ventilator days (p=0.001) and higher odds of death (p=0.004) with risk of death increasing by 5% for every one-unit increase in OI. HiOI was statistically a better predictor of LOS than O/E TFLV (p=0.007) and %LH (p=0.02). CONCLUSIONS: In isolated, left-sided CDH patients, HiOI is associated with higher mortality, greater length of stay, more ventilator days and increased respiratory support at discharge. HiOI is a better predictor of length of stay than O/E TFLV and %LH. TYPE OF STUDY: Retrospective Study LEVEL OF EVIDENCE: II. PMID- 29428595 TI - Galanin enhances systemic glucose metabolism through enteric Nitric Oxide Synthase-expressed neurons. AB - OBJECTIVE: Decreasing duodenal contraction is now considered as a major focus for the treatment of type 2 diabetes. Therefore, identifying bioactive molecules able to target the enteric nervous system, which controls the motility of intestinal smooth muscle cells, represents a new therapeutic avenue. For this reason, we chose to study the impact of oral galanin on this system in diabetic mice. METHODS: Enteric neurotransmission, duodenal contraction, glucose absorption, modification of gut-brain axis, and glucose metabolism (glucose tolerance, insulinemia, glucose entry in tissue, hepatic glucose metabolism) were assessed. RESULTS: We show that galanin, a neuropeptide expressed in the small intestine, decreases duodenal contraction by stimulating nitric oxide release from enteric neurons. This is associated with modification of hypothalamic nitric oxide release that favors glucose uptake in metabolic tissues such as skeletal muscle, liver, and adipose tissue. Oral chronic gavage with galanin in diabetic mice increases insulin sensitivity, which is associated with an improvement of several metabolic parameters such as glucose tolerance, fasting blood glucose, and insulin. CONCLUSION: Here, we demonstrate that oral galanin administration improves glucose homeostasis via the enteric nervous system and could be considered a therapeutic potential for the treatment of T2D. PMID- 29428597 TI - Possible involvement of tetrahydrobiopterin in the disturbance of redox homeostasis in sepsis - Induced brain dysfunction. AB - BACKGROUND AND AIM: Tetrahydrobiopterin (BH4) is an essential co-factor that regulates nitric oxide (NO) and reactive oxygen species (ROS) production by nitric oxide synthases (NOS). In this study, we evaluated the effects of sepsis on BH4 level and redox status in the brain by using the rat model of sepsis induced by cecal ligation and puncture (CLP) and examined whether BH4 and/or acetyl-L-carnitine (ALC) could prevent the neuronal apoptosis and neurological changes induced by sepsis. MATERIAL AND METHOD: Male albino rats were randomly and blindly divided into 8 groups: sham, sham + BH4, sham + ALC, sham +BH4+ ALC, CLP, CLP + BH4, CLP + ALC, and CLP+BH4+ ALC. We measured neurological indicators, brain levels of BH4, guanosine triphosphate cyclohydrolase (GTPCH), sepiapterin reductase (SR) and dihydropteridine reductase (DHPR) genes expression (Essential enzymes in BH4 biosynthesis and recycling pathways). We investigated also brain redox status and both endothelial and inducible NOS expressions. RESULTS: Brain of septic rats demonstrated a reduced BH4 bioavailability, downregulation of BH4 synthetic enzymes, increased production of hydrogen peroxide and impaired antioxidant enzymes activities. Treatments with BH4 and/or ALC increased BH4 level, upregulated BH4 synthetic enzymes expressions, and attenuated oxidative induced neuronal apoptosis. CONCLUSION: Our results suggest that BH4 and/or ALC might protect the brain against oxidative stress induced neuronal apoptosis by restoring bioavailability of BH4 and upregulating of BH4 synthetic enzymes in the brain during sepsis. PMID- 29428596 TI - Small molecule PGC-1alpha1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration. AB - OBJECTIVE: The peroxisome proliferator-activated receptor-gamma coactivator 1alpha1 (PGC-1alpha1) regulates genes involved in energy metabolism. Increasing adipose tissue energy expenditure through PGC-1alpha1 activation is potentially beneficial for systemic metabolism. Pharmacological PGC-1alpha1 activators could be valuable tools in the fight against obesity and metabolic disease. Finding such compounds has been challenging partly because PGC-1alpha1 is a transcriptional coactivator with no known ligand-binding properties. While, PGC 1alpha1 activation is regulated by several mechanisms, protein stabilization is a crucial limiting step due to its short half-life under unstimulated conditions. METHODS: We designed a cell-based high-throughput screening system to identify PGC-1alpha1 protein stabilizers. Positive hits were tested for their ability to induce endogenous PGC-1alpha1 protein accumulation and activate target gene expression in brown adipocytes. Select compounds were analyzed for their effects on global gene expression and cellular respiration in adipocytes. RESULTS: Among 7,040 compounds screened, we highlight four small molecules with high activity as measured by: PGC-1alpha1 protein accumulation, target gene expression, and uncoupled mitochondrial respiration in brown adipocytes. CONCLUSIONS: We identify compounds that induce PGC-1alpha1 protein accumulation and show that this increases uncoupled respiration in brown adipocytes. This screening platform establishes the foundation for a new class of therapeutics with potential use in obesity and associated disorders. PMID- 29428599 TI - Maternal high fructose diet and neonatal immune challenge alter offspring anxiety like behavior and inflammation across the lifespan. AB - AIMS: This study examined the interaction between maternal high fructose diet and neonatal inflammation in neonates (P7), juveniles (P26-34) and adults on measures of anxiety-like behavior and cognition. The study aimed to assess the potential synergistic effects of these two forms of early-life inflammation. MAIN METHODS: We fed Sprague-Dawley dams with high fructose (60%) diet or normal chow. Each litter was treated with either saline or lipopolysaccharide (LPS) on postnatal day (P)3 and P5 and two pups were tested for USVs after maternal separation on P7. Post-weaning, juveniles were tested on the elevated zero maze (EZM) and in a context-object discrimination (COD) task prior to tissue harvest. Adults were tested on the EZM and the COD task as well. Immunohistochemistry and ELISA were used to assess molecular and cellular changes in the offspring. KEY FINDINGS: This study demonstrates that maternal diet and neonatal inflammation altered peripheral inflammation in neonates, altered anxiety-like behavior in juveniles, and altered anxiety-like behavior in adulthood. Maternal diet and sex increased juvenile peripheral inflammation and altered memory on the context-discrimination task. SIGNIFICANCE: Maternal diet has a profound impact on fetal and neonatal development, especially as obesity rates are on the rise worldwide. Together, these findings reveal enduring effects of maternal diet on offspring, support the findings on the effects of neonatal inflammation on anxiety-like behaviors in later-life periods, and add to the complex relationship between gestational and neonatal inflammation and anxiety. PMID- 29428598 TI - Investigating the influence of polyplex size on toxicity properties of polyethylenimine mediated gene delivery. AB - AIMS: Gene therapy is a promising strategy for the treatment of various diseases. Polyethylenimine (PEI) has received considerable attention for gene delivery applications due to their appropriate properties. However, their toxicity has raised concerns which cause to be used with cautious. This study aimed to prepare different complexes of PEI/DNA and evaluate their parameters affecting in vitro cytotoxicity. Also, apoptosis rate was measured to determine the mechanism of cell toxicity. MATERIALS AND METHODS: The complexes were prepared through conjugation and characterized using dynamic light scattering, MTT and flow cytometry techniques. KEY FINDINGS: The particles' size was from 81 nm to 2785 nm and was increased in the HBS buffer compared to HBG buffer. In the case of branched PEIs, the size of particles was inversely associated with molecular weight. The cytotoxicity results showed that linear 250 KDa PEI was non-toxic whereas branched PEIs with lower molecular weights showed toxicity effects in a concentration dependent manner. Also, the cytotoxicity effects of branched PEIs were proportional with carrier/plasmid (C/P) ratio and were more for the polyplexes prepared in HBG buffer compared to HBS buffer after 24 h incubation. Flow cytometry results confirmed that apoptosis is the main mechanism of cell toxicity produced by polyplexes. SIGNIFICANCE: The results showed the effect of PEI size on its cytotoxicity. Also, the toxicity effects of PEI-derived polyplexes in vivo environment was evaluated. PMID- 29428600 TI - Contraction-dependent TGF-beta1 activation is required for thrombin-induced remodeling in human airway smooth muscle cells. AB - AIMS: Thrombin is a serine proteinase that is not only involved in coagulation cascade, but also mediates a number of biological responses relevant to tissues repair, and induces bronchoconstriction. TGF-beta plays a pivotal role in airway remodeling due to its effects on airway smooth muscle proliferation and extracellular matrix (ECM) deposition. Recently, bronchoconstriction itself is found to constitute a form of strain and is highly relevant to asthmatic airway remodeling. However, the underlying mechanisms remain unknown. Here, we investigated the role of contraction- dependent TGF-beta activation in thrombin induced remodeling in human airway smooth muscle (HASM) cells. MATERIALS AND METHODS: Primary HASM cells were treated with or without thrombin in the absence or presence of anti-TGF-beta antibody, cytochalasin D and formoterol. CFSE labeling index or CCK-8 assay were performed to test cell proliferation. RT-PCR and Western blotting were used to examined ECM mRNA level and collagen Ialpha1, alpha-actin protein expression, respectively. Immunofluorescence was also used to confirm contraction induced by thrombin in HASM cells. KEY FINDING: Thrombin stimulation enhanced HASM cells proliferation and activated TGF-beta signaling. Thrombin induced ECM mRNA and collagen Ialpha1 protein expression, and these effects are mediated by TGF-beta. Abrogation of TGF-beta activation by contraction inhibitors cytochalasin D and formoterol prevents the thrombin induced effects. SIGNIFICANCE: These findings suggest that contraction-dependent TGF-beta activation could be a mechanism by which thrombin leads to the development of asthmatic airway remodeling. Blocking physical forces with bronchodilator would be an intriguing way in reducing airway remodeling in asthma. PMID- 29428601 TI - Codon usage variation of Zika virus: The potential roles of NS2B and NS4A in its global pandemic. AB - A comprehensive demonstration of Zika virus (ZIKV) molecular evolution is essential for understanding its adaptation and expansion in its recent pandemics. Despite several studies on mutations and codon usage in ZIKVs, the variations in codon usage patterns across individual genes and their biological implication remains unclear. Here, we performed a gene-by-gene comparison of the codon usage variation in ZIKVs of the African and Asian lineages. We found that besides the evidence of positive selection (Ka/Ks >1) in the Asian lineage of the ZIKV genome, codon usage patterns were gene-specific and codon usage variation of ZIKV genes, was possibly constrained by their individual functional features, such as transmembrane domains, or antigenicity. In particular, the NS2B and NS4A genes showed distinct codon usage patterns, clearly separating them from the clusters of other genes in the correspondence analysis (CA). In the Asian lineage, the NS2B and NS4A genes showed the highest codon usage bias (ENC values: 51.01 +/- 0.72 and 48.89 +/- 0.99 respectively), and were subjected to the highest translation selection (ENCobs/ENCexp ratio: 0.847 +/- 0.0297 and 0.828 +/- 0.0233 respectively) in comparison to the African lineages of ZIKV. The CpG frequency of the NS2B showed a gradual ascending trend in the Asian ZIKV lineages, while in NS4A it was constrained along with the expansion of the Asian lineage. Furthermore, between the African and Asian lineages, differentiated and specific over-represented codons were more prominent in the NS2B and NS4A. Together, our study implies that ZIKVs are in the process of evolutionary fine tuning their codon as seen in the recent pandemics, and NS2B and NS4A could have played a potential role in the molecular evolution of the Asian lineage and their establishment. PMID- 29428602 TI - Tyr120Asp mutation alters domain flexibility and dynamics of MeCP2 DNA binding domain leading to impaired DNA interaction: Atomistic characterization of a Rett syndrome causing mutation. AB - Mutations in the X-linked MECP2 gene represent the main origin of Rett syndrome, causing a profound intellectual disability in females. MeCP2 is an epigenetic transcriptional regulator containing two main functional domains: a methyl-CpG binding domain (MBD) and a transcription repression domain (TRD). Over 600 pathogenic mutations were reported to affect the whole protein; almost half of missense mutations affect the MBD. Understanding the impact of these mutations on the MBD structure and interaction with DNA will foster the comprehension of their pathogenicity and possibly genotype/phenotype correlation studies. Herein, we use molecular dynamics simulations to obtain a detailed view of the dynamics of WT and mutated MBD in the presence and absence of DNA. The pathogenic mutation Y120D is used as paradigm for our studies. Further, since the Y120 residue was previously found to be a phosphorylation site, we characterize the dynamic profile of the MBD also in the presence of Y120 phosphorylation (pY120). We found that addition of a phosphate group to Y120 or mutation in aspartic acid affect domain mobility that samples an alternative conformational space with respect to the WT, leading to impaired ability to interact with DNA. Experimental assays showing a significant reduction in the binding affinity between the mutated MBD and the DNA confirmed our predictions. PMID- 29428603 TI - Field efficacy of Bacillus thuringiensis galleriae strain SDS-502 for the management of alfalfa weevil and its impact on Bathyplectes spp. parasitization rate. AB - Alfalfa weevil, Hypera postica Gyllenhal, is an important pest in forage alfalfa worldwide, and especially so on the Northern Plains of North America. Neither the weevil-specific fungus, Erynia phytonomi, nor the weevil's parasitoids are able to routinely suppress outbreaks as they do in the eastern U.S. A new Bacillus thuringiensis var. galleriae, having a Cry8Da coleopteran-active toxin, has been recently commercialized. We examined the efficacy of this B. thuringiensis product against the H. postica in replicated field trials in north central Montana. Because it has been suggested that efficiency of the parasitoids, Bathyplectes curculionis and Oomyzus incertus, was inversely proportional to host numbers (i.e., parasitoid efficiency increased when host population is low), we also sought to determine if a partial reduction of larval H. postica populations with a B. thuringiensis would yield to greater parasitoid efficiency, manifested as higher percent parasitism among the surviving larvae. The B. thuringiensis gave 27-40% reduction in weevil numbers at the low label rate, 55-59% for the high label rate. Mean parasitism at the two research locations varied from 5-26% and 17-36% respectively, but application of the B. thuringiensis had no significant effect on parasitism levels, i.e. parasitism was not greater in treated than in carrier control plots. PMID- 29428605 TI - Effect of hypercapnia on respiratory and peripheral skeletal muscle loss during critical illness - A pilot study. AB - INTRODUCTION: Critical illness has profound effects on muscle strength and long term physical morbidity. However, there remains a paucity of evidence for the aetiology of critical illness related weakness. Recent animal model research identified that hypercapnia may reduce the rate of muscle loss. The aim of this study was to determine the effect of hypercapnia on respiratory and peripheral skeletal muscle in patients with critical illness. METHODS: A pilot observational study of mechanically ventilated critically ill patients at a tertiary critical care unit who were retrospectively categorised as: 1) Respiratory failure with normocapnia; 2) Respiratory failure with hypercapnia; and 3) brain injury. Diaphragm thickness and quadriceps rectus femoris cross-sectional area (RFCSA) were measured using ultrasound imaging at baseline and at days 3, 5, 7 and 10 of mechanical ventilation. RESULTS: Significant reductions in RFCSA muscle loss were observed for all time-points when compared to baseline [day 10: -14.9%+/-8.2 p< 0.001], and in diaphragm thickness between baseline and day 7 [day 7: -5.8%+/-9.5 p=0.029). No correlation was identified between the rate of muscle mass loss in the diaphragm and RFCSA. CONCLUSION: In this pilot study, peripheral skeletal muscle weakness occurred early and rapidly within the critical care population, irrespective of carbon dioxide levels. PMID- 29428604 TI - Experimental neuropharmacology of Gelsemium sempervirens: Recent advances and debated issues. AB - Gelsemium sempervirens L. (Gelsemium) is traditionally used for its anxiolytic like properties and its action mechanism in laboratory models are under scrutiny. Evidence from rodent models was reported suggesting the existence of a high sensitivity of central nervous system to anxiolytic power of Gelsemium extracts and Homeopathic dilutions. In vitro investigation of extremely low doses of this plant extract showed a modulation of gene expression of human neurocytes. These studies were criticized in a few commentaries, generated a debate in literature and were followed by further experimental studies from various laboratories. Toxic doses of Gelsemium cause neurological signs characterized by marked weakness and convulsions, while ultra-low doses or high Homeopathic dilutions counteract seizures induced by lithium and pilocarpine, decrease anxiety after stress and increases the anti-stress allopregnanolone hormone, through glycine receptors. Low (non-Homeopathic) doses of this plant or its alkaloids decrease neuropathic pain and c-Fos expression in mice brain and oxidative stress. Due to the complexity of the matter, several aspects deserve interpretation and the main controversial topics, with a focus on the issues of high dilution pharmacology, are discussed and clarified. PMID- 29428606 TI - Influence of ward round order on critically ill patient outcomes. AB - PURPOSE: To examine the effect of order in which patients are seen on an Intensive Care Unit (ICU) ward round on ICU length of stay (LOS), mortality and duration of mechanical ventilation. MATERIALS AND METHODS: Retrospective observational study in a tertiary metropolitan ICU over a 12month period. All patients who occupied the first and last three bed spaces of the ICU ward round, without having moved bed spaces during admission, were included. Separate analyses were performed for the absolute first and last patients. RESULTS: 681 patients were included. There was no difference in the primary outcome, ICU LOS [median (IQR) 50 (23-102) hours for the first three patients seen vs. 51 (25-110) hours for the last three patients, p=0.594]. No differences were found in any secondary outcomes (hospital LOS, ICU mortality or duration of mechanical ventilation). CONCLUSIONS: The order in which patients were seen on an ICU ward did not affect ICU LOS nor related outcomes. PMID- 29428607 TI - It is time for catheter ablation to be considered a first-line treatment option in patients with atrial fibrillation and heart failure. PMID- 29428608 TI - Identifying the key catastrophic variables of urban social-environmental resilience and early warning signal. AB - Pursuit of sustainability requires a systematic approach to understand a system's specific dynamics to adapt and enhance from disturbances in social-environmental systems. We developed a systematic resilience assessment of social-environmental systems by connecting catastrophe theory and probability distribution equilibrium. Catastrophe models were used to calculate resilience shifts between slow and fast variables; afterwards, two resilience transition modes ("Less resilient" or "More resilient") were addressed by using probability distribution equilibrium analysis. A tipping point that occurs in "Less resilient" system suggests that the critical resilience transition can be an early warning signal of approaching threshold. Catastrophic shifts were explored between the interacting social-environmental sub-systems of land use and energy (fast variables) and environmental pollution (slow variables), which also identifies the critical factors in maintaining the integrated social-environmental resilience. Furthermore, the early warning signals enable the adaptability of urban systems and their resilience to perturbations, and provide guidelines for urban social-environmental management. PMID- 29428609 TI - Concentrations of legacy and novel brominated flame retardants in indoor dust in Melbourne, Australia: An assessment of human exposure. AB - Polybrominated diphenyl ethers (PBDEs) and novel brominated flame retardants (NBFR) have been used in a range of polymers to inhibit the spread of fires but also have a propensity to migrate out of consumer materials and contaminate indoor dust. In this study, a total of 57 dust samples were collected from 12 homes, eight offices and eight vehicles in Melbourne, Australia and analysed for eight PBDEs (-28, -47, -99, -100, -153, -154, -183 and -209) and seven NBFRs (PBT, PBEB, HBB, EH-TBB, BEH-TEBP, BTBPE and DBDPE) to determine human exposure risks from dust ingestion. Samples were analysed using selective pressurized liquid extraction (S-PLE) and gas chromatography coupled to tandem mass spectrometry (GC-MS/MS). Legacy and replacement flame retardants were detected in all samples with overall ?PBDE concentrations ranging from 120 to 1700,000 ng/g (median 2100 ng/g) and ?NBFRs ranging from 1.1 to 10,000 ng/g (median 1800 ng/g). BDE-209 and DBDPE were the dominant compounds in dust samples, followed by congeners associated with commercial Penta-BDE formulations (-47, -99, -100, -153 and -154) and then EH-TBB of the FireMaster 550 and BZ-54 products. ?Penta-BDE concentrations were elevated in office samples compared with homes and vehicles, while EH-TBB and BDE-209 measured higher concentrations in vehicles compared with their respective levels in homes and offices. Risk assessment estimates revealed the majority of exposure to occur in the home for both adults and toddlers in the City of Melbourne. Generally, body weight adjusted exposure to PBDEs and NBFRs was predicted to be 1 to 2 orders of magnitude higher for toddlers than adults. Estimated rates of BDE-47, -99, -153 and -209 ingestion were each 2 orders of magnitude or more below the USEPA's prescribed oral reference dose values (RfDs) for typical exposure scenarios. However, exposure rates for BDE-47 and -99 reached as high as 52 and 95% of RfDs, respectively, for adults and 4.4 and 7.4%, respectively, for toddlers in high exposure scenarios. This study provides the first wide-ranging survey of NBFRs in indoor dust from homes, offices and vehicles in Australia and offers further evidence of human exposure to legacy and novel brominated flame retardants via dust ingestion. PMID- 29428610 TI - Performance and microbial community structure of a polar Arctic Circle aerobic granular sludge system operating at low temperature. AB - The aim of this work was to study the performance and microbial community structure of a polar Arctic Circle aerobic granular sludge (AGS) system operating at low temperature. Thus, an AGS bioreactor was operated at 7, 5 and 3 degrees C of temperature using a cold-adapted sludge from Lapland. At 5 degrees C, it yielded acceptable conversion rates, in terms of nitrogen, phosphorous, and organic matter. However, under 3 degrees C a negligible nitrogen and phosphorous removal performance was observed. Below 5 degrees C, scanning electron microscopy studies showed a wispy, non-dense and irregular granular structure with a strong outgrowth of filamentous. Moreover, Illumina next-generation sequencing showed a heterogeneous microbial population where SM1K20 (Archaea), Trichosporon domesticum (Fungus), and Zooglea, Arcobacter and Acinetobacter (Bacteria) were the dominant phylotypes. Our study suggests that AGS technologies inoculated with North Pole sludge could be operated, in cold regions for a period longer than 3 months (winter season) under 5 degrees C of water temperature. PMID- 29428611 TI - High-level expression of an engineered beta-mannanase (mRmMan5A) in Pichia pastoris for manno-oligosaccharide production using steam explosion pretreated palm kernel cake. AB - An engineered beta-mannanase (mRmMan5A) from Rhizomucor miehei was successfully expressed in Pichia pastoris. Through high cell density fermentation, the expression level of mRmMan5A reached 79,680 U mL-1. The mRmMan5A showed maximum activity at pH 4.5 and 65 degrees C, and exhibited high specific activities towards mannans. To produce manno-oligosaccharides, palm kernel cake (PKC) was pretreated by steam explosion at 200 degrees C for 7.5 min, and then hydrolyzed by mRmMan5A. As a result, the total manno-oligosaccharide yield reached 34.8 g/100 g dry PKC, indicating that 80.6% of total mannan in PKC was hydrolyzed. Moreover, the kilo-scale production of manno-oligosaccharides was carried out to verify the feasibility of mass production. A total of 261.3 g manno oligosaccharides were produced from 1.0 kg of dry PKC. An effective beta mannanase for the bioconversion of mannan-rich biomasses and an efficient method for the production of manno-oligosaccharides from PKC are provided in this paper. PMID- 29428612 TI - Spirulina cultivated under different light emitting diodes: Enhanced cell growth and phycocyanin production. AB - This study evaluated light emitting diodes (LEDs) as a light source in Spirulina sp. LEB 18 cultures in terms of growth parameters and biomass composition. Different photoperiods (partial and integral) and colors (blue, green, red and white) were assessed. Blue, green, red and white LEDs increased biomass productivity and maximum specific growth rate of such cultivations. The maximum biomass concentration (1.77 +/- 0.02 g L-1) was obtained when red LEDs in integral light photoperiod were applied to cultivations. The biomass composition showed around 12.8% carbohydrates (w w-1), 57.4% proteins (w w-1) and 12.7% lipids (w w-1). The major fatty acids produced during cultivations were palmitic, linoleic and gamma-linolenic. Green LEDs in partial light photoperiod promoted a higher concentration of phycocyanin (126.39 mg gbiomass-1). The potential of LEDs as an energy source in Spirulina sp. LEB 18 cultures was demonstrated by the biomass and bioproducts photostimulation. PMID- 29428613 TI - Impact of temperature and substrate concentration on degradation rates of acetate, propionate and hydrogen and their links to microbial community structure. AB - The present study investigates the conversion of acetate, propionate and hydrogen consumption linked to the microbial community structure and related to temperature and substrate concentration. Biogas reactors were continuously fed with coffee powder (20 g-COD/L) or acetate (20, 40, and 60 g-COD/L) and operated for 193 days at 37 degrees C or 55 degrees C conditions. Starting HRT was 23 days which was then reduced to 7 days. The kinetics of acetate and propionate degradation and hydrogen consumption rates were measured in batch assays. At HRT 7 days, the degradation rate of propionate was higher in thermophilic batches, while acetate degradation rate was higher at mesophilic conditions. The gaseous hydrogen consumption in acetate reactors increased proportionally with temperature and substrate concentration, while the dissolved hydrogen was not affected. The relative high abundance of hydrogentrophic methanogens indicated that the methanogenesis was directed towards the syntrophic acetate oxidation pathway at high acetate concentration and high temperature. PMID- 29428614 TI - Investigating pyrolysis characteristics of moso bamboo through TG-FTIR and Py GC/MS. AB - This study was carried out to investigate pyrolysis characteristics of moso bamboo (Phyllostachys pubescens), including outer layer (OB), middle layer (MB) and inner layer (IB) and bamboo leaves (BL), through TG-FTIR and Py-GC/MS. The results showed that 70% of weight loss occurred at rapid pyrolysis stage with temperature of 200-400 degrees C. With increase in heating rate, pyrolysis process shifted toward higher temperature. IB, OB, MB and BL had a different activation energy at different conversion rates. BL had a higher activation energy than IB, OB and MB. The volatiles of bamboo was complicated with 2-30 of C atoms. IB, OB and MB mainly released benzofuran, hydroxyacetaldehyde and 2 Pentanone. BL released furan, acetic acid and phenol. The main pyrolysis products included H2O, CH4, CO2, CO, carboxylic acids, NO, NO2. Pyrolysis products of IB was the most and that of BL was the lowest. MB had the lowest pyrolysis temperature. PMID- 29428615 TI - Potential of hydrolyzed polyacrylamide biodegradation to final products through regulating its own nitrogen transformation in different dissolved oxygen systems. AB - Potential of hydrolyzed polyacrylamide (HPAM) biodegradation to final products was studied through regulating its own nitrogen transformation. Under the conditions of 2, 3 and 4 mg/L of DO, HPAM removal ratio reached 16.92%, 24.51% and 30.78% and the corresponding removal ratio reached 49.15%, 60.25% and 76.44% after anaerobic biodegradation. NO3--N concentration was 9.43, 14.10 and 17.99 mg/L in aerobic stages and the corresponding concentration was 0.17, 0.07 and 0.008 mg/L after anaerobic biodegradation. Oxygen as electron acceptors stimulated the activities of nitrification bacteria and other functional bacteria, thus further enhanced nitrification and HPAM biodegradation. NO3- (from HPAM oxidation) as electron acceptors stimulated the activities of nitrate reducing, acetate-producing and methanogenic microorganisms and they could form a synergistic effect on denitrification and methanogenesis. Thermodynamic opportunity window revealed that NOx- could accelerate anaerobic HPAM bioconversion to methane. Aerobic and anaerobic growth-process equations of cells verified that the metabolism on HPAM was feasible. PMID- 29428616 TI - Influence of reflux ratio on two-stage anoxic/oxic with MBR for leachate treatment: Performance and microbial community structure. AB - A lab-scale two-stage Anoxic/Oxic with MBR (AO/AO-MBR) system was operated for 81 days for leachate treatment with different reflux ratio (R). The best system performances were observed with a R value of 150%, and the average removal efficiencies of chemical oxygen demand, ammonia and total nitrogen were 85.6%, 99.1%, and 77.6%, respectively. The microbial community were monitored and evaluated using high-throughput sequencing. Proteobacteria were dominant in all process. Phylogenetic trees were described at species level, genus Thiopseudomonas, Amaricoccus, Nitrosomonas and Nitrobacter played significant roles in nitrogen removal. Co-occurrence analyzing top 20 genera showed that Nitrosomonas-Nitrobacter presented perfect positive relationship, as well as Paracoccus-Brevundimonas and Pusillimonas-Halobacteriovorax. PMID- 29428617 TI - Cytokines 2017 in Kanazawa: Looking beyond the horizon of integrated cytokine research from the sea of Japan. AB - At the 5th Annual meeting of the International Cytokine and Interferon Society held in Kanazawa, Japan from Oct. 29-Nov. 2 2017, new research was presented in the broad field of cytokine and interferon research. The meeting provided an outstanding platform for investigators in basic science and clinical research to communicate, share and discuss their recent findings in this fast moving area of research. PMID- 29428618 TI - Robustness of expression pattern formation due to dynamic equilibrium in gap gene system of an early Drosophila embryo. AB - The first manifestation of a segmentation pattern in the early Drosophila development is the formation of expression domains of genes belonging to the gap class. In our previous research the phenomenon of the gap system's robustness, exhibited as the ability to reduce highly variable gene expression in the course of development, was explained as a result of gene cross-regulation. In this paper we formulate the rigorous robustness conditions using the inherent properties of gap gene family. We propose an approach based on the observation that for the formation of a pattern with well-established domain borders it is necessary that there exist a stationary nucleus in which the gene expression level is almost constant in time. The dynamics of gap gene expression is described by a gene circuit model that correctly reproduces the observed principles of the border positioning. We take an advantage of the fact that the system behavior in a stationary nucleus is described by an algebraic equation and hence can be easily handled analytically. This enables us to explicitly characterize the gene cross regulation properties guaranteeing the system robustness through the spatial behavior of the patterning system along the main embryo axis. In particular, it is proved that if the total regulatory action of all the genes acting in the border formation area changes synchronously with the initial gene gradient, the system will filtrate the initial positioning error and action of highly variable external input factors. We will now show how this approach can be applied as an instrument for the analysis of the robustness mechanism and revealing new biological findings. PMID- 29428619 TI - Effect of dietary n-3 polyunsaturated fatty acid rich fish oil on the endometrial prostaglandin production in the doe (Capra hircus). AB - Recently, we showed that dietary supplementation of n-3 PUFA rich fish oil (FO) decreased the metabolites of serum prostaglandin (PG) F2alpha and E2 during the window of pregnancy recognition in the doe. In this study, we investigated its effect on the changes on endometrial PG production in vitro. Cycling does (n = 12) of Rohilkhand region were divided into two equal groups and fed a concentrate diet supplemented with either FO containing 26% n-3 PUFA (TRT; n = 6) or palm oil (CON; n = 6) @ 0.6 mL/kg body weight for 57 days. Estrus was synchronized by two injections of PGF2alpha analogue viz, on day 25 and 36 of supplementation and laparo-hysterotomy was performed to obtain endometrial tissue on day 16 of the synchronized estrus. Endometrial explant culture was done using a defined medium.The basal PG production was assayed at 6 and 12 h. Endometrial explant was stimulated with oxytocin (OXT) and/or recombinant ovine interferon tau (roIFN tau) and PGs were assayed at 3 and 12 h post-treatment. The relative expression of genes related to PG metabolism in the endometrium was done by Quantitative Real Time PCR technique (qRT-PCR). There was a significant (P < 0.05) decline in the basal production of PGF2alpha and PGE2 in the TRT as compared to the CON group. The cultured endometrial tissue produced PGF2alpha in a time- dependent fashion in both the groups (P < 0.05). Neither OXT nor roIFN-tau had a significant (P > 0.05) effect on the PGF2alpha and PGE2 production in the TRT group. Similarly, the PG production in the OXT and roIFN-tau was comparable with the control in TRT. Expression of mRNA for cyclooxygenase-2 (COX-2), cytosolic phospholipase A2 (cPLA2) and PGF synthase (PGFS) was lower (P < 0.05) whereas, PGE synthase and peroxisome proliferator-activated receptors such as PPAR-gamma and delta was increased (P < 0.05) in n-3 PUFA fed doe. In conclusion, dietary supplementation of FO decreased the endometrial production of PGF2alpha and PGE2 by downregulating the COX-2, cPLA2 and PGFS transcripts in the doe. The findings suggest that n-3 PUFA influence embryo survival by modulating the endometrial PG. PMID- 29428620 TI - Postoperative Chylothorax After Thoracoabdominal Aortic Aneurysm Repair. AB - Chylothorax is a potentially deadly complication that can occur after thoracoabdominal aortic aneurysm (TAAA) repair. We describe our contemporary experience (2005-2014) with this complication, our efforts to identify perioperative variables associated with it, and our attempts to assess treatment outcomes. We reviewed the records of 1092 consecutive patients who underwent TAAA repair between 2005 and 2014. Standard bivariate analysis was used to test for between-group differences. Eleven patients (0.9%) developed postoperative chylothorax. Nonoperative management was used in 8 of these patients (73%); 1 patient died after a lengthy hospital stay (297 days). The other 3 patients required thoracotomy with direct ligation; 1 of these patients required a second operation. Patients who developed chylothorax appeared to be similar to other patients in age, sex, extent of aneurysm, and metabolic or cardiovascular comorbidities. Patients who developed postoperative chylothorax were more likely to require drainage of a pleural effusion (P = 0.005), tracheostomy (P = 0.02), and longer stays in the intensive care unit (median, 6 [2-24] days, P < 0.001) and the hospital (median, 35 [24-88] days, P = 0.001), and these patients were more likely to develop a graft infection (n = 2, P < 0.001). The extent of TAAA repair (Crawford I-IV), reoperation, and clamping proximal to the left subclavian artery were not significantly associated with postoperative chylothorax. Chylothorax after TAAA repair can often be managed nonoperatively. Development of postoperative chylothorax may lead to significant morbidity, longer hospitalization, and increased likelihood of graft infection. PMID- 29428621 TI - The Congenital Heart Surgeon's Society Complete Atrioventricular Septal Defect Cohort: Baseline, Preintervention Echocardiographic Characteristics. AB - Quantifying unbalance, the threshold for single ventricle palliation vs biventricular repair in patients with unbalanced complete atrioventricular septal defect (AVSD), is challenging. Using a core laboratory review of baseline echocardiograms, we sought to assess the correlations among commonly used measures of unbalance and common atrioventricular valve (AVV) and ventricular sizes. A single reviewer evaluated baseline echocardiograms from an inception cohort of babies < age 1 year with complete AVSD admitted to 1 of 25 Congenital Heart Surgeon's Society institutions. A standardized echo review protocol of 111 quantitative and qualitative measures was used. Descriptive statistics were computed and Pearson correlation coefficients were calculated to assess correlation among unbalance indices with valvar and ventricular dimensions. Two hundred fifty-seven baseline echocardiograms of infants with complete AVSD were included. Median age at baseline echocardiogram was 11days (interquartile range 1 79) and mean atrioventricular valve index was 0.45 +/- 0.1. Mean right ventricle/left ventricle inflow angle was 90.2 +/- 15.6 degrees and median left ventricular inflow index was 0.46 (interquartile range 0.4-0.5). There are weak or moderate correlations between the measures of unbalance. Correlations between the measures of unbalance with common AVV leaflet or ventricular sizes are also weak to moderate, when statistically significant. Measures of unbalance in common clinical use correlate poorly, or not at all, with one another, common AVV, and ventricular dimensions. The concept of "unbalance" is difficult to define using baseline echocardiographic indices. These findings suggest that the indices may describe different morphologic and functional characteristics. Further analysis is necessary to quantify the contributions of unbalance indices to patient outcome. PMID- 29428622 TI - Targeted Increase in Pulmonary Blood Flow in a Bidirectional Glenn Circulation. AB - In patients with a Glenn shunt and unilateral pulmonary vascular abnormalities, supplemental pulmonary blood flow may improve antegrade flow in the target lung and may permit eventual Fontan completion, while mitigating the risks of uncontrolled additional flow to the contralateral lung. We attempted this by inserting a small aortopulmonary shunt into the affected pulmonary artery and banding the central pulmonary artery. We performed a retrospective review of all patients who underwent this procedure from 2000 to 2015. Comparisons of nonparametric variables were performed with the Wilcoxon signed rank test. Twenty patients were followed for a median of 36 months. Vascular abnormalities included recalcitrant unilateral pulmonary arterial (n = 8) or venous (n = 5) obstruction or hypoplasia, combined disease (n = 4), or abundant aortopulmonary collaterals (n = 3). Nine had retrograde flow from the affected lung. The most frequent complications were pleural effusions (n = 4) and shunt thrombosis (n = 4). Postoperatively, all patients demonstrated antegrade flow to the target lung at the earliest postoperative catheterization. Glenn pathway pressures and saturations were unchanged, whereas the shunted pulmonary arterial oxygen saturation and pressure increased by 4% (P = 0.04) and 6 mm Hg (P = 0.04), respectively. Three patients died; 9 achieved definitive palliation, 4 were deemed to have no improvement, and 4 continue to have a contralaterally shunted Glenn at this time. Targeted additional pulmonary blood flow may be useful for the palliation of single ventricle patients with abnormal pulmonary vasculature. However, morbidity and mortality are common in this high-risk population. PMID- 29428623 TI - Modified Repair of Type I and II Truncus Arteriosus Limits Early Right Ventricular Outflow Tract Reoperation. AB - Repair of truncus arteriosus often requires early right ventricular outflow tract (RVOT) reoperation. Using a modified repair, the branch pulmonary arteries are left in situ, which may avoid earlier RVOT reoperation. We hypothesized that our modified repair for type I and II truncus arteriosus would extend the time to RVOT reoperation. Infants with truncus arteriosus were divided into 2 groups: (1) traditional technique where the branch pulmonary arteries are excised from the truncal root, or (2) modified repair where the branch pulmonary arteries are left in situ and septated from the truncal root. Regardless of the approach, a bioprosthetic conduit or homograft was used to establish right ventricular to pulmonary artery continuity. Follow-up pulmonary artery angiograms were used to assess for branch pulmonary artery stenosis. From 54 infants (modified repair: 33, traditional technique: 21), there were no significant differences in age at repair, gender, or type of truncus arteriosus. With 100% follow-up, use of the modified repair resulted in a lower rate of branch pulmonary artery stenosis, and greater freedom from surgical branch pulmonary arterioplasty. Five- and 10-year freedom from RVOT reoperation (5 years: modified-81.5% vs traditional-30.5%, P = 0.004; 10 years: modified-53.3% vs traditional-30.5%, P = 0.01) favored the modified repair. Cox regression analysis demonstrated that the modified repair was associated with an independently lower risk for RVOT reoperation (hazard ratio: 0.08, confidence interval: 0.01, 0.75, P = 0.02). Thus, maintaining the branch pulmonary artery architecture resulted in greater freedom from RVOT reoperation. PMID- 29428624 TI - Current Readings: An Update on Prevention and Management of Atrial Fibrillation Post Cardiac Surgery. AB - Atrial fibrillation (afib) remains the most common complication following cardiac surgery and is associated with increased mortality and resource utilization. As increasing number of patients with multiple comorbidities undergo cardiac surgery, and, given the overall burden of afib in the perioperative setting, there is growing interest among clinicians to improve diagnosis and management of afib among cardiac surgery patients. Advances in technology, refinements in surgical techniques, and innovations in drug development also contributed to this changing landscape. Despite the promising results of recently published studies on afib management following cardiac surgery, afib remains a complex problem with various presentations. Although myriad medical and surgical therapies for high risk patients exist, determining patient-specific optimal treatment can be difficult. Understanding the context and relevance of contemporary studies is therefore critical to ensure appropriate patient selection and reduction of overall morbidity and mortality. This review closely examines 5 timely articles that delineate the most important results in the management of afib after cardiac surgery in the current era. PMID- 29428625 TI - Anterior versus posterior approaches for thoracic disc herniation: Association with postoperative complications. AB - OBJECTIVE: Thoracic disc herniations (TDH) represent 1.5-4% of all intervertebral disc herniations. Surgical treatment can be divided into anterior, lateral and posterior approaches and is an area of contention in the literature. Available evidence consists mostly of single-arm, single-institutional studies with limited sample sizes. The objective of this study is to investigate 30-day surgical outcomes following excision of TDH utilizing a national surgical registry. PATIENTS AND METHODS: The American College of Surgeons - National Surgical Quality Improvement Program (ACS-NSQIP) was queried for cases that underwent anterior (thoracotomy or thoracoscopy), lateral (extracavitary or costotransversectomy) or posterior (transpedicular or laminectomy) surgery for a primary diagnosis of TDH between 2012 and 2015. RESULTS: A total of 388 patients (48% females) were included in the analysis. An anterior approach was used in 65 patients, lateral approach in 34, transpedicular approach in 90 and laminectomy in 199. Overall, baseline demographics and clinical characteristics were similarly distributed between the four procedure groups. Patients undergoing an anterior approach spent, on average, 2-3 more days in the hospital compared to the other groups (p < .001). Furthermore, they were more likely to have developed a major complication (27%) compared to the lateral (8%), transpedicular (18%) or laminectomy group (14%) (p = .13). Unplanned 30-day readmission and return to the operating room occurred in 5-8% of patients (p = .69 and 0.63, respectively). Lastly, the majority of the patients were discharged to home or a home facility (anterior-74%; lateral-81%; transpedicular-68% and laminectomy-74%, p = .58). CONCLUSION: Anterior approaches had longer LOS and higher, although not statistically significant, complication rates. No difference was found with regard to discharge disposition. In light of these findings, surgeons should weigh the risks and benefits of each surgical technique during tailoring of decision making. PMID- 29428626 TI - [Feedback strategies for routine surveys of quality indicators in outpatient oncology care]. AB - OBJECTIVES: The study deals with the efficiency and possible improvements of quality promotion with quality indicators (QI). The goal is to investigate the practical use of feedback from QI surveys in the field of oncology office practices. It captures both the acceptance of results and the independent initiation of search- and improvement strategies. The value of best practice examples is of further interest. METHODS: Within one year, data of six QI of 31 physicians from 24 oncology practices were collected twice and the results were sent back in individual reports including a benchmarking. Practices with particularly good results in individual QI sectors were surveyed in semi structured telephone interviews about their processes. Based on these results, best practice examples were created and provided to all participating practices to stimulate improvement. Further, two paper-based surveys about the acceptance and handling of results as well as the use of best practice examples were conducted. RESULTS: The practices accepted the reported results as an instrument to assess their own care quality (70 %) and indicated that had been able to identify improvement potentials (75 %). Improvement strategies were developed or planned by approximately every second practice in the respective sectors. The practices were interested in the best practice examples and rated them as helpful (70 %). Many of them indicated that they were already taking up some of the suggestions for improving the organization of their own processes or were planning to do so. CONCLUSION: The extraction of information on QI from patient files is a tedious task for the practices. Both the implementation of the necessary internal measures after receiving the results report as well as the adaptation of external process examples to their own processes is challenging. Nevertheless, oncology practices benefit from the feedback of the results of QI surveys and best practice examples. Thus, QI surveys and the reporting of results can actively encourage quality development. PMID- 29428627 TI - [Competency requirements for executives in healthcare and social services organizations: Results of a Delphi study]. AB - BACKGROUND: Leadership in social services and healthcare organizations is marked by high levels of complexity and contradiction, which cannot be fully explained by politically, economically, and socially induced changes. Rather, it is the particularities of service provision in healthcare and social services that confront executives with specific demands. OBJECTIVE: This study aimed to capture and prioritize required leadership competencies in healthcare and social services organizations. METHODS: A three-step Delphi study was conducted with executives and managerial staff, who are job holders and thus experts on their occupation. For the first step, an explorative qualitative approach was chosen to record general opinion without prior assumptions. The following two steps weighted and selected the competency requirements in step one using rating- and ranking procedures. RESULTS: Results of the Delphi inquiry imply high relevance of social and personal competencies. Approximately 66 % of the competencies assessed in round three were social and personal competencies. 12 out of the 15 highest rated competencies in Delphi step three can be assigned to these two competency categories. In contrast, the importance of professional as well as methodical competencies was rated as less important. Only two methodical competencies and one professional competency were rated as very important by the panel. Nevertheless, the importance of executive professional and methodical competencies in healthcare and social services organizations is emphasized by high ratings of the competencies "Sector-specific expertise" and "Analytical skills". The methodical competency "Analytical skills" was identified by the Delphi respondents as the most important competency requirement. CONCLUSION: Social and personal requirements are of primary importance for leadership in healthcare and social services organizations. These results mostly correspond to leadership requirements posited in the literature on leadership skills. Emphasis should be on the specific relevance of professionalism, which can be traced back to the high proportion of professional activities in everyday working practices, the self-conception of executive staff based on professional qualifications and profession as well as the organizational form as expert organization. Healthcare and social services organizations are expert organizations with a strong emphasis on professional expertise. Professional knowledge is the most important means of production of expert organizations and imperative to leadership in healthcare and social services organization, given the high integration of executives into the professional system. Despite the dominance of social and personal competency requirements, the most important competency requirement is "Analytical skills", which can be described as the basis of every action. PMID- 29428629 TI - Reply by Authors. PMID- 29428630 TI - Re: The Effect of Metformin Use during Docetaxel Chemotherapy on Prostate Cancer Specific and Overall Survival of Diabetic Patients with Castration Resistant Prostate Cancer: M. J. Mayer, L. H. Klotz and V. Venkateswaran J Urol 2017;197:1068-1075. PMID- 29428628 TI - Advances in understanding neural mechanisms of social dominance. AB - Dominance hierarchy profoundly impacts social animals' survival, physical and mental health and reproductive success. As the measurements of dominance hierarchy in rodents become established, it is now possible to understand the neural mechanism mediating the intrinsic and extrinsic factors determining social hierarchy. This review summarizes the latest advances in assay development for measuring dominance hierarchy in laboratory mice. It also reviews our current understandings on how activity and plasticity of specific neural circuits shape the dominance trait and mediate the 'winner effect'. PMID- 29428632 TI - Reply by Authors. PMID- 29428631 TI - Re: Testicular Adrenal Rest Tumors in Boys and Young Adults with Congenital Adrenal Hyperplasia: M. S. Kim, F. Goodarzian, M. F. Keenan, M. E. Geffner, C. M. Koppin, R. E. De Filippo and P. J. Kokorowski J Urol 2017;197:931-936. PMID- 29428633 TI - Re: Urinary DNA Methylation Biomarkers for Noninvasive Prediction of Aggressive Disease in Patients with Prostate Cancer on Active Surveillance: F. Zhao, E. Olkhov-Mitsel, T. van der Kwast, J. Sykes, D. Zdravic, V. Venkateswaran, A. R. Zlotta, A. Loblaw, N. E. Fleshner, L. Klotz, D. Vesprini and B. Bapat J Urol 2017;197:335-341. PMID- 29428634 TI - Reply by Authors. PMID- 29428635 TI - Re: Robotic versus Open Level I-II Inferior Vena Cava Thrombectomy: A Matched Group Comparative Analysis: L. Gu, X. Ma, Y. Gao, H. Li, X. Li, L. Chen, B. Wang, Y. Xie, Y. Fan and X. Zhang J Urol 2017;198:1241-1246. PMID- 29428636 TI - Reply by Authors. PMID- 29428637 TI - Re: Prognostic Value of PD-1 and PD-L1 Expression in Patients with High Grade Upper Tract Urothelial Carcinoma: L. M. Krabbe, B. Heitplatz, S. Preuss, R. C. Hutchinson, S. L. Woldu, N. Singla, M. Boegemann, C. G. Wood, J. A. Karam, A. Z. Weizer, J. D. Raman, M. Remzi, N. Rioux-Leclercq, A. Haitel, L. M. Rapoport, P. V. Glybochko, M. Roscigno, C. Bolenz, K. Bensalah, A. I. Sagalowsky, S. F. Shariat, Y. Lotan, E. Xylinas and V. Margulis J Urol 2017;198:1253-1262. PMID- 29428639 TI - Speeding in highway work zone: An Evaluation of methods of speed control. AB - Highway workers frequently work in close proximity of live traffic in highway work zones, traffic accidents therefore have devastating effects on worker safety. In order to reduce the potential for such accidents, methods involving use of advisory signs and police presence have been used to mitigate accident risks and improve safety for highway workers. This research evaluates the magnitude of the speeding problem in highway work zones and the effects of four levels of police presence on improving work zone safety. Speed data were collected in six different work zone locations in northern and southern California and used to determine the magnitude and nature of speeding problem in highway work zones. In addition data were collected over 11 test-days in four work zones with four levels of police presence: radar speed display with police decal and lighting, passive use of a police vehicle with radar speed display, passive use of a police vehicle without radar speed display, and active police speed enforcement near work zones. This paper analyzes this data using statistical methods to evaluate the effectiveness of these different methods of speed control on the safety of the work zone. Four Measures of Effectiveness (MOE) were used in this evaluation consisting of average speed reduction, speed variance, 85th percentile speed, and proportion of high speed vehicles. The results indicate that all levels of police presence provided statistically significant improvements in one or more of the MOEs. PMID- 29428640 TI - The traffic climate in China: The mediating effect of traffic safety climate between personality and dangerous driving behavior. AB - Traffic safety climate is defined as road users' attitudes and perceptions of traffic in a specific context at a given point in time. The current study aimed to validate the Chinese version of the Traffic Climate Scale (TCS) and to explore its relation to drivers' personality and dangerous driving behavior. A sample of 413 drivers completed the Big Five Inventory (BFI), the Chinese version of the TCS, the Dula Dangerous Driving Index (DDDI) and a demographic questionnaire. Exploratory factor analysis and confirmatory factor analysis were performed to confirm a three-factor (external affective demands, internal requirements and functionality) solution of the TCS. The reliability and validity of the Chinese version of TCS were verified. More importantly, the results showed that the effect of personality on dangerous driving behavior was mediated by traffic climate. Specifically, the functionality of the TCS mediated the effect of neuroticism on negative cognitive/emotional driving and drunk driving, while openness had an indirect impact on aggressive driving, risky driving and drunk driving based on the internal requirements of the TCS. Additionally, agreeableness had a negative direct impact on four factors of the DDDI, while neuroticism had a positive direct impact on negative cognitive/emotional driving, drunk driving and risky driving. In conclusion, the Chinese version of the TCS will be useful to evaluate drivers' attitudes towards and perceptions of the requirements of traffic environment in which they participate and will also be valuable for comparing traffic cultures and environments in different countries. PMID- 29428638 TI - Elevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation. AB - Arterial stiffness plays a causal role in development of systolic hypertension. 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome P450 (CYP450)-derived arachidonic acid metabolite, is known to be elevated in resistance arteries in hypertensive animal models and loosely associated with obesity in humans. However, the role of 20-HETE in the regulation of large artery remodeling in metabolic syndrome has not been investigated. We hypothesized that elevated 20 HETE in metabolic syndrome increases matrix metalloproteinase 12 (MMP12) activation leading to increased degradation of elastin, increased large artery stiffness and increased systolic blood pressure. 20-HETE production was increased ~7 fold in large, conduit arteries of metabolic syndrome (JCR:LA-cp, JCR) vs. normal Sprague-Dawley (SD) rats. This correlated with increased elastin degradation (~7 fold) and decreased arterial compliance (~75% JCR vs. SD). 20 HETE antagonists blocked elastin degradation in JCR rats concomitant with blocking MMP12 activation. 20-HETE antagonists normalized, and MMP12 inhibition (pharmacological and MMP12-shRNA-Lnv) significantly improved (~50% vs. untreated JCR) large artery compliance in JCR rats. 20-HETE antagonists also decreased systolic (182 +/- 3 mmHg JCR, 145 +/- 3 mmHg JCR + 20-HETE antagonists) but not diastolic blood pressure in JCR rats. Whereas diastolic pressure was fully angiotensin II (Ang II)-dependent, systolic pressure was only partially Ang II dependent, and large artery stiffness was Ang II-independent. Thus, 20-HETE dependent regulation of systolic blood pressure may be a unique feature of metabolic syndrome related to high 20-HETE production in large, conduit arteries, which results in increased large artery stiffness and systolic blood pressure. These findings may have implications for management of systolic hypertension in patients with metabolic syndrome. PMID- 29428641 TI - Interpreting interaction effects in estimates of the risk of traffic injury associated with the use of illicit drugs. AB - Interactions characterise the relationship between use of amphetamines, cannabis and opiates as a driver and the risk of traffic injury associated with the use of these drugs. Inverse risk curves have been found for these drugs, meaning that the higher the proportion of drivers in normal traffic testing positive for the drugs, the lower is the increase in risk associated with them. The inverse risk curves can arise in many ways. The paper discusses ten different interpretations of the curves; seven of these are methodological and claim that the risk curves are statistical artefacts. Some support for these interpretations is found; however, this does not rule out that substantive interpretations, proposing causal mechanisms underlying the curves may also be correct. Unfortunately, there is insufficient evidence to assess the support for the substantive interpretations. There is, accordingly, a large element of uncertainty about how the inverse risk curves arise and whether they can be modified. PMID- 29428642 TI - Dual inhibition of mTORC1/2 by DCZ0358 induces cytotoxicity in multiple myeloma and overcomes the protective effect of the bone marrow microenvironment. AB - Interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes the proliferation, survival and chemoresistance of MM. The mTOR pathway plays a key role in these undesirable BM microenvironment mediated events. We synthesized a novel alkaloid compound, DCZ0358, that effectively inhibits mTOR signaling via dual mTORC1/2 inhibition and exhibits potent anti-MM activity in cultured and primary MM cells, as well as a MM xenograft model but has little effect on normal cells. Importantly, we show that this compound can block the BM stromal cell-mediated activation of mTOR/Akt signaling and antagonizes the protective effect of the BM microenvironment. Moreover, DCZ0358 abrogates the bortezomib-triggered activation of Akt, leading to the synergism of DCZ0358 and bortezomib in MM cells. Taken together, our results provide the proof-of-concept for clinical evaluation of DCZ0358, alone or in combination, as an anti-MM agent in MM therapy. PMID- 29428643 TI - Drug testing and characterization using human-on-chip (HoC) systems: some thoughts on the application of in vitro-in vivo correlation. PMID- 29428644 TI - SERS study of riboflavin on green-synthesized silver nanoparticles prepared by reduction using different flavonoids: What is the role of flavonoid used? AB - Spectroscopy of surface-enhanced Raman scattering (SERS) is nowadays widely used in the field of bio-science and medicine. These applications require new enhancing substrates with special properties. They should be non-toxic, environmentally friendly and (bio-) compatible with examined samples. Flavonoids are natural antioxidants with many positive effects on human health. Simultaneously, they can be used as reducing agent in preparation procedure of plasmonic enhancing substrate for SERS spectroscopy. The best amplifiers of Raman vibrational spectroscopic signal are generally silver nanoparticles (AgNPs). In this study, several flavonoids (forming a logical set) were used as reducing agent in AgNPs preparation procedures. Reactivity of 10 structurally arranged flavonoids (namely flavone, chrysin, apigenin, luteolin, tricetin, 3 hydroxyflavone, galangin, kaempferol, quercetin and myricetin) was compared and SERS-activity of prepared AgNPs was tested using model analyte riboflavin. Riboflavin was detected down to concentration 10-9mol/l. PMID- 29428645 TI - Risk management of hazardous substances in a circular economy. AB - The ambitions for a circular economy are high and unambiguous, but day-to-day experience shows that the transition still has many difficulties to overcome. One of the current hurdles is the presence of hazardous substances in waste streams that enter or re-enter into the environment or the technosphere. The key question is: do we have the appropriate risk management tools to control any risks that might arise from the re-using and recycling of materials? We present some recent cases that illustrate current practice and complexity in the risk management of newly-formed circular economy chains. We also highlight how separate legal frameworks are still disconnected from each other in these cases, and how circular economy initiatives interlink with the European REACH regulation. Furthermore, we introduce a novel scheme describing how to decide whether a(n)(additional) risk assessment is necessary with regard to the re-use of materials containing hazardous substances. Finally, we present our initial views on new concepts for the fundamental integration of sustainability and safety aspects. These concepts should be the building blocks for the near future shifts in both policy frameworks and voluntary initiatives that support a sound circular economy transition. PMID- 29428646 TI - Adsorption of phenanthrene by earthworms - A pathway for understanding the fate of hydrophobic organic contaminants in soil-earthworm systems. AB - The fate of hydrophobic organic contaminants (HOCs) in soil-earthworm systems is an important foundation for soil pollution risk assessment and pollution control. Equilibrium partitioning is considered to be the main mechanism by which HOCs enter earthworms and, as such, a mechanistic model has been developed to estimate the earthworm-water partition coefficients (Kw-w). In the present study, the adsorption of phenanthrene (PHE) by earthworm tissue was investigated to evaluate the validity of the mechanistic models. Results revealed that Kw-w derived from the mechanistic model (346.90) was lower than that derived from the sorption experiments (410.76), indicating that apart from lipid fractions, other components in earthworms, such as protein fractions, might also play an important role in the adsorption of HOCs by earthworm. Besides, the difference between the mechanistic model for earthworm and partition-limited model used for plants are few, indicating that uptake and accumulation mechanisms of HOCs by earthworms and plants are highly consistent internally and are, essentially actually identical. It is also suggested that environmental fate of HOCs in soil-soil biota systems is dominated by their high hydrophobicity. Based on these conclusions, an improved mechanistic model for predicting the uptake of organic contaminants by earthworms has been proposed, which needs to be further evaluated. Furthermore, the feasibility of using vermiaccumulation in vermiremediation of soil contaminated by HOCs was discussed. The adsorption of PHE by earthworm sub organism fractions (pre-clitellum, clitellum and post-clitellum) and tissue fractions (body wall and gut) were also investigated to interpret the distribution pattern of HOCs in earthworms. At the sub-organism level, the adsorption capacity of PHE by different regions of the earthworm followed the order: post-clitellum > clitellum > pre-clitellum, meaning the distribution of PHE along the earthworm contributes not only to their chemical composition but also to the life activity of earthworms such as circular system. At the tissue level, the gut showed greater affinity with PHE than that of the body wall indicating that the distribution of PHE is mainly due to chemical components at the tissue levels. These results might provide additional understanding of the fate of HOCs in soil-earthworm systems. PMID- 29428647 TI - Overview of As(V) adsorption on Zr-functionalized activated carbon for aqueous streams remediation. AB - The present work introduces a simple methodology of carbon modification with zirconium, using an organic complexing ligand, as efficient media for selective As(V) removal. It is hypothesized that the incorporation of Zr-nanoparticles improves the attraction of anionic species such as arsenates (HAsO42-/H2AsO4-) making the material highly selective. The effects of pH (3-11) and temperature (15, 25 and 35 degrees C) were studied. Furthermore, potentiometric titrations, the effect of competing anions, thermodynamics, and adsorption kinetics were evaluated in order to clarify the rate-controlling process and the adsorption mechanism for arsenic removal. Results demonstrated that OH and COOH groups play an important role during the arsenic adsorption process; a small amount of Zr(IV) species (0.77%) increased the adsorption capacity of activated carbon in about a 43%. Thermodynamic analysis showed the spontaneous exothermic nature of the adsorption process was favored at lower temperatures. The presence of anions, such as chloride, sulfate, carbonate, nitrate and phosphate, did not affect the adsorption capacity, while kinetic studies demonstrated that the arsenic adsorption process in Zr-modified activated carbon is not exclusively controlled by intraparticle diffusion. PMID- 29428649 TI - Metals and metalloids treatment in contaminated neutral effluents using modified materials. AB - Circumneutral surface water and groundwater can contain hazardous concentrations of metals and metalloids that can threaten organisms in surrounding ecosystems. Extensive research has been conducted over the past two decades to prevent, limit, and treat water pollution. Among the currently available treatment options is the use of natural and residual materials, which is generally regarded as effective and inexpensive. The modification of such materials enhances the removal capacity of metals and metalloids, as well as the physical and chemical stability of the materials and resulting sludge (after treatment). This paper reviews several modified materials that have produced and evaluated in the past twenty years to treat various contaminants in water under specific conditions. Important factors on performance improvement following the modifications are emphasized. Sorption capacity and kinetics, and element removal mechanisms are also discussed. Element recovery, material regeneration, water reuse, evaluation of treatment efficiency for real effluents are also considered, as well as the applicability of these materials in both active and passive treatment systems. Modified natural and residual materials are a promising option for the treatment of metals and metalloids in circumneutral contaminated waters. However, further research is necessary to evaluate their field-scale performance and to properly assess treatment costs. PMID- 29428648 TI - National scale assessment of total trihalomethanes in Irish drinking water. AB - Ireland reported the highest non-compliance with respect to total trihalomethanes (TTHMs) in drinking water across the 27 European Union Member States for the year 2010. We carried out a GIS-based investigation of the links between geographical parameters and catchment land-uses with TTHMs concentrations in Irish drinking water. A high risk catchment map was created using peat presence, rainfall (>1400 mm) and slope (<5%) and overlain with a map comprising the national dataset of routinely monitored TTHM concentrations. It appeared evident from the map that the presence of peat, rainfall and slope could be used to identify catchments at high risk to TTHM exceedances. Furthermore, statistical analyses highlighted that the presence of peat soil with agricultural land was a significant driver of TTHM exceedances for all treatment types. PARAFAC analysis from three case studies identified a fluorophore indicative of reprocessed humic natural organic matter as the dominant component following treatment at the three sites. Case studies also indicated that (1) chloroform contributed to the majority of the TTHMs in the drinking water supplies and (2) the supply networks contributed to about 30 MUg L-1 of TTHMs. PMID- 29428650 TI - Multispecies benefits of wetland conservation for marsh birds, frogs, and species at risk. AB - Wetlands conserved using water level manipulation, cattle exclusion, naturalization of uplands, and other techniques under the North American Waterfowl Management Plan ("conservation project wetlands") are important for ducks, geese, and swans ("waterfowl"). However, the assumption that conservation actions for waterfowl also benefit other wildlife is rarely quantified. We modeled detection and occupancy of species at sites within 42 conservation project wetlands compared to sites within 52 similar nearby unmanaged wetlands throughout southern Ontario, Canada, and small portions of the adjacent U.S., using citizen science data collected by Bird Studies Canada's Great Lakes Marsh Monitoring Program, including 2 waterfowl and 13 non-waterfowl marsh-breeding bird species (n = 413 sites) and 7 marsh-breeding frog species (n = 191 sites). Occupancy was significantly greater at conservation project sites compared to unmanaged sites in 7 of 15 (47%) bird species and 3 of 7 (43%) frog species, with occupancy being higher by a difference of 0.12-0.38 across species. Notably, occupancy of priority conservation concern or at-risk Black Tern (Chlidonias niger), Common Gallinule (Gallinula galeata), Least Bittern (Ixobrychus exilis), Sora (Porzana carolina), and Western Chorus Frog (Pseudacris triseriata) was significantly higher at conservation project sites compared to unmanaged sites. The results demonstrate the utility of citizen science to inform wetland conservation, and suggest that actions under the North American Waterfowl Management Plan are effective for conserving non-waterfowl species. PMID- 29428651 TI - The effects of transboundary air pollution following major events in China on air quality in the U.S.: Evidence from Chinese New Year and sandstorms. AB - Transboundary air pollution is a global environmental and public health problem including in the U.S., where pollution emissions from China, the largest emitter of anthropogenic air pollution in the world, can travel across the Pacific Ocean and reach places like California and Oregon. We examine the effects of transboundary air pollution following major events in China, specifically sandstorms, a natural-occurring source of air pollution, and Chinese New Year, a major 7-day holiday, on background air quality in the U.S. We focus on high elevation sites on the west coast between 2000 and 2013. We use regression analysis and a natural experiment to exploit the variation in the timing of these events in China, which are plausibly uncorrelated to other factors that affect air quality in China and the U.S. We find that sandstorms are associated with statistically significant increases in background coarse and fine particulate matter (PM) in the U.S., representing between 16 and 39% of average weekly PM levels. We also find Chinese New Year is associated with modest reductions in background air quality in the U.S., representing between 0.4 and 2.5% of PM levels. Findings are robust to different models and falsification tests. These results suggest that regression analysis could be a powerful tool to complement other, more widely used techniques in the environmental sciences that study this problem. This also has important implications for policymakers, who could track major sandstorms in China and prepare for possible increased foreign pollution emissions in the U.S. PMID- 29428652 TI - Novel approach for the use of dairy industry wastes for bacterial growth media production. AB - This work proposes a novel approach for the reuse and the recovery of dairy wastes valuable components. Thermal coagulation was performed for dairy effluents and the main responsible fraction for the organic matter content (protein and fat) was separated. Dairy curds were prepared for the formulation of bacterial growth media. Protein, sugar, fat and fatty acids contents have been assessed. Samples treated at 100 degrees C exhibited marked improvement in terms of protein (25-50%) recovery compared to those treated at 80 degrees C. Fatty acid analysis revealed the presence of unsaturated fatty acids (mainly oleic acid) that are essential to promote Lactobacillus growth. Previously isolated and identified bacterial strains from dairy wastes (Lactobacillus paracasei, Lactobacillus plantarum, Lactococcus lactis and Lactobacillus brevis) were investigated for their ability to grow on the formulated media. All the tested lactic acid bacteria exhibited greater bacterial growth on the formulated media supplemented with glucose only or with both glucose and yeast extract compared to the control media. By reference to the commercial growth medium, the productivity ratio of the supplemented bactofugate (B) and decreaming (D) formulated media exceeded 0.6 for L. paracasei culture. Whereas, the productivity ratio of the supplemented B medium was greater than 1 compared to the control medium for all the tested strains. As for the supplemented D medium, its productivity ratio was greater than 1 compared to the control medium for both L. paracasei and L. plantarum strains. PMID- 29428653 TI - Performance and microbial shift during acidification of a real pharmaceutical wastewater by using an anaerobic sequencing batch reactor (AnSBR). AB - In this study, a lab-scale anaerobic sequencing batch reactor (AnSBR) was used for the acidification of a pharmaceutical wastewater sourced from etodolac chemical synthesis tanks. The effects of the organic loading rate (OLR), and etodolac and sulfate concentrations on the acidification rate and microbial community in AnSBR were investigated at 35 degrees C with a hydraulic retention time (HRT) of 37 h, a pH of 5, and OLRs up to 5.2 kgCOD/m3.day. The AnSBR accomplished a 60% acidification ratio and 50-60% etodolac removal at OLRs up to 2.6 kgCOD/m3.day. However, at OLR = 3.9 kgCOD/m3.day, acidification was not achieved due to sulfite inhibition; pre-ozonation was applied to overcome this sulfite inhibition. Although etodolac and COD removals were improved, the wastewater was not successfully acidified. Real-time polymerase chain reaction (Q PCR) and fluorescent in situ hybridization (FISH) analyses revealed that acidification was inhibited by the dominance of sulfate reducing bacteria (SRB) over acidification bacteria in the AnSBR. However, increasing the OLR to 5.2 kgCOD/m3.day led to toxicity stress in the SRB due to increased sulfite concentrations. Sulfate load fundamentally affected acidification process and microbial community composition. The presence of etodolac with concentration up to 56 mg/L did not have a significant effect on VFA production and the microbial community. PMID- 29428654 TI - Power, influence and structure in Natura 2000 governance networks. A comparative analysis of two protected areas in Romania. AB - Successful management of complex social-ecological landscapes overlapping Natura 2000 sites requires collaboration between various actors such as law enforcement agencies, NGOs and enterprises. Natura 2000 governance is stimulated by central actors (e.g., Natura 2000 administrators), with successes and failures of management activities depending on the capacity of the network leader to implement a collaborative approach to environmental governance. By using social network analysis, we analysed the cooperation, information flow and capacity for collective action within Natura 2000 governance networks within two Romanian protected areas: Lower Siret Floodplain and Iron Gates Natural Park. The two networks represent protected areas managed by different types of organisations (i.e., Lower Siret Floodplain - by an NGO, Iron Gates Natural Park - by a public entity). Taking into consideration that NGOs may favour an adaptive co management, while the public bodies may take a top-down management approach, we hypothesize that Lower Siret Floodplain will have a more cohesive and collaborating network compared to Iron Gates Natural Park, and that there will be a greater representation of private and NGO sector in the network coordinated by Lower Siret Floodplain. Contrary to our expectations, the results show that collaboration patterns are similar in the two networks, although they are governed by two different types of institutions, both being less participative than expected, with low involvement of NGOs and private stakeholders. Furthermore, Lower Siret Floodplain network is surprisingly more centralized around a small number of public authorities, and the pre-existing power of public bodies likely inhibit the capacity of the NGO to collaborate with private stakeholders. We also found lower collaboration levels between actors in the network periphery with other organisations from the same cluster, denoting a clear top-down approach of the management in both networks. Our findings suggest that delegating the protected areas administration to NGOs, a solution to increase the use of co-management in protected areas, does not solve the poor representation of private stakeholders. PMID- 29428655 TI - Synthesis of Cr2O3/C3N4 composite for enhancement of visible light photocatalysis and anaerobic digestion of wastewater sludge. AB - Visible light photocatalysts of Cr2O3/C3N4 composites (with different melamine concentrations) were prepared by high temperature calcination method. The composites samples were characterized by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), scanning electron microscopy SEM, energy-dispersive X ray spectroscopy (EDX), UV-visible spectroscopy and particle size analysis, which clearly indicated the coexistence of both Cr2O3 and C3N4 in the composites. The Cr2O3/C3N4 catalysts were tested for photocatalytic degradation of 2-chlorophenol in wastewater and solubilization of sludge in anaerobic digestion process to enhance biomethane production. The co-catalytic performance of Cr2O3, with 6% of melamine (precursor of C3N4), improved the photocatalytic degradation of 2 chlorophenol (k = 0.0156 min-1) under visible light, where up to 94% removal was achieved at optimum pH 5.0, pollutant concentration of 60 mg/L, and time duration of 180 min. On another hand, application of Cr2O3/C3N4 for photocatalytic pretreatment of sludge released the soluble substances in solution in which sCOD was increased from 431 mg/L to 3666 mg/L after 6 h and VS content decrease by only 9.1%, which indicated that the short time pretreatment could avoid the further mineralization of organic to complete degradation. Thereafter, anaerobic digestion of solubilized sludge was achieved after 30 days with production of 634 ml kg-1VS of methane and 46% of organic matter removal efficiency (OMRE), compared with 472 ml kg-1VS and 402 ml kg-1VS of methane, 35 and 31% of OMRE respectively in photolytic and raw sludge (control) reactors. These results can provide a useful base and reference for the multi applications of visible light Cr2O3/C3N4 photocatalyst in enhancement of degradation of toxic pollutant in wastewater and sludge stabilization with bioenergy production in practice. PMID- 29428656 TI - Facilitative capture of As(V), Pb(II) and methylene blue from aqueous solutions with MgO hybrid sponge-like carbonaceous composite derived from sugarcane leafy trash. AB - Enhancing the contaminant adsorption capacity is a key factor affecting utilization of carbon-based adsorbents in wastewater treatment and encouraging development of biomass thermo-disposal. In this study, a novel MgO hybrid sponge like carbonaceous composite (HSC) derived from sugarcane leafy trash was prepared through an integrated adsorption-pyrolysis method. The resulted HSC composite was characterized and employed as adsorbent for the removal of negatively charged arsenate (As(V)), positively charged Pb(II), and the organic pollutant methylene blue (MB) from aqueous solutions in batch experiments. The effects of solution pH, contact time, initial concentration, temperature, and ionic strength on As(V), Pb(II) and MB adsorption were investigated. HSC was composed of nano-size MgO flakes and nanotube-like carbon sponge. Hybridization significantly improved As(V), Pb(II) and methylene blue (MB) adsorption when compared with the material without hybridization. The maximum As(V), Pb(II) and MB adsorption capacities obtained from Langmuir model were 157 mg/g, 103 mg/g and 297 mg/g, respectively. As(V) adsorption onto HSC was best fit by the pseudo-second-order model, and Pb(II) and MB with the intraparticle diffusion model. Increased temperature and ionic strength decreased Pb(II) and MB adsorption onto HSC more than As(V). Further FT-IR, XRD and XPS analysis demonstrated that the removal of As(V) by HSC was mainly dominated by surface deposition of MgHAsO4 and Mg(H2AsO4)2 crystals on the HSC composite, while carbon pi-pi* transition and carbon pi-electron played key roles in Pb(II) and MB adsorption. The interaction of Pb(II) with carbon matrix carboxylate was also evident. Overall, MgO hybridization improves the preparation of the nanotube-like carbon sponge composite and provides a potential agricultual residue-based adsorbent for As(V), Pb(II) and MB removal. PMID- 29428657 TI - Financial Pinch Analysis: Minimum opportunity cost targeting algorithm. AB - To achieve the market competitiveness as well as sustainable products and processes, a firm invests in different environmental and conservation projects. Capital budgeting essentially entails the decision of funding a set of acceptable projects from a larger pool of available projects, subject to different funding constraints. This paper proposes a new algorithm, the minimum opportunity cost targeting algorithm (MOCTA), to address the capital budgeting problems for selecting environmental management projects. This algorithm is based on the principles of Pinch Analysis, a well-established resource conservation methodology and can be directly applied to partially acceptable projects which can be formulated as a linear programming problem. The proposed algorithm, in coordination with the branch and bound technique, can further be applied to solve mixed integer linear programming (MILP) formulation of the problem, where projects should either be completely accepted or completely rejected. A hypothetical example demonstrates the applicability of the methodology through a complex search tree. The proposed methodologies are demonstrated through a case study of selecting energy conservation projects in the Indian Paper and Pulp industry. PMID- 29428658 TI - Three-dimensional imaging of active acid sulfate soil using a DUALEM-21S and EM inversion software. AB - One of the major environmental issues in Finland is the presence of large tracts of acid sulfate soil (ASS) landscapes along the coast. Accurately identifying the distribution of ASS sediments, and in particular soil pH, is essential for developing targeted management strategies. One approach is the use of digital soil mapping (DSM) with various ancillary information. Although electromagnetic (EM) induction data has shown potential in mapping ASS, few studies have been conducted to map the spatial distribution of pH at different depths. In this study, a DUALEM-21S was used to collect apparent soil electrical conductivity (ECa) data across a 23-ha field near Vaasa, which lies along the western coast of Finland. A quasi-3D inversion algorithm was used to calculate the estimated true electrical conductivity (sigma - mS m-1). A calibration relationship was developed between sigma and incubation-pH measured at various depths from topsoil (0-0.2 m), subsurface (0.2-0.4 m) and subsoil (e.g. 0.4-0.6 and 1.8-2 m) using an artificial neural network (ANN) model. The performance of the ANN model was good given the large R2 values for calibration (0.72) and validation (0.65). It was concluded that the combination of ECa data and quasi-3D inversion algorithm (in EM4Soil) was able to map the spatial distribution of incubation-pH associated within an ASS landscape. The approach has the potential to be applied across the coastal areas of Finland and elsewhere to map incubation-pH and identify active ASS areas and thereby improve the management of these areas. PMID- 29428659 TI - Removal of indoxyl sulfate by water-soluble poly-cyclodextrins in dialysis. AB - Indoxyl sulfate (IS) is a uremic toxin related to the progression of chronic kidney diseases. Removal of IS from the plasma would reduce the risk of cardiovascular disease. In this study, crosslinked poly-beta-cyclodextrins (PCDs) were used as a water-soluble adsorbent agent for IS in dialysis for the first time. The molecular weight of PCDs was found to be proportional to the crosslinking time between beta-cyclodextrin monomers and epichlorohydrin, yet the proportion of beta-cyclodextrin that reacted with epichlorohydrin decreased. It was observed that PCD after 2 h crosslinking yielded the best IS-binding capability in PBS, while reaching the binding equilibrium within 30 min and yielding a maximum binding capability of 45 mg g-1. Furthermore, the binding mechanism was investigated by two-dimensional nuclear magnetic resonance, Job's plot method, and salt treatments. To simulate the clinical removal of IS we established a macro-dialysis and added PCD obtained from 2 h crosslinking (PCD1) to the dialysate. The removal of plasma IS from the dialysate by PCD1 was about twice as much as that removed from the dialysate without PCD1. Therefore, crosslinked poly-beta-cyclodextrins may represent a simple, low-cost, and effective IS removal strategy with great potential for removing other hydrophobic plasma-bound toxins in dialysis. It could also serve as a supplement for the existing non-adsorbent added therapy. PMID- 29428660 TI - Differential expression of the receptors for thyroid hormone, thyroid stimulating hormone, vitamin D and retinoic acid and extracellular signal-regulated kinase in uterus of rats under influence of sex-steroids. AB - : Sex-steroids play important role in modulating uterine functions. We hypothesized that these hormones affect expression of proteins in the uterus related to thyroid hormone action. Therefore, changes in expression levels of receptors for thyroid hormone (TRalpha-1 and TRbeta-1), thyroid stimulating hormone (TSHR), vitamin D (VDR) and retinoid acid (RAR) as well as extracellular signal-regulated kinase (ERK1/2) in uterus were investigated under sex-steroid influence. METHODS: Two rat models were used: (i) ovariectomised, sex-steroid replaced and (ii) intact, at different phases of oestrous cycle. A day after completion of sex-steroid treatment or following identification of oestrous cycle phases, rats were sacrificed and expression and distribution of these proteins in uterus were identified by Western blotting and immunohistochemistry, respectively. RESULTS: Expression of TRalpha-1, TRbeta-1, TSHR, VDR, RAR and ERK1/2 in uterus was higher following estradiol (E2) treatment and at estrus phase of oestrous cycle when E2 levels were high. A relatively lower expression was observed following progesterone (P) treatment and at diestrus phases of oestrous cycle when P levels were high. Under E2 influence, TRalpha, TRbeta, TSHR, VDR, RAR and ERK1/2 were distributed in luminal and glandular epithelia while under P influence, TSHR, VDR abn RAR were distributed in the stroma. CONCLUSIONS: Differential expression and distribution of TRalpha-1, TRbeta-1, TSHR, VDR, RAR and ERK1/2 in different uterine compartments could explain differential action of thyroid hormone, TSH, vitamin D, and retinoic acid in uterus under different sex-steroid conditions. PMID- 29428661 TI - Gentiopicroside inhibits RANKL-induced osteoclastogenesis by regulating NF-kappaB and JNK signaling pathways. AB - Gentiopicroside, a main active component from the traditional Chinese herb medicine Gentiana manshurica Kitag, has been shown to possess anti-arthritis effect. However, the molecular mechanism of gentiopicroside on the osteoclast formation remains unclear. The present study was designed to investigate the effects and mechanisms of gentiopicroside on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis. The results showed that pre treatment with gentiopicroside significantly inhibited RANKL-induced osteoclast formation from mouse bone marrow macrophages (BMMs). In addition, we observed that gentiopicroside efficiently suppressed osteoclastogenesis-related marker genes expression in RANKL-stimulated BMMs. Mechanistically, gentiopicroside suppressed RANKL-induced the activation of JNK and NF-kappaB signaling pathways in BMMs. Taken together, the present study demonstrated that gentiopicroside inhibits RANKL-induced osteoclastogenesis through the inactivation of JNK and NF kappaB signaling pathways. Thus, gentiopicroside may be a promising agent for the treatment of osteoporosis. PMID- 29428662 TI - Antihypertensive and antioxidant effects of protocatechuic acid in deoxycorticosterone acetate-salt hypertensive rats. AB - Protocatechuic acid (PCA) is a natural antioxidant with beneficial cardiovascular properties. In this study, the effect of supplementation with PCA was investigated in deoxycorticosterone acetate (DOCA)-salt hypertension. Male Wistar rats received DOCA (25 mg/kg, s.c.) twice weekly and 1% NaCl in drinking water and simultaneously treated with PCA (50, 100 and 200 mg/kg, p.o.) for 4 weeks. Systolic blood pressure (SBP) was detected using tail-cuff method. Electrolytes including Na+, K+ and chloride, catalase activity, glutathione, total antioxidant capacity, malondialdehyde (MDA) and hydroperoxides concentration were measured in serum samples. Body and organs weight, water intake and, kidney and heart histopathology were also evaluated. Administration of PCA reversed the changes caused by DOCA-salt approximately at all doses. At the lowest dose, PCA significantly decreased SBP (132.5 +/- 4.0 vs 152.3 +/- 4.5 mmHg, P < .05), serum sodium (138.5 +/- 1.52 vs 141 +/- 1.50, P < .05) and chloride level (101.6 +/- 1.47 vs 110 +/- 1.39, P < .01) and raised serum potassium level (3.8 +/- 0.09 vs 3.1 +/- 0.17, P < .05) compared with DOCA-salt hypertensive rats. PCA increased serum catalase activity, total antioxidant capacity and glutathione concentration and reduced MDA and hydroperoxides levels. PCA also improved organ weight changes, reduced water intake and moderately prevented histopathological changes of kidney and heart upon DOCA-salt administration. The present study indicates the antihypertensive and antioxidant effects of PCA against DOCA-salt hypertension. PMID- 29428663 TI - Shengmai San-derived herbal prevents the development of a vulnerable substrate for atrial fibrillation in a rat model of ischemic heart failure. AB - OBJECTIVE: The study aimed to investigate whether a Shengmai San-derived herbal, Fumai granule (FM), which had a preventive effect on atrial fibrillation (AF) in myocardial infarction (MI)-induced heart failure (HF) rat and to determine the underlying mechanisms. DESIGN AND METHODS: MI was induced by a ligation of the left anterior descending coronary artery. One week after MI surgery, FM was gavaged for 4 weeks. AF inducibility was detected by transesophageal programmed electrical stimulation technology. Multielectrode array measurements, echocardiogram, histology, and western blotting were performed. RESULTS: The FM treated group had lower rates of AF inducibility and shorter AF duration compared to the MI group. FM improved the conduction velocity and homogeneity, decreased left atrial positive fibrosis areas and expression of type I and III collagen, inhibited cardiac fibroblast to myofibroblast differential, and increased the expression of connexin 43 and connexin 40 in the left atrium. CONCLUSIONS: These results suggest that FM reduced the AF inducibility after MI by improving the left atrial conduction function via inhibiting left atrial fibrosis and increasing the expression of connexin, indicating its benefit in preventing the MI-induced vulnerable substrate for AF. PMID- 29428664 TI - EIF5A1 promotes epithelial ovarian cancer proliferation and progression. AB - Epithelial ovarian cancer (EOC) is one of the most common gynecological cancers and has the highest mortality rate thereof. We found abundant eukaryotic translation initiation factor 5A1 (EIF5A1) in 54 EOC tissues, and high EIF5A1 levels predicted poor survival. EIF5A1 ectopic expression enhanced EOC cell proliferative, migration, and invasive capabilities, while EIF5A1 knockdown suppressed them. Most importantly, GC7 (N1-guanyl-1,7-diaminoheptane, an EIF5A1 hypusination inhibitor) could reverse the effect of EIF5A1 upregulation on EOC cell proliferation, migration, and invasion and mutant type EIF5A1K50A plasmid [bearing a single point mutation (K50 -> A50) that prevents hypusination] had no effects on these malignant behaviors. Our findings imply that EIF5A1 is a vital regulator of EOC proliferation and progression and is a potential prognostic marker and therapeutic target in EOC. PMID- 29428665 TI - Astragalus polysaccharide enhanced antitumor effects of Apatinib in gastric cancer AGS cells by inhibiting AKT signalling pathway. AB - Apatinib has been proved effective in the treatment of advanced gastric cancer. Traditional Chinese medicine is often considered as adjuvants which could increase the effects and counteract the side effects of chemotherapy. The present study aims to explore the antitumor effects of Astragalus polysaccharide (AsPs) in combination with Apatinib in gastric cancer AGS cells. Our results demonstrated that the expression of VEGFR-2 was observed in human gastric cancer line AGS. Both Apatinib and AsPs could significantly inhibit the proliferation of AGS cells in a dose-dependent manner and Apatinib in combination with AsPs showed enhanced inhibitory effects on cell proliferation, migration and invasion compared with Apatinib monotherapy. Moreover, there was a remarkable increase in apoptosis following Apatinib treatment which could be enhanced by the addition of AsPs. Western blotting showed that the combination of Apatinib and AsPs could inhibit the expression of phosphorylated AKT (p-AKT) and MMP-9 expression. In addition, both Apatinib alone and Apatinib in combination with AsPs induced celluar autophagy which could be attenuated by the autophagy inhibitor 3-MA. The suppression of autophagy leaded to further apoptosis induction and cell proliferation suppression. In conclusion, the current study showed AsPs enhanced antitumor effects of Apatinib on AGS cells by the mechanism which includes inhibition of AKT signaling pathway. Apatinib-induced autophagy could be attenuated by 3-MA, which subsequently increased the apoptosis rate. On the basis of our study, the combination of Apatinib and AsPs could be considered as a potential candidate in the gastric cancer treatment. PMID- 29428666 TI - MicroRNA-519d inhibits proliferation and induces apoptosis of human hypertrophic scar fibroblasts through targeting Sirtuin 7. AB - MicroRNAs (miRNAs) play critical roles in various pathological processes, including hypertrophic scar (HS) formation. However, the precise role of miRNAs in HS formation remains largely unknown. In this study, we aimed to investigate the role of miR-519d in HS formation. We found that miR-519d expression was significantly downregulated in HS tissues and fibroblasts. Overexpression of miR 519d inhibited the expression of type I collagen (Col I), type III collagen (Col III) and alpha-smooth muscle actin (alpha-SMA) in HS fibroblasts. Moreover, overexpression of miR-519d reduced the proliferation and induced the apoptosis of HS fibroblasts. In contrast, suppression of miR-519d showed the opposite effects. Interestingly, Sirtuin 7 (SIRT7) was identified as a target gene of miR-519d. The results showed that miR-519d directly targeted the 3'-untranslated region of SIRT7 and negatively regulated its expression. Furthermore, miR-519d regulated the expression of TGF-beta type I receptor (TGFBRI) and the phosphorylation of Smad2. Knockdown of SIRT7 by siRNA inhibited the expression of Col I, Col III and alpha-SMA, and reduced the proliferation and induced the apoptosis of HS fibroblasts. Overexpression of SIRT7 abrogated the effects mediated by miR-519d overexpression in HS fibroblasts. Overall, these results suggest that miR-519d inhibits the expression of extracellular matrix-associated genes, reduces the proliferation and induces the apoptosis of HS fibroblasts by targeting SIRT7, implying a suppressive role of miR-519d in HS formation. This study suggests that miR-519d may serve as a promising therapeutic target for treatment of human HS. PMID- 29428667 TI - Silybum marianum oil attenuates hepatic steatosis and oxidative stress in high fat diet-fed mice. AB - In the present study, the effects of Silybum marianum oil (SMO) on hepatic steatosis and oxidative stress were investigated during the development of nonalcoholic fatty liver disease (NAFLD) in high fat diet (HFD)-fed mice. The results showed that body weight, fat mass, and serum biochemical parameters such as triglyceride, free fatty acid, glucose and insulin were reduced by SMO treatment. Meanwhile, SMO decreased the histological injury of liver and the levels of hepatic triglyceride, cholesterol and free fatty acid in HFD-fed mice. SMO administration elevated the activities of superoxide dismutase (SOD) and catalase (CAT) and reduced the level of malondialdehyde (MDA) in the liver. Enzyme linked immunosorbent assay showed that SMO significantly decreased the levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in HFD mice. Furthermore, the mRNA levels of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase (FAS) and liver X receptor alpha (LXRalpha) were lower, but peroxisome proliferator-activated receptor alpha (PPARalpha) was higher in mice treated with SMO compared with the HFD group. The results indicated that SMO could play a certain protective role against HFD-induced NAFLD, and the protective effects might be associated with attenuating lipid accumulation, oxidative stress and inflammation, improving lipid metabolism. PMID- 29428668 TI - Immune cells involved in the pathogenesis of ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is an inflammatory autoimmune disease. AS is a prototype form of spondyloarthropathies (SpA). The precise etiology of AS has not been fully understood. But Inflammation has a critical role in the pathogenesis of the disease. The immune system by various cells, secreted-mediators and markers manage and regulate the immune responses and inflammation. Every factor which disturbed this regulation and hemostasis can cause chronic inflammation. In this review, we discussed the role of several innate and adaptive immune cells involved in the triggering, initiation, development, and regulation of AS. PMID- 29428669 TI - PSMB8 regulates glioma cell migration, proliferation, and apoptosis through modulating ERK1/2 and PI3K/AKT signaling pathways. AB - Glioma has been considered as one of the most aggressive and popular brain tumors of patients. It is essential to explore the mechanism of glioma. In this study, we established PSMB8 as a therapeutic target for glioma treatment. Expression of PSMB8 as well as Ki-67 was higher in glioma tissues demonstrated by western blot and immunohistochemistry. Then, the role of PSMB8 in migration and proliferation of glioma cells was investigated by conducting wound-healing, trans-well assay, cell counting kit (CCK)-8, flow cytometry assay and colony formation analysis. The data showed that interfering PSMB8 may inhibit the migration and proliferation of glioma cells by reducing expression of cyclin A, cyclin B1, cyclin D1, Vimentin, and N-cadherin, and by increasing expression of E-cadherin. Additionally, interfering PSMB8 may induce apoptosis of glioma cells by upregulating caspase-3 expression. Furthermore, these in vitro findings were validated in vivo and the ERK1/2 and PI3k/AKT signaling pathways were involved in PSMB8-triggered migration and proliferation of glioma cells. In an in vivo model, downregulation of PSMB8 suppressed tumor growth. In conclusion, PSMB8 is closely associated with migration, proliferation, and apoptosis of glioma cells, and might be considered as a novel prognostic indicator in patients with gliomas. PMID- 29428670 TI - Protective effects of Punica granatum (pomegranate) peel extract on concanavalin A-induced autoimmune hepatitis in mice. AB - Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of an unknown etiology, glucocorticoid therapy is currently recognized as an effective treatment for AIH, but conventional application and patient compliance are both hindered by its side effects. The exploration of the AIH pathogenesis and the searching for the new candidate drugs that exert potential activity and low toxicity are urgently needed. Pomegranate peel extract (PoPx) is a natural extract of Punica granatum and has been reported to have anti-inflammatory and antioxidative properties. The present study aimed to clarify the effect of PoPx on the concanavalin A (ConA)-induced autoimmune hepatitis in a mouse model that is well established at 12h after tail vein injection with a dose of 20 mg/kg of ConA. C57BL/6 female mice were pretreated with PoPx (250 mg/kg, once daily for 3 days) followed by a ConA challenge. Pretreatment with PoPx significantly alleviated ConA-induced liver injury by down-regulating the levels of plasma alanine transaminase (ALT), aspartate transaminase (AST) and cytokine, including TNF-alpha, interferon (IFN) -gamma and interleukin (IL)-6. Moreover, liver hematoxylin and eosin (H&E) staining displayed a lighter inflammatory infiltration around the portal area in the PoPx-pretreated mice. In addition, the flow cytometry (FCM) data showed that the immune response in the liver was died down in the PoPx-pretreated condition. Specially, pretreatment with PoPx reduced the infiltration of activated CD4+ and CD8+ T cells in the liver. Taken together, these findings contributed to a better understanding of the actions of PoPx against acute AIH and indicated that PoPx might be a potential compound in treating T cell-mediated autoimmune liver injury. PMID- 29428671 TI - Swertisin ameliorates diabetes by triggering pancreatic progenitors for islet neogenesis in Streptozotocin treated BALB/c mice. AB - In the present study, Swertisin's role in triggering resident pancreatic progenitors for islet neogenesis in Streptozotocin (STZ) diabetic mice was explored. STZ diabetic mice when treated with Swertisin demonstrated reversion to normoglycemia and significant elevation of fasting serum insulin levels. On screening the pancreatic tissue post Swertisin treatment in the STZ diabetic mice, we observed significant up-regulation of key transcription factors viz. Pdx1, Neurog3, MafA and Nkx6.1 required for islet neogenesis and beta cell homeostasis. We further observed increase in expression of Nestin and Neurog3 positive population; Nestin and Glut2 positive population and increase in c peptide and Glucagon positive population within the Islets of Langerhans indicating increased pancreatic progenitor activity and their differentiation into Insulin producing beta cells in Swertisin treated STZ diabetic mice. Thus, this short study highlights pancreatic innate capability to regenerate and recover using its own resident progenitors upon appropriate stimulus, which could culminate into an effective diabetic therapy. PMID- 29428672 TI - The metabolism of a natural product mogroside V, in healthy and type 2 diabetic rats. AB - Mogroside V, a natural compound isolated from the fruits of Siraitia grosvenorii (Swingle), is a promising candidate for anti-diabetic activity. The present study aims to develop a simple and practical strategy for comparing the in vivo metabolite profiling of mogroside V in healthy and type 2 diabetic (T2D) model rats. In this paper, a highly sensitive and rapid ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) with MetaboLynxTM software combined with mass defect filtering (MDF) method was established and successfully applied to detect and identify the metabolites in plasma, urine, bile and feces samples of healthy and model rats administrated with mogroside V. The distribution of metabolites in plasma, bile, urine and feces of healthy and model rats had obvious differences. A total of 23 metabolites were observed in healthy rats while 26 metabolites were detected in model rats. The results indicated that dehydrogenation, deoxidation, oxidation and isomerization were the major metabolic transformations of mogroside V. Additionally, it was noticed that the peak areas of metabolites in T2D rat plasma samples were much larger than those of metabolites in healthy rat plasma sample, whereas in T2D rat urine samples they were remarkably smaller compared with healthy rat urine sample. These high blood concentrations of metabolites might be beneficial for the treatment of T2D. The results of this study are valuable and important in understanding the metabolic process and therapeutic mechanism of mogroside V. PMID- 29428673 TI - Pharmacokinetic comparisons of six components from raw and vinegar-processed Daphne genkwa aqueous extracts following oral administration in rats by employing UHPLC-MS/MS approaches. AB - A sensitive UHPLC-MS/MS approach was developed and validated for the quantification of genkwanin, 3'-hydroxygenkwanin, apigenin, luteolin, yuanhuacine and genkwadaphnin in biological samples after oral administration of raw and vinegar-processed Daphne genkwa. Liquiritin and glycyrrhetinic acid were employed as internal standards. Six components were extracted by using protein precipitation with acetonitrile. Chromatographic separation was achieved on a Waters BEH C18 column (50 mm * 2.1 mm, 1.7 MUm) by using a mobile phase composed of water (containing 0.1% formic acid) and acetonitrile. Mass spectrometric detection was conducted using multiple reaction monitoring (MRM). The intra- and inter-day precisions of the six analytes were below 4.87%, and the accuracies were within +/-5.0%. The extraction recoveries of the six constituents were determined between 97.5% and 105.4% and the matrix effects ranged from 97.3% to 103.7%. All the samples showed satisfactory precision and accuracy after various stability tests. The established approach was successfully applied to the comparative pharmacokinetic study. Compared to the raw group, the parameters of Cmax and AUC0-t of genkwanin, 3'-hydroxygenkwanin, apigenin and luteolin elevated remarkably (p < 0.05) after oral delivery of vinegar-processed Daphne genkwa while the parameters of Cmax and AUC0-t of yuanhuacine and genkwadaphnin decreased significantly (p < 0.05). The results revealed that vinegar-processing could enhance bioavailability of genkwanin, 3'-hydroxygenkwanin, apigenin and luteolin but reduce the bioavailability of yuanhuacine and genkwadaphnin. PMID- 29428674 TI - Genes and Pathways Regulated by Androgens in Human Neural Cells, Potential Candidates for the Male Excess in Autism Spectrum Disorder. AB - BACKGROUND: Prenatal exposure to androgens during brain development in male individuals may participate to increase their susceptibility to develop neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability. However, little is known about the action of androgens in human neural cells. METHODS: We used human neural stem cells differentiated from embryonic stem cells to investigate targets of androgens. RESULTS: RNA sequencing revealed that treatment with dihydrotestosterone (DHT) leads to subtle but significant changes in the expression of about 200 genes, encoding proteins of extracellular matrix or involved in signal transduction of growth factors (e.g., insulin/insulin growth factor 1). We showed that the most differentially expressed genes (DEGs), RGCC, RNF144B, NRCAM, TRIM22, FAM107A, IGFBP5, and LAMA2, are reproducibly regulated by different androgens in different genetic backgrounds. We showed, by overexpressing the androgen receptor in neuroblastoma cells SH-SY5Y or knocking it down in human neural stem cells, that this regulation involves the androgen receptor. A chromatin immunoprecipitation combined with direct sequencing analysis identified androgen receptor-bound sequences in nearly half of the DHT-DEGs and in numerous other genes. DHT-DEGs appear enriched in genes involved in ASD (ASXL3, NLGN4X, etc.), associated with ASD (NRCAM), or differentially expressed in patients with ASD (FAM107A, IGFBP5). Androgens increase human neural stem cell proliferation and survival in nutrient deprived culture conditions, with no detectable effect on regulation of neurite outgrowth. CONCLUSIONS: We characterized androgen action in neural progenitor cells, identifying DHT-DEGs that appear to be enriched in genes related to ASD. We also showed that androgens increase proliferation of neuronal precursors and protect them from death during their differentiation in nutrient-deprived conditions. PMID- 29428675 TI - A human osteoarthritis osteochondral organ culture model for cartilage tissue engineering. AB - RATIONALE: In vitro human osteoarthritis (OA)-mimicking models enabling pathophysiological studies and evaluation of emerging therapies such as cartilage tissue engineering are of great importance. OBJECTIVE: We describe the development and characterization of a human OA osteochondral organ culture. We also apply this model for evaluation of the phenotype maintenance of a human MSC derived engineered cartilage, as an example of emerging therapeutics, under long term exposure to the OA-mimicking environment. We also test the sensitivity of the model to a series of external factors and a potential disease-modifying agent, in terms of chondrogenic phenotype maintenance of the engineered cartilage, under OA-mimicking environment. METHOD: Excised joint tissues from total knee replacement surgeries were carved into numerous miniaturized and standardized osteochondral plugs for subsequent OA organ culture. The organ cultures were characterized in detail before being co-cultured with a tissue engineered cartilage. The chondrogenic phenotype of the tissue engineered cartilage co-cultured in long term up to 8 weeks under this OA-mimicking microenvironment was evaluated. Using the same co-culture model, we also screened for a number of biomimetic environmental factors, including oxygen tension, the presence of serum and the application of compression loading. Finally, we studied the effect of a matrix metalloprotease inhibitor, as an example of potential disease-modifying agents, on the co-cultured engineered cartilage. RESULTS: We demonstrate that cells in the OA organ culture were viable while both the typical chondrogenic phenotype and the characteristic OA phenotype were maintained for long period of time. We then demonstrate that upon co-culture with the OA mimicking organ culture, the engineered cartilage initially exhibited a more fibrocartilage phenotype but progressively reverted back to the chondrogenic phenotype upon long term co-culture up to 8 weeks. The engineered cartilage was also found to be sensitive to all biomimetic environmental factors screened (oxygen tension, serum and compression). Moreover, under the effect of a MMP inhibitor, the chondrogenic phenotype of engineered cartilage was better maintained. CONCLUSION: We demonstrated the development of a human OA osteochondral organ culture and tested the feasibility and potential of using this model as an in vitro evaluation tool for emerging cartilage therapies. PMID- 29428676 TI - Controlled release of collagen-binding SDF-1alpha from the collagen scaffold promoted tendon regeneration in a rat Achilles tendon defect model. AB - It had been demonstrated that stromal cell-derived factor-1alpha (SDF-1alpha) could promote in situ tendon regeneration by recruiting endogenous cells. However, native SDF-1alpha diffuses too fast in vivo, reducing its local concentration and efficacy. In this study, we prepared a recombinant SDF-1alpha containing a collagen-binding domain (CBD-SDF-1alpha) and developed a functional collagen scaffold by tethering CBD-SDF-1alpha on the collagen scaffold for in situ tendon regeneration. CBD-SDF-1alpha could induce the migration of mesenchymal stem cells, dermal fibroblasts and Achilles tendon fibroblasts in vitro, and achieve controlled release from the collagen scaffold. In a rat Achilles tendon defect model, the functional scaffold could increase the recruitment of CXCR4 positive fibroblast-like cells and the deposition of Tenascin-C at 7 days after implantation. After 4 and 12 weeks, the functional collagen scaffold could promote the expression of type I collagen, increase the diameters of collagen fibrils and improve the mechanical properties of regenerated tendons. Hence, the functional scaffold increased the efficacy of tendon regeneration by controlling release of SDF-1alpha, enhancing the recruitment of fibroblast-like cells and providing instructive microenvironment and mechanical support for tendon regeneration. Therefore, CBD-SDF-1alpha modified collagen scaffold could serve as a practical application for tendon regeneration. PMID- 29428677 TI - Association of Resistance Exercise With the Incidence of Hypercholesterolemia in Men. AB - OBJECTIVE: To examine the associations of resistance exercise, independent of and combined with aerobic exercise, with the risk of development of hypercholesterolemia in men. PATIENTS AND METHODS: This study used data from the Aerobics Center Longitudinal Study, which is a cohort examining the associations of clinical and lifestyle factors with the development of chronic diseases and mortality. Participants received extensive preventive medical examinations at the Cooper Clinic in Dallas, Texas, between January 1, 1987, and December 31, 2006. A total of 7317 men aged 18 to 83 years (mean age, 46 years) without hypercholesterolemia at baseline were included. Frequency (times per week) and total amount (min/wk) of resistance and aerobic exercise were determined by self report. Hypercholesterolemia was defined as a total cholesterol level of 240 mg/dL or higher or physician diagnosis. RESULTS: During a median (interquartile range) follow-up of 4 (2 to 7) years, hypercholesterolemia developed in 1430 of the 7317 men (20%). Individuals meeting the resistance exercise guidelines (>=2 d/wk) had a 13% lower risk of development of hypercholesterolemia (hazard ratio [HR], 0.87; 95% CI, 0.76-0.99; P=.04) after adjustment for general characteristics, lifestyle factors, and aerobic exercise. In addition, less than 1 h/wk and 2 sessions per week of resistance exercise were associated with 32% and 31% lower risks of hypercholesterolemia (HR, 0.68; 95% CI, 0.54-0.86; P=.001; and HR, 0.69; 95% CI, 0.54-0.88; P=.003), respectively, compared with no resistance exercise. Higher levels of resistance exercise did not provide benefits. Meeting both resistance and aerobic exercise guidelines (>=500 metabolic equivalent task min/wk) lowered the risk of development of hypercholesterolemia by 21% (HR, 0.79; 95% CI, 0.68-0.91; P=.002). compared with meeting none of the guidelines. CONCLUSION: Compared with no resistance exercise, less than 1 h/wk of resistance exercise, independent of aerobic exercise, is associated with a significantly lower risk of development of hypercholesterolemia in men (P=.001). However, the lowest risk of hypercholesterolemia was found at 58 min/wk of resistance exercise. This finding suggests that resistance exercise should be encouraged to prevent hypercholesterolemia in men. However, future studies with a more rigorous analysis including major potential confounders (eg, diet, medications) are warranted. PMID- 29428678 TI - Profiling cytokine levels in chlorhexidine and EGCG-treated odontoblast-like cells. AB - OBJECTIVE: To screen the effect of two compounds, chlorhexidine diacetate (CHX) and epigallocatechin-gallate (EGCG), on the levels of cytokines produced by odontoblast-like cells (MDPC-23). METHODS: Cells were seeded at 24h and 48h with serial dilution of the compounds to determine cell metabolic activity by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (n=3). Cells with no compound treatment were used as control (Ctr). For the highest equal non cytotoxic compound dilution tested at 48h cell treatment, total protein concentration was measured using a Pierce bicinchoninic acid (BCA) assay (n=3), and expression of 23 cytokines was analyzed using the Bio-Plex cytokine assay (n=2). Data were analyzed by one-way ANOVA and Tukey's test (alpha=5%). RESULTS: The MTT assay revealed that at 24h and 48h, CHX and EGCG did not reduce cell metabolic activity at concentrations of 2.5-20MUM (CHX) and 2.5-160MUM (EGCG), respectively (p>0.05). At 48h, total protein levels were consistent across all groups for 20MUM compound dilution (Ctr: 1.04mg/mL; CHX: 0.98mg/mL; and EGCG: 1.06mg/mL). At 20MUM dilution, both CHX and EGCG significantly increased the secretion of IL-1beta, IL-10, IL-12, KC, MIP-1alpha, IFN-gamma and IL-6 (p<0.05). Treatment with CHX significantly increased secretion of IL-4 and RANTES (p<0.05). TREATMENT: with EGCG significantly increased Eotaxin secretion (p<0.05). Both CHX and EGCG significantly decreased secretion of IL-17 (p<0.05). GM-CSF and TNF alpha did not present significant change in secretion after treatment with either CHX or EGCG (p>0.05). SIGNIFICANCE: Both CHX and EGCG modulate secretion of various inflammatory and anti-inflammatory mediators in odontoblastic cells. PMID- 29428679 TI - Long-term Mortality in Community-acquired Pneumonia. PMID- 29428680 TI - Telemedicine, an Opportunity for Spirometry. PMID- 29428681 TI - Perception and Awareness of chronic obstructive pulmonary disease, Chronic Bronchitis and Pulmonary Emphysema in the Spanish Urban Population. PMID- 29428682 TI - Counting of peripheral extracellular vesicles in Multiple Sclerosis patients by an improved nanoplasmonic assay and dynamic light scattering. AB - Extracellular vesicles (EVs) are vesicles naturally secreted by the majority of human cells. Being composed by a closed phospholipid bilayer secluding proteins and RNAs they are used to transfer molecular information to other cells, thereby influencing the recipient cell functions. Despite the increasingly recognized relevance of EVs, the clarification of their physiological role is hampered by the lack of suitable analytical tools for their quantification and characterization. In this study, we have implemented a nanoplasmonic assay, previously proposed for the purity of the EV fractions, to achieve a robust analytical protocol in order to quantify the total phospholipid concentration (CPL) and the EVs number. We show how the coupling of the nanoplasmonic assay with serial dilutions of the unknown sample allows, by simple visual inspection, to detect deviations from the physiological EVs content. The use of a response that depends on the absorbance values at three wavelengths permits to reduce the limit of detection of CPL to 5 MUM (total) and the limit of quantification to 35 MUM. We also propose a method that takes into account the spread in EV size when the concentration of phospholipids is turned into a concentration of vesicles. The proposed analytical protocol is successfully applied to a small cohort of Multiple Sclerosis patients examined in different stages of their clinical diseases. PMID- 29428683 TI - DNA repair mechanisms in response to genotoxicity of warfare agent sulfur mustard. AB - Sulfur mustard (SM) is an alkylating agent that causes severe damages to the skin, eyes, and the respiratory system. DNA alkylation is one of the most critical lesions that could lead to monoadducts and cross-links, as well as DNA strand breaks. In response to these adducts, cells initiate a series of reactions to recruit specific DNA repair pathways. The main DNA repair pathways in human cells, which could be involved in the DNA SM-induced DNA damages, are base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end joining (NHEJ). There is, thus, a need for a short review to clarify which damage caused by SM is repaired by which repair pathway. Increasing our knowledge about different DNA repair mechanisms following SM exposure would lay the first step for developing new therapeutic agents to treat people exposed to SM. In this review, we describe the major DNA repair pathways, according to the DNA adducts that can be caused by SM. PMID- 29428684 TI - Constructing Cd0.5Zn0.5S@ZIF-8 nanocomposites through self-assembly strategy to enhance Cr(VI) photocatalytic reduction. AB - A novel and highly efficient photocatalyst of Cd0.5Zn0.5S@ZIF-8 nanocomposite has been developed by a facile self-assembly strategy. This is the first report on the application of CdxZn1-xS and metal-organic framework (MOF) nanocomposite as photocatalysts for the reduction of Cr(VI). The resulting Cd0.5Zn0.5S@ZIF-8 exhibited higher photocatalytic activity than that of pristine Cd0.5Zn0.5S and ZIF-8. Particularly, the CZS@Z60 composite with 60 wt% of ZIF-8 exhibited a photocatalytic activity that is about 1.6 times as high as that of Cd0.5Zn0.5S. The dominant reason for the improved photocatalytic reduction potential is proved to be the newly-formed interfacial SZn bonds that firmly connect Cd0.5Zn0.5S and ZIF-8 and substantially improve the separation efficiency of photo-excited electrons and holes. The newly-formed chemical bonds are confirmed by XPS analyses, and the prolonged lifetime of photo-excited electrons is evidenced by the electrochemical measurement of photocurrent, which shows that the photocurrent on Cd0.5Zn0.5S@ZIF-8 is much higher than that of Cd0.5Zn0.5S and ZIF 8. This study clearly demonstrates that the MOF-based composite nanomaterials hold great promises for applications in the field of environmental remediation and for design of novel photocatalytic materials. PMID- 29428685 TI - Inoculation with bacteria in floating treatment wetlands positively modulates the phytoremediation of oil field wastewater. AB - The aim of the present study was to investigate the potential of plant-bacterial synergism in floating treatment wetlands (FTWs) for efficient remediation of an oil field wastewater. Two plants, Brachiara mutica and Phragmites australis, were vegetated on floatable mats to develop FTWs, and inoculated with bacterial cons which were then inoculated with a consortium of hydrocarbon-degrading bacteria (Bacillus subtilis strain LORI66, Klebsiella sp. strain LCRI87, Acinetobacter Junii strain TYRH47, Acinetobacter sp. strain LCRH81). Both plants successfully removed organic and inorganic pollutants from wastewater, but bioaugmentation of P. australis significantly enhanced the plant's efficiency to reduce oil content (97%), COD (93%), and BOD (97%), in wastewater. Analysis of alkane-degrading gene (alkB) abundance and its expression profile further validated a higher microbial growth and degradation activity in water around P. australis as well as its roots and shoots. This study provides insight into the available phytotechnology for remediation of crude oil-contaminated water and introduces a wetland macrophyte, P. australis, with tailor-made bacterial consortium as an effective tool for improved phytoremediation efficiency of FTWs. PMID- 29428686 TI - Reconstruction of a Complex Foot Injury With Free Remodeled Fibular Osteocutaneous Flap: A Case Report and Literature Review. AB - Management of complex foot injuries, which involve open fractures and severe trauma to soft tissues, represent a challenge to orthopedic clinicians. In the present case report, we treated a complex foot injury with a remodeled fibular osteocutaneous free flap to reconstruct the anterior and lateral areas of the foot. The flap survived completely. At the 9-month follow-up examination, bony union of the graft bone was identified by radiographic examination. The reconstructed foot could bear body weight, and the patient could maintain a bipedal gait without discomfort. The remodeled fibular osteocutaneous free flap provides an option for functional reconstruction of foot defects. PMID- 29428687 TI - Changes in patellofemoral pain resulting from repetitive impact landings are associated with the magnitude and rate of patellofemoral joint loading. AB - BACKGROUND: Although a relationship between elevated patellofemoral forces and pain has been proposed, it is unknown which joint loading variable (magnitude, rate) is best associated with pain changes. The purpose of this study was to examine associations among patellofemoral joint loading variables and changes in patellofemoral pain across repeated single limb landings. METHODS: Thirty-one females (age: 23.5(2.8) year; height: 166.8(5.8) cm; mass: 59.6(8.1) kg) with PFP performed 5 landing trials from 0.25 m. The dependent variable was rate of change in pain obtained from self-reported pain scores following each trial. Independent variables included 5-trial averages of peak, time-integral, and average and maximum development rates of the patellofemoral joint reaction force obtained using a previously described model. Pearson correlation coefficients were calculated to evaluate individual associations between rate of change in pain and each independent variable (alpha = 0.05). Stepwise linear multiple regression (alphaenter = 0.05; alphaexit = 0.10) was used to identify the best predictor of rate of change in pain. FINDINGS: Subjects reported an average increase of 0.38 pain points with each landing trial. Although, rate of change in pain was positively correlated with peak force (r = 0.44, p = 0.01), and average (r = 0.41, p = 0.02) and maximum force development rates (r = 0.39, p = 0.03), only the peak force entered the predictive model explaining 19% of variance in rate of change in pain (r2 = 0.19, p = 0.01). INTERPRETATION: Peak patellofemoral joint reaction force was the best predictor of the rate of change in pain following repetitive singe limb landings. The current study supports the theory that patellofemoral joint loading contributes to changes in patellofemoral pain. PMID- 29428688 TI - Privacy, boundaries and smart homes for health: An ethnographic study. AB - This article explores how people negotiate borders and boundaries within the home, in the context of health and the introduction of new technologies. We draw on an ethnographic study involving a socially diverse group of people, which included people with experience of telecare or smart home energy systems. Participants engaged in various strategies to regulate the borders of their home, even though new technologies have begun to change the nature of these borders. Participants managed health conditions but also their use of technology through boundary work that permitted devices to be more or less visible and integrated within the home. Findings highlight that if smart healthcare technologies are to be accepted in the home then there is a need for mechanisms that allow people to control the interpretation of data and flow of information generated about them and their households. PMID- 29428689 TI - Impact of age on risk of complications after gastric bypass: A cohort study from the Scandinavian Obesity Surgery Registry (SOReg). AB - BACKGROUND: An increasing number of older patients undergo bariatric surgery. OBJECTIVE: To define the risk for complications and mortality in relation to age after gastric bypass. SETTING: A national registry-based study. METHODS: Patients (n = 47,660) undergoing gastric bypass between May 2007 and October 2016 and registered in the Scandinavian Obesity Register were included. Risk between age groups was compared by multivariate analysis. RESULTS: The 30-day follow-up rate was 98.1%. In the entire cohort of patients, any complication within 30 days was demonstrated in 8.4%. For patients aged 50 to 54, 55 to 59, and >=60 years, this risk was significantly increased to 9.8%, 10.0%, and 10.2%, respectively. Rates of specific surgical complications, such as anastomotic leak, bleeding, and deep infections/abscesses were all significantly increased by 14% to 41% in patients aged 50 to 54 years, with a small additional, albeit not significant, increase in risk in patients of older age. The risk of medical complications (thromboembolic events, cardiovascular, and pulmonary complications) was significantly increased in patients aged >=60 years. Mortality was .03% in all patients without differences between groups. CONCLUSIONS: In this large data set, rates of complications and mortality after 30 days were low. For many complications, an increased risk was encountered in patients aged >=50 years. However, rates of complications and mortality were still acceptably low in these age groups. Taking the expected benefits in terms of weight loss and improvements of co-morbidities into consideration, our findings suggest that patients of older age should be considered for surgery after thorough individual risk assessment rather than denied bariatric surgery based solely on a predefined chronologic age limit. PMID- 29428690 TI - Enteral stents in the management of post-bariatric surgery leaks. AB - A post-bariatric surgery leak is a rare but grave condition and remains every bariatric surgeon's nightmare. Endoscopic therapy with the insertion of self expandable stents provides an effective minimally invasive approach for the management of leaks. Self-expandable stents, however, are still hampered by their tendency for migration and are not always well tolerated. Recently, double pigtail stents have been proposed as an alternative endoscopic therapeutic modality. Both types of stents have been shown to be very effective in the management of leaks; however, most studies have pooled gastrointestinal leaks due to different etiologies together. In this article, we review the current status and foreseen innovations in gastrointestinal stenting for post-bariatric surgery leaks. PMID- 29428691 TI - Short-term changes in affective, behavioral, and cognitive components of body image after bariatric surgery. AB - BACKGROUND: Many bariatric surgery candidates report body image concerns before surgery. Research has reported post-surgical improvements in body satisfaction, which may be associated with weight loss. However, research has failed to comprehensively examine changes in affective, behavioral, and cognitive body image. OBJECTIVES: This research examined (1) short-term changes in affective, behavioral, and cognitive components of body image from pre-surgery to 1- and 6 months after bariatric surgery, and (2) the association between percent weight loss and these changes. SETTING: Participants were recruited from a private hospital in the midwestern United States. METHODS: Eighty-eight females (original N = 123; lost to follow-up: n = 15 at 1-month and n = 20 at 6-months post surgery) completed a questionnaire battery, including the Body Attitudes Questionnaire, Body Checking Questionnaire, Body Image Avoidance Questionnaire, and Body Shape Questionnaire, and weights were obtained from patients' medical records before and at 1- and 6-months post-surgery. RESULTS: Results indicated significant decreases in body dissatisfaction, feelings of fatness, and body image avoidance at 1- and 6-months after bariatric surgery, with the greatest magnitude of change occurring for body image avoidance. Change in feelings of fatness was significantly correlated with percent weight loss at 6-months, but not 1-month, post-surgery. CONCLUSIONS: These findings highlight the importance of examining short-term changes in body image from a multidimensional perspective in the effort to improve postsurgical outcomes. Unique contributions include the findings regarding the behavioral component of body image, as body image avoidance emerges as a particularly salient concern that changes over time among bariatric surgery candidates. PMID- 29428692 TI - Routine contrast imaging after bariatric surgery and the effect on hospital length of stay. AB - BACKGROUND: Although multiple studies demonstrate that routine postoperative contrast studies have a low yield in diagnosing patients with early gastrointestinal (GI) leak after bariatric surgery, the practice pattern is unknown. Additionally, routine imaging may hinder procedural pathways that lead to accelerated postoperative discharge. OBJECTIVES: To report on the nationwide use of routine upper GI studies (UGI) and evaluate the effect on hospital resource utilization. SETTING: Nationwide analysis of accredited centers. METHODS: The Metabolic and Bariatric Surgery Accreditation Quality and Improvement Program public use file for 2015 was used to identify patients who underwent routine UGI after nonrevisional Roux-en-Y gastric bypass or sleeve gastrectomy. Multivariable logistic regression models were developed to identify risk factors for early hospital discharge. RESULTS: Bariatric surgery was performed on 130,686 patients. Routine UGI was performed in 30.9% of Roux-en-Y gastric bypass and 43% of sleeve gastrectomy patients (P<.0001). Patients undergoing routine UGI were less likely to be discharged by postoperative day 1 (odds ratio .7, 95%; confidence interval .69-0.72). There was no difference in postoperative leak rate between the routine UGI versus nonroutine UGI group (.7% versus .8%, P = .208). Among patients who developed a GI leak, there was no significant difference in the rate of reoperation, readmission, and reintervention between the 2 groups. The time interval between index operation and any further management for the leak was longer in the routine UGI group. CONCLUSIONS: Routine UGI evaluation after bariatric surgery remains a common practice in accredited centers. This practice is associated with prolonged hospital length of stay, with no effect on the diagnosis of leak rate. PMID- 29428693 TI - Do acute care surgeons need bariatric surgical training to ensure optimal outcomes in obese patients with nonbariatric emergencies? AB - INTRODUCTION: Acute care surgeons care for the entire breadth of the American adult population, including obese patients. As the population gets heavier, more patients will present to acute case surgeons with nonbariatric surgical emergencies. Do these surgeons need bariatric training to properly care for obese population? OBJECTIVES: To evaluate our experience in obese population requiring acute surgery and compare outcomes based on surgeon expertise in bariatric surgery. SETTING: Community teaching hospital, United States. METHODS: Retrospective review of obese patients requiring acute surgical intervention. Surgeons were classified as bariatric surgeons (B, n = 2) versus nonbariatric surgeons (NB, n = 4). Demographic characteristics, co-morbidities, and outcomes based on surgeon training were compared. RESULTS: Two hundred three patients comprised the cohort. The mean body mass index was 37 +/-6 kg/m2. The majority of procedures were laparoscopic (cholecystectomies n = 75, appendectomies n = 45). The remaining nonroutine laparoscopic cases were intestinal obstructions (n = 9), incarcerated hernias (n = 17), traumatic injuries (n = 48), and intestinal ischemia or perforation (n = 9). Bariatric surgeons performed 35% of cases, and risk profiles were similar between groups. Operative times were similar for cholecystectomies and appendectomies. Bariatric surgeons performed more nonroutine cases laparoscopically (7% B versus 2% NB, P = .001). Surgical site infections were low (2% B versus 4% NB, P = .4). Hospital length of stay was higher in the NB group at 9 +/- 9 days versus 5 +/- 4 days for B (P = .05). Mortality was 5%. CONCLUSIONS: Acute surgical procedures were performed in obese patients. Bariatric expertise favorably affected length of stay and the application of laparoscopy. Bariatric expertise may improve outcomes in nonbariatric emergencies, but further study is warranted. PMID- 29428694 TI - Weekend woodsmen: Overview and comparison of injury patterns associated with power saw and axe utilization in the United States. AB - INTRODUCTION: Power saw and axe injuries are associated with significant morbidity and are increasingly managed in the emergency department (ED). However, these injuries have not been summarily reported in the literature. We aim to evaluate and compare the common injury patterns seen with use of power saws and axes. MATERIALS AND METHODS: Data from the National Electronic Injury Surveillance System- All Injury Program (NEISS-AIP) database was analyzed during 2006 to 2016. All patients with nonfatal injuries relating to the use of power saws or axes were included. Baseline demographics type and location of injuries were collected. Descriptive statistical analyses were performed using Chi Square or Fisher's exact test. RESULTS: Information on (n = 18,250) patients was retrieved from the NEISS-AIP database. Injuries were caused by power saw n = 16,384 (89%) and axe n = 1866 (11%) use, and mostly involved males (95%). The most frequently encountered injury was laceration axe n = 1166 (62.5%); power saw n = 11,298 (68.9%). Approximately half of all injuries in both groups involved the fingers and hand. Most injuries occurred at home (65%) and were attributed to power saw use (89%). CONCLUSIONS: Power saws and axes can cause significant injuries, the majority of which occurred at home and were primarily associated with power saw use. Lacerations and injuries to the finger and hand were prevalent in both study groups. Further research into power saw and axe injuries should place emphasis on preventative measures and personal protective equipment (PPE). LEVEL OF EVIDENCE: IV Study type: Retrospective review. PMID- 29428695 TI - Appendiceal outer diameter as an indicator of acute appendicitis in young children. PMID- 29428696 TI - An actionable test using loss of heterozygosity in identifying high-risk oral premalignant lesions. AB - OBJECTIVES: To develop an actionable test using fluorescence capillary electrophoresis (FCE) to assess loss of heterozygosity (LOH) of histologically similar low-grade lesions (LGLs) to identify high-risk lesions for oral cancer progression. STUDY DESIGN: To determine the cutoffs of LOH, the FCE results of 52 surgical margin samples were used to compare with the existing LOH results from the previously validated 32 P-GE approach. Using the developed FCE workflow, an independent set of 102 LGLs with known progression status was used to determine the LOH molecular risk (MR) patterns and associated risk of progression. RESULTS: Using 65% cutoff LOH-FCE, the agreement of LOH-32 P-GE had an average of 82.3% (76.8-87.8). Compared with nonprogressors (n = 61), anatomic site and MR patterns (LOH at 9 p21, 3 p14, or 17 p13) were independent risk factors. High-risk profile of tongue and MR3 (LOH at 9 p21 and/or 3 p14 and 17 p13) was significantly associated with progression (hazard ratio [HR] 6.7; 95% confidence interval [CI] 2.6-17.6) with specificity of 98.4% at identifying progressors. CONCLUSIONS: We have developed an objective test using LOH to stratify the risk of LGLs. With further validation, it can be used in the clinical settings to provide clinicians additional information guiding the management of these lesions. PMID- 29428697 TI - Transient bacteremia induced by dental cleaning is not associated with infection of central venous catheters in patients with cancer. AB - OBJECTIVE: The aim of this study was to determine the incidence of bacteremia resulting from dental cleaning and of subsequent established bloodstream infection (BSI) caused by oral microorganisms in patients with cancer with central venous catheters (CVCs). STUDY DESIGN: Twenty-six patients with cancer with CVCs and absolute neutrophil count over 1000 cells/uL received dental cleaning without antibiotic prophylaxis. Periodontal status was assessed at baseline by using the Periodontal Screening and Recording (PSR) score. Blood cultures were drawn via the CVCs at baseline, 20 minutes into cleaning, and 30 minutes and 24 hours after cleaning. Medical records were monitored for 6 months. RESULTS: Baseline blood culture results were negative in 25 patients. Nine of 25 patients (36%) had positive blood culture 20 minutes into cleaning, all associated with at least 1 microorganism typically found in the mouth. These 9 patients had significantly higher mean PSR score (3.22) compared with the other 16 (2.56; P = .035). These expected bacteremias did not persist, with blood culture results (0/25) at 30 minutes and 24 hours after cleaning showing no positivity (P = .001). There were no cases of CVC-related infection or BSI attributable to dental cleaning. CONCLUSIONS: Bacteremia resulting from dental cleaning is transient and unlikely to cause CVC-related infection or BSI in patients with absolute neutrophil count greater than 1000 cells/uL. PMID- 29428698 TI - Mast cells, basophils and eosinophils: From allergy to cancer. AB - Basophils, eosinophils and mast cells were first recognized by Paul Ehrlich in the late 19th century. These cells have common, but non-redundant roles, in the pathogenesis of allergic diseases and in the protection against parasites. Nevertheless, in virtue of their shared-adeptness to produce a huge variety of immunological mediators and express membrane-bound receptors, they are able to interact with immune and non-immune components of the tissue microenvironment, contributing to the regulation of tissue homeostasis and immune response while participating to further deregulation of tissues transforming into neoplasia. PMID- 29428699 TI - C-reactive protein (CRP) and long-term air pollution with a focus on ultrafine particles. AB - BACKGROUND: Long-term exposure to ambient air pollution contributes to the global burden of disease by particularly affecting cardiovascular (CV) causes of death. We investigated the association between particle number concentration (PNC), a marker for ultrafine particles, and other air pollutants and high sensitivity C reactive protein (hs-CRP) as a potential link between air pollution and CV disease. METHODS: We cross-sectionally analysed data from the second follow up (2013 and 2014) of the German KORA baseline survey which was conducted in 1999 2001. Residential long-term exposure to PNC and various other size fractions of particulate matter (PM10 with size of <10 MUm in aerodynamic diameter, PMcoarse 2.5-10 MUm or PM2.5 < 2.5 MUm, respectively), soot (PM2.5abs: absorbance of PM2.5), nitrogen oxides (nitrogen dioxide NO2 or oxides NOx, respectively) and ozone (O3) were estimated by land-use regression models. Associations between annual air pollution concentrations and hs-CRP were modeled in 2252 participants using linear regression models adjusted for several confounders. Potential effect modifiers were examined by interaction terms and two-pollutant models were calculated for pollutants with Spearman inter-correlation <0.70. RESULTS: Single pollutant models for PNC, PM10, PMcoarse, PM2.5abs, NO2 and NOx showed positive but non-significant associations with hs-CRP. For PNC, an interquartile range (2000 particles/cm3) increase was associated with a 3.6% (95% CI: -0.9%, 8.3%) increase in hs-CRP. A null association was found for PM2.5. Effect estimates were higher for women, non-obese participants, for participants without diabetes and without a history of cardiovascular disease whereas ex-smokers showed lower estimates compared to smokers or non-smokers. For O3, the dose-response function suggested a non-linear relationship. In two-pollutant models, adjustment for PM2.5 strengthened the effect estimates for PNC and PM10 (6.3% increase per 2000 particles/cm3 [95% CI: 0.4%; 12.5%] and 7.3% per 16.5 MUg/m3 [95% CI: 0.4%; 14.8%], respectively). CONCLUSION: This study adds to a scarce but growing body of literature showing associations between long-term exposure to ultrafine particles and hs-CRP, one of the most intensely studied blood biomarkers for cardiovascular health. Our results highlight the role of ultrafine particles within the complex mixture of ambient air pollution and their inflammatory potential. PMID- 29428701 TI - Influence of glycosaminoglycans on the properties of thin films based on chitosan/collagen blends. AB - Thin films based on chitosan, collagen, and glycosaminoglycans isolated from fish skin were obtained by solvent evaporation. The films were characterized by different analyses, e.g. surface free energy determination, swelling tests, roughness, mechanical and thermal measurements. Moreover, the degradation studies were carried out by the film treatment with collagenase. The results showed that the properties of the films based on chitosan and collagen can be modified by the glycosaminoglycans addition. It was noticed that the addition of glycosaminoglycans enhances the surface hydrophilicity and reduces surface free energy. Surfaces of films modified by glycosaminoglycans (GAGs) show more roughness which inhibits the risk of biofilm formation. The highest films swelling was obtained after 2 h immersion in phosphate-buffered saline (PBS). After their immersion in PBS, the films were more elastic, which was assumed on the basis of the elongation at break values higher than in the case of films on a dry surface. The proposed films can create biocompatible coatings for biomedical applications. PMID- 29428700 TI - Comparative effectiveness of upfront esophagectomy versus induction chemoradiation in clinical stage T2N0 esophageal cancer: A decision analysis. AB - OBJECTIVES: We compared the effectiveness of upfront esophagectomy versus induction chemoradiation followed by esophagectomy for overall survival in patients with clinical T2N0 (cT2N0) esophageal cancer. We also assessed the influence of the diagnostic uncertainty of endoscopic ultrasound on the expected benefit of chemoradiation. METHODS: We created a decision analysis model representing 2 treatment strategies for cT2N0 esophageal cancer: upfront esophagectomy that may be followed by adjuvant therapy for upstaged patients and induction chemoradiation for all patients with cT2N0 esophageal cancer followed by esophagectomy. Parameter values within the model were obtained from published data, and median survival for pathologic subgroups was derived from the National Cancer Database. In sensitivity analyses, staging uncertainty of endoscopic ultrasound was introduced by varying the probability of pathologic upstaging. RESULTS: The baseline model showed comparable median survival for both strategies: 48.3 months for upfront esophagectomy versus 45.9 months for induction chemoradiation and surgery. The sensitivity analysis demonstrated induction chemoradiation was beneficial, with probability of upstaging > 48.1%, which is within the published range of 32% to 65% probability of pathologic upstaging after cT2N0 diagnosis. The presence of any of 3 key variables (size larger than 3 cm, high grade, or lymphovascular invasion) was associated with > 48.1% risk of upstaging, thus conferring a survival advantage to induction chemoradiation. CONCLUSIONS: The optimal treatment strategy for cT2N0 esophageal cancer depends on the accuracy of endoscopic ultrasound staging. High-risk features that confer increased probability of upstaging can inform clinical decision making to recommend induction chemoradiation for select cT2N0 patients. PMID- 29428702 TI - Micromechanics of brain white matter tissue: A fiber-reinforced hyperelastic model using embedded element technique. AB - A transverse-plane hyperelastic micromechanical model of brain white matter tissue was developed using the embedded element technique (EET). The model consisted of a histology-informed probabilistic distribution of axonal fibers embedded within an extracellular matrix, both described using the generalized Ogden hyperelastic material model. A correcting method, based on the strain energy density function, was formulated to resolve the stiffness redundancy problem of the EET in large deformation regime. The model was then used to predict the homogenized tissue behavior and the associated localized responses of the axonal fibers under quasi-static, transverse, large deformations. Results indicated that with a sufficiently large representative volume element (RVE) and fine mesh, the statistically randomized microstructure implemented in the RVE exhibits directional independency in transverse plane, and the model predictions for the overall and local tissue responses, characterized by the normalized strain energy density and Cauchy and von Mises stresses, are independent from the modeling parameters. Comparison of the responses of the probabilistic model with that of a simple uniform RVE revealed that only the first one is capable of representing the localized behavior of the tissue constituents. The validity test of the model predictions for the corona radiata against experimental data from the literature indicated a very close agreement. In comparison with the conventional direct meshing method, the model provided almost the same results after correcting the stiffness redundancy, however, with much less computational cost and facilitated geometrical modeling, meshing, and boundary conditions imposing. It was concluded that the EET can be used effectively for detailed probabilistic micromechanical modeling of the white matter in order to provide more accurate predictions for the axonal responses, which are of great importance when simulating the brain trauma or tumor growth. PMID- 29428703 TI - The contribution of total and free iodothyronines to welfare maintenance and management stress coping in Ruminants and Equines: Physiological ranges and reference values. AB - In order to acquire a pattern of thyroid involvement in welfare maintenance in Ruminants and Equines, this review summarizes data concerning the reference values of total and free iodothyronines and their modifications in physiological conditions and in different management conditions (pregnancy, lactation, weaning, growth, isolation, restraint, shearing, confinement and transportation). Thyroidal and extrathyroidal tissues efficiently respond to management practices, giving a differentiated contribution to circulating iodothyronine changes. The hormonal response could be mainly attributed to the intracellular deiodination of T4 to T3. Triiodothyronine (T3) and free iodothyronines (fT3 and fT4) result more responsive to management stress, showing different pattern with species and to various conditions, as to environmental conditions in which activities are performed. Intrinsic seasonal changes of iodothyronines and a significant pregnancy effect for T3 were recorded in mares. Higher, although not significant, T3 and T4 concentrations in barren than pregnant mares were observed in donkeys. A positive significant correlation between T3 and T4 was described only in pregnant donkeys. Moreover, a significant effect of season on T3 and fT3 changes was observed both in pregnant and barren donkeys. A significant lactating effect compared with nonlactating stage for T3 and T4 was recorded in mares. In growing foals, body weight (BW) and age were positively correlated with T3 and negatively correlated with T4, fT4 and fT3. Weaning effects were shown for T3 and fT4 concentrations, indicating that weaning represents a severe stress and the presence of conspecific does not reduce psychological stress in this phase. Lambs showed significant decreased T3 and elevated T4 concentrations two weeks after weaning, with higher concentrations in both males and females compared to 24 h. Significant positive correlations were observed between BW and T4, fT3 and fT4 concentrations in lambs. A T3 decrease was detected after isolation, such as induced by confinement and weaning in lambs. Higher T3 concentration after restraint and shearing than after isolation and significant increases in T4, fT3 and fT4 values after restraint and shearing were recorded. The basal concentrations of fT3 in both the inexperienced and experienced transported horses were significantly higher than in untransported experienced horses. Moreover, increases of T3, T4 and fT4 after short road transportation, and significant correlations between T3 and rectal temperature (RT), body weight (BW) and heart rate (HR), confirmed their important role in coping strategy. Thyroid responsiveness to short transport is similar in domestic donkeys and horses, with a preferential release of T3 in horses. A greatest and constant release of T3 and T4, although differentiated, after simulated transportation and after conventional transport of horses confirmed that the degree of stress induced by confinement and additional stressful stimuli associated to road transportation could differently influence the iodothyronine release. Temperamental Limousin young beef bulls showed lower T4 and fT4 concentrations after prolonged transportation than calm subjects, and a concomitant decrease of circulating ACTH, cortisol, T3 and fT3 concentrations, probably induced by down regulation of HPA axis and cortisol negative feedback. These data reinforce the importance of taking into account the evaluation of iodothyronines, and notably of T3, as markers of welfare and stress and their role in ensuring energy homeostasis and productive and reproductive performances in Ruminants and Equines. PMID- 29428704 TI - The importance of animal models in research. PMID- 29428705 TI - Risk factors for failure in the newborn hearing screen test in very preterm twins. AB - BACKGROUND: We aimed to identify prenatal and postnatal risk factors associated with abnormal newborn hearing screen (NHS) results and subsequently confirmed sensorineural hearing loss (SNHL) in preterm twin neonates. METHODS: Electronic medical records of 159 twin neonates who were born alive after <=32 weeks were retrospectively reviewed for hearing loss in both ears. Histopathologic examination of the placenta was performed and clinical data, including method of conception and factors specific to twins, were retrieved from a computerized perinatal database. The main outcome measure was failure to pass the NHS test. The generalized estimation equations model was used for twins. RESULTS: Thirty two neonates (20.1%) had a "refer" result, and, on the confirmation test, permanent SNHL was identified in 4.4% (7/159) of all neonates. Neonates who had a "refer" result on the NHS test were more likely to be of lower birth weight, more likely to have been conceived with the use of in vitro fertilization (IVF), and more likely to have higher rates of intraventricular hemorrhage (IVH) and bronchopulmonary dysplasia. However, monochorionic placentation, death of the co twin, or being born first was not associated with a "refer" result on the NHS test. Multivariable logistic regression revealed that conception after IVF and the presence of IVH were the only variables to be statistically significantly associated with "refer" on the NHS test. No parameters studied were found to be significantly different between the SNHL and no SNHL groups, probably because of the relatively small number of cases of SNHL. CONCLUSION: In preterm twin newborns, IVF and the presence of IVH were independently associated with an increased risk of abnormal NHS results, whereas the factors specific to twins were not associated with abnormal NHS results. PMID- 29428706 TI - Oxidative potential of ambient PM2.5 in the coastal cities of the Bohai Sea, northern China: Seasonal variation and source apportionment. AB - Emissions of air pollutants from primary and secondary sources in China are considerably higher than those in developed countries, and exposure to air pollution is main risk of public health. Identifying specific particulate matter (PM) compositions and sources are essential for policy makers to propose effective control measures for pollutant emissions. Ambient PM2.5 samples covered a whole year were collected from three coastal cities of the Bohai Sea. Oxidative potential (OP) was selected as the indicator to characterize associated PM compositions and sources most responsible for adverse impacts on human health. Positive matrix factorization (PMF) and multiple linear regression (MLR) were employed to estimate correlations of PM2.5 sources with OP. The volume- and mass based dithiothreitol (DTTv and DTTm) activities of PM2.5 were significantly higher in local winter or autumn (p < 0.01). Spatial and seasonal variations in DTTv and DTTm were much larger than mass concentrations of PM2.5, indicated specific chemical components are responsible for PM2.5 derived OP. Strong correlations (r > 0.700, p < 0.01) were found between DTT activity and water soluble organic carbon (WSOC) and some transition metals. Using PMF, source fractions of PM2.5 were resolved as secondary source, traffic source, biomass burning, sea spray and urban dust, industry, coal combustion, and mineral dust. Further quantified by MLR, coal combustion, biomass burning, secondary sources, industry, and traffic source were dominant contributors to the water-soluble DTTv activity. Our results also suggested large differences in seasonal contributions of different sources to DTTv variability. A higher contribution of DTTv was derived from coal combustion during the local heating period. Secondary sources exhibited a greater fraction of DTTv in summer, when there was stronger solar radiation. Traffic sources exhibited a prevailing contribution in summer, and industry contributed larger proportions in spring and winter. Future abatement priority of air pollution should reduce the sources contributing to OP of PM2.5. PMID- 29428707 TI - Seasonal variation, phase distribution, and source identification of atmospheric polycyclic aromatic hydrocarbons at a semi-rural site in Ulsan, South Korea. AB - Polycyclic aromatic hydrocarbons (PAHs) in gaseous and particulate phases (n = 188) were collected in Ulsan, South Korea, over a period of one year (June 2013 May 2014) to understand the seasonal variation and phase distribution of PAHs as well as to identify the seasonal PAH emission sources. The target compounds were the 16 US-EPA priority PAHs, with the exception of naphthalene, acenaphthylene, and acenaphthene. Winter and spring had the highest and lowest PAH concentrations, respectively. The mean of the Sigma13 PAHs in the gaseous phase (4.11 ng/m3) was higher than that in the particulate phase (2.55 ng/m3). Fractions of the gaseous or 3- and 4-ring PAHs (i.e., Flu, Phe, and Ant) were high in summer, and those of the particulate or 5- and 6-ring PAHs (i.e., BkF, BaP, Ind, DahA, and BghiP) increased in winter. Gas/particle partitioning models also demonstrated the increased contributions of the particulate PAHs in spring and winter. Source identification of PAHs was undertaken using diagnostic ratios, principal component analysis, and positive matrix factorization. The results indicated that pyrogenic sources (e.g., coal combustion) were dominant in winter. Other types of pyrogenic (e.g., industrial fuel combustion) and petrogenic sources were the main PAH sources in summer and autumn. The influence of both sources, especially in summer, might be due to seasonal winds transporting PAHs from the industrial areas. Two types of pyrogenic sources, diesel and coal combustion, were identified as the main PAH sources in spring. This study clearly demonstrates a source-receptor relation of PAHs at a semi-rural site in a heavily industrialized city. PMID- 29428708 TI - Surface water flooding, groundwater contamination, and enteric disease in developed countries: A scoping review of connections and consequences. AB - Significant volumes of research over the past four decades has sought to elucidate the social, infrastructural, economic, and human health effects of climate change induced surface flooding. To date, epidemiological and public health studies of flooding events have focused on mental health effects, vector borne diseases, and infectious enteric disease due to floodwater contact (i.e. typically low consumption rates). The inherent nature of groundwater (i.e. out of sight, out of mind) and the widely held belief that aquifers represent a pristine source of drinking water due to natural attenuation may represent the "perfect storm" causing direct consumption of relatively large volumes of surface flood contaminated groundwater. Accordingly, the current study sought to systematically identify and synthesize all available peer-reviewed literature pertaining to the nexus between surface flooding, groundwater contamination and human gastroenteric outcomes. Just 14 relevant studies were found to have been published during the period 1980-2017, thus highlighting the fact that this potentially significant source of climate-related exposure to environmental infection has remained understudied to date. Studies differed significantly in terms of type and data reporting procedures, making it difficult to discern clear trends and patterns. Approximately 945 confirmed cases of flood-related enteric disease were examined across studies; these concurred with almost 10,000 suspected cases, equating to approximately 20 suspected cases per confirmed case. As such, no regional, national or global estimates are available for the human gastrointestinal health burden of flood-related groundwater contamination. In light of the demonstrable public health significance of the concurrent impacts of groundwater susceptibility and climate change exacerbation, strategies to increase awareness about potential sources of contamination and motivate precautionary behaviour (e.g. drinking water testing and treatment, supply interruptions) are necessary. Mainstreaming climate adaptation concerns into planning policies will also be necessary to reduce human exposure to waterborne sources of enteric infection. PMID- 29428709 TI - Assessment of winter air pollution episodes using long-range transport modeling in Hangzhou, China, during World Internet Conference, 2015. AB - A winter air pollution episode was observed in Hangzhou, South China, during the Second World Internet Conference, 2015. To study the pollution characteristics and underlying causes, the Weather Research and Forecasting with Chemistry model was used to simulate the spatial and temporal evolution of the pollution episode from December 8 to 19, 2015. In addition to scenario simulations, analysis of the atmospheric trajectory and synoptic weather conditions were also performed. The results demonstrated that control measures implemented during the week preceding the conference reduced the fine particulate matter (PM2.5) pollution level to some extent, with a decline in the total PM2.5 concentration in Hangzhou of 15% (7%-25% daily). Pollutant long-range transport, which occurred due to a southward intrusion of strong cold air driven by the Siberia High, led to severe pollution in Hangzhou on December 15, 2015, accounting for 85% of the PM2.5 concentration. This study provides new insights into the challenge of winter pollution prevention in Hangzhou. For adequate pollution prevention, more regional collaborations should be fostered when creating policies for northern China. PMID- 29428710 TI - Simultaneous removal of amoxicillin, ampicillin and penicillin by clay supported Fe/Ni bimetallic nanoparticles. AB - This study examined functional bentonite-supported nanoscale Fe/Ni (B-Fe/Ni) for the simultaneous removal of beta-lactam antibiotics such as amoxicillin (AMX), ampicillin (AMP) and penicillin (PEN). The results show only 94.6% of AMX, 80.6% of AMP and 53.7% of PEN were removed in the mixed antibiotic solution, while 97.5% of AMX, 85.1% of AMP and 74.5% of PEN were removed in individual antibiotic solution. The decreased removal in a mixed antibiotic solution was attributed to competition between antibiotics for: firstly, active sites of iron oxide for the adsorption; and secondly, accepted electrons for the degradation in passivation of the nZVI surface. These were confirmed by various characterization techniques. Kinetics studies of mixed antibiotics using B-Fe/Ni confirmed that adsorption and degradation occurred simultaneously as removing of antibiotics in the presence of particles. Furthermore, the stability and durability of B-Fe/Ni applied to remove beta-lactam antibiotics was demonstrated. Finally, B-Fe/Ni was used to reduce the concentration of mixed antibiotics from pharmaceutical wastewater, which indicated B-Fe/Ni is a promising material for antibiotics wastewater treatment. PMID- 29428711 TI - 2005-2014 trends of PM10 source contributions in an industrialized area of southern Spain. AB - : Particulate matter with a diameter of 10 MUm or less (PM10) using receptor modelling was determined at an urban (La Linea, LL) and an industrial area (Puente Mayorga, PMY) in Southern Spain with samples collected during 2005-2014. The concentrations of PM10 had been decreasing at both sites in three distinctive periods: 1) the initial PM10 levels approached or exceeded the Spain and EU PM10 annual guidelines of 40 MUg/m3 during 2005-2007 at LL and 2005-2009 at PMY; 2) then PM10 dropped by 25%-~30 MUg/m3 during 2008-2011 at LL and during 2010-2011 at PMY; 3) since 2012, the PM10 concentrations gradually decreased to <30 MUg/m3. Chemical compositions of PM10 revealed the important contributions of water soluble ions (sulfate, nitrate, ammonium, and chloride), carbonaceous aerosols, and other major elements. These PM components generally showed a decrease trend, in accord with the trend of PM10 reduction. A PMF model identified seven sources to PM10 contributions. Secondary sulfate, soil/urban/construction dust, and secondary nitrate showed significantly decreasing trends with reduction of 40-60% comparing to the initial levels. The road traffic contribution decreased by 14% from the first to third period. However, sea salt, oil combustion, and industrial metallurgical process had relative stable contributions. These source contribution changes are reasonably governed by the PM emission abatement actions implemented during the past decade, as well as the financial crisis, that accounted for a significant decrease of PM pollution in Southern Spain. THE MAIN FINDING OF THE WORK: We identified that the mitigation efforts on industry, fossil fuel combustion, and urban transportation during the past decade were successful for air quality improvement in a highly industrialized area in Southern Spain. PMID- 29428712 TI - Quantification of atmospheric emissions and energy metrics from simulated clamp kiln technology in the clay brick industry. AB - The quantification of atmospheric emissions from clamp kilns in the clay brick industry has met with limited success globally. The complex configuration of clamp kilns using coal or other carbonaceous fuels and uncertainties regarding kiln combustion conditions, has proven to be a hurdle in measurement of emissions and standardization of process and energy metrics. To enable quantification of these metrics, a model kiln was designed to simulate operating conditions and configuration similar to transverse slice of a typical full-scale clamp kiln, but with lower capacity (20,000 to 35,000 bricks per cycle). Hourly measurements of flue gas at extraction duct were recorded for thirteen firing cycles obtained from various source factories, each lasting 8-14 days, for SO2, NO2, NO, PM, CO and CO2 emissions in the extraction stack. A statistical mean efficiency for model kiln emissions capturing and channelling capacity was calculated from sulfur mass balance results of batches that lie within 95% confidence interval of assumed true mean (100%) to give 84.2%. Final emission factors (mean +/- standard deviation) were quantified as 22.5 +/- 18.8 g/brick for CO, 0.14 +/- 0.1 g/brick for NO, 0.0 g/brick for NO2, 0.14 +/- 0.1 g/brick for NOx, 1.07 +/- 0.7 g/brick for SO2, 378 +/- 223 g/brick for CO2; 0.96 +/- 0.5 g/brick for PM10; as well as 1.53 g/brick for hydrocarbons. Energy analysis indicate that a significant reduction of 0.9 MJ/kg (36%) in energy use could be achieved by clamp kiln operators, thereby reducing input costs, and significantly reducing atmospheric emissions. PMID- 29428713 TI - Cluster analysis of fine particulate matter (PM2.5) emissions and its bioreactivity in the vicinity of a petrochemical complex. AB - This study evaluated associations between the bioreactivity of PM2.5in vitro and emission sources in the vicinity of a petrochemical complex in Taiwan. The average PM2.5 was 30.2 MUg/m3 from 9 February to 23 March 2016, and the PM2.5 was clustered in long-range transport (with major local source) (12.8 MUg/m3), and major (17.3 MUg/m3) and minor industrial emissions (4.7 MUg/m3) using a k-means clustering model. A reduction in cell viability and increases in the cytotoxicity related lactate dehydrogenase (LDH), oxidative stress-related 8-isoprostane, and inflammation-related interleukin (IL)-6 occurred due to PM2.5 in a dose-dependent manner. The PM2.5 from major industrial emissions was significantly correlated with increased 8-isoprostane and IL-6, but this was not observed for long-range transport or minor industrial emissions. The bulk metal concentration was 9.52 ng/m3 in PM2.5. We further observed that As, Ba, Cd, and Se were correlated with LDH in the long-range transport group. Pb in PM2.5 from the major industrial emissions was correlated with LDH, whereas Pb and Se were correlated with 8 isoprostane. Sr was correlated with cell viability in the minor industrial emissions group. We demonstrated a new approach to investigate particle bioreactivity, which suggested that petrochemical-emitted PM2.5 should be a concern for surrounding residents' health. PMID- 29428714 TI - beta-amyloid deposition is associated with gait variability in usual aging. AB - BACKGROUND: Higher amyloid burden predicts gait slowing in aging. Whether and which gait characteristics are associated with amyloid burden is less clear. Gait variability may be more sensitive to amyloid burden than mean gait characteristics. METHODS: In the Baltimore Longitudinal Study of Aging, 99 older participants without neurological disease had concurrent amyloid imaging and assessment of gait characteristics. beta-amyloid burden was measured using 11C Pittsburgh compound B (PiB) positron emission tomography. PiB+/- status was based on a mean cortical distribution volume ratio (DVR) cut point. Gait characteristics were quantified by 3D motion analysis. Cross-sectional associations of PiB+/- status and DVR in motor-related regions (primary motor cortex, putamen, caudate) with gait characteristics were examined using linear regression, adjusted for age, sex, height, body mass index, gait speed and covariates (memory, executive function, visuoperceptual speed, depressive symptoms, cardiovascular risk, ApoE epsilon4, cerebrovascular burden, neurodegeneration, peripheral arterial disease, knee pain). RESULTS: Being PiB+ and higher DVR in motor-related regions were associated with greater gait speed variability, cadence variability, and gait cycle time variability but not with mean gait characteristics. Associations remained similar after adjustment for gait speed and covariates, except for memory, which attenuated associations of PiB+/- with cadence variability and gait cycle time variability. Associations were prominent in men but were not found in women. CONCLUSIONS: In usual aging, integrated temporal gait variability measures, but not mean performance, appear related to amyloid burden from cortical and motor-related cortical and subcortical regions, especially in men. Increased gait variability may be a subclinical indicator of increased amyloid burden in men. PMID- 29428716 TI - What's In a Word? PMID- 29428715 TI - Routine clinical anti-platelet agents have limited efficacy in modulating hypershear-mediated platelet activation associated with mechanical circulatory support. AB - INTRODUCTION: Continuous flow ventricular assist devices (cfVADs) continue to be limited by thrombotic complications associated with disruptive flow patterns and supraphysiologic shear stresses. Patients are prescribed complex antiplatelet therapies, which do not fully prevent recurrent thromboembolic events. This is partially due to limited data on antiplatelet efficacy under cfVAD-associated shear conditions. MATERIALS AND METHODS: We investigated the efficacy of antiplatelet drugs directly acting on three pathways: (1) cyclooxygenase (aspirin), (2) phosphodiesterase (dipyridamole, pentoxifylline, cilostazol), and (3) glycoprotein IIb-IIIa (eptifibatide). Gel-filtered platelets treated with these drugs were exposed for 10min to either constant shear stresses (30dyne/cm2 and 70dyne/cm2) or dynamic shear stress profiles extracted from simulated platelet trajectories through a cfVAD (Micromed DeBakey). Platelet activation state (PAS) was measured using a modified prothrombinase-based assay, with drug efficacy quantified based on PAS reduction compared to untreated controls. RESULTS AND CONCLUSIONS: Significant PAS reduction was observed for all drugs after exposure to 30dyne/cm2 constant shear stress, and all drugs but dipyridamole after exposure to the 30th percentile shear stress waveform of the cfVAD. However, only cilostazol was significantly effective after 70dyne/cm2 constant shear stress exposure, though no significant reduction was observed upon exposure to median shear stress conditions in the cfVAD. These results, coupled with the persistence of reported clinical thrombotic complication, suggest the need for the development of new classes of drugs that are especially designed to mitigate thrombosis in cfVAD patients, while reducing or eliminating the risk of bleeding. PMID- 29428717 TI - Visual Outcomes Following Bilateral lmplantation of Two Diffractive Trifocal Intraocular Lenses in 10 084 Eyes: Are Big Data Always Better? PMID- 29428718 TI - Synergistic effects of simvastatin and bone marrow-derived mesenchymal stem cells on hepatic fibrosis. AB - The beneficial effects of simvastatin on fibrosis in various organs have been reported. In addition, bone marrow (BM)-derived mesenchymal stem cells (MSCs) have been suggested as an effective therapy for hepatic fibrosis and cirrhosis. Recent evidence suggests that pharmacological treatment devoted to regulating stem cell function is a potential new therapeutic strategy that is drawing nearer to clinical practice. The aim of this study was to determine whether the combination treatment of simvastatin plus MSCs (Sim-MSCs) could have a synergistic effect on hepatic fibrosis in a thioacetamide (TAA)-induced cirrhotic rat model and hepatic stellate cells (HSCs). Cirrhotic livers from rats treated with Sim-MSCs exhibited histological improvement compared to those treated with simvastatin alone. Sim-MSCs combination treatment decreased hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment in rats with TAA-induced cirrhosis. These protective effects were more potent with Sim-MSCs than with simvastatin alone. The upregulation of collagen-1, alpha-smooth muscle actin (alpha-SMA), transforming growth factor (TGF)-beta1, and phospho-Smad3 in cirrhotic livers was prevented by the administration of Sim MSCs. Intriguingly, Sim-MSCs inhibited both TGF-beta/Smad3 signaling and alpha SMA in HSCs. The Sim-MSCs combination treatment exerted strong protective effects against hepatic fibrosis by suppressing TGF-beta/Smad signaling. Simvastatin could act synergistically with MSCs as an efficient therapeutic approach for intractable cirrhosis. PMID- 29428719 TI - Combination effects of alogliptin and pioglitazone on steatosis and hepatic fibrosis formation in a mouse model of non-alcoholic steatohepatitis. AB - This study aimed to evaluate the effects of combination therapy with a dipeptidyl peptidase-4 inhibitor, alogliptin, and a peroxisome proliferator-activated receptor-gamma agonist, pioglitazone, in a preclinical model of nonalcoholic steatohepatitis using low-density lipoprotein receptor-knockout mice fed a modified choline-deficient l-amino acid-defined diet. Monotherapy with either alogliptin (10-200 mg/kg) or pioglitazone (6-20 mg/kg) significantly decreased hepatic triglyceride content and fibrosis. The concomitant treatment of alogliptin (30 mg/kg), pioglitazone (20 mg/kg) also decreased hepatic triglyceride and hepatic collagen-I mRNA at greater extent compared to monotherapy. Hepatic expression of CD11b mRNA and monocyte chemoattractant protein-1 were also reduced by the concomitant treatment. These results suggest that via an anti-inflammatory potential in addition to anti-metabolic effects, the combination therapy of alogliptin and pioglitazone may provide therapeutic benefits to type 2 diabetes patients with nonalcoholic steatohepatitis, which will be proven in controlled clinical trials. PMID- 29428720 TI - Effects of pre-incubation with C-type natriuretic peptide on nuclear maturation, mitochondrial behavior, and developmental competence of sheep oocytes. AB - In vitro produced mammalian embryos suffer from developmental failure, with a large proportion showing embryonic retardation, degradation, or apoptosis. This failure is due, in part, to incomplete oocyte cytoplasmic maturation. C-type natriuretic peptide (CNP) has been reported to act as a meiotic inhibitor. Here we explored the potential effects of CNP pre-treatment sheep oocytes on nuclear maturation, changes in mitochondrial behavior and developmental competence of in vitro fertilized embryos. Sheep cumulus-oocyte complexes (COCs) were aspirated from abattoir-derived ovaries. Nuclear progression was assessed using DAPI chromatin staining, the expression of natriuretic peptide receptor 2 (NPR2) was evaluated by RT-qPCR, active mitochondria localization was assessed with a confocal laser scanning microscopy using MitoTracker Red, and the developmental competence of sheep oocytes subjected to one-step IVM or two-step IVM with or without CNP pretreatment was also investigated. Our results showed that 200 nM CNP could effectively maintain meiotic arrest of sheep COCs in vitro within 4 h. Furthermore, NPR2 mRNA was mainly expressed in cumulus cells. COCs pre-treated with 200 nM CNP for 4 h followed by 24 h IVM showed significantly higher (P < 0.05) cleavage rate and blastocyst rate after in vitro fertilization (IVF), and significantly lower (P < 0.05) proportion of DNA-fragmented nuclei in blastocysts when compared to the conventional 24 h IVM (standard IVM). Non-matured oocytes mainly displayed brilliant circumferential and fine diffuse distribution of mitochondria throughout the cytoplasm. By comparison, 200 nM CNP pre-treated COCs for 4 h led to cytoplasmic mitochondrial granule localization to the peripheral and perinuclear regions. Moreover, oocytes pre-treated with 200 nM CNP for 4 h followed by 24 h IVM, showed mitochondrial organization were similar to those of conventional 24 h matured oocytes in which mitochondria were aggregated more toward the cortical regions of the oocytes, but with larger clumps of stained mitochondria. These results indicate that CNP pre-treatment improves the quality and developmental competence of sheep oocytes and has great potential for facilitating in vitro embryo production. PMID- 29428721 TI - GAS5 silencing protects against hypoxia/ischemia-induced neonatal brain injury. AB - Hypoxic/ischemic brain damage (HIBD) leads to high neonatal mortality and severe neurologic morbidity. However, the molecular mechanism of HIBD in the neonatal infant is still elusive. Long non-coding RNAs are shown as important regulators of brain development and many neurological diseases. Here, we determined the role of long noncoding RNA-GAS5 in HIBD. GAS5 expression was significantly up regulated in hypoxic/ischemic-injured neonatal brain and hippocampal neurons. GAS5 silencing protected against hypoxic/ischemic-induced brain injury in vivo and primary hippocampal neuron injury in vitro. Mechanistically, GAS5 regulated hippocampal neuron function by sponging miR-23a. Intracerebroventricular injection of GAS5 shRNA significantly decreased brain GAS5 expression, reduced brain infarct size, and improved neurological function recovery. Collectively, this study suggests a promising therapeutic approach of GAS5 inhibition in the treatment of neonatal HIBD. PMID- 29428722 TI - PUM1 promotes ovarian cancer proliferation, migration and invasion. AB - BACKGROUND: Abnormal expression of the PUM1 gene (pumilio RNA binding family member 1) is closely related to chromosomal mutations and carcinogenesis. However, there is no report about expression or function of PUM1 in ovarian cancer. The present study explored the role of PUM1 in the development and progression of ovarian cancer. METHODS: Immunohistochemistry was used to detect the expression of PUM1 in normal ovarian tissues and ovarian cancer tissues. The PUM1 gene was silenced using small interfering RNAs in ovarian cancer cell line A2780. MTT, plate colony formation and EdU (5-ethynyl-2'-deoxyuridine) assays were used to detect cell growth, and cell apoptosis was detected by flow cytometry. Wound-healing and Transwell assays were performed to determine cell migration and invasion. Western blotting was used to detect the levels of cancer related proteins. RESULTS: Immunohistochemistry showed that the level of PUM1 in ovarian cancer tissues was higher than that in normal tissues. The cell proliferation, migration, and invasion ability decreased significantly, while cell apoptosis increased after silencing the PUM1 gene. Moreover, western blotting showed that downregulation of PUM1 decreased the levels of STAT3, BCL2, MMP2, and VEGFA. CONCLUSIONS: Thus, PUM1 promotes the development and progression of ovarian cancer, which may occur via the above-mentioned molecules. PMID- 29428723 TI - Yoda1-induced phosphorylation of Akt and ERK1/2 does not require Piezo1 activation. AB - Piezo1 is a mechanosensitive cation channel that is activated by shear stress in endothelial cells (ECs). It has been shown to mediate shear-induced EC responses, including increased calcium influx, and vascular functions, such as vascular tone and blood pressure. Yoda1, a selective Piezo1 activator, has been shown to mimic shear-induced responses in ECs. Since shear-induced calcium influx causes Akt and ERK1/2 activation in ECs, we examined the effects of Yoda1 and the role of Piezo1 on their activation. Here, we show that Yoda1 robustly activates Akt and ERK1/2 in ECs. Additionally, the Piezo1 antagonists, gadolinium and ruthenium red, but not GsMTx4, effectively blocks Yoda1-induced Akt activation. Our results suggest that Yoda1-induced Akt and ERK1/2 activation is not dependent on Piezo1. PMID- 29428724 TI - Dual inhibition of mTORC1 and mTORC2 perturbs cytoskeletal organization and impairs endothelial cell elongation. AB - Elongation of endothelial cells is an important process in vascular formation and is expected to be a therapeutic target for inhibiting tumor angiogenesis. We have previously demonstrated that inhibition of mTORC1 and mTORC2 impaired endothelial cell elongation, although the mechanism has not been well defined. In this study, we analyzed the effects of the mTORC1-specific inhibitor everolimus and the mTORC1/mTORC2 dual inhibitor KU0063794 on the cytoskeletal organization and morphology of endothelial cell lines. While both inhibitors equally inhibited cell proliferation, KU0063794 specifically caused abnormal accumulation of F actin and disordered distribution of microtubules, thereby markedly impairing endothelial cell elongation and tube formation. The effects of KU0063794 were phenocopied by paclitaxel treatment, suggesting that KU0063794 might impair endothelial cell morphology through over-stabilization of microtubules. Although mTORC1 is a key signaling molecule in cell proliferation and has been considered a target for preventing angiogenesis, mTORC1 inhibitors have not been sufficient to suppress angiogenesis. Our results suggest that mTORC1/mTORC2 dual inhibition is more effective for anti-angiogenic therapy, as it impairs not only endothelial cell proliferation, but also endothelial cell elongation. PMID- 29428725 TI - Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. AB - Mitochondria has been a promising target in blood cancer given their unique dependencies on mitochondrial functions compared to normal hematopoietic cells. In line with this concept, we show that an anthelminthic drug ivermectin selectively kills chronic myeloid leukemia (CML) cells via inducing mitochondrial dysfunctions and oxidative stress. Ivermectin is significantly more effective in inducing caspase-dependent apoptosis in CML cell line K562 and primary CML CD34 than normal bone marrow (NBM) CD34 cells. Ivermectin also augments in vitro and in vivo efficacy of standard CML tyrosine kinase inhibitors. Mechanistically, ivermectin inhibits respiratory complex I activity and suppresses mitochondrial respiration in K562 and CML CD34 cells. Interestingly, we demonstrate that mitochondrial respiration are lower in NBM CD34 compared to malignant CD34 cells. In addition, ivermectin also induces mitochondrial dysfunctions in NBM CD34 cells in a similar manner as in CML CD34 cells whereas NBM CD34 cells are significantly less sensitive to ivermectin than CML CD34 cells. These suggest that NBM CD34 cells are more tolerable to mitochondrial dysfunctions than CML CD34 cells. Consistently, ivermectin induces higher levels of oxidative stress and damage in CML than normal counterparts. Antioxidant NAC rescues ivermectin's effects, confirming oxidative stress as the mechanism of its action in CML. Our work provides the fundamental evidence to repurpose ivermectin for CML treatment. Our work also highlights the therapeutic value of targeting mitochondria respiration in CML. PMID- 29428726 TI - 7-Oxygenated cholesterol molecules differentially affect the expression of zonula occludens-1 in vascular smooth muscle cells and monocyte/macrophage cells. AB - To investigate the effects of 7-oxygenated cholesterol molecules on the expression of tight junction proteins, we examined the outcomes effects of 7 ketocholesterol (7K), 7alpha-hydroxycholesterol (7alphaOHChol) and 7beta hydroxycholesterol (7betaOHChol) on the expression of the tight-junction protein zonula occludens-1 (ZO-1) using vascular cells. Vascular smooth muscle cells (VSMCs) constitutively express ZO-1, and this expression remained unaffected in the presence of cholesterol. However, the level of ZO-1 protein decreased after exposure to 7K and, to a lesser extent, 7alphaOHChol and 7betaOHChol. ZO-1 was translocated to the nucleus following treatment with 7K; this translocation was inhibited by z-VAD-fmk, a pan-caspase inhibitor. ZO-1 protein was found to disintegrate in the aorta of ApoE knockout mice fed a high cholesterol diet, whereas it remained intact in the wild-type control. THP-1 monocyte/macrophage cells, which show no expression of ZO-1, were not influenced by treatment with cholesterol, 7K, and 7betaOHChol. However, the treatment of THP-1 cells with 7alphaOHChol resulted in ZO-1 expression, which largely remained localized on the cytoplasmic membrane. These results indicate the varying effects of 7-oxygenated cholesterol molecules on the expression and localization of ZO-1 depending on cell types, and suggest the contribution of 7-oxygeneted cholesterol molecules to the structural alteration of tight junctions. PMID- 29428727 TI - Establishment of mouse gingival junctional epithelial cell line using a bioengineered tooth system. AB - Junctional epithelium (JE), one of the constituents of periodontal tissue, has several unique features to prevent bacterial infection. However, the molecular mechanisms of these cells remain to be completely elucidated because there has been no JE cell line to date. We have succeeded in isolating JE cells expressing green fluorescent protein (GFP) by using a bioengineered tooth technique in mice. The gene expressions of GFP-positive JE cells, isolated from around the erupted bioengineered teeth using flow cytometry, were analyzed by RNA sequencing. GFP positive cells derived from the bioengineered tooth germs showed similar gene expression patterns to primary JE cells. The isolated GFP-positive JE cells were immortalized by transducing the simian virus 40 large T antigen using lentiviral vectors. The established GFP-positive JE cells maintained proliferative activity for more than 20 passages, and did not show cellular senescence as demonstrated by beta-galactosidase assay. These cells also expressed similar gene expression patterns to primary JE cells. The established cell lines may prove useful for future investigation of JE characteristics in vitro. PMID- 29428728 TI - Amorphous calcium carbonate: A precursor phase for aragonite in shell disease of the pearl oyster. AB - Amorphous calcium carbonate (ACC) has long been shown to act as an important constituent or precursor phase for crystalline material in mollusks. However, the presence and the role of ACC in bivalve shell formation are not fully studied. In this study, we found that brown deposits containing heterogeneous calcium carbonates were precipitated when a shell disease occurred in the pearl oyster Pinctada fucata. Calcein-staining of the brown deposits indicated that numerous amorphous calcium deposits were present, which was further confirmed by Fourier transform infrared spectroscopy (FTIR), Raman spectrum and X-ray difraction (XRD) analyses. So we speculate that ACC plays an important role in rapid calcium carbonate precipitation during shell repair process in diseased oysters. PMID- 29428729 TI - Downregulated CDKN1C/p57kip2 drives tumorigenesis and associates with poor overall survival in breast cancer. AB - CDKN1C, also known as p57kip2, is considered to be a potential tumor suppressor implicated in several kinds of human cancers. However, the current knowledge of CDKN1C in breast cancer remains obscure. In the present study, we demonstrated that CDKN1C was dramatically downregulated in breast cancer compared with normal tissues by using real-time quantitative polymerase chain reaction, western blot and two public data portals: The Cancer Genome Atlas (TCGA) and Oncomine datasets. Moreover, the expression of CDKN1C was correlated with age and tumor size in the TCGA cohort containing 708 cases of breast cancer. Low expression of CDKN1C was significantly associated with poor overall survival (OS) in the TCGA cohort and validated cohort composed of 1402 patients. Multivariate Cox regression analysis indicated that CDKN1C was an independent prognostic factor for worse OS (HR = 1.78, 95% CI: 1.09-2.89, p = 0.020). Furthermore, gene set enrichment analysis (GSEA) revealed that CDKN1C was significantly correlated with gene signatures involving DNA repair, cell cycle, glycolysis, adipogenesis, and two critical signaling pathways mTORC1 and PI3K/Akt/mTOR. In conclusion, our data suggested an essential role of CDKN1C in the tumorgenesis of breast cancer. Targeting CDKN1C may be a promising strategy for anticancer therapeutics. PMID- 29428730 TI - Targeting sphingosine kinase 2 by ABC294640 inhibits human skin squamous cell carcinoma cell growth. AB - The activity of ABC294640, a small-molecular sphingosine kinase 2 (SphK2) inhibitor, in human skin squamous cell carcinoma (SCC) cells was tested in this study. SphK2 mRNA and protein are expressed in established (A431 cheilocarcinoma cell line) and primary human skin SCC cells. ABC294640 dose-dependently inhibited survival, cell cycle progression and proliferation of skin SCC cells. Furthermore, ABC294640 induced caspase-3/-9 and apoptosis activation in skin SCC cells. The SphK2 inhibitor was however non-cytotoxic to SphK2-null skin melanocytes, keratinocytes and fibroblasts. ABC294640 induced ceramide accumulation, sphingosine-1-phosphate (S1P) reduction, Akt-S6K1 inhibition and JNK activation in skin SCC cells. Conversely, its cytotoxicity against SCC cells was largely attenuated by co-treatment of S1P, the Akt activator SC79, and the JNK inhibitor SP600125. In vivo, ABC294640 oral administration inhibited A431 xenograft tumor growth in nude mice. Akt-S6K1 inhibition and JNK activation were observed in ABC294640-treated tumors. Collectively, ABC294640 efficiently inhibits human skin SCC cell growth in vitro and in vivo. PMID- 29428731 TI - Snapshots of catalysis: Structure of covalently bound substrate trapped in Mycobacterium tuberculosis thiazole synthase (ThiG). AB - Increasing drug resistance in Mycobacterium tuberculosis (Mtb) has necessitated the design of new anti-mycobacterial drugs with novel targets. Thiazole synthase (ThiG) is an essential enzyme and a potential drug target in Mtb that catalyzes the formation of the thiazole moiety of thiamin-pyrophosphate from 1-deoxy-d xylulose-5-phosphate (DXP), dehydroglycine and ThiS-thiocarboxylate. To uncover the catalysis mechanism and design potent and selective anti-mycobacterial compounds targeting ThiG, we determined the crystal structure of MtbThiG at 1.5 A resolution, for the first time, snapshotting a covalently bound substrate trapped in the catalytic pocket. The structure showed a (beta/alpha)8 barrel overall fold as well as the dimer form of MtbThiG existing in solution. In the central pocket, Lys98 is the key residue forming a protonated carbinolamine intermediate, a functional Schiff base precursor, with DXP. The carbinolamine is further stabilized by active site residues mainly through hydrogen bonds. This work revealed that a protonated carbinolamine is initially formed and then it is dehydrated to the imine form of Schiff base during the early catalysis steps. Our research will provide useful information for understanding the ThiG function and lay the basis for future drug design by targeting this essential protein. PMID- 29428732 TI - Knockdown of long non-coding RNA MAP3K20 antisense RNA 1 inhibits gastric cancer growth through epigenetically regulating miR-375. AB - Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) play a critical role in tumorigenesis of gastric cancer. LncRNA MAP3K20 antisense RNA 1 (MLK7-AS1) has been identified as one of gastric cancer-specific lncRNAs. However, its precise role in gastric cancer remains unknown. In this study, we found that lncRNA MLK7-AS1 was significantly increased in gastric cancer tissues compared with in adjacent tissues. Gastric cancer patients with high MLK7-AS1 expression had a shorter survival and poorer prognosis. By loss-function assay, we demonstrated that knockdown of MLK7-AS1 inhibited cell proliferation and induced apoptosis in HGC27and MKN-45 cells. Furthermore, we identified miR-375 as a target of MLK7-AS1. MLK7-AS1 interacted with Dnmt1 and recruited it to miR-375 promotor, hyper-methylating miR-375 promotor and repressing miR-375 expression. Taken together, our findings demonstrate that knockdown of MLK7-AS1 by siRNA inhibits gastric cancer growth by epigenetically regulating miR-375. Thus, MLK7 AS1 may be a useful prognostic marker and therapeutic target for gastric cancer patients. PMID- 29428733 TI - Mice overexpressing latent matrix metalloproteinase-2 develop lung emphysema after short-term exposure to cigarette smoke extract. AB - Chronic obstructive pulmonary disease is the major growing cause of mortality and morbidity worldwide, and it is going to become the third most common cause of death by 2020. Chronic obstructive pulmonary disease is pathologically characterized by lung emphysema and small airway inflammation. Animal models are very important to get insights into the disease pathogenesis but current models of chronic obstructive pulmonary disease take a long time to develop. The need of a new model is compelling. In the present study we focus on the role of matrix metalloproteinases in the pathogenesis of chronic obstructive pulmonary disease and hypothesized that lung overexpression of latent matrix metalloproteinases-2 would allow the development of emphysema after short-term exposure to cigarette smoke extract inhalation. Human latent matrix metalloproteinases-2 transgenic mouse expressing high level of the protein in the lungs and wild type mouse were exposed to aerosolized cigarette smoke extract for two weeks. Transgenic mice showed significant lung emphysematous changes, increased infiltration of inflammatory cells and enhanced lung concentrations of inflammatory cytokines in the lungs compared to their wild type counterparts after inhalation of cigarette smoke extract. This novel mouse model will be a very useful tool for evaluating the mechanistic pathways and for development of novel therapies in cigarette smoke-associated lung emphysema. PMID- 29428734 TI - Co-transplantation of exosomes derived from hypoxia-preconditioned adipose mesenchymal stem cells promotes neovascularization and graft survival in fat grafting. AB - BACKGROUND: Adipose-derived stromal cells (ADSCs)-derived exosomes (ADSC-Exos) account for the proangiogenic potential of stem cell. This study aimed to investigate the effect of ADSC-derived exosomes (ADSC-Exos) on the survival in fat grafting. METHODS: A nude mouse model of subcutaneous fat grafting was adopted. Hypoxic preconditioned ADSC-Exos and ADSC-Exos were injected around the grafted tissue. The fat graft sample was weighed and examined by hematoxylin and eosin (H&E) staining and immunohistochemistry. Laser Doppler flowmetry and CD31 immunofluorescence staining were used to analyze neovascularization. RESULTS: ADSC-Exo and hypoxic ADSC-Exo groups had a significantly higher weight of fat graft and more perilipin-positive adipocytes than the control groups from 2 to 8 weeks after grafting, and the hypoxic ADSC-Exo group had better outcomes (all P < 0.05). H&E staining showed that ADSC-Exos attenuated infiltration of inflammatory cells around the fat grafts. Laser Doppler flowmetry showed that the two ADSC-Exo groups had better blood perfusion in the graft tissue than the control groups (all P < 0.05). Immunofluorescence demonstrated that the hypoxic ADSC-Exo group had significantly more CD31-positive cells than the ADSC-Exo group. In vitro study showed that hypoxic ADSC-Exos treatment significantly increased the migration (at 12 and 24 h) and in vitro capillary network formation (at 12 h) in the human umbilical vein endothelial cells (HUVECs) as compared with the ADSC-Exo group and control group (all P < 0.05). CONCLUSIONS: Co-transplantation of ADSC Exos can effectively promote the survival of graft, neovascularization and attenuated inflammation in the fat grafts. Hypoxia treatment can further enhance the beneficial effect of ADSC-Exos. PMID- 29428735 TI - Overexpression of germin-like protein GmGLP10 enhances resistance to Sclerotinia sclerotiorum in transgenic tobacco. AB - Germin-like proteins (GLPs) are ubiquitous water-soluble glycoproteins that are located in the extracellular matrix. These proteins have been reported to play vital roles in diverse biological processes. In the present study, a GLP in soybean (Glycine max L. Merr.), GmGLP10, was characterized. Sequence analysis revealed that the GmGLP10 gene (GenBank Accession Number EU916258) encodes a 213 amino acid (aa) protein, which contains a N-terminal signal peptide at 1-22 aa and is highly homologous to the members of the GER2 subfamily. GmGLP10 was highly expressed in the leaves, but very faint in the roots. The expression of GmGLP10 was induced by methyl jasmonate (MeJA), ethylene (ET), salicylic acid (SA), oxalate acid (OA), and the infection of Sclerotinia sclerotiorum. Overexpression of GmGLP10 in transgenic tobacco significantly enhanced tolerance to OA and S. sclerotiorum infection. Moreover, higher levels of H2O2 and the upregulated expression of a set of plant defense-related genes and HR (hypersensitive response)-associated genes were detected in the transgenic plants. These results suggest that GmGLP10 functions as a positive regulator of resistance to S. sclerotiorum. PMID- 29428736 TI - WITHDRAWN: Whole genome sequencing identifies novel NOTCH3 mutations for leukoaraiosis. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 29428737 TI - The UBA domain of SnRK1 promotes activation and maintains catalytic activity. AB - Sucrose non-fermenting 1-related protein kinase 1 (SnRK1) is a central metabolic regulator and the plant orthologue of the mammalian AMP-activated protein kinase (AMPK); both are energy-sensing heterotrimeric enzymes comprising a catalytic alpha- and regulatory beta- and gamma-subunits. alpha-Subunits contain a serine/threonine kinase domain (KD) at their N-terminus that is immediately followed by a small regulatory domain termed the auto-inhibitory domain (AID) in AMPK and the ubiquitin-associated domain (UBA) in SnRK1. Association of the AID with the AMPK KD inhibits activating phosphorylation of the KD by upstream kinases and promotes dephosphorylation, as well as inhibiting AMPK catalytic activity. Despite these mechanistic insights regarding the AMPK AID, the SnRK1 UBA regulatory implications have not been investigated. Using recombinant protein comprising either the KD-only or KD-AID/KD-UBA, we found that the UBA of SnRK1 acts in a distinct regulatory manner to its orthologous AID of AMPK. Firstly, the plant upstream kinase GRIK2 preferentially phosphorylates the SnRK1 KD-UBA. Secondly, the SnRK1 KD in the absence of the UBA shows near identical initial catalytic activity to the KD-UBA, but in comparison a rapid loss of catalytic activity is observed. Our findings indicate that the role of the UBA in SnRK1 regulation may be more akin to that of the UBA in the mammalian AMPK-related kinases rather than its immediate functional orthologue, AMPK. This study adds to a growing body of work demonstrating the divergent regulatory mechanisms of the orthologous plant SnRK1 and mammalian AMPK. PMID- 29428738 TI - Estimating the health care costs associated with recurrent cellulitis managed in the outpatient setting. AB - BACKGROUND: Recurrent cellulitis is diagnosed in 22% to 49% of all cellulitis cases, but little is known about the costs associated with these cases. OBJECTIVE: To characterize patients with recurrent cellulitis in the outpatient setting and estimate the associated costs. METHODS: A retrospective chart review was conducted for adult patients who presented to the outpatient facilities at our institution from January 1, 2007, to December 31, 2011, with recurrent cellulitis. Data provided by the Centers for Medicare and Medicaid Services were used. RESULTS: A total of 157 patients were identified; 56% were male, with a mean age of 62.7 years. The mean number of episodes of cellulitis per patient was 3. Antibiotics were prescribed for all patients with a diagnosis of recurrent cellulitis, with 93% treated with oral antibiotics and 17.6% treated with intravenous antibiotics. A total of 1081 laboratory and 175 radiologic imaging tests were ordered. The minimum average cost per cellulitis episode was $586.91; the average cost per visit was $292.50. LIMITATIONS: Retrospective study; use of a single, large academic institution; and utilization of cost estimates that may not adequately reflect the variation of costs across closed-system sites or geographic regions. There was no accounting for the nonfinancial or opportunity costs associated with hospitalization, such as lost days of employment or child care and any long-term morbidities, among others. CONCLUSIONS: Recurrent cellulitis in the outpatient setting costs about $586.91 per episode. Although there is no criterion standard for diagnosis or treatment of cellulitis, our analysis demonstrates the need for more evidence-based management to achieve better outcomes and reduce the significant health care costs. PMID- 29428739 TI - Air-drying is sufficient pre-treatment for in situ visualization of microbes on minerals with scanning electron microscopy. AB - Scanning electron microscopy (SEM) is a powerful tool for observing microbe mineral interactions in situ. Despite its wide usage in geomicrobiology there is no consensus on how the samples should be handled before visualizing in SEM. We compared response of artificial laboratory-grown bacterial community and natural in situ microbes on terrestrial basalt to different sample pre-treatment methods with the aim to preserve microbe-mineral interaction interface. Air-drying was the only method that maintained the location of loosely attached bacteria on a mineral surface, whereas chemical fixation and drying dislocated the cells. On the contrary, chemical fixation preserved the cellular morphology while air drying caused the collapse of most of the laboratory-grown cells. Natural microbial communities on dry terrestrial basalt were composed of desiccation resistant microbes which remained attached to the surface and partially maintained their morphology regardless of the sample pre-treatment method. None of the tested methods allowed visualization of microbe-mineral interface in a biofilm. We suggest air-drying as a main sample pre-treatment method for visualizing microbes on mineral surfaces when loss of morphology is secondary to potentially dislocated cells and to potential chemical changes in the sample caused by the chemical fixation reagents. PMID- 29428740 TI - New approach to distinguishing chemoattractants, chemorepellents and catabolised chemoeffectors for Campylobacter jejuni. AB - : Chemotactic behaviour is an important part of the lifestyle of motile bacteria and enables cells to respond to various environmental stimuli. The Hard Agar Plug (HAP) method is used to study the chemotactic behaviour of bacteria, including the fastidious microaerophile Campylobacter jejuni, an intestinal pathogen of humans. However, the traditional HAP assay is not quantitative, is unsuitable for chemotaxis observation over short time periods and for the investigation of repellent taxis, and is prone to false-positive and -negative results. Here we report an accurate, rapid, and quantitative HAP-based chemotaxis assay, tHAP, for the investigation of bacterial chemotactic responses. The critical component of the new assay is the addition of triphenyltetrazolium chloride (TTC). Enzymatic reduction of TTC to TFP-Red (1, 3, 5-Triphenylformazan) enables colourimetric detection of actively metabolising bacterial cells. Quantitative assessment of chemotaxis is achieved by colourimetric measurement or viability count over a period of 10 min to 3 h. Using the tHAP assay, we observed the dose-responsive chemotactic motility of C. jejuni cells along different concentrations of attractants aspartate and serine. Importantly, we have also designed a competitive tHAP assay to differentiate between repellents and attractants and to identify chemoeffectors that do not activate metabolism. IMPORTANCE: The modified tHAP assay described here enables the exploration of the chemoresponse of Campylobacter jejuni towards chemorepellents, and catabolizable and non catabolizable chemoattractants. PMID- 29428741 TI - Feed intake and behavior of dairy goats when offered an elevated feed bunk. AB - Goats are browsers and select vegetation at various heights when foraging. On commercial farms, dairy goats are typically fed from low-level feed bunks. The objective of this study was to determine how feed intake and feeding behavior vary when goats are offered feed at variable heights, with the potential of evaluating the benefits of offering an elevated feeder to dairy goats. Thirteen Saanen X dairy goats were housed in a home pen with a lying area of wood shavings, where they were pre-exposed for 24 d to 3 feeder heights designed to result in differences in head height while feeding: floor level (head lowered relative to body), head level (head level relative to body), and elevated level (head and neck angled upward). Nine groups of 3 goats each were randomly selected and housed for 24 h in a test pen identical to the home pen except that it contained 1 of each of the 3 feeder heights. Each feeder contained ad libitum chopped alfalfa silage and a top-dressed corn-based supplement, refreshed twice daily. Refusals from inside and under each feeder were weighed to calculate intake. Feed intake increased with increasing feeder height (mean +/- SE; 0.18, 0.29, and 0.34 +/- 0.04 kg of DM/goat for floor-level, head-level, and elevated level feeders, respectively). Total feeding time did not vary with feeder height, but feeding rate tended to be faster at the elevated-level feeder (14.5 +/- 2.1 g of DM/min) compared with head-level (9.2 +/- 2.3 g of DM/min) and floor-level (8.9 +/- 2.1 g of DM/min) feeders. Goats visited the floor-level feeder (36.4 +/- 8.4 visits/goat) less than the head-level (79.4 +/- 8.4 visits/goat) and elevated level (74.8 +/- 8.4 visits/goat) feeders. The number of displacements per minute of feeding time (physical removal of another goat from the feeding place) was greater at the elevated-level feeder (0.46 +/- 0.06 displacements/min) compared with the floor-level feeder (0.23 +/- 0.06 displacements/min) and tended to differ from the head-level feeder (0.27 +/- 0.06 displacements/min). We conclude that goats eat more from an elevated feeder and compete more to access this feeder. PMID- 29428742 TI - Short communication: Roles of outer membrane protein W (OmpW) on survival and biofilm formation of Cronobacter sakazakii under neomycin sulfate stress. AB - Cronobacter sakazakii is associated with severe infections including sepsis, neonatal meningitis, and necrotizing enterocolitis. Antibiotic resistance in Cronobacter species has been documented in recent years, but the genes involved in resistance in Cronobacter strains are poorly understood. In this study, we determined the role of outer membrane protein W (OmpW) on survival rates, morphologic changes, and biofilm formation between wild type (WT) and an OmpW mutant strain (DeltaOmpW) under neomycin sulfate stress. Results indicated that the survival rates of DeltaOmpW were significantly reduced after half minimum inhibitory concentration (1/2 MIC) treatment compared with the WT strain. Filamentation of C. sakazakii cells was observed after 1/2 MIC treatment in WT and DeltaOmpW, and morphologic injury, including cell disruption and leakage of cells, was more predominant in DeltaOmpW. Under 1/2 MIC stress, the biofilms of WT and DeltaOmpW were significantly decreased, but decreasing rates of biofilm formation in mutant strain were more predominant compared with WT strain. This is the first report to determine the role of OmpW on survival, morphological changes, and biofilm formation in C. sakazakii under neomycin sulfate stress. The findings indicated that OmpW contributed to survival and reduction of morphological injury under neomycin sulfate stress. In addition, enhancing biofilm formation in DeltaOmpW may be an alternative advantage for adaptation to neomycin sulfate stress. PMID- 29428743 TI - Circulating progesterone concentrations in nonlactating Holstein cows during reuse of intravaginal progesterone implants sanitized by autoclave or chemical disinfection. AB - The aim of this study was to compare plasma progesterone (P4) concentrations in nonlactating, multiparous Holstein cows (n = 24) treated with 2 types of intravaginal implants containing either 1.0 or 1.9 g of P4 either at the first use or during reuse of the implants after sanitizing the implant by autoclave or chemical disinfection. In a completely randomized design with a 2 * 3 factorial arrangement and 2 replicates, every cow underwent 2 of 6 treatments. Two sources of P4 [controlled internal drug release (1.9 g of P4) from Zoetis (Sao Paulo, Brazil), and Sincrogest (1.0 g of P4) from Ourofino (Cravinhos, Brazil)] and 3 types of processing, new (N), reused after autoclave (RA), and reused after chemical disinfection (RC), were used. After inducing luteolysis to avoid endogenous circulating P4, the cows were randomized in 1 of 6 treatments (1.9 g of N, 1.9 g of RA, 1.9 g of RC, 1.0 g of N, 1.0 g of RA, and 1.0 g RC). Cows were treated with the implants for 8 d and during this period blood samples were collected at 0, 2, 12, 24, 48, 72, 96, 120, 144, 168, and 192 h. Statistical analyses were performed using Proc-Mixed and the mean +/- standard error of the mean P4 concentrations were calculated using the Proc-Means procedures of SAS 9.4 (SAS Institute Inc., Cary, NC). No interaction between treatments was observed. Comparing types of implant, average P4 concentrations during treatments were greater for 1.9 g than 1.0 g (1.46 vs. 1.14 +/- 0.04 ng/mL). When types of processing were compared, average P4 concentrations did not differ between autoclaved and new inserts (1.46 vs. 1.37 +/- 0.05 ng/mL; respectively), but both were greater than chemically disinfected implants (1.09 +/- 0.04 ng/mL). Within 1.9-g P4 inserts, P4 concentrations from autoclaved implants were greater than new, which were greater than chemically disinfected (1.67 +/- 0.06 vs. 1.49 +/- 0.07 vs. 1.21 +/- 0.05 ng/mL; respectively). For 1.0-g P4 implants, P4 concentrations from autoclaved did not differ from new, but both were greater than chemically disinfected (1.20 +/- 0.08 vs. 1.24 +/- 0.06 vs. 0.97 +/- 0.05 ng/mL; respectively). In conclusion, the mean plasma P4 concentration in nonlactating Holstein cows was greater for 1.9 than 1.0 g of P4 and regardless of the type of implant, the autoclaving process provided greater circulating P4 in relation to chemical disinfection, and similar or greater P4 concentrations compared with a new implant. PMID- 29428744 TI - Short communication: Cow- and herd-level prevalence of hypoglycemia in hyperketonemic postpartum dairy cows. AB - The objective of this study was to quantify the prevalence of hypoglycemia in hyperketonemic dairy cows during the early postpartum period. A prospective observational study was conducted in 100 dairy herds selected by convenience. Within all participating herds, 40 cows (or the entire herd if smaller than 40 cows) were enrolled in the study (total of 3,776 enrolled cows). Herds were visited every 2 wk by an animal health technician. Cows were bled from their coccygeal vessels once between 1 and 14 d in milk, and cow-side testing was performed for ketonemia and glycemia using a device validated in cattle (Precision Xtra, Abbott, Mississauga, ON, Canada). Hyperketonemia was defined as beta-hydroxybutyrate >=1.4 mmol/L, and hypoglycemia was defined as glucose <=2.2 mmol/L. Descriptive statistics were computed at the cow and herd levels. The cow level prevalence of hyperketonemia, hypoglycemia, and simultaneous hypoglycemia and hyperketonemia was 20.0% (757/3,776), 13.8% (642/3,776), and 6.2% (235/3,776), respectively. Within the subset of hyperketonemic cows only, the prevalence of hypoglycemia was 31.0% (235/757). At the herd level, the median prevalence was 17.5% (minimum: 5.0%, first quartile: 10.0%, third quartile: 22.5%, maximum: 77.5%) for hyperketonemia, 15.0% (minimum: 5.0%, first quartile: 12.5%, third quartile: 20.0%, maximum: 47.5%) for hypoglycemia, and 7.5% (minimum: 2.5%, first quartile: 5.0%, third quartile: 12.5%, maximum: 17.5%) for simultaneous hypoglycemia and hyperketonemia. The herd-level median prevalence of hypoglycemia within the subset of hyperketonemic cows only was 30.6% (minimum: 2.5%, first quartile: 20.0%, third quartile: 39.1%, maximum: 63.0%). The results from this study show that the prevalence of simultaneous hyperketonemia and hypoglycemia is relatively low in the overall early postpartum cow population but also that approximately one-third of hyperketonemic cows are hypoglycemic, which might represent an opportunity to improve their management on the farm. PMID- 29428746 TI - Technical note: Quantification of caseins from a crude extract of mammary epithelial cells. AB - En masse secretion of milk proteins, notably the caseins in the form of casein micelles, is a unique feature of the milk-secreting mammary epithelial cell. Caseins are therefore specific markers of these cells and constitute an ideal tool to monitor their differentiation, as well as functional status, during the development of the gland. To use them as such, a reliable method for quantitative analysis of the caseins from mammary cells or tissue is needed. Here we show that the caseins are heat-stable, a feature that leads to their complete extraction from a complex cellular extract by boiling. This allows for high enrichment and direct analysis of the caseins, even when they are poorly expressed in the starting material. PMID- 29428745 TI - Technological characterization of Lactobacillus in semihard artisanal goat cheeses from different Mediterranean areas for potential use as nonstarter lactic acid bacteria. AB - The potential of 25 Lactobacillus isolates from 8 semihard artisanal goat cheeses manufactured in 4 different Mediterranean areas was examined for use as nonstarter lactic acid bacteria. The isolates were identified using 16S rDNA sequence analysis. Sixteen strains belonged to Lactobacillus paracasei and 9 to Lactobacillus rhamnosus. The isolates were first screened for salt tolerance, exopolysaccharide and diacetyl production, proteolytic and lipolytic activity, and acidification and autolyzing capacities. Most of the lactobacilli displayed strong salt tolerance [20 strains, including 13 of Lb. paracasei and 7 of Lb. rhamnosus, could grow at 6% (wt/vol) salt], low acidification activity (16 strains, including 9 of Lb. paracasei and 7 of Lb. rhamnosus, presented change in pH <=0.4 U after 6 h of growth), and high autolytic activity (14 strains, including 9 of Lb. paracasei and 5 of Lb. rhamnosus, showed autolysis values ranging between 25 and 65%). Eleven Lb. paracasei and 6 Lb. rhamnosus produced exopolysaccharide, whereas 8 Lb. paracasei and 4 Lb. rhamnosus produced diacetyl. Moreover, 9 Lb. paracasei and 6 Lb. rhamnosus showed proteolytic activity; none of the isolates showed lipolytic activity. Based on the above characteristics, 8 strains were further evaluated for peptidase activity, including aminopeptidase, dipeptidyl aminopeptidase, and dipeptidase activities. The results indicated that all strains showed peptidase activity toward selected substrates. The substrate specificity and extent of peptidase activities were strain-dependent. Four strains (A-3, B-4, D-3, and D-8) presented the best characteristics and represented the most promising nonstarter lactic acid bacteria candidates for use in industrial manufacturing of goat cheese. PMID- 29428747 TI - Peptidomic screening of bitter and nonbitter casein hydrolysate fractions for insulinogenic peptides. AB - Sodium caseinate hydrolysates (NaCaH) contain biologically active peptides that can positively influence human health. However, their intense bitterness hinders their inclusion in food products. To our knowledge, no studies have investigated whether a correlation between bitterness and bioactivity exists in NaCaH, so it is not yet known what effect selective removal of bitterness has on NaCaH bioactivity. A deeper understanding of the physicochemical characteristics affecting both bitterness and bioactivity is therefore needed. The aim of this study was to use in silico analysis to elucidate the relationship between bitterness and bioactivity of the insulinogenic NaCaH. The NaCaH fractions were generated by membrane filtration and flash chromatography and were subsequently evaluated for bitterness by a sensory panel. In this present study, peptidomic and bioinformatic processing of these NaCaH fractions allowed for the identification of insulinogenic peptides as well as other literature-identified peptides in each of the fractions. The results showed that the most bitter fraction contained the highest abundance of insulinogenic peptides, whereas another bitter fraction contained the highest abundance of other literature identified bioactive peptides exhibiting angiotensin-converting enzyme-inhibition activity. Although some bioactive peptides were identified in the least bitter fractions, the abundance of these peptides was very low. These observations show a correlation between bitter taste and bioactivity, highlighting potential complications in removing bitterness while maintaining bioactivity. However, as the most bitter fraction contained the highest abundance of insulinogenic peptides, there is potential for using a lower dose of this enriched bioactive fraction to exert health benefits. The second most bitter fraction contained a very low abundance of insulinogenic peptides and other bioactive peptides. Therefore, removal of this fraction could reduce the NaCaH product's bitterness without significantly altering overall bioactive potential. PMID- 29428748 TI - Plane of nutrition before and after 6 months of age in Holstein-Friesian bulls: I. Effects on performance, body composition, age at puberty, and postpubertal semen production. AB - The aim of this study was to examine the effect of plane of nutrition (1) during the first 6 mo of life and (2) from 6 mo of age to puberty on early growth characteristics, age at puberty, and postpubertal semen production in Holstein Friesian bulls. Holstein-Friesian bull calves (n = 83) with a mean (standard deviation) age and body weight of 17 (4.4) d and 52 (6.2) kg, respectively, were assigned to a high (Hi) or low (Lo) plane of nutrition for the first 6 mo of life. The Hi and Lo calves received 1,200 and 450 g of milk replacer, respectively; Hi calves were fed concentrate ad libitum and Lo were fed a maximum of 1 kg concentrate daily, and concentrate allowances remained the same after weaning. At 24 wk of age, bulls were reassigned within treatment to either remain on the same diet or to switch to the opposite diet until puberty, resulting in 4 treatment groups: Hi-Hi, Hi-Lo, Lo-Lo, and Lo-Hi. After puberty, all bulls were fed a moderate plane of nutrition until 60 wk of age; thereafter, the diet was ad libitum concentrates until slaughter at 72 wk of age. Bulls were weighed weekly before weaning and every 2 wk after weaning. Scrotal circumference (SC) was measured every 2 wk, beginning at 15 wk of age. Beginning at a SC of 24 cm, electro-ejaculation was carried out every 2 wk to establish the onset of puberty. Semen collection continued monthly after puberty. Thermal images of the scrotum were taken monthly from 28 to 36 wk of age. Scrotal skin thickness (SST) was measured monthly (from 16 wk of age to puberty) using a digital calipers. Bulls on the Hi diet had a higher scrotal temperature and SST at each time point than those on the Lo diet. Average daily gain (ADG) was greatest in Hi-Hi bulls, with Hi-Lo and Lo-Hi having similar ADG but both being greater than Lo-Lo. Bulls on the Hi diet pre-6 mo of age were younger at puberty, regardless of diet offered post-6 mo of age. Bulls offered a Hi diet post-6 mo were heavier at puberty. Neither scrotal temperature nor dietary treatment affected postpubertal semen production variables. In conclusion, a high plane of nutrition during the first 6 mo of age hastened the onset of puberty and the availability of saleable semen, regardless of plane of nutrition post-6 mo of age. PMID- 29428749 TI - Effect of altering the type of dietary carbohydrate early postpartum on reproductive performance and milk production in pasture-grazed dairy cows. AB - The objective of this study was to assess the effect of increasing dietary starch for approximately 30 d postpartum on reproduction outcomes in pasture-grazed, seasonal-calving dairy cows. Cows (n = 948) from 3 commercial herds were blocked by age (2, 3, and >3 yr), breed, and expected calving date and randomly assigned to 1 of 2 postpartum treatment groups: high starch (34.7 +/- 1.9% nonstructural carbohydrate; mean +/- SD) or low starch (22.5 +/- 0.4% nonstructural carbohydrate). The high-starch group in all 3 farms received 4.0 to 4.5 kg/d of a 75:25 cracked corn:barley grain mixture in the dairy parlor, split evenly between the morning and afternoon milkings. The low-starch cows received 5.0 to 5.5 kg/d of a 50:50 mixture of palm kernel meal:soy hulls (herds 1 and 3) fed in the parlor; low-starch cows in the remaining herd (herd 2) did not receive a concentrate feed. Cows were cograzed on ryegrass-white clover dominant pastures and were offered corn silage (herds 1 and 3) and canola, corn distillers grain, and palm kernel meal (herd 1) throughout the study. At 1 mo before the start of the seasonal breeding period, the high-starch supplement was removed, and within each herd treatment groups were managed similarly through breeding. Presence of purulent vaginal discharge was assessed at 28 DIM, and tail paint was assessed weekly from 2 to 6 wk postpartum for signs of estrus. The interval to first observed estrus was unaffected by treatment (32.7 vs. 33.5 +/- 2 d for high and low starch, respectively), but there were tendencies for a herd * treatment interaction for proportion of cows pregnant to first service and for pregnancy within 6 wk. This interaction was significant for the proportion of cows finally pregnant; a lower proportion of high-starch cows were pregnant to first service, pregnant by 6 wk, and pregnant by the end of the seasonal breeding period in herd 1, but diet did not affect these outcomes in the other herds. Our results do not support a positive effect on reproduction from increasing dietary starch in seasonally bred grazing dairy cows. However, the interactions indicate variability in the herd response to dietary starch early postpartum and imply that pregnancy rate could potentially be compromised through the provision of starch to grazing dairy cows in early lactation (i.e., prebreeding). The experiment was not designed to define the reasons for these interactions, but differences should be considered in future research on the subject. PMID- 29428750 TI - Effect of milk cessation method at dry-off on behavioral activity of dairy cows. AB - Drying cows off at the end of lactation is a routine management practice in dairy operations. Most dairies in the United States and many other countries dry cows off abruptly (e.g., stop milking cows on a set day), which has been shown to affect cow comfort. Gradually reducing milk production is another approach to dry cows off, routinely used in some countries and herds. The objective of the study was to evaluate the effects of abrupt and gradual milk cessation and milk yield at the time on cow activity after dry-off. Daily lying time, number of lying bouts per day, average lying bout length, and steps taken per day by abruptly and gradually dried-off cows were monitored by data loggers for 2 wk before and after the final milking at the end of lactation. Gradual cows were milked once daily for the last week of lactation, and abrupt cows were milked as usual (3*/d) until the end of lactation. Gradual cessation of milking significantly reduced milk yield by the day of dry-off. After dry-off, gradual cows tended to have longer lying bouts than abrupt cows, but no other differences in cow activity between the 2 treatments were observed. Regardless of the dry-off method, the average length of a lying bout decreased by 4 min and total daily lying time decreased by 19 min after dry-off for each 5-kg increase in milk yield before dry-off. Lying behavior of primiparous cows was more affected by the level of milk yield at dry off than that of older cows. A reduction in lying times with increasing milk yield may indicate discomfort due to the accumulating milk in the udder. Using a method that lowers milk production before dry-off and managing primiparous and multiparous cows separately around dry-off are beneficial for cow comfort after dry-off. PMID- 29428751 TI - Randomized double-blind controlled clinical trial of the blood pressure-lowering effect of fermented milk with Lactococcus lactis: A pilot study. AB - The blood pressure-lowering effect of fermented milk with Lactococcus lactis NRRL B-50571 was evaluated in a double-blind randomized controlled clinical trial with prehypertensive subjects. Participants were randomized into 2 groups (n = 18 each group): one group treated with fermented milk with Lactococcus lactis NRRL B 50571 and a control group treated with artificially acidified milk. Results revealed that during daily consumption of fermented milk for 5 wk, systolic [(116.55 +/- 12.26 mmHg vs. 124.77 +/- 11.04 mmHg) and diastolic blood pressure (80.7 +/- 9 vs. 84.5 +/- 8.5 mmHg)] from the fermented milk group was lower than the control group. Additionally, triglyceride, total cholesterol, and low-density lipoprotein in blood serum were lower in the fermented milk group than in the control group. Results demonstrated that daily consumption of fermented milk with Lactococcus lactis (NRRL B-50571) had a blood pressure-lowering effect on prehypertensive subjects. Regular consumption of this product may be used as a potential functional food. PMID- 29428752 TI - Effects of difructose anhydride III on serum immunoglobulin G concentration and health status of newborn Holstein calves during the preweaning period. AB - This experiment was performed to investigate the effects of increases in passively acquired immunoglobulin G (IgG) by difructose anhydride (DFA) III supplementation on subsequent serum IgG concentration and health status in calves during the preweaning period. Thirty newborn female Holstein calves were paired by birth order, and 2 calves in each pair were fed 2 L of the same batch of colostrum within 2 h and at 10 h after birth, and followed by 2 L of the same batch of pooled colostrum at 20 h after birth. One calf from each pair was assigned to the control (n = 15) or treatment (n = 15) group. All calves in the treatment group received 18 g of DFA III at each feeding from birth to 7 d of age, whereas calves in the control group did not receive DFA III. Blood samples were collected before feeding at 0, 10, 20, and 36 h, and 4 and 7 d of age, and sampling was repeated at 7-d intervals thereafter until 49 d of age for serum IgG analysis. Calves were monitored daily for diarrhea and respiratory diseases. Serum IgG concentrations peaked at 36 h of age in both groups. Apparent efficiency of IgG absorption and peak serum IgG concentration were higher in the treatment group than in the control group. Using multiple regression analysis, we showed that peak serum IgG concentration in the newborn calves was positively correlated with colostral IgG concentration and DFA III supplementation. Moreover, peak serum IgG concentration (36 h of age) positively influenced subsequent serum IgG concentration until 35 d of age for all calves in both groups. The treatment group had higher serum IgG concentration from 20 h to 21 d of age than the control group. However, we detected no differences between the groups in number of calves with diarrhea or respiratory disease. PMID- 29428753 TI - Effect of dietary fish oil supplements alone or in combination with sunflower and linseed oil on ruminal lipid metabolism and bacterial populations in lactating cows. AB - Fish oil (FO) alters ruminal biohydrogenation causing trans fatty acid (FA) intermediates to accumulate, but the effects of 18-carbon polyunsaturated FA supply on ruminal long-chain FA metabolism and microbial communities in cattle fed FO are not well established. Four cows fitted with rumen cannula were used in a 4 * 4 Latin square with 21-d experimental periods to evaluate the effects of FO alone or in combination with plant oils high in 18:2n-6 or 18:3n-3 on rumen microbial ecology and flow of FA at the omasum. Treatments comprised a basal grass silage-based diet containing no additional oil (control) or supplements of FO (200 g/d) or FO (200 g/d) plus 500 g/d of sunflower oil (SFO) or linseed oil (LFO). Flow of FA was determined using the omasal sampling technique. The relative abundance of key biohydrogenating bacteria was assessed by quantitative PCR on 16S rRNA genes in omasal digesta. Fish oil-supplemented treatments increased the amounts of trans-18:1, trans-18:2, and 20- to 22-carbon polyunsaturated FA escaping the rumen. Relative to the control, oil supplements had no effect on the amount of 18:0 leaving the rumen, but LFO decreased the flow of 18:0 at the omasum compared with SFO. Both SFO and LFO increased trans-18:1 relative to FO, whereas LFO resulted in the highest trans-18:2 and 20- to 22 carbon FA flow. Supplements of FO plus plant oils shifted biohydrogenation toward trans-10 18:1 formation. Compared with FO alone, the ruminal metabolism of 22:6n 3 in the rumen of lactating cows is more extensive on diets containing higher amounts of 18-carbon polyunsaturated FA. However, the biohydrogenation of 22:5n-3 was less extensive in LFO than SFO, but showed no difference between FO and diets containing plant oils. Ruminal outflow of 20:5n-3 was not altered when plant oils were added to FO. Alterations in the amount of intermediates at the omasum or ruminal biohydrogenation pathways were not accompanied by major changes in analyzed bacterial populations. In conclusion, dietary supplements of FO alone or in combination with plant oils increase the amount of biohydrogenation intermediates containing 1 or more trans double bonds escaping the rumen, which may have implications for host metabolism and the nutritional quality of ruminant foods. PMID- 29428754 TI - Follicular dynamics, circulating progesterone, and fertility in Holstein cows synchronized with reused intravaginal progesterone implants that were sanitized by autoclave or chemical disinfection. AB - This experiment aimed to compare circulating progesterone (P4), follicular dynamics, and fertility during reuse of intravaginal P4 implants that were sanitized by autoclave or chemical disinfection in lactating Holstein cows submitted to fixed-time artificial insemination (FTAI). For this, 123 primiparous and 226 multiparous cows from 2 farms, averaging (mean +/- standard deviation) 163.9 +/- 141.9 d in milk, 35.7 +/- 11.3 kg of milk/d, and a body condition score of 2.9 +/- 0.5, were enrolled in the study. Cows were randomly assigned to 1 of 2 treatments using a completely randomized design and each cow received a reused implant (1.9 g of P4; previously used for 8 d) that was either autoclaved (AUT; n = 177) or chemically disinfected (CHEM; n = 172) on d -10. Also on d -10, cows received 2 mg of estradiol benzoate and 100 MUg of GnRH. On d -3, cows received 25 mg of dinoprost (PGF2alpha). A second PGF2alpha was given on d -2, along with 1 mg of estradiol cypionate and P4 implant removal. Cows received FTAI on d 0. A subset of cows (n = 143) was evaluated by ultrasound on d -10, -8, -6, -3, -2, 0, and 5 to identify ovarian structures, and blood was sampled on d -10, -3, and -2 for P4 concentrations by RIA. Pregnancy diagnoses were performed at d 32 and 60. Statistical analyses was performed using PROC-MIXED for continuous variables and PROC-GLIMMIX of SAS 9.4 (SAS Institute Inc., Cary, NC) for binomial variables. The treatments did not differ in circulating P4 on d -10 or -3, but P4 was greater on d -2 in CHEM cows. Ovulation to the treatments on d -10 was associated with lower circulating P4 on d -10 (2.0 vs. 3.1 ng/mL) and resulted in greater P4 on d -3 (4.0 vs. 2.4 ng/mL) and more cows with a corpus luteum on d -3 (100 vs. 40%) than nonovulating cows. Cows that ovulated to d -10 treatments were more likely to have a synchronized new follicular wave (97.9 vs. 63.2%) and had an earlier wave emergence (1.9 vs. 2.6 d), resulting in less cows ovulating a persistent follicle (0.0 vs. 35.7%). Type of P4 implant, corpus luteum presence on d -10, and ovulation to d -10 treatments did not affect fertility (pregnancy per AI; P/AI). However, P/AI on farm A was greater than on farm B at 32 (40.8 vs. 27.8%) and 60 d (35.8 vs. 24.3%), independent of treatment. In conclusion, P4 implants with different P4 release patterns did not produce detectable differences in follicular dynamics, synchronization rate, or P/AI. Nevertheless, presence of corpus luteum or ovulation at the beginning of the FTAI protocol affected reproductive variables, such as timing and synchronization of follicular wave emergence, and size of the ovulatory follicle. Beyond that, more overall synchronized cows became pregnant to the FTAI protocol. PMID- 29428755 TI - Salmonella enterica and extended-spectrum cephalosporin-resistant Escherichia coli recovered from Holstein dairy calves from 8 farms in New Brunswick, Canada. AB - This study was carried out to determine the frequency of fecal carriage, antimicrobial susceptibility, and resistance genes in Salmonella enterica and Escherichia coli with reduced susceptibility to extended-spectrum cephalosporins (ESC) isolated from 488 dairy calves from 8 farms in New Brunswick, Canada. Both S. enterica and E. coli with reduced susceptibility to ESC were isolated using selective culture. Minimum inhibitory concentrations to a panel of antimicrobial drugs were determined for randomly selected E. coli isolates and all of the Salmonella isolates. Multiplex PCR were conducted on the selected ESC-resistant E. coli to assess the beta-lactamase resistance genes (blaCTX-M, blaCMY-2, blaSHV, and blaTEM) and plasmid-mediated qnrB and qnrS resistant genes. Information on ceftiofur use and other farm management practices were collected by the use of a questionnaire to determine the risk factors for the fecal recovery of E. coli with reduced susceptibility to ESC. Salmonella enterica frequency in calves' fecal samples was 3.3%, and all were pansusceptible. Salmonella isolates belonged to 3 serovars namely Salmonella Senftenberg, Salmonella Typhimurium, and Salmonella Derby. The frequency of fecal carriage of E. coli with reduced susceptibility to ESC in calves was 81.2%. Of the selected isolates (n = 100), all were multi-drug resistant, whereas 88% were ESC resistant based on minimum inhibitory concentration testing. From the selected ESC resistant E. coli isolates, blaTEM was detected in 84.1%, blaCMY-2 was detected in 52.2%, blaCTXM groups were detected in 30.7%, and blaSHV was detected in 1.1% of isolates. Plasmid-mediated quinolone resistance genes were identified in 7 of 9 isolates resistant to quinolones. Five isolates were positive for qnrB, whereas 2 isolates were positive for both qnrB and qnrS. Whereas neonatal calves [odds ratio (OR) = 2.42, 95% confidence interval (CI): 1.87-3.12], regular ceftiofur use on the farm (OR = 3.83, 95% CI: 2.29-6.39), feeding of unpasteurized nonsalable milk (OR = 1.6, 95% CI: 1.18-2.18), and use of florfenicol (OR = 2.02, 95% CI: 1.43-2.86) were statistically associated with fecal recovery of E. coli with reduced susceptibility to ESC, use of ceftiofur for the treatment of respiratory diseases (OR = 0.57, 95% CI: 0.41-0.79) was statistically associated with decreased recovery of E. coli with reduced susceptibility to ESC. This study has provided information on the resistance genes associated with the occurrence of ESC and fluoroquinolone resistance in dairy calves within this region. PMID- 29428756 TI - Effect of adding clay with or without a Saccharomyces cerevisiae fermentation product on the health and performance of lactating dairy cows challenged with dietary aflatoxin B1. AB - The study was conducted to examine the effect of supplementing bentonite clay with or without a Saccharomyces cerevisiae fermentation product (SCFP; 19 g of NutriTek + 16 g of MetaShield, both from Diamond V, Cedar Rapids, IA) on the performance and health of dairy cows challenged with aflatoxin B1 (AFB1). Twenty four lactating Holstein cows (64 +/- 11 d in milk) were stratified by parity and milk production and randomly assigned to 1 of 4 treatment sequences. The experiment had a balanced 4 * 4 Latin square design with 6 replicate squares, four 33-d periods, and a 5-d washout interval between periods. Cows were fed a total mixed ration containing 36.1% corn silage, 8.3% alfalfa hay, and 55.6% concentrate (dry matter basis). Treatments were (1) control (no additives), (2) toxin (T; 1,725 ug of AFB1/head per day), (3) T + clay (CL; 200 g/head per day; top-dressed), and (4) CL+SCFP (CL+SCFP; 35 g/head per day; top-dressed). Cows were adapted to diets from d 1 to 25 (predosing period) and then orally dosed with AFB1 from d 26 to 30 (dosing period), and AFB1 was withdrawn from d 31 to 33 (withdrawal period). Milk samples were collected twice daily from d 21 to 33, and plasma was sampled on d 25 and 30 before the morning feeding. Transfer of ingested AFB1 into milk aflatoxin M1 (AFM1) was greater in T than in CL or CL+SCFP (1.65 vs. 1.01 and 0.94%, respectively) from d 26 to 30. The CL and CL+SCFP treatments reduced milk AFM1 concentration compared with T (0.45 and 0.40 vs. 0.75 ug/kg, respectively), and, unlike T, both CL and CL+SCFP lowered AFM1 concentrations below the US Food and Drug Administration action level (0.5 ug/kg). Milk yield tended to be greater during the dosing period in cows fed CL+SCFP compared with T (39.7 vs. 37.7 kg/d). Compared with that for T, plasma glutamic oxaloacetic transaminase concentration, indicative of aflatoxicosis and liver damage, was reduced by CL (85.9 vs. 95.2 U/L) and numerically reduced by CL+SCFP (87.9 vs. 95.2 U/L). Dietary CL and CL+SCFP reduced transfer of dietary AFB1 to milk and milk AFM1 concentration. Only CL prevented the increase in glutamic oxaloacetic transaminase concentration, and only CL+SCFP prevented the decrease in milk yield caused by AFB1 ingestion. PMID- 29428757 TI - Short communication: Development of a rapid laboratory method to polymerize lactose to nondigestible carbohydrates. AB - Nondigestible carbohydrates with a degree of polymerization between 3 and 10 (oligosaccharides) are commonly used as dietary fiber ingredients in the food industry, once they have been confirmed to have positive effects on human health by regulatory authorities. These carbohydrates are produced through chemical or enzymatic synthesis. Polylactose, a polymerization product of lactose and glucose, has been produced by reactive extrusion using a twin-screw extruder, with citric acid as the catalyst. Trials using powdered cheese whey permeate as the lactose source for this reaction were unsuccessful. The development of a laboratory method was necessary to investigate the effect of ingredients present in permeate powder that could be inhibiting polymerization. A Mars 6 Microwave Digestion System (CEM Corp., Matthews, NC) was used to heat and polymerize the sugars. The temperatures had to be lowered from extrusion conditions to produce a caramel-like product and not decompose the sugars. Small amounts of water had to be added to the reaction vessels to allow consistent heating of sugars between vessels. Elevated levels of water (22.86 and 28.57%, vol/wt) and calcium phosphate (0.928 and 1.856%, wt/wt) reduced the oligosaccharide yield in the laboratory method. Increasing the citric acid (catalyst) concentration increased the oligosaccharide yield for the pure sugar blend and when permeate powder was used. The utility of the laboratory method to predict oligosaccharide yields was confirmed during extrusion trials of permeate when this increased acid catalyst concentration resulted in similar oligosaccharide concentrations. PMID- 29428758 TI - The unfolded protein response is involved in both differentiation and apoptosis of bovine mammary epithelial cells. AB - The unfolded protein response (UPR) describes a process involved in the homeostasis of endoplasmic reticulum (ER) and the differentiation of secretory cells. At present, the roles of UPR in the mammary gland tissue of dairy cattle are unknown. In the current study, we investigated the expression of UPR-related genes in Holstein cows during the developmental and lactating stages of the mammary gland tissue. To investigate the roles of UPR during the differentiation of mammary epithelial cells (MEC), we used MAC-T cells, a line of MEC. We collected samples of mammary gland tissue in dairy cows by biopsy during the late gestation and lactation periods and examined the expression of UPR-related genes by quantitative real-time PCR. Expression levels of the spliced X-box binding protein 1 (XBP1) and activating transcription factor 4 (ATF4) were found to be significantly higher in the mammary gland tissue 10 d before delivery compared with 40 d before delivery. An investigation before and after differentiation in MAC-T cells showed that the expression of ATF4 increased after differentiation of MEC, whereas that of the spliced XBP1 did not significantly change. Western blot analysis revealed that the differentiation-inducing stimulus induced phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) but reduced that of protein kinase RNA-like endoplasmic reticulum kinase (PERK). Additionally, in ATF4-knockdown bovine MEC, differentiation was significantly suppressed; ATF4 knockdown also significantly suppressed the expression of glucocorticoid and insulin receptors. These results revealed that ER stress independent ATF4 is involved in the cell differentiation mechanism, either directly or indirectly, via the control of the expression of lactogenic hormone receptors in bovine MEC. Immediately after parturition, gene expression levels of the spliced XBP1, ATF4, and C/EBP homologous protein (CHOP) markedly increased in mammary gland tissue, with a strong negative correlation between expression of CHOP and initial milk yield; CHOP is an apoptosis-related protein induced by ER stress. The above findings indicate that UPR is intrinsically associated with apoptosis of MEC, thus affecting the differentiation of these cells, as well as milk yield. PMID- 29428759 TI - Graded substitution of grains with bakery by-products modulates ruminal fermentation, nutrient degradation, and microbial community composition in vitro. AB - A new segment of feed industry based on bakery by-products (BBP) has emerged. Yet, information is lacking regarding the effects of inclusion of BBP in ruminant diets on ruminal fermentation and microbiota. Therefore, the aim of this study was to evaluate the effect of the gradual replacement of grains by BBP on ruminal fermentation, nutrient degradation, and microbial community composition using the rumen-simulation technique. All diets consisted of hay and concentrate mixture with a ratio of 42:58 (dry matter basis), but differed in the concentrate composition with either 45% cereal grains or BBP, whereby 15, 30, or 45% of BBP were used in place of cereal grains. The inclusion of increasing levels of BBP in the diet linearly enhanced ruminal degradation of starch from 84% (control) to 96% (45% BBP), while decreasing degradation of crude protein and fiber. The formation of methane was lowered in the 45% BBP diet compared with all other diets. Whereas the ammonia concentration was similar in the control and 15% BBP, a significant decrease was found in 30% BBP (-23%) and 45% BBP (-33%). Also, BBP feeding shifted fermentation profile toward propionate at the expense of acetate. Moreover, isobutyrate linearly decreased with increasing BBP inclusion. Bacterial 16S rRNA Illumina MiSeq (Microsynth AG, Balach, Switzerland) sequencing revealed a decreased microbial diversity for the 45% BBP diet. Furthermore, the replacement of cereal grains with BBP went along with an increased abundance of the genera Prevotella, Roseburia, and Megasphaera, while decreasing Butyrivibrio and several OTU belonging to Ruminococcaceae. In conclusion, the inclusion of BBP at up to 30% of the dry matter had no detrimental effects on pH, fiber degradability, and microbial diversity, and enhanced propionate production. However, a higher replacement level (45%) impaired ruminal fermentation traits and fiber degradation and is not recommended. PMID- 29428760 TI - Use of meta-analyses and joint analyses to select variants in whole genome sequences for genomic evaluation: An application in milk production of French dairy cattle breeds. AB - As a result of the 1000 Bull Genome Project, it has become possible to impute millions of variants, with many of these potentially causative for traits of interest, for thousands of animals that have been genotyped with medium-density chips. This enormous source of data opens up very interesting possibilities for the inclusion of these variants in genomic evaluations. However, for computational reasons, it is not possible to include all variants in genomic evaluation procedures. One potential approach could be to select the most relevant variants based on the results of genome-wide association studies (GWAS); however, the identification of causative mutations is still difficult with this method, partly because of weak imputation accuracy for rare variants. To address this problem, this study assesses the ability of different approaches based on multi-breed GWAS (joint and meta-analyses) to identify single-nucleotide polymorphisms (SNP) for use in genomic evaluation in the 3 main French dairy cattle breeds. A total of 6,262 Holstein bulls, 2,434 Montbeliarde bulls, and 2,175 Normande bulls with daughter yield deviations for 5 milk production traits were imputed for 27 million variants. Within-breed and joint (including all 3 breeds) GWAS were performed and 3 models of meta-analysis were tested: fixed effect, random effect, and Z-score. Comparison of the results of within- and multi-breed GWAS showed that most of the quantitative trait loci identified using within-breed approaches were also found with multi-breed methods. However, the most significant variants identified in each region differed depending on the method used. To determine which approach highlighted the most predictive SNP for each trait, we used a marker-assisted best unbiased linear prediction model to evaluate lists of SNP generated by the different GWAS methods; each list contained between 25 and 2,000 candidate variants per trait, which were identified using a single within- or multi-breed GWAS approach. Among all the multi-breed methods tested in this study, variant selection based on meta analysis (fixed effect) resulted in the most-accurate genomic evaluation (+1 to +3 points compared with other multi-breed approaches). However, the accuracies of genomic evaluation were always better when variants were selected using the results of within-breed GWAS. As has generally been found in studies of quantitative trait loci, these results suggest that part of the genetic variance of milk production traits is breed specific in Holstein, Montbeliarde, and Normande cattle. PMID- 29428761 TI - Phenotypic and genetic relationships between indicators of the mammary gland health status and milk composition, coagulation, and curd firming in dairy sheep. AB - The present study investigated the effect of somatic cell count, lactose, and pH on sheep milk composition, coagulation properties (MCP), and curd firming (CF) parameters. Individual milk samples were collected from 1,114 Sarda ewes reared in 23 farms. Milk composition, somatic cell count, single point MCP (rennet coagulation time, RCT; curd firming time, k20; and curd firmness, a30, a45, and a60), and CF model parameters were achieved. Phenotypic traits were statistically analyzed using a mixed model to estimate the effects of the different levels of milk somatic cell score (SCS), lactose, and pH, respectively. Additive genetic, herd, and residual correlations among these 3 traits, and with milk composition, MCP and CF parameters, were inferred using a Bayesian approach. From a phenotypic point of view, higher SCS levels caused a delayed gelification of milk. Lactose concentration and pH were significant for many milk quality traits, with a very intense effect on both coagulation times and curd firming. These traits (RCT, RCT estimated using the curd firming over time equation, and k20) showed an unfavorable increase of about 20% from the highest to the lowest level of lactose. Milk samples with pH values lower than 6.56 versus higher than 6.78 were characterized by an increase of RCT (from 6.00 to 14.3 min) and k20 (from 1.65 to 2.65 min) and a decrease of all the 3 curd firmness traits. From a genetic point of view, the marginal posterior distribution of heritability estimates evidenced a large and exploitable variability for all 3 phenotypes. The mean intra-farm heritability estimates were 0.173 for SCS, 0.418 for lactose content, and 0.206 for pH. Lactose (favorably), and SCS and pH (unfavorably), at phenotypic and genetic levels, were correlated mainly with RCT and RCT estimated using the curd firming over time equation and scarcely with the other curd firming traits. The SCS, lactose, and pH were significantly correlated with each other's. In conclusion, results reported in the present study suggest that SCS, pH, and lactose affect, contemporarily and independently, milk quality and MCP. These phenotypes, easily available during milk recording schemes measured by infrared spectra prediction, could be used as potential indicators traits for improving cheese-making ability of ovine milk. PMID- 29428762 TI - Characterization of a cryptic plasmid isolated from Lactobacillus casei CP002616 and construction of shuttle vectors based on its replicon. AB - The cryptic plasmid pLC2W was isolated from Lactobacillus casei CP002616. Nucleotide sequence analysis revealed that 4 putative open reading frames (ORF) were responsible for DNA replication. Four Escherichia coli-Lactobacillus shuttle vectors were constructed using different lengths of the pLC2W replicon to identify the shortest functional replicon. The length of the pLC2W replicon did not affect the stability of the plasmids. Green fluorescent protein (GFP) as a reporter was expressed successfully in several lactobacilli using our constructed vectors. The results suggested that the expression vectors pUE-F0GFP and pUE F1GFP are potential molecular tools for heterologous gene cloning and expression in lactobacilli. Moreover, 2 plasmid-curing methods were used to eliminate pLC2W from L. casei. We detected no difference between L. casei CP002616 and L. casei CP002616 pLC2WDelta-IC (mutant strain cured by plasmid incompatibility method) in production of exopolysaccharide (EPS) or acid. However, EPS and acid production were both reduced in L. casei CP002616 pLC2WDelta-HT (mutant strain cured by high temperature heat treatment method), demonstrating a difference between these 2 curing methods. Sequence analysis of pLC2W and plasmid curing data suggest that plasmid pLC2W is not involved in EPS synthesis. PMID- 29428763 TI - Characterization and milk coagulating properties of Cynanchum otophyllum Schneid. proteases. AB - The herbaceous plant Cynanchum otophyllum Schneid. is widely used as a milk coagulant to make a Chinese traditional milk product, milk cake. However, the milk-clotting compounds and their mechanism remain unclear. In this study, crude proteases were extracted from the dried leaves of Cynanchum otophyllum Schneid. using citric acid-phosphate buffer and then partially purified by weak anion exchange chromatography. Two proteases, QA and QC, with molecular weights of 14 and 27 kDa, respectively, were shown to exhibit milk-clotting activity. A study of the effects of pH and temperature on the milk-clotting activity and proteolytic activity of the proteases showed that they exhibited good pH stability from pH 5.5 to 7.5 and good thermal stability at temperatures from 50 to 70 degrees C. The QA and QC were the cysteine proteases, able to hydrolyze beta-casein and kappa-casein completely, and alpha-casein partially. The cleavage site on kappa-casein determined by Orbitrap (Thermo Fisher Scientific, San Jose, CA) analysis showed that QA and QC could cleave kappa-casein at Ser132-Thr133. Overall, the results suggest that the Cynanchum otophyllum Schneid. proteases are a promising milk-clotting enzyme that could be used for manufacturing milk cake and cheese. PMID- 29428764 TI - Temporal effects of ruminal propionic acid infusion on feeding behavior of Holstein cows in the postpartum period. AB - The objective of this study was to determine the temporal effects of intraruminal infusion of propionic acid at the initiation of meals on feeding behavior of cows in the postpartum period. Propionic acid derived from ruminal fermentation can reduce energy intake of dairy cows. The suppression of appetite by propionic acid is likely caused by a signal related to the hepatic oxidation of fuels. Greater propionate flux to the liver is expected to result in faster oxidation of acetyl coenzyme A, which can stimulate satiety and reduce feed intake. Therefore, the rate of propionate supply to the liver, within the timeframe of meals, might be an important limitation to feed intake. Our hypothesis was that faster rate of propionate infusion during meals would decrease meal size and feed intake by decreasing the time required to stimulate satiety within a meal. Six ruminally cannulated, multiparous Holstein cows in the postpartum period were used in a duplicated 3 * 3 Latin square design experiment balanced for carryover effects. Treatments included control (no infusion) or 1.25 mol of propionic acid infused over 5 min (FST) or 15 min (SLW) at each meal. Infusions were initiated at the conditioned meal at feeding (1200 h) and were triggered at each spontaneous meal for 22 h. Contrary to our hypothesis, SLW decreased meal size 29% (0.87 vs. 1.23 kg of dry matter) compared with FST, and FST decreased meal frequency 27% (8.5 vs. 11.2 per d) compared with SLW. Dry matter intake was similar between FST and SLW, but propionic acid decreased dry matter intake 46% compared with control. A potential explanation is that FST resulted in greater liver bypass of propionate compared with SLW, extending anaplerosis of the tricarboxylic acid cycle, hepatic oxidation of acetyl coenzyme A, and satiety over a longer time after meals. PMID- 29428765 TI - Short communication: Calf cleanliness does not predict diarrhea upon arrival at a veal calf facility. AB - The objective of this study was to validate the use of cleanliness scores to identify the presence of diarrhea in calves. On arrival at a milk-fed veal facility, 452 calves were scored for hide cleanliness and fecal consistency by 1 of 2 observers. Fecal consistency was scored on a scale of 0 to 3, where fecal score of 0 = normal consistency, 1 = semiformed or pasty, 2 = loose feces, and 3 = watery feces; calves with a fecal score of 2 or 3 were classified as positive for diarrhea. Hide cleanliness was also scored on a scale of 0 to 3, where 0 = clean thighs and body with little to no manure on lower legs; 1 = tail head region and back end of calf are soiled with manure; 2 = tail head region, back end of calf, and thighs or legs are soiled with manure; and 3 = tail head region, back end of calf, thighs, and legs are soiled with manure. Of the calves scored, 188 calves (42%) were identified as having diarrhea based on hide cleanliness; however, only 78 calves (17%) were identified with diarrhea based on fecal consistency. The level of agreement between the 2 scoring methods were calculated, and a weighted kappa of 0.22 indicated only fair agreement between the 2 scoring methods. However, the sensitivity and specificity, calculated using fecal consistency >=2 as the classification variable, were 67 and 63%, respectively, when a cut point of >=1 for cleanliness score was used. A total of 222 calves scored at arrival were scored once per day for an additional 2 d following arrival. Calves were more likely to have more days with abnormal hide cleanliness than abnormal fecal consistency; 91 calves (41%) had an abnormal cleanliness score for at least 2 d, whereas only 21 calves (9%) had an abnormal fecal score for at least 2 d. We found poor correlation between total number of days with an abnormal cleanliness score and total number of days with an abnormal fecal score, indicating that consecutive observations of hide cleanliness would not improve the validity of using hide cleanliness. Thus, hide cleanliness is not a good indicator for identifying diarrhea in calves, and scoring fecal samples for consistency should be used to more accurately identify diarrhea in calves. PMID- 29428766 TI - Short communication: Field study to investigate the associations between herd level risk factors for milk fat depression and bulk tank milk fat percent in dairy herds feeding monensin. AB - Fat is the most variable milk component, and maintaining milk fat continues to be a challenge on commercial dairy farms. Our objectives were to establish associations between herd-level risk factors for milk fat depression and bulk tank milk fat content in commercial dairy herds feeding monensin. Seventy-nine Holstein commercial dairy herds in the northeast and Upper Midwest United States were enrolled in an observational study. Data were collected on herd characteristics, total mixed ration (TMR) samples, all component silage samples, and bulk tank milk samples. The unconditional univariable association of each explanatory variable and bulk tank milk fat percentage was evaluated using simple linear regression and multivariable regression models. Milk fat content of trans 10 C18:1 had an exponentially negative relationship to herd milk fat percentage. In general, milk fat content of fatty acids synthesized de novo in the mammary gland were positively related to herd milk fat, and the content of several trans C18:1 fatty acids, which would be products of alternate pathways of ruminal biohydrogenation, were negatively related to herd milk fat. Variables related to TMR composition did not have univariable relationships with herd milk fat percentage. Herds that had >49.8% of the TMR particles on the middle screen of the Penn State particle separator had higher milk fat percentage than those with <=49.8%, and herds with >54.0% of TMR particles in the bottom pan had lower milk fat percentage than herds with <=54.0%. Dietary content of monounsaturated fatty acids (C16:1 and C18:1) had negative relationships with herd milk fat percentage; however, no single diet component accounted for more than 11% of the variation in herd-level milk fat percentage. Univariable monensin dose was not associated with herd milk fat percentage. The relative lack of significant univariate relationships with herd-level milk fat suggests many factors contribute to milk fat content, and herds experiencing low milk fat will need to examine many potential risk factors when working to troubleshoot this challenge. PMID- 29428767 TI - Legacy and emerging brominated flame retardants in China: A review on food and human milk contamination, human dietary exposure and risk assessment. AB - Brominated flame retardants (BFRs) are a large group of widely used chemicals, which have been produced and used since 1970s. As a consequence of substantial and long-term usage, BFRs have been found to be ubiquitous in humans, wildlife, and abiotic matrices around the world. Although several reports have reviewed BFRs contamination in general, none have focused specifically on foods and human milk, and the corresponding dietary exposure. Foods (including human milk) have long been recognized as a major pathway of BFRs intake for non-occupationally exposed persons. This review summarizes most available BFRs data in foods and human milk from China in recent years, and emphasizes several specific aspects, i.e., contamination levels of legacy and emerging BFRs, dietary exposure assessment and related health concerns, comparison between various BFRs, and temporal changes in BFRs contamination. PMID- 29428768 TI - High catalytic oxidation of As(III) by molecular oxygen over Fe-loaded silicon carbide with MW activation. AB - The catalytic oxidation of arsenite (As(III)) to arsenate (As(V)) and the removal of arsenic (As) in an iron loaded silicon carbide (Fe/SiC) system under microwave (MW) irradiation were studied. Fe/SiC was synthesized by electro-deposition and its capability of activating molecular oxygen was also characterized. Highly efficient As(III) removal in a wide pH range of 2.5-9.5 was achieved, involving oxidation by reactive oxidation species (OH and O2-) induced by MW irradiation and adsorption by the generated Fe (hrdro)oxide precipitates. Significant enhancement of As(III) oxidation was achieved at acidic pH, where sequential fresh Fe(0) exposure with MW irradiation could improve the Fenton-like reactions and oxidation efficiency for As(III). As(III) removal was accelerated via adsorption at alkaline conditions, where the adsorbed Fe(II) on Fe/SiC showed significant catalytic activity for molecular oxygen and high pH further favored the formation of (hydro)oxides and the As sequestration by adsorption. Fe/SiC showed superior performance for the treatment of As in water with MW irradiation. PMID- 29428769 TI - Impaired spatial pattern separation performance in temporal lobe epilepsy is associated with visuospatial memory deficits and hippocampal volume loss. AB - Individuals with chronic temporal lobe epilepsy (TLE) experience episodic memory deficits that may be progressive in nature. These memory decrements have been shown to increase with the extent of hippocampal damage, a hallmark feature of TLE. Pattern separation, a neural computational mechanism thought to play a role in episodic memory formation, has been shown to be negatively affected by aging and in individuals with known hippocampal dysfunction. Despite the link between poor pattern separation performance and episodic memory deficits, behavioral pattern separation has not been examined in patients with TLE. We examined pattern separation performance in a group of 22 patients with medically refractory TLE and 20 healthy adults, using a task hypothesized to measure spatial pattern separation with graded levels of spatial interference. We found that individuals with TLE showed less efficient spatial pattern separation performance relative to healthy adults. Poorer spatial pattern separation performance in TLE was associated with poorer visuospatial memory, but only under high interference conditions. In addition, left hippocampal atrophy was associated with poor performance in the high interference condition in TLE. These data suggest that episodic memory impairments in patients with chronic, refractory TLE may be partially due to less efficient pattern separation, which likely reflects their underlying hippocampal dysfunction. PMID- 29428770 TI - Pseudoneglect is maintained in aging but not in mild Alzheimer's disease: new insights from an enumeration task. AB - Neurologically healthy young adults display a behavioral bias, called pseudoneglect, which favors the processing of stimuli appearing in the left visual field. Pseudoneglect arises from the right hemisphere dominance for visuospatial attention. Previous studies investigating the effects of normal aging on pseudoneglect in line bisection and greyscale tasks have produced divergent results. In addition, scarce systematic investigations of visual biases in dementia have been reported. The aim of the present study was to evaluate whether the leftward bias appearing during an enumeration task in young adults would be preserved in normal aging and at different stages of severity of Alzheimer's disease. In Experiment 1, young and older healthy adults showed a comparable pseudoneglect, performing better when targets appeared in the left visual field. In Experiment 2, the leftward bias was maintained in amnesic mild cognitive impairment patients (aMCI), but it vanished in mild Alzheimer's disease patients (AD). The maintenance of pseudoneglect in normal aging and in aMCI patients is consistent with compensatory phenomena involving the right fronto parietal network, which allow maintaining the right hemisphere dominance. Conversely, the lack of pseudoneglect in the sample of AD patients likely results from a loss of the right hemisphere dominance, caused by the selective degeneration of the right fronto-parietal network. These results highlight the need of further systematic investigations of visuospatial biases along the continuum of normal and pathological aging, both for a better understanding of the changes characterizing cognitive aging and for improvements in the evaluation of neglect in Alzheimer's disease. PMID- 29428771 TI - Distinct neural engagement during implicit and explicit regulation of negative stimuli. AB - Neuroimaging research has characterized underlying neural mechanisms of attentional control and cognitive reappraisal, common implicit and explicit forms of emotion regulation, respectively. This research suggests attentional control and reappraisal may engage similar midline and lateral areas in the prefrontal cortex (PFC); however, findings are largely based on separate studies. Therefore, the extent to which mechanisms of implicit versus explicit regulation are independent or overlapping is not clear. In the current study, 49 healthy participants completed well-validated implicit and explicit regulation tasks in the form of attentional control and cognitive reappraisal during functional magnetic resonance imaging. During implicit regulation, participants identified a target letter in a string of letters superimposed on threatening faces. To manipulate attentional control, the letter string either consisted of all targets ('Threat Low' perceptual load), or was embedded among non-target letters ('Threat High' perceptual load). During cognitive reappraisal, participants were shown aversive images and instructed to use a cognitive approach to down-regulate negative affect ('Reappraise') or to naturally experience emotions without altering them ('Look-Negative'). Order of administration of tasks was counterbalanced across participants. Whole-brain results regarding frontal activity showed ventromedial PFC/rostral anterior cingulate cortex was recruited during Threat Low > Threat High. In contrast, Reappraise > Look-Negative resulted in engagement of the dorsolateral PFC, ventrolateral PFC and dorsomedial PFC. In addition, results showed no relationship between accuracy during attentional control and self-reported negative affect during cognitive reappraisal. Results indicate attentional control in the context of threat distractors and the reappraisal of negative images are supported by discrete, non-overlapping neurocircuitries. PMID- 29428772 TI - The effect of integration of hospitals and post-acute care providers on Medicare payment and patient outcomes. AB - In this paper we examine empirically the effect of integration on Medicare payment and rehospitalization. We use 2005-2013 data on Medicare beneficiaries receiving post-acute care (PAC) in the U.S. to examine integration between hospitals and the two most common post-acute care settings: skilled nursing facilities (SNFs) and home health agencies (HHA), using two measures of integration-formal vertical integration and informal integration representing preferential relationships between providers without formal relationships. Our identification strategy is twofold. First, we use longitudinal models with a fixed effect for each hospital-PAC pair in a market to test how changes in integration impact patient outcomes. Second, we use an instrumental variable approach to account for patient selection into integrated providers. We find that vertical integration between hospitals and SNFs increases Medicare payments and reduces rehospitalization rates. However, vertical integration between hospitals and HHAs has little effect, nor does informal integration between hospitals and either PAC setting. PMID- 29428773 TI - Self-perceived personality characteristics in seasonal affective disorder and their implications for severity of depression. AB - The personality traits Neuroticism and Extraversion may be involved in the development of seasonal affective disorder (SAD). However, the impact of personality traits on SAD severity and whether such self-reported traits fluctuate with season is unknown. We investigated the association between Neuroticism, as acquired in a symptom-free phase and depression severity in individuals with SAD and seasonal changes in personality traits in individuals with SAD compared to healthy controls. Twenty-nine individuals diagnosed with SAD and thirty demographically matched controls completed the NEO Personality Inventory-Revised and the Major Depression Inventory twice: in summer when individuals with SAD were symptom-free, and in winter when they experienced SAD symptoms. In summer, the groups scored similarly on their personality traits, and the controls did not score any different in winter compared to summer. High scores on Neuroticism in summer was associated with more severe depressive symptoms in winter in SAD individuals. In winter, individuals with SAD scored higher on Neuroticism and lower on Extraversion, both compared to controls and to their own summer scores. Our results support that Neuroticism may represent a vulnerability marker related to SAD, and during a depressive episode Neuroticism and Extraversion may be sensitive markers of SAD pathology. PMID- 29428774 TI - Affect labeling and other aspects of emotional experiences in relation to alexithymia following standardized emotion inductions. AB - Alexithymia is associated with increased risk for mental and physical health disorders but available assessments rely exclusively on self-report. The major aim of the current study was to develop and implement a performance-based task designed to characterize and quantify the relationship between one's description of emotional experience and self-reported alexithymia. Specifically, we examined performance-based measures of affect labeling of one's own emotions, emotional granularity and dialecticism. Healthy participants (N = 108) completed the Toronto Alexithymia Scale-20 Item Questionnaire. Participants viewed a series of film clips standardized to elicit discrete emotional states. After each clip, they indicated the emotion they experienced "the most" and rated a list of non primary emotions, which formed indices of emotional granularity and dialecticism. Alexithymia was associated with increased tendency to report experiencing "no emotion" following evocative film clips, reduced negative emotional granularity and dialecticism of experienced emotions. TAS-20 subscales were each associated with a unique set of emotional correlates. In a healthy population, alexithymia is associated with reduced awareness of emotional states, and reduced dialecticism and granularity of negative (but not positive) emotions. Our performance-based assessment enriches understanding of the mechanisms underlying alexithymia by underscoring the central importance of emotion awareness, negative emotional granularity and dialecticism. PMID- 29428775 TI - Evaluation of the DSM-5 severity ratings for anorexia nervosa in a clinical sample. AB - We examined the validity and utility of the DSM-5 severity ratings for anorexia nervosa (AN) in a clinical (treatment-seeking) sample (N = 273; 95.6% women). Participants classified with mild, moderate, severe, and extreme severity of AN based on their measured body mass index, differed significantly from each other in eating disorder features, putative maintenance factors, and illness-specific functional impairment (medium effect sizes). However, they were statistically indistinguishable in psychiatric-disorder comorbidity and distress, demographics, and age-of-AN onset. The implications of our findings, providing limited support for the DSM-5 severity ratings for AN, and directions for future research are outlined. PMID- 29428776 TI - A planned complex suicide by self-stabbing and vehicular crash: An original case and review of the literature. AB - Suicide is a frequent manner of unnatural death, especially from a forensic point of view. Complex suicide is defined as a recourse to more than one potentially lethal mechanism to deliberately induce death. This paper presents a complex suicide with a novel combination of self-killing methods. A 27 year-old man, working as a butcher, was found dead in his crashed car. The facts were initially in favour of an obvious traffic accident until a knife was discovered penetrating the driver's chest, requiring the police who were on the scene to carry out a criminal investigation. The cause of death was a major hemorrhagic process due to vascular thoracic lesions and internal blood loss. Based on the circumstances surrounding the death, the police investigations and the findings at the autopsy, the case was classified as a planned complex suicide. Through this original combination of two methods of suicide, this paper underlines the significance of a complete criminal investigation supported by a detailed crime scene inspection and autopsy examination. PMID- 29428777 TI - Inherent variation in multiple shoe-sole test impressions. AB - Shoeprints left at crime scenes are seldom perfect. Many prints are distorted or contaminated by various materials. Noisy background often contributes to vagueness on the shoeprints as well. Test impressions made from the suspect's shoes in the laboratory are considered a genuine replication of the shoe-sole. This naive attitude is far from being correct. Consecutive test impressions made in the laboratory under strict similar conditions revealed differences among the exemplars of the same sole. Some of them are minor, but some are major, and can mislead the less experienced practitioners during the comparison process. This article focuses on the inherent within source variability between controlled shoeprints made from the same shoe, as it appears on the RACs. To describe and analyze this variability, repeated test impressions were prepared, and datasets were created. Several RACs were marked on each test impression, using an expert assisting software tool (developed in the authors' lab). The variance in repeated test impressions is demonstrated and possible sources are discussed. This variance should be considered when trying to establish the degree of matching between individual characteristics. PMID- 29428778 TI - Base-catalyzed hydrolysis and speciation-dependent photolysis of two cephalosporin antibiotics, ceftiofur and cefapirin. AB - Lately, special attention has been given to veterinary cephalosporin antibiotics due to their broad activity spectrum and significant consumption. Indeed, the determination of hydrolytic and photolytic kinetics provides a better comprehension of the undesired persistence of cephalosporins in aqueous matrices. In this work, the two widely used veterinary antibiotics ceftiofur (CEF) and cefapirin (CEPA) showed high instability under alkaline conditions, degrading in few minutes at pH > 11. In buffered solutions at neutral pH and natural temperature (T = 22 +/- 1 degrees C), both drugs presented moderate stability (t1/2 = 3 d, CEPA and 1.4 d, CEF). Our study also demonstrated that CEPA and CEF speciation did not significantly influence the direct photolysis rates. Using a simulated water disinfection set-up (lambda = 254 nm), all ionic species of CEF and CEPA presented fast and similar pseudo-first order degradation rates, kapp 0.0095 +/- 0.0004 and 0.0092 +/- 0.001 cm2 mJ-1, respectively. Furthermore, using surface water in hydrolysis experiments, CEF demonstrated significant matrix dependent stability with a half-life (t1/2 = 14.7 d) tenfold higher than in buffered solutions. In contrast, CEPA presented a very similar hydrolysis rate in river water (t1/2 = 4.2 d) and a subtle faster photo-degradation rate in this same matrix (kapp 0.0128 +/- 0.001 cm2 mJ-1), highlighting the importance of disinfection radiation for cephalosporin depletion in aqueous environments. PMID- 29428779 TI - Health risks from exposure to Legionella in reclaimed water aerosols: Toilet flushing, spray irrigation, and cooling towers. AB - The use of reclaimed water brings new challenges for the water industry in terms of maintaining water quality while increasing sustainability. Increased attention has been devoted to opportunistic pathogens, especially Legionella pneumophila, due to its growing importance as a portion of the waterborne disease burden in the United States. Infection occurs when a person inhales a mist containing Legionella bacteria. The top three uses for reclaimed water (cooling towers, spray irrigation, and toilet flushing) that generate aerosols were evaluated for Legionella health risks in reclaimed water using quantitative microbial risk assessment (QMRA). Risks are compared using data from nineteen United States reclaimed water utilities measured with culture-based methods, quantitative PCR (qPCR), and ethidium-monoazide-qPCR. Median toilet flushing annual infection risks exceeded 10-4 considering multiple toilet types, while median clinical severity infection risks did not exceed this value. Sprinkler and cooling tower risks varied depending on meteorological conditions and operational characteristics such as drift eliminator performance. However, the greatest differences between risk scenarios were due to 1) the dose response model used (infection or clinical severity infection) 2) population at risk considered (residential or occupational) and 3) differences in laboratory analytical method. Theoretical setback distances necessary to achieve a median annual infection risk level of 10-4 are proposed for spray irrigation and cooling towers. In both cooling tower and sprinkler cases, Legionella infection risks were non-trivial at potentially large setback distances, and indicate other simultaneous management practices could be needed to manage risks. The sensitivity analysis indicated that the most influential factors for variability in risks were the concentration of Legionella and aerosol partitioning and/or efficiency across all models, highlighting the importance of strategies to manage Legionella occurrence in reclaimed water. PMID- 29428780 TI - Impact of copper on the diazotroph abundance and community composition during swine manure composting. AB - Biological nitrogen fixation is a major pathway in ecosystems. This study investigated the effects of adding Cu at different levels (0, 200, and 2000 mg kg 1) on the diazotroph community during swine manure composting. Quantitative PCR and high-throughput sequencing were used to analyze the abundances of diazotrophs and the community composition based on the nifH gene. The nifH gene copy number was relatively high in the early stage of composting and Cu had a significant inhibitory effect on the nifH copy number. Furthermore, Cu decreased the diversity of nifH and changed the microbial community structure in the early stage. The nifH genes from members of Firmicutes and Clostridium were most abundant. Co-occurrence ecological network analysis showed that the Cu treatments affected the co-occurrence patterns of diazotroph communities and reduced the associations between different diazotrophs. Interestingly, Cu may weaken symbiotic diazotrophic interactions and enhance the roles of free-living diazotrophs. PMID- 29428781 TI - Variation of antibiotics in sludge pretreatment and anaerobic digestion processes: Degradation and solid-liquid distribution. AB - Degradation and solid-liquid distribution of antibiotics in three sludge pretreatments (ultrasonic, alkaline and thermal hydrolysis pretreatment) and subsequent anaerobic digestion processes were investigated. The contamination of fluoroquinolones (FQs) was most serious in the raw sludge, while sulfonamides (SAs) were negligible. Obvious solubilization of antibiotics was observed after sludge pretreatments. The intracellular antibiotics were released after thermal hydrolysis pretreatment, meanwhile tetracyclines (TCs) were thermally decomposed. Compared to TCs and macrolides (MLs), FQs were hardly degraded in anaerobic digestion with removal efficiencies lower than 42.02%, and the residual FQs were mostly adsorbed on the digested sludge. The limiting step for FQs reduction was the biodegradation, rather than desorption of adsorbed antibiotics. Addition of pretreatments had no obvious effect on the degradation and distribution of antibiotics in the anaerobic digested sludge, except that the thermal hydrolysis enhanced the migration of antibiotics to the liquid phase. PMID- 29428782 TI - Aromatic hydrocarbon biodegradation activates neutral lipid biosynthesis in oleaginous yeast. AB - In this study, the biodegradation ability of oleaginous yeast Cryptococcus psychrotolerans IITRFD for aromatic hydrocarbons (AHs) was investigated. It was found to completely degrade range of AHs such as 1 g/L phenol, 0.75 g/L naphthalene, 0.50 g/L anthracene and 0.50 g/L pyrene with lipid productivity (g/L/h) of 0.0444, 0.0441, 0.0394 and 0.0383, respectively. This work demonstrated the ring cleavage pathways of AHs by this yeast which follow ortho route for phenol and naphthalene while meta route for anthracene and pyrene degradation. The end products generated during biodegradation of AHs are feed as precursors for de novo triacylglycerols (TAG) biosynthesis pathway of oleaginous yeast. A high quantity of lipid content (46.54%) was observed on phenol as compared to lipid content on naphthalene (46.38%), anthracene (44.97%) and pyrene (44.16%). The lipid profile revealed by GC-MS analysis shows elevated monounsaturated fatty acid (MUFA) content with improved biodiesel quality. PMID- 29428783 TI - Electric energy production from food waste: Microbial fuel cells versus anaerobic digestion. AB - A food waste resourceful process was developed by integrating the ultra-fast hydrolysis and microbial fuel cells (MFCs) for energy and resource recovery. Food waste was first ultra-fast hydrolyzed by fungal mash rich in hydrolytic enzymes in-situ produced from food waste. After which, the separated solids were readily converted to biofertilizer, while the liquid was fed to MFCs for direct electricity generation with a conversion efficiency of 0.245 kWh/kg food waste. It was estimated that about 192.5 million kWh of electricity could be produced from the food waste annually generated in Singapore, together with 74,390 tonnes of dry biofertilizer. Compared to anaerobic digestion, the proposed approach was more environmentally friendly and economically viable in terms of both electricity conversion and process cost. It is expected that this study may lead to the paradigm shift in food waste management towards ultra-fast concurrent recovery of resource and electricity with zero-solid discharge. PMID- 29428784 TI - Biomethanation of water hyacinth biomass. AB - The aim of this study was to test practical solutions to improve biogas yield during the anaerobic digestion of water hyacinth (WH) biomass. Increasing the WH (whole plant) solid content to ~40% through sun drying (6 h), and its subsequent digestion increased biogas yield by 14% with a higher biogas methane (75%) content. Ensilation of dried WH (40% moisture) was found effective for its preservation to ensure its continuous availability even during offseasons, but the biogas yield from six months ensilated biomass was 20% less compared with fresh WH. Co-digestion of WH with waste activated sludge and food waste revealed ~150 and ~400 ml biogas/g VS respectively against ~140 ml/g VS of WH alone. The practical approaches tested in this study like pre-treatment, preservation, and co-digestion of WH found to be effective to make its bio methanation more feasible. PMID- 29428785 TI - Micronutrient supplementation during pregnancy and the risk of pregnancy-induced hypertension: A randomized clinical trial. AB - BACKGROUND & AIMS: Increasing evidence suggests that iron-containing multiple micronutrient may reduce the risk of pregnancy-induced hypertension including gestational hypertension or preeclampsia. We aimed to examine whether 30 mg iron plus folic acid or multiple micronutrients during pregnancy reduces the risk of pregnancy-induced hypertension. METHODS: We conducted a secondary data analysis by the dataset from a double-blind randomized controlled trial in China from 2006 to 2009 that was conducted to investigate the effects of multiple micronutrient supplements on adverse pregnancy outcomes when provided to pregnant women with no/mild anemia. We used logistic regression to estimate the adjusted odds ratio and 95% confidence interval and test for effect modification. RESULTS: The incidence of pregnancy-induced hypertension was 7.1% (423/5923), 6.3% (374/5933) and 6.3% (372/5914) among the pregnant women who took folic acid only, iron-folic acid and multiple micronutrient supplements, respectively. The adjusted odds ratios associated with iron-folic acid supplements and multiple micronutrient supplements for pregnancy-induced hypertension were both nearly 0.88 (95% confidence interval, 0.76-1.02), compared with folic acid supplements only. Among pregnant women aged 20-24 years, iron-folic acid (adjusted odds ratios: 0.81, 95% confidence interval: 0.67-0.96) or multiple micronutrient supplementation (adjusted odds ratios: 0.83, 95% confidence interval: 0.70-0.99) can significantly reduce the risk of pregnancy-induced hypertension compared to folic acid supplementation. CONCLUSIONS: Overall, there were no significant differences in pregnancy-induced hypertension across supplement groups. However, among pregnant women aged 20-24 years, iron-containing multiple micronutrient supplementation was associated with a reduced risk of pregnancy-induced hypertension compared with folic acid supplements only. TRIAL REGISTRATION: ClinicalTrials.gov NCT00133744. PMID- 29428786 TI - The associations of dietary patterns with all-cause mortality and other lifestyle factors in the elderly: An age-specific prospective cohort study. AB - BACKGROUND & AIMS: The association between dietary pattern and mortality has been well studied in the general population; however, few studies have focused on the elderly. We aimed to examine the association of dietary pattern with subsequent overall mortality in elderly Japanese, and demonstrate the modifiable effect of lifestyle factors on this association. METHODS: Totally 2949 Japanese community dwelling residents aged 64 or 65 years were included in the NISSIN Project in 1996-2005. A validated food frequency questionnaire was adopted to collect dietary information and factor analysis was used to extract dietary patterns. Unadjusted and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated through the Cox proportional hazard regression model. RESULTS: Over 31,233 person-years, 253 persons died. Three different dietary patterns were identified: meat-fat, healthy, and dairy-bread pattern. Increased risk for all cause mortality for meat-fat pattern was observed among those who never smoked (HR, 2.81; 95% CI, 1.37-5.79); this association for dairy-bread pattern was observed among the never smokers (HR, 2.21; 95% CI, 1.20-4.06) and occasional drinkers (HR, 1.62; 95% CI, 1.09-2.39). For healthy pattern, decreased overall mortality risk was observed among never smokers (HR, 0.44; 95% CI, 0.24-0.80), occasional drinkers (HR, 0.63; 95% CI, 0.42-0.93), and those who walked >=1 h/day (HR, 0.47; 95% CI, 0.28-0.77). CONCLUSIONS: We found that tobacco use, alcohol consumption, and daily walking duration could modify the associations of three patterns with overall mortality. Healthy eating along with other healthy lifestyle factor among elderly populations can decrease the overall mortality risk. PMID- 29428787 TI - Trace element repletion following severe burn injury: A dose-finding cohort study. AB - BACKGROUND & AIMS: Major burn patients are characterized by large exudative losses of Cu, Se and Zn. Trace element (TE) repletion has been shown to improve clinical outcome. Having increased the TE doses over time, the study aimed at analysing if our repletion protocol corrected TE plasma concentrations and if the necessity for continuous renal replacement therapy (CRRT) might increase the TE needs. METHODS: Retrospective analysis of prospectively collected data in burn patients requiring intensive care (ICU) between 1999 and 2015. INCLUSION CRITERIA: Admission on day 1, full treatment, burned surface area (TBSA) >=20% and >=1 TE plasma determination during the stay. Four groups were constituted according to protocol changes. Period 1 (P1): 1999-2000, P2: 2001-2005, P3: 2006 2010, P4: 2011-2015. Changes consisted in increasing TE repletion doses and duration. Demographic data, daily TE intakes and weekly plasma concentrations were retrieved for the first 21 ICU-days. Data as median (IQR). RESULTS: 139 patients completed the criteria, aged 37 (28) years, burned on 35 (25) % TBSA. As a result of prescription, Cu, Se and Zn intakes increased significantly between P1 and P4, resulting in normalization of plasma Cu (16 MUmol/l) since P3 and Zn (13.5 MUmol/l) since P2. Median plasma Se were above reference range (1400 nmol/l) during P3 and P4. CRRT patients required higher doses of Cu for maintenance within normal ranges. CONCLUSION: This dose finding study shows that the latest repletion protocol is safe and normalizes Cu and Zn concentrations. Se doses result in supra-normal Se concentrations, suggesting prescription reduction. CRRT patients are at high risk of Cu depletion and require specific monitoring. PMID- 29428788 TI - A pilot study of a novel therapeutic approach to obesity: CNS modification by N.I.R. H.E.G. neurofeedback. AB - BACKGROUND & AIMS: Despite the thorough mapping of brain pathways involved in eating behavior, no treatment aimed at modulating eating dysregulation from its neurocognitive root has been established yet. We aimed to evaluate the effect of N.I.R. H.E.G. (Near Infra-Red Hemoencephalography) neurofeedback training on appetite control, weight and food-related brain activity. METHODS: Six healthy male participants with overweight or mild obesity went through 10 N.I.R. H.E.G. neurofeedback sessions designed to practice voluntary activation of the prefrontal cortex. Weight, eating behavior, appetite control and brain activity related to food and self-inhibition based on fMRI were evaluated before and after neurofeedback training. RESULTS: Our study group demonstrated a positive trend of increased self-control and inhibition related to food behavior, reduced weight and increased activation during an fMRI response-inhibition task (Go-No-Go - GNG) in the predefined region of interest (ROI): superior orbitofrontal cortex (sOFC). CONCLUSIONS: N.I.R. H.E.G. holds a promising potential as a feasible neurofeedback platform for modulation of cortical brain circuits involved in self control and eating behavior and should be further evaluated and developed as a brain modifying device for the treatment and prevention of obesity. PMID- 29428789 TI - [Re-irradiation of head and neck cancers: Target volumes, technical evolutions and prospects]. AB - Malignant tumors of the head and neck have a predominantly regional recurrence pattern, with most deaths resulting from this progression. Optimization of re radiation in recurrence setting is a major objective for these patients. Extensive research has been carried out with the PubMed search engine to find publications dealing with this topic. The first attempts to reirradiate the ORL sphere date back to the 1980s and the first to be performed by intensity modulation conformational radiotherapy (IMRT) date back to the late 1990s. Compared to 3 dimensional conformal radiotherapy, IMRT improves clinical outcomes and reduces toxicity. In IMRT series, associated or not with concomitant chemotherapy, the locoregional control obtained at 2 years was of the order of 45 to 65% and the overall survival of 15 to 60%, depending on predictive factors. Grade 3 acute toxicity occurred on the order of 10 to 30% and late-grade 3 toxicity on the order of 15 to 50%. In a selected population with low volumes tumors, stereotactic re-irradiation at a minimum dose of 35Gy obtained outcome comparable to IMRT. Re-irradiation of head and neck tumors by proton therapy is rare. The toxicity rate appears to be lower than that usually seen after photon therapy. However, we do not have a long follow-up. This technique therefore remains reserved for search protocols and represents a future perspective in these situations. PMID- 29428790 TI - Management of cervical premalignant lesions. AB - Treatment of cervical premalignant lesions (cervical intraepithelial neoplasia; CIN) of different grades is very effective, simple, and safe. The entire transformation zone of the cervix needs to be treated either by an ablative technique (cryotherapy or thermal ablation) or an excisional technique (large loop excision of transformation zone or cold knife conization); the choice of treatment depends on the size and location of the lesion and the type of the transformation zone. The cure rate after ablative treatment of high-grade CIN may be little lower than that after excisional treatment. The simplicity of the technique, low complication rate, and lesser cost make ablative technique the treatment of choice in the low resourced settings for the eligible lesions. In situations where organizing colposcopy and histopathology services is challenging, simple algorithms like screening with visual inspection with acetic acid test and immediate ablative treatment of the visual inspection with acetic acid-positive women has been recommended by the World Health Organization. Such a strategy is effective in preventing subsequent development of high-grade CIN and also ensures high compliance of the screen positive women to treatment. PMID- 29428791 TI - The therapeutic potential of polymersomes loaded with 225Ac evaluated in 2D and 3D in vitro glioma models. AB - Alpha emitters have great potential in targeted tumour therapy, especially in destroying micrometastases, due to their high linear energy transfer (LET). To prevent toxicity caused by recoiled daughter atoms in healthy tissue, alpha emitters like 225Ac can be encapsulated in polymeric nanocarriers (polymersomes), which are capable of retaining the daughter atoms to a large degree. In the translation to a (pre-)clinical setting, it is essential to evaluate their therapeutic potential. As multicellular tumour spheroids mimic a tumour microenvironment more closely than a two-dimensional cellular monolayer, this study has focussed on the interaction of the polymersomes with U87 human glioma spheroids. We have found that polymersomes distribute themselves throughout the spheroid after 4 days which, considering the long half-life of 225Ac (9.9 d) (Vaidyanathan and Zalutsky, 1996), allows for irradiation of the entire spheroid. A decrease in spheroidal growth has been observed upon the addition of only 0.1 kBq 225Ac, an effect which was more pronounced for the 225Ac in polymersomes than when only coupled to DTPA. At higher activities (5 kBq), the spheroids have been found to be destroyed completely after two days. We have thus demonstrated that 225Ac containing polymersomes effectively inhibit tumour spheroid growth, making them very promising candidates for future in vivo testing. PMID- 29428792 TI - Enhancement of lymphatic transport of lutein by oral administration of a solid dispersion and a self-microemulsifying drug delivery system. AB - Lutein is located in the macula lutea in the human eye. Since humans cannot synthesize lutein de novo, it must be digested as food. Some studies including our previous study showed very low absorption of lutein after oral administration. These studies also suggested that the absorption route of lutein from the small intestine involves not only the blood but also the lymph. The aim of this study was to clarify the transfer of lutein into lymph and the tissue distribution after oral administration of a solid dispersion (SD) and a self microemulsifying drug delivery system (SMEDDS) for improvement of the absorption. We used thoracic lymph-cannulated rats. It was shown that the plasma concentrations of lutein in the SD and SMEDDS groups were increased compared with that in the powder group. The absorption of lutein after oral administration of each formulation was clearly evaluated by its cumulative amount in lymph. Our data clearly showed that lutein is transferred into the lymph stream from the small intestine. PMID- 29428793 TI - Confocal Raman microspectroscopy as an alternative method to investigate the extraction of lipids from stratum corneum by emulsifiers and formulations. AB - The purpose of this study was to investigate the impact of emulsifiers and formulations on intercellular lipids of porcine stratum corneum (SC) and evaluate confocal Raman microscopy (CRM) as an alternative method in this research context. To this end, four different formulations were used: three conventional creams that contained ionic and/or non-ionic emulsifiers and one surfactants-free emulsion stabilized by a polymeric emulsifier. Additionally, all emulsifiers were tested in aqueous solution/dispersion in the respective concentrations as present in the formulations. CRM and HPTLC were used to analyse changes in SC lipid content after treatment. Furthermore, lipid extraction was visualized by fluorescence staining and SC thickness was measured by CRM and light microscopy. Various emulsifiers and emulsifier mixtures showed different impact on SC lipid content and SC thickness, while none of the tested formulations had any effect on SC lipids. Emulsifiers and their mixtures that reduced the lipids content also reduced SC thickness, indicating lipid extraction is the reason for SC thinning. Results from CRM and conventional methods showed a strong positive correlation for both lipid content and SC thickness measurements. With easy sample preparation and fast analytical readout, CRM has the potential to be a standardized analytical method for skin lipids investigation. PMID- 29428794 TI - Supramolecular cyclodextrin-based metal-organic frameworks as efficient carrier for anti-inflammatory drugs. AB - Drug delivery systems have been used to reduce adverse effects and improve the efficacy of therapies. Drug carriers have been developed over the years, but they have limitations. gamma-cyclodextrin-based metal-organic frameworks (gamma-CD MOF) have significant advantages due to their biocompatibility and environmental safety, besides crystallinity and porosity. Herein, gamma-CD-MOFs were synthesised with different metals as nodes and investigated. Uniform mesoporous gamma-CD-MOFs were obtained and showed an absence of toxicity in HepG2 and Caco-2 cells. The longer controlled release was verified for gamma-CD-MOFs, with a maximum of 62% released in 12 h. An inflammation experiment was performed in mice and activity equivalent to the positive control was verified. gamma-KCD-MOFs and gamma-NaCD-MOFs reached activity after 6 h of administration, however this happened after 24 h in gamma-FeCD-MOFs, being more effective than the positive control. Considering the ability for drug entrapment, easy preparation and controlled release, this class of material allows potential applications in drug delivery systems. PMID- 29428795 TI - Poly(anhydride) nanoparticles containing cashew nut proteins can induce a strong Th1 and Treg immune response after oral administration. AB - Cashew nut allergy is the second most commonly reported tree nut allergy. Traditional allergen immunotherapy presents several clinical drawbacks that can be reduced by using nanoparticles-basedallergen-delivery systems, modulating the immune response towards a protective one. In this context, the goal of this work was to assess the potential of poly(anhydride) nanoparticles (NP) for cashew nut oral immunization. Cashew nut allergens-loaded nanoparticles (CNE-NP) were prepared by solvent displacement method. After nanoparticles characterization, oral immunomodulation ability was evaluated in BALB/c mice. Our results demonstrated that CNE-NP induced a higher Th1/Th2 ratio in comparison with animals immunized with free cashew nut proteins. Indeed, a decrease in splenic Th2 cytokines (IL-4, IL-5, and IL-13), and an enhancement of pro-Th1 (IL-12 and IFN-gamma) and regulatory (IL-10) cytokines was observed. Furthermore, mice orally immunized with CNE-NP presented an increased expansion of CD4+ T regulatory cells, such as CD4+Foxp3+ and CD4+LAP+, in the mesenteric lymph nodes. In conclusion, oral immunization with a single dose of poly(anhydride) nanoparticles loaded with cashew nut proteins leaded to a pro-Th1 and Treg immune response. Furthermore, their immunomodulatory properties could be introduced as a new approach for management of cashew nut allergy. PMID- 29428796 TI - Long noncoding RNA growth arrest-specific 5 promotes proliferation and survival of female germline stem cells in vitro. AB - Female germline stem cells (FGSCs) are proposed to be a key factor for ameliorating female infertility. Previously we have shown that neonatal and adult FGSCs could be isolated and purified from mouse ovarian tissues. The long noncoding (lnc) RNA growth arrest-specific 5 sequence (GAS5) transcribed from mammalian genomes plays important regulatory roles in various developmental processes. However, there is no study on the relationship between GAS5 and FGSC development in vitro. In this study, we showed that GAS5 was highly expressed in the neonatal mouse ovary and was located in both FGSCs and oocytes. GAS5 facilitated FGSC proliferation and promoted their survival in vitro. Moreover, GAS5 also inhibited apoptosis of cultured FGSCs. These findings indicate that GAS5 is a crucial regulator of FGSC development. This might serve as a foundation for a strategy of lncRNA-directed diagnosis or treatment of female infertility. PMID- 29428797 TI - Identification, characterization and expression analysis of pigeonpea miRNAs in response to Fusarium wilt. AB - Upon confrontation with unfavourable conditions, plants invoke a very complex set of biochemical and physiological reactions and alter gene expression patterns to combat the situations. MicroRNAs (miRNAs), a class of small non-coding RNA, contribute extensively in regulation of gene expression through translation inhibition or degradation of their target mRNAs during such conditions. Therefore, identification of miRNAs and their targets holds importance in understanding the regulatory networks triggered during stress. Structure and sequence similarity based in silico prediction of miRNAs in Cajanus cajan L. (Pigeonpea) draft genome sequence has been carried out earlier. These annotations also appear in related GenBank genome sequence entries. However, there are no reports available on context dependent miRNA expression and their targets in pigeonpea. Therefore, in the present study we addressed these questions computationally, using pigeonpea EST sequence information. We identified five novel pigeonpea miRNA precursors, their mature forms and targets. Interestingly, only one of these miRNAs (miR169i-3p) was identified earlier in draft genome sequence. We then validated expression of these miRNAs, experimentally. It was also observed that these miRNAs show differential expression patterns in response to Fusarium inoculation indicating their biotic stress responsive nature. Overall these results will help towards better understanding the regulatory network of defense during pigeonpea -pathogen interactions and role of miRNAs in the process. PMID- 29428798 TI - Analysis of population structure and genetic diversity in an exotic germplasm collection of Eleusine coracana (L.) Gaertn. using genic-SSR markers. AB - Finger millet (Eleusine coracana (L.) Geartn.) is one of the important small millets serves as a food security crop because of its high nutritional values. The complex tetraploid genome of finger millet requires a large number of informative, functional DNA markers for different applications in genetics and breeding. Yet, less number of simple sequence repeat (SSR) markers have been developed from expressed sequence tags in finger millet. In the present study, 56 new genic SSR markers were developed from publicly available drought related ESTs. The 43 polymorphic markers were used to evaluate polymorphism, revealed a range of PIC value 0.41 to 0.79. Our results suggest that, analyzed genotypes have high genetic diversity with an average gene diversity (h) of 0.176 and Shannon's information index (I) of 0.315. We conclude that there was a higher gene exchange within populations, by the value of overall gene flow (Nm) of 0.7721. The unweighted pair group method with arithmetic mean and neighbor joining dendrogram generated three main clusters to differentiate genotypes and these results were also confirmed by PCA and PCoA analysis. The high genetic diversity (77%) was found within the populations in the analysis of molecular variance. A Bayesian model-based cluster analysis evidenced a high extent of admixture between the gene pools from the different geographical origins. Population based cluster analyses pointed out a strong pattern of 'isolation by distance'. Overall, these results underscored that this study showed a significantly high level of polymorphism, adequate genetic diversity and population structure which expand the modern genetic resources and its utility in various applications in genetics and genomics including association mapping and breeding. PMID- 29428799 TI - Evaluating the association between calpastatin (CAST) gene and keratoconus in the Han Chinese population. AB - PURPOSE: To investigate whether calpastatin (CAST) gene polymorphisms are in association with keratoconus (KC) in Han Chinese population. METHODS: Four SNPs (rs4434401, rs7704167, rs26504, and rs10053056) in CAST gene were genotyped in 120 unrelated Han Chinese KC patients and 305 age and gender matched healthy controls, using TaqMan SNP genotyping method. PLINK and LDmatrix software was used for data analysis. RESULTS: SNP rs4434401, whose contribution to KC susceptibility has been established in Caucasians, still kept its effect in our population. The C allele frequency of rs4434401 was markedly higher in cases (27.7%) than in the controls (20.7%, P = 0.03654, OR = 1.47, 95%CI = 1.02-2.11). The genotype distribution of rs4434401 showed marginal difference between KC cases and controls. The allelic and genotype frequencies of other three tested SNPs showed no significant difference between cases and controls. CONCLUSION: We confirmed previous report that SNP(s) in CAST gene conferred risk for KC susceptibility in Han Chinese population, suggesting the potential contribution of CAST gene to KC development. PMID- 29428800 TI - Hepatic transcriptional profiling response to fava bean-induced oxidative stress in glucose-6-phosphate dehydrogenase-deficient mice. AB - Favism is an acute hemolytic syndrome caused by the ingestion of fava bean (FB) in glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. However, little is known about the global transcripts alteration in liver tissue after FB ingestion in G6PD-normal and -deficient states. In this study, deep sequencing was used to analyze liver genes expression alterations underlying the effects of FB in C3H (Wild Type, WT) and G6PD-deficient (G6PDx) mice and to evaluate and visualize the collective annotation of a list of genes to Gene Ontology (GO) terms associated with favism. Our results showed that FB resulted in a decrease of glutathione (GSH)-to-oxidized glutathione (GSSG) ratio and an increase of malondialdehyde (MDA) both in the G6PDx and WT-control check (CK) mice plasma. Significantly, liver transcript differences were observed between the control and FB-treated groups of both WT and G6PDx mice. A total of 320 differentially expressed transcripts were identified by comparison of G6PDx-CK with WT-CK and were associated with immune response and oxidation-reduction function. A total of 149 differentially expressed genes were identified by comparison of WT-FB with WT CK. These genes were associated with immune response, steroid metabolic process, creatine kinase activity, and fatty acid metabolic process. A total of 438 differential genes were identified by comparing G6PDx-FB with G6PD-CK, associated with the negative regulation of fatty acid metabolic process, endoplasmic reticulum, iron binding, and glutathione transferase activity. These findings indicate that G6PD mutations may affect the functional categories such as immune response and oxidation-reduction. PMID- 29428802 TI - Corrigendum to "De novo assembly and characterization of seabass Lateolabrax japonicus transcriptome and expression of hepatic genes following different dietary phosphorus/calcium levels" [Comp. Biochem. Physiol. D Genomics Proteomics 24 (2017) 51-59]. PMID- 29428801 TI - HIPK2 polymorphisms rs2058265, rs6464214, and rs7456421 were associated with kidney stone disease in Chinese males not females. AB - BACKGROUND AND AIM: Recent studies have shown that genetic factors are involved in the development of kidney stone disease (KSD). A case-control association analysis was performed to investigate the association between homeodomain interacting protein kinase 2 (HIPK2; OMIM *606868) polymorphisms and KSD. METHODS: A total of 890 KSD patients and 920 healthy subjects were analyzed. Polymorphisms were genotyped using SNPscanTM high-throughput SNP classification technology. The genotypic and allelic frequencies in KSD patients and healthy individuals were analyzed using a Chi-square test. RESULTS: The genotype and allele distributions of the three polymorphisms (rs2058265, rs6464214, and rs7456421 in HIPK2) displayed strong associations with KSD in males (rs2058265: odds ratio [OR] 2.480,95%confidence interval [CI] 1.205-5.106, p = 0.014; rs6464214: OR 2.466, 95%CI 1.198-5.078, p = 0.014; rs7456421: OR 2.846, 95%CI 1.362-5.947, p = 0.005; perallele: r2058265T, OR 1.357, 95%CI 1.073-1.715, p = 0.011; rs6464214G, OR 1.340, 95%CI 1.060-1.693, p = 0.014; rs7456421C, OR 1.356, 95%CI 1.073-1.713, p = 0.011). Patients carrying the T allele of rs2058265, the G allele of rs6464214, or the C allele of rs7456421 showed higher systolic blood pressure, creatinine, and uric acid levels compared with wild-genotype individuals after adjusting for age, gender, and body mass index (p < 0.005). CONCLUSION: The association of HIPK2 gene polymorphisms with KSD was only observed in males but not in females. HIPK2 gene polymorphisms were also involved in the changes of KSD-related metabolic traits. PMID- 29428803 TI - In vivo tissue distribution and safety of polyacrylic acid-modified titanium peroxide nanoparticles as novel radiosensitizers. AB - Polyacrylic acid (PAA)-modified titanium peroxide nanoparticles (PAA-TiOx NPs) are promising radiosensitizers. PAA-TiOx NPs were synthesized from commercial TiO2 nanoparticles that were modified with PAA and functionalized by H2O2 treatment. To realize practical clinical uses for PAA-TiOx NPs, their tissue distribution and acute toxicity were evaluated using healthy mice and mice bearing tumors derived from xenografted MIAPaCa-2 human pancreatic cancer cells. Healthy mice were injected with PAA-TiOx NPs at 25 mg/kg body weight via the tail vein, and tumor-bearing mice were injected either into the tumor locally or via the tail vein. The concentration of PAA-TiOx NPs in major organs was determined over time using inductively coupled-plasma atomic emission spectrometry. After 1 h, 12% of the PAA-TiOx NP dose had accumulated in the tumor, and 2.8% of the dose remained after 1 week. Such high accumulation could be associated with enhanced permeability and retention effects of the tumor, as PAA-TiOx NPs are composed of inorganic particles and polymers, without tumor-targeting molecules. The liver accumulated the largest proportion of the injected nanoparticles, up to 42% in tumor-bearing mice. Blood biochemical parameters were also investigated after intravenous injection of PAA-TiOx NPs in healthy mice. PAA-TiOx NPs invoked a slight change in various liver-related biochemical parameters, but no liver injury was observed over the practical dose range. In the future, PAA-TiOx NPs should be modified to prevent accumulation in the liver and minimize risk to patients. PMID- 29428805 TI - More far is more right: Manual and ocular line bisections, but not the Judd illusion, depend on radial space. AB - Line bisection studies generally find a left-to-right shift in bisection bias with increasing distance between the observer and the target line, which may be explained by hemispheric differences in the processing of proximo-distal information. In the present study, the segregation between near and far space was further characterized across the motor system and contextual cues. To this aim, 20 right-handed participants were required to perform a manual bisection task of simple lines presented at three different distances (60, 90, 120 cm). Importantly, the horizontal spatial location of the line was manipulated along with the viewing distance to investigate more deeply the hemispheric engagement in the transition from near to far space. As the motoric component of the manual task producing activations of left premotor and motor areas may be partially responsible for the observed transition, participants were also involved in an ocular bisection task. Further, participants were required to bisect Judd variants of the target lines, which are known to elicit a Muller-Lyer-type illusion. Since the Judd illusion depends on areas in the ventral visual stream, we predicted that line bisections of Judd-type lines would be unaffected by viewing distance. Results showed that manual bisection of simple lines was modulated separately by viewing distance and the hemispace of presentation, with this pattern being similar for ocular bisection. Critically, bisections in the Judd illusion task were not modulated by viewing distance, whether performed by hand or by eye. Overall, these findings support the hypothesis that the right hemisphere plays a dominant role in the processing of space close to the body. They also present novel evidence for a general reduction of this dominance at farther distances, whether hand motor actions are involved or not. Finally, our study documents a dissociation between the processing of pure visuospatial information and that of a visual illusion as a function of viewing distance, supporting more generally the dorsal/near space and the ventral/far space segregation. PMID- 29428804 TI - Links between a biomarker profile, cold ischaemic time and clinical outcome following simultaneous pancreas and kidney transplantation. AB - In sepsis, trauma and major surgery, where an explicit physiological insult leads to a significant systemic inflammatory response, the acute evolution of biomarkers have been delineated. In these settings, Interleukin (IL) -6 and TNF alpha are often the first pro-inflammatory markers to rise, stimulating production of acute phase proteins followed by peaks in anti-inflammatory markers. Patients undergoing SPKT as a result of diabetic complications already have an inflammatory phenotype as a result of uraemia and glycaemia. How this inflammatory response is affected further by the trauma of major transplant surgery and how this may impact on graft survival is unknown, despite the recognised pro-inflammatory cytokines' detrimental effects on islet cell function. The aim of the study was to determine the evolution of biomarkers in omentum and serum in the peri-operative period following SPKT. The biochemical findings were correlated to clinical outcomes. Two omental biopsies were taken (at the beginning and end of surgery) and measured for CD68+ and CD206+ antibodies (M1 and M2 macrophages respectively). Serum was measured within the first 72 h post-SPKT for pro- and anti-inflammatory cytokines (IL -6, -10 and TNF alpha), inflammatory markers (WCC and CRP) and endocrine markers (insulin, C peptide, glucagon and resistin). 46 patients were recruited to the study. Levels of M1 (CD68+) and M2 (CD206+) macrophages were significantly raised at the end of surgery compared to the beginning (p = 0.003 and p < 0.001 respectively). Levels of C-peptide, insulin and glucagon were significantly raised 30 min post pancreas perfusion compared to baseline and were also significantly negatively related to prolonged cold ischaemic time (CIT) (p < 0.05). CRP levels correlated significantly with the Post-Operative Morbidity Survey (p < 0.05). The temporal inflammatory marker signature after SPKT is comparable to the pattern observed following other physiological insults. Unique to this study, we find that CIT is significantly related to early pancreatic endocrine function. In addition, this study suggests a predictive value of CRP in peri-operative morbidity following SPKT. PMID- 29428806 TI - TCRalphabeta+CD3+CD4-CD8- (double negative) T cells in autoimmunity. AB - TCRalphabeta+CD3+CD4-CD8- "double negative" (DN) T cells comprise a small subset of mature peripheral T cells. The origin and function of DN T cells are somewhat unclear and discussed controversially. While DN T cells resemble a rare and heterogeneous T cell subpopulation in healthy individuals, numbers of TCRalphabeta+ DN T cells are expanded in several inflammatory conditions, where they also exhibit distinct effector phenotypes and infiltrate inflamed tissues. Thus, DN T cells may be involved in systemic inflammation and tissue damage in autoimmune/inflammatory conditions, including SLE, Sjogren's syndrome, and psoriasis. Here, the current understanding of the origin and phenotype of DN T cells, and their role in the instruction of immune responses, autoimmunity and inflammation will be discussed in health and disease. PMID- 29428807 TI - The imprint of salivary secretion in autoimmune disorders and related pathological conditions. AB - Xerostomia is a state of oral dryness associated with salivary gland dysfunction and is induced by stress, radiation and chemical therapy, various systemic and autoimmune diseases, and specific medications. Fluid secretion is interrupted by the stimulation of neurotransmitter-induced increase in cytosolic calcium ([Ca2+]i) in salivary gland acinar cells, prompting the mobilization of ion channels and their transporters. Salivary fluid and protein secretion are principally dependent on parasympathetic and sympathetic nerves. Various inflammatory cytokines allied with lymphocytic infiltration cause glandular damage and Sjogren's syndrome, an autoimmune exocrinopathy associated with hyposalivation. A defect in IP3Rs, a major calcium release channel, prompts inadequate agonist-induced [Ca2+]i in acinar cells and deters salivary flow. The store-operated calcium entry-mediated Ca2+ movement into the acini activates K+ and Cl- channels, which further opens a water channel protein, aquaporin-5, and triggers the release of fluid secretion from the salivary glands. The cellular mechanism of salivary gland dysfunction and hyposalivation has not yet been elucidated. In this review, we focused mainly on the proteins responsible for deficient saliva, the correlation between inflammation and salivation, autoimmune disorders and other ailments or complications associated with hyposalivation. PMID- 29428808 TI - Cellular immune regulation in the pathogenesis of ANCA-associated vasculitides. AB - Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases characterized by necrotizing inflammation of small- to medium-sized blood vessels, affecting primarily the lungs and kidneys. Both animal and human studies show that the balance between inflammatory- and regulatory T- and B cells determines the AAV disease pathogenesis. Recent evidence shows malfunctioning of the regulatory lymphocyte compartment in AAV. In this review we summarize the immune regulatory properties of both T- and B cells in patients with AAV and discuss how aberrations herein might contribute to the disease pathogenesis. PMID- 29428809 TI - Urinary metabolite and lipid alterations in Colombian Hispanic women with breast cancer: A pilot study. AB - Metabolic biomarkers for breast cancer (BC) prognosis and diagnosis are required, given the increment of BC incidence rates in developing countries and its prevalence in women worldwide. Human urine represents a useful resource of metabolites for biomarker discovery, because it could reflect metabolic alterations caused by a particular pathological state. Furthermore, urine analysis is readily available, it is non-invasive and allows in-time monitoring. Therefore, in present study, a metabolic- and lipid fingerprinting of urine was performed using an analytical multiplatform approach. The study was conducted in order to identify alterated metabolites which can be helpful in the understanding of metabolic alterations driven by BC as well as their potential usage as biomarkers. Urine samples collected from healthy controls and BC subjects were analyzed using LC-MS and GC-MS. Subsequently, significantly altered metabolites were determined by employing univariate and multivariate statistical analyses. An overall decrease of intermediates of the tricarboxylic acid cycle and metabolites belonging to amino acids and nucleotides were observed, along with an increment of lipid-related compounds. Receiver operating characteristic analysis evaluated the combination of dimethylheptanoylcarnitine and succinic acid as potential urinary markers, achieving a sensitivity of 93% and a specificity of 86%. The present analytical multiplatform approach enabled a wide coverage of urine metabolites that revealed significant alterations in BC samples, demonstrating its usefulness for biomarker discovery in selected populations. PMID- 29428810 TI - Effect of intercalated chitosan/clay nanostructures on concentrated pluronic F127 solution: A FTIR-ATR, DSC and rheological study. AB - HYPOTHESIS: The thermoreversible gel-like behavior of pluronics can be affected by the presence of drugs or cosolvents. So far, the effects of polysaccharides and of clays singularly added on a pluronic water dispersion were investigated and the gelation and viscoelastic properties tuned by properly varying the concentration of the additives. The combined addition of chitosan and montmorillonite opens the possibility to join the properties of the single constituents to formulate bio-based temperature-sensitive vehicles. EXPERIMENTS: Chitosan, montmorillonite and chitosan-montmorillonite nanocomposites were added on a concentrated pluronic F127 aqueous solution. The pluronic-based systems were investigated by differential scanning calorimetry (DSC), X-ray diffraction (XRD), rheology and Fourier transform infrared attenuated total reflection spectroscopy (FTIR-ATR). The gelation and micellization behaviors of pluronic were compared to those of the pluronic-based composites and analyzed in terms of the different elasticity of the investigated samples. Then, FTIR-ATR spectroscopy was applied to analyze different vibrational modes in order to evidence differences in the conformational arrangements of the micelles. FINDINGS: The experiments evidenced that the chitosan/clay nanocomposites have a destructuring effect on the micellar arrangements of pluronic and that the chaotropic effect by chitosan dominates over the ordering effect by the clay. PMID- 29428811 TI - IR780-dye loaded gold nanoparticles as new near infrared activatable nanotheranostic agents for simultaneous photodynamic and photothermal therapy and intracellular tracking by surface enhanced resonant Raman scattering imaging. AB - Due to the good transparency of the human tissue in the biological spectral window, near-infrared (NIR)-dye loaded nanosystems enable more effective light activated therapy and better contrast imaging with major impact on nanomedicine. Herein, we prepare Pluronic coated gold nanoparticles incorporating the hydrophobic NIR dye, IR780 iodide (GNP-Plu-IR780) to provide water-solubility and stability and demonstrate the proficiency of combining photodynamic and photothermal therapeutic activity with surface-enhanced resonance Raman scattering (SERRS) imaging facility. The potential of GNP-Plu-IR780 to operate as NIR-activatable agents was first assessed in aqueous solution by singlet oxygen generation measurements and monitoring the temperature increase of the nanoparticles. Subsequent in vitro uptake studies by dark field and differential interference contrast (DIC) microscopy reveal massive internalization of GNP-Plu IR780 by murine colon carcinoma cells (C-26). Moreover, by exploiting the SERRS effect under 785 nm laser excitation we were able to perform intracellular tracking of GNP-Plu-IR780. Finally, NIR irradiation experiments conducted in vitro against C-26 cells show efficient phototherapeutic activity induced by GNP Plu-IR780 with no dark cytotoxicity. Moreover, when compared to the administration of free drug or non-loaded GNP-Plu, the higher phototherapeutic activity of GNP-Plu-IR780 indicates the occurrence of cooperative synergistic effects by simultaneous photodynamic and photothermal activity. PMID- 29428812 TI - Development of reduced graphene oxide (rGO)-isabgol nanocomposite dressings for enhanced vascularization and accelerated wound healing in normal and diabetic rats. AB - Treatment of chronic non-healing wounds in diabetes is still a major clinical challenge. Here, we have developed reduced graphene oxide (rGO) loaded isabgol nanocomposite scaffolds (Isab + rGO) to treat normal and diabetic wounds. rGO was synthesized by rapid reduction of graphene oxide (GO) under focused solar radiation. Then, rGO was uniformly dispersed into isabgol solution to prepare Isab + rGO nanocomposite scaffolds. These scaffolds were characterized using various physiochemical techniques. Isab + rGO nanocomposite scaffolds showed suitable cell viability, proliferation, and attachment. In vivo experiments were performed using Wistar rats to study the wound healing efficacy of these scaffolds in normal and diabetic rats. Results revealed that rGO stimulated collagen synthesis, collagen crosslinking, wound contraction, and reduced the wound re-epithelialization time significantly compared to control. Histology and immunohistochemistry analyses showed that Isab + rGO scaffold treatment enhanced angiogenesis, collagen synthesis, and deposition in treated wounds. Isab + rGO scaffold treatment also played a major role in shortening the inflammation phase and recruiting macrophages to enhance the early phase of wound healing. Overall, this investigation showed that Isab + rGO scaffold dressing could significantly accelerate the healing of normal and diabetic wounds. PMID- 29428813 TI - Gaging the impact of multiple substance use on community corrections involvement. AB - Historically, research has demonstrated that multiple substance use, compared to single substance use, poses additional challenges for treatment throughout the continuum of care including referrals, interventions, and relapse prevention. However, it appears that this pattern cannot be easily generalized to all criminal justice settings as evidenced by mixed findings across criminal justice samples. The purpose of the current study is to investigate possible differences in legal and substance-related outcomes between multiple substance users and single substance users within a community corrections sample. Structured clinical interviews were conducted to divide 531 individuals under community corrections supervision into three groups including multiple substance users, single substance users, and non-substance users. Results indicated that while multiple substance users were arrested more frequently and had more problems with family members, there were no differences compared to their single substance using counterparts in terms of depressive disorders, anxiety disorders, or types of offense. These findings contrast with previous research on samples outside of community corrections suggesting that multiple substance use requires tailored interventions with consideration to context of their use. Discussion includes limitations to generalizability and assessment of substance use as well as implications for treatment and future research. PMID- 29428814 TI - Profiles of childhood adversities in pathological gamblers - A latent class analysis. AB - Despite of high rates of adverse childhood experiences (ACEs) in pathological gamblers, researchers have rarely studied which types of ACEs often co-occur and how these profiles of ACEs are related to current psychopathology. We aimed to identify profiles of ACEs in pathological gamblers and examined how these profiles were related to gambling-related characteristics and current general psychopathology. In 329 current or lifetime pathological gamblers, diagnosed with the Composite Diagnostic Interview for DSM-IV, 10 types of ACEs were measured using the Adverse Childhood Experiences Questionnaire. Global psychopathology was assessed using the Symptom Checklist SCL-27. ACE profiles were identified using latent class analysis. Differences between ACE profiles in gambling-related characteristics and global psychopathology were analyzed using MANOVA. We found that four out of five gamblers (n=257, 78.1%) reported at least one ACE. Four distinct ACE profiles were identified: 'Low ACE', 'High ACE', 'Physical and emotional abuse', and 'Neglect'. The number of the fulfilled pathological gambling criteria and the severity of current global psychopathology differed between the ACE profiles: Gamblers with a 'High ACE' profile fulfilled more pathological gambling criteria and showed a more severe current psychopathology than gamblers of the 'Low ACE' profile. Gamblers with a 'Physical and emotional abuse' or an 'Emotion neglect' profile showed an intermediate severity of psychopathology. Our findings indicate that four different ACE profiles can be distinguished in pathological gamblers that differed in their gambling-related characteristics and current psychopathology. Systematic assessment of profiles of ACEs in pathological gamblers may inform about the severity of current global psychopathology that might be important to be addressed in addition to gambling specific treatment. PMID- 29428815 TI - Gasdermin C is induced by ultraviolet light and contributes to MMP-1 expression via activation of ERK and JNK pathways. AB - BACKGROUND: Ultraviolet (UV) radiation plays important roles in various skin diseases including premature aging and cancer. UV has been shown to regulate the expressions of many genes including matrix metalloproteinases (MMPs). Gasdermin C (GSDMC) belongs to Gasdermin family and is known to be expressed in the epithelial cells of many tissues including the skin. However, the functions of GSDMC remain poorly understood. OBJECTIVE: We aimed to investigate the role of GSDMC in UV-induced MMP-1, MMP-3, and MMP-9 expressions in human skin keratinocytes. METHODS: Primary human skin keratinocytes and an immortalized human skin keratinocyte cell line (HaCaT cells) were irradiated with UV. Knockdown and overexpression of GSDMC were performed to study the effect of GSDMC. The mRNA and protein levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. RESULTS: We found that GSDMC expression is increased by UV irradiation in human skin keratinocytes. Further studies showed that GSDMC expression is increased at relatively late time points after UV irradiation and that this GSDMC induction plays important roles in the expressions of MMP-1, but not of MMP-3 and MMP-9, and the activations of ERK and JNK induced by UV. In addition, we found that overexpression of GSDMC increases the MMP-1 expression and the activities of ERK and JNK and that GSDMC-induced MMP-1 expression is suppressed by inhibition of ERK or JNK activities. CONCLUSIONS: Our results suggest that GSDMC is increased by UV radiation and contributes to UV-induced MMP-1 expression through the activation of ERK and JNK pathways. PMID- 29428816 TI - Dermoscopic evaluation for skin grafts after surgery; neo-vascularization correlates with survival of skin grafts: A prospective study. PMID- 29428817 TI - Requirement of MHC class I on radioresistant cells for granzyme B expression from CD8+ T cells in murine contact hypersensitivity. PMID- 29428818 TI - Incidence of toxigenic fungi and zearalenone in rice grains from Brazil. AB - Rice (Oryza sativa L.) is one of the most important food crops worldwide. In Brazil, the southern region is the area with the highest production of rice in the country and also has a high average daily intake of rice by the population. The mycoflora, mainly toxigenic Aspergillus and Fusarium species, the presence of AFB1, DON and ZEA in rice grains, as well as daily intake estimates for the Southern Brazilian population were evaluated. The rice grain samples were collected during the 2017 crop from different harvest periods. According to the mycological tests, the samples presented a high count of fungal colonies in the pre and post-harvest, where the incidence of the F. graminearum species complex (52%) was significantly predominant. This group can be responsible for ZEA production, as found in this study in parboiled rice, mainly because most of the isolated strains were producers of high ZEA levels in the pre-harvest (77%) and post-harvest after natural (79%) and artificial (75%) drying of the rice. Only ZEA showed significant results in the rice grain analyzed (60%) at levels of 90.56 to 126.31 MUg/kg, where 36% of the samples were significantly higher than the current maximum limit stipulated in Brazilian regulations and by the European Commission. Despite this, the dietary exposure of ZEA estimated for the southern Brazilian population was below the provisional maximum tolerable daily intake level of 0.5 MUg/kg body weight/day set at international regulations. PMID- 29428819 TI - Modifying mental health help-seeking stigma among undergraduates with untreated psychiatric disorders: A pilot randomized trial of a novel cognitive bias modification intervention. AB - Help-seeking stigma is a potent barrier to the utilization of mental health services. This study aimed to determine if, compared to a psychoeducation condition, individuals randomized to a novel cognitive bias modification intervention for help-seeking stigma (CBM-HS) demonstrate greater reductions in help-seeking stigma, as well as increases in readiness to change and help-seeking behaviors. Participants included 32 undergraduates with a DSM-5 psychiatric disorder who denied past-year mental health treatment. Post-randomization, three intervention sessions were delivered in one-week intervals (45 min total). Participants were assessed at baseline, mid-intervention, one-week post intervention, and two-month follow-up. RM-ANOVAs were utilized among the intent to-treat sample. There were no significant differences across time points between the intervention groups for help-seeking stigma and readiness to change. At two month follow-up, 25% of participants initiated mental health treatment (29.4% CBM HS, 20.0% psychoeducation). Strikingly, across groups, there was a statistically significant reduction in help-seeking self-stigma (F[2.214,66.418] = 5.057, p = 0.007, etap2 = 0.144) and perceived public stigma (F[3,90] = 6.614, p < 0.001, etap2 = 0.181) from baseline to two-month follow-up, indicating large effects; 18.8% achieved clinically significant change, among whom two-thirds were in the CBM-HS condition. Two brief, scalable interventions appear to reduce help-seeking stigma among undergraduates with untreated psychiatric disorders. Studies are needed to evaluate these interventions against an inactive control. PMID- 29428820 TI - Structural and biochemical characterization of the plant type III polyketide synthases of the liverwort Marchantia paleacea. AB - Chalcone synthases (CHSs) of the type III polyketide synthases (PKSs), catalyze the formation of a tetraketide intermediate from a CoA-tethered starter and malonyl-CoA but use different cyclization mechanisms to produce distinct chemical scaffolds. Herein, we characterized CHS and CHS-like enzymes (designated MpCHS and MpCHSL1, 2 and 3) from Marchantia paleacea and determined the crystal structure of MpCHSL1. MpCHS catalyzed a Claisen condensation to form chalcone, while MpCHSLs catalyzed the formation of lactonized alpha-pyrones in vitro. Based on the structural, mutational and in vitro biochemical analyses, we established that MpCHSL1 is structurally and functionally closer to prototype CHS than stilbene synthase, and characterized the structural basis for the functional diversity of the type III PKSs. A chalcone-forming mutant of MpCHSL1 was build directed by the structural information. These findings pave the way for future studies to elucidate the functional diversity of type III PKSs in liverwort. PMID- 29428822 TI - Intranasal BDNF administration promotes visual function recovery in adult amblyopic rats. AB - Amblyopia is the most common cause of visual impairment in one eye, with a prevalence of 1-5% in the world population. While amblyopia can be efficiently treated in children, it becomes irreversible in adults, due to the decline in neural plasticity past the end of the visual cortex critical period. Accordingly, no pharmacological approaches are available to rescue visual functions in adult amblyopic subjects. We report that non-invasive intranasal infusion of BDNF increased levels of this neurotrophic factor in V1 and induced a recovery of visual acuity, ocular dominance and visual depth perception in adult amblyopic rats, both in reverse-occluded animals and in those with unrestricted binocular sight. Visual recovery was long-lasting, and was prevented by pharmacological blockade of TrkB signaling in the visual cortex. These results underscore the possibility to replace invasive BDNF central administration with a safe procedure of potential interest in a number of currently still cureless central nervous system pathologies. PMID- 29428821 TI - Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica. AB - Intravenous human immunoglobulin G (IVIG) may have therapeutic benefit in neuromyelitis optica spectrum disorders (herein called NMO), in part because of the anti-inflammatory properties of the IgG Fc region. Here, we evaluated recombinant Fc hexamers consisting of the IgM MU-tailpiece fused with the Fc region of human IgG1. In vitro, the Fc hexamers prevented cytotoxicity in aquaporin-4 (AQP4) expressing cells and in rat spinal cord slice cultures exposed to NMO anti-AQP4 autoantibody (AQP4-IgG) and complement, with >500-fold greater potency than IVIG or monomeric Fc fragments. Fc hexamers at low concentration also prevented antibody-dependent cellular cytotoxicity produced by AQP4-IgG and natural killer cells. Serum from rats administered a single intravenous dose of Fc hexamers at 50 mg/kg taken at 8 h did not produce complement-dependent cytotoxicity when added to AQP4-IgG-treated AQP4-expressing cell cultures. In an experimental rat model of NMO produced by intracerebral injection of AQP4-IgG, Fc hexamers at 50 mg/kg administered before and at 12 h after AQP4-IgG fully prevented astrocyte injury, complement activation, inflammation and demyelination. These results support the potential therapeutic utility of recombinant IgG1 Fc hexamers in AQP4-IgG seropositive NMO. PMID- 29428824 TI - High-flow nasal cannula oxygenation during interventional bronchoscopy in a patient with severe tracheal stenosis. PMID- 29428823 TI - Use of Long-Acting Reversible Contraception Among Adolescent and Young Adult Women and Receipt of Sexually Transmitted Infection/Human Immunodeficiency Virus Related Services. AB - PURPOSE: Long-acting reversible contraceptive (LARC) methods do not require annual clinic visits for continuation, potentially impacting receipt of recommended sexually transmitted infection (STI)/human immunodeficiency virus (HIV) services for young women. We assess service receipt among new and continuing LARC users versus moderately and less effective method users and non contraceptors. METHODS: Using 2011-2015 National Survey of Family Growth data from sexually active women aged 15-24 years (n = 2,018), we conducted logistic comparisons of chlamydia, any STI and HIV testing, and sexual risk assessment in the past year by current contraceptive type. RESULTS: Less than half of respondents were tested for chlamydia (40.9%), any STI (47.3%), or HIV (25.9%); 66.5% had their sexual risk assessed. Differences in service receipt between new and continuing LARC users as compared with moderately effective method users were not detected in multivariable models, except that continuing LARC users were less likely to be tested for HIV (adjusted prevalence ratio [aPR] = .52, 95% confidence interval [CI] = .32-.85). New, but not continuing, LARC users were more likely than less effective method users (aPR = 1.35, 95% CI = 1.03-1.76) and non-contraceptors (aPR = 1.43, 95% CI = 1.11-1.85) to have their sexual risk assessed, although both groups were more likely than non-contraceptors to be tested for chlamydia (new: aPR = 1.52, 95% CI = 1.08-2.15; continuing: aPR = 1.69, 95% CI = 1.24-2.29). CONCLUSIONS: We found little evidence that LARC use was associated with lower prevalence of STI testing. However, new, but not continuing, LARC users, as compared with those not using a method requiring a clinic visit, were more likely to have had their risk assessed, suggesting that initiating LARC may offer an opportunity to receive services that does not persist. PMID- 29428825 TI - Willingness to initiate a fight but not contest behaviour depends on intruder size in Lethrus apterus (Geotrupidae). AB - In resident-intruder contests, residents are expected to win more often than intruders unless the intruder has significantly higher competitive ability that is often determined by its size. Therefore, small intruders are expected to be less motivated to engage in contests than large ones and intruder size is predicted to have a positive relationship with the duration and escalation of the encounters. In a field experiment we tested these hypotheses in Lethrus apterus, a biparental beetle breeding in underground tunnels, by placing either a small or a large male in front of a tunnel occupied by a resident male. In agreement with our predictions residents won most of the encounters. Small intruders were less willing to engage in a contest and were less successful in their takeover attempts than large intruders. Contrary to many studies however, the duration and escalation (measured by the occurrence and latency of the different contest stages) of the fight in front of the burrow did not differ between the two intruder size categories. These findings suggest that in this species, small and large intruders adjust their prior decisions to their competitive abilities but once a fight started, they behave similarly during the contest. PMID- 29428826 TI - An integrated bayesian theory of phenotypic flexibility. AB - Phenotypic flexibility includes systems such as individual learning, social learning, and the adaptive immune system. Since the evolution of genes by natural selection is a relatively slow process, mechanisms of phenotypic flexibility are evolved to adapt to contingencies on the time scales ranging from a few hundred milliseconds (e.g. avoidance of immediate physical threats) to a few millennia (e.g. cultural adaptations to local environmental variation in the Holocene). Because environmental variation is non-stationary and fat tailed, systems of phenotypic flexibility sometimes have to be creative. They do this by means of random innovation, or exploration, and selective retention. The canonically rational way to deal with variable, uncertain environments is the Bayesian process of using new data to update priors based on past experience. Organic evolution updates the gene frequencies of populations based upon the fitness of alleles. Learning updates behavioral priors based upon the reinforcement of alternate behaviors. Genes and mechanisms of phenotypic flexibility are not isolated but richly interact. Classically, genes are said to code for the reinforcers that shape behavior in individual learning, for example. It is currently controversial whether or not these interactions include a role for the products phenotypic flexibility directly shaping selection on genes. PMID- 29428827 TI - Anterior subluxation of the glenohumeral joint during hyperextension. PMID- 29428828 TI - Participation in the Child and Adult Care Food Program Is Associated with Healthier Nutrition Environments at Family Child Care Homes in Mississippi. AB - OBJECTIVE: Describe foods and beverages offered, nutrition practices, and nutrition policies of family child care homes in Mississippi and differences by participation in the Child and Adult Care Food Program (CACFP). DESIGN: Cross sectional study conducted between fall, 2015 and spring, 2016. SETTING: Mississippi. PARTICIPANTS: Random, stratified sample of 134 family child care homes that enroll 3- to 5-year-olds. Providers completed a modified version of the Environment and Policy Assessment and Observation-self-report tool. VARIABLES MEASURED: Foods and beverages offered at lunch, provider practices regarding nutrition, and presence or absence of written nutrition policies. ANALYSIS: Descriptive statistics, likelihood ratio chi-square, and t tests. RESULTS: Most homes (>75%) provided components from the fruit, vegetable, grain/bread, meat/meat alternative, and milk food groups at lunch. At some homes, the food and beverage selections offered were high in fat, sugar, and refined grains. Providers at CACFP-participating homes (P < .05) reported healthier beverage selections, more healthful nutrition practices, and more written nutrition policies compared with providers at non-CACFP homes. CONCLUSION AND IMPLICATIONS: Interventions and regulatory standards are needed, particularly in non-CACFP homes, to ensure that food and beverage offerings, provider practices, and policies regarding nutrition support the development of healthful dietary behaviors in early childhood. PMID- 29428831 TI - Assessment of the Pneumatic Ischemia Technique Using the Limb Occlusion Pressure During Upper Limb Surgery. AB - PURPOSE: The purpose of our study was to evaluate effective ischemia and its associated complications using the limb occlusion pressure technique versus standard pneumatic ischemia technique. DESIGN: Single-centered randomized, controlled clinical trial. METHODS: One hundred sixty participants were randomized into two equal and parallel groups: (1) intervention group-LOP technique, and (2) control group-standard pneumatic ischemia technique. FINDINGS: Anesthetic incidences (need to administer analgesics for pain and/or hypnotics for anxiety) were similar in both groups. Statistically significant differences were observed for pain, hyperemia, and hospitalization, with higher values in the control group. Patients in the intervention group had, at 95% confidence, a 2.9 times greater chance of having optimal ischemia (assessed as 9 on the analog scale) than patients in the control group (odds ratio, 2.9; 95% confidence interval, 1.4 to 6.1). CONCLUSIONS: Intervention group patients had lower indexes of hyperemia, pain, and hospital stay. PMID- 29428830 TI - The effect of a randomized controlled physical activity trial on health related quality of life in metabolically unhealthy African-American women: FIERCE STUDY. AB - PURPOSE: African-American women (AAW) are more likely to be metabolically unhealthy than White women (WW). Metabolic syndrome (MetS) is associated with increased breast cancer risk and mortality from breast cancer is greater in AAW compared to WW. Data show MetS affects health-related quality of life (HRQoL). Exercise studies report improvements in MetS, however, no study to date has examined HRQoL in metabolically unhealthy AAW enrolled in an exercise trial. METHODS: This report examined the effect of a 6-month, 3-arm (supervised exercise, home-based exercise, control) randomized exercise controlled trial on HRQoL among 213 obese, metabolically unhealthy, postmenopausal AAW at high risk for breast cancer. RESULTS: Certain baseline participant characteristics were related to baseline HRQoL dimensions. The "exercise group" (supervised group combined with the home-based group) showed significantly greater improvement in health change scores (M = 13.6, SD = 3.1) compared to the control group (M = 0.7, SD = 4.4) (p = 0.02) over the 6-month study period. There were no significant differences in HRQoL change scores between the 3 study groups, however, although non-significant, data indicated most HRQoL change scores were more favorable in the supervised group. CONCLUSION: While significant improvement occurred in health change scores in the combined supervised and home-based group compared to the control group, we did not observe any significant differences on HRQoL change scores between all three study groups. However, while non-significant, there was a trend for more favorable HRQoL change scores in the supervised group versus the home-based and control groups. Additional research is needed to further explore this topic. PMID- 29428832 TI - Long-term efficacy and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibodies: A meta-analysis of 11 randomized controlled trials. AB - BACKGROUND: Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have been shown to significantly reduce low density lipoprotein cholesterol (LDL-C) levels. OBJECTIVE: The purpose of this study was to assess the long-term efficacy and safety of PCSK9 antibodies. METHODS: PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were searched for relevant studies. RESULTS: A total of 11 studies including 38,235 participants who were treated for at least 48 weeks were included in this meta analysis. The results suggested that PCSK9 antibody treatment significantly decreased LDL-C levels (mean difference, -50.23% [95% confidence interval {CI}, 56.65% to -43.82%]) compared with no PCSK9 antibody treatment and also decreased other atherogenic lipid fractions. PCSK9 antibody treatment also elicited a significant reduction in cardiovascular event rates compared with no antibody treatment (relative risk [RR], 0.86 [95% CI, 0.81-0.92]). This reduction consisted of separate significant reductions in the rates of myocardial infarction (RR, 0.73 [95% CI, 0.65-0.82]), coronary revascularization (RR, 0.79 [95% CI, 0.73-0.87]), and stroke (RR, 0.81 [95% CI, 0.68-0.96]). There were no clear differences in the incidences of treatment-emergent adverse events (TEAEs), serious TEAEs, or TEAEs of interest between the 2 groups; moreover, no differences between the 2 groups were found for other laboratory parameters. CONCLUSION: PCSK9 antibodies have significant effects on reducing LDL-C levels and improve cardiovascular outcomes. These antibodies have a satisfactory safety profile, which suggests that they are suitable for use as a long-term treatment. PMID- 29428829 TI - A sensitive and selective ELISA methodology quantifies a demyelination marker in experimental and clinical samples. AB - Sciatic nerve chronic constriction injury (CCI) in rodents produces nerve demyelination via proteolysis of myelin basic protein (MBP), the major component of myelin sheath. Proteolysis releases the cryptic MBP epitope, a demyelination marker, which is hidden in the native MBP fold. It has never been established if the proteolytic release of this cryptic MBP autoantigen stimulates the post injury increase in the respective circulating autoantibodies. To measure these autoantibodies, we developed the ELISA that employed the cryptic 84-104 MBP sequence (MBP84-104) as bait. This allowed us, for the first time, to quantify the circulating anti-MBP84-104 autoantibodies in rat serum post-CCI. The circulating IgM (but not IgG) autoantibodies were detectable as soon as day 7 post-CCI. The IgM autoantibody level continually increased between days 7 and 28 post-injury. Using the rat serum samples, we established that the ELISA intra assay (precision) and inter-assay (repeatability) variability parameters were 2.87% and 4.58%, respectively. We also demonstrated the ELISA specificity by recording the autoantibodies to the liberated MBP84-104 epitope alone, but not to intact MBP in which the 84-104 region is hidden. Because the 84-104 sequence is conserved among mammals, we tested if the ELISA was applicable to detect demyelination and quantify the respective autoantibodies in humans. Our limited pilot study that involved 16 female multiple sclerosis and fibromyalgia syndrome patients demonstrated that the ELISA was efficient in measuring both the circulating IgG- and IgM-type autoantibodies in patients exhibiting demyelination. We believe that the ELISA measurements of the circulating autoantibodies against the pathogenic MBP84-104 peptide may facilitate the identification of demyelination in both experimental and clinical settings. In clinic, these measurements may assist neurologists to recognize patients with painful neuropathy and demyelinating diseases, and as a result, to personalize their treatment regimens. PMID- 29428833 TI - Pedagogical differences: A comparative reflection between American and Chinese nursing education. AB - Significant financial resources are invested for Research and Learning Abroad Programs for Chinese nursing educators. These resources provide an opportunity to observe U.S. nursing education and bring "the lessons learned" back to China to create positive change to nursing education. PMID- 29428834 TI - Uncensored EEG: The role of DC potentials in neurobiology of the brain. AB - Brain direct current (DC) potentials denote sustained shifts and slow deflections of cerebral potentials superimposed with conventional electroencephalography (EEG) waves and reflect alterations in the excitation level of the cerebral cortex and subcortical structures. Using galvanometers, such sustained displacement of the EEG baseline was recorded in the early days of EEG recordings. To stabilize the EEG baseline and eliminate artefacts, EEG was performed later by voltage amplifiers with high-pass filters that dismiss slow DC potentials. This left slow DC potential recordings as a neglected diagnostic source in the routine clinical setting over the last few decades. Brain DC waves may arise from physiological processes or pathological phenomena. Recordings of DC potentials are fundamental electro-clinical signatures of some neurological and psychological disorders and may serve as diagnostic, prognostic, and treatment monitoring tools. We here review the utility of both physiological and pathological brain DC potentials in different aspects of neurological and psychological disorders. This may enhance our understanding of the role of brain DC potentials and improve our fundamental clinical and research strategies for brain disorders. PMID- 29428835 TI - Epicardial Pacing Wire Migration Into The Thoracic Aorta. PMID- 29428836 TI - Infrarenal to Innominate Artery Collateral Complicating a Chronic Residual Type B Dissection. AB - Residual type B aortic dissection following open surgical repair of a type A thoracic aortic dissection can sometimes be complicated by collateral blood supplies, which can impact existing flow patterns and result in progressive aneurysmal dilatation of the thoracic false lumens. We report a unique case that describes the clinical presentation of an infrarenal to innominate artery collateral blood flow that complicated a chronic residual type B dissection, which was diagnosed in a timely manner using multimodality imaging, and successfully managed through an innovative minimally invasive endovascular treatment strategy (without thoracotomy) with no neurological sequela. PMID- 29428837 TI - Ascending Aortic Stenting for Acute Supraaortic Stenosis From Graft Collapse. AB - A 78-year-old man with remote type-A dissection presented with acute-onset dyspnea. Twenty-two years prior, treatment for his aortic disease required replacement of ascending and arch aneurysms with a polyester graft (Dacron) using the graft inclusion technique. He presented currently in cardiogenic shock. Echocardiography demonstrated new severe hypokinesis of all apical segments. Left heart catheterization revealed a 120 mm Hg intragraft gradient. Computed tomography arteriography was unrevealing, but intraaortic ultrasound demonstrated critical intragraft stenosis. A balloon expandable stent (Palmaz stent, Cordis, Milpitas, CA) was deployed in the stenotic region with gradient resolution. The patient later underwent aortic root replacement and ascending aneurysm repair (Bio-Bentall technique) and is doing well at 24 months. PMID- 29428838 TI - Bilateral Pneumothorax and Pneumoperitoneum One Year After Thoracoscopic Esophagectomy. PMID- 29428839 TI - Unique insights to intrinsically disordered proteins provided by ion mobility mass spectrometry. AB - Entire functional proteins as well as large regions of proteins lack structural elements which are resolvable via crystallography or NMR. These intrinsically disordered proteins (IDPs) or regions (IDRs) are often involved in cell regulation processes, for example in signalling hubs and as a result aberrant behaviour can cause or be representative of disease. As a consequence there is a pressing need to develop alternative structural methods for IDPs and the interactions that they may form with other proteins and/or with potential inhibitors of binding. One such method is ion mobility mass spectrometry (IM-MS) coupled with careful application of electrospray ionisation, which shows great promise as a technique that does not 'care' if a protein is structured or not. We highlight recent work which has employed IM-MS to study conformational heterogeneity in disordered proteins, and discuss the opportunities, as well as the challenges of this approach. PMID- 29428840 TI - Organ uptake and release of inorganic nitrate and nitrite in the pig. AB - Numerous studies have shown beneficial cardiovascular and metabolic effects of dietary nitrate but the release or uptake of these anions on an organ level is still poorly elucidated. Here we administered sodium nitrate in the pig and measured acute changes in release/uptake of nitrate and nitrite across several organs as well as cardiovascular and metabolic functions. In 17 anesthetized pigs multiple venous catheters and arterial ultrasonic blood flow probes were positioned. After pretreatment with the NO synthase (NOS) inhibitor l-NAME to minimize involvement of NOS-dependent nitrate/nitrite generation, the animals received bolus injections of either sodium nitrate or sodium chloride. Organ blood flows and release/uptake of nitrate and nitrite were measured in the pulmonary, splanchnic, hepatic and renal circulations for up to two hours. In addition, small intestinal luminal NO, gut secretion of nitrate, as well as hepatic and renal NADPH oxidase activity were measured. At baseline there was a significant uptake of nitrite in the liver and kidneys together with a release of nitrite from the lungs. In the control pigs, arterial plasma nitrite progressively declined during the observation period (-54%) but was stable in the nitrate group, indicating conversion of nitrate to nitrite. Sodium nitrate led to a marked accumulation of nitrate in the small intestinal lumen with a parallel increase in luminal nitrite. This was coupled with release of nitrite in the portal vein and a concomitant uptake of this anion in the liver. There was a trend towards reduced NADPH oxidase-dependent superoxide generation in the liver but an increase in the kidney. Nitrate had no acute effects on cardiovascular parameters or regional and systemic oxygen consumption. In conclusion, we found a notable difference in release and uptake of nitrate and nitrite between the organs investigated. Our findings indicate an acute conversion of nitrate to nitrite, most likely independent of oral bacteria but by a mammalian nitrate reductase and/or gut bacteria. PMID- 29428842 TI - Social motivation in people with recent-onset schizophrenia spectrum disorders. AB - People with schizophrenia-spectrum disorders (SSD) often experience impairments in non-social motivation. In this study, we extended this line of investigation by examining specific components of social motivation and the extent to which these components work together in people with and without a recent-onset SSD. Sixty-four people with a recent-onset SSD and 26 controls completed a task that allowed us to examine changes in anticipated pleasure, decisions to trust, and effort expenditure over the course of repeated interactions with positive or negative outcomes. Compared to controls, we found that people in the SSD group placed less trust, tended to anticipate less pleasure, and expended less effort to increase the likelihood of future interactions with positive outcomes. Further, in the SSD group, effort expenditure was not associated with either anticipated pleasure or decisions to trust. While there were no group differences in anticipated pleasure or trust placed during interactions with negative outcomes, people in the SSD group expended less effort to decrease to the likelihood of future interactions. Taken together, our findings suggest that people with a recent-onset SSD may experience both impairment and disconnection between various components of social motivation for interactions with positive outcomes. Implications for interventions for social engagement in people with SSD are discussed. PMID- 29428841 TI - Nitrite potentiates the vasodilatory signaling of S-nitrosothiols. AB - Nitrite and S-nitrosothiols (SNOs) are both byproducts of nitric oxide (NO) metabolism and are proposed to cause vasodilation via activation of soluble guanylate cyclase (sGC). We have previously reported that while SNOs are potent vasodilators at physiological concentrations, nitrite itself only produces vasodilation at supraphysiological concentrations. Here, we tested the hypothesis that sub-vasoactive concentrations of nitrite potentiate the vasodilatory effects of SNOs. Multiple exposures of isolated sheep arteries to S-nitroso-glutathione (GSNO) resulted in a tachyphylactic decreased vasodilatory response to GSNO but not to NO, suggesting attenuation of signaling steps upstream from sGC. Exposure of arteries to 1 MUM nitrite potentiated the vasodilatory effects of GSNO in naive arteries and abrogated the tachyphylactic response to GSNO in pre-exposed arteries, suggesting that nitrite facilitates GSNO-mediated activation of sGC. In intact anesthetized sheep and rats, inhibition of NO synthases to decrease plasma nitrite levels attenuated vasodilatory responses to exogenous infusions of GSNO, an effect that was reversed by exogenous infusion of nitrite at sub-vasodilating levels. This study suggests nitrite potentiates SNO-mediated vasodilation via a mechanism that lies upstream from activation of sGC. PMID- 29428843 TI - Challenges in obstructive sleep apnoea. PMID- 29428844 TI - Effect of different chorionic gonadotropins on final growth of the dominant follicle in Bos indicus cows. AB - The aim of this study was to evaluate the effect of eCG or hCG on the final growth of the dominant follicle in Nelore (Bos indicus) cows submitted to fixed time AI (FTAI). Eighty-four lactating cows with body condition score (BCS) of 2.9 (range 1-5) were used. At a random day of the estrous cycle (D0) cows received 2 mg estradiol benzoate and a reused intravaginal progesterone device (1.9 g). At D8, when the device was removed, 0.5 mg cloprostenol and 1 mg estradiol cypionate was given i.m., and cows were randomly assigned to receive on D8 one of the following treatments: Control (no treatment; n = 17), eCG (300 IU i.m.; n = 17), hCG 300 (300 IU i.m.; n = 18), hCG 200 IM (200 IU i.m.; n = 16) and hCG 200 SC (200 IU s.c.; n = 16). On the same day and 2 days later, cows were subjected to ovarian ultrasonography to evaluate the diameter of the largest follicle and to calculate follicular growth rate (D8 to D10). No differences were observed for the diameter of the largest follicle on D8 (P = 0.3) or D10 (P = 0.4) among treatments. However, the growth rate of the dominant follicle between D8 and D10 was greater for the groups eCG and hCG 300 and there were no differences between the other treatments (Control = 1.1 mm/day; eCG = 1.8 mm/day; hCG 300 = 1.8 mm/day; hCG 200 IM = 1.3 mm/day; hCG 200 SC = 1.3 mm/day; P = 0.02). In addition, more cows from the Group hCG 300 presented premature ovulation (44.4%) than cows from Control (5.8%), eCG (0%), or hCG 200 IM (12.5%), but did not differ from Group hCG 200 SC (18.7%). Regardless of treatment, the size of the largest follicle on D8 was different between cows that presented premature ovulation vs. cows that did not ovulate prematurely (11.3 mm vs. 9.9 mm, respectively; P = 0.01). Treatment with different hCG doses on D8 of a FTAI protocol failed to produce similar effects compared to eCG in terms of final follicular growth support and greater ovulatory follicle size. In addition, the groups hCG 300 and hCG 200 SC induced premature ovulation in a greater portion of cows. Thus, a single administration of hCG on D8 does not appear to be a reliable alternative to eCG treatment in FTAI protocols. PMID- 29428845 TI - Decreasing from 9 to 7 days the permanence of progesterone inserts make possible their use up to 5 folds in suckled Nellore cows. AB - This study aimed to evaluate the effects of decreasing permanence period of progesterone (P4) inserts from 9 (9d) to 7 (7d) days in timed-AI (TAI) protocol, as well as their reuse on pregnancy per AI (P/AI) during 7d protocol. At the beginning of all protocols, cows received 2 mg of estradiol benzoate (EB) and a vaginal insert containing 1.9 g of P4. In the 7d protocol, the P4 insert was removed, and cows were given 25 mg of prostaglandin F2alpha, 0.6 mg of estradiol cypionate and 300 IU of eCG 7 days later. In the 9d protocol, the P4 insert was removed, and cows received the same hormones that were administrated in 7d protocol, however, they were applied on the 9th day of the protocol. In the experiment I, 302 suckled Nellore cows were undergone to 7d protocol, and AI was performed 10-14 h later after estrus detection. In the experiment II, 679 suckled Nellore cows were assigned to receive either 7d or 9d protocols. In the experiment III, 999 suckled Nellore cows were assigned to receive either a new P4 insert (CIDR1), or a P4 insert used previously for 7 (CIDR2), 14 (CIDR3), 21 (CIDR4) or 28 (CIDR5) days, and 227 Nellore heifers received a P4 insert used previously for 21 (CIDR4) or 35 (CIDR6) days during the 7d protocol. When 7d protocol was used, 45% of cows exhibited estrus 48 h after P4 removal. Thus, the AI was performed 55 h after P4 removal in experiments II and III when 7d protocol was used. There was no difference in estrus detection rate (72 vs 74%; P = 0.60), ovulation rate (80 vs 88%; P = 0.13) and P/AI (56 vs 54%; P = 0.49) between 7d and 9d protocols, respectively. In the 7d protocol, the P/AI was similar (P = 0.72) using a new P4 insert (47%), or a P4 insert used previously for 7 (48%), 14 (45%), 21 (54%), or 28 (49%) days in Nellore suckled cows. In addition, P/AI was similar (P = 0.15) in heifers that received a P4 insert used previously for 21 (52%), or 35 (61%) days during the 7d protocol. In conclusion, cows submitted to 7d or 9d protocols had similar reproductive performance, and the reuse of P4 inserts up to 6 folds (five in suckled cows plus one in heifers) did not affect reproductive performance of Nellore cattle in 7d protocol. PMID- 29428846 TI - Effect of different shipping temperatures (~22 degrees C vs. ~7 degrees C) and holding media on blastocyst development after overnight holding of immature equine cumulus-oocyte complexes. AB - Intracytoplasmic sperm injection (ICSI) is an important tool for equine embryo production in both clinical and research settings. In clinical ICSI programs, immature equine cumulus-oocyte complexes (COCs) are often collected at the mare's location and shipped to the ICSI laboratory. To simplify shipment and aid scheduling of subsequent procedures, COCs can be held overnight at room temperature (~22 degrees C) before placement into maturation culture, with no detrimental effect on meiotic or developmental competence. A recent study indicated that it might be possible to hold COCs overnight at cold (~4 degrees C) temperatures. If so, this might allow longer holding periods that would ease shipping requirements. In this study, we compared oocyte maturation rates, as well as cleavage and blastocyst rates after ICSI, for COCs held at either room or cold temperatures overnight before the onset of in vitro maturation. In Exp. 1, COCs were shipped overnight in a commercial embryo holding medium, ViGRO (Vg), in insulated containers designed to hold at either room temperature (RT, ~22 degrees C) or cold temperatures (Cold, ~7 degrees C). Subsequent rates of in vitro maturation, cleavage and blastocyst formation were significantly higher in the RT treatment (39%, 90% and 41%, respectively) than in the Cold treatment (23%, 60% and 17%, respectively, P < .05). In Exp. 2, we compared Vg medium with a second commercial embryo holding medium, SYNGRO (Sy). There was no significant difference between Vg and Sy groups in any evaluated parameter within either RT or Cold treatments. Within each medium group and for both media combined, the rates of in vitro maturation, cleavage and blastocyst formation were significantly higher in the RT treatment (42%, 81% and 42%, respectively for the combined media) than in the Cold treatment (29%, 54% and 10%, respectively for the combined media, P < .05). We conclude that shipment of immature equine COCs at cold temperatures (~7 degrees C) is detrimental to subsequent in vitro maturation and embryo production. PMID- 29428847 TI - Cryopreservation of domestic cat (Felis catus) ovarian tissue: Comparison of two vitrification methods. AB - We aimed to evaluate the effect of two vitrification methods on the morphology and functionality of vitrified feline preantral follicles. Feline ovarian tissue was vitrified with EG + trehalose combined or not with dimethyl sulphoxide (DMSO), using two different techniques (open or closed systems). Morphology, developmental capacity and mRNA expression of markers for follicle survival and quality were assessed before and after in vitro culture (IVC). Both vitrification and culture media were serum-free. Vitrification of feline ovarian tissue from five adult domestic cats was performed with EG + trehalose combined or not with DMSO. Two systems were used: the open system solid-surface vitrification (SSV) and the closed system ovarian tissue cryosystem (OTC). Histological analysis of follicle integrity showed that the percentages of normal follicles in previously vitrified ovarian fragments decreased after 7 days of in vitro culture (IVC), independently of the protocol used. Although follicular activation was observed by Ki-67 labelling, this was accompanied by extensive follicular degeneration as detected by a 3-4-fold decrease in follicular density. Remarkable follicle activation was observed in the ovarian tissue vitrified using OTC and subjected to IVC, probably due to a higher rate of degeneration of developing follicles. Even with such follicular loss, the results are promising for the combination of EG + DMSO + trehalose in a serum-free medium when applying the SSV method, with this approach resulting in the highest rates of normal developing follicles (19%) after 7 days IVC, together with granulosa cells proliferating at the same rate observed in fresh tissue. PMID- 29428848 TI - Molecular and endocrine factors involved in future dominant follicle dynamics during the induction of luteolysis in Bos indicus cows. AB - The growth profiles of the future dominant follicle (DF) and subordinate follicle (SF) and the gene expression of the granulosa cells during luteolysis induction in Bos indicus cows were evaluated. Forty cows were synchronized with a progesterone and estradiol based protocol. After synchronization, cows with a corpus luteum (CL) were evaluated by ultrasonography every 12 h, beginning at eight days post ovulation. Cows identified with a follicle of at least 6.0 mm in diameter in the second wave were split into two groups (BD-before follicular deviation and AD-after follicular deviation. In the BD group cows received 500 MUg of cloprostenol (a synthetic analogue of prostaglandin F2alpha) when the DF reached a mean diameter of 7.0 mm (6.5-7.5 mm). In the AD group, cows received 500 MUg of cloprostenol when the DF reached a mean diameter of 8.0 mm (7.5-8.5 mm). Cows in both groups were submitted to aspiration of the DF at 96 and 72 h after prostaglandin was given. Follicular aspirations were performed to quantify IGF1R, LHR and PAPPA transcripts in the granulosa cells. The diameter of the DF at the moment of prostaglandin administration (P = 0.001) and the growth rate of the SF (P = 0.05) were greater in the AD group. There was greater abundance of LHR transcripts in BD cows (P = 0.04). The remaining variables tested were similar between the experimental groups (P > 0.05). In conclusion, the induction of luteolysis before follicular deviation does not interfere with dominant follicle dynamics. However, it causes granulosa cell LHR down regulation. PMID- 29428849 TI - Generation of a human embryonic stem cell line, NERCe003-A-1, with lentivirus vector-mediated inducible CTNNB1 overexpression. AB - The human embryonic stem cell (hESC) line NERCe003-A-1 was generated by introducing lentiviral-vector-mediated tetracycline-inducible beta-catenin expression into a normal hESC line, NERCe003-A. The resulting cell line can overexpress the beta-catenin protein, encoded by the CTNNB1 gene, after exposure to doxycycline (Dox). CTNNB1 gene expression was confirmed by quantitative PCR (qPCR) and immunofluorescence assays. Further characterization confirmed that the NERCe003-A-1 cell line expresses typical pluripotency markers and has the ability to form the three germ layers both in vitro and in vivo. PMID- 29428850 TI - Exposure to routine availability of immediate postpartum LARC: effect on attitudes and practices of labor and delivery and postpartum nurses. AB - OBJECTIVES: Nurses play an integral role in intrapartum and postpartum patient education. This exploratory study aims to assess the attitudes, knowledge, and practices of labor and delivery and postpartum nurses regarding contraception and evaluate for changes in these measures 1 year after an institutional initiative allowing routine availability of immediate postpartum long-acting reversible contraception (LARC). STUDY DESIGN: In 2014, Montefiore Medical Center began to routinely offer comprehensive immediate postpartum contraception. The initiative included education and feedback sessions for labor and delivery and postpartum nurses on contraception, including immediate postpartum initiation of LARC. Nurses completed anonymous surveys at the beginning of the initiative (n=59) and at 1 year (n=56). We compared baseline and 1 year survey results of contraceptive knowledge, attitudes and practices using chi2 test, Fisher's Exact Test, or t test as appropriate. RESULTS: Nurses who stated they counseled patients on contraception "always" or "most of the time" increased from 27/59 (46%) to 40/56 (71%) (p=.005). The number of nurses who would recommend the intrauterine device and implant for postpartum contraception increased from 1/59 (2%) to 18/56 (32%) (p<.0001). Attitudes towards injectable contraception and breastfeeding remained negative; 27/59 nurses (46%) at baseline and 34/56 (61%) at 1 year agreed with the statement "DMPA [depot medroxyprogesterone acetate] has a negative effect on breastfeeding." CONCLUSIONS: Experience working in a location with routine access to immediate postpartum contraception is associated with increased awareness among nurses of postpartum contraceptive options, especially LARC, and increased contraceptive counseling. Concerns about the impact of hormonal contraception on breastfeeding, specifically DMPA, are persistent and prevalent. IMPLICATIONS: Labor and delivery and postpartum nurses' knowledge regarding immediate postpartum contraception, particularly LARC methods, may change with exposure to routine access to these methods. This exposure may also impact nurses' practices of providing patient counseling on what methods are appropriate for postpartum women. PMID- 29428851 TI - Therapeutic anticoagulation for pulmonary embolism during first-trimester surgical abortion: two case reports. AB - We report two patients with bilateral pulmonary embolism who presented to our county hospital reproductive health services clinic. Both patients underwent an uncomplicated first-trimester aspiration abortion while on therapeutic unfractionated heparin therapy. Anticoagulation therapy may be modified to safely perform first-trimester surgical termination without significant blood loss. PMID- 29428852 TI - Efficiency analysis of bioenergy potential on winter fallow fields: A case study of rape. AB - Rape is a non-grain feedstock with several characteristics that make it suitable for biofuel production, such as high oil yields and low environmental impact. Planting rape on winter fallow fields could allow for seasonal rotation between the bioenergy production and agricultural production. In the present study, the Global Agro-Ecological Zones model was used to estimate the production potential of rapeseed on winter fallow fields in the Yangtze River region from 2010 to 2015. Life cycle assessment was then conducted to calculate energy efficiency and greenhouse gas emissions from the entire energy-producing process and to estimate the number of bioenergy enterprises and their spatial distribution. The results indicated that the total area available of winter fallow fields in the Yangtze River region was 24.93millionha, accounting for 34.2% of the total cultivated land area. The total yield of winter rapeseed was up to 46.41milliontons (an average yield of 1.86tons/ha). Thus, the study area could potentially produce net energy of up to 3564millionMJ with energy return on energy investment (EROEI) as high as 1.52-1.84. The total reduction of greenhouse gas emissions may be up to 23.28milliontons, and the total number of bioenergy enterprises could be 589, from which the total biodiesel output could be 167.5milliontons. Hubei, Henan, Anhui and Jiangxi should be prioritized for generating biofuels from rapeseed planted on winter fallow fields. PMID- 29428853 TI - A critical analysis of published data to discern the role of soil and sediment properties in determining sorption of per and polyfluoroalkyl substances (PFASs). AB - Widespread usage of per- and polyfluoroalkyl substances (PFASs) has caused major environmental contamination globally. The hydrophilic and hydrophobic properties of PFASs affect the sorption behaviour and suggest organic carbon may not be the only factor affecting sorption. We reviewed the quality of all data published in peer-reviewed literature on sorption of PFASs to critically evaluate the role organic carbon (OC) and other properties have in sorption of PFASs in soils or sediments. The largest data sets available were for perfluorooctanoic acid (PFOA, n = 147) and perfluorooctane sulfonic acid (PFOS, n = 178), and these analyses showed very weak correlations between sorption coefficient (Kd) and OC alone (R2 = 0.05-0.07). When only laboratory-derived Kd values of PFASs and OC were analysed, the R2 values increased for PFOA (R2 = 0.24, n = 42), PFOS (R2 = 0.38, n = 69), perfluorononanoic acid (PFNA, R2 = 0.77 n = 12), and perfluorodecanoic acid (PFDA, R2 = 0.78, n = 13). However, the relationships were heavily skewed by one or two high OC values. Similarly there was no significant relationship between Kd values and pH for PFOS (R2 = 0.06) and PFOA (R2 = 0.07), across a range of environmental pH values. Our analyses showed sorption behaviour of a range of PFASs could not be explained by a single soil or sediment property. Multiple regression models better explained the sorption behaviour of a number of PFASs. Regressions of OC and pH together explained a significant proportion of the variation in Kd values for 9 out of 14 PFASs and 8 of these regressions had >=10 data points. This review highlighted that at least OC, pH and clay content are properties having significant effect on sorption. There is a clear need for more data and studies with thorough characterisation of soils or sediments to better understand their role in PFASs sorption. Current assessments based on OC alone are likely to be erroneous. PMID- 29428854 TI - Effects of application of inhibitors and biochar to fertilizer on gaseous nitrogen emissions from an intensively managed wheat field. AB - The effects of biochar combined with the urease inhibitor, hydroquinone, and nitrification inhibitor, dicyandiamide, on gaseous nitrogen (N2O, NO and NH3) emissions and wheat yield were examined in a wheat crop cultivated in a rice wheat rotation system in the Taihu Lake region of China. Eight treatments comprised N fertilizer at a conventional application rate of 150kgNha-1 (CN); N fertilizer at an optimal application rate of 125kgNha-1 (ON); ON+wheat-derived biochar at rates of 7.5 (ONB1) and 15tha-1 (ONB2); ON+nitrification and urease inhibitors (ONI); ONI+wheat-derived biochar at rates of 7.5 (ONIB1) and 15tha-1 (ONIB2); and, a control. The reduced N fertilizer application rate in the ON treatment decreased N2O, NO, and NH3 emissions by 45.7%, 17.1%, and 12.3%, respectively, compared with the CN treatment. Biochar application increased soil organic carbon, total N, and pH, and also increased NH3 and N2O emissions by 32.4 68.2% and 9.4-35.2%, respectively, compared with the ON treatment. In contrast, addition of urease and nitrification inhibitors decreased N2O, NO, and NH3 emissions by 11.3%, 37.9%, and 38.5%, respectively. The combined application of biochar and inhibitors more effectively reduced N2O and NO emissions by 49.1 49.7% and 51.7-55.2%, respectively, compared with ON and decreased NH3 emission by 33.4-35.2% compared with the ONB1 and ONB2 treatments. Compared with the ON treatment, biochar amendment, either alone or in combination with inhibitors, increased wheat yield and N use efficiency (NUE), while addition of inhibitors alone increased NUE but not wheat yield. We suggest that an optimal N fertilizer rate and combined application of inhibitors+biochar at a low application rate, instead of biochar application alone, could increase soil fertility and wheat yields, and mitigate gaseous N emissions. PMID- 29428855 TI - Immobilization of heavy metals in ceramsite produced from sewage sludge biochar. AB - Ceramsite was prepared from sewage sludge biochar (SSB). The migration, speciation evolution, leaching toxicity, and potential environmental risk of heavy metals (HMs) in sludge biochar ceramsite (SBC) were investigated. The characteristics of the SBC met the requirements for Chinese lightweight aggregate standards (GB/T 1743.1-2010 and JT/T 770-2009) and the heavy metals (HMs: Cu, Zn, Cr, Pb, and Cd) were well immobilized in the SBC. The leaching percentages of the HMs in SBC were remarkably reduced, in particular after preheating at 400 degrees C and sintering at 1100 degrees C. The leaching percentages of Cu, Zn, Cr, Cd, and Pb decreased from (19.099, 18.009, 0.010, 3.952, and 0.379) % to (2.122, 4.102, 0.002, 1.738, and 0.323) %, respectively. The RAC values of the HMs in SBC were all lower than 1%, and the risk index (RI) suggested that the SBC had no HMs contamination and very low potential ecological risk when used in the environment. Furthermore, the HM-immobilization mechanisms were mainly related to the formation of new crystal phases (silicate and phosphate minerals) by incorporation of HMs, and to vitrification and encapsulation with low concentration of HMs on the surface. This work provides a useful method for large scale reuse of SSB with very low leaching toxicity and low potential ecological risk of HMs. PMID- 29428856 TI - Sorption, plant uptake and metabolism of benzodiazepines. AB - Reuse of treated wastewater for irrigation of crops is growing in arid and semi arid regions, whilst increasing amounts of biosolids are being applied to fields to improve agricultural outputs. Due to incomplete removal in the wastewater treatment processes, pharmaceuticals present in treated wastewater and biosolids can contaminate soil systems. Benzodiazepines are a widely used class of pharmaceuticals that are released following wastewater treatment. Benzodiazepines are represented by a class of compounds with a range of physicochemical properties and this study was therefore designed to evaluate the influence of soil properties on the sorption behaviour and subsequent uptake of seven benzodiazepines (chlordiazepoxide, clonazepam, diazepam, flurazepam, oxazepam, temazepam and triazolam) in two plant species. The sorption and desorption behaviour of benzodiazepines was strongly influenced by soil type and hydrophobicity of the chemical. The partitioning behaviour of these chemicals in soil was a key controller of the uptake and accumulation of benzodiazepines by radish (Raphanus sativus) and silverbeet (Beta vulgaris). Benzodiazepines such as oxazepam that were neutral, had low sorption coefficients (Kd) or had pH-adjusted log octanol-water partition coefficients (log Dow, pH6.3) values close to 2 had the greatest extent of uptake. Conversely, benzodiazepines such as flurazepam that had an ionised functional groups and greater Kd values had comparatively limited accumulation in the selected plant species. Results also revealed active in-plant metabolism of benzodiazepines, potentially analogous to the known metabolic transformation pathway of benzodiazepines in humans. Along with this observed biological transformation of benzodiazepines in exposed plants, previously work has established the widespread presence of the plant signalling molecule gamma-amino butyric acid (GABA), which is specifically modulated by benzodiazepines in humans. This highlights the need for further assessment of the potential for biological activity of benzodiazepines following their plant uptake. PMID- 29428857 TI - Microbial communities associated with uranium in-situ recovery mining process are related to acid mine drainage assemblages. AB - A large fraction (47%) of the world's uranium is mined by a technique called "In Situ Recovery" (ISR). This mining technique involves the injection of a leaching fluid (acidic or alkaline) into a uranium-bearing aquifer and the pumping of the resulting solution through cation exchange columns for the recovery of dissolved uranium. The present study reports the in-depth alterations brought to autochthonous microbial communities during acidic ISR activities. Water samples were collected from a uranium roll-front deposit that is part of an ISR mine in operation (Tortkuduk, Kazakhstan). Water samples were obtained at a depth of ca 500 m below ground level from several zones of the Uyuk aquifer following the natural redox zonation inherited from the roll front deposit, including the native mineralized orebody and both upstream and downstream adjacent locations. Samples were collected equally from both the entrance and the exit of the uranium concentration plant. Next-generation sequencing data showed that the redox gradient shaped the community structures, within the anaerobic, reduced, and oligotrophic habitats of the native aquifer zones. Acid injection induced drastic changes in the structures of these communities, with a large decrease in both cell numbers and diversity. Communities present in the acidified (pH values < 2) mining areas exhibited similarities to those present in acid mine drainage, with the dominance of Sulfobacillus sp., Leptospirillum sp. and Acidithiobacillus sp., as well as the archaean Ferroplasma sp. Communities located up- and downstream of the mineralized zone under ISR and affected by acidic fluids were blended with additional facultative anaerobic and acidophilic microorganisms. These mixed biomes may be suitable communities for the natural attenuation of ISR mining affected subsurface through the reduction of metals and sulfate. Assessing the effect of acidification on the microbial community is critical to evaluating the potential for natural attenuation or active bioremediation strategies. PMID- 29428858 TI - Studies on adsorption of oxytetracycline from aqueous solutions onto hydroxyapatite. AB - The presence of antibiotics in the water and wastewater has raised problems due to potential impacts on the environment and consequently their removal is of great importance. For this reason, this article aims to perform a study on the possibility of oxytetracycline (OTC) adsorption from aqueous medium by using the hydroxyapatite (HA) nanopowders as adsorbent materials. The hydroxyapatite nanopowders were synthesized by wet precipitation method by using orthophosphoric acid and calcium hydroxide as raw materials and investigated by XRD, SEM-EDX, FTIR and BET methods. The uncalcined and calcined hydroxyapatite samples have hexagonal crystal structure with crystal sizes smaller than 100nm and a specific surface area of 316m2/g and 139m2/g, respectively. The adsorption behavior of oxytetracycline, a zwitterionic antibiotic, on nanohydroxyapatite was investigated as a function of pH, contact time, adsorbent dosage and drug concentration by means of batch adsorption experiments. High oxytetracycline removal rates of about 97.58% and 89.95% for the uncalcined and calcined nanohydroxyapatites, respectively, were obtained at pH8 and ambient temperature. The adsorption process of oxytetracycline onto nanohydroxyapatite samples was found to follow a pseudo-second order and intraparticle diffusion kinetic models. The maximum adsorption capacities of 291.32mg/g and 278.27mg/g for uncalcined and calcined nanohydroxyapatite samples, respectively, have been found. The adsorption mechanism of OTC on the hydroxyapatite surface at pH8 can be established via surface complexation. The obtained results are indicative of good hydroxyapatite adsorption ability towards oxytetracycline drug. PMID- 29428859 TI - Decoupled water-sediment interactions restrict the phosphorus buffer mechanism in agricultural streams. AB - Our study aimed to explore the effects of agriculture on the phosphorus buffer capacity of 11 headwater streams in Austria. We used phosphorus adsorption curves and re-suspension experiments to determine both, the potential of the sediments to act as phosphorus source or sink and the actual phosphorus exchange between water and sediments. Additionally, we determined the alkaline phosphatase activity (APA) in epilithic and epipsammic biofilms as indicator for the phosphorus demand of the benthic and hyporheic community. We hypothesized that highly polluted streams will show decreased phosphorus buffer capacities, which were either due to saturation or restricted water-sediment interactions. Our results support the second hypothesis. Fine sediment accumulations, organic matter content, and phosphorus concentrations in water and sediments increased with percent cropland in the catchment. Below SRP concentrations of 120MUgL-1 in the stream water, sediments showed a high potential for phosphorus release, with zero equilibrium phosphorus concentrations (EPC0) being more than twice as high as SRP concentrations. Above 150MUgL-1, EPC0 reached only 20-50% of SRP concentrations, indicating a high potential of the sediments to act as phosphorus sinks. These findings were confirmed by phosphorus uptake of these sediments during re-suspension. While APA in epilithic biofilms decreased with increasing SRP concentrations, APA in epipsammic biofilms showed the reverse pattern, indicating a restricted phosphorus supply of the hyporheic community despite phosphorus surplus in the water column. Our study shows that inputs of fine sediments from agricultural sources may reduce the phosphorus buffering mechanism of stream sediments through restrictions of water-sediment interactions. Consequently, water column and sediment processes are increasingly decoupled and phosphorus-rich stream water will not effectively reach the reactive sites in the sediments responsible for uptake. Therefore, phosphorus mitigation measures in stream ecosystems must comprise sediment management in the catchment as well as in-stream measures for the rehabilitation of the hyporheic zone. PMID- 29428860 TI - Effects of long-term fertilization on phoD-harboring bacterial community in Karst soils. AB - Phosphorus (P) acquisition by plants from soil organic P mainly relies on microorganisms. Examining the community of functional microbes that encode phosphatases (e.g. PhoD) under different fertilization managements may provide valuable information for promoting soil organic P availability. Here, we investigated how the abundance and community diversity of phoD-harboring bacteria responded to long-term fertilization in Karst soils. Six fertilization treatments were designed as follows: non-fertilized control (CK), inorganic fertilization only (NPK), and inorganic fertilization combined with low- and high amounts of straw (LSNPK and HSNPK), or cattle manure (LMNPK and HMNPK). We found that soil available phosphorus (AP) content and the activity of alkaline phosphatase (ALP) were significantly higher in all combined inorganic/organic fertilization treatments, while the abundance of the phoD gene was only higher in the HMPNK treatment, compared to NPK. The combination of inorganic/organic fertilizations had no effect on the diversity of phoD genes compared to NPK alone, but the phoD gene richness was greater in these treatments as compared to the control. Only organic fertilization combinations with high amounts of organic matter (both HSNPK and HMNPK) significantly affected the phoD community structure. A structure equation model demonstrated that soil organic carbon (SOC), rather than P, greatly affected the phoD community structure, suggesting that organic P mineralization in soils is decoupled from C mineralization. Our results suggested that optimized combinations of inorganic/organic fertilizations could promote P availability via regulating soil phoD-harboring bacteria community diversity and ALP activity. PMID- 29428861 TI - The effects of sediment used in beach nourishment: Study case El Portet de Moraira beach. AB - Actions taken to prevent or reduce coastal erosion often do not have the desired effect, leading to major problems instead of solving the original one. This research focuses on why a nourished beach- with borrowed sand and 0.05% of particles <0.063 mm- causes the presence of suspended particles that are observed by beach users as turbidity. This means that the colour of the water was not its characteristic blue, even with calm wave conditions. This research involved a shoreline evolution analysis and a sedimentological study of the sand from 1977 to 2017. The results show that the turbidity episodes that occurred after the beach fill of May 2017 do not coincide with major storms that affected the beach. Furthermore, prior to this beach nourishment, even after the most important storms turbidity was not so pronounced. However, when the pre-nourishment and post-nourishment sediment are compared and analysed in detail, by studying the microstructure and morphology of the sand particles, their composition and morphology were observed to be completely different. These differences are also reflected in the accelerated particle weathering test, with the post-nourishment particles showing greater dissolution of carbonates. From its mineralogy, the post-nourishment material presents a smaller proportion of quartz in its composition and a significant amount of particles (9.6%) formed by clusters of Calcium and Silicon. The separation of this mineralogical composition produced by waves explains the formation of particles measuring <0.063 mm, a fact that has also been confirmed by the accelerated particle weathering test. This is, therefore, the cause of turbidity in the swash zone of the beach. PMID- 29428862 TI - Glocal assessment of integrated wastewater treatment and recovery concepts using partial nitritation/Anammox and microalgae for environmental impacts. AB - This study explored the feasibility and estimated the environmental impacts of two novel wastewater treatment configurations. Both include combined bioflocculation and anaerobic digestion but apply different nutrient removal technologies, i.e. partial nitritation/Anammox or microalgae treatment. The feasibility of such configurations was investigated for 16 locations worldwide with respect to environmental impacts, such as net energy yield, nutrient recovery and effluent quality, CO2 emission, and area requirements. The results quantitatively support the applicability of partial nitritation/Anammox in tropical regions and some locations in temperate regions, whereas microalgae treatment is only applicable the whole year round in tropical regions that are close to the equator line. Microalgae treatment has an advantage over the configuration with partial nitritation/Anammox with respect to aeration energy and nutrient recovery, but not with area requirements. Differential sensitivity analysis points out the dominant influence of microalgal biomass yield and wastewater nutrient concentrations on area requirements and effluent quality. This study provides initial selection criteria for worldwide feasibility and corresponding environmental impacts of these novel municipal wastewater treatment plant configurations. PMID- 29428863 TI - Kinetic assessment of simultaneous removal of arsenite, chlorate and nitrate under autotrophic and mixotrophic conditions. AB - In this work, a kinetic model was proposed to evaluate the simultaneous removal of arsenite (As (III)), chlorate (ClO3-) and nitrate (NO3-) in a granule-based mixotrophic As (III) oxidizing bioreactor for the first time. The autotrophic kinetics related to growth-linked As (III) oxidation and ClO3- reduction by As (III) oxidizing bacteria (AsOB) were calibrated and validated based on experimental data from batch test and long-term reactor operation under autotrophic conditions. The heterotrophic kinetics related to non-growth linked As (III) oxidation and ClO3- reduction by heterotrophic bacteria (HB) were evaluated based on the batch experimental data under heterotrophic conditions. The existing kinetics related to As (III) oxidation with NO3- as the electron acceptor together with heterotrophic denitrification were incorporated into the model framework to assess the bioreactor performance in treatment of the three co occurring contaminants. The results revealed that under autotrophic conditions As (III) was completely oxidized by AsOB (over 99%), while ClO3- and NO3- were poorly removed. Under mixotrophic conditions, the simultaneous removal of the three contaminants was achieved with As (III) oxidized mostly by AsOB and ClO3- and NO3- removed mostly by HB. Both hydraulic retention time (HRT) and influent organic matter (COD) concentration significantly affected the removal efficiency. Above 90% of As (III), ClO3- and NO3- were removed in the mixotrophic bioreactor under optimal operational conditions of HRT and influent COD. PMID- 29428864 TI - Microbial functional gene patterns related to soil greenhouse gas emissions in oil contaminated areas. AB - Linking microbial community structure to physiology and ecological processes is a critical focus of microbial ecology. To understand the microbial functional gene patterns related to soil greenhouse gas [carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O)] emissions under oil contamination, we used functional gene array (GeoChip 5.0) analysis and network methods to investigate the feedback responses of soil microbial functional gene patterns and identify keystone genes in Shengli Oilfield, China. The microbial functional gene number, relative abundance and diversity involved in carbon degradation and nitrogen cycling decreased consistently with the reduced CO2 and N2O flux in oil contaminated soils, whereas the gene number and relative abundance of methane-production related genes increased with contamination. Functional molecular ecological networks were built based on random matrix theory, where network structures and properties showed significantly variation between oil contaminated and uncontaminated soils (P<0.05). Network nodes, connectivity and complexity all reduced under oil contamination. The sensitive and the highest connective genes in the network were identified as keystone genes, based on Mann-Whitney U tests and network analysis. Our findings improved the understanding of the microbe mediated mechanisms affecting soil greenhouse gas emissions. PMID- 29428865 TI - Attentional bias is more predictive of eating behavior after self-control exertion. AB - There is experimental evidence to suggest that attentional bias to food stimuli may predict food intake. The process model of ego-depletion (Inzlicht & Schmeichel, 2012) proposes that after self-control exertion, attention shifts toward rewarding objects such as palatable food, which in turn should prompt greater food consumption as an indicator of lower self-control. In the current study, 84 female restrained and unrestrained eaters engaged in a self-control or neutral task, followed by a measure of attentional bias and an eating task. Results indicated there were no differences in attentional bias or amount eaten between self-control conditions and dietary restraint groups. However, a moderated regression showed that attentional bias toward food or self-control images predicted eating behavior only in participants who previously exerted self control, while no effect was found for participants in the neutral condition. These results suggest that attentional bias may predict food intake, but only for individuals who have previously exerted self-control. PMID- 29428866 TI - Prognostic value of circulating biomarker score in advanced-stage head and neck squamous cell carcinoma. AB - BACKGROUND: Circulating biomarker (CB) is a convenient, emerging predictive tool for treatment response and outcomes in human cancers. Therefore, we examined the prognostic value of pre-treatment and early post-treatment CBs and their summated scores in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: This study prospectively included 310 consecutive patients who underwent definitive treatment for previously untreated advanced-stage HNSCC between 2010 and 2015. The CB score was determined by complete blood counts (CBCs) and blood chemistry before and 2 months after the treatment, and the number of abnormal CB was counted from 0 to 10. Univariate and multivariate analyses with Cox proportional hazards models were used to find factors associated with disease free survival (DFS) and overall survival (OS). RESULTS: Most CBC profiles were significantly changed at 2-months post-treatment compared with those at pre treatment. Univariate analyses showed that hypoalbuminemia, leucocytosis, C reactive protein, high CB scores (>=6), age, performance status and comorbidity and tumour site were significantly associated with DFS and OS (all P < 0.05). Both pre- and post-treatment CB scores were independent factors predictive of DFS and OS outcomes in the multivariate analyses (P < 0.05). High CB scores at pre treatment were associated with 7-10-fold increased risk of unfavourable DFS and OS outcomes, and those at 2-months post-treatment were associated with 2 to 4 fold increased risk of poor survival outcomes (all P < 0.05). CONCLUSIONS: CB scores at pre-treatment and early post-treatment are useful for predicting survival outcomes in patients with advanced-stage HNSCC. PMID- 29428867 TI - Raman spectroscopy for assessment of bone resection margins in mandibulectomy for oral cavity squamous cell carcinoma. AB - OBJECTIVES: The aim of this study was to investigate the potential of Raman spectroscopy for detection of oral cavity squamous cell carcinoma (OCSCC) in bone resection surfaces during mandibulectomy. MATERIALS & METHODS: Raman mapping experiments were performed on fresh mandible resection specimens from patients treated with mandibulectomy for OCSCC. A tumour detection algorithm was created based on water concentration and the high-wavenumber range (2800 cm-1-3050 cm-1) of the Raman spectra. RESULTS: Twenty-six ex vivo Raman mapping experiments were performed on 26 fresh mandible resection specimens obtained from 22 patients. The algorithm was applied on an independent test set and showed an accuracy of 95%, a sensitivity of 95%, and a specificity of 87%. CONCLUSION: These results form the basis for further development of a Raman spectroscopy tool as an objective method for intraoperative assessment of bone resection margins. PMID- 29428868 TI - Mapping the cancer patient information landscape: A comparative analysis of patient groups across Europe and North America. AB - AIM: Little is known about how patient groups provide information for patients. We invited 838 patient groups from Europe and North America to participate in an online survey. METHODS: The survey covered: (i) availability, accessibility and quality of information provided; (ii) methods by which patient groups communicate; (iii) ways in which patient groups acquire information and confirm its veracity/accuracy; (iv) how people access information online. RESULTS: European patient groups were significantly less effective in providing medical related information than their North American counterparts in: clinical trials, potential causes of cancer, medical research, diagnosis/screening, symptoms, treatments (all p < 0.0001); Recommendations of best practice/care (p < 0.03), healthcare services(p = 0.029) and complimentary medicine (p = 0.01). Clinical trials (p = 0.0006), medical research (p = 0.006) and diagnosis/screening (p = 0.0024) were also areas where North American patients were more likely to require medical-related information. Similar patterns emerged for non-medical information with nutrition (<0.0001), watchful waiting (p = 0.0003), self-management of care (p = 0.0003), prevention (p = 0.002) and emotional issues (p = 0.016) being less effectively communicated by European patient groups. Nutrition was also an area where North American patients were more likely to require non-medical-related information. The main barriers in accessing online information which showed differences between European and North American patients were: perceived lack of need, mainly due to faith in their doctors (p = 0.0001); limited access to the internet (p = 0.0005), limited computer skills (p = 0.02); and lower income (p = 0.027). CONCLUSION: These results emphasise the more mature nature of cancer patient engagement/information provision in North America, providing valuable insights and guidance to inform development of more robust and effective cancer patient information communication platforms in Europe. PMID- 29428870 TI - Physiological assesment of vestibular function and toxicity in humans and animals. AB - Physiological methods that can be similarly recorded in humans and animals have a major role in sensory toxicology, as they provide a bridge between human sensory perception data and the molecular and cellular data obtained in animal studies. Vestibular toxicity research lags well behind other sensory systems in many aspects, including the availability of methods for functional assessment in animals that could be robustly translated to human significance. Here we review the methods available for the assessment of vestibular function in both humans and laboratory animals, with an emphasis on their similarity or divergence, to highlight their potential utility for the predictive assessment of vestibular toxicity. PMID- 29428869 TI - Cross-sectional study to assess the association of color vision with mercury hair concentration in children from Brazilian Amazonian riverine communities. AB - BACKGROUND: Mercury exposure in the Brazilian Amazon region has been an important concern since the 1980s, when gold mining activities contaminated many Amazonian river basins and the fish therein. Mercury exposure in humans can lead to changes in neural function. The visual system has been used as a functional indicator of methylmercury (organic) and mercury vapour (inorganic) toxicity. Children are particularly vulnerable to this metal exposure. OBJECTIVE: To compare the color vision of children from riverine communities of mercury-exposed (Tapajos basin) and non-exposed Amazonian rivers (Tocantins basin). METHODS: The study sample was 176 children, aged 7-14 years old. Children from two locations in the mercury exposed Tapajos river basin, Barreiras (n = 71) and Sao Luiz do Tapajos (n = 41), were compared to children from Limoeiro do Ajuru (n = 64), a non-exposed area in the Tocantins river basin. No caregiver reported that any children had contact with mercury vapour during their lifetime, and probably most of the mercury in their bodies was obtained by fish consumption. Because of this, we decided to evaluate the mercury exposure by total mercury levels in hair samples, a good marker for organic mercury, and not in the urine, a marker for inorganic mercury. Color vision was assessed by the Lanthony Desaturated D-15 test. We used the Vingrys and King-Smith method (1988) to quantify the hue ordering test. The primary visual outcomes from this analysis were C-index (magnitude of the hue ordering error) and angle of the hue ordering. RESULTS: The Tapajos children had a higher mean hair mercury level (mean: 4.5 MUg/g; range: 0.26-22.38 MUg/g) than that of Tocantins children (mean: 0.49 MUg/g; range: 0.03-1.91 MUg/g) (p < 0.05). Mean difference was approximately 4.01 MUg/g with a 95% confidence interval of 2.79-5.23. The results of the Lanthony D-15d test showed no significant difference between the C-index mean values of the Tapajos and Tocantins groups (p > 0.05). There was a weak linear correlation in the average C-index obtained from both eyes and the total mercury concentration. Multiple logistic regression analysis indicated that the location of the community and the age had a greater influence on the visual outcomes than the sex of the children and within-locale variation in mercury concentration. CONCLUSION: Our results suggest a difference in one aspect of vision, that is, color vision, between children living in two different river basins in the Brazilian Amazon. The association may be related to Hg exposure but also appeared related to the location of the community and age. PMID- 29428871 TI - QR-decomposition based SENSE reconstruction using parallel architecture. AB - Magnetic Resonance Imaging (MRI) is a powerful medical imaging technique that provides essential clinical information about the human body. One major limitation of MRI is its long scan time. Implementation of advance MRI algorithms on a parallel architecture (to exploit inherent parallelism) has a great potential to reduce the scan time. Sensitivity Encoding (SENSE) is a Parallel Magnetic Resonance Imaging (pMRI) algorithm that utilizes receiver coil sensitivities to reconstruct MR images from the acquired under-sampled k-space data. At the heart of SENSE lies inversion of a rectangular encoding matrix. This work presents a novel implementation of GPU based SENSE algorithm, which employs QR decomposition for the inversion of the rectangular encoding matrix. For a fair comparison, the performance of the proposed GPU based SENSE reconstruction is evaluated against single and multicore CPU using openMP. Several experiments against various acceleration factors (AFs) are performed using multichannel (8, 12 and 30) phantom and in-vivo human head and cardiac datasets. Experimental results show that GPU significantly reduces the computation time of SENSE reconstruction as compared to multi-core CPU (approximately 12x speedup) and single-core CPU (approximately 53x speedup) without any degradation in the quality of the reconstructed images. PMID- 29428872 TI - The win ratio approach did not alter study conclusions and may mitigate concerns regarding unequal composite end points in kidney transplant trials. AB - OBJECTIVES: The aim of the study was to determine the impact of using the win ratio approach and investigate whether this approach alters the interpretations or conclusions of a randomized trial in kidney transplantation. STUDY DESIGN AND SETTING: We present an application of the win ratio approach in a kidney transplant trial that assessed the clinical effectiveness of ramipril treatment vs. placebo. The primary composite outcome included the time to death, kidney transplant failure, or doubling of serum creatinine. We compare the win ratio to a conventional hazard ratio (HR) from the original trial. A win ratio with a lower 95% confidence limit greater than 1 indicates a positive treatment effect with statistical significance. RESULTS: For the primary composite end point, ramipril treatment resulted in a win ratio of 1.21 (95% confidence interval [CI], 0.55-2.59) vs. a HR of 0.76 (95% CI, 0.38-1.51). With extended follow-up (mean 48 months), ramipril was associated with a win ratio of 1.02 (95% CI, 0.54-1.83) vs. a HR of 0.96 (95% CI, 0.55-1.65). CONCLUSION: The win ratio approach produced results similar to the original time-to-event analysis. Using this approach would not alter the conclusion of the original trial and lessens concerns associated with composite components of unequal clinical importance. PMID- 29428873 TI - Re-randomization increased recruitment and provided similar treatment estimates as parallel designs in trials of febrile neutropenia. AB - OBJECTIVE: Re-randomization trials allow patients to be re-enrolled for multiple treatment episodes. However, it remains uncertain to what extent re-randomization improves recruitment compared to parallel group designs or whether treatment estimates might be affected. STUDY DESIGN AND SETTING: We evaluated trials included in a recent Cochrane review of granulocyte colony-stimulating factors for patients with febrile neutropenia. We assessed the recruitment benefits of re randomization trials; compared treatment effect estimates between re randomization and parallel group designs; and assessed whether re-randomization led to higher rates of non-compliance and loss to follow-up in subsequent episodes. RESULTS: We included 14 trials (5 re-randomization and 9 parallel group). The re-randomization trials recruited a median of 25% (range 16-66%) more episodes on average than they would have under a parallel-group design. Treatment effect estimates were similar between re-randomization and parallel group trials across all outcomes, though confidence intervals were wide. The re-randomization trials in this review reported no loss to follow-up and low rates of non compliance (median 1.7%, range 0-8.9%). CONCLUSIONS: In the setting of febrile neutropenia, re-randomization increased recruitment while providing similar estimates of treatment effect to parallel group trials, with minimal loss to follow-up or non-compliance. It appears to be safe and efficient alternative to parallel group designs in this setting. PMID- 29428875 TI - Ultrasound-Guided Percutaneous Needle Tenotomy for Chronic Tensor Fascia Lata Tendinopathy: A Case Series and Description of Sonographic Findings. AB - : Proximal tensor fascia lata tendinopathy at its origin on the anterior superior iliac crest is one potential cause of lateral hip pain. However, there is limited literature regarding the mechanism, disease course, or management of this condition. There is growing evidence supporting the effective treatment of percutaneous needle tenotomy (PNT) for chronic tendinopathy. Only a single case series has examined the efficacy of PNT for tendinopathy about the hip and pelvis. Presented here are examples of 2 cases of chronic recalcitrant proximal ultrasound confirmed tensor fascia lata (tendinopathy effectively treated with ultrasound-guided PNT. LEVEL OF EVIDENCE: IV. PMID- 29428874 TI - A novel hepatitis B virus species discovered in capuchin monkeys sheds new light on the evolution of primate hepadnaviruses. AB - BACKGROUND & AIMS: All known hepatitis B virus (HBV) genotypes occur in humans and hominoid Old World non-human primates (NHPs). The divergent woolly monkey HBV (WMHBV) forms another orthohepadnavirus species. The evolutionary origins of HBV are unclear. METHODS: We analysed sera from 124 Brazilian monkeys collected during 2012-2016 for hepadnaviruses using molecular and serological tools, and conducted evolutionary analyses. RESULTS: We identified a novel orthohepadnavirus species in capuchin monkeys (capuchin monkey hepatitis B virus [CMHBV]). We found CMHBV-specific antibodies in five animals and high CMHBV concentrations in one animal. Non-inflammatory, probably chronic infection was consistent with an intact preCore domain, low genetic variability, core deletions in deep sequencing, and no elevated liver enzymes. Cross-reactivity of antisera against surface antigens suggested antigenic relatedness of HBV, CMHBV, and WMHBV. Infection-determining CMHBV surface peptides bound to the human HBV receptor (human sodium taurocholate co-transporting polypeptide), but preferentially interacted with the capuchin monkey receptor homologue. CMHBV and WMHBV pseudotypes infected human hepatoma cells via the human sodium taurocholate co transporting polypeptide, and were poorly neutralised by HBV vaccine-derived antibodies, suggesting that cross-species infections may be possible. Ancestral state reconstructions and sequence distance comparisons associated HBV with humans, whereas primate hepadnaviruses as a whole were projected to NHP ancestors. Co-phylogenetic analyses yielded evidence for co-speciation of hepadnaviruses and New World NHP. Bayesian hypothesis testing yielded strong support for an association of the HBV stem lineage with hominoid ancestors. Neither CMHBV nor WMHBV was likely the ancestor of the divergent human HBV genotypes F/H found in American natives. CONCLUSIONS: Our data suggest ancestral co-speciation of hepadnaviruses and NHP, and an Old World origin of the divergent HBV genotypes F/H. The identification of a novel primate hepadnavirus offers new perspectives for urgently needed animal models of chronic hepatitis B. LAY SUMMARY: The origins of HBV are unclear. The new orthohepadnavirus species from Brazilian capuchin monkeys resembled HBV in elicited infection patterns and could infect human liver cells using the same receptor as HBV. Evolutionary analyses suggested that primate HBV-related viruses might have emerged in African ancestors of New World monkeys millions of years ago. HBV was associated with hominoid primates, including humans and apes, suggesting evolutionary origins of HBV before the formation of modern humans. HBV genotypes found in American natives were divergent from those found in American monkeys, and likely introduced along prehistoric human migration. Our results elucidate the evolutionary origins and dispersal of primate HBV, identify a new orthohepadnavirus reservoir, and enable new perspectives for animal models of hepatitis B. PMID- 29428876 TI - Imaging of Spondylolysis: The Evolving Role of Magnetic Resonance Imaging. PMID- 29428877 TI - New insights on Parkinson's disease from differentiation of SH-SY5Y into dopaminergic neurons: An involvement of aquaporin4 and 9. AB - The purpose of this research was to explore the behavior of aquaporins (AQPs) in an in vitro model of Parkinson's disease that is a recurrent neurodegenerative disorder caused by the gradual, progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Because of postmortem studies have provided evidences for oxidative damage and alteration of water flow and energy metabolism, we carried out an investigation about AQP4 and 9, demonstrated in the brain to maintain water and energy homeostasis. As an appropriate in vitro cell model, we used SH-SY5Y cultures and induced their differentiation into a mature dopaminergic neuron phenotype with retinoic acid (RA) alone or in association with phorbol-12-myristate-13-acetate (MPA). The association RA plus MPA provided the most complete and mature neuron phenotype, as demonstrated by high levels of beta-Tubulin III, MAP-2, and tyrosine hydroxylase. After validation of cell differentiation, the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and H2O2 were applied to reproduce a Parkinson's-like stress. The results confirmed RA/MPA differentiated SH-SY5Y as a useful in vitro system for studying neurotoxicity and for using in a MPTP and H2O2-induced Parkinson's disease cell model. Moreover, the data demonstrated that neuronal differentiation, neurotoxicity, neuroinflammation, and oxidative stress are strongly correlated with dynamic changes of AQP4 and 9 transcription and transduction. New in vitro and in vivo experiments are needed to confirm these innovative outcomes. PMID- 29428878 TI - Gender differences in the effects of childhood maltreatment on adult depression and anxiety: A systematic review and meta-analysis. AB - Child maltreatment has well-documented long-term, adverse effects on mental health, but it is not clear whether there are gender differences in these effects. We conducted a systematic review to investigate whether there are gender differences in the effects of maltreatment on adult depression and anxiety. Medline, PsycINFO, Web of Science, and Lilacs were searched for relevant studies published up to May 2016. Eligible studies included population-based studies (with a cohort, case-control or cross-sectional design) which assessed maltreatment during childhood or adolescence (<=18 years) and its association with major depression or generalized anxiety disorder (DSM/ICD diagnostic criteria) in adulthood (>18 years) separately for females and males. Meta analysis was performed to estimate the association between each exposure and outcome using fixed and random effects models. Pooled odds ratios (OR) were estimated separately for women and men and compared. Five studies of physical and sexual abuse were included in the meta-analyses. These provided twenty-two effects sizes estimates (11 for men, 11 for women) for associations between physical/sexual abuse and depression/anxiety. Exposure to each kind of abuse increased the odds of depression/anxiety. Associations were larger for women than for men, however, these gender differences were not statistically significant. Physical and sexual abuse in childhood/adolescence are risk factors for depression/anxiety in adulthood and the effect could be larger for women; however, currently there is insufficient evidence to definitively identify gender differences in the effects of maltreatment. PMID- 29428879 TI - Examining the association between suicidal behaviors and referral for mental health services among children involved in the child welfare system in Ontario, Canada. AB - Although various studies have investigated factors associated with mental health service utilization, few studies have examined factors associated with referral for mental health services among maltreated children. The objective of this study was to examine the association between suicidal thoughts and self-harming behavior and referral for mental health services among children involved in the Child Welfare System in Ontario, Canada. Data for this study were obtained from the Ontario Incidence Study of Reported Child Abuse and Neglect 2013. An estimate 57,798 child maltreatment investigations was analyzed using binary logistic regression with referral for mental health service as the outcome variable. Of the 57,798 cases, 4709 (8.1%), were referred for mental health services. More than seven out of ten maltreated children who engaged in self-harming behavior and two out of three maltreated children who expressed suicidal thoughts were not referred for mental health services. In the multivariate logistic regression model, children who expressed suicidal thoughts had 2.39 times higher odds of being referred for mental health services compared to children with no suicidal thoughts (AOR = 2.39, 99% C.I. 2.05-2.77) and children who engaged in self harming behavior had 1.44 times higher odds of being referred for mental health services compared to children who did not engage in self-harming behavior (AOR = 1.44, 99% C.I. 1.24-1.67), both after controlling for child demographic characteristics, maltreatment characteristics, and child functioning concerns. Given that referral is the initial step towards mental health service utilization, it is important that child welfare workers receive the necessary training so as to carefully assess and refer children in care who expressed suicidal thoughts or engaged in self-harming behavior for appropriate mental health services. The paper discusses the results and their implications for child welfare policy and practice. PMID- 29428880 TI - Multiple traumas and resilience among street children in Haiti: Psychopathology of survival. AB - In Haiti, as in several developing countries, the phenomenon of street children has become a major public health issue. These children are often victims of traumas and adverse life events. This article aimed to investigate traumas experienced by street children and their coping and resilience strategies used to deal with adversities in a logic of survival, relying on a mixed method approach. A group of 176 street children, aged 7-18 (n = 21 girls), recruited in Port-au Prince, completed measures assessing PTSD, social support and resilience. Semi structured interviews were conducted to document traumatic experiences, factors related to resilience and coping strategies. After performing statistical analyses to evaluate prevalence and predictors associated with PTSD, and level of social support satisfaction and resilience, qualitative analysis using a grounded theory approach was conducted. Results showed that street children experienced multiple traumas such as neglect, maltreatment, psychological, physical and sexual abuse. However, they also showed self-efficacy to face their traumatic experiences and few of them (less than 15%) obtained scores reaching clinical rates of PTSD, while a large majority presented a level of resilience between moderate to very high. A socio-ecological model of multiple traumas and a model of coping, survival and resilience strategies are conceptualized. Data provide a better understanding of the traumas experienced by street children, their coping and resilience strategies. Results underscore ways to develop practices to offer psychological support, social and vocational integration based on the real needs of these children, in a perspective of social justice. PMID- 29428881 TI - Childhood adversity increases the risk of onward transmission from perinatal HIV infected adolescents and youth in South Africa. AB - Repeated exposure to childhood adversity (abuse, neglect and other traumas experienced before age 18) can have lifelong impacts on health. For HIV-infected adolescents and youth, such impacts may include onward transmission of HIV. To evaluate this possibility, the current study measured the burden of childhood adversity and its influence on risky health behaviors among perinatally-infected adolescents and youth. We surveyed 250 perinatally-infected adolescents and youth (13-24 years) receiving care in Soweto, South Africa. Both male and female participants reported on childhood adversity (using the ACE-IQ), sexual behavior, and psychosocial state. Viral load was also abstracted from their charts. We used logistic regressions to test the association between cumulative adversity and behavioral outcomes. Half the sample reported eight or more adversities. Overall, 72% experienced emotional abuse, 59% experienced physical abuse, 34% experienced sexual abuse, 82% witnessed domestic violence, and 91% saw someone being attacked in their community. A clear gradient emerged between cumulative adversities and behavioral risk. Having experienced one additional childhood adversity raised the odds of risky sexual behavior by almost 30% (OR 1.27, 95% CI 1.09-1.48). Viral suppression was poor overall (31% had viral loads >400 copies/ml), but was not related to adversity. Adversity showed a robust relationship to depression and substance abuse. Childhood adversity is common, influences the current health of HIV-positive adolescents and youth, and puts their sexual partners at risk for HIV infection. Greater primary prevention of childhood adversity and increased access to support services (e.g., mental health) could reduce risk taking among HIV-positive adolescents and youth. PMID- 29428882 TI - Salt content and minimum acceptable levels in whole-muscle cured meat products. AB - Reported salt levels in whole-muscle cured meat products differ substantially within and among European countries, providing substantial scope for salt reduction across this sector. The objective of this study was to identify the minimum acceptable salt levels in typical whole-muscle cured products in terms of physicochemical, microbial and sensorial properties. Salt levels in a small selection of commercial Irish meat products were determined to establish a baseline for reduction. Subsequently, eight different back bacon rasher and cooked ham products were produced with varying levels of salt: 2.9%, 2.5%, 2% and 1.5% for bacon, and 2%, 1.6%, 1.0% and 0.8% for ham. Salt reduction produced products with significantly harder texture and higher microbial counts, with no difference in the colour and affecting the sensory properties. Nonetheless, salt reduction proved to be feasible to levels of 34% and 19% in bacon and ham products, respectively, compared to baseline. PMID- 29428883 TI - Correlated responses to selection for intramuscular fat in several muscles in rabbits. AB - The aim of this study was to evaluate the effect of six generations of selection for intramuscular fat (IMF) in muscle Longissimus thoracis et lumborum (LTL) at 9 wk. in IMF and fatty acid (FA) composition of muscles with diverse metabolic profile in rabbits. Direct response to selection was 0.33 g of IMF/ 100 g of LTL, around 0.4 SD per generation. A positive correlated response was observed in IMF of Biceps femoris, Supraspinatus and Semimembranosus proprius muscles at 9 wk., representing around 0.2 SD of the trait per generation. Selection affected similarly the FA composition of all muscles at 9 wk., high-IMF line showing greater monounsaturated but lower polyunsaturated FA percentages than low-IMF line, whereas no differences were observed for saturated FA. Traits were also measured at 13 wk. and correlated responses were in the same direction. Our results suggest a common genetic background for IMF and FA composition in muscles with different metabolic profile in rabbits. PMID- 29428884 TI - Zinc-protoporphyrin content in commercial Parma hams is affected by proteolysis index and marbling. AB - The contents of zinc-protoporphyrin (ZnPP) and heme in twenty-four sliced Parma hams made without the addition of curing agents were determined. Expressed on a dry weight basis, ZnPP averaged 45 mg/kg and ranged from 23 to 85 mg/kg. The heme content averaged 37 mg/kg on a dry matter basis and ranged from 17 to 73 mg/kg. A Principal Component Analysis (PCA) and Partial Least Squares (PLS) regression analyses were carried out to examine the existing correlations between these pigments and various physicochemical parameters in the final product. PCA showed the existence of associations between ZnPP, sensory redness and salt content. PLS suggests that the conversion of ZnPP from heme is facilitated in those hams with a higher proteolysis index and higher marbling. PMID- 29428885 TI - Occurrence of Staphylococcus aureus in swine and swine workplace environments on industrial and antibiotic-free hog operations in North Carolina, USA: A One Health pilot study. AB - Occupational exposure to swine has been associated with increased Staphylococcus aureus carriage, including antimicrobial-resistant strains, and increased risk of infections. To characterize animal and environmental routes of worker exposure, we optimized methods to identify S. aureus on operations that raise swine in confinement with antibiotics (industrial hog operation: IHO) versus on pasture without antibiotics (antibiotic-free hog operation: AFHO). We associated findings from tested swine and environmental samples with those from personal inhalable air samplers on worker surrogates at one IHO and three AFHOs in North Carolina using a new One Health approach. We determined swine S. aureus carriage status by collecting swab samples from multiple anatomical sites, and we determined environmental positivity for airborne bioaerosols with inhalable and impinger samplers and a single-stage impactor (ambient air) cross-sectionally. All samples were analyzed for S. aureus, and isolates were tested for antimicrobial susceptibility, absence of scn (livestock marker), and spa type. Seventeen of twenty (85%) swine sampled at the one IHO carried S. aureus at >1 anatomical sites compared to none of 30 (0%) swine sampled at the three AFHOs. All S. aureus isolates recovered from IHO swine and air samples were scn negative and spa type t337; almost all isolates (62/63) were multidrug resistant. S. aureus was recovered from eight of 14 (67%) ambient air and two (100%) worker surrogate personal air samples at the one IHO, whereas no S. aureus isolates were recovered from 19 ambient and six personal air samples at the three AFHOs. Personal worker surrogate inhalable sample findings were consistent with both swine and ambient air data, indicating the potential for workplace exposure. IHO swine and the one IHO environment could be a source of potential pathogen exposure to workers, as supported by the detection of multidrug-resistant S. aureus (MDRSA) with livestock-associated spa type t337 among swine, worker surrogate personal air samplers and environmental air samples at the one IHO but none of the three AFHOs sampled in this study. Concurrent sampling of swine, personal swine worker surrogate air, and ambient airborne dust demonstrated that IHO workers may be exposed through both direct (animal contact) and indirect (airborne) routes of transmission. Investigation of the effectiveness of contact and respiratory protections is warranted to prevent IHO worker exposure to multidrug-resistant livestock-associated S. aureus and other pathogens. PMID- 29428886 TI - Family size effects on childhood obesity: Evidence on the quantity-quality trade off using the NLSY. AB - In this study, we use matched mother-child data from the National Longitudinal Surveys to study the effects of family size on child health. Focusing on excess body weight indicators as children's health outcome of interest, we examine the effects of exogenous variations in family size generated by twin births and parental preference for mixed sex composition of their children. We find no significant empirical support in favor of the quantity-quality trade-off theory in instrumental variable regression analysis. This result is further substantiated when we make use of the panel aspects of the data to study child health outcomes of arrival of younger siblings at later parities. Specifically, when we employ child fixed effects analysis, results suggest that birth of a younger sibling is related to a decline in the likelihood of being overweight by 4 percentage points and a drop in the probability of illness by approximately 5 percentage points. PMID- 29428887 TI - Older Maori understandings of alcohol use in Aotearoa/New Zealand. AB - BACKGROUND: The predominant framing of indigenous people's alcohol use as problematic has resulted in narrow understandings of indigenous alcohol use in general. In particular, there has been little exploration of how Maori, those indigenous to Aotearoa/New Zealand, contextualise and understand their alcohol use. To build on current understandings of Maori alcohol use, this study explored the broader and socially shared meanings of alcohol use from the perspectives of older Maori. METHODS: Hui (meeting/s) were held with five kaupapa whanau (groups with a common purpose) comprising older Maori (n = 19) who shared their perspectives on Maori alcohol use. Data were analysed using a master/counter discursive narrative analytical framework. RESULTS: The results show that older Maori drew on a number of discursive strategies to construct three cultural narratives of Maori alcohol use. These were: 'Not all Maori are problem drinkers', 'There is good Maori alcohol use', and 'Alcohol is not the problem'. These narratives simultaneously supported and challenged the dominant narrative that problematises Maori alcohol use. CONCLUSION: These findings can be used to inform future research to show Maori understandings of alcohol use. Such research will support the development of culturally responsive alcohol policy and health promotion initiatives aimed at addressing alcohol related issues among Maori and thereby improve Maori health and wellbeing. PMID- 29428888 TI - Medical provision and urban-rural differences in maternal mortality in late nineteenth century Scotland. AB - This paper examines the effect of variable reporting and coding practices on the measurement of maternal mortality in urban and rural Scotland, 1861-1901, using recorded causes of death and women who died within six weeks of childbirth. This setting provides data (n = 604 maternal deaths) to compare maternal mortality identified by cause of death with maternal mortality identified by record linkage and to contrast urban and rural settings with different certification practices. We find that underreporting was most significant for indirect causes, and that indirect causes accounted for a high proportion of maternal mortality where the infectious disease load was high. However, distinguishing between indirect and direct maternal mortality can be problematic even where cause of death reporting appears accurate. Paradoxically, underreporting of maternal deaths was higher in urban areas where deaths were routinely certified by doctors, and we argue that where there are significant differences in medical provision and reported deaths, differences in maternal mortality may reflect certification practices as much as true differences. Better health services might therefore give the impression that maternal mortality was lower than it actually was. We end with reflections on the interpretation of maternal mortality statistics and implications for the concept of the obstetric transition. PMID- 29428889 TI - A mini-multiplex SNaPshot assay for the triage of degraded human DNA. AB - Short Tandem Repeat (STR) genotyping is currently the primary DNA-based method for human identification, however it can have limited success when applied to degraded human remains. Massively parallel sequencing (MPS) provides new opportunities to obtain genetic data for hundreds of loci in a single assay with higher success from degraded samples. However, due to the extra requirement for specialised equipment, expertise and resources, routine use of MPS may not be feasible or necessary for many forensic cases. Here we describe the development of a mini-multiplex SNaPshot screening tool (Miniplex) for human samples which allows the qualitative comparison of short mitochondrial and nuclear DNA targets, as well as the interrogation of biogeographic ancestry, lineage, and phenotype single nucleotide polymorphisms (SNPs). This tool is useful to triage samples based on sample quality prior to downstream identification workflows and provides broad biological profile data for intelligence purposes. PMID- 29428890 TI - Construction and forensic genetic characterization of 11 autosomal haplotypes consisting of 22 tri-allelic indels. AB - Insertion/deletion polymorphisms (indels), which combine the advantages of both short tandem repeats and single-nucleotide polymorphisms, are suitable for parentage testing. To overcome the limitations of the low polymorphism of di allelic indels, we constructed a set of haplotypes with physically linked, multi allelic indels. Candidate haplotypes were selected from the 1000 Genomes Project database, and were subject to the following criteria for inclusion: (i) each marker must have a minimum allele frequency (MAF) of >=0.1 in the Han population of China; (ii) markers must exist in a non-coding region; (iii) the physical distance between a pair of candidate indels must be <500 bp; (iv) the allele length variation of each indel from 1 to 20 bp; (v) different haplotypes must be located on different chromosomes or chromosomal arms, or be more than 10 Mb apart if on the same chromosomal arm; and (vi) they must not be located across a recombination hotspot. A multiplex system with 11 haplotype markers, comprising 22 tri-allelic indel loci distributed over 10 chromosomes was developed. To validate the multiplex panel, we investigated the haplotype distribution in sets of two and three-generation pedigrees. The results demonstrated that the haplotypes consisting of multi-allelic indel markers exhibited higher polymorphism than a single indel locus, and thus provide Supplementary information for forensic kinship identification. PMID- 29428891 TI - Evaluation of parentage testing accuracy of child trafficking cases: Combining the exclusion probability and likelihood ratio approaches. AB - The Chinese government established a national anti-trafficking DNA database in 2009 to help reunite trafficked children with their families. The database collects DNA information from missing children's parents, trafficked and homeless children, then conducts parentage testing using 18 or more loci to find matched pairs. This article evaluates the matching accuracy of parentage testing in child trafficking cases, under both Hardy-Weinberg equilibrium and population substructure. Both one-parent and two-parent scenarios are considered, and mutations are taken into account. The number of random matches is first evaluated using exclusion probability (PE). It is found that there are a large number of single parent-child pairs that match at 18 loci, but the PE approach cannot tell which are the true positive ones. The likelihood ratio (LR) approach can help distinguish the true positive matches. So the second step is to obtain the true positive rate and false positive rate of matched pairs of single parent and child according to the LR approach. Based on the results of the two-step procedure, it is concluded that more than 18 loci should be used to ensure a correct match of single parent and child. PMID- 29428892 TI - A stimuli-responsive fluorescence platform for simultaneous determination of d isoascorbic acid and Tartaric acid based on Maillard reaction product. AB - An activatable fluorescence monitoring platform based on a novel Maillard reaction product from d-glucose and L-arginine was prepared through a facile one pot approach and applied for simultaneous detection of d-isoascorbic acid and tartaric acid. In this work, the new Maillard reaction product GLA was first obtained, and its fluorescence intensity can be effectively quenched by KMnO4, resulting from a new complex (GLA-KMnO4) formation between GLA and KMnO4. Upon addition of d-isoascorbic acid or tartaric acid, an enhanced fluorescence was observed under the optimumed experimental conditions, indicating a stimuli responsive fluorescence turn on platform for d-isoascorbic acid or tartaric acid can be developed. The corresponding experimental results showed that this turn on fluorescence sensing platform has a high sensitivity for d-isoascorbic acid or tartaric acid, because the detection limits were 5.9MUM and 21.5MUM, respectively. Additionally, this proposed sensing platform was applied to simultaneously detection of d-isoascorbic acid and tartaric acid in real tap water samples with satisfactory results. PMID- 29428893 TI - Detailed solvent, structural, quantum chemical study and antimicrobial activity of isatin Schiff base. AB - The ratios of E/Z isomers of sixteen synthesized 1,3-dihydro-3-(substituted phenylimino)-2H-indol-2-one were studied using experimental and theoretical methodology. Linear solvation energy relationships (LSER) rationalized solvent influence of the solvent-solute interactions on the UV-Vis absorption maxima shifts (numax) of both geometrical isomers using the Kamlet-Taft equation. Linear free energy relationships (LFER) in the form of single substituent parameter equation (SSP) was used to analyze substituent effect on pKa, NMR chemical shifts and numax values. Electron charge density was obtained by the use of Quantum Theory of Atoms in Molecules, i.e. Bader's analysis. The substituent and solvent effect on intramolecular charge transfer (ICT) were interpreted with the aid of time-dependent density functional (TD-DFT) method. Additionally, the results of TD-DFT calculations quantified the efficiency of ICT from the calculated charge transfer distance (DCT) and amount of transferred charge (QCT). The antimicrobial activity was evaluated using broth microdilution method. 3D QSAR modeling was used to demonstrate the influence of substituents effect as well as molecule geometry on antimicrobial activity. PMID- 29428894 TI - Optimizing laser crater enhanced Raman scattering spectroscopy. AB - The laser crater enhanced Raman scattering (LCERS) spectroscopy technique has been systematically studied for chosen sampling strategy and influence of powder material properties on spectra intensity enhancement. The same nanosecond pulsed solid state Nd:YAG laser (532 nm, 10 ns, 0.1-1.5 mJ/pulse) was used for laser crater production and Raman scattering experiments for l-aspartic acid powder. Increased sampling area inside crater cavity is the key factor for Raman signal improvement for the LCERS technique, thus Raman signal enhancement was studied as a function of numerous experimental parameters including lens-to-sample distance, wavelength (532 and 1064 nm) and laser pulse energy utilized for crater production. Combining laser pulses of 1064 and 532 nm wavelengths for crater ablation was shown to be an effective way for additional LCERS signal improvement. Powder material properties (particle size distribution, powder compactness) were demonstrated to affect LCERS measurements with better results achieved for smaller particles and lower compactness. PMID- 29428895 TI - Analysis of laser printer and photocopier toners by spectral properties and chemometrics. AB - The use of printers to generate falsified documents has become a common practice in today's world. The examination and identification of the printed matter in the suspected documents (civil or criminal cases) may provide important information about the authenticity of the document. In the present study, a total number of 100 black toner samples both from laser printers and photocopiers were examined using diffuse reflectance UV-Vis Spectroscopy. The present research is divided into two parts; visual discrimination and discrimination by using multivariate analysis. A comparison between qualitative and quantitative analysis showed that multivariate analysis (Principal component analysis) provides 99.59%pair-wise discriminating power for laser printer toners while 99.84% pair-wise discriminating power for photocopier toners. The overall results obtained confirm the applicability of UV-Vis spectroscopy and chemometrics, in the nondestructive analysis of toner printed documents while enhancing their evidential value for forensic applications. PMID- 29428896 TI - Research on the differences between 2-(2-Chlorophenyl)benzimidazole and 2-(4 Chlorophenyl)benzimidazole based on terahertz time domain spectroscopy. AB - Due to wide variety of biological and pharmacological activities of benzimidazole derivatives, the differences between 2-(2-Chlorophenyl)benzimidazole and 2-(4 Chlorophenyl) benzimidazole were researched by employing terahertz time-domain spectroscopy and density functional theory systematically. Although the only difference between their molecular configurations is the arrangement of chlorine atom on chlorophenyl ring, there are distinctive differences in their fingerprint spectra in the range of 0.2-2.5THz, such as amount, amplitude, and frequency position of absorption peaks. The validity of these results was confirmed by the theoretical results simulated by using density functional theory. The possible reasons of these differences originate from the different van der Waals forces and the different dihedral angles of the molecules within crystal cell. These results indicate the importance of this spectral range as a conformational fingerprint region where even minor changes in the molecular configuration lead to major differences in its THz absorption. PMID- 29428897 TI - The E3Sigma1+ (63S1)<-A3Pi0+(53P1) transition in CdAr revisited: The spectrum and new analysis of the E3Sigma1+ Rydberg state interatomic potential. AB - Revisited study of the E3Sigma1+ (63S1)<-A3Pi0+(53P1) transition in CdAr using both theoretical and experimental approach is presented. Systematic detection of the E3Sigma1+in,upsilon'<-A3Pi0+,upsilon"=6 transition frequencies with higher accuracy and spectrally narrower laser extended and improved analysis and simulation of the LIF excitation spectrum. More consistent characterization of the E3Sigma1+in-Rydberg state inner well using inversed perturbation approach methodology was achieved. Free<-bound transitions in the E3Sigma1+in< A3Pi0+,upsilon"=6 excitation were taken into account in the analysis and simulation of the recorded spectrum. The updated spectroscopic characterization of the A3Pi0+ state was also revisited. PMID- 29428898 TI - A fluorescent sensor based on thioglycolic acid capped cadmium sulfide quantum dots for the determination of dopamine. AB - A fluorescent sensor based on thioglycolic acid-capped cadmium sulfide quantum dots (TGA-CdS QDs) has been designed for the sensitive and selective detection of dopamine (DA). In the presence of dopamine (DA), the addition of 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) activates the reaction between the carboxylic group of the TGA and the amino group of dopamine to form an amide bond, quenching the fluorescence of the QDs. The fluorescence intensity of TGA-CdS QDs can be used to sense the presence of dopamine with a limit of detection of 0.68MUM and a working linear range of 1.0 17.5MUM. This sensor system shows great potential application for dopamine detection in dopamine drug samples and for future easy-to-make analytical devices. PMID- 29428899 TI - Efficacy of lacosamide in children and adolescents with drug-resistant epilepsy and refractory status epilepticus: A systematic review. AB - PURPOSE: Lacosamide, is one of the newer antiepileptic drug approved for focal drug-resistant epilepsy as an add-on treatment in patients older than 16 years. However, there is growing evidence of its use, safety and efficacy in children. We aim to evaluate efficacy and tolerability of lacosamide in focal and generalized drug-resistant epilepsy and refractory status epilepticus in the pediatric population. METHODS: We conducted a systematic review on MEDLINE, EMBASE, COCHRANE, Google Scholar and Scielo from January 2008 to January 2017. The primary outcome was the efficacy of lacosamide in children with drug resistant epilepsy and refractory status epilepticus. Efficacy and adverse events attributed to lacosamide were extracted from each publication and systematically reported. We performed no meta-analyses due to limited available data. RESULTS: Of 175 abstracts identified by the search, 82 were reviewed as full-text. Twenty six articles fulfilled eligibility criteria and described outcomes in 797 patients (57% male). The majority of studies were retrospective (69%) small series (84%). On average 51% of patients had 50% or greater seizure reduction. The mean seizure freedom rate was 24%. Adverse effects occurred in 18-59% of patients. The main events were dizziness, sedation, gastrointestinal upset, mood and behavioral changes. Half of the patients with Lennox Gastaut syndrome showed 50% or greater seizure reduction, 32% did not response to lacosamide and 17% suffered seizure aggravation. CONCLUSION: Current evidence shows lacosamide as a good option in pediatric patients with focal drug-resistant epilepsy and refractory status epilepticus as an add-on therapy given its efficacy on seizure control and safety profile. The use of lacosamide in Lennox-Gastaut syndrome shows conflicting data. Large randomized controlled studies in the pediatric population are necessary to substantiate these findings. PMID- 29428900 TI - The provision of care to adults with an intellectual disability in the UK. A Special report from the intellectual disability UK chapter ILAE. AB - PURPOSE: This article reflects the report by the British Branch of the International League Against Epilepsy (ILAE) Working Group on services for adults with epilepsy and intellectual disability (ID). Its terms of reference was to explore the current status of aspects of the care of people with an ID and epilepsy. METHODS: Survey content was developed from key themes identified by consensus of the working group. An electronic survey was distributed via email. The sample population was the membership of the ILAE UK, Royal College of Psychiatrists (RCPsych) Faculty of ID, Epilepsy Nurses Association (ESNA), and the Association of British Neurologists (ABN). Following a six week response period the data was then collated, anonymised and distributed to the working group in order that opinion statements could be gathered. RESULTS: The time taken for individuals with both new-onset and established epilepsy to undergo routine investigation was commonly at least 1-3 months, far beyond recommendations made by NICE (CG20). A small minority of clinicians would not consider non pharmacological interventions including epilepsy surgery, vagus nerve stimulation, and ketogenic diet for this population. Almost universally responders are actively involved in the assessment and management of key risk areas including risk of drowning, hospitalization, medication side effects, and sudden unexpected death in epilepsy (SUDEP). CONCLUSION: This investigation identifies key themes and recommendations relating to care delivery and meeting the complex needs of people with ID and epilepsy. Adults with ID and epilepsy appear to exist in a unique, but inadequate, segment of epilepsy care delivery. PMID- 29428901 TI - Fragile X mental retardation protein participates in non-coding RNA pathways. AB - Fragile X syndrome is one of the most common forms of inherited intellectual disability. It is caused by mutations of the Fragile X mental retardation 1(FMR1) gene, resulting in either the loss or abnormal expression of the Fragile X mental retardation protein (FMRP). Recent research showed that FMRP participates in non coding RNA pathways and plays various important roles in physiology, thereby extending our knowledge of the pathogenesis of the Fragile X syndrome. Initial studies showed that the Drosophila FMRP participates in siRNA and miRNA pathways by interacting with Dicer, Ago1 and Ago2, involved in neural activity and the fate determination of the germline stem cells. Subsequent studies showed that the Drosophila FMRP participates in piRNA pathway by interacting with Aub, Ago1 and Piwi in the maintenance of normal chromatin structures and genomic stability. More recent studies showed that FMRP is associated with lncRNA pathway, suggesting a potential role for the involvement in the clinical manifestations. In this review, we summarize the novel findings and explore the relationship between FMRP and non-coding RNA pathways, particularly the piRNA pathway, thereby providing critical insights on the molecular pathogenesis of Fragile X syndrome, and potential translational applications in clinical management of the disease. PMID- 29428902 TI - Recent advance on genome editing for therapy of beta-hemoglobinopathies. AB - beta-hemoglobinopathies are one of six groups of common illnesses affecting human health. Although the genetic mechanisms have been elucidated for several decades, curable treatment options, other than allogeneic bone marrow transplantation, are still lacking. In recent years, rapid development in genome editing technologies and their clinical applications have opened up new directions for treatment of beta-hemoglobinopathies. Genome editing technologies, as applied in autologous CD34 + hematopoietic stem and progenitor cells, represents a promising remedial means for the beta-globin disorders. Hemoglobin gene mutations could be corrected with homologous recombination-mediated DNA repair pathway to repair the genetic defects, while the nonhomologous end-joining pathway may be used to silence the key repressor of fetal globin expression and reactivate fetal hemoglobin expression, thereby alleviating the clinical symptoms of beta-hemoglobinopathies in patients. This review summarizes the recent advances on genome editing of beta hemoglobinopathies from the bench design to the establishment of clinical translational platforms, thereby providing critical insights and references on the application of genome editing technologies for the development of therapeutic strategies for beta-hemoglobinopathies. PMID- 29428903 TI - Research progress of epigenetic biomarkers in the early diagnosis and treatment of human diseases. AB - Abnormal epigenetic modifications are common in many diseases (such as tumors, senile and developmental diseases), and can influence the pathogenesis and progression of these diseases. Various studies demonstrated that abnormal epigenetic changes could be used as biomarkers for diagnosis of the disease status and prognosis of disease progression. The reversibility and controllability of epigenetic modifications also offer an opportunity to develop new strategies for the early prevention and treatment of diseases. In this review, we provide a brief overview of the latest discoveries in three areas of epigenetic research, i.e., DNA methylation, histone modifications and non-coding RNAs, and their potential applications in early diagnosis and treatment of tumors, senile and developmental diseases. We hope to provide some insights and references in developing strategies for the diagnosis and treatment of these diseases. PMID- 29428904 TI - Developmental disorder of podocytes and the related renal diseases. AB - Podocyte is one of the main components of glomerular filtration barrier in the kidney; the loss or dysfunction of podocyte could impair the functions of glomerular filtration barrier, leading to development of various renal diseases. Podocyte is a terminally differentiated cell, and thus does not possess any proliferative properties. Accordingly, its number and contribution to renal function are initially determined by its normal development. Information from the literature and results of our research indicate that genetic factors or prenatal adverse environment could cause developmental retardation of podocytes, thereby suggesting the potential fetal developmental origin(s) of kidney diseases, and involvement of epigenetic mechanisms in the regulation of key genes in podocyte development. In this review, we provide a brief overview on the podocyte normal development; discussion on the potential pathogenic mechanisms for developmental disorders of podocytes; as well as renal diseases associated with podocyte developmental retardation. We aim to provide some insights in articulating the strategies for diagnosis and treatments of renal diseases associated with podocyte developmental abnormalities. PMID- 29428905 TI - Research progress of the bitter taste receptor genes in primates. AB - Among the five basic tastes (umami, sweet, bitter, salty and sour), the perception of bitterness is believed to protect animals from digesting toxic and harmful substances, thus it is vital for animal survival. The taste of bitterness is triggered by the interaction between bitter substances and bitter taste receptors, which are encoded by Tas2rs. The gene numbers vary largely across species to meet different demands. So far, several ligands of bitter receptors have been identified in primates. They also discovered that the selective pressure of certain bitter taste receptor genes vary across taxa, genes or even different functional regions of the gene. In this review, we summarize the research progress of bitter taste receptor genes in primates by introducing the functional diversity of bitter receptors, the specific interaction between bitter taste receptors and ligands, the relationship between the evolutionary pattern of bitter taste receptors and diets, and the adaptive evolution of bitter taste receptor genes. We aim to provide a reference for further research on bitter receptor genes in primates. PMID- 29428906 TI - Structural characteristics of natural chimeric genes and their implications for gene design. AB - The natural chimeric gene is a novel gene fused by two or more independent genes. Its discovery extends the classical gene concept that one gene resides in one chromosomal locus. During tumorigenesis, many chimeric genes lead to tumor related diseases; therefore, it is one molecular marker for cancer diagnosis. In this review, we summarize the research progress of chimeric genes in terms of their feature, structure, transcription, regulation and function. We pinpoint the difficulties and challenges in the current research work, and discuss the application of chimeric gene in the new gene design. PMID- 29428907 TI - Generation of Chimeric RNAs by cis-splicing of adjacent genes (cis-SAGe) in mammals. AB - Chimeric RNA molecules, possessing exons from two or more independent genes, are traditionally believed to be produced by chromosome rearrangement. However, recent studies revealed that cis-splicing of adjacent genes (cis- SAGe) is one of the major mechanisms underlying the formation of chimeric RNAs. cis-SAGe refers to intergenic splicing of directly adjacent genes with the same transcriptional orientation, resulting in read-through transcripts, termed chimeric RNAs, which contain sequences from two or more parental genes. cis-SAGe was first identified in tumor cells, since then its potential in carcinogenesis has attracted extensive attention. More and more scientists are focusing on it. With the development of research, cis-SAGe was found to be ubiquitous in various normal tissues, and might make a crucial contribution to the formation of novel genes in the evolution of genomes. In this review, we summarize the splicing pattern, expression characteristics, possible mechanisms, and significance of cis-SAGe in mammals. This review will be helpful for general understanding of the current status and development tendency of cis-SAGe. PMID- 29428908 TI - Molecular cloning and expression analysis of the tyramine
receptor genes in Apis cerana cerana. AB - Tyramine is a biological polyamine, which serves important functions as neurotransmitters, neuromodulators and neurohormone of the central nervous system. It participates in the regulation of various behavior and physiological processes in insects. For example, tyramine and its receptor genes are involved in the regulation of learning and memory in the animals. In this study, the full length cDNA sequences of the tyramine receptor genes (Actyr1 and Actyr2) of the Chinese honeybee, Apis cerana cerana, were cloned and sequenced for the first time. Their expression patterns were examined in different tissues by qRT-PCR and localized in the head by in situ hybridization with digoxigenin (DIG)-labeled RNA probes. The full-length cDNAs of Actyr1 and Actyr2 are 1241 bp (GenBank accession no. KC814693) and 1270 bp (GenBank accession no.KC814693) in length and encode 297 amino acids and 399 amino acids, respectively. qRT-PCR results showed that the expression levels of both Actyr1 and Actyr2 were the highest in the head, followed by the abdomen, then the antennae and the lowest in the thorax. The expression level in the head was significantly higher than that in other tissues. Moreover, in situ hybridization showed that the expression of Actyr1 and Actyr2 genes were mainly localized to the Kenyon cells of the mushroom bodies and cells around the antennal lobes. These observations suggest that some interactions between these two genes in certain cells could be important in regulating various biological functions, such as learning and memory, in the honeybee. PMID- 29428909 TI - Comparison of common burden tests for genetic association studies of rare variants. AB - Common burden tests have different statistical performance in genetic association studies of rare variants. Here, we compare the statistical performance of burden tests, such as CMC, WST, SUM and extension methods, using the computer-simulated datasets of rare variants with different parameters of sample sizes, linkage disequilibrium (LD), and different numbers of mixed non-associated variants. The simulation results showed that the type I error for all methods is near 0.05. When the rare variants had the same direction of effect, the higher LD and the less non-associated variants, the higher the power of these method, except the data adaptive SUM test. When the direction was different, the power was significantly reduced for all methods. The methods that consider the direction yielded larger statistical power than those methods without considering the effect direction, except the strong LD condition. And the larger the sample size, the larger the power. The statistical performance of burden tests is affected by a variety of factors, including the sample size, effect direction of variants, non-associated variants, and LD. Therefore, when choosing the method and setting the collection unit and weight, the prior biological information of genetic variation should be integrated to improve study efficiency. PMID- 29428910 TI - A Review of CRISPR-Based Genome Editing: Survival, Evolution and Challenges. AB - Precise nucleic acid editing technologies have facilitated the research of cellular function and the development of novel therapeutics, especially the current programmable nucleases-based editing tools, such as the prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)-associated nucleases (Cas). As CRISPR-based therapies are advancing toward human clinical trials, it is important to understand how natural genetic variation in the human population may affect the results of these trials and even patient safety. The development of "base-editing" technique allows the direct, stable transformation of target DNA base into an alternative in a programmable way, without DNA double strand cleavage or a donor template. Genome-editing techniques hold promises for the treatment of genetic disease at the DNA level by blocking the sequences associated with disease from producing disease-causing proteins. Currently, scientists can select the gene they want to modify, use the Cas9 as a "molecular cutter" to cut it out, and transform it into a more desirable version. In this review, we focus on the recent advances of CRISPR/Cas system by outlining the evolutionary and biotechnological implications of current strategies for improving the specificity and accuracy of these genome-editing technologies. PMID- 29428911 TI - Illness script development in pre-clinical education through case-based clinical reasoning training. AB - Objectives: To assess illness script richness and maturity in preclinical students after they attended a specifically structured instructional format, i.e., a case based clinical reasoning (CBCR) course. Methods: In a within-subject experimental design, medical students who had finished the CBCR course participated in an illness script experiment. In the first session, richness and maturity of students' illness scripts for diseases discussed during the CBCR course were compared to illness script richness and maturity for similar diseases not included in the course. In the second session, diagnostic performance was tested, to test for differences between CBCR cases and non-CBCR cases. Scores on the CBCR course exam were related to both experimental outcomes. Results: Thirty two medical students participated. Illness script richness for CBCR diseases was almost 20% higher than for non-CBCR diseases, on average 14.47 (SD=3.25) versus 12.14 (SD=2.80), respectively (p<0.001). In addition, students provided more information on Enabling Conditions and less on Fault-related aspects of the disease. Diagnostic performance was better for the diseases discussed in the CBCR course, mean score 1.63 (SD=0.32) versus 1.15 (SD=0.29) for non-CBCR diseases (p<0.001). A significant correlation of exam results with recognition of CBCR cases was found (r=0.571, p<0.001), but not with illness script richness (r= 0.006, p=NS). Conclusions: The CBCR-course fosters early development of clinical reasoning skills by increasing the illness script richness and diagnostic performance of pre-clinical students. However, these results are disease-specific and therefore we cannot conclude that students develop a more general clinical reasoning ability. PMID- 29428912 TI - Survival of Children Living with Human Immunodeficiency Virus on Antiretroviral Therapy in Andhra Pradesh, India. AB - OBJECTIVE: To assess the survival probability and associated factors among children living with human immunodeficiency virus (CLHIV) receiving antiretroviral therapy (ART) in India. METHODS: The data on 5874 children (55% boys) from one of the high HIV burden states of India from the cohort were analyzed. Data were extracted from the computerized management information system of the National AIDS Control Organization (NACO). Children were eligible for inclusion if they had started ART during 2007-2013, and had at least one potential follow-up. Kaplan Meier survival and Cox proportional hazards models were used to measure survival probability. RESULTS: The baseline median (IQR) CD4 count at the start of antiretroviral therapy was 244 (153, 398). Overall, the mortality was 30 per 1000 child years; 39 in the <5 year age group and 25 in 5-9 year age group. Mortality was highest among infants (86 per 1000 child years). Those with CD4 count <= 200 were six times more likely to die (adjusted HR: 6.3, 95% CI 3.5, 11.4) as compared to those with a CD4 count of >=350/mm3. CONCLUSION: Mortality rates among CLHIV is significantly higher among children less than five years when the CD4 count at the start of ART is above 200. Additionally, lower CD4 count, HIV clinical staging IV, and lack of functional status seems to be associated with high mortality in children who are on ART. PMID- 29428913 TI - Anti-HBs Titers Following Pentavalent Immunization (DTwP-HBV-Hib) in Term Normal Weight vs Low Birthweight Infants. AB - OBJECTIVE: To compare anti-HBs titers between term low birth weight (1800-2499 g) infants and normal birthweight infants, 6 weeks after last dose of primary immunization with pentavalent vaccine, and to study adverse events following immunization (AEFI) with pentavalent vaccine. DESIGN: Cohort study. SETTING: Tertiary-care hospital predominantly catering to urban poor population of East Delhi. PARTICIPANTS: 265 low birthweight (1800-2499 g) and 265 normal birthweight (2500-4000 g) infants. Monovalent Hepatitis B vaccine was administered within 24 hours of birth followed by three primary doses of pentavalent vaccine at 6, 10 and 14 weeks. Anti-HBs titers were estimated after 6 weeks of third dose of pentavalent vaccine. Adverse events following immunization (AEFI) month were observed for a month after each dose of pentavalent vaccine. MAIN OUTCOME MEASURES: Anti HBs antibody titers after 6 weeks of primary immunization, and AEFI. RESULTS: 443 (83.5%) infants (225 low birthweight and 218 normal birthweight infants) completed the follow-up. Seroprotection against hepatitis B virus was achieved in both groups after pentavalent vaccine administration. Anti HBs GMTs in low birthweight infants (194.8 mIU/mL) and normal birthweight infants (204.2 mIU/mL) were comparable (P = 0.17). No serious adverse events were observed in either group. CONCLUSIONS: Three primary doses of pentavalent vaccine administered along with zero dose of Hepatitis B vaccine at birth provide good seroprotection. The vaccine appears to be safe in both low birth weight and normal birthweight infants born at term. PMID- 29428914 TI - Serum Interleukin-6 Levels in Children with Febrile Seizures. AB - OBJECTIVE: To compare levels of Interleukin-6 (IL-6) in children with febrile seizures and febrile controls. METHODS: Study conducted in a tertiary-care hospital in Northern India from November 2013 to April 2015, enrolling 160 children (80 each with febrile seizures and febrile controls), aged 6 - 60 months. Serum IL-6 estimated by ELISA method. Iron study done as per standard technique. All the cases of febrile seizure were followed up at 1 week, 3 months and 6 months for recurrence of seizures. RESULTS: The mean serum IL-6 levels in children with febrile seizures was 62.0 (63.9) pg/mL and febrile controls was 86.9 (70.6) pg/mL (P=0.025). CONCLUSION: Serum IL-6 levels were significantly lower in children with febrile seizures as compared to febrile controls. PMID- 29428915 TI - Second Dose of Scorpion Antivenom in Children with Indian Red Scorpion (Mesobuthus tamulus) Sting Envenomation. AB - OBJECTIVE: To study the effect of the second dose of scorpion antivenom in children with non-resolving or worsening scorpion sting envenomation. METHODS: 72 children aged <=12 years with scorpion sting envenomation grade 2 and above were enrolled. 61 received the first dose of three vials of antivenom at admission (group A). Children with persistent/worsening envenomation at 6 hours received the second dose (group B). The time required for resolution of autonomic symptoms, myocardial dysfunction, predictors of the second dose and side effects were studied. RESULTS: The mean time taken for resolution of autonomic symptoms were similar in GroupA and B (4.1 vs. 5.3 hours, P=0.452), and of myocardial dysfunction was shorter in Group A (10.8 vs. 37.6 hours, P=0.019). On regression analysis, abnormal echocardiography at admission was found to be a significant predictor of the second dose (OR=27.6, 95% CI, 4.7-162.5; P=<0.001). CONCLUSION: Children with severe scorpion sting envenomation with abnormal echocardiography may require a higher dose of scorpion antivenom. PMID- 29428916 TI - Clinical Profile of Neonates with Hypernatremic Dehydration in an Outborn Neonatal Intensive Care Unit. AB - This hospital-record review describes the clinical profile of hypernatremic dehydration in neonates. 49 neonates (3.4% of the total admitted newborns) developed hypernatremic dehydration between January 2014 and August 2015. The major presenting complaints were fever (34.6%), poor feeding (42.8%), loose stools (40.8%) and lethargy (26.5%). The mean (SD) time needed for correction of hypernatremia was 38.6 (15.1) hours. Exclusively breastfed neonates had lesser complication rates of hypernatremic dehydration. PMID- 29428917 TI - Correlation Between Blood Pressure Measurement by Non-invasive and Invasive Methods in Critically-ill Children. AB - OBJECTIVE: To determine the correlation of non-invasive blood pressure obtained by auscultatory and oscillometric methods, with invasive blood pressure in critically ill children. Methods: We compared invasive with auscultatory and oscillometric blood pressures using paired t-test, Pearson's correlation coefficient and Bland-Altman plot in 50 children (age 1-12 y) admitted in Pediatric intensive care unit. RESULTS: Systolic, diastolic, and mean arterial pressures of invasive methods significantly correlated with auscultatory and oscillometric methods (P<0.001). Auscultatory and oscillometric measurements under-estimated systolic arterial pressures [mean (SD) difference 5.4 (12.2) mmHg and 6.3 (14.0) mmHg, respectively; P<0.001] and overestimated diastolic arterial pressures [-4.1 (5.8) mmHg and -3.6 (7.2) mmHg; P<0.001] compared to invasive blood pressure. CONCLUSIONS: Mean arterial pressure obtained by NIBP measurement is more closer than systolic or diastolic pressures, when compared with invasive blood pressure measurement. PMID- 29428918 TI - Predictors and Outcome of Acute Kidney Injury in Children with Diabetic Ketoacidosis. AB - OBJECTIVE: To identify predictors and outcome of acute kidney injury (AKI) in children with diabetic ketoacidosis (DKA) admitted to a Pediatric Intensive Care Unit (PICU). METHODS: Retrospective case review of 79 children with DKA admitted between 2011-2014. RESULTS: Twenty eight children developed AKI during the hospital stay; 20 (71.4%) recovered with hydration alone. Serum chloride at 24 hours was independently associated with AKI. Children with AKI had prolonged acidosis and PICU stay and higher mortality. CONCLUSION: Majority of children with AKI and DKA, recover with hydration. Hyperchloremia at 24 hours had independent association with AKI, although cause-effect relation could not be ascertained. PMID- 29428919 TI - Pain Control Interventions in Preterm Neonates: A Randomized Controlled Trial. AB - OBJECTIVE: To compare individual efficacy and additive effects of pain control interventions in preterm neonates. DESIGN: Randomized controlled trial. SETTING: Level-3 University affiliated neonatal intensive care unit. PARTICIPANTS: 200 neonates (26-36 wk gestational age) requiring heel-prick for bedside glucose assessment. Exclusion criteria were neurologic impairment and critical illness precluding study interventions. INTERVENTION: Neonates were randomly assigned to Kangaroo mother care with Music therapy, Music therapy, Kangaroo Mother care or Control (no additional intervention) groups. All groups received expressed breast milk with cup and spoon as a baseline pain control intervention. MAIN OUTCOME MEASURES: Assessment of pain using Premature Infant Pain Profile (PIPP) score on recorded videos. RESULTS: The mean (SD) birth weight and gestational age of the neonates was 1.9 (0.3) kg and 34 (2.3) wk, respectively. Analysis of variance showed significant difference in total PIPP score across groups (P<0.001). Post hoc comparisons using Sheffe's test revealed that the mean (SD) total PIPP score was significantly lower in Kangaroo mother care group [7.7 (3.9) vs. 11.5 (3.4), 95% CI(-5.9, -1.7), P<0.001] as well as Kangaroo mother care with Music therapy group [8.5 (3.2) vs. 11.5 (3.4), 95%CI (-5.1, -0.9), P=0.001] as compared to Control group. PIPP score was not significantly different between Control group and Music therapy group. CONCLUSIONS: Kangaroo mother care with and without Music therapy (with expressed breast milk) significantly reduces pain on heel-prick as compared to expressed breast milk alone. Kangaroo mother care with expressed breast milk should be the first choice as a method for pain control in preterm neonates. PMID- 29428920 TI - Molecular Testing of MECP2 Gene in Rett Syndrome Phenotypes in Indian Girls. AB - OBJECTIVE: To assess yield of MECP2 gene sequence variations analysis and large deletions in suspected cases of Rett syndrome. DESIGN: Descriptive study. SETTING: Tertiary-care medical genetics center. PATIENTS: Girls with neuroregression, postnatal microcephaly and signs and symptoms suggestive of classical and atypical Rett syndrome were classified into two groups. Group I consisted of girls with Classical and atypical Rett syndrome on basis on the Revised Rett Syndrome diagnostic criteria, 2010. Group II included girls with neuroregression and postnatal microcephaly and other Rett like features but not fulfilling the above criteria. PROCEDURE: Sanger sequencing of coding regions and large deletional analysis of MECP2 gene. OUTCOME MEASURES: Identification of mutation in MECP2 gene. RESULTS: Mutation in MECP2 gene was identified in 74% (14/19) in group I and none (0/17) in group II. The mutation detection rate was 93% (13/14) in group I classical Rett syndrome girls (2 with large deletions identified with Multiplex ligation dependent probe amplification) and 20% (1/5) in group I atypical Rett syndrome girls. One novel MECP2 sequence variation was identified in group I classical Rett syndrome. CONCLUSIONS: The yield of the mutation detection in MECP2 is higher in classical Rett syndrome. In girls with some Rett like features, but not fulfilling revised Rett syndrome diagnostic criteria, mutation testing for MECP2 gene has a low yield. PMID- 29428921 TI - Long-term Seroprotection Rates Following Second Dose of Measles as MMR Vaccine at 15 months in Indian Children. AB - OBJECTIVE: To find out seropositivity rates at 4-6 and 9-12 years of age; among those who received one-dose measles at 9 months and one-dose MMR at 15 months of age. METHODS: 80 healthy children (53 males) at 4-6 or 9-12 years of age, attending outpatient department for vaccination were enrolled. Antibody titers were estimated using commercially available quantitative-IgG ELISA kits. RESULTS: The seropositivity rates against measles, mumps, rubella were 80% (40/50), 86% (43/50), and 96% (48/50), respectively at 4-6 years, and 83.3% (25/30), 96.7% (29/30) and 96.7% (29/30), respectively at 9-12 years of age. CONCLUSION: Single dose of rubella vaccine seems to provide adequate long-term protection; however, measles vaccine requires more doses for similar protection. PMID- 29428922 TI - Vitamin D Deficiency in Ambulant Children on Carbamazepine or Sodium Valproate Monotherapy. AB - OBJECTIVE: To assess the effect of monotherapy with Carbamazepine (CBZ) and Sodium valproate (VPA) on serum 25-OH Vitamin D levels in children with epilepsy compared to controls. DESIGN: Cross-sectional study. SETTING: Outpatient department of a tertiary-care Pediatric Neurology centre, and a nearby day-care centre and school. STUDY PERIOD: June 2012 to May 2013. PARTICIPANTS: Children with epilepsy aged 2 to 13 years on monotherapy with CBZ (n=28) or VPA (n=28) for at least 6 months; 109 age-matched controls from a nearby day-care centre and school. RESULTS: The median (IQR) values of 25 (OH) vitamin D was 18.0 ng/mL (13.7-27.3), 21.35 ng/mL (16.4 -25.2) and 30.5 ng/mL (19.1-43.7) in CBZ, VPA and control group, respectively (P= 0.008). 60.7% of patients in CBZ group and 35.7 % in VPA group had low 25 (OH) D levels (%20 ng/mL) compared to 27.8% in controls (P=0.001).The serum alkaline phosphatase level was higher in children on carbamazepine therapy (P=0.001) than controls. CONCLUSION: This study identifies significant risk of vitamin D deficiency in ambulant children with epilepsy on monotherapy with CBZ or VPA. PMID- 29428923 TI - Content Analysis of Commercially Available Probiotics. AB - We carried out content analysis of four batches each of 3 commercially available probiotic formulations of Bacillus clausii. Species identification was done using MALDI-TOF-MS technique while bacterial count was done using plate colony count. Only one of the three probiotic formulation analyzed was found to have homogeneous population of B. clausii while none was found to have the exact viable bacterial count as suggested on the label. PMID- 29428924 TI - Impact of Water, Sanitation and Hygiene Interventions on Growth, Non-diarrheal Morbidity and Mortality in Children Residing in Low- and Middle-income Countries: A Systematic Review. AB - OBJECTIVE: To evaluate the impact of water, sanitation and hygiene (WASH) interventions in children (age <18 y) on growth, non-diarrheal morbidity and mortality in children. DESIGN: Systematic review of randomized controlled trials, non-randomized controlled trials and controlled before-after studies. SETTING: Low- and middle-income countries. PARTICIPANTS: 41 trials with WASH intervention, incorporating data on 113055 children. INTERVENTION: Hygiene promotion and education (15 trials), water intervention (10 trials), sanitation improvement (7 trials), all three components of WASH (4 trials), combined water and sanitation (1 trial), and sanitation and hygiene (1 trial). OUTCOME MEASURES: (i) Anthropometry: weight, height, weight-for-height, mid-arm circumference; (ii) Prevalence of malnutrition; (iii) Non-diarrheal morbidity; and (iv) mortality. RESULTS: There may be little or no effect of hygiene intervention on most anthropometric parameters (low- to very-low quality evidence). Hygiene intervention reduced the risk of developing Acute respiratory infections by 24% (RR 0.76; 95% CI 0.59, 0.98; moderate quality evidence), cough by 10% (RR 0.90; 95% CI 0.83, 0.97; moderate quality evidence), laboratory-confirmed influenza by 50% (RR 0.5; 95% CI 0.41, 0.62; very low quality evidence), fever by 13% (RR 0.87; 95% CI 0.74, 1.02; moderate quality evidence), and conjunctivitis by 51% (RR 0.49; 95% CI 0.45, 0.55; low quality evidence). There was low quality evidence to suggest no impact of hygiene intervention on mortality (RR 0.65; 95% CI 0.25, 1.7). Improvement in water supply and quality was associated with slightly higher weight-for-age Z-score (MD 0.03; 95% CI 0, 0.06; low quality evidence), but no significant impact on other anthropometric parameters or infectious morbidity (low to very low quality evidence). There was very low quality evidence to suggest reduction in mortality (RR 0.45; 95% CI 0.25, 0.81). Improvement in sanitation had a variable effect on the anthropometry and infectious morbidity. Combined water, sanitation and hygiene intervention improved height-for-age Z scores (MD 0.22; 95% CI 0.12, 0.32) and decreased the risk of stunting by 13% (RR 0.87; 95% CI 0.81, 0.94) (very low quality of evidence). There was no evidence of significant effect of combined WASH interventions on non-diarrheal morbidity (fever, respiratory infections, intestinal helminth infection and school absenteeism) (low- to very-low quality of evidence). Any WASH intervention (considered together) resulted in lower risk of underweight (RR 0.81; 95% CI 0.69, 0.96), stunting (RR 0.77; 95% CI 0.68, 0.86) and wasting (RR 0.12, 0.85) (low- to very-low quality of evidence). CONCLUSIONS: Available evidence suggests that there may be little or no effect of WASH interventions on the anthropometric indices in children from low- and middle income countries. There is low- to very-low quality of evidence to suggest decrease in prevalence of wasting, stunting and underweight. WASH interventions (especially hygiene intervention) were associated with lower risk of non diarrheal morbidity (very low to moderate quality evidence). There was very low quality evidence to suggest some decrease to no change in mortality. These potential health benefits lend support to the ongoing efforts for provision of safe and adequate water supply, sanitation and hygiene. PMID- 29428925 TI - Adjuvant Therapy: YiqiDitanTongfu Decoction With External Diaphragm Pacer for Chronic Obstructive Pulmonary Disease Patients With Difficulty Weaning From Mechanical Ventilation. AB - : Context * Global morbidity from chronic obstructive pulmonary disease (COPD) is high worldwide. Diaphragm pacing (DP) can maintain the natural, negative pressure breathing of COPD patients with diaphragmatic muscle dysfunction. The YiqiDitanTongfu (YDTF) decoction has been used clinically with COPD patients to help them to wean from mechanical ventilation, with their ventilation functions being improved and the success rate of weaning being largely increased. Objective * The study intended to investigate the combined therapeutic effects of external DP and the YDTF decoction for COPD patients who have had difficulty weaning from mechanical ventilation. Design * This study was a retrospective cohort study. Setting * The study occurred at the Hebei General Hospital and Hebei Province Chest Hospital (Hebei Province, Shijiazhuang, China). Participants * Participants were 90 patients with COPD + type 1 respiratory failure, 101 patients with COPD + Type 2 respiratory failure, and 96 patients with COPD at the compensated stage. INTERVENTION: The participants were randomly divided into 3 groups: (1) traditional treatment (control group), (2) traditional treatment plus treatment with a diaphragm pacemaker (DP group), and (3) traditional treatment plus treatment with a DP and a YDTF decoction (DP + YDTF group). All treatments occurred for 12 d. Outcome Measures * Relevant outcomes were measured and compared at baseline and postintervention, including the rapid shallow breathing index, tidal volume, maximum inspiratory pressure, degree of diaphragmatic muscle activity, maximum expiratory pressure, the successful rates of weaning from mechanical ventilation, the potential of hydrogen, the partial pressure of oxygen, partial pressure of carbon dioxide, and oxygen saturation. Results * The patients treated with the DP plus the YDTF decoction were more successful in weaning from mechanical ventilation than those treated with DP. Of the patients with COPD + type 1 respiratory failure, 86.67% succeeded vs 70.00% of the DP patients. Of patients with COPD + type 2 respiratory failure, 87.88% succeeded vs 79.41% of the DP patients. Conclusion * The DP plus the YDTF concoction acted as a successful treatment for heart failure caused by CPOD in comparison with the DP or YDTF alone, providing evidence that the DP + YDTF concoction can serve as a competitive method for helping COPD patients to wean from mechanical ventilation. PMID- 29428926 TI - Immediate Changes After Manual Therapy in Patients With Persistent, Nonspecific Back Pain: A Randomized Controlled Trial. AB - Context * Thoracic manipulation decreases pain and disability. However, when such manipulation is contraindicated, the use of other manual techniques based on the regional interdependence of the thoracic spine, upper ribs, and shoulders is an alternative approach. Objective * The study intended to investigate the immediate changes resulting from 3 manual therapy treatments on spinal mobility, flexibility, comfort, and pain perception in patients with persistent, nonspecific back pain as well as changes in their sense of physical well-being and their perception of change after treatment. Design * The study was a randomized, double-blind, controlled trial. Setting * The study took place in the Department of Physiotherapy of the Faculty of Physiotherapy at the University of Valencia (Valencia, Spain). Participants * Participants were 112 individuals from the community-56.6% female, with a mean age of 21.8 +/- 0.2 y-who had persistent, nonspecific back pain. Intervention * Participants were randomly assigned to 1 of 3 groups, receiving (1) neurolymphatic therapy (NL group), (2) articulatory spinal manual therapy (AS group), or (3) articulatory costal manual therapy (AC group). Outcome Measures * Cervical mobility, lumbar flexibility, comfort, pain perception, and physical well-being were assessed at baseline and immediately postintervention. Perception of change was evaluated postintervention. Results * Between baseline and postintervention, the AC group showed a significant increase in cervical flexion (P = .010), whereas the NL and AS groups improved in lumbar flexibility, P = .047 and P = .012, respectively. For that period, significant changes were found in lumbar comfort for the AS group (P < .001) and the NL group (P < .026) and in thoracic comfort (P < .001) for the AC group. All groups improved in physical well-being and pain perception (P < .05). Changes in thoracic comfort, lumbar comfort, and physical well-being differed among the groups, with some differences being statistically significant. Conclusions * All treatments improved pain perception and increased physical well-being. The NL and AS treatments were more effective in lumbar flexibility, the AC treatment in cervical flexion and thoracic comfort, and the NL treatment in lumbar comfort. PMID- 29428927 TI - Dancing for Healthy Aging: Functional and Metabolic Perspectives. AB - : Context * Dancing has been used as a form of exercise to improve functional and metabolic outcomes during aging. The field lacks randomized, clinical trials (RCTs) evaluating metabolic outcomes related to dance interventions, but dancing may be a form of exercise that could induce positive effects on the metabolic health of older adults. However, primary studies seem very heterogonous regarding the trial designs, characteristics of the interventions, the methods for outcomes assessments, statistical powers, and methodological quality. Objective * The current research team intended to review the literature on the use of dance as a form of intervention to promote functional and metabolic health in older adults. Specifically, the research team aimed to identify and describe the characteristics of a large range of studies using dance as an intervention, summarizing them and putting them into perspective for further analysis. Design * The research team searched the following data sources-MEDLINE, Cochrane Wiley, Clinical Trials.gov, the Physiotherapy Evidence Database (PEDRO), and the Literatura Latino-Americana e do Caribe em Ciencias da Saude (LILACS)-for RCTs, quasi-experimental studies, and observational trials that compared the benefits of any style of dancing, combined with other exercises or alone, to nonexercising controls and/or controls practicing other types of exercise. Setting * The study took place at the Federal University of Rio Grande do Sul (Porto Alegre, Brazil). PARTICIPANTS: Participants were aging individuals, >55 y, both with or without health conditions. Interventions * Interventions should be supervised, taking form as group classes, in a dance setting environment. Dance styles were divided into 5 categories for the review: (1) cultural dances developed by groups of people to reflect the roots of a certain region, such as Greek dance; (2) ballroom dance (ie, dances with partners performed socially or competitively in a ballroom, such as foxtrot); (3) aerobic dance with no partner required, which mixes aerobic moves with dance moves; (4) dance therapies, whichare special dance programs including emotional and physical aspects; and (5) classical dances, which are dances with a unique tradition and technique, such as ballet or jazz dance. Outcome Measures * Studies needed to have evaluated functional and/or metabolic outcomes. Functional outcomes included (1) static and/or dynamic balance, (2) gait ability, (3) upper and/or lower muscle strength or power, (4) cardiorespiratory fitness, (5) flexibility, (6) risk of falls, and (7) quality of life. Metabolic outcomes included (1) lipid and glycemic profile; (2) systolic and diastolic blood pressure; (3) body composition; and (4) other specific cardiovascular risk factors or inflammatory or oxidative stress markers. Results * The research team retrieved 1042 articles, with 88 full texts assessed for eligibility, and 50 articles included in the analysis. Of the analyzed studies, 22 were RCTs evaluating dancing vs controls, and 3 were RCTs evaluating dancing vs other exercise. Regarding the participants of the reviewed studies: (1) 31 evaluated healthy individuals, (2) 7 evaluated patients suffering from Parkinson's disease, (3) 4 evaluated postmenopausal women, (4) 2 evaluated obese women, (5) 2 evaluated patients with chronic heart failure, (6) 1 evaluated frail older adults, (7) 1 evaluated individuals with visual impairments, (8) 1 evaluated persons with metabolic syndrome, and (9) 1 evaluated individuals with severe pain in the lower extremities. Regarding the interventions, most interventions were 12 wk long, 3 */wk, for 60 min each session. The dance styles most used were ballroom and cultural dances. Regarding the outcomes, functional and metabolic benefits were described in most of the included studies. Balance was the functional outcome most often assessed. Conclusions * Any dance style can induce positive functional adaptations in older adults, especially related to balance. Metabolic improvements may also be a result of dancing; however, more RCTs are needed. Dancing may be a potential exercise intervention to promote health-related benefits for aging individuals. PMID- 29428928 TI - New Concepts of Chronic Pain and the Potential Role of Complementary Therapies. AB - : Context * The mechanisms of chronic pain involve complex neuroplastic changes at all 3 orders of neurons involved in the transmission of pain as well as changes in the descending inhibitory pathway. Although traditional pharmaceutical therapies have some efficacy, substantial scope exists for a new model of individualized therapy, tailored to the specific response of each patient. Because changes occur at all levels of the pain pathway, successful treatment may require a combination of therapies with different mechanisms of action. Objective * The research team intended to examine the potential changes within the peripheral nervous system (PNS) and central nervous system (CNS) of patients with chronic pain and to propose a model of chronic pain treatment involving multimodal, complementary therapies for individualized treatment targeting multiple sites along the pain pathway. Design * The research team performed a review of the literature in the field. SETTING: The study took place in the School of Health and Human Sciences at Southern Cross University (Lismore, New South Wales, Australia). Interventions * A growing body of evidence supports the use of a variety of complementary therapies to treat chronic pain, including curcumin, capsaicin, vitamin D, omega-3 fatty acids, lipoic acid, acupuncture, yoga, meditation, and mindfulness meditation. These therapies vary with respect to the mechanisms by which they act and the potential areas of effect along the pain pathway. Results * The literature review showed a number of complementary therapies may be efficacious in reducing chronic pain and/or the need for analgesics, which may offer a reduced adverse effect profile. These therapies include curcumin, capsaicin, vitamin D, omega-3 fatty acids, lipoic acid, acupuncture, yoga, meditation, and mindfulness meditation. Response rates to treatment are likely to vary between people and within therapies. Conclusions * The available evidence suggests that efficacious complementary therapies exist that target all 3 orders of neurons and, therefore, the authors recommend multimodal individualized treatment for each patient. There is high interindividual variability between patients in responses to treatments. PMID- 29428929 TI - Improvements in Self-reported Lower Urinary Tract Symptoms With Prostate Health Supplement. AB - Context * Benign prostatic hyperplasia (BPH) produces lower urinary tract symptoms (LUTS) that diminish quality of life. Conventional treatments are often accompanied by adverse side effects. By contrast, consumers of phytochemicals based dietary supplements often report a reduction in symptoms without side effects. The field needs studies that quantify the strength and character of perceived benefits. Objectives * The study intended to quantify the character and strength of perceived improvements in LUTS in men, after the consumption of a prostate health supplement. Design * The research team sent questionnaires to 200 potential participants, requesting their self-reported retrospective assessments of their LUTS for the month prior to starting their use of a prostate health supplement, ProstaCaid (ie, at baseline from memory), and their assessments at the time of the study (ie, postintervention) based on their current symptoms. Setting * The study was conducted from consumers of ProstaCaid at their home through a mailed questionnaire from Econugenics (Santa Rosa, CA, USA). Participants * Participants were 65 male patients, ages 56 to 86 y, including those diagnosed with BPH, prostate cancer, or multiple diagnoses, or who had no formal diagnosis. Interventions * Participants had taken at least 2 capsules/d of the supplement for a minimum of 2 mo. Outcome Measures * Participants were asked to recall and rate urinary tract symptoms: (1) incomplete emptying (ie, sensation of not emptying the bladder), (2) urinary frequency, (3) intermittency, (4) urgency, (5) weak stream, (6) straining, and (7) nocturia, (ie, how many times the participant typically gets up at night to urinate). A questionnaire based on the international prostate symptom score questionnaire was used. Logistic regressions, based on the proportional odds ratios of LUTS scores, were used for statistical analysis. Results * The participants reported substantial improvements in a range of individual and composite LUTS scores. In addition, the variability of current scores was substantially reduced compared with recalled, past scores, indicating that the perceived improvements were shared among the respondents. Statistical analysis identified urgency and weak stream as the symptoms showing the greatest reduction in perceived severity, which therefore could be used as the subject of future case-controlled studies. Conclusions * When properly interpreted, retrospective, self-reported data can yield insights into the perceived benefits of supplements and help guide the care of patients who augment traditional treatment with alternative medicines. Reported improvements can also guide the development of testable hypotheses for randomized, case-controlled studies. PMID- 29428930 TI - Managing Hashimoto's Thyroiditis Through Personalized Care: A Case Report. AB - Hashimoto's thyroiditis (HT) affects more than 14 million individuals in the United States, most of them women. Thyroid replacement therapy has long been the foundation of medical treatment for HT; however, recent research supports a role for nutritional approaches. This case report describes the management of a 34-y old female with HT who declined thyroid replacement therapy and was successfully managed for a period of 5 mo. The patient was advised to follow a phytonutrient rich diet (eg, berries); avoid sensitive foods (gluten and soy); and consume quality fats, fermented foods, and filtered water. Nutritional supplementation of vitamins (B complex, D3), alpha-lipoic acid, coenzyme Q10, magnesium, omega-3 oil (DHA/EPA), and probiotics were used in conjunction with an herbal tincture. (Altern Ther Health Med. PMID- 29428931 TI - Increased Expression of the Innate Immune Receptor TLR10 in Obesity and Type-2 Diabetes: Association with ROS-Mediated Oxidative Stress. AB - BACKGROUND/AIMS: Metabolic diseases such as obesity and type-2 diabetes (T2D) are known to be associated with chronic low-grade inflammation called metabolic inflammation together with an oxidative stress milieu found in the expanding adipose tissue. The innate immune Toll-like receptors (TLR) such as TLR2 and TLR4 have emerged as key players in metabolic inflammation; nonetheless, TLR10 expression in the adipose tissue and its significance in obesity/T2D remain unclear. METHODS: TLR10 gene expression was determined in the adipose tissue samples from healthy non-diabetic and T2D individuals, 13 each, using real-time RT-PCR. TLR10 protein expression was determined by immunohistochemistry, confocal microscopy, and flow cytometry. Regarding in vitro studies, THP-1 cells, peripheral blood mononuclear cells (PBMC), or primary monocytes were treated with hydrogen peroxide (H2O2) for induction of reactive oxygen species (ROS)-mediated oxidative stress. Superoxide dismutase (SOD) activity was measured using a commercial kit. Data (mean+/-SEM) were compared using unpaired student's t-test and P<0.05 was considered significant. RESULTS: The adipose tissue TLR10 gene/protein expression was found to be significantly upregulated in obesity as well as T2D which correlated with body mass index (BMI). ROS-mediated oxidative stress induced high levels of TLR10 gene/protein expression in monocytic cells and PBMC. In these cells, oxidative stress induced a time-dependent increase in SOD activity. Pre-treatment of cells with anti-oxidants/ROS scavengers diminished the expression of TLR10. ROS-induced TLR10 expression involved the nuclear factor kappaB (NF-kappaB)/mitogen activated protein kinase (MAPK) signaling as well as endoplasmic reticulum (ER) stress. H2O2-induced oxidative stress interacted synergistically with palmitate to trigger the expression of TLR10 which associated with enhanced expression of proinflammatory cytokines/chemokine. CONCLUSION: Oxidative stress induces the expression of TLR10 which may represent an immune marker for metabolic inflammation. PMID- 29428932 TI - Metabolite Levels in Paediatric Brain Tumours Correlate with Histological Features. AB - AIMS: Metabolite levels can be measured non-invasively using in vivo 1H magnetic resonance spectroscopy (MRS). These tumour metabolite profiles are highly characteristic for tumour type in childhood brain tumours; however, the relationship between metabolite values and conventional histopathological characteristics has not yet been fully established. This study systematically tests the relationship between metabolite levels detected by MRS and specific histological features in a range of paediatric brain tumours. METHODS: Single voxel MRS was performed routinely in children with brain tumours along with the clinical imaging prior to treatment. Metabolites were quantified using LCModel. Histological features were assessed semi-quantitatively for 27 children on H&E and immunostained slides, blind to the metabolite values. Statistical analysis included 2-tailed independent-samples t tests and 2-tailed Spearman rank correlation tests. RESULTS: Ki67, cellular atypia, and mitosis correlated positively with choline metabolites, and phosphocholine in particular. Apoptosis and necrosis were both associated with lipid levels, with the relationship dependent on the use of long or short echo time MRS acquisitions. Neuronal components correlated negatively and glial components positively with N-acetyl aspartate. Glial components correlated positively with myoinositol. CONCLUSION: Metabolite levels in children's brain tumours measured by MRS are closely associated with key histological features routinely assessed by histopathologists in the diagnostic process. This further elucidates our understanding of this important non-invasive diagnostic tool and strengthens our understanding of the relationship between metabolites and histological features. PMID- 29428933 TI - A Comparison of the Effects of Grayanotoxin-Containing Honey (Mad Honey), Normal Honey, and Propolis on Fracture Healing. AB - OBJECTIVES: Delayed healing and non-union of fractures have a significant effect upon patient morbidity. Studies have therefore largely concentrated on accelerating fracture healing. This study was intended to compare the effect of "mad honey" and propolis on fracture healing using radiological and histopathological analysis. SUBJECTS AND METHODS: Femur fracture was surgically performed on 48 rats, followed by fixation. Animals were then divided into 8 groups: 2 control groups (15- and 30-day) and 6 treatment groups (15- and 30-day normal honey, 15- and 30-day "mad honey," and 15- and 30-day propolis). Rats were sacrificed at the end of these periods, and radiological and histological examinations were performed. RESULTS: Radiological healing in the propolis group after 15-day therapy was statistically better than in the control (p = 0.004) and normal honey (p = 0.006) groups. After 30-day therapy, healing in the propolis group (p = 0.005) and grayanotoxin-containing "mad honey" group (p = 0.007) were significantly better than in the control group. Histologically, there was a statistically significant difference between the 15-day propolis group and the other groups (control, honey, mad honey: p = 0.003, p = 0.003, and p = 0.002, respectively). We also found a statistically significant difference when the 30 day propolis group (p = 0.005) and "mad honey" group (p = 0.007) were compared to the control group. CONCLUSIONS: This study shows that grayanotoxin-containing "mad honey" and propolis can accelerate fracture healing. PMID- 29428934 TI - Campylobacter rectus in the Oral Cavity Correlates with Proteinuria in Immunoglobulin A Nephropathy Patients. AB - BACKGROUND: Periodontitis-related pathogens, such as Campylobacter or Treponema species, have recently been shown to be associated with immunoglobulin A nephropathy (IgAN). Some strains of Streptococcus mutans, a major pathogen of dental caries, harbour the cnm gene that encodes a collagen-binding protein (Cnm). This has also been demonstrated to be associated with urinary protein levels in IgAN patients. OBJECTIVES: The purpose of the present study was to analyse the association of IgAN with C. rectus, Treponema denticola and cnm positive S. mutans in the oral cavity of humans. METHODS: The presence of C. rectus, T. denticola and cnm-positive S. mutans strains in saliva samples of 117 IgAN patients and 56 healthy controls was evaluated by PCR, and the subjects' clinical parameters were analysed. RESULTS: C. rectus was significantly more prevalent in the IgAN group than in the control group (p < 0.05). The C. rectus positive group was significantly associated with proteinuria in the IgAN group (p < 0.05). In addition, the C. rectus-positive and cnm-positive S. mutans group was shown to be more closely associated with urinary protein levels than the other groups (p < 0.0083). CONCLUSION: Our results suggest that harbouring C. rectus in the oral cavity could be associated with proteinuria in IgAN patients. PMID- 29428935 TI - MiR-124 Promotes the Growth of Retinal Ganglion Cells Derived from Muller Cells. AB - BACKGROUND/AIMS: Retinal Muller cells could be induced to differentiate into retinal ganglion cells (RGCs), but RGCs derived from Muller cells have defects in axon growth, leading to a defect in signal conduction. In this study we aimed to explore the role of miR-124 in axon growth of RGCs derived from Muller cells. METHODS: Muller cells were isolated from rat retina and induced to dedifferentiate into retinal stem cells. The stem cells were infected by PGC-FU Atoh7-GFP lentivirus and then transfected with miR-124 or anti-miR-124, and the length of axon was compared. Furthermore, the cells were injected into the eyes of rat chronic ocular hypertension glaucoma model and axon growth in vivo was examined. The targeting of CoREST by miR-124 was detected by luciferase assay. RESULTS: In retinal stem cells, the length of axon was 1,792+/-64.54 um in miR 124 group, 509+/-21.35 um in control group, and only 87.9+/-9.24 um in anti-miR 124 group. In rat model, miR-124 promoted axon growth of RGCs differentiated from retinal stem cells. Furthermore, we found that miR-124 negatively regulated CoREST via directly targeting the binding site in CoREST 3' UTR. CONCLUSIONS: We provide the first evidence that miR-124 regulates axon growth of RGCs derived from Muller cells, and miR-124 has translational potential for gene therapy of glaucoma. PMID- 29428936 TI - Prognostic Role of High Gal-9 Expression in Solid Tumours: a Meta-Analysis. AB - BACKGROUND/AIMS: Recently, many studies have demonstrated that galectin-9 (Gal-9) exhibits altered expression and has a close association with metastasis and recurrence in various cancers. Therefore, we conducted a meta-analysis to assess the prognostic role of Gal-9 expression in solid tumours. METHODS: We searched PubMed, Embase, and Web of Science until June 2017 and identified fourteen eligible studies containing 2,408 patients to include in the meta-analysis. RESULTS: The pooled results indicated that higher Gal-9 expression in cancer tissue associated with an improved CSS (HR=0.48, 95% CI 0.39-0.58). In the subgroup analysis, a significant relationship was observed between higher Gal-9 expression and both CSS (HR=0.48, 95% CI 0.39-0.59) and OS (HR=0.62, 95% CI 0.49 0.78) in digestive cancers. CONCLUSIONS: The findings of this meta-analysis highlight the role of Gal-9 as a useful clinical prognostic biomarker, which may facilitate the treatment of patients with solid tumours. PMID- 29428937 TI - High-Throughput Data of Circular RNA Profiles in Human Temporal Cortex Tissue Reveals Novel Insights into Temporal Lobe Epilepsy. AB - BACKGROUND/AIMS: Circular RNAs (circRNAs) are a class of long noncoding RNAs with a closed loop structure that regulate gene expression as microRNA sponges. CircRNAs are more enriched in brain tissue, but knowledge of the role of circRNAs in temporal lobe epilepsy (TLE) has remained limited. This study is the first to identify the global expression profiles and characteristics of circRNAs in human temporal cortex tissue from TLE patients. METHODS: Temporal cortices were collected from 17 TLE patients and 17 non-TLE patients. Total RNA was isolated, and high-throughput sequencing was used to profile the transcriptome of dysregulated circRNAs. Quantitative PCR was performed for the validation of changed circRNAs. RESULTS: In total, 78983 circRNAs, including 15.29% known and 84.71% novel circRNAs, were detected in this study. Intriguingly, 442 circRNAs were differentially expressed between the TLE and non-TLE groups (fold change>=2.0 and FDR<=0.05). Of these circRNAs, 188 were up-regulated, and 254 were down-regulated in the TLE patient group. Eight circRNAs were validated by real-time PCR. Remarkably, circ-EFCAB2 was intensely up-regulated, while circ DROSHA expression was significantly lower in the TLE group than in the non-TLE group (P<0.05). Bioinformatic analysis revealed that circ-EFCAB2 binds to miR-485 5p to increase the expression level of the ion channel CLCN6, while circ-DROSHA interacts with miR-1252-5p to decrease the expression level of ATP1A2. CONCLUSIONS: The dysregulations of circRNAs may reflect the pathogenesis of TLE and circ-EFCAB2 and circ-DROSHA might be potential therapeutic targets and biomarkers in TLE patients. PMID- 29428938 TI - Expression of MicroRNA-448 and SIRT1 and Prognosis of Obese Type 2 Diabetic Mellitus Patients After Laparoscopic Bariatric Surgery. AB - BACKGROUND/AIMS: This study sought to investigate the expression and prognostic value of peripheral blood microRNA-448 (miR-448) and its target gene SIRT1 after laparoscopic bariatric surgery in obese type 2 diabetic mellitus (T2DM) patients. METHODS: Obese T2DM patients were selected and treated with laparoscopic bariatric surgery. Enzyme-linked immunosorbent assay (ELISA) was used to measure SIRT1 protein expression. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to determine the mRNA expression of the related gene. Endothelial progenitor cells (EPCs) were grouped into blank, negative control (NC), miR-448 mimic, miR-448 inhibitor, siRNA-SIRT1 and miR-448 inhibitor + siRNA-SIRT1 groups. Transwell assays and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assays were applied to determine cell invasion and cell viability. A tube formation assay and an adherence test were utilized to assess the angiogenic and adhesive capacities of the cells. RESULTS: In peripheral blood, the expression of miR-448 was reduced, whereas the mRNA and protein expression of SIRT1 was increased after surgery compared to before surgery. miR-448 expression was lower and mRNA and protein expression of SIRT1 was higher in the effective group than in the ineffective group after surgery. SIRT1 is a target gene of miR-448. miR-448 can suppress viability and invasion, and it reflects the angiogenic and adhesive capacity of EPCs and the protein expression of relative genes in EPCs through targeting SIRT1. CONCLUSION: The results demonstrated that miR-448 and its target gene SIRT1 can serve as prognostic indicators for obese T2DM patients after laparoscopic bariatric surgery. PMID- 29428939 TI - Early Diastolic Dysfunction after Cancer Chemotherapy: Primary Endpoint Results of a Multicenter Cardio-Oncology Study. AB - Asymptomatic diastolic dysfunction (DD) with preserved left ventricular ejection fraction (LVEF) is suspected to precede late cardiac events in cancer survivors treated by chemotherapy. We conducted the first multicenter study of early DD induced by chemotherapy. Patients who were candidates for standard dose chemotherapy were screened for the absence of cardiovascular risk factors, LVEF >=50%, normal-for-age diastolic function at echocardiography (E/A ratio, E wave deceleration time; DT), normal levels of potential DD biomarkers like Nt-proBNP (<=125 pg/mL), and cardiac troponin I (cTnI, <=0.05 ng/mL). Mitral Doppler (E/E') was left at the investigator's discretion. Chemotherapy-induced DD with preserved LVEF was diagnosed for patients showing LVEF >=50% and any of the following: Nt proBNP > 125 pg/mL, cTnI > 0.05 ng/mL, and out-of-range E/A and DT. Eighty patients (68 females, 12 males, median age 49 years) were evaluated at 1 week after chemotherapy (T1) [corrected]. Thirty-three protocol-defined diastolic events were observed (15 Nt-proBNP > 125 pg/mL, 14 grade I DD by E/A and DT, 4 cTnI > 0.05 ng/mL). The events occurred in 29 asymptomatic patients with LVEF >=50% (36% incidence of DD with preserved LVEF). Interactions occurred between biomarkers and grade I DD. E/E' abnormalities were not observed. Both anthracycline-based and nonanthracycline regimens induced DD. These findings show that biomarkers and echocardiography intercept early DD in otherwise asymptomatic low-risk cancer patients treated by standard dose chemotherapy. These findings therefore call for the adequate cardiac management of cancer patients. PMID- 29428941 TI - Editorial: The Journal Chemotherapy Is for Cardio-Oncologists Too. PMID- 29428940 TI - Analysis of Wire-Guided Hemostasis Introducer for Percutaneous Therapy of Bile Duct Stones. AB - BACKGROUND: Bile duct stones (BDS) are usually removed via endoscopic retrograde cholangiopancreatography (ERCP) or, if ERCP remains unsuccessful, percutaneous transhepatic cholangiodrainage (PTCD). However, PTCD provides limited access to large BDSs. We analyzed a modified approach of PTCD for percutaneous therapy of BDS. METHODS: We used a modified approach of PTCD with a 13-french (Fr) hemostasis introducer for transhepatic access to BDS. Short-wired balloon or basket catheter were applied for safe removal of BDS. Patient characteristics, effectiveness, and complications were analyzed. RESULTS: We identified 11 patients who underwent PTCD with hemostasis introducer. BDSs were either pushed forward to the duodenum (36%) or both partly pushed and extracted via hemostasis introducer (64%). In some cases, mechanical lithotripsy was necessary (45%). Complete removal of BDS was initially achieved in 36% of patients, 45% received additional PTCD, and in 19% stent implantation was performed. Finally, all BDSs could be removed. Laboratory analysis revealed significant reduction of alkaline phosphatase (p = 0.03) and C reactive protein (p = 0.03). Complications occurred only in 1 patient with post-interventional cholangitis. CONCLUSION: Our study showed feasibility and safety of a modified PTCD with hemostasis introducer. In addition, protection of liver tissue from sharp-edged catheters and stones was achieved. Therefore, our modification revealed an innovational approach for transhepatic removal of BDS. PMID- 29428942 TI - Outcomes of Patients Undergoing Endoscopic Hemostasis for the Upper Gastrointestinal Bleeding Were Not Influenced by the Timing of Hospital Emergency Visits: A Situation Prevailing in Japan. AB - BACKGROUND: The aim of the present study was to determine differences in the prognosis of patients in Japan who underwent emergency endoscopic hemostasis (i) during regular hours versus off hours and (ii) as outpatients versus hospitalized patients. METHODS: The present retrospective study included 443 patients who underwent emergency endoscopic hemostasis for non-variceal upper gastrointestinal bleeding from January 2008 to December 2014. These patients were classified into 2 groups: hospitalized patients and outpatients. The outpatients were further subclassified into those who visited the hospital during regular hours and those who visited during off hours. RESULTS: The outcomes of outpatients who underwent emergency hemostasis during off hours did not differ from patients treated during regular hours. Multivariate analysis revealed that outcomes of hospitalized patients, including mortality, need for blood transfusion and length of hospitalization, were worse than those of outpatients; it also revealed that patient age, malnutrition rate and prevalence of diabetes and neoplasms were higher among hospitalized patients than those in outpatients. CONCLUSIONS: The clinical outcomes of patients who underwent emergency endoscopic hemostasis for upper gastrointestinal bleeding during off hours did not differ from those of patients treated during regular hours. Outcomes were worse among hospitalized patients, mainly because of their bad general condition. PMID- 29428944 TI - Clusterin Reduces Cold Ischemia-Reperfusion Injury in Heart Transplantation Through Regulation of NF-kB Signaling and Bax/Bcl-xL Expression. AB - BACKGROUND/AIMS: Ischemia-reperfusion (I/R) injury is an unavoidable event occurring during heart transplantation and is a key factor in graft failure and the long-term survival rate of recipients. Therefore, there is an urgent need for the development of new therapies to prevent I/R injury. Clusterin is a hetero dimeric glycoprotein with an antiapoptotic function. In this study, we investigated whether clusterin was cardioprotective in heart transplantation against I/R injury using an in vivo rat model and an in vitro cell culture system, and examined the underlying mechanisms of I/R injury. METHODS: Heart grafts from wild-type C57BL/6 mice were preserved in UW solution (control) or UW solution containing recombinant human apolipoprotein-J (hr clusterin) for 24 h. The preserved hearts were implanted into recipient mice of the same strain as the donors for 72 h, and the heart grafts were then taken for histopathological and gene expression analyses. An in vitro ischemia reperfusion model using H9C2 cells or H9C2/clusterin cDNA cells was constructed. The expression of clusterin, p65, Bax, Bcl-xL, IL-1beta, and TNF-alpha protein and mRNA in heart tissue and H9C2 cells was detected by western blot, reverse transcription-polymerase chain reaction (RT-PCR), and quantitative RT-PCR assays; IL-1beta and TNF-alpha protein was detected by enzyme-linked immunosorbent assays; NF-kB activity was detected by an electrophoretic mobility shift assay; cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and flow cytometric analyses. RESULTS: Cold I/R caused severe morphologic myocardial injury to heart grafts from wild-type C57BL/6 mice, whereas grafts from hr clusterin preservation showed less damage, as demonstrated by decreased cell apoptosis/death, decreased neutrophil infiltration, and the preservation of the normal structure of the heart. Clusterin reduced the expression of p65, pre inflammatory IL-1beta, and TNF-alpha, and the pro-apoptotic gene Bax, while it enhanced the expression of the anti-apoptotic gene Bcl-xL in vitro and in vivo. Clusterin inhibited cell apoptosis/death and reduced pre-inflammatory. CONCLUSION: Clusterin is a promising target for preventing cold I/R injury in heart transplantation. This study also shows that the resultant protective effects of clusterin are mediated by NF-kappaB signaling and Bax/Bcl-xL expression. PMID- 29428943 TI - Comparison of Outcome of Hepatic Arterial Infusion Chemotherapy Combined with Radiotherapy and Sorafenib for Advanced Hepatocellular Carcinoma Patients with Major Portal Vein Tumor Thrombosis. AB - OBJECTIVE: To compare the outcome of hepatic arterial infusion chemotherapy combined with radiotherapy (HAIC + RT) versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombosis (PVTT). METHODS: This retrospective study included 108 HCC patients with PVTT of the main trunk or first branch and Child-Pugh <=7. Sixty-eight received HAIC + RT and 40 received sorafenib. Patients were then assigned to the HAIC + RT group (n = 36) and the sorafenib group (n = 36) through case-control matching. The decision to treat with HAIC + RT or sorafenib was left to the attending physician. RESULTS: The median overall, progression-free, and postprogression survival were significantly longer in the HAIC + RT group than in the sorafenib group (9.9 vs. 5.3, p = 0.002; 3.9 vs. 2.1, p = 0.048; and 3.7 vs. 1.9 months, p = 0.02, respectively). Multivariate analysis identified HAIC + RT (hazard ratio = 2.02; 95% confidence interval, 1.14-3.57; p = 0.01) as a significant and independent determinant of overall survival. CONCLUSIONS: In patients with advanced HCC and major PVTT, survival was significantly longer in those treated with HAIC + RT than with sorafenib. PMID- 29428945 TI - A Meta-Analysis of the Diagnostic Accuracy of Circular RNAs in Digestive System Malignancy. AB - BACKGROUND/AIMS: Circular RNAs (circRNAs), a novel class of noncoding RNAs, have been found to be dysregulated in various cancers. However, the clinical application value of these circRNAs in digestive system cancers remains to be clarified. We aimed to comprehensively explore the potential role of circRNAs as diagnostic indicators in digestive system malignancies. METHODS: Relevant studies were systematically retrieved from PubMed, Web of Science and the Cochrane Library. The data that were required to complete 2 * 2 contingency tables were obtained from the included studies. Stratified analyses by cancer type, sample size and publication year were performed. RESULTS: Thirteen studies with 2,276 individuals were included in the meta-analysis. The pooled sensitivity and specificity of circRNAs in the diagnosis of digestive system malignancy were 0.72 [95% confidence interval (CI): 0.65-0.77] and 0.77 (95% CI: 0.72-0.81), respectively. The overall positive likelihood ratio was 3.09 (95% CI: 2.64-3.62), and the overall negative likelihood ratio was 0.37 (95% CI: 0.31-0.44). The pooled diagnostic odds ratio was 8.38 (95% CI: 6.86-10.25), and the overall area under the curve was 0.81 (95% CI: 0.77-0.84), indicating good discriminative ability of circRNAs as biomarkers for digestive system malignancy. CONCLUSION: circRNAs distinguish patients with digestive system cancer from controls with relatively high diagnostic accuracy. circRNAs may be used as potential biomarkers for the diagnosis of digestive system malignancy. PMID- 29428946 TI - Determination of Cardiac Output in Pulmonary Hypertension Using Impedance Cardiography. AB - BACKGROUND: Cardiac output (CO) is a prognostic factor in pulmonary hypertension (PH). Right heart catheterisation using the direct Fick method or thermodilution (TD) is the reference technique for CO measurement. Impedance cardiography (IPc) is a known non-invasive method of measuring CO. OBJECTIVES: In our study, we assume that the measurement of CO by IPc using the PHYSIOFLOW(r) system is as accurate as TD or using the direct Fick method in patients with PH in group 1 or group 4. METHODS: A total of 75 patients were enrolled in a prospective study carried out at the hypertension reference centre of Toulouse University Hospital. Right heart catheterisation was performed for the diagnosis or follow-up of the disease. CO was measured using the Fick method, TD, and IPc simultaneously. A Bland-Altman analysis was plotted. RESULTS: CO was 5.7 +/- 1.9 L/min as measured by the Fick method, 5.4 +/- 1.5 L/min by TD, and 5.5 +/- 1.7 L/min by IPc. The bias between CO measurements by IPc and the direct Fick method was 0.149 L/min (95% CI, -0.298 to 0.596). The bias between CO measurements by IPc and the TD method was -0.153 L/min (95% CI, -0.450 to 0.153). The correlation decreased with the more extreme CO values (< 3 L/min or > 7 L/min). A few factors changed the agreement between measurements (BMI or membership in group 4). CONCLUSION: To conclude, this study shows that the measurement of CO by IPc in PH patients is reliable compared to the direct Fick method and TD obtained by right heart catheterisation. This accuracy decreases for extreme CO values. PMID- 29428947 TI - A Combination of the Aerosolized PPAR-gamma Agonist Pioglitazone and a Synthetic Surfactant Protein B Peptide Mimic Prevents Hyperoxia-Induced Neonatal Lung Injury in Rats. AB - BACKGROUND: Despite improvements in perinatal care, bronchopulmonary dysplasia (BPD) in extremely premature infants has not decreased. Postnatal surfactant therapy provides symptomatic relief from respiratory distress syndrome, but does not translate into a reduction in BPD. Therefore, the search for effective interventions to prevent BPD continues. OBJECTIVES: Since PPAR-gamma agonists have been demonstrated to promote neonatal lung maturation and injury repair, we hypothesized that a formulation of a PPAR-gamma agonist, pioglitazone (PGZ) and a synthetic lung surfactant (a surfactant protein B peptide mimic, B-YL) combined would stimulate lung maturation and block hyperoxia-induced neonatal lung injury more effectively than either modality alone. METHODS: One-day-old Sprague-Dawley rat pups were administered PGZ + B-YL via nebulization every 24 h for up to 72 h. The pups were exposed to either 21 or 95% O2, and then sacrificed. Their lungs were examined for markers of lung maturation (levels of PPAR-gamma, SP-C and choline-phosphate cytidylyltransferase [CCT-alpha] and [3H]triolein uptake) and injury repair (bronchoalveolar lavage cell count and protein content, and levels of LEF-1, fibronectin, ALK5, and beta-catenin) by Western blot analysis. RESULTS: Markers of alveolar epithelial/mesenchymal maturation (PPAR-gamma, SP-C, CCT alpha, and triolein uptake) increased significantly in the PGZ + B-YL group, more than with either drug alone. Similarly, markers of hyperoxia-induced lung injury were blocked effectively with PGZ + B-YL treatment. CONCLUSIONS: Nebulized PPAR gamma agonist PGZ with a synthetic lung surfactant accelerates lung maturation and prevents neonatal hyperoxia-induced lung injury more than either modality alone, with the potential to provide more effective prevention of BPD. PMID- 29428948 TI - Ratio of Immune Response to Tumor Burden Predicts Survival Via Regulating Functions of Lymphocytes and Monocytes in Diffuse Large B-Cell Lymphoma. AB - BACKGROUND/AIMS: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, and is the most common type of lymphoma in adults. Although significant progress in treatment has been made using chemotherapy combinations, there exist a large amount of relapse or refractory cases. Thus, effective clinical biomarkers for DLBCL are urgently needed. Our study aims to explore the predictive significance of using the immune response to tumor burden ratio [defined as the lymphocyte to monocyte ratio (LMR)/lactate dehydrogenase (LDH) levels] in 184 DLBCL patients and the potential mechanism underlying the use of the LMR to tumor burden ratio in predicting patient survival. METHODS: The correlation between serum LDH levels and tumor levels assessed by PET-CT was determined using Spearman's correlation analysis. Clinical data from 184 DLBCL patients was assessed using receiver operating characteristic curve analysis and survival analysis. The potential correlation between tumor burden and lymphocytes or monocytes was analyzed by immunohistochemical staining, flow cytometry, and ELISA analysis of patient samples. In addition, we performed in vitro studies to further determine the effects of tumor burden on the anti-tumor activity of T lymphocytes. RESULTS: We observed that serum LDH was an excellent surrogate marker of tumor burden in DLBCL patients, and that the ratio of LMR to LDH was an independent prognostic biomarker capable of predicting survival in DLBCL patients. Further analysis showed that a high tumor burden was correlated with decreased Ki67 expression in T cells, either in the solid tumor tissue or in the circulating blood. In addition, based on an in vitro co-culture study, a higher tumor burden led to the suppression of the anti-tumor response of T cells. Furthermore, we found that a higher tumor burden was correlated with the differentiation of monocytes to tumor associated macrophages in the tumor micro-environment. Both results demonstrate the importance of considering both the immune system and tumor burden for prognostic analysis. CONCLUSION: Our study has identified a novel clinical biomarker, namely, the immune response to tumor burden ratio, that can be used to distinguish survival outcomes in DLBCL patients, and demonstrated the potential mechanism underlying the use of this biomarker, that incorporates both the immune system and tumor burden, for use in future clinical applications. PMID- 29428949 TI - Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2. AB - Adult-onset neurological disorders are caused and influenced by a multitude of different factors, including epigenetic modifications. Here, using an ELISA kit selected upon careful testing, we investigated global 5-methylcytosine (5-mC) levels in sporadic and familial amyotrophic lateral sclerosis (sALS and fALS), spinocerebellar ataxia types 1 and 2 (SCA1 and SCA2), Huntington's disease, Friedreich's ataxia, and myotonic dystrophy type 1. We report a significant elevation in global 5-mC levels of about 2-7% on average for sALS (p < 0.01 [F(1, 243) = 9.159, p = 0.0027]) and various forms of fALS along with SCA1 (p < 0.01 [F(1, 83) = 11.285], p = 0.0012) and SCA2 (p < 0.001 [F(1, 122) = 29.996, p = 0.0001]) when compared to age- and sex-matched healthy controls. C9orf72 expansion carrier ALS patients exhibit the highest global 5-mC levels along with C9orf72 promoter hypermethylation. We failed to measure global 5 hydroxymethylcytosine (5-hmC) levels in blood, probably due to the very low levels of 5-hmC and the limitations of the commercially available ELISA kits. Our results point towards a role for epigenetics modification in ALS, SCA1, and SCA2, and help conclude a dispute on the global 5-mC levels in sALS blood. PMID- 29428950 TI - Severity of Diverticulitis Does Not Influence Abdominal Complaints during Long Term Follow-Up. AB - BACKGROUND: Diverticulitis can lead to localized or generalized peritonitis and consequently induce abdominal adhesion formation. If adhesions would lead to abdominal complaints, it might be expected that these would be more prominent after operation for perforated diverticulitis with peritonitis than after elective sigmoid resection. AIMS: The primary outcome of the study was the incidence of abdominal complaints in the long-term after acute and elective surgery for diverticulitis. METHODS: During the period 2003 through 2009, 269 patients were operated for diverticular disease. Two hundred eight of them were invited to fill out a questionnaire composed of the gastrointestinal quality of life index and additional questions and finally 109 were suitable for analysis with a mean follow-up of 7.5 years. RESULTS: Analysis did not reveal any significant differences in the incidence of abdominal complaints or other parameters. CONCLUSION: This retrospective study on patients after operation for diverticulitis shows that in the long term, the severity of the abdominal complaints is influenced neither by the stage of the disease nor by the fact of whether it was performed in an acute or elective setting. PMID- 29428951 TI - Molecular Epidemiology of Bovine Papillomatosis and Identification of Three Genotypes in Central Iraq. AB - OBJECTIVE: This study aims to provide a molecular and epidemiological characterization of bovine papillomavirus (BPV) infections in Iraq. METHODS: The present study focuses on identifying BPV based on clinical and epidemiological manifestations, histopathological examinations, and polymerase chain reactions (PCR). Samples were collected from 163 animals suffering from cutaneous bovine papillomatosis, including 129 females (79.14%) with an age range of 16-40 months and 34 males (20.85%) with an age range of 17-29 months. RESULTS: The incidence rate was significantly higher in females than in males. The most commonly affected sites were the teats and neck, though warts were found in other areas of the body. Histological sections were diagnosed as fibropapilloma. PCR results showed that 80.13% of the extracted papilloma DNA samples corresponded to the BPV 1 genotype. Furthermore, 7.94% of the samples showed a mixed infection of BPV-1 and BPV-13. While, 40.63% of the extracted DNA blood samples showed 2 DNA fragments corresponding to both genotypes BPV-1 and BPV-2. CONCLUSIONS: This study confirmed the presence of BPV-1, BPV-2, and BPV-13, which belong to the Deltapapillomavirus genera, for the first time in the DNA of Iraqi cattle. Understanding BPV diversity and epidemiology is of critical importance for starting prevention strategies. PMID- 29428952 TI - Transient Receptor Potential Ankyrin 1 and Substance P Mediate the Development of Gastric Mucosal Lesions in a Water Immersion Restraint Stress Rat Model. AB - BACKGROUND: Activation of substance P (SP) contributes to the development and maintenance of gastric lesions, but the mechanisms underlying the release of SP and SP-mediated damage to the gastric mucosa remain unknown. Transient receptor potential ankyrin 1 (TRPA1) is expressed in SP-positive neurons in the dorsal root ganglion (DRG) and stomach of rats. We hypothesized that water immersion restraint stress (WIRS) may activate and sensitize TRPA1 in DRG neurons, subsequently inducing the release of SP from DRG and stomach cells, causing the development of acute gastric mucosal lesions (AGML). METHODS: Changes in TRPA1 and SP expression in T8-11 DRG sensory neurons and the stomach in an AGML rat model were determined by reverse transcription polymerase chain reaction, western blotting and immunohistochemistry. The SP levels of serum and gastric mucosa were measured by using an enzyme-linked immunosorbent assay (ELISA). Gastric lesions were evaluated by histopathological changes. The TRPA1 antagonist HC-030031 and TRPA1 agonists allyl isothiocyanate were used to verify effect of TRPA1 and SP on AGML. RESULTS: SP and TRPA1 in the DRG and stomach were upregulated, and the serum and gastric mucosa levels of SP were increased after WIRS, which are closely associated with AGML. The release of SP was suppressed and AGML were alleviated following a selective TRPA1 antagonist HC-030031. TRPA1 agonists AITC increased release of SP and led to moderate gastric lesions. We confirmed that WIRS induced the release of SP in the DRG, stomach, serum and gastric mucosa, and in a TRPA1-dependent manner. CONCLUSIONS: Upregulated SP and TRPA1 in the DRG and stomach and increased serum and gastric mucosa SP levels may contribute to stress induced AGML. TRPA1 is a potential drug target to reduce stress-induced AGML development in patients with acute critical illnesses. This study may contribute to the discovery of drugs for AGML treatment. PMID- 29428953 TI - Medical Overtreatment: Friend or Foe? AB - "Overtreatment" is a neologism coined some 15 years ago to denote medical and surgical interventions that are unnecessary. It is a topical term for an old concept. However, it has rapidly become a shibboleth for those inclined toward finger-pointing and blaming in matters of health policy. As such, it is a "foe" that heats up rather than modulates debate. But if one examines the notion in the context of the contemporary patient-physician dialogue, it is anything but a foe. Overtreatment and its fellow travelers, overutilization and overprescription, face off with contrary notions when a patient contends with the challenge of evaluating any clinical option. PMID- 29428954 TI - Tumour Heterogeneity of Breast Cancer: From Morphology to Personalised Medicine. AB - Breast cancer (BC) displays striking clinical, morphological, and behavioural diversity within a single tumour and between tumours. Currently, mounting evidence indicates that the morphological heterogeneity of BC reflects an underlying spectrum of genetic and epigenetic portraits that control BC behaviour. Further understanding of BC heterogeneity will have an impact, not only on the routine diagnostic practices but also on patients' management decisions. Phenomena like diagnostic inconsistencies and therapeutic resistance, both primary and acquired, could be attributed, at least in part, to tumour heterogeneity within the same cancer and between the primary disease and subsequent recurrences. From a practical standpoint, and to minimise the impact of BC intratumoral heterogeneity, pragmatic approaches for adequate tumour sampling have been suggested in translational biomarker discovery and validation research studies and in the clinical setting. Here, we provide a brief overview of BC heterogeneity, with an emphasis on the clinical consequences of intratumoral heterogeneity. PMID- 29428956 TI - Prognosis of Ocular Myasthenia Gravis in an Argentinian Population. AB - BACKGROUND: We investigated the prognosis of patients with myasthenia gravis (MG) initially presenting with only ocular symptoms in an Argentinian population. SUMMARY: We performed a retrospective analysis of 61 patients with MG with pure ocular involvement at onset. Generalized MG (gMG) developed in 73.7% of patients, while the rest only exhibited ocular symptoms throughout the course of the disease (ocular MG [oMG]). The AChR antibody (AChR-ab) was found in 81.4% of the gMG and 50% of the oMG cases. AChR-ab titers were also significantly higher in the gMG than in the oMG group. Patients with oMG more frequently required treatment only with acetylcholinesterase inhibitors and showed more remissions. Key Messages: Our study showed high generalization in patients with MG debuting with ocular symptoms. Patients with AChR seropositivity and higher AChR-ab titers had an increased risk for gMG, while patients with oMG showed lower corticosteroid requirements and a higher remission rate. PMID- 29428955 TI - Clinicopathological Features and Magnifying Chromoendoscopic Findings of Non Ampullary Duodenal Epithelial Tumors. AB - BACKGROUND AND AIMS: We aimed to investigate an association between clinicopathological features, including immunohistochemical mucin phenotypes, and magnifying chromoendoscopic findings with crystal violet staining (ME-CV) in non ampullary duodenal epithelial tumors (NADETs). METHODS: A total of 55 patients with NADET were divided into 3 groups by mucin phenotype: intestinal, gastrointestinal, or gastric. ME-CV findings were classified into 4 patterns: convoluted, leaf-like, reticular/sulciolar, and pinecone. The clinicopathological features and ME-CV findings were compared among the mucin phenotypes. RESULTS: Tumors of the gastric type were located in the duodenal bulb (p < 0.001), and contained pyloric gland adenoma (p < 0.001) more frequently than the other types. White-light endoscopy indicated that milk-white mucosa was less frequent in tumors of the gastric type than in those of the gastrointestinal type (p = 0.006) and the intestinal type (p < 0.001). ME-CV findings were significantly different between the gastric type and the other type (p = 0.028). Totally, 5 of 8 tumors of the gastric type manifested a pinecone pattern, 4 of which were compatible with pyloric gland adenoma. CONCLUSIONS: The endoscopic findings of NADETs differ according to mucin phenotype. A pinecone pattern under ME-CV may be characteristic of NADETs of the gastric type, especially pyloric gland adenoma. PMID- 29428957 TI - Associations of Near-Miss Traffic Incidents with Attention and Executive Function among Older Japanese Drivers. AB - BACKGROUND: Attention and executive function may play an important role in ensuring safe driving as they involve paying attention to complex information and making an instantaneous judgment during driving. We hypothesized that poor performance in attention and executive function may increase the risk of near miss incidents among older drivers. OBJECTIVE: The aim of this study was to examine associations of current experience of near-miss traffic incidents with attention and executive function among older Japanese drivers. METHODS: The study included 3,421 general older drivers (mean age: 71.7 +/- 4.9 years; 56.3% men) with a valid driver's license who were currently driving at least once per week and who had participated in a community-based cohort study between February 2015 and August 2016. The participants were asked about their experiences of near-miss traffic incidents in 10 situations that had almost happened during driving in the previous year. RESULTS: Of the 3,421 older drivers, 1,840 (53.8%) had experienced near-miss incidents during driving in the previous year at least once. Male sex (OR 1.46, 95% CI 1.27-1.69) and high driving frequency (OR 1.11, 95% CI 1.07 1.15) were significantly associated with the current experience of near-miss traffic incidents when the overall data were analyzed. In young-old drivers aged 65-74 years, poor performance in attention as assessed by the Trail Making Test part A (OR 1.45, 95% CI 1.05-2.00) was significantly associated with near-miss traffic incidents. CONCLUSION: Male sex, high driving frequency, and poor performance in attention (in young-old drivers) were associated with near-miss traffic incidents. Improvement in attention may play a role in decreasing the risk of traffic accidents among older drivers. PMID- 29428958 TI - Down-Regulation of Neuropathy Target Esterase in Preeclampsia Placenta Inhibits Human Trophoblast Cell Invasion via Modulating MMP-9 Levels. AB - BACKGROUND/AIMS: Neuropathy target esterase (NTE, also known as neurotoxic esterase) is proven to deacylate phosphatidylcholine (PC) to glycerophosphocholine as a phospholipase B. Recently; studies showed that artificial phosphatidylserine/PC microvesicles can induce preeclampsia (PE)-like changes in pregnant mice. However, it is unclear whether NTE plays a key role in the pathology of PE, a pregnancy-related disease, which was characterized by deficient trophoblast invasion and reduced trophoblast-mediated remodeling of spiral arteries. The aim of this study was to investigate the expression pattern of NTE in the placenta from women with PE and normal pregnancy, and the molecular mechanism of NTE involved in the development of PE. METHODS: NTE expression levels in placentas from 20 pregnant women with PE and 20 healthy pregnant women were detected using quantitative PCR and immunohistochemistry staining. The effect of NTE on trophoblast migration and invasion and the underlying mechanisms were examined in HTR-8/SVneo cell lines by transfection method. RESULTS: NTE mRNA and protein expression levels were significantly decreased in preeclamptic placentas than normal control. Over-expression of NTE in HTR-8/SVneo cells significantly promoted trophoblast cells migration and invasion and was associated with increased MMP-9 levels. Conversely, shRNA-mediated down regulation of NTE markedly inhibited the cell migration and invasion. In addition, silencing NTE reduced the MMP-9 activity and phosphorylated Erk1/2 and AKT levels. CONCLUSIONS: Our results suggest that the decreased NTE may contribute to the development of PE through impairing trophoblast invasion by down-regulating MMP-9 via the Erk1/2 and AKT signaling pathway. PMID- 29428959 TI - Feasibility of Salvage Selective Neck Dissection after Primary Irradiation of Pharyngeal and Laryngeal Carcinoma. AB - INTRODUCTION: The concept of neck dissection (ND) in the management armamentarium of head and neck squamous cell carcinoma has evolved throughout the years. Nowadays, ND becomes more functional. METHODOLOGY: A retrospective study of 865 patients was performed at Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital to investigate the feasibility of selective ND (SND). All patients with squamous cell carcinoma of the pharynx and larynx who received primary radiation and underwent salvage ND were included in the study. RESULT: A total of 29 NDs were analyzed. In 17 neck sides, viable metastases were found (58%), whereas in the other 12 specimens there were no viable metastases. In 16 of the 17 necks (94%), the metastases were located either in level II, III, or IV or in a combination of these 3 levels. Level V was involved in only 1 case (6%). CONCLUSION: It is well justified to perform a salvage SND (levels II, III, and IV) for pharyngeal and laryngeal carcinoma after primary radiation. In carefully selected cases of supraglottic and oropharyngeal carcinoma, a superselective ND also appears as an efficient option. PMID- 29428960 TI - Sesquiterpene-Enriched Extract of Curcuma aeruginosa Roxb. Retards Axillary Hair Growth: A Randomised, Placebo-Controlled, Double-Blind Study. AB - BACKGROUND: Sesquiterpenes in Curcuma aeruginosa Roxb. inhibit steroid 5alpha reductase and dihydrotestosterone production, and reverse androgenic alopecia. This study sought to show that a high sesquiterpene C. aeruginosa extract (CA ext) retards axillary hair growth in women. METHODS: Thirty women (age 20-52 years) were recruited into a 12-week, double-blind, placebo-controlled intervention for CA-ext treatment, where they were randomly allocated to a left or right armpit group. At weekly intervals, axillary hair length was measured videometrically, the hair was shaved, and lotion was applied (to the contralateral axilla) twice daily via roll-on applicators containing either CA ext or placebo. The primary endpoint of the study was hair growth. RESULTS: Participants showed 22% (range 8-56%, p < 0.0001) reduced axillary hair growth with CA-ext compared to placebo, albeit delayed by 6 weeks. Participants were satisfied with the treatment and no apparent adverse effects were reported. The quantities of lotion used for each axilla were identical between test and placebo throughout the trial for each participant. Participants reported having shorter and finer armpit hair with the test lotion but disliked its smell, even though it was perfumed. The "free of irritation" description gained the highest questionnaire ratings. CONCLUSION: CA-ext in lotion is an efficacious inhibitor of axillary hair growth, the preparation was well accepted and matched the effectiveness of finasteride. Thus, with some refinement, it should provide an alternative pharmacological treatment for unwanted androgenic hair. PMID- 29428961 TI - ITRAQ-Based Proteomics Analysis of Triptolide On Human A549 Lung Adenocarcinoma Cells. AB - BACKGROUND/AIMS: Triptolide (TP) is a diterpenoid triepoxide extracted from the traditional Chinese medical herb Tripterygium wilfordii that exerts prominent broad-spectrum anticancer activity to repress proliferation and induce cancer cell apoptosis through various molecular pathways. We previously observed that TP inhibits the progression of A549 cells and pancreatic cancer cells (PNCA-1) in vitro. However, the complex molecular mechanism underlying the anticancer activity of TP is not well understood. METHODS: To explore the molecular mechanisms by which TP induces lung cancer cell apoptosis, we investigated changes in the protein profile of A549 cells treated with TP using a proteomics approach (iTRAQ [isobaric tags for relative and absolute quantitation] combined with NanoLC-MS/MS [nano liquid chromatography-mass spectrometry]). Changes in the profiles of the expressed proteins were analyzed using the bioinformatics tools OmicsBean and the Kyoto Encyclopedia of Genes and Genomes (KEGG) and were verified using western blotting. Apoptosis and cell cycle effects were analyzed using flow cytometry. RESULTS: TP induced apoptosis in A549 cells and blocked A549 cells at the G2/M phase. Using iTRAQ technology, we observed 312 differentially expressed proteins associated in networks and implicated in different KEGG pathways. Gene Ontology (GO) analysis showed the overviews of dysregulated proteins in the biological process (BP), cell component (CC), and molecular function (MF) categories. Moreover, some candidate proteins involved in PARP1/AIF and nuclear Akt signaling pathways or metastasis processes were validated by western blotting. CONCLUSION: TP exerted anti-tumor activity on non small cell lung cancer (NSCLC) A549 lung adenocarcinoma cells by dysregulating tumor-related protein expression. Herein, we provide a preliminary study of TP related cytotoxicity on A549 cells using proteomics tools. These findings may improve the current understanding of the anti-tumor effects of TP on lung cancer cells and may reveal candidate proteins as potential targets for the treatment of lung cancer. PMID- 29428962 TI - Ursolic Acid Attenuates High Glucose-Mediated Mesangial Cell Injury by Inhibiting the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) Signaling Pathway. AB - BACKGROUND To investigate the protective effect of ursolic acid (UA) on high glucose (HG)-induced human glomerular mesangial cell injury and to determine whether UA inhibits cell proliferation and reactive oxygen species (ROS) production by suppressing PI3K/Akt/mTOR pathway activation. MATERIAL AND METHODS Human mesangial cells were cultured with normal glucose (NG group), high glucose (HG group), mannitol (mannitol hypertonic control group), or high glucose with different concentrations (0.5, 1.0, and 2.0 mmol/L) of UA (HG+UA groups). Cell proliferation and intracellular ROS levels were assessed by methyl thiazolyl tetrazolium (MTT) and dichloro-dihydro-fluorescein diacetate (DCFH-DA) flow cytometry assays, respectively. Western blotting was used to detect mesangial cell expression of PI3K/Akt/mTOR pathway components, including Akt, p-Akt, mTOR, and p-mTOR, and proteins related to cell injury, including TGF-beta1 and fibronectin (FN). mRNA expression of TGF-beta1 and FN were evaluated using real time quantitative polymerase chain reaction (PCR). RESULTS Abnormal proliferation was observed in human glomerular mesangial cells at 48 h after treatment with HG, and UA suppressed the HG-induced proliferation of mesangial cells in a dose dependent manner. UA inhibited ROS generation and oxidative stress in mesangial cells and mitigated mesangial cell injury. Treatment with UA reduced Akt and mTOR phosphorylation levels in mesangial cells exposed to HG (p<0.05 vs. HG) and downregulated protein and mRNA expression of TGF-beta1 and FN in these cells (p<0.05 vs. HG). CONCLUSIONS UA attenuated mesangial cell proliferation and ROS generation by inhibiting HG-mediated PI3K/Akt/mTOR pathway activation, thereby ameliorating mesangial cell damage. PMID- 29428963 TI - Efficacy of Strain Elastography in Diagnosis and Staging of Acute Appendicitis in Pediatric Patients. AB - BACKGROUND In the present study, the role and efficiency of strain elastography (SE) were evaluated in diagnosis and staging of acute appendicitis in pediatric patients. MATERIAL AND METHODS We enrolled 225 pediatric patients with suspected clinical and laboratory findings of acute appendicitis. Gray-scale sonographic findings were recorded and staging was made by the colorization method of SE imaging. Appendectomy was performed in all patients and the results of the surgical pathology were compared with the imaging findings. The sensitivity, specificity, and accuracy of SE imaging were determined in terms of evaluating the "acute appendicitis". RESULTS Sonographic evaluation revealed acute appendicitis in 100 patients. Regarding the SE analysis, cases with appendicitis were classified into 3 groups as: mild (n=17), moderate (n=39), and severe (n=44). The pathological evaluation revealed 95 different stages of appendicitis and normal appendix in 5 cases: acute focal (n=10), acute suppurative (n=46), phlegmonous (n=27), and perforated (n=12), regarding the results of surgical pathology. Five patients with pathologically proven "normal" appendix were noted as "mild stage appendicitis" based on gray scale and SE analysis. In total, when gray-scale and SE results were compared with pathology results regardless of the stage of appendicitis, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rates were 96%, 96%, 95%, 96.8%, and 96%, respectively. No statistically significant difference was detected between other groups (P<0.05). CONCLUSIONS In acute appendicitis, the use of SE imaging as a supportive method for the clinical approach can be useful in diagnosis, and its results are closely correlated with the histopathologic stage of appendix inflammation. PMID- 29428964 TI - An emerging link between LIM domain proteins and nuclear receptors. AB - Nuclear receptors are ligand-activated transcription factors that partake in several biological processes including development, reproduction and metabolism. Over the last decade, evidence has accumulated that group 2, 3 and 4 LIM domain proteins, primarily known for their roles in actin cytoskeleton organization, also partake in gene transcription regulation. They shuttle between the cytoplasm and the nucleus, amongst other as a consequence of triggering cells with ligands of nuclear receptors. LIM domain proteins act as important coregulators of nuclear receptor-mediated gene transcription, in which they can either function as coactivators or corepressors. In establishing interactions with nuclear receptors, the LIM domains are important, yet pleiotropy of LIM domain proteins and nuclear receptors frequently occurs. LIM domain protein-nuclear receptor complexes function in diverse physiological processes. Their association is, however, often linked to diseases including cancer. PMID- 29428965 TI - The product of the gamma-secretase processing of ephrinB2 regulates VE-cadherin complexes and angiogenesis. AB - Presenilin-1 (PS1) gene encodes the catalytic component of gamma-secretase, which proteolytically processes several type I transmembrane proteins. We here present evidence that the cytosolic peptide efnB2/CTF2 produced by the PS1/gamma secretase cleavage of efnB2 ligand promotes EphB4 receptor-dependent angiogenesis in vitro. EfnB2/CTF2 increases endothelial cell sprouting and tube formation, stimulates the formation of angiogenic complexes that include VE-cadherin, Raf-1 and Rok-alpha, and increases MLC2 phosphorylation. These functions are mediated by the PDZ-binding domain of efnB2. Acute downregulation of PS1 or inhibition of gamma-secretase inhibits the angiogenic functions of EphB4 while absence of PS1 decreases the VE-cadherin angiogenic complexes of mouse brain. Our data reveal a mechanism by which PS1/gamma-secretase regulates efnB2/EphB4 mediated angiogenesis. PMID- 29428966 TI - SLC52A3 expression is activated by NF-kappaB p65/Rel-B and serves as a prognostic biomarker in esophageal cancer. AB - The human riboflavin transporter-3 (encoded by SLC52A3) plays a prominent role in riboflavin absorption. Interestingly, abnormal expression patterns of SLC52A3 in multiple types of human cancers have been recently noted. However, the molecular mechanisms underlying its dysregulation remain unclear. In this study, we find that SLC52A3 has two transcript variants that differ in the transcriptional start site, and encode different proteins: SLC52A3a and SLC52A3b. Importantly, aberrant expressions of SLC52A3 are associated with stepwise development of esophageal squamous cell carcinoma (ESCC) as well as the survival rates of ESCC patients. Functionally, SLC52A3a, but not SLC52A3b, strongly promotes the proliferation and colony formation of ESCC cells. Furthermore, SLC52A3 5'-flanking regions contain NF-kappaB p65/Rel-B-binding sites, which are crucial for mediating SLC52A3 transcriptional activity in ESCC cells. Chromatin immunoprecipitation and electrophoretic mobility shift assay reveal that p65/Rel-B bind to 5'-flanking regions of SLC52A3. Accordingly, NF-kappaB signaling upregulates SLC52A3 transcription upon TNFalpha stimulation. Taken together, these results elucidate the mechanisms underlying SLC52A3 overexpression in ESCC. More importantly, our findings identify SLC52A3 as both a predictive and prognostic biomarker for this deadly cancer. PMID- 29428967 TI - Consequences of interspecific variation in defenses and herbivore host choice for the ecology and evolution of Inga, a speciose rainforest tree. AB - We summarize work on a speciose Neotropical tree genus, Inga (Fabaceae), examining how interspecific variation in anti-herbivore defenses may have evolved, how defenses shape host choice by herbivores and how they might regulate community composition and influence species radiations. Defenses of expanding leaves include secondary metabolites, extrafloral nectaries, rapid leaf expansion, trichomes, and synchrony and timing of leaf production. These six classes of defenses are orthogonal, supporting independent evolutionary trajectories. Moreover, only trichomes show a phylogenetic signature, suggesting evolutionary lability in nearly all defenses. The interspecific diversity in secondary metabolite profiles does not arise from the evolution of novel compounds, but from novel combinations of common compounds, presumably due to changes in gene regulation. Herbivore host choice is determined by plant defensive traits, not host phylogeny. Neighboring plants escape each other's pests if their defenses differ enough, thereby enforcing the high local diversity typical of tropical forests. Related herbivores feed on hosts with similar defenses, implying that there are phylogenetic constraints placed on the herbivore traits that are associated with host use. Divergence in defensive traits among Inga appears to be driven by herbivore pressure. However, the lack of congruence between herbivore and host phylogeny suggests that herbivores are tracking defenses, choosing hosts based on traits for which they already have adaptations. There is, therefore, an asymmetry in the host-herbivore evolutionary arms race. PMID- 29428969 TI - Efficient workflow for automatic segmentation of the right heart based on 2D echocardiography. AB - The present study aimed to present a workflow algorithm for automatic processing of 2D echocardiography images. The workflow was based on several sequential steps. For each step, we compared different approaches. Epicardial 2D echocardiography datasets were acquired during various open-chest beating-heart surgical procedures in three porcine hearts. We proposed a metric called the global index that is a weighted average of several accuracy coefficients, indices and the mean processing time. This metric allows the estimation of the speed and accuracy for processing each image. The global index ranges from 0 to 1, which facilitates comparison between different approaches. The second step involved comparison among filtering, sharpening and segmentation techniques. During the noise reduction step, we compared the median filter, total variation filter, bilateral filter, curvature flow filter, non-local means filter and mean shift filter. To clarify the endocardium borders of the right heart, we used the linear sharpen. Lastly, we applied watershed segmentation, clusterisation, region growing, morphological segmentation, image foresting segmentation and isoline delineation. We assessed all the techniques and identified the most appropriate workflow for echocardiography image segmentation of the right heart. For successful processing and segmentation of echocardiography images with minimal error, we found that the workflow should include the total variation filter/bilateral filter, linear sharpen technique, isoline delineation/region growing segmentation and morphological post-processing. We presented an efficient and accurate workflow for the precise diagnosis of cardiovascular diseases. We introduced the global index metric for image pre-processing and segmentation estimation. PMID- 29428968 TI - Differentiation analysis for estimating individual ancestry from the Tibetan Plateau by an archaic altitude adaptation EPAS1 haplotype among East Asian populations. AB - Tibetans have adapted to the extreme environment of high altitude for hundreds of generations. A highly differentiated 5-SNP (Single Nucleotide Polymorphism) haplotype motif (AGGAA) on a hypoxic pathway gene, EPAS1, is observed in Tibetans and lowlanders. To evaluate the potential usage of the 5-SNP haplotype in ancestry inference for Tibetan or Tibetan-related populations, we analyzed this haplotype in 1053 individuals of 12 Chinese populations residing on the Tibetan Plateau, peripheral regions of Tibet, and plain regions. These data were integrated with the genotypes from the 1000 Genome populations and populations in a previously reported paper for population structure analyses. We found that populations representing highland and lowland groups have different dominant ancestry components. The core Denisovan haplotype (AGGAA) was observed at a frequency of 72.32% in the Tibetan Plateau, with a frequency range from 9.48 to 21.05% in the peripheral regions and < 2.5% in the plains area. From the individual perspective, 87.57% of the individuals from the Tibetan Plateau carried the archaic haplotype, while < 5% of the Chinese Han people carried the haplotype. Our findings indicate that the 5-SNP haplotype has a special distribution pattern in populations of Tibet and peripheral regions and could be integrated into AISNP (Ancestry Informative Single Nucleotide Polymorphism) panels to enhance ancestry resolution. PMID- 29428970 TI - Amycolatopsis vastitatis sp. nov., an isolate from a high altitude subsurface soil on Cerro Chajnantor, northern Chile. AB - The taxonomic position of a novel Amycolatopsis strain isolated from a high altitude Atacama Desert subsurface soil was established using a polyphasic approach. The strain, isolate H5T, was shown to have chemical properties typical of members of the genus Amycolatopsis such as meso-diaminopimelic acid as the diamino acid in the cell wall peptidoglycan, arabinose and galactose as diagnostic sugars and MK-9(H4) as the predominant isoprenologue. It also has cultural and morphological properties consistent with its classification in the genus, notably the formation of branching substrate hyphae which fragment into rod-like elements. 16S rRNA gene sequence analyses showed that the strain is closely related to the type strain of Amycolatopsis mediterranei but could be distinguished from this and other related Amycolatopsis strains using a broad range of phenotypic properties. It was separated readily from the type strain of Amycolatopsis balhymycina, its near phylogenetic neighbour, based on multi-locus sequence data, by low average nucleotide identity (92.9%) and in silico DNA/DNA relatedness values (51.3%) calculated from draft genome assemblies. Consequently, the strain is considered to represent a novel species of Amycolatopsis for which the name Amycolatopsis vastitatis sp. nov. is proposed. The type strain is H5T (= NCIMB 14970T = NRRL B-65279T). PMID- 29428971 TI - Emergence of anti-mitochondrial M2 antibody in patient with angioimmunoblastic T cell lymphoma. AB - A 68-year-old woman was referred to our hospital due to fever and rash on the neck and extremities. Laboratory findings revealed hepatic dysfunction and positivity for anti-mitochondrial M2 antibody (AMA-M2). Hepatosplenomegaly and systemic lymphadenopathy were detected by enhanced computed tomography. One week after her first visit, hypoxemia, ascites, and Coomb test-positive autoimmune hemolytic anemia had newly appeared in addition to worsened fever, hepatosplenomegaly, and lymphadenopathy. Results of axillary lymph node, skin, and bone-marrow biopsies led to the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), for which CEPP therapy (cyclophosphamide, etoposide, procarbazine, and prednisolone) was initiated. Her serum levels of hepatobiliary enzymes normalized and AMA-M2 became negative after treatment. The unexpected positivity for AMA-M2 might have been caused by AITL cell-activated intrahepatic immune cells or the tumor cells themselves inflicting bile duct injury that mimicked primary biliary cholangitis. Alternatively, cross reactivity due to the overproduction of immunoglobulins may have caused this phenomenon. The present case may shed light on of the mechanisms of liver dysfunction accompanying AITL. PMID- 29428972 TI - The role of brain barriers in fluid movement in the CNS: is there a 'glymphatic' system? AB - Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K+, Ca2+, and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations. PMID- 29428973 TI - Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway. PMID- 29428974 TI - Malignant rhabdoid tumors originating within and outside the central nervous system are clinically and molecularly heterogeneous. AB - Multifocal synchronous or metachronous atypical teratoid rhabdoid tumors (ATRTs) and non-central nervous system malignant rhabdoid tumors (extra-CNS MRTs) are rare cancers. We reviewed the clinical and radiologic characteristics of affected patients seen at our institution. Genotyping and analysis of copy number abnormalities (CNAs) in SMARCB1 were performed in germline and tumor samples. Tumor samples underwent genome-wide DNA methylation and CNA analysis. The median age at diagnosis of 21 patients was 0.6 years. Two-thirds of ATRTs and extra-CNS MRTs were diagnosed synchronously. Although kidney tumors predominated, including two patients with bilateral involvement, at least 30% of cases lacked renal involvement. Histopathologic review confirmed MRTs in all cases and INI1 expression loss in all tumors tested. Fourteen (78%) of 18 patients tested had heterozygous germline SMARCB1 abnormalities. At least one allelic SMARCB1 abnormality was confirmed in 81 and 88% of ATRTs and extra-CNS MRTs, respectively. Unsupervised hierarchical clustering analysis of DNA methylation in 27 tumors and comparison with a reference group of 150 ATRTs classified the CNS tumors (n = 14) as sonic hedgehog (64%), tyrosinase (21%), and MYC (14%). The MYC subgroup accounted for 85% of 13 extra-CNS MRTs. Of 16 paired ATRTs and extra-CNS MRTs, the tumors in seven of eight patients showed a different pattern of genome wide DNA methylation and/or CNAs suggestive of non-clonal origin. CNS and extra CNS tumors had an identical SMARCB1 amplification (n = 1) or very similar DNA methylation pattern (n = 1) suggestive of clonal origin. All patients died of tumor progression. The clinical and molecular characteristics of multifocal ATRTs and extra-CNS MRTs are heterogeneous with most patients harboring a cancer predisposition. Although independent tumor origin was confirmed in most cases, metastatic spread was also documented. The recognition of their distinct molecular characteristics is critical in selecting new biologic therapies against these deadly cancers. PMID- 29428975 TI - 5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma. AB - Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG. PMID- 29428976 TI - Spa type distribution in MRSA and MSSA bacteremias and association of spa clonal complexes with the clinical characteristics of bacteremia. AB - The genetic distribution of invasive methicillin-susceptible (MSSA) and resistant S. aureus (MRSA) strains has to be addressed in order to target infection control strategies. A large MRSA epidemic caused by a certain MRSA strain (spa type 067) broke out in 2001 in our health district. We wanted to investigate the current spa type distribution in MRSA and MSSA bacteremias and assess the potential association of spa clonal complexes (spaCC) with the clinical characteristics of S. aureus bacteremia. One hundred nine invasive MRSA isolates and 353 invasive MSSA isolates were spa typed and grouped into clonal complexes (spaCC). Spa type distribution was compared to that of colonizing MRSA strains. Spa type and spaCC data linked to clinical information on the course of bacteremic cases was used to search for differences in virulence between strains. Spa type distribution in MRSA is less heterogenic than in MSSA. t067 dominates both in MRSA colonisations and in invasive findings. Among MSSA, no such dominating strains were found. Of spaCCs, mortality was the highest in spaCC 067 (25.6%). SpaCC 008 was more often associated with endocarditis than other CCs (22.7 vs 5.8%, p = 0.013), spaCC 2133 with skin infections (68.4 vs 36.4%, p = 0.007), and spaCC 012 with foreign body infections (25.0 vs 9.3%, p = 0.029) than other clonal complexes. A single successful strain can explain the major proportion of MRSA among S. aureus bacteremias. Certain spaCCs showed association with certain clinical characteristics. These findings suggest that S. aureus strains differ in their virulence and invasiveness. PMID- 29428978 TI - Overexpression of GPNMB predicts an unfavorable outcome of epithelial ovarian cancer. AB - OBJECTIVE: Glycoprotein non-metastatic protein B (GPNMB) is a transmembrane glycoprotein that is expressed at higher levels in several malignant human tissues than those in matched normal tissues. Thus, GPNMB may serve as an attractive therapeutic target of cancer treatment. In this study, the prognostic value of GPNMB expression was examined in tumors derived from a cohort of patients with epithelial ovarian cancer (EOC). METHODS: GPNMB expression in matched formalin-fixed and paraffin-embedded tissue samples was evaluated by immunohistochemistry (IHC), whereas GPNMB mRNA expression in fresh-frozen biopsy tissues was detected using real-time quantitative PCR (qPCR). Meanwhile, the correlations of GPNMB expression with the clinical characteristics of EOC were assessed. Besides, survival data were analysed using Kaplan-Meier and Cox regression analyses, respectively. RESULTS: GPNMB expression was remarkably upregulated in EOC tissues compared with that in normal ovarian controls at both mRNA and protein levels. In addition, abundant GPNMB expression in EOC was correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.001), residual tumor (P = 0.036), and lymph node metastasis (P = 0.004). Furthermore, results of univariate and multivariate analyses indicated that GPNMB expression level was an independent prognostic factor of the progression-free survival (PFS) and overall survival (OS) (P < 0.001 and P < 0.001, respectively) for EOC patients. CONCLUSION: Upregulated GPNMB levels in EOC patients are associated with dismal prognosis. Moreover, findings in the current study indicate that GPNMB is a potentially useful prognostic predictor of the therapeutic approaches for EOC. PMID- 29428979 TI - Relationship between copper IUD complications and ultrasonographic findings. AB - OBJECTIVE: Intrauterine device (IUD) is a widely used long-acting contraceptive method; however, the side-effects related to IUD may lead to method discontinuation. The aim of this study is to evaluate the relation between the most common side-effects of IUD use; mainly dysmenorrhea, menorrhaghia, pelvic cramping and the relation of these complications with the position of the IUD device within the cavity and uterine dimensions evaluated by transvaginal ultrasonography. MATERIAL AND METHOD: Two hundred and eighty-four patients who had Cu-T380A IUD insertion at the Family Planning Clinic of a tertiary health center were evaluated at insertion and 6 and 12 weeks after the insertion. Demographic characteristics, medical history, symptoms and findings of the gynecological examination were recorded. Transvaginal ultrasonographic measurement of the uterine dimensions, the distance between the tip of the Cu-IUD and the fundus, myometrium and endometrium were measured to evaluate the displacement of the IUD. The relationship between the symptoms and IUD displacement diagnosed by ultrasonographic examination were investigated. RESULTS: Two hundred and sixty-seven patients were followed-up for 12 weeks as the remaining 16 had partial or complete IUD expulsion. A statistically significantly shorter uterine length was measured in patients who complained of menorrhagia in comparison to the ones without this complaint (54.27 +/- 6.11 vs 60.25 +/- 10.52 mm, p = 0.02) while uterine length was similar in patients with or without dysmenorrhea at 12 weeks (59.60 +/- 10.25 vs 60.33 +/- 10.68 mm, p = 0.71). The distances between the tip of the IUD and the endometrium, myometrium and the uterine fundus, were statistically and significantly longer in patients who experienced pelvic cramping at 3rd month, showing a downward movement of the IUD. (Endometrium; 0.29 +/- 0.72 vs 0.45 +/- 0.35 mm, p = 0.02, Myometrium; 1.25 +/- 1.39 vs 2.38 +/- 2.26 mm p < 0.05, Fundus; 1.68 +/- 2.39 vs 2.92 +/- 1.78 mm, p < 0.05). CONCLUSION: A shorter uterine cavity length seems to be a predictor of menorrhagia in patients with Cu-T 380A IUD. Patients experiencing pelvic cramping with IUD are more susceptible for IUD expulsion as the downward movement of IUD is more prominent in these patients. PMID- 29428977 TI - Sleep disorders associated with risk of rheumatoid arthritis. AB - BACKGROUND: Immune disorders impair sleep quality and sleep disorders (SDs) may derange immune function. PURPOSE: The study evaluated the incidence and risk of rheumatoid arthritis (RA) in patients with SDs using a nationwide cohort. METHODS: We recognized the patients with SDs from 1998 to 2002 by using the Taiwan National Health Insurance Research Database. One control patient for each SD patient was randomly selected and matched based on the proportion of age, sex, and index year. We calculated the person years of follow-up for each participant from the index date to RA diagnosis, censoring, or until December 31, 2011. The risk of RA was estimated by using Cox models incorporating demographics and comorbidities. RESULTS: We enrolled 65,754 patients with SDs and 65,753 controls and followed for 637,906 and 662,514 person-years, respectively. The patients with SDs exhibited a 1.49-fold greater risk of RA development compared with the comparison cohort when we adjusted for covariates. The patients with sleep apnea (SA) showed the greatest incidence density rate of RA, followed by those with non apnea SDs and the non-SD cohort (4.11, 3.29, and 2.15 per 10,000 person-years, respectively). The SA cohort had a 2.56-fold adjusted hazard ratio (aHR) of RA (95% confidence interval [CI] = 1.11-5.91) and the non-apnea SD cohort had a 1.47 fold aHR of RA (95% CI = 1.18-1.84) compared with the non-SD cohort. Women with SDs presented a considerable risk of developing RA. CONCLUSIONS: This nationwide cohort study indicates that SDs are associated with the risk of RA development. PMID- 29428980 TI - Bone flap salvage in acute surgical site infection after craniotomy for tumor resection. AB - Craniotomy surgical site infections are an inherent risk and dreaded complication for the elective brain tumor patient. Sequelae can include delays in resumption in adjuvant treatments for multiple surgeries if staged cranioplasty is pursued. Here, the authors review their experience in operative debridement of surgical site infections with single-stage reimplantation of the salvaged craniotomy bone flap. A prospectively maintained database of a single surgeon's neuro-oncology patients from 2009 to 2017 (JRF) was queried to identify 11 patients with surgical site infection after craniotomy for tumor resection. All patients underwent a protocol of aggressive operative debridement including drilling the bone edges and intraoperative flap sterilization with single-stage reimplantation, followed by tailored-antibiotic therapy. Ten of the 11 patients with frankly contaminated bone flaps from surgical site infection were able to be salvaged in a single-stage procedure. Five of these patients underwent adjuvant chemotherapy and/or radiation without secondary complication. There was one treatment failure in a delayed fashion which required additional surgery for craniectomy; however, this occurred after adjuvant treatment was administered. Surgical debridement and bone flap salvage is safe and cost-effective in managing acute surgical site infections after craniotomy for tumors. Additionally, this practice is likely beneficial in expediting the resumption of cancer therapy. PMID- 29428982 TI - Draft genome of the fungicidal biological control agent Burkholderia anthina strain XXVI. AB - Burkholderia anthina XXVI is a rhizosphere bacterium isolated from a mango orchard in Mexico. This strain has a significant biological control activity against the causal agent of mango anthracnose, Colletotrichum gloeosporioides, likely through the production of siderophores and other secondary metabolites. Here, we present a draft genome sequence of B. anthina XXVI (approximately 7.7 Mb; and G + C content of 67.0%), with the aim of gaining insight into the genomic basis of antifungal modes of action, ecological success as a biological control agent, and full biosynthetic potential. PMID- 29428981 TI - Factors associated with clinical and radiological status on admission in patients with aneurysmal subarachnoid hemorrhage. AB - Grading scales yield objective measure of the severity of aneurysmal subarachnoid hemorrhage and serve as to guide treatment decisions and for prognostication. The purpose of this cohort study was to determine what factors govern a patient's disease-specific admission scores in a representative Central European cohort. The Swiss Study of Subarachnoid Hemorrhage includes anonymized data from all tertiary referral centers serving subarachnoid hemorrhage patients in Switzerland. The 2009-2014 dataset was used to evaluate the impact of patient and aneurysm characteristics on the patients' status at admission using descriptive and multivariate regression analysis. The primary/co-primary endpoints were the GCS and the WFNS grade. The secondary endpoints were the Fisher grade, the presence of a thick cisternal or ventricular clot, the presence of a new focal neurological deficit or cranial nerve palsy, and the patient's intubation status. In our cohort of 1787 consecutive patients, increasing patient age by 10 years and low pre-ictal functional status (mRS 3-5) were inversely correlated with "high" GCS score (GCS >= 13) (OR 0.91, 95% CI 0.84-0.97 and OR 0.67, 95% CI 0.31 1.46), "low" WFNS grade (grade VI-V) (OR 1.21, 95% CI 1.04-1.20 and OR 1.47, 95% CI 0.66-3.27), and high Fisher grade (grade III-IV) (OR 1.08, 95% CI 1.00-1.17 and OR 1.54, 95% CI 0.55-4.32). Other independent predictors for the patients' clinical and radiological condition at admission were the ruptured aneurysms' location and its size. In sum, chronological age and pre-ictal functional status, as well as the ruptured aneurysm's location and size, determine the patients' clinical and radiological condition at admission to the tertiary referral hospital. PMID- 29428983 TI - Low-grade systemic inflammation is associated with functional disability in elderly people affected by dementia. AB - The decline in basic and instrumental activities of daily living (BADLs and IADLs, respectively) is a well-established clinical hallmark of dementia. Growing evidence has shown that systemic subclinical inflammation may be related to functional impairment. We evaluated the possible association between low-grade systemic inflammation and functional disability in older individuals affected by dementia. We explored the association between high-sensitivity C-reactive protein (hs-CRP) levels and BADLs/IADLs in older individuals affected by late onset Alzheimer's disease (LOAD; n 110), "mixed" dementia (n 135), or mild cognitive impairment (MCI; n 258), and compared them with 75 normal Controls. Independent of age, gender, comorbidity, and other potential confounders, higher hs-CRP was significantly associated with poorer BADLs (loss >= 1 function) in people with LOAD (odds ratio [OR] 3.14, 95% confidence interval [CI], 1.33-7.33) and mixed dementia (OR 2.48, 95%CI 1.12-5.55), but not in those with MCI (OR 1.38, 95%CI 0.83-2.45) or Controls (OR 2.98, 95%CI 0.54-10.10). No association emerged between hs-CRP and IADLs in any of the sub-group. Our data suggest that systemic low-grade inflammation may contribute to functional disability in older patients with dementia. PMID- 29428984 TI - Tibial component coverage and rotational alignment accuracy after mobile-bearing total knee arthroplasty. AB - BACKGROUND: Tibial component coverage (TCC) and tibial rotational angle (TRA) have been studied simultaneously in simulations, but not in clinical studies after total knee arthroplasty (TKA). The purposes of this study were (1) to evaluate TCC and rotational setting postoperatively in mobile-bearing TKA patients and (2) to compare the results with previously published simulation data. METHODS: We prospectively examined 100 patients who underwent primary TKA using the LCS(r) Total Knee System (LCS) posterior cruciate ligament-substituting prosthesis. Clinical outcomes, TCC (coverage area of the tibial component over the tibia), and TRA (relative to the femoral transepicondylar axis (TEA)) were assessed. Quantitative three-dimensional computed tomography was used to assess TCC and TRA. All values are expressed as median (25th percentile, 75th percentile) using minus (-) for internal and plus (+) for external rotation. RESULTS: Hospital for Special Surgery scores improved from 46 (36, 50) preoperatively to 92 (90, 92) postoperatively. TRA showed a median divergence of 2.0 degrees (- 4.75 degrees , + 2.74 degrees ). All knees were located within 10 degrees of the TEA (range - 10.0 degrees to + 9.7 degrees ). The median TCC of the knees was 82.7% (80.6, 84.7%), and there were no knees that hung over the tibial component in any direction. CONCLUSIONS: The LCS prosthesis had good clinical outcomes, comparable TCC, and improved TRA as compared to previous reports, as all knees were located within 10 degrees of the TEA. Simultaneous optimization of both TCC and TRA may contribute to the excellent long-term outcomes that have been observed with this system. LEVEL OF EVIDENCE: Level II, Prognostic study. PMID- 29428985 TI - Literature review and a case report of spontaneous subscapular abscess in a child. AB - Subscapular space is an uncommon site for abscess formation. There are only seven reports of subscapular abscesses in the literature. Only three of these cases are reported in children. We recently treated a child with subscapular abscess. We performed the literature search using a combination of the keywords: subscapular, scapular, abscess and infection. One case was diagnosed on post-mortem autopsy, and only three of these cases are reported in children. The organism was Staphylococcus aureus in five cases (two were methicillin-resistant S. aureus), Haemophilus influenzae in one case, and no organism was grown in the last case. (Patient received a course of empirical antibiotics and samples did not grow any organism.) We describe a case of spontaneous subscapular abscess in a 7-year-old boy. The abscess was visualised on magnetic resonance imaging (MRI), and the organism was identified as S. aureus bacteria. The abscess was treated surgically with debridement and antibiotics, and the patient had full recovery with no subsequent effects. Subscapular abscess needs high index of suspicion and early imaging investigation. MRI is the modality of choice for accurate diagnosis. Early intervention leads to favourable outcome, while delays in diagnosis can be fatal. PMID- 29428987 TI - Scope of Knowledge About Zika Among Women in US-Mexico Border Communities. AB - Maternal Zika virus infection (ZIKV) has serious health consequences for unborn offspring. Knowledge about prevention is critical to reducing risk, yet what women in the high-risk US-Mexico border region know about protecting themselves and their babies from ZIKV is mostly unknown. This study aimed to assess knowledge of ZIKV among pregnant and inter-conception women and to identify sources of information that might address knowledge gaps. Clients in five federally-funded, border region Healthy Start programs (N = 326) were interviewed in late 2016 about their knowledge of ZIKV prevention methods and whether they believed themselves or their babies to be at risk. Sources of information about ZIKV and demographic characteristics were also measured. Chi square tests identified important associations between variables; adjusted odds ratios (AOR) and 95% confidence intervals for knowledge and beliefs were calculated. Among the 305 women aware of ZIKV, 69.5% could name two ways to prevent infection. Only 16.1% of women named using condoms or abstaining from sex as a prevention method. While 75.3% heard about ZIKV first from TV/radio, just 9.5% found the information helpful. Women who received helpful information from health care providers had greater odds of knowing two prevention methods (AOR = 2.0; 1.1-3.7), when to test for ZIKV (AOR = 5.2; 2.1-13.2), and how long to delay pregnancy after infection in a male partner (AOR = 1.9; 1.1-3.2). Those who said web-based and social media sources were helpful had greater odds of knowing when to test for ZIKV (AOR = 2.8; 1.3-6.3). Results can inform messaging for safe pregnancy and ZIKV prevention. PMID- 29428986 TI - A Cardiovascular Health Intervention for Spanish Speakers: The Health Literacy and ESL Curriculum. AB - Spanish speakers in the United States are in need of effective interventions that address both cardiovascular disease (CVD) and health literacy. However, the literature lacks interventions that have used and evaluated a strategies that focus on both, particularly at the community level. The aim of this study was to explore the effect of a health literacy curriculum on cardiovascular health behavior among Spanish speaking adults. It used a randomized controlled pre posttest design. Participants included Hispanic adults with a low-to-intermediate level of English proficiency. The intervention group received the health literacy and English as a second language (ESL) Curriculum with CVD specific content, while the control group received a conventional ESL curriculum. Tools included the Spanish Cardiovascular Health Questionnaire (CSC), the test of functional health literacy in adults (TOFHLA), and the Combined English Language Skills Assessment. Analysis of change scores included independent sample t test and multiple linear regression. A total of 155 participants completed the study. There was a significant greater improvement for the intervention group in change of CSC score from pretest to posttest (P = 0.049) compared to controls. The study also found significantly improved TOFHLA (P = 0.011), however it did not find a relationship between changes in CVD behavior and health literacy or English proficiency. The Health Literacy and ESL Curriculum constitutes a valuable resource for addressing the cardiovascular health, literacy, and language needs of Spanish-speaking adults. Interventions that take a multilevel education and health approach may be more effective in addressing the needs of immigrants. Research should further explore the interactions between CVD behavior, health literacy, and English proficiency. PMID- 29428988 TI - Why Public Health Researchers Should Consider Using Disability Data from the American Community Survey. AB - The United States (US) federal government allocates hundreds of billions of dollars to provide resources to Americans with disabilities, older adults, and the poor. The American Community Survey (ACS) influences the distribution of those resources. The specific aim of the project is to introduce health researchers to Public Use Microdata Sample file from 2009 to 2011. The overall goal of our paper is to promote the use of ACS data relevant to disability status. This study provides prevalence estimates of three disability related items for the population at or over the age of 15 years who reside in one of the continental states. When population weights are applied to the 7,198,221 individuals in the sample under analysis, they are said to represent 239,641,088 of their counterparts in the US population. Detailed tabulations by state (provided as Microsoft Excel(r) spreadsheets in ACS output) clearly show disability prevalence varies from state-to-state. Because analyses of the ACS data have the ability to influence resources aiding individuals with physical mobility challenges, its use should be promoted. Particular attention should be given to monetary allocations which will improve accessibility of the existing built environment for the individuals with mobility impairment. PMID- 29428989 TI - Determination of oligomers in virgin and recycled polyethylene terephthalate (PET) samples by UPLC-MS-QTOF. AB - An oligomer is a molecule that consists of a few monomer units. It can be formed during polymer manufacturing and also due to polymer degradation processes or even during use conditions. Since oligomers are not included in chemical databases, their identification is a complex process. In this work, the oligomers present in 20 different PET pellet samples have been determined. Two different sample treatment procedures, solvent extraction and total dissolution, were applied in order to select the most efficient one. The analyses were carried out by UPLC-MS-QTOF. The use of high resolution mass spectrometry allowed the structural elucidation of these compounds and their correct identification. The main oligomers identified were cyclic as well as lineal from the first, second, and third series. All of them were composed of terephthalic acid (TPA), diethylene glycol (DEG), and ethylene glycol (EG). Quantitative values were very different in both procedures. In total dissolution of PET samples, the concentration of oligomers was always, at least, 10 times higher than in solvent extraction; some of the compounds were only detected when total dissolution was used. Results showed that the oligomers with the highest concentration values were dimers and trimers, cyclic, as well as lineal, from the first and second series. The oligomer with the maximum concentration value was TPA2-EG-DEG that was found in all the samples in a concentration range from 2493 to 19,290 ng/g PET. No differences between virgin and recycled PET were found. Migration experiments were performed in two PET bottles, and results showed the transference of most of these oligomers to a fat food simulant (ethanol 95%). Graphical abstract Graphical abstract of the two procedures developd and optimized for identifying oligomers in PET pellets and in migration form PET bottles. PMID- 29428990 TI - Fluorescent MUA-stabilized Au nanoclusters for sensitive and selective detection of penicillamine. AB - In this study, we have developed a facile method for preparation of highly fluorescent Au nanoclusters (AuNCs) using 11-mercaptoundecanoic acid (MUA) as both the reducing and stabilizing agent. The as-prepared MUA functionalized AuNCs (MUA-AuNCs) have good water solubility, excellent photostability, and strong fluorescence emission at 610 nm with a quantum yield of 7.28% in water. The fluorescence of MUA-AuNCs was first quenched by copper ions through electron transfer, subsequently caused obvious restoration by competitive effect after adding penicillamine, making it a potential fluorescent sensor for penicillamine with a detection limit of 0.08 MUM. Furthermore, the newly designed fluorescence "on-off-on" assay was explored for the measurement of penicillamine in complex real water and urine samples with satisfactory results. PMID- 29428991 TI - Development of orthogonal NISTmAb size heterogeneity control methods. AB - The NISTmAb is a monoclonal antibody Reference Material from the National Institute of Standards and Technology; it is a class-representative IgG1kappa intended to serve as a pre-competitive platform for harmonization and technology development in the biopharmaceutical industry. The publication series of which this paper is a part describes NIST's overall control strategy to ensure NISTmAb quality and availability over its lifecycle. In this paper, the development of a control strategy for monitoring NISTmAb size heterogeneity is described. Optimization and qualification of size heterogeneity measurement spanning a broad size range are described, including capillary electrophoresis-sodium dodecyl sulfate (CE-SDS), size exclusion chromatography (SEC), dynamic light scattering (DLS), and flow imaging analysis. This paper is intended to provide relevant details of NIST's size heterogeneity control strategy to facilitate implementation of the NISTmAb as a test molecule in the end user's laboratory. Graphical abstract Representative size exclusion chromatogram of the NIST monoclonal antibody (NISTmAb). The NISTmAb is a publicly available research tool intended to facilitate advancement of biopharmaceutical analytics. HMW = high molecular weight (trimer and dimer), LMW = low molecular weight (2 fragment peaks). Peak labeled buffer is void volume of the column from L-histidine background buffer. PMID- 29428992 TI - Sensitive analysis of N-blocked amino acids using high-performance liquid chromatography with paired ion electrospray ionization mass spectrometry. AB - In this study, a paired ion electrospray ionization (PIESI) mass spectrometry method was developed for sensitive detection of 9-fluorenylmethyl chloroformate (Fmoc)-derivatized amino acids. The structure-optimized ion-pairing reagent was introduced post column to form positively charged complexes which can be detected in the positive ion mode. These complexes are more surface-active than the original analytes, and meanwhile, the intensity of sodium adducts was significantly reduced. The limit of detection of the amino acids obtained with the optimal ion-pairing reagent was 0.5 to 20 pg which was 5-100 times lower than the negative mode. In addition, two mass spectrometry platforms-linear ion trap and triple quadrupole-were used to compare the PIESI improvements. Eventually, the method was applied to successfully detect the level of amino acids in human urine samples with high accuracy and the added benefit of minimizing matrix effects. Graphical abstract A HPLC-ESI-MS/MS method by using ion-pairing reagents for sensitive detection of Fmoc amino acids. PMID- 29428993 TI - High-performance liquid chromatography for the analytical characterization of anthocyanins in Vaccinium myrtillus L. (bilberry) fruit and food products. AB - Anthocyanins represent the most abundant class of bioactive compounds present in Vaccinium myrtillus L. (bilberry) fruit, conferring it several health-promoting properties. The content of anthocyanins in food products produced from bilberries can be affected by many parameters, making the study of their composition a critical issue. In this ambit, this work was aimed at a comprehensive profiling of anthocyanins in bilberry fruit and derivatives from the Italian Northern Apennines, including jam, juice, and liqueur ("Mirtillino"). Anthocyanins were extracted from the jams by means of a dynamic maceration with acidified methanol, while juice and liqueurs were directly analyzed. The analysis of anthocyanins in the extracts was carried out by means of HPLC-UV/DAD, HPLC-ESI-MS, and MS2, under gradient elution. As a comparison, authentic bilberry fruits were analyzed. The total anthocyanin content was in the range 582.4-795.2 mg/100 g (FW) for the fruit, 2.3-234.5 mg/100 g for the jams, 109.2-2252.2 mg/L for the juice, and 27.9 759.3 mg/L for the liqueurs. To deeper investigate the anthocyanin profile of the liqueurs that exhibited a remarkably different composition in comparison with the other products, an authentic bilberry liqueur was prepared in the lab, following a traditional recipe, and monitored weakly by HPLC. The percentage of degradation of 3-O-galactosides and 3-O-arabinosides of bilberry anthocyanidins was found to be higher than that of 3-O-glucosides. The results of this work demonstrated the importance of a suitable and reliable analysis of bilberry fruit and related food products to ensure their genuineness and quality. Graphical abstract Vaccinium myrtillus L. (bilberry) fruit and food products analyzed in this work. PMID- 29428994 TI - Occipitalis muscle: using for repetitive facial nerve stimulation in myasthenia gravis. AB - Repetitive nerve stimulation (RNS) is a highly sensitive electrophysiological test used for diagnosing myasthenia gravis (MG). Here, we evaluated electrodiagnostic value of RNS using facial nerve and occipitalis muscle. Patients with generalized MG were included. Clinical findings were assessed. RNS test was performed on occipitalis, nasalis, trapezius, abductor policis brevis (APB) and abductor digiti minimi (ADM) muscles. Twenty-five (78%) patients had relevant decrement during RNS test of at least one muscle. Nasalis muscle had the highest diagnostic potential (68.8%), followed by trapezius (53.3%), occipitalis (50%), APB (30%) and ADM (16.7%) muscles. There was not a significant relationship between clinical symptoms and facial RNS recorded on occipitalis muscle. In conclusion, we suggest that facial RNS recording over occipitalis muscle can be added in electrodiagnosis of MG because of cranial nerve innervation and proximal location. Facial RNS recording over occipitalis muscle provides a good choice under the conditions such as atrophy, cosmetic surgery, or botulinum toxin application in which nasalis muscle is unavailable for use. PMID- 29428996 TI - Enhancing Understanding of Postpartum Pain Among Migrant and Non-migrant Women Through a Qualitative Lens. PMID- 29428995 TI - Dyskinesias and levodopa therapy: why wait? AB - Throughout the years there has been a longstanding discussion on whether levodopa therapy in Parkinson's disease should be started in early vs. later stages, in order to prevent or delay motor complications such as fluctuations and dyskinesias. This controversial topic has been extensively debated for decades, and the prevailing view today is that levodopa should not be postponed. However, there is still fear associated with its use in early stages, especially in younger patients, who are more prone to develop dyskinesias. Even though dyskinesias are linked to levodopa use in Parkinson's disease, it has been shown that starting with a different medication (such as dopamine agonists) will not significantly delay their onset once levodopa is introduced. Since levodopa provides better symptomatic control, and other drugs may be associated with notable side effects, it is our view that there is insufficient evidence to justify levodopa-sparing strategies. The physician should try to assess each patient individually, taking into account motor and non-motor demands, as well as risk factors for potential complications, finding the optimum treatment strategy for each one. The following article provides an historical narrative perspective, as well as a literature review of those intrinsic and modifiable risk factors that have been associated with levodopa-induced dyskinesias, which should be taken into consideration when choosing the therapeutic strategy in individual Parkinson's disease patients. PMID- 29428997 TI - Synthesis of zeolite membranes on calcium silicate support and their bioactive response. AB - The synthesis of calcium silicate supported zeolite membrane was carried out by second growth method. The chemical nature of the functionalizing agent on the formation of homogenous zeolite membrane was evaluated. One monomer and two cationic polymers were used: 3-aminopropyltriethoxysilane (APS), polyethylenimine (PEI) and polydiallyldimethylammonium chloride (PDDA). The support was subjected to chemical functionalization and then it was rubbed with zeolite crystals. The W zeolite was used as zeolite seed in two different Si/Al ratios. The functionalized and rubbed supports were submitted to hydrothermal treatment at 150 degrees C for 48 h. The bioactivity of the homogeneous zeolite membranes was evaluated by the biomimetic method through the membranes soaking in a simulated body fluid (SBF) at 37 degrees C for 21 days. Two immersion methods were evaluated. The products were characterized by XRD and SEM techniques. The results indicated that the supported functionalization with PDDA and the Si/Al ratio (higher than 1.8) of zeolite enhanced the interaction between the support and the zeolite precursor enhancing the formation of homogeneous zeolite membrane on the surface. The presence of the functional groups of PDDA on the membrane was detected by FTIR. After immersion in SBF, the zeolite membrane was stable and led to the formation of Ca-P layer on its surface. The re-immersion method led to the formation of richer Ca/P layer (1.36). These findings allowed generating a zeolite membrane with combined properties of calcium silicate and the controllable porosity of zeolitic material making it potentially useful for bone regeneration and drug releasing. PMID- 29428998 TI - Turbulence accelerates the growth of drinking water biofilms. AB - Biofilms are found at the inner surfaces of drinking water pipes and, therefore, it is essential to understand biofilm processes to control their formation. Hydrodynamics play a crucial role in shaping biofilms. Thus, knowing how biofilms form, develop and disperse under different flow conditions is critical in the successful management of these systems. Here, the development of biofilms after 4 weeks, the initial formation of biofilms within 10 h and finally, the response of already established biofilms within 24-h intervals in which the flow regime was changed, were studied using a rotating annular reactor under three different flow regimes: turbulent, transition and laminar. Using fluorescence microscopy, information about the number of microcolonies on the reactor slides, the surface area of biofilms and of extracellular polymeric substances and the biofilm structures was acquired. Gravimetric measurements were conducted to characterise the thickness and density of biofilms, and spatial statistics were used to characterise the heterogeneity and spatial correlation of biofilm structures. Contrary to the prevailing view, it was shown that turbulent flow did not correlate with a reduction in biofilms; turbulence was found to enhance both the initial formation and the development of biofilms on the accessible surfaces. Additionally, after 24-h changes of the flow regime it was indicated that biofilms responded to the quick changes of the flow regime. Overall, this work suggests that different flow conditions can cause substantial changes in biofilm morphology and growth and specifically that turbulent flow can accelerate biofilm growth in drinking water. PMID- 29429000 TI - Prunus cerasoides fruit extract ameliorates inflammatory stress by modulation of iNOS pathway and Th1/Th2 immune homeostasis in activated murine macrophages and lymphocytes. AB - The present investigation assessed the potential of Prunus cerasoides fruit extract (PCFE) in alleviation of inflammatory stress in response to lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma)-stimulated murine peritoneal macrophages as well as in concanavalin A (Con A)-activated splenic lymphocytes. We observed a strong inhibition in production of nitric oxide (NO), reactive oxygen species (ROS), inflammatory cytokines (TNF-alpha/IL-6/IL-1beta), inducible nitric oxide synthase (iNOS), and NF-kB in macrophages treated with PCFE. Splenic lymphocytes treated with PCFE also showed a reduction in Con-A induced cell proliferation and numbers of CD3+CD4+ T cells. Furthermore, PCFE treatment to Con A-stimulated lymphocytes decreased the production of inflammatory cytokines (TNF-alpha/IL-6/IL-1beta) with a concomitant increase in IL-10 suggesting its possible role in alleviation of inflammation-driven Th1/Th2 immune imbalance. PCFE appeared to influence innate immune response even at lower concentrations (25 and 50 ug/ml), while such effects were more pronounced in lymphocytes only at higher concentrations (100 and 200 ug/ml). UPLC-ESI-MS of PCFE revealed the presence of major bioactive phenolics including catechin, naringin as well as ascorbic acid which could have contributed in above findings. Overall, it is indicative that P. cerasoides fruit could be a valuable source for the development of anti-inflammatory functional foods and nutraceuticals. PMID- 29428999 TI - Prospective evaluation of insulin and incretin dynamics in obese adults with and without diabetes for 2 years after Roux-en-Y gastric bypass. AB - AIMS/HYPOTHESIS: In this prospective case-control study we tested the hypothesis that, while long-term improvements in insulin sensitivity (SI) accompanying weight loss after Roux-en-Y gastric bypass (RYGB) would be similar in obese individuals with and without type 2 diabetes mellitus, stimulated-islet-cell insulin responses would differ, increasing (recovering) in those with diabetes but decreasing in those without. We investigated whether these changes would occur in conjunction with favourable alterations in meal-related gut hormone secretion and insulin processing. METHODS: Forty participants with type 2 diabetes and 22 participants without diabetes from the Longitudinal Assessment of Bariatric Surgery (LABS-2) study were enrolled in a separate, longitudinal cohort (LABS-3 Diabetes) to examine the mechanisms of postsurgical diabetes improvement. Study procedures included measures of SI, islet secretory response and gastrointestinal hormone secretion after both intravenous glucose (frequently sampled IVGTT [FSIVGTT]) and a mixed meal (MM) prior to and up to 24 months after RYGB. RESULTS: Postoperatively, weight loss and SI-FSIVGTT improvement was similar in both groups, whereas the acute insulin response to glucose (AIRglu) decreased in the non-diabetic participants and increased in the participants with type 2 diabetes. The resulting disposition indices (DIFSIVGTT) increased by three to ninefold in both groups. In contrast, during the MM, total insulin responsiveness did not significantly change in either group despite durable increases of up to eightfold in postprandial glucagon-like peptide 1 levels, and SI-MM and DIMM increased only in the diabetes group. Peak postprandial glucagon levels increased in both groups. CONCLUSIONS/INTERPRETATION: For up to 2 years following RYGB, obese participants without diabetes showed improvements in DI that approach population norms. Those with type 2 diabetes recovered islet-cell insulin secretion response yet continued to manifest abnormal insulin processing, with DI values that remained well below population norms. These data suggest that, rather than waiting for lifestyle or medical failure, RYGB is ideally considered before, or as soon as possible after, onset of type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00433810. PMID- 29429001 TI - Essential oil from waste leaves of Curcuma longa L. alleviates skin inflammation. AB - BACKGROUND: Curcuma longa L. is an important industrial crop used by medicinal and cosmetic industries in the world. Its leaves are a waste material after harvesting rhizomes. The aim of the study was to evaluate the chemical and pharmacological profile of essential oil from waste leaves of Curcuma longa (EOCl) against skin inflammation. METHODS: EOCl was subjected to gas chromatography (GC) analysis for identification of essential oil constituents and its anti-inflammatory evaluation through in vitro and in vivo models. RESULTS: Chemical fingerprinting using GC and GC-MS analysis of EOCl revealed the presence of 11 compounds, representing 90.29% of the oil, in which terpinolene (52.88%) and alpha-phellandrene (21.13%) are the major components. In the in vitro testing EOCl inhibited the production of pro-inflammatory cytokines (TNF-alpha, IL-6, IL 1beta) in lipopolysaccharide (LPS) and 12-O-tetradecanoylphorbol-13-acetate (TPA) induced inflammation in the human keratinocyte cell line (HaCaT). Topical application of EOCl produced anti-inflammatory effects by reducing ear thickness, ear weight and ameliorating the level of pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta) at protein and mRNA levels as well as regulating the overproduction of oxidative markers and restoring the histopathological damage in a TPA-induced mouse model of inflammation. CONCLUSION: These findings of topical anti-inflammatory properties of EOCl provide a scientific basis for medicinal use of this plant material against inflammatory disorders. PMID- 29429002 TI - Interleukin 6-Mediated Endothelial Barrier Disturbances Can Be Attenuated by Blockade of the IL6 Receptor Expressed in Brain Microvascular Endothelial Cells. AB - Compromised blood-brain barrier (BBB) by dysregulation of cellular junctions is a hallmark of many cerebrovascular disorders due to the pro-inflammatory cytokines action. Interleukin 6 (IL6) is implicated in inflammatory processes and in secondary brain injury after subarachnoid hemorrhage (SAH) but its role in the maintenance of cerebral endothelium still requires a precise elucidation. Although IL6 has been shown to exert pro-inflammatory action on brain microvascular endothelial cells (ECs), the expression of one of the IL6 receptors, the IL6R is controversially discussed. In attempt to reach more clarity in this issue, we present here an evident baseline expression of the IL6R in BBB endothelium in vivo and in an in vitro model of the BBB, the cEND cell line. A significantly increased expression of IL6R and its ligand was observed in BBB capillaries 2 days after experimental SAH in mice. In vitro, we saw IL6 administration resulting in an intracellular and extracellular elevation of IL6 protein, which was accompanied by a reduced expression of tight and adherens junctions, claudin-5, occludin, and vascular-endothelial (VE-) cadherin. By functional assays, we could demonstrate IL6-incubated brain ECs to lose their endothelial integrity that can be attenuated by inhibiting the IL6R. Blockade of the IL6R by a neutralizing antibody has reconstituted the intercellular junction expression to the control level and caused a restoration of the transendothelial electrical resistance of the cEND cell monolayer. Our findings add depth to the current understanding of the involvement of the endothelial IL6R in the loss of EC integrity implicating potential therapy options. PMID- 29429004 TI - Photodynamic therapy for periungual pyogenic granuloma-like during chemotherapy: our preliminary results. PMID- 29429003 TI - Parathyroid autotransplantation in thyroid surgery. AB - BACKGROUND: Careful parathyroid gland dissection and in situ preservation was the time-honored approach to prevent parathyroid failure after total thyroidectomy. The relative success of parathyroid autotransplantation of hyperplastic parathyroid tissue in patients with renal or hereditary hyperparathyroidism did popularize the use of normal parathyroid tissue autografts during thyroidectomy to prevent permanent hypoparathyroidism. Proof of autograft function in this setting, however, is controversial. PURPOSE: This narrative review aims at reviewing critically the current status of parathyroid autotransplantation during total thyroidectomy. It is also meant to analyze from the historical, methodological, and clinical points of view the claimed benefit of normal parathyroid gland autotransplantation. A focus is placed on the prevention of permanent hypoparathyroidism by parathyroid autotransplantation. CONCLUSIONS: Liberal parathyroid autotransplantation was proposed in the mid 1970s but evidence of function is scarce. Proofs are accumulating that parathyroid autografts not only increase the rate of postoperative hypocalcemia, but may be also contribute to permanent hypoparathyroidism. PMID- 29429005 TI - New frontier: cancer pain management clinical fellowship. AB - Cancer pain is a multi-dimensional experience, varies from person to person both physically and psycho-socially, and impacts all aspects of the patients' quality of life. Majority of patients with an advanced or metastatic cancer will experience pain. It is estimated that as many as half of cancer patients are under-treated and as many as 20% experience pain refractory to the conventional WHO ladder of pain management. The McGill University Health Centre (MUHC) Cancer Pain Clinic (CPC) was created to meet the needs of those patients with a diagnosis of cancer whose pain had become a main symptom and those who failed to respond to conventional treatment. The clinic offers a unique interdisciplinary approach with a core team that includes an anesthesiologist, a palliative care physician, a radiation oncologist, a nurse clinician specialist in oncology and palliative care, and, recently, also an interventional radiologist. A cancer pain clinical fellowship was offered for the first time in July 2016. It provides intense training in the classification, epidemiology, pathophysiology, and treatment of cancer pain. Through our education program, the fellow learns to appreciate, weigh, and respond to the full spectrum of factors influencing a specific patient's condition and to develop a tailor-made care plan. To our knowledge, it is the only fellowship program in existence that focuses exclusively on cancer pain. We see it as a beacon and hope that our graduate fellows become professional leaders with a quest not only to provide the best possible care but also to raise awareness of the humanitarian need to control cancer pain. PMID- 29429006 TI - Exercise capacity and cancer-specific quality of life following curative intent treatment of stage I-IIIA lung cancer. AB - PURPOSE: Lung cancer survivors are at risk for health impairments resulting from the effects and/or treatment of lung cancer and comorbidities. Practical exercise capacity (EC) assessments can help identify impairments that would otherwise remain undetected. In this study, we characterized and analyzed the association between functional EC and cancer-specific quality of life (QoL) in lung cancer survivors who previously completed curative intent treatment. METHODS: In a cross sectional study of 62 lung cancer survivors who completed treatment >= 1 month previously, we assessed functional EC with the 6-min walk distance (6MWD) and cancer-specific QoL with the European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC-QLQ-C30). Cancer-specific QoL was defined using a validated composite EORTC-QLQ-C30 summary score. Univariable (UVA) and multivariable linear regression analyses (MVA) were performed to assess the relationship between functional EC and cancer-specific QoL. RESULTS: Lung cancer survivors had reduced functional EC (mean 6MWD = 335 m, 65% predicted) and QoL (mean EORTC-QLQ-C30 summary score = 77, scale range 0-100). In UVA, 6MWD was significantly associated with cancer-specific QoL (R2 = 0.16, p = 0.001). In MVA, in a final model that also included heart failure, obstructive sleep apnea, and psychiatric illness, 6MWD was independently associated with cancer-specific QoL (partial R2 = 0.20, p = 0.001). CONCLUSIONS: Functional EC was independently associated with cancer-specific QoL in lung cancer patients postcurative intent treatment. Exercise-based interventions aimed at improving EC may improve cancer specific QoL in these patients. PMID- 29429007 TI - Cr(VI) reduction and physiological toxicity are impacted by resource ratio in Desulfovibrio vulgaris. AB - Desulfovibrio spp. are capable of heavy metal reduction and are well-studied systems for understanding metal fate and transport in anaerobic environments. Desulfovibrio vulgaris Hildenborough was grown under environmentally relevant conditions (i.e., temperature, nutrient limitation) to elucidate the impacts on Cr(VI) reduction on cellular physiology. Growth at 20 degrees C was slower than 30 degrees C and the presence of 50 MUM Cr(VI) caused extended lag times for all conditions, but once growth resumed the growth rate was similar to that without Cr(VI). Cr(VI) reduction rates were greatly diminished at 20 degrees C for both 50 and 100 MUM Cr(VI), particularly for the electron acceptor limited (EAL) condition in which Cr(VI) reduction was much slower, the growth lag much longer (200 h), and viability decreased compared to balanced (BAL) and electron donor limited (EDL) conditions. When sulfate levels were increased in the presence of Cr(VI), cellular responses improved via a shorter lag time to growth. Similar results were observed between the different resource (donor/acceptor) ratio conditions when the sulfate levels were normalized (10 mM), and these results indicated that resource ratio (donor/acceptor) impacted D. vulgaris response to Cr(VI) and not merely sulfate limitation. The results suggest that temperature and resource ratios greatly impacted the extent of Cr(VI) toxicity, Cr(VI) reduction, and the subsequent cellular health via Cr(VI) influx and overall metabolic rate. The results also emphasized the need to perform experiments at lower temperatures with nutrient limitation to make accurate predictions of heavy metal reduction rates as well as physiological states in the environment. PMID- 29429008 TI - From Using Tools to Using Language in Infant Siblings of Children with Autism. AB - Forty-one high-risk infants (HR) with an older sibling with autism spectrum disorder (ASD) were observed longitudinally at 10, 12, 18 and 24 months of age during a tool use task in a play-like scenario. Changes in grasp types and functional actions produced with a spoon were assessed during elicited tool use. Outcome and vocabulary measures were available at 36 months, distinguishing: 11 HR-ASD, 15 HR-language delay and 15 HR-no delay. Fewer HR-ASD infants produced grasp types facilitating spoon use at 24 months and functional actions at 10 months than HR-no delay. Production of functional actions in HR infants at 10 months predicted word comprehension at 12 months and word production at 24 and 36 months. PMID- 29429009 TI - Brief Report: Self-Injurious Behaviors in Preschool Children with Autism Spectrum Disorder Compared to Other Developmental Delays and Disorders. AB - We compared the prevalence of self-injurious behaviors (SIB) in preschoolers aged 30-68 months with autism spectrum disorder (ASD) (n = 691) versus other developmental delays and disorders (DD) (n = 977) accounting for sociodemographic, cognitive, and medical factors. SIB prevalence was higher in ASD versus all DD [adjusted odds-ratio (aOR) 2.13 (95% confidence interval (95% CI) 1.53, 2.97)]. In subgroup analyses, SIB prevalence was higher in ASD versus DD without ASD symptoms [aOR 4.42 (95% CI 2.66, 7.33)], but was similar between ASD and DD with ASD symptoms [aOR 1.09 (95% CI 0.68, 1.77)]. We confirmed higher prevalence of SIB in ASD versus DD, independent of confounders. In children with DD, SIB prevalence increased with more ASD symptoms. These findings are informative to clinicians, researchers, and policymakers. PMID- 29429010 TI - Shifts of methanogenic communities in response to permafrost thaw results in rising methane emissions and soil property changes. AB - Permafrost thaw can bring negative consequences in terms of ecosystems, resulting in permafrost collapse, waterlogging, thermokarst lake development, and species composition changes. Little is known about how permafrost thaw influences microbial community shifts and their activities. Here, we show that the dominant archaeal community shifts from Methanomicrobiales to Methanosarcinales in response to the permafrost thaw, and the increase in methane emission is found to be associated with the methanogenic archaea, which rapidly bloom with nearly tenfold increase in total number. The mcrA gene clone libraries analyses indicate that Methanocellales/Rice Cluster I was predominant both in the original permafrost and in the thawed permafrost. However, only species belonging to Methanosarcinales showed higher transcriptional activities in the thawed permafrost, indicating a shift of methanogens from hydrogenotrophic to partly acetoclastic methane-generating metabolic processes. In addition, data also show the soil texture and features change as a result of microbial reproduction and activity induced by this permafrost thaw. Those data indicate that microbial ecology under warming permafrost has potential impacts on ecosystem and methane emissions. PMID- 29429011 TI - A new subtype of Entamoeba gingivalis: "E. gingivalis ST2, kamaktli variant". AB - Entamoeba gingivalis is a protozoan that resides in the oral cavity. Using molecular biology techniques, we identified a novel organism that shares the same ecological niche as E. gingivalis. To differentiate this organism from E. gingivalis, we named it "kamaktli variant." By sequencing the 18S-ITS1-5.8S-ITS2 rRNA region, we demonstrated that kamaktli variant is 89% identical to E. gingivalis. To elucidate the relationship between kamaktli variant and E. gingivalis, we performed a phylogenetic analysis. Both taxa clustered in the same clade with high support, indicating that the amoebas are closely related (98/99/1.00, maximum parsimony/maximum likelihood/MrBayes, respectively). Given this information, we propose that these molecular differences between kamaktli variant and E. gingivalis ST1 are sufficient to distinguish them as independent subtypes, and we name the new subtype "E. gingivalis ST2, kamaktli variant." PMID- 29429014 TI - Intrasynovial spindle cell lipoma of the deep flexor of the middle finger causing intermittent carpal tunnel syndrome-case report and review of the literature. AB - Carpal tunnel syndrome (CTS) represents the most common entrapment neuropathy of the upper extremity. Intermittent CTS has been reported in the surgical literature and usually, related to masses associated to flexor tendons. We describe a patient with an intrasynovial lipoma involving the deep flexor of the middle finger causing intermittent CTS and snapping on flexion-extension. PMID- 29429012 TI - ER stress and genomic instability induced by gamma radiation in mice primary cultured glial cells. AB - Ionizing radiation induces various pathophysiological conditions by altering central nervous system (CNS) homeostasis, leading to neurodegenerative diseases. However, the potential effect of ionizing radiation response on cellular physiology in glial cells is unclear. In the present study, micronucleus test, comet assay, and RT-PCR were performed to investigate the potential effect of gamma radiation in cultured oligodendrocytes and astrocytes with respect to genomic instability, Endoplasmic Reticulum (ER) stress, and inflammation. Further, we studied the effect of alteration in ER stress specific gene expression in cortex post whole body radiation in mice. Results showed that exposure of gamma radiation of 2Gy in-vitro cultured astrocytes and oligodendrocytes and 7Gy in-vivo induced ER stress and Inflammation along with profuse DNA damage and Chromosomal abnormality. Additionally, we observed downregulation of myelin basic protein levels in cultured oligodendrocytes exposed to radiation. The present data suggests that ER stress and pro inflammatory cytokines serve as the major players in inducing glial cell dysfunction post gamma irradiation along with induction of genomic instability. Taken together, these results indicate that ER stress, DNA damage, and inflammatory pathways may be critical events leading to glial cell dysfunction and subsequent cell death following exposure to ionizing radiation. PMID- 29429013 TI - Demographic, presentation, and treatment factors and racial disparities in ovarian cancer hospitalization outcomes. AB - BACKGROUND: This study examines whether racial disparities in hospitalization outcomes persist between African-American and White women with ovarian cancer after matching on demographic, presentation, and treatment factors. METHODS: Using data from the Nationwide Inpatient Sample database, 5,164 African-American ovarian cancer patients were sequentially matched with White patients on demographic (e.g., age, income), presentation (e.g., stage, comorbidities), and treatment (e.g., surgery, radiation) factors. Racial differences in-hospital length of stay, post-operative complications, and in-hospital mortality were evaluated using conditional logistic regression models. RESULTS: White ovarian cancer patients had relatively higher odds of post-operative complications when matched on demographics (OR 1.35, 95% CI 1.05, 1.74), and presentation (OR 1.28, 95% CI 1.00, 1.65) but not when additionally matched on treatment (OR 1.03, 95% CI 0.78, 1.35). African-American patients had longer in-hospital length of stay (6.96 +/- 7.21 days) compared with White patients when matched on demographics (6.37 +/- 7.07 days), presentation (6.48 +/- 7.16 days), and treatment (6.53 +/- 7.59 days). Compared with African-American patients, White patients experienced lower odds of in-hospital mortality when matched on demographics (OR 0.78, 95% CI 0.66, 0.92), but this disparity was no longer significant when additionally matched on presentation (OR 0.88, 95% CI 0.75, 1.04) and treatment (OR 0.95, 95% CI 0.81, 1.12). CONCLUSION: Racial disparities in ovarian cancer hospitalization outcomes persisted after adjusting for demographic and presentation factors; however these differences were eliminated after additionally accounting for treatment factors. More studies are needed to determine the factors driving racial differences in ovarian cancer treatment in otherwise similar patient populations. PMID- 29429015 TI - Transcranial Doppler ultrasound in neurocritical care. AB - Multimodality monitoring is a common practice in caring for neurocritically ill patients, and consists mainly in clinical assessment, intracranial pressure monitoring and using several imaging methods. Of these imaging methods, transcranial Doppler (TCD) is an interesting tool that provides a non-invasive, portable and radiation-free way to assess cerebral circulation and diagnose and follow-up (duplex method) intracranial mass-occupying lesions, such as hematomas and midline shift. This article reviews the basics of TCD applied to neurocritical care patients, offering a rationale for its use as well as tips for practitioners. PMID- 29429016 TI - Usefulness of model-based iterative reconstruction in semi-automatic volumetry for ground-glass nodules at ultra-low-dose CT: a phantom study. AB - This study aimed to investigate the effects of parameter presets of the forward projected model-based iterative reconstruction solution (FIRST) on the accuracy of pulmonary nodule volume measurement. A torso phantom with simulated nodules [diameter: 5, 8, 10, and 12 mm; computed tomography (CT) density: - 630 HU] was scanned with a multi-detector CT at tube currents of 10 mA (ultra-low-dose: UL dose) and 270 mA (standard-dose: Std-dose). Images were reconstructed with filtered back projection [FBP; standard (Std-FBP), ultra-low-dose (UL-FBP)], FIRST Lung (UL-Lung), and FIRST Body (UL-Body), and analyzed with a semi automatic software. The error in the volume measurement was determined. The errors with UL-Lung and UL-Body were smaller than that with UL-FBP. The smallest error was 5.8% +/- 0.3 for the 12-mm nodule with UL-Body (middle lung). Our results indicated that FIRST Body would be superior to FIRST Lung in terms of accuracy of nodule measurement with UL-dose CT. PMID- 29429017 TI - Performance of breast cancer screening using digital breast tomosynthesis: results from the prospective population-based Oslo Tomosynthesis Screening Trial. AB - PURPOSE: Digital breast tomosynthesis (DBT) has the potential to overcome limitations of conventional mammography. This study investigated the effects of addition of DBT on interval and detected cancers in population-based screening. METHODS: Oslo Tomosynthesis Screening Trial (OTST) was a prospective, independent double-reading trial inviting women 50-69 years biennially, comparing full-field digital mammography (FFDM) plus DBT with FFDM alone. Performance indicators and characteristics of screen-detected and interval cancers were compared with two previous FFDM rounds. RESULTS: 24,301 consenting women underwent FFDM + DBT screening over a 2-year period. Results were compared with 59,877 FFDM examinations during prior rounds. Addition of DBT resulted in a non-significant increase in sensitivity (76.2%, 378/496, vs. 80.8%, 227/281, p = 0.151) and a significant increase in specificity (96.4%, 57229/59381 vs. 97.5%, 23427/24020, p < .001). Number of recalls per screen-detected cancer decreased from 6.7 (2530/378) to 3.6 (820/227) with DBT (p < .001). Cancer detection per 1000 women screened increased (6.3, 378/59877, vs. 9.3, 227/24301, p < .001). Interval cancer rate per 1000 screens for FFDM + DBT remained similar to previous FFDM rounds (2.1, 51/24301 vs. 2.0, 118/59877, p = 0.734). Interval cancers post-DBT were comparable to prior rounds but significantly different in size, grade, and node status from cancers detected only using DBT. 39.6% (19/48) of interval cancers had positive nodes compared with only 3.9% (2/51) of additional DBT-only detected cancers. CONCLUSIONS: DBT-supplemented screening resulted in significant increases in screen-detected cancers and specificity. However, no significant change was observed in the rate, size, node status, or grade of interval cancers. ClinicalTrials.gov: NCT01248546. PMID- 29429018 TI - MOBCdb: a comprehensive database integrating multi-omics data on breast cancer for precision medicine. AB - BACKGROUND: Breast cancer is one of the most frequently diagnosed cancers among women worldwide, characterized by diverse biological heterogeneity. It is well known that complex and combined gene regulation of multi-omics is involved in the occurrence and development of breast cancer. RESULTS: In this paper, we present the Multi-Omics Breast Cancer Database (MOBCdb), a simple and easily accessible repository that integrates genomic, transcriptomic, epigenomic, clinical, and drug response data of different subtypes of breast cancer. MOBCdb allows users to retrieve simple nucleotide variation (SNV), gene expression, microRNA expression, DNA methylation, and specific drug response data by various search fashions. The genome-wide browser /navigation facility in MOBCdb provides an interface for visualizing multi-omics data of multi-samples simultaneously. Furthermore, the survival module provides survival analysis for all or some of the samples by using data of three omics. The approved public drugs with genetic variations on breast cancer are also included in MOBCdb. CONCLUSION: In summary, MOBCdb provides users a unique web interface to the integrated multi-omics data of different subtypes of breast cancer, which enables the users to identify potential novel biomarkers for precision medicine. PMID- 29429019 TI - An inter-subunit disulfide bond of artemin acts as a redox switch for its chaperone-like activity. AB - Encysted embryos of Artemia are among the most stress-resistant eukaryotes partly due to the massive amount of a cysteine-rich protein termed artemin. High number of cysteine residues in artemin and their intramolecular spatial positions motivated us to investigate the role of the cysteine residues in the chaperone like activity of artemin. According to the result of Ellman's assay, there are nine free thiols (seven buried and two exposed) and one disulfide bond per monomer of artemin. Subsequent theoretical analysis of the predicted 3D structure of artemin confirmed the data obtained by the spectroscopic study. Native and reduced/modified forms of artemin were also compared with respect to their efficiency in chaperoning activity, tertiary structure, and stability. Since the alkylation and reduction of artemin diminished its chaperone activity, it appears that its chaperoning potential depends on the formation of intermolecular disulfide bond and the presence of cysteine residues. Comparative fluorescence studies on the structure and stability of the native and reduced protein revealed some differences between them. Due to the redox-dependent functional switching of artemin from the less to more active form, it can be finally suggested as a redox dependent chaperone. PMID- 29429020 TI - Leukemia-propagating cells demonstrate distinctive gene expression profiles compared with other cell fractions from patients with de novo Philadelphia chromosome-positive ALL. AB - Relapse remains one of the major obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) even after allogeneic hematopoietic stem cell transplantation. The persistence of leukemia-propagating cells (LPCs) may lead to the recurrence of Ph+ALL. Using a xenograft assay, LPCs enrichment in the CD34+CD38-CD58- fraction in Ph+ALL was recently identified. A further cohort study indicated that the LPCs phenotype at diagnosis was an independent risk factor for relapse of Ph+ALL. However, little is known about the potential molecular mechanism of LPCs-mediated relapse. Therefore, the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph+ALL were investigated using RNA sequencing (RNA-Seq). Most of the differentially expressed genes between the LPCs and other cell fractions were related to the regulation of the cell cycle and metabolism, as identified by the gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Consistent with the RNA-Seq results, the mRNA levels of cell cycle related genes, such as cyclin-dependent kinase 4, were significantly lower in the LPCs fraction than in other cell fractions. Moreover, the proportion of quiescent cells in LPCs was significantly higher than in other cell fractions. In summary, distinctive gene expression profiles and clusters, which were mostly related to the regulation of the cell cycle and metabolism, were demonstrated between LPCs and other cell fractions from patients with de novo Ph+ALL. Therefore, it would be beneficial to develop novel LPCs-based therapeutic strategies for Ph+ALL patients. PMID- 29429021 TI - Ozonation of offshore produced water: kinetic study and fuzzy inference system modeling. AB - Ozonation has been recently proposed as a treatment option to remove toxic and recalcitrant organics from offshore produced water (OPW). In this study, experimental and modeling approaches were used to investigate the removal of polycyclic aromatic hydrocarbons (PAHs) from OPW by ozonation. It was found that ozonation can effectively remove PAHs by following the pseudo first-order kinetic model, which could cover both direct and indirect ozonation pathways. The decay rate constants of most PAHs were as low as 0.01-0.16 min-1, possibly due to the interference caused by OPW matrix. The effects of ozone dose, bubble size, pH, and temperature on five representative PAHs were investigated along with their possible interactions. Based on the experimental results, a novel multi-output adaptive network-based fuzzy inference system (MO-ANFIS) was developed to model the removal of four individual PAHs and total PAHs. The overall RMSE and R between measured and modeled removal rates were 6.60% and 0.98, respectively, indicating a good model fit. This study demonstrated the effectiveness of ozonation in OPW treatment and the potential applicability of MO-ANFIS for process modeling and control. PMID- 29429022 TI - A new path for humanistic medicine. AB - According to recent approaches in the philosophy of medicine, biomedicine should be replaced or complemented by a humanistic medical model. Two humanistic approaches, narrative medicine and the phenomenology of medicine, have grown particularly popular in recent decades. This paper first suggests that these humanistic criticisms of biomedicine are insufficient. A central problem is that both approaches seem to offer a straw man definition of biomedicine. It then argues that the subsequent definition of humanism found in these approaches is problematically reduced to a compassionate or psychological understanding. My main claims are that humanism cannot be sought in the patient-physician relationship alone and that a broad definition of medicine should help to revisit humanism. With this end in view, I defend what I call an outcomes-oriented approach to humanistic medicine, where humanism is set upon the capacity for a health system to produce good health outcomes. PMID- 29429024 TI - Middle ear microvascularization: an "in vivo" endoscopic anatomical study. AB - PURPOSE: To describe the in vivo vascularization of middle ear by an endoscopic point of view, particularly focusing on the medial wall of tympanic cavity and incudostapedial region (ISR). STUDY DESIGN: Case series with surgical videos review and anatomical description. METHODS: 48 videos from exclusive endoscopic middle ear surgery performed at the University Hospital of Modena from November 2015 to July 2017 were reviewed. Data about anatomy of vessels, and blood flow direction (BFD) were collected in an appropriate database for further analyses. RESULTS: 48 cases were included in the present study. In 18/48 patients (37,5%), a clearly identifiable inferior tympanic artery (ITA) was present, running just anteriorly to the round window (RW), with a superior BFD (65% of cases) from the hypotympanic region toward the epitympanum. Some promontorial variants were described in 67% of cases and the most common finding was a mucosal vascular network with a multidirectional BFD. On the ISR, an incudostapedial artery (ISA) was detected in 65% of cases with BFD going from the long process of the incus (LPI) toward the pyramidal eminence in the majority of cases. CONCLUSION: The vascular anatomy and BFD of the medial wall of the tympanic cavity can be easily studied in transcanal endoscopy. ITA (with a superior BFD in most cases) and ISA (with a main BFD from the incus to the stapes) are the most constant identifiable vessels. PMID- 29429025 TI - Risk factors for complications in cochlear implant surgery. AB - PURPOSE: The objective of this study was to achieve uniform reporting of complications and failures in cochlear implantation, to analyze complications and failures and to identify risk factors for complications in a series of over 1300 cochlear implantations. METHODS: In a retrospective chart review and observational study, data from all cochlear implantations from 1987 to 2015 were entered in a custom-made database. Complications were classified using the contracted form of the Clavien-Dindo system and risk factors were identified by statistical analysis. RESULTS: A complication rate of 18.4% and a device failure rate of 2.9% were found. There was a higher rate of hematoma in patients with a clotting disorder and when a subtotal petrosectomy was performed, a higher rate of wound infections in patients who were not vaccinated against Streptococcus pneumoniae and a higher rate of meningitis in patients with an inner ear malformation. CONCLUSIONS: The use of a strict definition of a medical complication and device failure-in combination with the Clavien-Dindo classification system-enables uniform and objective registration of adverse events and prevents any tendency to downgrade complications. Complication and failure rates in this series are comparable to those reported in the literature. These results stress the need for pneumococcal vaccination, which may prevent general wound infections, but is especially important for patients with inner ear malformation, who have an increased risk of (postoperative) meningitis. PMID- 29429027 TI - Immunization Coverage in Children with Inflammatory Bowel Disease. AB - Patients suffering from inflammatory bowel diseases (IBD) are at increased risk of infections, mainly due to immunosuppressive treatment. Moreover, infections may cause flares of IBD. Vaccination is the most effective way of preventing many infections. The aim of this study was to evaluate the vaccination status of Polish children with IBD. Individual immunization cards of children with IBD and healthy controls were reviewed. Demographic data such as age, sex, and IBD history, including therapy type, were collected. We enrolled 267 children into the study, including 214 children with IBD and 53 controls. None of the children had completed the full up-to-date routine childhood immunization schedule recommended in Poland. Controls were more than 4 times more likely to be vaccinated than the IBD patients, with the vaccines that enjoy the insurance reimbursed (OR 4.1, 95% CI 2.2-7.9). In conclusion, the study demonstrates a poor vaccination status in children suffering from IBD. PMID- 29429026 TI - Modulation of renal sympathetic innervation: recent insights beyond blood pressure control. AB - Renal afferent and efferent sympathetic nerves are involved in the regulation of blood pressure and have a pathophysiological role in hypertension. Additionally, several conditions that frequently coexist with hypertension, such as heart failure, obstructive sleep apnea, atrial fibrillation, renal dysfunction, and metabolic syndrome, demonstrate enhanced sympathetic activity. Renal denervation (RDN) is an approach to reduce renal and whole body sympathetic activation. Experimental models indicate that RDN has the potential to lower blood pressure and prevent cardio-renal remodeling in chronic diseases associated with enhanced sympathetic activation. Studies have shown that RDN can reduce blood pressure in drug-naive hypertensive patients and in hypertensive patients under drug treatment. Beyond its effects on blood pressure, sympathetic modulation by RDN has been shown to have profound effects on cardiac electrophysiology and cardiac arrhythmogenesis. RDN can display anti-arrhythmic effects in a variety of animal models for atrial fibrillation and ventricular arrhythmias. The first non randomized studies demonstrate that RDN may promote the maintenance of sinus rhythm following catheter ablation in patients with atrial fibrillation. Registry data point towards a beneficial effect of RDN to prevent ventricular arrhythmias in patients with heart failure and electrical storm. Further large randomized placebo-controlled trials are needed to confirm the antihypertensive and anti arrhythmic effects of RDN. Here, we will review the current literature on anti arrhythmic effects of RDN with the focus on atrial fibrillation and ventricular arrhythmias. We will discuss new insights from preclinical and clinical mechanistic studies and possible clinical implications of RDN. PMID- 29429028 TI - Molecules of Damage-Associated Patterns in Bronchoalveolar Lavage Fluid and Serum in Chronic Obstructive Pulmonary Disease. AB - Chronic exposure to detrimental environmental factors may induce immunogenic cell death of structural airway cells in chronic obstructive pulmonary disease (COPD). Damage-associated molecular patterns (DAMPs) is a family of heterogeneous molecules released from injured or dead cells, which activate innate and adaptive immune responses on binding to the pattern recognition receptors on cells. This study seeks to define the content of DAMPs in the bronchoalveolar lavage fluid (BALF) and serum of COPD patients, and the possible association of these molecules with clinical disease features. Thirty COPD in advanced disease stages were enrolled into the study. Pulmonary function tests, arterial blood gas content, 6-minute walk test, and BODE index were assessed. The content of DAMPs was estimated using the commercial sandwich-ELISA kits. We found differential alterations in the content of various DAMP molecules. In the main, BALF DAMPs positively associated with age, forced expiratory volume in one second (FEV1), and residual volume (RV); and inversely with PaO2, residual volume/total lung capacity (RV/TLC) ratio, and the disease severity staging. In serum, DAMPS positively associated with the intensity of smoking and inversely with age, PaO2, and TLC. In conclusion, DAMPs are present in both BALF and serum of COPD patients, which points to enhanced both local in the lung environment as well as systemic pro-inflammatory vein in this disease. These molecules appear involved with the lung damage and clinical variables featuring COPD. However, since the involvement of various DAMPs in COPD is variable, the exact role they play is by far unsettled and is open to further exploration. PMID- 29429029 TI - Very High Frequency Oscillations of Heart Rate Variability in Healthy Humans and in Patients with Cardiovascular Autonomic Neuropathy. AB - Literature reports on the very high frequency (VHF) range of 0.4-0.9 Hz in heart rate variability (HRV) are scanty. The VHF presence in cardiac transplant patients and other conditions associated with reduced vagal influence on the heart encouraged us to explore this spectral band in healthy subjects and in patients diagnosed with cardiac autonomic neuropathy (CAN), and to assess the potential clinical value of some VHF indices. The study included 80 healthy controls and 48 patients with spinocerebellar ataxia type 2 (SCA2) with CAN. The electrocardiographic recordings of short 5-min duration were submitted to three different spectral analysis methods, including the most generally accepted procedure, and the two novel methods using the Hilbert-Huang transform. We demonstrated the presence of VHF activity in both groups of subjects. However, VHF power spectral density, expressed in relative normalized units, was significantly greater in the SCA2 patients than that in healthy subjects, amounting to 36.1 +/- 17.4% vs. 22.9 +/- 14.1%, respectively, as also was the instantaneous VHF spectral frequency, 0.58 +/- 0.05 vs. 0.64 +/- 0.07 Hz, respectively. These findings were related to the severity of CAN. We conclude that VHF activity of HRV is integral to the cardiovascular autonomic control. PMID- 29429030 TI - Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice. AB - Highly Active Antiretroviral Therapy (HAART) has significantly contributed to the increase of HIV-infected survivors over 50 years of age. Unfortunately, patients are required to stay on long-term HAART, which may be causally related to the development of neurological problems such as chronic pain. Little is known about the contribution of HAART or its therapeutic agents to the pathogenesis of pain during aging. In this study, we determined the effect of nucleoside reverse transcriptase inhibitors (NRTIs) on the development of mechanical allodynia and the potential underlying mechanism in aging mice (15.5 months). We found that systemic administration of individual NRTIs, including ddC (2'-3' dideoxycytidine), ddI (didanosine), AZT (3'-azido-3'-deoxythymidine) and d4T (2', 3'-didehydro-2', 3'-dideoxythymidine), induced allodynia in similar magnitudes and temporal profiles. We used ddC as a representative to investigate cellular and molecular processes induced by NRTIs in the spinal cord that probably underlie the development of allodynia. The results showed that ddC caused evident neuroinflammation in the spinal cord, suggested by the up-regulation of proinflammatory cytokines TNF-alpha and IL-1beta and the reactions of microglia and astrocytes. In addition, we found that Wnt5a, a critical regulator of neuroinflammation, was also up-regulated. Pharmacological inhibition of Wnt5a blocked ddC-induced up-regulation of TNF-alpha and astrocyte reaction, while activation of Wnt5a signaling potentiated these processes. Furthermore, our data showed that inhibition of Wnt5a significantly reversed ddC-induced mechanical allodynia in aging mice. The results collectively suggest that NRTIs may contribute to the development of chronic pain in aging patients by inducing Wnt5a regulated neuroinflammation. PMID- 29429031 TI - The changing multiple sclerosis treatment landscape: impact of new drugs and treatment recommendations. AB - PURPOSE: The purpose of this study is to describe the utilization of disease modifying treatments (DMTs) in relapsing-remitting multiple sclerosis (MS) and assess the impact of both the introduction of new drugs and treatment recommendations (local recommendation on rituximab use issued at the largest MS clinic in Stockholm and regional Drug and Therapeutics Committee (DTC) recommendation on how dimethyl fumarate should be used). METHODS: Interrupted time series analyses using monthly data on all MS patients treated with DMTs in the Stockholm County, Sweden, from January 2011 to December 2017. RESULTS: There were 4765 individuals diagnosed with MS residing in the Stockholm County from 2011 to 2017. Of these, 2934 (62%) were treated with an MS DMT. Since 2011, fingolimod, alemtuzumab, teriflunomide, dimethyl fumarate, peginterferon beta-1a, and daclizumab were introduced. Only fingolimod and dimethyl fumarate significantly impacted MS DMT utilization. In parallel, the use of rituximab off label increased steadily, reaching 58% of all DMT-treated MS patients by the end of the study period. The local recommendation on rituximab was associated with an increase in rituximab use. The regional DTC recommendation on dimethyl fumarate was associated with a decrease in dimethyl fumarate use. CONCLUSIONS: Three MS DMTs-fingolimod, dimethyl fumarate, and rituximab off-label-impacted MS DMT utilization in the Stockholm County. The associations between the treatment recommendations and the subsequent changes in MS DMT utilization indicate that such interventions can influence the uptake and utilization of new drugs used in the specialized care setting. PMID- 29429032 TI - Comparative risk/benefit profile of biosimilar and originator erythropoiesis stimulating agents (ESAs): data from an Italian observational study in nephrology. AB - PURPOSE: The aim of this multicenter prospective study was to evaluate efficacy and safety of biosimilar erythropoiesis-stimulating agents (ESAs) vs originator, based on data from clinical practice in patients with chronic kidney disease (CKD). METHODS: We collected data of the patients with diagnosis of CKD on conservative treatment from nine Italian structures. Patients were enrolled applying different exclusion criteria, and various individual parameters were registered at the beginning for descriptive analysis. Patients were treated with epoetin alfa, beta, and darbepoetin as originator and epoetin zeta as biosimilar. Hemoglobin levels have been analyzed at baseline and after 3, 6, and 12 months. Descriptive statistics were used to analyze the results. RESULTS: At baseline, 47 patients were in the biosimilar group and 57 in the originator; the basal level of hemoglobin was similar between the groups (mean Hb 9.4 and 9.3 g/dL, respectively). Median age, weight, and comorbidities were almost comparable. After 3 months, 44 patients remained in the biosimilar group and 48 in the originator; hemoglobin increase was significantly greater in patients treated with biosimilar [absolute increase 1.6 vs 1.0 g/dL, p < 0.001]. After 6 and 12 months, number of patients fall furthermore. Hemoglobin levels increased more in the biosimilar group after 6 months (2.1 vs 1.1 g/dL, p < 0.001) and 12 months (2.0 vs 1.0 g/dL, p < 0.001). CONCLUSIONS: Biosimilar ESAs have similar risk/benefit profile compared to originators. Our data are in agreement with relevant scientific literature and, on the other hand, they are in contrast with common thought that considers biosimilar less efficacious and less safe than originators. PMID- 29429033 TI - Implementing a fracture liaison service open model of care utilizing a cloud based tool. AB - PURPOSE: Although half of women and one-quarter of men aged 50 and older will sustain an acute low-trauma fracture, less than a quarter receive appropriate secondary fracture prevention. The goal of this quality improvement demonstration project was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in three open health care systems aided by a cloud-based tool. METHODS: The pre-post study design examined the proportion of men and women over age 50 who received appropriate assessment (bone mineral density, vitamin D levels) and treatment (calcium/vitamin D, pharmacologic therapy) in the six months following a recently diagnosed fracture. The pre-study (Pre FLS) included a retrospective chart review for baseline data (N = 344 patients) within each health care system. In the post-evaluation (Post FLS, N = 148 patients), the FLS coordinator from each health care system examined these parameters following enrollment and for 6 months following the recently diagnosed fracture. Data were managed in the cloud-based FLS application tool. RESULTS: Ninety-three participants completed the program. The FLS program increased the percentage of patients receiving bone mineral density testing from 21% at baseline to 93% (p < 0.001) Post FLS implementation. Assessments of vitamin D levels increased from 25 to 84% (p < 0.001). Patients prescribed calcium/vitamin D increased from 36% at baseline to 93% (p < 0.001) and those prescribed pharmacologic treatment for osteoporosis increased on average from 20 to 54% (p < 0.001) Post FLS. CONCLUSIONS: We conclude that the FLS model of care in an open health care system, assisted by a cloud-based tool, significantly improved assessment and/or treatment of patients with a recently diagnosed osteoporotic fracture. Future studies are necessary to determine if this model of care is scalable and if such programs result in prevention of fractures. Mini-Abstract: The goal was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in open health care systems aided by a cloud-based tool. This model significantly improved assessment and/or treatment of patients with a recently diagnosed fracture. PMID- 29429034 TI - Tetraspanin blockage reduces exosome-mediated HIV-1 entry. AB - HIV-1 is one of the most studied retroviruses. The role of exosomes in HIV-1 entry and pathogenesis are beginning to be appreciated. Exosomes can incorporate host proteins that are also contained in viruses (e.g., tetraspanins). PMID- 29429035 TI - Inhibitory effect of the green tea molecule EGCG against dengue virus infection. AB - Dengue virus (DENV) infection is a major public health problem worldwide; however, specific antiviral drugs against it are not available. Hence, identifying effective antiviral agents for the prevention of DENV infection is important. In this study, we showed that the reportedly highly biologically active green-tea component epigallocatechin gallate (EGCG) inhibited dengue virus infection regardless of infecting serotype, but no or minimal inhibition was observed with other flaviviruses, including Japanese encephalitis virus, yellow fever virus, and Zika virus. EGCG exerted its antiviral effect mainly at the early stage of infection, probably by interacting directly with virions to prevent virus infection. Our results suggest that EGCG specifically targets DENV and might be used as a lead structure to develop an antiviral drug for use against the virus. PMID- 29429036 TI - Development of a reverse transcription recombinase-aided amplification assay for the detection of coxsackievirus A10 and coxsackievirus A6 RNA. AB - Hand, foot and mouth disease (HFMD) is a serious public health problem, and coxsackievirus A6 (CVA6) and coxsackievirus A10 (CVA10) are two of the major causative pathogens, in addition to enterovirus 71 (EV71) and coxsackievirus A16 (CVA16). A simple and rapid reverse transcription recombinase-aided amplification assay (RT-RAA) was developed for the detection of CVA10 and CVA6 in this study. The analytical sensitivity for detection of CVA10 and CVA6 at 95% probability by probit regression analysis was 35 copies per reaction and 38 copies per reaction, respectively, with 100% specificity. Compared with commercial RT-qPCR assays, when testing 455 fecal specimens, the kappa value of the RT-RAA assay for CVA10 and CVA6 was 0.920 (p < 0.001) and 0.952 (p < 0.001), respectively. Moreover, four samples that were positive for CVA10 and five that were positive for CVA6 by RT-RAA but negative by RT-qPCR were further determined to be true positives. These results demonstrate that the proposed RT-RAA assays are very valuable tools for the detection of CVA10 and CVA6 and have potential for use in resource limited settings. PMID- 29429037 TI - Long-term follow-up of whiplash injuries reported to insurance companies: a cohort study on patient-reported outcomes and impact of financial compensation. AB - PURPOSE: The long-term outcome of Whiplash-associated disorder (WADs) has been reported to be poor in populations from medical settings. However, no trials have investigated the long-term prognosis of patients from medico-legal environment. For this group, the "compensation hypothesis" suggests financial compensation being associated with worsened outcome. The aims of this study were to describe long-term (2-4 years) non-recovery rates in participants with WAD recruited from insurance companies and to investigate the association between self-reported non recovery and financial compensation. METHODS: 144 participants, reporting neck pain after a motor vehicle accident, were recruited from two major insurance companies in Sweden. Self-reported recovery was measured at 6 months and 2-4 years. Those who received financial compensation from an insurance company were compared with those who received no compensation. RESULTS: The overall non recovery rate after 2-4 years was 55.9% (66/118). In the non-compensated group, the non-recovery rate was 51.0% (25/49) and in the compensated group 73% (27/37) (p = 0.039). Adjusted OR was 4.33 (1.37-13.66). High level of pain at baseline was a strong predictor of non-recovery [OR 46 (4.7-446.0)]. However, no association was found between pain level at baseline and financial compensation. CONCLUSIONS: The non-recovery rate among patients making insurance claims is high, especially among those receiving financial compensation even if causal relationship cannot be determined based on this study. However, lack of association between baseline level of pain and compensation supports the compensation hypothesis. PMID- 29429038 TI - Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens. AB - Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure-response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC50 for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies. PMID- 29429040 TI - Pediatric and Adult Recommendations Vary for Sibling Testing in Cystic Fibrosis. AB - Four to 5 % of cystic fibrosis (CF) patients are diagnosed as adults and often have subtler symptoms. Their siblings are at genetic risk to also have a subtler disease state. Diagnostic testing is recommended for siblings of newly diagnosed infants, but recommendations are less clear for later diagnoses. This study explored sibling testing recommendations in pediatric and adult practice using a survey that was emailed to CF clinicians. There were 58 respondents. Results revealed that 82.5% of pediatric and 36.4% of adult care respondents reported always recommending diagnostic testing for siblings of a newly diagnosed patient. In adult care, another 33.3% reported recommending diagnostic testing if the sibling has symptoms. In pediatric care, whether the sibling had newborn screening was most influential. Most pediatric respondents prefer the sweat chloride test, while 40% in adult practice prefer familial mutation analysis. Perceived barriers included cost, insurance coverage and logistical concerns in both settings, parental emotional state in pediatrics, and concern making recommendations for someone who is not the patient in adult care. Genetic counselors may be able to meet familial needs in CF care, including sibling testing. Many newly diagnosed patients/families do not see a genetic counselor, especially in adult care. These data reveal opportunities for practice guidelines and standardization. PMID- 29429039 TI - Health Survey of Adults with Neurofibromatosis 1 Compared to Population Study Controls. AB - Neurofibromatosis type 1 (NF1) is a genetic, autosomal dominant multi-organ disease characterized by susceptibility to tumor formation, changes in skin pigmentation, skeletal abnormalities, and neuropsychological deficits. Clinical studies have shown impaired health-related quality of life (HQoL) in adults with NF1. However, little is known about HQoL in non-clinical NF1 samples. We conducted a cross-sectional self-report survey of 142 persons with NF1 (M age = 50.3 years, SD = 12.0, range 32 to 80; 62.0% females) recruited from non-clinical settings. Several HQoL domains, including life satisfaction, mental health, sleep, pain, gastrointestinal problems, oral health, and social support, were compared between the NF1 sample and 46,293 controls from the HUNT3 population study. We also examined gender differences within the NF1 sample and predictors of HQoL. Compared to controls, the NF1 sample reported significantly poorer life satisfaction, mental health, sleep, and oral health, and more pain, gastrointestinal problems, comorbid diseases, and memory problems. Several HQoL domains were significantly correlated. Mental health was the only unique significant predictor of overall life satisfaction. Women with NF1 reported significantly more mental health, sleep, and pain problems than men with NF1. Mental health assessment and management should be integrated into clinical care of persons with NF1 to potentially improve their HQoL. PMID- 29429041 TI - An iPhone Application Intervention to Promote Surveillance Among Women with a BRCA Mutation: Pre-intervention Data. AB - Women with BRCA mutations, at significantly increased risk for breast and ovarian cancer, do not consistently adhere to management guidelines due to lack of awareness and challenges tracking appointments. We developed an iPhone application (app) to help BRCA carriers manage their surveillance. We explored baseline awareness and adherence to surveillance guidelines and analytic data from 21 months of app use. Descriptive statistics were calculated on responses (N = 86) to a survey about surveillance awareness and practices. The majority were aware of breast surveillance guidelines, but only one third were aware of ovarian surveillance guidelines. In practice, the majority reported a clinical breast exam within 6 months, just over half reported a mammogram and breast MRI in the last year, and under half reported ovarian surveillance in the last year. Nearly 50% reported difficulty remembering appointments. Although only 69 received access codes, 284 unique users attempted to enter the app, which was visible in the iTunes store but only available to those with a study code. Evaluation of analytic data demonstrated user engagement with study participants accessing the app 427 times over the 21-month time period (range 2-57; mean = 6.28). Results indicate participants were more likely to know screening guidelines than practice them. There was interest in the app and users were engaged, suggesting app value. We will send a follow-up survey after 18 months of app use for additional evaluation and feedback. PMID- 29429042 TI - The cytotoxicity effects of a novel Cu complex on MCF-7 human breast cancerous cells. AB - A variety of biological activities, such as anti-microbial and anti-tumor properties was reported for 1,10-phenanthroline and its copper complexes. In this study, the anti-proliferative activity of a novel [Cu(L)(phen)] complex was investigated on MCF-7 breast cancer cells using MTT assay. Since chemotherapy is lake of ability to distinguish between normal cells from cancerous cells, therefore we also investigated the effect of [Cu(L)(phen)] complex on normal L929 cells. The results showed that following 24 and 48 h exposure of cells with [Cu(L)(phen)] complex, the IC50 values for MCF-7 were significantly lower than that recorded for L929 and normal cells were less sensitive than cancerous cells to the complex. Additionally, the [Cu(L)(phen)] complex displayed a time- and concentration-dependent cytotoxic response, with MCF-7 and L929 cells. Also flow cytometry findings suggest that [Cu(L)(phen)] complex is capable of decreasing cancer cell viability through apoptosis and did not efficiently activate the necrosis process. PMID- 29429043 TI - Treatment Patterns, Healthcare Resource Utilization, and Spending Among Medicaid Enrolled Children with Chronic Idiopathic/Spontaneous Urticaria in the United States. AB - INTRODUCTION: Few studies have described chronic idiopathic/spontaneous urticaria (CIU/CSU) healthcare burden in adults, while this information remains largely unknown in children. We aimed to describe treatment patterns, healthcare resource utilization (HRU), and costs in CIU/CSU pediatric patients, as well as to compare HRU and costs in CIU/CSU and CIU/CSU-free pediatric patients. METHODS: Medicaid claims from four states (09/01/2013-03/31/2016) were used to identify patients less than 12 years old. The CIU/CSU cohort included patients with either at least two claims for idiopathic, other, or unspecified urticaria at least 6 weeks apart, or at least one claim for urticaria and at least one claim for angioedema at least 6 weeks apart (index date defined as the first claim). The control cohort included patients without urticaria/angioedema claims (index date randomly assigned). Patients without at least 6 months of continuous Medicaid eligibility pre- and post-index were excluded. HRU and costs were compared between propensity score-matched cohorts during the post-index follow-up. RESULTS: A total of 548 CIU/CSU patients (mean [SD] age 4.5 [3.3] years; 51.3% male) were matched 1:1 with controls. In the CIU/CSU cohort, 51.8% used non-sedating prescription H1 antihistamines, 24.3% used oral corticosteroids, and 23.5% used other prescription H1-antihistamines; 13.5% consulted allergist/immunologists and 2.4% consulted dermatologists in the first 6 months of follow-up. Compared to controls, CIU/CSU patients had significantly more per patient per year (PPPY) inpatient (incidence rate ratio [IRR] 2.05), outpatient (IRR 2.20), and emergency department (IRR 1.64) visits (all p values < 0.05). Moreover, CIU/CSU patients also had significantly higher PPPY healthcare costs (mean cost difference [MCD] $1853), driven by incremental outpatient (MCD $1286) costs (all p values < 0.01). CONCLUSIONS: CIU/CSU pediatric patients had low use of non-sedating H1 antihistamines and high use of oral corticosteroids. Compared to CIU/CSU-free controls in the same age group, CIU/CSU pediatric patients had higher HRU and healthcare costs. FUNDING: Novartis Pharmaceuticals Corporation. PMID- 29429044 TI - Timing, not magnitude, of force may explain sex-dependent risk of ACL injury. AB - PURPOSE: The anterior cruciate ligament is loaded through valgus moment, vertical ground reaction force, and internal rotation moment. The aim of this study was to compare the timing of force peaks during early stance between youth girls and boys. METHODS: One-hundred and twenty-nine team sport athletes aged 9-12 completed a total of 2540 cutting maneuvers captured with an 8-camera motion capture system. Timing of early force peaks was analyzed within 100 ms after ground contact. RESULTS: Genders showed different mean (95% CI) time to peak valgus-(32 ms (30-33 ms) vs 37 ms (36-38 ms), P < 0.001) and time to peak internal rotation moments (36 ms (35-37 ms) vs 38 ms (37-39 ms), P = 0.029) but not time to peak vertical ground reaction force [38 ms (37-40 ms) vs 37 ms (36-38 ms, n.s.)]. Girls showed a smaller time between vertical ground reaction force and valgus moment peaks (mean (95% CI) of 1 ms (1-2 ms) vs 7 ms (5-9 ms), P < 0.001), and valgus- and internal rotation moment peaks (0 ms (- 2 to 1.0 ms) vs - 5 ms (- 6 to - 3 ms), P = 0.0003) but not between internal rotation moment and vertical ground reaction force. CONCLUSIONS: Concurrent force peaks are more common for girls compared with boys, leading to more frequent multi-planar loading of the knee. Timing may explain sex-dependent risk of ACL injuries. Exposure to repeated cutting movements may result in greater ACL injury risk due to timing of knee forces as well as magnitude. Such exposure should be minimized for at-risk athletes. LEVEL OF EVIDENCE: III. PMID- 29429046 TI - Yoga and immune system functioning: a systematic review of randomized controlled trials. AB - Yoga is an ancient mind-body practice that is increasingly recognized to have health benefits in a variety of clinical and non-clinical conditions. This systematic review summarizes the findings of randomized controlled trials examining the effects of yoga on immune system functioning which is imperative to justify its application in the clinic. Fifteen RCTs were eligible for the review. Even though the existing evidence is not entirely consistent, a general pattern emerged suggesting that yoga can downregulate pro-inflammatory markers. In particular, the qualitative evaluation of RCTs revealed decreases in IL-1beta, as well as indications for reductions in IL-6 and TNF-alpha. These results imply that yoga may be implemented as a complementary intervention for populations at risk or already suffering from diseases with an inflammatory component. Beyond this, yoga practice may exert further beneficial effects by enhancing cell mediated and mucosal immunity. It is hypothesized that longer time spans of yoga practice are required to achieve consistent effects especially on circulating inflammatory markers. Overall, this field of investigation is still young, hence the current body of evidence is small and for most immune parameters, more research is required to draw distinct conclusions. PMID- 29429047 TI - The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity. AB - Parkinson's disease is associated with intracellular alpha-synuclein accumulation and ventral midbrain dopaminergic neuronal death in the Substantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has been suggested to participate to Parkinson's disease pathogenesis. Nevertheless, its exact contribution remains obscure. To unveil the participation of the Rho GTPase family to the molecular pathogenesis of Parkinson's disease, we first used C elegans to demonstrate the role of the small GTPase RAC1 (ced-10 in the worm) in maintaining dopaminergic function and survival in the presence of alpha synuclein. In addition, ced-10 mutant worms determined an increase of alpha synuclein inclusions in comparison to control worms as well as an increase in autophagic vesicles. We then used a human neuroblastoma cells (M17) stably over expressing alpha-synuclein and found that RAC1 function decreased the amount of amyloidogenic alpha-synuclein. Further, by using dopaminergic neurons derived from patients of familial LRRK2-Parkinson's disease we report that human RAC1 activity is essential in the regulation of dopaminergic cell death, alpha synuclein accumulation, participates in neurite arborization and modulates autophagy. Thus, we determined for the first time that RAC1/ced-10 participates in Parkinson's disease associated pathogenesis and established RAC1/ced-10 as a new candidate for further investigation of Parkinson's disease associated mechanisms, mainly focused on dopaminergic function and survival against alpha synuclein-induced toxicity. PMID- 29429048 TI - Peptide YY Causes Apathy-Like Behavior via the Dopamine D2 Receptor in Repeated Water-Immersed Mice. AB - Apathy is observed across several neurological and psychiatric conditions; however, its pathogenesis remains unclear. We clarified the involvement of brain gut signaling in the disruption of goal-directed behavior. Male C57BL/6J mice were exposed to water immersion (WI) stress for 3 days. Food intake and nesting behavior were measured as indexes of motivation. Repeated WI caused decrease in food intake and nesting behavior. Plasma levels of peptide YY (PYY), IL-6, and ratio of dopamine metabolites in the striatum were significantly elevated after WI. PYY and IL-6 administration significantly decreased nesting behavior. The reductions in feeding and nesting behavior were blocked by PYY receptor (Y2R) antagonist or dopamine agonist. The ameliorative effect of the Y2R antagonist was diminished by the dopamine D2 receptor (D2R) antagonist. The reduction in goal directed behavior is associated with dysfunction of D2R signaling via increased peripheral PYY, suggesting that PYY antagonism is a novel candidate for decline of motivation in several depressive diseases. PMID- 29429045 TI - Evidence-based clinical practice guidelines for inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn's disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese. PMID- 29429050 TI - Correction to: Roles of Retinoic Acid Signaling in Shaping the Neuronal Architecture of the Developing Amphioxus Nervous System. AB - The original version of this article unfortunately contained a mistake. The Fig. 7 sub-panel "f" was missing in the figure of the online first proofs of this article. The corrected Fig. 7 is hereby given below. PMID- 29429049 TI - Implication of Genes for the N-Methyl-D-Aspartate (NMDA) Receptor in Substance Addictions. AB - Drug dependence is a chronic brain disease with harmful consequences for both individual users and society. Glutamate is a primary excitatory neurotransmitter in the brain, and both in vivo and in vitro experiments have implicated N-methyl D-aspartate (NMDA) receptor, a glutamate receptor, as an element in various types of addiction. Recent findings from genetics-based approaches such as genome-wide linkage, candidate gene association, genome-wide association (GWA), and next generation sequencing have demonstrated the significant association of NMDA receptor subunit genes such as GluN3A, GluN2B, and GluN2A with various addiction related phenotypes. Of these genes, GluN3A has been the most studied, and it has been revealed to play crucial roles in the etiology of addictions. In this communication, we provide an updated view of the genetic effects of NMDA receptor subunit genes and their functions in the etiology of addictions based on the findings from investigation of both common and rare variants as well as SNP-SNP interactions. To better understand the molecular mechanisms underlying addiction related behaviors and to promote the development of specific medicines for the prevention and treatment of addictions, current efforts aim not only to identify more causal variants in NMDA receptor subunits by using large independent samples but also to reveal the molecular functions of these variants in addictions. PMID- 29429051 TI - Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model. AB - Nuclear receptor related 1 (Nurr1) orphan receptor has emerged as a promising contender in ameliorating Parkinson's disease; thus, finding a suitable activator of Nurr1 receptor is an attracting target for treating PD. Cilostazol, a phosphodiesterase-3 inhibitor, recently showed a favorable neuroprotective activity in multiple devastating central disorders, yet the possible antiparkinsonian activity of the drug has not been fully elucidated. Thus, the aim of this study is to explore the neuroprotective effect of cilostazol in rotenone-induced PD model in rats. Cilostazol successfully upregulated Nurr1 expression in PD rats, which resulted in successful preservation of the dopaminergic neuron functionality and integrity as verified by the marked improvement of motor performance in rotarod and open field tests, as well as the increased striatal tyrosine hydroxylase content. Moreover, cilostazol revealed an anti-inflammatory activity as manifested by hampering the global controller of inflammatory signaling pathway, nuclear factor-kappa B, together with its downstream pro-inflammatory cytokines, namely tumor necrosis factor-alpha and interleukin-1 beta, via Nurr-1 upregulation and glycogen synthase kinase 3 beta GSK-3beta inhibition. In turn, the increase in GSK-3beta inhibited form suppressed the measured downstream apoptotic biomarkers, viz. cytochrome C and caspase-3. Remarkably, cilostazol enhanced autophagy as depicted by hampering both LC3-II and P62 levels possibly through the prominent rise in sirtuin 1 level. In conclusion, cilostazol could be a promising candidate for PD treatment through modulating Nurr1 expression, as well as SIRT-1/autophagy, and GSK 3beta/apoptosis cross-regulation. Graphical Abstract In the rat rotenone model of Parkinson's disease (PD), Nurr1 expression was downregulated, GSK-3beta was activated, and autophagic flux was inhibited. Those deleterious effects were associated with deteriorated motor functions, striatal TH content, enhanced inflammatory state, and apoptotic cascade. Cilostazol, a phosphodiesterase-3 inhibitor, exerted a potential protective effect against PD through Nurr1 enhancement, GSK-3beta/apoptosis modulation, and SIRT-1/autophagy enhancement. Nurr1 nuclear receptor related 1, TH tyrosine hydroxylase, NF-kappaB nuclear factor kappaB, TNFalpha tumor necrosis factor alpha, ILs interleukins, GSK-3beta glycogen synthase kinase 3 beta, SIRT-1 sirtuin 1. PMID- 29429053 TI - Program of gastrointestinal rehabilitation and early postoperative enteral nutrition: a prospective study. AB - Nutritional depletion is commonly observed in patients undergoing surgical treatment for a gastrointestinal malignancy. An appropriate nutritional intervention could be associated with improved postoperative outcomes. The study was aimed to determine the effect of a program of gastrointestinal rehabilitation and early postoperative enteral nutrition upon complications and clinical outcomes in patients who experienced gastrointestinal surgery for cancer. This is a prospective study (2013 January-2015 December) of 465 consecutive patients submitted to gastrointestinal surgery for cancer and admitted to an Oncological Intensive Care Unit. The program of gastrointestinal rehabilitation and early postoperative enteral nutrition consisted on: (1) general rules: pain relive, early mobilization, antibiotic prophylaxis, deep vein thrombosis prophylaxis and respiratory physiotherapy; and (2) gastrointestinal rules: gastric protection, control of postoperative nausea and vomiting, early nasogastric tube remove and early enteral nutrition. The most frequent surgical sites were colorectal (44.9%), gynecological with intestinal suturing (15.7%) and esophagus/stomach (11.0%). Emergency surgery was performed in 12.7% of patients. The program of intestinal rehabilitation and early postoperative enteral nutrition reduced major complications (19.2 vs. 10.2%; p = 0.030), respiratory complications (p = 0.040), delirium (p = 0.032), infectious complications (p = 0.047) and gastrointestinal complications (p < 0.001). Intensive care unit mortality (p = 0.018), length of intensive care unit stay (p < 0.001) and length of hospitalization (p < 0.001) were reduced as well. A program of gastrointestinal rehabilitation and early postoperative enteral nutrition is associated with reduced postoperative complications and improved clinical outcomes in patients undergoing gastrointestinal surgery for cancer. PMID- 29429054 TI - Incidence of leukopenia and thrombocytopenia with cisplatin plus mitomycin-c versus melphalan in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). AB - INTRODUCTION: Cytopenia after hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS) has been reported in non-comparative studies with various chemotherapeutic regimens. This study compared the incidence of leukopenia and thrombocytopenia in patients who underwent CRS/HIPEC and received melphalan or cisplatin plus mitomycin-c (CIS + MMC). METHODS: This retrospective study included patients who underwent CRS/HIPEC at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia from March 2011 to March 2017 and received melphalan 60 mg/m2 or CIS 100 mg/m2 combined with MMC 30 mg/m2. Incidences and severity of leukopenia, neutropenia, thrombocytopenia, and anemia were compared between groups. RESULTS: This study included 46 patients who received CIS + MMC and 35 patients who received melphalan. The leukopenia incidence was 25.7% in the melphalan group and 17.3% in the CIS + MMC group (P = 0.362), with one patient (2.8%) in the melphalan group developed grade V leukopenia. The number of days to leukocyte nadir was 32.8 days for CIS + MMC group compared to 9.8 days for melphalan group(P = 0.035). Thrombocytopenia occurred at a similar rate in the melphalan (60%) and CIS + MMC (68.8%) groups (P = 0.4). Grade III thrombocytopenia developed in 3.2% and 5% of patients in the melphalan and the CIS + MMC groups, respectively. Neutropenia did not occur in any patient. In multivariate analysis, leukopenia predictors were female gender (P = 0.047) and baseline leukocyte counts (P = 0.029). Baseline platelet count predicted thrombocytopenia (P < 0.001). CONCLUSIONS: Melphalan and CIS + MMC regimens were associated with comparable incidences of leukopenia and thrombocytopenia. Severe leukopenia and severe thrombocytopenia were rare following CRS/HIPEC using both chemotherapy regimens. PMID- 29429052 TI - Molecular and Clinical Aspects of Protein Aggregation Assays in Neurodegenerative Diseases. AB - The presence of protein deposits is a common pathological hallmark in patients suffering from neurodegenerative conditions and other proteinopathies. Deciphering the molecular basis of protein misfolding and aggregation is a crucial step towards the full comprehension of the factors that trigger the onset of these diseases and for the development of efficient therapeutical strategies. In this regard, in vitro aggregation assays for misfolded proteins offer an excellent tool to study pathological processes of protein deposition under controlled conditions, where confounders can be easily discriminated. These methods are generally cost-effective and have been proved useful in many fields, including drug discovery and clinical diagnostics. Here, we review the bases of in vitro aggregation and seeding assays, recapitulate their main applications and offer a critical evaluation of their limitations. Comprehending the molecular mechanisms behind these assays and combining them with in vivo or cell-based experiments will maximize their potential and allow the necessary improvement to overcome some of the current drawbacks. PMID- 29429055 TI - Clinical study of guided bone regeneration with resorbable polylactide-co glycolide acid membrane. AB - The guided bone regeneration (GBR) technique is often applied to provide sufficient bone for ideal implant placement. The objective of this study was to evaluate whether GC membrane(r), which has already been used for guided tissue regeneration (GTR), can also be available for GBR. Twenty-three implants in 18 patients were evaluated in the study. All patients underwent implant placement with GBR using GC membrane(r). Cone-beam computed tomography was performed at 13 30 weeks after surgery and the amount of augmented bone was assessed. The implant stability quotient (ISQ) was measured at the second operation to evaluate implant stability. Although wound dehiscence was observed at 4 of 23 regions (17.4%), all wounds closed quickly without any events by additional antibiotic administration. GBR-induced bone augmentation of 0.70-2.56 mm horizontally and 0-6.82 mm vertically. Only 0.18 mm of bone recession was observed at 16-24 months after implant placement. GBR with GC membrane(r) induced sufficient bone augmentation, leading to successful implant treatment. The present results suggest that GC membrane(r) is available not only for GTR, but also for GBR. PMID- 29429056 TI - Histological healing after nonsurgical periodontal treatment with enamel matrix derivatives in canine experimental periodontitis. AB - The histological outcomes after nonsurgical periodontal treatment with enamel matrix derivatives (EMD) remain controversial. The present study evaluated periodontal wound healing after scaling and root planing (SRP) with subgingival application of EMD for treatment of experimental periodontitis. Periodontal breakdown was induced by applying silk ligatures around mandibular third and fourth premolars of six beagle dogs until radiographic bone loss progressed to approximately half of the root length. Probing pocket depth (PPD) and clinical attachment level (CAL) were proximally measured 2 weeks after ligature removal (baseline). Mesial and distal surfaces of the experimental teeth were subjected to SRP and randomized using a split-mouth design to subgingival application of EMD (test) or normal saline (control). PPD and CAL were re-evaluated at 11 weeks. Animals were sacrificed at 12 weeks for histological analyses. No significant differences were observed in PPD and CAL between both groups at baseline and at 11 weeks. Histologically, test sites exhibited a greater amount of new cementum than that did the control sites (p < 0.01). Moreover, the control sites revealed increased epithelial downgrowth compared with the test sites: (p < 0.05). On the other hand, no intergroup differences were detected in terms of bone position, connective tissue attachment, gingival recession, and planed root length. This study suggested that EMD has an increased potential to support formation of new cementum with decreased epithelial downgrowth when used as an adjunct to nonsurgical periodontal treatment. PMID- 29429057 TI - Evaluation of four instruments with different working motion using artificial plastic model with C-shaped single canal. AB - The purpose of this study was to evaluate four instruments with different working motion for preparation of a C-shaped single canal wall using the same artificial plastic models reproduced from a human tooth. One tooth with root canal morphology C1 (the shape is an uninterrupted "C" with no separation or division) was selected among three-dimensional micro-computed tomography (micro-CT) imaging data of extracted human teeth. Imaging data were then converted into STL form data, and twenty-four C-shaped root canal model blocks were manufactured using this STL form data. These blocks were randomly divided into four groups of six blocks each and instrumented as follows: stainless steel K-files (SSK), Self Adjusting File (SAF), ProTaper NEXT (PTN) and RECIPROC (REC). Micro-CT images taken before and after canal preparation were superimposed, and instrumented canal area, percentage of instrumented canal area, part of instrumented canal area, volume of instrumented canal and time taken for instrumentation were evaluated for each group. The greatest instrumented canal area, percentage of instrumented canal area and volume of instrumented canal were as follows (in decreasing order): SSK > SAF > PTN > REC (P < 0.05). The longest time taken for instrumentation was as follows (in decreasing order): SAF > SSK > PTN > REC (P < 0.05). The conscious shaping of SSK and the lattice structure of SAF were instrumented all root canal walls equally. PTN and REC required less time taken for instrumentation, but showed unequal instrumentation. PMID- 29429058 TI - Immunosuppressive monocytes (CD14+/HLA-DRlow/-) increase in childhood precursor B cell acute lymphoblastic leukemia after induction chemotherapy. AB - In tumor microenvironment, immunosuppression is a common event and results from the inhibition of activated immune cells and generation of cells with immunosuppressive capacity, as some subtypes of monocytes. The aim of this study was to evaluate the presence of immunosuppressive CD14+/HLA-DRlow/- monocytes in pediatric patients with the diagnosis of B-cell acute lymphoblastic leukemia (B ALL) and, moreover, verify whether the chemotherapeutic treatment has any effect on these cells. Peripheral blood (PB) and bone marrow (BM) samples were collected from 15 untreated pediatric patients. The presence of CD14+/HLA-DRlow/- monocytes was evaluated at diagnosis and in the end of induction chemotherapy by flow cytometry. CD14+/HLA-DRlow/- monocytes increase was observed in 60% (9/15) of the patients at the end of the induction therapy. We were able to detect an increase in CD14+/HLA-DRlow/- monocytes values in BM and PB samples of pediatric patients with B-ALL. This increase was observed in the end of induction chemotherapy, which leads us to believe that these changes probably could have been induced by the inflammatory process engendered by the cytotoxic treatment or by drugs used in the chemotherapy treatment. This finding may be useful to guide new therapeutic approaches contemplating immunomodulatory drugs that act in the depletion of immunosuppressive monocytes. PMID- 29429059 TI - Terpenoids from Vitex trifolia and their anti-inflammatory activities. AB - A new diterpenoid glucoside, (3S,5S,6S,8R,9R,10S)-3,6,9-trihydroxy-13(14)-labdean 16,15-olide 3-O-beta-D-glucopyranoside (1), and a new iridoid glucoside, (1S, 5S,6R,9R)-10-O-p-hydroxybenzoyl-5,6beta-dihydroxy iridoid 1-O-beta-D glucopyranoside (2), along with six known compounds (3-8) were isolated from Vitex trifolia L.. Their structures were elucidated by extensive spectroscopic analysis. All these isolated compounds were evaluated for their inhibitory effects on nitric oxide production in LPS-induced RAW 264.7 macrophages. Compounds 2, 4, 5, and 7 showed moderate inhibitory activities with IC50 values of 90.05, 88.51, 87.26, and 76.06 MUM, respectively. PMID- 29429060 TI - Electrophysiological differences in cholinergic signaling between the hearts of summer and winter frogs (Rana temporaria). AB - The striking seasonal difference in sensitivity of frog cardiac muscle to acetylcholine or stimulation of parasympathetic nervous fibers has been noted almost a century ago, although its electrophysiological basis has never been revealed. The present study compares the effects of the muscarinic agonist carbamylcholine chloride (CCh 10-8-10-5 M) on electrical activity in isolated atrial and ventricular preparations from dormant frogs (Rana temporaria) caught in January (winter-acclimatized, WA) and from active frogs caught in July (summer acclimatized, SA). Seasonal differences in the density of potassium acetylcholine dependent current (IKACh) were also studied in atrial and ventricular myocytes from both summer and winter groups. In atrial myocardium, CCh produced concentration-dependent shortening of action potentials (APs). CCh concentration producing a 50% reduction of AP duration was lower in WA (1.03 * 10-7 M) than SA atria (2.7 * 10-7 M). 10-6 M CCh induced drastic reduction of AP amplitude rendering the tissue unexcitable in both WA or SA atrial preparations. Ventricular preparations showed greater seasonal difference in CCh sensitivity. While 10-6 M induced inexcitability in 50% of tested WA preparations, in SA preparations even 10-5 M CCh was without effect. This striking difference between cholinergic effects in SA and WA frog ventricle could be explained by seasonal changes in the IKACh density. The density of IKACh induced by 10-5 M CCh and measured at 0 mV was 14.4 +/- 3.45 pA/pF in WA, but only 1.5 +/- 0.4 pA/pF in SA atrial cells. In ventricular cells, the respective values were 2.61 +/- 0.56 and 0.71 +/- 0.09 pA/pF. Thus, hibernating winter frog has a much greater electrophysiological cholinergic response than active summer frog due to up regulation of IKACh. PMID- 29429062 TI - Towards precision medicine; a new biomedical cosmology. AB - Precision Medicine has become a common label for data-intensive and patient driven biomedical research. Its intended future is reflected in endeavours such as the Precision Medicine Initiative in the USA. This article addresses the question whether it is possible to discern a new 'medical cosmology' in Precision Medicine, a concept that was developed by Nicholas Jewson to describe comprehensive transformations involving various dimensions of biomedical knowledge and practice, such as vocabularies, the roles of patients and physicians and the conceptualisation of disease. Subsequently, I will elaborate my assessment of the features of Precision Medicine with the help of Michel Foucault, by exploring how precision medicine involves a transformation along three axes: the axis of biomedical knowledge, of biomedical power and of the patient as a self. Patients are encouraged to become the managers of their own health status, while the medical domain is reframed as a data-sharing community, characterised by changing power relationships between providers and patients, producers and consumers. While the emerging Precision Medicine cosmology may surpass existing knowledge frameworks; it obscures previous traditions and reduces research-subjects to mere data. This in turn, means that the individual is both subjected to the neoliberal demand to share personal information, and at the same time has acquired the positive 'right' to become a member of the data sharing community. The subject has to constantly negotiate the meaning of his or her data, which can either enable self-expression, or function as a commanding Superego. PMID- 29429061 TI - Iterative Calibration: A Novel Approach for Calibrating the Molecular Clock Using Complex Geological Events. AB - During the past 50 years, the molecular clock has become one of the main tools for providing a time scale for the history of life. In the era of robust molecular evolutionary analysis, clock calibration is still one of the most basic steps needing attention. When fossil records are limited, well-dated geological events are the main resource for calibration. However, biogeographic calibrations have often been used in a simplistic manner, for example assuming simultaneous vicariant divergence of multiple sister lineages. Here, we propose a novel iterative calibration approach to define the most appropriate calibration date by seeking congruence between the dates assigned to multiple allopatric divergences and the geological history. Exploring patterns of molecular divergence in 16 trans-Bering sister clades of echinoderms, we demonstrate that the iterative calibration is predominantly advantageous when using complex geological or climatological events-such as the opening/reclosure of the Bering Strait providing a powerful tool for clock dating that can be applied to other biogeographic calibration systems and further taxa. Using Bayesian analysis, we observed that evolutionary rate variability in the COI-5P gene is generally distributed in a clock-like fashion for Northern echinoderms. The results reveal a large range of genetic divergences, consistent with multiple pulses of trans Bering migrations. A resulting rate of 2.8% pairwise Kimura-2-parameter sequence divergence per million years is suggested for the COI-5P gene in Northern echinoderms. Given that molecular rates may vary across latitudes and taxa, this study provides a new context for dating the evolutionary history of Arctic marine life. PMID- 29429063 TI - The moral obligation to be vaccinated: utilitarianism, contractualism, and collective easy rescue. AB - We argue that individuals who have access to vaccines and for whom vaccination is not medically contraindicated have a moral obligation to contribute to the realisation of herd immunity by being vaccinated. Contrary to what some have claimed, we argue that this individual moral obligation exists in spite of the fact that each individual vaccination does not significantly affect vaccination coverage rates and therefore does not significantly contribute to herd immunity. Establishing the existence of a moral obligation to be vaccinated (both for adults and for children) despite the negligible contribution each vaccination can make to the realisation of herd immunity is important because such moral obligation would strengthen the justification for coercive vaccination policies. We show that two types of arguments-namely a utilitarian argument based on Parfit's Principle of Group Beneficence and a contractualist argument-can ground an individual moral obligation to be vaccinated, in spite of the imperceptible contribution that any single vaccination makes to vaccine coverage rates. We add a further argument for a moral obligation to be vaccinated that does not require embracing problematic comprehensive moral theories such as utilitarianism or contractualism. The argument is based on a "duty of easy rescue" applied to collectives, which grounds a collective moral obligation to realise herd immunity, and on a principle of fairness in the distribution of the burdens that must be borne to realise herd immunity. PMID- 29429064 TI - A call for standardization of wound events reporting following ventral hernia repair. AB - INTRODUCTION: Postoperative wound events following ventral hernia repair are an important outcome measure. While efforts have been made by hernia surgeons to identify and address risk factors for postoperative wound events following VHR, the definition of these events lacks standardization. Therefore, the purpose of our study was to detail the variability of wound event definitions in recent ventral hernia literature and to propose standardized definitions for postoperative wound events following VHR. METHODS: The top 50 cited ventral hernia, peer-reviewed publications from 1995 through 2015 were identified using the search engine Google Scholar. The definition of wound event used and the incidence of postoperative wound events was recorded for each article. The number of articles that used a standardized definition for surgical site infection (SSI), surgical site occurrence (SSO), or surgical site occurrence requiring procedural intervention (SSOPI) was also identified. RESULTS: Of the 50 papers evaluated, only nine (18%) used a standardized definition for SSI, SSO, or SSOPI. The papers that used standardized definitions had a smaller variability in the incidence of wound events when compared to one another and their reported rates were more consistent with recently published ventral hernia repair literature. CONCLUSION: Postoperative wound events following VHR are intimately associated with patient quality of life and long-term hernia repair durability. Standardization of the definition of postoperative wound events to include SSI, SSO, and SSOPI following VHR will improve the ability of hernia surgeons to make evidence-based decisions regarding the management of ventral hernias. PMID- 29429065 TI - Anterior cervical arthrodesis for chronic hangman's fracture in a patient with osteopetrosis: a case report. AB - INTRODUCTION: Osteopetrosis is a clinical syndrome characterized by the failure of osteoclasts to resorb bone. Affected patients usually suffer from repetitive fractures due to this pathological state. Surgical treatment of these fractures is often complicated by the difficulty of working with the extremely hard and brittle bones. The purpose of this study was to report a case of chronic hangman's fracture in a patient with osteopetrosis who underwent surgery for cervical anterior interbody fusion. MATERIALS AND METHODS: A 76-year-old woman visited our institute 1 month after injury. Radiographs revealed a type II hangman's fracture with severe translation according to the Levine-Edwards classification. We performed anterior spinal arthrodesis from C2 to C3. RESULTS: We obtained successful anterior C2-C3 arthrodesis without major complications, but encountered some surgical difficulties in treatment due to hard and brittle bones. CONCLUSIONS: Anterior cervical arthrodesis can be considered an effective treatment for chronic unstable hangman's fracture in patients with osteopetrosis. However, great care must be taken when performing surgery and continued follow-up is warranted. PMID- 29429066 TI - Outcomes following surgical management of femoral neck fractures in elderly dialysis-dependent patients. AB - INTRODUCTION: Proximal femur fractures are one of the most common fractures observed in dialysis-dependent patients. Given the large comorbidity burden present in this patient population, more information is needed regarding post operative outcomes. The goal of this study was to assess morbidity and mortality following operative fixation of femoral neck fractures in the dialysis-dependent elderly. METHODS: The full set of medicare data from 2005 to 2014 was retrospectively analyzed. Elderly patients with femoral neck fractures were selected. Patients were stratified based on dialysis dependence. Post-operative morbidity and mortality outcomes were compared between the two populations. Adjusted odds were calculated to determine the effect of dialysis dependence on outcomes. RESULTS: A total of 320,629 patients met the inclusion criteria. Of dialysis-dependent patients, 1504 patients underwent internal fixation and 2662 underwent arthroplasty. For both surgical cohorts, dialysis dependence was found to be associated with at least 1.9 times greater odds of mortality within 1 and 2 years post-operatively. Blood transfusions within 90 days and infections within 2 years were significantly increased in the dialysis-dependent study cohort. Dialysis dependence alone did not contribute to increased mechanical failure or major medical complications. CONCLUSION: Regardless of the surgery performed, dialysis dependence is a significant risk factor for major post-surgical morbidity and mortality after operative treatment of femoral neck fractures in this population. Increased mechanical failure in the internal fixation group was not observed. The increased risk associated with caring for this population should be understood when considering surgical intervention and counseling patients. PMID- 29429067 TI - Hip malformation is a very common finding in young patients scheduled for total hip arthroplasty. AB - INTRODUCTION: In Denmark, 20% of all registered total hip arthroplasties (THA) from 1995 to 2014 has been patients younger than 60 years with primary idiopathic osteoarthritis (OA). It is speculated that hip malformations may be a major contributor to early OA development. It has been shown that hip malformation may compromise implant position and, therefore, identifying and knowing the incidence of malformations is important. Our aim was to assess the prevalence and type of hip malformations in a cohort of younger patients undergoing THA. MATERIALS AND METHODS: In this prospective two center cohort study, 95 consecutive patients (106 hips) met the inclusion criteria. One observer performed radiographic measurements for malformations and radiographic OA. Inter- and intraobserver variability was assessed. RESULTS: From 95 patients (male n = 52 and female n = 43) age ranged from 35 to 59 years and prevalences of hip malformations were; CAM deformity 50.9 and 25.5%, coxa profunda 33 and 27.4%, acetabular retroversion 33 and 29.2%, and acetabular dysplasia 10.4 and 3.8%. All patients showed minimum of one malformation. Prevalences of Tonnis grade 0-1 were 22.6% and 2-3 were 77.4%. CONCLUSION: All patients showed malformations, especially high prevalences were found for CAM-deformity, coxa profunda and acetabular retroversion. Identifying these malformations is fairly simple and recognizing the high prevalence may help surgeons avoid pitfalls during implant positioning in THA surgery. Further, focus on hip malformations may facilitate correct referral to joint-preserving surgery before OA develops. PMID- 29429068 TI - Stability of maxillary protraction therapy in children with Class III malocclusion: a systematic review and meta-analysis. AB - OBJECTIVE: The objective of this study was to evaluate the stability of treatment effects of maxillary protraction therapy in Class III children. MATERIALS AND METHODS: Multiple electronic databases were searched from 01/1996 to 10/2016. Randomized clinical trials, controlled clinical trials, and cohort studies with untreated Class III controls and a follow-up over 2 years were considered for inclusion. The methodological quality of the studies and publication bias were evaluated. Mean differences and 95% confidence intervals (CI) of six variables (SNA, SNB, ANB, mandibular plane angle, overjet, and lower incisor angle) were calculated. RESULTS: Ten studies were included in the qualitative analysis, and four studies were included in the quantitative analysis. Compared with the control group, after treatment, the treated group showed significant changes: SNA +1.79 degrees (95% CI: 1.23, 2.34), SNB -1.16 degrees (95% CI -2.08, -0.24), ANB +2.92 degrees (95% CI 2.40, 3.44), mandibular plane angle +1.41 degrees (95% CI 0.63, 2.20), overjet +3.94 mm (95% CI 2.17, 5.71) and lower incisor angle -3.07 degrees (95% CI -4.92, -1.22). During follow-up, the changes in five variables reflected significant relapse. Overall, the treated group showed significant changes only in ANB +1.66 degrees (95% CI 0.97, 2.35) and overjet +2.41 mm (95% CI 1.60, 3.23). CONCLUSIONS: Maxillary protraction can be a short term effective therapy and might improve sagittal skeletal and dental relationships in the medium term. But some skeletal and dental variables showed significant relapse during the follow-up period. Long-term studies are still required to further evaluate its skeletal benefits. CLINICAL RELEVANCE: The study evaluated the medium-term stability of skeletal and dental effects of maxillary protraction in Class III children and discussed whether the therapy can reduce the need for orthognathic surgery. PMID- 29429069 TI - Rare and changeable as a chameleon: paraneoplastic syndromes in renal cell carcinoma. AB - INTRODUCTION: Paraneoplastic syndromes (PNS) in renal cell carcinoma (RCC) are important to be recognized by the treating physician, because they may lead to diagnosis of underlying malignant disease. On the other hand, PNS may dominate the clinical picture and can hide the true disorder like a chameleon. When realized, a PNS can be used as a 'neoplastic tumour marker', especially in case of recurrence. Their occurrence can even be linked to prognosis of disease. METHODS: A PubMed search combining the MeSH terms renal cell carcinoma and paraneoplastic syndrome was executed in April 2015. All hits concerning these MeSH terms have been taken into account when writing this review. RESULTS: There is a big gap between reporting and incidence of paraneoplastic syndromes in renal cell carcinoma. Most of the articles in Medline are case reports and reviews of research done in the 1950s-1990s. One problem is that a clear definition of a paraneoplastic syndrome is still lacking. The most important PNS in RCC are hypercalcemia. It is important that PNS are not only arising in advanced stages of renal cell carcinoma; in contrast, a PNS can often be the first symptom of RCC. CONCLUSION: Paraneoplastic syndromes are often unrecognized but are important biomarkers in RCC. Further research into the underlying pathomechanisms of PNS may improve our understanding of the RCC tumour biology and is urgently needed. PMID- 29429070 TI - A 34-year longitudinal study on long-term cardiac outcomes in DM1 patients with normal ECG at baseline at an Italian clinical centre. AB - Cardiac conduction and/or rhythm abnormalities (CCRA) are the most frequent and life-threatening complications in DM1. In order to determine prevalence, incidence, characteristics, age of onset and predictors of CCRA, CCRA progression and sudden cardiac death (SCD) in DM1, we collected ECG/24hECG-Holter data from a yearly updated 34-year database of a cohort of 103 DM1 patients without cardiac abnormalities at baseline, followed for at least 1 year. Fifty-five patients developed CCRA [39 developed conduction abnormalities (CCA) and 16 rhythm abnormalities (CRA)], which progressed in 22. Nine had SCD. Risk and incidence of CCRA amounted to 53.4 and 6.83% person-years (CCA: 37.9 and 4.8%; CRA 15.5 and 2%), respectively; risk and incidence of SCD amounted to 8.74 and 0.67% person years, respectively. CTG expansion represented a predictor of CCRA incidence (HR 1.10, p = 0.04), CCRA progression (HR 1.28, p = 0.001) and SCD (HR 1.39, p = 0.002). MIRS progression during follow-up was associated with CCRA prevalence (OR 5.82, p = 0.004); older age and larger CTG expansion to SCD prevalence (OR 2.67, p = 0.012; OR 1.54, p = 0.005). Age of CCRA onset and CCRA progression was significantly lower in patients with larger CTG expansion and in those with MIRS progression. Age when SCD occurred was significantly lower in patients with larger CTG expansion. Amongst recorded cardiac abnormalities, both atrial flutter (OR 8.70; p = 0.031) and paroxysmal supraventricular tachycardia (OR 8.67; p = 0.040) were associated with SCD. Although all DM1patients may develop cardiac abnormalities at any time in their life, patients older than 30 years with larger CTG expansion and MIRS progression in particular should be carefully monitored via periodical ECG. PMID- 29429071 TI - Ammonia-oxidizing bacteria and archaea within biofilters of a commercial recirculating marine aquaculture system. AB - While biofilters are widely used to metabolize ammonia and other wastes in marine recirculating aquaculture systems, the ammonia-oxidizing bacterial and archaeal communities have not been characterized across a diversity of production systems. Using a metagenomics approach, we characterized the ammonia-oxidizing microbiological community of biofilters in a commercial recirculating marine aquaculture system producing hybrid grouper (Epinephelus lanceolatus * E. fuscoguttatus). Cloning and sequencing of the amoA gene showed that nitrifying bacteria included Nitrosomonas europea, N. stercoris, N. cryotolerans, N. eutropha, N. estuarii, eight strains of N. marina, and 15 strains not associated with described species. Nitrifying archaea included eight strains of Nitrosopumilus maritimus, N. koreensis, N. piranensis, N. adriaticus, undescribed congeners, and other undescribed archaea. The species composition of the bacterial and especially the archaeal communities was beyond that yet reported for aquaculture biofilters. While ammonia flux through the respective communities has yet to be estimated, the diverse environmental adaptations of the bacterial and archaeal communities suggest resilience of function under a range of environmental conditions. PMID- 29429073 TI - Non-capsulated mutants of a chemical-producing Klebsiella pneumoniae strain. AB - OBJECTIVES: To investigate the outcomes of capsule lost on cell transformation efficiency and chemicals (1,3-propanediol, 2,3-butanediol, and 2-ketogluconic acid) production by Klebsiella pneumoniae. RESULTS: The cps gene cluster showed low sequence homology with pathogenic strains. The wza is a highly conserved gene in the cps cluster that encodes an outer membrane protein. A non-capsulated mutant was constructed by deletion of wza. Phenotype studies demonstrated that non-capsulated cells were less buoyant and easy to sediment. The transformation efficiency of the non-capsulated mutant reached 6.4 * 105 CFU MUg-1 DNA, which is 10 times higher than that of the wild strain. 52.2 g 1,3-propanediol L-1, 30.7 g 2,3-butanediol L-1, and 175.9 g 2-ketogluconic acid L-1 were produced by non capsulated mutants, which were 10-40% lower compared to wild strain. Furthermore, viscosities of the three fermentation broths decreased to approximately 1.3 cP from the range of 1.8-2.2 cP. CONCLUSIONS: Non-capsulated K. pneumoniae mutants should allay concerns regarding biological safety, improve transformation efficiency, lower viscosity, and subsequently ameliorate the financial burden of the downstream process of chemicals production. PMID- 29429072 TI - An ex vivo ruminal ovine model to study the immediate immune response in the context of bacterial lipopolysaccharide. AB - We have set up an ex vivo ovine ruminal model, which can mimic the multicellular process to explore the early steps in Salmonella typhimurium lipopolysaccharide (LPS) stimulation using RNA-seq technology. Ovine ruminal explants were collected for histological and transcriptional analysis and supernatants collected to quantitate lactate dehydrogenase (LDH) enzymes. A total of 8 and 523 genes were significantly over-expressed between LPS-treated and control tissues at 6 and 12 h, respectively. However, six and seven hundred and thirteen genes were substantially repressed between the aforementioned tissues, correspondingly. Key genes up-regulated in response to the addition of LPS were tumor necrosis factor (TNF), interlukin (IL)-1 beta(b), IL-6, IL-8, IL-17B, IL-19, MMP-1, MMP-3, and integrin alpha 2 (ITGA8, 9). This study shows for the first time that galectin-1 is up-regulated in an ex vivo ruminal segment model exposed to bacterial lipopolysaccharide following 6 h of incubation. The ruminal segment model has been shown to be a suitable tool to study the bacterial lipopolysaccharide effects on the ovine ruminal tissues prior to in vivo assessment. PMID- 29429074 TI - Cyclic mechanical stretch enhances BMP9-induced osteogenic differentiation of mesenchymal stem cells. AB - PURPOSE: The purpose of this study was to investigate whether mechanical stretch can enhance the bone morphogenetic protein 9 (BMP9)-induced osteogenic differentiation in MSCs. METHODS: Recombinant adenoviruses were used to overexpress the BMP9 in C3H10T1/2 MSCs. Cells were seeded onto six-well BioFlex collagen I-coated plates and subjected to cyclic mechanical stretch [6% elongation at 60 cycles/minute (1 Hz)] in a Flexercell FX-4000 strain unit for up to 12 hours. Immunostaining and confocal microscope were used to detect cytoskeleton organization. Cell cycle progression was checked by flow cytometry. Alkaline phosphatase activity was measured with a Chemiluminescence Assay Kit and was quantified with a histochemical staining assay. Matrix mineralization was examined by Alizarin Red S Staining. RESULTS: Mechanical stretch induces cytoskeleton reorganization and inhibits cell proliferation by preventing cells entry into S phase of the cell cycle. Although mechanical stretch alone does not induce the osteogenic differentiation of C3H10T1/2 MSCs, co-stimulation with mechanical stretch and BMP9 enhances alkaline phosphatase activity. The expression of key lineage-specific regulators (e.g., osteocalcin (OCN), SRY related HMG-box 9, and runt-related transcription factor 2) is also increased after the co-stimulation, compared to the mechanical stretch stimulation along. Furthermore, mechanical stretch augments the BMP9-mediated bone matrix mineralization of C3H10T1/2 MSCs. CONCLUSIONS: Our results suggest that mechanical stretch enhances BMP9-induced osteoblastic lineage specification in C3H10T1/2 MSCs. PMID- 29429075 TI - Dietary Supplementation of Almond Prevents Oxidative Stress by Advocating Antioxidants and Attenuates Impaired Aversive Memory in Male Rats. AB - Scopolamine, an anti-muscarinic agent, has been shown to induce amnesia and oxidative stress similar to that observed in the older age. The present study was designed to determine the relationship between the oxidative status and memory improvement in scopolamine injected rats pre-administered with almonds. Rats (n = 8) in the almond group were administered orally with 400 mg/kg almond suspension for 28 days daily before the intraperitoneal injection of scopolamine (0.5 mg/kg). Passive avoidance task (PAT) was used to assess memory function at the end of treatment. The present study revealed that scopolamine injection significantly impaired the memory function in rats pre-treated with saline which was accompanied by increased oxidative stress as evident by increased brain malondialdehyde (MDA) levels and reduced activities of antioxidant enzymes as compared to healthy controls. Pre-treatment with almond significantly ameliorated scopolamine-induced oxidative stress and memory dysfunction. These findings suggest that dietary supplementation with almonds may have a beneficial effect in reducing the risk of oxidative stress-induced memory loss and delaying or preventing the onset of age-related memory impairment. PMID- 29429077 TI - The Diversity of Bacterial Chemosensing. AB - Bacteria have a continuous and urgent need to inform themselves about the chemistry of their surroundings. They must rapidly adjust their patterns of gene expression, their metabolic and transport functions, and their behavior to cope with every challenge and opportunity with which they are presented. This volume collates the most recent methods developed to monitor and manipulate the processes by which bacteria sense and respond to their chemical environment. PMID- 29429078 TI - Transmembrane Signal Transduction in Bacterial Chemosensing. AB - Like all living organisms, bacteria must communicate with the world around them. As they typically live as single cells, the communication with their environment must occur at the cell membrane, both in moving molecules in and out and in transmitting information about their surroundings to response elements within the cell. This volume is devoted primarily to methods used to study either the behavior of bacteria in response to their environment or methods used to study events that involve signaling pathways that are initiated by events at the cell membrane. The topics are arranged according to the scale of the events described: (1) Methods for studying bacterial chemotaxis at the population and whole-cell levels; (2) In vivo analysis of receptor function; (3) Cryo-EM methods for studying chemoreceptor structure; (4) Monitoring the intracellular movement of chemosensory proteins; (5) High-throughput methods for screening novel chemoeffectors; (6) Creating chemical tools for studying chemosensory signal transduction; (7) Computerized analysis of chemotaxis. Every effort has been made to get the most experienced and proficient practitioners of each of the methods described, and the editor is indebted to all who agreed to participate. PMID- 29429079 TI - Two Spatial Chemotaxis Assays: The Nutrient-Depleted Chemotaxis Assay and the Agarose-Plug-Bridge Assay. AB - This chapter describes two spatial chemotaxis assays, the nutrient-depleted chemotaxis assay and agarose-plug-bridge assay, which enable the evaluation of putative chemoeffectors. These two assays have worked well with Campylobacter jejuni and Helicobacter pylori, and techniques for using these assays with these microbes are described. PMID- 29429080 TI - Quantification of Bacterial Chemotaxis Responses at the Mouths of Hydrogel Capillaries. AB - Many chemotaxis assays allow for the assessment of bacterial chemotaxis by determining the number of cells migrating toward a chemoattractant or away from a chemorepellent. Some of these assays use a capillary filled with a chemoeffector/agarose mixture to allow cells to accumulate at the mouth of the capillary. Subsequently, assumptions about the relative strengths of chemotaxis strength are based on visual comparisons. Here, we describe a modification of this assay that uses a hydrogel matrix to enable quantitative time-course measurements by analyzing image pixel intensities. This approach allows a high throughput method when coupled with the aid of a motorized microscope stage. PMID- 29429076 TI - Cardiovascular Autonomic Dysfunction: Link Between Multiple Sclerosis Osteoporosis and Neurodegeneration. AB - The high prevalence of osteoporosis, observed in multiple sclerosis (MS) patients, has been attributed to reduced mobility and or the use of disease modifying drugs. However, MS-impaired cardiovascular autonomic nervous system (ANS) function has the potential of reducing bone mass density (BMD) by altering the expression and/or function of the neuronal, systemic, and local mediators of bone remodeling. This review describes the complex regulation of bone homeostasis with a focus on MS, providing evidence that ANS dysfunction and low BMD are intertwined with MS inflammatory and neurodegenerative processes, and with other MS-related morbidities, including depression, fatigue, and migraine. Strategies for improving ANS function could reduce the prevalence of MS osteoporosis and slow the rate of MS progression, with a significant positive impact on patients' quality of life. PMID- 29429081 TI - A Static Microfluidic Device for Investigating the Chemotaxis Response to Stable, Non-linear Gradients. AB - Microfluidic technology allows fast and precise measurement of chemotaxis responses to both attractant and repellent signals. One of the major drawbacks of current microfluidic chemotaxis assays is the presence of bacterial cells within the concentration gradient flow field, which has the potential for flow effects masking the chemotaxis response. This chapter describes a new microfluidic device for producing stable concentration gradients and measuring the response of cells to the gradient without exposing them to any flow. Unlike other methods described in the literature, this method is capable of producing gradients of any shape, almost instantaneously, allowing the measurement of time-dependent response of cells to a variety of signals. PMID- 29429082 TI - Visualizing Chemoattraction of Planktonic Cells to a Biofilm. AB - Bacterial chemotaxis in response to continuous chemical gradients has been extensively studied at the individual cell and population levels using a variety of well-established in vitro methods (Englert et al., Microfluidic techniques for the analysis of bacterial chemotaxis. Methods Mol Biol 571:1-23, 2009). In nature, bacteria are surrounded by heterogeneous chemical gradients; hence, it is essential to understand chemotaxis behavior under such conditions. Here, we describe a setup that allows visualization of the chemotaxis response of motile cells to the complex microenvironment of a biofilm maintained under static conditions. The biofilm is separated from the motile cells by a semi-permeable membrane. Cells swimming toward the biofilm are captured on the membrane and imaged using confocal laser scanning microscopy (CLSM). Chemotaxis toward specific molecules produced by the biofilm, such as autoinducer-2 (AI-2), can be studied using this setup. This system can be adapted to study chemotaxis toward poly-species biofilms, or even mammalian cells. PMID- 29429083 TI - Labeling Bacterial Flagella with Fluorescent Dyes. AB - We describe labeling of bacteria with amino-specific or sulfhydryl-specific Alexa Fluor dyes, methods that allow visualization of flagellar filaments, even in swimming cells. Bacterial flagellar filaments are long (~10 MUm), but of small diameter (~20 nm), and their rotation rates are high (>100 Hz), so visualization is difficult. Dark-field microscopy works well with isolated filaments, but visualization in situ is hampered by light scattered from cell bodies, which obscures short filaments or the proximal ends of long filaments. Differential interference contrast microscopy also works, but is technically difficult and suffers from a narrow depth of field and low image contrast; background subtraction and contrast enhancement are necessary. If filaments are fluorescent, they can be imaged in their entirety using standard fluorescence microscopes. For imaging in vivo, blurring can be prevented by strobing the light source or by using a camera with a fast shutter. The former method is preferred, since it minimizes bleaching. PMID- 29429084 TI - All-Codon Mutagenesis for Structure-Function Studies of Chemotaxis Signaling Proteins. AB - The technique of all-codon mutagenesis can generate mutants that represent all possible amino acid replacements at any particular residue in a protein. It is thus a powerful tool to probe structure-function relationships in proteins of interest. In this chapter, we describe how we used all-codon mutagenesis to obtain mutants of the Escherichia coli serine receptor Tsr with amino acid replacements at residue F373, a functionally important site in this protein. We provide general protocols for mutagenesis of a target codon in a plasmid-borne gene and for the selection and screening of the resultant mutants. These techniques should be adaptable for the study of a variety of bacterial proteins. PMID- 29429085 TI - Mutational Analysis of Binding Protein-Chemoreceptor Interactions. AB - Interactions between ligands and chemoreceptors in Escherichia coli and Salmonella enterica can be studied through genetic manipulation of the actors involved. Sequence analysis and modeling can reveal potential sites of interaction, and these sites can be deleted or mutated and the effects tested through various in vivo chemotaxis assays to ascertain their importance during interaction. Here, the approach for analysis of the interaction between a major E. coli chemoreceptor and its binding protein ligand is described. PMID- 29429086 TI - In Vitro Assay for Measuring Receptor-Kinase Activity in the Bacillus subtilis Chemotaxis Pathway. AB - The sensing apparatus of the Bacillus subtilis chemotaxis pathway involves a complex consisting of chemoreceptors, the CheA histidine kinase, and the CheV and CheW adaptor proteins. Attractants and repellents alter the rate of CheA autophosphorylation, either by directly binding the receptors or by indirectly interacting with them through intermediate binding proteins. We describe an in vitro assay for measuring receptor-kinase activity in B. subtilis. This assay has been used to investigate the mechanism of signal transduction in B. subtilis chemotaxis and the disparate mechanisms employed by this bacterium for sensory adaptation and gradient sensing. PMID- 29429087 TI - FRET Analysis of the Chemotaxis Pathway Response. AB - Most motile bacteria follow spatial gradients of chemical and physical stimuli in their environment. In Escherichia coli and other bacteria, the best characterized chemotaxis is in gradients of amino acids or sugars, but other physiological stimuli such as pH, osmolarity, redox potentials, and temperature are also known to elicit tactic responses. These multiple environmental stimuli are integrated and processed within a highly sophisticated chemotaxis network to generate coordinated chemotaxis behavior, which features high sensitivity, a wide dynamic range, and robustness against variations in background stimulation, protein levels, and temperature. Although early studies relied on behavioral analyses to characterize chemotactic responses in vivo, or on biochemical assays to study the pathway in vitro, we describe here a method to directly measure the intracellular pathway response using Forster resonance energy transfer (FRET). In E. coli, the most commonly used form of the FRET assay relies on the interaction between the phosphorylated response regulator CheY and its phosphatase CheZ to quantify activity of the histidine kinase CheA. We further describe a FRET assay for Bacillus subtilis, which employs CheY and the motor-associated phosphatase FliY as a FRET pair. In particular, we highlight the use of FRET to quantify pathway properties, including signal amplification, dynamic range, and kinetics of adaptation. PMID- 29429088 TI - Monitoring Two-Component Sensor Kinases with a Chemotaxis Signal Readout. AB - Bacteria use two-component signal transduction systems to elicit adaptive responses to environmental changes. The simplest of these systems comprises a transmembrane sensor with histidine kinase activity and its cytoplasmic response regulator partner. Stimulus-response studies of two-component signaling systems typically employ expression reporters, such as beta-galactosidase, that operate with relatively slow kinetics and low precision. In this chapter, we illustrate a new strategy for directly measuring the signaling activities of two-component sensor kinases in vivo. Our method exploits recent work that defines the recognition determinants for sensor-response regulator signaling transactions, which enabled us to couple histidine kinases to a FRET-based assay that uses signaling components of the E. coli chemotaxis system. We demonstrate the approach with NarX, a nitrate/nitrite sensor kinase, but the method should be applicable to other two-component sensor kinases. PMID- 29429089 TI - Analyzing Protein Domain Interactions in Chemoreceptors by In Vivo PEGylation. AB - The instability of some proteins can hamper in vitro studies. This is true for the membrane-bound aerotaxis receptor, Aer, which exhibits significant proteolysis during the preparation of membrane vesicles. Permeabilized cells can closely mimic in vivo conditions, maintaining the intracellular milieu and geometry of interacting domains. Here, we describe an optimized method for determining solvent accessibility in permeabilized Escherichia coli cells. In this method, E. coli expressing Aer with a series of cysteine replacements are treated with toluene and ethanol, after which a large sulfhydryl reactive probe, PEG-mal, is added. PEGylated protein is separated from un-PEGylated protein by its apparent size difference on SDS-PAGE. The extent to which each cysteine residue becomes PEGylated is then used as a measure of solvent accessibility. When a library of single-Cys replacements is mapped, regions of low accessibility can suggest interacting protein surfaces. We successfully used this method to reveal inaccessible surfaces on both the Aer PAS and HAMP domains that were then shown by disulfide cross-linking to interact. PMID- 29429090 TI - Tuning Chemoreceptor Signaling by Positioning Aromatic Residues at the Lipid Aqueous Interface. AB - Aromatic tuning facilitates stimulus-independent modulation of receptor output. The methodology is based upon the affinity of amphipathic aromatic residues, namely Trp and Tyr, for the polar-hydrophobic interfaces found within biological membranes. Here, we describe the application of aromatic tuning within the aspartate chemoreceptor of Escherichia coli (Tar). We have also employed the method within other related proteins, such as sensor histidine kinases (SHKs), and therefore hope that other research groups find it useful to modulate signal output from their receptor of interest. PMID- 29429091 TI - Analyzing Chemoreceptor Interactions In Vivo with the Trifunctional Cross-Linker TMEA. AB - Chemoreceptors are dimeric proteins that contain a periplasmic or extracellular domain for ligand binding and an extremely well-conserved cytoplasmic domain for output response control. This latter domain consists in a long alpha-helical hairpin that forms a four-helix coiled-coil bundle in the dimer. Dimers associate into trimers of dimers in the crystal structure obtained for the cytoplasmic domain of the Escherichia coli serine chemoreceptor, Tsr. Further studies confirmed that this crystal structure reflects the basic unit within the in vivo organization of chemoreceptors. The trimers of dimers form large and stable chemoreceptor clusters in all the prokaryotes that have been studied. Here, we describe the use of TMEA, a trifunctional cross-linker that reacts with sulfhydryl groups, as a tool to study the geometry and dynamics of the interaction between receptors of the same or different types in living cells. PMID- 29429092 TI - Use of Cryo-EM to Study the Structure of Chemoreceptor Arrays In Vivo. AB - Cryo-electron microscopy (cryo-EM) allows the imaging of intact macromolecular complexes in the context of whole cells. The biological samples for cryo-EM are kept in a near-native state by flash freezing, without the need for any additional sample preparation or fixation steps. Since transmission electron microscopy only generates 2D projections of the samples, the specimen has to be tilted in order to recover its 3D structural information. This is done by collecting images of the sample with various tilt angles in respect to the electron beam. The acquired tilt series can then be computationally back projected. This technique is called electron cryotomography (ECT), and has been instrumental in unraveling the architecture of chemoreceptor arrays. Here we describe the method of visualizing in vivo bacterial chemoreceptor arrays in three main steps: immobilization of bacterial cells on EM grids by plunge freezing; 2D image acquisition in tilt series; and 3D tomogram reconstruction. PMID- 29429093 TI - Visualizing Chemoreceptor Arrays in Bacterial Minicells by Cryo-Electron Tomography and Subtomogram Analysis. AB - Bacterial chemoreceptors form a highly ordered array in concert with the CheA kinase and the CheW coupling protein. The precise architecture of the array is responsible for high sensitivity, high dynamic range, and strong amplification of chemotaxis signaling. Cryo-electron tomography (cryo-ET) has emerged as a unique tool to visualize bacterial chemotaxis arrays at molecular level. Here we describe a detailed cryo-ET and subtomogram averaging procedure to determine in situ structure of the chemoreceptor arrays in Salmonella minicells. The procedure should be readily applicable to visualize other large macromolecular assemblies in their cellular context. PMID- 29429094 TI - Bacterial Chemoreceptor Imaging at High Spatiotemporal Resolution Using Photoconvertible Fluorescent Proteins. AB - We describe two methods for high-resolution fluorescence imaging of the positioning and mobility of E. coli chemoreceptors fused to photoconvertible fluorescent proteins. Chemoreceptors such as Tar and Tsr are transmembrane proteins expressed at high levels (thousands of copies per cell). Together with their cognate cytosolic signaling proteins, they form clusters on the plasma membrane. Theoretical models imply that the size of these clusters is an important parameter for signaling, and recent PALM imaging has revealed a broad distribution of cluster sizes. We describe experimental setups and protocols for PALM imaging in fixed cells with ~10 nm spatial precision, which allows analysis of cluster-size distributions, and localized-photoactivation single-particle tracking (LPA-SPT) in live cells at ~10 ms temporal resolution, which allows for analysis of cluster mobility. PMID- 29429095 TI - Imaging of Single Dye-Labeled Chemotaxis Proteins in Live Bacteria Using Electroporation. AB - For the last 2 decades, the use of genetically fused fluorescent proteins (FPs) has greatly contributed to the study of chemotactic signaling in E. coli, including the activation of the response regulator protein CheY and its interaction with the flagellar motor. However, this approach suffers from a number of limitations, both biological and biophysical. For example, not all fusions are fully functional when fused to a bulky FP, which can have a similar molecular weight to its fused counterpart. FPs may interfere with the native interactions of the protein, and their chromophores have low brightness and photostability, and fast photobleaching rates. Electroporation allows for internalization of purified CheY proteins labeled with organic dyes into E. coli cells in controllable concentrations. Using fluorescence video microscopy, it is possible to observe single CheY molecules diffusing within cells and interacting with the sensory clusters and the flagellar motors in real time. PMID- 29429096 TI - Fluorescence Anisotropy to Detect In Vivo Stimulus-Induced Changes in Chemoreceptor Packing. AB - The anisotropy of the fluorescence emitted from fluorescent proteins, such as yellow fluorescent protein (YFP), is sensitive to Homo-FRET between the proteins. This effect can be used to detect in vivo ligand-induced changes in packing or conformation of tagged chemoreceptors. Such measurements of clustered or dispersed core-signaling units revealed quantitative dose-dependent responses of these sensors. PMID- 29429097 TI - Chemotaxis to Atypical Chemoattractants by Soil Bacteria. AB - Although the mechanism of bacterial chemotaxis has been extensively studied in enteric bacteria, the hunt for novel and atypical chemoeffectors (in enterics and distantly-related species alike) has necessitated the modification of classic chemotaxis assays to deal with recalcitrant and potentially toxic chemicals. Here, we describe detailed protocols for the quantitative and qualitative assessment of chemotaxis responses that are categorized into short-term direct population response assays and long-term metabolism-based assays that can be used to identify novel chemoeffector molecules and the specific chemoreceptors involved. We emphasize the importance of behavior-based assays to verify the biochemical and physiological relevance of newly identified chemoeffector receptor pairs. PMID- 29429098 TI - Screening Chemoreceptor-Ligand Interactions by High-Throughput Thermal-Shift Assays. AB - Identifying the ligands sensed by chemoreceptors remains challenging, in part because current screening methods are low-throughput, costly, and/or time consuming. In contrast, fluorescence thermal shift (FTS) assays provide a fast and inexpensive approach to chemoreceptor-ligand screening. In FTS assays, the temperature at which a protein denatures is measured by monitoring the fluorescence of a dye with affinity for hydrophobic regions of the protein, which are exposed as the protein unfolds. A detectable increase (or "shift") in the melting temperature (T m ) of the protein in the presence of a potential ligand indicates binding. Here, we present our protocol for using FTS assays for the screening of chemoreceptor ligands in a high-throughput, 96-well plate format. We have also included details on the use of Biolog Phenotype Microarray plates as a convenient ligand library, although the methods described should be generally applicable to other library formats as well. PMID- 29429099 TI - High-Throughput Screening to Identify Chemoreceptor Ligands. AB - The majority of bacterial chemoreceptors remain functionally un-annotated. The knowledge of chemoreceptor function, however, is indispensable to understanding the evolution of the chemotaxis system in bacteria with different lifestyles. Significant progress in the annotation of chemoreceptor function has been made using experimental strategies that are based on the individual, genetically engineered ligand binding domain (LBD) of chemoreceptors. There is now evidence that all major classes of LBDs can be produced as individual domains that retain their ligand binding activity. Here, we provide a protocol for the combined use of high-throughput ligand screening using Differential Scanning Fluorimetry followed by Isothermal Titration Calorimetry to identify and characterize ligands that bind to recombinant chemoreceptor LBDs. This approach has been shown to be very efficient for determining the function of novel chemoreceptors. PMID- 29429100 TI - Identification of Specific Ligands for Sensory Receptors by Small-Molecule Ligand Arrays and Surface Plasmon Resonance. AB - Ligand-receptor interactions triggering signal transduction components of many sensory pathways, remain elusive due to paucity of high-throughput screening methods. Here we describe our use of small molecule microarrays comprising of small glycans, amino and organic acids, salts, and other known chemoeffectors, for screening of ligands specific to various sensory receptors, followed by surface plasmon resonance to verify the veracity and to determine the affinity constants of the interactions. This methodology allows for rapid and identification of the direct ligand binding between the sensory receptors and their specific ligands. PMID- 29429101 TI - Fluorescence Measurement of Kinetics of CheY Autophosphorylation with Small Molecule Phosphodonors. AB - The Escherichia coli chemotaxis protein CheY is a model receiver domain containing a native tryptophan residue that serves as a fluorescent probe for CheY autophosphorylation with small molecule phosphodonors. Here we describe fluorescence measurement of apparent bimolecular rate constants for reaction of wild type and mutant CheY with phosphodonors acetyl phosphate, phosphoramidate, or monophosphoimidazole. Step-by-step protocols to synthesize phosphoramidate (K+ salt) and monophosphoimidazole (Na+ salt), which are not commercially available, are provided. Key factors to consider in developing autophosphorylation assays for other response regulators are also discussed. PMID- 29429102 TI - Synthesis of a Stable Analog of the Phosphorylated Form of CheY: Phosphono-CheY. AB - CheY is a response regulator of bacterial chemotaxis that is activated by phosphorylation of a conserved aspartate residue. However, studies of CheY phosphate have proven challenging due to rapid hydrolysis of the aspartyl phosphate in vitro. To combat this issue, we have designed a stable analog suitable for structural and functional studies. Herein, we describe a method for the chemical modification of Thermotoga maritima CheY to produce a phospho-analog designated as phosphono-CheY. Our modification produces a stable analog in the constitutively active form that enables the study of signal transfer to the downstream target. PMID- 29429103 TI - Quantitative Modeling of Flagellar Motor-Mediated Adaptation. AB - The bacterial flagellar motor is capable of adapting to changes in the concentrations of extracellular chemical stimuli by changing the composition of the switch complex of the flagellar motor. Such remodeling-based adaptation complements the receptor-mediated adaptation in the chemotaxis network to help maintain high sensitivity in the response of the motor to phospho-CheY concentrations, despite cell-to-cell variability in the abundances of chemotaxis proteins. In this chapter, a modeling approach is described that explains the mechanisms of switch-remodeling and motor-mediated adaptation. The approach is based on observations of structural differences, associated with the direction of motor rotation, that modulate the strength of FliM/FliN binding within the switch. By modulating the number of CheY-P-binding sites within the motor, remodeling maximizes sensitivity over a range of signal levels. PMID- 29429104 TI - Molecular Modeling of Chemoreceptor:Ligand Interactions. AB - Docking algorithms have been widely used to elucidate ligand:receptor interactions that are important in biological function. Here, we introduce an in house developed docking-refinement protocol that combines the following innovative features. (1) The use of multiple short molecular dynamics (MD) docking simulations, with residues within the binding pocket of the receptor unconstrained, so that the binding modes of the ligand in the binding pocket may be exhaustively examined. (2) The initial positioning of the ligand within the binding pocket based on complementary shape, and the use of both harmonic and quartic spherical potentials to constrain the ligand in the binding pocket during multiple short docking simulations. (3) The selection of the most probable binding modes generated by the short docking simulations using interaction energy calculations, as well as the subsequent application of all-atom MD simulations and physical-chemistry based free energy calculations to elucidate the most favorable binding mode of the ligand in complex with the receptor. In this chapter, we provide step-by-step instructions on how to computationally investigate the binding of small-molecule ligands to protein receptors by examining as control and test cases, respectively, the binding of L-serine and R 3,4-dihydroxymandelic acid (R-DHMA) to the Escherichia coli chemoreceptor Tsr. Similar computational strategies can be used for the molecular modeling of a series of ligand:protein receptor interactions. PMID- 29429105 TI - Phylogenetic and Protein Sequence Analysis of Bacterial Chemoreceptors. AB - Identifying chemoreceptors in sequenced bacterial genomes, revealing their domain architecture, inferring their evolutionary relationships, and comparing them to chemoreceptors of known function become important steps in genome annotation and chemotaxis research. Here, we describe bioinformatics procedures that enable such analyses, using two closely related bacterial genomes as examples. PMID- 29429106 TI - Catalytic oxidation of trichloroethylene from gas streams by perovskite-type catalysts. AB - Three perovskite-type catalysts including LaMnO3, La0.8Ce0.2MnO3, and La0.8Ce0.2 Mn0.8Ni0.2O3 are prepared using citric acid sol-gel method and evaluated as catalyst for the oxidation of trichloroethylene (TCE) in air with temperature ranging from 100 to 600 degrees C. The physicochemical properties of three perovskite-type catalysts were characterized by SEM, EDS, XRD, BET, and XPS to investigate the relationship with catalytic activities. The results show that the removal efficiency of TCE achieved with La0.8Ce0.2Mn0.8Ni0.2O3 (the best one) reaches 100% at 400 degrees C and the mineralization efficiency reaches 100% at 600 degrees C. The enhanced activity can be attributed to the addition of Ce and Ni which increases the surface areas, active oxygen species, and the redox ability of the Mn4+/Mn3+ ratio on the catalyst surface. As La0.8Ce0.2Mn0.8Ni0.2O3 is applied for TCE oxidation, the main intermediate chlorinated byproduct detected is tetrachloroethylene (C2Cl4) which is generated by the reaction of TCE and chlorine (Cl2). The activation energy for the TCE oxidation with La0.8Ce0.2Mn0.8Ni0.2O3 catalyst is 51 kJ/mol using kinetic models of power-law type. PMID- 29429107 TI - Improvement studies on emission and combustion characteristics of DICI engine fuelled with colloidal emulsion of diesel distillate of plastic oil, TiO2 nanoparticles and water. AB - Experimentation was conducted on a single cylinder CI engine using processed colloidal emulsions of TiO2 nanoparticle-water-diesel distillate of crude plastic diesel oil as test fuel. The test fuel was prepared with plastic diesel oil as the principal constituent by a novel blending technique with an aim to improve the working characteristics. The results obtained by the test fuel from the experiments were compared with that of commercial petro-diesel (CPD) fuel for same engine operating parameters. Plastic oil produced from high density polyethylene plastic waste by pyrolysis was subjected to fractional distillation for separating plastic diesel oil (PDO) that contains diesel range hydrocarbons. The blending process showed a little improvement in the field of fuel oil-water nanometal oxide colloidal emulsion preparation due to the influence of surfactant in electrostatic stabilization, dielectric potential, and pH of the colloidal medium on the absolute value of zeta potential, a measure of colloidal stability. The engine tests with nano-emulsions of PDO showed an increase in ignition delay (23.43%), and decrease in EGT (6.05%), BSNOx (7.13%), and BSCO (28.96%) relative to PDO at rated load. Combustion curve profiles, percentage distribution of compounds, and physical and chemical properties of test fuels ascertains these results. The combustion acceleration at diffused combustion phase was evidenced in TiO2 emulsion fuels under study. PMID- 29429108 TI - Distribution of phosphorous pools in western river sediments of the Urmia Lake basin, Iran. AB - Impact of anthropogenic loading of phosphorous (P) to an aquatic ecosystem can be qualitatively assessed by measuring the buildup and distribution of P in sediments and by differentiating bioavailable and recalcitrant P pools. Distribution of P pools in sediments is affected by the physico-chemical properties including specific elements, particle size distribution, pH, electrical conductivity (EC), and carbonate content. We applied X-ray fluorescence and scanning electron microscopy (SEM) methods to characterize sediments from western rivers in the Urmia Lake basin in Iran with a particular focus on properties that are relevant to P speciation. Phosphorous pools were sequentially extracted into operationally defined exchangeable (EXCH-P), iron and aluminum oxide-bound (Fe/Al-P), calcium-bound (Ca-P), and residual (RES-P) P pools. In river sediments, the size of P pool was found to be in the order of Ca P > RES-P > Fe/Al-P > EXCH-P indicating small fraction of bioavailable P pool and Ca-P minerals being the most dominant P sink. Carbonate-related properties had an inverse relationship with bioavailable P pools in the river sediments studied. The principal component analysis (PCA) of the sequential extraction data with sediment properties revealed that four principal components described 82.7% of total variation. Similarly, particle size-related properties were found to have the highest eigenvalues in the first PC. Electron diffraction spectra (EDS) and X ray fluorescence (XRF) analyses showed a largely uniform distribution of P in the upstream sediment. However, limited evidence of local enrichment of P with Fe, Al, and Ca contents was observed in the downstream river sediments. Correlation of Fe/Al-P pool size with Al2O3 and SiO2 contents indicated that P was associated with Al oxide and clay minerals in the sediment matrix. Overall, the results from this study provide insights into the variability of upstream and downstream river processes and their relationship with P pools with regard to their bioavailability. These results are expected to be useful in assessing the potential impact of P loading on the aquatic ecosystem in the Urmia Lake basin. PMID- 29429109 TI - Behaviour and risk assessment of fluopyram and its metabolite in cucumber (Cucumis sativus) fruit and in soil. AB - A field experiment was conducted to estimate residue persistence of fluopyram and its metabolite benzamide in cucumber fruits and soil and their risk assessment in humans and soil environment. Fluopyram (Kafka, 400 SC) was applied as soil drench twice at the interval of 15 days at the rate of 250 (standard dose) and 500 (double dose) g a.i. ha-1 (active ingredient per hectare). Cucumber fruits were collected at 0 (1 h), 1, 3, 5, 7, 10, 15, 20, 30, 40 and 50 days after second application. Soil samples were collected on 15th day after second application. Drench application resulted in detection of residues on the third day in standard dose at the levels of 0.056 mg kg-1 in cucumber fruit. The residue level increased until 20 days reaching 0.092 mg kg-1 followed by decrease to 0.068 mg kg-1 on 30th day after application. In double dose, the residues started accumulating from 0 day with initial levels of 0.093 mg kg-1 and persisted until 30th day. The levels varied between 0.123 and 0.184 mg kg-1 until 15th day of application followed by decrease to 0.127 mg kg-1 by 30th day. The residues reached below determination level (< 0.05 mg kg-1) on 40th day in both the doses after second application. The residue of metabolite benzamide was below determination level (< 0.05 mg kg-1) at both the doses. Hazard quotient (HQ) for residues levels at 15th and 30th day was less than one (HQ < 1). Hence, a pre harvest interval of 15 days is suggested. Present data can be used to establish maximum residue limit (MRL) in India. The residue of fluopyram in soil on 15th day and the data on soil adsorption coefficient of fluopyram from literature suggests moderate mobility of fluopyram in soil. However, residues of metabolite of benzamide were not detected in soil. Further studies on translocation of fluopyram in soil over the time can be conducted for better understanding of environmental risk. To our knowledge, this is the first report on residue levels of fluopyram in any crop when applied as soil drench. PMID- 29429110 TI - Phosphorus sorption capacity of biochars varies with biochar type and salinity level. AB - Biochar is recognized as an effective material for recovering excess nutrients, including phosphorus (P), from aqueous solutions. Practically, that benefits the environment through reducing P losses from biochar-amended soils; however, how salinity influences P sorption by biochar is poorly understood and there has been no direct comparison on P sorption capacity between biochars derived from different feedstock types under non-saline and saline conditions. In this study, biochars derived from wheat straw, hardwood, and willow wood were used to compare P sorption at three levels of electrical conductivity (EC) (0, 4, and 8 dS m-1) to represent a wide range of salinity conditions. Phosphorus sorption by wheat straw and hardwood biochars increased as aqueous solution P concentration increased, with willow wood biochar exhibiting an opposite trend for P sorption. However, the pattern for P sorption became the same as the other biochars after the willow wood biochar was de-ashed with 1 M HCl and 0.05 M HF. Willow wood biochar had the highest P sorption (1.93 mg g-1) followed by hardwood (1.20 mg g 1) and wheat straw biochars (1.06 mg g-1) in a 25 mg L-1 P solution. Although the pH in the equilibrium solution was higher with willow wood biochar (~ 9.5) than with the other two biochars (~ 6.5), solution pH had no or minor effects on P sorption by willow wood biochar. The high sorption rate of P by willow wood biochar could be attributed to the higher concentrations of salt and other elements (i.e., Ca and Mg) in the biochar in comparison to that in wheat straw and hardwood biochars; the EC values were 2.27, 0.53, and 0.27 dS m-1 for willow wood, wheat straw, and hardwood biochars, respectively. A portion of P desorbed from the willow wood biochar; and that desorption increased with the decreasing P concentration in the aqueous solution. Salinity in the aqueous solution influenced P sorption by hardwood and willow wood but not by wheat straw biochar. We conclude that the P sorption capacity of the studied biochars is dependent on the concentration of the soluble element in the biochar, which is dependent on the biochar type, as well as the salinity level in the aqueous solution. PMID- 29429111 TI - Health risk assessment of drinking arsenic-containing groundwater in Hasilpur, Pakistan: effect of sampling area, depth, and source. AB - Currently, several news channels and research publications have highlighted the dilemma of arsenic (As)-contaminated groundwater in Pakistan. However, there is lack of data regarding groundwater As content of various areas in Pakistan. The present study evaluated As contamination and associated health risks in previously unexplored groundwater of Hasilpur-Pakistan. Total of 61 groundwater samples were collected from different areas (rural and urban), sources (electric pump, hand pump, and tubewell) and depths (35-430 ft or 11-131 m). The water samples were analyzed for As level and other parameters such as pH, electrical conductivity, total dissolved solids, cations, and anions. It was found that 41% (25 out of 61) water samples contained As (>= 5 MUg/L). Out of 25 As-contaminated water samples, 13 water samples exceeded the permissible level of WHO (10 MUg/L). High As contents have been found in tubewell samples and at high sampling depths (> 300 ft). The major As-contaminated groundwater in Hasilpur is found in urban areas. Furthermore, health risk and cancer risk due to As contamination were also assessed with respect to average daily dose (ADD), hazard quotient (HQ), and carcinogenic risk (CR). The values of HQ and CR of As in Hasilpur were up to 58 and 0.00231, respectively. Multivariate analysis revealed a positive correlation between groundwater As contents, pH, and depth in Hasilpur. The current study proposed the proper monitoring and management of well water in Hasilpur to minimize the As-associated health hazards. PMID- 29429112 TI - Suspended particulate matter determines physical speciation of Fe, Mn, and trace metals in surface waters of Loire watershed. AB - This study investigates the spatiotemporal variability of major and trace elements, dissolved organic carbon (DOC), total dissolved solids (TDS), and suspended particulate matter (SPM) in surface waters of several hydrosystems of the Loire River watershed in France. In particular, this study aims to delineate the impact of the abovementioned water physicochemical parameters on natural iron and manganese physical speciation (homoaggregation/heteroaggregation) among fine colloidal and dissolved (< 10 nm), colloidal (10-450 nm) and particulate (> 450 nm) phases in Loire River watershed. Results show that the chemistry of the Loire River watershed is controlled by two end members: magmatic and metamorphic petrographic context on the upper part of the watershed; and sedimentary rocks for the middle and low part of the Loire. The percentage of particulate Fe and Mn increased downstream concurrent with the increase in SPM and major cations concentration, whereas the percentage of colloidal Fe and Mn decreased downstream. Transmission electron microscopy analyses of the colloidal and particulate fractions (from the non-filtered water sample) revealed that heteroaggregation of Fe and Mn rich natural nanoparticles and natural organic matter to the particulate phase is the dominant mechanism. The heteroaggregation controls the partitioning of Fe and Mn in the different fractions, potentially due to the increase in the ionic strength, and divalent cations concentration downstream, and SPM concentration. These findings imply that SPM concentration plays an important role in controlling the fate and behavior of Fe and Mn in various sized fractions. Graphical abstract Physical speciation by heteroaggregation of (Fe-Mn) compounds: high [SPM] -> [Fe-Mn] particulate faction; low {SPM] -> [Fe-Mn] colloid-dissolved fraction. PMID- 29429113 TI - Effects of sewage sludge modified by coal gasification slag and electron beam irradiation on the growth of Alhagi sparsifolia Shap. and transfer of heavy metals. AB - A greenhouse experiment was performed to investigate the feasibility of sewage sludge modified by coal gasification slag pretreatment and electron beam irradiation in soil application for cultivation of Alhagi sparsifolia Shap . The results showed that modified sewage sludge had an active effect on the growth of Alhagi sparsifolia Shap . The sandy soil and modified sludge at the volume ratio of 2:1 were optimal, and the growth potential of Alhagi sparsifolia Shap . was highest. In the sandy soil, the values of bioconcentration factor of most heavy metals were below 1.0 except for Zn and Cu. The average bioconcentration factor values of heavy metals in Alhagi sparsifolia Shap . decreased in a sequence of Zn>Cu>Ni> Mn>Co>Pb>Cr>Fe>V>Cd>Mo for all treatments. Alhagi sparsifolia Shap . could decrease the eco-toxicity and bioavailability of Ni, Fe, and Mo in all mixed soil, and Alhagi sparsifolia Shap . could reduce the eco-toxicity and bioavailability of all heavy metals discussed in this study (except for Mn) in the mixed soil of SS:MSS = 2:1. PMID- 29429114 TI - D-Cloprostenol enhances estrus synchronization in tropical hair sheep. AB - To compare the effects of PGF2alpha (dinoprost tromethamine) and D-cloprostenol in a two-dose protocol for estrus synchronization in hair sheep during breeding season in Yucatan, Mexico, two experiments were conducted. In experiment 1, 61 cyclic hair sheep were divided into two groups: G1 (control n = 30), two doses of 50 MUg of dinoprost tromethamine IM with 12 days between applications, and G2 (n = 31), two doses of 50 MUg of D-cloprostenol IM at the same time interval. For determination of progesterone levels, 16 ewes from each group were randomly selected. In experiment 2, 70 cyclic hair sheep were assigned at the same treatments (G1 and G2, n = 35) and 48 h after the second application, the ewes in estrus were detected by two vasectomized rams. Sheep with detected estrus were inseminated, and 45 days after, pregnant animals were identified by ultrasonography. An exact Fisher's test was performed for the analysis of ewes in estrus (experiments 1 and 2) and number of pregnant ewes (experiment 2); for the comparison of time between end of treatment-estrus presentation, a survival analysis was used. Duration of estrus in hours was analyzed using a generalized mixed model (GLM) ANOVA whereas plasma progesterone concentrations were analyzed by non-linear regression. There were significant differences (P < 0.05) in the proportion of ewes in estrus upon treatments (G1, 57% vs G2, 87% and G1, 37.1% vs G2, 65.7% in experiments 1 and 2, respectively), and between the end of treatment onset estrus interval (P < 0.01), survival curves showed the highest number of sheep in estrus between 40 and 48 h (G1, 43.7 + 8.05 h vs G2, 42.9 + 6.7 h, experiment 1). There were no significant differences (P > 0.05) in duration of estrus (G1, 42 + 6.1 h, vs G2, 41.1 + 11.2 h, experiment 1) and pregnancy in the ewes that presented estrus, and were inseminated (G1, 38.4% vs 52.1%, experiment 2). With regard to concentrations of progesterone, significant differences (P < 0.01) were found between treatments, and progesterone levels before the second application of D-cloprostenol were higher. In consideration of the results, it can be concluded that in a two-dose protocol of a luteolytic agent, more ewes presented estrus in response to D-cloprostenol compared to dinoprost tromethamine with similar pregnancy rates. PMID- 29429115 TI - Frequency of enterotoxins, toxic shock syndrome toxin-1, and biofilm formation genes in Staphylococcus aureus isolates from cows with mastitis in the Northeast of Brazil. AB - Staphylococcus aureus is among the microorganisms more frequently associated with subclinical bovine mastitis. S. aureus may produce several virulence factors. This study aimed at determining the frequency of virulence factors such as enterotoxins, toxic shock syndrome toxin 1, and ica adhesion genes. In addition, we assessed antimicrobial drug resistance in S. aureus isolated from clinical and subclinical cases of mastitis. A total of 88 cows with clinical or subclinical mastitis were sampled, resulting in 38 S. aureus isolates, from which 25 (65.78%) carried toxin genes, including seb, sec, sed, tst, and icaD adhesion gene. These S. aureus isolates belong to 21 ribotypes and three S. aureus strains belonged to the same ribotype producing ica adhesion gene. Approximately 90% of S. aureus strains obtained in our study demonstrated multiple resistance to different antimicrobial agents. The most efficacious antimicrobial agents against the isolates were gentamicin, amoxicillin, and norfloxacin. Gentamicin was the most efficacious agent inhibiting 78.95% of the S. aureus isolates. The least efficacious were penicillin, streptomycin, and ampicillin. Our results can help in understanding the relationship between virulence factors and subclinical mastitis caused by S. aureus. Further research about diversity of S. aureus isolates and genes responsible for the pathogenicity of subclinical mastitis is essential. PMID- 29429116 TI - Listening to Bedouin Mothers of Children with Autism. AB - This article examines how Bedouin mothers in Israel describe, perceive, and interpret their experiences raising a child with autism. Data were collected using semi-structured ethnographic interviews with 18 Bedouin mothers of children with autism, aged 6-16, living in recognized and unrecognized settlements in the Negev. Analysis of the study findings shows how the subaltern status of Bedouin women, which includes their husbands' constant threats of divorce or taking a second wife, makes it difficult for them to be mobile and interact in the public sphere without the presence of a man and creates an experience unique to these mothers, which we call "Exclusion within Exclusion". The Bedouin mothers report not only stigmatization, a lack of social support and loneliness but also structural-cultural characteristics that prevent them from obtaining information and participating in decision-making about the child with autism and that restrict their agency in dealing with and coping with their child's autism. In light of this situation, the discussion highlights the unique connection between local cultural scripts and the phenomenology of autism. PMID- 29429117 TI - CT and MR myelography in superficial siderosis. PMID- 29429118 TI - Latent systemic lupus erythematosus presenting with hypokalaemic quadriparesis and central pontine myelinolysis. PMID- 29429119 TI - The development of a new tool for the evaluation of handicap in elderly: the Geriatric Handicap Scale (GHS). AB - BACKGROUND: To date, the comprehensive geriatric assessment (CGA) does not include an evaluation tool for handicap. AIM: To develop a new instrument for assessing handicap in the elderly: the Geriatric Handicap Scale (GHS). METHODS: 656 community-dwelling elderly were enrolled in this study. We identified the thematic areas investigated by the CGA which showed a significant correlation with the handicap condition (handicap yes/not) to be included in our scale (Phase 1). Afterwards, we evaluated the possible correlations between: (1) the score obtained in each area of GHS and those obtained in CGA tests investigating similar dimensions, (2) GHS total score and the Multidimensional Prognostic Index (MPI) total score (Phase 2). RESULTS: In Phase 1, data analysis showed several significant correlations between the handicap condition and the scores obtained to the CGA tests exploring cognition, mood, functional impairment, comorbidity, social and environmental variables. Thus, we developed a tool considering five variables: (1) cognition and mood; (2) functional impairment; (3) hearing/visual impairment; (4) any additional comorbidity factors; (5) environmental/social risk factors. In Phase 2, data analysis showed significant correlations between the score obtained in each area of GHS and those obtained in the CGA tests investigating similar dimensions. A positive correlation between GHS total score and MPI total score (r = 68; p = 0.001) was also reported. Cut-off score for the GHS was established. Psychometric properties of GHS were also investigated and adequate estimates of internal reliability were demonstrated. CONCLUSIONS: Our tool could prove useful to correctly categorize the disadvantageous condition related to patient's disability. PMID- 29429120 TI - A local strain of Paprika mild mottle virus breaks L3 resistance in peppers and is accelerated in Tomato brown rugose fruit virus-infected Tm-22-resistant tomatoes. AB - During October 2014, unfamiliar mild mosaic and mottling symptoms were identified on leaves of pepper (Capsicum chinense cv. Habanero) seedlings grown in the Arava valley in Israel 2-3 weeks post planting. Symptomatic plants were tested positive by ELISA using laboratory-produced antisera for tobamovirus species. Typical tobamovirus rod-shaped morphology was observed by transmission electron microscopy (TEM) analysis of purified virion preparation that was used for mechanical inoculation of laboratory test plants for the completion of Koch's postulates. The complete viral genome was sequenced from small interfering RNA purified from symptomatic pepper leaves and fruits by next-generation sequencing (NGS) using Illumina MiSeq platform. The contigs generated by the assembly covered 80% of the viral genome. RT-PCR amplification and Sanger sequencing were employed in order to validate the sequence generated by NGS technology. The nucleotide sequence of the complete viral genome was 99% identical to the complete genome of Paprika mild mottle virus isolate from Japan (PaMMV-J), and the deduced amino acid sequence was 99% identical to PaMMV-J protein. Amplicons from seed RNA showed 100% identity to the viral isolate from the collected symptomatic pepper plants. Partial host range analysis revealed a slow development of systemic infection in inoculated tomato plants (Lycopersicon esculentum). Interestingly, double inoculation of susceptible wild-type tomato plants and Tm-22-resistant tomato plants with the PaMMV-IL and Tomato brown rugose fruit virus (ToBRFV) resulted in accelerated viral expression in the plants. PMID- 29429121 TI - On a nonlocal system for vegetation in drylands. AB - Several mathematical models are proposed to understand spatial patchy vegetation patterns arising in drylands. In this paper, we consider the system with nonlocal dispersal of plants (through a redistribution kernel for seeds) proposed by Pueyo et al. (Oikos 117:1522-1532, 2008) as a model for vegetation in water-limited ecosystems. It consists in two reaction diffusion equations for surface water and soil water, combined with an integro-differential equation for plants. For this system, under suitable assumptions, we prove well-posedness using the Schauder fixed point theorem. In addition, we consider the stationary problem from the viewpoint of vegetated pattern formation, and show a transition of vegetation patterns when parameter values (rainfall, seed dispersal range, seed germination rate) in the system vary. The influence of the shape of the redistribution kernel is also discussed. PMID- 29429122 TI - Optimal control approach for establishing wMelPop Wolbachia infection among wild Aedes aegypti populations. AB - Wolbachia-based biocontrol has recently emerged as a potential method for prevention and control of dengue and other vector-borne diseases. Major vector species, such as Aedes aegypti females, when deliberately infected with Wolbachia become less capable of getting viral infections and transmitting the virus to human hosts. In this paper, we propose an explicit sex-structured population model that describes an interaction of uninfected (wild) male and female mosquitoes and those deliberately infected with wMelPop strain of Wolbachia in the same locality. This particular strain of Wolbachia is regarded as the best blocker of dengue and other arboviral infections. However, wMelPop strain of Wolbachia also causes the loss of individual fitness in Aedes aegypti mosquitoes. Our model allows for natural introduction of the decision (or control) variable, and we apply the optimal control approach to simulate wMelPop Wolbachia infestation of wild Aedes aegypti populations. The control action consists in continuous periodic releases of mosquitoes previously infected with wMelPop strain of Wolbachia in laboratory conditions. The ultimate purpose of control is to find a tradeoff between reaching the population replacement in minimum time and with minimum cost of the control effort. This approach also allows us to estimate the number of Wolbachia-carrying mosquitoes to be released in day-by-day control action. The proposed method of biological control is safe to human health, does not contaminate the environment, does not make harm to non-target species, and preserves their interaction with mosquitoes in the ecosystem. PMID- 29429123 TI - Platelet-activating factor acetylhydrolase in primary antiphospholipid syndrome. PMID- 29429124 TI - Brain metastasis in gastroesophageal adenocarcinoma and HER2 status. AB - The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011-2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1-9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study. PMID- 29429125 TI - CyberKnife robotic radiosurgery in the multimodal management of acromegaly patients with invasive macroadenoma: a single center's experience. AB - Surgery is the primary treatment for acromegaly. However, surgery may not be curative of some tumors, particularly invasive macroadenomas. Adjuvant radiation, specifically robotic stereotactic radiosurgery (rSRS), may improve the endocrine outcome. We retrospectively reviewed hormonal and radiological data of 22 acromegalic patients with invasive macroadenomas treated with rSRS at Stanford University Medical Center between 2000 and 2016. Prior to treatment, the tumor's median maximal diameter was 19 mm (2.5-50 mm). Cavernous sinus invasion occurred in 19 patients (86.3%) and compression of the optic chiasm in 2 (9.0%). At last follow up, with an average follow up of 43.2 months, all patients had a reduction in their IGF-1 levels (median IGF-1% upper limit of normal (ULN) baseline: 136% vs last follow up: 97%; p = 0.05); 9 patients (40.9%) were cured, and 4 (18.1%) others demonstrated biochemical control of acromegaly. The median time to cure was 50 months and the mean interval to cure or biochemical control was 30.3 months (+/- 24 months, range 6-84 months). Hypopituitarism was present in 8 patients (36.3%) and new pituitary deficits occurred in 6 patients with a median latency of 31.6 +/- 14.5 months. At final radiologic follow-up, 3 tumors (13.6%) were smaller and 19 were stable in size. The mean biologically effective dose (BED) was higher in subjects cured compared to those with persistent disease, 163 Gy3 (+/- 47) versus 111 Gy3 (+/- 43), respectively (p = 0.01). No patient suffered visual deterioration. Robotic SRS is a safe and effective treatment for acromegaly: radiation-induced visual complications and hypopituitarism is rare. PMID- 29429128 TI - Flow rate dependent continuous hydrolysis of protein isolates. AB - Food protein hydrolysates are often produced in unspecific industrial batch processes. The hydrolysates composition underlies process-related fluctuations and therefore the obtained peptide fingerprint and bioactive properties may vary. To overcome this obstacle and enable the production of specific hydrolysates with selected peptides, a ceramic capillary system was developed and characterized for the continuous production of a consistent peptide composition. Therefore, the protease Alcalase was immobilized on the surface of aminosilane modified yttria stabilized zirconia capillaries with a pore size of 1.5 um. The loading capacity was 0.3 ug enzyme per mg of capillary with a residual enzyme activity of 43%. The enzyme specific peptide fingerprint produced with this proteolytic capillary reactor system correlated with the degree of hydrolysis, which can be controlled over the residence time by adjusting the flow rate. Common food proteins like casein, sunflower and lupin protein isolates were tested for continuous hydrolysis in the developed reactor system. The peptide formation was investigated by high-performance liquid chromatography. Various trends were found for the occurrence of specific peptides. Some are just intermediately occurring, while others cumulate by time. Thus, the developed continuous reactor system enables the production of specific peptides with desired bioactive properties. PMID- 29429127 TI - Tissue- and strain-specific effects of a genotoxic carcinogen 1,3-butadiene on chromatin and transcription. AB - Epigenetic effects of environmental chemicals are under intense investigation to fill existing knowledge gaps between environmental/occupational exposures and adverse health outcomes. Chromatin accessibility is one prominent mechanism of epigenetic control of transcription, and understanding of the chemical effects on both could inform the causal role of epigenetic alterations in disease mechanisms. In this study, we hypothesized that baseline variability in chromatin organization and transcription profiles among various tissues and mouse strains influence the outcome of exposure to the DNA damaging chemical 1,3-butadiene. To test this hypothesis, we evaluated DNA damage along with comprehensive quantification of RNA transcripts (RNA-seq), identification of accessible chromatin (ATAC-seq), and characterization of regions with histone modifications associated with active transcription (ChIP-seq for acetylation at histone 3 lysine 27, H3K27ac). We collected these data in the lung, liver, and kidney of mice from two genetically divergent strains, C57BL/6J and CAST/EiJ, that were exposed to clean air or to 1,3-butadiene (~600 ppm) for 2 weeks. We found that tissue effects dominate differences in both gene expression and chromatin states, followed by strain effects. At baseline, xenobiotic metabolism was consistently more active in CAST/EiJ, while immune system pathways were more active in C57BL/6J across tissues. Surprisingly, even though all three tissues in both strains harbored butadiene-induced DNA damage, little transcriptional effect of butadiene was observed in liver and kidney. Toxicologically relevant effects of butadiene in the lung were on the pathways of xenobiotic metabolism and inflammation. We also found that variability in chromatin accessibility across individuals (i.e., strains) only partially explains the variability in transcription. This study showed that variation in the basal states of epigenome and transcriptome may be useful indicators for individuals or tissues susceptible to genotoxic environmental chemicals. PMID- 29429126 TI - Individual susceptibility to arsenic-induced diseases: the role of host genetics, nutritional status, and the gut microbiome. AB - Arsenic (As) contamination in water or food is a global issue affecting hundreds of millions of people. Although As is classified as a group 1 carcinogen and is associated with multiple diseases, the individual susceptibility to As-related diseases is highly variable, such that a proportion of people exposed to As have higher risks of developing related disorders. Many factors have been found to be associated with As susceptibility. One of the main sources of the variability found in As susceptibility is the variation in the host genome, namely, polymorphisms of many genes involved in As transportation, biotransformation, oxidative stress response, and DNA repair affect the susceptibility of an individual to As toxicity and then influence the disease outcomes. In addition, lifestyles and many nutritional factors, such as folate, vitamin C, and fruit, have been found to be associated with individual susceptibility to As-related diseases. Recently, the interactions between As exposure and the gut microbiome have been of particular concern. As exposure has been shown to perturb gut microbiome composition, and the gut microbiota has been shown to also influence As metabolism, which raises the question of whether the highly diverse gut microbiota contributes to As susceptibility. Here, we review the literature and summarize the factors, such as host genetics and nutritional status, that influence As susceptibility, and we also present potential mechanisms of how the gut microbiome may influence As metabolism and its toxic effects on the host to induce variations in As susceptibility. Challenges and future directions are also discussed to emphasize the importance of characterizing the specific role of these factors in interindividual susceptibility to As-related diseases. PMID- 29429129 TI - An intronless form of the tobacco extensin gene terminator strongly enhances transient gene expression in plant leaves. AB - KEY MESSAGE: We have found interesting features of a plant gene (extensin) 3' flanking region, including extremely efficient polyadenylation which greatly improves transient expression of transgenes when an intron is removed. Its use will greatly benefit studies of gene expression in plants, research in molecular biology, and applications for recombinant proteins. Plants are a promising platform for the production of recombinant proteins. To express high-value proteins in plants efficiently, the optimization of expression cassettes using appropriate regulatory sequences is critical. Here, we characterize the activity of the tobacco extensin (Ext) gene terminator by transient expression in Nicotiana benthamiana, tobacco, and lettuce. Ext is a member of the hydroxyproline-rich glycoprotein (HRGP) superfamily and constitutes the major protein component of cell walls. The present study demonstrates that the Ext terminator with its native intron removed increased transient gene expression up to 13.5-fold compared to previously established terminators. The enhanced transgene expression was correlated with increased mRNA accumulation and reduced levels of read-through transcripts, which could impair gene expression. Analysis of transcript 3'-ends found that the majority of polyadenylated transcripts were cleaved at a YA dinucleotide downstream from a canonical AAUAAA motif and a UG rich region, both of which were found to be highly conserved among related extensin terminators. Deletion of either of these regions eliminated most of the activity of the terminator. Additionally, a 45 nt polypurine sequence ~ 175 nt upstream from the polyadenylation sites was found to also be necessary for the enhanced expression. We conclude that the use of Ext terminator has great potential to benefit the production of recombinant proteins in plants. PMID- 29429130 TI - Ultrastructure of the larval Malpighian tubules in Terrobittacus implicatus (Mecoptera: Bittacidae). AB - The larvae of Bittacidae, a cosmopolitan family in Mecoptera, have an interesting habit of spraying the body surface with soil through the anus after hatching, and each molts. The fine structure of Malpighian tubules, however, remains largely unknown in the larvae of Bittacidae to date. Here, we studied the ultrastructure of the larval Malpighian tubules in the hangingfly Terrobittacus implicatus (Huang & Hua) using scanning and transmission electron microscopy. The larvae of T. implicatus have six elongate Malpighian tubules at the junction of the midgut and hindgut. The tubule comprises a basal lamina, a single-layered epithelium, and a central lumen. The basal plasma membranes of the epithelial cells are conspicuously infolded and generate a labyrinth. The epithelium consists of two types of cells: large principal cells and scattered stellate cells. Mitochondria and cisterns of rough endoplasmic reticulum are numerous in the principal cells but are sparsely distributed in the stellate cells, indicating that the principal cells are active in transport. On the other hand, spherites are only abundant in the principal cells and are likely associated with the soil-spraying habit of the larvae. PMID- 29429132 TI - Sustainability of a Community-Based CHOICE Program to Improve the Health and Nutrition Status of Mothers and Infants in Indonesia. AB - Objectives Few studies have been undertaken to determine whether and how project results are sustained. University of Notre Dame (ND) and Project Concern International conducted a Post-Project Sustainability Study (PSS) of a USAID funded program (CHOICE), implemented in Indonesia, Banten province, between 2003 and 2007, in order to determine lasting effects and improve PSS methodologies. Methods Sustainability was measured through a comparison of data collected on mother-infant pairs in 2014 with final evaluation data from 2007; and through a comparison of 2014 data collected from the CHOICE villages and comparison villages. Results The analysis showed positive differences in multiple indicators in CHOICE villages between 2007 and 2014, including births attended by skilled personnel (Mean Difference 48.56, 95% CI 38.68 to 58.43) and treatment of diarrhea (MD 16.42, 95% CI - 0.94 to 33.37). However, only one statistically significant difference between intervention and comparison groups in 2014 was observed, infants with diarrhea whose mothers sought advice or treatment (MD - 5.48, 95% CI - 9.55 to 1.39), showing more mothers in intervention group sought advice or treatment. Because contextual factors were not studied in detail and baseline data was not available for the comparison villages, it is difficult to determine the reasons for the results. Given that longitudinal data was not collected, it is also difficult to determine whether results fluctuated between 2007 and 2014. Conclusions for practice This PSS contributes to the limited body of knowledge in sustainability research. Lessons learned from this study will increase potential for sustainable impact of projects, as more rigorous measurement will lead to greater overall understanding of how sustainability actually "happens". PMID- 29429131 TI - Mortality associated with bevacizumab intravitreal injections in age-related macular degeneration patients after acute myocardial infarct: a retrospective population-based survival analysis. AB - BACKGROUND: Intraocular injections of antivascular endothelial growth factor (VEGF) agents are currently the main therapy in age-related macular degeneration (AMD). The safety of bevacizumab, an anti-VEGF compound frequently delivered off label, is debated, particularly for high-group risks. We aim to analyze the mortality associated with intravitreal injections of bevacizumab for AMD in patients previously diagnosed with acute myocardial infarct (MI). METHODS: In a national database, we identified bevacizumab-treated AMD patients with a diagnosis of MI prior to their first bevacizumab injection, delivered between September 2008 and October 2014 (n = 2100). We then generated sub-groups of patients treated within 3 months (n = 11), 6 months (n = 24), 12 months (n = 52), and 24 months (n = 124) after MI. Those patients were compared to age- and gender matched members that had a MI at the same time and had never been exposed to anti VEGF. Survival analysis was performed using propensity score-adjusted Cox regression. RESULTS: Bevacizumab-treated patients were slightly and insignificantly older than controls (mean age 83.25 vs 83.19 year, P = .75). Gender distribution was similar. In a Cox regression adjusted with propensity score, the following differences in mortality were found: within 3 months between MI and initiation of bevacizumab treatment, OR = 6.22 (95% C.I 1.08-35.97, P < .05); within 6 months, OR = 2.37 (95% C.I 0.93-6.02, P = .071); within 12 months, OR = 3.00 (95% C.I 1.44-6.28, P < .01); within 24 months after MI, OR = 2.24 (95% C.I 1.35-3.70, P < .01); and MI any time prior to first bevacizumab injection, OR = 1.71 (95% C.I 1.53-1.92, P < .001). CONCLUSIONS: We report increased mortality associated with the use of intravitreal bevacizumab in AMD patients after MI, compared to age- and gender-matched post-MI patients with no exposure to any anti VEGF agent. Caution should be taken while offering bevacizumab to AMD patients after MI. PMID- 29429133 TI - Having Older Siblings Is Associated with Lower Rates of Depression, ADD/ADHD, Anxiety and Behavior Problems Among Children with ASD. AB - Objective Within the social determinants of mental health framework, this article investigated whether children with ASD who have older siblings are less likely to experience depression, anxiety, behavior problems or have ADD/ADHD after controlling for standard social determinants of mental health such as household income, parental education and adverse childhood experiences (ACEs). Methods Using the National Survey of Children's Health 2011-2012, children with ASD spectrum disorders (n = 1624) were categorized into three groups: only child, oldest child and has older siblings. Design corrected cross-tabulations, univariate and multivariate logistic regressions were estimated. Results The three groups of children with ASD were comparable in demographic characteristics (except age), ACEs, and parent-reported ASD severity. Children with ASD who had older siblings were significantly less likely to experience depression, anxiety or behavior problems. They were also less likely to have been diagnosed with ADD or ADHD. Adjusted odds ratios ranged from 0.12 to 0.53 indicating robust associations. Conclusions for Practice Children with ASD who have older siblings were less likely to have comorbid mental health disorders than other children with ASD. Conversely, oldest and only children with ASD were at increased risk for these disorders. Further research is needed to understand how this protection is conferred on children with ASD, and whether it can be adapted into interventions for only and oldest children with ASD. PMID- 29429134 TI - One Year Follow-up of Outcomes from the Randomized Clinical Trial of the Building on Family Strengths Program. AB - Objectives Test the 12-month efficacy of an inclusive non-diagnosis-specific, parent education program with seven in-person sessions. Methods Parents of 110 children, 2-11 years old, with a variety of special health care conditions, were recruited to participate in a randomized clinical trial. At twelve months data from 104 parents were available for longitudinal analysis. Linear mixed models, with the interaction term of group by time, were used to assess the efficacy of the intervention over 12 months using data from 3 time points: baseline, 6 and 12 months. The outcome measures were self-efficacy, parent and child shared management of chronic condition, coping skills, parental depressive symptoms and quality of life. Results All of the outcomes improved within the intervention group over 12 months. Self-efficacy was the strongest outcome which remained significantly different from the control group 12 months post intervention, without any statistical adjustment (p = 0.045). The coefficient of the interaction term for study group (intervention or control) by time, quantifying the intervention effect, was statistically significant for four of five pre specified study outcomes, favorably so toward the intervention group (p < 0.05, with the 5th outcome, parental depression, p = 0.052). Conclusions for Practice The Building on Family Strengths intervention was efficacious in improving self efficacy, shared management, coping skills, and quality of life and decreasing depressive symptoms in parents, in particular for parents who were most impacted by the lack of these strengths and skills at baseline. These results are encouraging and future studies to investigate the efficacy of this intervention in an Internet-based setting or other modalities are encouraged. PMID- 29429135 TI - A Qualitative Exploration of Co-location as an Intervention to Strengthen Home Visiting Implementation in Addressing Maternal Child Health. AB - Objectives The aim of this paper is to explore the process and impact of co locating evidence-based maternal and child service models to inform future implementation efforts. Methods As part of a state-wide evaluation of maternal and child home visiting programs, we conducted semi-structured interviews with administrators and home visitors from home visiting agencies across Pennsylvania. We collected 33 interviews from 4 co-located agencies. We used the Consolidated Framework for Implementation Research (CFIR) to describe the key elements mitigating implementation of multiple home visiting models. Results A primary advantage of co-location described by participants was the ability to increase the agency's base of eligible clients through the implementation of a model with different program eligibility (e.g. income, child age) than the existing agency offering. Model differences related to curriculum (e.g. content or intensity/meeting frequency) enabled programs to more selectively match clients to models. To recruit eligible clients, new models were able to build upon the existing service networks of the initial program. Co-location provided organizational opportunities for shared trainings, enabling administrative efficiencies and collaborative staff learning. Programs implemented strategies to build synergies with complementary model features, for instance using the additional program option to serve waitlisted clients and to transition services after one model is completed. Conclusions for Practice Considerable benefits are experienced when home visiting models co-locate. This research builds on literature encouraging collaboration among community agencies and provides insight on a specific facilitative approach. This implementation strategy informs policy across the social services spectrum and competitive funding contexts. PMID- 29429136 TI - Cognitive Processing for Step Precision Increases Beta and Gamma Band Modulation During Overground Walking. AB - The aim of this study was to investigate whether cognitive processing for defining step precision during walking could induce changes in electrocortical activity. Ten healthy adults (21-36 years) were asked to walk overground in three different conditions: (1) normal walking in a straight path (NW); (2) walking in a pre-defined pathway forcing variation in step width and length by stepping on green marks on the floor (only one color: W1C), and (3) walking in the same pre defined W1C pathway while evaluating different combinations among the colors green, yellow and red, in which only one color was the footfall target (evaluating two colors: W2C). Walking speed, stride duration and scalp electroencephalography (EEG) were recorded from all conditions. Event-related spectral perturbation was calculated for channels Fz, Cz, C3, C4, Pz and Oz in each condition, which were all time-normalized in relation to the gait cycle. The results showed that walking speed was reduced and stride duration was increased for W2C when compared to both NW and W1C (p < 0.01). Moreover, Event-related spectral perturbation analysis revealed significant changes (p < 0.05) during mid stance in the frontal lobe and motor/sensorimotor regions, a phase in the gait cycle in which participants define the correct foot placement for the next step. These results suggest that greater cognitive demands during precision stepping influences electrocortical dynamics especially towards step transitions. Therefore, increased electrocortical activity in cognitive, motor and sensorimotor areas may be relevant to produce patterned and safe locomotion through challenging paths. PMID- 29429137 TI - COMT and GAD1 gene polymorphisms are associated with impaired antisaccade task performance in schizophrenic patients. AB - Genetic influences modulating executive functions engaging prefrontal cortical brain systems were investigated in 141 male subjects. The effects of variations in two genes implicated in dopamine and GABA activities in the prefrontal cortex: rs4680 (Val158/Met polymorphism of the catechol-o-methyltransferase gene-COMT) and rs3749034 (C/T) substitution in the promoter region of the glutamic acid decarboxylase gene (GAD1) were studied on antisaccade (AS) performance in healthy subjects and schizophrenic patients. Genotyping revealed a trend towards a reduced proportion of COMT Val/Met heterozygotes and a significantly increased frequency of the GAD1 rs3749034 C allele in schizophrenic patients relative to controls. Patients had elevated error rates, increased AS latencies and increased latency variability (coefficient of variation) compared to controls. The influence of polymorphisms was observed only in patients but not in controls. A substantial effect of the COMT genotype was noted on the coefficient of variation in latency, and this measure was higher in Val homozygotes compared to Met allele carriers (p < 0.05) in the patient group. The outcome from rs3749034 was also disclosed on the error rate (higher in T carriers relative to C homozygotes, p < 0.01) and latency (increased in C homozygotes relative to T carriers, p < 0.01). Binary logistic regression showed that inclusion of the genotype factor (i.e., selective estimation of antisaccade measures in CC carriers) considerably increased the validity of the diagnostic model based on the AS measures. These findings may well be derived from specific genetic associations with prefrontal cortex functioning in schizophrenia. PMID- 29429139 TI - Comment on: "Talent Identification in Sport: A Systematic Review". PMID- 29429138 TI - QTc prolongation in short-term treatment of schizophrenia patients: effects of different antipsychotics and genetic factors. AB - Antipsychotics are effective in treating schizophrenia but may lead to a higher cardiovascular risk due to QTc prolongation. Besides drugs, genetic and clinical factors may contribute to QTc prolongation. The aim of this study is to examine the effect of candidate genes known for QTc prolongation and their interaction with common antipsychotics. Thus, 199 patients were genotyped for nine polymorphisms in KCNQ1, KCNH2, SCN5A, LOC10537879, LOC101927066, NOS1AP and NUBPL. QTc interval duration was measured before treatment and weekly for 5 weeks while being treated with risperidone, quetiapine, olanzapine, amisulpride, aripiprazole and haloperidol in monotherapy. Antipsychotics used in this study showed a different potential to affect the QTc interval. We found no association between KCNH2, KCNQ1, LOC10537879, LOC101927066, NOS1AP and NUBPL polymorphisms and QTc duration at baseline and during antipsychotic treatment. Mixed general models showed a significant overall influence of SCN5A (H558R) on QTc duration but no significant interaction with antipsychotic treatment. Our results do not provide evidence for an involvement of candidate genes for QTc duration in the pathophysiology of QTc prolongation by antipsychotics during short-term treatment. Further association studies are needed to confirm our findings. With a better understanding of these interactions the cardiovascular risk of patients may be decreased. PMID- 29429140 TI - Comparison of fecal preservation and extraction methods for steroid hormone metabolite analysis in wild crested macaques. AB - Since the non-invasive field endocrinology techniques were developed, several fecal preservation and extraction methods have been established for a variety of species. However, direct adaptation of methods from previous studies for use in crested macaques should be taken with caution. We conducted an experiment to assess the accuracy and stability of fecal estrogen metabolite (E1C) and glucocorticoid metabolite (GCM) concentrations in response to several preservation parameters: (1) time lag between sample collection and fecal preservation; (2) long-term storage of fecal samples in 80% methanol (MeOH) at ambient temperature; (3) different degrees of feces drying temperature using a conventional oven; and (4) different fecal preservation techniques (i.e., freeze drying, oven-drying, and field-friendly extraction method) and extraction solvents (methanol, ethanol, and commercial alcohol). The study used fecal samples collected from crested macaques (Macaca nigra) living in the Tangkoko Reserve, North Sulawesi, Indonesia. Samples were assayed using validated E1C and GCM enzyme immunoassays. Concentrations of E1C and GCM in unprocessed feces stored at ambient temperature remained stable for up to 8 h of storage after which concentrations of both E1C and GCM changed significantly compared to controls extracted at time 0. Long-term storage in 80% MeOH at ambient temperature affected hormone concentrations significantly with concentrations of both E1C and GCM increasing after 6 and 4 months of storage, respectively. Drying fecal samples using a conventional oven at 50, 70, and 90 degrees C did not affect the E1C concentrations, but led to a significant decline for GCM concentrations in samples dried at 90 degrees C. Different fecal preservation techniques and extraction solvents provided similar results for both E1C and GCM concentrations. Our results confirm previous studies that prior to application of fecal hormone analysis in a new species, several preservation parameters should be evaluated for their effects on hormone metabolite stability. The results also provide several options for fecal preservation, extraction, and storage methods that can be selected depending on the condition of the field site and laboratory. PMID- 29429141 TI - Utility of second-generation single-energy metal artifact reduction in helical lung computed tomography for patients with pulmonary arteriovenous malformation after coil embolization. AB - PURPOSE: The quality of images acquired using single-energy metal artifact reduction (SEMAR) on helical lung computed tomography (CT) in patients with pulmonary arteriovenous malformation (PAVM) after coil embolization was retrospectively evaluated. MATERIALS AND METHODS: CT images were reconstructed with and without SEMAR. Twenty-seven lesions [20 patients (2 males, 18 females), mean age 61.2 +/- 11.0 years; number of embolization coils, 9.8 +/- 5.0] on contrast-enhanced CT and 18 lesions of non-enhanced lung CT concurrently performed were evaluated. Regions of interest were positioned around the coils and mean standard deviation value was compared as noise index. Two radiologists visually evaluated metallic coil artifacts using a four-point scale: 4 = minimal; 3 = mild; 2 = strong; 1 = extensive. RESULTS: Noise index was significantly improved with SEMAR versus without SEMAR (median [interquartile range]; 194.4 [161.6-211.9] Hounsfield units [HU] vs. 243.9 [220.4-286.0] HU; p < 0.001). Visual score was significantly improved with SEMAR versus without SEMAR (Reader 1, 3 [3] vs.1 [1]; Reader 2, 3 [3] vs.1 [1]; p < 0.001). Significant differences were similarly demonstrated on lung CT (p < 0.001). CONCLUSION: SEMAR provided clear chest CT images in patients who underwent PAVM coil embolization. PMID- 29429142 TI - Erratum to: Forskolin Induces Hyperphosphorylation of Tau Accompanied by Cell Cycle Reactivation in Primary Hippocampal Neurons. PMID- 29429144 TI - Results of ethanol-assisted epithelium-on corneal cross-linking with and without intrastromal corneal ring implantation. AB - PURPOSE: To evaluate the topographic, refractive, and pachymetric changes after ethanol-assisted transepithelial corneal cross-linking (CXL) to stabilize progression of keratoconus (KC). PATIENTS AND METHODS: This study retrospectively evaluated the long-term topographic, refractive, and pachymetric changes in patients diagnosed with KC who underwent corneal cross-linking and/or intrastromal corneal ring segment (ICRS) implantation. The subjects were divided into three groups, corresponding to eyes treated with CXL alone (group 1), CXL and ICRS at the same time (group 2), and CXL after ICRS implantation (group 3). Corrected visual acuity and refraction, steep keratometry (SteepK) values, steepest keratometry reading on sagittal curvature map, and corneal thickness were recorded preoperatively and at each visit. Changes between measurements were assessed during follow-up. RESULTS: Corrected distant visual acuity (CDVA) values improved in all groups compared with baseline, but the differences were not statistically significant except for the first year (p > 0.05). In groups 1 and 3, SteepK values did not change statistically significantly during the entire follow-up (p > 0.05). In group 2, SteepK values statistically significantly decreased at all follow-up examinations compared with baseline, determined as the first month after ICRS implantation (p < 0.05). Complication rates were acceptable without any need for surgical intervention. CONCLUSIONS: Single session ethanol-assisted transepithelial CXL with or without ICRS implantation was a safe and effective procedure to halt progression of KC. PMID- 29429145 TI - Impact of an Interprofessional Primary Care Training on Fear of Cancer Recurrence on Clinicians' Knowledge, Self-Efficacy, Anticipated Practice Behaviors, and Attitudes Toward Survivorship Care. AB - There are an estimated 15.5 million cancer survivors in the United States, with numbers projected to increase. Many cancer survivors are receiving survivorship care in primary care settings, yet primary care providers report a need for additional training on addressing medical and psychosocial concerns of cancer survivors. This paper presents findings from a pilot study on the effectiveness of a novel training for interprofessional primary care providers on the clinically significant issue of fear of cancer recurrence. The on-site training was provided to a total of 46 participants, including physicians (61%), physician assistants (11%), nurse practitioners (7%), nurses (17%), and social workers (4%) in six different primary care practices. The average number of years of professional experience was 18.8, with standard deviation of 10.9. Results of paired-sample t tests indicated that the training increased knowledge and self efficacy of providers in identifying and addressing FCR. The training was well received by participants, who had high confidence in implementing practice behavior changes, although they also identified barriers. Results suggest the feasibility of a brief training for continuing education and have implications for models of care delivery in cancer survivorship. PMID- 29429146 TI - Graft type for femoro-popliteal bypass surgery. AB - BACKGROUND: Femoro-popliteal bypass is implemented to save limbs that might otherwise require amputation, in patients with ischaemic rest pain or tissue loss; and to improve walking distance in patients with severe life-limiting claudication. Contemporary practice involves grafts using autologous vein, polytetrafluoroethylene (PTFE) or Dacron as a bypass conduit. This is the second update of a Cochrane review first published in 1999 and last updated in 2010. OBJECTIVES: To assess the effects of bypass graft type in the treatment of stenosis or occlusion of the femoro-popliteal arterial segment, for above- and below-knee femoro-popliteal bypass grafts. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Vascular Specialised Register (13 March 2017) and CENTRAL (2017, Issue 2). Trial registries were also searched. SELECTION CRITERIA: We included randomised trials comparing at least two different types of femoro-popliteal grafts for arterial reconstruction in patients with femoro-popliteal ischaemia. Randomised controlled trials comparing bypass grafting to angioplasty or to other interventions were not included. DATA COLLECTION AND ANALYSIS: Both review authors (GKA and CPT) independently screened studies, extracted data, assessed trials for risk of bias and graded the quality of the evidence using GRADE criteria. MAIN RESULTS: We included nineteen randomised controlled trials, with a total of 3123 patients (2547 above-knee, 576 below-knee bypass surgery). In total, nine graft types were compared (autologous vein, polytetrafluoroethylene (PTFE) with and without vein cuff, human umbilical vein (HUV), polyurethane (PUR), Dacron and heparin bonded Dacron (HBD); FUSION BIOLINE and Dacron with external support). Studies differed in which graft types they compared and follow-up ranged from six months to 10 years.Above-knee bypassFor above-knee bypass, there was moderate-quality evidence that autologous vein grafts improve primary patency compared to prosthetic grafts by 60 months (Peto odds ratio (OR) 0.47, 95% confidence interval (CI) 0.28 to 0.80; 3 studies, 269 limbs; P = 0.005). We found low-quality evidence to suggest that this benefit translated to improved secondary patency by 60 months (Peto OR 0.41, 95% CI 0.22 to 0.74; 2 studies, 176 limbs; P = 0.003).We found no clear difference between Dacron and PTFE graft types for primary patency by 60 months (Peto OR 1.67, 95% CI 0.96 to 2.90; 2 studies, 247 limbs; low-quality evidence). We found low quality evidence that Dacron grafts improved secondary patency over PTFE by 24 months (Peto OR 1.54, 95% CI 1.04 to 2.28; 2 studies, 528 limbs; P = 0.03), an effect which continued to 60 months in the single trial reporting this timepoint (Peto OR 2.43, 95% CI 1.31 to 4.53; 167 limbs; P = 0.005).Externally supported prosthetic grafts had inferior primary patency at 24 months when compared to unsupported prosthetic grafts (Peto OR 2.08, 95% CI 1.29 to 3.35; 2 studies, 270 limbs; P = 0.003). Secondary patency was similarly affected in the single trial reporting this outcome (Peto OR 2.25, 95% CI 1.24 to 4.07; 236 limbs; P = 0.008). No data were available for 60 months follow-up.HUV showed benefits in primary patency over PTFE at 24 months (Peto OR 4.80, 95% CI 1.76 to 13.06; 82 limbs; P = 0.002). This benefit was still seen at 60 months (Peto OR 3.75, 95% CI 1.46 to 9.62; 69 limbs; P = 0.006), but this was only compared in one trial. Results were similar for secondary patency at 24 months (Peto OR 4.01, 95% CI 1.44 to 11.17; 93 limbs) and at 60 months (Peto OR 3.87, 95% CI 1.65 to 9.05; 93 limbs).We found HBD to be superior to PTFE for primary patency at 60 months for above-knee bypass, but these results were based on a single trial (Peto OR 0.38, 95% CI 0.20 to 0.72; 146 limbs; very low-quality evidence). There was no difference in primary patency between HBD and HUV for above-knee bypass in the one small study which reported this outcome.We found only one small trial studying PUR and it showed very poor primary and secondary patency rates which were inferior to Dacron at all time points.Below-knee bypassFor bypass below the knee, we found no graft type to be superior to any other in terms of primary patency, though one trial showed improved secondary patency of HUV over PTFE at all time points to 24 months (Peto OR 3.40, 95% CI 1.45 to 7.97; 88 limbs; P = 0.005).One study compared PTFE alone to PTFE with vein cuff; very low-quality evidence indicates no effect to either primary or secondary patency at 24 months (Peto OR 1.08, 95% CI 0.58 to 2.01; 182 limbs; 2 studies; P = 0.80 and Peto OR 1.22, 95% CI 0.67 to 2.23; 181 limbs; 2 studies; P = 0.51 respectively)Limited data were available for limb survival, and those studies reporting on this outcome showed no clear difference between graft types for this outcome. Antiplatelet and anticoagulant protocols varied extensively between trials, and in some cases within trials.The overall quality of the evidence ranged from very low to moderate. Issues which affected the quality of the evidence included differences in the design of the trials, and differences in the types of grafts they compared. These differences meant we were often only able to combine and analyse small numbers of participants and this resulted in uncertainty over the true effects of the graft type used. AUTHORS' CONCLUSIONS: There was moderate-quality evidence of improved long-term (60 months) primary patency for autologous vein grafts when compared to prosthetic materials for above-knee bypasses. In the long term (two to five years) there was low-quality evidence that Dacron confers a small secondary patency benefit over PTFE for above-knee bypass. Only very low-quality data exist on below-knee bypasses, so we are uncertain which graft type is best. Further randomised data are needed to ascertain whether this information translates into an improvement in limb survival. PMID- 29429143 TI - Seeds as oil factories. AB - KEY MESSAGE: Studying seed oil metabolism. The seeds of higher plants represent valuable factories capable of converting photosynthetically derived sugars into a variety of storage compounds, including oils. Oils are the most energy-dense plant reserves and fatty acids composing these oils represent an excellent nutritional source. They supply humans with much of the calories and essential fatty acids required in their diet. These oils are then increasingly being utilized as renewable alternatives to petroleum for the chemical industry and for biofuels. Plant oils therefore represent a highly valuable agricultural commodity, the demand for which is increasing rapidly. Knowledge regarding seed oil production is extensively exploited in the frame of breeding programs and approaches of metabolic engineering for oilseed crop improvement. Complementary aspects of this research include (1) the study of carbon metabolism responsible for the conversion of photosynthetically derived sugars into precursors for fatty acid biosynthesis, (2) the identification and characterization of the enzymatic actors allowing the production of the wide set of fatty acid structures found in seed oils, and (3) the investigation of the complex biosynthetic pathways leading to the production of storage lipids (waxes, triacylglycerols). In this review, we outline the most recent developments in our understanding of the underlying biochemical and molecular mechanisms of seed oil production, focusing on fatty acids and oils that can have a significant impact on the emerging bioeconomy. PMID- 29429147 TI - Effects of Several Cosmetic Preservatives on ROS-Dependent Apoptosis of Rat Neural Progenitor Cells. AB - Benzalkonium chloride, diazolidinyl urea, and imidazolidinyl urea are commonly used preservatives in cosmetics. Recent reports suggested that these compounds may have cellular and systemic toxicity in high concentration. In addition, diazolidinyl urea and imidazolidinyl urea are known formaldehyde (FA) releasers, raising concerns for these cosmetic preservatives. In this study, we investigated the effects of benzalkonium chloride, diazolidinyl urea, and imidazolidinyl urea on ROS-dependent apoptosis of rat neural progenitor cells (NPCs) in vitro. Cells were isolated and cultured from embryonic day 14 rat cortices. Cultured cells were treated with 1-1,000 nM benzalkonium chloride, and 1-50 MUM diazolidinyl urea or imidazolidinyl urea at various time points to measure the reactive oxygen species (ROS). PI staining, MTT assay, and live-cell imaging were used for cell viability measurements. Western blot was carried out for cleaved caspase-3 and cleaved caspase-8 as apoptotic protein markers. In rat NPCs, ROS production and cleaved caspase-8 expression were increased while the cell viability was decreased in high concentrations of these substances. These results suggest that several cosmetic preservatives at high concentrations can induce neural toxicity in rat brains through ROS induction and apoptosis. PMID- 29429148 TI - Fasiglifam (TAK-875), a G Protein-Coupled Receptor 40 (GPR40) Agonist, May Induce Hepatotoxicity through Reactive Oxygen Species Generation in a GPR40-Dependent Manner. AB - Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration- (>50 uM) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to 500 uM. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at 25 uM. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40 dependent manner. PMID- 29429149 TI - Carbon Monoxide Ameliorates 6-Hydroxydopamine-Induced Cell Death in C6 Glioma Cells. AB - Carbon monoxide (CO) is well-known as toxic gas and intrinsic signaling molecule such as neurotransmitter and blood vessel relaxant. Recently, it has been reported that low concentration of CO exerts therapeutic actions under various pathological conditions including liver failure, heart failure, gastric cancer, and cardiac arrest. However, little has been known about the effect of CO in neurodegenerative diseases like Parkinson's disease (PD). To test whether CO could exert a beneficial action during oxidative cell death in PD, we examined the effects of CO on 6-hydroxydopamine (6-OHDA)-induced cell death in C6 glioma cells. Treatment of CO-releasing molecule-2 (CORM-2) significantly attenuated 6 OHDA-induced apoptotic cell death in a dose-dependent manner. CORM-2 treatment decreased Bax/Bcl2 ratio and caspase-3 activity, which had been increased by 6 OHDA. CORM-2 increased phosphorylation of NF-E2-related factor 2 (Nrf2) which is a transcription factor regulating antioxidant proteins. Subsequently, CORM-2 also increased the expression of heme oxygenase-1 and superoxide dismutases (CuZnSOD and MnSOD), which were antioxidant enzymes regulated by Nrf2. These results suggest that CO released by CORM-2 treatment may have protective effects against oxidative cell death in PD through the potentiation of cellular adaptive survival responses via activation of Nrf2 and upregulation of heme oxygenase-1, leading to increasing antioxidant defense capacity. PMID- 29429150 TI - MiR-199a/b-5p Inhibits Lymphangiogenesis by Targeting Discoidin Domain Receptor 1 in Corneal Injury. AB - Discoidin domain receptor 1 (DDR1) is involved in tumorigenesis and angiogenesis. However, its role in lymphangiogenesis has been unknown. Here, we tested whether downregulation of DDR1 expression by miR-199a/b can suppress lymphangiogenesis. We also aimed to identify miRNA target site(s) in the 3' untranslated region (UTR) of DDR1. Transfection with miR-199a/b-5p mimics reduced expression of DDR1 and tube formation in primary human dermal lymphatic endothelial cells, whereas miR-199a/b-5p inhibitors showed the opposite effects. Critically, injection of miR-199a/b-5p mimics suppressed DDR1 expression and lymphangiogenesis in a corneal alkali-burn rat model. The three well-conserved seed matched sites for miR-199a/b-5p in the DDR1 3'-UTR were targeted, and miRNA binding to at least two sites was required for DDR1 inhibition. Our data suggest that DDR1 promotes enhanced lymphangiogenesis during eye injury, and miR-199a/b-5p suppresses this activity by inhibiting DDR1 expression. Thus, this miRNA may be useful for the treatment of lymphangiogenesis-related eye diseases. PMID- 29429151 TI - The Role of Hippo Pathway in Cancer Stem Cell Biology. AB - The biological significance and deregulation of the Hippo pathway during organ growth and tumorigenesis have received a surge of interest in the past decade. The Hippo pathway core kinases, MST1/2 and LATS1/2, are tumor suppressors that inhibit the oncogenic nuclear function of YAP/TAZ and TEAD. In addition to earlier studies that highlight the role of Hippo pathway in organ size control, cell proliferation, and tumor development, recent evidence demonstrates its critical role in cancer stem cell biology, including EMT, drug resistance, and self-renewal. Here we provide a brief overview of the regulatory mechanisms of the Hippo pathway, its role in cancer stem cell biology, and promising therapeutic interventions. PMID- 29429152 TI - Mass Spectrometry-Based Screening Platform Reveals Orco Interactome in Drosophila melanogaster. AB - Animals use their odorant receptors to receive chemical information from the environment. Insect odorant receptors differ from the G protein-coupled odorant receptors in vertebrates and nematodes, and very little is known about their protein-protein interactions. Here, we introduce a mass spectrometric platform designed for the large-scale analysis of insect odorant receptor protein-protein interactions. Using this platform, we obtained the first Orco interactome from Drosophila melanogaster. From a total of 1,186 identified proteins, we narrowed the interaction candidates to 226, of which only two-thirds have been named. These candidates include the known olfactory proteins Or92a and Obp51a. Around 90% of the proteins having published names likely function inside the cell, and nearly half of these intracellular proteins are associated with the endomembrane system. In a basic loss-of-function electrophysiological screen, we found that the disruption of eight (i.e., Rab5, CG32795, Mpcp, Tom70, Vir-1, CG30427, Eaat1, and CG2781) of 28 randomly selected candidates affects olfactory responses in vivo. Thus, because this Orco interactome includes physiologically meaningful candidates, we anticipate that our platform will help guide further research on the molecular mechanisms of the insect odorant receptor family. PMID- 29429153 TI - Cancer Prevention with Green Tea and Its Principal Constituent, EGCG: from Early Investigations to Current Focus on Human Cancer Stem Cells. AB - Cancer preventive activities of green tea and its main constituent, (-) epigallocatechin gallate (EGCG) have been extensively studied by scientists all over the world. Since 1983, we have studied the cancer chemopreventive effects of EGCG as well as green tea extract and underlying molecular mechanisms. The first part of this review summarizes ground-breaking topics with EGCG and green tea extract: 1) Delayed cancer onset as revealed by a 10-year prospective cohort study, 2) Prevention of colorectal adenoma recurrence by a double-blind randomized clinical phase II trial, 3) Inhibition of metastasis of B16 melanoma cells to the lungs of mice, 4) Increase in the average value of Young's moduli, i.e., cell stiffness, for human lung cancer cell lines and inhibition of cell motility and 5) Synergistic enhancement of anticancer activity against human cancer cell lines with the combination of EGCG and anticancer compounds. In the second part, we became interested in cancer stem cells (CSCs). 1) Cancer stem cells in mouse skin carcinogenesis by way of introduction, after which we discuss two subjects from our review on human CSCs reported by other investigators gathered from a search of PubMed, 2) Expression of stemness markers of human CSCs compared with their parental cells, and 3) EGCG decreases or increases the expression of mRNA and protein in human CSCs. On this point, EGCG inhibited self renewal and expression of pluripotency-maintaining transcription factors in human CSCs. Human CSCs are thus a target for cancer prevention and treatment with EGCG and green tea catechins. PMID- 29429154 TI - Cancer Risk in Patients with Intestinal Behcet's Disease: A Nationwide Population Based Study. AB - Background/Aims: The relationship between intestinal Behcet's disease (BD) and cancer remains unclear. We conducted a nationwide, population-based study to determine the risk of cancer in patients with intestinal BD. Methods: Using the National Health Insurance claims records, we collected data on 365 patients who had been diagnosed with intestinal BD between 2011 and 2014. Standardized incidence ratios (SIRs) of overall and site-specific cancers in patients with intestinal BD in comparison with the general population were calculated. Results: Among 167 men with intestinal BD, four cases of cancer were observed; among 191 women with BD, eight cases of cancer were observed. The risk of all cancers was significantly higher in women with intestinal BD than in women of the general population (SIR, 4.27; 95% confidence interval [CI], 1.84 to 8.41). However, in men with intestinal BD, the risk of all cancers was not significantly higher than that in men of the general population (SIR, 2.08; 95% CI, 0.57 to 5.33). The risk of hematologic cancer was significantly higher in both men and women with intestinal BD than in their counterparts in the general population (SIR, 23.90; 95% CI, 2.89 to 86.32 in men; SIR, 34.47; 95% CI, 4.17 to 124.51 in women). In particular, patients with intestinal BD showed a higher risk of leukemia and myelodysplastic syndrome than the general population. Conclusions: Patients with intestinal BD demonstrated a higher risk of hematologic cancer, especially leukemia, than the general population. Furthermore, women with intestinal BD showed a higher risk of all cancers. PMID- 29429157 TI - [Clinico-radiologic-pathologic criteria for diagnosis of idiopathic pulmonary fibrosis in China]. PMID- 29429155 TI - Continuous Use of Thienopyridine May Be as Safe as Low-Dose Aspirin in Endoscopic Resection of Gastric Tumors. AB - Background/Aims: Current guidelines recommend withholding antiplatelets for 5-7 days before high-risk endoscopic procedures. We investigated whether this reduces post-endoscopic submucosal dissection (ESD) bleeding. Methods: Gastric ESD cases with antiplatelets were retorospectively reviewed. Withholding antiplatelets for 5-7 days before ESD was defined as cessation and 0-4 days as continuation. The rate and risk of post-ESD bleeding according to the types and cessation of antiplatelets were assessed. Results: Among the 215 patients (117 adenoma and 98 early gastric cancer), 161 patients were on single (94 aspirin, 56 thienopyridine, and 11 other agents), 51 on dual, and 3 on triple antiplatelets. Post-ESD bleeding rates were 12.8% in aspirin users, 3.6% in thienopyridine, 27.5% in dual, 33.3% in triple therapy, and 9.7% in the cessation and 15.0% in the continuation group. Multiple antiplatelets (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.01 to 5.76) and specimen size >= 5.5 cm (OR, 2.84; 95% CI, 1.04 to 7.73) were the risk of bleeding, while continuation of thienopyridine (OR, 0.23; 95% CI, 0.05 to 1.09) and antiplatelets (OR, 1.83; 95% CI, 0.68 to 4.94) did not increase the risk of bleeding. Conclusions: Continuing thienopyridine and aspirin did not increase the risk of post-ESD. Multiple antiplatelet therapy and a large specimen size were independent risk factors of post-ESD bleeding. PMID- 29429156 TI - Guideline Adherence to Colonoscopic Surveillance Intervals after Polypectomy in Korea: Results from a Nationwide Survey. AB - Background/Aims: People around the world are increasingly choosing to undergo colorectal cancer screening via colonoscopy. As a result, guideline adherence to postpolypectomy colonoscopy surveillance has drawn increasing attention. The present study was performed to assess recognition and adherence to guidelines among primary care physicians and gastroenterologists and to identify characteristics associated with compliance. Methods: A nationwide sample of primary care physicians employed at cancer screening facilities and registered members of the Korean Society of Gastrointestinal Endoscopy were recruited. Participants were asked to complete a survey of six hypothetical clinical scenarios designed to assess their potential course of action in response to screening or follow-up colonoscopy results. Frequencies and odds ratios and 95% confidence intervals for guideline adherence were estimated. Results: The proportions of doctors recommending shortened colonoscopy surveillance intervals for low- and high-risk adenomas were greater than 90% among primary physicians and were much lower among gastroenterologists. Guideline adherence was relatively good among groups of doctors who were young, had a specialty in gastroenterology, worked at tertiary hospitals, and cared for an appropriate number of patients. Conclusions: The present study reveals a remaining discrepancy between practitioner recommendations and current guidelines for postpolypectomy surveillance. Several factors were shown to be related to guideline adherence, suggesting a need for appropriate control and continuing education or training programs among particular groups of practitioners. PMID- 29429158 TI - [Pleomorphic and dedifferentiated leiomyosarcoma: a clinicopathologic analysis]. AB - Objective: To investigate the clinicopathologic features, differential diagnosis and biological behavior of pleomorphic leiomyosarcoma (PLMS) and dedifferentiated leiomyosarcoma (DLMS). Methods: Forty-nine cases were collected from November 2007 to December 2016, including eight that diagnosed at Fudan University Shanghai Cancer Center, and 41 consultation cases. The clinical findings and pathologic features were reviewed. Immunophenotype was obtained in 33 cases and follow-up information was available in 38 cases. Results: There were 22 males and 27 females with ages ranging from 24 to 83 years (mean 52.5 years). Fifteen cases occurred in extremities, 14 in deep body cavity, 11 in the trunk, 4 in the head and neck, 2 in the bladder, and 1 each in the inguinal region, perineum and femoral vein, respectively. Tumor sizes ranged from 3 to 30 cm (mean 9.1 cm). The tumors were composed of at least small foci of typical leiomyosarcoma (LMS) and areas of high-grade pleomorphic/undifferentiated sarcoma. The typical LMS component showed the characteristic morphology of smooth muscle differentiation and was low to intermediate grade in most cases. Pleomorphic areas were mainly composed of atypical spindle and polygonal cells admixed with variable large, bizarre atypical cells and multinuclear giant cells, mostly mimicking undifferentiated pleomorphic sarcoma. The pleomorphic and leiomyosarcomatous areas were usually intermixed, but the demarcation may be distinct or gradual in some cases. The classical LMS component was positive for at least one myogenic marker: alpha-SMA in 97.0%(32/33), desmin in 72.7%(24/33), H-caldesmon in 90.9% (20/22), MSA in 14/16, and calponin in 15/15 of cases. The pleomorphic sarcoma component was reactive for at least one myogenic marker in 87.9% (29/33) of cases, usually showing focal and less intense immunoreactivity than classical LMS component: alpha-SMA was positive in 81.8%(27/33), desmin in 48.5%(16/33), H caldesmon in 72.7% (16/22), MSA in 12/16, and calponin in 11/15 of cases. Based on staining for muscle markers in the pleomorphic component, 29 cases were designated as PLMS, 4 as DLMS. Ki-67 index ranged from 15% to 70% (mean 40%). Follow-up data was available in 38 cases (77.6%), of which 11 patients (28.9%) died of disease, 12 patients were alive with unresectable or recurrent disease, 14 patients were alive with no evidence of disease and another one died of unrelated cause. The median disease-free and overall survival was 6 and 10 months respectively. Twelve patients exhibited local recurrence and 11 developed metastases. The median interval to progression was 8 months. Conclusions: The identification of areas of typical LMS is crucial for accurate diagnosis of PLMS and DLMS. Both PLMS and DLMS show more aggressive behavior and poorer prognosis than ordinary LMS. PMID- 29429159 TI - [Retroperitoneal dedifferentiated liposarcoma with rhabdomyoblastic differentiation: a clinicopathological analysis]. AB - Objective: To investigate the clinicopathological features, differential diagnosis, treatment and prognosis of dedifferentiated liposarcoma with rhabdomyoblastic differentiation. Methods: Six cases of retroperitoneal dedifferentiated liposarcoma with rhabdomyoblastic features were collected from December 2014 to August 2017 at Peking University International Hospital. The clinical manifestations, histomorphology, immunophenotype, treatment and follow up data were analyzed, and relevant literature reviewed. Results: The six patients included two males and four females, with age range of 47 to 66 years (mean 56 years). One case was primary and the five cases were recurred; four cases received radiotherapy and/or chemotherapy. The tumor diameters were 10 to 30 cm. Microscopically, the dedifferentiated areas were well demarcated from the well-differentiated areas, and resembled malignant fibrous histiocytoma, fibrosarcoma or solitary fibrous tumor with obvious mitotic figures or necrosis. Rhabdomyoblastic cells made up 10% to 30% of dedifferentiated area, and were scattered or focally distributed, being rounded, band-like or spindled, mostly with abundant eosinophilic cytoplasm. No striated structure was found, and the nucleis were rounded, oval or irregular shape with central or eccentric prominent nucleoli. Rare rhabdomyoblastic cells were lymphocytoid. The tumors encroached the muscular layer of intestinal wall in two cases and perirenal adipose tissue in one case. By immunohistochemical staining, the rhabdomyoblastic cells of all cases were all positive for desmin, myogenin, myoD1 and SMA; S-100 protein was expressed in one case (1/6). Well-differentiated area in two cases and dedifferentiated areas in all six cases were positive for MDM2, CDK4 and p16. After resection of the tumor and adjacent organs, one case recurred three months later, but there was no distant metastasis. Conclusions: Dedifferentiated liposarcoma with rhabdomyoblastic differentiation is a rare dedifferentiated liposarcoma. Pathological diagnosis is based on morphology, with supplementary immunohistochemical or molecular evaluation for further differential diagnosis. Multiple relapses may occur after surgical ablation plus adjuvant therapy. PMID- 29429160 TI - [Clinicopathologic features of atypical spindle cell lipomatous tumor]. AB - Objective: To investigate the clinicopathologic characteristics, immunophenotype, differential and diagnostic features of atypical spindle cell lipomatous tumor (ASLT). Methods: Three cases of ASLT were collected from January 2010 to March 2017 at Zhejiang Provincial People's Hospital. The clinical and imaging features, histomorphology, immunophenotype and prognosis were analyzed. Fluorescence in situ hybridization (FISH) was used to detect MDM2 gene amplification, and relevant literature was reviewed. Results: All three patients were adult males, aged 38, 43 and 54 years, respectively. One tumor originated in the subcutaneous soft tissue in the head and neck, one was located in the left primary bronchus and one in the latissimus dorsi muscle. Grossly, all three tumors were circumscribed and ranged from 4.0 to 5.8 cm in size. Microscopically, all showed a focally infiltrative front. These tumors were composed of variable proportions of spindle-shaped and adipocytic cells in a background of variable fibrous and edematous matrix. Scattered lipoblasts were easily seen. One tumor was composed predominately of spindle tumor cells, one of adipocytic cells, and one of equally mixed cell populations. The spindle tumor cells were generally bland-appearing with focal nuclear enlargement and hyperchromasia noted in one case. Mitosis was not seen in neither the spindle cells nor the adipocytic cells. By immunohistochemistry, diffuse and strong reactivity to CD34 of the spindle cells was noted in all cases, definite loss of Rb expression was noted in one of three cases, and S-100 protein was expressed only in the adipocytic cells. INI-1 was intact and Ki-67 index was 1% to 3%. All other markers including CDK4, MDM2, STAT6, SOX10, CD99, bcl-2, beta-catenin, CD117, GFAP, CK, EMA, SMA and desmin were negative. FISH of MDM2 was done in two cases, and both showed no amplification. The ASLT in the head and neck had two recurrences during 17 months of follow-up, whereas the tumor in the latissimus dorsi was free of disease during 33 months of follow-up. Conclusions: ASLT is a rare subtype of low-grade adipocytic neoplasm and is distinctive from atypical lipomatous tumor/well differentiated liposarcoma. The histomorpholgy of ASLT has significant heterogeneity and forms a continuous spectrum. ASLT needs to be distinguished from a series of benign and malignant soft tissue tumors. PMID- 29429161 TI - [Classification of cardiac amyloidosis: an immunohistochemical analysis]. AB - Objective: To evaluate the sensitivity and specificity of immunohistochemistry (IHC) in the classification of cardiac amyloidosis on endomyocardial biopsy (EMB) and heart allograft. Methods: Twenty cardiac tissues from 19 patients at Fuwai Hospital from January, 1990 to April, 2017 with histopathologic features of amyloidosis and Congo red staining positivity were included. IHC was performed with monoclonal antibodies against AA amyloid and polyclonal antibodies against transthyretin (ATTR), lambda-light chain (AL-lambda), kappa-light chain (AL kappa), ApoAI, ApoAII, ApoA IV and beta(2)-microglobin. The extent of interstitial staining was evaluated by light microscopy, and three patterns were recognized; these included diffuse pericellular pattern, discrete pericellular pattern, and nodular pattern. Two patterns of vascular deposition were also noted, including arterial pattern and venous pattern. Endocardial involvement was also assessed and recorded. Results: Nineteen cases were divided into three groups according to the pattern of proteins expression in specimens. The first group (5 cases) only showed single protein expression on EMB. The second group (6 cases) showed more than one protein expression, but one of them was intensely stained or any staining of any protein together with ApoA IV co-staining. The third group (8 cases) also showed more than one protein expression and all of them had intense staining. Amyloid deposits were successfully subtyped as AL lambda, ATTR, AL-kappa and ApoAIby IHC in the former two groups with the sensitivity of 11/19. In the third group, amyloid deposits could not be subtyped by immunohistochemistry due to their poor specificity. The pericellular pattern tended to favor AL over ATTR amyloidosis and vascular deposition tended to favor ATTR. Conclusions: Amyloid deposits can be reliably subtyped in diagnostic cardiac specimens using IHC. The co-deposition of chaperon proteins, the distribution of amyloid proteins and clinical features are also auxiliary to subtype cardiac amyloidosis. PMID- 29429162 TI - [Pulmonary microcystic fibromyxoma: report of a case with review of literature]. AB - Objective: To study the clinicopathologic features, diagnosis and differential diagnosis of pulmonary microcystic fibromyxoma. Methods: In March 2014, at the First Affiliated Hospital to Nanjing Medical University a 58-year-old female patient of pulmonary microcystic fibromyxoma was collected. The clinicopathologic, immunohistochemical and genetic profile of a case of pulmonary microcystic fibromyxoma were studied, and the relevant literature reviewed. Results: The patient was a 58-year-old female who presented with cough and sputum for 1 month. CT scan disclosed a 15 mm nodule in her right middle lobe of lung. The patient underwent a wedge resection with negative margin. Grossly, a well demarcated peripheral lung nodule was detected, measuring 1.5 cm*1.5 cm*1.0 cm, with myxoid tan-white cut surface containing microcysts. Microscopically, the tumor was composed of bland spindled to stellate-shaped cells widely spaced within prominent fibromyxoid stroma with prominent cystic change. No mitosis or necrosis was present. There were inconspicuous slim curvilinear capillaries and occasional collection of stromal lymphocytes and plasma cells. Immunohistochemically, the tumor cells were positive for vimentin, but negative for CD34, SMA, desmin, S-100 protein, ALK, CKpan, EMA, calretinin and TTF1. Fluorescence in situ hybridization did not show chromosomal translocation involving EWSR1, DDIT3 or FUS genes. The patient was recurrence or metastasis free after follow-up for 38 months. Conclusion: Pulmonary microcystic fibromyxoma is a rare benign lesion that should be differentiated from other lung tumors with myxoid characteristics. PMID- 29429163 TI - [Clinicopathologic features and prognosis of inflammatory pseudotumor-like follicular dendritic cell sarcomas in liver and spleen: an analysis of seven cases]. AB - Objective: To investigate the clinicopathological features and prognostic parameters of the inflammatory pseudotumor-like follicular dendritic cell sarcoma (IPT-like FDCS) of liver and spleen. Methods: Ninteen cases of inflammatory pseudotumor (IPT) and 5 cases of IPT-like FDCS of the liver and spleen were collected at the First Affiliated Hospital, Army Medical University from 2006 to 2016. HE sections, immunohistochemical staining, and Epstein-Barr virus encoded nuclear RNA (EBER) in situ hybridization were reviewed along with a summary of the literature. Results: Among the previously diagnosed 19 cases of IPT of the liver and spleen, 2 cases were misdiagnosed (the ratio of 2/19). Among 7 new cases including 3 males and 4 females, 3 cases involved the liver and 4 cases involved the spleen. The age range was 37-64 years (mean 53 years). The maximum tumor diameter ranged from 3.0 to 11.0 cm (mean 6.5 cm). Surgical resections were performed in all patients with follow-up time ranging from 3 to 84 months.All patients were disease-free.7 new cases were all positive for EBER, and showed the expression of at least one of the FDC markers, including CD21, CD23, and CD35. The rest of 17 cases of IPT were all negative for EBER and essentially negative for FDC markers, but were all positive for SMA. Conclusions: IPT-like FDCS of the liver and spleen is a rare low-grade malignant tumor morphologically mimicking inflammatory pseudotumor, and is easy to be misdiagnosis due to under recognition. EBER in situ hybridization and FDC markers are indispensable for confirming the diagnosis. PMID- 29429164 TI - [Expression of betaF1 and T cell receptor gamma in T lymphoblastic lymphoma/leukemia]. AB - Objective: To evaluate the expression of betaF1 and T cell receptor (TCR)gamma in T lymphoblastic lymphoma/leukemia(T-LBL/ALL), and investigate the clinicopathological features. Methods: Fifty-one cases of T-LBL/ALL were collected at Guangdong General Hospital from 2010 to 2016, the expression of betaF1 and TCRgamma was assessed by immunohistochemistry. Results: There were 13 cases of children and adolescents, and 38 cases of adults. The expression rates of betaF1 and TCRgamma were 27.5%(14/51) and 15.7%(8/51) respectively. The proportion of adults in alphabeta T-LBL/ALL, TCR-silent T-LBL/ALL and gammadelta T-LBL/ALL was 7/14, 79.3%(23/29)and 8/8 respectively, and the difference was significant (P=0.023). There was no statistical difference in sex, LDH, bone marrow involvement and Ann arbor stage among these three groups(P>0.05). gammadelta T-LBL/ALLs included 6 cases of CD4(-)/CD8(-) phenotype, whereas alphabeta T-LBL/ALL included 7 cases of CD4(+) /CD8(+) phenotype. There was significant difference in CD4/CD8 expression among these three groups(P<0.01). Conclusions: gammadelta T-LBL/ALL occurred only in adults, with predominantly CD4(-)/CD8(-) phenotype. alphabeta T-LBL/ALL occurred more common in children and adolescents, with predominantly CD4(+) /CD8(+) phenotype. PMID- 29429165 TI - [Clinicopathologic features with collecting duct carcinoma of kidney: report of 10 cases]. AB - Objective: To study the pathological features, immunophenotypes, differential diagnoses and prognostic parameters of collecting duct carcinoma of the kidney (CDC). Methods: Clinical imaging, histopathology, immunohistochemistry, and survival data of 10 patients at First Affiliated Hospital of Nanjing Medical University from January 2009 to August 2017 were retrospectively analyzed along with a review of literatures. Results: The clinical symptoms of CDC were not specific, and image examinations showed space-occupying mass lesions. Tumors were mainly located in renal medulla with grey and firm cut face and the presence of focal hemorrhage and necrosis. Microscopically, there were predominant tubular or tubular-papillary structures with associated focal sarcomatoid areas, desmoplastic stromal reaction and lymphoplasmacytic cells infiltration. Tumor cells had marked cytological atypia with high grade nuclei, conspicuous nucleolus and numerous mitoses. Immunohistochemically, tumor cells were strongly positive for CK19, E-cadherin, vimentin, HCK, CK7 and PAX8. The main treatment was radical nephrectomy in the patients. Seven cases died of CDC with median survival of 10 months. Conclusions: CDC is a rare, highly aggressive malignancy of kidney with poor prognosis. Definitive diagnosis should be made by histology and immunohistochemistry. Differential diagnoses include papillary renal cell carcinoma(type II), renal medullary carcinoma, infiltrating high grade urothelial carcinoma, renal pelvis adenocarcinoma and metastatic adenocarcinomas. PMID- 29429167 TI - [Expression of CD10 in fibrous histiocytoma and its significance]. PMID- 29429166 TI - [Herpes simplex virus infection in cervix uteri: a clinicopathologic analysis of 69 cases]. PMID- 29429168 TI - [Comparison of roles between acid-fast staining and real time PCR in auxiliary diagnosis of tuberculosis]. PMID- 29429169 TI - [Bartholin's gland nodular hyperplasia with cyst formation: report of a case]. PMID- 29429170 TI - [Secondary hemochromatosis: report of a case]. PMID- 29429171 TI - [Recent advances in the diagnosis and classification of testicular sex cord stromal tumors]. PMID- 29429172 TI - [Clinicopathologic features of secretory carcinoma of salivary glands]. PMID- 29429173 TI - [Application and progress of blood-based microRNA detection in tumor liquid biopsy]. PMID- 29429174 TI - [PI3K/AKT-mTOR signaling pathway related mutations and malformations of cortical development]. PMID- 29429175 TI - [Middle ear teratoma in infant: report of three cases and review of the literatures]. AB - Objective: To summarize the clinical characteristics and therapeutic experiences of the middle ear teratoma in infants. Methods: Three cases of middle ear teratoma, from 2012-2015 in Beijing Friendship Hospital were analyzed. Results: The three cases all developed slowly and presented unilateral otorrhea and hearing loss. Otoscopy showed the granulation tissue in the external ear canal. Audiological changes varied according to the degree of severity. Imaging features showed the pocket-like occupancy lesions in the Eustachian tube area. The temporal bone CT showed mass with soft tissue density usually involved in the mastoid and tympanic cavity. MRI showed mixed signal intense on both T1 and T2 weighted imaging. All the three cases received neoplasm resection of the middle ear. Only one case received tympanoplasty surgery at the same time. And all the pathology results displayed mature teratoma. The follow-up time was 17 to 54 months. MRI showed complete removal of the tumor. Conclusions: Teratoma are rare in the head and neck neoplasm. When the infants suffer from the unilateral otorrhea, hearing loss, and granulation tissue formed in the external ear canal, it should be vigilant for teratoma. The differential diagnosis is middle ear cholesteatoma, congenital first branchial cyst or fistula, and middle ear carcinoma. Temporal bone CT combined with MRI could improve the accuracy of diagnosis. It should be totally resection as soon as possible if there is no contraindication. Postoperative follow-up and imaging examination are necessary to eliminate tumor recurrence. PMID- 29429176 TI - [Analysis of curative effect of transoral radiofrequency ablation microsurgery on glottic carcinoma with anterior commissure involvement at the early stage]. AB - Objective: To explore the key technique and outcome of transoral radiofrequency ablation microsurgery for early stage of glottic carcinoma with anterior commissure involvement (ACI). Methods: A retrospective analysis was conducted on 31 patients, who were diagnosed as early stage glottic carcinoma during January 2010 to March 2016 in ENT Department. According to whether the anterior commissure was involved or not, two groups were divided. There were eleven cases with ACI (stages T1a, T1b, and T2). Twenty cases without ACI (stages Tis, T1a, and T2). All the patients received transoral radiofrequency ablation microsurgery and followed up closely.Only one case received radiotheraphy after surgery. SPSS19.0 software was used to analyze data. Results: The follow-up time was 12-67 months, and the median follow-up time was 30 months. Nine among 11 cases with ACI obtained good oncologic outcomes, initial local recurrence was identified in 2/11 cases, including 2 cases of T2. Two cases ultimately required salvage total laryngectomy. Meanwhile, initial local recurrence was identified in 2/20 cases without ACI, including 1 case of T1a and 1 case of T2. One case underwent elective neck dissection, and another one received salvage total laryngectomy.Compared to the patients without ACI, it seemed that the cases with ACI always accomponied with a little higher initial local recurrence and lower overall laryngealpreservation, but the difference had no significance (P>0.05). Conclusions: Transoral radiofrequency ablation microsurgery is an effective treatment for glottic carcinoma with ACI. Its advantages, such as more flexibility and deformability, make it more feasible to operate at the narrow space of anterior commissure assisted with laryngeal endoscopy.Good oncologic outcomes can be obtained by this technique with lower initial local recurrence as well as higher overall laryngeal preservation rate. PMID- 29429177 TI - [Planned neck dissection in the treatment of locally advanced head and neck squamous cell carcinoma]. AB - Objective: To investigate the value of planned neck dissection combined with induction chemotherapy and concurrent chemoradiotherapy in regional control and the outcome of locally advanced head and neck squamous cell carcinoma. Methods: A prospective randomized controlled study totally enrolled sixty-four patients of head and neck squamous cell carcinomas(include oropharynx, hypopharynx, and larynx) in stages IVa-IVb with lymph node metastase was were N2-N3. All patients firstly received 2-3 cycles of induction chemotherapy(ICT), then divided into two groups randomly, according to the efficacy of ICT. Group A(the study group) received planned neck dissection(PND) and concurrent chemoradiotherapy(CCRT). Group B(the control group) received concurrent chemoradiotherapy(CCRT). The differences in clinicopathologic features, local recurrence(LR), regional recurrence(RR), disease-free survival(DFS), and overall survival(OS) between the two groups were estimated. SPSS 19.0 software was used to analyze the data. Results: Group A enrolled twenty-one patients, and group B enrolled forty-three patients.The follow-up of all patients were 4-55 months, median follow-up time was 22 months. In study group, two-year OS and DFS were 80.9% and 68.3%, respectively. In control group, two-year OS and DFS were 90.7% and 67.1%, respectively. There was no significant difference in gender(P=0.215), age(P=0.828), primary tumor site(P=0.927), LR(P=0.126), DFS(P=0.710), and OS(P=0.402) between the two groups, while the RR(chi(2)=5.640, P<0.05) and distant metastasis(chi(2)=10.363, P<0.01) showed significant differences between the two groups. Conclusion: The ICT+ PND+ CCRT treatment model has benefit on regional control of locally advanced head and neck squamous cell carcinoma. PMID- 29429179 TI - [Evaluation of central lymph node dissection for papillary thyroid carcinoma in cN0 T1/T2]. AB - Objective: To evaluate the application of the central lymph node dissection (CLND) for papillary thyroid carcinoma (PTC) in cN0 T1/T2. Methods: Retrospective analysis of 532 cases with PTC in cN0 T1/T2 who underwent CLND between October 2014 and September 2016 in the Department of Thyroid Surgery, the First Affiliated Hospital of the Kunming Medical University. The incidence of central lymph node (CLN) metastasis and risk factors were analyzed. Results: CLN metastasis rates: 41.2% (42/102) in males vs 34.9% (150/430) in females, P=0.252; 33.9% (116/342) in single focal carcinoma vs 40.4% (74/183) in multifocal carcinoma, P=0.157; 44.0% (125/284) in patients with 45 years old or less vs 27.0% (67/248) in patients more than 45 years old, P=0.000; 30.3% (113/373) in microcarcinoma vs 50.9% (81/159) in non-microcarcinoma, P=0.000.In unilateral lesions, ipsilateral CLN metastasis was correlated with the tumor diameter (P=0.012), but not with the number of lesions (P=0.653). also contralateral CLN metastasis was correlated with the tumor diameter (P=0.000), but not with the number of lesions (P=0.815). For the left or right unilateral single focal lesion, the tumor diameter was not correlated with the metastasis of the posterior to right recurrent laryngeal nerve central lymph nodes (LN-prRLN-CLN) (P=0.652, P=0.088). But in bilateral multifocal carcinoma the tumor diameter was correlated with metastasis of LN-prRLN-CLN (P=0.039). Conclusions: Prophylactic CLND is reasonable for PTC in cN0 T1/T2. A bilateral CLND should be conducted for patients with bilateral multi-focus cancer and unilateral or bilateral non microcarcinoma, especially in patients more than 45 years old. For unilateral single focal microcarcinoma on the right, the content of CLND should be from laryngeal nerve on right center to posterior branche; for unilateral single focal microcarcinoma on the left side, the left CLND should be conducted. An ipsilateral CLND can be considered in patients with unilateral multifocal microcarcinoma, and generally a routine dissection of the LN-prRLN-CLN is not required, however for bilateral non-microcarcinoma and the the non-microcarcinoma on the right side, the LN-prRLN-CLN dissection should be conducted. PMID- 29429178 TI - [Long-term efficacy of supracricoid partial laryngectomy for 298 patients with laryngeal carcinoma]. AB - Objective: To evaluate the oncologic and functional outcomes of supracricoid partial laryngectomy (SCPL) in the treatment of laryngeal carcinoma. Methods: A total of 298 laryngeal carcinoma patients who underwent SCPL treatment from January 2005 to December 2013 were reviewed retrospectively. Clinical data of demographic and clinical characteristics, postoperative complications, rehabilitation information, recurrence and metastasis were analysed. Survival and local control were used to evaluate the clinical outcome.Data were analyzed by SPSS 23.0 software. Results: Thirty-one patients with supraglottic carcinoma underwent cricohyoidoepiglottopexy (CHEP)and 267 with glottic carcinoma underwent cricohyoidopexy (CHP) were enrolled in this study. The mean duration of followed up was 74 months, ranging from 12 to 146 months. Fifty-four cases died at last follow-up. With respect to 31 patients with supraglottic carcinoma, 5- and 10 year overall survival rates and disease specific survival rates all were 78.1%; 5 and 10-year disease free survival rates were 72.1% and 63.7% respectively; and 5 and 10-year local control rates were both 84.2%. In 267 patients with glottic carcinoma, 5- and 10-year overall survival rates were 85.8% and 77.1% respectively; 5- and 10-year disease specific survival rates were 86.6% and 78.4% respectively; 5- and 10-year disease free survival rates were 80.6% and 74.2% respectively; and 5- and 10-year local control rates were 90.0% and 89.4% respectively. The survival rate of patients with glottic carcinoma at stage T1 was higher than that at stage T2 or T3, and the disease free survival rate of patients with early stage was superior than that of patients with advance stage. Cox regression analysis showed that tumor stage T2, and T3, tumor recurrence, and tumor metastasis were independent risk factors for survival. Furthermore, nasogastric feeding tube removal rate was 100% and the decannulation rates of SCPL were 96% in the patients with SCPL. Conclusions: SCPL is a safe procedure with tumor resection for laryngeal carcinoma, with preserving of swallowing, respiration, and phonation functions, and has excellent survival and local control rates. This procedure could be considered as a standard function-sparing treatment for selected patients with laryngeal carcinoma of stages T1b-T3. PMID- 29429180 TI - [The experimental study on endoplasmic reticulum stress-participated outer hair cell apoptosis in cadherin 23 gene mutant mice]. AB - Objective: To test the mechanism and upstream pathway of outer hair cell apoptosis in Cadherin 23 (Cdh23) gene mutant mice. Method: The mutant Cdh23(erl/erl)(erl) mice were collected as the study group, while the C57BL/6J (B6) mice were chosen as the control group. A total of 70 mice per group were used in this study. The study group and control group underwent auditory-evoked brainstem response (ABR) tests at the same age. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to detect outer hair cell(OHC) apoptosis. The qRT-PCR was conducted to test the expression of ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP) mRNA. The expression and location of BiP and CHOP protein in OHC were detected by immunostaining. The expression of BiP protein in cochleae was identified by Western blot. The expression and location of CDH23 protein in OHC were discovered by immunostaining. Results: The ABR thresholds in erl mice were significantly higher than those in B6 mice at the age of 1 and 3 months (both P<0.05). The surface preparation with TUNEL staining confirmed OHC apoptosis in erl mouse cochleae which showed a higher TUNEL positive cell ratio than B6 mouse(t=11.291, P<0.01). The ER stress marker Bip and Chop mRNA were upregulated in the erl mouse inner ear, when compared with those in the B6 mouse(both P<0.05). The BiP protein extracted from the erl mouse cochleae was significantly higher than that of B6 mouse measured by Western blot (t=3.66, P=0.02). Immunostaining showed that BiP and CHOP were highly detected in the OHC in erl mouse cochleae, and was mainly detected in the perinuclear region of OHC. However, a bare BiP and CHOP signal were shown in B6 mouse cochleae. The CDH23 protein was specifically localized at the top of the OHC in B6 mice, indicating the localization of the tip links in hair bundle stereocilia. On the contrary, the CDH23(erl) protein was found to be localized from the top to the nuclei of the OHC in erl mice. Portions of the CDH23(erl) proteins failed to reach the top of the hair bundles and remained in the OHC cytoplasm. Conclusion: As the downstream response of the Cdh23 gene mutation, portions of the mutant CDH23(erl) protein was accumulated in ER lumen resulting in the increase of ER loading and ultimately triggered ER stress and hair cell apoptosis in erl mouse cochleae. PMID- 29429182 TI - [The effect of miR-497 on laryngeal squamous cell carcinoma invasion through modulating PlexinA4]. AB - Objective: To study the roles of miR-497 and PlexinA4 in the progression of laryngeal squamous cell carcinoma. Methods: The expressions of miR-497 and PlexinA4 in fresh tumor specimens and adjacent normal mucosa tissues as well as in cell lines of laryngeal squamous cell carcinoma (LSCC) were detected with qRT PCR and immunohistochemistry. The association of miR-497 and PlexinA4 expressions with clinicopathologic factors and their prognostic values in LSCC were evaluated PlexinA4 siRNA and pcDNA3.1 (+ )/PlexinA4 plasmid were transfected into the LSCC and measured by Transwell to evaluate their effect on the invasion of LSCC. Results: miR-497 was low expression in LSCC, which related to pathological differentiation, while PlexinA4 mRNA was high expression in LSCC. Kaplan-Meier method showed that the prognosis of patients with high miR-497 expression was better than that of patients with low miR-497 expression (chi(2)=10.342, P=0.001); . Cox regression analysis showed that miR-497 was an independent prognostic factor for LSCC. The double luciferase reporter gene showed that the variation of the fluorescence activity of wild type PlexinA4 was significantly different from that of the control group (P<0.01). In Hep-2 and TU212 cell line, the number of cells with PlexinA4 siRNA passing through the compartments was 70.00+/-10.85 and 85.00+/-6.45, significantly higher than control (F values were 30.251 and 23.936, both P<0.05), the number of cells with pcDNA3.1 (+ ) /PlexinA4 was 170.56+/-11.95 and 142.00+/-10.43, also significantly less than control (F values were 35.104 and 29.643, both P<0.05). Conclusion: The expression of miR 497 in LSCC is decreased, indicating poor prognosis, which is as an independent risk factor for prognosis of LSCC. miR-497 may modulate LSCC invasion through PlexinA4. PMID- 29429181 TI - [Effect of melatonin on expression of Prestin protein in the inner ear of mice following radiotherapy]. AB - Objective: To investigate the effect of melatonin on the expression of prestin protein in the inner ear of mice following a single dose radiation therapy, so as to provide the basis for the mechanism study of radiation induced inner ear injury and its prevention. Methods: Sixty 4-week-old male mice were randomly divided into six groups, including the control group (A group), 50 mg/kg MLT group (B group), 5 mg/kg MLT group (C group), 50 mg/kg MLT + radiotherapy group (D group), 5 mg/kg MLT+ radiotherapy group (E group), and 16 Gy radiotherapy group (F group). Each experimental group was randomly subdivided into two subgroups, which were killed to harvest the cochlea on the 3rd and 7th days following 16 Gy radiation. The specimens were used for immunostaining and Western blot to detect the expression of prestin protein. SPSS 19.0 software was used for statistical analysis. Results: Prestin protein mainly distributed in the lateral membrane above the outer hair cell nucleus. When compared with A, B and C group, the expression of prestin protein in the inner ear was significantly up-regulated in F group (P<0.05). However, D and E group reduced the abnormal expression of prestin following radiotherapy when compared with F group, the difference was statistically significant (P<0.05), and the effect of D group was more significant than E group (P<0.05). Conclusions: The prestin protein of cochlea is mainly distributed in the lateral membrane above the outer hair cell nucleus. Following the high-dose radiotherapy, the prestin expression is upregulated, and melatonin can control the abnormal expression of prestin protein induced by radiotherapy with dose dependent. PMID- 29429183 TI - [Correlation between patulous Eustachian tube with habitual nasal extraction and acquired middle ear cholesteatoma]. AB - Objective: By comparing the clinical characteristics of patulous Eustachian tube with habitual nasal extraction and those of non-Eustachian tube abnormalities, we aimed to investigate the relationship between patulous Eustachian tube and acquired cholesteatoma of middle ear. Methods: A total of 218 patients in Affiliated Hospital of Qingdao University from November 2011 to November 2016 who underwent surgical treatment and with complete data of acquired cholesteatoma of middle ear were enrolled. The patients were divided into two groups: patulous Eustachian tube with habitual nasal extraction and non-Patulous Eustachian tube. Their ages of onset , sides, characteristics of acoustic immitance, clinical manifestations, prognosis and complications were compared. The statistical analysis was carried out with SPSS 19.0 software. Results: Among the 218 cases of acquired cholesteatoma of the middle ear, 22 cases were diagnosed as patulous Eustachian tube with habitual nasal extraction [with average age of (35.7+/-7.5) years]; 196 cases were diagnosed as non-patulous Eustachian tube [with average age of (47.8+/-20.1) years]. The average age of the patulous Eustachian tube with habitual nasal extraction was significantly lower than that of the non-patulous Eustachian tube group (t=4.25, P<0.01). Ratio of bilateral middle ear cholesteatoma in patulous Eustachian tube [68.2%(15/22)] was significantly higher than that of the non-patulous Eustachian tube group [18.9%(37/196)] (chi(2)=26.47, P<0.01). Conclusions: Some acquired cholesteatoma patients are associated with the patulous Eustachian tube with habitual nasal extraction. The patients have a lower age, and are susceptible for bilateral middle ear cholesteatoma. PMID- 29429184 TI - [Study on bone metabolism in postmenopausal women with idiopathic benign paroxysmal positional vertigo]. AB - Objective: To analyze the bone mineral density and serum osteocalcin levels in postmenopausal women with idiopathic benign paroxysmal positional vertigo. Methods: A total of 64 postmenopausal women with idiopathic BPPV were selected as the study group, and 98 postmenopausal healthy women were selected as the control group. Bone mineral density and serum osteocalcin levels were analyzed and compared between the groups.chi(2) test was used for numeration data and t test was used for measurement data. Results: The prevalence of osteoporosis or osteopenia in BPPV group 67.2% (43/64) was significantly higher than that in the control group 51.0% (50/98) (chi(2)=4.139, P=0.042). Among BPPV subjects, there was a negative correlation between osteocalcin and bone density T (r=-0.469, P<0.001). Osteocalcin was found in normal bone mass subgroup (13.61+/-4.32)MUg/L, decreased bone mass subgroup (17.49+/-7.61)MUg/L, and osteoporosis subgroup (20.83+/-6.72)MUg/L, respectively, and the difference was statistically significant (F=5.39, P=0.007). Conclusions: Bone mineral density in BPPV group is lower than that in control group. The lower the bone mineral density of the patients, the higher the osteocalcin in BPPV group. PMID- 29429185 TI - [Chylous leakage attributable to post-operation on piriformis undifferentiated sarcoma combined with squamous cell carcinoma: a case report]. PMID- 29429186 TI - [IgG4-related sclerosing disease with initial ear symptom: a case report]. PMID- 29429187 TI - [One case of ossifying fibroma of the temporal bone with middle ear cholesteatoma]. PMID- 29429188 TI - [Paranasal peripheral primitive neuroectodermal tumor: a case report]. PMID- 29429189 TI - [Inflammatory myofibroblastic tumor of thyroid: a case report]. PMID- 29429190 TI - [Research progress of functional magnetic resonance imaging in mechanism studies of tinnitus]. AB - Tinnitus is a subjective symptom of phantom sound in the ear or brain without sound or electrical stimulation in the environment. The mechanism of tinnitus is complicated and mostly unclear. Recent studies suggested that the abnormal peripheral auditory input lead to neuroplasticity changes in central nervous system followed by tinnitus. More research concerned on the tinnitus central mechanism. A rapid development of functional magnetic resonance imaging (fMRI) technique made it more widely used in tinnitus central mechanism research. fMRI brought new findings but also presented some shortages in technology and cognition in tinnitus study. This article summarized the outcomes of fMRI research on tinnitus in recent years, exploring its existing problems and application prospects. PMID- 29429192 TI - [Investing for children's early development: the role of maternal and child health practitioners]. PMID- 29429191 TI - [Mechanisms underlying glucocorticoid resistance in chronic rhinosinusitis with nasal polyps]. AB - Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease that occurs in the nasal and sinus mucosa, which is a common disease in otorhinolaryngology. At present, CRSwNP can be effectively treated by glucocorticoids (GC). GC binds to GC receptors in the nasal mucosa, affects the expression of inflammatory genes, inhibits the activation and action of eosinophils, T cell-associated inflammatory responses in nasal polyps, as well as tissue remodeling. However, there are some patients fall reponse to GC, so called GC resistance. The study suggests that the possible mechanism of CRSwNP GC resistance is mainly related to GC receptor abnormal, the role of cytokines and transcription factors, such as Th cells and IL-8. In addition, MAPK-related kinases and histone deacetylase in the GC signaling pathway also play important roles in the GC resistance process. This paper reviews the mechanism of GC treatment of CRSwNP, the mechanism of GC resistance and alternative treatment of GC. PMID- 29429194 TI - [Evidence-based guideline on diagnosis and treatment of lupus nephritis (2016)]. PMID- 29429193 TI - [Assessment tool for early childhood development and its development and application in China]. PMID- 29429195 TI - [Interpretation of evidence-based guideline on diagnosis and treatment of lupus nephritis (2016)]. PMID- 29429196 TI - [Introduction to expert consensus statement of China on the use of catheter ablation in children]. PMID- 29429197 TI - [Early childhood development and risk factors in rural China: a cohort study]. AB - Objective: To investigate the development status and risk factors of infants and toddlers in rural China. Methods: In this cohort study, 603 infants (6-12 months of age, Phase I) in the rural areas of QinLing-Bashan (Qin-Ba) in Shaanxi were recruited in the control group that received no intervention from April 2013 to October 2015. Three follow-up visits were performed every six months (Phase II(12 18 months of age), Phase III (18-24 months of age) and Phase IV(24-30 months of age)). In all the 4 phases (I-IV), general data of the children and the families were collected by questionnaires, early childhood growth and development were assessed by door to door visits, children's hemoglobin levels were determined by laboratory tests, and the cognitive and motor development screening was conducted by the Bayley Scales of Infant and Toddler Development. Logistic regression was used to analyze the risk factors affecting the development of infants and toddlers in rural areas and the data were analyzed in terms of risk factors from infants, guardians and family. Results: Phase II, Phase III and Phase IV survey recruited 497, 483 and 486 participants respectively. The incidences of cognitive impairment (mental development scores<80) in rural areas of southern Shaanxi were 13.4% (81/603) in Phase I(6-12 months), 20.1%(100/497) in PhaseII(12-18 months), 42.9% (207/483) in Phase III(18-24 months) and 50.4%(245/486) in Phase IV(24-30 months) respectively, which showed a significant increase with age (chi(2)=233.40, P<0.01); the incidences of psychomotor impairment (psychomotor development scores<80) of Phase I, Phase II, Phase III and Phase IV were 25.0% (151/603), 26.8% (133/497), 8.3% (40/483) and 11.9% (58/486), which showed a significant decrease with age (chi(2)=87.08, P<0.01). Multivariate logistic regression analysis showed that the leading risk factor of the cognitive development of 24-30-month-old children was the mothers' poor education background (<=9 years of school education) (OR=2.56, P<0.01), and the main risk factors affecting psychomotor development were the mothers' poor education background (<=9 years of school education) (OR=2.64, P<0.05) and growth retardation (OR=2.95, P=0.07). Conclusions: The early childhood development (especially cognitive development) in the rural areas of Qin-Ba in Shaanxi of China is not optimistic. More attention should be paid to the early childhood development in rural China, especially to the development of children from the mothers with poor education background. PMID- 29429198 TI - [Effectiveness of integrated early childhood development intervention on nurturing care for children aged 0-35 months in rural China]. AB - Objective: To explore whether Integrated Early Childhood Development (IECD) program has effectively improved the nurturing care for children aged 0-35 months in rural China. Methods: IECD has been implemented by the government of China with support from the United Nations Children's Fund (UNICEF) in four poverty stricken rural counties since 2014. The interventions targeting the five key components of nurturing care (i.e. child and caregiver health, child nutrition, early learning support, child protection and social security) were delivered through the IECD program to children aged 0 to 35 months and their caregivers. A population-based intervention trial was designed to evaluate intervention effectiveness with data collected in 2013 (baseline) and 2016 (mid-term). The changes of nurturing care in the intervention and control group were analyzed by using a difference-in-differences (DID) model. This approach provided adjustment for sociodemographic and other confounding factors. Results: The baseline and mid term survey enrolled 1 468 and 1 384 children in the intervention group, and 1 485 and 1 361 in the control group. After two years of implementation, the prevalence of caregiver's depression in the intervention group showed a decrease of 9.1% (mid-term 34.8% (479/1 377) vs. baseline 43.9% (621/1 414)), whereas that in control group showed a decrease of 1.6% (mid-term 34.3% (464/1 353) vs. baseline 35.9% (509/1 419)). With the confounding adjusted in the difference-in differences model, the decrease of the caregiver's depression prevalence in the intervention group was 7.0% greater than that in the control group (P=0.008). The qualified rate of minimum meal frequency in the intervention group showed an increase of 10.4% (mid-term 69.0% (532/771) vs. baseline 58.6% (481/821)), whereas the qualified rate in the intervention group showed an increase of 2.9% (mid-term 66.4% (469/706) vs. baseline 63.5% (508/800)). With the confounding adjusted in the difference-in-differences model, the increase of the qualified rate in the intervention group was 8.2% greater than that in the control group (P=0.021). The proportion of violent discipline by caregivers in the intervention group showed a decrease of 6.2% (mid-term 49.1% (478/973) vs. baseline 55.3% (554/1 001)), whereas the proportion in control group showed an increase of 4.5% (mid-term 58.4% (560/959) vs. baseline 53.9% (558/1 036)), and with the confounding adjusted in the difference-in-differences model, the difference in increase rate between two groups was 11.0% (P=0.001). The proportion of families with three or more children's books in the intervention group showed an increase of 12.7% (mid-term 42.7% (588/1 378) vs. baseline 30.0% (432/1 440)), whereas the proportion of the control group showed an increase of 4.2% (mid-term 25.7% (349/1 357) vs. baseline 21.5% (298/1 388)), and with the confounding adjusted in the difference-in-differences model, the difference in increase rate between two groups was 6.1% (P=0.007). Conclusions: The IECD intervention strategy implemented in rural China effectively improved the mental health of caregivers, optimizes families' child feeding and early stimulation behaviors, while reducing violent discipline and other risk factors. IECD provides better nurturing care for the early development of children aged 0-35 months in rural China. PMID- 29429199 TI - [Impact of maternal risky behaviors on the behaviors of children born to adolescent and young mothers]. AB - Objective: To examine the impact of maternal risky behaviors on the behaviors of children born to adolescent and young mothers. Methods: Adolescents and young Chinese mothers were recruited from an integrated young mother supportive program in Hong Kong between January and June 2015. Eligible mothers were asked to complete a questionnaire on their sociodemographic characteristics and history of risky behavior as well as their children's behaviors. Multiple regression analyses were conducted to explore the association between maternal risky behaviors and their children's behaviors. Results: Among 201 respondents, there were 187 (93.0%) ex-drinkers, 136 (67.7%) ex-smokers, and 83 (41.3%) ex-addicts. Compared to the reference group, children of mothers with drug use behaviors were more likely to have abnormal SDQ total difficulties scores (odds ratio 2.60, P=0.01), those of ex-drinking mothers had more behavioral difficulties and more conduct problems (B=3.82 and 1.37, P both=0.01) and those of ex-smoking mothers had more conduct problems (B=0.74, P=0.01) after adjustment for confounders. Children of active drug-taking mothers also had more emotional symptoms (B=1.77, P=0.04) and hyperactivity/inattention problems (B=2.14, P=0.03). Conclusion: The history of mother's risky behavior was significantly associated with the behavioral problems of the children. PMID- 29429200 TI - [Outcome of pediatric extracorporeal membrane oxygenation in a single center]. AB - Objective: To investigate the application and outcome of pediatric extracorporeal membrane oxygenation (ECMO) in a single center. Methods: The clinical data of 52 pediatric patients with cardiopulmonary failure received ECMO support in Bayi Children's Hospital Affiliated to General Hospital of Beijing Military Command of PLA were collected from January 2012 to October 2016. All patients were divided into two stages by time. January 2012 to December 2014 was stage one. January 2015 to October 2016 was stage two. A retrospective analysis was done for these patients between two stages. In addition, all clinical data were compared with the data of extracorporeal life support organization (ELSO). The constituent ratio differences in different groups were tested by chi square test. Results: In 52 cases, there were 40 boys and 12 girls, aging from 1 day to 7 years, weighing from 2 to 20 kg. There were 35 cases who successfully weaned from ECMO (67%), and 25 cases were able to be discharged alive (48%). In stage one, there were 24 ECMO cases, 18 boys and 6 girls. There were 15 cases successfully weaned from ECMO (63%). Nine patients survived until discharge (38%). Complications were found in 15 cases during ECMO support (63%). In stage two, there were 28 ECMO cases, 22 were boys and 6 were girls. There were 20 cases successfully weaned from ECMO (71%). Sixteen patients survived until discharge (57%). Complications were found in 12 cases during ECMO support (43%). There was no significant difference in survival rates between two stages. However, the neonatal survival rate was higher in stage two than in stage one (71% (12/28) vs. 31% (5/24), chi(2)=5.107, P=0.038). The proportion of respiratory support was higher in stage two than in stage one (50% (14/28) vs. 21% (5/24), chi(2)=4.741, P=0.029), while the proportion of extracorporeal cardiopulmonary resuscitation (ECPR) decreased significantly (21% (6/28) vs. 67% (16/24), chi(2)=10.835, P=0.001). Application of peritoneal dialysis treatment in stage two was higher (6 vs. 0 cases, chi(2)=8.097, P=0.025). Mortality of ECMO was still higher than that of ELSO (48% (25/52) vs. 62% (34 655/55 886), chi(2)=4.281, P<0.05). The constituent ratio of different types of support varied between ECMO and ELSO patients (chi(2)=19.562, P<0.001). Conclusions: ECMO technology can provide effective support for severe cardiopulmonary failure in critically ill children. Due to the multidisciplinary nature of ECMO technology, the complexity and characteristics of pediatric patients, it takes long time to improve ECMO management and prognosis. PMID- 29429201 TI - [Survey on the prevalence of continuous blood purification in Chinese pediatric critical care]. AB - Objective: To investigate the current application status of continuous blood purification (CBP) technology and equipment in pediatric intensive care unit (PICU) in China. Methods: A cross-sectional survey was conducted to understand the current popularization of CBP technology and equipment, the management of CBP equipment and consumables, and the application of CBP in different diseases. A questionnaire named Application Status of Continuous Blood Purification Technology was applied. Children's hospitals and polyclinic hospitals with the pediatric qualification (pediatric emergency or critical care unit members of Chinese Medical Association and Chinese Medical Doctor Association) were selected. Results: From December 2016 to February 2017, 53 hospitals completed the questionnaire, including 7 in northeast, 6 in north China, 16 in east China, 9 in south China, 5 in central China, 4 in the northwest, and 6 in the southwest region. Continuous renal replacement therapy (CRRT), the most widely used technology, was carried out in 51 hospitals. Other technologies were peritoneal dialysis (IPD) (n=37), artificial liver support (ALSS) (n=26) and blood adsorption (PA) (n=13). There were 107 CBP machines in the 51 hospitals used CBP technology, with an average of 2.10/hospital. In 36 hospitals CBP machines were managed independently by PICU (70%). Hospitals made their own displacement liquid (n=40, 78%), or purchased displacement liquid (n=11, 22%). Hospitals prepared dialysate on their own (n=38, 75%), or purchased dialysate (n=13 hospitals, 25%). In 46 (90%) hospitals, hemodialysis catheter was placed independently by PICU doctors. The routine operation and maintenance of CBP were mainly completed by the PICU nurses in 36 hospitals (71%). There were 39 hospitals (76%) where professional nurses manage and maintain CBP. Puncture sites were femoral vein (n=26, 51%), internal jugular vein (n=21, 41%) and venae subclavia (n=4, 8%). Forty-two hospitals (82%) selected B-mode ultrasound positioning and guidance when performing internal jugular vein puncture. A total of 40 (78%) hospitals have developed post dilution and combined dilution techniques during the implementation of CBP. The most common indications of CBP technology were different in different regions. They were sepsis in northeast (24.0%, 243/1 011) and east China region (32.0%, 982/3 069), multiple organ dysfunction syndrome in south China (29.2%, 444/1 520), north China (15.8%, 126/796), and southwest region (30.1%, 460/1 526), drug poisoning in central China region (21.6%, 325/1 506), and renal failure in northwest region (53.0%, 44/83). Conclusions: CBP technology is widely used in the field of pediatric severe diseases in China. The eastern regions possess more CBP equipment than the western regions. CBP is widely used in the treatment of sepsis. PMID- 29429202 TI - [Cilia ultrastructural and gene variation of primary ciliary dyskinesia: report of three cases and literatures review]. AB - Objective: To analyze the clinical manifestations, cilia ultrastructure and gene variations of primary ciliary dyskinesia (PCD). Methods: Analysis of three cases diagnosed as PCD by transmission electron microscopy of the endobronchial biopsy material in Division of Pediatric Pulmonology of Shandong Provincial Hospital between 2013 and 2016. Target gene sequence capture and next generation sequencing were used to analyze the gene. Related literatures on gene variation of PCD in Chinese were reviewed from Online Mendelian Inheritance in Man, Human Gene Mutation Database, PubMed and CNKI up to July 2017 by using search terms of "PCD" , "gene" , "Chinese". Results: There were one male and two females aged from 10 to 11 years. The common symptoms included recurrent respiratory infection, sinusitis and bronchiectasis. Two of them had situs inversus. Case 1 had lack of outer and inner dynein arms with compound heterozygous mutation of LRRC6. Case 2 had outer and inner dynein arms defects with heterozygous mutations of DNAH5 and DNAH11. Case 3 had abnormality in microtubule and inner dynein arms with homozygous mutation of CCDC39. All the variations mentioned above have not been reported before. Twelve cases have been reported about gene variations in PCD in Chinese from eight reports. All these patients had recurrent respiratory infection starting soon after birth, rhinosinusitis, and bronchiectasis. Nine of them had dextrocardia. Four cases have taken an effective nasal (or bronchial) mucosal biopsy. 1 case had inner and outer dynein arms defects. One case had inner dynein arms and radial spokes defects. One case had microtubule and central pair defects. And 1 case had normal cilia ultrastructure. Eight kinds of gene variations were found. Three cases had gene variations of DNAH5. 2 cases had gene variations of DYX1C1. 2 cases had gene variations of CCNO. There was 1 case with gene variations of CCDC39, CCDC40, HYDIN, ARMC4 and DNAI1 separately. Conclusions: Recurrent respiratory infection starting soon after birth, rhinosinusitis, and bronchiectasis are the common symptoms of PCD. Eleven of fifteen Chinese PCD patients with positive gene mutations were Kartagener syndrome. Cilia ultrastructure showed defects of inner and outer dynein arms, radial spokes, microtubule and central pair. Ten kinds of gene variations were found: DNAH5, DYX1C1, CCNO, CCDC39, CCDC40, HYDIN, ARMC4, DNAI1, LRRC6,DNAH11. PMID- 29429203 TI - [Bainbridge-Ropers syndrome with ASXL3 gene variation in a child and literature review]. AB - Objective: To investigate the clinical manifestations and genetic features of a child with Bainbridge-Ropers syndrome caused by ASXL3 gene variation and review the literature. Methods: Clinical data and genetic features were collected and analyzed from a child with Bainbridge-Ropers syndrome who was diagnosed in Bao'an Maternity and Child Health Hospital in November 2016. "ASXL3" and "Bainbridge Ropers" were used as key words to search at China National Knowledge Infrastructure, Wangfang Data Knowledge Service Platform, PubMed and Human Gene Mutation Database up to June 2017. Results: A 2(9/12) years old girl was presented with psychomotor retardation, feeding difficulty, hypotonia and specific craniofacial phenotype. She showed severe growth retardation (height: 84 cm, body weight: 8.0 kg (both were less than 3(rd) percentile rank of the children at the same age) and head circumference: 46 cm(=3rd percentile rank)), without obvious abnormalities in laboratory tests and neuroimaging tests. A de novo heterozygous nonsense variation: c.3349C>T(p.R1117*) in ASXL3 gene was identified by the whole exome sequencing, and the novel variation was classified into pathologic variant based on Standards and guidelines for the interpretation of sequence variants from ACMG. According to literature retrieval, no Chinese cases with ASXL3 variation had been reported. Totally 28 cases including the present girl harboring ASXL3 variations with detailed clinical information were reported. Thirty-one variations in ASXL3 gene were involved, including 1 missense variation and 30 loss of function variations, which were all de novo variations. Conclusions: The clinical features of Bainbridge-Ropers syndrome include severe psychomotor retardation, feeding difficulties, hypotonia and specific facial features. The heterozygous nonsense variation in ASXL3 gene is the cause of the patient. All the pathogenic variations in ASXL3 gene are de novo and loss of function variations. PMID- 29429205 TI - [Neonatal Kasabach-Merrit syndrome originated from stomach wall]. PMID- 29429206 TI - [Two cases of NDUFAF6 related Leigh syndrome]. PMID- 29429204 TI - [Small vessel-childhood primary angiitis of the central nervous system: a case report and literature review]. AB - Objective: To summarize the clinical and pathological features of small vessel childhood primary angiitis of the central nervous system (SV-cPACNS), discuss the immune therapy and increase the attention to brain biopsy in SV-cPACNS. Methods: The clinical data, pathology of brain biopsy, treatment and outcome of an SV cPACNS patient hospitalized in Beijing Children's Hospital in February 2016 were analyzed retrospectively. The cases reported at Pubmed, CNKI and Wanfang databases from 2007 to 2017 were searched, the clinical and pathological features, immunotherapy and prognosis of the disease were summarized according to the literature review. Results: A 70 months old girl had 6 times relapses during 5 months' disease course. Symptoms included convulsions, limb paralysis, blurred vision and speech difficulty. Multiple cortical lesions were found successively in brain MRI but CT angiography was negative. The pathology of brain biopsy revealed thickening of small vessel walls together with lymphocytic infiltration. After the treatment with rituximab, remission was achieved and remained stable without recurrence in 1 year follow up. A total of 44 pathologically confirmed cases reported in nearly 10 years were retrieved. Male to female ratio was 1?3.5. The average onset age was 9.8 years. Clinical manifestations included seizures (37/45, 82%), headache (35/45, 78%), cognitive decline (28/45, 62%), speech regression(20/45, 44%), paralysis (15/45, 33%), and so on; 70% (19/27) patients experienced relapses. Erythrocyte sedimentation rate and C-reactive protein slightly elevated, antinuclear antibody and other autoimmune antibodies were mostly negative. Mild lymphocytosis in cerebrospinal fluid was found in 67%(29/43) patients. 53%(23/43) patients had elevated CSF protein level, several had elevated IgG and positive oligoclonal band. Bilateral multifocal lesions were revealed in 80% (36/45) brain MRIs, meanwhile all angiographies were unremarkable. The pathology showed small angiitis and immunohistochemistry positive for CD3 and CD20. Twenty-seven patients had detailed therapeutic information; 25 of them received immunosuppressive agents, including cyclophosphamide, mycophenolate mofetil and rituximab. One patient died, 26 patients achieved remission with 54% (22/44) had neurological sequelae. Conclusions: SV-cPACNS had varied clinical manifestations, there was no specificity in laboratory and imaging examination and angiography was often negative. The definite diagnosis relied on brain biopsy, which showed lymphocytic inflammation of small vessels. SV-cPACNS tended to relapse and induce neurologic deterioration. Treatment required long-term use of steroids and immunosuppressive agents. Rituximab could be an effective agent. PMID- 29429207 TI - [Neurobehavior development of children with the transposition of the great arteries after arteries switch operation]. PMID- 29429208 TI - [Impact of gut microbiota on host immune responses after vaccinations]. PMID- 29429209 TI - [Current advances in pathogenesis of autosomal recessive polycystic kidney disease]. PMID- 29429210 TI - [Therapy of hemoptysis caused by pulmonary hypertension]. PMID- 29429211 TI - [The harmfulness of non-tuberculous mycobacterium tuberculosis]. PMID- 29429212 TI - [The sources of emboli in patients with pulmonary embolism diagnosed by autopsy]. AB - Objective: To study the sources of emboli in patients with pulmonary embolism diagnosed by autopsy, and therefore to provide help in the diagnosis and treatment of thromboembolism. Methods: We retrospectively analyzed the pathology and clinical data of 43 patients with pulmonary embolism diagnosed by autopsy from 1962 to 2012 in Beijing Hospital. Results: In patients with pulmonary embolism diagnosed by autopsy, 32.6% of the emboli came from deep veins of the lower extremities, 9.3% from the renal vein, 9.3% from the prostate sinus, 7.0% from the venous plexus around the prostate, 7.0% from the hepatic vein and 7.0% from the submucosal vein of the bladder. Other sources included the right atrium 4.7%, portal vein 4.7%, pancreatic peripheral vein 4.7%, prostate, heart, esophageal vein 4.7%, right common iliac vein 2.3%, right upper limb brachial vein 2.3%. No source of emboli was found in 4.7% patients with pulmonary embolism. Non-lower extremity deep vein emboli accounted for 60.5%. Only 9.3% of the cases were diagnosed with pulmonary embolism with deep vein thrombosis before death. Conclusion: There was a wide range of sources of emboli in patients with pathologically proven pulmonary embolism. Although the deep veins of lower extremities are the most common, more than 60% of the emboli came from the renal vein, prostate vein, hepatic vein and other abdominal or pelvic veins, the heart, and the upper extremity deep veins. In addition to the lower extremity deep veins, other sources of emboli should be actively examined when the patient was diagnosed with acute pulmonary embolism. PMID- 29429213 TI - [Effect of acidic oligosaccharides on P-selectin of pulmonary hypertensive rats induced by monocrotaline]. AB - Objective: To observe the effects of acidic oligosaccharides (AOS) on P-selectin levels in the serum and the pulmonary arteries of pulmonary hypertensive rats induced by monocrotaline. Methods: Sixty healthy adult male Sprague-Dawley rats were randomly divided into control group (n=10), model group (n=10), Alprostadil group (n=10), low-dose AOS group (AOS-L, n=10), medium-dose AOS group (AOS-M, n=10) and high-dose AOS group (AOS-H, n=10). The rat model of pulmonary arterial hypertension was made by a single intraperitoneal injection of monocrotaline(60 mg/kg). Five weeks after injection, pulmonary arterial (PA) acceleration time (PAT) and ejection time (ET) were measured by color Doppler ultrasound. Then, the Alprostadil group was treated by Alprostadil 5 MUg.kg(-1).d(-1)intraperitoneally. Acidic oligosaccharides was administered by intraperitoneal injection to rats in the AOS-L group(5 kg(-1).d(-1)), AOS-M group (10 mg.kg(-1).d(-1))and AOS-H group (20 mg.kg(-1).d(-1)). Control group and model group were given normal saline instead. At the end of experiments, the death rate was recorded and PAT/ET was measured. We calculated the right ventricular hypertrophy index (RVHI) of all rats sacrificed under anesthesia. Precision-cut lung slices were stained with HE for observation of the structure of middle and small arteries. The expression level of P-selectin in serum and pulmonary arterial tissues were detected by ELISA and Western blot respectively. Results: AOS significantly increased the level of PAT/ET (P<0.01), and attenuated RVHI (P<0.01). AOS significantly improved intima-media proliferation in small-to medium-sized pulmonary arteries, and attenuated perivascular inflammation. AOS and Alprostadil significantly down regulated the protein expression of P-selectin in serum and pulmonary arteries (P<0.01). Conclusion: In this rat model of monocrotaline-induced pulmonary hypertension, AOS decreased the expressions of P-selectin in serum and pulmonary arteries in a dose-dependent manner. PMID- 29429214 TI - [Correlation between N-terminal probrainnatriuretic peptide and prognosis of acute exacerbations of chronic obstructive pulmonary disease]. AB - Objective: To evaluate the correlation between N-terminal probrainnatriuretic peptide (NT-proBNP) and the prognosis of death in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease(COPD). Methods: A cohort study of 169 patients with acute exacerbations COPD. According to the age and NT-proBNP value measured on admission, cases were divided into 3 groups. The risk ratio of mortality among the three group were analyzed. Results: Thirty-two patients died within 1 year. There are 93 cases in group A (NT-proBNP < 300 ng/L), 45 cases in group B (aged 75 and below with NT-proBNP 300-900 ng/L, older than 75 with NT-proBNP 300-1 800 ng/L), 31 cases in group C (aged 75 and below with NT-proBNP>900 ng/L, older than 75 with NT-proBNP>1 800 ng/L); The in hospital mortalities were 3.2%, 11.1% and 32.3%respectively, and mortalities within a year were 5.4%, 17.8% and 61.3% . The risk ratio (RR) and 95%CI for dying in hospital of group C to group A and B were 10.00 (3.61-56.50) and 2.90 (1.15-12.60), RR and 95%CI for dying within 1 years after hospitalization were 11.40 (8.78-88.46) and 3.45 (2.56-20.97, P<0.05). Conclusion: The NT-proBNP values measured at admission were associated with the short-term and long-term prognosis of patients with AECOPD. PMID- 29429215 TI - [A clinican linical analysis of 29 cases of chronic pulmonary aspergillosis]. AB - Objective: To improve the understanding of chronic pulmonary aspergillosis (CPA) by analyzing the clinical manifestations, imaging and pathological features, diagnosis, treatment and prognosis of this disease. Methods: Cases of CPA, proven by microbiological evidence based on pathological study in Fuzhou General Hospital of the People's Liberation Army and Affiliated Fuzhou City First Hospital of Fijian Medical University from January 2006 to October 2016 were retrospectively analyzed. Results: The patients consisted of 17 males and 12 females, aged 24 to 75 years, mean (42+/-16) years. The underlying disorders included post-tuberculosis infection (n=11), bronchiectasis (n=8), chronic obstructive pulmonary disease (n=3) and diabetes mellitus (n=2). The main clinical symptoms included productive cough (n=25), chronic sputum production (n=18) and hemoptysis (n=15). Serum GM antigen tests were performed in 19 cases, and the result was positive in 12 patients. BALF GM antigen tests were performed in 2 cases, both of which were positive. Chest CT showed that the lesions were located predominantly in the upper lobes (n=24). Single cavity with interior irregular intraluminal material (n=16) and multiple cavities with interior irregular intraluminal material (n=10) were the most frequent CT findings, while the "air crescent sign" was found in 13 cases. In the 22 patients who underwent surgical treatment, Aspergillus filaments were found in the cavity (n=20) or the bronchi (n=2) of lung samples, and histological examination didn't show tissue invasion by fungi. Surgical therapy was performed in 22 patients, with complete remission in 19 cases, and death in 3 cases. Anti-fungal therapy was administered in 6 patients, with partial remission in 4, and stable disease in 2 cases. One patient was not treated. Conclusions: CPA is more frequently seen in patients with underlying chronic pulmonary diseases. The common CT findings are single or multiple cavities with interior irregular intraluminal materials. Aspergillus filament in the cavity or bronchi of lung samples, without parenchymal invasion, is the proof of CPA. The surgical cure rate for simple aspergilloma and aspergillus nodule is high, while the risk of operation for chronic cavitary disease is high. GM antigen test may be an evidence for diagnosing CPA. PMID- 29429216 TI - [Comparison of the efficacies of cross priming amplification and RealAmp with XpertMTB/RIF for the diagnosis of pulmonary tuberculosis at peripheral microscopic center]. AB - Objective: To compare the efficacies of cross priming amplification (CPA) and RealAmp with XpertMTB/RIF for the diagnosis of pulmonary tuberculosis(TB) at peripheral microscopic centers. Methods: From December of 2014 to December of 2015, 3 193 patients suspected with TB were enrolled consecutively at 3 county level TB clinical clinics in Zhongmu, Xinmi and Dengzhou of Henan province. Totally 3 193 collected sputum samples were detected by smear microscopy, L-J media culture, CPA, RealAmp and Xpert MTB/RIF. The culture positive samples were tested by MPB64 for strain identification. The sensitivity and specificity of CPA, RealAmp and Xpert MTB/RIF were calculated according to L-J solid culture results and clinical diagnosis results. Results: The sensitivity of CPA, RealAmp and Xpert MTB/RIF were 85.5%(413/483), 85.5%(413/483) and 87.9%(422/480), respectively, compared with L-J solid culture, the difference among the 3 methods being not significant(chi(2)=1.6, P>0.05). The specificity of CPA, RealAmp and Xpert MTB/RIF were 96.8%(2 624/2 170), 93.2%(2 527/2 170) and 95.3%(2 567/2 170) compared with culture; and there was a significantly statistic difference among the 3 methods(chi(2)=37.8, P<0.001). The sensitivity of smear microscopy, culture, CPA, RealAmp and Xpert MTB/RIF was 21.7%(300/1 383), 34.9%(483/1 383), 34.6%(478/1 383), 39.2%(542/1 383) and 38.1%(526/1 381) compared with clinical diagnosis. The sensitivity of CPA, RealAmp and Xpert MTB/RIF was higher than that of smear (chi(2) =31.9, P<0.01), but there was no significantly statistic difference between the 3 molecular methods(chi(2)=2.9, P>0.05). The specificity of smear microscopy, L-J solid culture, CPA, RealAmp and Xpert MTB/RIF was 100%(1 810/1 810), 100%(1 810/1 810), 98.8%(1 789/1 810), 98.8%(1 756/1 810) and 97.0%(1 788/1 810), and there was no significantly statistic difference among the 3 molecular methods(chi(2)=0.16, P>0.05). Conclusion: The capability of CPA and RealAmp for diagnosing pulmonary TB was similar to Xpert MTB/RIF.The former 2 methods were more suitable to apply to the diagnoses of pulmonary TB in peripheral laboratories. PMID- 29429217 TI - [Phrenic nerve stimulation protects against mechanical ventilation-induced diaphragmatic dysfunction through myogenic regulatory factors]. AB - Objective: To explore the protective effect of electrical stimulation of phrenic nerve on diaphragmatic function during mechanical ventilation. Methods: Forty healthy adult SD rats were randomly divided into 5 groups: blank control group (BC), spontaneous breathing group (SB), electrical stimulation group (ES), mechanical ventilation group (MV), and electrical stimulation and mechanical ventilation group (MS). The rats in each group were treated for 18 h except for the BC group. After treatment, the diaphragm muscle tissue was obtained and the diaphragm contractility including peak-to-peak value(Vpp) and maximum rate of contraction(+ dT/dt max) were measured. Expression of MyoD and myogenin were detected. Results: Except for the ES and the MS groups, there was a significant difference for peak-to-peak value (Vpp) between each 2 groups (P<0.05). Expression levels of MyoD in treatment groups were also significantly different (P<0.05). Expressions of MS(Q-PCR 2(-DeltaDeltaCt) value: 11.66+/-2.80) and MV(Q PCR 2(-DeltaDeltaCt) value: 40.89+/-24.71) in the treatment group were significantly different (P<0.05). The expression of myogenin in the MS and the MV groups were significantly different from those of the BC group(P<0.05), however there was no significant difference between the MS(Q-PCR 2(-DeltaDeltaCt) value: 2.58+/-2.75) and the MV group(Q-PCR 2(-DeltaDeltaCt) value: 1.63+/-0.71). Conclusions: Electrical stimulation of the phrenic nerve can change the expression level of MyoD and myogenin to offset mechanical ventilation induced diaphragmatic function damage, and therefore plays a protective effect on the diaphragm. PMID- 29429218 TI - [Recent advances of growth factor in the pathogenesis of pulmonary arterial hypertension]. PMID- 29429219 TI - [Malignancy related thrombotic microangiopathies and one special type of pulmonary tumor thrombotic microangiopathy]. PMID- 29429220 TI - [Influential factors and application value of pulmonary function in patients with bronchiectasis]. PMID- 29429221 TI - [Advances in the mechanisms of targeted therapy resistance in non-small-cell lung cancer harboring ALK fusion gene]. PMID- 29429222 TI - [The application of high-flow nasal cannula therapy in respiratory sleep diseases]. PMID- 29429223 TI - [Neck lymphatic metastasis, surgical methods and prognosis in early tongue squamous cell carcinoma]. AB - Objective: To investigate the different pattern of neck lymph node metastasis, the choice of surgical methods and prognosis in early tongue squamous cell carcinoma. Methods: A total of 157 patients with early oral tongue squamous cell carcinoma were included in this study. Statistical analysis was performed to identify the pattern of lymph node metastasis, to determine the best surgical procedure and to analyze the prognosis. Results: The occurrence of cervical lymph node metastasis rate was 31%(48/157). Neck lymphatic metastasis was significantly related to tumor size (P=0.026) and histology differentiation type (P=0.022). The rate of metastasis was highest in level II [33% (16/48)]. In level IV, the incidence of lymph node metastasis was 5%(7/157), and there was no skip metastases. The possibility of level IV metastasis was higher, when level II (P=0.000) or III (P=0.000) involved. The differentiation tumor recurrence, neck lymphatic metastasis and adjuvant radiotherapy were prognostic factors (P<0.05). Multivariate analyses revealed histology differentiation type, neck lymphatic metastases and adjuvant radiotherapy were the independent prognostic factors. Conclusions: Neck lymphatic metastasis rate is high in early tongue squamous cell carcinoma, simultaneous glossectomy and neck dissection should be performed. Level IV metastasis rate is extremely low, so supraomohyoid neck dissection is sufficient for most of the time. The histology differentiation type, neck lymphatic metastasis and adjuvant radiotherapy are independent prognostic factors. PMID- 29429224 TI - [Correlation of perceptive temperature threshold of oral mucosa and sympathetic skin response]. AB - Objectives: To explore the critical values of temperature perception in various mucosa sites of oral cavity and to draw the perceptive temperature threshold maps in healthy volunteers. To observe the interrelationship between subjective cognitive perception and sympathetic skin response (SSR) under various levels of thermal stimuli. Methods: Forty-two healthy volunteers (recruited from the students of Tianjin Medical University, 16 females and 26 males) were enrolled in the present study. The whole oral mucosa of each subject was divided into multiple partitions according to the mucosa type as well as tooth position. Peltier patch (commodity name) semiconductor chip was placed in the central part of each subarea of the mucosa. The stimulus was increased or decreased at 1 C each time from a baseline temperature of 37 C. Warm (WT) and cold (CT) perception thresholds were measured thereafter respectively. A topographic temperature map of the oral mucosa for each subject was drew. Furthermore, the SSR was elicited and recorded at three temperature levels of 50 C, 55 C, 60 C respectively. Analog test with visual analogue scale (VAS) and McGill scales were also performed. Data were statistically analyzed with variance and generalized estimation equation. Results: The tip of the tongue was the most sensitive area with both WT [(38.8+/ 2.1) C, P<0.05] and CT [(23.5+/-4.2) C, P<0.05]. The highest heat threshold of gingival mucosa was in the left lower posterior teeth area [(49.9+/-3.7) C, P<0.05], and the highest cold threshold of gingival mucosa was in the left upper posterior teeth area [(15.9+/-5.5) C, P<0.05]. The perceptive temperature threshold increased gradually from the midline to both left and right sides were observed symmetrically and bilaterally. There was no statistically significant differences in temperature perception threshold between males and females [WT, male (44.8+/-3.1) C, female (44.8+/-3.2) C, OR=1.100, P=0.930; CT, Male (18.4+/ 4.9) C, female (20.8+/-4.8) C, OR=0.157, P=0.210]. The SSR amplitude at sites of the tongue tip and the lower lip were increased with the rise of temperature [tongue tip (4.58+/-4.04) mv, P<0.05, lower lip (2.89+/-3.01) mv, P<0.05]. However, SSR amplitude values had no significant differences between males and females [tongue tip, male (2.00+/-2.16) mv, female (1.89+/-1.20) mv, P=0.890; lower lip, male (0.94+/-0.82) mv, female (0.85+/-0.68) mv, P=0.887]. Nevertheless, the amplitude of SSR and the VAS score of subjects showed a similar trend. Conclusions: The temperature perception levels were different amongst sites of lip, buccal mucosa, tongue dorsal mucosa and gingival mucosa. SSR amplitude values could reflect the responses of the mouth to the thermal stimuli. PMID- 29429225 TI - [Development of a novel absorbable nanofiber chitosan-collagen membrane by electrospinning and the preliminary study on guided bone regeneration]. AB - Objective: To evaluate the application effect of nanofiber chitosan-collagen membrane (NCM) on guided bone regeneration (GBR). Methods: The mixture of collagen, chitosan, polyethylene oxide was used to make up the NCM by electrospinning, then the NCM was crosslinked by glutaraldehyde vapor. The physical property of the NCM was measured by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). MC3T3-E1 osteoblasts were cultured on NCM to characterize the biocompatibility. The effectiveness of four groups [contrast group, Bio-gide membrane (BGM), compressed chitosan-collagen menbrane (CCM), NCM/CCM] on bone regeneration were evaluated in critical-sized defects (diameter=5 mm) in SD rats. Results: When the mixed solution consists of 4.0% collagen, 1.0% chitosan and 3.5% polyethylene oxide, the NCM could be validly fabricated by electrospinning. After cross-linking by glutaraldehyde vapor, the tensile strength and the stability of NCM in damp was enhanced. No cytotoxicity of the NCM was detected on MC3T3-E1 osteoblasts. In vivo study showed that the new bone regeneration ratio of NCM/CCM group was [(43.10+/ 1.49)%], and this was similar to that of the group of BGM [(41.36+/-2.60)%] (P>0.05), but higher than that of the CCM group [(33.10+/-1.41)%] and the contrast group [(7.22+/-2.46)%] (P<0.05). Conclusions: The NCM can promote new bone regeneration effectively in GBR procedure. PMID- 29429226 TI - [Effect of low dose aspirin on osseointegration around titanium implants in osteoporotic rats]. AB - Objective: To investigate the effect of aspirin on osseointegration around titanium implants in ostoeporotic rats and to provide evidence for future researches and clinical application. Methods: A total of 60 female SD rats, aged 3-4 months, were divided into ovariectomy group (Ovx group, n=48) and sham ovariectomy group (Sham group, n=12). The rats in Ovx group received ovariectomy and those in Sham group underwent sham-ovariectomy. Twelve weeks later, six rats in each group were randomly selected to confirm the osteoporosis models. The Ovx group was divided into 4 subgroups with 12 rats in each group, namely the osteoporosis group (OP group), and Aspirin groups (A1, A2, A3 group). Pure screw titanium implants were placed in the right tibia near metaphysis of all rats. Three days after implant surgery, aspirin groups were intragastrically administered aspirin at a dose of 2.06, 4.11, 8.21 mg.kg(-1).d(-1) (A1, A2, A3), and OP group and Sham group were fed the same amount of normal saline. Four and 12 weeks following implantations surgery, half of the rats in each group were randomly chosen and sacrificed. Implant bone contact rate (IBCR), combined bone lamella width (CBLW) and trabercular width (TW) were observed and calculated using histomorphometric measurement. Results: Four weeks after implantations surgery, the TW and CBLW of rats in A1 group [(39.60+/-2.77) and (27.56+/-4.14) MUm] and the IBCR, TW and CBLW of rats in A2 group and A3 group [A2: (47.21+/ 4.19)%, (48.74+/-3.20) and (35.91+/-3.79) MUm; A3: (47.35+/-6.07)%, (50.27+/ 5.25) and (40.66+/-2.11) MUm] were much higher than those in OP group [(33.89+/ 7.17)%, (32.20+/-6.10) and (19.77+/-6.80) MUm](P<0.05). In term of CBLW, there were no difference between A3 group and Sham group [(46.11+/-5.87) MUm](P>0.05). Twelve weeks after implantations surgery, the IBCR and CBLW of rats in A1 group [ (85.86+/-3.64) %, (53.12+/-8.68) MUm], and the IBCR, TW and CBLW of rats in A2 group and A3 group [A2: (85.64+/-3.97)%, (69.42+/-6.78) and (54.19+/-3.12) MUm; A3: (86.22+/-3.48)%, (75.43+/-3.50) and (55.79+/-5.60) MUm] were much higher than those in OP group [(77.20+/-7.14)%, (55.10+/-2.26) and (41.77+/-3.13) MUm](P<0.05). In term of IBCR, there were no difference among A1 group, A2 group, A3 group and Sham group [(90.09+/-2.21)%](P>0.05). Conclusions: The low dose aspirin could promote IBCR, CBLW and TW of osteoporotic rats implants. PMID- 29429227 TI - [Effect of nerve growth factor on osteogenic potential of type 2 diabetic mice bone marrow stromal cell in vitro]. AB - Objective: To study the effects of nerve growth factor (NGF) on the proliferation, osteogenic differentiation and mineralization of type 2 diabetic mice bone marrow stromal cell (BMSC), providing basis for clinical application of NGF. Methods: Three 8-week-old male db/db mice and two 8-week-old male C57BL/6J mice were used in the study. BMSC derived from femur were cultured though adherence method. BMSC of C57BL/6J mice and db/db mice was divided into normal group and diabetic group to conduct the osteogenic potential experiment, named experiment one. In experiment two, diabetic BMSC was divided into 3 groups: diabetic control group, NGF group, and K252a+NGF group [K252a was the inhibitor of tyrosine kinase A (TrkA), which was the high affinity receptor of NGF], to investigate effect of NGF on osteogenic potential of diabetic mice BMSC. After seeding BMSC, K252a was added into K252a+NGF group, then NGF was added 30 min later. NGF was added into NGF group and K252a+NGF group, but not diabetic control group. The proliferation of BMSC at 1, 3, 5 and 7 d in experiment one and the proliferation of BMSC at 1, 2 and 3 d in experiment two were evaluated through methyl thiazolyl tetrazolium, and the level of alkaline phosphatase (ALP) at 3, 5 and 7 d in both experiments were measured. After being osteogenic induced for 14 d, mineralized nodules in both experiments were quantitated by alizarin red calcium stain. Five holes were set in every group, and all experiments were repeated 3 times. Results: The BMSC proliferation of diabetic group was significantly higher than that of the normal group at 3, 5 and 7 d (P<0.05). After being osteogenic inducted for 3, 5 and 7 d, ALP level of diabetic group were significantly lower than that of normal group (P<0.05). After being osteogenic inducted for 14 d, calcium nodule count of diabetic group [(23.1+/ 6.4) nodule/field] were significantly lower than that of normal group [(36.9+/ 7.9) nodule/field](P<0.05). At 1, 2 and 3 d, BMSC proliferations of diabetic control group, NGF group and K252a+NGF group were not statistically different (P>0.05). After being osteogenic inducted for 3 and 5 d, ALP level of NGF group was significantly higher than that of diabetic control group (P<0.05). After being osteogenic inducted for 3, 5, and 7 d, ALP level of K252a+NGF group was significantly lower than that of NGF group (P<0.05) and diabetic control group (P<0.05). After being osteogenic induced for 14 d, calcium nodule count of NGF group [(45.2+/-6.8) nodule/field] was significantly more than that of diabetic control group [(23.1+/-6.4) nodule/field](P<0.05); while calcium nodule count of K252a+NGF group [(18.0+/-4.5) nodule/field] was significantly less than that of NGF group (P<0.05) and diabetic control group (P<0.05). Conclusions: The differentiation and mineralization of type 2 diabetic mice BMSC was significantly reduced. NGF promoted the osteoblastic differentiation and mineralization of diabetic mice BMSC in viro though combining with TrkA. PMID- 29429228 TI - [Clinical retrospective study of navigation guided impacted maxillary supernumerary tooth extraction]. AB - Objective: To analyze the efficiency and safety of navigation guided extraction of impacted supernumerary tooth. Methods: Twenty-five cases of navigation guided supernumerary tooth extraction and 25 cases of non-navigation guided supernumerary tooth extraction (control group) were included in the study. Each group had 3 cases with one impacted supernumerary tooth and 22 cases with two impacted teeth. Results: Preoperative navigation system designing time was (45.0+/-8.0) min in average. Navigation system installation time was (15.0+/-2.8) min. The average operation time was (0.64+/-0.08) hour in navigation group and (0.91+/-0.09) hour in control group. Conclusions: Navigation guided extraction of impacted supernumerary tooth takes less time for operation but more time for the preoperative navigation system design. PMID- 29429229 TI - [Analysis of adverse reaction induced by articaine hydrochloride and epinephrine tartrate injection in 75 cases]. AB - Objective: To investigate the causes and clinical manifestation of adverse reaction of articaine hydrochloride and epinephrine tartrate injection. Methods: A retrospective analysis was conducted on the adverse drug reactions (ADR) of local anesthetic articaine hydrochloride and epinephrine tartrate injection. Results: In 75 cases of adverse reactions, there were 40 cases of female and 35 cases of male. Adverse reactions occured more frequently at the age of 3-10 [33% (25/75)] and 1-10 min and one day after injection, respectively accounting for 20% (15/75), and two days, accounting for 15% (15/75), 10-21 days accounting for 8% (6/75). The main manifestations were injection site ulcers, followed by skin reactions such as pain, swelling, necrosis and pruritus at the injection site. Conclusions: The main adverse reactions of articaine hydrochloride and epinephrine tartrate injection are the injection site ulceration, followed by injection site pain, rash, pruritus and drowsiness, nausea and dizziness, palpitations, sweat and hypotension. Doctors should ask the medical history in detail and pay close attention to the patient's medication safety. PMID- 29429230 TI - [Effects of different concentrations of MgSiF(6) as electrolyte for micro-arc oxidation on the bond strength between titanium and porcelain]. AB - Objective: To investigate the effects of different concentrations of MgSiF(6) as electrolyte on the bond strength between titanium and porcelain after micro-arc oxidation (MAO) treatment and screen the suitable concentration of MgSiF(6) that can improve the bond strength between titanium and porcelain. Methods: Four different concentrations of MgSiF(6) (10, 20, 30, 40 g/L) were chosen as MAO reaction solutions. Sandblasting treatment was selected as a control group. After porcelain was fused to each specimen, titanium-porcelain bond strengths were evaluated by the three-point bending test according to ISO 9693. Scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS) were adopted to evaluate the morphologies and elemental compositions of both the MAO coatings and the interfaces of the titanium-porcelain restoration. Results: The surface of titanium specimen in the control group was sharp and rough, while specimens in both 10 g/L group and 20 g/L group were porous and homogeneous. However, the pores found on the specimens in the latter group were larger in diameter (approximately 1.0-2.0 MUm) than those on the former one (0.2-0.5 MUm). The bond strengths of the control group and the experimental groups (10, 20, 30, 40 g/L MgSiF(6)) were (27.08+/-3.16), (38.18+/-2.65), (44.75+/-2.21), (36.44+/-2.04), (31.04+/-2.59) MPa, respectively. All the experimental groups showed higher bond strengths than the control group did (P<0.05), and the bond strength of 20 g/L MgSiF(6) group was significantly higher than those of the other groups (P<0.05). Besides, the interfaces between titanium and porcelain were tight and compact in the 20 g/L group, while different amounts of pores and cracks were visible in the other groups. Additionally, after the three-point bending test, few residual porcelains could be observed on the surfaces of specimens in the control group. Conclusions: MAO treatment with 20 g/L MgSiF(6) on titanium can improve bonding strength between titanium and porcelain. PMID- 29429231 TI - [Combined periodontal-orthodontic treatment and nine-year follow-up of a patient with generalized aggressive periodontitis: a case report]. PMID- 29429232 TI - [Reconstruction of orbital defect with craniomaxillofacial implant]. AB - To evaluate the clinical results of reconstruction orbital defect with craniomaxillofacial implant. Three patients with orbital defect were treated with ten implants. The magnetic abutments were attached six months after one stage operation and the prostheses were fabricated. Within 11 to 47 months of follow up, all implants were stable with successful osseointegration. The prosthesis fit the orbital defects well. Reconstruction of orbital defect with craniomaxillofacial implant can be considered as a viable alternative treatment. PMID- 29429233 TI - [Clinical application of vacuum sealing drainage combined with chymotrypsin in the treatment of post-traumatic mandibular osteomyelitis]. AB - This article introduces the combined application of vacuum sealing drainage (VSD) and chymotrypsin in the treatment of post-operative mandibular osteomyelitis. The lesion was washed by chymotrypsin (4000U) and saline (500 ml). VSD is effective in the treatment of traumatic mandibular osteomyelitis. This study investigates the effect of VSD combined with chymotrypsin in the treatment of patients with osteomyelitis after mandibular trauma. It is proved that it has a good effect in ensuring drainage, controlling infection and retaining internal fixation, and can create a good environment for fracture healing. PMID- 29429234 TI - [Mandibular intraosseous lipoma: a case report]. PMID- 29429235 TI - [Primary mandibular meningioma: a case report]. PMID- 29429236 TI - [The complications, prevention and treatment of sinus floor elevation through lateral window approach]. AB - Several systematic reviews and many clinical articles have shown that maxillary sinus floor elevation through lateral window approach (LSFE) is a predictable and reliable procedure, which has been routinely performed for more than 30 years. The complication rate is low, but some cases may require additional surgery, and the outcome of implant may be affected if not treated properly. The survival rates of implants are still high after early diagnosis and proper early treatments. The purpose of this article is to discuss the intraoperative and postoperative complications of LSFE, including perforation, bleeding, postoperative infection and implant displacement into sinus with special attention to prevalence rate, prevention and treatment. PMID- 29429237 TI - [Advances in the p75 neurotrophic factor receptor in stomatology]. AB - The p75 neurotrophic factor receptor is a low affinity receptor for neurotrophic factors and plays an important role in nerve growth, development and function integrity. It is closely related to dental development, oral and maxillofacial tumor, nerve repair and tissue engineering. It shows good prospect for application. In this paper, the research progress of p75 neurotrophic factor receptor in Stomatology is reviewed. PMID- 29429238 TI - [Research status of tooth preparation quantitative guide technique]. AB - Tooth preparation is a basic operation in prosthodontics treatment and the quality of preparation influences the effect of treatment directly. How to achieve a precise and quantitative tooth preparation is always one of the main aims of dental prosthodontics. The known types of tooth preparation guide technique can be divided into visual guidance, passive constraint guidance and active constraint guidance (automated tooth preparation), respectively represented by silicon rubber index, tooth preparation guide plate and computerized numerical control cutting system (CNC cutting system). Studies in advanced manufacturing technologies such as robot systems and numerical control ultra-short pulse laser (USPL) have also been reported recently. This review comprehensively introduced tooth preparation quantitative guide techniques and partially summarized the application effects and limitations to provide reference for relative researches and clinical application. PMID- 29429240 TI - [Current status and prospects of glioma immune escape and countermeasure strategies]. PMID- 29429239 TI - [Research progress in CoCr metal-ceramic alloy fabricated by selective laser melting]. AB - Cobalt-chromium alloys have been applied to dental porcelain fused to metal (PFM) restorations over the past decades owing to their excellent corrosion resistance, good biocompatibility and low price. The production of CoCr metal-ceramic restorations has always been based on traditional lost-wax casting techniques. However, in recent years, selective laser melting (SLM) is becoming more and more highly valued by dental laboratories and dental practitioners due to its individuation, precision and efficiency. This paper mainly reviews the recent researches on the production process of copings, microstructure, mechanical property, metal-ceramic bond strength, fit of copings, corrosion resistance and biocompatibility of SLM CoCr metal-ceramic alloy. PMID- 29429241 TI - [Prognostic significance of neoplastic central nervous system tumor classification for patients with low grade glioma]. AB - Objective: To explore the prognostic impact of 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors on patients with low grade gliomas (LGG). Methods: A total of 482 patients diagnosed with LGG in Beijing Tiantan Hospital affiliated to Capital Medical University from January 2009 to May 2016 were pathologically reclassified and retrospectively reviewed. In the survival analysis, Kaplan-Meier Plot was used to univariate analysis and Cox proportional hazards model was used to multivariate analysis. Results: According to the 2016 WHO CNS criterion, a total of 232 LGG were reclassified as O 1p/19q-deleted and IDH-mutant, 134 as A IDH-mutant and 116 as A IDH-wildtype. Univariate analysis showed that 2016 WHO CNS divided LGG into three subgroups with distinct survival (P<0.001). Multivariate analysis showed that both 2007 WHO CNS and 2016 WHO CNS were independent prognostic factors, but the Hazard ratio (HR) of 2016 WHO CNS was significantly higher than that of 2007 WHO CNS (P<0.01). Conclusions: 2016 WHO CNS classification criteria can divide LGG into three subgroups with significantly distinct survival, which has further improved the clinical prognostic value of it and fully reflected its advantages in predicting prognosis. PMID- 29429242 TI - [The changes of plasma coagulation function in patients with glioma and its correlation with malignant grade of glioma]. AB - Objective: To investigate the changes of activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time(TT), fibrinogen(FIB) and platelet counts(PLT) in plasma of patients with glioma, and to explore the correlations between PT, APTT, TT, FIB and PLT with malignant grades of glioma. Methods: One hundred and seventy-two patients with glioma and 47 health controls were investigated in a retrospective analysis. All patients were diagnosed and identified the WHO grade by pathologist after operation. Including 40 cases with glioblastoma multiforme, WHO IV grade, 45 cases with anaplastic astrocytoma, WHO III grade, 46 cases with astrocytoma and oligodendroglia astrocytoma, WHO II grade, and 41 cases with pilocytic astrocytoma. Results: PT was significantly shorter in patients with WHO I-IV grade glioma than that in normal controls (P<0.05); APTT was significantly shorter in patients with WHO III and IV grade glioma than that in normal controls and WHO I grade glioma patients (P<0.05); FIB of WHO IV grade glioma was higher than that in normal control and WHO I to III grade glioma (P<0.05). While, there was no significant difference of TT and PLT among patients with WHO I to IV and normal controls (P>0.05). Spearman correlation analysis showed that there was negative correlation between APTT and WHO grade (r=-0.200, P=0.007) as well as positive correlation between FIB and WHO grade (r=0.175, P=0.020); Pearson linear correlation analysis showed that there was negative correlation between APTT and Ki67 in patients with glioma. Conclusions: the levels of FIB and APTT in patients with glioma were correlated with WHO grade of glioma, and higher FIB, shorter APTT and PT in patients with WHO IV grade glioma indicated that there exist hypercoagulation states. PMID- 29429243 TI - [Experimental studies on correlation between nucleolus spindle-related protein 1 and the malignant progression and prognosis of human glioblastoma multiforme]. AB - Objective: To investigate the correlation between nucleolus spindle-related protein 1 (NUSAP1) and malignant progression and prognosis of human glioblastoma multiforme (GBM). Methods: RT-PCR and immunohistochemical technique were applied to analyze NUSAP1 expression level in GBM surgical specimens. Correlations between NUSAP1 expression and molecular classification and survival of patients with GBM were also investigated in TCGA database. The gene silencing technique was used to silence NUSAP1 expression in U87 cells, CCK-8 assay was used to detect cell proliferation, flow cytometry was used to detect cell cycle changes, and in vivo tumorigenicity was evaluated after NUSAP1 silencing in tumor-bearing mice. Results: NUSAP1 expression level in GBM was higher than that in non-tumor brain tissue. Survival curve analysis showed that the survival time of GBM patients with high NUSAP1 expression decreased significantly (P<0.01). NUSAP1 expression was relatively lower in mesenchymal and neural molecular subtypes of GBM, when compared with the other two molecular subtypes. And it was closely related with specific genetic aberrations (such as PTEN loss and IDH1 mutation). Silencing NUSAP1 inhibited G2/M cell cycle progression of GBM cells, and inhibited cell proliferation both in vitro and in vivo. Conclusion: Expression of NUSAP1 is closely related to progress and prognosis of GBM, and can be a biomarker reflecting GBM prognosis and act as a therapeutic target with potential clinical application value. PMID- 29429244 TI - [Assessment of renal function with intravoxel incoherent motion and diffusion tensor imaging in type 2 diabetic patients]. AB - Objective: To evaluate the application value of intravoxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) in detecting early-stage diabetic nephropathy and to assess the damage of ralated renal function. Methods: A total of 52 patients with type 2 diabetes diagnosed in Zhongda Hospital were collected from April 2016 to May 2017 and were assigned to DM group (diabetes without nephropathy, n=32) and DN group (diabetes with nephropathy, n=20) according to detection of microalbuminuria, a cohort of healthy recipients were included as control group (n=27) in the meantime. All of the subjects underwent IVIM and DTI examination. The cortical and medullary parameters[IVIM: perfusion fraction f, tissue diffusivity D, pseudodiffuvisity D(*;) DTI: fractional anisotropy FA, apparent diffusion coefficient ADC, principal diffusivities (lambda1, lambda2, lambda3)]were obtained respectively and were compared among groups. The relationship between MRI related parameters and estimated glomerular filtration rate (eGFR) were statistically investigated; and diagnostic performance of IVIM and DTI in discriminating DM and DN group was evaluated by receiver operating characteristic analysis. Results: The cortical and medullary f, D values in DN group were lower than those in DM group and control group (F=17.32, 15.69, 6.71, 10.94, all P<0.05). D values of all subjects showed positive correlations with eGFR (cortex r=0.518, medulla r=0.538, both P<0.05). The diagnostic efficiency of cortical f values to discriminate diabetes and diabetic nephropathy was 0.817, the cut-off value was 0.205. The medullary FA value in DM group was lower than that in control group ((0.371+/-0.051 vs 0.423+/-0.043, t=4.188, P<0.05); and the medullary FA value in DN group (0.315+/-0.062) was lower than that in control and DM group (F=25.08, P<0.05). The medullary lambda3 values in DM group and DN group were all significantly higher than that in control group (F=7.86, P<0.05). The diagnostic efficiency of medullary FA values to discriminate diabetes and diabetic nephropathy was 0.763, the cut-off value was 0.344. Conclusion: IVIM and DTI can reflect the abnormal perfusion and diffusion during early-stage diabetic nephropathy and have the potential value to assess the damage of ralated renal function. PMID- 29429245 TI - [Effects of expanded anterolateral approach for tibial plateau fractures involved the posterolateral column]. AB - Objective: To explore the short-term effects of expanded anterolateral approach in treating fracture involved the posterolateral tibial plateau. Methods: A retrospective analysis of the clinical data from 16 patients undergoing extended anterolateral approach for fracture involved the posterolateral tibial plateau in the First Affiliated Hospital of Wannan Medical College between January 2013 and July 2016 was done. The patients were treated with 3.5 mm proximal "L" type proximal tibial locking compression plate with four locking screws through the nail row technique. The X-rays examinations were carried out immediately after the operation and at 1.5, 3, 6, and 12 months later, to continuously measure the tibial plateau angle (TPA) and posterior slope angle (PA). The Rasmussen radiology score was used to assess the reduction. One year later, the modified Rasmussen knee score was used to assess the recovery of knee function, the Lysholm score was applied to evaluate the cartilage injury, softening and degeneration, and lateral stress test and dial test were carried out to evaluate the stability of the knee. Results: The group consisted of 11 males and 5 females; aged 25 to 71 years, mean (47+/-12) years; schatzker type II 9 cases, type V 6 cases and type VI 1 case. There were 9 cases of type B in Orthopedic Trauma Association (OTA) classification, and 7 cases of type C. X-ray was immediately performed after operation and it showed that 14 cases got anatomic reduction, 2 cases left<2 mm of steps. Rasmussen radiology score was 14 to 18 points, mean (17.0+/-1.5) points. X-ray examination showed no significant difference in TPA immediately after operation and 1.5, 3, 6, 12 months later (F=0.05, P=0.99), and there was no significant difference in PA among the time points (F=0.02, P=1.00). At one-year of follow-up, the modified Rasmussen knee score ranged from 18 to 29 with an average of (25.0+/-3.3) points, of which 7 were excellent, 8 were good and 1 was fair. The excellent and good rate was 93.75%. Knee range of motion was 110 degrees -135 degrees with a mean of (122+/ 8) degrees . Lysholm score was 93+/-4. Evaluation of lateral stress test and dial test were both negative. Conclusions: The short-term curative effect of expanded anterolateral approach in treating fracture involved the posterolateral tibial plateau with the 3.5 mm proximal "L" type proximal tibial locking compression plate proximal to the locking screw is satisfactory, it provides sufficient exposure and effective fixation, the joint function and stability are satisfying. PMID- 29429246 TI - [Comparative study of proximal femoral nail anti-rotation and dynamic hip screw in the unstable intertrochanteric fractures in the elderly]. AB - Objective: To compare the effect of proximal femoral nail anti-rotation and dynamic hip screw in treating the femoral intertrochanteric fractures in elderly patients. Methods: From June 2011 to June 2014, totally 158 elderly patients of femoral intertrochanteric fracture were treated by surgery, among whom 68 cases were treated with dynamic hip screws (DHS), and 90 patients were treated with proximal femoral nail anti-rotation (PFNA). The operative time, hospitalization time, weight-bearing time, fracture-healing time, blood loss and the hip function score after the operation were compared between the two groups by using the t test; and the incidence of the postoperative complication was compared between the two groups by using the Chi square test. Results: All the patients were followed-up for 6 to 18 months (12. 6 months on average). There was no statistic differences in the gender, age, the surgical time after injury and the fracture type between the two groups (chi(2)=0.025, t=1.461, 1.329, chi(2)=2.070, all P>0.05). While, the operative time, blood loss, hospitalization time and the weight-bearing time in the PFNA group were all significantly lower than those in the DHS group[(47+/-14) vs (114+/-20) min, (121+/-26) vs (281+/-44) ml, (10.2+/ 3.3) vs (13.5+/-2.8) d, (29+/-8) vs (53+/-10) d, t=8.376, 6.669, 2.176, 2.664, all P<0.05]; and the Harris hip score of 6 months post operation in PFNA group was significantly higher than that in the DHS group (90+/-17 vs 87+/-15, t=2.337, P<0.05). However, no significant difference in fracture healing time was found between the two groups[(11.8+/-2.3) vs (12.2+/-2.7) weeks, t=1.114, P>0.05]. Moreover, the incidence of complications in the DHS group was 16.2% while it was 7.8% in the PFNA group, the latter was obviously lower (chi(2)=4.801, P<0.05). Conclusions: DHS is suitable for the patients with good physical condition or for the patients with stable fracture types. While, PFNA has the advantages of firmly fixation, less tissue damage, lower complications and wide indications. So, it is superior in the femoral intertrochanteric fractures. PMID- 29429247 TI - [Clinical research on acute paraplegia resulting from intrathecal chemotherapy]. AB - Objective: To investigate the potential pathogenesis of acute paraplegia resulting from intrathecal chemotherapy and to analyze the factors influencing prognosis. Methods: Six cases presented with acute paraplegia after intrathecal chemotherapy for leukemia from January 1(st,) 2015 to June 1(st,) 2017 in our hospital. The patients' clinical manifestation, data of imaging and cerebrospinal fluid were analyzed. Result: Six patients with leukemia were with an average age of 27.3 (7 to 55) years old. Four cases were intrathecally injected with cytarabine, and two cases were intrathecally injected with cytarabine and methotrexate. Paraplegia occurred in 5 patients during or immediately after the injection; pain occurred in 1 patient immediately after the injection followed with paraplegia 2 h later. Four patients underwent MRI scan of the spinal cord but failed to show responsible lesions. The youngest patient who received the most frequent intrathecal injections, the highest dosage of cytarabine, combination with methotrexate set up the most serious symptoms and the poorest prognosis. Conclusions: Cytarabine has close relationship with the occurrence of paraplegia. The possible risk factors of poor prognosis might be younger age, more frequent injections, higher dosage, combination of cytarabine and methotrexate. PMID- 29429248 TI - [Clinical analysis of multiple myeloma-associated amyloidosis]. AB - Objective: To investigate the clinical features and survival of multiple myeloma associated amyloidosis patients. Methods: Twenty three multiple myeloma associated amyloidosis patients were retrospectively analyzed from January 2009 to December 2016. Results: The overall response rate(ORR)was 65.2% and the remission rate (sCR+ CR) was 21.7%. The median progression-free survival(PFS) was fourteen months(1-63), and the median overall survival(OS)was fifteen months(3 63). The early death rate (death rate within one year)was 33.3%. The median OS of patients(n=9)with the performance status(PS) score >2 was seven months(1-15), and the median OS of patients(n=14)with the PS score <=2 was thirty months(10-63). There was a statistically significant difference in OS(P<0.05); the median PFS and OS of the patients (n=15) who responded to inductive treatment were seventeen months(2-63) and twenty four months (4-63)respectively, and the median PFS and OS of the patients (n=8)who did not respond to inductive treatment were three months(1-8) and eleven months (3-15) respectively. There was a statistically significant difference in PFS and OS(P<0.05). There was a statistically significant difference in PFS and OS between patients treated with remission (n=5)and those who did not(n=18) (P<0.05). Conclusions: The multiple myeloma associated amyloidosis patients had a high early death rate and short survival time. Early identification and effective treatment are the preconditions for improving the poor prognosis. PMID- 29429249 TI - [The roles of IL-17 and CXCR4 in chronic allograft nephropathy in rat models]. AB - Objective: To investigate the role and mechanism of IL-17 and CXCR4 in chronic graft nephropathy (CAN) in rat models. Methods: CAN rat models were established using Fisher 344 to Lewis rats. In the control group(n=10), Lewis rats were performed isotransplantation. CAN rat models were established in experimental group(n=10). All the rats were havested 6 weeks after transplantation. Kidneys were examined by pathology to evaluate the injury of the renal allograft. SDF 1/CXCR4, IL-17 and alpha-SMA expression level in serum and renal graft were detected by immunohistochemical staining and Enzyme-linked immunosorbent assays(ELISA). The percent and the absolute amount of CD4(+) cells,CXCR4(+) cells and IL-17(+) cells were detected by flow cytometry. Results: The graft of the experiment group showed obvious pathological features of CAN. The protein expression levels of SDF-1/CXCR4 and IL-17 in the experiment group are significantly higher than in the control group. We could also observe the number of Th17 cells has a significant increase in the experiment group[blood (0.19+/ 0.05)% vs (0.12+/-0.03)%; kidney (0.52+/-0.21)% vs (0.17+/-0.12)%]. The IL-17 level also showed the same differences between the experiment[blood (243.12+/ 17.63) pg/ml, kidney (521.54+/-21.76) pg/ml]and the control group[blood (35.78+/ 7.3) pg/ml, kidney (77.34+/-11.1) pg/ml]. Conclusions: The Th17 cells increase in the CAN rats model, maybe the SDF-1/CXCR4 has a chemotaxis to collect Th17 cells to the injured kidney. And its expression of IL-17 may promote the renal cells to transform into fibroblasts. PMID- 29429250 TI - [Heparin induced thrombocytopenia should be standaridized for diagnosis and treatment]. PMID- 29429251 TI - [Comparison of the pulmonary function between adolescent patients with Chiari malformation associated scoliosis and idiopathic scoliosis]. AB - Objective: To compare the pulmonary function between adolescent patients with Chiari malformation associated scoliosis (CMS) and adolescent idiopathic scoliosis (AIS). Methods: A retrospective analysis was performed on 52 patients with CMS, and 52 patients with AIS were selected as the control group to match the CMS patients by age, sex, and Cobb angle. Preoperative pulmonary function tests were completed by all the patients, including vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV(1)), maximal mid-expiratory flow (MMEF), and ratio of FEV(1) to FVC. The difference of pulmonary function parameters was analyzed between the two groups; Correlation between pulmonary function and radiographic parameters was analyzed in patients with CMS. Results: There were no significant differences in terms of sex, age, and the main coronal Cobb angle between the two groups. There were 42(80.7%) and 44(84.6%) of patients with restrictive ventilatory dysfunction (the percentage of predicted FVC<80%) in CMS and AIS group respectively. 18(42.8%) and 10 (22.7%) out of these patients were also with obstructive ventilation dysfunction (FEV(1)/FVC<92%) in CMS and AIS group respectively. Types of ventilation dysfunction distributed between the two groups had no significant difference (P>0.05). No significant difference was noted between the two groups in the percentage of predicted VC, FVC, FEV(1) and FEV(1)/FVC (P>0.05). The percentage of predicted MMEF in patients with CMS was lower compared to those with AIS[(57.9+/-13.3)% vs (67.2+/-23.3)%, P=0.053]. In patients with CMS, the percentage of predicted VC, FVC, FEV(1) and MMEF had significantly negative correlation with the number of vertebrae involved (P<0.01). Main coronal Cobb angle had negative correlation with the percentage of predicted VC, FVC and FEV(1) (P<0.05). The percentage of predicted VC, FVC and FEV(1) had positive correlation with thoracic kyphosis (P<0.05). Conclusions: There are no significant differences in characteristics of the pulmonary dysfunction between patients with AIS and CMS without obviously neural deficit. Both groups mainly present with restrictive ventilation dysfunction. PMID- 29429252 TI - [Long-term follow-up of C(1)-C(2) pedicle screw fixation for pediatric atlantoaxial dislocation]. AB - Objective: To investigate the clinical curative effect of C(1)-C(2) pedicle screw fixation for pediatric atlantoaxial dislocation after a long-term follow-up. Methods: From March 2005 to April 2011, a total of 12 male and 9 female patients were included, with age from 3 to 9 years old (mean, 6.1 years old). Among them, 14 cases (67%) had typeIinstability atlantoaxial dislocation, 7 cases (33%) had type II reducible atlantoaxial dislocation. All 21 pediatric patients with atlantoaxial dislocation underwent posterior pedicle screw fixations. Frankel Grade was used to evaluate function before and after treatment. Furthermore, the information of C(1)-C(2) bony fusion, cervical spine alignment, angle of sagittal curvature, and instability of the subaxial spine were collected from all patients preoperatively, immediately postoperatively and during follow-up period. Results: All 21 patients had regular follow-up with an average duration of 96.4 months (range, 65 to 127 months). All children had good bony fusion within 6 months after treatment. There were 9 patients with lordotic alignment and 12 patients with straight alignment before surgery. After surgery, there were 12 patients with lordotic alignment and 9 patients with straight alignment. At the time of the last follow-up, 17 patients had lordotic alignment and 4 patients had straight alignment. No difference was found between pre- and post-operation (P=0.354). The same result was found between post-operation and last follow-up (P=0.095). Neither kyphotic nor swan-neck deformity was found in any of the 21 patients. The mean angle of sagittal curvature decreased from 31.7 degrees +/-4.3 degrees preoperatively to 15.5 degrees +/-2.5 degrees postoperatively (P<0.001). The mean angle of sagittal curvature increased from 15.5 degrees +/-2.5 degrees postoperatively to 19.1 degrees +/-2.7 degrees at the final follow-up (P=0.343). No spinal deformities or subaxial instabilities were found. Of the four patients with preoperative neurological defects, Frankel Grade was significantly improved at 3 months follow-up compared with pretreatment values. None of the patients experienced worsening neurological symptoms or injury to the vertebral artery. Conclusion: The results demonstrate that C(1)-C(2) pedicle screw fixation could achieve satisfactory clinical effects for the management of pediatric atlantoaxial dislocation with long-term follow-up. PMID- 29429253 TI - [Diagnostic significance of serum free DNA human telomerase reverse transcriptase quantitative determination on spinal cord injury]. AB - Objective: To investigate the relationship between the content of human telomerase reverse transcriptase (hTERT) and its clinical features in serum free DNA in patients with different degree of spinal cord injury. Methods: From December 2013 to December 2016, inpatients of the Central Hospital of Bazhong, Sichuan Province were enrolledand divided into the experimental group, the disease control group and the negative control group. For the experimental group: 46 patients with spinal cord injury were graded according to the criteria of the American Association of Spinal Cord Injury (ASIA), including 12 cases of grade A, 10 cases of grade B, 10 cases of grade C, 7 cases of grade D and 7 cases of grade E; for the disease control group: 15 patients with spinal fractures (without spinal cord injury) at the same period were included; and for the negative control group: 20 healthy adult volunteers aged 18-50 years were selected.Real time fluorescence quantitative PCR and immunoblotting were performed to detect the content of hTERT in serum free DNA both in patients and healthy controls and to compare the difference between them. The results of the somatosensory evoked potential (SEP) of all patients were compared and analyzed.The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of hTERT content in serum free DNA in patients with spinal cord injury. Results: Comparison of serum free DNA hTERT content: in the experimental group, the serum free DNA hTERT content of grade A, B, C, D, E was (99.63+/-8.23), (76.24+/-4.37), (46.07+/-5.43), (16.30+/-0.95) and (15.74+/-1.12)MUg/L, respectively.While it was (15.01+/-1.39)MUg/L in the disease control group and (14.54+/-1.03)MUg/L in the negative control group. The total difference was statistically significant between patients of each group and the control group (F=857.917, P<0.001). Comparison of the protein content of TERT: in the experimental group, the protein content of TERT of grade A, B, C, D, E was 0.736+/-0.214, 0.641+/-0.172, 0.606+/ 0.184, 0.411+/-0.132 and 0.307+/-0.152, respectively.The protein content of TERT in the disease control group and the negative control group was about 0.312+/ 0.098 and 0.322+/-0.177, the difference between patients of each group and the control group was statistically significant (F=62.461, P<0.001). Detection results of surface evoked potential (SEP) showed that in the experimental group, level A patients all had conduction block.Two cases of level B patients had conduction block and 8 cases had delayed conduction.Among level C patients, 1 case had conduction block, 9 cases had delayed conduction.Among level D patients and patients from the control group and the negative control group, SEP detection all had no conduction block. Conclusion: The detection of the hTERT content in serum free DNA in patients with spinal cord injury has a certain guiding significance for the diagnosis of spinal cord injury and the degree of injury. PMID- 29429254 TI - [Evaluation of the diagnosis value of carcinoembryonic antigen in malignant pleural effusion]. AB - Objective: To investigate the diagnostic value of serum and pleural fluid carcinoembryonic antigen (CEA) for malignant pleural effusion (MPE). Methods: The concentration of CEA in serum and pleural fluid of 286 patients with the diagnosis confirmed by pleural biopsy through medical thoracoscopy were retrospectively analyzed. MPE was confirmed in 171 cases which were divided into two groups (adenocarcinoma group with 121cases and non-adenocarcinoma group with 50 cases) and benign pleural effusion in 115 cases. The optimal cutoff for MPE and MPE caused by adenocarcinoma were determined by using the ROC curve. Results: The concentration of serum CEA 12.27(3.80, 58.45) MUg/L was significantly higher in MPE caused by adenocarcinoma than that of non-adenocarcinoma 1.91(1.08, 4.55) MUg/L and benign effusion 1.32(0.86, 2.27) MUg/L (both P<0.001), but there was no statistically significant difference between benign and non-adenocarcinoma effusion (P=0.728). The concentration of pleural fluid CEA 160.70(30.48, 1 000.00) MUg/L was significantly higher in MPE caused by adenocarcinoma than that of non-adenocarcinoma 1.77(0.51, 11.39) MUg/L and benign effusion 1.09(0.60, 1.68) MUg/L (both P<0.001), and higher in non-adenocarcinoma effusion than that of benign effusion (P<0.05). The cutoff value of serum and pleural fluid CEA for MPE was 3.10 and 5.83 MUg/L, the sensitivity respectively was 67.3% and 74.3%, the specificity respectively was 87.8% and 98.3%, positive predictive value respectively was 89.2% and 98.5%, negative predictive value respectively was 64.3% and 72.0%. The cutoff value of serum and pleural fluid CEA for MPE caused by adenocarcinoma was 3.54 and 7.30 MUg/L, the sensitivity respectively was 76.0% and 91.7%, the specificity respectively was 74.0% and 72.0%, positive predictive value respectively was 87.6% and 88.8%, negative predictive value respectively was 56.1% and 78.3%. Conclusions: The concentration of serum and pleural fluid CEA have diagnostic significance to MPE, especially MPE caused by adenocarcinoma. The diagnostic value of pleural fluid CEA is superior to serum CEA. PMID- 29429255 TI - [A study of the relations of foramen rotundum structure direction and the approach of percutaneous puncturing of radiofrequency thermocoagulation for treating V2 of primary trigeminal neuralgia]. AB - Objective: To investigate the relations of foramen rotundum structure direction and surrounding structure systematically in order to choose the best approach of percutaneous puncturing of radiofrequency thermocoagulation for treating V2 of primary trigeminal neuralgia. Methods: A total of 122 patients with V2 of primary trigeminal neuralgia for radiofrequency thermocoagulation were enrolled from August 2012 to May 2017 at the First Hospital of Jiaxing. CT scan images were observed retrospectively, to find the inside and outside of the foramen rotundum. The direction of foramen rotundum were recorded and the best approach of puncturing were analyzed. Results: The images were divided into four quadrants with the semi - coronal CT scan plane of the lower margin of the zygomatic arch and the outer edge of foramen rotundum for horizontal axis, and the sagittal plane for the vertical axis. In 122 cases, foramen rotundum direction in outer upper quadrant were 77 cases(63.1%), and in outer under quadrant were 22 cases(18.0%), and in inner upper quadrant were 19 cases(15.6%), and in inner under quadrant were 4 cases(3.3%). Conclusion: The most common foramen rotundum direction is in outer upper quadrant, so the best approach of percutaneous puncturing of radiofrequency thermocoagulation for treating V2 of primary trigeminal neuralgia is the upper side against zygomatic and the inner side against the wall of maxillary sinus. PMID- 29429256 TI - [Prevalence and risk factors of diabetic retinopathy in hospital patients]. AB - Objective: To analyze the prevalence and risk factors of diabetic retinopathy (DR) in ophthalmic patients. Methods: A cross-sectional study was performed. Diabetic patients who were admitted to Department of Ophthalmology, Traditional Chinese Medicine Hospital of Muping between October 2012 and June 2013 were included. General information and medical history were obtained from each subject by questionaires. Laboratory and detailed ophthalmic examinations were performed during the study. DR was diagnosed and graded by mydriatic fundus photography. Prevalence of DR was calculated and logistic regression was used to analyze the relationship between DR and various factors. Results: A total of 676 diabetic patients were included, and 455 of them presented with DR at a morbidity rate of 67.31%. Among DR patients, the number of mild, moderate, severe non-proliferative diabetic retinopathy (NPDR) patients and proliferative diabetic retinopathy (PDR) patients were 211 (46.37%), 167 (36.70%), 57 (12.53%) and 20 (4.40%), respectively. There was no significant difference in the prevalence of DR among different age groups (chi(2)=6.527, P=0.089). However, there was a significant difference between different disease duration groups (chi(2)=39.401, P<0.001), as well as between insulin therapy group and non-insulin therapy group (chi(2)=7.378, P=0.007). The multivariate logistic regression analysis demonstrated the independent risk factors for DR occurrence were hemoglobin A1c (HbA1c) (OR=1.131, 95%CI: 1.022-1.252, P=0.011) and duration of diabetes (OR=1.077, 95%CI: 1.046-1.108, P<0.001). Conclusions: The prevalence of DR in ophthalmic patients was associated with duration of diabetes, HbA1c, obesity, smoke, nephropaty and insulin therapy. Increased HbA1c level and longer duration of diabetes were independent risk factors for DR in diabetic patients. PMID- 29429257 TI - [Clinical features and gene analysis of TBC1D24 gene mutation related early-onset focal myoclonic epilepsy]. AB - Objective: To investigate the clinical features and genetic characteristics of patients with TBC1D24 gene mutation related early-onset focal myoclonic epilepsy. Methods: Clinical data of 3 patients with TBC1D24 gene mutation related early onset focal myoclonic epilepsy of Xuanwu Hospital from November 2016 to June 2017 was collected and analyzed.Candidate gene mutations were screened by second generation sequencing. Results: Among the 3 patients, 1 was male and 2 were females.Seizure onset age was 4 months, 3 years and 5 years after birth respectively. Two patients had family history of epilepsy.They all had prolonged episodes of focal myoclonus. Two patients had mental retardation.Scalp electroencephalograms (EEG) was recorded in all 3 cases and myoclonic seizures were captured.The ictal EEGs were normal in all cases. In one patient, the ictal EEG of generalized seizure showed alpha rhythm originating from left fronto central region. Brain magnetic resonance imaging (MRI) was normal in 2 patients. Abnormal signal was found bilaterally in cerebellum in 1 patient. The gene screening showed that two patients carried compound heterozygous mutation of TBC1D24 gene and one carried homozygous mutation, all of which were de novo mutations.All the patients were treated with multiple antiepileptic drugs (AEDs) and seizures were uncontrolled in 2 patients. One patient was followed up for 10 months without recurrence. Conclusions: TBC1D24 gene related early-onset focal myoclonic epilepsy is clinically characterized by early onset, prolonged focal myoclonus which relieved with sleep, mental retardation and poor response to AEDs.The interictal and ictal EEG usually show normal. Genetic analysis can assist in diagnosis and genetic counseling. PMID- 29429258 TI - [Clinical features of chronic relapsing inflammatory optic neuropathy]. AB - Objective: To explore the clinical characteristics and prognosis of chronic relapsing inflammatory optic neuropathy (CRION). Methods: A retrospective analysis was conducted. Clinical features, disease course, prognosis and magnetic resonance imaging (MRI) of patients with CRION who were admitted to Department of Neurology between 2014 and 2016 were reviewed and analyzed. Results: Totally, there were 27 patients (10 males and 17 females), with an age range of 17-59 years. The disease duration was between 40 days and 8 years. There were 2 to 9 CRION episodes. The mean frequency of CRION episodes was 3.30+/-1.56. The outcome of visual acuity showed that the more episodes frequency was, the worse outcome became. There was 25 abnormal optic nerve signals in MRI. And in 22 cases, the abnormal signals were in intraorbital segment or inner pipe section. The antinuclear antibodies (ANA) titers were elevated in 5 patients. Five cases relapsed during reduction or withdrawal of steroids, but steroids was not added in time. The final outcome of these 5 patients was poor. Conclusions: CRION was more common in female than male patients. Most patients were companied by pain, and the lesions were more common in the intraorbital segment of optic nerve. The more episode frequency was, the worse prognosis became. If a relapse happened, steroids or other immunosuppressive agents should be used. PMID- 29429259 TI - [Clinical analysis for preset double J tube in percutaneous nephrolithotripsy]. AB - Objective: To evaluate the clinical application and effect of preseting Double-J ureteric stent in percutaneous nephrolithotripsy. Method: 74 cases of renal calculi treated with PCNL in our hospital during June 2014 to February 2017 were retrospectively analyzed. Of 74 cases, 54 was male, 20 was female. All cases were aged 27 to 78, the mean age was (49.5+/-12.3) years old. The diameter of the stone was 20 to 59 mm, and the mean diameter was of (29.4+/-4.3) mm.Our Surgical methods was first putingFr6 double J tube in abnormal ureteral in advance in lithotomy position, then indwellingthree-way Foley catheter and clipping drainage port, perfusingirrigation port with 3 000 ml saline from 60-80 cm height.Perfusingsaline through irrigation port in prone position, we produce artificial hydronephrosis, then indwelling channel Fr20 through B ultrasound guided percutaneous nephrostomy, and removing renal calculi using holmium laser lithotripsy. Results: All patients were successfully completed percutaneous nephrostomy and indwell Fr20 channel, mean channel set up time (8.0 +/-2.0) min, mean operation time (79+/-46) min, mean decline of hemoglobin (17.0+/-4.0) g/L, mean serum creatinine increased(3.1+/-1.1) MUmol/L, one-stage stone-free rates 81.1%, complication rate 8.1% (1 case injured pleura and suffered from pneumothorax, 1 case suffered from massive hemorrhage of renal arteriovenous fistula after operation, 4 cases suffered postoperative fever). Conclusion: Advance in percutaneous nephrolithotripsy indwelling double J tube is a safe and feasible method, which is advantageous to the percutaneous renal puncture and the establishment of channels, and can avoid the blindness of along the line of indwelling double J. PMID- 29429260 TI - [The influence and mechanisms of purple sweet potato anthocyanins on the growth of bladder cancer BIU87 cell]. AB - Objective: To observe the effect of purple sweet potato anthocyanins on the proliferation of bladder cancer cell line BIU87 and to investigate the molecular mechanisms. Methods: Bladder cancer BIU87 cells were cultured and exposed to anthocyanins at the different concentrations of 100, 200, 400, and 800 MUg/ml respectively. The growth inhibition of anthocyanins on BIU87 cells were evaluated by morphometry and cell counting kit-8 (CCK-8) assay, and the cell apoptosis rate was detected by Flow cytometry (FCM). Results: Morphometry showed that the number of BIU87 cells decreased, the volume shrank, the intercellular space enlarged, the ability of cell adherence weakened, and the cell shape changed when the concentration of anthocyanins increased. CCK-8 assay showed that when 100, 200, 400, 800 MUg/ml anthocyanins treated BIU87 cells for 48 h, the absorbance was 24 +/- 0.07, 1.15 +/- 0.11, 0.90 +/- 0.08, 0.56 +/- 0.09, respectively. Compared with the control group, anthocyanins-treated groups significantly inhibited the proliferation of BIU87 cells (P<0.05). FCM test showed that after treatment with different doses of anthocyanins, the apoptosis rate was 7.31%, 11.11%, 25.96%, 36.28%, respectively, and with the concentration of anthocyanins being higher, the apoptosis rate of BIU87 cells was being higher. Conclusion: Purple sweet potato anthocyanins can inhibit the growth of bladder cancer BIU87 cells through inducing cell apoptosis in a dose-dependent manner. PMID- 29429261 TI - [Correlation of baseline serum interleukin-6, 10 and its ratio with 7-year all cause mortality in 11 communities of Beijing]. AB - Objective: To evaluate whether baseline interleukin-6 (IL-6), interleukin-10 (IL 10) as well as their ratio was associated with overall mortality risk over 7 years of follow-up in 11 communities of Beijing. Methods: Data from a prospective cohort study conducted between 2005 and 2012 in 11 communities of Beijing was analyzed to examine the above associations. Serum IL-6 and IL-10 were analyzed using enzyme-linked immunosorbent assay (ELISA) kits. Follow-up surveys were conducted in 2007, 2010 and 2012 to collect data about participant's survival. Cox regression model was used to estimate the impact of IL-6, IL-10 and their ratio on overall mortality risk. Results: Among 1 539 eligible participants (10 263 total person-years), 77 deaths occurred in 7 years of follow-up. The rates of all-cause death were 4.86, 7.24, and 10.56 per 1 000 person-years (P=0.009) in the first, second, and third tertile of IL-6, respectively. The corresponding age sex-adjusted hazard ratios (HR) were 1.00, 1.18 (95% CI: 0.64-2.19), and 1.80 (95% CI: 1.01-3.23) and full-adjusted HR were 1.00, 1.17 (95% CI: 0.63-2.19) and 1.87 (95% CI: 1.04-3.36). The corresponding rates of all-cause deaths were not significantly different among three tertiles of IL-10. The age-sex and full adjusted HR were not significantly different in Cox model. The rates of all-cause death were 4.63, 8.99, and 8.93 per 1 000 person-years (P=0.043) in the first, second, and third tertile of IL-6/IL-10 ratio, respectively. The corresponding age-sex-adjusted HR were 1.00, 1.67 (95% CI: 0.91-3.06), and 1.98 (95% CI: 1.08 3.64) and full-adjusted HR were 1.00, 1.66 (95% CI: 0.90-3.06), and 2.09 (95% CI: 1.13-3.87). Conclusion: High IL-6 and IL-6/IL-10 ratio may be new risk factors to all-cause death. However, IL-10 is not significantly associated with death. PMID- 29429262 TI - [Evaluation of asthma disease perception from China national asthma control survey]. AB - Objective: In order to evaluate disease perception of asthma patients in urban China and provide evidence for further specific patient education. Methods: A multi-center, cross-sectional, questionnaire-based survey was carried out in 30 general hospitals dispersed in 30 provinces of mainland China (except for Tibet) during Oct 2015 to May 2016. Information of disease perception [Question 1: the disease nature of asthma; Question 2: medication choice of first-line in chronic asthma; Question 3: the occasion of using short-acting aerosols of receptor agonists; Question 4: perception of asthma treatment goal; Question 5: reason for not using peak flow meter (PFM)] were collected from asthma patients of outpatient department. These results were compared with the same type of survey results from 2007-2008. Results: Altogether 3 875 asthmatic outpatients were recruited. 69.0% (2 660/3 857) of the patients had right perception on the disease nature of asthma, 60.2% (2 321/3 857) of the patients considered inhaled corticosteroids (ICS)/inhaled corticosteroids plus long-acting beta2-agonists (ICS+ LABA) as daily-used first-line medication for chronic asthma. 85.7% (3 277/3 823) of the patients had right perception on the condition of using short acting beta2-agonists (SABA). 75.4% (2 761/3 661) of the patients had right perception on asthma treatment goal. Only 10.1% (388/3 837) of the patients used PFM. Of the reasons for not using PFM, 65.2% (2 518/3 860) of the patients chose doctors never introduced. Among the 10 cities, which were also involved in the asthma control survey in 2007-2008, 71.1% (968/1 361) of the patients had right perception on the disease nature of asthma, 61.6% (839/1 362) of the patients considered ICS/ICS+ LABA as daily-used first-line medication for chronic asthma. 88.7% (1 207/1 361) of the patients had right perception on the condition of using SABA. 74.5% (1 013/1 360) of the patients had right perception on asthma treatment goal. 17.9% (244/1 360) of the patients used PFM. Of the reasons for not using PFM, 76.2% (931/1 221) of the patients chose doctors never introduced. Compared to the survey conducted in 2007-2008, the perception on disease nature and medication choice as daily-used first-line medication for chronic asthma significantly improved, the perception on occasion of using SABA and asthma treatment goal was comparable, while the rate of PFM usage showed no significant improvement. In reasons of not using PFM, doctors never introduced ranked the first. Conclusions: Compared to the similar survey conducted in 2007-2008, the overall status of disease perception of asthma patients has been improved in urban China, while the rate of PFM usage showed no significant improvement. Asthma education on asthma and asthma self-management should be further pushed forward. PMID- 29429263 TI - [Prospective thoughts of nutrition landscape]. PMID- 29429264 TI - [Surveillance of contamination level and antimicrobial resistance analysis of Salmonella on broiler carcasses after chilling in 4 poultry slaughterhouses of Henan Province]. AB - Objective: Tests were carried out for obtaining contamination level and antimicrobial resistance of Salmonella on broiler carcasses after chilling in four poultry slaughterhouses in Henan. Methods: Totally, two hundred sixty nine broiler carcasses after chilling were collected in four slaughterhouses with the daily slaughter amount around 15 000 to 50 000. For qualitative analysis of Salmonella EFSA method was used and for quantitative analysis of Salmonella modified Rappaport-Vassiliadis most probable number (MSRV-MPN) method was used. All of the isolates were subjected to antimicrobial susceptibility testing of 8 antibiotics by minimum inhibitory concentration (MIC). Results: Overall, 48.7% (131/269) of the broiler carcasses after chilling were contaminated by Salmonella, and the average of contamination level is 1.32 most probable number MPN/g. Eight serotypes were detected. The dominant serotype is Salmonella enteritidis (93, 71.0%) followed by Salmonella Indiana (21, 16.0%). Only 2 (1.5%) Salmonella enteritidis strains were sensitive to all the tested antibiotics and the remaining 129 isolates were resistant to at least one kind of eight class antibiotics. Among them, resistant to NAL was the common (104, 79.4%) and 51 (38.9%) Salmonella isolates were multidrug-resistant. Conclusion: The contamination rate and multiple antimicrobial resistant of Salmonella on broiler carcasses after chilling from slaughterhouses was very serious, while the isolates contained various serotypes. PMID- 29429265 TI - [Laboratory-based characterization and traceability of an outbreak of necrotising enterocolitis]. AB - Objective: Laboratory-based characterization and traceability were performed on an outbreak of necrotising enterocolitis (NEC) happened in a maternal and child health care hospital in China. Methods: Thirty-seven samples were collected from 3 NEC cases, that the clinical manifestations was bloody stools. Clostridium spp. isolation and identification were carried out on stool, breast milk, milk-based infant powder and environmental swab samples collected during NEC outbreak from October to November in 2016. Meanwhile, twenty-four swabs samples from ward environmental, staffs' hand as well as articles for neonates daily use were also collected and tested for Clostridium spp. after disinfection following outbreak. Pulsed-field gel electrophoresis (PFGE) analysis was performed on all Clostridium strains obtained. Results: 46% (17/37) samples were positive for a presumptive Clostridium spp. during the outbreak of NEC. One type of Clostridium spp. isolates was cultured from 10 samples including the hands of medical staffs, some medical equipments in the ward and milk-based infant powder ingested by the case, it was identified as C.butyricum. Another type of Clostridium spp. isolates was cultured from 2 samples including breast milk and inner wall of breast milk fresh keeping bag, it was identified as C.sporogens. Both of these two types isolates were cultured from 5 samples including inner wall of breast milk box, inner wall of refrigerator, the handle of case's incubator and the case's stool. PFGE analysis showed that all 15 strains of C. butyricum and 7 strains of C.sporogens isolated from the samples mentioned above produced indistinguishable pulsotypes respectively. No NEC cases were found after disinfection following the outbreak and all samples collected after outbreak were negative for Clostridium spp. Conclusion: The outbreak of NEC was highly related to C. butyricum contamination within the hospital. PMID- 29429266 TI - [Analysis on infertility status and influencing factors of female workers among reproductive age in China's nine industries]. AB - Objective: To investigate the infertility rate and influencing factors of female workers in China's nine industries. Methods: Using multi-stage sampling method, from January to November in 2016. A cross-sectional survey was conducted on the infertility of 33 685 female workers in the nine industries including medical and health, petrochemical, metallurgy, railway, machinery manufacturing and electronics,a questionnaire survey. First, three provincial capitals were randomly selected in seven regions. And then we consulted and communicated with the hospital of the provincial city's occupational disease prevention and treatment, marking and coding the target enterprise within its jurisdiction, In these enterprises, we randomly selected five companies. Finally, all women workers who meet the inclusion criteria were surveyed in those enterprises which were drawn. Use the"female workers reproductive health questionnaire" to collect female workers demographic status, occupational status and reproductive status and other data. The single factor analysis of infertility was performed by chi square test. Multivariate analysis of infertility was carried out by logistic regression model. Results: The age of female workers in the nine industries was (35.98+/-7.98) years. The infertility rate for one year of female workers in typical industry was 24.81% (8 358/33 685), the infertility rate for two years being13.47% (4 537/33 685), the infertility rate for two years being 10.78% (3 632/33 685). Compared to the east China region, the infertility rate was the highest in the south region (OR=1.90, 95%CI: 1.66-2.17). Compared to non-working women, the infertility rate was the highest among railroad (OR=1.68, 95%CI: 1.43 1.98) and financial industries (OR=1.64, 95%CI: 1.38-1.95). Occupational exposure to heavy metals (OR=1.15, 95%CI:1.04-1.27) and occupational exposure to hazardous physical factors (OR=1.09, 95%CI:1.01-1.17) were infertility risk factors. Conclusion: The infertility rate of female workers in the nineindustries was high. And the region, industry, occupational exposure to heavy metals and occupational exposure to hazardous physical factors, were independent risk factors for infertility. PMID- 29429267 TI - [Comparison of Dengue viral nonstructural protein 1 antigen testing kits]. AB - Objective: To investigate the sensitivity and specificity of commercial nonstructural protein 1 (NS1) testing kits for Dengue fever diagnose, and provide the evidence for diagnostic criteria revision. Methods: 300 PCR or virus isolation positive blood samples for dengue virus were collected from sentinel hospitals for dengue surveillance in Guangzhou, Dongguang and Zhongshang from May 2015 to Nov. 2016. At the same time, 308 PCR negative samples for Dengue virus were collected as control group. The information of the sample was collected using questionnaires. These samples were tested using imported and domestic ELISA and the colloidal gold-labeled kits that were widely used for detecting dengue NS1. Sensitivity, specificity and coincidence were calculated and analyzed, and Z hongshan's result was regarded as the reslut of the third part. Results: The positive group includes 133 males and 167 females, average ages are 47.2+/-13.3, 179, 110 and 11 of them is Dengue I, II and III respectively. The negative group includes 154 males and 154 females, average ages are (40.1+/-11.6) years old. The sensitivity of domestic ELISA Kits (94.5%) is less than imported (99.5%), and the result has statistical significance (chi(2)=8.59, P=0.030), the specificity is 99.7% and 97.7% respectively; The sensitivity of imported and domestic the colloidal gold-labeled Kits is 97.5% and 96.5% respectively, both of specificities are 100%. The sensitivity and specificity of Dengue I for NS1 test are more than 97.0%. The sensitivity of domestic ELISA and gold-labeled Kits is 90.0% and 95.0%, and the specificity is 96.8% and 100% respectively for Dengue II test. The sensitivity of imported ELISA and gold-labeled Kits is 100% and 98.0%, and the specificity is 99.4% and 100% respectively for Dengue II test. The result of the third party show the sensitivity and specificity of domestic ELISA and gold-labeled Kits are 90.0% and 98.0%, the differences has statistical significance (chi(2)=5.67, P=0.020). Conclusion: NS1 testing can be used as early dengue fever diagnose for higher sensitivity and specificity. PMID- 29429268 TI - [Analysis on the incidence of influenza-like syndromes and related health behavior factors among Beijing residents]. AB - Objective: The objective was to identify the incidence of influenza-like syndromes and related health behavior factors among Beijing residents. Methods: From December 6, 2013 to January 16, 2014, we selected 150 villages or communities from 30 towns or streets as survey locations using a multi-stage random sampling method, and then conducted a cross-sectional study among 7 354 residents who aged 18 years or above and had live in Beijing for more than a half year using self-administered anonymous questionnaires, and totally 7 327 valid questionnaires are collected. The questionnaire consisted of demographic information, self-reported influenza-like syndromes in the past two weeks, and health behaviors. Multiple logistic regression models were used to identify the factors associated with self-reported influenza-like syndromes. Results: The mean (SD) age of the partcipants was 44.6 (15.2) years. Among them, 6.9% (506 cases) reported having influenza like illness during the past two weeks. The multiple logistic regression analysis indicated that regular physical exercise, optimal hand hygiene, and avoidance of going to the crowded places during respiratory infectious disease epidemics were significantly associated with a lower likelihood of reporting influenza-like syndromes, compared with those without regular physical exercises, without optimal hand hygiene, and not avoiding going to the crowded places, and the OR(95%CI) were 0.80 (0.66-0.97), 0.75 (0.57-0.99) and 0.80 (0.65-0.98), respectively. Conclusion: Personal health behaviors were associated with the incidence of respiratory infectious diseases such as influenza in Beijing, and future interventions to improve personal hygiene behaviors are needed to prevent the spread of respiratory infectious diseases. PMID- 29429269 TI - [Multilevel logistic regression analysis on hypercholesterolemia related risk factors among adults in China]. AB - Objective: To investigate the prevalence of hypercholesterolemia among Chinese adults in different geographic areas, and to analyze the related factors. Methods: China Chronic and Non-Communicable Disease and Risk Factor Surveillance was conducted in 2013, based on 298 counties/districts in 31 provinces of Chinese mainland. The adults aged 18 years old were randomly selected using multi-stage stratified clustering sampling method. Information on chronic disease and risk factors was collected using face-to-face questionnaire interview and physical measurement. Blood samples were collected by local staffs. Serum total cholesterol (TC) was determined using standard method in a central laboratory. After excluding 565 participants missing key variables and 1 558 participants with abnormal TC values, a total of 174 976 participants were included. Weighted prevalence of hypercholesterolemia was calculated. Hypercholesterolemia related individual or geographic determinants were defined using multilevel logistic regression. Results: The prevalence of hypercholesterolemia in Chinese adults age 18 years old and above was 6.9% (95%CI: 6.4%-7.3%), ranged from 3.0% (95%CI: 2.5% 3.4%) in the northwest of China to 14.2% (95%CI: 12.9%-15.5%) in the south (chi(2)=183.42, P<0.001). The prevalence of hypercholesterolemia was higher in 6 provinces including Tianjin, Liaoning, Fujian, Guangdong, Guangxi, and Hainan (>=9.0%), but lower in 7 provinces including Shanxi, Shannxi, Gansu, Qinghai, Ningxia, Xinjiang, and Tibet (<3.9%). There was a 1.27 fold variation in hypercholesterolemia prevalence by provincial level, and 72.5% of the geographical variation in hypercholesterolemia prevalence was account for by area level determinants. With multilevel logistic analysis, the individual risk factors associated with hypercholesterolemia included aging, higher education level or annual household income per capita, regular drinking, too much red meal intake, inactivity, overweight or obesity. For geographic factors, residents living at south China, counties/districts with higher urbanization rates, higher education level or lower standardized death rates were more likely to have hypercholesterolemia (all P<0.05). Conclusion: The prevalence of hypercholesterolemia was high in Chinese adults, it was different between regions and related with characteristics of population, individual behaviors and geographical regions. PMID- 29429270 TI - [Geographical variation and related factors in prediabetes prevalence in Chinese adults in 2013]. AB - Objective: To investigate the geographical variation of prediabetes in adults in different regions of China, and to analyze the related factors of prediabetes. Methods: Data was obtained from China Chronic Disease and Related Risk Factor Surveillance in 2013. The surveillance adopted multiple-stage stratified cluster random sampling method, which sampled 177 099 residents aged above 18 years old among 298 surveillance points in 31 provinces of Chinese Mainland. Questionnaire interview was used to obtain demographic variables, personal living style, and socio-economical information. Physical examination was conducted and fasting venous blood sample and (oral glucose tolerance test-2 hours, OGTT-2 h) venous blood sample were obtained from the participants. A total of 171 567 residents aged 18 and above were included in the analysis. The prevalence of prediabetes was analyzed by provinces and by China's geographical regions, after complex weighting. Multilevel logistic models were established to explore the related factors of prediabetes on the area level and individual level. Results: The prevalence of prediabetes among residents aged 18 and above was 16.6% (95%CI: 15.6%-17.6%) in China. The prevalence of prediabetes was the highest (18.3%) in the south China and lowest (13.1%) in the northwest area. The difference of the prevalence in different areas were not statistically significant (P=0.510). If categorized the prevalence of prediabetes into 5 groups by quintile, Hainan, Jilin, Shandong, Anhui, Hunan and Chongqing were in the highest group of prevalence of prediabetes (18.6%-22.7%), and Tibet, Qinghai, Gansu, Ningxia, Guizhou, and Jiangxi were in the lowest group (7.6%-12.6%). The variance of prevalence of prediabetes on the county level (MOR: 1.60 (95%CI:1.53-1.67)) was more diverse than the province level (MOR: 1.21(95%CI:1.08-1.29)) and higher than the street level (1.23 (95%CI:1.14-1.30)). Several factors increased risk of pre diabetes, including smoking, hazardous drinking and harmful drinking, drinking in the past 30 days, overweight, obesity, central obesity, sugary drink intake, hypertension, high total cholesterol, high triglycerides, high blood low-density lipoprotein cholesterol, low blood high-density lipoprotein cholesterol (all P<0.05). After adjusted the above variables, 92.5% of variance of prediabetes prevalence conld be explained on the provincial level. Conclusion: The geographical distribution of prediabetes in adults in China differed by geographic areas, and it significantly varied on the county level. The related variables included demographic variables, personal behavior, and geographic related variables. PMID- 29429271 TI - [Provincial representativeness assessment of China Non-communicable and Chronic Disease Risk Factor Surveillance System in 2013]. AB - Objective: To evaluate the provincial representativeness of China Non communicable and Chronic Disease Risk Factor Surveillance System, 2013. Methods: The Sixth National Population Census data which was collected by National Bureau of Statistics of People's Republic of China was used to calculate proportion of population who aged 65 and above, mortality rate, the proportion of non agriculture population, the illiteracy rate and urbanization rate in order to evaluate the surveillance system in each province. The Mann-Whitney U test was used to determine the statistically differences between the surveillance system and corresponding general population. Results: Among the 298 disease surveillance points (DSPs) in China Non-communicable and Chronic Disease Risk Factor Surveillance System, there were 111, 85, and 102 DSPs located in the east, middle, and west area of China, which covering 13.90%, 11.48%, and 12.28% of the total population, respectively. The surveillance system covered 169 million of the population of China, accounting for 12.70% of Chinese population. The number of DSPs by provinces ranges from 6 (Hainan, Qinghai, and Ningxia) to 14 (Shandong, Guangdong and Henan). It indicated that mortality rate (DSP: 0.238%; Province: 0.482%) and the illiteracy rate (DSP: 15.54%; Province: 26.22%) among DSPs in Tibet were significantly lower than the provincial level, on the other hand, the proportion of non-agriculture population among DSPs (40.6%) was significantly higher than the provincial level (18.8%). The urbanization rate among Jiangxi DSPs (43.4%) was significantly lower than the provincial level (59.9%). The proportion of non-agriculture population among Shandong DSPs (32.8%) was significantly higher than the provincial level (24.2%), however, the illiteracy rate among Shandong DSPs (3.86%) was significantly lower than the provincial level (5.25%). Other than the provinces mentioned above, there was no statistical differences (P>0.05) among proportions of population who aged 65 and above, mortality rates, the proportions of non-agriculture population, the illiteracy rates and urbanization rate between provincial surveillance system and corresponding area. Conclusion: Other than 3 provinces, in general, China Non communicable and Chronic Disease Risk Factor Surveillance System had provincial representativeness. PMID- 29429272 TI - [Multivariate analysis of the association between consumption of fried food and gastric cancer and precancerous lesions]. AB - Objective: To investigate the effect of fried food intake on the pathogenesis of gastric cancer and precancerous lesions. Methods: From 2005 to 2013, the residents aged 40-69 years from 11 counties/cities where cancer screening of upper gastrointestinal cancer were conducted in rural areas of Henan province as the subjects (82 367 cases). The information such as demography and lifestyle was collected. The residents were screened with endoscopic examination. The biopsy sampleswere diagnosed pathologically, according to pathological diagnosis criteria, the subjects with high risk were divided into the groups with different pathological degrees. The multivariate ordinal logistic regression analysis was used to analyze the relationship between the frequency of fried food intake and gastric cancer and precancerous lesions. Results: The study coverd 46 425 males and 35 942 females, with a age of (53.46+/-8.07)years. The study collected 6 707 cases of normal stomach, 2 325 cases of low grade intraepithelial neoplasia, 226 cases of high grade intraepithelial neoplasia and 331 cases of gastric cancer. Multivariate logistic regression analysis showed that, compared with those whoeat fried food less than one time per week, fried foods intake (<2 times/week: OR=1.89, 95%CI: 1.57-2.28; >= 2 times/week: OR=1.91, 95%CI: 1.66-2.20) were a risk factor for gastric cancer and precancerous lesions after adjustment for age, sex, marital status, educational level, body mass index (BMI), smoking and drinking status. Conclusion: The intake of fried food is a risk factor for gastric cancer and precancerous lesions. Therefore, reducing the intake of fried food can prevent the occurrence of gastric carcinoma and precancerous lesions. PMID- 29429273 TI - [Effects of monobutyl phthalate on migration and invasion of mouse Leydig tumor cells]. AB - Objective: This study aimed to investigate the influence of monobutyl phthalate (MBP) on the expressions of epithelial-mesenchymal transition (EMT)-related proteins, migration and invasion of mouse Leydig tumor cells (MLTC-1) cells. Methods: After exposed to different doses of MBP (0,10(-7),10(-6), 10(-5), 10( 4), 10(-3) mol/L) for 24 h or 48 h, cell viability was determined by 3-(4 5 dimethyl-2-thiazolyl)-2 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Expressions of vimentin, E-cadherin, N-cadherin and Snail proteins related to EMT were detected by Western blot. The ability of migration and invasion of MLTC-1 were assessed by wound healing assay and Transwell Boyden chamber assay, respectively. Results: Relative expressions of vimentin, Snail and N-cadherin proteins were promoted ((1.56+/-0.07) vs (1.78+/-0.08), (1.22+/-0.06) vs (1.44+/ 0.07), (1.33+/-0.11) vs (2.19+/-0.06), all P values were<0.001) and E-cadherin (0.66+/-0.09) vs (0.47+/-0.06), P<0.001,protein was inhibited after the cells stimulated with MBP (0, 10(-7) and 10(-6) mol/L). The capability of wound closure of MLTC-1 cells were (6.64+/-2.07)%, (15.61+/-2.83)%, (39.91+/-0.33)%, respectively and the invading/migrating cells were (32.67+/-3.51), (57.67+/ 2.52), (82.67+/-6.51), respectively, which were obviously increased under MBP treatments (0, 10(-7) and 10(-6) mol/L) (all P values were <0.001). Conclusion: Monobutyl phthalate affected the expressions of EMT-related proteins and enhanced the migration and invasion of MLTC-1 cells. PMID- 29429274 TI - [Analysis on occupational health laboratories' proficiency testing program for determination of bovine blood lead and urinary cadmium]. AB - Objective: To analyze the results obtained from the proficiency testing program for determination of bovine blood lead and urinary cadmium, so as to evaluate the proficiency of the laboratories, and improve the detection and quality control capability of occapational health laboratory. Methods: Prepared 3 levels of lead samples with bovine blood as base material, taking Technical Norm of Primary Reference Material as Operating standard, 60, 80, 180 MUg/L were used as the standard concentration. All samples were made for 200 bottles. Normal urine were used to prepared 3 levels of cadmium samples with 5.0, 7.0, 10.0 MUg/L as standard concentration, then 3 level of samples were made for 200 bottles respectively. Blood lead and urinary cadmium samples were sent to each laboratory in the form of sample pairs. One-way ANOVA was used to investigate the homogeneity. The results of each laboratory were statistically analyzed by robust statistical method, and the detection ability of the laboratory was evaluated by the Z ratio score method. By consulting the test reports and original records of each participating laboratory, the reasons for the unsatisfactory results were analyzed. Results: The statistical F of the uniformity of blood lead 1.42, 1.37 and 2.85, F<3.13, P were 0.294, 0.314 and 0.059, respectively in 31 labs. There is no statistical significance in the difference of blood lead (P>0.05). And urine cadmium was less than the critical value (P>0.05). In all, 31 laboratories participated in the test of blood lead, and 28 loboratories paticipated in urine cadmium verification. The statistical F of the uniformity of urinary cadmium 1.90, 1.35 and 1.19, F<3.13. The homogeneity of the samples were in accordance with the requirements of proficiency testing program. The satisfactory rate of the results for blood lead was 84% (26/31) , and the satisfactory rate of urinary cadmium was 93% (26/28) . In the test of blood lead, 21 of the 31 laboratories were controlled by the standard material method. Totally, 20 of them get an satisfactory level, the rate was 95%. Conclusion: Most of the laboratory test results were satisfactory, which showed that the detection capability for blood lead and urine cadmium was good. The main causes of unsatisfactory results were detection methods, tools of quality control ortraceability standards. PMID- 29429275 TI - [Full-length genome analysis of a coxsackievirus B5 strain isolated from Shandong Province in 2014]. PMID- 29429276 TI - [Evaluation the impact of community intervention on heat wave in Nanjing, China]. PMID- 29429277 TI - [Scheme of the Chinese chronic non-communicable disease and risk factor surveillance]. PMID- 29429278 TI - [The relationship between gut microbiota and diet and nutrition related diseases]. AB - The human gastro-intestinal tract is not only the habitat of gut microbiota, but also the main place that the body gets available nutrients. Therefore, the gut microbiota of human can be inseparable associated with the human nutrition. The common technologies used among gut microbiota research included metageonomic, metatranscriptomics, metaproteomics, and metabolomics. The research of gut microbiota based on above omics methods confirmed that diets were the main factors influencing the composition and expression of gut microbiota. The proportion, quantity, stable state, and metabolic changes of gut microbiota were closely related to obesity, diabetes mellitus, cardiovascular disease, and other nutritional-related diseases. Reasonable dietary intervention can adjust the disorders of gut microbiota, which can achieve prevention and treatment of obesity, diabetes, cardiovascular diseases, and other nutritional-related diseases. Although the single omics methods can be used to study the problems of some aspects of gut microbiota, the combination of multi-omics is needed to achieve the above objectives. PMID- 29429279 TI - [Biomonitoring application in the exposome assessment]. AB - Biomonitoring can be applied to assess internal exposure and environmental exposure by exposure markers with providing internal exposure to biological characterization and individual exposure information, which is a key tool to evaluate the risk exposure to disease by biological alternation information. With the development of high throughput, broad spectrum and high efficiency screening and detection technology, biomonitoring is defined as traditional biological monitoring (targeted monitoring) and non targeted monitoring analysis (exposomic approaches). An exposomic approach differs from traditional biomonitoring in that it can theoretically include all exposures of potential health significance, whether they are derived from exogenous sources. Both traditional and nontraditional biomonitoring methods should be used to understand the complexity of exposures faced throughout the lifespan. Through hybrid approaches, emerging techniques and the integration of bioinformatics, and developing the detection methods for low abundance chemicals, improving the differentiation ability between endogenous and exogenous chemical, the health outcomes and exposures can be widely recognized and characterized, which can finally contribute to improving the precise prevention and intervention for diseases under the new exposomic model. PMID- 29429280 TI - [Occupational health status of electronics manufacturing female employees in China]. AB - Electronics industry is a typical labor-intensive industry in China. There are a lot of female workers and various occupational hazard factors in the workplace. This article reviewed the characteristics of employment of women in electronics industry, occupational hazards of exposure, protective measures, occupational disease situation, influence of reproductive health and mental health, and occupational health management. Electronics female emplyees have the priority in reproductive health and mental health. Besides, this group has poor protective measures, occupational health management and policy should be taken to enhance the level of women health in electronics industry. PMID- 29429281 TI - [Physiological characteristics of Echinococcus and their association with interventions against echinococcosis]. AB - Alveolar and cystic echinococcosis are important zoonotic diseases caused by the dog/fox tapeworms of Echinococcus granulosus and E. multilocularis, which are distributed in almost whole the world. The diseases remarkably impact on the people's health and economic development of communities. Echinococcus tapeworms need two mammalian animals to complete their lifecycle. The worms undergo different developmental stages (adult, egg/oncosphere, cyst, and protoscolex). Each stage has its own distinct physiological characteristics. We summarize the characteristics and emphasize that some features that strongly impact on design of control program. Based on the lifecycle of these worms, two stages are infectious, one is egg the only stage for primarily infecting humans and intermediate host, and another stage is protoscolex, the only stage for infecting the definite hosts of the worms. Eggs are produced by the adult worms parasitized in the intestine of definite hosts. It takes 45 days for eggs becoming mature in dogs. With this feature of the tapeworm, New Zealand and Tasmania in Australia designed control program for deworming 8 times annually with an interval between deworms at 45 days. E. multilocularis takes 28-30 days in dog/fox producing mature eggs. Given that co-existence of E. granulosus and E. multilocularis in western China, a control measure so called "prepatent deworming control measure" has been used in these endemic areas with dosing worms in dogs every month. It normally takes 12-15 months for producing protosocleces in E. granulosus cysts in sheep. If meat markets attract most lambs, that is an effective measure for controlling cystic echinococcosis given that there are no protoscoleces produced from those lambs. In addition, Echinococcus has its own unique biological characteristics, such as sexual reproduction and asexual reproduction, single cell layer structure of cyst, bidirectional development of protoscoleces induced by bile salts, and long term of infection causing host asymptomatic reaction make the parasites a models for addressing some biological and biomedical issues. And more, hydatid cyst fluid is the antigen resource for identifying diagnostic reagents; the specific gene expressed in oncospheres has been developed as an effective vaccine used for control program. With the development and application of high-throughput omics, including genomics, transcriptomics and proteomics, we can use the physiological characteristics of Echinococcus for searching diagnostic reagents, developing preventive vaccines and identify new drug targets. PMID- 29429282 TI - [Problems and challenges in the development of corneal refractive surgery]. AB - Corneal refractive surgery, as one of the common visual correction methods, has been increasingly accepted in China. There are a large number of people in China who undergo the corneal refractive surgery due to the high incidence of myopia in the country. It is essential that the safest and most effective surgery should be used to correct refractive errors in the cases involved with relatively normal eyes and corneas. In recent years, corneal refractive surgery has been rapidly developing with new technologies and techniques emerging all the time, such as SMILE (small incision lenticule extraction) surgery, which has been extensively applied in China since five years ago when it was approved by FDA. However, little known are these new technologies and techniques, and the clinical and basic researches need further investigations by various approaches including histopathology and molecular biology, combined with mathematics, computer science, physics, chemistry and corneal biomechanics. To achieve minimal tissue damage and optimal clinical outcomes on visual quality by corneal refractive surgery requires the multidisciplinary partnerships of medical practitioners and researchers. (Chin J Ophthalmol, 2018, 54: 3-6). PMID- 29429283 TI - [Advantages and disadvantages of femtosecond laser assisted LASIK and SMILE]. AB - With the development of excimer laser and femtosecond laser equipment, application of diversified and customized surgical decision in modern corneal refractive surgery has been an inevitable trend. However, how to make a personalized decision with an accurate surgical design to achieve better visual quality becomes the main focus in clinical applications. Small-incision lenticule extraction (SMILE) and femtosecond assisted laser in situ keratomileusis (FS LASIK) have been commonly acknowledged as the mainstream of corneal refractive surgery for ametropia correction nowadays. Both methods have been verified by clinical practice for many years. This article compares and elaborates the different characteristics with advantages and disadvantages of the two methods so as to provide some reasonable treatment options for refractive surgery. (Chin J Ophthalmol, 2018, 54: 7-10). PMID- 29429284 TI - [Clinical observation on corneal transparency after small incision lenticule extraction surgery]. AB - Objective: To evaluate the changes of corneal transparency over the 1-year period after small incision lenticule extraction (SMILE) according to corneal Scheimpflug densitometry. Methods: Prospective cohort study. Fifty-five patients (100 eyes) with myopia (19 male and 36 female, aged 18 to 39 years with average of 24) who underwent SMILE and regular follow-up for at least 1 year at Tianjin Eye Hospital were enrolled. Examinations took place before SMILE and postoperatively at 1 day, 1 week, and 1, 3, 6, and 12 months. The preoperative spherical equivalent of surgical refractive correction was (-5.75+/-1.64) D. Corneal densitometry (CD) data were calculated automatically by the Pentacam Scheimpflug system and expressed in gray scale units (GSU), from 0 (completely transparent) to 100 (completely opaque). During the analysis of corneal densitometry, the average corneal optical density of three concentric radial zones centered on the apex of the cornea <=2 mm, >2 mm and <=6 mm, >6 mm and <=10 mm diameter) were applied, and three layers were defined according to different corneal depths (the anterior 120 MUm as 1st layer, and the posterior 60 MUm as 3rd layer, and the center part between them of the cornea as 2nd layer). The automatic release mode was applied in order to avoid operator-induced errors. The preoperative and postoperative values in different corneal layers and different concentric radial zones were compared using Kruskal-Wallis. Results: Ninty-three eyes(93%) of all eyes achieved uncorrected distance visual acuity (UCVA) of 0.8 or better on the first day postoperatively, and 96% (96 of 100 eyes) achieved UCVA of 0.8 or better in the first week postoperatevely, and all eyes 100% (100 of 100 eyes) achieved UCVA 0.8 or better until the end of our follow-up (in 1 year postoperatively). In general, the difference preoperative and postoperative corneal average optical density is of no statistical significance (chi(2)=8.446, P=0.207), specifically, the overall postoperative CD increased in the first week after surgery (1 day to 15.90, 1 week to 15.65), and then decreased to the equivalent of baseline levels and maintained such level until 6 months after surgery (1 month to 15.60; 3 month to 15.50, 6 month to 15.55), though at the 12 month follow-up, densitometry values had spiked significantly again (12 month, 15.90). The difference between the preoperative and postoperative CD values in the central two zones (<=2 mm, >2 mm and <=6 mm), but not the outer (>6 mm and <=10 mm), were of statistical significance (chi(2)=61.961, 52.397, P<0.000). When subdivided by corneal layer, significant changes in CD were detected in the anterior 120 MUm layer (chi(2)=27.774, P<0.000). The CD increased significantly (i.e., corneal transparency decreased) as compared to the preoperative baseline on the first postoperative day, and lasted through the first week. There were no significant changes in the CD of the central layer (chi(2)=0.918, P=0.986). Significant increases in the posterior 60 MUm of the cornea after surgery were found only at the 6-month and 1-year follow-up examinations (chi(2)=17.469, P=0.008). No correlation was found in the preoperative refractive error, ablation depth, postoperative UCVA and the CD. The CD at 6 months was found negatively correlated with SE at 6 months (r=-0.219, P=0.028). Conclusions: SMILE reduced corneal transparency temporarily and primarily within the surgically altered area, however such change has no significant correlation with the ablation depth, SE, and the postoperative UCVA. Transparency recovered within a month, but patients should be monitored for at least 1 year. (Chin J Ophthalmol, 2018, 54: 27-32). PMID- 29429285 TI - [Analysis on the role of Sirius combined topography and tomography system in screening for suspect keratoconus]. AB - Objective: To evaluate the role of Sirius combined topography and tomography system in screening for suspect keratoconus among the corneal refractive surgery candidates. Methods: Retrospective case series study. Eight hundred and sixteen consecutive ametropic patients (1 632 eyes) who underwent routine examinations before corneal refractive surgery at Peking University Third Hospital from January 2016 to September 2016 were reviewed. All the cases were analyzed with Sirius combined topography and tomography system. Fifty-nine eyes of 37 patients, aged (28.9+/-7.4) years, classified as suspect keratoconus by the system were enrolled in the suspect group, including 25 females (40 eyes) and 12 males (19 eyes). A random eye of the first 59 patients, aged (27.1+/-6.4)years, whose both eyes were classified as normal by Sirius system were enrolled in the control group, including 38 females and 21 males. The corneal anterior surface, posterior surface and minimum thickness data of the suspect group were analyzed and then compared with the control group. The classified results were further verified by Pentacam system. Independent-samples t test and Mann-Whitney U test were applied to analyze the normal distribution and non-normal distribution data respectively. Results: The medians of anterior surface and posterior surface symmetry index and Baiocchi Calossi Versaci index of anterior surface and posterior surface of the suspect group were 0.84, 0.22, 0.58 and 0.51 D, and that of the control group were 0.05, 0.04, 0.09 and 0.06 D, and the differences were of statistical significance (Z=-18.764, -8.351, -12.248, -10.709, P<0.01). Mean corneal minimum thickness data of the suspect group were (504.4+/-30.0)MUm, and that of the control group were (541.2+/-32.1)MUm, the differences were of statistical significance (t=-6.408, P<0.01). In the suspect group, the eyes related with suspect or abnormal corneal anterior indices accounted for 47.5% (28/59), the eyes related with suspect or abnormal corneal posterior indices accounted for 55.9% (33/59), and the eyes related with suspect or abnormal corneal minimum thickness accounted for 40.7% (24/59). In the suspect group, 45 eyes (76.3%) were classified as suspect or abnormal according to the overall variance index "D" by Belin-Ambrosio Display (BAD) of the Pentacam system, and the other 14 eyes exhibited at least one abnormal index related with keratoconus. Conclusions: Sirius 3D combined topography and tomography and its integral automatic classification system is capable to screen out the suspect keratoconus simply and effectively. These indices maybe arranged in descending order in terms of the sensitivity as corneal posterior surface, followed by corneal anterior surface and then corneal thinnest point thickness. (Chin J Ophthalmol, 2018, 54: 33-38). PMID- 29429286 TI - [Study on the change of optical zone after femtosecond laser assisted laser in situ keratomileusis]. AB - Objective: To explore the change of optical zone after femtosecond laser assisted laser in sitn keratomileusis(FS-LASIK) so as to provide the reference for measurement and design of clinical optical zone. Methods: This retrospective case series study covers 41 eyes of 24 patients (7 males and 17 females, aged from 18 to 42 years old) with myopia and myopic astigmatism who have received FS-LASIK surgery at Corneal Refractive Department of Qingdao Eye Hospital and completed over 6 months of clinical follow-up. Pentacam system (with the application of 6 corneal topographic map modes including: the pure axial curvature topographic map, the pure tangential curvature topographic map, the axial curvature difference topographic map, the tangential curvature difference topographic map, the postoperative front elevation map and the corneal thickness difference topographic map), combined with transparent concentric software (a system independently developed by Qingdao Eye Hospital) was used to measure the optical zone at 1, 3 and 6 months postoperatively, the optical zone diameters measurement results among different follow-up times in group were analyzed with the repeated measures analysis of variance, and the actual measured values and the theoretical design values of the optical zone were analyzed with independent-samples t testing. Spearman correlation coefficient (r(s)) have been applied to evaluate the relationship between postoperative optical zone measurement values and the potential influencing factors. Results: The optical zone diameters measured by pure axial curvature topographic map at 1, 3 and 6 months after FS-LASIK showed (6.55+/-0.50)mm, (6.50+/-0.53)mm and (6.48+/-0.53)mm respectively. The differences between values are of no statistical significance (F=1.60, P=0.21), the optical zone diameter measured by pure tangential curvature topographic map at 1, 3 and 6 months after FS-LASIK showed (5.44+/-0.46)mm, (5.46+/-0.52)mm and (5.44+/-0.50)mm respectively, the differences between values are of no statistical significance (F=0.17, P=0.85). The optical zone diameters measured by postoperative front elevation map at 1, 3 and 6 months after FS-LASIK showed (5.06+/-0.28)mm, (5.12+/-0.32)mm and (5.17+/-0.28)mm respectively. The differences between the values of 3 and 6 months postoperatively are of no statistical significance (F=6.14, P=0.15), the optical zone diameters measured by axial curvature difference topographic map at 1, 3 and 6 months after FS-LASIK showed (6.51+/-0.37)mm, (6.45+/-0.41)mm and (6.41+/-0.40)mm respectively, and the differences between the values of 3 and 6 months postoperatively are of no statistical significance (F=7.25, P=0.05). The optical zone diameters measured by tangential curvature difference topographic map at 1, 3 and 6 months after FS LASIK showed (5.21+/-0.23)mm, (5.16+/-0.19)mm and (5.17+/-0.20) mm respectively, and the differences between the values of 1 and 3 months postoperatively are of statistical significance (F=1.75, P=0.04). The optical zone diameters measured by corneal thickness difference topographic map at 1, 3 and 6 months after FS-LASIK showed (6.53+/-0.40)mm, (6.39+/-0.43)mm and (6.41+/-0.47)mm respectively, and the differences between the values of 1 and 3 months postoperatively are of statistical significance (F=1.67, P=0.032). The actual measured optical zone values from the 6 different modes of Pentacam system are less than the theoretical design values (7.75 mm), and the differences were statistical significance (t=-15.42, -29.39, -59.27, -21.47, -81.69, -18.22, P<0.01). Conclusions: The optical zone measurement values tend to be stable at 3 months after FS-LASIK. The actual measured values from all the 6 different modes of Pentacam system were less than the theoretical design values. The results from pure tangential curvature topographic map, the tangential curvature difference topographic map and the postoperative front elevation map showed greater variation with clear border, which was beneficial for eccentric research. The results from pure axial curvature topographic map, the axial curvature difference topographic map and the corneal thickness difference topographic map were close to the theoretically designed values. Furthermore, the axial curvature difference topographic map showed clearer border and less variation thus maybe more favorable for measuring optical zone in clinical application.(Chin J Ophthalmol, 2018, 54: 39-47). PMID- 29429287 TI - [Observational study on the impact of corneal power on refractive status of patients after small incision lenticule extraction surgery]. AB - Objective: To observe the change of refractive status and possible influencing factors for patients with different corneal power who underwent small incision lenticule extraction (SMILE) surgery. Methods: Prospective cohort study was performed for patients who underwent small incision lenticule extraction (SMILE) surgery at Daping Hospital and Research Institute of Surgery of Third Military Medical University between January and August 2016. The patients were divided into 3 groups according to their corneal power: low curvature group (K(1)<=41.00 D), common curvature group (41.00 D= 46.00 D). Preoperative and postoperative (1 day, 1 week, 1, 3 and 6 month) ophthalmic examination results of the patients including uncorrected distance visual acuity (UCDVA), refractive status, intraocular pressure (IOP) and slip lamp microscope examination were recorded. Subjective refraction and Pentacam HR were detected at 6 month after operation so as to monitor the incidence of intraoperative and postoperative complications. The total corneal refractive power (TCRP) based on Ray Tracing technique was applied to evaluate the changes of corneal curvature before and after the surgery. Power vector analysis was applied to evaluate the refraction status based on preoperative and postoperative corneal topography. At 6 months postoperatively, Hotelling t(2) test was applied to compare the refractive status among the groups, and multiple linear regression was applied to analyze the potential influencing factors of under-correction/over-correction. Results: Fifty-four patients (108 eyes) were enrolled, among which 34 were male (68 eyes) and 20 were female (40 eyes). The 3 groups had the same sample size (18 patients and 36 eyes). The low curvature group was featured with youngest average age [(22+/-4) years, chi(2)=8.94, P<0.05], largest male patients proportion (15/18, chi(2)=11.20, P<0.01) and largest average pupil diameter [(3.26+/-0.36) mm, F=4.83, P<0.05], as compared to the other 2 groups. The incidence of severe OBL (25/36) was significantly higher in the high curvature group (chi(2)=65.06, P<0.01). All patients showed no diminution of vision and their UCDVA averaged 5.1 at 6 months postoperatively, however patients with low curvature were slightly "under-corrected" in 1-mm and 2 mm zones (Error values<0). The preoperative spherical equivalent (SE) and postoperative spherical aberration in 6-mm zone were the significant factors affecting the relationship between preoperative corneal curvature and postoperative refractive status (r=0.392, 2.745, P<0.05). Conclusions: SMILE is safe and effective for patients with both low and high curvature, but the incidence of intraoperative OBL is significantly higher in high curvature group. Patients with low curvature were slightly "under-corrected" in 1-mm and 2-mm zones, which may imply that the design of the lenticule may be aspheric and that the cornea reshaping process of younger patients may be of particular characteristics. (Chin J Ophthalmol, 2018, 54: 48-54). PMID- 29429288 TI - [Study on the difference of binocular accommodative response between atients with intermittent exotropia under different viewing condition]. AB - Objective: To evaluate the accommodative response of patients with intermittent exotropia (IXT) objectively, and study the changes of accommodative response of intermittent exotropia patients when maintaining binocular fusion. Methods: The prospective cohort study was used in this study. Twenty-four patients diagnosed with basic intermittent exotropia who visited the eye hospital of Wenzhou Medical University during October 2016 through January 2017 together with 24 normal volunteers were included, the 48 participants aged from 10 to 27 years old. The participants were divided into the case group and the control group. There were 11 males and 13 females in the case group, and 7 males and 17 females in the control group. The Open-filed autorefractor WAM-5500 (Grand Seiko, Japan) was used to measure the accommodative response of each eye under binocular and monocular viewing conditions at 5 m and 40 cm respectively. During the measurement, patients wore full correction spectacles to achieve distant best corrected visual acuity of both eyes. The accommodative responses of each eye under binocular and monocular viewing conditions at distance or near between fellow eyes and groups were compared. Results: Under near fixation (40cm) binocular viewing conditions, the accommodative response of the fixating eye ( 1.915+/-0.301)D was different from the deviating eye -1.649(-2.020, -0.304)D in the case group (Z=-3.714, P<0.001). Under near fixation monocular viewing conditions, the accommodative response of the fixating eye (-1.653+/-0.271)D was also different from the deviating eye -1.565 (-2.031, -0.667)D in the case group (Z=-2.971, P=0.003). During binocular viewing, the asymmetric value of the accommodative response between both eyes of the case group was 0.389(0.102, 1.458)D which was more significant than the normal controls' 0.155(0.009, 0.573)D (Z=-3.505, P<0.001), but during monocular viewing, there was no significant difference between the groups (Z=-1.908, P=0.056). Under near viewing conditions, the variation value of the fixating eyes of the case group was -0.228(-0.796, 0.382)D, which was greater than the variation value -0.086(-0.606, 0.628)D of the right eye of the normal controls, such difference is of statistical significance (Z=-2.279, P=0.023). Under distance viewing conditions, there was no significant difference in the accommodative response between fixating eyes and deviating eyes in case group neither during monocular viewing nor binocular viewing (t=-1.525, 1.729, P>0.05). Besides, the asymmetric values of accommodative response between groups were not significantly different (Z=-1.433, P=0.152. Z=-0.938, P=0.348). Under distance viewing conditions, the changes in accommodative response of each eye during both monocular viewing and binocular viewing were not significantly different between case group and normal controls (Z=-0.041, P=0.967. Z=-1.433, P=0.152). Conclusions: The accommodative responses of the fixating eye and deviating eye of patients with intermittent exotropia were asymmetric under near fixation binocular viewing conditions, and the accommodative response of the deviating eye tends to decrease. Besides, the change of accommodative response of the patients with intermittent exotropia when maintaining binocular fusion is more significant than that of the normal controls. (Chin J Ophthalmol, 2018, 54: 55-61). PMID- 29429289 TI - [Clinical observation on the evolution process of macular ganglion cell complex and peripapillary retinal nerve fiber layer of neuritis patients]. AB - Objective: To discuss the dynamic changes and correlation of macular ganglion cell (mGCC) and peripapillary retinal nerve fiber layer (pRNFL) of neuritis patients through optical coherence tomography (OCT). Methods: A retrospective case series study. Eleven eyes from 11 patients who have been diagnosed with neuritis and received regular follow-up during June 2013 through June 2015 were included. The dynamic characteristic changes of mGCC and pRNFL over the course of disease, as well as their correlations between best visual acuity and visual field have been analyzed based on OCT measurements. Results: According to the observation on the 11 eyes of the 11 patients, patients showed symptoms of decreased vision, abnormal visual field, swollen mGCC and pRNFL with normal or increased thickness during the subnormal period. During the advance-separation period (around 3 weeks), the thickness of mGCC decreased resulting from atrophy while pRNFL was still swollen. Druing the late period (usually 6-8 weeks after onset of the disease), both mGCC and pRNFL were getting thinner due to atrophy. Vision acuity and visual field of the patients improved after treatment, however, they were still not comparable with the normal level before the disease. Conclusions: The thickness changes of mGCC and pRNFL differs in neuritis patients over time. OCT can help us in detecting these changes, thus provide a foundation for us to further explore the treatment and anatomical changes of neuritis patients. (Chin J Ophthalmol, 2018, 54: 62-68). PMID- 29429290 TI - [The application progress of 3D printing technology in ophthalmology]. AB - 3D printing is a kind of technology that makes 3D models from computer-aided designs through additive manufacturing, in which successive layers of the material are deposited onto underlying layers to construct 3D objects. In recent years, 3D printing is gradually applied in the field of ophthalmology, such as the cornea, retina, orbital operation, ocular tumor radiotherapy, ocular implants and ophthalmology teaching. This article reviews the application status of 3D printing technology in the basic research and clinical treatment in ophthalmology. (Chin J Ophthalmol, 2018, 54: 72-76). PMID- 29429291 TI - [Focusing on the management of chronic dry eye disease]. AB - Dry eye has become the most common ophthalmic disease besides ametropia. As a chronic ophthalmic disease, dry eye, which in serious cases might even lead to blindness, not only affects the life quality of the patient, but also poses adverse impact on social productivity and work efficiency, and moreover influences the development of society and economy. The incidence of dry eye has been rising in recent years because of the widespread use of video terminals, which poses greater challenges for us. Therefore, we put forward the concept of chronic disease management for dry eye in the hope of drawing extensive attention and planning ahead of time, so as to meet the needs of dry eye patients in China. (Chin J Ophthalmol, 2018, 54: 81-83). PMID- 29429292 TI - [Focusing on the ocular surface problems induced by cosmetology]. AB - Making oneself more beautiful has always been part of humans' civilized life. Accordingly, the side effects of various cosmetic product and cosmetic procedure long exist. The ocular-surface problems induced by cosmetology mainly include cornea and conjunctiva damages, and tear film damages. Specifically, cornea and conjunctiva damage included: (1) physical injury caused by nonstandard operational procedure, (2) toxic and side effect of cosmetic product, and (3) infection induced by using cosmetic contact lenses, while tear film damage included: (1) injury of normal eyelid structure, (2) decrease of tear production from lacrimal gland, and (3) function and morphology injury of meibomian gland. (Chin J Ophthalmol, 2018, 54: 84-86). PMID- 29429293 TI - [Deep anterior lamellar keratoplasty combined with antiviral therapy in the treatment of severe herpes necrotizing stromal keratitis]. AB - Objective: To evaluate the efficacy of modified deep lamellar keratoplasty (DLKP) combined with antiviral medications for severe herpes necrotizing stromal keratitis. Methods: Retrospective case series study. Modified DLKP was performed in combination with antiviral medications in fifty patients (50 eyes) with severe necrotizing stromal keratitis, which was unresponsive to systemic and topical antiviral treatment for 1 week, at Shandong Eye Hospital. Before surgery, the operated eyes were examined using slit-lamp microscopy. The size of corneal ulceration and inflammatory infiltration and the depth of ulceration were observed in all of the patients. Corneal scraping and microbial culture and confocal laser scanning microscopy were used to exclude fungal, bacterial, Acanthamoeba, or other infections, and check the number of corneal endothelial cells. Anterior segment optical coherence tomography was used to examine the depth of infiltration, especially the thickness of the remaining cornea below the deepest ulceration. Antiviral drugs were used topically and systemically to control the infection and inflammation. Postoperatively, both antiviral drugs and low-dose corticosteroids were used. The ocular inflammation, corneal graft status and viral recurrence were monitored intraoperatively and postoperatively. Results: All of the fifty patients showed obvious inflammatory infiltration and stromal ulcers, and the corneal stroma in 23 patients (46%) remained less than 1/5 of the corneal thickness. Nine (18%) of the patients presented with descemetocele. The depth of infiltration ranged from 128 MUm to 519 MUm [mean, (265+/-84) MUm]. The depth of corneal ulcers was deeper than 2/3 of the corneal thickness in 36 eyes (72%). The endothelial cells were visible in 26 eyes. The density of endothelial cells ranged from 1 275 cells/mm(2) to 2 994 cells/mm(2) [mean, (2 053+/-507) cells/mm(2)]. No fungal or bacterial infection was detected by corneal scraping. The microbial culture results were negative. All the inflammations in patients with severe herpes necrotizing stromal keratitis were under control by DLKP. No intraoperative corneal perforation occurred, and 6 eyes (12%) healed following amniotic membrane transplantation due to slow corneal epithelial healing. The infection was exacerbated two days following the surgery in two eyes (4%). These infections were controlled with enhanced antiviral medications in addition to the immediate withdrawal of corticosteroids. The corneal grafts returned to transparency at 1-2 weeks in 42 eyes (84%). Ten eyes (20%) exhibited recurrence due to medication withdrawal without the doctors' advice and a lack of regular visit during 2-year follow-up. Two patients (4%) developed stromal graft rejection for the same reasons. Conclusions: DLKP can achieve the results of ulcer healing for severe herpes necrotizing stromal keratitis. Combined antiviral therapy and close follow-up can reduce the viral recurrence. (Chin J Ophthalmol, 2018, 54: 97-104). PMID- 29429294 TI - [Pre-descement membrane endothelial keratoplasty for treatment of patients with corneal endothelial decompensation]. AB - Objective: To investigate the clinical outcomes of Pre-descement membrane endothelial keratoplasty (PDEK) for treatment of patients with corneal endothelial decompensation. Methods: Retrospective study of case series. The cases of 20 patients (20 eyes) who were diagnosed with corneal endothelial decompensation induced by various original diseases and received PDEK during July 2016 and December 2016 at Zhongshan Ophthalmic Center have been analyzed. The participants included 8 males and 12 females with an average age of (59.3+/-11.8) years. All 20 patients received PDEK operation, the Dua's layer, descement membrane and endothelium of donor tissue were separated from the underlying stroma with the application of big-bubble technique, and donor discs with diameters of 7.75 or 8.00 mm were harvested with scissors. The donor discs were stained with 0.06% trypan blue and loaded on inserters which were then gently inserted into the anterior chamber of the recipient. When the rolled inserted graft was unfolded, air was carefully injected into the anterior chamber underneath the graft so that the graft can attach to the stroma of the recipient. Post-operation follow-ups of over 6 months have been conducted for all patients, the best spectacle corrected visual acuity (BSCVA), the position of donor disc, corneal thickness and corneal endothelial cell density (ECD) were documented. The pre-operation and post-operation (6 months postoperatively) corneal thickness data of the patients were analyzed with paired sample t test. Results: The success rate of preparing PDMEK donor disc with big-bubble technique is 90% (18/20). Eighteen patients (90%) received PDMEK surgery successfully. Anterior segment optical coherence tomography (AS-OCT) results indicated that sixteen donor discs (16/18) were well attached to the back surface of the recipient stroma, and that two discs (2/18) dislocated at 6 days after surgery. At 6 months post-operatively, the corneas of 14 patients (14/18) turned clear with their BSCVA ranging 0.4 to 1.0, and the ECD was (1 389.3+/-373.2) cells/mm(2) for the patients with clear corneas. At 6 months post-operatively, the average corneal thickness of the patients reduced to (605+/-45) MUm from the preoperative level of (655+/-56) MUm, and the differences are of statistical significance (t=2.137, P=0.032). Conclusions: Application of big-bubble technique could effectively secure the success rate of PDEK disc preparation and control the loss of donated corneas. PDEK disc can be easily handled and unrolled in the anterior chamber, which could improve the postoperative clinical outcomes. (Chin J Ophthalmol, 2018, 54: 105-110). PMID- 29429295 TI - [Etiological and drug sensitivity analysis of lacrimal canaliculitis]. AB - Objective: To analyze the etiology and drug sensitivity of lacrimal canaliculitis. Methods: Retrospective study of case series. The general information, culture results and drug sensitivity results of 52 patients (including 10 males and 42 females with an average age of 60.3 years) clinically diagnosed with lacrimal canaliculitis during 2011 and 2016 at Beijing Tongren Hospital of Capital Medical University have been analyzed. The enumeration data have been tested with Chi-square method. Results: The positive rate of bacterial culture was 78.8%, and the fungal culture tests of all cases showed negative results. Sixty strains of bacteria were isolated from 41 patients whose bacterial culture tests showed positive results, Gram-positive bacteria have been confirmed as the main among the isolated bacteria with Streptococcus (18.3%), Propionibacterium (18.3%), and Streptococcus (15.0%) identified as the three common genera. Thirteen cases (25.0%, all the 13 patients were female) involved with mixed infection, 13.3% (8/60) of the isolated strains were multi-drug resistant bacteria. The drug sensitive rate of the bacteria to fluoroquinolones antibiotics(79.3%, 230/290) was higher than that to cephalosporins(62.1%, 36/58) and aminoglycoside antibiotics(56.3%, 98/174), and such differences are of statistical significance (chi(2)=7.977, 27.738, P<0.05). Except for the fact that gram-positive bacteria are mostly sensitive to vancomycin, the sensitive rate of the bacteria to gatifloxacin was the highest and that to tobramycin was the lowest. Conclusion: Lacrimal canaliculitis tend to affect women and elderly patients. Staphylococcus, Propionibacterium, and Streptococcus are the three most common genera. Gatifloxacin may be the preferred antibiotic. Antibiotics combination therapy should be applied for multi-drug resistant bacteria. (Chin J Ophthalmol, 2018, 54: 111-114). PMID- 29429296 TI - [Analysis of corneal and conjunctival sensitivities and its related factors of premature babies]. AB - Objective: To analyse the corneal and conjunctival sensitivities of premature babies and to study the relevant influencing factors. Methods: Cross-sectional study. One hundred premature infants born at Women's Hospital School of Medicine Zhejiang University between May 2015 and September 2015 were enrolled, among which 51 were male (51%) and 49 were female (49%), the mean gestational age was (30.93+/-1.75)w, the mean corrected gestational age was (33.65+/-1.53)w, the mean birth weight was (1 592+/-336)g. The thresholds of cornea and conjunctiva of infants' left or right eyes were measured with Cochet-Bonnet aesthesiometer at 8 10 o'clock every morning when they naturally woke up, the minimum length of nylon wire that induced three successive times of eye-blink responses was recorded. Paired sample t test was used to compare the corneal and conjunctival sensitivities, the ocular surface sensitivities of preterm infants of different gender were compared using independent samples t-test, Pearson correlation and multiple linear regression analysis was conducted to analyze the correlation of corneal and conjuncitval sensitivities with gestational age, birth weight, age and corrected gestational age. Results: The mean corneal sensitivity was (44.85+/ 5.53) mm and the mean conjunctival sensitivity was (23.50+/-5.48)mm in premature babies, corneal sensitivity was significantly higher than conjunctival sensitivity (t=25.620, P<0.001). No statistical significance was found between male and female preterm infants in corneal sensitivity [(44.80+/-5.83) mm vs. (44.90+/-5.25) mm, t=-0.085, P=0.933] and conjunctival sensitivity[(23.14+/-5.83) mm vs. (23.88+/-5.13) mm, t=-0.673, P=0.502]. Pearson correlation analysis showed that corneal sensitivity was significantly associated with conjunctival sensitivity in prematurity(r=0.676, P<0.001). There was significant correlation between corneal sensitivity and age, corrected gestational age (r=0.238, P=0.017; r=0.679, P<0.001), however no significant correlation was found between corneal sensitivity and gestational age, birth weight in preterm infants (r=0.067, P=0.510; r=-0.179, P=0.075). There was significant correlation between conjunctival sensitivity and corrected gestational age (r=0.490, P<0.001), however no significant correlation was found between conjunctival sensitivity and gestational age, birth weight and age in preterm infants (r=0.078, P=0.439; r= 0.096, P=0.344; r=0.151, P=0.133). Multiple linear regression revealed that corneal sensitivity(Y1) was positively correlated with corrected gestational age(X), the regression equation was Y1=2.45X-37.52, the conjunctical sensitivity(Y2) was also positively correlated with corrected gestational age(X), the regression equation was Y2=1.75X-35.41. Conclusions: The corneal sensitivity is higher than conjunctival sensitivity in premature babies.No statistical significance is found between male and female preterm infants in corneal sensitivity and conjunctival sensitivity. The corneal sensitivity and conjunctival sensitivity are correlated with corrected gestational age in preterm infants. The corneal and conjunctival sensitivities of premature babies tend to increase along with the increase of corrected gestational age. (Chin J Ophthalmol, 2018, 54: 115-119). PMID- 29429297 TI - [Preliminary study on reading speed test with IReST for normally-sighted young Chinese readers]. AB - Objective: To assess the reading speed of normally-sighted young Chinese with the International Reading Speed Texts (IReST) Chinese version, and evaluate the normal range of the texts, the equivalence of the ten different texts and the potential clinical value. Methods: Evaluation of diagnostic techniques. Participants aged 18 to 35 years old with junior high school or above education and best corrected visual acuity no less than 0.6 were recruited. Best corrected visions of both eyes and binocular vision were tested, and ocular and nervous system diseases were excluded with slit-lamp microscope and funduscope. All the ten texts were read aloud at a distance of 40cm one by one according to a random sequence for each participant. Reading speeds were calculated based on the reading time measured with a stopwatch and number of characters read correctly. The procedure was repeated once again a week later. Data were collected with Epidata and further analyzed with R software. Data accorded with normal distribution and homogeneity of variance were compared by t-test, or by rank sum test. Results: One hundred and three volunteers aged (26.0+/-2.8) years old participated in the survey. Among them, 66% were female, 96.1% had college education, 53.4% wear glasses in daily life. The best corrected vision of both distance and near were 1.0 (decimal). For the first test, average reading speed for all the participants and texts was (295+/-51) characters/min,much faster than the normal range provided by the reading cards. No significant difference was found between different texts, and the biggest variance between texts was 11 characters/min(P>0.05). The average reading speed of the second test was (315+/ 53) characters/min, which was faster than the first one (P<0.05) . No statistic relationship was found between reading speed and age, education level or wearing of glasses. However, women read faster than men, and significant difference was found between male and female volunteers in 5 texts during the first test. Conclusions: Normally-sighted young Chinese readers read faster than the normal range provided by IReST cards. There is significant variance of reading speed between different individuals. Although learning effect due to the repeated tests should be considered, the ten texts are of favorable consistency. IReST can be a useful tool for assessing reading performance, especially for comparing results before and after interventions with different texts. (Chin J Ophthalmol, 2018, 54: 120-124). PMID- 29429298 TI - [The influence of EphA2 overexpression on proliferation and apoptosis of human lens epithelial cells exposed to high-concentration dexamethasone in vitro]. AB - Objective: To construct lentiviral-mediated EphA2 overexpression vectors, transfect them into human lens epithelial cells (HLE-B3) in vitro, and investigate the effect of EphA2 gene overexpression on the proliferation and apoptosis of HLE-B3 exposed to high-concentration dexamethasone. Methods: Experimental Study. The pCDH-CMV- MCS-EF1-RFP plasmid was set up by the digestion of NOTIand XbaI double restriction enzyme and ligation of CE ligase, and then the plasmid was transformed into DH10B cells. Seven clons were picked for enzymatic digestion and the clons with correct results were chosen for sequencing. The 293 T/17 cells were co-transfected with the pCDH-CMV-MCS-EF1-RFP-EphA2 and the packaging mixture by Lipofectamine 2000. At different multiplicities of infection (MOI=20, 50, 100, and 200) after 72-hour infection, we observed the expression of RFP and morphological changes of HLE-B3 by an inverted fluorescence microscope, and calculated the transfection efficiency through the flow cytometry. EphA2 protein expression was detected by Western blot. The following experiments were divided into four groups: normal control group (group A), EphA2 overexpression vector transfection group (group B), HLE-B3 cells exposed to dexamethasone group (group C) and EphA2 overexpression vector transfection HLE-B3 cells exposed to dexamethasone group (group D). Statistical analysis method was single factor or two factors variance analysis. Cell survival rate was detected by the Cell Counting Kit-8 assay. Cell apoptosis index was detected by Tunel. Results: Restriction enzyme digestion and sequencing indicated that EphA2 cDNA fragment was successfully inserted in the vector. The infection efficiency was up to 38.6%+/-3.9%, 49.2%+/-4.2%, 79.5%+/-5.5% and 80.2%+/-6.0% when the MOI was 20, 50, 100 and 200, respectively. There was statistically significant difference (F=2 600.8, P=0.001) among the four groups and between any two groups except between the MOI=100 group and MOI=200 group (P=2.507) . The relative quantity of EphA2 protein of the normal control group, empty vector transfection group and EphA2 gene overexpression vector transfection group was (0.561 2+/-0.031 7) , (0.559 7+/-0.012 8) and (3.032 0+/-0.041 9) , respectively. There was statistically significant difference (F=2 646.0, P=0.001) among the three groups and between any two groups except between the normal control group and empty vector transfection group (P=0.868) . The survival rate of groups A, B, C and D was 98.18%+/-1.85%, 122.01%+/-3.89%, 52.32%+/-1.99% and 76.18%+/-3.74%, respectively. There was statistically significant difference among the four groups (F=497.6, P=0.001) . The survival rate of group B was greater than group A (P=0.001) . The survival rate of group D was greater than group C (P=0.001) . Tunel results showed that the apoptosis index of groups A, B, C and D was 5.4%+/ 1.5%, 5.0%+/-1.3%, 23.0%+/-3.9% and 14.4%+/-2.7%, respectively. There was statistically significant difference among the four groups (F=397.6, P=0.001) . The apoptosis index of group B was lower than group A, but there was no statistically significant difference between them (P=0.415) ; the apoptosis index of group D was lower than group C (P=0.018). Conclusions: The lentiviral vector carrying human EphA2 gene has been successfully constructed and efficiently expressed in HLE-B3 cells. EphA2 gene overexpression could increase the HLE-B3 cell survival rate and protect HLE-B3 cells from high-concentration dexamethasone induced reduction of the cell survival rate. EphA2 gene overexpression could protect HLE-B3 cells from high-concentration dexamethasone-induced apoptosis, but it has no remarkable effect on apoptosis of HLE-B3 cells under physiological conditions. (Chin J Ophthalmol, 2018, 54: 125-132). PMID- 29429299 TI - [Research progress of intense pulsed light treatment on meibomian gland dysfunction and relevant dry eye diseases]. AB - Intense pulsed light (IPL) is a broad spectrum incoherent light which is produced by high-output xenon lamp. Since the invention of the first-generation IPL in 1994, IPL technology has been developing rapidly and extensively utilized in multiple fields relevant to dermatology across the world. In 2004, the fourth generation IPL system was introduced with the optimal pulse technology (OPT) and has soon been used for cosmetic purposes all over the world. In 2002, Dr. Toyos found that the meibomian gland dysfunction (MGD) and dye eye disease (DED)symptoms of the rosacea patients who received IPL treatment have been improving significantly, therefore he started to explore the application of IPL system to treatment of dry eye disease. Several recent clinical studies have demonstrated the therapeutic potential of IPL for improving the symptoms and signs of MGD and DED. However, the published data of IPL treatment for MGD and DED is limited, the mechanism of IPL treatment for MGD and DED remained unclear and more relevant researches needed to be done in the future. This article discusses the clinical application history and general mechanism of IPL, and introduces the treatment of IPL for MGD and DED. (Chin J Ophthalmol, 2018, 54: 140-143). PMID- 29429300 TI - [Research progress of conscious pain and neurosensory abnormalities in dry eye disease]. AB - Dry eye is one of the most common ocular problems in ophthalmology clinic. With the change of social environment and people's life style, the prevalence of dry eye disease is increasing. Currently, the diagnosis criteria for dry eye is controversial, diagnosis of dry eye mainly rely on the comprehensive assessment of symptoms and the presence of associated ocular surface signs. However, previous studies have shown a poor correlation between dry eye symptoms and objective clinical signs in patients. Recent studies have found that neuropathic pain plays an important role in the occurrence of discordance between symptoms and signs in dry eye disease. The purpose of this paper is to present the conception of pain, the distribution and function of sensory nerves in ocular surface, the prevalence and mechanism of neuropathic pain and analgesic treatment in dry eye disease. (Chin J Ophthalmol, 2018, 54: 144-148). PMID- 29429301 TI - [Research progress of corneal Langerhans cells' role in the pathogenesis of dry eye disease]. AB - Dry eye disease (DED) is the most common ocular surface diseasenowadays. DED can be divided into different types based on the pathogenesis. The progression of DED is strongly related to chronic ocular surface inflammation, regardless of the type of DED. The corneal Langerhans cells (LC) are the dedicated antigen presenting cells in the ocular surface immune system. Along with further understanding of LC recently, its double-sided functions have been discovered: on one hand, LC phagocytize antigen and induce immune tolerance, and on the other hand, LC process and present antigen, and initiate immune response. Therefore, the functional status of LC is of profound impact on the progression and prognosis of DED. Previous researches on DED pathogenesis were mainly focused on T lymphocyte while the importance of LC have not been emphasized. This article reviews the researches on corneal LC in DED of recent years. (Chin J Ophthalmol, 2018, 54: 149-153). PMID- 29429302 TI - [Research progress of ocular sustained-release corticosteroid delivery systems]. AB - Ocular drug delivery by conventional routes of administration cannot reach or maintain therapeutic drug concentrations in the target tissues for a long duration due to the presence of various anatomical and physiological barriers. Treatment of chronic ocular diseases especially posterior segment of ocular diseases requires novel drug delivery systems that is capable overcome these barriers for efficacious delivery. In recent years, the ocular sustained-release drug delivery system, as a new drug delivery approach, has drawn tremendous attention for its advantages of improving local drug concentration, prolonging action time and reducing frequency of injection. Researchers have been devoted to the developing more effective sustained-release drug delivery systems in order to achieve better clinical efficacy. This article discusses various current sustained-release corticosteroids delivery systems. (Chin J Ophthalmol, 2018, 54: 154-160). PMID- 29429303 TI - Biodegradation of Feather Waste Keratin by the Keratin-Degrading Strain Bacillus subtilis 8. AB - Bacillus subtilis 8 is highly efficient at degrading feather keratin. We observed integrated feather degradation over the course of 48 h in basic culture medium while studying the entire process with scanning electron microscopy. Large amounts of ammonia, sulfite, and L-cysteic acid were detected in the fermented liquid. In addition, four enzymes (gamma-glutamyltranspeptidase, peptidase T, serine protease, and cystathionine gamma-synthase) were identified that play an important role in this degradation pathway, all of which were verified with molecular cloning and prokaryotic expression. To the best of our knowledge, this report is the first to demonstrate that cystathionine gamma-synthase secreted by B. subtilis 8 is involved in the decomposition of feather keratin. This study provides new data characterizing the molecular mechanism of feather degradation by bacteria, as well as potential guidance for future industrial utilization of waste keratin. PMID- 29429304 TI - Characterization of a Thermophilic Lignocellulose-Degrading Microbial Consortium with High Extracellular Xylanase Activity. AB - A microbial consortium, TMC7, was enriched for the degradation of natural lignocellulosic materials under high temperature. TMC7 degraded 79.7% of rice straw during 15 days of incubation at 65 degrees C. Extracellular xylanase was effectively secreted and hemicellulose was mainly degraded in the early stage (first 3 days), whereas primary decomposition of cellulose was observed as of day 3. The optimal temperature and initial pH for extracellular xylanase activity and lignocellulose degradation were 65 degrees C and between 7.0 and 9.0, respectively. Extracellular xylanase activity was maintained above 80% and 85% over a wide range of temperature (50-75 degrees C) and pH values (6.0-11.0), respectively. Clostridium likely had the largest contribution to lignocellulose conversion in TMC7 initially, and Geobacillus, Aeribacillus, and Thermoanaerobacterium might have also been involved in the later phase. These results demonstrate the potential practical application of TMC7 for lignocellulosic biomass utilization in the biotechnological industry under hot and alkaline conditions. PMID- 29429306 TI - The voice of haemochromatosis journeys in regional Australia - A qualitative study exploring self-management AB - DISCUSSION: Hereditary haemochromatosis is a common inherited disorder of iron metabolism with avoidable long-term sequalae if it is detected early and managed well.Semi-structured focus group interviews were held in local community libraries. Data were transcribed verbatim, uploaded to NVivo data management software, descriptively coded and thematically analysed.Participants talked about living with haemochromatosis as an individual journey that requires balancing their changing symptoms, treatment and the demands of their daily life. Data analysis revealed four major themes: 'Discovering my haemochromatosis', 'Talking about venesection', 'Managing with diet', and 'Living with haemochromatosis'.People living with haemochromatosis had a positive attitude to the condition, but there were individual variations in the ways they engaged in self-management. A doctor–patient partnership is crucial in the management of haemochromatosis, especially in rural areas. Patients' symptom experiences and self-management decisions need to be seriously considered.
. PMID- 29429307 TI - Guiding patients through complexity: Motivational interviewing for patients with multimorbidity AB - BACKGROUND: Multimorbidity is an increasing and complex issue in Australian general practice. General practitioners (GPs) face the challenge of navigating multiple potential intervention pathways. Emerging guidelines for multimorbidity recommend patient-centred care and addressing the lifestyle factors of the patient. Motivational interviewing is a patient-centred approach that is focused on behavioural change and effective across a range of lifestyle factors. OBJECTIVE: The aim of this article is to provide a practical introduction to motivational interviewing skills that may be helpful in working with patients who have multimorbidity. Key skills discussed in this article include agenda setting, giving advice, responding to resistance, and asking questions to evoke a patient’s own motivation for change. DISCUSSION: GPs are ideally placed to assist patients with multimorbidity to navigate recommendations and identify which recommendations will work. Navigating complexity is at the heart of general practice, and multimorbidity demands more than an ‘assess-and-advise’ model of care. Motivational interviewing provides a promising and readily applicable framework to empower patients living with multimorbidity. PMID- 29429308 TI - A comparison of policies and guidelines related to multimorbidity in the UK, Australia and Sri Lanka AB - DISCUSSION: Increased rates of multimorbidity, evident in developed and developing countries, should be addressed by health policy. The aim of this study was to compare policies and guidelines related to multimorbidity in primary healthcare in countries with different health systems, to identify initiatives, gaps and opportunities for further improvement.We conducted a content analysis of UK, Australian and Sri Lankan policy documents and guidelines published between 2006 and 2017, in electronic databases, references and government repositories, tabulating data extracted for content, implementation plans, gaps and opportunities for development.Overall, 38 of the 56 identified documents explicitly or implicitly addressed multimorbidity or its prevention. The UK had four policy documents and guidelines specifically on multimorbidity. Australia and Sri Lanka lacked specific policies on multimorbidity, but policies did address chronic conditions and non-communicable diseases.Important differences exist in how national policies seek to address multimorbidity. Policy implementation, how this affects quality of care and outcomes, and the role of primary care should be examined. PMID- 29429309 TI - The experiences of patients and carers living with multimorbid, non-communicable diseases AB - BACKGROUND: Non-communicable diseases (NCDs) are increasing in prevalence and straining health systems globally. This creates a so-called 'burden of disease', which can be traced in terms of fiscal health system matters and in terms of quality of life and lived experiences of people with NCDs. The United Nations has called for a global agenda to manage NCDs and reduce their burden. OBJECTIVE: The purpose of this article is to summarise key findings from the Serious and Continuing Illness Policy and Practice Study concerning patients’ and carers’ experiences of multimorbid NCDs in Australia. We focus on the relevance of findings for policy and general practitioners in Australia. DISCUSSION: We suggest that a complex multimorbidity policy is needed to contextualise and guide single-illness NCD policies. Our research suggests that specialist NCD nurses and allied health professionals could have important roles in improving care coordination between general practices and community health centres.
. PMID- 29429310 TI - What are chronic conditions that contribute to multimorbidity? AB - BACKGROUND: There is currently no accepted standard definition for chronic conditions. OBJECTIVE: The objective of this article is to provide an overview of the characteristics that define health conditions as chronic. DISCUSSION: A list of health conditions classified as chronic should be made available to all general practitioners and policymakers in Australia. This will assist in the claims process for chronic disease management and aid the selection of patients for healthcare home enrolment. Based on assessment of the usual duration, prognosis, sequelae and pattern of recurrence or deterioration, a defined list of chronic conditions classified according to the International Classification of Primary Care, version 2 (ICPC-2) is available for consideration. PMID- 29429311 TI - Management of faecal incontinence AB - BACKGROUND: Faecal incontinence significantly affects a patient's quality of life, and limited research has been conducted into effective interventions that are specific to residential aged care. Australian and New Zealand prevalence data indicate a general faecal incontinence rate of 12-13% in older adults and up to 50% in residential aged care. OBJECTIVE: The objective of this article is to describe the suggested initial investigation and management of faecal incontinence in older adults residing in residential aged care. Discussion of invasive management strategies is outside the scope of this article. DISCUSSION: Faecal incontinence is difficult to treat and there is limited evidence to support any treatment beyond three to six months. However, recognition remains the major barrier to treatment with non-invasive interventions that are available to reduce episode frequency and prevent complications. A combination of exercise programs and integrated continence care in residential aged care may provide significant benefit
if there are sufficient staffing resources available.
. PMID- 29429312 TI - Programmed shared medical appointments AB - BACKGROUND: In 2013, the Australasian Society of Lifestyle Medicine (ASLM) introduced shared medical appointments (SMAs) for managing chronic disease in clinical practice. The popularity of SMAs has increased with the shift towards a Health Care Homes model. Programmed shared medical appointments (PSMAs) are an extension of the standard SMA model, designed to help manage more complex and specific chronic disease issues. OBJECTIVE: The objective of this article is to describe the process of PSMAs and consider their use in primary care. DISCUSSION: PSMAs combine sequential medical consultations with peer support and interaction in a semi-structured group education arrangement. SMAs and PSMAs are ideally suited to the Health Care Homes model of clinical care currently proposed by the federal Department of Health. Proof of concept is currently being tested for PSMAs. Conditions suitable for future trials include overweight and obesity, diabetes (including pre-diabetes), cardiovascular diseases, chronic kidney disease, chronic obstructive pulmonary disease or emphysema, chronic pain or arthritis, mild anxiety or depression, perisurgical management and cancer survival.
. PMID- 29429313 TI - eReferrals: Why are we still faxing? AB - Background and objectives: eReferrals have the potential to be a transformative technology in the healthcare space. This study explored attitudes, behaviours and barriers to eReferral use and electronic communication in general. Methods: A survey of doctors and allied health staff was undertaken in north-west Tasmania. Data were analysed using descriptive statistics and thematic analysis. Results: The response rate was 57% (n = 204). For 80% (n = 164) of respondents, fax or post was the main method of sending letters to other healthcare professionals, and 72% (n = 147) wanted to increase the number of letters sent and received electronically. Barriers and enablers to eReferral use included peer behaviour, software factors, security issues and workplace culture. Discussion: Somewhat ironically, the key barrier to eReferral use was peers not using eReferrals. A greater emphasis on software usability and interoperability is required. Despite eReferrals being promoted as the more secure alternative, security remains a key concern. Workplaces could influence adoption by encouraging eReferral use. PMID- 29429314 TI - Interpreting tests for coeliac disease AB - BACKGROUND: Coeliac disease is one of most prevalent autoimmune illnesses encountered in general practice, and general practitioners have a central role in its diagnosis and follow-up. Key challenges are improving its poor rate of detection, distinguishing it from 'gluten sensitivity', and monitoring and optimising treatment to enhance long-term outcomes. OBJECTIVE: The objective of this article is to review the evidence-based use of serology, histology and genetic testing in the diagnosis and follow-up care of adults and children with coeliac disease. DISCUSSION: Recognition and testing of at-risk patients are keys to expediting the diagnosis of coeliac disease. Knowing when and how to use serology, histology, human leukocyte antigen typing and gluten challenge will increase the accuracy of both diagnosis and disease monitoring.
. PMID- 29429315 TI - A general practice street health service AB - DISCUSSION: People who are homeless or marginalised have poor engagement with mainstream healthcare services. The aim of this study was to explore patient and staff perspectives of a street-based, primary health service, to help identify factors influencing patient access and management.A qualitative study was undertaken from April to September 2016. Interviews (n = 27) explored patients' experiences of accessing healthcare services. Interviews with allied service staff (n = 5) explored referral pathways and patients' access to healthcare. Factors influencing patients' willingness to access primary healthcare through the street health service were identified as doctor-patient empathy, better understanding of patient circumstances, fostering of social capital, facilitating referral pathways and supporting the transition to mainstream general practice as circumstances improve. Hospital discharge planning and follow-up management were identified as gaps in the continuity of service.Ease of access provided by a street-based health service facilitates access to the healthcare system for homeless and marginalised patients.
. PMID- 29429317 TI - The power of renaming PMID- 29429316 TI - Editorial Multimorbidity PMID- 29429318 TI - Perineal tears - A review AB - BACKGROUND: The female perineum is the diamond-shaped inferior outlet of the pelvis. This structure is at risk of trauma during labour because of spontaneous perineal tears of varying degrees or iatrogenic episiotomies. These injuries can result in disabling immediate and long-term complications in the woman. OBJECTIVE: The aim of this article is to provide general practitioners (GPs) with a good understanding of perineal tears by discussing the different classifications, immediate and long-term management, and recommendations for future deliveries. DISCUSSION: Although the majority of perineal tears are managed by obstetricians and gynaecologists, it is important for GPs to understand their management in the event that a patient presents to general practice with concerns during the antenatal or postpartum period.
. PMID- 29429320 TI - Clinical Challenge Jan Feb PMID- 29429319 TI - The importance of adequate referrals for chronic kidney disease AB - DISCUSSION: Regional Australia remains a district of workforce shortage for nephrology. Thus, it is imperative that patients who have the greatest need for nephrologist services are effectively identified upon referral. The aim of this study was to assess referrals to a regional nephrology service against Australian guidelines by assessing the patient's renal function and the information contained in the referral document at the time of first consultation.We conducted a retrospective study of all referrals to a regional Australian nephrology service between 2013 and 2015. The 582 referrals that met the inclusion criteria were compared with Australian nephrology referral guidelines.Less than half of the referral documents (n = 253; 43.5%) described a clinical situation that met referral guidelines, typically due to insufficient pathology investigation. However, after consideration of renal functional test results performed at the initial consultation, an additional 82 cases met referral guidelines (n = 335; 57.6%).More than 40% of nephrology referrals to a regional Australian service did not meet Australian nephrology referral guidelines. This has implications for a regional nephrology service that is experiencing workforce pressures, in addition to the health system more broadly, and for patients. Many referrals contained insufficient information to allow differentiation of patients who would benefit most from nephrology care from patients who could be appropriately managed within primary care. PMID- 29429321 TI - Expression and Characterization of Calcium- and Zinc-Tolerant Xylose Isomerase from Anoxybacillus kamchatkensis G10. AB - The enzyme xylose isomerase (E.C. 5.3.1.5, XI) is responsible for the conversion of an aldose to ketose, especially xylose to xylulose. Owing to the ability of XI to isomerize glucose to fructose, this enzyme is used in the food industry to prepare high-fructose corn syrup. Therefore, we studied the characteristics of XI from Anoxybacillus kamchatkensis G10, a thermophilic bacterium. First, the gene coding for XI (xylA) was inserted into the pET-21a(+) expression vector and the construct was transformed into the Escherichia coli competent cell BL21 (DE3). The expression of recombinant XI was induced in the absence of isopropyl-thio beta-galactopyranoside and purified using Ni-NTA affinity chromatography. The optimum temperature of recombinant XI was 80 degrees C and measurement of the heat stability indicated that 55% of residual activity was maintained after 2 h incubation at 60 degrees C. The optimum pH was found to be 7.5 in sodium phosphate buffer. Magnesium, manganese, and cobalt ions were found to increase the enzyme activity; manganese was the most effective. Additionally, recombinant XI was resistant to the presence of Ca2+ and Zn2+ ions. The kinetic properties, Km and Vmax, were calculated as 81.44 mM and 2.237 MUmol/min/mg, respectively. Through redundancy analysis, XI of A. kamchatkensis G10 was classified into a family containing type II XIs produced by the genera Geobacillus, Bacillus, and Thermotoga. These results suggested that the thermostable nature of XI of A. kamchatkensis G10 may be advantageous in industrial applications and food processing. PMID- 29429322 TI - Biophysical Studies Reveal Key Interactions between Papiliocin-Derived PapN and Lipopolysaccharide in Gram-Negative Bacteria. AB - Papiliocin, isolated from the swallowtail butterfly (Papilio xuthus), is an antimicrobial peptide with high selectivity against gram-negative bacteria. We previously showed that the N-terminal helix of papiliocin (PapN) plays a key role in the antibacterial and anti-inflammatory activity of papiliocin. In this study, we measured the selectivity of PapN against multidrug-resistant gram-negative bacteria, as well as its anti-inflammatory activity. Interactions between Trp2 of PapN and lipopolysaccharide (LPS), which is a major component of the outer membrane of gram-negative bacteria, were studied using the Trp fluorescence blue shift and quenching in LPS micelles. Furthermore, using circular dichroism, we investigated the interactions between PapN and LPS, showing that LPS plays critical roles in peptide folding. Our results demonstrated that Trp2 in PapN was buried deep in the negatively charged LPS, and Trp2 induced the alpha-helical structure of PapN. Importantly, docking studies determined that predominant electrostatic interactions of positively charged arginine residues in PapN with phosphate head groups of LPS were key factors for binding. Similarly, hydrophobic interactions by aromatic residues of PapN with fatty acid chains in LPS were also significant for binding. These results may facilitate the development of peptide antibiotics with anti-inflammatory activity. PMID- 29429324 TI - Crystal Structure of Acyl-CoA Oxidase 3 from Yarrowia lipolytica with Specificity for Short-Chain Acyl-CoA. AB - Acyl-CoA oxidases (ACOXs) play important roles in lipid metabolism, including peroxisomal fatty acid beta-oxidation by the conversion of acyl-CoAs to 2-trans enoyl-CoAs. The yeast Yarrowia lipolytica can utilize fatty acids as a carbon source and thus has extensive biotechnological applications. The crystal structure of ACOX3 from Y. lipolytica (YlACOX3) was determined at a resolution of 2.5 A. It contained two molecules per asymmetric unit, and the monomeric structure was folded into four domains; Nalpha, Nbeta, Calpha1, and Calpha2 domains. The cofactor flavin adenine dinucleotide was bound in the dimer interface. The substrate-binding pocket was located near the cofactor, and formed at the interface between the Nalpha, Nbeta, and Calpha1 domains. Comparisons with other ACOX structures provided structural insights into how YlACOX has a substrate preference for short-chain acyl-CoA. In addition, the structure of YlACOX3 was compared with those of medium- and long-chain ACOXs, and the structural basis for their differences in substrate specificity was discussed. PMID- 29429325 TI - Influence of Water Depth on Microalgal Production, Biomass Harvest, and Energy Consumption in High Rate Algal Pond Using Municipal Wastewater. AB - The high rate algal ponds (HRAP) powered and mixed by a paddlewheel have been widely used for over 50 years to culture microalgae for the production of various products. Since light incidence is limited to the surface, water depth can affect microalgal growth in HRAP. To investigate the effect of water depth on microalgal growth, a mixed microalgal culture constituting three major strains of microalgae including Chlorella sp., Scenedesmus sp., and Stigeoclonium sp. (CSS), was grown at different water depths (20, 30, and 40 cm) in the HRAP, respectively. The HRAP with 20cm of water depth had about 38% higher biomass productivity per unit area (6.16 +/- 0.33 g.m-2.d-1) and required lower nutrients and energy consumption than the other water depths. Specifically, the algal biomass of HRAP under 20c m of water depth had higher settleability through larger floc size (83.6% settleability within 5 min). These results indicate that water depth can affect the harvesting process as well as cultivation of microalgae. Therefore, we conclude that water depth is an important parameter in HRAP design for mass cultivation of microalgae. PMID- 29429326 TI - Denosumab-Treated Giant Cell Tumor of the Bone Mimicking Low-Grade Central Osteosarcoma. PMID- 29429327 TI - Preoperative Cytologic Diagnosis of Warthin-like Variant of Papillary Thyroid Carcinoma. AB - BACKGROUND: Warthin-like variant of papillary thyroid carcinoma (WLV-PTC) is a relatively rare variant of papillary thyroid carcinoma with favorable prognosis. However, preoperative diagnosis using fine-needle aspiration (FNA) specimens is challenging especially with lymphocytic thyroiditis characterized by Hurthle cells and lymphocytic background. To determine a helpful cytological differential point, we compared WLV-PTC FNA findings with conventional papillary thyroid carcinoma with lymphocytic thyroiditis (PTC-LT) and conventional papillary thyroid carcinoma without lymphocytic thyroiditis (PTC) regarding infiltrating inflammatory cells and their distribution. Preoperative diagnosis or potential for WLV-PTC will be helpful for surgeons to decide the scope of operation. METHODS: Of the 8,179 patients treated for papillary thyroid carcinoma between January 2007 and December 2012, 16 patients (0.2%) were pathologically confirmed as WLV-PTC and four cases were available for cytologic review. For comparison, we randomly selected six PTC-LT cases and five PTC cases during the same period. The number of intratumoral and background lymphocytes, histiocytes, neutrophils, and the presence of giant cells were evaluated and compared using conventional smear and ThinPrep preparations. RESULTS: WLV-PTC showed extensive lymphocytic smear with incorporation of thyroid follicular tumor cell clusters and frequent histiocytes. WLV-PTC was associated with higher intratumoral and background lymphocytes and histiocytes compared with PTC-LT or PTC. The difference was more distinct in liquid-based cytology. CONCLUSIONS: The lymphocytic smear pattern and the number of inflammatory cells of WLV-PTC are different from those of PTC-LT or PTC and will be helpful for the differential diagnosis of WLV-PTC in preoperative FNA. PMID- 29429328 TI - Multilevel Regulation of Bacterial Gene Expression with the Combined STAR and Antisense RNA System. AB - Synthetic small RNA regulators have emerged as a versatile tool to predictably control bacterial gene expression. Owing to their simple design principles, small size, and highly orthogonal behavior, these engineered genetic parts have been incorporated into genetic circuits. However, efforts to achieve more sophisticated cellular functions using RNA regulators have been hindered by our limited ability to integrate different RNA regulators into complex circuits. Here, we present a combined RNA regulatory system in Escherichia coli that uses small transcription activating RNA (STAR) and antisense RNA (asRNA) to activate or deactivate target gene expression in a programmable manner. Specifically, we demonstrated that the activated target output by the STAR system can be deactivated by expressing two different types of asRNAs: one binds to and sequesters the STAR regulator, affecting the transcription process, while the other binds to the target mRNA, affecting the translation process. We improved deactivation efficiencies (up to 96%) by optimizing each type of asRNA and then integrating the two optimized asRNAs into a single circuit. Furthermore, we demonstrated that the combined STAR and asRNA system can control gene expression in a reversible way and can regulate expression of a gene in the genome. Lastly, we constructed and simultaneously tested two A AND NOT B logic gates in the same cell to show sophisticated multigene regulation by the combined system. Our approach establishes a methodology for integrating multiple RNA regulators to rationally control multiple genes. PMID- 29429329 TI - Tandem Histone-Binding Domains Enhance the Activity of a Synthetic Chromatin Effector. AB - Fusion proteins that specifically interact with biochemical marks on chromosomes represent a new class of synthetic transcriptional regulators that decode cell state information rather than DNA sequences. In multicellular organisms, information relevant to cell state, tissue identity, and oncogenesis is often encoded as biochemical modifications of histones, which are bound to DNA in eukaryotic nuclei and regulate gene expression states. We have previously reported the development and validation of the "polycomb-based transcription factor" (PcTF), a fusion protein that recognizes histone modifications through a protein-protein interaction between its polycomb chromodomain (PCD) motif and trimethylated lysine 27 of histone H3 (H3K27me3) at genomic sites. We demonstrated that PcTF activates genes at methyl-histone-enriched loci in cancer derived cell lines. However, PcTF induces modest activation of a methyl-histone associated reporter compared to a DNA-binding activator. Therefore, we modified PcTF to enhance its binding avidity. Here, we demonstrate the activity of a modified regulator called Pc2TF, which has two tandem copies of the H3K27me3 binding PCD at the N-terminus. Pc2TF has a smaller apparent dissociation constant value in vitro and shows enhanced gene activation in HEK293 cells compared to PcTF. These results provide compelling evidence that the intrinsic histone binding activity of the PCD motif can be used to tune the activity of synthetic histone-binding transcriptional regulators. PMID- 29429330 TI - Ferritin Nanocages with Biologically Orthogonal Conjugation for Vascular Targeting and Imaging. AB - Genetic incorporation of biologically orthogonal functional groups into macromolecules has the potential to yield efficient, controlled, reproducible, site-specific conjugation of affinity ligands, contrast agents, or therapeutic cargoes. Here, we applied this approach to ferritin, a ubiquitous iron-storage protein that self-assembles into multimeric nanocages with remarkable stability, size uniformity (12 nm), and endogenous capacity for loading and transport of a variety of inorganic and organic cargoes. The unnatural amino acid, 4 azidophenylalanine (4-AzF), was incorporated at different sites in the human ferritin light chain (hFTL) to allow site-specific conjugation of alkyne containing small molecules or affinity ligands to the exterior surface of the nanocage. The optimal positioning of the 4-AzF residue was evaluated by screening a library of variants for the efficiency of copper-free click conjugation. One of the engineered ferritins, hFTL-5X, was found to accommodate ~14 small-molecule fluorophores (AlexaFluor 488) and 3-4 IgG molecules per nanocage. Intravascular injection in mice of radiolabeled hFTL-5X carrying antibody to cell adhesion molecule ICAM-1, but not control IgG, enabled specific targeting to the lung due to high basal expression of ICAM-1 (43.3 +/- 6.99 vs 3.48 +/- 0.14%ID/g for Ab vs IgG). Treatment of mice with endotoxin known to stimulate inflammatory ICAM-1 overexpression resulted in 2-fold enhancement of pulmonary targeting (84.4 +/- 12.89 vs 43.3 +/- 6.99%ID/g). Likewise, injection of fluorescent, ICAM-targeted hFTL-5X nanocages revealed the effect of endotoxin by enhancement of near infrared signal, indicating potential utility of this approach for both vascular targeting and imaging. PMID- 29429331 TI - Investigation of Lipid Metabolism by a New Structured Lipid with Medium- and Long Chain Triacylglycerols from Cinnamomum camphora Seed Oil in Healthy C57BL/6J Mice. AB - In the present study, a new structured lipid with medium- and long-chain triacylglycerols (MLCTs) was synthesized from camellia oil (CO) and Cinnamomum camphora seed oil (CCSO) by enzymatic interesterification. Meanwhile, the antiobesity effects of structured lipid were investigated through observing the changes of enzymes related to lipid mobilization in healthy C57BL/6J mice. Results showed that after synthesis, the major triacylgeride (TAG) species of intesterificated product changed to LaCC/CLaC (12.6 +/- 0.46%), LaCO/LCL (21.7 +/ 0.76%), CCO/LaCL (14.2 +/- 0.55%), COO/OCO (10.8 +/- 0.43%), and OOO (18.6 +/- 0.64%). Through second-stage molecular distillation, the purity of interesterified product (MLCT) achieved 95.6%. Later, male C57BL/6J mice were applied to study whether the new structured lipid with MLCT has the efficacy of preventing the formation of obesity or not. After feeding with different diets for 6 weeks, MLCTs could reduce body weight and fat deposition in adipose tissue, lower plasma triacylglycerols (TG) (0.89 +/- 0.16 mmol/L), plasma total cholesterol (TC) (4.03 +/- 0.08 mmol/L), and hepatic lipids (382 +/- 34.2 mg/mice) by 28.8%, 16.0%, and 30.5%, respectively, when compared to the control 2 group. This was also accompanied by increasing fecal lipids (113%) and the level of enzymes including cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), hormone-sensitive lipase (HSL), and adipose triglyceride lipase (ATGL) related to lipid mobilization in MLCT group. From the results, it can be concluded that MLCT reduced body fat deposition probably by modulating enzymes related to lipid mobilization in C57BL/6J mice. PMID- 29429332 TI - In Situ Construction of Protein-Based Semisynthetic Biosensors. AB - Chemically constructed biosensors consisting of a protein scaffold and an artificial small molecule have recently been recognized as attractive analytical tools for the specific detection and real-time monitoring of various biological substances or events in cells. Conventionally, such semisynthetic biosensors have been prepared in test tubes and then introduced into cells using invasive methods. With the impressive advances seen in bioorthogonal protein conjugation methodologies, however, it is now becoming feasible to directly construct semisynthetic biosensors in living cells, providing unprecedented tools for life science research. We discuss here recent efforts regarding the in situ construction of protein-based semisynthetic biosensors and highlight their uses in the visualization and quantification of biomolecules and events in multimolecular and crowded cellular systems. PMID- 29429333 TI - Orthogonal Information Encoding in Living Cells with High Error-Tolerance, Safety, and Fidelity. AB - Information encoding in DNA is of great interest but its applications in vivo might be questionable since errors could be enriched exponentially by cellular replications and the artificial sequences may interfere with the natural ones. Here, a novel self-error-detecting, three-base block encoding scheme (SED3B) is proposed for reliable and orthogonal information encoding in living cells. SED3B utilizes a novel way to add error detecting bases in small data blocks which can combine with the inherent redundancy of DNA molecules for effective error correction. Errors at a rate of 19% can be corrected as shown by error-prone PCR experiments with E. coli cells. Calculations based on this preliminary result show that SED3B encoded information in E. coli can be reliable for more than 12 000 years of continuous replication. Importantly, SED3B encoded sequences do not share sequence space to all reported natural DNA sequences except for some short tandem repeats, indicating a low biological relevance of encoded sequences for the first time. These features make SED3B attractive for broad orthogonal information encoding purposes in living cells, for example, comments/barcodes encoding in synthetic biology. For proof of concept, 10 different barcodes were encoded in E. coli cells. After continuous replications for 10 days including exposure to ultraviolet for 2-3 min (lethality >60%) per day, all barcodes were fully recovered, proving the stability of the encoded information. An online encoding-decoding system is implemented and available at http://biosystem.bt1.tu harburg.de/sed3b/ . PMID- 29429334 TI - Ni Nanobuffer Layer Provides Light-Weight CNT/Cu Fibers with Superior Robustness, Conductivity, and Ampacity. AB - Carbon nanotube (CNT) fiber has not shown its advantage as next-generation light weight conductor due to the large contact resistance between CNTs, as reflected by its low conductivity and ampacity. Coating CNT fiber with a metal layer like Cu has become an effective solution to this problem. However, the weak CNT-Cu interfacial bonding significantly limits the mechanical and electrical performances. Here, we report that a strong CNT-Cu interface can be formed by introducing a Ni nanobuffer layer before depositing the Cu layer. The Ni nanobuffer layer remarkably promotes the load and heat transfer efficiencies between the CNT fiber and Cu layer and improves the quality of the deposited Cu layer. As a result, the new composite fiber with a 2 MUm thick Cu layer can exhibit a superhigh effective strength >800 MPa, electrical conductivity >2 * 107 S/m, and ampacity >1 * 105 A/cm2. The composite fiber can also sustain 10 000 times of bending and continuously work for 100 h at 90% ampacity. PMID- 29429335 TI - Formation of Stable Mixed Guanidinium-Methylammonium Phases with Exceptionally Long Carrier Lifetimes for High-Efficiency Lead Iodide-Based Perovskite Photovoltaics. AB - Methylammonium (MA)- and formamidinium (FA)-based organic-inorganic lead halide perovskites provide outstanding performance as photovoltaic materials, due to their versatility of fabrication and their power conversion efficiencies reaching over 22%. The proposition of guanidinium (GUA)-doped perovskite materials generated considerable interest due to their potential to increase carrier lifetimes and open-circuit voltages as compared to pure MAPbI3. However, simple size considerations based on the Goldschmidt tolerance factor suggest that guanidinium is too big to completely replace methylammonium as an A cation in the APbI3 perovskite lattice, and its effect was thus ascribed to passivation of surface trap states at grain boundaries. As guanidinium was not thought to incorporate into the MAPbI3 lattice, interest waned since it appeared unlikely that it could be used to modify the intrinsic perovskite properties. Here, using solid-state NMR, we provide for the first time atomic-level evidence that GUA is directly incorporated into the MAPbI3 and FAPbI3 lattices, forming pure GUA xMA1- xPbI3 or GUA xFA1- xPbI3 phases, and that it reorients on the picosecond time scale within the perovskite lattice, which explains its superior charge carrier stabilization capacity. Our findings establish a fundamental link between charge carrier lifetimes observed in photovoltaic perovskites and the A cation structure in ABX3-type metal halide perovskites. PMID- 29429336 TI - Rearrangement of Coenzyme A-Acylated Carbon Chain Enables Synthesis of Isobutanol via a Novel Pathway in Ralstonia eutropha. AB - Coenzyme A (CoA)-dependent pathways have been explored extensively for the biosynthesis of fuels and chemicals. While CoA-dependent mechanisms are widely used to elongate carbon chains in a linear fashion, branch-making chemistry has not been incorporated. In this study, we demonstrated the production of isobutanol, a branched-chain alcohol that can be used as a gasoline substitute, using a novel CoA-dependent pathway in recombinant Ralstonia eutropha H16. The designed pathway is constituted of three modules: chain elongation, rearrangement, and modification. We first integrated and optimized the chain elongation and modification modules, and we achieved the production of ~200 mg/L n-butanol from fructose or ~30 mg/L from formate by engineered R. eutropha. Subsequently, we incorporated the rearrangement module, which features a previously uncharacterized, native isobutyryl-CoA mutase in R. eutropha. The engineered strain produced ~30 mg/L isobutanol from fructose. The carbon skeleton rearrangement chemistry demonstrated here may be used to expand the range of the chemicals accessible with CoA-dependent pathways. PMID- 29429337 TI - Cathode Dependence of Liquid-Alloy Na-K Anodes. AB - Alkali ions can be plated dendrite-free into a liquid alkali-metal anode. Commercialized Na-S battery technology operates above 300 degrees C. A low-cost Na-K alloy is liquid at 25 degrees C from 9.2 to 58.2 wt% of sodium; sodium and/or potassium can be plated dendrite-free in the liquid range at room temperature. The co-existence of two alkali metals in an anode raises a question: whether the liquid Na-K alloy acts as a Na or a K anode. Here we show the alkali metal that is stripped from the liquid Na-K anode is dependent on the preference of the cathode host. It acts as the anode of a sodium rechargeable cell if the cathode host structure selectively accepts only Na+ ions; as the anode of a potassium rechargeable cell if the cathode accepts K+ ions in preference to Na+ ions. This dual-anode behavior means the liquid Na-K alkali-alloy can be applied as a dendrite-free anode in Na-metal batteries as well as K-metal batteries. PMID- 29429338 TI - Investigating the Sources and Transport of Benzotriazole UV Stabilizers during Rainfall and Snowmelt across an Urbanization Gradient. AB - Benzotriazole UV stabilizers (BT-UVs) have attracted increasing attention due to their bioaccumulative nature and ubiquitous presence in surface waters. We apply high-frequency sampling in paired watersheds to describe, for the first time, the behavior of BT-UVs in stream channels during snowmelt and rainfall. Relative to a largely agricultural watershed, concentrations of BT-UVs in an urban watershed were 4-90 times greater during rainfall and 3-21 times greater during snowmelt. During rainfall, a decrease in BT-UV concentrations on particles with increasing suspended sediments and streamflow occurred at all urban sites due to input of relatively clean sediments, while both decreases and increases were observed at rural sites. Where increases occurred in the rural watershed, road sediments were consistently suggested as the source. Contrasts between the urban and rural sites were also observed during snowmelt. While BT-UV concentrations on particles peaked with peak suspended sediment levels at urban stream sites, the opposite was true at rural stream sites. This appeared to be driven partially by different snowpack melt rates in the two watersheds, with earlier melt and presumably higher streamflow facilitating suspension or erosion of more contaminated sediment in the urban stream. In general, it appears that relatively high, consistent emissions in the form of informal (plastic) debris disposal by consumers or industrial releases have likely led to more homogeneous BT-UV profiles and temporal behavior in the urban watershed. In the rural watershed, low emissions instead entail that emissions variability is more likely to translate to variability in chemical profiles and temporal behavior. PMID- 29429339 TI - Planar Is Better: Monodisperse Three-Layered MoS2 Quantum Dots as Fluorescent Reporters for 2,4,6-Trinitrotoluene Sensing in Environmental Water and Luggage Cases. AB - In this study, we present a simple but effective fluorescent system for highly sensitive and versatile sensing of 2,4,6-trinitrotoluene (TNT) using few layered planar MoS2 quantum dots (QDs) as reporters. Excitation-independent emitting MoS2 QDs were first fabricated by using the proposed ultrasonic-hydrothermal-based top down method assisted by carbon-free hydroxylamine hydrochloride. The obtained pristine MoS2 QDs were then modified with cysteine for introducing amino groups as TNT binding sites. The as-prepared MoS2 QDs possess a planar structure, which can more adequately interact with flat aromatic TNT molecules due to pi-pi attraction and decreased steric effects, compared with traditional spherical/quasi-spherical QDs. As a result, they exhibit extremely high sensitivity for TNT sensing (1 nM and 2 ng for solution and substrate assay, respectively). The common ions containing in environmental water samples do not interfere with the sensing. Furthermore, the QDs-decorated test paper shows an instantaneous (within 1 min) response to trace amounts of deposited TNT, and the fluorescence quenching can even be well-visualized by the naked eye. Because of favorable analytical performances, the proposed MoS2 QDs-based TNT sensing system has potential applications in both environmental water monitoring and security screening. PMID- 29429340 TI - Effects of Chain Length and Degree of Unsaturation of Fatty Acids on Structure and in Vitro Digestibility of Starch-Protein-Fatty Acid Complexes. AB - The effects of chain length and degree of unsaturation of fatty acids (FAs) on structure and in vitro digestibility of starch-protein-FA complexes were investigated in model systems. Studies with the rapid visco analyzer (RVA) showed that the formation of ternary complex resulted in higher viscosities than those of binary complex during the cooling and holding stages. The results of differential scanning calorimetry (DSC), Raman, and X-ray diffraction (XRD) showed that the structural differences for ternary complexes were much less than those for binary complexes. Starch-protein-FA complexes presented lower in vitro enzymatic digestibility compared with starch-FAs complexes. We conclude that shorter chain and lower unsaturation FAs favor the formation of ternary complexes but decrease the thermal stability of these complexes. FAs had a smaller effect on the ordered structures of ternary complexes than on those of binary complexes and little effect on enzymatic digestibility of both binary and ternary complexes. PMID- 29429341 TI - Reduced Thermal Transport in the Graphene/MoS2/Graphene Heterostructure: A Comparison with Freestanding Monolayers. AB - The thermal conductivity of the graphene-encapsulated MoS2 (graphene/MoS2/graphene) van der Waals heterostructure is determined along the armchair and zigzag directions with different twist angles between the layers using molecular dynamics (MD) simulations. The differences in the predictions relative to those of the monolayers are analyzed using the phonon power spectrum and phonon lifetimes obtained by spectral energy density analysis. The thermal conductivity of the heterostructure is predominantly isotropic. The out-of-plane phonons of graphene are suppressed because of the interaction between the adjacent layers that results in the reduced phonon lifetime and thermal conductivity relative to monolayer graphene. The occurrence of an additional nonzero phonon branch at the Gamma point in the phonon dispersion curves of the heterostructure corresponds to the breathing modes resulting from stacking of the layers in the heterostructure. The thermal sheet conductance of the heterostructure being an order of magnitude larger than that of monolayer MoS2, this van der Waals material is potentially suitable for efficient thermal packaging of photoelectronic devices. The interfacial thermal conductance of the graphene/MoS2 bilayer as a function of the heat flow direction shows weak thermal rectification. PMID- 29429343 TI - Strategy To Prepare 3-Bromo- and 3-Chloropyrazoles. AB - A general strategy to prepare substituted 3-bromo- and 3-chloropyrazoles is described. The three-step method involves condensation of crotonates or beta chloro carboxylic acids with hydrazines, followed by halogenation and oxidation. Several condensation and oxidation protocols were developed to enable preparation of a wide variety of 3-halopyrazoles with good to excellent yields and regiocontrol. PMID- 29429342 TI - Modular Engineering Intracellular NADH Regeneration Boosts Extracellular Electron Transfer of Shewanella oneidensis MR-1. AB - Efficient extracellular electron transfer (EET) of exoelectrogens is essentially for practical applications of versatile bioelectrochemical systems. Intracellular electrons flow from NADH to extracellular electron acceptors via EET pathways. However, it was yet established how the manipulation of intracellular NADH impacted the EET efficiency. Strengthening NADH regeneration from NAD+, as a feasible approach for cofactor engineering, has been used in regulating the intracellular NADH pool and the redox state (NADH/NAD+ ratio) of cells. Herein, we first adopted a modular metabolic engineering strategy to engineer and drive the metabolic flux toward the enhancement of intracellular NADH regeneration. We systematically studied 16 genes related to the NAD+-dependent oxidation reactions for strengthening NADH regeneration in the four metabolic modules of S. oneidensis MR-1, i.e., glycolysis, C1 metabolism, pyruvate fermentation, and tricarboxylic acid cycle. Among them, three endogenous genes mostly responsible for increasing NADH regeneration were identified, namely gapA2 encoding a NAD+ dependent glyceraldehyde-3-phosphate dehydrogenase in the glycolysis module, mdh encoding a NAD+-dependent malate dehydrogenase in the TCA cycle, and pflB encoding a pyruvate-formate lyase that converted pyruvate to formate in the pyruvate fermentation module. An exogenous gene fdh* from Candida boidinii encoding a NAD+-dependent formate dehydrogenase to increase NADH regeneration in the pyruvate fermentation module was further identified. Upon assembling these four genes in S. oneidensis MR-1, ~4.3-fold increase in NADH/NAD+ ratio, and ~1.2 fold increase in intracellular NADH pool were obtained under anaerobic conditions without discharge, which elicited ~3.0-fold increase in the maximum power output in microbial fuel cells, from 26.2 +/- 2.8 (wild-type) to 105.8 +/- 4.1 mW/m2 (recombinant S. oneidensis), suggesting a boost in the EET efficiency. This modular engineering method in controlling the intracellular reducing equivalents would be a general approach in tuning the EET efficiency of exoelectrogens. PMID- 29429345 TI - Improved UHPLC-MS/MS Methods for Analysis of Isoprene-Derived Organosulfates. AB - Secondary organic aerosol (SOA) is an important yet not fully characterized constituent of atmospheric particulate matter. A number of different techniques and chromatographic methods are currently used for the analysis of SOA, so the comparison of results from different laboratories poses a challenge. So far, tentative structures have been suggested for many organosulfur compounds that have been identified as markers for the formation of SOA, including isoprene derived organosulfates. Despite the effectiveness and robustness of LC-MS/MS analyses, the structural profiling of positional isomers of recently discovered organosulfates with molecular weights (MWs) of 214 and 212 from isoprene was entirely unsuccessful. Here, we developed a UHPLC combined with high-resolution tandem mass spectrometric method that significantly improves the separation efficiency and detection sensitivity of these compounds in aerosol matrices. We discovered that selection of the proper solvent for SOA extracts was a key factor in improving the separation parameters. Later, we took advantage of the enhanced sensitivity, combined with a short scan time window, to perform detailed structural mass-spectrometric studies. For the first time, we elucidate a number of isomers of the MW 214 and the MW 212 organosulfates and provide strong evidence for their molecular structures. The structure of trihydroxyketone sulfate MW 214 that we propose has not been previously reported. The methods we designed can be easily applied in other laboratories to foster an easy comparison of related qualitative and quantitative data obtained throughout the world. PMID- 29429344 TI - Half-Sandwich Ruthenium Carbene Complexes Link trans-Hydrogenation and gem Hydrogenation of Internal Alkynes. AB - The hydrogenation of internal alkynes with [Cp*Ru]-based catalysts is distinguished by an unorthodox stereochemical course in that E-alkenes are formed by trans-delivery of the two H atoms of H2. A combined experimental and computational study now provides a comprehensive mechanistic picture: a metallacyclopropene (eta2-vinyl complex) is primarily formed, which either evolves into the E-alkene via a concerted process or reacts to give a half sandwich ruthenium carbene; in this case, one of the C atoms of the starting alkyne is converted into a methylene group. This transformation represents a formal gem-hydrogenation of a pi-bond, which has hardly any precedent. The barriers for trans-hydrogenation and gem-hydrogenation are similar: whereas DFT predicts a preference for trans-hydrogenation, CCSD(T) finds gem-hydrogenation slightly more facile. The carbene, once formed, will bind a second H2 molecule and evolve to the desired E-alkene, a positional alkene isomer or the corresponding alkane; this associative pathway explains why double bond isomerization and over-reduction compete with trans-hydrogenation. The computed scenario concurs with para-hydrogen-induced polarization transfer (PHIP) NMR data, which confirm direct trans-delivery of H2, the formation of carbene intermediates by gem-hydrogenation, and their evolution into product and side products alike. Propargylic -OR (R = H, Me) groups exert a strong directing and stabilizing effect, such that several carbene intermediates could be isolated and characterized by X-ray diffraction. The gathered information spurred significant preparative advances: specifically, highly selective trans-hydrogenations of propargylic alcohols are reported, which are compatible with many other reducible functional groups. Moreover, the ability to generate metal carbenes by gem hydrogenation paved the way for noncanonical hydrogenative cyclopropanations, ring expansions, and cycloadditions. PMID- 29429346 TI - Ligand-Mediated Nanocrystal Growth. AB - A microfluidic platform combined with a deterministic model accounting for surface ligands reveals precious insights into the nanocrystal formation process. The comparison of on-line kinetic information with model predictions enables the derivation of temperature-dependent kinetic parameters for the CdSe model system. This fully generalizable approach represents a step forward toward a quantitative prediction of the nanocrystal size distribution, enabling the control and optimization of process performance and material properties. PMID- 29429347 TI - Hyperbranched Multiarm Copolymers with a UCST Phase Transition: Topological Effect and the Mechanism. AB - A novel thermoresponsive hyperbranched multiarm copolymer with a hydrophobic hyperbranched poly[3-ethyl-3-(hydroxymethyl)oxetane] core and many poly(acrylamide- co-acrylonitrile) (P(AAm- co-AN)) arms was for the first time synthesized through a reversible addition-fragmentation chain-transfer polymerization. These copolymers show reversible, sharp, and controlled temperature-responsive phase transitions at the upper critical solution temperature (UCST) in water and electrolyte solution. It is the first report on the hyperbranched copolymers with a UCST transition. Two series copolymers with variable AN content (series A) and variable arm length (series B) were synthesized to study the influence of molecular structure on the UCST transition. It was found that the UCST of copolymers could be raised by increasing the AN content or decreasing the arm length. Most interestingly, the amplification effect of the hyperbranched topological structure leads to a broad change of the UCST from 33.2 to 65.2 degrees C with the little change of AN content (5.9%). On the basis of variable temperature nuclear magnetic resonance, dynamic light scattering, and transmission electron microscopy, a UCST transition mechanism, in combination with hydrophilic/hydrophobic balance and multimicelle aggregate (MMA), was proposed. This work enriches the UCST copolymer topology and may extend the knowledge on the structure-activity relationship as well as the mechanism of the UCST polymers. PMID- 29429348 TI - Postoperative Antibiotics Following Cochlear Implantation: Are They Necessary? AB - OBJECTIVE: Evaluate whether prophylactic antibiotics administered following cochlear implant (CI) surgery impact short-term infection rates. DESIGN: Retrospective, concurrent, case-control. SETTING: Tertiary referral center. PATIENTS: All patients (range, 9 months-91 years) undergoing cochlear implantation between 2013 and 2017 (n = 188). INTERVENTION(S): Starting in 2015, one surgeon stopped prescribing postoperative antibiotics after CI surgery. We compared infection rates in a control group that received antibiotics in the 18 months prior to this change (n = 95) to the cohort of patients that did not receive postoperative antibiotics (n = 49). In a second analysis, 44 patients that underwent CI surgery concurrently from a second surgeon and were prescribed postoperative antibiotics were compared to the 49 patients who did not receive postoperative antibiotics. MAIN OUTCOME MEASURE(S): Postoperative infection rates in the perioperative period (0-30 days) following cochlear implantation. RESULTS: None of the 49 cases and none of the 95 historic controls or 44 concurrent controls experienced postoperative infection. CONCLUSIONS: In this sample, postoperative antibiotics following cochlear implantation did not impact perioperative infection rates. Unnecessary antibiotics can lead to increased resistance, allergic sequelae, and unnecessary costs while having little effect on reducing infection rates. This pilot study should encourage surgeons to reevaluate standard practice around antibiotic use after CI surgery. PMID- 29429349 TI - [The role of miRNAs in the pathogenesis of pituitary adenomas]. AB - MicroRNAs (miRNAs) are short, single stranded RNA molecules which play regulatory roles through posttranscriptional regulation of their target genes. Based on our current knowledge, more than 30% of the human protein-coding genes are regulated by miRNAs, hence influencing basic cellular mechanisms including cell proliferation, differentiation and cell death. Differential miRNA expression pattern has been detected in many different types of tumors and, recently, several publications have referred to miRNAs as potential therapeutic targets. Through adjustment of miRNA levels by artificial miRNAs administration or miRNA inhibition, we can influence not only one target gene but also complex biological pathways. Pituitary adenoma is the second most frequent intracranial tumor. In spite of this, the molecular mechanism of the pituitary adenoma formation is not yet entirely revealed. Recently, more and more evidences have been found suggesting that miRNAs have an important role in pituitary adenoma pathogenesis. Here, we summarize the recent results related to this role and highlight the therapeutic potentials in pituitary adenomas. Orv Hetil. 2018; 159(7): 252-259. PMID- 29429350 TI - [Steroid 21-hydroxylase deficiency, the most frequent cause of congenital adrenal hyperplasia]. AB - Congenital adrenal hyperplasia is a group of genetic diseases due to the disablement of 7 genes; one of them is steroid 21-hydroxylase deficiency. The genes of congenital adrenal hyperplasia encode enzymes taking part in the steroidogenesis of adrenal gland. Steroid 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations of the steroid 21-hydroxylase gene. The mutations of steroid 21-hydroxylase gene cause 95% of the congenital adrenal hyperplasia cases. Although the non-classic steroid 21-hydroxylase deficiency with mild symptoms is seldom diagnosed, the classic steroid 21 hydroxylase deficiency may lead to life-threatening salt-wasting and adrenal crises due to the insufficient aldosterone and cortisol serum levels. The classic type requires life-long steroid replacement which may result in cushingoid side effects, and typical comorbidities may be also developed. The patients' quality of life is decreased, and their mortality is much higher than that of the population without steroid 21-hydroxylase deficiency. The diagnosis, consequences and the patients' life-long clinical care require a multidisciplinary approach: the specialists in pediatrics, internal medicine, endocrinology, laboratory medicine, genetic diagnostics, surgery, obstetrics-gynecology and psychology need to work together. Orv Hetil. 2018; 159(7): 269-277. PMID- 29429351 TI - [Genetic factors in hypopituitarism. The role of transcription factors in pituitary hormone deficiency]. AB - Developmental disorders affecting the hypothalamic-pituitary system can result in pituitary hormone deficiency showing a diverse clinical presentation. A significant majority of these disorders are closely linked to defects in transcription factor genes which play a major role in pituitary development. Those affecting the early phase of organogenesis typically lead to complex conditions affecting the pituitary as well as structures in the central nervous system. Transcription factors involved in the late phase can result in combined but rarely isolated pituitary hormone deficiency without extra-pituitary manifestation. Identifying the defects in these pituitary transcription factor genes may provide a useful tool in predicting disease progression as well as screening family members. Several pituitary transcription factors can be detected in the adult gland as well which is strongly emphasized in the World Health Organization's most recent guideline for pituitary tumor classification. Our review summarizes the current essential knowledge relevant for clinical endocrinologists. Orv Hetil. 2018; 159(7): 278-284. PMID- 29429352 TI - [Extraadrenal glucocorticoid synthesis]. AB - Endogenous glucocorticoids exert a diverse array of physiological processes and play an important role in immune modulatory and anti-inflammatory responses. The secretion of cortisol by the adrenal gland is regulated through two mechanisms. Systemic regulation is substantiating by the hypothalamo-pituitary-adrenal axis. Furthermore, a tissue-specific local regulatory system, containing the 11beta hydroxysteroid dehydrogenase enzyme responsible for local glucocorticoid synthesis and the glucocorticoid receptor, has also been demonstrated. Based on the recent evidences, an extra-adrenal corticosteroid synthesis exists in various tissues. Steroidogenic enzymes necessary for this de novo corticosteroid synthesis have been observed in the skin, intestine, thymus and possibly in the brain, heart and lung. These locally synthesized steroids most likely act in an autocrine and paracrine manner and their regulation is mediated by local regulatory loops. The importance of this de novo corticosteroid synthesis seems to be important in the regulation of local homeostasis, immune processes and tissue-specific inflammatory reactions. Orv Hetil. 2018; 159(7): 260-268. PMID- 29429353 TI - [Evolution of molecular genetic methods in the clinical diagnosis of hereditary endocrine tumour syndromes]. AB - The common features of hereditary endocrine tumour syndromes or multiple endocrine neoplasias (MEN) are the association of various tumours of different endocrine organs in one patient or within the same family. Different types can be distinguished from among which type 1 and type 2 are the most common. The mode of inheritance is autosomal dominant, meaning that there is a 50% chance to inherit the pathogenic alteration. The pathogenic variants of genes responsible for MEN syndromes have also been identified in sporadic endocrine tumours and many cases initially referred to as sporadic have been later categorized as familiar based on genetic analysis. The main role of the molecular genetic analysis in these syndromes is to identify the pathogenic variant, then, after appropriate genetic counseling, to perform the genetic screening of first-degree relatives. Following molecular genetic analysis, the state-of-the-art clinical follow-up of the clinically healthy mutation carriers may decrease or even prevent the morbidity and mortality. Due to technological developments in recent years, the molecular genetic analysis of hereditary tumour syndromes has also been changed. Using next generation based sequencing methods in routine clinical diagnostics, the number of pathogenic genes in endocrine tumours has also increased. The present review focuses on the genetic background of hereditary endocrine tumour syndromes and the recently used molecular biological methods will also be presented. Orv Hetil. 2018; 159(7): 285-292. PMID- 29429354 TI - [Pathogenic and diagnostic roles of microRNAs in adrenocortical tumours]. AB - Adrenocortical tumours are quite prevalent. Most of these tumours are benign, hormonally inactive adrenocortical adenomas. Rare hormone-secreting adrenocortical adenomas are associated with severe clinical consequences, whereas the prognosis of the rare adrenocortical cancer is rather poor in its advanced stages. The pathogenesis of these tumours is only partly elucidated. MicroRNAs are small, non-coding RNA molecules that are pivotal in the regulation of several basic cell biological processes via the posttranscriptional regulation of gene expression. Their altered expression has been described in many tumours. Several tissue microRNAs, such as miR-483-5p, miR-503, miR-210, miR-335 and miR-195 were found to be differentially expressed among benign and malignant adrenocortical tumours, and these could also have pathogenic relevance. Due to their tissue specific and stable expression, microRNAs can be exploited in diagnostics as well. As the histological diagnosis of adrenocortical malignancy is difficult, microRNAs might be of help in the establishment of malignancy. Novel data show that microRNAs are secreted in various body fluids, projecting their applicability as biomarkers as part of liquid biopsy. In this review, we attempt to present a synopsis on the pathogenic relevance of microRNAs in adrenocortical tumours and their potential diagnostic applicability. Orv Hetil. 2018; 159(7): 245-251. PMID- 29429355 TI - [Editor's commentary]. PMID- 29429356 TI - [ECG pearls: Pseudoinfarct Q waves and low voltage]. AB - Therapy refracter heart failure is presented. The admission ECG shows low voltage and pseudoinfarct Q waves highly diagnostic for the etiology of heart failure. Orv Hetil. 2018; 159(8): 327-329. PMID- 29429357 TI - [The role of laryngeal electromyography in the diagnosis of vocal cord movement disorders]. AB - The development of the therapeutic possibilities of vocal cord immobility necessitated the parallel renewal of diagnostic methods. In the last years, laryngeal electromyography, which was first introduced more than 70 years ago, has been re-discovered. After reviewing the international literature and their own experience, the authors present the indications, technical requirements, method and, particularly, the evaluation of the results of this procedure. Laryngeal electromyography makes the differentiation between mechanical fixation and immobility with neurological origin of the vocal folds possible. In case of laryngeal paralysis/paresis it also evaluates objectively the severity of neural injury, the prognosis of the disease and the necessity of any glottis-widening procedure. The widespread application of dynamic rehabilitation interventions is not conceivable without the routine application of laryngeal electromyography, so this sensitive diagnostic tool has to be introduced in all laryngological centers. Orv Hetil. 2018; 159(8): 303-311. PMID- 29429358 TI - [Change of paradigm in the surgical treatment of metastatic diseases of the bone. Part II. Treatment of spinal metastases]. AB - The incidence of spinal metastases is constantly growing, but due to the advancements in oncologic treatment methods, the survival and the quality of life of the patients are persistently improving. Choosing the optimal treatment method is essential, and several factors should be considered: type of the primary tumor, segmental stability, the symptoms caused by the metastasis and the general condition of the patient. Using modern radiotherapeutic methods combined with minimally invasive surgical techniques (minimally invasive stabilization, separation surgery) in the majority of patients permits adequate local control with low complication rate. In our review, we describe the state-of-the-art, modern spinal metastasis treatment options based on the recently published evidence. Orv Hetil. 2018; 159(8): 297-302. PMID- 29429359 TI - [General practitioners and eldercare reflected in a survey by questionnaire]. AB - According to statistical data, the number of healthy life years is not increasing in proportion with the longer average life expectancy. In the ageing societies, the long-term care systems are increasingly overburdened; cost-efficient operation and the related coordination of services is one of the key questions for their sustainability. The present separation of the health care and social care systems causes numerous difficulties. One aim of the online research by questionnaire was to survey the attitude of general practitioners - who play a very important part in care for the elderly - towards their elder patients, the patients' family members, and social workers providing eldercare. The other aim was to gather information on shortcomings experienced by doctors in the care system and on what possibilities general practitioners see for the improvement of eldercare. Semi-structured questionnaires were applied and analysed by descriptive and content methodology. The questionnaires were sent out to 5060 addresses around the country: a total of 145 were returned filled in. The respondents made many recommendations for the improvement of eldercare in the categories of development of social services, family support, development of health services, and societal cooperation. The areas in need of development named by the general practitioners are closely interrelated: the reform of social care would support the health care system and vice versa. More effective operation of the health and social care systems would ease the burdens of families, and at the same time encourage more active participation of families in the care process. And the systematic education of society and communities is a long-term investment that would strengthen a positive attitude towards old age and a value-oriented view of the ageing process that is one of the basic conditions for successful social integration of the elderly. Orv Hetil. 2018; 159(8): 312-319. PMID- 29429360 TI - [Professor Arpad Peterffy has turned 80]. PMID- 29429363 TI - Recent advances in the management of chronic migraine in children. AB - INTRODUCTION: Migraine is a chronic-recurrent disorder that progresses in some adults and also in many children. Chronic migraine (CM) is the clinical result of this process. Since migraine does not progress in most children, identifying the risk factors for progression is an important public health priority that should be matched by evidence-based treatment. Areas covered: Herein we conduct a systematic review on the comorbidities and treatment of CM in children and adolescents in the last ten years, summarizing evidence-based recommendations for disease management. Expert commentary: By conceptualizing CM as the result of migraine progression from an episodic form, we suggest avoiding CM at the outset through development of aggressive, preventive interventions as the goal of headache management in the pediatric population. Key interventions include: Decreasing headache frequency with behavioral and pharmacologic interventions; Monitoring body mass index and encouraging maintenance of normal weight; Avoiding medication overuse; Screening and treating comorbidities. PMID- 29429361 TI - [Evaluation of diabetic microangiopathy using optical coherence tomography angiography]. AB - INTRODUCTION: Optical coherence tomography angiography is a non-invasive imaging technique that is able to visualize the different retinal vascular layers using motion contrast to detect blood flow without intravenous dye injection. This method might help to assess microangiopathy in diabetic retinopathy during screening and follow-up. AIM: To quantify retinal microvasculature alterations in both eyes of diabetic patients in relation to systemic risk factors using optical coherence tomography angiography. METHOD: Both eyes of 36 diabetic patients and 45 individuals without diabetes were examined. Duration of diabetes, insulin therapy, blood pressure, HbA1c, dyslipidemia, axial length and the presence of diabetic retinopathy were recorded. Retinal vessel density was measured by optical coherence tomography angiography. The effect of risk factors on vessel density and between-eye asymmetry was assessed using multivariable regression analysis. RESULTS: Vessel density was significantly lower and between-eye difference was significantly higher in diabetic patients compared to controls (p<0.05). Both vessel density and between-eye asymmetry significantly correlated with diabetes duration (p<0.05) after controlling for the effect of risk factors. The between-eye asymmetry in vessel density was significantly higher in patients without clinically detectable diabetic retinopathy compared to control subjects (p<0.001). CONCLUSIONS: There is a decrease in retinal vessel density and an increase in between-eye asymmetry in patients with diabetes compared to healthy subjects. By using optical coherence tomography angiography, the detection of these microvascular alterations is possible before clinically detectable diabetic retinopathy and might serve as a useful tool in both screening and timing of treatment. Orv Hetil. 2018; 159(8): 320-326. PMID- 29429364 TI - Development, optimization and evaluation of curcumin loaded biodegradable crosslinked gelatin film for the effective treatment of periodontitis. AB - OBJECTIVE: Aim of the present study was to prepare curcumin (CUR) loaded biodegradable crosslinked gelatin (GE) film to alleviate the existing shortcomings in the treatment of periodontitis. SIGNIFICANCE: Gelatin film was optimized to provide anticipated mucoadhesive strength, mechanical properties, folding endurance, and prolonged drug release over treatment duration, for successful application in the periodontitis. METHODS: The film was developed by using solvent casting technique and "Design of Experiments" approach was employed for evaluating the influence of independent variables on dependent response variables. Solid-state characterization of the film was performed by FTIR, XRD, and SEM. Further, prepared formulations were evaluated for drug content uniformity, surface pH, folding endurance, swelling index, mechanical strength, mucoadhesive strength, in vitro biodegradation, and in vitro drug release behavior. RESULTS: Solid state characterization of the formulation showed that CUR is physico-chemically compatible with other excipients and CUR was entrapped in an amorphous form inside the smooth and uniform film. The optimized film showed degree of crosslinking 51.04 +/- 2.4, swelling index 138.10 +/- 1.25, and folding endurance 270 +/- 3 with surface pH around 7.0. Crosslinker concentrations positively affected swelling index and biodegradation of film due to altered matrix density of the polymer. Results of in vitro drug release demonstrated the capability of the developed film for efficiently delivering CUR in a sustained manner up to 7 days. CONCLUSIONS: The developed optimized film could be considered as a promising delivery strategy to administer medicament locally into the periodontal pockets for the safe and efficient management of periodontitis. PMID- 29429365 TI - Undergraduate mental health issues: the challenge of the second year of study. AB - BACKGROUND: Student mental health is a global issue. Macaskill reported that the second year was associated with the most significant increases in psychiatric symptoms in UK students. Qualitative data were collected to explore this further. METHOD: Twenty-three second-year undergraduate students were interviewed using a narrative interviewing method to explore their experience of their second year of study. They also completed the General Health Questionnaire-28. Students were grouped according to their psychiatric caseness scores, giving two groups, a well group with scores <=5 and a clinical case group with scores >=6 and their interview data were compared. RESULTS: Using thematic analysis, various themes and subthemes were identified. While both groups identified the same issues namely, the first-year concerns impacting on the second year, course issues, careers and future employability and student debt, the groups reported very different coping styles. CONCLUSION: There were shared anxieties across both groups. The majority related to institutional practices and the unintended impact they may be having on student mental health. While specialist interventions would help the clinical caseness group, arguably the anxiety levels of both groups would benefit equally from relatively easy to implement, inexpensive institutional changes and/or additions to current practices in universities. PMID- 29429366 TI - The enhancement of serotonin-induced contraction of rat femoral artery is mediated by angiotensin II release from intact endothelium. AB - We have performed an in vitro study on isolated intact or denuded femoral artery (FA) of healthy, diabetic, and/or rats submitted to the FA occlusion. The aim was to determine the contribution of endothelium and endothelial dysfunction (ED) on serotonin-induced action in FA. Further, the contribution of angiotensin II and cyclooxygenase products of arachidonic acid was investigated. A marker of ED, vWF was measured in animal serum. Serotonin induced contraction-dependent contraction of isolated FA, which was increased in preparations with endothelium. Pathological conditions such as endothelial denudation, nicotine-induced ED, diabetes or occlusion of FA reduced serotonin-induced contraction. Comparable reduction of serotonin-induced contraction was achieved after inhibition of AT1 receptors with losartan in isolated FA with intact endothelium. Our results demonstrate that angiotensin II contributes to the enhancement of serotonin induced contraction of femoral arteries with intact endothelium. This increase is attenuated by endothelium removal, nicotine treatment, vascular occlusion, and/or hyperglycemia. PMID- 29429367 TI - Obestatin protects and reverses nonalcoholic fatty liver disease and its associated insulin resistance in rats via inhibition of food intake, enhancing hepatic adiponectin signaling, and blocking ghrelin acylation. AB - This study investigated the ameliorative and protective effects of long-term obestatin administration (80 nmol/kg/ intraperitoneal injection (i.p.)) on the pathogenesis of high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD) in rats. Rats (n = 8/group) were divided as control, NAFLD, NAFLD + Simvastatin, NAFLD + obestatin, NAFLD then obestatin, and obestatin then NAFLD. Obestatin co -or post-therapy significantly reduced hepatomegaly and reversed hyperlipidemia, hepatic lipid accumulation, and insulin resistance (IR). Mechanistically obestatin treatments in these rats significantly prevented the increases in final body weights and food intake. Concomitantly, it enhanced circulatory adiponectin levels and hepatic signaling as evident by elevated hepatic protein levels of adiponectin receptors (adipoRII), carnitine palmitoyltransferase-1 (CPT-1), peroxisome proliferator-activated receptor- alpha (PPAR-alpha), and phosphor-AMPK (p-AMPK). In addition, obestatin enhanced total circulatory ghrelin levels and significantly increased deacylated ghrelin to acylated ghrelin (DAG/AG) ratio. These data suggest that obestatin reverses and protects against development or progression of NAFLD directly by modulating ghrelin and adiponectin signaling or indirectly by lowering food intake. PMID- 29429368 TI - Effects of statins on all-cause mortality at different low-density-lipoprotein cholesterol levels in Asian patients with type 2 diabetes. AB - OBJECTIVE: To investigate the effects of statins on all-cause mortality risk at different low-density lipoprotein cholesterol (LDL-C) levels, and to compare the mortality risk between statin users and non-users with identical LDL-C levels in a type 2 diabetes cohort. METHODS: In total, 10,582 outpatients aged >=18 years with type 2 diabetes mellitus (T2DM) between 2009 and 2012 were enrolled in this retrospective cohort study in central Taiwan. All-cause mortality events were followed up until the end of 2014. According to the medical records during the follow-up period, the patients were classified into statin (+) and statin (-) groups. Patients were categorized into different LDL-C segments based on their mean LDL-C levels during the 2.8-year follow-up. RESULTS: Non-cardiovascular mortality accounted for more than half the deaths. Overall, statin therapy significantly reduced the all-cause mortality risk in both univariable and multivariable models (hazard ratios = 0.39 and 0.38, respectively). Sub-group analyses showed that the lowest mortality risk occurred in the 80-89 mg/dL segment in the statin (-) group and in the 90-99 mg/dL segment in the statin (+) group. Statin therapy significantly reduced the mortality risk at all LDL-C levels except for low LDL-C (<60 mg/dL). CONCLUSIONS: In addition to reducing LDL C levels, statin therapy reduced all-cause mortality risk in Taiwanese patients with T2DM. Statins further reduced the mortality risk at most LDL levels. However, at low LDL-C levels, the positive effects of statins may have been nullified. PMID- 29429369 TI - Self-Efficacy and Collective Efficacy as Moderators of the Psychological Consequences of Exposure of Palestinian Parents in Israel to Community Violence. AB - This study examined the rates of exposure to community violence (ECV; that is, witnessing and directly experiencing violence) as well as the detrimental consequences of such exposure as reflected in posttraumatic stress symptoms (PTSS) and a decline in psychological well-being (PWB) among parents. In addition, the study examined whether self-efficacy and collective efficacy moderate these consequences. A self-administered questionnaire was filled out by a systematic random sample of 760 Palestinian parents in Israel. The findings indicate that most of them had witnessed such violence, and almost half of them had directly experienced such violence in their lifetime. The rates of ECV were higher for the fathers than the mothers. ECV was found to predict high levels of PTSS and low levels of PWB among parents. In addition, collective efficacy was found only to moderate the relationship between witnessing community violence and PTSS. There is a need to identify adults who are exposed to community violence, as well as to develop culturally adapted and sociopolitically sensitive therapeutic and preventive interventions and projects for provision of assistance following exposure to such violence. PMID- 29429370 TI - Facile development, characterization, and optimization of new metformin-loaded nanocarrier system for efficient colon cancer adjunct therapy. AB - PURPOSE: Metformin hydrochloride (MF) repurposing as adjuvant anticancer therapy for colorectal cancer (CRC) proved effective. Several studies attempted to develop MF-loaded nanoparticles (NPs), however the entrapment efficiency (EE%) was poor. Thus, the present study aimed at the facile development of a new series of chitosan (CS)-based semi-interpenetrating network (semi-IPN) NPs incorporating Pluronic(r) nanomicelles as nanocarriers for enhanced entrapment and sustained release of MF for efficient treatment of CRC. METHODS: The NPs were prepared by ionic gelation and subsequently characterized using FTIR, DSC, TEM, and DLS. A full factorial design was also adopted to study the effect of various formulation variables on EE%, particle size, and zeta-potential of NPs. RESULTS: NPs had a spherical shape and a mean particle size ranging between 135 and 220 nm. FTIR and DSC studies results were indicative of successful ionic gelation with the drug being dispersed in its amorphous form within CS-Pluronic(r) matrix. Maximum EE% reaching 57.00 +/- 12.90% was achieved using Pluronic(r)-123 based NPs. NPs exhibited a sustained release profile over 48 h. The MF-loaded NPs sensitized RKO CRC cells relative to drug alone. CONCLUSION: The reported results highlighted the novel utility of the developed NPs in the arena of colon cancer treatment. PMID- 29429371 TI - A best-worst scaling in Colombian patients to rank the characteristics of HIV/AIDS treatment. AB - AIM: To elicit patients' preferences for HIV/AIDS treatment characteristics in Colombia. MATERIALS AND METHODS: A best-worst scaling case was used to provide a ranking of 26 HIV/AIDS treatment characteristics that were similar to a previous study conducted in Germany. In each choice task, participants were asked to choose the most important and the least important treatment characteristics from a set of five from the master list. Using the Hierarchical Bayes method, relative importance scores were calculated. Sub-group analyses were conducted according to sex, education, source of infection, symptoms, and age. RESULTS: A total of 195 patients fully completed the questionnaire. The three most important characteristics were "drug has very high efficacy" (relative importance score [RIS] = 10.1), "maximum prolongation of life expectancy" (RIS = 9.7), and "long duration of efficacy" (RIS = 7.4). Sub-group analysis showed only three significant (but minor) differences between older and younger people. CONCLUSION: This study suggests that treatment characteristics regarding efficacy and prolongation of life are particularly important for patients in Colombia. Further investigation on how patients make trade-offs between these important characteristics and incorporating this information in clinical and policy decision-making would be needed to improve adherence with HIV/AIDS medication. PMID- 29429372 TI - Anti-Inflammatory Effects of Intra-Articular Hyaluronic Acid: A Systematic Review. AB - Objective Osteoarthritis (OA) is one of the leading causes of disability in the adult population. Common nonoperative treatment options include nonsteroidal anti inflammatory drugs (NSAIDs), intra-articular corticosteroids, and intra-articular injections of hyaluronic acid (HA). HA is found intrinsically within the knee joint providing viscoelastic properties to the synovial fluid. HA therapy provides anti-inflammatory relief through a number of different pathways, including the suppression of pro-inflammatory cytokines and chemokines. Methods We conducted a systematic review to summarize the published literature on the anti-inflammatory properties of hyaluronic acid in osteoarthritis. Included articles were categorized based on the primary anti-inflammatory responses described within them, by the immediate cell surface receptor protein assessed within the article, or based on the primary theme of the article. Key findings aimed to describe the macromolecules and inflammatory-mediated responses associated with the cell transmembrane receptors. Results Forty-eight articles were included in this systematic review that focused on the general anti inflammatory effects of HA in knee OA, mediated through receptor-binding relationships with cluster determinant 44 (CD44), toll-like receptor 2 (TLR-2) and 4 (TLR-4), intercellular adhesion molecule-1 (ICAM-1), and layilin (LAYN) cell surface receptors. Higher molecular weight HA (HMWHA) promotes anti inflammatory responses, whereas short HA oligosaccharides produce inflammatory reactions. Conclusions Intra-articular HA is a viable therapeutic option in treating knee OA and suppressing inflammatory responses. HMWHA is effective in suppressing the key macromolecules that elicit the inflammatory response by short HA oligosaccharides. PMID- 29429373 TI - Long-Term Clinical and MRI Results of Matrix-Assisted Autologous Chondrocyte Implantation for Articular Cartilage Defects of the Knee. AB - Objective To evaluate the long-term clinical and radiological outcome of matrix assisted autologous chondrocyte implantation (mACI) for articular cartilage defects in the knee joint. Design Clinical evaluation was assessed in 21 patients with full-thickness cartilage defects, International Cartilage Repair Society (ICRS) grade IV. Clinical scoring was performed preoperatively and 12 years after transplantation using the International Knee Documentation Committee (IKDC) score, the Lysholm score, the Knee injury and Osteoarthritis Outcome Score (KOOS), and the Noyes sports activity rating scale. Morphologic evaluation of the repair tissue was assessed by magnetic resonance imaging (MRI) in 14 patients using the Kreuz-Henderson score. Results Clinical evaluation revealed significant improvement in the IKDC, the Lysholm, the KOOS, and the Noyes score. Morphological evaluation by MRI showed moderate to complete defect filling in 10 of 14 patients, demonstrating normal to nearly normal values in mean 74.29% of all assessed parameters. Significant correlation of the parameter cartilage signal and clinical outcome was found with the IKDC, Lysholm, and KOOS subscales ADL (activities of daily living) and QoL (quality of life). Conclusions The clinical and radiological outcomes 12 years after transplantation suggest the confirmation of the promising results of the mid-term follow-up. This study therefore provides first indications that the implantation of mACI might be a suitable option for long-term cartilage repair. Future controlled studies need to address the exact parameters influencing the long-term outcome of mACI. PMID- 29429374 TI - Maternal gestational diabetes mellitus: is it associated with long-term pediatric ophthalmic morbidity of the offspring? AB - PURPOSE: To determine whether children born to mothers with gestational diabetes mellitus (GDM) are at increased risk to develop of pediatric ophthalmic morbidity. MATERIALS AND METHODS: In this population based cohort study, all deliveries between 1991 and 2014 were included. Congenital malformations, multiple gestations, and patients lacking prenatal care were excluded from analysis. Mothers were defined as either having no GDM, having diet-treated GDM, or medically treated GDM. Outcomes were defined as different ophthalmic morbidities of the offspring until the age of 18. Kaplan-Meier curves were used to compare the cumulative morbidity in each group, and a Cox proportional hazard model was used to control for possible confounders. RESULTS: During the study period, 238,622 deliveries met the inclusion criteria, of those 4.0% (n = 9601) of mothers were diagnosed with GDM treated by diet, and an additional 1.0% (n = 2398) were diagnosed with GDM treated by medication. Offsprings of patients with GDM treated by medication had a higher cumulative incidence of ophthalmic morbidity when compared to the other groups (Kaplan-Meier log rank test p = .038). GDM treated by medication was found to be an independent risk factor for long-term ophthalmic morbidity, in a cox multivariable model (adjusted HR: 1.5, 95%CI: 1.05-2.1, p = .025). CONCLUSIONS: Gestational diabetes mellitus treated by medication is associated with an increased risk for long-term pediatric ophthalmic morbidity. PMID- 29429376 TI - Therapeutic strategies for organ-confined and non-organ-confined bladder cancer after radical cystectomy. AB - INTRODUCTION: In patients with muscle invasive or Bacillus Calmette-Guerin refractory urothelial carcinoma of the urinary bladder (UCUB) radical cystectomy represents the standard of care. However, a proportion of patients experience disease progression, local recurrence and/or metastatic disease. Areas covered: This review provides an overview of available therapeutic strategies after radical cystectomy and examines ongoing clinical trials including cytotoxic chemotherapy and immunotherapy. Expert commentary: Cytotoxic chemotherapy offers limited benefit in UCUB patients. However, the recent introduction of immunotherapy provides new hope for durable responses or possibly complete cures. PMID- 29429375 TI - Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system. AB - PURPOSE: High intensity focussed ultrasound (HIFU) can non-invasively treat tumours with minimal or no damage to intervening tissues. While continuous-wave HIFU thermally ablates target tissue, the effect of hundreds of microsecond-long pulsed sonications is examined in this work. The objective of this study was to characterise sonication parameter-dependent thermomechanical bioeffects to provide the foundation for future preclinical studies and facilitate clinical translation. METHODS AND MATERIALS: Acoustic power, number of cycles/pulse, sonication time and pulse repetition frequency (PRF) were varied on a clinical magnetic resonance imaging (MRI)-guided HIFU (MR-HIFU) system. Ex vivo porcine liver, kidney and cardiac muscle tissue samples were sonicated (3 * 3 grid pattern, 1 mm spacing). Temperature, thermal dose and T2 relaxation times were quantified using MRI. Lesions were histologically analysed using H&E and vimentin stains for lesion structure and viability. RESULTS: Thermomechanical HIFU bioeffects produced distinct types of fractionated tissue lesions: solid/thermal, paste-like and vacuolated. Sonications at 20 or 60 Hz PRF generated substantial tissue damage beyond the focal region, with reduced viability on vimentin staining, whereas H&E staining indicated intact tissue. Same sonication parameters produced dissimilar lesions in different tissue types, while significant differences in temperature, thermal dose and T2 were observed between the parameter sets. CONCLUSION: Clinical MR-HIFU system was utilised to generate distinct types of lesions and to produce targeted thermomechanical bioeffects in ex vivo tissues. The results guide HIFU research on thermomechanical tissue bioeffects, inform future studies and advice sonication parameter selection for direct tumour ablation or immunomodulation using a clinical MR-HIFU system. PMID- 29429377 TI - Strategies for implementing effective mealtime insulin therapy in type 2 diabetes. AB - BACKGROUND: Type 2 diabetes mellitus (T2D) is a growing global epidemic. Due to the progressive nature of the disease, many people with T2D require insulin at some point, most commonly a long-acting (basal) insulin to assist with 24-h control of glucose levels. OBJECTIVE: This opinion paper provides an overview of considerations for primary care providers (PCPs) in intensifying the treatment regimen when basal insulin therapy is inadequate. RESULTS: Control of mealtime hyperglycemia, in addition to fasting hyperglycemia, has been shown to be crucial in reaching A1c goals of <7.0%. However, initiating and optimizing mealtime insulin therapy can be challenging for both people with T2D and PCPs, due to a perceived lack of efficacy and burden of insulin treatment, causing "psychological insulin resistance" in people with T2D and clinical inertia among PCPs. Successful implementation of mealtime insulin therapy requires not only choosing appropriate treatment strategies, but also addressing patient-related behavioral and emotional barriers. Simplified treatment algorithms, combined with the use of advanced technology (devices such as insulin pens, pumps, and patches), and collaborative decision-making can help decrease barriers to effective mealtime insulin therapy. CONCLUSIONS: It is possible to implement an effective basal-bolus insulin regimen in people with T2D in a way that improves glucose control while minimizing negative effects on quality-of-life, treatment satisfaction, and psychological well-being. PMID- 29429378 TI - Project Transform: engaging patient advocates to share their perspectives on improving research, treatment and policy. AB - OBJECTIVE: Incorporating the patient perspective into lung cancer research, policy and treatment is becoming increasingly recognized as important. This project sought to create an engagement partnership with lung cancer patient advocates and to explore their views on transforming lung cancer healthcare systems, treatment and policy to be more patient centered. METHODS: A patient action committee (PAC) of patient advocates living with lung cancer was engaged through group meetings, in-person and phone interviews, and email correspondence. Group meetings (two 1 hour meetings, one 3 hour meeting) served to discuss engagement strategies and project goals, while individual interviews (n = 19) (30 75 minutes) provided in-depth exploration of individuals' perspectives. Meetings and interviews were recorded to identify priorities for addressing issues within lung cancer research, treatment and policy. PAC members corroborated the results through email and in-person meetings. RESULTS: PAC members identified three general objectives: (i) for healthcare systems, increasing access to care through accessible, coordinated and affordable care, (ii) for treatment, addressing patient needs in treatment and research through patient education, shared decisions and clinical trials, and (iii) for policy, shining a light on lung cancer through screening policies, public awareness and research funding. CONCLUSION: Patient advocates expressed their views that lung cancer is a neglected disease that is not highly prioritized in healthcare systems, treatment approaches and public perceptions. This project represents an integral step in developing an ongoing partnership between researchers and these advocates. PMID- 29429379 TI - Formulation development and evaluation of nifedipine as pylorospasm inhibitor. AB - INTRODUCTION: In this study, different nifedipine-loaded formulations were prepared to treat pylorospasm, a sphincter muscle disorder characterized by delayed gastric emptying process. The efficacy of formulation was evaluated in patients by subjective assessment, gamma scintigraphic approaches, and confocal microscopy. METHODS: Nifedipine-loaded different formulations such as sucrose bead, pellets, and microparticles (slugging method, ionotropic gelation, and chemical denaturation) were designed. The studies were performed on 50 subjects, of which 30 subjects were treated with optimized nifedipine loaded microcapsules while 20 subjects were given capsule becosule-Z as a control. The efficacy of formulation was assessed by comparing symptoms like dyspepsia, abdominal pain, abdominal fullness, poor appetite, nausea, vomiting, and irregular motion. The effectiveness of formulation was also assessed by gamma scintigraphic studies by determining the rate of emptying of a radioactivity labeled standard meal from patients' stomach into the duodenum. Confocal microscopy was used to assess targeting potential of developed formulation. RESULTS: Drug-loaded alginate chitosan microcapsules were found to be satisfactory, in terms of controlled drug release, surface morphology, and bioadhesive properties and thus selected for in vivo studies. Clinical studies revealed the efficacy of formulation in abolishing various GI symptoms at high altitude. Associated symptoms such as dyspepsia, abdominal pain, poor appetite, nausea, vomiting, and irregular motion were recovered by 75, 62, 76.5, 86.7, 85.7, and 37.5%, respectively in nifedipine treated patients. In comparison, 73.7, 40, 33.3, 40, 20, and 0% recoveries were observed in patients given control treatment only. Gamma Scintigraphic studies in lab also revealed 2.425 +/- 0.245 (p < .05) times improvement in gastric emptying rate in patients with diabetic gastroparesis. Confocal analysis showed better targeting and penetration in pyloric region when formulation was administered in form of high-density microcapsules. CONCLUSIONS: Results strongly suggest that nifedipine loaded mucoadhesive formulation has a targeting potential which accelerates gastric emptying process in gastroparesis patients, and thus the formulation might prove useful as a potent prokinetic agent. PMID- 29429380 TI - Cardiovascular and metabolic consequences of the association between chronic stress and high-fat diet in rats. AB - Obesity and chronic stress are considered independent risk factors for the development of cardiovascular diseases and changes in autonomic system activity. However, the cardiovascular consequences induced by the association between high fat diet (HFD) and chronic stress are not fully understood. We hypothesized that the association between HFD and exposure to a chronic variable stress (CVS) protocol for four weeks might exacerbate the cardiovascular and metabolic disturbances in rats when compared to these factors singly. To test this hypothesis, male Wistar rats were divided into four groups: control-standard chow diet (SD; n = 8); control-HFD (n = 8); CVS-SD (n = 8); and CVS-HFD (n = 8). The CVS consisted of repeated exposure of the rats to different inescapable and unpredictable stressors (restraint tress; damp sawdust, cold, swim stress and light cycle inversion). We evaluated cardiovascular function, autonomic activity, dietary intake, adiposity and metabolism. The HFD increased body weight, adiposity and blood glucose concentration (~15%) in both control and CVS rats. The CVS-HFD rats showed decreased insulin sensitivity (25%) compared to CVS-SD rats. The control-HFD and CVS-HFD rats presented increased intrinsic heart rate (HR) values (~8%). CVS increased cardiac sympathetic activity (~65%) in both SD- and HFD-fed rats. The HFD increased basal HR (~10%). Blood pressure and baroreflex analyzes showed no differences among the experimental groups. In conclusion, the present data indicate absence of interaction on autonomic imbalance evoked by either CVS or HFD. Additionally, HFD increased HR and evoked metabolic disruptions which are independent of stress exposure. PMID- 29429381 TI - Health literacy among older persons in Turkey. AB - AIM: The aim of this study was to investigate the health literacy and cognitive functions of individuals age 65 and over and the relationship between them. METHOD: The research was conducted between September 2016 and February 2017, among individuals age 65 and over, at the Family Health Center. The participants were given the Health Literacy Survey - European Union (HLS-EU) scale and the Mini-Mental Test. RESULTS: In this sampling, health literacy was found as "problematic or inadequate" in 85.1% of the elderly population. Among the health literacy issues, rate of "problematic-inadequate" results was 63.5% in benefiting from health services, 86.9% in protection from diseases, and 87.6% in improvement of health. The issues that older persons feel most inadequate were adult vaccinations and periodic examinations and they felt sufficient in terms of what to do in emergency cases. CONCLUSION: The older population needs support in health literacy issues particularly related to judgments. It would be appropriate to set up a standard care algorithm in older people. PMID- 29429382 TI - Comparison of Angiographic Dissection Patterns Caused by Long vs Short Balloons During Balloon Angioplasty of Chronic Femoropopliteal Occlusions. AB - PURPOSE: To describe the feasibility of balloon angioplasty using a long balloon for chronic femoropopliteal occlusions by evaluating angiographic dissection patterns for optimization of outcomes in balloon angioplasty. METHODS: A retrospective, single-center analysis examined 101 symptomatic patients (mean age 75.6+/-9.9 years; 65 men) with single de novo femoropopliteal occlusive lesions treated with balloon angioplasty between August 2012 and October 2016. The patients were classified into 2 groups for comparison of angiographic dissection patterns: 51 patients were treated with balloon angioplasty using long balloons (L-BA; defined as >=220 mm in length) and 50 patients were treated with short balloon angioplasty (S-BA; defined as <150-mm-long balloons). RESULTS: Severe vessel dissection patterns, defined as type C or higher, were fewer in the L-BA group (47.1% vs 70.0% in the S-BA group, p=0.019) and the total dissection length was shorter (92.7+/-72.6 vs 160.4+/-84.6 mm in the S-BA group, p<0.001). Although the results showed no significant differences between the two groups regarding the length of chronic total occlusions (L-BA: 228.6+/-73.2 vs S-BA: 226.0+/-53.8 mm, p=0.83), inflation pressure (L-BA; 8.2+/-2.6 vs S-BA: 8.1+/-2.9 atm, p=0.86), and the other lesion characteristics, inflation time was significantly longer in the L-BA group (161.2+/-68.7 seconds vs 51.1+/-54.0 seconds in the S-BA group, p<0.001). Multivariate analysis identified a balloon length >=220 mm as an independent negative predictor of severe vessel dissection (odds ratio 0.29, 95% confidence interval 0.11 to 0.83, p=0.02). CONCLUSION: Using long balloons for balloon angioplasty may help prevent severe vessel dissection in chronic femoropopliteal occlusions. PMID- 29429383 TI - Additional evidence of the link between mtDNA copy number and the body mass index. PMID- 29429384 TI - Differences in cognitive performance in nondemented Parkinson's disease: A latent profile analysis of cognitive subtypes. AB - INTRODUCTION: Cognitive impairments are common in Parkinson's disease (PD) patients without dementia. These deficits are quite heterogeneous, which makes it difficult to recognize and treat them. For this reason, many authors have attempted to classify patients into more homogeneous groups with diverse results. The present study was designed to analyze the cognitive heterogeneity in PD patients using a novel data-driven approach, latent profile analysis (LPA), to classify patients according to cognitive characteristics. This methodology, which has been used in previous studies focused on motor and psychiatric symptomatology, seems to be better than traditional cluster analysis for the establishment and comparison between different subgroups because it does not require prior decision making about some theoretical or methodological aspects. METHOD: LPA was applied to 71 PD patients evaluated with a broad neuropsychological battery including different memory and executive function tests. The clusters obtained from the analysis were described by making comparisons with a control group of 51 healthy subjects matched in age, sex, and educational level. RESULTS: The LPA resulted in a four-cluster solution, which could be described as: (a) executive dysfunction (32.4%), (b) memory and executive dysfunction (28.2%), (c) memory dysfunction (23.9%), and (d) noncognitive dysfunction (15.5%). These four PD cluster differ in age and Mini Mental State Examination (MMSE) score. However, there were no differences between clusters in disease duration, clinical impression of severity index, depression, and cognitive reserve. CONCLUSIONS: LPA is a very interesting method for the establishment of more homogeneous groups of PD patients based on their neuropsychological characteristics. Moreover, the distinction between different cognitive profiles will allow us to design interventions better adapted to each patient. PMID- 29429386 TI - R516Q mutation in Melanoma differentiation-associated protein 5 (MDA5) and its pathogenic role towards rare Singleton-Merten syndrome; a signature associated molecular dynamics study. AB - Singleton-Merten syndrome, a critical and rare multifactorial disorder that is closely linked to R516Q mutation in MDA5 protein associated with an enhanced interferon response in the affected individual. In the present study, we provide conclusive key evidence on R516Q mutation and their connectivity towards sequence structural basis dysfunction of MDA5 protein. Among the various mutations, we found R516Q is the most pathogenic mutation based on mutational signature Q-A [RE]-G-R-[GA]-R-A-[ED]-[DE]-S-[ST]-Y-[TSAV]-L-V designed from our work. Further, we derived a distant ortholog for this mutational signature from which we identified 343 intra-residue interactions that fall communally in the position required to maintain the structural and functional integration of protein architecture. This identification served us to understand the critical role of hot spots in residual aggregation that holds a native form of folding conformation in the functional region. In addition, the long-range molecular dynamics simulation demarcated the residual dependencies of conformational transition in distinct regions (L29360-370alpha18, alpha19380-410L31, alpha21430 480L33-alpha22-L35 and alpha24510-520L38) occurring upon R516Q mutation. Together, our results emphasise that the dislocation of functional hot spots Pro229, Arg414, Val498, Met510, Ala513, Gly515 and Arg516 in MDA5 protein which is important for interior structural packing and fold arrangements. In a nutshell, our findings are perfectly conceded with other experimental reports and will have potential implications in immune therapeutical advancement for rare singleton-merten syndrome. PMID- 29429388 TI - Experiences of Intimate Partner Violence: Findings From Interviews With South Asian Women in the United States. AB - Eleven South Asian women were recruited from three domestic violence agencies in the United States and interviewed to examine their experiences with intimate partner violence (IPV). The interviews were analyzed using a grounded theory approach. Themes included detailed barriers and facilitators to disclosure of the abuse and leaving the abusive relationship. Findings suggest that families of origin and in-laws play a significant role in the process of leaving the relationship. Children are often cited as a source of strength for the women. The process of healing and recovery after leaving a relationship with IPV was also discussed by women enrolled in this study. Pragmatic approaches to addressing IPV among South Asian women in health care settings are also considered. PMID- 29429389 TI - Preventing Sexual Violence in Adolescence: Comparison of a Scientist-Practitioner Program and a Practitioner Program Using a Cluster-Randomized Design. AB - Numerous school-based prevention programs have been developed by scientists and practitioners to address sexual violence in adolescence. However, such programs struggle with two major challenges. First, the effectiveness of many well established practitioner programs has not been rigorously evaluated. Second, effective scientific programs may be hard to implement into everyday school practice. Combining the knowledge of scientists and practitioners in a scientist practitioner program could be a helpful compromise. The aim of the present study is to evaluate the effects of a scientist-practitioner program and a practitioner program using a cluster-randomized experimental design. Twenty-seven school classes were randomly assigned to either one of two programs or a control group. Outcome variables (knowledge, attitudes, behavior, and iatrogenic effects) were assessed at pretest, posttest, and a 6-month follow-up for 453 adolescents (55% female, Mage = 14.18). Short-term effects were found in both programs regarding general knowledge, knowledge of professional help, and victim-blaming attitudes. Long-term effects were found in both programs regarding general knowledge and knowledge of professional help and, in the practitioner program, in a reduction of victimization. No other effects were found on attitudes and behavior. No iatrogenic effects in the form of increased anxiety were found. Both the scientist-practitioner and the practitioner program show promise for the prevention of sexual violence in adolescence; in particular, the practitioner program may be a more cost-effective method. PMID- 29429387 TI - Long non-coding RNA LOC100507600 functions as a competitive endogenous RNA to regulate BMI1 expression by sponging miR128-1-3p in Hirschsprung's disease. AB - Recently studies reported that long non-coding RNAs (lncRNAs) may take part in a lot of congenital diseases, meanwhile, Hirschsprung's disease (HSCR) is a major congenital digestive tract malformation. Nevertheless whether lncRNAs participate in the occurrence of HSCR and how it contributes to this disease are still unknown. LOC100507600 was selected from our gene expression microarray data obtained from bowel tissues from HSCR patients and negative controls. Subsequently, we used qRT-PCR to prove the result in 64 pairs of HSCR disease bowel stenosis tissues and negative controls. Transwell assay, CCK-8 assay and flow cytometry were employed to explore whether cellular functions change after knocking down the LOC100507600 in SH-SY5Y cell and human 293T cell. Dual luciferase reporter assay was used to confirm the competitive relationship between BMI1 and LOC100507600 through their association with hsa-miR128-1-3p. Protein extraction and Western blotting were used to further confirm the relationship between LOC100507600 and BMI1. We found that LOC100507600 was obvious reduced in tissues from HSCR patients with noteworthy correlation with BMI1. Furthermore, Downregulation of LOC100507600 repressed cell migration and proliferation and didn't affect cell apoptosis or cycle. Dual-luciferase reporter assay, qRT-PCR and Western blotting assay verified that LOC100507600 serves as a competitive endogenous RNA of miR128-1-3p and down-regulates BMI1 expression by sponging miR128-1-3p in HSCR. In sum, our study researches the potential diagnostic value of LOC100507600 in HSCR and deduces that LOC100507600 can contributes to HSCR as a competitive endogenous RNA to regulate BMI1 expression by sponging miR128-1-3p. PMID- 29429390 TI - Belgian guidelines for non-occupational HIV post-exposure prophylaxis 2017. AB - We present the updated Belgian guidelines for the use of non-occupational HIV post-exposure prophylaxis (NONOPEP). This document is inspired by UK guidelines 2015, adapted to the Belgian situation and approved by all AIDS reference centers in Belgium. When recommended, NONOPEP should be initiated as soon as possible, preferably within 24 h of exposure but can be offered up to 72 h. The duration of NONOPEP should be 28 days. These current guidelines include epidemiologic estimations, which can be used to calculate the risk of infection after a potential exposure and help to decide whether or not to start prophylaxis. We review which medications to use in the context of the last Belgian NONOPEP convention, provide a checklist for initial assessment, and make recommendations for monitoring individuals receiving NONOPEP. PMID- 29429391 TI - Comparative effectiveness of oral pharmacologic interventions for knee osteoarthritis: A network meta-analysis. AB - OBJECTIVES: To explore the relative efficacy of oral pharmacologic interventions in the treatment of knee OA. METHODS: A systematic literature review was conducted using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases to identify trials conducted in patients with knee OA with a minimum 6 weeks of follow-up. The standardized mean differences of the change from baseline to week 6 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain between the treatment groups were estimated using Bayesian random-effects network meta-analyses. Subgroup analyses of baseline pain status (high, pain score >=60 mm; low, pain score <60 mm) were performed. RESULTS: Of 4067 manuscripts, 44 were included in the evidence synthesis. Etoricoxib had the highest ranking for improving WOMAC pain (probability of being top ranked, p (best) = .43) followed by naproxen (p (best) = .12), acetaminophen (AAP) (p (best) = .04), and celecoxib (p (best) = .02). The top three ranked interventions were etoricoxib, celecoxib and aceclofenac in the higher pain group, and tramadol, celecoxib, and diclofenac in the lower pain group. CONCLUSION: In the overall analysis, etoricoxib, celecoxib, and aceclofenac had the highest rankings for improving WOMAC pain. The ability to improve knee OA symptoms may differ depending on baseline pain and radiologic features. PMID- 29429392 TI - Erratum. PMID- 29429393 TI - Erratum. PMID- 29429394 TI - Understanding the resistance mechanism of penicillin binding protein 1a mutant against cefotaxime using molecular dynamic simulation. AB - Antibiotic resistance is a threatening challenge for global health, as the expansion of resistance to current antibiotics has made serious therapeutic problems. Genome mutations are key evolutionary mechanisms conferring antibiotic resistance in bacterial pathogens. For example, penicillin and cephalosporins resistance is mostly mediated by mutations in penicillin binding proteins to change the affinity of the drug. Accordingly, threonine point mutations were reported to develop antibiotic resistance in various bacterial infections including pneumococcal infections. In this study, conventional molecular dynamics simulations, umbrella sampling simulations and MM/GBSA free energy calculations were applied to figure out how the Threonine to Alanine mutation (T to A) at STMK motif affects the binding of cefotaxime to Penicillin Binding Protein 1a and to reveal the resistance mechanism induced by the T to A mutation. The results obtained from the computational methods demonstrate that the T to A mutation increases the flexibility of the binding pocket and changes its conformation, which leads to increased conformational entropy change (-TDeltaS) and attenuates the bonds between the ligand and the receptor. In brief, our findings indicate that both of the alterations of the conformational enthalpy and entropy contribute to the T to A-induced resistance in the binding of cefotaxime into penicillin binding protein 1a. PMID- 29429396 TI - Using transcranial direct current stimulation to improve verbal working memory: A detailed review of the methodology. AB - INTRODUCTION: Transcranial direct current stimulation (tDCS) is a noninvasive electrical brain stimulation technique that has been used extensively over prefrontal cortex in an effort to enhance verbal working memory (WM). However, inconsistent and contradictory outcomes from similar stimulation protocols have created a strong need to examine methodologies in greater detail. This review undertook an in-depth look at both positive and negative prefrontal tDCS-WM findings in adult populations to shed light on methodological parameters that may be driving the inconsistent outcomes in the literature. METHOD: To facilitate comprehension of the protocols employed in each study and aid between-study comparisons, we illustrated study design alongside key findings. To aid clinical translation, we reviewed separately by population (healthy young adults versus WM impaired) performance changes during stimulation (online) versus following stimulation (offline), which offers more therapeutic promise. RESULTS: Our dissection of the literature highlighted design factors that are likely adding unnecessary noise and obscuring outcomes. Of note, a major blind spot in the literature relates to cognitive factors, including influential characteristics pertaining to the details of the WM test used to assess tDCS effects and participant characteristics that influence WM abilities and the organization of WM in the brain, and can impact the efficacy of tDCS-WM protocols through complex interactions. CONCLUSIONS: By attending to both cognitive- and tDCS-related factors in the design phase of the study, future researchers can reduce unintended variation that may obscure positive outcomes or lead to spurious results, thereby advancing the field forward toward developing more effective tDCS-WM protocols. PMID- 29429397 TI - Pre-movement and during-movement visual search behaviours vary depending on expertise and anxiety levels in ten-pin bowling. AB - This study investigated the pre-movement and during-movement visual search behaviour (VSB) and quiet eye (QE) of 11 elite versus 10 sub-elite ten-pin bowlers, performing under high-anxiety and low-anxiety conditions. Pre-movement and independent of expertise, bowlers had more fixations and directed them to more locations when performing under high-anxiety compared with low-anxiety. Elite bowlers fixated at more locations closer to the pins in pre-movement than during-movement, with pre-movement QE occurring mostly at the breakpoint and middle arrows. During movement however, bowlers fixated closer to the foul-line at the middle and right dots and arrows, with during-movement-QE occurring at the middle dots and right arrows. Elite bowlers recorded longer QE durations during movement rather than pre-movement, albeit a later onset during the longish five step approach prior to ball release compared with sub-elite bowlers. Our results suggest that QE during-movement instead of pre-movement could be more pertinent in differentiating expertise during sporting tasks with a long movement phase and far-aiming target. The relevance of pre-movement or movement-QE in characterising expertise and performance could therefore be sport-dependent. This should be considered when investigating skilled action and developing training programs for skill acquisition. PMID- 29429400 TI - Histologic processing artifacts and inter-pathologist variation in measurement of inked margins of canine mast cell tumors. AB - Although quantitative assessment of margins is recommended for describing excision of cutaneous malignancies, there is poor understanding of limitations associated with this technique. We described and quantified histologic artifacts in inked margins and determined the association between artifacts and variance in histologic tumor-free margin (HTFM) measurements based on a novel grading scheme applied to 50 sections of normal canine skin and 56 radial margins taken from 15 different canine mast cell tumors (MCTs). Three broad categories of artifact were 1) tissue deformation at inked edges, 2) ink-associated artifacts, and 3) sectioning-associated artifacts. The most common artifacts in MCT margins were ink-associated artifacts, specifically ink absent from an edge (mean prevalence: 50%) and inappropriate ink coloring (mean: 45%). The prevalence of other artifacts in MCT skin was 4-50%. In MCT margins, frequency-adjusted kappa statistics found fair or better inter-rater reliability for 9 of 10 artifacts; intra-rater reliability was moderate or better in 9 of 10 artifacts. Digital HTFM measurements by 5 blinded pathologists had a median standard deviation (SD) of 1.9 mm (interquartile range: 0.8-3.6 mm; range: 0-6.2 mm). Intraclass correlation coefficients demonstrated good inter-pathologist reliability in HTFM measurement (kappa = 0.81). Spearman rank correlation coefficients found negligible correlation between artifacts and HTFM SDs ( r <= 0.3). These data confirm that although histologic artifacts commonly occur in inked margin specimens, artifacts are not meaningfully associated with variation in HTFM measurements. Investigators can use the grading scheme presented herein to identify artifacts associated with tissue processing. PMID- 29429401 TI - Evaluation of serum neutrophil gelatinase-associated lipocalin as a novel biomarker of cardiorenal syndrome in dogs. AB - Worsening renal function and azotemia in patients with heart failure (HF) are strongly associated with disease severity and poor prognosis. Increasing interest in this correlation led to the description and classification of cardiorenal syndrome (CRS). We evaluated the role of neutrophil gelatinase-associated lipocalin (NGAL) in the early detection of CRS in dogs with HF. Ten healthy dogs and 31 dogs admitted with HF were included in our study. NGAL and troponin-I were measured on samples collected on the day of admission; creatinine was measured on admission and again on day 7. The CRS group was defined as subsequently developing renal azotemia. Of 31 dogs with HF, 20 were included in the HF group, and 11 were included in the CRS group. The admission NGAL concentrations of the CRS group were significantly higher than those of other groups ( p < 0.001). The severity of HF evaluation based on the modified New York Heart Association classification showed significant correlation with NGAL ( p < 0.001) and troponin I ( p = 0.009) concentration. However, only serum NGAL concentration at admission was significantly associated with the development of CRS in dogs with HF ( p = 0.021). The admission serum NGAL >= 16.0 ng/mL (optimal cutoff value) had a sensitivity of 90.9% and specificity of 90.0% in predicting the development of CRS. PMID- 29429402 TI - Parapoxviral vulvovaginitis in Holstein cows. AB - A group of Holstein first-calved heifers developed small pustules and ulcers on the vulva and in the vagina during the first 1-4 wk postpartum. The lesions varied from small red pinpoint foci to pustules and ulcers, 3-5 mm diameter. Some ulcers coalesced to form large ulcerated areas up to 15 mm diameter. In some animals, these ulcers progressed to become deep ulceration of the vaginal and vulvar mucosa with >50% of the mucosa involved. Vaginal biopsies from 4 heifers and vaginal individual swabs from 8 heifers for a combined sampling of 9 heifers were taken for clinical assessment. Six of the 9 heifers had parapoxvirus based on histopathology and/or PCR. Histologic examination of the biopsies of the pustules identified ballooning degeneration of the epithelium with degenerate epithelium containing eosinophilic intracytoplasmic inclusions consistent with a parapoxvirus in 3 of 4 biopsies. Testing for bovine herpesvirus 1, 2, and 4, bovine viral diarrhea virus, bovine papular stomatitis virus, and orf virus remained negative. PMID- 29429403 TI - Comparison of the performance of laboratory tests in the diagnosis of feline infectious peritonitis. AB - We compared the performance of clinicopathologic and molecular tests used in the antemortem diagnosis of feline infectious peritonitis (FIP). From 16 FIP and 14 non-FIP cats, we evaluated retrospectively the sensitivity, specificity, and likelihood ratios (LRs) of serum protein electrophoresis, alpha1-acid glycoprotein (AGP) on peripheral blood, screening reverse-transcription nested PCR (RT-nPCR) on the 3'-untranslated region (3'-UTR), and spike (S) gene sequencing on peripheral blood, body cavity effusions, and tissue, as well as body cavity cytology and delta total nucleated cell count (DeltaTNC). Any of these tests on blood, and especially the molecular tests, may support or confirm a clinical diagnosis of FIP. A negative result does not exclude the disease except for AGP. Cytology, 3'-UTR PCR, and DeltaTNC may confirm a clinical diagnosis on effusions; cytology or 3'-UTR PCR may exclude FIP. Conversely, S gene sequencing is not recommended based on the LRs. On tissues, S gene sequencing is preferable when histology is highly consistent with FIP, and 3'-UTR PCR when FIP is unlikely. Combining one test with high LR+ with one with low LR- (e.g., molecular tests and AGP on blood, DeltaTNC and cytology in effusions) may improve the diagnostic power of the most used laboratory tests. PMID- 29429406 TI - Editorial: dose-dependent ZnO particle-induced acute phase response in humans warrants re-evaluation of occupational exposure limits for metal oxides. AB - Epidemiological studies link inhalation of particles to increased risk of cardiovascular disease. Inhaled particles may induce cardiovascular disease by several different mechanisms including translocation of particles to systemic circulation, activation of airway sensory nerves resulting in autonomic imbalance and particle-induced pulmonary inflammation and acute phase response.The acute phase response is the systemic response to acute and chronic inflammatory states caused by for example bacterial infection, virus infection, trauma and infarction. It is characterized by differential expression of ca. 50 different acute phase proteins including C-reactive protein and Serum amyloid A, which are the most differentially up-regulated acute phase response proteins. Blood levels of these two acute phase proteins are closely associated with risk of cardiovascular disease in epidemiological studies and SAA has been causally related to the formation of plaques in the aorta in animal studies.In a recent paper in Particle and Fibre Toxicology, Christian Monse et al. provide evidence that inhalation of ZnO nanoparticles induces dose-dependent acute phase response in humans at dose levels well below the current mass-based occupational exposure limits in a number of countries including Germany, The Netherlands, UK, Sweden, Denmark and the US.Given the evidence suggesting a causal relationship between increased levels of serum amyloid A and atherosclerosis, the current results call for a re-evaluation of occupational exposure limits for a number of particle exposures including ZnO taking induction of acute phase response into account. Furthermore, it underscores cardiovascular disease as an occupational disease. PMID- 29429407 TI - Non-invasive differentiation of idiopathic inflammatory myopathy with cardiac involvement from acute viral myocarditis using cardiovascular magnetic resonance imaging T1 and T2 mapping. AB - BACKGROUND: Idiopathic inflammatory myopathy (IIM) is a group of autoimmune diseases with systemic myositis which may involve the myocardium. Cardiac involvement in IIM, although often subclinical, may mimic clinical manifestations of acute viral myocarditis (AVM). Our aim was to investigate the usefulness of the combined analysis of cardiovascular magnetic resonance (CMR) T1 and T2 mapping parameters measured both in the myocardium and in the thoracic skeletal muscles to differentiate AVM from IIM cardiac involvement. METHODS: Sixty subjects were included in this retrospective study (36 male, age 45 +/- 16 years): twenty patients with AVM, twenty patients with IIM and cardiac involvement and twenty healthy controls. Study participants underwent CMR imaging with modified Look-Locker inversion-recovery (MOLLI) T1 mapping and 3-point balanced steady-state-free precession T2 mapping. Relaxation times were quantified after endocardial and epicardial delineation on basal and medial short axis slices, as well as in different thoracic skeletal muscle groups present in the CMR field-of-view. ROC-Analysis was performed to assess the ability of mapping indices to discriminate the study groups. RESULTS: Mapping parameters in the thoracic skeletal muscles were able to discriminate between AVM and IIM patients. Best skeletal muscle parameters to identify IIM from AVM patients were reduced post-contrast T1 and increased extracellular volume (ECV), resulting in an area under the ROC curve (AUC) of 0.95 for post-contrast T1 and 0.96 for ECV. Conversely, myocardial mapping parameters did not discriminate IIM from AVM patients but increased native T1 (AUC 0.89 for AVM; 0.84 for IIM) and increased T2 (AUC 0.82 for AVM; 0.88 for IIM) could differentiate both patient groups from healthy controls. CONCLUSION: CMR myocardial mapping detects cardiac inflammation in AVM and IIM compared to normal myocardium in healthy controls but does not differentiate IIM from AVM. However, thoracic skeletal muscle mapping was able to accurately discern IIM from AVM. PMID- 29429408 TI - Concentration-dependent systemic response after inhalation of nano-sized zinc oxide particles in human volunteers. AB - BACKGROUND: Inhalation of high concentrations of zinc oxide particles (ZnO) may cause metal fume fever. In an earlier human inhalation study, no effects were observed after exposure to ZnO concentrations of 0.5 mg/m3. Further data from experimental studies with pure ZnO in the concentration range between 0.5 and 2.5 mg/m3 are not available. It was the aim of this experimental study to establish the concentration-response relationship of pure nano-sized ZnO particles. METHODS: Sixteen healthy subjects were exposed to filtered air and ZnO particles (0.5, 1.0 and 2.0 mg/m3) for 4 h on 4 different days, including 2 h of cycling with a low workload. The effects were assessed before, immediately after, and about 24 h after each exposure. Effect parameters were symptoms, body temperature, inflammatory markers and clotting factors in blood, and lung function. RESULTS: Concentration-dependent increases in symptoms, body temperature, acute phase proteins and neutrophils in blood were detected after ZnO inhalation. Significant effects were detected with ZnO concentrations of 1.0 mg/m3 or higher, with the most sensitive parameters being inflammatory markers in blood. CONCLUSION: A concentration-response relationship with nano-sized ZnO particles in a low concentration range was demonstrated. Systemic inflammatory effects of inhaled nano-sized ZnO particles were observed at concentrations well below the occpational exposure limit for ZnO in many countries. It is recommended to reassess the exposure limit for ZnO at workplaces. PMID- 29429409 TI - Medical students' perceptions of a career in family medicine. AB - BACKGROUND: In Israel, there is a shortage of family medicine (FM) specialists that is occasioned by a shortage of students pursuing a FM career. METHODS: A questionnaire, based on methods adapted from marketing research, was used to provide insight into the medical specialty selection process. It was distributed to 6th-year medical students from two Israeli medical schools. RESULTS: A response rate of 66% resulted in collecting 218 completed questionnaires. Nineteen of the students reported that they were interested in FM, 68% of them were women. When compared to students not interested in FM, the selection criteria of students interested in FM reflected greater interest in a bedside specialty which provides direct long-term patient care. These latter students were also more interested in a controllable lifestyle that allowed time to be with family and children and working outside the hospital especially during the daytime. These selection criteria aligned with their perceptions of FM, which they perceived as providing them with a controllable lifestyle, allowing them to work limited hours with time for family and having a reasonable income to lifestyle ratio. The students not interested in FM, agreed with those interested in FM, that the specialty affords a controllable lifestyle and the ability to work limited hours Yet, students not interested in FM more often perceived FM as being a boring specialty and less often perceived it as providing a reasonable income to lifestyle ratio. Additionally, students not interested in FM rated the selection criteria, academic opportunities and a prestigious specialty, more highly than did students interested in FM. However, they perceived FM as neither being prestigious nor as affording academic opportunities CONCLUSION: This study enriches our understanding of the younger generation's attitudes towards FM and thus provides administrators, department chairs and residency program directors with objective information regarding selection criteria and the students' perceptions of FM. We identified the disconnect between the selection criteria profiles and the perceptions of FM of students not inclined to pursue a residency in FM. This allowed for recommendations on how to possibly make FM more attractive to some of these students. PMID- 29429410 TI - The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester. AB - BACKGROUND: Human fetal adrenal glands are highly active and, with the placenta, regulate circulating progesterone, estrogen and corticosteroids in the fetus. At birth the adrenals are essential for neonate salt retention through secretion of aldosterone, while adequate glucocorticoids are required to prevent adrenal insufficiency. The objective of this study was to carry out the first comprehensive analysis of adrenal steroid levels and steroidogenic enzyme expression in normal second trimester human fetuses. METHODS: This was an observational study of steroids, messenger RNA transcripts and proteins in adrenals from up to 109 second trimester fetuses (11 weeks to 21 weeks) at the Universities of Aberdeen and Glasgow. The study design was balanced to show effects of maternal smoking. RESULTS: Concentrations of 19 intra-adrenal steroids were quantified using liquid chromatography and mass spectrometry. Pregnenolone was the most abundant steroid while levels of 17alpha-hydroxyprogesterone, dehydroepiandrosterone sulphate (DHEAS) and progesterone were also high. Cortisol was present in all adrenals, but aldosterone was undetected and Delta4 androgens were low/undetected. CYP17A1, CYP21A2 and CYP11A1 were all highly expressed and the proteins localized to the adrenal fetal zone. There was low-level expression of HSD3B and CYP11B2, with HSD3B located mainly in the definitive zone. Maternal smoking altered fetal plasma adrenocorticotropic hormone (ACTH) (P = 0.052) and intra-adrenal progesterone, 17alpha-hydroxyprogesterone and 16alpha hydroxyprogesterone, but not plasma or intra-adrenal cortisol, or intra-adrenal DHEAS. Fetal adrenal GATA6 and NR5A1 were increased by maternal smoking. CONCLUSIONS: The human fetal adrenal gland produces cortisol but very low levels of Delta4 androgens and no detectable aldosterone throughout the second trimester. The presence of cortisol in fetal adrenals suggests that adrenal regulation of circulating fetal ACTH remains a factor in development of congenital adrenal hyperplasia during the second trimester, while a relative lack of aldosterone explains the salt-wasting disorders frequently seen in extreme pre term neonates. Finally, maternal smoking may alter fetal adrenal sensitivity to ACTH, which could have knock-on effects on post-natal health. PMID- 29429412 TI - Animal-assisted intervention in the ICU: a tool for humanization. PMID- 29429411 TI - Gastro-oesophageal reflux: a mixed methods study of infants admitted to hospital in the first 12 months following birth in NSW (2000-2011). AB - BACKGROUND: Gastro-oesophageal reflux (GOR) is common in infants. When the condition causes pathological symptoms and/or complications it is considered gastro-oesophageal reflux disease (GORD). It appears to be increasingly diagnosed and causes great distress in the first year of infancy. In New South Wales (NSW), residential parenting services support families with early parenting difficulties. These services report a large number of babies admitted with a label of GOR/GORD. The aim of this study was to explore the maternal and infant characteristics, obstetric interventions, and reasons for clinical reporting of GOR/GORD in NSW in the first 12 months following birth (2000-2011). METHODS: A three phase, mixed method sequential design was used. Phase 1 included a linked data population based study (n = 869,188 admitted babies). Phase 2 included a random audit of 326 medical records from admissions to residential parenting centres in NSW (2013). Phase 3 included eight focus groups undertaken with 45 nurses and doctors working in residential parenting centres in NSW. RESULTS: There were a total of 1,156,020 admissions recorded of babies in the first year following birth, with 11,513 containing a diagnostic code for GOR/GORD (1% of infants admitted to hospitals in the first 12 months following birth). Babies with GOR/GORD were also more likely to be admitted with other disorders such as feeding difficulties, sleep problems, and excessive crying. The mothers of babies admitted with a diagnostic code of GOR/GORD were more likely to be primiparous, Australian born, give birth in a private hospital and have: a psychiatric condition; a preterm or early term infant (37-or-38 weeks); a caesarean section; an admission of the baby to SCN/NICU; and a male infant. Thirty six percent of infants admitted to residential parenting centres in NSW had been given a diagnosis of GOR/GORD. Focus group data revealed two themes: "It is over diagnosed" and "A medical label is a quick fix, but what else could be going on?" CONCLUSIONS: Mothers with a mental health disorder are nearly five times as likely to have a baby admitted with GOR/GORD in the first year after birth. We propose a new way of approaching the GOR/GORD issue that considers the impact of early birth (immaturity), disturbance of the microbiome (caesarean section) and mental health (maternal anxiety in particular). PMID- 29429413 TI - A case of a patient infected with a hepatitis C virus genotype 3a multidrug resistant variant in Pakistan. AB - BACKGROUND: Approximately 10 million people in Pakistan are infected with the hepatitis C virus (HCV). Most patients develop chronic hepatitis, with rare cases of spontaneous clearance. However, little is known about multidrug resistant viral variants in Pakistan. FINDINGS: This case study describes a 47-year-old male diagnosed with chronic HCV genotype 3a infection in 2003. After an initial diagnosis of viral infection, the patient remained treatment naive for 5 years. He received two therapy cycles of interferon (IFN) plus ribavirin (RBV) in 2007 and 2010, however, he was non-responsive to the therapy. The patient then received an additional two treatment cycles of pegylated IFN alpha-2b plus RBV (in 2011 and 2013); he was still non-responsive. In 2016, the patient underwent sofosbuvir plus RBV combination therapy, however, the sustained virological response was still not achieved. The host genetic factor was found to be heterozygous guanine and thymine (GT) and cytosine and thymine (CT) genotypes of rs8099917 and rs12979860 polymorphism of IL28B, respectively. Phylogenetic analysis suggests that the resistant variant belong to an out-group and may require triple therapy. CONCLUSIONS: This is the first case that reports on a HCV infected individual who was a non-responder to multiple IFN therapies in Pakistan. Further studies are needed to understand multidrug-resistant HCV variants in the Pakistani population. PMID- 29429414 TI - Rapidly progressive neovascular glaucoma following coronary artery bypass graft surgery in a patient with type 1 diabetes mellitus: a case report. AB - BACKGROUND: Proliferative diabetic retinopathy leading to vitreous hemorrhage, tractional retinal detachment, and neovascular glaucoma is a major cause of severe sight impairment in adults of working age worldwide. Neovascular glaucoma occurs in 2.5% of patients with proliferative diabetic retinopathy, which is difficult to treat and often leads to blindness. Onset of neovascular glaucoma with rapid progression to blindness within a few weeks of a successful coronary artery bypass graft procedure is not known with this clinical entity. CASE PRESENTATION: A 34-year-old white man with type 1 diabetes mellitus presented to our hospital with severe, rapidly progressive bilateral neovascular glaucoma following coronary artery bypass graft surgery. The patient was previously treated for proliferative diabetic retinopathy with complete peripheral pan retinal photocoagulation. Prompt and adequate treatment with antiglaucoma medication and cyclodiode laser did not halt the progression of the disease. The patient ended up with no perception of light within a few weeks of initial presentation. CONCLUSIONS: Vision loss following coronary artery bypass graft surgery is usually associated with nonarteritic anterior ischemic optic neuropathy. Rapid progression to bilateral blindness resulting from neovascular glaucoma within a few weeks of presentation following coronary artery bypass graft is not a common presentation with this clinical entity. Our patient had been treated with erythropoietin-stimulating factor for severe anemia preceding and following his coronary artery bypass graft surgery. The improvement in ocular perfusion following coronary artery bypass graft surgery, coupled with the administration of erythropoietin-stimulating factor, could have contributed to the onset and rapid progression of neovascular glaucoma. Close monitoring of patients with proliferative diabetic retinopathy undergoing coronary artery bypass graft surgery, even if adequately treated, is advised because there is increased ocular morbidity leading to blindness. PMID- 29429415 TI - Sibling bullying in middle childhood and psychotic disorder at 18 years: a prospective cohort study. AB - BACKGROUND: Being bullied by a sibling has been recently identified as a potential risk factor for developing depression and self-harm. It is unknown whether this risk extends to other serious mental health problems such as psychosis. We investigated whether sibling bullying victimization or perpetration in middle childhood was prospectively associated with psychotic disorder in early adulthood. METHODS: The current study investigated 6988 participants of the Avon Longitudinal Study of Parents and Children, a UK community-based birth cohort. Sibling bullying was reported at 12 years and psychotic disorder was assessed via a semi-structured interview at 18 years. RESULTS: Involvement in sibling bullying was associated with psychotic disorder in a dose-response fashion, even after controlling for a range of confounders. Those involved several times a week were 2-3 times more likely to meet criteria for a psychotic disorder [odds ratio (OR); 95% confidence interval (CI)]: victimization (OR 2.74; CI 1.28-5.87); perpetration (OR 3.16; CI 1.35-7.41). Categorical analysis indicated that particularly victims (OR 3.10; CI 1.48-6.50) and bully-victims (OR 2.66; CI 1.24 5.69) were at increased risk of psychotic disorder. Involvement in both sibling and peer bullying had a dose-effect relationship with a psychotic disorder, with those victimized in both contexts having more than four times the odds for a psychotic disorder (OR 4.57; CI 1.73-12.07). CONCLUSION: Parents and health professionals should be aware of the adverse long-term effects of sibling bullying. PMID- 29429417 TI - Focal Cortical Dysplasia Type IIIb with Oligodendroglioma in a Seizure-Free Patient. PMID- 29429416 TI - Microbiology and antimicrobial susceptibility of otitis externa: a changing pattern of antimicrobial resistance. AB - OBJECTIVE: Otitis externa is a common presentation to secondary care otolaryngology clinics. Despite this, few studies have investigated the microbiology and antimicrobial resistance of otitis externa. This study aimed to examine these issues. METHODS: Analysis identified 302 swabs taken from 217 patients (100 male, 117 female), between 1 January 2015 and 30 March 2016, at our rapid access otolaryngology clinic. RESULTS: In total, 315 organisms were isolated; the most frequent was Pseudomonas aeruginosa (31.1 per cent), followed by candida species (22.9 per cent) and Staphylococcus aureus (11.7 per cent). P aeruginosa was sensitive to ciprofloxacin in 97.7 per cent of cases and to gentamicin in 78.4 per cent. CONCLUSION: Compared with studies worldwide, the relative proportions of different organisms causing otitis externa and the patterns of antimicrobial resistance differ. Increasing resistance of P aeruginosa to aminoglycosides demonstrates a changing pattern of antimicrobial resistance that has not been previously reported. Reassuringly, quinolone antibiotics remain highly effective when treating P aeruginosa. PMID- 29429418 TI - Host availability affects the interaction between pupal parasitoid Coptera haywardi (Hymenoptera: Diiapridae) and larval-pupal parasitoid Diachasmimorpha longicaudata (Hymenoptera: Braconidae). AB - The use of multiple species in biological control programmes is controversial when interactions among them are not fully understood. We determined the response of the pupal parasitoid Coptera haywardi (Oglobin) to different availability of Anastrepha ludens (Loew) pupae previously parasitized or not by larval-pupal Diachasmimorpha longicaudata (Ashmead). The two types of pupae were exposed at different ages and proportions to different numbers of C. haywardi females for 48 h. The performance of C. haywardi adults emerging from parasitized and unparasitized pupae was measured. Coptera haywardi prefers to attack unparasitized A. ludens pupae rather than pupae parasitized by D. longicaudata. However, when the availability of unparasitized pupae was low or the number of foraging females was high, C. haywardi competed against early immature stages of the D. longicaudata, or hyperparasitized, feeding directly on the advanced immature developmental stages of the early acting species. Adults of C. haywardi emerging as hyperparasitoids were no different in size, fecundity and longevity from those emerging as primary parasitoids. Our data suggest that simultaneous use of these species in augmentative biological control projects may be feasible but should be carefully planned in order to avoid any detrimental effect of its interaction. PMID- 29429419 TI - Altered fear processing in adolescents with a history of severe childhood maltreatment: an fMRI study. AB - BACKGROUND: Children with a history of maltreatment suffer from altered emotion processing but the neural basis of this phenomenon is unknown. This pioneering functional magnetic resonance imaging (fMRI) study investigated the effects of severe childhood maltreatment on emotion processing while controlling for psychiatric conditions, medication and substance abuse. METHOD: Twenty medication naive, substance abuse-free adolescents with a history of childhood abuse, 20 psychiatric control adolescents matched on psychiatric diagnoses but with no maltreatment and 27 healthy controls underwent a fMRI emotion discrimination task comprising fearful, angry, sad happy and neutral dynamic facial expressions. RESULTS: Maltreated participants responded faster to fearful expressions and demonstrated hyper-activation compared to healthy controls of classical fear processing regions of ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex, which survived at a more lenient threshold relative to psychiatric controls. Functional connectivity analysis, furthermore, demonstrated reduced connectivity between left vmPFC and insula for fear in maltreated participants compared to both healthy and psychiatric controls. CONCLUSIONS: The findings show that people who have experienced childhood maltreatment have enhanced fear perception, both at the behavioural and neurofunctional levels, associated with enhanced fear-related ventromedial fronto-cingulate activation and altered functional connectivity with associated limbic regions. Furthermore, the connectivity adaptations were specific to the maltreatment rather than to the developing psychiatric conditions, whilst the functional changes were only evident at trend level when compared to psychiatric controls, suggesting a continuum. The neurofunctional hypersensitivity of fear-processing networks may be due to childhood over-exposure to fear in people who have been abused. PMID- 29429420 TI - Diverse single-amino-acid repeat profiles in the genus Cryptosporidium. AB - Genome sequencing has greatly contributed to our understanding of parasitic protozoa. This is particularly the case for Cryptosporidium species (phylum Apicomplexa) which are difficult to propagate. Because of their polymorphic nature, simple sequence repeats have been used extensively as genotypic markers to differentiate between isolates, but no global analysis of amino acid repeats in Cryptosporidium genomes has been reported. Taking advantage of several newly sequenced Cryptosporidium genomes, a comparative analysis of single-amino-acid repeats (SAARs) in seven species was undertaken. This analysis revealed a striking difference between the SAAR profile of the gastric and intestinal species which infect mammals and one species which infects birds. In average, total SAAR length in gastric species is only 25% of the cumulative SAAR length in the genome of Cryptosporidium parvum, Cryptosporidium hominis and Cryptosporidium meleagridis, species infectious to humans. The SAAR profile in the avian parasite Cryptosporidium baileyi stands out due to the presence of long asparagine repeats. Cryptosporidium baileyi proteins with repeats ?20 residues are significantly enriched in regulatory functions. As postulated for the related apicomplexan species Plasmodium falciparum, these observations suggest that Cryptosporidium SAARs evolve in response to selective pressure. The putative selective mechanisms driving SAAR evolution in Cryptosporidium species are unknown. PMID- 29429421 TI - Epidemiology and risk factors for hepatitis C virus infection in a high prevalence population. AB - To understand increasing rates of hepatitis C virus (HCV) infection in Tennessee, we conducted testing, risk factor analysis and a nested case-control study among persons who use drugs. During June-October 2016, HCV testing with risk factor assessment was conducted in sexually transmitted disease clinics, family planning clinics and an addiction treatment facility in eastern Tennessee; data were analysed by using multivariable logistic regression. A nested case-control study was conducted to assess drug-using risks and behaviours among persons who reported intranasal or injection drug use (IDU). Of 4753 persons tested, 397 (8.4%) were HCV-antibody positive. HCV infection was significantly associated with a history of both intranasal and IDU (adjusted odds ratio (aOR) 35.4, 95% confidence interval (CI) 24.1-51.9), IDU alone (aOR 52.7, CI 25.3-109.9), intranasal drug use alone (aOR 2.6, CI 1.8-3.9) and incarceration (aOR 2.7, CI 2.0-3.8). By 4 October 2016, 574 persons with a reported history of drug use; 63 (11%) were interviewed further. Of 31 persons who used both intranasal and injection drugs, 26 (84%) reported previous intranasal drug use, occurring 1-18 years (median 5.5 years) before their first IDU. Our findings provide evidence that reported IDU, intranasal drug use and incarceration are independent indicators of risk for past or present HCV infection in the study population. PMID- 29429423 TI - Aberrant topographical organization in default-mode network in first-episode remitted geriatric depression: a graph-theoretical analysis. AB - : ABSTRACTBackground:Neuroimaging studies have shown that major depressive disorder is associated with altered activity patterns of the default-mode network (DMN). In this study, we sought to investigate the topological organization of the DMN in patients with remitted geriatric depression (RGD) and whether RGD patients would be more likely to show disrupted topological configuration of the DMN during the resting-state. METHODS: Thirty-three RGD patients and thirty-one healthy control participants underwent clinical and cognitive evaluations as well as resting-state functional magnetic resonance imaging scans. The functional connectivity (FC) networks were constructed by thresholding Pearson correlation metrics of the DMN regions defined by group independent component analysis, and their topological properties (e.g. small-world and network efficiency) were analyzed using graph theory-based approaches. RESULTS: Relative to the healthy controls, the RGD patients showed decreased FC in the posterior regions of the DMN (i.e. the posterior cingulate cortex/precuneus, angular gyrus, and middle temporal gyrus). Furthermore, the RGD patients showed abnormal global topology of the DMN (i.e. increased characteristic path length and reduced global efficiency) when compared with healthy controls. Importantly, significant correlations between these network measures and cognitive performance indicated their potential use as biomarkers of cognitive dysfunction in RGD. CONCLUSIONS: The present study indicated disrupted FC and topological organization of the DMN in the context of RGD, and further implied their contribution to cognitive deficits in RGD patients. PMID- 29429422 TI - The role of sleep difficulties in the vasomotor menopausal symptoms and depressed mood relationships: an international pooled analysis of eight studies in the InterLACE consortium. AB - BACKGROUND: Many women experience both vasomotor menopausal symptoms (VMS) and depressed mood at midlife, but little is known regarding the prospective bi directional relationships between VMS and depressed mood and the role of sleep difficulties in both directions. METHODS: A pooled analysis was conducted using data from 21 312 women (median: 50 years, interquartile range 49-51) in eight studies from the InterLACE consortium. The degree of VMS, sleep difficulties, and depressed mood was self-reported and categorised as never, rarely, sometimes, and often (if reporting frequency) or never, mild, moderate, and severe (if reporting severity). Multivariable logistic regression models were used to examine the bi directional associations adjusted for within-study correlation. RESULTS: At baseline, the prevalence of VMS (40%, range 13-62%) and depressed mood (26%, 8 41%) varied substantially across studies, and a strong dose-dependent association between VMS and likelihood of depressed mood was found. Over 3 years of follow up, women with often/severe VMS at baseline were more likely to have subsequent depressed mood compared with those without VMS (odds ratios (OR) 1.56, 1.27 1.92). Women with often/severe depressed mood at baseline were also more likely to have subsequent VMS than those without depressed mood (OR 1.89, 1.47-2.44). With further adjustment for the degree of sleep difficulties at baseline, the OR of having a subsequent depressed mood associated with often/severe VMS was attenuated and no longer significant (OR 1.13, 0.90-1.40). Conversely, often/severe depressed mood remained significantly associated with subsequent VMS (OR 1.80, 1.38-2.34). CONCLUSIONS: Difficulty in sleeping largely explained the relationship between VMS and subsequent depressed mood, but it had little impact on the relationship between depressed mood and subsequent VMS. PMID- 29429424 TI - Trends in rotavirus from 2001 to 2015 in two paediatric hospitals in Atlanta, Georgia. AB - We compared rotavirus detection patterns before (2001-2006) and after (2008-2015) rotavirus vaccine introduction. We also compared rotavirus detection patterns in odd (2009, 2011, 2013, 2015) and even (2008, 2010, 2012, 2014) years post-vaccine separately. Results of stool rotavirus antigen testing from inpatient, outpatient and emergency department encounters from July 2000 to July 2015 at two paediatric hospital laboratories in Atlanta, Georgia were reviewed. Post-vaccine, rotavirus detection declined (30.2% vs. 13.7% (overall 54.6% decline, P <0.001)), occurred more frequently outside the rotavirus season (19.8% vs. 3.5%; P < 0.001), and was more common among older children (26 vs. 13 median months of age; P < 0.001). During odd years post-vaccine, rotavirus detection was significantly higher than even years (20.2% vs. 6.4%; P < 0.001). Rotavirus detection declined substantially and developed a biennial pattern in the post-vaccine era. The intensity and temporality of rotavirus detection in odd years post-vaccine resembled that observed pre-vaccine, although considerably reduced in magnitude. PMID- 29429425 TI - Association between alcohol and substance use disorders and psychiatric service use in patients with severe mental illness: a nationwide Danish register-based cohort study. AB - BACKGROUND: Substance use disorder is highly prevalent in people with psychiatric disorders, and known to impede the psychiatric treatment. Some studies show increased rates of service use, while others show a decrease. These conflicting results are further hampered by a lack of large-scale studies. The aim of this study was to investigate the association between substance use disorder and psychiatric service use in psychiatric patients. METHODS: The study was a prospective registry-based cohort study including patients with severe mental illness. The primary outcome was the number of hospitalisations, bed days and the number of psychiatric emergency department contacts. The association was calculated with incidence rate ratio with 95% confidence intervals. RESULTS: The study included all psychiatric patients born since 1955. In total, 21 558 patients with schizophrenia (47.54% with substance use disorder), 80 778 patients with depression (28.78% with substance use disorder), 10 560 patients with bipolar affective disorder (40.08% with substance use disorder) and 69 252 patients with a personality disorder (39.18% with substance use disorder) were included. Patients with comorbid substance use disorder had significantly increased rates of hospitalisations, bed days and psychiatric emergency department contacts (p < 0.001) for the majority of the included substances, compared with patients without such disorders. CONCLUSION: Substance use disorder was associated with an increased number of hospitalisations, bed days and increased number of psychiatric emergency department contacts for the majority of the included substances. PMID- 29429426 TI - Do patients with p16-positive oropharyngeal squamous cell carcinoma get more bone metastasis than p16-negative patients? AB - BACKGROUND: Oropharyngeal squamous cell carcinoma is thought to rarely metastasise to bone. This study hypothesised that in p16-positive disease there is a significant incidence of bony metastasis. METHODS: This was an ambispective cohort review. All patients with oropharyngeal squamous cell carcinoma diagnosed and treated at one centre were included. RESULTS: A total of 180 consecutive patients were identified over 5 years. Fifteen patients were excluded because of lack of p16 status, none of whom had bony metastasis. The final analysis included 165 patients: 48 (29.09 per cent) in the p16-negative group and 117 (70.91 per cent) in the p16-positive group. Ten patients (8.55 per cent) in the p16-positive group developed bony metastasis, compared with zero in the p16-negative group; this difference was statistically significant (p = 0.036). CONCLUSION: Expression of p16 was associated with an increased incidence in bony metastasis in this cohort. This is the first study to explore this specific question. PMID- 29429427 TI - Moving beyond depression screening: integrating perinatal depression treatment into OB/GYN practices. AB - In 2015, the American College of Obstetricians and Gynecologists issued a recommendation to screen women for depression and anxiety symptoms at least once during the perinatal period. Nevertheless, many identified women will not receive care from a behavioral health specialist. Listening Visits (LV), developed for delivery by nurses and validated in the United Kingdom, have recently been evaluated in a US-based randomized controlled trial (RCT) which recruited research participants from three home-visiting programs and an urban OB/GYN practice. RCT results indicated clinically and significant improvement in depression symptoms. To bridge the gap between evidence and practice, and based on experiences garnered at the OB/GYN site during the RCT, this development paper proposes a strategy for implementing depression screening and LV into routine clinical care in this practice setting. PMID- 29429428 TI - Hospital-Onset Staphylococcus aureus Bacteremia Is A Better Measure Than MRSA Bacteremia for Assessing Infection Prevention: Evaluation of 50 US Hospitals. AB - Of 500 hospital-onset Staphylococcus aureus bacteremia events (58% methicillin susceptible S. aureus [MSSA]; 42% methicillin-resistant S. aureus [MRSA]), we found no significant differences in S. aureus bacteremia rates between medium sized and large hospitals. However, the proportion of S. aureus bacteremia caused by MSSA was greater in medium-sized hospitals and did not correlate with MRSA bacteremia. Infect Control Hosp Epidemiol 2018;39:476-478. PMID- 29429429 TI - Functional determinants of dietary intake in community-dwelling older adults: a DEDIPAC (DEterminants of DIet and Physical ACtivity) systematic literature review. AB - OBJECTIVE: The identification of determinants of dietary intake is an important prerequisite for the development of interventions to improve diet. The present systematic literature review aimed to compile the current knowledge on individual functional determinants of dietary intake in community-dwelling older adults. DESIGN: A systematic search was performed in PubMed, Scopus, Web of Science and the Cochrane Library. Titles, abstracts and full texts were screened according to predefined inclusion and exclusion criteria. Studies were included when focusing on dietary intake as an outcome and on chemosensory, oral, cognitive or physical function as a determinant. SETTING: Community. SUBJECTS: Older adults at least 65 years old without acute or specific chronic diseases. RESULTS: From initially 14 585 potentially relevant papers, thirty-six were included. For chemosensory, cognitive and physical function only a few papers were found, which reported inconsistent results regarding the relationship to dietary intake. In contrast, oral function was extensively studied (n 31). Different surrogates of oral function like dental status, number of teeth, bite force or chewing problems were associated with food as well as nutrient intakes including fibre. As all except six studies had a cross-sectional design, no causal relationships could be derived. CONCLUSIONS: Among functional determinants of dietary intake oral factors are well documented in older adults, whereas the role of other functional determinants remains unclear and needs further systematic research. PMID- 29429430 TI - Review of implementation strategies to change healthcare provider behaviour in the emergency department. AB - OBJECTIVES: Advances in emergency medicine research can be slow to make their way into clinical care, and implementing a new evidence-based intervention can be challenging in the emergency department. The Canadian Association of Emergency Physicians (CAEP) Knowledge Translation Symposium working group set out to produce recommendations for best practice in the implementation of a new science in Canadian emergency departments. METHODS: A systematic review of implementation strategies to change health care provider behaviour in the emergency department was conducted simultaneously with a national survey of emergency physician experience. We summarized our findings into a list of draft recommendations that were presented at the national CAEP Conference 2017 and further refined based on feedback through social media strategies. RESULTS: We produced 10 recommendations for implementing new evidence-based interventions in the emergency department, which cover identifying a practice gap, evaluating the evidence, planning the intervention strategy, monitoring, providing feedback during implementation, and desired qualities of future implementation research. CONCLUSIONS: We present recommendations to guide future emergency department implementation initiatives. There is a need for robust and well-designed implementation research to guide future emergency department implementation initiatives. PMID- 29429431 TI - Early-life exposures to environmental tobacco smoke and indoor air pollution in the Drakenstein Child Health Study: Impact on child health. PMID- 29429432 TI - The African Hospitalist Fellowship. PMID- 29429433 TI - Failure to perform assisted deliveries is resulting in an increased neonatal and maternal morbidity and mortality: An expert opinion. AB - The need to perform assisted vaginal delivery (AVD) has been regarded as self evident. In high-income countries, rates of AVD range between 5% and 20% of all births. In South Africa, the rate of AVD is only 1%. This has resulted in increased neonatal morbidity and mortality due to intrapartum asphyxia, and increased maternal morbidity and mortality due to a rise in second-stage caesarean deliveries. In this article, we address the possible causes leading to a decrease in AVD and propose measures to be taken to increase the rates of AVD and subsequently reduce morbidity and mortality. PMID- 29429434 TI - Truvada (emtricitabine/tenofovir) pre-exposure prophylaxis roll-out among South African university students: Lots of positives, but let us keep an eye on possible surprises. AB - Antiretroviral therapy (ART) has fundamentally altered the natural history of HIV/AIDS, sharply reducing HIV-related morbidity and prolonging longevity. However, there seems to be a resurgence in HIV infection rates in some parts of the world that has prompted consideration of pre-exposure prophylaxis (pre-EP) and vaccination. Despite their good viral suppression profiles, most drugs used as part of ART also have unwanted adverse drug reactions/effects (ADRs). In this article we acknowledge the utility of pre-EP in combating HIV transmission, but we also highlight the need to prepare for management of other unexpected outcomes such as ADRs and viral resistance, to ensure the success of the programme. PMID- 29429435 TI - Is there transparency in the pricing of medicines in the South African private sector? AB - Recent investigations by the Competition Commission of South Africa (SA) of suspected excessive pricing of cancer medicines in SA by three global pharmaceutical companies have once again drawn attention to increasing medicine pricing transparency and warrant further public debate. PMID- 29429436 TI - Burkitt's lymphoma: The prevalence of HIV/AIDS and the outcome of treatment. AB - The prevalence of HIV in Burkitt's lymphoma (BL) patients and the outcome of treatment in Cameroon were unknown. Records of all patients diagnosed with BL at three Cameroon Baptist Convention hospitals were reviewed to ascertain the recorded HIV status and outcome of treatment. Of 979 patients diagnosed with BL, 717 were tested for HIV and 11 (1.5%) were HIV-positive. Three of eight patients treated with both cyclophosphamide (CPM)-based chemotherapy and antiretrovirals were alive at 62, 96 and 111 months, respectively. The HIV rate was comparable to that of 1% for the general population of children aged <15 years. Low-cost high frequency CPM was the only available treatment option for BL and was associated with 37.5% long-term survival in a resource-limited setting. PMID- 29429437 TI - The development of hospital-based palliative care services in public hospitals in the Western Cape, South Africa. AB - With the recent approval of a South African (SA) National Policy Framework and Strategy for Palliative Care by the National Health Council, it is pertinent to reflect on initiatives to develop palliative care services in public hospitals. This article reviews the development of hospital-based palliative care services in the Western Cape, SA. Palliative care services in SA started in the non governmental sector in the 1980s. The first SA hospital-based palliative care team was established in Charlotte Maxeke Johannesburg Academic Hospital in 2001. The awareness of the benefit of palliative care in the hospital setting led to the development of isolated pockets of excellence providing palliative care in the public health sector in SA. This article describes models for palliative care at tertiary, provincial and district hospital level, which could inform development of hospital-based palliative care as the national policy for palliative care is implemented in SA. PMID- 29429438 TI - Validation of the Simplified Motor Score in patients with traumatic brain injury at a major trauma centre in South Africa. AB - BACKGROUND: This study used data from a large prospectively entered database to assess the efficacy of the motor score (M score) component of the Glasgow Coma Scale (GCS) and the Simplified Motor Score (SMS) in predicting overall outcome in patients with traumatic brain injury (TBI). OBJECTIVE: To safely and reliably simplify the scoring system used to assess level of consciousness of trauma patients in the acute setting. METHODS: A retrospective observational review of the Pietermaritzburg Metropolitan Trauma Service hybrid electronic medical registry database was performed during the period January 2013 - December 2015. Patients were classified into three groups using their GCS as an injury severity score. These were mild TBI (GCS 13 - 15), moderate TBI (GCS 9 - 12) and severe TBI (GCS <9). The Glasgow M score was specifically evaluated to determine the relationship between the individual motor component and patient outcome. RESULTS: GCS scores and M scores were analysed in a total of 830 patients. There was a decline in survival rate when the M score on admission was <=4. The decline was more significant when the M score was <=3. Survival rates were 26.8% (11/41) for patients with an M score of 1, 63.6% (14/22) for those with a score of 2, 56.5% (13/23) for those with a score of 3, 80.0% (20/25) for those with a score of 4, and 95.5% (121/128) for those with a score of 5. Of 591 patients with an M score of 6, 580 (98.1%) survived. Mortality rose dramatically with declining SMS. This was highly significant. When the M score was plotted against mortality in 830 patients, there was a correct prediction in 769 cases (accuracy 92.7%, sensitivity 67.6%, specificity 95%). The area under the receiver operating characteristic (ROC) curve was 0.9037, with a standard deviation (area) of 0.0227. When comparing the SMS against mortality, the accuracy was 77.1%, the sensitivity 84.5% and the specificity 76.4%. The fitted ROC area was 0.891 and the empirical ROC area 0.86. CONCLUSION: The M score component of the GCS and the SMS accurately predict outcome in patients with TBI. In cases where the full GCS is difficult to assess, the M score and SMS can be used safely as a triage tool. PMID- 29429439 TI - Clinical characteristics and causes of heart failure, adherence to treatment guidelines, and mortality of patients with acute heart failure: Experience at Groote Schuur Hospital, Cape Town, South Africa. AB - BACKGROUND: There is limited information on acute heart failure (AHF) and its treatment in sub-Saharan Africa. OBJECTIVE: To describe the clinical characteristics and causes of heart failure (HF), adherence to HF treatment guidelines, and mortality of patients with AHF presenting to Groote Schuur Hospital (GSH), Cape Town, South Africa. METHODS: This sub-study of The Sub Saharan Africa Survey of Heart Failure (THESUS-HF) was a prospective and observational survey that focused on the enrolment and follow-up of additional patients with AHF presenting to GSH and entered into the existing registry after publication of the primary THESUS-HF article in 2012. The patients were classified into prevalent (existing) or incident (new) cases of HF. RESULTS: Of the 119 patients included, 69 (58.0%) were female and the mean (standard deviation) age was 49.9 (16.3) years. The majority of prevalent cases were patients of mixed ancestry (63.3%), and prevalent cases had more hypertension (70.0%), diabetes mellitus (36.7%), hyperlipidaemia (33.3%) and ischaemic heart disease (IHD) (36.7%) than incident cases. The top five causes of HF were cardiomyopathy (20.2%), IHD (19.3%), rheumatic valvular heart disease (RHD) (18.5%), cor pulmonale (11.8%) and hypertension (10.1%), with the remaining 20.1% consisting of miscellaneous causes including pericarditis, toxins and congenital heart disease. Most patients received renin-angiotensin system blockers and loop diuretics on discharge. There was a low rate of beta-blocker, aldosterone antagonist and digoxin use. Rehospitalisation within 180 days occurred in 25.2% of cases. In-hospital mortality was 8.4% and the case fatality rate at 6 months was 26.1%. CONCLUSION: In Cape Town, the main causes of AHF are cardiomyopathy, IHD and RHD. AHF affects a young population and is associated with a high rate of rehospitalisation and mortality. There is serious under-use of beta-blockers, aldosterone antagonists and digoxin. Emphasis on the rigorous application of treatment guidelines is needed to reduce readmission and mortality. PMID- 29429440 TI - Neonatal and paediatric bloodstream infections: Pathogens, antimicrobial resistance patterns and prescribing practice at Khayelitsha District Hospital, Cape Town, South Africa. AB - BACKGROUND: The epidemiology of neonatal and paediatric community-acquired and healthcare-associated bloodstream infections (BSI) at South African (SA) district hospitals is under-researched. OBJECTIVE: Retrospective review of neonatal and paediatric BSI (0 - 13 years) at Khayelitsha District Hospital, Cape Town, SA, over 3 years (1 March 2012 - 28 February 2015). METHODS: We used laboratory, hospital, patient and prescription data to determine BSI rates, blood culture yield and contamination rates, pathogen profile, antimicrobial resistance, patient demographics, BSI outcome and antibiotic prescribing practice. RESULTS: From 7 427 blood cultures submitted, the pathogen yield was low (2.1%, 156/7 427) while blood culture contamination rates were high (10.5%, 782/7 427). Paediatric and neonatal BSI rates were 4.5 and 1.4/1 000 patient days, respectively. Gram positive BSI predominated (59.3%); Staphylococcus aureus (26.8%) and Escherichia coli (21.6%) were common pathogens. The median patient age was 3 months, with a predominance of males (57.7%) and a 12.8% prevalence of HIV infection. Crude BSI associated mortality was 7.1% (11/156), the death rate being higher in neonates than in infants and children (6/40 (15.0%) v. 5/116 (4.3%), respectively; p=0.03) and in patients with Gram-negative compared with Gram-positive bacteraemia (6/66 (9.1%) v. 5/89 (5.6%), respectively; p=0.5). Most BSI episodes were community acquired (138/156; 88.5%), with high levels of extended-spectrum beta-lactamase (ESBL) carriage among Klebsiella pneumoniae and E. coli isolates (5/5 (100%) and 8/33 (24.2%), respectively). Antimicrobial management of BSI was inappropriate in 30.6% of cases (45/147), including incorrect empirical antibiotic (46.7%), dual antibiotic cover (33.3%) and inappropriately broad-spectrum antibiotic use (17.8%). CONCLUSIONS: Antimicrobial-resistant pathogens (notably ESBL-producing Enterobacteriaceae) were common in community-acquired BSI. Paediatric clinicians at district hospitals require ongoing training in antibiotic stewardship and blood culture sampling. PMID- 29429441 TI - Characteristics and early outcomes of children and adolescents treated with darunavir/ritonavir-, raltegravir- or etravirine-containing antiretroviral therapy in the Western Cape Province of South Africa. AB - BACKGROUND: There is an increasing need for third-line treatment regimens in HIV infected children with antiretroviral treatment (ART) failure. Data are limited on darunavir/ritonavir (DRV/r)-, raltegravir (RAL)- and etravirine (ETR) containing regimens in treatment-experienced children from resource-constrained settings receiving these drugs as part of routine care. OBJECTIVE: To describe the characteristics and early outcomes of treatment-experienced children (<20 years of age) in the Western Cape Province of South Africa treated with DRV/r-, RAL- or ETR-containing regimens. METHODS: This was a retrospective review of treatment-experienced children receiving a DRV/r-, RAL- or ETR-containing regimen as recommended by a paediatric expert review committee, based on HIV drug resistance testing. RESULTS: Thirty-five children of median age 8.8 years (interquartile range (IQR) 5.5 - 11) who had received ART for a median of 6.9 years (IQR 5 - 9.9) and started a DRV/r-, RAL- or ETR-containing regimen were included. Before starting such a regimen, the median CD4+ lymphocyte count and HIV-1 RNA level were 405.5 cells/MUL (IQR 251.5 - 541) and 28 314 copies/mL (IQR 5 595.5 - 120 186.5) (log 4.5 (IQR 3.7 - 5)), respectively, in 24 subjects with available results. After a median of 2 years (IQR 1.3 - 4) on treatment, 29/30 (96.7%) and 23/30 (76.7%) subjects with available results had HIV-1 RNA levels of <400 and <50 copies/mL, respectively. CONCLUSIONS: This study found DRV/r-, RAL- and ETR-containing regimens to be effective in a group of treatment-experienced children and adolescents with multidrug-resistant HIV. Although the treatment regimens in this study were individualised based on HIV genotyping results, further research evaluating the safety and efficacy of standardised third-line treatment regimens in children of all ages is needed. PMID- 29429442 TI - Heroin detoxification during pregnancy: A systematic review and retrospective study of the management of heroin addiction in pregnancy. AB - BACKGROUND: There is general consensus that methadone maintenance is the gold standard in the management of pregnant heroin users. However, in South African state hospitals, methadone withdrawal is the routine procedure offered to these patients, as methadone maintenance programmes are unavailable in the public sector. OBJECTIVES: To conduct a systematic review of the literature on heroin detoxification in pregnancy, and to document pregnancy outcomes in heroin users detoxified with methadone at Groote Schuur Hospital (GSH), Cape Town, from 2006 to 2010. METHODS: A literature search was undertaken to identify key publications on the management of heroin addiction in pregnancy. Patients for the study were identified from the GSH methadone registry, and data were collected from the clinical files. RESULTS: A total of 20 relevant publications were identified and reviewed. Early case reports described an increased risk of stillbirths and fetal distress after methadone detoxification, but more recent case series involving larger numbers of patients showed positive outcomes. In our study, six pregnant patients received methadone withdrawal over a 5-year period at GSH, and all the neonates had good Apgar scores and were discharged home within 3 days of delivery. CONCLUSIONS: There is limited evidence on the management of heroin addiction during pregnancy, and the only two guidelines identified suggest that methadone maintenance is preferable to methadone withdrawal. The favourable pregnancy outcomes in this small sample of patients managed with methadone withdrawal suggest that it may be safe and deserves further study. PMID- 29429443 TI - Colorectal cancer in South Africa: An assessment of disease presentation, treatment pathways and 5-year survival. AB - BACKGROUND: Colorectal cancer (CRC) is the fourth most common cancer in South Africa (SA), and the sixth most lethal. Approximately 25% of patients will have synchronous metastatic disease at the time of their primary CRC diagnosis. Although chemotherapy is used in most stages of the disease, surgical resection of the primary tumour and metastases remains the most successful treatment modality to achieve cure or prolong survival. To date, no data on CRC presentation and management have been published in SA. OBJECTIVES: To determine CRC presentation, general management patterns and overall survival in the SA private healthcare sector. METHODS: A retrospective review of a private healthcare funder's database from 1 January 2008 to 31 December 2015. International Statistical Classification of Diseases and Related Health Problems (10th revision) (ICD-10) diagnosis codes were used to identify colorectal cancer and liver and/or pulmonary metastatic disease. Procedure codes assigned to hospital admissions were used to identify type of surgical treatment. Chemotherapy was identified by the World Health Organization Anatomical Therapeutic Chemical Classification System of medicines. Treatment patterns were determined and 5-year survival rates for these were calculated. Survival was estimated using the Kaplan-Meier method, and Cox proportional hazards regression was used for between-group comparisons of survival. Data analysis was carried out using SAS version 9.4 for Windows. RESULTS: A total of 3 412 patients were included in the study, 2 267 with CRC only and 1 145 with liver (LM) or pulmonary metastases (PM). The mean age was 64.1 years (range 21 - 97), and 54.6% were male; these did not differ statistically between the study groups. Twenty percent of patients with LM or PM underwent surgical resection of their metastases. Five year survival rates following surgical resection of all disease for CRC only, CRCLM, CRCPM and CRCLMPM were 71.7%, 57.3%, 31.5% and 26.0%, respectively. CONCLUSIONS: SA CRC patients treated in the private healthcare sector have similar disease presentation to that in published international series, with similar outcomes following various treatment pathways; however, it seems that fewer resections of metastases are undertaken compared with international trends. PMID- 29429444 TI - Safety and affordability of an elective Saturday list at Pietersburg Hospital, Limpopo, South Africa. AB - BACKGROUND: The backlog of patients waiting for operations continues to be a problem in many public hospitals in South Africa (SA), with elective surgery procedures being postponed for up to 2 years. OBJECTIVE: To determine the rate of death in hospital or out of hospital within 30 days of an elective procedure performed on a Saturday, and to determine the cost incurred by paying staff members who perform these operations. METHOD: A prospective, observational descriptive cohort study of all patients undergoing inpatient general surgery operations during weekdays and weekends between 1 September 2015 and 31 August 2016 (1 year) at Pietersburg Hospital (PBH), Limpopo, SA. Microsoft Excel 2010 (Microsoft, USA) was used to analyse and derive descriptive statistics. The finance department at the hospital calculated the overtime pay for theatre staff who operated on Saturdays. RESULTS: The study included 1 352 operations (607 elective and 745 emergency procedures). Saturday elective operations contributed 133/607 (22%), and the rate of death for these operations was 1.5%. The most common procedures performed on a Saturday were hernia repair and amputation. The cost for 8 hours of work on a Saturday was ZAR13 900, amounting to a total of ZAR333 600 for 24 Saturdays. CONCLUSION: Performing minor surgery on a Saturday had a mortality rate of 1.5%, and a theatre staff cost of ~ZAR2 317 per patient, excluding surgeons' fees. If surgeons were to be paid the costs would be ZAR3 450 per patient. PMID- 29429445 TI - Physical activity levels in urban-based South African learners: A cross-sectional study of 7 348 participants. AB - BACKGROUND: Establishing profiles of physical activity (PA) is critical in tackling the chronic diseases associated with lack of PA and avoiding healthcare costs. OBJECTIVE: To investigate PA levels in urban-based South African (SA) primary school learners. METHODS: The Physical Activity Questionnaire for Older Children was completed by 7 348 learners (3 867 males and 3 481 females) aged 8 - 14 years, of whom 49% were white, 39% black and 12% from other ethnic groups. Differences in PA levels by ethnic origin and province were determined using an analysis of covariance after adjusting for gender (p<0.05). Bonferroni corrections controlled for multiple comparisons. A fitted regression model examined age-related differences in PA adjusting for province. RESULTS: Of SA learners aged 8 - 14 years, 57% (n=4 224) engaged in moderate levels of PA. Thirty-one percent (n=2 247) did not meet internationally recommended amounts of moderate to vigorous physical activity. Overall, males reported higher PA levels than females (p<0.0001). PA levels declined with age from 11 to 14 years by 14% and 20% in males and females, respectively. Black learners had higher PA levels than white learners (p=0.0039). There were also significant differences in PA levels between the provinces (p<0.0001). CONCLUSION: This study provides evidence of differences in PA levels between gender, age and ethnic groups, and between provinces. A targeted approach to increase PA in high-risk populations in SA is warranted. Increased PA will help reduce the risk of chronic diseases and will contribute to the health of SA's population and the growth of the country's economy. PMID- 29429446 TI - Congenital adrenal hyperplasia due to 21-hydroxylase deficiency in South Africa. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) caused by deficiency of the 21 hydoxylase (21-OH) enzyme is the most common form of CAH worldwide. OBJECTIVE: To evaluate the prevalence of CAH due to 21-OH deficiency, and its clinical presentation and biochemical profiles in affected children. METHODS: We performed a retrospective subset analysis of 44 children with confirmed CAH. RESULTS: All the children had classic CAH. The majority (59.8%) had classic salt-wasting (CSW) CAH and 40.1% had simple virilising (SV) CAH. The median age of presentation was 8.1 years (interquartile range (IQR) 4.5 - 11) in the SV group and 2 months (IQR 2 weeks - 5 months) in the CSW group (p=0.0001). No difference in age of presentation was noted between males and females (p=0.541). The clinical presentation was significantly different between the CSW and SV groups, and between males and females in the CSW group (p<0.0001). Most of the females with 46,XX CSW CAH (66.7%) presented with disorders of sex development (DSD), while the remaining 33.3% presented with DSD and dehydration and shock. All the males with 46,XY CSW CAH presented with dehydration and shock. Overall, 37.9% (11/29) of the children were obese or overweight at presentation. Gonadotrophin-releasing hormone-dependent central precocious puberty was observed on follow-up in 29.4% (10/34) of the children at a median of 6.7 years (IQR 5 - 7.7). CONCLUSION: The diagnosis of CAH is delayed in males and females in both SV and CSW forms of the disorder, which probably contributes to under-reporting of cases and a high mortality rate. PMID- 29429447 TI - Five-year follow-up of participants diagnosed with chronic airflow obstruction in a South African Burden of Obstructive Lung Disease (BOLD) survey. AB - BACKGROUND: A community-based prevalence survey performed in two suburbs in Cape Town, South Africa (SA), in 2005, using the international Burden of Obstructive Lung Disease (BOLD) method, confirmed a prevalence of chronic airflow obstruction (CAO) in 23.1% of adults aged >40 years. OBJECTIVES: To study the clinical course and prognosis over 5 years of patients with CAO identified in the 2005 survey. METHODS: Patients with CAO in 2005 were invited to participate. Standard BOLD and modified questionnaires were completed. Spirometry was performed using spirometers of the same make as in 2005. RESULTS: Of 196 eligible participants from BOLD 2005, 45 (23.0%) had died, 8 from respiratory causes, 10 from cardiovascular causes and 6 from other known causes, while in 21 cases the cause of death was not known. On multivariate analysis, only age and Global initiative for Obstructive Lung Disease (GOLD) stage 4 disease at baseline were significantly associated with death. Of the 151 survivors, 11 (5.6% of the original cohort) were unavailable and 33 (16.8%) declined or had medical exclusions. One hundred and seven survivors were enrolled in the follow-up study (54.6%, median age 63.1 years, 45.8% males). Post-bronchodilator spirometry performed in 106 participants failed to confirm CAO, defined as a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of <0.7, in 16 participants (15.1%), but CAO was present in 90. The median decline in FEV1 was 28.9 mL/year (interquartile range -54.8 - 0.0) and was similar between GOLD stages. The median total decline in FVC was 75 mL, and was significantly greater in GOLD stage 1 (-350 mL) than in stages 2 or 3 (-80 mL and +140 mL, respectively; p<0.01). Fifty-eight participants with CAO in 2005 (64.4%) remained in the same GOLD stage, while 21 (23.3%) deteriorated and 11 (12.2%) improved by >=1 stage. Only one-third were receiving any treatment for chronic obstructive pulmonary disease (COPD). CONCLUSIONS: The prevalence, morbidity and mortality of CAO and COPD in SA are high and the level of appropriate treatment is very low, pointing to underdiagnosis and inadequate provision of and access to effective treatments and preventive strategies for this priority chronic non-communicable disease. PMID- 29429448 TI - Acne in South African black adults: A retrospective study in the private sector. PMID- 29429449 TI - Investigation of function and regulation of the YB-1 cellular factor in HIV replication. AB - Y-box binding protein 1 (YB-1) is a member of the cold-shock domain (CSD) protein superfamily. It participates in a wide variety of cellular events, including transcription, RNA splicing, translation, DNA repair, drug resistance, and stress responses. We investigated putative functions of YB-1 in HIV-1 replication. Functional studies using overexpression or knockdown of YB-1 in conjunction with transfection of proviral DNA showed that YB-1 enhances virus production. We found YB-1 regulates HIV-1 production by stimulating viral transcription using HIV-1 LTR sequence U3RU5 with Luciferase assay. We also identified a specific region from amino acids 1 to 324 of YB-1 as necessary for the participation of the protein in the production of virions. [BMB Reports 2018; 51(6): 290-295]. PMID- 29429450 TI - Human amnion-derived mesenchymal stem cells induced osteogenesis and angiogenesis in human adipose-derived stem cells via ERK1/2 MAPK signaling pathway. AB - Mesenchymal stem cells (MSCs) have shown great potential in treating bone deficiency. Human adipose-derived stem cells (HASCs) are multipotent progenitor cells with multi-lineage differentiation potential. Human amnion-derived mesenchymal stem cells (HAMSCs) are capable of promoting osteogenic differentiation of MSCs. In this study, we investigated the effect of HAMSCs on HASCs by a transwell co-culture system. HAMSCs promoted proliferation, osteogenic differentiation, angiogenic potential and adiponectin (APN) secretion of HASCs. Moreover, the positive effect of HAMSCs was significantly inhibited by U0126, a highly selective inhibitor of extracellular signaling-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway. These observations suggested that HAMSCs induced bone regeneration in HASCs via ERK1/2 MAPK signaling pathway. [BMB Reports 2018; 51(4): 194-199]. PMID- 29429452 TI - Sex as an important biological variable in biomedical research. AB - Experimental results obtained from research using only one sex are sometimes extrapolated to both sexes without thorough justification. However, this might cause enormous economic loss and unintended fatalities. Between years 1997 and 2000, the US Food and Drug Administration suspended ten prescription drugs producing severe adverse effects on the market. Eight of the ten drugs caused greater health risks in women. Serious male biases in basic, preclinical, and clinical research were the main reason for the problem. This mini-review will describe why and how funding organizations such as the European Commission, the Canadian Institutes of Health Research, and the US National Institutes of Health have tried to influence researchers to integrate sex/gender not only in clinical research, but also in basic and preclinical research. Editorial policies of prominent journals for sex-specific reporting will also be introduced, and some considerations in integrating sex as a biological variable will be pointed out. To produce precise and reproducible results applicable for both men and women, sex should be considered as an important biological variable from basic and preclinical research. [BMB Reports 2018; 51(4): 167-173]. PMID- 29429451 TI - Emerging role of RUNX3 in the regulation of tumor microenvironment. AB - A number of genes have been therapeutically targeted to relieve cancer, but cancer relapse is still a growing issue. The concept that the surrounding tumor environment is critical for the progression of cancer may foster an answer to the issue of cancer malignancy. Runt domain transcription factors (RUNX1, 2, and 3) are evolutionarily conserved and have been intensively studied for their roles in normal development and pathological conditions. During tumor growth, a hypoxic microenvironment and infiltration of the tumor by immune cells are common phenomena. In this review, we briefly introduce the consequences of hypoxia and immune cell infiltration into the tumor microenvironment with a focus on RUNX3 as a critical regulator. Furthermore, based on our current knowledge of the functional role of RUNX3 in hypoxia and immune cell maintenance, a probable therapeutic intervention is suggested for the effective management of tumor growth and malignancy. [BMB Reports 2018; 51(4): 174-181]. PMID- 29429453 TI - [Correlation between magnetic resonance imaging score and clinical grading in neonatal hypoxic-ischemic encephalopathy]. AB - OBJECTIVE: To investigate the correlation between magnetic resonance imaging (MRI) score and clinical grading in neonatal hypoxic-ischemic encephalopathy (HIE). METHODS: Clinical grading was performed for 61 neonates with HIE according to the HIE clinical grading standard. The modified MRI scoring system was used to determine the injury scores on different MRI sequences. The correlation between HIE imaging score and clinical severity was analyzed. RESULTS: The MRI score in neonates with moderate HIE was significantly lower than that in those with severe HIE (P<0.01). Neonates aged 0-7 days had the highest correlation coefficient between diffusion weighted imaging (DWI) score and total MRI score (r>0.9), and neonates aged >7 days had the highest correlation coefficient between T1-weighted imaging score and total MRI score (r=0.963). Brain MRI showed injuries in the basal ganglia/thalamus+brainstem and even the whole brain in neonates with severe HIE, while the neonates with moderate HIE had injuries in the cerebral watershed, with little involvement of the brainstem (P<0.01). CONCLUSIONS: There is a good correlation between the MRI scoring system and clinical grading in neonatal HIE, suggesting the system can help with the clinical diagnosis and grading of HIE. PMID- 29429454 TI - [Association of leptin, adiponectin, and ghrelin in breast milk with the growth of infants with exclusive breastfeeding]. AB - OBJECTIVE: To investigate the association of leptin, adiponectin, and ghrelin in breast milk with the weight growth velocity of infants with exclusive breastfeeding. METHODS: A total of 67 full-term singleton infants who received regular child care and exclusive breastfeeding and their mothers were enrolled. The nutritional status was evaluated based on the measurements of body weight and body length (underweight, growth retardation, emaciation, overweight, and obesity). Z score was used to calculate growth velocity, and according to the DeltaZ score, the infants were divided into poor growth group, low growth velocity group, and normal growth velocity group. Mature breast milk samples were collected from their mothers, and ELISA was used to measure the levels of leptin, adiponectin, and ghrelin. RESULTS: The emaciation group had a significantly lower level of leptin in breast milk than the non-emaciation group (P<0.05), and the overweight/obesity group had a significantly lower level of adiponectin than the non-overweight/obesity group (P<0.05). The correlation analysis showed that the level of ghrelin in breast milk was positively correlated with Z score of current body weight and DeltaZ score compared with birth weight (rs=0.280 and 0.290 respectively; P<0.05). The regression analysis showed that the level of ghrelin in breast milk was an important influencing factor for the Z score of body weight (beta=0.161, P<0.05). CONCLUSIONS: Various active constituents in breast milk, including leptin, adiponectin, and ghrelin, may regulate the growth and development of infants to a certain degree, but long-term studies and observation are needed to investigate their association with offspring growth and development and the health-promoting effect of breast milk on offspring. PMID- 29429456 TI - [Role of donor human milk feeding in preventing nosocomial infection in very low birth weight infants]. AB - OBJECTIVE: To investigate the role of donor human milk in the prevention of nosocomial infection in very low birth weight infants. MeETHODS: A total of 105 hospitalized preterm infants with a very low birth weight were enrolled. They were classified into mother's own milk feeding group, donor human milk feeding group, and preterm formula feeding group, with 35 infants in each group. The three groups were compared in terms of incidence rates of nosocomial infection, necrotizing enterocolitis, and feeding intolerance, time to full enteral feeding, and early growth indices. RESULTS: Compared with the preterm formula feeding group, the donor human milk feeding group and the mother's own milk feeding group had significantly lower incidence rates of nosocomial infection and necrotizing enterocolitis and shorter time to full enteral feeding (P<0.05). There were no significant differences in head circumference, body length, and weight growth velocity among the three groups. CONCLUSIONS: Donor human milk can be used in case of a lack of mother's own milk and may help to reduce nosocomial infection. PMID- 29429455 TI - [Early rehabilitation intervention reduces the incidence of extrauterine growth retardation in preterm infants]. AB - OBJECTIVE: To investigate the effect of early rehabilitation intervention on the incidences of extrauterine growth retardation (EUGR) and early diseases in preterm infants. METHODS: The appropriate-for-gestational-age preterm infants with a gestational age of <34 weeks and a birth weight of 1 000 to <2 000 g who were admitted to the neonatal intensive care unit (NICU) within 24 hours after birth were enrolled in a prospective randomized controlled trial. These infants were randomly divided into rehabilitation intervention group and control group. The infants in the rehabilitation intervention group were given early rehabilitation after their vital signs became stable, including oral sensory and muscle strength training and pressure touching of the head, chest, abdomen, extremities, hands, and feet. The primary outcome measures were the time to independent oral feeding, length of hospital stay, and incidence rate of EUGR. The secondary outcome measures were the incidence rates of related diseases in preterm infants, such as apnea, feeding intolerance, and sepsis. RESULTS: A total of 97 preterm infants who met the inclusion criteria and had complete data were enrolled, with 48 in the control group and 49 in the rehabilitation intervention group. The rehabilitation intervention group had a shorter time to independent oral feeding than the control group (P<0.05). Compared with the control group, the rehabilitation intervention group had a shorter length of hospital stay and a lower corrected gestational age at discharge (P<0.05), as well as a lower incidence rate of EUGR (P<0.05). The rehabilitation intervention group ONCLUSIONS: Early rehabilitation intervention for preterm infants in the NICU may reduce the incidence rates of apnea, feeding intolerance, and EUGR and help them to achieve independent oral feeding early. PMID- 29429457 TI - [Association between vasoactive-inotropic score and prognosis in children with septic shock]. AB - OBJECTIVE: To investigate the association between vasoactive-inotropic score (VIS) and prognosis in children with septic shock. METHODS: A total of 117 children with decompensated septic shock who received the treatment with vasoactive agents were enrolled. According to their prognosis, they were divided into death group with 41 children and survival group with 76 children. With the maximum VIS within the first 24 hours (24hVIS max) as the cut-off value (29.5), the children were divided into low VIS group with 78 children and high VIS group with 39 children. The 24hVIS max and the mean VIS within the first 24 hours (24hVIS mean) were calculated for all children. A receiver operating characteristic (ROC) curve analysis was performed for the association between VIS and the prognosis of septic shock. RESULTS: Compared with the survival group, the death group had significantly higher 24hVIS max, 24hVIS mean, PRISM III score, and level of lactate before the use of vasoactive agents and after 24 hours of use (P<0.05). 24hVIS max, 24hVIS mean, PRISM III score, level of lactate before the use of vasoactive agents and after 24 hours of use, and 24-hour pH had a certain value in predicting the prognosis of septic shock, but 24hVIS max had the largest area under the ROC curve. Compared with the low VIS group, the high VIS group had significantly higher number of deaths, PRISM III score, and level of lactate before treatment and after 24 hours of treatment (P<0.05). CONCLUSIONS: VIS is associated with the mortality of children with septic shock, and the severity and mortality of patients increase with the increase in VIS. PMID- 29429458 TI - [Burkholderia cepacia infection in children: a clinical analysis of 16 cases]. AB - OBJECTIVE: To investigate the distribution characteristics and clinical features of Burkholderia cepacia infection in children. METHODS: A retrospective analysis was performed for the clinical data of 16 children with Burkholderia cepacia infection who were hospitalized between June 2012 and September 2017. RESULTS: All 16 children with Burkholderia cepacia infection were sporadic cases. A total of 16 strains of Burkholderia cepacia were isolated, among which 8 were detected by sputum culture, 5 were detected by blood culture, 2 were detected by tracheal intubation tip culture, and 1 was detected by lung biopsy culture. Of the 16 children, there were 11 boys and 5 girls, with an age of 5 days to 6 years, and the children aged <1 year accounted for 69%. As for department distribution, 10 children were in the PICU/NICU and 6 were in the general wards. As for clinical manifestations, one child had disseminated intravascular coagulation, and the other 15 children had pulmonary infection, among who 11 had severe pneumonia (8 of them underwent mechanical ventilation during treatment). As for underlying diseases, 2 had severe congenital heart disease, 4 had primary immunodeficiency, 3 were highly suspected of immunodeficiency or inherited metabolic diseases, 1 had tracheal stenosis, 1 had Kawasaki disease, 1 was a preterm infant with bronchopulmonary dysplasia, 1 had severe cleft lip and palate, and 3 had no definite underlying diseases. Of all the children, 7 also had infections with adenovirus and Mycoplasma. The average length of hospital stay was 20.3 days for all children, and 12 were improved and 4 died after treatment. All 16 strains of Burkholderia cepacia had a drug resistance rate of 100% to amikacin and gentamicin and >=80% to ampicillin/sulbactam and ticarcillin/clavulanic acid, as well as the lowest drug resistance rate to levofloxacin. CONCLUSIONS: Burkholderia cepacia is an opportunistic pathogen often found in immunocompromised children and can produce drug resistance. The presence or absence of underlying diseases should be considered during anti-infective therapy. The children with Burkholderia cepacia infection often have a poor prognosis, and an understanding of the disease spectrum of Burkholderia cepacia infection helps with clinical diagnosis and treatment. PMID- 29429459 TI - [Clinical effect of Saccharomyces boulardii powder combined with azithromycin sequential therapy in treatment of children with diarrhea secondary to Mycoplasma pneumoniae pneumonia]. AB - OBJECTIVE: To investigate the clinical effect of Saccharomyces boulardii powder combined with azithromycin sequential therapy in the treatment of children with diarrhea secondary to Mycoplasma pneumoniae pneumonia. METHODS: A total of 88 children with diarrhea secondary to Mycoplasma pneumoniae pneumonia between June 2015 and March 2017 were divided into control group and study group using a random number table, with 44 children in each group. The children in the control group were given routine treatment combined with azithromycin sequential therapy, and those in the study group were given oral Saccharomyces boulardii powder in addition to the treatment in the control group until the end of azithromycin sequential therapy. After the treatment ended, the two groups were compared in terms of time to improvement of clinical symptoms, length of hospital stay, clinical outcome, defecation frequency before and after treatment, condition of intestinal dysbacteriosis, and incidence of adverse events. RESULTS: Compared with the control group, the study group had significantly shorter time to improvement of clinical symptoms and length of hospital stay (P<0.05). The study group had a significantly higher response rate than the control group (P<0.05). On days 3 and 5 of treatment, the study group had a significant reduction in defecation frequency compared with the control group (P<0.05). The study group had a significantly lower rate of intestinal dysbacteriosis than the control group (P<0.05). There was no significant difference in the incidence of adverse events between the two groups (P>0.05). CONCLUSIONS: In the treatment of children with diarrhea secondary to Mycoplasma pneumoniae pneumonia, Saccharomyces boulardii powder combined with azithromycin sequential therapy can improve clinical symptoms, shorten the length of hospital stay, reduce defecation frequency and the incidence of intestinal dysbacteriosis, and improve clinical outcomes, and does not increase the risk of adverse events. PMID- 29429460 TI - [A clinical analysis of children with invasive pulmonary fungal infections after biliary atresia surgery]. AB - OBJECTIVE: To investigate the clinical features of invasive pulmonary fungal infections (IPFIs) after biliary atresia (BA) surgery and related risk factors. METHODS: A retrospective analysis was performed for the clinical data of 49 children with IPFIs after BA surgery, including clinical features, lung imaging findings, and pathogenic features. The risk factors for IPFIs after BA surgery were also analyzed. RESULTS: The most common pathogens of IPFIs after BA surgery was Candida albicans (17 strains, 45%), followed by Candida tropicalis (7 strains, 18%), Aspergillus (6 strains, 16%), Candida krusei (3 strains, 8%), Candida glabrata (3 strains, 8%), and Candida parapsilosis (2 strains, 5%). Major clinical manifestations included pyrexia, cough, and shortness of breath, as well as dyspnea in severe cases; the incidence rate of shortness of breath reached 78%, and 35% of all children had no obvious rale. The multivariate logistic regression analysis showed that age at the time of surgery, time of glucocorticoid application, cumulative time of the application of broad-spectrum antibiotics, and recurrent cholangitis were major risk factors for IPFIs after BA surgery. CONCLUSIONS: The three most common pathogens of IPFIs after BA surgery are Candida albicans, Candida tropicalis, and Aspergillus. It is important to perform surgery as early as possible, avoid recurrent cholangitis, and shorten the course of the treatment with broad-spectrum antibiotics and glucocorticoids for decreasing the risk of IPFIs. PMID- 29429461 TI - [Gene mutations in unexplained infantile epileptic encephalopathy: an analysis of 47 cases]. AB - OBJECTIVE: To investigate the characteristics of gene mutations in unexplained infantile epileptic encephalopathy (EE). METHODS: A total of 47 infants with unexplained infantile EE were enrolled, and next-generation sequencing was used to analyze gene mutations in these infants and their parents. RESULTS: Of all 47 infants, 23 were found to have gene mutations, among whom 13 had de novo mutations and 10 had heterozygous mutations inherited from their father or mother. Among the 23 infants with gene mutations, 17 were found to have the gene mutations related to EE (among whom 14 had ion channel gene mutations), 2 had the gene mutations related to congenital inherited metabolic diseases, 2 had the gene mutations related to brain structural abnormality, and 2 had the gene mutations related to mental retardation. CONCLUSIONS: Unexplained infantile EE may have gene mutations, mainly ion channel gene mutations. PMID- 29429462 TI - [Association between SCN1A rs3812718 polymorphism and generalized epilepsy with febrile seizures plus]. AB - OBJECTIVE: To investigate the association between SCN1A rs3812718 polymorphism and generalized epilepsy with febrile seizures plus (GEFS+), and to provide potential molecular targets for the diagnosis and treatment of GEFS+. METHODS: The iPLEX technique in the MassARRAY system was used to determine SCN1A rs3812718 polymorphism, genotype frequency, and allele frequency in 50 patients with GEFS+ and 50 healthy controls. RESULTS: As for the frequencies of CC, CT, and TT genotypes in SCN1A rs3812718, there was a significant difference in the frequency of TT genotype between the GEFS+ group and the control group (P<0.05). There was also a significant difference in the frequency of T allele between the two groups (P<0.05). Compared with those carrying CC genotype or C allele, the individuals with CT genotype , TT genotype or T allele had a higher risk of developing GEFS+ (CT/CC: OR=4.05, 95%CI: 1.04-15.69; TT/CC: OR=30.60, 95%CI: 6.46-144.85; T/C: OR=4.64, 95%CI: 2.54-8.48). CONCLUSIONS: SCN1A rs3812718 polymorphism is a risk factor for GEFS+, and the population carrying T allele may have an increased risk of GEFS. PMID- 29429463 TI - [Abnormal processing characteristics to basic emotional faces in the early phase in children with autism spectrum disorder]. AB - OBJECTIVE: To explore the recognition ability and abnormal processing characteristics to basic emotional faces in the early phase in children with autism spectrum disorders (ASD). METHODS: Photos of Chinese static faces with four basic emotions (fearful, happy, angry and sad) were used as stimulus. Twenty five ASD children and twenty-two age- and gender-matched typical developed children (normal controls) were asked to match the emotional faces with words. Event-related potential (ERP) data were recorded concurrently. RESULTS: N170 latencies for total emotion and fearful face in the left temporal region were faster than in the right one in normal controls (P<0.05), but the results were not noted in ASD children. Further, N170 latencies in the left temporal region of ASD children were slower than normal controls for total emotion, fearful and happy faces (P<0.05), and their N170 latencies in the right temporal region were prone to slower than normal controls for angry and fearful faces. CONCLUSIONS: The holistic perception speed of emotional faces in the early cognitive processing phase in ASD children is slower than normal controls. The lateralized response in the early phase of recognizing emotional faces may be aberrant in children with ASD. PMID- 29429464 TI - [Association between dopamine D4 receptor gene exon III 48bp VNTR polymorphism and temperament in school-aged children]. AB - OBJECTIVE: To investigate the association between dopamine D4 receptor gene DRD4 exon III 48bp variable number of tandem repeat (VNTR) polymorphism and temperament in school-aged children. METHODS: Randomized cluster sampling was used to select 350 healthy children aged 8-12 years, and a questionnaire survey was performed. Oral epithelial samples were collected from half of these children. The complete questionnaire data of 164 children with a high level of DNA in oral epithelial samples were included in this study. PCR was used for the typing of DRD4 exon III 48bp VNTR, and the effect of this gene and its interaction with the environment on temperament was analyzed. RESULTS: Compared with the children with S-DRD4 genotype, the children with L-DRD4 genotype had significantly lower scores on the four dimensions of activity level, reaction intensity, emotion essence, and persistence (P<0.05). The main effects of mother's rejection/denial (OR=2.281, P<0.05) and sex (OR=2.766, P<0.05) and the interaction between sex and DRD4 exon III 48bp VNTR (OR=0.582, P<0.05) had an influence on activity level. The main effect of DRD4 exon III 48bp VNTR (OR=0.314, P<0.01) and the interaction between this gene and mother's rejection/denial (OR=1.872, P<0.01) had an influence on reaction intensity. The main effect of DRD4 exon III 48bp VNTR (OR=0.420, P<0.05) and mother's rejection/denial (OR=2.236, P<0.05) had an influence on persistence. CONCLUSIONS: DRD4 exon III 48bp VNTR and its interaction with other factors may affect the activity level and reaction intensity of school-aged children. PMID- 29429465 TI - [Effect of vitamin A as an adjuvant therapy for pneumonia in children: a Meta analysis]. AB - OBJECTIVE: To investigate the effect and safety of vitamin A supplementation in children with pneumonia through a systematic review. METHODS: Cochrane Library, EMbase, PubMed, China Biology Medicine disc, CNKI, and Wanfang Data were searched for randomized controlled trials (RCTs) on vitamin A as an adjuvant therapy for pneumonia in children. Two reviewers independently screened the studies and evaluated their quality according to the inclusion and exclusion criteria. RevMan5.3 was used for the Meta analysis. RESULTS: A total of 15 RCTs with 3 021 patients were included. The Meta analysis showed that vitamin A supplementation did not reduce the mortality of children with pneumonia (P>0.05), but it increased the overall clinical response rate (P<0.05) and shortened the duration of pyrexia and cough, clearance time of signs and abnormal chest X-ray results, and length of hospital stay (P<0.05). As an adjuvant therapy, vitamin A did not increase the incidence rates of adverse reactions such as nausea, vomiting, diarrhea, allergy, and bregma bulging. CONCLUSIONS: Current evidence shows that in the treatment of pneumonia in children, vitamin A supplementation helps to relieve clinical symptoms and signs and shorten the length of hospital stay.The adjuvant therapy does not increase the incidence rates of adverse reactions. PMID- 29429466 TI - [Recurrent convulsion and pulmonary infection complicated by psychomotor retardation in an infant]. AB - A 4-month-old girl developed convulsion in the neonatal period, which was focal motor seizures in the initial stage and later became spasm and tonic spasm. And the girl also had psychomotor retardation and recurrent pulmonary infection. Electroencephalography showed hypsarrhythmia, normal results were obtained from cranial magnetic resonance imaging, cerebrospinal fluid examination, and urine organic acid analysis, as well as the spectral analyses of blood ammonia, blood lactic acid, blood amino acids, and acylcarnitines. Gene detection revealed a de novo heterozygous mutation, c.607G>A (p.G203R) , in GNAO1. The girl was then diagnosed with GNAO1-associated early infantile epileptic encephalopathy (EIEE type 17). The seizures were well controlled by topiramate and vigabatrin, but there was no improvement in psychomotor development. She also suffered from recurrent pulmonary infection and died at the age of 12 months due to severe pneumonia. For children with unexplained early infantile epileptic encephalopathy, GNAO1 gene mutations should be considered and genetic tests should be performed as early as possible. Recurrent pulmonary infection should also be taken seriously. PMID- 29429467 TI - [Effects of Toll-like receptor blockers on intestinal mucosal injury in mice with endotoxemia]. AB - OBJECTIVE: To investigate the effects of Toll-like receptor blockers TLR2-Ab and TLR4-Ab on the tight junction protein ZO-1 in intestinal epithelial cells in mice, as well as their effects on nuclear factor-kappa B (NF-kappaB) and tumor necrosis factor-alpha (TNF-alpha). METHODS: A total of 32 BALB/C mice were divided into control group, model group, TLR4 treatment group, and TLR2 treatment group, with 8 mice in each group. A mouse model of endotoxemia was established by intraperitoneal injection of lipopolysaccharide. The mice in the TLR4 treatment group and the TLR2 treatment group were given intraperitoneal injection of TLR4 antibody and TLR2 antibody (10 MUg each mouse), respectively, and those in the control group were given normal saline. The distal small intestinal tissue was collected, and RT-PCR and immunohistochemistry were used to measure the mRNA and protein expression of ZO-1, NF-kappaBp65, and TNF-alpha. RESULTS: Compared with the control group, the model group had significantly lower mRNA and protein expression of ZO-1 and significantly higher mRNA expression of NF-kappaBp65 and TNF-alpha (P<0.05). Compared with the model group, the TLR4 treatment group and the TLR2 treatment group had significantly higher mRNA and protein expression of ZO-1 and significantly lower mRNA and protein expression of NF-kappaBp65 and TNF alpha (P<0.05). There were no significant differences in the mRNA and protein expression of ZO-1, NF-kappaBp65, and TNF-alpha between the TLR4 treatment group and the TLR2 treatment group (P>0.05). CONCLUSIONS: Anti-TLR2 and anti-TLR4 monoclonal antibodies can reduce the activation of nuclear transcription factors, inhibit the secretion of inflammatory factors, and protect tight junction protein, which is expected to provide new ideas for the treatment of enterogenous infectious diseases. PMID- 29429470 TI - ? PMID- 29429469 TI - ? PMID- 29429468 TI - [Research advances in necrotizing enterocolitis in neonates]. AB - Necrotizing enterocolitis (NEC) is a catastrophic disease caused by a variety of factors in neonates, especially preterm infants. Severe NEC has a high fatality rate, and most survivors may face short- and long-term adverse prognosis. Risk factors for NEC include preterm birth, non-breastfeeding, microbial abnormalities in the digestive tract, and ischemia-reperfusion injury. High-resolution abdominal ultrasound helps with the early diagnosis of NEC. The preventive measures for NEC include protecting the intestinal mucosa through nutritional intervention, interfering with intestinal injury signals, changing intestinal microflora, and performing early minimal enteral nutrition. This disease progresses rapidly, and there are still no effective measures. Supportive care is mainly used for the treatment of this disease, and patients in severe conditions may need surgical treatment. Celastrol, lipopolysaccharide, and fecal transplantation help with the treatment of NEC, but further studies are needed to confirm their clinical effects. PMID- 29429471 TI - ? PMID- 29429472 TI - ? PMID- 29429473 TI - ? PMID- 29429474 TI - ? PMID- 29429475 TI - [Osteosynthesis of rib fractures, unstable chest wall, pseudoarthroses, and acquired defects of the chest wall]. AB - Several patients suffer from rib fractures after traumas, and in severe cases it can be life-threatening. Until recently, attempts to perform surgical fixation in patients with instability have been unsuccessful. Chronic non-union causes persistent pain, disability and loss of quality of life. Implementation of surgical stabilization of rib fractures with tailored plates seems to improve pain relief, especially in cases of non-union but also in patients with instability of the chest wall after severe traumas, where advanced pain treatment (epidural catheter) is insufficient or weaning off fails. PMID- 29429476 TI - [Diagnosis and treatment of maturity onset diabetes of the young type 3]. AB - Maturity onset diabetes of the young type 3 (MODY3) is the most prevalent type of monogenetic diabetes. Treatment guidelines differ from both Type 1 diabetes and Type 2 diabetes. First-line treatment is a long-acting sulphonylurea, which lowers the plasma glucose level effectively, however with the risk of hypoglycaemia. When hypoglycaemia is a problem, short-acting sulphonylureas, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors may be used as alternatives. Metformin, glitazones and sodium glucose transporter 2-inhibitors have only limited applicability in MODY3. Further research needs to evaluate combinational therapy. PMID- 29429477 TI - [Novel antidiabetic drugs and cardiovascular complications]. AB - This review summarizes the cardiovascular non-inferiority trials of novel antidiabetic drugs performed since 2008, when regulatory agencies started mandating thorough examination of their cardiovascular safety. So far, eight randomized trials on three different drug classes have been completed. Sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists may reduce cardiovascular risk and possibly mortality, while dipeptidyl dipeptidase-4 inhibitors may increase the risk of heart failure. A brief discussion of potential mechanisms and clinical implications is provided. PMID- 29429478 TI - [Femur shaft fractures in infants should be considered despite no known trauma]. AB - Femur shaft fractures in infants are rare and associated with abuse or fall from heights. The fracture is often easy to recognize on X-ray, however, the determination of the indication can be difficult. It is important to pay attention to pain signals from the extremity and the objective findings, such as a swollen and tight thigh. Early recognition of the fracture is of importance to the prognosis and to detection of possible violence resulting in battered child syndrome. Exploration for injuries of the extremities is of utmost necessity in these cases, despite the absence of trauma in the anamnesis. PMID- 29429479 TI - [Chronic post-dural headache secondary to meningitis]. AB - In this case report a young man was admitted with fever and headache, and a lumbar puncture revealed viral meningitis. After discharge, the patient experienced persistent headache, which worsened, when he was in upright position. The condition was considered secondary to the meningitis. After 14 months, the patient was diagnosed with post-dural puncture headache and treated with an epidural blood patch (EBP). The patient experienced no headache for three months, whereafter it returned. Subsequent EBP's were unsuccessful. This case emphasizes the importance of paying attention to orthostatic components in headaches. PMID- 29429480 TI - [Review of a new subtype of hereditary angio-oedema with normal complement C1 inhibitor]. AB - Hereditary angio-oedema (HAE) is a rare, potentially fatal disease characterized by recurrent swelling of skin and mucosa. Besides HAE with quantitative (type I) or qualitative (type II) deficiency of complement C1-inhibitor (C1-INH), a new subtype of HAE is now described with normal levels of C1-INH. This subtype is possibly underdiagnosed, and a treatment regimen and general knowledge about the condition is still in its infancy. The purpose of this article is to inform Danish doctors about the disease to identify more Danish patients. PMID- 29429482 TI - Enteric coronavirus infection in adult horses. AB - A new enteric virus of adult horses, equine coronavirus (ECoV), has recently been recognized. It is associated with fever, lethargy, anorexia, and less frequently, colic and diarrhea. This enteric virus is transmitted via the feco-oral route and horses become infected by ingesting fecally contaminated feed and water. Various outbreaks have been reported since 2010 from Japan, Europe and the USA. While the clinical signs are fairly non-specific, lymphopenia and neutropenia are often seen. Specific diagnosis is made by the detection of ECoV in feces by either quantitative real-time PCR, electron microscopy or antigen-capture ELISA. Supportive treatment is usually required, as most infections are self-limiting. However, rare complications, such as endotoxemia, septicemia and hyperammonemia associated encephalopathy, have been reported, and have been related to the loss of barrier function at the intestinal mucosa. This review article will focus on the latest information pertaining to the virus, epidemiology, clinical signs, diagnosis, pathology, treatment and prevention of ECoV infection in adult horses. PMID- 29429481 TI - Construction of a ptfA chitosan nanoparticle DNA vaccine against Pasteurella multocida and the immune response in chickens. AB - The aim of this study was to evaluate the effect of chitosanon the immune response induced by a DNA vaccine based on the ptfA gene of avian Pasteurella multocida. Naked DNA vaccine was packed with chitosanmolecules, resulting in a chitosannanoparticle DNA vaccine. The encapsulation efficiency, shape, size and resistance to DNA degradation were determined. The vaccine was administered to chickens and serum antibody, interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and interleukin-4 (IL-4) concentrations were determined and lymphocyte proliferation assays were performed. After challenge with virulent avian P. multocida, protective efficacy was evaluated. The encapsulation efficiency of the chitosan nanoparticle DNA vaccine was 95.3%. The particle size was approximately 200nm and close to spherical in shape and it could effectively resist degradation by DNases. Following vaccination, serum antibodies, stimulation index (SI) value and concentrations of IFN-gamma and IL-2 in chickens vaccinated with the chitosan nanoparticle DNA vaccine were significantly higher than those that were vaccinated with the naked DNA vaccine (P-values are 0.026, 0.045, 0.039 and 0.024, respectively). However, the concentrations of IL-4 in the two DNA vaccines group were no significant difference (P=0.157). The protective efficacy rate provided by naked DNA vaccine, chitosan nanoparticle DNA vaccine and the attenuated live vaccine were 56%, 68% and 88%, respectively. The results indicated that chitosan was able to enhance the immune response to a naked DNA vaccine based on the ptfA gene of P. multocida. PMID- 29429483 TI - A cost-benefit analysis and the potential trade effects of the bovine viral diarrhoea eradication programme in Styria, Austria. AB - This study evaluated the voluntary and compulsory implementation of a bovine viral diarrhoea virus (BVDV) eradication programme in the Austrian Federal State of Styria, Austria, from an economic point of view using ex-post assessment of costs and benefits (disease losses avoided). An economic net benefit (benefit:cost ratio, BCR=1.18) of the programme was demonstrated during the voluntary programme phase (January 1998-July 2004). The break-even point was reached in 2003. If investments in the compulsory programme (August 2004-December 2016) were taken into account, a net economic loss (BCR=0.16) was demonstrated. In contrast to on-going annual testing of all cattle herds, annual testing in accordance with a revised sampling scheme could reduce total surveillance costs by more than 77%. A Bayesian structural time series model was applied to analyse a hypothesised positive impact of the compulsory BVDV programme on the Styrian cattle export market. The average number of exported cows and bulls increased significantly by 42% (P=0.03) and 47% (P=0.01), respectively, and the producer price increased by 14% (P=0.00) and 5% (P=0.16), respectively, during the compulsory programme period compared with the period prior to intervention. This equates to an average revenue increase of ?29,754 for cows and ?137,563 for bulls per month. These results justify the implementation of eradication programmes, which initially may not appear to be economically viable, particularly if trade effects are not included in the calculations. PMID- 29429484 TI - Complex segregation analysis of craniomandibular osteopathy in Deutsch Drahthaar dogs. AB - This study investigated familial relationships among Deutsch Drahthaar dogs with craniomandibular osteopathy and examined the most likely mode of inheritance. Sixteen Deutsch Drahthaar dogs with craniomandibular osteopathy were diagnosed using clinical findings, radiography or computed tomography. All 16 dogs with craniomandibular osteopathy had one common ancestor. Complex segregation analyses rejected models explaining the segregation of craniomandibular osteopathy through random environmental variation, monogenic inheritance or an additive sex effect. Polygenic and mixed major gene models sufficiently explained the segregation of craniomandibular osteopathy in the pedigree analysis and offered the most likely hypotheses. The SLC37A2:c.1332C>T variant was not found in a sample of Deutsch Drahthaar dogs with craniomandibular osteopathy, nor in healthy controls. Craniomandibular osteopathy is an inherited condition in Deutsch Drahthaar dogs and the inheritance seems to be more complex than a simple Mendelian model. PMID- 29429485 TI - Paradigm shifts in understanding equine laminitis. AB - Laminitis, one of the most debilitating conditions of all equids, is now known to be the result of several systemic disease entities. This finding, together with other recent developments in the field of laminitis research, have provoked a rethink of our clinical and research strategies for this condition. First, laminitis is now considered to be a clinical syndrome associated with systemic disease (endocrine disease, sepsis or systemic inflammatory response syndrome, SIRS) or altered weight bearing rather than being a discrete disease entity. Next, laminitis associated with endocrine disease (endocrinopathic laminitis) is now believed to be the predominant form in animals presenting (primarily) for lameness. Third, the designation of laminitis as a primary and severe basement membrane pathology now requires revision. Instead, current data now proposes a variable subclinical phase associated with gross changes in the hoof capsule, with stretching and elongation of the lamellar cells an early and key event in the pathophysiology. These findings have fuelled new mechanistic hypotheses and research directions that will be discussed, together with their implications for future clinical management. PMID- 29429486 TI - Use of rumination and activity data as health status and performance indicators in beef cattle during the early fattening period. AB - The aim of this study was to measure the level of activity and rumination in young bulls and to assess whether these data can be used as indicators of health status and average daily weight gain (ADG). Two groups of animals (period 1: n=108 animals; period 2: n=106 animals) were fitted with sensors to measure daily activity and rumination, were weighed on arrival and at the end of the trial (70 days) and were checked twice daily to verify their health condition. Any clinical signs and therapies were recorded. The dishomogeneity index of rumination (DR), and the daily dishomogeneity indices of activity (DDA) and rumination (DDR), were calculated. Bulls had an ADG of 1.42+/-0.38kg/day and showed an average duration of daily rumination of 404+/-63min and an average activity of 474+/-46 bits, respectively. Animals characterised by low ADG had lower values of minimum daily rumination (P=0.01) and DDA (P<0.001), and a greater rumination range (P=0.007) and DR (P=0.003). Bovine respiratory disease and lameness were detected 31 and five times, respectively; among affected animals, the average daily activity, rumination and DDA were lower (P<0.05) at 3-6days before the onset of visible clinical signs, whereas DDR increased compared to the values when individuals were apparently healthy. The use of individual sensors appears promising for the early diagnosis of disease in beef cattle and for improving herd management. PMID- 29429487 TI - Dynamic changes in DNA methylation patterns in canine lymphoma cell lines demonstrated by genome-wide quantitative DNA methylation analysis. AB - DNA methylation is the conversion of cytosine to 5-methylcytosine, leading to changes in the interactions between DNA and proteins. Methylation of cytosine guanine (CpG) islands (CGIs) is associated with gene expression silencing of the involved promoter. Although studies focussing on global changes or a few single loci in DNA methylation have been performed in dogs with certain diseases, genome wide analysis of DNA methylation is required to prospectively identify specific regions with DNA methylation change. The hypothesis of this study was that next generation sequencing with methylation-specific signatures created by sequential digestion of genomic DNA with SmaI and XmaI enzymes can provide quantitative information on methylation levels. Using blood from healthy dogs and cells obtained from canine lymphoma cell lines, approximately 100,000CpG sites across the dog genome were analysed with the novel method established in this study. CpG sites in CGIs broadly were shown to be either methylated or unmethylated in normal blood, while CpG sites not within CpG islands (NCGIs) were largely methylated. Thousands of CpG sites in lymphoma cell lines were found to gain methylation at normally unmethylated CGI sites and lose methylation at normally methylated NCGI sites. These hypermethylated CpG sites are located at promoter regions of hundreds of genes, such as TWIST2 and TLX3. In addition, genes annotated with 'Homeobox' and 'DNA-binding' characteristics have hypermethylated CpG sites in their promoter CGIs. Genome-wide quantitative DNA methylation analysis is a sensitive method that is likely to be suitable for studies of DNA methylation changes in cancer, as well as other common diseases in dogs. PMID- 29429488 TI - A digital archive of The Veterinary Journal. PMID- 29429489 TI - The possible role of Stomoxys calcitrans in equine sarcoid transmission. AB - The association between bovine papillomavirus (BPV) and equine sarcoids is well established, but it is unclear how the virus spreads. Although evidence in support of viral spread through direct animal contact exists, this does not explain sarcoid development in isolated equids. BPV DNA has been detected in flies, which could indicate that these insects serve as a vector. This study aimed to investigate whether BPV-negative stable flies (Stomoxys calcitrans) become positive for BPV DNA after exposure to equine sarcoid or bovine papilloma tissue under experimental conditions and, if so, for how long. A total of 420 stable flies were caught alive and exposed to BPV positive equine sarcoid or bovine papilloma tissue. During the following week, dead flies were collected daily and BPV loads were determined by quantitative PCR. There was a significant rise in BPV load after tissue exposure both in sarcoid and papilloma exposed flies, but the viral load was higher and remained high for a longer time after exposure to papilloma tissue compared to sarcoid tissue. Within days, viral loads decreased again and became indifferent from loads before exposure. The results of these experiments indicate that BPV transmission by S. calcitrans seems possible and is more likely to occur after contact with bovine papillomas than with equine sarcoids. Transmission seems only possible shortly after tissue exposure. Further research could include experimental induction of sarcoids with BPV positive stable flies, or a repeat of the experiment with micro-dissection prior to PCR. PMID- 29429491 TI - The Journal of School Psychology: Promoting science at JSP: Focus on special content and current status of the journal. PMID- 29429492 TI - Initial development and evaluation of the student intervention matching (SIM) form. AB - There is currently a large gap in both research and practice between student identification practices for those at-risk (i.e., universal screening, teacher referral, or extant data as early identification methods) and the selection of appropriate Tier 2 interventions for social, emotional, and behavioral concerns. The purpose of this study was to develop and test the treatment validity of the Student Intervention Matching (SIM) Form, an intervention matching protocol designed for use at Tier 2. To this end, single-case design methodology was employed to systematically evaluate outcomes associated with use of the SIM Form in the intervention selection process. Participants included eight elementary-age students arranged in sets of four student dyads. A multiple baseline design was used in order to examine the relative effectiveness of matched interventions according to the SIM Form, and mismatched interventions according to the SIM Form. Results indicated that interventions matched using the SIM Form were functionally related to improved student outcomes across a variety of dependent variables when compared to mismatched phases. Implications for practice and future research are discussed. PMID- 29429493 TI - A universal behavioral screener linked to personalized classroom interventions: Psychometric characteristics in a large sample of German schoolchildren. AB - The current study represents the first psychometric evaluation of an American English into German translation of a school-based universal screening measure designed to assess academic and disruptive behavior problems. This initial study examines the factor structure and diagnostic accuracy of the newly translated measure in a large sample of 1009 German schoolchildren attending grades 1-6 in Western Germany. Confirmatory factor analysis supported a two-factor model for both male- and female- students. Configural invariance was supported between male and female-samples. However scalar invariance was not supported, with higher thresholds for ratings of female students. Results of receiver operating characteristic (ROC) curve analyses were indicative of good to excellent diagnostic accuracy with areas under the curve ranging from 0.89 to 0.93. Optimal cut-off scores were 10, 5, and 13 for the Academic Productivity/Disorganization, Oppositional/Disruptive, and the Total Problems Composite scores of the Integrated System Teacher Rating Form respectively. This initial study of the newly translated measure supports further investigations into its utility for universal screening in German speaking schools. PMID- 29429494 TI - Advancing the science and practice of precision education to enhance student outcomes. AB - School psychology research and practice has considerable room for growth to go beyond "did an intervention work?" to "what intervention worked for whom and how did it work?" The latter question reflects a more precise understanding of intervention, and involves strategic efforts to enhance the precision of services students with academic, behavioral, emotional, or physical health problems receive to enhance the degree to which interventions are appropriately tailored to and produce benefit for individual students. The purpose of this special issue is to advance the notion and science of precision education, which is defined as an approach to research and practice that is concerned with tailoring preventive and intervention practices to individuals based on the best available evidence. This introductory article provides context for the special issue by discussing reasons why precision education is needed, providing definitions/descriptions of precision education research, and outlining opportunities to advance the science of precision education. Six empirical studies and one methodological-oriented article were compiled to provide examples of the breadth of research that falls under precision education. Although each of the article focuses on students with different needs (literacy deficits, math deficits, emotional and behavior problems, and intellectual disability), there is a common thread that binds them together, and that is each one captures the heterogeneity among students with particular problems or deficits and highlights the need to select and deliver more precise interventions to optimize student outcomes. PMID- 29429495 TI - Selecting effective intervention strategies for escape-maintained academic performance problems: Consider giving 'em a break! AB - This study compared consequence-and antecedent-based strategies to determine which treatments or combination of treatments produced the strongest improvements in math computation fluency with four elementary-aged students whose math computation was under the control of an escape contingency. Functional analyses were conducted to identify elementary-school students whose academic responding was under a negative-reinforcement contingency. A multielement design was then used to examine the impact of four treatments (DNRA, DRA, task choice, and task choice plus DRA) on each student's rate of correct digits per min. All four treatments increased rate of responding. Differentiated results were obtained for all participants, indicating a reliable effect. Yet, participants responded differently to the treatments, illustrating the need to investigate and adapt interventions for escape-motivated behavior on a case-by-case basis. Results are also discussed in terms of the effectiveness of choice relative to reinforcement procedures, whether there were additional benefits to combining treatments, and which type of reinforcement procedures (DRA or DNRA) appears to be more effective for students whose behavior is under the control of an escape contingency. PMID- 29429496 TI - Meta-analysis of targeted small-group reading interventions. AB - Small-group reading interventions are commonly used in schools but the components that make them effective are still debated or unknown. The current study meta analyzed 26 small-group reading intervention studies that resulted in 27 effect sizes. Findings suggested a moderate overall effect for small-group reading interventions (weighted g=0.54). Interventions were more effective if they were targeted to a specific skill (g=0.65), then as part of a comprehensive intervention program that addressed multiple skills (g=0.35). There was a small correlation between intervention effects and group size (r=0.21) and duration (r=0.11). Small-group interventions led to a larger median effect size (g=0.64) for elementary-aged students than for those in middle or high school (g=0.20), but the two confidence intervals overlapped. Implications for research and practice are discussed. PMID- 29429497 TI - Personalized reading intervention for children with Down syndrome. AB - The purpose of this replication study was to evaluate the potential efficacy and feasibility of an early reading intervention for children with Down syndrome. The intervention was developed in alignment with the Down syndrome behavioral phenotype. Six children between the ages of seven and ten years participated in a series of multiple-probe across lessons single-case design studies. Results indicate a functional relation between intervention and reading outcomes for four children. Results were mixed for one participant and no functional relation was demonstrated for another. The potential promise of pursuing aptitude-by-treatment interaction research for subgroups of learners with similar characteristics as an effort to personalize intervention is discussed. PMID- 29429498 TI - Getting "SMART" about implementing multi-tiered systems of support to promote school mental health. AB - With the growing adoption and implementation of multi-tiered systems of support (MTSS) in school settings, there is increasing need for rigorous evaluations of adaptive-sequential interventions. That is, MTSS specify universal, selected, and indicated interventions to be delivered at each tier of support, yet few investigations have empirically examined the continuum of supports that are provided to students both within and across tiers. This need is compounded by a variety of prevention approaches that have been developed with distinct theoretical foundations (e.g., Positive Behavioral Interventions and Supports, Social-Emotional Learning) that are available within and across tiers. As evidence-based interventions continue to flourish, school-based practitioners greatly need evaluations regarding optimal treatment sequencing. To this end, we describe adaptive treatment strategies as a natural fit within the MTSS framework. Specifically, sequential multiple assignment randomized trials (SMART) offer a promising empirical approach to rigorously develop and compare adaptive treatment regimens within this framework. PMID- 29429499 TI - Magnetic Resonance Spectroscopy Gamma-Aminobutyric Acid: A Promising Biomarker for Antipsychotic Treatment? PMID- 29429500 TI - Excitatory Amino Acids in Schizophrenia: Both What You Have, and What You Do With Them. PMID- 29429501 TI - The Ups and Downs of Thalamocortical Connectivity in Schizophrenia. PMID- 29429502 TI - Translating Schizophrenia Population Genetics Findings to Neurobiological Mechanisms: The Case of KALRN-9. PMID- 29429503 TI - [What's new in clinical dermatology?] AB - Zika virus: what the dermatologist should know. Probably a new vaccine against herpes zoster and postherpetic neuralgia in older adults. Defining moderate, significant and extensive types of pemphigus with ABSIS et PDAI scores. Biologic Therapies and serious infections in patients with psoriasis. We can be cautiously optimistic, in that tuberculosis is rare but still occurs despite adherence to tuberculosis prevention guidelines. Others serious infections are rare, mainly pneumonia and cellulitis. Hidradenitis suppurativa: an unrecognized paradoxical effect of biologic agents. There is an association between Inflammatory Bowel Disease (IBD) and Hidradenitis suppurativa (HS), mostly with Crohn's disease, suggesting the need to look for signs and symptoms of IBD in HS patients. A study of 550 twins found that genetic and environmental factors each contribute to approximately half of the score of rosacea. Telangiectasia Macularis Eruptiva Perstans is a difficult to diagnose type of mastocytosis, often with a delay and which is associated with a systemic involvement in 50% of cases. Vitiligo. Management and development of new scores for the dermatologist and the patient. Livedoid vasculopathy. Anticoagulation with new molecules could prove an efficient means of treatment. Pyoderma Gangrenosum. Don't forget the toxic etiology. Daily practice: Laboratory monitoring for liver function tests and serum lipid profile during isotretinoin therapy for acne is currently recommended at baseline and every 3 months, depending on the results. Daily practice: Mikailov and al., challenge our habits by their medico economic study and propose an empirical treatment with terbinafine for patients with suspected onychomycosis that is cost effective with minimal effect on patient safety as terbinafine induced liver injury is very rare. It makes think and especially propose studies to update our recommendations. PMID- 29429504 TI - [What's new in instrumental dermatology (laser)?] AB - This year, What's new in Interventional Dermatology will be dedicated to lasers and other interventional devices. Many articles have been published these past two years emphasizing how dynamic this field of dermatology is. However, most of published papers were case reports or open series. Thus, innovative approaches, prospective randomized trials and large retrospective studies were the main criteria of selection of the articles. PMID- 29429505 TI - [What's new in dermatological research?] AB - Many research studies dedicated to skin have been published in 2016 in high impact factor journals. This article summarises a selection of research works published between December 2015 and September 2016. New insights into the understanding of the mechanisms involved in psoriasis and atopic dermatitis can lead to better management of these chronic inflammatory disorders. Moreover, a better understanding of the relation between the host and the environment could lead to new therapeutic strategies. Finally, new devices first dedicated to skin inflammatory diseases have been developed with success that could be extended to other chronic inflammatory disorders. PMID- 29429506 TI - [What's new in internal medecine?] AB - Answering the question " what's new in internal medecine in 2016? " is very challenging. We used 3 methods of article selection to reduce the selection bias: 3 authors, a systematic review of the articles discussed in the weekly bibliographic meeting of our unit (Dermatology department, Saint-Louis Hospital, Paris, France) and a selection of the best articles by several internal medecine practitioners in Paris. Eleven " hot topics " were analyzed: i/lowering cholesterol level but not blood blessure has a significant impact on cardiovascular morbi-mortality in cardiovascular intermediate risk patients; ii/the " treat to treat target " is efficient in psoriatic arthritis; iii/ a genotype/ phenotype correlation favors the separation of ileal Crohn's disease, colonic Crohn's disease and ulcerative colitis; iv/ tocilizumab treatment (anti IL-6 monoclonal antibody ) is very efficient in giant cell arteritis and slightly efficient in systemic sclerosis; v/ combination therapy using methotrexate plus steroids compared with steroids alone becomes the " gold standard " treatment for juvenile dermatomyositis; vi/ dupilumab treatment (antibody blocking IL-4 and IL 13 receptors) is not only efficient in atopic dermatitis but also in asthma; vii/ think of eosinophilic oesophagitis in a patient with atopic dermatitis and dypshagia or food impaction; viii/ genetic A2 protein dysfunction induces NF-kB hyperactivation and an autoinflammatory disorder with features similar to Behcet's disease; ix/ no new biotherapies have shown high efficacy in systemic lupus erythematosus; x/ nanoparticles loaded with autoantigens induce Tregs and Bregs and may be a promising therapeutic option to treat auto-immune disease in the future; xi/ ipilimumab treatment (anti-CTLA4 antibody, immune checkpoint inhibitor) may induce complete remission in acute myeloid leukemia patients relapsing after haematological stem cell transplantation. Year 2016 is full of great discoveries in internal medicine keeping the dermatologist brain fully open minded. PMID- 29429507 TI - [What's new in pediatric dermatology?] AB - The association of a birth defect and a segmental hemangioma is well established, a consensus concerning evaluation and monitoring of infants with PHACE or LUMBAR syndromes has been published. The efficacy of propranolol in infantile hemangioma is proven; however there were still unresolved issues concerning the safety in children; after 8 years of use on thousands of children safety data collection did not show any unexpected side effects. Topical treatment of infantile hemangiomas with beta-blockers, such as timolol, is very popular, but recent publications revealed a significant systemic absorption that could be responsible for severe side effects, such as bradycardia, in low birthweight infants. As a consequence, this therapeutic option should be considered with caution. In the last 2 years mTOR inhibitors have been tested in low-flow vascular malformations with varying success, but progress remains to be done in the treatment of vascular abnormalities. Today, genetics has led to advances in the understanding of the pathophysiology and in the future targeted therapies could probably be feasible. Skin barrier deficiency is responsible for the development of allergic phenomena in atopic patients, since it has been shown that sensibilisation, even to food, could probably be induced by skin contact. Unfortunately, the topical treatment with crisaborole, a phosphodiesterase 4 inhibitor, does not look like a revolution in children atopic dermatitis, its efficacy seems equivalent to emollient application. In the field of infectious diseases, changes in viral outbreaks are the most reported. Furthermore epidemic Zika virus, enteroviruses are responsible for expanded dermatological manifestations and also severe meningoencephalitis. Paraviral character of various eruptions, such as gloves and socks syndrome or eruptive pseudoangiomatosis is challenged. PMID- 29429508 TI - [What's new in dermatological therapy?] AB - Over the last year there has been major publications related to therapeutic trials in infectious dermatology, not only with regard to Herpes zoster subunit vaccine but also for the treatment of uncomplicated abscesses or scabies. In addition, biological treatments continue to be on the forefront, not only in the treatment of psoriasis but also in other chronic inflammatory dermatologic diseases such as atopic dermatitis and hidradenitis suppurativa, two diseases that significantly impact quality of life and for which there are to date, few therapeutic alternatives in moderate to severe forms. In addition, the treatment of cyclin-resistant papulopustular rosacea was also the subject of a large French controlled randomized controlled trial that could modify our therapeutic approach by the use of isotretinoin. Finally, the prevention of rashes induced by erlotinib with oral doxycyline is also part of this 2016 "what's new in dermatological therapeutics". PMID- 29429509 TI - Physical stimulation and scaffold composition efficiently support osteogenic differentiation of mesenchymal stem cells. AB - BACKGROUND: Despite significant achievements in the field of tissue engineering, simplification and improvement of the existing protocols are of great importance. The use of complex differentiation media, due to the presence of multiple factors, may have some undesired effects on cell health and functions. Thus, minimizing the number of involved factors, while maintaining the differentiation efficiency, provides less costly and controllable conditions. Adipose-derived Mesenchymal stem cells (ASCs), the adult stem cells present in adipose tissue, can be a suitable source of stem cells due to abundant and ease of access. The aim of this study is to optimize the osteogenic differentiation of ASCs by chemical composition of scaffold, in the first step, and then by electromagnetic treatments. METHODS: ASCs were cultured on PVA/PES scaffold and tissue culture polystyrene surfaces (TCPS) and osteogenic differentiation was performed with either osteogenic medium, or electromagnetic field or both. The impact of each treatment on ASCs growth and proliferation was measured by MTT assay. Changes in gene expression levels of osteogenic-specific markers including ALP and RUNX2 were determined by Real Time PCR. Furthermore, alkaline phosphatase activity and calcium deposition were measured. RESULTS: The MTT assay showed the significant effects on cell growth and respiration in scaffold-seeded ASCs treated with electromagnetic field, compared to control TCPS plate. Also, the electromagnetic treatment, increased alkaline phosphatase activity and calcium deposition. Finally, Real Time PCR showed higher expression of ALP and RUNX2 genes in electromagnetic field groups compared to control groups. CONCLUSION: It can be concluded that PVA/PES scaffold used in this study improved the osteogenic capacity of ASCs. Moreover, the osteogenic potential of ASCs seeded on PVA/PES scaffold could be augmented by electromagnetic field without any chemical stimulation. PMID- 29429510 TI - Characterization and spatial relationships of the hepatic vascular-biliary tracts, and their associated pancreocytes and macrophages, in the model fish guppy (Poecilia reticulata): A study of serial sections by light microscopy. AB - The guppy is a tropical fish that has been used as an experimental model organism in science. It is a species well adapted to the natural environment and that can support adverse environmental conditions, and so, at occasions, its presence can be indicative of environmental disturbances. Moreover, as the liver is very important when studying fish diseases, the knowledge of normal microanatomy is essential to assess histological changes, e.g., related to environmental change or toxic pollutants. The target organ of this histological study is the liver. The main objective is to contribute to the identification of anatomical and structural variations of this organ in different teleost species. We studied the distribution and spatial organization of the different types of blood vessels and biliary ducts and the relationships between them are established. For this, each liver was totally sectioned and the serial sections inspected in detail. The guppy liver presented intra-hepatic pancreatic tissue and so reported its association with the vascular and biliary elements. We observed that the input of afferent vessels (i.e., bringing blood into the liver) occur not only in the hilum but pierce and enter the organ at various points. Within the liver, venous vessels and bile ducts are seen, isolated or associated as venous-arteriolar tracts (VAT), and venous-biliary- arteriolar tracts (VBAT). Sometimes, pancreocytes appear within the liver surrounding isolated veins, forming venous tract with pancreatic acini (VT-P), or dual associations with afferent vessels, forming venous-arteriolar tracts with pancreatic acini (VAT-P). Intrahepatic pancreatic ducts were tiny and rare, putting in question the functional role of the acini. Contrary to other fish species, we did not spot isolated arterioles and associations between these and biliary ducts (BAT).We found aggregates of macrophages, namely associated with afferent and efferent (i.e., draining blood out) venous vessels; the latter fact not commonly reported in other fish species. There was a reduced arterialization of the organ (as arterioles were extremely rare), contrasting with an over predominance of a random distribution of the venous vascularization. The guppy differs to some extent from other previously studied models, highlighting the importance of making this kind of study to offer specific frameworks that can explain specific physiological processes or avoid misinterpretations; for instance about gene expression, as the whole liver specific expression will reflect the presence of hepatocytes and pancreocytes as well. PMID- 29429511 TI - Hypoxia perturbs endothelium by re-organizing cellular actin architecture: Nitric oxide offers limited protection. AB - Exposure to hypoxia causes structural changes in the endothelial cell (EC) monolayer that alter its permeability. There was a report earlier of impairment of nitric oxide (NO) production in endothelium. The intervention of NO in the altered cellular arrangements of actin cytoskeleton in endothelium for rectification of paracellular gaps in endothelium under hypoxia was observed. The present study demonstrates hypoxia inducing paracellular gaps in hypoxia-exposed blood capillaries in chick embryo extravascular model. Phalloidin staining confirmed significant polymerization of actin and unique cellular localization of the F-actin bands under hypoxia treatments. Addition of spermine NONOate (SPNO), a NO donor, or reoxygenation to endothelial monolayer attenuated hypoxia-mediated effects on endothelial permeability with partial recovery of endothelial integrity through actin remodeling. The present study indicates link of hypoxia induced actin-associated cytoskeletal rearrangements and paracellular gaps in the endothelium with a low NO availability in the hypoxia milieu. The author concludes that NO confers protection against hypoxia-mediated cytoskeletal remodeling and endothelial leakiness. PMID- 29429512 TI - Effect of human umbilical cord blood derived CD34+ hematopoietic stem cell on the expression of Wnt4 and P53 genes in a rat model of hepatocellular carcinoma. AB - BACKGROUND AND AIM OF THE WORK: Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy. Chronic liver injuries as chronic hepatitis C and hepatitis B viruses, aflatoxins consumption and nonalcoholic fatty liver disease are well-established causes of HCC. HCC is associated with a series of molecular changes, as alternation in glypican-3, P53 expression and Wnt/beta catenin pathway. Hepatic cancer progenitor cells could contribute to HCC development. This research aimed to study the effectiveness of human CD34+ hematopoietic stem cell on Wnt4 and P53 genes expression, histopathological grading and hepatic progenitor cells percentage in HCC rat model. MATERIALS AND METHODS: HCC was induced in the experimental group of outbred Sprague Dawley rats by administration of 50 mg/L N-nitroso-Di-Ethylamine (DEN) in drinking water for 15 weeks. Forty-six animals were used in total, they were initially subdivided into two groups; control (n = 6) and experimental (n = 40), the latter consisting of 4 DEN-unaffected, 6 DEN-lethalities and 30 surviving DEN-animals with elevated AFP. These 30 animals with elevated AFP were then subdivided into a new HCC control group (n = 15) and the stem cell treated group (n = 15). The latter group was injected with CD34+ human hematopoietic stem cell (1 * 106 cells/rat) in the rat's tail vein. Cyclosporine A (10 mg/kg) was injected intraperitoneal, starting 24 h before human stem cell transplantation. After 20 weeks passing since the beginning of the experiment, all rats were sacrificed and liver specimens were subjected to histopathological examination, RT-PCR in order to examine Wnt4 and P53 gene expression and flow cytometry to measure hepatic progenitor OV6 positive cells percentage. RESULTS: The saline-treated HCC group (with prior 15 week DEN exposure) showed higher levels of wnt4 and p53 gene expression (1.59 and 1.36 fold, respectively) and increased percentage in OV6+ progenitor cells (+4.9% in absolute terms) compared to saline-treated controls (p < 0.01, ANOVA). Compared with the saline HCC-group, transplantation with CD34+ human hematopoietic stem cells produced a further increase in the levels of wnt4 (+19.4%) and p53 gene expression (+53%), a 2-fold increase in the percentage of cancer progenitor cells and increased HCC pathology grading (all p < 0.01). The positive correlation between p53 and HCC grade (Spearman rho +0.73, p < 0.05) and negative correlation between wnt and OV6+% levels (rho -0.65, p < 0.05) in the saline-HCC group were not observed in the CD34+ HCC group. CONCLUSIONS: Human CD34+ cells transplantation has a deteriorating effect on HCC. PMID- 29429513 TI - Protective roles of Rutin against restraint stress on spermatogenesis in testes of adult mice. AB - In order to investigate the effects of Rutin against restraint stress, 50 adult male mice were divided into five groups: control, restraint stress (RS), and RS with 2 doses of Rutin treatments. Mice were restrained in a conical tube for 4 h daily and Rutin was injected intraperitoneally for 15 consecutive days. Restraint stress significantly decreases body weights, testis and epididymis weights, thymus weights, visceral fats, serum concentrations of testosterone, sperm counts, sperm motility and sperm viability, while it increases serum epinephrine levels, adrenal gland weights and abnormal sperms. In addition, restraint stress severely damages the testicular histoarchitecture and spermatogenesis. Stressed groups also showed broken seminiferous tubules, few spermatozoa in lumen, less population of Leydig cells between the interstitial spaces, spermiation arrest in stage I-III and degenerated population of round spermatids in the lumen; as well as missing cells in stages IV-VI. Furthermore, lumen sizes increased in stages VII, VIII, IX and X. Residual bodies increased in stages IV-VI, VII-VIII and vacuoles found in stages XI-XII after restraint stress. PARP1 signaling is involved in apoptosis. In this study, expressional levels of cleaved PARP1 and cleaved Caspase-3 are significantly increased in testes after restraint stress. We demonstrate that Rutin significantly ameliorates the side effects induced by restraint stress. PMID- 29429514 TI - Culturing substrates influence the morphological, mechanical and biochemical features of lung adenocarcinoma cells cultured in 2D or 3D. AB - Alternative models such as three-dimensional (3D) cell cultures represent a distinct milestone towards capturing the realities of cancer biology in vitro and reduce animal experimentation in the preclinical stage of drug discovery. Significant work remains to be done to understand how substrates used in in vitro alternatives influence cancer cells phenotype and drug efficacy responses, so that to accurately link such models to specific in vivo disease scenarios. Our study describes how the morphological, mechanical and biochemical properties of adenocarcinoma (A549) cells change in response to a 3D environment and varying substrates. Confocal Laser Scanning (LSCM), He-Ion (HIM) and Atomic Force (AFM) microscopies, supported by ELISA and Western blotting, were used. These techniques enabled us to evaluate the shape, cytoskeletal organization, roughness, stiffness and biochemical signatures of cells grown within soft 3D matrices (PuraMatrixTM and MatrigelTM), and to compare them to those of cells cultured on two-dimensional glass substrates. Cell cultures are also characterized for their biological response to docetaxel, a taxane-type drug used in Non-Small-Cell Lung Cancer (NSCLC) treatment. Our results offer an advanced biophysical insight into the properties and potential application of 3D cultures of A549 cells as in vitro alternatives in lung cancer research. PMID- 29429515 TI - Mice dental pulp and periodontal ligament endothelial cells exhibit different proangiogenic properties. AB - Dental pulp is a highly vascularized tissue with a high regenerative capacity. This is attributed to its unique blood supply and the presence of progenitor or postnatal dental pulp stem cells. Here we aimed to isolate and compare the angiogenic properties of endothelial cells (EC) prepared from mouse dental pulp and periodontal ligament (PDL). EC were isolated from 4-week-old wild type immorto mice. Mice were sacrificed and after mandible isolation, the molar and incisor teeth and the PDL from molar teeth were dissected. EC were prepared by collagenase digestion of tissues and affinity purification using magnetic beads coated with platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) antibody. EC prepared from incisor and molar pulps and PDL were examined for expression of appropriate markers by fluorescence-activated cell sorting (FACS) analysis. The proliferation, migration, and capillary morphogenesis of EC were evaluated. Ex vivo sprouting angiogenesis from various tissues was also compared. Data were analyzed at the level of significance of P<0.05. Pulp EC prepared from incisors proliferated and migrated significantly faster than molar and PDL EC (P<0.05). In addition, molar and PDL EC formed a more extensive capillary network when plated on Matrigel. This is consistent with the lower proliferative and migratory characteristics of these cells compared with incisor EC (P<0.05). However, PDL tissue showed significantly more sprouting area than molar and incisor pulp tissues (P<0.05). Thus, pulp EC from molar and incisor and PDL EC present different proangiogenic properties. Collectively our results suggest that EC from different tooth tissue have unique characteristics related to their target tissue and function. PMID- 29429516 TI - Lipoic acid inhibited desflurane-induced hippocampal neuronal apoptosis through Caspase3 and NF-KappaB dependent pathway. AB - Desfluraneis a widely-used general anesthetics. However, recent reports showed its significant side effect in the nervous system. Desflurane could lead to the neuronal death and affect the working memory. Unfortunately, the mechanism underlying the action of desflurane is still not clear and there is still no potent medicine to prevent the lesion in the central nervous system caused by general anesthetics. In this study, we found alpha-lipoic acid, an antioxidant exerting protective effect on multiple cells tissues, could resist the neurotoxicity caused by desflurane exposure. Lipoic acid possessed strong anti apoptotic effect on the desflurane-treated hippocampal neurons, which was mediated by the Caspase-3 dependent pathway and NF-kappaB signaling. Collectively, we found a promising candidate to be clinically applied in intervention against the damage in nervous system by the desflurane. PMID- 29429517 TI - In vitro identification of a stem cell population from canine hair follicle bulge region. AB - Skin is an extensive and easily accessible organ possessing various cell types that are constantly renewed. Previous studies have suggested the presence of a stem cell niche at the bulge region of the hair follicle, which contains cells positive for CD200 and CD34. Thus, this study sought to identify these cell populations in canine skin cells using the following methods 1- collecting samples of adult and fetal skin and isolating and culturing these cells using a method of simple enzymatic digestion and 2- testing the cell cultures for CD200 and CD34 in vitro and comparing them with skin tissue samples (in situ). Immunofluorescence results were negative for both CD200 and CD34 in frozen and paraffin embedded tissue, whereas the analysis showed that cultured cells positive for CD34, CD200 and double positive cells could be visualized in different percentages. Additionally, the pluripotency marker OCT4 was positive in the isolated cells. Analysis of CD34, CD200 and OCT4 by RT-qPCR showed that there is expression in fetal and adult cells, although no difference was observed between groups. Our results suggest that bulge stem cells from both fetuses and adult dogs were reported with the use of CD34 and CD200 markers in this study, and further techniques for cell isolation and in vitro cultivation are needed in order to obtain enriched populations of skin stem cells in dogs. PMID- 29429518 TI - Epigenetic status of buffalo fibroblasts treated with sodium butyrate a chromatin remodeling agent. AB - The somatic cells having higher levels of DNA methylation and reducing it in donor cells before nuclear transfer (NT) by treating them with chemicals, may improve cloning efficiency of NT embryos by providing donor cells with similar epigenetic characteristics as in vivo embryos. Therefore, the present study was planned to understand mechanism of epigenetic changes in donor cells (buffalo fibroblasts) treated with different concentration of sodium butyrate (NaBu)-a chromatin remodeling agent. The cultured fibroblasts purity and lineage were confirmed by fibroblast specific protein and gene markers (Vimentin, Tubulin and Cytokeratin) at different passages using immuno-staining and qPCR respectively. The buffalo fibroblast cells were treated with 1, 3 and 5 mM of NaBu and observations were taken on their morphological changes, population doubling time and cell proliferation after 48 h of treatment. The epigenetic changes were observed using acetylation (H3K9ac) and methylation (H3K27me3) markers expression. The fibroblast cells derived from new born ear tissue started emerging and anchoring to cell culture flasks within 24 h and showed spindle shaped morphology. The confluent culture was cryopreserved at different time interval. The post thaw culture behavior of the cryopreserved cells was also observed at different time interval and passages. The morphology of NaBu treated cells were changed with increase of dosages of NaBu treatment. The increase population doubling times and decreases the proliferation rate in the dose dependent manner. The NaBu treatment showed that the significantly increased the acetylation (H3K9ac) and methylation (H3K27me3) level over the control. Based on the observations of fibroblast characterization as well as epigenetic modifications of these cells after treatment with NaBu, results suggest that the cells may provide a useful approach for better epigenetic reprogramming in SCNT embryos. PMID- 29429519 TI - A method for the long-term cultivation of mammalian cells in the absence of oxygen: Characterization of cell replication, hypoxia-inducible factor expression and reactive oxygen species production. AB - The center of tumors, stem cell niches and mucosal surfaces all represent areas of the body that are reported to be anoxic. However, long-term study of anoxic cell physiology is hindered by the lack of a sustainable method permitting cell cultivation in the complete absence of oxygen. A novel methodology was developed that enabled anoxic cell cultivation (17d maximum time tested) and cell passage. In the absence of oxygen, cell morphology is significantly altered. All cells tested exhibited morphologic changes, i.e., a combination of tethered (monolayer like) and runagate (suspension-like) morphologies. Both morphologies replicated (Vero and HeLa cells tested) and could be passaged anaerobically. In the absence of exogenous oxygen, anoxic cells produced reactive oxygen species (ROS). Anaerobic runagate HeLa and Vero cells increased ROS production from day 3 to day 10 by 2- and 3-fold, respectively. In contrast, anoxic tethered HeLa and Vero cells either showed no significant change in ROS production between days 3 and 10 or exhibited a 3-fold decrease in ROS, respectively. Detection of ROS was inversely related to detection of hypoxia-inducible factor-1alpha (HIF1) mRNA and HIF-1 protein expression which cycled over a 10-day period. This methodology has broad applications for the study of tumor and stem cell physiology as well as gastrointestinal cell-microbiome interactions. In addition, sustainable anaerobic cell culture may lead to the identification of novel pathways and targets for chemotherapeutic drug development. PMID- 29429520 TI - Osteogenesis induced by a three-dimensional bioimplant composed of demineralised bone matrix, collagen, hydroxyapatite, and bone marrow-derived cells in massive bone defects: An experimental study. AB - : Treatment of massive bone defects is one of the most difficult problems to solve in orthopedics. At present, there is no consensus on the best way to resolve these problems. The aim of our study was to evaluate the effect of a three-dimensional bioimplant over massive bone defects, and to analyse if it improves the speed and quality of integration in recipient bone compared to allograft treatment. Fifteen female lambs with massive bone defects, surgically created in their tibias, were randomly divided into three groups of five lambs each: Group I -treated with the bioimplant; Group 2 -treated with the bioimplant plus nucleated cells of autologous bone marrow; Group 3 -treated with a frozen allograft. Radiographs were taken post-treatment at weeks 1, 6, and 12. Animals were euthanized to obtain the studied bone segment for morphological analyses. TREATMENT: with bioimplants vs. bioimplant plus bone marrow nucleated cells (BMNCs) showed a notorious osteogenic effect, but with greater osteoid synthesis and cellularity in the latter. These results suggest that combined treatment with bioimplants and BMNCs have an additive effect on massive bone defects in lambs. These experimental results could be applied to repair damaged human bone. PMID- 29429521 TI - Sex steroid receptors profiling is influenced by nandrolone decanoate in the ampulla of the fallopian tube: Post-treatment and post-recovery analyses. AB - Anabolic androgenic steroids (AAS) are recommended for therapeutic clinic, but their use has increased in recent decades for aesthetic reasons. No study has evaluated the impact of AAS in the fallopian tube, after treatment and recovery periods. Herein, the aim of study was to investigate the effects of Nandrolone Decanoate (ND), administered in different doses (1.87; 3.75; 7.5 and 15 mg/kg) on the ampulla of the fallopian tube in rats, following post-treatment (PT; 15 consecutive days) and post-recovery (PR; 30 consecutive days) periods. The control group received mineral oil. Estrous cycle was monitored daily during both periods and in sequence the rats (n = 8/group/period) were killed. All ND-treated animals showed estral acyclicity during the PT and PR periods, but the histomorphometric changes in the fallopian tube varied according to the ND dose level. The expression of AR, ERalpha and ERbeta varied in the nucleus and cytoplasm of epithelial cells. No AR expression was observed in the stroma. The muscle cells exhibited variation in immunostaining. In conclusion, ND promoted histomorphometric and immunohistochemical changes in the ampullary portion of the fallopian tube after treatment and recovery periods in a dose-independent manner. PMID- 29429523 TI - Allicin ameliorates cognitive impairment in APP/PS1 mice via Suppressing oxidative stress by Blocking JNK Signaling Pathways. AB - In middle and old age, Alzheimer's disease (AD) is a progressive neurodegenerative disorder of brain. As an increasingly aging population, AD represents a huge burden for the patients' family and the country. However, current therapeutical strategies have shown limited effectiveness. Allicin, which is the main composition of garlic, was reported to prevent the learning and memory impairment of AD mouse model. As the mechanism is not clear, in this study, we used the APP (amyloid precursor protein)/PS1 (presenilin 1) double transgenic mice, which express human mutant APP and PS1, to determine the protective effect of allicin on neurons. AD involves a broad range of clinical, cellular, and biochemical manifestations. This has led to many views of AD, e.g. the amyloid, presenilin, oxidative stress, and mitochondrial dysfunction. We confirmed that allicin improves the cognitive function of APP/PS1 double transgenic mice by reducing the expression levels of Abeta, oxidative stress, and improving mitochondrial dysfunction. Application of behavioral, morphological and molecular biology, and other means were conducted to investigate the effect of allicin, which provide an experimental basis for the reliable application of allicin in the treatment of neurodegenerative diseases. PMID- 29429522 TI - Neurochemical characteristics of calbindin-like immunoreactive coeliac-cranial mesenteric ganglion complex (CCMG) neurons supplying the pre-pyloric region of the porcine stomach. AB - The present study was designed to determine the distribution, morphology and co localization of calbindin-D28k (CB) with other neuroactive substances in the coeliac-cranial mesenteric ganglion complex (CCMG) neurons supplying the prepyloric region of the porcine stomach. In all animals, a median laparotomy was performed and the fluorescent retrograde neuronal tracer Fast Blue was injected into the wall of the stomach prepyloric area. On the 28th day, all animals were euthanized and the CCMG complexes were then collected and processed for double labelling immunofluorescence for CB and tyrosine hydroxylase (TH), galanin (GAL), somatostatin (SOM), leu 5-enkephalin (LENK), vasoactive intestinal peptide (VIP), substance P (SP) and cocaine- and amphetamine-regulated transcript peptide (CART), Immunohistochemistry revealed that 8.27+/-0.51% of FB-positive neurons expressed CB-like immunoreactivity. Furthermore, CB co-localized with TH, GAL and SOM in retrogradely labelled cell bodies, whereas CART, LENK, VIP and SP were detected only in nerve terminals surrounding FB+/CB+ neurons. The presence of CB in the stomach-projecting neurons may indicate the contribution of CB in the sympathetic regulation of the stomach function. Furthermore, CB-LI neurons had a catecholaminergic character and co-localized with TH, GAL and SOM, which suggests multiple functions of this neuroactive substance in the CCMG neurons supplying the porcine prepyloric area. PMID- 29429524 TI - Nintedanib effects on delaying cancer progression and decreasing COX-2 and IL-17 in the prostate anterior lobe in TRAMP mice. AB - Prostate cancer is the most prevalent type of cancer in men around the world. Due to its high incidence, new therapies have been evaluated, including drugs capable of inhibiting the FGF/VEGF pathways, as Nintedanib. The aim herein was to evaluate the Nintedanib therapeutic effects on morphology and COX-2 and IL-17 levels in the prostate anterior lobe in different grades of the tumor progression in TRAMP mice. Animals were treated with Nintedanib at a dose of 10 mg/kg/day in initial and intermediate grades of tumor development. At the end of treatment, the prostate anterior lobe was collected and submitted to morphological, immunohistochemical and Western Blotting analyses. The results showed that Nintedanib delayed the prostate carcinogenesis progression, with over 20% of reduction in frequency of tissue injuries, particularly in the group treated from 12 to 16 weeks of age. Also, decreased COX-2 and IL-17 levels were observed in both groups treated with Nintedanib in the prostate anterior lobe. Thus, we concluded that Nintedanib was effective in delaying tumor progression and, despite not directly acting on inflammation, Nintedanib may adversely affect inflammatory pathways, favoring prostate cancer delay. PMID- 29429525 TI - Editorial. PMID- 29429526 TI - Neurochemical Characterization of PSA-NCAM+ Cells in the Human Brain and Phenotypic Quantification in Alzheimer's Disease Entorhinal Cortex. AB - Polysialylated neural cell adhesion molecule (PSA-NCAM) is widely expressed in the adult human brain and facilitates structural remodeling of cells through steric inhibition of intercellular NCAM adhesion. We previously showed that PSA NCAM immunoreactivity is decreased in the entorhinal cortex in Alzheimer's disease (AD). Based on available evidence, we hypothesized that a loss of PSA NCAM+ interneurons may underlie this reduction. PSA-NCAM expression by interneurons has previously been described in the human medial prefrontal cortex. Here we used postmortem human brain tissue to provide further evidence of PSA NCAM+ interneurons throughout the human hippocampal formation and additional cortical regions. Furthermore, PSA-NCAM+ cell populations were assessed in the entorhinal cortex of normal and AD cases using fluorescent double labeling and manual cell counting. We found a significant decrease in the number of PSA-NCAM+ cells per mm2 in layer II and V of the entorhinal cortex, supporting our previous description of reduced PSA-NCAM immunoreactivity. Additionally, we found a significant decrease in the proportion of PSA-NCAM+ cells that co-labeled with NeuN and parvalbumin, but no change in the proportion that co-labeled with calbindin or calretinin. These results demonstrate that PSA-NCAM is expressed by a variety of interneuron populations throughout the brain. Furthermore, that loss of PSA-NCAM expression by NeuN+ cells predominantly contributes to the reduced PSA-NCAM immunoreactivity in the AD entorhinal cortex. PMID- 29429527 TI - A comparison of three methods to assess body composition. AB - OBJECTIVE: The aim of this study was to compare the accuracy of measurements of body composition made using dual x-ray absorptiometry (DXA), analysis of computed tomography (CT) scans at the L3 vertebral level, and bioelectrical impedance analysis (BIA). METHODS: DXA, CT, and BIA were performed in 47 patients recruited from two clinical trials investigating metabolic changes associated with major abdominal surgery or neoadjuvant chemotherapy for esophagogastric cancer. DXA was performed the week before surgery and before and after commencement of neoadjuvant chemotherapy. BIA was performed at the same time points and used with standard equations to calculate fat-free mass (FFM). Analysis of CT scans performed within 3 mo of the study was used to estimate FFM and fat mass (FM). RESULTS: There was good correlation between FM on DXA and CT (r2 = 0.6632; P < 0.0001) and FFM on DXA and CT (r2 = 0.7634; P < 0.0001), as well as FFM on DXA and BIA (r2 = 0.6275; P < 0.0001). Correlation between FFM on CT and BIA also was significant (r2 = 0.2742; P < 0.0001). On Bland-Altman analysis, average bias for FM on DXA and CT was 0.2564 with 95% limits of agreement (LOA) of -9.451 to 9.964. For FFM on DXA and CT, average bias was -0.1477, with LOA of -8.621 to 8.325. For FFM on DXA and BIA, average bias was -3.792, with LOA of -15.52 to 7.936. For FFM on CT and BIA, average bias was -2.661, with LOA of -22.71 to 17.39. CONCLUSION: Although a systematic error underestimating FFM was demonstrated with BIA, it may be a useful modality to quantify body composition in the clinical situation. PMID- 29429528 TI - Changes in lipid metabolism in pediatric patients with severe sepsis and septic shock. AB - OBJECTIVES: Limited knowledge exists regarding the lipid profiles of critically ill pediatric patients with systemic inflammatory response syndrome. The aim of this study was to evaluate the relationship between the intensity of the inflammatory response and changes in the lipid profiles of critically ill pediatric patients admitted to a pediatric intensive care unit (PICU) with severe sepsis/septic shock. METHODS: This was a prospective and observational study at a 15-bed PICU at a public university hospital. We analyzed the lipid profiles of 40 patients with severe sepsis/septic shock admitted to the PICU on the first and seventh days of hospitalization. C-reactive protein was used as a marker for systemic inflammation. Forty-two pediatric patients seen in the emergency department and without systemic inflammatory response syndrome were used to provide control values. RESULTS: On day 1 of admission to the PICU, the patients had significantly lower levels of total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) as well as higher concentrations of triacylglycerols compared with the control group. There was a significant increase in the TC, HDL, LDL, and apolipoprotein levels from day 1 to day 7 of the study. CONCLUSIONS: During severe sepsis/septic shock, we found lower serum levels of lipoproteins and apolipoproteins, and these were negatively correlated with C-reactive protein. As the inflammatory response improved, the levels of TC, HDL, LDL, and apolipoproteins increased, suggesting a direct relationship between changes in the lipid profiles and inflammation. PMID- 29429529 TI - Management and prevention of refeeding syndrome in medical inpatients: An evidence-based and consensus-supported algorithm. AB - OBJECTIVES: Refeeding syndrome (RFS) can be a life-threatening metabolic condition after nutritional replenishment if not recognized early and treated adequately. There is a lack of evidence-based treatment and monitoring algorithm for daily clinical practice. The aim of the study was to propose an expert consensus guideline for RFS for the medical inpatient (not including anorexic patients) regarding risk factors, diagnostic criteria, and preventive and therapeutic measures based on a previous systematic literature search. METHODS: Based on a recent qualitative systematic review on the topic, we developed clinically relevant recommendations as well as a treatment and monitoring algorithm for the clinical management of inpatients regarding RFS. With international experts, these recommendations were discussed and agreement with the recommendation was rated. RESULTS: Upon hospital admission, we recommend the use of specific screening criteria (i.e., low body mass index, large unintentional weight loss, little or no nutritional intake, history of alcohol or drug abuse) for risk assessment regarding the occurrence of RFS. According to the patient's individual risk for RFS, a careful start of nutritional therapy with a stepwise increase in energy and fluids goals and supplementation of electrolyte and vitamins, as well as close clinical monitoring, is recommended. We also propose criteria for the diagnosis of imminent and manifest RFS with practical treatment recommendations with adoption of the nutritional therapy. CONCLUSION: Based on the available evidence, we developed a practical algorithm for risk assessment, treatment, and monitoring of RFS in medical inpatients. In daily routine clinical care, this may help to optimize and standardize the management of this vulnerable patient population. We encourage future quality studies to further refine these recommendations. PMID- 29429530 TI - Combined nutritional assessment methods to predict clinical outcomes in patients on the waiting list for liver transplantation. AB - OBJECTIVES: Nutritional diagnosis is essential given that malnutrition negatively affects morbidity and mortality in patients with liver disease. In the absence of a standard method, limited accuracy has been reported in relation to nutritional assessment. The aim of the study was to evaluate the use of subjective global assessment (SGA) and different methods of nutritional assessment, isolated and in combination with SGA to predict clinical outcomes. METHODS: This was a longitudinal study with patients waiting for liver transplantation. Nutritional status was classified according to SGA. Anthropometric parameters, standard phase angle (SPA), handgrip strength, and 6-min walk test (6MWT) were evaluated. Univariate and multivariate analysis and receiver operator characteristic curve were performed. P < 0.05 was statistically significant. RESULTS: Seventy-three patients with an average age of 52.3 +/- 11.4 y were evaluated. Of these, 63% were men. Low midarm muscle area (MAMA; P < 0.001), malnutrition by SGA + low MAMA (P < 0.001), and malnutrition by SGA + low SPA (P < 0.001) were independent predictors of clinical features of advanced cirrhosis. SGA + SPA presented the greater area under the curve (AUC: 0.6431). Death was predicted by low midarm circumference (MAC; P = 0.037) and slow gait speed on the 6MWT (GS-6MWT; P = 0.017), with both parameters isolated or concomitantly linked to malnutrition. SGA + GS-6MWT presented the highest predictive power for death (AUC: 0.6673) slightly greater than SGA+MAC (AUC: 0.6346). CONCLUSION: The results indicate that SGA together with SPA has greater predictive power for features of advanced cirrhosis, and SGA plus gait speed is able to better predict mortality in patients on the waiting list for liver transplant. PMID- 29429531 TI - Early feeding practices and consumption of ultraprocessed foods at 6 y of age: Findings from the 2004 Pelotas (Brazil) Birth Cohort Study. AB - OBJECTIVE: The aim of this study was to examine the association between early feeding practices and consumption of ultraprocessed foods in children at age 6 y. METHODS: This was a prospective cohort study using data from 3427 children who participated in the 2004 Pelotas Cohort Study and who had available food frequency questionnaire information at 6 y. Information about exclusive and total breastfeeding duration as well as age at introduction of semisolid and solid foods was used to define early feeding practices. Consumption of ultraprocessed foods was defined as proportion of total daily energy intake that came from ultraprocessed foods at age 6 y. Crude and adjusted linear regression models were employed to analyze the effect of early feeding practices on ultraprocessed foods consumption. RESULTS: It was determined that 40.3% of total daily energy intake at 6 y came from ultraprocessed foods. In crude linear regression models, early feeding practices (exclusive and total breastfeeding duration, and age at introduction of semisolid and solid foods) were negatively associated with ultraprocessed foods consumption. After adjustment, only exclusive breastfeeding duration and age at introduction of solid foods remained associated with consumption of ultraprocessed foods, although the observed effects size was small. Children exclusively breastfed for >=3 mo and those who had solid foods introduced at >=4 mo consumed a lower proportion of daily energy intake from ultraprocessed foods. CONCLUSION: This study supports the need to promote healthy early feeding practices including the support of breastfeeding to promote healthier eating habits later in childhood. PMID- 29429532 TI - Vitamin K2 alleviates type 2 diabetes in rats by induction of osteocalcin gene expression. AB - OBJECTIVES: The biological mechanisms behind the association between vitamin K (Vit K) and glucose metabolism are uncertain. We aimed to analyze the expression of insulin 1 (Ins 1), insulin 2 (Ins 2) and cyclin D2, the expression of adiponectin and UCP-1 . In addition, we aimed to estimate the doses of Vit K2 able to affect various aspects of glucose and energy metabolism in type 2 diabetes. METHODS: Thirty adult male rats were allocated equally into five groups: control group, diabetes mellitus group, and groups 3, 4, and 5, which received Vit K2 at three daily dose levels (10, 15, and 30 mg/kg, respectively) for 8 wk. At the end of the study, blood samples were collected to quantify total osteocalcin, fasting plasma glucose, fasting insulin, and relevant variables. The expression of OC, Ins 1, Ins 2, cyclin D2, adiponectin, UCP-1 genes was analyzed by real-time polymerase chain reaction. RESULTS: After administration of Vit K2, a dose-dependent decrease in fasting plasma glucose, hemoglobin A1c and homeostatic model assessment method insulin resistance, and a dose-dependent increase in fasting insulin and homeostatic model assessment method beta cell function levels, when compared with diabetes mellitus rats, were detected. There was significant upregulation of OC, Ins 1, Ins 2, or cyclin D2 gene expression in the three treated groups in a dose-dependent manner when compared with the diabetic rats. However, expression of adiponectin and UCP-1 were significantly increased at the highest dose (30 mg/kg daily) only. CONCLUSIONS: Vit K2 administration could improve glycemic status in type 2 diabetic rats by induction of OC gene expression. Osteocalcin could increase beta-cell proliferation, energy expenditure, and adiponectin expression. Different concentrations of Vit K2 were required to affect glucose metabolism and insulin sensitivity. PMID- 29429533 TI - The effect of chemotherapy on nutritional status and weakness in geriatric gastrointestinal system cancer patients. AB - OBJECTIVES: Malnutrition is common in patients with geriatric gastrointestinal system (GIS) cancer. This study aimed to evaluate patients with geriatric GIS cancer in terms of nutritional status and weakness and determine the changes caused by chemotherapy (CT). METHODS: Patients with geriatric GIS cancer who received CT were included in the study. Their nutritional status was assessed with the Mini Nutritional Assessment, and weakness was assessed with the handgrip strength/body mass index ratio. After CT (minimum 4 wk and maximum 6 wk later), patients were assessed for the same parameters. RESULTS: A total of 153 patients aged >=65 y (mean age, 70.5 +/- 5.6 y; 44 female and 109 male) were evaluated. The population consisted of patients who were diagnosed with colorectal (51.6%), gastric (26.8%), pancreatic (11.8%), hepatic (7.2%), biliary tract (2%), and esophageal (0.7%) cancer. Of these patients, 37.9% were malnourished, 34.6% were at risk of malnutrition, and 27.5% were well nourished. After one course of CT, the frequency of malnutrition increased to 46.4% (P = 0.001). The patient groups with the highest rates of weakness were those who were diagnosed with biliary tract, hepatic, and colorectal cancer (33.3%, 27.3%, and 20%, respectively). Weakness was significantly increased after one course of CT in patients who received CT before (P = 0.039). CONCLUSIONS: Malnutrition and weakness were common in patients with geriatric GIS cancer, and even one course of CT worsened the nutritional status of the patients. Patients who have received CT previously should be carefully monitored for weakness. PMID- 29429534 TI - Parboiled rice metabolism differs in healthy and diabetic individuals with similar improvement in glycemic response. AB - BACKGROUND: White rice is a popular staple food; however, its high glycemic effect makes it an unfavorable choice for people with type 2 diabetes. OBJECTIVES: We hypothesized that the consumption of parboiled rice (PBR) reduces postprandial blood glucose concentration and appetite similarly to brown rice (BR) in diabetic people compared to white rice (WR). The objectives were to explore the effect of PBR on the pattern of blood glucose concentration and satiety in type 2 diabetic patients compared with healthy individuals. METHODS: Subjects were randomly administered 50 g of available carbohydrate from PBR, WR, or BR. Blood glucose and appetite were measured at 0, 15, 30, 45, 60, 90, and 120 min after ingestion of the rice samples. RESULTS: The postprandial blood glucose responses were significant among the healthy and diabetic subjects after consumption of the three rice samples. On the subjective appetite assessment, the response to the amount of food subjects could consume was significantly lower for healthy subjects after ingestion of PBR only. Despite these differences in rice metabolism between the two study groups, the area under the curve for the blood glucose response was reduced by 35% and 38% after consumption of PBR in diabetic and healthy subjects, respectively. Blood glucose responses to WR and BR however, were not significantly different from each other in either group. CONCLUSIONS: We conclude that PBR is a better alternative to WR or BR for diabetic individuals to control postprandial hyperglycemia. PMID- 29429535 TI - Dietary intakes of fat soluble vitamins as predictors of mortality from heart failure in a large prospective cohort study. AB - OBJECTIVES: A few reports have investigated the association of dietary vitamin intakes with risk of heart failure in Asia. Therefore, we examined the relation between dietary intakes of fat-soluble vitamins A, K, E, and D and mortality from heart failure in the Japanese population. METHODS: A total of 23 099 men and 35 597 women ages 40 to 79 y participated in the Japan Collaborative Cohort Study and completed a food frequency questionnaire from which dietary intakes of vitamins A, K, E, and D were calculated. The Cox proportional hazard model was used to estimate the sex-specific risks of heart failure mortality according to increasing quintiles of fat-soluble vitamin intakes. RESULTS: During the median 19.3 y follow-up period, there were 567 deaths from heart failure (240 men, 327 women). Dietary vitamin A intake showed no association with heart failure mortality in both sexes; however, the reduced risk was observed in women but not in men with dietary intakes of vitamins K, E, and D. The multivariable hazard ratios (95% confidence interval) in the highest versus the lowest intake quintiles among women were 0.63 (0.45-0.87; P for trend = 0.006) for vitamin K, 0.55 (0.36-0.78; P for trend = 0.006) for vitamin E, and 0.66 (0.48-0.93; P for trend = 0.01) for vitamin D. The association for each vitamin was slightly attenuated but remained statistically significant after mutual adjustment for intakes of the other vitamins. CONCLUSIONS: High dietary intakes of fat-soluble vitamins K, E, and D were associated with a reduced risk of heart failure mortality in Japanese women but not men. PMID- 29429536 TI - Are patients affected by mitochondrial disorders at nutritional risk? AB - OBJECTIVES: Patients with mitochondrial disorders (MD) frequently present with gastrointestinal complaints, mainly gastrointestinal dysmotility, that interfere with their food intake. A deterioration of their nutritional state may worsen the course of the disease. Our study aimed to evaluate a simple screening tool to identify nutritional risk and perform an extended nutritional assessment to explore the potential presence of deficiencies in this population compared with controls. METHODS: A prospective cohort study was conducted to compare outpatients with MD to matched healthy controls. Nutritional screening and full nutritional assessments were performed, including quantitative and qualitative dietary habits (7-d food log), body function and composition, and resting energy expenditure and quality of life (QoL) measurements. Blood and 24-h urine sample analyses were performed in the patient group. RESULTS: Twenty-six subjects were included in the study, with 11 in the patient group and 15 in the control group. No patient was deemed malnourished according to the nutritional risk score NRS 2002. When compared with the controls, however, the patients with MD had significantly lower muscle mass (P = 0.04), reduced handgrip strength (P = 0.07), and significant changes in QoL and pathologic creatinine height index, which indicate malnutrition. The patients with MD also had a significantly lower protein intake (P = 0.01). CONCLUSIONS: According to the current definition by the European Society of Clinical Nutrition and Metabolism (ESPEN) and the American Society of Parenteral and Enteral Nutrition (ASPEN), all patients fulfilled the criteria for malnutrition. Thus, the usual nutritional screening tool is less sensitive for chronically ill outpatients. These results provide a rationale to increase protein intake and adapt patients' energy stores to improve symptoms and QoL. PMID- 29429537 TI - The effect of soluble fiber dextrin on postprandial appetite and subsequent food intake in healthy adults. AB - OBJECTIVES: This crossover study investigated the effect of consuming a beverage that contains soluble fiber dextrin (SFD) on appetite and food intake in adults to test the hypothesis that beverages that contain 10 or 20 g of fiber from SFD would be more satiating than the control beverage. METHODS: Forty-one participants consumed lunch with a beverage that contained 0 g, 10 g, or 20 g of fiber from SFD. Appetite questionnaires were completed and blood samples collected immediately before lunch and at regular intervals over the following 150 min. Then, participants were provided with an afternoon snack and the amount eaten was recorded. Participants then left the laboratory but were asked to complete hourly appetite questionnaires and record food intake for the remainder of the day. RESULTS: Consuming SFD had no effect on appetite over the 150 min after consumption of the lunch meal (P > 0.05). Hunger and desire to eat were lower and fullness higher after consumption of the beverage that contained 20 g of fiber from SFD (P < 0.05) after participants left the laboratory. There was no effect of consuming SFD on food intake at the snack meal or for the rest of the day (P > 0.05). Plasma glucose-dependent insulintropic polypeptide was lower during the 150 min after consumption of 20 g fiber from the SFD beverage (P < 0.05). There was no treatment effect on the plasma concentration of other biomarkers of glycemic response or appetite (P > 0.05). CONCLUSIONS: Overall, the study results did not show an effect of SFD on appetite, food intake, and plasma markers of appetite for the first 150 min postconsumption. Further research is required to quantify how SFD influences appetite several hours after consumption. PMID- 29429538 TI - Dietary non-enzymatic antioxidant capacity and DNA damage in a working population. AB - OBJECTIVE: The aim of this study was to investigate the potential links between dietary non-enzymatic antioxidant capacity (NEAC) in overall diet and separately from foods and beverages and markers of DNA damage. METHODS: The participants were 513 employees, 20 to 65 y of age. Urinary levels of 8-hydroxydeoxyguanosine (8-OHdG) and 7-methylguanine (m7 Gua) were measured using column-switching high performance liquid chromatography. Dietary NEAC was determined from databases of NEAC measurements obtained by different assays: ferric reducing-antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), and total radical-trapping antioxidant parameter (TRAP). Dietary NEAC for each participant was calculated by multiplying the estimated NEAC values with the consumed amount and summing up those values, which was ascertained by a validated brief self-administered diet history questionnaire. Multiple-regression analyses were performed to assess the associations between dietary NEAC and 8-OHdG and m7 Gua, with adjustment for potential confounders. RESULTS: No statistically significant associations were found between overall dietary NEAC or NEAC from either foods or beverages and urinary 8-OHdG levels, after adjustment for potential confounders (overall: FRAP, Ptrend = 0.40; ORAC, P = 0.27; TRAP, P = 0.45). Likewise, no association was found between overall dietary NEAC and m7 Gua levels (FRAP, Ptrend = 0.30; ORAC, P = 0.65; TRAP, P = 0.41). However, we did identify significant inverse association between NEAC from foods, as estimated by TRAP, and m7 Gua levels (Ptrend = 0.049). CONCLUSION: Overall, dietary NEAC was not associated with 8 OHdG or m7 Gua levels. In contrast, dietary NEAC from foods but not beverages may be inversely associated with DNA damage caused by methylation. PMID- 29429539 TI - Poor vitamin D status increases the risk of anemia in school children: National Food and Nutrition Surveillance. AB - OBJECTIVES: This study aimed to investigate the association between 25 hydroxyvitamin D (25[OH]D) concentrations and the risk of anemia in a large cohort of children with consideration for the effects of sex, body mass index (BMI), serum intact parathyroid hormone (iPTH) concentrations, and iron level status. METHODS: A total of 937 children (493 boys, 444 girls) ages 9 to 12 y were enrolled in a cross-sectional study. The children underwent various examinations including anthropometric measurements and blood sampling. RESULTS: Overall, 13.3% of the children were anemic and 64.2% and 28.1% of the subjects had a vitamin D deficiency (<25 nmol/L) and insufficiency (25-50 nmol/L), respectively. Approximately 13% of the children had concurrent low hemoglobin and hypovitaminosis D levels. The prevalence of hypovitaminosis D in the group of children with anemia was 96.8% compared with 91.6% in the non-anemic group (P = 0.046). Mean 25(OH)D concentrations were significantly lower in the anemic children compared with the non-anemic children (19.6 +/- 13.3 vs. 24.0 +/- 23.1 nmol/L; P = 0.003). After controlling for sex and BMI, children with a vitamin D deficiency were almost 3.45 times more likely to be anemic compared with children with a vitamin D sufficiency (95% confidence interval [CI], 1.21-9.81). The increased risk of anemia was found to start significantly at 25(OH)D < 44 nmol/L (17.6 ng/mL; odds ratio: 2.29; 95% CI, 1.07-4.91, P = 0.032). CONCLUSIONS: These findings strongly suggest an association between low circulating concentrations of 25(OH)D and anemia in a large, representative sample of children, even after adjustment for sex, age, BMI, and iPTH. PMID- 29429540 TI - Sodium butyrate modulates adipocyte expansion, adipogenesis, and insulin receptor signaling by upregulation of PPAR-gamma in obese Apo E knockout mice. AB - OBJECTIVES: Studies suggest that sodium butyrate reduces obesity-associated inflammation and insulin resistance in in vitro and in vivo models. Apo E-/- mice have high basal oxidative stress and naturally develop dyslipidemia and atherosclerosis. Because these disorders are present in obesity, the aim of this study was to determine whether Apo E-/- mice could be a more realistic model for studying obesity and insulin resistance. METHODS: We evaluated the action of orally administered sodium butyrate on adipose tissue expansion and insulin resistance using diet-induced obese Apo E-/- mice. RESULTS: Findings from the present study demonstrated that obese mice fed a sodium butyrate-supplemented diet presented a modest reduction of weight gain associated with reduction of adipocyte expansion, induction of adipogenesis and angiogenesis, and adiponectin production. Sodium butyrate also improved insulin sensitivity, by increasing insulin receptor expression associated with activation of Akt signaling pathway. These results were associated with increased peroxisome proliferator-activated receptor-gamma expression and nuclear factor-kappaB downregulation. CONCLUSION: These results suggested that oral supplementation of butyrate could be useful as an adjuvant in the treatment of obesity, metabolic syndrome, and insulin resistance. PMID- 29429541 TI - Association of the Gly482Ser PPARGC1A gene variant with different cholesterol outcomes in response to two energy-restricted diets in subjects with excessive weight. AB - OBJECTIVES: The aim of this study was to investigate the influence of two PPARGC1A gene polymorphisms on metabolic outcomes in response to two energy restricted diets. METHODS: A 4-mo nutritional intervention was conducted that involved two different hypo-energetic diets based on low-fat (LF) and moderately high-protein (MHP) dietary patterns. Unrelated subjects with excessive weight were genotyped for two PPARGC1A polymorphisms: Rs8192678 (Gly482Ser) and rs3755863 (G > A). Genotyping was performed by next-generation sequencing and haplotypes were screened. Anthropometric measurements and biochemical tests were assessed with standardized methods. RESULTS: Different cholesterol outcomes were observed by diet and Gly482Ser genotype. The Gly482 Gly homozygotes after an LF diet had lower reductions in total cholesterol (-9 mg/dL vs. -27 mg/dL; P = 0.017) and low-density lipoprotein cholesterol levels (-5 mg/dL vs. -18 mg/dL; P = 0.016) than the subjects who were carriers of 482 Ser allele. However, this finding was not recorded in the MHP group where Gly482 Gly homozygotes underwent similar cholesterol decreases as the 482 Ser allele carriers. Likewise, all genotype carriers had significant reductions in the frequencies of hypercholesterolemia (total cholesterol >=200 mg/dL) except for Gly482 Gly homozygotes in the LF group. Meanwhile, the rs3755863 polymorphism and PPARGC1A haplotypes showed borderline effects with regard to cholesterol decreases. CONCLUSIONS: An energy-restricted MHP diet might be more beneficial than an LF diet to reduce serum cholesterol among subjects who are carriers of the PPARGC1A Gly482Gly genotype. The analysis of this genetic variant might be the basis for a precise, nutrigenetic management of hypercholesterolemia based on genetic makeup. PMID- 29429542 TI - Does planning of births affect childhood undernutrition? Evidence from demographic and health surveys of selected South Asian countries. AB - OBJECTIVE: The prevalence of child undernutrition in South Asia is high, as is also the unmet need for family planning. In previous literature, the biodemographic relationship of family planning, particularly birth order and birth spacing, and nutritional status of children have been assessed separately. The aim of this study was to work on the hypothesis that the planning of births comprising timing, spacing, and number of births improves child undernutrition, especially in the areas with high prevalence of stunting and underweight. METHODS: We used recent Demographic and Health Survey data from four selected South Asian countries. Binary logistic regression models were applied to estimate the adjusted percentage of stunting and underweight by identified independent factors. RESULTS: Findings suggested that after controlling for other socioeconomic factors, children in the first birth order with >24 mo of interval between marriage and first birth have a lower risk for stunting (20%; p <0.01) and underweight (14%; p <0.05), respectively, than other scenarios of the planning of births. The probability of child undernutrition is lower among children born with >24 mo of birth spacing than its counterpart in all birth orders, but the significance of birth spacing reduces with increasing birth orders. CONCLUSION: Appropriate planning of births using family planning methods in countries with high birth rates has the potential to reduce childhood undernutrition. Thus, the planning of births emerges as an important biodemographic approach to eradicate childhood undernutrition especially in developing regions like South Asia and thereby to achieve sustainable development goals by 2030. PMID- 29429543 TI - Effect of parenteral glutamine supplementation combined with enteral nutrition on Hsp90 expression and Peyer's patch apoptosis in severely burned rats. AB - OBJECTIVES: The aim of this study was to investigate the effects of parenteral glutamine (GLN) supplementation combined with enteral nutrition (EN) on heat shock protein (Hsp) 90 expression and Peyer's patch (PP) apoptosis in severely burned rats. METHODS: Male Sprague-Dawley (SD) rats were randomly assigned to four groups: Sham burn + EN + GLN-free amino acid (AA; n = 10), sham burn + EN + GLN (n = 10), burn + EN + AA (n = 10), and burn + EN + GLN (n = 10). Two hours after a 30% total body surface area (TBSA), full-thickness scald burn injury on the back, burned rats in two of the experimental groups (burn + EN + AA and burn + EN + GLN groups) were fed with a conventional EN solution by oral gavage for 7 d. Simultaneously, rats in the burn + EN + GLN group were given 0.35 g GLN/kg body weight/d once via a tail vein injection for 7 d and rats in the burn + EN + AA group were administered isocaloric/isonitrogenous GLN-free amino acid solution (Tyrosine) for comparison. Rats in two sham burn control groups (sham burn + EN + AA and sham burn + EN + GLN groups) were treated in the same manner except for the burn injury. All rats in the four groups were given 175 kcal/kg body wt/d. There was isonitrogenous, isovolumic, and isocaloric intake among the four groups. At the end of the seventh day after completion of the nutritional program, all rats were anesthetized and samples were collected for further analysis. PP apoptosis was measured by terminal deoxyuridine nick-end labeling (TUNEL). The expression of Hsp90 in PPs was analyzed by western blotting. Caspase 3 activity of PPs was also assessed. Levels of proinflammatory cytokines of gut tissues were evaluated by enzyme-linked immunosorbent assay (ELISA). The intestinal immunoglobulin A (IgA) content was also determined by ELISA. RESULTS: The results revealed that intestinal IgA content in rats of the burn + EN + GLN group were significantly increased compared with those in the burn + EN + AA group (P < 0.05). The expression of Hsp90 of PPs in rats in the burn + EN + GLN group was significantly upregulated compared with those in the burn + EN + AA group (P < 0.05). On the other hand, levels of proinflammatory cytokines of gut tissues, caspase-3 activity, and the number of TUNEL-stained cells of PPs in rats of the burn + EN + GLN group were markedly decreased compared with those of the burn + EN + AA group (P < 0.05). CONCLUSIONS: The results of this study show that parenteral glutamine supplementation combined with EN may upregulate the expression of Hsp90, reduce caspase-3 activity, lessen the release of proinflammatory cytokines, attenuate PP apoptosis, and improve intestinal IgA response in burned rats. Clinically, therapeutic efforts to improve intestinal immunity may contribute to a favorable outcome in severely burned patients. PMID- 29429544 TI - Ebola Virus Localization in the Macaque Reproductive Tract during Acute Ebola Virus Disease. AB - Sexual transmission of Ebola virus (EBOV) has been demonstrated more than a year after recovery from the acute phase of Ebola virus disease (EVD). The mechanisms underlying EBOV persistence and sexual transmission are not currently understood. Using the acute macaque model of EVD, we hypothesized EBOV would infect the reproductive tissues and sought to localize the infection in these tissues using immunohistochemistry and transmission electron microscopy. In four female and eight male macaques that succumbed to EVD between 6 and 9 days after EBOV challenge, we demonstrate widespread EBOV infection of the interstitial tissues and endothelium in the ovary, uterus, testis, seminal vesicle, epididymis, and prostate gland, with minimal associated tissue immune response or organ pathology. Given the widespread involvement of EBOV in the reproductive tracts of both male and female macaques, it is reasonable to surmise that our understanding of the mechanisms underlying sexual transmission of EVD and persistence of EBOV in immune-privileged sites would be facilitated by the development of a nonhuman primate model in which the macaques survived past the acute stage into convalescence. PMID- 29429546 TI - Percutaneous cholecystostomy: A simple bridge to surgery or an alternative option for the management of acute cholecystitis? AB - BACKGROUND: Percutaneous cholecystostomy (PC) is an alternative among high-risk surgical patients or those with multiple comorbidities, but its indications have not been clearly established in the literature. The aim of this paper is to provide the reader with an updated review of the literature summarizing what is known on this topic. DATA SOURCES: We reviewed articles from 1979 to 2016 using the PubMed/Medline Database on PC and especially those evaluating this option as a bridge to surgery. CONCLUSIONS: There remains a paucity of randomized control trials to ascertain the use of PC as a definitive treatment for acute cholecystitis. In most studies, more than 50% of patients underwent PC as a definite treatment without subsequent cholecystectomy. A newer avenue of endoscopic ultrasound is also discussed, which requires rigorous trials to determine its appropriate applications. PMID- 29429545 TI - The Presence of Cyclooxygenase 2, Tumor-Associated Macrophages, and Collagen Alignment as Prognostic Markers for Invasive Breast Carcinoma Patients. AB - Inflammation, and the organization of collagen in the breast tumor microenvironment, is an important mediator of breast tumor progression. However, a direct link between markers of inflammation, collagen organization, and patient outcome has yet to be established. A tumor microarray of 371 invasive breast carcinoma biopsy specimens was analyzed for expression of inflammatory markers, including cyclooxygenase 2 (COX-2), macrophages, and several collagen features in the tumor nest (TN) or the tumor-associated stroma (TS). The tumor microarray cohort included females, aged 18 to 80 years, with a median follow-up of 8.4 years. High expression of COX-2 (TN), CD68 (TS), and CD163 (TN and TS) predicted worse patient overall survival (OS). This notion was strengthened by the finding from the multivariate analysis that high numbers of CD163+ macrophages in the TS is an independent prognostic factor. Overall collagen deposition was associated with high stromal expression of COX-2 and CD163; however, total collagen deposition was not a predictor for OS. Conversely, local collagen density, alignment and perpendicular alignment to the tumor boundary (tumor-associated collagen signature-3) were predictors of OS. These results suggest that in invasive carcinoma, the localization of inflammatory cells and aligned collagen orientation predict poor patient survival. Additional clinical studies may help validate whether therapy with selective COX-2 inhibitors alters expression of CD68 and CD163 inflammatory markers. PMID- 29429547 TI - Importance of mesh overlap on hernia recurrence after open umbilical hernia repair with bilayer prosthesis. AB - BACKGROUND: importance of mesh overlap on recurrence after open umbilical hernia repair has been poorly studied. METHODS: a retrospective cohort study was performed with patients who underwent open umbilical hernia repair with bilayer prosthesis between 2004 and 2015. RESULTS: 1538 patients were included. Fifty patients (3.3%) had a mesh overlap lower than 1 cm. After a mean follow-up of 4.1 years 53 patients (3.5%) developed a recurrence. Recurrence was associated with a mesh overlap smaller than 1 cm (10.2% vs. 3.3%, p = 0.010, OR = 3.3). In the logistic regression model an overlap smaller than 1 cm was not statistically associated with recurrence (OR = 2.5, p = 0.123). Female gender, postoperative complications and prosthesis size were associated with hernia recurrence. CONCLUSIONS: mesh overlap seems to be an important factor for hernia recurrence. A mesh overlap of at least 1 cm should be used until more studies are performed about this issue. PMID- 29429548 TI - Exploring the temporal stability of global road safety statistics. AB - Given the importance of rigorous quantitative reasoning in supporting national, regional or global road safety policies, data quality, reliability, and stability are of the upmost importance. This study focuses on macroscopic properties of road safety statistics and the temporal stability of these statistics at a global level. A thorough investigation of two years of measurements was conducted to identify any unexpected gaps that could highlight the existence of inconsistent measurements. The database used in this research includes 121 member countries of the United Nation (UN-121) with a population of at least one million (smaller country data shows higher instability) and includes road safety and socioeconomic variables collected from a number of international databases (e.g. WHO and World Bank) for the years 2010 and 2013. For the fulfillment of the earlier stated goal, a number of data visualization and exploratory analyses (Hierarchical Clustering and Principal Component Analysis) were conducted. Furthermore, in order to provide a richer analysis of the data, we developed and compared the specification of a number of Structural Equation Models for the years 2010 and 2013. Different scenarios have been developed, with different endogenous variables (indicators of mortality rate and fatality risk) and structural forms. The findings of the current research indicate inconsistency phenomena in global statistics of different instances/years. Finally, the results of this research provide evidence on the importance of careful and systematic data collection for developing advanced statistical and econometric techniques and furthermore for developing road safety policies. PMID- 29429549 TI - Mucocutaneous Manifestations of Infection by Histoplasma capsulatum in HIV Negative Immunosuppressed Patients. AB - Histoplasmosis is a systemic mycosis caused by the dimorphous fungus Histoplasma capsulatum (H. capsulatum). The fungus enters the body through the respiratory tract in the form of microconidia, which are transformed into intracellular yeast like structures in the lungs before disseminating hematogenously. Primary infection is usually asymptomatic and self-resolving. Some patients develop severe disease with acute or chronic respiratory involvement. Immunosuppressed patients, mainly those with altered cellular immunity, may have disseminated disease with variable mucocutaneous involvement characterized by papules, nodules, gummas, or ulcers with a granulomatous base. We report the case of 3 HIV negative patients infected by H capsulatum in whom diagnosis based on the skin lesions proved essential for early initiation of treatment. PMID- 29429550 TI - Imatinib: A New Tool for the Management of Chronic Sclerodermatous Graft-Vs-Host Disease. PMID- 29429551 TI - Dermatology and Immunoglobulin Therapy: Who to Treat and How to Administer Immunoglobulins. AB - Intravenous immunoglobulin (IVIG) replacement therapy has been used in immune deficiency diseases for more than 50 years. The indications for this treatment have evolved, however, and IVIG therapy is now used in various diseases in which the immune system plays a prominent role. IVIG therapy has carved out a niche in dermatology for the treatment of such conditions as dermatomyositis, autoimmune bullous diseases, and toxic epidermal necrolysis. Special attention has been paid to this therapy in recent years. New guidelines have been published and should be taken into consideration in dermatology. This review provides a practical guide to IVIG use in our specialty. PMID- 29429552 TI - ? PMID- 29429553 TI - Intubation in two patients with difficult airway management and tracheal stenosis after tracheostomy in thoracic surgery. AB - Lung isolation in thoracic surgery is a challenge, this is even more complex in the presence of unknown tracheal stenosis (TS). We report two cases of unknown TS and its airway management. TS appears most frequently after long term intubation close to the endotracheal tube cuff or in the stoma of tracheostomy that appears as a consequence of the granulation tissue after the surgical opening of the trachea. Clinical history, physical examination, difficult intubating predictors and imaging tests (CT scans) are crucial, however most of tracheal stenosis may be unnoticed and symptoms depend on the degree of obstruction. In our cases, the patients presented anatomical changes due to surgery and previous tracheostomy that led to a TS without symptoms. There is scarce literature about the intubation in patients with previous tracheostomy in thoracic surgery. In the first case, a Univent(r) tube was used using a flexible fiberscope but an acute tracheal hemorrhage occurred. In the second case, after intubation with VivaSight SL(r) in an awake patient, the insertion of a bronchial blocker was performed through an endotracheal tube guided by its integrated camera without using flexible fiberscopy. PMID- 29429554 TI - Identification of small non-coding RNA classes expressed in swine whole blood during HP-PRRSV infection. AB - It has been established that reduced susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV) has a genetic component. This genetic component may take the form of small non-coding RNAs (sncRNA), which are molecules that function as regulators of gene expression. Various sncRNAs have emerged as having an important role in the immune system in humans. The study uses transcriptomic read counts to profile the type and quantity of both well and lesser characterized sncRNAs, such as microRNAs and small nucleolar RNAs to identify and quantify the classes of sncRNA expressed in whole blood between healthy and highly pathogenic PRRSV-infected pigs. Our results returned evidence on nine classes of sncRNA, four of which were consistently statistically significantly different based on Fisher's Exact Test, that can be detected and possibly interrogated for their effect on host dysregulation during PRRSV infections. PMID- 29429555 TI - [Pigmentary Planet]. PMID- 29429556 TI - Infection with gram-negative bacteria among children in a tertiary pediatric hospital in Egypt. AB - BACKGROUND: Patients in pediatric intensive care units (PICUs) are susceptible to infections with gram-negative bacteria (GNB). METHODS: A prospective observational study was conducted in 2 PICUs at Cairo University Hospitals to determine the incidence and outcome of GNB infections over 1 year. Variables of interest included age, gender, isolated organism, susceptibility to antibiotics, and final outcome. RESULTS: During the study period, 1420 patients were admitted to the PICU; of these, 291 developed GNB infections. The median age of the studied GNB patients was 50 months (interquartile range [IQR], 22-80 months). The mortality rate was 37.1%. Organisms were isolated from blood in the majority (86.6%) of patients, with Klebsiella (36.0%) being the most frequently isolated organism. Among patients with GNB infection, 235 patients, one had a multidrug resistant (MDR) infection. The length of hospital stay was statistically significantly longer in the MDR group (25 days; IQR, 20-30) than in the non-MDR group (15 days; IQR, 10-20) (P < .01). Mortality was similar in both groups (37.4% vs 35.7% in the MDR and non-MDR groups, respectively; P = .88). CONCLUSION: This study highlights high rates of pediatric MDR-GNB infections and emphasizes the need for a continuous surveillance system in the management of these critically ill children. PMID- 29429557 TI - Prevalence of incidental clinically relevant pancreatic cysts at diagnosis based on current guidelines. AB - BACKGROUND: Most pancreatic cysts (PCs) found incidentally by CT and MRI scans might not be clinically important according to the Fukuoka guidelines, the American Gastroenterological Association (AGA) guidelines and European guidelines. AIMS: To determine and compare the prevalence of incidental clinically important PCs (CIPCs). METHODS: Abdominal contrast-enhanced CT or MRI scans performed during a one-year period were retrospectively reviewed to identify incidental PCs. CIPCs were defined as those cysts that would be capable of triggering further evaluation with endoscopic ultrasound, immediate surveillance (within 3-6 months) and/or surgery. Prevalence was calculated as the number of patients with CIPCs per 100 subjects imaged (%). RESULTS: Sixty patients (mean age 70+/-14 years) out of 565 were found to have incidental PCs, representing a prevalence of 8.7% (95% CI 6.3-11.5) in CT scans and 27.5% (95% CI 16-41) in MRI scans. Seven patients (11.6%, 95% CI 5-22) had CIPCs based on size >= 30mm (n=5), size >= 30mm and pancreatic duct (PD) dilation (n=1) and PD dilation and presence of solid component (n=1). Based on the Fukuoka guidelines, the prevalence of CIPCs was 1.2% (95% CI 0.4-2.5) in CT scans (6/507) and 1.7% (95% CI 0.1-9) in MRI scans (1/58). Based on the AGA and European guidelines, the prevalence of CIPCs was 0.2% (95% CI 0.1-1) in CT scans (1/507) and 1.7% (95% CI 0.1-9) in MRI scans (1/58). Patients with PCs initially classified as "AGA- or European-positive" had a higher surgical probability and this decision was taken earlier in the follow-up. CONCLUSIONS: In our cohort, the prevalence of important incidental pancreatic cysts was not negligible at around 1% according to current guidelines. PMID- 29429558 TI - Guillain-Barre syndrome and optic neuritis after Mycoplasma pneumoniae infection. AB - We report the case of a 12-year-old girl who developed Guillain-Barre syndrome (GBS) and optic neuritis (ON) following Mycoplasma pneumoniae infection. Her symptoms, including bilateral vision impairment and tingling in her hands and right foot, were resolved after methylprednisolone pulse therapy. Serum anti galactocerebroside (Gal-C) IgM antibodies were detected in our patient. This is the first report of a child with GBS and ON associated with M. pneumoniae infection. PMID- 29429560 TI - Outreach: Change the world, change yourself. PMID- 29429559 TI - EPO improved neurologic outcome in rat pups late after traumatic brain injury. AB - : In adult rats, erythropoietin improved outcomes early and late after traumatic brain injury, associated with increased levels of Brain Derived Neurotrophic Factor. Using our model of pediatric traumatic brain injury, controlled cortical impact in 17-day old rats, we previously showed that erythropoietin increased hippocampal neuronal fraction in the first two days after injury. Erythropoietin also decreased activation of caspase3, an apoptotic enzyme modulated by Brain Derived Neurotrophic Factor, and improved Novel Object Recognition testing 14 days after injury. Data on long-term effects of erythropoietin on Brain Derived Neurotrophic Factor expression, histology and cognitive function after developmental traumatic brain injury are lacking. We hypothesized that erythropoietin would increase Brain Derived Neurotrophic Factor and improve long term object recognition in rat pups after controlled cortical impact, associated with increased neuronal fraction in the hippocampus. METHODS: Rats pups received erythropoietin or vehicle at 1, 24, and 48 h and 7 days after injury or sham surgery followed by histology at 35 days, Novel Object Recognition testing at adulthood, and Brain Derived Neurotrophic Factor measurements early and late after injury. RESULTS: Erythropoietin improved Novel Object Recognition performance and preserved hippocampal volume, but not neuronal fraction, late after injury. CONCLUSIONS: Improved object recognition in erythropoietin treated rats was associated with preserved hippocampal volume late after traumatic brain injury. Erythropoietin is approved to treat various pediatric conditions. Coupled with exciting experimental and clinical studies suggesting it is beneficial after neonatal hypoxic ischemic brain injury, our preliminary findings support further study of erythropoietin use after developmental traumatic brain injury. PMID- 29429561 TI - [DRESS syndrome secondary to pyrazinamide: An uncommon complication of tuberculosis treatment]. AB - INTRODUCTION: The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe drug-induced reaction. CASE REPORT: We report the case of a 35-year-old man treated by RHEZ for a first episode of a smear positive pulmonary tuberculosis and who developed a DRESS syndrome due to pyrazinamide after twenty days of treatment, associated with a viral reactivation to Human Herpes Virus 6 (HHV6). He had a skin eruption, liver involvement and hypereosinophilia. He fully recovered after drug withdrawal, associated with local and general corticosteroids. He died two weeks after discharge. CONCLUSIONS: Discovery of DRESS syndrome during tuberculosis treatment is an uncommon complication and requires a searching for the responsible drug. That should be difficult because tuberculosis drugs are often given as fixed-dose combination. Physicians have to bear in mind the potential role of pyrazinamide. PMID- 29429562 TI - Evaluation of the Translation Distance of the Glenohumeral Joint and the Function of the Rotator Cuff on Its Translation: A Cadaveric Study. AB - PURPOSE: To evaluate the distance and position of humeral head translation during glenohumeral motion and to investigate the function of the rotator cuff in glenohumeral translation. METHODS: Using 9 cadavers, glenohumeral translation during passive pendulum motion was tracked by an optical motion capture system. Tension was applied to 5 compartments of the rotator cuff muscles, and 7 different conditions of rotator cuff dysfunction were sequentially simulated. Three-dimensional glenohumeral structure was reconstructed from the computed tomography images of the specimens, and the distance and position of glenohumeral translation were compared among the conditions. RESULTS: The average radius of glenohumeral translation was 10.6 +/- 4.3 mm when static loading was applied to all rotator cuff muscles. The radius increased significantly in the models without traction force on the supraspinatus and total subscapularis tendons (P = .030). The position of the translation center did not change in the mediolateral direction (P = .587) and in the anteroposterior direction (P = .138), but it moved significantly superiorly in the models without supraspinatus and infraspinatus loading (P = .011) and in those without supraspinatus, infraspinatus, and teres minor loading (P < .001). CONCLUSIONS: The distance and position of humeral head translation during glenohumeral motion changed with rotator cuff deficiency. The present study indicated that the subscapularis plays an important role in maintaining the central position of the humeral head, and that the infraspinatus acts as a major depressor of the humeral head during shoulder motion. CLINICAL RELEVANCE: The results of this study suggest that extension of a tear into the subscapularis should be avoided to maintain the centering function of the glenohumeral joint in cases with rotator cuff tear. PMID- 29429563 TI - Return to Work or Sport After Multiligament Knee Injury: A Systematic Review of 21 Studies and 524 Patients. AB - PURPOSE: To systematically review multiligament knee injury (MLKI) outcome studies to determine overall rates of return to work or sport after MLKI and risk factors for lack of return to work or sport after MLKI. METHODS: A search was performed of MLKI outcome studies from 1950 to March 1, 2017. Ninety-two studies were identified. All included reported return to work, return to sport, or Tegner activity scores. Rates of return to work or sport were determined for overall population and by obesity status, injury severity, and presence of peroneal nerve or vascular injury. RESULTS: A total of 524 patients (21 studies) were included. Return to high-level sport was low (22%-33%). Return to any level of sport was 53.6% overall (178/332), with a higher rate reported in studies with all surgical patients (59.1%, 114/193 patients) versus studies with mixed surgical and nonoperative treatment (46.0%, 64/139 patients) (P = .02). Rate of return to work with little or no modifications was 62.1% (146/200) and return to any work was 88.4% (190/215). Obese patients had lower postoperative Tegner scores than a general population (obese: mean 1.7 +/- 1.2; nonobese: mean 4.5 +/- 1.0; P < .001). Among studies without Schenck grade IV and V injuries, return to work with no or minimal modifications (100%, 12/12 patients) was higher than studies including grade IV and V patients (66.0%, 70/106 patients) (P = .017). Return to any work was higher in studies without vascular injuries (96.3%, 105/109) versus those including them (80.2%, 85/106) (P < .001). CONCLUSIONS: Return to sport after MLKI occurs in approximately 60% of surgically treated patients, though return to high-level sport is lower. Return to work is frequently possible after MLKI though it may require workplace or job duty modifications. Obesity, nonoperative treatment, higher injury severity, and vascular injury are associated with poorer functional outcomes. LEVEL OF EVIDENCE: Level IV, systematic review of level III and IV studies. PMID- 29429564 TI - Genomic comparison between members of the Salinibacteraceae family, and description of a new species of Salinibacter (Salinibacter altiplanensis sp. nov.) isolated from high altitude hypersaline environments of the Argentinian Altiplano. AB - The application of tandem MALDI-TOF MS screening with 16S rRNA gene sequencing of selected isolates has been demonstrated to be an excellent approach for retrieving novelty from large-scale culturing. The application of such methodologies in different hypersaline samples allowed the isolation of the culture-recalcitrant Salinibacter ruber second phylotype (EHB-2) for the first time, as well as a new species recently isolated from the Argentinian Altiplano hypersaline lakes. In this study, the genome sequences of the different species of the phylum Rhodothermaeota were compared and the genetic repertoire along the evolutionary gradient was analyzed together with each intraspecific variability. Altogether, the results indicated an open pan-genome for the family Salinibacteraceae, as well as the codification of relevant traits such as diverse rhodopsin genes, CRISPR-Cas systems and spacers, and one T6SS secretion system that could give ecological advantages to an EHB-2 isolate. For the new Salinibacter species, we propose the name Salinibacter altiplanensis sp. nov. (the designated type strain is AN15T=CECT 9105T=IBRC-M 11031T). PMID- 29429565 TI - AGC kinases in cancer metastasis, immune checkpoint regulation and drug resistance. PMID- 29429566 TI - Tongue Fasciculations and Electrocardiographic Tremors in Spinal Muscular Atrophy. PMID- 29429567 TI - Pseudopseudohypoparathyroidism: A Diagnostic Consideration in a Patient with Brachydactyly. PMID- 29429568 TI - Testicular Torsion in an Infant with Undescended Testis. PMID- 29429569 TI - Function of child anger and sadness in response to a blocked goal. AB - Drawing from the functional theory of emotion, anger is proposed to serve adaptive functions such as motivating children to persist in overcoming difficulties to achieve their goals, whereas sadness helps children to shift attention away from goals that they determine cannot be attained. Despite the theorized importance of anger to persistence, it does not always relate to persistence in expected ways empirically; the role that sadness might play in how anger relates to persistence is often not considered even though children often experience both anger and sadness when goals are blocked. We hypothesized that how anger relates to persistence would depend on the level of sadness that children felt and, thus, tested sadness as a moderator of the relation of anger to persistence. We expected that the relation of anger to persistence would be stronger when sadness is lower. Child anger, sadness, and persistence were observed in a locked-box frustration task when children were 4 or 5 years old (N = 116). Although higher levels of child anger were associated with more persistence, the association between anger and persistence was stronger when sadness was lower than when sadness was higher. The findings indicate that children's ability to use the motivational aspects of anger to promote persistence may depend on the levels of sadness felt. PMID- 29429570 TI - Outcomes for haematological cancer patients admitted to an intensive care unit in a university hospital. AB - BACKGROUND: Haematological cancer (HC) patients are increasingly requiring intensive care (ICUs). The aim of this study was to investigate the outcome of HC patients in our ICU and evaluate 5 days-full support as a breakpoint for patients' re-assessment for support. METHODS: Retrospective study enrolling 112 consecutive HC adults, requiring ICU in January-December 2015. Patients' data were collected from medical records and Infection Control Committee surveillance reports. Logistic regression analysis was performed to identify independent risk factors for ICU mortality. RESULTS: Sixty-one were neutropenic, and 99 (88%) had infection at ICU admission. Acute myeloid leukaemia was diagnosed in 43%. Thirty five (31%) were hematopoietic stem cell transplant recipients. Only 17 (15%) were in remission. Eighty-nine underwent mechanical ventilation on admission. Fifty three patients acquired ICU-infection (35 bacteremia) being gram negative bacteria (Klebsiella pneumoniae and non-fermenters) the top pathogens. However, ICU-acquired infection had no impact on mortality. The overall ICU and 1-year survival rate was 27% (30 patients) and 7% (8 patients), respectively. Moreover, only 2/62 patients survived with APACHE II score >=25. The median time for death was 4 days. APACHE II score >=25 [OR:35.20], septic shock [OR:8.71] and respiratory failure on admission [OR:10.55] were independent risk factors for mortality in multivariate analysis. APACHE II score >=25 was a strong indicator for poor outcome (ROC under curve 0.889). CONCLUSIONS: APACHE II score >=25 and septic shock were criteria of ICU futility. Our findings support the full support of patients for 5 days and the need to implement a therapeutic limitations protocol. PMID- 29429571 TI - NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals with Leigh-like Encephalomyopathy. AB - Respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases. Clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies. To date, disease-causing variants in genes coding for 27 complex I subunits, including 7 mitochondrial DNA genes, and in 11 genes encoding complex I assembly factors have been reported. Here, we describe rare biallelic variants in NDUFB8 encoding a complex I accessory subunit revealed by whole-exome sequencing in two individuals from two families. Both presented with a progressive course of disease with encephalo(cardio)myopathic features including muscular hypotonia, cardiac hypertrophy, respiratory failure, failure to thrive, and developmental delay. Blood lactate was elevated. Neuroimaging disclosed progressive changes in the basal ganglia and either brain stem or internal capsule. Biochemical analyses showed an isolated decrease in complex I enzymatic activity in muscle and fibroblasts. Complementation studies by expression of wild-type NDUFB8 in cells from affected individuals restored mitochondrial function, confirming NDUFB8 variants as the cause of complex I deficiency. Hereby we establish NDUFB8 as a relevant gene in childhood-onset mitochondrial disease. PMID- 29429574 TI - Paleoimaging of a modern mummy from Lithuania (circa 19th-20th century). AB - An anthropogenic human mummy curated in the Museum of the History of Medicine, Vilnius University, was recently examined by means of computed tomography. Although the mummy lacked data regarding its specific context and historical information on its identity and chronology, the investigation focused on the embalming method adopted to preserve it. Some pathological alterations were also recorded. This research appears to suggest that this body was prepared for educational and/or scientific purposes rather than funerary purposes. Hence, the case could be categorized as a "medical mummy" prepared between the mid-19th and the mid-20th centuries. PMID- 29429572 TI - Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome. AB - Variants affecting the function of different subunits of the BAF chromatin remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity. PMID- 29429575 TI - Mechanistic analyses of the suppression of amyloid beta42 aggregation by apomorphine. AB - (R)-Apomorphine (1) has the potential to reduce the accumulation of amyloid beta protein (Abeta42), a causative agent of Alzheimer's disease (AD). Although the inhibition of Abeta42 aggregation by 1 is ascribable to the antioxidative effect of its phenol moiety, its inhibitory mechanism at the molecular level remains to be fully elucidated. LC-MS and UV analyses revealed that 1 is autoxidized during incubation to produce an unstable o-quinone form (2), which formed a Michael adduct with Lys 16 and 28 of Abeta42. A further autoxidized form of 1 (3) with o quinone and phenanthrene moieties suppressed Abeta42 aggregation comparable to 1, whereas treating 1 with a reductant, tris(2-carboxyethyl)phosphine diminished its inhibitory activity. 1H-15N SOFAST-HMQC NMR studies suggested that 1 interacts with Arg5, His13,14, Gln15, and Lys16 of the Abeta42 monomer. These regions form intermolecular beta-sheets in Abeta42 aggregates. Since 3 did not perturb the chemical shift of monomeric Abeta42, we performed aggregation experiments using 1,1,1,3,3,3-hexafluoro-2-propanol-treated Abeta42 to investigate whether 3 associates with Abeta42 oligomers. Compounds 1 and 3 delayed the onset of the oligomer-driven nucleation phase. Despite their cytotoxicity, they did not exacerbate Abeta42-mediated neurotoxicity in SH-SY5Y neuroblastoma cells. These results demonstrate that extension of the conjugated system in 1 by autoxidation can promote its planarity, which is required for intercalation into the beta sheet of Abeta42 nuclei, thereby suppressing further aggregation. PMID- 29429573 TI - Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility. AB - Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function. PMID- 29429576 TI - In silico studies, synthesis and pharmacological evaluation to explore multi targeted approach for imidazole analogues as potential cholinesterase inhibitors with neuroprotective role for Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit. PMID- 29429577 TI - Epidemiology of distal radius fractures in polytrauma patients and the influence of high traumatic energy transfer. AB - INTRODUCTION: For several extremity fractures differences in morphology, incidence rate and functional outcome were found when polytrauma patients were compared to patients with an isolated injury. This is not proven for distal radius fractures (DRF). Therefore, this study aimed to analyse fracture morphology in relation to energy transfer in both poly- and mono-trauma patients with a DRF. METHODS: This was a retrospective cohort study. All patients aged 16 years and older with a DRF were included. Patients with an Injury Severity Score of 16 or higher were classified as polytrauma patients. Injuries were defined as high or low energy. All DRFs were classified using the AO/OTA fracture classification system. RESULTS: A total of 830 patients with a DRF were included, 12% were polytrauma. The incidence rate of DRF in polytrauma patients was 3.5%. Ipsilateral upper extremity injury was found in >30% of polytrauma and high energy monotrauma patients, compared to 5% in low-energy monotrauma patients. More type C DRF were found in polytrauma and high-energy monotrauma patients versus low-energy monotrauma patients. Operative intervention rates for all types of DRF were similar for polytrauma and high-energy monotrauma patients. Non-union rates were higher in polytrauma patients. CONCLUSION: Higher energy mechanisms of injury, in polytrauma and high-energy monotrauma patients, were associated with more severe complex articular distal radius fractures and more ipsilateral upper extremity injuries. Polytrauma and high-energy monotrauma patient have a similar fracture morphology. However, polytrauma patients have in addition to more injured body regions also more non-union related interventions than high-energy monotrauma patients. PMID- 29429578 TI - Thoracic duct cyst presenting as abdominal pain. PMID- 29429579 TI - Databases for surgical health services research: National Trauma Data Bank and Trauma Quality Improvement Program. PMID- 29429580 TI - The Newest Threat to Emergency Department Procedural Sedation. PMID- 29429581 TI - Is Hyperpronation More Effective Than Supination for Reduction of a Radial Head Subluxation? PMID- 29429582 TI - ? PMID- 29429583 TI - ? PMID- 29429584 TI - Differential daptomycin resistance development in Staphylococcus aureus strains with active and mutated gra regulatory systems. AB - The first-in-class lipopeptide antibiotic daptomycin (DAP) is highly active against Gram-positive pathogens including beta-lactam and glycopeptide resistant strains. Its molecular mode of action remains enigmatic, since a defined target has not been identified so far and multiple effects, primarily on the cell envelope have been observed. Reduced DAP susceptibility has been described in S. aureus and enterococci after prolonged treatment courses. In line with its pleiotropic antibiotic activities, a unique, defined molecular mechanism of resistance has not emerged, instead non-susceptibility appears often accompanied by alterations in membrane composition and changes in cell wall homeostasis. We compared S. aureus strains HG001 and SG511, which differ primarily in the functionality of the histidine kinase GraS, to evaluate the impact of the GraRS regulatory system on the development of DAP non-susceptibility. After extensive serial passing, both DAPR variants reached a minimal inhibitory concentration of 31 MUg/ml and shared some phenotypic characteristics (e.g. thicker cell wall, reduced autolysis). However, based on comprehensive analysis of the underlying genetic, transcriptomic and proteomic changes, we found that both strains took different routes to achieve DAP resistance. Our study highlights the impressive genetic and physiological capacity of S. aureus to counteract pleiotropic activities of cell wall- and membrane-active compounds even when a major cell wall regulatory system is dysfunctional. PMID- 29429585 TI - Fruit Softening: Revisiting the Role of Pectin. AB - Fruit softening, which is a major determinant of shelf life and commercial value, is the consequence of multiple cellular processes, including extensive remodeling of cell wall structure. Recently, it has been shown that pectate lyase (PL), an enzyme that degrades de-esterified pectin in the primary wall, is a major contributing factor to tomato fruit softening. Studies of pectin structure, distribution, and dynamics have indicated that pectins are more tightly integrated with cellulose microfibrils than previously thought and have novel structural features, including branches of the main polymer backbone. Moreover, recent studies of the significance of pectinases, such as PL and polygalacturonase, are consistent with a causal relationship between pectin degradation and a major effect on fruit softening. PMID- 29429586 TI - Plant Ribonomics: Proteins in Search of RNA Partners. AB - Research into the regulation of gene expression underwent a shift from focusing on DNA-binding proteins as key transcriptional regulators to RNA-binding proteins (RBPs) that come into play once transcription has been initiated. RBPs orchestrate all RNA-processing steps in the cell. To obtain a global view of in vivo targets, the RNA complement associated with particular RBPs is determined via immunoprecipitation of the RBP and subsequent identification of bound RNAs via RNA-seq. Here, we describe technical advances in identifying RBP in vivo targets and their binding motifs. We provide an up-to-date view of targets of nucleocytoplasmic RBPs collected in arabidopsis. We also discuss current experimental limitations and provide an outlook on how the approaches may advance our understanding of post-transcriptional networks. PMID- 29429587 TI - Brokenbrough-Braunwald-Morrow Sign. PMID- 29429588 TI - Expanding our Understanding of the Role of the Microbiome in Health and Disease. PMID- 29429589 TI - Measurement of Instantaneous Angular Displacement Fluctuation and its applications on gearbox fault detection. AB - Recently, Instantaneous Angular Speed (IAS) measurement is successfully established and prevalently applied to a wide variety of machines due to the hypothesis that the speed fluctuation of rotating machinery carries plentiful dynamic responses. Nevertheless, exploration and application based on angular signal are still insufficient. Under the same hypothesis, in this paper, we introduced an extended algorithm named Instantaneous Angular Phase Demodulation (IAPD), together with the selection of optimal sideband family to extract the Instantaneous Angular Displacement Fluctuation (IADF) signal. In order to evaluate the performance of IADF signal, an effective approach was demonstrated using IADF signal to address the fault detection and diagnosis issue. After extracting the IADF signal, a much effective method was developed to deal with the large amount of data generated during the signal collection process. Then, we used the well-developed techniques, i.e., empirical mode decomposition (EMD) and envelope analysis, to undertake the signal de-noising and feature extraction task. The effectiveness and capability of the IADF signal were evaluated by two kinds of gearboxes under differentconditions in practice. In particular, the prevalent IAS signal and vibration signal were also involved and testified by the proposed procedure. Experimental results demonstrated that by means of the IADF signal, the combination of EMD and envelope analysis not only provided accurate identification results with a higher signal-to-noise ratio, but was also capable of revealing the fault characteristics significantly and effectively. In contrast, although the IAS signal had the potential ability to diagnose the serious fault, it failed for the slight crack case. Moreover, the same procedure even its improvements, i.e., ensemble empirical mode decomposition and local mean decomposition, all failed to recognize the faults in terms of vibration signals. PMID- 29429590 TI - Coordinated control system modelling of ultra-supercritical unit based on a new T S fuzzy structure. AB - The thermal power plant, especially the ultra-supercritical unit is featured with severe nonlinearity, strong multivariable coupling. In order to deal with these difficulties, it is of great importance to build an accurate and simple model of the coordinated control system (CCS) in the ultra-supercritical unit. In this paper, an improved T-S fuzzy model identification approach is proposed. First of all, the k-means++ algorithm is employed to identify the premise parameters so as to guarantee the number of fuzzy rules. Then, the local linearized models are determined by using the incremental historical data around the cluster centers, which are obtained via the stochastic gradient descent algorithm with momentum and variable learning rate. Finally, with the proposed method, the CCS model of a 1000 MW USC unit in Tai Zhou power plant is developed. The effectiveness of the proposed approach is validated by the given extensive simulation results, and it can be further employed to design the overall advanced controllers for the CCS in an USC unit. PMID- 29429591 TI - Early stage mucinous ovarian cancer: A review. AB - Mucinous ovarian carcinomas (MOCs) are an uncommon subset of epithelial neoplasms, both clinically and molecularly distinct from other ovarian cancers. Pathologic diagnosis proves challenging, and metastatic disease from other sites especially the digestive tract-must be excluded. Fortunately, most patients are diagnosed at an early stage of disease and often present with large, unilateral adnexal masses. Survival for patients with stage IA disease approaches over 90%, and surgery alone is sufficient. Patients with stage IB-II disease should receive adjuvant treatment but the specific regimen is controversial. In the following review, we provide an overview of mucinous ovarian carcinomas, with a particular focus on the treatment of patients with early stage disease. PMID- 29429592 TI - gamma-Glutamyl cyclotransferase contributes to tumor progression in high grade serous ovarian cancer by regulating epithelial-mesenchymal transition via activating PI3K/AKT/mTOR pathway. AB - OBJECTIVE: High grade serous ovarian cancer (HGSC) remains one of the most lethal malignancies in females. We previously reported that gamma-glutamyl cyclotransferase (GGCT) was significantly upregulated in serous ovarian cancer. The current study was aimed to explore the function and underlying mechanism of GGCT in HGSC. METHODS: GGCT expression was assessed by immunohistochemistry in 128 HGSC patients. Stable cell lines with GGCT gene overexpression or knockdown were established to investigate the function of GGCT in HGSC in vitro and in vivo. RESULTS: GGCT is highly upregulated in HGSC tissues and associated with FIGO stage, lymph node metastasis and ascitic fluid volume. High expression of GGCT is associated with poor survival in HGSC patients. The Harrell's c-indexes of the prognostic models for overall survival and progression-free survival prediction were 0.758 and 0.726, respectively. GGCT knockdown suppresses proliferation, clone formation, migration, and invasion of tumor cells in vitro while forced GGCT overexpression presents opposite results. Furthermore, GGCT silencing inhibits tumor growth and spread in vivo. Epithelial-mesenchymal transition (EMT) and PI3K/AKT/mTOR signaling pathway are suppressed in GGCT silenced cells and enhanced in GGCT overexpressed cells. Inactivation of PI3K/AKT/mTOR signaling pathway in GGCT overexpressed cells induces EMT inhibition. CONCLUSIONS: Our data reveals an important role of GGCT in regulating EMT and progression of HGSC, providing a valuable prognostic marker and potential target for treatment of HGSC patients. PMID- 29429594 TI - Filling the gaps in COPD: the TRIBUTE study. PMID- 29429593 TI - Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. AB - BACKGROUND: Evidence is scarce on the relative risk-benefit of inhaled triple therapy, consisting of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting beta2-agonist, versus dual bronchodilation for chronic obstructive pulmonary disease (COPD). We aimed to compare a single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium (IND/GLY) in terms of the rate of moderate-to severe COPD exacerbations over 52 weeks of treatment. METHODS: This randomised, parallel-group, double-blind, double-dummy study was done at 187 sites across 17 countries. Eligible patients had symptomatic COPD, severe or very severe airflow limitation, at least one moderate or severe exacerbation in the previous year, and were receiving inhaled maintenance medication. After a 2 week run-in period with one inhalation per day of IND/GLY (85 MUg/43 MUg), patients were randomly assigned (1:1), via an interactive response technology system, to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G (87 MUg/5 MUg/9 MUg) twice per day or one inhalation of IND/GLY (85 MUg/43 MUg) per day. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02579850. FINDINGS: Between May, 29 2015, and July 10, 2017, 1532 patients received BDP/FF/G (n=764) or IND/GLY (n=768). Moderate-to-severe exacerbation rates were 0.50 per patient per year (95% CI 0.45-0.57) for BDP/FF/G and 0.59 per patient per year (0.53-0.67) for IND/GLY, giving a rate ratio of 0.848 (0.723-0.995, p=0.043) in favour of BDP/FF/G. Adverse events were reported by 490 (64%) of 764 patients receiving BDP/FF/G and 516 (67%) of 768 patients receiving IND/GLY. Pneumonia occurred in 28 (4%) patients receiving BDP/FF/G versus 27 (4%) patients receiving IND/GLY. One treatment-related serious adverse event occurred in each group: dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY. INTERPRETATION: In patients with symptomatic COPD, severe or very severe airflow limitation, and an exacerbation history despite maintenance therapy, extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY, without increasing the risk of pneumonia. FUNDING: Chiesi Farmaceutici. PMID- 29429595 TI - Department of Error. PMID- 29429596 TI - Quality assurance and sustainability of cancer care: A European network is needed. PMID- 29429597 TI - Clinicopathologic features and prognoses of different histologic types of triple negative breast cancer: A large population-based analysis. AB - PURPOSE: To examine the clinicopathologic characteristics and survival outcomes of different histologic types of triple-negative breast cancer (TNBC). METHODS: We used the SEER database to identify patients with TNBC diagnosed between 2010 and 2014. Our analysis focused on the seven most prevalent histologic types. Differences were compared between invasive carcinoma of no special type (NST) and the other six types. RESULTS: Significant differences were observed in age at diagnosis, tumor grade, size, nodal status and treatment. As tumor size increased, the number of positive lymph nodes increased markedly in invasive lobular carcinoma (ILC) and mixed NST and lobular carcinoma (NST-ILC), while in metaplastic carcinoma the number only increased slightly. In multivariate survival analyses, compared with patients with invasive carcinoma NST, breast cancer-specific survival (BCSS) and overall survival (OS) were worse for those with NST-ILC (BCSS: hazard ratio [HR] 1.81, P < .001; OS: HR 1.56, P = .005) or metaplastic carcinoma (BCSS: HR 1.95, P < .001; OS: HR 1.73, P < .001). By contrast, patients with medullary (HR 0.40, P = .010) or apocrine carcinoma (HR 0.27, P = .008) showed better BCSS. Time-dependent receiver operating characteristic (ROC) analyses indicated that T category in ILC and N category in metaplastic carcinoma were of less prognostic value. CONCLUSIONS: According to the histologic classification of TNBC, this heterogeneous disease can be divided into several entities with different clinicopathologic features and prognoses. In the era of molecular subtyping of breast cancer, the histologic classification of TNBC is still of considerable clinical significance. PMID- 29429598 TI - Does the site of the orthotopic neobladder outlet matter? A prospective randomized comparative study. AB - BACKGROUND: To compare the results of urethral anastomosis to a button hole and to the lowest part of the anterior suture line during orthotopic neobladder substitution. METHODS: From January 2012 to December 2015, 87 consecutive male patients with invasive bladder cancer underwent radical cystectomy and Hautmann ileal neobladder. Patients were randomly divided into two groups; group I (44 patients), the outlet was created as a button-hole at the most dependent part of the pouch, group II (43 patients), the lowest 1 cm of the anterior suture line of the pouch was left open as an outlet. Patients were randomly assigned to either group using computer-generated random numbers (JMP, Version 12.0.1; SAS Institute, Cary, NC, USA) via a sealed envelope. The functional outcomes of both groups were compared especially at the urethro-enteric anastomosis. RESULTS: There were no intraoperative complications. Early postoperative complications occurred in 9 patients (5 in group I and 4 in group II, p = 0.484). Prolonged urinary leakage persisted for 11 and 14 days in 2 patients in group I and 10 and 16 days in 2 patients in group II. Delayed postoperative complications occurred in 11 patients (5 [12.5%] in group I and 6 [15.6%] in group II) (p = 0.711). Three patients developed urethro-enteric strictures (2 in group I and 1 in group II) (p = 0.571). CONCLUSION: The "non-hole" technique of urethral anastomosis was not associated with a significant increase in the complication rate when compared to the commonly performed "hole" technique. PMID- 29429599 TI - Behavioral Nutraceuticals and Diets. AB - Behavioral problems of companion animals are becoming more widely recognized. As a result, there are a growing number of behavioral nutraceuticals and diets on the market. These products may be useful for the treatment of mild conditions, for clients who are hesitant to give their pet a psychopharmacologic agent, or sometimes in conjunction with psychopharmacologic agents. Veterinarians should critically review the research associated with nutraceuticals and diets, and have an understanding of the functional ingredients and their mechanisms of action before prescribing treatment. This article provides an overview of nutraceuticals, their mechanisms of action, and relevant research regarding their use. PMID- 29429600 TI - Diagnosing Behavior Problems: A Guide for Practitioners. AB - Clinicians play an important role in diagnosing problem behaviors as a precursor to treating them. This requires a protocol for gathering historical behavioral and health information, direct observation and examination of the animal, and a broad knowledge base of medical and behavioral differential diagnoses for those findings. Aggression and anxiety are the most commonly reported behavior problems in dogs. In cats, elimination problems and aggression are the most prevalent. Other important diagnoses for these species are cognitive dysfunction and abnormal repetitive behaviors. PMID- 29429601 TI - Managing Canine Aggression in the Home. AB - Canine aggression occurring in the home can be a dangerous diagnosis with costly consequences to all members of the household. Management is a key modality in the treatment of canine aggression in the home. A thorough history will detail each trigger, target, and context and allow for the veterinary team to put together a comprehensive management plan. Management allows for the avoidance of future aggressive episodes and minimizes the risks associated with living with a patient with these diagnoses. Although risk cannot be mitigated 100%, thorough management can create a safe environment for the implementation of the behavior treatment plan. PMID- 29429603 TI - Saturation reduces in-vitro leakage of monomers from composites. AB - OBJECTIVE: Accurate knowledge of the quantity of released monomers from composites is important. To evaluate the elution of monomers, polymerized composites are typically immersed in an extraction solvent. The objective was to determine whether the volume of extraction solvent and the immersion time influences monomer leachability from dental composite materials. METHODS: Composite disks of two commercial composites, (Filtek Supreme XTE, 3M ESPE and G aenial Universal Flo, GC) were prepared. The disks (n=10) were placed in a glass vial with 1ml, 2ml or 3ml of extraction solvent (100% ethanol with deuterated diethylphalate as internal standard). After either 7 or 30 days at 37 degrees C, the supernatant was collected and the amount of released monomers (BisEMA, BisGMA, UDMA, TEGDMA) and bisphenol A was measured with liquid chromatography mass spectroscopy. RESULTS: For both tested composites, the highest amount of released monomers was measured after sample incubation in 3ml, while the lowest amount was measured in 1ml of extraction solvent. Furthermore, 30 days did not result in much more monomer release compared to 7 days, and for most monomers, there was no statistically significant difference in release between 7 and 30 days. SIGNIFICANCE: Release kinetics in in-vitro experiments are also influenced by saturation of the extraction solvent with the leached monomers. This is important as it is unlikely that saturation can be reached in an in-vivo situation, where saliva (or pulpal fluid) is continuously refreshed. Saturation of the extraction solvent can be avoided in-vitro by refreshing the extraction medium after equal time intervals. PMID- 29429602 TI - [Characteristics and health status of homeless women born in France and abroad: Results of Insee-Ined 2012 survey]. AB - BACKGROUND: French national surveys among the homeless population in 2001 and 2012 provided a general description of the homeless beneficiaries of medical and social aids. However, given the increasing number of women in this population, mostly born abroad and accompanied by their children, a descriptive study of homeless women according to the fact of being born in France or abroad was conducted. METHODS: A probability sample of 1470 French-speaking homeless women was recruited for the Insee-Ined 2012 survey. Socio-demographic characteristics, life trajectories, work and employment over the last 12 months, perceived health, reported morbidity, use of care and medical coverage have been described, comparing homeless women born abroad with those born in France. RESULTS: Homeless women are young (median age=34 y.), often single (55%), without a partner (71%) and often accompanied by children (52%). The vast majority (60%) reported no salary during the previous 12 months. Housing conditions were less precarious in women born in France, but these women had a more difficult life history, a more unfavorable perception of their health status, and a higher frequency of chronic health problems. Homeless women born abroad seemed to have more precarious conditions of life and more difficulties to access aids and medical coverage. Overall, despite a relatively good availability of medical insurance, homeless women, regardless of the place of birth, often reported health problems, which were not treated. CONCLUSION: This study suggests that homeless women often have to deal with chronic health problems that are not treated. Homeless women born abroad are characterized by more precarious living conditions that women born in France. Although younger, with an overall favorable perception of their health and declaring less often an addiction, their general state of health appears to be as fragile as for women born in France. Actions towards homeless women should be implemented to promote their access to care. PMID- 29429604 TI - The declaration of authors' conflict of interests must obey rules. PMID- 29429605 TI - E-cigarette and Smokeless Tobacco Use and Switching Among Smokers: Findings From the National Adult Tobacco Survey. AB - INTRODUCTION: Assessing the extent that cigarette smokers use or switch to e cigarettes and smokeless tobacco can help inform the population health impact of these products. This study estimated the prevalence of e-cigarette and smokeless tobacco use and switching among current and recent former adult cigarette smokers. METHODS: Data from the 2012-2013 (n=8,891) and 2013-2014 (n=11,379) National Adult Tobacco Survey were analyzed in 2016. Response rates for this telephone survey were 44.9% and 36.1%, respectively. Tobacco product use was assessed by smoking status. RESULTS: Current e-cigarette use increased for all groups, with a greater increase among recent quitters, 9.1% (95% CI=7.1%, 11.1%) in 2012-2013 and 15.8% (95% CI=13.7%, 17.9%) in 2013-2014, than smokers with an unsuccessful quit attempt, 10.4% (95% CI=9.1%, 11.7%) in 2012-2013 and 14.8% (95% CI=13.5%, 16.1%) in 2013-2014, or smokers with no quit attempt, 5.9% (95% CI=4.8%, 6.9%) in 2012-2013 and 10.7% (95% CI=9.4%, 12.0%) in 2013-2014. Between 2012-2013 and 2013-2014, current use of smokeless tobacco remained steady for recent quitters (4.6% to 4.7%, p=0.92) and smokers with no quit attempt (4.0% to 4.3%, p=0.97), and decreased in smokers with an unsuccessful quit attempt (5.7% to 3.8%, p=0.004). More recent quitters completely switched to e-cigarettes in the past year (15.3% in 2012-2013, 25.7% in 2013-2014) than to smokeless tobacco (4.6% in 2012-2013, 4.5% in 2013-2014). CONCLUSIONS: Current and recent former adult smokers are more likely to use e-cigarettes than smokeless tobacco. Current e-cigarette use was most prevalent among unsuccessful quitters and recent quitters, who were substantially more likely to report complete switching to e cigarettes than smokeless tobacco. PMID- 29429606 TI - Challenges Implementing Lung Cancer Screening in Federally Qualified Health Centers. AB - INTRODUCTION: The purpose of this study is to identify issues faced by Federally Qualified Health Centers (FQHCs) in implementing lung cancer screening in low resource settings. METHODS: Medical directors of 258 FQHCs serving communities with tobacco use prevalence above the median of all 1,202 FQHCs nationally were sampled to participate in a web-based survey. Data were collected between August and October 2016. Data analysis was completed in June 2017. RESULTS: There were 112 (43%) FQHC medical directors or surrogates who responded to the 2016 survey. Overall, 41% of respondents were aware of a lung cancer screening program within 30 miles of their system's largest clinic. Although 43% reported that some providers in their system offer screening, it was typically at a very low volume (less than ten/month). Although FQHCs are required to collect tobacco use data, only 13% indicated that these data can identify patients eligible for screening. Many FQHCs reported important patient financial barriers for screening, including lack of insurance (72%), preauthorization requirements (58%), and out-of-pocket cost burdens for follow-up procedures (73%). Only 51% indicated having adequate access to specialty providers to manage abnormal findings, and few reported that leadership had either committed resources to lung cancer screening (12%) or prioritized lung cancer screening (12%). CONCLUSIONS: FQHCs and other safety-net clinics, which predominantly serve low-socioeconomic populations with high proportions of smokers eligible for lung cancer screening, face significant economic and resource challenges to implementing lung cancer screening. Although these vulnerable patients are at increased risk for lung cancer, reducing patient financial burdens and appropriately managing abnormal findings are critical to ensure that offering screening does not inadvertently lead to harm and increase disparities. PMID- 29429607 TI - Using Behavioral Analytics to Increase Exercise: A Randomized N-of-1 Study. AB - INTRODUCTION: This intervention study used mobile technologies to investigate whether those randomized to receive a personalized "activity fingerprint" (i.e., a one-time tailored message about personal predictors of exercise developed from 6 months of observational data) increased their physical activity levels relative to those not receiving the fingerprint. STUDY DESIGN: A 12-month randomized intervention study. SETTING/PARTICIPANTS: From 2014 to 2015, 79 intermittent exercisers had their daily physical activity assessed by accelerometry (Fitbit Flex) and daily stress experience, a potential predictor of exercise behavior, was assessed by smartphone. INTERVENTION: Data collected during the first 6 months of observation were used to develop a person-specific "activity fingerprint" (i.e., N-of-1) that was subsequently sent via email on a single occasion to randomized participants. MAIN OUTCOME MEASURES: Pre-post changes in the percentage of days exercised were analyzed within and between control and intervention groups. RESULTS: The control group significantly decreased their proportion of days exercised (10.5% decrease, p<0.0001) following randomization. By contrast, the intervention group showed a nonsignificant decrease in the proportion of days exercised (4.0% decrease, p=0.14). Relative to the decrease observed in the control group, receipt of the activity fingerprint significantly increased the likelihood of exercising in the intervention group (6.5%, p=0.04). CONCLUSIONS: This N-of-1 intervention study demonstrates that a one-time brief message conveying personalized exercise predictors had a beneficial effect on exercise behavior among urban adults. PMID- 29429608 TI - Technological strategies to overcome the mucus barrier in mucosal drug delivery. PMID- 29429609 TI - Rising time restoration for nuclear pulse using a mathematic model. AB - The rising time of a nuclear pulse is slowed before being digitized because of the effect of distributed capacitance and resistance. This results in the waveform distortion of a shaped pulse. In this study, the effect of distributed capacitance and resistance is equivalent to the result of RC network. The mathematical model of the network is established to restore the rising time of the input nuclear pulse. Experimental results show that the leading edge of the nuclear pulse becomes steep after rising time restoration, and the shape of the shaped pulse is also improved. The energy spectrum obtained with rising time restoration is compared with that without rising time restoration. The comparison result indicates that using rising time restoration can extend the measurement range of pulse amplitude without affecting the energy resolution of the system. PMID- 29429610 TI - Automated ultrafast kilovoltage-megavoltage cone-beam CT for image guided radiotherapy of lung cancer: System description and real-time results. AB - PURPOSE: To establish a fully automated kV-MV CBCT imaging method on a clinical linear accelerator that allows image acquisition of thoracic targets for patient positioning within one breath-hold (~15s) under realistic clinical conditions. METHODS AND MATERIALS: Our previously developed FPGA-based hardware unit which allows synchronized kV-MV CBCT projection acquisition is connected to a clinical linear accelerator system via a multi-pin switch; i.e. either kV-MV imaging or conventional clinical mode can be selected. An application program was developed to control the relevant linac parameters automatically and to manage the MV detector readout as well as the gantry angle capture for each MV projection. The kV projections are acquired with the conventional CBCT system. GPU-accelerated filtered backprojection is performed separately for both data sets. After appropriate grayscale normalization both modalities are combined and the final kV MV volume is re-imported in the CBCT system to enable image matching. To demonstrate adequate geometrical accuracy of the novel imaging system the Penta Guide phantom QA procedure is performed. Furthermore, a human plastinate and different tumor shapes in a thorax phantom are scanned. Diameters of the known tumor shapes are measured in the kV-MV reconstruction. RESULTS: An automated kV MV CBCT workflow was successfully established in a clinical environment. The overall procedure, from starting the data acquisition until the reconstructed volume is available for registration, requires ~90s including 17s acquisition time for 100 degrees rotation. It is very simple and allows target positioning in the same way as for conventional CBCT. Registration accuracy of the QA phantom is within +/-1mm. The average deviation from the known tumor dimensions measured in the thorax phantom was 0.7mm which corresponds to an improvement of 36% compared to our previous kV-MV imaging system. CONCLUSIONS: Due to automation the kV-MV CBCT workflow is speeded up by a factor of >10 compared to the manual approach. Thus, the system allows a simple, fast and reliable imaging procedure and fulfills all requirements to be successfully introduced into the clinical workflow now, enabling single-breath-hold volume imaging. PMID- 29429611 TI - Associations of multiple plasma metals with incident type 2 diabetes in Chinese adults: The Dongfeng-Tongji Cohort. AB - The long-term associations between multiple metals and incident diabetes are uncertain. We aimed to examine the relationship between plasma concentrations of 23 metals and the incidence of type 2 diabetes among Chinese senior adults. We quantified fasting plasma concentrations of 23 metals by inductively coupled plasma mass spectrometry among 1039 incident diabetes cases and 1039 controls (age and sex matched) nested in a prospective study, the Dongfeng-Tongji cohort. Both cases and controls were free of diabetes at baseline (2008-2010), incident diabetes were identified using the following criteria: fasting glucose >= 7.0 mmoL/l; or hemoglobin A1c (HbA1c) >= 6.5%; or self-reported physician diagnosis of diabetes or use of anti-diabetic medication during the follow-up visits in 2013. In the conditional logistic regression models, the multivariable adjusted ORs (95% CIs) of diabetes across quartiles (Q1-Q4) of metal concentrations were as follows: titanium, 1.00, 0.92, 1.31, 1.38 (1.00-1.91, Ptrend = 0.011); selenium, 1.00, 1.08, 1.45, 1.27 (0.93-1.74, Ptrend = 0.05); and antimony, 1.00, 0.79, 0.77, 0.60 (0.44-0.83, Ptrend = 0.002). Arsenic was significantly associated with diabetes in the crude model (ORs comparing extreme quartiles 1.30; 1.02-1.65; Ptrend = 0.006), but was not significant after adjustment for socio-demographic factors. No significant associations were found for other metals. In conclusion, titanium and selenium were positively while antimony was negatively associated with incident diabetes. PMID- 29429612 TI - The Effect of Lenalidomide on Health-Related Quality of Life in Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes: Results From the MDS-005 Study. AB - BACKGROUND: The phase III MDS-005 study compared lenalidomide versus placebo in red blood cell transfusion-dependent (RBC-TD) patients with lower-risk non del(5q) myelodysplastic syndromes (MDS), ineligible/refractory to erythropoiesis stimulating agents. Lenalidomide-treated patients were more likely to achieve transfusion independence (TI) >= 8 weeks (26.9% vs. 2.5%; P < .001) and hemoglobin increase >= 1.5 g/dL (19.4% vs. 2.5%) versus placebo. PATIENTS AND METHODS: Patients were randomized 2:1 to oral lenalidomide 10 mg once daily or placebo once daily (both on 28-day cycles). Patients with creatinine clearance 40 to 60 mL/min were given lenalidomide 5 mg once daily. Health-related quality of life (HRQoL), a predefined secondary end point, was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 questionnaire at baseline, week 12, week 24, every 12 weeks thereafter, and at discontinuation. RESULTS: At week 24, lenalidomide was associated with benefit versus placebo across all 5 preselected questionnaire scales (fatigue, dyspnea, global quality of life, physical functioning, and emotional functioning). After adjustment for baseline scores, only emotional functioning achieved significance (P = .047). Further improvement versus baseline was observed for patients who continued lenalidomide after week 24. In post hoc analyses, achievement of TI >= 8 weeks was associated with significant improvements across all scales (P < .01); an increase in hemoglobin level correlated with significant improvements in all scales at week 24, except emotional functioning (P < .05). CONCLUSION: Lenalidomide did not adversely affect HRQoL in RBC-TD patients with lower-risk non-del(5q) MDS and response to lenalidomide was associated with significant improvements in HRQoL. PMID- 29429613 TI - Self-Control in Chimpanzees Relates to General Intelligence. AB - For humans, there appears to be a clear link between general intelligence and self-control behavior, such as sustained delay of gratification [1-9]. Chimpanzees also delay gratification [10-12] and can be given tests of general intelligence (g) [13-15], but these two constructs have never been compared within the same sample of nonhuman animals. We presented 40 chimpanzees with the hybrid delay task (HDT) [16, 17], which measures inter-temporal choices and the capacity for sustained delay of gratification, and the primate cognitive test battery (PCTB), which measures g in chimpanzees [13-15]. Importantly, none of the sub-tasks in the PCTB directly assesses self-control or other forms of behavioral inhibition. Rather, they assess areas of physical cognition (e.g., quantity discrimination) or social cognition (e.g., gaze following). In three phases of testing, we consistently found that the strongest relation was between chimpanzee g scores and efficiency in the HDT. Chimpanzee g was not most closely related to the proportion of trials the chimpanzees chose to try to wait for delayed rewards, but rather most closely related to how good they were at waiting for those rewards when they chose to do so. We also found the same strong relation between HDT efficiency and those factors in the PCTB that loaded most strongly on chimpanzee g. These results highlight that, as with humans, there is a strong relation between chimpanzees' self-control and overall intelligence-a relation that likely reflects the role of successful inhibitory control during cognitive processing of information and intelligent decision-making. PMID- 29429614 TI - Inversely Active Striatal Projection Neurons and Interneurons Selectively Delimit Useful Behavioral Sequences. AB - Understanding neural representations of behavioral routines is critical for understanding complex behavior in health and disease. We demonstrate here that accentuated activity of striatal projection neurons (SPNs) at the beginning and end of such behavioral repertoires is a supraordinate representation specifically marking previously rewarded behavioral sequences independent of the individual movements making up the behavior. We recorded spike activity in the striatum and primary motor cortex as individual rats learned specific rewarded lever-press sequences, each one unique to a given rat. Motor cortical neurons mainly responded in relation to specific movements regardless of their sequence of occurrence. By contrast, striatal SPN populations in each rat fired preferentially at the initiation and termination of its acquired sequence. Critically, the SPNs did not exhibit this bracketing signal when the same rats performed unreinforced sequences containing the same sub-movements that were present in their acquired sequence. Thus, the SPN activity was specifically related to a given repetitively reinforced movement sequence. This striatal beginning-and-end activity did not appear to be dependent on motor cortical inputs. However, strikingly, simultaneously recorded fast-spiking striatal interneurons (FSIs) showed equally selective but inverse firing patterns: they fired in between the initiation and termination of the acquired sequences. These findings suggest that the striatum contains networks of neurons representing acquired sequences of behavior at a level of abstraction higher than that of the individual movements making up the sequence. We propose that such SPN-FSI networks of the striatum could underlie the acquisition of chunked behavioral units. PMID- 29429615 TI - Sexually Dimorphic unc-6/Netrin Expression Controls Sex-Specific Maintenance of Synaptic Connectivity. AB - Nervous systems display intriguing patterns of sexual dimorphisms across the animal kingdom, but the mechanisms that generate such dimorphisms remain poorly characterized. In the nematode Caenorhabditis elegans, a number of neurons present in both sexes are synaptically connected to one another in a sexually dimorphic manner as a result of sex-specific synaptic pruning and maintenance [1 3]. We define here a mechanism for the male-specific maintenance of the synaptic connections of the phasmid sensory neuron PHB and its male-specific target, the sex-shared AVG interneuron. We show that the C. elegans Netrin ortholog UNC-6, signaling through its cognate receptor UNC-40/DCC and the CED-5/DOCK180 guanine nucleotide exchange factor, is both required and sufficient for male-specific synaptic maintenance. The dimorphism of unc-6 activity is brought about by sex specific regulation of unc-6 transcription. Although unc-6 is transcribed in the AVG neuron of males and hermaphrodites during juvenile stages, unc-6 expression is downregulated in AVG in hermaphrodites during sexual maturation but is maintained during sexual maturation of males. unc-6 downregulation in hermaphrodites is conferred by the master regulator of hermaphrodite sexual identity, the Gli/CI homolog TRA-1, which antagonizes the non-sex-specific function of the LIM homeobox gene lin-11, a terminal selector and activator of unc-6 in AVG. Preventing the downregulation of unc-6 in AVG of hermaphrodites through ectopic expression of unc-6 in transgenic animals results in the maintenance of the PHB>AVG synapses in hermaphrodites. Taken together, intersectional transcriptional regulation of unc-6/Netrin is required and sufficient to cell autonomously pattern sexually dimorphic synapses. PMID- 29429616 TI - A Novel Form of Stereo Vision in the Praying Mantis. AB - Stereopsis is the ability to estimate distance based on the different views seen in the two eyes [1-5]. It is an important model perceptual system in neuroscience and a major area of machine vision. Mammalian, avian, and almost all machine stereo algorithms look for similarities between the luminance-defined images in the two eyes, using a series of computations to produce a map showing how depth varies across the scene [3, 4, 6-14]. Stereopsis has also evolved in at least one invertebrate, the praying mantis [15-17]. Mantis stereopsis is presumed to be simpler than vertebrates' [15, 18], but little is currently known about the underlying computations. Here, we show that mantis stereopsis uses a fundamentally different computational algorithm from vertebrate stereopsis-rather than comparing luminance in the two eyes' images directly, mantis stereopsis looks for regions of the images where luminance is changing. Thus, while there is no evidence that mantis stereopsis works at all with static images, it successfully reveals the distance to a moving target even in complex visual scenes with targets that are perfectly camouflaged against the background in terms of texture. Strikingly, these insects outperform human observers at judging stereoscopic distance when the pattern of luminance in the two eyes does not match. Insect stereopsis has thus evolved to be computationally efficient while being robust to poor image resolution and to discrepancies in the pattern of luminance between the two eyes. VIDEO ABSTRACT. PMID- 29429617 TI - Spatial Receptive Fields for Odor Localization. AB - Animals rely on olfaction to navigate through complex olfactory landscapes, but the mechanisms that allow an animal to encode the spatial structure of an odorous environment remain unclear. To acquire information about the spatial distribution of an odorant, animals may rely on bilateral olfactory organs and compare side differences of odor intensity and timing [1-6] or may perform spatial and temporal signal integration of subsequent samplings [7]. The American cockroach can efficiently locate a source of sex pheromone even after the removal of one antenna, suggesting that bilateral comparison is not a prerequisite for odor localization in this species [8, 9]. Cognate olfactory sensory neurons (OSNs) originating from different locations on the flagellum, but bearing the same olfactory receptor, converge onto the same glomerulus within the antennal lobe, which is thought to result in a loss of spatial information. Here, we identified 12 types of pheromone-responsive projection neurons (PNs), each with spatially tuned receptive field. The combination of (1) the antennotopic organization of OSNs terminals and (2) the stereotyped compartmentalization of PNs' dendritic arborization within the macroglomerulus (MG), allows encoding the spatial position of the pheromone. Furthermore, each PN type innervates a different compartment of the mushroom body, providing the means for encoding spatial olfactory information along the olfactory circuit. Finally, MG PNs exhibit both excitatory and inhibitory spatial receptive fields and modulate their responses based on changes in stimulus geometry. In conclusion, we propose a mechanism for encoding information on the spatial distribution of a pheromone, expanding both our understanding of odor coding and of the strategies insects adopt to localize a sexual mate. PMID- 29429620 TI - Evidence for Myelin Sheath Remodeling in the CNS Revealed by In Vivo Imaging. AB - The length of myelin sheaths affects conduction speed along axons and information propagation. It has recently become clear that myelin may be adaptively modified to modulate circuit function, implying that length remodeling of myelin sheaths should occur. However, direct evidence for such events is lacking. We have investigated how myelination patterns are formed, maintained, and remodeled using long-term imaging and myelin ablation in zebrafish. We demonstrate that length differences between myelin sheaths are established by rapid and variable growth within 3 days after their formation, independently of their time of formation, and even along discontinuously myelinated axons. Afterward, sheaths continue extending at similar rates to compensate for overall animal growth. In consequence, once axon myelination patterns are established, they are maintained over long periods of time. We tested whether mature myelin sheaths can remodel by removing individual sheaths from single axons by targeted ablation. Remarkably, extensive changes in sheath length and number occurred, which frequently restored the original myelination pattern. Our results show that axons can control myelin growth and remodeling, and we provide evidence for a homeostatic control of axon myelination patterns by maintenance and remodeling of myelin sheath length, with implications for circuit development, function, and repair. PMID- 29429618 TI - Hidden Complexity of Yeast Adaptation under Simple Evolutionary Conditions. AB - Few studies have "quantitatively" probed how adaptive mutations result in increased fitness. Even in simple microbial evolution experiments, with full knowledge of the underlying mutations and specific growth conditions, it is challenging to determine where within a growth-saturation cycle those fitness gains occur. A common implicit assumption is that most benefits derive from an increased exponential growth rate. Here, we instead show that, in batch serial transfer experiments, adaptive mutants' fitness gains can be dominated by benefits that are accrued in one growth cycle, but not realized until the next growth cycle. For thousands of evolved clones (most with only a single mutation), we systematically varied the lengths of fermentation, respiration, and stationary phases to assess how their fitness, as measured by barcode sequencing, depends on these phases of the growth-saturation-dilution cycles. These data revealed that, whereas all adaptive lineages gained similar and modest benefits from fermentation, most of the benefits for the highest fitness mutants came instead from the time spent in respiration. From monoculture and high-resolution pairwise fitness competition experiments for a dozen of these clones, we determined that the benefits "accrued" during respiration are only largely "realized" later as a shorter duration of lag phase in the following growth cycle. These results reveal hidden complexities of the adaptive process even under ostensibly simple evolutionary conditions, in which fitness gains can accrue during time spent in a growth phase with little cell division, and reveal that the memory of those gains can be realized in the subsequent growth cycle. PMID- 29429619 TI - First-Pass Processing of Value Cues in the Ventral Visual Pathway. AB - Real-world value often depends on subtle, continuously variable visual cues specific to particular object categories, like the tailoring of a suit, the condition of an automobile, or the construction of a house. Here, we used microelectrode recording in behaving monkeys to test two possible mechanisms for category-specific value-cue processing: (1) previous findings suggest that prefrontal cortex (PFC) identifies object categories, and based on category identity, PFC could use top-down attentional modulation to enhance visual processing of category-specific value cues, providing signals to PFC for calculating value, and (2) a faster mechanism would be first-pass visual processing of category-specific value cues, immediately providing the necessary visual information to PFC. This, however, would require learned mechanisms for processing the appropriate cues in a given object category. To test these hypotheses, we trained monkeys to discriminate value in four letter-like stimulus categories. Each category had a different, continuously variable shape cue that signified value (liquid reward amount) as well as other cues that were irrelevant. Monkeys chose between stimuli of different reward values. Consistent with the first-pass hypothesis, we found early signals for category-specific value cues in area TE (the final stage in monkey ventral visual pathway) beginning 81 ms after stimulus onset-essentially at the start of TE responses. Task-related activity emerged in lateral PFC approximately 40 ms later and consisted mainly of category-invariant value tuning. Our results show that, for familiar, behaviorally relevant object categories, high-level ventral pathway cortex can implement rapid, first-pass processing of category-specific value cues. PMID- 29429621 TI - Rampant Host Switching Shaped the Termite Gut Microbiome. AB - The gut microbiota of animals exert major effects on host biology [1]. Although horizontal transfer is generally considered the prevalent route for the acquisition of gut bacteria in mammals [2], some bacterial lineages have co speciated with their hosts on timescales of several million years [3]. Termites harbor a complex gut microbiota, and their advanced social behavior provides the potential for long-term vertical symbiont transmission, and co-evolution of gut symbionts and host [4-6]. Despite clear evolutionary patterns in the gut microbiota of termites [7], a consensus on how microbial communities were assembled during termite diversification has yet to be reached. Although some studies have concluded that vertical transmission has played a major role [8, 9], others indicate that diet and gut microenvironment have been the primary determinants shaping microbial communities in termite guts [7, 10]. To address this issue, we examined the gut microbiota of 94 termite species, through 16S rRNA metabarcoding. We analyzed the phylogeny of 211 bacterial lineages obtained from termite guts, including their closest relatives from other environments, which were identified using BLAST. The results provided strong evidence for rampant horizontal transfer of gut bacteria between termite host lineages. Although the majority of termite-derived phylotypes formed large monophyletic groups, indicating high levels of niche specialization, numerous other clades were interspersed with bacterial lineages from the guts of other animals. Our results indicate that "mixed-mode" transmission, which combines colony-to offspring vertical transmission with horizontal colony-to-colony transfer, has been the primary driving force shaping the gut microbiota of termites. PMID- 29429622 TI - Step length determines minimum toe clearance in older adults and people with Parkinson's disease. AB - Reduced foot clearance when walking may increase the risk of trips and falls in people with Parkinson's disease (PD). Changes in foot clearance in people with PD are likely to be associated with temporal-spatial characteristics of gait such as walking slowly which evokes alterations in the temporal-spatial control of stepping patterns. Enhancing our understanding of the temporal-spatial determinants of foot clearance may inform the design of falls prevention therapies. Thirty-six people with PD and 38 age-matched controls completed four intermittent walks under two conditions: self-selected and fast gait velocity. Temporal-spatial characteristics of gait and foot (heel and toe) clearance outcomes were obtained using an instrumented walkway and 3D motion capture, respectively. A general linear model was used to quantify the effect of PD and gait velocity on gait and foot clearance. Regression evaluated the temporal and spatial gait predictors of minimum toe clearance (MTC). PD walked slower regardless of condition (p = .016) and tended to increase their step length to achieve a faster gait velocity. Step length and the walk ratio consistently explained the greatest proportion of variance in MTC (>28% and >33%, respectively) regardless of group or walking condition (p < .001). Our results suggest step length is the primary determinant of MTC regardless of pathology. Interventions that focus on increasing step length may help to reduce the risk of trips and falls during gait, however, clinical trials are required for robust evaluation. PMID- 29429623 TI - 2nd international workshop on spinal loading and deformation. PMID- 29429625 TI - Continuing the search for mutational drivers in esophageal adenocarcinoma. PMID- 29429626 TI - Making computed tomographic screening accessible for all. PMID- 29429627 TI - Discussion. PMID- 29429628 TI - Discussion. PMID- 29429624 TI - Macrophages and lipid metabolism. AB - Distinct macrophage populations throughout the body display highly heterogeneous transcriptional and epigenetic programs. Recent research has highlighted that these profiles enable the different macrophage populations to perform distinct functions as required in their tissue of residence, in addition to the prototypical macrophage functions such as in innate immunity. These 'extra' tissue-specific functions have been termed accessory functions. One such putative accessory function is lipid metabolism, with macrophages in the lung and liver in particular being associated with this function. As it is now appreciated that cell metabolism not only provides energy but also greatly influences the phenotype and function of the cell, here we review how lipid metabolism affects macrophage phenotype and function and the specific roles played by macrophages in the pathogenesis of lipid-related diseases. In addition, we highlight the current questions limiting our understanding of the role of macrophages in lipid metabolism. PMID- 29429629 TI - Matrix metalloproteinase 12 promotes tumor propagation in the lung. AB - OBJECTIVE: Past studies are inconsistent with regard to the role of matrix metalloproteinase 12 in lung tumorigenesis. This is due, in part, to differential tumorigenesis based on tumor-derived versus immune-derived matrix metalloproteinase 12 expression. Our study aims to thoroughly dissect the role of matrix metalloproteinase 12 in lung tumorigenesis. METHODS: We tested matrix metalloproteinase 12 expression and the association with prognosis using a tissue array and a published non-small cell lung cancer gene expression database. In addition, we characterized the contribution of matrix metalloproteinase 12 to tumor propagation in the lung using a series of in vitro and in vivo studies. RESULTS: Tumor cells of a diverse set of human lung cancers stained positive for matrix metalloproteinase 12, and high matrix metalloproteinase 12 mRNA levels in the tumor were associated with reduced survival. The lung microenvironment stimulated endogenous production of matrix metalloproteinase 12 in lung cancer cells (human 460 lung cancer cell line, Lewis lung carcinoma). In vitro, matrix metalloproteinase 12 knockout Lewis lung carcinoma and Lewis lung carcinoma cells had the same proliferation rate, but Lewis lung carcinoma showed increased invasiveness. In vivo, deficiency of matrix metalloproteinase 12 in Lewis lung carcinoma cells, but not in the host, reduced tumor growth and invasiveness. CONCLUSIONS: We suggest that tumor cell-derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target. PMID- 29429631 TI - Sequential injection of radioactive nanosized colloids followed by indocyanine green for sentinel lymph node detection in oral squamous cell carcinoma: A proof of concept. PMID- 29429630 TI - Transcatheter aortic valve replacement in patients with severe mitral or tricuspid regurgitation at extreme risk for surgery. AB - OBJECTIVES: Patients with symptomatic severe aortic stenosis and severe mitral regurgitation or severe tricuspid regurgitation were excluded from the major transcatheter aortic valve replacement trials. We studied these 2 subgroups in patients at extreme risk for surgery in the prospective, nonrandomized, single arm CoreValve US Expanded Use Study. METHODS: The primary end point was all-cause mortality or major stroke at 1 year. A favorable medical benefit was defined as a Kansas City Cardiomyopathy Questionnaire overall summary score greater than 45 at 6 months and greater than 60 at 1 year and with a less than 10-point decrease from baseline. RESULTS: There were 53 patients in each group. Baseline characteristics for the severe mitral regurgitation and severe tricuspid regurgitation cohorts were age 84.2 +/- 6.4 years and 84.9 +/- 6.5 years; male, 29 (54.7%) and 22 (41.5%), and mean Society of Thoracic Surgeons score 9.9% +/- 5.0% and 9.2% +/- 4.0%, respectively. Improvement in valve regurgitation from baseline to 1 year occurred in 72.7% of the patients with severe mitral regurgitation and in 61.8% of patients with severe tricuspid regurgitation. A favorable medical benefit occurred in 31 of 47 patients (66.0%) with severe mitral regurgitation and 33 of 47 patients (70.2%) with severe tricuspid regurgitation at 6 months, and in 25 of 44 patients (56.8%) with severe mitral regurgitation and 24 of 45 patients (53.3%) with severe tricuspid regurgitation at 1 year. All-cause mortality or major stroke for the severe mitral regurgitation and severe tricuspid regurgitation cohorts were 11.3% and 3.8% at 30 days and 21.0% and 19.2% at 1 year, respectively. There were no major strokes in either group at 1 year. CONCLUSIONS: Transcatheter aortic valve replacement in patients with severe mitral regurgitation or severe tricuspid regurgitation is reasonable and safe and leads to improvement in atrioventricular valve regurgitation. PMID- 29429632 TI - Bowman Birk Inhibitors (BBI) in interception of inflammation and malignant transformation of OPMDs. PMID- 29429634 TI - Central leptin and autonomic regulation: A melanocortin business. PMID- 29429633 TI - NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. AB - Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE2 for immune evasion and that could be exploited for cancer therapy. PMID- 29429635 TI - Clinical findings after bioresorbable vascular scaffold implantation in an unrestricted cohort of patients with ST-segment elevation myocardial infarction (from the RAI registry). AB - BACKGROUND: The bioresorbable vascular scaffold (BVS) technology may be an appealing option in ST-segment elevation myocardial infarction (STEMI) patients. However, the available evidence on its use in this challenging subset is limited. METHODS: Registro Absorb Italiano (RAI) is a multicenter, prospective registry that aims to assess BVS performance through a 5-year follow-up of all consecutive patients who undergone at least 1 successful BVS implantation. As a part of it, a subgroup analysis in STEMI patients was performed and the outcomes of this cohort compared to the remaining population (defined as "non-STEMI") are reported here. RESULTS: Among the 1505 patients enrolled, 317 (21.1%) had STEMI on admission. Among those, 232 (73.2%) underwent primary percutaneous coronary intervention (PCI) within 12 h from symptom onset; 64 (20.2%) were late-comers (>12 h); 16 (5%) underwent PCI after successful thrombolysis while 5 (1.6%) underwent rescue PCI. At a median follow-up time of 12 months (IQR 6-20 months) no differences were noticed between STEMI and "non-STEMI" groups in terms of device-oriented composite endpoint (4.1% vs. 5.6%; p = 0.3) and its singular components: ischemia driven target lesion revascularization (3.2% vs. 3.6%; p = 0.7), target-vessel myocardial infarction (3.2% vs. 2.8%; p = 0.7) and cardiac death (0.6% vs. 0.6%; p = 0.9). The rate of definite/probable scaffold thrombosis (ScT) was numerically higher but not significant in the STEMI group (2.5% vs. 1.3%; p = 0.1). CONCLUSIONS: BVS implantation in an unrestricted cohort of STEMI patients is associated with a numerically higher rate of ScT compared to the non-STEMI group. Further studies exploring the potential clinical impact of a pre-specified BVS implantation strategy in this high-risk clinical setting are needed. PMID- 29429637 TI - Coronary microembolization and microvascular dysfunction. AB - Plaque erosion, fissuring or rupture occurs spontaneously or during coronary interventions. At some residual blood flow, the atherothrombotic debris is washed into the coronary microcirculation, causing physical obstruction, vasoconstriction, inflammation and ultimately microinfarction. Coronary microembolization also contributes to microvascular obstruction in reperfused acute myocardial infarction. Patients with microvascular obstruction after reperfused myocardial infarction have worse prognosis. Cardioprotective strategies to avoid acute coronary microembolization and rescue myocardium from microvascular obstruction have not yet been established in clinical practice. Subclinical coronary microembolization together with release of thrombogenic, vasoconstrictor and inflammatory substances from a culprit lesion can sensitize the coronary microcirculation and contribute to angina in the absence of major epicardial coronary obstruction. Repetitive coronary microembolization can induce progressive loss of functional cardiomyocytes and induce heart failure in the absence of overt myocardial infarction. PMID- 29429636 TI - The EXPAND study: Efficacy and safety of rivaroxaban in Japanese patients with non-valvular atrial fibrillation. AB - AIMS: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients >=20 years of age (mean, 71.6 +/- 9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (+/-206.8) days with a high follow-up rate (99.65%). The mean CHADS2 score at baseline was 2.1 (1.3) (0-1, 37%; 2, 29%; >=3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS2 scores of 0-1, 2, and >=3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0 1 CHADS2), as shown for warfarin in the XANTUS international prospective post marketing study. CONCLUSIONS: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS2 scores 0-1, resulted in low rates of stroke and SE, and major and non-major bleeding. PMID- 29429638 TI - Association between intraoperative hypotension and 30-day mortality, major adverse cardiac events, and acute kidney injury after non-cardiac surgery: A meta analysis of cohort studies. AB - BACKGROUND: The association between intraoperative hypotension (IOH) and postoperative outcomes is not fully understood. We performed a meta-analysis to determine whether IOH is associated with increased risk of 30-day mortality, major adverse cardiac events (MACEs) and acute kidney injury (AKI) after non cardiac surgery. METHODS: We searched PubMed and Embase through May 2016 to identify cohort studies that investigated the association between IOH and risk of 30-day mortality, MACEs, or AKI in adult patients after non-cardiac surgery. Ascertainment of IOH and assessment of outcomes were defined by the individual study. Considering the level of clinical heterogeneity, adjusted odds ratios (ORs) with 95% confidence interval (CIs) were pooled using a random-effects model. This meta-analysis is registered on PROSPERO (CRD42016049405). RESULTS: We included 14 cohort studies that were heterogeneous in terms of definition of IOH. IOH alone was associated with increased risk of 30-day mortality (OR 1.29 [95% CI, 1.19-1.41]), MACEs (OR 1.59 [95% CI, 1.23-2.05]), especially myocardial injury (OR 1.67 [95% CI, 1.31-2.13]), and AKI (OR 1.39 [95% CI, 1.09-1.77]). Triple low (IOH coincident with low bispectral index and low minimum alveolar concentration) also predicts increased risk of 30-day mortality (OR 1.32 [95% CI, 1.03-1.68]). CONCLUSIONS: IOH alone significantly increases the risk of postoperative 30-day mortality, MACEs, especially myocardial injury, and AKI in adult patients after non-cardiac surgery. Triple low also predicts increased risk of 30-day mortality after non-cardiac surgery. These findings provide evidence that IOH should be recognized as an independent risk factor for postoperative adverse outcomes after non-cardiac surgery. PMID- 29429639 TI - Tilt testing and what you should know about it - Experience with 835 consecutive patients with syncope of unknown origin. AB - BACKGROUND: Numerous tilt testing protocols with and without a preceding passive phase or the administration of nitrates have already been investigated. However, a truely standardized method for the investigation does not yet exist. METHODS AND RESULTS: A total of 835 consecutive patients who underwent tilt testing between January 2005 and March 2015 were included in this study. Results of a passive tilt test (PTT), a nitrate-stimulated tilt test (NSTT) with a preceding passive phase of 20 min, or an early nitrate-stimulated tilt test (ENSTT) without a preceding passive phase were compared and analyzed retrospectively in 735 patients. In addition, a further 100 consecutive patients were prospectively randomized 1:1 to compare NSTT and ENSTT. In the retrospective analysis, 38% of the patients in the ENSTT group had a positive test response compared with 45% in the NSTT group and only 27% in the PTT group (p = 0.0002). In the prospective study, 34% of the patients had a positive test response in the ENSTT group compared with 42% in the NSTT group (p = 0.537). The mean duration to a positive test response was significantly shorter in the ENSTT group (retrospective and prospective p < 0.001). The nitrate-stimulated groups did not differ significantly with respect to the hemodynamic characteristics of a positive test response (retrospective: p = 0.773; prospective: p = 0.086). CONCLUSION: Due to the rate of positive test response being comparable to other protocols and its significantly shorter test duration, nitrate-stimulated tilt testing without a preceding passive tilt test may be favored for use in a busy clinical practice. PMID- 29429640 TI - Neurotoxicity of manganese: Indications for future research and public health intervention from the Manganese 2016 conference. AB - Manganese is an essential trace element, but also at high levels a neurotoxicant. Manganese neurotoxicity has been extensively studied since its discovery in highly exposed workers. The International conference MANGANESE2016 held at the Icahn School of Medicine at Mount Sinai in New York provided relevant updates on manganese research in relation to both occupational and environmental exposures. Epidemiological, toxicological and cellular studies reported at the conference have yielded new insights on mechanisms of manganese toxicity and on opportunities for preventive intervention. Strong evidence now exists for causal associations between manganese and both neurodevelopmental and neurodegenerative disorders. The neurodevelopmental effects of early life exposures are an example of the developmental origin of health and disease (DOHAD) concept. Brain imaging has rapidly become an important tool for examining brain areas impacted by manganese at various life stages. Candidate biomarkers of exposure are being identified in hair, nails, and teeth and reflect different exposure windows and relate to different health outcomes. Sex differences were reported in several studies, suggesting that women are more susceptible. New evidence indicates that the transporter genes SLC30A10 and SLC39A8 influence both manganese homeostasis and toxicity. New potential chelation modalities are being developed. PMID- 29429641 TI - Influence of the seasonal variation of environmental conditions on biogas upgrading in an outdoors pilot scale high rate algal pond. AB - The influence of the daily and seasonal variations of environmental conditions on the quality of the upgraded biogas was evaluated in an outdoors pilot scale high rate algal pond (HRAP) interconnected to an external absorption column (AC) via a conical settler. The high alkalinity in the cultivation broth resulted in a constant biomethane composition during the day regardless of the monitored month, while the high algal-bacterial activity during spring and summer boosted a superior biomethane quality. CO2 concentrations in the upgraded biogas ranged from 0.1% in May to 11.6% in December, while a complete H2S removal was always achieved regardless of the month. A limited N2 and O2 stripping from the scrubbing cultivation broth was recorded in the upgraded biogas at a recycling liquid/biogas ratio in the AC of 1. Finally, CH4 concentration in the upgraded biogas ranged from 85.6% in December to 99.6% in August. PMID- 29429642 TI - Reply - Preventing the cheese-wire effect by combining Steri-StripsTM and sutures for the management of lacerations in thin-skinned individuals. January 2017 Volume 70, Issue 1, Pages 134-136. PMID- 29429644 TI - The Canadian Cannabis Act legalizes and regulates recreational cannabis use in 2018. AB - Canada is on the cusp of an unprecedented change in its governmental approach to recreational cannabis consumption. By July of 2018 the country will legalize and regulate recreational cannabis use across the country via the implementation of the Cannabis Act, representing the second country in the world and the first in North America to do so. With almost half of Canadians having admitted to using the drug illegally, this change in policy has been long advocated. While medical cannabis has been legal since 2001 this represents the first time in recent history that recreational cannabis will be legal on a federal level. As the country moves away from criminal prohibition into a framework centered on harm minimization and public health and safety, the policy specifics are being worked out by a variety of stakeholders. With limited peer-reviewed research and similar regulatory schemes to shape the Cannabis Act off of, Canada is entering unchartered territory. As other countries around the world struggle with illegal cannabis consumption, the Canadian example and novel regulatory scheme could prove a useful guiding tool for future policy in other jurisdictions. The following paper discusses key areas to watch and a brief intro of how Canada got to where it is and the foundational need for a shift in policy. PMID- 29429643 TI - Development and validation of impedance-based equations for the prediction of total body water and fat-free mass in children aged 8-11 years. AB - BACKGROUND/OBJECTIVES: Accuracy of impedance analysis depends on population specific prediction equations. The aim of this study was to propose new prediction equations to estimate body composition using impedance analysis for healthy Tunisian children and validate them using the deuterium oxide dilution (D2O) technique. SUBJECTS/METHODS: Body composition was estimated by the Tanita impedance analyzer. The validity of this system was investigated in 134 school children aged between 8 and 11 years. The validity of other published equations was also tested in our sample. Total body water (TBW) and Fat-Free Mass (FFM) were determined using the D2O technique. Participants were divided equally into development (n = 67) and validation groups (n = 67) to develop prediction equation using linear regression models. RESULTS: The comparison between body composition obtained by Tanita system and by D2O technique illustrated a significant difference (p < 0.01). Compared to D2O technique, Tanita impedance analysis underestimates fat mass and overestimates FFM and TBW. The prediction equations for TBW and FFM were developed with sex, age, weight and resistance index as possible predictor variables. The selected equations presented the highest adjusted coefficient of determination (R2), the lowest standard error of the estimate (SEE) value and the lowest p-values. The pure error was 1.263 for the TBW equation and 1.646 for the FFM. The Bland Altman plot illustrated the good level of concordance between the TBW and FFM predicted by the new equations and measured by isotope dilution. CONCLUSIONS: Our study provides valid prediction equations for estimation of TBW, FFM from impedance analysis measures for Tunisian children. These equations are applicable to children aged between 8 and 11 years. PMID- 29429645 TI - Daytime sleepiness in dementia with Lewy bodies is associated with neuronal depletion of the nucleus basalis of Meynert. AB - INTRODUCTION: Excessive daytime sleepiness is a commonly reported clinical feature of dementia with Lewy bodies (DLB) that can occur early in the disease. Cholinergic depletion is known to be severe in DLB, even when dementia severity is mild. The nucleus basalis of Meynert serves as a primary source of cortical acetylcholine, and has a role in facilitating cortical activation and arousal. We sought to determine whether daytime sleepiness at the initial evaluation of patients with DLB was associated with neuronal loss in the nucleus basalis of Meynert. METHODS: Autopsy-confirmed patients who met clinical criteria for probable DLB at their initial evaluation and who were administered the informant completed Epworth Sleepiness Scale were included in the study (n = 40). Each patient had a dementia at baseline (80% with mild severity) and two or more features of parkinsonism, visual hallucinations, fluctuations, or probable REM sleep behavior disorder. Quantitative digital pathology of the nucleus basalis of Meynert was performed in the DLB group and in 20 non-DLB autopsy controls. RESULTS: DLB had greater neuronal depletion in the nucleus basalis of Meynert (p < 0.0001) than pathologic controls. Sleepiness was present in 58% of the DLB group and those with daytime sleepiness had significantly lower neuron counts in the nucleus basalis of Meynert than their non-sleepy counterparts (p = 0.001). Regression modeling revealed that sleepiness was a stronger predictor of neuronal loss in the nucleus basalis of Meynert than visual hallucinations, fluctuations or dementia severity (p = 0.003). CONCLUSIONS: Excessive daytime sleepiness in early DLB is indicative of a more profound loss of basal forebrain cholinergic integrity. PMID- 29429646 TI - A rare cause of orofacial dyskinesias. PMID- 29429647 TI - 4-Hydroxybenzoic acid for multiple system atrophy? AB - Increasing evidence supports a link between multiple system atrophy and coenzyme Q10 (CoQ10) biosynthesis. However, so far this knowledge was not translated into tangible benefits for affected patients. Poor bioavailability of oral CoQ10 might constitute a major problem. Current research suggests that 4-hydroxybenzoic acid might constitute an interesting alternative treatment option. PMID- 29429648 TI - The usefulness of fibrin glue as a support in the dissection of malignant cystic brain tumors. AB - BACKGROUND: If the complete microsurgical resection of a brain tumor is a logical oncologic goal, the surgical strategy for the cystic component remains controversial secondary to the risk of morbidity. The objective of this study was to analyze the interest of using fibrin glue in the resection of malignant cystic brain tumors (MCBT). METHODS: Seven patients (median: 60-years-old (range [52 72]/sex ratio M/F: 2.5) were analyzed prospectively in the Neurosurgery Department at Strasbourg University Hospital, from October 2014 to November 2016. The surgical technique consisted of injecting fibrin glue into the tumor cyst after partial drainage. After the solidification of the glue, the cysts walls were removal by following the dissection plan around the fibrin glue. The primary objective was to evaluate the quality of surgical resection on brain MRI scans postoperatively with the use of ITK-SNAP software for precise measurements of tumor volume. RESULTS: Four metastases and 3 glial lesions were operated on with this technique. An average reduction in cystic volume of 64.6% (P=0.016) and 82.1% (P=0.016) for contrast enhancement volume were observed. If two cases (#2 and #7) were excluded, the average contrast enhancement reduction was respectively 94% and 72% for the cystic volume. In addition, there were no complications, tumor recurrence or difference between gliomas and metastases and the Karnofsky score increased by at least 10% in all patients. CONCLUSION: This procedure allowed to extend the resection to the cystic component of MCBT without increasing the risk of morbidity related to injury on the underlying parenchyma. PMID- 29429649 TI - Effects of ultrasound energy density on the non-thermal pasteurization of chocolate milk beverage. AB - This study presents the emerging high-intensity ultrasound (HIUS) processing as a non-thermal alternative to high-temperature short-time pasteurization (HTST). Chocolate milk beverage (CMB) was subjected to different ultrasound energy densities (0.3-3.0 kJ/cm3), as compared to HTST pasteurization (72 degrees C/15 s) aimed to verify the effect of the HIUS processing on the microbiological and physicochemical characteristics of the beverage. The application of HIUS at an energy density of 3.0 kJ/cm3 was able to reduce 3.56 +/- 0.02 logarithmic cycles in the total aerobic counts. In addition, the ultrasound energy density affected the physical properties of the beverage as the size distribution of fat globule and rheological behavior, as well as the chemical properties such as antioxidant activity, ACE inhibitory activity, fatty acid profile, and volatile profile. In general, the different energetic densities used as a non-thermal method of pasteurization of CMB were more effective when compared to the conventional pasteurization by HTST, since they improved the microbiological and physicochemical quality, besides preserving the bioactive compounds and the nutritional quality of the product. PMID- 29429650 TI - Ultrasound-assisted d-tartaric acid whole-cell bioconversion by recombinant Escherichia coli. AB - d-Tartaric acid has wide range of application in the pharmaceutical industry and scarcely exists in nature. In this study, cis-epoxysuccinate hydrolase (CESH) containing Escherichia coli was used to perform whole-cell bioconversion of cis epoxysuccinate (CES) to D-tartaric acid and the catalytic efficiency was investigated by ultrasound treatment. The bioconversion rate of CES sodium reached 70.36% after 60 min treated after ultrasound, which is 3-fold higher than that in the control. The specific rate could be further improved by 2-fold after 5 repeated batches compared with the first one, however, the specific rate gradually decreased with the increase of repeat batches (>5 batches). The CESH from Bordetella sp. BK-52 was a typical Michaelis-Menten enzyme with Vmax and Km values of 28.17 mM/h/g WCW (wet of cell weight) and 30.18 mM, respectively. The process for the d-tartaric acid bioconversion, which consisted of 102.31 g/L CES sodium, 8.78 mg/mL whole cell and ultrasound power of 79.36 W, is further optimized using response surface methodology. The specific rate finally reached 194.79 +/- 1.78 mM/h/g WCW under the optimal conditions. Furthermore, the permeability of inner and outer membrane was improved approximately 1.6 and 1.4 fold after ultrasound treatment, respectively, which may be a crucial factor for improvement of the bioconversion efficiency. PMID- 29429651 TI - Ultrasound assisted synthesis of amide functionalized metal-organic framework for nitroaromatic sensing. AB - Nano plates of zinc(II) based metal-organic framework (MOF) were prepared via ultrasonic method without any surfactants at room temperature and atmospheric pressure. Control of particle size and morphology was enhanced in this synthesis method. Nano plates of an interpenetrated amide-functionalized metal-organic framework, [Zn2(oba)2(bpfb)].(DMF)5, TMU-23, (H2oba = 4,4'-oxybis(benzoic acid); bpfb = N,N'-bis-(4-pyridylformamide)-1,4-benzenediamine, DMF = N,N-dimethyl formamide), was synthesized under ultrasound irradiation in different concentrations of initial precursor. The nano structure and morphology of the synthesized MOF were characterized by Field Emission Scanning Electron Microscopy (FE-SEM), powder X-ray diffraction, thermo gravimetric analysis (TGA), elemental analysis and FTIR spectroscopy. Moreover, Fluorescence emissions of nanoplates have been studied. Amide-functionalized MOF shows high selectivity for sensing of nitroaromatic compounds such as nitrophenol, nitroaniline, and nitrobenzene in acetonitrile solution. Fluorescence intensity decreased with increasing contents of nitroaromatics in acetonitrile solution due to fluorescence quenching effect. PMID- 29429652 TI - A selective synthesis of the fullerene-fused dioxane adduct via heterogeneous reaction of C60 with alpha-diols and NaOH under ultrasonication. AB - A novel ultrasonic-mediated approach to the synthesis of 1,9-dihydro[C60 Ih][5,6](1,4-dioxano)fullerene based on the heterogeneous reaction of fullerene with alpha-diols and NaOH has been developed. It allows producing the fullerene derivatives with high yields and selectivity. PMID- 29429653 TI - Sonochemically synthesized blue fluorescent functionalized graphene oxide as a drug delivery system. AB - Ultrasound assisted the copper-catalyzed cross-coupling reaction to synthesis 1 (10-bromoanthracene-9-yl)-1H-imidazole-4,5-dicarboxylic acid (A-Im). The obtained product was employed to modify graphene oxide (GO) surface to produce GO-A-Im. The resulted hybrid was characterized with Scanning Electron Microscope (SEM/EDS); X-ray Diffraction spectroscopy (XRD); X-ray photoelectron spectroscopy (XPS); Fluorescence spectroscopy; Fourier transformed infrared spectroscopy (FT IR), Brunauer-Emmett-Teller (BET), and UV-Vis absorption spectroscopy. The synthesized (A-Im) moiety that was used for functionalization of GO, display a cyan emission around (496 nm), however, the GO hybrid exhibited blue photoluminescence around (403 nm). It has been proposed that the chemical attachment of the A-Im moiety onto GO surface leads to a distortion in the bandgap of the GO and the blue shift of luminescence [93 nm] was observed. Indeed the cytotoxicity properties of the synthesized hybrid were measured. The IC50 value for the hybrid was 23 ug/ml. The model drug (DOX) was loaded up to 91% on the carrier, and the release profile indicated a pH-dependent discharge with more release in acidic pH. The GO-A-Im/DOX was injected to the 4T1 tumor (murine breast cancer) bearing BALB/c mice and after 10 days the tumor was disappeared. PMID- 29429654 TI - Ultrasonic-assisted synthesis and the structural characterization of novel the zig-zag Cd(II) metal-organic polymer and their nanostructures. AB - A sonochemical method was used to synthesize nano-rods of a novel cadmium(II) metal-organic coordination polymer, [Cd(p-2yeinh)(NO2)]n (1) (p-2yeinh = pyridin 2-yl ethylidene-isonicotinohydrazide). The effect of the synthesis parameters such as time, concentrations and irradiation power has been studied and optimized. It was shown that the thickness of rods has changed from 27 nm to 45 nm. The compounds were characterized by scanning electron microscopy (SEM), elemental analysis, IR spectroscopy, X-ray powder diffraction (XPRD), and single crystal X-ray analysis. The X-ray structure analysis revealed that the Cd(II) atom is coordinated by one oxygen and three nitrogen atoms from two p-2yeinh ligands and two oxygen atoms of single nitrite anion with a CuN3O3 donor set with distorted octahedral geometry. The crystal taking the form of a one-dimensional zig-zag polymer. The adjacent chains connected by pi-pi of adjacent aromatic rings of p-2yeinh and other weak interactions. Consequently, the weak interactions also allow the 1D zig-zag structure to form a 3D metal-organic coordination polymer. CdO nanoparticles were prepared by thermolysis of compound 1 at 180 degrees C with oleic acid as a surfactant. The average diameter of the nanoparticles was estimated by XPRD to be 23 nm. The morphology and size of the prepared CdO nanoparticles were further studied using SEM. PMID- 29429655 TI - Impact of ultrasonic assisted triangular lattice like arranged dispersion of nanoparticles on physical and mechanical properties of epoxy-TiO2 nanocomposites. AB - Emerging ex-situ technique, ultrasonic dual mixing (UDM) offers unique and hitherto unapproachable opportunities to alter the physical and mechanical properties of polymer nanocomposites. In this study, triangular lattice-like arranged dispersion of TiO2 nanoparticles (average size ~ 48 nm) in the epoxy polymer has been attained via concurrent use of a probe ultra-sonicator and 4 blades pitched impeller which collectively named as UDM technique. The UDM processing of neat epoxy reveals the generation of triangular lattice-like arranged nanocavities with nanoscale inter-cavity spacing. The UDM processing of epoxy-TiO2 nanocomposites reveals two unique features such as partial and complete entrapping of the nanoparticles by the nanocavities leading the arranged dispersion of particles in the epoxy matrix. Pristine TiO2 nanoparticles were dispersed in the epoxy polymer at loading fractions of up to 20% by weight. The results display that the arranged dispersion of nanoparticles is very effective at enhancing the glass transition temperature (Tg) and tensile properties of the epoxy at loading fractions of 10 wt%. We quantify a direct relationship among three important parameters such as nanoparticle content, cluster size, and inter particle spacing. Our results offer a novel understanding of these parameters on the Tg and tensile properties of the epoxy nanocomposites. The tensile fracture surfaces revealed several toughening mechanisms such as particle pull-out, plastic void growth, crack deflection, crack bridging and plastic deformation. We show that a strong nanoparticle-matrix interface led to the enhanced mechanical properties due to leading toughening mechanisms such as crack deflection, plastic deformation and particle pull-out. We showed that the UDM has an inordinate prospective to alter the dispersion state of nanoparticles in viscous polymer matrices. PMID- 29429656 TI - Ultrasonic-assisted synthesis of nano lead(II) coordination polymer as precursors for preparation of lead(II) oxide nano-structures: Thermal, optical properties and XRD studies. AB - Nano structure of a lead (II) coordination polymer [Pb2(C2Cl3O2)2(NO3)2(Cl2H8N2)2]n (1), has been synthesized by a sonochemical method in different concentrations. The nano particles were characterized by scanning electron microscopy (SEM) X-ray powder diffraction (XRD), FT-IR spectroscopy and elemental analyses. The thermal stability of nano structure is closely investigated via thermal gravimetric (TGA), and compared with crystalline structure. The compounds are then heated to 600 degrees C to produce PbO nano particles. The resulting PbO is characterized through XRD and SEM analyses. Concentration of initial reagents effects on size and morphology of nano structured compound 1 have been studied and show that low concentrations of initial reagents decreased particles size and leaded to uniform nano particles morphology. The photoluminescence properties of the prepared compound, as crystalline and as nanoparticles, have been investigated. The result showed a good correlation between the size and emission wavelength. PMID- 29429657 TI - Constructing regions of attainable sizes and achieving target size distribution in a batch cooling sonocrystallization process. AB - The application of ultrasound to a crystallization process has several interesting benefits. The temperature of the crystallizer increases during ultrasonication and this makes it difficult for the temperature controller of the crystallizer to track a set temperature trajectory precisely. It is thus necessary to model this temperature rise and the temperature-trajectory tracking ability of the crystallizer controller to perform model-based dynamic optimization for a given cooling sonocrystallization set-up. In our previous study, we reported a mathematical model based on population balance framework for a batch cooling sonocrystallization of l-asparagine monohydrate (LAM). Here we extend the previous model by including energy balance equations and a Generic Model Control algorithm to simulate the temperature controller of the crystallizer that tracks a cooling profile during crystallization. The improved model yields very good closed-loop prediction and is conveniently used for studies related to particle engineering by optimization. First, the model is used to determine the regions of attainable particle sizes for LAM batch cooling sonocrystallization process by solving appropriate dynamic optimization problems. Then the model is used to determine optimal operating conditions for achieving a target crystal size distribution. The experimental evidence clearly demonstrates the efficiency of the particle engineering approach by optimization. PMID- 29429658 TI - Nd2O3-SiO2 nanocomposites: A simple sonochemical preparation, characterization and photocatalytic activity. AB - Nd2O3-SiO2 nanocomposites with enhanced photocatalytic activity have been obtained through simple and rapid sonochemical route in presence of putrescine as a new basic agent, for the first time. The influence of the mole ratio of Si:Nd, basic agent and ultrasonic power have been optimized to obtain the best Nd2O3 SiO2 nanocomposites on shape, size and photocatalytic activity. The produced Nd2O3-SiO2 nanocomposites have been characterized utilizing XRD, EDX, TEM, FT-IR, DRS and FESEM. Application of the as-formed Nd2O3-SiO2 nano and bulk structures as photocatalyst with photodegradation of methyl violet contaminant under ultraviolet illumination was compared. Results demonstrated that SiO2 has remarkable effect on catalytic performance of Nd2O3 photocatalyst for decomposition. By introducing of SiO2 to Nd2O3, decomposition efficiency of Nd2O3 toward methyl violet contaminant under ultraviolet illumination was increased. PMID- 29429659 TI - A scalable ultrasonic-assisted and foaming combination method preparation polyvinyl alcohol/phytic acid polymer sponge with thermal stability and conductive capability. AB - In this article, polyvinyl alcohol/phytic acid polymer (PVA/PA polymer) is synthesized from PVA and PA via the esterification reaction of PVA and PA in the case of acidity and ultrasound irradiation, and PVA/PA polymer sponge is prepared via foaming PVA/PA polymer in the presence of n-pentane and ammonium bicarbonate, and the structure of PVA/PA polymer and the structure, morphology and crystallinity of PVA/PA polymer sponge are characterized, and the thermal stability and surface resistivity of PVA/PA polymer sponge are investigated. Based on these, it has been attested that PVA/PA polymer synthesized under the acidity and ultrasound irradiation and PVA/PA polymer sponge are structured by the chain of PVA and the cricoid PA connected in the form of ether bonds and phosphonate bonds, and the thermal stability of PVA/PA polymer sponge attains 416.5 degrees C, and the surface resistivity of PVA/PA polymer sponge reaches 5.76 * 104 ohms/sq. PMID- 29429660 TI - A simple sonochemical approach to fabricate a urea biosensor based on zinc phthalocyanine/graphene oxide/urease bioelectrode. AB - A novel zinc phthalocyanine/graphene oxide (ZnPh/GO) nanocomposite modified glassy carbon electrode (GCE) was prepared by using sonochemical approach and simple drop casting method. Urease (Urs) was used as the specific enzyme for urea detection and was physically immobilized onto the surface of ZnPh/GO nanocomposite. The fabricated ZnPh/GO/Urs matrix was successfully characterized by UV-vis-spectroscopy, FT-IR spectroscopy, scanning electron microscopy (SEM), raman spectrum, thermogravimetric analysis, cyclic voltammetric (CV) and amperometric techniques. The electrocatalytic performance of the ZnPh/GO/Urs electrode was investigated by urea biosensor. Our results demonstrate that the modified electrode has excellent electrocatalytic activity towards the sensing of urea in 0.1 M phosphate buffer solution (PBS, pH 7.2). The biosensor tolerated a wide linear concentration range for urea from 0.4 to 22 MUM (R2 = 0.991), with a detection limit of 0.034 uM (S/N = 3). The ZnPh/GO/Urs bioectrode has several excellent properties, including a fast response time, high reproducibility and stability. PMID- 29429661 TI - Sonochemical synthesis of a new nano-sized barium coordination polymer and its application as a heterogeneous catalyst towards sono-synthesis of biodiesel. AB - A new nano-sized barium coordination polymer, {(bipyH)[Ba2(pydc)2(Hpydc)(H2O)2]}n.nH2O (1), (bipy = 4,4'-bipyridine and H2pydc = pyridine-2,6-dicarboxylic acid), has been sonochemically synthesized and fully characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), FT-IR spectroscopy, thermogravimetric analysis (TGA) and elemental analyses. Compound 1 was structurally characterized by single crystal X-ray diffraction and it was shown that this compound consists of 1D anionic coordination polymers and bipyH+ cationic species that construct a three dimensional supramolecular architecture via non-covalent interactions i.e. ion pairing and hydrogen bonding. The role of compound 1 as a heterogeneous catalyst in the production of biodiesel was also investigated. A full conversion of soybean oil to biodiesel was accomplished in an exceptionally short timeframe through an ultrasonic-assisted transesterification process in the presence of compound 1. PMID- 29429662 TI - Application of ultrasound-aided method for the synthesis of NdVO4 nano photocatalyst and investigation of eliminate dye in contaminant water. AB - This paper presents a new approach to preparation of neodymium vanadate nanostructures via facile sonochemical route. Several parameters were compared to reach optimum size and uniformity of as-made samples. These factors include sonication time, sonication power, solvent and using ethylenediamine as alkaline and capping agent, for the first time. Neodymium vanadate nano-photocatalyst applied in decolouration of dye as organic contaminant. Effect of type of dye, type of irradiation source, pH and catalyst loading was described on improving efficiency of catalyst function. Numerous techniques were specified in order to determine purity, morphology and optical properties of products consist XRD, FT IR, EDX, SEM, TEM and DRS. PMID- 29429663 TI - Mechanically robust dual responsive water dispersible-graphene based conductive elastomeric hydrogel for tunable pulsatile drug release. AB - Nanohybrid hydrogels based on pristine graphene with enhanced toughness and dual responsive drug delivery feature is opening a new era for smart materials. Here pristine graphene hydrogels are synthesized by in situ free radical polymerization where graphene platelets are the nanobuiliding blocks to withstand external stress and shows reversible ductility. Such uniqueness is a mere reflection of rubber-like elasticity on the hydrogels. These nanobuilding blocks serve also the extensive physisorption which enhances the physical crosslinking inside the gel matrix. Besides the pH-responsive drug release features, these hydrogels are also implemented as a pulsatile drug delivery device. The electric responsive drug release behaviours are noticed and hypothesized by the formation of conducting network in the polyelectrolytic hydrogel matrix. The hydrogels are also tested as good biocompatibility and feasible cell-attachment during live dead cell adhesion study. The drug release characteristics can also be tuned by adjusting the conducting filler loading into the gel matrix. As of our knowledge, this type of hydrogels with rubber-like consistency, high mechanical property, tunable and dual responsive drug delivery feature and very good human cell compatible is the first to report. PMID- 29429664 TI - Removal of bacteria Legionella pneumophila, Escherichia coli, and Bacillus subtilis by (super)cavitation. AB - In sufficient concentrations, the pathogenic bacteria L. pneumophila can cause a respiratory illness that is known as the "Legionnaires" disease. Moreover, toxic Shiga strains of bacteria E. coli can cause life-threatening hemolytic-uremic syndrome. Because of the recent restrictions imposed on the usage of chlorine, outbreaks of these two bacterial species have become more common. In this study we have developed a novel rotation generator and its effectiveness against bacteria Legionella pneumophila and Escherichia coli was tested for various types of hydrodynamic cavitation (attached steady cavitation, developed unsteady cavitation and supercavitation). The results show that the supercavitation was the only effective form of cavitation. It enabled more than 3 logs reductions for both bacterial species and was also effective against a more persistent Gram positive bacteria, B. subtilis. The deactivation mechanism is at present unknown. It is proposed that when bacterial cells enter a supercavitation cavity, an immediate pressure drop occurs and this results in bursting of the cellular membrane. The new rotation generator that induced supercavitation proved to be economically and microbiologically far more effective than the classical Venturi section (super)cavitation. PMID- 29429665 TI - Sonochemical-solvothermal synthesis of guanine embedded copper based metal organic framework (MOF) and its effect on oprD gene expression in clinical and standard strains of Pseudomonas aeruginosa. AB - The guanine incropped Cu based metal-organic framework (Guanine-Cu-MOF) was synthesized by facile one-step sonochemical method by simply mixing of 4-4, biphenyldicarboxylic, guanine and copper nitrate (Bio-Cu-H2bpdc-Gu). The prepared guanine-MOF was characterized by using X-Ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and Field emission scanning electron microscopy (FE SEM) techniques. The morphology of prepared material was sponge-shaped which it was well documented, together with the presence of existing functional groups. The effect of prepared material on oprD Gene Expression was investigated in Clinical and Standard Strains of Pseudomonas aeruginosa (PAO-1) and minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of prepared samples against P. aeruginosa strains were determined through the broth micro-dilution method. The expression of oprD gene in strains affected by Cu H2bpdc-Gu was quantitatively investigated through real-time PCR. MIC of Bio-Cu H2bpdc-Gu was 400 MUg/mL for the standard and clinical strains of P. aeruginosa, while, MBC of this compound was 700 MUg/mL for standard strain and 800 MUg/mL for clinical strains. The highest and the lowest rate of oprD gene expression were found to be 3.6 and 1.1 fold in the strains, respectively. PMID- 29429666 TI - Application of nisin-assisted thermosonication processing for preservation and quality retention of fresh apple juice. AB - The effects of thermosonication (TS) and 100 ppm nisin-assisted TS (TS + nisin) on the inactivation of naturally occurring microorganisms, retention of nutritional quality and extension of shelf life of fresh apple juice were evaluated, with nisin and mild heat (nisin + MH) treatments as control. Fresh apple juice was addressed by nisin + MH, TS and TS + nisin at 37, 42, 47, and 52 degrees C for 5-40 min. After processing, microbial growth was evaluated during storage at 8 degrees C at every 5 days. Temperature played a vital role in the inactivation of aerobic bacteria and yeasts and molds by TS and TS + nisin, higher temperature up to 52 degrees C could cause a considerable inactivation of microbial cells in apple juice. As apple juice was subjected to TS and TS + nisin at 52 degrees C for 30 min, retention of original quality including 89% ascorbic acid, non-visible color change, no significant alteration in BD, pH, TA and TSS values of fresh apple juice, and extension shelf life to 15 d at 8 degrees C were obtained. Nisin exhibit additional inactivation effect of aerobic bacteria in apple juice while not obviously effect on yeast and molds. These results indicated a potential application of TS and TS + nisin (100 ppm) to produce fresh like quality apple juice and/or to extend its shelf life. PMID- 29429667 TI - Effects of ultrasonic and graft treatments on grafting degree, structure, functionality, and digestibility of rapeseed protein isolate-dextran conjugates. AB - Rapeseed protein isolate (RPI) and dextran conjugates were prepared by traditional and ultrasonic assisted wet-heating. The effects on the grafting degree (GD), structure, functionality, and digestibility of conjugates were studied. Ultrasonic frequency, temperature, and time all significantly affected the GD. Under the optimum conditions (temperature of 90 degrees C and time of 60 min), compared to traditional wet-heating, ultrasonic treatment at 28 kHz significantly increased the GD by 2.12 times. Compared to RPI, surface hydrophobicities of conjugates were significantly decreased by graft and ultrasonic treatments. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and amino acid composition results confirmed that traditional graft reaction involved cysteine (Cys) and lysine (Lys) whereas the ultrasonic assisted one involved only Cys. Both were from the 12S globulin subunit and cruciferin. Fourier transform infrared spectrum (FT-IR) and circular dichroism (CD) results showed that graft treatment significantly changed secondary structure and ultrasonic treatment had the greatest impact on the decrease in the beta-sheet (19.1%) and the increase in the random coil (49.6%). Graft and ultrasonic treatments both made surface structure looser and more porous. The two treatments also caused molecular weight to become bigger, and ultrasonic treatment had the greatest effect on the increase (68.2%) in 110-20.5 kDa. Structural modifications of RPI by grafting to dextran caused improvements of solubility (at pH 5-6), emulsifying activity (at pH 4-10), emulsion stability (at pH 4-5 and 9-10), and thermal stability (at temperature 90-100 degrees C). The digestibility of conjugates was decreased by graft and ultrasonic treatments and the conjugates were mainly digested in the intestinal phase. The ultrasonic assisted wet-heating was an efficient and safe method for producing RPI-dextran conjugates and improving the utilization value of rapeseed meal. PMID- 29429668 TI - Peat moss-derived biochar for sonocatalytic applications. AB - Peat-moss derived biochar was used as a sonocatalyst for the degradation of rhodamine B (RhB) at different ultrasonic frequencies (40 kHz and 300 kHz). The biochar was prepared by pyrolysis of peat-moss at 300 degrees C under N2 saturated conditions. High removal efficiency was achieved when biochar (1000 mg L-1) was used as a sonocatalyst in the 40 kHz system, and high removal could be achieved by pre-adsorption and radical oxidation reactions on the surface of the biochar. This was validated in experiments employing radical scavengers. Sonochemiluminescence images and real images of the systems with no biochar, 100 mg L-1 biochar, and 1000 mg L-1 biochar also supported this observation. On the other hand, the addition of the biochar was less effective than expected for the degradation of RhB at 300 kHz. This was due to low dispersion of the biochar in solution in the high frequency system, where relatively weaker sonophysical effects could be obtained. PMID- 29429669 TI - Ultrasonic irradiation to modify the functionalized bionanocomposite in sulfonated polybenzimidazole membrane for fuel cells applications and antibacterial activity. AB - In this article the new proton exchange membranes were prepared from sulfonated polybenzimidazole (s-PBI) and various amounts of sulfonated titania/cellulose nanohybrids (titania/cellulose-SO3H) via ultrasonic waves. The ultrasonic irradiation effectively changes the rheology and the glass transition temperature and the crystallinity of the composite polymer. Ultrasonic irradiation has a very strong mixing and dispersion effect, much stronger than conventional stirring, which can improve the dispersion of titania/cellulose-SO3H nanoparticles in the polymer matrix. The strong -SO3H/-SO3H interaction between s-PBI chains and titania/cellulose-SO3H hybrids leads to ionic cross-linking in the membrane structure, which increases both the thermal stability and methanol resistance of the membranes. After acid doping with phosphoric acid, s-PBI/titania/cellulose SO3H nanocomposite membranes exhibit depressions on methanol permeability and enhancements on proton conductivity comparing to the pristine s-PBI membrane. The chemical structure of the functionlized titania was characterized with FTIR, and energy-dispersive X-ray. Imidazole and sulfonated groups on the surface of modified nanoparticles forming linkages with s-PBI chains, improved the compatibility between s-PBI and nanoparticles, and enhanced the mechanical strength of the prepared nanocomposite membranes. From SEM and TEM analysis could explain the homogeneous dispersion of titania/cellulose-SO3H in nanocomposite membranes. Moreover, the membranes exhibited excellent antibacterial activities against S. aureus and E. coli. A. PMID- 29429670 TI - Fe3O4 nanocubes assembled on RGO nanosheets: Ultrasound induced in-situ and eco friendly synthesis, characterization and their excellent catalytic performance for the production of liquid fuel in Fischer-tropsch synthesis. AB - In this study, Fe3O4 nanocubes (NCs) decorated on RGO nanosheets (NSs) structures were successfully synthesized through an innovative and environmentally-friendly rapid sonochemical method. More importantly, iron(II) sulfate heptahydrate and GO were employed as precursors and water as reaction medium, meanwhile, NaOH within the generated free radicals from the high intensity ultrasound were sufficient as reducing and base agent in our clean synthesis. Moreover, the hydrothermal method as a conventional approach was employed to synthesize the same catalysts for the comparison with the ultrasonocation technique. The as-synthesized Fe3O4 and RGO/Fe3O4 NSs catalysts were exposed to industrially relevant Fischer-tropsch synthesis (FTS) conditions at various reaction temperatures (250-290 degrees C), and they subjected to fully characterization before and after FTS reaction using XRD, TEM, HRTEM, EDS mapping, XPS, FTIR, BET, H2-TPR, H2-TPD and CO-TPD to understand the structure-performance relationships. Notably, the catalysts produced using the sonochemical method had a better CO conversion rate [Fe3O4 (80%), RGO/Fe3O4 (82%)] than the hydrothermally synthesized catalysts. However, compared to the naked-Fe3O4 catalysts, the sonochemically and hydrothermally synthesized RGO-supported Fe3O4 catalysts had higher long chain hydrocarbon (C5+) selectivity values (72% and 67%) and C2-C4 olefin/paraffin selectivity ratio (3.2 and 2) and low CH4 selectivity values (6% and 8.5%), respectively. This can be attributed to their high surface area, the degree of reducibility, and content of Hagg iron carbide (chi-Fe5C2) as the most active phase of the FTS reaction. Proposed reaction mechanisms for the sonochemical and hydrothermal reaction synthesis of Fe3O4 and RGO/Fe3O4 nanoparticles are discussed. In conclusion, our developed surfactantless-sonochemical method holds promise for the eco-friendly synthesis of highly efficient catalysts materials for FTS reaction. PMID- 29429671 TI - Using low frequency and intensity ultrasound to enhance start-up and operation performance of Anammox process inoculated with the conventional sludge. AB - A lab-scale ultrasound enhancing Anammox reactor (R1) was established and irradiated once a week by ultrasound with the optimal parameter (frequency of 25 kHz, intensity of 0.2 W cm-2 and exposure time of 3 min) obtained by batch experiments. R1 and the controlled Anammox reactor (R2) without exposure to the ultrasound were operated in parallel. The start-up period of Anammox process (53 days) in R1 was shorter than that (61 days) in R2. The nitrogen loading-enhancing period (day 53-day 135) in R1 was also shorter than that (day 61-day 151) in R2. At the end of the nitrogen loading-enhancing period, NLR (0.76 kg N m-3 d-1) and NRR (0.68 kg N m-3 d-1) of R1 were both higher than NLR (0.66 kg N m-3 d-1) and NRR (0.56 kg N m-3 d-1) of R2. Moreover, The stability of Anammox process in R1 was better than that in R2. The results demonstrated that the periodical irradiation of ultrasound enhanced the start-up and operational performance of Anammox reactor. Microbial community analysis indicated that the ultrasound accelerated the microbial succession from some other bacteria to Anammox bacteria so that shorten the start-up period of Anammox process from the conventional activated sludge. It also indicated that the ultrasound strengthened the competitive advantage of Candidatus Kuenenia stuttgartiensis in Anammox bacteria of the mature sludge so as to enhance the nitrogen removal performance of the Anammox reactor under the operation condition of high nitrogen loading. PMID- 29429672 TI - Effect of employing ultrasonic waves during pulse electrochemical deposition on the characteristics and biocompatibility of calcium phosphate coatings. AB - In the present work, we investigated the effect of employing ultrasonic waves during pulse electrochemical deposition on surface topography, chemical composition and biocompatibility of calcium phosphate (Ca-P) coatings. The SEM and 3D AFM images showed that the anodized titanium surface was covered with the uniform and refined size of plate-like Ca-P crystals, when the ultrasonic treatment of the electrolyte with power of 60 W was carried out during deposition. In contrast, for the Ca-P; 0 W coating applied under only the magnetic stirring of the electrolyte, the microstructure was non-uniform and some Ca-P crystals with the larger size were randomly observed in different regions, causing a rougher surface. The FTIR results also revealed that employing the ultrasound increases the deposition of a coating involved in only the most stable Ca-P phase of carbonated hydroxyapatite (CHA). However, in the absence of ultrasound, besides the prominent phase of CHA, some less stable Ca-P phases like octa calcium phosphate (OCP) and brushite were also formed in the Ca-P; 0 W coating. The Ca-P; 60 W coating showed the higher ability for apatite biomineralization after a 7-day immersion in the simulated body fluid (SBF). This coating also provided a better surface for the cellular activity, as compared to the Ca-P; 0 W coating. PMID- 29429673 TI - Green synthesis of nanocrystalline faujasite zeolite. AB - In this work, the synthesis of 28 and 38 nm Na-Y zeolite nanocrystals is reported. The process was performed via green synthesis without any organic structure directing agents (SDAs), at low temperature and applying ultrasound assisted aging. The zeolite nanoparticles obtained were characterized by X ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and N2 adsorption - desorption isotherm at 77 K. A simple, fast, efficient and environmentally friendly procedure to synthetize nanocrystalline FAU zeolite is described in the present study. The sonochemical pretreatment was found to directly affect the Na-Y zeolite properties. The final product obtained via ultrasound pretreatment shows high phase purity and crystallinity degree with crystal size smaller than 38 nm and elevated surface area (SBET ~ 950 m2 g-1). The hierarchical micro- and mesoporous FAU zeolites exhibit a pore volume of ~0.4 cm3 g-1. PMID- 29429674 TI - Ultrasound-initiated synthesis of cationic polyacrylamide for oily wastewater treatment: Enhanced interaction between the flocculant and contaminants. AB - Weak interaction between flocculants and oil is a main bottleneck in the treatment of oil-containing wastewater. To solve this problem, a novel flocculant PAB with cationic micro-block structure and hydrophobic groups of benzene rings was synthesized by ultrasound initiated polymerization technique and applied to remove turbidity and oil from water. To avoid unnecessary addition of reagents in traditional template and micellar copolymerization, surface-active monomer benzyl(methacryloyloxyethyl)dimethylammonium chloride (BMDAC) with self-assembly ability in aqueous solution was employed to synthesize flocculants. The critical association concentration of BMDAC measured by conductivity and surface tension methods was 0.014 mol.L-1. The results of reactivity ratio, statistical analysis of sequence-length distribution and 1H NMR provided evidence for the synthesis of copolymer with cationic micro-block. In addition, the apparent viscosity measurement indicated that PAB had an obvious hydrophobic association property. Finally, flocculation tests demonstrated that flocculation performance was greatly improved by adding PAB and the removal rate of oil and turbidity both reached the maximum (87.5% and 92%) at dosage of 40 mg.L-1 and pH of 7.0. Flocculation mechanism investigation demonstrated that the cooperation of charge neutralization, adsorption bridging, and hydrophobic association effect played an important role. The formed flocs by PAB was large, compact, difficult to break, and easy to regrow because of the enhanced interaction between flocculants and oil. In summary, this study can provide important reference in the design of organic flocculants in oily wastewater treatment applications. PMID- 29429675 TI - Sonochemical synthesis of two novel Pb(II) 2D metal coordination polymer complexes: New precursor for facile fabrication of lead(II) oxide/bromide micro nanostructures. AB - Two new lead(II) coordination polymer complexes (CSCs) (2D), [Pb2(L)2(Br)2]n.H2O (1), [Pb2(HL/)(L/)(H2O)2]n.H2O (2), where L = C6H5NO2 (2-pyridinecarboxylic acid) and L/ = C9H6O6 (1,3,5-tricarboxylic acid), have been synthesized under different experimental conditions. Micrometric crystals (bulk) or microsized materials have been obtained depending on using the branch tube method or sonochemical irradiation. All materials have been characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and FT-IR spectroscopy. Single crystal X-ray analyses on complexes 1 and 2 shows that Pb2+ ions are 8 coordinated, 7 and 9-coordinated, respectively. Topological analysis shows that the compound 1 and 2 are 4,6L26 and bnn net, respectively. However, neither the shape nor the morphology is maintained, showing the role of sonochemistry to modulate both morphology and dimensions of the resulting crystalline material, independently of whether we have a 2D coordination polymer (CP). Finally, micro structuration of lead(II) bromide oxide and lead(II) oxide have been prepared by calcination of two different lead (II) CPs at 700 degrees C that were characterized by SEM and XRD. PMID- 29429676 TI - Sonochemical synthesis of a novel nanoscale 1D lead(II) [Pb2(L)2(I)4]n coordination Polymer, survey of temperature, reaction time parameters. AB - One new lead(II) coordination supramolecular complex (CSC) (1D), [Pb2(L)2(I)4]n, L = C4H6N2 (1-methyl imidazole), has been synthesized under different experimental conditions. Micrometric crystals (bulk) or nano-sized materials have been obtained depending on using the branch tube method or sonochemical irradiation. All materials have been characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and FT-IR spectroscopy. Single crystal X-ray analyses on complex 1 showed that Pb2+ ion is 4-coordinated. Topological analysis shows that the complex 1 is 2,3,5C2 net. Finally, the role of reaction time and temperature on the growth and final morphology of the structures obtained by sonochemical irradiation have been studied. PMID- 29429677 TI - Numerical investigation of the inertial cavitation threshold by dual-frequency excitation in the fluid and tissue. AB - Inertial cavitation thresholds, which are defined as bubble growth by 2-fold from the equilibrium radius, by two types of ultrasonic excitation (at the classical single-frequency mode and dual-frequency mode) were calculated. The effect of the dual-frequency excitation on the inertial cavitation threshold in the different surrounding media (fluid and tissue) was studied, and the paramount parameters (driving frequency, amplitude ratio, phase difference, and frequency ratio) were also optimized to maximize the inertial cavitation. The numerical prediction confirms the previous experimental results that the dual-frequency excitation is capable of reducing the inertial cavitation threshold in comparison to the single frequency one at the same output power. The dual-frequency excitation at the high frequency (i.e., 3.1 + 3.5 MHz vs. 1.1 + 1.3 MHz) is preferred in this study. The simulation results suggest that the same amplitudes of individual components, zero phase difference, and large frequency difference are beneficial for enhancing the bubble cavitation. Overall, this work may provide a theoretical model for further investigation of dual-frequency excitation and guidance of its applications for a better outcome. PMID- 29429678 TI - Novel cavitation fluid jet polishing process based on negative pressure effects. AB - Traditional abrasive fluid jet polishing (FJP) is limited by its high-pressure equipment, unstable material removal rate, and applicability to ultra-smooth surfaces because of the evident air turbulence, fluid expansion, and a large polishing spot in high-pressure FJP. This paper presents a novel cavitation fluid jet polishing (CFJP) method and process based on FJP technology. It can implement high-efficiency polishing on small-scale surfaces in a low-pressure environment. CFJP uses the purposely designed polishing equipment with a sealed chamber, which can generate a cavitation effect in negative pressure environment. Moreover, the collapse of cavitation bubbles can spray out a high-energy microjet and shock wave to enhance the material removal. Its feasibility is verified through researching the flow behavior and the cavitation results of the negative pressure cavitation machining of pure water in reversing suction flow. The mechanism is analyzed through a computational fluid dynamics simulation. Thus, its cavitation and surface removal mechanisms in the vertical CFJP and inclined CFJP are studied. A series of polishing experiments on different materials and polishing parameters are conducted to validate its polishing performance compared with FJP. The maximum removal depth increases, and surface roughness gradually decreases with increasing negative outlet pressures. The surface becomes smooth with the increase of polishing time. The experimental results confirm that the CFJP process can realize a high material removal rate and smooth surface with low energy consumption in the low-pressure environment, together with compatible surface roughness to FJP. PMID- 29429679 TI - Intensified synthesis of medium chain triglycerides using ultrasonic reactors at a capacity of 4L. AB - Lipids are considered as one of the most crucial nutrients for humans and among the various classes, medium chain triglycerides (MCTs) are considered as the most important functional foods and nutraceuticals. The present work deals with the intensification of synthesis of MCTs at a large capacity of 4L based on the use of ultrasonic bath and ultrasonic longitudinal horn. The effect of operating parameters like molar ratio of the reactants, type of catalyst and catalyst loading as well as the temperature on the extent of conversion has been investigated. The effect of molar ratio of lauric acid and glycerol was investigated over the range of 1:2 to 1:8 whereas the effect of loading of sulfuric acid was studied over the range of 4 ml/L-10 ml/L and zinc chloride loading over the range of 1 g/L-4 g/L. The effect of temperature was also studied using the conventional approach where it has been observed that 90 degrees C is an optimum temperature giving the extent of conversion as 72%. Also, the use of homogeneous catalyst as sulphuric acid was found to be more effective as compared to the solid catalyst as zinc chloride. It was observed that the maximum extent of conversion as 77.5% was obtained at 8 ml/L of sulfuric acid and molar ratio of 1:6 using ultrasonic longitudinal horn with US bath giving lower conversion as compared to US longitudinal horn but higher than the conventional approach under same operating conditions. The present work clearly established the intensification benefits in terms of reduction in time and higher conversion using cavitational reactors. PMID- 29429680 TI - Preparation of Ce4+-doped BaZrO3 by hydrothermal method and application in dual frequent sonocatalytic degradation of norfloxacin in aqueous solution. AB - In this paper, the dual-frequent sonocatalytic degradation of norfloxacin (NOR), an antibiotic, caused by Ce4+-doped BaZrO3 is studied. The used Ce4+-doped BaZrO3 as a novel sonocatalyst with highly efficient and stable sonocatalytic activity is prepared via hydrothermal method. The prepared sample is characterized by X ray diffractometer (XRD), scanning electron microscopy (SEM), energy dispersive X ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance spectra (DRS) and Fourier transform infrared spectra (FT-IR) in order to investigate the structure, morphology and chemical composition. The dual frequent sonocatalytic activity of prepared Ce4+-doped BaZrO3 powder is evaluated through sonocatalytic degradation of norfloxacin (NOR) as a model organic pollutant. Some influencing factors such as single/dual-frequent ultrasonic frequent, cerium and zirconium molar proportions, ultrasonic irradiation time and used times are studied in detail by using UV-vis spectra. The generated reactive oxygen species (ROS) during the dual-frequent sonocatalytic degradation process of norfloxacin (NOR) are confirmed by using two different trapping agents. The holes (h+) and hydroxyl radicals (OH) are identified and the holes plays a major role during the oxidation process. Finally, the possible mechanism for the dual frequent sonocatalytic degradation of norfloxacin (NOR) caused by Ce4+-doped BaZrO3 is proposed. The experimental results show that the Ce4+-doped BaZrO3 displays a good sonocatalytic activity under dual-frequent ultrasonic irradiation. Under optimal conditions, the most of norfloxacin (NOR) can be removed under dual-frequent ultrasonic irradiation for 150 min. PMID- 29429681 TI - Research of megasonic electroforming equipment based on the uniformity of electroforming process. AB - Megasonic has obvious advantages in overcoming the limitations of electroforming process based on its low cavitation effect, high sound intensity and acoustic streaming. In this paper, megasonic was employed to achieve uniform electroformed layer in electroforming process. Impedance values, resonant frequencies were measured in order to get a high-efficiency megasonic source. Considering the directions of acoustic radiation and combining with other functional modules, an integrated megasonic electroforming equipment was designed and set up. Then, nickel was electroformed on copper substrates without megasonic wave, with single directional megasonic wave and with bidirectional alternating megasonic wave, respectively. The planeness value (PV) of electroformed layer is 15.03 MUm without megasonic agitation, and the PV of electroformed layer is 15.36 MUm with single directional megasonic wave radiation. Bidirectional alternating megasonic wave assisted electroforming has an outstanding performance on the uniformity of electroformed layer, which achieves the lowest planeness value (PV = 10.91 MUm) of all the electroforming experiments. Besides, the bidirectional megasonic wave assisted electroforming can achieve better surface quality than other conditions too. PMID- 29429682 TI - Ultrasonic assisted synthesis of a new one-dimensional nanostructured Mn(II) coordination polymer derived from azide and new multi-topic nitrogen donor ligand. AB - A new Mn(II) coordination polymer, [Mn(L1)2(N3)2]n (1), L1 = 3,4-bis(4-pyridyl) 5-(2-pyridyl)-1,2,4-triazole, was synthesized by the reaction of ligand L1 and mixtures of manganese(II) acetate and sodium azide via branched tube method. Compound 1 was structurally characterized by single-crystal X-ray diffraction. The results show that 1 is a 1D helix coordination polymer. Also nanostructures of 1 have been prepareded by sonochemical process at ambient temperature. The effects of two different concentrations of initial reagents on the size and morphology of the nanoparticles were studied and the products were characterized by X-ray powder diffraction and scanning electron microscopy (SEM). Also the comparison of the thermal stability of bulk form and nanoparticles of 1 was investigated by thermal gravimetric and differential thermal analyses. PMID- 29429683 TI - Comprehensive facilitating of water oxidation reaction by ultrasonic attenuation of hydrogen-bonded structure of water. AB - The balance between water-metal interactions and water-water hydrogen bonding (HBs) controls the process of water adsorption on metallic surfaces. In other hand, the yield of oxygen evolution reaction (OER) is dependent on the binding energy of H2O at electrode surface. Therefore, on a specific metal substrate, attenuation of HBs may be a promising route for improving OER. In this study, the computational and experimental evidences indicate that the performance of ultrasonically irradiated deionized water (USI-DW), participated in water oxidation reaction (WOR), is different from its in the intact bulk water. To date, establishing of new electrocatalysts with lower overpotentials (eta) and higher current densities (J) in OER have been mostly considered based on metals and oxide materials. Here, we ultrasonically agitated the water clusters formed by strong HBs, and as a sustainable improvement route explored its particular effects on the efficiency of OER. The molecular modeling (MM) of the (H2O)n clusters (n = 1-100 molecules), the corresponding IR spectra, the molecular orbitals energy levels and the adsorption of free and cluster confined H2O molecules on the Pt surface were studied by the appropriate quantum mechanical (QM) methods. The result of deconvolution of FTIR spectra recorded for USI-DW in the -OH stretching region (~2600-3900 cm-1) properly confirmed the expected increase of the single water molecules. The reduction in overpotentials was 82 +/ 8 mV and 158 +/- 12 mV, to reach the J of 1 mA cm-1 at the typical pHs 12.2 and 13.1, respectively. PMID- 29429684 TI - Enhanced removal of basic violet 10 by heterogeneous sono-Fenton process using magnetite nanoparticles. AB - The removal of basic violet 10 (BV10), which is known as a cationic dye, from aqueous solution was studied by employing a heterogeneous sono-Fenton process over the nano-sized magnetite (Fe3O4) which had been prepared by the milling of magnetite mineral using a high-energy planetary ball milling process. The magnetite samples were characterized using the X-ray diffraction (XRD), high resolution scanning electron microscopy (HR-SEM), energy-dispersive X-ray spectroscopy (EDX), Brunauer-Emmett-Teller (BET), Fourier transform infrared spectroscopy (FTIR), and inductively couple plasma mass spectrometer (ICP-MS). It was found that the catalytic activity of the ball-milled magnetite sample was enhanced along with the improvement in its physicochemical properties; also, the ball-milled magnetite of 6 h displayed the highest catalytic activity in BV10 removal by the heterogeneous sono-Fenton process as compared with that for 4 h (66.12% after 120 min) and 2 h (48% after 120 min).The effect of operational parameters, namely, pH solution, catalyst dosage, the initial H2O2 concentration, ultrasonic power and the initial BV10 concentration, on the removal efficiency (RE%) of BV10 was investigated. The optimum conditions for the BV10 RE% were: the pH value of 3, the catalyst dosage of 1.5 g L-1, the initial H2O2 concentration of 36 mM, the ultrasonic power of 450 W L-1, and the initial BV10 concentration of 30 mg L-1. The RE% of BV10 was 75.94% at these conditions after the reaction time of 120 min. The trapping experiments revealed that OH radicals were the dominant oxidative species, but O2-/HO2 radicals also had a partial role in the removal of BV10.The reusability of the magnetite nanoparticles revealed about 28% decrease in the removal efficiency within five consecutive runs. The results obtained through GC-MS analysis also confirmed the efficient removal of BV10 molecules in the aqueous solution during the process. PMID- 29429685 TI - Homogeneous (Cu, Ni)6Sn5 intermetallic compound joints rapidly formed in asymmetrical Ni/Sn/Cu system using ultrasound-induced transient liquid phase soldering process. AB - Homogeneous (Cu, Ni)6Sn5 intermetallic compound (IMC) joints were rapidly formed in asymmetrical Ni/Sn/Cu system by an ultrasound-induced transient liquid phase (TLP) soldering process. In the traditional TLP soldering process, the intermetallic joints formed in Ni/Sn/Cu system consisted of major (Cu, Ni)6Sn5 and minor Cu3Sn IMCs, and the grain morphology of (Cu, Ni)6Sn5 IMCs subsequently exhibited fine rounded, needlelike and coarse rounded shapes from the Ni side to the Cu side, which was highly in accordance with the Ni concentration gradient across the joints. However, in the ultrasound-induced TLP soldering process, the intermetallic joints formed in Ni/Sn/Cu system only consisted of the (Cu, Ni)6Sn5 IMCs which exhibited an uniform grain morphology of rounded shape with a remarkably narrowed Ni concentration gradient. The ultrasound-induced homogeneous intermetallic joints exhibited higher shear strength (61.6 MPa) than the traditional heterogeneous intermetallic joints (49.8 MPa). PMID- 29429686 TI - Experimental and numerical investigation of acoustic pressures in different liquids. AB - In an attempt to quantify the instantaneous pressure field in cavitating liquids at large forcing signals, pressures were measured in four different liquids contained in vessels with a frequency mode in resonance with the forcing signal. The pressure field in liquid metal was quantified for the first time, with maximum pressures of the order of 10-15 MPa measured in liquid aluminium. These high pressures are presumed to be responsible for deagglomeration and fragmentation of dendritic intermetallics and other inclusions. Numerical modelling showed that acoustic shielding attenuates pressure far from the sonotrode and it is prominent in the transparent liquids studied but less so in aluminium, suggesting that aluminium behaviour is different. Due to acoustic shielding, the numerical model presented cannot adequately capture the pressure field away from the intense cavitation zone, but gives a good qualitative description of the cavitation activity. The results obtained contribute to understanding the process of ultrasonic melt treatment (UST) of metal alloys, while facilitating further the guidelines formulation and reproducible protocols for controlling UST at industrial levels. PMID- 29429687 TI - Formation of inorganic nitrogenous byproducts in aqueous solution under ultrasound irradiation. AB - The effects of ultrasonic frequency, power intensity, temperature and sparged gas on the generation of nitrogenous by-products NO2- and NO3- have been investigated, and the new kinetics model of NO2- and NO3- generation was also explored. The results show that the highest primary generation rate of NO2- and NO3- by direct sonolysis in the cavitation bubbles (represented by k1' and k2', respectively) was obtained at 600 kHz and 200 kHz, respectively, in the applied ultrasonic frequency range of 200 to 800 kHz. The primary generation rate of NO2- (represented by k1') increased with the increasing ultrasonic intensity while the primary generation rate of NO3- (represented by k2') decreased. The lower temperature is beneficial to the primary generation of both NO2- and NO3- in the cavitation bubbles. The optimal overall yields of both NO2- and NO3- were obtained at the N2/O2 volume (in the sparged gas) ratio of 3:1 which is near to the ratio of N2/O2 in air. The dissolved O2 is the dominant oxygen element source for both NO and NO2, compared with water vapor. Ultrasonic irradiation can significant enhance the recovery rates of dissolved N2 and O2 and thus keep the N2 fixation reaction going even without aeration. PMID- 29429688 TI - A simple approach for the sonochemical loading of Au, Ag and Pd nanoparticle on functionalized MWCNT and subsequent dispersion studies for removal of organic dyes: Artificial neural network and response surface methodology studies. AB - In this study, the artificial neural network (ANN) and response surface methodology (RSM) based on central composite design (CCD) were applied for modeling and optimization of the simultaneous ultrasound-assisted removal of quinoline yellow (QY) and eosin B (EB). The MWCNT-NH2 and its composites were prepared by sonochemistry method and characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and energy dispersive spectroscopy (EDS) analysis's. Initial dyes concentrations, adsorbent mass, sonication time and pH contribution on QY and EB removal percentage were investigated by CCD and replication of experiments at conditions suggested by model has results which statistically are close to experimented data. The ultrasound irradiation is associated with raising mass transfer of process so that small amount of the adsorbent (0.025 g) is able to remove high percentage (88.00% and 91.00%) of QY and EB, respectively in short time (6.0 min) at pH = 6. Analysis of experimental data by conventional models is good indication of Langmuir efficiency for fitting and explanation of experimented data. The ANN based on the Levenberg-Marquardt algorithm (LMA) combined of linear transfer function at output layer and tangent sigmoid transfer function at hidden layer with 20 hidden neurons supply best operation conditions for good prediction of adsorption data. Accurate and efficient artificial neural network was obtained by changing the number of neurons in the hidden layer, while data was divided into training, test and validation sets which contained 70, 15 and 15% of data points respectively. The Average absolute deviation (AAD)% of a collection of 128 data points for MWCNT NH2 and composites is 0.58%.for EB and 0.55 for YQ. PMID- 29429689 TI - Copper electroplating of PCB interconnects using megasonic acoustic streaming. AB - In this research experimental and simulated analysis investigates the influence of megasonic (MS; 1 +/- 0.05 MHz) acoustic-assisted electroplating techniques, with respect to the fabrication of through-hole via (THV) and blind-via (BV) interconnects for the Printed Circuit Board (PCB) industry. MS plating of copper down THV and BV interconnects was shown to produce measurable benefits such as increased connectivity throughout a PCB and cost savings. More specifically, a 700% increase of copper plating rate was demonstrated for THVs of 175 um diameter and depth-to-width aspect ratio (ar) of 5.7:1, compared with electrodeposition under no-agitation conditions. For BVs, a 60% average increase in copper thickness deposition in 150 um and 200 um, ar 1:1, was demonstrated against plating under standard manufacturing conditions including bubble agitation and panel movement. Finite element modelling simulations of acoustic scattering revealed 1st harmonic influence for plating rate enhancement. PMID- 29429690 TI - Design of an ultrasonic tank reactor for copper deposition at electrodes separated by a narrow gap. AB - This work describes the design and testing of an ultrasonic reactor suitable for processes which require agitation within a narrow gap in a tank geometry. A maskless microfabrication process was used to validate the ultrasonic reactor design. This mask-less electrodeposition method requires the inter-electrode distance between the anode tool and the cathode substrate to be maintained at 300 MUm, and sufficient stirring of the electrolyte by ultrasound agitation. A design was proposed allowing 74 mm * 105 mm size substrates to be mounted into an electrode holder and loaded into an 18 L ultrasonic reactor. Experiments were carried out to test the uniformity of the mass transfer within the narrow electrode gap at different locations on the substrate, and to validate the feasibility of a mask-less metal plating technique by depositing features of MUm scale. When increasing ultrasonic powers from 30 to 60 W L-1, increasing agitation was observed at the centre of the substrate, but not at its edges. A Sherwood number correlation showed developing turbulence within the narrow gap, even in the centre of the plate. Micron scale features were plated onto A7 substrates, but the deposited features were 2.5 times the original width. The work showed that sonic streaming can produce sufficient agitation in long sub millimetre channels which can be employed to overcome mass transfer limitations. PMID- 29429691 TI - Controllable synthesis of (NH4)Fe2(PO4)2(OH).2H2O using two-step route: Ultrasonic-intensified impinging stream pre-treatment followed by hydrothermal treatment. AB - (NH4)Fe2(PO4)2(OH).2H2O samples with different morphology are successfully synthesized via two-step synthesis route - ultrasonic-intensified impinging stream pre-treatment followed by hydrothermal treatment (UIHT) method. The effects of the adoption of ultrasonic-intensified impinging stream pre-treatment, reagent concentration (C), pH value of solution and hydrothermal reaction time (T) on the physical and chemical properties of the synthesised (NH4)Fe2(PO4)2(OH).2H2O composites and FePO4 particles were systematically investigated. Nano-seeds were firstly synthesized using the ultrasonic intensified T-mixer and these nano-seeds were then transferred into a hydrothermal reactor, heated at 170 degrees C for 4 h. The obtained samples were characterized by utilising XRD, BET, TG-DTA, SEM, TEM, Mastersizer 3000 and FTIR, respectively. The experimental results have indicated that the particle size and morphology of the obtained samples are remarkably affected by the use of ultrasonic-intensified impinging stream pre-treatment, hydrothermal reaction time, reagent concentration, and pH value of solution. When such (NH4)Fe2(PO4)2(OH).2H2O precursor samples were transformed to FePO4 products after sintering at 650 degrees C for 10 h, the SEM images have clearly shown that both the precursor and the final product still retain their monodispersed spherical microstructures with similar particle size of about 3 MUm when the samples are synthesised at the optimised condition. PMID- 29429692 TI - Synthesis of graphene/epoxy resin composite via 1,8-diaminooctane by ultrasonication approach for corrosion protection. AB - In this work, the preparation of the graphene/epoxy resin composite and its corrosion protection on the copper substrate were presented. The 1,8 diaminooctane-grafted-graphene (1,8-D-g-G) was synthesized using the carboxyl functional graphite and 1,8-diaminooctane by a one-pot process under ultrasonication in supercritical CO2. The structure and morphology of the as prepared samples characterized by FTIR, XPS, TEM, AFM, and SEM confirmed that the graphite was exfoliated into the graphene and the latter reacted with the 1,8 diaminooctane via amidation to form the 1,8-D-g-G. The graphene/epoxy resin composite was readily achieved by the reaction of the epoxy resin with the 1,8-D g-G. The electrochemical and salt spray tests were applied to assess the corrosion protection of the composite coating on the copper substrate. The results demonstrated that the composite exhibited excellent corrosion protection. Also, the mechanism of the co-occurred exfoliating process and the amidation reaction in one-pot under ultrasonication in supercritical CO2 was explored. PMID- 29429693 TI - Swirling cavitation improves the emulsifying properties of commercial soy protein isolate. AB - Since emulsifying properties are important functional properties of soy protein, many physical, chemical, and enzymatic methods have been applied to treat soy protein to improve emulsifying properties. In this study, we investigated the effects of swirling cavitation at different pressures and for different times on emulsifying and physicochemical properties of soy protein isolate (SPI). The SPI treated with swirling cavitation showed a significant decrease in particle size and increase in solubility. Emulsions formed from treated SPI had higher emulsifying activity and emulsifying stability indexes, smaller oil droplet sizes, lower flocculation indexes, higher adsorbed proteins, lower interfacial protein concentrations, and lower creaming indexes than those formed from untreated SPI, indicating that swirling cavitation improved the emulsifying properties of the SPI. Furthermore, swirling cavitation treatment significantly enhanced the surface hydrophobicity, altered the disulfide bond and exposed sulfhydryl group contents of the SPI. The secondary structure of the SPI was also influenced by swirling cavitation, with an increase in beta-sheet content and a decrease in alpha-helix, beta-turn, and random coil contents. In addition, several significant correlations between physicochemical and emulsifying properties were revealed by Pearson correlation analysis, suggesting that the physicochemical changes observed in treated SPI, including the decreased particle size, increased solubility and surface hydrophobicity, and enhanced beta-sheet formation, may explain the improved emulsifying properties of the isolate. Thus, our findings implied that swirling cavitation treatment may be an effective technique to improve the emulsifying properties of SPI. PMID- 29429694 TI - Correlating ultrasonic impulse and addition of ZnO promoter with CO2 conversion and methanol selectivity of CuO/ZrO2 catalysts. AB - The thermal characteristics of Cu-based catalysts for CO2 utilization towards the synthesis of methanol were analysed and discussed in this study. The preparation process were varied by adopting ultrasonic irradiation at various impulses for the co-precipitation route and also, by introducing ZnO promoters using the solid state reaction route. Prepared catalysts were characterised using XRD, TPR, TPD, SEM, BET and TG-DTA-DSC. In addition, the CO2 conversion and CH3OH selectivity of these samples were assessed. Calcination of the catalysts facilitated the interaction of the Cu catalyst with the respective support bolstering the thermal stability of the catalysts. The characterisation analysis clearly reveals that the thermal performance of the catalysts was directly related to the sonication impulse and heating rate. Surface morphology and chemistry was enhanced with the aid of sonication and introduction of promoters. However, the impact of the promoter outweighs that of the sonication process. CO2 conversion and methanol selectivity showed a significant improvement with a 270% increase in methanol yield. PMID- 29429695 TI - Histo-cytochemistry and scanning electron microscopy for studying spatial and temporal extraction of metabolites induced by ultrasound. Towards chain detexturation mechanism. AB - There are more than 1300 articles in scientific literature dealing with positive impacts of Ultrasound-Assisted Extraction (UAE) such as reduction of extraction time, diminution of solvent and energy used, enhancement in yield and even selectivity, intensification of diffusion, and eliminating wastes. This present study aims to understand what are the mechanism(s) behind these positive impacts which will help to design a decision tool for UAE of natural products. Different microscopic observations (Scanning Electron Microscopy (SEM), Environmental Scanning Electron Microscopy (e-SEM), Cyto-histochemistry) have been used for spacial and temporal localization of metabolites in rosemary leaves, which is one of the most studied and most important plant for its antioxidant metabolites used in food industry, during conventional and ultrasound extraction. The study permits to highlight that ultrasound impacted rosemary leaves not by a single or different mechanisms in function of ultrasound power, as described by previous studies, but by a chain detexturation mechanism in a special order: local erosion, shear forces, sonoporation, fragmentation, capillary effect, and detexturation. These detexturation impacts followed a special order during ultrasound treatment leading at the end to the total detexturation of rosemary leaves. These mechanisms and detexturation impacts were identified in glandular trichomes, non-glandular-trichomes and the layer adaxial and abaxial cuticle. Modelling metabolites diffusion phenomenon during conventional and ultrasound extraction with the second Fick's law allowed the estimation of diffusivities and solvent penetration into the inner tissues and in meantime to accelerate the release of valuable metabolites. PMID- 29429696 TI - Current knowledge and potential applications of cavitation technologies for the petroleum industry. AB - Technologies based on cavitation, produced by either ultrasound or hydrodynamic means, are part of growing literature for individual refinery unit processes. In this review, we have explained the mechanism through which these cavitation technologies intensify individual unit processes such as enhanced oil recovery, demulsification of water in oil emulsions during desalting stage, crude oil viscosity reduction, oxidative desulphurisation/demetallization, and crude oil upgrading. Apart from these refinery processes, applications of this technology are also mentioned for other potential crude oil sources such as oil shale and oil sand extraction. The relative advantages and current situation of each application/process at commercial scale is explained. PMID- 29429697 TI - Ultrasonic waveform upshot on mass variation within single cavitation bubble: Investigation of physical and chemical transformations. AB - The mechanical disturbance created by an ultrasonic wave travelling through a liquid medium induces the formation of cavitation that oscillates due to rarefaction and compression of the wave. The duration and the magnitude of the pressure applied by the ultrasonic wave at each instant would generate a specific impact on the variation of the bubble radius, the temperature, the pressure and the mass inside it. In this paper, a numerical study is conducted to simulate four waveforms (sinusoidal, square, triangular and sawtooth) travelling an aqueous media saturated with oxygen with an amplitude of 1.5 and 2 atm and a frequency of 200, 300 and 500 kHz. The purpose is to highlight the mass evolution within acoustic cavitation bubble during one cycle due to physical transformations and sonochemical effect. The obtained results demonstrated that square signal enhances temperature and pressure growth inside the bubble, as well as mass transfer by evaporation and condensation. This leads to an improvement of produced quantities of free radicals but also to a selectivity of O as a major product in the detriment of HO2 and OH. These trends are less and less observed when passing to sinusoidal, triangular and square signal. PMID- 29429698 TI - Combination of ultrasound-treated 2D g-C3N4 with Ag/black TiO2 nanostructure for improved photocatalysis. AB - Herein, nanosheets of g-C3N4 (CN), prepared using a green ultrasonication process under various conditions, were combined with Ag/black TiO2 nanocomposites (AgBT) to create two-dimensional (2D) CN/Ag/black TiO2 tri-composites (CNAgBT). The thickness of the CN sheets varied with the ultrasonication conditions. The CNAgBT sample prepared using ultrasound-treated CN exhibited the highest average photocatalytic efficiencies for the degradation of two model pollutants, followed in decreasing order by AgBT, black TiO2 (BT), sheet CN, bulk CN, and TiO2. The order of pollutant degradation efficiencies by the photocatalysts was consistent with that of the charge carrier separation efficiencies. The degradation efficiency of the CNAgBT increased as the CN-to-AgBT ratio increased from 0.05 to 0.1, but decreased gradually for higher ratios between 0.15 and 0.20, indicating a lower optimal CN-to-AgBT ratio. A plausible photocatalytic degradation mechanism for the CNAgBT nanocomposites was proposed. Additionally, CNAgBT with a CN-to-AgBT ratio of 0.1 displayed a higher hydrogen generation rate with a maximum value of 21.5 mmol g-1 over 5 h than those of the AgBT and BT. Overall, the CNAgBT prepared using ultrasonication-treated CNs showed enhanced photocatalytic performance for both pollutant degradation and hydrogen generation. PMID- 29429699 TI - Sonochemiluminescence in an aqueous solution of Ru(bpy)3Cl2. AB - The sonochemiluminescence spectra of electron-excited ions *[Ru(bpy)3]2+ was registered for the first time during sonolysis of argon saturated aqueous solutions of Ru(bpy)3Cl2 with low concentration. At single-bubble sonolysis, the luminescence band of ruthenium is recorded at a concentration of Ru(bpy)3Cl2 from 10-6 M, and at multibubble from 10-5 M. Possible mechanisms for the appearance of the band of a tris-bipyridyl ruthenium(II) complex on the background of an structureless continuum of water in the spectra of sonoluminescence are analyzed. Based on the results of the comparison of the sonoluminescence spectra of Ru(bpy)3Cl2 aqueous solutions with the sonoluminescence spectra of aqueous solutions of rhodamine B (which has a high quantum yield of photoluminescence) it was established that a possible mechanism of sonophotoluminescence does not play a decisive role in ruthenium sonoluminescence. The effect of radical acceptors (O2, C2H5OH, Cd2+, I-) on ruthenium sonoluminescence is analyzed. The most significant mechanism for the formation of electron-excited ions *[Ru(bpy)3]2+ during sonolysis is the sonochemiluminescence in oxidation-reduction reactions involving [Ru(bpy)3]2+ ions and radical products of sonolysis of water (OH, H, e aq) in the solution volume. PMID- 29429700 TI - Energy efficient room temperature synthesis of cardanol-based novolac resin using acoustic cavitation. AB - The present study deals with synthesis of cardanol-cased novolac (CBN) resin by the condensation reaction between cardanol and formaldehyde using acoustic cavitation. It is a step-growth polymerization which occurs in the presence of an acid catalyst such as adipic acid, citric acid, oxalic acid, sulphuric acid and hydrochloric acid. CBN was also synthesised by a conventional method for the sake of comparison of techniques. The effect of molar ratio, effect of catalyst, effect of different catalyst and effect of power on the conversion to CBN has been studied. The synthesised CBN was characterized using the Fourier Transform Infra Red Spectroscopy (FTIR), Gel Permeation Chromatography (GPC), Nuclear Magnetic Resonance (NMR) Spectroscopy and Thermogravimetric Analysis (TGA). The reaction was monitored by the Acid value, free formaldehyde content and viscosity of the synthesised product. The reaction time required for the conventionally synthesised CBN was 5 h (300 min) with 120 degrees C as an operating temperature while sonochemically the time reduced to 30 min at room temperature. The amount of time and energy saved can be quantified. Ultrasound facilitated synthesis was found to be an energy efficient and time-saving method for the synthesis of novolac resin. PMID- 29429701 TI - Fundamental study of sterilization effects on marine Vibrio sp. in a cylindrical water chamber with supply of only underwater shock waves. AB - The effect of shock sterilization on marine Vibrio sp. is investigated by carrying out a bio-experiment based on a bubble-shockwave interaction. In the experiments, underwater shock waves with different strength and frequencies are produced by a high-voltage power supply in a cylindrical water chamber. The bio experimental results show marine Vibrio sp. is completely inactivated in a short time by a 1.0-Hz electric discharge. However, a high sterilization effect requires a strong and high frequency of the bubble motion, and it also depends on the lifetime of the bubble. Subsequently, by an experiment with an air gap to prevent the underwater shock waves entering the cell suspension, it is found that the introduction of a strong shock pressure is not entirely required to obtain the effective sterilization. On the other hand, the direct effect of the sterilization by rebound shock wave resulting from the bubble-shock wave interaction is examined in the experiments. The results suggest that free radicals mainly contribute to killing marine bacteria, and direct mechanical effects of the bubble motion are not responsible. In addition, the creation of the OH radical is indirectly confirmed by measuring the H2O2 concentration. Finally, the Herring equation is solved to investigate the condition of free radical generation when considering the effect of thermal conductivity at the bubble interface. As a result, the effective sterilization conditions based on the bubble-shock wave interaction are clearly obtained. PMID- 29429702 TI - Water-molecular emission from cavitation bubbles affected by electric fields. AB - Orange emission was observed during multibubble sonoluminescence at 1 MHz in water saturated with noble gas. The emission arose in the vicinity of the peeled ground electrode of a piezoceramic transducer exposed to water, suggesting that cavitation bubbles were affected by the electric fields that leaked from the transducer. The spectrum of the emission exhibited a broad component whose intensity increased towards the near-infrared region with peaks at 713 and 813 nm. The spectral shape was independent of the saturation gas of He, Ne, or Kr. The broad component was attributed to the superposition of lines due to vibration rotation transitions of water molecules, each of which was broadened by the high pressure and electric fields at bubble collapse. An emission mechanism based on charge induction by electric fields and the charged droplet model is proposed. PMID- 29429703 TI - Synthesis and multifunctionality of (CeO2-NiO) nanocomposites synthesized via sonochemical technique. AB - CeO2, NiO and their nanocomposite were synthesized using facile sonochemical technique. XRD assure single phase CeO2 and NiO while the nanocomposite consists of the two phases only. CeO2 nanoparticles possess cubic shape, NiO was formed in nanorods, and CeO2 decorated the NiO nanorods in the nanocomposite. The magnetic behavior of the nanocomposite lies between those of the two parents with a ferromagnetic tendency. Metal oxide nanoparticles acted as catalyst in the formation of carbon nanofibers (CNFs), while the nanocomposite leads to the production of carbon nanotubes. The photocatalyst (CeO2-NiO) achieved complete dye degradation (100%) in light for the tested dye at 50 min. The decay products were analyzed using GC mass confirming mineralization of Bb red dye. PMID- 29429704 TI - Ultra-sonication assisted cross-linking of cellulose polymers. AB - Cross-linked cellulose-epichlorohydrin polymers were synthesized by a conventional heating with stirring (C-EP heating) and a parallel process using ultra-sonication (C-EP sonication) in the presence of aqueous ammonia. Structural characterization of modified cellulose was carried out using FTIR/13C solid state NMR spectroscopy and thermal methods (DSC and TGA). Evidence of products with variable textural properties and morphology was supported by nitrogen gas adsorption, solvent swelling, and microscopy (SEM, TEM) results. C-EP sonication possess greater cross-linker content judging by the loss of the cellulose fibril structure which was facilitated by acoustic cavitation effects due to ultra sonication. Equilibrium sorption studies in aqueous solution with 2-naphthoxy acetic acid (NAA) revealed that C-EP heating had slightly greater sorption capacity than C-EP sonication at alkaline pH. By contrast, C-EP sonication had greater uptake of NAA at acidic pH. Kinetic uptake studies at pH 3 is described by the pseudo-second order model, where the surface sites of C-EP heating became saturated within ca. 75 min; whereas, ca. 350 min occurred for C-EP sonication. This study demonstrates that the yield of sonication assisted cross-linking of cellulose is greater with improved adsorption properties. The study also reveals the utility of sonication assisted synthesis for the valorization and utilization of cellulose modified materials. PMID- 29429705 TI - Synthesis of novel sonocatalyst Er3+:YAlO3/Nb2O5 and its application for sonocatalytic degradation of methamphetamine hydrochloride. AB - The composited sonocatalyst Er3+:YAlO3/Nb2O5 was prepared by ultrasonic dispersion and high temperature calcinations method. The microstructure of Er3+:YAlO3 was prepared via sol-gel method and Nb2O5 was prepared by hydrothermal method. The samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectrometer (EDX), ultraviolet-visible (UV-vis) spectra and photoluminescence (PL) spectra, respectively. The sonocatalytic decomposition activity of composite sonocatalyst Er3+:YAlO3/Nb2O5 was investigated by using ultrasound as sound source and methamphetamine hydrochloride as the target degradation product. The influences of composite sonocatalyst Er3+:YAlO3/Nb2O5 with different ratios, calcination temperature, ultrasonic power, ultrasonic temperature and recycle times were investigated. The results showed that the sonocatalytic degradation rate was 82.17% after 5 h sonocatalytic decomposition under the condition of ultrasonic power of 700 W, frequency of 45 kHz and surrounding temperature of 30 degrees C. The sonocatalytic degradation ability of composite sonocatalyst for methamphetamine hydrochloride in aqueous solution was still good after recycled five times. The hydroxyl radicals (OH) and holes (h+) are identified and hydroxyl radicals (OH) plays a major role during the oxidation process. The experimental results show that sonocatalytic is a new idea for the harmless treatment of amphetamine-type stimulants. PMID- 29429706 TI - Ultrasound-assisted synthesis of Zinc(II)-based metal organic framework nanoparticles in the presence of modulator for adsorption enhancement of 2,4 dichlorophenol and amoxicillin. AB - In this study, under a sonochemical method, a 3D, porous Zn(II)-based metal organic framework [Zn(TDC)(4-BPMH)]n.n(H2O) is produced, which is called compound 1. To this end, the dicarboxylate linker of TDC, (2,5-thiophene dicarboxylic acid) and the pillar spacer of 4-BPMH, (N,N-bis-pyridin-4-ylmethylene-hydrazine) were employed. Moreover, variations in the morphology and growth of the micro/nanoparticles of compound 1 were investigated in terms of the effect of temperature, ultrasound irradiation power, sonication time, initial reagent concentrations, and pyridine concentration as a modulator. DFT model was used to examine the sonication effect on the distribution of the pore sizes. Moreover, the preparation method effect on the porosity and removal of two sample pollutants (i.e., 2,4-dichlorophenol (24-DCP) and amoxicillin (AMX)) from wastewater was studied. PMID- 29429707 TI - Investigation of stability, consistency, and oil oxidation of emulsion filled gel prepared by inulin and rice bran oil using ultrasonic radiation. AB - Inulin, rice bran oil and rosemary essential oil were used to produce high quality emulsion filled gel (EFG) using ultrasonic radiation. Response surface methodology was used to investigate the effects of oil content, inulin content and power of ultrasound on the stability and consistency of prepared EFG. The process conditions were optimized by conducting experiments at five different levels. Second order polynomial response surface equations were developed indicating the effect of variables on EFG stability and consistency. The oil content of 18%; inulin content of 44.6%; and power of ultrasound of 256 W were found to be the optimum conditions to achieve the best EFG stability and consistency. Microstructure and rheological properties of prepared EFG were investigated. Oil oxidation as a result of using ultrasonic radiation was also investigated. The increase of oxidation products and the decrease of total phenolic compounds as well as radical scavenging activity of antioxidant compounds showed the damaging effect of ultrasound on the oil quality of EFG. PMID- 29429708 TI - Morphology- and size-controlled synthesis of a metal-organic framework under ultrasound irradiation: An efficient carrier for pH responsive release of anti cancer drugs and their applicability for adsorption of amoxicillin from aqueous solution. AB - In this study, we have reported a biocompatible metal-organic framework (MOF) with ultra-high surface area, which we have shown to have uses as both a cancer treatment delivery system and for environmental applications. Using a sonochemical approach, highly flexible organic H3BTCTB and ditopic 4,4'-BPDC ligands, along with modulators of acetic acid and pyridine were combined to prepare a Zn(II)-based metal-organic framework, DUT-32, [Zn4O(BPDC)(BTCTB)4/3(DEF)39.7(H2O)11.3]. Powder X-ray diffraction (PXRD), field emission scanning electron microscopy (FE-SEM), and Fourier transform infrared spectroscopy (FTIR) were used to characterize, the particle size, shape, and structure of the DUT-32. To show the effects of shape and size of DUT-32 micro/nano-structures on doxorubicin (DOX) drug release and amoxicillin (AMX) adsorption, time of sonication, initial reagent concentrations, irradiation frequency, and acetic acid to pyridine molar ratios were optimized. The drug loaded DUT-32 was soaked in simulated body fluid (SBF) and the drug release ratio was monitored through release time to perform in vitro drug release test. A slow and sustained release was observed for DUT-32 micro/nano-structures, having a considerable drug loading capacity. At the pH values 7.4-4.5, various profiles of pH-responsive release were achieved. Also, the prepared DUT-32 micro/nano structures are found to be biocompatible with PC3 (prostate cancer) and HeLa (cervical cancer) cell lines, when tested by MTT assay. Moreover, DUT-32 micro/nano-structures were studied to show AMX adsorption from aqueous solution. Finally, kinetic studies indicated that AMX adsorption and drug release of DOX via this MOF are of first-order kinetics. PMID- 29429709 TI - Synergetic pretreatment of waste activated sludge by hydrodynamic cavitation combined with Fenton reaction for enhanced dewatering. AB - The dewatering of waste activated sludge by integrated hydrodynamic cavitation (HC) and Fenton reaction was explored in this study. We first investigated the effects of initial pH, sludge concentration, flow rate, and H2O2 concentration on the sludge dewaterability represented by water content, capillary suction time and specific resistance to filtration. The results of dewatering tests showed that acidic pH and low sludge concentration were favorable to improve dewatering performance in the HC/Fenton system, whereas optimal flow rate and H2O2 concentration applied depended on the system operation. To reveal the synergism of HC/Fenton treatment, a suite of analysis were implemented: three-dimensional excitation emission matrix (3-DEEM) spectra of extracellular polymeric substances (EPS) such as proteins and polysaccharides, zeta potential and particle size of sludge flocs, and SEM/TEM imaging of sludge morphology. The characterization results indicate a three-step mechanism, namely HC fracture of different EPS in sludge flocs, Fenton oxidation of the released EPS, and Fe(III) re-flocculation, that is responsible for the synergistically enhanced sludge dewatering. Results of current study provide a basis to improve our understanding on the sludge dewatering performance by HC/Fenton treatment and possible scale-up of the technology for use in wastewater treatment plants. PMID- 29429710 TI - Numerical simulation of single bubble dynamics under acoustic travelling waves. AB - The objective of this paper is to apply CLSVOF method to investigate the single bubble dynamics in acoustic travelling waves. The Naiver-Stokes equation considering the acoustic radiation force is proposed and validated to capture the bubble behaviors. And the CLSVOF method, which can capture the continuous geometric properties and satisfies mass conservation, is applied in present work. Firstly, the regime map, depending on the dimensionless acoustic pressure amplitude and acoustic wave number, is constructed to present different bubble behaviors. Then, the time evolution of the bubble oscillation is investigated and analyzed. Finally, the effect of the direction and the damping coefficient of acoustic wave propagation on the bubble behavior are also considered. The numerical results show that the bubble presents distinct oscillation types in acoustic travelling waves, namely, volume oscillation, shape oscillation, and splitting oscillation. For the splitting oscillation, the formation of jet, splitting of bubble, and the rebound of sub-bubbles may lead to substantial increase in pressure fluctuations on the boundary. For the shape oscillation, the nodes and antinodes of the acoustic pressure wave contribute to the formation of the "cross shape" of the bubble. It should be noted that the direction of the bubble translation and bubble jet are always towards the direction of wave propagation. In addition, the damping coefficient causes bubble in shape oscillation to be of asymmetry in shape and inequality in size, and delays the splitting process. PMID- 29429711 TI - Ultrasonic irradiation preparation of graphitic-C3N4/polyaniline nanocomposites as counter electrodes for dye-sensitized solar cells. AB - In this research, polyaniline/graphitic carbon nitride (PANI/g-C3N4) nanocomposites were synthesized via in-situ electrochemical polymerization of aniline monomer whit different number of cyclic voltammetry scans (10, 20 and 30 cycles) after electrode surface pre-preparation using a potential shock under ultrasonic irradiation. PANI/g-C3N4 nanocomposites with two values of g-C3N4 (0.010 wt% and 0.015 wt%) were deposited on the surface of the transparent conducting film (FTO glass) by immersing FTO into the aniline solution and g-C3N4 during the electro-polymerization. The resulting PANI/g-C3N4 films were characterized by Fourier transformed infra-red (FTIR), power X-ray diffraction (PXRD), field emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM) techniques. The prepared electrodes were applied as counter electrode in dye-sensitized solar cells. Among them, the prepared electrode with 10 cycles and 0.01 wt% g-C3N4 showed the best efficiency. These hybrids show good catalytic activity in elevating tri-iodide reduction and due to the synergistic effect of PANI and g-C3N4, PANI/g-C3N4 nanocomposite electrode shows power conversion efficiency about 1.8%. PMID- 29429712 TI - The effects of solvent and ultrasonic irradiation in synthesis of thallium(I) nano supramolecular polymers and use them as template for synthesis of thallium(III) oxide nanostructures with desirable morphology. AB - In order to study the effects of solvent and ultrasonic irradiation on formation of [Tl(HTar)]n (1) and/or [Tl2(Tar)]n (2), [H2Tar = (+)-tartaric acid] supramolecular polymers, we designed some experiments and synthesized four samples of 1 under the reaction of H2Tar and TlNO3 by sonochemical process and as the bulk samples. Nanostructures of compounds 1 and 2 as the bulk samples could be synthesized without ultrasonic irradiation, too. In the presence of ultrasonic waves, with acetonitrile solvent, more discrete nanoparticles were obtained. These four samples have been used as new precursors for preparation of thallium(III) oxide nanostructures via solid-state thermal decomposition process. There is a direct relationship between the morphology of initial precursors and resulting thallium(III) oxide nanostructures. These nanostructures were characterized by IR spectroscopy, X-ray powder diffraction (XRD) and Scanning Electron Microscopy (SEM). PMID- 29429713 TI - Synthesis and sonocatalytic performance of a ternary magnetic MIL 101(Cr)/RGO/ZnFe2O4 nanocomposite for degradation of dye pollutants. AB - In this study, new ternary magnetic MIL-101(Cr)/RGO/ZnFe2O4 catalyst (with 30% wt of ZnFe2O4) was synthesized via a hydrothermal route for sonodegradation of organic dyes. The structural, optical and magnetic properties of the nanocomposite were detected by means of X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), UV-visible spectroscopy (UV-visible), field emission scanning electron microscopy (FESEM), energy dispersive X-ray (EDX) spectroscopy, vibrating sample magnetometer (VSM), atomic force microscopy (AFM), Raman spectroscopy and BET surface area analysis. To evaluate the sonocatalytic activity of the as-prepared MIL-101(Cr)/RGO/ZnFe2O4 nanocomposite, the H2O2-assisted degradation of organic dyes such as congo red (CR), methylene blue (MB), Rhodamine B (RhB) and methyl orange (MO) in aqueous solution was studied under ultrasound irradiation. The obtained results indicated that the ternary MIL-101(Cr)/RGO/ZnFe2O4 nanocomposite had better performance for sonodegradation of these dyes than MIL-101(Cr)/RGO, pure MIL-101(Cr) or ZnFe2O4. The enhanced sonocatalytic performance of the as-prepared ternary nanocomposite could be attributed to the fast generation and separation of charge carriers (electrons and holes) in ZnFe2O4and MIL-101(Cr) and their transfer to the surface of graphene sheets. Moreover, the relatively high specific surface area of the MIL-101(Cr)/rGO and magnetic property of ZnFe2O4 improve the degradation efficiency of the dyes. The recovery of the ternary magnetic sonocatalyst from treated water could be easily achieved using an external magnetic field. The main influence factors on the sonocatalytic activity such as catalyst dosage and dye initial concentration were also investigated. The trapping experiments indicated that OH radicals are the prominent active species in dye degradation. In addition, the reusability test, was also carried out to ensure the stability of the employed sonocatalyst. PMID- 29429714 TI - A comparison of nitrogen-doped sonoelectrochemical and chemical graphene nanosheets as hydrogen peroxide sensors. AB - Nitrogen-doped graphene nanosheet (N-SEGN) with pyrrolic nitrogen and 5-9 vacancy defects has been successfully prepared from a hydrothermal reaction of tetra-2 pyridinylpyrazine and sonoelectrochemistry-exfoliated graphene nanosheet, with point defects. Additionally, based on the same reaction using chemically reduced graphene oxide, nitrogen-doped chemically reduced graphene oxide (N-rGO) with graphitic nitrogen was prepared. The N-SEGN and N-rGO were used as a non enzymatic H2O2 sensors. The sensitivity of the N-SEGN was 231.3 MUA.mM-1.cm-2, much greater than 57.3 MUA.mM-1.cm-2 of N-rGO. The N-SEGN showed their potential for being a H2O2 sensor. PMID- 29429715 TI - Ultrasonic-microwave assisted synthesis of three-dimensional polyvinyl alcohol carbonate/graphene oxide sponge and studies of surface resistivity and thermal stability. AB - In the article, graphene oxide (GO) was prepared by flake graphite, nitric acid and peroxyacetic acid via the sonochemical method and characterized, and polyvinyl alcohol carbonate/GO composite (PVAC/GO composite) was synthesized by polyvinyl alcohol (PVA), dimethyl carbonate (DMC) and GO via the approach of transesterification in the case of ultrasonic-microwave synergistic effects and characterized, and three-dimensional PVAC/GO sponge (3D PVAC/GO sponge) was manufactured by PVAC/GO composite via the foaming approach and characterized, and the thermal stability and surface resistivity of 3D PVAC/GO sponge were investigated. Based on those, it had been attested that PVAC polymer was structured by DMC and PVA and had the six-membered lactone rings and the ether bonds, and PVAC/GO composite was constituted by 2D GO lattice and PVAC polymer, and 3D PVAC/GO sponge was constructed by PVAC/GO composite, and the surface resistivity of 3D PVAC/GO sponge with 0.00, 0.60, 1.20, 1.80 and 2.40 g of GO were 9.07 * 107, 6.02 * 107, 4.65 * 107, 2.47 * 107 and 1.06 * 107 O/sq, and the thermal stability of 3D PVAC/GO sponge had improved. PMID- 29429716 TI - Cavitation field analysis for an increased efficiency of ultrasonic sludge pre treatment using a novel hydrophone system. AB - The generation of cavitation fields for the pre-treatment of anaerobic sludge was studied by means of a novel acoustic measuring system. The influence of different reactor dimensions (i.e., choosing reaction chamber widths of 40, 60 and 80 mm) on the cavitation intensity was determined at various solid contents, flow rates and static pressures. Results suggest that the cavitation intensity is significantly reduced by the sonication of liquids with a high solid content. By increasing the pressure to 1 bar, the intensity of bubble implosions can be enhanced and the sound attenuation in the solid fraction is partly compensated compared to ambient pressure. However, a further increase in pressure to 2 bars has a detrimental effect due to the suppression of powerful bubbles. A reduction of the reactor gap permits an intensification of the treatment of waste activated sludge (WAS) by concentrating the ultrasound power from 6 to 18 dB. This effect is less relevant in digested sludge (DS) with its markedly lower total solids content (2.2% vs. 6.9% of solids in WAS). Increasing the flow rate, resulting in a flow velocity of up to 7 m/min, has no influence on the cavitation intensity. By adapting the reactor design and the static pressure to the substrate characteristics, the intensity of the sonication can be notably improved. This allows the design of sonication devices that are suitable for the intensive treatment of wastewater sludge. PMID- 29429717 TI - In-Situ sonosynthesis of Hedgehog-like nickel nanoparticles on polyester fabric producing magnetic properties. AB - Recently, nano finishing of textiles is increasingly attracted many researchers to create new features on the products. Here a new fabric is introduced through simultaneous aminolysis and hydrolysis of polyester along with in-situ sonosynthesis of hedgehog shaped nickel nanoparticles on the fabric with magnetic properties. To do this, nickel sulfate, hydrazine hydrate, sodium hydroxide and polyvinylpyrrolidone (PVP) were used as a precursor, reducing agent, alkali and stabilizer respectively. Nickel sulfate was reduced to nickel nanoparticles with hydrazine hydrate at the adjusted pH with NaOH in the presence of PVP at 75 degrees C for 2 h. The polyester fabric was aminolyzed and hydrolyzed produced various functional groups on the fabric surface assisted nucleation and stabilization of nickel nanoparticles. The morphology, crystal phase, magnetic properties and chemical structure of the treated fabrics were characterized by field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), vibrating sample magnetometry (VSM), and energy dispersive X-ray spectroscopy (EDX). The optimized sample treated with 3.19 (mL) hydrazine hydrate, 3.99 (mL) sodium hydroxide and 0.41 (g) nickel sulfate showed reasonable saturation magnetization value of 4.5 emu g-1. The treated fabrics showed no antibacterial and antifungal behavior indicating the safety of the products. PMID- 29429718 TI - Effect of fluid properties on ultrasound assisted liquid-liquid extraction in a microchannel. AB - When immiscible liquids are subjected to an ultrasonic field, they form emulsions. This principle has been used to improve the mass transfer characteristics of a liquid-liquid extraction process in microreactor systems. The formation of emulsion and its characteristics are prominently dependent on the properties of the liquids used and this also holds true for emulsion brought about by ultrasound. This paper focuses on the properties of fluids that are reported to have an influence on the cavitation behaviour, namely viscosity, interfacial tension and vapour pressure. These properties were examined by changing the solvent of the organic phase in the hydrolysis of p-nitrophenyl acetate. The study is performed by comparing pairs of solvents that are different in one property but similar in the other two. The pairs selected are toluene - chlorobenzene for viscosity, toluene - methyl Isobutyl ketone for interfacial tension and methyl isobutyl ketone - 2-Methyl tetrahydrofuran for vapour pressure effects. A qualitative study was performed with a high-speed camera in flow to understand the emulsification initiation mechanisms and behaviours. These findings were further explored by performing the sonicated emulsion in a batch sonicated reactor. The quantitative analysis of the fluid properties was evaluated and compared based on the relative percentage increase in yield upon sonication with respect to their individual silent conditions. The quantitative results were further supported by the quantification of the emulsion performed with an FBRM probe. The results indicate a two times improvement in yield with solvent of lower viscosity as 2 times more droplets were formed in the emulsion. Both the solvent systems with higher interfacial tension and vapour pressure had an improved yield of 1.4 times owing to larger number of droplets formed. PMID- 29429719 TI - Introducing ultrasonic falling film evaporator for moderate temperature evaporation enhancement. AB - In the present study, Ultrasonic Falling Film (USFF), as a novel technique has been proposed to increase the evaporation rate of moderate temperature liquid film. It is a proper method for some applications which cannot be performed at high temperature, such as foodstuff industry, due to their sensitivity to high temperatures. Evaporation rate of sodium chloride solution from an USFF on an inclined flat plate compared to that for Falling Film without ultrasonic irradiation (FF) at various temperatures was investigated. The results revealed that produced cavitation bubbles have different effects on evaporation rate at different temperatures. At lower temperatures, size fluctuation and collapse of bubbles and in consequence induced physical effects of cavitation bubbles resulted in more turbulency and evaporation rate enhancement. At higher temperatures, the behavior was different. Numerous created bubbles joined together and cover the plate surface, so not only decreased the ultrasound vibrations but also reduced the evaporation rate in comparison with FF. The highest evaporation rate enhancement of 353% was obtained at 40 degrees C at the lowest Reynolds number of 250. In addition, the results reveal that at temperature of 40 degrees C, USFF has the highest efficiency compared to FF. PMID- 29429720 TI - Ultrafast monitoring and control of subharmonic emissions of an unseeded bubble cloud during pulsed sonication. AB - In the aim of limiting the destructive effects of collapsing bubbles, the regime of stable cavitation activity is currently targeted for sensitive therapeutic applications such as blood-brain barrier opening by ultrasound. This activity is quantified through the emergence of the subharmonic component of the fundamental frequency. Due to the intrinsically stochastic behavior of the cavitation phenomenon, a better control of the different (stable or inertial) cavitation regimes is a key requirement in the understanding of the mechanisms involving each bubble-induced mechanical effect. Current strategies applied to stable cavitation control rely on the use of either seeded microbubbles or a long lasting pulse to reinitiate subharmonic emission. The present work aims at developing an ultrafast (inferior to 250 MUs) monitoring and control of subharmonic emissions during long-pulsed (50 ms) sonication. The use of a FPGA based feedback loop provides reproducible level of subharmonic emissions combined with temporal stability during the sonication duration. In addition, stable cavitation events are differentiated from the broadband noise characterizing inertial cavitation activity, with perspectives in the discrimination of the involved mechanisms underlying bubble-mediated therapeutic applications. PMID- 29429722 TI - Ultrasound-assisted crystallization of lactose in the presence of whey proteins and kappa-carrageenan. AB - The conventional process of lactose crystallization is prolonged, hardly controllable and the crystals have low quality. In this work, the effect of ultrasound on the crystallization of lactose in an aqueous system was assessed. Additionally, it was studied how the presence of whey proteins (which are a common impurity) and kappa-carrageenan (that possess high water-binding capacity) could modify the process of lactose crystallization. Lactose solutions at 25% were sonicated in a continuous flow chamber at two different energy densities (9 and 50 J mL-1) before the start of crystallization. Some of these lactose solutions were previously added with kappa-carrageenan (0, 150 and 300 mg L-1), with whey proteins (0.64%) or with both at the same time. Ultrasound sped up the rate of crystallization, decreased the crystal's size and narrowed the crystal size distribution (CSD). The presence of whey proteins accelerated the process of crystallization but induced the formation of amorphous lactose. Likewise, the rate of lactose crystallization was improved by the addition of 150 mg L-1 of carrageenan. Whereas, the combination of carrageenan and whey proteins generated the smallest crystals (6 MUm), the narrowest CSD and minimized the formation of amorphous lactose. PMID- 29429721 TI - Impact of ultrasound pretreatment on hydrolysate and digestion products of grape seed protein. AB - The effects of ultrasound pretreatment with different working modes, including mono frequency ultrasound (MFU), simultaneous dual frequency ultrasound (SDFU) and alternate dual frequency ultrasound (ADFU) using energy-gather counter flow ultrasound equipment, on the degree of hydrolysis (DH) of grape seed protein (GSP) hydrolysate and IC50 of GSP digestion products were studied. Amino acid composition analysis (AACA), ultraviolet-visible (UV) spectroscopy and atomic force microscopy (AFM) of GSP with different ultrasound pretreatments were measured. The results showed that MFU, SDFU and ADFU pretreatments improved the DH and reduced the IC50 of GSP significantly (P < .05). The MFU of 20 kHz and SDFU of 20/40 kHz showed higher ACE inhibitory activity within the MFU and SDFU groups, respectively. ADFU of 20/35 kHz produced the highest ACE inhibitory activity among the three working modes (MFU, SDFU and ADFU). AACA showed that all the working modes of the ultrasound pretreatment could increase the amount of hydrophobic amino acids and the total amino acids. The changes in UV spectra and amino acid analysis indicated the unfolding of protein structure and exposure of more hydrophobic groups by SDFU and ADFU pretreatments. AFM analysis of the GSP indicated that the microstructures were destroyed and the particle size reduced after dual-frequency ultrasound pretreatments. Therefore, energy-gather counter flow ultrasound pretreatment is an effective method to improve the DH and reducing the IC50 due to the changes of molecular conformation and effects on the microstructure by sonochemistry of GSP. In conclusion, it is necessary to select the frequency and working modes of ultrasound pretreatment for the preparation of ACE inhibitory peptide of GSP. PMID- 29429723 TI - Design a sensitive optical thin film sensor based on incorporation of isonicotinohydrazide derivative in sol-gel matrix for determination of trace amounts of copper (II) in fruit juice: Effect of sonication time on immobilization approach. AB - A new selective and sensitive optical sensor based on the incorporation of new synthesized N'-(2-hydroxy-5-iodobenzylidene) isonicotinohydrazide (HIBIN) as an effective reagent into the nanoporous of a transparent glass like material through the sol-gel process was developed which was suitable for the determination of copper (II) ions in aqueous solutions. The thin film sensors were constructed by spin-coating of prepared sol onto glass plate and their surface morphology were studied by field emission scanning electron microscopy (FE-SEM) and atomic force microscope (AFM) technique. Influence of sonication time on immobilization of HIBIN into silica matrix was investigated through calculation of leaching percentage. The Results shown that sonication time of 35 min is suitable to give more stable thin films without fluctuation in sensitivity and response time of presented sensor for a long period of time. The proposed optical sensor can be used for determination of copper (II) ions in the range of 9.1 * 10-8-1.12 * 10-5 mol L-1with a detection limit of 1.8 * 10-8 mol L-1. It also showed relative standard deviation 3.4 and 0.72% for reproducibility and repeatability respectively, along with a fast response time about of 2 min. The constructed optode is stable in wet conditions and could be stored for at least 6 weeks without observing any change in its sensitivity. The developed sensor was successfully applied to the determination of copper (II) in fruit juice and water samples which results were confirmed by atomic absorption spectrometry method. PMID- 29429724 TI - Electrochemical mechanism of tin membrane electrodeposition under ultrasonic waves. AB - Tin was electrodeposited from chloride solutions using a membrane cell under ultrasonic waves. Cyclic voltammetry (CV), linear sweep voltammetry (LSV), chronoamperometry (CHR), and chronopotentiometry were applied to investigate the electrochemical mechanism of tin electrodeposition under ultrasonic field. Chronoamperometry curves showed that the initial process of tin electrodeposition followed the diffusion controlled three-dimensional nucleation and grain growth mechanism. The analysis of the cyclic voltammetry and linear sweep voltammetry diagrams showed that the application of ultrasound can change the tin membrane electro-deposition reaction from diffusion to electrochemical control, and the optimum parameters for tin electrodeposition were H+ concentration 3.5 mol.L-1, temperature 35 degrees C and ultrasonic power 100 W. The coupling ultrasonic field played a role in refining the grain in this process. The growth of tin crystals showed no orientation preferential, and the tin deposition showed a tendency to form a regular network structure after ultrasonic coupling. While in the absence of ultrasonic coupling, the growth of tin crystals has a high preferential orientation, and the tin deposition showed a tendency to form tin whiskers. Ultrasonic coupling was more favorable for obtaining a more compact and smoother cathode tin layer. PMID- 29429725 TI - Novel synthesis of WSe2-Graphene-TiO2 ternary nanocomposite via ultrasonic technics for high photocatalytic reduction of CO2 into CH3OH. AB - In the present work, we report the development of a WSe2-Graphene-TiO2 ternary nanocomposite via ultrasonic techniques and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. The band gap of the WSe2-Graphene-TiO2 was estimated to be about 1.62 eV which is suitable for photodegradation process under under ultraviolet UV/Visible light irradiation. The photocatalytic potential of nanocomposites is investigated for CO2 reduction to CH3OH. WSe2-G-TiO2 with an optimum loading of graphene of 8 wt% showed the high photoactivity, gaining a total CH3OH yield of 6.3262 umol g-1 h-1 after 48 h. This excellent photoreduction activity is owing to the progressive synergistic relation between WSe2/TiO2 and graphene components in our heterogeneous system. PMID- 29429726 TI - A sonochemical synthesis of cyclodextrin functionalized Au-FeNPs for colorimetric detection of Cr6+ in different industrial waste water. AB - This paper describes a simple, selective and sensitive colorimetric sensing of Cr6+ ions using beta-Cyclodextrin (beta-CD) functionalized gold-iron nanoparticles (beta-CD/Au-FeNPs). The sonochemically synthesized nanoparticles are winered in colour due to the SPR band of beta-CD functionalized bimetalic nanoparticles Au-FeNPs. The capping and stabilizing of Au-FeNPs by redox beta-CD is confirmed by FT-IR. The particles are spherical in shape and it posses the effective diameter of 18-20 nm. Under optimized conditions, in the presence of Cr6+ the wine red Au-FeNPs solution was turned to colourless, accompanying the broadening and red shifting of SPR band. The ratio between the absorbance wavelength at 573 nm to 535 nm (A573/A535) is linearly correlated with the Cr6+ concentrations ranging from 50 nM to 500 nM, with a detection limit of Cr6+ of 2.5 nM was achieved for the first time using beta-CD/Au-FeNPs by spectrophotometry. The selectivity of the beta-CD/Au-FeNPs towards other interfering metal ions. Finally the proposed method has been successfully employed for the determination of Cr6+ ion in various industrial waste water with good recoveries. PMID- 29429727 TI - Research on removing reservoir core water sensitivity using the method of ultrasound-chemical agent for enhanced oil recovery. AB - The phenomenon of water sensitivity often occurs in the oil reservoir core during the process of crude oil production, which seriously affects the efficiency of oil extraction. In recent years, near-well ultrasonic processing technology attaches more attention due to its safety and energy efficient. In this paper, the comparison of removing core water sensitivity by ultrasonic wave, chemical injection and ultrasound-chemical combination technique are investigated through experiments. Results show that: lower ultrasonic frequency and higher power can improve the efficiency of core water sensitivity removal; the effects of removing core water sensitivity under ultrasonic treatment get better with increase of core initial permeability; the effect of removing core water sensitivity using ultrasonic treatment won't get better over time. Ultrasonic treatment time should be controlled in a reasonable range; the effect of removing core water sensitivity using chemical agent alone is slightly better than that using ultrasonic treatment, however, chemical injection could be replaced by ultrasonic treatment for removing core water sensitivity from the viewpoint of oil reservoir protection and the sustainable development of oil field; ultrasound-chemical combination technique has the best effect for water sensitivity removal than using ultrasonic treatment or chemical injection alone. PMID- 29429728 TI - Iodine-enhanced ultrasound degradation of sulfamethazine in water. AB - This study investigated sulfamethazine (SMT) ultrasound degradation, enhanced by iodine radicals, generated by potassium iodide (KI) and hydrogen peroxide (H2O2) in situ. The results showed that the ultrasound/H2O2/KI (US/H2O2/KI) combination treatment achieved an 85.10 +/- 0.45% SMT removal (%) in 60 min under the following conditions: pH = 3.2, ultrasound power of 195 W, initial SMT concentration of 0.04 mmol.L-1, H2O2 concentration of 120 mmol.L-1, and KI concentration of 2.4 mmol.L-1. UV-Vis spectrophotometric monitoring of molecular iodine (I2) and triiodide (I3-) revealed a correlation between the SMT degradation and the iodine change in the solution. Quenching experiments using methanol, t-butanol and thiamazole as radical scavengers indicated that iodine radicals, such as I and I2-, were more important than hydroxyl radicals (HO) for SMT degradation. SMT degradation under the US/H2O2/KI treatment followed pseudo first order reaction kinetics. The activation energy (Ea) of SMT degradation was 7.75 +/- 0.61 kJ.mol-1, which suggested the reaction was controlled by the diffusion step. Moreover, TOC removal was monitored, and the obtained results revealed that it was not as effective as SMT degradation under the US/H2O2/KI system. PMID- 29429729 TI - Ultrasound-assisted extraction of antimicrobial compounds from Thymus daenensis and Silybum marianum: Antimicrobial activity with and without the presence of natural silver nanoparticles. AB - The present study is devoted to prepare a new antibacterial and antifungal agent based on in situ-synthesized silver nanoparticles at room temperature using Rosmarinus officinalis (R. officinalis) leaf extract. The Ag-NPs characterization by UV-visible, SEM, TEM and XRD revealed that the particles sizes were in the range of 10-33 nm. In this study, hydroalcoholic extracts were used with ultrasonic method. Ultrasonication has recently received attention as a novel bioprocessing tool for process intensification in many areas of downstream processing. The antimicrobial activities of T. daenensis and S. marianum extracts with and without the presence of Ag-NPs were investigated at concentrations from 12.5 to 50 mg/mL against Staphylococcus aureus (S. aureus, Gram-positive organism) and Escherichia coli (E. coli, Gram-negative organism), and fungal strains were Aspergillus oryzae (A. oryzae) and Candida albicans (C. albicans). Antimicrobial activity determined using agar disc diffusion method revealed that the activities of Ag-NPs/T. daenensis were superior to Ag-NPs/S. marianum and extracts (T. daenensis and S. marianum). The medicinal plant extract can be used to synthesize the Ag-NPs as an eco-friendly and inexpensive method in large scale. The results showed that the prepared Ag-NPs/extracts as good antibacterial and antifungal agents can be potentially applied against rapidly increasing of antibiotic resistance. PMID- 29429730 TI - Comparison of conventional and ultrasonic method for dyeing of spunbond polyester nonwoven fabric. AB - Nonwoven spunbonded polyester has wide applications for both household goods and home furnishings and their usage has continually been growing. Nowadays, coloration of nonwoven fabrics is performed using conventional methods. Conventional polyester dyeing is an energy-intensive process as the dyeing is carried out above 120 degrees C to obtain efficient diffusion of dye. Furthermore, these high temperatures may cause some harmful effects on delicate nonwoven structures. Ultrasound assisted textile dyeing is an alternative method of conventional dyeing of textile materials, providing energy saving by reduced process temperature and time, lower consumptions of auxiliaries with increased dyeing efficiency. This paper focuses on comparing the conventional (high temperature (HT) and carrier dyeing) and ultrasonic dyeing of nonwoven spunbonded polyester fabrics to investigate the effect of ultrasound energy on dyeing performance. Experimental results indicated that highest or comparable dyeing performance can be achieved with ultrasound dyeing at lower temperature (85 degrees C, 60 min.) without carrier as compared to carrier dyeing (100 degrees C, 60 min.) and HT dyeing (130 degrees C, 60 min.), providing an increase of dye depth depending on the dye concentration and basis weight of the fabric. It was evidently seen that highest basis weight of fabric (107 g/m2) used in this study exhibited greater color yield for each dye concentrations (K/S value of 4.90 at 0.2% dye concentration) as compared to conventional ones. The effect of ultrasound energy on reductive washing and fastness properties were also evaluated. PMID- 29429731 TI - Ultrasound-accelerated synthesis of gold nanoparticles modified choline chloride functionalized graphene oxide as a novel sensitive bioelectrochemical sensor: Optimized meloxicam detection using CCD-RSM design and application for human plasma sample. AB - In this research, gold nanoparticles modified choline chloride functionalized graphene oxide (AuNPs-ChCl-GO) was synthesized through the assistance of ultrasound and fabricated as a novel bioelectrochemical sensor and utilized for the sensitive detection of meloxicam (MEL). The morphological and structural features of the AuNPs-ChCl-GO were characterized using different techniques including FTIR, TEM, FE-SEM, EDX, and XRD. The modified electrode showed a remarkable improvement in the anodic oxidation activity of MEL due to the enhancement in the current response compared to the bare carbon paste electrode (CPE). The biosensor composition and measurement conditions were optimized using an experimental design. The differential pulse voltammetry (DPVs) exhibited expanded linear dynamic in the range of 9.0 * 10-9 to 8.5 * 10-7 M for MEL in Britton-Robinson buffer at pH = 4.0 with a detection limit of 1.008 * 10-9 M. The practical utility of the modified electrode was demonstrated by the accurate detection of MEL in human plasma sample. PMID- 29429732 TI - Influence of sound directions on acoustic field characteristics within a rectangle-shaped sonoreactor: Numerical simulation and experimental study. AB - Acoustic field intensity and distribution are the most important factors for the efficiency of ultrasonic processing. Recent simulation studies suggested that sound direction could influence both acoustic field intensity and distribution, but this influence has scarcely been investigated experimentally so far. In this work, we systematically studied the influence of sound directions on the acoustic field with up to five directions via both simulation and experiment. Fluid structure interaction (FSI) harmonic response simulation and aluminum foil erosion experiment were employed to study the acoustic field under different directional combinations of ultrasonic sources. Results of simulation coincided well with that of experiment, which indicated that acoustic intensity, uniformity and cavitation characteristics were significantly affected by sound directions. Based on the results, several influence rules of sound directions were proposed. Optimal acoustic field with sound intensity of 30 times higher than that of single-wall excitation and severe cavitation volume of 95% was obtained. This work provides useful guidelines for acoustic field design of high-intensity ultrasonic apparatus. PMID- 29429733 TI - Microstructural and techno-functional properties of cassava starch modified by ultrasound. AB - This work was focused on the correlation between the structural and techno functional properties of ultrasound treated cassava starch for the preparation of tailor-made starch-based ingredients and derivatives. Furthermore, the effect of treatment time, sample conditioning and ultrasound amplitude was studied. Ultrasonic treatment of cassava starch induced structural disorganization and microstructural changes evidenced mainly in the morphological characteristics of the granules and in their degrees of crystallinity. These structural modifications were supported by ATR-FTIR and SEM and CSLM studies as well as DRX and thermal analysis. The selection of the processing conditions is critical due to the complete gelatinization of the starch was produced with the maximum amplitude tested and without temperature control. Rheological dynamical analysis indicated changes at the molecular level in starch granules due to the ultrasound treated, revealing the paste stability under refrigeration condition. PCA allow to establish the interrelationships between microstructural and techno-functional properties. In summary, different starch derivatives could be obtained by adjusting the ultrasound treatment conditions depending on their potential applications. PMID- 29429734 TI - Ultrasound assisted enzymatic degumming of crude soybean oil. AB - The present work deals with ultrasound assisted enzymatic degumming (UAED) of crude soybean oil quantifying the extent of degumming (EOD), cavitational yield and synergistic index (f) for the combination approaches. The effect of different operating parameters such as enzyme loading, pH, presence of water, temperature and ultrasonic power on the EOD has been investigated. Ultrasound combined with enzyme at loading of 2.0 ml/L resulted in EOD as 92.2% under ambient conditions. Addition of water (5%) in combination with ultrasound and enzyme at 2.0 ml/L loading and pH of 5 resulted in maximum EOD (98.4%) in 120 min of treatment. The extent of phospholipid separation was also observed to be dependent on the power dissipation and maximum phospholipids separation was obtained at 100 W. Scale-up studies were performed at 500 ml and 1 L operating volume under optimized conditions of 2.0 ml/L as the enzyme loading, pH of 5, 5% water addition and ultrasonic power of 100 W where 93.63% and 91.15% phospholipid separation respectively was obtained. The effects of ultrasonic treatment were also quantified in terms of the acid value reduction and oxidative stability for the processed oil. It was demonstrated that suitable reduction in acid value (final value less than 1) and oxidative stability (TOTOX less than 4) is effectively obtained using UAED. Overall the approach of UAED was established to show much higher efficacy for soybean oil processing as compared to only ultrasound or only enzymatic treatment. PMID- 29429735 TI - Effects of ultrasonic vibration on microstructure and mechanical properties of nano-sized SiC particles reinforced Al-5Cu composites. AB - Ultrasonic vibration (UV) treatment has been successfully applied to improve the particles distribution of nano-sized SiC particles (SiCp) reinforced Al-5Cu alloy matrix composites which were prepared by combined processes of dry high energy ball milling and squeeze casting. When UV treatment is applied, the distribution of nano-sized SiCp has been greatly improved. After UV for 1 min, large particles aggregates are broken up into small aggregates due to effects of cavitation and the acoustic streaming. After UV for 5 min, all the particles aggregates are dispersed and the particles are uniformly distributed in the composites. Compared with the Al-5Cu matrix alloy, the ultimate tensile strength, yield strength and elongation of the 1 wt% nano-sized SiCp/Al-5Cu composites treated by UV for 5 min are 270 MPa, 173 MPa and 13.3%, which are increased by 7.6%, 6.8% and 29%, respectively. The improvements of mechanical properties after UV are attributed to the uniform distribution of nano particles, grain refinement of aluminum matrix alloy and reduction of porosity in the composites. PMID- 29429736 TI - Effect of ultrasound on size, morphology, stability and antioxidant activity of selenium nanoparticles dispersed by a hyperbranched polysaccharide from Lignosus rhinocerotis. AB - The differences between ultrasonic and non-ultrasonic approaches in synthesizing Lignosus rhinocerotis polysaccharide-selenium nanoparticles (LRP-SeNPs) were compared in terms of size, morphology, stability and antioxidant activity by UV VIS, FT-IR, X-ray diffraction (XRD), dynamic light scattering (DLS), transmission electron microscopy (TEM), and energy dispersive X-ray (EDX) with high resolution TEM. Results indicated that the SeNPs were associated with the LRP macromolecules in a physical adsorption pattern without breaking chemical bonds, and the ultrasonic treatment reduced the size of SeNPs, narrowed the size distribution as well as improved the stability. Due to the LRP compact coil structure loosed under ultrasonic cavitation, the SeNPs could be easily diffused into the LRP internal branches instead of gathering on the LRP surface and were well dispersed and eventually stabilized throughout the extended branches. After ultrasound treatment, the SeNPs had a minimum average diameter of ~50 nm and the LRP-SeNPs could remain homogeneous and translucent for 16 days within 200 nm size. Furthermore, the ultrasound-treated LRP-SeNPs exhibited higher DPPH and ABTS radical-scavenging abilities than those untreated with ultrasound. This difference may be attributed to the reason that ultrasound can reduce the SeNPs size and increase the specific surface area, which provides sufficient active sites to react with the free radicals and suppress the oxidizing reactions. The integrated results demonstrated that ultrasound played a crucial role in the dispersion, size control, stabilization and antioxidant activity of SeNPs. PMID- 29429737 TI - Retraction notice to Size-controlled spherical polymer nanoparticles: synthesis with tandem acoustic emulsification followed by soap-free emulsion polymerization and one-step fabrication of colloidal crystal films of various colors: Size controlled spherical polymer nanoparticles: synthesis with tandem acoustic emulsification followed by soap-free emulsion polymerization and one-step fabrication of colloidal crystal films of various colors 21/6 (2014) 1921 - 1927. PMID- 29429738 TI - Structural features of hydroxyapatite and carbonated apatite formed under the influence of ultrasound and microwave radiation and their effect on the bioactivity of the nanomaterials. AB - The samples of hydroxyapatite and carbonate substituted hydroxyapatite (CHA) were obtained under the influence of physical factors, namely ultrasound (US) and microwave (MW) radiations. The results of Fourier transform infrared spectroscopy and X-ray diffraction analysis have proved the formation of the calcium deficient hydroxyapatite and B-type CHA with the Ca/P ratio in the ranges 1.62-1.87. In vitro studies have showed the increased bioactivity of the samples, synthesized under the influence of physical factors as compared to the standard ones. The samples of both groups, synthesized under the influence of 600 W MW, have shown the greatest stability in biological environment. In vivo tests confirm that obtained under US and MW radiations hydroxyapatite-based biomaterials are biocompatible, non-toxic and exhibit osteoconductive properties. The usage of US and MW radiations can significantly shorten the time (up to 5-20 min) of obtaining of calcium deficient hydroxyapatite and B-type CHA in nanopowder form, close in structure and composition to the biological hydroxyapatite. PMID- 29429739 TI - Crystallization and solid solution attainment of samarium doped ZnO nanorods via a combined ultrasonic-microwave irradiation approach. AB - An advanced sol-gel method is developed via combined ultrasound-microwave irradiation and utilized for the crystallization of pristine and samarium doped zinc oxide nanorods. Organic structure directing agents directed one dimensional growth and air-annealing was applied as post-thermal treatment. Microstructural, optical, and solid state survey was pursued by PXRD, FESEM, TEM, EDS, FTIR, DRS, PL, micro-Raman, H2-TPR, and ESR techniques. Phase analysis by diffraction patterns confirmed the efficacy of irradiation strategy as it improves the crystallinity degree, expedites the hexagonal close pack morphology, and conducts lattice imperfection. Accordingly, aspect ratio and electronic evolution parallel to dopant content is favored. Electron microscopy demonstrated the flake-like rearrangement of nanorods as well as a structure-related growth where a direct proportion exists between atomic packing factor in lattice and aspect ratio. Textural investigation by EDS and FTIR rejected the presence of any impurity verifying an integrated composition. Reflectance and luminescence spectra exhibited characteristic optical behavior with shifts corresponding to dopant concentration. Also, band gap energies increased with samarium addition depicting an opposite trend with respect to unit cell variation. Finally, Raman, TPR, and ESR spectra provided detailed dopant-dependent trends on the internal solid state and defect chemistry of the nanorods. In this regard, maximum shifts in E2high and E1LO phonon modes duly correlated with the vibrations of zinc and oxygen atoms, surface oxygen and bulk ZnO reduction bands, emergence and alteration of samarium centers, along with the dominance of zinc and oxygen vacancies were all resulted due to the utmost lattice imperfection in SZO1. PMID- 29429740 TI - An automated staining protocol for seven-colour immunofluorescence of human tissue sections for diagnostic and prognostic use. AB - Multiplex immunofluorescence (mIF) allows simultaneous antibody-based detection and quantification of the expression of up to six markers, plus a nuclear counterstain, on a single tissue section. Recent studies have shown the potential for mIF to advance our understanding of complex disease processes, including cancer. It is important that the technique be standardised and validated to facilitate its transition into clinical use. Traditional approaches to mIF rely on manual processing of sections, which is time-consuming and a source of significant variation between samples/individuals. Here we determined if an automated diagnostic tissue stainer could be used for mIF incorporating tyramide signal amplification (TSA), and how the final image quality compared with sections stained semi-automatically or manually. Using tissue microarrays of fixed human breast tumour sections, we observed comparable antibody labelling between the diagnostic autostainer and manual technique. The diagnostic autostainer produced higher signal intensity with similar spectral unmixing efficiency. We also found that microwave treatment for antibody stripping during TSA labelling could be replaced by the heating option incorporated within the diagnostic-use autostainer. These data show that diagnostic autostainers used for traditional immunohistochemistry protocols can be readily adapted to achieve rapid preparation of high-quality sections using a TSA method for clinical mIF. PMID- 29429741 TI - WITHDRAWN: The nematophagous fungus Duddingtonia flagrans reduces the gastrointestinal parasitic nematode larvae population in faeces of orally treated calves maintained under tropical conditions. Dose/Response assessment. PMID- 29429742 TI - Critical evaluation of several techniques for the analysis of phthalates and terephthalates: Application to liquids used in electronic cigarettes. AB - This study describes several original methods that were developed with the goal of measuring phthalates and terephthalates. These methods include gas chromatography/mass spectrometry (GC/MS), GC/MS/MS, liquid chromatography with UV detection (LC/UV), LC/MS, and LC/MS/MS. The study compares the advantages and disadvantages of these methods and their applicability to measuring phthalates and terephthalates in the liquids used in electronic cigarettes (e-liquids). The analytes evaluated include eight phthalates and two terephthalates. The phthalates were diethyl, dibutyl, benzyl butyl, diphenyl, bis(2-ethylhexyl), di-n octyl, diisononyl and diisodecyl. The terephthalates were dimethyl and bis(2 ethylhexyl). Intentionally, no cleanup or concentration step were used in the methods. The methods used two chromatographic standards, dimethyl phthalate 3,4,5,6-d4, and di-(2-ethylhexyl) phthalate-3,4,5,6-d4. All techniques were validated for selectivity/specificity, precision, sensitivity (evaluation of LOD and LOQ), as well as for repeatability and matrix interference. The GC methods were not adequate for the analysis of diphenyl, diisononyl, and diisodecyl phthalates which were not volatile enough to be seen in the conditions used for the GC separation. Also, alcohols should not be used as solvents for the injection of the sample in the GC system to avoid transesterification in the hot injection port. The single quadrupole MS detection in GC offers sensitivities around 1 MUg/mL in the e-liquid and was not sensitive enough for the analysis of trace phthalates and terephthalates. Compared to all evaluated methods, the MS/MS detection in GC offered the best sensitivity (below 10 ng/mL in the e-liquid). The LC is adequate for the separation of all the evaluated analytes. However, the UV detection in LC does not offer good sensitivity compared to all the other techniques. The MS detection in LC provides poor sensitivity for terephthalates, but better than the UV for the rest of the analytes. The MS/MS detection for LC offers slightly better sensitivity than the MS detection, but both LC/MS and LC/MS/MS were only able to measure levels above about 100 ng/mL of analytes in the e-liquid. A group of 39 e-liquids were analyzed by three of the evaluated procedures. Benzyl butyl phthalate, bis(2-ethylhexyl) terephthalate, and di-n octyl phthalate were not detected in the e-liquids. Some of the other evaluated phthalates were present at trace levels in certain e-liquids while most e-liquids did not contain phthalates at detectable levels. PMID- 29429743 TI - Homochiral zeolite-like metal-organic framework with DNA like double-helicity structure as stationary phase for capillary electrochromatography enantioseparation. AB - In recent years, artificial materials with double helix structure have attracted widespread attention due to their unique properties such as the DNA like double helicity, intrinsic chirality and diverse functional groups. Developing novel chiral stationary phases (CSPs) for capillary electrochromatography enantioseparation is of intriguing interest. Herein, a novel homochiral zeolite like metal-organic framework (ZMOF) JLU-Liu23 with unique DNA like double helicity structure was firstly utilized as the CSP in open tubular capillary electrochromatography (OT-CEC) for enantioseparation of chiral monoamine neurotransmitters and analogues. Owing to the unique DNA like double-helicity structure of the homochiral ZMOF JLU-Liu23, the good enantioseparation of four monoamine neurotransmitters and analogues was achieved on the prepared homochiral ZMOF JLU-Liu23 coated capillary column. The relative standard deviations (RSDs) of the analytes migration time for intra-day, inter-day and column-to-column were in the range of 0.3-0.6%, 0.8-2.2% and 3.5-6.5%, respectively. PMID- 29429744 TI - Thermally condensed humic acids onto silica as SPE for effective enrichment of glucocorticoids from environmental waters followed by HPLC-HESI-MS/MS. AB - Pristine humic acids (HAs) were thermally condensed onto silica microparticles by a one-pot, inexpensive and green preparation route obtaining a mixed-mode sorbent (HA-C@silica) with good sorption affinity for glucocorticoids (GCs). The carbon based material, characterized by various techniques, was indeed applied as the sorbent for fixed-bed solid-phase extraction of eight GCs from river water and wastewater treatment plant effluent, spiked at different concentration levels in the range 1-400 ng L-1. After sample extraction, the target analytes were simultaneously and quantitatively eluted in a single fraction of methanol, achieving enrichment factor 4000 and 1000 in river water and wastewater effluent, respectively. Full recovery for all compounds, was gained in the real matrices studied (80-125% in river water, 79-126% in wastewater effluent), with inter-day precision showing relative standard deviations (RSD) below 15% and 18% (n = 3), for river and wastewater effluent, correspondingly. The high enrichment factors coupled with high-performance liquid chromatography tandem mass spectrometry quantification (MRM mode) provided method quantification limits of 0.009-0.48 ng L-1 in river water and 0.06-3 ng L-1 in wastewater effluent and, at the same time, secure identification of the selected drugs. As also evidenced by comparison with literature, HA-C@silica proved to be a valid alternative to the current commercial sorbents, in terms of extraction capability, enrichment factor, ease of preparation and cost. The batch-to-batch reproducibility was assessed by recovery tests on three independently prepared HA-C@silica powders (RSD lower than 7%). PMID- 29429745 TI - Core-shell structured magnetic metal-organic framework composites for highly selective detection of N-glycopeptides based on boronic acid affinity chromatography. AB - Boronic acid affinity chromatography (BAAC) is one of the most significant methods in glycoproteomics research due to its low bias towards glycopeptides and easy enrichment process. In this work, core-shell structured magnetic metal organic framework (MOF) composites with abundant boronic acid groups were designed and synthesized for selective glycopeptide enrichment based on BAAC. The as-prepared core-shell structured magnetic MOF composites (denoted as Fe3O4@PVP/PEI@MOF (B)) inherited strong magnetic responsiveness from the Fe3O4 core as well as ultrahigh surface area and abundant boronic acid sites from the MOF shell. The affinity between boronic acid and cis-diols groups endowed the composites with improved sensitivity (0.5 fmol/MUL) and selectivity (1:100) towards glycopeptides, achieving remarkable results in glycopeptides detection from standard glycoprotein digests as well as complex bio-samples. As a result, a total of 209 N-glycosylation peptides from 89 different glycoproteins were identified from human serum digests, indicating its broad prospect in glycoproteome study. PMID- 29429747 TI - Treatment of corneal chemical alkali burns with a crosslinked thiolated hyaluronic acid film. AB - PURPOSE: The study objective was to test the utilization of a crosslinked, thiolated hyaluronic acid (CMHA-S) film for treating corneal chemical burns. METHODS: Burns 5.5mm in diameter were created on 10 anesthetized, male New Zealand white rabbits by placing a 1N NaOH soaked circular filter paper onto the cornea for 30s. Wounds were immediately rinsed with balanced salt solution (BSS). CMHA-S films were placed in the left inferior fornix of five injured and five uninjured animals. Five animals received no treatment. At 0h, 48h, 96h, and on day 14 post chemical burn creation, eyes were evaluated by white light imaging, fluorescein staining, and optical coherence tomography (OCT). Corneal histology was performed using H&E and Masson's Trichrome stains. RESULTS: Image analysis indicated biocompatible CMHA-S treatment resulted in significant decreases in the areas of corneal opacity at 48h, 96h, and on day 14 postoperatively. A significant increase in re-epithelialization was seen 14days post injury. CMHA-S treated corneas showed significantly less edema than untreated burns. No pathological differences were observed in corneal histological samples as a result of CMHA-S treatment. CONCLUSIONS: CMHA-S films facilitate re epithelialization and decrease the area of corneal opacity in our corneal alkali burn rabbit model. PMID- 29429746 TI - Children with severe burns display no sex differences in exercise capacity at hospital discharge or adaptation after exercise rehabilitation training. AB - BACKGROUND AND OBJECTIVE: Females have a 50% increased risk of death from burn injury compared to males. However, whether exercise capacity and exercise induced training adaptations differ between burned boys and girls is unknown. This project tested the hypothesis that girls with burns have lower exercise capacity and different exercise induced training adaptations. METHODS: Twenty-five girls were matched to 26 boys (mean, 95%CI; years 13 [12,14], cm 151 [143,161], kg 54 [45,63]; each P>0.05) for burn injury (% total body surface area burn, 54 [45,62]; P=0.82). Lean body mass (LBM), strength (peak torque) and cardiorespiratory fitness (peak VO2) were normalized to kg LBM and compared as a percentage of age-sex matched non-burned children (n=26 boys, years 13 [12,14]; n=25 girls, years 13 [12,14]) at discharge (DC) and after aerobic and resistance rehabilitation exercise training (RET). RESULTS: Using a 2-way factorial ANOVA (group*time), we found both groups had similar 11% change in LBM (87.3% of non burned values [82.2,92.3]) and after the RET (92.8% [87.2,98.3]; main effect, time P<0.0001). Peak torque increased similarly by 16% in both groups (% of age sex matched non-burned DC, 55.9 [51.3,60.5]; after RET, 77.5 [72.1,82.9]; main effect, time P<0.0001). Likewise, peak VO2 increased in both groups by 15% (% of age-sex matched non-burned DC, 56.8 [52.4,61.2] to RET, 72.2 [67.6,76.8]; main effect, time; P<0.0001). Burned children exercise at greater percentage of their peak VO2 and peak HR compared to non-burned children (Interaction, group*time, P<0.0001). CONCLUSION: The burn injury does not have sex-dependent effects on LBM or exercise capacity in severely burn injured children. Differences in relative peak VO2 and peak HR suggest the need for burn specific exercise programs for improving the efficacy of a rehabilitation program. PMID- 29429748 TI - The Syndrome of Tubulointerstitial Nephritis With Uveitis (TINU). AB - The syndrome of tubulointerstitial nephritis and uveitis (TINU) is a multisystemic autoimmune disorder that may occur in response to various environmental triggers, including drugs and microbial pathogens. Evidence exists of HLA antigen-related genetic predisposition to developing TINU. The resulting inflammation affects chiefly the ocular uvea and renal tubules, although other organs may be involved. TINU is uncommon; only about 200 cases are on record since its original description 40 years ago, although it is possible that new ones are no longer being reported. Although its incidence is highest in children and adolescents, all ages may be affected. Renal and ocular inflammation may be clinically severe and persistent, but the prognosis for the majority of patients with TINU is favorable. Owing to its low prevalence, no standard therapeutic protocols have been established, but most reported cases have been treated with corticosteroids or other immunomodulatory agents. TINU has many features in common with sarcoidosis, the main clinical entity from which it must be distinguished. This article begins with an illustrative case vignette, followed by an overview of the syndrome and current theories regarding its pathogenesis. PMID- 29429749 TI - Total Renal Artery Occlusion: Recovery of Function After Revascularization. AB - Current trends in managing atherosclerotic renal artery stenosis favor medical therapy, on account of negative results from prospective trials of revascularization, such as CORAL and ASTRAL. One result of this trend has been encountering occasional patients with progressive disease, sometimes leading to total arterial occlusion. We illustrate a case of accelerated hypertension with complete renal artery occlusion in which the patient recovered function after surgical bypass and we review the clinical approach used and the advanced imaging modalities available to us. A high index of suspicion and careful radiologic imaging play important roles in selecting patients who may have residual function and may benefit from revascularization. This case illustrates an example whereby restoring renal artery perfusion for carefully selected patients can be life changing, with recovery of kidney function and improved blood pressure, pill burden, and overall quality of life. PMID- 29429750 TI - Arteriovenous Fistula Maturation in Prevalent Hemodialysis Patients in the United States: A National Study. AB - BACKGROUND: Arteriovenous fistulas (AVFs) are the preferred form of hemodialysis vascular access, but maturation failures occur frequently, often resulting in prolonged catheter use. We sought to characterize AVF maturation in a national sample of prevalent hemodialysis patients in the United States. STUDY DESIGN: Nonconcurrent observational cohort study. SETTING & PARTICIPANTS: Prevalent hemodialysis patients having had at least 1 new AVF placed during 2013, as identified using Medicare claims data in the US Renal Data System. PREDICTORS: Demographics, geographic location, dialysis vintage, comorbid conditions. OUTCOMES: Successful maturation following placement defined by subsequent use identified using monthly CROWNWeb data. MEASUREMENTS: AVF maturation rates were compared across strata of predictors. Patients were followed up until the earliest evidence of death, AVF maturation, or the end of 2014. RESULTS: In the study period, 45,087 new AVFs were placed in 39,820 prevalent hemodialysis patients. No evidence of use was identified for 36.2% of AVFs. Only 54.7% of AVFs were used within 4 months of placement, with maturation rates varying considerably across end-stage renal disease (ESRD) networks. Older age was associated with lower AVF maturation rates. Female sex, black race, some comorbid conditions (cardiovascular disease, peripheral artery disease, diabetes, needing assistance, or institutionalized status), dialysis vintage longer than 1 year, and catheter or arteriovenous graft use at ESRD incidence were also associated with lower rates of successful AVF maturation. In contrast, hypertension and prior AVF placement at ESRD incidence were associated with higher rates of successful AVF maturation. LIMITATIONS: This study relies on administrative data, with monthly recording of access use. CONCLUSIONS: We identified numerous associations between AVF maturation and patient-level factors in a recent national sample of US hemodialysis patients. After accounting for these patient factors, we observed substantial differences in AVF maturation across some ESRD networks, indicating a need for additional study of the provider, practice, and regional factors that explain AVF maturation. PMID- 29429751 TI - Pulmonary Hypertension, Mortality, and Cardiovascular Disease in CKD and ESRD Patients: A Systematic Review and Meta-analysis. AB - BACKGROUND: Pulmonary hypertension is common in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) and may be associated with poor outcomes. The magnitude of the association between pulmonary hypertension and mortality is uncertain due to the small size and variable findings of observational studies. STUDY DESIGN: Systematic review and meta-analysis of observational studies using subgroup analyses and metaregression. SETTING & POPULATION: Patients with ESRD or earlier stages of CKD. SELECTION CRITERIA FOR STUDIES: Observational studies reporting clinical outcomes in patients with co existing pulmonary hypertension and CKD or ESRD identified using a systematic search of PubMed and Embase. PREDICTOR: Pulmonary hypertension diagnosed by Doppler echocardiography. OUTCOMES: All-cause mortality, cardiovascular mortality, and cardiovascular events. RESULTS: 16 studies, with 7,112 patients with an overall pulmonary hypertension prevalence of 23%, were included. Pulmonary hypertension was associated with increased risk for all-cause mortality among patients with CKD (relative risk [RR], 1.44; 95% CI, 1.17-1.76), with ESRD receiving maintenance dialysis (RR, 2.32; 95% CI, 1.91-2.83), and with a functioning kidney transplant (RR, 2.08; 95% CI, 1.35-3.20). Pulmonary hypertension was associated with increased risk for cardiovascular events in patients with CKD (RR, 1.67; 95% CI, 1.07-2.60) and ESRD receiving dialysis (RR, 2.33; 95% CI, 1.76-3.08). There was an association between pulmonary hypertension and increased risk for cardiovascular mortality in patients with CKD or ESRD (RR, 2.20; 95% CI, 1.53-3.15). LIMITATIONS: Heterogeneity of included studies, possibility of residual confounding, unavailability of individual patient-level data, and possibility of outcome reporting bias. CONCLUSIONS: Pulmonary hypertension is associated with a substantially increased risk for death and cardiovascular events in patients with CKD and ESRD. Risk is higher in patients with ESRD receiving dialysis compared with patients with CKD stages 1 to 5. Understanding the effect of interventions to lower pulmonary artery pressure on the survival of these patents awaits their evaluation in randomized controlled trials. PMID- 29429752 TI - Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy. AB - BACKGROUND: Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab. STUDY DESIGN: Case series of C3 glomerulopathy. SETTING & PARTICIPANTS: Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Quebec, Canada. OUTCOMES: Global or partial clinical renal response. MEASUREMENTS: Evolution of serum creatinine and proteinuria values. RESULTS: 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders. LIMITATIONS: Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases. CONCLUSIONS: Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited. PMID- 29429753 TI - Perspective of Spanish medical students regarding undergraduate education in infectious diseases, bacterial resistance and antibiotic use. AB - INTRODUCTION: One of the main tools to optimize antibiotics use is education of prescribers. The aim of this article is to study undergraduate education in the field of infectious diseases, antimicrobial resistance and antibiotic stewardship from the perspective of Spanish medical students. MATERIAL AND METHODS: An anonymous online questionnaire was distributed among sixth grade students using different channels in Europe, within the ESGAP Student-Prepare survey. The questionnaire included 45 questions about knowledge, attitudes and perceptions about diagnosis, bacterial resistance, use of antibiotics and undergraduate training in infectious diseases. We present here the Spanish results. RESULTS: A total of 441 surveys were received from 21 medical schools. A total of 374 responses (84.8%) were obtained from the 8 most represented faculties, with a response rate of 28.9%. Most students felt adequately prepared to identify clinical signs of infection (418; 94.8%) and to accurately interpret laboratory tests (382; 86.6%). A total of 178 (40.4%) acknowledged being able to choose an antibiotic with confidence without consulting books or guidelines. Only 107 (24.3%) students considered that they had received sufficient training in judicious use of antibiotics. Regarding learning methods, the discussion of clinical cases, infectious diseases units rotatories and small group workshops were considered the most useful, being evaluated favorably in 76.9%, 76% and 68.8% of the cases. CONCLUSION: Medical students feel more confident in the diagnosis of infectious diseases than in antibiotic treatment. They also feel the need to receive more training in antibiotics and judicious antibiotic use. PMID- 29429754 TI - Spontaneous bacterial peritonitis due to Helicobacter pylori in a cirrhotic patient with human immunodeficiency virus and hepatitis C virus coinfection. PMID- 29429755 TI - Corrigendum to "MiR-590-5p, a density-sensitive microRNA, inhibits tumorigenesis by targeting YAP1 in colorectal cancer", [Canc. Lett. 399 (2017) 53-63]. PMID- 29429756 TI - Corrigendum to "SDF-1 improves wound healing ability of glucocorticoid-treated adipose tissue-derived mesenchymal stem cells" [Biochem. Biophys. Res. Commun. 493/2 (2017) 1010-1017]. PMID- 29429757 TI - Association of Internet addiction and alexithymia - A scoping review. AB - It has been hypothesized that individuals with alexithymia who have difficulty in identifying, expressing, and communicating emotions may overuse Internet as a tool of social interaction to better regulate their emotions and to fulfill their unmet social needs. Similarly, an increasing body of evidence suggests that alexithymia may also play an essential role in the etiopathogenesis of addictive disorders. We conducted a scoping review of questionnaire-based studies of problematic Internet use/Internet addiction and alexithymia. From initial 51 studies, all of the final 12 included studies demonstrated a significant positive association between scores of alexithymia and severity of Internet addiction. However, the causal direction of the association is not clear because the interplay of numerous other variables that could affect the relation has not been studied. There are limitations in the methodology of the studies conducted. Hence, we emphasise the need for longitudinal studies with stronger methodologies. PMID- 29429758 TI - The immunobiology of mucosal-associated invariant T cell (MAIT) function in primary biliary cholangitis: Regulation by cholic acid-induced Interleukin-7. AB - Mucosal-associated invariant T (MAIT) cells are novel innate-like T cells constituting a significant proportion of circulating and hepatic T cells. Herein, we extensively examine the phenotypical and functional alterations of MAIT cells and their regulation in a cohort of 56 patients with Primary Biliary Cholangitis (PBC) and 53 healthy controls (HC). Additionally alterations of MAIT cells were assessed before and after UDCA treatment. Finally the localization of MAIT cell in liver was examined using specific tetramer staining and the underlying mechanisms of these alterations in PBC were explored. Our data demonstrated that the frequency and number of circulating MAIT cells were decreased, whereas hepatic MAIT cells were increased in PBC compared to HC. Moreover, circulating MAIT cells were more activated in PBC than HC, reflected by elevated expression levels of granzyme B. Six months of UDCA treatment significantly attenuated the circulating MAIT cells differences in PBC. Of note, the expression levels of IL-7 were significantly increased in both plasma and liver from PBC as compared to HC, which promoted the production of inflammatory cytokines and granzyme B by inducing signal transduction and activation of transcription 5 (STAT5) phosphorylation in MAIT cells. Finally, cholic acid, one of the major bile acids in liver, upregulated IL-7 expression in hepatocyte cell line L02 by inducing Farnesoid X Receptor (FXR) binding to the IL-7 promoter. Hence MAIT cells are activated and enriched in the liver of PBC. Cholic acid-induced IL-7 production in hepatocytes plays a critical role in regulating MAIT cell function, highlighting that hepatocytes may bridge cholangiocyte injury and innate immunity through a bile acid signaling pathway. PMID- 29429759 TI - Corrigendum to "Quantitative analysis of menthol and identification of other flavoring ingredients in capsule cigarettes marketed in Korea" [Regul. Toxicol. Pharmacol. 92C (2018) 420-428]. PMID- 29429760 TI - Switch and Trace: Recombinase Genetics in Zebrafish. AB - Transgenic approaches are instrumental for labeling and manipulating cells and cellular machineries in vivo. Transgenes have traditionally been static entities that remained unaltered following genome integration, limiting their versatility. The development of DNA recombinase-based methods to modify, excise, or rearrange transgene cassettes has introduced versatile control of transgene activity and function. In particular, recombinase-controlled transgenes enable regulation of exogenous gene expression, conditional mutagenesis, and genetic lineage tracing. In zebrafish, transgenesis-based recombinase genetics using Cre/lox, Flp/FRT, and PhiC31 are increasingly applied to study development and homeostasis, and to generate disease models. Intersected with the versatile imaging capacity of the zebrafish model and recent breakthroughs in genome editing, we review and discuss past, current, and potential future approaches and resources for recombinase based techniques in zebrafish. PMID- 29429761 TI - Analysis of mortality in a cohort of 650 cases of bacteremic osteoarticular infections. AB - OBJECTIVES: The mortality of patients with bacteremic osteoarticular infections (B-OAIs) is poorly understood. Whether certain types of OAIs carry higher mortality or interventions like surgical debridement can improve prognosis, are unclarified questions. METHODS: Retrospective analysis of a prospective cohort of patients with B-OAIs treated at a teaching hospital in Barcelona (1985-2014), analyzing mortality (30-day case-fatality rate). B-OAIs were categorized as peripheral septic arthritis or other OAIs. Factors influencing mortality were analyzed using logistic regression models. The association of surgical debridement with mortality in patients with peripheral septic arthritis was evaluated with a multivariate logistic regression model and a propensity score matching analysis. RESULTS: Among 650 cases of B-OAIs, mortality was 12.2% (41.8% of deaths within 7 days). Compared with other B-OAI, cases of peripheral septic arthritis were associated with higher mortality (18.6% vs 8.3%, p < 0.001). In a multiple logistic regression model, peripheral septic arthritis was an independent predictor of mortality (adjusted odds ratio [OR] 2.12; 95% CI: 1.22 3.69; p = 0.008). Cases with peripheral septic arthritis managed with surgical debridement had lower mortality than those managed without surgery (14.7% vs 33.3%; p = 0.003). Surgical debridement was associated with reduced mortality after adjusting for covariates (adjusted OR 0.23; 95% CI: 0.09-0.57; p = 0.002) and in the propensity score matching analysis (OR 0.81; 95% CI: 0.68-0.96; p = 0.014). CONCLUSIONS: Among patients with B-OAIs, mortality was greater in those with peripheral septic arthritis. Surgical debridement was associated with decreased mortality in cases of peripheral septic arthritis. PMID- 29429762 TI - Enthesitis: A hallmark of psoriatic arthritis. AB - OBJECTIVE: To describe the growing importance of enthesitis in patients with psoriatic arthritis (PsA) and discuss the advantages and disadvantages of clinical and imaging methods currently used to assess enthesitis. METHODS: PubMed literature searches were conducted using the terms psoriatic arthritis, entheses, enthesitis, pathology, imaging, ultrasound, magnetic resonance imaging, clinical, and indices. Articles were deemed relevant if they provided insight into the pathology, monitoring, and/or diagnosis of enthesitis in PsA, or if they discussed clinical or imaging indices used to assess enthesitis. RESULTS: Enthesitis is an early manifestation of PsA that is associated with increased disease activity and reduced quality of life. A variety of clinical indices exist to assess enthesitis in PsA; however, the Leeds Enthesitis Index and Maastricht Ankylosing Spondylitis Enthesitis Score index have been the most frequently used indices in recent clinical trials. Limitations of these indices include an inability to discern structural involvement, risk of missing subclinical enthesitis, and lack of sensitivity in detecting enthesitis, especially in patients with central sensitization and/or pain amplification. Such limitations have led to the emergent importance of imaging techniques in the assessment of enthesitis. Although there have been recent advances in magnetic resonance imaging, ultrasound (US) appears to be the preferred method for detecting enthesitis because it allows for accurate assessment of the soft-tissue components of entheses and also for new bone formation. Hypoechogenicity, increased thickness of tendon insertion, calcifications, enthesophytes, erosions, and Doppler activity have been identified as important US characteristics of enthesitis. CONCLUSION: Enthesitis is thought to be integrally involved in the pathogenesis of PsA and is associated with worse prognostic outcomes in patients with PsA. A validated US index with entheses that are less confounded by mechanical factors and obesity would be the most effective measure of enthesitis in PsA. As imaging techniques continue to advance, our understanding of enthesitis and its involvement in PsA will also improve. PMID- 29429763 TI - A broad-range PCR technique for the diagnosis of infective endocarditis. AB - Infective endocarditis (IE) remains a severe and potentially fatal disease demanding sophisticated diagnostic strategies for detection of the causative microorganisms. The aim of the present study was to develop a broad-range 16S ribosomal RNA gene polymerase chain reaction in the routine diagnostic of IE for the early diagnosis of fatal disease. A broad-range PCR technique was selected and evaluated in terms of its efficiency in the diagnosis of endocarditis using 19 heart valves from patients undergoing cardiovascular surgeries at the Habib Bourguiba Hospital of Sfax, Tunisia, on the grounds of suspected IE. The results demonstrated the efficiency of this technique particularly in cases involving a limited number of bacteria since it helped to increase detection sensitivity. The technique proved to be efficient, particularly, in the bacteriological diagnosis of IE in contexts involving negative results from conventional culture methods and other contexts involving bacterial species that were not amenable to identification by phenotypic investigations. Indeed, the sequencing of the partial 16S ribosomal RNA gene revealed the presence of Bartonella henselae, Enterobacter sp., and Streptococcus pyogenes in three heart valves with the negative culture. It should be noted that the results obtained from the polymerase chain reaction-sequencing identification applied to the heart valve and the strain isolated from the same tissue were not consistent with the ones found by the conventional microbiological methods in the case of IE caused by Gemella morbillorum. In fact, the results from the molecular identification revealed the presence of Lactobacillus jensenii. Overall, the results have revealed that the proposed method is sensitive, reliable and might open promising opportunities for the early diagnosis of IE. PMID- 29429765 TI - Temporal Dynamism of Resource Capture: A Missing Factor in Ecology? AB - Temporal dynamism of plant resource capture, and its impacts on plant-plant interactions, can have important regulatory roles in multispecies communities. For example, by modifying resource acquisition timing, plants might reduce competition and promote their coexistence. However, despite the potential wide ecological relevance of this topic, short-term (within growing season) temporal dynamism has been overlooked. This is partially a consequence of historic reliance on measures made at single points in time. We propose that with current technological advances this is a golden opportunity to study within growing season temporal dynamism of resource capture by plants in highly informative ways. We set out here an agenda for future developments in this research field, and explore how new technologies can deliver this agenda. PMID- 29429764 TI - Safety and Efficacy of Adalimumab in Patients with Noninfectious Uveitis in an Ongoing Open-Label Study: VISUAL III. AB - PURPOSE: To evaluate safety and efficacy of adalimumab in patients with noninfectious intermediate, posterior, or panuveitis. DESIGN: Phase 3, open label, multicenter clinical trial extension (VISUAL III). PARTICIPANTS: Adults meeting treatment failure (TF) criteria or who completed VISUAL I or II (phase 3, randomized, double-masked, placebo-controlled) without TF. METHODS: Patients received adalimumab 40 mg every other week. Interim follow-up data were described from VISUAL III weeks 0 through 78. MAIN OUTCOME MEASURES: Disease quiescence, steroid-free quiescence, active inflammatory chorioretinal/retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, best-corrected visual acuity (BCVA), and corticosteroid dose. Binary data were reported using nonresponder imputation (NRI), continuous data using last observation carried forward and as-observed analysis, and corticosteroid dose using observed-case analysis. Adverse events (AEs) were reported from first adalimumab dose in VISUAL III through interim cutoff. RESULTS: Of 424 patients enrolled, 371 were included in intent-to-treat analysis. At study entry, 242 of 371 (65%) patients had active uveitis; 60% (145/242, NRI) achieved quiescence at week 78, and 66% (95/143, as observed) of those were corticosteroid free. At study entry, 129 of 371 (35%) patients had inactive uveitis; 74% (96/129, NRI) achieved quiescence at week 78, and 93% (89/96, as-observed) of those were corticosteroid free. Inflammatory lesions, anterior chamber grade, and vitreous haze grade showed initial improvement followed by decline in patients with active uveitis and remained stable in patients with inactive uveitis. BCVA improved in patients with active uveitis from weeks 0 to 78 (0.27 to 0.14 logMAR; left and right eyes; as observed) and remained stable in patients with inactive uveitis. Mean corticosteroid dose decreased from 13.6 mg/day (week 0) to 2.6 mg/day (week 78) in patients with active uveitis and remained stable in those with inactive uveitis (1.5-1.2 mg/day). AEs (424 events/100 patient-years) and serious AEs (16.5 events/100 patient-years) were comparable with previous VISUAL trials. CONCLUSIONS: Patients with active uveitis at study entry who received adalimumab therapy were likely to achieve quiescence, improve visual acuity, and reduce their daily uveitis-related systemic corticosteroid use. Most patients with inactive uveitis at study entry sustained quiescence without a systemic corticosteroid dose increase. No new safety signals were identified. PMID- 29429766 TI - Type 1 Diabetes and Periodontal Health. AB - It is well established that hyperglycemia affects periodontal outcomes. A body of evidence, predominantly over the past 20 years supports significant independent associations between periodontal disease and glycemic control or complications of diabetes. Association between periodontal tissue and hyperglycemia is possible through altered cellular immunity, increased proliferation of bacteria, microangiopathy, and formation of the advanced glycation end products. However, most studies focus solely on patients with type 2 diabetes or diabetes in general. There is still the paucity of data concerning patients with type 1 diabetes (T1D). Here, the authors consider the possible mechanisms linking periodontal disease with diabetes, focusing mainly on T1D and discuss possible diagnostic and therapeutic approaches. PMID- 29429767 TI - Epidemiological characteristics of Hirschsprung's disease (HSCR): Results of a case series of fifty patients from Bangladesh. AB - BACKGROUND: The epidemiology of Hirschsprung's disease (HSCR) in Bangladesh has never been studied. The aim of this study was to determine the epidemiological characteristics of HSCR in Bangladesh. METHODS: Data from fifty patients were collected prospectively from two hospitals in Chittagong, Bangladesh. RESULTS: The rate of consanguinity (16%) among parents of HSCR patients was higher than that of the general population (10%). Maternal age at the time of birth of the affected child was <=30years in all cases except one. No association was found between parents' occupation and HSCR. No patient was born preterm and only three patients (6%) had low birth weight. Nine patients (18%) had associated anomalies. We found coexistence of bilateral accessory tragi and ankyloglossia in one patient, and coexistence of rectal duplication cyst in another. Neither anomaly had been previously reported in HSCR patients. CONCLUSIONS: Our study suggests that consanguinity might increase the risk of HSCR whereas advanced maternal age does not. HSCR patients were found more likely to born at term and with normal birth weight. The coexistence of HSCR with previously unreported anomalies highlights the diversity of conditions that can co-occur with HSCR. LEVELS OF EVIDENCE: IV. PMID- 29429768 TI - Are Senna based laxatives safe when used as long term treatment for constipation in children? AB - BACKGROUND AND AIM: Senna is a stimulant laxative commonly used by pediatricians, pediatric gastroenterologists, and pediatric surgeons. Many clinicians avoid Senna for reasons such as tolerance or side effects but this has little scientific justification. We recently found several patients we were caring for developed perineal blistering during the course of Senna treatment. Because of this we chose to review the literature to identify side effects in children taking this medication as well as to analyze our Center's experience with Senna's secondary effects. METHODS: We performed a literature review (MEDLINE, PUBMED) using the keywords of Senna, sen, sennosides and children, and pediatric and functional (idiopathic) constipation. We looked for articles with information regarding perineal blisters related to Senna as well as other secondary effects of Senna laxatives in children when used on a long-term basis. We also reviewed the charts of our patients who had previously taken Senna or are currently taking Senna, looking for adverse reactions. RESULTS: Eight articles in the literature reported perineal blisters after administration of Senna laxatives in 28 patients. Of those occurrences, 18 patients (64%) had accidental administration of Senna and 10 (36%) had Senna prescribed as a long term treatment. All of the blistering episodes were related to high dose, night-time accidents, or intense diarrhea with a long period of stool to skin contact. At our institution, from 2014 to 2017, we prescribed Senna and have recorded data to 640 patients. During the study period, 17 patients (2.2%) developed blisters during their treatment. Patients who developed blisters had higher doses 60mg/day; 60 [12-100] vs. 17.5 [1.7-150] (p<0.001). All of the blistering episodes were related to night-time accidents, with a long period of stool to skin contact. 83 (13%) patients presented minor side effects such as abdominal cramping, vomiting or diarrhea which resolved once the type of laxatives were changed or enemas were started. The doses of Senna was not significantly different in these patients 15mg/day [4.4-150] vs. 17.5mg/day [1.5-150]. There were no other long-term side effects from Senna found in the pediatric literature for long-term treatment besides abdominal cramping or diarrhea during the first weeks of administration. We found no evidence of tolerance to Senna in our review. CONCLUSION: There is a paucity of information in the literature regarding side effects of sennosides as a long term therapy, and to our knowledge, this is the first review of Senna side effects in children. Senna induced dermatitis is rare, but may occur when patients need a higher dose. All of the cases described had a long period of exposure of the skin to stool. Besides the perineal rash with blisters, we could find no other described major side effect with Senna administration in the pediatric population or evidence of the frequently mentioned concern of the development of tolerance to Senna. Pediatric caregivers should advise families of the rare side effect of skin blistering and educate them to change the diaper frequently in children who are not toilet- trained to reduce stool to skin exposure. We can conclude from this review that Senna is a safe treatment option for constipation in children. LEVEL OF EVIDENCE: IV. PMID- 29429769 TI - Neurodevelopmental outcomes of infants with esophageal atresia and tracheoesophageal fistula. AB - BACKGROUND: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is a complex disorder, and most outcome data are confined to mortality and feeding-related morbidities. Our objective was to examine mortality, growth and neurodevelopmental outcomes in a large recent cohort of infants with EA/TEF. METHODS: Single center study of EA/TEF infants referred from January 2000 to December 2015. Data collected included associated defects, neonatal morbidity and mortality and growth and neurodevelopmental outcomes at age 12-36months. Multiple regression analysis was used to determine variables associated with adverse outcome. RESULTS: Of the 253 infants identified, 102 infants (40%) were preterm. Overall mortality was 8.3%, the majority from major cardiac malformations (p<0.001) Neurodevelopmental assessments (n=182) showed that 76% were within normal, while some delay was seen in 24%, most often in expressive and receptive language. Nine infants had hearing impairment and 5 had visual impairment. Gastrostomy tubes were required in 47 patients and 15% continued to have weight growth velocities less than the 10th centile. A number of specialist interventions were required, Speech/Language being frequent. CONCLUSION: Mortality in EA/TEF is primarily related to concomitant anomalies, especially cardiac. Multidisciplinary follow up is important for early identification and intervention for growth failure and developmental delay. TYPE OF STUDY: Retrospective study LEVEL OF EVIDENCE: Level II. PMID- 29429770 TI - Structural airway abnormalities contribute to dysphagia in children with esophageal atresia and tracheoesophageal fistula. AB - BACKGROUND: Long-term dysphagia occurs in up to 50% of repaired esophageal atresia and tracheoesophageal fistula (EA/TEF) patients. The underlying factors are unclear and may include stricture, esophageal dysmotility, or associated anomalies. Our purpose was to determine whether structural airway abnormalities (SAA) are associated with dysphagia in EA/TEF. METHODS: We conducted a retrospective chart review of children who underwent EA/TEF repair in our hospital system from 2007 to 2016. Children with identified SAA (oropharyngeal abnormalities, laryngeal clefts, laryngomalacia, vocal cord paralysis, and tracheomalacia) were compared to those without airway abnormalities. Dysphagia outcomes were determined by the need for tube feeding and the modified pediatric Functional Oral Intake Scale (FOIS) at 1 year. RESULTS: SAA was diagnosed in 55/145 (37.9%) patients with EA/TEF. Oropharyngeal aspiration was more common in children with SAA (58.3% vs. 36.4%, p=0.028). Children with SAA were more likely to require tube feeding both at discharge (79.6% vs. 48.3%, p<0.001) and at 1 year (52.7% vs. 13.6%, p<0.001) and had lower mean FOIS (4.18 vs. 6.21, p<0.001). In the logistic regression model adjusting for gestational age, long gap EA, and esophageal stricture, the presence of SAA remained a significant risk factor for dysphagia (OR 4.17 (95% CI 1.58-11.03)). CONCLUSION: SAA are common in children with EA/TEF and are associated with dysphagia, even after accounting for gestational age, esophageal gap and stricture. This study highlights the need for a multidisciplinary approach, including early laryngoscopy and bronchoscopy, in the evaluation of the EA/TEF child with dysphagia. LEVEL OF EVIDENCE: Level II retrospective prognostic study. PMID- 29429771 TI - Gonocyte transformation in a congenitally cryptorchid rat is normal and may be similar to the situation reported in human acquired cryptorchidism. AB - BACKGROUND: In congenital undescended testis (UDT) in humans, thermal insult damages early germ cell development during mini-puberty (3-6months) causing increased risk of both cancer and infertility. In rodents however, UDT causes infertility but not cancer. In the TS rat with congenital UDT we hypothesized that early germ cell development would be normal as UDT only becomes manifest at 3-4weeks (and the germ cells only become sensitive to thermal injury) after minipuberty is complete at 1week. METHODS: Normal testis and potential UDT from unilateral cryptorchid TS rats were collected at week 1 and 4 and processed into paraffin sections labeled for Sertoli cells (AMH), early germ cells (MVH) and spermatogonial stem cells (PLZF). Confocal microscopic images and Fiji Image J were used to count cells in testicular tubules with paired T-test statistical analysis. RESULTS: Total germ cells/tubule, basement membrane-bound germ cells/tubule, and Sertoli cells/tubule were unchanged between normally descending and future UDT at 1-4weeks old (P>0.05) Total germ cells/tubule and spermatogonial stem cells/tubule increased dramatically between weeks 1 and 4. CONCLUSION: Rat gonocyte transformation is normal in both normally descending and future UDT. This suggests that congenitally cryptorchid rats may not develop testicular cancer because gonocytes (the putative origin of malignant degeneration) normally transform into spermatogonial stem cells before UDT occurs and the risk of thermal injury develops. This suggests the TS rat may be a good model for acquired UDT in human where the abnormal testicular position develops after gonocyte transformation is completed in the first year. PMID- 29429772 TI - Reliability of Glasgow Coma Score in pediatric trauma patients. AB - BACKGROUND: Discordant assessments of Glasgow Coma Score (GCS) following trauma can result in inappropriate triage. This study sought to determine the reliability of prehospital GCS compared to emergency department (ED) GCS. METHODS: We conducted a retrospective review of traumas from 01/2000 to 12/2015 at a Level-1 pediatric trauma center. We evaluated reliability between field and ED GCS using Pearson's correlation. We ascertained the difference between prehospital and ED GCS (delta-GCS). Associations between patient characteristics and delta-GCS were modeled using Poisson and linear regression, adjusting for demographic and clinical covariates. RESULTS: We identified 5306 patients. Pearson's correlation for GCS measurements was 0.57 for ages 0-3, and 0.67-0.77 for other age groups. Mean delta-GCS was highest for age<3years (0.95, SD=2.4). Poisson regression demonstrated that compared to children 0-3years, higher age was associated with lower delta-GCS (RR 0.65 95% CI 0.56-0.74). Linear regression showed that in those with a delta-GCS, more severe injury (higher ISS, worse ED disposition) and older age were associated with a negative change, signifying decline in score. CONCLUSIONS: GCS is generally unreliable in pediatric trauma patients aged 0-3years, particularly the verbal score component. This may impact accuracy of triage priority for pediatric trauma patients. LEVEL OF EVIDENCE: III, Prognostic. PMID- 29429773 TI - Left prefrontal neuronavigated electrode localization in tDCS: 10-20 EEG system versus MRI-guided neuronavigation. AB - Transcranial direct current stimulation (tDCS) involves positioning two electrodes at specifically targeted locations on the human scalp. In neuropsychiatric research, the anode is often placed over the left dorsolateral prefrontal cortex (DLPFC), while the cathode is positioned over a contralateral cephalic region above the eye, referred-to as the supraorbital region. Although the 10-20 EEG system is frequently used to locate the DLPFC, due to inter-subject brain variability, this method may lack accuracy. Therefore, we compared in forty participants left DLPFC-localization via the 10-20 EEG system to MRI-guided neuronavigation. In one participant, with individual electrode positions in close proximity to the mean electrode position across subjects, we also investigated whether distinct electrode localizations were associated with different tDCS induced electrical field distributions. Furthermore, we aimed to examine which neural region is targeted when placing the reference-electrode on the right supraorbital region. Compared to the 10-20 EEG system, MRI-guided neuronavigation localizes the DLPFC-targeting anode more latero-posteriorly, targeting the middle prefrontal gyrus. tDCS-induced electric fields (n = 1) suggest that both localization methods induce significantly different electric fields in distinct brain regions. Considering the frequent application of tDCS as a neuropsychiatric treatment, an evaluation and direct comparison of the clinical efficacy of targeting methods is warranted. PMID- 29429774 TI - Normal saline for intravenous fluid therapy in critically ill patients. AB - The efficacy and safety of normal saline (NS) for fluid therapy in critically ill patients remain controversy. In this review, we summarized the evidence of randomized controlled trials (RCTs) which compared NS with other solutions in critically ill patients. The results showed that when compared with 6% hydroxyethyl starch (HES), NS may reduce the onset of acute kidney injury (AKI). However, there is no significant different in mortality and incidence of AKI when compared with 10% HES, albumin and buffered crystalloid solution. Therefore, it is important to prescribe intravenous fluid for patients according to their individual condition. PMID- 29429775 TI - Effect of retension sutures on abdominal pressure after abdominal surgery. AB - PURPOSE: To evaluate the effect of retention sutures on abdominal pressure and postoperative prognosis in abdominal surgery patients. METHODS: This prospective cohort study included patients who were admitted to Daping Hospital from May 15, 2014 to October 11, 2014. A total of 57 patients were enrolled, including 18 patients in the "U" type retention suture group, 17 patients in the intermittent retention suture group, and 22 patients in non-retention suture group. The demographic data, clinical data and risk factors for abdominal wound dehiscence were recorded. The bladder pressure (IVP) was monitored preoperatively, intraoperatively, and four days postoperatively. Additionally, the incidence of abdominal wound dehiscence and infection 14 days after the operation was recorded. RESULTS: During the operation, the IVP decreased and then increased; it was at its lowest 1 h after the start of the operation (5.3 mmHg +/- 3.2 mmHg) and peaked after tension-reducing (8.8 mmHg +/- 4.0 mmHg). The IVP values in the "U" type retention suture group and intermittent retention suture group were higher than in the non-retention suture group 4 days after operation (p < 0.005). The Visual Analogue Scale (VAS) pain scores were 3.9 +/- 2.2, 3.8 +/- 2.0, and 3.0 +/- 1.0 in the retention suture group, intermittent retention suture group and non-retention suture group, respectively. The VAS pain scores in the "U" type tension-reducing group and intermittent tension-reducing group were higher than in the non-tension-reducing group (p < 0.005). CONCLUSION: Although retention sutures may reduce the incidence of postoperative wound dehiscence in abdominal surgery patients, they can increase the IVP and postoperative pain. PMID- 29429776 TI - Interventional treatment experience in multiple injury with major abdominal or pelvic injuries: 160 cases analysis. AB - PURPOSE: To observe the therapeutic effect of interventional embolization and haemorrhage control in multiple trauma patients with a major abdominal or pelvic injury. METHODS: Data of 160 multiple trauma patients with a major abdominal or pelvic injury were retrospectively analyzed. They were admitted into the Department of Emergency of the First Affiliated Hospital of Zunyi Medical College from October 2013 to April 2016. Eighty-seven patients who received emergent intervention for embolization and haemorrhage control were set as group A, including 72 males and 15 females, with an average age of (39.32 +/- 14.0) years. Patients underwent emergent intervention for embolization and hemostasis. The other 73 patients who received traditional surgeries were set as group B, including 62 males and 11 females, with an average age of (38.48 +/- 13.12) years. The time from admission to emergency intervention, the time of interventional embolization, transfusion during hospitalization, length of stay and prognosis were observed. The whole treatment and prognosis were compared between group A and group B. RESULTS: In group A, the average time from admission to intervention exploration was (132.05 +/- 86.80) min, the average operation time was (149 +/- 49.69) min, the average hospitalization time was (18.37 +/- 4.71) days, the average amount of RBC transfusion during hospitalization was (7.2 +/- 4.33) units, and the mortality was 4.60% (4 patients died). The corresponding data in group B were respectively (138.95 +/- 82.49) min, (183 +/- 52.39) min, (22.72 +/- 6.63) days, (12.23 +/- 5.43) units, and 9.59% (7 cases died). There was no statistical difference in the time from admission to operation between the two groups (p > 0.05), but there was statistical difference in operation time, RBC transfusion, hospitalization time, prognosis, and mortality between the two groups (all p < 0.05). CONCLUSION: The emergent intervention for embolization and haemorrhage control of multiple trauma patients with a major abdominal or pelvic injury and visceral organ haemorrhage has the advantages of less trauma, shorter operation time, shorter hospital stay, less blood transfusion in comparison to the traditional emergency surgeries. PMID- 29429777 TI - Effects of surgical and nonoperative treatment on wrist function of patients with distal radius fracture. AB - PURPOSE: To study the effects of surgical and nonoperative treatment on wrist function in patients with distal radius fracture. METHODS: In total, 97 patients treated for distal radius fracture in the Department of Orthopedic Trauma at the People's Hospital of Peking University from Jan. 2010 to Jun. 2016 were selected for outpatient follow-up, including manipulative reduction and dorsal splint fixation in 24 cases, bivalve cast fixation in 19 cases and open reduction and internal fixation in 54 cases. Evaluation was based on Sartiento's modification of the Gartland and Werley score. Efficacy was assessed with wrist pain as the focus. RESULTS: The wrist function scores of the surgical group were better than nonoperative groups. There was no significant difference in wrist function scores between the dorsal splint group and the bivalve cast group. The ulnar wrist pain incidence had no significant difference in surgical and nonoperative groups. The displace rate in dorsal splint group was higher than other groups. CONCLUSION: The overall effect of surgical treatment of distal radius fracture is better than nonoperative treatment. The ulnar wrist pain incidence has no significant difference in these groups. Dorsal splint fixation is more prone to displace than bivalve cast fixation. PMID- 29429778 TI - Hydrocephalus in Pediatric Traumatic Brain Injury: National Incidence, Risk Factors, and Outcomes in 124,444 Hospitalized Patients. AB - BACKGROUND: Hydrocephalus is a life-threatening sequela of traumatic brain injury (TBI) with poorly defined epidemiology in children. Here, we report the national incidence, risk factors, and outcomes associated with post-traumatic hydrocephalus (PTH). METHODS: The Kids Inpatient Database (2003, 2006, 2009, 2012) was queried using the International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes to identify all patients (age 0 to 20) with TBI (850.xx to 854.xx) and noncongenital hydrocephalus (331.3 to 331.5, exclude 742.3). Variables included patient demographics and comorbidities, TBI severity (level of consciousness, injury type), treatment, and outcome related measures. Risk factors associated with PTH were identified using univariate and multivariable analyses. RESULTS: PTH occurred in 1265 of 124,444 patients (1.0%) hospitalized with TBI and was managed by ventriculoperitoneal shunt (32.7%) and extraventricular drain (10.7%). PTH had the highest rate in shaken baby syndrome (6.7%, n = 19) and firearm injury (3.4%, n = 74). PTH varied by type of TBI: subdural hematoma (2.4%), subarachnoid hemorrhage (1.4%), epidural hematoma (1.0%), cerebral laceration (0.9%), concussion (0.2%). Multivariable risk factors for PTH included age zero to five years old (versus six to 20), Medicaid (versus private), electrolyte disorder, chronic neurological condition, weight loss, subarachnoid hemorrhage, subdural hematoma, open wound, postoperative neurological complication (iatrogenic stroke), and septicemia (P < 0.05). PTH rates are higher among surgically managed patients (6.0% vs 0.5%) unless managed within the first 24 hours (0.8% vs 4.1%) (P < 0.05). PTH was associated with greater length of stay (25 days versus five days) and hospital costs ($86,596 vs $16,791), but lower mortality (1.1% vs 5.4%). CONCLUSIONS: PTH in children is relatively uncommon compared with adults. Risk factors identified here, along with the influence of surgical intervention, warrant further investigation. PMID- 29429779 TI - Ataxia With Hypodontia: A Unique Leukodystrophy. PMID- 29429780 TI - Complete Atrioventricular Heart Block From an Epilepsy Treatment. PMID- 29429781 TI - High Prevalence and Incidence of Diabetic Peripheral Neuropathy in Children and Adolescents With Type 1 Diabetes Mellitus: Results From a Five-Year Prospective Cohort Study. AB - BACKGROUND: In this prospective cohort study, we investigated the prevalence of diabetic peripheral neuropathy at baseline and after five years of follow-up in children and adolescents with type 1 diabetes mellitus using both measurements of nerve conduction velocity and clinical neurological examination. METHODS: A total of 38 patients who underwent insulin pump or intensive insulin therapy were included. The subjects averaged 12.6 +/- 2.4 years of age and their diabetes duration averaged 5.6 +/- 3.2 years. All patients underwent a detailed physical, neurological, and electrophysiological examination, as well as laboratory testing at their annual checkup. RESULTS: At baseline, the prevalence of diabetic peripheral neuropathy diagnosed using neurological examination was 13.2%, whereas nerve conduction velocity testing revealed diabetic peripheral neuropathy in 31.6%, highlighting a high prevalence of subclinical diabetic peripheral neuropathy. During follow-up, there was a strong increase in the prevalence of clinically diagnosed diabetic peripheral neuropathy, which reached 34.2% (P = 0.039) after five years; the proportion of patients with subclinical diabetic peripheral neuropathy even reached 63.2% (P = 0.002). The most significant changes in electrophysiological parameters were observed in the tibial sensory nerve (P = 0.001). CONCLUSIONS: The prevalence of diabetic peripheral neuropathy in children and adolescents with type 1 diabetes mellitus was high, and there was a rapid increase in the prevalence of diabetic peripheral neuropathy during a five-year follow-up interval. Importantly, our data show that a mere clinical evaluation is not sensitive enough to diagnose diabetic peripheral neuropathy in these patients. Nerve conduction velocity measurement, which is regarded as the gold standard for the assessment of diabetic peripheral neuropathy, should be applied more broadly. PMID- 29429782 TI - Long-Term Treatment of Niemann-Pick Type C1 Disease With Intrathecal 2 Hydroxypropyl-beta-Cyclodextrin. AB - BACKGROUND: Intrathecal 2-hydoxypropyl-beta-cyclodextrin has been found to mobilize cholesterol, extend life, reduce cerebellar pathology, and delay onset of ataxia in the mouse and cat models of Niemann-Pick disease, type C1, a clinically variable progressive and ultimately fatal neurodegenerative storage disorder characterized by endolysosomal accumulation of unesterified cholesterol. OBJECTIVE: In this study, the long-term effects of intrathecal 2-hydoxypropyl beta-cyclodextrin treatment for 2.5 to three years in humans with Niemann-Pick disease, type C, were evaluated. METHODS: Three patients with Niemann-Pick disease, type C, in different stages of progression and displaying varying disease manifestations were treated with intrathecal 2-hydoxypropyl-beta cyclodextrin (VTS-270) delivered by lumbar puncture infusion through an intermediate-size patient population investigational new drug application for expanded access. Disease progression was monitored with the Niemann-Pick disease, type C, Neurological Severity Scale and numerous objective measures of function in five neurological domains typically impacted by the disease: cognitive/language, gait/balance, fine motor, swallowing, and eye movement. RESULTS: No worsening in any domain except eye movements (vertical pursuit gain) was seen for any of the three patients, and in the other domains, improved scores on measures were seen over time for one or more patients. The Niemann-Pick disease type C (NPC) Neurological Severity Scale (NSS) showed stable to slightly improved ratings. CONCLUSIONS: These trajectories are not consistent with the typical trajectory of the disease and suggest that intrathecal 2-hydoxypropyl beta-cyclodextrin has stabilized the disease over an extended period of time, supporting the current phase 2/3 controlled registration trial with VTS-270. PMID- 29429783 TI - Pediatric Stroke and Its Mimics: Limitations of a Pediatric Stroke Clinical Pathway. AB - BACKGROUND: Acute stroke protocols improve delivery of care but it is unclear whether these resource intensive protocols are able to differentiate stroke from mimics in children. The aim of this study is to describe our institution's experience with stroke mimics identified through our pediatric stroke clinical pathway (PSCP). METHODS: The PSCP was implemented in our level 1 pediatric emergency department in June 2014 for children aged one month to 18 years. For patients managed using the PSCP from June 2014 to December 2016, demographic and clinical data were compared for patients diagnosed with stroke or a stroke mimic. RESULTS: A total of 59 children were evaluated with the PSCP. Fourteen children were identified as having a stroke and 45 children had stroke mimics. The most common stroke mimics were functional neurological disorders (20.0%), transient neurological deficits (17.8%), migraine (15.6%), and seizure (11.1%). Patient demographics and time to neuroimaging did not differ between patients with and without stroke. Vomiting was commonly reported by patients with stroke (odds ratio: 4.00, 95% confidence interval: 1.12 to 14.35), whereas weakness was not (odds ratio: 0.7, 95% confidence interval: 0.07 to 0.90), but the physical examination did not differ between patients with and without stroke. CONCLUSIONS: The PSCP ensures timely evaluation of patients presenting with neurological deficits but fails to reliably differentiate between patients with stroke and patients with stroke mimics. Further multicentered studies are needed to develop a "stroke screen" that reliably distinguishes pediatric stroke from its mimics. PMID- 29429784 TI - Rapid progressive visual decline and visual field defects in two patients with the Heidenhain variant of Creutzfeld-Jakob disease. AB - BACKGROUND: Heidenhain variant of Creutzfeldt-Jakob (HvCJD) is a rare disease, patients presenting with loss of visual acuity and a decline in visual fields. CASE PRESENTATION: Two patients with rapid loss of visual acuity and declining visual fields presented with homonymic hemianopsia over several weeks. Cranial MRI showed neither stroke nor other morphological changes explaining the severe visual field defects. Neurological examination revealed no pathologies. However, lumbar puncture showed an increase in total protein in cerebrospinal fluid (CSF). Visual field testing revealed further deterioration during follow-up. Several weeks later, patients' behaviour changed markedly, exhibiting aggression, declining memory function and physical degeneration. The suspected diagnosis was the Heidenhain variant of Creutzfeld-Jakob disease (HvCJD). CSF analysis showed evidence of PrPSc and 14-3-3 protein. Both patients died within 8 weeks of the CJD diagnosis. CONCLUSIONS: Loss of visual acuity and a decline in visual fields without corresponding MRI findings and marked changes in behaviour should lead to a diagnosis of HvCJD. Corresponding diagnostic tests should be performed for confirmation. The prognosis for survival is poor and should be immediately communicated to affected patients and their relatives. PMID- 29429785 TI - Spinal primary central nervous system lymphoma: Case report and literature review. AB - Primary central nervous system lymphoma (PCNSL) is a very rare tumor of increasing incidence. It is often misdiagnosed due to the unspecific presentation or unavailable biopsy, and results in poor prognosis. PCNSL involved the spinal cord is extremely sparse. Here we report a gentleman presented with one-year history of progressive tremor in the left limbs and slight dysarthria as well as three-month history of paraparesis, tinnitus and insomnia. MR images disclosed the swollen cerebellum and cauda equine, with contrast enhancement in both meninges and nerve roots. The cerebrospinal fluid (CSF) revealed extremely high protein level. Tubercular meningitis was considered and anti-tuberculosis therapy was given for weeks but without relief. With progressive deterioration, the PCNSL was eventually presumed according to positive CSF cytology and exclusion of systemic involvement. However, the patient passed away within days. We then reviewed the current diagnostic methods of PCNSL. The biopsy, as the gold standard for PCNSL diagnosis, is not eligible for all patients suspected PCNSL. The presurgical diagnostic algorithm of PCNSL has been fixed by clinicians and we suggest the early and repeated CSF cytology should be included for definitive diagnosis. PMID- 29429786 TI - Evaluation and management of small dural tears in primary lumbar spinal decompression and discectomy surgery. AB - Incidental dural tear is one of the most common intraoperative complications in lumbar spine surgery. Yet, its technical management for the prevention of CSF leak is controversial. The technique of managing dural tears depends on the location of the dural tears as well on the length and anatomical characteristics of the dural tear. We propose an anatomical classification for small (less than one cm) dural tears and report on the outcome of managing these dural tears types using different technique for different type. 62 patients underwent spinal dural repair after microdiscectomy or lumbar spinal decompression. Group 1 consisted of 20 patients, with Type I or mild dural tear who had tissue-glue coated collagen sponge or fibrin glue application. Group 2 comprised 21 patients with Type II or moderate dural tear who had both tissue-glue coated collagen sponge and fibrin glue application. Group 3 comprised 21 patients with Type III or severe dural tear who had polypropylene suture and tissue-glue coated collagen sponge and/or fibrin glue application. Evident postoperative CSF leak was used to determine the patient's postoperative result. Postoperative CSF leak was not evident during a minimum 1 year follow up in group 1. Internal CSF leak was evident in group 2 (n = 3) and group 3 (n = 3) during same follow up. Three patients underwent re-do spinal surgery for CSF leak repair. We recommend different management technique depending on the type of tear. For type I, we recommend the use of tissue-glue coated collagen sponge or fibrin glue application, without dural suturing. PMID- 29429787 TI - The difficulty of predicting clinical outcome after intended submaximal resection of large vestibular Schwannomas. AB - INTRODUCTION: Intended subtotal resection of large vestibular schwannomas (T4a and b according to the Hannover classification system) has been shown to be safe and, in combination with stereotactic radiosurgery, might enable sufficient tumor control. However, risk factors for postoperative neurological deterioration in these surgically challenging lesions are largely unknown. METHODS: Pre- and postoperative symptoms, clinical and radiological data of patients who underwent intended subtotal resection for vestibular schwannoma in our department between 2010 and 2014 were reviewed. Risk factors for postoperative neurological deterioration were analyzed in uni- and multivariate analyses. RESULTS: 63 patients harboring T4a (N = 33, 52%) or T4b (N = 30, 48%) tumors were included. At time of discharge, facial nerve and hearing function had deteriorated from a serviceable to a non-serviceable level (H&B grades I + II vs. >II) in 24% (N = 15/63) and 21% (N = 6/29), respectively. Deterioration of vertigo was more common after near (N = 3/9, 33% vs. 2/38, 5%) than after subtotal resection (<.25 ccm vs. >= .25 ccm tumor remnant on the initial postoperative MRI; p = .042). No further correlation with patient age, sex, neurofibromatosis, resection extent and tumor volume, or -cyst volume was found. Patients were reevaluated after a median of 3 months after surgery. At that time, facial nerve function and hearing had both decreased from a preoperative serviceable to a non-serviceable level in 5%. In univariate analyses, risk of deterioration of facial nerve function increased with preoperative tumor volume (p = .037). CONCLUSION: Intended submaximal resection provides satisfactory neurological outcome for patients with large VS. Risk factors for postoperative neurological deterioration remain unclear. PMID- 29429788 TI - Novel SGCE mutation in a patient with myoclonus-dystonia syndrome - Diagnostic delay of more than 40 years. AB - We present a case of myoclonus-dystonia syndrome illustrated by three videos in which we found a novel SGCE mutation. As the patient described here was suffering from predominant psychiatric comorbidities it took more than 40 years from the first manifestation of the disease until the diagnosis. Having detected the genetically proven cause for his motor and non-motor symptoms was an enormous relief to our patient. We want to share this instructive case in order to prompt neurologists and psychiatrists to look closely at both movement disorders and neuropsychiatric signs in order to diagnose and treat patients to the latest standard. PMID- 29429789 TI - A purely functional Imaging based approach for transcortical resection of lesion involving the dominant atrium: Towards safer, imaging-guided, tailored cortico leucotomies. AB - BACKGROUND AND STUDY OBJECT: The Dominant Atrium (DA) is a crossroad of eloquent white matter bundles difficult to preserve with a standard "anatomical" approach. The aim of this work is to evaluate the results of a cohort of patients who underwent surgery with the aid of a purely functional MRI and DTI-based approach. MATERIALS AND METHODS: 43 patients suffering from lesions involving the DA have been included in the final cohort and studied in regards to quality of life (KPS); a special attention was lent on the incidence of new or worsening of preexisting neurological deficits, with a focus on motor, visual and speech disturbances after the surgical treatment. Patient, surgery and lesion-related data were recorded to identify the relationships with outcome. Eloquent areas fMRI and the course of Arcuate Fasciculus (AF), Inferior frontooccipital fasciculus (IFOF), Optic radiation (OR) and corticospinal tract (CST) have been investigated with preoperative MRI sequences and DTI reconstruction. RESULTS: The final cohort consisted of 43 patients, 19 males and 24 females; average age was 56.8 years. We recorded 9 transient and 3 permanent postoperative deficits, only one of those was caused by an edema interference with DTI reconstruction. Preoperative functional status, histology and volume of the lesion proved to be independent factors affecting results. CONCLUSIONS: A purely functional surgical approach to the DA provided promising preliminary results. A direct DTI-fMRI visualization of the eloquent structures proximal to DA allows surgeon to conceive an ultra-precise and "tailored" cortico-leucotomy for an optimal exposure of the lesion. PMID- 29429790 TI - The effect of cisplatin administration on certain trace elements homeostasis in rats and the protective effect of silver birch (Betula pendula) sap. AB - BACKGROUND: A clinically active structure with known antitumor activities is cisplatin (CDDP), but this it comes with toxicity characteristics which can be faded by the beneficial effects of Silver birch (Betula pendula) sap. OBJECTIVE: We aimed to assess the cisplatin activity on: Mn, Mg, Cu, Fe and Zn homeostasis in rats and to observe the effect of birch sap. METHODS: Healthy Wistar rats (n = 10/group) were divided in four groups: Control: receiving 1 mL saline I.P. way + water; E1: cisplatin 20 mg kgbw-1, I.P.; E2: cisplatin 20 mg kgbw-1, I.P. + birch sap and Control sap group: 1 mL saline I.P. + birch sap. Blood was collected: at the trial's start and after 48 h, and blood and organs (liver, kidney and spleen) for the cytoarchitecture investigation and readings were sampled after seven days. Samples were processed in nitric acid by microwave digestion and readings were completed by flame atomic absorption spectroscopy, the outcomes being statistically analyzed by ANOVA. RESULTS: Cisplatin produced a significant imbalance in the trace elements homeostasis, the birch sap administration recovering them usual homeostasis status. Comparatively with the Control, rats exposed to cisplatin presented a not significant (p > 0.05) decrease of Zn ( 26.74%) and Mg (-10.25%), a significant (p < 0.05) decrease of Cu (-27.73%) at 48 h, a highly significant (p < 0.01) decrease of Cu (-56.08%) and Fe (-85.35%) at seven days after administration and a not significant (p > 0.05) increase of Mn (+28.16%). Birch sap administration after Cisplatin was followed by restoration or nevertheless significant increase (p < 0.05) of the investigated trace elements Zn (+56.88% to 48 h/+89.94% after seven days), Mg (+26.86%/+95.74%), Cu (+23.13%/+74.56%), Fe (+39.64%/+440.11%) and Mn (+4.30%/+15.87%), suggesting them defence against cisplatin. Histology revealed the order of main altered organs after the CDDP exposure: kidney, spleen and liver. CONCLUSIONS: The study recommended the important protective role of Betula pendula sap against diverse cisplatin deleterious side-effects. PMID- 29429791 TI - Corrigendum to "Accumulation, elimination, sequestration, and genetic variation of lead (Pb2+) loads within and between generations of Drosophila melanogaster" [Chemosphere 181 (2017) 368-375]. PMID- 29429792 TI - Postprandial Mineral Handling in Patients on Maintenance Hemodialysis. AB - OBJECTIVE: Patients on maintenance hemodialysis (HD) are unable to compensate for an enlarged mineral load with increased excretion of calcium and phosphate in the urine. Hence, excess calcium and phosphate must be neutralized by other mechanisms to avoid toxicity. The present study examined the acute handling of a mineral load in HD patients as compared with healthy subjects. DESIGN: Controlled intervention study. SUBJECTS: Twelve HD patients and 12 matched healthy subjects. INTERVENTION: After a weight-adjusted standardized meal, blood samples were collected for the following 9 hours for ionized calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF23). The fractional excretion of calcium and phosphate was measured in controls. The patients were not allowed to take phosphate binders 24 hours before the experiment, and the study was performed on a non-HD day. RESULTS: In healthy subjects, plasma calcium and phosphate did not change significantly from baseline, whereas HD patients demonstrated a decrease in plasma phosphate from 60 to 120 minutes by maximum 10% ([6; 13%], mean [95% confidence interval], P < .001) below baseline. PTH increased in both HD patients and controls and peaked 300 minutes after the meal 11% ([4; 19%], P < .004) above baseline in both groups. No changes in FGF23 were observed in HD patients, whereas FGF23 steadily decreased in controls, reaching nadir values at the end of the study 16% ([10; 21%], P < .001) below baseline. Control subjects demonstrated an immediate postprandial increase in the fractional excretion of both calcium and phosphate CONCLUSIONS: In HD patients, the mineral load paradoxically induced a decrease in plasma phosphate, whereas ionized calcium remained unchanged although PTH increased. These findings suggest that excess calcium and phosphate may be disposed of by mineral deposition, which may include soft tissue and vascular calcification. PMID- 29429793 TI - Soluble Toll-like Receptor 4: A New Player in Subclinical Inflammation and Malnutrition in Hemodialysis Patients. AB - OBJECTIVE: Toll-like receptor 4 (TLR4) promotes inflammation in hemodialysis patients (HD). A soluble form of extracellular TLR4 (sTLR4) has been recently characterized, which showed the ability to attenuate TLR4 signalling. In this study, we describe the sTLR4 profile in regular HD patients. SUBJECTS: In a cross sectional study we enrolled forty prevalent HD patients (68.2 +/- 16.3 years, twenty-five males) with a median dialysis vintage of 41 months. Nineteen patients were undergoing standard bicarbonate HD (BHD) and 21 patients on-line hemodiafiltration (HDF). Ten healthy sex-matched subjects constituted the controls (C). INTERVENTION: Before and after the HD session, serum was tested for sTLR4 levels by ELISA. Moreover, clinical and biochemical data were collected, including body mass index, albumin, and C-reactive protein (CRP) levels. Body composition was expressed as a 3-compartment model, providing lean tissue index and fat tissue index (FTI). MAIN OUTCOME MEASURE: Describe the profile of sTLR4 in HD patients, evaluating the correlations among sTLR4 levels and the main clinical characteristics, inflammatory and nutritional parameters. RESULTS: Patients with subclinical inflammation (i.e., high CRP levels without clinical symptomatology) presented higher sTLR4 levels (0.42 +/- 0.25 ng/mL) with respect to both C and not inflamed HD patients (0.23 +/- 0.19 ng/mL, P < .05). There was a significant direct correlation between predialysis sTLR4 and body mass index, FTI (r = 0.55), and CRP levels (r = 0.52) and inverse correlation with lean tissue index and albumin (r = -0.4). In multivariate analysis, sTLR4 resulted directly associated with FTI (P = .038). Notably, sTLR4 levels resulted higher in bicarbonate hemodialysis versus hemodiafiltration (0.37 +/- 0.18 vs. 0.19 +/- 0.21 ng/mL, P < .05). CONCLUSIONS: sTLR4 correlates with inflammatory and nutritional parameters, presenting as a new potential player in modulating subclinical inflammation in HD patients. PMID- 29429794 TI - Treatment plan quality and delivery accuracy assessments on 3 IMRT delivery methods of stereotactic body radiotherapy for spine tumors. AB - Stereotactic body radiotherapy (SBRT) for spine tumors has demonstrated clinical effectiveness. The treatment planning and delivery techniques have evolved from dynamic conformal arc therapy, to fixed gantry angle intensity modulated radiotherapy (IMRT), and most recently to volumetric modulated arc therapy (VMAT). A hybrid-arc (HARC) planning and delivery method combining dynamic conformal arc therapy delivery with a number of equally spaced IMRT beams is proposed. In this study we investigated plan quality, delivery accuracy, and efficiency of 3 delivery techniques: IMRT, HARC, and VMAT. Patients who underwent spine SBRT treatments were randomly selected from an Institutional Review Board approved registry. For each patient, the prescription dose was 14 to 16 Gy in a single fraction to cover >90% of the tumor (without planning margin) while constraining V10Gy <= 10% of the spinal cord and the maximum point dose (MPD) of the spinal cord <= 14 Gy. All cases were clinically treated with fixed gantry step-shoot IMRT plans and then re-planned with VMAT using Pinnacle 9.0 and with HARC using Brainlab iPlan 4.5. Student t-test was used to compare the dosimetric end points, including V16Gy to the planning target volume, homogeneity index, MPDPTV, the conformity index, V10Gy of the spinal cord, and MPDcord. To compare the accuracy of delivery, we delivered all plans on a phantom and conducted gamma index (GI) comparisons with 3 mm/3% and 2 mm/2% criteria. All plans met our clinical requirements. Among 3 techniques, there were no differences on dose coverage to the tumor volume, maximum dose to the spinal cord, and plan homogeneity index (p > 0.05). The average V10Gy of the spinal cord was 6.66 +/- 0.03%, 5.49 +/- 0.03%, and 4.76 +/- 0.02% for IMRT, HARC, and VMAT plans, respectively. Accordingly, the conformity indices were 1.30 +/- 0.11 and 1.29 +/- 0.20, 1.53 +/- 0.29, respectively. VMAT plans were significantly (p < 0.05) less conformal but significantly (p < 0.05) lower V10Gy of the spinal cord than those from HARC and IMRT plans. With delivery accuracy measured by GIs, the average GIs of 3%/3 mm were 92.6 +/- 1.1%, 96.5 +/- 2.7%, 99.0 +/- 1.1% for IMRT, HARC, and VMAT plans, respectively. The differences were significant (p < 0.05). Accordingly, the average monitor units were 9238 +/- 2242, 9853 +/- 2548 and 5091 +/- 910. The plan quality created from the 3 planning techniques can meet the clinical requirement. Adding arc beams in delivery such as in HARC and VMAT plans improves the delivery accuracy. VMAT is the most efficient delivery method. PMID- 29429795 TI - Comparison of two types of laryngoscopy for face-to-face intubation of a patient entrapped in a vehicle. PMID- 29429796 TI - Severe deep venous thromboembolism presenting with syncope associated with airplane travel: A public health quandary. PMID- 29429797 TI - Effect of rivaroxaban starter packs on emergency department throughput. PMID- 29429798 TI - Ventricular fibrillation in conscious patients witnessed by the emergency medical service. PMID- 29429799 TI - Accelerated idioventricular rhythm degenerating into bidirectional ventricular tachycardia following acute myocardial infarction. AB - Bidirectional ventricular tachycardia (BVT) is a rare ventricular tachyarrhythmia. It is usually regular, demonstrating a beat-to-beat alternation in the QRS frontal axis that varies between -20 degrees to -30 degrees and +110 degrees . The tachycardia rate is typically between 140 and 180 beats/min and the QRS is relatively narrow, with a duration of 120 to 150 ms. The etiology of published BVT cases is most commonly digitalis toxicity and, rarely, herbal aconitine poisoning, hypokalemic periodic paralysis, catecholaminergic polymorphic ventricular tachycardia (CPVT), myocarditis, and Andersen-Tawil syndrome. We report a case of accelerated idioventricular rhythm (AIVR) degenerating into BVT following acute myocardial infarction, and briefly discuss the proposed mechanisms underlying BVT. PMID- 29429800 TI - Definite chemoradiotherapy is a competent treatment option in FIGO stage IB2 cervical cancer compared with radical surgery +/- neoadjuvant chemotherapy. AB - BACKGROUND: To compare the treatment outcomes of different treatment modalities for International Federation of Gynecology and Obstetrics (FIGO) stage IB2 cervical cancer. METHODS: From January 2002 to July 2016, 91 patients with FIGO stage IB2 squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma of the cervix were enrolled. All of them received one of the following treatment modalities, including intensity-modulated radiotherapy (IMRT) with concurrent platinum-based chemotherapy (CCRT group, n = 27), radical surgery with or without adjuvant treatment (RH group, n = 25), or neoadjuvant chemotherapy followed by radical surgery with or without adjuvant treatment (NACT group, n = 39). Overall survival (OS), disease free survival (DFS), loco-regional failure-free survival (LRFFS) and distant metastasis-free survival (DMFS) were compared among the three different groups. RESULTS: The median follow up durations were 63.3 months for the CCRT group, 83.5 months for the NACT group, and 89.8 months for the RH group, respectively. The 5-year OS, DFS, LRFFS and DMFS for CCRT group vs. NACT group vs. RH group were 80.1% vs. 94.1% vs. 93.8% (p = 0.197), 79.5% vs. 79.3% vs. 91.0% (p = 0.401), 88.1% vs. 81.8% vs. 95.8% (p = 0.253), and 83.3% vs. 88.8% vs. 95.2% (p = 0.422). No significant prognostic factor was found in OS. Age > 48 was significant in predicting poor DFS and DMFS. The non-squamous cell carcinoma was a significant predictor of poor DFS, LRFFS and DMFS. CONCLUSION: CCRT is a feasible therapeutic option with acceptable acute and chronic treatment-related toxicities for patients who cannot tolerate radical surgery or neoadjuvant chemotherapy. PMID- 29429801 TI - Short Diffusion Time Diffusion-Weighted Imaging With Oscillating Gradient Preparation as an Early Magnetic Resonance Imaging Biomarker for Radiation Therapy Response Monitoring in Glioblastoma: A Preclinical Feasibility Study. AB - PURPOSE: To investigate a novel alternative diffusion-weighted imaging (DWI) approach using oscillating gradients preparation (OGSE) to obtain much shorter effective diffusion times (Deltaeff) for tumor response monitoring by apparent diffusion coefficient (ADC) mapping in a glioblastoma mouse model. METHODS AND MATERIALS: Twenty-four BALB/c nude mice inoculated with U87 glioblastoma cells were randomized into a control group and an irradiation group, which underwent a 15-day fractioned radiation therapy (RT) course with 2 Gy/d. Therapy response was assessed by mapping of ADCs at 6 time points using an in-house implementation of a cos-OGSE DWI sequence with Deltaeff = 1.25 ms and compared with a standard pulsed gradient DWI protocol (PGSE) with typical clinical diffusion time Deltaeff = 18 ms. Longitudinal ADC changes in tumor and contralateral white matter (WM) were statistically assessed using repeated-measures analysis of variance and post hoc (Sidak) testing. RESULTS: On short Deltaeff OGSE maps tumor ADC was generally 30%-50% higher than in surrounding WM. Areas correlated well with histology. Tumor identification was generally more difficult on PGSE maps owing to nonsignificant WM/tumor contrast. During RT, OGSE maps also showed significant tumor ADC increase (approximately 15%) in response to radiation, consistently seen after 14-Gy RT dose. The clinical reference (PGSE) showed lower sensitivity to radiation changes, and no significant response across the radiation group and time course could be detected. CONCLUSION: Our short Deltaeff DWI method using OGSE better reflected histologically defined tumor areas and enabled more consistent and earlier detection of microstructural radiation changes than conventional methods. Oscillating gradients preparation offers significant potential as a robust microstructural RT response biomarker, potentially helping to shift important therapy decisions to earlier stages in the RT time course. PMID- 29429802 TI - [Does the core subjects have a future?] PMID- 29429803 TI - Re: A Randomized Study of Intraoperative Autologous Retropubic Urethral Sling on Urinary Control After Robotic Assisted Radical Prostatectomy. PMID- 29429804 TI - Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study. AB - BACKGROUND: Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. OBJECTIVE: To determine whether gDDRm status impacts benefit from established therapies in mPC. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used. RESULTS AND LIMITATIONS: The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm-]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p=0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm- (5.1 mo), and RRs were similar (gDDRm+=61%; gDDRm-=54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+=8.3 mo, gDDRm-=8.3 mo; gDDRm+=46%, gDDRm-=56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28-1.25; p=0.17). Results are limited by the retrospective nature of the analysis. CONCLUSIONS: mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum. PATIENT SUMMARY: Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients. PMID- 29429805 TI - Respiration-Entrained Brain Rhythms Are Global but Often Overlooked. AB - We revisit recent evidence showing that nasal respiration entrains oscillations at the same frequency as breathing in several regions of the rodent brain. Moreover, respiration modulates the amplitude of a specific gamma sub-band (70 120Hz), most prominently in frontal regions. Since rodents often breathe at delta and theta frequencies, we caution that previous studies on delta and theta power and their cross-regional synchrony, as well as on delta-gamma and theta-gamma coupling, may have detected the respiration-entrained rhythm and respiration gamma coupling. We argue that the simultaneous tracking of respiration along with electrophysiological recordings is necessary to properly identify brain oscillations. We hypothesize that respiration-entrained oscillations aid long range communication in the brain. PMID- 29429806 TI - A live attenuated Vibrio anguillarum vaccine induces efficient immunoprotection in Tiger puffer (Takifugu rubripes). AB - Tiger puffer (Takifugu rubripes) is becoming an economic promising aquaculture species in China. However, the development of Tiger puffer breeding industry is restricted by some serious aquatic disease such as vibriosis. An effective live attenuated vaccine MVAV6203 was developed in our previous studies by curing the virulence plasmid pEIB1 and unmarked inframe-deletion of the aroC gene from the virulent V. anguillarum. Here, we evaluated whether this live vaccine was suitable for Tiger puffer against disease caused by Vibrio genus. The live vaccine show virulence attenuation in both juvenile and adult fish vaccinated with either a single or high dose (50-fold single dose). In addition, administration of the live vaccine shew limited growth in fish and did not affect fish body weight significantly, with no adverse impact on growth between vaccinated and saline control fish. Furthermore, increased expression of cytokines involved in pro-inflammatory (IL-1beta, TNFalpha and IL-6), cell mediated immunity inducing (IL-12p35, IL-12p40 and IL-18), antiviral/intracellular pathogen killing (I-IFN-1, IFN-gamma and Mx), peripheral T cell expansion and survival controlling (IL-2, IL-7 and IL-15) and antigen processing maker and anti-inflammatory (MHC I and IL-10) were elicited significantly after the vaccination. These cellular responses correlate with protection against virulent strain challenge and high RPS of 90.67% and 80.31% in juvenile and adult fish were obtained, respectively. These data indicated for the first time that the live attenuated V. anguillarum vaccine is suitably applied for the development of an effective and safe vaccine for prevention of vibriosis in Tiger puffer aquaculture industry. PMID- 29429807 TI - Post hoc analysis of the efficacy of the 13-valent pneumococcal conjugate vaccine against vaccine-type community-acquired pneumonia in at-risk older adults. AB - BACKGROUND: Individuals with certain chronic medical conditions are at higher risk of developing pneumonia and pneumococcal disease than those without. Using data from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), this post hoc analysis assessed the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged >=65 years with at-risk conditions. METHODS: The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) was a double-blind, parallel-group, randomized, placebo-controlled study in the Netherlands in which adults aged >=65 years received either PCV13 or placebo. Outcomes of interest were identified using prespecified clinical criteria, radiographic confirmation, routine microbiologic testing, and a serotype-specific urinary antigen detection assay. In this post hoc analysis, participants were classified by at-risk status based on self-reporting of any of the following chronic medical conditions: heart disease, lung disease, asthma, diabetes, liver disease, and smoking. The objective of this analysis was to assess PCV13 vaccine efficacy (VE) against a first episode of vaccine-serotype community-acquired pneumonia (VT-CAP) in at-risk participants. RESULTS: Of the 84,496 adults enrolled in the study, 41,385 (49.2%) were considered at risk owing to chronic medical conditions. Of the 139 VT-CAP cases, 115 (82.7%) occurred in these participants. VE of PCV13 against a first episode of VT-CAP among participants with at-risk conditions was 40.3% (95.2% CI: 11.4%, 60.2%). Average duration of follow-up since vaccination was 3.95 years for at-risk participants; protection did not wane over the study period. CONCLUSIONS: This post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) showed significant and persistent efficacy of PCV13 against VT-CAP in at-risk older adults. ClinicalTrials.gov identifier: NCT00744263. PMID- 29429809 TI - Turning up the heat: Effect of new vaccine for children's (VFC) program recommendations for use of temperature monitors upon incorrect product storage adverse event reporting. AB - BACKGROUND: The Centers for Disease Control and Prevention (CDC) coordinates the Vaccines For Children (VFC) program, which provides free vaccines to qualified children in the US. In 2009, the CDC issued Vaccine Storage Requirements, which were later replaced (2012) with an interim guidance and toolkit for vaccine storage and handling. The guidance called for use of Digital Data Loggers (DDL) to monitor vaccine storage temperatures. We describe a change in frequency of Incorrect Product Storage Reports (IPSRs) following issuance of the 2009 CDC guidance. METHODS: Merck & Co., Inc., Kenilworth, NJ, USA, systematically evaluates vaccine safety concerns for all products. The safety database was queried (01-Jan-2004 through 31-December-2016) to identify all IPSRs associated with 10 vaccines. We compared IPSRs received prior to and following the 2009 CDC guidance, comparing reports received from the US with those received from international sources during the same period. RESULTS: Following the release of the DDL guidance, a progressive increase in IPSRs was identified in the US (1 report received in 2004, 12,993 reports in 2016). In contrast, non-US IPSRs - have not had a similar increase: no reports received in 2004, 216 reports received in 2016. US reports of IPSRs 2004 through 2016 account for 96% of reports worldwide. There were no serious reports found in the database in conjunction with IPSRs, nor were there any additional safety findings in any of the reports with additional events reported. CONCLUSION: VFC DDL guidance was followed by an increase in IPSRs. No similar trend was seen outside the US (where no broad change in DDL guidance occurred). Despite the increase in IPSRs, there have been few associated adverse events (AEs) reported; no new safety concerns were identified. These findings suggest that the increase in IPSRs was associated with the introduction of use of DDLs, and suggests the need for further impact assessment. PMID- 29429808 TI - Immune parameters to p67C antigen adjuvanted with ISA206VG correlate with protection against East Coast fever. AB - East Coast fever (ECF) is a lymphoproliferative disease caused by the tick transmitted protozoan parasite Theileria parva. ECF is one of the most serious cattle tick-borne diseases in Sub-Saharan Africa. We have previously demonstrated that three doses of the C-terminal part of the sporozoite protein p67 (p67C) adjuvanted with ISA206VG confers partial protection against ECF at a herd level. We have tested the efficacy of two doses of this experimental vaccine, as reducing the vaccination regimen would facilitate its deployment in the field. We reconfirm that three antigen doses gave a significant level of protection to severe disease (46%, ECF score < 6) when compared with the control group, while two doses did not (23%). Animals receiving three doses of p67C developed higher antibody titers and CD4+ T-cell proliferation indices, than those which received two doses. A new panel of immune parameters were tested in order to identify factors correlating with protection: CD4+ proliferation index, total IgG, IgG1, IgG2 and IgM half maximal titers and neutralization capacity of the sera with and without complement. We show that some of the cellular and humoral immune responses provide preliminary correlates of protection. PMID- 29429810 TI - Envelope proteins of two HIV-1 clades induced different epitope-specific antibody response. AB - Using HIV-1 envelope protein (Env)-based immunogens that closely mimic the conformation of functional HIV-1 Envs and represent the isolates prevalent in relevant geographical region is considered a rational approach towards developing HIV vaccine. We recently reported that like clade B Env, JRFL, membrane bound Indian clade C Env, 4-2.J41 is also efficiently cleaved and displays desirable antigenic properties for plasmid DNA immunization. Here, we evaluated the immune response in rabbit by injecting the animals with plasmid expressing membrane bound efficiently cleaved 4-2.J41 Env followed by its gp140-foldon (gp140-fd) protein boost. The purified 4-2.J41-gp140-fd protein is recognized by a wide panel of broadly neutralizing antibodies (bNAbs) including the quaternary conformation-dependent antibody, PGT145 with high affinity. We have also evaluated and compared the quality of antibody response elicited in rabbits after immunizing with plasmid DNA expressing the membrane bound efficiently cleaved Env followed by gp140-fd proteins boost with either of clade C Env, 4-2.J41 or clade B Env, JRFL or in combination. In comparison to JRFL group, 4-2.J41 group elicited autologous as well as limited low level cross clade neutralizing antibody response. Preliminary epitope-mapping of sera from animals show that in contrast to JRFL group, no reactivity to either linear peptides or V3-loop is detected in 4-2.J41 group. Furthermore, the presence of conformation-specific antibody in sera from animals immunized with 4-2.J41 Env is observed. However, unlike JRFL group, in 4-2.J41 group of animals, CD4-binding site-directed antibodies cannot be detected. Additionally, we have demonstrated that the quality of antibody response in combination group is guided by JRFL Env-based immunogen suggesting that the selection and the quality of Envs in multicade candidate vaccine are important factors to elicit desirable response. PMID- 29429811 TI - Hospital-based surveillance for rotavirus diarrhea in Ulaanbaatar, Mongolia, April 2009 through March 2016. AB - BACKGROUND: Diarrheal disease is one of the leading causes of illness and death in young children in the world, especially the developing countries. Diarrheal disease results in about half a million childhood death per year, ranking second among all causes worldwide. Diarrheal disease due to rotavirus infection is currently the most common cause of severe diarrhea in infants and young children worldwide. Rotavirus immunization of infants is a safe and effective public health intervention for rotavirus infection control and expected to lead to a reduction of childhood morbidity and mortality. METHODS: We conducted hospital based surveillance at two representative hospitals in Mongolia to estimate the burden of hospitalizations for rotavirus diarrhea among children aged <5 years and to describe strain distribution patterns during 6-year study period. Fecal specimens were tested by rotavirus antigen detection enzyme immunoassay (EIA). Specimens that tested positive for rotavirus were further characterized to determine the genotype of strains by reverse-transcriptase polymerase chain reaction. RESULTS: Between April 2009 and March 2016, among 7076 eligible children with diarrhea 6078 patients were enrolled nationally. Forty-six percent (2794/6078) of EIA a specimens were positive for rotavirus. Ninety-three percent (5649/6078) of hospitalizations for diarrhea involved children less than 2 years. No deaths were recorded due to rotavirus diarrhea. The most common genotype was G3P [8] (47.7%) followed by G9P [6] (14.4%), G2P [4] (12%), and G9P [8] (7.1%). CONCLUSIONS: This study found a relatively high prevalence of severe rotavirus associated diarrhea disease in Mongolia and infants were the most affected. It highlights the urgent need for introduction of rotavirus vaccine into the national immunization program. Continued surveillance is crucial and pre-vaccine introduction rotavirus genotype patterns in Mongolia are valuable and can be followed post-introduction to assess vaccine impact. PMID- 29429812 TI - Bordetella pertussis (Bp) disease: Before (2003-2011) and after (2013-2016) maternal immunization strategy in a pediatric hospital. AB - INTRODUCTION: Whooping cough continues to be a major cause of morbidity and mortality in infants younger than 1 year. In 2012, Argentina introduced Tdap in pregnancy to prevent infant mortality. The aim of this study is to describe the impact of maternal immunization on the hospitalization and mortality rates of confirmed Bordetella pertussis (Bp) cases by comparing pre- and post-Tdap vaccine recommendation periods. MATERIAL AND METHODS: All PCR-confirmed Bp cases from "R. Gutierrez" Children's Hospital identified between December 2003 and December 2016 were included in. Analysis was performed comparing hospitalization rates (per 10,000 discharges) between pre-vaccination (PreV) 2003-2011 and post-vaccination (PostV) 2013-2016 time periods, excluding the intervention year (2012). RESULTS: During the study time frame, there were 1046 suspected Bp cases, of which 337 (32.2%) were confirmed. Three-hundred eight cases were analyzed (excluding year 2012): 237 in PreV and 71 in PostV. In comparison with PreV, PostV cases were older (3 vs 9 months; p < 0.001), and required less hospitalization (86.9% vs 67.6%; p < 0.001). Bp hospitalization rate (HR) decreased (22.3 vs 11.6; p < 0.001). The mortality rate in PreV 5.9% (14 cases); there were not deaths during PostV (p = 0.036). CONCLUSIONS: Confirmed cases were among infants younger than 1 year In PostV, Bp cases were older and there was a significant decrease in the hospitalization rate. There were no fatal cases in our center after the pregnancy Tdap recommendation was implemented. PMID- 29429813 TI - Exceptional influenza morbidity in summer season of 2017 in Israel may predict the vaccine efficiency in the coming winter. AB - Influenza infections are the leading cause of respiratory viral infections worldwide, and are mostly common in the winter season. The seasonal influenza vaccine is currently the most effective preventive modality against influenza infection. Immediately following each winter season the World Health Organization (WHO) announces the vaccine composition for the following winter. Unexpectedly, during the summer of 2017, in Israel, we observed in hospitalized patients, an exceptionally high numbers of Influenza positive cases. The majority of the influenza B infections were caused by influenza B/Yamagata lineage, which did not circulate in Israel in the previous winter, and most of the influenza A infections were caused by influenza A/H3N2, a strain similar to the strain that circulated in Israel in the previous winter. We therefore predict that these two viruses will circulate in the coming winter of 2017/18 and that the trivalent vaccine, which includes antigenically different viruses will be inefficient. PMID- 29429814 TI - Vaccination timeliness and co-administration among Kenyan children. AB - BACKGROUND: Timely administration of recommended vaccines requires children to have multiple vaccines co-administered in the first year of life. The objectives of this study were to estimate the proportion of timely vaccinations and the proportion of co-administered vaccines, and to assess the relationship between vaccine co-administration and vaccine timeliness in Kenyan children. METHODS: Using the 2014 Kenyan Demographic and Health Survey (DHS), we calculated the proportion of children who received co-administered and timely vaccine doses. Co administration was defined as doses administered on the same day with dates recorded on vaccination cards. Vaccines were considered timely if given within four days before to four weeks after the recommended interval for administration. RESULTS: 10,385 children aged 1-4 years in the Kenyan 2014 DHS dataset had vaccination cards which comprised the study sample. Analysis revealed wide a range for receipt of timely doses, from 90.2% for OPV0 to 56.0% for Measles. Co administration of the 6-week dose was associated with 2.81 times higher odds of a timely Penta dose 1 (95% CI: 2.28, 3.46) and birth-dose co-administration was associated with a substantial increase in timely BCG vaccination: AOR 7.43 (95% CI: 6.31, 8.75). CONCLUSIONS: Though vaccine coverage in Kenya was high, timely vaccination was markedly low, with resultant implications for population immunity and potential spread of communicable diseases in unvaccinated infants. Co administration of vaccines, place of residence, wealth index, and child age were consistently related to the odds of timely vaccine receipt. These relationships reinforce the importance of dedicating resources to programs that educate low socio-economic groups about the importance of vaccine co-administration. PMID- 29429816 TI - Comments on the SEPAR Guidelines for the Diagnosis and Treatment of Drug Resistant Tuberculosis. PMID- 29429815 TI - Long-term immunogenicity of an initial booster dose of an inactivated, Vero cell culture-derived Japanese encephalitis vaccine (JE-VC) and the safety and immunogenicity of a second JE-VC booster dose in children previously vaccinated with an inactivated, mouse brain-derived Japanese encephalitis vaccine. AB - BACKGROUND: This study was performed with the aim of determining the long-term immunogenicity of an inactivated, Vero cell culture-derived Japanese encephalitis (JE) vaccine (JE-VC) and an inactivated, mouse brain-derived JE vaccine (JE-MB) after the 1st booster dose at 2 years of age, as well as the safety and immunogenicity of the 2nd booster dose of JE-VC at 6 years of age, in children primed and given a 1st booster dose of either JE-VC or JE-MB. METHOD: In this multicenter, open-label clinical trial, the study population consisted of healthy Korean children (aged 6 years) who participated in the previous JE vaccine trial. All subjects were subcutaneously vaccinated once for the booster immunization with Boryung Cell Culture Japanese Encephalitis Vaccine(r) (JE-VC). RESULT: Approximately 4 years after the 1st booster dose of JE-VC, the seroprotection rate (SPR) and geometric mean titer (GMT) of the neutralizing antibody were 100% and 1113.8, respectively. In children primed and given a 1st booster dose of JE MB, the SPR and GMT were 88.5% and 56.3, respectively. After the 2nd booster dose of JE-VC, all participants primed and given a 1st booster dose of either JE-MB or JE-VC were seroprotective against JE virus. The GMT of the neutralizing antibody was higher in children primed and given a 1st booster dose of JE-VC (8144.1) than in those primed and given a 1st booster dose of JE-MB (942.5) after the vaccination (p < 0.001). In addition, the 2nd booster dose of JE-VC showed a good safety profile with no serious vaccine-related adverse events. CONCLUSION: The 1st booster dose of JE-VC and JE-MB showed long-term immunogenicity of at least 4 years, and the 2nd booster dose of JE-VC showed a good safety and immunogenicity profile in children primed and given a 1st booster dose of either JE-VC or JE-MB. ClinicalTtrials.gov Identifier: NCT02532569. PMID- 29429817 TI - Assessing the Effect of Adherence on Patient-reported Outcomes and Out of Pocket Costs Among Patients With Multiple Myeloma. AB - BACKGROUND: The present study characterized the effect of multiple myeloma (MM) on work productivity, health care resource usage, and out of pocket costs (OOPCs) and examined the association of adherence with quality of life (QoL) and productivity loss. MATERIALS AND METHODS: The present cross-sectional study included 162 patients categorized by their 4-item Morisky Medication Adherence Scale (MMAS-4) score (4 vs. <= 3). Online surveys included the Work Productivity and Activity Impairment questionnaire, Functional Assessment of Cancer Therapy Multiple Myeloma (FACT-MM), and MM-specific questions. RESULTS: On average, patients reported FACT-MM scores of 98.5 +/- 29.3, absenteeism of 18.3% +/- 17.8%, presenteeism of 51.8% +/- 30.2%, overall work productivity impairment of 57.3% +/- 31.7%, and activity impairment of 49.9% +/- 29.5% in the previous 7 days. During the previous 3 months, the mean OOPCs were $709 +/- $1307; prescription medications accounted for 55% of these costs. Patients attended 4.1 +/- 4.6 visits to oncologists or hematologists during that time, which accounted for 45% of the OOPCs. Patients spent an average of 6.8 +/- 8.3 hours at MM related monthly appointments, and 35.2% reported frustration while at the doctor's office. Patients with an MMAS-4 score of 4 reported higher FACT-MM scores (106.9 vs. 89.2; P < .001). Patients with an MMAS-4 score of <= 3 reported greater activity impairment (56.5% vs. 39.8%; P = .015) and feeling overwhelmed or frustrated with rescheduling MM appointments (64.0% vs. 26.0%; P = .002). CONCLUSION: MM was associated with significant workplace and functional impairment, high OOPCs, and frequent office visits. High medication adherence was associated with better outcomes across these domains. As survival for patients with MM improves, patient QoL should be considered to enhance these outcomes. PMID- 29429819 TI - How Marginalized Young People Access, Engage With, and Navigate Health-Care Systems in the Digital Age: Systematic Review. AB - PURPOSE: This systematic review examines how marginalized young people access and engage with health services and navigate health-care systems in high-income countries. METHODS: Medline, CINAHL, PsychInfo, The University of Sydney Library database, and Google Scholar were searched to identify qualitative and quantitative original research, published from 2006 to 2017, that focused on selected definitions of marginalized young people (12 to 24 years), their parents/carers, and/or health professionals working with these populations. A thematic synthesis was undertaken identifying themes across and between groups on barriers and/or facilitators to access, engagement, and/or navigation of health care systems. RESULTS: Of 1,796 articles identified, 68 studies in the final selection focused on marginalized young people who were homeless (n = 20), living in rural areas (n = 14), of refugee background (n = 11), gender and/or sexuality diverse (n = 11), indigenous (n = 4), low income (n = 4), young offenders (n = 2), or living with a disability (n = 2). Studies were from the United States, Australia, Canada, United Kingdom, New Zealand, and Portugal, including 44 qualitative, 16 quantitative, and 8 mixed-method study types. Sample sizes ranged from 3 to 1,388. Eight themes were identified relating to ability to recognize and understand health issues; service knowledge and attitudes toward help seeking; structural barriers; professionals' knowledge, skills, attitudes; service environments and structures; ability to navigate the health system; youth participation; and technology opportunities. CONCLUSIONS: Marginalized young people experience barriers in addition to those common to all young people. Future studies should consider the role of technology in access, engagement, and health system navigation, and the impact of intersectionality between marginalized groups. PMID- 29429818 TI - Undertreatment of Older Patients With Newly Diagnosed Multiple Myeloma in the Era of Novel Therapies. AB - BACKGROUND: With the expanding armamentarium of therapeutic agents for multiple myeloma (MM), it is important to identify any undertreated patient populations to mitigate outcome disparities. MATERIALS AND METHODS: We extracted the data for all plasma cell myeloma cases (International Classification of Disease for Oncology, third revision [ICD-O-3] code 9732) in the Surveillance, Epidemiology, End Results (SEER)-Medicare database from 2007 to 2011. The ICD-O-3 histologic code 9732 captures both active MM and smoldering/asymptomatic myeloma. We defined active MM as either claims indicating receipt of treatments approved for MM or ICD-9 codes for MM-defining clinical features, referred to as the CRAB criteria (calcium [elevated], renal failure, anemia, bone lesions). Multivariate logistic regression was performed to determine the variables that were independently associated with receipt of no treatment. RESULTS: Of the initial 4187 patients included in the present study, 373 had no claims indicating receipt of treatments approved for MM and had no ICD-9 codes associated with the CRAB criteria and were excluded from the analyses. Of the 3814 patients with active MM, 1445 (38%) did not have any claims confirming that they had received systemic treatment. Older age, poor performance indicators, comorbidities, African-American race, and lower socioeconomic status, including enrollment in Medicaid, were statistically significant factors associated with the receipt of no systemic treatment. CONCLUSIONS: In the present retrospective study of data from the SEER-Medicare database, we found that age, health status, race, and socioeconomic status were associated with receipt of MM treatment. These factors have previously been linked to reduced usage of specific treatments for MM, such as stem cell transplantation. To the best of our knowledge, however, ours is the first study to show their association with the receipt of any MM therapy. PMID- 29429820 TI - Direct bone conduction stimulation: Ipsilateral effect of different transducer attachments in active transcutaneous devices. AB - Active transcutaneous bone conduction devices, where the transducer is implanted, are used for rehabilitation of hearing impaired patients by directly stimulating the skull bone. The transducer and the way it is attached to the bone play a central role in the design of such devices. The actual effect of varying the contact to bone has not been addressed yet. The aim of this study is therefore to compare how different attachment methods of the transducer to the bone for direct stimulation affect the ear canal sound pressure and vibration transmission to the ipsilateral cochlea. Three different attachments to the bone were tested: (A) via a flat small-sized surface, (B) via a flat wide surface and (C) via two separated screws. Measurements were done on four human heads on both sides. The attachments were compared in terms of induced cochlear promontory velocity, measured by a laser Doppler vibrometer, and ear canal sound pressure, measured by a low noise microphone. A swept sine stimulus was used in the frequency range 0.1-10 kHz. On an average level, the attachment method seems to affect the transmission mainly at frequencies above 5 kHz. Furthermore, the results suggest that a smaller contact surface might perform better in terms of transmission of vibrations at mid and high frequencies. However, when considering the whole frequency range, average results from the different attachment techniques are comparable. PMID- 29429821 TI - Obstructive Sleep Apnea Screening Among Surgical Patients: A Quality Improvement Project. AB - PURPOSE: Obstructive sleep apnea (OSA) increases the risk of respiratory depression in surgical patients. This project screened patients for OSA and explored its relationship with respiratory complications. DESIGN: Quality improvement project. METHODS: Neurosurgical patients were preoperatively screened using STOP-Bang questionnaire scores of 5 or greater as high risk and less than 5 as low risk for moderate-to-severe OSA. Postoperative respiratory complications were compared between both OSA groups. Perioperative staff and patient education included an OSA care protocol using STOP-Bang screening. FINDINGS: Of the 161 patients screened, 29.8% scored high risk for OSA, noting elevated end tidal CO2, increased oxygen desaturation, and required pulse oximetry with supplemental oxygen compared with the low-risk group (P < .05). Education improved nurses' awareness of OSA risks by 81%, and 87.5% of patients were satisfied with the OSA care protocol. CONCLUSIONS: The OSA care protocol decreased risk for postoperative respiratory complications. Education is essential for safer perioperative outcomes. PMID- 29429822 TI - 12-month Success of Cracked Teeth Treated with Orthograde Root Canal Treatment. AB - INTRODUCTION: Long-term studies examining the treatment outcomes of "cracked teeth" that received orthograde root canal treatment in the United States do not exist. The purpose of the present study was to examine the distribution and 1 year treatment outcomes of cracked teeth receiving orthograde root canal treatment in 1 private endodontic practice over a 25-year period. METHODS: A total of 3038 cracked teeth were initially examined, and data from 2086 unique patients were analyzed. Pulpal and periapical diagnoses, year of treatment, tooth type, restorative material, and number of restored surfaces at the time of examination were recorded for all patients. Periodontal probing depths were also recorded. The patients' age and sex were added retrospectively for all patients whose data were available. Univariate frequency distributions for all collected variables were evaluated. Bivariate associations were analyzed between explanatory variables and the success of the root canal therapy. RESULTS: Of the 2086 cracked teeth observed among unique patients, the most common were mandibular second molars (36%) followed by mandibular first molars (27%) and maxillary first molars (18%). Among the 363 teeth eligible for multivariable regression analysis, 296 (82%) were deemed successes after 1 year. There were no statistically significant differences in success based on pulpal diagnosis (irreversible pulpitis, 85%; necrosis, 80%; previously treated, 74%), patients' age, sex, year of treatment, tooth type, restorative material, or number of restored surfaces at the time of examination. The 3 factors most significant in bivariate analyses were pocket depth, distal marginal ridge crack, and periapical diagnosis, which were used to generate a prognostic index for success of orthograde root canal therapy in cracked teeth called the Iowa Staging Index. CONCLUSIONS: The results of this study suggest that cracked teeth that received root canal treatment can have prognoses at higher success rates than previously reported. The Iowa Staging Index may prove to be useful in clinical treatment decision making. PMID- 29429823 TI - Effects of three interventions in facilitating voluntary pelvic floor muscle contraction in women: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of vaginal palpation, vaginal palpation associated with posterior pelvic tilt, and intravaginal electrical stimulation in facilitating voluntary contraction of the pelvic floor muscles in women. METHODS: A randomized controlled trial in which 132 women with pelvic floor muscles function graded at 0 or 1 using the Modified Oxford Scale were randomized into four groups: vaginal palpation (n=33); vaginal palpation with posterior pelvic tilt (n=33); intravaginal electrical stimulation (n=33) and a control group (n=33) that only received verbal instructions. The primary outcome was evaluated by the Modified Oxford Scale and the secondary using the ICIQ-UI-SF. The assessment was performed at baseline with follow-up assessment after eight weeks. RESULTS: A total of 69.7% of the women from posterior pelvic tilt; 63.6% from vaginal palpation; 33.3% from intravaginal electrical stimulation; and 18.2% from control group (p<0.001) were able to attain Modified Oxford Scale greater than or equal to 2 after eight weeks. In comparison with control group, the posterior pelvic tilt (OR=10.35; 95% CI=3.26-32.84) and vaginal palpation (OR=7.87; 95% CI=2.53-24.47) had the most significant improvement as opposed to intravaginal electrical stimulation (OR=2.25; 95% CI=0.72-7.06). There was significant improvement among all of the groups in UI. The largest changes respectively were noted in the vaginal palpation, posterior pelvic tilt, intravaginal electrical stimulation and control group. There were no reports of adverse effects. CONCLUSION: Vaginal palpation with posterior pelvic tilt and vaginal palpation were more effective interventions to facilitate pelvic floor muscles contraction when compared with intravaginal electrical stimulation and controls. Vaginal palpation was the most effective in improving urinary incontinence. Clinical Trials Identifier: ClinicalTrial.gov: NCT02062242. PMID- 29429826 TI - Response to Letter to the Editor re 'Global minimally invasive pyeloplasty study in children: Results from the pediatric urology expert group of the EAU young academic urologists working party'. PMID- 29429825 TI - Emerging roles of microRNAs in cancer. AB - MicroRNAs (miRNAs) have emerged as important regulators of human carcinogenesis by affecting the expression of key oncogenes and tumor suppressor genes. MiRNAs elicit their function through post-transcriptional regulation of the mRNA translation into protein as well as functioning as ligands for proteic receptors called miRceptors. Our understanding of the role of miRNAs in cancer biology has enormously improved in the last few years, providing the rationale for new therapeutics. Here we discuss the most recent findings on the role of miRNAs in modulating cancer biology with a specific focus on their role as modulators of the biology of the tumor microenvironment both as cargo of extracellular vesicles and as extra-vesicular miRNAs. PMID- 29429824 TI - The Polyploid State Plays a Tumor-Suppressive Role in the Liver. AB - Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate polyploidy while avoiding irreversible manipulations of essential cell-cycle genes, we developed orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no detectable impact of ploidy alterations on liver function, metabolism, or regeneration, mice with more polyploid hepatocytes suppressed tumorigenesis and mice with more diploid hepatocytes accelerated tumorigenesis in mutagen- and high-fat-induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that polyploidy differentially protected the liver from distinct genomic aberrations. This suggests that polyploidy evolved in part to prevent malignant outcomes of liver injury. PMID- 29429827 TI - Reviewing scientific manuscripts. PMID- 29429828 TI - Re. "Pre-incision urethral plate width does not impact short-term tubularized incised plate urethroplasty outcomes". PMID- 29429829 TI - Diagnostic scores, questionnaires, quality of life, and outcome measures in pediatric continence: A review of available tools from the International Children's Continence Society. AB - PURPOSE: We reviewed and collated information concerning the available tools for the measurement of symptoms and outcomes in pediatric continence. MATERIALS AND METHODS: MEDLINE, EMBASE, and CINHAL databases were searched for relevant articles published prior to December 2016 and independently screened by two researchers. Expert opinion was also widely sought through consultation with the ICCS Board membership and their professional networks and the multidisciplinary authorship group. The most relevant materials were then selected for analysis and inclusion and resulted in a document available on the ICCS website for all members to review. Insights and feedback were considered with consensus and agreement reached to modify the document. RESULTS AND CONCLUSIONS: A variety of useful tools for the assessment and measurement of bladder and bowel dysfunction and quality of life and behavioral comorbidities are presented together with their indications and potential pitfalls. ICCS cannot recommend one over another as the most useful for each clinician will vary depending on the clinical setting, available time, and patient population. We provide a framework for choosing those that are most appropriate based on our findings. PMID- 29429830 TI - Nursing Care of Incarcerated Women During Pregnancy and the Postpartum Period. PMID- 29429831 TI - Predictors of poor outcome in children with steroid sensitive nephrotic syndrome. AB - BACKGROUND AND OBJECTIVE: Nearly 50% of the children with steroid sensitive nephrotic syndrome (SSNS) have a frequently relapsing (FR) or steroid dependent (SD) course, experiencing steroid toxicities and complications of immunosuppression. The study aimed to compare parameters between children with infrequent relapsing (IFR) and FR/SD nephrotic syndrome and to identify the factors associated with a FR/SD course. METHODS: A retrospective analysis of medical records from 2009 to 2014, of children with SSNS attending the pediatric nephrology clinic in a tertiary care medical college and hospital. RESULTS: Out of 325 children (226 males) with SSNS, 213 were IFR and 112 were FRNS/SDNS. The median age of onset was 34 (IQR 24-48) months. The median time to the first relapse was 4 (IQR 3-7) months and 6 (IQR 4-12) months in FR/SD and IFR group respectively. Multivariate logistic regression analysis showed "adequate treatment (>=12 weeks) of the first episode" (odds ratio 0.56, 95% CI 0.34-0.91; p value=0.02) and "shorter median time to the first relapse" (odds ratio 1.04, 95% CI=1.01-1.08; p value=0.04) to be independent predictors of FR/SD course. An ROC curve was constructed which showed that time to first relapse <5.5 months was associated with a sensitivity of 69% and specificity of 60% in predicting a FR/SD course. CONCLUSION: Adequate treatment of the first episode is associated with less chance of an FR/SD course. After treatment of first episode, the first relapse occurring within 5.5 months may predict a frequently relapsing or steroid dependent course. PMID- 29429832 TI - Design and synthesis of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N (5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine as a highly potent and selective cyclin-dependent kinases 4 and 6 inhibitors and the discovery of structure-activity relationships. AB - Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4 (2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-(piperazin-1 ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d, which exhibits approximate potency on CDK4/6 (IC50 = 7.4/0.9 nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219. Overall, compound 10d could be a promising candidate and a good starting point as anticancer drugs. PMID- 29429833 TI - Synthesis of polyozellin, a prolyl oligopeptidase inhibitor, and its structural revision. AB - Polyozellin is a p-terphenyl compound which was isolated from Polyozellus multiplex, and exhibits an inhibitory activity against prolyl oligopeptidase (POP). Its structure was assigned as 1 having a p-terphenyl skeleton including a p-substituted dibenzofuran moiety by spectroscopic analyses and chemical means. This paper describes the total syntheses of the proposed structure 1 for polyozellin and its o-isomer 2, revising the structure of polyozellin to the latter. These syntheses involved a double Suzuki-Miyaura coupling using chlorophenylboronic acid as a common key building block, and Cu mediated Ullmann cyclization as key steps. The inhibitory activities of synthetic compounds against POP and cancer cells were also evaluated. PMID- 29429835 TI - An alternative topical anesthesia technique for prosthetic implant procedures. PMID- 29429834 TI - Curcumin inspired 2-chloro/phenoxy quinoline analogues: Synthesis and biological evaluation as potential anticancer agents. AB - Synthesis of twenty new curcumin inspired 2-chloro/phenoxy quinoline derivatives is outlined in this study. The obtained new chemical entities were screened in vitro for their cytotoxic activity towards various tumor cell lines. Of the compounds screened, 6c and 9d exhibited significant activity and the most active analogue 6c displayed promising cytotoxicity against PC-3 (IC50 of 3.12 +/- 0.11 MUM), DU-145, NCI-H460 and 4 T1 cell lines. Further, 6c and 9d have 2.1 and 1.4 times more aqueous solubility, respectively, than curcumin. Additionally, the promising candidate 6c could induce G2/M cell cycle arrest and apoptosis in PC-3 cells, as determined by AO-EB staining, DAPI staining, analysis of ROS levels as well as annexin binding assay. PMID- 29429836 TI - Diagnosis and treatment of orofacial pain in a patient with unserviceable complete dentures: A clinical report. AB - An ill-fitting complete denture has the potential to create pain and discomfort as well as conceal or confound the diagnosis of other primary sources of orofacial pain such as trigeminal neuralgia. Guidelines of the American Academy of Orofacial Pain offer an evidence-based approach for the assessment, diagnosis, and management of orofacial pain. A complete and accurate differential diagnosis is paramount to the success of treatment as well as to the circumvention of unnecessary therapy. The purpose of this clinical report was to emphasize an evidence-based approach to the diagnosis and treatment of orofacial pain in a patient with edentulism and a history of prolonged denture wear. PMID- 29429837 TI - Direct 3D printing of silicone facial prostheses: A preliminary experience in digital workflow. AB - Direct silicone printing may be applied to the fabrication of maxillofacial prostheses, although its clinical feasibility is unknown. The present clinical report shows an early application of a directly printed silicone prosthesis for the rehabilitation of a nasal defect. Two extraoral scanning systems were used to capture the face and the defect. The virtual construction of the nasal prosthesis was performed with free-form software. Two prostheses were printed in silicone and post-processed by manual sealing and coloring. The clinical outcome was acceptable for an interim prosthesis; however, the marginal adaptation and color match were not satisfactory without further individualization. PMID- 29429838 TI - Multidisciplinary management of a partially edentulous patient with oromandibular dystonia: A clinical report. AB - Oromandibular dystonia (OMD) is defined as a subset of movement disorders characterized by involuntary muscle contraction in different parts of the oromandibular region. This clinical report presents a multidisciplinary approach to the management of a patient with OMD. The involuntary movement of her mandible and tongue was improved with a mandibular custom occlusal device and maxillary modified removable complete denture together with botulinum toxin A injections. PMID- 29429839 TI - Comparison of digital surface displacements of maxillary dentures based on noninvasive anatomic landmarks. AB - STATEMENT OF PROBLEM: Artificial markers called fiducials are commonly used to orient digitized surfaces for analysis. However, when these markers are tangible and placed in the region of interest, they may alter surface topography and influence data analysis. PURPOSE: The purpose of this in vitro study was to apply a modified digital surface fitting method based on anatomic landmarks to evaluate denture accuracy and to use 2 different denture processing techniques to evaluate the method. The goal was to noninvasively measure and describe any surface differences in denture processing techniques at the intaglio and denture tooth levels. MATERIAL AND METHODS: Twenty standardized maxillary complete dentures were waxed on standardized edentulous casts and processed by using acrylic resin compression (COM, n=10) and injection molding (INJ, n=10) methods. Digital scans were recorded of the anatomic surface of the cast, the intaglio and cameo surfaces of the acrylic resin dentures, and the cameo surface of the wax dentures. Three anatomic fiducials were identified on denture intaglio and cast scans and 4 on the cameo surfaces of waxed and acrylic resin denture scans. These fiducials were then used to digitally align the anatomic with the processed intaglio surfaces and the waxed with the processed cameo surfaces. Surface displacements were compared among processed dentures expressed at specific points (9 tissue landmarks and 8 tooth landmarks). The accuracy of surface displacements was assessed by changes in the number and location of anatomic fiducials. The scanning precision and the intraobserver repeatability in the selection of dental landmarks were also determined. For each landmark, the spatial (x, y, and z) mean differences between the 2 processing techniques were calculated for the intaglio and the cameo surfaces and presented on each orthogonal plane. Statistical nonparametric comparison of these means was analyzed with the Mann-Whitney U test (alpha=.05). Benjamini-Hochberg corrections for multiple comparisons were used. RESULTS: Changing the number and the location of anatomic landmarks had a small effect on the precision of the surface fitting. Repeated scans yielded high precision levels. In contrast, intraobserver repeatability had a larger error. In general, injection-molded dentures showed less displacement after polymerization than did the compression-molded ones. These differences were more substantial at the denture tooth level than on the intaglio surfaces. CONCLUSIONS: Anatomic noninvasive fiducials chosen at distinct locations of maxillary edentulous areas seem to be reliable markers for the superposition of corresponding digital surface scans. Maxillary dentures processed with the injection molding technique have minimal deformation. Posterior denture teeth displace in 3 dimensions with the compression molding technique. PMID- 29429840 TI - Virtually guided alveolar ridge reduction combined with computer-aided implant placement for a bimaxillary implant-supported rehabilitation: A clinical report. AB - Insufficient crown height space, particularly in the interforaminal region of edentulous ridges with knife-edge morphology, may prevent successful prosthetic rehabilitation. Such conditions require osteoplasty, which might complicate computer-guided implant placement. This clinical report illustrates the treatment of a patient with complete edentulism rehabilitated with a mandibular implant supported fixed dental prosthesis by using a virtually guided approach. Both alveolar ridge reduction and prosthetically driven implant insertions were computer-guided by surgical stents to increase accuracy and predictability. This approach enabled the immediate loading of the implants with an interim prosthesis before the delivery of a definitive screw-retained fixed prosthesis. At the 1 year follow-up visit, clinical and radiographic examination revealed a stable outcome. PMID- 29429841 TI - Modification of clinically short Locator abutments using laser welding. AB - As dental implants continue to survive longer, managing and maintaining implant prostheses can be complicated by the lack of compatible parts or the discontinuation of implant systems. This report describes a laser welding procedure for the management of clinically short Locator abutments (Zest Anchors Inc) that lacked a commercially available, compatible alternative. PMID- 29429842 TI - Trabectedin in Ovarian Cancer: is it now a Standard of Care? AB - In patients with recurrent ovarian cancer, the choice of second-line therapy is complex. Several factors have to be considered, such as platinum-free interval (PFI), residual toxicity from the previous treatments, BRCA1/2 gene mutation status. Trebectedin is a minor groove DNA binder derived from a marine organism that has shown efficacy in different settings in ovarian cancer therapy. It has been approved in the treatment of partially platinum sensitive (PPS) (PFI between 6 and 12 months) relapsed ovarian cancer according to the statistically significant progression-free survival (7.3 versus 5.8 months) and overall survival (22.2 versus 18.9 months) benefit compared with single-agent pegylated liposomal doxorubicin (PLD) in the OVA 301 phase III trial. This drug has been shown to prolong the time to first subsequent treatment and improve the efficacy of further platinum-based chemotherapy. The role of trabectedin/PLD followed by platinum combination compared with the reverse sequence in PPS is actually in evaluation in the INOVATYON phase III study, which will clarify the best sequence to be adopted in this setting. Trabectedin has been shown to be active in patient carriers of BRCA mutations, probably for its mechanism of action directly affecting DNA and it is actually tested as a single agent in some phase III trials in BRCA mutated and BRCAness ovarian cancer patients. Trabectedin is also active on the immune system. There is, therefore, the rational for new trials of a combination with immune checkpoint inhibitors. PMID- 29429843 TI - Invasive "in the cath-lab" assessment of myocardial ischemia in patients with coronary artery disease: When does the gold standard not apply? AB - International guidelines recommend that revascularization for coronary artery disease (CAD) should be guided by evidence of myocardial ischemia. Fractional flow reserve (FFR) and instantaneous free wave ratio (iFR) are the main invasive indices for assessing the ischemic potential of angiographically intermediate coronary stenosis as a large body of evidence supports their routine application. Both indices have been tested and validated in patients with isolated stable CAD, but notably their application outside this specific context is a matter of debate and investigation. In the present review we aim to look into the available evidence about the reliability and feasibility of FFR and iFR in clinical contexts different from stable angina where these techniques have been validated. We aim to shed light on which technique can be used to invasively assess ischemia when an angiographic moderate coronary stenosis is observed in a clinical setting other than isolated stable CAD. PMID- 29429844 TI - Study of surgical treatment for elderly patients with head and neck cancer. AB - The aim of this study was to evaluate the clinical results of surgery for head and neck cancer (HNC) in elderly patients and to determine whether surgery for elderly HNC patients is safe and what types of surgery result in the most favourable outcomes for this age group. The cases of 637 elderly patients who were diagnosed with HNC and underwent surgical treatment were studied retrospectively. Patient demographic characteristics and treatment data were extracted from the appropriate patient records and analysed. Age did not significantly predict postoperative complications or death rates. Flap reconstruction surgery had no significant association with necrosis, haemorrhage, infection, need for rescue treatment, or length of intensive care unit stay. Age was not a risk factor for surgical treatment of HNC in the elderly patients. Flap reconstruction should not be considered riskier for elderly patients. The treatment choice for elderly patients with HNC should be based on medical assessments but not on age. PMID- 29429845 TI - Star polymer-based unimolecular micelles and their application in bio-imaging and diagnosis. AB - As a novel kind of polymer with covalently linked core-shell structure, star polymers behave in nanostructure in aqueous medium at all concentration range, as unimolecular micelles at high dilution condition and multi-micelle aggregates in other situations. The unique morphologies endow star polymers with excellent stability and functions, making them a promising platform for bio-application. A variety of functions including imaging and therapeutics can be achieved through rational structure design of star polymers, and the existence of plentiful end groups on shell offers the opportunity for further modification. In the last decades, star polymers have become an attracting platform on fabrication of novel nano-systems for bio-imaging and diagnosis. Focusing on the specific topology and physicochemical properties of star polymers, we have reviewed recent development of star polymer-based unimolecular micelles and their bio-application in imaging and diagnosis. The main content of this review summarizes the synthesis of integrated architecture of star polymers and their self-assembly behavior in aqueous medium, focusing especially on the recent advances on their bio-imaging application and diagnosis use. Finally, we conclude with remarks and give some outlooks for further exploration in this field. PMID- 29429846 TI - Bacterial communities of three plant species from Pb-Zn contaminated sites and plant-growth promotional benefits of endophytic Microbacterium sp. (strain BXGe71). AB - The endophytic bacterial community of two hyperaccumulators (Arabis alpine, Dysphania ambrosioides) and Veronica ciliate was investigated by Illumina sequencing technology. In addition, the culturable endophytic bacteria (EB) were isolated and their plant-growth promotion capabilities were studied. A dataset consisting of 221,075 filtered high-quality and classifiable unique 16S rDNA gene tags, and an average of 36,846 tags with a mean length of 464-bp for each sample was generated. In total, 10801 different operational taxonomic units (OTUs) were detected, belonging to 18 bacterial phyla, 41 classes, 91 orders, 135 families, and 215 genera. Pseudomonas was the most dominant genus in both shoots and roots of the two hyperaccumulators, making up 81.56% and 81.13%, 41.60% and 77.06% of the total number of OTUs, respectively. However, both Chao 1 and Shannon indices of EB of the two hyperaccumulators were significantly lower than those of V. ciliate (P <. 05), except the Shannon index of D. ambrosioides shoots. The endophytic bacterial community of roots and shoots of A. alpine showed greater similarity with that of D. ambrosioides roots (12 km away), and clustered to one group in dendrogram, in clear contrast to that of V. ciliate, which grew closer to A. alpine (60 m away). Combining results of soil and plant analyses, we suggest that the soil properties, especially heavy metal concentration, may influence the plants endophytic bacterial community composition. Pot experiments showed that the strain BXGe71 (Microbacterium sp.) from A. alpine significantly enhanced host plants' growth under multi-heavy metal (HM) stress (P < .05, t test). PMID- 29429848 TI - Learned helplessness in doctors with dyslexia: Time for a change in discourse? PMID- 29429847 TI - The impact of geriatric focused nurse assessment and intervention in the emergency department: A systematic review. AB - BACKGROUND: Nursing assessment of elderly patients is imperative in Emergency Departments (ED) while providing interventions that increase independence facilitating discharge to primary healthcare. AIMS: To systematically review the impact of geriatric focused nurse assessment and intervention in the ED on hospital utilisation in terms of admission rate, ED revisits and length of hospital stay (LOHS). METHODS: Search strategy used following databases; Cochrane, Medline, CINAHL, Embase, Scopus and Web of Knowledge; And terms; geriatric nurse assessment, nurse discharge planning, geriatric nurse specialist, nurse intervention, emergency department, accident and emergency, patient outcomes, discharge, admissions, readmissions, hospital utilization, hospitalization, length of stay/hospital stay. RESULTS: Nine studies were included: seven RCTs and two prospective pre/post-intervention designed studies. Geriatric focused nursing assessment and interventions did not have a statistical impact on hospitalization, readmissions, LOHS and ED revisits. Risk screening and comprehensive geriatric assessment extending into primary care may reduce readmission rates but not affect hospitalization. An increase in ED visits in the intervention group at 30 days post-intervention was noted. CONCLUSION: Inconsistencies in assessment and interventions for the older person in ED are apparent. Further research evaluating a standardised risk assessment tool and innovative interventions extending into primary healthcare is required. PMID- 29429849 TI - Regulation of hematopoiesis by the chemokine system. AB - Although chemokines are best known for their role in directing cell migration, accumulating evidence indicate their involvement in many other processes. This review focus on the role of chemokines in hematopoiesis with an emphasis on myelopoiesis. Indeed, many chemokine family members are an important component of the cytokine network present in the bone marrow that controls proliferation, retention, and mobilization of hematopoietic progenitors. PMID- 29429850 TI - The first report of human meningitis and pyogenic ventriculitis caused by Streptococcus suis: A case report. AB - Streptococcus suis, a gram-positive facultative anaerobe commonly found in pigs, is an emerging zoonotic pathogen. Herein, we describe a case of a 45-year-old male Japanese meat wholesaler with S. suis meningitis and pyogenic ventriculitis. S. suis was isolated from his blood and cerebrospinal fluid culture, and sequence type (ST) and serotype were confirmed to be ST1 and serotype 2, respectively, by multilocus sequence typing and the Quellung reaction. Magnetic resonance imaging (MRI) revealed right labyrinthitis and pyogenic ventriculitis. The patient was treated with ceftriaxone and ampicillin for 24 days; the treatment was deemed successful based on negative blood cultures on day 4. However, the patient experienced hearing loss and a vestibular nerve disorder. S. suis is a rare pathogen in Japan but can cause severe infection and sequelae. To the best of our knowledge, this is the first report of a human case of pyogenic ventriculitis caused by S. suis. Our findings suggest that S. suis infection should be considered when hearing impairment is present in a patient with bacterial infection and that MRI can help detect ventriculitis, which can necessitate a prolonged treatment duration. PMID- 29429851 TI - Fermented meats (and the symptomatic case of the Flemish food pyramid): Are we heading towards the vilification of a valuable food group? PMID- 29429853 TI - Evaluating Photographs as a Replacement for the In-Person Physical Examination of the Scored Patient-Generated Subjective Global Assessment in Elderly Hospital Patients. AB - BACKGROUND: Undernourished patients discharged from the hospital require follow up; however, attendance at return visits is low. Teleconsultations may allow remote follow-up of undernourished patients; however, no valid method to remotely perform physical examination, a critical component of assessing nutritional status, exists. OBJECTIVE: This study aims to compare agreement between photographs taken by trained dietitians and in-person physical examinations conducted by trained dietitians to rate the overall physical examination section of the scored Patient Generated Subjective Global Assessment (PG-SGA). DESIGN: Nested cross-sectional study. PARTICIPANTS/SETTING: Adults aged >=60 years, admitted to the general medicine unit at Flinders Medical Centre between March 2015 and March 2016, were eligible. All components of the PG-SGA and photographs of muscle and fat sites were collected from 192 participants either in the hospital or at their place of residence after discharge. MAIN OUTCOME MEASURES: Validity of photograph-based physical examination was determined by collecting photographic and PG-SGA data from each participant at one encounter by trained dietitians. A dietitian blinded to data collection later assessed de-identified photographs on a computer. STATISTICAL ANALYSES PERFORMED: Percentage agreement, weighted kappa agreement, sensitivity, and specificity between the photographs and in-person physical examinations were calculated. All data collected were included in the analysis. RESULTS: Overall, the photograph-based physical examination rating achieved a percentage agreement of 75.8% against the in-person assessment, with a weighted kappa agreement of 0.526 (95% CI: 0.416, 0.637; P<0.05) and a sensitivity-specificity pair of 66.9% (95% CI: 57.8%, 75.0%) and 92.4% (95% CI: 82.5%, 97.2%). CONCLUSIONS: Photograph-based physical examination by trained dietitians achieved a nearly acceptable percentage agreement, moderate weighted kappa, and fair sensitivity-specificity pair. Methodological refinement before field testing with other personnel may improve the agreement and accuracy of photograph-based physical examination. PMID- 29429852 TI - Corrigendum to "LMD proteomics provides evidence for hippocampus field-specific motor protein abundance changes with relevance to Alzheimer's disease" [BBAPAP 1865 (6) (2017) 703-714]. PMID- 29429854 TI - Using Infographics to Teach the Evidence Analysis Process to Senior Undergraduate Students. PMID- 29429855 TI - Accurate Coding Impacts the Geometric Length of Stay for Malnourished Inpatients. PMID- 29429856 TI - eHealth interventions for family carers of people with long term illness: A promising approach? AB - Family carers of people who have long term illness often experience physical and mental health morbidities, and burden. While there is good evidence to suggest that carers benefit from psychosocial interventions, these have primarily been delivered via face-to-face individual or group-formats. eHealth interventions offer a novel, accessible and self-paced approach to care delivery. Whether these are effective for carers' wellbeing has been little explored. This paper reports the first comprehensive systematic review in this area. A total of 78 studies, describing 62 discrete interventions, were identified. Interventions commonly aimed to promote carers' knowledge, self-efficacy, caregiving appraisal, and reduce global health morbidities. Interventions were offered to carers of people with a wide range of long term illness; dementia has been the most researched area, as reported in 40% of studies. Clinical and methodological heterogeneity in interventions precluded meta-analyses, and so data were analysed narratively. The most popular approach has comprised psychoeducational interventions delivered via an enriched online environment with supplementary modes of communication, such as network support with professionals and peers. Overall, carers appreciate the flexibility and self-paced nature of eHealth interventions, with high rates of satisfaction and acceptability. More studies using robust designs are needed to extend the evidence base. PMID- 29429858 TI - [Neuropathology of sudden infant death syndrome: Review of the literature and proposal of a protocol for neuropathological examination]. AB - According to the French High Authority for Health, sudden unexpected death in infants (SUDI) is defined as "a sudden death that occurs in an infant, whereas nothing in its known history could have predicted it". This is an exclusion diagnosis. There are great interregional disparities despite the professional recommendations established in February 2007. For the examination of the brain, instructions are not adapted to current and research practice. The role of the pathologist, like anyone involved in SUDI, is to eliminate an abuse head trauma and to determine the cause of death. Major neuropathological lesions by definition do not exist. Lesions of hypoxia/ischemia are the most frequent but not specific. The accessibility of anti-APP immunoblotting has highlighted the role of anoxia in the development of axonal diffuse damages. Many studies are looking for a neurological substratum of the SUDI (neuropathological and/or neurobiochinic). This article aims to define a detailed sampling protocol based on foreign consensus and current data of science in order to assist pathologists and to promote a homogeneous data bank in France. PMID- 29429857 TI - Risk factors for trochanteric and femoral neck fracture. AB - INTRODUCTION AND OBJECTIVES: The differences between the two main types of fracture of proximal end of the femur, trochanteric and cervical fractures, are still a subject of study, and could be the key to a better understanding of its pathophysiology and prevention. The aim of this study is to determine whether epidemiological differences in the distribution of risk factors associated with hip fracture exist between these two entities. PATIENTS AND METHOD: A descriptive cross-sectional study of 428 patients over the age of 65 admitted for trochanteric or cervical fractures in 2015, in which gender, age, previous diagnosis, external causes associated with fracture and place of the event were recorded. RESULTS: There were 220 patients with a cervical fracture (51.4%) and 208 patients with a trochanteric fracture (48.6%). The average age was higher in the trochanteric fracture, observing a constant increase with age only in women with trochanteric fractures. Cervical fracture showed a significant association with cerebrovascular disease (p=0.039) and trochanteric fracture with accidental falls (p=0.047) and presence of 5-9 previous diseases (p=0.014). A regression analysis maintained this association in the case of a cerebrovascular disease (OR 2.6, 95%CI 1.1-6.4) and the presence of 5-9 diseases (OR 1.5, 95%CI 1.1-2.3). CONCLUSIONS: Trochanteric fractures are associated with women patients of more advanced ages, 5-9 previous diseases and accidental falls. Cerebrovascular disease shows a higher prevalence in cervical fractures. PMID- 29429859 TI - New Tuberculosis Vaccine Strategies: Taking Aim at Un-Natural Immunity. AB - Despite some major progress made in developing tuberculosis (TB) vaccine strategies, with a dozen novel vaccines currently in the clinical pipeline, the world is still missing an effective TB vaccine. This questions whether any major breakthroughs can be achieved without making a drastic departure from the current strategy, which creates a state of 'near-natural immunity', imitating the natural immunity developed after Mycobacterium tuberculosis (Mtb) infection. Here, we argue instead that mounting evidence suggests an effective strategy ought to induce a state of all-around 'un-natural' immunity comprising trained innate immunity (TII), tissue-resident memory T cells (TRM), and anti-Mtb surface antibodies in the lung. Thus, here we summarize the latest information, thinking, and development in the field of TB and vaccines. PMID- 29429860 TI - Newer glomerular filtration rate estimating equations for the full age spectrum based on serum creatinine and cystatin C in predicting mortality in patients with ischemic stroke. AB - BACKGROUND: Renal dysfunction is associated with increased risk of mortality. The novel Full Age Spectrum (FAS) equations estimating the glomerular filtration rate (GFR) based on serum creatinine (FAScrea) and cystatin C (FAScysC) are validated across the entire age spectrum and are superior markers of renal function compared to other equations. Possible association of these equations with mortality in patients with ischemic stroke is not known. PATIENTS AND METHODS: We included 390 patients (207 men, 183 women) in our observational cohort study who had suffered from an ischemic stroke and followed-up on for 3 years. Serum creatinine and cystatin C were measured at admission; GFR was estimated according to the FAScrea, CKD-EPIcrea, FAScysC and CKD-EPIcysC equations. The values of estimated GFRs were divided into quintiles. RESULTS: During the follow-up period, 173 (44.4%) patients died. The association of hazard ratios for FAScrea and CKD EPIcrea with all-cause mortality was J-shaped and only significantly higher when comparing the fifth quintile hazard ratio for mortality with the first quintile (P < 0.001). For FAScysC and CKD-EPIcysC, hazard ratios increased from the first to the fifth quintile linearly. In an adjusted analysis, FAScrea and CKD-EPIcrea were not associated with all-cause mortality and the hazard ratios of the fifth quintile of FAScysC (P = 0.008) and CKD-EPIcysC (P = 0.042) were significantly associated with mortality compared to the first quintile. CONCLUSIONS: In patients with an ischemic stroke, estimated GFR based on serum cystatin (FAScysC and CKD-EPIcysC) was a better predictor of all-cause and cardiovascular mortality than estimated GFR based on serum creatinine. PMID- 29429861 TI - [Challenges and opportunities in the vertical transmission of Chagas disease]. PMID- 29429862 TI - [Intracranial hypertension: Ultrasound measurement of the optic nerve sheath]. PMID- 29429863 TI - [Ventilation during cardiopulmonary resuscitation in the infant. Mouth to mouth and nose, or bag-valve-mask? A quasi-experimental study]. AB - INTRODUCTION: It has been observed that health professionals have difficulty performing quality cardiopulmonary resuscitation (CPR). The aim of this study was to compare the quality of ventilations performed by Nursing students on an infant model using different methods (mouth-to-mouth-and-nose or bag-valve-mask). MATERIAL AND METHODS: A quasi-experimental cross-sectional study was performed that included 46 second-year Nursing students. Two quantitative 4-minute tests of paediatric CPR were performed: a) mouth-to-mouth-and-nose ventilations, and b) ventilations with bag-valve-mask. A Resusci Baby QCPR Wireless SkillReporter(r) mannequin from Laerdal was used. The proportion of ventilations with adequate, excessive, and insufficient volume was recorded and analysed, as well as the overall quality of the CPR (ventilations and chest compressions). RESULTS: The students were able to give a higher number of ventilations with adequate volume using the mouth-to-mouth-and-nose method (55+/-22%) than with the bag-valve-mask (28+/-16%, P<.001). The overall quality of the CPR was also significantly higher when using the mouth-to-mouth-and-nose method (60+/-19 vs. 48+/-16%, P<.001). CONCLUSIONS: Mouth-to-mouth-and-nose ventilation method is more efficient than bag-valve-mask ventilations in CPR performed by nursing students with a simulated infant model. PMID- 29429864 TI - Prevalence and correlates of recent injecting drug use among gay and bisexual men in Australia: Results from the FLUX study. AB - BACKGROUND: While illicit drug use is prevalent among gay and bisexual men (GBM) in Australia, little is known about the factors associated with injecting drug use among GBM. METHODS: The Following Lives Undergoing Change (FLUX) study is a national, online prospective observational cohort investigating drug use among Australian GBM. Eligible participants were men living in Australia who were aged 16.5 years or older, identified as gay or bisexual or had sex with at least one man in the last year. We examined baseline data for associations between socio demographic and behavioural characteristics and recent (last six months) injecting using log-binomial regression. RESULTS: Of 1995 eligible respondents, 206 (10.3%) reported ever injecting drugs and 93 (4.7%) had injected recently, most commonly crystal (91.4%) and speed (9.7%). Among recent injectors, only 16 (17.2%) reported injecting at least weekly; eight (8.6%) reported recent receptive syringe sharing. Self-reported HIV and HCV prevalence was higher among recent injectors than among other participants (HIV: 46.2% vs 5.0%, p < .001; HCV: 16.1% vs. 1.2%, p < .001). Recent injecting was associated with lifetime use of more drug classes (adjusted prevalence ratio (APR) = 1.31, 95% Confidence Interval (95%CI) 1.21-1.41), longer time since initiating party drug use (APR = 1.02, 95%CI 1.01-1.04), greater numbers of sex partners (2-10 sex partners: APR = 3.44, 95%CI 1.45-8.20; >10 sex partners: APR = 3.21, 95%CI 1.30-7.92), group sex (APR = 1.42, 95%CI 1.05-1.91) and condomless anal intercourse with casual partners (APR = 1.81, 95%CI 1.34-2.43) in the last six months. CONCLUSIONS: Observed associations between injecting and sexual risk reflect a strong relationship between these practices among GBM. The intersectionality between injecting drug use and sex partying indicates a need to integrate harm reduction interventions for GBM who inject drugs into sexual health services and targeted sexual health interventions into Needle and Syringe Programs. PMID- 29429865 TI - Mental health, drug use and sexual risk behavior among gay and bisexual men. AB - BACKGROUND: Compared to the general population, among gay and bisexual men (GBM) prevalence rates of anxiety and depression, and of drug use, are high. OBJECTIVE: This paper explores the relationship between mental health, sexual risk behavior, and drug use among Australian GBM. We identify factors associated with indicators of poor mental health. METHODS: Between September 2014 and July 2017, 3017 GBM responded to measures of anxiety and depression in an online cohort study of drug use. RESULTS: Mean age was 35.3 years (SD 12.8). 17.9% screened positive for current moderate-severe anxiety and 28.3% for moderate-severe depression. The majority (52.2%) reported use of illicit drugs in the previous six months, including 11.2% who had used methamphetamine. One third had high (20.4%) or severe (10.6%) risk levels of alcohol consumption, and 18.3% who were current daily smokers. Most illicit drug use in general was not associated with either anxiety or depression, but men who used cannabis were more likely to show evidence of depression (p = 0.005). Among recent methamphetamine users, 28.0% were assessed as dependent: dependent users were more likely to show evidence of both depression and anxiety than were non-dependent users. High or severe risk drinking was associated with depression and daily tobacco use was associated with both anxiety and depression. Depression and anxiety was associated with: less personal support, viewing oneself as 'feminine', and being less socially engaged with gay men. Sexual risk behavior was not associated with either depression or anxiety. CONCLUSION: Prevalence of anxiety and depression was high, as was prevalence of licit and illicit drug use. Substance use was associated with anxiety and depression only when the use was considered problematic or dependent. Social isolation and marginalization are strong drivers of poor mental health, even within this population for whom anxiety and depression are common. PMID- 29429866 TI - Breakthrough fungemia caused by Rhodotorula mucilaginosa during anidulafungin therapy. PMID- 29429867 TI - Description of an rf field-strength controller for solid-state NMR experiments. AB - Some MAS NMR experiments are sensitive to fluctuations or drifts in rf field strengths. We examine the simple 1H-13C CPMAS experiment and show that the 13C signal intensities vary over time due to drifts in rf field strengths. The causes of the drifts in rf field strengths are studied. Stabilization of the rf field strengths are obtained by using an rf field-strength controller. The controller is a stand-alone unit, which can be easily incorporated in any spectrometer system. Details of the controller, including circuit design, are provided. PMID- 29429868 TI - From rodent heart to inborn errors of human metabolism. PMID- 29429870 TI - 2017 Year in Review: Editor's Letter to the Readers of the American Journal of Geriatric Psychiatry. PMID- 29429869 TI - Pharmacogenetic Decision Support Tools: A New Paradigm for Late-Life Depression? AB - Clinicians still employ a "trial-and-error" approach to optimizing treatment regimens for late-life depression (LLD). With LLD affecting a significant and growing segment of the population, and with only about half of older adults responsive to antidepressant therapy, there is an urgent need for a better treatment paradigm. Pharmacogenetic decision support tools (DSTs), which are emerging technologies that aim to provide clinically actionable information based on a patient's genetic profile, offer a promising solution. Dozens of DSTs have entered the market in the past 15 years, but with varying level of empirical evidence to support their value. In this clinical review, we provide a critical analysis of the peer-reviewed literature on DSTs for major depression management. We then discuss clinical considerations for the use of these tools in treating LLD, including issues related to test interpretation, timing, and patient perspectives. In adult populations, newer generation DSTs show promise for the treatment of major depression. However, there are no primary clinical trials in LLD cohorts. Independent and comparative clinical trials are needed. PMID- 29429871 TI - Case study comparison of functional vs. organic stability approaches for assessing threat potential at closed landfills in the USA. AB - Municipal solid waste (MSW) landfills in the USA are regulated under Subtitle D of the Resource Conservation and Recovery Act (RCRA), which includes the requirement to protect human health and the environment (HHE) during the post closure care (PCC) period. Several approaches have been published for assessment of potential threats to HHE. These approaches can be broadly divided into organic stabilization, which establishes an inert waste mass as the ultimate objective, and functional stability, which considers long-term emissions in the context of minimizing threats to HHE in the absence of active controls. The objective of this research was to conduct a case study evaluation of a closed MSW landfill using long-term data on landfill gas (LFG) production, leachate quality, site geology, and solids decomposition. Evaluations based on both functional and organic stability criteria were compared. The results showed that longer periods of LFG and leachate management would be required using organic stability criteria relative to an approach based on functional stability. These findings highlight the somewhat arbitrary and overly stringent nature of assigning universal stability criteria without due consideration of the landfill's hydrogeologic setting and potential environmental receptors. This supports previous studies that advocated for transition to a passive or inactive control stage based on a performance-based functional stability framework as a defensible mechanism for optimizing and ending regulatory PCC. PMID- 29429872 TI - Updated database on natural radioactivity in building materials in Europe. AB - The paper presents the latest collection of activity concentration data of natural radionuclides (226Ra, 232Th and 4 K) in building materials. This database contains about 24200 samples of both bulk materials and their constituents (bricks, concrete, cement, aggregates) and superficial materials used in most European Union Member States and some European countries. This collection also includes radiological information about some NORM residues and by-products (by product gypsum, metallurgical slags, fly and bottom ashes and red mud) which can be of radiological concern if recycled in building materials as secondary raw materials. Moreover, radon emanation and radon exhalation rate data are reported for bricks and concrete. PMID- 29429873 TI - Deposition of artificial radionuclides in sediments of Loch Etive, Scotland. AB - The nuclear fuel reprocessing plants on the Sellafield site (UK) have released low-level effluents into the Irish Sea under authorisation since 1952. This has led to the labelling of nearby offshore sediments with a range of artificial radionuclides. In turn, these sediments act as a long-term secondary source of both soluble and particle-associated radionuclides to coastal areas. These radionuclides are of interest both in assessing possible environmental impacts and as tracers for marine processes. Here we present results from a study of the geochemistry of natural (234, 238U) and artificial (137Cs, 241Am, 238Pu, 239+240Pu, and 236U) radionuclides and their accumulation in sediments from Loch Etive, Scotland. The data are interpreted in the context of the historical radioactive discharges to the Irish Sea and biogeochemical processes in marine sediments. Loch Etive is divided into two basins; a lower, seaward basin where the sedimentation rate (~0.6 cm/yr) is about twice that of the more isolated upper basin (~0.3 cm/yr). These accumulation rates are consistent with the broad distribution of 137Cs in the sediment profiles which can be related to the maximum Sellafield discharges of 137Cs in the mid-1970s and suggest that 137Cs was mainly transported in solution to Loch Etive during that period. Enrichments of Mn, Fe, and Mo in sediment and porewater from both Loch Etive basins result from contemporary biogeochemical redox processes. Enrichments of 238U and 234U in the lower basin may be a result of the cycling of natural U. By contrast, the Sellafield-derived artificial isotope 236U does not seem to be affected by the redox-driven reactions in the lower basin. The 238Pu/239,240Pu ratios suggest contributions from both historical Sellafield discharges and global fallout Pu. The uniform sediment distributions of Pu and Am, which do not reflect Sellafield historical discharges, suggest the existence of a homogenous secondary source. This could be the offshore 'mud patch' in the vicinity of Sellafield from which the supply of radionuclides reflects time-integrated Sellafield discharges. This source could also account for the continuing supply of Cs to Loch Etive, even after substantial reductions in discharge from the Sellafield site. PMID- 29429875 TI - Molecular Mechanistic Insights into Drosophila DHX36-Mediated G-Quadruplex Unfolding: A Structure-Based Model. AB - Helicase DHX36 plays essential roles in cell development and differentiation at least partially by resolving G-quadruplex (G4) structures. Here we report crystal structures of the Drosophila homolog of DHX36 (DmDHX36) in complex with RNA and a series of DNAs. By combining structural, small-angle X-ray scattering, molecular dynamics simulation, and single-molecule fluorescence studies, we revealed that positively charged amino acids in RecA2 and OB-like domains constitute an elaborate structural pocket at the nucleic acid entrance, in which negatively charged G4 DNA is tightly bound and partially destabilized. The G4 DNA is then completely unfolded through the 3'-5' translocation activity of the helicase. Furthermore, crystal structures and DNA binding assays show that G-rich DNA is preferentially recognized and in the presence of ATP, specifically bound by DmDHX36, which may cooperatively enhance the G-rich DNA translocation and G4 unfolding. On the basis of these results, a conceptual G4 DNA-resolving mechanism is proposed. PMID- 29429874 TI - Nondipping heart rate: A neglected cardiovascular risk factor based on autonomic imbalance? PMID- 29429876 TI - "To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase Clinical Drug Complexes by Neutron Crystallography and Simulation. AB - Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX. PMID- 29429877 TI - The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth. AB - Alkaloids isolated from the Amaryllidaceae plants have potential as therapeutics for treating human diseases. Haemanthamine has been studied as a novel anticancer agent due to its ability to overcome cancer cell resistance to apoptosis. Biochemical experiments have suggested that hemanthamine targets the ribosome. However, a structural characterization of its mechanism has been missing. Here we present the 3.1 A resolution X-ray structure of haemanthamine bound to the Saccharomyces cerevisiae 80S ribosome. This structure reveals that haemanthamine targets the A-site cleft on the large ribosomal subunit rearranging rRNA to halt the elongation phase of translation. Furthermore, we provide evidence that haemanthamine and other Amaryllidaceae alkaloids also inhibit specifically ribosome biogenesis, triggering nucleolar stress response and leading to p53 stabilization in cancer cells. Together with a computer-aided interpretation of existing structure-activity relationships of Amaryllidaceae alkaloids congeners, we provide a rationale for designing molecules with enhanced potencies and reduced toxicities. PMID- 29429878 TI - Raf-1 Cysteine-Rich Domain Increases the Affinity of K-Ras/Raf at the Membrane, Promoting MAPK Signaling. AB - K-Ras4B preferentially activates Raf-1. The high-affinity interaction of Ras binding domain (RBD) of Raf with Ras was solved, but the relative position of Raf's cysteine-rich domain (CRD) in the Ras/Raf complex at the membrane and key question of exactly how it affects Raf signaling are daunting. We show that CRD stably binds anionic membranes inserting a positively charged loop into the amphipathic interface. Importantly, when in complex with Ras/RBD, covalently connected CRD presents the same membrane interaction mechanism, with CRD locating at the space between the RBD and membrane. To date, CRD's role was viewed in terms of stabilizing Raf-membrane interaction. Our observations argue for a key role in reducing Ras/RBD fluctuations at the membrane, thereby increasing Ras/RBD affinity. Even without K-Ras, via CRD, Raf-1 can recruit to the membrane; however, by reducing the Ras/RBD fluctuations and enhancing Ras/RBD affinity at the membrane, CRD promotes Raf's activation and MAPK signaling over other pathways. PMID- 29429879 TI - Multispecific Substrate Recognition in a Proton-Dependent Oligopeptide Transporter. AB - Proton-dependent oligopeptide transporters (POTs) are important for uptake of dietary di- and tripeptides in many organisms, and in humans are also involved in drug absorption. These transporters accept a wide range of substrates, but the structural basis for how different peptide side chains are accommodated has so far remained obscure. Twenty-eight peptides were screened for binding to PepTSt from Streptococcus thermophilus, and structures were determined of PepTSt in complex with four physicochemically diverse dipeptides, which bind with millimolar affinity: Ala-Leu, Phe-Ala, Ala-Gln, and Asp-Glu. The structures show that PepTSt can adapt to different peptide side chains through movement of binding site residues and water molecules, and that a good fit can be further aided by adjustment of the position of the peptide itself. Finally, structures were also determined in complex with adventitiously bound HEPES, polyethylene glycol, and phosphate molecules, which further underline the adaptability of the binding site. PMID- 29429881 TI - Short-term Morbidity and Readmissions Increase With Skilled Nursing Facility Discharge After Total Joint Arthroplasty in a Medicare-Eligible and Skilled Nursing Facility-Eligible Patient Cohort. AB - BACKGROUND: The benefits of discharge to a skilled nursing facility (SNF) in Medicare-eligible patients after total joint arthroplasty (TJA) have recently been scrutinized. The purpose of this study was to determine short-term complication and readmission rates for SNF versus home discharge in patients eligible for Medicare and SNF discharge. METHODS: Patients who underwent TJA between 2012 and 2013 were identified in the National Surgical Quality Improvement Project database. Patients over 65 years and who discharged at or after postoperative day 3, and thus SNF eligible by Medicare rule, were included. Patient demographics and comorbidities were compared in the 2 cohorts (home versus SNF), and subsequent univariate and multivariate analyses were used to determine risk factors for short-term complications. RESULTS: We identified 34,610 Medicare- and SNF-eligible TJA patients; 54.8% discharged home. Patients with SNF discharge were older, had higher rates of comorbidities, and were more frequently American Society of Anesthesiologists class 3 or 4 (P < .001). Univariate analysis revealed that patients with SNF discharge had higher rates of any complication (7.9% vs. 4.7%, P < .001) and readmission (5.3% vs. 3.3%, P < .001). Multivariate regression analysis identified SNF discharge (adjusted odds ratio 1.9, 95% confidence interval 1.7-2.0) as an independent risk factor for a 30-day complication and readmission. CONCLUSIONS: In a cohort of Medicare- and SNF-eligible patients, SNF discharge was the strongest predictor of 30-day complication after TJA. SNF discharge was also an independent predictor of readmission after TJA. PMID- 29429880 TI - Deciphering the "Fuzzy" Interaction of FG Nucleoporins and Transport Factors Using Small-Angle Neutron Scattering. AB - The largely intrinsically disordered phenylalanine-glycine-rich nucleoporins (FG Nups) underline a selectivity mechanism that enables the rapid translocation of transport factors (TFs) through the nuclear pore complexes (NPCs). Conflicting models of NPC transport have assumed that FG Nups undergo different conformational transitions upon interacting with TFs. To selectively characterize conformational changes in FG Nups induced by TFs we performed small-angle neutron scattering (SANS) with contrast matching. Conformational-ensembles derived from SANS data indicated an increase in the overall size of FG Nups is associated with TF interaction. Moreover, the organization of the FG motif in the interacting state is consistent with prior experimental analyses defining that FG motifs undergo conformational restriction upon interacting with TFs. These results provide structural insights into a highly dynamic interaction and illustrate how functional disorder imparts rapid and selective FG Nup-TF interactions. PMID- 29429883 TI - Total Hip Arthroplasty Bearing Surface Trends in the United States From 2007 to 2014: The Rise of Ceramic on Polyethylene. AB - BACKGROUND: Wear of the bearing surface is a critical element in determining the longevity of a total hip arthroplasty (THA). Over the past decade, concerns related to modern metal-on-metal (MoM) bearings and corrosion at the femoral head neck interface have influenced surgeon selection of bearing surfaces. The purpose of this study is to analyze trends in THA bearing surface selection from 2007 through 2014 using a large national database. METHODS: The Nationwide Inpatient Sample database was used to extract bearing surface data from patients who underwent a primary THA between 2007 and 2014. Patients were grouped by bearing surface type: metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), MoM, and ceramic-on-ceramic (CoC) bearings. Descriptive statistics were employed to describe trends. Univariate and multivariate analyses were performed to identify differences between bearing surface groups. RESULTS: During the study period, 2,460,640 THA discharges were identified, of which 1,059,825 (43.1%) had bearing surface data. A total of 496,713 (46.9%) MoP, 307,907 (29.1%) CoP, 210,381 (19.9%) MoM, and 44,823 (4.2%) CoC cases were identified. MoM utilization peaked in 2008 representing 40.1% of THAs implanted that year and steadily declined to 4.0% in 2014. From 2007 to 2014, the use of CoP bearing surfaces increased from 11.1% of cases in 2007 to 50.8% of cases in 2014. In 2014, CoP utilization surpassed MoP which represented 42.1% of bearing surfaces that year. CONCLUSION: During the study period, MoM bearing surfaces decreased precipitously, while CoP surpassed MoP as the most popular bearing surface used in a THA. PMID- 29429882 TI - Mepivacaine Spinal Anesthesia Facilitates Rapid Recovery in Total Knee Arthroplasty Compared to Bupivacaine. AB - BACKGROUND: Mepivacaine as a spinal anesthetic for rapid recovery in total knee arthroplasty (TKA) has not been assessed. The purpose of this study is to compare spinal mepivacaine vs bupivacaine for postoperative measures in patients undergoing primary TKA. METHODS: Retrospective review of a prospectively collected single-institution database was performed on 156 consecutive patients who underwent primary TKA. Fifty-three patients were administered mepivacaine and 103 patients were administered bupivacaine. Primary outcomes were urinary retention, length of stay, pain control, opioid consumption, and distance associated with physical therapy. Statistical analysis with univariate logistic regression was performed to evaluate the effect of anesthetic with primary outcomes. RESULTS: Patients undergoing TKA with mepivacaine had a shorter length of stay (28.1 +/- 11.2 vs 33.6 +/- 14.4 hours, P = .002) and fewer episodes of straight catheterization (3.8% vs 16.5%, P = .021) compared to bupivacaine. Patients administered mepivacaine exhibited slightly higher VAS pain scores and morphine consumption in the postanesthesia care unit (1.3 +/- 1.9 vs 0.5 +/- 1.3, P = .002; 2.2 +/- 3.3 vs 0.8 +/- 2.1 equivalents/h, P = .002), but otherwise exhibited no difference in VAS scores or morphine consumption afterwards. There was no need to convert to general anesthesia or transient neurologic symptom complication in either group. CONCLUSION: Mepivacaine for spinal anesthesia with TKA had adequate duration to complete the surgery and facilitated a more rapid recovery with less urinary complications and a shorter length of stay. Patients administered mepivacaine did not display worse pain control or transient neurologic symptoms afterwards. PMID- 29429884 TI - Midterm Prospective Comparative Analysis of 2 Hard-on-Hard Bearing Total Hip Arthroplasty Designs. AB - INTRODUCTION: Hard-on-hard (HoH) bearing surfaces in total hip arthroplasty (THA) are commonly utilized in younger patients and may decrease mechanical wear compared to polyethylene bearing surfaces. To our knowledge, no study has prospectively compared the 2 most common HoH bearings, ceramic-on-ceramic (CoC) and metal-on-metal (MoM) THA. MATERIALS AND METHODS: We prospectively enrolled 40 patients to undergo an MoM THA and 42 patients to undergo a CoC THA utilizing the same acetabular component. Patients were followed up for a minimum of 2 years. Comparative outcomes included clinical scores, revision or reoperation for any reason, complication rates, and radiographic outcomes. RESULTS: The average follow-up was significantly longer in the CoC cohort (94 vs 74 months; P = .005). The CoC cohort had significantly improved Harris Hip Scores (95 vs 84; P = .0009) and pain scores (42 vs 34; P = .0003). The revision (0% vs 31%; P = .0001), reoperation (7.5% vs 36%; P = .004), and complication rates (10% vs 56%; P = .0001) were significantly lower in the CoC cohort. There were no statistically significant differences in radiographic parameters. CONCLUSION: The clinical outcomes in the CoC cohort exceeded the MoM cohort. It is unlikely that another prospective comparative study of HoH THAs will be conducted. Our midterm results support the use of CoC THA as a viable option that may reduce long-term wear in younger patients. Close surveillance of MoM THA patients is recommended considering the higher failure and complication rates reported in this cohort. PMID- 29429885 TI - Safety and Feasibility of the 6-Minute Walk Test in Patients with Acute Stroke. AB - BACKGROUND: Our objective was to investigate the safety and feasibility of the 6 minute walk test in patients with acute stroke. MATERIALS AND METHODS: Consecutive patients with acute stroke, admitted to the Itami Kosei Neurosurgical Hospital from September 2016 to April 2017 were enrolled. Walking capacity was assessed by a physical therapist using the 6-minute walk test in 94 patients with acute stroke within 14 days of hospital admission. The primary outcomes were safety (i.e., the prevalence of new adverse events during and after the test) and feasibility (i.e., test completion rate) of the 6-minute walk test. RESULTS: The 6-minute walk test was performed for a mean duration of 5.1 days (standard deviation, 2.6 days) after hospital admission. Seventy patients (74.5%) could walk without standby assistance or a walking aid, and 24 patients (25.5%) could walk without standby assistance but with a walking aid. The average distance walked by patients during the 6-minute walk test was 331 m (standard deviation, 107.2 m). Adverse events following the 6-minute walk test occurred in 6 patients (6.4%) and included stroke progression, stroke recurrence, seizures, and neurological deterioration. Heart rate increase (>120 beats/min) occurred in 3 patients (3.2%) during the test. Lastly, 6 patients (6.4%) were unable to complete the 6-minute walk test. CONCLUSIONS: Although performance in the 6 minute walk test was decreased in patients with acute stroke, the test itself appears to be safe and feasible in this patient population. PMID- 29429886 TI - Sex Differences in Stroke Attack, Incidence, and Mortality Rates in Northern France. AB - BACKGROUND: Age and sex have a major impact on stroke onset. AIMS: We aimed to compare the attack, incidence, and 28-day mortality rate for stroke as well as risk factors in men and women aged 35 and over. METHODS: Data were obtained between 2008 and 2015 from the stroke population-based registry covering the city of Lille (northern France). RESULTS: A total of 2426 strokes (1917 incident strokes) were recorded. The number of strokes was lower in women than in men when considering individuals under the age of 75 but was twice as high when considering individuals aged 75 or over. Overall, there were 25% more strokes in women than in men. The age-adjusted attack (P = .017) and incident (P = .027) rates of stroke were ~30% lower in women than in men (a ~30% lower risk of ischemic stroke (P = .02) and a ~40% lower risk of intracerebral hemorrhage (ICH) (P = .004)). The age-adjusted mortality rate after ICH was ~35% lower in women than in men (P = .014). With regard to cardiovascular risk factors, women with stroke were older, smoked less, and were more likely to have a history of migraine or atrial fibrillation than the men. CONCLUSION: The risk of stroke is lower in women than in men under the age of 75 but is similar when comparing women and men after that age. Nevertheless, the age structure of the population (with more elderly women than elderly men) translates into a higher absolute number of strokes in women than in men. PMID- 29429887 TI - Assessment of Capture and Amplicon-Based Approaches for the Development of a Targeted Next-Generation Sequencing Pipeline to Personalize Lymphoma Management. AB - Targeted next-generation sequencing panels are increasingly used to assess the value of gene mutations for clinical diagnostic purposes. For assay development, amplicon-based methods have been preferentially used on the basis of short preparation time and small DNA input amounts. However, capture sequencing has emerged as an alternative approach because of high testing accuracy. We compared capture hybridization and amplicon sequencing approaches using fresh-frozen and formalin-fixed, paraffin-embedded tumor samples from eight lymphoma patients. Next, we developed a targeted sequencing pipeline using a 32-gene panel for accurate detection of actionable mutations in formalin-fixed, paraffin-embedded tumor samples of the most common lymphocytic malignancies: chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and follicular lymphoma. We show that hybrid capture is superior to amplicon sequencing by providing deep more uniform coverage and yielding higher sensitivity for variant calling. Sanger sequencing of 588 variants identified specificity limits of thresholds for mutation calling, and orthogonal validation on 66 cases indicated 93% concordance with whole-genome sequencing. The developed pipeline and assay identified at least one actionable mutation in 91% of tumors from 219 lymphoma patients and revealed subtype specific mutation patterns and frequencies consistent with the literature. This pipeline is an accurate and sensitive method for identifying actionable gene mutations in routinely acquired biopsy materials, suggesting further assessment of capture-based assays in the context of personalized lymphoma management. PMID- 29429888 TI - Risk factors for local recurrence after total en bloc spondylectomy for metastatic spinal tumors: A retrospective study. AB - BACKGROUND: The aim of this study was to evaluate local recurrence and survival outcomes after frozen autograft total en bloc spondylectomy for metastatic spinal tumors. METHODS: We retrospectively analyzed data from 91 patients with metastatic spinal tumors who underwent frozen autograft total en bloc spondylectomy at our institution between May 2010 and April 2015. We assessed the incidence, primary cancer type, and sites of local recurrence. Risk factors for local recurrence were also examined through the statistical analysis of 17 items, including clinico-pathological characteristics, treatment history, and preoperative or surgical complications. Survival outcomes were evaluated with particular attention paid to the presence of local recurrence. RESULTS: The median follow-up duration was 27.4 months (range, 4-66 months). Local recurrence was diagnosed in 10 of 91 patients (11.0%). The sites of recurrence were intradural in 4 cases, epidural in 3 cases, in a vertebral body adjacent to the resected vertebral body in 2 cases, and in the paraspinal muscle in 3 cases. None of the patients had recurrence from the liquid nitrogen-treated tumor-bearing autograft. There were no local recurrences of renal cell carcinoma, thyroid cancer, or lung cancer. Multivariate analysis indicated that radiotherapy history was the only risk factor for local recurrence (odds ratio, 6.26; 95% confidence interval, 1.21-45.62; p = 0.04). The 2-year survival rate was significantly lower for the recurrence group than for the non-recurrence group (p < 0.05). CONCLUSIONS: A history of radiation was the only risk factor for local recurrence. Patients with recurrence had a significantly worse prognosis than those without recurrence. PMID- 29429889 TI - Comparison with the osteoconductivity and bone-bonding ability of the iodine supported titanium, titanium with porous oxide layer and the titanium alloy in the rabbit model. AB - BACKGROUND: One of the serious postoperative complications associated with joint replacement is bacterial infection. In our recent investigations, iodine supported titanium implants demonstrated antibacterial activity in both in vitro and in vivo studies. The surfaces of the implants have porous anodic oxide layer with the antiseptic properties of iodine. According to the literature the titanium with porous anodic oxide have good osteoconductivity. But it is not clear whether the properties of iodine influence bone bonding of implants. OBJECTIVES: The aim of this study is to evaluate the influence of the properties of iodine and porous anodic oxide layer in the bone bonding ability of titanium implants. STUDY DESIGN & METHODS: Titanium rods were implanted in intramedullary rabbit femur models, in regard to the cementless hip stem. The implant rods were 5 mm in diameter and 25 mm in length. Three types of titanium rods were implanted.One was untreated titanium (control group (CL)), another was titanium with oxide layer without iodine (oxide layer group (OL)), and the other was Iodine treated Titanium (iodine group (ID)). The rods were inserted into the distal femur. We assessed the bonding strength by a measuring pull-out test at 4, 8, and 12 weeks after implantation. The bone-implant interfaces were evaluated at 4 weeks after implantation. RESULTS: Pull-out test results of the ID implants were 202, 355, and 344 N, and those of the OL implants were 220, 310, 329 N at 4, 8, and 12 weeks, significantly higher than those of the CL implants (102, 216, and 227 N). But there were no significant difference in ID implants and OL implants. Histological examination revealed that new bone formed on the surface of each types of implants, but significantly more bone made direct contact with the surfaces of the ID implants and OL implants. CONCLUSIONS: This research showed that new type of coating, iodine coated titanium has low toxicity and good osteoconductivity. PMID- 29429890 TI - Response evaluation of giant-cell tumor of bone treated by denosumab: Histogram and texture analysis of CT images. AB - BACKGROUND: This study aimed to compare computed tomography (CT) features, including tumor size and textural and histogram measurements, of giant-cell tumors of bone (GCTBs) before and after denosumab treatment and determine their applicability in monitoring GCTB response to denosumab treatment. METHODS: This retrospective study included eight patients (male, 3; female, 5; mean age, 33.4 years) diagnosed with GCTB, who had received treatment by denosumab and had undergone pre- and post-treatment non-contrast CT between January 2010 and December 2016. This study was approved by the institutional review board. Pre- and post-treatment size, histogram, and textural parameters of GCTBs were compared by the Wilcoxon signed-rank test. Pathological findings of five patients who underwent surgery after denosumab treatment were evaluated for assessment of treatment response. RESULTS: Relative to the baseline values, the tumor size had decreased, while the mean attenuation, standard deviation, entropy (all, P = 0.017), and skewness (P = 0.036) of the GCTBs had significantly increased post treatment. Although the difference was statistically insignificant, the tumors also exhibited increased kurtosis, contrast, and inverse difference moment (P = 0.123, 0.327, and 0.575, respectively) post-treatment. Histologic findings revealed new bone formation and complete depletion or decrease in the number of osteoclast-like giant cells. CONCLUSION: The histogram and textural parameters of GCTBs changed significantly after denosumab treatment. Knowledge of the tendency towards increased mean attenuation and heterogeneity but increased local homogeneity in post-treatment CT histogram and textural features of GCTBs might aid in treatment planning and tumor response evaluation during denosumab treatment. PMID- 29429892 TI - Osteosarcoma subtypes: Magnetic resonance and quantitative diffusion weighted imaging criteria. AB - INTRODUCTION: Osteosarcoma (OS) is a primary bone malignancy, characterized by spindle cells producing osteoid. The objective of this study is to describe the magnetic resonance imaging (MRI) features of different OS subtypes, record their attenuation diffusion coefficient (ADC) values and to point to the relation of their pathologic base and their corresponding ADC value. PATIENTS AND METHODS: We performed a retrospective observational lesion-based analysis for 31 pathologically proven osteosarcoma subtypes: osteoblastic (n = 9), fibroblastic (n = 8), chondroblastic (n = 6), para-osteal (n = 3), periosteal (n = 1), telangiectatic (n = 2), small cell (n = 1) and extra-skeletal (n = 1). On conventional images we recorded: bone of origin, epicenter, intra-articular extension, and invasion of articulating bones, skip lesions, distant metastases, pathological fractures, ossified matrix, hemorrhage and necrosis. We measured the mean ADC value for each lesion. RESULTS: Among the included OS lesions, 51.6% originated at the femur, 29% showed intra-articular extension, 16% invaded neighboring bone, 9% were associated with pathological fracture and 25.8% were associated with distant metastases. On MRI, all lesions showed ossified matrix, 35.5% showed hemorrhage and 58% showed necrosis. The mean ADC values for OS lesions ranged from 0.74 * 10-3 mm2/s (recorded for conventional osteoblastic OS) to 1.50 * 10-3 mm2/s (recorded for telangiectatic OS) with an average value of 1.16 +/- 0.18 * 10-3 mm2/s. Conventional chondroblastic OS recorded higher values compared to the other two conventional subtypes. CONCLUSION: Osteosarcoma has different pathologic subtypes which correspondingly vary in their imaging criteria and their ADC values. PMID- 29429894 TI - Prevalence, patterns, and associations of dyslipidemia among Sri Lankan adults Sri Lanka Diabetes and Cardiovascular Study in 2005-2006. AB - BACKGROUND: Dyslipidemia is a major risk factor for cardiovascular disease. Prevalence patterns and determinants of dyslipidemia in Sri Lanka are unkown. OBJECTIVES: We aimed to determine the prevalence and correlates of dyslipidemia among Sri Lankan adults. METHODS: A nationally representative sample was recruited by multistage random cluster sampling in Sri Lanka Diabetes and Cardiovascular Study, a cross-sectional study. Data collected by an interviewer administered questionnaire, physical examination, anthropometric measurements lipid analysis from take 12-hour fasting blood samples were used. RESULTS: Among 4451 participants 60.5% were women and mean age was 46 years. Mean (standard deviation) total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), triglycerides (TGs), and TC/HDLC levels were 206.7 mg/dL (+/-43.5), 46.8 mg/dL (+/-10.6), 135.5 mg/dL (+/-37.6), 121.7 mg/dL (+/-66.8), and 4.6 (+/-1.1), respectively. Women had higher mean TC, HDLC, LDLC, and TG values compared to men across all age groups. Mean TC, LDLC, and TGs increased with age in both genders; 77.4% of participants had some form of dyslipidemia. Low HDLC was the commonest type (49.6%) of dyslipidemia. Increasing age, female sex, living in urban sector, high body mass index, central obesity, diabetes, hypertension, insufficient physical activity, and smoking were associated with having some form of dyslipidemia. CONCLUSION: Three in four Sri Lankan adults have some form of dyslipidemia. Physical inactivity, obesity, hypertension, and diabetes are the leading modifiable risk factors. PMID- 29429891 TI - Vinorelbine Potently Induces Placental Cell Death, Does Not Harm Fertility and is a Potential Treatment for Ectopic Pregnancy. AB - Ectopic pregnancies complicate 1-2 pregnancies and are a leading cause of maternal death. An effective oral drug therapy that replaces surgery might make its treatment safer, cheaper, simpler and therefore more widely accessible. The only current medical treatment offered to women is intramuscular methotrexate, but this only reliably resolves smaller ectopic pregnancies. As such, many ectopic pregnancies require surgical excision. We show that vinorelbine, an orally available chemotherapeutic agent, potently induced placental cell death but did not harm fertility in mice. Vinorelbine was 100-1000 times more potent than methotrexate in inducing placental cell death in vitro, and more potent than combination methotrexate and gefitinib (another proposed treatment for ectopic pregnancy being evaluated in phase III trials). Mechanistically, it caused microtubule condensation, blocked mitosis and activated the apoptosis cascade in placental cells. Vinorelbine was more efficacious than methotrexate+/-gefitinib in reducing the volume of placental cell tumors xenografted subcutaneously in SCID mice. Mice exposed to vinorelbine and allowed to breed, following a four week washout period, displayed normal fertility, however long-term fertility was not assessed. Human Fallopian tubes treated with vinorelbine did not exhibit up regulation of apoptosis molecules. Our findings show that placental cells appear sensitive to vinorelbine and it has potential as a tablet-only approach to treat ectopic pregnancy. PMID- 29429893 TI - Prevalence of high cholesterol levels suggestive of familial hypercholesterolemia in Brazilian adolescents: Data from the study of cardiovascular risk in adolescents. AB - BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder with an estimated worldwide prevalence ranging from 1 in 200 individuals to 1 in 500 individuals in its heterozygous form. Individuals with FH exhibit high low-density lipoprotein cholesterol (LDLc) levels from birth, which leads to premature cardiovascular events. In Brazil, like in most countries around the world, FH is considered a public health problem but remains underdiagnosed and undertreated. OBJECTIVE: The aim of this study was to evaluate the prevalence of LDLc or non-high-density lipoprotein cholesterol (non-HDLc) levels suggestive of FH among Brazilian adolescents. METHODS: The Study of Cardiovascular Risk in Adolescents (ERICA) was a nationwide, school-based, cross-sectional study that assessed the prevalence of cardiovascular risk factors in approximately 75,000 adolescents between 12 and 17 years old. Data were analyzed according to sex, age, type of school (public or private), and geographic regions of Brazil. Adolescents with untreated fasting LDLc levels of 160 mg/dL or higher or non-HDLc levels of 190 mg/dL or higher were suspected to have FH. We also evaluated the prevalence of LDLc levels of 190 mg/dL or higher, which is highly suggestive of a diagnosis of FH in this age group. RESULTS: A total of 38,069 adolescents were evaluated; more than half (59.9%) were female and most (74%) attended public schools. The prevalence of LDLc levels of 160 mg/dL or higher or non-HDLc levels of 190 mg/dL or higher among the adolescents was 0.49% (95% confidence interval: 0.34-0.71; n = 209). Moreover, 0.12% of the adolescents (95% confidence interval: 0.04-0.34; n = 44) had LDLc levels of 190 mg/dL or higher. We estimate that approximately 100,000 (1 in 200) Brazilian adolescents aged 12 to 17 years are suspected to have FH on the basis of LDLc and non-HDLc levels. CONCLUSION: We identified a significant prevalence of cholesterol levels suggestive of FH among Brazilian adolescents. Further evaluation is needed to confirm the diagnoses among the students. Our results reinforce the importance of universal screening as a critical tool for early diagnosis and treatment of FH. PMID- 29429897 TI - Role of immunotherapy in bacillus Calmette-Guerin-unresponsive non-muscle invasive bladder cancer. AB - Intravesical instillation of live attenuated bacillus Calmette-Guerin (BCG) is the gold standard for patients with intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). BCG-failures include a heterogenous population of patients who share a designation of disease recurrence or progression following BCG and include patients with complete unresponsiveness to BCG, patients who respond initially but develop relapse and, in some cases, patients who are intolerant to BCG due to side effects. Given the efficacy and relatively rapid approval of several monoclonal antibodies against PD-L1 or PD-1 for advanced and metastatic bladder cancer, the role of these checkpoint inhibitors in BCG-relapsing disease at various disease stages is under consideration. Data supporting a role for immune checkpoint inhibitors is largely theoretical with limited supportive data from animal models and from clinical evidence of increased PD-L1 expression in BCG-unresponsive tumors. Current trials in BCG unresponsive disease are underway and expected to provide insight regarding these concepts. PMID- 29429896 TI - Metabolic syndrome is not associated with greater evidences of proliferative inflammatory atrophy and inflammation in patients with suspected prostate cancer. AB - INTRODUCTION AND OBJECTIVES: To evaluate the association between metabolic syndrome (MetS) and proliferative inflammatory atrophy (PIA) in patients with suspected prostate cancer (PCa). PATIENTS AND METHODS: From June 2015 to July 2016, we conducted the FIERY (Flogosis Increased Events of pRostatic biopsY) study at the Urology section, Department of Surgery of the University of Catania (Local registration number: #131/2015). A total of 205 patients with elevated prostate-specific antigen (>= 4 ng/ml) or clinical suspicion of PCa who underwent primary transperineal prostate biopsy were included in this cross-sectional study. The assessment of PIA, HGPIN, and PCa were performed by 2 experienced pathologists and samples were investigated for the presence of an inflammatory infiltrate, according to the Irani score. Primary and secondary Gleason grade of tumor in positive biopsies were evaluated according to the 2016 ISUP Modified Gleason System. RESULTS: In the entire cohort, median age was 68.0 (interquartile range: 62.0-74.5), median prostate-specific antigen was 6.5 (interquartile range: 5.51-9.57). The prevalence of MetS was 34.1%, the detection rate of PCa was 32.7%, the rate of PIA was 28.3%, the rate of HGPIN was 32.2%, whereas the rate of severe intraprostatic inflammation (Irani-score >=4) was 28.8%. When comparing clinical and histological variables in patients without and with PIA, metabolic aberrations where not significantly different in both groups. We did not find statistical association in detection rate of PCa (29.3% vs. 34.0%; P = 0.07) and HGPIN (27.6% vs. 34.0%; P = 0.37) in patients with and without PIA, respectively. When considering metabolic aberrations, MetS was not associated with Irani-score >=4 (28.6% vs. 28.4%; P = 0.96) and none of each component was statistically predictive of severe inflammation. At the multivariable logistic regression analysis, PIA, HGPIN, and MetS were not associated with greater risk of PCa. CONCLUSION: In this study, we did not show an association between MetS and PIA and PCa. Although the small sample size and the cross-sectional nature of the study, we do not suppose that MetS could be associated with greater evidence of PIA. Further studies should be conducted to evaluate the exact nature of this pathological lesion. PMID- 29429895 TI - First postoperative PSA is associated with outcomes in patients with node positive prostate cancer: Results from the SEARCH database. AB - OBJECTIVE: To analyze factors associated with metastases, prostate cancer specific mortality, and all-cause mortality in pN1 patients. MATERIALS AND METHODS: We analyzed 3,642 radical prostatectomy patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Pathologic Gleason grade, number of lymph nodes (LN) removed, and first postoperative prostate-specific antigen (PSA) (<0.2 ng/ml or >=0.2 ng/ml) were among covariates assessed. Cox regression was used to analyze the association between characteristics and survival outcomes. Kaplan-Meier was used to estimate survival in pN1 patients stratified by first postoperative PSA. RESULTS: Of 3,642 patients, 124 (3.4%) had pN1. There were 71 (60%) patients with 1 positive LN, 32 (27%) with 2 positive LNs, and 15 (13%) with >=3. Among men with pN1, first postoperative PSA was<0.2ng/ml in 46 patients (51%) and >=0.2ng/ml in 44 patients (49%). Univariable Cox regression determined pathological Gleason grade (P = 0.021), seminal vesicle invasion (P = 0.010), and first postoperative PSA >=0.2 ng/ml (P = 0.005) were associated with metastases. First postoperative PSA >=0.2ng/ml was associated with metastasis on multivariable analysis (P = 0.046). Log-rank analysis revealed a more favorable metastases-free survival in patients with a first postoperative PSA<0.2ng/ml (P = 0.001). Estimated 5-year metastases-free survival rate was 99% for patients with a first postoperative PSA<0.2ng/ml and 87% for >=0.2ng/ml. CONCLUSIONS: pN1 patients with a first postoperative PSA >=0.2ng/ml were more likely to develop metastases. First postoperative PSA may be useful in identifying pN1 patients who harbor distant disease and aid in secondary treatment decisions. PMID- 29429898 TI - Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase. AB - Kynurenine 3-monooxygenase (KMO) inhibitors have been developed for the treatment of neurodegenerative disorders. The mechanisms of flavin reduction and hydrogen peroxide production by KMO inhibitors are unknown. Herein, we report the structure of human KMO and crystal structures of Saccharomyces cerevisiae (sc) and Pseudomonas fluorescens (pf) KMO with Ro 61-8048. Proton transfer in the hydrogen bond network triggers flavin reduction in p-hydroxybenzoate hydroxylase, but the mechanism triggering flavin reduction in KMO is different. Conformational changes via pi-pi interactions between the loop above the flavin and substrate or non-substrate effectors lead to disorder of the C-terminal alpha helix in scKMO and shifts of domain III in pfKMO, stimulating flavin reduction. Interestingly, Ro 61-8048 has two different binding modes. It acts as a competitive inhibitor in scKMO and as a non-substrate effector in pfKMO. These findings provide understanding of the catalytic cycle of KMO and insight for structure-based drug design of KMO inhibitors. PMID- 29429899 TI - Engineered Glycocalyx Regulates Stem Cell Proliferation in Murine Crypt Organoids. AB - At the base of the intestinal crypt, long-lived Lgr5+ stem cells are intercalated by Paneth cells that provide essential niche signals for stem cell maintenance. This unique epithelial anatomy makes the intestinal crypt one of the most accessible models for the study of adult stem cell biology. The glycosylation patterns of this compartment are poorly characterized, and the impact of glycans on stem cell differentiation remains largely unexplored. We find that Paneth cells, but not Lgr5+ stem cells, express abundant terminal N-acetyllactosamine (LacNAc). Employing an enzymatic method to edit glycans in cultured crypt organoids, we assess the functional role of LacNAc in the intestinal crypt. We discover that blocking access to LacNAc on Paneth cells leads to hyperproliferation of the neighboring Lgr5+ stem cells, which is accompanied by the downregulation of genes that are known as negative regulators of proliferation. PMID- 29429900 TI - N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production. AB - The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the antioxidative effects of NAC have remained uncertain. Here we show that NAC derived cysteine is desulfurated to generate hydrogen sulfide, which in turn is oxidized to sulfane sulfur species, predominantly within mitochondria. We provide evidence suggesting the possibility that sulfane sulfur species produced by 3 mercaptopyruvate sulfurtransferase and sulfide:quinone oxidoreductase are the actual mediators of the immediate antioxidative and cytoprotective effects provided by NAC. PMID- 29429902 TI - Reply to letter: "Brain MRI abnormalities resembling unidentified bright objects in a patient with Phelan- McDermid syndrome". PMID- 29429903 TI - Increased infiltration of CD11 c+/CD123+ dendritic cell subsets and upregulation of TLR/IFN-alpha signaling participate in pathogenesis of oral lichen planus. AB - OBJECTIVE: Investigation of dendritic cell (DC) subsets and expression patterns of Toll-like receptors (TLRs) was conducted to understand the pathogenesis in oral lichen planus (OLP). STUDY DESIGN: Blood, OLP lesion, and control samples were collected. Four DC subsets (CD11c+CD123-myeloid DC1 [mDC1], CD141+mDC2, CD11c-CD123+plasmacytoid DC [pDC], and CD1a+CD207+Langerhans cells [LC]) were investigated via flow cytometry (FCM) and immunohistochemical staining. Expression patterns of TLRs and their downstream molecules were analyzed via quantitative real-time polymerase chain reaction and immunohistochemistry in situ. RESULTS: Thirty-two samples were collected (9 controls and 23 OLP patients). FCM results found that the percentages of LC, mDC1, mDC2, and pDC in situ were 0.0119 +/- 0.0251%, 0.0064 +/- 0.0134%, 0.0005 +/- 0.0011%, and 0.0022 +/- 0.0019% in control mucosa, respectively. The mDC1 (0.0300 +/- 0.0276%) and pDC (0.0204 +/- 0.0186%) subsets were significantly increased in OLP lesions (P < .01). No marked differences were evident, when comparing all 4 DC subsets from blood, between control and OLP groups. Significant upregulation of TLR7, TLR8, and TLR9 were disclosed in OLP (P < .01), along with their downstream interferon alpha (IFN-alpha) signaling molecules (IRF7 and IFN-alpha, P < .01). CONCLUSION: Our findings of increased infiltration of pDC and mDC1, along with upregulation of TLR/IFN-alpha signaling, provide valuable information for further understanding the immunity in OLP. PMID- 29429904 TI - Longitudinal clinicopathologic data of the progression of oral mucosal melanoma report of 2 cases and literature review. AB - Oral mucosal melanoma (OMM) is notorious for having a poor prognosis. Recognition of the early features of OMM by both clinicians and pathologists can play an important role in improving survival. Therefore, the purpose of this report is to increase awareness of the early features of OMM, by presenting 2 cases with longitudinal clinical and histopathologic documentation showing progression of OMM from a deceptively bland premalignant (noninvasive) oral melanocytic lesion (POML). By analyzing the clinical and histopathologic features of POML in our cases, and those in the literature, we found that the concerning features are (1) clinically, a pigmented lesion violating the ABCDE criteria or showing multiple recurrences; and (2) histologically, a melanocytic proliferation, in either a lentiginous or pagetoid pattern with or without cellular atypia. Making a diagnosis of POML prospectively is often challenging. Increasing awareness of the clinical and histopathologic features and complete surgical excision of POML are emphasized. PMID- 29429901 TI - Circulating biomarkers in extremely preterm infants associated with ultrasound indicators of brain damage. AB - AIM: To assess to what extent the blood concentrations of proteins with neurotrophic and angiogenic properties measured during the first postnatal month convey information about the risk of sonographically-identified brain damage among very preterm newborns. METHODS: Study participants were 1219 children who had a cranial ultrasound scan during their stay in the intensive care nursery and blood specimens collected on 2 separate days at least a week apart during the first postnatal month. Concentrations of selected proteins in blood spots were measured with electrochemiluminescence or with a multiplex immunobead assay and the risks of cranial ultrasound images associated with top-quartile concentrations were assessed. RESULTS: High concentrations of multiple inflammation-related proteins during the first 2 postnatal weeks were associated with increased risk of ventriculomegaly, while high concentrations of just 3 inflammation-related proteins were associated with increased risk of an echolucent/hypoechoic lesion (IL-6, IL-8, ICAM-1), especially on day 7. Concomitant high concentrations of IL6R and bFGF appeared to modulate the increased risks of ventriculomegaly and an echolucent lesion associated with inflammation. More commonly high concentrations of putative protectors/repair enhancers did not appear to diminish these increased risks. CONCLUSION: Our findings provide support for the hypothesis that endogenous proteins are capable of either protecting the brain against damage and/or enhancing repair of damage. PMID- 29429906 TI - Suicide risk, temperament traits, and sleep quality in patients with refractory epilepsy. AB - OBJECTIVES: The objective of the study was to access the suicide risk (SR) in patients with refractory epilepsy and its association with temperament and sleep quality. METHODS: A total of 50 consecutive patients referred for epilepsy surgery evaluation in the Porto Alegre Epilepsy Surgery Program were included. All patients had a detailed neurologic and psychiatric evaluation, including video-electroencephalogram (VEEG), high-resolution magnetic ressonance imaging (MRI), and neuropsychologic assessment. In addition, structured questionnaires were applied: module C of the MINI-plus (International Neuropsychiatric Interview Brazilian version 5.0.0), Affective and Emotional Composite Temperament Scale (AFECTS), and Pittsburgh Sleep Quality Index (PSQI). RESULTS: Ten patients (20.0%) showed an increased SR. The most frequent location of the epileptic focus was in the temporal lobe (50%; n=25). Final diagnosis on VEEG comprised epilepsy in 74.0% (n=37), psychogenic nonepileptic seizures (PNES) in 8.0% (n=4), and both in 12%. Thirty patients (60.0%) received surgery indication. Mood disorders were the main psychiatric diagnosis, found in 19 subjects (70.4%), with major depressive disorder (MDD) encountered in 15 patients (55.6%). In the group, SR was more frequent in patients with sleep disorders (p=0.001) and elevated scores of high emotional sensitivity (p=0.003). CONCLUSION: In this cohort of patients with highly refractory epilepsy, there was a significant association between SR, sleep disorders, and high emotional sensitivity. Careful evaluation of these factors should be performed in these patients to fully access SR. PMID- 29429905 TI - Health-related quality of life in patients with poststroke epilepsy. AB - BACKGROUND: Lesional epilepsy is an important long-term sequela of stroke. Data on health-related quality of life (HrQoL) in patients with poststroke epilepsy are limited. We investigated HrQoL in patients with epilepsy after ischemic stroke and identified independent HrQoL-determinants. METHODS AND PATIENTS: All patients with acute ischemic stroke, who were permanent residents in the district Marburg-Biedenkopf (Hessia, Germany, reference population 240,000 inhabitants) were recruited within 12months in the population-based Marburg Stroke Register (MARSTREG). Follow-up visits were performed after 6, 12, and 24months, and patients who developed poststroke epilepsy were identified. Data on demographics, antiepileptic drugs (AEDs), stroke severity (National Institute of Heath Stroke Scale (NIHSS), Barthel-Index, modified Rankin Scale), depression (Geriatric Depression Scale), and HrQoL (EQ-5D and EQ VAS) were collected. A multiple regression analysis was performed to identify HrQoL-determinants. RESULTS: Among the study participants (n=374), 23 (6.1%) developed poststroke epilepsy. The HrQoL of patients with poststroke epilepsy was reduced in comparison with patients without seizures (24-month follow-up: EuroQol Visual Analogue Scale (EuroQol-VAS): 55.3+/-10.7 versus 64.2+/-11.4, p=0.03). Seizure frequency, depression, and functional impairment (Barthel-Index) were identified as independent determinants of HrQoL. The adjustment of AEDs between 6-month and 24 month follow-ups resulted in decrease of seizure frequency by 40% and reduction of complications (dizziness by 27.8%, nausea by 52.2%, fatigue by 84.2%). CONCLUSION: Lesional epilepsy is associated with decreased HrQoL in patients with stroke. We identified HrQoL-determinants, which would improve the management of patients with poststroke epilepsy. These determinants include proper adjustment of AEDs with reduction of seizure frequency, treatment of depression, and focused rehabilitation programs for poststroke epilepsy. PMID- 29429907 TI - Relationship between office-based provider visits and emergency department encounters among publicly-insured adults with epilepsy. AB - INTRODUCTION: The proportion of adults with epilepsy using the emergency department (ED) is high. Among this patient population, increased frequency of office-based provider visits may be associated with lesser frequency of ED encounters, and key patient features may be linked to more ED encounters. METHODS: We analyzed the Medical Expenditure Panel Survey Household Component (MEPS-HC) dataset for years 2003-2014, which represents a weighted sample of 842,249 publicly-insured US adults aged >=18years. The Hurdle Poisson model that accommodates excess zeros was used to estimate the association between office based and ED visits. RESULTS: Annual mean ED and office-based visits for publicly insured adults with epilepsy were 0.70 and 10.8 respectively. Probability of at least one ED visit was 0.4% higher for every unit of office-based visit. Individuals in the high income category were less likely to visit the ED at least once while women with epilepsy had a higher likelihood of visiting the ED at least once. Among those who visited the ED at least once, there was a 0.3% higher likelihood of visiting the ED for every unit of office-based visit. Among individuals who visited the ED at least once, being aged 45-64years, residing in the West, and the year 2011/14 were associated with higher ED visits. CONCLUSION: In this representative sample of publicly-insured adults with epilepsy, higher frequency of office visits was not associated with lower ED utilization, which may be due to underlying greater disease severity or propensity for more treatment complications. PMID- 29429908 TI - Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center. AB - Medically refractory epilepsy continues to be a challenge worldwide, and despite an increasing number of medical therapies, approximately 1 in 3 patients continues to have seizures. Cannabidiol (CBD), one of many constituents of the Cannabis sativa or marijuana plant, has received renewed interest in the treatment of epilepsy. While highly purified CBD awaits Food and Drug Administration (FDA) approval, artisanal formulations of CBD are readily available and are seeing increased use in our patient population. Although randomized controlled trials of CBD are ongoing and promising, data regarding artisanal formulations of CBD are minimal and largely anecdotal. Here, we report a retrospective study to define the efficacy of artisanal CBD preparations in children with epilepsy. Given the known interaction between CBD and clobazam, we also conducted a subgroup comparison to determine if clobazam use was related to any beneficial effects of CBD. Additionally, we compared response rates with CBD and with clobazam alone within an overlapping patient cohort. A pediatric cohort with epilepsy of 108 patients was identified through a medical record search for patients using CBD oil. The addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The responder rate for clobazam was similar. No patients achieved CBD monotherapy, although the weaning of other antiepileptic drugs (AEDs) became possible in 22% of patients. A comparable proportion had AED additions during CBD therapy. With concomitant use of clobazam, 44% of patients had a 50% reduction in seizures upon addition of CBD compared with 33% in the population not taking clobazam; this difference was not statistically significant. The most common reported side effect of CBD was sedation in less than 4% of patients, all of whom were also taking clobazam. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. Benefits were more marked in the CBD alone group, in contrast to the CBD and clobazam group, but this difference was not statistically significant. In summary, these findings support efficacy of artisanal CBD preparations in seizure reduction with few significant side effects. The response to CBD was independent of concurrent clobazam use, although clobazam may contribute to the sedation seen with concurrent CBD use. PMID- 29429909 TI - Adherence to antiepileptic drugs in adolescents with epilepsy. AB - INTRODUCTION: The aims of the current study were to identify patterns and predictors of adherence in adolescents with epilepsy over one year, as well as its impact on seizures and health-related quality of life (HRQOL). METHODS: Forty eight adolescents with epilepsy (Mage=14.8+1.5, 69% female, 73% White: NonHispanic) and their caregivers completed questionnaires assessing demographics, epilepsy knowledge, side effects, adherence barriers, family functioning, and HRQOL at quarterly clinic visits over one year. Adherence was monitored electronically via MEMS TrackCaps. Seizures were determined via chart review. RESULTS: Baseline adherence was 86.05% and significantly decreased over 12months (b=-2.07, p<0.001). Higher adherence was predicted by higher socioeconomic status (SES) (b=0.04, p<0.05), more side effects (b=0.06, p<0.01), fewer caregiver-reported adherence barriers (b=0.18, p<0.05), and lower family conflict (b=-0.19, p<0.05). Change in adherence over 12months did not significantly predict HRQOL or seizures. CONCLUSIONS: This is the first longitudinal study of objective adherence in adolescents with epilepsy. Given adolescence is a period of vulnerability during development, including declining adherence, caregivers are encouraged to continue collaborating with their adolescents around epilepsy management. Adherence barriers represent an ideal target for intervention and can be implemented in the clinic by frontline providers. Multidisciplinary care can address low SES (social work, financial advocates) and family conflict (psychologists, therapists) in patients with the ultimate goal of optimizing adherence and health outcomes. PMID- 29429911 TI - Tumour-treating fields complement glioblastoma treatment. PMID- 29429910 TI - Natural history of patients with non cirrhotic portal hypertension: Comparison with patients with compensated cirrhosis. AB - BACKGROUND: The knowledge of natural history of patients with portal hypertension (PH) not due to cirrhosis is less well known than that of cirrhotic patients. AIM: To describe the clinical presentation and the outcomes of 89 patients with non-cirrhotic PH (25 with non-cirrhotic portal hypertension, INCPH, and 64 with chronic portal vein thrombosis, PVT) in comparison with 77 patients with Child A cirrhosis. METHODS: The patients were submitted to a standardized clinical, laboratory, ultrasonographic and endoscopic follow-up. Variceal progression, incidence of variceal bleeding, portal vein thrombosis, ascites and survival were recorded. RESULTS: At presentation, the prevalence of varices, variceal bleeding and ascites was similar in the 3 groups. During follow-up, the rate of progression to varices at risk of bleeding (p < 0.0001) and the incidence of first variceal bleeding (p = 0.02) were significantly higher in non-cirrhotic then in cirrhotic patients. A PVT developed in 32% of INCPH patients and in 18% of cirrhotics (p = 0.02). CONCLUSIONS: In the patients with non-cirrhotic PH variceal progression is more rapid and bleeding more frequent than in cirrhotics. Patients with INCPH are particularly prompt to develop PVT. This observational study suggests that the management of patients with non-cirrhotic PH should take into consideration the natural history of portal hypertension in these patients and cannot be simply derived by the observation of cirrhotic patients. PMID- 29429912 TI - Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. AB - BACKGROUND: Multiple myeloma is characterised by monoclonal paraprotein production and osteolytic lesions, commonly leading to skeletal-related events (spinal cord compression, pathological fracture, or surgery or radiotherapy to affected bone). Denosumab, a monoclonal antibody targeting RANKL, reduces skeletal-related events associated with bone lesions or metastases in patients with advanced solid tumours. This study aimed to assess the efficacy and safety of denosumab compared with zoledronic acid for the prevention of skeletal-related events in patients with newly diagnosed multiple myeloma. METHODS: In this international, double-blind, double-dummy, randomised, active-controlled, phase 3 study, patients in 259 centres and 29 countries aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one documented lytic bone lesion were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomisation list with a block size of four) to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (both groups also received investigators' choice of first-line antimyeloma therapy). Stratification was by intent to undergo autologous transplantation, antimyeloma therapy, International Staging System stage, previous skeletal-related events, and region. The clinical study team and patients were masked to treatment assignments. The primary endpoint was non inferiority of denosumab to zoledronic acid with respect to time to first skeletal-related event in the full analysis set (all randomly assigned patients). All safety endpoints were analysed in the safety analysis set, which includes all randomly assigned patients who received at least one dose of active study drug. This study is registered with ClinicalTrials.gov, number NCT01345019. FINDINGS: From May 17, 2012, to March 29, 2016, we enrolled 1718 patients and randomly assigned 859 to each treatment group. The study met the primary endpoint; denosumab was non-inferior to zoledronic acid for time to first skeletal-related event (hazard ratio 0.98, 95% CI 0.85-1.14; pnon-inferiority=0.010). 1702 patients received at least one dose of the investigational drug and were included in the safety analysis (850 patients receiving denosumab and 852 receiving zoledronic acid). The most common grade 3 or worse treatment-emergent adverse events for denosumab and zoledronic acid were neutropenia (126 [15%] vs 125 [15%]), thrombocytopenia (120 [14%] vs 103 [12%]), anaemia (100 [12%] vs 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]). Renal toxicity was reported in 85 (10%) patients in the denosumab group versus 146 (17%) in the zoledronic acid group; hypocalcaemia adverse events were reported in 144 (17%) versus 106 (12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab and zoledronic acid groups (35 [4%] vs 24 [3%]; p=0.147). The most common serious adverse event for both treatment groups was pneumonia (71 [8%] vs 69 [8%]). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related. INTERPRETATION: In patients with newly diagnosed multiple myeloma, denosumab was non-inferior to zoledronic acid for time to skeletal-related events. The results from this study suggest denosumab could be an additional option for the standard of care for patients with multiple myeloma with bone disease. FUNDING: Amgen. PMID- 29429913 TI - CAR T-cells for relapsed B-cell ALL in children and young adults. PMID- 29429914 TI - Selinexor and dexamethasone in multiple myeloma. PMID- 29429915 TI - CAR T-cells for relapsed B-cell ALL in adults. PMID- 29429916 TI - Denosumab for myeloma bone disease: ready for prime time? PMID- 29429917 TI - Cancer-related productivity losses in BRICS countries. PMID- 29429918 TI - 'Spare' Luteinizing Hormone Receptors: Facts and Fiction. AB - It is common opinion that maximal activation of luteinizing hormone (LH) dependent steroidogenic signal occurs at <1% of human LH/choriogonadotropin (hCG) receptor (LHCGR) occupancy. This effect would be a consequence of an excess of receptors expressed on the surface of theca cells, resulting in a pool of LHCGRs remaining unbound (spare). This concept was borrowed from historical pharmacological studies, when discrepancies between ligand-receptor binding and dose-response curves of cAMP were evaluated by treating mouse or rat Leydig cells with hCG in vitro. Recent findings demonstrated the specificity of LH- and hCG dependent effects, receptor heterodimerization, and differing behaviors of rodent versus human gonadotropin-responsive cells, which may help to revise the 'spare' LHCGRs concept applied to human ovarian physiology and assisted reproduction. PMID- 29429919 TI - A letter to our children. PMID- 29429920 TI - Impact of a clinical pathway tool on appropriate palliative radiation therapy for bone metastases. AB - PURPOSE: Clinical pathways increase compliance with treatment guidelines, improve outcomes, and reduce costs. Guidelines recommend single fraction radiation therapy (SFRT) for palliation of uncomplicated bone metastases, but implementation is variable. We examined the effects of a pathway tool on SFRT rates in an academic radiation oncology practice. METHODS AND MATERIALS: Using published literature, clinical guidelines, and expert input, we designed a clinical pathway for bone metastases radiation therapy displayed on a Web-based electronic interface. In March 2016, the pathway launched on a palliative radiation service at the Dana Farber/Brigham and Women's Cancer Center main campus and at affiliated community sites. Providers were surveyed pre- and postimplementation to assess expectations and elicit feedback. Rates of pathway utilization, compliance with SFRT recommendations, and reasons for noncompliance were assessed. RESULTS: The final pathway includes 20 endpoints and several validated prognostic scoring systems. It was used in 38% of 723 bone metastases radiation prescriptions, with appropriate SFRT rates rising from 18% before implementation to 48% after launch (P < .01). Major reasons for rejecting recommendations included disagreement with life expectancy prognostication and patient convenience. The pathway increased physicians' confidence regarding compliance with treatment guidelines and made it easier to find well-supported treatment recommendations. Workflow disruptions and the inability to handle nuanced situations emerged as limitations. CONCLUSIONS: Our experience demonstrates the utility of clinical pathway decision support for bone metastases radiation in complex academic settings. Next steps include increasing the pathway's ease of use, refining the pathway's prognostic abilities, and measuring cost savings related to the pathway. PMID- 29429921 TI - Comparison of lung tumor motion measured using a model-based 4DCT technique and a commercial protocol. AB - PURPOSE: To compare lung tumor motion measured with a model-based technique to commercial 4-dimensional computed tomography (4DCT) scans and describe a workflow for using model-based 4DCT as a clinical simulation protocol. METHODS AND MATERIALS: Twenty patients were imaged using a model-based technique and commercial 4DCT. Tumor motion was measured on each commercial 4DCT dataset and was calculated on model-based datasets for 3 breathing amplitude percentile intervals: 5th to 85th, 5th to 95th, and 0th to 100th. Internal target volumes (ITVs) were defined on the 4DCT and 5th to 85th interval datasets and compared using Dice similarity. Images were evaluated for noise and rated by 2 radiation oncologists for artifacts. RESULTS: Mean differences in tumor motion magnitude between commercial and model-based images were 0.47 +/- 3.0, 1.63 +/- 3.17, and 5.16 +/- 4.90 mm for the 5th to 85th, 5th to 95th, and 0th to 100th amplitude intervals, respectively. Dice coefficients between ITVs defined on commercial and 5th to 85th model-based images had a mean value of 0.77 +/- 0.09. Single standard deviation image noise was 11.6 +/- 9.6 HU in the liver and 6.8 +/- 4.7 HU in the aorta for the model-based images compared with 57.7 +/- 30 and 33.7 +/- 15.4 for commercial 4DCT. Mean model error within the ITV regions was 1.71 +/- 0.81 mm. Model-based images exhibited reduced presence of artifacts at the tumor compared with commercial images. CONCLUSION: Tumor motion measured with the model-based technique using the 5th to 85th percentile breathing amplitude interval corresponded more closely to commercial 4DCT than the 5th to 95th or 0th to 100th intervals, which showed greater motion on average. The model-based technique tended to display increased tumor motion when breathing amplitude intervals wider than 5th to 85th were used because of the influence of unusually deep inhalations. These results suggest that care must be taken in selecting the appropriate interval during image generation when using model-based 4DCT methods. PMID- 29429922 TI - Five years' experience with a customized electronic checklist for radiation therapy planning quality assurance in a multicampus institution. AB - INTRODUCTION: An electronic checklist has been designed with the intention of reducing errors while minimizing user effort in completing the checklist. We analyze the clinical use and evolution of the checklist over the past 5 years and review data in an incident learning system (ILS) to investigate whether it has contributed to an improvement in patient safety. METHODS AND MATERIALS: The checklist is written as a standalone HTML application using VBScript. User selection of pertinent demographic details limits the display of checklist items only to those necessary for the particular clinical scenario. Ten common clinical scenarios were used to illustrate the difference between the maximum possible number of checklist items available in the code versus the number displayed to the user at any one time. An ILS database of errors and near misses was reviewed to evaluate whether the checklist influenced the occurrence of reported events. RESULTS: Over 5 years, the number of checklist items available in the code nearly doubled, whereas the number displayed to the user at any one time stayed constant. Events reported in our ILS related to the beam energy used with pacemakers, projection of anatomy on digitally reconstructed radiographs, orthogonality of setup fields, and field extension beyond match lines, did not recur after the items were added to the checklist. Other events related to bolus documentation and breakpoints continued to be reported. CONCLUSION: Our checklist is adaptable to the introduction of new technologies, transitions between planning systems, and to errors and near misses recorded in the ILS. The electronic format allows us to restrict user display to a small, relevant, subset of possible checklist items, limiting the planner effort needed to review and complete the checklist. PMID- 29429923 TI - Corrigendum to "Diving into the mammalian swamp of respiratory rhythm generation with the bullfrog" [Respir. Physiol. Neurobiol. 224 (2016) 37-51]. PMID- 29429924 TI - The TIA1 RNA-Binding Protein Family Regulates EIF2AK2-Mediated Stress Response and Cell Cycle Progression. AB - TIA1 and TIAL1 encode a family of U-rich element mRNA-binding proteins ubiquitously expressed and conserved in metazoans. Using PAR-CLIP, we determined that both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' as well as 3' splice sites. Double knockout (DKO) of TIA1 and TIAL1 increased target mRNA abundance proportional to the number of binding sites and also caused accumulation of aberrantly spliced mRNAs, most of which are subject to nonsense-mediated decay. Loss of PRKRA by mis-splicing triggered the activation of the double-stranded RNA (dsRNA)-activated protein kinase EIF2AK2/PKR and stress granule formation. Ectopic expression of PRKRA cDNA or knockout of EIF2AK2 in DKO cells rescued this phenotype. Perturbation of maturation and/or stability of additional targets further compromised cell cycle progression. Our study reveals the essential contributions of the TIA1 protein family to the fidelity of mRNA maturation, translation, and RNA-stress-sensing pathways in human cells. PMID- 29429925 TI - A Metabolic Basis for Endothelial-to-Mesenchymal Transition. AB - Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor beta (TGF-beta) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2E-KO) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2E-KO mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions. PMID- 29429927 TI - Postoperative Acute Kidney Injury and Blood Product Transfusion After Synthetic Colloid Use During Cardiac Surgery-A Response to Tobey et al. PMID- 29429926 TI - N6-Methyladenosine Guides mRNA Alternative Translation during Integrated Stress Response. AB - The integrated stress response (ISR) facilitates cellular adaptation to stress conditions via the common target eIF2alpha. During ISR, the selective translation of stress-related mRNAs often relies on alternative mechanisms, such as leaky scanning or reinitiation, but the underlying mechanism remains incompletely understood. Here we report that, in response to amino acid starvation, the reinitiation of ATF4 is not only governed by the eIF2alpha signaling pathway, but is also subjected to regulation by mRNA methylation in the form of N6 methyladenosine (m6A). While depleting m6A demethylases represses ATF4 reinitiation, knocking down m6A methyltransferases promotes ATF4 translation. We demonstrate that m6A in the 5' UTR controls ribosome scanning and subsequent start codon selection. Global profiling of initiating ribosomes reveals widespread alternative translation events influenced by dynamic mRNA methylation. Consistently, Fto transgenic mice manifest enhanced ATF4 expression, highlighting the critical role of m6A in translational regulation of ISR at cellular and organismal levels. PMID- 29429928 TI - Effect of Remote Ischemic Preconditioning on Intestinal Ischemia-Reperfusion Injury in Adults Undergoing On-Pump CABG Surgery: A Randomized Controlled Pilot Trial. AB - OBJECTIVE: Cardiopulmonary bypass (CPB) surgery commonly threatens the heart and remote organs with ischemia-reperfusion injury. Transient episodes of ischemia to nonvital tissue, known as remote ischemic preconditioning (RIPC), is thought to help local and remote vital organs to withstand subsequent ischemic insults. DESIGN: Prospective, randomized, double-blinded control trial. SETTING: Tertiary referral academic teaching hospital. PARTICIPANTS: Thirty patients undergoing elective CPB surgery INTERVENTION: RIPC was achieved via three 5-minute cycles of upper limb ischemia using a blood pressure cuff or control (sham cuff). MEASUREMENTS AND MAIN RESULTS: Primary outcome was the occurrence of intestinal injury, as measured by an increase in intestinal fatty acid binding protein (I FABP). Secondary outcomes included incidence of gastrointestinal complications and duration of intensive care unit (ICU) stay. RIPC did not affect serum IFABP levels at the end of surgery and on the first postoperative day (p = 0.697 and p = 0.461, respectively). For all patients, mean I-FABP levels significantly increased at the end of surgery and decreased to under baseline levels on the first postoperative day (from a mean [+/- standard deviation] baseline value of 764 +/- 492 pg/mL to 2,002 +/- 974 pg/mL and decreased to 568 +/- 319 pg/mL, p < 0.001). All patients remained clinically absent of gastrointestinal complications until hospital discharge. Duration of ICU stay was not correlated with I-FABP levels at the end of surgery. Neither duration of CPB nor duration of aortic clamping significantly correlated with postoperative I-FABP levels. CONCLUSIONS: These findings suggest that RIPC does not affect intestinal injury in patients undergoing CPB surgery. In patients undergoing cardiac surgery, intestinal injury appears to be moderate and transient without any clinical relevant complication. PMID- 29429929 TI - Extracorporeal Membrane Oxygenation-Assisted Airway Management for Difficult Airways. PMID- 29429930 TI - Atypical Presentation of a Large Pericardial Effusion after Heart Transplantation in a Patient with Dilated Cardiomyopathy. PMID- 29429931 TI - Protecting the Right Ventricle in ARDS: The Role of Prone Ventilation. PMID- 29429932 TI - The use of complementary and alternative medicine (CAM) for pregnancy related low back and/ or pelvic girdle pain: An online survey. AB - Low back and pelvic girdle pain (LBPGP) is a common complaint among pregnant women, which increases throughout pregnancy and women use various complementary and alternative medicine (CAM) therapies to manage their pain. Using an online survey, CAM treatments used by pregnant women in the UK and their perceptions of these therapies to relieve LBPGP were investigated. 191 women completed the survey and 70% experienced LBPGP lasting more than one week. Over half of women who sought treatment from a GP or physiotherapist were dissatisfied. 25% of participants used CAM during pregnancy, the most popular being aromatherapy (21%), acupuncture (21%), and reflexology (15%). 81% of women used CAM to manage their LBPGP and 85% found it useful for pregnancy symptoms. Women experience high levels of pain during pregnancy with limited treatment options. Research into effective CAM treatments for LBPGP is required to allow women to make informed decisions regarding treatment options. PMID- 29429933 TI - Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation. AB - Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report that the activity dependent transcription factor Npas4 selectively regulates the structure and strength of MF-CA3 synapses by restricting the number of their functional synaptic contacts without affecting the other synaptic inputs onto CA3 pyramidal neurons. Using an activity-dependent reporter, we identified CA3 pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling the expression of the polo like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation. PMID- 29429934 TI - Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability. AB - Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2-/-) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2-/- mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability. PMID- 29429935 TI - Deconvolution of Voltage Sensor Time Series and Electro-diffusion Modeling Reveal the Role of Spine Geometry in Controlling Synaptic Strength. AB - Most synaptic excitatory connections are made on dendritic spines. But how the voltage in spines is modulated by its geometry remains unclear. To investigate the electrical properties of spines, we combine voltage imaging data with electro diffusion modeling. We first present a temporal deconvolution procedure for the genetically encoded voltage sensor expressed in hippocampal cultured neurons and then use electro-diffusion theory to compute the electric field and the current voltage conversion. We extract a range for the neck resistances of =100+/ 35MOmega. When a significant current is injected in a spine, the neck resistance can be inversely proportional to its radius, but not to the radius square, as predicted by Ohm's law. We conclude that the postsynaptic voltage cannot only be modulated by changing the number of receptors, but also by the spine geometry. Thus, spine morphology could be a key component in determining synaptic transduction and plasticity. PMID- 29429936 TI - alpha-Actinin Anchors PSD-95 at Postsynaptic Sites. AB - Despite the central role PSD-95 plays in anchoring postsynaptic AMPARs, how PSD 95 itself is tethered to postsynaptic sites is not well understood. Here we show that the F-actin binding protein alpha-actinin binds to the very N terminus of PSD-95. Knockdown (KD) of alpha-actinin phenocopies KD of PSD-95. Mutating lysine at position 10 or lysine at position 11 of PSD-95 to glutamate, or glutamate at position 53 or glutamate and aspartate at positions 213 and 217 of alpha-actinin, respectively, to lysine impairs, in parallel, PSD-95 binding to alpha-actinin and postsynaptic localization of PSD-95 and AMPARs. These experiments identify alpha actinin as a critical PSD-95 anchor tethering the AMPAR-PSD-95 complex to postsynaptic sites. PMID- 29429937 TI - A Calmodulin C-Lobe Ca2+-Dependent Switch Governs Kv7 Channel Function. AB - Kv7 (KCNQ) voltage-gated potassium channels control excitability in the brain, heart, and ear. Calmodulin (CaM) is crucial for Kv7 function, but how this calcium sensor affects activity has remained unclear. Here, we present X-ray crystallographic analysis of CaM:Kv7.4 and CaM:Kv7.5 AB domain complexes that reveal an Apo/CaM clamp conformation and calcium binding preferences. These structures, combined with small-angle X-ray scattering, biochemical, and functional studies, establish a regulatory mechanism for Kv7 CaM modulation based on a common architecture in which a CaM C-lobe calcium-dependent switch releases a shared Apo/CaM clamp conformation. This C-lobe switch inhibits voltage dependent activation of Kv7.4 and Kv7.5 but facilitates Kv7.1, demonstrating that mechanism is shared by Kv7 isoforms despite the different directions of CaM modulation. Our findings provide a unified framework for understanding how CaM controls different Kv7 isoforms and highlight the role of membrane proximal domains for controlling voltage-gated channel function. VIDEO ABSTRACT. PMID- 29429938 TI - Signaling Mode of the Broad-Spectrum Conserved CO2 Receptor Is One of the Important Determinants of Odor Valence in Drosophila. AB - Odor detection involves hundreds of olfactory receptors from diverse families, making modeling of hedonic valence of an odorant difficult, even in Drosophila melanogaster where most receptors have been deorphanised. We demonstrate that a broadly tuned heteromeric receptor that detects CO2 (Gr21a, Gr63a) and other odorants is a key determinant of valence along with a few members of the Odorant receptor family in a T-maze, but not in a trap assay. Gr21a and Gr63a have atypically high amino acid conservation in Dipteran insects, and they use both inhibition and activation to convey positive or negative valence for numerous odorants. Inhibitors elicit a robust Gr63a-dependent attraction, while activators, strong aversion. The attractiveness of inhibitory odorants increases with increasing background CO2 levels, providing a mechanism for behavior modulation in odor blends. In mosquitoes, valence is switched and activation of the orthologous receptor conveys attraction. Reverse chemical ecology enables the identification of inhibitory odorants to reduce attraction of mosquitoes to skin. PMID- 29429940 TI - Review of Novel Sentinel Lymph Node Biopsy Techniques in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy. AB - Breast cancer patients who present with nodal metastasis receive neoadjuvant chemotherapy (NAC) with increasing frequency and can have complete pathologic response after treatment. In this clinical scenario, sentinel node mapping and biopsy are gaining acceptance instead of axillary dissection to avoid morbidity. Biopsy proven positive lymph nodes must be reliably excised and examined after NAC to further decrease the false negativity rate of sentinel lymph node (SLN) surgery. The standard method for axillary staging in breast cancer patients even after NAC is SLN biopsy (SLNB) with a radioisotope, blue dye, or both (dual technique). Currently, preoperative axillary staging with ultrasound and biopsy, along with placement of an image-detectable marker to be removed at the time of definitive surgery is recommended. In this study, we evaluated some methods of SLNB for patients treated with NAC like indocyanine green fluorescence, superparamagnetic iron oxide nanoparticles, indigocarmine blue dye, contrast enhanced ultrasound using microbubbles, and tattooing. Some methods are also needed to ensure that the initially biopsy proven positive node is removed at the time of surgery to be carefully evaluated for residual disease after chemotherapy like clip placement to the suspected or involved nodes before NAC, and removing the clipped node with the guidance of 125I-labeled radioactive seed or guide wires. PMID- 29429939 TI - An Attractive Reelin Gradient Establishes Synaptic Lamination in the Vertebrate Visual System. AB - A conserved organizational and functional principle of neural networks is the segregation of axon-dendritic synaptic connections into laminae. Here we report that targeting of synaptic laminae by retinal ganglion cell (RGC) arbors in the vertebrate visual system is regulated by a signaling system relying on target derived Reelin and VLDLR/Dab1a on the projecting neurons. Furthermore, we find that Reelin is distributed as a gradient on the target tissue and stabilized by heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM). Through genetic manipulations, we show that this Reelin gradient is important for laminar targeting and that it is attractive for RGC axons. Finally, we suggest a comprehensive model of synaptic lamina formation in which attractive Reelin counter-balances repulsive Slit1, thereby guiding RGC axons toward single synaptic laminae. We establish a mechanism that may represent a general principle for neural network assembly in vertebrate species and across different brain areas. PMID- 29429941 TI - Quantitative analysis of composite umbilical cord tissue health using a standardized explant approach and an assay of metabolic activity. AB - BACKGROUND: Umbilical cord (UC) tissue can be collected in a noninvasive procedure and is enriched in progenitor cells with potential therapeutic value. Mesenchymal stromal cells (MSCs) can be reliably harvested from fresh or cryopreserved UC tissue by explant outgrowth with no apparent impact on functionality. A number of stem cell banks offer cryopreservation of UC tissue, alongside cord blood, for future cell-based applications. In this setting, measuring and monitoring UC quality is critical. MATERIALS AND METHODS: UC explants were evaluated using a plating and scoring system accounting for cell attachment and proliferation. Explant scores for fresh and cryopreserved-then thawed tissue from the same UC were compared. Metabolic activity of composite UC tissue was also assayed after exposure of the tissue to conditions anticipated to affect UC quality and compared with explant scores within the same UC. RESULTS: All fresh and cryopreserved tissues yielded MSC-like cells, and cryopreservation of the tissue did not prevent the ability to isolate MSCs by the explant method. Thawed UC tissue scores were 91% (+/-0.6%; P = 0.0009) that of the fresh, biologically identical tissue. Within the same UC, explant scores correlated well to both cell yield (R2 = 0.85) and tissue metabolic activity (R2 = 0.69). DISCUSSION: A uniform explant scoring assay can provide information about the quality of composite UC tissue. Such quantitative measurement is useful for analysis of tissue variability and process monitoring. Additionally, a metabolic assay of UC tissue health provides results that correlate well to explant scoring results. PMID- 29429942 TI - Pooled human serum: A new culture supplement for bioreactor-based cell therapies. Preliminary results. AB - BACKGROUND: Bone Marrow MSCs are an appealing source for several cell-based therapies. Many bioreactors, as the Quantum Cell Expansion System, have been developed to generate a large number of MSCs under Good Manufacturing Practice conditions by using Human Platelet Lysate (HPL). Previously we isolated in the human bone marrow a novel cell population, named Mesodermal Progenitor Cells (MPCs), which we identified as precursors of MSCs. MPCs could represent an important cell source for regenerative medicine applications. As HPL gives rise to a homogeneus MSC population, limiting the harvesting of other cell types, in this study we investigated the efficacy of pooled human AB serum (ABS) to provide clinically relevant numbers of both MSCs and MPCs for regenerative medicine applications by using the Quantum System. METHODS: Bone marrow aspirates were obtained from healthy adult individuals undergoing routine total hip replacement surgery and used to generate primary cultures in the bioreactor. HPL and ABS were tested as supplements to culture medium. Morphological observations, cytofluorimetric analysis, lactate and glucose level assessment were performed. RESULTS: ABS gave rise to both heterogeneous MSC and MPC population. About 95% of cells cultured in HPL showed a fibroblast-like morphology and typical mesenchymal surface markers, but MPCs were scarcely represented. DISCUSSION: The use of ABS appeared to sustain a large scale MSC production, as well as the recovery of a subset of MPCs, and resulted a suitable alternative to HPL in the cell generation based on the Quantum System. PMID- 29429943 TI - CD157 Marks Tissue-Resident Endothelial Stem Cells with Homeostatic and Regenerative Properties. AB - The generation of new blood vessels via angiogenesis is critical for meeting tissue oxygen demands. A role for adult stem cells in this process remains unclear. Here, we identified CD157 (bst1, bone marrow stromal antigen 1) as a marker of tissue-resident vascular endothelial stem cells (VESCs) in large arteries and veins of numerous mouse organs. Single CD157+ VESCs form colonies in vitro and generate donor-derived portal vein, sinusoids, and central vein endothelial cells upon transplantation in the liver. In response to injury, VESCs expand and regenerate entire vasculature structures, supporting the existence of an endothelial hierarchy within blood vessels. Genetic lineage tracing revealed that VESCs maintain large vessels and sinusoids in the normal liver for more than a year, and transplantation of VESCs rescued bleeding phenotypes in a mouse model of hemophilia. Our findings show that tissue-resident VESCs display self-renewal capacity and that vascular regeneration potential exists in peripheral blood vessels. PMID- 29429945 TI - Could Failure in Preimplantation Genetic Diagnosis Justify Editing the Human Embryo Genome? PMID- 29429946 TI - Physician Gender Is Associated with Press Ganey Patient Satisfaction Scores in Outpatient Gynecology. AB - BACKGROUND: Patient satisfaction is gaining increasing attention as a quality measure in health care, but the methods used to assess it may negatively impact women physicians. OBJECTIVE: Our objective was to examine the relationship between physician gender and patient satisfaction with outpatient gynecology care as measured by the Press Ganey patient satisfaction survey. STUDY DESIGN: This cross-sectional study analyzed 909 Press Ganey patient satisfaction surveys linked to outpatient gynecology visits at a single academic institution (March 2013-August 2014), including self-reported demographics and satisfaction. Surveys are delivered in a standardized fashion electronically and by mail. Surveys were completed by 821 unique patients and 13,780 gynecology visits occurred during the study period. The primary outcome variable was likelihood to recommend (LTR) a physician. We used chi2 tests of independence to assess the effect of demographic concordance on LTR and two generalized estimating equations models were run clustered by physician, with topbox physician LTR as the outcome variable. Analysis was performed in SAS Enterprise Guide 7.1 (SAS, Inc., Cary, NC). RESULTS: Nine hundred nine surveys with complete demographic data were completed by women during the study period (mean age, 49.3 years). Age- and race-concordant patient-physician pairs received significantly higher proportions of top LTR score than discordant pairs (p = .014 and p < .0001, respectively). In contrast, gender-concordant pairs received a significantly lower proportion of top scores than discordant pairs (p = .027). In the generalized estimating equations model adjusting for health care environment, only gender remained statistically significant. Women physicians had significantly lower odds (47%) of receiving a top score (odds ratio, 0.53; 95% CI, 0.37-0.78; p = .001). CONCLUSIONS: Women gynecologists are 47% less likely to receive top patient satisfaction scores compared with their male counterparts owing to their gender alone, suggesting that gender bias may impact the results of patient satisfaction questionnaires. Therefore, the results of this and similar questionnaires should be interpreted with great caution until the impact on women physicians is better understood. PMID- 29429944 TI - Engineering Stem and Stromal Cell Therapies for Musculoskeletal Tissue Repair. AB - Stem cells and tissue-derived stromal cells stimulate the repair of degenerated and injured tissues, motivating a growing number of cell-based interventions in the musculoskeletal field. Recent investigations have indicated that these cells are critical for their trophic and immunomodulatory role in controlling endogenous cells. This Review presents recent clinical advances where stem cells and stromal cells have been used to stimulate musculoskeletal tissue repair, including delivery strategies to improve cell viability and retention. Emerging bioengineering strategies are highlighted, particularly toward the development of biomaterials for capturing aspects of the native tissue environment, altering the healing niche, and recruiting endogenous cells. PMID- 29429947 TI - Hospital readmission rates and risk factors for readmission following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal surface malignancies. AB - BACKGROUND: Cytoreductive surgery and Hyperthermic intra-peritoneal chemotherapy (CRS/HIPEC) for peritoneal surface malignancies is associated with high morbidity. The increased numbers of patients undergoing CRS/HIPEC in recent years mandates risk analysis and quality assurance. However, only scarce data exist regarding causative parameters for readmission. The aim of this study was to assess readmission rates and risk factors associated with readmission. METHODS: A retrospective-cohort study including patients from two high-volume centers who underwent CRS/HIPEC surgery between the years 2007-2016 was performed. Patients' demographics, peri-operative data and readmission rates were recorded. RESULTS: 223 patients were included in the study. The 7 and 30-day readmission rates were 3.5% (n = 8) and 11% (n = 25), respectively. Late readmission rates (up to 90 days) were 11% (n = 25). The most common causes of readmission were surgical related infections (35%), small bowel obstruction (17.5%) and dehydration (14%). Post-operative complications were associated with higher readmission rates (p = 0.0001). PCI score was not associated with higher rates of readmission. CONCLUSION: Readmissions following CRS/HIPEC occur mainly due to infectious complications and dehydrations. Patients following CRS/HIPEC should be discharged after careful investigation to a community based continuing care with access for IV fluid replacement or antibiotics administration when required. PMID- 29429948 TI - Virtual-reality-based cognitive behavioural therapy versus waiting list control for paranoid ideation and social avoidance in patients with psychotic disorders: a single-blind randomised controlled trial. AB - BACKGROUND: Many patients with psychotic disorders have persistent paranoid ideation and avoid social situations because of suspiciousness and anxiety. We investigated the effects of virtual-reality-based cognitive behavioural therapy (VR-CBT) on paranoid thoughts and social participation. METHODS: In this randomised controlled trial at seven Dutch mental health centres, outpatients aged 18-65 years with a DSM-IV-diagnosed psychotic disorder and paranoid ideation in the past month were randomly assigned (1:1) via block randomisation to VR-CBT (in addition to treatment as usual) or the waiting list control group (treatment as usual). VR-CBT consisted of 16 individual therapy sessions (each 1 h long). Assessments were done at baseline, after treatment (ie, 3 months from baseline), and at a 6 month follow-up visit. The primary outcome was social participation, which we operationalised as the amount of time spent with other people, momentary paranoia, perceived social threat, and momentary anxiety. Analysis was by intention to treat. This trial was retrospectively registered with ISRCTN, number 12929657. FINDINGS: Between April 1, 2014, and Dec 31, 2015, 116 patients with a psychotic disorder were randomly assigned, 58 to the VR-CBT group and 58 to the waiting list control group. Compared with the control, VR-CBT did not significantly increase the amount of time spent with other people at the post treatment assessment. Momentary paranoid ideation (b=-0.331 [95% CI -0.432 to 0.230], p<0.0001; effect size -1.49) and momentary anxiety (-0.288 [-0.438 to 0.1394]; p=0.0002; -0.75) were significantly reduced in the VR-CBT group compared with the control group at the post-treatment assessment, and these improvements were maintained at the follow-up assessment. Safety behaviour and social cognition problems were mediators of change in paranoid ideation. No adverse events were reported relating to the therapy or assessments. INTERPRETATION: Our results suggest that the addition of VR-CBT to standard treatment can reduce paranoid ideation and momentary anxiety in patients with a psychotic disorder. FUNDING: Fonds NutsOhra, Stichting tot Steun VCVGZ. PMID- 29429949 TI - Virtual-reality-assisted therapy in patients with psychosis. PMID- 29429950 TI - Integrating mental and physical health care: the mind and body approach. PMID- 29429951 TI - Intraperitoneal insulin therapy in patients with type 1 diabetes. Does it fit into the current therapeutic arsenal? PMID- 29429952 TI - Primary hyperparathyroidism diagnosed and treated surgically during pregnancy. PMID- 29429953 TI - Post-operative deep brain stimulation assessment: Automatic data integration and report generation. AB - BACKGROUND: The gold standard for post-operative deep brain stimulation (DBS) parameter tuning is a monopolar review of all stimulation contacts, a strategy being challenged by recent developments of more complex electrode leads. OBJECTIVE: Providing a method to guide clinicians on DBS assessment and parameter tuning by automatically integrating patient individual data. METHODS: We present a fully automatic method for visualization of individual deep brain structures in relation to a DBS lead by combining precise electrode recovery from post operative imaging with individual estimates of deep brain morphology utilizing a 7T-MRI deep brain atlas. RESULTS: The method was evaluated on 20 STN DBS cases. It demonstrated robust automatic creation of 3D-enabled PDF reports visualizing electrode to brain structure relations and proved valuable in detecting miss placed electrodes. DISCUSSION: Automatic DBS assessment is feasible and can conveniently provide clinicians with relevant information on DBS contact positions in relation to important anatomical structures. PMID- 29429954 TI - Report of transient events in a cocaine-dependent volunteer who received iTBS. PMID- 29429955 TI - Corrigendum to "Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA" [Tuberculosis 107 (December 2017) 133-136]. PMID- 29429956 TI - Response to Letter to editor "2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults". PMID- 29429957 TI - A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells. AB - Human pluripotent stem cells (hPSCs) maintain a highly fragmented mitochondrial network, but the mechanisms regulating this phenotype remain unknown. Here, we describe a non-cell death function of the anti-apoptotic protein, MCL-1, in regulating mitochondrial dynamics and promoting pluripotency of stem cells. MCL-1 is induced upon reprogramming, and its inhibition or knockdown induces dramatic changes to the mitochondrial network as well as loss of the key pluripotency transcription factors, NANOG and OCT4. Aside from localizing at the outer mitochondrial membrane like other BCL-2 family members, MCL-1 is unique in that it also resides at the mitochondrial matrix in pluripotent stem cells. Mechanistically, we find MCL-1 to interact with DRP-1 and OPA1, two GTPases responsible for remodeling the mitochondrial network. Depletion of MCL-1 compromised the levels and activity of these key regulators of mitochondrial dynamics. Our findings uncover an unexpected, non-apoptotic function for MCL-1 in the maintenance of mitochondrial structure and stemness. PMID- 29429958 TI - Human iPSC-Derived Posterior Gut Progenitors Are Expandable and Capable of Forming Gut and Liver Organoids. AB - Early endoderm progenitors naturally possess robust propagating potential to develop a majority of meter-long gastrointestinal tracts and are therefore considered as a promising source for therapy. Here, we demonstrated the reproducible generation of human CDX2+ posterior gut endoderm cells (PGECs) from five induced pluripotent stem cell clones by manipulating FGF, TGF, and WNT signaling. Transcriptome analysis suggested that putative PGECs harbored an intermediate signature profile between definitive endoderm and organ-specific endoderm. We found that combinatorial EGF, VEGF, FGF2, Chir99021, and A83-01 treatments selectively amplify storable PGECs up to 1021 cell scale without any gene transduction or feeder use. PGECs, compared with induced pluripotent stem cells, showed stable differentiation propensity into multiple endodermal lineages without teratoma formation. Furthermore, transplantation of PGEC-derived liver bud organoids showed therapeutic potential against fulminant liver failure. Together, the robustly amplified PGECs may be a promising cellular source for endoderm-derived organoids in studying human development, modeling disease, and, ultimately, therapy. PMID- 29429959 TI - Low Resting Membrane Potential and Low Inward Rectifier Potassium Currents Are Not Inherent Features of hiPSC-Derived Cardiomyocytes. AB - Human induced pluripotent stem cell (hiPSC) cardiomyocytes (CMs) show less negative resting membrane potential (RMP), which is attributed to small inward rectifier currents (IK1). Here, IK1 was measured in hiPSC-CMs (proprietary and commercial cell line) cultured as monolayer (ML) or 3D engineered heart tissue (EHT) and, for direct comparison, in CMs from human right atrial (RA) and left ventricular (LV) tissue. RMP was measured in isolated cells and intact tissues. IK1 density in ML- and EHT-CMs from the proprietary line was similar to LV and RA, respectively. IK1 density in EHT-CMs from the commercial line was 2-fold smaller than in the proprietary line. RMP in EHT of both lines was similar to RA and LV. Repolarization fraction and IK,ACh response discriminated best between RA and LV and indicated predominantly ventricular phenotype in hiPSC-CMs/EHT. The data indicate that IK1 is not necessarily low in hiPSC-CMs, and technical issues may underlie low RMP in hiPSC-CMs. PMID- 29429960 TI - ADAM8 Is an Antigen of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia Cells Identified by Patient-Derived Induced Pluripotent Stem Cells. AB - Properties of cancer stem cells involved in drug resistance and relapse have significant effects on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myeloid leukemia (CML), TKIs have not fully cured CML due to TKI-resistant CML stem cells. Moreover, relapse after discontinuation of TKIs has not been predicted in CML patients with the best TKI response. In our study, a model of CML stem cells derived from CML induced pluripotent stem cells identified ADAM8 as an antigen of TKI-resistant CML cells. The inhibition of expression or metalloproteinase activity of ADAM8 restored TKI sensitivity in primary samples. In addition, residual CML cells in patients with optimal TKI response were concentrated in the ADAM8+ population. Our study demonstrates that ADAM8 is a marker of residual CML cells even in patients with optimal TKI response and would be a predictor of relapse and a therapeutic target of TKI-resistant CML cells. PMID- 29429961 TI - Generation of Functioning Nephrons by Implanting Human Pluripotent Stem Cell Derived Kidney Progenitors. AB - Human pluripotent stem cells (hPSCs) hold great promise for understanding kidney development and disease. We reproducibly differentiated three genetically distinct wild-type hPSC lines to kidney precursors that underwent rudimentary morphogenesis in vitro. They expressed nephron and collecting duct lineage marker genes, several of which are mutated in human kidney disease. Lentiviral transduced hPSCs expressing reporter genes differentiated similarly to controls in vitro. Kidney progenitors were subcutaneously implanted into immunodeficient mice. By 12 weeks, they formed organ-like masses detectable by bioluminescence imaging. Implants included perfused glomeruli containing human capillaries, podocytes with regions of mature basement membrane, and mesangial cells. After intravenous injection of fluorescent low-molecular-weight dextran, signal was detected in tubules, demonstrating uptake from glomerular filtrate. Thus, we have developed methods to trace hPSC-derived kidney precursors that formed functioning nephrons in vivo. These advances beyond in vitro culture are critical steps toward using hPSCs to model and treat kidney diseases. PMID- 29429963 TI - Impact of comorbidity on tolerability and survival following curative intent intensity modulated radiotherapy in older patients with nasopharyngeal cancer. AB - OBJECTIVE: This study aimed to evaluate the predictive factors for survival and acute toxicities in older patients with NPC treated with curative intent IMRT. MATERIALS AND METHODS: Older patients aged 65 years and above with non-metastatic NPC treated with curative intent IMRT between 2003 and 2013 were retrospectively analysed. Variables examined were gender, age, overall stage, chemotherapy use, Eastern Cooperative Oncology Group (ECOG) performance status and comorbidity. The comorbidity severity was determined by adult comorbidity evaluation (ACE-27). We considered hospitalization or placement of feeding tube during and up to one month post radiotherapy as surrogate endpoint for significant acute toxicities. Other endpoints examined were: OS (overall survival), DFS (disease free survival), DSS (disease specific survival). RESULTS: A total of 185 patients were eligible for analysis. Median age was 70 (65-86 years). Most of the patients presented with Stage III and IVA/B (n = 127, 68.7%), of good performance status of ECOG 0-1 (n = 176, 95.1%) and had low comorbidities with ACE-27 score of 0-1 (n = 141, 76.2%). Chemotherapy was delivered to 84 patients (45.4%). OS, DFS, and DSS were 64.5%, 51.4%, and 72.8% respectively. High comorbidity burden but not chemotherapy had significant impact on OS and DFS in patients with advanced stage. Fifty patients (27%) required tube feeding or hospitalization during the course of RT. Males, chemotherapy use and ECOG score >=2 were significant predictors of tube feeding or hospitalization during RT. CONCLUSION: Curative IMRT was associated with excellent survival outcomes in older patients with NPC. Comorbidity but not chemotherapy was associated with prognosis in advanced stage. Careful monitoring and intensive support should be instituted in older males with ECOG score >=2 receiving chemo-radiotherapy. PMID- 29429962 TI - The Satellite Cell Niche Regulates the Balance between Myoblast Differentiation and Self-Renewal via p53. AB - Satellite cells are adult muscle stem cells residing in a specialized niche that regulates their homeostasis. How niche-generated signals integrate to regulate gene expression in satellite cell-derived myoblasts is poorly understood. We undertook an unbiased approach to study the effect of the satellite cell niche on satellite cell-derived myoblast transcriptional regulation and identified the tumor suppressor p53 as a key player in the regulation of myoblast quiescence. After activation and proliferation, a subpopulation of myoblasts cultured in the presence of the niche upregulates p53 and fails to differentiate. When satellite cell self-renewal is modeled ex vivo in a reserve cell assay, myoblasts treated with Nutlin-3, which increases p53 levels in the cell, fail to differentiate and instead become quiescent. Since both these Nutlin-3 effects are rescued by small interfering RNA-mediated p53 knockdown, we conclude that a tight control of p53 levels in myoblasts regulates the balance between differentiation and return to quiescence. PMID- 29429964 TI - Endocytosis as a stabilizing mechanism for tissue homeostasis. AB - Cells in tissues communicate by secreted growth factors (GF) and other signals. An important function of cell circuits is tissue homeostasis: maintaining proper balance between the amounts of different cell types. Homeostasis requires negative feedback on the GFs, to avoid a runaway situation in which cells stimulate each other and grow without control. Feedback can be obtained in at least two ways: endocytosis in which a cell removes its cognate GF by internalization and cross-inhibition in which a GF down-regulates the production of another GF. Here we ask whether there are design principles for cell circuits to achieve tissue homeostasis. We develop an analytically solvable framework for circuits with multiple cell types and find that feedback by endocytosis is far more robust to parameter variation and has faster responses than cross inhibition. Endocytosis, which is found ubiquitously across tissues, can even provide homeostasis to three and four communicating cell types. These design principles form a conceptual basis for how tissues maintain a healthy balance of cell types and how balance may be disrupted in diseases such as degeneration and fibrosis. PMID- 29429965 TI - Mast cells promote small bowel cancer in a tumor stage-specific and cytokine dependent manner. AB - Mast cells (MCs) are tissue resident sentinels that mature and orchestrate inflammation in response to infection and allergy. While they are also frequently observed in tumors, the contribution of MCs to carcinogenesis remains unclear. Here, we show that sequential oncogenic events in gut epithelia expand different types of MCs in a temporal-, spatial-, and cytokine-dependent manner. The first wave of MCs expands focally in benign adenomatous polyps, which have elevated levels of IL-10, IL-13, and IL-33, and are rich in type-2 innate lymphoid cells (ILC2s). These vanguard MCs adhere to the transformed epithelial cells and express murine mast cell protease 2 (mMCP2; a typical mucosal MC protease) and, to a lesser extent, the connective tissue mast cell (CTMC) protease mMCP6. Persistence of MCs is strictly dependent on T cell-derived IL-10, and their loss in the absence of IL-10-expressing T cells markedly delays small bowel (SB) polyposis. MCs expand profusely in polyposis-prone mice when T cells overexpress IL-10. The frequency of polyp-associated MCs is unaltered in response to broad spectrum antibiotics, arguing against a microbial component driving their recruitment. Intriguingly, when polyps become invasive, a second wave of mMCP5+/mMCP6+ CTMCs expands in the tumor stroma and at invasive tumor borders. Ablation of mMCP6 expression attenuates polyposis, but invasive properties of the remaining lesions remain intact. Our findings argue for a multistep process in SB carcinogenesis in which distinct MC subsets, and their elaborated proteases, guide disease progression. PMID- 29429966 TI - Transformation of Summary Statistics from Linear Mixed Model Association on All or-None Traits to Odds Ratio. AB - Genome-wide association studies (GWAS) have identified thousands of loci that are robustly associated with complex diseases. The use of linear mixed model (LMM) methodology for GWAS is becoming more prevalent due to its ability to control for population structure and cryptic relatedness and to increase power. The odds ratio (OR) is a common measure of the association of a disease with an exposure (e.g., a genetic variant) and is readably available from logistic regression. However, when the LMM is applied to all-or-none traits it provides estimates of genetic effects on the observed 0-1 scale, a different scale to that in logistic regression. This limits the comparability of results across studies, for example in a meta-analysis, and makes the interpretation of the magnitude of an effect from an LMM GWAS difficult. In this study, we derived transformations from the genetic effects estimated under the LMM to the OR that only rely on summary statistics. To test the proposed transformations, we used real genotypes from two large, publicly available data sets to simulate all-or-none phenotypes for a set of scenarios that differ in underlying model, disease prevalence, and heritability. Furthermore, we applied these transformations to GWAS summary statistics for type 2 diabetes generated from 108,042 individuals in the UK Biobank. In both simulation and real-data application, we observed very high concordance between the transformed OR from the LMM and either the simulated truth or estimates from logistic regression. The transformations derived and validated in this study improve the comparability of results from prospective and already performed LMM GWAS on complex diseases by providing a reliable transformation to a common comparative scale for the genetic effects. PMID- 29429967 TI - Primary central nervous system vasculitis associated with lymphoma. AB - OBJECTIVES: To record the clinical findings, response to therapy, and course of patients with primary CNS vasculitis (PCNSV) associated with lymphoma. PATIENTS AND METHODS: We reviewed the histories of 936 patients with a diagnosis of any type of vasculitis and lymphoma who were seen at the Mayo Clinic over a 32-year period. Ten patients with both PCNSV and lymphoma were identified. We compared the findings in these 10 patients with those from 158 patients with PCNSV without lymphoma seen over 29 years. RESULTS: Ten of a total of 168 (5.9%) patients with PCNSV also had a history of lymphoma: 6 with Hodgkin lymphoma (HL) and 4 with non HL (NHL). A granulomatous vasculitis was found in all 8 patients with cerebral biopsies, accompanied by vascular deposits of beta-amyloid peptide in 2. In 7 patients, medical diagnostic workup for PCNSV revealed the lymphoma. Compared to the 158 patients with PCNSV without lymphoma, patients with lymphoma were more frequently male (p = 0.04), had increased gadolinium leptomeningeal enhancement (p = 0.03) at presentation, and had more neurologic disability at last follow-up (p = 0.01). No significant differences in treatment response were observed in the 2 groups (p = 0.202). Considering all 168 patients, increased disability at last follow-up was associated with increasing age at diagnosis (odds ratio [OR] 1.4), lymphoma (OR 5.9), and cerebral infarction (OR 3.2), while reduced disability was associated with gadolinium-enhanced lesions (OR 0.43) and amyloid angiopathy (OR O.23). CONCLUSIONS: Lymphoma may be diagnosed simultaneously with PCNSV, suggesting an immunologic paraneoplastic mechanism. PMID- 29429968 TI - Inherited neuropathy precision classification: What's in a name? PMID- 29429969 TI - Updating the classification of inherited neuropathies: Results of an international survey. AB - OBJECTIVE: The continual discovery of disease-causing gene mutations has led to difficulties in the complex classification of Charcot-Marie-Tooth diseases (CMT) that needs to be revised. METHODS: We recently published a proposal to update the classification of inherited neuropathies. The reactions from colleagues prompted us to diffuse the proposal and ask people if they would be ready for such a change. We therefore performed an internet survey (from October 1, 2016, to December 1, 2016) that included more than 300 CMT worldwide specialists (practitioners and scientists) from various countries. A questionnaire (with proposals to update and simplify the way in which CMT is classified) was sent by e-mail to all participants in the last International Charcot-Marie-Tooth and Related Neuropathy Consortium meeting held in Venice, September 8-10, 2016 (as identified through an e-mail list). RESULTS: Of the 107 CMT specialists who answered the survey, 65% considered that changes are needed and that our proposals constituted an improvement over the historical classification of CMT. CONCLUSIONS: Based on recent proposals in the medical literature, these results highlight that most specialists think that changes are needed to the classification of CMT. PMID- 29429970 TI - Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era. AB - OBJECTIVE: To determine the rate of relapse occurrence during pregnancy and postpartum. METHODS: In a cross-sectional study using the national multiple sclerosis (MS) registry, pregnant women with relapsing MS were identified. Data on demographics, clinical characteristics, and disease-modifying therapies (DMTs), including washout periods, were collected. Timings and durations of relapses were extracted. A multivariate logistic regression was used to assess the relationship between relapses and prior use of different DMTs. RESULTS: Completed data were available for 99 pregnancies (87 patients). Mean age and mean age at onset were 31.8 +/- 5 and 24.4 +/- 5.6 years, respectively, while the mean disease duration was 7.4 +/- 4.6 years. Most pregnancies (89.9%) occurred in patients who were on DMTs in the year preceding pregnancy with a mean treatment duration of 63.4 +/- 29 months. The rates of occurrence of relapses during pregnancy and postpartum were 17.2% and 13.7%, respectively. Most of the relapses occurred during the first (n = 6) and third (n = 7) trimesters. Rate of relapse was highest among patients receiving natalizumab and fingolimod before pregnancy. A longer washout period was significantly associated with relapse occurrence. CONCLUSION: The relapse occurrence during pregnancy is higher than the previously published rates. The use of high-efficacy therapies with long washout periods before conception was associated with an increased risk of relapses during pregnancy. Postpartum relapse occurrence was similar to that in previous reports. PMID- 29429973 TI - Sifting through a failed Alzheimer trial: What biomarkers tell us about what happened. PMID- 29429972 TI - Neurogranin as a predictor of memory and executive function decline in MCI patients. AB - OBJECTIVE: To determine whether high CSF levels of neurogranin (Ng) predict longitudinal decline in memory and executive function during early-stage Alzheimer disease (AD). METHODS: Baseline levels of CSF Ng were studied in relation to cross-sectional and longitudinal cognitive performance over 8 years. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database, and participants with normal cognition (n = 111) and mild cognitive impairment (MCI) (n = 193) were included. RESULTS: High levels of CSF Ng were associated with poor baseline memory scores (beta = -0.21, p < 0.0001). CSF Ng predicted both memory and executive function decline over time (beta = -0.0313, p = 0.0068 and beta = -0.0346, p = 0.0169, respectively) independently of age, sex, education, and APOE epsilon4 status. When the rate of decline by tertiles was examined, CSF Ng was a level-dependent predictor of memory function, whereby the group with highest levels of Ng showed the fastest rates of decline in both memory and executive function. When examined separately, elevated Ng was associated with cognitive decline in participants with MCI but not in those with normal cognition. The levels of CSF Ng were not associated with cognitive measures when tau and amyloid 42 (Abeta42) were controlled for in these analyses. CONCLUSIONS: High CSF Ng associates with poor memory scores in participants with MCI cross-sectionally and with poor memory and executive function longitudinally. The association of Ng with cognitive measures disappears when tau and Abeta42 are included in the statistical models. Our findings suggest that CSF Ng may serve as a biomarker of cognition. Synaptic dysfunction contributes to cognitive impairment in early-stage AD. PMID- 29429974 TI - A benchmark approach to hemorrhage risk management of cavernous malformations. AB - OBJECTIVE: Despite the low annual risk of hemorrhage associated with a cavernous malformation (CM) (0.6%-1.1% per year), the risk of rehemorrhage rate and severity of neurologic deficits is significantly higher; therefore, we aimed to evaluate the rupture risk of CMs depending on various factors. METHODS: We retrospectively analyzed medical records of all patients with CM admitted to our institution between 1999 and April 2016. Cavernoma volume, location of the lesion, existence of a developmental venous anomaly (DVA), number of cavernomas, and patient characteristics (sex, age, hypertension, and antithrombotic therapy) were assessed. RESULTS: One hundred fifty-four patients with CM were included; 89 (58%) ruptured CMs were identified. In statistical univariable analysis, the existence of a DVA was significantly higher in the ruptured cavernoma group (p < 0.001; odds ratio [OR] 4.6). A multivariable analysis of all included independent risk factors designated young age (<45 years) (p < 0.05; OR 2.2), infratentorial location (p < 0.01; OR 2.9), and existence of a DVA (p < 0.0001; OR 4.7) with significantly higher risk of rupture in our patient cohort. A separate analysis of these anatomical locations, supratentorial vs infratentorial, indicated that the existence of a DVA (p < 0.01; OR 4.16) in ruptured supratentorial cases and CM volume (>=1 cm3) (p < 0.0001; OR 3.5) in ruptured infratentorial cases were significant independent predictors for hemorrhage. CONCLUSIONS: Young age (<45 years), infratentorial location, and the presence of a DVA are associated with a higher hemorrhage risk. CM volume (>=1 cm3) and the existence of a DVA were independently in accordance with the anatomical location high risk factors for CM rupture. PMID- 29429975 TI - Teratogenicity of antiepileptic dual therapy: Dose-dependent, drug-specific, or both? AB - OBJECTIVE: To determine the relative risk (RR) of major congenital malformations (MCMs) in infants with antenatal exposure to antiepileptic drug (AED) dual therapy and to explore the influence of specific AEDs vs dose. METHODS: All completed pregnancies prospectively enrolled in the Kerala Registry of Epilepsy and Pregnancy from 1998 until December 2013 on AED dual therapy exposure during the first trimester were analyzed for the outcome, MCMs. Dose was expressed as ratio of prescribed to daily defined dose (PDD/DDD), and the RR for malformation was referenced to lamotrigine monotherapy. RESULTS: Of 1,688 completed pregnancies, 368 women were on dual therapy. The risk of MCM with dual therapy was 1.6 times more than with monotherapy (p = 0.0015). The frequency of renal, alimentary, and skeletal malformations was higher with dual therapy, while cardiac malformations were more common with monotherapy. The risk of MCM was highest with topiramate dual therapy (14.82, 95% confidence interval [CI] 1.88 113.83). No MCMs were seen with levetiracetam or lamotrigine dual therapy. There was a marked reduction in the risk of MCM when dual therapies involving topiramate or valproate were excluded (RR 1.78, 95% CI 1.00-3.15). The risk of MCM with dual therapy was higher even at lower doses (8.2%, PDD/DDD 0.5-1), and the subsequent dose-dependent increment was less profound than with monotherapy. CONCLUSIONS: Our data indicate that the excess risk of dual therapy over monotherapy is contributed largely by topiramate or valproate. The complex pharmacokinetic and pharmacodynamic effects of dual therapy adversely influence MCM risk. PMID- 29429971 TI - Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab. AB - OBJECTIVE: To evaluate whether amyloid-related imaging abnormalities with edema/effusion (ARIA-E) observed in bapineuzumab clinical trials was associated with specific biomarker patterns. METHODS: Bapineuzumab, an anti-beta-amyloid monoclonal antibody, was evaluated in patients with mild to moderate Alzheimer disease. Amyloid PET imaging, CSF biomarkers, or volumetric MRI (vMRI) were assessed. RESULTS: A total of 1,512 participants underwent one or more biomarker assessments; 154 developed incident ARIA-E. No differences were observed at baseline between ARIA-E and non-ARIA-E participants in brain amyloid burden by PET, the majority of vMRI measures, or CSF biomarkers, with the exception of lower baseline CSF Abeta42 in APOE epsilon4 noncarrier ARIA-E vs non-ARIA-E groups (bapineuzumab non-ARIA-E p = 0.027; placebo non-ARIA-E p = 0.012). At week 71, bapineuzumab-treated participants with ARIA-E vs non-ARIA-E showed greater reduction in brain amyloid PET, greater reductions in CSF phosphorylated tau (p tau) (all comparisons p < 0.01), and total tau (t-tau) (all comparisons p < 0.025), and greater hippocampal volume reduction and ventricular enlargement (all p < 0.05). Greater reduction in CSF Abeta40 concentrations was observed for ARIA E versus both non-ARIA-E groups (bapineuzumab/placebo non-ARIA-E p = 0.015/0.049). No group differences were observed at week 71 for changes in whole brain volume or CSF Abeta42. CONCLUSIONS: Baseline biomarkers largely do not predict risk for developing ARIA-E. ARIA-E was associated with significant longitudinal changes in several biomarkers, with larger reductions in amyloid PET and CSF p-tau and t-tau concentrations, and paradoxically greater hippocampal volume reduction and ventricular enlargement, suggesting that ARIA-E in bapineuzumab-treated cases may be related to increased Abeta efflux from the brain and affecting downstream pathogenic processes. PMID- 29429976 TI - Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures. AB - Thrombopoietin (TPO) is a critical cytokine regulating hematopoietic stem cell maintenance and differentiation into the megakaryocytic lineage. However, the transcriptional and chromatin dynamics elicited by TPO signaling are poorly understood. Here, we study the immediate early transcriptional and cis-regulatory responses to TPO in hematopoietic stem/progenitor cells (HSPCs) and use this paradigm of cytokine signaling to chromatin to dissect the relation between cis- regulatory activity and chromatin architecture. We show that TPO profoundly alters the transcriptome of HSPCs, with key hematopoietic regulators being transcriptionally repressed within 30 minutes of TPO. By examining cis-regulatory dynamics and chromatin architectures, we demonstrate that these changes are accompanied by rapid and extensive epigenome remodeling of cis-regulatory landscapes that is spatially coordinated within topologically associating domains (TADs). Moreover, TPO-responsive enhancers are spatially clustered and engage in preferential homotypic intra- and inter-TAD interactions that are largely refractory to TPO signaling. By further examining the link between cis-regulatory dynamics and chromatin looping, we show that rapid modulation of cis-regulatory activity is largely independent of chromatin looping dynamics. Finally, we show that, although activated and repressed cis-regulatory elements share remarkably similar DNA sequence compositions, transcription factor binding patterns accurately predict rapid cis-regulatory responses to TPO. PMID- 29429977 TI - ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream of transcription start sites at the majority of CpG island promoters. AB - High expression of the transcription factor ZFX is correlated with proliferation, tumorigenesis, and patient survival in multiple types of human cancers. However, the mechanism by which ZFX influences transcriptional regulation has not been determined. We performed ChIP-seq in four cancer cell lines (representing kidney, colon, prostate, and breast cancers) to identify ZFX binding sites throughout the human genome. We identified ~9,000 ZFX binding sites and found that the majority of the sites are in CpG island promoters. Moreover, genes with promoters bound by ZFX are expressed at higher levels than genes with promoters not bound by ZFX. To determine if ZFX contributes to regulation of the promoters to which it is bound, we performed RNA-seq analysis after knockdown of ZFX by siRNA in prostate and breast cancer cells. Many genes with promoters bound by ZFX were downregulated upon ZFX knockdown, supporting the hypothesis that ZFX acts as a transcriptional activator. Surprisingly, ZFX binds at +240 bp downstream of the TSS of the responsive promoters. Using Nucleosome Occupancy and Methylome Sequencing (NOMe seq), we show that ZFX binds between the open chromatin region at the TSS and the first downstream nucleosome, suggesting that ZFX may play a critical role in promoter architecture. We have also shown that a closely related zinc finger protein ZNF711 has a similar binding pattern at CpG island promoters, but ZNF711 may play a subordinate role to ZFX. This functional characterization of ZFX provides important new insights into transcription, chromatin structure, and the regulation of the cancer transcriptome. PMID- 29429979 TI - Who let the dogs out? The ever-present threat of autoreactive T cells. AB - Islet-reactive cytotoxic CD8+ T cells home to the pancreas in type 1 diabetes but circulate at similar frequencies in patients and healthy controls. PMID- 29429980 TI - What can I TIL you? Decoding TCR antigens. AB - Novel unbiased strategy for identification of peptide antigens bound by tumor infiltrating lymphocyte T cell receptors. PMID- 29429981 TI - Flora-ishing guts assist cancer immunotherapies. AB - Gut bacteria influence patient response to cancer therapy. PMID- 29429982 TI - Gallic Acid Attenuates Postoperative Intra-Abdominal Adhesion by Inhibiting Inflammatory Reaction in a Rat Model. PMID- 29429978 TI - Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. AB - The human leukocyte antigen-A2 (HLA-A2)-restricted zinc transporter 8186-194 (ZnT8186-194) and other islet epitopes elicit interferon-gamma secretion by CD8+ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8186-194-reactive CD8+ T cells express private T cell receptors and display equivalent functional properties in T1D and healthy individuals. Ex vivo analyses further revealed that CD8+ T cells reactive to ZnT8186-194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naive phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186-194-reactive CD8+ T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8186-194-reactive CD8+ T cell clonotypes were found to cross-recognize a Bacteroides stercoris mimotope. Whereas ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expression levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+ T cells. In contrast, ZnT8186-194-reactive cells were enriched in the pancreata of T1D patients versus nondiabetic and type 2 diabetic individuals. Thus, islet reactive CD8+ T cells circulate in most individuals but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a proinflammatory islet microenvironment. PMID- 29429983 TI - Baculoviral IAP Repeat Containing 6 (BIRC6) Is a Predictor of Prognosis in Prostate Cancer. PMID- 29429984 TI - Detection of miR-22, miR-140 and Bone Morphogenetic Proteins (BMP)-2 Expression Levels in Synovial Fluid of Osteoarthritis Patients Before and After Arthroscopic Debridement. AB - BACKGROUND Osteoarthritis (OA) is a degenerative joint disease often present on the surface and edge of the joint and beneath cartilage forming new bone. Arthroscopy had been used for the treatment of knee OA. This study aimed to measure the expression of miR-22, miR-140, and BMP-2 in patients with OA before and after arthroscopy operation. MATERIAL AND METHODS The synovial fluid of 80 patients and 60 healthy volunteers were aspirated using a syringe before OA operation and again six months post-operation in patients with OA. The total RNA was extracted and analyzed by quantitative PCR. RESULTS The level of miR-22 was elevated in the progression of OA. The expression of miR-140 level in the synovial fluid was significantly reduced in the patients with OA and was negatively correlated with OA severity compared to controls. Expression of miR-22 and miR-120 returned to normal levels post-operatively. BMP-2 expression was reduced in patients with OA, and returned to normal levels post-operatively. Bioinformatics analysis showed that miR-22 and miR-140 closely target with 3'-UTR of BMP-2 in different positions. The correlation between BMP-2 and miR-22 was negative. The correlation between BMP-2 and miR-140 was positive. CONCLUSIONS The present study identified a change in miR-22, miR-140, and BMP-2 expression in the synovial fluid of patients with OA before and after arthroscopic debridement. Results provide a novel characterization of the pathogenesis and therefore underlying therapeutic target for OA. PMID- 29429985 TI - Posterior Associative and Cingulate Cortex Involvement of Brain Single-Photon Emission Computed Tomography (SPECT) Imaging in Semantic Dementia with Probable Alzheimer Disease Pathology: A Case Report. AB - BACKGROUND Semantic dementia (SD) is a type of primary progressive aphasia with prominent language dysfunction, mostly within the spectrum of frontotemporal lobar degeneration (FTLD). Although there is an overlap in clinical manifestations of SD attributable to FTLD and neuropathologically proven Alzheimer disease (AD), clinical diagnostic clues are not readily available. We present a characteristic finding based on a single-photon emission computed tomography (SPECT)-based regional cerebral blood flow study and its statistical imaging analysis for a rare case of SD with AD-like pathology. CASE REPORT A 61 year-old male was referred to our hospital due to difficulties in self-management and impaired comprehension of word meaning suggestive of SD. Although his brain MRI revealed mild frontal lobe atrophy, his SPECT with three-dimensional stereotactic surface projections (3D-SSP) analysis showed left-sided hypo perfusion that was more prominent in the inferior temporal gyrus and the inferior parietal lobule, with bilateral frontal lobe hypo-perfusion. The SPECT scan also showed involvement of the right inferior parietal area and, in medial aspects, the posterior cingulate cortex and adjacent precuneus; these finding were compatible with early hypo-perfused areas seen in AD. The lumbar cerebrospinal fluid biomarker findings seemed to fit SD in association with probable AD pathology. CONCLUSIONS This is the first reported case to use SPECT with 3D-SSP statistical analysis as a potential, useful imaging modality for the diagnosis of SD with probable AD pathology. PMID- 29429986 TI - Comparison of photodynamic therapy and navigated microsecond laser for chronic central serous chorioretinopathy. AB - OBJECTIVES: To compare the visual and anatomical outcomes after photodynamic therapy (PDT) and navigated microsecond laser (nMSL) for chronic central serous chorioretinopathy (CSCR). METHODS: This retrospective study included eyes with chronic CSCR who underwent either PDT or nMSL with a minimum of 6 months' follow up. Eyes with a history of treatment with any other modalities in the past or during 6 months post PDT or microsecond laser follow-up were excluded. Primary outcome measures included change in best-corrected visual acuity (BCVA) and central macular thickness (CMT). Secondary outcome measures included changes in subretinal fluid, hyper-reflective foci, cystic spaces, subfoveal choroidal thickness, and outer retinal structure integrity. RESULTS: Forty-five eyes of 39 subjects (PDT group-23 eyes, nMSL group-22 eyes) with chronic CSCR were analyzed. At 6 months' follow-up, the nMSL group had significantly higher improvement in visual acuity compared to the PDT group (0.12 +/- 0.24 vs -0.02 +/- 0.20 (p = 0.039)). Reduction in central macular thickness was significantly higher in nMSL group compared to the PDT (85.5 +/- 93.26 vs 24.47 +/- 73.18 microns (p = 0.02)). Thirteen (59%) eyes in nMSL group had complete resolution of the SRF at 6 months compared to 5 (21.7%) eyes in PDT group. There was no significant difference in rest of the anatomical features between the groups. CONCLUSIONS: nMSL seems to be superior over PDT in improving visual and anatomical outcomes at 6 months and can be considered as a cheap alternative to PDT in treatment of CSCR. PMID- 29429987 TI - Foetal haemoglobin, blood transfusion, and retinopathy of prematurity. PMID- 29429988 TI - The deubiquitylase USP15 regulates topoisomerase II alpha to maintain genome integrity. AB - Ubiquitin-specific protease 15 (USP15) is a widely expressed deubiquitylase that has been implicated in diverse cellular processes in cancer. Here we identify topoisomerase II (TOP2A) as a novel protein that is regulated by USP15. TOP2A accumulates during G2 and functions to decatenate intertwined sister chromatids at prophase, ensuring the replicated genome can be accurately divided into daughter cells at anaphase. We show that USP15 is required for TOP2A accumulation, and that USP15 depletion leads to the formation of anaphase chromosome bridges. These bridges fail to decatenate, and at mitotic exit form micronuclei that are indicative of genome instability. We also describe the cell cycle-dependent behaviour for two major isoforms of USP15, which differ by a short serine-rich insertion that is retained in isoform-1 but not in isoform-2. Although USP15 is predominantly cytoplasmic in interphase, we show that both isoforms move into the nucleus at prophase, but that isoform-1 is phosphorylated on its unique S229 residue at mitotic entry. The micronuclei phenotype we observe on USP15 depletion can be rescued by either USP15 isoform and requires USP15 catalytic activity. Importantly, however, an S229D phospho-mimetic mutant of USP15 isoform-1 cannot rescue either the micronuclei phenotype, or accumulation of TOP2A. Thus, S229 phosphorylation selectively abrogates this role of USP15 in maintaining genome integrity in an isoform-specific manner. Finally, we show that USP15 isoform-1 is preferentially upregulated in a panel of non-small cell lung cancer cell lines, and propose that isoform imbalance may contribute to genome instability in cancer. Our data provide the first example of isoform-specific deubiquitylase phospho-regulation and reveal a novel role for USP15 in guarding genome integrity. PMID- 29429990 TI - Non-canonical activation of hedgehog in prostate cancer cells mediated by the interaction of transcriptionally active androgen receptor proteins with Gli3. AB - Hedgehog (Hh) is an oncogenic signaling pathway that regulates the activity of Gli transcription factors. Canonical Hh is a Smoothened- (Smo-) driven process that alters the post-translational processing of Gli2/Gli3 proteins. Though evidence supports a role for Gli action in prostate cancer (PCa) cell growth and progression, there is little indication that Smo is involved. Here we describe a non-canonical means for activation of Gli transcription in PCa cells mediated by the binding of transcriptionally-active androgen receptors (ARs) to Gli3. Androgens stimulated reporter expression from a Gli-dependent promoter in a variety of AR + PCa cells and this activity was suppressed by an anti-androgen, Enz, or by AR knockdown. Androgens also upregulated expression of endogenous Gli dependent genes. This activity was associated with increased intranuclear binding of Gli3 to AR that was antagonized by Enz. Fine mapping of the AR binding domain on Gli2 showed that AR recognizes the Gli protein processing domain (PPD) in the C-terminus. Mutations in the arginine-/serine repeat elements of the Gli2 PPD involved in phosphorylation and ubiquitinylation blocked the binding to AR. beta TrCP, a ubiquitin ligase that recognizes the Gli PPD, competed with AR for binding to this site. AR binding to Gli3 suppressed its proteolytic processing to the Gli3 repressor form (Gli3R) whereas AR knockdown increased Gli3R. Both full length and truncated ARs were able to activate Gli transcription. Finally, we found that an ARbinding decoy polypeptide derived from the Gli2 C-terminus can compete with Gli3 for binding to AR. Exogenous overexpression of this decoy suppressed Gli transcriptional activity in PCa cells. Collectively, this work identifies a novel pathway for non-canonical activation of Hh signaling in PCa cells and identifies a means for interference that may have clinical relevance for PCa patients. PMID- 29429991 TI - p53 isoforms regulate premature aging in human cells. AB - Cellular senescence is a hallmark of normal aging and aging-related syndromes, including the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), a rare genetic disorder caused by a single mutation in the LMNA gene that results in the constitutive expression of a truncated splicing mutant of lamin A known as progerin. Progerin accumulation leads to increased cellular stresses including unrepaired DNA damage, activation of the p53 signaling pathway and accelerated senescence. We previously established that the p53 isoforms ?133p53 and p53beta regulate senescence in normal human cells. However, their role in premature aging is unknown. Here we report that p53 isoforms are expressed in primary fibroblasts derived from HGPS patients, are associated with their accelerated senescence and that their manipulation can restore the replication capacity of HGPS fibroblasts. We found that in near-senescent HGPS fibroblasts, which exhibit low levels of ?133p53 and high levels of p53beta, restoration of Delta133p53 expression was sufficient to extend replicative lifespan and delay senescence, despite progerin levels and abnormal nuclear morphology remaining unchanged. Conversely, Delta133p53 depletion or p53beta overexpression accelerated the onset of senescence in otherwise proliferative HGPS fibroblasts. Our data indicate that Delta133p53 exerts its role by modulating full-length p53 (FLp53) signaling to extend the replicative lifespan and promotes the repair of spontaneous progerin-induced DNA double-strand breaks (DSBs). We showed that Delta133p53 dominant-negative inhibition of FLp53 occurs directly at the p21/CDKN1A and miR-34a promoters, two p53 senescence-associated genes. In addition, Delta133p53 expression increased the expression of DNA repair RAD51, likely through upregulation of E2F1, a transcription factor that activates RAD51, to promote repair of DSBs. In summary, our data indicate that Delta133p53 modulates p53 signaling to repress progerin-induced early onset of senescence in HGPS cells. Therefore, restoration of ?133p53 expression may be a novel therapeutic strategy to treat aging-associated phenotypes of HGPS in vivo. PMID- 29429989 TI - Nucleolus as an emerging hub in maintenance of genome stability and cancer pathogenesis. AB - The nucleolus is the major site for synthesis of ribosomes, complex molecular machines that are responsible for protein synthesis. A wealth of research over the past 20 years has clearly indicated that both quantitative and qualitative alterations in ribosome biogenesis can drive the malignant phenotype via dysregulation of protein synthesis. However, numerous recent proteomic, genomic, and functional studies have implicated the nucleolus in the regulation of processes that are unrelated to ribosome biogenesis, including DNA-damage response, maintenance of genome stability and its spatial organization, epigenetic regulation, cell-cycle control, stress responses, senescence, global gene expression, as well as assembly or maturation of various ribonucleoprotein particles. In this review, the focus will be on features of rDNA genes, which make them highly vulnerable to DNA damage and intra- and interchromosomal recombination as well as built-in mechanisms that prevent and repair rDNA damage, and how dysregulation of this interplay affects genome-wide DNA stability, gene expression and the balance between euchromatin and heterochromatin. We will also present the most recent insights into how malfunction of these cellular processes may be a central driving force of human malignancies, and propose a promising new therapeutic approach for the treatment of cancer. PMID- 29429992 TI - SRSF10-mediated IL1RAP alternative splicing regulates cervical cancer oncogenesis via mIL1RAP-NF-kappaB-CD47 axis. AB - High-risk human papillomavirus oncoproteins E6 and E7 are the major etiological factors of cervical cancer but are insufficient for malignant transformation of cervical cancer. Dysregulated alternative splicing, mainly ascribed to aberrant splicing factor levels and activities, contributes to most cancer hallmarks. However, do E6 and E7 regulate the expression of splicing factors? Does alternative splicing acts as an "accomplice" of E6E7 to promote cervical cancer progression? Here, we identified that the splicing factor SRSF10, which promotes tumorigenesis of cervix, was upregulated by E6E7 via E2F1 transcriptional activation. SRSF10 modulates the alternate terminator of interleukin-1 receptor accessory protein exon 13 to increase production of the membrane form of interleukin-1 receptor accessory protein. SRSF10-mediated mIL1RAP upregulates the expression of the "don't eat me" signal CD47 to inhibit macrophage phagocytosis by promoting nuclear factor-kappaB activation, which is pivotal in inflammatory, immune, and tumorigenesis processes. Altogether, these data reveal a close relationship among HPV infection, alternative splicing and tumor immune evasion, and also suggests that the SRSF10-mIL1RAP-CD47 axis could be an attractive therapeutic target for the treatment of cervical cancer. PMID- 29429993 TI - The non-canonical Wnt pathway leads to aged dendritic cell differentiation. PMID- 29429994 TI - Flip the switch: BTG2-PRMT1 protein complexes antagonize pre-B-cell proliferation to promote B-cell development. PMID- 29429995 TI - miR-125b-5p and miR-99a-5p downregulate human gammadelta T-cell activation and cytotoxicity. AB - As an important component of innate immunity, human circulating gammadelta T cells function in rapid responses to infections and tumorigenesis. MicroRNAs (miRNAs) play a critical regulatory role in multiple biological processes and diseases. Therefore, how the functions of circulating human gammadelta T cells are regulated by miRNAs merits investigation. In this study, we profiled the miRNA expression patterns in human peripheral gammadelta T cells from 21 healthy donors and identified 14 miRNAs that were differentially expressed between peripheral alphabeta T cells and gammadelta T cells. Of the 14 identified genes, 7 miRNAs were downregulated, including miR-150-5p, miR-450a-5p, miR-193b-3p, miR 365a-3p, miR-31-5p, miR-125b-5p and miR-99a-5p, whereas the other 7 miRNAs were upregulated, including miR-34a-5p, miR-16-5p, miR-15b-5p, miR-24-3p, miR-22-3p, miR-22-5p and miR-9-5p, in gammadelta T cells compared with alphabeta T cells. In subsequent functional studies, we found that both miR-125b-5p and miR-99a-5p downregulated gammadelta T cell activation and cytotoxicity to tumor cells. Overexpression of miR-125b-5p or miR-99a-5p in gammadelta T cells inhibited gammadelta T cell activation and promoted gammadelta T cell apoptosis. Additionally, miR-125b-5p knockdown facilitated the cytotoxicity of gammadelta T cells toward tumor cells in vitro by increasing degranulation and secretion of IFN-gamma and TNF-alpha. Our findings improve the understanding of the regulatory functions of miRNAs in gammadelta T cell activation and cytotoxicity, which has implications for interventional approaches to gammadelta T cell-mediated cancer therapy.Cellular and Molecular Immunology advance online publication, 12 February 2018; doi:10.1038/cmi.2017.164. PMID- 29429996 TI - Application of light sheet microscopy for qualitative and quantitative analysis of bronchus-associated lymphoid tissue in mice. AB - Bronchus-associated lymphoid tissue (BALT) develops at unpredictable locations around lung bronchi following pulmonary inflammation. The formation and composition of BALT have primarily been investigated by immunohistology that, due to the size of the invested organ, is usually restricted to a limited number of histological sections. To assess the entire BALT of the lung, other approaches are urgently needed. Here, we introduce a novel light sheet microscopy-based approach for assessing lymphoid tissue in the lung. Using antibody staining of whole lung lobes and optical clearing by organic solvents, we present a method that allows in-depth visualization of the entire bronchial tree, the lymphatic vasculature and the immune cell composition of the induced BALT. Furthermore, three-dimensional analysis of the entire lung allows the qualitative and quantitative enumeration of the induced BALT. Using this approach, we show that a single intranasal application of the replication-deficient poxvirus MVA induces BALT that constitutes up to 8% of the entire lung volume in mice deficient in CCR7, in contrast to wild type mice (WT). Furthermore, BALT induced by heat inactivated E. coli is dominated by a pronounced T cell infiltration in Cxcr5 deficient mice, in contrast to WT mice.Cellular and Molecular Immunology advance online publication, 12 February 2018; doi:10.1038/cmi.2017.150. PMID- 29429997 TI - De novo vs. inherited copy number variations in multiple sclerosis susceptibility. PMID- 29429998 TI - ZDHHC11 modulates innate immune response to DNA virus by mediating MITA-IRF3 association. AB - MITA is a central adaptor in innate immune responses to DNA viruses. The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic. Here we identified ZDHHC11, a member of DHHC palmitoyl transferase family, as a positive regulator of DNA virus-triggered signaling. Overexpression of ZDHHC11 activated the IFN-beta promoter, while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes. Zdhhc11-/- mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection. Mechanistically, ZDHHC11 facilitated the optimal recruitment of IRF3 to MITA. Our findings support an important role for ZDHHC11 in mediating MITA-dependent innate immune responses against DNA viruses.Cellular and Molecular Immunology advance online publication, 12 February 2018; doi:10.1038/cmi.2017.146. PMID- 29430001 TI - Environmental microbiology: Attracting bacteria in the soil. PMID- 29430000 TI - Recurrent BCOR internal tandem duplication and BCOR or BCL6 expression distinguish primitive myxoid mesenchymal tumor of infancy from congenital infantile fibrosarcoma. AB - This corrects the article DOI: 10.1038/modpathol.2017.12. PMID- 29430002 TI - Marine microbiology: A new tale for oceanic viruses. PMID- 29430003 TI - Bacterial physiology: Spacers go off-site. PMID- 29430004 TI - Antimicrobials: Bacterial enzymes 'straighten out' antibiotics. PMID- 29430006 TI - Biofilms: Naturally modified cellulose in bacterial biofilms. PMID- 29430007 TI - Viral infection: Breathing alone may spread the flu. PMID- 29430008 TI - Corrigendum: Variation-preserving normalization unveils blind spots in gene expression profiling. AB - This corrects the article DOI: 10.1038/srep42460. PMID- 29430005 TI - Rewiring cellular networks by members of the Flaviviridae family. AB - Members of the Flaviviridae virus family comprise a large group of enveloped viruses with a single-strand RNA genome of positive polarity. Several genera belong to this family, including the Hepacivirus genus, of which hepatitis C virus (HCV) is the prototype member, and the Flavivirus genus, which contains both dengue virus and Zika virus. Viruses of these genera differ in many respects, such as the mode of transmission or the course of infection, which is either predominantly persistent in the case of HCV or acutely self-limiting in the case of flaviviruses. Although the fundamental replication strategy of Flaviviridae members is similar, during the past few years, important differences have been discovered, including the way in which these viruses exploit cellular resources to facilitate viral propagation. These differences might be responsible, at least in part, for the various biological properties of these viruses, thus offering the possibility to learn from comparisons. In this Review, we discuss the current understanding of how Flaviviridae viruses manipulate and usurp cellular pathways in infected cells. Specifically, we focus on comparing strategies employed by flaviviruses with those employed by hepaciviruses, and we discuss the importance of these interactions in the context of viral replication and antiviral therapies. PMID- 29430009 TI - Real-time fMRI neurofeedback to down-regulate superior temporal gyrus activity in patients with schizophrenia and auditory hallucinations: a proof-of-concept study. AB - Neurocognitive models and previous neuroimaging work posit that auditory verbal hallucinations (AVH) arise due to increased activity in speech-sensitive regions of the left posterior superior temporal gyrus (STG). Here, we examined if patients with schizophrenia (SCZ) and AVH could be trained to down-regulate STG activity using real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF). We also examined the effects of rtfMRI-NF training on functional connectivity between the STG and other speech and language regions. Twelve patients with SCZ and treatment-refractory AVH were recruited to participate in the study and were trained to down-regulate STG activity using rtfMRI-NF, over four MRI scanner visits during a 2-week training period. STG activity and functional connectivity were compared pre- and post-training. Patients successfully learnt to down-regulate activity in their left STG over the rtfMRI NF training. Post- training, patients showed increased functional connectivity between the left STG, the left inferior prefrontal gyrus (IFG) and the inferior parietal gyrus. The post-training increase in functional connectivity between the left STG and IFG was associated with a reduction in AVH symptoms over the training period. The speech-sensitive region of the left STG is a suitable target region for rtfMRI-NF in patients with SCZ and treatment-refractory AVH. Successful down-regulation of left STG activity can increase functional connectivity between speech motor and perception regions. These findings suggest that patients with AVH have the ability to alter activity and connectivity in speech and language regions, and raise the possibility that rtfMRI-NF training could present a novel therapeutic intervention in SCZ. PMID- 29430010 TI - Corrigendum: Novel concept for neutron detection: proportional counter filled with 10B nanoparticle aerosol. AB - This corrects the article DOI: 10.1038/srep41699. PMID- 29430012 TI - Cloud computing for genomic data analysis and collaboration. AB - This corrects the article DOI: 10.1038/nrg.2017.113. PMID- 29430013 TI - Risk factors: Childhood kidney disease increases the risk of ESRD in adulthood. PMID- 29430014 TI - Autoimmunity: TLR7 evades silencing in human immune cells. PMID- 29430011 TI - Neisseria gonorrhoeae host adaptation and pathogenesis. AB - The host-adapted human pathogen Neisseria gonorrhoeae is the causative agent of gonorrhoea. Consistent with its proposed evolution from an ancestral commensal bacterium, N. gonorrhoeae has retained features that are common in commensals, but it has also developed unique features that are crucial to its pathogenesis. The continued worldwide incidence of gonorrhoeal infection, coupled with the rising resistance to antimicrobials and the difficulties in controlling the disease in developing countries, highlights the need to better understand the molecular basis of N. gonorrhoeae infection. This knowledge will facilitate disease prevention, surveillance and control, improve diagnostics and may help to facilitate the development of effective vaccines or new therapeutics. In this Review, we discuss sex-related symptomatic gonorrhoeal disease and provide an overview of the bacterial factors that are important for the different stages of pathogenesis, including transmission, colonization and immune evasion, and we discuss the problem of antibiotic resistance. PMID- 29430015 TI - Immunotherapy: Cytokine boost for CAR T cells. PMID- 29430016 TI - Regulation of T cell signalling by membrane lipids. AB - This corrects the article DOI: 10.1038/nri.2016.103. PMID- 29430017 TI - Schools at the Rural-Urban Boundary - Blurring the Divide? AB - Schools mirror the communities in which they are located. Research on school inequality across the rural-urban spectrum tends to focus on the contrast between urban, suburban, and rural schools and glosses over the variation within these areas as well as the similarities between them. To address this gap and provide a richer description of the spatial distribution of educational inequality, we examine the school composition, achievement, and resources of all U.S. elementary schools in 2010-2011. We apply standard census definitions of what areas fall within central cities, the remainder of metropolitan regions, and in rural America. We then apply spatially explicit methods to reveal blurred boundaries and gradual gradients rather than sharp breaks at the edges of these zones. The results show high levels of variation within the suburbs and substantial commonality between rural and urban areas. PMID- 29430018 TI - School Segregation and Disparities in Urban, Suburban, and Rural Areas. AB - Much of the literature on racial and ethnic educational inequality focuses on the contrast between Black and Hispanic students in urban areas and white suburban students. This study extends past research on school segregation and racial/ethnic disparities by highlighting the importance of rural areas and regional variation. Although schools in rural America are disproportionately white, they nevertheless are like urban schools, and disadvantaged relative to suburban schools, in terms of poverty and test performance. The group most affected by rural school disadvantage is Native Americans, who are a small share of students nationally but much more prominent and highly disadvantaged in rural areas, particularly in some parts of the country. These figures suggest a strong case for including rural schools in the continuing conversation about how to deal with unfairness in public education. PMID- 29430019 TI - Local in Practice: Professional Distinctions in Angolan Development Work. AB - Development workers employed by international nongovernmental organizations (NGOs) are commonly classified as national (local) or international (expatriate) staff members. The distinction is presumed to reflect the varieties of expertise required for the work and the workers' different biographies. I examine the experiences of Angolans working in an international democratization program to demonstrate how some professionals at the lowest tiers of international development NGOs engage in social practices that strategically emphasize or conceal certain skills, kinds of knowledge, or family circumstances to fulfill industry expectations of "local staff." Doing so allows them access to employment with international organizations and pursuit of a variety of personal and professional goals. These practices reinforce hierarchical inequalities within the development industry, however, limiting these workers' influence over programmatic action. I argue that professional distinctions among development workers are social achievements and instruments of strategic manipulation by individuals and NGOs rather than accurate reflections of work or workers. The case study provides insight into the institutional reproduction of hierarchical inequalities and the complexly social reasons why those who suffer their limitations may act in ways that reinforce, rather than resist, unequal social structures. PMID- 29430020 TI - Abducting Economics. AB - Abduction is the process of generating and choosing models, hypotheses and data analyzed in response to surprising findings. All good empirical economists abduct. Explanations usually evolve as studies evolve. The abductive approach challenges economists to step outside the framework of received notions about the "identification problem" that rigidly separates the act of model and hypothesis creation from the act of inference from data. It asks the analyst to engage models and data in an iterative dynamic process, using multiple models and sources of data in a back and forth where both models and data are augmented as learning evolves. PMID- 29430021 TI - Shale Gas Development and Drinking Water Quality. PMID- 29430022 TI - Plasmonic micropillars for precision cell force measurement across a large field of-view. AB - A plasmonic micropillar platform with self-organized gold nanospheres is reported for the precision cell traction force measurement across a large field-of-view (FOV). Gold nanospheres were implanted into the tips of polymer micropillars by annealing gold microdisks with nanosecond laser pulses. Each gold nanosphere is physically anchored in the center of a pillar tip and serves as a strong, point source-like light scattering center for each micropillar. This allows a micropillar to be clearly observed and precisely tracked even under a low magnification objective lens for the concurrent and precision measurement across a large FOV. A spatial resolution of 30 nm for the pillar deflection measurement has been accomplished on this platform with a 20* objective lens. PMID- 29430023 TI - Hubble COS Spectroscopy of the Dwarf Nova CW Mon: The White Dwarf in Quiescence? AB - We present a synthetic spectral analysis of the HST COS spectrum of the U Geminorum-type dwarf nova CW Mon, taken during quiescence as part of our COS survey of accreting white dwarfs in Cataclysmic Variables. We use synthetic photosphere and optically thick accretion disk spectra to model the COS spectrum as well as archival IUE spectra obtained decades ago when the system was in an even deeper quiescent state. Assuming a reddening of E(B-V)=0.06, an inclination of 60 degrees (CW Mon has eclipses of the accretion disk, and a white dwarf mass of 0.8M?, our results indicate the presence of a 22-27,000 K white dwarf and a low mass accretion rate [Formula: see text], for a derived distance o ~200 to ~300 pc. PMID- 29430024 TI - DETECTING EXOMOONS AROUND SELF-LUMINOUS GIANT EXOPLANETS THROUGH POLARIZATION. AB - Many of the directly imaged self-luminous gas giant exoplanets have been found to have cloudy atmospheres. Scattering of the emergent thermal radiation from these planets by the dust grains in their atmospheres should locally give rise to significant linear polarization of the emitted radiation. However, the observable disk averaged polarization should be zero if the planet is spherically symmetric. Rotation-induced oblateness may yield a net non-zero disk averaged polarization if the planets have sufficiently high spin rotation velocity. On the other hand, when a large natural satellite or exomoon transits a planet with cloudy atmosphere along the line of sight, the asymmetry induced during the transit should give rise to a net non-zero, time resolved linear polarization signal. The peak amplitude of such time dependent polarization may be detectable even for slowly rotating exoplanets. Therefore, we suggest that large exomoons around directly imaged self-luminous exoplanets may be detectable through time resolved imaging polarimetry. Adopting detailed atmospheric models for several values of effective temperature and surface gravity which are appropriate for self-luminous exoplanets, we present the polarization profiles of these objects in the infrared during transit phase and estimate the peak amplitude of polarization that occurs during the inner contacts of the transit ingress/egress phase. The peak polarization is predicted to range between 0.1 and 0.3 % in the infrared. PMID- 29430025 TI - Reconnection-Driven Magnetohydrodynamic Turbulence in a Simulated Coronal-Hole Jet. AB - Extreme-ultraviolet and X-ray jets occur frequently in magnetically open coronal holes on the Sun, especially at high solar latitudes. Some of these jets are observed by white-light coronagraphs as they propagate through the outer corona toward the inner heliosphere, and it has been proposed that they give rise to microstreams and torsional Alfven waves detected in situ in the solar wind. To predict and understand the signatures of coronal-hole jets, we have performed a detailed statistical analysis of such a jet simulated with an adaptively refined magnetohydrodynamics model. The results confirm the generation and persistence of three-dimensional, reconnection-driven magnetic turbulence in the simulation. We calculate the spatial correlations of magnetic fluctuations within the jet and find that they agree best with the Muller-Biskamp scaling model including intermittent current sheets of various sizes coupled via hydrodynamic turbulent cascade. The anisotropy of the magnetic fluctuations and the spatial orientation of the current sheets are consistent with an ensemble of nonlinear Alfven waves. These properties also reflect the overall collimated jet structure imposed by the geometry of the reconnecting magnetic field. A comparison with Ulysses observations shows that turbulence in the jet wake is in quantitative agreement with that in the fast solar wind. PMID- 29430026 TI - Heating and Cooling of Coronal Loops with Turbulent Suppression of Parallel Heat Conduction. AB - Using the "enthalpy-based thermal evolution of loops" (EBTEL) model, we investigate the hydrodynamics of the plasma in a flaring coronal loop in which heat conduction is limited by turbulent scattering of the electrons that transport the thermal heat flux. The EBTEL equations are solved analytically in each of the two (conduction-dominated and radiation-dominated) cooling phases. Comparison of the results with typical observed cooling times in solar flares shows that the turbulent mean free path lambdaT lies in a range corresponding to a regime in which classical (collision-dominated) conduction plays at most a limited role. We also consider the magnitude and duration of the heat input that is necessary to account for the enhanced values of temperature and density at the beginning of the cooling phase and for the observed cooling times. We find through numerical modeling that in order to produce a peak temperature ?1.5 * 107 K and a 200 s cooling time consistent with observations, the flare-heating profile must extend over a significant period of time; in particular, its lingering role must be taken into consideration in any description of the cooling phase. Comparison with observationally inferred values of post-flare loop temperatures, densities, and cooling times thus leads to useful constraints on both the magnitude and duration of the magnetic energy release in the loop, as well as on the value of the turbulent mean free path lambdaT . PMID- 29430027 TI - Principal weighted support vector machines for sufficient dimension reduction in binary classification. AB - Sufficient dimension reduction is popular for reducing data dimensionality without stringent model assumptions. However, most existing methods may work poorly for binary classification. For example, sliced inverse regression (Li, 1991) can estimate at most one direction if the response is binary. In this paper we propose principal weighted support vector machines, a unified framework for linear and nonlinear sufficient dimension reduction in binary classification. Its asymptotic properties are studied, and an efficient computing algorithm is proposed. Numerical examples demonstrate its performance in binary classification. PMID- 29430028 TI - Generalized R-squared for detecting dependence. AB - Detecting dependence between two random variables is a fundamental problem. Although the Pearson correlation coefficient is effective for capturing linear dependence, it can be entirely powerless for detecting nonlinear and/or heteroscedastic patterns. We introduce a new measure, G-squared, to test whether two univariate random variables are independent and to measure the strength of their relationship. The G-squared statistic is almost identical to the square of the Pearson correlation coefficient, R-squared, for linear relationships with constant error variance, and has the intuitive meaning of the piecewise R-squared between the variables. It is particularly effective in handling nonlinearity and heteroscedastic errors. We propose two estimators of G-squared and show their consistency. Simulations demonstrate that G-squared estimators are among the most powerful test statistics compared with several state-of-the-art methods. PMID- 29430029 TI - On pseudolikelihood inference for semiparametric models with boundary problems. AB - Consider a semiparametric model indexed by a Euclidean parameter of interest and an infinite-dimensional nuisance parameter. In many applications, pseudolikelihood provides a convenient way to infer the parameter of interest, where the nuisance parameter is replaced by a consistent estimator. The purpose of this paper is to establish the asymptotic behaviour of the pseudolikelihood ratio statistic under semiparametric models. In particular, we consider testing the hypothesis that the parameter of interest lies on the boundary of its parameter space. Under regularity conditions, we establish the equivalence between the asymptotic distributions of the pseudolikelihood ratio statistic and a likelihood ratio statistic for a normal mean problem with a misspecified covariance matrix. This result holds when the nuisance parameter is estimated at a rate slower than the usual rate in parametric models. We study three examples in which the asymptotic distributions are shown to be mixtures of chi-squared variables. We conduct simulation studies to examine the finite-sample performance of the pseudolikelihood ratio test. PMID- 29430030 TI - Roy's largest root test under rank-one alternatives. AB - Roy's largest root is a common test statistic in multivariate analysis, statistical signal processing and allied fields. Despite its ubiquity, provision of accurate and tractable approximations to its distribution under the alternative has been a longstanding open problem. Assuming Gaussian observations and a rank-one alternative, or concentrated noncentrality, we derive simple yet accurate approximations for the most common low-dimensional settings. These include signal detection in noise, multiple response regression, multivariate analysis of variance and canonical correlation analysis. A small-noise perturbation approach, perhaps underused in statistics, leads to simple combinations of standard univariate distributions, such as central and noncentral [Formula: see text] and [Formula: see text]. Our results allow approximate power and sample size calculations for Roy's test for rank-one effects, which is precisely where it is most powerful. PMID- 29430031 TI - An improved and explicit surrogate variable analysis procedure by coefficient adjustment. AB - Unobserved environmental, demographic and technical factors canadversely affect the estimation and testing of the effects ofprimary variables. Surrogate variable analysis, proposed to tacklethis problem, has been widely used in genomic studies. To estimatehidden factors that are correlated with the primary variables,surrogate variable analysis performs principal component analysiseither on a subset of features or on all features, but weightingeach differently. However, existing approaches may fail to identifyhidden factors that are strongly correlated with the primaryvariables, and the extra step of feature selection and weightcalculation makes the theoretical investigation of surrogatevariable analysis challenging. In this paper, we propose an improvedsurrogate variable analysis, using all measured features, that has anatural connection with restricted least squares, which allows us tostudy its theoretical properties. Simulation studies and real-dataanalysis show that the method is competitive with state-of-the-artmethods. PMID- 29430032 TI - Covariate-assisted spectral clustering. AB - Biological and social systems consist of myriad interacting units. The interactions can be represented in the form of a graph or network. Measurements of these graphs can reveal the underlying structure of these interactions, which provides insight into the systems that generated the graphs. Moreover, in applications such as connectomics, social networks, and genomics, graph data are accompanied by contextualizing measures on each node. We utilize these node covariates to help uncover latent communities in a graph, using a modification of spectral clustering. Statistical guarantees are provided under a joint mixture model that we call the node-contextualized stochastic blockmodel, including a bound on the misclustering rate. The bound is used to derive conditions for achieving perfect clustering. For most simulated cases, covariate-assisted spectral clustering yields results superior both to regularized spectral clustering without node covariates and to an adaptation of canonical correlation analysis. We apply our clustering method to large brain graphs derived from diffusion MRI data, using the node locations or neurological region membership as covariates. In both cases, covariate-assisted spectral clustering yields clusters that are easier to interpret neurologically. PMID- 29430033 TI - Multiple robustness in factorized likelihood models. AB - We consider inference under a nonparametric or semiparametric model with likelihood that factorizes as the product of two or more variation-independent factors. We are interested in a finite-dimensional parameter that depends on only one of the likelihood factors and whose estimation requires the auxiliary estimation of one or several nuisance functions. We investigate general structures conducive to the construction of so-called multiply robust estimating functions, whose computation requires postulating several dimension-reducing models but which have mean zero at the true parameter value provided one of these models is correct. PMID- 29430034 TI - Joint sufficient dimension reduction and estimation of conditional and average treatment effects. AB - The estimation of treatment effects based on observational data usually involves multiple confounders, and dimension reduction is often desirable and sometimes inevitable. We first clarify the definition of a central subspace that is relevant for the efficient estimation of average treatment effects. A criterion is then proposed to simultaneously estimate the structural dimension, the basis matrix of the joint central subspace, and the optimal bandwidth for estimating the conditional treatment effects. The method can easily be implemented by forward selection. Semiparametric efficient estimation of average treatment effects can be achieved by averaging the conditional treatment effects with a different data-adaptive bandwidth to ensure optimal undersmoothing. Asymptotic properties of the estimated joint central subspace and the corresponding estimator of average treatment effects are studied. The proposed methods are applied to a nutritional study, where the covariate dimension is reduced from 11 to an effective dimension of one. PMID- 29430036 TI - Robust reduced-rank regression. AB - In high-dimensional multivariate regression problems, enforcing low rank in the coefficient matrix offers effective dimension reduction, which greatly facilitates parameter estimation and model interpretation. However, commonly used reduced-rank methods are sensitive to data corruption, as the low-rank dependence structure between response variables and predictors is easily distorted by outliers. We propose a robust reduced-rank regression approach for joint modelling and outlier detection. The problem is formulated as a regularized multivariate regression with a sparse mean-shift parameterization, which generalizes and unifies some popular robust multivariate methods. An efficient thresholding-based iterative procedure is developed for optimization. We show that the algorithm is guaranteed to converge and that the coordinatewise minimum point produced is statistically accurate under regularity conditions. Our theoretical investigations focus on non-asymptotic robust analysis, demonstrating that joint rank reduction and outlier detection leads to improved prediction accuracy. In particular, we show that redescending [Formula: see text]-functions can essentially attain the minimax optimal error rate, and in some less challenging problems convex regularization guarantees the same low error rate. The performance of the proposed method is examined through simulation studies and real-data examples. PMID- 29430035 TI - Identification and estimation of causal effects with outcomes truncated by death. AB - It is common in medical studies that the outcome of interest is truncated by death, meaning that a subject has died before the outcome could be measured. In this case, restricted analysis among survivors may be subject to selection bias. Hence, it is of interest to estimate the survivor average causal effect, defined as the average causal effect among the subgroup consisting of subjects who would survive under either exposure. In this paper, we consider the identification and estimation problems of the survivor average causal effect. We propose to use a substitution variable in place of the latent membership in the always-survivor group. The identification conditions required for a substitution variable are conceptually similar to conditions for a conditional instrumental variable, and may apply to both randomized and observational studies. We show that the survivor average causal effect is identifiable with use of such a substitution variable, and propose novel model parameterizations for estimation of the survivor average causal effect under our identification assumptions. Our approaches are illustrated via simulation studies and a data analysis. PMID- 29430037 TI - Expandable factor analysis. AB - Bayesian sparse factor models have proven useful for characterizing dependence in multivariate data, but scaling computation to large numbers of samples and dimensions is problematic. We propose expandable factor analysis for scalable inference in factor models when the number of factors is unknown. The method relies on a continuous shrinkage prior for efficient maximum a posteriori estimation of a low-rank and sparse loadings matrix. The structure of the prior leads to an estimation algorithm that accommodates uncertainty in the number of factors. We propose an information criterion to select the hyperparameters of the prior. Expandable factor analysis has better false discovery rates and true positive rates than its competitors across diverse simulation settings. We apply the proposed approach to a gene expression study of ageing in mice, demonstrating superior results relative to four competing methods. PMID- 29430039 TI - Distribution-free tests of independence in high dimensions. AB - We consider the testing of mutual independence among all entries in a [Formula: see text]-dimensional random vector based on [Formula: see text] independent observations. We study two families of distribution-free test statistics, which include Kendall's tau and Spearman's rho as important examples. We show that under the null hypothesis the test statistics of these two families converge weakly to Gumbel distributions, and we propose tests that control the Type I error in the high-dimensional setting where [Formula: see text]. We further show that the two tests are rate-optimal in terms of power against sparse alternatives and that they outperform competitors in simulations, especially when [Formula: see text] is large. PMID- 29430038 TI - Semiparametric analysis of complex polygenic gene-environment interactions in case-control studies. AB - Many methods have recently been proposed for efficient analysis of case-control studies of gene-environment interactions using a retrospective likelihood framework that exploits the natural assumption of gene-environment independence in the underlying population. However, for polygenic modelling of gene environment interactions, which is a topic of increasing scientific interest, applications of retrospective methods have been limited due to a requirement in the literature for parametric modelling of the distribution of the genetic factors. We propose a general, computationally simple, semiparametric method for analysis of case-control studies that allows exploitation of the assumption of gene-environment independence without any further parametric modelling assumptions about the marginal distributions of any of the two sets of factors. The method relies on the key observation that an underlying efficient profile likelihood depends on the distribution of genetic factors only through certain expectation terms that can be evaluated empirically. We develop asymptotic inferential theory for the estimator and evaluate its numerical performance via simulation studies. An application of the method is presented. PMID- 29430040 TI - Projection correlation between two random vectors. AB - We propose the use of projection correlation to characterize dependence between two random vectors. Projection correlation has several appealing properties. It equals zero if and only if the two random vectors are independent, it is not sensitive to the dimensions of the two random vectors, it is invariant with respect to the group of orthogonal transformations, and its estimation is free of tuning parameters and does not require moment conditions on the random vectors. We show that the sample estimate of the projection correction is [Formula: see text]-consistent if the two random vectors are independent and root-[Formula: see text]-consistent otherwise. Monte Carlo simulation studies indicate that the projection correlation has higher power than the distance correlation and the ranks of distances in tests of independence, especially when the dimensions are relatively large or the moment conditions required by the distance correlation are violated. PMID- 29430042 TI - On two-stage estimation of structural instrumental variable models. AB - Two-stage least squares estimation is popular for structural equation models with unmeasured confounders. In such models, both the outcome and the exposure are assumed to follow linear models conditional on the measured confounders and instrumental variable, which is related to the outcome only via its relation with the exposure. We consider data where both the outcome and the exposure may be incompletely observed, with particular attention to the case where both are censored event times. A general class of two-stage minimum distance estimators is proposed that separately fits linear models for the outcome and exposure and then uses a minimum distance criterion based on the reduced-form model for the outcome to estimate the regression parameters of interest. An optimal minimum distance estimator is identified which may be superior to the usual two-stage least squares estimator with fully observed data. Simulation studies demonstrate that the proposed methods perform well with realistic sample sizes. Their practical utility is illustrated in a study of the comparative effectiveness of colon cancer treatments, where the effect of chemotherapy on censored survival times may be confounded with patient status. PMID- 29430041 TI - Doubly robust nonparametric inference on the average treatment effect. AB - Doubly robust estimators are widely used to draw inference about the average effect of a treatment. Such estimators are consistent for the effect of interest if either one of two nuisance parameters is consistently estimated. However, if flexible, data-adaptive estimators of these nuisance parameters are used, double robustness does not readily extend to inference. We present a general theoretical study of the behaviour of doubly robust estimators of an average treatment effect when one of the nuisance parameters is inconsistently estimated. We contrast different methods for constructing such estimators and investigate the extent to which they may be modified to also allow doubly robust inference. We find that while targeted minimum loss-based estimation can be used to solve this problem very naturally, common alternative frameworks appear to be inappropriate for this purpose. We provide a theoretical study and a numerical evaluation of the alternatives considered. Our simulations highlight the need for and usefulness of these approaches in practice, while our theoretical developments have broad implications for the construction of estimators that permit doubly robust inference in other problems. PMID- 29430043 TI - Optimal designs for active controlled dose-finding trials with efficacy-toxicity outcomes. AB - We derive optimal designs to estimate efficacy and toxicity in active controlled dose-finding trials when the bivariate continuous outcomes are described using nonlinear regression models. We determine upper bounds on the required number of different doses and provide conditions under which the boundary points of the design space are included in the optimal design. We provide an analytical description of minimally supported optimal designs and show that they do not depend on the correlation between the bivariate outcomes. PMID- 29430044 TI - Research resource environment in Canada. Gathering knowledge in advance to inform chiropractic research priorities. AB - Objective: To better understand the research resources and environment within the Canadian chiropractic profession. Methods: All members of the Canadian Chiropractic Association (n=7200) were invited to access an electronic survey on research capacity, activity, and resources. Canadian chiropractic stakeholder organizations received an invitation to participate in a related survey. Results: 505 CCA members completed the survey (7.0% completed response rate, 65% males, 19% with graduate degrees). Researchers (26 full-time and 67 part-time) produced over 530 authorships in the past five years. Clinical research and systematic reviews were the most common areas of involvement. Regular meetings were rarely reported between researchers and chiropractic stakeholder organizations. Stakeholders indicated using research for member education, negotiation with government or funders, direct inquiries, and increased credibility. Fewer than half of the organizations regularly evaluated their research needs. Conclusions: Chiropractic research resources in Canada are growing, but inconsistent communication and coordination between researchers and knowledge users persists. PMID- 29430045 TI - The Journal of the Canadian Chiropractic Association's 60th Anniversary Issue: Time to consider the future. PMID- 29430046 TI - Canadian Chiropractic Guideline Initiative (CCGI) progress and future directions: December 2017. PMID- 29430047 TI - Informing a research agenda for the Canadian chiropractic profession. AB - Our research group recently published a Delphi study that identified Canadian chiropractic profession research priority areas. At the same time, the Canadian Chiropractic Research Foundation (CCRF) was developing their own research priority areas. In this commentary, we discuss the results of the Delphi study, compare and contrast these results to the research priorities of the CCRF, and report new data from a survey about where members of the chiropractic profession think that available research funding should be spent. Ongoing dialogue is needed with all Canadian chiropractic stakeholders to turn these research priorities into action. PMID- 29430048 TI - World Spine Care: providing sustainable, integrated, evidence-based spine care in underserved communities around the world. PMID- 29430051 TI - JCCA Special Issue December 2017 -Sports Chiropractic. PMID- 29430050 TI - Our future in the hands of Millennials. AB - The future of any profession is in the hands of its students and early career practitioners. The Millennial generation of chiropractors embody attributes that are uniquely suited to the evolving landscape of 21st century healthcare. Globalization and rapid advancements in technology demand different styles of communication, attitudes toward diversity, styles of professional engagement, and perhaps most importantly, idealism about the future. Millennial chiropractors have a clear vision for this future of the profession, and are equipped to actualize that ideal. PMID- 29430049 TI - Developing clinical procedures to diagnose specific motor control impairments associated with low back pain: prone hip extension (PHE), active straight leg raise (ASLR), and gait variability. PMID- 29430052 TI - 'I didn't pay her to teach me how to fix my back': a focused ethnographic study exploring chiropractors' and chiropractic patients' experiences and beliefs regarding exercise adherence. AB - Aim: To inform future research and exercise prescription for patients with chronic low back pain (CLBP), this study explored chiropractors' and chiropractic patients' experiences and beliefs regarding the barriers and facilitators to prescribed exercise adherence. Methods: A focused ethnographic approach was used involving 16 semi-structured interviews, including pilot interviews (n = 4) followed by interviews with chiropractors (n = 6) and chiropractic patients with CLBP (n = 6). Results: Barriers and facilitators to prescribed exercise adherence revolved around four themes: diagnostic and treatment beliefs motivating behavior, passive-active treatment balance, the therapeutic alliance and patient centered care, and exercise delivery. Conclusion: Exercise adherence may be facilitated in patients with CLBP with simple exercise prescription changes made by chiropractors. However, changing chiropractors' and patients' diagnostic and treatment beliefs that are barriers to exercise adherence appears challenging. Training chiropractors in pain neuroscience education and the intentional use of behavior change techniques warrants future investigation. PMID- 29430053 TI - Exercise as a vital sign: a preliminary pilot study in a chiropractic setting. AB - Background: The association between physical inactivity and non-communicable disease risk has been well documented in recent literature. An exercise vital sign (EVS) is a measure that can routinely capture vital information about a patient's physical activity behaviour. The objective of this study is to understand if (1) patient exercise minutes per week (EMPW) are being recorded by chiropractic interns, and (2) whether these patients are exceeding, meeting or falling short of the current recommendations provided by the Canadian Physical Activity Guidelines (CPAG). Methods: Electronic medical records obtained from two Canadian Memorial Chiropractic College (CMCC) teaching clinics for patients seen between August 01, 2015 and January 31, 2017 (N=273). EMPW, age, and gender were used to compare patient files relative to the CPAG. Results: Overall, 86.4% of patient files had recorded data to the question of how many EMPW they perform. The majority (68.8%) of individuals appear to be meeting or exceeding the CPAG, leaving nearly one third (31.2%) of individuals failing to meet these guidelines. Conclusions: In this pilot study with two sports specialist clinicians an exercise vital sign had been integrated alongside traditional vital signs in order to identify issues of physical inactivity and improve opportunities for continued exercise counselling. PMID- 29430054 TI - Concussion knowledge among Sport Chiropractic Fellows from the Royal College of Chiropractic Sports Sciences (Canada). AB - Objectives: The objective of this study was to investigate the degree of knowledge that sports chiropractors have in regard to concussion diagnosis and management. Methods: A concussion knowledge survey was administered to Sport Chiropractic Fellows of the Royal College of Chiropractic Sports Sciences - Canada (RCCSS(C)) (n=44) via SurveyMonkey.com. Results: Sports chiropractors scored statistically higher on the survey when compared to chiropractic residents (mean =5.57 vs. 5.25; t=2.12; p=0.04) and to fourth year chiropractic interns (mean = 5.57 vs 5.2; t=2.45; p=0.02). Additionally, with our modified scoring, the sports chiropractors scored 85.3%. A few knowledge gaps were identified in the sample population. Conclusion: Sports chiropractors demonstrated the skills and knowledge to diagnose concussion and excel at identifying the definition and mechanism of concussion, but knowledge gaps regarding diagnosis and management of concussion were found in the sample population. PMID- 29430055 TI - Conservative management of MRI-confirmed knee osteoarthritis with instrument assisted soft-tissue mobilization, joint manipulation, and platelet-rich plasma. AB - Objective: To describe the successful conservative management of a patient with chronic degenerative knee pain. Clinical Features: An active 47 year-old female office-worker with intermittent right knee pain inferolateral to the right patella for eight months described difficulty ascending stairs, sitting on a chair for one hour, and squatting. A physical exam led to the diagnosis of a suspected chronic degenerative tear of the posterior horn of the right medial meniscus and chronic right subpatellar chondrosis, in addition to extensive cartilaginous degeneration revealed by an MRI study conducted prior to initial presentation. Intervention and Outcome: A conservative chiropractic treatment plan was implemented in addition to two successive intra-articular and subpatellar platelet-rich plasma injections. The patient reported no pain after sixteen weeks and 93.75% functionality six months after the second injection. PMID- 29430056 TI - Osteochondral lesion of the distal tibial plafond in an adolescent soccer player: a case report. AB - Introduction: Osteochondral lesions of the tibial plafond account for approximately 2.6% of osteochondral lesions in the ankle. There are few cases describing this lesion in the literature, with little information on mechanism of injury, history/physical findings or recommendations for management. Case Presentation: A 17-year-old male competitive soccer player presented with a 6-7 month history of medial ankle pain after an inversion sprain. He presented with locking and giving way of the ankle with weight-bearing and pushing off the foot to the contralateral side. Radiographs were negative for fracture or osteochondral involvement. Magnetic resonance imaging revealed an osteochondral lesion of the tibial plafond with no injury to the talar dome. Summary: This case discusses the clinical presentation, imaging findings, management and outcomes of this osteochondral lesion of the distal tibial plafond. PMID- 29430057 TI - Ganglion cyst of the wrist treated with electroacupuncture: a case report. AB - Objective: To illustrate the clinical management of a ganglion cyst presenting on the right dorsal wrist. Clinical Features: A 38-year-old female complaining of a symptomatic right dorsal wrist ganglion of four years duration. Intervention and Outcome: The patient was treated with high-frequency electroacupuncture in six consecutive treatments over a four week period and reported symptomatic improvement and a decrease in the size of the cyst following therapeutic intervention. Conclusion: Ganglion cysts of the wrist are rather common benign connective tissue masses with variable treatment interventions. Electroacupuncture may be a novel and non-invasive conservative approach for the treatment of ganglion cysts. Further evaluation of the efficacy is warranted. PMID- 29430059 TI - Expectation of life at old age: revisiting Horiuchi-Coale and reconciling with Mitra. AB - Data quality issues at advanced old age, such as incompleteness of registration of vital events and age misreporting, compromise estimates of the death rates and remaining life expectancy at those ages. Following up on Horiuchi and Coale (Population Studies 36: 317-326, 1982), Mitra (Population Studies 38: 313-319, 1984, Population Studies 39: 511-512, 1985), and Coale (Population Studies 39: 507-509, 1985), we examine the conventional approaches to constructing life tables from data deficient at advanced ages and the two adjustment methods by the mentioned authors. Contrary to earlier reports by Horiuchi, Coale, and Mitra, we show that the two methods are consistent and useful in drastically reducing the estimation errors in life expectancy as compared to the conventional approaches, i.e., the classical open age interval model and extrapolation of the death rates. Our results suggest complementing the classical estimates of life expectancy by adjustments using Horiuchi-Coale, Mitra, or other appropriate methods and avoiding the extrapolation method as a tool for estimating the life expectancy. PMID- 29430060 TI - Effective in-field thermal conductivity of ferrofluids. AB - A structural model to predict in-field thermal conductivity of ferrofluids is proposed in this study and is validated by the experimental data from the literature. The model is able to capture the aggregation development of the magnetic particles with increasing magnetic field strength. Introducing a compression function that can be found empirically, the model can accurately predict the thermal conductivity, especially the plateauing at low and high magnetic fields. PMID- 29430061 TI - Biodegradable Polymeric Injectable Implants for Long-Term Delivery of Contraceptive Drugs. AB - Development of injectable, long-lasting, contraceptive drug delivery formulations and implants are highly desired to avoid unplanned pregnancies while improving patient compliance and reducing adverse side effects and treatment costs. The present study reports on the fabrication and characterization of two levonorgestrel (LNG) microsphere injectable formulations. Poly(epsilon caprolactone) (PCL) with 12.5% and 24% (w/w) LNG were fabricated into microspheres, measuring 300+/-125 MUm, via the oil-in-water (o/w) emulsion solvent evaporation technique. Formulations showed sustained drug release up to 120 days. FTIR, XRD, DSC, and TGA confirmed the absence of LNG chemical interaction with PCL as well as its molecular level distribution. The in vitro release of LNG was calculated to be Fickian diffusion controlled and properly characterized. The inclusion of multiple elevated release temperatures allowed for the application of the Arrhenius model to calculate drug release constants and representative sampling intervals, demonstrating the use of elevated temperatures for accelerated-time drug release studies. PMID- 29430058 TI - Natural products as inspiration for the development of new synthetic methods. AB - Natural products have played an important role in shaping modern synthetic organic chemistry. In particular, their complex molecular skeletons have stimulated the development of many new synthetic methods. We highlight in this article some recent examples of synthetic design inspired by the biosynthesis of natural products. PMID- 29430062 TI - Bromofluorination of Unsaturated Compounds using DMPU/HF as a Fluorinating Reagent. AB - Bromofluorination reactions were performed by treating of a variety of unsaturated compounds with N-bromosuccinimide (NBS) and DMPU/HF as the fluorinating reagent. The DMPU/HF complex showed to be an efficient fluorinating reagent to convert alkenes into their corresponding bromofluoro compounds. It showed to have high reactivity and the process afforded bromofluorinated products with good Markovnikov regioselectivity. These fluorinated compounds are useful starting materials and serve as building blocks for many fluorinated biologically active molecules. PMID- 29430063 TI - Carbonate substitution in the mineral component of bone: Discriminating the structural changes, simultaneously imposed by carbonate in A and B sites of apatite. AB - The mineral component of bone and other biological calcifications is primarily a carbonate substituted calcium apatite. Integration of carbonate into two sites, substitution for phosphate (B-type carbonate) and substitution for hydroxide (A type carbonate), influences the crystal properties which relate to the functional properties of bone. In the present work, a series of AB-type carbonated apatites (AB-CAp) having varying A-type and B-type carbonate weight fractions were prepared and analyzed by Fourier transform infrared spectroscopy (FTIR), powder X ray diffraction (XRD), and carbonate analysis. A detailed characterization of A site and B-site carbonate assignment in the FTIR nu3 region is proposed. The mass fractions of carbonate in A-site and B- site of AB-CAp correlate differently with crystal axis length and crystallite domain size. In this series of samples reduction in crystal domain size correlates only with A-type carbonate which indicates that carbonate in the A-site is more disruptive to the apatite structure than carbonate in the B-site. High temperature methods were required to produce significant A-type carbonation of apatite, indicating a higher energy barrier for the formation of A-type carbonate than for B-type carbonate. This is consistent with the dominance of B-type carbonate substitution in low temperature synthetic and biological apatites. PMID- 29430064 TI - Survival analysis with functions of mismeasured covariate histories: the case of chronic air pollution exposure in relation to mortality in the nurses' health study. AB - Environmental epidemiologists are often interested in estimating the effect of functions of time-varying exposure histories, such as the 12-month moving average, in relation to chronic disease incidence or mortality. The individual exposure measurements that comprise such an exposure history are usually mis measured, at least moderately, and, often, more substantially. To obtain unbiased estimates of Cox model hazard ratios for these complex mis-measured exposure functions, an extended risk set regression calibration method for Cox models is developed and applied to a study of long-term exposure to the fine particulate matter (PM2.5) component of air pollution in relation to all-cause mortality in the Nurses' Health Study. Simulation studies under several realistic assumptions about the measurement error model and about the correlation structure of the repeated exposure measurements were conducted to assess the finite sample properties of this new method, and found that the method has good performance in terms of finite sample bias reduction and nominal confidence interval coverage. PMID- 29430065 TI - From Heterogeneity to Concentration: Latino Immigrant Neighborhoods and Collective Efficacy Perceptions in Los Angeles and Chicago. AB - Latino immigrant presence in urban neighborhoods has been linked with reduced neighborhood cohesion in social disorganization-based ethnic heterogeneity hypotheses and enhanced cohesion in immigration revitalization approaches. Using the 2000-2002 Los Angeles Family and Neighborhood Survey and the 1994-1995 Project on Human Development in Chicago Neighborhoods Community Survey, we explore the association between Latino immigrant concentration and both levels of, and agreement about, neighborhood collective efficacy. Findings from multilevel models with heteroskedastic variance indicate that Latino immigrant concentration exhibits a nonlinear association with collective efficacy. At low levels, increases in Latino immigrant concentration diminish collective efficacy, consistent with a heterogeneity hypothesis. The negative association between Latino immigrant concentration and collective efficacy declines in magnitude as immigrant concentration increases and, particularly in LA, becomes positive beyond a threshold, consistent with an immigration revitalization effect. We also find an inverse nonlinear pattern of association with the variance of collective efficacy. At low levels, increasing Latino immigrant concentration increases the variance of collective efficacy (reflecting more disagreement), but beyond a threshold, this association becomes negative (reflecting increasing agreement). This pattern is observed in both LA and Chicago. The prevalence of social interaction and reciprocated exchange within neighborhoods explains a modest proportion of the Latino immigrant concentration effect on mean levels of collective efficacy in Chicago, but does little to explain effects on the mean in LA or effects on the variance in either LA or Chicago. These findings offer insight into the complex role Latino immigrant presence plays in shaping neighborhood social climate. PMID- 29430066 TI - The synthesis of lactone-bridged 1,3,5-triphenylbenzene derivatives as pi expanded coumarin triskelions. AB - Two triply lactone-bridged 1,3,5-triphenylbenzene derivatives with solubilizing moieties have been synthesized in five and six steps from commercially available starting materials. Compounds containing the 1,3,5-triphenylbenzene core with two atom bridges are relatively unknown. This new class of pi-expanded coumarins contain triskelion architectures and X-ray crystallographic studies of one of the triskelions indicates that the 1,3,5-triphenylbenzene core adopts a near-planar geometry. This is the only known example of a two atom-bridged 1,3,5 triphenylbenzene derivative to adopt a planar structure. PMID- 29430067 TI - NETWORK STRUCTURE, MULTIPLEXITY, AND EVOLUTION AS INFLUENCES ON COMMUNITY-BASED PARTICIPATORY INTERVENTIONS. AB - This study applies an ecological perspective to the context of community-based participatory research (CBPR). Specifically, it examines how endogenous and exogenous factors influence the dynamics of CBPR partnerships, including the tendency toward reciprocity and transitivity, the organizational type, the level of resource sufficiency, the level of organizational influence, and the perceived CBPR effect on organizations. The results demonstrate that network structure is related to the selection and retention of interorganizational networks over time, and organizations of the same type are more likely to form partnerships with each other. It shows that the dynamics of the CBPR initiative presented in this article were driven by the structure of the interorganizational networks rather than their individual organizational attributes. Implications for sustaining CBPR partnerships are drawn from the findings. PMID- 29430068 TI - Restoration of Monotonicity Respecting in Dynamic Regression. AB - Dynamic regression models, including the quantile regression model and Aalen's additive hazards model, are widely adopted to investigate evolving covariate effects. Yet lack of monotonicity respecting with standard estimation procedures remains an outstanding issue. Advances have recently been made, but none provides a complete resolution. In this article, we propose a novel adaptive interpolation method to restore monotonicity respecting, by successively identifying and then interpolating nearest monotonicity-respecting points of an original estimator. Under mild regularity conditions, the resulting regression coefficient estimator is shown to be asymptotically equivalent to the original. Our numerical studies have demonstrated that the proposed estimator is much more smooth and may have better finite-sample efficiency than the original as well as, when available as only in special cases, other competing monotonicity-respecting estimators. Illustration with a clinical study is provided. PMID- 29430069 TI - Conditional Spectral Analysis of Replicated Multiple Time Series with Application to Nocturnal Physiology. AB - This article considers the problem of analyzing associations between power spectra of multiple time series and cross-sectional outcomes when data are observed from multiple subjects. The motivating application comes from sleep medicine, where researchers are able to non-invasively record physiological time series signals during sleep. The frequency patterns of these signals, which can be quantified through the power spectrum, contain interpretable information about biological processes. An important problem in sleep research is drawing connections between power spectra of time series signals and clinical characteristics; these connections are key to understanding biological pathways through which sleep affects, and can be treated to improve, health. Such analyses are challenging as they must overcome the complicated structure of a power spectrum from multiple time series as a complex positive-definite matrix-valued function. This article proposes a new approach to such analyses based on a tensor product spline model of Cholesky components of outcome-dependent power spectra. The approach exibly models power spectra as nonparametric functions of frequency and outcome while preserving geometric constraints. Formulated in a fully Bayesian framework, a Whittle likelihood based Markov chain Monte Carlo (MCMC) algorithm is developed for automated model fitting and for conducting inference on associations between outcomes and spectral measures. The method is used to analyze data from a study of sleep in older adults and uncovers new insights into how stress and arousal are connected to the amount of time one spends in bed. PMID- 29430070 TI - Bayesian Nonparametric Ordination for the Analysis of Microbial Communities. AB - Human microbiome studies use sequencing technologies to measure the abundance of bacterial species or Operational Taxonomic Units (OTUs) in samples of biological material. Typically the data are organized in contingency tables with OTU counts across heterogeneous biological samples. In the microbial ecology community, ordination methods are frequently used to investigate latent factors or clusters that capture and describe variations of OTU counts across biological samples. It remains important to evaluate how uncertainty in estimates of each biological sample's microbial distribution propagates to ordination analyses, including visualization of clusters and projections of biological samples on low dimensional spaces. We propose a Bayesian analysis for dependent distributions to endow frequently used ordinations with estimates of uncertainty. A Bayesian nonparametric prior for dependent normalized random measures is constructed, which is marginally equivalent to the normalized generalized Gamma process, a well-known prior for nonparametric analyses. In our prior, the dependence and similarity between microbial distributions is represented by latent factors that concentrate in a low dimensional space. We use a shrinkage prior to tune the dimensionality of the latent factors. The resulting posterior samples of model parameters can be used to evaluate uncertainty in analyses routinely applied in microbiome studies. Specifically, by combining them with multivariate data analysis techniques we can visualize credible regions in ecological ordination plots. The characteristics of the proposed model are illustrated through a simulation study and applications in two microbiome datasets. PMID- 29430071 TI - Trajectories of problem behaviors from 4 to 23 years in former preterm infants. AB - Premature infants have significant risk for later behavior problems. This study examined growth trajectories of three problem behaviors across five developmental age points from preschool to early adulthood in a well-characterized sample of premature infants. The effects of neonatal risk, gender, and socioeconomic context were modeled on these trajectories. The longitudinal sample was comprised of preterm infants (N = 160) with full variation of neonatal morbidity and birth weight (640-1950 grams). Trajectories of externalizing, internalizing and attention problem behaviors from 4 to 23 years, measured by the Child Behavior Checklist, were tested using latent growth curve modeling. The results indicate individual variation in the number of externalizing and internalizing problems over time. Externalizing problems were not significantly different for males and females, but male scores were consistently higher. Neonatal risk was significantly associated with higher internalizing problems at age 4, but was not predictive at school age and beyond. Attention problem scores increased from early preschool through adolescence for males, but females had little change over the same ages. SES was not predictive of any problem behavior trajectories and no significant two-way interactions were found. The results advance understanding of stability and change of three important problem behaviors through preschool, childhood and adolescence to young adulthood in prematurely born infants in order to inform clinicians about timely assessment and the refinement of effective interventions. PMID- 29430072 TI - Mental Health Symptoms and Parenting Among Father-Only and Dual Substance Use Disorder Couples. AB - In the present study, we examined associations between fathers' and mothers' mental health symptoms as related to their own and their partner's parenting in couples in which fathers (n = 38 families) or both partners (n = 30 families) had substance use disorder (SUD). Each partner reported on symptoms of depression, anxiety, and hostility; children reported on each parent's parenting behaviors, including acceptance, psychological control, and knowledge of children. Actor partner interdependence models indicated that when substance-abusing fathers have more symptoms of anxiety and depression, non-substance-abusing mothers report greater knowledge of children, whereas non-substance-abusing mothers' mental health symptoms were related to less paternal knowledge of children. In dual SUD couples, mothers' depressive symptoms were associated with more paternal knowledge of children. These preliminary findings offer select support for family systems theory. PMID- 29430073 TI - N-Heterocycle-Ligated Borocations as Highly Tunable Carbon Lewis Acids. AB - The relative (to BEt3) hydride ion affinity (HIA) of a series of acridine borenium salts has been calculated, with some HIAs found to be similar to that for [Ph3C]+. The HIA at the acridine C9 position is controlled by both acridine and the boron substituents, the latter presumably affecting the strength of the B=N bond in the acridane-BY2 products from hydride transfer. Through a range of hydride abstraction benchmarking reactions against organic hydride donors the experimental HIA of [F5acr-BCat]+ (cat = catechol, F5acr = 1,2,3,4,7 pentafluoroacridine) has been confirmed to be extremely high and closely comparable to that of [Ph3C]+. The high HIA of [F5acr-BCat]+ enables H2 and alkene activation in a FLP with 2,6-di-tert-butylpyridine. Finally, the HIA of pyridine and quinoline borenium cations has been determined, with the HIA at boron in [PinB(amine)]+ (pin = pinacol, amine = pyridine or quinoline) found to be relatively low. This enabled the hydroboration of pyridine and quinoline by HBPin to be achieved through the addition of 5-10 mol % of bench-stable cationic carbon Lewis acids such as 2-phenyl-N,N-dimethylimidazolium salts. PMID- 29430074 TI - Low blood lead levels and hemoglobin concentrations in preschool children in China. AB - It is well known that lead (Pb) produces reduced haemoglobin (Hb) levels and risk of anemia when blood lead levels (BPb) are greater than 20 ug dL-1. Two recent studies reported an increased risk of anemia in children with BPb between 10-20 ug dL-1, but few studies examined the association between Hb levels or risk of anemia and BPb under 10 ug dL-1. In the present study this association was examined using data of 140 preschool children from a larger prospective cohort study in China. Data showed that compared to children with BPb <5 ug dL-1, children with BPb between 7.5-10 ug dL-1 had significantly lower Hb levels, but there were no marked differences for other groups. A linear regression model showed a negative relationship between BPb and Hb levels after controlling for age, gender, height, weight, and iron (Fe) deficiency. This finding, although limited by a small sample size, suggests it may be important to examine Pb induced hemosynthesis effect at concentrations less than 10 ug dL-1. PMID- 29430076 TI - Associations between the Epithelial-Mesenchymal Transition Phenotypes of Circulating Tumor Cells and the Clinicopathological Features of Patients with Colorectal Cancer. AB - In this study, we identified CTCs using the previously reported CanPatrol CTC enrichment technique from peripheral blood samples of 126 patients with colorectal cancer (CRC) and found that CTCs could be classified into three subpopulations based on expression of epithelial cell adhesion molecule (EpCAM) (E-CTCs), the mesenchymal cell marker vimentin (M-CTCs), or both EpCAM and vimentin (biphenotypic E/M-CTCs). Circulating tumor microemboli (CTMs) were also identified in peripheral blood samples. Meanwhile, E-CTCs, M-CTCs, E/M-CTCs, and CTMs were detected in 76.98%, 42.06%, 56.35%, and 36.51% of the 126 patients, respectively. Interestingly, the presence of CTMs and each CTC subpopulation was significantly associated with blood lymphocyte counts and tumor-node-metastasis stage (P < 0.001). Lymphocyte counts and the neutrophil-to-lymphocyte ratio (NLR) in patients lacking CTCs were significantly different from those in patients testing positive for CTMs and each CTC subpopulation (P < 0.001). Our results indicate that tumor metastasis is more significantly associated with the presence of CTMs and M-CTCs than with other CTC subpopulations and suggest that EMT may be involved in CTC evasion of lymphocyte-mediated clearance. PMID- 29430075 TI - Polymorphisms in the SP110 and TNF-alpha Gene and Susceptibility to Pulmonary and Spinal Tuberculosis among Southern Chinese Population. AB - Objective: To investigate the association of single-nucleotide polymorphisms (SNPs) in SP110 gene and TNF-alpha gene among pulmonary TB (PTB) and spinal TB (STB) patients. Methods: In a total of 190 PTB patients, 183 STB patients were enrolled as the case group and 362 healthy individuals at the same geographical region as the control group. The SP110 SNPs (rs722555 and rs1135791) and the promoter -308G>A (rs1800629) and -238G>A (rs361525) polymorphisms in TNF-alpha were genotyped. Results. TNF-alpha -238G>A polymorphism was involved in susceptibility to STB, but not to PTB. The TNF-alpha -238 A allele was a protective factor against STB (A versus G: OR [95% CI] = 0.331 [0.113-0.972], P = 0.044). Furthermore, the presence of the -238 A allele was considered a trend to decrease the risk of STB (AG versus GG: P = 0.062, OR [95% CI] = 0.352 [0.118 1.053]; AA + AG versus GG: P = 0.050, OR [95CI%] = 0.335 [0.113-0.999]). However, SP110 SNPs (rs722555 and rs1135791) and TNF-alpha -308G>A (rs1800629) showed no association with PTB and STB in all genetic models. Conclusion: The TNF-alpha 238 A allele appeared a protective effect against STB, whereas the SP110 SNPs (rs722555 and rs1135791) and TNF-alpha -308G>A (rs1800629) showed no association with susceptibility to PTB and STB patients in southern China. PMID- 29430078 TI - Multigrid Methods for A Mixed Finite Element Method of The Darcy-Forchheimer Model. AB - An efficient nonlinear multigrid method for a mixed finite element method of the Darcy-Forchheimer model is constructed in this paper. A Peaceman-Rachford type iteration is used as a smoother to decouple the nonlinearity from the divergence constraint. The nonlinear equation can be solved element-wise with a closed formulae. The linear saddle point system for the constraint is reduced into a symmetric positive definite system of Poisson type. Furthermore an empirical choice of the parameter used in the splitting is proposed and the resulting multigrid method is robust to the so-called Forchheimer number which controls the strength of the nonlinearity. By comparing the number of iterations and CPU time of different solvers in several numerical experiments, our multigrid method is shown to convergent with a rate independent of the mesh size and the Forchheimer number and with a nearly linear computational cost. PMID- 29430077 TI - Hypoxia-Inducible Factor-1alpha in Antarctic notothenioids contains a polyglutamine and glutamic acid insert that varies in length with phylogeny. AB - The long evolution of the Antarctic perciform suborder of Notothenioidei in the icy, oxygen-rich waters of the Southern Ocean may have reduced selective pressure to maintain a hypoxic response. To test this hypothesis, cDNA of the key transcriptional regulator of hypoxic genes, hypoxia-inducible factor-1alpha (HIF 1alpha), was sequenced in heart ventricles of the red-blooded notothenioid, Notothenia coriiceps, and the hemoglobinless icefish, Chaenocephalus aceratus. HIF-1alpha cDNA is 4500 base pairs (bp) long and encodes 755 amino acids in N. coriiceps, and in C. aceratus, HIF-1alpha is 3576 bp long and encodes 779 amino acids. All functional domains of HIF-1alpha are highly conserved compared to other teleosts, but HIF-1alpha contains a polyglutamine/glutamic acid (polyQ/E) insert 9 amino acids long in N. coriiceps and 34 amino acids long in C. aceratus. Sequencing of this region in four additional species, representing three families of notothenioids, revealed that the length of the polyQ/E insert varies with phylogeny. Icefishes, the crown family of notothenioids, contain the longest polyQ/E inserts, ranging between16 and 34 amino acids long, whereas the basal, cold-temperate notothenioid, Eleginops maclovinus, contains a polyQ/E insert only 4 amino acids long. PolyQ/E inserts may affect dimerization of HIF-1alpha and HIF 1beta, HIF-1 translocation into the nucleus and/or DNA binding. PMID- 29430079 TI - Solution-Grown CsPbBr3 Perovskite Single Crystals for Photon Detection. PMID- 29430080 TI - High-Yielding Automated Convergent Synthesis of No-Carrier-Added [11C-Carbonyl] Labeled Amino Acids Using the Strecker Reaction. AB - A new variant of the Strecker synthesis using no-carrier-added [11C]cyanide for the synthesis of radiolabeled amino acids is described. The protocol is fully automated using a radiochemistry synthesis module and applied to the production of a number of new PET radiotracers. [11C-Carbonyl]sarcosine, [11C carbonyl]methionine, [11C-carbonyl]-N-phenylglycine, and [11C-carbonyl]glycine are all synthesized in moderate to good radiochemical yields. The synthesis of [11C-carbonyl]sarcosine has been validated for production of doses for clinical use, and preliminary evaluation of the new radiotracer in PC3 tumor-bearing mice is also reported. PMID- 29430081 TI - Association between Scale-Free Brain Dynamics and Behavioral Performance: Functional MRI Study in Resting State and Face Processing Task. AB - The scale-free dynamics of human brain activity, characterized by an elaborate temporal structure with scale-free properties, can be quantified using the power law exponent (PLE) as an index. Power laws are well documented in nature in general, particularly in the brain. Some previous fMRI studies have demonstrated a lower PLE during cognitive-task-evoked activity than during resting state activity. However, PLE modulation during cognitive-task-evoked activity and its relationship with an associated behavior remain unclear. In this functional fMRI study in the resting state and face processing + control task, we investigated PLE during both the resting state and task-evoked activities, as well as its relationship with behavior measured using mean reaction time (mRT) during the task. We found that (1) face discrimination-induced BOLD signal changes in the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), amygdala, and fusiform face area; (2) PLE significantly decreased during task-evoked activity specifically in mPFC compared with resting state activity; (3) most importantly, in mPFC, mRT significantly negatively correlated with both resting state PLE and the resting-task PLE difference. These results may lead to a better understanding of the associations between task performance parameters (e.g., mRT) and the scale free dynamics of spontaneous and task-evoked brain activities. PMID- 29430082 TI - Might Climate Change the "Healthy Migrant" Effect? PMID- 29430084 TI - Serum Interleukin-23 in Polish Patients with Systemic Lupus Erythematosus: Association with Lupus Nephritis, Obesity, and Peripheral Vascular Disease. AB - Objectives: To analyze the correlation between the serum concentration of interleukin- (IL-) 23 and atherosclerotic changes, traditional atherosclerotic risk factors, the autoantibody profile, and involvement of selected organs in systemic lupus erythematosus (SLE) patients. Patients and Methods: We studied 94 SLE patients and 27 controls. We analyzed the IL-23 serum concentration, autoantibodies, carotid intima-media thickness and atherosclerotic plaque, the ankle-brachial index, atherosclerotic risk factors, and organ manifestations. Results: Concentrations of IL-23 significantly differed between SLE patients and the controls (p = 0.0015). On the basis of multivariate stepwise analysis, we revealed that high levels of IL-23 were associated with atherosclerotic plaque in common femoral arteries (OR = 12.67; 95% CI: 1.41-113.84), lupus nephritis (OR = 3.69; 95% CI: 1.16-12.22), and obesity (OR = 4.21; 95% CI: 1.40-12.67). Autoantibodies related to IL-23 were anti-phosphatidylethanolamine antibodies (OR = 11.06; 95% CI: 1.24-98.65) and anti-SS-B/La antibodies (OR = 15.43; 95% CI: 1.73-137.25). Conclusions: IL-23 may be involved in lupus nephritis pathogenesis. Through its association with obesity and selected antiphospholipid antibodies, IL 23 might promote a hypercoagulable state contributing to atherothrombosis development in SLE patients. PMID- 29430086 TI - Greetings from the editorial committee. PMID- 29430083 TI - Autotaxin-Lysophosphatidic Acid: From Inflammation to Cancer Development. AB - Lysophosphatidic acid (LPA) is a ubiquitous lysophospholipid and one of the main membrane-derived lipid signaling molecules. LPA acts as an autocrine/paracrine messenger through at least six G protein-coupled receptors (GPCRs), known as LPA1 6, to induce various cellular processes including wound healing, differentiation, proliferation, migration, and survival. LPA receptors and autotaxin (ATX), a secreted phosphodiesterase that produces this phospholipid, are overexpressed in many cancers and impact several features of the disease, including cancer-related inflammation, development, and progression. Many ongoing studies aim to understand ATX-LPA axis signaling in cancer and its potential as a therapeutic target. In this review, we discuss the evidence linking LPA signaling to cancer related inflammation and its impact on cancer progression. PMID- 29430087 TI - Clinical evaluation of flowable resin composite versus conventional resin composite in carious and noncarious lesions: Systematic review and meta-analysis. AB - The purpose of this systematic review was to evaluate clinical performance of flowable composite in carious and noncarious lesions. An electronic search was conducted using specific databases (PubMed, Embase, Cochrane Library, and LILACS) through March 2017. Clinical trials for restoration of carious and noncarious lesions were included with no date restrictions; follow-up was 6 months at least and dental restorations were evaluated using the United States Public Health Service criteria. The systematic search generated 908 papers, of which 35 papers were included for full-text review. Inclusion criteria were met by eight papers, six papers were for noncarious lesions and two papers were for restoration of carious lesions. The results of this review have shown no statistical or clinical difference between flowable and conventional composites for all tested outcomes in both carious and noncarious lesions. Both materials have shown clinically acceptable scores for all criteria, with no evidence of clinically unacceptable scores except in retention, with a retention rate of 83% in both materials after 36 months. Flowable composites had clinical efficacy after 3 years of service similar to that of conventional composite in both carious and noncarious lesions, these results are based on low quality of evidence. Based on the available literature and the best available evidence, flowable composites can be used in restoration of noncarious cervical lesions and minimally invasive occlusal cavities. PMID- 29430085 TI - Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence. AB - There is good epidemiological evidence that patients with autoimmune rheumatic disease states, particularly rheumatoid arthritis, have an increased risk of cardiovascular morbidity and mortality when compared to the general population. The presence of a chronic systemic proinflammatory state in this patient group disrupts the structural and functional integrity of the endothelium and the arterial wall, favouring the onset and progression of atherosclerosis. A significant role in the detrimental effects of inflammation on endothelial function and vascular homeostasis is played by specific proatherosclerotic cytokines such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6). Recent systematic reviews and meta-analyses have shown that treatment with methotrexate, a first-line disease-modifying antirheumatic drug (DMARD), is associated with a significant reduction in atherosclerosis mediated cardiovascular events, such as myocardial infarction and stroke, and mortality, when compared to other DMARDs. This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease. This review discusses the available evidence regarding the potential antiatherosclerotic effects of methotrexate through the inhibition of TNF-alpha, IL-1, and IL-6 and provides suggestions for future experimental and human studies addressing this issue. PMID- 29430088 TI - Incremental techniques in direct composite restoration. AB - Polymerization shrinkage is one of the dental clinician's main entanglements when placing resin-based composite restorations. None of the method can assure a perfectly sealed restoration for adhesive restorative materials; clinicians must abode problems of polymerization shrinkage and its possible ill effects. The objective of this article is to review different incremental techniques that can ruin the polymerization shrinkage stress of direct composite restoration. PMID- 29430089 TI - Effect of incorporation of a new antimicrobial nanomaterial on the physical chemical properties of endodontic sealers. AB - Objectives: The objective of the study is to incorporate the nanostructured silver vanadate (AgVO3) decorated with silver nanoparticles at endodontic sealers AH Plus, Sealapex, Sealer 26, and Endofill, at concentrations of 2.5%, 5%, and 10%, and to evaluate physical-chemical properties. Materials and Methods: The study was to evaluate the radiopacity using digital radiography (n = 5), the tooth color change in 48 incisors (n = 3) for 7, 30, 90, and 180 days in a spectrophotometer, and the topographic distribution in a confocal laser (n = 5). The radiopacity was analyzed by Kruskal-Wallis test and the permutation (alpha = 0.05) and the color and topographical distribution by descriptive statistical analysis. Results: The AgVO3 had no effect on the radiopacity of Endofill and Sealapex (P > 0.05) and at 2.5% concentrations increased the radiopacity of Sealer 26 and AH Plus (P < 0.05). The Endofill 10% showed less color change, and the major changes were the modified groups in 180 days. The AgVO3 showed a circular topographic distribution in areas of the sealers. Conclusion: It was found that the addition of AgVO3 did not affect the radiopacity of Endofill and Sealapex however, increased the radipacity of Sealer 26 and AH Plus. For modified groups, the greatest color change was promoted after 180 days, except for Endofill with 10%. Topographic distribution of nanomaterial affected the color change of theevaluated sealers. PMID- 29430090 TI - Evaluation of antibacterial efficacy of biosynthesized silver nanoparticles derived from fungi against endo-perio pathogens Porphyromonas gingivalis, Bacillus pumilus, and Enterococcus faecalis. AB - Background: Even after rapid progress in contemporary dental practice, we encounter the failures due to endodontic, periodontal, or combined lesions. Complex anatomy of tooth and resistant microbes demands the development of new treatment strategies. Aim: The aim of this study is to biosynthesize silver nanoparticles (AgNPs) using fungi and determine the antibacterial efficacy against Porphyromonas gingivalis, Bacillus pumilus, and Enterococcus faecalis. Materials and Methods: Fungi isolated from healthy leaves of Withania somnifera were used to biosynthesize AgNPs. The biosynthesized AgNPs were characterized by different methods, and antibacterial efficacy was evaluated by agar well diffusion method measuring the zone of inhibition. Test microorganisms were divided as Group 1: B. pumilus 27142 (American Type Culture Collection [ATCC]), Group 2: E. faecalis 29212 (ATCC), and Group 3: P. gingivalis 33277 (ATCC). Agents used for antibacterial efficacy were grouped as: AgNPs: A (20 MUl), B (40 MUl), C (60 MUl), D (80 MUl), E (100 MUl), F (0.2% chlorhexidine [CHX]), G (2% CHX), H (Ampicillin), and I (sterile distilled water). Results: Characterization studies showed the color change from colorless to reddish brown color; ultraviolet spectrum showed peak at 420 nm, transmission electron microscope revealed the particles spherical in shape and 10-20 nm size. Fourier transform infrared spectroscopy analysis revealed the presence of functional groups. Data collected for antibacterial efficacy were analyzed using one-way ANOVA and post hoc Tukey's multiple shows no significant difference among three groups (P < 0.0001). AgNPs were as effective as CHX and positive control ampicillin. No zones were seen for I (distilled water). Conclusion: Biosynthesized AgNPs showed efficient antibacterial efficacy. Therefore, it creates a new horizon in the management of endodontic, periodontal, and combined lesions. PMID- 29430091 TI - Endodontic treatment of chronically infected primary teeth using triple antibiotic paste: An in vivo study. AB - Aim: Maintenance of primary dentition is imperative for the development of arch form, esthetics, function, mastication, and normal eruption of permanent teeth. Premature loss can cause various problems such as ectopic eruption, space loss for the successor permanent teeth, alterations in speech, and impairment of function. Hence, decayed primary teeth should not be extracted and treated whenever possible. Pulpectomy is generally recommended as a treatment of choice in such cases. The purpose of this study was to evaluate the clinical and radiographic success of pulpectomized primary teeth with chronic infection using a mixture of metronidazole, ciprofloxacin, and minocycline (3MIX)-MP as an intracanal medicament before the obturation. Methodology: Sixty primary teeth were selected, which were randomly divided into two groups (Group A and Group B) with thirty teeth in each group. In Group A, 3MIX-MP was used as intracanal medicament whereas in Group B, conventional pulpectomy was performed. Resolution of clinical signs and symptoms were evaluated within 2 weeks after the treatment and at recalled 3rd, 6th, and 12th month intervals. The treated teeth were evaluated clinically and radiographically. Results: High success rate was observed in Group A samples both clinically and radiographically. Although the difference in clinical success was not statistically significant, the difference in radiographic success was statistically significant. Conclusion: All the primary teeth with chronic infection which were treated using 3MIX-MP, followed by the instrumentation and obturation provided excellent clinical and radiographic success when compared to conventional pulpectomy and noninstrumentational lesion sterilization tissue repair therapy. PMID- 29430092 TI - Comparative evaluation of the amount of debris extruded apically using conventional syringe, passive ultrasonic irrigation and EndoIrrigator Plus system: An in vitro study. AB - Aim: The aim of this study is to compare the effects of conventional syringe, passive ultrasonic irrigation (PUI), and EndoIrrigator Plus on the amount of apically extruded debris. Materials and Methods: Thirty extracted human mandibular premolars were selected and randomly assigned to three groups (n = 10). The root canals were irrigated with conventional syringe, PUI, and EndoIrrigator Plus. Sodium hypochlorite was used as an irrigant, and debris was collected in a previously described experimental model (Myers and Montgomery 1991). It was then stored in an incubator at 37 degrees C for 10 days to evaporate the irrigant before weighing the dry debris. The mean weight of debris was assessed, one-way analysis of variance was used for comparison of values, and post hoc Tukey's test was used between groups (P = 0.05). Results: The EndoIrrigator Plus group extruded significantly less debris than PUI and conventional syringe groups (P < 0.05). Furthermore, PUI group extruded significantly less debris than conventional syringe irrigation group (P < 0.05). Conclusions: 1. All the three irrigation systems were associated with apical extrusion of debris, 2. EndoIrrigator Plus system extruded significantly less debris than the PUI system and the conventional syringe irrigation system, 3. PUI system extruded significantly less debris than the conventional syringe irrigation system. PMID- 29430093 TI - Grape seed extract: An innovation in remineralization. AB - Aim: The aim of this study was to determine remineralizing potential of grape seed extract (GSE) compared to casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and calcium glycerophosphate (CaGP) through pH-cycling model and subsequent evaluation using polarized light microscope (PLM). Subjects and Methods: Twenty sound human teeth fragments of ten teeth were obtained from the cervical portion of the roots and were stored in demineralizing solution for 96 h at 37 degrees C to induce artificial root carious lesion. The sections then were divided into four treatment groups including: 6.5% GSE, CPP-ACP, 0.5% CaGP, and control group (no treatment). The demineralized samples were then pH cycled through treatment solutions, acidic buffer, and neutral buffer for 8 days at six cycles per day. The samples were subsequently evaluated using PLM. Statistical Analysis Used: Data were analyzed using ANOVA and Scheffe post hoc comparison test (P < 0.001). Results: PLM data revealed a significantly thicker mineral precipitation band on the surface layer of the GSE-treated lesions compared to the other groups (P < 0.001). Conclusion: GSE positively affects the demineralization and/or remineralization processes of artificial root caries lesions. PMID- 29430094 TI - Effect of ultrasonic activation of photosensitizer dye temoporfin (Foscan) on antimicrobial photodynamic therapy: An ex vivo study. AB - Aim: The aim of this study is to evaluate the effectiveness of ultrasonic activation of photosensitizer (PS) drug Foscan in the elimination of endodontic pathogen from root canal system. Materials and Methods: The minimal bactericidal concentration of "Foscan" was determined using disc diffusion and broth dilution method. Forty-eight extracted single-rooted premolars with periapical pathology were used for the study. After access opening, the first microbial sample was taken. The teeth were then randomly divided into four groups: Group 1: Chemomechanical debridement (CMD), Group 2: CMD and passive ultrasonic irrigation (CMD + PUI), Group 3: CMD and antimicrobial photodynamic therapy (aPDT), and Group 4: CMD and aPDT with activation by ultrasonics. After antimicrobial protocols, the second microbiological sample was collected. The samples were analyzed by multiplex polymerase chain reaction for the effectiveness of four antimicrobial protocols on Fusobacterium nucleatum, Prevotella intermedia, Porphyromonas gingivalis, and Treponema denticola. Statistical Analysis Used: Wilcoxon signed-rank test and Mann-Whitney U-test with the significant level P < 0.05, using IBM SPSS statistics 20 version software. Results: Foscan at concentration of 3.125 MUg/ml was chosen for antimicrobial analysis. The prevalence of T. denticola, F. nucleatum, P. gingivalis, and P. intermedia was 79.17%, 70.84%, 70.83%, and 58.33%, respectively. Group 4 showed highest bacterial reduction of 99.51%, followed by Group 1 which showed bacterial reduction of 97.35%. Conclusions: Foscan can be used as an effective PS dye at low concentration with minimal tendency for tooth discoloration. Ultrasonic activation of PS dye facilitated better diffusion into dentinal tubules and biofilm obtaining greater bacterial reduction. PMID- 29430095 TI - Comparative evaluation of effect of rotary and reciprocating single-file systems on pericervical dentin: A cone-beam computed tomography study. AB - Aim and Objective: The aim of this study is to evaluate and compare the effect of one shape, Neolix rotary single-file systems and WaveOne, Reciproc reciprocating single-file systems on pericervical dentin (PCD) using cone-beam computed tomography (CBCT). Materials and Methods: A total of 40 freshly extracted mandibular premolars were collected and divided into two groups, namely, Group A Rotary: A1 - Neolix and A2 - OneShape and Group B - Reciprocating: B1 - WaveOne and B2 - Reciproc. Preoperative scans of each were taken followed by conventional access cavity preparation and working length determination with 10-k file. Instrumentation of the canal was done according to the respective file system, and postinstrumentation CBCT scans of teeth were obtained. 90 MUm thick slices were obtained 4 mm apical and coronal to the cementoenamel junction. The PCD thickness was calculated as the shortest distance from the canal outline to the closest adjacent root surface, which was measured in four surfaces, i.e., facial, lingual, mesial, and distal for all the groups in the two obtained scans. Results: There was no significant difference found between rotary single-file systems and reciprocating single-file systems in their effect on PCD, but in Group B2, there was most significant loss of tooth structure in the mesial, lingual, and distal surface (P < 0.05). Conclusion: Reciproc single-file system removes more PCD as compared to other experimental groups, whereas Neolix single file system had the least effect on PCD. PMID- 29430096 TI - Clinical and radiographic assessment of periapical pathology in single versus multivisit root canal treatment: An in vivo study. AB - Objective: The objective of the study was to compare and evaluate the clinical and radiographic outcome of single- versus multivisit endodontic treatment in teeth with periapical pathology at the end of 1, 3, and 6 months. Materials and Methods: Sixty single- and multi-rooted teeth indicated for root canal treatment with periapical pathology were included in the study. The teeth were assigned randomly into two groups Group I and Group II (n = 30 each), which were further subdivided into subgroup IA, subgroup IB and subgroup IIA, subgroup IIB (n = 15 each), respectively. Group I was medicated with ApexCal paste and obturated using the standardized protocol in second visit 7-10 days later, whereas Group II was obturated at the first visit. In subgroup IA and subgroup IIA, obturation was done using Apexit Plus sealer, whereas, in subgroup IB and subgroup IIB, AH Plus sealer was used. Patients were recalled at intervals of 1, 3, and 6 months to evaluate teeth for periapical healing. Results: Kruskal-Wallis and one-way ANOVA test showed no significant difference between Groups I and II, whereas Wilcoxon signed-rank test showed improvement in all the subgroups with highly significant P value (<=0.001). Conclusion: Single-visit root canal treatment can be considered as a viable option for treatment of teeth with periapical pathology. PMID- 29430098 TI - Comparison of different agitation methods for the removal of calcium hydroxide from the root canal: Scanning electron microscopy study. AB - Aim: This ex vivo study compared the efficiency of different irrigations systems to remove calcium hydroxide from root canal walls, especially from the apical third by using scanning electron microscopy (SEM). Materials and Methods: Eighty four single-rooted teeth were divided into 4 groups of 20 teeth each, according to different irrigation protocols using a 30-gauge slot-tipped needle, ultrasonic irrigation system, erbium-doped yttrium aluminum garnet laser (Er: YAG) laser, and EndoVac system. The rest 4 teeth were used as control groups (2 positive and 2 negative control groups). After coronal access, all teeth were instrumented by Protaper Next rotary files (Dentsply-Maillefer, Ballaigues, Switzerland) up to size X3, followed an irrigation protocol and filled with pure calcium hydroxide powder mixed with saline. Teeth were stored in an incubator for 7 days, and then, calcium hydroxide was removed using 3 techniques: Manually (Group 1), by ultrasonic irrigation (Group 2), by laser Er: YAG and x-pulse tip (Group 3), and by EndoVac system (Group 4). The teeth of control groups were instrumented as the experimental groups; no removal technique was applied in positive group, whereas in negative one, the root canals were left empty. Teeth were sectioned longitudinally and observed under SEM Results were statistically analyzed with the Kruskal-Wallis Test and Mann-Whitney Test. Results: The results showed a significant difference between laser and the other three groups in coronal and middle root third, but no statistic difference in apical third. Conclusion: Laser improved the removal of calcium hydroxide in comparison with conventional techniques. PMID- 29430097 TI - Cone-beam computed tomography assessment of root canal transportation using WaveOne Gold and Neoniti single-file systems. AB - Introduction: The aim of this study was to compare canal transportation of two single-file systems, WaveOne Gold and Neoniti, using cone-beam computed tomography (CBCT). Methodology: A total of 40 mesiobuccal canals of maxillary first molars with curvatures of 15 degrees -30 degrees were chosen and randomly divided into two experimental groups (n = 20). In both groups, glide path was established using ProGlider. In group 1, canals were shaped with WaveOne Gold and in group 2 with Neoniti A1, respectively. According to manufacturer's instructions, canal preparation was made. Canals were scanned before and after instrumentation using CBCT scanner to evaluate root canal transportation at 3, 5, and 7 mm from the apex. Data were statistically analyzed, and significance level was set at P < 0.05. Results: Mesiodistal and buccolingual transportation showed a statistically significant difference at 3 mm (P = 0.009) and 7 mm (P = 0.002), respectively, when instrumented with Neoniti than WaveOne Gold. Conclusion: WaveOne Gold single reciprocation file respected original canal anatomy better than Neoniti single continuous file. PMID- 29430099 TI - Comparative evaluation of fracture resistance of root canals obturated with four different obturating systems. AB - Aim and Objectives: The aim of this study is to evaluate and compare the fracture resistance of root canals obturated with four different obturating systems in endodontically treated teeth. Materials and Methods: One hundred and twenty single-rooted teeth were selected and decoronated at cementoenamel junction. Instrumentation of teeth (except control group) was done with Mtwo rotary files up to size 25/0.06 using a step-back technique. All teeth were divided into four experimental groups (n = 25) and two control groups (n = 10). In Group I (negative control), teeth were neither instrumented nor obturated, in Group II (positive control), instrumentation was done, but no obturation was performed, in Group III, obturation was done with cold lateral compaction technique, in Group IV, obturation was done with cold free-flow compaction technique, in Group V, obturation was done with warm vertical compaction technique, and in Group VI, obturation was done with injection-molded thermoplasticized technique. All prepared teeth were embedded in an acrylic resin block, and their fracture strength was measured using Universal Testing Machine. Statistical data were analyzed using one-way analysis of variance and Tukey's honestly significant difference test. Results: Negative control Group I showed highest fracture resistance and positive control Group II had lowest fracture resistance. Among experimental groups, cold free-flow compaction technique with GuttaFlow2 (Group IV) showed higher fracture resistance as compared to the Group III, Group V, and Group VI. Conclusion: GuttaFlow2 has the potential to strengthen the endodontically treated roots to a level that is similar to that of intact teeth. PMID- 29430100 TI - Comparison and evaluation of two reciprocating root canal instruments on removal of smear layer by using two irrigants at apical one-third of the root canal-an ex vivo-scanning electron microscopic study. AB - Aim: To compare and evaluate the cleaning ability of two reciprocating systems, that is, WaveOne (WO) and self-adjusting files (SAF) in terms of removal of smear layer using sodium hypochlorite (NaOCl) and chlorhexidine gluconate (CHX) at apical one-third of the root canal. Materials and Methods: Forty-three human maxillary anterior teeth were selected. The canal was instrumented manually up to a number 25 K-file size. WO and SAF were used to prepare the root canals. The following groups were studied: Group 1 using WO:-Group 1a = 5% NaOCl + 17% ethylenediaminetetraacetic acid (EDTA), Group 1b = 2% CHX + 17% EDTA, Group 2 using SAF:-Group 2a = 5% NaOCl + 17% EDTA, Group 2b = 2% CHX + 17% EDTA. All roots were split longitudinally and subjected to scanning electron microscopic. The presence of smear layer apical thirds was evaluated using a 5-score evaluation system. Chi-square tests were used for statistical analysis. Results: The results showed no significant difference in smear layer removal among both reciprocating system and among the irrigants. Group 2a exhibited the best results and was close to significant difference in score (P > 0.05). The NaOCl + EDTA solution used in Group 1a and Group 2a could effectively remove the smear layer in most of the specimens. However, SAF was more effective than WO in the apical third of the canal. Conclusion: The results obtained from the present study suggest that using the SAF system and continuous irrigation action with NaOCl and EDTA solution could overcome the difficulty of removing smear layer even in hard to-reach regions of the root canal. PMID- 29430101 TI - Incidence of dentinal defects during root canal preparation with hand files using different irrigants: An in vitro study. AB - Introduction: The purpose of this in vitro study was to compare the incidence of dentinal defects during root canal preparation with hand files using different irrigants. Materials and Methods: A total of 120 extracted mandibular incisors were randomly divided into onecontrol group and five experimental groups (n = 20) depending on the irrigant used. Biomechanical preparation was not done in control group. Teeth in experimental groups were prepared with hand K-files to a master apical file #35 with 1-mm increments step-back up to #50. In Group 2, saline was used as an irrigant. In Groups 3, 4, 5, and 6, 3% sodium hypochlorite (NaOCL), SmearClear, 17% ethylenediaminetetraacetic acid (EDTA), and 2% chlorhexidine (CHX), respectively, were used as an irrigant. Specimens were sectioned perpendicular to the long axis at 3, 6, and 9 mm from the apex. Sections were observed under a digital stereomicroscope at 30* magnification. Two-tailed t-test was used for statistical analysis. Results: There was a statistically significant difference between the six groups. Group 5 (17% EDTA) had the highest number of dentinal defects, followed by Group 3 (3% NaOCl), Group 4 (SmearClear), and Group 6 (2% CHX). Conclusions: 17% EDTA causes more dentinal defects as compared to 3% NaOCl, SmearClear, 2% CHX, and saline. PMID- 29430102 TI - Comparative evaluation of remineralizing potential of Fluoride using three different remineralizing protocols: An in vitro study. AB - Background: Remineralization of noncavitated enamel is dependent on the bioavailability of calcium, phosphate, and hydroxyl ions in saliva. However, it is enhanced by the presence of fluoride. This study compared the remineralizing potential of three different topical fluoride agents. Materials and Methods: Fifteen extracted premolars were selected for the study. The crown of each tooth was longitudinally sectioned buccolingually and mesiodistally using a diamond disc so as to obtain sixty specimens which were embedded in acrylic molds. The specimens were immersed in demineralizing solution for 3 days. The specimens were randomly assigned to four groups, namely Duraphat fluoride varnish, ReminPro paste, ClinPro Tooth Creme, and control group (no surface treatment). A pH cycling includes alternate demineralization and remineralization. Surface mean hardness (SMH) was recorded with 50 g load for 5 s using VHN machine at baseline, after demineralization and pH cycling. The four groups were compared for difference in SMH using one-way ANOVA followed by Tukey-Kramer test. All testing was done with alpha 0.05. Results: SMH recovery results for ClinPro, Duraphat, and ReminPro were 54.88%, 43.42%, and 26.86%, respectively. The difference in the percentage SMH recovery for ClinPro paste was better than Duraphat and ReminPro, and this difference was statistically significant (P < 0.05). Conclusions: ClinPro tooth Creme showed the best remineralization potential among the three materials tested followed by Duraphat and ReminPro. PMID- 29430104 TI - Fracture resistance of reattached fragments using three different techniques with emphasis on vertical grooves and fiber-reinforced composite post: A novel technique. AB - Background: The aim of this study was to evaluate and compare relatively less explored fragment reattachment methods following traumatic injury. Materials and Methods: Eighty sound permanent maxillary incisors were selected and mounted in acrylic blocks. Teeth were sectioned using the diamond disc and randomly divided into 4 groups (n = 20), Group A, B, C, D. In Group A, after reattachment with composite, a 1 mm-depth circumferential chamfer was placed in the fracture line using a diamond disc bur and filled with composite. In Group B, two vertical grooves 1 mm deep, 1 mm wide, and 4 mm length were placed on the labial surface perpendicular to the fracture line and filled with two fiber-reinforced composite (FRC) posts and composite. In Group C, dentin is removed from the fragment and filled with composite. In Group D, the teeth were intact which served as control group. The force required to fracture the reattached teeth were recorded in Newton's using an onscreen calibration tool of the universal testing machine. Results: Teeth in Groups A, B, C required lesser force to fracture when compared with the teeth of the Group D. When compared to Group D, Group A showed a fracture resistance of 36%, Group B 62%, and Group C 32%. Conclusion: This study proves that reattachment by vertical grooves with FRC posts showed highest fracture resistance and it is the most preferred method. So far no attempt has been made to reattach fractured fragment using vertical grooves and reinforcing with FRC posts. PMID- 29430103 TI - Effect of three different rotary instrumentation systems on postinstrumentation pain: A randomized clinical trial. AB - Background: Endodontic instrumentation is liable to cause some postinstrumentation pain (PIP). Rotary endodontic instruments differ in their design, metallurgy, surface treatment, etc. Aim: This randomized clinical trial aimed to assess the incidence of PIP after root canal instrumentation with three different rotary endodontic systems which differ in their design, namely, ProTaper, Mtwo, and K3. Materials and Methods: A total of 150 patients between the ages of 25 and 50 were chosen for the study. Teeth with asymptomatic irreversible pulpitis due to carious exposure were selected. The patients received local anesthesia by inferior alveolar nerve block. After preparing the access cavity, root canal instrumentation was done with one of the three instruments (n = 50) and closed dressing was given. PIP was assessed every 12 h for 5 days, and tenderness to percussion was analyzed at the end of 1, 3, and 7 days. Statistical Analysis: Mann-Whitney U-test to determine significant differences at P < 0.01. Results: The PIP and tenderness were less in Mtwo group when compared to ProTaper and K3 groups up to 84 h and 72 h respectively and statistically significant (P < 0.05). There was no statistically significant difference between ProTaper and K3 both in PIP and tenderness. Conclusion: Rotary endodontic instrumentation causes some degree of PIP and tenderness to percussion. Among the instruments used, Mtwo causes less PIP and tenderness when compared to ProTaper and K3, and there was no difference between ProTaper and K3. Clinical Relevance: PIP is highly subjective and may vary among different subjects. The apical (3 mm) taper of ProTaper was 0.08 followed by a smaller taper, whereas, the other two files were of a constant 0.06 taper, which means there could have been a greater apical extrusion and therefore more PIP. Despite, the mean of the age was similar, there could have been a difference in the size of the canal and therefore a difference in apical extrusion and PIP. PMID- 29430105 TI - Accessory branch of canalis sinuosus mimicking external root resorption: A diagnostic dilemma. AB - The aim of this study was to recognize the importance of canalis sinuosus in Endodontics. A 60-year-old male patient reported with the chief complaint of pain and swelling in upper front tooth region for 2 weeks with a history of trauma 21 years back. Clinical examination revealed fractured tooth 21 (maxillary left central incisor) with an associated sinus tract. Radiographic examination revealed diffuse periapical radiolucency in relation to tooth 21 and external resorptive defect in apical third of the root of tooth 11 (maxillary right central incisor). Cone-beam computed tomography advised to plan surgical treatment for the same disclosed the presence of an anatomic variation of canalis sinuosus. The location and course of this canal illuded as a resorptive defect, which is a very rare occurrence. This led to a change in diagnosis with relation to tooth 11 and treatment plan was formulated accordingly. PMID- 29430106 TI - Radiation Dose to the Occupational Worker during the Synthesis of 188Re-labeled Radiopharmaceuticals in the Nuclear Medicine Department. AB - Aim: The aim of this study is to estimate whole-body radiation dose to the radiopharmacist involved in labeling of three different 188Re-labeled compounds, namely, 188Re-Lipiodol, 188Re-tin colloid, and 188Re-hydroxyl-ethylidene diphosphonate (HEDP) and to compare the occupational burden with the dose limits recommended by Atomic Energy Regulatory Board, India. Materials and Methods: The Department of Nuclear Medicine at Fortis Memorial Research Institute currently synthesizes three different Rhenium-188 labeled compounds, namely, 188Re Lipiodol, 188Re-HEDP, and 188Re-tin colloid. To estimate the radiation exposure to the radiopharmacist involved in the synthesis, a survey meter was used to measure radiation level before the start of labeling procedure in the radiopharmacy by keeping it at the location where the radiopharmacist normally stands during preparation. Data were collected for 6 syntheses of each 188Re Lipiodol, 4 for 188Re-HEDP, and 3 for 188Re-tin colloid followed by the quality control. The pocket dosimeter was used by the radiopharmacistat chest level, performing the labeling of 188Re-labeled compounds. All radiopharmaceuticals were synthesized by a single radiopharmacist. Results: 1850 MBq (50 mCi) 188W-188Re generator was eluted before the preparation of each radiopharmaceutical. The amount of 188ReO4- used for labeling with lipiodol/4-hexadecyl-1,2,9,9 tetramethyl-4,7-diaza-1,10-decanethiol, HEDP, and Tin colloid was in the range of 3182-4440 MBq (86-120 mCi), 2812-3774 MBq (76-102 mCi), and 962-1295 MBq (26-35 mCi), respectively. Meantime required to complete the synthesis was 95, 40, and 131.5 min, respectively. Mean whole-body effective dose received was 0.052, 0.009, and 0.004 mSv, respectively, as measured by using the pocket dosimeter. Conclusion: From this small study, we observed that the whole-body radiation dose to the radiopharmacist in radiolabeling and quality control of 188Re-labeled radiopharmaceuticals is within prescribed limits at the current synthesis frequency. PMID- 29430107 TI - Reduction of Radiation Exposure to Patients and Professionals by Reducing the Administered Activity of 18F-Fluorodeoxyglucose in a Positron-emission Tomography/Computed Tomography Study. AB - Aim: With increased clinical indications for positron-emission tomography/computed tomography (PET/CT) and repeated PET/CT scans, there is a need to reduce the radiation burden to the patient, professionals as well as public. This requires a redefining of the workflow and the 18-F fluorodeoxyglucose (18F-FDG) administered activity. The objective of our study is to observe the impact of strike out reduction of administered activity on the radiation exposure to personnel and public, as well as the absorbed dose to the patient with no compromise on image quality by increasing the image acquisition time. Materials and Methods: Nineteen patients evaluated in this study (11 males, 8 females) were put into two groups, namely, A and B. Patients in Group A (n = 10) were administered with 18F-FDG equivalent to the recommended dose (7-8 MBq/kg body weight) whereas patients in Group B (n = 9) were administered with 18F-FDG equivalent to half the recommended dose (3-4MBq/kg body weight). The exposure rates from the patients at the body surface and 100 cm distance were measured immediately and 1 h postinjection. Results: The average surface dose rate and 100 cm dose rate of the adult patients immediately postinjection for patients of Group A were 0.94 +/- 0.19 mSv/h and 0.057 +/- 0.007 mSv/h, and for Group B were 0.34 +/- 0.24 mSv/h and 0.031 +/- 0.01 mSv/h. Conclusion: This study suggests that reduction in injected 18F-FDG activity reduces the radiation exposure rate from the patient, absorbed dose to the patient with reportable image quality. PMID- 29430108 TI - Impact of the Amount of Liquid Intake on the Dose Rate of Patients Treated with Radioiodine. AB - Purpose: Despite therapeutic effects of radioiodine in patients with differentiated thyroid cancer, there are some disadvantages due to harmful radiation to other tissues. According to the current guidelines, patients are recommended to drink lots of water and frequent voiding to reduce the amount of 131I in the body. This study was designed to assess the impact of the amount of liquid intake on reduction of the measured dose rate of radioiodine-treated patients. Materials and Methods: A total of 42 patients with differentiated thyroid cancer without metastasis who had undergone total thyroidectomy and had been treated with radioiodine were selected. The patients were divided into two groups according to the amount of their fluid intake which was measured during the first 48 h after 131I administration. In all patients, the dose rate was measured immediately and 48 h after iodine administration. Results: Each group included 21 patients. Dose rate ratio (the ratio of the second dose rate to the first dose rate) and dose rate difference ratio (the ratio of the difference between the two measured dose rates to the first dose rate) were calculated for each patient. Despite the significant difference in the amount of the liquid drunk, no statistically significant difference was seen between the different groups in parameters of dose-rate ratio and dose-rate difference ratio. Conclusion: Higher fluid intake (>60 ml/h in our study) alone would not effectively reduce the patient's radiation dose rate at least not more than a well-hydrated state. It seems that other interfering factors in the thyroidectomized patients may also have some impacts on this physiologic process. PMID- 29430109 TI - Comparison of Left Ventricular Phase Parameters Analysis between Two Software Programs in Patients with Normal Gated Single-photon Emission Computed Tomography Myocardial Perfusion Imaging. AB - Background: Phase analysis can be easily performed by different software to assess the left ventricular dyssynchrony from gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) with high precision. However, the normal values of histogram bandwidth (HBW) and phase standard deviation (PSD) and their comparison using different programs have not been fully elucidated and actively being evaluated at present. The aim of this study was to determine the phase analysis parameters values and to compare the phase indices of two commonly used programs in a group of patients with normal gated SPECT-MPI. Methods: Phase parameters were retrospectively evaluated in 138 consecutive nondiabetic patients having a normal gated SPECT-MPI using the quantitative gated SPECT (QGS) and Emory Cardiac Toolbox (ECTb) software. HBW, PSD, and phase entropy were calculated separately using both programs. Results: The fair correlation between software programs was observed. HBW and PSD in QGS and ECTb were 26.20 +/- 9.7 and 25.46 +/- 8.0 (r-value. 56, SEE 6.65) and 6.64 +/ 2.5 and 7.65 +/- 2.5 (r = 0.54, SEE 2.14), respectively. The value of phase entropy in QGS program was 45.08 +/- 6.3. A fair correlation between phase entropy and PSD in QGS was observed (r = 0.44, 95% confidence interval-0.29 0.56). Conclusion: Phase analysis parameters derived from gated SPECT-MPI in patients with normal myocardial perfusion are program dependent and may differ. The results cannot be interchangeably used in the same patients. PMID- 29430110 TI - Vitamins E and C Prevent DNA Double-strand Breaks in Peripheral Lymphocytes Exposed to Radiations from Iodine-131. AB - Purpose: Iodine-131 is used as a radiopharmaceutical to treat thyroid cancer. The current study aimed to evaluate the effects of vitamins E and C on the level of DNA double-strand breaks (DSBs) caused by Radioiodine-131 (I-131) in human lymphocytes. Materials and Methods: Whole blood samples from human volunteers were incubated with a certain concentration of vitamins. After 1-h incubation, the samples were incubated with 20 MUCi I-131/2 mL (blood + NaCl) for 1 h. To evaluate the effects of antioxidants, lymphocytes were separated, and the mean DSBs/cell was measured for each sample through gamma-H2AX assay. Results: After 1 h incubation with 20 MUCi I-131/2 mL (blood + NaCl), iodine-131 increased the level of DSBs by 102.9%, compared with the background group. Vitamins E and C reduced the level of DSBs by 21.5% and 36.4%, respectively. Conclusion: Using vitamins E and C as antioxidants can reduce the toxicity of I-131. Furthermore, vitamin C provided the more protection for DNA, compared with vitamin E. PMID- 29430111 TI - Scintigraphic Evaluation of Esophageal Motility and Gastroesophageal Reflux in Patients Presenting with Upper Respiratory Tract Symptoms. AB - Purpose of Study: The purpose is to evaluate the findings and utility of esophageal transit scintigraphy (ETS) and gastroesophageal reflux scintigraphy (GES) in patients presenting with upper respiratory tract (URT) symptoms suspected to be due to gastroesophageal reflux (GER) disease. Materials and Methods: Thirty patients aged between 19 and 60 years underwent nasopharyngolaryngoscopy (NPL), ETS, and GES. Correlation between GER, esophageal motility, and NPL was evaluated. Inclusion criteria include patients with recurrent URT symptoms such as chronic dry cough/hoarseness of voice and itching/foreign body sensation in throat. Those with typical gastrointestinal (GI) symptoms of GER, URT symptoms relieved by antibiotics, surgical intervention in abdomen, cardiac/hepatobiliary diseases, etc. were excluded from the study. Results: Significant correlation was found between GER and NPL in 28/30 patients. More the grade of reflux, more severe was the NPL findings. Two patients with Grade II reflux had normal NPL suggesting structural inflammatory changes due to acidic pH of refluxate which have not yet manifested or symptoms could be due to nonacid refluxate. Incidence of esophageal motility disorder was statistically significant in patients with GER disease (GERD). Patients who had symptoms, but no demonstrable GER showed delayed ET in supine position suggesting the presence of esophageal motility disorder even before GERD. Conclusion: GES demonstrated GER in patients presenting with URT symptoms without typical GI symptoms. ETS showed coexistence of esophageal motility disorder in most patients presenting with URT symptoms even without an associated reflux disease. We hypothesize that primary abnormal esophageal motility leads to delayed esophageal clearance and consequently to URT symptoms. Addition of ETS to GES is easily feasible with no significant additional cost, time, or radiation burden. PMID- 29430112 TI - Role of Myocardial Perfusion Study in Differentiating Ischemic versus Nonischemic Cardiomyopathy Using Quantitative Parameters. AB - Purpose: Ischemic cardiomyopathy (ICM) and non-ICM (NICM) causes of dilated cardiomyopathy with similar clinical presentation have different management and prognosis. This study employed myocardial perfusion imaging (MPI) to differentiate between the two using quantitative parameters in Indian population. Methods and Materials: Fifty patients prospectively underwent MPI and 18F fluorodeoxyglucose metabolism studies. P values (0.05 as significant) were calculated for the left ventricular ejection fraction (EF), end diastolic volume (EDV) at rest and stress, end systolic volume (ESV) at rest and stress, summed rest score (SRS), summed difference score (SDS), and eccentricity. On 6-month follow-up, rate of hospital admission, change in management and death was correlated for ICM and NICM. Coronary angiography (CAG) being gold standard, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and level of agreement were calculated for MPI. Results: MPI and CAG had a moderate level of agreement (kappa = 0.463) for differentiating ICM and NICM. The sensitivity, specificity, PPV, NPV, and diagnostic accuracy were 79.31%, 66.67%, 76.67%, 70.0%, and 74% for ICM and 66.67%, 79.31%, 70%, 76.67%, and 74% for NICM, respectively. Significant differences were seen in EDV stress (P = 0.045), EDV rest (P = 0.031), ESV rest (P = 0.034), SRS (P = 0.004), Left ventricular EF rest (P = 0.049) and SDS in ICM and NICM, respectively. Conclusion: EDV at rest and stress, ESV at rest, SRS, SDS, and EF at rest obtained using MPI provides precise quantitative information to differentiate ICM and NICM. It is wide and easy availability, noninvasiveness, objectivity, and near absence of complications favors it as a preferable diagnostic tool with its given sensitivity, specificity, and accuracy for the purpose. PMID- 29430113 TI - Comparison of the F+20 and F-15 Diuresis Technetium-99m Diethylenetriaminepentacetate Renography Protocols for Diagnosis of Ureteropelvic Junction Obstruction in Adult Patients with Hydronephrosis. AB - Introduction: Hydronephrosis (HDN) in adults is a common presentation and may be due to congenital ureteropelvic junction obstruction. Diuresis renography is the method of choice for differentiating a dilated unobstructed urinary system from a true obstruction. The aim of this study was to compare the F+20 protocol with F 15 protocol and see whether this new protocol can reduce inconclusive results. Materials and Methods: It was a prospective, comparative study included 51 adult patients of primary HDN. Each patient underwent both F+20 and F-15 diuretic Technetium-99m diethylenetriaminepentacetate (Tc-DTPA) renography protocol studies. The results of diuretic Tc-DTPA renography studied in terms of obstructive, nonobstructive, or equivocal. Results: A total 60 renal units (RU) with HDN were included in this study. The mean age of patients was 25.25 years. 36 RU presented with specific symptoms and 24 RU with vague symptoms or diagnosed incidentally. The equivocal results were significantly lower in F-15 protocol than F+20 protocol. The equivocal results in F+20 protocol were significantly higher with incidentally diagnosed HDN and patients presented with vague symptoms. Most of the equivocal results of F+20 protocol were converted into either obstructive or nonobstructive by the F-15 protocol. Conclusion: The F-15 diuretic renogram protocol was associated with significantly less equivocal results than F+20 protocol. Moreover, F-15 protocol allowed clarification in cases of equivocal results of F+20 protocol. Therefore, we suggest the F-15 diuresis protocol as a single test for confirmation or exclusion of obstruction especially in the adult patient of HDN presented with vague symptoms or diagnosed incidentally. PMID- 29430114 TI - Dacroscintigraphy by Pediatric Dropper Technique: A User-friendly Instillation Procedure of Radiotracer. AB - Context: Instillation or application of the radiotracer over the tear film is one of the important parts of dacroscintigraphy. Our study explains the value of an improvised dropper technique so that desired amount of radioactivity in desired volume can be instilled over the tear film. Aim: The aim of the study is to introduce a simple and convenient instillation method based on dropper technique for performing dacroscintigraphy. This improvised dropper technique can be used so that desired amount of radioactivity in desired volume can be instilled over the tear film. The objectives of this experiment are to measure the volume and activity of each drop from the dropper. Settings and Design: Experiment of volume and activity measurement standardization was carried out in two parts. In the first part, we calculated the volume of each drop indirectly to standardize the volume of drop. In the second part, we standardized the activity in each drop by measuring it in a dose calibrator. Subjects and Methods: In this study, we used a common pediatric dropper of approximately 1 ml capacity, radioactivity (99mTcO4 pertechnetate), sample vial (container), vial holder, a pair of nonsterile gloves, dose calibrator, etc., Experiments of volume and radioactivity standardization were carried out in two parts. The first part of experiment calculated volume of each drop indirectly, and in the second, we standardized the activity in each drop by measuring it in dose calibrator. Statistical analysis used: Analysis of variance test was used to calculate the correlation of readings by same individual as well as among the three individuals. Results: After analysis of result obtained, it was understood that there was no significant difference found in volume and activity of each drop in the readings recorded by same individual as well as among the three individuals. The calculated activity and observed activity were 86.64 and 79.16 MUCi, respectively. The difference was only 8.63% lying within acceptable limits. PMID- 29430115 TI - 18F-Fluorodeoxyglucose Positron Emission Tomography-computed Tomography in Evaluation of Large Vessel Vasculitis. AB - 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) is a rapidly evolving hybrid imaging technique in evaluation of infection and inflammation. Usually, functional changes often precede anatomical changes. 18F-FDG PET-CT, a noninvasive diagnostic test and it is useful for the early detection of inflammation. Most of the large vessel vasculitis patients present with nonspecific signs and symptoms, which are difficult to diagnose clinically. Here, we discuss three cases of large vessel vasculitis with different clinical presentations, identified by 18F-FDG PET-CT scan. PMID- 29430116 TI - Sinonasal Adenoid Cystic Carcinoma with Rare Renal Metastasis on Fluorodeoxyglucose Positron Emission Tomography Scan: A Case Report and Literature Review. AB - Adenoid cystic carcinoma (ACC) of sinonasal cavity is not the frequent entity. It is characterized by indolent growth and clinical course and high rate of recurrences, perineural spread, and late metastases. We represent a patient with rare renal metastasis from sinonasal ACC in pretreatment fluorodeoxyglucose positron emission tomography-computed tomography scan, and pathological confirmation has been obtained from both the primary and metastatic sites. Metastatic lesion was asymptomatic and found during the early course of disease. As per our knowledge, this is the second case report of sinonasal ACC with renal metastasis and the first case of metastatic ACC in patient prior receiving any type treatment. PMID- 29430117 TI - Trails on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Leading to Diagnosis of Testicular Adrenal Rest Tumor. AB - Testicular adrenal rest tumors (TARTs) are secondary to hypertrophy of adrenal rest cells in the rete testis in settings of hypersecretion of androgens. We present a case of congenital adrenal hyperplasia with TART with clues to the diagnosis on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). To the best of our knowledge, this is the first reported case on the role of 18F-FDG PET/CT in TART. PMID- 29430118 TI - Penile Metastasis from Prostate Cancer Presenting as Malignant Priapism Detected Using Gallium-68 Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography. AB - Gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (Ga-68 PSMA PET/CT) is a promising diagnostic tool for patients with prostate cancer. Penile metastasis from prostate cancer is a rare phenomenon that infrequently manifests as malignant priapism. We present a case of 79-year-old patient diagnosed as a case of adenocarcinoma prostate presenting with penile metastases imaged using Ga-68 PSMA PET/CT. PMID- 29430119 TI - A Rare Case of Synchronous Papillary Microcarcinoma and Metastatic Neuroendocrine Tumor of Unknown Primary. AB - Thyroid papillary microcarcinomas (PMCs) usually follow a very benign clinical course and are rarely metastatic. Any case of PMC presenting with distant metastases without any rising thyroglobulin level should be suspected to have any other primary apart from the thyroid and a meticulous clinical and diagnostic approach should be considered to identify the second primary. We hereby present a case of 52-year-old female treated as PMC with metastatic liver lesion, which was initially thought to be of thyroidal origin. Later, it was diagnosed as a metastatic neuroendocrine tumor of unknown primary. PMID- 29430120 TI - Role of Positron Emission Tomography-computed Tomography in a Case of Suspected Paraneoplastic Inflammatory Polymyositis with Urinary Bladder Tumor. AB - Idiopathic inflammatory myositis is characterized by rapidly progressive, symmetric weakness of the muscles that produce severe disability. In the majority of these patients, myositis appears to be a paraneoplastic feature associated with cancer. Fluorodeoxyglucose positron emission tomography-computed tomography has been increasingly used in the detection and evaluation of occult malignancy responsible for the paraneoplastic syndromes. PMID- 29430122 TI - Incidental Detection of Perinephric Urinary Leak on Bone Scintigraphy in a Patient with Urinary Bladder Carcinoma. AB - A 71-year-old male patient with urothelial carcinoma of the bladder was referred for 99mTc-methylene diphosphonate bone scintigraphy to assess for skeletal metastasis. While the bone scan showed no abnormal skeletal uptake, tracer activity was detected in the extrarenal region of the left renal fossa on the planar image; single photon emission computed tomography-computed tomography (CT) demonstrated tracer pooling in the perirenal collection. In addition, the CT detected nontracer-avid parenchymal lung nodules and hypodense liver lesions consistent with metastatic disease. The perinephric urinary leak was drained by percutaneous drainage, confirmed by diuretic renography the following day. PMID- 29430121 TI - Locked-in Syndrome and 18F-fluorodeoxyglucose-positron Emission Tomography/Computed Tomography: Observations from a Case of Basilar Artery Thrombosis. AB - We report the case of a 59-year-old male patient suffering from locked-in syndrome (LIS) following basilar artery thrombosis despite an attempt of thrombolysis. Neurological examination showed quadriplegia and aphonia and a state of coma requiring mechanical ventilation was diagnosed. The use of 18F fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) allowed to detect a normal 18F-FDG uptake in the main cerebral cortical areas and a significant reduction of 18F-FDG uptake in both cerebellar hemispheres, compatible with a functional deafferentation, helping confirming the clinical suspicion of LIS. The diagnosis of LIS, according to literature, is based on the clinical assessment and the utilization of scores as the Coma Recovery Scale-Revised. The standard neuroimaging techniques, although recognize the site of injury, are not able to differentiate the different conditions affecting a state of altered consciousness. Performing 18F-FDG-PET in patients with LIS might help addressing the correct diagnosis and prompting subsequent appropriate treatment, and therefore, ultimately improving the patient outcome. Therefore, 18F-FDG-PET should be taken into account in the early clinical assessment of doubtful cases. PMID- 29430123 TI - Testicular Metastasis from Recurrent Gastroesophageal Junction Adenocarcinoma: Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Findings. AB - Testicular metastasis from gastroesophageal junction (GEJ) adenocarcinoma is a very rare condition. A 57-year-old male with a history of neoadjuvant chemotherapy and surgery for HER-2-positive GEJ adenocarcinoma underwent a follow up 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). It revealed multiple metastases including bilateral testicular and L4 laminar metastasis. The patient received multiple chemotherapies, but follow-up PET/CT showed interval progression of disease. Here, we present a case highlighting one of the unusual sites of metastasis from GEJ cancer, role of PET/CT as a surveillance tool in such patients, and the importance of radiologists to be aware of such uncommon sites of metastasis to avoid interpretative errors. PMID- 29430124 TI - Incidental Global Hypometabolism in the Brain of Patient with AIDS-related Dementia Seen on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - Human immunodeficiency virus (HIV)-related dementia is the most severe form of neurocognitive disorder in patients with AIDS. It is relatively uncommon in postantiretroviral therapy (HAART) era and is associated with a high cerebrospinal fluid CSF/plasma viral load. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has proven useful in malignancies, infections, and central nervous system lesions in HIV-infected patients and has been used to explore regional cerebral glucose metabolism patterns in HIV-positive patients with and without cognitive impairment. We present the case of a 36-year-old male with AIDS presenting as pyrexia of unknown origin, where global brain hypometabolism was noted incidentally on FDG PET/CT referred for identification of the infective focus/tumor causing the fever. PMID- 29430125 TI - Significance of 18F-sodium Fluoride Positron Emission Tomography in Characterization of POEMS Osteosclerotic Lesions Better Than 18F fluorodeoxyglucose Positron Emission Tomography. AB - Crow-Fukase syndrome (POEMS syndrome) is a rare systemic paraneoplastic syndrome. Bone lesions are manifested by sclerotic osteoblastic lesions often associated with bone pain. Characterization of osseous lesions is always crucial for clinical correlation and better patient management. We present a case where 18F fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) was unable to characterize a clinically symptomatic patient, and 18F-fluoride PET/CT showed excellent characterization of osteosclerotic lesions. The results were in correlation with already published data and showed that 18F-fluoride PET/CT has better uptake in osteoblastic lesions in POEMS syndrome when compared to 18F-FDG PET/CT and have superior imaging quality in assessing the bone lesions. PMID- 29430126 TI - Incidental Detection of Bilateral Large Urinary Bladder Diverticulae on Tc99m Ethylene Dicysteine Renography with Single-photon Emission Computed Tomography Computed Tomography. AB - The complementary anatomical and functional information provided by hybrid imaging with single-photon emission computed tomography-CT (SPECT-CT) is a very useful imaging tool in selected cases where anatomical information is lacking as in the scenario of dynamic renal scintigraphy. The authors present a case of a 5 year-old male child with symptoms suggestive of cutis laxa with urinary tract infection. The child underwent dynamic renal scintigraphy with Tc99m ethylene dicysteine for cortical function and drainage assessment. Hybrid SPECT/CT proved valuable in the child in identification of the bilateral gross urinary bladder diverticulae. PMID- 29430127 TI - Pigmented Villonodular Synovitis: A Close Mimic of Metastasis on 18F fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. PMID- 29430128 TI - Absence of Iodine/Iodide in Cough/Expectorant Medications: A True Disclaimer or not? PMID- 29430129 TI - Pseudocirrhosis of the Liver in Setting of Metastatic Carcinoma Breast: An Ominous Sign to be Remembered. PMID- 29430130 TI - Cerebral Hemisphere Hypoperfusion with Ipsilateral Internal Jugular Vein and Upper Extremity Deep Vein Thrombosis in Lung Carcinoma on 18F-Fluorodeoxyglucose Positron Emission Tomography/Contrast-enhanced Computed Tomography. PMID- 29430132 TI - Reply by Author. PMID- 29430131 TI - Role of Positron Emission Tomography Imaging in Myeloid Sarcoma. PMID- 29430133 TI - Erratum: Exploitation of solid targetry for Scandium-44 production at INMAS- A potential alternative to generator produced radioisotopes. AB - [This corrects the article on p. S2 in vol. 32.]. PMID- 29430134 TI - Study validity. PMID- 29430135 TI - A comparative evaluation of the marginal adaptation of a thermoplastic resin, a light cured wax and an inlay casting wax on stone dies: An in vitro study. AB - Background: Different pattern materials do not produce copings with satisfactory, marginal accuracy when used on stone dies at varying time intervals. Purpose: The purpose of this study was to evaluate and compare the vertical marginal accuracy of patterns formed from three materials, namely, thermoplastic resin, light cured wax and inlay casting wax at three-time intervals of 1, 12, and 24 h. Methodology: A master die (zirconia abutment mimicking a prepared permanent maxillary central incisor) and metal sleeve (direct metal laser sintering crown #11) were fabricated. A total of 30 stone dies were obtained from the master die. Ten patterns were made each from the three materials and stored off the die at room temperature. The vertical marginal gaps were measured using digital microscope at 1, 12, and 24 h after reseating with gentle finger pressure. Results: The results revealed a significant statistical difference in the marginal adaptation of three materials at all the three-time intervals. Light cured wax was found to be most accurate at all time intervals, followed by thermoplastic resin and inlay casting wax. Furthermore, there was a significant difference between all pairs of materials. The change in vertical marginal gap from 1 to 24 h between thermoplastic resin and light cured wax was not statistically significant. Conclusion: The marginal adaptation of all the three materials used, was well within the acceptable range of 25-70 MUm. The resin pattern materials studied revealed significantly less dimensional change than inlay casting wax on storage at 1, 12, and 24 h time intervals. They may be employed in situations where high precision and delayed investing is expected. PMID- 29430136 TI - A comparative evaluation of fatigue resistance of two different implant overdenture stud attachments with two different denture base materials: An in vitro study. AB - Introduction: The two implant-supported overdentures have overcome the retention and stability-related problems of conventional mandibular denture. Stud attachments are widely available, less expensive, and easy to use. Aims and Objectives: To determine fatigue resistance of two different stud attachments with two denture base materials - autopolymerizing and heat cure acrylic resin till 4320 cycles simulating 03 years of service. Materials and Methods: Stud implant overdenture attachments, i.e., ball and socket and Dalla Bona attachments were tightened over the implants in two different mandibular edentulous base models. The housings were incorporated with both direct (chairside) and indirect (laboratory) technique into conventional mandibular dentures. These overdentures were subjected to continuous removal and insertion on Universal Testing Machine till 4320 cycles simulating 3 years of service assuming that patient takes out denture, 4 times in a day. The fatigue resistance was calculated for 0, 1440 (1 year), 2800 (2 years), and 4320 (3 years) cycles. Unpaired and paired t-tests were applied to find the level of significance. Results: Ball and socket attachments housed with heat cure acrylic resin (indirect technique) had the highest values of fatigue resistance at all cycles. Following were Dalla Bona attachments with autopolymerizing acrylic resin (direct technique), ball and socket attachments with autopolymerizing acrylic resin (direct technique), and Dalla Bona attachments with heat cure acrylic resin (indirect technique) as per statistical analysis. Conclusion: Two implant-supported mandibular overdenture with ball and socket attachments incorporated by indirect technique showed higher values in terms of retention and absence of disengagement/fracture of components. PMID- 29430137 TI - A clinico-radiographic study to compare and co-relate sagittal condylar guidance determined by intraoral gothic arch tracing method and panoramic radiograph in completely edentulous patients. AB - Purpose: The purpose of this study was to compare and correlate sagittal condylar guidance determined by intraoral gothic arch tracing method and panoramic radiograph in edentulous patients. Materials and Methods: Twelve completely edentulous patients were selected by the inclusion and exclusion criteria. Conventional steps in the fabrication of complete denture till jaw relation were carried out. Intraoral gothic arch tracing and protrusive interocclusal records were obtained for each patient. Protrusive interocclusal record was used to program the Hanau Wide-Vue semi-adjustable articulator, thus obtaining the sagittal condylar guidance angle. Using RadiAnt DICOM software, on the orthopantomogram obtained for each patient in the study, two reference lines were drawn. The Frankfort's horizontal plane and the mean curvature line (joining the most superior and the inferior points on the glenoid fossa curvature) were drawn. The mean curvature line was extended to intersect the Frankfort's horizontal plane, thus obtaining the radiographic sagittal condylar guidance angle. The condylar guidance angles obtained by these two methods were compared and subjected to paired t-test. Results: There was no statistically significant difference between the sagittal condylar guidance angles obtained between right and left sides with intraoral gothic arch tracing and radiographic methods (P = 0.107 and 0.07, respectively). Conclusion: Within the limitations of this study, it was concluded that the protrusive condylar guidance angles obtained by panoramic radiograph may be used for programming semi-adjustable articulators. PMID- 29430138 TI - Relative presence of Streptococcus mutans, Veillonella atypica, and Granulicatella adiacens in biofilm of complete dentures. AB - Aims and Objective: Oral biofilms in denture wearers are populated with a large number of bacteria, a few of which have been associated with medical conditions such as sepsis and infective endocarditis (IE). The present study was designed to investigate the relative presence of pathogenic bacteria in biofilms of denture wearers specifically those that are associated with IE. Methods: Biofilm samples from 88 denture wearers were collected and processed to extract total genomic DNA. Eight of these samples were subjected to 16S rRNA gene sequencing analysis to first identify the general bacterial occurrence pattern. This was followed by species-specific quantitative polymerase chain reaction (qPCR) on entire batch of 88 samples to quantify the relative copy numbers of IE-associated pathogens. Results: 16S rRNA gene analysis of eight biofilm samples identified bacteria from Firmicutes, Actinobacteria, Proteobacteria, Bacteroidetes, and Fusobacteria species. Interestingly, Streptococcus mutans, Veillonella atypica, and Granulicatella adiacens from Firmicutes, all known to be associated with early onset sepsis and IE was present in five of eight biofilm samples. The other three samples carried bacteria from genus Proteobacteria with Neisseria flava and Neisseria mucosa, which are known to be commensals, as dominant species. Species specific qPCR of S. mutans V. atypica, and G. adiacens on 88 biofilm DNA samples identified the presence of S. mutans in 83%, V. atypica in 79%, and G. adiacens in 76% of samples. Conclusion: The findings from the present study demonstrate co occurrence of S. mutans, V. atypica, and G. adiacens in a majority of denture wearers, which is clinically significant as elderly patients with compromised immune system are more prone to develop IE. To the best of our knowledge, the co occurrence of S. mutans, V. atypica, and G. adiacens is being reported for the first time in biofilms of denture wearers. PMID- 29430139 TI - Cytotoxic effect of indigenously fabricated dental magnets for application in prosthodontics. AB - Context: Dental magnets are used for retaining removable prostheses such as a removable partial denture, complete denture, and maxillofacial prosthesis. They provide good retention for the prostheses. However, the elements released from the magnets may be cytotoxic for the tissues. Therefore, it is necessary to evaluate their cytotoxic effect on cell lines. Aim: The aim of the study is to check the cytotoxic effect of indigenously fabricated dental magnets on animal cell lines. Materials and Methods: Neodymium-iron-boron (Nd-Fe-B) magnet was tested for cytotoxicity. The magnet was encased in a teflon cylinder. Magnets were placed in the well tissue-cultured plates together with a suspension containing NIH 3T3 mouse fibroblasts (5 * 105 cells/ml). After 3 days of incubation at 37 degrees C, cell viability was determined by mean transit time (MTT) assay. Cells were subsequently dissolved in 100 MUl dimethyl sulfoxide with gentle shaking for 2 h at room temperature followed by measurement of absorbance at 570 nm. Eight replicate wells were used at each point in each of four separate measurements. Measured absorbance values were directly used for calculating percent of viable cells remaining after the respective treatment. Data were analyzed statistically with significance level set at P < 0.05. Results: The control group had highest absorbance reading for the MTT assay followed by test group. The lowest values were found with bare Nd-Fe-B magnets. One-way ANOVA test was performed for the data obtained. There was a statistical significant difference seen in the positive control (bare magnets, 44.96) and the test (teflon cased magnets, 96.90) group. Conclusion: More number of viable cells was visible in test group cells indicating that the indigenously fabricated dental magnet did not show any cytotoxicity. PMID- 29430140 TI - An in vitro study to evaluate the accuracy of orthopantomograph as an aid to determine condylar guidance. AB - Purpose: The study was conducted to evaluate the accuracy of orthopantomograph (OPG) as an aid to determine condylar guidance. Methodology: The condylar guidance was measured using the impressions of glenoid fossae and radiographs (OPG) on thirty dried human skulls. Frankfurt horizontal plane (FHP) was used as a reference plane in both the methods and wire markers were adapted to make the contours of glenoid fossae discernible for both the methods. The condylar inclination angle was measured between FHP and a line joining the most concave point on the glenoid fossa with the most inferior point on the articular eminence on both right and left sides. Results: Pearson correlation was used for statistical analysis, and it showed a strong correlation between anatomic and radiographic methods (r = 0.864 for the left side, r = 0.873 for the right side) as well as between right and left sides (r = 0.830). The data were also subjected to regression analysis (linear and panel estimation approach) which showed that OPG could be effectively used to predict the condylar guidance (r2 = 0.6160). Conclusion: Although OPG shows a higher value than anatomic method, it can be used as an aid to set condylar guidance on semi-adjustable articulator. PMID- 29430141 TI - Evaluation of the role of skull anthropometry for complete denture teeth selection: A cross-sectional study. AB - Background: Success of complete denture treatment lies in the ability to make it indiscernible from the natural. The selection of the six maxillary anterior teeth is of utmost importance as it contributes most to denture esthetics. Although various techniques and methods to determine the width of maxillary anterior teeth and its relation to various body measurements were done, the simple technique of using circumference of head has been less documented, specifically for Indian population. Aims and Objective: The aim of this study was to determine whether a relationship exists between the widths of the upper six anterior teeth to head circumference and the objective was to decide whether head circumference can be used as a deciding criterion to select size of maxillary anterior teeth for Central Indian population. Materials and Methods: This study was done on 300 people who included 135 males and 165 females. The circumference of head (A) and the combined width of the six anterior maxillary teeth (B) were measured and the ratio of A: B was determined. Results: EPO Info software version 6 was used to derive the statistical analysis with unpaired Student's t-tests. In male students, the mean of the ratio between the head circumferences to the combined widths of the anterior maxillary teeth was 10.14:1. In female students, the mean of the ratio between the head circumferences to the widths of the anterior maxillary teeth was 10.09:1. The average circumference of head to mesiodistal width of six anterior teeth ratio was concluded to be 10. Conclusion: Within the limitations of this study, the results suggest that head circumference divided by 10 can be used to select a teeth set with the resulting value as the combined mesiodistal width of six anterior teeth. This can be used as a starting point for determining the width of the anterior maxillary teeth for edentulous patients, which can be further confirmed with the esthetic appearance and with other facial measurements. PMID- 29430142 TI - Comparative evaluation of marginal fit and axial wall adaptability of copings fabricated by metal laser sintering and lost-wax technique: An in vitro study. AB - Purpose: The present study aims to compare and evaluate the marginal fit and axial wall adaptability of Co-Cr copings fabricated by metal laser sintering (MLS) and lost-wax (LW) techniques using a stereomicroscope. Materials and Methods: A stainless steel master die assembly was fabricated simulating a prepared crown; 40 replicas of master die were fabricated in gypsum type IV and randomly divided in two equal groups. Group A coping was fabrication by LW technique and the Group B coping fabrication by MLS technique. The copings were seated on their respective gypsum dies and marginal fit was measured using stereomicroscope and image analysis software. For evaluation of axial wall adaptability, the coping and die assembly were embedded in autopolymerizing acrylic resin and sectioned vertically. The discrepancies between the dies and copings were measured along the axial wall on each halves. The data were subjected to statistical analysis using unpaired t-test. Results: The mean values of marginal fit for copings in Group B (MLS) were lower (24.6 MUm) than the copings in Group A (LW) (39.53 MUm), and the difference was statistically significant (P < 0.05). The mean axial wall discrepancy value was lower for Group B (31.03 MUm) as compared with Group A (54.49 MUm) and the difference was statistically significant (P < 0.05). Conclusions: The copings fabricated by MLS technique had better marginal fit and axial wall adaptability in comparison with copings fabricated by the LW technique. However, the values of marginal fit of copings fabricated that the two techniques were within the clinically acceptable limit (<50 MUm). PMID- 29430143 TI - A comparative analysis of salivary factors and maxillary denture retention in different arch forms: An in vivo study. AB - Aims: This study aims to find the effect of change in different salivary factors before and after complete denture insertion and to measure the maxillary denture retention in different arch forms. Materials and Methods: Thirty completely edentulous individuals (10 each of square, tapered, and ovoid arch form of maxilla) belonging to the age group of 40-70 years were selected. Salivary factors (flow, density, pH, viscosity, and total protein) were evaluated before and after denture insertion. Retention of maxillary denture was measured in all the different arch forms. Statistical Analysis: Student's independent sample's t test was applied. The correlation was analyzed by Pearson's correlation analysis. Results: While mean flow rate and pH of saliva increased, mean viscosity, total protein, and density of saliva decreased after maxillary complete denture insertion. A positive correlation was found between retention and total maxillary basal surface area. Retention value was found to be greatest in square type and least in tapered type. Conclusions: Complete denture acts as a mechanical stimulant thus increasing flow rate and pH immediately after complete denture insertion. Density, total protein, and viscosity of saliva decreased after complete denture insertion which may be due to increase in water content of saliva. The retention of maxillary complete denture does not seem to depend on the rate of change of the salivary factors, before and after complete denture insertion. Total basal surface area and maxillary denture retention values were highest in square arch form and least in tapered arch form. PMID- 29430144 TI - Comparative evaluation of the depth of curve of Spee between individuals with normal dentition and individuals with occlusal wear using conventional and digital software analysis techniques: An in vivo study. AB - Objectives: The objective of this study is to evaluate and compare the depth of curve of Spee in normal dentitions and dentitions with occlusal wear using conventional and digital software techniques. Materials and Methods: A total of 70 healthy human subjects were selected for this study in an age group of 20-50 years. Group A includes the stone models (dental casts) of 35 individuals with healthy (nonattrited) dentition. Group B includes stone models of 35 individuals with occlusal wear (generalized attrited) dentition. Two methods were used for measuring the curve of Spee, i.e., conventional method and three-dimensional digital analysis method. Results: Depth of the curve of Spee between these two groups was statistically the same. The Digital software analysis (Method II) gives more accurate readings when compared with the Conventional (Method I) of measuring the depth of the curve of Spee. Conclusion: Depth of curve of Spee is maintained through the life. There is no statistical difference in depth of curve of Spee between the two groups and digital method give more accurate measurements. PMID- 29430145 TI - Nasal reconstruction with silicone using customised impression technique. AB - Facial defects can result from a variety of reasons including trauma, burns, infections, congenital disorders, and neoplasms which require surgical correction or prosthetic rehabilitation or both. Prosthetic replacement using various materials is the treatment of choice when other surgical options are not possible. This report presents a case of acquired nasal defect secondary to a surgically operated adenoid cystic carcinoma using silicone as the material of choice. PMID- 29430146 TI - Fabrication of a magnetic holder for the removal of ocular prosthesis. AB - Long-term success of ocular prostheses is dictated by the retentive quality which is usually ensured by maximum possible extension into the sulcus of the eyelids. Majority of the patients experience difficulty during manual placement and removal of the prosthesis, especially when the sulcus is very deep. Ocular prosthesis is commonly removed with fingers or suction cups. Although the suction cups are popular, its efficiency lasts only for a limited period. Moreover, it is not easily available in the rural Indian market. This article presents the design of a magnetic instrument for the placement and removal of the ocular prosthesis. PMID- 29430147 TI - Prosthetic rehabilitation in neurosurgical cranioplasty. AB - The defects of the skull cause mechanical vulnerability of the brain, esthetic disfigurement, and transmission of vibrations and pulsation of the brain. Subsequent cranioplasty may be required to compensate for the defect and to alleviate various signs and symptoms. When long-term outcome of biomaterial use in pediatric cases is limited, alloplastic cranioplasty in adults are supported by several large case series. This case report narrates cranioplasty using titanium alloplastic implant material. PMID- 29430148 TI - Prosthetic rehabilitation of a partially amputated finger using a customized ring wire substructure. AB - Defects of fingers or hands due to congenital reasons or trauma can be a catastrophic setback to an individual physically, emotionally, and psychologically. An artificial finger prosthesis is a lucrative option to camouflage such defects. The anatomy of the residual stump of the defect is of extreme importance and will dictate the mode of retention to be used, and the level of esthetics one can expect. Despite the availability of the advanced skills, best of materials, and laboratory support, sometimes, the anatomy of the defect may be a hindrance in furnishing a better prosthesis. This case report describes a cost-effective and simple approach of rehabilitation of a partially amputated finger with bulbous distal anatomy using a custom-made ring-wire substructure and maxillofacial silicone, thereby striking a balance between adequate retention and optimal esthetics. PMID- 29430149 TI - From the Editor's Desk. PMID- 29430150 TI - On the Origins of the Semen Analysis: A Close Relationship with the History of the Reproductive Medicine. AB - The spermatozoa were first seen in ejaculates in the 17th century. However, the basic mechanisms of human fertilization have been only fully understood after the discovery of ovum in 1827. As a result, the interest in developing technologies for semen analysis arose from the early 1900s. Indeed, standard methodologies for semen analysis were designed mostly along the first half of the 20th century. Before the 1930s, semen analysis was nearly unavailable clinically, since there were still no robust methodologies for assessing sperm characteristics, as well as to set up standard references that could be able to assess the reproductive capacity of men. However, joining some methodologies reported from 1910 up to 1930, standardization was attained and thereby semen analysis increasingly assumed its role in laboratory practice for investigating men in barren marriage. This article aims in reviewing historical backgrounds on the semen analysis, up to its insertion in laboratory practice. Emphasis is given to the major studies that contributed either directly or indirectly in developing the earliest routine for the semen analysis. PMID- 29430151 TI - Azoospermia Factor C Subregion of the Y Chromosome. AB - The azoospermia factor (AZF) region on the Y chromosome consists of genes required for spermatogenesis. Among the three subregions, the AZFc subregion located at the distal portion of AZF is the driver for genetic variation in Y chromosome. The candidate gene of AZFc is known as deleted in azoospermia gene, which is studied with interest because it is involved in germ cell development and most frequently deleted genes leading to oligozoospermia and azoospermia. Recently, two partial deletions in AZFc gr/gr and b2/b3 are characterized at the molecular level which showed homologous recombination between amplicons, affecting spermatogenesis process. There are novel methods and commercially available kits for accurate screening and characterization of microdeletions. It is important to detect the AZFc microdeletions through genetic screening and counseling those infertile men who planned to avail assisted reproduction techniques such as undergoing intracytoplasmic sperm injection or in vitro fertilization. PMID- 29430152 TI - Ovulation Induction Using Clomiphene Citrate Using Stair - Step Regimen versus Traditional Regimen in Polycystic Ovary Syndrome Women - A Randomized Control Trial. AB - Objective: To determine the efficacy of the stair-step protocol (SSP) using clomiphene citrate (CC) in patients with polycystic ovary syndrome (PCOS) and compare it with traditional regimen. Design: This was randomized control trial. Setting: Infertility Clinic. Patients: Sixty infertile PCOS women. Interventions: Patients were randomized into the study (SSP - 30 patients) and control group (traditional protocol - 30 patients). In the SSP, patients were treated with CC 50 mg/day for 5 days and in nonresponsive patients, the dosage was increased to 100 mg/day for 5 days in the same cycle. Maximum dose of 150 mg was given until the dominant follicle was generated. In control group, the dose increment in nonovulatory cases was done in subsequent cycle. Ultrasonography follow-up was done to detect ovulation. Main Outcome Measures: Ovulation rate and duration of treatment. Results: Ovulation (66.7% vs. 50% respectively) and pregnancy rates (26.7% vs. 15.7%) were similar between the stair step and the control group. The duration of treatment was significantly shorter in stair step compared to traditional protocol (17.23 vs. 53 days). CC 100 mg was the most effective dose for ovulation in either group. There were no significant differences in the systemic side effect. Conclusions: By using SSP, effective treatment is provided in significantly shorter time period without any detrimental effect on the ovulation and pregnancy rates. PMID- 29430153 TI - The Impact of Progesterone Level on Day Of hCG Injection in IVF Cycles on Clinical Pregnancy Rate. AB - Background: Premature progesterone rise (PPR) has long been implicated as contributing to implantation failure. Despite the use of gonadotropin-releasing hormone (GnRH) analogues, subtle increases in serum progesterone (P4) levels beyond a threshold progesterone concentration were observed on the day of trigger in controlled ovarian hyperstimulation cycles. Aims: The purpose of the study was to evaluate the incidence of PPR on the day of trigger in conventional IVF/ICSI cycles and its impact on clinical pregnancy rate. Settings and Design: A total of 235 patients undergoing conventional IVF/IVF-ICSI by fresh embryo transfer cycles from January 2016 to December 2016 at the infertility unit of a tertiary care hospital were prospectively analyzed. Material and Methods: Patients included in the study were subjected to GnRH agonist long/antagonist protocol. Ovulation induction was given with rFSH and/or HMG in both the protocols. The cutoff for defining PPR was P4>= 1.5 ng/ml, and an analysis of the role of P4on clinical pregnancy rate was performed. Statistical analysis was performed with the Statistical Package for the Social Sciences trial version 23.0 software for Windows and Primer software. Results and Conclusion: The overall clinical pregnancy rate per embryo transfer was 30.6%. The clinical pregnancy rate in the patients with P4 <1.5 ng/ml was significantly higher than those with elevated levels, P4>= 1.5 ng/ml (33.3% vs. 12.9%; P = 0.037). Premature progesterone elevation in ART cycles is possibly associated with lower clinical pregnancy rates. PMID- 29430154 TI - Repeat Dose of Gonadotropin-releasing Hormone Agonist Trigger in Polycystic Ovarian Syndrome Undergoing In Vitro Fertilization Cycles Provides a Better Cycle Outcome - A proof-of-concept Study. AB - Objective: Is a single dose of gonadotropin-releasing hormone agonist (GnRHa) trigger to induce final oocyte maturation in polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization (IVF) cycles with GnRH antagonist protocol sufficient to provide optimal oocyte maturity? Design: This is a prospective, randomized, double-blind, proof-of-concept study. Setting: This study was carried out at a tertiary care center. Material and Methods: A total of 125 patients diagnosed with PCOS defined as per the ESHRE/ASRM Rotterdam criteria (2003) undergoing IVF in antagonist protocol were randomized into two groups. Group A: single dose of GnRHa 0.2 mg, 35 h prior to oocyte retrieval, and Group B: 0.2 mg GnRHa 35 h prior to oocyte retrieval + repeat dose of 0.1 mg 12 h following the 1st dose. 12 h post-trigger, luteinizing hormone (LH), progesterone (P4), and follicle-stimulating hormone (FSH) values were estimated. Statistical Analysis: Continuous variables were expressed as mean +/- standard deviation and categorical variables as proportions where applicable. Independent sample t-test was used for continuous variables which were normally distributed and Mann Whitney U-test for data not normally distributed. Chi-square test or Fisher's exact test was used for categorical variables where appropriate. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated. In addition, receiver operating characteristic curve was used to evaluate the post-trigger LH, P4, and FSH values at 12 h as predictors of oocyte maturity. Main Outcome Measures: Primary outcome: maturity rate of the oocytes. Secondary outcomes: oocyte yield, fertilization rate, availability of good quality embryos on day 3, blastocyst conversion, OHSS rates, post-trigger serum LH (IU/L), FSH (IU/L), and P4 (ng/mL) levels implantation rate and clinical pregnancy rate. Results: A higher number of mature (metaphase II) oocytes were obtained in Group B compared to Group A (OR of 0.47; CI: 0.38-0.57; P < 0.01). Significantly a higher number of blastocysts were obtained in Group B than Group A (4.00 vs. 3.04; P = 0.023). The odds of clinical pregnancy per patient were higher in Group B (OR = 0.56; CI [0.27-1.24]), with a trend towards better clinical pregnancy in Group B than in Group A. Conclusions: A repeat dose of GnRHa trigger 12 h following the first dose probably by maintaining a sustained level of gonadotropins yielded a better maturity of oocytes, higher number of blastocysts, and a trend towards higher clinical pregnancy than a single dose in PCOS patients undergoing IVF in antagonist cycles. PMID- 29430155 TI - Does Perifollicular Vascularity on the Day of Oocyte Retrieval Affect Pregnancy Outcome in an In Vitro Fertilization Cycle? AB - Background: The vascularization status of ovarian follicles affects reproductive competence of oocytes and in turn embryo quality by regulating its oxygen supply. Transvaginal power Doppler ultrasound can noninvasively map this vascularity of the ovarian follicles. Thus, we aimed to study the association of perifollicular vascularity and pregnancy outcome in women while on treatment for an in vitro fertilization cycle. Material and Methods: A prospective study on 200 participants evaluated the vascularity of 1008 follicles on the day of oocyte retrieval to outline a map depicting perfusion of each follicle. The vascularity was graded based on percentage of the perifollicular outline in the map depicting vascularity which was Grade 1 <=25%, Grade 2 26-50%, Grade 3 51-75%, Grade 4 76 100%. Results: Of 1008 follicles aspirated, only 733 follicles were analyzed as per the exclusion criteria. Grades III and IV follicles were high vascular grade follicle whereas Grades I and II were low perfused follicles. Six hundred and twenty-seven oocytes were retrieved from 733 follicles with majority from Grade III and IV vascularity (75.8%: Grade III and IV vs. 24.2%: Grade I and II). The number of oocytes exhibiting maturity and their fertilization rates were significantly higher in high vascularity follicles. Three hundred and forty-one Grade I embryos formed and 89.1% were from better-perfused follicles versus 10.9% from lower ones. Conclusions: The association between perifollicular perfusion and follicular oxygenation and oocyte maturation does exist which ultimately gets translated to quality of embryos. If other confounding factors such as endometrial receptivity and transfer technique are controlled, it influences the implantation potential too. PMID- 29430156 TI - Effect of Endometrial Cavity Fluid On Pregnancy Rate of Fresh Versus Frozen In Vitro Fertilization Cycle. AB - Objective: This study aims to study the difference in etiology and outcome in terms of implantation rate and abortion rate in fresh (self-stimulated) versus frozen (oocyte donation cycle) in vitro fertilization (IVF) and in transient versus persistent fluid. Material and Methods: This retrospective study was conducted in the Department of Reproductive Medicine of tertiary care center from January 2012 to November 2015. Data were collected retrospectively from the departmental files. Twenty-four patients from fresh IVF-stimulated cycles and 24 from frozen oocyte donation cycle with their endometrium prepared by hormone replacement treatment were included in the study. All patients selected in the study had grade-A embryo transfer of day 3-4 with maximum three embryo transferred. Pregnancy was defined by rising serum beta-human chorionic gonadotrophin levels performed after 14 days of embryo transfer and further confirmed by ultrasonographic visualization of gestational sac at 6 weeks. All biochemical pregnancies were included in implantation failure. All pregnant patients were followed till the termination of pregnancy and further noted as live birth or abortion. Results: Clinical pregnancy rate was seen more in self stimulated cycle (62.5%) with live birth rate of 50% than hormone replacement treatment cycle, in which clinical pregnancy rate was 45.83% with live birth rate of 33.33%. Clinical pregnancy rate was highest in group with very less fluid in cavity (1-2 mm) 63% and with live birth of 52.63%. Clinical pregnancy was seen only in two patients of group B with anterior and posterior (AP) diameter of fluid in cavity of 2-3 mm with live birth of only one, whereas in group C, with AP diameter of 3-5 mm, none of the patient conceived. This difference was statistically significant. Clinical pregnancy rate was 65.62% in transient fluid accumulation with live birth rate of 53.25%, which was significantly higher than persistent fluid accumulation (P value - 0.0337 for pregnancy rate and 0.0312 for live birth rate). Conclusion: Fluid accumulation seen in fresh cycles are generally associated with better outcome because it may be associated with good prognostic factors - small AP diameter of fluid, with transient fluid accumulation and more with poly cystic ovarian syndrome as an etiological factor; however, in frozen cycle, it can be associated with poor outcome. PMID- 29430157 TI - Pregnancy Outcome of Home Intravaginal Insemination in Couples with Unconsummated Marriage. AB - : Unconsummated marriage are mainly due to vaginismus or erectile dysfunction. They contribute to about 5% of couples in an infertility clinic. Their incidence is increasing in the metropolitan cities because of stressful lifestyles. Many of couples are advised intrauterine insemination as fertility treatment. However, home insemination is a simple, inexpensive and effective way of achieving pregnancy in such couples. We present the first study to document pregnancy rates of artificial home intravaginal insemination in couples with unconsummated marriage. Aim: To assess the pregnancy rates (PR) with intravaginal insemination (IVI) by couples with nonconsummation of marriage. Setting: Infertility outpatient clinic, New Delhi. Design: Retrospective analysis. Material and Methods: 55 couples of unconsummated marriage were evaluated in a period of two years. Group 1 contains 29 patients aged between 20 to 33 years; group 2 includes 14 patients aged between 33 to 36 years and group 3 includes 12 patients aged more than 36 years. Results: Unconsummated marriage was caused by vaginismus in 67% of the cases, erectile dysfunction in 22% and premature ejaculation in 11%. Clinical pregnancy rate was 69% in group 1; 43% in group 2 and 25% in group 3 after 6 cycles of AI. Conclusions: Intravaginal insemination is a simple, short, economical, effective and painless procedure for conception in nonconsummation of marriage. PMID- 29430158 TI - Delayed Presentation of Turner Syndrome: Challenge to Optimal Management. AB - Background: Turner syndrome (TS) is a chromosomal disorder associated with dysmorphic features and comorbidities, with recent trends focusing on early diagnosis for adequate management. Aim: The aim is to study the age and mode of presentation of TS, associated comorbidities and look for any correlation with the genotype. Material and Methods: This was a retrospective analysis of girls with TS attending the endocrinology clinic of a tertiary care center. Their age, mode of presentation, and clinical features were noted. All participants underwent ear examination, echocardiography, and ultrasonography of the abdomen. Laboratory investigations included serum T4, thyroid-stimulating hormone, thyroid peroxidase antibodies, follicle-stimulating hormone, fasting, and 2-h plasma glucose after 75 g glucose load and a karyotype. Simple descriptive statistical methods were used. Results: Seventeen cases of TS were seen with a median age of presentation of 18 years (range 14-42 years). Primary amenorrhea was the most common reason for seeking medical attention (76.4%) followed by short stature and diabetes mellitus (11.8% each). The mean height at presentation was 137.5 +/- 5.4 cm. Monosomy of X chromosome (45,X) was the most common karyotype obtained in 58.8% of the patients, followed by 45,X/46, XX in 17.6%, 45,X/46X,i(X)(q10) in 11.8%, and 45,X/47,XXX and 46X,delXp11.2 in 5.9% patients each. Bicuspid aortic valve was seen in two patients having a 45,X/46,XX karyotype. Conclusion: Primary amenorrhea is the most common presenting feature in girls with TS leading to a delayed age of presentation. Short stature and dysmorphic features are often overlooked in infancy and childhood due to socioeconomic factors. This late age of presentation is a cause of concern as early detection and management is important for height outcomes, bone health, and psychosocial support. Assessment of comorbidities becomes important in this setting. PMID- 29430159 TI - Prevalence of Cytogenetic Anomalies in Couples with Recurrent Miscarriages: A Case-control Study. AB - Background: About 15%-20% of couples get affected by recurrent miscarriages (RM) and chromosomal abnormality in one partner affects 3%-6% of RM couples. Aims: The present study aimed to determine the prevalence of cytogenetic anomalies in couples with RM. Settings and Design: A case-control study was undertaken, in which 243 couples who had experienced 2 or >2 miscarriages were investigated for chromosomal abnormalities and compared with 208 healthy, age-matched control couples who had at least one healthy live born and no history of miscarriages. Material and Methods: Peripheral blood (PB) lymphocytes were cultured using PB Max Karyotyping medium (GIBCO) for chromosomal analysis and 20 metaphases were analyzed for each individual. Statistical Analysis: Student's t-test was used for statistical evaluation and P < 0.05 was considered statistically significant for all instances. Results: The current study revealed 3.1% RM cases showing structural chromosomal aberrations, of which balanced translocations and Robertsonian translocations constituted 66.7% and 26.7% cases, respectively, while inversions constituted 6.7% abnormal RM cases. Polymorphic variations were observed in 1.9% RM patients and 1.2% controls as well. However, the number of abortions were significantly more (P = 0.027) in male carriers of balanced translocations as compared to female carriers in the RM group. There was no significant difference for age (P = 0.539) between RM women and control women. Conclusions: Although similar studies exist in literature, our study is the first of its kind from our region that has compared the chromosomal anomalies between the RM group and the control group. We observed 3.1% of balanced translocations and an increased number (though nonsignificant) of polymorphic variations and satellite associations in the RM group as compared to the control group. PMID- 29430160 TI - A Case of Primary Amenorrhea with Swyer Syndrome. AB - Swyer syndrome with complete gonadal dysgenesis is associated with an absence of testicular differentiation in a phenotypic female with a 46, XY karyotype. A 14 year-old unmarried girl was referred with complaints of primary amenorrhea and nondevelopment of breast. Her built was normal. Examination of her secondary sexual characteristics revealed no breast development, absent axillary hairs, and sparse pubic hairs. External genitalia was of female type. Karyotype showed genotype of 46, XY. Magnetic resonance imaging revealed hypoplastic uterus with absent fallopian tubes and ovaries. A diagnosis of Swyer syndrome was made. Laparoscopy showed infantile uterus, normal fallopian tubes, and streak gonads. Laparoscopic removal of streak gonads was done as there is a risk of gonadoblastoma in such cases. The patient was started on hormonal replacement therapy. Swyer syndrome results mainly due to mutation in certain genes such as SRY gene, which leads to failure of development of testis. PMID- 29430161 TI - Predicting seizure by modeling synaptic plasticity based on EEG signals - a case study of inherited epilepsy. AB - This paper explores the internal dynamical mechanisms of epileptic seizures through quantitative modeling based on full brain electroencephalogram (EEG) signals. Our goal is to provide seizure prediction and facilitate treatment for epileptic patients. Motivated by an earlier mathematical model with incorporated synaptic plasticity, we studied the nonlinear dynamics of inherited seizures through a differential equation model. First, driven by a set of clinical inherited electroencephalogram data recorded from a patient with diagnosed Glucose Transporter Deficiency, we developed a dynamic seizure model on a system of ordinary differential equations. The model was reduced in complexity after considering and removing redundancy of each EEG channel. Then we verified that the proposed model produces qualitatively relevant behavior which matches the basic experimental observations of inherited seizure, including synchronization index and frequency. Meanwhile, the rationality of the connectivity structure hypothesis in the modeling process was verified. Further, through varying the threshold condition and excitation strength of synaptic plasticity, we elucidated the effect of synaptic plasticity to our seizure model. Results suggest that synaptic plasticity has great effect on the duration of seizure activities, which support the plausibility of therapeutic interventions for seizure control. PMID- 29430162 TI - Development of colloidally stable carbazole-based fluorescent nanoaggregates. AB - Fluorescent nanomaterials require high colloidal stability for effective use in imaging and sensing applications. We herein report the synthesis of carbazole based organic fluorescent nanoaggregates, and demonstrate the superior colloidal stability of alkyl-substituted dye aggregates over their non-alkylated analogs. The role of alkyl chains in self-assembly and stability of such nanoaggregates is discussed based on both experimental and molecular dynamics simulation data, and spectral characteristics of the precursor dyes and their aggregates are described. The obtained results provide new insights on development of colloidally stable organic fluorescent nanomaterials with low polydispersity. PMID- 29430163 TI - An alternative error bound for linear complementarity problems involving [Formula: see text]-matrices. AB - An alternative error bound for linear complementarity problems for [Formula: see text]-matrices is presented. It is shown by numerical examples that the new bound is better than that provided by Garcia-Esnaola and Pena (Appl. Math. Lett. 25(10):1379-1383, 2012) in some cases. New perturbation bounds of [Formula: see text]-matrices linear complementarity problems are also considered. PMID- 29430165 TI - Parents' Reports of Children's Internalizing Symptoms: Associations with Parents' Mental Health Symptoms and Substance Use Disorder. AB - This brief report examined the unique associations between parents' ratings of child internalizing symptoms and their own depression and anxiety in families with parental substance use disorder (SUD). Further, we examined whether parental SUD (father only, mother only, both parents) was related to discrepancy in mothers' and fathers' reports of children's internalizing symptoms. Participants were 97 triads (fathers, mothers) in which one or both parents met criteria for SUD. Polynomial regression analyses were conducted to examine whether father mother reports of child internalizing symptoms had unique associations with parents' own symptoms of depression and anxiety while controlling for child gender, child age, and SUD diagnoses. Controlling for fathers' symptoms and other covariates, mothers experiencing more depression and anxiety symptoms reported more symptoms of child internalizing symptoms than did fathers. Mothers' and fathers' SUD was associated with higher anxiety symptoms among mothers after controlling for other variables. A second set of polynomial regressions examined whether father-mother reports of child internalizing symptoms had unique associations with parents' SUD diagnoses while controlling for child gender and child age. After controlling for mothers' symptoms and other covariates, parents' reports of children's internalizing symptoms were not significantly associated with either parent's SUD or parental SUD interactions (i.e., both parents have SUD diagnoses). Taken together, mothers' ratings of children's internalizing symptoms may be accounted for, in part, by her reports of depression and anxiety symptoms. PMID- 29430164 TI - Advances in Tissue Engineering Techniques for Articular Cartilage Repair. AB - The limited repair potential of human articular cartilage contributes to development of debilitating osteoarthritis and remains a great clinical challenge. This has led to evolution of cartilage treatment strategies from palliative to either reconstructive or reparative methods in an attempt to delay or "bridge the gap" to joint replacement. Further development of tissue engineering-based cartilage repair methods have been pursued to provide a more functional biological tissue. Currently, tissue engineering of articular cartilage has three cornerstones; a cell population capable of proliferation and differentiation into mature chondrocytes, a scaffold that can host these cells, provide a suitable environment for cellular functioning and serve as a sustained release delivery vehicle of chondrogenic growth factors and thirdly, signaling molecules and growth factors that stimulate the cellular response and the production of a hyaline extracellular matrix (ECM). The aim of this review is to summarize advances in each of these three fields of tissue engineering with specific relevance to surgical techniques and technical notes. PMID- 29430166 TI - Riemannian Nonlinear Mixed Effects Models: Analyzing Longitudinal Deformations in Neuroimaging. AB - Statistical machine learning models that operate on manifold-valued data are being extensively studied in vision, motivated by applications in activity recognition, feature tracking and medical imaging. While non-parametric methods have been relatively well studied in the literature, efficient formulations for parametric models (which may offer benefits in small sample size regimes) have only emerged recently. So far, manifold-valued regression models (such as geodesic regression) are restricted to the analysis of cross-sectional data, i.e., the so-called "fixed effects" in statistics. But in most "longitudinal analysis" (e.g., when a participant provides multiple measurements, over time) the application of fixed effects models is problematic. In an effort to answer this need, this paper generalizes non-linear mixed effects model to the regime where the response variable is manifold-valued, i.e., f : Rd -> M. We derive the underlying model and estimation schemes and demonstrate the immediate benefits such a model can provide - both for group level and individual level analysis - on longitudinal brain imaging data. The direct consequence of our results is that longitudinal analysis of manifold-valued measurements (especially, the symmetric positive definite manifold) can be conducted in a computationally tractable manner. PMID- 29430167 TI - The genetic dissection of Myo7a gene expression in the retinas of BXD mice. AB - Purpose: Usher syndrome (US) is characterized by a loss of vision due to retinitis pigmentosa (RP) and deafness. US has three clinical subtypes, but even within each subtype, the severity varies. Myosin VIIA, coded by Myo7a, has been identified as one of the causal genes of US. This study aims to identify pathways and other genes through which Myo7a interacts to affect the presentation of US symptoms. Methods: In this study, we used the retinal tissue of BXD recombinant inbred (RI) mice to examine the expression of Myo7a and perform genetic mapping. Expression quantitative trait locus (eQTL), single nucleotide polymorphism (SNP), and gene correlation analysis were performed using GeneNetwork. Gene set enrichment analysis was performed using WebGestalt, and gene network construction was performed using the Gene Cohesion Analysis Tool. Results: We found Myo7a to be cis-regulated, with varied levels of expression across BXD strains. Here, we propose a genetic network with 40 genes whose expression is highly correlated with Myo7a. Among these genes, six have been linked to retinal diseases, three to deafness, and five share a transcription factor with Myo7a. Gene ontology and pathway analysis revealed a strong connection among ion channel activity, Myo7a, and US. Conclusions: Although Myo7a is a causal gene of US type I, this gene works with many other genes and pathways to affect the severity of US. Many of the genes found in the genetic network, pathways, and gene ontology categories of Myo7a are related to either deafness or blindness. Further investigation is needed to examine the specific relationships between these genes, which may assist in the treatment of US. PMID- 29430168 TI - Assessment of p16 expression and HPV infection in adenoid cystic carcinoma of the lacrimal gland. AB - Purpose: Adenoid cystic carcinoma (ACC) in the lacrimal gland is a rare malignancy. P16 is encoded by the CDKN2A gene, which is recognized as a tumor suppressor due to its inactivation in many types of tumors. However, p16 overexpression is also linked to adverse tumor parameters. These contradictory observations have also been confirmed in ACCs in the salivary glands. Furthermore, evidence of human papilloma virus (HPV) infection is found in a proportion of ACCs in the salivary glands. P16 is often overexpressed in HPV related squamous cell carcinoma in parallel. To our knowledge, the role of p16 and HPV in ACCs in the lacrimal gland is still unknown. Methods: Twenty-one ACCs in the lacrimal gland and ten matched healthy lacrimal glands were studied. P16 was detected with immunohistochemistry (IHC), and HPV was detected with in situ hybridization (ISH) and PCR in all cases. Other cell cycle proteins were also detected with IHC, including cyclin D1 and Ki67. The methylation status of the p16 promoter was detected with methylation-specific PCR (MSP) to further investigate the regulation of p16 expression. Results: The expression rates of p16 (47.6%, 10/21), cyclin D1 (100%, 21/21), and Ki67 (52.4%, 11/21) were increased in ACCs compared to healthy lacrimal glands (negative). The results showed p16 expression was limited to the inner ductal epithelial cells in the majority of the tubular and cribriform patterns. In solid ACCs, p16 was uniformly positive. HPV was negative in all 21 cases with ISH and PCR. P16 overexpression was associated with cyclin D1 overexpression (p=0.013). Only 13 cases were tested successfully with MSP. The expression rate of p16 methylation was 23.1% (3/13) of the ACCs. Compared with primary ACCs, recurrent ACCs showed higher p16, cyclin D1, and Ki67 expression (p=0.011, p=0.026, p=0.049, respectively). Conclusions: In summary, p16 overexpression was cell-type dependent in ACCs in the lacrimal gland, while HPV infection was negative. P16 overexpression was unrelated to HPV infection. The mechanism of p16 overexpression needs to be further investigated in ACCs in the lacrimal gland. PMID- 29430169 TI - Hexafluoroisopropanol mediated benign synthesis of 2H-pyrido[1,2-a]pyrimidin-2 ones by using a domino protocol. AB - Domino strategy has been used for the synthesis of 2H-pyrido[1,2-a]pyrimidin-2 ones. Four sequential reactions: aza-Michael addition, water elimination, intramolecular acyl substitution, and [1,3]-H shift were observed in this domino protocol. Hexafluoroisopropanol is used as a promotor and recyclable solvent in this cascade process. Availability of inexpensive 2-aminopyridines and wide variety of Michael acceptors such as commercially available acrylates and unactivated Baylis-Hillman adducts makes this methodology a huge reservoir of novel fused N-heterocycles as bioactive and potential therapeutic agents. The reaction mechanism has been proposed and rationalized by density functional theory calculation. Products are obtained up to 95% yield. PMID- 29430170 TI - Analytical characterization of recombinant hCG and comparative studies with reference product. AB - Introduction: Regulatory agencies recommend a stepwise approach for demonstrating biosimilarity between a proposed biosimilar and reference biological product emphasizing for functional and structural characterization to trace if there is any difference which may impact safety and efficacy. We studied the comparative structural and biological attributes of recombinant human chorionic gonadotropin (rhCG), SB005, with reference product, Ovidrel(r) and Ovitrelle(r). Recombiant hCG was approved in 2000 by the US Food and Drug Administration for the induction of final follicular maturation, early luteinization in infertile women as part of assisted reproductive technology program. It is also indicated for the induction of ovulation and pregnancy in ovulatory infertile patients whose cause of infertility is not due to ovarian failure. Materials and methods: Primary structure was studied by intact mass analysis, peptide fingerprinting, peptide mass fingerprinting and sequence coverage analysis. Higher order structure was studied by circular dichroism, ultraviolet-visible spectroscopy, fluorescence spectroscopy, and disulfide bridge analysis. Different isoforms of reference product and SB005 were identified using capillary isoelectric focusing and capillary zone electrophoresis. Glycosylation was studied by N-glycan mapping using LC-ESI-MS, point of glycosylation, released glycan analysis using ultra performance liquid chromatography and sialic acid analysis. Product related impurities such as oligomer content analysis and oxidized impurities were studied using size exclusion chromatography and reverse phase high performance liquid chromatography, respectively. Biological activity in term of potency of reference product and SB005 was studied by in vivo analysis. Results and Conclusion: In this study we have compared analytical similarity of recombinant rhCG (SB005) produced at Sun Pharmaceuticals with the reference product with respect to its primary, higher order structure, isoforms, charge variants, glycosylation, sialyation pattern, pharmacodynamic and in vivo efficacy. Our studies show that the in house produced rhCG has a high degree of structural and functional similarity with the reference product available in the market. PMID- 29430171 TI - Correlation between HLA haplotypes and the development of antidrug antibodies in a cohort of patients with rheumatic diseases. AB - Introduction: The aim of this study was to investigate the correlation between human leukocyte antigen (HLA) haplotypes and the development of antidrug antibodies (ADAs) in a cohort of patients with rheumatic diseases. Patients and methods: We evaluated the presence of ADAs in 248 patients with inflammatory rheumatic diseases after 6 months of treatment with anti-TNF drugs: 26 patients were treated with infliximab (IFX; three with rheumatoid arthritis [RA], 13 with ankylosing spondylitis [AS], 10 with psoriatic arthritis [PsA]); 83 treated with adalimumab (ADA; 24 with RA, 36 with AS, 23 with PsA); 88 treated with etanercept (ETA; 35 with RA, 27 with AS, 26 with PsA); 32 treated with certolizumab (CERT; 25 with RA, two with AS, five with PsA); and 19 treated with golimumab (GOL; three with RA, seven with AS, nine with PsA). Serum drug and ADA levels were determined using Lisa-Tracker Duo, the ADA-positive samples underwent an inhibition test, and the true-positive samples underwent genetic HLA typing. To have a homogeneous control population, we also performed genetic HLA typing of 11 ADA-negative patients. Results: After inhibition test, the frequency of ADAs was 2/26 patients treated with IFX (7.69%), 4/83 treated with ADA (4.81%), 0/88 treated with ETA (0%), 4/32 treated with CERT (12.5%), and 1/19 treated with GOL (5.26%). The frequency of HLA alleles in the examined patients was HLA-DRbeta-11 0.636, HLA-DQ-03 0.636, and HLA-DQ-05 0.727. The estimated relative risks between the ADA-positive patients and the ADA-negative patients were HLA-DRbeta-11 2.528 (95% CI 0.336-19.036), HLA-DQ-03 1.750 (95% CI 0.289-10.581), and HLA-DQ-05 2.424 (95% CI 0.308-15.449). Conclusion: This is the first study that shows an association between HLA and genetic factors associated with the occurrence of ADAs in patients with rheumatic diseases, but the number of samples is too small to draw any definite conclusion. PMID- 29430172 TI - Dysregulation of Neuregulin-1/ErbB signaling in the hippocampus of rats after administration of doxorubicin. AB - Objective: Long-term use of doxorubicin (Dox) can cause neurobiological side effects associated with depression, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in neural function, much is still unknown concerning the biological link between the NRG1/ErbB pathway and the Dox-induced neurotoxicity. Therefore, we examined the protein expression of NRG1 and ErbB receptors in the hippocampus of rats following Dox treatment. Materials and methods: The drug was administered every 2 days at a dose of 2.5 mg/kg, and the animals in different groups were treated with intraperitoneal injection for three or seven times, respectively. Results: Our data showed that the rats treated with Dox for seven times (DoxL group) exhibited depression-like behaviors, whereas the short-term treatment (DoxS group) had no effect on the behavioral changes. Dox treatment also induced the neural apoptosis with more severe neurotoxicity. Intriguingly, the expression of NRG1 and the ratio of pErbB4/ErbB4 and pErbB2/ErbB2 were significantly decreased in the DoxL group, but enhanced activation of ErbB receptors was observed in the DoxS group. In parallel, administration of Dox for seven times suppressed the downstream Akt and ERK phosphorylation, while the Akt phosphorylation was enhanced with the administration of Dox for three times. Conclusion: Our data first showed the Dox induced alterations of the NRG1/ErbB system in the hippocampus, indicating the potential involvement of the NRG1/ErbB pathway in the Dox-induced nervous system dysfunction. PMID- 29430173 TI - Exploring the experiences of older Chinese adults with comorbidities including diabetes: surmounting these challenges in order to live a normal life. AB - Background: Many people with diabetes have comorbidities, even multimorbidities, which have a far-reaching impact on the older adults, their family, and society. However, little is known of the experience of older adults living with comorbidities that include diabetes. Aim: The aim of this study was to explore the experience of older adults living with comorbidities including diabetes. Methods: A qualitative approach was employed. Data were collected from a selected field of 12 patients with diabetes mellitus in a medical center in northern Taiwan. The data were analyzed by Colaizzi's phenomenological methodology, and four criteria of Lincoln and Guba were used to evaluate the rigor of the study. Results: The following 5 themes and 14 subthemes were derived: 1) expecting to heal or reduce the symptoms of the disease (trying to alleviate the distress of symptoms and trusting in health practitioners combining the use of Chinese and Western medicines); 2) comparing complex medical treatments (differences in physician practices and presentation, conditionally adhering to medical treatment, and partnering with medical professionals); 3) inconsistent information (inconsistent health information and inconsistent medical advice); 4) impacting on daily life (activities are limited and hobbies cannot be maintained and psychological distress); and 5) weighing the pros and cons (taking the initiative to deal with issues, limiting activity, adjusting mental outlook and pace of life, developing strategies for individual health regimens, and seeking support). Surmounting these challenges in order to live a normal life was explored. Conclusion: This study found that the experience of older adults living with comorbidities including diabetes was similar to that of a single disease, but the extent was greater than a single disease. The biggest difference is that the elderly think that their most serious problem is not diabetes, but rather, the comorbidities causing life limitations. Therefore, compared to the elderly suffering from a single disease of diabetes, medical professionals not only care about physiological data of the elderly but also pay attention to the impact of comorbidity on their lives. PMID- 29430174 TI - Management of airway mucus hypersecretion in chronic airway inflammatory disease: Chinese expert consensus (English edition). AB - Airway mucus hypersecretion is one of the most important characteristics of chronic airway inflammatory diseases. Evaluating and managing airway mucus hypersecretion is of great importance for patients with chronic airway inflammatory diseases. This consensus statement describes the pathogenesis, clinical features, and the management of airway mucus hypersecretion in patients with chronic airway inflammatory diseases in the People's Republic of China. The statement has been written particularly for respiratory researchers, pulmonary physicians, and patients. PMID- 29430175 TI - The YKL-40 protein is a potential biomarker for COPD: a meta-analysis and systematic review. AB - Background: Many studies have found that YKL-40 may play an important pathogenic role in COPD. However, the results of these studies were inconsistent. Therefore, we performed a systematic review and meta-analysis to investigate the role of YKL 40 in COPD. Methods: We performed a systematic literature search in many database and commercial internet search engines to identify studies involving the role of YKL-40 in patients with COPD. The standardized mean difference (SMD) and Fisher's Z-value with its 95% confidence interval (CI) were used to investigate the effect sizes. Results: A total of 15 eligible articles including 16 case-control/cohort groups were included in the meta-analysis. The results indicated that the serum YKL-40 levels in patients with COPD were significantly higher than those in healthy controls (SMD =1.58, 95% CI =0.68-2.49, P=0.001), and it was correlated with lung function (pooled r=-0.32; Z=-0.33; P<0.001). The results of subgroup analysis found that the serum YKL-40 levels were statistically different between the exacerbation group and the stable group in patients with COPD (SMD =1.55, 95% CI =0.81-2.30, P<0.001). Moreover, the results indicated that the sputum YKL-40 levels in patients with COPD were also significantly higher than those in healthy controls (SMD =0.70, 95% CI =0.10-1.30, P=0.022). Conclusion: The current study suggests that YKL-40 may be implicated in bronchial inflammation and remodeling in COPD and may be considered as a useful biomarker for COPD diagnosis and monitoring. PMID- 29430176 TI - Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications. AB - Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987. However, there remained considerable interest in selecting appropriate outcome measures that could confirm clinical efficacy in a randomized controlled trial setting. Using computed tomography as the primary measure of decline in lung density, the capacity for intravenously administered AAT replacement therapy to slow and modify the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha 1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of alpha 1 antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications for clinical considerations with respect to diagnosis, treatment and management of emphysema due to alpha 1 antitrypsin deficiency. PMID- 29430177 TI - Cadmium nanoparticles citrullinate cytokeratins within lung epithelial cells: cadmium as a potential cause of citrullination in chronic obstructive pulmonary disease. AB - Objective: The objective of the study was to determine whether the cadmium derived materials induce intracellular protein citrullination. Methods: Human A549 lung epithelial cells were exposed to cadmium in soluble and nanoparticulate forms represented by cadmium chloride (CdCl2) and cadmium oxide (CdO), respectively, and their combinations with ultrafine carbon black (ufCB) produced by high temperature combustion, imitating cigarette burning. Protein citrullination in cell lysates was analyzed by Western immunoblotting and verified by immunofluorescent confocal microscopy. Target citrullinated proteins were identified by proteomic analysis. Results: CdO, ufCB and its combination with CdCl2 and CdO after high temperature combustion induced protein citrullination in cultured human lung epithelial cells, as detected by immunoblotting with anti-citrullinated protein antibody. Cytokeratins of type II (1, 2, 5, 6A, 6B and 77) and type I (9, 10) were identified as major intracellular citrullination targets. Immunofluorescent staining confirmed the localization of citrullinated proteins both in the cytoplasm and cell nuclei. Conclusion: Cadmium oxide nanoparticle exposure facilitated post-translational citrullination of proteins. PMID- 29430178 TI - Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells. AB - Introduction: Exosomes are closed-membrane nanovesicles that are secreted by a variety of cells and exist in most body fluids. Recent studies have demonstrated the potential of exosomes as natural vehicles that target delivery of functional small RNA and chemotherapeutics to diseased cells. Methods: In this study, we introduce a new approach for the targeted delivery of exosomes loaded with functional miR-26a to scavenger receptor class B type 1-expressing liver cancer cells. The tumor cell-targeting function of these engineered exosomes was introduced by expressing in 293T cell hosts, the gene fusion between the transmembrane protein of CD63 and a sequence from Apo-A1. The exosomes harvested from these 293T cells were loaded with miR-26a via electroporation. Results: The engineered exosomes were shown to bind selectively to HepG2 cells via the scavenger receptor class B type 1-Apo-A1 complex and then internalized by receptor-mediated endocytosis. The release of miR-26a in exosome-treated HepG2 cells upregulated miR-26a expression and decreased the rates of cell migration and proliferation. We also presented evidence that suggest cell growth was inhibited by miR-26a-mediated decreases in the amounts of key proteins that regulate the cell cycle. Conclusion: Our gene delivery strategy can be adapted to treat a broad spectrum of cancers by expressing proteins on the surface of miRNA loaded exosomes that recognize specific biomarkers on the tumor cell. PMID- 29430179 TI - Sodium deoxycholate-decorated zein nanoparticles for a stable colloidal drug delivery system. AB - Background: The use of biopolymers is increasing in drug delivery, thanks to the peculiar properties of these compounds such as their biodegradability, availability, and the possibility of modulating their physico-chemical characteristics. In particular, protein-based systems such as albumin are able to interact with many active compounds, modulating their biopharmaceutical properties. Zein is a protein of 20-40 kDa made up of many hydrophobic amino acids, generally regarded as safe (GRAS) and used as a coating material. Methods: In this investigation, zein was combined with various surfactants in order to obtain stable nanosystems by means of the nanoprecipitation technique. Specific parameters, eg, temperature, pH value, Turbiscan Stability Index, serum stability, in vitro cytotoxicity and entrapment efficiency of various model compounds were investigated, in order to identify the nanoformulation most useful for a systemic drug delivery application. Results: The use of non-ionic and ionic surfactants such as Tween 80, poloxamer 188, and sodium deoxycholate allowed us to obtain nanoparticles characterized by a mean diameter of 100-200 nm when a protein concentration of 2 mg/mL was used. The surface charge was modulated by means of the protein concentration and the nature of the stabilizer. The most suitable nanoparticle formulation to be proposed as a colloidal drug delivery system was obtained using sodium deoxycholate (1.25% w/v) because it was characterized by a narrow size distribution, a good storage stability after freeze-drying and significant feature of retaining lipophilic and hydrophilic compounds. Conclusion: The sodium deoxycholate-coated zein nanoparticles are stable biocompatible colloidal carriers to be used as useful drug delivery systems. PMID- 29430180 TI - Color preferences in participants with high or low hypnotic susceptibility. AB - Purpose: Color preferences vary among normal individuals and psychiatric patients, and this might be related to their different levels of hypnotic susceptibility. We hypothesized that individuals with higher hypnotic susceptibility prefer more arousing colors such as red. Patients and methods: Out of 440 participants, we selected 70 with higher (HIGH) and 66 with lower (LOW) hypnotic susceptibilities, and asked them to undergo the Stanford Hypnotic Susceptibility Scale: Form C (SHSSC) test, then to order their preferences of 11 colors. Results: The HIGH group preferred red more and scored higher on the total SHSSC. The preference order of black was negatively predicted by the SHSSC Taste hallucination but positively by Arm rigidity, and the preference of yellow was positively predicted by Posthypnotic amnesia and Taste hallucination in the HIGH group. Conclusion: The red preference and the SHSSC associations with black and yellow preferences in participants with high hypnotic susceptibility help to clarify the individual difference of color preference and provide research hints for behavioral studies in normal individuals and psychiatric patients. PMID- 29430181 TI - Off-label prescriptions in intensive care unit: the Chinese experience. AB - Background and purpose: Off-label prescriptions for critically ill patients pose several ethical and legal dilemmas for intensive care unit (ICU) clinicians. Yet, few data are available on the prevalence of this practice in critical care environment in China. This nationwide survey was performed to evaluate the conditions of off-label prescriptions in ICU within China. Methods: The survey was performed at the scene of the national ICU conferences in 2016. ICU clinicians attending the congress from 23 provinces across the country were invited. The features of the clinician's off-label prescription practice were investigated and analyzed. Results: A total of 1,318 ICU clinicians completed the anonymous questionnaire. Of these, 76.2% prescribed off-label in clinical practice. A significant difference (p<0.005) was observed between the ICU clinicians with different years of working experience and professional levels, respectively. For 69.2% of the ICU clinicians, the proportion of off-label prescriptions did not exceed 10%, while for fewer prescribers (2.9%), the proportion exceeded 25%. The main reasons for off-label prescriptions were life threatening or terminal medical condition without other substitutes (48.3%), new treatments with strong scientific evidence (38.1%), and limited indications of drug labels (22.7%). Of the ICU clinicians surveyed, 87.5% worried about causing medical disputes, and 26.5% encountered medical disputes caused by off-label prescriptions. The risk of medical disputes was positively associated with the proportion of off-label prescriptions (p=0.009). Among the ICU clinicians, 92.5% expected the national policy for off-label prescriptions in future. Gastrointestinal and respiratory drug classes were noted to have the highest prevalence of off-label use. Conclusion: Off-label prescriptions have been commonly practiced by ICU clinicians in China. A concerted effort should be made to develop a practical and explicit guidance for off-label prescriptions. PMID- 29430182 TI - New horizons in surgical treatment of ground-glass nodules of the lung: experience and controversies. AB - Ground-glass nodule (GGN) is defined as a nodular shadow with ground-glass opacity that is generally associated with the early-stage lung adenocarcinoma. Nowadays, GGNs of the lung are increasingly detected with thin-section computed tomography scan. GGNs are categorized as pure GGNs and mixed GGNs according to the images from a high-resolution computed tomography. Meanwhile, it is routine to divide GGNs into different categories according to the number, solitary, or multiple, the management of which there is very different. A great number of studies have been conducted to analyze the different characteristics of GGNs in various aspects ranging from radiology, pathology, and surgery to molecular biology. However, plenty of problems still remain unsolved, ranging from the preoperative localization to intraoperative surgical resection procedure, the lymphadenectomy, and sampling of lymph nodes, as well as the accuracy of frozen sections. There has been a large volume of updated published information summarizing recently emerging and rapidly progressing aspects of surgical treatment of solitary and multiple GGNs with the unsolved problems mentioned above. However, there have been few specific reviews of surgical treatment of GGNs so far. This review presents a timely outline of advances in relevant experience and controversies of GGNs for a better understanding of this kind of lesion. PMID- 29430183 TI - Ruralization of students' horizons: insights into Australian health professional students' rural and remote placements. AB - Introduction: Health workforce shortages have driven the Australian and other Western governments to invest in engaging more health professional students in rural and remote placements. The aim of this qualitative study was to provide an understanding of the lived experiences of students undertaking placements in various nonmetropolitan locations across Australia. In addition to providing their suggestions to improve rural placements, the study provides insight into factors contributing to positive and negative experiences that influence students' future rural practice intentions. Methods: Responses to open-ended survey questions from 3,204 students from multiple health professions and universities were analyzed using two independent methods applied concurrently: manual thematic analysis and computerized content analysis using Leximancer software. Results: The core concept identified from the thematic analysis was "ruralization of students' horizons," a construct representing the importance of preparing health professional students for practice in nonmetropolitan locations. Ruralization embodies three interrelated themes, "preparation and support," "rural or remote health experience," and "rural lifestyle and socialization," each of which includes multiple subthemes. From the content analysis, factors that promoted students' rural practice intentions were having a "positive" practice experience, interactions with "supportive staff," and interactions with the "community" in general. It was apparent that "difficulties," eg, with "accommodation," "Internet" access, "transport," and "financial" support, negatively impacted students' placement experience and rural practice intentions. Conclusions: The study findings have policy and practice implications for continuing to support students undertaking regional, rural, and remote placements and preparing them for future practice in nonmetropolitan locations. This study may, therefore, further inform ongoing strategies for improving rural placement experiences and enhancing rural health workforce recruitment, retention, and capacity building. PMID- 29430184 TI - Application of serum microRNA-9-5p, 21-5p, and 223-3p combined with tumor markers in the diagnosis of non-small-cell lung cancer in Yunnan in southwestern China. AB - Purpose: Xuanwei City is located in late Permian coal-accumulating areas of the northeastern region of Yunnan Province. In China, morbidity and mortality from lung cancer are highest in Yunnan. Identifying useful circulating markers suitable for the diagnosis of lung cancer in this region is quite meaningful. In this study, we evaluated diagnostic roles of serum miR-9-5p, 21-5p, 223-3p, 135b 5p, 339-5p, and 501-5p in patients with non-small-cell lung cancer (NSCLC) in Yunnan. Moreover, we evaluated the diagnostic performance of several tumor markers, including carcinoembryonic antigen (CEA), cytokeratin 19 fragment 21-1 (CYFRA21-1), and squamous cell carcinoma-related antigen (SCC). Methods: Quantitative real-time polymerase chain reaction detected six miRNAs in the serum of 104 NSCLC patients and 50 cancer-free controls. Other markers, including CEA, CYFRA21-1, and SCC, in serum were also measured. The diagnostic ability of miRNAs and tumor markers was evaluated by receiver operating characteristic (ROC) curve analysis. The diagnostic performance of these serum markers was also evaluated in Xuanwei and non-Xuanwei subjects, because the etiological and the epidemiological characteristics of lung cancer in Xuanwei were quite different from those in other regions. Results: Serum miR-9-5p, miR-21-5p, miR-223-3p, CEA, CYFRA21-1, and SCC were upregulated in NSCLC patients, compared with cancer-free controls. No significant difference was found in miR-135b-5p, miR-339-5p, and miR-501-5p expression. The area under ROC curves (AUCs) of miR-9-5p, miR-21-5p, miR-223-3p, CEA, CYFRA21-1, and SCC were 0.706, 0.765, 0.744, 0.749, 0.735, and 0.616, respectively. When combined, miRNAs and tumor markers yielded the highest diagnostic power, with AUC of 0.886, sensitivity of 82.69%, and specificity of 88.00%. In Xuanwei subjects, miR-223-3p and CEA may be suitable biomarkers to distinguish NSCLC from cancer-free states with AUCs of 0.752 and 0.791, respectively. The diagnostic power of the combination of miRNAs and tumor markers was still the highest in both subgroups (region: Xuanwei and non-Xuanwei; stages: I-II and III-IV). Conclusion: Serum miR-9-5p, miR-21-5p, miR-223-3p, CEA, CYFRA21 1, and SCC could be potential diagnostic biomarkers for NSCLC patients in Yunnan. miRNAs and tumor markers should be combined to diagnose NSCLC, as it showed better ability for screening patients with NSCLC. PMID- 29430185 TI - ALDH1A2 suppresses epithelial ovarian cancer cell proliferation and migration by downregulating STAT3. AB - Epithelial ovarian cancer is the deadliest gynecological malignancy worldwide. A better understanding of epithelial ovarian cancer pathogenesis and the molecular mechanism underlying its metastasis may increase overall survival rates. Previous studies have indicated that aldehyde dehydrogenase 1 family member A2 (ALDH1A2) is a candidate tumor suppressor in epithelial ovarian cancer. However, the potential role of ALDH1A2 in the molecular mechanisms of epithelial ovarian cancer remains largely unclear. In the present study, we found lower expression of ALDH1A2 in high-grade epithelial ovarian cancer tissues than in low-grade epithelial ovarian cancer tissues. Overexpression of ALDH1A2 decreased the proliferation and migration of epithelial ovarian cancer cell lines, whereas ALDH1A2 knockdown significantly increased cell growth and migration. Moreover, upregulation of ALDH1A2 also reduced the activation of signal transducer and activator of transcription 3 (STAT3). In conclusion, these findings suggest that ALDH1A2 suppresses epithelial ovarian cancer cell proliferation and migration by downregulating STAT3. PMID- 29430186 TI - Identification of genomic expression differences between right-sided and left sided colon cancer based on bioinformatics analysis. AB - Introduction: More and more findings have demonstrated that right-sided colon cancers (RCC) and left-sided colon cancers (LCC) are distinct clinical and biological entities and suggest that they should be treated as different diseases. However, the reasons why RCC and LCC harbor different clinical and biological features remain unclear. Materials and methods: To identify the genomic expression differences between RCC and LCC and uncover the mechanisms underlying these differences, we chose the gene expression profiles of GSE14333 from the Gene Expression Omnibus (GEO) database as an object of study. Then, a systematic and integrative bioinformatics analysis was performed to research the possible mechanism of the differentially expressed (DE) genes from the Gene Expression Omnibus dataset including gene ontology (GO) analysis, pathway enrichment analysis, protein-protein interaction (PPI) network construction, and module analysis. Totally, we extracted 3,793 DE genes from samples of colon cancer including 1,961 genes upregulated in RCC and 1,832 genes upregulated in LCC from the selected dataset. Results: The results of GO and pathway enrichment analysis indicated that RCC and LCC could predispose to different pathways regulated by different genes. Based on the PPI network, PCNA, TP53, HSP90AA1, CSNK2A1, UBB, LRRK2, ABL1, PRKACA, CAV1, and JUN were identified as the key hub genes. Also, significant modules were screened from the PPI network. Conclusion: In conclusion, the present study indicated that the identified genes and pathways may promote new insights into the underlying molecular mechanisms contributing to the difference between RCC and LCC and might be used as specific therapeutic targets and prognostic markers for the personalized treatment of RCC and LCC. PMID- 29430187 TI - The lncRNA PCAT1 is correlated with poor prognosis and promotes cell proliferation, invasion, migration and EMT in osteosarcoma. AB - Introduction: Osteosarcoma is a malignant primary bone cancer and is lethal to children and adolescents. Recently, the dysregulation of long noncoding RNAs (lncRNAs) has been shown in various types of cancers. Aim: The present study aimed to examine the role of the lncRNA prostate cancer-associated transcript 1 (PCAT1) in osteosarcoma progression. Materials and methods: The expression levels of relevant genes in clinical samples and cell lines were determined by quantitative real-time polymerase chain reaction. Cell proliferation, invasion and migration were examined by CCK-8 assay, transwell invasion and migration assay, respectively. Cell apoptosis and cell cycle were detected by flow cytometry. Protein levels were detected by Western blot. Results: Our results showed that PCAT1 was upregulated in osteosarcoma tissues when compared to normal bone tissues. PCAT1 was also upregulated in osteosarcoma cell lines when compared to normal bone cell line. The upregulation of PCAT1 was significantly associated with advanced clinical stage, tumor metastasis and shorter overall survival in patients with osteosarcoma. In vitro studies showed that overexpression of PCAT1 in MG-63 cells enhanced cell proliferation, cell invasion and migration and epithelial-to-mesenchymal transition (EMT); decreased cell apoptotic rate; and also caused an increase in cell population at S phase with a decrease in cell population at G0/G1 phase. Knockdown of PCAT1 in U2OS cells suppressed cell proliferation, cell invasion and migration, and EMT; increased cell apoptotic rate; and caused an increase in the cell population at G0/G1 phase with a decrease in cell population at S phase. Conclusion: Taken together, our results suggest the oncogenic role of PCAT1 in osteosarcoma progression. PMID- 29430188 TI - LincRNA-ROR promotes metastasis and invasion of esophageal squamous cell carcinoma by regulating miR-145/FSCN1. AB - Background and objective: In an attempt to discover a new biomarker for early diagnosis and prognosis of esophageal squamous cell carcinoma (ESCC), the regulation mechanism of large intergenic non-coding RNA-regulator of reprogramming (lincRNA-ROR) as a microRNA (miRNA) sponge was studied. Patients and methods: ROR expression in 91 pairs of ESCC tissue samples and matched adjacent tissues was quantified with real-time fluorescent quantitative polymerase chain reaction (qRT-PCR). The ROR-miRNA-mRNA regulatory network was built with 161 esophageal cancer (EC) tissues and 11 adjacent tumor tissues from The Cancer Genome Atlas (TCGA) database. A total of 96 cases of ESCC from TCGA database were collected for analysis on survival rates. The regulatory relationship between ROR, miR-145 and FSCN1 was verified in ESCC cells via qRT PCR, dual luciferase reporter (DLR) assay, RNA immunoprecipitation (RIP) and Western blotting. The transwell method was used to detect cell migration and invasion. Results: ROR expression in ESCC tumor tissues was significantly higher than in the adjacent tissues, p<0.001. The survival rate of ESCC patients with high ROR expression levels was lower than that of patients with low ROR expression levels (p<0.001). ROR overexpression could downregulate miR-145 by up to 50% was proven by RIP, DLR assay, and qRT-PCR. Two effective binding sites of ROR to miR-145 were verified by DLR assay. One of the sites has never been cited in the literature. The Western blotting results showed that FSCN1 was a downstream target of ROR/miR-145 (p<0.05). Transwell assays were used to show that overexpression of ROR enhanced migration and invasion behavior of ESCC and miR-145 hindered these effects. Conclusion: ROR acted as a competitive endogenous RNA (ceRNA) of miR-145 in ESCC. A novel, effective miR-145 binding site of ROR was discovered. The ROR/miR-145/FSCN1 pathway was shown to take part in the metastasis of ESCC. ROR is likely an oncogene biomarker for ESCC early diagnosis and prognosis. PMID- 29430189 TI - The correlation between CT features and glycosylated hemoglobin level in patients with T2DM complicated with primary pulmonary tuberculosis. AB - To investigate the correlation between computed tomography (CT) features and glycosylated hemoglobin (HbAlc) levels in patients with type 2 diabetes mellitus (T2DM) complicated with primary pulmonary tuberculosis (PTB). One hundred and eighty untreated PTB patients complicated with T2DM were selected. Based on the HbAlc level, the patients were divided into three groups: HbAlc level <7% (Group I: 32 patients), 7%-9% (Group II: 48 patients), and >9% (Group III: 100 patients). The changes of CT manifestations and HbAlc were analyzed after TB and T2DM treatment. In the three groups, the detection rate of large segmented leafy shadow was 50%, 56.2%, and 87%; the air bronchogram sign detection rate was 40.6%, 47.9%, and 77%; the discovery rate of mouth-eaten cavity was 31.2%, 45.8%, and 65%; thick wall cavity detection rate was 25%, 31.2%, and 52%; the rate of multiple cavities was 34.3%, 50%, and 73%; and bronchial TB was found in 33.3%, 21.8%, and 46%, respectively. The detection rates of lesions in Group III were significantly higher than in Group II and Group I (p<0.05), and this increase was significant (p<0.05). After treatment, the HbAlc level reached control target (<7%) among all three groups and CT absorption improvement rates were 100%, 72.9%, and 56% respectively. The therapeutic efficacy of group I was better than group II (p<0.01), and the treatment efficacy of group II was better than group III (p<0.05). CT manifestations of T2DM complicated with PTB were closely related to HbAlc level. The effect is better when HbAlc level <7%. HbAlc level effectively reflects the severity and therapeutic effect to a certain extent. CT scan can provide some important information for clinical imaging. The above two examinations can guide clinicians to formulate the appropriate diagnosis and treatment in a timely manner. PMID- 29430190 TI - Salmonella enterica serovars Typhimurium and Enteritidis causing mixed infections in febrile children in Mozambique. AB - Background and purpose: Invasive nontyphoidal salmonellosis, mostly caused by serovars Typhimurium and Enteritidis of Salmonella enterica, has emerged as a major public health problem in sub-Saharan Africa. The aim of this study was the clinical and microbiological characterization of nontyphoidal salmonellosis episodes affecting febrile children in Mozambique. Patients and methods: The clinical records of the patients were evaluated, and S. enterica isolates were characterized with regard to serovar, phage type, antimicrobial resistance (phenotype/responsible genes), plasmid content, pulsed-field gel electrophoresis, and multilocus sequence typing. Results: Fifteen S. Typhimurium and 21 S. Enteritidis isolates were recovered from blood samples of 25 children, the majority with underlying risk factors. With regard to phage typing, most isolates were either untypeable or reacted but did not conform, revealing that a number of previously unrecognized patterns are circulating in Mozambique. Most isolates were multidrug-resistant, with nearly all of the responsible genes located on derivatives of serovar-specific virulence plasmids. ST313 and ST11 were the predominant sequence types associated with S. Typhimurium and S. Enteritidis, respectively, and the uncommon ST1479 was also detected in S. Enteritidis. A distinct XbaI fragment of ~350 kb was associated with pulsed-field gel electrophoresis patterns of multidrug-resistant isolates of S. Enteritidis. Nearly half of the children were coinfected with both serovars, a fact expected to aggravate the disease and hamper the treatment. However, particularly poor outcomes were not observed for the coinfected patients. Conclusion: Mixed Salmonella infections could frequently occur in febrile children in Mozambique. Additional studies are required to determine their actual impact and consequences, not only in this country, but also in other African countries. PMID- 29430191 TI - Current eradication rate of Helicobacter pylori with clarithromycin-based triple therapy in a gastroenterology practice in the New York metropolitan area. AB - Background: In order to mitigate potential issues with antibiotic resistance in the treatment of patients with Helicobacter pylori infection, the selection of a therapeutic regimen is optimized by being aware of local eradication rates as well as the patient's medication history and previous diagnoses. Purpose: This study primarily aimed to calculate the eradication rate of H. pylori infection in the New York Metropolitan area when using clarithromycin-based triple therapy per the dosing instructions for Omeclamox(r)-Pak. A secondary objective was to determine risk factors for therapeutic failure. Patients and methods: A retrospective analysis was performed on 156 patients treated with clarithromycin based triple therapy between 2011 and 2017 at a gastroenterology practice in Edison, New Jersey. Results: The cumulative eradication rate for the intent-to treat population was 84%, while the per-protocol rate was 86%. No differences were seen in the rates of subgroups defined by demographics or medication history. Conclusion: Despite evidence and predictions from other sources in the last decade that clarithromycin-based treatments for H. pylori are becoming less effective, the results of this study support the use of clarithromycin-based triple therapy as a first-line treatment in the New York Metropolitan region. PMID- 29430192 TI - The prevalence and determinants of poor glycemic control among adults with type 2 diabetes mellitus in Saudi Arabia. AB - Background: Although the prevalence of type 2 diabetes mellitus (T2DM) is rising sharply in Saudi Arabia, data on glycemic control, crucial to reducing diabetes mellitus complications, remain scarce. This study therefore investigated glycemic control status and the factors influencing poor glycemic control among adult T2DM patients in Saudi Arabia. Methods: This cross-sectional study examined 423 T2DM patients at a diabetic center in Tabuk, Saudi Arabia between September 2016 and July 2017. Glycemic levels were measured via fasting blood glucose (FBG) levels, and "poor glycemic control" was defined as FBG >130 mg/dL. Poor glycemic control's risk factors were identified using a logistic regression. Results: In the sample, 74.9% of the patients had poor blood glycemic control. Logistic regression revealed that T2DM patients had an increased chance of poorly controlled diabetes if they had family histories of diabetes (adjusted odds ratio [AOR] =7.38, 95% CI 4.09-13.31), longer diabetic durations (AOR =2.33, 95% CI 1.14-4.78 for 5-10 years and AOR =5.19, 95% CI 2.50-10.69 for >10 years), insufficient physical exercise (AOR =19.02, 95% CI 6.23-58.06), or were overweight (AOR =3.79, 95% CI 2.00-7.18), or obese (AOR =5.35, 95% CI 2.72 12.59). Conclusion: A high proportion of the sampled patients had poor glycemic control, therefore, health care professionals should manage the associated risk factors to limit disease complications and improve the health of patients with diabetes. PMID- 29430193 TI - Tolvaptan in the treatment of autosomal dominant polycystic kidney disease: patient selection and special considerations. AB - Standard of care therapies for autosomal dominant polycystic kidney disease (ADPKD) may limit morbidity and mortality due to disease-related complications, but they do not delay disease progression. Tolvaptan, a selective vasopressin V2 receptor antagonist, delays the increase in kidney volume (a surrogate marker for disease progression), slows the decline in renal function, and reduces pain in ADPKD patients with relatively preserved renal function. The most common adverse events of tolvaptan are linked to its aquaretic effect, and rare cases of idiosyncratic hepatitis were observed. Additional ongoing studies will determine whether the benefits are sustained over time, whether they can be observed in patients with advanced kidney disease, and whether they can be translated in terms of quality of life and cost/effectiveness parameters. Tolvaptan is currently approved in Europe and several countries throughout the world. In real life conditions, selection of patients that would be good theoretical candidates to tolvaptan is a key but complex question. Eligibility criteria slightly differ from one country to another, and several models (based on conventional data, genetics, renal volume) were recently proposed to identify patients with evidence or risk of rapid disease progression. Eligible patients will ultimately make the decision to start tolvaptan, after complete information, consideration, and balancing of benefits, adverse events, and risks. PMID- 29430194 TI - Effectiveness of palivizumab immunoprophylaxis in preterm infants against respiratory syncytial virus disease in Qatar. AB - Objective: The primary objective of this study was to document the hospitalization rate due to respiratory syncytial virus (RSV) and compliance with palivizumab use in preterm infants receiving palivizumab immunoprophylaxis during 2009-2012 RSV seasons. Design: This is a descriptive single-center cohort study. Infants who were <=35-week gestational age were eligible for enrollment if they received the first palivizumab dose between November 1 and March 31 (2009-2010, 2010-2011, 2011-2012). Primary endpoint was defined as RSV hospitalization of duration 24 hours or longer. Results: The cumulative RSV hospitalization rate in the registry (2009-2012) was 1.9%. The compliance rate was 85.7%. It showed steady increase across the 3 successive RSV seasons, 2009-2010, 2010-2011, and 2011-2012 (57.7% vs 92.6%, 94.2%, respectively, p<0.05). The RSV hospitalization rate decreased from 3.7% for 2009-2010 to 1.3% for 2010-2011 and 1.7% for 2011 2012 RSV seasons. No deaths and no side effects linked to palivizumab injections were reported for any subjects enrolled. Conclusion: Our study provides national data regarding characteristics, compliance rate, and hospitalization outcomes for preterm infants receiving palivizumab in Qatar. Our data is consistent with the previously reported efficacy and safety profile of palivizumab. PMID- 29430195 TI - Computed tomography-guided percutaneous ozone injection of the Gasserian ganglion for the treatment of trigeminal neuralgia. AB - Objective: The aim of this study was to evaluate the therapeutic effect of computed tomography (CT)-guided percutaneous ozone injection for refractory trigeminal neuralgia. Design: A retrospective evaluation was performed in the study. Setting: The study was conducted at a university hospital pain center. Patients and methods: A total of 29 patients with a clinical diagnosis of refractory trigeminal neuralgia were enrolled. All patients were treated with a percutaneous ozone injection and one patient was excluded. There were 21 patients with classical trigeminal neuralgia (group A) and seven patients with painful trigeminal neuropathy caused by post-herpetic neuralgia (group B). The percutaneous injection was an oxygen-ozone mixture at an ozone concentration of 30 MUg/mL into the Gasserian ganglion performed under CT guidance. The number of procedures performed varied from one to as many as 16. Outcomes were evaluated using visual analog scale (VAS) pain scores. Results: The combined VAS scores were 7.11 +/- 1.23 pretreatment, 2.86 +/- 1.69 posttreatment (P < 0.05) and 3.25 +/- 2.01 after 6-month follow-up (P < 0.05). In group A, the VAS scores were 7.10 +/- 1.04 pretreatment and 2.90 +/- 1.84 posttreatment (P < 0.05). In group B, the VAS scores were 7.14 +/- 1.77 pretreatment and 2.71 +/- 1.25 posttreatment (P < 0.05). After 6-months follow-up, the VAS score was 3.38 +/- 2.18 in group A and 2.86 +/- 1.46 in group B, a decrease compared to pretreatment (P < 0.05). VAS of Group A and B showed no difference not only in pretreatment but also in postreatment and follow-up. Conclusion: Percutaneous ozone injection is a safe and effective treatment for patients with refractory trigeminal neuralgia. PMID- 29430196 TI - Clinimetric properties of the Nepali version of the Pain Catastrophizing Scale in individuals with chronic pain. AB - Background: Pain catastrophizing is an exaggerated negative cognitive response related to pain. It is commonly assessed using the Pain Catastrophizing Scale (PCS). Translation and validation of the scale in a new language would facilitate cross-cultural comparisons of the role that pain catastrophizing plays in patient function. Purpose: The aim of this study was to translate and culturally adapt the PCS into Nepali (Nepali version of PCS [PCS-NP]) and evaluate its clinimetric properties. Methods: We translated, cross-culturally adapted, and performed an exploratory factor analysis (EFA) of the PCS-NP in a sample of adults with chronic pain (N=143). We then confirmed the resulting factor model in a separate sample (N=272) and compared this model with 1-, 2-, and 3-factor models previously identified using confirmatory factor analyses (CFAs). We also computed internal consistencies, test-retest reliabilities, standard error of measurement (SEM), minimal detectable change (MDC), and limits of agreement with 95% confidence interval (LOA95%) of the PCS-NP scales. Concurrent validity with measures of depression, anxiety, and pain intensity was assessed by computing Pearson's correlation coefficients. Results: The PCS-NP was comprehensible and culturally acceptable. We extracted a two-factor solution using EFA and confirmed this model using CFAs in the second sample. Adequate fit was also found for a one factor model and different two- and three-factor models based on prior studies. The PCS-NP scores evidenced excellent reliability and temporal stability, and demonstrated validity via moderate-to-strong associations with measures of depression, anxiety, and pain intensity. The SEM and MDC for the PCS-NP total score were 2.52 and 7.86, respectively (range of PCS scores 0-52). LOA95% was between -15.17 and +16.02 for the total PCS-NP scores. Conclusion: The PCS-NP is a valid and reliable instrument to assess pain catastrophizing in Nepalese individuals with chronic pain. PMID- 29430197 TI - Profile of buparlisib and its potential in the treatment of breast cancer: evidence to date. AB - Alteration of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling pathway is key for the growth and survival of several cancers, including breast cancer. In addition, dysregulation of PI3K signaling may contribute to resistance to several anticancer agents. PI3K inhibitors may, therefore, be effective as antineoplastic therapy. Buparlisib is a potent and highly specific oral inhibitor of the pan-class I PI3K family. Buparlisib specifically inhibits class I PIK3 in the PI3K/AKT kinase signaling pathway in an ATP-competitive manner, thus inhibiting the production of the secondary messenger phosphatidylinositol (3,4,5)-trisphosphate and activation of the PI3K signaling pathway. This may induce inhibition of tumor cell growth and survival in susceptible tumor cell populations. Buparlisib is currently under investigation in patients with a variety of solid tumors, including breast cancer. Buparlisib has been validated as a promising anticancer agent, and tremendous efforts have been taken to develop it. However, buparlisib monotherapy has resulted in humble benefit so far. Results from studies combining buparlisib with different anticancer agents - namely, endocrine therapy, anti-HER2 therapy, and chemotherapy - have showed variable efficacy with consistent substantial toxicity. PMID- 29430198 TI - Acute kidney injury and infections in patients taking antihypertensive drugs: a self-controlled case series analysis. AB - Background: The relative risk of acute kidney injury (AKI) following different infections, and whether angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) modify the risk, is unclear. We aimed to determine the risks of hospital admission with AKI following infections (urinary tract infection [UTI], lower respiratory tract infection [LRTI], and gastroenteritis) among users of antihypertensive drugs. Methods: We used UK electronic health records from practices contributing to the Clinical Practice Research Datalink linked to the Hospital Episode Statistics database. We identified adults initiating ACEIs/ARBs or alternative antihypertensive therapy (beta-blockers, calcium channel blockers, or thiazide diuretics) between April 1997 and March 2014 with at least 1 year of primary care registration prior to first prescription, who had a hospital admission for AKI, and who had a primary care record for incident UTI, LRTI, or gastroenteritis. We used a self-controlled case series design to calculate age-adjusted incidence rate ratios (IRRs) for AKI during risk periods following acute infection relative to noninfected periods (baseline). Results: We identified 10,219 eligible new users of ACEIs/ARBs or other antihypertensives with an AKI record. Among these, 2,012 had at least one record for a UTI during follow-up, 2,831 had a record for LRTI, and 651 had a record for gastroenteritis. AKI risk was higher following infection than in baseline noninfectious periods. The rate ratio was highest following gastroenteritis: for the period 1-7 days postinfection, the IRR for AKI following gastroenteritis was 43.4 (95% CI=34.0-55.5), compared with 6.0 following LRTI (95% CI=5.0-7.3), and 9.3 following UTI (95% CI=7.8-11.2). Increased risks were similar for different antihypertensives. Conclusion: Acute infections are associated with substantially increased transient AKI risk among antihypertensive users, with the highest risk after gastroenteritis. The increase in relative risk is not greater among users of ACEIs/ARBs compared with users of other antihypertensives. PMID- 29430199 TI - Rapid recovery of vision following early intervention with fractionated stereotactic radiotherapy for optic nerve sheath meningioma. AB - Purpose: To report the outcomes of early intervention with fractionated stereotactic radiotherapy (FSRT) in a patient with primary optic nerve sheath meningioma (ONSM). Patient and methods: A male patient in his early 40s underwent 5-beam FSRT at a prescribed dose of 50 Gy in 25 fractions over 35 days. The patient had an 11-month history of progressive visual impairment at the time of FSRT. Results: On day 14 of treatment, the patient reported early improvement in his vision. Two weeks after the completion of FSRT, his left eye visual acuity and field recovered completely. However, the tumor regressed only slightly in the 2 years of follow-up. Conclusion: Early intervention with FSRT for optic nerve sheath meningioma resulted in a rapid response and complete improvement of visual impairment. PMID- 29430200 TI - Exploring sleep disorders in patients with chronic kidney disease. AB - Kidney disorders have been associated with a variety of sleep-related disorders. Therefore, researchers are placing greater emphasis on finding the role of chronic kidney disease (CKD) in the development of obstructive sleep apnea and restless legs syndrome. Unfortunately, the presence of other sleep-related disorders with CKDs and non-CKDs has not been investigated with the same clinical rigor. Recent studies have revealed that myriad of sleep disorders are associated with CKDs. Furthermore, there are a few non-CKD-related disorders that are associated with sleep disorders. In this narrative review, we provide a balanced view of the spectrum of sleep disorders (as identified in International Classification of Sleep disorders-3) related to different types of renal disorders prominently including but not exclusively limited to CKD. PMID- 29430201 TI - Outcomes in adult pectus excavatum patients undergoing Nuss repair. AB - Pectus excavatum (PEx) is one of the most common congenital chest wall deformities. Depending on the severity, presentation of PEx may range from minor cosmetic issues to disabling cardiopulmonary symptoms. The effect of PEx on adult patients has not been extensively studied. Symptoms may not occur until the patient ages, and they may worsen over the years. More recent publications have implied that PEx may have significant cardiopulmonary implications and repair is of medical benefit. Adults presenting for PEx repair can undergo a successful repair with a minimally invasive "Nuss" approach. Resolution of symptoms, improved quality of life, and satisfying results are reported. PMID- 29430202 TI - Specialty Training's Organizational Readiness for curriculum Change (STORC): validation of a questionnaire. AB - Background: The field of postgraduate medical education (PGME) is continuously evolving as a result of social demands and advancing educational insights. Change experts contend that organizational readiness for change (ORC) is a critical precursor for successful implementation of change initiatives. However, in PGME, assessing change readiness is rarely considered while it could be of great value for managing educational change such as curriculum change. Therefore, in a previous Delphi study the authors developed an instrument for assessing ORC in PGME: Specialty Training's Organizational Readiness for curriculum Change (STORC). In this study, the psychometric properties of this questionnaire were further explored. Methods: In 2015, STORC was distributed among clinical teaching teams in the Netherlands. The authors conducted a confirmatory factor analysis on the internal factor structure of STORC. The reliability of the measurements was estimated by calculating Cronbach's alpha for all sub-scales. Additionally, a behavioral support-for-change measure was distributed as well to assess correlations with change-related behavior. Results: In total, the STORC questionnaire was completed by 856 clinical teaching team members from 39 specialties. Factor analysis led to the removal of 1 item but supported the expected factor structure with very good fit for the other 43 items. Supportive behavior was positively correlated to a higher level of ORC. Discussion: In this study, additional steps to collect validity evidence for the STORC questionnaire were taken successfully. The final subscales of STORC represent the core components of ORC in the literature. By breaking down this concept into multiple measurable aspects, STORC could help to enable educational leaders to diagnose possible hurdles in implementation processes and to perform specifically targeted interventions when needed. PMID- 29430204 TI - Whitefly predation and extensive mesonotum color polymorphism in an Acletoxenus population from Singapore (Diptera, Drosophilidae). AB - Acletoxenus is a small genus of Drosophilidae with only four described species that are closely associated with whiteflies (adults and larvae). Here, the first video recordings of larvae feeding on whiteflies (Aleurotrachelus trachoides) are presented. Typical morphological adaptations for predation by schizophoran larvae are also described: the larval pseudocephalon lacks a facial mask and the cephaloskeleton is devoid of cibarial ridges that could be used for saprophagy via filtration. Despite being a predator, Acletoxenus is unlikely to be a good candidate for biological control of whiteflies because the life cycle is fairly long (24 days), lab cultures could not be established, and the puparia have high parasitization rates by a pteromalid wasp (Pachyneuron leucopiscida). Unfortunately, a confident identification of the Singapore Acletoxenus population to species was not possible because species identification and description in the genus overemphasize coloration characters of the mesonotum which are shown to be unsuitable because the Singapore population has flies with coloration patterns matching three of the four described species. Based on morphology and DNA sequences, the population from Singapore is tentatively assigned to Acletoxenus indicus or a closely related species. PMID- 29430203 TI - Approach to Hemoptysis in the Modern Era. AB - Hemoptysis is a frequent manifestation of a wide variety of diseases, with mild to life-threatening presentations. The diagnostic workup and the management of severe hemoptysis are often challenging. Advances in endoscopic techniques have led to different new therapeutic approaches. Cold saline, vasoconstrictive and antifibrinolytic agents, oxidized regenerated cellulose, biocompatible glue, laser photocoagulation, argon plasma coagulation, and endobronchial stents and valves are amongst the tools available to the bronchoscopist. In this article, we review the evidence regarding the definition, etiology, diagnostic modalities, and treatment of severe hemoptysis in the modern era with emphasis on bronchoscopic techniques. PMID- 29430205 TI - Species limits within the widespread Amazonian treefrog Dendropsophus parviceps with descriptions of two new species (Anura, Hylidae). AB - The genus Dendropsophus is one of the most speciose among Neotropical anurans and its number of described species is increasing. Herein, molecular, morphological, and bioacoustic evidence are combined to assess species limits within D. parviceps, a widely distributed species in the Amazon Basin. Phylogenetic relationships were assessed using 3040 bp sequences of mitochondrial DNA, genes 12S, ND1, and CO1. The phylogeny shows three well-supported clades. Bioacoustic and morphological divergence is congruent with those clades demonstrating that Dendropsophus parviceps is a species complex. Dendropsophus parvicepssensu stricto occurs in the Amazon basin of Ecuador, northern Peru, southern Colombia and northwestern Brazil. It is sister to two previously undescribed species, D. kubrickisp. n. from central Peru and D. kamagarinisp. n. from southern Peru, northeastern Bolivia, and northwestern Brazil. Genetic distances (uncorrected p, gene 12S) between D. parviceps and the new species is 3 to 4%. Dendropsophus kamagarinisp. n. can be distinguished from D. parviceps by having a prominent conical tubercle on the distal edge of the upper eyelid (tubercle absent in D. parviceps). Dendropsophus kubrickisp. n. differs from D. parviceps by having scattered low tubercles on the upper eyelids (smooth in D. parviceps). Dendropsophus parviceps and both new species differ from all their congeners by their small size (adult maximum SVL = 28.39 mm in females, 22.73 mm in males) and by having a bright orange blotch on the hidden areas of the shanks and under arms. The advertisement call of the two new species has lower dominant frequency relative to D. parviceps. Probable speciation modes are discussed. Available evidence indicates that ecological speciation along an elevation gradient is unlikely in this species complex. PMID- 29430206 TI - The first fossil brown lacewing from the Miocene of the Tibetan Plateau (Neuroptera, Hemerobiidae). AB - A new species of Hemerobiidae, Wesmaelius makarkini Yang, Pang & Ren, sp. n. is described from the Lower Miocene, Garang Formation of Zeku County, Qinghai Province (northeastern Tibetan Plateau), China. The species is assigned to the widely distributed extant genus Wesmaelius Kruger (Hemerobiinae). The species represents the first named fossil of this family from China, which sheds light on the historical distribution of Wesmaelius and early divergences within Hemerobiinae. PMID- 29430207 TI - Distribution of endangered Italian gudgeon Romanogobio benacensis (Cypriniformes, Cyprinidae, Gobioninae) with remarks on distinguishing morphological characters. AB - Distribution data on many freshwater fish species in Croatia are scarce and species identifications are difficult, requiring further detailed studies. This paper presents a report of the Italian gudgeon Romanogobio benacensis from the Mirna River in the Istra Peninsula in Croatia, in the south-east from its previously known distribution range. The identification of R. benacensis in Croatia was supported by a morphological comparison with R. benacensis from Italy and Slovenia, the common gudgeon Gobio gobio, and the Danubian gudgeon Gobio obtusirostris from geographically close locations. A combination of character states (number of scales between anus and anal-fin origin, branched pectoral-fin rays, lateral-line scales, total, abdominal, and caudal vertebrae, and the size and number of lateral blotches) distinguishes R. benacensis from both G. gobio and G. obtusirostris. The phylogenetic analyses using mitochondrial sequences of cytochrome b gene confirmed that specimens from the Mirna River belong to R. benacensis. Also, Reka River system (Adriatic Sea basin) in Slovenia is inhabited by a possibly introduced Danubian gudgeon, G. obtusirostris, and not by R. benacensis. PMID- 29430208 TI - Amphipod family distributions around Iceland. AB - Amphipod crustaceans were collected at all 55 stations sampled with an epibenthic sledge during two IceAGE expeditions (Icelandic marine Animals: Genetics and Ecology) in 2011 and 2013. In total, 34 amphipod families and three superfamilies were recorded in the samples. Distribution maps are presented for each taxon along with a summary of the regional taxonomy for the group. Statistical analyses based on presence/absence data revealed a pattern of family distributions that correlated with sampling depth. Clustering according to the geographic location of the stations (northernmost North Atlantic Sea and Arctic Ocean) can also be observed. IceAGE data for the Amphilochidae and Oedicerotidae were analysed on species level; in case of the Amphilochidae they were compared to the findings from a previous Icelandic benthic survey, BIOICE (Benthic Invertebrates of Icelandic waters), which also identified a high abundance of amphipod fauna. PMID- 29430209 TI - The effect of soil on human health: an overview. AB - Soil has a considerable effect on human health, whether those effects are positive or negative, direct or indirect. Soil is an important source of nutrients in our food supply and medicines such as antibiotics. However, nutrient imbalances and the presence of human pathogens in the soil biological community can cause negative effects on health. There are also many locations where various elements or chemical compounds are found in soil at toxic levels, because of either natural conditions or anthropogenic activities. The soil of urban environments has received increased attention in the last few years, and they too pose a number of human health questions and challenges. Concepts such as soil security may provide a framework within which issues on soil and human health can be investigated using interdisciplinary and transdisciplinary approaches. It will take the contributions of experts in several different scientific, medical and social science fields to address fully soil and human health issues. Although much progress was made in understanding links between soil and human health over the last century, there is still much that we do not know about the complex interactions between them. Therefore, there is still a considerable need for research in this important area. PMID- 29430212 TI - DEEP ATTRACTOR NETWORK FOR SINGLE-MICROPHONE SPEAKER SEPARATION. AB - Despite the overwhelming success of deep learning in various speech processing tasks, the problem of separating simultaneous speakers in a mixture remains challenging. Two major difficulties in such systems are the arbitrary source permutation and unknown number of sources in the mixture. We propose a novel deep learning framework for single channel speech separation by creating attractor points in high dimensional embedding space of the acoustic signals which pull together the time-frequency bins corresponding to each source. Attractor points in this study are created by finding the centroids of the sources in the embedding space, which are subsequently used to determine the similarity of each bin in the mixture to each source. The network is then trained to minimize the reconstruction error of each source by optimizing the embeddings. The proposed model is different from prior works in that it implements an end-to-end training, and it does not depend on the number of sources in the mixture. Two strategies are explored in the test time, K-means and fixed attractor points, where the latter requires no post-processing and can be implemented in real-time. We evaluated our system on Wall Street Journal dataset and show 5.49% improvement over the previous state-of-the-art methods. PMID- 29430211 TI - Investigation of synthetic spider silk crystallinity and alignment via electrothermal, pyroelectric, literature XRD, and tensile techniques. AB - The processes used to create synthetic spider silk greatly affect the properties of the produced fibers. This paper investigates the effect of process variations during artificial spinning on the thermal and mechanical properties of the produced silk. Property values are also compared to the ones of the natural dragline silk of the N. clavipes spider, and to unprocessed (as-spun) synthetic silk. Structural characterization by scanning pyroelectric microscopy is employed to provide insight into the axial orientation of the crystalline regions of the fiber and is supported by XRD data. The results show that stretching and passage through liquid baths induce crystal formation and axial alignment in synthetic fibers, but with different structural organization than natural silks. Furthermore, an increase in thermal diffusivity and elastic modulus is observed with decreasing fiber diameter, trending towards properties of natural fiber. This effect seems to be related to silk fibers being subjected to a radial gradient during production. PMID- 29430213 TI - NAPLIB: AN OPEN SOURCE TOOLBOX FOR REAL-TIME AND OFFLINE NEURAL ACOUSTIC PROCESSING. AB - In this paper, we introduce the Neural Acoustic Processing Library (NAPLib), a toolbox containing novel processing methods for real-time and offline analysis of neural activity in response to speech. Our method divides the speech signal and resultant neural activity into segmental units (e.g., phonemes), allowing for fast and efficient computations that can be implemented in real-time. NAPLib contains a suite of tools that characterize various properties of the neural representation of speech, which can be used for functionality such as characterizing electrode tuning properties, brain mapping and brain computer interfaces. The library is general and applicable to both invasive and non invasive recordings, including electroencephalography (EEG), electrocorticography (ECoG) and magnetoecnephalography (MEG). In this work, we describe the structure of NAPLib, as well as demonstrating its use in both EEG and ECoG. We believe NAPLib provides a valuable tool to both clinicians and researchers who are interested in the representation of speech in the brain. PMID- 29430214 TI - Angular photodiode array-based device to detect bacterial pathogens in a wound model. AB - We have developed a device that is able to rapidly and specifically diagnose bacterial pathogens in a wound model based on Mie scatter spectra from a tissue surface. The Mie scatter spectra collected is defined as the intensity of Mie scatter over the angle of detection from a tissue surface. A 650 nm LED perpendicular to the surface illuminates a tissue sample (90 degrees ) and photodiodes positioned in 10 degrees increments from 10 degrees to 80 degrees of backscatter act as the detectors to collect these Mie scatter spectra. Through principal component analysis of the Mie scatter spectra collected, we have shown significant differences between Mie scatter spectra of tissues with bacterial pathogens versus those without, as well as significant differences between each species of bacteria tested. The device developed has been tested with a porcine dermis wound model, with samples inoculated with one of three bacterial species (Staphylococcus aureus, Escherichia coli, or Salmonella Typhimurium). Such a device could be critical in the monitoring of a wound for infection and rapid, specific diagnosis of a bacterial wound infection, which would significantly reduce the time and cost associated with specific diagnosis of a bacterial wound infection currently. PMID- 29430215 TI - Fidelity of Implementation of a State Antibullying Policy With a Focus on Protected Social Classes. AB - Bullying threatens the mental and educational well-being of students. All states have enacted antibullying laws. This study surveyed 634 educators about the implementation of the North Carolina School Violence Prevention Act, which enumerated social classes protected from bullying: race, national origin, gender, socioeconomic status, sexual orientation, gender identity, appearance, and disability. Results showed that local antibullying policies most often included race as a protected class and least often included sexual orientation and gender identity. More educators had been trained on bullying based on race than any other social class. Students were more often informed that bullying based on race was prohibited and were least often informed about prohibitions regarding sexual orientation and gender identity. Reporting, investigating, and remediating bullying was highest for racial bullying, followed by disability bullying, and was lowest for bullying based on sexual orientation and gender identity. PMID- 29430216 TI - A Recipe for inferference: Start with Causal Inference. Add Interference. Mix Well with R. AB - In causal inference, interference occurs when the treatment of one subject affects the outcome of other subjects. Interference can distort research conclusions about causal effects when not accounted for properly. In the absence of interference, inverse probability weighted (IPW) estimators are commonly used to estimate causal effects from observational data. Recently, IPW estimators have been extended to handle interference. Tchetgen Tchetgen and VanderWeele (2012) proposed IPW methods to estimate direct and indirect (or spillover) effects that allow for interference between individuals within groups. In this paper, we present inferference, an R package that computes these IPW causal effect estimates when interference may be present within groups. We illustrate use of the package with examples from political science and infectious disease. PMID- 29430217 TI - Direct Oxidation of Aldehydes to Methyl Esters with Urea Hydrogen Peroxide and p Toluenesulfonyl Chloride. AB - Combination of urea hydrogen peroxide and p-toluenesulfonyl chloride in methanol was proved to be facile and highly efficient for the oxidative methyl esterification of various aldehydes to the corresponding carboxylic methyl esters. PMID- 29430218 TI - Metabolomic characterization of experimental ovarian cancer ascitic fluid. AB - Introduction: Malignant ascites (MA) is a major cause of morbidity that occurs in 37% of ovarian cancer patients. The accumulation of MA in the peritoneal cavity due to cancer results in debilitating symptoms and extremely poor quality of life. There is an urgent unmet need to expand the understanding of MA to design effective treatment strategies, and to improve MA diagnosis. Objective: Our purpose here is to contribute to a better characterization of MA metabolic composition in ovarian cancer. Method: We determined the metabolic composition of ascitic fluids resulting from orthotopic growth of two ovarian cancer cell lines, the mouse ID8-vascular endothelial growth factor (VEGF)-Defb29 cell line and the human OVCAR3 cell line using high-resolution 1H MRS. ID8-VEGF-Defb29 tumors induce large volumes of ascites, while OVCAR3 tumors induce ascites less frequently and at smaller volumes. To better understand the factors driving the metabolic composition of the fluid, we characterized the metabolism of these ovarian cancer cells in culture by analyzing cell lysates and conditioned culture media with 1H NMR. Results: Distinct metabolite patterns were detected in ascitic fluid collected from OVCAR3 and ID8-VEGF-Defb29 tumor bearing mice that were not reflected in the corresponding cell culture or conditioned medium. Conclusion: High-resolution 1H NMR metabolic markers of MA can be used to improve characterization and diagnosis of MA. Metabolic characterization of MA can provide new insights into how MA fluid supports cancer cell growth and resistance to treatment, and has the potential to identify metabolic targeting strategies to reduce or eliminate the formation of MA. PMID- 29430219 TI - Disease Control on Lanreotide Autogel(r) 120 mg in a Patient with Metastatic Gastrinoma: A Case Report. AB - Gastrinomas are functionally active pancreatic neuroendocrine tumors (NETs) secreting gastrin and are associated with local or regional metastases in 60% of the cases. Somatostatin analogs (SSAs) are currently recommended as a first-line treatment for the symptomatic treatment of NETs. Although antiproliferative activity of SSAs has been demonstrated in various cancer types in several in vivo and in vitro studies, clinical benefits with SSAs have been only achieved in a small proportion of patients. We report a disease control on a long-acting SSA lanreotide in a patient with metastatic gastrinoma. A 60-year-old man, who had previously undergone a surgical resection of metastatic pancreatic gastrinoma, presented with abdominal bloating, edema in the lower limbs, fatigue, and weight loss. The gastrinoma relapse with additional metastases in the pancreas, duodenum, and liver was confirmed by positron emission tomography-computed tomography (PET-CT) scan; the patient's blood gastrin level was >5,000 ng/L. Treatment with the SSA octreotide long-acting release was initiated to treat the gastrinoma relapse. On the CT scan done in September 2011, the liver metastases were still identifiable. In December 2011, the treatment was switched to lanreotide Autogel(r) (120 mg every 2 weeks). Following the treatment, the gastrin levels were reduced to <1,200 ng/L in September 2013, and 812 ng/L in July 2016. Since November 2012, the gastrinoma lesions were no longer visible in abdominal CT. At the time of this report, the patient's gastrinoma was under control with lanreotide Autogel(r). This case report supports the use of lanreotide Autogel(r) as effective treatment for metastatic gastrinoma. PMID- 29430220 TI - Esophageal Metastatic Adenocarcinoma Diagnosed with Endoscopic Ultrasound. AB - Metastasis to the esophagus from a distant primary cancer is a rare manifestation in a patient with a history of oncological disease presenting with obstructive upper gastrointestinal symptoms. Computed tomography of the thorax or esophagogastroduodenoscopy can be non-diagnostic as the disease tends to be submucosal. In such a situation, endoscopic ultrasound (EUS) with fine needle aspiration (FNA) can be directed to characterize and sample the submucosal esophageal lesion. We present a case series of metastatic esophageal strictures diagnosed with EUS and FNA. PMID- 29430222 TI - Long-Term Colon Stent Patency for Obstructing Colorectal Cancer Combined with Bevacizumab. AB - Self-expanding metal stents can be considered as initial treatment for malignant large bowel obstruction in the palliative setting. It is suggested that systemic anti-angiogenic therapy increases the risk of stent perforation. We report a 65 year-old woman with a metastatic, obstructing colon tumor who has been successfully treated with stent placement and chemoimmunotherapy consisting of capecitabine and bevacizumab for 8 years. PMID- 29430221 TI - Successful Treatment of Oral Lichen Planus with Direct-Acting Antiviral Agents after Liver Transplantation for Hepatitis C Virus-Associated Hepatocellular Carcinoma. AB - Hepatitis C virus (HCV) infection is frequently associated with various extrahepatic manifestations, such as autoimmune features and immune complex deposit diseases. Oral lichen planus (OLP) is one such extrahepatic manifestation of HCV infection. Recently, direct-acting antivirals (DAA) have proved to be highly effective and safe for the eradication of HCV. Herein, we report a case of OLP accompanied by HCV-related hepatocellular carcinoma (HCC) that disappeared after liver transplantation and achievement of sustained virological response following interferon (IFN)-free treatment with ledipasvir (LDV) and sofosbuvir (SOF). The 50-year-old patient developed erosive OLP during IFN therapy, with hyperthyroidism at 53 years of age and HCC at 55 years. He received immunosuppressive drugs and IFN-free DAA treatment after liver transplantation at 60 years of age, which led to disappearance of the symptoms of OLP. The patient was treated safely and effectively with LDV/SOF, although it is not known whether the disappearance of OLP resulted from the eradication of HCV or the immunosuppressive therapy. PMID- 29430223 TI - Successful Emergency Endoscopic Treatment of Gastric Outlet Obstruction due to Gastric Bezoar with Gastric Pneumatosis. AB - Gastric bezoars are rare and are usually found incidentally. They can sometimes cause severe complications, including gastric outlet obstruction (GOO) or gastric pneumatosis (GP). In cases of bezoars with GP, the optimal treatment strategy has not yet been defined. We report the case of an 89-year-old man with a history of type 2 diabetes mellitus and hypertension who presented to our emergency room with a 2-day history of upper abdominal pain, nausea, and vomiting. Physical examination revealed no rebound tenderness or guarding, and laboratory values revealed no elevation of the serum lactate level. A computed tomography scan of the abdomen showed a dilated stomach with significant fluid collection, GOO, and GP due to a 42 * 40 mm mass composed of fat and air densities. Emergency esophagogastroduodenoscopy revealed two gastric bezoars, one of which was incarcerated in the pyloric region. We used various endoscopic devices to successfully break and remove the bezoars. We used endoscopic forceps and a water jet followed by an endoscopic snare to cut the bezoars into several pieces and remove them with an endoscopic net. Follow-up endoscopy confirmed that the gastric bezoar had been completely removed. As seen in this case, endoscopic treatment may be a safe and viable option for the extraction of gastric bezoars presenting with GOO and GP. PMID- 29430224 TI - Multilocular Hepatic Abscess Formation and Sepsis due to Yersinia enterocolitica in a Patient with Hereditary Hemochromatosis and Type 2 Diabetes Mellitus. AB - Infection with Yersinia enterocolitica (YE) typically presents with mild gastroenteritis without systemic infection. However, systemic YE infection has been described in states of iron overload. We present the case of a patient with sepsis with hepatic abscesses due to YE infection. Workup revealed a past diagnosis of diabetes mellitus and hemochromatosis which had been untreated for the previous 5 years due to patient refusal. This case highlights risk factors for systemic infection with YE. A high degree of suspicion for YE infection is warranted in patients with iron overload, diabetes mellitus, or immunosuppression. PMID- 29430225 TI - Superior Mesenteric Artery Syndrome Improved by Enteral Nutritional Therapy according to the Controlling Nutritional Status Score. AB - Superior mesenteric artery syndrome (SMAS) is a relatively rare disease that involves bowel obstruction symptoms, such as vomiting and gastric distension, owing to the compression of the third portion of the duodenum from the front by the superior mesenteric artery (SMA) and from the rear by the abdominal aorta and the spine. SMAS is diagnosed on the basis of an upper gastrointestinal examination series indicating the obstruction of the third portion of the duodenum or a computed tomography scan indicating the narrowing of the branch angle between the aorta and the SMA (i.e., the aorta-SMA angle). Here, we report the case of a 78-year-old woman diagnosed with SMAS after a laparoscopic right hemicolectomy for cecal cancer, whose condition was improved by enteral nutritional therapy. We used her controlling nutritional status (CONUT) score as a nutrition assessment and noted the changes in the aorta-SMA angle over the course of the disease. This patient appeared to develop SMAS, on the basis of a worsened CONUT score and a decreased aorta-SMA angle, owing to the inflammation resulting from the intraoperative dissection of the tissues around the SMA and prolonged postoperative fasting. After the initiation of enteral nutritional therapy, the patient exhibited body weight gain and an improved aorta-SMA angle and CONUT score. Hence, assessment of the aorta-SMA angle and CONUT score is an important preoperative consideration. PMID- 29430226 TI - A Hepatitis C Virus-Associated Chronic Hepatitis Patient Developing Various Adverse Events Including Severe Gingivitis, Gingival Bleeding, and Inflammation of Genital Vulva during the Course of Antiviral Therapy with Elbasvir/Grazoprevir. AB - Oral direct-acting antivirals comprise the main therapy for hepatitis C virus (HCV)-associated liver disease in Japan. Daclatasvir/asunaprevir is the primary agent and sofosbuvir/ledipasvir is the secondary agent for HCV genotype 1b. Ombitasvir/paritaprevir/ritonavir was also recommended as a therapy for HCV genotype 1b. More recently, elbasvir (NS5A inhibitor)/grazoprevir (NS3/4A protease inhibitor) was also recommended as a potent therapy for HCV genotype 1b infection. This agent achieved an SVR12 as high as 96.5% for HCV virus-associated chronic hepatitis. We recently encountered a case treated with this agent and the female patient showed various adverse events, such as severe gingivitis, gingival bleeding, severe tonsillitis, inflammation of the genital vulva, and the sustained sensation of being hungry. In spite of the gingival bleeding, there was no depletion of the platelet count, nor elongation of the prothrombin time. She tolerated these adverse events and finally completed the therapy and achieved SVR12. PMID- 29430227 TI - Levonorgestrel-Releasing Intrauterine Device-Related Acute Liver Injury. AB - Oral contraceptives have long been associated with liver injury. However, very little attention is paid to the metabolic side effects of hormone-releasing intrauterine devices (IUDs). These devices are generally considered safe and commonly used. We report for the first time acute liver injury associated with a levonorgestrel-releasing IUD. Our patient did not have any comorbidities that could have caused or exacerbated liver injury. A detailed workup and liver biopsy remained negative for any other potential cause of liver injury. The patient's symptoms resolved with removal of the device. She remained symptom free on subsequent outpatient follow-ups. PMID- 29430228 TI - Routine Treatment-Resistant Clostridium difficile Infection during Recovery from Myxedema. AB - Development of the extreme form of hypothyroidism defined as myxedema is very rare. Acute symptoms and their management have been described in detail previously. However, not much attention has been devoted to therapeutic challenges that are faced in the recovery phase of the treatment, especially pertaining to the gastrointestinal system. The link between myxedema and the appearance of severe Clostridium difficile infection (CDI) has not been established so far. A 61-year-old woman with no significant medical record was admitted to hospital because of infected heel pressure and thyroid dysfunction. A week later, due to hypothermia, hypotension, and unconsciousness, she was transferred to the intensive care unit. The clinical picture and the results of laboratory tests confirmed diagnosis of myxedema. After the introduction of resuscitative measures and hormonal substitution, patient's condition stabilized within 10 days. Due to concomitant sepsis, initially piperacillin/tazobactam and later cefuroxime were administered. After 20 days of antibiotic therapy, the patient developed CDI that was resistant to the routine mode of treatment. The clinical recovery was achieved only after a fecal microbiota transplantation procedure. The function of the digestive tract in myxedema is disturbed by gastric achlorydia and reduced peristalsis, which in turn can predispose the small intestine to overgrowth of bacteria. The use of antibiotics can additionally decrease the intestinal bacterial diversity, favoring the overgrowth of Clostridium difficile. The authors conclude that myxedema may increase the likelihood of a treatment-resistant form of CDI that requires the implementation of fecal microbiota transplantation. PMID- 29430229 TI - Pancreatic Pseudocyst Ruptured due to Acute Intracystic Hemorrhage. AB - Rupture of pancreatic pseudocyst is one of the rare complications and usually results in high mortality. The present case was a rupture of pancreatic pseudocyst that could be treated by surgical intervention. A 74-year-old man developed abdominal pain, vomiting, and diarrhea, and he was diagnosed with cholecystitis and pneumonia. Three days later, acute pancreatitis occurred and computed tomography (CT) showed slight hemorrhage in the cyst of the pancreatic tail. After another 10 days, CT showed pancreatic cyst ruptured due to intracystic hemorrhage. Endoscopic retrograde cholangiopancreatography revealed leakage of contrast agent from pancreatic tail cyst to enclosed abdominal cavity. His left hypochondrial pain was increasing, and CT showed rupture of the cyst of the pancreatic tail into the peritoneal cavity was increased in 10 days. CT showed also two left renal tumors. Therefore we performed distal pancreatectomy with concomitant resection of transverse colon and left kidney. We histopathologically diagnosed pancreatic pseudocyst ruptured due to intracystic hemorrhage and renal cell carcinoma. Despite postoperative paralytic ileus and fluid collection at pancreatic stump, they improved by conservative management and he could be discharged on postoperative day 29. He has achieved relapse-free survival for 6 months postoperatively. The mortality of pancreatic pseudocyst rupture is very high if some effective medical interventions cannot be performed. It should be necessary to plan appropriate treatment strategy depending on each patient. PMID- 29430230 TI - Mind the Gap: Successful Endoscopic Closure of a Large Gastric Sleeve Leak Using an Endoscopic Stent and Over-the-Scope Clips. AB - Laparoscopic sleeve gastrectomy (LSG) is gaining popularity for the treatment of morbid obesity. It is regarded as a simple, low-cost procedure achieving significant weight loss within a short period of time. LSG is considered a safe procedure with a relatively low complication rate. The complications encountered nevertheless can result in significant morbidity and may even be lethal. The most significant complications are staple-line bleeding, stricture, and staple-line leak. The purpose of this paper is to present a case of a 31-year-old patient complicated by a 3.06 cm staple-line leak 10 days after LSG. Review of the current literature regarding this complication as well as outline of a strategy for the management of large post-LSG gastric leaks is suggested. PMID- 29430231 TI - Babesiosis Presenting as Acute Liver Failure. AB - Babesiosis is a zoonotic, tick-borne infection caused by the protozoan Babesia. It is transmitted by the Ixodes ticks which transmit the infection to humans. Babesia microti, Babesia duncani, Babesia divergens, and Babesia venatorum are species that have been identified as being infectious to humans worldwide. The most common species causing infection to humans is B. microti which is endemic to the Northeast and Midwestern United States with most infections occurring between the months of May and October. We report a case of an elderly man with acute liver failure due to an infection with B. microti. PMID- 29430232 TI - Linfoma Nasal de Celulas T/Natural Killer Extranodal Refractario Mal Diagnosticado, Tratado de Manera Exitosa: Informe de Caso. AB - El linfoma de celulas T/natural killer extranodal ("extranodal natural killer/T cell lymphoma", ENKL) nasal es un linfoma no Hodgkin (LNH) agresivo y poco comun para el cual no se ha establecido un tratamiento de referencia claro, especialmente en el escenario de la enfermedad recidivante/refractaria. Debido a su rareza, no se han llevado a cabo ensayos aleatorizados especificamente en ENKL nasal; sin embargo, los informes de caso y las series de caso pequenas ofrecen un conocimiento importante sobre nuevos tratamientos potenciales. Presentamos el informe de caso de un paciente con ENKL nasal (previamente mal diagnosticado como una sinusitis cronica recidivante) en quien la enfermedad progreso durante la quimioterapia con multiples agentes pero respondio al tratamiento de segunda linea con pralatrexato como agente unico. Analizamos opciones de tratamiento para el ENKL nasal recidivante/refractario y sugerimos que el pralatrexato se evalue mas a fondo en este escenario clinico. PMID- 29430233 TI - Durable and Complete Response to Herceptin Monotherapy in Patients with Metastatic Gastroesophageal Cancer. AB - Gastroesophageal cancer is the sixth leading cause of cancer-related death worldwide. The 2 most common histologies are squamous cell carcinoma and adenocarcinoma, which has seen an increase in incidence correlating with an increase in obesity in developed countries. Gastroesophageal adenocarcinoma has a preponderance to metastasize early, making it a highly lethal cancer with a low 5 year survival rate of ~15-25%. Therefore, for the majority of patients, treatment focuses on palliation and prolongation of survival. Combination chemotherapy regimens, mostly platinum-based, have only modestly prolonged survival in patients with stage IV disease. Recently, it was discovered that the activation of the HER2 receptor plays an important role in a minority of adenocarcinomas of the distal esophagus and stomach. This introduced the treatment option of trastuzumab (Herceptin), a monoclonal antibody directed at the HER2 receptor, which has demonstrated improvement in overall and progression-free survival as noted in the ToGA trial. Currently, the role of Herceptin therapy beyond first line therapy and outside of combination regimens is not well established. In this case report we review 2 cases of patients with gastroesophageal cancer, with HER2 overexpression, who achieved a robust response to trastuzumab in combination with chemotherapy and were able to maintain a durable response with maintenance trastuzumab monotherapy. PMID- 29430234 TI - Excision of an Elusive Tiny Ectopic Parathyroid Adenoma. AB - An elderly lady was diagnosed with primary hyperparathyroidism after being admitted to hospital with pyelonephritis and constipation. A sestamibi parathyroid scan demonstrated increased uptake in the upper mediastinum, suggesting an ectopic mediastinal parathyroid adenoma. The 4-mm adenoma was successfully removed through a mini-sternotomy incision using a gamma probe to identify the gland from the surrounding tissue. The patient made an uneventful recovery. PMID- 29430235 TI - Herpes Encephalitis: A Mortal Complication in a Patient Treated with Immunosuppressive Drugs because of Immune-Related Adverse Events after Ipilimumab Treatment. AB - Until a few years ago, metastatic melanoma had a poor prognosis with limited treatment options. These therapeutics options and thereby median survival have increased obviously over 5 years with the arrival of immunotherapeutic drugs like ipilimumab, nivolumab, and pembrolizumab. Nowadays, ipilimumab is often used in patients with metastatic melanoma. In this paper, we report a case of a 68-year old man who developed, and eventually died of, herpes encephalitis after introducing ipilimumab as treatment for metastatic melanoma. To our knowledge, this is the first report in which herpes encephalitis as a complication after ipilimumab and infliximab treatment is described and we would like to make physicians aware of this possible serious neurological complication, especially when a patient has a history of herpes simplex infection. PMID- 29430236 TI - Idiopathic Thrombocytopenia Purpura Masking Hodgkin Disease: A Paraneoplastic Syndrome or Simply a Mere Association? AB - We report a 74-year-old female who presented to the emergency department complaining of bruising and stroke-like symptoms. She underwent a negative stroke work-up but was found to have profoundly low platelets and splenomegaly on examination. An abdominal CT scan was ordered, showing pelvic lymphadenopathy. Lymphoma was suspected. However, subsequent bone marrow and lymph node biopsies showed no evidence of this. She was treated for immune thrombocytopenia purpura (ITP) to no avail while a lymphoma work-up continued. Months later, a third and final lymph node biopsy yielded evidence of Hodgkin disease (HD) and she began treatment shortly thereafter. She is currently undergoing standard treatment for this malignancy and her platelet counts have normalized. The case not only outlines the importance of the physician's gestalt in arriving at the proper diagnosis, but it also posits the thought that perhaps ITP should be considered a paraneoplastic syndrome of HD. PMID- 29430237 TI - Downgrading of a G3 Neuroendocrine Tumor to a G2 Tumor: Can First-Line Cytotoxic Chemotherapy Change the Tumor Biology? AB - The antiproliferative treatment options for neuroendocrine tumors (NET)/neuroendocrine carcinomas of the gastrointestinal tract critically depend on the proliferation rate, evaluated by immunohistochemical staining for Ki-67. According to their grading, tumors are treated with somatostatin analogs, mTOR inhibitors, or cytotoxic substances. This case illustrates downgrading of a primarily highly proliferative NET achieved by a variation of cytotoxic chemotherapy regimens, followed by a combination therapy using everolimus together with lanreotide. The latter medication might lead to a good clinical response as far as tumor growth is concerned. PMID- 29430238 TI - A Case of Advanced Submandibular Gland Cancer in Which Increased Prostate Specific Antigen and Multiple Bone Metastases Wrongly Suggested Concurrent Prostate Cancer. AB - A 73-year-old man, followed for prostatic hyperplasia, developed submandibular gland cancer. Initially, because of the concurrent presence of elevated serum prostate-specific antigen (PSA) and multiple bone metastases, he was clinically determined as having stage IV prostate cancer in addition to stage II submandibular gland cancer, and radical surgery for his submandibular gland cancer was performed first. However, subsequent detailed examinations of the prostate gland showed no prostate cancer, and a diagnosis of advanced submandibular gland cancer with increased PSA and multiple bone metastases was established. Serum PSA is highly specific for prostate diseases and is widely used as a tumor marker of prostate cancer. However, clinicians should be aware that, in patients with non-prostate cancer, the detection of increased PSA and multiple bone metastases does not necessarily indicate the concurrent presence of prostate cancer. PMID- 29430239 TI - A Case of Paraneoplastic Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome Improved by Chemotherapy. AB - The patient was a 69-year-old male who had started experiencing acute-onset pain in both shoulder joints and edema of both hands and feet. His symptoms progressively worsened within 1 month. Laboratory data indicated elevated CRP and erythrocyte sedimentation rate despite the normal range of antinuclear antibodies and rheumatoid factor and normal organ function. Furthermore, imaging data of the hand indicated synovitis without bone erosions. Meanwhile, chest CT revealed a lung tumor, leading to a diagnosis of primary lung adenocarcinoma with EGFR mutation (cT2aN3M0, stage IIIB). Based on these findings, he was diagnosed as suffering from paraneoplastic remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Thereafter, his symptoms disappeared as the tumor size was rapidly decreased by gefitinib therapy for lung adenocarcinoma. Currently, RS3PE syndrome can be classified as a vascular endothelial growth factor (VEGF)-associated disorder. Given that his symptoms improved by chemotherapy, the present case further supported the possible hypothesis that paraneoplastic RS3PE syndrome might be caused by tumor-induced VEGF. Therefore, the present case suggested that the symptoms of acute-onset joint pain accompanied by pitting edema in elderly patients should be considered suspicious for a malignant tumor, thereby warranting a detailed full-body examination. PMID- 29430240 TI - High-Grade Left Atrial Pleomorphic Sarcoma: Case Report and Review. AB - Primary pleomorphic sarcoma of the left atrium is a rare tumor. There is no actual evidence of the management of this pathological entity, so the main treatment is individualized, surgical management being the cornerstone of the treatment. We present a 78-year-old female who had a clinical picture of heart failure, documenting an atrial mass of the left atrium, with high-grade pleomorphic sarcoma revealed in histopathology. The tumor was surgical removed, with no clinical evidence of residual mass. The tumor recurred again within 3 years, to which the patient succumbed. PMID- 29430241 TI - Neuroendocrine Tumor Involving the Epicardium. AB - Neuroendocrine tumors (NETs) are rare malignancies that usually arise from the digestive tract or lungs. Metastases of NETs to the heart (epicardium) are a rare complication. We present a case of a metastatic NET involving the epicardium. PMID- 29430242 TI - Gustatory Dysfunction as an Early Symptom of Semantic Dementia. AB - Objective: To investigate the gustatory function in patients with semantic dementia (SD). Methods: Detection and recognition thresholds of the 4 basic tastes (sweet, salty, sour, and bitter), taste discrimination, and taste identification were evaluated in 18 patients with SD, 18 patients with Alzheimer disease (AD), and 22 healthy controls. Results: Total detection and recognition threshold values were significantly higher in the SD and AD groups than in the control group. Patients with early-stage SD (Clinical Dementia Rating Scale score 0.5) exhibited significantly higher detection and recognition thresholds relative to controls, while increases in recognition threshold were only noted in patients with AD. Patients with SD exhibited significantly higher thresholds for the detection of sweet and salty tastes and the recognition of salty, sour, and bitter tastes, while patients with AD exhibited significantly higher thresholds only for the recognition of salty and sour tastes. Taste discrimination was preserved, whereas taste identification was disturbed, in both the SD and AD groups. Conclusions: Gustatory dysfunction at both the sensory and semantic levels may be among the early symptoms of SD. Although patients with SD had difficulty detecting sweet tastes, they more easily recognized these tastes than others, which may explain their strong preference for sweets. PMID- 29430243 TI - The Effect of Motion Artifacts on Near-Infrared Spectroscopy (NIRS) Data and Proposal of a Video-NIRS System. AB - Aims: The aims of this study were (1) to investigate the influence of physical movement on near-infrared spectroscopy (NIRS) data, (2) to establish a video-NIRS system which simultaneously records NIRS data and the subject's movement, and (3) to measure the oxygenated hemoglobin (oxy-Hb) concentration change (Deltaoxy-Hb) during a word fluency (WF) task. Experiment 1: In 5 healthy volunteers, we measured the oxy-Hb and deoxygenated hemoglobin (deoxy-Hb) concentrations during 11 kinds of facial, head, and extremity movements. The probes were set in the bilateral frontal regions. The deoxy-Hb concentration was increased in 85% of the measurements. Experiment 2: Using a pillow on the backrest of the chair, we established the video-NIRS system with data acquisition and video capture software. One hundred and seventy-six elderly people performed the WF task. The deoxy-Hb concentration was decreased in 167 subjects (95%). Experiment 3: Using the video-NIRS system, we measured the Deltaoxy-Hb, and compared it with the results of the WF task. Deltaoxy-Hb was significantly correlated with the number of words. Conclusion: Like the blood oxygen level-dependent imaging effect in functional MRI, the deoxy-Hb concentration will decrease if the data correctly reflect the change in neural activity. The video-NIRS system might be useful to collect NIRS data by recording the waveforms and the subject's appearance simultaneously. PMID- 29430244 TI - Lexical Retrieval or Semantic Knowledge? Which One Causes Naming Errors in Patients with Mild and Moderate Alzheimer's Disease? AB - Background: The purpose of the study was to analyze naming errors in patients with Alz-heimer's disease in comparison to healthy subjects and determine the underlying cause of naming errors in these patients. Method: In this study, we included 35 healthy elderly subjects, 23 patients with mild Alzheimer's disease, and 23 with moderate Alzheimer's disease. Forty-five images were used to determine the type of naming errors, and to identify the underlying cause of errors, matching an image with a written word was used. Results: Patients with Alz-heimer's disease had more naming errors compared with the group of healthy elderly, and patients with moderate Alzheimer's disease showed a slower reaction in matching an image with a written word. Conclusion: Anomia in the initial phase of Alzheimer's disease is due to problems in lexical retrieval; however, as the disease advances, in addition to lexical retrieval problems, conceptual knowledge causes naming problems. PMID- 29430245 TI - Measuring Electrodermal Activity to Improve the Identification of Agitation in Individuals with Dementia. AB - Background: Understanding and interpreting the complexity of agitation in people with dementia is challenging. Objective: To explore whether a sensor measuring electrodermal activity (EDA) can improve the identification of agitation in individuals with dementia. Methods: Nine individuals with dementia wore a sensor that measured EDA. During the same time, assistant nurses annotated the observed behavior of the person with dementia. A binary logistic regression model was applied to assess the relationship between the sensor and the assistant nurses' structured observations of agitation. Results: The sensor values correlated with the assistant nurses' observations both at the time of the observation and 1 and 2 h prior to the observation. Conclusion: A sensor measuring EDA can support early detection of agitation in persons with dementia. PMID- 29430246 TI - Hearing Impairment, Mild Cognitive Impairment, and Dementia: A Meta-Analysis of Cohort Studies. AB - Background: To estimate a pooled association between hearing impairment and risk of mild cognitive impairment and dementia. Methods: PubMed, Embase, and Web of Science were searched for prospective cohort studies that examined the association between hearing impairment and risk of mild cognitive impairment and/or dementia. Random-effects models were fitted to estimate the summary risk ratios (RRs) and 95% confidence interval (CIs), which represents the pooled association between hearing impairment with risk of mild cognitive impairment and dementia, compared to subjects free of hearing impairment. Results: Four studies on hearing impairment with mild cognitive impairment and 7 studies on hearing impairment with dementia were included in the meta-analysis. A total of 15,521 subjects were studied with follow-up periods between 2 and 16.8 years. Hearing impairment was associated with a greater risk of mild cognitive impairment (RR = 1.30, 95% CI: 1.12, 1.51) and dementia (RR = 2.39, 95% CI: 1.58, 3.61). Conclusions: The meta-analysis showed that hearing impairment is associated with a higher risk of mild cognitive impairment and dementia among older adults. PMID- 29430247 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000468923.]. PMID- 29430248 TI - Decreased Muscle Strength and Quality in Diabetes-Related Dementia. AB - Background/Aims: Diabetes-related dementia (DrD), a dementia subgroup associated with specific diabetes mellitus (DM)-related metabolic abnormalities, is clinically and pathophysiologically different from Alzheimer disease (AD) and vascular dementia. We determined whether skeletal muscle strength, quality, and mass decrease in individuals with DrD. Methods: We evaluated grip and knee extension strength, muscle mass, and gait speed in 106 patients with probable AD and without type 2 DM (AD[-DM] group), 74 patients with probable AD and with DM (AD[+DM] group), and 36 patients with DrD (DrD group). Muscle quality was defined as the ratio of muscle strength to muscle mass. Results: Both female and male subjects with DrD showed significantly decreased muscle strength and quality in the upper extremities compared with the subjects with AD[-DM] or AD[+DM]. Female subjects with DrD showed significantly decreased muscle quality in the lower extremities compared with the subjects with AD[-DM]. Both female and male subjects with DrD had a significantly lower gait speed compared with the subjects with AD[-DM]. However, there were no significant differences in muscle mass and the prevalence of sarcopenia between the groups. Conclusion: Subjects with DrD showed decreased muscle strength and quality, but not muscle mass, and had a low gait speed. PMID- 29430249 TI - Clustering Categorical Data Using Community Detection Techniques. AB - With the advent of the k-modes algorithm, the toolbox for clustering categorical data has an efficient tool that scales linearly in the number of data items. However, random initialization of cluster centers in k-modes makes it hard to reach a good clustering without resorting to many trials. Recently proposed methods for better initialization are deterministic and reduce the clustering cost considerably. A variety of initialization methods differ in how the heuristics chooses the set of initial centers. In this paper, we address the clustering problem for categorical data from the perspective of community detection. Instead of initializing k modes and running several iterations, our scheme, CD-Clustering, builds an unweighted graph and detects highly cohesive groups of nodes using a fast community detection technique. The top-k detected communities by size will define the k modes. Evaluation on ten real categorical datasets shows that our method outperforms the existing initialization methods for k-modes in terms of accuracy, precision, and recall in most of the cases. PMID- 29430250 TI - Impact on the Quality of Erections after Completing a Low-Intensity Extracorporeal Shock Wave Treatment Cycle on a Group of 710 Patients. AB - Objective: The aim of this study is to evaluate the response to low-intensity extracorporeal shock wave therapy in a group of patients with organic vascular erectile dysfunction. Materials and Methods: This is an observational retrospective study. The researchers reviewed 710 patients with a clinical diagnosis of organic vascular erectile dysfunction (ED) of more than 3-month duration from male sexual health clinics of the Boston Medical Group from 12 cities in Spain and 4 in Mexico. Patients received 5 outpatient shock wave therapy sessions. They were evaluated with the erection hardness score (EHS) before the first session (n = 710), at the end of the last session (n = 710), and one month after the last session (n = 412). Results: In the first examination, the EHS improved in 43.1% (306/710) of subjects compared to the baseline measurement and ability to penetrate increased from 26.8% to 44% (p < 0.0001). In the second examination, the ability to penetrate was 37.9%, lower than in the first (p=0.042) but higher than the baseline (p=0.0001). Conclusions: The results suggest that the shock wave therapy with or without concomitant treatments improved the quality of erections in patients with erectile dysfunction treated in specialised male sexual health clinics. This trial is registered with NCT03237143. PMID- 29430251 TI - Association of Paraoxonase-1 Q192R (rs662) Single Nucleotide Variation with Cardiovascular Risk in Coffee Harvesters of Central Colombia. AB - Paraoxonase 1 (PON1), a high-density lipoprotein-associated antioxidant enzyme, hydrolyzes several organophosphate pesticides and oxidized lipids. The PON1 Q192R polymorphism affects the catalytic efficiency and is considered a risk factor for pesticide intoxication and cardiovascular disease (CVD) but the association is not consistent between individuals or populations. We aimed to study the association of PON1 Q192R polymorphism with CVD risk in coffee harvesters of central Colombia. Demographics were collected from 205 subjects via standardized questionnaires. Lipid profiles and serum butyrylcholinesterase (BChE) were measured by standard procedures. The calculated 10-year atherosclerotic CVD (ASCVD) risk was used as the cardiovascular risk estimate. Q192R genotype was determined by real-time PCR. Prevalence of hypertension, hypercholesterolemia, and the 10-year ASCVD risk was 33%, 62%, and 22%, respectively. BChE levels were no indicative of recent pesticide exposure, although a positive correlation was observed with BChE and hypercholesterolemia. The Q192R genotype frequencies were 38% (QQ), 44% (QR), and 18% (RR). We found an association of the 192Q genotype with hypertension. The results of this study signal the importance to evaluate the influence and potential interactions of BChE and PON1 192Q allele with known genetic and environmental factors implicated in the pathogenesis of CVD. PMID- 29430252 TI - Oral Yeast Colonization and Fungal Infections in Peritoneal Dialysis Patients: A Pilot Study. AB - Peritonitis and exit-site infections are important complications in peritoneal dialysis (PD) patients that are occasionally caused by opportunistic fungi inhabiting distant body sites. In this study, the oral yeast colonization of PD patients and the antifungal susceptibility profile of the isolated yeasts were accessed and correlated with fungal infection episodes in the following 4 years. Saliva yeast colonization was accessed in 21 PD patients and 27 healthy controls by growth in CHROMagar-Candida(r) and 18S rRNA/ITS sequencing. PD patients presented a lower oral yeast prevalence when compared to controls, namely, Candida albicans. Other species were also isolated, Candida glabrata and Candida carpophila. The antifungal susceptibility profiles of these isolates revealed resistance to itraconazole, variable susceptibility to caspofungin, and higher MIC values of posaconazole compared to previous reports. The 4-year longitudinal evaluation of these patients revealed Candida parapsilosis and Candida zeylanoides as PD-related exit-site infectious agents, but no correlation was found with oral yeast colonization. This pilot study suggests that oral yeast colonization may represent a limited risk for fungal infection development in PD patients. Oral yeast isolates presented a variable antifungal susceptibility profile, which may suggest resistance to some second-line drugs, highlighting the importance of antifungal susceptibility assessment in the clinical practice. PMID- 29430253 TI - The Efficacy and Safety of Shen Guo Lao Nian Granule for Common Cold of Qi Deficiency Syndrome: Study Protocol for a Randomized, Double-Blind, Placebo Controlled, Multicenter, Phase II Clinical Trial. AB - Background: Common cold is one of the most frequently occurring illnesses in primary healthcare services and represents considerable disease burden. Common cold of Qi-deficiency syndrome (CCQDS) is an important but less addressed traditional Chinese medicine (TCM) pattern. We designed a protocol to explore the efficacy, safety, and optimal dose of Shen Guo Lao Nian Granule (SGLNG) for treating CCQDS. Methods/Design: This is a multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. A total of 240 eligible patients will be recruited from five centers. Patients are randomly assigned to high-dose group, middle-dose group, low-dose group, or control group in a 1 : 1 : 1 : 1 ratio. All drugs are required to be taken 3 times daily for 5 days with a 5-day follow-up period. Primary outcomes are duration of all symptoms, total score reduction on Jackson's scale, and TCM symptoms scale. Secondary outcomes include every single TCM symptom duration and score reduction, TCM main symptoms disappearance rate, curative effects, and comparison between Jackson's scale and TCM symptom scale. Ethics and Trial Registration: This study protocol was approved by the Ethics Committee of Clinical Trials and Biomedicine of West China Hospital of Sichuan University (number IRB-2014-12) and registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-15006349). PMID- 29430254 TI - Anti-Inflammatory Activity of Babassu Oil and Development of a Microemulsion System for Topical Delivery. AB - Babassu oil extraction is the main income source in nut breakers communities in northeast of Brazil. Among these communities, babassu oil is used for cooking but also medically to treat skin wounds and inflammation, and vulvovaginitis. This study aimed to evaluate the anti-inflammatory activity of babassu oil and develop a microemulsion system with babassu oil for topical delivery. Topical anti inflammatory activity was evaluated in mice ear edema using PMA, arachidonic acid, ethyl phenylpropiolate, phenol, and capsaicin as phlogistic agents. A microemulsion system was successfully developed using a Span(r) 80/Kolliphor(r) EL ratio of 6 : 4 as the surfactant system (S), propylene glycol and water (3 : 1) as the aqueous phase (A), and babassu oil as the oil phase (O), and analyzed through conductivity, SAXS, DSC, TEM, and rheological assays. Babassu oil and lauric acid showed anti-inflammatory activity in mice ear edema, through inhibition of eicosanoid pathway and bioactive amines. The developed formulation (39% A, 12.2% O, and 48.8% S) was classified as a bicontinuous to o/w transition microemulsion that showed a Newtonian profile. The topical anti-inflammatory activity of microemulsified babassu oil was markedly increased. A new delivery system of babassu microemulsion droplet clusters was designed to enhance the therapeutic efficacy of vegetable oil. PMID- 29430255 TI - The Anti-Inflammatory Effects of a Yin Zhi Huang Soup in an Experimental Autoimmune Prostatitis Rat Model. AB - The present study aimed to investigate the therapeutic effects of the Chinese herbal medicine Yin Zhi Huang soup (YZS) in an experimental autoimmune prostatitis (EAP) rat model. In total, 48 rats were randomly divided into the following four groups (n = 12/group): saline group, pathological model group, Qianlietai group, and YZS group. We determined the average wet weight of the prostate tissue, the ratio of the wet weight of the prostate tissue to body weight, tumor necrosis factor-alpha (TNF-alpha) levels in the blood serum, the expression of inducible nitric oxide synthase (iNOS) in the rats' prostate tissues, and the pathological changes in the prostate tissue using light microscopy. YZS reduced the rats' prostate wet weight, the ratio of the prostate wet weight to body weight, and TNF-alpha levels in the blood serum and inhibited the expression of iNOS in the rats' prostate tissues (P < 0.05). Following YZS treatment, the pathological changes in the rats' prostates were improved compared with those in the model group (P < 0.05). Furthermore, YZS treatment reduced inflammatory changes in the prostate tissue. It also significantly suppressed proinflammatory cytokines, such as TNF-alpha, and chemokines, such as iNOS, in the rat model of EAP. PMID- 29430256 TI - Tobacco Use Among People Who Have Been in Prison: Relapse and Factors Associated with Trying to Quit. AB - Introduction: Tobacco use is common among people who have been in prison. The relationship between social stressors, risky health behaviours, and smoking cessation has not been studied in people recently released from prison. Studying this relationship could yield information that guides strategic and cost effective tobacco cessation interventions for an under-resourced population. Methods: One hundred and forty-three smokers were interviewed 7 to 21 days after they had been released from USA prisons. Independent variables included employment status, housing security, relationship problems, educational achievement, risky drinking behaviour, recent drug use, history of drug dependence, and depression. The primary outcome was 'trying to quit smoking.' Data were analysed using Pearson chi-square tests and single and multivariable logistic regression models. Results: Of those who had to quit smoking due to tobacco-free prison policies, 98% reported relapsing on tobacco after release. Trying to quit smoking was associated with the absence of risky drinking behaviour in the past 30 days (adjusted odds ratio [AOR] 6.44, 95% confidence interval [CI] 2.02-20.48). Conclusions: The absence of risky drinking behaviour is associated with trying to quit smoking among people recently released from prison. Further research may determine whether interventions addressing risky alcohol use can reduce smoking relapse. PMID- 29430257 TI - When Traits Match States: Examining the Associations between Self-Report Trait and State Mindfulness following a State Mindfulness Induction. AB - Previous research has found inconsistent relationships between trait mindfulness and state mindfulness. To extend previous research, we sought to examine the unique associations between self-report trait mindfulness and state mindfulness by levels of meditation experience (meditation-naive vs. meditation-experienced) and by mindfulness induction (experimentally induced mindful state vs. control group). We recruited 299 college students (93 with previous mindfulness meditation experience) to participate in an experiment that involved the assessment of five facets of trait mindfulness (among other constructs), followed by a mindfulness induction (vs. control), followed by the assessment of state mindfulness of body and mind. Correlational analyses revealed limited associations between trait mindfulness facets and facets of state mindfulness, and demonstrated that a brief mindfulness exercise focused on bodily sensations and the breath elicited higher state mindfulness of body but not state mindfulness of mind. We found significant interactions such that individuals with previous meditation experience and higher scores on the observing facet of trait mindfulness had the highest levels of state mindfulness of body and mind. Among individuals with meditation experience, the strengths of the associations between observing trait mindfulness and the state mindfulness facets increased with frequency of meditation practice. Some other interactions ran counter to expectations. Overall, the relatively weak associations between trait and state mindfulness demonstrates the need to improve our operationalizations of mindfulness, advance our understanding of how to best cultivate mindfulness, and reappraise the ways in which mindfulness can manifest as a state and as a trait. PMID- 29430258 TI - Mindfulness and Psychological Health Outcomes: A Latent Profile Analysis among Military Personnel and College Students. AB - Previous research on trait mindfulness facets using person-centered analyses (e.g., latent profile analysis [LPA]) has identified four distinct mindfulness profiles among college students: a high mindfulness group (high on all facets of the Five-Factor Mindfulness Questionnaire [FFMQ]), a judgmentally observing group (highest on observing, but low on non-judging of inner experience and acting with awareness), a non-judgmentally aware group (high on non-judging of inner experience and acting with awareness, but very low on observing), and a low mindfulness group (low on all facets of the FFMQ). In the present study, we used LPA to identify distinct mindfulness profiles in a community based sample of U.S. military personnel (majority veterans; n = 407) and non-military college students (n = 310) and compare these profiles on symptoms of psychological health outcomes (e.g., suicidality, PTSD, anxiety, rumination) and percentage of participants exceeding clinically significant cut-offs for depressive symptoms, substance use, and alcohol use. In the subsample of college students, we replicated previous research and found four distinct mindfulness profiles; however, in the military subsample we found three distinct mindfulness profiles (a combined low mindfulness/judgmentally observing class). In both subsamples, we found that the most adaptive profile was the "high mindfulness" profile (i.e., demonstrated the lowest scores on all psychological symptoms and the lowest probability of exceeding clinical cut-offs). Based on these findings, we purport that the comprehensive examination of an individual's mindfulness profile could help clinicians tailor interventions/treatments that capitalize on individual's specific strengths and work to address their specific deficits. PMID- 29430259 TI - THE EFFECTS OF THE ALKALOID SCOPOLAMINE ON THE PERFORMANCE AND BEHAVIOR OF TWO CATERPILLAR SPECIES. AB - Plants have evolved many defenses against insect herbivores, including numerous chemicals that can reduce herbivore growth, performance, and fitness. One group of chemicals, the tropane alkaloids, is commonly found in the nightshade family (Solanaceae) and has been thought to reduce performance and fitness in insects. We examined the effects of the tropane alkaloid scopolamine, the alkaloid constituent of Datura wrightii, which is the most frequent host plant for the abundant and widespread insect herbivore Manduca sexta in the southwestern United States. We exposed caterpillars of two different species to scopolamine: M. sexta, which has a shared evolutionary history with Datura and other solanceous plants, and Galleria mellonella, which does not. We showed that the addition of ecologically-realistic levels of scopolamine to both the diet and the hemolymph of these two caterpillar species (M. sexta and G. mellonella) had no effect on the growth of either species. We also showed that M. sexta has no behavioral preference for or against scopolamine incorporated into an artificial diet. These results are contrary to other work showing marked differences in performance for other insect species when exposed to scopolamine, and provide evidence that scopolamine might not provide the broad-spectrum herbivore resistance typically attributed to it. It also helps to clarify the coevolutionary relationship between M. sexta and one of its main host plants, as well as the physiological mechanism of resistance against scopolamine. PMID- 29430260 TI - Sex Differences in the LDL Receptor Knockout Mouse Model of Atherosclerosis. PMID- 29430261 TI - Petrodiesel and Waste Grease Biodiesel (B20) Emission Particles at a Rural Recycling Center: Characterization and Effects on Lung Epithelial Cells and Macrophages. AB - Diesel engine emissions are an important source of ultrafine particulate matter (PM) in both ambient air and many occupational settings. Biodiesel is a popular, 'green' alternative to petroleum diesel fuel, but little is known about the impact of 'real world' biodiesel combustion on workplace PM concentrations and particle characteristics including size, morphology, and composition; or on biological responses. The objectives of the present work were to characterize PM workplace concentrations and tailpipe emissions produced by the combustion of commercially purchased low sulfur petrodiesel and a waste grease B20 blend (20% biodiesel/80% petrodiesel by volume) in heavy duty diesel (HDD) nonroad equipment operating in a 'real world' rural recycling center. Furthermore, we assessed the in vitro responses of cell lines representing human lung epithelial cells (BEAS 2B) and macrophages (THP-1) after 24 h of exposure to these real-world particles. Compared to petroleum diesel, use of B20 in HDD equipment resulted in lower mass concentrations of PM2.5, PM<0.25 (particle diameter less than 2.5 and 0.25 micrometer, respectively), and elemental carbon. Transmission electron analysis of PM showed that primary particle size and morphology were similar between fuel types. Metals composition analysis revealed differences between fuels, with higher Fe, Al, V, and Se measured during B20 use, and higher As, Cd, Cu, Mn, Ni and Pb concentrations measured during petrodiesel use. In vitro responses varied between fuels but data supported that waste grease B20 particles elicited inflammatory responses in human macrophages and lung epithelial cells comparable to petrodiesel particles. However, the effects were more pronounced with B20 than petrodiesel at the same mass concentration. Since the primary particle size and morphology were similar between fuels, it is likely that the differential results seen in the in vitro assays points to differences in the composition of the PM. Future research should focus on the organic carbon and metals speciation and potential impact of real world particles on reactive oxygen species generation and mechanisms for differences in the cellular inflammatory responses. PMID- 29430262 TI - Evaluation of the Effect of Light and Scanning Time Delay on The Image Quality of Intra Oral Photostimulable Phosphor Plates. AB - Background: Nowadays, digital radiography is widely used in dental practice. One of the most common types is Photo Stimulated Phosphor Plate (PSP). Objective: The aims of this experimental study were to evaluate the impacts of different combinations of storage conditions and varying delays in reading of digital images captured using PSPs. Methods: Standardized images of a step wedges were obtained using PSPs from the Digora digital systems. Plates were exposed and immediately scanned to produce the baseline gold standard. The plates were re exposed and stored in four different storage conditions: white light, yellow light, natural light environment and dark room, then scanned after 10 and 30 minutes and 4 and 8 hours. Objective analysis was conducted by density measurements and the data were analyzed statistically using GEE test. Subjective analysis was performed by two oral and maxillofacial radiologists and the results were analyzed using McNemar's test. Results: The results from GEE analysis show that in the natural light environment, the densities in 10 minutes did not differ from the baseline. The mean densities decreased significantly during the time in all environments. The mean densities in step 2 for the dark room environment decreased with a slighter slope in comparison to yellow environment significantly. Conclusion: PSP images showed significant decrease in the density in plates scanned for 10 minutes or longer after exposure which may not be detected clinically. The yellow light environment had a different impact on the quality of PSP images. The spatial resolution did not change significantly with time. PMID- 29430264 TI - Controversies in the Management of the First Time Shoulder Dislocation. AB - Background: Traditionally, initial management of first anterior shoulder dislocations consists of reduction of the glenohumeral joint followed by a period of immobilization and subsequent physical therapy to recover shoulder range of motion and strength. This traditional approach in management is now controversial due to the high rate of recurrence. The aim of this paper is to review and discuss the literature about the global management of patients presenting with first-time traumatic anterior glenohumeral dislocation, analyzing the factors that affect shoulder instability after the first episode of dislocation. Methods: Scientific publications about the management of first-time shoulder dislocations are reviewed. Pubmed is used for that and no limit in the year of publication are stablished. These papers and their conclusions are discussed. Results: Younger patients, patient's activities and the kind of injury are the most important factors related to the shoulder instability after a first time traumatic dislocation. Authors that recommend surgical treatment after the first episode of dislocation argue that the possibilities of recurrence are high and therefore surgery should be performed before its occurrence. Other authors, however, argue that surgical treatment is demanding, and keep in mind that complications, such as recurrence, stiffness and pain after surgery, are still present. Conclusion: Currently, there is still no consensus in the literature with regard to the management of first episode of shoulder dislocation. It is necessary to analyze carefully every individual case to manage them more or less aggressive to obtain the best result in our practice. PMID- 29430263 TI - Traumatic Dental Injuries Resulting from Sports Activities; Immediate Treatment and Five Years Follow-Up: An Observational Study. AB - Background: Traumatic dental injuries (TDIs) represent 18-30% of all oral pathologies and a considerable number of these are sports related. It is very important to treat sports-related injuries and prevent complications. However, very few studies investigate the most expedient therapeutic strategies for the treatment of dental trauma correlated to sports. Objective: The aim of this work was to focus on the average recovery time for different lesions, to assess adequate times for each athlete, to identify any association with complications and to investigate whether or not the use of mouth-guards interfered with a full recovery to normal health. Methods: This study involved a group of 30 athletes (15 male and 15 female) who had dental injuries of varying severity.For the purposes of data collection, two classifications were taken into account: a classification for hard tissue trauma and another for periodontal lesions. The athletes were subdivided in "type of lesion' groups".They were then treated depending on their individual lesions and followed up for 5 years. A statistical analysis was carried out to study the association between recovery time, lesion types and occurrence of complications. Results: The time for recovery was different for each type of lesion and ranged from 3-5 days (only uncomplicated fractures) to 14 days (all hard-periodontal tissue traumas). The total number of recorded pulp complications amounted to 6 cases. Among 30 athletes, 20 had begun and maintained, during the five-year follow-up period, the habit of using mouth guards when practicing their sport activities. Conclusions: Recovery time and the severity of lesions are statistically associated: the more serious the injury, the more time an athlete needs to recover and return to competitive sports events. Furthermore, recovery time and precautionary measures (mouth-guards) did not influence the onset of complications. The subjects' habit of wearing a mouth guard continued even after the end of the therapy and follow-up periods. PMID- 29430265 TI - Nonoperative Treatment of Midshaft Clavicle Fractures in Adults. AB - Clavicle fractures are among the most common skeletal injuries accounting for 2 5% of all adult fractures. Historically, nonoperative treatment of midshaft clavicular fractures was considered the gold standard of care. Furthermore, nonoperative treatment has been challenged by an increasing popularity and rate of surgical fixations in recent years despite a lack of clear evidence in the current literature. Most fractures are suitable for conservative treatment. There is solid evidence in favour of nonoperative treatment for fractures with a displacement of less than 2cm and remaining contact of the bone fragments. Clear indications for conservative treatment versus surgical fixation of displaced midshaft fractures have not finally been established yet, leaving some questions and problems unanswered. Furthermore, there are no evidence-based recommendations concerning the kind and duration of shoulder immobilisation with no clear advantage for any treatment modality. PMID- 29430266 TI - Minimally Invasive Sacroiliac Joint Fusion: 2-Year Radiographic and Clinical Outcomes with a Principles-Based SIJ Fusion System. AB - Background: Sacroiliac joint (SIJ) degeneration is a common source of low back pain (LBP). Minimally invasive (MI) SIJ fusion procedures have demonstrated meaningful clinical improvement. A recently developed MI SIJ fusion system incorporates decortication, placement of bone graft and fixation with threaded implants (DC/BG/TF). Patients and Methods: Nineteen patients who had MI SIJ fusion with DC/BG/TF were enrolled at three centers. Fusion was assessed in CT images obtained 12 and 24 months postoperatively by an independent radiographic core laboratory. LBP was assessed using a 0-10 numerical pain scale (NPS) preoperatively and at 12 and 24 months postoperatively. Results: At 12 months, 15/19 patients (79%) had bridging bone across the SIJ, and at 24 months 17/18 patients (94%) available for follow-up had SIJ fusion. Of the patients with bridging bone 88% had fusion within the decorticated area, with solid fusion in 83%. A significant reduction in NPS scores was demonstrated, representing a 73% reduction in average low back pain. Conclusion: The patients in this series demonstrated significant improvement in LBP. Fusion rates at 24 months demonstrate promise for this system, which utilizes the established orthopedic principles of DC/BG/TF to achieve arthrodesis. Further study is warranted to demonstrate comparative fusion rates for different implant systems. PMID- 29430267 TI - Patient-centred goal setting using functional outcome measures in geriatric rehabilitation: is it feasible? AB - Background: Patient-centred goal setting is regarded as a beneficial intervention for geriatric rehabilitation. Nevertheless, its known laborious implementation in clinical practice remains an ongoing challenge. To improve implementation of patient-centred goal setting, the integration of goal setting with standardized measures has been proposed. Our objective of the current study was to explore the feasibility of Collaborative Functional Goal Setting (CFGS), i.e., using standardized functional measures to set and evaluate functional goals during geriatric rehabilitation. Materials and methods: Three medical professionals working in two geriatric rehabilitation wards were trained in CFGS and interviewed at the end of the study. We aimed at including 20 patients who underwent the CFGS intervention and could participate in open interviews. Both interviews of the professionals and patients were qualitatively analyzed. Results: Eight patients were included in the study, five of which could be interviewed. Both patients and professionals expressed a need for patient-centred goal setting. Patients indicated that goals were mainly set by the professional and that a rehabilitation plan was either not presented or its content was not clear to them. In contrast, the professionals regarded CFGS as patient-centred and potentially helpful in facilitating the goal-setting process. Nevertheless, the professionals indicated having difficulty with the implementation of the intervention. Conclusion: In the current study, we demonstrated that patient centred goal setting supported by functional measurements was not feasible in its present form which confirms the evidence from the literature that is difficult to perform patient-centred goal setting in clinical practice. PMID- 29430210 TI - Production of [Formula: see text] and [Formula: see text] in p-Pb collisions at [Formula: see text] TeV. AB - The transverse momentum distributions of the strange and double-strange hyperon resonances ([Formula: see text], [Formula: see text]) produced in p-Pb collisions at [Formula: see text] TeV were measured in the rapidity range [Formula: see text] for event classes corresponding to different charged-particle multiplicity densities, [Formula: see text]d[Formula: see text]/d[Formula: see text]. The mean transverse momentum values are presented as a function of [Formula: see text]d[Formula: see text]/d[Formula: see text], as well as a function of the particle masses and compared with previous results on hyperon production. The integrated yield ratios of excited to ground-state hyperons are constant as a function of [Formula: see text]d[Formula: see text]/d[Formula: see text]. The equivalent ratios to pions exhibit an increase with [Formula: see text]d[Formula: see text]/d[Formula: see text], depending on their strangeness content. PMID- 29430268 TI - The involvement of older inpatients in medical student education. AB - Objectives: To examine older inpatients' experiences with medical student education, their views on future interactions, and to seek their opinion on the most important curricular topics related to geriatric medicine. Methods: The study involved 112 non-confused inpatients older than 65 years of age, who completed a uniformed questionnaire on the day of their discharge from a teaching hospital. Results: The mean age was 81 years, with equal number of male and female participants. 57% interacted with the students during their admission, the majority being interviewed and examined. Almost all (92%) of these patients described their experience as positive, some described it as time-consuming (23%), repetitive (19%) and tiresome (9%). 92% of all participants agreed that the older patients should be part of medical students' education. Dementia, cardiac conditions, cancer, arthritis, isolation/loneliness were highlighted as the most important topics to teach medical students related to geriatric medicine, while patience and listening were listed as important skills. They suggested practical, easily implemented advice for the improvement of the interaction between students and older patients; including allowing more time for interactions and for students to speak louder. Conclusions: Older patients felt positively about their interactions with medical students, and believed that older patients should be involved in medical student education. As well as medical conditions such as dementia, cardiac disease and cancer, these patients highlighted isolation and loneliness as important topics for undergraduate geriatric medical education, implying that students should learn about broader aspects of older patients' health and wellbeing. PMID- 29430269 TI - Meningioma surgery in younger and older adults: patient profile and surgical outcomes. AB - Background: Due to increasing life expectancy, the number of older patients harboring a meningioma is expected to increase. We determined whether preoperative variables and postoperative clinical outcome differ between younger and older adults. Methods: Medical records of meningioma patients were retrospectively analyzed. Preoperative variables were age, gender, neurological symptoms, Karnofsky Performance Status (KPS), American Society of Anesthesiologists Physical Status (ASA)-classification and tumor characteristics. Clinical outcome was assessed using complication rates, length of hospital stay and destination after discharge. After 6-12 and 12-18-month KPS, neurological symptoms and Glasgow Outcome Scale (GOS) scores were assessed for older (age >= 65 years) and younger adults (18-65 years) using Mann-Whitney U, T test, Pearson's Chi square or Fisher's exact. Results: 89 patients were included (23 >= 65 years). Before surgery, older patients scored higher on ASA classification (p = 0.003) and lower on KPS (p = 0.017). There was no significant difference postoperatively in mortality, complications and duration of hospital stay. Less older patients were discharged directly to home compared to younger adults (52 vs 80%, respectively; p = 0.004). In surviving patients, less older subjects had a good recovery (GOS 4-5) at 6-12 months' follow-up compared to younger subjects (64 vs 93%, respectively; p = 0.035). At 12-18 months, there was no significant difference in good recovery between both age groups (82 vs 92%). Conclusion: In this cohort, outcome was worse for patients >= 65 years old in terms of discharge destination and good recovery at 6-12 months. At 12-18 months follow-up, older subjects performed not significantly different from younger ones. Careful patient selection seems essential to reach good results in meningioma surgery for patients >= 65 years old. PMID- 29430273 TI - Helical micropumps near surfaces. AB - Recent experiments proposed to use confined bacteria in order to generate flows near surfaces. We develop a mathematical and a computational model of this fluid transport using a linear superposition of fundamental flow singularities. The rotation of a helical bacterial flagellum induces both a force and a torque on the surrounding fluid, both of which lead to a net flow along the surface. The combined flow is in general directed at an angle to the axis of the flagellar filament. The optimal pumping is thus achieved when bacteria are tilted with respect to the direction in which one wants to move the fluid, in good agreement with experimental results. We further investigate the optimal helical shapes to be used as micropumps near surfaces and show that bacterial flagella are nearly optimal, a result which could be relevant to the expansion of bacterial swarms. PMID- 29430270 TI - Perceived Barriers and Facilitators of Farm-to-Consumer Retail Outlet Use Among Participants of the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in Alabama. AB - This research aimed to identify perceived barriers and facilitators of farm-to consumer (FTC) retail outlet (eg, farmers' markets, farm/roadside stands) usage among Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) participants residing in Birmingham, Alabama. Additionally, associations between barriers and facilitators reported and daily fruit and vegetable (F&V) intake were examined. A sample of 312 lower income women (mean age = 27.6; 67.0% non-Hispanic black; 45.3% obese) who participate in the Birmingham WIC program were surveyed between October 2014 and January 2015. Fischer's exact test was used to assess associations between barriers (eg, outlet location, price, transportation), facilitators (eg, produce quality, produce variety), and high F&V intake (ie, consuming >= 5 servings per day). Approximately 81 (26.1%) participants reported using an FTC outlet to purchase produce in 2014. Lack of awareness (39.3%), outlet location (32.8%), and lack of interest (28.4%) were the barriers most often reported. Produce quality (69.1%), produce variety (49.4%), and price (39.5%) were the facilitators most often reported. Barriers and facilitators mentioned were not associated with high F&V intake. Lack of awareness and lack of interest are key barriers to FTC outlet usage among Birmingham WIC recipients. Interventions aiming to promote use of FTC outlets should consider the perceived barriers and facilitators to usage. PMID- 29430274 TI - Direct enrichment of pathogens from physiological samples of high conductivity and viscosity using H-filter and positive dielectrophoresis. AB - The full potential of microfluidic techniques as rapid and accurate methods for the detection of disease-causing agents and foodborne pathogens is critically limited by the complex sample preparation process, which commonly comprises the enrichment of bacterial cells to detectable levels. In this manuscript, we describe a microfluidic device which integrates H-filter desalination with positive dielectrophoresis (pDEP) for direct enrichment of bacterial cells from physiological samples of high conductivity and viscosity, such as cow's milk and whole human blood. The device contained a winding channel in which electrolytes in the samples continuously diffused into deionized (DI) water (desalination), while the bacterial cells remained in the samples. The length of the main channel was optimized by numerical simulation and experimentally evaluated by the diffusion of fluorescein into DI water. The effects of another three factors on H filter desalination were also investigated, including (a) the flow rate ratio between the sample and DI water, (b) sample viscosity, and (c) non-Newtonian fluids. After H-filter desalination, the samples were withdrawn into the dielectrophoresis chamber in which the bacterial cells were captured by pDEP. The feasibility of the device was demonstrated by the direct capture of the bacterial cells in 1* PBS buffer, cow's milk, and whole human blood after H-filter desalination, with the capture efficiencies of 70.7%, 90.0%, and 80.2%, respectively. We believe that this simple method can be easily integrated into portable microfluidic diagnosis devices for rapid and accurate detection of disease-causing agents and foodborne pathogens. PMID- 29430272 TI - Surface enhanced Raman scattering (SERS) based biomicrofluidics systems for trace protein analysis. AB - In recent years, Surface Enhanced Raman Scattering (SERS) has been widely applied to many different areas, including chemical analysis, biomolecule detection, bioagent diagnostics, DNA sequence, and environmental monitor, due to its capabilities of unlabeled fingerprint identification, high sensitivity, and rapid detection. In biomicrofluidic systems, it is also very powerful to integrate SERS based devices with specified micro-fluid flow fields to further focusing/enhancing/multiplexing SERS signals through molecule registration, concentration/accumulation, and allocation. In this review, after a brief introduction of the mechanism of SERS detection on proteins, we will first focus on the effectiveness of different nanostructures for SERS enhancement and light to-heat conversion in trace protein analysis. Various protein molecule accumulation schemes by either (bio-)chemical or physical ways, such as immuno, electrochemical, Tip-enhanced Raman spectroscopy, and magnetic, will then be reviewed for further SERS signal amplification. The analytical and repeatability/stability issues of SERS detection on proteins will also be brought up for possible solutions. Then, the comparison about various ways employing microfluidic systems to register, concentrate, and enhance the signals of SERS and reduce the background noise by active or passive means to manipulate SERS nanostructures and protein molecules will be elaborated. Finally, we will carry on the discussion on the challenges and opportunities by introducing SERS into biomicrofluidic systems and their potential solutions. PMID- 29430271 TI - Point-of-care testing in the early diagnosis of acute pesticide intoxication: The example of paraquat. AB - Acute pesticide intoxication is a common method of suicide globally. This article reviews current diagnostic methods and makes suggestions for future development. In the case of paraquat intoxication, it is characterized by multi-organ failure, causing substantial mortality and morbidity. Early diagnosis may save the life of a paraquat intoxication patient. Conventional paraquat intoxication diagnostic methods, such as symptom review and urine sodium dithionite assay, are time consuming and impractical in resource-scarce areas where most intoxication cases occur. Several experimental and clinical studies have shown the potential of portable Surface Enhanced Raman Scattering (SERS), paper-based devices, and machine learning for paraquat intoxication diagnosis. Portable SERS and new SERS substrates maintain the sensitivity of SERS while being less costly and more convenient than conventional SERS. Paper-based devices provide the advantages of price and portability. Machine learning algorithms can be implemented as a mobile phone application and facilitate diagnosis in resource-limited areas. Although these methods have not yet met all features of an ideal diagnostic method, the combination and development of these methods offer much promise. PMID- 29430275 TI - Engineering a simple lateral flow device for animal blood coagulation monitoring. AB - Increasing numbers of animals are diagnosed with thromboembolism, requiring anticoagulation treatment to prevent thrombotic events. Frequent and periodic coagulation monitoring is critical to ensure treatment effectiveness and patient safety by limiting blood coagulation ability within the desired therapeutic range. Point-of-care diagnostics is an ideal candidate for frequent coagulation monitoring due to rapid test results and no need for laboratory setting. This article reports the first utilization of no-reaction lateral flow assay (nrLFA) device for simple and low-cost animal blood coagulation monitoring in resource limited setting. The nrLFA device consists of sample pad, analytical membrane and wicking pad, without conjugate pad, reagent printing or membrane drying. Citrated and heparinized animal blood were utilized to mimic different blood coagulation abilities in vitro by adding reversal agents CaCl2 and protamine sulfate. The travel distance of red blood cells (RBCs) on the nrLFA after a pre-determined test time serves as endpoint marker. Upon adding 500 mM CaCl2 solution to citrated bovine, canine, rabbit and equine blood, the average travel distance decreases from 10.9 to 9.4 mm, 8.8 to 5.7 mm, 12.6 to 9 mm, and 15.3 to 11.3 mm, respectively. For heparinized bovine and rabbit blood, the average distance decreases from 14.5 to 11.4 mm and from 9.8 to 7.2 mm, respectively, when adding 300 mg/l protamine sulfate solution. The effect of hematocrit on RBC travel distance in the nrLFA was also investigated. The nrLFA device will potentially improve treatment efficiency, patient safety, quality of life, and satisfaction for both animal patients and their owners. PMID- 29430276 TI - Corrosion Properties of 34CrMo4 Steel Modified by Shot Peening. AB - A nanocrystalline layer was prepared on the surface of 34CrMo4 steel by time controlling shot peening (SP, i.e., 1, 5, 10, and 20 minutes). Field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) analysis, and transmission electron microscope (TEM) were applied to analyze the surface, cross sections, and grain size of the specimens before and after SP. The electrochemical corrosion behavior was used to simulate a liquid under the oil and gas wells environment. It was characterized by the potentiodynamic polarization test and electrochemical impedance spectroscopy (EIS). The analysis results show that the surfaces of the SP samples were very rough and had numerous cracks. A passive film on SP surface was formed by nanocrystalline grains. However, the passive film formed in the initial stage was not dense or uniform, and cracks occurred in the passive film during peening, resulting in a decrease in corrosion resistance. PMID- 29430277 TI - A comparison of self-reported sexual effects of alcohol, marijuana, and ecstasy in a sample of young adult nightlife attendees. AB - Alcohol, marijuana, and ecstasy (3,4-methylenedioxymethamphetamine [MDMA], 'Molly') are among the most prevalent substances used by young adults; however, few studies have focused on the specific sexual effects associated with use. Examining subjective sexual effects (e.g. increased libido) associated with use can inform prevention efforts. Data were analysed from 679 nightclub and dance festival attendees in New York City (ages 18-25) to examine and compare self reported sexual effects associated with use of alcohol, marijuana, and ecstasy. Results suggest that compared to marijuana, alcohol and ecstasy were more strongly associated with heightened perceived sexual effects (i.e. perceived sexual attractiveness of self and others, sexual desire, length of intercourse, and sexual outgoingness). Increased body and sex organ sensitivity and increased sexual intensity were most commonly associated with ecstasy use. Sexual dysfunction was most common while using alcohol or ecstasy, especially among males, and females were more likely to report sexual dysfunction after using marijuana. Post-sex regret was most common with alcohol use. Alcohol, marijuana, and ecstasy each have different sexual effects; therefore, each is associated with different risks and benefits for users. Findings can inform prevention and harm reduction as young adults are prone to use these substances. PMID- 29430278 TI - Absorption and Elimination of Oat Avenanthramides in Humans after Acute Consumption of Oat Cookies. AB - Background: Avenanthramides (AVA) are a group of diphenolic acids found only in oats that have anti-inflammatory and antioxidant effects. Absorption of AVAs in humans after oral consumption of natural oat flour is unknown. Objective: To examine the appearance of AVAs in plasma after oral ingestion of oat cookies and estimate key pharmacokinetic parameters. Methods: Male and female nonobese participants (n = 16) consumed three cookies made with oat flour containing high (229.6 mg/kg, H-AVA) or low (32.7 mg/kg, L-AVA) amounts of AVAs, including AVA-A, AVA-B, and AVA-C. Blood samples were collected at 0, 0.5, 1, 2, 3, 5, and 10 h after ingestion. Plasma total (conjugated and free) AVA concentrations were quantified using UPLC-MS, and pharmacokinetic parameters for each AVA were estimated. Results: AVAs reached peak concentrations in plasma between 2 and 3 h for the H-AVA group and between 1 and 2 h for the L-AVA group. Maximal plasma concentrations for AVAs were higher in the H-AVA than in the L-AVA group. AVA-B demonstrated a longer half-life and slower elimination rate than AVA-A and AVA-C. Conclusions: AVAs found naturally in oats are absorbed in the plasma after oral administration in humans. AVA-B has the slowest elimination rate and the longest half-life compared to AVA-A and AVA-C, while AVA-C demonstrated the lowest plasma concentrations. This study is registered with ClinicalTrials.gov identifier NCT02415374. PMID- 29430281 TI - Antioxidant and Hepatoprotective Activities of Polysaccharides from Spent Mushroom Substrates (Laetiporus sulphureus) in Acute Alcohol-Induced Mice. AB - In order to contribute to the exploitation and utilization of spent mushroom substrates (SMS) of Laetiporus sulphureus, hot-water-extractable polysaccharides (H-SMPS) and enzymatic-extractable polysaccharides (E-SMPS) were successfully isolated from SMS of L. sulphureus. Both H-SMPS and E-SMPS were found to have high reducing power and potential scavenging activities against hydroxyl, DPPH, and superoxide anion radicals. In vivo assays showed that the administration of H SMPS and E-SMPS has potential hepatoprotective effects against alcohol-induced alcoholic liver disease (ALD), possibly brought about by improving liver function, increasing antioxidant status, and reducing lipid peroxidation. Furthermore, monosaccharide composition analysis showed that fucose may play a vital role in guaranteeing stronger hepatoprotection. These results may provide references for the exploitation of the SMS of L. sulphureus as a source of H-SMPS and E-SMPS, which in turn can be used as functional foods or natural drugs for the prevention of ALD and other liver diseases. PMID- 29430282 TI - Ginsenoside Rb1 for Myocardial Ischemia/Reperfusion Injury: Preclinical Evidence and Possible Mechanisms. AB - Ginseng is an important herbal drug that has been used worldwide for many years. Ginsenoside Rb1 (G-Rb1), the major pharmacological extract from ginseng, possesses a variety of biological activities in the cardiovascular systems. Here, we conducted a preclinical systematic review to investigate the efficacy of G-Rb1 for animal models of myocardial ischemia/reperfusion injury and its possible mechanisms. Ten studies involving 211 animals were identified by searching 6 databases from inception to May 2017. The methodological quality was assessed by using the CAMARADES 10-item checklist. All the data were analyzed using RevMan 5.3 software. As a result, the score of study quality ranged from 3 to 7 points. Meta-analyses showed that G-Rb1 can significantly decrease the myocardial infarct size and cardiac enzymes (including lactate dehydrogenase, creatine kinase, and creatine kinase-MB) when compared with control group (P < 0.01). Significant decrease in cardiac troponin T and improvement in the degree of ST-segment depression were reported in one study (P < 0.05). Additionally, the possible mechanisms of G-Rb1 for myocardial infarction are antioxidant, anti-inflammatory, antiapoptosis, promoting angiogenesis and improving the circulation. Thus, G-Rb1 is a potential cardioprotective candidate for further clinical trials of myocardial infarction. PMID- 29430279 TI - Unfolded Protein Response of the Endoplasmic Reticulum in Tumor Progression and Immunogenicity. AB - The endoplasmic reticulum (ER) is a pivotal regulator of folding, quality control, trafficking, and targeting of secreted and transmembrane proteins, and accordingly, eukaryotic cells have evolved specialized machinery to ensure that the ER enables these proteins to acquire adequate folding and maturation in the presence of intrinsic and extrinsic insults. This adaptive capacity of the ER to intrinsic and extrinsic perturbations is important for maintaining protein homeostasis, which is termed proteostasis. Failure in adaptation to these perturbations leads to accumulation of misfolded or unassembled proteins in the ER, which is termed ER stress, resulting in the activation of unfolded protein response (UPR) of the ER and the execution of ER-associated degradation (ERAD) to restore homeostasis. Furthermore, both of the two axes play key roles in the control of tumor progression, inflammation, immunity, and aging. Therefore, understanding UPR of the ER and subsequent ERAD will provide new insights into the pathogenesis of many human diseases and contribute to therapeutic intervention in these diseases. PMID- 29430283 TI - Possible Mechanisms of Mercury Toxicity and Cancer Promotion: Involvement of Gap Junction Intercellular Communications and Inflammatory Cytokines. AB - A number of observations indicate that heavy metals are able to alter cellular metabolic pathways through induction of a prooxidative state. Nevertheless, the outcome of heavy metal-mediated effects in the development of human diseases is debated and needs further insights. Cancer is a well-established DNA mutation linked disease; however, epigenetic events are perhaps more important and harmful than genetic alterations. Unfortunately, we do not have reliable screening methods to assess/validate the epigenetic (promoter) effects of a physical or a chemical agent. We propose a mechanism of action whereby mercury acts as a possible promoter carcinogen. In the present contribution, we resume our previous studies on mercury tested at concentrations comparable with its occurrence as environmental pollutant. It is shown that Hg(II) elicits a prooxidative state in keratinocytes linked to inhibition of gap junction-mediated intercellular communication and proinflammatory cytokine production. These combined effects may on one hand isolate cells from tissue-specific homeostasis promoting their proliferation and on the other hand tamper the immune system defense/surveillance checkmating the whole organism. Since Hg(II) is not a mutagenic/genotoxic compound directly affecting gene expression, in a broader sense, mercury might be an example of an epigenetic tumor promoter or, further expanding this concept, a "metagenetic" effector. PMID- 29430284 TI - A Carotenoid Extract from a Southern Italian Cultivar of Pumpkin Triggers Nonprotective Autophagy in Malignant Cells. AB - Carotenoids, including beta-carotene, lycopene, and derivatives, such as retinoic acid, have been studied for their significant antiproliferative and differentiating activity on cancer cells in experimental models and in clinics. We are presenting here data on the mechanism of action of a carotenoid-enriched extract obtained from the pumpkin Cucurbita moschata, variety "long of Naples," on two malignant human cell lines, Caco-2 and SAOs, derived from a colon adenocarcinoma and an osteosarcoma, respectively. The carotenoid extract has been obtained from pumpkin pulp and seeds by supercritical CO2 extraction and employed to prepare oil-in-water nanoemulsions. The nanoemulsions, applied at a final carotenoid concentration of 200-400 MUg/ml, were not cytotoxic, but induced a delay in cell growth of about 40% in both SAOs and Caco-2 cell lines. This effect was associated with the activation of a "nonprotective" form of autophagy and, in SAOs cells, to the induction of cell differentiation via a mechanism that involved AMPK activation. Our data suggest the presence of a pool of bioactive compounds in the carotenoid-enriched extract, acting additively, or synergistically, to delay cell growth in cancer cells. PMID- 29430285 TI - Phagocytosis of Advanced Glycation End Products (AGEs) in Macrophages Induces Cell Apoptosis. AB - Advanced glycation end products (AGEs) are the products of a series of nonenzymatic modifications of proteins by reducing sugars. AGEs play a pivotal role in development of diabetic complications and atherosclerosis. Accumulation of AGEs in a vessel wall may contribute to the development of vascular lesions. Although AGEs have a diverse range of bioactivities, the clearance process of AGEs from the extracellular space, including the incorporation of AGEs into specific cells, subcellular localization, and the fate of AGEs, remains unclear. In the present study, we examined the kinetics of the uptake of AGEs by mouse macrophage J774.1 cells in vitro and characterized the process. We demonstrated that AGEs bound to the surface of the cells and were also incorporated into the cytoplasm. The temperature- and time-dependent uptake of AGEs was saturable with AGE concentration and was inhibited by cytochalasin D but not chlorpromazine. We also observed the granule-like appearance of AGE immunoreactivity in subcellular localizations in macrophages. Higher concentrations of AGEs induced intracellular ROS and 4-HNE, which were associated with activation of the NF-kappaB pathway and caspase-3. These results suggest that incorporation of AGEs occurred actively by endocytosis in macrophages, leading to apoptosis of these cells through NF-kappaB activation. PMID- 29430280 TI - NADPH Oxidase Deficiency: A Multisystem Approach. AB - The immune system is a complex system able to recognize a wide variety of host agents, through different biological processes. For example, controlled changes in the redox state are able to start different pathways in immune cells and are involved in the killing of microbes. The generation and release of ROS in the form of an "oxidative burst" represent the pivotal mechanism by which phagocytic cells are able to destroy pathogens. On the other hand, impaired oxidative balance is also implicated in the pathogenesis of inflammatory complications, which may affect the function of many body systems. NADPH oxidase (NOX) plays a pivotal role in the production of ROS, and the defect of its different subunits leads to the development of chronic granulomatous disease (CGD). The defect of the different NOX subunits in CGD affects different organs. In this context, this review will be focused on the description of the effect of NOX2 deficiency in different body systems. Moreover, we will also focus our attention on the novel insight in the pathogenesis of immunodeficiency and inflammation-related manifestations and on the protective role of NOX2 deficiency against the development of atherosclerosis. PMID- 29430286 TI - Differential Alterations of the Mitochondrial Morphology and Respiratory Chain Complexes during Postnatal Development of the Mouse Lung. AB - Mitochondrial biogenesis and adequate energy production in various organs of mammals are necessary for postnatal adaptation to extrauterine life in an environment with high oxygen content. Even though transgenic mice are frequently used as experimental models, to date, no combined detailed molecular and morphological analysis on the mitochondrial compartment in different lung cell types has been performed during postnatal mouse lung development. In our study, we revealed a significant upregulation of most mitochondrial respiratory complexes at protein and mRNA levels in the lungs of P15 and adult animals in comparison to newborns. The majority of adult animal samples showed the strongest increase, except for succinate dehydrogenase protein (SDHD). Likewise, an increase in mRNA expression for mtDNA transcription machinery genes (Polrmt, Tfam, Tfb1m, and Tfb2m), mitochondrially encoded RNA (mt-Rnr1 and mt-Rnr2), and the nuclear-encoded mitochondrial DNA polymerase (POLG) was observed. The biochemical and molecular results were corroborated by a parallel increase of mitochondrial number, size, cristae number, and complexity, exhibiting heterogeneous patterns in distinct bronchiolar and alveolar epithelial cells. Taken together, our results suggest a specific adaptation and differential maturation of the mitochondrial compartment according to the metabolic needs of individual cell types during postnatal development of the mouse lung. PMID- 29430287 TI - Impact of Hot Environment on Fluid and Electrolyte Imbalance, Renal Damage, Hemolysis, and Immune Activation Postmarathon. AB - Previous studies have demonstrated the physiological changes induced by exercise exposure in hot environments. We investigated the hematological and oxidative changes and tissue damage induced by marathon race in different thermal conditions. Twenty-six male runners completed the Sao Paulo International Marathon both in hot environment (HE) and in temperate environment (TE). Blood and urine samples were collected 1 day before, immediately after, 1 day after, and 3 days after the marathon to analyze the hematological parameters, electrolytes, markers of tissue damage, and oxidative status. In both environments, the marathon race promotes fluid and electrolyte imbalance, hemolysis, oxidative stress, immune activation, and tissue damage. The marathon runner's performance was approximately 13.5% lower in HE compared to TE; however, in HE, our results demonstrated more pronounced fluid and electrolyte imbalance, renal damage, hemolysis, and immune activation. Moreover, oxidative stress induced by marathon in HE is presumed to be related to protein/purine oxidation instead of other oxidative sources. Fluid and electrolyte imbalance and protein/purine oxidation may be important factors responsible for hemolysis, renal damage, immune activation, and impaired performance after long-term exercise in HE. Nonetheless, we suggested that the impairment on performance in HE was not associated to the muscle damage and lipoperoxidation. PMID- 29430288 TI - Synthesis and Biological Evaluations of Ring Substituted Tetrahydroisoquinolines (THIQs) as Anti-Breast Cancer Agents. AB - Breast cancer is a leading cause of mortality among women, resulting in more than half a million deaths worldwide every year. Although chemotherapeutic drugs remain the main stay of cancer treatment, it is observed that toxicity to normal cells poses a limitation to their therapeutic values. Moreover, the patient recovery rate from advanced breast cancer by chemotherapy is still unacceptably low. Tetrahydroisoqinoline derivatives (THIQs) were reported to act as selective subtype estrogen receptor antagonists/agonists and may serve as potential therapeutic agents for breast cancer. In continuation of previous work we systematically synthesized and characterized the tetrahydroisoquinoline (THIQs) analogs. In-vitro antiproliferative activity of new substituted tetrahydroisoquinoline analogs were evaluated against human ER (+) MCF-7 (breast), ER (-) MDA-MB-231 (breast) and Ishikawa (endometrial) cancer cell lines using the CellTiter-Glo luminescent cell viability assay. The most active compounds obtained in this study were 2b, 2i, and 3 g as demonstrated by their activity (IC50=0.2 MUg/mL, 0.08 MUg/mL; 0.61 MUg/mL, 0.09 MUg/mL; 0.25 MUg/mL, 0.11 MUg/mL) against MCF-7 and Ishikawa cell lines respectively, in comparison to Tamoxifen activity (IC50=3.99 MUg/mL, 7.87 MUg/ml). The newly synthesized molecules were docked in the active sites of the ER-alpha (PDB: 3ERT), ER-beta (PDB: 1QKN) and alpha-beta tubulin taxol complex (1JFF) crystal structures to determine the probable binding modes (bioactive conformations) of the active compounds. PMID- 29430289 TI - Quality of life in patients with melasma in Turkish women. PMID- 29430290 TI - HUBBLE SPACE TELESCOPE FAR ULTRAVIOLET SPECTROSCOPY OF THE RECURRENT NOVA T PYXIDIS. AB - With six recorded nova outbursts, the prototypical recurrent nova T Pyxidis (T Pyx) is the ideal cataclysmic variable system to assess the net change of the white dwarf mass within a nova cycle. Recent estimates of the mass ejected in the 2011 outburst ranged from a few ~10-5M? to 3.3 * 10-4M?, and assuming a mass accretion rate of 10-8-10-7M? yr-1 for 44 yr, it has been concluded that the white dwarf in T Pyx is actually losing mass. Using NLTE disk modeling spectra to fit our recently obtained Hubble Space Telescope COS and STIS spectra, we find a mass accretion rate of up to two orders of magnitude larger than previously estimated. Our larger mass accretion rate is due mainly to the newly derived distance of T Pyx (4.8 kpc, larger than the previous 3.5 kpc estimate), our derived reddening of E(B - V) = 0.35 (based on combined IUE and GALEX spectra), and NLTE disk modeling (compared to blackbody and raw flux estimates in earlier works). We find that for most values of the reddening (0.25 <= E(B-V) <= 0.50) and white dwarf mass (0.70 M? <= Mwd <= 1.35 M?) the accreted mass is larger than the ejected mass. Only for a low reddening (~0.25 and smaller) combined with a large white dwarf mass (0.9 M? and larger) is the ejected mass larger than the accreted one. However, the best results are obtained for a larger value of reddening. PMID- 29416850 TI - People who report anomalous information reception have higher dissociation symptom scores. AB - Background : Dissociative states exist on a continuum from nonpathological expressions, such as highway hypnosis and day-dreaming, to pathological states of derealization and depersonalization. Claims of communication with deceased individuals or mediumship have been dismissed as dissociative symptoms in the past, although current definitions of dissociative pathologies have been qualified to include distress from the disorder and functional disability. This study examined the relationship between dissociative symptoms and mediumship or anomalous information reception (AIR) in a large convenience sample. Methods : Secondary analyses of cross-sectional survey data were conducted. The survey included demographics, the Dissociation Experience Scale Taxon (DES-T), and AIR data. Summary statistics and linear and logistic regressions evaluated the relationship between dissociative symptoms and AIR endorsement with and without covariates. Results : 3,023 participants were included and were mostly middle aged (51 years +/- 16; range 17-96), female (70%), Caucasian (85%), college educated (88%), had an annual income over $50,000 (55%), were raised Christian (71%) and now affiliated as Spiritual but not Religious (60%). AIR ability was endorsed by 42% of participants. AIR experiences usually began in childhood (81%). Also, 53% had family members with similar AIR experiences. The mean DES-T score was 14.4 +/- 17.3 (range 0-100) for all participants and was significantly higher for AIR claimants (18.2 +/- 19.3) non-claimants (11.8 +/- 15.2; t = -10.3, p<0.0005). In total, 11% of non-claimants and 22% of claimants had a cut-off score greater than 30 (X 2 = 63.0, p=<0.0005). Conclusions : Mean DES-T scores for all participants were lower than a clinical cutoff for pathological dissociation. Future studies comparing AIR claimants and non-claimants may benefit from using a more comprehensive measure of dissociative symptoms. In addition, evaluating the participant's functional impairment would help discern the pathological versus non-pathological nature of purported AIR experiences. PMID- 29416850 TI - People reporting experiences of mediumship have higher dissociation symptom scores than non-mediums, but below thresholds for pathological dissociation. AB - Background: Dissociative states exist on a continuum from nonpathological forms, such as highway hypnosis and day-dreaming, to pathological states of derealization and depersonalization. Claims of communication with deceased individuals, known as mediumship, were once regarded as a pathological form of dissociation, but current definitions recognize the continuum and include distress and functional disability as symptoms of pathology. This study examined the relationship between dissociative symptoms and mediumship in a large convenience sample. Methods: Secondary analyses of cross-sectional survey data were conducted. The survey included demographics, the Dissociation Experience Scale Taxon (DES-T, score range 0-100), as well as questions about instances of mediumship experiences. Summary statistics and linear and logistic regressions explored the relationship between dissociative symptoms and mediumship endorsement. Results: 3,023 participants were included and were mostly middle aged (51 years +/- 16; range 17-96), female (70%), Caucasian (85%), college educated (88%), had an annual income over $50,000 (55%), and were raised Christian (71%) but were presently described as Spiritual but not Religious (60%). Mediumship experiences were endorsed by 42% of participants, the experiences usually began in childhood (81%), and 53% had family members who reported similar experiences. The mean DES-T score across all participants was 14.4 +/- 17.3, with a mean of 18.2 +/- 19.3 for those claiming mediumship experiences and 11.8 +/- 15.2 for those who did not (t = -10.3, p < 0.0005). The DES-T threshold score for pathological dissociation is 30. Conclusions: On average, individuals claiming mediumship experiences had higher dissociation scores than non-claimants, but neither group exceeded the DES-T threshold for pathology. Future studies exploring dissociative differences between these groups may benefit from using more comprehensive measures of dissociative symptoms as well as assessments of functional impairment, which would help in discerning between pathological and non-pathological aspects of these experiences. PMID- 29416851 TI - Effects of stress or infection on rat behavior show robust reversals due to environmental disturbance. AB - Background: The behavior of animals is intricately linked to the environment; a relationship that is often studied in laboratory conditions by using environmental perturbations to study biological mechanisms underlying the behavioral change. Methods: This study pertains to two such well-studied and well-replicated perturbations, i.e., stress-induced anxiogenesis and Toxoplasmagondii -induced loss of innate fear. Here, we demonstrate that behavioral outcomes of these experimental manipulations are contingent upon the ambient quality of the wider environment where animal facilities are situated. Results: During late 2014 and early 2015, a building construction project started adjacent to our animal facility. During this phase, we observed that maternal separation stress caused anxiolysis, rather than historically observed anxiogenesis, in laboratory rats. We also found that Toxoplasma gondii infection caused an increase, rather than historically observed decrease, in innate aversion to predator odors in rats. Conclusion: These observations suggest that effects of stress and Toxoplasma gondii are dependent on variables in the environment that often go unreported in the published literature. PMID- 29430295 TI - Diastereoselective One Pot Five-Component Reaction toward 4-(Tetrazole)-1,3 Oxazinanes. AB - A diastereoselective one pot five-component reaction toward the synthesis of 4 (tetrazole)-1,3-oxazinanes has been reported. The sonication-accelerated, catalyst-free, simple, general and highly time efficient, Asinger-Ugi-tetrazole reaction was used for the synthesis of diverse 4-(tetrazole)-1,3-oxazinanes. The reaction exhibit excellent diastereoselectivity and broad substrate scope. PMID- 29430294 TI - Novel method for the formation of monodisperse superheated perfluorocarbon nanodroplets as activatable ultrasound contrast agents. AB - Microbubble (MB) contrast agents have positively impacted the clinical ultrasound (US) community worldwide. Their use in molecular US imaging applications has been hindered by their limited distribution to the vascular space. Acoustic droplet vaporization (ADV) of nanoscale superheated perfluorocarbon nanodroplets (NDs) demonstrates potential as an extravascular contrast agent that could facilitate US-based molecular theranostic applications. However these agents are metastable and difficult to manufacture with high yields. Here, we report a new formulation technique that yields reliable, narrowly dispersed sub-300 nm decafluorobutane (DFB) or octafluoropropane (OFP)-filled phospholipid-coated NDs that are stable at body temperature, using small volume microfluidization. Final droplet concentration was high for DFB and lower for OFP (>1012vs. >1010 NDs per mL). Superheated ND stability was quantified using tunable resistive pulse sensing (TRPS) and dynamic light scattering (DLS). DFB NDs were stable for at least 2 hours at body temperature (37 degrees C) without spontaneous vaporization. These NDs are activatable in vitro when exposed to diagnostic US pressures delivered by a clinical system to become visible microbubbles. The DFB NDs were suficiently stable to allow their processing into functionalized NDs with anti-epithelial cell adhesion molecule (EpCAM) antibodies to target EpCAM positive cells. PMID- 29430297 TI - Dietary assessment in UK Biobank: an evaluation of the performance of the touchscreen dietary questionnaire. AB - UK Biobank is an open access prospective cohort of 500 000 men and women. Information on the frequency of consumption of main foods was collected at recruitment with a touchscreen questionnaire; prior to examining the associations between diet and disease, it is essential to evaluate the performance of the dietary touchscreen questionnaire. The objectives of the present paper are to: describe the repeatability of the touchscreen questionnaire in participants (n 20 348) who repeated the assessment centre visit approximately 4 years after recruitment, and compare the dietary touchscreen variables with mean intakes from participants (n 140 080) who completed at least one of the four web-based 24-h dietary assessments post-recruitment. For fish and meat items, 90 % or more of participants reported the same or adjacent category of intake at the repeat assessment visit; for vegetables and fruit, and for a derived partial fibre score (in fifths), 70 % or more of participants were classified into the same or adjacent category of intake (kappaweighted > 0.50 for all). Participants were also categorised based on their responses to the dietary touchscreen questionnaire at recruitment, and within each category the group mean intake of the same food group or nutrient from participants who had completed at least one web-based 24-h dietary assessment was calculated. The comparison showed that the dietary touchscreen variables, available on the full cohort, reliably rank participants according to intakes of the main food groups. PMID- 29430296 TI - Ramadan during pregnancy and birth weight of newborns. AB - Previous studies suggest that Ramadan exposure during pregnancy might affect the health of women and their babies, particularly through the effect of fasting. This study aimed to evaluate the association between Ramadan exposure and fasting during pregnancy on the birth weight of newborns. This study concerned 1351 pregnant women from a prospective cohort in Jakarta, Indonesia. Ramadan exposure was based on the actual overlap between Ramadan and pregnancy. Women's fasting behaviour was recorded among 139 women who came for antenatal care between 10 July 2013 and 7 August 2013, and those who had fasted for at least 1 d (n 110) were classified as exposed to Ramadan fasting. Furthermore, a 24 h dietary recall was performed and repeated 1 month later. Birth weight of newborns who were exposed to Ramadan during pregnancy did not significantly differ from those who were not, both in the total and trimester-specific analysis. Maternal fasting did not seem to affect the birth weight of newborns (-72 (95 % CI -258, 114) g; P = 0.44), although there was a non-significant trend towards lower birth weight with fasting in the second and third trimester. Women who fasted had significantly lower total energy, macronutrient and water intake as compared with women who did not. Women's intake was also lower during Ramadan (regardless of their fasting behaviour) as compared with 1 month later. Lifestyle changes that occur with Ramadan and fasting during pregnancy are associated with lower reported energy intake. We cannot conclude on the effect of fasting on birth weight due to low statistical power. PMID- 29430298 TI - Macronutrient manipulations of cheese resulted in lower energy content without compromising its satiating capacity. AB - Manipulation of food's macronutrient composition in order to reduce energy content without compromising satiating capacity may be helpful in body weight control. For cheeses, substituting fat with protein may provide such opportunity. We aimed at examining the acute effect of cheeses with different macronutrient compositions on accumulated energy intake and subjective appetite sensation. A total of thirty-nine normal-weight (average BMI 24.4 kg/m2) men and women completed the partly double-blind, randomised crossover study with high protein/low-fat (HP/LF, 696 kJ), high-protein/high-fat (HP/HF, 976 kJ) and low protein/high-fat (LP/HF, 771 kJ) cheeses. After overnight fasting, 80 g cheese were served with 70 g bread, 132 g juice and 125 g coffee/tea/water. Ad libitum spaghetti bolognaise was served after 3 h and energy intake assessed. Subjective appetite ratings were assessed using visual analogue scales. Composite appetite scores were calculated and evaluated relatively to energy intake. Total accumulated energy intake was 188.3 (se 97.4) kJ lower when consuming the HP/LF compared with the HP/HF (P <= 0.05), but, compared with the LP/HF cheese, the difference was not significant (177.0 (se 100.4) kJ lower; P = 0.08). In relation to energy intake, the composite appetite score was lower when consuming the HP/LF compared with the HP/HF (P = 0.003) and the LP/HF (P = 0.007) cheeses. Thereby, no compensatory eating following consumption of the HP/LF compared with the HP/HF cheese was found. The HP/LF cheese resulted in an increased feeling of satiety in relation to its lower energy content compared with both HP/HF and LP/HF cheeses. PMID- 29430299 TI - Serum carotenoids and macular pigment optical density in patients with intestinal resections and healthy subjects: an exploratory study. AB - Reduced absorption capacity in patients with intestinal resections (IR) could result in malabsorption of fat-soluble components like carotenoids, which are of clinical interest in relation to visual health. In this case cohort, we investigated the association between IR and serum lutein, zeaxanthin, beta carotene and macular pigment optical density, when compared with healthy controls. Ten patients with IR and twelve healthy controls were included in the study. Baseline characteristics were comparable between groups, except for higher serum TAG (P < 0.05) and shorter bowel length (P < 0.0001) in the group with IR. Serum lutein, zeaxanthin, beta-carotene and macular pigment optical density were >15 % lower in the patient group compared with healthy controls (P < 0.05, adjusted for age) and, in the case of serum lutein and zeaxanthin, also for dietary intake of carotenoids. Results suggest that for a test of macular carotenoid supplementation, subjects with a potentially clinically significant carotenoid deficit could be recruited among patients with IR. PMID- 29430301 TI - L-carnitine Derived Zwitterionic Betaine Materials. AB - An L-carnitine derived zwitterionic betaine material was developed. The synthesized L-carnitineMA was the first zwitterionic betaine monomer from natural feedstocks. In the models of Surface coating and hydrogel, the L-carnitineMA material was able to achieve superior anti-fouling performance as good as state of-the-art zwitterionic betaine materials. PMID- 29430302 TI - Impact of the Synthesis Method on the Solid-State Charge Transport of Radical Polymers. AB - There are conflicting reports in the literature about the presence of room temperature conductivity in poly(2,2,6,6-tetramethylpiperidinyloxy methacrylate) (PTMA), a redox active polymer with radical groups pendent to an insulating backbone. To understand the variability in the findings across the literature and synthetic methods, we prepared PTMA using three living methods - anionic, ATRP and RAFT polymerization. We find that all three synthetic methods produce PTMA with radical yields of 70 - 80%, controlled molecular weight, and low dispersity. Additionally, we used on-chip EPR to probe the robustness of radical content in solid films under ambient air and light, and found negligible change in the radical content over time. Electrically, we found that PTMA is highly insulating conductivity in the range 10-11 S/cm - regardless of the synthetic method of preparation. These findings provide greater clarity for potential applications of PTMA in energy storage. PMID- 29430303 TI - Modulating the Catalytic Activity of Enzyme-like Nanoparticles Through their Surface Functionalization. AB - The inclusion of transition metal catalysts into nanoparticle scaffolds permits the creation of catalytic nanosystems (nanozymes) able to imitate the behaviour of natural enzymes. Here we report the fabrication of a family of nanozymes comprised of bioorthogonal ruthenium catalysts inserted in the protective monolayer of gold nanoparticles. By introducing simple modifications to the functional groups at the surface of the nanozymes, we have demonstrated control over the kinetic mechanism of our system. Cationic nanozymes with hydrophobic surface functionalities tend to replicate the classical Michaelis Menten model, while those with polar groups display substrate inhibition behaviour, a key mechanism present in 20 % of natural enzymes. The structural parameters described herein can be used for creating artificial nanosystems that mimic the complexity observed in cell machinery. PMID- 29430300 TI - Responsive Hybrid (Poly)peptide-Polymer Conjugates. AB - (Poly)peptide-polymer conjugates continue to garner significant interest in the production of functional materials given their composition of natural and synthetic building blocks that confer select and synergistic properties. Owing to opportunities to design predefined architectures and structures with different morphologies, these hybrid conjugates enable new approaches for producing micro- or nanomaterials. Their modular design enables the incorporation of multiple responsive properties into a single conjugate. This review presents recent advances in (poly)peptide-polymer conjugates for drug-delivery applications, with a specific focus on the utility of the (poly)peptide component in the assembly of particles and nanogels, as well as the role of the peptide in triggered drug release. PMID- 29430304 TI - All nurses need to be research nurses. AB - Introduction: Nurses are critical to the research enterprise. However all nurses are not prepared to participate as members of the research team since education and training in clinical research nursing and nurse-specific Good Clinical Practice are not consistently included in nursing curricula. The lack of nurse education and training in clinical research and Good Clinical Practice leaves research participants vulnerable with a nursing workforce that is not prepared to balance fidelity to protocol and patient quality care and safety. Methods: A collaborative network of nurses within Clinical and Translational Science Awards and beyond was established to address this education and training need. Over a 2 year period, using expert opinion, Delphi methods, and measures of validity and reliability the team constructed curriculum and knowledge test items. Results: A pilot modular electronic curriculum, including knowledge pretest and post-tests, in clinical research nursing and nurse-specific Good Clinical Practice competencies was developed. Conclusions: As the scope and setting of clinical research changes, it is likely that all practicing nurses, regardless of their practice setting or specialty, will care for patients on research protocol, making all nurses, in essence, clinical research nurses. The curriculum developed by this protocol will address that workforce education and training need. PMID- 29430306 TI - A Pilot Study of Immune Activation and Rifampin Absorption in HIV-Infected Patients without Tuberculosis Infection: A Short Report. AB - Background: Rifampin malabsorption is frequently observed in tuberculosis patients coinfected with human immunodeficiency virus (HIV) but cannot be predicted by patient factors such as CD4+ T cell count or HIV viral load. Methods: We sought to describe the relationship between HIV-associated immune activation, measures of gut absorptive capacity and permeability, and rifampin pharmacokinetic parameters in a pilot study of 6 HIV-infected, tuberculosis uninfected patients who were naive to antiretroviral therapy. Results: The median rifampin area under the concentration-versus-time curve during the 8-hour observation period was 42.8 mg.hr/L (range: 21.2 to 57.6), with a median peak concentration of 10.1 mg/L (range: 5.3 to 12.5). We observed delayed rifampin absorption, with a time to maximum concentration greater than 2 hours, in 2 of 6 participants. There was a trend towards increased plasma concentrations of sCD14, a marker of monocyte activation in response to bacterial translocation, among participants with delayed rifampin absorption compared to participants with rapid absorption (p = 0.06). Conclusions: Delayed rifampin absorption may be associated with elevated markers of bacterial translocation among HIV-infected individuals naive to antiretroviral therapy. This trial is registered with NCT01845298. PMID- 29430305 TI - Nonsurgical Procedures for Keratoconus Management. AB - Objectives: To describe the past 20 years' correction modalities for keratoconus and their visual outcomes and possible complications. Methods: A review of the published literature related to the visual outcomes and possible complications in the context of keratoconus management using nonsurgical procedures for the last 20 years (glasses and contact lenses) was performed. Original articles that reported the outcome of any correction modalities of keratoconus management were reviewed. Results: The most nonsurgical procedure used on keratoconus management is the contact lens fitting. Soft contact lenses and soft toric contact lenses, rigid gas-permeable contact lenses, piggyback contact lens system, hybrid contact lenses, and scleral and corneoscleral contact lenses form the contemporary range of available lens types for keratoconus management with contact lenses. All of them try to restore the vision, improve the quality of life, and delay surgical procedures in patients with this disease. Complications are derived from the intolerance of using contact lens, and the use of each depends on keratoconus severity. Conclusions: In the context of nonsurgical procedures, the use of contact lenses for the management of keratoconic patients represents a good alternative to restore vision and improve the quality of live in this population. PMID- 29430307 TI - Pre- and Postintervention Factor Structure of Functional Independence Measure in Patients with Spinal Cord Injury. AB - Objective: To evaluate the factor structure of Functional Independence Measure (FIM(r)) scale amongst people with spinal cord injury (SCI). Methods: This was a retrospective, register-based cohort study on 155 rehabilitants with SCI. FIM was assessed at the beginning and at the end of multidisciplinary inpatient rehabilitation. The internal consistency of the FIM was assessed with Cronbach's alpha and exploratory factor analysis was employed to approximate the construct structure of FIM. Results: The internal consistency demonstrated high Cronbach's alpha of 0.95 to 0.96. For both pre- and postintervention assessments, the exploratory factor analysis resulted in 3-factor structures. Except for two items ("walking or using a wheelchair" and "expression"), the structures of the identified three factors remained the same from the beginning to the end of rehabilitation. The loadings of all items were sufficient, exceeding 0.3. Both pre- and postintervention chi-square tests showed significant p values < 0.0001. The "motor" domain was divided into two factors with this 2-factor structure enduring through the intervention period. Conclusions: Amongst rehabilitants with SCI, FIM failed to demonstrate unidimensionality. Instead, it showed a 3-factor structure that fluctuated only little depending on the timing of measurement. Additionally, when measured separately, also motor score was 2-dimensional, not 1 dimensional. Using a total or subscale FIM, scores seem to be unjustified in the studied population. PMID- 29430308 TI - Anomalous Coronary Artery Origin in a Young Patient with Marfan Syndrome. AB - Marfan syndrome is an autosomal dominant genetic disorder that affects connective tissue and is caused by mutations in the fibrillin 1 gene present at chromosome 15. Aortic aneurysm is its main complication, and along the dilation of the aorta root and its descending portion (60-100%), with secondary aortic insufficiency, it increases risk of acute aortic dissection and death. Coronary artery anomalies affect between 0.3% and 1.6% of the general population and are the second leading cause of sudden death in young adults, especially if the anomalous coronary passes through aorta and pulmonary artery. The anomalous origin of the left main coronary artery in the right Valsalva sinus has a prevalence of 0.02%-0.05% and is commonly related to other congenital cardiac anomalies, such as transposition of great vessels, coronary fistulas, bicuspid aortic valve, and tetralogy of Fallot. Its association with Marfan syndrome is not known, and there is no previous report in the literature. We describe here a case of a female with Marfan syndrome diagnosed with symptomatic anomalous origin of the left coronary artery in the right Valsalva sinus. PMID- 29430309 TI - A Case of Disseminated Hypopigmented Keratoses Improved with Oral Acitretin. AB - Disseminated hypopigmented keratosis is a distinct clinical entity and only few cases have been reported so far. Here, we present a 21-year-old man with almost 10-year history of hypopigmented, nonfollicular, keratotic lichenoid papules occurring on the extensor surfaces of the extremities, back and lumber region. Histopathological examination showed orthohyperkeratosis, irregular acanthosis, and sporadic papillomatosis with a normal amount of melanin and number of melanocytes. In addition, no marked inflammation or melanophages were seen. In order to exclude other possible causes, we performed laboratory tests and radiological examination which were all found to be normal. As the clinical and histopathological features of our patient were taken into account, it was considered to be compatible with the diagnosis of disseminated hypopigmented keratoses. So far, only topical therapies have been used with failure in the previously reported cases except one patient. Considering the extensive lesions, we treated the present patient with 5% salicylic acid in addition to oral acitretin and significant regression in all lesions was achieved, particularly on the keratosis. PMID- 29430310 TI - Morphological Transformation of Myeloma Cells into Multilobated Plasma Cell Nuclei within 7 Days in a Case of Secondary Plasma Cell Leukemia That Finally Transformed as Anaplastic Myeloma. AB - A 48-year-old man was diagnosed with multiple myeloma (IgG-k) and was treated with high-dose dexamethasone as an induction therapy followed by thalidomide based regimens. Approximately 22 months after the initial diagnosis, the patient developed secondary plasma cell leukemia (PCL) with a white blood cell (WBC) count of 20.2 * 109/L including 79.5% plasma cells. A G-banding chromosomal analysis in the bone marrow showed an t(11;14) abnormality of up to 5%, which was not detected at initial diagnosis. We immediately started bortezomib and dexamethasone therapy, but in just 7 days, the WBC count elevated to 48.5 * 109/L, and approximately 95% of them were medium-sized atypical lymphoid cells with multilobated nuclei. Although we subsequently initiated alternative regimens, the patient's condition deteriorated, and he died 4 months after developing PCL. Approximately 2 months before his death, the diameter of myeloma cells in the bone marrow enlarged by approximately twofold, and pleomorphic nuclei were present, indicating an anaplastic myeloma transformation. Concurrently, a 100% increase of the t(11;14) clone frequency was observed in the G-banding-analyzed bone marrow cells. Morphological transformation of myeloma cells into multilobated plasma cell nuclei can be considered as the starting point of the sequential process leading to anaplastic myeloma. PMID- 29430311 TI - Transvaginal Management of Vaginal Cuff Dehiscence with Bowel Evisceration following Delayed Diagnosis. AB - One of the most serious complications that can arise from hysterectomy is vaginal cuff dehiscence with subsequent bowel evisceration. Treatment via vaginal approach has been utilized in early cases of vaginal cuff dehiscence where the need for bowel resection is less likely. Our case examines the treatment of vaginal cuff dehiscence through a vaginal approach approximately 36 hours after apparent vaginal dehiscence with subsequent bowel evisceration. In this case, we chose a vaginal approach even in the setting of possible bowel obstruction and a significant leukocytosis. We utilized CT scan findings to help guide our surgical approach. Although the subjective appearance of the bowel protruding through the vaginal cuff was reassuring, this played little role in guiding our decision with regard to surgical approach. Vaginal cuff dehiscence with evisceration can be managed successfully via a vaginal approach even with prolonged exposure of the bowel to vaginal flora. CT scan should be utilized to evaluate bowel integrity when considering a vaginal dehiscence repair. A high index of suspicion is warranted as these cases can present up to many years after hysterectomy. PMID- 29430312 TI - Extreme Anemia (Hemoglobin 1.8 g/dL) Secondary to Abnormal Uterine Bleeding. AB - We present the case of a 39-year-old G5P5 woman who presented to the emergency department with complaints of shortness of breath, lightheadedness, and excessive uterine bleeding for 14 days, with a heart rate of 123 and a blood pressure of 137/65. Menses had been heavy for several months. A hemoglobin of 1.8 g/dL was discovered. An ultrasound revealed an 11.8 cm fibroid uterus, and the patient was transfused with 6 units of blood and placed on oral contraceptive pills. PMID- 29430313 TI - Atypical Amniotic Fluid Embolism Managed with a Novel Therapeutic Regimen. AB - Amniotic fluid embolism (AFE) is the second leading cause of maternal mortality in the USA with an incidence of 1 : 15,200 births. The case fatality rate and perinatal mortality associated with AFE are 13-30% and 9-44%, respectively. This rare but devastating complication can be difficult to diagnose as many of the early signs and symptoms are nonspecific. Compounding this diagnostic challenge is a lack of effective treatment regimens which to date are mostly supportive. We present the case of a 26-year-old woman who suffered from suspected AFE and was successfully treated with the novel regimen of Atropine, Ondansetron, and Ketorolac (A-OK). The authors acknowledge that this case does not meet the new criteria proposed, by Clark in 2016, but feel that it is important to share this case report, due to dramatic patient response to the provided supportive therapy presented in this case report. We hope this case report will prompt further research into this novel approach to treating AFE with Atropine, Ondansetron, and Ketorolac. PMID- 29430314 TI - Cilioretinal Artery Occlusion Combined with Central Retinal Vein Occlusion: What Is the Best Imaging Modality for the Follow-Up? AB - We report retinal structural changes of a 37-year-old man diagnosed with the concomitant occlusion of cilioretinal artery and central retinal vein. Comprehensive ophthalmological evaluation was performed, followed by spectral domain optical coherence tomography (SD-OCT, Heidelberg), optical coherence tomography angiography (OCT angiography, Optovue Inc., Fremont, California, USA), fluorescein angiography, and color fundus photography. The use of OCT angiography and en face SD-OCT imaging as an adjunct test to map out correlative paracentral scotomas during follow-up allowed us to evaluate cilioretinal artery occlusion in the best way due to obtaining satisfactory images of the normal retinal vascular networks and areas of nonperfusion and congestion at various retinal levels. PMID- 29430315 TI - Structural Failure of a Modern Knee Tumor Megaendoprosthesis. AB - Modular knee megaendoprotheses are commonly used devices for distal femur or proximal tibia replacement in tumor surgery as well as for treatment of some periprosthetic fractures around a loose or failed total knee arthroplasty. Structural failures of the prosthesis are well-known postoperative complications and have been reported for various prosthesis types. In the majority of the cases, the polyethylene parts fail. We would like to present an unusual case of a broken femoral component of an MRH(r) endoprosthesis four years after implantation. PMID- 29430316 TI - Neonatal Pneumopericardium in a Nonventilated Term Infant: A Case Report and Review of the Literature. AB - Neonatal pneumopericardium (PPC) is a rare form of neonatal air leak syndrome with high morbidity and mortality. Air leak syndrome in the newborn is usually associated with active resuscitation, respiratory distress syndrome, meconium aspiration syndrome, mechanical ventilation, or trauma associated with labour. Neonatal PPC can be associated with other air leak syndromes such as pneumomediastinum, pneumothorax, pneumoperitoneum, and subcutaneous and interstitial emphysema. Spontaneous PPC is a rare event in the neonatal period. We report a case of PPC in association with pneumothorax in a nonventilated term infant. The infant responded to thoracocentesis without the need for pericardiocentesis. PMID- 29430317 TI - Bowel Resection and Ileotransverse Anastomosis as Preferred Therapy for 15 Typhoid Ileal Perforations and Severe Peritoneal Contamination in a Very Elderly Patient. AB - Typhoid ileal perforation (TIP) is the most lethal complication of typhoid fever. Although TIP is a surgical emergency by consensus, there is still much controversy regarding the most appropriate surgical approach to be used. Bowel exteriorization and secondary closure are usually recommended for patients presenting late with multiple TIPs and heavy peritoneal soiling. We, however, discuss a unique case of an 86-year-old patient with 15 typhoid ileal perforations successfully treated with one-step surgery comprising bowel resection and ileotransverse anastomosis in a resource-constrained setting of Cameroon. PMID- 29430318 TI - Testicular Inflammatory Myofibroblastic Tumor: A Known Entity at a Very Rare Site. AB - Inflammatory myofibroblastic tumors (IMT) are distinctive lesions of unknown etiology, composed of myofibroblastic spindle cells with an associated inflammatory background. They can occur in a wide age range and at all anatomic sites, but most frequently they can be observed in the lung (especially in pediatric cases), abdomen, or retroperitoneum. The urinary bladder is one of the most common sites in urological cases. We present a very rare case of IMT of the testis. Clinically, a 40-year-old patient showed a palpable painless lesion of the right testis. Ultrasound examination showed two solid intratesticular foci. During surgical intervention, the intraoperative frozen section revealed mesenchymal tumors admixed with an uncommon inflammatory infiltrate, consistent with a reorganized abscess. Despite the benign result, orchiectomy was performed due to the multifocal presentation and the large size of 3 cm. The final diagnosis was IMT without ALK-rearrangement. Incomplete resection increases the risk of local relapses to 30%. In this case, a complete resection could be achieved and the patient is free of tumor 15 months later. PMID- 29430319 TI - Prostatic Utricle Cyst as the Most Likely Cause in a Case of Recurrent Episodes of Hematospermia. AB - Hematospermia is a clinical symptom that raises anxiety in patients and has various causes, benign and malignant. We report a case of hematospermia for which appropriate multidisciplinary expertise favored a conservative management of a benign prostatic cyst, namely, a prostatic utricle cyst. A cystic lesion found by transrectal ultrasound in the context of hematospermia related to masturbation in a young virgin male patient was investigated with a high-field magnetic resonance imaging (MRI) and an endorectal coil. The association of high-field MRI and endorectal coil leads to high quality images. PMID- 29430320 TI - Recurrent Stroke after Transcatheter PFO Closure in Cryptogenic Stroke or Tia: Long-Term Follow-Up. AB - Background: There are few data on the mechanism of recurrent neurological events after transcatheter closure of patent foramen ovale (PFO) in cryptogenic stroke or TIA. Methods: We retrospectively reviewed PFO closure procedures for the secondary prevention of cryptogenic stroke/TIA performed between 1999 and 2014 in Bologna, Italy. Results: Written questionnaires were completed by 402 patients. Mean follow-up was 7 +/- 3 years. Stroke recurred in 3.2% (0.5/100 patients-year) and TIA in 2.7% (0.4/100 patients-year). Ninety-two percent of recurrent strokes were not cryptogenic. Recurrent stroke was noncardioembolic in 69% of patients, AF related in 15% of patients, device related in 1 patient, and cryptogenic in 1 patient. AF was diagnosed after the procedure in 21 patients (5.2%). Multivariate Cox's proportion hazard model identified age >= 55 years at the time of closure (OR 3.16, p=0.007) and RoPE score < 7 (OR 3.21, p=0.03) as predictors of recurrent neurological events. Conclusion: Recurrent neurological events after PFO closure are rare, usually noncryptogenic and associated with conventional vascular risk factors or AF related. Patients older than 55 years of age and those with a RoPE score < 7 are likely to get less benefit from PFO closure. After transcatheter PFO closure, lifelong strict vascular risk factor control is warranted. PMID- 29430321 TI - Interaction between stress responses and circadian metabolism in metabolic disease. AB - Circadian rhythms play crucial roles in orchestrating diverse physiological processes that are critical for health and disease. Dysregulated circadian rhythms are closely associated with various human metabolic diseases, including type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Modern lifestyles are frequently associated with an irregular circadian rhythm, which poses a significant risk to public health. While the central clock has a set periodicity, circadian oscillators in peripheral organs, particularly in the liver, can be entrained by metabolic alterations or stress cues. At the molecular level, the signal transduction pathways that mediate stress responses interact with, and are often integrated with, the key determinants of circadian oscillation, to maintain metabolic homeostasis under physiological or pathological conditions. In the liver, a number of nuclear receptors or transcriptional regulators, which are regulated by metabolites, hormones, the circadian clock, or environmental stressors, serve as direct links between stress responses and circadian metabolism. In this review, we summarize recent advances in the understanding of the interactions between stress responses (the endoplasmic reticulum (ER) stress response, the oxidative stress response, and the inflammatory response) and circadian metabolism, and the role of these interactions in the development of metabolic diseases. PMID- 29430322 TI - Monitoring inflammatory bowel disease during pregnancy: Current literature and future challenges. AB - Inflammatory bowel disease has a high prevalence in women of childbearing age and can have a significant impact on pregnancy, from conceiving to carrying the pregnancy. Active disease during pregnancy is known to have negative effects on pregnancy outcomes; therefore, careful monitoring during this period is an important but challenging aspect of care and is crucial as it affects important management decisions. Recent data seems to suggest that endoscopy is a relatively safe procedure during all trimesters of pregnancy. Serum biomarkers such as C reactive protein and fecal calprotectin are helpful non-invasive markers, but have shown conflicting results for correlation with disease activity in some initial studies. Further work is necessary to establish standard of care monitoring during pregnancy. PMID- 29430323 TI - Declining use of combination infliximab and immunomodulator for inflammatory bowel disease in the community setting. AB - AIM: To describe trends of combination therapy (CT) of infliximab (IFX) and immunomodulator (IMM) for inflammatory bowel disease (IBD) in the community setting. METHODS: A retrospective study was conducted of all IBD patients referred for IFX infusion to our community infusion center between 04/01/01 and 12/31/14. CT was defined as use of IFX with either azathioprine, 6 mercaptopurine, or methotrexate. We analyzed trends of CT usage overall, for Crohn's disease (CD) and ulcerative colitis (UC), and for the subgroups of induction patients. We also analyzed the trends of CT use in these groups over the study period, and compared the rates of CT use prior to and after publication of the landmark SONIC trial. RESULTS: Of 258 IBD patients identified during the 12 year study period, 60 (23.3%) received CT, including 35 of 133 (26.3%) induction patients. Based on the Cochran-Armitage trend test, we observed decreasing CT use for IBD patients overall (P < 0.0001) and IBD induction patients, (P = 0.0024). Of 154 CD patients, 37 (24.68%) had CT, including 20 of 77 (26%) induction patients. The Cochran Armitage test showed a trend towards decreasing CT use for CD overall (P < 0.0001) and CD induction, (P = 0.0024). Overall, 43.8% of CD patients received CT pre-SONIC vs 7.4% post-SONIC (P < 0.0001). For CD induction, 40.0% received CT pre-SONIC vs 10.8% post-SONIC (P = 0.0035). Among the 93 patients with UC, 19 (20.4%) received CT. Of 50 induction patients, 14 (28.0%) received CT. The trend test of the 49 patients with a known year of induction again failed to demonstrate any significant trends in the use of CT (P = 0.6). CONCLUSION: We observed a trend away from CT use in IBD. A disconnect appears to exist between expert opinion and evidence favoring CT with IFX and IMM, and evolving community practice. PMID- 29430324 TI - Erratum for factors associated with visceral fat accumulation in the general population in Okinawa, Japan (World J Gastrointest Pharmacol Ther 2016; 7: 261 267). AB - [This corrects the article on p. 261 in vol. 7, PMID: 27158542.]. PMID- 29430325 TI - [Minimally invasive extraforaminal lumbar interbody fusion]. AB - Objectives: The objective of the present study was to determine the indications, surgical technique, results, and complications of minimally invasive extraforaminal lumbar interbody fusion (ELIF). Introduction: ELIF is characterized as removal of the superior articular process (SAP) to access the intra-canalicular root and disc through Kambin's triangle. Methods: A retrospective study was conducted of 40 patients operated upon between 2013 and 2015. Patients with low back pain or root pain due to degenerative disc disease, spondylolisthesis grade 1 and 2, recurrent disc herniation, and recess-foraminal stenosis were included. A visual analogue scale (VAS), the Oswestry index, the Weiner scale and the modified MacNab criteria were used to assess pain, clinical and functional results and patient satisfaction one year after surgery. Complications were documented and rated according to their severity, in four degrees. Results: We operated on 25 women and 15 men of average age 57 years. Of the forty, 47.5% were treated for spondylolisthesis, 25% by recess foraminal stenosis. In total, 54 interbody cages and 188 percutaneous pedicle screws were placed; and the mean duration of surgery was 245 (+/-25.4) minutes. The mean hospitalization time was 3.5 (+/-0.49) days. We observed nine Grade 1 and one Grade 2 complication. The mean preoperative ODI score was 51.9 +/- 4.96, which improved to 12.2 +/- 3.19 at one year (P < 0.0001). The mean VAS low back pain rating improved from 8.81 +/- 0.62 to 2.12 +/- 0.89 (P < 0.0001). By one year post-operatively, 77.5% of the patients had fusion (Bridwell grade 1 or 2). Conclusions: ELIF is a safe and effective surgical approach. Satisfactory clinical outcomes, comparable to traditional techniques, can be achieved with facet resection limited to the superior articular process. PMID- 29430326 TI - [Adult Grisel Syndrome and Cervical Skull instability. Transnasal endoscopic odontoidectomy and occipito-cervical fusion. Case report and literature review]. AB - Background: Craniocervical junction pathology is infrequent in daily neurosurgical practice. In general, most of these lesions are of traumatic or rheumatic origin. Atlantoaxial instability of inflammatory origin (Grisel syndrome) is a rare entity of which only 16 adult cases have been reported in the literature. This pathology is characterized by the development of an osteolytic lesion at the level of the atlantoaxial joint after an infectious event, usually of the upper airways. Case Description: We present the case of a 76-year-old patient who attended our office for clinical symptoms of spinal instability secondary to an osteolytic lesion, with involvement of C1 and C2. The symptomatology began after an infectious respiratory process. A posterior cervical occiput fixation and an endoscopic transnasal odontoidectomy with anterior decompression were performed. The patient evolved with complete resolution of symptoms. The cultures were negative, and the pathological anatomy study concluded nonspecific inflammatory changes. Conclusion: Until a few years ago, the only option to address this pathology was the transoral pathway with microsurgical technique. Nowadays, endoscopy offers many technical advantages. This is an option to be considered when planning approaches to craniocervical junction. PMID- 29430327 TI - [Mild head injury]. AB - Introduction: Mild traumatic brain injury (TBI) represents a major health concern, because a sizeable number of patients with mild TBI will develop potentially life-threatening complications. The target of this study was to describe a large series of adult patients suffering from mild TBI, treated at University Hospital of Getafe, between 2010 and 2015 (n = 2480). We examined the patients' epidemiological and baseline clinical profile, diagnosis, treatment and ultimate outcomes, to identify major prognostic factors that influence the final result. Methods: We retrospectively extracted patient data from medical records and performed both bivariate and multivariate statistics. Results: In our sample, mild TBI was more common in men, and the most common causative mechanism was a traffic accident. We proposed a model for classifying patients according to risk, dividing them into low, intermediate and high risk, based upon their baseline clinical picture. This classification scheme correlated well with final outcomes. We investigated indications for skull radiography and computed tomography (CT), as well as for hospital admission for clinical observation. Conclusions: In this study, the presence of a neurological focus on clinical examination, the existence of a fracture on plain radiographs, advanced age and the presence of a coagulation disorder were associated with the increased likelihood of intracranial complications and a poor prognosis. The Glasgow Coma Scale was deficient predicting patient outcomes, because it failed to account for concussion-related symptoms like amnesia and loss of consciousness, both very common in patients with mild TBI. PMID- 29430328 TI - [Invasive sinonasal papilloma with intracranial invasion: Case report and bibliographic review]. AB - Introduction: Inverted papilloma is a locally-aggressive benign neoplasm of the paranasal sinuses with a high potential for recurrence and malignancy. Intracranial extension is infrequent, and dural penetration even more so, typically associated with recurrence of the disease or its degeneration into squamous cell carcinoma. Clinical Case: A 32-year-old female patient consulted us for an exophytic lesion in her right nostril and exophthalmos, associated with headache, anosmia and dysgeusia. Craniofacial and brain CT and brain MRI demonstrated a lesion in the right nostril, extending into the aerial sinuses, orbital lateral wall and anterior fossa, with osteolysis and intracranial invasion towards the right frontal region. A mass effect and brain compression were noted. A histological diagnosis of inverted papilloma was made initially. Upon later resection of the lesion by double access, with reconstruction of the anterior cranial fossa, a definitive diagnosis was made of inverted papilloma of the Schneiderian type, with areas of atypical transformation in situ. Post operatively, the patient has had a favorable course, with full upper airway patency and neither complications nor signs of recurrence after four years of follow-up. Conclusions: Intracranial invasion of this pathology is extremely uncommon. When it exists, the tumor has a high potential for local recurrence. Consequently, complete excision of the lesion determines the patient's prognosis. PMID- 29430329 TI - [Spino-pelvic sagittal parameters in an asymptomatic population in Argentina]. AB - Objectives: To assess and describe spinal and pelvic sagittal parameters in a series of 100 Argentinian volunteers. Methods: Lateral full-spine X-rays were obtained prospectively from 100 volunteers (30 males and 70 females), average age 34.1 years. All the volunteers were asymptomatic at the time of the study. Full length left lateral spine radiographs (36'' cassette) were made using Kodak Elite CR equipment. The authors made determinations for the digital X-rays using Surgimap(r), version 2.2.9.9.2. The following parameters were recorded: C7 SVA, C2-C7 CL, TK, LL, TPA, T1SPi, PI, PT, SS, L4-S1 angle, L1-L4 angle, PI-LL mismatch and CTPA. The data were analyzed using Medcalc 11.2 software. Descriptive statistics were calculated for each parameter according to its own measure score and distribution. Estimates of 95% reference and confidence intervals were calculated for each parameter. P = 0.05 was set as the threshold for statistical significance. Volunteers were classified using the Roussouly morphometric classification system. Results: Respective means for the above listed variables were: CL -10.04, TK 30.14, T1SPi -6.5, L1-L4 -12.45, L4-S1 46.16, CTPA 2.5, TPA 4.65, PT 11.22, PI 48.04, LL -59. 10, PI-LL -11.11, C7 SVA mm -23.68. Plus/minus two standard deviations (SD) for the variables were: CL ( 33.26, 13.12); TK (17.15, 43.30); T1SPi (-11.78, -1.25), L1-L4 (-25.55, 0.25), L4 S1 (-64.44, -27.55), CTPA (0.33, 4.80), TPA (-8.64, 18.22), PT (-1.99, 24.75), PI (25.23, 71.44), LL (-78.74, -39.89), PI-LL (-29.10, 7.04), and C7 SVA mm (-79.45, 32.08). Conclusions: In this prospective series of 100 adult volunteers, normal values for spinal and pelvic sagittal parameters were determined in Argentinian adults. PMID- 29430330 TI - MOLIERE: Automatic Biomedical Hypothesis Generation System. AB - Hypothesis generation is becoming a crucial time-saving technique which allows biomedical researchers to quickly discover implicit connections between important concepts. Typically, these systems operate on domain-specific fractions of public medical data. MOLIERE, in contrast, utilizes information from over 24.5 million documents. At the heart of our approach lies a multi-modal and multi-relational network of biomedical objects extracted from several heterogeneous datasets from the National Center for Biotechnology Information (NCBI). These objects include but are not limited to scientific papers, keywords, genes, proteins, diseases, and diagnoses. We model hypotheses using Latent Dirichlet Allocation applied on abstracts found near shortest paths discovered within this network, and demonstrate the effectiveness of MOLIERE by performing hypothesis generation on historical data. Our network, implementation, and resulting data are all publicly available for the broad scientific community. PMID- 29430331 TI - An Active Alkali-Exchanged Faujasite Catalyst for p-Xylene Production via the One Pot Diels-Alder Cycloaddition/Dehydration Reaction of 2,5-Dimethylfuran with Ethylene. AB - The one-pot Diels-Alder cycloaddition (DAC)/dehydration (D) tandem reaction between 2,5-dimethylfuran and ethylene is a potent pathway toward biomass-derived p-xylene. In this work, we present a cheap and active low-silica potassium exchanged faujasite (KY, Si/Al = 2.6) catalyst. Catalyst optimization was guided by a computational study of the DAC/D reaction mechanism over different alkali exchanged faujasites using periodic density functional theory calculations complemented by microkinetic modeling. Two types of faujasite models were compared, i.e., a high-silica alkali-exchanged faujasite model representing isolated active cation sites and a low-silica alkali-exchanged faujasite in which the reaction involves several cations in the proximity. The mechanistic study points to a significant synergetic cooperative effect of the ensemble of cations in the faujasite supercage on the DAC/D reaction. Alignment of the reactants by their interactions with the cationic sites and stabilization of reaction intermediates contribute to the high catalytic performance. Experiments confirmed the prediction that KY is the most active catalyst among low-silica alkali exchanged faujasites. This work is an example of how the catalytic reactivity of zeolites depends on multiple interactions between the zeolite and reagents. PMID- 29430332 TI - Catalytic Activity of an Iron-Based Water Oxidation Catalyst: Substrate Effects of Graphitic Electrodes. AB - The synthesis, characterization, and electrochemical studies of the dinuclear complex [(MeOH)Fe(Hbbpya)-MU-O-(Hbbpya)Fe(MeOH)](OTf)4 (1) (with Hbbpya = N,N bis(2,2'-bipyrid-6-yl)amine) are described. With the help of online electrochemical mass spectrometry, the complex is demonstrated to be active as a water oxidation catalyst. Comparing the results obtained for different electrode materials shows a clear substrate influence of the electrode, as the complex shows a significantly lower catalytic overpotential on graphitic working electrodes in comparison to other electrode materials. Cyclic voltammetry experiments provide evidence that the structure of complex 1 undergoes reversible changes under high-potential conditions, regenerating the original structure of complex 1 upon returning to lower potentials. Results from electrochemical quartz crystal microbalance experiments rule out that catalysis proceeds via deposition of catalytically active material on the electrode surface. PMID- 29430333 TI - An Assessment of Five (PANSS, SAPS, SANS, NSA-16, CGI-SCH) commonly used Symptoms Rating Scales in Schizophrenia and Comparison to Newer Scales (CAINS, BNSS). AB - Scales measuring positive and negative symptoms in schizophrenia remain the primary mo Scales measuring positive and negative symptoms in schizophrenia remain the primary mode of assessing and diagnosing schizophrenia by clinicians and researchers. The scales are mainly used to monitor the severity of positive and negative symptoms and track treatment response in schizophrenics. Although these scales are widely used, quality as well as general utility of each scale varies. The quality is determined by the validity and reliability of the scales. The utility of the scale is determined by the time of administration and the settings for which the scales can be administered in research or clinical settings. There are relatively fewer articles on the utility of newer scales like CAINS (Clinical Assessment Interview for Negative Symptoms) and the BNSS (Brief Negative Symptom Scale) that compare them to the older scales PANSS (Positive and Negative Symptoms Scale), SAPS (Scale for the Assessment of Positive Symptoms) SANS (the Scale for the Assessment of Negative Symptoms), NSA-16 (Negative Symptom Assessment-16) and CGI-SCH (Clinical Global Impression Schizophrenia. The older scales were developed more than 30 years ago. Since then, our understanding of negative symptoms has evolved and currently there are newer rating scales evaluating the validity of negative symptoms. The older scales do not incorporate the latest research on negative symptoms. CAINS and BNSS are attractive for both their reliability and their concise accessible format, however, a scale that is simpler, accessible, user-friendly, that incorporates a multidimensional model of schizophrenia, addresses the psychosocial and cognitive component has yet to be developed. PMID- 29430334 TI - New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production. AB - Patients with systemic lupus erythematosus (SLE) often have elevated levels of type I interferon (IFN, particularly IFNalpha), a cytokine that can drive many of the symptoms associated with this autoimmune disorder. Additionally, the presence of autoantibody-secreting plasma cells contributes to the systemic inflammation observed in SLE and IFNalpha supports the survival of these cells. Current therapies for SLE are limited to broad immunosuppression or B cell-targeting antibody-mediated depletion strategies, which do not eliminate autoantibody secreting plasma cells. Recent clinical trials testing the efficacy of IFNalpha neutralization in SLE have delivered disappointing results, with primary endpoints not being met or with minimal improvements, while studies evaluating antibody therapy targeting the type I IFN receptor was more successful and is currently being tested in phase III clinical studies. As many studies have supported the idea that plasmacytoid dendritic cells (pDCs) are the main source of IFNalpha in SLE, specifically targeting pDCs in SLE represents a new therapeutic option. Murine models suggest pDC ablation effectively ameliorates or reduces lupus-like disease development in spontaneous models of lupus and pre clinical and phase I clinical trials support the safety of such a therapy in humans. Here we review animal studies and the current status of clinical trials targeting IFNalpha, type I interferon receptor and pDCs in SLE. PMID- 29430335 TI - THz imaging system for in vivo human cornea. AB - Terahertz (THz) imaging of corneal tissue water content (CTWC) is a proposed method for early, accurate detection and study of corneal diseases. Despite promising results from ex vivo and in vivo cornea studies, interpretation of the reflectivity data is confounded by the contact between corneal tissue and rigid dielectric window used to flatten the imaging field. This work develops a novel imaging system and image reconstruction methods specifically for nearly spherical targets such as human cornea. A prototype system was constructed using a 650 GHz multiplier source and Schottky diode detector. Resolution and imaging field strength measurement from characterization targets correlate well with those predicted by the quasioptical theory and physical optics analysis. Imaging experiments with corneal phantoms and ex vivo corneas demonstrate the hydration sensitivity of the imaging system and reliable measurement of CTWC. We present successful acquisition of non-contact THz images of in vivo human cornea, and discuss strategies for optimizing the imaging system design for clinical use. PMID- 29430336 TI - Influence of Bile Acids on Colorectal Cancer Risk: Potential Mechanisms Mediated by Diet - Gut Microbiota Interactions. AB - Purpose of review: To review the evidence for the tumorigenic effects of food stimulated bile acids on the colon and interaction with the gut microbiota. Recent Findings: High-fat diets promote the hepatic synthesis of bile acids and increase their delivery to the colonic lumen. Here, they stimulate the growth and activity of 7alpha-dehydroxylating bacteria, which convert primary into secondary bile acids that show tumorigenic activity, especially deoxycholic acid (DCA). Fecal levels of secondary bile acids correlate with mucosal and metabolic markers of colorectal cancer (CRC) risk in high and low risk adult individuals and can be modified within a few weeks by dietary change. While gut bacteria regulate the bile acid pool via complex microbial biotransformation, bile acids alter the gut microbiota composition due to their antimicrobial properties. This mutual reaction induces altered bile acid pools and dysbiotic compositions of the gut microbiota that may show tumor-promoting activity of bile acids beyond their conversion to DCA. Summary: Bile acids act as tumor promoters in the colon. Diet and the gut microbiota are most likely the key drivers that mediate and confer bile acid-associated tumorigenic activity. Bacterial conversion of bile acids in the colon has a significant impact on their tumorigenic activity, substantiating the hypothesis that diet affects CRC risk through its effects on colonic microbial metabolism. PMID- 29430337 TI - Nerve Fiber Flux Analysis Using Wide-Field Swept-Source Optical Coherence Tomography. AB - Purpose: To devise a method to quantify nerve fibers over their arcuate courses over an extended peripapillary area using optical coherence tomography (OCT). Methods: Participants were imaged with 8 * 8-mm volumetric OCT scans centered at the optic disc. A new quantity, nerve fiber flux (NFF), represents the cross sectional area transected perpendicular to the nerve fibers. The peripapillary area was divided into 64 tracks with equal flux. An iterative algorithm traced the trajectory of the tracks assuming that the relative distribution of the NFF was conserved with compensation for fiber connections to ganglion cells on the macular side. Average trajectory was averaged from normal eyes and use to calculate the NFF maps for glaucomatous eyes. The NFF maps were divided into eight sectors that correspond to visual field regions. Results: There were 24 healthy and 10 glaucomatous eyes enrolled. The algorithm converged on similar patterns of NFL tracks for all healthy eyes. In glaucomatous eyes, NFF correlated with visual field sensitivity in the arcuate sectors (Spearman rho = 0.53-0.62). Focal nerve fiber loss in glaucomatous eyes appeared as uniform tracks of NFF defects that followed the expected arcuate fiber trajectory. Conclusions: Using an algorithm based on the conservation of flux, we derived nerve fiber trajectories in the peripapillary area. The NFF map is useful for the visualization of focal defects and quantification of sector nerve fiber loss from wide-area volumetric OCT scans. Translational Relevance: NFF provides a cumulative measure of volumetric loss along nerve fiber tracks and could improve the detection of focal glaucoma damage. PMID- 29430338 TI - Test-Retest Reproducibility of the Microperimeter MP3 With Fundus Image Tracking in Healthy Subjects and Patients With Macular Disease. AB - Purpose: To evaluate the test-retest reproducibility of a novel microperimeter with fundus image tracking (MP3, Nidek Co, Japan) in healthy subjects and patients with macular disease. Methods: Ten healthy subjects and 20 patients suffering from range of macular diseases were included. After training measurements, two additional microperimetry measurements were scheduled. Test retest reproducibility was assessed for mean retinal sensitivity, pointwise sensitivity, and deep scotoma size using the coefficient of repeatability and Bland-Altman diagrams. In addition, in a subgroup of patients microperimetry was compared with conventional perimetry. Results: Average differences in mean retinal sensitivity between the two study measurements were 0.26 +/- 1.7 dB (median 0 dB; interquartile range [IQR] -1 to 1) for the healthy and 0.36 +/- 2.5 dB (median 0 dB; IQR -1 to 2) for the macular patient group. Coefficients of repeatability for mean retinal sensitivity and pointwise retinal sensitivity were 1.2 and 3.3 dB for the healthy subjects and 1.6 and 5.0 dB for the macular disease patients, respectively. Absolute agreement in deep scotoma size between both study days was found in 79.9% of the test loci. Conclusion: The microperimeter MP3 shows an adequate test-retest reproducibility for mean retinal sensitivity, pointwise retinal sensitivity, and deep scotoma size in healthy subjects and patients suffering from macular disease. Furthermore, reproducibility of microperimetry is higher than conventional perimetry. Translational Relevance: Reproducibility is an important measure for each diagnostic device. Especially in a clinical setting high reproducibility set the basis to achieve reliable results using the specific device. Therefore, assessment of the reproducibility is of eminent importance to interpret the findings of future studies. PMID- 29430339 TI - Union Status, Educational Attainment, and Body Mass Index Among Emerging Adults. AB - This study uses fixed-effects regression modeling and three waves of data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to examine whether union status and educational attainment interact to influence change in body mass index (BMI) during emerging adulthood. The results support the hypothesis that the effect of union status on change in BMI is smaller for those with more educational attainment. In particular, emerging adults with no college education experience significant increases in BMI associated with both marriage and cohabitation. The increases in BMI associated with marriage and cohabitation are significantly smaller for those with some college education-but are still somewhat present. Among emerging adults with college degrees, however, involvement in cohabitation/marriage is not associated with increases in BMI at all. Potential explanations for this pattern of results and suggestions for future research are discussed. PMID- 29430340 TI - Laccase/Mediator Systems: Their Reactivity toward Phenolic Lignin Structures. AB - Laccase-mediator systems (LMS) have been widely studied for their capacity to oxidize the nonphenolic subunits of lignin (70-90% of the polymer). The phenolic subunits (10-30% of the polymer), which can also be oxidized without mediators, have received considerably less attention. Consequently, it remains unclear to what extent the presence of a mediator influences the reactions of the phenolic subunits of lignin. To get more insight in this, UHPLC-MS was used to study the reactions of a phenolic lignin dimer (GBG), initiated by a laccase from Trametes versicolor, alone or in combination with the mediators HBT and ABTS. The role of HBT was negligible, as its oxidation by laccase occurred slowly in comparison to that of GBG. Laccase and laccase/HBT oxidized GBG at a comparable rate, resulting in extensive polymerization of GBG. In contrast, laccase/ABTS converted GBG at a higher rate, as GBG was oxidized both directly by laccase but also by ABTS radical cations, which were rapidly formed by laccase. The laccase/ABTS system resulted in Calpha oxidation of GBG and coupling of ABTS to GBG, rather than polymerization of GBG. Based on these results, we propose reaction pathways of phenolic lignin model compounds with laccase/HBT and laccase/ABTS. PMID- 29430341 TI - High Rate Biomethanation of Carbon Monoxide-Rich Gases via a Thermophilic Synthetic Coculture. AB - Carbon monoxide-fermenting microorganisms can be used for the production of a wide range of commodity chemicals and fuels from syngas (generated by gasification of, e.g., wastes or biomass) or industrial off-gases (e.g., from steel industry). Microorganisms are normally more resistant to contaminants in the gas (e.g., hydrogen sulfide) than chemical catalysts, less expensive and self regenerating. However, some carboxydotrophs are sensitive to high concentrations of CO, resulting in low growth rates and productivities. We hypothesize that cultivation of synthetic cocultures can be used to improve overall rates of CO bioconversion. As a case study, a thermophilic microbial coculture, consisting of Carboxydothermus hydrogenoformans and Methanothermobacter thermoautotrophicus was constructed to study the effect of cocultivation on conversion of CO-rich gases to methane. In contrast to the methanogenic monoculture, the coculture was able to efficiently utilize CO or mixtures of H2/CO/CO2 to produce methane at high efficiency and high rates. In CSTR-bioreactors operated in continuous mode, the coculture converted artificial syngas (66.6% H2:33.3% CO) to an outflow gas with a methane content of 72%, approaching the 75% theoretical maximum. CO conversion efficiencies of 93% and volumetric production rates of 4 m3methane/m3liquid/day were achieved. This case shows that microbial cocultivation can result in a significant improvement of gas-fermentation of CO-rich gases. PMID- 29430344 TI - High yield production of folates from soybean callus cultures in response to elicitors. AB - Soybean (Indian variety, JS 335) callus growth and its folate content was sustained on Murashige and Skoog (MS) medium supplemented with optimized levels of auxins and cytokinins. Callus cultures exhibited moderate production of total folate. Callus growth was stimulated with highest biomass content of 21.3 g/L DW (24 days culture) on medium supplemented with 1.5 mg/L 2,4-dichlorophenoxy acetic acid (2,4-D) and 0.1 mg/L Kinetin (Kn). Total folate production was enhanced by an increase in indole-3-acetic acid (IAA) from 0.5 to 1.0 mg/L and decreased thereafter up to 1.5 mg/L. 2,4-D at 1.5 mg/L repressed the callus growth and also folate production. A concentration of 1.0 mg/L IAA and 0.2 mg/L Kn elicited folate production to a maximum total folate content of 323.82 ug/100 g DW. The results indicate that optimized medium for callus suspension cultures conceivably are applied for scale-up studies in bioreactors. PMID- 29430343 TI - Molecular marker of high glycyrrhizic acid content based on the SNPs of liquorice IPT gene. AB - Previous studies found that cytokinins (CTKs) are able to significantly promote glycyrrhizic acid (GA) accumulation. This study analyzed the correlation between the contents of GA and CTKs in 98 one-year-old liquorice plants by the combination of high-performance liquid chromatography and enzyme-linked immunosorbent assay. The full length of the liquorice IPT gene was cloned and the Single-nucleotide polymorphisms (SNPs) of the IPT gene in the samples were obtained. The molecular marker of high GA content was found by performing correlation analysis on the SNPs of the IPT gene. Results indicated that the contents of GA and CTKs were positively correlated. The full-length sequence of the IPT gene was 1002 bps, and five SNPs were found in the 98 liquorice samples. One of five SNPs was 348 bps, exhibiting missense mutation and the rest displaying synonymous mutations. In the five SNPs, 348 bps was primarily associated SNP, whereas 821 and 848 bps were auxiliary associated SNP. The findings of this study provided insight into the molecular mechanism of GA genetic variation, serving as basis for improving the GA content in cultivated liquorice and the good varieties breeding. PMID- 29430342 TI - Molecular structure and catalytic mechanism of fungal family G acidophilic xylanases. AB - Industrial applications of xylanases have made this enzyme an important subject of applied research work. Function of this particular enzyme is to degrade or hydrolyze the plentiful polysaccharide xylan, an important component of hemicellulose. It mainly cleaves the backbone of xylan that is made up of a number of xylose residues connected with beta-1,4-glycosidic linkages. Fungi with mycelia are regarded as the best producer of xylanases. These varied xylanases not only differ in their sizes and shapes but also differ in their physicochemical properties. Depending on the optimum pH in which they work best, they have been classified into (1) acidophilic xylanases active at low pH or acidic pH range, (2) alkaliphilic xylanases that are active at high or alkaline pH range and (3) neutral xylanases having pH optima in the neutral range between pH 5 and 7. Other researchers have classified the xylanases also on the basis of their structural properties, kinetic parameters, etc. This review discusses the molecular structures of some acidophilic xylanases and the molecular basis of low pH optima observed for their activities. It also discusses their unique catalytic mechanism and actual role of the catalytic residues found in them. Apart from these, the review also discusses different applications of these acidophilic xylanases in different industries. The article concludes with brief suggestions about how these acidophilic xylanases can be created employing the techniques of genetic engineering and concepts of synthetic evolution, using the traits of the known acidophilic xylanases discussed in the review. PMID- 29430345 TI - Design of peptide-based epitope vaccine and further binding site scrutiny led to groundswell in drug discovery against Lassa virus. AB - Lassa virus (LASV) is responsible for an acute viral hemorrhagic fever known as Lassa fever. Sequence analyses of LASV proteome identified the most immunogenic protein that led to predict both T-cell and B-cell epitopes and further target and binding site depiction could allow novel drug findings for drug discovery field against this virus. To induce both humoral and cell-mediated immunity peptide sequence SSNLYKGVY, conserved region 41-49 amino acids were found as the most potential B-cell and T-cell epitopes, respectively. The peptide sequence might intermingle with 17 HLA-I and 16 HLA-II molecules, also cover 49.15-96.82% population coverage within the common people of different countries where Lassa virus is endemic. To ensure the binding affinity to both HLA-I and HLA-II molecules were employed in docking simulation with suggested epitope sequence. Further the predicted 3D structure of the most immunogenic protein was analyzed to reveal out the binding site for the drug design against Lassa Virus. Herein, sequence analyses of proteome identified the most immunogenic protein that led to predict both T-cell and B-cell epitopes and further target and binding site depiction could allow novel drug findings for drug discovery field against this virus. PMID- 29430346 TI - Identification and molecular characterization of Dof transcription factor gene family preferentially expressed in developing spikes of Eleusine coracana L. AB - We report 48 putative DNA binding with one finger (Dof) TF genes from genome and transcriptome data of finger millet (Eleusine coracana L.; FM), involved in plant developmental process. To characterize seed-specific Dof genes, transcript profiles of 32 EcDof identified from transcriptome data of developing spikes of FM genotypes were further analyzed in different tissues (root, stem, and leaf) and developmental stages of spikes (S1, S2, S3, and S4) in two FM genotypes [GE1437 (low protein genotype; LPG) and GE3885 (high protein genotype; HPG)]. More than 50% of identified EcDof genes showed expression during seed development processes. Among these, seven genes (EcDof 3, EcDof 5, EcDof 15, EcDof 18, EcDof 22, EcDof 23, and EcDof 31) expressed maximally at specific stages of seed development. Fourteen EcDof genes showed that differential transcript accumulation in vegetative tissue as well as in developing spikes suggests involvement during seed filling and also throughout the plant development. In addition, three EcDof genes (EcDof 9, EcDof 25, and EcDof 28) expressed preferentially at root and stem tissue. The 3D structural prediction of EcDof proteins showed variability in structural attributes. Molecular docking results showed strong binding affinity for seed-specific EcDof-EcO2 with alpha-prolamine promoters. The identified and characterized EcDof genes will help to dissect the roles of FM seed-specific Dof genes. PMID- 29430347 TI - Carica papaya (Papaya) latex: a new paradigm to combat against dengue and filariasis vectors Aedes aegypti and Culex quinquefasciatus (Diptera: Culicidae). AB - This study manifests the larvicidal efficacy of Carica papaya latex extract and silver nanoparticles (CPAgNPs) synthesized using latex, against developing immature juveniles of Aedes aegypti and Culex quinquefasciatus. Briefly, the latex was collected and fractioned with different solvents such as chloroform, methanol and aqueously. The obtained crude extracts were subjected to larvicidal activity in the dose-dependent method. After 24 h, the mortality rate was calculated and statistically analyzed. From the results, it was demonstrated that the chloroform extract displayed prominent activity in IInd and IIIrd instar larvae of A. aegypti and C. quinquefasciatus with better LC50 values followed by methanol and aqueous extract. Subsequently, we profiled the qualitative analysis of a chloroform extract through biochemical tests; Fourier transform infrared spectroscopy and gas chromatography-mass spectrometry. Moreover, we authenticated the major secondary metabolites and activated larvicidal compound present in the extract. Further, we synthesized CPAgNPs using aqueous latex extract and challenged with IInd and IIIrd instar larvae of A. aegypti and C. quinquefasciatus. Noticeably, the synthesized nanoproducts were showed 100% mortality in a 24-h treatment with significant LC50 values. Hence, this study has opened up new vistas in the field of parasitological research to develop Carica papaya latex as a new stratagem in the insect vector management program. PMID- 29430348 TI - Purification and biochemical characterization of an extracellular beta-d fructofuranosidase from Aspergillus sp. AB - This study focused on the purification and characterization of an extracellular beta-d-fructofuranosidase or invertase from Aspergillus sojae JU12. The protein was purified by size exclusion chromatography with 5.41 fold and 10.87% recovery. The apparent molecular mass of the enzyme was estimated to be ~ 35 kDa using SDS PAGE and confirmed by deconvoluted mass spectrometry. The fungal beta-d fructofuranosidase was suggested to be a monomer by native PAGE and zymography, and was found to be a glycoprotein possessing 68.92% carbohydrate content. The products of enzyme hydrolysis were detected by thin layer chromatography and revealed the monosaccharide units, d-glucose and d-fructose. beta-d fructofuranosidase showed enhanced activity at broad pH 4.0-9.0 and activity at a temperature range from 30 to 70 degrees C, while the enzyme was stable at pH 8.0 and 40 degrees C, respectively. The beta-d-fructofuranosidase activity was lowered by metal ion inhibitors Ag2+ and Hg2+ whereas elevated by SDS and beta ME. The fungal beta-d-fructofuranosidase was capable of hydrolyzing d-sucrose and the kinetics were determined by Lineweaver-Burk plot with Km of 10.17 mM and Vmax of 0.7801 umol min-1. Additionally, the extracellular beta-d-fructofuranosidase demonstrated tolerance to high ethanol concentrations indicating its applicability in the production of alcoholic fermentation processes. PMID- 29430349 TI - beta-Ecdysterone accumulation and regulation in Ajuga multiflora Bunge suspension culture. AB - Ajuga multiflora Bunge cells contain beta-ecdysterone (beta-EC) that regulates the molting process of insect larvae. In this study, different conditions of culture have been studied to optimize the production of beta-EC. A. multiflora Bunge growth fitted the curve of logistic equation with one growth cycle of 17 days. The electric conductivity of medium had a negative correlation with not only the weight of dry cell but also the beta-EC accumulation, and thus, could be used for monitoring the peak of both cell growth and beta-EC accumulation. The pH value of the culture medium varied from 4.67 to 5.84 and reached the maximum at the end of the culture (on the 17th day). The relation of cell growth and nutrient consumption in A. multiflora Bunge cell suspension culture was distinctly correlated. Continuous subculture caused a reduction in beta-EC synthesis; passages 7-15, the beta-EC content declined (p < 0.05). At passage 11, the beta-EC content was only 42.72% of that at passage 5. Additives such as mevalonic acid (MVA), l-phenylalanine (l-Phe), alpha-pinene, terpineol, and nitric oxide (NO) in the suspension culture medium, could significantly promote the cell growth and stimulate beta-EC accumulation. The optimal concentrations of l-Phe, MVA, terpineol, and alpha-pinene were 0.2 mmol/l, 10 mg/l, 1 mmol/l and 6 mmol/l, respectively, with the beta-EC concentrations as 1.914 +/- 0.1948 mg/g (p < 0.01), 6.012 +/- 0.4252 mg/g (p < 0.01), 5.147 +/- 0.4819 mg/g (p < 0.01), 2.801 +/- 0.1253 mg/g (p < 0.01), respectively. The optimal concentration of sodium nitroprusside, the provider of NO, was 3 mmol/l with the beta-EC concentration 2.87 +/- 0.2493 mg/g (p < 0.01). The results offer a strategy for massive production of beta-EC. PMID- 29430350 TI - Bioactive properties of Chamaerops humilis L.: antioxidant and enzyme inhibiting activities of extracts from leaves, seeds, pulp and peel. AB - In this work we evaluated methanolic extracts from different parts (leaves, seeds, fruit peel and pulp) of Chamaerops humilis L. for antioxidant activity and the ability to inhibit enzymes linked with neurodegenerative diseases: acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase (TYR). The total content of phenolics, flavonoids and condensed tannins was also determined. The antioxidant and inhibitory activities of the extracts varied significantly according to the tissue. Seed extracts showed the greatest ability to scavenge DPPH (IC50 = 81.28 ug mL-1) and ABTS (1440.42 umolTE [Formula: see text]) and to reduce iron (1142.46 umolAAE [Formula: see text]). Seed and peel extracts strongly inhibited AChE (IC50 = 660.16 and 653.68 ug mL-1, respectively) and BChE (IC50 = 304.86 and 701.54 ug mL-1, respectively). The strongest inhibition of TYR was achieved by the seed and pulp extracts (268.97 and 279.99 ug mL-1, respectively). The highest levels of phenolics and condensed tannins were found in the seed extract (1564.88 umolGAE [Formula: see text] and 170.00 umolcE [Formula: see text], respectively) whereas the leaf extract was the richest in flavonoids (139.88 umolQE [Formula: see text]). HPLC-DAD analysis indicated the presence of flavonoids and phenolic acids (hydroxycinnamic acids) in the leaf and pulp extracts. A high correlation was found between the total condensed tannins content and the antioxidant and enzyme inhibition activities, suggesting these compounds are responsible for the biological activity of the extracts. Overall, our results indicate that C. humilis extracts may provide a new and alternative source of agents for medical and industrial applications. PMID- 29430351 TI - Salt stress relief potency of whortleberry extract biopriming in maize. AB - Berries have gained public attention for their presumed positive effects on cancer patients. In contrast, the potential of berries to mitigate damage caused by abiotic stress in plants has not received significant attention. This is the first quantitative analysis of the efficacy of Vaccinium arctostaphylos L. (Ericaceae) fruit extract (VAFE) used to bioprime maize to limit damage caused by salt stress. Salt stressed maize seedlings exhibit lower quantum efficiency of photosystem II (Fv/Fm) and photosynthetic pigment content relative to untreated controls however, Fv/Fm increase caused by VAFE was found marginal. VAFE biopriming limited pigment loss and increased levels of antioxidant enzymes. It improved the growth of salt stressed seedlings by reducing salt-induced biomass loss, damage to roots and shoots, lipid oxidation, proline synthesis and endogenous hydrogen peroxide concentrations. In sum, VAFE biopriming may provide a new approach to improve yields in soils containing high salt levels as an alternative to traditional agricultural practice. PMID- 29430352 TI - Purification and characterization of fibrinolytic enzyme from a bacterium isolated from soil. AB - A novel extracellular enzyme with strong fibrinolytic activity, produced by Bacillus tequilensis, which was isolated from the soil of Zhuhai City (China) was purified and characterized. The enzyme was secreted by cultured B. tequilensis in solid state and purified at a high efficiency using the combination of salting out, ion exchange chromatography, and size exclusion chromatography. The enzyme was estimated to have a molecular weight of approximately 27 kDa, pI of 8.9 +/- 0.1, to stable at pH 5.0-12.0 and up to 50 degrees C; the optimum pH and temperature are 10.5 and 45 degrees C (2373.59 +/- 54.81 U/mg), respectively. The fibrinolytic activity was enhanced by K+, Na+, Mg2+, Mn2+, Ca2+, and Ba2+ and inhibited by Cu2+, Zn2+, and Fe3+. Moreover, the activity was slightly enhanced by PMSF and EDTA at low concentrations and inhibited by beta-mercaptoethanol. The N-terminal amino acid sequence is AQSVPYGISQI. The enzyme has a higher enzymatic activity than most other fibrinolytic enzymes. The high thermal stability indicated that it is easy to preserve and could be activated under high temperature conditions. PMID- 29430354 TI - Identification of a monopartite begomovirus associated with yellow vein mosaic of Mentha longifolia in Saudi Arabia. AB - Mentha is a very important crop grown and used extensively for many purposes in the Kingdom of Saudi Arabia. Begomoviruses are whitefly-transmitted viruses causing serious disease in many important plants exhibiting variable symptoms with significant economic loss globally. During farmers' field survey, yellow vein mosaic disease was observed in Mentha longifolia plants growing near tomato fields in Saudi Arabia. The causative agent was identified in 11 out of 19 samples using begomovirus-specific primers and the association of begomovirus with yellow vein mosaic disease in M. longifolia was confirmed. The full-length viral genome and betasatellite were amplified, cloned, and sequenced bidirectionally. The full DNA-A genome was found to have 2785 nucleotides with 1365 bp-associated betasatellite molecule. An attempt was made to amplify DNA-B, but none of the samples produced any positive amplicon of expected size which indicated the presence of monopartite begomovirus. The sequence identity matrix and phylogenetic analysis, based on full genome showed the highest identity (99.6%) with Tomato yellow leaf curl virus (TYLCV) and in phylogenetic analysis it formed a closed cluster with Tomato leaf curl virus infecting tomato and Corchorus crop in Saudi Arabia. The sequence analysis results of betasatellites showed the highest identity (98.9%) with Tomato yellow leaf curl betasatellites infecting tomato and phylogenetic analysis using betasatellites formed a close cluster with Tomato yellow leaf curl betasatellites infecting tomato and Corchorus crops, which has already been reported to cause yellow vein mosaic and leaf curl disease in many cultivated and weed crops growing in Saudi Arabia. The identified begomovirus associated with yellow vein mosaic disease in mentha could be a mutated strain of TYLCV and tentatively designated as TYLCV-Mentha isolate. Based on published data and latest information, this is the first report of identification of Tomato yellow leaf curl virus associated with yellow vein mosaic disease of M. longifolia from Saudi Arabia. PMID- 29430353 TI - Characterization of OglDREB2A gene from African rice (Oryza glaberrima), comparative analysis and its transcriptional regulation under salinity stress. AB - In this study, AP2 DNA-binding domain-containing transcription factor, OglDREB2A, was cloned from the African rice (Oryza glaberrima) and compared with 3000 rice genotypes. Further, the phylogenetic and various structural analysis was performed using in silico approaches. Further, to understand its allelic variation in rice, SNPs and indels were detected among the 3000 rice genotypes which indicated that while coding region is highly conserved, yet noncoding regions such as UTR and intron contained most of the variation. Phylogenetic analysis of the OglDREB2A sequence in different Oryza as well as in diverse eudicot species revealed that DREB from various Oryza species were diversed much earlier than other genes. Further, structural features and in silico analyses provided insights into different properties of OglDREB2A protein. The neutrality test on the coding region of OglDREB2A from different genotypes of O. glaberrima showed the lack of selection in this gene. Among the different developmental stages, it was upregulated at tillering and flag leaf under salinity treatment indicating its positive role in seedling and reproductive stage tolerance. Real time PCR analysis also indicated the conserve expression pattern of this gene under salinity stress across the three different Oryza species having different degree of salinity tolerance. PMID- 29430355 TI - Microbial communities associated with the co-metabolism of free cyanide and thiocyanate under alkaline conditions. AB - This study focused on the identification of free cyanide (CDO) and thiocyanate (TDO) degrading microbial communities using a culture-dependent and independent approach. Culturable microbial species were isolated from the CDOs (n = 13) and TDOs (n = 18). The CDOs were largely dominated by Bacillus sp. while the TDOs were dominated by Bacillus sp., Klebsiella oxytoca, Providencia sp. and Pseudomonas sp. However, 16S rRNA amplicon gene-sequencing revealed the complexity and diversity of the microbial communities in contrast to the organisms that were detected using culture-dependent technique. Overall, the organisms were mainly dominated by Myroides odoratimimus and Proteus sp. at 37.82 and 30.5% for CDOs, and 35.26 and 17.58% for TDOs, respectively. The co-culturing of the CDOs and TDOs resulted in biochemical changes of key metabolic enzymes, and this resulted in the complete degradation of CN- and SCN- simultaneously; a phenomenon which has not been witnessed, especially under alkaline conditions. Current ongoing studies are focused on the application of these organisms for the biodegradation of CN- and SCN- in a continuous system, under changing operational parameters, to assess their effectiveness in the biodegradation of CN- and SCN-. PMID- 29430356 TI - Preliminary molecular detection of the somatic embryogenesis receptor-like kinase (VpSERK) and knotted-like homeobox (VpKNOX1) genes during in vitro morphogenesis of Vanilla planifolia Jacks. AB - This work aimed to evaluate the embryogenic competence of different tissues from different stages (friable callus, bud-regenerating callus, and whole buds) of Vanilla planifolia, through the molecular detection of the somatic embryogenesis receptor-like kinase (VpSERK) and knotted-like homeobox (VpKNOX1) genes. RNA was extracted with Trizol(r), cDNA was obtained, and the studied transcripts were amplified. Using non-specific primers, VpSERK and VpSTM gene expression was detected in the three stages evaluated. This study might contribute to providing an explanation for the recalcitrance of this Vanilla species to somatic embryogenesis. PMID- 29430357 TI - Cross-genera transferability of rice and finger millet genomic SSRs to barnyard millet (Echinochloa spp.). AB - Barnyard millet (Echinochloa spp.) is an important crop from nutritional point of view, nevertheless, the genetic information is very scarce. In the present investigation, rice and finger millet genomic SSRs were used for assessing cross transferability, identification of polymorphic markers, syntenic regions, genetic diversity and population structure analysis of barnyard millet genotypes. We observed 100% cross transferability for finger millet SSRs, of which 91% were polymorphic, while 71% of rice markers were cross transferable with 48% polymorphic out of them. Twenty-nine and sixteen highly polymorphic finger millet and rice SSRs yielded a mean of 4.3 and 3.38 alleles per locus in barnyard millet genotypes, respectively. The PIC values varied from 0.27 to 0.73 at an average of 0.54 for finger millet SSRs, whereas it was from 0.15 to 0.67 at an average of 0.44 for rice SSRs. High synteny was observed for markers related to panicle length, yield-related traits, spikelet fertility, plant height, root traits, leaf senescence, blast and brown plant hopper resistance. Although the rice SSRs located on chromosome 10 followed by chromosome 6 and 11 were found to be more transferable to barnyard millet, the finger millet SSRs were more polymorphic and transferable to barnyard millet genotypes. These SSR data of finger millet and rice individually as well as combined together grouped the 11 barnyard millet genotypes into 2 major clusters. The results of population structure analysis were similar to cluster analysis. PMID- 29430358 TI - Comparative de novo transcriptome analysis of male and female Sea buckthorn. AB - Sea buckthorn is a dioecious medicinal plant found at high altitude. The plant has both male and female reproductive organs in separate individuals. In this article, whole transcriptome de novo assemblies of male and female flower bud samples were carried out using Illumina NextSeq 500 platform to determine the role of the genes involved in sex determination. Moreover, genes with differential expression in male and female transcriptomes were identified to understand the underlying sex determination mechanism. The current study showed 63,904 and 62,272 coding sequences (CDS) in female and male transcriptome data sets, respectively. 16,831 common CDS were screened out from both transcriptomes, out of which 625 were upregulated and 491 were found to be downregulated. To understand the potential regulatory roles of differentially expressed genes in metabolic networks and biosynthetic pathways: KEGG mapping, gene ontology, and co expression network analysis were performed. Comparison with Flowering Interactive Database (FLOR-ID) resulted in eight differentially expressed genes viz. CHD3 type chromatin-remodeling factor PICKLE (PKL), phytochrome-associated serine/threonine-protein phosphatase (FYPP), protein TOPLESS (TPL), sensitive to freezing 6 (SFR6), lysine-specific histone demethylase 1 homolog 1 (LDL1), pre mRNA-processing-splicing factor 8A (PRP8A), sucrose synthase 4 (SUS4), ubiquitin carboxyl-terminal hydrolase 12 (UBP12), known to be broadly involved in flowering, photoperiodism, embryo development, and cold response pathways. Male and female flower bud transcriptome data of Sea buckthorn may provide comprehensive information at genomic level for the identification of genetic regulation involved in sex determination. PMID- 29430359 TI - Kinetic study of gold nanoparticle mediated photocatalytic degradation of Victoria blue. AB - In the study, biogenic gold nanoparticles (AuNPs) were used for the photocatalytic degradation of triphenylmethane dyes Victoria blue B (VBB) and R (VBR). The process was found to result in an approximate degradation of 65 and 52%, respectively, for VBB and VBR within a period of 8 h. The relative rate of photocatalytic degradation of VBB and VBR was identified to be 0.0195 +/- 0.0031/min and 0.0295 +/- 0.0025/min, respectively, by using the Langmuir Hinshelwood model. By using the Vigna unguiculata model system, the degradation products were demonstrated to have non-toxic effect. Moreover, the less toxic nature of AuNPs used for dye removal highlights its feasibility for large-scale application. Hence, the AuNPs-based photocatalytic dye degradation as described in the study is cost-effective, rapid and environment-friendly. PMID- 29430361 TI - Influence of auxin and its polar transport inhibitor on the development of somatic embryos in Digitalis trojana. AB - The present study reports the role of auxin and its transport inhibitor during the establishment of an efficient and optimized protocol for the somatic embryogenesis in Digitalis trojana Ivan. Hypocotyl segments (5 mm long) were placed vertically in the Murashige and Skoog medium supplemented with three sets [indole-3-acetic acid (IAA) alone or 2,3,5-triiodobenzoic acid (TIBA) alone or IAA-TIBA combination] of formulations of plant growth regulators, to assess their differential influence on induction and proliferation of somatic embryos (SEs). IAA alone was found to be the most effective, at a concentration of 0.5 mg/l, inducing ~ 10 SEs per explant with 52% induction frequency. On the other hand, the combination of 0.5 mg/l of IAA and 1 mg/l of TIBA produced significantly fewer (~ 3.6 SEs) and abnormal (enlarged, oblong, jar and cup-shaped) SEs per explant with 24% induction frequency in comparison to that in the IAA alone. The explants treated with IAA-TIBA exhibited a delayed response along with the formation of abnormal SEs. Our study revealed that IAA induces high-frequency SE formation when used singly, but the frequency gradually declines when IAA was coupled with increasing levels of TIBA. Eventually, our findings bring new insights into the roles of auxin and its polar transport in somatic embryogenesis of D. trojana. PMID- 29430360 TI - Comparative study on the antileishmanial activities of chemically and biologically synthesized silver nanoparticles (AgNPs). AB - The present study was conducted to investigate the antileishmanial activity of biogenic silver nanoparticles (AgNPs) compared to chemically synthesized AgNPs. A nano dimension size (10-15 nm) biogenic AgNPs was produced and characterized by UV-Vis spectroscopy and X-rays diffraction. The chemically synthesized AgNPs was recovering from our previous study with a nanoparticle (NP) size in the range of 10-40 nm. The antileishmanial activities were investigated through 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. The infectivity was determined by Giemsa staining of the infected macrophages cells. Nitric oxide (NO) accumulation was measured by Griess reagent using NaNO2 as a positive control. After 24 h of exposure with nanoparticles (NPs), a concentration-dependent growth inhibition was observed. The IC50 values were determined against promastigotes of L. infantum as 19.42 +/- 2.76 ug/ml for leaves aqueous extract mediated AgNPs, 30.71 +/- 1.91 ug/ml for stem mediated AgNPs and 51.23 +/- 2.20 ug/ml for chemically synthesized AgNPs. It was also detected that all types of NPs produced NO at a significant level. However, the production of a high-level of NO in the biologically synthesized NPs activated macrophage cells, infected with L. infantum promastigotes indicates that NO radicals are mainly responsible for induced cell death and a decrease in the pathogenicity of the parasites. Since, biogenic nanoparticles are cost-effective, eco-friendly, simple to synthesize, and more effective than chemically synthesized silver nanoparticles, therefore, it could be used as a potential alternative for the development of antileishmanial drugs. PMID- 29430362 TI - Enhancement of gold and silver recovery from discarded computer printed circuit boards by Pseudomonas balearica SAE1 using response surface methodology (RSM). AB - Two-step bioleaching was applied using a cyanogenic bacterium Pseudomonas balearica SAE1 to recover gold (Au) and silver (Ag) from the computer printed circuit boards (CPCBs) via central composite design of a response surface methodology (CCD-RSM). To enhance Au and Ag recovery, factors like pH level, pulp density, temperature and glycine concentration were optimized and their interactions were studied. CCD-RSM optimization resulted in 73.9 and 41.6% dissolution of Au and Ag, respectively, at initial pH 8.6, pulp density 5 g/L, temperature 31.2 degrees C, and glycine concentration 6.8 g/L, respectively. Two quadratic models were proposed by RSM which can be utilized as an efficient tool to predict Au and Ag recovery through bioleaching. The experimental results are in line with the predicted results, indicating reliability of RSM model in enhancing the Au and Ag recovery from CPCBs. The increased bioleaching yield of Au and Ag from discarded CPCBs has its importance in industrial e-waste recycling and safe disposal. PMID- 29430363 TI - Optimization of gluco-amylase production from Aspergillus spp. for its use in saccharification of liquefied corn starch. AB - Fungal gluco-amylase is required for the production of sugars from starchy substrates. Commercially available fungal gluco-amylase is quite costly which makes the process uneconomical. This study was undertaken to standardize physico chemical parameters for optimum production of gluco-amylases from Aspergillus spp. Two fungal cultures, i.e., Aspergillus niger and Aspergillus terreus, were compared for gluco-amylase activity both under stationary and shake flask conditions. Among two fungal cultures, maximum gluco-amylase activity was shown by A. niger (243.09 U/ml) under stationary conditions as compared to A. terreus (126.34 U/ml). Gluco-amylase activity of A. niger increases by 42.48% from 243.09 to 346.35 U/ml after optimization using response surface methodology, whereby a substrate concentration of 7%, yeast extract 0.25%, temperature 32.5 degrees C and pH 5.5 were found to be optimum for gluco-amylase production. Crude enzyme was compared with commercial enzyme and it was found that when 500 U of Glucoamylase ex. Rhizopus were inoculated into starch-supplemented minimal media (SSMM) liquefied using 2 g of fungal diastase, it increases the reducing sugar concentration from 2.19 to 21.15 mg/ml and a saccharification efficiency of 77.7% was achieved, whereas 1.5 ml of crude enzyme (extracted from A. niger) was able to produce 14.46 mg/ml of reducing sugars with a saccharification efficiency of 53.2%. PMID- 29430364 TI - Daminozide reduces red color intensity in herbaceous peony (Paeonia lactiflora Pall.) flowers by inhibiting the expression of flavonoid biosynthetic genes. AB - Daminozide is a plant growth retardant that inhibits 2-oxoglutarate-dependent dioxygenase activity in the gibberellin biosynthesis pathway, but few studies have focused on its effect on the flavonoid biosynthesis pathway involved in flower color. In the present study, the effect of daminozide on the regulation of flower color was investigated. An herbaceous peony (Paeonia lactiflora Pall.) cultivar 'Fenzhu Pan' was used as the material and treated with daminozide. Color parameters of petals were measured; flavonoid composition and content as well as flavonoid biosynthetic gene expression were monitored. The results showed that daminozide treatment caused less red coloration in herbaceous peony. The content of total anthocyanins was decreased by 23%, and the content of total anthoxanthins was increased by 8%; thus, it appeared that less red coloration in daminozide-treated flowers was associated with restricted anthocyanin accumulation. Furthermore, the gene expression patterns of flavonoid 3' hydroxylase, dihydroflavonol 4-reductase and anthocyanidin synthase were lower after daminozide treatment, which could decrease anthocyanin accumulation and lead to less red coloration in flowers. These findings would improve our understanding of daminozide regulation of flower color in herbaceous peony. PMID- 29430365 TI - Bioactive compounds from mangrove derived rare actinobacterium Saccharomonospora oceani VJDS-3. AB - A rare actinobacterium was isolated from Nizampatnam mangrove ecosystem of Andhra Pradesh, India, and was screened for its ability to produce bioactive compounds. The potential strain was identified as Saccharomonospora oceani VJDS-3 by polyphasic taxonomy. Purification of the biologically active compounds by column chromatography led to the isolation of three compounds, namely methoxy ethyl cinnamate (ethyl(E)-3-(4-methoxyphenyl)acrylate) (R1), 4-hydroxy methyl cinnamate (methyl(E)-3-(4-hydroxyphenyl)acrylate) (R2) and 4-methylbenzoic acid (R3). The structure of the compounds was elucidated on the basis of spectroscopic analysis including FTIR, EIMS, 1HNMR and 13CNMR spectroscopies. The antimicrobial activity of the bioactive compounds produced by the strain was tested against a panel of bacteria and fungi, and expressed in terms of minimum inhibitory concentration. Compound (R1) exhibited higher antimicrobial potential (50 ug/ml) against Staphylococcus aureus, Bacillus megaterium and Candida albicans compared to R2 and R3. Antioxidant activity of compounds was determined by DPPH and ABTS radical scavenging activities. The results revealed that compound R3 effectively scavenged DPPH (73.08 +/- 1.29) and ABTS (99.74 +/- 0.00) radicals at a concentration of 25 and 50 ug/ml, respectively. Antidiabetic and anti-obesity activities were evaluated by inhibitory potential of compounds against alpha glucosidase, alpha-amylase and pancreatic lipase by spectrophotometric assays. Compound R1 showed effective inhibition against alpha-glucosidase (66.8 +/- 1.2) at 20 ug/ml while moderate to weak activities were found against alpha-amylase and pancreatic lipase. To the best of our knowledge, this is the first report on the isolation of supra said compounds from the genus Saccharomonospora. PMID- 29430366 TI - Morphological, pathological and mycotoxicological variations among Fusarium verticillioides isolated from cereals. AB - Among the 194 Fusarium verticillioides isolates screened from 127 cereal samples, 176 were fumonisin producers and others were non-producers. Representative nine Fusarium verticillioides strains along with one reference standard strain MTCC156 were selected to study their morphological, pathological and mycotoxicological variations by conventional and molecular approaches. Fusarium verticillioides strains FVM86, FVM146, FV200 and FVS3 showed significant pathogenicity and also in pigmentation production but varied in fumonisin production. Fusarium verticillioides strain FVP19 recorded variations in all the assays. Fusarium verticillioides strain FVM42 showed drastic phenotypic variation and it also produced fumonisin. Genetic variation among the strains was independent of geographic area of origin but depended on their ability to produce fumonisin. The strains were independent in their cultural characteristics, pigmentation production, pathogenicity assays, fumonisin production and in their genetic variability without having any correlation. PMID- 29430367 TI - Draft genome sequence of Penicillium chrysogenum strain HKF2, a fungus with potential for production of prebiotic synthesizing enzymes. AB - In this study, we have characterized a novel set of extracellular enzymes produced by Penicillium chrysogenum strain HKF2. A draft genome data of 31.5 Mbp was generated and annotation suggested a total of 11,243 protein-coding genes out of which 609 were CAZymes, majority of which were found to have homology with Penicillium rubens, Penicillium chrysogenum followed by Penicillium expansum and Penicillium roqueforti. The prominent CAZyme genes identified in the draft genome encoded for enzymes involved in the production of prebiotics such as inulo oligosaccharides and fructo-oligosaccharides. Corresponding enzyme assay indicated that the isolate possessed the potential to produce 11.8 and 3.8 U/mL of beta-fructofuranosidase and inulinase, respectively. This study highlights the significance of Effluent Treatment Plants as novel and under-explored niche for isolation of fungi having the potential for production of prebiotics synthesizing enzymes. PMID- 29430368 TI - Molecular and biochemical characterization of a thermostable keratinase from Bacillus altitudinis RBDV1. AB - A thermostable keratinase designated as KBALT was purified from Bacillus altitudinis RBDV1 from a poultry farm in Gujarat, India. The molecular weight of the native KBALT (nKBALT) purified using ammonium sulfate and ion exchange and gel permeation chromatography with a 40% yield and 80-fold purification was estimated to be ~ 43 kDa. The gene for KBALT was successfully cloned, sequenced and expressed in Escherichia coli. Recombinant KBALT (rKBALT) when purified using a single step Ni-NTA His affinity chromatography achieved a yield of 38.20% and a 76.4-fold purification. Comparison of the deduced amino acid sequence of rKBALT with known proteases of Bacillus species and inhibitory effect of PMSF suggest that rKBALT was a subtilisin-like serine protease. Both native and rKBALT exhibited higher activity at 85 degrees C and pH 8.0 in the presence of Mg2+, Mn2+, Zn2+, Ba2+ and Fe3+ metal ions. Interestingly, 70% of their activity was retained at temperatures ranging from 35 to > 95 degrees C. The keratinolytic activity of both nKBALT and rKBALT was enhanced in the presence of reducing agents. They exhibited broad substrate specificity towards various protein substrates. KBALT was determined for its kinetic properties by calculating its Km (0.61 mg/ml) and Vmax (1673 U/mg/min) values. These results suggest KBALT as a robust and promising contender for enzymatic processing of keratinous wastes in waste processing plants. PMID- 29430369 TI - Optimisation of culture composition for glyphosate degradation by Burkholderia vietnamiensis strain AQ5-12. AB - The herbicide glyphosate is often used to control weeds in agricultural lands. However, despite its ability to effectively kill weeds at low cost, health problems are still reported due to its toxicity level. The removal of glyphosate from the environment is usually done by microbiological process since chemical process of degradation is ineffective due to the presence of highly stable bonds. Therefore, finding glyphosate-degrading microorganisms in the soil of interest is crucial to remediate this glyphosate. Burkholderia vietnamiensis strain AQ5-12 was found to have glyphosate-degrading ability. Optimisation of biodegradation condition was carried out utilising one factor at a time (OFAT) and response surface methodology (RSM). Five parameters including carbon and nitrogen source, pH, temperature and glyphosate concentration were optimised. Based on OFAT result, glyphosate degradation was observed to be optimum at fructose concentration of 6, 0.5 g/L ammonia sulphate, pH 6.5, temperature of 32 degrees C and glyphosate concentration at 100 ppm. Meanwhile, RSM resulted in a better degradation with 92.32% of 100 ppm glyphosate compared to OFAT. The bacterium was seen to tolerate up to 500 ppm glyphosate while increasing concentration results in reduced degradation and bacterial growth rate. PMID- 29430370 TI - Genetic variability in selected date palm (Phoenix dactylifera L.) cultivars of United Arab Emirates using ISSR and DAMD markers. AB - Nine (9) different date palm (Phoenix dactylifera L.) cultivars from UAE, which differ in their flower timings were selected to determine the polymorphism and genetic relationship between these cultivars. Hereditary differences and interrelationships were assessed utilizing inter-simple sequence repeat (ISSR) and directed amplification of minisatellite DNA region (DAMD) primers. Analysis on eight DAMD and five ISSR markers produced total of 113 amplicon including 99 polymorphic and 14 monomorphic alleles with a polymorphic percentage of 85.45. The average polymorphic information content for the two-marker system was almost similar (DAMD, 0.445 and ISSR, 0.459). UPGMA based clustering of DAMD and ISSR revealed that mid-season cultivars, Mkh (Khlas) and MB (Barhee) grouped together to form a subcluster in both the marker systems. The genetic similarity analysis followed by clustering of the cumulative data from the DAMD and ISSR resulted in two major clusters with two early-season cultivars (ENg and Ekn), two mid-season cultivars (MKh and MB) and one late-season cultivar (Lkhs) in cluster 1, cluster 2 includes two late-season cultivars, one early-season cultivar and one mid season cultivar. The cluster analysis of both DAMD and ISSR marker revealed that, the patterns of variation between some of the tested cultivars were similar in both DNA marker systems. Hence, the present study signifies the applicability of DAMD and ISSR marker system in detecting genetic diversity of date palm cultivars flowering at different seasons. This may facilitate the conservation and improvement of date palm cultivars in the future. PMID- 29430371 TI - Drought stress impact on leaf proteome variations of faba bean (Vicia faba L.) in the Qinghai-Tibet Plateau of China. AB - Water scarcity is a major abiotic stress factor that strongly influences growth, development and yield of grain legumes in arid and semi-arid area of the world. Drought stress frequently occurs during the seedling stage and finally affects yield of faba bean (Vicia faba L.). However, the responses of plant leaf to drought have not been documented very well at the proteomic level. "Ga da dou" of the drought-tolerant faba bean cultivar was exposed to drought to examine the proteome changes of leaves. In this study, 2-week-old seedlings were subjected to water deficit by 7 days drought stress, whereas control plants were regularly irrigated. After withdrawing water, plants exposed to drought for 7 days and control plants at the same developmental stage were included in quantitative proteomic analysis using two-dimensional electrophoresis gels of proteins in combination with mass spectrometry. Over 300 proteins were detected by 2-DE, 50 differentially expressed proteins were detected by t test and 30 proteins were successfully identified by MALDI-TOF/TOF, in which 25 proteins were clearly downregulated and five proteins were upregulated. The quantified proteins were grouped into five functional groups, mainly regulatory proteins (46.7%), energy metabolism (23.3%), cell cytoskeleton (6.7%), other functions (20%) and unknown function (3.3%). Chitinase was upregulated under drought, suggesting that it was an important part of the plant defense system, playing an important role in stress resistance. 50S ribosomal protein was upregulated under drought, suggesting its role in protecting plants against stress by re-establishing normal protein conformations. The abundance of proteins involved in protein synthesis such as chitinase, Bet protein and glutamate-glyoxylate aminotransferase was upregulated under drought stress. These proteins could play important roles in drought tolerance and contribute to the relatively stronger drought tolerance of "Ga da dou". PMID- 29430372 TI - Analysis of differential transcript expression in chickpea during compatible and incompatible interactions with Fusarium oxysporum f. sp. ciceris Race 4. AB - The present study reports the transcriptome analysis of resistance (WR315) and susceptible (JG62) genotypes of chickpea in response to Fusarium oxysporum f. sp. ciceris (Foc) race 4 using the method of suppression subtractive hybridization. Altogether, 162 chickpea-expressed sequence tags (ESTs) were identified from two libraries and analyzed to catalog eight functional categories. These ESTs could be assembled into 18 contigs and 144 singletons with 10 contigs and 68 singletons from compatible and 8 contigs and 70 singletons from incompatible interaction. The largest category consisted of ESTs which encode for proteins related to hypothetical proteins (22.8%), followed by energy and metabolism (20.3%)-related genes, defense and cell rescue-related genes (17.9%) and signal transduction related genes (16%). Among them, 17.1 and 18.7% were defense-related genes in compatible and incompatible interaction, respectively. These ESTs mainly includes various putative genes related to oxidative burst, pathogenesis and secondary metabolism. Induction of putative superoxide dismutase, metallothionein, 4 coumarate-CoA ligase, heat shock proteins and cysteine proteases indicated oxidative burst after infection. The ESTs belonged to various functional categories which were directly and indirectly associated with defense signaling pathways. Quantitative and semi-quantitative polymerase chain reaction exhibited differential expression of candidate genes and detected higher levels in incompatible interaction compared to compatible interaction. The present study revealed partial molecular mechanism associated with the resistance in chickpea against Foc, which is the key to design a strategy for incorporation of resistance via either biotechnological means or introgression of resistance genes. PMID- 29430373 TI - Understanding the molecular basis of differential grain protein accumulation in wheat (Triticum aestivum L.) through expression profiling of transcription factors related to seed nutrients storage. AB - Increasing nutritional value of cereals is one of the important research and breeding objectives to overcome malnutrition in developing countries. The synthesis of grain seed proteins during grain filling is controlled by several mechanisms including transcriptional and posttranscriptional modifications. In the current investigation, transcript abundance analysis of three allelic variants of seed storage protein activator (Spa A, Spa B and Spa D) and NAM-B1 affecting seed nutrient concentration was carried out in two genotypes (UP 2672 and HS 540) of bread wheat differing in grain protein content. Expression profiling of transcription factor genes was performed using quantitative real time PCR (qRT-PCR). Positive correlation and significant p value > 0.05 was observed among the fold expression in developing stages of both the genotypes. Maximum expression of Spa genes was observed at S3 stage and maximum fold expression was observed for Spa B gene in case of UP 2672, the genotype with high protein content. The transcript profiling of NAM-B1 gene revealed threefold higher expression in UP 2672 than that of HS 490 at S4 stage. The findings revealed the role of transcriptional regulation in differential grain protein accumulation through varied expression and existence of their allelic variants in wheat genotypes. PMID- 29430374 TI - Synthesis of gold nanomaterials and their cancer-related biomedical applications: an update. AB - Recently, the advances in the synthesis of new types of nanomaterials have created several opportunities in drug delivery and targeted therapy applications. Among the various nanostructures, gold nanostructures with controllable physical and chemical properties have received attention for various biomedical uses, including sensing of biomolecules, in vitro and in vivo bioimaging (as advanced contrast agents for photothermal and bioimaging techniques), photothermolysis of cancer cells, and targeted drug delivery. The attractive properties of gold nanomaterials, particularly, anti-angiogenic properties, are highly useful in a variety of cancers studies. In addition, they can bind many proteins and drugs and can be actively targeted to cancer cells over-expressing cell surface receptors and they are biocompatible in nature with a high atomic number, which directs to greater absorption of kilovoltage X-rays and provides greater contrast than standard agents. In this review, we have summarized the synthesis, structure and functionalization of gold nanostructures, and their biomedical applications with special reference to cancer studies. PMID- 29430375 TI - Complete genome sequence of Bacillus velezensis 157 isolated from Eucommia ulmoides with pathogenic bacteria inhibiting and lignocellulolytic enzymes production by SSF. AB - Bacillus velezensis 157 was isolated from the bark of Eucommia ulmoides, and exhibited antagonistic activity against a broad spectrum of pathogenic bacteria and fungi. Moreover, B. velezensis 157 also showed various lignocellulolytic activities including cellulase, xylanase, alpha-amylase, and pectinase, which had the ability of using the agro-industrial waste (soybean meal, wheat bran, sugarcane bagasse, wheat straw, rice husk, maize flour and maize straw) under solid-state fermentation and obtained several industrially valuable enzymes. Soybean meal appeared to be the most efficient substrate for the single fermentation of B. velezensis 157. Highest yield of pectinase (19.15 +/- 2.66 U g 1), cellulase (46.69 +/- 1.19 U g-1) and amylase (2097.18 +/- 15.28 U g-1) was achieved on untreated soybean meal. Highest yield of xylanase (22.35 +/- 2.24 U g 1) was obtained on untreated wheat bran. Here, we report the complete genome sequence of the B. velezensis 157, composed of a circular 4,013,317 bp chromosome with 3789 coding genes and a G + C content of 46.41%, one circular 8439 bp plasmid and a G + C content of 40.32%. The genome contained a total of 8 candidate gene clusters (bacillaene, difficidin, macrolactin, butirosin, bacillibactin, bacilysin, fengycin and surfactin), and dedicates over 15.8% of the whole genome to synthesize secondary metabolite biosynthesis. In addition, the genes encoding enzymes involved in degradation of cellulose, xylan, lignin, starch, mannan, galactoside and arabinan were found in the B. velezensis 157 genome. Thus, the study of B. velezensis 157 broadened that B. velezensis can not only be used as biocontrol agents, but also has potentially a wide range of applications in lignocellulosic biomass conversion. PMID- 29430376 TI - Whole-genome resequencing and transcriptomic analysis of genes regulating anthocyanin biosynthesis in black rice plants. AB - Anthocyanins are involved in many diverse functions in rice, but their benefits have yet to be clearly demonstrated. Our objective in this study was to identify anthocyanin-related genes in black rice plants. We identified anthocyanin-related genes in black rice plants using a combination of whole-genome resequencing, RNA sequencing (RNA-seq), microarray experiments, and reverse-transcriptase polymerase chain reaction (RT-PCR). Using multi-layer screening from 30 rice accessions, we identified 172,922 single-nucleotide polymorphisms (SNPs) and 1276 differentially expressed genes that appear to be related to anthocyanin biosynthesis. We identified 18 putative genes from 172,922 SNPs using intensive selective sweeps. The 18 candidate genes identified from SNPs were not significantly correlated with the RNA-seq expression pattern or other well-known anthocyanin biosynthesis/metabolism genes. We also identified nine putative genes from 1276 differentially expressed genes using RNA-seq transcriptome analysis. In addition, we identified four phylogenetic groups from these nine candidate genes and 51 pathway-network genes. Finally, we verified nine anthocyanin-related genes using a newly designed microarray and semi-quantitative RT-PCR. We suggest that these nine identified genes appear to be related to the regulation of anthocyanin biosynthesis and/or metabolism. PMID- 29430377 TI - Molecular characterization of phytoplasma associated with four important ornamental plant species in India and identification of natural potential spread sources. AB - Phytoplasma suspected symptoms of phyllody, witches' broom, leaf yellowing, stunting and little leaf were observed in Chrysanthemum morifolium, Bougainvillea glabra, Jasminum sambac and Callistephus chinensis during survey of flower nurseries and experimental ornamental fields at Delhi, Maharashtra, Tamil Nadu and Karnataka from 2014 to 2016. Pleomorphic bodies typical to phytoplasma structures were observed in the phloem sieve elements of ultrathin sections of all the four symptomatic ornamental plants (stem tissue) in transmission electron microscope. Amplification of 1.8 and 1.2 kb phytoplasma DNA products was observed in all the four test plants in PCR assays using universal primer pairs P1/P7 followed by nested primer pair R16F2n/R16R2, respectively. Pairwise sequence comparison, phylogeny and virtual RFLP analysis of 16S rDNA sequences confirmed the association of two phytoplasma subgroups (16SrI-B and 16SrII-D) in four ornamental plant species. 'Ca. P. aurantifolia' subgroup D (16SrII-D) was found associated with chrysanthemum phyllody and leaf yellowing at Delhi and Tamil Nadu, bougainvillea little leaf and yellowing at Delhi and Chinese aster phyllody at Bengaluru, Karnataka. However, jasmine little leaf and yellowing at Bengaluru, Karnataka and chrysanthemum stunting at Pune were found to be associated with 'Ca. P. asteris' subgroup B-related strains (16SrI-B). The identification of 16SrII-D subgroup phytoplasma infecting bougainvillea and 16SrI-B subgroup infecting jasmine are the new reports to the world. Besides weed species, Cannabis sativa showing witches' broom in jasmine fields at Bengaluru and Parthenium hysterophorus showing witches' broom symptoms in chrysanthemum fields at Delhi were identified to be caused by phytoplasma strains classified under subgroups 16SrI-B and 16SrII-D, respectively, by PCR assays and 16Sr DNA sequence comparison analysis. Among the three major leafhopper species identified, only Hishimonas phycitis was identified positive for 16SrI-B and 16SrII-D subgroups of phytoplasmas from chrysanthemum fields at Delhi and jasmine fields at Bengaluru, respectively. The identity of similar phytoplasma strains infecting ornamental species in leafhopper and the weed species in the present study suggested that H. phycitis and weeds may act as potential natural sources for secondary spread of the identified phytoplasma strains. PMID- 29430378 TI - Characterisation of the simultaneous molybdenum reduction and glyphosate degradation by Burkholderia vietnamiensis AQ5-12 and Burkholderia sp. AQ5-13. AB - In this novel study, we report on the use of two molybdenum-reducing bacteria with the ability to utilise the herbicide glyphosate as the phosphorus source. The bacteria reduced sodium molybdate to molybdenum blue (Mo-blue), a colloidal and insoluble product, which is less toxic. The characterisation of the molybdenum-reducing bacteria was carried out using resting cells immersed in low phosphate molybdenum media. Two glyphosate-degrading bacteria, namely Burkholderia vietnamiensis AQ5-12 and Burkholderia sp. AQ5-13, were able to use glyphosate as a phosphorous source to support molybdenum reduction to Mo-blue. The bacteria optimally reduced molybdenum between the pHs of 6.25 and 8. The optimum concentrations of molybdate for strain Burkholderia vietnamiensis strain AQ5-12 was observed to be between 40 and 60 mM, while for Burkholderia sp. AQ5 13, the optimum molybdate concentration occurred between 40 and 50 mM. Furthermore, 5 mM of phosphate was seen as the optimum concentration supporting molybdenum reduction for both bacteria. The optimum temperature aiding Mo-blue formation ranged from 30 to 40 degrees C for Burkholderia vietnamiensis strain AQ5-12, whereas for Burkholderia sp. AQ5-13, the range was from 35 to 40 degrees C. Glucose was the best electron donor for supporting molybdate reduction, followed by sucrose, fructose and galactose for both strains. Ammonium sulphate was the best nitrogen source in supporting molybdenum reduction. Interestingly, increasing the glyphosate concentrations beyond 100 and 300 ppm for Burkholderia vietnamiensis strain AQ5-12 and Burkholderia sp. AQ5-13, respectively, significantly inhibited molybdenum reduction. The ability of these bacteria to reduce molybdenum while degrading glyphosate is a useful process for the bioremediation of both toxicants. PMID- 29430380 TI - Single and combined effects of acetic acid, furfural, and sugars on the growth of the pentose-fermenting yeast Meyerozyma guilliermondii. AB - The tolerance of the pentose-fermenting yeast Meyerozyma guilliermondii to the inhibitors released after the biomass hydrolysis, such as acetic acid and furfural, was surveyed. We first verified the effects of acetic acid and cell concentrations and initial pH on the growth of a M. guilliermondii strain in a semi-synthetic medium containing acetic acid as the sole carbon source. Second, the single and combined effects of furfural, acetic acid, and sugars (xylose, arabinose, and glucose) on the sugar uptake, cell growth, and ethanol production were also analysed. Growth inhibition occurred in concentrations higher than 10.5 g l-1 acetic acid and initial pH 3.5. The maximum specific growth rate (u) was 0.023 h-1 and the saturation constant (ks) was 0.75 g l-1 acetic acid. Initial cell concentration also influenced u. Acetic acid (initial concentration 5 g l-1) was co-consumed with sugars even in the presence of 20 mg l-1 furfural without inhibition to the yeast growth. The yeast grew and fermented sugars in a sugar based medium with acetic acid and furfural in concentrations much higher than those usually found in hemicellulosic hydrolysates. PMID- 29430379 TI - Genomic insights of aromatic hydrocarbon degrading Klebsiella pneumoniae AWD5 with plant growth promoting attributes: a paradigm of soil isolate with elements of biodegradation. AB - This research employs draft genome sequence data of Klebsiella pneumoniae AWD5 to explore genes that contribute to the degradation of polyaromatic hydrocarbon (PAH) and stimulate plant growth, for rhizosphere-mediated bioremediation. Annotation analysis suggests that the strain AWD5 not only possess gene clusters for PAH utilization, but also for utilization of benzoate, fluorobenzoate, phenylacetate (paa), hydroxyphenylacetic acid (hpa), 3-hydroxyphenyl propionate (mhp). A comparative genome analysis revealed that the genome of AWD5 was highly similar with genomes of environmental as well as clinical K. pneumoniae isolates. The artemis output confirmed that there are 139 different genes present in AWD5 which were absent in genome of clinical strain K. pneumoniae ATCC BAA-2146, and 25 genes were identified to be present in AWD5 genome but absent in genome of environmental strain K. pneumoniae KP-1. Pathway analyzed using Kyoto Encyclopedia of Genes and Genomes enzyme database revealed the presence of gene clusters that code for enzymes to initiate the opening of aromatic rings. The polyaromatic hydrocarbon and benzoate degradation were found to be metabolized through ortho-cleavage pathway, mineralizing the compounds to TCA cycle intermediates. Genes for plant growth promoting attributes such as Indole acetic acid (IAA) synthesis, siderophore production, and phosphate solubilization were detected in the genome. These attributes were verified in vitro, including IAA (14.75 ug/ml), siderophore production (13.56%), phosphate solubilization (198.28 ng/ml), and ACC deaminase (0.118 mM alpha-ketobutyrate/mg) in the presence of pyrene, and also compared with results obtained in glucose amended medium. K. pneumoniae AWD5 enhanced the growth of Jatropha curcas in the presence of pyrene contaminated soil. Moreover, AWD5 harbors heavy metal resistance genes indicating adaptation to contaminants. The study revealed the genomic attributes of K. pneumoniae AWD5 for its catabolic characteristics for different aromatic compounds, which makes it suitable for rhizoremediation of PAH-contaminated soil. PMID- 29430381 TI - Characterization of a glycoside hydrolase family 78 alpha-l-rhamnosidase from Bacteroides thetaiotaomicron VPI-5482 and identification of functional residues. AB - A putative glycoside hydrolase family 78 alpha-l-rhamnosidase BtRha78A from Bacteroides thetaiotaomicron VPI-5482 was heterologously over-expressed in Escherichia coli. Enzymatic properties of recombinant BtRha78A were characterized in detail. Recombinant BtRha78A might efficiently hydrolyze p-nitrophenyl alpha-l rhamnopyranoside. BtRha78A displayed the highest activity at 60 degrees C in pH 6.5. BtRha78A exhibited a good pH stability and relatively high thermostability. BtRha78A could be tolerant of a low concentration of alcohols. These attractive advantages made it a promising alternative biocatalyst for industrial applications. The catalytic general acid Asp335 and general base Glu595 of BtRha78A were confirmed by site-directed mutagenesis. Alanine scanning mutagenesis based on sequence alignment and structural analysis revealed that the conserved residues Asp330, Arg334, Trp339, Asp342, Tyr383, Trp440, and His620 were crucial for enzyme catalysis. Most functional residues located at the conserved general acid motif (Asp330-Asp342) and were completely conserved in the subfamily I Rha78s. PMID- 29430382 TI - The acyl-CoA binding protein affects Monascus pigment production in Monascus ruber CICC41233. AB - The present study verified whether acyl-coenzyme A (acyl-CoA)-binding protein (ACBP) affected the production of Monascus pigments (MPs) in Monascus ruber CICC41233 (MrACBP). Phylogenetic analysis revealed that the cloned Mracbp gene, which encoded the MrACBP protein, exhibited the closest match (99% confidence level) to the gene from Penicilliopsis zonata. The MrACBP and maltose-binding protein (MBP) were simultaneously expressed in Escherichia coli Rosetta DE3 in the form of a fusion protein. The microscale thermophoresis binding assay revealed that the purified MBP-MrACBP exhibited a higher affinity for myristoyl CoA (Kd = 88.16 nM) than for palmitoyl-CoA (Kd = 136.07 nM) and octanoyl-CoA (Kd = 270.9 nM). Further, the Mracbp gene was homologously overexpressed in M. ruber CICC41233, and a positive transformant M. ruber ACBP5 was isolated. The fatty acid myristic acid in M. ruber ACBP5 was lower than that in the parent strain M. ruber CICC41233. However, when compared with the parent strain, the production of total MPs, water-soluble pigment, and ethanol-soluble pigment in M. ruber ACBP5 increased by 11.67, 9.80, and 12.70%, respectively, after 6 days. The relative gene expression level, as determined by a quantitative real-time polymerase chain reaction analysis, of the key genes acbp, pks, mppr1, fasA, and fasB increased by 4.03-, 3.58-, 1.67-, 2.11-, and 2.62-fold after 6 days. These data demonstrate the binding preference of MrACBP for myristoyl-CoA, and its influence on MPs production. PMID- 29430383 TI - Propensity Score Analysis with Survey Weighted Data. AB - Propensity score analysis (PSA) is a common method for estimating treatment effects, but researchers dealing with data from survey designs are generally not properly accounting for the sampling weights in their analyses. Moreover, recommendations given in the few existing methodological articles on this subject are susceptible to bias. We show in this article through derivation, simulation, and a real data example that using sampling weights in the propensity score estimation stage and the outcome model stage results in an estimator that is robust to a variety of conditions that lead to bias for estimators currently recommended in the statistical literature. We highly recommend researchers use the more robust approach described here. This article provides much needed rigorous statistical guidance for researchers working with survey designs involving sampling weights and using PSAs. PMID- 29430384 TI - Exercise as a Prevention for Substance Use Disorder: A Review of Sex Differences and Neurobiological Mechanisms. AB - Purpose of Review: This report provides an update on clinical and preclinical findings for the efficacy of exercise to prevent substance use disorder with a focus on recent evidence for sex differences and neurobiological mechanisms. Recent Findings: Exercise/physical activity is associated with decreased drug use in humans. Preclinical results further indicate that exercise decreases vulnerability to drug use and the development of features of substance use disorder, and suggest that females have an enhanced sensitivity to its reward substitution effects. However, certain exercise conditions may sensitize the reward pathway and enhance vulnerability suggesting that parallel observations in humans (e.g., increased prescription opioid misuse and heroin use in high-school athletes) may be biologically-based. Summary: Exercise is a promising prevention strategy for substance use disorder. Further work is needed to establish its efficacy as a sex-specific strategy using larger samples, and to understand the exercise conditions that induce beneficial versus risk-enhancing effects. PMID- 29430386 TI - Tumor microenvironment heterogeneity: challenges and opportunities. AB - The tumor microenvironment (TME) has been recognized as an integral component of malignancies in breast and prostate tissues, contributing in confounding ways to tumor progression, metastasis, therapy resistance and disease recurrence. Major components of the TME are immune cells, fibroblasts, pericytes, endothelial cells, mesenchymal stroma/stem cells (MSCs), and extracellular matrix (ECM) components. Herein, we discuss the molecular and cellular heterogeneity within the TME and how this presents unique challenges and opportunities for treating breast and prostate cancers. PMID- 29430388 TI - Arthroscopic Labral Repair in the Setting of Recurrent Posterior Shoulder Instability. AB - Posterior shoulder instability, although relatively rare in the general population, is more commonly seen in athletes, especially those in contact sports. Although nonoperative treatment has been associated with satisfactory results in the setting of posterior shoulder instability, conservative management may ultimately fail and lead to recurrence particularly in young, male patients. Both arthroscopic and open repair techniques to address posterior instability have been described, with each showing positive patient-reported outcomes, low risk of recurrence, and considerably high return-to-sport rates. In particular, arthroscopic treatment includes the following: capsular plication and knotted and/or knotless suture anchor fixation. The purpose of this technique is to describe our preferred technique to treat recurrent posterior shoulder instability through arthroscopic labral repair using knotless suture anchor fixation. PMID- 29430387 TI - Skeletal Stem Cells: Origins, Functions and Uncertainties. AB - The development and maintenance of the skeleton requires a steady source of skeletal progenitors to provide the osteoblasts and chondrocytes necessary for bone and cartilage growth and development. The current model for skeletal stem cells (SSCs) posits that SSC/progenitor cells are present in bone marrow (BM) and other osteogenic sites such as cranial sutures where they undergo self-renewal and differentiation to give rise to the main skeletal tissues. SSCs hold great promise for understanding skeletal biology and genetic diseases of bone as well as for the advancement of bone tissue engineering and regenerative medicine strategies. In the past few years, a considerable effort has been devoted to identifying and purifying skeletal stem cells and determining their contribution to bone formation and homeostasis. Here, we review recent progress in this area with particular emphasis on the discovery of specific SSC markers, their use in tracking the progression of cell populations along specific lineages and the regulation of SSCs in both the appendicular and cranial skeleton. PMID- 29430389 TI - Arthroscopic Lateral Meniscal Allograft Transplantation With the Key-Hole Technique. AB - The efficacy of meniscus allograft transplantation (MAT) for the meniscus deficient knee has been widely recognized as being excellent in terms of pain relief and functional improvement. Lateral MAT is usually performed with the bone bridge technique that uses a bone bridge connecting the anterior and posterior horns of an allograft. The slot position for the meniscal graft insertion is of great importance with the bone bridge technique, especially in the key-hole method. The purpose of this Technical Note is to describe lateral MAT using the key-hole technique in which an allograft with a bone bridge carved to accommodate the key-hole-shaped slot is properly secured to the slot. PMID- 29430385 TI - Host response to pulmonary fungal infections: A highlight on cell-driven immunity to Cryptococcus species and Aspergillus fumigatus. PMID- 29430390 TI - Arthroscopic Shoelace Side-to-Side Repair Technique Using Ultratape for the Treatment of Longitudinal Midsubstance Rotator Cuff Tears. AB - Shoulder arthroscopy is a promising tool for assessing and treating patients with a rotator cuff tear. Arthroscopic rotator cuff repair with suture anchor fixation such as the single-row, double-row, and suture bridge technique are popular procedures that can provide excellent clinical outcomes. On the other hand, longitudinal midsubstance, U-shape, or L-shape tears may benefit more from a side to-side/margin convergence technique. Despite following the standard side-to side/margin convergence technique, we continue to see disruption at the site of side-to-side suture margin even with strong sutures. Here, we show our preferred arthroscopic shoelace rotator cuff repair technique using the more durable body tape for a longitudinal U-shape rotator cuff tear. PMID- 29430391 TI - Modifications to the Hip Arthroscopy Technique When Performing Combined Hip Arthroscopy and Periacetabular Osteotomy. AB - In the realm of hip preservation, hip arthroscopy is often used to address intra articular impingement pathology, whereas periacetabular osteotomy (PAO) is used to address dysplasia and instability. Indications to combine these 2 procedures include hip dysplasia and symptomatic instability with a concomitant symptomatic labral tear or the other symptomatic intra-articular pathology (i.e., loose body, chondral flap). The arthroscopic portion of the procedure allows repair of the injured labrum and close inspection of the hip joint, and the PAO addresses undercoverage and/or inappropriate version of the acetabulum. The open approach used in PAO also allows access to the peripheral compartment to debride a cam lesion, if present, and the subspine region is accessible to perform subspine decompression, if needed. In this technique, we highlight special considerations pertaining to hip arthroscopy that is performed in combination with a PAO. Hip arthroscopy is the first procedure that takes place in this combined case, and modifications to the standard hip arthroscopic technique can prevent unnecessary difficulty during the PAO that follows. PMID- 29430392 TI - Surgical Technique to Bring Down the Patellar Height and to Reconstruct the Tendon for Chronic Patellar Tendon Rupture. AB - Although surgical treatment is the gold standard for chronic patellar tendon rupture, the technique of patellar tendon reconstruction is still difficult. Basically, good clinical results of surgical repair for acute patellar tendon rupture have been reported. However, the results of reconstructive surgery for chronic patellar tendon rupture are still inconsistent. Some surgical options have been previously reported. For example, surgeons need to choose between 1- and 2-stage reconstruction. Furthermore, contralateral bone-tendon-bone graft, ipsilateral semitendinosus tendon graft, Achilles tendon allograft, and an artificial ligament have been used to reconstruct the patellar tendon. Generally, surgeons are concerned about postoperative complications, including loss of knee flexion, quadriceps weakness, and wound problems. One of the key points to avoid these complications is to improve proximal patellar migration. The purpose of this article is to present an easy and safe technique to bring down the patellar height with polyethylene tape and to reconstruct the patellar tendon with an artificial ligament. Although it has limitations, the described technique can facilitate reconstruction of chronic patellar tendon rupture. PMID- 29430393 TI - Arthroscopic Posterior Glenoid Fracture Fixation Using Knotless Suture Anchors. AB - Shoulder instability after a posterior glenoid rim fracture is rare and potentially difficult pathology to treat. Operative techniques often involve a large dissection to view the fragments resulting in local soft tissue injury. Internal fixation is often achieved with interfragmentary screws; however, this may not be possible with small or multifragmentary fracture patterns. We describe an arthroscopic technique for posterior glenoid rim fracture fixation using knotless suture anchors. These anchors can be inserted without cannulas allowing easier access to the posterior glenoid. This procedure is simple, safe, and offers good visualization of the glenohumeral joint whilst avoiding the detrimental effects of larger surgical dissection. PMID- 29430394 TI - Both Posterior Root Lateral-Medial Meniscus Tears With Anterior Cruciate Ligament Rupture: The Step-by-Step Systematic Arthroscopic Repair Technique. AB - The occurrence of posterior root tear of both the lateral and medial menisci, combined with anterior cruciate ligament rupture, is rare. Problems may be encountered such as the difficulty to access the medial meniscal root tear, the confusing circumstances about which structure to repair first, and the possibility of the tunnel for each repair to become taut inside the tibial bone. We present the arthroscopy technique step by step to overcome the difficulties in an efficient and time-preserving manner. PMID- 29430395 TI - Anterior Capsule Reconstruction Technique With an Acellular Dermal Allograft. AB - An irreparable subscapularis may have a debilitating influence on glenohumeral joint biomechanics. Traditional treatment approaches are focused on tendon transfers, among which the most popular are pectoralis major and latissimus dorsi transfers. However, these techniques present significant retear rates, possible nerve injuries, and altered biomechanics. Other techniques like tibialis anterior or iliotibial autograft grafting also have many reported failures. We describe an all-arthroscopic anterior capsule reconstruction technique with an acellular dermal graft. PMID- 29430396 TI - Arthroscopic Biceps Tenodesis Using Interference Screw Fixation in the Bicipital Groove. AB - Arthroscopic repair of the long head of the biceps (LHB) is performed to treat various biceps pathologies yet the choice between tenotomy or tenodesis remains controversial. Although tenotomy is simpler and quicker, tenodesis results in fewer complications, and there are several techniques available using various fixation devices and sites. This Technical Note describes an all-arthroscopic, suprapectoral tenodesis technique using a bioresorbable interference screw, without motorized devices to create the humeral tunnel in the bicipital groove. The LHB tendon is detached from its glenoid insertion using an arthroscopic cutting instrument or electrocautery. Two portals are created 50 mm distal to the acromioclavicular joint and at 15 mm on either side of the bicipital groove. The arthroscope is introduced through the distal lateral portal till it makes contact with the humerus. The LHB is fastened within its groove using a grasper, reinforced, and then fixed in the humeral tunnel using an interference screw. The present technique is safe, simple, and reproducible. It requires 2 portals in addition to the standard posterior portal and the intra-articular working portal. It minimizes iatrogenic intra-articular damage and thereby limits possible complications. It also limits the intra-articular operative time compared with SLAP repairs. PMID- 29430397 TI - Multicompartmental Osteochondral Allografts of Knee and Concomitant High Tibial Osteotomy. AB - Chondral lesions of the knee can occur secondary to limb malalignment. To address these interrelated problems, a high tibial osteotomy with concomitant osteochondral allograft transfer may be performed. It is important to address these chondral lesions as they often affect the young and active population and cause morbidity in an otherwise healthy population. Although numerous approaches for the treatment of chondral lesions have been described, long-term results demonstrating regeneration of hyaline cartilage have yet to be reported. Furthermore, larger, full-thickness cartilage defects, which can be caused by limb malalignment, have proven to be particularly challenging to treat. This Technical Note details our technique for multicompartmental osteochondral allograft transplantation with concomitant high tibial osteotomy in a patient with 2 focal cartilage lesions in the knee. PMID- 29430398 TI - Revision of Failed Rotator Cuff Reconstruction With a Large Humeral Head Cyst. AB - A revision rotator cuff repair is a technically challenging surgical procedure. This can be further complicated by the presence of poor quality of the cuff tissue, as well as a large greater tuberosity cyst, typically located at the rotator cuff footprint. This Technical Note discusses the surgical approach to deal with a revision rotator cuff tear with a large humeral head cyst. This described arthroscopic technique is performed in a single-stage procedure using a human dermal allograft (GraftJacket) for augmentation. This technique was specifically designed to (1) address the limited area for anchor placement, (2) use a bone graft, demineralized bone matrix, for repairing the bone cyst, and (3) optimize the biology for healing by augmenting the reconstruction with GraftJacket. PMID- 29430399 TI - Associated Reconstruction of Anterior Cruciate and Anterolateral Ligaments With Single Asymmetric Hamstring Tendons Graft. AB - The anterior cruciate ligament (ACL) rupture is a common disease that accounts for 250,000 cases/year in the United States. The anterolateral ligament (ALL) has been suggested to be an important restraint for rotational instability, and its reconstruction provides a reinforcement to the ACL reconstruction in this aspect, especially in high-demand athletes and in knees with high-grade pivot shift. Different techniques for associated ACL and ALL reconstruction have been described, but the ideal technique remains unclear. Several facts of these techniques may entail a concern to the surgeon, such as the need for several grafts or several bone tunnels. A technique for associated ACL and ALL is presented, using a single hamstring tendons graft, which is prepared asymmetrically, leaving one-third of the length with single diameter and two thirds with double diameter. A single femoral tunnel is created, using a screw for fixation and differentiation of the grafts. A suspension device is used for tibial fixation, allowing for length adjustment according to the graft's length. The objective of this Technical Note is to provide the orthopaedic surgeon with a resource for ACL and ALL reconstruction even with relatively short grafts, saving bone stock and avoiding the need for allografts. PMID- 29430400 TI - "Double-Row Rip-Stop" Technique for Arthroscopic Rotator Cuff Repair. AB - Rotator cuff repair depends on both the fixation strength of the chosen repair construct and the local healing response of the repaired tissue. Among a growing discussion surrounding the superiority of one surgical technique over another, the surgeon's ability to complete a rotator cuff repair with technical acuity in a timely manner remains paramount. Double-row repairs as well as rip-stop configurations have been proposed to limit failures found after arthroscopic rotator cuff repairs. Implementation of both techniques during arthroscopic shoulder surgery may represent a technical challenge for the average orthopaedist. The purpose of this article is to give simple instructions for reproduction of an arthroscopic double-row rip-stop repair for rotator cuff fixation. PMID- 29430401 TI - Ethical issues related to clinical research and rare diseases: 15th Gordon L. Snider Critical Issues Workshop, April 1, 2016, Bethesda, Maryland. PMID- 29430402 TI - Effects of mineralocorticoid receptor antagonists on responses to hemorrhagic shock in rats. AB - AIM: To evaluate the effects of mineralocorticoid receptor (MR) antagonists on mortality and inflammatory responses after hemorrhagic shock (HS) in rats. METHODS: One hundred and two male Sprague-Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone (EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor alpha (TNF-alpha) concentrations, and arterial blood gas at 8 h after HS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery. RESULTS: The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF alpha concentrations among the three groups (P = 0.888). CONCLUSION: Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats. PMID- 29430403 TI - Adverse events in critical care: Search and active detection through the Trigger Tool. AB - AIM: To investigate the incidence of disadvantageous events by using the Global Trigger Tool in an intensive care unit (ICU). METHODS: A retrospective descriptive study was performed in a 12-bed university ICU in the city of Medellin, Colombia. Clinical charts of hospitalized patients were reviewed, between January 1 and December 31, 2016, with the following inclusion criteria: subjects aged over 18 years, with at least 24 h of hospitalization and who had a complete medical history that could be accessed. Interventions: Trained reviewers conducted a retrospective examination of medical charts searching for clue events that elicit investigation, in order to detect an unfavorable event. Measurements: Information was processed through SPSS software version 21; for numerical variables, the mean was reported with standard deviation (SD). Percentages were calculated for qualitative variables. RESULTS: Two hundred and forty-four triggers occurred, with 82.4% of subjects having presented with at least one and an average of 3.37 (SD 3.47). A total of 178 adverse events (AEs) took place in 48 individuals, with an incidence of 52.1%. On average, four events per patient were recorded, and for each unfortunate event, 1.98 triggers were presented. The most frequent displeasing issues were: pressure ulcers (17.6%), followed by complications or reactions to medical devices (4.3%), and lacerations or skin defects (3.7%); the least frequent was delayed diagnosis or treatment (0.56%). Thirty-eight point four percent of mishap events caused temporary damage that required intervention, and 48.9% of AEs were preventable. Comparison between AEs and admission diagnoses found that hypertension and sepsis were the only diagnoses that had statistical significance (P = 0.042 and 0.022, respectively). CONCLUSION: Almost half of the unfavorable issues were classified as avoidable, which leaves a very wide field of work in terms of preventative activities. PMID- 29430404 TI - Spectrum of cardiac manifestations and its relationship to outcomes in patients admitted with scrub typhus infection. AB - AIM: To study the spectrum of cardiac manifestations in scrub typhus infection and assess its relationship to outcomes. METHODS: Demographic data, electrocardiographic (ECG) changes, left ventricular (LV) systolic and diastolic function, myocardial injury (defined as troponin T > 14 pg/mL), and pericardial effusion were documented. Myocarditis was diagnosed when myocardial injury was associated with global LV systolic dysfunction. The relationship between myocarditis and outcomes was assessed using logistic regression analysis and expressed as odds ratio (OR) with 95%CI. RESULTS: The cohort (n = 81; 35 males) aged 49.4 +/- 16.1 years (mean, SD) presented 8.1 +/- 3.1 d after symptom onset. The APACHE-II score was 15.7 +/- 7.0. Forty-eight (59%) patients were ventilated, and 46 (56%) required vasoactive agents. Mortality was 9.9%. ECG changes were non specific; sinus tachycardia was the most common finding. Myocardial injury was evident in 61.7% of patients and LV systolic dysfunction in 30.9%. A diagnosis of myocarditis was made in 12.3%. In addition, seven patients with regional wall motion abnormalities had LV systolic dysfunction and elevated cardiac enzymes. Mild diastolic dysfunction was observed in 18 (22%) patients. Mild to moderate pericardial effusion was seen in 51%. On multivariate logistic regression analysis, patients with myocarditis tended to be older (OR = 1.04, 95%CI: 0.99 1.09), had shorter symptom duration (OR = 0.69, 95%CI: 0.49-0.98), and tended to stay longer in hospital (OR = 1.17, 95%CI: 0.98-1.40). Myocarditis was not associated with increased mortality. CONCLUSION: In scrub typhus infection, cardiac manifestations are frequent and associated with increased morbidity but not mortality. PMID- 29430405 TI - Respiratory mechanics, ventilator-associated pneumonia and outcomes in intensive care unit. AB - AIM: To evaluate the predictive capability of respiratory mechanics for the development of ventilator-associated pneumonia (VAP) and mortality in the intensive care unit (ICU) of a hospital in southern Brazil. METHODS: A cohort study was conducted between, involving a sample of 120 individuals. Static measurements of compliance and resistance of the respiratory system in pressure controlled ventilation (PCV) and volume-controlled ventilation (VCV) modes in the 1st and 5th days of hospitalization were performed to monitor respiratory mechanics. The severity of the patients' illness was quantified by the Acute Physiology and Chronic Health Evaluation II (APACHE II). The diagnosis of VAP was made based on clinical, radiological and laboratory parameters. RESULTS: The significant associations found for the development of VAP were APACHE II scores above the average (P = 0.016), duration of MV (P = 0.001) and ICU length of stay above the average (P = 0.003), male gender (P = 0.004), and worsening of respiratory resistance in PCV mode (P = 0.010). Age above the average (P < 0.001), low level of oxygenation on day 1 (P = 0.003) and day 5 (P = 0.004) and low lung compliance during VCV on day 1 (P = 0.032) were associated with death as the outcome. CONCLUSION: The worsening of airway resistance in PCV mode indicated the possibility of early diagnosis of VAP. Low lung compliance during VCV and low oxygenation index were death-related prognostic indicators. PMID- 29430406 TI - Effect of Remote Ischemic Preconditioning on Troponin I in CABG. AB - Background: Elective open heart surgery is associated with troponin release in some cases due to myocyte necrosis. Objectives: The aim of this study was to measure cardiac troponin I (cTnI) preoperatively in elective CABG after remote ischemic preconditioning. Methods: Twenty-eight patients were selected for elective CABG. They were randomized to receive remote ischemic preconditioning (induced by three 5-min cycles of inflation with a pneumatic tourniquet and 5-min deflation between inflation episodes as reperfusion). Outcomes: Primary outcomes were cardiac troponin I levels at 6 and 24 hours after the procedure, and the secondary outcomes included creatine phosphokinase, lactate dehydrogenase, and serum creatinine levels. Hemodynamic changes were evaluated between the treatment and control groups. Results: Cardiac troponin I at 6 hours after preconditioning was significantly lower compared to the control group (P = 0.036), and after 24 hours, there was still a significant difference between the two groups (P < 0.05). Conclusions: Remote ischemic preconditioning reduces ischemic biomarkers during coronary artery bypass graft and attenuates procedure-related cardiac troponin I release and eventually reduces cardiovascular events such as myocardial infarction, chest pain, and hemodynamic changes after cardiac surgery. PMID- 29430407 TI - Anesthetic Considerations in Patients Undergoing Bariatric Surgery: A Review Article. AB - Context: This article discusses the anesthetic considerations in patients undergoing bariatric surgery in the preoperative, intraoperative, and postoperative phases of surgery. Evidence Acquisition: This review includes studies involving obese patients undergoing bariatric surgery. Searches have been conducted in PubMed, MEDLINE, EMBASE, Google Scholar, Scopus, and Cochrane Database of Systematic Review using the terms obese, obesity, bariatric, anesthesia, perioperative, preoperative, perioperative, postoperative, and their combinations. Results: Obesity is a major worldwide health problem associated with many comorbidities. Bariatric surgery has been proposed as the best alternative treatment for extreme obese patients when all other therapeutic options have failed. Conclusions: Anesthetists must completely assess the patients before the surgery to identify anesthesia- related potential risk factors and prepare for management during the surgery. PMID- 29430409 TI - A Novel and Modified Technique in the Prone Position for Radiotherapy Processes in Children. AB - The i-gel has a thick airway tube and occasionally, achieving the airway can be difficult because of obstruction in the prone position. The authors aimed at solving this problem and used a modified i-gel airway in the prone position for radiotherapy processes in children. PMID- 29430408 TI - Using Bronchoscopy to Detect Acquired Tracheoesophageal Fistula in Mechanically Ventilated Patients. AB - Introduction: An acquired Tracheoesophageal fistula (TEF) is commonly caused by a malignancy or trauma, with pulmonary infection or aspiration being the presenting symptom. However, in the critical care setting the presentation can be subtle and may present with difficult ventilation. High endotracheal tube cuff pressures can lead to tracheal erosions and thus increasing the chances for developing a TEF. Prolonged intubation in the presence of other risk factors like poor general state of health, episodic hypotension, nasogastric tubes, and repeated intubations can increase the likelihood of developing an acquired TEF. Angioedema of the airway is a rare but potentially devastating complication of angiotensin converting enzyme inhibitors (ACE-I) that could further add insult to the tracheal mucosa, predisposing to an acquired TEF. Case Presentation: An elderly woman with multiple comorbidities and requiring mechanical ventilation, developed angioedema following intake of ACE inhibitor for hypertension. The ensuing airway edema made weaning off mechanical ventilation difficult. After repeated attempts at extubation, tracheostomy was performed. With the loss of airway after tracheostomy, the possibility of TEF was considered given her multiple risk factors and intra-operative findings of the tracheal mucosa. Conclusions: While it may be difficult to predict who will actually develop a TEF, it is prudent to identify those at risk and take precautionary measures to prevent one. Emphasis should be placed on daily endotracheal cuff manometric pressure check to prevent ischemic changes of the tracheal mucosa resulting from high cuff pressures. Also, bronchoscopy could be used after extubating susceptible patients to detect an acquired TEF. PMID- 29430410 TI - Managing diabetes patients in India: Is the future more bitter or less sweet? PMID- 29430411 TI - Comparison of efficacy and pharmacoeconomics of two Helicobacter pylori eradication regimens in peptic ulcer disease. AB - Background: Helicobacter pylori, the cause of most peptic ulcer diseases, infects approximately 50% of the population worldwide. Indian data on cost and effectiveness of the standard first-line therapies for H. pylori eradication are scarce. Thus, the present study was aimed at comparing the cost and efficacy of two standard first-line therapies: Regimen I comprising pantoprazole (40 mg) plus amoxicillin (750 mg) plus clarithromycin (500 mg) (PAC) and Regimen II comprising rabeprazole (20 mg) plus amoxicillin (625 mg) plus metronidazole (200 mg) (RAM). Methodology: This prospective, observational, bottom-up study collected demographic, economic, diagnostic, and therapeutic data from 60 H. pylori positive patients. The study was carried out for 6 months in the Gastroenterology Department of a Tertiary Care Hospital in Hyderabad, Telangana, India. Results: Health-care system perspective was used to account for direct costs. Average cost per patient for complete H. pylori eradication was Rs. 10,221 and Rs. 8568 for Regimen I and Regimen II, respectively. Inpatient cost was considerably higher than the outpatient cost. Diagnostic costs ranked first in direct costs, followed by hospitalization costs, medication costs, and finally, physician's office visit cost. Individual patient's costs difference between two regimens was found to be statistically significant. Overall, Regimen I proved to be more efficacious than Regimen II, but Regimen II proved to be more cost-effective than Regimen I. Furthermore, incremental cost-effectiveness analysis revealed additional cost of Rs. 127 per patient if the patient was treated with Regimen I instead of Regimen II. Conclusion: Our study showed that Regimen II (RAM) was more cost-effective than Regimen I (PAC), but PAC achieved faster H. pylori eradication than RAM. We assume that this study provides local clinical data as to which regimen may be useful in a particular patient. National Level Clinical Trials are required to further ascertain this conclusion. PMID- 29430412 TI - Study of drug-Drug interactions among the hypertensive patients in a tertiary care teaching hospital. AB - Aim: Drug-drug interactions (DDIs) are one of the major but preventable cause of adverse drug reaction. Study of prevalence and prediction of DDIs will make the physician easier to provide better patient care and mitigate patient's harm. Hence, the study was planned to evaluate the potential DDIs among medication prescribed to hypertensive patients in our hospital. Materials and Methods: A prospective, cross-sectional study was conducted among the hypertensive patients in medicine (outpatient/inpatient) department over the period of three months in a tertiary care hospital. Adult hypertensive patients of either sex with comorbidities were included in the study. The prescriptions were collected and analyzed for DDI using Medscape interaction checker. Data were analyzed using SPSS (version 16.0) software and expressed in percentage. Pearson's correlation and regression analysis were done. Results: Among 125 patients, 48% were exposed to at least one DDI. Totally 123 DDI were identified and majority of them were significant (85.36%). No serious interactions were identified. Pharmacodynamic and pharmacokinetic drug interactions were found to be 37.39% and 28.76%, respectively. Logistic regression analysis showed advanced male gender and polypharmacy was associated with increased risk of DDI. About 51 interacting pairs of DDI were identified and most frequently occurring pair was amlodipine with atenolol. Aspirin was found to have commonly involved in DDI with enalapril, atenolol, frusemide, spironolactone, carvedilol, and metoprolol. Conclusion: The study highlighted that patients with hypertension are particularly vulnerable to DDI. The comorbidities, advanced age, and polypharmacy are the important factors associated with the occurrence of DDI. PMID- 29430413 TI - An evaluation of the impact of antidiabetic medication on treatment satisfaction and quality of life in patients of diabetes mellitus. AB - Aims: This study aims to measure the quality of life (QOL), treatment satisfaction, and tolerability of antidiabetic drugs in patients suffering from type 2 diabetes mellitus (DM). Methods: The prospective, observational study was conducted in consenting patients of type 2 DM attending the outpatient department of a tertiary care hospital in Western India. The QOL instrument for Indian diabetes (QOLID) patients questionnaire and the Diabetes Treatment Satisfaction Questionnaire were administered to all patients at baseline, 3 months, and 6 months of treatment. Tukey-Kramer comparison test was used to analyze the difference in QOLID scores in various domains at baseline, 3 months, and 6 months. WHO-UMC scale, Naranjo's probability scale, Hartwig and Siegel, and Schumock and Thornton modified criteria were used to analyze the adverse drug reactions. Results: A male preponderance was observed in 200 patients enrolled in the study. The mean duration of diabetes was 10.96 +/- 5.99 years. The patients received metformin alone (40), metformin and glipizide (47), metformin, glipizide and other oral hypoglycemic agents (OHAs) (78), and OHAs and insulin (35). A significant improvement in fasting and postprandial blood sugar was observed at 6 months as compared to the baseline (P < 0.05). A total of 39 (19.5%) patients suffered from adverse effects to metformin and insulin. Physical health and physical endurance improved in patients receiving metformin alone or in combination with glipizide as compared to patients receiving other OHAs and/or insulin. Treatment satisfaction, highest in patients receiving metformin and least in those receiving insulin, was unaltered during the study period. Conclusions: While polypharmacy is evident, using lesser medicines offers better treatment satisfaction and QOL in DM. Periodic assessment of QOL and treatment satisfaction are recommended in DM. PMID- 29430414 TI - Pattern and impact of drugs targeted toward toxicity amelioration in patients receiving cancer chemotherapy. AB - Background: Drug therapy today is remarkably safe and efficacious. Still, some drugs - particularly anticancer drugs - are fraught with numerous adverse drug reactions (ADRs), severely jeopardizing quality of life of cancer patients. Fortunately, most of these ADRs are preventable provided adequate prophylactic drugs are administered along with chemotherapy. Aims: The aim of this study is to assess the pattern and impact of cytoprotective prophylactic drugs on anticancer ADRs in patients receiving cancer chemotherapy. Subjects and Methods: We included 200 patients receiving anticancer therapy for the first time. Patient details and for each cycle: details of baseline investigations, anticancer treatment given, ADRs observed and interventions done to prevent and manage the ADRs were recorded. Preventability and predictability scales were applied to assess the impact of drugs and strategies toward toxicity amelioration. Data were analyzed using descriptive statistics. Results: Adjuvant drugs were administered prophylactically along with anticancer drugs for the prevention of nausea and vomiting, gastritis, immediate allergic reactions, nephrotoxicity, ototoxicity, hemorrhagic cystitis, and other anticipated ADRs. About 94.80% reactions were found to be predictable and 5.20% unpredictable. Maximum reactions (56.47%) were probably preventable. Paracetamol, filgrastim, mucaine, etc., were used to manage a variety of ADRs. Conclusions: Although the predictability of ADRs was almost 95%, we could prevent only about 56% of them. Surprisingly, we have no ADRs that appear definitely preventable. This could be due to less attention being paid to the ADRs that could have been prevented by the appropriate use of prophylactic measures. PMID- 29430415 TI - Impact of data transparency: Scientific publications. AB - Data transparency has been an important aspect of medical research as it helps in enabling evidence-based decisions in medicine which leads to foster trust among the patients and research community alike. Currently, it is one of the key talking points owing to a number of initiatives taken by the pharmaceutical organizations, regulatory bodies, and the other decision enablers of the industry. Thanks to this, there are a number of ways by which a single piece of datum is available through multiple access points, namely, clinical trial disclosures (CTDs), clinical study reports (CSRs), plain language summaries, and scientific publications including abstracts, posters, and manuscripts, to name a few. This may pose a burden of documentation on the pharmaceutical organizations, demanding downsizing of medical writing documents. Since CTDs, CSRs, and other regulatory document are more or less template driven; there may not be much scope to interfere with their structure and submission timings. Scientific publications, on the other hand, provide the flexibility of presenting the clinical data that is typically not dependent on a particular format and timelines. The present paper discusses how the upcoming data transparency initiatives could affect the publication practices across the pharmaceutical industry and what could pharmaceutical companies do to get the maximum benefit out of the data transparency initiatives. PMID- 29430416 TI - Managing conflict of interest in Ethics Committee. AB - The article discusses conflict of interest (COI) situations and how to manage COI in ethics committee (EC). PMID- 29430417 TI - Common pitfalls in statistical analysis: Understanding the properties of diagnostic tests - Part 1. AB - In this article in our series on common pitfalls in statistical analysis, we look at some of the attributes of diagnostic tests (i.e., tests which are used to determine whether an individual does or does not have disease). The next article in this series will focus on further issues related to diagnostic tests. PMID- 29430418 TI - Audiovisual recording of the consenting process in clinical research: Experiences from a tertiary referral center. AB - The quality of the written informed consent process is one of the most important aspects of clinical research, as it is the single tool that serves as a metric of autonomy. Several challenges have been identified with the informed consent process in developing countries the most important of which is the ability to assimilate and understand the information presented in the consent form. In India, a unique aspect of the informed consent process is the need for audio video [AV] recording of the process for vulnerable populations and new chemical entities. The present narrative summates authors' experiences as investigators with A-V recording of the informed consent process as also providing a brief narrative review of relevant literature. It also offers potential solutions for challenges faced during this process. PMID- 29430419 TI - Indian Regulatory Update: January-December 2017. AB - This document provides updates in regulatory requirements regarding conduct of clinical trials in India. PMID- 29430420 TI - Drug safety alerts of pharmacovigilance programme of India: A scope for targeted spontaneous reporting in India. AB - Background: The National Coordination Centre-Pharmacovigilance Programme of India (NCC-PvPI), Indian Pharmacopoeia Commission works under the aegis of Ministry of Health and Family Welfare, Government of India. It promotes patient safety in India and also supports postmarketing surveillance programs. Currently, almost hundred thousand case reports are submitted to NCC-PvPI each year through its 250 ADR Monitoring Centers (AMCs) located across India, and India is the one of the top ten contributor countries under WHO-Uppsala Monitoring Centre since 2012 and start issuing drug safety alerts from March 2016. Aim: This study aims to highlight the drug safety alerts issued by NCC-PvPI from March 2016 to June 2017 and urgent need for further monitoring by adopting targeted spontaneous reporting (TSR) methodology at AMCs and its impact on the NCC's drug safety database, i.e., VigiFlow in India. Methodology: A retrospective analysis was done for the reported unlisted ADRs by various AMCs to PvPI through VigiFlow, i.e., individual case safety report (ICSR) management system at NCC, where these unlisted drug-ADR combinations considered and issued as drug safety alerts for further reporting these to NCC, if any detected at healthcare settings during routine clinical practice by healthcare professionals. Results: From July 2011 to June 2017, NCC PvPI was collated 250,787 ICSRs and contributed to WHO international drug safety database, i.e., VigiBase, from these ICSRs; NCC-PvPI was issued 56 drug safety alerts from March 2016 to June 2017. Conclusion: In India, spontaneous reporting of ADRs existed since 1998 under passive surveillance method, but there is an urgent need to initiate TSR, which is a complementary method to spontaneous reporting on these drug safety alerts for further regulatory action by Central Drugs Standard Control Organization. PMID- 29430421 TI - Intentional or unintentional, it is never alright to plagiarize: A note on how Indian universities are advised to handle plagiarism. PMID- 29430422 TI - Early Clinical Experience with Sutureless Aortic Valve Replacement for Severe Aortic Stenosis. AB - Background: Sutureless aortic valve replacement (SU-AVR) has been developed as an alternative surgical treatment for patients with symptomatic severe aortic stenosis (AS). The aim of this study was to evaluate the clinical outcomes of SU AVR through an assessment of hemodynamic performance and safety. Methods: From December 2014 to June 2016, a total of 12 consecutive patients with severe AS underwent SU-AVR. The endpoints were overall survival and valve-related complications (paravalvular leakage, valve thrombosis, migration, endocarditis, and permanent pacemaker implantation). The mean follow-up duration was 18.1+/-8.6 months. Results: The mean age of the patients was 77.1+/-5.8 years and their mean Society of Thoracic Surgeons score was 9.2+/-17.7. The mean cardiopulmonary bypass and aortic cross-clamp times were 94.5+/-37.3 minutes and 54.9+/-12.5 minutes, respectively. Follow-up echocardiography showed good prosthesis function with low transvalvular pressure gradients (mean, 13.9+/-8.6 mm Hg and peak, 27.2+/-15.0 mm Hg) at a mean of 9.9+/-4.2 months. No cases of primary paravalvular leakage, valve thrombosis, migration, or endocarditis were reported. A new permanent pacemaker was implanted in 1 patient (8.3%). The 1-year overall survival rate was 83.3%+/-10.8%. Conclusion: Our initial experience with SU-AVR demonstrated excellent early clinical outcomes with good hemodynamic results. However, there was a high incidence of permanent pacemaker implantation compared to the rate for conventional AVR, which is a problem that should be solved. PMID- 29430423 TI - Mid-Term Results of Minimally Invasive Direct Coronary Artery Bypass Grafting. AB - Background: Minimally invasive direct coronary artery bypass grafting (MIDCAB) has the advantage of allowing arterial grafting on the left anterior descending artery without a sternotomy incision. We present our single-center clinical experience of 66 consecutive patients. Methods: All patients underwent MIDCAB through a left anterior small thoracotomy between August 2007 and July 2015. Preoperative, intraoperative, postoperative and follow-up data-including major adverse cardiovascular and cerebrovascular events (MACCE), graft patency, and the need for re-intervention-were collected. Results: The mean age of the patients was 69.4+/-11.1 years and 73% were male. There was no conversion to an on-pump procedure or a sternotomy incision. The 30-day mortality rate was 1.5%. There were no cases of stroke, although 2 patients had to be re-explored for bleeding, and 81.8% were extubated in the operating room or on the day of surgery. The median stay in the intensive care unit and in the hospital were 1.5 and 9.6 days, respectively. The median follow-up period was 11 months, with a 5-year overall survival rate of 85.3%+/-0.09% and a 5-year MACCE-free survival rate of 72.8%+/ 0.1%. Of the 66 patients, 32 patients with 36 grafts underwent a postoperative graft patency study with computed tomography angiography or coronary angiography, and 88.9% of the grafts were patent at 9.7+/-10.8 months postoperatively. Conclusion: MIDCAB is a safe procedure with low postoperative morbidity and mortality and favorable mid-term MACCE-free survival. PMID- 29430424 TI - Outcomes of Reoperative Valve Replacement in Patients with Prosthetic Valve Endocarditis: A 20-Year Experience. AB - Background: Prosthetic valve endocarditis (PVE) is a serious complication of cardiac valve replacement, and many patients with PVE require reoperation. The aim of this study was to review our institutional 20-year experience of surgical reoperative valve replacement in patients with PVE. Methods: A retrospective study was performed on 84 patients (mean age, 54.8+/-12.7 years; 51 males) who were diagnosed with PVE and underwent reoperative valve replacement from January 1995 to December 2016. Results: PVE was found in 1 valve in 61 cases (72.6%), and in 2 or more valves in 23 cases (27.4%). The median follow-up duration was 47.3 months (range, 0 to 250 months). Postoperative complications occurred in 39 patients (46.4%). Reinfection occurred in 6 cases, all within 1 year. The freedom from reinfection rate at 5 years was 91.0%+/-3.5%. The overall survival rates at 5 and 10 years were 64.4%+/-5.8% and 54.3%+/-7.3%, respectively. In stepwise multivariable Cox proportional hazard models, older age (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.05 to 2.10; p=0.027) and cardiopulmonary bypass (CPB) time (HR, 1.03; 95% CI, 1.00 to 1.01; p=0.033) emerged as independent risk factors for death. Conclusion: Older age and a longer CPB time were associated with an increased risk of overall mortality in PVE patients. PMID- 29430425 TI - Clinical Outcomes of Lung Transplantation: Experience at Asan Medical Center. AB - Background: Lung transplantation is a life-saving procedure in patients with end stage lung disease, and is increasingly performed in Korea. Methods: We retrospectively evaluated the outcomes of patients who received a lung transplant at Asan Medical Center between January 2008 and December 2016. Thirteen of 54 patients experienced multiorgan transplantation; the remaining 41 who received only lung grafts were included. Results: The mean age of the lung transplant recipients was 44.6 years; 27 were men and 14 were women. The most frequent reasons were idiopathic interstitial pneumonia (21 of 41 patients, 51.2%), interstitial lung disease (9 of 41, 22.0%), and bronchiolitis obliterans after bone marrow transplantation (7 of 41, 17.1%). The median waiting time was 47 days, and many patients received preoperative intensive care (27 of 41, 65.9%), ventilator support (26 of 41, 63.4%), or extracorporeal life support (19 of 41, 46.3%). All 41 patients received bilateral lung grafts. Ten deaths occurred (24.3%), including 5 cases of early mortality (12.2%) and 5 cases of late mortality (12.2%). The 1-, 3-, and 5-year survival rates were 78.9%, 74.2%, and 69.3%, respectively. Conclusion: Despite a high percentage of patients who required preoperative intensive care, the transplantation outcomes were acceptable. PMID- 29430426 TI - Outcomes of Pulmonary Resection and Mediastinal Node Dissection by Video-Assisted Thoracoscopic Surgery Following Neoadjuvant Chemoradiation Therapy for Stage IIIA N2 Non-Small Cell Lung Cancer. AB - Background: We evaluated the feasibility and outcomes of pulmonary resection and mediastinal node dissection (MND) by video-assisted thoracoscopic surgery (VATS) following neoadjuvant therapy for stage IIIA N2 non-small cell lung cancer (NSCLC). Methods: From November 2009 to December 2013, a total of 35 consecutive patients with pathologically or radiologically confirmed stage IIIA N2 lung cancer underwent pulmonary resection and MND, performed by a single surgeon, following neoadjuvant chemoradiation. Preoperative patient characteristics, surgical outcomes, postoperative drainage, postoperative complications, and mortality were retrospectively analyzed. Results: VATS was completed in 17 patients. Thoracotomy was performed in 18 patients, with 13 planned thoracotomies and 5 conversions from the VATS approach. The median age was 62.7+/-7.9 years in the VATS group and 60+/-8.7 years in the thoracotomy group. The patients in the VATS group tended to have a lower diffusing capacity for carbon monoxide (p=0.077). There were no differences between the 2 groups in the method of diagnosing the N stage, tumor response and size after induction, tumor location, or histologic type. Complete resection was achieved in all patients. More total and mediastinal nodes were dissected in the VATS group than in the thoracotomy group (p<0.05). The median chest tube duration was 5.3 days (range, 1 to 33 days) for the VATS group and 7.2 days (range, 2 to 28 days) for the thoracotomy group. The median follow-up duration was 36.3 months. The 5-year survival rates were 76% in the VATS group and 57.8% in the thoracotomy group (p=0.39). The 5-year disease free survival rates were 40.3% and 38.9% in the VATS and thoracotomy groups, respectively (p=0.8). Conclusion: The VATS approach following neoadjuvant treatment was safe and feasible in selected patients for the treatment of stage IIIA N2 NSCLC, with no compromise of oncologic efficacy. PMID- 29430427 TI - Outcomes of the Multimodal Treatment of Malignant Pleural Mesiothelioma: The Role of Surgery. AB - Background: The treatment of malignant pleural mesothelioma (MPM) is challenging, and multimodal treatment including surgery is recommended; however, the role of surgery is debated. The treatment outcomes of MPM in Korea have not been reported. We analyzed the outcomes of MPM in the context of multimodal treatment, including surgery. Methods: The records of 29 patients with pathologically proven MPM from April 1998 to July 2015 were retrospectively reviewed. The treatment outcomes of the surgery and non-surgery groups were compared. Results: The overall median survival time was 10.6 months, and the overall 3-year survival rate was 25%. No postoperative 30-day or in-hospital mortality occurred in the surgery group. Postoperative complications included tachyarrhythmia (n=4), pulmonary thromboembolism (n=1), pneumonia (n=1), chylothorax (n=1), and wound complications (n=3). The treatment outcomes between the surgery and non-surgery groups were not significantly different (3-year survival rate: 31.3% vs. 16.7%, respectively; p=0.47). In a subgroup analysis, there was no significant difference in the treatment outcomes between the extrapleural pneumonectomy group and the non-surgery group (3-year survival rate: 45.5% vs. 16.7%, respectively; p=0.23). Conclusion: Multimodal treatment incorporating surgery did not show better outcomes than non-surgical treatment. A nationwide multicenter data registry and prospective randomized controlled studies are necessary to optimize the treatment of MPM. PMID- 29430428 TI - Prognostic Implications of Postoperative Infectious Complications in Non-Small Cell Lung Cancer. AB - Background: Few studies have evaluated the long-term impact of postoperative infectious complications in patients with non-small cell lung cancer (NSCLC). We aimed to determine the impact of infectious complications on long-term outcomes after surgical resection for NSCLC. Methods: We performed a retrospective study of 1,380 eligible patients who underwent pulmonary resection for NSCLC from 2003 to 2012. Complications were divided into infectious complications and non infectious complications. Kaplan-Meier survival analysis was used to compare unadjusted 5-year cancer-specific survival (CSS) rates and recurrence-free survival (RFS) rates. Cox regression was used to determine the impact of infectious complications on 5-year CSS and RFS. Results: The rate of total complications and infectious complications was 24.3% and 4.3%, respectively. In the node-negative subgroup, the 5-year CSS and RFS rates were 75.9% and 57.1% in patients who had infectious complications, compared to 87.9% and 78.4% in patients who had no complications. Infectious complications were a negative prognostic factor for 5-year RFS (hazard ratio, 1.92; 95% confidence interval, 1.00-3.69; p=0.049). In the node-positive subgroup, the 5-year CSS rate and RFS were 44.6% and 48.4% in patients who had infectious complications, compared to 70.5% and 48.4% for patients who had no complications. Conclusion: Postoperative infectious complications had a negative impact on CSS and RFS in node-negative NSCLC. Our findings may help improve risk assessment for tumor recurrence after pulmonary resection for node-negative NSCLC. PMID- 29430429 TI - Extracardiac Conduit Fontan Operation with Reduction Aortoplasty for Left Pulmonary Artery Compression after a Norwood Procedure in a Patient with Double Inlet Left Ventricle. AB - Patients with double-inlet left ventricle usually have a small ascending aorta. In the Norwood procedure, which involves a staged operation, a neoaorta is constructed with a homograft, and the pulmonary artery plays a role in the systemic circulation. Dilatation or aneurysmal changes can occur over time due to the exposure of the neoaorta to systemic pressure, which may induce adverse effects on adjacent structures. We report a rare case of surgical repair for neoaortic root dilataiton with aortic regurgitation, compressing the left pulmohary artery, in a patient who underwent the Norwood procedure. PMID- 29430430 TI - Airway Improvement with Medium-Term Compression Duration after Right Pulmonary Artery Anterior Translocation. AB - Left main bronchus compression occasionally occurs in patients with cardiac disease. A 19-month-old female patient weighing 6.7 kg was admitted for recurrent pneumonia and desaturation. She had an a trial septal defect (AS D) with a right aortic arch. Her left main bronchus had been compressed between the enlarged right pulmonary artery (RPA) and the descending thoracic aorta for 14 months. We conducted ASD closure and RPA anterior translocation via sternotomy. The left main bronchus compression was relieved despite the medium-term duration of compression. PMID- 29430431 TI - Minimally Invasive Mitral Valve Repair in a Woman with Marfan Syndrome and Type B Dissection. AB - We report the case of a patient with mitral regurgitation complicated by type B dissection and Marfan syndrome (MFS) who was managed successfully with minimally invasive mitral valve repair. Without type A aortic dissection or aortic root dilation, MFS patients may develop mitral valve regurgitation, as in this case, and need valve surgery to improve their symptoms and long-term survival. However, it is not clear that a full sternotomy and prophylactic aortic surgery are necessary. Although retrograde perfusion to the dissected aorta is controversial, our approach minimizes the risk of future anticipated aortic surgery in MFS patients. PMID- 29430432 TI - Hughes-Stovin Syndrome as an Outcome of Behcet Disease or as a Different Entity. AB - Hughes-Stovin syndrome is a rare disorder of unknown etiology. Although the association between multiple pulmonary artery aneurysms and venous thrombosis of the lower limbs was reported by Beattie and Hall in 1911, it was not until 1962 that the eponym "Hughes-Stovin syndrome" was formally introduced in the medical literature. We describe 2 patients with Hughes-Stovin syndrome who presented with pulmonary artery aneurysm, thrombophlebitis, hemoptysis, and oral ulcers, review the manifestations of the disease, and compare its similarities with and differences from Behcet disease. PMID- 29430433 TI - A Life-Threatening Bronchogenic Cyst. AB - A bronchogenic cyst causing cardiac tamponade is a rare condition. We report an unusual case of a bronchogenic cyst that caused cardiac tamponade. A 49-year-old female patient presented at our emergency room with complaints of palpitations and shortness of breath that had lasted for 5 days preceding the visit. Echocardiography revealed a very large cystic mass compressing the left a trium posteriorly, and a large amount of pericardial effusion caused the diastolic collapse of the ventricles. Atrial fibrillation and aggravated dyspnea were observed, and the patient's vital signs were unstable after admission. We therefore performed an emergency operation. The bronchogenic cyst was resected by thoracotomy and the patient was discharged 12 days after the operation without any complications over 5 years of follow-up. PMID- 29430434 TI - Spontaneous Disappearance of a Pericardial Cyst: Case Report and Literature Review. AB - Pericardial cysts are rare benign anomalies generally discovered as incidental findings on radiographic images. Rarely, pericardial cysts cause symptoms and may lead to complications. A 56-year-old woman presented to the emergency department for mild chest pain. A cardiovascular and respiratory examination revealed no abnormalities, while a chest X-ray and subsequent thoracic computed tomography (CT) showed a pericardial cyst. The patient refused both percutaneous treatment and thoracic surgery. Three years later, a thoracic CT scan showed that the pericardial cyst had disappeared. Although the spontaneous resolution of these lesions is rare, this article highlights the possibility of conservative management in select cases. PMID- 29430435 TI - Esophageal Endoscopic Vacuum Therapy with Enteral Feeding Using a Sengstaken Blakemore Tube. AB - Early diagnosis followed by primary repair is the best treatment for spontaneous esophageal perforation. However, the appropriate management of esophageal leakage after surgical repair is still controversial. Recently, the successful adaptation of vacuum-assisted closure therapy, which is well established for the treatment of chronic surface wounds, has been demonstrated for esophageal perforation or leakage. Conservative treatment methods require long-term fasting with total parenteral nutrition or enteral feeding through invasive procedures, such as percutaneous endoscopic gastrostomy or a feeding jejunostomy. We report 2 cases of esophageal leakage after primary repair treated by endoscopic vacuum therapy with continuous enteral feeding using a Sengstaken-Blakemore tube. PMID- 29430436 TI - The World Database for Pediatric and Congenital Heart Surgery: Use of an International Congenital Database in South Korea. PMID- 29430437 TI - Barriers to use contraceptive methods among rural young married couples in Maharashtra, India: Qualitative findings. AB - Introduction: In rural India contraceptive use remains uncommon among newly married couples. non-use in rural young couples contributes to higher fertility rates. Objectives: To identify barriers of spacing contraceptive use among young married couples in rural Maharashtra. Methods: In-depth interviews were conducted with husbands (N=30), wives (N=20), and village health providers (N=12); additionally, 3 focus groups were conducted with mothers of husbands (N= 42 focused on understanding contraceptive use and barriers. Interviews and focus groups ranged in length from 90-120 minutes. Detailed notes taken during interviews were analysed using a grounded theory approach and the data was analysed using atlas-ti software. Results: Major barriers to spacing contraception are: pro-natal social norms, pregnancy expectations early in marriage, to produce multiple sons, limited access to modern spacing contraceptives, family resistance to adopt contraceptives, lack of husband's involvement on family planning issues, myths, misconceptions, perceived side effects and negative attitudes toward specific contraceptives. Conclusion: Findings highlight the intersection of norms against spacing contraception, traditional gender ideologies and lack of male involvement as major barriers to the use of contraception. Male oriented outreach programmes on family planning. Promoting gender equity should be made through health programme deliveries with special focus in rural areas. PMID- 29430439 TI - Bringing translational research in acute lung injury closer. PMID- 29430438 TI - Recent advances in the reconstruction of cranio-maxillofacial defects using computer-aided design/computer-aided manufacturing. AB - With the development of computer-aided design/computer-aided manufacturing (CAD/CAM) technology, it has been possible to reconstruct the cranio maxillofacial defect with more accurate preoperative planning, precise patient specific implants (PSIs), and shorter operation times. The manufacturing processes include subtractive manufacturing and additive manufacturing and should be selected in consideration of the material type, available technology, post processing, accuracy, lead time, properties, and surface quality. Materials such as titanium, polyethylene, polyetheretherketone (PEEK), hydroxyapatite (HA), poly DL-lactic acid (PDLLA), polylactide-co-glycolide acid (PLGA), and calcium phosphate are used. Design methods for the reconstruction of cranio-maxillofacial defects include the use of a pre-operative model printed with pre-operative data, printing a cutting guide or template after virtual surgery, a model after virtual surgery printed with reconstructed data using a mirror image, and manufacturing PSIs by directly obtaining PSI data after reconstruction using a mirror image. By selecting the appropriate design method, manufacturing process, and implant material according to the case, it is possible to obtain a more accurate surgical procedure, reduced operation time, the prevention of various complications that can occur using the traditional method, and predictive results compared to the traditional method. PMID- 29430441 TI - Macrolide therapy is associated with reduced mortality in acute respiratory distress syndrome (ARDS) patients. AB - Background: Macrolides have been associated with favorable immunological effects in various inflammatory disease states. We investigated the association between macrolide therapy and mortality in patients with the acute respiratory distress syndrome (ARDS). Methods: This was an unplanned secondary analysis of patients with ARDS within a large prospective observational study of critically ill patients in the intensive care units (ICUs) of two university-affiliated hospitals in the Netherlands. The exposure of interest was low-dose macrolide use prescribed for another reason than infection; we excluded patients who received high-dose macrolides for an infection. The primary endpoint was 30-day mortality. The association between macrolide therapy and mortality was determined in the whole cohort, as well as in a propensity score matched cohort; the association was compared between pulmonary versus non-pulmonary ARDS, and between two biological phenotypes based on plasma levels of 20 biomarkers. Results: In total, 873 patients with ARDS were analyzed, of whom 158 patients (18%) received macrolide therapy during stay in ICU for a median duration of 3 (interquartile range, 1-4) days. Erythromycin was the most frequent prescribed macrolide (97%). Macrolide therapy was associated with reduced 30-day mortality in the whole cohort [22.8% vs. 31.6%; crude odds ratio (OR), 0.64 (interquartile range, 0.43 0.96), P=0.03]. The association in the propensity score matched cohort remained significant [22.8% vs. 32.9%; OR, 0.62 (interquartile range, 0.39-0.96), P=0.03]. Propensity matched associations with mortality were different in patients with non-pulmonary ARDS vs. pulmonary ARDS and also varied by biological phenotype. Conclusions: These data together show that low-dose macrolide therapy prescribed for another reason than infection is associated with decreased mortality in patients with ARDS. PMID- 29430440 TI - Interaction between peri-operative blood transfusion, tidal volume, airway pressure and postoperative ARDS: an individual patient data meta-analysis. AB - Background: Transfusion of blood products and mechanical ventilation with injurious settings are considered risk factors for postoperative lung injury in surgical Patients. Methods: A systematic review and individual patient data meta analysis was done to determine the independent effects of peri-operative transfusion of blood products, intra-operative tidal volume and airway pressure in adult patients undergoing mechanical ventilation for general surgery, as well as their interactions on the occurrence of postoperative acute respiratory distress syndrome (ARDS). Observational studies and randomized trials were identified by a systematic search of MEDLINE, CINAHL, Web of Science, and CENTRAL and screened for inclusion into a meta-analysis. Individual patient data were obtained from the corresponding authors. Patients were stratified according to whether they received transfusion in the peri-operative period [red blood cell concentrates (RBC) and/or fresh frozen plasma (FFP)], tidal volume size [<=7 mL/kg predicted body weight (PBW), 7-10 and >10 mL/kg PBW] and airway pressure level used during surgery (<=15, 15-20 and >20 cmH2O). The primary outcome was development of postoperative ARDS. Results: Seventeen investigations were included (3,659 patients). Postoperative ARDS occurred in 40 (7.2%) patients who received at least one blood product compared to 40 patients (2.5%) who did not [adjusted hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.25-4.33; P=0.008]. Incidence of postoperative ARDS was highest in patients ventilated with tidal volumes of >10 mL/kg PBW and having airway pressures of >20 cmH2O receiving both RBC and FFP, and lowest in patients ventilated with tidal volume of <=7 mL/kg PBW and having airway pressures of <=15 cmH2O with no transfusion. There was a significant interaction between transfusion and airway pressure level (P=0.002) on the risk of postoperative ARDS. Conclusions: Peri-operative transfusion of blood products is associated with an increased risk of postoperative ARDS, which seems more dependent on airway pressure than tidal volume size. PMID- 29430442 TI - Effects of peep on lung injury, pulmonary function, systemic circulation and mortality in animals with uninjured lungs-a systematic review. AB - It is well-known that positive end-expiratory pressure (PEEP) can prevent ventilator-induced lung injury (VILI) and improve pulmonary physiology in animals with injured lungs. It's uncertain whether PEEP has similar effects in animals with uninjured lungs. A systematic review of randomized controlled trials (RCTs) comparing different PEEP levels in animals with uninjured lungs was performed. Trials in animals with injured lungs were excluded, as were trials that compared ventilation strategies that also differed with respect to other ventilation settings, e.g., tidal volume size. The search identified ten eligible trials in 284 animals, including rodents and small as well as large mammals. Duration of ventilation was highly variable, from 1 to 6 hours and tidal volume size varied from 7 to 60 mL/kg. PEEP ranged from 3 to 20 cmH2O, and from 0 to 5 cmH2O, in the 'high PEEP' or 'PEEP' arms, and in the 'low PEEP' or 'no PEEP' arms, respectively. Definitions used for lung injury were quite diverse, as were other outcome measures. The effects of PEEP, at any level, on lung injury was not straightforward, with some trials showing less injury with 'high PEEP' or 'PEEP' and other trials showing no benefit. In most trials, 'high PEEP' or 'PEEP' was associated with improved respiratory system compliance, and better oxygen parameters. However, 'high PEEP' or 'PEEP' was also associated with occurrence of hypotension, a reduction in cardiac output, or development of hyperlactatemia. There were no differences in mortality. The number of trials comparing 'high PEEP' or 'PEEP' with 'low PEEP' or 'no PEEP' in animals with uninjured lungs is limited, and results are difficult to compare. Based on findings of this systematic review it's uncertain whether PEEP, at any level, truly prevents lung injury, while most trials suggest potential harmful effects on the systemic circulation. PMID- 29430443 TI - Electrical impedance tomography. AB - Continuous assessment of respiratory status is one of the cornerstones of modern intensive care unit (ICU) monitoring systems. Electrical impedance tomography (EIT), although with some constraints, may play the lead as a new diagnostic and guiding tool for an adequate optimization of mechanical ventilation in critically ill patients. EIT may assist in defining mechanical ventilation settings, assess distribution of tidal volume and of end-expiratory lung volume (EELV) and contribute to titrate positive end-expiratory pressure (PEEP)/tidal volume combinations. It may also quantify gains (recruitment) and losses (overdistention or derecruitment), granting a more realistic evaluation of different ventilator modes or recruitment maneuvers, and helping in the identification of responders and non-responders to such maneuvers. Moreover, EIT also contributes to the management of life-threatening lung diseases such as pneumothorax, and aids in guiding fluid management in the critical care setting. Lastly, assessment of cardiac function and lung perfusion through electrical impedance is on the way. PMID- 29430445 TI - Mechanical stretch modulates cell migration in the lungs. AB - Cell migration is a core process to preserve homeostasis. Release of chemotactic signals induces changes in cell cytoskeleton to facilitate migration. This includes the rearrangement of cytoskeleton, genomic reprogramming and the modification of the surrounding extracellular matrix (ECM) to allow the motion of cells through. In the special case of repair after acute lung injury, cells must migrate while exposed to an increased mechanical stretch caused either by an increased work of breathing or positive-pressure ventilation. Interestingly, the cell response to this increased mechanical load can modify virtually all the mechanisms involved in cell migration. In this review we explore the interplay between stretch and the machinery responsible for cell migration. A translational approach to find new therapies in acute lung injury must take into account these interactions in order to develop effective treatments that promote lung repair. PMID- 29430444 TI - Heart-lung interactions in acute respiratory distress syndrome: pathophysiology, detection and management strategies. AB - Acute respiratory distress syndrome (ARDS) is the most severe form of acute respiratory failure characterized by diffuse alveolar and endothelial damage. The severe pathophysiological changes in lung parenchyma and pulmonary circulation together with the effects of positive pressure ventilation profoundly affect heart lung interactions in ARDS. The term pulmonary vascular dysfunction (PVD) refers to the specific involvement of the vascular compartment in ARDS and is expressed clinically by an increase in pulmonary arterial (PA) pressure and pulmonary vascular resistance both affecting right ventricular (RV) afterload. When severe, PVD can lead to RV failure which is associated to an increased mortality. The effect of PVD on RV function is not only a consequence of increased pulmonary vascular resistance as afterload is a much more complex phenomenon that includes all factors that oppose efficient ventricular ejection. Impaired pulmonary vascular mechanics including increased arterial elastance and augmented wave-reflection phenomena are commonly seen in ARDS and can additionally affect RV afterload. The use of selective pulmonary vasodilators and lung protective mechanical ventilation strategies are therapeutic interventions that can ameliorate PVD. Prone positioning and the open lung approach (OLA) are especially attractive strategies to improve PVD due to their effects on increasing functional lung volume. In this review we will describe some pathophysiological aspects of heart-lung interactions during the ventilatory support of ARDS, its clinical assessment and discuss therapeutic interventions to prevent the occurrence and progression of PVD and RV failure. PMID- 29430446 TI - Models of disuse muscle atrophy: therapeutic implications in critically ill patients. AB - Skeletal muscle weakness is common in the intensive care units (ICU). Approximately 50% of patients under mechanical ventilation for more than 7 days show signs of ICU-acquired muscle weakness. In these patients, muscle weakness may be the result of axonal polyneuropathy, myopathy or a combination of both. The commonest risk factors in patients with ICU-acquired weakness (AW) are the severity and duration of the systemic inflammatory response, duration of the stay in the ICU and of mechanical ventilation, hyperglycemia, hypoalbuminemia, parenteral nutrition, and administration of corticosteroids and of neuromuscular blocking agents. Loss of thick filaments (myosin), atrophy of the myofibers, necrosis, and regeneration features has been consistently shown in muscle samples during critical illness. Moreover, a slow-to-fast fiber type shift, reduced muscle fiber cross-sectional area of the myofibers, alterations in muscle contractility, reduced aerobic capacity and protein synthesis, and the electromechanical properties of the nerve-muscle interface are also relevant features in skeletal muscles of critically ill patients and experimental models. Several diagnostic tools are currently available to identify patients at risk of ICU-AW. Early rehabilitation in combination with nutritional support constitutes the basis of the therapeutic strategies to be implemented in ICU. Future research will need to shed light on additional cellular processes that could also be targeted pharmacologically. An overview of all these aspects has been provided during the Second International Symposium on Acute Pulmonary Injury Translational Research organized by Hospital Universitario de Getafe (Madrid, Spain) in November 2017 and it is being described in the present review. PMID- 29430447 TI - Mechanisms involved in brain dysfunction in mechanically ventilated critically ill patients: implications and therapeutics. AB - Critical illness may lead to significant long-term neurological morbidity and patients frequently develop neuropsychological disturbances including acute delirium or memory impairment after intensive care unit (ICU) discharge. Mechanical ventilation (MV) is a risk factor to the development of adverse neurocognitive outcomes. Patients undergoing MV for long periods present neurologic impairment with memory and cognitive alteration. Delirium is considered an acute form of brain dysfunction and its prevalence rises in mechanically ventilated patients. Delirium duration is an independent predictor of mortality, ventilation time, ICU length of stay and short- and long-term cognitive impairment in the ICU survivors. Although, neurocognitive sequelae tend to improve after hospital discharge, residual deficits persist even 6 years after ICU stay. ICU-related neurocognitive impairments occurred in many cognitive domains and are particularly pronounced with regard to memory, executive functions, attentional functions, and processing speed. These sequelae have an important impact on patients' lives and ICU survivors often require institutionalization and hospitalization. Experimental studies have served to explore the possible mechanisms or pathways involved in this lung to brain interaction. This communication can be mediated via a complex web of signaling events involving neural, inflammatory, immunologic and neuroendocrine pathways. MV can affect respiratory networks and the application of protective ventilation strategies is mandatory in order to prevent adverse effects. Therefore, strategies focused to minimize lung stretch may improve outcomes, avoiding failure of distal organ, including the brain. Long-term neurocognitive impairments experienced by critically ill survivors may be mitigated by early interventions, combining cognitive and physical therapies. Inpatient rehabilitation interventions in ICU promise to improve outcomes in critically ill patients. The cross-talk between lung and brain, involving specific pathways during critical illness deserves further efforts to evaluate, prevent and improve cognitive alterations after ICU admission, and highlights the crucial importance of tailoring MV to prevent adverse outcomes. PMID- 29430448 TI - Extracorporeal carbon dioxide removal in acute exacerbations of chronic obstructive pulmonary disease. AB - Extracorporeal carbon dioxide removal (ECCO2R) has been proposed as an adjunctive intervention to avoid worsening respiratory acidosis, thereby preventing or shortening the duration of invasive mechanical ventilation (IMV) in patients with exacerbation of chronic obstructive pulmonary disease (COPD). This review will present a comprehensive summary of the pathophysiological rationale and clinical evidence of ECCO2R in patients suffering from severe COPD exacerbations. PMID- 29430450 TI - Diagnosis of acute respiratory distress syndrome by exhaled breath analysis. AB - The acute respiratory distress syndrome (ARDS) is a complication of critical illness that is characterized by acute onset, protein rich, pulmonary edema. There is no treatment for ARDS, other than the reduction of additional ventilator induced lung injury. Prediction or earlier recognition of ARDS could result in preventive measurements and might decrease mortality and morbidity. Exhaled breath contains volatile organic compounds (VOCs), a collection of hundreds of small molecules linked to several physiological and pathophysiological processes. Analysis of exhaled breath through gas-chromatography and mass-spectrometry (GC MS) has resulted in an accurate diagnosis of ARDS in several studies. Most identified markers are linked to lipid peroxidation. Octane is one of the few markers that was validated as a marker of ARDS and is pathophysiologically likely to be increased in ARDS. None of the currently studied breath analysis methods is directly applicable in clinical practice. Two steps have to be taken before any breath test can be allowed into the intensive care unit. External validation in a multi-center study is a prerequisite for any of the candidate breath markers and the breath test should outperform clinical prediction scores. Second, the technology for breath analysis should be adapted so that it is available at a decentralized lab inside the intensive care unit and can be operated by trained nurses, in order to reduce the analysis time. In conclusion, exhaled analysis might be used for the early diagnosis and prediction of ARDS in the near future but several obstacles have to be taken in the coming years. Most of the candidate markers can be linked to lipid peroxidation. Only octane has been validated in a temporal external validation cohort and is, at this moment, the top-ranking breath biomarker for ARDS. PMID- 29430452 TI - How to improve quality of research in intensive care medicine. AB - This paper discusses several approaches to improve quality of research in intensive care medicine. The baseline standard of care is important in randomized controlled trials. If standard of care is low, trialists could consider improving this before starting the trial. Implementation studies and efficacy trials should not be mixed up. Trialists could further try to increase prognostic as well as predictive enrichment, e.g., through biological phenotyping. Robustness of statistical findings can increase by enrolling sufficiently high numbers of patients and minimizing loss to follow-up. PMID- 29430449 TI - New insights into the mechanisms of pulmonary edema in acute lung injury. AB - Appearance of alveolar protein-rich edema is an early event in the development of acute respiratory distress syndrome (ARDS). Alveolar edema in ARDS results from a significant increase in the permeability of the alveolar epithelial barrier, and represents one of the main factors that contribute to the hypoxemia in these patients. Damage of the alveolar epithelium is considered a major mechanism responsible for the increased pulmonary permeability, which results in edema fluid containing high concentrations of extravasated macromolecules in the alveoli. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of pro-coagulant processes, cell death and mechanical stretch. The disruption of tight junction (TJ) complexes at the lateral contact of epithelial cells, the loss of contact between epithelial cells and extracellular matrix (ECM), and relevant changes in the communication between epithelial and immune cells, are deleterious alterations that mediate the disruption of the alveolar epithelial barrier and thereby the formation of lung edema in ARDS. PMID- 29430451 TI - MicroRNAs as biomarkers of acute lung injury. AB - Acute respiratory distress syndrome (ARDS) is a common and complex inflammatory lung diseases affecting critically ill patients requiring mechanical ventilation. MicroRNAs (miRNAs), a novel pathway of non-coding RNA molecules that regulate gene expression at the post-transcriptional level, have emerged as a novel class of gene expression, and can play important roles in inflammation or apoptosis, which are common manifestations of ARDS and diffuse alveolar damage (DAD). In the present review, we discuss the role of miRNAs as biomarkers of ARDS and DAD, and their potential use as therapeutic targets for this condition. PMID- 29430454 TI - Effects of hypercapnia in acute respiratory distress syndrome. AB - In patients with acute respiratory distress syndrome (ARDS) hypercapnia is a marker of poor prognosis, however there is controversial information regarding the effect of hypercapnia on outcomes. Recently two studies in a large population of mechanical ventilation patients showed higher mortality associated independently to hypercapnia. Key roles responsible for the poor clinical outcomes observed in critically ill patients exposed to hypercapnia are not well known, two possible mechanisms involved are the effect of CO2 on the muscle and the alveolar epithelium. Hypercapnia frequently coexists with muscle atrophy and dysfunction, moreover patients surviving ARDS present reduced muscle strength and decreased physical quality of life. One of the possible mechanisms responsible for these abnormalities could be the effects of hypercapnia during the course of ARDS. More over controversy persists about the hypercapnia role in the alveolar space, in the last years there is abundant experimental information on its deleterious effects on essential functions of the alveolar epithelium. PMID- 29430453 TI - Anticoagulant therapy in acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) presents a complex pathophysiology characterized by pulmonary activated coagulation and reduced fibrinolysis. Despite advances in supportive care of this syndrome, morbidity and mortality remains high, leading to the need of novel therapies to combat this disease. Focus these therapies in the inhibition of ARDS development pathophysiology is essential. Beneficial effects of anticoagulants in ARDS have been proved in preclinical and clinical trials, thanks to its anticoagulant and anti inflammatory properties. Moreover, local administration by nebulization in the alveolar compartment increases local efficacy and does not produce systemic bleeding. In this review the coagulation and fibrinolytic pathway and its pharmacological targets to treat ARDS are summarized. PMID- 29430455 TI - Effectiveness of the mHealth technology in improvement of healthy behaviors in an elderly population-a systematic review. AB - Demographic changes in the 21st century, increased population of the elderly and high prevalence of related diseases call for new healthcare strategies that can change the behavior and lifestyle of elderly individuals. Innovative information and communication technology, such as mobile health (mHealth), can play a significant role. The present study was conducted aiming to assess the effectiveness of mHealth in improving health behaviors among an elderly population. This paper presents a systematic review involving a search of PubMed, Web of Science (ISI), Scopus, Science Direct and Embase databases from [2012 2016]. Our search resulted after initial evaluations 12 articles. Inclusion criteria mostly revolved around interventional studies, other studies were excluded because of their methodology, non-elderly target groups and irrelevant to the subject. Findings showed that mHealth can improve care, self-management, self-efficacy, behavior promotion (quality of sleep, diet, physical activity mental health) and medication adherence. The mHealth technology has proven effective for disease prevention, lifestyle changes, management of cardiovascular disease and diabetes, and is a suitable tool for elderly people. In conclusion, it seems that mHealth can facilitate behavioral changes; although, further research is necessary in this regard. PMID- 29430456 TI - Text-mining analysis of mHealth research. AB - In recent years, because of the advancements in communication and networking technologies, mobile technologies have been developing at an unprecedented rate. mHealth, the use of mobile technologies in medicine, and the related research has also surged parallel to these technological advancements. Although there have been several attempts to review mHealth research through manual processes such as systematic reviews, the sheer magnitude of the number of studies published in recent years makes this task very challenging. The most recent developments in machine learning and text mining offer some potential solutions to address this challenge by allowing analyses of large volumes of texts through semi-automated processes. The objective of this study is to analyze the evolution of mHealth research by utilizing text-mining and natural language processing (NLP) analyses. The study sample included abstracts of 5,644 mHealth research articles, which were gathered from five academic search engines by using search terms such as mobile health, and mHealth. The analysis used the Text Explorer module of JMP Pro 13 and an iterative semi-automated process involving tokenizing, phrasing, and terming. After developing the document term matrix (DTM) analyses such as single value decomposition (SVD), topic, and hierarchical document clustering were performed, along with the topic-informed document clustering approach. The results were presented in the form of word-clouds and trend analyses. There were several major findings regarding research clusters and trends. First, our results confirmed time-dependent nature of terminology use in mHealth research. For example, in earlier versus recent years the use of terminology changed from "mobile phone" to "smartphone" and from "applications" to "apps". Second, ten clusters for mHealth research were identified including (I) Clinical Research on Lifestyle Management, (II) Community Health, (III) Literature Review, (IV) Medical Interventions, (V) Research Design, (VI) Infrastructure, (VII) Applications, (VIII) Research and Innovation in Health Technologies, (IX) Sensor based Devices and Measurement Algorithms, (X) Survey-based Research. Third, the trend analyses indicated the infrastructure cluster as the highest percentage researched area until 2014. The Research and Innovation in Health Technologies cluster experienced the largest increase in numbers of publications in recent years, especially after 2014. This study is unique because it is the only known study utilizing text-mining analyses to reveal the streams and trends for mHealth research. The fast growth in mobile technologies is expected to lead to higher numbers of studies focusing on mHealth and its implications for various healthcare outcomes. Findings of this study can be utilized by researchers in identifying areas for future studies. PMID- 29430457 TI - Evaluating the behavior of cultured sertoli cells in the presence and absence of spermatogonial stem cell. AB - Background: The complex process of spermatogenesis is regulated by various factors. Several studies have been conducted to proliferate cells involved in the spermatogenesis process, in culture by used growth factors, different hormones and feeder cells. This study was conducted to evaluate the role of Sertoli cells on gene expression of fibroblast growth factor (FGF2) and glial cell derived neurotrophic factor (GDNF) after removal of spermatogonial stem cells (SSCs) from the culture medium. Methods: Following isolation, bovine SSCs were co-cultured with Sertoli cells and follicular stimulating hormone (FSH) for 12 days. In the treatment group, SSCs were removed from the culture medium; in the control group no intervention was done in the culture. Colony formation of SSCs was evaluated by using an inverted microscope. Then, the expression of factors genes were assessed by quantitative RT-PCR. Data was analyzed by using paired-samples t test. Results: The results showed that removal of SSCs led to the increase in expression of GDNF and FGF2. These findings suggest that loss of SSCs population or decline in its population leads to changing in behavior of somatic cells which forming niche and consequently stimulates self-renewal and inhibits differentiation of SSCs. Conclusions: The present study showed that removal of SSCs from the culture medium could be a model for damage to SSCs; the results revealed that niche cells respond to SSCs removal by upregulation of FGF2 and GDNF to stimulate self-renewal of SSCs and abrogation of differentiation. PMID- 29430458 TI - Integrin alpha7: a novel promising target in glioblastoma stem cells. PMID- 29430459 TI - Organoids recapitulate organs? PMID- 29430460 TI - Cancer stem cells and evolving novel therapies: a paradigm shift. AB - Accumulating evidence of stem-like cells/cancer stem cells (CSCs) has been gaining attention of cancer researchers over the last decade. Though many tumors harbor CSCs in their dedicated niches, identifying and exterminating those cells has proved to be difficult, due to their heterogenous nature, as the CSC phenotype vary substantially and may undergo reversible phenotypic changes. As a tumor propagation initiator, CSCs are considered as an exciting novel therapy for a better therapeutic outcome. This review discusses the major advances in the development of CSC-based therapies of most common cancers which includes lung, cervix and liver cancers. PMID- 29430461 TI - A Simple Model for Inducing Optimal Increase of SDF-1 with Aminoglycoside Ototoxicity. AB - Objectives: As a homing factor of stem cell, stromal derived factor-1 (SDF-1) is important for the regenerative research in ototoxicity. Mice models with aminoglycoside ototoxicity have been widely used to study the regeneration capacity of MSCs in repair of cochlear injury. We developed a mouse model with maximal increase in SDF-1 levels in the inner ear, according to the "one-shot" doses of kanamycin and furosemide. Methods: C57BL/6 mice had kanamycin (420, 550, and 600 mg/kg) dissolved in PBS, followed by an intraperitoneal injection of furosemide (130 mg/kg). The injuries of inner ear were measured with hearing thresholds, histology, and outer hair cell counts at 0, 3, 5, 7, 10, and 14 days before the sacrifice. The levels of SDF-1 in the inner ear were tested by real time RT-PCR and immunohistochemistry. Results: There were a significant reduction in hearing thresholds and a maximal increase of SDF-1 levels in the furosemide 130 mg/kg + kanamycin 550 mg/kg group, but severe hearing deterioration over time was observed in the furosemide 130 mg/kg + kanamycin 600 mg/kg group and four mice were dead. SDF-1 was detected mostly in the stria vascularis and organ of Corti showing the highest increase in expression. Conclusion: We observed optimal induction of the stem cell homing factor in the newly generated aminoglycoside induced ototoxicity mouse model using a "one-shot" protocol. This study regarding high SDF-1 levels in our mouse model of ototoxicity would play a major role in the development of therapeutic agents using MSC homing. PMID- 29430462 TI - Aging in HIV-Infected Subjects: A New Scenario and a New View. AB - The prevalence of HIV-infected people aged 50 years or older is increasing rapidly; the proportion will increase from 28% to 73% in 2030. In addition, HIV infected individuals may be more vulnerable to age-related condition. There is growing evidence that the prevalence of comorbidities and other age-related conditions (geriatric syndromes, functional or neurocognitive/mental problems, polypharmacy, and social difficulties) is higher in the HIV-infected population than in their uninfected counterparts. However, despite the potential impact of this situation on health care, little information exists about the optimal clinical management of older HIV-infected people. Here we examine the age-related conditions in older HIV-infected persons and address clinical management according to author expertise and published literature. Our aim is to advance the debate about the most appropriate management of this population, including less well-studied aspects, such as frequency of screening for psychological/mental and social and functional capabilities. PMID- 29430463 TI - Comparison of Host Gene Expression Profiles in Spleen Tissues of Genetically Susceptible and Resistant Mice during ECTV Infection. AB - Ectromelia virus (ECTV), the causative agent of mousepox, has emerged as a valuable model for investigating the host-Orthopoxvirus relationship as it relates to pathogenesis and the immune response. ECTV is a mouse-specific virus and causes high mortality in susceptible mice strains, including BALB/c and C3H, whereas C57BL/6 and 129 strains are resistant to the disease. To understand the host genetic factors in different mouse strains during the ECTV infection, we carried out a microarray analysis of spleen tissues derived from BALB/c and C57BL/6 mice, respectively, at 3 and 10 days after ECTV infection. Differential Expression of Genes (DEGs) analyses revealed distinct differences in the gene profiles of susceptible and resistant mice. The susceptible BALB/c mice generated more DEGs than the resistant C57BL/6 mice. Additionally, gene ontology and KEGG pathway analysis showed the DEGs of susceptible mice were involved in innate immunity, apoptosis, metabolism, and cancer-related pathways, while the DEGs of resistant mice were largely involved in MAPK signaling and leukocyte transendothelial migration. Furthermore, the BALB/c mice showed a strong induction of interferon-induced genes, which, however, were weaker in the C57BL/6 mice. Collectively, the differential transcriptome profiles of susceptible and resistant mouse strains with ECTV infection will be crucial for further uncovering the molecular mechanisms of the host-Orthopoxvirus interaction. PMID- 29430464 TI - IGF-1R and Leptin Expression Profile and the Effects of Metformin Treatment on Metabolic and Endocrine Parameters in PCOS Mice. AB - We aim to assess the effects of metformin treatment on metabolic and endocrine parameters and genes expression related to the insulin-responsive pathway in polycystic ovary syndrome (PCOS). This study comprises twenty-eight obese mice divided into three metformin-treated groups for seven and twenty days and eight nonobese and nontreated ones. We found a significant decrease in glycemia after metformin treatment at days seven and twenty. However, we did not observe differences in body weight measurement. Histologically, after twenty days we observed follicular development with regression of androgenic effects. Levels of IGF-1R protein expression were low after twenty days of treatment, but LEP proteins showed an overexpression in the ovarian stroma. We assessed the IGF-1R and LEP mRNAs levels; data showed a significant overexpression of LEP after seven days of treatment, while the IGF-1R was downregulated. Metformin therapy seems to exert a beneficial effect on histological and anovulatory features, reducing follicular number and pyknosis formation, possibly involved in the reversion of androgenic stimulus. Expression of IGF-1 and LEPR indicates a relevant role in androgenic features reversion present in PCOS, hormonal equilibrium, body weight regulation, and glucose metabolism, therefore, under phenotype obesity and infertility regulation in this model. PMID- 29430465 TI - Measures of Adherence and Challenges in Using Glucometer Data in Youth with Type 1 Diabetes: Rethinking the Value of Self-Report. AB - Purpose: The current study compares the relative strength of associations of different adherence measures with glycemic control in adolescents with type 1 diabetes, while highlighting the challenges in using more objective measures (i.e., glucometer data). Methods: Adolescents with type 1 diabetes (n = 149) and their caregivers completed a questionnaire measure assessing adolescents' adherence (Self-Care Inventory (SCI)) to the diabetes regimen. Adolescents' glucometers were downloaded to determine average blood glucose checks per day, as an objective measure of adherence. A measure of glycemic control (hemoglobin A1c (HbA1c)) was obtained as part of adolescents' regular clinic visits. Results: Adolescents' self-reported adherence to the treatment regimen was more strongly correlated with HbA1c than caregivers' reports of adherence. In multivariate analyses, both adolescents' self-report of adherence and average blood glucose checks per day (obtained via a glucometer) were significant predictors of HbA1c. Challenges to obtaining glucometer data were identified. Conclusions: The findings highlight adolescents' self-report of adherence using the SCI as a brief and meaningful measure to understand and improve adolescents' glycemic control, particularly when glucometer data is difficult to obtain. PMID- 29430467 TI - Dissecting Cellulitis of the Scalp: A Rare Dermatological Manifestation of Crohn's Disease. AB - Dissecting cellulitis is an inflammatory disease of the skin. We report a case of recurrent dissecting cellulitis in a patient with Crohn's disease. A 31-year-old man with a history of purulent scalp lesions presented with night sweats, weight loss, abdominal pain, and hematochezia. Colonoscopy revealed a diffuse friable mucosa with extensive pseudopolyps. Scalp biopsy demonstrated epidermoid inclusion cysts with granulation tissue and chronic inflammatory cell infiltration, indicative of dissecting cellulitis. The incidence of dissecting cellulitis with Crohn's disease is underreported. This dermatologic condition has a tendency to recur, and considering an underlying disease is key for its appropriate treatment. PMID- 29430468 TI - Endoscopic Submucosal Dissection of Rectal Cancer Close to the Dentate Line Accompanied by Mucosal Prolapse Syndrome. AB - A 37-year-old man presented to our hospital for early rectal cancer accompanied by mucosal prolapse syndrome. Biopsy confirmed an adenocarcinoma, and endoscopic ultrasonography indicated proximity to the dentate line but no submucosal invasion. The tumor was removed en bloc via endoscopic submucosal dissection without complications, and its margin was free of tumor cells. The total procedure duration was 37 minutes, and the resected specimen measured 23 * 13 mm. There was no recurrence during the 3-year observation period. Although close to the dentate line and accompanied by mucosal prolapse syndrome, a rectal cancer lesion was safely resected en bloc using endoscopic submucosal dissection. PMID- 29430466 TI - Regulatory T Cells and Their Prognostic Relevance in Hematologic Malignancies. AB - Regulatory T cells (Tregs) have a fundamental function in monitoring the immune homeostasis in healthy individuals. In cancer and, in particular, in hematological malignancies, Tregs exert a major immunosuppressive activity, thus playing a critical role in tumor cell growth, proliferation, and survival. Here, we summarize published data on the prognostic significance of Tregs in hematological malignancies and show that they are highly conflicting. The heterogeneity of the experimental approaches that were used explains-at least in part-the discordant results reported by different groups that have investigated the role of Tregs in cancer. In fact, different tissues have been studied (i.e., peripheral blood, bone marrow, and lymph node), applying different methods (i.e., flow cytometry versus immunohistochemistry, whole blood versus isolated peripheral blood mononuclear cells versus depletion of CD25+ cells, various panels of monoclonal antibodies, techniques of fixation and permeabilization, and gating strategies). This is of relevance in order to stress the need to apply standardized approaches in the study of Tregs in hematological malignancies and in cancer in general. PMID- 29430469 TI - Posttransplant Lymphoproliferative Disorder Isolated to the Adrenal Gland in a Liver Transplant Patient. AB - Posttransplant lymphoproliferative disorder (PTLD) is a serious complication that accounts for up to 20% of malignancies after solid organ transplantation. We describe a rare case of isolated PTLD in the adrenal gland occurring 7 months after liver transplant in a patient who developed a primary Epstein-Barr virus infection. He was treated with rituximab and his immunosuppression regimen was minimized. We review the incidence, pathogenesis, presentation, and management of PTLD in the liver-transplant population. Our case highlights the variation in the presentation of PTLD and the importance of a high index of suspicion among the at risk group. PMID- 29430470 TI - Transjugular Intrahepatic Portosystemic Shunt for Refractory Variceal Bleeding in a Patient with a Left Ventricular Assist Device. AB - Transjugular intrahepatic portosystemic shunt (TIPS) is an attractive therapeutic option in cirrhotic patients with recurrent variceal bleeding refractory to medical and endoscopic therapy. There is little known about the use of TIPS in patients with left ventricular assist devices (LVAD). We describe a patient with a durable continuous-flow LVAD and concurrent decompensated cardiac cirrhosis who underwent successful TIPS placement for recurrent variceal bleeding. The patient has had no rebleeding or encephalopathy in >12 months since TIPS placement. PMID- 29430471 TI - Motion artifact detection and correction in functional near-infrared spectroscopy: a new hybrid method based on spline interpolation method and Savitzky-Golay filtering. AB - Motion artifact contamination in near-infrared spectroscopy (NIRS) data has become an important challenge in realizing the full potential of NIRS for real life applications. Various motion correction algorithms have been used to alleviate the effect of motion artifacts on the estimation of the hemodynamic response function. While smoothing methods, such as wavelet filtering, are excellent in removing motion-induced sharp spikes, the baseline shifts in the signal remain after this type of filtering. Methods, such as spline interpolation, on the other hand, can properly correct baseline shifts; however, they leave residual high-frequency spikes. We propose a hybrid method that takes advantage of different correction algorithms. This method first identifies the baseline shifts and corrects them using a spline interpolation method or targeted principal component analysis. The remaining spikes, on the other hand, are corrected by smoothing methods: Savitzky-Golay (SG) filtering or robust locally weighted regression and smoothing. We have compared our new approach with the existing correction algorithms in terms of hemodynamic response function estimation using the following metrics: mean-squared error, peak-to-peak error ([Formula: see text]), Pearson's correlation ([Formula: see text]), and the area under the receiver operator characteristic curve. We found that spline-SG hybrid method provides reasonable improvements in all these metrics with a relatively short computational time. The dataset and the code used in this study are made available online for the use of all interested researchers. PMID- 29430472 TI - Phantom-based study exploring the effects of different scatter correction approaches on the reconstructed images generated by contrast-enhanced stationary digital breast tomosynthesis. AB - Stationary digital breast tomosynthesis (sDBT) is an emerging technology in which the single rotating x-ray tube is replaced by a fixed array of multiple carbon nanotube-enabled sources, providing a higher spatial and temporal resolution. As such, sDBT offers a promising platform for contrast-enhanced (CE) imaging. However, given the minimal enhancement above background with standard operational tube settings and iodine dosing, CE breast imaging requires additional acquisition steps to isolate the iodine signal, using either temporal or dual energy subtraction (TS or DES) protocols. Also, correcting for factors that limit contrast is critical, and scatter and noise pose unique challenges during tomosynthesis. This phantom-based study of CE sDBT compared different postacquisition scatter correction approaches on the quality of the reconstructed image slices. Beam-pass collimation was used to sample scatter indirectly, from which an interpolated scatter map was obtained for each projection image. Scatter corrected projections provided the information for reconstruction. Comparison between the application of different scatter maps demonstrated the significant effect that processing has on the contrast-to-noise ratio and feature detectability ([Formula: see text]) in the final displayed images and emphasized the critical importance of scatter correction during DES. PMID- 29430473 TI - Dose and diagnostic performance comparison between phase-contrast mammography with synchrotron radiation and digital mammography: a clinical study report. AB - Two dosimetric quantities [mean glandular dose (MGD) and entrance surface air kerma (ESAK)] and the diagnostic performance of phase-contrast mammography with synchrotron radiation (MSR) are compared to conventional digital mammography (DM). Seventy-one patients (age range, 41 to 82 years) underwent MSR after a DM examination if questionable or suspicious breast abnormalities were not clarified by ultrasonography. The MGD and the ESAK delivered in both examinations were evaluated and compared. Two on-site radiologists rated the images in consensus according to the Breast Imaging Reporting and Data System assessment categories, which were then correlated with the final diagnoses by means of statistical generalized linear models (GLMs). Receiver operating characteristic curves were also used to assess the diagnostic performance by comparing the area under the curve (AUC). An important MGD and ESAK reduction was observed in MSR due to the monoenergetic beam. In particular, an average 43% reduction was observed for the MGD and a reduction of more than 50% for the ESAK. GLM showed higher diagnostic accuracy, especially in terms of specificity, for MSR, confirmed by AUC analysis ([Formula: see text]). The study design implied that the population was characterized by a high prevalence of disease and that the radiologists, who read the DM images before referring the patient to MSR, could have been influenced in their assessments. Within these limitations, the use of synchrotron radiation with the phase-contrast technique applied to mammography showed an important dose reduction and a higher diagnostic accuracy compared with DM. These results could further encourage research on the translation of x-ray phase-contrast imaging into the clinics. PMID- 29430474 TI - Characterization and validation of the thorax phantom Lungman for dose assessment in chest radiography optimization studies. AB - This work concerns the validation of the Kyoto-Kagaku thorax anthropomorphic phantom Lungman for use in chest radiography optimization. The equivalence in terms of polymethyl methacrylate (PMMA) was established for the lung and mediastinum regions of the phantom. Patient chest examination data acquired under automatic exposure control were collated over a 2-year period for a standard x ray room. Parameters surveyed included exposure index, air kerma area product, and exposure time, which were compared with Lungman values. Finally, a voxel model was developed by segmenting computed tomography images of the phantom and implemented in PENELOPE/penEasy Monte Carlo code to compare phantom tissue equivalent materials with materials from ICRP Publication 89 in terms of organ dose. PMMA equivalence varied depending on tube voltage, from 9.5 to 10.0 cm and from 13.5 to 13.7 cm, for the lungs and mediastinum regions, respectively. For the survey, close agreement was found between the phantom and the patients' median values (deviations lay between 8% and 14%). Differences in lung doses, an important organ for optimization in chest radiography, were below 13% when comparing the use of phantom tissue-equivalent materials versus ICRP materials. The study confirms the value of the Lungman for chest optimization studies. PMID- 29430475 TI - H-scan analysis of thyroid lesions. AB - The H-scan analysis of ultrasound images is a matched-filter approach derived from analysis of scattering from incident pulses in the form of Gaussian-weighted Hermite polynomial functions. This framework is applied in a preliminary study of thyroid lesions to examine the H-scan outputs for three categories: normal thyroid, benign lesions, and cancerous lesions within a total group size of 46 patients. In addition, phantoms comprised of spherical scatterers are analyzed to establish independent reference values for comparison. The results demonstrate a small but significant difference in some measures of the H-scan channel outputs between the different groups. PMID- 29430476 TI - Determination and verification of the x-ray spectrum of a CT scanner. AB - The accuracy of Monte Carlo (MC) simulations in estimating the computed tomography radiation dose is highly dependent on the proprietary x-ray source information. To address this, this study develops a method to precisely estimate the x-ray spectrum and bowtie (BT) filter thickness of the x-ray source based on physical measurements and calculations. The static x-ray source of the CT localizer radiograph was assessed to measure the total filtration at the isocenter for the x-ray spectrum characterization and the BT profile (air-kerma values as a function of fan angle). With these values, the utilized BT filter in the localizer radiograph was assessed by integrating the measured air kerma in a full 360-deg cycle. The consistency observed between the integrated BT filter profiles and the directly measured profiles pointed to the similarity in the utilized BT filter in terms of thickness and material between the static and rotating x-ray geometries. Subsequently, the measured air kerma was used to calculate the BT filter thickness and was verified using MC simulations by comparing the calculated and measured air-kerma values, where a very good agreement was observed. This would allow a more accurate computed tomography simulation and facilitate the estimation of the dose delivered to the patients. PMID- 29430477 TI - Automated segmentation of hyperreflective foci in spectral domain optical coherence tomography with diabetic retinopathy. AB - We propose an automated segmentation method to detect, segment, and quantify hyperreflective foci (HFs) in three-dimensional (3-D) spectral domain optical coherence tomography (SD-OCT). The algorithm is divided into three stages: preprocessing, layer segmentation, and HF segmentation. In this paper, a supervised classifier (random forest) was used to produce the set of boundary probabilities in which an optimal graph search method was then applied to identify and produce the layer segmentation using the Sobel edge algorithm. An automated grow-cut algorithm was applied to segment the HFs. The proposed algorithm was tested on 20 3-D SD-OCT volumes from 20 patients diagnosed with proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). The average dice similarity coefficient and correlation coefficient ([Formula: see text]) are 62.30%, 96.90% for PDR, and 63.80%, 97.50% for DME, respectively. The proposed algorithm can provide clinicians with accurate quantitative information, such as the size and volume of the HFs. This can assist in clinical diagnosis, treatment, disease monitoring, and progression. PMID- 29430478 TI - Use of clinical MRI maximum intensity projections for improved breast lesion classification with deep convolutional neural networks. AB - Deep learning methods have been shown to improve breast cancer diagnostic and prognostic decisions based on selected slices of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). However, incorporation of volumetric and temporal components into DCE-MRIs has not been well studied. We propose maximum intensity projection (MIP) images of subtraction MRI as a way to simultaneously include four-dimensional (4-D) images into lesion classification using convolutional neural networks (CNN). The study was performed on a dataset of 690 cases. Regions of interest were selected around each lesion on three MRI presentations: (i) the MIP image generated on the second postcontrast subtraction MRI, (ii) the central slice of the second postcontrast MRI, and (iii) the central slice of the second postcontrast subtraction MRI. CNN features were extracted from the ROIs using pretrained VGGNet. The features were utilized in the training of three support vector machine classifiers to characterize lesions as malignant or benign. Classifier performances were evaluated with fivefold cross-validation and compared based on area under the ROC curve (AUC). The approach using MIPs [Formula: see text] outperformed that using central-slices of either second postcontrast MRIs [Formula: see text] or second postcontrast subtraction MRIs [Formula: see text], at statistically significant levels. PMID- 29430479 TI - Toward quantitative quasistatic elastography with a gravity-induced deformation source for image-guided breast surgery. AB - Biomechanical breast models have been employed for applications in image registration and diagnostic analysis, breast augmentation simulation, and for surgical and biopsy guidance. Accurate applications of stress-strain relationships of tissue within the breast can improve the accuracy of biomechanical models that attempt to simulate breast deformations. Reported stiffness values for adipose, glandular, and cancerous tissue types vary greatly. Variations in reported stiffness properties have been attributed to differences in testing methodologies and assumptions, measurement errors, and natural interpatient differences in tissue elasticity. Therefore, the ability to determine patient-specific in vivo breast tissue properties would be advantageous for these procedural applications. While some in vivo elastography methods are not quantitative and others do not measure material properties under deformation conditions that are appropriate to the application of concern, in this study, we developed an elasticity estimation method that is performed using deformations representative of supine therapeutic procedures. More specifically, reconstruction of mechanical properties appropriate for the standard-of-care supine lumpectomy was performed by iteratively fitting two anatomical images before and after deformations taking place in the supine breast configuration. The method proposed is workflow-friendly, quantitative, and uses a noncontact, gravity-induced deformation source. PMID- 29430480 TI - Further characterization of changes in axial strain elastograms due to the presence of slippery tumor boundaries. AB - Elastography measures tissue strain, which can be interpreted under certain simplifying assumptions to be representative of the underlying stiffness distribution. This is useful in cancer diagnosis where tumors tend to have a different stiffness to healthy tissue and has also shown potential to provide indication of the degree of bonding at tumor-tissue boundaries, which is clinically useful because of its dependence on tumor pathology. We consider the changes in axial strain for the case of a symmetrical model undergoing uniaxial compression, studied by characterizing changes in tumor contrast transfer efficiency (CTE), inclusion to background strain contrast and strain contrast generated by slip motion, as a function of Young's modulus contrast and applied strain. We present results from a finite element simulation and an evaluation of these results using tissue-mimicking phantoms. The simulation results show that a discontinuity in displacement data at the tumor boundary, caused by the surrounding tissue slipping past the tumor, creates a halo of "pseudostrain" across the tumor boundary. Mobile tumors also appear stiffer on elastograms than adhered tumors, to the extent that tumors that have the same Young's modulus as the background may in fact be visible as low-strain regions, or those that are softer than the background may appear to be stiffer than the background. Tumor mobility also causes characteristic strain heterogeneity within the tumor, which exhibits low strain close to the slippery boundary and increasing strain toward the center of the tumor. These results were reproduced in phantom experiments. In addition, phantom experiments demonstrated that when fluid lubrication is present at the boundary, these effects become applied strain-dependent as well as modulus dependent, in a systematic and characteristic manner. The knowledge generated by this study is expected to aid interpretation of clinical strain elastograms by helping to avoid misinterpretation as well as provide additional diagnostic criteria stated in the paper and stimulate further research into the application of elastography to tumor mobility assessment. PMID- 29430481 TI - Robotic drill guide positioning using known-component 3D-2D image registration. AB - A method for x-ray image-guided robotic instrument positioning is reported and evaluated in preclinical studies of spinal pedicle screw placement with the aim of improving delivery of transpedicle K-wires and screws. The known-component (KC) registration algorithm was used to register the three-dimensional patient CT and drill guide surface model to intraoperative two-dimensional radiographs. Resulting transformations, combined with offline hand-eye calibration, drive the robotically held drill guide to target trajectories defined in the preoperative CT. The method was assessed in comparison with a more conventional tracker-based approach, and robustness to clinically realistic errors was tested in phantom and cadaver. Deviations from planned trajectories were analyzed in terms of target registration error (TRE) at the tooltip (mm) and approach angle (deg). In phantom studies, the KC approach resulted in [Formula: see text] and [Formula: see text], comparable with accuracy in tracker-based approach. In cadaver studies with realistic anatomical deformation, the KC approach yielded [Formula: see text] and [Formula: see text], with statistically significant improvement versus tracker ([Formula: see text] and [Formula: see text]). Robustness to deformation is attributed to relatively local rigidity of anatomy in radiographic views. X-ray guidance offered accurate robotic positioning and could fit naturally within clinical workflow of fluoroscopically guided procedures. PMID- 29430483 TI - Determination of Boron Content Using a Simple and Rapid Miniaturized Curcumin Assay. AB - To determine boron quantity in soil, water and biological samples, several protocols are available. Colorimetric assays are the simplest and cheapest methods which can be used to determine boron concentration. However, published protocols do not give straightforward guidance for beginners to adopt these protocols for routine use in the laboratory. Based on a previously published available procedure, we present a detailed and modified version of a curcumin based colorimetric protocol to determine boron concentration extracted from any sample. Our modified protocol is able to determine up to 0.2 nmole of Boron in a sample volume of 300 MUl. PMID- 29430482 TI - Photodissociation of aligned CH3I and C6H3F2I molecules probed with time-resolved Coulomb explosion imaging by site-selective extreme ultraviolet ionization. AB - We explore time-resolved Coulomb explosion induced by intense, extreme ultraviolet (XUV) femtosecond pulses from a free-electron laser as a method to image photo-induced molecular dynamics in two molecules, iodomethane and 2,6 difluoroiodobenzene. At an excitation wavelength of 267 nm, the dominant reaction pathway in both molecules is neutral dissociation via cleavage of the carbon iodine bond. This allows investigating the influence of the molecular environment on the absorption of an intense, femtosecond XUV pulse and the subsequent Coulomb explosion process. We find that the XUV probe pulse induces local inner-shell ionization of atomic iodine in dissociating iodomethane, in contrast to non selective ionization of all photofragments in difluoroiodobenzene. The results reveal evidence of electron transfer from methyl and phenyl moieties to a multiply charged iodine ion. In addition, indications for ultrafast charge rearrangement on the phenyl radical are found, suggesting that time-resolved Coulomb explosion imaging is sensitive to the localization of charge in extended molecules. PMID- 29430484 TI - Characterising Maturation of GFP and mCherry of Genomically Integrated Fusions in Saccharomyces cerevisiae. AB - Single-molecule fluorescence microscopy enables unrivaled sub-cellular quantitation of genomically encoded fusions of native proteins with fluorescent protein reporters. Fluorescent proteins must undergo in vivo maturation after expression before they become photoactive. Maturation effects must be quantified during single-molecule analysis. Here we present a method to characterise maturation of GFP and mCherry genetic protein fusions in budding yeast Saccharomyces cerevisiae. PMID- 29430485 TI - Effects of Pre-Retirement Personality, Health and Job Lock on Post-Retirement Subjective Well-being. AB - Retirement can be difficult, and experiences vary greatly. Although health, financial status, and family responsibilities have been associated with retirement adjustment, individual psychosocial characteristics may also play a role. Moreover, relatively little is known about the impact of perceived 'job lock'-the belief that retirement is impossible due to financial or health constraints-and its relationship with later retirement adjustment. The current study addresses these limitations in the literature by examining the retirement transition over four years in a large sample of U.S. adults, with a particular focus on the ways in which personality may affect this transition. Data collected at baseline (2008/2010) and again four years later (2012/2014) included the Big Five personality traits, pre-retirement job lock, self-rated health, and multiple indicators of post-retirement well-being, such as global and experienced well being (anchored within activities in a single day). Participants were drawn from the Health and Retirement Study (N = 716; Mage = 61.9 at baseline). Results indicated that experienced positive affect was the only post-retirement well being outcome with a significant association with job lock, although only for those with low conscientiousness. Findings also suggest that pre-retirement personality and subjective health play an important role for post-retirement well being. Thus, the current study highlights the importance for researchers and practitioners to consider both pre-retirement personality and health when evaluating individuals' management of the retirement transition. Word Count: 224. PMID- 29430486 TI - DO YOU HAVE TO WIN IT TO FIX IT? A Longitudinal Study of Lottery Winners and Their Health-Care Demand. AB - We exploit lottery wins to investigate the effects of exogenous changes to individuals' income on the utilization of health care services, and the choice between private and public health care in the United Kingdom. Our empirical strategy focuses on lottery winners in an individual fixed effects framework and hence the variation of winnings arises from within-individual differences in small versus large winnings. The results indicate that lottery winners with larger wins are more likely to choose private health services than public health services from the National Health Service. The positive effect of wins on the choice of private care is driven largely by winners with medium to large winnings (win category > L500 (or US$750); mean = L1922.5 (US$2,893.5), median = L1058.2 (US$1592.7)). There is some evidence that the effect of winnings vary by whether individuals have private health insurance. We also find weak evidence that large winners are more likely to take up private medical insurance. Large winners are also more likely to drop private insurance coverage between approximately 9 and 10 months earlier than smaller winners, possibly after their winnings have been exhausted. Our estimates for the lottery income elasticities for public health care (relative to no care) are very small and are not statistically distinguishable from zero; those of private health care range from 0 - 0.26 for most of the health services considered, and 0.82 for cervical smear. PMID- 29430487 TI - ISKAST; the Way We Have Made and Upfront. PMID- 29430488 TI - Medial Collateral Ligament Injury; A New Classification Based on MRI and Clinical Findings. A Guide for Patient Selection and Early Surgical Intervention. PMID- 29430490 TI - Does a Previous High Tibial Osteotomy (HTO) Influence the Long-term Function or Survival of a Total Knee Arthroplasty (TKA)? AB - High tibial osteotomy (HTO) is a well established technique for the treatment of medial osteoarthritis of the knee with varus malalignment. The outcome of total knee arthroplasty (TKA) after HTO remains uncertain. The aim of this paper is to revise the literature with the aim of answering the following question: Does a previous (HTO) influence the long-term function or survival of a TKA?. The search engine was MedLine. The keywords used were: total knee arthroplasty after high tibial osteotomy. One hundred and ten articles were found. Of those, only 19 were selected and reviewed because they were strictly focused on the topic and the question of this article. The reports published so far have a low grade of evidence (levels III and IV). Most of them are prospective case series (level IV). One is a systematic review of level III studies reported in 2009. Two recent studies based in a great number of cases (registers) showed similar survival in the 2 groups: around 92% at 10 years, and 88% at 15 years. The review of the literature suggests that a previous HTO does not influence the function or survival of a TKA in the long-term. Level of evidence: III. PMID- 29430489 TI - Posterior Cruciate Ligament: Current Concepts Review. AB - The posterior cruciate ligament (PCL) is the largest and strongest ligament in the human knee, and the primary posterior stabilizer. Recent anatomy and biomechanical studies have provided an improved understanding of PCL function. PCL injuries are typically combined with other ligamentous, meniscal and chondral injuries. Stress radiography has become an important and validated objective measure in surgical decision making and post-operative assessment. Isolated grade I or II PCL injuries can usually be treated non-operatively. However, when acute grade III PCL ruptures occur together with other ligamentous injury and/or repairable meniscal body/root tears, surgery is indicated. Anatomic single-bundle PCL reconstruction (SB-PCLR) typically restores the larger anterolateral bundle (ALB) and represents the most commonly performed procedure. Unfortunately, residual posterior and rotational tibial instability after SB-PCLR has led to the development of an anatomic double-bundle (DB) PCLR to restore the native PCL footprint and co-dominant behavior of the anterolateral and posteromedial bundles and re-establish normal knee kinematics. The purpose of this article is to review the pertinent details regarding PCL anatomy, biomechanics, injury diagnosis and treatment options, with a focus on arthroscopically assisted DB-PCLR. Level of evidence: IV. PMID- 29430491 TI - Total Knee Arthroplasty in Patients with Retention of Prior Hardware Material: What is the Outcome? AB - Background: There is an information gap in literature regarding postoperative outcome of total knee arthroplasty (TKA) in patients with hardware in-situ from the previous knee surgery. The present study aims to evaluate impact of retained hardware on short-term outcome of TKA patients. Methods: Perioperative radiographs of patients who had undergone TKA between 2007 and 2012 were reviewed and patients in whom partial or complete retention of hardware was evident after TKA were included. These patients were matched in 1 to 2 ratio based on age (+/- 2 years), gender, surgeon and year of surgery to a group of patients that underwent primary TKA without hardware in the affected knee. The average follow up of these patients was 43.45 (range 12-155.2) months. Complication rates were compared between the two groups using statistical tests that took into account the matched data structure. Results: We included a total of 55 cases and 110 controls. The incidence of complications was higher, although not all statistically significant, in the case group. Only mechanical complications were significantly different in the cases group (5.5% versus 0%, P=0.01). Time to event analysis using the mixed-effects Cox model didn't show a statistically significant difference between two groups for various outcomes. Conclusion: Presence of retained hardware around the knee may predispose the patient to a higher rate of complications particularly mechanical complications of the implant after TKA. Further studies are required to investigate impact of retained hardware around the knee in patients undergoing TKA.Level of evidence: III. PMID- 29430492 TI - A Single Femoral Component for All Total Hip Replacements Performed by a Trust? Does This Affect Early Clinical and Radiological Outcomes? AB - Background: Hospitals may be under pressure to implement cost saving strategies regarding prosthesis choice. This may involve the use of components which are not the first preference of individual surgeons, or those they have little experience with. We aim to examine the effect of standardizing the type of femoral stem used in a single trust, and determine whether this is safe practice, particularly in those who have never used this particular stem before. Methods: We report results at 2 years of 151 primary total hip arthroplasties performed using a single femoral stem. Data was split into 2 groups: those in which the operating surgeon was previously using this femoral stem, and those who were not. Radiographic outcomes measured were leg length discrepancy, cement mantle grade, and femoral stem alignment. We also report on clinical outcomes, complications, and construct survivability. Results: No significant differences in clinical outcomes were observed. Cement quality was generally worse in those with no prior use of this stem. Leg length inequality was greater in those previously using the stem (+1.57mm vs 3.83mm), however this did not correlate to clinical outcomes. Alignment was similar between the groups (P=0.464). Conclusion: Our findings suggest that although clinical outcomes are similar at 2 years, radiological differences can be observed even at this early stage in follow up. Choice of components for arthroplasty should remain surgeon led until long term follow up studies can prove otherwise.level of evidence: III. PMID- 29430493 TI - Preoperative Sterilization Preparation of the Shoulder: A Comparative Study Evaluating Gauze Sponge and Commercially Available Applicator Prep Stick. AB - Background: Surgical site infection (SSI) remains a concern in shoulder surgery, especially during arthroplasty. While many studies have explored the characteristics and efficacy of different sterilizing solutions, no study has evaluated the method of application. The purpose of this study was to compare two popular pre-surgical preparatory applications (two 4 x 4 cm gauze sponges and applicator stick) in their ability to cover the skin of the shoulder. Methods: Two orthopedic surgeons simulated the standard pre-surgical skin preparation on 22 shoulders of volunteer subjects. Each surgeon alternated between an applicator stick and two sterile 4x4 cm gauze sponges. Skin preparation was performed with a commercially available solution that can be illuminated under UV-A light. Advanced image-analysis software was utilized to determine un-prepped areas. A two-tailed paired t-test was performed to compare percentage of un-prepped skin. Results: The applicator stick method resulted in a significantly higher percentage of un-prepped skin (27.25%, Range 10-49.3) than the gauze sponge method (15.37%, Range 5-32.8, P=0.002). Based on image evaluation, most un prepped areas were present around the axilla. Conclusion: Based on our findings, the use of simple gauze sponges for pre-surgical preparatory application of sterilization solution may result in a lower percent of un-prepped skin than commercially available applicator stick. Orthopaedic surgeons and operating room staff should be careful during the pre-surgical sterile preparation of the shoulder, especially the region around the axilla, in order to reduce the potential risk of surgical site infection.Level of evidence: III. PMID- 29430494 TI - Elastic Stable Intramedullary Nailing of Femoral Shaft Fracture-Experience in 48 Children. AB - Background: Femoral shaft fractures are an incapacitating pediatric injury accounting for 1.6% of all pediatric bony injuries. Management of these fractures is largely directed by age, fracture pattern, associated injuries, built of the child and socioeconomic status of the family. We retrospectively evaluated the use of elastic stable intramedullary nail (ESIN) in surgical management of femoral shaft fractures in children and its complications. Methods: Fifty two children were treated with titanium elastic nails (TEN) from June 2009 to June 2014 at our institution. At the end of the study there were 48 children. Fractures were classified according to Winquest and Hansen's as Grade I (n=32), Grade II (n=10), Grade III (n=6) and compound fractures by Gustilo and Anderson's classification, Grade I (n=5), Grade II (n=3). There were 36 mid-shaft fractures, 7 proximal third shaft fractures, 5 distal third shaft fractures. The final results were clinically evaluated by using Flynn's criteria and radiologically by Anthony et al's criteria. Results: The mean duration of follow-up was 20 months (range 12 - 40 months). All fractures healed radiologically with grade III callus formation at 9 - 12 weeks (mean 9.7 weeks). The results were analyzed using Flynn's criteria and were excellent in 40 children (83%) and satisfactory in 8 children (17%). The soft tissue discomfort near the knee produced by nail ends was the most common problem in our study (25%). Other complications include limb shortening (n=5), Varus malunion (n=4), Nail protruding site infection (n=4) and nail migration (n=2). There was no delayed union, non-union or refractures. Conclusion: TEN is minimally invasive, safe, relatively easy to use and an effective treatment for fracture shaft of femur in properly selected children.Level of evidence: III. PMID- 29430495 TI - A Comparison of the Postoperative Complications between Two Drainage Methods after Total Knee Arthroplasty. AB - Background: The role of wound drainage after total knee arthroplasty is still considered controversial as although closed drainage systems have been believed to be effective in decreasing the post-operative complications, they could also facilitate the bleeding and increase the rate of transfusion and infection. We have conducted the current study to compare the outcomes superficial subcutaneous, one deep, and two deep drain techniques after total knee arthroplasty. Methods: Between 2014 and 2015 sixty consecutive patients were prospectively selected and underwent primary total knee arthroplasty. Patients randomized to receive one superficial, one deep and two deep drains at the end of operation. Tourniquet was used and opened at the end of the surgery after dressing. Patients were studied for volume of blood loss, hemoglobin drop, number of transfusion, and any complications. Knee range of motion and diameter were measured and compared with contralateral side in all cases at the end of the third day. Results: There was no statistical difference regarding red blood cell volume loss, Hb drop, and transfusion rate between groups. Patients in one superficial group had the most sever post-operative ecchymosis. Knee flexion and swelling were the same in all groups. Patients in one superficial drain group had the worst VAS for the pain. Need for early blood transfusion was significantly higher in two deep drain group. In one deep drain group returned back to operating room for sever hemarthrosis and wound dehiscence was occurred in a patient. One patient in one deep group had also developed mild thrombo-emboli. Conclusion: Regarding the blood volume loss after total knee arthroplasty there is no difference between superficial drainage and even more effective intra articular techniques. Outcome and complication rates are the same.Level of evidence: II. PMID- 29430496 TI - Injury to the Infrapatellar Branch of the Saphenous Nerve during ACL Reconstruction with Hamstring Tendon Autograft: A Comparison between Oblique and Vertical Incisions. AB - Background: Injury to the infrapatellar branch of the saphenous nerve (IPBSN) is common after arthroscopic ACL reconstruction with hamstring tendon autograft, as reported in up to 88% of the cases. Due to close relationship between the IPBSN with pes anserine tendons insertion skin incision may sever IPBSN while harvesting gracillis and semitendinous tendons. As the IPBSN course at the anterior of knee is oblique, we hypothesized a parallel skin incision with nerve passage may decrease nerve injury. Methods: Vertical and oblique incisions were compared in 79 patients in this clinical trial. The sensory loss area and patients' complain of numbness were measured at 2 and 8 weeks as well as 6 months after surgery. Results: Both the sensory loss area and patients' complain of numbness decreased significantly in the oblique incision group (P<0001). Conclusion: According to our findings, oblique incision is suggested instead of traditional vertical incision when hamstring tendons are being harvested in arthroscopic ACL reconstruction with hamstring tendon autograft.Level of evidence: IV. PMID- 29430497 TI - Evaluation of Bone Mineral Density in Perimenopausal Period. AB - Background: The menopausal transition called perimenopause, happens after the reproductive years, and is specified with irregular menstrual cycles, perimenopause symptoms and hormonal changes. Women going through peri menopausal period are vulnerable to bone loss . Osteoporosis is one of the most common debilitating metabolic bone diseases, especially in the women almost around 50 years. This study was intended to evaluate the prevalence of osteopenia/osteoporosis amongst asymptomatic individuals during the menopause transition period. Methods: A total of 714 asymptomatic peri-menopausal female volunteers were recruited through a billboard invitation for participation in the study. The subjects were selected based on already defined inclusion and exclusion criteria. The project, which was conducted between 2010 and 2014 was affiliated to the Educational and Therapeutic Center, Imam Reza Hospital, Mashhad, Iran. Bone Mineral Densitometry (BMD) measured by DEXA (dual-energy X ray absorptiometry) was carried out on two distinct sites, the proximal femur and the lumbar vertebrae from L1 to L4. Pertained data were analyzed. Results: The mean age of the subjects was 49.7+/-2.years. The overall prevalence of osteopenia and osteoporosis in these peri-menopausal individuals were 37.6 % and 10% respectively. Thirty five point two percent of 714 women presented with osteopenia and eight percent of them have osteoporosis in the femoral neck, respectively. Nonetheless, BMD values at the lumbar spine indicated 41.6% and 12% of individual participants being affected by osteopenia and osteoporosis. Conclusion: In general osteopenia or osteoporosis, occurred in 48% of this study population, implying that special attention is required for the bone health status of Iranian women who undergo menopause.Level of evidence: II. PMID- 29430498 TI - A Comparison between Single and Double Tourniquet Technique in Distal Upper Limb Orthopedic Surgeries with Intravenous Regional Anesthesia. AB - Background: Several studies have put an effort to minimize the tourniquet pain and complications after conventional double tourniquet intravenous regional anesthesia (IVRA). We expressed in our hypothesis that an upper arm single wide tourniquet (ST) may serve a better clinical efficacy rather than the conventional upper arm double tourniquet (DT) in distal upper extremity surgeries. Methods: In this randomized controlled trial, 80 patients undergoing upper limb orthopedic surgeries were randomized into two groups. IVRA was administered using lidocaine in both groups. Tourniquet pain was recorded based on visual analogue scale (VAS). In case of pain (VAS>3) in the DT group, the proximal tourniquet was replaced with a distal tourniquet while fentanyl 50ug was injected in the ST group. The onset time of tourniquet pain, time to reach to maximum tourniquet pain and the amount of fentanyl consumption were compared between the two groups. Results: No significant difference was seen in demographic characteristics. The onset time of tourniquet pain (VAS=1) in the ST group (26.9+/-13.2 min) was longer than that of the DT group (13.8+/-4.8 min) (P<0.0001). The median of time to reach to maximum tourniquet pain (VAS>3) in DT and ST groups were 25 and 40 minutes, respectively; indicating that the patients in ST group reached to pain level at a significantly later time (P<0.0001). The total opioid consumption in the DT group (61 ug) was significantly lower than the ST group (102 ug) (P<0.0001); however, both groups were similar regarding fentanyl consumption before 40 minutes of surgeries. Conclusion: It seems that in upper limb orthopedic surgeries with less than 40-minute duration, a single tourniquet may serve as a proper alternative opposed to the conventional double tourniquet technique.Level of evidence: II. PMID- 29430499 TI - Translation and Validation of the Persian Version the Boston Carpal Tunnel Syndrome Questionnaire. AB - Background: Carpal tunnel syndrome (CTS) is recognized as the most common type of neuropathies. Questionnaires are the method of choice for evaluating patients with CTS. Boston Carpal Tunnel Syndrome (BCTS) is one of the most famous questionnaires that evaluate the functional and symptomatic aspects of CTS. This study was performed to evaluate the validity and reliability of the Persian version of BCTS questionnaire. Methods: First, both parts of the original questionnaire (Symptom Severity Scale and Functional Status Scale) were translated into Persian by two expert translators. The translated questionnaire was revised after merging and confirmed by an orthopedic hand surgeon. The confirmed questionnaire was interpreted back into the original language (English) to check for any possible content inequality between the original questionnaire and its final translated version. The final Persian questionnaire was answered by 10 patients suffering from CTS to elucidate its comprehensibility; afterwards, it was filled by 142 participants along with the Persian version of the Quick-DASH questionnaire. After 2 to 6 days, the translated questionnaire was refilled by some of the previous patients who had not received any substantial medical treatment during that period. Results: Among all 142 patients, 13.4 % were male and 86.6 % were female. The reliability of the questionnaire was tested using Cronbach's alpha and Intraclass correlation coefficient (ICC). Cronbach's alpha was 0.859 for symptom severity scale (SSS) and 0.878 for functional status scale (FSS). Also, ICCs were calculated as 0.538 for SSS and 0.773 for FSS. In addition, construct validity of SSS and FSS against QuickDASH were 0.641 and 0.701, respectively. Conclusion: Based on our results, the Persian version of the BCTQ is valid and reliable.Level of evidence: II. PMID- 29430500 TI - Topiramate-induced Neuropathy Mimicking Carpal Tunnel Syndrome: A Case Report. AB - Carpel tunnel syndrome (CTS) is a condition in which median nerve compression results in paresthesias and pain in the wrist and hand. We are going to report a rare case of topiramate-induced neuropathy which clinically resembles CTS. Discontinuation of topiramate resulted in spontaneous resolution of numbness, paresthesia and pain in a few days. High clinical suspicion is advised in patients who are on topiramate and present with signs of compressive neuropathy. Level of evidence: V. PMID- 29430501 TI - Modified Internal Fixation Technique for Acromio-Clavicular (AC) joint dislocation: The "Hidden Knot Technique". AB - Acromioclavicular (AC) joint injuries are common and often seen in contact athletes, resulting from a fall on the shoulder tip with adducted arm. This joint is stabilized by both static and dynamic structures including the coracoclavicular (CC) ligament. Most reconstruction techniques focus on CC ligament augmentation as the primary stabilizer of the AC joint. The best surgical technique for some AC joint dislocations is still controversial. In this study, we explained a modification of the CC ligament reconstruction technique described by Wellmann. The method is based on minimally invasive CC ligament augmentation with a flip button/polydioxanone (PDS) repair, typically used for extracortical ACL graft fixation. Patients commonly complain that heavy sutures under the skin in subcutaneous tissue irritate the skin and sometimes require reoperation for suture removal. We present an augmentation technique that resolves this issue by changing the suture knot location to the sub-clavicular position. Level of evidence: II. PMID- 29430502 TI - Immune Responses to Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer. AB - The secondary effects of chemotherapy, with bone marrow depression and risk of leukopenia, has traditionally been considered being detrimental for the immune system. However, growing evidence suggests a main role for chemotherapy in antitumor immunomodulation. With reference to cisplatin, which is the basis of neoadjuvant chemotherapy in muscle invasive bladder cancer, four different aspects of immunomodulation has thus far been described; increased MHC class I expression, recruitment and proliferation of effector cells, enhancement of tumor lytic activity of cytotoxic effectors and downregulation of immunosuppressive actors in the microenvironment. Consequently, the role of chemotherapy in cancer is changing from a therapy solely aimed at inducing tumor cell death, to a potent inducer of immune responses and a potential future major partaker in cancer immunotherapy. This is a great opportunity for the urological community to broaden research in this field in order to increase knowledge, optimize and improve the neoadjuvant regimens of muscle invasive bladder cancer to ultimately improve patient outcome. PMID- 29430503 TI - Molecular and Clinical Insights into the Role and Significance of Mutated DNA Repair Genes in Bladder Cancer. PMID- 29430504 TI - Liquid Biopsy-Analysis of Circulating Tumor DNA (ctDNA) in Bladder Cancer. AB - Recent advances in DNA profiling techniques have enabled sensitive detection of tumor-associated genomic aberrations in peripheral blood. This type of minimally invasive molecular interrogation has the potential to guide subsequent treatment selection. The potential utility of ctDNA in bladder cancer (BC) is bolstered by the high somatic mutation rate, meaning that very small numbers of genes or target regions can be informative. First reports indicate that analysis of ctDNA may represent a sensitive method for disease surveillance in patients with different stages of BC. Moreover, recent evidence suggests that ctDNA analysis reveals previously unknown genomic alterations in metastatic patients. Since some of these gene alterations represent therapeutic targets, ctDNA analysis provides an attractive tool to guide individualized therapy in BC. PMID- 29430506 TI - Toward Personalised Liquid Biopsies for Urothelial Carcinoma: Characterisation of ddPCR and Urinary cfDNA for the Detection of the TERT 228 G>A/T Mutation. AB - Background: TERT promotor mutations are present in >75% of bladder tumours; these mutations are also detectable in urine. Previous studies have used urinary pellet DNA, and semi-quantitative methods unsuitable for detecting very low mutant allele frequencies. Objective: In this proof-of-principle study we use ddPCR to count the DNA molecules with wt and mutant TERT sequences in urinary cfDNA from patients whose bladder cancers harbour TERT mutations. Methods: Urinary cfDNA prepared from the urine from 104 bladder cancer patients was analysed. We determined the mutant allele frequency across stages and grades of disease, analysed concordance between cfDNA and tumour DNA, compared cfDNA with pellet DNA, and analysed the quantity and size distribution of cfDNA. Results: In 71 of 77 patients with a 228 G>A/T mutant tumour, the mutation was also detected in urinary cfDNA by ddPCR; all 6 "false negatives" were low grade pTa tumours. Overall concordance between tissue and cfDNA mutation status was 92%, and 100% was achieved for high grade disease. Median mutant allele frequencies in urinary cfDNA were 3.4, 13.4 and 32.1% in grade 1, 2 and 3 disease. The 228 G>A/T mutation was not detected in urinary cfDNA in 26 out of 27 mutation-negative patients (96% specificity). Conclusions: Concordance between tumour DNA and urinary cfDNA is high, and TERT 228 G>A/T ddPCR may prove useful for monitoring patients that harbour this mutation. Mutant allele frequencies in cfDNA are often high, but assays capable of detecting very low mutant allele frequencies will be required to achieve high sensitivity in low grade disease. PMID- 29430505 TI - Role of Radical Cystectomy in Non-Organ Confined Bladder Cancer: A Systematic Review. AB - Background: Currently, a diagnosis of non-organ confined bladder cancer (NOCBCa) confers a grave prognosis. The mainstay of treatment consists of systemic chemotherapy. However, it must be recognized that NOCBCa is a heterogeneous disease state with important clinical distinctions. While surgical extirpation has traditionally been regarded as overly aggressive for all NOCBCa patients, its utility as part of a multimodal treatment strategy in various clinical scenarios has not been thoroughly investigated. Objective: To perform a review of the literature regarding the role of radical cystectomy and pelvic lymph node dissection (RC-LND) in the setting of NOCBCa. Methods: Medline, and Pubmed electronic database were queried for English language articles from January 1990 to Nov 2016 on RC-LND for cT4, lymph node positive, and metastatic urothelial cancer. NOCBCa was separated into four distinct clinical scenarios: 1. Locally advanced/unresectable disease (cT4bN0M0); 2. Occult pelvic nodal disease (pN+) (cTxN0M0 and pTxN1-3Mx); 3. Clinical node positive disease (cN+) (cTxN1-3M0); and 4. Distant metastatic disease (TxNxM1). Evidence for the role of RC-LND in each of these clinical scenarios was summarized. Results: cT4b may be more effectively treated by presurgical chemotherapy (PSC) than other forms of NOCBCa. Although clinical response predicted improved survival, surgical factors, such as surgical margin status may also play a role in determining outcomes. In well selected patients, 5-year CSS may reach 60% after consolidative RC-LND. Survival in patients found to have pathologic nodal metastases without PSC was dictated not only by the histologically verified metastatic nodal disease burden, but also by the meticulousness of the lymph node dissection. In these patients, adjuvant chemotherapy may improve survival. On the other hand, in patients undergoing RC LND after PSC, pathologic complete response (pCR) was the strongest predictor of improved CSS. The results of population based studies have suggested a therapeutic role by consolidative RC-LND in both patients with cN+ and metastatic BCa (mBCa). For the cN+ population, 5-year OS was 31% in patients undergoing RC LND after PSC vs. 14% in those receiving chemotherapy alone. Similarly, consolidative intensive local therapy improved OS by approximately 5 months in patients with mBCa. Metastasectomy has also been shown to be effective in small retrospective series and may especially be useful in patients with solitary pulmonary lesions. Conclusions: Extirpative treatment of the primary tumor may be an important step in the management of de novo NOCBCa. The current retrospective and population based studies have demonstrated improved survival outcomes in patients with NOCBCa following RC-LND, especially in those with favorable response to PSC. With the advent of minimally invasive surgery and the enhanced post-surgical recovery protocols, RC-LND has not only been demonstrated to be feasible, but also tolerable in the setting of advanced BCa. Well designed, prospective trials are needed to definitively assess the value of surgical extirpation for NOCBCa patients. PMID- 29430507 TI - Peri-Operative Chemotherapy for Bladder Cancer: A Survey of Providers to Determine Barriers and Enablers. AB - Background: Utilization of chemotherapy for patients with muscle-invasive bladder cancer (MIBC) is low. In earlier qualitative work we used the Theoretical Domains Framework (TDF) to determine barriers and enablers of chemotherapy use. In this project we aimed to determine the prevalence of these barriers and enablers in Canadian physicians. Methods: Practicing Canadian urologists, medical oncologists (MOs) and radiation oncologists (ROs) participated in a specialty-specific web based quantitative survey to assess potential barriers and enablers to chemotherapy use. Survey questions were developed that were thematically mapped to TDF domains. Logistic regression was used to identify TDF domains associated with high referral/use of chemotherapy. Results: 110 urologists, 47 MOs and 43 ROs completed the survey; response rates were 20%, 35% and 31% respectively. The mean reported survival gain associated with neoadjuvant chemotherapy (NACT) was 9%, 8%, and 7% for urologists, MOs, and ROs respectively. Among participating urologists, the TDF domains 'social and professional role' (OR = 16.5, 95% CI 4.6 59.2), 'social influences' (OR = 5.7, 95% CI 2.4-13.4) 'beliefs about consequences' (OR = 4.9, 95% CI 1.8-13.3) and 'memory, attention and decision making' (OR = 0.50, 95% CI 0.27-0.91) were associated with MO referral rates. Among MOs, the TDF domains 'behavioural regulation', 'social influences', and 'social and professional role' were associated with greater use of chemotherapy (p < 0.05). No TDF domains were associated with RO referral to MO. Conclusions: We have identified several factors associated with referral/use of chemotherapy for MIBC. Optimization of multidisciplinary patient care needs to be considered when designing future interventions to close the gap between evidence and practice. PMID- 29430508 TI - Decreased Invasion of Urothelial Carcinoma of the Bladder by Inhibition of Matrix Metalloproteinase 7. AB - Objectives: To measure and to modulate the invasive potential of urothelial carcinoma of the bladder (UCB) cells in a standardized preclinical setting using broad-spectrum matrix-metalloproteinase (MMPs) inhibitors and specific targeting of MMP7. Materials and Methods: MMP expression levels in UCB cells were determined by quantitative real-time PCR (qRT-PCR) and gel zymographies of cell supernatants (MMP9, MMP2 and MMP1) and cell lysates (MMP7). The invasiveness of human UCB cells (HT1197 and T24/83) and human benign urothelial cells (UROtsa) was modulated by a broad-spectrum MMP inhibitor (4-Aminobenzoyl-Gly-Pro-D-Leu-D Ala hydroxamic acid; AHA) and by MMP7 specific siRNAs. MMP7 knockdown efficiency was assessed by qRT-PCR and western blot. Invasive potential of UCB cells was measured by a standardized trans-epithelial electrical resistance (TEER) assay. Results: Different MMP secretion profiles were measured in UCB cells. The active form of MMP7 was exclusively detected in HT1197 cells. Characteristic TEER breakdown patterns were observed in UCB cells when compared to benign cells. Invasive potentials were significantly higher in HT1197 cells than in T24/83 and in UROtsa cells [14.8+/-5.75 vs. 1.5+/-0.56 and 1.2+/-0.15, respectively; p < 0.01]. AHA treatment reduced the invasive potential of HT1197 cells. Also the specific downregulation of MMP7 by siRNA lowered the HT1197 cell invasiveness [20+/-1.0 vs. 16+/-2.8; p < 0.05]. Neither AHA nor MMP-7 siRNA transfection altered the invasive potential of T24/83 cells. Conclusions: Invasion of UCB is partially dependent on MMPs. Specific targeting of MMP7 by siRNA reduces the invasive potential in a subgroup of UCB cells. Therefore, MMP7 represents a potential therapeutic target which warrants further investigation. PMID- 29430510 TI - Body Mass Index, Diet-Related Factors, and Bladder Cancer Prognosis: A Systematic Review and Meta-Analysis. AB - Background: Urologists are frequently confronted with questions of urinary bladder cancer (UBC) patients about what they can do to improve their prognosis. Unfortunately, it is largely unknown which lifestyle factors can influence prognosis. Objective: To systematically review the available evidence on the association between body mass index (BMI), diet, dietary supplements, and physical activity and UBC prognosis. Methods: We searched PubMed and Embase up to May 2017. We included thirty-one articles reporting on observational and randomized controlled trials investigating BMI, diet and dietary supplements in relation to recurrence, progression, cancer-specific or all-cause mortality in UBC patients. Results: In non-muscle invasive bladder cancer (NMIBC) patients, both overweight (3 studies, pooled hazard ratio (HR) 1.29, 95% CI 1.05-1.58, I2 = 0%) as well as obesity (3 studies, pooled HR 1.82, 95% CI 1.12-2.95, I2 = 79%) were associated with increased risk of recurrence when compared to normal weight. No association of BMI with risk of progression was found. Results for BMI and prognosis in muscle-invasive or in all stages series were inconsistent. Observational studies on diet and randomized controlled trials with dietary supplements showed inconsistent results. No studies on physical activity and UBC prognosis have been published to date. Conclusions: Evidence for an association of lifestyle factors with UBC prognosis is limited, with some evidence for an association of BMI with risk of recurrence in NMIBC. Well-designed, prospective studies are needed to develop evidence-based guidelines on this topic. PMID- 29430511 TI - Disparities in the Use of Continent Urinary Diversions after Radical Cystectomy for Bladder Cancer. AB - Background: Radical cystectomy (RC) with ileal conduit (IC) or continent diversion (CD) is standard treatment for high-risk non-invasive and muscle invasive bladder cancer. Objective: Our aim is to study contemporary trends in the utilization of ICs and CDs in patients undergoing RC. Methods: Using the National Inpatient Sample 2001-2012, we identified all patients diagnosed with a malignant bladder neoplasm who underwent RC followed by IC or CD. Patient demographics, comorbidities, length of stay (LOS), and in-hospital complications, mortality, and costs were compared. Multivariable logistic regression analysis, Chi square, and t-tests were used for analysis. Results: Between 2001-2012, approximately 69,049 ICs and 6,991 CDs were performed. CDs increased from 2001 to 2008, but declined after 2008 (p < 0.0001). Patients of all ages received ICs at a higher rate than CDs (40-59 years: 79.5% vs. 20.5%; 60-69 years: 88.0% vs. 12.0%; p < 0.0001). There was a difference in males vs. females (10.2% vs. 4.0%; OR 2.36) and Caucasians vs. African Americans (9.0% vs. 6.7%; OR 1.49) when comparing CD rates. CD rates were highest in the West, urban teaching centers, and large hospitals (p < 0.001). ICs were associated with higher rates of overall postoperative complications (p = 0.0185) including infection (p = 0.002) and mortality (p < 0.0001). In-hospital costs were greater for the CD group. Conclusions: The number of CDs has declined recently. Patients of all ages are more likely to receive ICs than CDs. Gender, racial, and geographic disparities exist among those receiving CDs. CDs are associated with lower rates of in hospital complications and mortality, but higher in-hospital costs. PMID- 29430509 TI - Molecular Correlates of In Vitro Responses to Dacomitinib and Afatinib in Bladder Cancer. AB - Background: The HER family of proteins (EGFR, HER2, HER3 and HER4) have long been thought to be therapeutic targets for bladder cancer, but previous clinical trials targeting these proteins have been disappointing. Second generation agents may be more effective. Objective: The aim of this study was to evaluate responses to two second-generation irreversible tyrosine kinase inhibitors, dacomitinib and afatinib, in bladder cancer cell lines. Methods: Cell lines were characterized by targeted next generation DNA sequencing, RNA sequencing, western blotting and flow cytometry. Cell survival responses to dacomitinib or afatinib were determined using (3-[4,5-dimethylthioazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT) or [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium (MTS) and phenazine methosylfate (PMS) cell survival assays. Results: Only two cell lines of 12 tested were sensitive to afatinib. Sensitivity to afatinib was significantly associated with mutation in either HER2 or HER3 (p < 0.05). The two cell lines sensitive to afatinib were also responsive to dacomitinib ralong with an additional 4 other cell lines out of 16 tested. No characteristic was associated with dacomitinib sensitivity. Molecular profiling demonstrated that only two genes were high in both afatinib and dacomitinib sensitive cells. Further rhigher expression of RAS pathway genes was noted for dacomitinib responsive cells. Conclusions: This study confirms that cell line screening can be useful in pre-clinical evaluation of targeted small molecule inhibitors and suggests that compounds with similar structure(s) and target(s) may have distinct sensitivity profiles. Further rcombinational targeting of additional molecularly relevant pathways may be important in enhancing responses to HER targeted agents in bladder cancer. PMID- 29430512 TI - Defining Priorities to Improve Patient Experience in Non-Muscle Invasive Bladder Cancer. AB - Background: Although approximately 75% of bladder cancers are non-muscle invasive (NMIBC) at diagnosis, most research tends to focus on invasive disease (e.g., experiences related to radical cystectomy and urinary diversion). There is a lack of studies on quality of life, and especially qualitative research, in bladder cancer generally. As a result, relatively little is known about the experiences and needs of NMIBC patients. Objective: To understand patient experience, define care priorities, and identify targets for care improvement in NMIBC across the cancer continuum. Methods: Through focus groups, patients treated for NMIBC (stage 0.05). Among the patients with HIV infection, the presence of anemia and central nervous system toxoplasmosis infection was associated with prolonged auditory and visual reaction times. Conclusion: There was a high rate of cognitive dysfunction in patients with HIV infection in this study. PMID- 29430536 TI - Knowledge and practice concerning swallowing disorders in hemiplegic patients among nurses of Bobo-Dioulasso urban primary health care centers in Burkina Faso. AB - Introduction: The quality of management of swallowing disorders (SD) from admission onwards influences the patients' nutritional status and their prognosis. Neurological diseases are the main causes of SD, affecting one in three patients with hemiplegia (Hp). In Burkina Faso (BF), primary health care center (PHCC) nurses are the first to manage these patients, but there are no data related to their management of SD. The study aimed to assess knowledge and practices regarding SD in Hp among PHCC nurses in Bobo-Dioulasso, a main center for care of Hp in BF. Methods: This cross-sectional study was performed August 1 September 15 2014. Subjects underwent a standardized survey to determine their knowledge and practices concerning SD in Hp. Results: Of 125 nurses surveyed (83.3% of the targeted workers), 82.4% had experience of caring for Hp. The role of the central nervous system in cases of Hp and SD was recognized by 56.8% of nurses; 42.3% knew that SD can cause aspiration, and 36.0% were aware of rescue techniques to use when aspiration occurs; 39.2% correctly assessed the impact on nutritional status of SD. Knowledge in this area was better among respondents who recently completed training school. 65.6% and 1.6% respectively knew about the impact of posture and the texture of food on the ability to swallow. Among the 103 nurses with experience of treating Hp, 68.0% considered clinical interview the best way to detect SD, and 30.1% did not give the patient advice in this area. In multivariate analysis, detection of SD was associated with good knowledge of the value of voice disorders (OR = 3.5, 95% CI = 1.4-8.1; p = 0.005). Conclusion: Few nurses had been warned of the connection between Hp and SD, which are classic issues and potential complications. Practices varied, but most were not in accord with what are recognized as good strategies for SD screening and management. In order to improve care of Hp, neurological and nutritional training should be accompanied by specific training in SD, emphasizing screening and simple management. PMID- 29430539 TI - Nodding syndrome: 2015 International Conference Report and Gulu Accord. AB - Nodding syndrome is a pediatric epileptic encephalopathy of apparent environmental origin that was first described in Tanzania, with recent epidemics in South Sudan and Uganda. Following a brief description of the medical geography, setting and case definition of this progressive brain disorder, we report recent advances relating to etiology, diagnosis and treatment described in papers given at the 2nd International Conference on Nodding Syndrome held in July 2015 in Gulu, Uganda. The target audience for this report includes: anthropologists, entomologists, epileptologists, health care workers, helminthologists, medical researchers, neuroepidemiologists, neurologists, neuroscientists, neuropathologists, nurses, nutritional scientists, primary health care physicians, psychiatrists, public health practitioners, toxicologists, and virologists. PMID- 29430538 TI - Socio-cultural adaptation and standardization of Dubois' five words testing in a population of normal subject in Mali, West Africa. AB - Introduction: Dubois' five words testing (5WT) is a verbal memory test that depends on many parameters. The aim of this study is to adapt Dubois' 5WT to the Malian socio-cultural conditions to (i) determine performances of normal subjects to the 5WT and (ii) provide reference scores of the 5WT. Methods: A sample of 276 normal subjects aged >= 50 years (154 males and 122 females; 144 literates and 132 illiterates) were enrolled from February 2008 to January 2009. Subjects with a history of symptoms likely to modify cognitive functions and those who were found disabled under Lawton's four simplified item test were excluded. Results: The learning score in illiterates was 1.51 in Dubois' 5WT and 4.90 in the modified 5WT. The mean value of the modified 5WT total score was 9.71. Majority (90.22%) of the subjects scored the maximum (10). The modified 5WT reduced with both the age (p < 0.006) and education level (p < 0.04). Conclusion: Our results show that Dubois' 5WT is influenced by culture and the socio-educative level in French. Its adaptation to the socio-cultural context could prove useful and efficient in countries with a low literacy rate and a diverse cultural background. PMID- 29430540 TI - Impact of country-specific characteristics on scientific productivity in clinical neurology research. AB - Objectives: The objective of this study was to identify the top 50 countries in the world in clinical neurology research and to use their data to assess the impact of a number of country-specific characteristics on scientific productivity in clinical neurology. Methods: The SCImago Journal & Country Rank (SCR) web site was used to identify the top 50 countries in the world based on their total documents in clinical neurology. Using their data 5 country-specific characteristics and 6 productivity indicators (total documents, total cites, h index, citable documents, self-cites and citations per document) were correlated and examined statistically. Results: The number of universities in the world top 500 and the number of clinical neurology journals enlisted in SCR correlated significantly with each of the 6 indicators. The gross domestic product (GDP) per capita and the percentage of GDP spent on research and development (R & D) correlated significantly with 3 and 4 out of the 6 indicators respectively. The population size did not correlate significantly with any of the 6 indicators. Conclusions: The number of universities in the world top 500 and the number of clinical neurology journals enlisted in SCR appear to have a strong impact on scientific productivity. GDP per capita and spending on R & D appear to have a moderate impact on productivity that is influenced by the indicator used. Furthermore, population size appears to have no significant impact on productivity in clinical neurology research. PMID- 29430541 TI - Intrathecal Noggin administration in rats temporally ameliorates mechanical allodynia induced by a chronic constriction injury. AB - Chronic intractable neuropathic pain after central or peripheral nervous system injury remains refractory to therapeutic intervention. Using microarray and RT qPCR methods, we found that Noggin mRNA is downregulated in the lumbar enlargement 2 weeks after chronic constriction injury (CCI) in rats. Eight-week old female Sprague Dawley rats were used for the CCI model. Two weeks after CCI, rats underwent a laminectomy at L5 under halothane anesthesia, and a silicone tube connected to an osmotic minipump was inserted intrathecally for 14 days. Rats were administered Noggin ranging from 10 ng/ml to 10 MUg/ml. Phosphate buffered saline (PBS) was used as a control. The time course of mechanical allodynia was assessed for 5 weeks using von Frey filaments. An ANOVA showed that rats administered Noggin at 2 MUg/ml had significantly less mechanical allodynia compared with controls. We next compared the effect of intrathecal administration (14 days) of Noggin (2 MUg/ml), bone morphogenetic protein 4 (BMP4; 2 MUg/ml), or BMP4 (MUg/ml) + Noggin (MUg/ml) with controls. Only Noggin administration significantly reduced mechanical allodynia in the CCI model. Fluorescence immunohistochemistry indicated that Noggin administration decreased astrocyte accumulation in the dorsal horn compared with PBS after administration for one week. BMP4-driven conversion of oligodendrocyte progenitor cells (OPCs) to type 2 astrocytes is inhibited by Noggin Hampton et al. (2007) . We speculated that Noggin administration inhibits the conversion of OPCs to astrocytes, and decreases glial fibrillar acidic protein expression. This histological condition could decrease neuropathic pain. PMID- 29430542 TI - MELAS and Kearns-Sayre overlap syndrome due to the mtDNA m. A3243G mutation and large-scale mtDNA deletions. AB - This paper reported an unusual manifestation of a 19-year-old Chinese male patient presented with a complex phenotype of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome and Kearns-Sayre syndrome (KSS). He was admitted to our hospital with the chief complaint of "acute fever, headache and slow reaction for 21 days". He was initially misdiagnosed as "viral encephalitis". This Chinese man with significant past medical history of intolerating fatigue presented paroxysmal neurobehavioral attacks that started about 10 years ago. During this span, 3 or 4 attack clusters were described during which several attacks occurred over a few days. The further examination found that the hallmark signs of this patient included progressive myoclonus epilepsy, cerebellar ataxia, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy and bifascicular heart block (Wolff Parkinson-White syndrome). By young age the disease progression is characterized by the addition of migraine, vomiting, and stroke-like episodes, symptoms of MELAS expression, which indicated completion of the MELAS/KSS overlap syndrome. The m. A3243G mitochondrial DNA mutation and single large-scale mtDNA deletions were found in this patient. This mutation has been reported with MELAS, KSS, myopathy, deafness and mental disorder with cognitive impairment. This is the first description with a MELAS/KSS syndrome in Chinese. PMID- 29430543 TI - Hospital-based study on emergency admission of patients with Parkinson's disease. AB - Objective: Parkinson's disease (PD) is a progressive neurodegenerative disease. As the severity of disease worsens, patients have lower tolerance for treatments and occasionally need to be hospitalized. This study focuses on characteristics of patients with PD who were emergently admitted to our hospital and evaluates their prognosis during hospitalization. Methods: Hospital-based study on emergency admission was conducted in a consecutive series of patients with PD between April 2009 and March 2015. Results: A total of 164 admissions involving 136 patients with PD with available medical records were identified. Among these, 40 admissions involving 38 patients were emergency admissions. The most common cause of hospitalization was aspiration pneumonia (n = 17) followed by parkinsonism hyperpyrexia syndrome (n = 6), cerebrovascular disease (n = 2), dehydration (n = 2), and others (n = 13). The mean Hoehn and Yahr stage at admission and discharge were 3.5 and 4.2, respectively, with significant differences between time points (p < 0.001). All patients except one presented with either postural instability gait difficulty phenotype (PIGD) or mixed phenotype with PIGD and tremor. All 17 patients with aspiration pneumonia had various combinations of three components: abnormalities seen on videofluoroscopy swallowing study, cognitive impairment, and history of psychiatric symptoms. Conclusion: Aspiration pneumonia was the most common reason for emergency admission in patients afflicted with PD for more than five years. Abnormalities seen in videofluoroscopy, PIGD and mixed phenotypes, cognitive impairment, and history of psychiatric symptoms could potentially be predictors for aspiration pneumonia in patients with PD. PMID- 29430544 TI - Screening tools for clinical characteristics of probable REM sleep behavior disorder in patients with Parkinson's disease. AB - Introduction: The REM sleep behavior disorder (RBD) screening questionnaire (RBDSQ) has been used as a screening tool for RBD. We investigated the clinical characteristics of probable RBD (pRBD) using the RBDSQ in patients with Parkinson's disease (PD). Methods: Seventy patients with PD (age: 69.2 +/- 8.9 years old, 31 males and 49 females, length of PD morbidity: 7.4 +/- 6.4 years, Hoehn and Yahr: 2.7 +/- 0.8) underwent examination including the RBDSQ and Mini Mental State Examination (MMSE) in both 2011 and 2013. We assessed the changes and characteristics of pRBD associated with PD during the two year interval. Results: Nineteen patients (27.1%) in 2011 and 27 patients (38.6%) in 2013 were diagnosed as having pRBD because they scored 6 or higher on the RBDSQ. During the 2 year interval, twelve patients showed persistent pRBD, 15 developed pRBD, and 7 showed improved pRBD. In 2013, PD patients with pRBD took higher amounts of levodopa equivalents and scored lower on the MMSE than those without pRBD. Also, more PD patients with pRBD had dementia than those without pRBD. Similarly, more patients with persistent and developed pRBD had dementia than those without. Conclusion: We found that RBD symptoms might fluctuate during the clinical course of PD, and RBD symptoms might temporarily affect cognitive impairment. PMID- 29430545 TI - Fatigue is associated with the onset of hallucinations in patients with Parkinson's disease: A 3-year prospective study. AB - Hallucinations remain problematic in Parkinson's disease (PD). Various factors have been studied, and many previous studies identified risk factors for hallucinations, such as sleep disorders. At the same time, fatigue is a common symptom in Parkinson's disease, and any factors associated with fatigue in PD have been reported. Factors associated with fatigue in PD are likely to be similar to risk factors for hallucinations. However, fatigue has been not been reported to be a risk factor for hallucinations in previous studies. We prospectively studied non-hallucinators with PD during 3 years to identify factors associated with the onset of hallucinations, including fatigue. We initially screened 100 consecutive patients and registered 78 patients with PD. During 3 years of follow-up, 31 patients newly presented with visual hallucinations. A total of 18 variables were evaluated by logistic regression analysis. Brief Fatigue Inventory (BFI) (OR = 1.027, p = 0.045, 95% CI = 1.001 1.053) was related to first-onset hallucinations on multivariate logistic regression analysis. The present study is the first to demonstrate an association of fatigue with the onset of hallucinations. Fatigue, especially mental fatigue, can be a risk factor for future hallucinations. PMID- 29430546 TI - Characterization of patients with ocular myasthenia gravis - A case series. AB - Ocular myasthenia gravis (OMG) is sometimes difficult to diagnose and is probably both under-diagnosed and misdiagnosed. We studied the epidemiological parameters, relevant serology, electromyographic (EMG) findings, and the relationship between OMG and thymoma, thymus hyperplasia and other autoimmune disorders compared to generalized MG (GMG) in a case control study of 133 patients with MG (32 patients with OMG and 101 patients with GMG). The proportion of OMG among all MG patients was relatively high (24.1%). It affected more males than females and its onset was at an older age. Although anti-AChR Ab was detected in fewer OMG patients compared to GMG patients, the rate of positive serology in OMG patients was higher than previously reported. Male OMG patients had a higher positive serology rate than female OMG patients. OMG patients tended to have less supportive EMG evidence of neuromuscular disorder. Female OMG patients had higher rates of thymus hyperplasia and higher rates of other autoimmune disorders than males. Diagnosing MG in patients with solitary ocular manifestation may be difficult due to lower rates of paraclinic supportive tests. Awareness of the characteristics of OMG is important in order to avoid delayed or misdiagnosis of MG and to prevent avoidable iatrogenic complications. PMID- 29430547 TI - How do people with drug-resistant mesial temporal lobe epilepsy sleep? A clinical and video-EEG with EOG and submental EMG for sleep staging study. AB - This study aimed to assess subjective and objective sleep parameters in a homogeneous group of drug-resistant mesial temporal lobe epilepsy (MTLE) patients through internationally validated clinical questionnaires, video electroencephalographic (VEEG) and polysomnographic (PSG) studies. Fifty-six patients with definite diagnosis of MTLE who were candidates for epilepsy surgery underwent a detailed clinical history, the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS), neurological examination, 1.5 T brain magnetic resonance imaging, VEEG and PSG. Sixteen percent of patients reported significant daytime sleepiness as measured by ESS and 27% reported low levels of sleep quality as measured by PSQI. Patients with medically resistant epilepsy by MTLE showed increased wakefulness after sleep onset (WASO) with mean +/- standard deviation of 17.4 +/- 15.6, longer non-rapid eye movement (NREM) 1 (7.5 +/- 4.6%) and NREM3 sleep (26.6 +/- 11.8%), abnormal rapid eye movement (REM) latency in 30/56 patients, shorter REM sleep (16.7 +/- 6.6%), and abnormal alpha delta patterns were observed in 41/56 patients. The analysis of interictal epileptic discharges (IEDs) evidenced highest spiking rate during NREM3 sleep and higher concordance with imaging data when IEDs were recorded in sleep, mainly during REM sleep. We concluded that patients with MTLE showed disrupted sleep architecture that may result in daytime dysfunction and sleep complaints. Furthermore, NREM sleep activated focal IEDs and them - when recorded during sleep - had higher localizing value. PMID- 29430549 TI - Guillain-Barre syndrome after allogeneic bone marrow transplantation: Case report and literature review. AB - A 50-year-old man with acute myelogenous leukemia underwent allogeneic bone marrow transplantation (BMT). He presented with severe diarrhoea 86 days post BMT and was diagnosed with graft-versus-host disease (GVHD) based on skin and rectal biopsies. He complained of numbness and weakness in the distal extremities at 114 days after BMT. His symptoms rapidly deteriorated and he required mechanical ventilation for respiratory failure. His clinical course and the findings of a nerve conduction study fulfilled the criteria for diagnosis of Guillain-Barre syndrome (GBS). Sural nerve biopsy revealed active demyelination and infiltration of macrophages and CD8+ T-cells. After three cycles of intravenous immunoglobulin therapy, his symptoms gradually improved, and he could eventually walk unassisted. Although GBS has been known to develop after allogeneic BMT, the pathogenesis remains unclear, and specific treatment regimens have not been well established. Here, we report a case of GBS, caused by an immune-mediated mechanism related to GVHD, which was successfully treated using intravenous immunoglobulin therapy. PMID- 29430548 TI - Antiepileptic drugs in development pipeline: A recent update. AB - Epilepsy is the most common neurological disorder which significantly affects the quality of life and poses a health as well as economic burden on society. Epilepsy affects approximately 70 million people in the world. The present article reviews the scientific rationale, brief pathophysiology of epilepsy and newer antiepileptic drugs which are presently under clinical development. We have searched the investigational drugs using the key words 'antiepileptic drugs,' 'epilepsy,' 'Phase I,' 'Phase II' and 'Phase III' in American clinical trial registers (clinicaltrials.gov), the relevant published articles using National Library of Medicine's PubMed database, company websites and supplemented results with a manual search of cross-references and conference abstracts. This review provides a brief description about the antiepileptic drugs which are targeting different mechanisms and the clinical development status of these drugs. Besides the presence of old as well as new AEDs, still there is a need of new drugs or the modified version of old drugs in order to make affected people free of seizures. An optimistic approach should be used to translate the success of preclinical testing to clinical practice. There is an urgent need to improve animal models and to explore new targets with better understanding in order to develop the novel drugs with more efficacy and safety. PMID- 29430550 TI - Intravenous rtPA versus mechanical thrombectomy in acute ischemic stroke: A historical cohort in Joinville, Brazil. AB - Groundbreaking results concerning ischemic stroke (IS) hyperacute treatment worldwide were published in 2014 and 2015. We aimed to compare functional status after 3 months in patients treated with intra-arterial thrombectomy (IAT) and those treated with intravenous thrombolysis (IVT) alone in Joinville, Brazil. From the Joinville Stroke Registry, we extracted and compared all consecutive IVT patients treated with r-tPA within 4.5 h in the period 2009-2011 versus all consecutive IAT treated within 6 h with the Solitaire FR device plus IVT in the period 2012-2014. We registered 82 patients in the IVT group and 31 patients in the IAT group. At hospital admission, patients in the IAT group were significantly younger (p < 0.001), had a higher educational level (p = 0.001), had a slightly higher prevalence of atrial fibrillation (p = 0.057) and had more severe strokes measured by the NIH stroke scale (p = 0.011). After 90 days, 45% of patients in the IAT group and 27% in the IVT group were independent (0-1 points) according to the modified Rankin scale (adjusted odds ratio: 4.53; 95% CI: 1.22 to 16.75). Symptomatic hemorrhage was diagnosed in 10% of patients in both groups (p = 1.0). The 90-day case-fatality was 39% (32/82) in the IVT group and 26% (8/31) in the IAT group (p = 0.27). In this small cohort, a greater rate of functional independence was achieved in patients treated with IAT plus IVT, compared with patients treated with IVT lysis alone. Our "real-world" findings are consistent with results of controlled, randomized clinical trials. PMID- 29430551 TI - Subcortical Vascular Cognitive Impairment staged through cdr's functional subsum (cdr-func): Preliminary results from an outpatient sample. AB - Background: Staging vascular cognitive impairment (VCI) might be useful for sample selection in clinical trials and for guiding clinical decision-making. Clinical dementia rating (CDR) has been applied for staging cognitive impairments of different etiologies, but it may underestimate severity of non-Alzheimer's disease cognitive deficits. Methods: Out of a total of 147 elderly subjects, 23 (mean age: 72.95 +/- 7.51 years; 56% female; mean schooling: 9.52 +/- 5.11 years) fulfilled clinical and neuroimaging criteria for VCI. Correlations among cognitive and functional status and scores in CDR and its subsums (CDR Sum of Boxes - CDR-SoB - and CDR Functional Subsum - CDR-FUNC) were performed. Results: Both CDR-SoB and CDR-FUNC correlated with global cognitive performance, functional status, CLOX 2, working memory and abstraction tests. CDR global score only correlated with functional status. Discussion: CDR-FUNC, as well as CDR-SoB, appear to be better indexes of severity in VCI than CDR global score. PMID- 29430552 TI - Brief considerations on the dispensation profile of the botulinum toxin type A by the Brazilian Unified Health System for treatment of dystonias: Datasus data. AB - Botulinum toxin injections are the most effective approach for the treatment of focal dystonia. Despite growing demand and clinical indications over the years, there are few reports or publications of its use and benefit to patients seen at the Sistema Unico de Saude - SUS (Unified Health System). Analyzing the Datasus data (Unified Health System Information Department of Brazilian Ministry of Health), it was noticed that in Brazil the percentage of dystonic patient benefited from this procedure is still low. We therefore suggest some strategies to increase the dispensation of the toxin by the Brazilian Unified Health system for the dystonic patients. PMID- 29430553 TI - Predictive model for falling in Parkinson disease patients. AB - Background/aims: Falls are a common complication of advancing Parkinson's disease (PD). Although numerous risk factors are known, reliable predictors of future falls are still lacking. The aim of this study was to develop a multivariate model to predict falling in PD patients. Methods: Prospective cohort with forty nine PD patients. The area under the receiver-operating characteristic curve (AUC) was calculated to evaluate predictive performance of the purposed multivariate model. Results: The median of PD duration and UPDRS-III score in the cohort was 6 years and 24 points, respectively. Falls occurred in 18 PD patients (30%). Predictive factors for falling identified by univariate analysis were age, PD duration, physical activity, and scores of UPDRS motor, FOG, ACE, IFS, PFAQ and GDS (p-value < 0.001), as well as fear of falling score (p-value = 0.04). The final multivariate model (PD duration, FOG, ACE, and physical activity) showed an AUC = 0.9282 (correctly classified = 89.83%; sensitivity = 92.68%; specificity = 83.33%). Conclusions: This study showed that our multivariate model have a high performance to predict falling in a sample of PD patients. PMID- 29430554 TI - Evaluation of the INECO Frontal Screening and the Frontal Assessment Battery in Peruvian patients with Alzheimer's disease and behavioral variant Frontotemporal dementia. AB - Background: The physicians often confuse the early symptoms of Frontotemporal dementia (FTD) with Alzheimer dementia (AD), leading to misdiagnosis. There are some cognitive tests to discriminate between AD and behavioral variant FTD (bvFTD), and the INECO Frontal Screening (IFS) is a promising test for this purpose. Objective: To assess the performance of the IFS to differentiate patients with AD from patients with bvFTD, compared with the Frontal Assessment Battery (FAB). Methods: A prospective study with 117 patients of our cognitive unit (35 case-patients with AD, 34 case-patients with bvFTD, and 48 control subjects). They were submitted to the following successive phases of evaluation: 1) screening; 2) dementia diagnosis; and 3) dementia sub-type diagnosis. The IFS and FAB were blind and independently applied by one neurologist to all the participants to end of phase 1 (screening), before to the definitive diagnosis establishment. Results: bvFTD showed a lower performance than AD patients on the IFS total score (F(1, 66) = 70.10, p < 0.01) and FAB total score (F(1, 66) = 17.91, p < 0.01). The IFS and FAB showed a sensitivity of 94.12% (95%CI = 80.3 99.2) and 82.3% (95%CI = 65.4-93.2), and a specificity of 94.2% (95%CI = 80.8 99.3) and 48.5% (95%CI = 31.3, 66.1), respectively. The IFS showed significantly superior discriminatory accuracy than the FAB (AuCIFS = 0.98; AuCFAB = 0.73, p < 0.00001). Conclusion: The IFS is useful for discriminating between AD and bvFTD patients. The performance of the IFS to differentiate patients with AD from patients with bvFTD is greater than FAB. PMID- 29430556 TI - eNeurologicalSci - Special Issue on Neurological Disorders in South America. PMID- 29430555 TI - Ischemic cerebrovascular burden evaluated by magnetic resonance imaging in an elderly Brazilian community: The Pieta study. AB - In developing countries, cardiovascular risk factors are poorly controlled, leading to high prevalence of cerebrovascular diseases. The aim of the study was to evaluate the burden of white matter lesions in magnetic resonance through the Fazekas scale in a population aged 75 + years living in the community, and to investigate possible associations between vascular lesions, cardiovascular risk factors and cognitive status. Subjects were selected from a community-based study on brain aging conducted in Caete (Minas Gerais state), Brazil. Overall, 177 participants (112 cognitively healthy, 36 with cognitive impairment-no dementia and 29 with dementia), being 108 women, aged 79.3 +/- 3.8 years, with 3.1 +/- 2.9 years of educational level, underwent a 3 Tesla magnetic resonance scanner with fluid attenuated image recovery acquisition. Severity of white matter lesions was assessed through the Fazekas scale. Severe white matter lesions were present in 31.1% of the whole sample and in 25.0% of the cognitively healthy individuals. A significant association was found between severe white matter lesions and cognitive impairment (OR = 2.20, 95% CI 1.17-6.53; p = 0.021), as well as with hypertension (OR = 1.92, 95% CI 1.03-7.39; p = 0.043). In conclusion, a high prevalence of severe white matter lesions was observed in this elderly Brazilian population sample, and white matter lesions were associated with hypertension and cognitive status. Importantly, the prevalence of white matter lesions was also high in cognitively healthy subjects. PMID- 29430557 TI - Environmental Toxin Acrolein Alters Levels of Endogenous Lipids, Including TRP Agonists: A Potential Mechanism for Headache Driven by TRPA1 Activation. AB - Exposure to airborne toxins can trigger headaches, but the mechanisms are not well understood. Some environmental toxins, such as acrolein, activate transient receptor potential ankyrin 1 (TRPA1), a receptor involved in pain sensation that is highly expressed in the trigeminovascular system. It has been shown in rat models that repeated exposure to acrolein induces trigeminovascular sensitization to both TRPA1 and TRP vanilloid 1 (TRPV1) agonists, a phenomenon linked to headache. In this study, we test the hypothesis that the sensitization of trigeminovascular responses in rats after acrolein exposure via inhalation is associated with changes in levels of endogenous lipids, including TRPV1 agonists, in the trigeminal ganglia, trigeminal nucleus, and cerebellum. Lipidomics analysis of 80 lipids was performed on each tissue after acute acrolein, chronic acrolein, or room air control. Both acute and chronic acrolein exposure drove widespread alterations in lipid levels. After chronic acrolein exposure, levels of all 6 N-acyl ethanolamines in the screening library, including the endogenous cannabinoid and TRPV1 agonist, N-arachidonoyl ethanolamine, were elevated in trigeminal tissue and in the cerebellum. This increase in TRPV1 ligands by acrolein exposure may indicate further downstream signaling, in that we also show here that a combination of these TRPV1 endogenous agonists increases the potency of the individual ligands in TRPV1-HEK cells. In addition to these TRPV1 agonists, 3 TRPV3 antagonists, 4 TRPV4 agonists, and 25 orphan lipids were up and down regulated after acrolein exposure. These data support the hypothesis that lipid signaling may represent a mechanism by which repeated exposure to the TRPA1 agonist and environmental toxin, acrolein, drives trigeminovascular sensitization. PMID- 29430558 TI - Therapeutic Angiogenesis for Peripheral Artery Disease: Lessons Learned in Translational Science. AB - Peripheral arterial disease (PAD) is a major health care problem. There have been limited advances in medical therapies, and a huge burden of symptomatic patients with intermittent claudication and critical limb ischemia who have limited treatment options. Angiogenesis is the growth and proliferation of blood vessels from existing vasculature. For approximately 2 decades, "therapeutic angiogenesis" has been studied as an investigational approach to treat patients with symptomatic PAD. Despite literally hundreds of positive preclinical studies, results from human clinical studies thus far have been disappointing. Here we present an overview of where the field of therapeutic angiogenesis stands today and examine lessons learned from previously conducted clinical trials. The objective is not to second-guess past efforts but to place the lessons in perspective to allow for trial success in the future to improve agent development, trial design, and ultimately, clinical outcomes for new therapeutics for PAD. PMID- 29430559 TI - Developmental Lead and/or Prenatal Stress Exposures Followed by Different Types of Behavioral Experience Result in the Divergence of Brain Epigenetic Profiles in a Sex, Brain Region, and Time-Dependent Manner: Implications for Neurotoxicology. AB - Over a lifetime, early developmental exposures to neurocognitive risk factors, such as lead (Pb) exposures and prenatal stress (PS), will be followed by multiple varied behavioral experiences. Pb, PS and behavioral experience can each influence brain epigenetic profiles. Our recent studies show a greater level of complexity, however, as all three factors interact within each sex to generate differential adult variation in global post-translational histone modifications (PTHMs), which may result in fundamentally different consequences for life-long learning and behavioral function. We have reported that PTHM profiles differ by sex, brain region and time point of measurement following developmental exposures to Pb+/-PS, resulting in different profiles for each unique combination of these parameters. Imposing differing behavioral experience following developmental Pb+/ PS results in additional divergence of PTHM profiles, again in a sex, brain region and time-dependent manner, further increasing complexity. Such findings underscore the need to link highly localized and variable epigenetic changes along single genes to the highly-integrated brain functional connectome that is ultimately responsible for governing behavioral function. Here we advance the idea that increased understanding may be achieved through iterative reductionist and holistic approaches. Implications for experimental design of animal studies of developmental exposures to neurotoxicants include the necessity of a 'no behavioral experience' group, given that epigenetic changes in response to behavioral testing can confound effects of the neurotoxicant itself. They also suggest the potential utility of the inclusion of salient behavioral experiences as a potential effect modifier in epidemiological studies. PMID- 29430560 TI - Epilepsy is associated with ventricular alterations following convulsive status epilepticus in children. AB - Objective: Convulsive status epilepticus can exert profound cardiovascular effects in adults including ventricular depolarization-repolarization abnormalities. Whether status epilepticus adversely affects ventricular electrical properties in children is less understood. Therefore, we sought to characterize ventricular alterations and the associated clinical factors in children following convulsive status epilepticus. Methods: We conducted a 2-year retrospective, case-control study. Children between 1 month and 21 years of age were included if they were admitted to the pediatric intensive care unit with primary diagnosis of convulsive status epilepticus and had 12-lead electrocardiogram (ECG) within 24 hours of admission. Children with heart disease, ion channelopathy, or on vasoactive medications were excluded. Age matched control subjects had no history of seizures or epilepsy. The primary outcome was ventricular abnormalities represented by ST segment changes, abnormal T wave, QRS axis deviation, and corrected QT (QTc) interval prolongation. The secondary outcomes included QT/RR relationship, beat-to-beat QTc interval variability, ECG interval measurement between groups, and clinical factors associated with ECG abnormalities. Results: Of 317 eligible children, 59 met the inclusion criteria. History of epilepsy was present in 31 children (epileptic) and absent in 28 children (non-epileptic). Compared with the control subjects (n = 31), the status epilepticus groups were more likely to have an abnormal ECG with overall odds ratio of 3.8 and 7.0 for the non-epileptic and the epileptic groups respectively. Simple linear regression analysis demonstrated that children with epilepsy exhibited impaired dependence and adaptation of the QT interval on heart rate. Beat-to-beat QTc interval variability, a marker of ventricular repolarization instability, was increased in children with epilepsy. Significance: Convulsive status epilepticus can adversely affect ventricular electrical properties and stability in children, especially those with epilepsy. These findings suggest that children with epilepsy may be particularly vulnerable to seizure-induced arrhythmias. Therefore postictal cardiac surveillance may be warranted in this population. PMID- 29430561 TI - The CGRP receptor antagonist BIBN4096 inhibits prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization. AB - Introduction: Cortical spreading depression (CSD) is believed to promote migraine headache by enhancing the activity and mechanosensitivity of trigeminal intracranial meningeal afferents. One putative mechanism underlying this afferent response involves an acute excitation of meningeal afferents by cortical efflux of K+ and the ensuing antidromic release of proinflammatory sensory neuropeptides, such as calcitonin gene-related peptide (CGRP). Objectives: We sought to investigate whether (1) a brief meningeal K+ stimulus leads to CGRP dependent enhancement of meningeal afferent responses and (2) CSD-induced meningeal afferent activation and sensitization involve CGRP receptor signaling. Methods: Extracellular single-unit recording were used to record the activity of meningeal afferents in anesthetized male rats. Stimulations included a brief meningeal application of K+ or induction of CSD in the frontal cortex using pinprick. Cortical spreading depression was documented by recording changes in cerebral blood flow using laser Doppler flowmetery. Calcitonin gene-related peptide receptor activity was inhibited with BIBN4096 (333 MUM, i.v.). Results: Meningeal K+ stimulation acutely activated 86% of the afferents tested and also promoted in ~65% of the afferents a 3-fold increase in ongoing activity, which was delayed by 23.3 +/- 4.1 minutes and lasted for 22.2 +/- 5.6 minutes. K+ stimulation did not promote mechanical sensitization. Pretreatment with BIBN4096 suppressed the K+-induced delayed afferent activation, reduced CSD-evoked cortical hyperemia, but had no effect on the enhanced activation or mechanical sensitization of meningeal afferents following CSD. Conclusion: While CGRP mediated activation of meningeal afferents evoked by cortical efflux of K+ could promote headache, acute activation of CGRP receptors may not play a key role in mediating CSD-evoked headache. PMID- 29430563 TI - Abstracts from Proceedings Cork CRPS 2017: IASP Special Interest Group in Complex Regional Pain Syndrome (CRPS). PMID- 29430562 TI - Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber polyneuropathy. AB - Introduction: Multiple studies now confirm that ~40% of patients with fibromyalgia syndrome meet diagnostic criteria for small-fiber polyneuropathy (SFPN) and have objective pathologic or physiologic evidence of SFPN, whereas 60% do not. Given possibilities that tens or hundreds of millions globally could have SFPN, developing screening tools becomes important. Objectives: This analysis explored whether specific symptoms might help distinguish these fibromyalgia endophenotypes. Methods: With institutional review board approval, all adults tested for SFPN by distal-leg skin biopsy or autonomic function testing at Massachusetts General Hospital in 2014 to 2015 were queried about symptoms. Inclusion required a physician's fibromyalgia syndrome diagnosis plus meeting the American College of Rheumatology 2010 Fibromyalgia Criteria. The primary outcome was the validated Small-fiber Symptom Survey, which captures severity of all known SFPN-associated symptoms. The Composite Autonomic Symptom Score-31, Short Form Health Survey-36, and Short-Form McGill Pain Questionnaires provided secondary outcomes. Results: Among the 39 participants, 14 had test-confirmed SFPN (SFPN+) and 25 did not (SFPN-). Their pain severity did not differ. Paresthesias ("tingling") were different (worse) in the SFPN+ group (3.14 +/- 0.9 vs 2.28 +/- 1.1; P = 0.16). Their component subscore for dysautonomia symptoms was also worse (10.42 +/- 4.0 vs 7.16 +/- 4.0; P = 0.019). Receiver operating characteristic analyses revealed that each item had fair diagnostic utility in predicting SFPN, with areas under the curve of 0.729. No secondary questionnaires discriminated significantly. Conclusion: Among patients with fibromyalgia, most symptoms overlap between those with or without confirmed SFPN. Symptoms of dysautonomia and paresthesias may help predict underlying SFPN. The reason to screen for SFPN is because-unlike fibromyalgia-its medical causes can sometimes be identified and definitively treated or cured. PMID- 29430564 TI - Sensory symptom profiles differ between trigeminal and thoracolumbar postherpetic neuralgia. AB - Introduction: Animal experimental evidence suggests that mechanisms of pain generation and response to treatment differ between neuropathic pain in the cephalic and the extracephalic innervation territories. Objectives: The objective of the study was to examine whether in humans an identical peripheral painful neuropathy is associated with different pain qualities and sensory abnormalities in the face as compared with the thoracic region. Methods: We retrospectively analysed epidemiological and clinical data of 639 patients with postherpetic neuralgia (PHN) in the face and at the trunk who were collected within a cross sectional cohort survey and compared the respective sensory symptom profiles captured with the painDETECT questionnaire. Results: Two hundred twenty-four patients suffered from trigeminal PHN and 415 from thoracolumbar PHN. There were no significant differences in sex-ratio, age, body mass index, and pain duration. Patients with trigeminal PHN were more often severely depressed. Anxiety and sleep scores were not different. The average pain intensity was slightly higher in thoracolumbar PHN than trigeminal PHN (visual analogue scale 5.0 vs 4.6). Postherpetic neuralgia in the thoracolumbar region showed significantly more intense burning sensations, allodynia, painful attacks, and significantly less prickling and numbness than PHN in the face. Conclusions: The differences in sensory symptom profiles between facial PHN and truncal PHN might be associated with different pathophysiological mechanisms and different treatment response. Drugs that primarily act on sensitization processes in the peripheral nociceptive system may work better in thoracolumbar PHN than in trigeminal PHN. If new medications are tested in patients with PHN, it would therefore be of interest to include an analysis of the treatment results in regard to subgroups based on the localisation of pain in patients with PHN. PMID- 29430565 TI - Discharge prescription patterns of opioid and nonopioid analgesics after common surgical procedures. AB - Introduction: Recent literature has shown a wide variation in the prescribing patterns of opioids after elective surgery. We conducted an evaluation of discharge opioid prescribing after elective surgical procedures to determine whether opioid-prescribing patterns varied at our institution. Method: A single academic medical center retrospective review of patients undergoing laparoscopic cholecystectomy, laparoscopic appendectomy, open umbilical hernia repair, simple mastectomy, or thyroidectomy between July 2015 and July 2016. Results: Among a total of 615 unique surgical cases, we found a wide variation in the number of pills and morphine milligram equivalents prescribed for each procedure evaluated. In addition, 94.8% of all patients discharged received a prescription for opioids, whereas only 15.6% of patients received a prescription for a nonopioid analgesic. Conclusion: The number and strength of opioids prescribed after surgery can vary widely at a single institution. Further research is needed to elucidate variations in prescribing. PMID- 29430566 TI - Oxidized HDL and Isoprostane Exert a Potent Adipogenic Effect on Stem Cells: Where in the Lineage? PMID- 29430567 TI - N-back versus Complex Span Working Memory Training. AB - Working memory (WM) is the ability to maintain and manipulate task-relevant information in the absence of sensory input. While its improvement through training is of great interest, the degree to which WM training transfers to untrained WM tasks (near transfer) and other untrained cognitive skills (far transfer) remains debated and the mechanism(s) underlying transfer are unclear. Here we hypothesized that a critical feature of dual n-back training is its reliance on maintaining relational information in WM. In Experiment 1, using an individual differences approach, we found evidence that performance on an n-back task was predicted by performance on a measure of relational WM (i.e., WM for vertical spatial relationships independent of absolute spatial locations); whereas the same was not true for a complex span WM task. In Experiment 2, we tested the idea that reliance on relational WM is critical to produce transfer from n-back but not complex span task training. Participants completed adaptive training on either a dual n-back task, a symmetry span task, or on a non-WM active control task. We found evidence of near transfer for the dual n-back group; however, far transfer to a measure of fluid intelligence did not emerge. Recording EEG during a separate WM transfer task, we examined group-specific, training-related changes in alpha power, which are proposed to be sensitive to WM demands and top-down modulation of WM. Results indicated that the dual n-back group showed significantly greater frontal alpha power after training compared to before training, more so than both other groups. However, we found no evidence of improvement on measures of relational WM for the dual n-back group, suggesting that near transfer may not be dependent on relational WM. These results suggest that dual n-back and complex span task training may differ in their effectiveness to elicit near transfer as well as in the underlying neural changes they facilitate. PMID- 29430568 TI - Selective aerobic oxidation reactions using a combination of photocatalytic water oxidation and enzymatic oxyfunctionalisations. AB - Peroxygenases offer attractive means to address challenges in selective oxyfunctionalisation chemistry. Despite their attractiveness, the application of peroxygenases in synthetic chemistry remains challenging due to their facile inactivation by the stoichiometric oxidant (H2O2). Often atom inefficient peroxide generation systems are required, which show little potential for large scale implementation. Here we show that visible light-driven, catalytic water oxidation can be used for in situ generation of H2O2 from water, rendering the peroxygenase catalytically active. In this way the stereoselective oxyfunctionalisation of hydrocarbons can be achieved by simply using the catalytic system, water and visible light. PMID- 29430569 TI - Social capital and cognitive decline in the aftermath of a natural disaster: a natural experiment from the 2011 Great East Japan Earthquake and Tsunami. AB - Background: We examined prospectively whether social capital mitigates the adverse effects of natural disaster on cognitive decline. Methods: The baseline for our study was established seven months before the 2011 Great East Japan Earthquake and Tsunami in a survey of older community-dwelling adults who lived 80 kilometers west of the epicenter (59.0% response rate). Approximately two and a half years after the disaster, the follow-up survey gathered information about personal experiences of disaster as well as incidence of cognitive disability (82.1% follow-up rate). Our primary outcome was cognitive disability (measured on an 8-level scale) assessed by in-home assessment. Findings: The experience of housing damage was associated with risk of cognitive impairment (coefficient = 0.04, 95% confidence interval: 0.02 to 0.06). Factor analysis of our analytic sample (n = 3,566) established two sub-scales of social capital: a cognitive dimension (perceptions of community social cohesion) and a structural dimension (informal socializing and social participation). Fixed effects regression showed that informal socializing and social participation buffered the risk of cognitive decline resulting from housing damage. Interpretation: Informal socializing and social participation may prevent cognitive impairment following natural disaster. Funding: National Institutes of Health (R01AG042463-04), the Japan Society for the Promotion of Science, the Japanese Ministry of Health, Labour and Welfare and the Japanese Ministry of Education, Culture, Sports, Science and Technology. PMID- 29430570 TI - Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. AB - Multiple Sclerosis (MS), Myalgic Encephalomyelitis (ME), and Chronic Fatigue syndrome are debilitating chronic illnesses, with some overlapping symptoms. However, few studies have compared and contrasted symptom and disability profiles for these illnesses for the purpose of further differentiating them. The current study was an online self-report survey that compared symptoms from a sample of individuals with MS (N = 120) with a sample of individuals with ME or CFS (N = 269). Respondents completed the self-report DePaul Symptom Questionnaire. Those individuals with ME or CFS reported significantly more functional limitations and significantly more severe symptoms than those with MS. The implications of these findings are discussed. PMID- 29430572 TI - Transcriptional and Functional Plasticity Induced by Chronic Insulin Exposure in a Mast Cell-Like Basophilic Leukemia Cell Model. AB - Objective: Secretory granules (SG) and lipid bodies (LB) are the primary organelles that mediate functional responses in mast cells. SG contains histamine and matrix-active proteases, while LB are reservoirs of arachidonic acid and its metabolites, precursors for rapid synthesis of eicosanoids such as LTC4. Both of these compartments can be dynamically or ontologically regulated, with metabolic and immunological stimuli altering lipid body content and granule numbers responding to contextual signals from tissue. We previously described that chronic in vitro or in vivo hyperinsulinemia expands the LB compartment with a concomitant loss of SG capacity, suggesting that this ratio is dynamically regulated. The objective of the current study is to determine if chronic insulin exposure initiates a transcriptional program that biases model mast cells towards a lipogenic state with accompanying loss of secretory granule biogenesis. Methods: We used a basophilic leukemic cell line with mucosal mast cell-like features as a model system. We tested the hypothesis that chronic insulin exposure initiates a transcriptional program that biases these model mast cells towards a lipogenic state with accompanying loss of secretory granule biogenesis. Transcriptional arrays were used to map gene expression patterns. Biochemical, immunocytochemical and mediator release assays were used to evaluate organelle numbers and functional responses. Results: In a mucosal mast cell model, the rat basophilic leukemia line RBL2H3, mast cell granularity and SG numbers are inversely correlated with LB numbers. Chronic insulin exposure appears to modulate gene networks involved in both lipid body biogenesis and secretory granule formation. Western blot analysis confirms upregulation of protein levels for LB proteins, and decreases in proteins that are markers for SG cargo. Conclusions: The levels of insulin in the extracellular milieu may modify the phenotype of mast cell-like cells in vitro. PMID- 29430573 TI - Learning-Based Estimation of Functional Correlation Tensors in White Matter for Early Diagnosis of Mild Cognitive Impairment. AB - It has been recently demonstrated that the local BOLD signals in resting-state fMRI (rs-fMRI) can be captured for the white matter (WM) by functional correlation tensors (FCTs). FCTs provide similar orientation information as diffusion tensors (DTs), and also functional information concerning brain dynamics. However, FCTs are susceptible to noise due to the low signal-to-noise ratio nature of WM BOLD signals. Here we introduce a robust FCT estimation method to facilitate individualized diagnosis. First, we develop a noise-tolerating patch-based approach to measure spatiotemporal correlations of local BOLD signals. Second, it is also enhanced by DTs predicted from the input rs-fMRI using a learning-based regression model. We evaluate our trained regressor using the high-resolution HCP dataset. The regressor is then applied to estimate the robust FCTs for subjects in the ADNI2 dataset. We demonstrate for the first time the disease diagnostic value of robust FCTs. PMID- 29430571 TI - Bayesian Cox Proportional Hazards Model in Survival Analysis of HACE1 Gene with Age at Onset of Alzheimer's Disease. AB - Alzheimer's disease (AD), the most common form of dementia, is a chronic neurodegenerative disease. The HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) gene is expressed in human brain and may play a role in the pathogenesis of neurodegenerative disorders. Till now, no previous study has reported the association of the HACE1 gene with the risk and age at onset (AAO) of AD; while few studies have checked the proportional hazards assumption in the survival analysis of AAO of AD using Cox proportional hazards model. In this study, we examined the associations of 14 single nucleotide polymorphisms (SNPs) in the HACE1 gene with the risk and the AAO of AD using 791 AD patients and 782 controls. Multiple logistic regression model identified one SNP (rs9499937 with p = 1.8*10-3) to be associated with the risk of AD. For survival analysis of AAO, both classic Cox regression model and Bayesian survival analysis using the Cox proportional hazards model were applied to examine the association of each SNP with the AAO. The hazards ratio (HR) with its 95% confidence interval (CI) was estimated. Survival analysis using the classic Cox regression model showed that 4 SNPs were significantly associated with the AAO (top SNP rs9499937 with HR=1.33, 95%CI=1.13-1.57, p=5.0*10-4). Bayesian Cox regression model showed similar but a slightly stronger associations (top SNP rs9499937 with HR=1.34, 95%CI=1.11-1.55) compared with the classic Cox regression model. Using an independent family-based sample, one SNP rs9486018 was associated with the risk of AD (p=0.0323) and the T-T-G haplotype from rs9786015, rs9486018 and rs4079063 showed associations with both the risk and AAO of AD (p=2.27*10-3 and 0.0487, respectively). The findings of this study provide first evidence that several genetic variants in the HACE1 gene were associated with the risk and AAO of AD. PMID- 29430574 TI - How the personalities of medical students at the National University of Singapore differ from the local non-medical undergraduate population: a cross-sectional study. AB - INTRODUCTION: Integrity and willingness to contribute to society are desired traits of medical students beyond academic excellence. We investigated the personality traits of medical students at the National University of Singapore (NUS), Singapore, as they were about to become doctors. Personality traits were compared with a peer population of local university students. METHODS: This study was conducted between October 2013 and December 2014. Year 4 medical students were administered the Revised NEO (Neuroticism-Extraversion-Openness) Personality Inventory (NEO PI-R), a 240-item Likert scale personality test. Test data was analysed by an institutional psychologist and compared to a separate sample of 377 non-medical students, who were peers at the same university taking psychology as a module. Data was collated and analysed. RESULTS: 65 year 4 medical students completed the NEO PI-R personality test. The personalities of year 4 medical students at NUS differed from their peers in all domains except for openness. NUS medical students generally had less neuroticism, were more extroverted and agreeable, and had more conscientiousness than their peers. CONCLUSION: Personality testing of NUS year 4 medical students showed many of the desired traits of a doctor when compared to their peers at the same university. PMID- 29430575 TI - Knowledge and attitudes of Singapore schoolchildren learning cardiopulmonary resuscitation and automated external defibrillator skills. AB - INTRODUCTION: Victims of out-of-hospital cardiac arrests require timely cardiopulmonary resuscitation (CPR) and early defibrillation. Callers to emergency medical services are asked to provide dispatcher-guided responses until an ambulance arrives. Knowing what to expect in such circumstances should reduce both delay and confusion. METHODS: This study was conducted among schoolchildren aged 11-17 years using ten-item pre- and post-training surveys. We aimed to observe any knowledge and attitude shifts regarding CPR and automated external defibrillator (AED) use subsequent to the training. RESULTS: A total of 1,196 students across five schools completed the pre- and post-training surveys. Survey questions tested basic CPR knowledge and attitudes towards CPR and AED use. The overall response rate was 80.8% and 81.5% in the pre- and post-training surveys, respectively. There was a statistically significant improvement in the students' CPR knowledge. The number of students who selected all the correct answers for the knowledge-based questions in the post-training survey increased by 64.7% (95% confidence interval 61.9%-67.5%; p < 0.001). There was also an improvement in their willingness to administer CPR (likely/very likely to administer CPR pre training vs. post-training: 13.0% vs. 71.0%; p < 0.001) and use AED (likely/very likely to administer AED pre-training vs. post-training: 11.7% vs. 78.0%; p < 0.001) after training. CONCLUSION: The training programme imparted new information and skills, and improved attitudes towards providing CPR and using AED. However, some concerns persisted about hurting the victim while performing CPR. PMID- 29430576 TI - Prevalence and correlates of diabetes mellitus and dyslipidaemia in a long-stay inpatient schizophrenia population in Singapore. AB - INTRODUCTION: Patients with schizophrenia have shorter life expectancy and one of the main causes of death is cardiovascular disease (CVD). Modifiable risk factors for CVD include diabetes mellitus (DM) and dyslipidaemia. This study aimed to establish: (a) the prevalence and correlates of DM and dyslipidaemia; (b) the proportion of those whose condition was well controlled; and (c) the incidence of undiagnosed DM and dyslipidaemia in a long-stay inpatient schizophrenia population. METHODS: Data was collected to assess the physical health status of 110 inpatients with schizophrenia who had been in hospital for over one year. Information on sociodemographic characteristics, diagnosis of physical and mental illnesses, and current medications was obtained from their medical records. The overall prevalence of DM and dyslipidaemia was based on diagnosis in the medical records, current medications and fasting blood test results. RESULTS: The patient group was predominantly male (85.5%), with a mean age of 55.9 +/- 9.9 (range 25 90) years. Overall prevalence of DM and dyslipidaemia was 19.1% and 62.7%, respectively. Multivariate logistic regression analysis showed that Malay (odds ratio [OR] 14.97) and Indian (OR 25.71) patients were significantly more likely to have DM when compared to Chinese patients. CONCLUSION: In comparison to the general population, the prevalence of DM and dyslipidaemia was found to be higher in inpatients with schizophrenia. However, the two chronic illnesses were well controlled in inpatients and few were undiagnosed, perhaps due to the regular monitoring, supervised diet and regular physical activities arranged for inpatients in the long-stay inpatient wards. PMID- 29430577 TI - Phenotypic and metabolic dichotomy in obesity: clinical, biochemical and immunological correlates of metabolically divergent obese phenotypes in healthy South Asian adults. AB - INTRODUCTION: Metabolic heterogeneity among obese individuals is thought to translate into variations in cardiovascular risk. Identifying obese people with an unfavourable metabolic profile may allow preventive strategies to be targeted at high-risk groups. This study aimed to identify clinical, biochemical and immunological differences between insulin-sensitive and insulin-resistant obese subgroups, to understand the population-specific pathophysiological basis of the adverse cardiovascular risk profile in the latter group. METHODS: Cardiovascular risk indicators, including anthropometric parameters, blood pressure, acanthosis nigricans area, and related biochemical, endocrine and inflammatory markers, were determined in 255 healthy South Asian volunteers aged 18-45 years, with a 2:1 ratio of obese/overweight to normal-weight individuals. Lifetime atherosclerotic cardiovascular disease (ASCVD) risk was also calculated. RESULTS: Body mass index (BMI) and insulin sensitivity-based tertiles independently showed incremental trends in waist-hip ratio, skinfold thickness, acanthosis nigricans area, blood pressure, serum lipids, hepatic enzymes, adipokines, inflammatory markers and ten year ASCVD risk. The anthropometric, biochemical and inflammatory parameters of obese insulin-sensitive and obese insulin-resistant groups differed significantly. Extreme group analysis after excluding the middle tertiles of both insulin resistance and BMI also showed significant difference in anthropometric indicators of cardiovascular risk and estimated lifetime ASCVD risk between the two obese subgroups. CONCLUSION: Obese insulin-sensitive individuals had a favourable metabolic profile compared to the obese insulin-resistant group. The most consistent discriminative factor between these phenotypic classes was anthropometric parameters, which underscores the importance of clinical parameters as cardiovascular risk indicators in obesity. PMID- 29430578 TI - Interspecific Cross-Attraction between the South American Cerambycid Beetles Cotyclytus curvatus and Megacyllene acuta is Averted by Minor Pheromone Components. AB - During field screening trials conducted in Brazil in 2015, adults of both sexes of the cerambycid beetles Cotyclytus curvatus (Germar) and Megacyllene acuta (Germar) (subfamily Cerambycinae, tribe Clytini) were significantly attracted to racemic 3-hydroxyhexan-2-one and racemic 2-methylbutan-1-ol, chemicals which previously have been identified as male-produced aggregation-sex pheromones of a number of cerambycid species endemic to other continents. Subsequent analyses of samples of beetle-produced volatiles revealed that males of C. curvatus sex specifically produce only (R)-3-hydroxyhexan-2-one, whereas males of M. acuta produce the same compound along with lesser amounts of (2S,3S)-2,3-hexanediol and (S)-2-methylbutan-1-ol. Follow-up field trials showed that both sexes of both species were attracted to synthetic reconstructions of their respective pheromones, confirming that males produce aggregation-sex pheromones. The minor pheromone components of M. acuta, (S)-2-methylbutan-1-ol and (2S,3S)-2,3 hexanediol, synergized attraction of that species, but antagonized attraction of C. curvatus to (R)-3-hydroxyhexan-2-one. Beetles of other cerambycine species also were attracted in significant numbers, including Chrysoprasis linearis Bates, Cotyclytus dorsalis (Laporte & Gory), and Megacyllene falsa (Chevrolat). Our results provide further evidence that 3-hydroxyhexan-2-one is a major component of attractant pheromones of numerous cerambycine species world-wide. Our results also highlight our increasing understanding of the crucial role of minor pheromone components in imparting species specificity to cerambycid pheromone blends, as is known to occur in numerous species in other insect families. PMID- 29430579 TI - The ability of silver(I) thiocyanate 4-methoxyphenyl phosphine to induce apoptotic cell death in esophageal cancer cells is correlated to mitochondrial perturbations. AB - First generation silver(I) phosphines have garnered much interest due to their vast structural diversity and promising anticancer activity. Increasing incidences of cancer, side-effects to chemotherapeutic agents and redevelopment of tumors due to resistance prompts the exploration of alternative compounds showing anticancer activity. This study revealed the effective induction of cell death by a silver(I) thiocyanate 4-methoxyphenyl phosphine complex in a malignant esophageal cell line. Apoptotic cell death was confirmed in treated cells. Moreover, mitochondrial targeting via the intrinsic cell death pathway was evident due to low levels of ATP, altered ROS activity, mitochondrial membrane depolarization, cytochrome c release and caspase-9 cleavage. The complex displayed low cytotoxicity towards two human non-malignant, skin and kidney, cell lines. The findings reported herein give further insight into the selective targeting of silver(I) phosphines and support our belief that this complex shows great promise as an effective chemotherapeutic drug. PMID- 29430580 TI - Devices and interventions for the prevention of adverse outcomes of tachycardia on heart failure. AB - Heart failure (HF) is the leading cause of hospitalization in the USA. Despite advances in pharmacologic management, the incidence of HF is on the rise and survivability is persistently reduced. Sympathetic overdrive is implicated in the pathophysiology of HF, particularly HF with reduced ejection fraction (HFrEF). Tachycardia can be particularly deleterious and thus has spurred significant investigation to mitigate its effects. Various modalities including vagus nerve stimulation, baroreceptor activation therapy, spinal cord stimulation, renal sympathetic nerve denervation, left cardiac sympathetic denervation, and carotid body removal will be discussed. However, the effects of these modalities on tachycardia and its outcomes in HFrEF have not been well-studied. Further studies to characterize this are necessary in the future. PMID- 29430581 TI - Plagioneurin B, a potent isolated compound induces apoptotic signalling pathways and cell cycle arrest in ovarian cancer cells. AB - Plagioneurin B belongs to acetogenin group has well-established class of compounds. Acetogenin group has attracted worldwide attention in the past few years due their biological abilities as inhibitors for several types of tumour cells. Plagioneurin B was isolated via conventional chromatography and tested for thorough mechanistic apoptosis activity on human ovarian cancer cells (CAOV-3). Its structure was also docked at several possible targets using Autodock tools software. Our findings showed that plagioneurin B successfully inhibits the growth of CAOV-3 cells at IC50 of 0.62 uM. The existence of apoptotic bodies, cell membrane blebbing and chromatin condensation indicated the hallmark of apoptosis. Increase of Annexin V-FITC bound to phosphatidylserine confirmed the apoptosis induction in the cells. The apoptosis event was triggered through the extrinsic and intrinsic pathways via activation of caspases 8 and 9, respectively. Stimulation of caspase 3 and the presence of DNA ladder suggested downstream apoptotic signalling were initiated. Further confirmation of apoptosis was conducted at the molecular levels where up-regulation in Bax, as well as down regulation of Bcl-2, Hsp-70 and survivin were observed. Plagioneurin B was also seen to arrest CAOV-3 cells cycle at the G2/M phase. Docking simulation of plagioneurin B with CD95 demonstrated that the high binding affinity and hydrogen bonds formation may explain the capability of plagioneurin B to trigger apoptosis. This study is therefore importance in finding the effective compound that may offer an alternative drug for ovarian cancer treatment. PMID- 29430582 TI - The impact of liver resection on the dihydrouracil:uracil plasma ratio in patients with colorectal liver metastases. AB - PURPOSE: The dihydrouracil (DHU):uracil (U) plasma ratio is a promising marker for identification of dihydropyrimidine dehydrogenase (DPD)-deficient patients. The objective of this study was to determine the effect of liver resection on the DHU:U plasma ratio in patients with colorectal liver metastases (CRLM). METHODS: An observational study was performed in which DHU:U plasma ratios in patients with CRLM were analyzed prior to and 1 day after liver resection. In addition, the DHU:U plasma ratio was quantified in six additional patients 4-8 weeks after liver resection to explore long-term effects on the DHU:U plasma ratio. Quantification of U and DHU plasma levels was performed using a validated ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay. RESULTS: The median (range) DHU:U plasma ratio in 15 patients prior to liver resection was 10.7 (2.6-14.4) and was significantly reduced to 5.5 (< quantification limit (LLOQ-10.5) 1 day after resection (p = 0.0026). This reduction was caused by a decrease in DHU plasma levels from 112.0 (79.8-153) ng/mL to 41.2 (< LLOQ-160) ng/mL 1 day after resection (p = 0.0004). Recovery of the DHU:U plasma ratio occurred 4-8 weeks after liver resection, which was shown by a median (range) DHU:U plasma ratio in six patients of 9.1 (6.9-14.5). CONCLUSION: Liver resection leads to very low DHU:U plasma ratios 1 day after liver resection, which is possibly caused by a reduction in DPD activity. Quantification of the DHU:U plasma ratios directly after liver resection could lead to false-positive identification of DPD deficiency and is therefore not advised. PMID- 29430583 TI - Impacts of bioprocess engineering on product formation by Acetobacter pasteurianus. AB - Aerobic Acetobacter pasteurianus is one of the most widely used bacterial species for acetic acid and vinegar production. The acetic acid condition is the primary challenge to the industrial application of A. pasteurianus. Thus, numerous endeavors, including strain improvement and process control, have been performed to improve the product formation and acetic acid tolerance of A. pasteurianus. The metabolic features of A. pasteurianus have been gradually elucidated through omic techniques, such as genomics and proteomics. In this mini review, we summarized bioprocess engineering methods that improved product formation of A. pasteurianus by exploiting its metabolic features. Moreover, given that A. pasteurianus is an important functional microorganism in traditional vinegar production, we discuss its metabolism when cocultured with other microorganisms in traditional vinegar production. PMID- 29430584 TI - Succession sequence of lactic acid bacteria driven by environmental factors and substrates throughout the brewing process of Shanxi aged vinegar. AB - Lactic acid bacteria (LAB) are essential microbiota for the fermentation and flavor formation of Shanxi aged vinegar, a famous Chinese traditional cereal vinegar that is manufactured using open solid-state fermentation (SSF) technology. However, the dynamics of LAB in this SSF process and the underlying mechanism remain poorly understood. Here, the diversity of LAB and the potential driving factors of the entire process were analyzed by combining culture independent and culture-dependent methods. Canonical correlation analysis indicated that ethanol, acetic acid, and temperature that result from the metabolism of microorganisms serve as potential driving factors for LAB succession. LAB strains were periodically isolated, and the characteristics of 57 isolates on environmental factor tolerance and substrate utilization were analyzed to understand the succession sequence. The environmental tolerance of LAB from different stages was in accordance with their fermentation conditions. Remarkable correlations were identified between LAB growth and environmental factors with 0.866 of ethanol (70 g/L), 0.756 of acetic acid (10 g/L), and 0.803 of temperature (47 degrees C). More gentle or harsh environments (less or more than 60 or 80 g/L of ethanol, 5 or 20 g/L of acetic acid, and 30 or 55 degrees C temperature) did not affect the LAB succession. The utilization capability evaluation of the 57 isolates for 95 compounds proved that strains from different fermentation stages exhibited different predilections on substrates to contribute to the fermentation at different stages. Results demonstrated that LAB succession in the SSF process was driven by the capabilities of environmental tolerance and substrate utilization. PMID- 29430585 TI - Dendritic Cell Factor 1-Knockout Results in Visual Deficit Through the GABA System in Mouse Primary Visual Cortex. AB - The visual system plays an important role in our daily life. In this study, we found that loss of dendritic cell factor 1 (DCF1) in the primary visual cortex (V1) caused a sight deficit in mice and induced an abnormal increase in glutamic acid decarboxylase 67, an enzyme that catalyzes the decarboxylation of glutamate to gamma aminobutyric acid and CO2, particularly in layer 5. In vivo electrophysiological recordings confirmed a decrease in delta, theta, and beta oscillation power in DCF1-knockout mice. This study presents a previously unknown function of DCF1 in V1, suggests an unknown contact between DCF1 and GABA systems, and provides insight into the mechanism and treatment of visual deficits. PMID- 29430588 TI - Witnessing Death, Witnessing Truth. PMID- 29430587 TI - Preliminary experience with sofosbuvir-based treatment regimens for patients dependent on hemodialysis. PMID- 29430586 TI - The Antidepressant Effect of Light Therapy from Retinal Projections. AB - Observations from clinical trials have frequently demonstrated that light therapy can be an effective therapy for seasonal and non-seasonal major depression. Despite the fact that light therapy is known to have several advantages over antidepressant drugs like a low cost, minimal side-effects, and fast onset of therapeutic effect, the mechanism underlying light therapy remains unclear. So far, it is known that light therapy modulates mood states and cognitive functions, involving circadian and non-circadian pathways from retinas into brain. In this review, we discuss the therapeutic effect of light on major depression and its relationship to direct retinal projections in the brain. We finally emphasize the function of the retino-raphe projection in modulating serotonin activity, which probably underlies the antidepressant effect of light therapy for depression. PMID- 29430589 TI - Factors Associated with Length of Stay in a Swiss Mental Hospital. AB - The aim of this study was to identify factors which are associated with the length of stay in a Swiss mental hospital. Demographical and clinical data of all patients who were admitted to the adult inpatient psychiatric service of the Federal State of Aargau in 2016 were examined regarding their association with the length of stay. The study sample included N = 1479 patients. Mean length of stay was 33 days and the median equalled 26 days. Higher age and a primary diagnosis of psychotic or affective disorder were associated with increased length of stay. In contrast, foreign nationality and compulsory admission were associated with reduced length of stay. While some of our findings were in line with recent findings from Italy and the United Kingdom, others could not be replicated. PMID- 29430591 TI - Shifting to Value-Based Principles in Sickness Insurance: Challenges in Changing Roles and Culture. AB - Purpose Management principles in insurance agencies influence how benefits are administered, and how return to work processes for clients are managed and supported. This study analyses a change in managerial principles within the Swedish Sickness Insurance Agency, and how this has influenced the role of insurance officials in relation to discretion and accountability, and their relationship to clients. Methods The study is based on a qualitative approach comprising 57 interviews with officials and managers in four insurance offices. Results The reforms have led to a change in how public and professional accountability is defined, where the focus is shifted from routines and performance measurements toward professional discretion and the quality of encounters. However, the results show how these changes are interpreted differently across different layers of the organization, where New Public Management principles prevail in how line managers give feedback on and reward the work of officials. Conclusions The study illustrates how the introduction of new principles to promote officials' discretion does not easily bypass longstanding management strategies, in this case managing accountability through top-down performance measures. The study points out the importance for public organizations to reconcile new organizational principles with the current organizational culture and how this is manifested through managerial styles, which may be resistant to change. Promoting client-oriented and value-driven approaches in client work hence needs to acknowledge the importance of organizational culture, and to secure that changes are reflected in organizational procedures and routines. PMID- 29430590 TI - Patterns of Health Care Service Utilization by Individuals with Mental Health Problems: a Predictive Cluster Analysis. AB - This study aimed at identifying and characterizing clusters of mental health service users based on various characteristics in a sample of individuals with mental health problems. Data were collected in the epidemiological catchment area of South-West Montreal, Quebec in 2011 and 2014. Among the 746 participants who reported experiencing a mental health problem (high psychological distress and/or a mental disorder), 29% had used mental health services. A Two-Step cluster analysis was carried out to generate participant profiles based on their visit to mental health professional. Four clusters were identified: 1) young males with high quality of life and social support and who were less likely to have mental health problems and to utilize mental health services; 2) older females living with a partner and having a family doctor who were less likely to have mental health problems and to utilize mental health services; 3) single females with generalized anxiety disorder and somatic illness who were more likely to utilize mental health services, and 4) depressed females with high psychological distress, low quality of life and social support who were likely to utilize mental health services. The results reinforce the importance to develop programs that target the specific needs of subgroups of people experiencing mental health problems, given their considerable heterogeneity. PMID- 29430592 TI - Patterns and Predictors of Failed and Sustained Return-to-Work in Transport Injury Insurance Claimants. AB - : Purpose To determine the incidence of employed people who try and fail to return-to-work (RTW) following a transport crash. To identify predictors of RTW failure. METHODS: A historical cohort study was conducted in the state of Victoria, Australia. People insured through the state-based compulsory third party transport accident compensation scheme were included. Inclusion criteria included date of crash between 2003 and 2012 (inclusive), age 15-70 years at the time of crash, sustained a non-catastrophic injury and received at least 1 day of income replacement. A matrix was created from an administrative payments dataset that mapped their RTW pattern for each day up to 3 years' post-crash. A gap of 7 days of no payment followed by resumption of a payment was considered a RTW failure and was flagged. These event flags were then entered into a regression analysis to determine the odds of having a failed RTW attempt. RESULTS: 17% of individuals had a RTW fail, with males having 20% lower odds of experiencing RTW failure. Those who were younger, had minor injuries (sprains, strains, contusions, abrasions, non-limb fractures), or were from more advantaged socio economic group, were less likely to experience a RTW failure. Most likely to experience a RTW failure were individuals with whiplash, dislocations or particularly those admitted to hospital. CONCLUSIONS: Understanding the causes and predictors of failed RTW can help insurers, employers and health systems identify at-risk individuals. This can enable earlier and more targeted support and more effective employment outcomes. PMID- 29430593 TI - Identification of a novel homozygous UNC80 variant in a child with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2). AB - The UNC80 gene encodes for a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. In this study, we report on a novel homozygous mutation in UNC80 in a Palestinian-Emirati patient suffering infantile hypotonia with psychomotor retardation and characteristic facies. This mutation was detected by whole exome sequencing and confirmed using Sanger sequencing in the patient-parents trio. Numerous elements in the patient's phenotype were in agreement with the few reported cases of UNC80 mutations; however there are some notable differences. We present comprehensive clinical and molecular accounts of this mutation in addition to a full review of previously reported patients of UNC80 mutations. PMID- 29430594 TI - Fast in silico assessment of physical stress for peripheral nerves. AB - The level of physical stress rules the adaptative response of peripheral nerves, which is crucial to assess their physiological and pathological states. To this aim, in this work, different computational approaches were presented to model the stress response of in vitro peripheral nerves undergoing longitudinal stretch. More specifically, the effects of geometrical simplifications were studied with respect to the amount of computational time needed to obtain relevant information. Similarly, the variation of compressibility of the peripheral nervous tissue was investigated with respect to the variation of longitudinal stress and transversal stretch variations, and with reference to the computational time needed for simulations. Finally, the effect of small dimensional changes was investigated to better understand whether the variation of time was only due to the amount of nodes or elements. In conclusion, since fast in silico models, able to assess the nerve stress, could be a strategic advantage in case of time constraints or on-line evaluation (e.g., surgical interventions), a synergistic use of these approaches was proposed as a possible strategy to decrease the computational time needed for simulations from minutes to seconds. Graphical Abstract A synergistic approach involving both symmetry and tuning of compressibility allows the computational time to be considerably decreased. PMID- 29430595 TI - The C19S Substitution Enhances the Stability of Hepcidin While Conserving Its Biological Activity. AB - Hepcidin, the key hormone of iron homeostasis is responsible for lowering the serum iron level through its interaction with iron exporter ferroportin. Thus, hepcidin agonists provide a promising opportunity in the treatment of iron disorders caused by lacking or decreased hepcidin expression. We investigated the importance of each of the eight highly conserved cysteines for the biological activity of hepcidin. Eight cysteine mutants were created with site directed mutagenesis. The binding ability of these hepcidin mutants to the hepcidin receptor ferroportin was determined using bacterial two-hybrid system and WRL68 human hepatic cells. The biological activity of hepcidin mutants was determined by western blot analysis of ferroportin internalization and ferroportin ubiquitination. To investigate the effect of mutant hepcidins on the iron metabolism of the WRL68 cells, total intracellular iron content was measured with a colorimetric assay. The stability of M6 hepcidin mutant was determined using ELISA technique. Our data revealed that serine substitution of the sixth cysteine (M6) yielded a biologically active but significantly more stable peptide than the original hormone. This result may provide a promising hepcidin agonist worth testing in animal models. PMID- 29430596 TI - Five-year Outcomes of Laparoscopic Sleeve Gastrectomy: a Comparison Between Adults and Adolescents. AB - BACKGROUND: Bariatric surgery in adolescents is still under debate. Literature about the long-term impact of laparoscopic sleeve gastrectomy (LSG) on adolescents' obesity and associated morbidities is scarce. It is unknown if LSG shows better long-term results in the adolescent or adult group. AIM: To compare the long-term effectiveness of LSG on obesity and associated comorbidities between adolescents and adults. METHODS: This retrospective study analyzed all patients with morbid obesity who underwent LSG in (2011-2012) and were followed for up to 5 years. Patients were divided into two groups: adolescents and adults. Data were compared between the two groups. RESULTS: LSG was performed in 139 adults and 91 adolescents. The mean ages of the adults and adolescents were 37.4 +/- 11.4 and 17 +/- 1.5 years, respectively. The preoperative body mass index values of the adults and adolescents were 48.4 +/- 8.7 and 47.6 +/- 7.5 kg/m2, respectively (P = 0.95). At 5 years, percentage of total weight loss increased in adolescents (to 35.8 +/- 11.5%), while it remained almost the same in adults (26.3 +/- 10%). At 1 year, about 68.2% of adults and 62.5% of adolescents were cured from diabetes though, 13% of diabetic adults had relapse at 5 years and none of the adolescents relapsed. Postoperative complications occurred in both groups. CONCLUSION: LSG showed comparable weight loss results in adults and adolescents, with better results in adolescents. LSG is more effective in preventing and treating diabetes/prediabetes in the adolescent group. PMID- 29430598 TI - Simultaneous quantification of caffeine and chlorogenic acid in coffee green beans and varietal classification of the samples by HPLC-DAD coupled with chemometrics. AB - A chromatographic procedure (HPLC-DAD) using a relatively rapid gradient has been combined with a chemometric curve deconvolution method, multivariate curve resolution-alternating least squares (MCR-ALS), in order to quantify caffeine and chlorogenic acid in green coffee beans. Despite that the HPLC analysis (at these specific operating conditions) presents some coeluting peaks, MCR-ALS allowed their resolution and, consequently, the creation of a calibration curve to be used for the quantification of the analytes of interest; this procedure led to a high accuracy in the quantification of caffeine and chlorogenic acid present in the samples. In a second part of this study, the possibility of classifying the green coffee beans on the basis of their cultivar (Arabica or Robusta), by partial least squares discriminant analysis (PLS-DA) and soft independent modeling of class analogies (SIMCA), has been explored. SIMCA resulted in 100% of sensitivity and specificity for the Arabica class, while for the Robusta, it reached 66.7% of sensitivity and 100% of specificity, or 100% of sensitivity and 100% of specificity, depending on the extraction procedure followed prior to the chromatographic analysis; PLS-DA achieved 100% of correct classification independently of the procedure used for the extraction. PMID- 29430597 TI - Wet deposition of atmospheric nitrogen contributes to nitrogen loading in the surface waters of Lake Tanganyika, East Africa: a case study of the Kigoma region. AB - Lake Tanganyika, an African Great Lake, is a complex tropical ecosystem that has been subjected to extreme climate-related changes in the last century, including seasonal changes in temperature and rainfall, decreased overall annual rainfall, and greater frequency of rainstorms. Atmospheric nitrogen (N) is an important component of the lake's N loading, but how long-term and seasonal changes in precipitation affect this loading still needs clarification. This study aimed to improve our understanding of the seasonal features of N deposition in the lake, by monitoring atmospheric N deposition concentrations and fluxes from March 2013 to February 2014. There was a significant temporal variation in wet N depositions in the study area. The distribution of the annual rainfall into major (March-May 299.8 mm) and minor (October-December 343.2 mm) rainy seasons translated into 20 and 30% of N deposition. In September and January-February, there was 10 and 12% precipitation, representing 43 and 7% of N deposition in the lake. Nitrogen deposition was highest in September due to farmlands' burning during the dry season (June-August), leading to N accumulation in the atmosphere. In conclusion, the pattern of N deposition appears to be driven by the unique climatic characteristics of the lake basin and to be closely associated with local anthropogenic activities. PMID- 29430599 TI - Inexpensive, effective novel activated carbon fibers for sample cleanup: application to multipesticide residue analysis in food commodities using a QuEChERS method. AB - Phenolic resin based activated carbon fibers (ACFs) were applied for the first time as a reversed-dispersive solid-phase extraction (r-DSPE) sorbent. A modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) method was applied to determine 26 pesticides (organophosphates, organochlorines, synthetic pyrethroids, and herbicides) in different complex matrices, including cauliflower, cucumber, banana, apple, wheat, and black gram. Different physicochemical characterization techniques were used to investigate the engineering and structural properties of the r-DSPE sorbent. All the chromatographic analyses were performed with a gas chromatograph equipped with an electron capture detector. The recoveries of all 26 pesticides were acceptable (70-120%), with relative standard deviations of less than 15%. The limit of detection and the limit of quantification were 1.13-5.48 ng/g and 3.42-16.60 ng/g, respectively. In the original QuEChERS method, primary secondary amine is extensively used as the r-DSPE sorbent in the cleanup process, but it is eightfold more expensive than the ACFs used in this study. Therefore, the modified QuEChERS method using ACFs during the cleanup process is more efficient, cheaper, and more robust to determine pesticides from different types of matrices, including vegetables, grains, and fruits, and ACFs could be used as a cost-effective alternative to primary secondary amine. Graphical Abstract Sample clean-up using PSA and ACF as r-DSPE sorbent in QuEChERS method. PMID- 29430600 TI - The NISTmAb Reference Material 8671 lifecycle management and quality plan. AB - Comprehensive analysis of monoclonal antibody therapeutics involves an ever expanding cadre of technologies. Lifecycle-appropriate application of current and emerging techniques requires rigorous testing followed by discussion between industry and regulators in a pre-competitive space, an effort that may be facilitated by a widely available test metric. Biopharmaceutical quality materials, however, are often difficult to access and/or are protected by intellectual property rights. The NISTmAb, humanized IgG1kappa Reference Material 8671 (RM 8671), has been established with the intent of filling that void. The NISTmAb embodies the quality and characteristics of a typical biopharmaceutical product, is widely available to the biopharmaceutical community, and is an open innovation tool for development and dissemination of results. The NISTmAb lifecyle management plan described herein provides a hierarchical strategy for maintenance of quality over time through rigorous method qualification detailed in additional submissions in the current publication series. The NISTmAb RM 8671 is a representative monoclonal antibody material and provides a means to continually evaluate current best practices, promote innovative approaches, and inform regulatory paradigms as technology advances. Graphical abstract The NISTmAb Reference Material (RM) 8671 is intended to be an industry standard monoclonal antibody for pre-competitive harmonization of best practices and designing next generation characterization technologies for identity, quality, and stability testing. PMID- 29430601 TI - Detection of 1,3-dihydroxyacetone by tris(2,2'-bipyridine)ruthenium(II) electrochemiluminescence. AB - 1,3-Dihydroxyacetone, a common cosmetic material and food additive, has been successfully explored as an efficient electrochemiluminescence coreactant of Ru(bpy)32+ for the first time. It is about 25 times more effective than the well known coreactant sodium oxalate. The high electrochemiluminescence efficiency allows sensitive detection of 1,3-dihydroxyacetone without any derivatization. The electrochemiluminescence method shows two linear electrochemiluminescence responses over the range of 5.0-500 MUM and 500 MUM-6.0 mM with a detection limit of 1.79 MUM. The proposed method is at least two orders of magnitude more sensitive than other reported methods. Graphical abstract ECL intensity-potential profile of 1,3-dihydroxyacetone (DHA) and oxalate. PMID- 29430602 TI - A unique arsenic speciation profile in Elaphomyces spp. ("deer truffles") trimethylarsine oxide and methylarsonous acid as significant arsenic compounds. AB - Arsenic and its species were investigated for the first time in nine collections of Elaphomyces spp. ("deer truffles") from the Czech Republic with inductively coupled plasma mass spectrometry (ICPMS) and high-performance liquid chromatography coupled to ICPMS. The total arsenic concentrations ranged from 12 to 42 mg kg-1 dry mass in samples of E. asperulus and from 120 to 660 mg kg-1 dry mass in E. granulatus and E. muricatus. These concentrations are remarkably high for terrestrial organisms and demonstrate the arsenic-accumulating ability of these fungi. The dominating arsenic species in all samples was methylarsonic acid which accounted for more than 30% of the extractable arsenic. Arsenobetaine, dimethylarsinic acid, and inorganic arsenic were present as well, but only at trace concentrations. Surprisingly, we found high amounts of trimethylarsine oxide in all samples (0.32-28% of the extractable arsenic). Even more remarkable was that all but two samples contained significant amounts of the highly toxic trivalent arsenic compound methylarsonous acid (0.08-0.73% of the extractable arsenic). This is the first report of the occurrence of trimethylarsine oxide and methylarsonous acid at significant concentrations in a terrestrial organism. Our findings point out that there is still a lot to be understood about the biotransformation pathways of arsenic in the terrestrial environment. Graphical abstract Trimethylarsine oxide and methylarsonous acid in "deer truffles". PMID- 29430603 TI - A comparative study of single-stage transpedicular debridement, fusion, and posterior long-segment versus short-segment fixation for the treatment of thoracolumbar spinal tuberculosis in adults: minimum five year follow-up outcomes. AB - DESIGN: This a retrospective study in single centre. OBJECTIVE: The objective of this retrospective clinical study is to compare the long-term clinical efficacy of posterior long-segment and short-segment fixation with single-stage transpedicular debridement and fusion for the treatment of thoracolumbar spinal tuberculosis in adults. METHODS: Sixty-six cases of thoracolumbar tuberculosis were treated by single-stage transpedicular debridement, bone graft fusion, and pedicle screw fixation. Thirty-five cases were under long-segment fixation (group A) and 31 cases were under short-segment fixation (group B). These patients were followed up for a minimum of five years. The clinical and radiographic results for these patients were analyzed and compared. RESULTS: All 66 patients were completely cured during the follow-up. All patients had significant improvement of neurological condition and visual analogue scale pain scores at the final follow-up. The average operation duration and blood loss in group A were more than that in group B. Kyphosis Cobb angle of both groups was significantly corrected after surgical management. The correction rate of Cobb angle in group A was significantly higher than that in group B at the time of immediate post operative period or the last follow-up (P < 0.05). The correction loss of group A was significantly less than that in group B (P < 0.05). CONCLUSION: Both posterior long-segment and short-segment pedicle screw fixations for the treatment of thoracolumbar spinal tuberculosis have significant effects in the correction of kyphosis and the improvement of neurological function. Although the blood loss and operation time of long-segment fixation were more than that of short-segment fixation, long-segment fixation was superior to the short-segment fixation in the correction of kyphosis and the maintenance of spinal stability, especially in the prevention of long-term correction loss. PMID- 29430604 TI - Comparison of culture and broad-range polymerase chain reaction methods for diagnosing periprosthetic joint infection: analysis of joint fluid, periprosthetic tissue, and sonicated fluid. AB - PURPOSE: This study compared the diagnostic capabilities of culture and broad range polymerase chain reaction (PCR) using joint fluid (JF), periprosthetic tissue (PT), and sonicated fluid (SF) for the diagnosis of periprosthetic joint infection (PJI). METHODS: Sixty-seven subjects underwent knee or hip revision surgery, with 53 PJI and 14 aseptic failure (AF) cases included retrospectively. JF, PT, and SF samples were collected after a suspension of antibiotics more than two weeks, and culture and broad-range PCR were performed for all samples. RESULTS: The sensitivities of SF culture (83.0%), JF-PCR (83.0%), and SF-PCR (84.9%) were similar (P > 0.05), but each was significantly more sensitive than JF culture (69.8%), PT culture (71.7%), and PT-PCR (34.0%) (P < 0.05). The specificities of JF culture, PT culture, SF culture, JF-PCR, PT-PCR, and SF-PCR were similar (100, 100, 85.7, 85.7, 100, and 78.6%, respectively) (P > 0.05). PCR was unable to accurately detect six polymicrobial infections and two fungal infections. CONCLUSIONS: SF culture, JF-PCR, and SF-PCR were more sensitive than JF culture, PT culture, and PT-PCR for diagnosing PJI among patients who have stopped taking antibiotics for two weeks or more. Compared with PCR methods, SF culture has the advantage of detecting polymicrobial or fungal infections. PT-PCR proved to be insufficiently sensitive for providing correct diagnoses. PMID- 29430606 TI - Epidemiology of acetabular fractures in Qatar. AB - OBJECTIVES: This study aimed to review the epidemiological aspects of acetabular fractures treated at Hamad Medical Corporation in Qatar. The study is the first orthopaedic trauma epidemiological study in Qatar and will provide a platform to advance high-level clinical research. METHODS: We obtained data for 103 patients who presented to our level I trauma centre from 2008 to 2010 with a diagnosis of acetabular fracture. Age, sex, the cause of injury, fracture classification, mode of treatment, associated nerve injuries, and other complications were analyzed. RESULTS: The incidence of acetabular fracture was 2/100,000/year. Males (93.2%) predominated. The mean age at injury time was 36 years, and the most common cause of injury was motor vehicle collisions (49.5%). Injuries were mostly primary acetabular fractures (73.6%) in comparison to (26.4%) for associated fractures. Posterior wall fractures were the most common pattern (25.2%). Associated posterior hip dislocation occurred in 21.3% of cases. Data revealed a lower incidence of post-traumatic sciatic nerve palsy (7%) that was present at the time of injury. There were no cases of reported mortality. CONCLUSION: Acetabular fractures are uncommon injuries with motor vehicle collision being the most common cause of injury. Posterior wall fracture was the most frequent pattern, and most of the patients were males. The incidence of post-traumatic sciatic nerve palsy and the proportion of injured women were lower than those reported in literature. Well-trained surgeons and specialized centres for treating these injuries are recommended. PMID- 29430605 TI - Analysis of single cage position in transforaminal lumbar interbody fusion through digital images. AB - PURPOSE: The purpose of this study was to investigate the position of single cage inserted using oblique-oriented technique in transforaminal lumbar interbody fusion (TLIF) on digital images of computed tomography (CT). METHODS: From January to August 2015, 44 consecutive patients with degenerative lumbar disease who underwent TLIF in the L4/5 level were retrospectively studied in our department. The single cage was inserted using the oblique-oriented technique; as the main purpose of the study, its position was analyzed using post-operative digital computed tomography images. RESULTS: All cages used in the study had the same length of 36 mm, which were inserted into the discs with a 46.04 +/- 3.09-mm horizontal diameter and 34.25 +/- 3.59-mm longitudinal diameter. The horizontal and longitudinal diameter of the treated disk established the coordinate. The horizontal and longitudinal coordinate values of the centre of the cage were 0.08 +/- 4.12 and 1.20 +/- 2.76 mm, respectively. The horizontal distance of the cage centre from the midpoint of the disc negatively correlated with that of the entry point from the midpoint of the disc in the coronal plane. CONCLUSION: A longer single cage can be placed into the L4/5 level disk by inserting it using the oblique-oriented technique. Its center can reach the midpoint of the treated disk in the coronal plane and the anterior position of the disk in the sagittal plane. The entry point of the cage is the further away from the midpoint of the disk; the cage is the more apt to reach the center of the disk in the coronal plane. PMID- 29430607 TI - The fates of pedicle screws and functional outcomes in a geriatric population following polymethylmethacrylate augmentation fixation for the osteoporotic thoracolumbar and lumbar burst fractures with mean ninety five month follow-up. AB - PURPOSE: Polymethylmethacrylate (PMMA) augmentation is a common method to increase pullout strength fixed for osteoporotic spines. However, few papers evaluated whether these pedicle screws migrated with time and functional outcome in these geriatrics following PMMA-augmented pedicle screw fixation. METHODS: From March 2006 to September 2008, consecutive 64 patients were retrospectively enrolled. VAS and ODI were used to evaluate functional outcomes. Kyphotic angle at instrumented levels and horizontal and vertical distances (HD and VD) between screw tip and anterior and upper cortexes were evaluated. To avoid bias, we used horizontal and vertical migration index (HMI and VMI) to re-evaluate screw positions with normalization by the mean of superior and inferior endplates or anterior and posterior vertebral body height, respectively. RESULTS: Forty-six patients with 282 PMMA-augmented screws were analyzed with mean follow-up of 95 months. Nine patients were further excluded due to bed-ridden at latest follow up. Twenty-six females and 11 males with mean T score of - 2.7 (range, - 2.6 to - 4.1) and mean age for operation of 77.6 +/- 4.3 years (range, 65 to 86). The serial HD and kyphotic angle statistically progressed with time. The serial VD did not statistically change with time (p = 0.23), and neither HMI nor VMI (p = 0.772 and 0.631). Pre-operative DEXA results did not correlate with kyphotic angle. Most patients (80.4%) maintained similar functional outcomes at latest follow-up. The incidence of screws loosening was 2.7% of patients and 1.4% of screws, respectively. The overall incidences of systemic post-operative co morbidities were 24.3% with overall 20.2 days for hospitalization. CONCLUSION: Most patients (80%) remained similar functional outcomes at latest follow-up in spite of kyphosis progression. The incidence of implant failure was not high, but the post-operative systemic co-morbidities were higher, which has to be informed before index surgery. PMID- 29430608 TI - Freedom from Tritrichomonas foetus infection in cattle in St. Kitts. AB - Trichomonosis is an endemic disease in cattle that are reared under extensive conditions and bred by natural mating. It causes profound economic losses to the producers by increasing calving interval, increasing embryo losses, and decreasing pregnancy rates. The aim of this study was to determine whether Tritrichomonas foetus infections were absent from cattle in St. Kitts. Using the modified hypergeometric method, preputial samples from bulls (n = 78) were tested using the InPouchTM culture for presence of T. foetus. Results highlighted an absence of trichomoniasis in bulls on St. Kitts with a 95% confidence. PMID- 29430609 TI - Genetic parameter estimation and implementation of the genetic evaluation for gaits in a breeding program for assisted-therapy in donkeys. AB - Genetic analyses in donkeys are likely to face compromises in terms of sample size and population structure. This study aims at implementing a suitable model to estimate breeding values and genetic parameters for gaits in Andalusian donkeys. Empirical observation revealed that ambling donkeys (showing a slightly uneven, non-isochronous 1-2, 3-4 lateral sequence gait) did not walk (i.e. presented an isochronous, even 1-2-3-4 sequence gait) and vice versa. However, the two donkey groups could trot, equally. In this study, 2700 gait records were registered from 300 donkeys. The sample included 1350 gait records from 169 ambling/trotting donkeys and 1350 gait records from 131 walking/trotting donkeys. Fixed effects included year, season, sex, farm/owner, husbandry system, weather, ground type and appraisers. Weight and age were included as covariates. MTDFREML software was used to estimate (co)variance components, genetic parameters and predict breeding values and their accuracies in both sets, separately. Gaits' heritability +/- SE estimates were 0.56 +/- 0.155, 0.53 +/- 0.317 and 0.67 +/- 0.166 for amble, walk and trot, respectively. Genetic correlations were 0.31 +/- 0.216, 0.42 +/- 0.115 and 0.28 +/- 0.178, for amble and walk, amble and trot and walk and trot, respectively. Not all gaits are suitable to treat every human sensomotor condition. We developed a locomotion selection index, assessing the relative loss/gain in index accuracy when each gait modality was excluded to develop different gait specific therapeutic lines to genetically select the best performing donkeys from each gait modality. Our results suggest that gait genetic lines could be developed and may be potential selection criteria to consider in assisted-therapy donkey breeding programs. PMID- 29430610 TI - Mentoring, Training, and Scholarly Productivity Experiences of Cancer-Related Health Disparities Research Trainees: Do Outcomes Differ for Underrepresented Scientists? AB - The study aims to explore variation in scholarly productivity outcomes by underrepresented status among a diverse sample of researchers in a community engaged training program. We identified 141 trainees from a web-based survey of researchers in the National Cancer Institute-funded, Community Networks Program Centers (CNPCs) (2011-2016). We conducted a series of multiple logistic regression models to estimate the effect of National Institutes of Health (NIH) defined underrepresented status on four, self-reported, scholarly productivity outcomes in the previous 5 years: number of publications (first-authored and total) and funded grants (NIH and any agency). Sixty-five percent (n = 92) indicated NIH underrepresented status. In final adjusted models, non-NIH underrepresented (vs. underrepresented) trainees reported an increased odds of having more than the median number of total publications (> 9) (OR = 3.14, 95% CI 1.21-8.65) and any grant funding (OR = 5.10, 95% CI 1.77-14.65). Reporting >= 1 mentors (vs. none) was also positively associated (p < 0.05) with these outcomes. The CNPC underrepresented trainees had similar success in first-authored publications and NIH funding as non-underrepresented trainees, but not total publications and grants. Examining trainees' mentoring experiences over time in relation to scholarly productivity outcomes is needed. PMID- 29430611 TI - Radiotherapy alters the composition, structural and mechanical properties of root dentin in vitro. AB - OBJECTIVES: Post-radiation dental lesions affect mainly the cervical area of the tooth. Until now, there are quite few evidences regarding the effects of radiation exposure on root dentin breakdown. To better understand this effect, we used human root dentin specimens obtained from third molars from similarly aged individuals. MATERIALS AND METHODS: Twenty specimens were analyzed by the surface hardness (SH), energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD) to evaluate the baseline properties of their root dentin. Other six human teeth were prepared and analyzed by scanning electron microscopy (SEM). Then the specimens were randomly distributed between two groups (n = 13 per group) and irradiated with a total dose of 55 or 70 Gy in a linear accelerator. The percentage of EDX and surface hardness loss (%SHL) were determined based on measurements before and after irradiation. The specimens were also analyzed after irradiation by SEM and XRD. The Ca/P weight ratio was calculated. RESULTS: Based on SEM analysis, radiation exposure induced dehydration of the dentin. The Ca/P weight ratio decreased (p = 0.0045). The %SHL of specimens irradiated with 70 Gy was higher than that of the 55-Gy group (p < 0.05), although even the lower dose induced root dentin breakdown. CONCLUSIONS: Overall, we can state that radiation exposure changes the composition and structure of human root dentin, which detrimentally affect its hardness. CLINICAL RELEVANCE: The changes reported herein might influence the selection of the dental materials and will bring new knowledge in this field to prevent radiation-related caries in root dentin. PMID- 29430612 TI - Comparison of two intraoral scanners based on three-dimensional surface analysis. AB - BACKGROUND: This in vivo study evaluated the difference of two well-known intraoral scanners used in dentistry, namely iTero (Align Technology) and TRIOS (3Shape). METHODS: Thirty-two participants underwent intraoral scans with TRIOS and iTero scanners, as well as conventional alginate impressions. The scans obtained with the two intraoral scanners were compared with each other and were also compared with the corresponding model scans by means of three-dimensional surface analysis. The average differences between the two intraoral scans on the surfaces were evaluated by color-mapping. The average differences in the three dimensional direction between each intraoral scans and its corresponding model scan were calculated at all points on the surfaces. RESULTS: The average differences between the two intraoral scanners were 0.057 mm at the maxilla and 0.069 mm at the mandible. Color histograms showed that local deviations between the two scanners occurred in the posterior area. As for difference in the three dimensional direction, there was no statistically significant difference between two scanners. CONCLUSIONS: Although there were some deviations in visible inspection, there was no statistical significance between the two intraoral scanners. PMID- 29430613 TI - Evaluation of dimensional behavior of peri-implant tissues in implants immediately exposed or submerged in fresh extraction and healed sites: a histological study in dogs. AB - BACKGROUND: The aim of this study was to compare histologically the dimensional behavior of peri-implant tissues during osseointegration of immediately exposed or submerged implant placement in fresh extraction and healed sites. METHODS: Four fresh extraction and four delayed implant sites were placed in each hemimandible of five dogs at the bone crest level. In 2 implants of each side were installed a healing abutment (exposed) and two cover screw (submerged) and formed four groups: implant installed in fresh extraction submerged (group 1), implants in fresh extraction immediately exposed (group 2), implants installed in healed site submerged (group 3), and implants in healed site immediately exposed (group 4). After 12 weeks of healing period, histomorphometric analyses of the specimens were carried out to measure the crestal bone level values and the tissue thickness in the implant shoulder portion. RESULTS: The measure of crestal bone level showed some higher values for implants installed in fresh extraction sites in the buccal aspect: 1.88 +/- 0.42 mm for group 1 and 2.33 +/- 0.33 mm for group 2, with statistical significance among all four groups tested (P < 0.001). For peri-implant tissue thickness, a significative higher statistical difference (P < 0.001) for implants installed in healed sites (groups 3 and 4) was found. CONCLUSIONS: Within the limitations of the present animal study, our findings suggest that the implants placed in fresh extraction or healed site and with regards to the moment of exposition (immediately or no) are important factors to the amount of peri-implant tissues after remodeling over a period of 12 weeks. The null hypothesis was rejected. PMID- 29430614 TI - Non-enhanced MRI in combination with color Doppler flow imaging for improving diagnostic accuracy of parotid gland lesions. AB - PURPOSE: To determine the value of non-enhanced MRI in combination with color Doppler flow imaging (CDFI) for differentiating malignant parotid tumors from benign ones. METHODS: This retrospective study analyzed 51 parotid gland lesions (39 benign and 12 malignant) in 51 patients who underwent preoperative CDFI as well as non-enhanced MRI including T1-weighted, T2-weighted, and diffusion weighted imaging (DWI). Degrees of intratumor vascularity were categorized into four grades basing on CDFI findings. The relationships between the lesion and its adjacent external carotid artery and retromandibular vein were inspected on T1 weighted and T2-weighted images. Apparent diffusion coefficient (ADC) values were calculated from diffusion-weighted images, and were used to classify the parotid gland lesions with and without reference to the CDFI findings. The classification results were compared using the McNemar test. Sensitivity, specificity, and accuracy percentages were calculated when the non-enhanced MRI/CDFI findings were used to differentiate benign lesions from malignant ones. RESULTS: The diagnostic accuracy (96.1 vs 82.4%) was significantly improved when ADCs were used together with CDFI findings for classifying parotid gland lesions compared to when ADCs were used alone. Pleomorphic adenomas had the highest ADCs. The ADC thresholds were 1.425 * 10-3 mm2/s for differentiating pleomorphic adenomas from carcinomas, 0.999 * 10-3 mm2/s for differentiating pleomorphic adenomas from other benign lesions, and 0.590 * 10-3 mm2/s for differentiating benign lesions other than pleomorphic adenomas from lymphomas. CONCLUSION: Combining CDFI with non-enhanced MRI can improve the diagnostic accuracy of MRI for classifying parotid gland lesions. PMID- 29430615 TI - Development of obesity can be prevented in rats by chronic icv infusions of AngII but less by Ang(1-7). AB - Considering that obesity is one of the leading risks for death worldwide, it should be noted that a brain-related mechanism is involved in AngII-induced and AT1-receptor-dependent weight loss. It is moreover established that activation of the Ang(1-7)/ACE2/Mas axis reduces weight, but it remains unclear whether this Ang(1-7) effect is also mediated via a brain-related mechanism. Additionally to Sprague Dawley (SD) rats, we used TGR(ASrAOGEN) selectively lacking brain angiotensinogen, the precursor to AngII, as we speculated that effects are more pronounced in a model with low brain RAS activity. Rats were fed with high calorie cafeteria diet. We investigated weight regulation, food behavior, and energy balance in response to chronic icv.-infusions of AngII (200 ng*h-1), or Ang(1-7) (200/600 ng*h-1) or artificial cerebrospinal fluid. High- but not low dose Ang(1-7) slightly decreased weight gain and energy intake in SD rats. AngII showed an anti-obese efficacy in SD rats by decreasing energy intake and increasing energy expenditure and also improved glucose control. TGR(ASrAOGEN) were protected from developing obesity. However, Ang(1-7) did not reveal any effects in TGR(ASrAOGEN) and those of AngII were minor compared to SD rats. Our results emphasize that brain AngII is a key contributor for regulating energy homeostasis and weight in obesity by serving as a negative brain-related feedback signal to alleviate weight gain. Brain-related anti-obese potency of Ang(1-7) is lower than AngII but must be further investigated by using other transgenic models as TGR(ASrAOGEN) proved to be less valuable for answering this question. PMID- 29430616 TI - Cognitive Control of Eating: the Role of Memory in Appetite and Weight Gain. AB - PURPOSE OF REVIEW: The present review organises the recent literature on the role of memory in eating behaviours and provides an overview of the current evidence relating to the associations between memory and weight gain. RECENT FINDINGS: Research over the last few years has highlighted working memory as an important cognitive process that underpins many aspects of appetite control. Recent work on episodic memory and appetite has replicated work showing that manipulating memory for recent eating affects later consumption and extended this work to examine associations between individual differences in memory and eating behaviours. Poorer episodic memory ability is related to a reduced sensitivity to internal states of hunger and satiety and a tendency towards uncontrolled eating. There is also recent evidence to suggest that working memory and episodic memory impairments are related to weight gain and high BMI. Working memory and episodic memory are core cognitive processes that are critical for food-related decision making, and disruption to these processes contributes to problems with appetite control and weight gain, which suggests that weight loss programmes might be improved by the addition of cognitive training. PMID- 29430618 TI - Design, Synthesis, and In Vitro Evaluation of a Novel Probucol Derivative: Protective Activity in Neuronal Cells Through GPx Upregulation. AB - Recent studies have shown that probucol (PB), a hipocholesterolemic agent with antioxidant and anti-inflammatory properties, presents neuroprotective properties. On the other hand, adverse effects have limited PB's clinical application. Thus, the search for PB derivatives with no or less adverse effects has been a topic of research. In this study, we present a novel organoselenium PB derivative (RC513) and investigate its potential protective activity in an in vitro experimental model of oxidative toxicity induced by tert-butyl hydroperoxide (tBuOOH) in HT22 neuronal cells, as well as exploit potential protective mechanisms. tBuOOH exposure caused a significant decrease in the cell viability, which was preceded by (i) increased reactive species generation and (ii) decreased mitochondrial maximum oxygen consumption rate. RC513 pretreatment (48 h) significantly prevented the tBuOOH-induced decrease of cell viability, RS generation, and mitochondrial dysfunction. Of note, RC513 significantly increased glutathione peroxidase (GPx) activity and mRNA expression of GPx1, a key enzyme involved in peroxide detoxification. The use of mercaptosuccinic acid, an inhibitor of GPx, significantly decreased the protective activity of RC513 against tBuOOH-induced cytotoxicity in HT22 cells, highlighting the importance of GPx upregulation in the observed protection. In summary, the results showed a significant protective activity of a novel PB derivative against tBuOOH-induced oxidative stress and mitochondrial dysfunction, which was related to the upregulation of GPx. Our results point to RC513 as a promising neuroprotective molecule, even though studies concerning potential beneficial effects and safety aspects of RC513 under in vivo conditions are well warranted. PMID- 29430617 TI - Estrogen Receptor beta Agonist Attenuates Endoplasmic Reticulum Stress-Induced Changes in Social Behavior and Brain Connectivity in Mice. AB - Impaired social interaction is a key feature of several major psychiatric disorders including depression, autism, and schizophrenia. While, anatomically, the prefrontal cortex (PFC) is known as a key regulator of social behavior, little is known about the cellular mechanisms that underlie impairments of social interaction. One etiological mechanism implicated in the pathophysiology of the aforementioned psychiatric disorders is cellular stress and consequent adaptive responses in the endoplasmic reticulum (ER) that can result from a variety of environmental and physical factors. The ER is an organelle that serves essential roles in protein modification, folding, and maturation of proteins; however, the specific role of ER stress in altered social behavior is unknown. In this study, treatment with tunicamycin, an ER stress inducer, enhanced the phosphorylation level of inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) and increased X box-binding protein 1 (XBP1) mRNA splicing activity in the mouse PFC, whereas inhibition of IRE1/XBP1 pathway in PFC by a viral particle approach attenuated social behavioral deficits caused by tunicamycin treatment. Reduced estrogen receptor beta (ERbeta) protein levels were found in the PFC of male mice following tunicamycin treatment. Pretreatment with an ERbeta specific agonist, ERB-041 significantly attenuated tunicamycin-induced deficits in social behavior, and activation of IRE1/XBP1 pathway in mouse PFC. Moreover, ERB-041 inhibited tunicamycin-induced increases in functional connectivity between PFC and hippocampus in male mice. Together, these results show that ERbeta agonist attenuates ER stress-induced deficits in social behavior through the IRE-1/XBP1 pathway. PMID- 29430619 TI - A Regulatory Circuitry Between Gria2, miR-409, and miR-495 Is Affected by ALS FUS Mutation in ESC-Derived Motor Neurons. AB - Mutations in fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS). FUS is a multifunctional protein involved in the biogenesis and activity of several types of RNAs, and its role in the pathogenesis of ALS may involve both direct effects of disease-associated mutations through gain- and loss-of-function mechanisms and indirect effects due to the cross talk between different classes of FUS-dependent RNAs. To explore how FUS mutations impinge on motor neuron specific RNA-based circuitries, we performed transcriptome profiling of small and long RNAs of motor neurons (MNs) derived from mouse embryonic stem cells carrying a FUS-P517L knock-in mutation, which is equivalent to human FUS-P525L, associated with a severe and juvenile-onset form of ALS. Combining ontological, predictive and molecular analyses, we found an inverse correlation between several classes of deregulated miRNAs and their corresponding mRNA targets in both homozygous and heterozygous P517L MNs. We validated a circuitry in which the upregulation of miR 409-3p and miR-495-3p, belonging to a brain-specific miRNA subcluster implicated in several neurodevelopmental disorders, produced the downregulation of Gria2, a subunit of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor with a significant role in excitatory neurotransmission. Moreover, we found that FUS was involved in mediating such miRNA repression. Gria2 alteration has been proposed to be implicated in MN degeneration, through disturbance of Ca2+ homeostasis, which triggers a cascade of damaging "excitotoxic" events. The molecular cross talk identified highlights a role for FUS in excitotoxicity and in miRNA-dependent regulation of Gria2. This circuitry also proved to be deregulated in heterozygosity, which matches the human condition perfectly. PMID- 29430621 TI - Ageing-related aorta remodelling and calcification occur earlier and progress more severely in rats with spontaneous hypertension. AB - : The effects of hypertension on vascular remodelling, ageing and calcification are not fully understood. In this study, we monitored the dynamic changes of aorta remodelling, senescence and calcification in spontaneously hypertensive rats (SHRs) during ageing. RESULTS: Vascular remodelling and senescence cells occurred in SHR aortas at 24 weeks. The calcium content and calcium deposition of the aorta increased in SHRs at 48 weeks. All of these changes became increasingly significant with ageing. In contrast, these pathologic changes appeared in Wistar Kyoto (WKY) normotensive rats at a much later stage (72 weeks). These data showed that the ageing-related aorta remodelling, senescence and calcification in SHRs occurred earlier and progressed more severely than in WKY rats. CONCLUSION: Ageing-related vascular remodelling and calcification were accelerated and augmented in SHR aortas. PMID- 29430620 TI - Herp Promotes Degradation of Mutant Huntingtin: Involvement of the Proteasome and Molecular Chaperones. AB - In neurodegenerative diseases, pathogenic proteins tend to misfold and form aggregates that are difficult to remove and able to induce excessive endoplasmic reticulum (ER) stress, leading to neuronal injury and apoptosis. Homocysteine induced endoplasmic reticulum protein (Herp), an E3 ubiquitin ligase, is an important early marker of ER stress and is involved in the ubiquitination and degradation of many neurodegenerative proteins. However, in Huntington's disease (HD), a typical polyglutamine disease, whether Herp is also involved in the metabolism and degradation of the pathogenic protein, mutant huntingtin, has not been reported. Therefore, we studied the relationship between Herp and N-terminal fragments of huntingtin (HttN-20Q and HttN-160Q). We found that Herp was able to bind to the overexpressed Htt N-terminal, and this interaction was enhanced by expansion of the polyQ fragment. Confocal microscopy demonstrated that Herp was co-localized with the HttN-160Q aggregates in the cytoplasm and tightly surrounded the aggregates. Overexpression of Herp significantly decreased the amount of soluble and insoluble HttN-160Q, promoted its ubiquitination, and inhibited its cytotoxicity. In contrast, knockdown of Herp resulted in more HttN 160Q protein, less ubiquitination, and stronger cytotoxicity. Inhibition of the autophagy-lysosomal pathway (ALP) had no effect on the function of Herp. However, blocking the ubiquitin-proteasome pathway (UPP) inhibited the reduction in soluble HttN-160Q caused by Herp. Interestingly, blocking the UPP did not weaken the ability of Herp to reduce HttN-160Q aggregates. Deletions of the N-terminal of Herp weakened its ability to inhibit HttN-160Q aggregation but did not result in a significant increase in its soluble form. However, loss of the C-terminal led to a significant increase in soluble HttN-160Q, but Herp still maintained the ability to inhibit aggregate formation. We further found that the expression level of Herp was significantly increased in HD animal and cell models. Our findings suggest that Herp is a newly identified huntingtin-interacting protein that is able to reduce the cytotoxicity of mutant huntingtin by inhibiting its aggregation and promoting its degradation. The N-terminal of Herp serves as the molecular chaperone to inhibit protein aggregation, while its C-terminal functions as an E3 ubiquitin ligase to promote the degradation of misfolded proteins through the UPP. Increased expression of Herp in HD models may be a pro survival mechanism under stress. PMID- 29430622 TI - Prehospital stroke scales and large vessel occlusion: A systematic review. AB - BACKGROUND AND PURPOSE: Time sensitivity for pharmacological and mechanical arterial recanalization in acute ischemic stroke influences the choice of the reference hospital. The accurate selection and identification of patients with high probability of a large vessel occlusion (LVO) in the prehospital setting improve the rationalization of the transport in the more suitable centers. Aim of this analysis was to determine the diagnostic accuracy of prehospital stroke scales detecting LVO. MATERIAL AND METHODS: Studies were searched into MEDLINE, EMBASE, and CINHAL databases between January 1990 and September 2017. Principal measurements of the meta-analysis were the overall accuracy level, sensitivity, and specificity of prehospital stroke scales. RESULTS: Nineteen scoring systems were included in the analysis coming from 13 studies. A total of 9824 patients were considered. Although a higher heterogeneity was observed in the analysis, three scores showed better results in predicting a LVO (the stroke Vision, Aphasia, Neglect assessment, the National Institute of Health Stroke scale and the Los Angeles Motor Scale). We observed significant differences of overall accuracy only for scores including hemineglect as cortical neurological sign (P < .05). CONCLUSIONS: This meta-analysis suggests that some prehospital scoring systems including cortical signs showed better accuracy to predict stroke due to LVO. However, the assessment of these signs could be difficult to investigate by paramedics and personnel of Emergency Medical Services, and for this reason, further prospective evaluations are needed. PMID- 29430623 TI - Perinatal outcome of monochorionic and dichorionic twins after spontaneous and assisted conception: a retrospective cohort study. AB - INTRODUCTION: The aim of this study was to compare pregnancy outcomes in twin pregnancies after assisted conception and spontaneous conception, according to chorionicity. MATERIAL AND METHODS: Retrospective cohort study of 1305 twin pregnancies between 1995 and 2015. All spontaneous (n = 731) and assisted conception conceived (n = 574) twin pregnancies with antenatal care and delivery in University Medical Center Utrecht, the Netherlands, a tertiary obstetric care center were studied according to chorionicity. RESULTS: Maternal age and incidence of nulliparity were higher among the assisted conception twins. Hypertensive disorders also appeared to be more frequent in assisted conception pregnancies, which could largely be explained by the higher proportion of elderly nulliparous women in this group. Spontaneously conceived twins were born earlier than twins after assisted conception, with subsequent lower birthweights and more admissions to a neonatal intensive care unit with increased neonatal morbidity. Monochorionic twins had worse pregnancy outcomes compared with dichorionic twins, irrespective of mode of conception; monochorionic twins conceived by assisted reproduction had more neonatal morbidity (mainly respiratory distress syndrome and necrotizing enterocolitis) and late neonatal deaths compared with spontaneously conceived monochorionic twins. CONCLUSIONS: Spontaneously conceived twins have worse pregnancy outcome compared with twins after assisted conception, probably due to a lower incidence of monochorionicity in the assisted conception group. The already increased perinatal risks in monochorionic twins are even higher in monochorionic twins conceived after infertility treatments compared with spontaneously conceived monochorionic twins, which warrants extra attention to these high-risk pregnancies. PMID- 29430625 TI - HELLP syndrome, risk factors in first and second pregnancy: a population-based cohort study. AB - INTRODUCTION: HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) may have specific risk factors and risk factors varying from first to second pregnancy. The aims of the study were to estimate the risk of HELLP syndrome by potential risk factors in first and second pregnancy, respectively. MATERIAL AND METHODS: A population-based cohort study including all women in Norway having their first baby (>=22 gestational weeks) during 1999 to 2014, registered in the Medical Birth Registry (n = 418 897). A subset of women with at least two births (n = 249 070) was used for estimates in second pregnancy. Relative risks with 95% CIs for HELLP syndrome were estimated using logistic regression and adjusted for maternal age and year of childbirth. RESULTS: Body mass index >=30 kg/m2 and diabetes were associated with HELLP syndrome in first, but not in second pregnancy. Chronic hypertension and multiple pregnancy were associated with HELLP syndrome both in first and second pregnancy. In second pregnancy the strongest risk factors were a history of HELLP syndrome or preterm preeclampsia in the first. The risk was inversely correlated with gestational age at first delivery. The overall relative risk for recurrence of HELLP syndrome was 54.4 (95% CI 34.3-86.2) and 129.5 (95% CI 45.7-367.2) after HELLP syndrome before 29 weeks of gestation in first pregnancy. CONCLUSIONS: Important risk factors for HELLP syndrome differ from first to second pregnancy. HELLP syndrome in second pregnancy is rare, but the relative risk is very high in women with HELLP syndrome or preterm preeclampsia in their first pregnancy. PMID- 29430624 TI - Phylogenetic and environmental effects on limb bone structure in gorillas. AB - OBJECTIVES: The effects of phylogeny and locomotor behavior on long bone structural proportions are assessed through comparisons between adult and ontogenetic samples of extant gorillas. MATERIALS AND METHODS: A total of 281 wild-collected individuals were included in the study, divided into four groups that vary taxonomically and ecologically: western lowland gorillas (G. g. gorilla), lowland and highland grauer gorillas (G. b. graueri), and Virunga mountain gorillas (G. b. beringei). Lengths and articular breadths of the major long bones (except the fibula) were measured, and diaphyseal cross-sectional geometric properties determined using computed tomography. Ages of immature specimens (n = 145) were known or estimated from dental development. Differences between groups in hind limb to forelimb proportions were assessed in both adults and during development. RESULTS: Diaphyseal strength proportions among adults vary in parallel with behavioral/ecological differences, and not phylogeny. The more arboreal western lowland and lowland grauer gorillas have relatively stronger forelimbs than the more terrestrial Virunga mountain gorillas, while the behaviorally intermediate highland grauer gorillas have intermediate proportions. Diaphyseal strength proportions are similar in young infants but diverge after 2 years of age in western lowland and mountain gorillas, at the same time that changes in locomotor behavior occur. There are no differences between groups in length or articular proportions among either adults or immature individuals. CONCLUSION: Long bone diaphyseal strength proportions in gorillas are developmentally plastic, reflecting behavior, while length and articular proportions are much more genetically canalized. These findings have implications for interpreting morphological variation among fossil taxa. PMID- 29430627 TI - A novel homozygous missense variant in NECTIN4 (PVRL4) causing ectodermal dysplasia cutaneous syndactyly syndrome. AB - Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare form of ectodermal dysplasia including anomalies of hair, nails, and teeth along with bilateral cutaneous syndactyly of hands and feet. In the present report, we performed a clinical and genetic characterization of a consanguineous Pakistani family with four individuals affected by EDSS1. We performed exome sequencing using DNA of one affected individual. Exome data analysis identified a novel homozygous missense variant (c.242T>C; p.(Leu81Pro)) in NECTIN4 (PVRL4). Sanger sequencing validated this variant and confirmed its cosegregation with the disease phenotype in the family members. Thus, our report adds a novel variant to the NECTIN4 mutation spectrum and contributes to the NECTIN4-related clinical characterization. PMID- 29430626 TI - Body size and body composition effects on heat loss from the hands during severe cold exposure. AB - OBJECTIVES: This study investigated the influence of body size and composition on maintaining hand temperature during severe cold exposure. The hand's high surface area-to-volume ratio predisposes the hand to heat loss, increasing the risk of cold injury and even hypothermia, which are major selective pressures in cold environments. While vasoregulation may reduce heat loss from the hand, the effect of body form, tissue thermogenesis, and body insulation on heat loss is unknown. MATERIALS AND METHODS: Thermal imaging was used to determine heat loss during a 3 min ice-water hand immersion test carried out on 114 volunteers (female = 63, male = 51). Established anthropometric measures were used to quantify body size, and bioelectrical impedance analysis determined skeletal muscle and fat mass. RESULTS: Skeletal muscle mass relative to body mass was a highly significant predictor of heat loss, while body mass, fat mass, and stature were not. Body composition and body size had little to no significant influence during rewarming after immersion. DISCUSSION: The thermogenic properties of muscle mass support maintenance of hand temperature during severe cold exposure. The findings here suggest that muscular individuals are less susceptible to heat loss and cold injury, and may be better at manual tasks in cold conditions than nonmuscular individuals. PMID- 29430628 TI - Association between GOLGB1 tag-polymorphisms and nonsyndromic cleft palate only in the Brazilian population. AB - Nonsyndromic oral clefts are common congenital birth defects that exhibit variable prevalence around the world, often influenced by population-dependent genetic predisposition. Few studies have been performed with nonsyndromic cleft palate only (NSCPO), limiting the knowledge of the genetic risk factors related to this type of oral cleft. Genetic variants in golgin subfamily B member 1 (GOLGB1), a gene that is essential for normal murine palatogenesis, were analyzed in this study to establish its potential association with NSCPO risk in the Brazilian population. Five tag-single nucleotide polymorphisms (SNPs) of GOLGB1 (rs1169, rs7153, rs9968051, rs9819530, and rs6794341), which capture the majority of alleles spanning within gene, were genotyped in a case-control study with 270 patients with NSCPO and 284 unrelated healthy controls. The samples were also genotyped for 40 biallelic polymorphic markers to characterize the genetic ancestry. After adjustment for co-variants, the GOLGB1 tag-SNPs and the haplotypes formed by those SNPs were not significantly associated with NSCPO in this Brazilian case-control cohort. Our results suggest that common polymorphisms of GOLGB1 are not associated NSCPO susceptibility in the Brazilian population. PMID- 29430629 TI - Recent advances and development in epidermal and dermal drug deposition enhancement technology. AB - Skin is the largest and easily accessible organ of the body. Increases in incidences of dermatological disorders, demand for drug targeting, and patient compliance have increased the popularity of topical drug delivery amongst the people. However, drug delivery across the skin is still a challenge for researchers because permeation of maximum drugs is hindered by the upper layer of the epidermis (stratum corneum). Several approaches like use of chemical permeation enhancers and physical methods such as sonophoresis, iontophoresis, electroporation, microneedles, etc., have been used to deliver the drugs topically. These methods of topical drug delivery have some limitations and drawbacks. Therefore new techniques based on nano drug delivery system such as ultradeformable liposomes, nanostructured lipid carriers, nanoemulsions, solid lipid nanoparticles, lipospheres, nanoparticles, and ethosomes have been exploited for enhancing epidermal and dermal drug deposition. Development of these nanosytems requires a good understanding of mechanism of drug permeation, physicochemical properties of drug and carriers, and technological advancements in methodology. Therefore, this article covers recent advances in epidermal and dermal drug deposition enhancement approaches, biopharmaceutical challenges with dermal drug delivery, issues in formulation development, and regulatory aspects of nanosystem. This review article also discusses the concern of topical drug delivery in immunization, gene delivery, and cosmeceuticals. PMID- 29430630 TI - Does needle biopsy cause an increased risk of extracapsular extension in the diagnosis of metastatic lymph node in melanoma? AB - BACKGROUND: Needle biopsy is a rapid, reliable, and reproducible procedure for histological confirmation of metastatic melanoma localization. Nonetheless, this procedure presents a theoretical risk of a mechanical weakening of the lymph node capsule with perinodal tumor seeding. The objective of the study was to evaluate the incidence of extracapsular extension after needle biopsy in comparison with surgical adenectomy in patients suspected of metastatic lymph node of melanoma. METHODS: We conducted a retrospective study of 1056 patients who underwent lymphadenectomy for melanoma between 2000 and 2016 in our unit. Sixty-nine patients were clinically and/or radiologically suspected of metastatic lymph node of melanoma. Patients were divided according to external lymph node biopsy or surgical adenectomy before lymphadenectomy. The primary endpoint was the histopathological identification of extracapsular extension in analyzed lymph nodes. RESULTS: The two populations were comparable except for the mitotic index, which was more frequently > 1/mm2 in the group with surgical adenectomy (P = 0.005). The proportion of extracapsular extension was significantly greater in the needle biopsy group (28/37) than in patients who underwent surgical adenectomy (14/32) (P = 0.0067; OR = 4 [95% CI: 1.4-11]). CONCLUSION: Our results suggest an increased risk of extracapsular extension after external lymph node biopsy in cases of suspicion of metastatic lymph node of melanoma. Thus, this encourages us to prefer surgical adenectomy in patients with suspected adenopathy accessible surgically. In other cases, needle biopsy should be carried out under radiological guidance using devices limiting tumor seeding. PMID- 29430631 TI - Colchicine in dermatology: A review. AB - Colchicine is an anti-inflammatory agent that has been used for decades for the treatment of various diseases including gout, familial Mediterranean fever and pericarditis and in recent years for dermatological indications including chronic urticaria, cutaneous vasculitis and psoriasis. Despite its efficacy in various cutaneous diseases, the use of colchicine may be limited by concerns over its side-effects and the potential for toxicity. This article reviews the current literature on the pharmacology of colchicine and its clinical applications in dermatology. PMID- 29430632 TI - Cancer gene-panel testing identifies two loss-of-function alleles in PALB2 and PTEN. AB - Synchronous loss-of-function mutations in the cancer predisposing genes, PTEN and PALB2 identified by multigene panel. PMID- 29430633 TI - Phacomatosis pigmentokeratotica: a case of HRAS mosaicism causing rhabdomyosarcoma. AB - A 17-year-old male presented with a large sebaceous naevus (SN) comprising part of his right face and scalp and a speckled lentiginous naevus (SLN) on his left trunk, hip, neck and scalp with a checkerboard pattern. His right oral hemimucosa showed extensive papillomatous lesions, which were contiguous with the upper-lip SN lesions. He also showed extracutaneous manifestations including cardiac, musculoskeletal and ocular alterations. Internally, he had developed two primary rhabdomyosarcomas. DNA samples of the SN, SLN, oral papillomatous hyperplasia and both rhabdomyosarcomas were analysed by Sanger sequencing. An HRAS c.37G>C mutation was detected in all of them. Skin and blood DNA were wild-type. Phacomatosis pigmentokeratotica (PPK) is characterized by the association of an SN with a papular naevus spilus and extracutaneous manifestations. Until recently, the aetiopathogenetic hypothesis of didymosis was accepted. However, in 2013 Groesser et al. proved the existence of an activating HRAS mutation as the cause of this syndrome. A higher incidence of cancer has been observed in germline RASopathies. Furthermore, up to 30% of human cancers show dysregulation of the Ras-Raf-MEK-ERK pathways. In our patient, an HRAS mosaic mutation explains not only the cutaneous but also the extracutaneous manifestations. To our knowledge this is the first described case of PPK in which the existence of an HRAS mosaic mutation is the confirmed cause of rhabdomyosarcoma. Furthermore, the HRAS c.37G>C mutation has never been related to any type of rhabdomyosarcoma. Mosaicisms could be underdiagnosed causes of childhood tumours. As dermatologists we stand in a privileged position of being able to detect these alterations. PMID- 29430634 TI - Trajectories of income and social benefits for mothers and fathers of children with cancer: A national cohort study in Sweden. AB - BACKGROUND: The contribution of different income sources from work and social benefits to trajectories of income for the parents of children with cancer has not been empirically investigated. METHODS: Using Swedish registers, parents of children with an incidence cancer diagnosis between 2004 and 2009 were identified and matched with parents of children without cancer (reference parents). A total of 20,091 families were followed from the year before the diagnosis to a maximum of 8 years. Generalized linear models estimated the ratios of mean incomes from work and social benefits and of its total. RESULTS: Around the time of the child's cancer diagnosis, the total income was on average up to 6% higher among the mothers of children with cancer compared with reference mothers, but no differences were noted among fathers. Income from work dropped to the lowest level around the time of a cancer diagnosis, with swift recovery noted for fathers but not for mothers. Sickness and childcare-related benefits were up to 6 times larger for the parents of children with cancer than reference parents. As social benefits diminished after approximately 3 years, the total income of mothers of children with cancer became lower than that of reference mothers, and the gap widened over time. CONCLUSIONS: Social benefits appeared to ease the financial burden during the years around a cancer diagnosis. However, mothers experienced persistently lower income after benefits diminished. Experiences differed by single-parent versus dual-parent households, the survival of the child with cancer, and other relevant characteristics. Further investigation is needed for potential long-term consequences for mothers, including their career and future pension in retirement. Cancer 2018;124:1492-500. (c) 2018 American Cancer Society. PMID- 29430635 TI - HPV-testing versus HPV-cytology co-testing to predict the outcome after conization. AB - INTRODUCTION: The purpose of this study was to determine the feasibility of human Papillomavirus (HPV) testing alone as a prognostic tool to predict recurrent disease within a three-year follow-up period after treatment for cervical intraepithelial neoplasia (CIN)2+ . MATERIAL AND METHODS: Retrospectively, 128 women with histologically verified CIN2+ who had a conization performed at Southern Jutland Hospital in Denmark between 1 January 2013 and 31 December 2013 were included. Histology, cytology and HPV test results were obtained for a three year follow-up period. RESULTS: 4.7% (6/128) of the cases developed recurrent disease during follow-up. Of the cases without free margins, recurrent dysplasia was detected normal in 10.4% (5/48), whereas in the group with free margins it was 1.3% (1/80). The post-conization HPV test was negative in 67.2% (86/128) and Pap smear normal in 93.7% (120/128). Combining resection margins, cytology and HPV had sensitivity for prediction of recurrent dysplasia of 100%. Specificity was 45.8%, positive predictive value (PPV) 8.5% and negative predictive value (NPV) 100%. Using HPV test alone as a predictor of recurrent dysplasia gave a sensitivity of 83.3%, specificity 69.7%, PPV 11.9% and NPV 98.8%. Combining resection margin and HPV test had a sensitivity of 100%, specificity 45.9%, PPV 8.3% and NPV 100%. CONCLUSION: HPV test at six months control post-conization gave an NPV of 98.8% and can be used as a solitary test to identify women at risk for recurrent disease three years after treatment for precursor lesions. Using both resection margin and HPV test had a sensitivity of 100% and NPV 100%. Adding cytology did not increase the predictive value. PMID- 29430636 TI - Sex differences in life span: Females homozygous for the X chromosome do not suffer the shorter life span predicted by the unguarded X hypothesis. AB - Life span differs between the sexes in many species. Three hypotheses to explain this interesting pattern have been proposed, involving different drivers: sexual selection, asymmetrical inheritance of cytoplasmic genomes, and hemizygosity of the X(Z) chromosome (the unguarded X hypothesis). Of these, the unguarded X has received the least experimental attention. This hypothesis suggests that the heterogametic sex suffers a shortened life span because recessive deleterious alleles on its single X(Z) chromosome are expressed unconditionally. In Drosophila melanogaster, the X chromosome is unusually large (~20% of the genome), providing a powerful model for evaluating theories involving the X. Here, we test the unguarded X hypothesis by forcing D. melanogaster females from a laboratory population to express recessive X-linked alleles to the same degree as males, using females exclusively made homozygous for the X chromosome. We find no evidence for reduced life span or egg-to-adult viability due to X homozygozity. In contrast, males and females homozygous for an autosome both suffer similar, significant reductions in those traits. The logic of the unguarded X hypothesis is indisputable, but our results suggest that the degree to which recessive deleterious X-linked alleles depress performance in the heterogametic sex appears too small to explain general sex differences in life span. PMID- 29430637 TI - SAVing Cognitive Function: What Can We Learn About Risk of Cognitive Impairment from Studies of Small Area Variation? PMID- 29430638 TI - Effect of Area-Level Socioeconomic Deprivation on Risk of Cognitive Dysfunction in Older Adults. AB - OBJECTIVES: To investigate the relationship between area-level deprivation and risk of cognitive dysfunction. DESIGN: Cross-sectional analysis. SETTING: The Trinity, Ulster, and Department of Agriculture (TUDA) study from 2008 to 2012. PARTICIPANTS: Community-dwelling adults aged 74.0 +/- 8.3 without dementia (N = 5,186; 67% female). MEASUREMENTS: Adopting a cross-jurisdictional approach, geo referenced address-based information was used to map and link participants to official socioeconomic indicators of deprivation within the United Kingdom and the Republic of Ireland. Participants were assigned an individual deprivation score related to the smallest administrative area in which they lived. These scores were categorized into comparable quintiles, that were then used to integrate the datasets from both countries. Cognitive health was assessed using the Mini-Mental State Examination (MMSE); cognitive dysfunction was defined as a MMSE score of 24 or less. RESULTS: Approximately one-quarter of the cohort resided within the most-deprived districts in both countries. Greater area-level deprivation was associated with significantly lower MMSE scores; fewer years of formal education; greater anxiety, depression, smoking and alcohol use, and obesity; and more adverse outcomes, including higher blood pressure and diabetes risk. After adjustment for relevant covariates, area deprivation was associated with significantly higher risk of cognitive dysfunction (odds ratio = 1.40, 95% confidence interval = 1.05-1.87, P = .02, for most vs least deprived). CONCLUSION: This analysis combining data from two health systems shows that area deprivation is an independent risk factor for cognitive dysfunction in older adults. Adults living in areas of greatest socioeconomic deprivation may benefit from targeted strategies aimed at improving modifiable risk factors for dementia. Further cross-national analysis investigating the impact of area- level deprivation is needed to address socioeconomic disparities and shape future policy to improve health outcomes in older adults.(c) 2018 American Geriatrics Society and Wiley Periodicals, Inc. PMID- 29430639 TI - Benzodiazepine Use in Older Adults in the United States, Ontario, and Australia from 2010 to 2016. AB - OBJECTIVES: To detail annual trends in benzodiazepine incidence and prevalence in older adults between 2010 and 2016 in three countries. DESIGN: Observational multicountry cohort study with harmonized study protocol. SETTING: The United States (veteran population); Ontario, Canada; and Australia. PARTICIPANTS: All people aged 65 and older (8,270,000 people). MEASUREMENTS: Annual incidence and prevalence of benzodiazepine use stratified according to age group (65-74, 75-84, >=85) and sex. We performed multiple regression analyses to assess whether rates of incident and prevalent use changed significantly over time. RESULTS: Over the study period, we observed a significant decrease in incident benzodiazepine use in the United States (2.6% to 1.7%) and Ontario (6.0% to 4.4%) but not Australia (7.0% to 6.7%). We found significant declines in prevalent use in all countries (United States: 9.2% to 7.3%; Ontario: 18.2% to 13.4%; Australia: 20.2% to 16.8%). Although incidence and prevalence increased with age in Ontario and Australia, they decreased with age in the United States. Incidence and prevalence were higher in women in all countries. CONCLUSION: Consistent with other international studies, there have been small but significant reductions in the incidence and prevalence of benzodiazepine use in older adults in all three countries, with the exception of incidence in Australia, although use remains inappropriately high-particularly in those aged 85 and older-which warrants further attention from clinicians and policy-makers. PMID- 29430640 TI - Comparison of self-reported and directly measured weight and height among women of reproductive age: a systematic review and meta-analysis. AB - INTRODUCTION: The use of self-report as a strategy for collecting data on women's weight and height is widespread in both clinical practice and epidemiological studies. This study aimed to compare self-reported and directly measured weight and height among women of reproductive age. MATERIAL AND METHODS: In July 2015 we searched MEDLINE, EMBASE, COCHRANE, CINHAL, LILACS and gray literature. We included women of reproductive age (12-49 years old) independently of their weight or height at the time of the study. Women with any condition that implies regular tracking of their weight (for example, eating disorder) were excluded. Two reviewers independently selected, extracted and assessed the risk of bias of the studies. We used REVMAN 5.3 to perform the meta-analysis. Heterogeneity was assessed using the I2 statistic. RESULTS: Following eligibility assessment, 21 studies of 18 749 women met the inclusion criteria. The results of the meta analysis showed an underestimation of weight by -0.94 kg (95% CI -1.17 to -0.71 kg; p < 0.0001; I2 = 0%) in the overall sample and an overestimation of height by 0.36 cm (95% CI 0.20-0.51; p < 0.0001; I2 = 35%) based on self-reported vs. directly measured values. CONCLUSION: This review shows that self-reported weight and height of women of reproductive age differs slightly from direct measures. We consider that the magnitude at which self-reported data over- or underestimates the real value, is negligible regarding clinical and research use. PMID- 29430641 TI - Comparative effect of antipsychotics on risk of self-harm among patients with schizophrenia. AB - OBJECTIVE: To investigate the association of different antipsychotic treatments with hospitalization due to self-harm among patients with schizophrenia. METHOD: This retrospective cohort study was based on Taiwan's universal health insurance database. Patients aged 15-45 years with a newly diagnosed schizophrenic disorder in 2001-2012 were included. The study outcome was the first hospitalization due to self-harm or undetermined injury after the diagnosis of schizophrenic disorders. The exposure status of antipsychotics was modeled as a time-dependent variable. The analyses were stratified by antipsychotic dosage based on defined daily dose (DDD). RESULTS: Among 70 380 patients with a follow-up of 500 355 person-years, 2272 self-harm hospitalization episodes were identified. Compared with none or former use, current use of several second-generation antipsychotics with a dose of one DDD or above, including amisulpride, aripiprazole, clozapine, risperidone, and sulpiride, was associated with decreased risk of self-harm hospitalization, with clozapine showing the strongest effect (adjusted rate ratio = 0.26, 95% confidence interval 0.15-0.47). CONCLUSION: The protective effect on self-harm may vary across different antipsychotics. Further studies are needed to replicate the findings. PMID- 29430643 TI - Erratum. PMID- 29430644 TI - Factors associated with nurses' perceptions about quality of end-of-life care. AB - AIM: To examine the factors associated with nurses' perceptions of the quality of end-of-life care. BACKGROUND: With increasing demand for hospitals to provide end of-life care, the low quality of palliative care provided in hospital settings is an issue of growing concern in developing countries. Most dying patients receive their care from general nurses, irrespective of the nurses' specialty or level of training. METHOD: A structured cross-sectional questionnaire survey was conducted of 553 nurses working at a teaching hospital in Malaysia. RESULTS: The mean scores for nurses' knowledge about end-of-life care, their attitudes towards end of-life care and the perceived quality of end-of-life care were low. The factors identified as significantly associated with the quality of end-of-life care were nurses' levels of knowledge and their attitudes towards end-of-life care. DISCUSSION: Factors that contributed to the low quality of end-of-life care were inadequate knowledge and negative attitudes. These findings may reflect that end of-life care education is not well integrated into nursing education. CONCLUSION: The findings of this study suggest that there is a need to increase the nurses' level of knowledge and improve their attitude towards end-of-life care in order to enhance the quality of care provided to dying patients. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Nurse managers and hospital policymakers should develop strategies to enhance nurses' level of knowledge, as well as providing adequate emotional support for nurses who care for dying patients and their families. Nurses should be proactive in increasing their knowledge and adopting more positive attitudes towards end-of-life care. PMID- 29430642 TI - Should Structured Exercise Be Promoted As a Model of Care? Dissemination of the Department of Veterans Affairs Gerofit Program. AB - Exercise provides a wide range of health-promoting benefits, but support is limited for clinical programs that use exercise as a means of health promotion. This stands in contrast to restorative or rehabilitative exercise, which is considered an essential medical service. We propose that there is a place for ongoing, structured wellness and health promotion programs, with exercise as the primary therapeutic focus. Such programs have long-lasting health benefits, are easily implementable, and are associated with high levels of participant satisfaction. We describe the dissemination and implementation of a long-standing exercise and health promotion program, Gerofit, for which significant gains in physical function that have been maintained over 5 years of follow-up, improvements in well-being, and a 10-year 25% survival benefit among program adherents have been documented. The program has been replicated at 6 Veterans Affairs Medical Centers. The pooled characteristics of enrolled participants (n = 691) demonstrate substantial baseline functional impairment (usual gait speed 1.05 +/- 0.3 m/s, 8-foot up and go 8.7 +/- 6.7 seconds, 30-second chair stands 10.7 +/- 5.1, 6-minute walk distance 404.31 +/- 141.9 m), highlighting the need for such programs. Change scores over baseline for 3, 6, and 12 months of follow up are clinically and statistically significant (P < .05 all measures) and replicate findings from the parent program. Patient satisfaction ratings of high ranged from 88% to 94%. We describe the implementation process and present 1-year outcomes. We suggest that such programs be considered essential elements of healthcare systems. PMID- 29430645 TI - Berries grown in Brazil: anthocyanin profiles and biological properties. AB - BACKGROUND: Phytochemical profiles of two Brazilian native fruits - pitanga (red and purple) and araca (yellow and red) - as well as strawberry cultivars Albion, Aromas and Camarosa, blackberry cultivar Tupy and blueberry cultivar Bluegen cultivated in Brazil were characterized for total phenolic content and total anthocyanin content by liquid chromatography coupled to a photodiode array and a quadrupole time-of-flight mass spectrometer. Radical scavenging, antiherpes and cytotoxic activities of these berry extracts were also evaluated. RESULTS: Blueberry presented the highest total anthocyanin content (1202 mg cyanidin-O glucoside equivalents kg-1 fresh fruit), while strawberry cultivar Aromas presented the highest total phenolic content (13 550 mg gallic acid equivalents kg-1 fresh fruit). Liquid chromatographic-mass spectrometric analysis resulted in the identification of 21 anthocyanins. To the best of our knowledge this is the first report of cyanidin-O-glucoside in yellow and red Araca fruit and the first time eight anthocyanins have been reported in pitanga fruits. DPPH and ABTS assays showed that blueberry cultivar Bluegen, blackberry cultivar Tupy and pitanga (red and purple) showed the most promising antiradical activities, respectively. No relevant cytotoxicity against three cancer cell lines or antiherpes activity was detected under the experimental conditions tested. CONCLUSION: Total anthocyanin content of all fruits had a strong positive correlation with their free radical scavenging activity, suggesting anthocyanins contribute to the antioxidant potential of these fruits. (c) 2018 Society of Chemical Industry. PMID- 29430646 TI - Internationally educated nurses in Canada: perceived benefits of bridging programme participation. AB - AIM: To examine internationally educated nurses' perceptions of the extent to which participating in bridging programmes is beneficial for preparing to practise nursing in Canada. BACKGROUND: Internationally educated nurses continue to migrate from low-income to high-income countries. Many experience challenges when attempting to practise their profession in the destination country. Canada and other top destination countries offer educational support, such as bridging programmes, to assist internationally educated nurses' with preparing to practise nursing in the destination country. The research evidence falls short in demonstrating the usefulness of bridging programmes. METHODS: A subsample of 360 internationally educated nurse participants from a Canadian cross-sectional survey conducted in 2014. All were permanent residents, employed as regulated nurses and participants of bridging programmes. Multiple linear regression was employed to examine the influence of internationally educated nurses' human capital (academic preparation, language proficiency, professional experience) and the economic status of their source country on perceived benefits of bridging programme participation. RESULTS: Regression model explained 11.5% of variance in perceived benefits of bridging programme participation. Two predictors were statistically significant: source country and professional experience. CONCLUSION: Bridging programmes help internationally educated nurses address gaps in their cultural, practical and theoretical knowledge. Source country and amount of professionally experience influences the extent to which internationally educated nurses benefit from participating in bridging programmes in Canada. IMPLICATIONS FOR NURSING POLICY: Provides emerging evidence for decision-makers globally when developing policies and supports to help internationally educated nurses integrate into the destination country's nursing workforce. PMID- 29430648 TI - Effect of castration and carcass suspension method on the quality and fatty acid profile of beef from male dairy cattle. AB - BACKGROUND: The use of bulls rather than steers for beef production offers some considerable advantages; however, the eating quality of bull beef is an issue of marketing concern. This study assessed the physicochemical characteristics of young Holstein-Friesian (HF) bull and steer beef. Steer carcasses were suspended by the Achilles tendon (AS) and by pelvic suspension (PS). RESULTS: HF steer beef had higher redness, yellowness and chroma values, whereas bulls had higher ultimate pH and darker muscle. Warner-Bratzler shear force, cook loss at different ageing times, moisture, and insoluble and total collagen were higher for HF bull beef, whereas intramuscular fat, soluble collagen and collagen solubility were higher for steer beef. HF steer beef had a higher proportion of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA), whereas bull beef had higher proportions of polyunsaturated fatty acids (PUFA), PUFA/SFA and n 6/n-3 PUFA ratios. In comparison to AS, PS increased redness and chroma after 24 h blooming; PS improved tenderness up to 7 days of ageing and accelerated the ageing process. CONCLUSION: For young dairy cattle, steer beef would likely have superior eating quality but a relatively less favourable nutritional fatty acid profile to bull beef. Suspension method affected the tenderness and colour intensity of dairy steer beef at different ageing times. (c) 2018 Society of Chemical Industry. PMID- 29430647 TI - The cells and conductance mediating cholinergic neurotransmission in the murine proximal stomach. AB - KEY POINTS: Enteric neurotransmission is essential for gastrointestinal (GI) motility, although the cells and conductances responsible for post-junctional responses are controversial. The calcium-activated chloride conductance (CaCC), anoctamin-1 (Ano1), was expressed by intramuscular interstitial cells of Cajal (ICC-IM) in proximal stomach and not resolved in smooth muscle cells (SMCs). Cholinergic nerve fibres were closely apposed to ICC-IM. Conductances activated by cholinergic stimulation in isolated ICC-IM and SMCs were determined. A CaCC was activated by carbachol in ICC-IM and a non-selective cation conductance in SMCs. Responses to cholinergic nerve stimulation were studied. Excitatory junction potentials (EJPs) and mechanical responses were evoked in wild-type mice but absent or greatly reduced with knockout/down of Ano1. Drugs that block Ano1 inhibited the conductance activated by carbachol in ICC-IM and EJPs and mechanical responses in tissues. The data of the present study suggest that electrical and mechanical responses to cholinergic nerve stimulation are mediated by Ano1 expressed in ICC-IM and not SMCs. ABSTRACT: Enteric motor neurotransmission is essential for normal gastrointestinal (GI) motility. Controversy exists regarding the cells and ionic conductance(s) that mediate post junctional neuroeffector responses to motor neurotransmitters. Isolated intramuscular ICC (ICC-IM) and smooth muscle cells (SMCs) from murine fundus muscles were used to determine the conductances activated by carbachol (CCh) in each cell type. The calcium-activated chloride conductance (CaCC), anoctamin-1 (Ano1) is expressed by ICC-IM but not resolved in SMCs, and CCh activated a Cl- conductance in ICC-IM and a non-selective cation conductance in SMCs. We also studied responses to nerve stimulation using electrical-field stimulation (EFS) of intact fundus muscles from wild-type and Ano1 knockout mice. EFS activated excitatory junction potentials (EJPs) in wild-type mice, although EJPs were absent in mice with congenital deactivation of Ano1 and greatly reduced in animals in which the CaCC-Ano1 was knocked down using Cre/loxP technology. Contractions to cholinergic nerve stimulation were also greatly reduced in Ano1 knockouts. SMCs cells also have receptors and ion channels activated by muscarinic agonists. Blocking acetylcholine esterase with neostigmine revealed a slow depolarization that developed after EJPs in wild-type mice. This depolarization was still apparent in mice with genetic deactivation of Ano1. Pharmacological blockers of Ano1 also inhibited EJPs and contractile responses to muscarinic stimulation in fundus muscles. The data of the present study are consistent with the hypothesis that ACh released from motor nerves binds muscarinic receptors on ICC-IM with preference and activates Ano1. If metabolism of acetylcholine is inhibited, ACh overflows and binds to extrajunctional receptors on SMCs, eliciting a slower depolarization response. PMID- 29430650 TI - Competition-driven niche segregation on a landscape scale: Evidence for escaping from syntopy towards allotopy in two coexisting sibling passerine species. AB - The role of interspecific competition for generating patterns in species' distribution is hotly debated and studies taking into account processes occurring at both large and small spatial scales are almost missing. Theoretically, competition between species with overlapping niches should result in divergence of their niches in sympatry to reduce the costs of competition. Many species show a mosaic distribution within sympatric zones, with the syntopic sites occupied by both species, and allotopic sites where only one species occurs. It is unclear whether such mosaics arise as a consequence of competition-driven niche segregation or due to the decline of their abundances towards range edges driven by environmental gradients. If the interspecific competition matters, we should observe (1) a shift in habitat preferences of one or both species between syntopy and allotopy, and (2) between allopatry and allotopy. Moreover, (3) species should show greater divergence in their habitat preferences in allotopy than in allopatry where (4) no differences in habitat preferences may occur. Finally, (5) shifts should be generally greater in the competitively subordinate species than in the dominant species. We used a unique dataset on abundance of two closely related passerine species, the Common Nightingale (Luscinia megarhynchos) and the Thrush Nightingale (Luscinia luscinia), collected across their syntopy, allotopy and allopatry. The predictions were tested within a generalized mixed-effects modelling framework. After accounting for environmental gradients perpendicular to the species' contact zone, we found a strong support for all but one prediction. Habitat preferences of both species shifted markedly between syntopy and allotopy, as well as between allopatry and allotopy. Whereas the species preferred the same habitats in allopatry, their preferences became strikingly different in allotopy where the abundance of the Common Nightingale increased towards dry and warm sites with low coverage of pastures, while the abundance of the Thrush Nightingale showed exactly opposite trends. Fifth prediction was not supported. Our results indicate that the competition between closely related species can result in considerable changes in habitat use across their geographic ranges accompanied with divergence in their habitat preferences in sympatry. Here, the species "escape" from competition to allotopic sites covered by habitats avoided by the competitor. Therefore, we argue that the interspecific competition is an important driver of species' distribution at both large and small spatial scales. PMID- 29430649 TI - The Anatomical Society's core anatomy syllabus for undergraduate nursing. AB - The Anatomical Society has developed a series of learning outcomes in consultation with nursing educators delivering anatomical content to undergraduate (preregistration) nursing students. A Delphi panel methodology was adopted to select experts within the field that would recommend core anatomical content in undergraduate nursing programmes throughout the UK. Using the Anatomical Society's Core Gross Anatomy Syllabus for Medical Students as a foundation, a modified Delphi technique was used to develop discipline-specific outcomes to nursing graduates. The Delphi panel consisted of 48 individuals (n = 48) with a minimum of 3 years' experience teaching anatomy to nursing students, representing a broad spectrum of UK Higher Education Institutions. The output from this study was 64 nursing specific learning outcomes in anatomy that are applicable to all undergraduate (preregistration) programmes in the UK. The new core anatomy syllabus for Undergraduate Nursing offers a basic anatomical framework upon which nurse educators, clinical mentors and nursing students can underpin their clinical practice and knowledge. The learning outcomes presented may be used to develop anatomy teaching within an integrated nursing curriculum. PMID- 29430651 TI - Foraging responses of sheep to plant spatial micro-patterns can cause diverse associational effects of focal plant at individual and population levels. AB - Multiple-scale foraging decisions by large herbivores can cause associational effects of focal plant individuals neighboured with different species. Spatial micro-patterns between the focal plant and its neighbouring species within patches can affect herbivore foraging selectivity at within- and between-patch scales, which may consequently lead to associational plant effects occurring at both plant individual and population levels. However, these associational effects have not been explored together in the plant-herbivore interaction studies. We aim to evaluate how plant spatial micro-pattern within different quality patches mediate herbivore foraging selectivity, thereby affecting the associational effects of focal plant individuals and population. Using sheep as the model herbivore and a medium preferred species as the focal plant, we conducted a manipulative experiment by allowing sheep grazing freely among three different quality patches, each of which consisted of preferred, unpreferred and focal plant species with different abundances forming spatially aggregated or dispersed micro-patterns. Results showed that, compared with the aggregated plant micro pattern, dispersed plant micro-patterns within different quality patches increased sheep within-patch selectivity, and caused diverse associational effects of focal plant individuals. Focal plant individuals experienced neighbour contrast defence (i.e. got protection in the high quality patch) and associational defence (i.e. got protection in the low quality patch), respectively, when plants distributed dispersedly in the low and high quality patch. Focal plant individuals simultaneously experienced associational susceptibility (i.e. got damage in the high quality patch) and neighbour contrast susceptibility (i.e. got damage in the low quality patch) when plants distributed dispersedly in the medium quality patch. Furthermore, dispersed plant micro patterns reduced sheep foraging selectivity between patches, and led to a lower consumption of focal plant population compared with the aggregated plant micro pattern. Herbivores adopt different within- and between-patch foraging decisions to maintain a high intake of the preferred species in response to various plant micro-patterns, and consequently cause diverse associational effects of both focal plant individuals and population. These associational effects have important implications for understanding the species coexistence and plant community assembly in the grazing ecosystems. PMID- 29430652 TI - The many faces of vascular cognitive impairment. AB - This Preface introduces the articles of the special issue on "Vascular Dementia" in which several recognized experts provide an overview of this research field. The brain is a highly vascularized organ and consequently, vascular dysfunction and related pathways affect cognitive performance and memory. Vascular dementia or vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease, and both disorders often occur in parallel. With this special issue, we hope to provide insight and a stimulating discussion for the future development of this research field. This article is part of the Special Issue "Vascular Dementia". PMID- 29430654 TI - Enhanced efficacy of AZD3759 and radiation on brain metastasis from EGFR mutant non-small cell lung cancer. AB - The prognosis of patients with brain metastasis (BM) is poor. In our study, we demonstrated that AZD3759, an EGFR tyrosine kinase inhibitors (TKIs) with excellent blood-brain barrier (BBB) penetration, combined with radiation enhanced the antitumor efficacy in BM model from EGFR mutant (EGFRm) NSCLC. Besides, the antitumor activity displayed no difference between radiation concurrently with AZD3759 and radiation sequentially with AZD3759. Mechanistically, we found that two factors determined the enhanced efficacy: cells with EGFRm which were sensitive to AZD3759, and a relative high concentration of AZD3759. We have validated mechanisms underlying the radiosensitizing effect of AZD3759, which were involved in decreased cell proliferation and survival, and suppressed repair of DNA damage. Moreover, our study found that AZD3759 inhibited both the non homologous end joining (NHEJ) and homologous recombination (HR) DNA double-strand breaks (DSBs) repair pathway, and abrogated the G2/M checkpoint to suppress DNA damage repair. We also detected the BBB penetration of AZD3759 when combined with cranial radiation. The results showed the BBB penetration of AZD3759 was decreased within 24 hr after radiation, however, the free concentration of AZD3759 in brain kept at a high level in the context of radiation. In conclusion, our findings suggest that AZD3759 combined with radiation enhances the antitumor activity in BM from EGFRm NSCLC, this combination therapy may be an effective treatment option for BM from EGFRm NSCLC. PMID- 29430653 TI - Regression equations for calculation of z scores for echocardiographic measurements of left heart structures in healthy Han Chinese children. AB - OBJECTIVE: Clinical decision making in children with heart disease relies on detailed measurements of cardiac structures using two-dimensional and M-mode echocardiography. However, no echocardiographic reference values are available for the Chinese children. We aimed to establish z-score regression equations for left heart structures in a population-based cohort of healthy Chinese Han children. METHOD: Echocardiography was performed in 545 children with a normal heart. The dimensions of the aortic valve annulus (AVA), aortic sinuses of Valsalva (ASV), sinotubular junction (STJ), ascending aorta (AAO), left atrium (LA), mitral valve annulus (MVA), interventricular septal end-diastolic thickness (IVSd), interventricular septal end-systolic thickness (IVSs), left ventricular end-diastolic diameter (LVIDd), left ventricular end-systolic diameter (LVIDs), left ventricular posterior wall end-diastolic thickness (LVPWd), left ventricular posterior wall end-systolic thickness (LVPWs) were measured. Regression analyses were conducted to relate the measurements of left heart structures to body surface area (BSA). Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were calculated. Several models were used, and the adjusted R2 values were compared for each model. RESULTS: AVA, ASV, STJ, AAO, LA, MVA, IVSd, IVSs, LVIDd, LVIDs, LVPWd, and LVPWs had a cubic relationship with BSA. LVEF and LVFS fell within a narrow range. CONCLUSIONS: Our results provide reference values for z scores and regression equations for left heart structures in Han Chinese children. These data may help make a quick and accurate judgment of the routine clinical measurement of left heart structures in children with heart disease. PMID- 29430655 TI - Obesity and steatosis promotes mitochondrial remodeling that enhances respiratory capacity in the liver of ob/ob mice. AB - We investigated if obesity/steatosis promotes mitochondrial remodeling in the liver of ob/ob mice (an obesity model). Liver mitochondria from ob/ob mice (21 weeks with significant steatosis) had ~ 2-fold increases in state III respiration compared with control (C57BL/6J, C57BL/6NJ) for all respiratory substrates examined (glutamate/malate, succinate, octanoate, and glycerol 3-phosphate). A corresponding 2-fold increase in the expression of respiratory complexes (I, IV, and V) and other respiratory proteins (glycerol phosphate dehydrogenase-2 and medium-chain acyl-coenzyme A dehydrogenase) occur in liver mitochondria of mature ob/ob mice. Conversely, respiration in liver mitochondria from young ob/ob mice (6 weeks) does not differ from control with any respiratory substrates examined. Overall, mitochondrial remodeling that enhances respiration increases with obesity/steatosis in the liver of ob/ob mice. PMID- 29430656 TI - Plant cell wall sugars: sweeteners for a bio-based economy. AB - Global warming and the consequent climate change is one of the major environmental challenges we are facing today. The driving force behind the rise in temperature is our fossil-based economy, which releases massive amounts of the greenhouse gas carbon dioxide into the atmosphere. In order to reduce greenhouse gas emission, we need to scale down our dependency on fossil resources, implying that we need other sources for energy and chemicals to feed our economy. Here, plants have an important role to play; by means of photosynthesis, plants capture solar energy to split water and fix carbon derived from atmospheric carbon dioxide. A significant fraction of the fixed carbon ends up as polysaccharides in the plant cell wall. Fermentable sugars derived from cell wall polysaccharides form an ideal carbon source for the production of bio-platform molecules. However, a major limiting factor in the use of plant biomass as feedstock for the bio-based economy is the complexity of the plant cell wall and its recalcitrance towards deconstruction. To facilitate the release of fermentable sugars during downstream biomass processing, the composition and structure of the cell wall can be engineered. Different strategies to reduce cell wall recalcitrance will be described in this review. The ultimate goal is to obtain a tailor-made biomass, derived from plants with a cell wall optimized for particular industrial or agricultural applications, without affecting plant growth and development. PMID- 29430658 TI - Medium-chain dehydrogenase/reductase and aldo-keto reductase scavenge reactive carbonyls in Synechocystis sp. PCC 6803. AB - Reactive carbonyls (RCs), which are inevitably produced during respiratory and photosynthetic metabolism, have the potential to cause oxidative damage to photosynthetic organisms. Previously, we proposed a scavenging model for RCs in the cyanobacterium Synechocystis sp. PCC 6803 (S. 6803). In the current study, we constructed mutants deficient in the enzymes medium-chain dehydrogenase/reductase (DeltaMDR) and aldo-keto reductase (DeltaAKR) to investigate their contributions to RC scavenging in vivo. We found that treatment with the lipid-derived RC acrolein causes growth inhibition and promotes greater protein carbonylation in DeltaMDR, compared with the wild-type and DeltaAKR. In both DeltaMDR and DeltaAKR, photosynthesis is severely inhibited in the presence of acrolein. These results suggest that these enzymes function as part of the scavenging systems for RCs in S. 6803 in vivo. PMID- 29430657 TI - The role of OleA His285 in orchestration of long-chain acyl-coenzyme A substrates. AB - Renewable production of hydrocarbons is being pursued as a petroleum-independent source of commodity chemicals and replacement for biofuels. The bacterial biosynthesis of long-chain olefins represents one such platform. The process is initiated by OleA catalyzing the condensation of two fatty acyl-coenzyme A substrates to form a beta-keto acid. Here, the mechanistic role of the conserved His285 is investigated through mutagenesis, activity assays, and X-ray crystallography. Our data demonstrate that His285 is required for product formation, influences the thiolase nucleophile Cys143 and the acyl-enzyme intermediate before and after transesterification, and orchestrates substrate coordination as a defining component of an oxyanion hole. As a consequence, His285 plays a key role in enabling a mechanistic strategy in OleA that is distinct from other thiolases. PMID- 29430659 TI - Coronary sinus thrombosis: Echocardiographic visualization in a patient with known risk factors. AB - Coronary sinus thrombosis is a rare and often overlooked diagnosis that can have fatal consequences. We report a case of acute coronary sinus thrombosis in a patient with systolic heart failure who had undergone recent right-heart catheterization. The patient presented with recurrent presyncope, syncope, and shortness of breath. An echogenic focus consistent with a coronary sinus thrombus was visualized on transthoracic echocardiography that had not been seen previously on recent imaging. The patient was managed on oral anticoagulation. Awareness of patients at risk for coronary sinus thrombosis can lead to early detection via bedside echocardiography and early management. PMID- 29430660 TI - The heme auxotroph Caenorhabditis elegans can cleave the thioether bonds of c type cytochromes. AB - Heme is essential and synthesized via highly regulated processes. For this reason, most organisms strive to recycle it or acquire it from their environment. When heme is bound to proteins noncovalently, degradation of the polypeptide is sufficient to release it. However, in some hemoproteins, such as c-type cytochromes, heme is covalently bound to the protein backbone. We use the heme auxotroph Caenorhabditis elegans to investigate if cytochromes c can be a heme source, and we show that this organism must encode a novel system which specifically cleaves the thioether bonds of c-type cytochromes. We also find that at limiting heme concentrations, while somatic tissues develop normally the germline fails to proliferate, suggesting the presence of a heme-sensing checkpoint in C. elegans. PMID- 29430661 TI - Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse. AB - KEY POINTS: Synapses have high energy demands which increase during intense activity. We show that presynaptic terminals can utilise extracellular glucose or lactate to generate energy to maintain synaptic transmission. Reducing energy substrates induces a metabolic stress: presynaptic ATP depletion impaired synaptic transmission through a reduction in the number of functional synaptic vesicle release sites and a slowing of vesicle pool replenishment, without a consistent change in release probability. Metabolic function is compromised in many pathological conditions (e.g. stroke, traumatic brain injury and neurodegeneration). Knowledge of how synaptic transmission is constrained by metabolic stress, especially during intense brain activity, will provide insights to improve cognition following pathological insults. ABSTRACT: The synapse has high energy demands, which increase during intense activity. Presynaptic ATP production depends on substrate availability and usage will increase during activity, which in turn could influence transmitter release and information transmission. We investigated transmitter release at the mouse calyx of Held synapse using glucose or lactate (10, 1 or 0 mm) as the extracellular substrates while inducing metabolic stress. High-frequency stimulation (HFS) and recovery paradigms evoked trains of EPSCs monitored under voltage-clamp. Whilst postsynaptic intracellular ATP was stabilised by diffusion from the patch pipette, depletion of glucose increased EPSC depression during HFS and impaired subsequent recovery. Computational modelling of these data demonstrated a reduction in the number of functional release sites and slowed vesicle pool replenishment during metabolic stress, with little change in release probability. Directly depleting presynaptic terminal ATP impaired transmitter release in an analogous manner to glucose depletion. In the absence of glucose, presynaptic terminal metabolism could utilise lactate from the aCSF and this was blocked by inhibition of monocarboxylate transporters (MCTs). MCT inhibitors significantly suppressed transmission in low glucose, implying that lactate is a presynaptic substrate. Additionally, block of glycogenolysis accelerated synaptic transmission failure in the absence of extracellular glucose, consistent with supplemental supply of lactate by local astrocytes. We conclude that both glucose and lactate support presynaptic metabolism and that limited availability, exacerbated by high-intensity firing, constrains presynaptic ATP, impeding transmission through a reduction in functional presynaptic release sites as vesicle recycling slows when ATP levels are low. PMID- 29430662 TI - On the feasibility of automatically selecting similar patients in highly individualized radiotherapy dose reconstruction for historic data of pediatric cancer survivors. AB - PURPOSE: The aim of this study is to establish the first step toward a novel and highly individualized three-dimensional (3D) dose distribution reconstruction method, based on CT scans and organ delineations of recently treated patients. Specifically, the feasibility of automatically selecting the CT scan of a recently treated childhood cancer patient who is similar to a given historically treated child who suffered from Wilms' tumor is assessed. METHODS: A cohort of 37 recently treated children between 2- and 6-yr old are considered. Five potential notions of ground-truth similarity are proposed, each focusing on different anatomical aspects. These notions are automatically computed from CT scans of the abdomen and 3D organ delineations (liver, spleen, spinal cord, external body contour). The first is based on deformable image registration, the second on the Dice similarity coefficient, the third on the Hausdorff distance, the fourth on pairwise organ distances, and the last is computed by means of the overlap volume histogram. The relationship between typically available features of historically treated patients and the proposed ground-truth notions of similarity is studied by adopting state-of-the-art machine learning techniques, including random forest. Also, the feasibility of automatically selecting the most similar patient is assessed by comparing ground-truth rankings of similarity with predicted rankings. RESULTS: Similarities (mainly) based on the external abdomen shape and on the pairwise organ distances are highly correlated (Pearson rp >= 0.70) and are successfully modeled with random forests based on historically recorded features (pseudo-R2 >= 0.69). In contrast, similarities based on the shape of internal organs cannot be modeled. For the similarities that random forest can reliably model, an estimation of feature relevance indicates that abdominal diameters and weight are the most important. Experiments on automatically selecting similar patients lead to coarse, yet quite robust results: the most similar patient is retrieved only 22% of the times, however, the error in worst case scenarios is limited, with the fourth most similar patient being retrieved. CONCLUSIONS: Results demonstrate that automatically selecting similar patients is feasible when focusing on the shape of the external abdomen and on the position of internal organs. Moreover, whereas the common practice in phantom-based dose reconstruction is to select a representative phantom using age, height, and weight as discriminant factors for any treatment scenario, our analysis on abdominal tumor treatment for children shows that the most relevant features are weight and the anterior-posterior and left-right abdominal diameters. PMID- 29430663 TI - DNA hydroxymethylation rate in the AChE and HoxC4 promoter associated with human sperm quality. AB - The relationship of altered DNA 5'-hydroxymethylation in human spermatozoa with seminal parameters remains unclear. The aim of the study was to investigate the association between the 5'-hydroxymethylcytosine (5hmC) rate in the promoters of acetylcholinesterase (AChE) and homeobox C4 (HoxC4) genes and human sperm concentration/motility. The study population consisted of three groups: asthenozoospermia (AZ), oligoasthenozoospermia (OAZ) and normozoospermia (NZ). The 5hmC rate in the promoter was measured by CCGG loci-dependent MspI/HpaII restriction mapping of glycosylation-modified sperm DNA combined with a hydroxymethylation-specific real-time polymerase chain reaction assay. The 5hmC rate in the AChE promoter in group AZ and OAZ was higher than that in group NZ (p < .05). A weak inverse correlation between 5hmC rate of AChE and sperm motility was observed in all subjects (r = -.172, p < .05). The 5hmC rate in the HoxC4 promoter in group OAZ was lower than that in group NZ (p < .05). These results indicated that altered 5hmC rates of AChE and HoxC4 promoters are associated with low sperm motility and sperm concentration respectively. PMID- 29430664 TI - BLIMP-1 is insufficient to induce antibody secretion in the absence of IRF4 in DT40 cells. AB - Differentiation of B cells into antibody-secreting cells (ASCs), plasmablasts and plasma cells is regulated by a network of transcription factors. Within this network, factors including PAX5 and BCL6 prevent ASC differentiation and maintain the B cell phenotype. In contrast, BLIMP-1 and high IRF4 expression promote plasma cell differentiation. BLIMP-1 is thought to induce immunoglobulin secretion, whereas IRF4 is needed for the survival of ASCs. The role of IRF4 in the regulation of antibody secretion has remained controversial. To study the role of IRF4 in the regulation of antibody secretion, we have created a double knockout (DKO) DT40 B cell line deficient in both IRF4 and BCL6. Although BCL6 deficient DT40 B cell line had upregulated BLIMP-1 expression and secreted antibodies, the DKO cell line did not. Even enforced BLIMP-1 expression in DKO cells or IRF4-deficient cells could not induce IgM secretion while in WT DT40 cells, it could. However, enforced IRF4 expression in DKO cells induced strong IgM secretion. Our findings support a model where IRF4 expression in addition to BLIMP-1 expression is required to induce robust antibody secretion. PMID- 29430665 TI - Health-related physical fitness and quality of life in men with congenital hypogonadotropic hypogonadism. AB - Congenital hypogonadotropic hypogonadism is a rare disorder characterised by impaired testosterone secretion since birth, and represents a valuable model for studying the effects of testosterone replacement therapy (TRT) in humans. This cross-sectional study aimed to investigate all health-related physical fitness (HRPF) components and quality of life in a series of eight men with hypogonadotropic hypogonadism under regular TRT. The study group was compared to a control group of 16 healthy subjects paired for age, body mass index and physical activity. Body composition, aerobic capacity, muscular strength and endurance, and joint flexibility were evaluated in two different 7-day interval time points, based on the pharmacokinetics of testosterone in the hypogonadal group. Quality of life was assessed by the WHOQOL-brief questionnaire. Both groups had similar performances in all HRPF components evaluated, independently of plasma testosterone levels (p > .05). Quality of life was also similar in the four domains analysed (p > .05). The results of this pilot study suggest that regular testosterone replacement was efficient in providing HRPF and quality of life in a series of congenitally hypogonadal men to levels like those observed in healthy men. In addition, acute fluctuations in plasma testosterone did not correlate with changes in muscle strength and endurance. PMID- 29430666 TI - Remembering the Good Times: The Influence of Relationship Nostalgia on Relationship Satisfaction Across Time. AB - We conducted two studies to understand if reminiscing about early parts of a romantic relationship can increase positive affect and relationship satisfaction. In Study 1, we examined the psychometrics of an adapted relationship nostalgia measure, if relationship nostalgia changes positive affect, and if relationship nostalgia and relationship satisfaction are associated. In Study 2, we tested the longitudinal link between relationship nostalgia and relationship satisfaction. Rather than increasing positive affect, relationship nostalgia is associated with a movement toward emotional homeostasis. Additionally, relationship nostalgia is positively associated with relationship satisfaction at the same time point but in the short term, the association is negative-long term, this association disappears. Implications for using a relationship history in therapy are discussed. PMID- 29430667 TI - Using endocardial unipolar mapping to identify epicardial scar: When and how to adjust the voltage amplitude slider bar? PMID- 29430668 TI - ASVCP guidelines: Allowable total error hematology. AB - The purpose of this document is to provide total allowable error (TEa ) recommendations for commonly analyzed hematology measurands for veterinary personnel. These guidelines define relevant terminology and highlight considerations specific to hematology measurands. They also provide reasons and guidelines for using TEa in instrument performance evaluation, including recommendations for when the total observed error exceeds the recommended TEa . Biological variation-based quality specifications are briefly discussed. The appendix describes the derivation of the hematology TEa recommendations and provides resources for external quality assurance/proficiency testing programs and a worksheet for implementation of the guidelines. PMID- 29430669 TI - Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. AB - BACKGROUND: The epidemiology of Helicobacter pylori infection is poorly understood. AIM: To establish the reported regional and national prevalence of H. pylori infection, stratified by age and gender. METHODS: All relevant English publications from 2000 to 2017 cited by PubMed and Scopus were retrieved using comprehensive combinations of keywords. The overall prevalence of H. pylori was estimated using both random effect and fixed effect meta-analyses, and presented as prevalence rate (% and 95% CI). The analyses were extended by separation into gender and age groups. RESULTS: A total of 14 056 records were obtained initially. After applying exclusion criteria in several steps, 183 studies were selected. Analysis of 410 879 participants from 73 countries in six continents revealed an overall prevalence of 44.3% (95% CI: 40.9-47.7) worldwide. This rate ranged from 50.8% (95% CI: 46.8-54.7) in developing countries compared with 34.7% (95% CI: 30.2-39.3) in developed countries. The global H. pylori infection rate was 42.7% (95% CI: 39-46.5) in females compared to 46.3% (95% CI: 42.1-50.5) in males. The prevalence in adults (>=18 years) was significantly higher than in children (48.6% [95% CI: 43.8-53.5] vs 32.6% [95% CI: 28.4-36.8], respectively). There was a statistically nonsignificant decrease in the prevalence in 2009-2016 compared with the 2000-2009 period. CONCLUSIONS: The observed differences between countries appear to be due to economic and social conditions. H. pylori infection can be a benchmark for the socioeconomic and health status of a country. Further studies are suggested to investigate the natural history of the acquisition of H. pylori infection from childhood into adult life. PMID- 29430670 TI - The effect of 3 resuscitative fluid therapies on hemostasis as measured by rotational thromboelastometry in dogs. AB - BACKGROUND: Evidence suggests that administration of intravenous fluids impairs hemostasis. Thromboelastometry (TEM) may provide a more sensitive measure of the fluid effects on hemostasis than traditional coagulation tests. OBJECTIVE: The study aim was to determine if resuscitative fluid therapy affects hemostasis, as measured by TEM. MATERIALS AND METHODS: Using a randomized crossover design, 6 healthy dogs were administered intravenous colloid, crystalloid, and hypertonic saline at therapeutic doses. Whole blood samples were taken at baseline, 1, 4, and 8 h posttreatment for TEM analysis and measurement of PT, APTT, and fibrinogen. Univariate ANOVA on transformed data evaluated differences between groups and within groups. When significant differences were noted (P = .003), a Tukey test was performed. RESULTS: A statistically significant interaction between individual dogs and treatment was noted for most TEM variables. There was a significant decrease in clot firmness from baseline in the TEM assessment of the intrinsic pathway. Colloid treatment correlated with significantly higher clot firmness in the TEM extrinsic pathway assessment, which decreased over time, and PT was significantly shorter in colloid-treated dogs. Overall, PT was significantly prolonged at one hour; however, all PT values were within the RI. The fibrinogen concentration was significantly different between all treatments. CONCLUSIONS: Clinically relevant doses of resuscitative fluids resulted in a decreased clot firmness in the intrinsic pathway, as measured by TEM, which affected hemostatic variables in healthy dogs. There was also a significant individual response to treatment. The changes noted in this study are not expected to result in clinically apparent bleeding. PMID- 29430671 TI - Excretion/defecation patterns in Triatoma infestans populations that are, respectively, susceptible and resistant to deltamethrin. AB - Pyrethroid resistance has been detected in Triatoma infestans (Klug) (Hemiptera: Reduviidae) specimens from different areas of Argentina and Bolivia. Genes conferring resistance can have a pleiotropic effect with epidemiological and evolutionary consequences. This research studied excretion/defecation patterns in deltamethrin-resistant T. infestans in order to elucidate its biological performance, adaptive consequences and role in the transmission of Chagas' disease. One deltamethrin-susceptible strain and two deltamethrin-resistant strains were used. Fifth-instar nymphs were fed ad libitum and their defecations recorded during and after the first or second feeding in the stadium. Resistant insects began to defecate later, defecated less, showed a lower proportion of defecating individuals and lower defecation indices compared with susceptible insects during the first hour after feeding. The number of bloodmeals in the stadium did not affect the main variables determining the pattern of defecation. The present study suggests that alterations in the excretion/defecation pattern in resistant insects entail an adaptive cost and, considering only this pattern, determine a lower capacity for transmission of Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae) compared with susceptible insects. PMID- 29430672 TI - Review article: predictors of response to vedolizumab and ustekinumab in inflammatory bowel disease. AB - BACKGROUND: Increased knowledge of pathways involved in the pathogenesis of IBD has led to the development of new treatment options for Crohn's disease (CD) and ulcerative colitis (UC). Two new biological agents have been recently approved for IBD: vedolizumab and ustekinumab. They have different therapeutic targets (alpha4 beta7 integrin for vedolizumab and interleukin-12/23 pathways for ustekinumab) than the primary biological class, anti-tumour necrosis factor alpha (anti-TNF) agents. As the armamentarium for IBD increases in coming years, it will become important to understand factors associated with response in order to best position and personalise therapy. AIM: To summarise the current data on predictors of response to vedolizumab and ustekinumab in IBD patients. METHODS: We conducted a comprehensive literature review. A PubMed search was performed using pre-defined key words and terms to identify relevant studies on predictors of response. RESULTS: Patients with severe disease (by clinical activity and inflammatory biomarkers), or prior anti-TNF exposure are less likely to respond to vedolizumab. Ileocolonic disease, no prior surgery and uncomplicated phenotype were associated with better responses to ustekinumab in CD. Initial response seems to predict a better long-term maintenance in both therapies (P < 0.001). Contrary to anti-TNF therapies, immunogenicity appears to play less of a role in response. CONCLUSION: As the number of new biological therapies increase in IBD, identifying patients who are most likely to benefit from specific agents is of paramount importance to help best position IBD therapies. PMID- 29430673 TI - Microtubule Inner Proteins: A Meshwork of Luminal Proteins Stabilizing the Doublet Microtubule. AB - Motile eukaryotic cilia and flagella are hair-like organelles responsible for cell motility and mucociliary clearance. Using cryo-electron tomography, it has been shown that the doublet microtubule, the cytoskeleton core of the cilia and flagella, has microtubule inner protein structures binding periodically inside its lumen. More recently, single-particle cryo-electron microscopy analyses of isolated doublet microtubules have shown that microtubule inner proteins form a meshwork inside the doublet microtubule. High-resolution structures revealed new types of interactions between the microtubule inner proteins and the tubulin lattice. In addition, they offered insights into the potential roles of microtubule inner proteins in the stabilization and assembly of the doublet microtubule. Herein, we review our new insights into microtubule inner proteins from the doublet microtubule together with the current body of literature on microtubule inner proteins. PMID- 29430674 TI - Surviving Starvation: AMPK Protects Germ Cell Integrity by Targeting Multiple Epigenetic Effectors. AB - Acute starvation can have long-term consequences that are mediated through epigenetic change. Some of these changes are affected by the activity of AMP activated protein kinase (AMPK), a master regulator of cellular energy homeostasis. In Caenorhabditis elegans, the absence of AMPK during a period of starvation in an early larval stage results in developmental defects following their recovery on food, while many of them become sterile. Moreover, the loss of AMPK during this quiescent period results in transgenerational phenotypes that can become progressively worse with each successive generation. Our recent data describe a chromatin-based mechanism of how AMPK mediates adjustment to acute starvation in the germ cells, however, the heritable aspect of this AMPK mutant phenotype remains unresolved. Here, we explore how AMPK might affect this process and speculate how the initial transcription that occurs in the germ cells may adversely affect subsequent germline gene expression and/or genomic integrity. PMID- 29430675 TI - Ultrasound Elastographic Measurement of Sciatic Nerve Displacement and Shear Strain During Active and Passive Knee Extension. AB - There is current need for objective measures of sciatic nerve mobility in patients with sciatic-type pain. The objective of the study was to assess the feasibility and reliability of ultrasound elastography to quantify sciatic nerve displacement and shear strain at the sciatic nerve-hamstring muscle interface during active and passive knee extension-flexion exercises performed while sitting in healthy people. Ultrasound elastography showed excellent intrarater within-session reliability for assessing sciatic nerve displacement and sciatic nerve-hamstring muscle interface shear strain during active knee extension flexion exercises. These findings will inform similar future work conducted in patients with sciatic-type pain. PMID- 29430676 TI - Metabolite identification of the antimalarial naphthoquine using liquid chromatography-tandem high-resolution mass spectrometry in combination with multiple data-mining tools. AB - Naphthoquine (NQ) is one of important partner drugs of artemisinin-based combination therapy (ACT), which is recommended for the treatment of uncomplicated Plasmodium falciparum. NQ shows a high cure rate after a single oral administration. It is absorbed quickly (time to peak concentration 2-4 h) and has a long elimination half-life (255 h). However, the metabolism of NQ has not been clarified. In this work, the metabolite profiling of NQ was studied in six liver microsomal incubates (human, cynomolgus monkey, beagle dog, mini pig, rat and CD1 mouse), seven recombinant CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and rat (plasma, urine, bile and feces) using liquid chromatography tandem high-resolution LTQ-Orbitrap mass spectrometry (HRMSn ) in conjunction with online hydrogen/deuterium exchange. The biological samples were pretreated by protein precipitation and solid-phase extraction. For data processing, multiple data-mining tools were applied in tandem, i.e. background subtraction and followed by mass defect filter. NQ metabolites were characterized by accurate MS/MS fragmentation characteristics, the hydrogen/deuterium exchange data and cLogP simulation. As a result, five phase I metabolites (M1-M5) of NQ were characterized for the first time. Two metabolic pathways were involved: hydroxylation and N-oxidation. This study demonstrates that LC-HRMSn in combination with multiple data-mining tools in tandem can be a valuable analytical strategy for rapid metabolite profiling of drugs. PMID- 29430678 TI - Zebularine treatment is associated with deletion of FT-B1 leading to an increase in spikelet number in bread wheat. AB - The number of rachis nodes (spikelets) on a wheat spike is a component of grain yield that correlates with flowering time. The genetic basis regulating flowering in cereals is well understood, but there are reports that flowering time can be modified at a high frequency by selective breeding, suggesting that it may be regulated by both epigenetic and genetic mechanisms. We investigated the role of DNA methylation in regulating spikelet number and flowering time by treating a semi-spring wheat with the demethylating agent, Zebularine. Three lines with a heritable increase in spikelet number were identified. The molecular basis for increased spikelet number was not determined in 2 lines, but the phenotype showed non-Mendelian inheritance, suggesting that it could have an epigenetic basis. In the remaining line, the increased spikelet phenotype behaved as a Mendelian recessive trait and late flowering was associated with a deletion encompassing the floral promoter, FT-B1. Deletion of FT-B1 delayed the transition to reproductive growth, extended the duration of spike development, and increased spikelet number under different temperature regimes and photoperiod. Transiently disrupting DNA methylation can generate novel flowering behaviour in wheat, but these changes may not be sufficiently stable for use in breeding programs. PMID- 29430677 TI - Cutaneous refractile foreign body microemboli with intravascular injection of oral medication. AB - Injection drug abuse (IDA) is known to cause a spectrum of systemic and cutaneous complications. Despite the increasing incidence of IDA around the world, there is a paucity of literature discussing cutaneous complications from a dermatopathologic perspective. We present a case of a 35-year-old male with a complex medical history of Von Willebrand disease, Bechet disease and diverticular disease. Following a sigmoidectomy/colostomy for diverticular perforation, he presented with fever and an indurated right arm displaying livedoid purpura. The right distal fingertips showed purpura with focal ulceration. A punch biopsy of the right wrist did not show evidence of inflammatory vasculitis or pyogenic infection, but instead showed a focus of polarizing, refractile material occluding a dilated arterial lumen within the mid dermis. The patient admitted to injecting a suspension of crushed ondansetron (Zofran) tablets into the antecubital area to control post-operative nausea. It is known that direct intravascular injection of foreign material can cause distal ischemia and necrosis, either by local vasoconstriction, thrombosis, or formation of microemboli, as in this patient. Our objective is to bring awareness to this rarely reported phenomenon, and to raise clinical suspicion for IDA when confronted with such a unique vasculopathic pattern. PMID- 29430679 TI - Seeking certainty through narrative closure: men's stories of prostate cancer treatments in a state of liminality. AB - Radical treatments of prostate cancer often lead to a pervasive liminal state that is characterised by multiple uncertainties that relate both to a possible recurrence of cancer and recovery from side effects, such as erectile and urinary dysfunctions. Liminality can make it difficult for cancer patients to narrate their experiences, as their stories lack a definite ending. After interviews with 22 Finnish men who had undergone radical prostatectomy, we analysed how men produce closure in their illness narratives. Focusing on the timelines of control visits or their anticipated recovery from side effects, these interviewees sought provisional certainty within a seemingly chaotic future. By locating erectile dysfunction in the wider context of a life-course and interpreting their fading sexuality as a 'natural' consequence of ageing, these men were adjusting to their post-operative lives. Our study further shows that the inability to adjust personal experiences to positive culturally available storylines that provide a chance for the narrative reconstruction of life, can cause materialised negative consequences, such as relationship breakdowns. PMID- 29430680 TI - Study on correlation of sperm quality parameters with antioxidant and oxidant status of buffalo bull semen during various stages of cryopreservation. AB - This investigation was carried out to study the correlation of sperm quality parameters with antioxidant and oxidant status of buffalo bull semen during various stages of cryopreservation. Semen samples were evaluated for sperm parameters (mass motility [MM], concentration [CON], progressive motility [PM], viability [VIB], acrosomal integrity [AI] and hypo-osmotic swelling [HOS] response), antioxidants (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx] and total antioxidant capacity [TAC]) and oxidants (Lipid peroxidation [LPO] and reactive oxygen species [ROS]) at fresh, pre-freeze and post-thaw stages. Sperm parameters (PM, VIB, AI and HOS response) and antioxidants (SOD, CAT and TAC) were significantly (p < .05) reduced at fresh stage, and oxidants (LPO and ROS) were significantly (p < .05) increased at pre freeze and post-thaw stages. At fresh stage, MM was negatively correlated with LPO (p < .05), and CON was positively correlated with SOD, TAC and CAT, negatively correlated with LPO and CAT was positively (p < .01) correlated with VIB and HOS response. At pre-freeze stage, CAT was positively correlated with PM and AI (p < .05), and AI was negatively (p < .05) correlated with ROS. At post thaw stage, CAT was positively correlated with PM, VIB, HOS response and AI,, and LPO was negatively correlated with HOS, AI and VIB. The study of correlations of these parameters at different preservation stages with bull fertility may play an important role in developing models for predicting future fertility of bulls in the absence of conception rate data. PMID- 29430681 TI - Effects of p.o. administered xylitol in cats. AB - Xylitol is commonly used as sugar substitute in households. While it has numerous beneficial effects on human health, it is highly toxic to dogs. The goal of this study was to examine whether xylitol has similar deleterious effects, such as hypoglycaemia and acute hepatic failure, on cats. Our research included six healthy middle-aged cats. Xylitol was dissolved in deionized water and administered p.o. at three doses (100, 500 and 1,000 mg/kg body weight). These dosages have been considered toxic and can cause liver failure or even death in dogs. After every xylitol administration, the basic health status and the blood glucose of cats were observed regularly. Additionally, prior to and 6, 24 and 72 hr after xylitol administration, blood samples were taken to check complete blood count, clinical biochemical parameters and enzymes such as ALT, ALKP, GGT, GLDH, bile acids, BUN, creatinine, phosphate, total protein, albumin, sodium and potassium. There were no significant changes (p > .05) in any of the haematological or biochemical parameters. Blood glucose concentrations did not show any significant alterations, except at 1,000 mg/kg dose, where a mild but significant increase was observed, but it was in physiological range. Based on our results, xylitol did not induce toxic effects on cats. PMID- 29430682 TI - Enolase-1 expression in the stratum corneum is elevated with parakeratosis of atopic dermatitis and disrupts the cellular tight junction barrier in keratinocytes. AB - OBJECTIVE: Previous studies have shown that enolase-1 (ENO1) in the stratum corneum (SC) is more highly expressed in patients with atopic dermatitis (AD) than in healthy individuals, suggesting that it is a novel biomarker for evaluating skin condition in patients with AD. However, the mechanism underlying high ENO1 expression in the SC and its pathological relevance in AD are unclear. In this study, the relationship between ENO1 expression and keratinization of epidermis was investigated, and the role of high ENO1 expression in keratinocytes was characterized. METHODS: ENO1 expression and morphological characteristics were examined in SC from the cheeks of 24 patients with AD. Additionally, the localization of ENO1 in the excised human epidermis was observed. Moreover, to analyse the role of ENO1 in cellular barrier function, tight junction proteins (TJs) and transepithelial electrical resistance (TEER) in keratinocytes with ENO1 overexpression were evaluated. Furthermore, the localization of ENO1 and plasminogen in keratinocytes was evaluated by immunostaining, and the cellular barrier function in keratinocytes was examined after treatment with tranexamic acid (TXA). RESULTS: ENO1 expression was substantially correlated with the rate of nucleated corneocytes in AD. In addition, ENO1 localized in the basal to spinous layers, but was its expression dramatically decreased in healthy human SC. ENO1 overexpression in human epidermal keratinocytes reduced the expression of TJs (claudin-4, E-cadherin, tricellulin, and occludin) and TEER, and treatment with anti-ENO1 IgG reversed these effects. ENO1 colocalized with plasminogen in keratinocytes. Treatment with TXA rescued the ENO1-induced reductions in TJ and TEER expression. CONCLUSION: We found a substantial correlation between ENO1 expression and the rate of nucleated corneocytes in AD and decreased ENO1 expression with nuclear disappearance. These results suggest that high ENO1 expression in the SC of AD is caused by deficient keratinization, which is an AD characteristic. Moreover, ENO1 overexpression in keratinocytes promoted dysfunction of TJ dynamics, leading to reduced integrity of the cellular barrier, and these effects might be mediated by plasmin activity. We propose that ENO1 is a useful indicator of parakeratosis and might have a potential role in cellular TJ barrier function in the epidermis. PMID- 29430683 TI - Supramolecular separation mechanism of pentafluorophenyl column using ibuprofen and omeprazole as markers: LC-MS and simulation study. AB - The pentafluorophenyl (PFP) column is emerging as a new advancement in separation science to analyze a wide range of analytes and, thus, its separation mechanism at supramolecular level is significant. We developed a mechanism for the separation of ibuprofen and omeprazole using different combinations (ranging from 50:50 to 60:40) of water-acetonitrile containing 0.1% formic acid as the mobile phase. The column used was Waters Acquity UPLC HSS PFP (75 * 2.1 mm, 1.8 MUm). The reverse order of elution was observed in different combinations of the mobile phases. The docking study indicated hydrogen bonding between ibuprofen and PFP stationary phase (binding energy was -11.30 kJ/mol). Separation at PFP stationary phase is controlled by hydrogen bonding along with pi-pi interactions. This stationary phase may be used to analyze both aromatic and aliphatic analytes. The developed mechanism will be useful to separate various analytes by considering the possible interactions, leading to saving of energy, time and money. In addition, this work will be highly useful in preparative chromatography where separation is the major problem at a large scale. Moreover, the developed LC-MS QTOF method may be used to analyze ibuprofen and omeprazole in an unknown sample owing to the low value of detection limits. PMID- 29430684 TI - Comparison of milk and plasma pharmacokinetics of meloxicam in postpartum versus mid-lactation Holstein cows. AB - The objective of this study reported here was determine whether differences occurred in meloxicam pharmacokinetics between postpartum cows and mid-lactation cows. Preliminary data from a separate study (P. J. Gorden, unpublished data) in postpartum cows demonstrated elevated plasma and milk concentration profiles compared to previously published data (Malreddy, Coetzee, KuKanich, & Gehring, ). Two different groups were enrolled, each with 10 cows. The treatment group (TRT) was postpartum cows treated with meloxicam, and the positive control (PC) group was cows in mid-lactation treated with meloxicam. Plasma and milk meloxicam concentrations between the TRT and PC group were compared. Significant differences in meloxicam concentration in plasma were determined at all time points from 8 hr to 120 hr post-treatment. In milk, there was a treatment (p = .003), time (p < .001), and treatment by time interaction (p < .001). Significant differences in milk meloxicam concentration were determined at all time points from 8 hr to 96 hr post-treatment, except for the 16-hr time point. The time needed for meloxicam to no longer be detected in milk of the TRT group was longer compared to the PC group, indicating that a longer milk withdrawal is needed. These data suggest higher bioavailability as the underlying mechanism. Further research is needed to determine the mechanisms underlying differences this outcome. PMID- 29430685 TI - High temperature exposure did not affect induced 2n pollen viability in Populus. AB - High temperature exposure is widely used as a physical mutagenic agent to induce 2n gametes in Populus. However, whether high temperature exposure affects induced 2n pollen viability remains unknown. To clarify whether high temperature exposure affected the induced 2n pollen viability, 2n pollen induced by 38 and 41 degrees C temperatures, pollen morphology, 2n pollen germination in vitro, and crossing induced 2n pollen with normal gametes to produce a triploid was, based on observations of meiosis, conducted in Populus canescens. We found that the dominant meiotic stages (F = 56.6, p < .001) and the treatment duration (F = 21.4, p < .001) significantly affected the occurrence rate of induced 2n pollen. A significant decrease in pollen production and an increase in aborted pollen were observed (p < .001). High temperature sometimes affected in ectexine deposition and some narrow furrows were also analysed via details of ectexine structure. However, no significant difference in 2n pollen germination rate was observed between natural 2n pollen (26.7%) and high-temperature-induced 2n pollen (26.2%), and 42 triploids were created by crossing high-temperature-induced 2n pollen, suggesting that 38 and 41 degrees C temperatures exposure will not result in dysfunctional induced 2n pollen. PMID- 29430686 TI - What is your diagnosis? Unusual cells in feline blood. PMID- 29430687 TI - The protective effect of melatonin on sperm quality in rat after radioiodine treatment. AB - This study was designed to investigate the potential radioprotective impact of melatonin on the testicular tissue and sperm quality in rat given radioactive iodine (RAI) therapy. Thirty-six male Wistar albino rats were randomly divided into three groups as untreated control (Group 1); oral radioiodine group (RAI, 111 MBq, administrated rats); and RAI+melatonin group (oral radioiodine and intraperitoneal 12 mg/kg/day melatonin, starting 2 days before and continuing for 1 week after oral RAI administration). Twenty-four hours after the injection of the last melatonin dose, blood samples were taken for hormone analyses and the determination of the total antioxidant capacity. Sperm samples taken from the cauda epididymis were examined for spermatological parameters. Tissue samples taken from the rat testes were stained by TUNEL assay and with haematoxylin-eosin to detect apoptosis and histological alterations. It was demonstrated a significant decrease in epididymal spermatozoa viability and motility in all of the treatment groups, in comparison with the control group (p < .001). A significant decrease was also detected in sperm DNA fragmentation, follicle stimulating hormone (FSH) level and the index of apoptotic germ cells in the RAI+melatonin group when compared to the radioiodine group. It was concluded that melatonin prevents the adverse affects of RAI on apoptosis and spermatozoa quality. PMID- 29430688 TI - Radioiodination and bioevaluation of rolipram as a tracer for brain imaging: In silico study, molecular modeling and gamma scintigraphy. AB - Brain imaging is considered one of the most fruitful applications of radioisotope scanning. Rolipram, a selective phospodiesterase-4 inhibitor, has been labeled using [125 I] with chloramine-T (Ch-T) as an oxidizing agent. Factors, such as the amount of substrate, pH, the amount of oxidizing agent, temperature, and the reaction time, have been systematically studied to optimize the iodination process. In addition, bio-distribution studies have indicated that the brain uptake of [125 I]iodorolipram is 7.6 +/- 0.33 injected dose/g organ at 10 minutes post-injection, which cleared from the brain with time until it reaches 1.30 +/- 0.17% at 1 hour post-injection. Therefore, iodorolipram could be considered as a potential, new selective radiotracer for brain imaging. PMID- 29430689 TI - Dystrophic calcinosis cutis within burns, successfully treated with excision and secondary intention wound healing. PMID- 29430691 TI - Left ventricular function of patients with pregnancy-induced hypertension evaluated using velocity vector imaging echocardiography and N-terminal pro-brain natriuretic peptide. AB - PURPOSE: To investigate whether acute and transient pressure overload in patients with pregnancy-induced hypertension (PIH) affects left ventricular (LV) systolic function. METHODS: From pregnancy to 3 months after delivery, 82 patients were analyzed: 27, 25, and 30 with gestational hypertension, preeclampsia, and the healthy control group, respectively. Conventional echocardiography and velocity vector imaging (VVI) were performed, and blood levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) were analyzed. RESULTS: Compared with the control group, patients with gestational hypertension had significantly lower mean LV peak global longitudinal strain. Importantly, during both pregnancy and after delivery, patients with preeclampsia had significantly lower global longitudinal, circumferential, and radial strain compared with the control group. The NT-pro-BNP levels were significantly higher in patients with PIH compared with normotensive pregnancies, and this situation continued for 3 months after delivery in women with preeclampsia. CONCLUSIONS: In pregnancies complicated by pregnancy-induced hypertension, especially preeclampsia, the systolic function is impaired and NT-pro-BNP levels are elevated compared with normal pregnancy. Velocity vector imaging (VVI) is more sensitive than left ventricular ejection fraction to evaluate heart function in patients with PIH. PMID- 29430690 TI - A meta-analysis approach with filtering for identifying gene-level gene environment interactions. AB - There is a growing recognition that gene-environment interaction (G * E) plays a pivotal role in the development and progression of complex diseases. Despite a wealth of genetic data on various complex diseases/traits generated from association and sequencing studies, detecting G * E via genome-wide analysis remains challenging due to power issues. In genome-wide G * E studies, a common strategy to improve power is to first conduct a filtering test and retain only the genetic variants that pass the filtering step for subsequent G * E analyses. Two-stage, multistage, and unified tests have been proposed to jointly consider the filtering statistics in G * E tests. However, such G * E tests based on data from a single study may still be underpowered. Meanwhile, large-scale consortia have been formed to borrow strength across studies and populations. In this work, motivated by existing single-study G * E tests with filtering and the needs for meta-analysis G * E approaches based on consortia data, we propose a meta analysis framework for detecting gene-based G * E effects, and introduce meta analysis-based filtering statistics in the gene-level G * E tests. Simulations demonstrate the advantages of the proposed method-the ofGEM test. We apply the proposed tests to existing data from two breast cancer consortia to identify the genes harboring genetic variants with age-dependent penetrance (i.e., gene-age interaction effects). We develop an R software package ofGEM for the proposed meta-analysis tests. PMID- 29430692 TI - Mental health care needs and preferences for mothers of children with a disability. AB - BACKGROUND: Mothers of children with a disability are at increased risk of poor mental health compared with mothers of typically developing children. The aim of the study was to describe the mental health care needs and preferences for support of mothers of children and young people aged 0-25 years with a disability. METHODS: A cross-sectional study was used, using an online survey with 294 mothers of children with a disability. Questions were asked about mental health, perceived need for support, barriers to accessing mental health care, and preferences for support. Descriptive and chi-squared analyses were performed. RESULTS: High rates of mental ill health were self-identified in the previous 12 months, with reported clinically significant depression (44%), anxiety (42%), and suicidality (22%). Nearly half (48%) of the mothers reported high to very high psychological distress. Although 75% of mothers perceived a need for professional support, only 58% attempted to access this. Key barriers to accessing support were caregiving duties making it difficult to schedule appointments (45%) and not perceiving the mental health problem as serious enough to require help (36%). Individual counselling was the preferred type of support (66%) followed by professionally guided relaxation (49%) and education about mental health (47%). Support was considered most critical at the time of diagnosis and during medical intervention for their child. CONCLUSIONS: Although mental health problems were common and mothers perceived the need for professional help, several key barriers were preventing mothers from accessing help. Our study suggests that improving mothers' knowledge of when and where to seek help (mental health literacy) may encourage their access to support. There also needs to be more accessible treatment to mothers given the high care demands that are placed upon them. PMID- 29430693 TI - "NOTA-PRGD2 and NODAGA-PRGD2 : Bioconjugation, characterization, radiolabelling, and design space". AB - This work reports on the development of amide bond bioconjugation for the production of -NOTA and -NODAGA PRGD2 using batch strategy and microfluidic reactor technology. The final radiolabelling step was fully optimized using Design of Experiments and Design Space approaches, hence targeting robust labelling yields in routine. Optimal labelling conditions were defined in sodium acetate buffer as 168 MUg/mL peptide concentration, 4.9 pH, 47.5 degrees C temperature, and 12.5-minute reaction time. Upon optimization, the Gallium-68 radiolabelling was fully automated. All the work was designed to be compliant to the GMP environment and to support the pharmaceutical scale-up. PMID- 29430694 TI - Do we have enough evidence for recommending therapeutic apheresis for natalizumab related progressive multifocal leukoencephalopathy patients? Comment on "Guidelines on the use of therapeutic apheresis in clinical practice-evidence based approach from the Writing Committee of the American Society for apheresis: The seventh special issue." PMID- 29430695 TI - Immunocryosurgery as monotherapy for lentigo maligna or combined with surgical excision for lentigo maligna melanoma. AB - The incidence of lentigo maligna (LM), in situ (LM) or invasive (lentigo maligna melanoma, LMM), has increased during the last decades. Due to functional or cosmetic outcomes, optimal treatment with surgical excision may not be appropriate in some cases. We tried less invasive therapy, immunocryosurgery, as a single treatment for LM or combined with surgery for LMM, with better aesthetic results. Three patients with LM or LMM not amenable to complete surgical excision were selected. LMM patients underwent limited surgical resection of the invasive area. Subsequently, a combined treatment with topical imiquimod and cryosurgery was performed. The LM patient received immunocryosurgery directly. All of them were free of local and systemic disease at 48, 42 and 41 months after discontinuation of therapy. We consider that immunocryosurgery is an alternative option for LM or even for LMM (after removal of the invasive tissue with narrow margins) in poor surgical candidates, with good therapeutic, functional and cosmetic results. PMID- 29430696 TI - Morphological study of the ureterovesical junction in children. AB - Morphological and morphometric assessment of the elements of the ureterovesical junction in children was performed in the present study in different age groups ranging from 24 weeks of gestation to 16 years old. We tried to answer the question whether, in human ontogenesis, there is a period of anatomical predisposition to primary vesicoureteral reflux. The study included 210 urinary bladders with juxtavesical parts of the ureters that had been obtained from routine autopsies. As a result of the study, we showed that provided the pregnancy is uncomplicated there is no inherited susceptibility that would account for reducing or disturbing the development of ureterovesical junction elements. Based on the analysis of our results concerning the anatomy and morphological changes taking place in the elements of the ureterovesical junction in different age groups, one could put forward a hypothesis that anatomical predisposition to primary vesicoureteral reflux occurs in age group II, i.e. between 28 and 37 weeks of gestation. The parameters that define interrelations between elements of the ureterovesical junction and that are considered essential for normal functioning of antireflux mechanism were still observed in age group VI in our study. This suggests that these relations are not unambiguous in children with normally structured and functionally competent vesicoureteral junction. PMID- 29430698 TI - Benign cephalic histiocytosis: A case with infiltration of CD1a-positive langerin negative cells. PMID- 29430697 TI - Ethosuximide-induced Stevens-Johnson syndrome: Beneficial effect of early intervention with high-dose corticosteroid therapy. AB - We report two rare cases of childhood epilepsy patients who developed ethosuximide-induced Stevens-Johnson syndrome (SJS). Unlike typical SJS, the initial eruption of both patients presented well-demarcated, infiltrating firm papules mainly on the cheeks and the extensor aspects of the arms (case 1), and multiple vesicles on the soles and oral aphthosis (case 2), which closely mimicked viral exanthema. We diagnosed both patients with ethosuximide-induced SJS, based on the dosing period and the positive results of drug-induced lymphocyte stimulation test. Systemic corticosteroids are usually selected as a standard therapy for SJS, despite controversial results regarding their effectiveness. In case 1, an i.v. pulse therapy of methylprednisolone (30 mg/kg, 3 days consecutively) was initiated on day 7 from the onset of illness, and an i.v. immunoglobulin (400 mg/kg, 5 days consecutively) was added the following day. In case 2, an i.v. prednisone treatment (1 mg/kg, for 1 week) was initiated on day 4 from the onset. Eventually, the early therapeutic interventions resulted in good outcomes in both patients. PMID- 29430699 TI - Case of deep vein thrombosis in a patient with advanced malignant melanoma treated with dabrafenib and trametinib. PMID- 29430700 TI - A monoclonal antibody against SV40 large T antigen (PAb416) does not label Merkel cell carcinoma. AB - AIMS: Merkel cell carcinoma represents poorly differentiated neuroendocrine carcinoma of cutaneous origin. In most studies, the vast majority of Merkel cell carcinomas are Merkel cell polyomavirus (MCPyV)-associated. SV40 polyomavirus immunohistochemistry is typically used in the diagnosis of other polyomavirus associated diseases, including tubulointerstitial nephritis and progressive multifocal leukoencephalopathy, given cross-reactivity with BK and JC polyomaviruses. MCPyV-specific immunohistochemistry is commercially available, but, if antibodies against SV40 also cross-reacted with MCPyV, that would be advantageous from a resource-utilisation perspective. METHODS AND RESULTS: Tissue microarrays were constructed from 39 Merkel cell carcinomas, 24 small-cell lung carcinomas, and 18 extrapulmonary visceral small-cell carcinomas. SV40 large T antigen immunohistochemistry (clone PAb416) was performed; MCPyV large T antigen immunohistochemistry (clone CM2B4) had been previously performed. UniProt was used to compare the amino acid sequences of the SV40, BK, JC and MCPyV large T antigens, focusing on areas recognised by the PAb416 and CM2B4 clones. SV40 immunohistochemistry was negative in all tumours; MCPyV immunohistochemistry was positive in 38% of Merkel cell carcinomas and in 0% of non-cutaneous poorly differentiated neuroendocrine carcinomas. UniProt analysis revealed a high degree of similarity between SV40, BK, and JC viruses in the region recognised by PAb416. There was less homology between SV40 and MCPyV in this region, which was also interrupted by two long stretches of amino acids unique to MCPyV. The CM2B4 clone recognises a unique epitope in one of these stretches. CONCLUSIONS: The PAb416 antibody against the SV40 large T antigen does not cross-react with MCPyV large T antigen, and thus does not label Merkel cell carcinoma. PMID- 29430701 TI - Predictive value of the new renal response criteria in AL amyloidosis treated with high dose melphalan and stem cell transplantation. PMID- 29430702 TI - EDTA-related degranulation mimicking Storage Pool Disease. PMID- 29430703 TI - Prenatal diagnosis of Berry syndrome by fetal echocardiography: A report of four cases. AB - Berry syndrome is a rare congenital cardiac malformation. We describe 4 cases of Berry syndrome diagnosed by fetal echocardiography. Based on our experience, the three-vessel view is important for diagnosing the aortopulmonary window and aortic origin of the right pulmonary artery. Furthermore, the true cross sectional and sagittal views obtained by continuously scanning from the three vessel-trachea view to the long-axis view of the aortic arch are required to image the interruption or coarctation of the aortic arch. An early and accurate prenatal diagnosis of Berry syndrome is feasible and helps to improve patient outcomes. PMID- 29430704 TI - Malignant mesothelioma with squamous differentiation. AB - AIMS: We report the autopsy findings of a 58-year-old man with malignant mesothelioma in the left pleural cavity. METHODS AND RESULTS: The patient had a history of asbestos exposure, and the chest computed tomography scan on initial admission demonstrated an extrapleural sign, suggesting a nodular lesion in the chest wall. However, no nodular lesions were detectable in either of his lungs. In spite of chemotherapy, he died 4 months after the initial admission. An autopsy revealed markedly thickened pleura in a large section of the left pleural cavity without visible intrapulmonary primary tumour lesions. Histological examination of a biopsy specimen obtained prior to chemotherapy and that of an autopsy specimen showed that the pleural tumour was composed of a mixture of mesothelioma and tumour cells with squamous differentiation mimicking squamous cell carcinoma. CONCLUSIONS: To the best of our knowledge, this is the first case report of mesothelioma with extensive squamous differentiation in the English language literature. The extensive squamous differentiation reminiscent of squamous cell carcinoma can be a pitfall in the pathological diagnosis of pleural cytology and that of biopsy specimens from patients with mesothelioma. Here, we report autopsy findings of a case of malignant mesothelioma with portions of extensive squamous differentiation, mimicking a squamous cell carcinoma. PMID- 29430705 TI - Allergic contact dermatitis resulting from cetyl PEG/PPG-10/1 dimethicone in a deodorant cream. PMID- 29430706 TI - Photo-contact allergy to octocrylene: a decreasing trend? PMID- 29430707 TI - Lymphomatoid contact dermatitis caused by limonene hydroperoxides confirmed by an exposure provocation test with the involved personal hygiene products. PMID- 29430708 TI - Allergic contact dermatitis caused by topical ketoconazole: a relevant issue? Review of ketoconazole-positive patch tests. PMID- 29430709 TI - Spiramycin-related cutaneous eruption confirmed by patch testing. PMID- 29430710 TI - Possible role of regional variation in allergic contact dermatitis: case report. PMID- 29430711 TI - Methotrexate does not impede the development of contact allergy. PMID- 29430712 TI - Vulvar oedema. PMID- 29430713 TI - Spindle cell-predominant epithelioid fibrous histiocytoma. PMID- 29430714 TI - Concomitant lipomatous hypertrophy and left atrial mass: Distinguishing benign from malignant. AB - Masses in and near the interatrial septum may be either benign or malignant. The most common mass near the interatrial septum is lipomatous atrial septal hypertrophy (LASH). LASH can be present in patients with intracardiac malignancies, myxomas, lipomas, or other cardiac masses. It is important to recognize the transesophageal echocardiography (TEE) characteristics of these pathologies to arrive at an accurate diagnosis with an appropriate plan for intraoperative resection. At the authors' institution, patients have been referred for surgery due to a finding of significant LASH masquerading as a left atrial myxoma. In challenging cases, TEE offers a thorough evaluation of the interatrial septum to delineate between multiple intracardiac masses. PMID- 29430715 TI - Characterization and comparison of rat monosodium iodoacetate and medial meniscal tear models of osteoarthritic pain. AB - Osteoarthritis (OA) is a degenerative form of arthritis that can result in loss of joint function and chronic pain. The pathological pain state that develops with OA disease involves plastic changes in the peripheral and central nervous systems, however, the cellular mechanisms underlying OA are not fully understood. We characterized the medial meniscal tear (MMT) surgical model and the intra articular injection of monosodium iodoacetate (MIA) chemical model of OA in rats. Both models produced histological changes in the knee joint and associated bones consistent with OA pathology. Both models also increased p38 activation in the L3, but not L4 dorsal root ganglia (DRG), increased tyrosine hydroxylase immunostaining in the L3 DRG indicating sympathetic sprouting, and increased phosphorylated (p)CREB in thalamic neurons. In MIA-OA, but not MMT-OA rats, p38 and pERK were increased in the spinal cord, and pCREB was enhanced in the prefrontal cortex. Using in vivo electrophysiology, elevated spontaneous activity and increased responsiveness of wide dynamic range neurons to stimulation of the knee was found in both models. However, a more widespread sensitization was observed in the MIA-OA rats as neurons with paw receptive fields spontaneously fired at a greater rate in MIA-OA than MMT-OA rats. Taken together, the MIA and MMT models of OA share several common features associated with histopathology and sensitization of primary somatosensory pathways, but, observed differences between the models highlights unique consequences of the related specific injuries, and these differences should be considered when choosing an OA model and when interpreting data outcomes. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 29430716 TI - Imoxin attenuates high fructose-induced oxidative stress and apoptosis in renal epithelial cells via downregulation of protein kinase R pathway. AB - Double-stranded RNA (dsRNA)-activated protein kinase R (PKR), a ubiquitously expressed serine/threonine kinase, is a key inducer of inflammation, insulin resistance, and glucose homeostasis in obesity. Recent studies have demonstrated that PKR can respond to metabolic stress in mice as well as in humans. However, the underlying molecular mechanism is not fully understood. The aim of this study was to examine the effect of high fructose (HF) in cultured renal tubular epithelial cells (NRK-52E) derived from rat kidney and to investigate whether inhibition of PKR could prevent any deleterious effects of HF in these cells. PKR expression was determined by immunofluorescence staining and Western blotting. Oxidative damage and apoptosis were measured by flow cytometry. HF-treated renal cells developed a significant increase in PKR expression. A significant increase in reactive oxygen species generation and apoptosis was also observed in HF treated cultured renal epithelial cells. All these effects of HF were attenuated by a selective PKR inhibitor, imoxin (C16). In conclusion, our study demonstrates PKR induces oxidative stress and apoptosis, is a significant contributor involved in vascular complications and is a possible mediator of HF-induced hypertension. Inhibition of PKR pathway can be used as a therapeutic strategy for the treatment of cardiovascular and metabolic disorders. PMID- 29430717 TI - Cutaneous infiltration of plasmacytoid dendritic cells and T regulatory cells in skin lesions of polymorphic light eruption. AB - BACKGROUND: Polymorphic light eruption (PLE) is the most common autoimmune photodermatosis. Plasmacytoid dendritic cells (PDCs) are important mediators of innate antimicrobial immunity involved in the pathogenesis of many inflammatory skin diseases. In addition to PDCs, regulatory T cells (Tregs) are involved in controlling inflammation and adaptive immunity in skin by their immunosuppressive capacity. OBJECTIVE: The aim of this study was to investigate the presence of PDCs and Tregs in photoexposed skin from PLE compared to healthy skin. METHODS: Patients with PLE diagnosis and healthy controls were recruited and underwent a photoprovocative test. A 4-mm punch biopsy was taken from the site of positive photoprovocation test reaction, and immunohistochemistry for BDCA2 as marker for PDCs, CD4 and FOXP3 as markers for Tregs was performed. Double immunostain for FOXP3 and CD4 was performed as well. Absolute counts for CD4, BDCA2 and FOXP3 were performed in at least 5 High Power Fields (HPF). Percentage of CD4-, BDCA2- and CD4FOXP3-positive cells over the total inflammatory infiltrate was assessed for each case. RESULTS: We enrolled 23 patients and controls. BDCA2+ cells were present in 91.3% of PLE skin samples and 100% of healthy volunteer. Both in PLE patients and healthy controls, PDCs distribution was mainly dermic (P < 0.05). Compared to healthy controls, both epidermic and dermic BDCA2+ cells count were significantly higher in PLE patients (P < 0.05). Both in PLE patients and healthy controls, Tregs distribution was mainly dermic (P < 0.05). The presence of both CD4+ cells and FOXP3+ cells was significantly higher in the dermis of PLE patients compared to controls (P < 0.05). Relative percentages of cellular infiltrations confirmed these results. CONCLUSIONS: D-PDCS and Tregs may play a significant role in the development of PLE, and dermal distribution of PDCs in PLE skin biopsies seems to confirm a possible overlap with cutaneous lupus erythematosus (CLE). PMID- 29430718 TI - Renal fungus ball in a patient with retroperitoneal fibrosis: Unique complication in a rare disease. AB - Candida fungus ball is a rare presentation of urinary tract infections among adult patients and is associated with considerable morbidity. Because clinical signs are not specific, diagnosis is often delayed. Furthermore, treatment is occasionally difficult, and the approach to such cases varies widely among different centers. In this report, we describe a patient with retroperitoneal fibrosis who developed a renal fungus ball. Management of this challenging case is discussed, and review of the literature is presented. PMID- 29430719 TI - Focal facial hyperhidrosis associated with internal carotid artery dissection successfully treated with botulinum toxin A. PMID- 29430720 TI - Psoriatic arthritis screening by the dermatologist: development and first validation of the 'PURE-4 scale'. AB - BACKGROUND: Dermatologists are recommended to ask psoriasis patients about musculoskeletal complaints to allow early detection and treatment of psoriatic arthritis (PsA). Screening tools have been developed to help identify patients warranting further rheumatologic assessment, but evidence suggests room for improvement in their diagnostic value and ease of use for outpatient practice. OBJECTIVE: To develop and internally validate a brief tool for dermatologists to screen patients to refer to a rheumatologist for PsA diagnosis. METHODS: After the literature review, 23 items were selected, covering pain at various locations and inflammatory signs of PsA. The validation study was conducted in medically diagnosed psoriasis patients consecutively recruited between 2012 and 2014 (Saint Joseph Hospital, Paris, France). Patients were enrolled by a dermatologist who helped to complete the questionnaire. Diagnosis of PsA was established by a rheumatologist based on CASPAR criteria. Multivariate logistic regression models were performed to build the scale, assessing discrimination through sensitivity, specificity and area under the ROC curve (AUC). Final model was internally validated using bootstrapping techniques. RESULTS: One hundred and sixty-eight patients were recruited, of whom nine were excluded for known PsA and 21 did not attend the rheumatologist consultation. Of 137 included patients (median age 43 years, 59.6% men), 21 (15.3%) had a PsA diagnosis. Final regression model retained four independent items, including evocative signs of dactylitis, inflammatory heel pain, bilateral buttock pain and peripheral joint pain with swelling in patients aged <50. A total score (the PURE-4) was computed (0-4 points) that demonstrated excellent discriminative power (AUC = 87.6%; Sensitivity = 85.7% and Specificity = 83.6% at the threshold of >=1/4 points), with no evidence for over-optimism in bootstrapped internal validation. CONCLUSION: These findings demonstrate the good diagnostic properties of a new screening scale using only four easy-to-collect items. If confirmed in other populations, it may prove useful in outpatient dermatology clinics for triage of psoriasis patients requiring further assessment by the rheumatologist. PMID- 29430721 TI - Association of the NOD-like receptor 3 (NLRP3) gene variability with recurrent aphthous stomatitis in the Czech population. AB - BACKGROUND: Recurrent aphthous stomatitis (RAS) is a multifactorial disease with unclear etiopathogenesis in which disturbance of immunological processes may be involved. The aim of our study was to investigate three single nucleotide polymorphisms (SNPs) rs3806265, rs4612666, rs10754558 in NOD-like receptor 3 (NLRP3), the gene encoding the component of inflammasome, in patients with RAS and healthy controls in the Czech population. METHODS: A total of 207 subjects were included in this case-control study. Sixty-four patients with RAS and 143 healthy controls were genotyped by a method based on polymerase chain reaction using 5' nuclease TaqMan(r) assays. Detailed anamnestic, clinical, and laboratory data were obtained from all subjects. RESULTS: The allele and genotype frequencies of NLRP3 polymorphisms (rs10754558 and rs3806265) between both groups were similar. However, statistically significant differences in NLRP3 rs4612666 genotypes between the patients with RAS and controls were found; carriers of the TT genotype had a higher risk of developing RAS than subjects with the CT+CC genotypes (OR = 14.69, 95%CI = 1.73-124.72, P = .004, Pcorr < .05). No associations between NLRP3 haplotypes and RAS were observed. CONCLUSIONS: Our study indicates that the NLRP3 rs4612666 polymorphism may be involved in the development of RAS in the Czech population. PMID- 29430722 TI - Patients affected by dent disease 2 could be predisposed to hidradenitis suppurativa. PMID- 29430723 TI - Artisanal tanneries: Potential application of inoculants formulated with lactic acid bacteria. AB - In artisanal tanneries, the skins are immersed in cereals fermented by natural microbial flora in order to reduce the pH of the skin, an essential condition for carrying out the final step. The environmental thermal variation alters the fermentation process and affects the quality of the final product. The aim of this work was to isolate lactic acid bacteria from cereals mixture fermented in an artisanal tannery and to evaluate in vitro the acidifying activity of the strains as a first step for the formulation of a starter culture. In most samples, a prevalence of cocci (95%) was observed with respect to bacilli. The best acidifying strains were identified by phenotypic and genotypic techniques as Enterococcus faecium CRL 1943 (rapid acidification at 37 degrees C) and Leuconostoc citreum CRL 1945 (high acidifying activity at 18 degrees C). In addition, the biomass production of the selected strains was analyzed at free and controlled pH (bioreactors 1.5 L). The production of biomass was optimal at controlled pH, with a higher growth (0.5-1.1 log units). Both strains were compatible, allowing their inclusion in a mixed culture. These lactic strains could contribute to the systematization of the tanning process. PMID- 29430724 TI - Dermoscopic features of tungiasis. PMID- 29430725 TI - Engineered Living Materials: Prospects and Challenges for Using Biological Systems to Direct the Assembly of Smart Materials. AB - Vast potential exists for the development of novel, engineered platforms that manipulate biology for the production of programmed advanced materials. Such systems would possess the autonomous, adaptive, and self-healing characteristics of living organisms, but would be engineered with the goal of assembling bulk materials with designer physicochemical or mechanical properties, across multiple length scales. Early efforts toward such engineered living materials (ELMs) are reviewed here, with an emphasis on engineered bacterial systems, living composite materials which integrate inorganic components, successful examples of large scale implementation, and production methods. In addition, a conceptual exploration of the fundamental criteria of ELM technology and its future challenges is presented. Cradled within the rich intersection of synthetic biology and self-assembling materials, the development of ELM technologies allows the power of biology to be leveraged to grow complex structures and objects using a palette of bio-nanomaterials. PMID- 29430726 TI - Comparison of L-selectin blood level and gene polymorphism in tuberculosis patients with healthy individuals. AB - BACKGROUND: The inflammatory response to Mycobacterium tuberculosis bacilli influences tuberculosis (TB) progression. In this study, we aimed to identify the Phe206Leu polymorphism and serum L-selectin level in TB patients, compared to healthy individuals. METHODS: Ninety patients with a diagnosis of TB and 90 healthy controls were selected in this study. The serum L-selectin level was determined, using ELISA. L-selectin polymorphism was also evaluated using PCR. For data analysis, SPSS was used at a significance level of 0.05. RESULTS: According to the findings, the mean+/-SD age of the participants was 57.5 +/- 18.4 and 56.5 +/- 17.5 years in the TB and healthy groups, respectively. The TB group showed a significantly higher serum L-selectin level (1721.1 +/- 330.9) versus the healthy controls (1624 +/- 279). The L-selectin Phe allele frequencies were higher than the Leu allele frequencies in the main population, whereas the patients and controls were not significantly different. Eight (0.04%) subjects had Leu/Leu genotypes, 84 (46.6%) carried Phe/Leu genotypes, and 88 (48.8%) had Phe/Phe genotypes. Our results showed that the groups were not significantly different regarding L-selectin genotypes. CONCLUSION: TB patients had a significantly higher serum L-selectin level, compared to the controls. Based on the findings, the incidence of TB and L-selectin polymorphism in the Phe206Leu gene had no significant association. PMID- 29430727 TI - The Sda and Cad glycan antigens and their glycosyltransferase, beta1,4GalNAcT-II, in xenotransplantation. AB - Antibody-mediated rejection is a barrier to the clinical application of xenotransplantation, and xenoantigens play an important role in this process. Early research suggested that N-acetyl-D-galactosamine (GalNAc) could serve as a potential xenoantigen. GalNAc is the immunodominant glycan of the Sda antigen. Recently, knockout of beta1,4-N-acetylgalactosaminyltransferase 2 (beta1,4GalNAcT II) from the pig results in a decrease in binding of human serum antibodies to pig cells. It is believed that this is the result of the elimination of the GalNAc on the Sda antigen, which is catalyzed by the enzyme, beta1,4GalNAcT-II. However, research into human blood group antigens suggests that only a small percentage (1%-2%) of people express anti-Sda antibodies directed to Sda antigen, and yet a majority appear to have antibodies directed to the products of pig B4GALNT2. Questions can therefore be asked as to (i) whether the comprehensive structure of the Sda antigen in humans, that is, the underlying sugar structure, is identical to the Sda antigen in pigs, (ii) whether the human anti-Sda antibody binds ubiquitously to pig cells, but not to human cells, and (iii) what role the Sda++ (also called Cad) antigen is playing in this discrepancy. We review what is known about these antigens and discuss the discrepancies that have been noted above. PMID- 29430728 TI - Plasma CXCL1 levels and TRAF3IP2 variants in patients with myocardial infarction. AB - BACKGROUND: IL-17A plays an important role in inflammatory responses in myocardial infarction (MI). IL-17A signals through its receptor, for which, Act1 (TRAF3IP2) functions as a key upstream adaptor in the pathway. AIM: To compare frequencies of functional polymorphisms of TRAF3IP2 (rs13210247, rs33980500) between patients with MI and healthy controls. METHODS: The selected SNPs were studied in 201 Iranian MI patients and 201 healthy blood donors from Fars Province by PCR-RFLP in association with clinicopathologic criteria of patients. CXCL1 plasma levels in 126 MI patients and 50 normal subjects were measured by ELISA. RESULTS: A significant increase in the mutant (T) allele of TRAF3IP2 rs33980500 in patients with diastolic dysfunction of the heart (P = .01) was observed. The highest correlation, however, was observed between the TRAF3IP2 rs33980500 TT genotype and T allele with left main coronary artery stenosis (P = .01, P < .001; OR = 31.03). T allele of TRAF3IP2 rs33980500 was also associated with female gender, family history of cardiovascular disease, and mechanical complications of heart (P = .04, P = .02, and P = .01, respectively). Moreover, TRAF3IP2 rs13210247 (G) correlated with mechanical complications of the heart (P = .01). A significant increase in the plasma levels of CXCL1 chemokine in patients (P = .0006) associated with TT genotype of TRAF3IP2 (rs33980500) was observed (P = .04). CONCLUSION: The gene variants of Act1 adaptor are associated with correlates of poor outcome in patients with MI and plasma CXCL1 levels. PMID- 29430729 TI - Beyond catharsis: the nuanced emotion of patient storytellers in an educational role. AB - CONTEXT: As health care organisations seek to cultivate patient and family centred care, patient storytelling has emerged as a valued educational resource. However, repeatedly harnessing patient perspectives to educate health care professionals may have consequences. We need robust insight into what it means to be a patient storyteller in order to ensure ethical and appropriate engagement with patients as an educational resource. METHODS: Constructivist grounded theory was used to explore the experience of patients involved in a storytelling curriculum as part of hospital staff continuing education. All 33 storytellers were invited by e-mail to participate in the study. Twenty-six storytellers responded to the invitation, and 25 could be scheduled to participate. Using theoretical sampling, semi-structured interviews were conducted and analysed in a process that was inductive, iterative and comparative. RESULTS: Participants described the central role of emotions in their storytelling experience, which varied from 1 to 25 tellings over a period of 1 month to 2 years. These emotions were shaped by the passage of time, repetition of storytelling and audience acknowledgement. However, emotion remained unpredictable and had lingering implications for storytellers' vulnerability. CONCLUSION: The multiple storytelling experiences of our participants and ongoing educational nature of their role provides unique insight into how emotions ebb and flow across tellings, how emotions can be both a surprise and a rhetorical strategy, and how emotions are influenced by audience acknowledgement. These findings contribute to an emerging conversation regarding the power and politics of selecting and using storytellers for organisational purpose. Implications include how we support patient storytellers in educational roles and how we can sustainably integrate patient storytelling into health professional education. PMID- 29430730 TI - Cerebral ischemia during hemodialysis-finding the signal in the noise. AB - Hemodialysis patients have multiple risk factors for small vessel cerebrovascular disease and cognitive dysfunction. Hemodialysis itself may cause clinically significant neurological injury through repetitive cerebral ischemia. However, supporting evidence to date consists of epidemiological associations, expert opinion, and small, single-centre studies of variable methodological quality. Isolating the impact of intra-dialytic hemodynamic instability from underlying renal and vascular disease on clinically relevant functional outcomes would require very large, controlled studies, given the heterogeneity and confounding comorbidities of the population, and the complex relationship between blood pressure and cerebral oxygen delivery. There has been an increase in complementary physiological studies looking directly at intra-dialytic cerebral oxygen balance, which have provided supporting evidence for the occurrence of cerebral ischemia, often independently of hemodynamics. Data suggesting a relationship between these measures of oxygen balance and functional outcomes is only hypothesis-generating at this stage. We advocate the testing of interventions that aim to reduce intra-dialytic cerebral hypoxia (rather than hypotension) in sufficiently powered studies, followed by correlation with validated, longitudinal assessment of clinically relevant neurological damage. PMID- 29430731 TI - Rapid improvement of psoriasis in a patient with lung cancer after treatment with erlotinib. PMID- 29430732 TI - Stable Metal-Organic Frameworks: Design, Synthesis, and Applications. AB - Metal-organic frameworks (MOFs) are an emerging class of porous materials with potential applications in gas storage, separations, catalysis, and chemical sensing. Despite numerous advantages, applications of many MOFs are ultimately limited by their stability under harsh conditions. Herein, the recent advances in the field of stable MOFs, covering the fundamental mechanisms of MOF stability, design, and synthesis of stable MOF architectures, and their latest applications are reviewed. First, key factors that affect MOF stability under certain chemical environments are introduced to guide the design of robust structures. This is followed by a short review of synthetic strategies of stable MOFs including modulated synthesis and postsynthetic modifications. Based on the fundamentals of MOF stability, stable MOFs are classified into two categories: high-valency metal carboxylate frameworks and low-valency metal-azolate frameworks. Along this line, some representative stable MOFs are introduced, their structures are described, and their properties are briefly discussed. The expanded applications of stable MOFs in Lewis/Bronsted acid catalysis, redox catalysis, photocatalysis, electrocatalysis, gas storage, and sensing are highlighted. Overall, this review is expected to guide the design of stable MOFs by providing insights into existing structures, which could lead to the discovery and development of more advanced functional materials. PMID- 29430733 TI - The relationship between clinical characteristics including presence of exposed lesions and health-related quality of life (HRQoL) in patients with psoriasis: analysis from the nationwide epidemiologic study for psoriasis in Korea (EPI PSODE study). AB - BACKGROUND: Psychological aspect and quality of life should be considered in treating patients with psoriasis. OBJECTIVE: We sought to ascertain which clinical characteristics including presence of exposed lesions are associated with impairment of health-related quality of life (HRQoL) in patients with psoriasis. METHODS: The EPI-PSODE study was a nationwide, multicenter, cross sectional study conducted in Korea that included 1260 adult patients with psoriasis. In addition to clinical characteristics including presence of exposed lesions, data were collected using the Psoriatic Arthritis (PsA) Screening and Evaluation (PASE), Dermatology Life Quality Index (DLQI), MOS 36-Item Short-Form Health Survey (SF-36), Work Productivity and Activity Impairment Questionnaire Psoriasis (WPAI: PSO) and Medication Satisfaction Questionnaire (MSQ). RESULTS: Patients with a DLQI score > 5 (n = 990) were younger, had an earlier onset of psoriasis, scored higher on the Psoriasis Area and Severity Index (PASI), had higher body surface area (BSA) and had higher PASE scores than patients with DLQI <= 5 (n = 266). The group of patients with exposed lesions (n = 871) were younger and male predominance, earlier onset of psoriasis, longer disease duration, higher PASI/BSA score and a higher proportion with drinking and smoking history each than the group of patients without exposed lesions (n = 389). Presence of exposed lesions negatively influenced DLQI, 36-Item Short-Form Health Survey (SF 36) (mental component), presenteeism, total work productivity impairment and total activity impairment in the WPAI: PSO. In multiple regression model, PASI score was the only variable which was significantly associated with all HRQoL measures. Presence of exposed lesions was a significant factor affecting DLQI and SF-36 (mental). CONCLUSION: The presence of exposed lesions has a negative impact on quality of life, mental health and work productivity. Therefore, effective treatments are particularly needed for psoriasis patients with exposed lesions. PMID- 29430734 TI - GABA- and serotonin-expressing neurons take part in inhibitory as well as excitatory input pathways to the circadian clock of the Madeira cockroach Rhyparobia maderae. AB - In the Madeira cockroach, pigment-dispersing factor-immunoreactive (PDF-ir) neurons innervating the circadian clock, the accessory medulla (AME) in the brain's optic lobes, control circadian behaviour. Circadian activity rhythms are entrained to daily light-dark cycles only by compound eye photoreceptors terminating in the lamina and medulla. Still, it is unknown which neurons connect the photoreceptors to the clock to allow for light entrainment. Here, we characterized by multiple-label immunocytochemistry the serotonin (5-HT)-ir anterior fibre fan and GABA-ir pathways connecting the AME- and optic lobe neuropils. Colocalization of 5-HT with PDF was confirmed in PDF-ir lamina neurons (PDFLAs). Double-labelled fibres were traced to the AME originating from colabelled PDFLAs branching in accessory laminae and proximal lamina. The newly discovered GABA-ir medial layer fibre tract connected the AME to the medulla's medial layer fibre system, and the distal tract fibres connected the AME to the medulla. With Ca2+ imaging on primary cell cultures of the AME and with loose patch-clamp recordings in vivo, we showed that both neurotransmitters either excite or inhibit AME clock neurons. Because we found no colocalization of GABA and 5-HT in any optic lobe neuron, GABA- and 5-HT neurons form separate clock input circuits. Among others, both pathways converged also on AME neurons that coexpressed mostly inhibitory GABA- and excitatory 5-HT receptors. Our physiological and immunocytochemical studies demonstrate that GABA- and 5-HT immunoreactive neurons constitute parallel excitatory or inhibitory pathways connecting the circadian clock either to the lamina or medulla where photic information from the compound eye is processed. PMID- 29430736 TI - Probing the limits of alpha power lateralisation as a neural marker of selective attention in middle-aged and older listeners. AB - In recent years, hemispheric lateralisation of alpha power has emerged as a neural mechanism thought to underpin spatial attention across sensory modalities. Yet, how healthy ageing, beginning in middle adulthood, impacts the modulation of lateralised alpha power supporting auditory attention remains poorly understood. In the current electroencephalography study, middle-aged and older adults (N = 29; ~40-70 years) performed a dichotic listening task that simulates a challenging, multitalker scenario. We examined the extent to which the modulation of 8-12 Hz alpha power would serve as neural marker of listening success across age. With respect to the increase in interindividual variability with age, we examined an extensive battery of behavioural, perceptual and neural measures. Similar to findings on younger adults, middle-aged and older listeners' auditory spatial attention induced robust lateralisation of alpha power, which synchronised with the speech rate. Notably, the observed relationship between this alpha lateralisation and task performance did not co-vary with age. Instead, task performance was strongly related to an individual's attentional and working memory capacity. Multivariate analyses revealed a separation of neural and behavioural variables independent of age. Our results suggest that in age-varying samples as the present one, the lateralisation of alpha power is neither a sufficient nor necessary neural strategy for an individual's auditory spatial attention, as higher age might come with increased use of alternative, compensatory mechanisms. Our findings emphasise that explaining interindividual variability will be key to understanding the role of alpha oscillations in auditory attention in the ageing listener. PMID- 29430735 TI - Reassembly of 89 Zr-Labeled Cancer Cell Membranes into Multicompartment Membrane Derived Liposomes for PET-Trackable Tumor-Targeted Theranostics. AB - Nanoengineering of cell membranes holds great potential to revolutionize tumor targeted theranostics, owing to their innate biocompatibility and ability to escape from the immune and reticuloendothelial systems. However, tailoring and integrating cell membranes with drug and imaging agents into one versatile nanoparticle are still challenging. Here, multicompartment membrane-derived liposomes (MCLs) are developed by reassembling cancer cell membranes with Tween 80, and are used to conjugate 89 Zr via deferoxamine chelator and load tetrakis(4 carboxyphenyl) porphyrin for in vivo noninvasive quantitative tracing by positron emission tomography imaging and photodynamic therapy (PDT), respectively. Radiolabeled constructs, 89 Zr-Df-MCLs, demonstrate excellent radiochemical stability in vivo, target 4T1 tumors by the enhanced permeability and retention effect, and are retained long-term for efficient and effective PDT while clearing gradually from the reticuloendothelial system via hepatobiliary excretion. Toxicity evaluation confirms that the MCLs do not impose acute or chronic toxicity in intravenously injected mice. Additionally, 89 Zr-labeled MCLs can execute rapid and highly sensitive lymph node mapping, even for deep-seated sentinel lymph nodes. The as-developed cell membrane reassembling route to MCLs could be extended to other cell types, providing a versatile platform for disease theranostics by facilely and efficiently integrating various multifunctional agents. PMID- 29430737 TI - Binary FeCo Oxyhydroxide Nanosheets as Highly Efficient Bifunctional Electrocatalysts for Overall Water Splitting. AB - Bifunctional catalysts that are highly active toward both the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) are attractive for efficient electrochemical water splitting. Herein, we report a bifunctional FeCoOOH nanosheet catalyst for highly efficient electrochemical water splitting in an alkaline electrolyte. The FeCoOOH nanosheet arrays were grown directly on the surface of a porous Ni foam by using a simple hydrothermal method. Because of their binary oxyhydroxide structure and high electrical conductivity intrinsic to direct growth, these FeCoOOH nanosheets exhibited excellent activities toward both the HER and OER. With the use of this bifunctional FeCoOOH catalyst, an alkaline water electrolyzer in a two-electrode configuration achieved 10 mA cm-2 only at a cell voltage of 1.62 V without iR compensation in 1 m KOH, which outperformed that based on the combination of commercial IrO2 and Pt/C catalysts. PMID- 29430738 TI - Neonatal adoptive transfer of lymphocytes rescues social behaviour during adolescence in immune-deficient mice. AB - Accumulating evidence has shown that lymphocytes modulate behaviour and cognition by direct interactions with the central nervous system. Studies have shown that reconstitution by adoptive transfer of lymphocytes from wild type into immune deficient mice restores a number of neurobehavioural deficits observed in these models. Moreover, it has been shown that these effects are mostly mediated by T lymphocytes. Studies of adoptive transfer thus far have employed adult mice, but whether lymphocytes may also modulate behaviour during development remains unknown. In this study, neonate lymphocyte-deficient Rag2-/- mice were reconstituted within 48 hours after birth with lymphoid cells from transgenic donors expressing green fluorescent protein, allowing for their identification in various tissues in recipient mice while retaining all functional aspects. Adolescent Rag2-/- and reconstituted Rag2-/- along with C57BL/6J wild-type mice underwent a series of behavioural tests, including open field, social interaction and sucrose preference tests. At 12 weeks, they were evaluated in the Morris water maze (MWM). Reconstituted mice showed changes in almost all aspects of behaviour that were assessed, with a remarkable complete rescue of impaired social behaviour displayed by adolescent Rag2-/- mice. Consistent with previous reports in adult mice, neonatal reconstitution in Rag2-/- mice restored spatial memory in the MWM. The presence of donor lymphocytes in the brain of neonatally reconstituted Rag2-/- mice was confirmed at various developmental points. These findings provide evidence that lymphocytes colonize the brain during post-natal development and modulate behaviour across the lifespan supporting a role for adaptive immunity during brain maturation. PMID- 29430739 TI - Racial disparities in kidney transplant waitlist appearance in Chicago: Is it race or place? AB - BACKGROUND: Prior work has demonstrated how neighborhood poverty and racial composition impact racial disparities in access to the deceased donor kidney transplant waitlist, both nationally and regionally. We examined the association between neighborhood characteristics and racial disparities in time to transplant waitlist in Chicago, a diverse city with continued neighborhood segregation. METHODS: Using data from the United States Renal Data System (USRDS) and the US Census, we investigated time from dialysis initiation to kidney transplant waitlisting for African American and white patients in Chicago using cause specific proportional hazards analyses, adjusting for individual sociodemographic and clinical characteristics, as well as neighborhood poverty and racial composition. RESULTS: In Chicago, African Americans are significantly less likely than whites to appear on the renal transplant waitlist (HR 0.73, P < .05). Compared to whites in nonpoor neighborhoods, African Americans in poor neighborhoods are significantly less likely to appear on the transplant waitlist (HR 0.61, P < .05). Over 69% of African Americans with ESRD live in these neighborhoods. CONCLUSIONS: Consistent with national data, African Americans in Chicago have a lower likelihood of waitlisting than whites. This disparity is explained in part by neighborhood poverty, which impacts the majority of African American ESRD patients in Chicago. PMID- 29430740 TI - Synthesis of Terminal Vinylindoles via RhIII -Catalyzed Direct C-H Alkenylation with Potassium Vinyltrifluoroborate. AB - An efficient RhIII -catalyzed direct C2-alkenylation of indoles using readily available potassium vinyltrifluoroborate under mild conditions has been developed. This protocol features wide substrate scope and excellent functional group compatibility, enabling a facile access to diverse terminal vinylindoles in moderate to good yields. Furthermore, the C2-alkenylated indole can be easily transformed into 9H-carbazole through a ring-closing metathesis/aromatization cascade. PMID- 29430741 TI - Childhood Sexual Abuse and Suicidal Ideation Among Bipolar Patients: Existential But Not Religious Well-Being as a Protective Factor. AB - Individuals diagnosed with bipolar disorder (BD) are at an increased risk of Suicidal ideation, attempts, and death. Moreover, a strong association exists between childhood sexual abuse (CSA) and suicidal ideation among individuals with BD. Yet growing evidence suggests that existential well-being (EWB) may be a protective factor against suicidality. In this study, adult BD patients (N = 112) provided data on CSA, religious well-being (RWB; spiritual life in relation to God), EWB (purpose/meaning in life), and suicidal ideation. Participants were between 19 and 65 years of age. The majority was female and described their race/ethnicity as African American. Results indicated that CSA was negatively associated with EWB and was not related to RWB. Further, EWB mediated the association between CSA and suicidal ideation, whereas RWB did not. Having meaning/purpose in life may serve as a protective factor against suicidal ideation among individuals with BD who experienced CSA, whereas having a relationship/belief in God may not serve the same function. PMID- 29430742 TI - Probing Magnetic-Exchange Coupling in Supramolecular Squares Based on Reducible Tetrazine-Derived Ligands. AB - Reducible 3,6-bis(3,5-dimethyl-pyrazolyl)1,2,4,5-tetrazine was employed to isolate supramolecular air-stable [Co4 ] and [Zn4 ] squares, which were achieved via careful selection of counterions rather than the use of reducing agents. Magnetic susceptibility studies revealed a strong radical-CoII exchange coupling (Jrad-Co /hc=-118 cm-1 , -2J formalism) with a spin ground state of ST =4, whereas the unreduced analogue revealed negligible coupling between the Co centers (JCo-Co /hc=-0.64 cm-1 ). Radical-radical coupling was also probed in the [Zn4 ] congener, which led to Jrad-rad /hc=-15.9(5) cm-1 . These results highlight the versatile air-stable coordination chemistry of tetrazine and the importance of exploiting easily reducible delocalized radical to promote strong exchange coupling between spin carriers. PMID- 29430743 TI - Primed Conversion: The New Kid on the Block for Photoconversion. AB - In 2015, a novel way to convert photoconvertible fluorescent proteins was reported that uses the intercept of blue and far-red light instead of traditional violet or near-UV light illumination. This Minireview describes and contrasts this distinct two-step mechanism termed primed conversion with traditional photoconversion. We provide a comprehensive overview of what is known to date about primed conversion and focus on the molecular requirements for it to take place. We provide examples of its application to axially confined photoconversion in complex tissues as well as super-resolution microscopy. Further, we describe why and when it is useful, including its advantages and disadvantages, and give an insight into potential future development in the field. PMID- 29430744 TI - Rapid discrimination of different Apiaceae species based on HPTLC fingerprints and targeted flavonoids determination using multivariate image analysis. AB - INTRODUCTION: Species of Apiaceae are used in folk medicine as spices and in officinal medicinal preparations of drugs. They are an excellent source of phenolics exhibiting antioxidant activity, which are of great benefit to human health. Discrimination among Apiaceae medicinal herbs remains an intricate challenge due to their morphological similarity. OBJECTIVE: In this study, a combined "untargeted" and "targeted" approach to investigate different Apiaceae plants species was proposed by using the merging of high-performance thin layer chromatography (HPTLC)-image analysis and pattern recognition methods which were used for fingerprinting and classification of 42 different Apiaceae samples collected from Egypt. METHODOLOGY: Software for image processing was applied for fingerprinting and data acquisition. HPTLC fingerprint assisted by principal component analysis (PCA) and hierarchical cluster analysis (HCA)-heat maps resulted in a reliable untargeted approach for discrimination and classification of different samples. The "targeted" approach was performed by developing and validating an HPTLC method allowing the quantification of eight flavonoids. RESULTS: The combination of quantitative data with PCA and HCA-heat-maps allowed the different samples to be discriminated from each other. CONCLUSION: The use of chemometrics tools for evaluation of fingerprints reduced expense and analysis time. The proposed method can be adopted for routine discrimination and evaluation of the phytochemical variability in different Apiaceae species extracts. PMID- 29430745 TI - Liquid-Crystalline Dynamic Networks Doped with Gold Nanorods Showing Enhanced Photocontrol of Actuation. AB - A near-infrared-light (NIR)- and UV-light-responsive polymer nanocomposite is synthesized by doping polymer-grafted gold nanorods into azobenzene liquid crystalline dynamic networks (AuNR-ALCNs). The effects of the two different photoresponsive mechanisms, i.e., the photochemical reaction of azobenzene and the photothermal effect from the surface plasmon resonance of the AuNRs, are investigated by monitoring both the NIR- and UV-light-induced contraction forces of the oriented AuNR-ALCNs. By taking advantage of the material's easy processability, bilayer-structured actuators can be fabricated to display photocontrollable bending/unbending directions, as well as localized actuations through programmed alignment of azobenzene mesogens in selected regions. Versatile and complex motions enabled by the enhanced photocontrol of actuation are demonstrated, including plastic "athletes" that can execute light-controlled push-ups or sit-ups, and a light-driven caterpillar-inspired walker that can crawl forward on a ratcheted substrate at a speed of about 13 mm min-1 . Moreover, the photomechanical effects arising from the two types of light triggered molecular motion, i.e., the trans-cis photoisomerization and a liquid crystalline-isotropic phase transition of the azobenzene mesogens, are added up to design a polymer "crane" that is capable of performing light-controlled, robot like, concerted macroscopic motions including grasping, lifting up, lowering down, and releasing an object. PMID- 29430746 TI - Reversible and Precisely Controllable p/n-Type Doping of MoTe2 Transistors through Electrothermal Doping. AB - Precisely controllable and reversible p/n-type electronic doping of molybdenum ditelluride (MoTe2 ) transistors is achieved by electrothermal doping (E-doping) processes. E-doping includes electrothermal annealing induced by an electric field in a vacuum chamber, which results in electron (n-type) doping and exposure to air, which induces hole (p-type) doping. The doping arises from the interaction between oxygen molecules or water vapor and defects of tellurium at the MoTe2 surface, and allows the accurate manipulation of p/n-type electrical doping of MoTe2 transistors. Because no dopant or special gas is used in the E doping processes of MoTe2 , E-doping is a simple and efficient method. Moreover, through exact manipulation of p/n-type doping of MoTe2 transistors, quasi complementary metal oxide semiconductor adaptive logic circuits, such as an inverter, not or gate, and not and gate, are successfully fabricated. The simple method, E-doping, adopted in obtaining p/n-type doping of MoTe2 transistors undoubtedly has provided an approach to create the electronic devices with desired performance. PMID- 29430747 TI - Left atrial rather than left ventricular impaired mechanics are associated with the pro-fibrotic ST2 marker and outcomes in heart failure with preserved ejection fraction. AB - AIMS: Left ventricular (LV) mechanics have been extensively investigated in heart failure with preserved ejection fraction (HFpEF) overshadowing for a long time the potential role of left atrium (LA) in that setting. Soluble suppression of tumorigenicity-2 receptor (ST2) is a novel biomarker of pro-fibrotic burden in HF. We hypothesized that due to the thinner LA wall, the fibrotic myocardial changes in HFpEF as indicated by elevated ST2 levels might more readily be reflected by impairments in the LA rather than the LV performance. METHODS AND RESULTS: In 86 patients with HFpEF, enrolled in the Karolinska Rennes (KaRen) biomarker prospective substudy, global LA strain (GL-LS) along with other echocardiographic as well as haemodynamic parameters and ST2 levels were measured. ST2 levels were inversely associated with LA-GS (r = -0.30, P = 0.009), but not with LA size, LV geometry, systolic or diastolic LV function (P > 0.05 for all). Furthermore, symptom severity correlated with ST2 and LA-GS, but not with LV structural or functional indices. Finally, during a median 18-month follow-up, LA-GS independently predicted the composite endpoint of HF hospitalization and all-cause mortality, even after adjustment for potential clinical and cardiac mechanical confounders, including LV global longitudinal strain and filling pressures (odds ratio: 4.15; confidence interval: 1.2-14, P = 0.023). CONCLUSIONS: Reduced LA-GS but not LV functional systolic and diastolic parameters were associated with the pro-fibrotic ST2 marker, HF symptoms and outcome in HFpEF. PMID- 29430748 TI - High-Performance n-Channel Organic Transistors Using High-Molecular-Weight Electron-Deficient Copolymers and Amine-Tailed Self-Assembled Monolayers. AB - While high-performance p-type semiconducting polymers are widely reported, their n-type counterparts are still rare in terms of quantity and quality. Here, an improved Stille polymerization protocol using chlorobenzene as the solvent and palladium(0)/copper(I) as the catalyst is developed to synthesize high-quality n type polymers with number-average molecular weight up to 105 g mol-1 . Furthermore, by sp2 -nitrogen atoms (sp2 -N) substitution, three new n-type polymers, namely, pBTTz, pPPT, and pSNT, are synthesized, and the effect of different sp2 -N substitution positions on the device performances is studied for the first time. It is found that the incorporation of sp2 -N into the acceptor units rather than the donor units results in superior crystalline microstructures and higher electron mobilities. Furthermore, an amine-tailed self-assembled monolayer (SAM) is smoothly formed on a Si/SiO2 substrate by a simple spin coating technique, which can facilitate the accumulation of electrons and lead to more perfect unipolar n-type transistor performances. Therefore, a remarkably high unipolar electron mobility up to 5.35 cm2 V-1 s-1 with a low threshold voltage (~1 V) and high on/off current ratio of ~107 is demonstrated for the pSNT based devices, which are among the highest values for unipolar n-type semiconducting polymers. PMID- 29430749 TI - Patterns of use of near-infrared spectroscopy in neonatal intensive care units: international usage survey. AB - AIM: To assess uptake and applications of near-infrared spectroscopy (NIRS) by neonatal intensive care units (NICUs). METHODS: A pre-piloted online questionnaire was distributed in May 2015 to 12 perinatal societies in Asia, Europe, Australasia, North America and Middle East for dissemination to NICUs. Questions surveyed demographics, NIRS research/clinical applications, usage frequency, training approaches and target infant populations. RESULTS: In total, 255 responses from 235 NICUs were obtained. Of these, 85 (36%) owned a NIRS device. Australian and New Zealand NICUs were more likely to own NIRS technology than Asian (OR 1.12, 95% CI: 0.38-3.37) and North American (OR 2.63, 95% CI: 1.07 6.45) NICUs. A total of 69 (71%) used NIRS within clinical or mixed clinical research settings, however routine reliance for management and prognostication was low (9% and 3%, respectively). Of those without NIRS technology, 96 (64%) had no acquisition intentions. The main limiting factors were controversial evidence on efficacy (59%) and financial considerations (50%). About 51% of respondents received in-house NIRS training and 32% had access to written guidelines. CONCLUSION: There is considerable geographical variation in NIRS usage in NICUs that is, on the whole, limited by consumer perception of lack of evidence for its clinical utility. This knowledge gap should be addressed by future research. PMID- 29430750 TI - Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study. PMID- 29430751 TI - Anion Recognition in Water, Including Sulfate, by a Bicyclam Bimetallic Receptor: A Process Governed by the Enthalpy/Entropy Compensatory Relationship. AB - The dimetallic system [CuII2 (L)]4+ contains two facing equivalent metallocyclam subunits and incorporates ambidentate anions, mono- (halides) and poly-atomic (sulfate), which bridge the two CuII centres. Isothermal titration calorimetry (ITC) experiments in water showed that the log K values of the inclusion equilibria for halides and sulfate varied over a restricted interval (3.6+/-0.2), which indicated lack of selectivity and that similarity of DeltaG degrees values resulted from the unbalanced contribution of the DeltaH degrees and TDeltaS degrees terms: the more favourable the one, the less favourable the other. In particular, a linear dependence of DeltaH degrees and TDeltaS degrees was observed (a typical enthalpy/entropy compensatory diagram), which assigned a major role to hydration terms: 1) a more hydrated anion resulted in a more endothermic dehydration process; and 2) a larger number of water molecules released to the solution resulted in a more positive TDeltaS degrees . Limiting cases refer to the complexation 1) of the poorly hydrated iodide (highly exothermic process, entropically disfavoured), and 2) of the highly hydrated sulfate (moderately endothermic process, entropically very favoured). Anion receptors operating in water belong to two main domains: 1) those exhibiting positive DeltaH degrees and positive TDeltaS degrees (+/+ signature), and 2) those displaying the opposite behaviour: (-/- signature). The receptor investigated herein connects the two domains, along the DeltaH degrees /TDeltaS degrees straight line, thanks to the hidden role of the versatile metal-anion interaction. PMID- 29430752 TI - Discrimination of Cynanchum wilfordii and Cynanchum auriculatum by terahertz spectroscopic analysis. AB - INTRODUCTION: Precise identification of botanical origin of plant species is crucial for the quality control of herbal medicine. In Korea, the root part of Cynanchum auriculatum has been misused for C. wilfordii in the herbal drug market due to their morphological similarities. Currently, DNA analysis using the polymerase chain reaction (PCR) method is employed to discriminate between these species. OBJECTIVE: In order to develop a new analytical tool for the rapid discrimination of C. wilfordii and C. auriculatum, terahertz (THz) spectroscopy was employed. METHODOLOGY: Authentic samples of C. wilfordii and C. auriculatum were provided from the National Institute and standardized pellets for each species were prepared to get optimum results with terahertz time-domain spectroscopy (THz-TDS) in frequency range 0.2-1.20 THz. RESULTS: The C. wilfordii pellet showed longer time delay compare to the sample of C. auriculatum and this was due to the difference in permittivity. The pellet samples of C. wilfordii and C. auriculatum showed a permittivity difference of about 0.08 at 0.2-1.20 THz. CONCLUSION: The experimental results indicated that THz-TDS analysis can be an effective and rapid method for the discrimination of C. wilfordii and C. auriculatum, and this application can be expanded for the discrimination of other similar herbal medicines. PMID- 29430753 TI - Reduced low-frequency power and phase locking reflect restoration in the auditory continuity illusion. AB - Interruptions in auditory input can be perceptually restored if they coincide with a masking sound, resulting in a continuity illusion. Previous studies have shown that this continuity illusion is associated with reduced low-frequency neural oscillations in the auditory cortex. However, the precise contribution of oscillatory amplitude changes and phase alignment to auditory restoration remains unclear. Using electroencephalography, we investigated induced power changes and phase locking in response to 3 Hz amplitude-modulated tones during the interval of an interrupting noise. We experimentally manipulated both the physical continuity of the tone (continuous vs. interrupted) and the masking potential of the noise (notched vs. full). We observed an attenuation of 3 Hz power during continuity illusions in comparison with both continuous tones and veridically perceived interrupted tones. This illusion-related suppression of low-frequency oscillations likely reflects a blurring of auditory object boundaries that supports continuity perception. We further observed increased 3 Hz phase locking during fully masked continuous tones compared with the other conditions. This low frequency phase alignment may reflect the neural registration of the interrupting noise as a newly appearing object, whereas during continuity illusions, a spectral portion of this noise is delegated to filling the interruption. Taken together, our findings suggest that the suppression of slow cortical oscillations in both the power and phase domains supports perceptual restoration of interruptions in auditory input. PMID- 29430754 TI - Host-pathogen metapopulation dynamics suggest high elevation refugia for boreal toads. AB - Emerging infectious diseases are an increasingly common threat to wildlife. Chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), is an emerging infectious disease that has been linked to amphibian declines around the world. Few studies exist that explore amphibian-Bd dynamics at the landscape scale, limiting our ability to identify which factors are associated with variation in population susceptibility and to develop effective in situ disease management. Declines of boreal toads (Anaxyrus boreas boreas) in the southern Rocky Mountains are largely attributed to chytridiomycosis but variation exists in local extinction of boreal toads across this metapopulation. Using a large-scale historic data set, we explored several potential factors influencing disease dynamics in the boreal toad-Bd system: geographic isolation of populations, amphibian community richness, elevational differences, and habitat permanence. We found evidence that boreal toad extinction risk was lowest at high elevations where temperatures may be suboptimal for Bd growth and where small boreal toad populations may be below the threshold needed for efficient pathogen transmission. In addition, boreal toads were more likely to recolonize high elevation sites after local extinction, again suggesting that high elevations may provide refuge from disease for boreal toads. We illustrate a modeling framework that will be useful to natural resource managers striving to make decisions in amphibian-Bd systems. Our data suggest that in the southern Rocky Mountains high elevation sites should be prioritized for conservation initiatives like reintroductions. PMID- 29430755 TI - Expecting the worst? The relationship between retrospective and prospective appraisals of illness on quality of life in prostate cancer survivors. AB - OBJECTIVE: Despite a generally good prognosis, many prostate cancer survivors have poor quality of life (QOL). A greater understanding of how psychological appraisals influence QOL is merited given their potentially modifiable nature. In this study, we considered how elements of survivors' retrospective and prospective appraisals relate to QOL. METHODS: A total of 1229 prostate cancer survivors between 2 and 5 years post-diagnosis, identified from a population based National Cancer Registry, were asked questions on their socio-demographics, health, treatment received, and adverse-effects using a cross-sectional design. QOL was assessed using the EORTC QLQ-C30. Retrospective appraisals were assessed by asking survivors to reflect on their experience of treatment-related adverse effects compared with their prior expectations. A fear of recurrence scale assessed prospective appraisals of future disease course. A multiple regression model explored the impact of psychological appraisals on QOL, after controlling for socio-demographic, treatment, and health-related factors. RESULTS: The model was significant explaining 37% of variance in QOL. The strongest associate with QOL was fear of recurrence (beta = -.29; P < .001). Survivors who experienced side effects that were worse than expected had significantly lower QOL (beta = .10; P = .002). Other significant correlates of lower QOL were presence of comorbidities, having undergone a less invasive treatment, and having more advanced disease. Working at diagnosis and having a higher level of education were significantly associated with higher QOL. CONCLUSIONS: Results suggest both retrospective and prospective appraisals are independently related to QOL in prostate cancer. Providing survivors with more information about possible adverse effects of treatment, as well as providing appropriate information regarding future disease progression, may improve QOL. PMID- 29430756 TI - Experiences of internationally educated nurses holding management positions in the United States: Descriptive phenomenological study. AB - AIMS: The purpose of this study was to explore the experiences of internationally educated nurses in management positions in United States health care organisations to understand the obstacles and support these individuals' experience when pursuing and working in managerial roles. BACKGROUND: Although internationally educated nurses are an integral part of the US health care industry, few work in managerial roles. Little is known about the experiences of internationally educated nurses who do obtain management positions. METHODS: In this qualitative, phenomenological study, seven internationally educated nurses who were managers in Chicago, Illinois, responded to open-ended interview questions. RESULTS: Supervisors contributed to the participants' acceptance of management positions. The participants experienced challenges such as cultural differences, language, and communication. Despite these challenges, the participants had positive working relationships with staff and supervisors. Further, the participants had opportunities for education and professional growth. CONCLUSIONS: Internationally educated nurses benefit from participating in organisational committees. They face challenges related to work responsibilities, cultural differences and communication but can succeed in management roles through developing strategies to overcome the challenges and through receiving support from staff, colleagues and supervisors. IMPLICATIONS FOR NURSING MANAGEMENT: More internationally educated nurses may obtain managerial positions if supervisors provide encouragement and support. PMID- 29430757 TI - Serum bilirubin level predicts postoperative overall survival in oral squamous cell carcinoma. AB - BACKGROUND: Aberrant level of serum bilirubin, marker of hepatobiliary and hematological disorders, was associated with patient prognosis in several human malignancies. In this study, we aim to evaluate the predictive value of serum bilirubin for clinicopathologic characteristics and survival of patients with oral squamous cell carcinoma (OSCC). METHODS: This study retrospectively reviewed 129 patients with OSCC and 129 normal controls matched for age and sex. The association between levels of preoperative direct bilirubin (DBIL), indirect bilirubin (IBIL), total bilirubin (TBIL), and clinical variables was analyzed. A proportional hazards regression model was used to find out the independent predictors of survival. RESULTS: Significantly lower TBIL (P = .009) and IBIL (P < .001) were found in OSCC patients compared with normal controls. DBIL (P = .011) and lymph-node metastasis (P = .031) were found to be independent prognostic factors. Patients with higher DBIL (>=4.0 MUmol/L) had longer overall survival than those with lower DBIL (P = .002). Patients with both lymph-node metastasis and lower DBIL showed the shortest overall survival (P = .001). CONCLUSIONS: Lower DBIL was associated with a poorer prognosis and may be regarded as an independent prognostic marker for patients with OSCC. PMID- 29430758 TI - Breaking the silence: A new story of nursing. PMID- 29430759 TI - "It's Just a Lot of Work": Adolescents' Self-Presentation Norms and Practices on Facebook and Instagram. AB - We explored adolescents' (12- to 18-year-olds; n = 51) awareness of their audience and subsequent self-presentation practices on Facebook and Instagram through focus group discussions. Findings suggest that teens, who are developmentally able to perceive a situation from the third-person perspective and who value peer approval, purposefully share content to appear interesting, well liked, and attractive. Some teens invested great effort into posting by these norms, even asking their friends to help; however, this was more common among girls. Older teens especially discussed taking the perspective of their audience when deciding what to post, which is consistent with the finding that perspective taking continues to develop throughout adolescence. These findings suggest that perspective taking skills and need for peer approval influence self presentation online. PMID- 29430760 TI - Corrected US opioid-involved drug poisoning deaths and mortality rates, 1999 2015. AB - BACKGROUND AND AIMS: Most prior estimates of opioid-involved drug poisoning mortality counts or rates are understated because the specific drugs leading to death are frequently not identified on death certificates. This analysis provides corrected national estimates of opioid and heroin/synthetic opioid-involved counts and mortality rates, as well as changes over time in them from 1999 to 2015. METHODS: Data on drug poisoning deaths to US residents from 1999 to 2015, obtained from the Centers for Disease Control and Prevention (CDC) Multiple Cause of Death (MCOD) files, were used with the drugs involved in fatal overdoses imputed when not identified on the death certificates. RESULTS: The official CDC figure that 33 091 drug deaths involved opioids in 2015 is an undercount, with the actual number being approximately 39 999. Corrected counts and rates of any opioid and heroin/synthetic opioid-involved drug deaths are 20-35% higher in every year than reported figures. The corrections almost always raise the changes estimated to have occurred since 1999, with the largest differences observed in 2011 for any opioids (5677 deaths and 1.7 per 100 000) and in 2015 for heroin/synthetic opioids (3228 deaths and 1.0 per 100 000). However, percentage growth since 1999 is sometimes slower when based on corrected rather than reported fatality data, and with sensitivity to the choice of base years. CONCLUSIONS: Death certificate reports understate the prevalence of and changes over time in opioid and heroin/synthetic opioid-involved drug mortality in the United States. Adjustments imputing the drugs involved for cases where none are identified on the death certificates are likely to provide more accurate estimates. PMID- 29430761 TI - NOD-like receptor pyrin domain-containing-3 (NLRP3) regulates inflammation induced pro-labor mediators in human myometrial cells. AB - PROBLEM: Inflammation plays a major role in preterm birth. Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) plays a role in inflammatory diseases. The aims of this study were to determine the effect of term labor on the expression of NLRP3 in human myometrium and the effect of NLRP3 silencing on pro-labor mediators in myometrial cells. METHOD OF STUDY: NLRP3 expression was assessed in myometrium from non-laboring and laboring women by qRT-PCR and Western blotting. Human primary myometrial cells were transfected with NLRP3 siRNA (siNLRP3), treated with pro-inflammatory cytokines and toll-like receptor (TLR) ligands, and assayed for pro-inflammatory mediators' expression. RESULTS: NLRP3 expression was higher in myometrium after term spontaneous labor and by TNF, IL1B, fsl-1, and flagellin. In siNLRP3-transfected cells, there was a significant decrease in the expression of pro-inflammatory cytokines (IL1A, IL6), chemokines (CXCL8, CCL2), and adhesion molecules (ICAM1 and VCAM1) stimulated with IL1B, TNF, or TLR ligands; decrease in IL1B-stimulated PTGS2 and PTGFR mRNA expression and PGF2alpha release; and increase in TNF stimulated myometrial gel shrinkage as assessed by an in vitro cell contraction assay. CONCLUSION: NLRP3 is increased with labor in myometrial, and knockdown of NLRP3 is associated with an attenuation of inflammation-induced expression of pro inflammatory and pro-labor mediators in human myometrium. PMID- 29430762 TI - Assessment of cost-effective changes to the current and potential provision of smoking cessation services: an analysis based on the EQUIPTMOD. AB - BACKGROUND AND AIMS: Increasing the reach of smoking cessation services and/or including new but effective medications to the current provision may provide significant health and economic benefits; the scale of such benefits is currently unknown. The aim of this study was to estimate the cost-effectiveness from a health-care perspective of viable national level changes in smoking cessation provision in the Netherlands and England. METHODS: A Markov-based state transition model [European study on Quantifying Utility of Investment in Protection from Tobacco model (EQUIPTMOD)] was used to estimate costs and benefits [expressed in quality-adjusted life years (QALY)] of changing the current provision of smoking cessation programmes in the Netherlands and England. The changes included: (a) increasing the reach of top-level services to increase potential quitters (e.g. brief physician advice); (b) increasing the reach of behavioural support (group-based therapy and SMS text-messaging support) to increase the success rates; (c) including a new but effective medication (cytisine); and (d) all changes implemented together (combined change). The costs and QALYs generated by those changes over 2, 5, 10 years and a life-time were compared with that of the current practice in each country. Results were expressed as incremental net benefit (INB) and incremental cost-effectiveness ratio (ICER). A sequential analysis from a life-time perspective was conducted to identify the optimal change. RESULTS: The combined change was dominant (cost saving) over all alternative changes and over the current practice, in both countries. The combined change would generate an incremental net benefit of ?11.47 (2 years) to ?56.16 (life-time) per smoker in the Netherlands and ?9.96 (2 years) to ?60.72 (life-time) per smoker in England. The current practice was dominated by all alternative changes. CONCLUSION: Current provision of smoking cessation services in the Netherlands and England can benefit economically from the inclusion of cytisine and increasing the reach of brief physician advice, text-messaging support and group-based therapy. PMID- 29430763 TI - Accuracy of four ultrasonography techniques in predicting histopathological classification of canine mammary carcinomas. AB - Due to the importance of presurgical, noninvasive, and accurate diagnostic tools in mammary carcinoma characterization, this prospective secondary observational cohort study was designed to evaluate and compare the diagnostic accuracy of B mode, Doppler, contrast enhancement ultrasonography, or acoustic radiation force impulse-elastography in identifying mammary carcinomas types with high degree of malignancy. A total of 246 mammary carcinomas from 141 female dogs were analyzed using B-mode, Doppler, contrast enhancement ultrasonography, and acoustic radiation force impulse ultrasonography prior to their histopathological classification according to types (simple, complex, or special) and grade (I, II, or III). Qualitative and quantitative variables were compared between carcinoma types and grades by Fisher's or analysis of variance. Diagnostic performance was estimated by receiver-operating characteristic analysis, using histopathological classification as a reference. Deformability (acoustic radiation force impulse) had a diagnostic specificity of 100% and sensitivity of 12% in identifying special carcinomas. A width:length ratio greater than 0.53 can be suggestive of special carcinoma, with 80% sensitivity and 76% specificity. Contrast wash-in and peak enhancement times lower than 7.5 and 13.5 s, respectively, were indicative of complex carcinoma at 62% sensitivity and 60% specificity. Contrast wash-in, peak enhancement, and wash-out times greater than 6.5, 12.5, and 64.5 s, respectively; were indicative of grade II and III carcinoma at 68% sensitivity and 62% specificity. In conclusion, B-mode ultrasonography, contrast enhancement ultrasonography, and acoustic radiation force impulse-elastography enabled the identification of some of the characteristics of high-grade mammary carcinoma types and grades in female dogs with limited accuracy. The findings from this study may contribute to oncology research and clinical management canine patients. PMID- 29430764 TI - PLCgamma2 promotes apoptosis while inhibits proliferation in rat hepatocytes through PKCD/JNK MAPK and PKCD/p38 MAPK signalling. AB - OBJECTIVES: The PLCG2 (PLCgamma2) gene is a member of PLC gene family encoding transmembrane signalling enzymes involved in various biological processes including cell proliferation and apoptosis. Our earlier study indicated that PLCgamma2 may be involved in the termination of regeneration of the liver which is mainly composed of hepatocytes, but its exact biological function and molecular mechanism in liver regeneration termination remains unclear. This study aims to examine the role of PLCgamma2 in the growth of hepatocytes. MATERIALS AND METHODS: A recombinant adenovirus expressing PLCgamma2 was used to infect primary rat hepatocytes. PLCgamma2 mRNA and protein levels were detected by qRT-PCR and Western blot. The subcellular location of PLCgamma2 protein was tested by an immunofluorescence assay. The proliferation of hepatocytes was measured by MTT assay. The cell cycle and apoptosis were analysed by flow cytometry. Caspase-3, 8 and -9 activities were measured by a spectrophotometry method. Phosphorylation levels of PKCD, JNK and p38 in the infected cells were detected by Western blot. The possible mechanism underlying the role of PLCgamma2 in hepatocyte growth was also explored by adding a signalling pathway inhibitor. RESULTS: Hepatocyte proliferation was dramatically reduced, while cell apoptosis was remarkably increased. The results demonstrated that PLCgamma2 increased the phosphorylation of PKCD, p38 and JNK in rat hepatocytes. After PKCD activity was inhibited by the inhibitor Go 6983, the levels of both p-p38 and p-JNK MAPKs significantly decreased, and PLCgamma2-induced cell proliferation inhibition and cell apoptosis were obviously reversed. CONCLUSIONS: This study showed that PLCgamma2 regulates hepatocyte growth through PKCD-dependently activating p38 MAPK and JNK MAPK pathways; this result was experimentally based on the further exploration of the effect of PLCgamma2 on hepatocyte growth in vivo. PMID- 29430765 TI - Identifying the target genes of SUPPRESSOR OF GAMMA RESPONSE 1, a master transcription factor controlling DNA damage response in Arabidopsis. AB - In mammalian cells, the transcription factor p53 plays a crucial role in transmitting DNA damage signals to maintain genome integrity. However, in plants, orthologous genes for p53 and checkpoint proteins are absent. Instead, the plant specific transcription factor SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1) controls most of the genes induced by gamma irradiation and promotes DNA repair, cell cycle arrest, and stem cell death. To date, the genes directly controlled by SOG1 remain largely unknown, limiting the understanding of DNA damage signaling in plants. Here, we conducted a microarray analysis and chromatin immunoprecipitation (ChIP)-sequencing, and identified 146 Arabidopsis genes as direct targets of SOG1. By using ChIP-sequencing data, we extracted the palindromic motif [CTT(N)7 AAG] as a consensus SOG1-binding sequence, which mediates target gene induction in response to DNA damage. Furthermore, DNA damage triggered phosphorylation of SOG1 is required for efficient binding to the SOG1 binding sequence. Comparison between SOG1 and p53 target genes showed that both transcription factors control genes responsible for cell cycle regulation, such as CDK inhibitors, and DNA repair, whereas SOG1 preferentially targets genes involved in homologous recombination. We also found that defense-related genes were enriched in the SOG1 target genes. Consistent with this finding, SOG1 is required for resistance against the hemi-biotrophic fungus Colletotrichum higginsianum, suggesting that SOG1 has a unique function in controlling the immune response. PMID- 29430766 TI - Normative data for the Montreal Cognitive Assessment (MoCA) and the Memory Index Score (MoCA-MIS) in Brazil: Adjusting the nonlinear effects of education with fractional polynomials. AB - OBJECTIVE: To provide age-corrected and education-corrected norms for the Montreal Cognitive Assessment (MoCA) and the Memory Index Score (MoCA-MIS) in Brazil. METHODS: Community-dwelling outpatients were enrolled if they had no history of neurologic or psychiatric diseases and were not taking any drugs with effects on the central nervous system. Dementia has been excluded with the Functional Activities Questionnaire. The final sample consisted of 597 cognitively healthy Brazilians aged 50 to 90 years. To account for nonlinear relationships, we have used fractional polynomials that provide a flexible parameterization for continuous variables. RESULTS: According to the original proposed cutoff (<=25 points), 87% of our sample would be considered impaired. Even using a more conservative suggestion (<=22 points), 67% of our normative sample would be regarded as impaired. These data reinforce the need of adjusting cutoffs for schooling in populations with heterogeneous educational backgrounds. MoCA scores presented a nonlinear positive association with education tending to a plateau at higher levels (P < 0.001). On the other hand, MoCA-MIS scores presented a nonlinear negative relationship with age, with an accelerated pattern at higher age levels (P < 0.001). CONCLUSIONS: We presented normative data for the MoCA and the MoCA-MIS that will facilitate the use of the test in Brazil and, potentially, in other populations with substantial proportions of low-educated individuals. Moreover, we described a systematic approach for adjusting the effects of age and education using fractional polynomials and provided suggestions on how to account for the nonlinear relationship that is frequently encountered between demographic factors and measures of cognitive performance. PMID- 29430767 TI - Sexual function, psychosocial adjustment to illness, and quality of life among Chinese gynaecological cancer survivors. AB - BACKGROUND: Disrupted sexual function is a prevalent and sustained side effect of gynaecological cancer and its related treatment. This problem may pose challenges to the survivors in the process of illness adjustment, leading to elevated psychological distress and impaired quality of life. However, care and interventions in this area have been neglected in most countries. OBJECTIVES: To investigate sexual function, psychosocial adjustment to illness, and quality of life among Chinese gynaecological cancer survivors in Hong Kong and to explore their associations. METHODS: A cross-sectional design was adopted. Gynaecological cancer survivors were recruited from a gynaecological oncology outpatient clinic at a regional hospital in Hong Kong. RESULTS: A total of 225 Chinese gynaecological cancer survivors were recruited. Their sexual function was found to be impaired. They had satisfactory performance in psychosocial adjustment to illness, but the worst domain was sexual relationships. Their quality of life was fair, with physical and social functioning performing best. Path analysis demonstrated that psychosocial adjustment to illness played a significant mediating role in the relationship between sexual function and quality of life among those who were married or had a regular sex partner. CONCLUSIONS: Impaired sexual function was prevalent among Chinese gynaecological cancer survivors, and psychosocial adjustment to illness mediates the relationship between sexual function and quality of life. In Chinese clinical settings without routine sexuality assessments, early sexual function and psychosocial adjustment assessment should be integrated into routine nursing practice. In addition, a culturally appropriate practice model should be developed to guide sexuality care delivery. PMID- 29430768 TI - Uncovering the Circular Polarization Potential of Chiral Photonic Cellulose Films for Photonic Applications. AB - Circularly polarized light (CPL) is central to photonic technologies. A key challenge lies in developing a general route for generation of CPL with tailored chiroptical activity using low-cost raw materials suitable for scale-up. This study presents that cellulose films with photonic bandgaps (PBG) and left-handed helical sense have an intrinsic ability for circular polarization leading to PBG based CPL with extraordinary |g | values, well-defiend handedness, and tailorable wavelength by the PBG change. Using such cellulose films, incident light ranging from near-UV to near-IR can be transformed to passive L-CPL and R-CPL with viewing-side-dependent handedness and |g | values up to 0.87, and spontaneous emission transformed to R-CPL emission with |g | values up to 0.68. Unprecedented evidence is presented with theoretical underpinning that the PBG effect can stimulate the R-CPL emission. The potential of cellulose-based CPL films for polarization-based encryption is illustrated. The evaporation-induced self assembly coupled with nanoscale mesogens of cellulose nanocrystals opens new venues for technological advances and enables a versatile strategy for rational design and scalable manufacturing of organic and inorganic CPL films for photonic applications. PMID- 29430769 TI - Illuminating structure and acyl donor sites of a physiological transglutaminase substrate from Streptomyces mobaraensis. AB - Transglutaminase from Streptomyces mobaraensis (MTG) has become a powerful tool to covalently and highly specifically link functional amines to glutamine donor sites of therapeutic proteins. However, details regarding the mechanism of substrate recognition and interaction of the enzyme with proteinaceous substrates still remain mostly elusive. We have determined the crystal structure of the Streptomyces papain inhibitory protein (SPIp ), a substrate of MTG, to study the influence of various substrate amino acids on positioning glutamine to the active site of MTG. SPIp exhibits a rigid, thermo-resistant double-psi-beta-barrel fold that is stabilized by two cysteine bridges. Incorporation of biotin cadaverine identified Gln-6 as the only amine acceptor site on SPIp accessible for MTG. Substitution of Lys-7 demonstrated that small and hydrophobic residues in close proximity to Gln-6 favor MTG-mediated modification and are likely to facilitate introduction of the substrate into the front vestibule of MTG. Moreover, exchange of various surface residues of SPIp for arginine and glutamate/aspartate outside the glutamine donor region influences the efficiency of modification by MTG. These results suggest the occurrence of charged contact areas between MTG and the acyl donor substrates beyond the front vestibule, and pave the way for protein engineering approaches to improve the properties of artificial MTG-substrates used in biomedical applications. PMID- 29430770 TI - Structuring of Hydrogels across Multiple Length Scales for Biomedical Applications. AB - The development of new materials for clinical use is limited by an onerous regulatory framework, which means that taking a completely new material into the clinic can make translation economically unfeasible. One way to get around this issue is to structure materials that are already approved by the regulator, such that they exhibit very distinct physical properties and can be used in a broader range of clinical applications. Here, the focus is on the structuring of soft materials at multiple length scales by modifying processing conditions. By applying shear to newly forming materials, it is possible to trigger molecular reorganization of polymer chains, such that they aggregate to form particles and ribbon-like structures. These structures then weakly interact at zero shear forming a solid-like material. The resulting self-healing network is of particular use for a range of different biomedical applications. How these materials are used to allow the delivery of therapeutic entities (cells and proteins) and as a support for additive layer manufacturing of larger-scale tissue constructs is discussed. This technology enables the development of a range of novel materials and structures for tissue augmentation and regeneration. PMID- 29430771 TI - Factors associated with romantic relationship formation difficulties in women with breast cancer. AB - OBJECTIVE: Many un-partnered women report difficulty in forming romantic relationships after breast cancer, characterized by high dating-related anxiety and low perceived interpersonal competence. This study examined the relationship between poor body image (appearance investment and body dissatisfaction) and self compassion, and women's ability to form romantic relationships post-breast cancer. METHODS: Women (N = 152) diagnosed with breast cancer, who were either un partnered and expressed interest in romantic dating, or who had commenced a relationship post-diagnosis, completed an online survey. Assessments included the Interpersonal Competence Questionnaire, Dating Anxiety Scale, Self-compassion Scale, Appearance Schemas Inventory-Revised, Body Image Scale, and Experiences in Close Relationships Scale. Multiple regression analyses assessed the relationships between these variables. RESULTS: Partnered and un-partnered women differed in levels of dating anxiety, interpersonal competence, anxious attachment, and the self-evaluative salience facet of appearance investment. Analyses revealed a significant model for dating anxiety, with high self evaluative salience, body image dissatisfaction, and attachment avoidance independently associated with this outcome. The model for interpersonal competence was also significant, with low attachment avoidance and high self compassion independently associated with this outcome. CONCLUSIONS: Un-partnered women who place high importance on appearance for their self-worth and who report poor body image and low self-compassion are at risk of experiencing difficulties in forming new romantic relationships after breast cancer. Future interventions should target these variables to facilitate romantic dating during cancer survivorship. PMID- 29430772 TI - A practical diastereoselective synthesis of (-)-bestatin. AB - Diastereoselective addition of nitromethane to Boc-D-Phe-H in the presence of sodium hydride in diethyl ether/hexane containing 15-crown-5 and subsequent N,O protection with 2,2-dimethoxypropane gave trans-oxazolidine in a diastereomeric ratio of >16:1. The oxazolidine was easily separated by column chromatography, which after Nef reaction was coupled to H-Leu-OtBu. The 8-step synthesis afforded (-)-bestatin in an overall yield of 24.7% after deprotection and ion exchange. PMID- 29430775 TI - The continually changing epidemiology of cerebral palsy. PMID- 29430773 TI - Work satisfaction and future career intentions of experienced nurses transitioning to primary health care employment. AB - AIM: To explore registered nurses' reflections on transitioning from acute to primary health care employment, and future career intentions. BACKGROUND: Reforms in primary health care have resulted in increasing demands for a skilled primary health care nursing workforce. To meet shortfalls, acute care nurses are being recruited to primary health care employment, yet little is known about levels of satisfaction and future career intentions. METHOD: A sequential mixed methods study consisting of a survey and semi-structured interviews with nurses who transition to primary health care. RESULTS: Most reported positive experiences, valuing work/life balance, role diversity and patient/family interactions. Limited orientation and support, loss of acute skills and inequitable remuneration were reported negatively. Many respondents indicated an intention to stay in primary health care (87.3%) and nursing (92.6%) for the foreseeable future, whilst others indicated they may leave primary health care as soon as convenient (29.6%). CONCLUSION: Our findings provide guidance to managers in seeking strategies to recruit and retain nurses in primary health care employment. IMPLICATIONS FOR NURSING MANAGEMENT: To maximize recruitment and retention, managers must consider factors influencing job satisfaction amongst transitioning nurses, and the impact that nurses' past experiences may have on future career intentions in primary health care. PMID- 29430776 TI - Computed tomographic findings in a Bluetick Coonhound with a longitudinal thoracic tracheal tear. AB - A 9-year-old intact male Bluetick Coonhound presented for progressive subcutaneous emphysema of 5 days' duration due to a suspected tracheal tear. Cervical computed tomography (CT) and thoracic CT were performed after failure to identify the tracheal tear with tracheoscopy. A longitudinal tracheal tear was identified starting 4.3 cm cranial to the tracheal bifurcation and extending caudally over a distance of 3.6 cm. Severe pneumomediastinum, subcutaneous emphysema, and retroperitoneal gas were also present. A follow-up CT 7 days postoperatively confirmed the successful repair of the tear with partial resolution of the presurgical secondary pathology and the patient recovered uneventfully. PMID- 29430777 TI - Evaluation of two autoinducer-2 quantification methods for application in marine environments. AB - AIM: This study evaluated two methods, namely high performance liquid chromatography with fluorescence detection (HPLC-FLD) and Vibrio harveyi BB170 bioassay, for autoinducer-2 (AI-2) quantification in marine samples. Using both methods, the study also investigated the stability of AI-2 in varying pH, temperature and media, as well as quantified the amount of AI-2 signals in marine samples. METHODS AND RESULTS: HPLC-FLD method showed a higher level of reproducibility and precision compared to V. harveyi BB170 bioassay. Alkaline pH (>8) and high temperature (>37 degrees C) increased the instability of AI-2. The AI-2 concentrations in seawater were low, c. 3.2-27.6 pmol l-1 , whereas 8-week old marine biofilm grew on an 18.8 cm2 substratum accumulated c. 0.207 nmol of AI 2. CONCLUSION: Both methods have pros and cons for AI-2 quantification in marine samples. Regardless, both methods reported a ubiquitous presence of AI-2 in both planktonic and biomass fractions of seawater, as well as in marine biofilm. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, AI-2 signals were for the first time enumerated in marine samples to reveal the ubiquitous presence of AI-2 in this environment. The findings suggest a possible role of AI-2 in biofilm formation in marine environment, and the contribution of AI-2 in biofilm associated problems such as biofouling and biocorrosion. PMID- 29430778 TI - Incidence and risk factors for urinary retention in critically ill patients. PMID- 29430779 TI - Editorial: Who, when, and how to BAV in the TAVR era? PMID- 29430780 TI - Editorial: Spontaneous coronary artery dissection: A new dilemma, or just new recognition of an old problem? PMID- 29430781 TI - Editorial: Retrograde via epicardial collaterals: With power comes responsibility. PMID- 29430782 TI - Is index procedure complete revascularization really essential for ST-elevation myocardial infarction with cardiogenic shock? PMID- 29430783 TI - Editorial: Orbital atherectomy: A portal opens. PMID- 29430784 TI - Editorial: Just clip it, then ReClip it again: Expanding populations for transcatheter mitral repair and options for recurrent mitral regurgitation. PMID- 29430785 TI - Diabetic retinopathy screening programme utilising non-mydriatic fundus imaging in slum populations of New Delhi, India. AB - OBJECTIVES: To develop and implement a community-based programme for screening of diabetic retinopathy (DR) in urban populations of Delhi. METHODS: Known diabetics (KDs) aged 40 years and older were identified through house-to-house surveys, volunteers and publicity. All KDs were referred to DR screening camps organised locally where procedures included brief medical history, ocular examination and non-mydriatic fundus photography using portable handheld camera. Fundal images were graded on the spot by trained optometrists for DR. Patients with DR were referred to tertiary centre for management. RESULTS: A total of 11 566 KDs were identified, of whom 9435 (81.6%) visited DR screening camps and 8432 (89.4%) had DR gradable images. DR was identified in 13.5% of subjects; 351 cases were mild NPDR, 567 moderate, 92 severe. Seventy-seven had PDR, and 49 had DME, and 2.7% of participants were blind (presenting visual acuity <3/60 in better eye). Non-use of lifestyle management, presence of systemic complications, BMI <18.5 kg/m2 , disease duration of >5 years and uncontrolled diabetes were associated with increased odds of DR. All cases with DR were referred, and 420 (37%) successful referrals to base hospital were observed. CONCLUSION: The programme of creating awareness about DR, identifying KDs and optometrist-led DR screening using non mydriatic fundus camera based in slums was successful. PMID- 29430786 TI - The persistent decline of patterned woody vegetation: The tiger bush in the context of the regional Sahel greening trend. AB - Following 25 years of below average annual rainfall in the Sahel between 1970 and 1995, the return to more humid conditions has led to rapid postdrought recovery of the woody cover. However, the increase in the woody cover is not spatially homogeneous raising questions about the resilience of some woody vegetation types. Based on the analysis of field and remote sensing data collected on the tiger bush systems in the northern Sahel in Mali, this study noted the current and persistent degradation of these systems in the Sahel since the 1970s despite the recent improvement in rainfall since the mid-1990s and the general Sahel re greening. Profound changes in the woody population pattern, tree density and cover, and floristic composition took place regardless of the site location along the south-north rainfall gradient. Associated with definite structural changes of the woody population, surface hydrology shifted from a sheet to concentrated run off accelerating the collapse of the patterned woody population. Currently, there is no evidence in favour of reversing the current degradation process, at least at a decadal scale, although very sparse recolonization by pioneer woody vegetation has been observed in the driest sites along recently formed gullies. These observations support the hypothesis of an ecosystem shift, with long-term implications for the structure and functioning of the patterned vegetation, as well as the whole watershed landscape through increased run-off leading to stronger water flows in enlarged wadis, increased soil erosion upstream and sediment deposition downstream, enhanced water storage in ponds, and greater recharge of aquifers, which is an illustration of the "Sahelian paradox". PMID- 29430787 TI - Overdenture Prostheses with Metal Copings: A Retrospective Analysis of Survival and Prosthodontic Complications. AB - PURPOSE: To retrospectively evaluate complications associated with overdentures and abutment teeth restored with metal copings, including post-procedural and prosthetic problems; also to analyze the frequency and influencing factors associated with these problems. MATERIALS AND METHODS: A total of 80 subjects (48 females, 32 males, mean age 62 years) wearing root-supported overdentures were enrolled in the study. All participants were thoroughly examined by a single examiner, and appropriate maintenance care was performed. The 80 subjects had 270 abutments, which were endodontically treated teeth. All 80 subjects were carefully interviewed, inspected, and evaluated for post-procedural and clinical problems with their overdentures for an observation period of up to 5 years. RESULTS: Of the post-procedural problems evaluated, the most common problems were gingival inflammation (69%) and root caries (36%) because of poor oral hygiene (41%) and loss of metal copings (34%), followed by overdenture base fracture over abutment teeth (34%). Other post-procedural problems reported were loss of overdenture stability (23%), incidence of overdenture repair (20%), poor retention (18%), incidental finding of root fragments (unplanned) in the jaws (15%), and up to two grade net change in the mobility of overdenture abutments (8%). All prostheses were in use at the time of data collection and observation up to 5 years. CONCLUSIONS: Overdenture therapy was satisfactory; however, post procedural and prosthetic complications and aftercare maintenance must not be underestimated. PMID- 29430788 TI - Structural Engineering of 2D Nanomaterials for Energy Storage and Catalysis. AB - Research on 2D nanomaterials is rising to an unprecedented height and will continue to remain a very important topic in materials science. In parallel with the discovery of new candidate materials and exploration of their unique characteristics, there are intensive interests to rationally control and tune the properties of 2D nanomaterials in a predictable manner. Considerable attention is focused on modifying these materials structurally or engineering them into designed architectures to meet requirements for specific applications. Recent advances in such structural engineering strategies have demonstrated their ability to overcome current material limitations, showing great promise for promoting device performance to a new level in many energy-related applications. Existing in many forms, these strategies can be categorized based on how they intrinsically or extrinsically alter the pristine structure. Achieved through various synthetic routes and practiced in a range of different material systems, they usually share common descriptors that predestine them to be effective in certain circumstances. Therefore, understanding the underlying mechanism of these strategies to provide fundamental insights into structural design and property tailoring is of critical importance. Here, the most recent development of structural engineering of 2D nanomaterials and their significant effects in energy storage and catalysis technologies are addressed. PMID- 29430789 TI - Intratumoral Delivery of Interferongamma-Secreting Mesenchymal Stromal Cells Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo. AB - Neuroblastoma, the most common extracranial solid tumor in childhood, remains a therapeutic challenge. However, one promising patient treatment strategy is the delivery of anti-tumor therapeutic agents via mesenchymal stromal cell (MSC) therapy. MSCs have been safely used to treat genetic bone diseases such as osteogenesis imperfecta, cardiovascular diseases, autoimmune diseases, and cancer. The pro-inflammatory cytokine interferon-gamma (IFNgamma) has been shown to decrease tumor proliferation by altering the tumor microenvironment (TME). Despite this, clinical trials of systemic IFNgamma therapy have failed due to the high blood concentration required and associated systemic toxicities. Here, we developed an intra-adrenal model of neuroblastoma, characterized by liver and lung metastases. We then engineered MSCs to deliver IFNgamma directly to the TME. In vitro, these MSCs polarized murine macrophages to the M1 phenotype. In vivo, we attained a therapeutically active TME concentration of IFNgamma without increased systemic concentration or toxicity. The TME-specific IFNgamma reduced tumor growth rate and increased survival in two models of T cell deficient athymic nude mice. Absence of this benefit in NOD SCID gamma (NSG) immunodeficient mouse model indicates a mechanism dependent on the innate immune system. IL-17 and IL-23p19, both uniquely M1 polarization markers, transiently increased in the tumor interstitial fluid. Finally, the MSC vehicle did not promote tumor growth. These findings reveal that MSCs can deliver effective cytokine therapy directly to the tumor while avoiding systemic toxicity. This method transiently induces inflammatory M1 macrophage polarization, which reduces tumor burden in our novel neuroblastoma murine model. Stem Cells 2018;36:915-924. PMID- 29430790 TI - Altered frontal-amygdala effective connectivity during effortful emotion regulation in bipolar disorder. AB - OBJECTIVES: Sufficient prefrontal top-down control of limbic affective areas, especially the amygdala, is essential for successful effortful emotion regulation (ER). Difficulties in effortful ER have been seen in patients with bipolar disorder (BD), which could be suggestive of a disturbed prefrontal-amygdala regulation circuit. The aim of this study was to investigate whether BD patients show abnormal effective connectivity from the prefrontal areas to the amygdala during effortful ER (reappraisal). METHODS: Forty participants (23 BD patients and 17 healthy controls [HC]) performed an ER task during functional magnetic resonance imaging. Using dynamic causal modeling, we investigated effective connectivity from the dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) to the amygdala, as well as connectivity between the DLPFC and VLPFC during reappraisal. RESULTS: Both BD patients and HC showed decreased negative affect ratings following reappraisal compared to attending negative pictures (P < .001). There were no group differences (P = .10). There was a differential modulatory effect of reappraisal on the connectivity from the DLPFC to amygdala between BD patients and HC (P = .04), with BD patients showing a weaker modulatory effect on this connectivity compared to HC. There were no other group differences. CONCLUSION: The disturbance in BD patients in effective connectivity from the DLPFC to the amygdala while reappraising is indicative of insufficient prefrontal control. This impairment should be studied further in relation to cycling frequency and polarity of switches in BD patients. PMID- 29430791 TI - Feasibility of applying the psychosocial intervention STrAtegies for RelaTives to family caregivers of patients with dementia: a case report. AB - As the number of people with dementia in Japan continues to rise, family caregivers are experiencing an increasing care burden. Previous research has shown that this care burden can affect family caregivers' physical and mental health. Therefore, providing support for caregivers of family members with dementia has become an urgent issue in the country. The purpose of this study was to investigate the feasibility of applying STrAtegies for RelaTives (START), a psychosocial intervention programme developed in the UK to improve caregivers' moods and quality of life, to Japanese family caregivers. Specifically, in this paper, we provide a detailed description of the application of the Japanese version of START to a female caregiver. Our investigation found that the Japanese version of START is a feasible option for alleviating the mental and physical burden on family caregivers of patients with dementia. This result provides preliminary support for the wider application of START in Japan, as it can decrease care burden and improve the daily lives of caregivers of people with dementia. It also supports the development and implementation of other systems that can provide similar services for other caregivers. PMID- 29430792 TI - Manifold decoding for neural representations of face viewpoint and gaze direction using magnetoencephalographic data. AB - The main challenge in decoding neural representations lies in linking neural activity to representational content or abstract concepts. The transformation from a neural-based to a low-dimensional representation may hold the key to encoding perceptual processes in the human brain. In this study, we developed a novel model by which to represent two changeable features of faces: face viewpoint and gaze direction. These features are embedded in spatiotemporal brain activity derived from magnetoencephalographic data. Our decoding results demonstrate that face viewpoint and gaze direction can be represented by manifold structures constructed from brain responses in the bilateral occipital face area and right superior temporal sulcus, respectively. Our results also show that the superposition of brain activity in the manifold space reveals the viewpoints of faces as well as directions of gazes as perceived by the subject. The proposed manifold representation model provides a novel opportunity to gain further insight into the processing of information in the human brain. PMID- 29430793 TI - Medial habenula cholinergic signaling regulates cocaine-associated relapse-like behavior. AB - Propensity to relapse, even following long periods of abstinence, is a key feature in substance use disorders. Relapse and relapse-like behaviors are known to be induced, in part, by re-exposure to drug-associated cues. Yet, while many critical nodes in the neural circuitry contributing to relapse have been identified and studied, a full description of the networks driving reinstatement of drug-seeking behaviors is lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral and medial (MHb) substructures, each with unique cell and target populations. Although well conserved across vertebrate species, the functions of the MHb are not well understood. Recent research has demonstrated that the MHb regulates nicotine aversion and withdrawal. However, it remains undetermined whether MHb function is limited to nicotine and aversive stimuli or if MHb circuit regulates responses to other drugs of abuse. Advances in circuit level manipulations now allow for cell-type and temporally specific manipulations during behavior, specifically in spatially restrictive brain regions, such as the MHb. In this study, we focus on the response of the MHb to reinstatement of cocaine-associated behavior, demonstrating that cocaine-primed reinstatement of conditioned place preference engages habenula circuitry. Using chemogenetics, we demonstrate that MHb activity is sufficient to induce reinstatement behavior. Together, these data identify the MHb as a key hub in the circuitry underlying reinstatement and may serve as a target for regulating relapse-like behaviors. PMID- 29430794 TI - Liebowitz Social Anxiety Scale (LSAS): Optimal cut points for remission and response in a German sample. AB - The Liebowitz Social Anxiety Scale (LSAS) is the most frequently used instrument to assess social anxiety disorder (SAD) in clinical research and practice. Both a self-reported (LSAS-SR) and a clinician-administered (LSAS-CA) version are available. The aim of the present study was to define optimal cut-off (OC) scores for remission and response to treatment for the LSAS in a German sample. Data of N = 311 patients with SAD were used who had completed psychotherapeutic treatment within a multicentre randomized controlled trial. Diagnosis of SAD and reduction in symptom severity according to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition, served as gold standard. OCs yielding the best balance between sensitivity and specificity were determined using receiver operating characteristics. The variability of the resulting OCs was estimated by nonparametric bootstrapping. Using diagnosis of SAD (present vs. absent) as a criterion, results for remission indicated cut-off values of 35 for the LSAS-SR and 30 for the LSAS-CA, with acceptable sensitivity (LSAS-SR: .83, LSAS-CA: .88) and specificity (LSAS-SR: .82, LSAS-CA: .87). For detection of response to treatment, assessed by a 1-point reduction in the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition, rating, a reduction of 28% for the LSAS-SR and 29% for the LSAS-CA yielded the best balance between sensitivity (LSAS-SR: .75, LSAS-CA: .83) and specificity (LSAS-SR: .76, LSAS-CA: .80). To our knowledge, we are the first to define cut points for the LSAS in a German sample. Overall, the cut points for remission and response corroborate previously reported cut points, now building on a broader data basis. PMID- 29430795 TI - Pediatric renal transplantation: A retrospective single-center study on epidemiology and morbidity due to EBV. AB - Pediatric R-Tx patients are at high risk of developing EBV primary infection. Although high DNA replication is a risk factor for PTLD, some patients develop PTLD with low viral load. In this retrospective single-center study including all pediatric patients having received R-Tx (2003-2012 period), we aimed to identify risk factors for uncontrolled reactions to EBV (defined as the presence of a viral load >10 000 copies/mL or PTLD). A Cox proportional hazard model was performed. A total of 117 patients underwent R-Tx at a mean age of 9.7 +/- 5.3 years, 46 of them being seronegative for EBV at the time of R-Tx. During follow up, 54 patients displayed positive EBV viral load, 22 of whom presenting with primary infection. An uncontrolled reaction to EBV was observed in 24 patients, whilst 4 patients developed PTLD. Univariate and multivariate analyses suggested the following risk factors for an uncontrolled reaction: age below 5 years, graft from a deceased donor, >=5 HLA mismatches, EBV-seronegative status at the time of R-Tx, and a secondary post-Tx loss of anti-EBNA. Monitoring anti-EBNA after R-Tx may contribute to the early identification of patients at risk for uncontrolled reaction. PMID- 29430796 TI - Effect of denosumab on fasting glucose in women with diabetes or prediabetes from the FREEDOM trial. AB - BACKGROUND: RANKL is a key regulator of bone resorption that may also modulate glucose metabolism. Denosumab (DMAb) is a fully human monoclonal antibody that binds RANKL and was associated with fracture risk reduction in the FREEDOM trial. We hypothesized that DMAb treatment decreased fasting serum glucose (FSG) relative to placebo in women with diabetes or prediabetes enrolled in FREEDOM trial. METHODS: Post hoc analysis of FREEDOM, in which 7808 postmenopausal osteoporotic women were randomized to receive DMAb or placebo every 6 months for 36 months. All diabetes group included subjects with a self-report of diabetes, use of antidiabetic medication (ADM), or an FSG >= 126 mg/dL at baseline. The diabetes group without prior ADM use included subjects with a self-reported history of diabetes or FSG level >= 126 mg/dL at baseline. Prediabetes was defined as an FSG of 100 to 125 mg/dL on no ADM. Average postbaseline FSG across visits was estimated and compared between DMAb and placebo. Main outcome measures are the difference in average postbaseline FSG across follow-up visits between DMAb and placebo. RESULTS: Estimated average postbaseline FSG across visits was not different between DMAb and placebo in either all diabetes group (P = .20) or those with prediabetes (P = .42); in diabetic women not on ADM, estimated average postbaseline FSG across visits was lower with DMAb than placebo (-6.8 mg/dL; 95% CI, -12.6 to -1.0; P = .02). CONCLUSIONS: DMAb did not affect FSG in postmenopausal osteoporotic women with prediabetes or diabetes. There was evidence of modest FSG lowering with DMAb in those with diabetes who were not on ADM. It remains to be determined whether blockade of RANKL has a clinically important effect on glucose metabolism. PMID- 29430797 TI - Inherently Eu2+ /Eu3+ Codoped Sc2 O3 Nanoparticles as High-Performance Nanothermometers. AB - Luminescent nanothermometers have shown competitive superiority for contactless and noninvasive temperature probing especially at the nanoscale. Herein, we report the inherently Eu2+ /Eu3+ codoped Sc2 O3 nanoparticles synthesized via a one-step and controllable thermolysis reaction where Eu3+ is in-situ reduced to Eu2+ by oleylamine. The stable luminescence emission of Eu3+ as internal standard and the sensitive response of Eu2+ emission to temperature as probe comprise a perfect ratiometric nanothermometer with wide-range temperature probing (77-267 K), high repeatability (>99.94%), and high relative sensitivity (3.06% K-1 at 267 K). The in situ reduction of Eu3+ to Eu2+ ensures both uniform distribution in the crystal lattice and simultaneous response upon light excitation of Eu2+ /Eu3+ . To widen this concept, Tb3+ is codoped as additional internal reference for tunable temperature probing range. PMID- 29430798 TI - Type 2 diabetes after gestational diabetes: Can the progression be prevented? PMID- 29430799 TI - Direct medical costs of diabetes mellitus in the year of mortality and year preceding the year of mortality. AB - AIM: To report the health resource use and estimate the direct medical costs among patients with diabetes mellitus (DM) in the year of mortality and the year preceding the year of mortality. MATERIALS AND METHODS: We analysed data from a population-based, retrospective cohort study including all adults with a DM diagnosis in Hong Kong between 2009 and 2013, and who died between January 1, 2010 and December 31, 2013. The annual direct medical costs in the year of mortality and the year preceding the year of mortality were determined by summing the costs of health services utilized within the respective year. The costs were analysed by gender, the presence of comorbidities, diabetic complications and primary cause of death. RESULTS: A total of 10 649 patients met the eligibility criteria for analysis. On average, the direct medical costs in the year of death were 1.947 times higher than those in the year before death. Men and women with DM incurred similar costs in the year preceding the year of mortality and in the mortality year. Patients with any diabetic complications incurred greater costs in the year of mortality and the year before mortality than those without. CONCLUSIONS: This analysis provides new evidence on incorporating additional direct medical costs in the mortality year, and refining the structure of total cost estimates for use in costing and cost-effectiveness analyses of interventions for DM. PMID- 29430800 TI - Ocular protrusion in sitting and supine position. PMID- 29430801 TI - Dulaglutide 1.5 mg as an add-on option for patients uncontrolled on insulin: Subgroup analysis by age, duration of diabetes and baseline glycated haemoglobin concentration. AB - AIMS: To assess efficacy and safety of dulaglutide 1.5 mg combined with insulin, categorized by subgroups of baseline glycated haemoglobin (HbA1c; <=9% and >9% [<=74.9 and >74.9 mmol/mol]), age (<65 and >=65 years), and duration of diabetes (<10 and >=10 years) at 6 months in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: This pooled analysis was conducted in a population of patients with T2D with similar baseline characteristics who were included in the AWARD-4 and AWARD-9 clinical trials and randomized to dulaglutide 1.5 mg (pooled mean baseline age 59 years, duration of diabetes 13 years, HbA1c 8.4% [68.3 mmol/mol]). Weight and hypoglycaemia were analysed by individual trial. In AWARD 4, dulaglutide plus lispro three times daily was assessed against glargine plus lispro three times daily. In AWARD-9, dulaglutide added to glargine was assessed against placebo added to glargine. Insulins were titrated to target in both trials. RESULTS: A total of 445 patients were included in this analysis (73% with HbA1c <=9%, 27% [<=74.9 mmol/mol] with HbA1c >9% [>74.9 mmol/mol]; 70% aged <65 years, 30% aged >=65 years; 36% with duration of diabetes <10 years, 64% with duration of diabetes >=10 years). At 6 months, dulaglutide 1.5 mg significantly reduced HbA1c in all subgroups (P < .001), with the highest reduction observed in patients with baseline HbA1c >9% (>74.9 mmol/mol) (range - 1.3% to -2.5% [-14.2 to -27.3 mmol/mol]). The incidence rates of documented symptomatic and severe hypoglycaemia were similar in all subgroups in both trials. The most common adverse events observed in each trial were gastrointestinal in nature. CONCLUSION: Dulaglutide 1.5 mg combined with basal or prandial insulin is efficacious for patients with T2D irrespective of age, duration of diabetes or baseline HbA1c. PMID- 29430802 TI - Surgery for oligometastatic prostate cancer: ready for prime time? PMID- 29430803 TI - An initial experience with an Extraluminal EZ-Blocker(r) : A new alternative for 1-lung ventilation in pediatric patients. AB - BACKGROUND: The need for 1-lung ventilation in school age, pediatric patients is uncommon and as a result there are relatively few devices available to facilitate lung isolation in this population. Furthermore, little is known about the efficacy and techniques of placement of the currently available devices. One of the newest devices available that may be appropriate in this age group is the EZ Blocker. AIMS: We aimed to examine our initial experience with the EZ-Blocker to evaluate the performance of this device with respect to potential improvements in technique and patient selection going forward. METHODS: We performed a retrospective chart review of all pediatric patients who underwent 1-lung ventilation with an EZ-Blocker since the blocker became available at our institution. We recorded demographics, details of placement, intraoperative course, number of repositions, and any postoperative morbidity related to blocker placement or 1-lung ventilation. RESULTS: We were able to correctly place the EZ Blocker and achieve lung isolation in 8 of 11 patients. There was a single episode of repositioning required during 1-lung ventilation with an EZ-Blocker. CONCLUSION: The EZ-Blocker was successful in providing lung isolation for a majority of our school age patients. Size constraints in children <6 years of age, excessive secretions, and distortions of tracheal anatomy seemed to be the greatest hindrances to successful placement and positioning of the device. Once correctly positioned, however, the EZ-Blocker may be more stable than the Arndt endobronchial blocker. PMID- 29430804 TI - Reversal of Hartmann's procedure: a single-centre experience of 533 consecutive cases. AB - AIM: Hartmann's procedure (HP) is common. However, restoration of intestinal continuity is not so frequent. The aim of this study was to determine predictive factors which might influence outcomes following the reversal of HP. METHOD: All consecutive patients who underwent elective and emergency HP in a single institution between January 1999 and December 2014 were included. Data concerning patient, disease and treatment features were collected. Univariate and multivariate binary logistic regression models were used to determine prognostic factors. RESULTS: A total of 533 consecutive patients underwent HP over the 16 year period. Factors that were associated with a higher probability of reversal were age (< 69 years), American Society of Anesthesiologists (ASA) grade (I or II), indication for HP (likelihood of anastomotic leakage) and length of rectal stump reaching or exceeding the sacral promontory. A reduced probability of intestinal reconstruction was associated with anal incontinence, Stage IV cancer, postoperative transfusion or elective surgery. CONCLUSION: Age, ASA grade, the indication for HP, the length of rectal stump, anal incontinence, tumour stage, postoperative transfusion and elective surgery determine the probability of reversal. PMID- 29430805 TI - The localization and function of p38alpha mitogen-activated protein kinase in rat oocytes. AB - P38alpha mitogen-activated protein kinase (MAPK), which is a member of the canonical MAPK family, is activated in response to various extracellular stresses and plays a role in multiple cellular processes. In this study, we investigated the expression, subcellular localization and functional roles of p38alpha MAPK during the meiotic maturation of rat oocytes. We found that p38alpha MAPK phosphorylation (p-p38alpha MAPK, indicative of p38alpha MAPK activation) was low at the germinal vesicle (GV) stage, increased 3 hr after germinal vesicle breakdown (GVBD) and maintained its maximum at metaphase I (MI) or metaphase II (MII). The p-p38alpha MAPK mainly accumulated in the GV and had no obvious expression in the nucleus. From GVBD to MII, p-p38alpha MAPK was distributed in the cytoplasm around either the chromosomes or the spindle. We used SB203580, an inhibitor of p38alpha MAPK, to investigate the possible functional role of p38alpha MAPK during rat oocyte meiotic maturation. Treatment of GV stage oocytes with 20 MUM SB203580 blocked p-p38alpha MAPK activity, and the spindles appeared abnormal. Additionally, the rate of GVBD after 3 hr of culture with 20 MUM SB203580 (58.8%) was significantly inhibited compared with the control (82.5%, p < .05), and the polar body extrusion rate after 12 hr of culture with SB203580 was also significantly decreased compared with the control (40.1% vs 73.3%, p < .05). Taken together, these data indicate that p38alpha MAPK may play a vital role in rat oocyte meiotic maturation. PMID- 29430807 TI - Microtensile Bond Strength of CAD/CAM Resin Blocks to Dual-Cure Adhesive Cement: The Effect of Different Sandblasting Procedures. AB - PURPOSE: To investigate the effect of sandblasting powder particles on microtensile bond strength (MUTBS) of dual-cure adhesive cement to CAD/CAM blocks. MATERIALS AND METHODS: CAD/CAM blocks (Cerasmart, VITA, and LAVA) were cut in slabs and divided into groups: group 1, no sandblasting; group 2, sandblasted with 27-MUm Al2 O3 ; group 3, sandblasted with 30-MUm CoJet; group 4, sandblasted with 50-MUm Al2 O3 . After sandblasting, all specimens were silanized and luted using dual-cure adhesive cement (G-CEM LinkForce). After 24 hours, bonded specimens were cut into 1 +/- 0.2 mm2 sticks, and MUTBS values were obtained (N = 30). Additionally, 132 CAD/CAM block sections were prepared for surface roughness testing and scanning electron microscopy (SEM) evaluations. Results were analyzed using Kruskal-Wallis One-way ANOVA and Dunn's Post Hoc Test (p < 0.05). RESULTS: Group 1 exhibited significantly lower MUTBS than the other groups (p < 0.05). The highest bond strength values were obtained from group 4 (p > 0.05). For LAVA, MUTBS values of specimens that were sandblasted with 50-MUm Al2 O3 powder were significantly higher than 30-MUm-SiO2 and 27-MUm Al2 O3 (p < 0.05). CONCLUSIONS: The sand particles investigated (27-MUm Al2 O3 , 30-MUm SiO2 , or 50-MUm Al2 O3 ) did not significantly affect MUTBS results of CAD/CAM blocks for Cerasmart and VITA, although the results changed significantly for LAVA. The ideal bond protocol for CAD/CAM blocks is specific to the material used. PMID- 29430808 TI - Synthesis of Alternating Donor-Acceptor Ladder-Type Molecules and Investigation of Their Multiple Charge-Transfer Pathways. AB - We describe the synthesis as well as the optical and charge-transport properties of a series of donor-acceptor (D-A) ladder-type heteroacenes. These molecules are stable, soluble, and contain up to 24 fused rings. Structural analyses indicated that the backbones of S 10r and Se 10r are bent in single crystals. The three 10 ring heteroacenes were functionalized with thiol anchoring groups and used for single-molecular conductance measurements. The highest conductance was observed for molecular wires containing a benzoselenadiazole (BSD) moiety, which exhibits the narrowest band gap. Multiple charge-transport pathways were observed in molecular wires containing either benzothiadiazole (BTD) or BSD. The conductance is a complex function of both energy gap and orbital alignment. PMID- 29430806 TI - Cannabis use is associated with lower rates of initiation of injection drug use among street-involved youth: A longitudinal analysis. AB - INTRODUCTION AND AIMS: Street-involved youth are known to be at elevated risk of initiating injection drug use. However, the impact of so-called 'gateway' drugs, such as cannabis, on injection initiation is unknown. The objective of this study was to examine the association between cannabis use and initiation of injection drug use among a prospective cohort of street-involved youth in Vancouver, Canada. DESIGN AND METHODS: Data for this study were collected from the At-Risk Youth Study. From September 2005 to May 2015, participants aged 14-26 who reported illicit drug use were recruited into this open prospective cohort study. An extended Cox regression model with time-updated covariates was used to identify factors independently associated with injection initiation. RESULTS: During the study period, 481 street-involved youth were included in this study. Of these, 228 (47.4%) reported at least daily cannabis use, and 103 (21.4%) initiated injection drug use. In a multivariable analysis, >=daily cannabis use was associated with slower rates of injection initiation (adjusted relative hazard 0.66, 95% confidence interval 0.45-0.98; P = 0.038). Sub-analyses revealed that cannabis use was negatively associated with initiation of injection stimulants but not initiation of injection opioids. DISCUSSION AND CONCLUSIONS: Given the expansion of cannabis legalisation throughout North America, it is encouraging that cannabis use was associated with slower time to initiation of injection drug use in this cohort. This finding challenges the view of cannabis as a gateway substance that precipitates the progression to using harder and more addictive drugs. PMID- 29430809 TI - Morbidity and mortality meetings: gold, silver or bronze? AB - BACKGROUND: Morbidity and mortality (M&M) meetings contribute to surgical education and improvements in patient care through the review of surgical outcomes; however, they often lack defined structure, objectives and resource support. The aim of this study was to investigate the factors that impact the effective conduct of M&M meetings. METHODS: We conducted a rapid systematic literature review. Three biomedical databases (PubMed, the Cochrane Library and the University of York Centre for Reviews and Dissemination), clinical practice guideline clearinghouses and grey literature sources were searched from May 2009 to September 2016. Studies that evaluated the function of a hospital-based M&M process were included. Two independent reviewers conducted study selection and data extraction. Study details and key findings were reported narratively. RESULTS: Nineteen studies identified enablers, and seven identified barriers, to the effective conduct of M&M meetings. Enabling factors for effective M&M meetings included a structured meeting format, a structured case identification and presentation, and a systems focus. Absence of key personnel from meetings, lack of education regarding the meeting process, poor perceptions of the process, logistical issues and heterogeneity in case evaluation were identified as barriers to effective M&M meetings. CONCLUSION: Taking steps to standardize and incorporate the enabling factors into M&M meetings will ensure that the valuable time spent reviewing M&M is used effectively to improve patient care. PMID- 29430810 TI - Extreme streams: species persistence and genomic change in montane insect populations across a flooding gradient. AB - The ecological and evolutionary consequences of extreme events are poorly understood. Here, we tested predictions about species persistence and population genomic change in aquatic insects in 14 Colorado mountain streams across a hydrological disturbance gradient caused by a one in 500-year rainfall event. Taxa persistence ranged from 39 to 77% across sites and declined with increasing disturbance in relation to species' resistance and resilience traits. For taxa with mobile larvae and terrestrial adult stages present at the time of the flood, average persistence was 84% compared to 25% for immobile taxa that lacked terrestrial adults. For two of six species analysed, genomic diversity (allelic richness) declined after the event. For one species it greatly expanded, suggesting resilience via re-colonisation from upstream populations. Thus, while resistance and resilience traits can explain species persistence to extreme disturbance, population genomic change varies among species, challenging generalisations about evolutionary responses to extreme events at landscape scales. PMID- 29430811 TI - A Smart Superwetting Surface with Responsivity in Both Surface Chemistry and Microstructure. AB - Recently, smart surfaces with switchable wettability have aroused much attention. However, only single surface chemistry or the microstructure can be changed on these surfaces, which significantly limits their wetting performances, controllability, and applications. A new surface with both tunable surface microstructure and chemistry was prepared by grafting poly(N-isopropylacrylamide) onto the pillar-structured shape memory polymer on which multiple wetting states from superhydrophilicity to superhydrophobicity can be reversibly and precisely controlled by synergistically regulating the surface microstructure and chemistry. Meanwhile, based on the excellent controllability, we also showed the application of the surface as a rewritable platform, and various gradient wettings can be obtained. This work presents for the first time a surface with controllability in both surface chemistry and microstructure, which starts some new ideas for the design of novel superwetting materials. PMID- 29430812 TI - Identifying elevated blood pressure and hypertension in children and adolescents. PMID- 29430813 TI - Reversible Phase Transfer of Carbon Dots between an Organic Phase and Aqueous Solution Triggered by CO2. AB - Carbon dots (CDs) have attracted increasing attention in applications such as bio imaging, sensors, catalysis, and drug delivery. However, unlike metallic and semiconductor nanoparticles, the transfer of CDs between polar and non-polar phases is little understood. A class of amine-terminated CDs is developed and their phase transfer behavior has been investigated. It is found that these CDs can reversibly transfer between aqueous and organic solvents by alternatively bubbling and removing CO2 at atmospheric pressure. The mechanism of such CO2 switched phase transfer involves reversible acid-base reaction of amine terminated CDs with CO2 and the reversible formation of hydrophilic ammonium salts. By using the CDs as catalysts, the phase transfer is applied in the Knoevenagel reaction for efficient homogeneous reaction, heterogeneous separation, and recycling of the catalysts. PMID- 29430815 TI - Microscopic study on the concretion of ceramics in the "Nanhai I" shipwreck of China, Southern Song Dynasty (1,127-1,279 A.D.). AB - "Nanhai I" shipwreck of China Southern Song Dynasty is the oldest and the most integrally preserved shipwreck in the world. The related conservation and archeological research have caught great attention of different experts all over the world. In this study, different types of concretion covered on the surface of the ceramics in "Nanhai I" shipwreck were analyzed by X-ray diffractometer, micro Raman spectrometer, and scanning electron microscope equipped with energy dispersive spectroscopy. Based on the analyses, we found that the grey concretion was mainly composed of quartz, aragonite, and calcite while the reddish concretion was mainly composed of pyrite and quartz. Our study indicated that the formation process of the grey concretion probably included the crystallization and transformation of aragonite, while the corrosion of iron implements and crystallization of pyrite were highly involved in the formation of reddish concretion. PMID- 29430814 TI - SGLT-2 inhibitors and the risk of lower-limb amputation: Is this a class effect? AB - Inhibitors of the sodium-glucose co-transporter-2 (SGLT-2) are a novel class of glucose-lowering agents that show promising results. However, the use of canagliflozin has been associated with an increased risk of lower-limb amputation. Whether this risk concerns other SGLT-2 inhibitors is unclear, and our objective was to address this issue. We performed a disproportionality analysis using the WHO global database of individual case safety reports (VigiBase). Among the 8 293 886 reports available between January 2013 and December 2017, we identified 79 reports of lower-limb amputation that were associated with SGLT-2 inhibitors. Among all blood glucose lowering drugs, the proportional reporting ratio (PRR) was increased only for SGLT-2 inhibitors (5.55 [4.23, 7.29]). While we observed an expected signal for canagliflozin (7.09 [5.25, 9.57]), the PRR was also high for empagliflozin (4.96 [2.89, 8.50]) and, for toe amputations only, for dapagliflozin (2.62 [1.33, 5.14]). In conclusion, our results reveal a positive disproportionality signal for canagliflozin, and also for empagliflozin, and, for toe amputations only, for dapagliflozin. However, our analysis relies on a limited number of cases and is exposed to the biases inherent to pharmacovigilance studies. Further prospective data are therefore needed to better characterize the risk of amputations with different SGLT-2 inhibitors. PMID- 29430816 TI - Helicobacter pylori purine nucleoside phosphorylase shows new distribution patterns of open and closed active site conformations and unusual biochemical features. AB - : Even with decades of research, purine nucleoside phosphorylases (PNPs) are enzymes whose mechanism is yet to be fully understood. This is especially true in the case of hexameric PNPs, and is probably, in part, due to their complex oligomeric nature and a whole spectrum of active site conformations related to interactions with different ligands. Here we report an extensive structural characterization of the apo forms of hexameric PNP from Helicobacter pylori (HpPNP), as well as its complexes with phosphate (Pi ) and an inhibitor, formycin A (FA), together with kinetic, binding, docking and molecular dynamics studies. X ray structures show previously unseen distributions of open and closed active sites. Microscale thermophoresis results indicate that a two-site model describes Pi binding, while a three-site model is needed to characterize FA binding, irrespective of Pi presence. The latter may be related to the newly found nonstandard mode of FA binding. The ternary complex of the enzyme with Pi and FA shows, however, that Pi binding stabilizes the standard mode of FA binding. Surprisingly, HpPNP has low affinity towards the natural substrate adenosine. Molecular dynamics simulations show that Pi moves out of most active sites, in accordance with its weak binding. Conformational changes between nonstandard and standard binding modes of nucleoside are observed during the simulations. Altogether, these findings show some unique features of HpPNP and provide new insights into the functioning of the active sites, with implications for understanding the complex mechanism of catalysis of this enzyme. DATABASES: The atomic coordinates and structure factors have been deposited in the Protein Data Bank: with accession codes 6F52 (HpPNPapo_1), 6F5A (HpPNPapo_2), 6F5I (HpPNPapo_3), 5LU0 (HpPNP_PO4), 6F4W (HpPNP_FA) and 6F4X (HpPNP_PO4_FA). ENZYMES: Purine nucleoside orthophosphate ribosyl transferase, EC2.4.2.1, UniProtID: P56463. PMID- 29430818 TI - Isolation and identification of Acinetobacter spp. from healthy canine skin. AB - BACKGROUND: Acinetobacter species can exhibit widespread resistance to antimicrobial agents. They are already recognized as important nosocomial pathogens of humans, but are becoming increasingly recognized in opportunistic infections of animals. HYPOTHESIS/OBJECTIVES: This study aimed to determine whether Acinetobacter spp. are carried on skin of healthy dogs and, if present, to identify the species. ANIMALS: Forty dogs were sampled at veterinary practices and rescue centres. They were free from skin disease and receiving no systemic or topical treatments. METHODS: Skin swab samples were collected from four sites on each dog and cultured. Acinetobacter spp. isolates were detected by biochemical tests and gas chromatography. The species was determined by sequencing the RNA polymerase beta-subunit (rpoB) gene. Isolates were screened for OXA carbapenemase genes and class 1 integrons capable of carrying resistance genes, and subjected to antimicrobial susceptibility tests. RESULTS: For 25% dogs sampled (10 of 40), Acinetobacter spp. were isolated at one or more skin sites. Thirteen Acinetobacter spp. isolates were recovered from 160 samples. The most frequently cultured was A. lwoffii (seven of 13), followed by A. baumannii (two of 13), A. junii (one of 13), A. calcoaceticus (one of 13), A. pittii (one of 13) and a novel Acinetobacter species (one of 13). Class 1 integrons and blaOXA-23-like were not detected. Isolates were susceptible to most antibiotics. CONCLUSIONS AND CLINICAL IMPORTANCE: The study confirms that Acinetobacter spp. can survive on canine skin, where they may be potential reservoirs for infection. This highlights the importance of good hygiene in veterinary practice, adhering to aseptic principles in surgery, and treatment based on culture and susceptibility testing where possible. PMID- 29430819 TI - Intranasal Nanovaccine Confers Homo- and Hetero-Subtypic Influenza Protection. AB - Cross-protective and non-invasively administered vaccines are attractive and highly desired for the control of influenza. Self-assembling nanotechnology provides an opportunity for the development of vaccines with superior performance. In this study, an intranasal nanovaccine is developed targeting the conserved ectodomain of influenza matrix protein 2(M2e). 3-sequential repeats of M2e (3M2e) is presented on the self-assembling recombinant human heavy chain ferritin (rHF) cage to form the 3M2e-rHF nanoparticle. Intranasal vaccination with 3M2e-rHF nanoparticles in the absence of an adjuvant induces robust immune responses, including high titers of sera M2e-specific IgG antibodies, T-cell immune responses, and mucosal secretory-IgA antibodies in mice. The 3M2e-rHF nanoparticles also confer complete protection against a lethal infection of homo subtypic H1N1 and hetero-subtypic H9N2 virus. An analysis of the mechanism of protection underlying the intranasal immunization with the 3M2e-rHF nanoparticle indicates that M2e-specific mucosal secretory-IgA and T-cell immune responses may play critical roles in the prevention of infection. The results suggest that the 3M2e-rHF nanoparticle is a promising, needle-free, intranasally administered, cross-protective influenza vaccine. The use of self-assembling nanovaccines could be an ideal strategy for developing vaccines with characteristics such as high immunogenicity, cross-protection, and convenient administration, as well as being economical and suitable for large-scale production. PMID- 29430817 TI - The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant. AB - A significant aspect of the control of cellular zinc in eukarya is its subcellular re-distribution. One of the four human vesicular zinc transporters, ZnT8, supplies the millimolar zinc concentrations of insulin granules in pancreatic beta-cells, affecting insulin processing, crystallisation and secretion. ZnT8 has a transmembrane and a C-terminal cytosolic domain; the latter has important functions and purportedly mediates protein-protein interactions, senses cytosolic zinc and/or channels zinc to the transport site in the transmembrane domain (TMD). A common variant W325R in the C-terminal domain (CTD) increases the risk to develop type 2 diabetes and affects autoantibody specificity in type 1 diabetes. To investigate the differences between the two protein variants, we purified and biophysically characterised both variants of the ZnT8 CTD [R325 variant of ZnT8 CTD (aa267-369) (ZnT8cR) and W325 variant of ZnT8 CTD (aa267-369) (ZnT8cW)]. The domains fold independently of the TMD. Remarkably, the ZnT8cW variant (diabetes protection in the full-length protein) is less thermostable than the ZnT8cR variant (diabetes risk in the full-length protein). The ZnT8cW monomers associate with higher affinity. Both CTD variants bind zinc with a stoichiometry that differs from bacterial homologues, emphasising the limitation of the latter as models for the structure and function of the human proteins. The relatively small but reproducible differences between the two ZnT8 CTD variants begin to provide a molecular basis for the different diabetes susceptibility caused by the full-length ZnT8 proteins. PMID- 29430820 TI - Controlling the Diameters of Nanotubes Self-Assembled from Designed Peptide Bolaphiles. AB - Controlling the diameters of nanotubes represents a major challenge in nanostructures self-assembled from templating molecules. Here, two series of bolaform hexapeptides are designed, with Set I consisting of Ac-KI4 K-NH2 , Ac KI3 NleK-NH2 , Ac-KI3 LK-NH2 and Ac-KI3 TleK-NH2 , and Set II consisting of Ac KI3 VK-NH2 , Ac-KI2 V2 K-NH2 , Ac-KIV3 K-NH2 and Ac-KV4 K-NH2 . In Set I, substitution for Ile in the C-terminal alters its side-chain branching, but the hydrophobicity is retained. In Set II, the substitution of Val for Ile leads to the decrease of hydrophobicity, but the side-chain beta-branching is retained. The peptide bolaphiles tend to form long nanotubes, with the tube shell being composed of a peptide monolayer. Variation in core side-chain branching and hydrophobicity causes a steady shift of peptide nanotube diameters from more than one hundred to several nanometers, thereby achieving a reliable control over the underlying molecular self-assembling processes. Given the structural and functional roles of peptide tubes with varying dimensions in nature and in technological applications, this study exemplifies the predictive templating of nanostructures from short peptide self-assembly. PMID- 29430821 TI - Alanine and Lysine Scans of the LL-37-Derived Peptide Fragment KR-12 Reveal Key Residues for Antimicrobial Activity. AB - The human host defence peptide LL-37 is a broad-spectrum antibiotic with immunomodulatory functions. Residues 18-29 in LL-37 have previously been identified as a minimal peptide (KR-12) that retains antibacterial activity with decreased cytotoxicity. In this study, analogues of KR-12 were generated by Ala and Lys scans to identify key elements for activity. These were tested against a panel of human pathogens and for membrane permeabilisation on liposomes. Replacements of hydrophobic and cationic residues with Ala were detrimental for antibiotic potency. Substitutions by Lys increased activity, as long as the increase in cationic density did not disrupt the amphiphilic disposition of the helical structure. Importantly, substitutions showed differential effects against different organisms. Replacement of Gln5 with Lys and Asp9 with Ala or Lys improved the broad-spectrum activity most, each resulting in up to an eightfold increase in potency against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. The improved analogues displayed no significant toxicity against human cells, and thus, KR-12 is a tuneable template for antibiotic development. PMID- 29430822 TI - Rapid and sensitive detection of the phenoxy acid herbicides in environmental water samples by magnetic solid-phase extraction combined with liquid chromatography-tandem mass spectrometry. AB - Phenoxy acid herbicides are widely used herbicides that play an important role in improving the yield and quality of crops. However, some research has shown that this kind of herbicide is poisonous to human and animals. In this study, a rapid and sensitive method was developed for the detection of seven phenoxy acid herbicides in water samples based on magnetic solid-phase extraction followed by liquid chromatography and tandem mass spectrometry. Magnetic amino-functionalized multiwalled carbon nanotubes were prepared by mixing bare magnetic Fe3 O4 nanoparticles with commercial amino-functionalized multiwalled carbon nanotubes in water. Then the amino-functionalized multiwalled carbon nanotubes were used to enrich phenoxy acid herbicides from water samples based on hydrophobic and ionic interactions. The effects of experimental variables on the extraction efficiency have been studied in detail. Under the optimized conditions, the method validation was performed. Good linearities for seven phenoxy acid herbicides were obtained with squared regression coefficients ranging from 0.9971 to 0.9989. The limits of detection ranged from 0.01 to 0.02 MUg/L. The method recoveries of seven phenoxy acid herbicides spiked at three concentration levels in a blank sample were from 92.3 to 103.2%, with inter- and intraday relative standard deviations less than 12.6%. PMID- 29430823 TI - Creating Graphitic Carbon Nitride Based Donor-pi-Acceptor-pi-Donor Structured Catalysts for Highly Photocatalytic Hydrogen Evolution. AB - Conjugated polymers with tailored donor-acceptor units have recently attracted considerable attention in organic photovoltaic devices due to the controlled optical bandgap and retained favorable separation of charge carriers. Inspired by these advantages, an effective strategy is presented to solve the main obstructions of graphitic carbon nitride (g-C3 N4 ) photocatalyst for solar energy conversion, that is, inefficient visible light response and insufficient separation of photogenerated electrons and holes. Donor-pi-acceptor-pi-donor polymers are prepared by incorporating 4,4'-(benzoc 1,2,5 thiadiazole-4,7-diyl) dianiline (BD) into the g-C3 N4 framework (UCN-BD). Benefiting from the visible light band tail caused by the extended pi conjugation, UCN-BD possesses expanded visible light absorption range. More importantly, the BD monomer also acts as an electron acceptor, which endows UCN-BD with a high degree of intramolecular charge transfer. With this unique molecular structure, the optimized UCN-BD sample exhibits a superior performance for photocatalytic hydrogen evolution upon visible light illumination (3428 umol h-1 g-1 ), which is nearly six times of that of the pristine g-C3 N4 . In addition, the photocatalytic property remains stable for six cycles in 3 d. This work provides an insight into the synthesis of g-C3 N4 -based D-pi-A-pi-D systems with highly visible light response and long lifetime of intramolecular charge carriers for solar fuel production. PMID- 29430824 TI - DNA methylation analyses of the candidate genes identified by a methylome-wide association study revealed common epigenetic alterations in schizophrenia and bipolar disorder. AB - AIM: Schizophrenia (SZ) and bipolar disorder (BD) have been known to share genetic and environmental risk factors, and complex gene-environmental interactions may contribute to their pathophysiology. In contrast to high genetic overlap between SZ and BD, as revealed by genome-wide association studies, the extent of epigenetic overlap remains largely unknown. In the present study, we explored whether SZ and BD share epigenetic risk factors in the same manner as they share genetic components. METHODS: We performed DNA methylation analyses of the CpG sites in the top five candidate regions (FAM63B, ARHGAP26, CTAGE11P, TBC1D22A, and intergenic region [IR] on chromosome 16) reported in a previous methylome-wide association study (MWAS) of SZ, using whole blood samples from subjects with BD and controls. RESULTS: Among the five candidate regions, the CpG sites in FAM63B and IR on chromosome 16 were significantly hypomethylated in the samples from subjects with BD as well as those from subjects with SZ. On the other hand, the CpG sites in TBC1D22A were hypermethylated in the samples from subjects with BD, in contrast to hypomethylation in the samples from subjects with SZ. CONCLUSION: Hypomethylation of FAM63B and IR on chromosome 16 could be common epigenetic risk factors for SZ and BD. Further comprehensive epigenetic studies for BD, such as MWAS, will uncover the extent of similarity and uniqueness of epigenetic alterations. PMID- 29430825 TI - Dynamically PEGylated and Borate-Coordination-Polymer-Coated Polydopamine Nanoparticles for Synergetic Tumor-Targeted, Chemo-Photothermal Combination Therapy. AB - Multifunctional nanomaterials with efficient tumor-targeting and high antitumor activity are highly anticipated in the field of cancer therapy. In this work, a synergetic tumor-targeted, chemo-photothermal combined therapeutic nanoplatform based on a dynamically PEGylated, borate-coordination-polymer-coated polydopamine nanoparticle (PDA@CP-PEG) is developed. PEGylation on the multifunctional nanoparticles is dynamically achieved via the reversible covalent interaction between the surface phenylboronic acid (PBA) group and a catechol-containing poly(ethylene glycol) (PEG) molecule. Due to the acid-labile PBA/catechol complex and the weak-acid-stable PBA/sialic acid (SA) complex, the nanoparticles can exhibit a synergetic targeting property for the SA-overexpressed tumor cells, i.e., the PEG-caused "passive targeting" and PBA-triggered "active targeting" under the weakly acidic tumor microenvironment. In addition, the photothermal effect of the polydopamine core and the doxorubicin-loading capacity of the porous coordination polymer layer endow the nanoparticles with the potential for chemo-photothermal combination therapy. As expected, the in vitro and in vivo studies both verify that the multifunctional nanoparticles possess relatively lower systematic toxicity, efficient tumor targeting ability, and excellent chemo photothermal activity for tumor inhibition. It is believed that these multifunctional nanoparticles with synergetic tumor targeting property and combined therapeutic strategies would provide an insight into the design of a high-efficiency antitumor nanoplatform for potential clinical applications. PMID- 29430826 TI - beta-Cyclodextrin-modified three-dimensional graphene oxide-wrapped melamine foam for the solid-phase extraction of flavonoids. AB - A new three-dimensional graphene oxide-wrapped melamine foam was prepared and used as a solid-phase extraction substrate. beta-Cyclodextrin was fabricated onto the surface of three-dimensional graphene oxide-wrapped melamine foam by a chemical covalent interaction. In view of a specific surface area and a large delocalized pi electron system of graphene oxide, in combination with a hydrophobic interior cavity and a hydrophilic peripheral face of beta cyclodextrin, the prepared extraction material was proposed for the determination of flavonoids. In order to demonstrate the extraction properties of the as prepared material, the adsorption energies were theoretically calculated based on periodic density functional theory. Static-state and dynamic-state binding experiments were also investigated, which revealed the monolayer coverage of flavonoids onto the beta-cyclodextrin/graphene oxide-wrapped melamine foams through the chemical adsorption. 1 H NMR spectroscopy indicated the formation of flavonoids-beta-cyclodextrin inclusion complexes. Under the optimum conditions, the proposed method exhibited acceptable linear ranges (2-200 MUg/L for rutin and quercetin-3-O-rhamnoside; 5-200 MUg/L for quercetin) with correlation coefficients ranging from 0.9979 to 0.9994. The batch-to-batch reproducibility (n = 5) was 3.5-6.8%. Finally, the as-established method was satisfactorily applied for the determination of flavonoids in Lycium barbarum (Goji) samples with relative recoveries in the range of 77.9-102.6%. PMID- 29430828 TI - Microwave-Assisted Regeneration of Single-Walled Carbon Nanotubes from Carbon Fragments. AB - Direct growth of chirality-controlled single-walled carbon nanotubes (SWNTs) with metal catalyst free strategy, like cloning or epitaxial growth, has suffered from the low efficiency. The underlying problem is the activation of seed edge. Here an unexpectedly efficient microwave-assisted pathway to regenerate SWNTs from carbon fragments on SiO2 /Si substrate is demonstrated via Raman spectroscopy and atomic force microscope (AFM) characterization. In this attempt, microwave irradiation provides fast heating to remove polar groups bonded to carbon nanotubes and reduce the spontaneous closure of tubes' open ends. The survived SWNT and carbon fragments connected to it after plasma treatment are simply microwaved and then they serve as the template for regeneration. Scanning electron microscope and AFM characterizations indicate that the efficiency of the regeneration can reach 100%. And the regenerated SWNT has been proved without any change in chirality compared to the original SWNT. Electrical measurements on regenerated carbon nanotube films indicate 1 and 2 times increase in on/off ratio and on-state current respectively than original carbon nanotube films obtained from solution-phase separation, confirming the improvement of SWNT's quality. The microwave-assisted regeneration is found to be highly effective and would be applied to improve the cloning efficiency of carbon nanotubes potentially. PMID- 29430827 TI - Solution structure of the PHD finger from the human KIAA1045 protein. AB - Cross-brace structural motifs are required as a scaffold to design artificial RING fingers (ARFs) that function as ubiquitin ligase (E3) in ubiquitination and have specific ubiquitin-conjugating enzyme (E2)-binding capabilities. The Simple Modular Architecture Research Tool database predicted the amino acid sequence 131 190 (KIAA1045ZF) of the human KIAA1045 protein as an unidentified structural region. Herein, the stoichiometry of zinc ions estimated spectrophotometrically by the metallochromic indicator revealed that the KIAA1045ZF motif binds to two zinc atoms. The structure of the KIAA1045ZF motif bound to the zinc atoms was elucidated at the atomic level by nuclear magnetic resonance. The actual structure of the KIAA1045ZF motif adopts a C4 HC3 -type PHD fold belonging to the cross-brace structural family. Therefore, the utilization of the KIAA1045ZF motif as a scaffold may lead to the creation of a novel ARF. PMID- 29430829 TI - The 'Two Bridges Technique' for sternal wound closure. The use of vacuum-assisted closure for the treatment of deep sternal wound defects: a centre-specific technique. AB - The objective is to describe the 'Two Bridges Technique' (TBT), which has proven to be successful and has been the standard technique at our centre for vacuum assisted closure (VAC) of post-sternotomy mediastinitis. An extensive literature search was performed in four databases to identify all published articles concerning VAC for post-sternotomy mediastinitis. Several VAC methods have been used; however, no article has described our specific technique. TBT consists of a two-bridges construction using two types of foam with different pore sizes, which ensures an equally divided negative pressure over the wound bed and stabilisation of the chest. This guarantees a continuous treatment of the sternal defect and prevents foam displacement. It maintains an airtight seal that prevents skin maceration and provides enough protection to avoid right ventricular rupture. The main advantage of TBT is the prevention of shifting or tilting of the foam during chest movements such as breathing or couching. Along with targeted antibiotic treatment, this alternative VAC technique can be an asset in the sometimes cumbersome treatment of post-sternotomy mediastinitis. PMID- 29430830 TI - Design and Synthesis of Spherical Multicomponent Aggregates Composed of Core Shell, Yolk-Shell, and Hollow Nanospheres and Their Lithium-Ion Storage Performances. AB - Micrometer-sized spherical aggregates of Sn and Co components containing core shell, yolk-shell, hollow nanospheres are synthesized by applying nanoscale Kirkendall diffusion in the large-scale spray drying process. The Sn2 Co3 -Co3 SnC0.7 -C composite microspheres uniformly dispersed with Sn2 Co3 -Co3 SnC0.7 mixed nanocrystals are formed by the first-step reduction of spray-dried precursor powders at 900 degrees C. The second-step oxidation process transforms the Sn2 Co3 -Co3 SnC0.7 -C composite into the porous microsphere composed of Sn Sn2 Co3 @CoSnO3 -Co3 O4 core-shell, Sn-Sn2 Co3 @CoSnO3 -Co3 O4 yolk-shell, and CoSnO3 -Co3 O4 hollow nanospheres at 300, 400, and 500 degrees C, respectively. The discharge capacity of the microspheres with Sn-Sn2 Co3 @CoSnO3 -Co3 O4 core shell, Sn-Sn2 Co3 @CoSnO3 -Co3 O4 yolk-shell, and CoSnO3 -Co3 O4 hollow nanospheres for the 200th cycle at a current density of 1 A g-1 is 1265, 987, and 569 mA h g-1 , respectively. The ultrafine primary nanoparticles with a core shell structure improve the structural stability of the porous-structured microspheres during repeated lithium insertion and desertion processes. The porous Sn-Sn2 Co3 @CoSnO3 -Co3 O4 microspheres with core-shell primary nanoparticles show excellent cycling and rate performances as anode materials for lithium-ion batteries. PMID- 29430831 TI - Specific Oxygenated Groups Enriched Graphene Quantum Dots as Highly Efficient Enzyme Mimics. AB - Significant progress is achieved for the utilization of graphene quantum dots as enzyme mimics in various biomedical fields recently. Although promising, the biocatalytic performance is far from satisfactory. Here, the rational design and synthesis of specific oxygenated groups enriched graphene quantum dots (o-GQDs) via a facile oxidation reflux route is reported. These well-prepared o-GQDs with uniform size exhibit an ultrahigh peroxidase-like activity in a wide range of pH values, and their superior performance is verified by using glucose detection as a typical model. Compared with classical nanozymes, these o-GQDs show multiple times higher enzymatic activity. It is believed that the super facile synthesis strategy can greatly facilitate the practical use of o-GQDs as enzyme mimics in the future. PMID- 29430832 TI - Co Nanoparticles Confined in 3D Nitrogen-Doped Porous Carbon Foams as Bifunctional Electrocatalysts for Long-Life Rechargeable Zn-Air Batteries. AB - Proper design and simple preparation of nonnoble bifunctional electrocatalysts with high cost performance and strong durability for the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) is highly demanded but still full of enormous challenges. In this work, a spontaneous gas-foaming strategy is presented to synthesize cobalt nanoparticles confined in 3D nitrogen doped porous carbon foams (CoNCF) by simply carbonizing the mixture of citric acid, NH4 Cl, and Co(NO3 )2 .6H2 O. Thanks to its particular 3D porous foam architecture, ultrahigh specific surface area (1641 m2 g-1 ), and homogeneous distribution of active sites (C-N, Co-Nx , and Co-O moieties), the optimized CoNCF-1000-80 (carbonized at 1000 degrees C, containing 80 mg Co(NO3 )2 .6H2 O in precursors) catalyst exhibits a remarkable bifunctional activity and long-term durability toward both ORR and OER. Its bifunctional activity parameter (DeltaE) is as low as 0.84 V, which is much smaller than that of noble metal catalyst and comparable to state-of-the-art bifunctional catalysts. When worked as an air electrode catalyst in rechargeable Zn-air batteries, a high energy density (797 Wh kg-1 ), a low charge/discharge voltage gap (0.75 V), and a long-term cycle stability (over 166 h) are achieved at 10 mA cm-2 . PMID- 29430833 TI - Spray-Dried Nanoparticle-in-Microparticle Delivery Systems (NiMDS) for Gene Delivery, Comprising Polyethylenimine (PEI)-Based Nanoparticles in a Poly(Vinyl Alcohol) Matrix. AB - Nucleic acid-based therapies rely on efficient formulations for nucleic acid protection and delivery. As nonviral strategies, polymeric and lipid-based nanoparticles have been introduced; however, biological efficacy and biocompatibility as well as poor storage properties due to colloidal instability and their unavailability as ready-to-use systems are still major issues. Polyethylenimine is the most widely explored and promising candidate for gene delivery. Polyethylenimine-based polyplexes and their combination with liposomes, lipopolyplexes, are efficient for DNA or siRNA delivery in vitro and in vivo. In this study, a highly potent spray-dried nanoparticle-in-microparticle delivery system is presented for the encapsulation of polyethylenimine-based polyplexes and lipopolyplexes into poly(vinyl alcohol) microparticles, without requiring additional stabilizing agents. This easy-to-handle gene delivery device allows prolonged nanoparticle storage and protection at ambient temperature. Biological analyses reveal further advantages regarding profoundly reduced cytotoxicity and enhanced transfection efficacies of polyethylenimine-based nanoparticles from the nanoparticle-in-microparticle delivery system over their freshly prepared counterparts, as determined in various cell lines. Importantly, this nanoparticle in-microparticle delivery system is demonstrated as ready-to-use dry powder to be an efficient device for the inhalative delivery of polyethylenimine-based lipopolyplexes in vivo, as shown by transgene expression in mice after only one administration. PMID- 29430835 TI - Methodologies toward Highly Efficient Perovskite Solar Cells. AB - A perovskite solar cell (PSC) employing an organic-inorganic lead halide perovskite light harvester, seeded in 2009 with power conversion efficiency (PCE) of 3.8% and grown in 2011 with PCE of 6.5% in dye-sensitized solar cell structure, has received great attention since the breakthrough reports ~10% efficient solid-state PCSs demonstrating 500 h stability. Developments of device layout and high-quality perovskite film eventually lead to a PCE over 22%. As of October 31, 2017, the highest PCE of 22.7% is listed in an efficiency chart provided by NREL. In this Review, the methodologies to obtain highly efficient PSCs are described in detail. In order to achieve a PCE of over 20% reproducibly, key technologies are disclosed from the viewpoint of precursor solution chemistry, processing for defect-free perovskite films, and passivation of grain boundaries. Understanding chemical species in precursor solution, crystal growth kinetics, light-matter interaction, and controlling defects is expected to give important insights into not only reproducible production of high PCE over 20% but also further enhancement of the PCE of PCSs. PMID- 29430834 TI - Nonenzymatic acetylation of ubiquitin Lys side chains is modulated by their neighboring residues. AB - Nonenzymatic acetylation of Lys side chains (Lys-SCs) by various in vivo reactive molecules has been suggested to play novel regulatory roles. Ubiquitin (UB) has seven Lys residues that are utilized for synthesis of specific poly-UB chains. To understand the nature of these Lys-SC modifications, the chemical acetylation rate and pKa and Hill coefficient of each UB-Lys-SC were measured. Mutagenesis studies combined with the determination of activation energy indicated that specific neighboring residues of the Lys-SCs have a potential catalytic activity during nonenzymatic acetylation. Based on the shared chemistry between nonenzymatic Lys acetylation and ubiquitylation, the characterized chemical properties of the UB-Lys-SCs could be a reference for deciphering both mechanisms. Our NMR approaches could be useful for studying general nonenzymatic Lys acylations of various proteins. PMID- 29430836 TI - Layered Manufacturing of Dental Ceramics: Fracture Mechanics, Microstructure, and Elemental Composition of Lithography-Sintered Ceramic. AB - PURPOSE: To compare the fracture mechanics, microstructure, and elemental composition of lithography-based ceramic manufacturing with pressing and CAD/CAM. MATERIALS AND METHODS: Disc-shaped specimens (16 mm diameter, 1.2 mm thick) were used for mechanical testing (n = 10/group). Biaxial flexural strength of three groups (In-Ceram alumina [ICA], lithography-based alumina, ZirkonZahn) were determined using the "piston on 3-ball" technique as suggested in test Standard ISO-6872. Vickers hardness test was performed. Fracture toughness was calculated using fractography. Results were statistically analyzed using Kruskal-Wallis test followed by Dunnett T3 (alpha = 0.05). Weibull analysis was conducted. Polished and fracture surface characterization was made using scanning electron microscope (SEM). Energy dispersive spectroscopy (EDS) was used for elemental analysis. RESULTS: Biaxial flexural strength of ICA, LCM alumina (LCMA), and ZirkonZahn were 147 +/- 43 MPa, 490 +/- 44 MPa, and 709 +/- 94 MPa, respectively, and were statistically different (P <= 0.05). The Vickers hardness number of ICA was 850 +/- 41, whereas hardness values for LCMA and ZirkonZahn were 1581 +/- 144 and 1249 +/- 57, respectively, and were statistically different (P <= 0.05). A statistically significant difference was found between fracture toughness of ICA (2 +/- 0.4 MPa?m1/2 ), LCMA (6.5 +/- 1.5 MPa?m1/2 ), and ZirkonZahn (7.7 +/- 1 MPa?m1/2 ) (P <= 0.05). Weibull modulus was highest for LCMA (m = 11.43) followed by ZirkonZahn (m = 8.16) and ICA (m = 5.21). Unlike LCMA and ZirkonZahn groups, a homogeneous microstructure was not observed for ICA. EDS results supported the SEM images. CONCLUSIONS: Within the limitations of this in vitro study, it can be concluded that LCM seems to be a promising technique for final ceramic object manufacturing in dental applications. Both the manufacturing method and the material used should be improved. PMID- 29430838 TI - Porous Carbon-Hosted Atomically Dispersed Iron-Nitrogen Moiety as Enhanced Electrocatalysts for Oxygen Reduction Reaction in a Wide Range of pH. AB - As one of the alternatives to replace precious metal catalysts, transition-metal nitrogen-carbon (M-N-C) electrocatalysts have attracted great research interest due to their low cost and good catalytic activities. Despite nanostructured M-N-C catalysts can achieve good electrochemical performances, they are vulnerable to aggregation and insufficient catalytic sites upon continuous catalytic reaction. In this work, metal-organic frameworks derived porous single-atom electrocatalysts (SAEs) were successfully prepared by simple pyrolysis procedure without any further posttreatment. Combining the X-ray absorption near-edge spectroscopy and electrochemical measurements, the SAEs have been identified with superior oxygen reduction reaction (ORR) activity and stability compared with Pt/C catalysts in alkaline condition. More impressively, the SAEs also show excellent ORR electrocatalytic performance in both acid and neutral media. This study of nonprecious catalysts provides new insights on nanoengineering catalytically active sites and porous structures for nonprecious metal ORR catalysis in a wide range of pH. PMID- 29430837 TI - Architecture and hydration of the arginine-binding site of neuropilin-1. AB - : Neuropilin-1 (NRP1) is a transmembrane co-receptor involved in binding interactions with variety of ligands and receptors, including receptor tyrosine kinases. Expression of NRP1 in several cancers correlates with cancer stages and poor prognosis. Thus, NRP1 has been considered a therapeutic target and is the focus of multiple drug discovery initiatives. Vascular endothelial growth factor (VEGF) binds to the b1 domain of NRP1 through interactions between the C-terminal arginine of VEGF and residues in the NRP1-binding site including Tyr297, Tyr353, Asp320, Ser346 and Thr349. We obtained several complexes of the synthetic ligands and the NRP1-b1 domain and used X-ray crystallography and computational methods to analyse atomic details and hydration profile of this binding site. We observed side chain flexibility for Tyr297 and Asp320 in the six new high-resolution crystal structures of arginine analogues bound to NRP1. In addition, we identified conserved water molecules in binding site regions which can be targeted for drug design. The computational prediction of the VEGF ligand-binding site hydration map of NRP1 was in agreement with the experimentally derived, conserved hydration structure. Displacement of certain conserved water molecules by a ligand's functional groups may contribute to binding affinity, whilst other water molecules perform as protein-ligand bridges. Our report provides a comprehensive description of the binding site for the peptidic ligands' C terminal arginines in the b1 domain of NRP1, highlights the importance of conserved structural waters in drug design and validates the utility of the computational hydration map prediction method in the context of neuropilin. DATABASE: The structures were deposited to the PDB with accession numbers PDB ID: 5IJR, 5IYY, 5JHK, 5J1X, 5JGQ, 5JGI. PMID- 29430839 TI - Effects of l-Carnosine Supplementation on Sleep Disorders and Disease Severity in Autistic Children: A Randomized, Controlled Clinical Trial. AB - Sleep disorders are frequently reported in autistic patients. Evidences suggest that increased oxidative stress and reduced antioxidants may play a major role in the pathogenesis of these disorders. Carnosine acts as an antioxidant, antitoxic and neuroprotective agent. The aim of this trial study was to examine the effects of carnosine supplementation on the sleep disorders and severity of autism core symptoms in autistic patients. In this double-blind, randomized clinical trial, 43 autistic patients (31 boys and 12 girls; aged 4 to 16 years) were divided into two groups of carnosine and control that received 500 mg of carnosine and 500 mg of placebo per day for 2 months, respectively. Sleep disorders were measured using Children's Sleep Habits Questionnaires. Gilliam Autism Rating Scale 2 was used to assess the effects of carnosine supplementation on the autism severity. Carnosine supplementation did not change anthropometric indices (p > 0.05) and showed no effect on autism severity (p > 0.05), whereas it significantly reduced sleep duration (p = 0.04), parasomnias (p = 0.02) and total sleep disorders score by 7.59% (p = 0.006) when compared with the control group. The results suggest that carnosine supplementation could be effective in improving sleep disturbances, in particular sleep duration and parasomnias subscales. PMID- 29430841 TI - Carbon and Carbon Hybrid Materials as Anodes for Sodium-Ion Batteries. AB - Sodium-ion batteries (SIBs) have attracted much attention for application in large-scale grid energy storage owing to the abundance and low cost of sodium sources. However, low energy density and poor cycling life hinder practical application of SIBs. Recently, substantial efforts have been made to develop electrode materials to push forward large-scale practical applications. Carbon materials can be directly used as anode materials, and they show excellent sodium storage performance. Additionally, designing and constructing carbon hybrid materials is an effective strategy to obtain high-performance anodes for SIBs. In this review, we summarize recent research progress on carbon and carbon hybrid materials as anodes for SIBs. Nanostructural design to enhance the sodium storage performance of anode materials is discussed, and we offer some insight into the potential directions of and future high-performance anode materials for SIBs. PMID- 29430840 TI - Screening and analysis of potentially active components in Shenxiong glucose injection using UHPLC coupled with photodiode array detection and MS/MS. AB - Shenxiong glucose injection, a pharmaceutical preparation containing a water extract of the roots of Salvia miltiorrhizae and ligustrazine hydrochloride, is widely used in clinical to treat cardiovascular diseases in China. The chemical components of the water extract have been reported and the cardioprotective effects of the injection have been evaluated. However, the chemical constituents of the injection and their correlations with its pharmacological effects have not been established. In this study, 13 chemical constituents of the injection have been identified or characterized by ultra-high performance liquid chromatography with diode array detection and electrospray ionization quadrupole time-of-flight tandem mass spectrometry. Besides, the potentially active compounds of this preparation that directly act on cardiac cells have been screened by cell extraction and ultra high performance liquid chromatography targeted multiple reaction monitoring. As a result, eight potentially active compounds, danshensu (1), ligustrazine hydrochloride (4), salvianolic acid I/H (7), lithospermic acid (8), salvianolic acid D (9), rosmarinic acid (10), salvianolic acid B (12), and salvianolic acid C (13), were obtained and structurally characterized from the 11 target compounds used for screening. The liquid chromatography with quadrupole time-of-flight mass spectrometry and liquid chromatography with multiple reaction monitoring tandem mass spectrometry combination method has demonstrated its potency for the screening, detection, and structural identification of bioactive compounds in a complex matrix. PMID- 29430842 TI - Glucagon-Like Peptide-1 (GLP-1)-Based Therapeutics: Current Status and Future Opportunities beyond Type 2 Diabetes. AB - Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L-cells following food intake, and plays an important role in glucose homeostasis due to its stimulation of glucose-dependent insulin secretion. Further, GLP-1 is also associated with protective effects on pancreatic beta-cells and the cardiovascular system, decreased appetite, and weight loss, making GLP-1 derivatives an exciting treatment for type 2 diabetes and obesity. Despite these benefits, wild-type GLP 1 exhibits a short circulation time due to its poor metabolic stability and rapid renal clearance, and must be administered by injection, making it a poor therapeutic agent. Many strategies have been used to improve the circulation time of GLP-1 (e.g., mutations, unnatural amino acids, depot formulations, use of exendin-4 sequences, and fusions with high-molecular-weight proteins or polymers), with its therapeutic utility further improved by adding agonist activity for gastric inhibitory peptide and glucagon receptors. This minireview focuses on strategies that have been used to improve the pharmacokinetics of GLP 1 and provides an overview of GLP-1-based therapeutics in the pipeline. PMID- 29430843 TI - FT-Raman spectroscopy, u-EDXRF spectrometry, and microhardness analysis of the dentin of primary and permanent teeth. AB - The chemical compositions (organic and inorganic contents) and mechanical behaviors of the dentin of permanent and deciduous teeth were analyzed and compared using X-ray fluorescence spectrometry (u-EDXRF) Fourier transform Raman spectroscopy (FT-Raman) and a microhardness test (HD). Healthy fresh human primary and permanent molars (n = 10) were selected, The buccal surfaces facing upwards were stabilized in an acrylic plate, flattened, polished, and submitted to the u-EDXRF, FT-Raman, and HD analysis. The results of the analysis were subjected to ANOVAs and Mann-Whitney U/Student's t multiple comparisons tests. The data showed similar values for the dentin of the primary and permanent teeth in P content, organic content (amide I peak), inorganic content ( PO43- - 430 and 590), and microhardness, Nevertheless, Ca content and Ca/P weight ratio were higher, and the CO32- peak was lower in the dentin of the permanent teeth compared to primary teeth. It be concluded that despite permanent teeth showed more Ca element, both substrates showed similar behavior of chemical and physical properties. PMID- 29430844 TI - Human infection with avian influenza A(H7N2) virus-Virginia, 2002. AB - BACKGROUND: In March 2002, an outbreak of low-pathogenic avian influenza (LPAI) A(H7N2) was detected among commercial poultry operations in Virginia. METHODS: We performed a serosurvey of 80 government workers involved in efforts to control the outbreak. RESULTS: One study participant who assisted with disposal of infected birds tested positive for neutralizing antibodies to influenza A(H7N2) by microneutralization assay and H7-specific IgM antibodies by enzyme-linked immunosorbent assay (ELISA). The acute infection was temporally associated with an influenza-like illness that resolved without hospitalization. CONCLUSION: This study documents the earliest evidence of human infection with an H7 influenza virus of the North American lineage. PMID- 29430846 TI - Low Grip Strength is a Strong Risk Factor of Osteoporosis in Postmenopausal Women. AB - OBJECTIVE: To investigate the effect of grip strength on bone mineral density (BMD) in postmenopausal women. Low BMD is related to risk of fracture and falling is the strongest factor for fragility fractures. Handgrip strength is a reliable indicator of muscle strength and muscle strength is associated with falling. METHODS: For the present study 120 women were divided into two groups: those <=65 years and those >65 years. Serum 25 hydroxyvitamin D (25OHD), BMD, and handgrip strength were measured to observe the effect of age on 25OHD, grip strength, and BMD, as well as the effect of 25OHD on grip strength and BMD. The correlation between grip strength and BMD was investigated. RESULTS: In the 120 patients, 25OHD was 24.31 +/- 8.29 ng/mL. There were 37 cases with 25OHD <20 ng/mL and 83 cases with 25 OHD >=20 ng/mL. The patients with 25OHD <20 ng/mL had significantly lower femoral neck BMD, most of them with a T score <=-2.5 (P < 0.05). BMD measurement showed 66 patients with femoral neck T <=-2.5, 30 cases with total hip T <=-2.5 and 90 cases with lumbar BMD T <=-2.5. The maximum grip strength in the group is 22.28 +/- 6.17 kg. There were 38 cases with the maximum grip strength <20 kg and 82 cases with the maximum grip strength >=20 kg. Patients >65 years had lower 25OHD, lower maximum grip strength, and lower BMD. The osteoporosis risk in postmenopausal women with a maximum grip strength <20 kg and who were >65 years was significantly elevated. CONCLUSION: Handgrip strength and 25OHD decrease with aging in postmenopausal women. The patients with lower 25OHD level had significantly lower BMD of femoral neck. The patients with lower handgrip strength had significantly lower BMD of lumbar spine, femoral neck, and total hip. Grip strength measurement is the simplest muscle strength measurement method. Our study confirmed that low grip strength was correlated with low BMD and was a strong risk factor for osteoporosis in postmenopausal women. PMID- 29430845 TI - Peer counselling versus standard-of-care on reducing high-risk behaviours among newly diagnosed HIV-positive men who have sex with men in Beijing, China: a randomized intervention study. AB - INTRODUCTION: Reducing high-risk behaviours (i.e. multiple partnership, condomless anal/vaginal sex, alcohol use before sex, illicit drug use) after HIV diagnosis is critical for curtailing HIV transmission. We designed an intervention to explore peer- counselling in reducing high-risk behaviours among newly diagnosed HIV-positive Chinese men who have sex with men (MSM). METHODS: We randomized 367 newly diagnosed HIV-positive men to either standard-of-care (SOC; n = 183) or peer-counselling intervention (n = 184), and followed them for 12 months (visit at 0-, 3-, 6-, 9- and 12-month). SOC participants received counselling on high-risk behaviour reduction by clinic staff. Intervention participants received both SOC and peer counselling. A generalized estimating equation was used to compare pre-post diagnosis high-risk behaviour change; logistic regression was used to assess the likelihood of practicing high-risk behaviours between intervention and SOC participants. Both intent-to-treat and per-protocol (full-dosage) approaches were used for the analyses. RESULTS: For pre- and post-diagnosis comparisons, multiple partnership fell from 50% to 16% (p < 0.001), alcohol use before sex from 23% to 9% (p = 0.001), illicit drug use from 33% to 6% (p < 0.001), condomless anal sex from 47% to 4% (insertive from 23% to 2%; receptive from 36% to 3%; p < 0.001). In the intent-to-treat analysis accounting for repeated measures, peer counselling was more likely to reduce insertive anal sex (AOR = 0.65; 95% CI: 0.45 to 0.94), condomless anal sex (AOR = 0.27; 95% CI: 0.10 to 0.64) and illicit drug use (AOR = 0.32; 95% CI: 0.16 to 0.64). In the per-protocol analysis, peer counselling was associated with a lower likelihood of using illicit drug (OR = 0.23; 95% CI: 0.07 to 0.81) and having condomless vaginal sex with women (OR = 0.12; 95% CI: 0.07 to 0.98). CONCLUSIONS: We observed a 14 to 43% decrease in the prevalence of selected high-risk behaviours after HIV diagnosis. Peer counselling had a greater impact in reducing condomless anal sex with men, illicit drug use and condomless vaginal sex with women over time. Future studies with exclusive peer-counselling arm are necessary to test its efficacy and effectiveness among Chinese MSM. Clinical Trial Number: NCT01904877. PMID- 29430848 TI - Imaging assessment of rounded atelectasis: A pictorial essay. AB - Rounded atelectasis is an increasingly recognized but under-diagnosed and sometimes misdiagnosed pulmonary entity. This pictorial essay will present a broad range of examples of rounded atelectasis across different imaging modalities with inclusion of typical and atypical presentations. These examples will highlight imaging features that allow confident diagnosis and those that warrant further management, such as imaging surveillance, alternate imaging or invasive procedures for histological evaluation. PMID- 29430847 TI - Dual Labeling of the CBP/p300 KIX Domain for 19 F NMR Leads to Identification of a New Small-Molecule Binding Site. AB - Protein-Observed Fluorine NMR (PrOF NMR) spectroscopy is an emerging technique for screening and characterizing small-molecule-protein interactions. The choice of which amino acid to label for PrOF NMR can be critical for analysis. Here we report the first use of a protein containing two different fluoroaromatic amino acids for NMR studies. Using the KIX domain of the CBP/p300 as a model system, we examine ligand binding of several small-molecule compounds elaborated from our previous fragment screen and identify a new ligand binding site distinct from those used by native transcription factors. This site was further supported by computational modeling (FTMap and Schrodinger) and 1 H,15 N HSQC/HMQC NMR spectroscopy. Metabolic labeling with multiple fluorinated amino acids provides useful probes for further studying ligand binding and has led to new insight for allosterically regulating transcription-factor protein interactions with small molecule ligands. PMID- 29430849 TI - MAGE-A gene expression in peripheral blood serves as a poor prognostic marker for patients with lung cancer. AB - BACKGROUND: MAGE-A genes belong to the cancer/testis antigens family. The prognostic significance of MAGE-A expression in the peripheral blood of patients with lung cancer is unknown. Therefore, this study evaluated the expression and possible prognostic significance of MAGE-A in the peripheral blood of patients with lung cancer. METHODS: In this study, we detected MAGE-A gene expression in the peripheral blood of 150 patients with lung cancer and 30 healthy donors using multiplex semi-nested PCR and analyzed their correlation with clinicopathological risk factors. RESULTS: MAGE-A expression was associated with factors indicating poor prognosis. The expression of MAGE-A and each individual MAGE-A gene were also associated with low overall survival in patients with lung cancer. CONCLUSION: The expression of MAGE-A genes in peripheral blood may act as a poor prognostic marker in patients with lung cancer. PMID- 29430851 TI - Alpha Lead Oxide (alpha-PbO): A New 2D Material with Visible Light Sensitivity. AB - Even though transition metal dichalcogenides (TMDCs) are deemed to be novel photonic and optoelectronic 2D materials, the visible band gap being often limited to monolayer, hampers their potential in niche applications due to fabrication challenges. Uncontrollable defects and degraded functionalities at elevated temperature and under extreme environments further restrict their prospects. To address such limitations, the discovery of a new 2D material, alpha PbO is reported. Micromechanical as well as sonochemical exfoliation of 2D atomic sheets of alpha-PbO are demonstrated and its optical behavior is investigated. Spectroscopic investigations indicate layer dependent band gaps. In particular, even multilayered PbO sheets exhibit visible band gap > 2 eV (direct) which is rare among semiconducting 2D materials. The emission lifetime of multilayer PbO atomic sheets is 7 ns (dim light) as compared to the monolayer which gives 2.5 ns lifetime and an intense light. Density functional theory calculations of layer dependent band structure of alpha-PbO matches well with experimental results. Experimental findings suggest that PbO atomic sheets exhibit hydrophobic nature, thermal robustness, microwave stability, anti-corrosive behaviour and acid resistance. This new low-cost, abundant and robust 2D material is expected to find many applications in the fields of electronics, optoelectronics, sensors, photocatalysis and energy storage. PMID- 29430850 TI - Probing Ligand Structure-Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8-Hydroxyefavirenz Exhibit Divergence in Activation. AB - Efavirenz (EFV), an antiretroviral that interacts clinically with co-administered drugs via activation of the pregnane X receptor (PXR), is extensively metabolized by the cytochromes P450. We tested whether its primary metabolite, 8-hydroxyEFV (8-OHEFV) can activate PXR and potentially contribute to PXR-mediated drug-drug interactions attributed to EFV. Luciferase reporter assays revealed that despite only differing from EFV by an oxygen atom, 8-OHEFV does not activate PXR. Corroborating this, treatment with EFV for 72 h elevated the mRNA abundance of the PXR target gene, Cyp3a11, by approximately 28-fold in primary hepatocytes isolated from PXR-humanized mice, whereas treatment with 8-OHEFV did not result in a change in Cyp3A11 mRNA levels. FRET-based competitive binding assays and isothermal calorimetry demonstrated that even with the lack of ability to activate PXR, 8-OHEFV displays an affinity for PXR (IC50 12.1 MUm; KD 7.9 MUm) nearly identical to that of EFV (IC50 18.7 MUm; KD 12.5 MUm). The use of 16 EFV analogues suggest that other discreet changes to the EFV structure beyond the 8 position are well tolerated. Molecular docking simulations implicate an 8-OHEFV binding mode that may underlie its divergence in PXR activation from EFV. PMID- 29430852 TI - Insights into the evolution of the new variant rabbit haemorrhagic disease virus (GI.2) and the identification of novel recombinant strains. AB - Rabbit haemorrhagic disease (RHD) is a viral disease that affects the European rabbit. RHD was detected in 1984 in China and rapidly disseminated worldwide causing a severe decline in wild rabbit populations. The aetiological agent, rabbit haemorrhagic disease virus (RHDV), is an RNA virus of the family Caliciviridae, genus Lagovirus. Pathogenic (G1-G6 or variants GI.1a-GI.1d) and non-pathogenic strains (GI.4) have been characterized. In 2010, a new variant of RHDV, RHDV2/RHDVb/GI.2, was detected in France. GI.2 arrived to the Iberian Peninsula in 2011, and several recombination events were reported. Here, we sequenced full genomes of 19 samples collected in Portugal between 2014 and 2016. New GI.2 recombinant strains were detected, including triple recombinants. These recombinants possess a non-structural protein p16 related to a non-pathogenic strain. Evolutionary analyses were conducted on GI.2 VP60 sequences. Estimated time to the most recent common ancestor (tMRCA) suggests an emergence of GI.2 in July 2008, not distant from its first detection in 2010. This is the first study on GI.2 evolution and highlights the need of continued monitoring and characterization of complete genome sequences when studying lagoviruses' evolution. PMID- 29430853 TI - Nfix Promotes Survival of Immature Hematopoietic Cells via Regulation of c-Mpl. AB - Hematopoietic stem and progenitor cells (HSPCs) are necessary for life-long blood production and replenishment of the hematopoietic system during stress. We recently reported that nuclear factor I/X (Nfix) promotes HSPC survival post transplant. Here, we report that ectopic expression of Nfix in primary mouse HSPCs extends their ex vivo culture from about 20 to 40 days. HSPCs overexpressing Nfix display hypersensitivity to supportive cytokines and reduced apoptosis when subjected to cytokine deprivation relative to controls. Ectopic Nfix resulted in elevated levels of c-Mpl transcripts and cell surface protein on primary murine HSPCs as well as increased phosphorylation of STAT5, which is known to be activated down-stream of c-MPL. Blocking c-MPL signaling by removal of thrombopoietin or addition of a c-MPL neutralizing antibody negated the antiapoptotic effect of Nfix overexpression on cultured HSPCs. Furthermore, NFIX was capable of binding to and transcriptionally activating a proximal c-Mpl promoter fragment. In sum, these data suggest that NFIX-mediated upregulation of c-Mpl transcription can protect primitive hematopoietic cells from stress ex vivo. Stem Cells 2018;36:943-950. PMID- 29430855 TI - Dynorphinergic system alterations in the corticostriatal circuitry of neuropathic mice support its role in the negative affective component of pain. AB - The dynorphinergic system is involved in pain transmission at spinal level, where dynorphin exerts antinociceptive or pronociceptive effects, based on its opioid or non-opioid actions. Surprisingly, little evidence is currently available concerning the supraspinal role of the dynorphinergic system in pain conditions. The present study aimed to investigate whether neuropathic pain is accompanied by prodynorphin (Pdyn) and kappa-opioid receptor (Oprk1) gene expression alterations in selected mouse brain areas. To this end, mice were subjected to chronic constriction injury of the right sciatic nerve and neuropathic pain behavioral signs were ascertained after 14 days. At this interval, a marked increase in Pdyn mRNA in the anterior cingulate cortex (ACC) and prefrontal cortex (PFC) was observed. Oprk1 gene expression was increased in the PFC, and decreased in the ACC and nucleus accumbens (NAc). No changes were observed in the other investigated regions. Because of the relationship between dynorphin and the brain derived neurotrophic factor, and the role of this neurotrophin in chronic pain related neuroplasticity, we investigated brain-derived neurotrophic factor gene (Bdnf) expression in the areas showing Pdyn or Oprk1 mRNAs changes. Bdnf mRNA levels were increased in both the ACC and PFC, whereas no changes were assessed in the NAc. Present data indicate that the dynorphinergic system undergoes quite selective alterations involving the corticostriatal circuitry during neuropathic pain, suggesting a contribution to the negative affective component of pain. Moreover, parallel increases in Pdyn and Bdnf mRNA at cortical level suggest the occurrence of likely interactions between these systems in neuropathic pain maladaptive neuroplasticity. PMID- 29430854 TI - Darunavir/cobicistat showing similar effectiveness as darunavir/ritonavir monotherapy despite lower trough concentrations. AB - INTRODUCTION: When darunavir (DRV) 800 mg is boosted with 150 mg cobicistat (DRVcobi ), DRV trough concentration (Ctrough ) is about 30% lower as compared to 100 mg ritonavir (DRVrtv ). DRVcobi shows similar virological efficacy as DRVrtv when combined with two nucleos(t)ide analogue reverse-transcriptase inhibitors, but it is unknown whether a lower DRV Ctrough would undermine the effectiveness of DRVcobi when given as monotherapy (mtDRVcobi ). METHODS: Prospective observational study on virologically suppressed HIV-infected subjects who switched to mtDRVcobi . Virological failure was defined as two consecutive HIV RNA >200 copies/mL. Efficacy was evaluated by intention-to-treat (ITT) and on treatment (OT) analyses, and compared with data from a previous cohort of subjects on mtDRVrtv conducted at our centre. Plasma DRV Ctrough was measured using LC-MS/MS. RESULTS: A total of 234 subjects were enrolled. At week 96, the efficacy rates were 67.8% (CI95 , 61.8 to 73.7) by ITT and 86.9% (CI95 , 78.0 to 87.7) by OT analyses. The corresponding rates in our historical DRVrtv controls were 67.6% (CI95 , 60.0 to 75.2) and 83.6% (CI95 : 77.2 to 90.0). A total of 135 DRV determinations were performed in 83 subjects throughout the follow-up period, with a median plasma DRV Ctrough of 1305 ng/mL (range, 150 to 5895) compared with 1710 ng/mL (range, 200 to 3838) in subjects on monotherapy with DRVrtv (p = 0.05). CONCLUSIONS: DRV Ctrough was lower in HIV-infected subjects receiving DRVcobi than with DRVrtv . However, this did not appear to influence the efficacy of DRVcobi , when administered as monotherapy. PMID- 29430856 TI - Feasibility study on 3D image reconstruction from 2D orthogonal cine-MRI for MRI guided radiotherapy. AB - INTRODUCTION: In-room MRI is a promising image guidance strategy in external beam radiotherapy to acquire volumetric information for moving targets. However, limitations in spatio-temporal resolution led several authors to use 2D orthogonal images for guidance. The aim of this work is to present a method to concurrently compensate for non-rigid tumour motion and provide an approach for 3D reconstruction from 2D orthogonal cine-MRI slices for MRI-guided treatments. METHODS: Free-breathing sagittal/coronal interleaved 2D cine-MRI were acquired in addition to a pre-treatment 3D volume in two patients. We performed deformable image registration (DIR) between cine-MRI slices and corresponding slices in the pre-treatment 3D volume. Based on an extrapolation of the interleaved 2D motion fields, the 3D motion field was estimated and used to warp the pre-treatment volume. Due to the lack of a ground truth for patients, the method was validated on a digital 4D lung phantom. RESULTS: On the phantom, the 3D reconstruction method was able to compensate for tumour motion and compared favourably to the results of previously adopted strategies. The difference in the 3D motion fields between the phantom and the extrapolated motion was 0.4 +/- 0.3 mm for tumour and 0.8 +/- 1.5 mm for whole anatomy, demonstrating feasibility of performing a 3D volumetric reconstruction directly from 2D orthogonal cine-MRI slices. Application of the method to patient data confirmed the feasibility of utilizing this method in real world scenarios. CONCLUSION: Preliminary results on phantom and patient cases confirm the feasibility of the proposed approach in an MRI guided scenario, especially for non-rigid tumour motion compensation. PMID- 29430857 TI - Phenotype diffusion and one health: A proposed framework for investigating the plurality of obesity epidemics across many species. AB - We propose the idea of "phenotype diffusion," which is a rapid convergence of an observed trait in some human and animal populations. The words phenotype and diffusion both imply observations independent of mechanism as phenotypes are observed traits with multiple possible genetic mechanisms and diffusion is an observed state of being widely distributed. Recognizing shared changes in phenotype in multiple species does not by itself reveal a particular mechanism such as a shared exposure, shared adaptive need, particular stochastic process or a transmission pathway. Instead, identifying phenotype diffusion suggests the mechanism should be explored to help illuminate the ways human and animal health are connected and new opportunities for optimizing these links. Using the plurality of obesity epidemics across multiple species as a prototype for shared changes in phenotype, the goal of this review was to explore eco-evolutionary theories that could inform further investigation. First, evolutionary changes described by hologenome evolution, pawnobe evolution, transposable element (TE) thrust and the drifty gene hypothesis will be discussed within the context of the selection asymmetries among human and animal populations. Secondly, the ecology of common source exposures (bovine milk, xenohormesis and "obesogens"), niche evolution and the hygiene hypothesis will be summarized. Finally, we synthesize these considerations. For example, many agricultural breeds have been aggressively selected for weight gain, microbiota (e.g., adenovirus 36, toxoplasmosis) associated with (or infecting) these breeds cause experimental weight gain in other animals, and these same microbes are associated with human obesity. We propose applications of phenotype diffusion could include zoonotic biosurveillance, biocontainment, antibiotic stewardship and environmental priorities. The One Health field is focused on the connections between the health of humans, animals and the environment, and so identification of phenotype diffusion is highly relevant for practitioners (public health officials, physicians and veterinarians) in this field. PMID- 29430858 TI - Clinical Gait Evaluation of Patients with Lumbar Spine Stenosis. AB - OBJECTIVE: The third generation Intelligent Device for Energy Expenditure and Activity (IDEEA3, MiniSun, CA) has been developed for clinical gait evaluation, and this study was designed to evaluate the accuracy and reliability of IDEEA3 for the gait measurement of lumbar spinal stenosis (LSS) patients. METHODS: Twelve healthy volunteers were recruited to compare gait cycle, cadence, step length, velocity, and number of steps between a motion analysis system and a high speed video camera. Twenty hospitalized LSS patients were recruited for the comparison of the five parameters between the IDEEA3 and GoPro camera. Paired t test, intraclass correlation coefficient, concordance correlation coefficient, and Bland-Altman plots were used for the data analysis. RESULTS: The ratios of GoPro camera results to motion analysis system results, and the ratios of IDEEA3 results to GoPro camera results were all around 1.00. All P-values of paired t tests for gait cycle, cadence, step length, and velocity were greater than 0.05, while all the ICC and CCC results were above 0.950 with P < 0.001. CONCLUSIONS: The measurements for gait cycle, cadence, step length, velocity, and number of steps with the GoPro camera are highly consistent with the measurements with the motion analysis system. The measurements for IDEEA3 are consistent with those for the GoPro camera. IDEEA3 can be effectively used in the gait measurement of LSS patients. PMID- 29430859 TI - Rabies risk and use of post-exposure prophylaxis associated with dog bites in Tennessee. AB - The canine variant of the rabies virus has been eliminated in the United States. Among the public and many healthcare providers, however, dog bites are still associated with risk for rabies transmission. This study examined the risk of rabies in biting dogs and the use of rabies post-exposure prophylaxis (rPEP) for dog bite victims in Tennessee. The study included a retrospective analysis of laboratory testing requisitions for dogs from 2002 to 2016, collection of clinical data on confirmed rabies-positive dogs from 2008 to 2016 and analysis of hospital discharge data for rPEP from 2007 to 2014. Among dogs submitted for rabies testing, those having a recent history of biting were significantly less likely to test positive for rabies than dogs with no reported bite (OR = 0.01; 95% CI [0.003-0.04]). The most common clinical signs reported among rabies positive dogs were anorexia, dysphagia, ataxia, limb paresis or paralysis, and lethargy; aggressiveness was uncommon. Among hospital patients with an animal related injury who received rPEP, more than half (52%) presented with dog bites. These data show that laboratory submissions for rabies testing and prescriptions for rPEP do not reflect the epidemiology of rabies in Tennessee. Education and outreach targeting the public and healthcare providers should emphasize the animal species and situations associated with a greater risk for rabies transmission, such as bites from rabies reservoir species or animals exhibiting signs of neurologic disease. PMID- 29430860 TI - Factors associated with influenza vaccination among healthcare workers in acute care hospitals in Canada. AB - BACKGROUND: Influenza vaccine coverage rates among healthcare workers (HCWs) in acute care facilities in Canada remain below national targets. OBJECTIVE: To determine factors associated with influenza vaccine uptake among HCWs. METHODS: This secondary analysis of a prospective cohort study included HCWs aged 18-69 years, working >=20 h/wk in a Canadian acute care hospital. Questionnaires were administered to participants in the fall of the season of participation (2011/12 2013/14) which captured demographic/household characteristics, medical histories, occupational, behavioural and risk factors for influenza. Generalized estimating equation logistic regression was used to determine factors associated with vaccine uptake in the season of participation. RESULTS: The adjusted odds ratio for influenza vaccination in the current season was highest for those vaccinated in 3 of 3 previous seasons (OR 156; 95% CI 98, 248) followed by those vaccinated in 2 of 3 and 1 of 3 previous seasons when compared with those not vaccinated. Compared with nurses, physicians (OR 4.2; 95% CI 1.4, 13.2) and support services staff (OR 1.8; 95% CI 1.3, 2.4) had higher odds ratios for vaccine uptake. Conversely, HCWs identifying as Black had lower odds of uptake compared with those with European ancestry (OR 0.44, 95% CI 0.26-0.75) when adjusted for other factors in the model. CONCLUSION: Healthcare workers differ in their annual uptake of influenza vaccine based on their past vaccination history, occupation and ethnicity. These findings indicate a need to determine whether there are other vaccine-hesitant groups within healthcare settings and learn which approaches are successful in increasing their uptake of influenza vaccines. PMID- 29430862 TI - Nylon as an in vitro scaffold for three-dimensional study of neural cells. AB - The requirement for improved modeling of cells in culture for study of cell-to cell interactions has led to an increased focus on three-dimensional (3D) in vitro models. In this study, NG108-15 neural cells and rat sciatic nerve Schwann cells were successfully grown as monocultures and as a coculture on the biocompatible nylon mesh substrates. This has allowed proliferation and interactions between the two cell types to be monitored on the mesh over time. Electrophysiological recordings validated the NG108-15 neural cell differentiation which confirmed the similarity of recorded action potentials in two-dimensional culture environments. A variety of assays have been used, demonstrating the use of nylon as an appropriate substrate for neural cell in vitro studies, and nylon can easily be imaged using inverted microscopy. These studies confirm the suitability of the nylon 3D culture presented for modeling neural cell behavior. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1575-1584, 2018. PMID- 29430861 TI - Clinical course of type 1 autoimmune pancreatitis patients without steroid treatment: a Japanese multicenter study of 97 patients. AB - BACKGROUND: Sporadic autoimmune pancreatitis (AIP) cases showing remission without steroid treatment have been reported, however, the clinical course of these patients has not been clarified. This study sought to clarify the clinical course in AIP patients with hesitation for steroid treatment. METHODS: We collected clinical data for AIP patients from high-volume centers in Japan. Data for AIP patients with and those without steroid treatment (steroid treatment vs. wait and see policy or W&S) were then compared. The primary point was the relapse free survival rate (RFS) in patients with and those without steroid treatment, as determined using Kaplan-Meier curve. The secondary point was the identification of predictors of remission and risks of relapse in AIP patients without steroid treatment. RESULTS: There were 510 AIP patients in the steroid treatment group and 97 patients in the W&S group. Overall, 55.7% (54/97) of type 1 AIP patients in the W&S group experienced transient remission without steroid treatment. The W&S group had a significantly higher patient age and significantly lower incidences of jaundice, diffuse pancreas swelling, proximal-type sclerosing cholangitis, and stent placement and a lower remission rate than the steroid treatment group (each P < 0.05). The RFS reached a plateau at 10 years in both the W&S group (50%) and steroid treatment group (52.9%). As for the RFS (W&S vs. group with steroid), 89.4% vs. 74.4% within 3 years, 81.8% vs. 65.3% within 5 years, and 50% vs. 52.9% within 10 years (log-rank, P = 0.064). Female gender (OR 0.340, P = 0.027) and stent placement for jaundice (OR 4.552, P = 0.008) were identified as predictors of transient remission in the W&S group. New-onset diabetes mellitus (OR 8.333, P = 0.012) and the presence of extensive multi-organ involvement (OR 35, P = 0.006) were identified as risks of relapse in the W&S group. CONCLUSION: Some type 1 AIP patients without steroid treatment experience transient remission. These cases tend to have lower disease activities than AIP patients receiving steroids. Female gender and stent placement for jaundice may be predictors of transient remission among patients not receiving steroid treatment, however, relapses can occur in these patients with new-onset diabetes mellitus and the presence of extensive multi-organ involvement. Therefore, steroid treatment is still imperative for these patients. PMID- 29430863 TI - Colloid-Interface-Assisted Laser Irradiation of Nanocrystals Superlattices to be Scalable Plasmonic Superstructures with Novel Activities. AB - High-efficient charge and energy transfer between nanocrystals (NCs) in a bottom up assembly are hard to achieve, resulting in an obstacle in application. Instead of the ligands exchange strategies, the advantage of a continuous laser is taken with optimal wavelength and power to irradiate the film-scale NCs superlattices at solid-liquid interfaces. Owing to the Au-based NCs' surface plasmon resonance (SPR) effect, the gentle laser irradiation leads the Au NCs or Au@CdS core/shell NCs to attach each other with controlled pattern at the interfaces between solid NCs phase and liquid ethanol/ethylene glycol. A continuous wave 532 nm laser (6.68-13.37 W cm-2 ), to control Au-based superlattices, is used to form the monolayer with uniformly reduced interparticle distance followed by welded superstructures. Considering the size effect to Au NCs' melting, when decreasing the Au NCs size to ~5 nm, stronger welding nanostructures are obtained with diverse unprecedented shapes which cannot be achieved by normal colloidal synthesis. With the help of facile scale-up and formation at solid-liquid interfaces, and a good connection of crystalline between NCs, the obtained plasmonic superstructured films that could be facilely transferred onto different substrates exhibit broad SPR absorption in the visible and near-infrared regime, enhanced electric conductivities, and wide applications as surface enhanced Raman scattering (SERS)-active substrates. PMID- 29430864 TI - Blending Non-Group-3 Transition Metal and Rare-Earth Metal into a C80 Fullerene Cage with D5h Symmetry. AB - Rare-earth metals have been mostly entrapped into fullerene cages to form endohedral clusterfullerenes, whereas non-Group-3 transition metals that can form clusterfullerenes are limited to titanium (Ti) and vanadium (V), and both are exclusively entrapped within an Ih -C80 cage. Non-Group-3 transition-metal containing endohedral fullerenes based on a C80 cage with D5h symmetry, Vx Sc3-x N@D5h -C80 (x=1, 2), have now been synthesized, which exhibit two variable cluster compositions. The molecular structure of VSc2 N@D5h -C80 was unambiguously determined by X-ray crystallography. According to a comparative study with the reported Ti- and V-containing clusterfullerenes based on a Ih -C80 cage and the analogous D5h -C80 -based metal nitride clusterfullerenes containing rare-earth metals only, the decisive role of the non-Group-3 transition metal on the formation of the corresponding D5h -C80 -based clusterfullerenes is unraveled. PMID- 29430865 TI - Relationship between social engagement and diabetes incidence in a middle-aged population: Results from a longitudinal nationwide survey in Japan. AB - AIMS/INTRODUCTION: Social engagement can positively affect health status, but its effect on diabetes incidence remains unclear. The present study aimed to assess the relationship between social engagement and diabetes incidence in a middle aged Japanese population. MATERIALS AND METHODS: We analyzed data on 31,615 people aged 50-59 years from a prospective national survey carried out in Japan from 2005 to 2013. Diabetes incidence was measured by asking respondents annually whether they had been diagnosed with diabetes by a physician in the previous year. We used the complementary log-log model for interval-censored survival time analysis. Social engagement was assessed at baseline as participation in social activities, having the companionship of friends, living with someone and employment status. Covariates including sex, age, health status and health behaviors were also measured at baseline. RESULTS: After adjusting for covariates measured at baseline, the effect size of social engagement on diabetes incidence was the same as or larger than that of the covariates. Respondents who participated in social activities (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.87-0.92), had the companionship of friends (HR 0.97, 95% CI: 0.95 1.00), lived with someone (HR 0.85, 95% CI: 0.82-0.89) and were employed (HR 0.94, 95% CI: 0.92-0.96) were significantly less vulnerable to diabetes than were those who did not. CONCLUSIONS: The present study found a prospective association between social engagement and diabetes incidence among a middle-aged population. Future strategies to prevent diabetes in Japan should focus on both social and personal factors. PMID- 29430866 TI - Difference in normal limit values of nerve conduction parameters between Westerners and Japanese people might need to be considered when diagnosing diabetic polyneuropathy using a Point-of-Care Sural Nerve Conduction Device (NC stat(r)/DPNCheckTM). AB - AIM/INTRODUCTION: Studies on a novel point-of-care device for nerve conduction study called DPNCheck have been limited to Westerners. We aimed to clarify Japanese normal limits of nerve action potential amplitude (Amp) and conduction velocity by DPNCheck (investigation I), and the validity of DPNCheck to identify diabetic symmetric sensorimotor polyneuropathy (DSPN; investigation II). MATERIALS AND METHODS: For investigation I, 463 non-neuropathic Japanese participants underwent DPNCheck examinations. Regression formulas calculating the normal limits of Amp and conduction velocity (Japanese regression formulas [JRF]) were determined by quantile regression and then compared with regression formulas of individuals from the USA (USRF). For investigation II, in 92 Japanese diabetes patients, 'probable DSPN' was diagnosed and nerve conduction abnormalities (NCA1: one or more abnormalities, and NCA2: two abnormalities in Amp and conduction velocity) were determined. Validity of NCAs to identify 'probable DSPN' was evaluated by determining sensitivity, specificity, reproducibility (kappa coefficient) and the area under the curve of receiver operating characteristic curves. RESULTS: For investigation I, JRF was different from USRF, and normal limits by JRF were higher than that of USRF. The prevalence of Amp abnormality calculated by JRF was significantly higher than that of USRF. For investigation II, the sensitivity, specificity and reproducibility of NCA1 and NCA2 judged from JRF were 85%, 86% and 0.57, and 43%, 100% and 0.56, respectively. These values of JRF were higher than those of USRF. The area under the curve of JRF (0.89) was larger than USRF (0.82). CONCLUSIONS: A significant difference in the normal limits of nerve conduction parameters by DPNCheck between Japanese and USA individuals was suggested. Validity to identify DSPN of NCAs might improve by changing the judgment criteria from USRF to JRF. PMID- 29430867 TI - Rheopheresis for Adjuvant Treatment in Resistant Calciphylaxis. PMID- 29430868 TI - A novel homozygous AP4B1 mutation in two brothers with AP-4 deficiency syndrome and ocular anomalies. AB - Adaptor protein complex-4 (AP-4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with an autosomal recessive phenotype, consisting of spastic tetraplegia, and intellectual disability (ID). The overlapping clinical picture among individuals carrying mutations in any of these genes has prompted the terms "AP-4 deficiency syndrome" for this clinically recognizable phenotype. Using whole-exome sequencing, we identified a novel homozygous mutation (c.991C>T, p.Q331*, NM_006594.4) in AP4B1 in two siblings from a consanguineous Pakistani couple, who presented with severe ID, progressive spastic tetraplegia, epilepsy, and microcephaly. Sanger sequencing confirmed the mutation was homozygous in the siblings and heterozygous in the parents. Similar to previously reported individuals with AP4B1 mutations, brain MRI revealed ventriculomegaly and white matter loss. Interestingly, in addition to the typical facial gestalt reported in other AP-4 deficiency cases, the older brother presented with congenital left Horner syndrome, bilateral optic nerve atrophy and cataract, which have not been previously reported in this condition. In summary, we report a novel AP4B1 homozygous mutation in two siblings and review the phenotype of AP-4 deficiency, speculating on a possible role of AP-4 complex in eye development. PMID- 29430869 TI - Monoclonal Cell Line Generation and CRISPR/Cas9 Manipulation via Single-Cell Electroporation. AB - Stably transfected cell lines are widely used in drug discovery and biological research to produce recombinant proteins. Generation of these cell lines requires the isolation of multiple clones, using time-consuming dilution methods, to evaluate the expression levels of the gene of interest. A new and efficient method is described for the generation of monoclonal cell lines, without the need for dilution cloning. In this new method, arrays of patterned cell colonies and single cell transfection are employed to deliver a plasmid coding for a reporter gene and conferring resistance to an antibiotic. Using a nanofountain probe electroporation system, probe positioning is achieved through a micromanipulator with sub-micron resolution and resistance-based feedback control. The array of patterned cell colonies allows for rapid selection of numerous stably transfected clonal cell lines located on the same culture well, conferring a significant advantage over slower and labor-intensive traditional methods. In addition to plasmid integration, this methodology can be seamlessly combined with CRISPR/Cas9 gene editing, paving the way for advanced cell engineering. PMID- 29430870 TI - Editorial: Magnetic Resonance Imaging Signals in the Sacroiliac Joints of Healthy Athletes: Refining Disease Thresholds and Treatment Strategies in Axial Spondyloarthritis. PMID- 29430871 TI - Excitation-Dependent Theranostic Nanosheet for Cancer Treatment. AB - In this work, a novel ruthenium complex loaded monolayer layered double hydroxide (LDH) (denoted as Ru(C-bpy)2 /mLDH) as supramolecular nanosensor is synthesized, which is greatly exclusive to the hypoxic tumor microenvironment. The Ru(C-bpy)2 /mLDH ultrathin sheet displays not only enhanced luminescence lifetime compared to the parent Ru(C-bpy)2 alone, but also improved oxygen responsibility under an excitation of 488 or 800 nm. Moreover, the Ru(C-bpy)2 /mLDH is possessed of two photon fluorescence imaging ability under the 800 nm irradiation. In addition, the Ru(C-bpy)2 /mLDH can generate singlet oxygen with a high yield (phi? ) of 0.28 under the 520 nm irradiation, while the phi? of Ru(C-bpy)2 is 0.19. Therefore, the Ru(C-bpy)2 /mLDH can be applied as a supramolecular theranostic agent with light-switchable cancer imaging and photodynamic therapy properties. PMID- 29430873 TI - Identification of the new HLA-DPB1 allele, DPB1*647:01, in an Italian patient with leukemia. AB - A novel HLA-DPB1 allele, named HLA-DPB1*647:01, identified in a leukemia patient. PMID- 29430872 TI - Semaphorin 3A receptor inhibitor as a novel therapeutic to promote innervation of bioengineered teeth. AB - The sensory innervation of the dental pulp is essential for tooth function and protection. It is mediated by axons originating from the trigeminal ganglia and is spatio-temporally regulated. We have previously shown that the innervation of bioengineered teeth can be achieved only under immunosuppressive conditions. The aim of this study was to develop a model to determine the role of Semaphorin 3A (Sema3A) in the innervation of bioengineered teeth. We first analysed innervation of the dental pulp of mandibular first molars in newborn (postnatal day 0: PN0) mice deficient for Sema3A (Sema3A-/- ), a strong inhibitor of axon growth. While at PN0, axons detected by immunostaining for peripherin and NF200 were restricted to the peridental mesenchyme in Sema3A+/+ mice, they entered the dental pulp in Sema3A-/- mice. Then, we have implanted cultured teeth obtained from embryonic day-14 (E14) molar germs of Sema3A-/- mice together with trigeminal ganglia. The dental pulps of E14 cultured and implanted Sema3A-/- teeth were innervated, whereas the axons did not enter the pulp of E14 Sema3A+/+ cultured and implanted teeth. A "Membrane Targeting Peptide NRP1," suppressing the inhibitory effect of Sema3A, has been previously identified. The injection of this peptide at the site of implantation allowed the innervation of the dental pulp of bioengineered teeth obtained from E14 dental dissociated mesenchymal and epithelial cells reassociations of ICR mice. In conclusion, these data show that inhibition of only one axon repellent molecule, Sema3A, allows for pulp innervation of bioengineered teeth. PMID- 29430876 TI - Hard onset therapy for functional hypoadduction and presbylaryngis: Our experience in 22 patients. PMID- 29430874 TI - Characterizing human decellularized crystalline lens capsules as a scaffold for corneal endothelial tissue engineering. AB - The idea of transplanting a sheet of laboratory-grown corneal endothelium dates back to 1978; however, the ideal scaffold is still lacking. We hypothesized that human crystalline lens capsules (LCs) could qualify as a scaffold and aimed to characterize the properties of this material for endothelial tissue engineering. LCs were isolated from donor eyes, stored at -80 degrees C, and decellularized with water and trypsin-EDTA. The decellularization was investigated by nuclear staining and counting and the capsule thickness was determined by optical coherence tomography and compared with Descemet's membrane (DM). Transparency was examined by spectrometry, and collagenase degradation was performed to evaluate its resistance to degradation. Cell-scaffold interaction was assessed by measuring focal adhesions surface area on LC and plastic. Finally, primary corneal endothelial cells were grown on LCs to validate the phenotype. Trypsin EDTA decellularized most effectively, removing 99% of cells. The mean LC thickness was 35.76 +/- 0.43 MUm, whereas DM measured 25.93 +/- 0.26 MUm (p < .0001). Light transmission was 90% for both LC and DM. On a collagenase challenge, LC and amniotic membrane were digested after 13 hr, whereas DM was digested after 17 hr. The surface area of focal adhesions for cells grown on coated LCs was at least double that compared with other conditions, whereas tight junctions, ion pumps, and hexagonal morphology were well maintained when endothelial cells were cultured on LCs. In conclusion, LCs demonstrate excellent scaffolding properties for tissue engineering and sustain the cell phenotype and can be considered a suitable substrate for ocular tissue engineering or as a template for future scaffolds. PMID- 29430875 TI - Novel 3-substituted N-methylcarbazole-imidazolium salt derivatives: Synthesis and cytotoxic activity. AB - A series of novel 3-substituted N-methylcarbazole-imidazolium salt derivatives has been prepared and evaluated in vitro against a panel of tumor cell lines (Hep G-2, Hela and PC12). The results suggest that the presence of substituted 2 methyl-imidazole or imidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl or 4-bromophenacyl group were important for improving cytotoxic activity. Compounds 17, 18, 27, and 28 with 4-bromophenacyl and naphthylacyl groups displayed good activities with IC50 values of 0.09-7.20 MUm against three tumor cell lines investigated and more active than DDP. Compound 35 exhibited cytotoxic activity selectively against Hela cell. PMID- 29430877 TI - Detection of prohibited substances in equine hair by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry - application to doping control samples. AB - The detection of drugs in human hair samples has been performed by laboratories around the world for many years and the matrix is popular in disciplines, such as workplace drug testing. To date, however, hair has not become a routinely utilised matrix in sports drug detection. The analysis of hair samples offers several potential advantages to doping control laboratories, not least of which are the greatly extended detection window and the ease of sample collection and storage. This article describes the development, validation, and utilisation of a sensitive ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-MS/MS) method for the detection of 50 compounds. This provides significantly improved coverage for those analytes which would be of particular interest if detected in hair, such as anabolic steroid esters and selective androgen receptor modulators (SARMs). Qualitative validation of the method resulted in estimated limits of detection as low as 0.1 pg/mg for the majority of compounds, with all being detected at 2 pg/mg or below. The suitability of the method for the detection of prohibited substances in incurred material was demonstrated by the successful detection of several compounds, such as stanozolol, boldenone undecylenate, clenbuterol, and GW-501516, in genuine equine hair samples. Estimated concentrations of the detected substances ranged from 0.27 to 8.6 pg/mg. The method has been shown to be fit-for-purpose for routine screening of equine hair samples by the analysis of over 400 genuine hair samples. PMID- 29430878 TI - Placental implantation over prior cesarean scar causes activation of fetal regulatory T cells. AB - INTRODUCTION: Maternal-fetal chimerism is miniscule, a testament to the integrity of the uteroplacental interface. The soundness of this border region is potentially altered through cesarean delivery of prior babies with uncertain consequences for the following pregnancies. METHODS: Using multicolor flow cytometry and quantitative PCR of non-inherited maternal antigens we performed a retrospective case control pilot study and formulated the null hypothesis that placental implantation over a prior uterine scar does not result in the presence of memory Treg (CD45RO+) in the fetus. We then performed a power calculation and performed a blinded, appropriately powered prospective case control study to test the null hypothesis. RESULTS: Fetuses born to mothers with prior uterine scar have a roughly five times higher maternal to fetal microchimerism when the placenta directly interacts with the uterine scar. Unlike exposure to antigens in adult life, in utero antigenic exposure induces tolerogenic (Treg) responses in fetuses and we here report the presence of fetal Treg with a memory phenotype (CD45RO+). However, we only find such CD45RO+ fetal Tregs when the placenta abuts the uterine scar (Risk Ratio = 5 [p < 0.05 CI:(1.448 to 17.27)]). These memory fetal Tregs are functionally highly suppressive compared to CD45RA-expressing fetal Tregs, and have specificity for non-inherited maternal antigens. CONCLUSIONS: We found that uterine scars, in the case of our study these scars are from prior c-sections, fundamentally impair uterine integrity allowing for increased antigen exposure of the fetus; with our appropriately powered study we rejected the null hypothesis and accepted the alternative hypothesis that placental implantation over a prior uterine scar results in the presence of memory Treg (CD45RO+) in the fetus. Thus, our study demonstrates a previously unappreciated role for uterine integrity in limiting fetal antigenic exposure, a key element to avoid the formation of inappropriate tolerances by the fundamentally tolerogenic fetal immune system. PMID- 29430879 TI - Four novel alleles in Korean individuals, HLA-B*40:323, DRB1*14:177, DQB1*03:200, and DQB1*06:205. AB - Four novel HLA alleles identified in Korean individuals and confirmed by monoallelic sequencing. PMID- 29430880 TI - Frequency and Anatomic Distribution of Magnetic Resonance Imaging Features in the Sacroiliac Joints of Young Athletes: Exploring "Background Noise" Toward a Data Driven Definition of Sacroiliitis in Early Spondyloarthritis. AB - OBJECTIVE: Low-grade bone marrow edema (BME) has been reported in the sacroiliac (SI) joints of 25% of healthy individuals and patients with nonspecific mechanical back pain, thus challenging the specificity and predictive value of magnetic resonance imaging (MRI) for the discrimination of early spondyloarthritis (SpA). It is unknown whether stress injury in competition sports may trigger BME. This study sought to explore the frequency and anatomic distribution of SI joint MRI lesions in recreational and elite athletes. METHODS: After pretest calibration, semicoronal MRI scans of the SI joints of 20 recreational runners before and after running and 22 elite ice hockey players were assessed for BME and structural lesions. Three readers assessed the MRI scans in a blinded manner, using an SI joint quadrant-based module; scans from tumor necrosis factor inhibitor-treated patients with SpA served for masking. The readers recorded subjects who met the Assessment of SpondyloArthritis international Society (ASAS) definition of active sacroiliitis. For descriptive analysis, the frequency of SI joint quadrants exhibiting BME and structural lesions, as concordantly recorded by >=2 of 3 readers, and their distribution in 8 anatomic SI joint regions (the upper and lower ilium and sacrum, subdivided in anterior and posterior slices) were determined. RESULTS: The proportions of recreational runners and elite ice hockey players fulfilling the ASAS definition of active sacroiliitis, as recorded concordantly by >=2 of 3 readers, were 30-35% and 41%, respectively. In recreational runners before and after running, the mean +/- SD number of SI joint quadrants showing BME was 3.1 +/- 4.2 and 3.1 +/- 4.5, respectively, while in elite ice hockey players, it was 3.6 +/- 3.0. The posterior lower ilium was the single most affected SI joint region, followed by the anterior upper sacrum. Erosion was virtually absent. CONCLUSION: In recreational and elite athletes, MRI revealed BME in an average of 3-4 SI joint quadrants, meeting the ASAS definition of active sacroiliitis in 30-41% of subjects. The posterior lower ilium was the single most affected SI joint region. These findings in athletes could help refine data-driven thresholds for defining sacroiliitis in early SpA. PMID- 29430881 TI - [Actualization of methodological problems of reglamentation of chemical pollutions on the environment] AB - There has been demonstrated a sharp increase of chemical pressing on the environment and human health, detection of hundreds of chemical compounds in different environmental objects, most of such chemicals have no hygienic standards. There are presented main disadvantages oKikuworks on the risks assessment of the impact ofpolluted environment on human health. There are indicated priority directions of the improvement of the analysis methodology and risk management, based on modern international achievements, as well as evaluation of detriments to the environment and human health with taking into account world systems as follows: AirQ (WHO), IEHIA and APHEIS (EU), FERET and EPA (USA), EAHEAP and COMEAP (GreatBritain), ECOSENSE (Germany), AirPack (EU, France), AQVM (Canada), and also domestic of TERA 2,5 (module EpidRisk). The integral evaluation of the scientific disciplines "Human Ecology", "EnvironmentalHealth" and "EnvironmentalMedicine" is given. Comparative conceptual considertion of the terms "Environment", "Habitat" and their international application is given. PMID- 29430882 TI - [Chemical pollution of baby food products in the Russian Federation]. AB - One of the main problems of nutrition of children and adolescents is to assess chemical contamination of baby food products and the establishment of the relation with the health of the child population. With the entering different chemical compounds in the body of the child there can be observed disorders of the nervous, urinary, cardiovascular system, gastrointestinal tract, as well as metabolic deteriorations, degenerative processes in parenchymal organs and bone destruction. The aim of the study was to analyze data on chemical contamination of baby food products in the Russian Federation for 2012-2014. The analysis was executed on the data of Federal Information Fund of social and hygienic monitoring of the Russian Federation. There were identified priority pollutants (toxic elements, nitrites, nitrates, nitrosamines, pesticides, hydroxymethylfurfural, mycotoxins) and risk areas (the Lipetsk region, the Krasnodar Territory, the Republic of Adygea, city of Moscow, Tatarstan, the Kabardino-Balkar Republic, the Ryazan region). There are detected contamination levels not exceeding MAC (in the dynamics of the three years offollow up, on average 22%), requiring their hygienic assessment. There were determined the baby food products containing most common occurred chemical contaminants: fruits and vegetables products, canned products, canned meat, cereals, dairy products, liquid and adapted and partially adapted milk formalas. Identified data indicate to a need for further studies of chemical substances in products for children's nutrition in order to establish the causal relationships with a various diseases and the substantiation of methodological approaches to the risk assessment of combined exposure to chemical contaminants in concentrations up to the MPC on health of children, including infants. PMID- 29430883 TI - Models to predict length of stay in the Intensive Care Unit after coronary artery bypass grafting: a systematic review. AB - INTRODUCTION: Intensive Care Units (ICU) length of stay (LoS) prediction models are used to compare different institutions and surgeons on their performance, and is useful as an efficiency indicator for quality control. There is little consensus about which prediction methods are most suitable to predict (ICU) length of stay. The aim of this study is to systematically review models for predicting ICU LoS after coronary artery bypass grafting and to assess the reporting and methodological quality of these models to apply them for benchmarking. EVIDENCE ACQUISITION: A general search was conducted in Medline and Embase up to 31-12-2016. Three authors classified the papers for inclusion by reading their title, abstract and full text. All original papers describing development and/or validation of a prediction model for LoS in the ICU after CABG surgery were included. We used a checklist developed for critical appraisal and data extraction for systematic reviews of prediction modeling and extended it on handling specific patients subgroups. We also defined other items and scores to assess the methodological and reporting quality of the models. EVIDENCE SYNTHESIS: Of 5181 uniquely identified articles, fifteen studies were included of which twelve on development of new models and three on validation of existing models. All studies used linear or logistic regression as method for model development, and reported various performance measures based on the difference between predicted and observed ICU LoS. Most used a prospective (46.6%) or retrospective study design (40%). We found heterogeneity in patient inclusion/exclusion criteria; sample size; reported accuracy rates; and methods of candidate predictor selection. Most (60%) studies have not mentioned the handling of missing values and none compared the model outcome measure of survivors with non-survivors. For model development and validation studies respectively, the maximum reporting (methodological) scores were 66/78 and 62/62 (14/22 and 12/22). CONCLUSIONS: There are relatively few models for predicting ICU length of stay after CABG. Several aspects of methodological and reporting quality of studies in this field should be improved. There is a need for standardizing outcome and risk factor definitions in order to develop/validate a multi-institutional and international risk scoring system. PMID- 29430884 TI - The association between aortic cross clamp time and postoperative morbidity and mortality in mitral valve repair: a retrospective cohort study. AB - BACKGROUND: The aim of this study was to estimate the association between aortic cross clamp time and postoperative morbidity and mortality in patients undergoing mitral valve repair. METHODS: A retrospective cohort study between 2006 and 2014 was performed as a single Center study in the University Medical Center Utrecht. In total 1007 patients who underwent mitral valve repair were included. The patients were divided into a group who underwent isolated mitral valve repair and a group who underwent mitral valve repair with concomitant intervention(s). The primary endpoint was a composite consisting of in-hospital mortality or postoperative major complications. RESULTS: In the isolated mitral valve group (N.=405), patients were significantly younger, healthier and had fewer complications (9.9%). Patients with concomitant intervention(s) had a twofold higher rate of postoperative complications and mortality (18.1%). After adjustment for confounding there was no association between aortic cross clamp time and the primary endpoint in both the isolated mitral valve group (odds ratio 1.04; 95% CI: 0.98-1.11) and the group with concomitant interventions (odds ratio 1.02; 95% CI: 0.97-1.06). CONCLUSIONS: In patients undergoing mitral valve repair surgery a longer aortic cross clamp time was not associated with postoperative complications and mortality. The higher postoperative morbidity and mortality in combined procedures appears to be due to a higher age, more comorbidities and an extra intervention rather than to the duration of aortic cross clamp time. PMID- 29430885 TI - Abdominal aortic aneurysm calcification: trying to identify a reliable semiquantitative method. AB - BACKGROUND: The main objective of this study was to assess the correlation between three semiquantitative and one computerized method based on Agatston Score (AS), when measuring abdominal aortic calcification (AAC) in abdominal aortic aneurysm (AAA) patients. Secondary aim was to access differences in AAC upon clinical variables, when different methods of calcium scoring are used. METHODS: This was an observational, retrospective, cross-sectional study. A database of AAA patients consecutively submitted to elective repair between 2008 and 2015 was used. Patients were excluded if they did not have preoperative imaging or presented scans incompatible with at least one of the whole set of calcification methods tested. Calcification measures were performed using AS, aortic calcification index (ACI), AAC-8 and AAC-24 methods. The Pearson's correlation was used for primary analysis. RESULTS: Study population comprised 102 patients, 95% males, with a median age of 71 (interquartile range, IQR 66-76) years. AAAs presented median aortic diameter of 60 (54- 70) mm. Pearson's correlation with AS was 0.816 for ACI, 0.703 for AAC-8 and 0.648 for AAC-24. ACI also presented the highest ICC for intraobserver agreement (0.972) and for interobserver agreement (0.966). ACI was associated more often to demographic and clinical variables in the dataset that associated with the computerized method. CONCLUSIONS: ACI is suggested as a fast and easy-to-use method of assessing AAC in AAA patients. Its use should be encouraged to study AAC in AAA over other semiquantitative methods, in research settings. PMID- 29430886 TI - Endovascular treatment of para-anastomotic aneurysms after open abdominal aortic surgery. AB - INTRODUCTION: The repair of long-term complications of open abdominal aortic repair such as para-anastomotic aneurysm (PAA) and pseudoaneurysm (PSA) is very challenging. The aim of this study was to assess the outcomes of endovascular repair of PAA/PSA after previous open aortic surgery for aneurismal or occlusive disease. EVIDENCE ACQUISITION: A systematic review was undertaken; a search was performed (PRISMA) in MEDLINE, CENTRAL, Cochrane databases and key references of all studies of endovascular treatment of PAA/PSA after open aortic surgery. EVIDENCE SYNTHESIS: Eighteen studies included totally 433 patients (86.3% males) with mean age of 71+/-2.5 years were identified. Most of the patients were asymptomatic (76%) and diagnosed with PAA (60.5%), while 81.6% had history of open aortic reconstruction for aneurismal disease. The mean diameter of para- anastomotic aneurysms was 59.7mm (from 23mm to 110mm) and the mean duration until their diagnosis was 10+/-2 years. Standard bifurcated (23.7%), fenestrated (23.4%) and aorto-uniiliac stentgrafts (16.3%) were mostly used. The technical success rate was 97.8% (391/400) with 1.4% (6/433) 30 day-mortality rate and mean hospital stay of 6+/-3 days. The mean 1- and 2- year survival rate was 87.8% and 78.8%, respectively. The follow up ranged from 9 to 43 months, with presenting complications such as Endoleak type I (24/378; 6.3%), type II (15/354; 4.3%), type III (3/378;0.8%), migration (4/378; 1%) and limb occlusion (5/310;1.6%). Additionally, 5.7% (19/332) of the patients underwent open conversion, while the total re- intervention rate was 11.4% (39/340; time of re-intervention ranged from 7 to 30 months). In cases in which a stent was used for splanchnic vessels (renal artery: 188, superior mesenteric artery: 98, celiac artery: 64), the primary patency rate was 97.4% (341/350). CONCLUSIONS: Endovascular treatment of PAAs and PSAs after previous open aortic surgery is a feasible and efficient option with high technical success rate, low 30-day mortality and good mid-term outcomes. PMID- 29430887 TI - Results of hybrid procedures for treatment of aortoiliac Trans-Atlantic Inter Society Consensus II D lesions with self-expanding covered heparin-bonded stent grafts. AB - INTRODUCTION: According to the guidelines aortoiliac TASC D lesions should be treated by bypass. The purpose of this study was to examine the results of hybrid procedures with the use of a self-expanding covered heparin-bonded stent graft (Viabahn) in patients with extensive aorto-iliac lesions who were not considered to be suitable for open aorto-iliac surgery. METHODS: All patients who received a hybrid procedure in combination with a Viabahn stent in our clinic to treat aortoiliac lesions between October 2011 and April 2017 were included in this retrospective analysis. Study endpoints were primary patency, amputation free survival (AFS) and major adverse limb event (MALE) free survival after 2 years. RESULTS: We included 23 hybrid procedures (endarterectomy of the common femoral artery or cross over bypass and aortoiliac stent) in 20 patients (median age 59 years). Indication was critical limb ischemia in 70.0%. The reasons why patients were on high risk for alternative open aortoiliac revascularization were hostile abdomen in 35.0%, cardiopulmonary contraindications in 35%, cancer in 10.0%, age > 80 years in 10.0% and alcoholic cirrhosis in 10.0%. The 30 day mortality was 15.0%, the major amputation rate was 4.3%. We had no early graft occlusion. After 2 years primary patency was 100%, AFS 58.2% and MALE free survival 95.7%. CONCLUSIONS: A hybrid procedure with the use of a Viabahn stent in severe aortoiliac pathologies showed good patency results in this selected patient group. Therefore, it should be considered a feasible alternative to aortoiliac bypass surgery in surgical high risk patients. PMID- 29430888 TI - Early post-approval experience with transcatheter aortic valve replacement in the USA. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is changing the treatment of aortic stenosis. We compared cost and clinical outcomes of TAVR versus surgical aortic valve repair (SAVR) in the real-world setting since USA TAVR approval in 2012. METHODS: The Nationwide Inpatient Sample (NIS) dataset was analyzed by quarter (June 2012 to December 2014). Patients (>65 years old) undergoing TAVR or SAVR were identified and risk stratified based on APR-DRG Mortality risk score. Outcomes were in-hospital mortality, length of stay (LOS), discharge location, and hospitalization cost. RESULTS: TAVR cases per quarter increased from 1900 to 5445 over the study period. TAVR patients were older and had more comorbidities (P<0.001). TAVR patients had longer LOS (8 vs. 7 days; P<0.001), were less likely to discharge to home (67% vs. 73%; P<0.001), had higher inpatient mortality (5.5% vs. 0.69%; P<0.001) and overall hospital cost ($ 227,985 vs. $ 148,019; P<0.001) than SAVR patients. On multivariate analysis TAVR was associated with increased cost (beta=0.42; P<0.001) and increased mortality (OR=5.228, CI: 3.508-7.791; P<0.001) but not associated with increased LOS (beta=0.297; P=0.078) or discharge to facility (OR=1.004, CI: 0.833-1.213; P=0.960). In the last two quarters of 2014 there was no difference between TAVR and SAVR LOS, however TAVR cost did not decrease over the study period. CONCLUSIONS: TAVR patients represented a sicker population, however LOS and discharge location outcomes were equivalent to SAVR. TAVR remained significantly more expensive across all risk groups and cost did not fall over the course of the study. PMID- 29430889 TI - Current treatment of superficial femoral artery disease: a national survey. PMID- 29430890 TI - Tricuspid valve replacement: results of an orphan procedure - which is the best prosthesis? AB - BACKGROUND: Replacement of the tricuspid valve is uncommon. Prostheses specifically designed for this position are not available. Bovine, porcine as well as mechanical valve prostheses are currently used, however, the most suitable prosthesis type has not been defined. METHODS: We retrospectively analyzed all consecutive patients who underwent tricuspid valve replacement (TVR) at the Medical University of Vienna from 1996 to 2014. Baseline patient characteristics, prosthesis type, and postoperative outcome data were collected. RESULTS: A total of 58 patients underwent TVR. Forty-one patients (71%) received biological (18 bovine, 23 porcine), and 17 patients (29%) mechanical prostheses. One-year survival (70.2% vs. 76.5%, P=0.18), and freedom from reoperation at one year (86.3% vs. 94.1%, P=0.35) was not significantly different bioprostheses and mechanical valves. Freedom from reoperation rates for bovine versus porcine prostheses (one-year: 88.2% vs. 84.4%, P=0.145) were also not significantly different. However, three bovine prosthesis had to be reoperated due to high grade central regurgitation without any signs of endocarditis or structural valve degeneration. CONCLUSIONS: There is a lack of clinical trials on tricuspid valve replacement and no specific guidelines for the choice of prosthesis. In the current study we have not identified significant differences in mortality between mechanical and biological valves. However, bovine prostheses seem less suitable for the tricuspid position due to the high closing volume with consecutive severe postoperative regurgitation. PMID- 29430892 TI - [Actual problem of methodology and development of evidence-based health risk assessment associated with chemical exposure]. AB - Paramount problems of the development of the assessment of population health risks associated with the chemical exposure in Russia are considered on the ground of critical analysis of reports devoted to methodological issues of the risk assessment and guidelines published since 2010. Causes of the lack in progress of risk assessment are discussed. The information of executed research revealed the significant retardation number of Russian publications devoted to the evidence-based health risk assessment compare to worldwide trend. The analysis of publications according to evidence-based health risk assessment in Russia in 1998 - 2012 demonstrated methodical problems to be leading to the underestimation of the real risk to population's health. There are demonstrated directions in the renewal of methodology and practice of hygienic standardization on the basis of the risk assessment. The comparative analysis of values of uncertainty factors (modifying factors, conversion factors) used for extrapolation and accepted in different countries and organizations was made. The system of extrapolation coefficients of DNEL (Derive No-Effect Level) is presented. The leading principles of modern toxicology and risk assessment based on strict scientific proofs are showed. Criteria of evidence-based toxicology and risk assessment are presented.Among actual problems which demand their decision there are considered: the assessment of combined action in regulatory toxicology; expansion of spheres of the application of health risk assessment methodology; the improvement ofpreparation and certification of experts in the field of health risk assessment; need of check of dispersion models and their replacement by more modern models; the improvement of exposure assessment with taking into account the international requirements; the assessment of regional exposure factors; expansion of atmospheric air monitoring in all the large cities of Russia. PMID- 29430891 TI - Flexible robotics in pelvic disease: does the catheter increase applicability of embolic therapy? AB - Interventional radiology procedures, equipment, and techniques as well as image guidance have developed dramatically over the last few decades. The evidence for minimally invasive interventions in vascular and oncology fields is rapidly growing and several procedures are considered the first line management. However, radiation exposure, image guidance and innovative solutions to known anatomical challenges are still lagging behind. Robotic technology and its role in surgery have been developing at a steady speed. Endovascular robotics are following suit with a different set of problems and targets. This article discusses the advances and limitations in one aspects of endovascular robotic, namely pelvic pathology that includes aneurysms, fibroids, benign prostatic hypertrophy and vascular malformation. PMID- 29430893 TI - [About the formation of legislation in the field of chemical and biological safety of the Russian Federation]. AB - The realization of the package of measures directed at the consecutive decrease of the negative effect of hazardous chemical and biological factors on the population and environment to the acceptable risk level stipulates the development of standard legal regulation in the field of ensuring the chemical and biological safety. For this purpose article presents substantiation and conceptual approaches to the creation of legislation in the field of the chemical and biological security of the Russian Federation within the pursued state policy. In determination of conceptual approaches, in the article there are reported: the main idea, the purpose, a subject of legal regulation, the circle of people who will be subjected to the laws, the place offuture laws in the system of current legislation, the provisions of the Constitution of the Russian Federation, the Federal backbone laws of the Russian Federation to realization of which laws are directed, there is given the general characteristic and an assessment of a condition of legal regulation in this field, results of the analysis of the information on the need for correspondence of Russian laws to provision of international treaties, concerning prohibitions of the biological and chemical weapon, safe handling with biological agents and chemicals, and also the development of uniform procedures of ensuring chemical and biological safety. The major aspect in the shaping of the legislation is the global character ofproblems of chemical and biological safety in this connection in article there is indicated the need of rapprochement of rules of law for this area with partners in economic cooperation and integration. Taking into account an orientation of future laws on the decrease in the level of the negative impact of dangerous chemical and biological factors on the population and environment, there are designated medical, social, economic and political consequences of their implementation. There are presented the proposed structure for bills: "About biological safety", "On Chemical Safety" and "On the National collection of pathogens. PMID- 29430894 TI - [Environmental protection and health of the population at using of a new cotton defoliant "uzdef-k" in agriculture]. AB - Toxicity parameters of a new cotton defoliant "UzDEF-K" were studied in various ways of exposure. The preparation is established to be referred to the IV hazard class. Hygienic standards of a defoliant in environment objects andfoodstuffs (maximum concentration limit in reservoir's water - 2,0 mg/l, in working zone air - 2,5 mg/m and atmospheric ambient air - 0,2 mg/m were set). Maximum allowable limit in foodstuffs - cotton oil: "it isn't allowed", APC in the soil - 1,15 mg/kg), were scientifically based regulations of safe using of a preparation in agriculture are: a sanitary protection zone-100 m, in terms of attendance at work - 5 days. PMID- 29430895 TI - [Hygienic assessment of living conditions and morbidity of the population in the port cities of the Sakhalin region]. AB - The aim of this study was to perform a comprehensive hygienic assessment of environmental conditions in the port cities of the Sakhalin region to identify priority risk factors affecting on population health and management decisions for the optimization of living conditions. As a result of the assessment of risk and damages for public health from the effects of air pollution on the dose-response, effects were found to excess of impact on the target organs by 10 times. The main ecotoxicant was determined to be manganese oxide, which is associated with a priority manganese content in soil samples ofport cities. The positive dynamics of the gain in the accumulation of soil heavy metals according to the total index indicates to the existence of problems for soil contamination. Analysis of demographic variables shows that the population of the Sakhalin region in general and the port cities in particular relates to a regressive type. The main causes of the population decline are mortality and migration outflow of able-bodied population in other regions of Russia. However, in the port cities there is an increase in the number of work places, contributing to an increase in the labor force. The primary and general morbidity of the population ofport cities is characterized by higher levels compared with the average for the Sakhalin Region and the Far Eastern Federal District. Among all the classes of diseases as priority ones there are marked "neoplasm", "diseases of the nervous system", "respiratory diseases", "diseases of the skin and subcutaneous tissue". Port cities occupy the top ranking places on the incidence of malignant tumors among the cities of the Sakhalin region. PMID- 29430896 TI - [Monitoring of public health in the Kashagan oil and gas field]. AB - According to explored hydrocarbon reserves the Republic of Kazakhstan (RK) is among ten top countries rich in oil deposits. In connection with the intensive development of oil and gas industry environmental protection and public health issues became subject of a great interest from both scientists ' and health practitioners ' side. Results of the study included in this article are devoted to the study of health of the population, living near the "Bolashak" installation of complex preparation of oil and gas. There is a preliminary oil refining process coming from the Kashagan field and its further export. Analysis proved air pollution to be the one of the major risk factors for the health of the residing people. In the area there are problems of fresh water supply and frequent accidents at sewage plants. Landfills for municipal solid waste does not meet sanitary standards. The health care system of Makat district is characterized by uncompleted personnel and lack of beds. Indices of the mortality rate over the study period declined by 28.8%. As a result, population growth over the study the period was characterized by a tendency to increase. In 2013 population sought medical advice due to respiratory diseases, injuries and poisoning, diseases of blood and hemopoietic organs, diseases of the skin and subcutaneous tissue and nervous system. PMID- 29430897 TI - [State of kidneys of the population of the industrial city]. AB - The assessment of renal functions of the adult population of Atyrau (West Kazakhstan) exposed to Atyrau oil refinery and other industrial objects (enterprises in the city), as well as employees of this refinery has been performed by virtue of the identification ofpathological changes in the urine with the use ofphotometric screening, determination of serum levels of creatinine, urea, uric acid and the calculation of glomerular filtration rate. There were obtained evident data testifying to the development of statistically significant exertion of renal function in residents of this city as compared with those of control area residents. There was revealed a statistically significant decrease in the relative density of urine in in 42% of the population, leucocyturia - in 20%, erythrocyturia - in 25%. Decreased glomerularfiltration rate was noted in these people. A statistically significant elevation of the level of uric acid in the blood in combination with an acidic reaction and sharply acidic urine reaction indicates to the possibility of the development of urate urolithiasis which is confirmed by cases of discharge of stones in the urine in 20% of the population according to data of previously executed questionnaire survey. The above mentioned changes in the functional renal reserve and hyperuricemia are equally often found among the residents of the city - Atyrau refinery workers, and the rest of the city people as well. The results of the study allow to recommend the screening ofurine with quantitative registration ofpathological changes as a mean of the most optimal objective methods for early detection of renal dysfunction in population exposed to nephrotoxic impact of environmental techno-genic pollutants. PMID- 29430898 TI - [Individual risks to adolescent health, caused by contaminating the air, and their relationship with the levels of specific autoantibodies]. AB - The high levels of the air pollution create prerequisites for the development of the pathology of target organs exposed to chemical agents. Big enterprises of oil refining and chemical industry of the Irkutsk region are located in the cities of Angarsk and Sayansk. The average level of the air pollution for several years in these cities is assessed as high and moderate, respectively. The use of the personalized approach may allow to more correctly evaluate the risk for the damage to health and the body's response to external impacts. The purpose of this study was to assess the risk offormation ofpathological processes in the body of adolescents in the conditions of inhalation exposure to chemicals, taking into account the individual load and study of the level of specific autoantibodies. The study included 373 adolescents from the city with high levels of air pollution and 188 schoolchildren from the city with a moderate level pollution. There was made an evaluation of the individual chemical hazard load on adolescents ' body due to the air pollution, physiologicalfeatures and the organization of educational process and leisure. There were studied the levels of specific autoantibodies, reflecting the state of the organs - targets for the impact ofpollutants. The calculation of the individual chemical load allows to calculate indices of the hazard for the health problems of each individual and to identify individuals at increased risk of developing diseases of organs and systems, which are targets for exposure to pollutants. The increase in the hazard index of developing respiratory diseases was found to be accompanied by an increase of the relative content of autoantibodies against membrane antigens of the lung tissue. There was revealed the elevation in autoantibodies levels to the proteins of vascular endothelial with increasing hazard index of disturbances in the cardiovascular system in adolescents living in city with high levels of air pollution. PMID- 29430899 TI - [Risk assessment from exposure to chemical contaminants in food]. AB - There was investigated the impact of chemical substances contained in the public health foodstuffs in eight regions of the Republic of Tatarstan on 11 product groups: meat and meat products, fish and fish products, milk and dairy products, bread and bakery products, sugar and confectionery products, vegetables and melons (excluding potatoes), potatoes, fruits and berries, vegetable oil, eggs and egg products, salt. In total there were analyzed more than 240 thousand samples offood raw materials andfood products over the period offrom 2006 to 2014. The study took place on 27 priority chemicals, including thirteen carcinogens (benzo (a) pyrene, DDT, hexachlorobenzene, hexachloran, heptachlor, alpha-lindane, beta-lindane, lindane, cadmium, arsenic, lead, derivatives of 2,4 D acid, cypermethrin). Exposition load is calculated by the 50 (median), and 90 percentiles of the content ofpollutants in food products. There were calculated carcinogenic risks, HQ coefficients and HI indices for chronic non-cancer exposure. High values of the total cancer risk (3.31*10 at the median level of 1.49*10+ at the 90 percentile) are associated with the exposure to tohexachlorane and alpha-lindane seem to be alarming (from 1.73*10 to 9.68*10) with the effect of lindane, cadmium and lead with dominant contribution to the total risk in the use of meat and meat products, milk and dairy products. The warning value of Hazard ratios (HQ 1.1-3) at 90-percentile were shown on nitrate, lead, beta lindane, high (HQ >3), for DDT and its metabolites, lindane and arsenic, with the dominant contribution to the exposure of vegetables and melons (excluding potatoes), potato, milk and milk products. PMID- 29430900 TI - [Ecological-hygienic aspects of the prevalence of respiratory diseases in adolescents and children of the Primorsky Krai]. AB - There was executed the ecologic-hygienic assessment of the distribution of respiratory diseases prevalence in bioclimatic zones of the Primorsky Krai. The aim of the study was a systematic assessment of the impact of ecological-hygienic factors of environment on the distribution of respiratory diseases in adolescents and children of the Primorsky region. As an information database there were used indices of the prevalence of diseases of the respiratory system of the ICD-10 class of the official statistical report forms for the period of2000-2013 and the parameters of the environment offactor modules (6 - socio-sanitary, 5 - environmental). The numerical values of modules offactors were determined according to a specially developed scoring scale. The study of the prevalence was carried out with the use of a classical method of data analysis - descriptive statistics, Chi-square criteria. By means of the method of regression analysis from the SPSS package software there was established the relationship of environmental factors and the level of the prevalence of diseases, and were calculated values of the factor loadings influencing on the morbidity rate of children and adolescents. The study revealed that in the structure of morbidity diseases of the respiratory system account of 39% in adolescents, 61% - in children. Constructed predictive models describe the trend of the increasing in the prevalence in adolescents and children. Over the past 15 years, the level of respiratory diseases morbidity rate increased by 46.1%. It is established that the prevalence of respiratory diseases in children and adolescents from various districts of the Primorsky territory depends on the features of the bioclimatic zones and the degree of sanitary-hygienic situation, as well as combinations of parameters that form these zones; the highest cumulative level of the prevalence is observed in the bioclimatic zone of the coast, that is caused by the various degree of the impact of biotropic factors of environment; The prevalence of diseases of respiratory system is mainly affected by bioclimatic factors: residence in an area of high humidity, temperature swings, movements of air masses in combination with air pollution. PMID- 29430901 TI - [The work and health of adolescents: the gender aspects]. AB - The purpose of the research is to study the gender aspects of the employment of adolescents, working in the time free from their study, and its impact on the livestyle and health, to assess the risks to health of students. There was studied the employment of senior pupils and students of vocational schools (1.2 thousand persons at the age from 14 till 18 years) in 5 regions of the Russian Federation. The results indicate to a prevalence of illegal employment of the minors. Among young men 62% work part time, among young women - 37%. Violations of hygienic requirements for working conditions and labor law violations are more common in young men employment. The first experience of work can render negative impact on the lifestyle and the state of health. In the working adolescents there is observed the higher prevalence of the behavioral risk factors (smoking, alcohol, drugs, sleep deprivation and others). Adolescents with work experience have lower health status. The analysis of odds ratio (OR), relative risk (RR), etiological fraction (EF) showed that to the higher health risk there are exposed teenagers working constantly throughout the year. In this group among girls there is a high prevalence of chronic diseases (RR = 2; OR = 3.9), of complaints of indigestion (RR = 2; OR = 2.5). In the group of young men, working continuously, the percentage of frequently ill with acute respiratory infections is higher (RR = 3.3; OR = 3.7), there is a higher number of complaints of heartburn (RR = 2.1; OR = 2.6), back pain (RR = 1.8; OR = 2.2). Working young men have higher health risk by comparison with working young women. PMID- 29430902 TI - [The impact of ecological and socio-hygienic factors on the health status of children of school age]. AB - Negative trends in incidence rates of children and adolescents of the city of Penza are due to the influence of both environmental factors as well as the educational process. Hygienic trouble in the city of Penza determines air pollution emissions of road transport, as evidenced by the high levels of morbidity rate in children and adolescents. The priorities for the correction factors are conditions and the organization of nutrition, physical education. There are identified the most important lifestyle factors for senior pupils that need the solution. PMID- 29430903 TI - [Cytogenetic status of children in the hygienic assessment of the air pollution by odorous substances]. AB - For the first time the impact of odorous emissions from the enterprise for the production of chewing gum on the cytogenetic status of children, residing in the distance of 0,9 and 6 km, was studied. Specific weak mint and fruity odour in the air in the placement of the enterprise may be related to the presence of menthol, menthone, pinene, limonene, ethyl acetate and other compounds containing in the emissions. There were no differences in cytogenetic status of children in both groups (by frequency of micronuclei, protrusions, binucleated cells, apoptosis). PMID- 29430904 TI - [Differential diagnostic method of initial implications and degree I of the chronic mercury intoxication]. AB - Currently available methods for diagnosis of chronic mercury intoxication (CMI) are applied at the any stage of the disease. Changes in these indices sometimes have no the specificity for any CMI stage, and a conclusion on them has the descriptive character. In addition, the above mentioned methods possess not sufficiently high accuracy in the diagnosis of intoxication at early stages of the development of the disease. The purpose of the research is the development of the method permitting to make the differential diagnosis between the initial symptoms of mercury poisoning and its first degree. 118 men who work/worked in the contact with mercury vapor were examined. There were evaluated electroencephalogram, long-latency auditory and cognitive evoked potentials, cerebral hemodynamics, noradrenaline (NA)content in the blood plasma. Statistical processing was performed with the use of "Statistica 6.0" software. The levels of NA in the development of CMI were shown to increase, by the time of the shaping of this disease the noted change was decompensated in the nature. The study of reactivity of cerebral vessels revealed the presence of abnormal responses during hypercapnic load in 14 - 24% of examined cases. In the analysis of auditory evoked potentials there was established the change in indices of latency and amplitude of the V- wave, which pronounced in the prolong response time, significant elongation in the P1 peak latency and the gain in the latency of N1 peak. There was established the presence of the wave-like change in the index of the latency of P300. In workers without an occupational disease, there was noted the marked elongation of the latent period of cognitive potential, while in patients with the newly made diagnosis the latency of P300 corresponded to standard values, and in the long term there was observed a sharp deterioration in this index. With the aid of the discriminant analysis with the calculation of canonical value there were revealed the most informative neurobiochemical indices, reoencephalogric ones and evoked potentials. The developed method of diagnosis allows to distinguish between the initial symptoms of mercury intoxication and the first stage of the disease. PMID- 29430905 TI - [Methodological aspects of the assessment of phytotoxicic properties of ice melter reagents]. AB - One of the main criteria which determine the possibility of the use of a particular type of ice-melter reagents (IMR) is the degree of their safety for the environment and human health, which is reflected in the establishment of safe doses and concentrations. In this regard, the current area of research is to improve the ecological and epidemiological principles of risk assessment of modern types of anti-icing agents. Currently available data concerning monitoring soil studies and the snow held in various cities of Russia, show that there is a process of accumulation of the main components of IMR - sodium and chlorine ions in the areas related to the roadway. The article is designated a problem of existing methodological approaches to the assessment of the phytotoxic impact in the investigation of anti-icing agents in the laboratory. There was executed the comparative characteristics of the results of the preliminary pilot studies on the phytotoxic properties of IMR under using different substrates for germination of seeds - soil and filter paper. The data obtained are characterized by differences in the degree of phytotoxic action of the same species depending upon ice-melter reagents methodical setting circuit laboratory experiment. As a result, there was shown the imperfection of the existing method of rapid analysis in relation to ice-melter materials (IMM). PMID- 29430906 TI - [Toxicological characteristics of the cinnamic]. AB - The toxic properties of the cinnamic alcohol with an aim of its hygienic rating are studied. DL for male rats, male and female mice are respectively 3300, 3000 and 2700 mg/kg. It refers to the substances of hazard class 3. The clinical picture of acute poisoning was characterized by the general depression, muscle relaxation, disorder of the movement coordination, decrease in body temperature and death in the first and the second days after the poisoning. The differences in sex and species sensitivity of the animals to the substance are not observed: the rates of species differences and sex sensitivity are ~1. Single and repeated (10 days) inhalation of the vapors of the cinnamic alcohol at the greatest possible saturation neither cause the death of mice no signs of toxicity. It has a weak ability to cumulation: the cumulation coefficient is 5.4. It has no local irritating action to the skin. Skin-resorptive and sensitizing effects are not revealed. It has a weak irritating effect on the mucous membranes of the eyes. In the subacute experiment after the introduction of the substance into the stomach in a total dose equal to 5.2 DL we noted the lag of the experimental animals in body weight gain from the control ones, the increase in the activity of y glutamyl transpeptidase and transaminases in serum. In the peripheral blood the decrease in hemoglobin, erythrocytes and eosinophils count is revealed. The threshold of the acute inhalation effect is 140 mg/m (by the reduction in the number of erythrocytes and hemoglobin in peripheral blood). Tentative safe level of the exposure to the cinnamic alcohol in the air of the working zone is 5 mg/m (vapors). PMID- 29430908 TI - [study in the experimental conditions of pesticide action on microorganisms characterizing sanitary-epidemiological safety of reservoirs]. AB - The paper presents experimental data on the pesticides action (molinate (OrdramA), Dinitroortocresolum and chlorophos) at concentrations of 0.01 mg /l to 10 mg/l on sanitary-indicative (TBC, total coliform bacteria, E. coli, E. faecalis), potentially pathogenic ( Ps. aeruginosa) and pathogenic (S. Derby) microflora of the river water. As the test cultures there were used isolated from the reservoir and museum strains of microorganisms. Due to the fact that the rate of decomposition ofpesticides in water increases in direct proportion to the extent of its biological contamination, the experiments were performed with the river water: native and sterilized by autoclaving. There were identified species and strain differences in the microbial response to the action of pesticides. The selectivity of OrdramA action at a concentration of 0.1 to 10 mg/l on Salmonella and of chlorophos at a concentration of 10 mg/l for Salmonella and E. coli is manifested in the stimulation of the reproduction of these bacteria. Dinitroortocresolum in concentrations of 10 mg/l and 1 mg/l gives rise in the reproduction of Pseudomonas aeruginosa and inhibits the growth of total coliform bacteria and E. coli, in a concentration of 0.1 mg/l the preparation stimulates the viability of all the studied microorganisms. When entering the body of water, pesticides were found to cause changes of biocenosis in the river water and disturb bacterial self-cleaning processes. In conditions of pesticide pollution total coliform bacteria, E. coli and E. faecalis unable to maintain their indicative value and therefore the use of only them for the evaluation of the sanitary-epidemiological status of the water source appears to be insufficient. Due to the fact that the epidemic potential of water is directly dependent on quantitative content ofpathogenic and opportunistic pathogenic microorganisms in it, the reproduction Salmonella and Pseudomonas bacteria is a negative moment from the sanitary and epidemiological point of view. PMID- 29430907 TI - [Modification of the pattern of fatty acids of erythrocytes' membranes due to the acetone intoxication]. AB - Results of the study of the impact of acetone intoxication on the fatty acids pattern of the general lipids of erythrocytes' membranes in rats are presented. The inhalation exposure of acetone was carried out in the inoculation chamber with the volume of 100 liters. The chamber was designed for the type of B.A. Kurlyandsky with self-contained system of purification and air regeneration and specified parameters of temperature (20-22S) and air humidity. The flow rate of the air and aerosolized acetone passed through the chamber accounted of 10 liters/min. Concentration of acetone in the chamber was sustained at the level of 206 +/- 3,9 mg/m that corresponds to maximum permissible concentration for acetone vapor in the air of a working area. The time of exposure was 6 hours per day for 3 weeks in a monotonous mode, excluding weekend, and was based upon specific parameters of environment simulation in industry. The acetone impact was shown to be accompanied by the gain in the quantity of all kinds of saturated fatty acids and the fall of unsaturated fatty acids in general lipids of erythrocytes ' membranes in rats and in the structure ofphospholipid fractions. In the content of phosphatydilcholine and phosphatydilethanolamine, as a basic structural phospholipids of biological membranes, there was noted the increase in palmitic and stearic acids. In the range offatty acids of the n-6 family the amount of linoleic and arachidonic acids decreased. In the array of fatty acids of the n-3 family the content of linolenic, eicosapentaenoic and docosahexaenoic acids (n-3 family) declined. Redistribution of fatty acids in the erythrocytes membrane towards to such alteration in quantity as the increasing of saturation and decreasing of the unsaturated fatty acids supposes the change of its physical and chemical properties, permeability, lability and complexity of passing erythrocyte via microcircular channels. PMID- 29430909 TI - [The decision of the Plenum of the Scientific Council of the Russian Federation for Human Ecology and Environmental Health]. PMID- 29430910 TI - [Methodological problems of noninfectious epidemiology and hygiene under chemical pollution of the environment]. AB - In modern conditions the base of the assurance of the safety of human being from harmful factors of environment is the hygienic rationing for the latters. The use of this methodological principle led to the considerable decline in the level of chemical pollution of environment objects. However tens of millions of Russians are exposed to the impact of chemicals above admissible hygienic level. There was noted the high prevalence and mortality rate due to noninfectious diseases of the population. The hygienic science needs to develop and introduce methodology of personification prevention on protection of the person against chemical environmental pollution. PMID- 29430911 TI - [Medical hydrogeology is an independent interdisciplinary branch of the science about groundwater]. AB - The use of groundwater in population water supply systems gains more and more importance because of increasing degradation of the quality of surface water sources. At the same time there are changed concepts on ubiquitous high quality of groundwater. The executed analysis offoreign and domestic literature allowed authors to determine the character and causes of negative changes in the composition of groundwater. In the large body of investigations there were established cause-and-effect relationships between a number of noninfectious (including cardiovascular and cancer) and infectious diseases and anthropogenic pollution and the natural composition of groundwater. In the article there is substantiated the formation of a new interdisciplinary scientific direction - medical hydrogeology. On the basis of current data on the medical and ecological significance of the quality, quantity and regime of the groundwater, geological conditions of the shaping of their composition, there was shown the need of the consideration of the hydrological situation in making water supply management solutions safe for the health of the population. In this regard, there were considered the interrelationship and interdependence of allied disciplines - hygiene, ecological toxicology and epidemiology, hydrogeochemistry, hydrogeology. There was pointed the importance of the acquisition of based on hydrogeology medical specialists of the water supply profile for sharing with hygienists of the effective solution of tasks of the management of groundwater sources. PMID- 29430912 TI - [Scientific potential of phenomics - functional direction of genetics]. AB - In this paper on the based on the integration of known theories, doctrines and concepts - principles of consistency and self-regulation of physiological functions (Pavlov I.P., 1950), the theory offunctional systems (Anokhin P.K., 1973), the theory of adaptive reactions (Selye H., 1960 ; Garkavi LKh et al, 1979), the doctrine of the dominant (Ukhtomsky A.A., 1966), doctrine on health (Baevsky R.M.), doctrine on the body type of the human by Merlin VS. conception on the "the interrelationship between the function and genetic apparatus" by Meyerson F.Z., Pshennikova M.G., Platonov V.N., and others, there is proposed to select phenomics - functional division of genetics considering the poolability of specific mechanisms of the body in an integral system of the adaptive act in favor of the development of a personalized approach to the diagnosis and prevention of non-communicable diseases, increasing life expectancy of working age into the particular scientific direction. The task of phenomics is the establishment of the phenotypic characteristics of the person, norms of the response of systems of his body, determination of the deviation of the level of the functioning of the each system from the norm of its response and the elaboration of the tactics for the correction of the functional state of the organism (the optimization of its life activity), with taking into account the directedness of the interaction of body systems. The description of the shaping of the mechanism of stereotyped response of the organism generated an important contribution to the development of phenomics. Stereotyped response being initiated by the non-specific response of the body is aimed at the shaping of the activity of its systems after a fashion of norms of the activity, promotes the recovery of the specificity of the body, plays an important role in the establishment of cause-effect relations of the disease. PMID- 29430913 TI - [Methodical complex for the assessment of mass noninfectious prevalence rate and the medico-ecological situation in the territory]. AB - The purpose of this article - the narration of main provisions of the algorithm of the system use of techniques and methods for the determination of the epidemiological risk for the morbidity of the population for the identification and assessment of mass noninfectious diseases, local variants ofpopulation health and the degree of stringency of medical and environmental conditions (or ecological trouble), in areas of industrial and non-administrative units of the area (region). Control-flow chartfor the evaluation of mass non-communicable diseases and medical-ecological situation in the territory on the basis of techniques and methods of risk assessment for decision-making control includes the following steps: 1) determination of the conditional regional level of the background prevalence rate as the unit of regional type of population health, shaped by regional climatic and geographic and other features of the environmental conditions; 2) detection of the epidemiological relative risk of the morbidity rate and mass non-infectious diseases; 3) determination of the wave like character of the dynamics of the riskfor mass non-infectious morbidity rate of the population and the adaptation process shaping it in the territories; 4) separating the leading mass non-communicable diseases, especially shaping peculiarities of local variants of population health in the special industrial and non-industrial areas; 5) determination of the degree of stringency of medical and environmental situation (or ecological trouble) in the studied area, with local variants ofpopulation health; 6) a forecast of the expected trends in the dynamics of the risk for mass non-infectious prevalence rate; 7) justification of the main directions of the development of medical and environmental preventive measures on the reduction of mass non-infectious diseases and the improvement of the quality of health of the population in the studied areas. The given methodical complex will allow to more effectively solve problems ofprevention of mass non-infectious prevalence of the population and improve health and environmental conditions in the study area based on public health monitoring data. PMID- 29430914 TI - [Heavy metals and hydrocarbons content in soils of settlements of the Yamal Nenets autonomous region]. AB - In August 2015 there were executed investigations on the study of the soils diversity of the Yamal-Nenets Autonomous Okrug. One of the directions of this work got be the study of urban soils of settlements of the Yamal-Nenents Autonomous Okrug. The sectors for the observation were settlement of Harsaim, village Aksarka, city of Salekhard, settlement Harp and city of Labytnangi. About 20 soil samples were collected during the field work. Samples were collected from a depth of 0-5 cm and 5-20 cm. Heavy metals (HM) were detected with the use of X ray fluorescent analyzer "Spectroscan-MAX". The HM content values were compared with the corresponding Approxible Permissible Concentrations and Maximum Allowable Concentrations (MAC) adopted in Russia. Hydrocarbons content was determined by gravimetric method. Values of the hydrocarbons content in studied soils were compared with the existing regulations of the Russian Federation. The levels of soil contamination by hydrocarbons were determined. The study of soil samples from different settlements allowed to reveal characteristic features of soil contamination of separate settlements by HM and hydrocarbons and to compare them against each other. The vast majority of samples are characterized by arsenic exceedance of MAC, which should indicate to a high regional background of this element. For a more adequate assessment of the Zc meaning as the value of the total pollution index of soils there were used not only arithmetical average values of the coefficients of the chemical composition concentration (Kc), but also their average geometric values. According to levels of total soil contamination most of soil samples are characterized as non-hazardous (Zc<16). Calculation of soil pollution index showed that the most of soil samples have values less than 1. It characterizes soils as unpolluted. Statistical processing of obtained data in the media of the analytical software interface STATISTICA 10 showed a statistically significant difference in the content ofHM and hydrocarbons for the layer of 0-20 cm of the soils for three elements (Cu, Zn, Ni). PMID- 29430915 TI - Zinc Porphyrin/Imidazolium Integrated Multivariate Zirconium Metal-Organic Frameworks for Transformation of CO2 into Cyclic Carbonates. AB - The design and synthesis of metal-organic frameworks (MOFs) enclosed with multiple catalytic active sites is favorable for cooperative catalysis, but is is still challenging. Herein, we developed a sequential postsynthetic ionization and metalation strategy to prepare bifunctional multivariate Zr-MOFs incorporating zinc porphyrin and imidazolium functionalities. Using this facile strategy, tetratopic [5,10,15,20-tetrakis(4-carboxyphenyl)porphyrinato]zinc(II) (ZnTCPP) ligands were successfully installed into the cationic Zr-MOF to obtain ZnTCPP?(Br )Etim-UiO-66. These MTV-MOFs, including TCPP?Im-UiO-66, TCPP?(Br-)Etim-UiO-66, and ZnTCPP?(Br-)Etim-UiO-66, were well characterized and used in CO2 capture and conversion into cyclic carbonate from allyl glycidyl ether and CO2 under cocatalyst-free and 1 bar CO2 pressure conditions. It was found that the structural features and CO2 affinity properties of these MTV-MOFs can be tuned by introducing imidazolium groups or doping zinc sites. Additionally, ZnTCPP?(Br )Etim-UiO-66 exhibited enhanced catalytic activities compared to other MTV-MOFs herein for obtaining the 3-allyloxy-1,2-proplyene carbonate product, which was attributed to the cooperative effect of Zn2+ sites and Br- ions in this microporous ionic MTV-MOF. ZnTCPP?(Br-)Etim-UiO-66 can be recycled easily and used at least three times. PMID- 29430916 TI - Diffusion- and pH-Dependent Reactivity of Layer-Type MnO2: Reactions at Particle Edges versus Vacancy Sites. AB - Layer-type manganese oxides are among the strongest solid-phase oxidants in surface environments and readily oxidize a range of chemical species. However, knowledge of the role played by different surface sites in contaminant oxidation is scarce. In this study, we investigate the reactivity of particle edges versus vacancy sites in delta-MnO2 by combining Co sorption kinetic experiments with quick X-ray absorption spectroscopy. During the fast kinetic phase ( t < 10 min), Co sorption and oxidation occurred dominantly at edge sites at pH 8; at pH 6 and pH 4, reactions also occurred at vacancy sites but were limited in extent. At longer reaction times ( t > 10 min), continuous accumulation of Co at vacancy sites was observed, while the amount of Co at particle edges decreased or remained constant depending on the absence or presence of aqueous Co(II), respectively. These data are consistent with the diffusion-limited transport of metal cations to vacancy sites. In addition, at pH 8, the kinetics and extent of reaction at particle edges are greater than at pH 4-6. These results suggest that, although particle edges will be the first to react, layer vacancies will serve as the long-term sorption and oxidation sites for contaminant metals in MnO2-rich systems. PMID- 29430917 TI - Untargeted Metabolomics Reveal Lipid Alterations upon 2-Deoxyglucose Treatment in Human HaCaT Keratinocytes. AB - The glucose analogue 2-deoxyglucose (2-DG) impedes cancer progression in animal models and is currently being assessed as an anticancer therapy, yet the mode of action of this drug of high clinical significance has not been fully delineated. In an attempt to better characterize its pharmacodynamics, an integrative UPLC-Q Exactive-based joint metabolomic and lipidomic approach was undertaken to evaluate the metabolic perturbations induced by this drug in human HaCaT keratinocyte cells. R-XCMS data processing and subsequent multivariate pattern recognition, metabolites identification, and pathway analyses identified eight metabolites that were most significantly changed upon a 3 h 2-DG exposure. Most of these dysregulated features were emphasized in the course of lipidomic profiling and could be identified as ceramide and glucosylceramide derivatives, consistently with their involvement in cell death programming. Even though metabolomic analyses did not generally afford such clear-cut dysregulations, some alterations in phosphatidylcholine and phosphatidylethanolamine derivatives could be highlighted as well. Overall, these results support the adequacy of the proposed analytical workflow and might contribute to a better understanding of the mechanisms underlying the promising effects of 2-DG. PMID- 29430918 TI - Decoding the Nonvolatile Sensometabolome of Orange Juice ( Citrus sinensis). AB - Activity-guided fractionation in combination with the taste dilution analysis, followed by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance experiments, led to the identification of 10 polymethoxylated flavones (PMFs), 6 limonoid glucosides, and 2 limonoid aglycones as the key bitterns of orange juice. Quantitative studies and calculation of dose-over-threshold factors, followed by taste re-engineering, demonstrated for the first time 25 sensometabolites to be sufficient to reconstruct the typical taste profile of orange juices and indicated that not a single compound can be considered a suitable marker for juice bitterness. Intriguingly, the taste percept of orange juice seems to be created by a rather complex interplay of limonin, limonoid glucosides, PMFs, organic acids, and sugars. For the first time, sub-threshold concentrations of PMFs were shown to enhance the perceived bitterness of limonoids. Moreover, the influence of sugars on the perceived bitterness of limonoids and PMFs in orange juice relevant concentration ranges was quantitatively elucidated. PMID- 29430920 TI - Long-Term Experimental Acidification Drives Watershed Scale Shift in Dissolved Organic Matter Composition and Flux. AB - Over the last several decades dissolved organic carbon concentrations (DOC) in surface waters have increased throughout much of the northern hemisphere. Several hypotheses have been proposed regarding the drivers of this phenomenon including decreased sulfur (S) deposition working via an acidity- change mechanism. Using fluorescence spectroscopy and data from two long-term (24+ years at completion of this study) whole watershed acidification experiments, that is, the Bear Brook Watershed in Maine (BBWM) and Fernow Experimental Forest in West Virginia (FEF) allowed us to control for factors other than the acidity-change mechanism (e.g., differing vegetation, shifting climate), resulting in the first study we are aware of where the acidity change mechanism could be experimentally isolated at the whole ecosystem and decadal scales as the driver of shifts in DOM dynamics. The multidecadal record of stream chemistry at BBWM demonstrates a significantly lower DOC concentration in the treated compared to the reference watershed. Additionally, at both BBWM and FEF we found significant and sustained differences in stream fluorescence index (FI) between the treated and reference watersheds, with the reference watersheds demonstrating a stronger terrestrial DOM signature. These data, coupled with evidence of pH shifts in upper soil horizons support the hypotheses that declines in S deposition are driving changes in the solubility of soil organic matter and increased flux of terrestrial DOC to water bodies. PMID- 29430919 TI - Photoresponsive Hydrogels with Photoswitchable Mechanical Properties Allow Time Resolved Analysis of Cellular Responses to Matrix Stiffening. AB - As cell function and phenotype can be directed by the mechanical characteristics of the surrounding matrix, hydrogels have become important platforms for cell culture systems, with properties that can be tuned by external stimuli, such as divalent cations, enzymatic treatment, and pH. However, many of these stimuli can directly affect cell behavior, making it difficult to distinguish purely mechanical signaling events. This study reports on the development of a hydrogel that incorporates photoswitchable cross-linkers, which can reversibly alter their stiffness upon irradiation with the appropriate wavelength of light. Furthermore, this study reports the response of bone-marrow-derived mesenchymal stem cells (MSCs) on these hydrogels that were stiffened systematically by irradiation with blue light. The substrates were shown to be noncytotoxic, and crucially MSCs were not affected by blue-light exposure. Time-resolved analysis of cell morphology showed characteristic cell spreading and increased aspect ratios in response to greater substrate stiffness. This hydrogel provides a platform to study mechanosignaling in cells responding to dynamic changes in stiffness, offering a new way to study mechanotransduction signaling pathways and biological processes, with implicit changes to tissue mechanics, such as development, ageing, and fibrosis. PMID- 29430921 TI - MALDI-MS Imaging Reveals Asymmetric Spatial Distribution of Lipid Metabolites from Bisphenol S-Induced Nephrotoxicity. AB - With the continuous exposure of environmental pollutants in organisms, determination of abundance variation and spatial distribution of lipids might expand our understanding of toxicological mechanisms occurring in the kidney. Herein, an integrated method involving mass spectrometry (MS)-based lipidomics and matrix-assisted laser desorption/ionization-MS imaging (MALDI-MSI) was developed for the study of nephrotoxicity in mice exposed to 10 and 100 MUg bisphenol S (BPS)/kg body weight/day. The BPS exposure remarkable perturbed abundances of 91 potential markers that mainly involved in five metabolic pathways. We elucidated the lipids spatial heterogeneity by using morphological analysis, probabilistic latent semantic analysis, and coregistered multimodal three-dimensional (3D)-MSI. In morphological analysis, both 10 and 100 MUg BPS induced significant nephrotoxicity to mice, including glomerular necrosis in renal cortex, cloudy swelling in renal medulla, and interstitial collapsing in renal pelvis. Significant differential signaling lipids such as sphingomyelin (SM) (d22:0/20:4), ceramide (Cer) (d18:2/24:1), and sphingosine (d18:0) related to inflammation were found to be up-regulated and colocalized in the renal cortex, medulla, and pelvis, respectively. Also, seven significant differential lipids, which are considered to be involved in membrane homeostasis and cellular function, were found to be colocalized in the renal cortex. The observed significant variations of morphology, lipid accumulation, and metabolism in the renal cortex implicated that lipids in the renal cortex were more sensitive to BPS exposure than those in the renal medulla and pelvis. Moreover, we reconstructed a 3D-MSI model of kidney and identified two heterogeneous-related substructures in the renal cortex and pelvis upon 100 MUg BPS exposure. It might be used in novel specificity evaluation and early diagnosis for environmental pollutant-induced kidney diseases. PMID- 29430922 TI - Nanohydrogel Formation within the Halloysite Lumen for Triggered and Sustained Release. AB - An easy strategy to obtain nanohydrogels within the halloysite nanotube (HNTs) lumen was investigated. Inorganic reverse micelles based on HNTs and hexadecyltrimethylammonium bromides were dispersed in chloroform, and the hydrophilic cavity was used as a nanoreactor to confine the gel formation based on alginate cross-linked by calcium ions. Spectroscopy and electron microscopy experiments proved the confinement of the polymer into the HNT lumen and the formation of calcium-mediated networks. Biological tests proved the biocompatibility of the hybrid hydrogel. The nanogel in HNTs was suitable for drug loading and sustained release with the opportunity of triggered burst release by chemical stimuli. Here, we propose a new strategy based on inorganic reverse micelles for nanohydrogel formation, which are suitable for industrial and biological applications as well as for selective and triggered adsorption and/or release. PMID- 29430923 TI - Interactive Visual Exploration of 3D Mass Spectrometry Imaging Data Using Hierarchical Stochastic Neighbor Embedding Reveals Spatiomolecular Structures at Full Data Resolution. AB - Technological advances in mass spectrometry imaging (MSI) have contributed to growing interest in 3D MSI. However, the large size of 3D MSI data sets has made their efficient analysis and visualization and the identification of informative molecular patterns computationally challenging. Hierarchical stochastic neighbor embedding (HSNE), a nonlinear dimensionality reduction technique that aims at finding hierarchical and multiscale representations of large data sets, is a recent development that enables the analysis of millions of data points, with manageable time and memory complexities. We demonstrate that HSNE can be used to analyze large 3D MSI data sets at full mass spectral and spatial resolution. To benchmark the technique as well as demonstrate its broad applicability, we have analyzed a number of publicly available 3D MSI data sets, recorded from various biological systems and spanning different mass-spectrometry ionization techniques. We demonstrate that HSNE is able to rapidly identify regions of interest within these large high-dimensionality data sets as well as aid the identification of molecular ions that characterize these regions of interest; furthermore, through clearly separating measurement artifacts, the HSNE analysis exhibits a degree of robustness to measurement batch effects, spatially correlated noise, and mass spectral misalignment. PMID- 29430925 TI - Full-Range pH Stable Au-Clusters in Nanogel for Confinement-Enhanced Emission and Improved Sulfide Sensing in Living Cells. AB - The sensitive and selective detection of hydrogen sulfide is of great importance due to its crucial role in pathological and physiological processes. Herein, we report a novel fluorescent platform, AuNCs@GC, for selective detection of hydrogen sulfide in living cells by impregnating the Au nanoclusters (AuNCs) into a biocompatible cationic polymer matrix, glycol-chitosan (GC) nanogel. The confinement effect significantly increased the emissive Au(I) units, resulting in a 6-fold enhancement of quantum yield (from 6.38% to 36.42%). In addition, the prepared positively charged AuNCs@GC nanogel exhibits excellent selectivity and improved sensitivity to aqueous sulfides. Moreover, the as-fabricated AuNCs@GC showed very good biocompatibility and super fluorescence stability across the full pH range and good salt tolerance, which demonstrated excellent adaptability toward intracellular sulfide imaging. PMID- 29430926 TI - Development of a Thiolysis HPLC Method for the Analysis of Procyanidins in Cranberry Products. AB - The objective of this study was to develop a thiolysis HPLC method to quantify total procyanidins, the ratio of A-type linkages, and A-type procyanidin equivalents in cranberry products. Cysteamine was utilized as a low-odor substitute of toluene-alpha-thiol for thiolysis depolymerization. A reaction temperature of 70 degrees C and reaction time of 20 min, in 0.3 M of HCl, were determined to be optimum depolymerization conditions. Thiolytic products of cranberry procyanidins were separated by RP-HPLC and identified using high resolution mass spectrometry. Standards curves of good linearity were obtained on thiolyzed procyanidin dimer A2 and B2 external standards. The detection and quantification limits, recovery, and precision of this method were validated. The new method was applied to quantitate total procyanidins, average degree of polymerization, ratio of A-type linkages, and A-type procyanidin equivalents in cranberry products. Results showed that the method was suitable for quantitative and qualitative analysis of procyanidins in cranberry products. PMID- 29430924 TI - Optical Voltage Sensing Using DNA Origami. AB - We explore the potential of DNA nanotechnology for developing novel optical voltage sensing nanodevices that convert a local change of electric potential into optical signals. As a proof-of-concept of the sensing mechanism, we assembled voltage responsive DNA origami structures labeled with a single pair of FRET dyes. The DNA structures were reversibly immobilized on a nanocapillary tip and underwent controlled structural changes upon application of an electric field. The applied field was monitored through a change in FRET efficiency. By exchanging the position of a single dye, we could tune the voltage sensitivity of our DNA origami structure, demonstrating the flexibility and versatility of our approach. The experimental studies were complemented by coarse-grained simulations that characterized voltage-dependent elastic deformation of the DNA nanostructures and the associated change in the distance between the FRET pair. Our work opens a novel pathway for determining the mechanical properties of DNA origami structures and highlights potential applications of dynamic DNA nanostructures as voltage sensors. PMID- 29430927 TI - Characterization of Sesquiterpene Dimers from Resina Commiphora That Promote Adipose-Derived Stem Cell Proliferation and Differentiation. AB - The new sesquiterpene dimers commiphoroids A-D (1-4) were isolated from Resina Commiphora, and their structures were assigned by spectroscopic methods and X-ray diffraction analysis. Compounds 1 and 2 are stereoisomers of putative [2 + 4] cycloaddition reactions, and 3 is a trinorsesquiterpene dimer containing a 6/6/5/6/6/6 hexacyclic framework, while 4 possesses a 8-oxabicyclo[3.2.1]oct-6 ene skeletal core. Plausible biosynthetic pathways for 1-4 are proposed. Biochemical studies show that compound 1 promotes ca. 60% expression of keratinocyte-specific markers in adipose-derived stem cells at 10 MUM. PMID- 29430928 TI - Luminescent Device for the Detection of Oxidative Stress Biomarkers in Artificial Urine. AB - A luminescent paper-based device for the visual detection of oxidative stress biomarkers is reported. The device consists of a polyvinylidene fluoride membrane impregnated with poly(3-alkoxy-4-methylthiophene) (PT) for colorimetric detection. 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker associated with oxidative stress, is used as a model system for validating the proposed methodology. The detection strategy is based on monitoring the changes in optical properties of PT associated with its conformational changes upon interaction with an aptamer in the presence and in the absence of 8-OHdG. Fluorometric and colorimetric monitoring revealed linear responses for 8-OHdG concentrations between 50 pM and 500 nM (~14 pg/mL to 140 ng/mL), with limits of detection of ~300 pM and ~350 pM, respectively for ( n = 3). Colorimetric responses in artificial urine ascertained rapid, sensitive, and selective detection of 8-OHdG at clinically relevant (pM to nM) concentration levels. Furthermore, the proposed methodology enables point-of-care diagnostics for oxidative stress without requiring sophisticated instrumentation. PMID- 29430929 TI - Hydrochloric Acid-Promoted Intermolecular 1,2-Thiofunctionalization of Aromatic Alkenes. AB - An efficient method for making 1,2-thiofunctionalized products via the difunctionalization of aromatic alkenes was developed. In this method, cheap and readily available hydrochloric acid was used to promote 1,2-thiofunctionalization of aryl alkenes with N-arylsulfenylphthalimide and different types of nucleophiles. Importantly, extension of nucleophiles can reach aryl ethers, indoles, and carboxylic acids with good reactivity. This practical and convenient method has broad substrate scope and high yields under metal-free and mild conditions. Furthermore, we achieved conversion and application for making sulfoxide and sulfone by oxidation. PMID- 29430930 TI - Construction of a DNA Origami Based Molecular Electro-optical Modulator. AB - An electro-optical modulator was constructed using a DNA nanostructure scaffold with oligomers of poly(phenylenevinylene) and polyaniline. A molecular device containing one each of the functional molecules was assembled in a DNA origami. The constructs formed an "X" shape and were visualized by atomic force microscopy. In response to redox reconfiguration, the device reversibly altered fluorescence signal output. This molecular self-assembly strategy provides opportunities to make unique material composites that are difficult to achieve by blending. The strategy offers a "plug and play" format that may lead to many new functions. PMID- 29430931 TI - NHC-Catalyzed Hetero-Diels-Alder Reaction of Allenoate with Chalcone: Synthesis of Polysubstituted Pyranyl Carboxylate. AB - An NHC-catalyzed hetero-Diels-Alder and isomerization process of chalcones with allenoates was discovered, which furnished highly functionalized multisubstituted pyranyl carboxylates successfully. This method features a convergent assembly, mild reaction conditions, moderate to good yields, and high atom economy. PMID- 29430932 TI - Experimental and Theoretical Insights into the Structure of Tellurium Chloride Glasses. AB - The structure of the binary chalcohalide glasses Te1- xCl x (0.35 <= x <= 0.65) is considered by combining experimental and theoretical results. The structural network properties are influenced by a competition between ionic and covalent bonding in such glasses. At first, a focus is placed on the detailed information available by using the complementary high-energy X-ray and the neutron diffractions in both the reciprocal and real spaces. The main characteristic suggested by the structure factors S( Q) concerns the presence of three length scales in the intermediate range order. The total correlation function T( r) lets us also suppose that the structure of these glasses is more complicated than Te chain fragments with terminal Cl as demonstrated in crystalline Te3Cl2. Molecular dynamics simulations were subsequently performed on Te3Cl2 and Te2Cl3, and coupled with the experimental data, a highly reticulated network of chalcogen atoms, with a fair amount of chlorine atoms bonded in a bridging mode, is proposed. The simulations clearly lead to a glass description that differs markedly from the simple structural model based on only Te atom chains and terminal Cl atoms. Solid-state NMR experiments and NMR parameters calculations allowed validation of the presence of Te highly coordinated with chlorine in these glasses. PMID- 29430933 TI - A letter in response to 'Liquid chromatography tandem mass spectrometry: challenges in introducing published methods into the clinical laboratory' by Khedr et al. PMID- 29430934 TI - Liquid chromatography tandem mass spectrometry: challenges in introducing published methods into the clinical laboratory. PMID- 29430935 TI - The effect of glioblastoma heterogeneity on survival stratification: a multimodal MR imaging texture analysis. AB - Background Quantitative evaluation of the effect of glioblastoma (GBM) heterogeneity on survival stratification would be critical for the diagnosis, treatment decision, and follow-up management. Purpose To evaluate the effect of GBM heterogeneity on survival stratification, using texture analysis on multimodal magnetic resonance (MR) imaging. Material and Methods A total of 119 GBM patients (65 in long-term and 54 in short-term survival group, separated by overall survival of 12 months) were selected from the Cancer Genome Atlas, who underwent the T1-weighted (T1W) contrast-enhanced (CE), T1W, T2-weighted (T2W), and FLAIR sequences. For each sequence, the co-occurrence matrix, run-length matrix, and histogram features were extracted to reflect GBM heterogeneity on different scale. The recursive feature elimination based support vector machine was adopted to find an optimal subset. Then the stratification performance of four MR sequences was evaluated, both alone and in combination. Results When each sequence used alone, the T1W-CE sequence performed best, with an area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity of 0.7915, 80.67%, 78.45%, and 83.33%, respectively. When the four sequences combined, the stratification performance was basically equal to that of T1W-CE sequence. In the optimal subset of features extracted from multimodality, those from the T2W sequence weighted the most. Conclusion All the four sequences could reflect heterogeneous distribution of GBM and thereby affect the survival stratification, especially T1W-CE and T2W sequences. However, the stratification performance using only the T1W-CE sequence can be preserved with omission of other three sequences, when investigating the effect of GBM heterogeneity on survival stratification. PMID- 29430936 TI - Tailored CT angiography in follow-up after endovascular aneurysm repair (EVAR): combined dose reduction techniques. AB - Background Endovascular aneurysm repair (EVAR) requires lifelong surveillance by computed tomography angiography (CTA). This is attended by a substantial accumulation of radiation exposure. Iterative reconstruction (IR) has been introduced to approach dose reduction. Purpose To evaluate adaptive statistical iterative reconstruction (ASIR) at different levels of tube voltage concerning image quality and dose reduction potential in follow-up post EVAR. Material and Methods One hundred CTAs in 67 patients with EVAR were examined using five protocols: protocol A (n = 40) as biphasic standard using filtered back projection (FBP) at 120 kV; protocols B (n = 40), C (n = 10), and D1 (n = 5) biphasic using ASIR at 120, 100, and 80 kV, respectively; and protocol D2 (n = 5) with a monophasic splitbolus ASIR protocol at 80 kV. Image quality was assessed quantitatively and qualitatively. Applied doses were determined. Results Applied doses in ASIR protocols were significantly lower than FBP standard (up to 75%). Compared to protocol A, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) (e.g. arterial CNR intra-/extra-stent lumen: A = 35.4 +/- 13.5, B = 34.2 +/ 10.0, C = 29.6 +/- 6.8, D1 = 32.1 +/- 6.3, D2 = 40.8 +/- 23.1) in protocol B were equal and in protocols C and D equal to partially inferior, however not decisive for diagnostic quality. Subjective image quality ratings in all protocols were good to excellent without impairments of diagnostic confidence (A D2: 5), with high inter-rater agreement (60-100%). Conclusion ASIR contributes to significant dose reduction without decisive impairments of image quality and diagnostic confidence. We recommend an adapted follow-up introducing ASIR and combined low-kV in the long-term surveillance after EVAR. PMID- 29430937 TI - Removal of evidential motion-contaminated and poorly fitted image data improves IVIM diffusion MRI parameter scan-rescan reproducibility. AB - Background It has been reported that intravoxel incoherent motion (IVIM) diffusion magnetic resonance imaging (MRI) scan-rescan reproducibility is unsatisfactory. Purpose To study IVIM MRI parameter reproducibility for liver parenchyma after the removal of motion-contaminated and/or poorly fitted image data. Material and Methods Eighteen healthy volunteers had liver scans twice in the same session to assess scan-rescan repeatability, and again in another session after an average interval of 13 days to assess reproducibility. Diffusion weighted images were acquired with a 3-T scanner using respiratory-triggered echo planar sequence and 16 b-values (0-800 s/mm2). Measurement was performed on the right liver with segment-unconstrained least square fitting. Image series with evidential anatomical mismatch, apparent artifacts, and poorly fitted signal intensity vs. b-value curve were excluded. A minimum of three slices was deemed necessary for IVIM parameter estimation. Results With a total 54 examinations, six did not satisfy inclusion criteria, leading to a success rate of 89%, and 14 volunteers were finally included for the repeatability/reproducibility study. A total of 3-10 slices per examination (mean = 5.3 slices, median = 5 slices) were utilized for analysis. Using threshold b-value = 80 s/mm2, the coefficient of variation and within-subject coefficient of variation for repeatability were 2.86% and 3.36% for Dslow, 3.81% and 4.24% for perfusion fraction (PF), 18.16% and 24.88% for Dfast; and those for reproducibility were 2.48% and 3.24% for Dslow, 4.91% and 5.38% for PF, and 21.18% and 30.89% for Dfast. Conclusion Removal of motion-contaminated and/or poorly fitted image data improves IVIM parameter reproducibility. PMID- 29430938 TI - Visibility of the graft hepatic artery using superb microvascular imaging in liver transplantation recipients: initial experience. AB - Background Hepatic artery (HA) obstruction is one of the most threatening complications following liver transplantation (LT); however, conventional color Doppler imaging (CDI) suffers from technical limitations regarding the visualization of fine vessels and low-velocity blood flow. Purpose To test the visibility of HA in postoperative evaluation of LT using a superb microvascular imaging (SMI). Material and Methods This retrospective study was approved by our institutional review board. Fifty-five consecutive patients (58 grafts; mean age = 56 years) who underwent LT with Doppler ultrasonography (US) on postoperative day 1 were included. We compared the subjective visibility of HA and objective measurements of HA caliber, visible HA length on CDI, monochrome SMI (mSMI), contrast-enhanced mSMI (CE-mSMI), and contrast harmonic imaging (CHI). Reproducibility of HA caliber measurements on SMI techniques were also evaluated by using intraclass correlation coefficients (ICCs). Results The subjective image quality for visibility of HA tended to be graded higher with mSMI than CDI, and with CE-mSMI than mSMI ( P < 0.001). The overall reproducibility of HA caliber measurements was good to excellent for both mSMI and CE-mSMI (ICC = 0.674-0.855). HA caliber measurements on mSMI and CE-mSMI strongly correlated with CHI ( R = 0.785, 0.798, P < 0.001), while mean HA length on mSMI was significantly longer than on CDI (1.88 +/- 0.83 vs. 1.42 +/- 1.01cm, P = 0.004), and even longer on CE mSMI (vs. 3.28 +/- 1.11 cm, P < 0.001). Conclusion The mSMI technique shows good reproducibility and correlates well with currently used methods for postoperative evaluation of HA in LT recipients. It is further improved by administration of an US contrast agent. PMID- 29430939 TI - Assessing referral and practice patterns of patients with chronic cough referred for behavioral cough suppression therapy. AB - The purpose of this exploratory research was to describe current referral and practice patterns for behavioral cough suppression therapy (BCST) throughout the United States, and to assess the need for improving the efficiency of BCST referral patterns. In study I, 126 speech-language pathologists, who treat patients with refractory chronic cough (RCC) in the United States, completed a survey about referral patterns, cough duration, and patient frustration level. In study II, 36 adults with RCC referred for BCST completed a four-part survey about cough symptoms and treatment. The survey included the Leicester Cough Questionnaire (LCQ) before and after BCST. Study I revealed significant patient frustration about the treatment process and the wait-time for BCST. Participants in study II reported average cough duration of over 2 years before BCST. Twenty seven of 31 participants in study II improved by at least 1.3 on the LCQ, indicating a clinically significant improvement in 87% of patients. This study suggests that the current management model for CC may be unduly time-consuming, and expensive for patients with CC who are successfully treated with BCST. Practitioners are encouraged to consider BCST earlier in the treatment process. PMID- 29430940 TI - Positive Effects of a Short-Term Intense Elastic Resistance Training Program on Body Composition and Physical Functioning in Overweight Older Women. AB - : The aim of this study was to investigate the effects of a resistance training program (RTP) in older overweight women (OOW) using two different types of elastic devices. METHODS: This study was a randomized controlled trial with pre- and postintervention measures. Participants included OOW, aged 60-85 years, with no medical history of disease that would preclude them from engaging in physical exercise. Participants were randomly divided into the following groups: elastic tubes with handles group (ETG; n = 22), traditional elastic bands group ( n = 21), and control group (CG; n = 20). Exercise groups (EGs) performed the following supervised RTP: 8 weeks, twice weekly, six overall body exercises, and 3-4 sets of 10 repetitions at a rate of perceived exertion (RPE) of 7-9 on the OMNI-Resistance Exercise Scale of perceived exertion. The controls did not change their usual lifestyle. Outcome measures included body composition (BC; total and regional percentage of fat mass [FM] and fat-free mass [FFM]) and physical performance (PP; dynamic and isometric strength, flexibility, agility/dynamic balance, and endurance). RESULTS: Both EGs exhibited significantly reduced FM in the upper limbs (ULs) and trunk and increased FFM in the UL, while the ETG exhibited a significantly increased trunk FFM. Both EGs improved in PP, and there were no intergroup differences. Trunk FM and FFM and meters walked differed significantly between the ETG and CG. The CG did not exhibit any significant changes. CONCLUSION: Training with elastic devices at a moderate-high RPE produces short-term improvements in BC and PP in OOW. PMID- 29430942 TI - Quorum sensing inhibitors from marine bacteria Oceanobacillus sp. XC22919. AB - In this study, three active compounds isolated from Oceanobacillus sp. XC22919 were identified as 2-methyl-N-(2'-phenylethyl) butyramide (1), 3-methyl-N-(2' phenylethyl)-butyramide (2) and benzyl benzoate (3), and were first reported to exhibit the apparent quorum sensing inhibitory activities against C. violaceum 026 and P. aeruginosa. Compounds 1-3 inhibited violacein production of C. violaceum 026 by 10.5-55.7, 11.2-55.7, and 27.2%-95.7%, respectively, and inhibited pyocyanin production of P. aeruginosa by 1.7-50.8, 39.1-90.7, and 57.2% 98.7%, respectively. The azocasein-degrading proteolytic rates of P. aeruginosa were observed by 13.4-31.5, 13.4-28.8, and 11.3%-21.1%, respectively. With respect to elastase, the range of inhibition of activity of compounds 1-3 was 2.1 30.3, 4.2-18.2, and 8.9%-15.7%, respectively. Compounds 1 and 3 also showed a concentration-dependent attenuation in biofilm formation, with the maximum of 50.6% inhibition, and 37.7% inhibition at 100 MUg/mL, respectively. PMID- 29430943 TI - Two new compounds from the fruit of Ailanthus altissima. AB - A new phenolic derivative, 4-hydroxyphenol-1-O-[6-O-(E)-feruloyl-beta-d glucopyranosyl]-(1->6)-beta-d-glucopyranoside (1), and a new terpenylated coumarin, named altissimacoumarin H (2) were identified from the fruit of Ailanthus altissima (Mill.) Swingle (Simaroubaceae), together with ten known compounds (3-12), including two coumarins and eight phenylpropanoids. Their structures were determined on the basis of chemical method and spectroscopic data. Antiviral effect against Tobacco mosaic virus (TMV) of all the compounds obtained were evaluated using leaf-disc method. PMID- 29430941 TI - The Not-So-Global Blood Oxygen Level-Dependent Signal. AB - Global signal regression is a controversial processing step for resting-state functional magnetic resonance imaging, partly because the source of the global blood oxygen level-dependent (BOLD) signal remains unclear. On the one hand, nuisance factors such as motion can readily introduce coherent BOLD changes across the whole brain. On the other hand, the global signal has been linked to neural activity and vigilance levels, suggesting that it contains important neurophysiological information and should not be discarded. Any widespread pattern of coordinated activity is likely to contribute appreciably to the global signal. Such patterns may include large-scale quasiperiodic spatiotemporal patterns, known also to be tied to performance on vigilance tasks. This uncertainty surrounding the separability of the global BOLD signal from concurrent neurological processes motivated an examination of the global BOLD signal's spatial distribution. The results clarify that although the global signal collects information from all tissue classes, a diverse subset of the BOLD signal's independent components contribute the most to the global signal. Further, the timing of each network's contribution to the global signal is not consistent across volunteers, confirming the independence of a constituent process that comprises the global signal. PMID- 29430944 TI - Social partner gaze direction and conversational phase; factors affecting social attention during face-to-face conversations in autistic adults? AB - Social attention is atypical in autism. However, the majority of evidence for this claim comes from studies where the social partner is not physically present and the participants are children. Consequently, to ensure acquisition of a comprehensive overview of social attention in autism, systematic analysis of factors known to influence face-to-face social attention in neurotypicals is necessary and evidence from adulthood is required. This study assessed the influence of experimenter gaze direction (direct or averted) and conversational phase (speaking or listening) on social attention during a face-to-face conversation. Eye-tracking analyses indicated that when the experimenter looked directly at the participant, autistic adults looked at the experimenter's face less than did neurotypical adults. However, this between-group difference was significantly reduced when the experimenter's gaze was averted. Therefore, opportunities for reciprocal social gaze are missed by autistic adults when the social partner makes direct eye contact. A greater proportion of time was spent fixating the experimenter's eye region when participants were speaking compared to listening in both neurotypical and autistic adults. Overall, this study provides a rich picture of the nature of social attention in face-to-face conversations adopted by autistic adults and demonstrates individual variation in social attention styles. PMID- 29430945 TI - Diterpenoid alkaloids from Aconitum brevicalcaratum as autophagy inducers. AB - A new C19 diterpenoid alkaloid, brevicanine (1) and six known ones (2-7) were isolated from Aconitum brevicalcaratum (Finet et Gagnep.) Diels. Their structures were elucidated on the basis of extensive spectroscopic analyses. The cytotoxicity of those compounds was investigated against HCT116 human cancer cell line, which showed none of them possessing considerable anti-proliferative activities. To evaluate the autophagy effect of compounds 1-7, Western blot was used to detect the expression of autophagic marker by stimulating human cancer HCT116 cells. The results showed that compound 6 induced protective autophagy in HCT116 cells. Mechanistic insight showed that compound 6 induced protective autophagy through p53 activation, ERK1/2 and p38 MAPK signaling cascade. PMID- 29430947 TI - Successful Implementation of a Simple Algorithm to Manage Penicillin Allergy in an Acute Care Community Hospital. PMID- 29430946 TI - Mesenteric arteries from stroke-prone spontaneously hypertensive rats exhibit an increase in nitric-oxide-dependent vasorelaxation. AB - The endothelium is crucial for the maintenance of vascular tone by releasing several vasoactive substances, including nitric oxide (NO). Systemic mean arterial pressure is primarily regulated by the resistance vasculature, which has been shown to exhibit increased vascular reactivity, and decreased vasorelaxation during hypertension. Here, we aimed to determine the mechanism for mesenteric artery vasorelaxation of the stroke-prone spontaneously hypertensive rat (SHRSP). We hypothesized that endothelial NO synthase (eNOS) is upregulated in SHRSP vessels, increasing NO production to compensate for the endothelial dysfunction. Concentration-response curves to acetylcholine (ACh) were performed in second order mesenteric arteries; we observed decreased relaxation responses to ACh (maximum effect elicited by the agonist) as compared with Wistar-Kyoto (WKY) controls. Vessels from SHRSP incubated with Nomega-nitro-l-arginine methyl ester and (or) indomethacin exhibited decreased ACh-mediated relaxation, suggesting a primary role for NO-dependent relaxation. Vessels from SHRSP exhibited a significantly decreased relaxation response with inducible NO synthase (iNOS) inhibition, as compared with WKY vessels. Western blot analysis showed increased total phosphorylated NF-kappaB, and phosphorylated and total eNOS in SHRSP vessels. Overall, these data suggest a compensatory role for NO by increased eNOS activation. Moreover, we believe that iNOS, although increasing NO bioavailability to compensate for decreased relaxation, leads to a cycle of further endothelial dysfunction in SHRSP mesenteric arteries. PMID- 29430949 TI - Heliotropium bacciferum Forssk. (Boraginaceae) extracts: chemical constituents, antioxidant activity and cytotoxic effect in human cancer cell lines. AB - Heliotropium bacciferum (Boraginaceae) is a perennial herb, growing in the Bechar region of Algeria, where it is traditionally used for skin diseases and tonsillitis. Herein, we report the isolation and characterization of sixteen secondary metabolites from the aerial part extracts. They include a sterol (1), megastigman type nor-isoprenoids (2, 3, 4, 6, 8, 10), C-11 terpene lactones (5 and 9), and a monoterpene (7) from the chloroform extract (HB-C); monoterpene glucoside (14), and phenolic compounds (11-13, 15, 16) from the methanol one (HB M). Their structures were elucidated by spectroscopic methods including 1D and 2D NMR experiments, and ESIMS analysis. HB-M showed a significant and concentration dependent scavenging activity in vitro against the radicals DPPH and ABTS, related to the phenol derivatives (11-13, and 15-16), and HB-C inhibited the growth of colon cancer cell lines, mainly for the presence of the antiproliferative C-11 terpene lactones (5 and 9). PMID- 29430957 TI - Anxiety, depression, and health-related quality of life in aging people living with HIV compared to diabetes patients and patients with minor health conditions: a longitudinal study. AB - HIV infection has evolved from a fatal to a treatable condition, leading to an increase in the rate of elderly People Living with HIV (PLWH). However, little is known about the psychosocial burden of elderly PLWH. Thus, the aim of this longitudinal multi-center cohort study was to investigate whether elderly PLWH experience more anxiety and depression and reduced health related quality of life (HRQOL) compared to elderly patients with other chronic conditions. PLWH were compared to diabetes patients (DM) and patients with minor health conditions (MHC), e.g. patients with hypertension or allergic conditions. All patients were over 50 years old. Anxiety and depression (HADS) as well as HRQOL (SF-36) were assessed at baseline and after 12 months. 218 PLWH, 249 DM and 254 MHC were included. At baseline, the study groups did not differ in anxiety, depression, and physical HRQOL. However, PLWH indicated lower mental HRQOL than DM and MHC patients (p = 0.001). We did not obtain any moderating effects showing a differential effect of patient characteristics on anxiety, depression, and HRQOL in the three patient groups. At follow-up, the level of anxiety, depression, and HRQOL did not change significantly. The prevalence of anxiety ranged between 27 and 35%, and that of depression between 17 and 28%. Thus, the results of our investigation tentatively suggest that the psychosocial adaptation to HIV among elderly PLWH resembles those of other chronic diseases. There may be some subtle impairments, though, as PLWH experienced lower mental HRQOL. PMID- 29430958 TI - Cytotoxicity, oxidative stress, and apoptosis in K562 leukemia cells induced by an active compound from pyrano-pyridine derivatives. AB - Recent studies have reported the potential of pyrano-pyridine compounds in inhibiting cell growth and apoptosis induction in cancer cells. Here, we investigated the effect of new pyrano-pyridine derivatives on proliferation, oxidative damages, and apoptosis in K562 leukemia cells. Among different tested compounds, we found 8-(4-chlorobenzylidene)-2-amino-4-(4-chlorophenyl)-5, 6, 7, 8 tetrahydro-6-phenethyl-4H-pyrano-[3,2-c]pyridine-3-carbonitrile (4-CP.P) as the most effective compound with IC50 value of 20 MUM. Gel electrophoresis, fluorescence microscopy, and flow cytometry analyses indicated the apoptosis induction ability of 4-CP.P in K562 cells. Further analyses revealed that 4-CP.P induces significant increase in cellular reactive oxygen species production, lipid peroxidation, protein oxidation, and total thiol depletion. Interestingly, while 4-CP.P significantly increased the activity of superoxide dismutase, it reduced the catalase activity in a time-dependent manner. These data propose that 4-CP.P treatment causes free radicals accumulation that ultimately leads to oxidative stress condition and apoptosis induction. Therefore, we report the 4 CP.P as a novel, potent compound as a chemotherapeutic agent in cancer treatment. PMID- 29430962 TI - Effect of a mouthrinse containing Malva sylvestris on the viability and activity of microcosm biofilm and on enamel demineralization compared to known antimicrobials mouthrinses. AB - The purpose of this study was to evaluate the antimicrobial (anti-biofilm) and anti-caries (enamel demineralization prevention) effects of Malva sylvestris (Malvatricin(r) Plus) compared with known antimicrobial mouthrinses. Microcosm biofilm was produced on enamel, using inoculum from pooled human saliva mixed with McBain saliva (0.2% sucrose) for 14 days. The biofilm was treated with mouthrinses for 1 min day-1. Oral-B(r) Complete, Listerine(r) Zero and Malvatricin(r) Plus had the greatest effect on the reduction of biofilm viability (p < 0.0001). On the other hand, lactic acid production was reduced significantly with PerioGard(r), Noplak(r) Max and Listerine(r) Zero compared with the control (p < 0.0001). No significant differences were found among the mouthrinses with respect to the colony-forming unit counting (total microorganisms, total streptococci, mutans streptococci and lactobacilli) and extracellular polysaccharide production. Enamel demineralization was reduced significantly with PerioGard(r), Noplak(r) Max and Malvatricin(r) Plus compared with the control (p < 0.0001). Malva sylvestris has a comparable anti-caries effect to chlorhexidine mouthrinses. PMID- 29430964 TI - Challenges in Sex- and Gender-Centered Prevention and Management of Cardiovascular Disease: Implications of Genetic, Metabolic, and Environmental Paths. AB - The recognition of cardiovascular disease (CVD) as a "male" privilege has been a commonly held concept. However, emerging data describe another reality. Heterogeneities have been convincingly demonstrated regarding CVD manifestations, risk factor burden, and prognosis between males and females. The aim of the present narrative review was to highlight sex- and gender-related discrepancies in primary and secondary CVD prevention, underscoring plausible underlying mechanisms. Manifestation of CVD in women is characterized by atypical symptoms/signs and inadequately studied pathophysiology features challenging accurate diagnosis and effective treatment. Regarding CVD risk assessment, the burden and effect size of conventional, novel, and female-specific risk factors needs better clarification. Hitherto outcomes are nonconsistent, while most importantly, the interpretation of the attendant metabolic paths remains a challenge; the interactions among genetic, metabolic, and environmental factors are of high complexity regulated by genomic and nongenomic sex hormones effects. To deal with these key points, the National Institutes of Health currently calls upon investigators to provide a sex- and gender-specific reporting in all health research hypotheses. The implementation of high-quality studies addressing these issues is an imperative need to maximize cost-effectiveness in prevention and management strategies. PMID- 29430965 TI - Extraction optimization, total phenolic, flavonoid contents, HPLC-DAD analysis and diverse pharmacological evaluations of Dysphania ambrosioides (L.) Mosyakin & Clemants. AB - The present study aims to evaluate phytochemical and pharmacological potentials of Dysphania ambrosioides (L.) Mosyakin & Clemants previously known as Chenopodium ambrosioides L. Extraction was carried out using 14 solvents with wide range of polarity to find out the best solvent system for each bioactivity. Total phenolic and flavonoids contents were measured colorimetrically and polyphenolics were quantified via HPLC-DAD analysis. The samples were screened for inhibitory potentials against free radicals, leishmania, cancer cell lines, protein kinase, alpha-Amylase enzymes and microbial strains. Among all solvents, maximum percentage of extract was recovered from methanol-water fraction of leaves. HPLC analysis exhibited the presence of rutin, myricetin and quercetin. In DPPH assay, methanolic leaf extract exhibited IC50 value of 130.7 +/- 0.57 MUg/mL. Considerable alpha-amylase inhibitory, cytotoxic, leishmanicidal and antimicrobial potentials were exhibited by plant samples. D. ambrosioides revealed significant antioxidant, cytotoxic, antimicrobial and anti-diabetic potentials and thus warrant further detailed studies to find novel drugs. PMID- 29430966 TI - Major terpenoids from Telekia speciosa flowers and their cytotoxic activity in vitro. AB - In addition to known constituents of Telekia speciosa, an acetone extract from ray florets of the plant yielded: 5,5'-dibutoxy-2,2'-bifuran (1), 5,5' diisobutoxy-2,2'-bifuran (2), alpha-tocopherol (3), beta-tocopherol (4), loliolide palmitate (5), a mixture of calenduladiol esters - 16beta-hydroxylupeol 3-O-palmitate (7) and 16beta-hydroxylupeol-3-O-myristate (8), 1-epiinuviscolide (12), inuviscolide (13), 3-epiisotelekin (16), 4alpha-hydroxy-9beta,10beta-epoxy 1beta(H)-11(13)-guaien-8alpha,12-olide (17), 4alpha-hydroxy-1beta(H)-9(10),11(13) guaiadien-8alpha,12-olide (18), loliolide (19) and 4beta,10beta-dihydroxy 1alpha(H),5alpha(H)-11(13)-guaien-8alpha,12-olide (20). Calenduladiol esters and asperilin (14) were the major constituents of the extract. Their cytotoxic effect on human normal prostate epithelial cells (PNT-2), human prostate carcinoma cell lines, human skin fibroblasts (HSF) and human melanoma cell lines was examined in vitro. Triterpene esters showed no cytotoxicity against nearly all cell lines tested, except for Du145 prostate carcinoma cells (IC50 - 62.0 MUMU). Asperilin displayed activity against the cell lines under study, especially against three tested lines of melanomas (A375, IC50 - 17.6 MUMU, WM793, IC50 - 28.2 MUMU and Hs 294T, IC50 - 29.5 MUMU). PMID- 29430969 TI - Retrospective Analysis of Short-Term Outcomes After Monopolar Versus Laser Endoscopic Enucleation of the Prostate: A Single Center Experience. AB - INTRODUCTION: Endoscopic enucleation of the prostate (EEP) has been recognized as a viable treatment modality for men with benign prostatic hyperplasia (BPH). The aim of our study was to compare the efficacy and functional outcomes of three different techniques of EEP, including monopolar enucleation (MEP), holmium laser enucleation of the prostate (HoLEP), and thulium laser enucleation of the prostate (ThuLEP). METHODS: The study consisted of a retrospective comparison of pre- and postoperative parameters in men undergoing three types of EEP: MEP, HoLEP, and ThuLEP. Functional parameters were evaluated before and 6 months after surgery, which included the International Prostate Symptom Score, maximum flow rate, postvoid residual volume, prostate volume, and sodium levels of all patients. RESULTS: A total of 551 men with the mean age of 67.1 years were included in the study. Of these, MEP was performed on 95 patients, HoLEP was performed on 254 patients, and ThuLEP on 202 patients. The mean mass of morcellated tissue obtained during the three techniques did not differ significantly (p > 0.05). Mean procedure times of ThuLEP and HoLEP were shorter than MEP demonstrating 72, 76, and 86 minutes, respectively (p < 0.01). The mean catheterization time following laser EEPs was shorter than MEP as shown by 1.3, 1.3, and 3.8 days, respectively (p < 0.01). Hospital stay times of HoLEP and ThuLEP were shorter than MEP demonstrated by 3.3, 3.4, and 6.9 days, respectively (p < 0.01). Patients after MEP had significant decrease in postoperative hemoglobin and sodium levels. All the groups showed statistically significant improvement in the aforementioned parameters following treatment. CONCLUSIONS: Both techniques of laser enucleation proved to be efficacious in the management of BPH. MEP of the prostate seems to be a highly promising addition to the list of enucleation techniques and was determined to be an effective and acceptable procedure, despite a higher complication rate. PMID- 29430971 TI - Insulin-like 3 expression and fibrosis induction after intra-testicular injection of magnetic nanoparticles in rat testis and the ameliorative role of Echinacea purpurea extract. AB - The World Health Organization has approved magnetic nanoparticles (MNP) for use as a contrast agent for magnetic resonance imaging or tumor hyperthermia treatment. MNP are toxic over time after intra-testicular injection. A clear strategy to ameliorate the toxic side effects of MNP in normal tissues after medical application has not yet been developed. We used an extract of Echinacea purpurea (EP) as a natural source of antioxidant and free radical scavenging product for detoxification of MNP in testicular tissues. MNP localization in the interstitial area of testicular tissue reduced the expression of insulin-like factor 3 (INSL3) proteins as well as serum testosterone levels. Further, MNP caused accumulation of both collagen and elastin in the interstitial area and increased the thickness of the tunica albuginea. Injection of MNP during administration of EP extract for short periods slightly reduced the toxic side effects of MNP. After extended exposure to EP extract, INSL3 expression and testosterone returned to near control levels. Also, collagen and elastin accumulation caused by MNP was reduced after extended exposure to EP extract. We believe that the ameliorative effect of EP extract is due to its antioxidant properties. PMID- 29430970 TI - Pain Exposure Physical Therapy versus conventional treatment in complex regional pain syndrome type 1-a cost-effectiveness analysis alongside a randomized controlled trial. AB - OBJECTIVE: To analyze cost-effectiveness of Pain Exposure Physical Therapy compared to conventional treatment alongside a randomized controlled trial (NCT00817128) in patients with complex regional pain syndrome type 1, where no clinical difference was shown between the two groups in an intention-to-treat analysis. DESIGN: Randomized controlled trial with 9 months follow-up. SETTING: Patients were recruited from hospitals and general practitioners in the region around a university hospital. SUBJECTS: A total of 56 patients, 45 (80.4%) female, were randomized. About 4 patients in the intervention and 11 patients in the conventional group switched groups. The mean (SD) age was 44.3 (16.6) years, and in 37 (66.1%) patients, the upper extremity was affected. INTERVENTIONS: Patients received either Pain Exposure Physical Therapy (maximum of five sessions), or conventional treatment conforming with the Dutch multidisciplinary guideline. MAIN MEASURES: For the economic evaluation difference between the groups in health-related quality of life (quality-adjusted life years (QALYs)), and the clinical outcomes Impairment level Sum Score-Restricted Version and Pain Disability was determined based on the intention-to-treat analysis as well as differences in both healthcare-related costs and travel expenses. Cost effectiveness planes were constructed using bootstrapping to compare effects and costs. RESULTS: No significant effects were found for QALYs (mean difference = 0.02; 95% confidence interval (CI) -0.10 to 0.04) and clinical outcomes. A cost minimization analysis showed a significant difference in costs between groups. The conventional treatment was 64% more expensive than the Pain Exposure Physical Therapy. CONCLUSION: This economic analysis shows that Pain Exposure Physical Therapy compared to conventional treatment is cost-effective. PMID- 29430973 TI - A case of twin IVF pregnancy complicated with sclerosing encapsulating peritonitis diagnosed at caesarean delivery. PMID- 29430972 TI - The behaviour of pelvic floor muscles during uterine contractions in spontaneous and oxytocin-induced labour. AB - Term pregnant women were divided into oxytocin infusion and control groups. The electrical activities of pelvic floor muscles (PFM) were recorded at rest and during contractions electromyographically. The beginning and the end of each contraction were marked on the recorded electromyographic trace. A trace was regarded as 'negative' if no increase in electrical activity was observed and 'positive' if increased electrical activity was observed during the contractions. To evaluate the relative frequency of the areas of electrical activity during uterine contractions (UC) a 'positive electrical activity percentage' was used and calculated as: (total count of positive electrical activity areas)/(total count of UC) * 100. Positive and negative electrical activity percentages were compared. The percentages were significantly different between the groups (p <.01). Positive traces increased in 56.1 and 18.8% in study and control groups, respectively, (p < .01). Multiparous women showed more positive traces than nulliparous women, both in oxytocin-treated and spontaneous labour groups (p < .01). The rate of performed episiotomies was higher in the oxytocin-infused labours (p = .01). During physiological labour contractions the predominant behaviour of PFM seemed to be a relative silent status compared to a more contractile status caused by oxytocin administration. Contracted muscles may produce a counterpressure against expulsive UC leading to obstetrical injuries of these muscles and clinically higher rates in episiotomy decisions. This is the first report of behaviour of PFM during labour contractions and further prospective studies are needed to assess the role of oxytocin administration on PFM and associated clinical consequences. Impact statement What is already known on this subject? The physiological functions of pelvic floor muscles depend on the coordinated actions of these muscles and rely also on unique interactions between the somatic and autonomic nervous systems. Oxytocin is commonly used for the induction and augmentation of uterine contractions and such an induced labour may be more painful for the woman. What do the results of this study add? Pelvic floor muscles tend to contract more frequently during uterine contractions as labour progresses. This difference was more pronounced in labours which were treated with oxytocin infusion. What are the implications of these findings for clinical practice and/or further research? This is the first report of electrophysiological behaviour of pelvic floor muscles during labour contractions in spontaneous and oxytocin-induced labour. Oxytocin administration seems to interfere with the coordination of uterine and pelvic floor muscle contractions. This study may be of interest for researchers to investigate the effect of the worldwide liberal use of oxytocin for induction of labour on pelvic floor muscle damage during parturition. PMID- 29430974 TI - Maternal serum irisin levels in early and late-onset pre-eclamptic and healthy pregnancies. AB - The aim of the study was to investigate whether plasma irisin concentrations differ between uncomplicated, early-onset and late-onset pre-eclamptic pregnancies. This cross-sectional study was conducted on 27 women with early onset, 27 women with late-onset pre-eclampsia (PE) and 26 healthy pregnant women. Maternal levels of serum irisin were measured with the use of an enzyme-linked immunosorbent assay kit. The mean maternal serum irisin level of early-onset PE was significantly lower than late-onset PE (1.14 +/- 0.56 vs. 1.46 +/- 0.59, p < .05) and control subjects (1.14 +/- 0.56 vs. 3.14 +/- 0.81, p < 0.001). The mean maternal serum irisin level of late-onset PE was significantly lower than the control group (1.46 +/- 0.59 vs. 3.14 +/- 0.81, p < 0.001). Maternal serum irisin levels are decreased in pre-eclamptic pregnancies. Low levels of irisin may be the result or the cause of pathologic changes in PE. Impact statement What is already known on this subject? There are only two studies in the literature evaluating maternal serum irisin levels in pre-eclamptic pregnancies. One study demonstrated decreased maternal serum irisin levels in pre-eclamptic patients and the other found no significant difference between pre-eclamptic and control pregnancies. What do the results of this study add? The present study demonstrates that serum irisin levels were significantly lower in pre-eclampsia than normotensive pregnancies. Furthermore, we have also demonstrated for the first time that women with EO-PE had significantly lower levels of serum irsin than women with LO-PE. What are the implications of these findings for clinical practice and/or further research? Low levels of irisin may be the result or the cause of pathologic changes in pre-eclampsia. More studies are needed to evaluate the relationship between irisin and pre-eclampsia. PMID- 29430976 TI - Loteprednol etabonate for inflammatory conditions of the anterior segment of the eye: twenty years of clinical experience with a retrometabolically designed corticosteroid. AB - INTRODUCTION: Topical corticosteroids are an important pharmacotherapy for the management of various inflammatory conditions affecting the anterior segment of the eye. However, medications in this class are associated with well-known risks including increased intraocular pressure (IOP) and development of cataracts. The topical corticosteroid loteprednol etabonate (LE) was developed with the specific intention of minimizing these side effects. Areas covered: The focus of this review is to examine published efficacy and safety data for LE, a drug engineered to undergo rapid metabolism to inactive metabolites with the goal of improved safety. Two decades of clinical research focused on LE formulations are reviewed, including the use of LE in combination with tobramycin. The cumulative body of experience affirms the concept that the molecular design of LE confers certain safety benefits without compromising the desired anti-inflammatory efficacy of a topical corticosteroid. Expert opinion: Loteprednol etabonate is a mainstay for topical therapy of a wide variety of commonplace and niche conditions of the ocular surface and the anterior segment, including in the healing post-operative patient. Its versatility and safety allow eye care providers to recommend both acute induction as well as chronic maintenance therapy with appropriate follow up. PMID- 29430977 TI - Amenorrhoea and reversible infertility due to obstructive hydrocephalus: literature review and case report. AB - BACKGROUND: Endocrine abnormalities are well-recognized consequences of intracranial pathology such as pituitary tumours. Less commonly, hydrocephalus may lead to dysfunction of the endocrine system, presenting as amenorrhoea or precocious puberty. We present a case report and literature review of hydrocephalus causing endocrine abnormalities including reversible infertility. CASE DESCRIPTION: A 34 year-old female presented with amenorrhoea and infertility. MRI showed a third ventricular mass and hydrocephalus. The amenorrhoea resolved within weeks of endoscopic third ventriculostomy and tumour biopsy; pregnancy ensued within 6 months. Thirty-two cases of hydrocephalus related amenorrhoea were reported between 1915 and 2007. All patients who underwent modern hydrocephalus treatment experienced partial or complete resolution of endocrine dysfunction. Successful pregnancy was reported in three patients, as in our case presentation. While mechanisms of dysfunction have not been completely elucidated, studies point toward loss of GnRH pulsatility due to compression of the medio-basal hypothalamic structures. CONCLUSION: Hydrocephalus can cause endocrine dysfunction, including amenorrhoea, which may reverse with CSF diversion. Therefore, cranial imaging is an important component in the evaluation of such endocrine abnormalities. PMID- 29430978 TI - Biomarkers for immune-related toxicities of checkpoint inhibitors: current progress and the road ahead. AB - INTRODUCTION: Immune checkpoint pathways are key immune regulatory pathways that play a physiologic role in maintaining immune-homeostasis and are often co-opted by cancer cells to evade the host immune system. Recent developments in cancer immunotherapy, mainly drugs blocking the immune checkpoint pathways, have revolutionized the treatment paradigm for many solid tumors. A wide spectrum of immune-related adverse events (irAEs) have been described with the use of these agents which necessitate treatment with immunosuppression, lead to disruption of therapy and can on occasion be life-threatening. There are currently no clinically validated biomarkers to predict the risk of irAEs. Areas covered: In this review, the authors describe the current progress in identifying biomarkers for irAEs and potential future directions. Literature search was conducted using PubMed-MEDLINE, Embase and Scopus. In addition, abstracts from major conference proceedings were reviewed for relevant content. Expert commentary: The discovery of biomarkers for irAEs is currently in its infancy, however there are a lot of promising candidate biomarkers that are currently being investigated. Biomarkers that can identify patients at a higher risk of developing irAEs or lead to early detection of autoimmune toxicities are crucial to optimize patient selection for immune-oncology agents and to minimize toxicity with their use. PMID- 29430979 TI - An effective treatment approach of DPP-IV inhibitor encapsulated polymeric nanoparticles conjugated with anti-CD-4 mAb for type 1 diabetes. AB - Nanotechnology based biomedical approaches and surface modification techniques made it easier for targeting specific site and improving the treatment efficacy. The present study reports on targeted polymeric nanoparticles conjugated with antibody as a site-specific carrier system for effective treatment of type 1 diabetes. Sitagliptin (SP)-loaded Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP) were prepared by nanoprecipitation cum solvent evaporation method and were characterized in terms of morphology, size, surface charge, and entrapment efficiency. Optimized batch demonstrated a particle size of 105.24 nm, with significant entrapment efficacy. In vitro release studies exhibited a controlled release pattern of 67.76 +/- 1.30% in 24 h, and a maximum of 96.59 +/- 1.26% at the end of 48 h. Thiol groups were introduced on the surface of SP-NPs whose concentration on SP-NPs was 27 +/- 2.6 mmol/mol PLGA-NPs, anti-CD4 antibody clone Q4120 was conjugated to the thiolated SP-NPs via a sulfo-MBS cross-linker, ~70% conjugation was observed. The in vitro cytotoxicity studies performed on RIN 5 F cells for mAb-SP-NPs presented an IC50 of 76 ug/mL, and the insulin release assay had revealed an increased release at 5.15 +/- 0.16 IU/mL. The results indicate that mAb-SP-NPs allowed a controlled release of SP and thereby produced insulin levels comparable with control. Therefore, mAb-SP-NPs system appears to be effective in the treatment of auto immune diabetes, subject to further analysis. PMID- 29430980 TI - Chronic non-puerperal uterine inversion in an asymptomatic woman. PMID- 29430981 TI - The Diabetic Foot Attack: "'Tis Too Late to Retreat!" AB - The "diabetic foot attack" is one of the most devastating presentations of diabetic foot disease, typically presenting as an acutely inflamed foot with rapidly progressive skin and tissue necrosis, at times associated with significant systemic symptoms. Without intervention, it may escalate over hours to limb-threatening proportions and poses a high amputation risk. There are only best practice approaches but no international protocols to guide management. Immediate recognition of a typical infected diabetic foot attack, predominated by severe infection, with prompt surgical intervention to debride all infected tissue alongside broad-spectrum antibiotic therapy is vital to ensure both limb and patient survival. Postoperative access to multidisciplinary and advanced wound care therapies is also necessary. More subtle forms exist: these include the ischemic diabetic foot attack and, possibly, in a contemporary categorization, acute Charcot neuroarthropathy. To emphasize the importance of timely action especially in the infected and ischemic diabetic foot attack, we revisit the concept of "time is tissue" and draw parallels with advances in acute myocardial infarction and stroke care. At the moment, international protocols to guide management of severe diabetic foot presentations do not specifically use the term. However, we believe that it may help increase awareness of the urgent actions required in some situations. PMID- 29430982 TI - A Profile of the Assisted Living Direct Care Workforce in the United States. AB - BACKGROUND AND OBJECTIVES: The purpose of this article was to develop a profile of direct care workers (DCWs) in assisted living (AL). RESEARCH DESIGN AND METHODS: We used data from 2014 American Community Survey (ACS) to identify the demographic and employment characteristics of AL DCWs. We collected state training requirements for AL DCWs from the administrative rules of state agencies and interviews with state officials. RESULTS: AL DCWs were more likely than other DCWs to be younger, male, White, English speaking, U.S.-born, never married, and to have attended college. Two Affordable Care Act (ACA)-designated training topics (self-care and the role of the personal care aide) were not required in any state. Discussion and Implications: AL has tapped a unique pool of workers (i.e., younger, male as well as female, and with some college education) but needs to address its workforce needs via training, improvements to overall job quality, and the development of career opportunities. PMID- 29430983 TI - C-reactive protein and white blood cell count as predictors of maternal and neonatal infections in prelabour rupture of membranes between 34 and 41 weeks of gestation. AB - Prelabour rupture of the membranes (PLROM) is defined as rupture of membranes before the onset of labour. It is one of the most common clinical events, where pregnancy can turn into a high-risk situation for mother and foetus. As prevention of PLROM is difficult, one has to concentrate on management to reduce its complications. Accurate prediction of infection remains a main challenge in cases of PLROM. We conducted a prospective study of all women admitted for PLROM at or after 34-41 weeks of gestation to investigate the predictive value of C reactive protein (CRP) and white blood cell (WBC) count for early-onset neonatal infection (EONI) and maternal chorioamnionitis. The analysis was done by comparing areas under ROC curves and sensitivity. Lowest best cut off of maternal serum CRP level >4.9 mg/l and lowest cut off of WBC count 12,450/cumm have good predictive values for maternal chorioamnionitis and EONI. Impact statement What is already known on this subject? The ability to detect chorioamnionitis and predict neonatal infection at an early stage would be helpful in its treatment and would make it possible to prolong the pregnancy. What do the results of this study add? Maternal serum CRP level and WBC count obtained at admission are predictors of chorioamnionitis and EONI although WBC count alone is not a good indicator of them. A lowest best cut off of serum CRP level >4.9 mg/l and lowest cut off of WBC count 12,450/cumm have good predictive values for maternal chorioamnionitis and EON. What are the implications of these findings for clinical practice and/or further research? We propose that maternal serum CRP level and WBC count should be used as screening test for EONI and chorioamnionitis rather than a diagnostic test. PMID- 29430984 TI - Is Chemerin associated with gestational diabetes mellitus? An evidence-based clinical research from Chinese women. AB - The present study aimed to explore the association between gestational diabetes mellitus (GDM) and Chemerin, by analysing Chemerin level, clinical data and biochemical parameters among 46 GDM patients and 43 controls. It was found that the Chemerin levels from cord blood, peripheral blood, adipose tissue and placenta tissue were all significantly higher in the GDM group than those in the control group (p < .05 for all). Maternal insulin resistance (IR) index and serum inflammation parameters, including C-reactive protein and white blood cells, were also higher in GDM group (p < .05 for all). Moreover, maternal IR index and circulating insulin level were both positively correlated with maternal circulating Chemerin level (p < .05 for both). Our findings suggest that Chemerin, associated with IR and more expressed in GDM women, might participate in the pathogenesis of GDM. Impact Statement What is already known on this subject: Chemerin, a recently-discovered adipocytokine, has been widely considered to be involved in metabolic diseases, and several studies have investigated it in gestational diabetes mellitus (GDM), but with no consensus about the level comparison between GDM and controls. What the results of this study add: The present case-control study found that the levels of Chemerin from cord blood, peripheral blood, adipose tissue and placenta tissue were all significantly higher in the GDM group. What the implications are of these findings for clinical practice and/or further research: Also, the circulating Chemerin level was positively correlated with insulin index, which we thought would add to the evidence that Chemerin does be associated with GDM, contributing to elucidating the pathogenesis of GDM. PMID- 29430988 TI - Protective Effect of D-Methionine on Body Weight Loss, Anorexia, and Nephrotoxicity in Cisplatin-Induced Chronic Toxicity in Rats. AB - D-methionine is a sulfur-containing amino acid that can act as a potent antioxidant. Anorexia and nephrotoxicity are side effects of cisplatin. The protective effects of D-methionine on cisplatin-induced anorexia and renal injury were investigated. The model of chronic cisplatin administration (5 mg/kg body weight) involved intraperitoneal injection on days 1, 8, and 15 and oral D methionine (300 mg/kg body weight) coadministration daily for 20 days. On the 21st day of treatment, food intake and body weight in the cisplatin-treated group significantly decreased by 52% and 31%, respectively, when compared with a control group. D-methionine coadministration with cisplatin decreased food intake and body weight by 29% and 8%, respectively. In cisplatin-treated rats, white blood cell, mean corpuscular volume, and platelet values significantly decreased, while mean corpuscular hemoglobin concentration significantly increased by 8.6% when compared with control rats. Cisplatin administration resulted in significantly decreased feeding efficiency, elevated renal oxidative stress, and reduced antioxidative activity. Leukocyte infiltration, tubule vacuolization, tubular expansion, and swelling were observed in the kidneys of cisplatin-treated rats. Oral D-methionine exhibited an antianorexic effect, with improvement in food intake, feeding efficiency, and hematological toxicities, as well as a protective effect against nephrotoxicity by elevated antioxidative activity. D methionine may serve as a chemoprotectant in patients receiving cisplatin as part of a chemotherapy regimen. PMID- 29430989 TI - NK1R/5-HT1AR interaction is related to the regulation of melanogenesis. AB - Substance P (SP) is a candidate mediator along the brain-skin axis and can mimic the effects of stress to regulate melanogenesis. Previously, we and others have found that the regulation of SP for pigmentary function was mediated by neurokinin 1 receptor (NK1R). Emerging evidence has accumulated that psychologic stress can induce dysfunction in the cutaneous serotonin 5-hydroxytryptamine (5 HT)-5-HT1A/1B receptor system, thereby resulting in skin hypopigmentation. Moreover, NK1R and 5-HTR (except 5-HT3) belong to GPCR. The present study aimed at assessing the possible existence of NK1R-5-HTR interactions and related melanogenic functions. Western blot and PCR detection revealed that SP reduced expression of 5-HT1A receptor via the NK1 receptor. Biochemical analyses showed that NK1R and 5-HT1AR could colocalize and interact in a cell and in the skin. When the N terminus of the NK1R protein was removed NK1R surface targeting was prevented, the interaction between NK1R-5-HT1AR decreased, and the depigmentation caused by SP and WAY100635 could be rescued. Importantly, pharmaceutical coadministration of NK1R agonist (SP) and 5-HT1A antagonist (WAY100635) enhanced the NK1-5-HT1A receptor coimmunoprecipitation along with the depigmentary response. SP and WAY100635 cooperation elicited activation of a signaling cascade (the extracellular, regulated protein kinase p-JNK signaling pathway) and inhibition of p70S6K1 phosphorylation and greatly reduced melanin production in vitro and in vivo in mice and zebrafish. Moreover, the SP-induced depigmentation response did not be occur in 5-htr1aa+/- zebrafish embryos. Taken together, the results of our systemic study increases our knowledge of the roles of NK1R and 5 HT1AR in melanogenesis and provides possible, novel therapeutic strategies for treatment of skin hypo/hyperpigmentation.-Wu, H., Zhao, Y., Huang, Q., Cai, M., Pan, Q., Fu, M., An, X., Xia, Z., Liu, M., Jin, Y., He, L., Shang, J. NK1R/5 HT1AR interaction is related to the regulation of melanogenesis. PMID- 29430991 TI - Platelets directly regulate DNA damage and division of Staphylococcus aureus. AB - Platelets (PLTs) are classically used in the clinical setting to maintain hemostasis. Recent evidence supports important roles for PLTs in host inflammatory and immune responses, and PLT-rich plasma has been demonstrated to inhibit the growth of bacteria in vitro and in vivo; however, few studies have examined whether PLTs can inhibit bacterial growth directly, and related mechanisms have not been elucidated further. Accordingly, in this study, we evaluated the effects of PLTs on bacterial growth. We washed and purified PLTs from peripheral blood, then confirmed that PLTs significantly inhibited the growth of Staphylococcus aureus when cocultured in vitro. Moreover, PLTs damaged DNA and blocked cell division in S. aureus. During coculture, PLT-derived TGF beta1 was dramatically down-regulated compared with that in PLT culture alone, and the addition of TGF-beta1 to the coculture system promoted the inhibition of PLTs on S. aureus. Analysis of a murine S. aureus infection model demonstrated that the depletion of PLTs exacerbated the severity of infection, whereas the transfusion of PLTs alleviated this infection. Our observations demonstrate that PLTs could directly inhibit the growth of S. aureus by damaging DNA and blockage cell division, and that PLT-derived TGF-beta1 may play an important role in this machinery.-Xu, J., Yi, J., Zhang, H., Feng, F., Gu, S., Weng, L., Zhang, J., Chen, Y., An, N., Liu, Z., An, Q., Yin, W., Hu, X. Platelets directly regulate DNA damage and division of Staphylococcus aureus. PMID- 29430990 TI - The metalloprotease ADAM10 (a disintegrin and metalloprotease 10) undergoes rapid, postlysis autocatalytic degradation. AB - The transmembrane protein, ADAM10 (a disintegrin and metalloprotease 10), has key physiologic functions-for example, during embryonic development and in the brain. During transit through the secretory pathway, immature ADAM10 (proADAM10) is converted into its proteolytically active, mature form (mADAM10). Increasing or decreasing the abundance and/or activity of mADAM10 is considered to be a therapeutic approach for the treatment of such diseases as Alzheimer's disease and cancer. Yet biochemical detection and characterization of mADAM10 has been difficult. In contrast, proADAM10 is readily detected-for example, in immunoblots which suggests that mADAM10 is only a fraction of total cellular ADAM10. Here, we demonstrate that mADAM10, but not proADAM10, unexpectedly undergoes rapid, time dependent degradation upon biochemical cell lysis in different cell lines and in primary neurons, which prevents the detection of the majority of mADAM10 in immunoblots. This degradation required the catalytic activity of ADAM10, was efficiently prevented by adding active site inhibitors to the lysis buffer, and did not affect proADAM10, which suggests that ADAM10 degradation occurred in an intramolecular and autoproteolytic manner. Inhibition of postlysis autoproteolysis demonstrated efficient cellular ADAM10 maturation with higher levels of mADAM10 than proADAM10. Moreover, a cycloheximide chase experiment revealed that mADAM10 is a long-lived protein with a half-life of approximately 12 h. In summary, our study demonstrates that mADAM10 autoproteolysis must be blocked to allow for the proper detection of mADAM10, which is essential for the correct interpretation of biochemical and cellular studies of ADAM10.-Brummer, T., Pigoni, M., Rossello, A., Wang, H., Noy, P. J., Tomlinson, M. G., Blobel, C. P., Lichtenthaler, S. F. The metalloprotease ADAM10 (a disintegrin and metalloprotease 10) undergoes rapid, postlysis autocatalytic degradation. PMID- 29430994 TI - Aortic arch anomalies detected in foetal life by echocardiography. AB - Aortic arch anomalies refer to congenital malformations of position or branching pattern of the aortic arch. To-date, only a few small studies have documented prenatal detection of aortic arch anomalies. In this article, we share our experience in detecting aortic arch anomalies. Foetal echocardiograms, clinic and genetic histories of 33 patients who had been diagnosed with aortic arch anomaly from 2007 to 2015 were reviewed. In 15 patients, right aortic arch with mirror image branching; in 13 patients, right aortic arch with left ductus arteriosus and aberrant left subclavian artery; in three patients, left aortic arch with aberrant right subclavian artery; in one patient bilateral ductus and right aortic arch with aberrant left subclavian artery and in one patient double aortic arch were detected. In a patient with isolated right aortic arch, 22q11 microdeletion had been revealed. Given this data, we strongly suggest foetal karyotype analysis when aortic arch anomalies are identified. Impact Statement What is already known on this subject: The data about the prenatal diagnosis of aortic arch anomalies are limited. What the results of this study add: In our study, 653 patients were examined by foetal echocardiography during the study period. Thirty three patients who had been diagnosed with aortic arch anomaly prenatally and confirmed after delivery were enrolled in the study. In 15 patients, right aortic arch with mirror image branching; in 13 patients, right aortic arch with left ductus arteriosus and aberrant left subclavian artery; in three patients, left aortic arch with aberrant right subclavian artery; in one patient bilateral ductus and right aortic arch with aberrant left subclavian artery and in one patient double aortic arch were detected. Trisomy 18 was detected in the patient with bilateral ductus arteriosus and Di George syndrome (22q11 microdeletion) was determined in two patients with right aortic arch. While in the first patient, there were no other intracardiac anomalies; in the second patient with 22q11 microdeletion, Fallot tetralogy accompanied the right aortic arch. What the implications are of these findings for clinical practice and/or further research: This results showed that aortic arch anomalies can be associated with genetic anomalies even when they are found without other congenital heart disease. Given these data, we strongly suggest foetal karyotype analysis and genetic testing when aortic arch anomalies are identified. PMID- 29430995 TI - [11C]( R)-Rolipram positron emission tomography detects DISC1 inhibition of phosphodiesterase type 4 in live Disc1 locus-impaired mice. AB - Although still a matter of controversy, disrupted in schizophrenia protein 1 (DISC1) was suggested as a potential inhibitor of phosphodiesterase 4 (PDE4). We used Disc1 locus impairment (LI) mice to investigate the interaction between PDE4 and DISC 1 in vivo and in vitro. [11C]( R)-Rolipram binding was measured by PET in LI ( n = 11) and C57BL/6 wild-type (WT, n = 9) mice. [11C]( R)-Rolipram total distribution volumes ( VT) were calculated and corrected for plasma-free fraction ( fP) measured in a separate group of LI ( n = 6) and WT ( n = 7) mice. PDE4 enzyme activity was measured using in vitro samples of cerebral cortices from groups of LI ( n = 4), heterozygote ( n = 4), and WT ( n = 4) mice. Disc1 LI mice showed a 41% increase in VT (18 +/- 6 vs. 13+/-4 mL/cm3, P = 0.04) compared to WT mice. VT/ fP showed a 73% significant increase (90 +/- 31 vs. 52 +/- 15 mL/cm3, P = 0.004) in Disc1 LI compared to WT mice. PDE4 enzymatic activity assay confirmed in vivo findings showing significant group differences ( p < 0.0001). In conclusion, PDE4 activity was increased in the absence of critical DISC1 protein isoforms both in vivo and in vitro. Additionally, [11C]( R)-Rolipram PET was sensitive enough to assess altered PDE4 activity caused by PDE4-DISC1 interaction. PMID- 29430996 TI - The problem of using standardised base excess as a measure of metabolic acidosis. PMID- 29430997 TI - Opportunity to participate in planning and evaluation of support for children with disabilities: Parents' and professionals' perspectives. AB - A random sample of parents of children with disabilities ( n = 144) from three Swedish municipalities participated in a structured telephone interview including seven questions on child participation and 156 professionals from the same municipalities completed a web-based survey including six questions on child participation. The aim of the study was to explore parents' and professionals' (1) ratings of the opportunities available to children with disabilities to participate in planning, decision-making and evaluation of support and (2) satisfaction with the children's current level of such participation. The results indicated that opportunities for children with disability to participate directly in decision-making processes were limited. Parents and professionals rated older children's opportunities to participate as better compared to younger. Most professionals relied more on parents' descriptions of the child's needs and opinions of support services than on direct communication with the child. PMID- 29431002 TI - Commentary: Hard Times for Oncologists? PMID- 29430998 TI - Comparable achievement of client-identified, self-rated goals in intervention and no-intervention groups: reevaluating the use of Goal Attainment Scaling as an outcome measure. AB - Goal Attainment Scaling (GAS) is widely used as a measure of client-centered outcomes in clinical interventions. There are few well-controlled studies using GAS, however, and this limits the conclusions that can be drawn about the determinants of goal attainment post-intervention. In collaboration with researchers, 67- community-dwelling older adults used GAS to establish individualised goals for lifestyle change and memory strategy use in a randomised controlled trial of a multidimensional memory program (ClinicalTrials.gov: NCT02087137). Participants were allocated to an intervention or no-contact control group. Goal attainment was self-rated by participants at baseline, immediate post-intervention, and six-week follow-up. A mixed-model analysis of variance revealed a main effect of time, but no main effect of group and no interaction between time and group. In both the intervention and control groups, respectively, T-scores increased from baseline (Ms = 37 and 37) to post intervention (Ms = 52 and 50) and were stable at follow-up (Ms = 52 and 51). Results were similar using ordinal data interpretation. Comparable goal attainment in participants receiving intervention versus no intervention underscores the importance of control groups in evaluation studies utilising GAS as an outcome measure, and supports a possible therapeutic contribution of setting and rating goals with GAS. PMID- 29431003 TI - Reprise: State of Oncology Practice. PMID- 29431004 TI - National Oncology Practice Benchmark, 2011 Report on 2010 Data. AB - Benchmarking is widely recognized as the best, most efficient way to find opportunities to improve a practice and then monitor progress after corrective action is taken. The National Practice Benchmark provides important and meaningful data for oncology practices to use in today's challenging practice environment. PMID- 29431005 TI - Reduced blood oxygenation level dependent connectivity is related to hypoperfusion in Alzheimer's disease. AB - Functional connectivity of blood oxygenation level dependent signal fluctuations (BOLD-FC) is decreased in Alzheimer's disease (AD), and suggested to reflect reduced coherence in neural population activity; however, as both neuronal and vascular-hemodynamic processes underlie BOLD signals, impaired perfusion might also contribute to reduced BOLD-FC; 42 AD patients and 27 controls underwent simultaneous PET/MR imaging. Resting-state functional MRI assessed BOLD co activity to quantify BOLD-FC, pulsed arterial spin labeling (pASL) assessed cerebral blood flow (CBF) as proxy for vascular hemodynamics, and 18F fluorodeoxyglucose PET assessed glucose metabolism (GluMet) to index neuronal activity. Patients' BOLD-FC, CBF, and GluMet were reduced within the same precuneal parietal regions. BOLD-FC was positively associated with mean CBF, specifically in patients and controlled for GluMet levels, suggesting that BOLD FC reductions correlate with pASL-derived hypoperfusion in AD, independently from 18F-fluorodeoxyglucose PET-derived hypometabolism. Data indicate that impaired vascular hemodynamic processes contribute to reduced BOLD connectivity in AD. PMID- 29431006 TI - Cell Density-Dependent Cytological Stage Profile and Its Application for a Screen of Cytostatic Agents Active Toward Leukemic Stem Cells. AB - Proliferation and expansion of leukemia is driven by leukemic stem cells (LSCs). Multidrug resistance (MDR) of LSCs is one of the main reasons of failure and relapses in acute myeloid leukemia (AML) treatment. In this study, we show that maintaining HL-60 at low cell culture density or applying a 240-day treatment with anthrapyridazone (BS-121) increased the percentage of primitive cells, which include LSCs determining the overall stage profile. This change manifested in morphology, expression of both cell surface markers and redox-state proteins, as well as mitochondrial potential. Moreover, four sublines were generated, each with unique and characteristic stage profile and cytostatic sensitivity. Cell density-induced culture alterations (affecting stage profiles) were exploited in a screen of anthrapyridazones. Among the compound tested, C-123 was the most potent against primitive cell stages while generating relatively low amounts of reactive oxygen species (ROS). Furthermore, it had low toxicity in vivo and weakly affected blood morphology of healthy mice. The cell density-dependent stage profiles could be utilized in preliminary drug screens for activity against LSCs or in construction of patient-specific platforms to find drugs effective in case of AML relapse (drug extrapolation). The correlation between ROS generation in differentiated cells and toxic effect observed in HL-60 has a potential application in myelotoxicity predictions. The discovered properties of C-123 indicate its potential application in AML treatment, specifically in conditioned myeloablation preceding allogeneic transplantation and/or ex vivo treatment preceding autologous transplantation. PMID- 29431007 TI - Associative strength or gist extraction: Which matters when DRM lists have two critical lures? AB - The Deese-Roediger-McDermott (DRM) paradigm is often used in the study of false memories. This paradigm typically uses lists of words associated with one critical lure. The primary objective of our study was to understand the production of false memories using the DRM paradigm when lists of words are associated with two critical lures. Three experiments were performed, and it was observed that the critical lures associated with the first set were significantly more frequently recalled than the critical lures associated with the second set. This result was verified when the words were presented in descending order of association with the critical lure (Experiment 1), when the words of the second set were presented in ascending order of association with the critical lure (Experiment 2), and when all the words in the list had the same associative strength (Experiment 3). Results are explained by the activation/monitoring and fuzzy-trace theories. PMID- 29431008 TI - Gasoline-related injuries and fatalities in the United States, 1995-2014. AB - This descriptive study examines twenty years of gasoline-related fatalities and emergency department treated injuries in the United States, based on data from the US Consumer Product Safety Commission. Thermal burns consistently accounted for the majority (56%) of gasoline-related injuries and for most (82%) gasoline related deaths, and were commonly (57-71%) associated with the use of gasoline as an accelerant. Poisoning accounted for 13% of injuries and 17% of deaths. The primary poisoning injury pattern was ingestion; the primary fatality pattern was inhalation, with about half of those associated with deliberate abuse. The estimated number of ingestions decreased from 60 to 23% of poisoning-related injuries, while injuries associated with inhalation abuse increased from 6 to 23%. Chemical burns and dermatitis were less represented in the injury data and were primarily associated with gasoline spills or splashes. Gasoline cans reportedly ignited or exploded in about 5% of thermal burn injuries and fatalities. While mandatory requirements for child resistant closures on gasoline cans (a primary intervention) have potentially impacted poisonings, the use of flame mitigation devices to address thermal injuries, if successful, would be a secondary intervention, and could address only a small percentage (about 5%) of injuries and deaths. PMID- 29431009 TI - A questionnaire survey of second year graduate-entry medical students' perception of obstetrics and gynaecology as a future career speciality. AB - The aim of this study was to explore the impressions of second year graduate entry medical students of Obstetrics and Gynaecology, before their attachment in the speciality in the subsequent year, so as to improve its appeal to them and increase their recruitment into it. A total of 74 questionnaires were distributed at the end of the Learning Opportunities in Clinical Setting (LOCS) week in the speciality and 66 (89.19%) completed questionnaires were returned. Over 4% of the respondents were considering the speciality as their career choice and less than half would consider it as a second option. Whilst more than a third perceived some of the demerits of the speciality, more than a third endorsed its merits. This showed the need to explore and address their concerns about training and working in the speciality. Having a health-related primary degree, prior employment and being female were significantly associated with choosing the speciality as a career (p < .001). Barriers for male respondents were flagged, which need to be addressed, and a bias towards Obstetrics was noted, which reflects the narrow focus on the Labour Ward and necessitates a broader exposure to the speciality. Impact statement What is already known on this subject? The perception of third year graduate-entry medical students of Obstetrics and Gynaecology is biased towards Obstetrics, and they have apprehensions about the challenges of training and working in the speciality. What do the results of this study add? The views of second year graduate-entry medical students are consistent with the views of third year graduate-entry medical students, which shows that these views may be formed early. What are the implications of these findings for clinical practice and/or further research? More research is needed to establish and understand the perception of the speciality earlier than second year and explore the value of practical steps that may improve this perception and increase the interest in it and recruitment into its training programmes. PMID- 29431010 TI - Commentary on pelvic venous reflux in males with varicose veins and recurrent varicose veins. PMID- 29431011 TI - Incidence and predictors of roller derby injuries among female roller derby athletes. AB - Little is known about roller derby injuries. To describe the types of injuries that female roller derby athletes experience, quantify the incidence of injuries and examine the relationship between selected demographic variables and injuries. Women's roller derby leagues were contacted explaining the study and requesting participation. A second message was sent with the link to the electronic questionnaire to collect data from March to June 2015. Of the 1 395 respondents, 48.7% (679) reported having at least one injury in the previous 12 months. The skaters' average age was 32 and have played roller derby for four years. The most common injuries were to the ankles (22.5%), knees (21%) and head (11%). Of the head injuries, 75% were diagnosed with a concussion. This is the first study of woman's roller derby injuries. Understanding injuries that skaters incur may help leagues as they develop policies and specific injury prevention programmes. PMID- 29431013 TI - Medicare's Hospital Outpatient Prospective Payment System: OPPS 101 (part 2 of 2). PMID- 29431014 TI - Comparison of 2D versus M-mode echocardiography for assessing fetal myocardial wall thickness. AB - OBJECTIVE: M-mode and 2D have been proposed for evaluating fetal myocardial thickness. However, studies comparing the performance of both modalities are lacking. We aimed to compare 2D versus M-mode reproducibility for assessing myocardial wall thicknesses. METHODS: A prospective study including 45 healthy fetuses from low-risk pregnancies evaluated between 18 and 41 weeks of gestation. Left and right ventricular free-wall and septal myocardial thicknesses were measured at end-diastole (ED) and end-systole (ES) in transverse 4-chamber view using 2D and M-mode. Intra- and interobserver reproducibility was evaluated by the concordance correlation coefficient (CCC). Both techniques were compared by t test of the CCC. RESULTS: 2D and M-mode demonstrated excellent and similar intraobserver repeatability, with the best concordance in ES septal thickness (M mode CCC 0.956 versus 2D-mode CCC 0.914). Interobserver reproducibility demonstrated also a high concordance, optimal in ES left ventricular free wall (M mode 0.925 versus 2 D 0.855). Comparison of both techniques demonstrated a high concordance in all measurements, except for ED septal thickness with better reproducibility using M-mode (CCC 0.954 versus 0.847, p = .017). CONCLUSIONS: 2D and M-mode can be used in a reproducible manner for measuring fetal myocardial thickness, with a slightly better performance of M-mode for assessing ED septal wall thickness. PMID- 29431015 TI - Miami Prospective Memory Test in the Canadian Longitudinal Study on Aging. AB - OBJECTIVE: The aim of this study was to verify the effect of age, education and sex on Miami Prospective Memory Test (MPMT) performance obtained at baseline of the Canadian Longitudinal Study on Aging (CLSA) by neurologically healthy French- and English-speaking subsamples of participants (N = 18,511). METHOD: The CLSA is a nation-wide large epidemiological study with participants aged 45-85 years old at baseline. The MPMT is an event- and time-based measure of prospective memory, with scores of intention, accuracy and need for reminders, administered as part of the Comprehensive data collection. Participants who did not self-report any conditions that could impact cognition were selected, which resulted in 15,103 English- and 3408 French-speaking participants. The samples are stratified according to four levels of education and four age groups (45-54; 55-64; 65-74; 75+). RESULTS: There is a significant age effect for English- and French-speaking participants on the Event-based, Time-based, and Event- + Time-based scores of the MPMT. The effect of the education level was also demonstrated on the three MPMT scores in the English-speaking group. The score 'Intention to perform' was the most sensitive to the effect of age in both the English and French samples. Sex had no impact on performance on the MPMT. CONCLUSIONS: This study confirms the impact of age and level of education on this new prospective memory task. It informs future research with this measure including the development of normative data in French- and English-speaking Canadians on the Event-based and Time-based MPMT. PMID- 29431016 TI - Assessment and management of constipation for patients receiving palliative care in specialist palliative care settings: A systematic review of the literature. AB - BACKGROUND: Constipation is an important issue for patients receiving palliative care within specialist palliative care settings. Questions and ambiguity, however, persist about international best practice and management. AIM: To synthesise the current evidence base on the assessment and management of constipation for palliative care patients within a specialist palliative care setting. DESIGN: This is a systematic review. DATA SOURCES: MEDLINE, Embase, CINAHL, Scopus and Cochrane databases were systematically searched in April 2017 for empirical studies, written in English, on the assessment and management of constipation in specialist palliative care settings, published between 2007 and 2017. Two researchers independently reviewed and critically appraised all studies, conducted data extraction, and undertook a thematic analysis. RESULTS: In total, 13 studies were included in the review comprising randomised trials ( n = 3), observational ( n = 4) and descriptive studies ( n = 6). Most research was conducted in specialist palliative care units, targeting either healthcare professionals or patients. The analysis highlighted a lack of standard definition of constipation, raising questions on the existence and comparability of baseline prevalence figures, the physical and psychological impact on patients, resource impact on staff and service, the subjective and objective methods of assessing constipation, and key aspects of constipation management, including a lack of focus on non-pharmacological management in this setting. CONCLUSION: The results of this review are being used to inform the development of an educational intervention targeting healthcare professionals. Gaps in the evidence base include lack of consistent definition of constipation, constipation prevention, non-pharmacological management, and the consideration of the management of constipation for the dying patient. PMID- 29431017 TI - Touchless computer interfaces in hospitals: A review. AB - The widespread use of technology in hospitals and the difficulty of sterilising computer controls has increased opportunities for the spread of pathogens. This leads to an interest in touchless user interfaces for computer systems. We present a review of touchless interaction with computer equipment in the hospital environment, based on a systematic search of the literature. Sterility provides an implied theme and motivation for the field as a whole, but other advantages, such as hands-busy settings, are also proposed. Overcoming hardware restrictions has been a major theme, but in recent research, technical difficulties have receded. Image navigation is the most frequently considered task and the operating room the most frequently considered environment. Gestures have been implemented for input, system and content control. Most of the studies found have small sample sizes and focus on feasibility, acceptability or gesture-recognition accuracy. We conclude this article with an agenda for future work. PMID- 29431018 TI - Multimodality treatment of operable gastric and oesophageal adenocarcinoma: evaluating neoadjuvant, adjuvant and perioperative approaches. AB - INTRODUCTION: Treatment patterns for locally advanced operable gastric and oesophageal adenocarcinoma vary, with the optimal approach an area of debate within oncology. Strategies for treatment include a variety of neo-adjuvant, adjuvant and peri-operative regimens involving differing chemotherapy and radiotherapy combinations. Areas covered: This review will critically appraise the evidence base underpinning the main treatment approaches in operable oesophagogastric adenocarcinoma, highlighting variations in treatment by factors such as geographical area and primary tumor site. Expert commentary: The expert commentary will focus on the optimal evidence-based approaches for clinicians at the present time and explore how increased understanding of the molecular and genetic determinants of the disease may lead to refinements in treatment through the development of both biomarker-driven approaches and the application of novel targeted and immune-modulating agents to early treatment. PMID- 29431022 TI - Effects of global and local task repetition proportion on n - 2 repetition costs. AB - In task switching research, one of the most straightforward indications for the involvement of inhibitory processes are n - 2 repetition costs. The present study aimed at investigating effects of different types of repetition proportion on n - 2 repetition costs. In Experiments 1 and 2, repetition proportion was varied globally (i.e., equally for all tasks). The occurrence of 33% task repetitions reduced n - 2 repetition costs when varied within as well as between subjects, but no further decline was visible from 33% to 50% task repetitions. This result is interpreted in terms of a shift of balance between task inhibition and task activation due to the occurrence of task repetitions that is independent of the specific repetition proportion. In contrast, when repetition proportion was varied locally (i.e., by differentially manipulating the occurrence of task repetitions for the three tasks involved), n - 2 repetition costs were reduced monotonically from 0% to 50% task repetitions. This result indicates that when the utility inhibition is tied to individual tasks, the cognitive system is able to adjust the deployment of inhibition accordingly, possibly by modulating processes of overcoming inhibition, not releasing it. PMID- 29431023 TI - I before U: Temporal order judgements reveal bias for self-owned objects. AB - A multitude of studies demonstrate that self-relevant stimuli influence attention. Self-owned objects are a special class of self-relevant stimuli. If a self-owned object can indeed be characterised as a self-relevant stimulus then, consistent with theoretical predictions, a behavioural effect of ownership on attention should be present. To test this prediction, a task was selected that is known to be particularly sensitive measure of the prioritisation of visual information: the temporal order judgement. Participants completed temporal order judgements with pictures of "own" and "experimenter" owned objects (mugs) presented on either side of a central fixation cross. There was a variable onset delay between each picture, ranging between 0 ms and 105 ms, and participants were asked to indicate which mug appeared first. The results indicated a reliable change in the point of subjective simultaneity (PSS) in favour of their own mug. Such a change in the PSS was not observed for two groups of participants who were exposed to a mug but did not keep the mug. A further experiment indicated that the source of the bias in PSS was more consistent with a criterion shift or top down attentional prioritisation rather than a perceptual bias. These findings suggest that ownership, beyond mere-touch, mere-choice, or familiarity, leads to prioritised processing and responses, but the mechanism underlying the effect is not likely to be perceptual in nature. PMID- 29431024 TI - Relationship between serostatus disclosure and categories of HIV transmission risk in men who have sex with men living with HIV. AB - In prior studies, the relationship between serostatus disclosure and reduced HIV transmission risk has been mixed. The demonstration of a clear connection may be restricted by three main methodological limitations. This study evaluates the relationship between (1) more refined measures of serostatus disclosure and (2) eight categories of HIV transmission risk (lowest to highest risk) among men who have sex with men (MSM) living with HIV, while (3) considering a number of control variables. Results demonstrate that disclosure is more likely in sexual encounters involving no intercourse or involving protected and unprotected anal intercourse with HIV-positive partners than unprotected insertive anal intercourse with HIV-negative/unknown status partners. Additionally, substance use prior to sexual encounters is less likely in lower risk categories than the highest risk category. Results of this study are important to the design of future studies, prevention, and intervention programs for MSM and to the methods used to evaluate their effectiveness. PMID- 29431025 TI - Highlighting the clinical need for diagnosing Mycoplasma genitalium infection. AB - Despite Mycoplasma genitalium (MG) being increasingly recognised as a genital pathogen in men and women, awareness and utility of commercially available MG testing has been low. The opinion of UK sexual health clinicians and allied professionals was sought on how MG-testing should be used. Thirty-two consensus statements were developed by an expert group and circulated to clinicians and laboratory staff, who were asked to evaluate their level of agreement with each statement; 75% agreement was set as the threshold for defining consensus for each statement. A modified Delphi approach was used and high levels of agreement obviated the need to test the original statement set further. Of 201 individuals who received questionnaires, 60 responded, most (48) being sexual health consultants, more than 10% of the total in the UK. Twenty-seven (84.4%) of the statements exceeded the 75% threshold. Respondents strongly supported MG-testing of patients with urethritis, pelvic inflammatory disease or unexplained persistent vaginal discharge, or post-coital bleeding. Fewer favoured testing patients with proctitis and support was divided for routinely testing Chlamydia positive patients. Testing of current sexual contacts of MG-positive patients was supported, as was a test of cure for MG-positive patients, although agreement fell below the 75% threshold. Respondents agreed that all consultant- or specialist-led services should have access to testing for MG (98.3%). There was strong agreement for having MG-testing available for specific patient groups, which may reflect concern over antibiotic resistance and the desire to comply with clinical guidelines that recommend MG-testing in sexual health clinic settings. PMID- 29431026 TI - The potential of aldehyde dehydrogenase 2 as a therapeutic target in cardiovascular disease. AB - INTRODUCTION: Mitochondrial aldehyde dehydrogenase (ALDH-2) plays a major role in the ethanol detoxification pathway by removing acetaldehyde. Therefore, ALDH-2 inhibitors such as disulfiram represent the first therapeutic targeting of ALDH-2 for alcoholism therapy. Areas covered: Recently, ALDH-2 was identified as an essential bioactivating enzyme of the anti-ischemic organic nitrate nitroglycerin, bringing ALDH-2 again into the focus of clinical interest. Mechanistic studies on the nitroglycerin bioactivation process revealed that during bioconversion of nitroglycerin and in the presence of reactive oxygen and nitrogen species the active site thiols of ALDH-2 are oxidized and the enzyme activity is lost. Thus, ALDH-2 activity represents a useful marker for cardiovascular oxidative stress, a concept, which has been meanwhile supported by a number of animal disease models. Mechanistic studies on the protective role of ALDH-2 in different disease processes identified the detoxification of 4 hydroxynonenal by ALDH-2 as a fundamental process of cardiovascular, cerebral and antioxidant protection. Expert opinion: The most recent therapeutic exploitation of ALDH-2 includes activators of the enzyme such as Alda-1 but also cell-based therapies (ALDH-bright cells) that deserve further clinical characterization in the future. PMID- 29431027 TI - A Controlled Trial of Sheng-Yu-Tang for Post-Hematopoietic Stem Cell Transplantation Leukemia Patients: A Proposed Protocol and Insights From a Preliminary Pilot Study. AB - INTRODUCTION: Hematopoietic stem cell transplantation has become a well established treatment for hematologic disorders including acute leukemia. However, long-term survival rates following this procedure are still extremely low, due to posttransplantation relapse, infections, and graft-versus-host disease. We propose that adjunctive Chinese herbal medicine may benefit posttransplantation patients. In preparation for a randomized clinical trial, we conducted a pilot trial. Methods and Analysis: Between September 2015 and June 2017, 18 patients were consecutively enrolled at China Medical University Hospital and followed for up to 1 year. Fresh blood samples were obtained on a monthly basis, and immune reconstitution was analyzed. In addition to the standard-care treatment administered by their oncologist, a number of patients also received a Chinese herbal formula (Sheng-Yu-Tang) for up to 6 months. Results were used to improve on study protocol and estimate required sample size for a future randomized trial. Ethics and Dissemination: Study protocol was approved by the institutional review board of China Medical University Hospital (DMR-105-005), and all participants provided informed consent. PMID- 29431028 TI - Is the environment in kindergarten associated with the vegetables served and eaten? The BRA Study. AB - AIM: The aim of the present study was to explore the associations between the economic, political, sociocultural and physical environments in kindergartens, along with the frequency and variety of vegetables served, and the amount of vegetables eaten. METHOD: The BRA Study collected data through two paper-based questionnaires answered by the kindergarten leader and pedagogical leader of each selected kindergarten, and a five-day vegetable diary from kindergartens ( n = 73) in Vestfold and Buskerud Counties, Norway. The questionnaires assessed environmental factors, and the frequency and variety of vegetables served. The non-parametric Mann-Whitney U and Kruskal-Wallis tests were used to explore the associations between factors in the kindergarten environments and vegetables served and eaten. RESULTS: Kindergartens that included expenditures for food and beverages in the parental fees served a larger variety of vegetables ( p = 0.046). A higher frequency of served vegetables ( p = 0.014) and a larger amount ( p = 0.027) of vegetables eaten were found in kindergartens where parents paid a monthly fee of 251 NOK or more. Similarly, the amount of vegetables eaten was higher ( p = 0.017) in kindergartens where the employees paid a monthly fee to eat at work. Furthermore, a larger amount ( p = 0.046) of vegetables was eaten in kindergartens that had written guidelines for food and beverages that were offered. CONCLUSIONS: This study indicates that the economic environment in a kindergarten seems to be positively associated with the vegetables served and eaten there. This is of high relevance for public health policy as vegetable consumption is an important factor in reducing the risk of non-communicable diseases. PMID- 29431030 TI - Angiogenic Activity of Human Adipose-Derived Mesenchymal Stem Cells Under Simulated Microgravity. AB - Multipotent mesenchymal stem/stromal cells (MSCs) are strongly involved in tissue homeostasis mainly through paracrine regulation. In this study, we examined the influence of simulated microgravity on the angiogenic potential of adipose derived MSCs (ASCs). The conditioned medium (CM) from random positioning machine (RPM)-exposed ASCs stimulated the formation of vessel network in ovo, endothelial cell (EC) capillary-like network, and nondirected EC migration in vitro. These effects were driven by alteration of both angiogenesis-related gene and protein expression. The elevation of angiogenic regulators Serpin E1, Serpin F1, IGFBP, VEGF, and IL-8 was detected in ASC-CM after 3D-clinorotation. In addition, transcription of genes encoding growth factors with proangiogenic activity were upregulated including VEGF-c and VEGF-a. These data evidenced that besides direct effect on ECs, microgravity could provoke MSC-mediating specific microenvironment for ECs supporting their functions, that is, proliferation and migration via increased production of IL-8 and VEGF as well as other paracrine factors involved in angiogenesis regulation. PMID- 29431031 TI - Impact of cephalosporin restriction on incidence of infections with extended spectrum beta-lactamase-producing Klebsiella pneumoniae in an endemic setting. AB - Decreasing cephalosporin use was described as an effective intervention in decreasing the incidence of infections caused by Klebsiella pneumoniae harbouring extended-spectrum beta-lactamase (ESBLKP). Due to sustained increased levels of infections caused by ESBLKP, a multifaceted antibiotic stewardship intervention aimed to decrease cephalosporin use was carried out at a large medical unit of a teaching hospital. All cephalosporins except the first-generation were restricted and could only be prescribed after authorization by an infectious disease physician. The use of cephalosporins decreased significantly after intervention. The effect was most prominent for the third-generation cephalosporins (7.9-1.5 DDD/100 OBD). There was an increase in the consumption of piperacillin/tazobactam, carbapenems and fluoroquinolones. In contrast to our expectations the ESBLKP incidence increased, but the changes were not statistically significant. The intervention was successful in controlling the prescribing of cephalosporins, but had no impact on incidence of ESBLKP infections. PMID- 29431029 TI - Oversized Biodegradable Arterial Grafts Promote Enhanced Neointimal Tissue Formation. AB - Most tissue-engineered arterial grafts are complicated by aneurysmal dilation secondary to insufficient neotissue formation after scaffold degradation. The optimal graft would form an organized multilayered structure with a robust extracellular matrix that could withstand arterial pressure. The purpose of the current study was to determine how oversizing a biodegradable arterial scaffold affects long-term neotissue formation. Size-matched (1.0 mm, n = 11) and oversized (1.6 mm, n = 9) electrospun polycaprolactone/chitosan scaffolds were implanted as abdominal aortic interposition grafts in Lewis rats. The mean lumen diameter of the 1.6 mm grafts was initially greater compared with the native vessel, but matched the native aorta by 6 months. In contrast, the 1.0 mm grafts experienced stenosis at 6 and 9 months. Total neotissue area and calponin positive neotissue area were significantly greater in the 1.6 mm grafts by 6 months and similar to the native aorta. Late-term biomechanical testing was dominated by remaining polymer, but graft oversizing did not adversely affect the biomechanics of the adjacent vessel. Oversizing tissue-engineered arterial grafts may represent a strategy to increase the formation of organized neotissue without thrombosis or adverse remodeling of the adjacent native vessel by harnessing a previously undescribed process of adaptive vascular remodeling. PMID- 29431032 TI - Decellularized Muscle Supports New Muscle Fibers and Improves Function Following Volumetric Injury. AB - Current strategies to treat volumetric muscle loss use primarily pedicle or free muscle transfers, but these grafts fail to adequately regenerate functional tissue. Decellularized soft tissue grafts possess physical and chemical cues to promote muscle regeneration, suggesting their potential for use in large muscle defects. In this study, we developed a decellularized muscle matrix (DMM) graft using rat gastrocnemius. Anisotropy and chemical components of the extracellular matrix were retained, including laminin, fibronectin, and collagen. We compared the ability of DMM, autologous muscle grafts (clinical standard), and type I collagen plugs (negative control) to support muscle regeneration. DMM supported regeneration over a 56-day period in 1 * 1 cm and 1.5 * 1 cm gastrocnemius defects in rats. Muscle function tests demonstrated improved muscle recovery in rats with DMM grafts when compared to collagen. Histological sections were assessed using morphometrics and immunostaining. DMM supported muscle regeneration with less fibrosis and more de novo neuromuscular receptors than either autograft or collagen. Overall, our results indicate that DMM may be used as a muscle replacement graft based on its ability to improve muscle function recovery, promote muscle regeneration, and support new neuromuscular junctions. PMID- 29431033 TI - Hotspots of road traffic crashes in a redeveloping area of Shanghai. AB - To identify high-risk locations (hotspots) of road traffic crashes (RTC) in a redeveloping area of Shanghai, for formulating relevant countermeasures in similar areas. After geocoding the crash locations on electronic map, assessment of spatial clustering of accidents and hotspots spatial densities was conducted following Moran's I method, the kernel density estimation, the Ripley's K function and the network-based kernel density estimation (NKDE). A total of 21,679 RTC incidents resulting in 24,147 victims were recorded from 2010 to 2012. RTCs tended to occur among male (81.8%) aged 20-49 years old (84.9%) riding buses (60.1%) or electric bikes (16.1%) in working time (15%). The network spatial analysis pinpointed the hotspots of RTC at the street level in the Songjiang new urban area, and more RTCs occurred at road intersections than on road segments. Findings from this research may help the authorities develop efficient programmes to target high-risk locations and specific vulnerable populations. PMID- 29431035 TI - Patient perspectives on electronic health record accessibility and patient participation: a questionnaire survey. AB - Objectives To explore patient perceptions on personal comfort with participation in their own care process and on support of this patient participation through electronic health record (EHR) accessibility. Methods Explorative quantitative questionnaire study in ambulatory patients visiting the departments of General Internal Medicine or Head, Neck and Maxillo-Facial Surgery of a Belgian tertiary referral center. Results Patients were recruited by convenience sampling of 438 out of the total of 1270 patients visiting either one of these departments within a time period of two weeks. Overall response rate was 97.3% (n = 426; 45.3% male; mean age 42.5 +/- 15.4 years). Most patients (89.7%) indicated a desire to make healthcare decisions in partnership with their physician. They were in need of transparent and comprehensible health information. The EHR was perceived as a suitable and effective means to inform patients about their health and to increase involvement in care and treatment (77.6%). Furthermore, access to the EHR was perceived to result in a more effective communication transfer between physician and patient (65.5%), increased patient compliance (64.3%), and satisfaction (57.4%). Conclusion Patients indicate a desire for proactive participation in their individual care process. They felt that medical record accessibility could support decision-making and assist in managing and coordinating individual and personalized care choices. PMID- 29431036 TI - Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma and predictors of survival. AB - BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) benefits selected patients with peritoneal mesothelioma. We present the outcomes of this treatment strategy in a UK peritoneal malignancy national referral centre. METHODS: Observational retrospective analysis of data prospectively collected in a dedicated peritoneal malignancy database between March 1998 and January 2016. RESULTS: Of 1586 patients treated for peritoneal malignancy, 76 (4.8%) underwent surgery for peritoneal mesothelioma. Median age was 49 years (range 21-73 years). 34 patients (45%) were female. Of the 76 patients, 39 (51%) had low grade histological subtypes (mostly multicystic mesothelioma), and 37 (49%) had diffuse malignant peritoneal mesothelioma (DMPM; mostly epithelioid mesothelioma). Complete cytoreduction was achieved in 52 patients (68%) and maximal tumour debulking (MTD) was performed in 20 patients (26%); the remaining 4 patients (5%) underwent a laparotomy with biopsy only. HIPEC was administered in 67 patients (88%). Median overall (OS) and disease-free survival (DFS) after CRS was 97.8 (80.2-115.4) and 58.8 (47.4-70.3) months, respectively. After complete cytoreduction, 100% overall survival was observed amongst patients with low-grade disease. Ki-67 proliferation index was significantly associated with survival outcomes after complete cytoreduction for DMPM and was an independent predictor of decreased survival. CONCLUSION: With adequate patient selection (guided by histological classification and Ki-67 proliferation index) and complete cytoreduction with HIPEC, satisfactory outcomes can be achieved in selected patients with peritoneal mesothelioma. PMID- 29431037 TI - Practice-Changing Strategies to Deliver Affordable, High-Quality Cancer Care: Summary of an Institute of Medicine Workshop. AB - The authors summarize presentations and discussion from the Delivering Affordable Cancer Care in the 21st Century workshop and focus on proposed strategies to improve the affordability of cancer care while maintaining or improving the quality of care. PMID- 29431038 TI - Financial Distress, Use of Cost-Coping Strategies, and Adherence to Prescription Medication Among Patients With Cancer. AB - The authors found that cost-related medication nonadherence was prevalent among patients with cancer who sought financial assistance. PMID- 29431039 TI - Reprise: Transformation. PMID- 29431040 TI - Can Patients Afford to Be Adherent to Expensive Oral Cancer Drugs?: Unintended Consequences of Pharmaceutical Development. PMID- 29431041 TI - The National Practice Benchmark for Oncology, 2013 Report on 2012 Data. AB - Today, in the face of price and quality pressures, it is necessary that every oncology business unit produce, monitor, and benchmark basic metrics to meet current business pressures for increased efficiency and efficacy of care. PMID- 29431042 TI - Practice Benchmarking in the Age of Targeted Auditing: Radiation Oncology. AB - The authors conclude that there is no substitute for staying up to date on proper billing methodology and investing in continuing education for coders, billing personnel, and clinical staff, including physicians. PMID- 29431043 TI - The Oncology Ecosystem: Oncology Practice Trends From the National Practice Benchmark. AB - Practices that participate in the National Practice Benchmark and are engaged in the management of their business in their local market will exhibit greater resilience, adaptability, and transformability than those who do not actively measure and manage. PMID- 29431044 TI - Meaningful Physician Payment Reform in Oncology. AB - The authors describe various new models of physician payment that can serve as a foundation for a shift away from the current reimbursement system for cancer care to support better outcomes and avoid preventable costs, as well as how these reforms can be supported in a blended payment model that transitions away from but still contains elements of fee-for-service payments. PMID- 29431045 TI - Journal Correction. PMID- 29431046 TI - Intermediate Care Units: A Survey of Organization Practices Across the United States. AB - PURPOSE: Intermediate care units (IMCUs) represent an alternative care setting with nurse staffing levels between those of the general ward and the intensive care unit (ICU). Despite rising prevalence, little is known about IMCU practices across US hospitals. The purpose of this study is to characterize utilization patterns and assess for variation. MATERIALS AND METHODS: A 14-item survey was distributed to a random nationwide sample of pulmonary and critical care physicians between January and April 2017. RESULTS: A total of 51 physicians from 24 different states completed the survey. Each response represented a unique institution, the majority of which were public (59%), academic (73%), and contained at least 1 IMCU (65%). Of the IMCUs surveyed, 58% operated as 1 mixed unit that admitted medical, cardiac, and surgical patients as opposed to having separate subspecialty units. Ninety-one percent of units admitted step-down patients from the ICU, but 39% of units accepted a mix of step-up patients, step down patients, postoperative patients, and patients from the emergency department. Intensivists managed care in 21% of units whereas 36% had no intensivist involvement. CONCLUSION: Organization practices vary considerably between IMCUs across institutions. The impact of different organization practices on patient outcomes should be assessed. PMID- 29431047 TI - CAR T-cells for cancer therapy. AB - Chimeric antigen receptor (CAR) T-cells are redirected T-cells that can recognize cancer antigens in a major histocompatibility complex (MHC)-independent fashion. A typical CAR is comprised of two main functional domains: an extracellular antigen recognition domain, called a single-chain variable fragment (scFv), and an intracellular signaling domain. Based on the number of intracellular signaling molecules, CARs are categorized into four generations. CAR T-cell therapy has become a promising treatment for hematologic malignancies. However, results of its clinical trials on solid tumors have not been encouraging. Here, we described the structure of CARs and summarized the clinical trials of CD19-targeted CAR T cells. The side effects, safety management, challenges, and future prospects of CAR T-cells for the treatment of cancer, particularly for solid tumors, were also discussed. PMID- 29431048 TI - Bayesian estimation of ELISA and gamma interferon test accuracy for the detection of bovine tuberculosis in caudal fold test-negative dairy cattle in Kuwait. AB - Bovine tuberculosis (TB) is endemic in Kuwait; cattle identified as TB-positive using the caudal fold test (CFT) are culled. We used a Bayesian approach to estimate the sensitivity (Se) and specificity (Sp) of the IFNgamma assay and ELISA, which are not routinely used in Kuwait in CFT-negative dairy cattle. Blood samples from CFT-negative cattle ( n = 384) collected from 38 dairy farms were tested by IFNgamma assay and ELISA. The Se and Sp (95% CI) of the IFNgamma were 85.0% (67.6-95.3%) and 90.4% (86.7-95.3%), respectively, whereas estimates for the ELISA were 61.1% (33.1-84.6%) and 85.4% (81.7-88.8%). TB prevalence (95 CI%) in CFT-negative cattle was estimated as 2.6% (0.5-9.5%). The IFNgamma assay may play a role as an ancillary test for the identification of Mycobacterium bovis infected cattle that are undetected by CFT. PMID- 29431049 TI - Vitamin D supplementation attenuates the behavioral scores of neuropathic pain in rats. AB - OBJECTIVE(S): Neuropathic pain due to lesion or dysfunction of the peripheral or central nervous system is often refractory to the conventional analgesics. Currently, there is no proven treatment to prevent or cure neuropathic pain. A recent surge of new data suggests the potential effects of vitamin D in the medical community. This study was designed to determine whether acute or chronic vitamin D administration was effective in alleviating symptoms of neuropathic pain in a rat model of neuropathic pain. MATERIALS AND METHODS: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in the rats that resulted in thermal hyperalgesia, mechanical, and cold allodynia. RESULTS: Acute vitamin D injections (250, 500, and 1000 unit/kg i.p.) on the 7th, 14th, and 21st postoperative days could not attenuate mechanical and cold allodynia as well as heat hyperalgesia compared to CCI group. But when vitamin D (1000 unit/kg i.p.) administration was started on the first day after surgery and given daily until the 21st day, cold allodynia and heat hyperalgesia considerably were attenuated. However, no differences in paw withdrawal thresholds were observed. CONCLUSION: These results indicate that chronic vitamin D administrations can attenuate the behavioral scores of neuropathic pain in rats. PMID- 29431050 TI - TDP-43 post-translational modifications in health and disease. AB - INTRODUCTION: Nuclear factor TDP-43 is a ubiquitously expressed RNA binding protein that plays a key causative role in several neurodegenerative diseases, especially in the ALS/FTD spectrum. In addition, its aberrant aggregation and expression has been recently observed in other type of diseases, such as myopathies and Niemann-Pick C, a lysosomal storage disease. Areas covered: This review aims to specifically cover the post-translational modifications (PTMs) that can affect TDP-43 function and cellular status both in health and disease. To this date, these include phosphorylation, formation of C-terminal fragments, disulfide bridge formation, ubiquitination, acetylation, and sumoylation. Recently published articles on these subjects have been reviewed in this manuscript. Expert opinion: Targeting aberrant TDP-43 expression in neurodegenerative diseases is a very challenging task due to the fact that both its overexpression and downregulation are considerably toxic to cells. This characteristic makes it difficult to therapeutically target this protein in a generalized manner. An alternative approach could be the identification of specific aberrant PTMs that promote its aggregation or toxicity, and developing novel therapeutic approaches toward their selective modification. PMID- 29431051 TI - Intracranial and Extracranial Injury Burden as Drivers of Impaired Cerebrovascular Reactivity in Traumatic Brain Injury. AB - Impaired cerebrovascular reactivity has been associated with outcome following traumatic brain injury (TBI), but it is unknown how it is affected by trauma severity. Thus, we aimed to explore the relationship between intracranial (IC) and extracranial (EC) injury burden and cerebrovascular reactivity in TBI patients. We retrospectively included critically ill TBI patients. IC injury burden included detailed lesion and computerized tomography (CT) scoring (i.e., Marshall, Rotterdam, Helsinki, and Stockholm Scores) on admission. EC injury burden was characterized using the injury severity score (ISS) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC were used to assess autoregulation/cerebrovascular reactivity. We used univariate and multi-variate logistic regression techniques to explore relationships between IC and EC injury burden and autoregulation indices. A total of 358 patients were assessed. ISS and all IC CT scoring systems were poor predictors of impaired cerebrovascular reactivity. Only subdural hematomas and thickness of subarachnoid hemorrhage (SAH; p < 0.05, respectively) were consistently associated with dysfunctional cerebrovascular reactivity. High age (p < 0.01 for all) and admission APACHE II scores (p < 0.05 for all) were the two variables most strongly associated with abnormal cerebrovascular reactivity. In summary, diffuse IC injury markers (thickness of SAH and the presence of a subdural hematoma) and APACHE II were most associated with dysfunction in cerebrovascular reactivity after TBI. Standard CT scoring systems and evidence of macroscopic parenchymal damage are poor predictors, implicating potentially both microscopic injury patterns and host response as drivers of dysfunctional cerebrovascular reactivity. Age remains a major variable associated with cerebrovascular reactivity. PMID- 29431052 TI - Corrigendum. PMID- 29431055 TI - Medically Unlikely Edits. PMID- 29431053 TI - Nanoparticle-Mediated Cell Capture Enables Rapid Endothelialization of a Novel Bare Metal Stent. AB - Incomplete endothelialization of intracoronary stents has been associated with stent thrombosis and recurrent symptoms, whereas prolonged use of dual antiplatelet therapy increases bleeding-related adverse events. Facilitated endothelialization has the potential to improve clinical outcomes in patients who are unable to tolerate dual antiplatelet therapy. The objective of this study was to demonstrate the feasibility of magnetic cell capture to rapidly endothelialize intracoronary stents in a large animal model. A novel stent was developed from a magnetizable duplex stainless steel (2205 SS). Polylactic-co-glycolic acid and magnetite (Fe3O4) were used to synthesize biodegradable superparamagnetic iron oxide nanoparticles, and these were used to label autologous blood outgrowth endothelial cells. Magnetic 2205 SS and nonmagnetic 316L SS control stents were implanted in the coronary arteries of pigs (n = 11), followed by intracoronary delivery of magnetically labeled cells to 2205 SS stents. In this study, we show extensive endothelialization of magnetic 2205 SS stents (median 98.4% cell coverage) within 3 days, whereas the control 316L SS stents exhibited significantly less coverage (median 48.9% cell coverage, p < 0.0001). This demonstrates the ability of intracoronary delivery of magnetic nanoparticle labeled autologous endothelial cells to improve endothelialization of magnetized coronary stents within 3 days of implantation. PMID- 29431057 TI - Evolution in the management of thyroid cancer: an observational study in two referral centres in Belgium. AB - Objective Thyroid cancer incidence is increasing. The rise is most pronounced for microcancers (<=10 mm, T1a). In 2006, landmark European and American guidelines for the management of thyroid cancer were published. We studied thyroid cancer characteristics and initial management before and after 2006. Methods We conducted a retrospective observational study of non-medullary thyroid cancer patients that underwent thyroidectomy in two Belgian referral centres comparing pre-, per- and post-operative management in a cohort before and after 2006. Results Cancer subtypes and dimensions in cohort 1 (C1, n = 69) and cohort 2 (C2, n = 60) were comparable, with papillary thyroid cancer (PTC) as main subtype (86 and 82%, respectively), and T1a as main dimension (30 and 38%). In C2, a comparable proportion presented as incidentaloma (20 vs. 14% in C1). Pre-surgical fine needle aspiration (FNA) was performed in 75% in C1 and 83% in C2. The indications for thyroidectomy were comparable, with Bethesda 5-6 as main indication (43% in C1, 52% in C2). No differences were observed for execution of lymph node dissection in the PTC subgroup, hypoparathyroidism and recurrent nerve paresis after 1 year. Less radioiodine was administered in C2 (57 vs 74% in C1, p = 0.04). More neck ultrasonography at 1 year was performed in >T1aN0/x patients (73 vs 49% in C1, p = 0.02). Conclusion The use of FNA is high and established. The proportion of T1a cancers is stable. A shift in the post-operative management is observed towards more restrictive use of radioiodine and increased use of ultrasonography, in accordance with the international guidelines. PMID- 29431056 TI - Characteristics of systemic lupus erythematosus in a sample of the Egyptian population: a retrospective cohort of 1109 patients from a single center. AB - Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that can vary among different ethnic and racial groups. Objective The objective of this paper is to study the prevalence of various manifestations of SLE in a sample of the Egyptian population. Patients and methods Information in this study was derived from the medical records of SLE patients who sought medical advice at a private clinic in Cairo from January 1980 to June 2016. Results This study included 1109 SLE patients, of whom 114 (10.3%) were males and 995 were females (89.7%). Mean age of onset was 25.89 +/- 10.81 years, while the median of disease duration from the onset of the disease till the last recorded visit was 26 months. The most common cumulative manifestations were arthritis (76.7%), malar rash (48.5%), leukopenia (45.7%), and photosensitivity (45.6%). A total of 33.1% of the patients had nephritis, and neuropsychiatric lupus was present in 6.4% of the patients. Secondary antiphospholipid syndrome was present in 11.5% of the patients. Antinuclear antibody and anti-double-stranded deoxyribonucleic acid were present in 1060/1094 (96.9%) and 842/1062 (79.3%) of the patients, respectively. Antiphospholipid antibodies were present in 266/636 (41.8%) of the patients, anti-Smith in 54/240 (22.5%), anti-SSA/Ro in 61/229 (20.4%), and anti-SSB/La in 32/277 (11.6%) of the patients. Male patients had a statistically higher prevalence of nephritis ( p = 0.01), whereas arthritis and alopecia were statistically higher in females ( p = 0.012 and p = 0.006, respectively). Patients with juvenile onset had a statistically higher prevalence of nephritis and seizures ( p < 0.001 and p = 0.012, respectively). Conclusions Arthritis and malar rash represented the most common clinical manifestations. Male and juvenile-onset patients had a predilection toward a more severe disease. These results are in agreement with many studies conducted in the Middle East and worldwide. On the other hand, major organ involvement was exceptionally low, which is contradictory to several reports from the Middle East and across the globe. PMID- 29431058 TI - Three decades of Cognition & Emotion: A brief review of past highlights and future prospects. AB - Over the past three decades, Cognition & Emotion has been one of the world's leading outlets for emotion research. In this article, we review past highlights of and future prospects for the journal. Our tour of history covers three periods: The first period, from 1987 to 1999, was a pioneering era in which cognitive theories began to be applied to the scientific analysis of emotion. The second period, from 2000 to 2007, was characterised by a sharp increase in the number of empirical research papers, a lot of which were concerned with automatic processing biases and their implications for clinical psychology. During the third period, from 2008 to 2017, a new focus emerged on self-regulatory processes and their implications for emotion. We then turn to the present profile of Cognition & Emotion and introduce our new editorial team. Finally, we consider how the journal's future success can be continued and increased by a) providing authors with fast and high-quality feedback; b) offering attractive publication formats, including the newly introduced Registered Reports for pre-registered studies; and c) consolidating key methodological paradigms with reproducible findings. PMID- 29431059 TI - Superficial vein thrombosis. PMID- 29431060 TI - DNA Damage in Wistar Rats Exposed to Organophosphate Pesticide Fenthion. AB - In the last several decades, exposure to pesticides has become a concern to environmental and human health. Many pesticides are environmentally persistent and are characterized by varying degrees of toxicity and adverse effects, including DNA damage. The present study was undertaken to evaluate the genotoxic potential of organophosphate pesticide fenthion in Wistar rats, as assessed by the comet assay. Adult male Wistar rats were treated with a solution of fenthion at a concentration of 40 mg/kg/day, administered intraperitoneally for 18 consecutive days. Rats were killed 24 hours after the last pesticide administration, and the comet assay was performed in peripheral blood cells. The comet assay results revealed that the damage index (19.29 +/- 3.59 vs. 7.80 +/- 2.25) and the damage frequency (17.00 +/- 3.46 vs. 7.5 +/- 2.46) found in fenthion-treated rats were significantly higher than those found in the control group (p = 0.001 and p = 0.0006, respectively). The results show that fenthion affects the DNA integrity of rat cells and may induce DNA damage in exposed organisms. PMID- 29431061 TI - Oral Insulin: Current Status, Challenges, and Future Perspectives. AB - Oral delivery of insulin is one of the most promising and anticipated areas in the treatment of diabetes, primarily because it may significantly improve the quality of life of diabetics who receive insulin regularly. Several problems have been reported regarding the subcutaneous delivery of insulin, ranging from cardiovascular complications to weight gain. One of the approaches to overcoming these issues is to administer insulin through the oral route. However, there are several challenges in developing an oral route for insulin delivery; insulin has extremely poor bioavailability and a low diffusion rate through the mucus layer. A wide range of oral insulin delivery techniques have recently been researched, ranging from nanoparticles to liposomes, self-emulsifying systems, and hydrogels. These techniques have shown promising potential in the oral delivery of insulin. This review considers the current literature on the advances and challenges in the development of oral insulin. PMID- 29431062 TI - The Hepatoprotective Effect of Clidemia hirta against Carbon Tetrachloride (CCl4) Induced Oxidative Stress and Hepatic Damage in Mice. AB - Liver diseases still represents a major health burden worldwide. Moreover, medicinal plants have gained popularity in the treatment of several diseases, including liver disease. Clidemia hirta possesses many medicinal properties for healing several diseases and for health maintenance. However, the hepatoprotective effects and antioxidative potential of C. hirta have not been fully investigated. In the present study, we evaluated the hepatoprotective and antioxidative potential of C. hirta against carbon tetrachloride (CCl4)-induced liver injuries and oxidative damage in a murine model. Various biochemical changes associated with liver damage and oxidative stress were measured. The mice were pretreated for 14 consecutive days with aqueous extract of C. hirta at selected doses (150 mg/kg body weight [b.w.], 300 mg/kg b.w. and 600 mg/kg b.w.) followed by two doses of CCl4 (1.0 mL/kg b.w.) orally on days 14 and 15. All animals were sacrificed 24 hours after the last dose of CCl4 or saline. Blood and liver tissues were taken quickly for biochemical and histopathological studies to assess the derangement in the functioning of liver. The development of oxidative stress was observed through the escalation of hepatic lipid peroxidation, depletion of glutathione, and reduced antioxidant enzymes (glutathione peroxidase, glutathione reductase, catalase, glutathione S-transferase and quinone reductase). Hepatic damage was evaluated by measuring serum transaminase (ALT and AST). In addition, CCl4-induced hepatic damage was further evaluated using histopathological assessments. However, most of these changes were dependently ameliorated by the pretreatment of mice with a C. hirta dose. These results indicate that the hepatoprotective effect of C. hirta might be due to its antioxidant and free-radical scavenging properties. PMID- 29431063 TI - Is It a Protective Factor of Helicobacter pylori Infection in Overall Survival of All Gastric Cancer? Evidence from Meta-Analysis. AB - Purpose - We aimed to assess whether Helicobacter pylori infection influences prognosis in gastric cancer patients (GC). Methods - We systematically searched MEDLINE, PubMed, EBSCO, EMBASE, and the Cochrane Library (CENTRAL) Register from inception to June 1, 2017. Overall survival (mean OS) or disease-free survival (mean DFS) in GC patients were calculated using the hazard ratio (HR) and 95% confidence intervals (95% CIs). Results - In total, 19 articles with 4,321 GC patients were enrolled. Helicobacter pylori infection is associated with longer OS (HR 0.73; 95% CI 0.60-0.89; P < 0.001) and DFS (HR 0.75; 95% CI 0.53-1.07; P = 0.002) in GC patients overall. For our subgroup analysis, the pooled HRs and 95% CIs were as follows: China (OS: HR 0.95; 95% CI 0.63-1.42; P = 0.804 and DFS: HR 0.88; 95% CI 0.50-1.56; P = 0.658), Europe (OS: HR 0.69; 95% CI 0.52-0.92; P = 0.010 and DFS: HR 0.62; 95% CI 0.32-1.17; P = 0.141), United States (OS: HR 0.77: 95% CI 0.56-1.06; P = 0.105), Korea (OS: HR 0.45; 95% CI 0.27-0.75; P = 0.002 and DFS: HR 0.45; 95% CI 0.24-0.83, P = 0.011), and Turkey (OS: HR 0.94; 95% CI 0.52 1.70; P = 0.839 and DFS: HR 0.95; 95% CI 0.53-1.71, P = 0.864). Moreover, for R0 or M0 patients, H. pylori infection is associated with better OS and DFS (P all values < 0.05). Conclusions - Helicobacter pylori infection has a better prognosis in GC patients from Korea and Europe. Helicobacter pylori infection has no association with prognosis for China, the United States, or Turkey. Also, H. pylori infection has a better prognosis in R0 resection or M0 GC patients. PMID- 29431064 TI - Correlative Studies Unravelling the Possible Mechanism of Cell Death in Tideglusib-Treated Human Ovarian Teratocarcinoma-Derived PA-1 Cells. AB - This study aims to unravel the use of GSK-3 inhibitors as viable apoptotic inducers for teratocarcinoma-derived ovarian PA-1 cells. MTT assay was carried out to assess inhibitory concentrations of LiCl and TDG. AO/EB staining and Hoechst 33258 staining were employed to assess the damage. Mitochondrial membrane potential (DeltaPsim) and ROS generation were assessed with IC50 concentrations of LiCl and TDG. Tumor-related genes (p53, p21, IL-8, TNF-alpha, MMP-2, Fas-L, Cox-2, and caspase-3) were assessed with 1/4 IC50, 1/2 IC50, IC50 concentrations by semi-quantitative RT- PCR. Cell cycle analysis was performed with IC50 concentration of LiCl and TDG. Western blot analysis was performed for caspase-3, caspase-7, caspase-9, PARP to estimate the possible damage induced by GSK-3 inhibitors and regulation of GSK-3beta, pGSK-3beta, Cox-2. GSK-3 inhibitors demonstrated a concentration and time-dependent reduction in cell viability, exhibiting significant ROS generation and reduced DeltaPsim at their IC50 values. Substantial concentration-dependent gene expression changes with significant upregulation of P21, Cox-2, TNF-alpha, caspase-3, Fas-L were observed. Protein expression of caspase-3 caspase-7, caspase-9, PARP exhibited significant cleavage in LiCl and TDG-treated cells. Protein expression of Cox-2 was significantly increased in IC50 concentration of TDG. Cell cycle analysis showed significant accumulation of cells at sub-G0-G1. PMID- 29431065 TI - Dual Roles of Oxidative Stress in Metal Carcinogenesis. AB - It has been well established that environmental and occupational exposure to heavy metal causes cancer in several organs. Although the exact mechanism of heavy metal carcinogenesis remains elusive, metal-generated reactive oxygen species (ROS) are essential. ROS can play two roles in metal carcinogenesis; two stages in the process of metal carcinogenesis differ in the amounts of ROS activating a dual redox-mediated mechanism. In the early stage of metal carcinogenesis, ROS acts in an oncogenic role. However, in the late stage of metal carcinogenesis, ROS plays an antioncogenic role. Similarly, NF-E2-related factor 2 (Nrf2) also has two different roles, which makes it a key molecule for separating metal carcinogenesis into two different stages. In the early stage, inducible Nrf2 fights against elevated ROS to decrease cell transformation by its antioxidant protection property. In the late stage, constitutively activated Nrf2 manipulates reduced ROS to perform a comfortable environment for apoptosis resistance through an oncogenic role. Interestingly, a cunning carcinogenic mechanism takes advantage of the dual role of Nrf2 to implement the dual role of ROS through a series of redox adaption mechanisms. In this review, we discuss the paradox in the rationales behind the two opposite ROS roles and focus on their potential pharmacological application. The dual role of ROS represents a 'double edged sword' with many possible novel ROS-mediated strategies in cancer therapy in metal carcinogenesis. PMID- 29431066 TI - A Polysaccharide Isolated from Mycelia of the Lion's Mane Medicinal Mushroom Hericium erinaceus (Agaricomycetes) Induced Apoptosis in Precancerous Human Gastric Cells. AB - Hericium erinaceus is typically used in traditional Chinese medicine for mucosal protection, healing of gastric ulcers, and treatment of gastritis. We purified from the cultured mycelia of H. erinaceus a polysaccharide with anti-gastric ulcer and antigastritis activity, but its effects on gastric malignancy have not been elucidated. We examined the differential effects of this purified polysaccharide, named EP-1, on the human gastric (GES-1) cell line and a precancerous cell line (MC) that was transformed from GES-1 using N-methyl-N' nitro-N-nitrosoguanidine. We observed that the polysaccharide potently induced cell apoptosis and cell cycle arrest at the G0/G1 phase in the MC cell line but did not have any effect on the GES-1 cell line at the same doses. Further mechanistic studies revealed that the polysaccharide exerted its activity through an apoptosis-associated pathway by modulating the expression of Bax, Bcl-2, and caspase-3. Differential effects of the polysaccharide on the GES-1 and MC cell lines indicate that the polysaccharide was effective in preventing gastric cancer progression. PMID- 29431067 TI - Identification of Chinese Caterpillar Medicinal Mushroom, Ophiocordyceps sinensis (Ascomycetes) from Counterfeit Species. AB - Ophiocordyceps sinensis is a valuable traditional Chinese medicine with a high market price. In this study, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method based on 2 enzymes was developed to distinguish O. sinensis from 6 common counterfeit species. To verify the applicability of this method, we experimentally tested O. sinensis organisms, tablet preparations made from O. sinensis, and cultured mycelia isolated from O. sinensis. To validate the results from this PCR-RFLP method, all real samples were identified by internal transcribed spacer sequencing. This is, to our knowledge, the first time the PCR-RFLP method has been applied to identify O. sinensis. The selection of 2 restrictive enzymes for identification dramatically improved the accuracy and efficiency of this method. It is the great advantage of this method that sampling from either of 2 parts of O. sinensis-the fruiting body or the caterpillar body-would not cause any difference in the final experimental results. Therefore, this method is not only feasible for testing crude drugs of O. sinensis but it is also useful when the crude drugs are broken down into powder or made into tablets, demonstrating the promising prospect of application in quality control. PMID- 29431068 TI - Blood Glucose-Reducing and Fat-Reducing Effects of a Novel Medicinal Mushroom, Grifola gargal (Agaricomycetes). AB - Grifola gargal Singer is a medicinal mushroom with biological effects such as antiatherogenic and antiosteoporotic activities. The objective of this study was to examine a blood glucose-reducing effect and a fatreducing effect of G. gargal supplementation in vivo. The effects of G. gargal powder (GGP) in a high molecular weight hot water extract (GGH) and a low-molecular weight hot water extract (GGL) on blood glucose were investigated in streptozotocin (STZ)-induced diabetic ICR mice (STZ diabetic mice). A significant decrease in blood glucose was observed after 5 weeks of GGL supplementation (fraction with a molecular weight <= 6000 Da) in STZ diabetic mice. In the next test, we examined the antihyperglycemic and fat-reducing effects of GGL in diet-induced obesity (DIO) mice fed a high-fat diet. GGL facilitated reductions in blood glucose and body fat. This study confirms, to our knowledge for the first time, that administration of G. gargal extract has antihyperglycemic and body fat-reducing effects in STZ diabetic mice and DIO mice. Therefore, G. gargal is a promising functional food to prevent and treat diabetes and lifestyle-related diseases. PMID- 29431070 TI - Acute Toxicity Study and the In Vitro Cytotoxicity of a Black Lingzhi Medicinal Mushroom, Amauroderma rugosum (Agaricomycetes), from Malaysia. AB - Amauroderma rugosum is a wild medicinal mushroom also known as budak cendawan sawan. Members of the indigenous Malaysian Temuan community wear the fresh stipes as a necklace to prevent epileptic seizure and unremitting crying by babies. In our previous studies, A. rugosum exhibited significant antioxidant and anti inflammatory activities. The aim of this study was to determine the toxicity (in the event that a stipe is accidentally bitten) and cytotoxicity of this mushroom on Sprague-Dawley rats and selected cell lines. A. rugosum was orally administered to test chemicals according to Organisation for Economic and Co operation and Development guidelines (TG 425, adopted October 3, 2008). Blood samples were hematologically and biochemically analyzed and multiple tissue sections from each organ were examined using light microscopy. Cytotoxicity of various A. rugosum extracts was also determined against MCF-7 and A-549 cell lines. Our results showed that oral administration of a single dose of mycelial powder (2000 mg/kg) had no adverse effect on the growth rate or hematological and clinical biochemical parameters. Histological studies showed that the treatments did not induce any pathological changes in the organs of the tested animals. All the treated rats survived beyond the 14-day observation period. Methanol and cold and hot water extracts of the freeze-dried mycelial culture of A. rugosum exhibited no or little cytotoxic effect against the MCF-7 and A-549 cell lines. PMID- 29431069 TI - Analysis of Antibacterial Activity and Bioactive Compounds of the Giant Mushroom, Macrocybe gigantea (Agaricomycetes), from India. AB - The antibacterial activity, phenolic profile, and bioactive compounds of fruiting bodies from 2 strains (MA1 and MA2) of the giant mushroom Macrocybe gigantea were evaluated to access their nutraceutical efficacy. The antibacterial activity was higher in MA2 against all selected pathogenic bacteria. Selected phenolics were analyzed by high-performance liquid chromatography coupled with ultraviolet visible detection. Gallic acid, ferulic acid, quercetin, p-hydroxy benzoic acid, cinnamic acid, and rutin contents (micrograms per gram dry weight) were quantified. Quercetin and rutin were absent in both strains of M. gigantea. M. gigantea MA2 showed relatively higher phenolic content (915.8 MUg/g dry weight) than M. gigantea MA1 (854.4 MUg/g dry weight). Among the phenolics, gallic acid is found in the largest amount; in M. gigantea MA2, it was 847.9 +/- 2.67 MUg/g dry weight. Gas chromatography-mass spectrometry analysis showed the presence of bioactive compounds in both strains; most compounds were antibacterial. Thus, the selected strains of M. gigantea can combat oxidative damage and can be used in foods, pharmaceuticals, and cosmetics because of their antioxidant potential. PMID- 29431071 TI - Lipid-Modulating Effect of Black Lingzhi Medicinal Mushroom, Amauroderma rugosum (Agaricomycetes), on Oleate-Induced Human Hepatocellular Liver Carcinoma Cells. AB - Dyslipidemia is the key precursor of atherosclerotic cardiovascular disease. The aim of this study was to investigate the lipid-modifying potential of organic solvent-partitioned extracts from fruiting bodies of Amauroderma rugosum in vitro using oleate-induced human hepatocellular liver carcinoma (HepG2) cells. Our results demonstrated that oleate-induced HepG2 cells treated with ethyl acetate (EA) extract greatly decreased intracellular and secreted total triglyceride (TG) and total cholesterol (TC) compared with other extracts. Further investigation of cellular expression of selected apolipoproteins also revealed that oleate-induced HepG2 cells treated with the EA extract best attenuated the apolipoprotein (Apo) profile by downregulating ApoB-100 and ApoE while upregulating ApoA1. Because both ApoB-100 and ApoE are key components of low-density lipoprotein (LDL) and very LDL (VLDL), which are recognized as "bad cholesterol," this result indicates that treatment with the EA extract inhibited LDL and VLDL production in oleate induced HepG2 cells. On the other hand, increasing ApoA1 evidence shows antiatherogenic benefits to increasing ApoA1, the key component of high-density lipoprotein (HDL), particularly in relation to its role in promoting reverse cholesterol transport and preventing LDL oxidation; this indicates that the EA extract upregulated the production of HDL ("good cholesterol"). Hence, the EA extract is a good source of lipid-ameliorating agents in the management of dyslipidemia. PMID- 29431072 TI - Extraction Optimization, Composition Analysis, and Antioxidation Evaluation of Polysaccharides from White Jelly Mushroom, Tremella fuciformis (Tremellomycetes). AB - We investigated the sonication-assisted extraction (SAE) conditions of Tremella fuciformis polysaccharides. Single-factor experiments showed that the optimal sonication intensity was 6 W/cm2; the other SAE conditions were further optimized using response surface experimental design. A Box-Behnken experiment exhibited that the optimal SAE conditions were temperature, 85 degrees C; ratio of liquid to solid, 46 mL/g; and sonication time, 2 hours. The maximal polysaccharide yield (8.95 g/100 g) was obtained under the optimal extraction conditions. Polysaccharides extracted by sonication or traditional hot water extraction (TWE) were further separated and purified using DEAE-Sepharose and Sephadex G-100 column chromatography. Polysaccharide fractions (SAE-1, SAE-2, TWE-1, and TWE-2) were obtained; their molecular weights were 9.85 * 104, 6.64 * 104, 4.75 * 105, and 2.81 * 105 Da, respectively. The total sugar content of SAE-1 and SAE-2 was lower and the protein and nucleic acid contents were higher than those of TWE-1 and TWE-2. In addition, SAE-1 and SAE-2 showed stronger Fe2+-chelating activities and superoxide radical scavenging activities than TWE-1 and TWE-2. This suggests that polysaccharides extracted by sonication possess high antioxidant activities. PMID- 29431073 TI - Lectin from the Late Oyster Mushroom, Hohenbuehelia serotina (Agaricomycetes), and Its Novel Effect as an Adjuvant of the HBV DNA Vaccine. AB - The biological macromolecule Hohenbuehelia serotina lectin (HSL) was first isolated from dried fruiting bodies of the mushroom H. serotina and identified as a heterodimer with 2 subunits of the same molecular weight (15.6 kDa) but different isoelectric points. Lactose and d-galactose inhibited the hemagglutinating activity of HSL, whereas mental ions Mn2+ and Ca2+ could stimulate its hemagglutination. The HSL hemagglutinating activity was stable for 1 hour in NaOH and HCl solutions up to a concentration of 12.5 or 6 mmol/L. In addition, HSL was stable up to 50 degrees C for 30 minutes; its hemagglutinating activity was halved at 60 degrees C and totally inactivated above 90 degrees C. HSL (10 MUg) as an immune adjuvant co-inoculated with the proVAX/S2 vaccine enhanced the level of hepatitis B surface antigen in C57BL/6 mice, induced a high level of T-cell proliferation, and induced the expression of IFN- of CD4+ cells. We further illustrate that HSL, as an adjuvant upregulating the expression of major histocompatibility complex II, contributed to the maturation of dendritic cells. As the first lectin isolated from H. serotina, HSL is a potential adjuvant to chronic hepatitis B virus DNA vaccines and lays a foundation for the prevention of HBV infection. PMID- 29431074 TI - Mycelial Growth and Antimicrobial Activity of Species of Genus Lentinus (Agaricomycetes) from Brazil. AB - The objective of this study was to analyze the mycelial growth under different culture conditions and the antimicrobial activity of Lentinus citrinus Walleyn & Rammeloo DPUA 1535 and Neolentinus lepideus (Fr.) Redhead & Ginns DPUA 1536 against some fungi and bacteria. The growth of Lentinus spp. was evaluated in natural and complex media, with and without light, at 25 degrees C and 28 degrees C for 8, 15, and 30 days. To test antimicrobial activity, we used Candida albicans DPUA 1336, Cryptococcus laurentii DPUA 1501, Aspergillus flavus DPUA 1836, Escherichia coli DAUPE 224, and Mycobacterium smegmatis ATCC 607. L. citrinus showed strong growth in potato dextrose and rice meal agars in the absence and presence of light, at 28 degrees C, and over 8, 15, and 30 days. N. lepideus grew well in Sabouraud agar in the absence and presence of light at 25 degrees C for 8 and 15 days. L. citrinus evidenced mycelial growth and high density in potato dextrose agar, although lesser mycelial density was observed in rice bran extract agar. N. lepideus showed less abundant mycelial growth and density in the 3 culture media. Organic mycelial extracts of Lentinus species demonstrated a potential antibacterial and antifungal activity, with selectivity to the test-microorganisms under in vitro growth conditions. PMID- 29431076 TI - Roles of Dectin-1 in Allergic Airway Inflammation. AB - Asthma is a chronic allergic inflammatory disease of the airways. The symptoms can be controlled by inhaled corticosteroids together with long-acting beta2 agonists in the majority of patients; however, in some patients, their symptoms remain uncontrolled even under intensive treatment. Although underlying mechanisms of the heterogeneous responses to the treatment are largely unknown, a series of recent epidemiological studies have suggested a link between the severity of asthma and the sensitization to fungi. Dectin-1, a C-type lectin receptor expressed on myeloid cells and plays protective roles against fungi by recognizing a cell-wall component of fungi, has recently been suggested to be involved in the development of severe asthma. In this review, we summarize the roles of Dectin-1 in the pathogenesis of severe asthma and discuss the possibility of its therapeutic application. PMID- 29431075 TI - The Role of Forkhead Box 1 (FOXO1) in the Immune System: Dendritic Cells, T Cells, B Cells, and Hematopoietic Stem Cells. AB - Forkhead box-O (FOXO) transcription factors have a fundamental role in the development and differentiation of immune cells. FOXO1 and FOXO3 are FOXO members that are structurally similar and bind to the same conserved consensus DNA sequences to induce transcription. FOXO1 has been studied in detail in the activation of dendritic cells (DCs), where it plays an important role through the regulation of target genes such as ICAM-1, CCR7, and the integrin alphavbeta3. FOXO1 is activated by bacteria challenge in DCs and promotes DC bacterial phagocytosis, migration, homing to lymph nodes, DC stimulation of CD4+ T cells and resting B cells, and antibody production. Deletion of FOXO1 in DCs enhances susceptibility to bacteria-induced periodontal disease. FOXO1 and FOXO3 maintain naive T cell quiescence and survival. FOXO1 and FOXO3 enhance the formation of regulatory T cells and inhibit the formation of T-helper 1 (Th1) and Th17 cells. FOXO1 promotes differentiation, proliferation, survival, immunoglobulin gene rearrangement, and class switching in B cells, but FOXO3 has little effect. Both FOXO1 and FOXO3 are important in the maintenance of hematopoietic stem cells by protecting them from oxidative stress. This review examines FOXO1/FOXO3 in the adaptive immune response, key target genes, and FOXO inhibition by the phosphoinositide 3-kinase/AKT pathway. PMID- 29431077 TI - Lung Injury and Loss of Regulatory T Cells Primes for Lung-Restricted Autoimmunity. AB - Lung transplantation is a life-saving therapy for several end-stage lung diseases. However, lung allografts suffer from the lowest survival rate predominantly due to rejection. The pathogenesis of alloimmunity and its role in allograft rejection has been extensively studied and multiple approaches have been described to induce tolerance. However, in the context of lung transplantation, dysregulation of mechanisms, which maintain tolerance against self-antigens, can lead to lung-restricted autoimmunity, which has been recently identified to drive the immunopathogenesis of allograft rejection. Indeed, both preexisting as well as de novo lung-restricted autoimmunity can play a major role in the development of lung allograft rejection. The three most widely studied lung-restricted self-antigens include collagen type I, collagen type V, and k alpha 1 tubulin. In this review, we discuss the role of lung-restricted autoimmunity in the development of both early as well as late lung allograft rejection and recent literature providing insight into the development of lung restricted autoimmunity through the dysfunction of immune mechanisms which maintain peripheral tolerance. PMID- 29431078 TI - SLE-Associated Defects Promote Altered T Cell Function. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease linked to profound defects in the function and phenotype of T lymphocytes. Here, we describe abnormal signaling pathways that have been documented in T cells from patients with SLE and discuss how they impact gene expression and immune function, in order to understand how they contribute to disease development and progression. PMID- 29431079 TI - Effect of Lymphodepletion on Donor T Cells and the Role of Recipient Cells Persisting after Cytotoxic Treatments in Cancer Immunotherapies. AB - The effectiveness of lymphodepletion in antitumor immunity has been well established. Although recent studies have elucidated some of the broad mechanisms underlying the augmentation of antitumor immunity by lymphodepletion, such as increased availability of cytokines due to the elimination of cellular elements and improvement in tumor antigen presentation, the precise mechanisms remain unclear. Previous studies have focused on the enhancement of the functions of transferred antitumor CD8+ T cells after lymphodepletion. In this review, we discuss the important role of other immune cells in the effectiveness of lymphodepletion. Recent studies have demonstrated that lymphodepletion enhances not only transferred tumor-specific CD8+ T cells but also tumor-specific CD4+ T cells and polyclonal naive T cells. Moreover, recipient immune cells, including CD8+ T cells, regulatory T cells, dendritic cells, and macrophages, are involved in the augmentation of antitumor effects by lymphodepletion. These host cells can survive lymphodepletive therapies and play a role in the development of antitumor immunity after lymphodepletion. Improvements in the understanding of lymphodepletion allow us to design effective cancer immunotherapy. PMID- 29431080 TI - Highlights of the Fifth International Workshop on Nitric Oxide and Cancer. AB - Nitric oxide (NO) is an endogenous molecule that performs key physiological signaling functions. The overall biological effect exerted by NO strongly depends on its concentration. Indeed, at a low concentration NO acts as a signal transducer affecting many physiological processes, such as blood flow regulation, iron homeostasis, and neurotransmission, while at a high concentration it preferentially exerts cytotoxic effects. Gaining knowledge about the molecular pathways involved in the NO-tumor response represents a great scientific and clinical challenge for developing novel anticancer strategies based on either endogenous or exogenous NO regulation and induction. This review summarizes the most recent advances in the pathological and therapeutic roles of NO in cancer achieved by prominent experts in the field. In particular, the following topics are reviewed: the role of inducible nitric oxide synthase (iNOS) in chronic inflammation and tumorigenesis; the connection between NOS and IL-10 and their function in immunity at the tumor site; the role of NO in photodynamic therapy; and the role of S-nitrosylation in cancer. Finally, an overview of NO-mediated therapies for cancer treatment is provided, including iNOS inhibitors, NO releasing compounds, and molecular conjugates and nanoparticles that induce NO formation upon irradiation with light. PMID- 29431081 TI - Nitric Oxide and PGE-2 Cross-Talk in EGFR-Driven Epithelial Tumor Cells. AB - Nitric oxide (NO) exerts physiopathological effects based mainly on its concentration. Thus, it facilitates or inhibits cancer-promoting characteristics. This review discusses the role of NO and its network of partners in tumor progression and angiogenesis: prostaglandin E 2 (PGE-2) and its producing enzymes, cyclooxigenase 2 (COX-2) and microsomal PGE synthase 1 (mPGES-1), and epidermal growth factor receptor (EGFR) signaling. Understanding the molecular mechanisms and cross-talk modulating NO effects by PGE-2 and EGFR and vice versa allows us to develop better therapeutic strategies for cancer treatment. PMID- 29431082 TI - Review of Triple Negative Breast Cancer and the Impact of Inducible Nitric Oxide Synthase on Tumor Biology and Patient Outcomes. AB - Triple negative breast cancers (TNBCs), which are defined as estrogen-receptor, progesterone-receptor, and HER2-receptor negative, account for 10-20% of breast cancers, and they are associated with early metastasis, chemotherapeutic resistance, and poor survival rates. One aspect of TNBC that complicates its prognosis and the development of new molecular therapeutic targets is its clinical and molecular heterogeneity. Herein we compare TNBC and basal cytokeratin-positive breast cancers. We examine the different TNBC molecular subtypes, based on gene expression profiling, which include basal-like, mesenchymal, and luminal androgen receptors, in the context of their biology and impact on TNBC prognosis. We explore the potential role of inducible nitric oxide synthase (iNOS) in TNBC tumor biology and treatment responses. iNOS has been shown to induce p53 mutation accumulation, basal-like gene signature enrichment, and transactivation of the epidermal growth factor receptor (EGFR) via S nitrosylation, all of which are key components of TNBC biology. Moreover, iNOS predicts poor outcome in TNBC, and iNOS inhibitors show efficacy against TNBC when used in combination with chemotherapy. We discuss molecular targeted approaches, including EGFR, PARP, and VEGF inhibitors and immunotherapeutics, that are under consideration for the treatment of TNBC and what role, if any, iNOS may play in their success. PMID- 29431084 TI - Nitric Oxide's Contribution to Selective Apoptosis Induction in Malignant Cells through Multiple Reaction Steps. AB - Nitric oxide (NO) induces apoptosis selectively in NADPH oxidase-1-expressing malignant cells through peroxynitrite formation after the interaction of NO with extracellular superoxide anions. Membrane-associated proton pumps ensure the protonation of peroxynitrite, followed by decomposition into NO2 and hydroxyl radicals that cause lipid peroxidation and thus trigger the mitochondrial pathway of apoptosis. Distant from the cell membrane, NO is oxidized by oxygen, whereas peroxynitrite preferentially reacts with CO2. These consumption reactions attenuate apoptosis-inducing NO/peroxynitrite signaling. There is mutual interference between NO/peroxynitrite and HOCl signaling, based on complex NO/H2O2 interactions. Tumor progression leads to resistance of tumor cells against NO/peroxynitrite-dependent signaling through expression of membrane associated catalase that oxidizes NO and decomposes peroxynitrite. There is a fine-tuned balance between catalase-mediated oxidation of NO and NO-dependent inhibition of catalase. Increasing the NO concentration through enhancement of NOS activity or inhibition of NO dioxygenase causes local inhibition of catalase. Then the interaction between free peroxynitrite and H2O2 allows the generation of singlet oxygen, which inactivates additional catalase molecules, allowing for the generation of additional singlet oxygen. Alternatively, singlet oxygen may activate the FAS receptor and thus cause enhancement of NOX1 activity and NOS expression. This leads to an autoamplificatory enhancement of catalase inactivation, followed by intercellular ROS/RNS-mediated apoptosis-inducing signaling. In addition, the signaling molecules HOCl and peroxynitrite seem to trigger immunogenic cell death and thus might establish a beneficial cytotoxic T cell response. PMID- 29431085 TI - IAPs: Mediators of Oncogenesis and Targets for Anticancer Therapy. AB - The inhibitor of apoptosis (IAP) family members are potent regulators of cell homeostasis able to regulate several fundamental cellular processes that include cell death, cell proliferation, cell differentiation, and inflammation. Regarding this broad spectrum of activity, it is now becoming clear that some members of the family possess oncogenic properties. Analysis of genomic database from tumor sequencing studies has revealed a number of genetic alterations affecting some IAP genes and resulting in gain or loss of function. In this review, we discuss the importance of IAP alterations in cell transformation and their link with key oncogenic pathways, focusing on nuclear factor-kappa B (NF-kappaB)-activating signaling pathways. Then we highlight the therapeutic potential of IAP antagonists and nitric oxide (NO) donors as inhibitors of NF-kappaB in anticancer therapy. PMID- 29431083 TI - Role of Endogenous Nitric Oxide in Hyperaggressiveness of Tumor Cells that Survive a Photodynamic Therapy Challenge. AB - Many malignant tumors exploit nitric oxide (NO) for a survival, growth, and migration/invasion advantage, and also to withstand the cytotoxic effects of chemo- and radiotherapies. Endogenous NO has also been shown to antagonize photodynamic therapy (PDT), a unique minimally invasive modality involving a photosensitizing (PS) agent, PS-exciting light in the visible- to near-infrared range, and molecular oxygen. The anti-PDT effects of NO were discovered about 20 years ago, but the underlying mechanisms are still not fully understood. More recent studies in the author's laboratory using breast, prostate, and brain cancer cell lines have shown that inducible NO synthase (iNOS/NOS2) is dramatically upregulated after a PDT challenge using 5-aminolevulinic acid (ALA-) -induced protoporphyrin IX as the PS. The parallel increase in NO resulted not only in a greater resistance to cell killing but also in a striking increase in the growth and migration/invasion rate of surviving cells. These in vitro findings and their recent recapitulation at the in vivo level are discussed in this article, along with how iNOS/NO's negative effects on PDT can be attenuated by the use of select iNOS inhibitors as PDT adjuvants. PMID- 29431086 TI - Antitumoral Activity of Sorafenib in Hepatocellular Carcinoma: Effects on Cell Survival and Death Pathways, Cell Metabolism Reprogramming, and Nitrosative and Oxidative Stress. AB - Sorafenib is an oral multikinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC). Its antitumor activity is attributed to inhibition of tyrosine kinase receptors (VEGFR, PDGFR, c-kit) and intracellular serine/threonine kinases (Raf), which alter gene expression to promote apoptosis and downregulate survival and angiogenesis pathways. The beneficial properties of sorafenib have also been related to a reduction in liver fibrosis trough regulation of TGF-betaR-related STAT3 signaling. Sorafenib plays a role in the regulation of mitochondrial function, ATP, and autophagy, a process leading to either survival or apoptotic cell death depending on its intensity and duration, by altering several cellular pathways such as mTOR, AMPK, activating endoplasmic reticulum stress responses, and deregulating miRNAs that modulate autophagy. Sorafenib reduces S-nitrosation of cell death receptors and caspase-3, triggering a switch to caspase-3 from caspase-8. In this paper, we review the antitumor effects of sorafenib by interaction with cell survival and apoptosis pathways, metabolic reprogramming, and effect on oxidative and nitrosative stress, along with different mechanisms that might be involved in resistance to the drug. PMID- 29431087 TI - Tumor Suppressor Roles of the Denitrosylase GSNOR. AB - Nitric oxide (NO) is a gaseous pleiotropic molecule that can both induce irreversible oxidative damages and modulate physiological signal transductions by transient protein modifications, the most important of which is the S nitrosylation of cysteine residues. Being noxious and healthy, the role of NO in cancer is seemingly contradictory, as at low concentrations it mediates tumor growth and proliferation whereas at high concentrations it promotes apoptosis and cancer growth inhibition. However, it is becoming evident that when endogenously produced, such as upon inducible nitric oxide synthase (NOS) activation, NO acts to sustain tumorigenesis. Similarly, although less explored, defects and deficiency in the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR) have been associated with the development and malignancy of liver and breast cancers, suggesting a primary role for NO signaling-that is, S-nitrosylation, being deeply involved in neoplastic transformation and progression. In this review, we summarize past and recent evidence on the role of S-nitrosylation and GSNOR in different processes that contribute to cell transformation when deregulated, such as DNA damage repair, energetic metabolism, and cell death. We also outline possible S-nitrosylation-targeted proteins that might contribute to tumorigenesis, and, finally, we speculate on the role of GSNOR in regulating the oncogenic effects induced downstream. PMID- 29431088 TI - Therapeutic Potential of Nitric Oxide Donors in Cancer: Focus on Angiogenesis. AB - A new challenge to overcoming tumor resistance to conventional treatment is represented by the development of novel nitric oxide (NO) donors. It is now clear that while low doses of NO have proneoplastic properties, high doses exert antitumor/antiangiogenic activities through multiple mechanisms. This review focuses on the role of exogenous NO in cancer therapy and reports the state of the art regarding different NO-donating agents in cancer treatment, particularly in relation to angiogenesis inhibition. PMID- 29431089 TI - Computed Tomography Image Matching in Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD), characterized by progressive airflow obstruction due to the combined effects of emphysema and small airways disease, is associated with high morbidity and mortality. The complex link between emphysema and airways disease is associated with significant heterogeneity in clinical presentation. Spirometry is the current gold standard for diagnosis and stratification of the severity of airflow obstruction in COPD. Although spirometry is simple to use, it does not enable the separation of emphysema from airways disease. Computed tomography (CT), on the other hand, provides the anatomic localization of disease and has been increasingly used to phenotype COPD. The majority of current CT measures are extracted from a single volume CT scan and although useful to characterize emphysema and airways disease, they do not link structural and functional abnormalities. Alternatively, CT image matching combines information from both inspiratory and expiratory CT scans, thus enabling determination of functional changes such as regional ventilation and mechanical properties of the lung. In this review, we discuss recent applications of CT image matching that provide clinically meaningful information beyond spirometry and single-volume CT scan measures. PMID- 29431090 TI - Design and Construction of a Heteronuclear 1H and 31P Double Tuned Coil for Breast Imaging and Spectroscopy. AB - Magnetic resonance imaging (MRI) is a noninvasive imaging modality that uses radio frequency (RF) energy to excite nuclei in the presence of a strong magnetic field and linear spatially encoding magnetic field gradients. Clinically, MRI takes advantage of the spin properties of hydrogen (1H) nuclei due to the high concentration and relative abundance in tissue water and fats. However, other nuclei having the quantum mechanical property of spin can also be probed. One of the most common is phosphorous (31P), which has 100% natural abundance and reasonable in vivo concentrations that are measurable at clinical MRI field strengths. Phosphorous measurements can provide an understanding of important metabolic pathways within tissues, which ultimately can help in better understanding disease and treatment. However, clinical MRIs do not routinely come with the ability to assess non-1H nuclei. Hence, hardware and pulse sequences need development, while considering the need to easily interface with standard clinical MRI hardware and protocols. This review describes the motivation for and development of MRI RF hardware designs for a human breast imaging system that can acquire 31P data from a clinically approved breast MR imaging and biopsy table. PMID- 29431092 TI - The Virtual Microbiome: Computational Approaches to the Study of Microbe-Host Interactions. AB - The GI tract of a normal adult human contains on the order of 1014 foreign living organisms, collectively known as the gut microbiome, the proper maintenance of which is critical for health. Because the gut microbiome is a dynamic system of vast complexity, computational modeling is assuming an increasingly important role in helping us to understand how and why it behaves as it does. In particular, computational models can serve as a rapid, cost-effective means of simulating the microbiome on multiple scales, from that of an individual bacterium to the microbiome as a whole. This not only allows questions to be addressed in ways that are impractical in the experimental laboratory; it also permits competing hypotheses to be interrogated for feasibility before they are subjected to expensive and time-consuming experimental testing. Here we review some of the differential equation-based and agent-based approaches that have been applied to the computational modeling of the gut microbiome and its effects on the rest of the body. The models discussed are helping us understand how the microbiome works as a system, how it maintains its crucial symbiotic relationship with its host, and, in particular, how its malfunctions can lead to a number of important and often serious pathologies. PMID- 29431093 TI - Imaging Chronic Traumatic Encephalopathy: A Biomedical Engineering Perspective. AB - A disease initially associated with boxers ninety years ago, chronic traumatic encephalopathy (CTE) is now recognized as a significant risk to boxers, American football players, ice hockey players, military personnel or anyone to whom recurrent head injuries are a distinct possibility. Diagnosis is currently confirmed at autopsy, although CTE's presumed sufferers have symptoms of depression, suicidal thoughts, mood and personality changes, and loss of memory. CTE sufferers also complain of losing cognitive ability, dysfunction in everyday activities, inability to keep regular employment, violent tendencies and marital strife. Dementia may develop over the long term. Unfortunately, there is no clear consensus in regards to pathology, with both number and severity of head injuries being linked to disease progression. Despite the slow advancement of this disease, there are no clinical methods to diagnose or monitor prognosis in presumed patients, limiting clinicians' efforts to symptom management. The lack of diagnostic tools fuels the need for biomedical engineers to develop techniques for in vivo detection of CTE. This review examines efforts made with various magnetic resonance and nuclear imaging techniques, with a view towards improving the sensitivity and specificity of diagnostic imaging for CTE. PMID- 29431091 TI - Thermal Therapy Approaches for Treatment of Brain Tumors in Animals and Humans. AB - Primary brain tumors are often aggressive, with short survival from time of diagnosis even with standard of care therapies such as surgery, chemotherapy, and radiation therapy. Thermal therapies have been extensively investigated as both primary and adjuvant therapy. Although thermal therapies are not yet widely used clinically, there have been several promising approaches demonstrated in both animals and humans. This review presents thermal therapy approaches in animal and human studies, including both hyperthermia (temperatures ~42 degrees C-45 degrees C) and thermal ablation (temperatures > 50 degrees C). Hyperthermia is primarily used as adjuvant to chemotherapy and radiotherapy, and is the most widely studied radiation sensitizer where enhanced efficacy has been shown in human patients with brain cancer. Hyperthermia has additional beneficial effects such as immunogenic effects, and opening of the bloodbrain barrier to potentially enhance drug delivery, for example in combination with nanoparticle drug delivery systems. Thermal ablation uses high temperatures for direct local tumor destruction, and it found its way into clinical use as laser interstitial thermal therapy (LITT). This review presents various hyperthermia and ablation approaches, including a review of different devices and methods that have been used for thermal therapies, such as radiofrequency/microwaves, laser, high intensity focused ultrasound, and magnetic nanoparticles. Current research efforts include the combination of advanced thermal therapy devices, such as focused ultrasound with radiation, as well as the use of thermal therapies to enhance chemotherapy delivery across the blood-brain barrier. PMID- 29431094 TI - Deep Learning in Gastrointestinal Endoscopy. AB - Gastrointestinal (GI) endoscopy is used to inspect the lumen or interior of the GI tract for several purposes, including, (1) making a clinical diagnosis, in real time, based on the visual appearances; (2) taking targeted tissue samples for subsequent histopathological examination; and (3) in some cases, performing therapeutic interventions targeted at specific lesions. GI endoscopy is therefore predicated on the assumption that the operator-the endoscopist-is able to identify and characterize abnormalities or lesions accurately and reproducibly. However, as in other areas of clinical medicine, such as histopathology and radiology, many studies have documented marked interobserver and intraobserver variability in lesion recognition. Thus, there is a clear need and opportunity for techniques or methodologies that will enhance the quality of lesion recognition and diagnosis and improve the outcomes of GI endoscopy. Deep learning models provide a basis to make better clinical decisions in medical image analysis. Biomedical image segmentation, classification, and registration can be improved with deep learning. Recent evidence suggests that the application of deep learning methods to medical image analysis can contribute significantly to computer-aided diagnosis. Deep learning models are usually considered to be more flexible and provide reliable solutions for image analysis problems compared to conventional computer vision models. The use of fast computers offers the possibility of real-time support that is important for endoscopic diagnosis, which has to be made in real time. Advanced graphics processing units and cloud computing have also favored the use of machine learning, and more particularly, deep learning for patient care. This paper reviews the rapidly evolving literature on the feasibility of applying deep learning algorithms to endoscopic imaging. PMID- 29431095 TI - Molecular mechanisms underlying the impact of mutations in SOD1 on its conformational properties associated with amyotrophic lateral sclerosis as revealed with molecular modelling. AB - BACKGROUND: So far, little is known about the molecular mechanisms of amyotrophic lateral sclerosis onset and progression caused by SOD1 mutations. One of the hypotheses is based on SOD1 misfolding resulting from mutations and subsequent deposition of its cytotoxic aggregates. This hypothesis is complicated by the fact that known SOD1 mutations of similar clinical effect could be distributed over the whole protein structure. RESULTS: In this work, a measure of hydrogen bond stability in conformational states was studied with elastic network analysis of 35 SOD1 mutants. Twenty-eight hydrogen bonds were detected in nine of 35 mutants with their stability being significantly different from that with the wild-type. These hydrogen bonds were formed by the amino acid residues known from the literature to be located in contact between SOD1 aggregates. Additionally, residues disposed between copper binding sites of both protein subunits were found from the models to form a stiff core, which can be involved in mechanical impulse transduction between these active centres. CONCLUSIONS: The modelling highlights that both stability of the copper binding site and stability of the dimer can play an important role in ALS progression. PMID- 29431096 TI - Introduction of Pediatric Physiological and Anatomical Triage Score in Mass Casualty Incident. AB - BACKGROUND: Triage has an important role in providing suitable care to the largest number of casualties in a disaster setting, but there are no secondary triage methods suitable for children. This study developed a new secondary triage method named the Pediatric Physiological and Anatomical Triage Score (PPATS) and compared its accuracy with current triage methods. METHODS: A retrospective chart review of pediatric patients under 16 years old transferred to an emergency center from 2014 to 2016 was performed. The PPATS categorized the patients, defined the intensive care unit (ICU)-indicated patients if the category was highest, and compared the accuracy of prediction of ICU-indicated patients among PPATS, Physiological and Anatomical Triage (PAT), and Triage Revised Trauma Score (TRTS). RESULTS: Among 137 patients, 24 (17.5%) were admitted to ICU. The median PPATS score of these patients was significantly higher than that of patients not admitted to ICU (11 [IQR: 9-13] versus three [IQR: 2-4]; P<.001). The optimal cut off value of the PPTAS was six, yielding a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 95.8%, 86.7%, 60.5%, and 99.0%. The area under the receiver-operating characteristic curve (AUC) was larger for PPTAS than for PAT or TRTS (0.95 [95% CI, 0.87-1.00] versus 0.65 [95% CI, 0.58-0.72]; P<.001 and 0.79 [95% CI, 0.69-0.89]; P=.003, respectively). Regression analysis showed a significant association between the PPATS and the predicted mortality rate (r2=0.139; P<.001), ventilation time (r2=0.320; P<.001), ICU stay (r2=0.362; P<.001), and hospital stay (r2=0.308; P<.001). CONCLUSIONS: The accuracy of PPATS was superior to other methods for secondary triage of children. Toida C , Muguruma T , Abe T , Shinohara M , Gakumazawa M , Yogo N , Shirasawa A , Morimura N . Introduction of pediatric physiological and anatomical triage score in mass-casualty incident. Prehosp Disaster Med. 2018;33(2):147-152. PMID- 29431099 TI - Abscess inside craniopharyngioma: diagnostic and management implications. AB - Abscess inside the pituitary fossa is very rare. Such abscess can be primary, occurring in an otherwise healthy pituitary gland, or secondary, developing inside a diseased gland (ie, harbouring craniopharyngioma, Rathke's cleft cyst, etc). Secondary pituitary abscess inside a craniopharyngioma remains an extremely rare occurrence. Our literature search revealed only six such cases reported so far. In this report, we present the seventh case of craniopharyngioma with abscess in a 38-year-old woman. We describe the uniqueness of the clinical presentation of our case, the radiological pointers to the possible diagnosis and the management issues in our patient. A review of literature is also included to provide a comprehensive picture of this rare condition to the readers. PMID- 29431098 TI - Multiloculated mesothelial cyst presenting as a malignant mimic. AB - A 46-year-old woman was referred for a second opinion regarding an intra abdominal mass discovered on imaging performed for abdominal pain and distension. The tumour appeared to involve the small bowel, left colon and mesentery and was initially thought to be consistent with an infiltrative tumour or loculated mucinous ascites. Due to the unusual appearance of the tumour and suspicion for an omental-based mass, a laparoscopic resection was recommended to the patient. Intraoperatively, the tumour was found to be a multiloculated, benign appearing, omental cyst without involvement of the bowel and was completely resected laparoscopically. Pathology demonstrated a multiloculated peritoneal mesothelial cyst. PMID- 29431097 TI - An FGF-driven feed-forward circuit patterns the cardiopharyngeal mesoderm in space and time. AB - In embryos, multipotent progenitors divide to produce distinct progeny and express their full potential. In vertebrates, multipotent cardiopharyngeal progenitors produce second-heart-field-derived cardiomyocytes, and branchiomeric skeletal head muscles. However, the mechanisms underlying these early fate choices remain largely elusive. The tunicate Ciona emerged as an attractive model to study early cardiopharyngeal development at high resolution: through two asymmetric and oriented divisions, defined cardiopharyngeal progenitors produce distinct first and second heart precursors, and pharyngeal muscle (aka atrial siphon muscle, ASM) precursors. Here, we demonstrate that differential FGF-MAPK signaling distinguishes between heart and ASM precursors. We characterize a feed forward circuit that promotes the successive activations of essential ASM determinants, Hand-related, Tbx1/10 and Ebf. Finally, we show that coupling FGF MAPK restriction and cardiopharyngeal network deployment with cell divisions defines the timing of gene expression and permits the emergence of diverse cell types from multipotent progenitors. PMID- 29431100 TI - Sheehan's syndrome presenting as cardiac tamponade. AB - A 50-year-old woman presented with progressive dyspnoea and oedema with rapid deterioration over the last few days. Clinical examination revealed hypotension with cold clammy skin, raised jugular venous pressure and muffled heart sounds and was diagnosed to have cardiac tamponade, later confirmed on two-dimensional echocardiography. However, patient had bradycardia, and the other striking examination findings were coarse facies with pallor, madarosis, absent axillary and pubic hair and breast atrophy. Her blood sugar level was also low. Detailed history revealed an episode of postpartum haemorrhage with lactation failure and early menopause. Pericardiocentesis was done with a pig-tail catheter. Hormone profile and MRI brain confirmed the diagnosis of Sheehan's syndrome. Patient improved on treatment with thyroxine and hydrocortisone supplementation and was discharged with education about stress dosing. PMID- 29431101 TI - Marfan syndrome presenting with diffuse emphysematous change of the lung. PMID- 29431102 TI - Pediatric Dilated Cardiomyopathy-Associated LRRC10 (Leucine-Rich Repeat Containing 10) Variant Reveals LRRC10 as an Auxiliary Subunit of Cardiac L-Type Ca2+ Channels. AB - BACKGROUND: Genetic causes of dilated cardiomyopathy (DCM) are incompletely understood. LRRC10 (leucine-rich repeat-containing 10) is a cardiac-specific protein of unknown function. Heterozygous mutations in LRRC10 have been suggested to cause DCM, and deletion of Lrrc10 in mice results in DCM. METHODS AND RESULTS: Whole-exome sequencing was carried out on a patient who presented at 6 weeks of age with DCM and her unaffected parents, filtering for rare, deleterious, recessive, and de novo variants. Whole-exome sequencing followed by trio-based filtering identified a homozygous recessive variant in LRRC10, I195T. Coexpression of I195T LRRC10 with the L-type Ca2+ channel (Cav1.2, beta2CN2, and alpha2delta subunits) in HEK293 cells resulted in a significant ~0.5-fold decrease in ICa,L at 0 mV, in contrast to the ~1.4-fold increase in ICa,L by coexpression of LRRC10 (n=9-12, P<0.05). Coexpression of LRRC10 or I195T LRRC10 did not alter the surface membrane expression of Cav1.2. LRRC10 coexpression with Cav1.2 in the absence of auxiliary beta2CN2 and alpha2delta subunits revealed coassociation of Cav1.2 and LRRC10 and a hyperpolarizing shift in the voltage dependence of activation (n=6-9, P<0.05). Ventricular myocytes from Lrrc10-/- mice had significantly smaller ICa,L, and coimmunoprecipitation experiments confirmed association between LRRC10 and the Cav1.2 subunit in mouse hearts. CONCLUSIONS: Examination of a patient with DCM revealed homozygosity for a previously unreported LRRC10 variant: I195T. Wild-type and I195T LRRC10 function as cardiac-specific subunits of L-type Ca2+ channels and exert dramatically different effects on channel gating, providing a potential link to DCM. PMID- 29431103 TI - Interaction of Body Mass Index on the Association Between N-Terminal-Pro-b-Type Natriuretic Peptide and Morbidity and Mortality in Patients With Acute Heart Failure: Findings From ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). AB - BACKGROUND: Higher body mass index (BMI) is associated with lower circulating levels of N-terminal-pro-b-type natriuretic peptide (NT-proBNP). The Interaction between BMI and NT-proBNP with respect to clinical outcomes is not well characterized in patients with acute heart failure. METHODS AND RESULTS: A total of 686 patients from the biomarker substudy of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HF ) clinical trial with documented NT-proBNP levels at baseline were included in the present analysis. Patients were classified by the World Health Organization obesity classification (nonobese: BMI <30 kg/m2, Class I obesity: BMI 30-34.9 kg/m2, Class II obesity BMI 35-39.9 kg/m2, and Class III obesity BMI >=40 kg/m2). We assessed baseline characteristics and 30- and 180-day outcomes by BMI class and explored the interaction between BMI and NT-proBNP for these outcomes. Study participants had a median age of 67 years (55, 78) and 71% were female. NT-proBNP levels were inversely correlated with BMI (P<0.001). Higher NT-proBNP levels were associated with higher 180-day mortality (adjusted hazard ratio for each doubling of NT proBNP, 1.40; 95% confidence interval, 1.16, 1.71; P<0.001), but not 30-day outcomes. The effect of NT-proBNP on 180-day death was not modified by BMI class (interaction P=0.24). CONCLUSIONS: The prognostic value of NT-proBNP was not modified by BMI in this acute heart failure population. NT-proBNP remains a useful prognostic indicator of long-term mortality in acute heart failure even in the obese patient. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852. PMID- 29431105 TI - LRRC10 (Leucine-Rich Repeat Containing Protein 10) and REEP5 (Receptor Accessory Protein 5) as Novel Regulators of Cardiac Excitation-Contraction Coupling Structure and Function. PMID- 29431104 TI - REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function. AB - BACKGROUND: Heart failure is a complex syndrome characterized by cardiac contractile impairment with high mortality. Defective intracellular Ca2+ homeostasis is the central cause under this scenario and tightly links to ultrastructural rearrangements of sarcolemmal transverse tubules and the sarcoplasmic reticulum (SR); however, the modulators of the SR architecture remain unknown. The SR has been thought to be a specialized endoplasmic reticulum membrane system. Receptor accessory proteins (REEPs)/DP1/Yop1p are responsible for shaping high-curvature endoplasmic reticulum tubules. This study aimed to determine the role of REEPs in SR membrane shaping and thus cardiac function. METHODS AND RESULTS: We identified REEP5 (receptor accessory protein 5) as more highly expressed than other REEP members in adult rat ventricular myocardium, and it was downregulated in the failing hearts. Targeted inactivation of REEP5 in rats specially deformed the cardiac SR membrane without affecting transverse tubules, and this was visualized by focused ion beam scanning electron microscopy based 3-dimensional reconstruction. Accordingly, simultaneous recordings of depolarization-induced Ca2+ currents and Ca2+ transients in REEP5-null cardiomyocytes revealed normal L-type Ca2+ channel currents but a depressed SR Ca2+ release. Consequently, the excitation-contraction coupling gain of cardiomyocytes and consequent cardiac contractility were compromised. REEP5 deficiency did not alter the expression of major proteins involved in Ca2+ handling in the heart. CONCLUSIONS: REEP5 modulates cardiac function by shaping the SR. REEP5 defect deforms the SR architecture to depress cardiac contractility. REEP5-dependent SR shaping might have potential as a therapeutic target for heart failure. PMID- 29431106 TI - Beneficial Effect of Mas Receptor Deficiency on Vascular Cognitive Impairment in the Presence of Angiotensin II Type 2 Receptor. AB - BACKGROUND: The classical renin-angiotensin system is known as the angiotensin (Ang)-converting enzyme/Ang II/Ang type 1 receptor axis, which induces various organ damage including cognitive decline. The angiotensin-converting enzyme 2/Ang (1-7)/Mas axis is known to exert antagonistic actions against the classical renin angiotensin system axis in the cardiovascular system. However, its roles in the brain remain unclear. We examined possible roles of the angiotensin-converting enzyme 2/Ang-(1-7)/Mas axis in cognitive function, employing vascular cognitive impairment model mice. METHODS AND RESULTS: Male 10-week-old C57BL6 (wild-type mice, Mas1 knockout mice, Ang II type 2 receptor knockout mice, and Ang II type 2 receptor/Mas1 double knockout mice were subjected to bilateral carotid artery stenosis (BCAS) surgery. Six weeks after treatment, they were subjected to cognitive tasks. Brain samples were used for histopathological analysis. Cognitive function was significantly impaired in wild-type and double knockout mice after BCAS. On the other hand, the cognitive function of Mas1 knockout mice was maintained in spite of the reduction of cerebral blood flow with BCAS. Total cell number in the dentate gyrus region was significantly reduced after BCAS in wild-type but not in Mas1 knockout mice. The number of doublecortin-positive cells in the subgranular zone was not significantly different between wild-type and Mas1 knockout mice. Ang-(1-7) administration did not improve cognitive function in all mice after BCAS surgery. CONCLUSIONS: Lack of the Mas receptor may have a protective effect against chronic brain ischemia when the Ang II type 2 receptor exists. PMID- 29431108 TI - Health Behaviors and Calcific Aortic Valve Disease. PMID- 29431107 TI - Ideal Cardiovascular Health and the Prevalence and Severity of Aortic Stenosis in Elderly Patients. AB - BACKGROUND: The relationship between ideal cardiovascular health reflected in the cardiovascular health score (CVHS) and valvular heart disease is not known. The purpose of this study was to determine the association of CVHS attainment through midlife to late life with aortic stenosis prevalence and severity in late life. METHODS AND RESULTS: The following 6 ideal cardiovascular health metrics were assessed in ARIC (Atherosclerosis Risk in Communities) Study participants at 5 examination visits between 1987 and 2013 (visits 1-4 in 1987-1998 and visit 5 in 2011-2013): smoking, body mass index, total cholesterol, blood pressure, physical activity, and blood glucose. Percentage attained CVHS was calculated in 6034 participants as the sum of CVHS at each visit/the maximum possible score. Aortic stenosis was assessed by echocardiography at visit 5 on the basis of the peak aortic valve velocity. Aortic stenosis was categorized sclerosis, mild stenosis, and moderate-to-severe stenosis. Mean age was 76+/-5 years, 42% were men, and 22% were black. Mean percentage attained CVHS was 63+/-14%, and the prevalence of aortic stenosis stages were 15.9% for sclerosis, 4.3% for mild stenosis, and 0.7% for moderate-to-severe stenosis. Worse percentage attained CVHS was associated with higher prevalence of aortic sclerosis (P<0.001 for trend), mild stenosis (P<0.001), and moderate-to-severe stenosis (P=0.002), adjusting for age, sex, and race. CONCLUSIONS: Greater attainment of ideal cardiovascular health in midlife to late life is associated with a lower prevalence of aortic sclerosis and stenosis in late life in a large cohort of older adults. PMID- 29431109 TI - Whole genome sequencing in the clinic: empowerment or too much information? PMID- 29431111 TI - Aortic and cardiac air emboli in an older woman. PMID- 29431112 TI - Argyria caused by chronic ingestion of silver. PMID- 29431113 TI - What role does humanity play in assessing and treating alcohol use disorder? PMID- 29431114 TI - Heroin history. PMID- 29431115 TI - American doctors expect to save money under new US tax law. PMID- 29431110 TI - The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants. AB - BACKGROUND: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers. METHODS: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant. RESULTS: Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set (n = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in BRCA1 or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants - associated with cancer, cardiac or neurodegenerative phenotypes - remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual. INTERPRETATION: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care. PMID- 29431116 TI - More doctors providing abortion after federal rules change. PMID- 29431118 TI - Knifeless ultrasound brain surgery promises to cut risks, recovery time. PMID- 29431117 TI - Urgent need for federal investment in research on cannabis health impacts, say researchers. PMID- 29431119 TI - Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation. AB - OBJECTIVES: Accelerated atherosclerotic disease typically complicates rheumatoid arthritis (RA), leading to premature cardiovascular death. Inflammatory macrophages are key effector cells in both rheumatoid synovitis and the plaques of coronary artery disease (CAD). Whether both diseases share macrophage dependent pathogenic mechanisms is unknown. METHODS: Patients with RA or CAD (at least one myocardial infarction) and healthy age-matched controls were recruited into the study. Peripheral blood CD14+ monocytes were differentiated into macrophages. Metabolic profiles were assessed by Seahorse Analyzer, intracellular ATP concentrations were quantified and mitochondrial protein localisation was determined by confocal image analysis. RESULTS: In macrophages from patients with RA or CAD, mitochondria consumed more oxygen, generated more ATP and built tight interorganelle connections with the endoplasmic reticulum, forming mitochondria associated membranes (MAM). Calcium transfer through MAM sites sustained mitochondrial hyperactivity and was dependent on inactivation of glycogen synthase kinase 3b (GSK3b), a serine/threonine kinase functioning as a metabolic switch. In patient-derived macrophages, inactivated pGSK3b-Ser9 co-precipitated with the mitochondrial fraction. Immunostaining of atherosclerotic plaques and synovial lesions confirmed that most macrophages had inactivated GSK3b. MAM formation and GSK3b inactivation sustained production of the collagenase cathepsin K, a macrophage effector function closely correlated with clinical disease activity in RA and CAD. CONCLUSIONS: Re-organisation of the macrophage metabolism in patients with RA and CAD drives unopposed oxygen consumption and ultimately, excessive production of tissue-destructive enzymes. The underlying molecular defect relates to the deactivation of GSK3b, which controls mitochondrial fuel influx and as such represents a potential therapeutic target for anti-inflammatory therapy. PMID- 29431120 TI - Tracking digital ulcers in systemic sclerosis: a feasibility study assessing lesion area in patient-recorded smartphone photographs. PMID- 29431121 TI - Methotrexate limits inflammation through an A20-dependent cross-tolerance mechanism. AB - OBJECTIVES: Methotrexate (MTX) is the anchor drug for treatment of rheumatoid arthritis (RA), but the mechanism of its anti-inflammatory action is not fully understood. In RA, macrophages display a proinflammatory polarisation profile that resembles granulocyte-macrophage colony-stimulating factor (GM-CSF) differentiated macrophages and the response to MTX is only observed in thymidylate synthase+ GM-CSF-dependent macrophages. To determine the molecular basis for the MTX anti-inflammatory action, we explored toll-like receptor (TLR), RA synovial fluid (RASF) and tumour necrosis factor receptor (TNFR)-initiated signalling in MTX-exposed GM-CSF-primed macrophages. METHODS: Intracellular responses to TLR ligands, TNFalpha or RASF stimulation in long-term low-dose MTX exposed human macrophages were determined through quantitative real-time PCR, western blot, ELISA and siRNA-mediated knockdown approaches. The role of MTX in vivo was assessed in patients with arthritis under MTX monotherapy and in a murine sepsis model. RESULTS: MTX conditioned macrophages towards a tolerant state, diminishing interleukin (IL)-6 and IL-1beta production in LPS, LTA, TNFalpha or RASF-challenged macrophages. MTX attenuated LPS-induced MAPK and NF kappaB activation, and toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF1)-dependent signalling. Conversely, MTX increased the expression of the NF kappaB suppressor A20 (TNFAIP3), itself a RA-susceptibility gene. Mechanistically, MTX-induced macrophage tolerance was dependent on A20, as siRNA mediated knockdown of A20 reversed the MTX-induced reduction of IL-6 expression. In vivo, TNFAIP3 expression was significantly higher in peripheral blood cells of MTX-responsive individuals from a cohort of patients with arthritis under MTX monotherapy, whereas MTX-treated mice exhibited reduced inflammatory responses to LPS. CONCLUSIONS: MTX impairs macrophage proinflammatory responses through upregulation of A20 expression. The A20-mediated MTX-induced innate tolerance might limit inflammation in the RA synovial context, and positions A20 as a potential MTX-response biomarker. PMID- 29431122 TI - Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis. AB - OBJECTIVES: The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) transfers negatively charged ADP-ribose units to target proteins. This modification can have pronounced regulatory effects on target proteins. Recent studies showed that PARP-1 can poly(ADP-ribosyl)ate (PARylate) Smad proteins. However, the role of PARP-1 in the pathogenesis of systemic sclerosis (SSc) has not been investigated. METHODS: The expression of PARP-1 was determined by quantitative PCR and immunohistochemistry. DNA methylation was analysed by methylated DNA immunoprecipitation assays. Transforming growth factor-beta (TGFbeta) signalling was assessed using reporter assays, chromatin immunoprecipitation assays and target gene analysis. The effect of PARP-1 inactivation was investigated in bleomycin-induced and topoisomerase-induced fibrosis as well as in tight-skin-1 (Tsk-1) mice. RESULTS: The expression of PARP-1 was decreased in patients with SSc, particularly in fibroblasts. The promoter of PARP-1 was hypermethylated in SSc fibroblasts and in TGFbeta-stimulated normal fibroblasts. Inhibition of DNA methyltransferases (DNMTs) reduced the promoter methylation and reactivated the expression of PARP-1. Inactivation of PARP-1 promoted accumulation of phosphorylated Smad3, enhanced Smad-dependent transcription and upregulated the expression of TGFbeta/Smad target genes. Inhibition of PARP-1 enhanced the effect of TGFbeta on collagen release and myofibroblast differentiation in vitro and exacerbated experimental fibrosis in vivo. PARP-1 deficiency induced a more severe fibrotic response to bleomycin with increased dermal thickening, hydroxyproline content and myofibroblast counts. Inhibition of PARylation also exacerbated fibrosis in Tsk-1 mice and in mice with topoisomerase-induced fibrosis. CONCLUSION: PARP-1 negatively regulates canonical TGFbeta signalling in experimental skin fibrosis. The downregulation of PARP-1 in SSc fibroblasts may thus directly contribute to hyperactive TGFbeta signalling and to persistent fibroblast activation in SSc. PMID- 29431123 TI - Evaluation of patient-reported outcome protocol content and reporting in UK cancer clinical trials: the EPiC study qualitative protocol. AB - INTRODUCTION: Patient-reported outcomes (PROs) are increasingly included within cancer clinical trials. If appropriately collected, analysed and transparently reported, these data might provide invaluable evidence to inform patient care. However, there is mounting indication that the design and reporting of PRO data in cancer trials may be suboptimal. This programme of research will establish via three interlinked studies whether these findings are applicable to UK cancer trials, and if so, how to best enhance the way PROs are assessed, managed and reported in clinical trials. This study will explore with key stakeholders factors that influence optimal PRO protocol content, implementation and reporting and make recommendations for training and guidance. METHODS AND ANALYSIS: Semistructured interviews will be conducted with members of key stakeholder groups. The purposive sample of up to 48 participants will include: (1) trial chief investigators, trial management group members, statisticians and research nurses of cancer trials including primary or secondary PRO recruited via the National Cancer Research Institute (NCRI) Clinical Studies Group and Consumer Liaison Group and the UK Clinical Research Collaboration Registered UK Clinical Trial Unit Network; (2) NCRI Consumer Liaison Group members; (3) international experts in PRO oncology trial design; and (4) journal editors and funding bodies. Data will be analysed using directed thematic analysis employing a coding frame and modified as analysis progresses. Formal triangulation of coding and member checking will be employed to enhance credibility. ETHICS AND DISSEMINATION: This study was approved by the University of Birmingham Ethics Committee (Ref: ERN_17 0085). Findings will be disseminated via conference presentations, peer-reviewed journals, patient groups and social media (@CPROR_UoB; http://www.birmingham.ac.uk/cpror). PROSPERO REGISTRATION NUMBER: CRD42016036533. PMID- 29431124 TI - Development and piloting of a survey to estimate the frequency and nature of potentially harmful preventable problems in primary care from a UK patient's perspective. AB - OBJECTIVES: To design and pilot a survey to be used at the population level to estimate the frequency of patient-perceived potentially harmful preventable problems occurring in UK primary care. To explore the nature of the problems, patient-suggested strategies for prevention and opinions of clinicians and the public regarding the potential for harm. DESIGN: A survey was codesigned by three members of the public and one researcher and piloted through public and patient involvement and engagement networks. SETTING: Self-selected sample of the UK population. PARTICIPANTS: 977 members of the public accessed the online survey during October and November 2015. PRIMARY OUTCOME MEASURES: Respondent feedback about the ease of completion of the survey, quality of responses in terms of review by clinicians and members of the public, preliminary estimates of the frequency and nature of patient-perceived potentially harmful problems occurring in the last 12 months. RESULTS: 638 (65%) members of the public completed the survey and few respondents reported any difficulty in understanding or completing the survey. 132 (21%) respondents reported experiencing a potentially harmful preventable problem during the past 12 months and 108 (82%) of these respondents provided a description that was adequate for at least one clinician to form an opinion about the potentially harmful problem. Respondents were older than the UK generally, more likely to work or volunteer in the healthcare sector and tended to use primary care more frequently but their confidence and trust in their own general practitioner (GP) was similar to that of the UK population as measured by the annual English GP patient survey. CONCLUSIONS: The survey was acceptable to patients and mostly provided data of sufficient quality for review by clinicians and members of the public. It is now ready to use at a population level to estimate the frequency and nature of potentially harmful preventable problems in primary care from a patient's perspective. PMID- 29431125 TI - Follow Your Virtual Trainer (FYVT): a randomised controlled trial protocol of IT based lifestyle intervention programme to promote physical activity and health among middle-aged Hong Kong Chinese. AB - INTRODUCTION: Hong Kong is a highly urbanised city where many people work long hours. The limited time and lack of professional instruction are the typical barriers to exercise. The purpose of this study is to test the effectiveness of an information technology-based lifestyle intervention programme on improving physical activity (PA) level and health status in a sample of middle-aged Hong Kong adults. METHODS AND ANALYSIS: A two-arm parallel randomised controlled trial named 'Follow Your Virtual Trainer' will be conducted among 200 physically inactive Chinese adults aged from 40 to 65 years. Those randomly allocated to an intervention group will be under the instruction of a web-based computer software termed 'Virtual Trainer (VT)' to conduct a 3-month self-planned PA programme. A series of online seminars with healthy lifestyle information will be released to the participants biweekly for 3 months. After that, 6 months observation will follow. Those in the control group will only receive a written advice of standard PA recommendation and the textual content of the seminars. The assessments will be implemented at baseline, the 3rd, 6th and 9th months. The primary outcome is PA measured by accelerometer and International Physical Activity Questionnaire. The secondary outcomes include cardiorespiratory fitness, resting energy expenditure, anthropometrics, body composition, blood pressure, health-related quality of life, sleep quality and quantity, fatigue, behaviour mediators and maintenance of PA. The main effectiveness of the intervention will be assessed by a linear mixed model that tests the random effect of treatment on outcomes at the 3rd, 6th and 9th months. ETHICS AND DISSEMINATION: This trial has been approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CRE 2015235). The study results will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02553980. PMID- 29431126 TI - Repetitive transcranial magnetic stimulation for depression after basal ganglia ischaemic stroke: protocol for a multicentre randomised double-blind placebo controlled trial. AB - INTRODUCTION: Studies suggest that repetitive transcranial magnetic stimulation (rTMS) is effective for the treatment of depression and promotes the repair of white matter. This study aims to assess the effectiveness of rTMS in treating depression after basal ganglia ischaemic stroke and to examine whether such effects are related to restoration of white matter integrity. METHODS AND ANALYSIS: Sixty-six participants will be recruited from Zhujiang Hospital, Nanfang Hospital and Sichuan Bayi Rehabilitation Hospital and randomised in a 1:1 ratio to receive active rTMS treatment or sham rTMS treatment in addition to routine supportive treatments. The data will be collected at 0, 2 and 4 weeks after the commencement of treatment. The primary outcome is the measurement of 24 item Hamilton Depression Rating Scale scores, and the secondary outcomes include diffusion tensor imaging results and the results of neuropsychological tests including the National Institutes of Health Stroke Scale, Activities of Daily Living Scale, Montreal Cognitive Assessment, Clinical Global Impressions scales, Aphasia Battery in Chinese, Social Support Revalued Scale and Medical Coping Modes Questionnaire. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of Zhujiang Hospital of Southern Medical University. The findings will be disseminated by publication in a peer-reviewed journal and by presentation at international conferences. TRIAL REGISTRATION NUMBER: NCT03159351. PMID- 29431127 TI - Perceived bullying among Norwegian doctors in 1993, 2004 and 2014-2015: a study based on cross-sectional and repeated surveys. AB - OBJECTIVES: To examine 12-month prevalence of perceived bullying at work for doctors in different job categories and medical disciplines in 1993, 2004 and 2014-2015, and personality traits, work-related and health-related factors associated with perceived workplace bullying. DESIGN: Cross-sectional questionnaire surveys in 1993, 2004 and 2014-2015 where the 2004 and the 2012 2015 samples are partly overlapping. SETTING: Norway. PARTICIPANTS: Response rates were 72.8% (2628/3608) in 1993, 67% (1004/1499) in 2004 and 78.2% (1261/1612) in 2014-2015. 485 doctors responded both in 2004 and 2014-2015. OUTCOME MEASURE: Perceived bullying at work from colleagues or superiors at least a few times a month during the last year. RESULTS: Between the samples from 1993, 2004 and 2014-2015, there were no significant differences in the prevalence of perceived bullying at work. More senior hospital doctors and surgeons reported being bullied. Doctors with higher scores on the personality trait neuroticism were more likely to perceive bullying, as were female doctors, doctors with poor job satisfaction and poor self-rated health. CONCLUSIONS: The fraction of doctors who experienced bullying at work was stable over a 20-year period. Psychological, psychosocial and cultural factors are predictors of perceived bullying. PMID- 29431128 TI - Correlates of intensity-specific physical activity in children aged 9-11 years: a multilevel analysis of UK data from the International Study of Childhood Obesity, Lifestyle and the Environment. AB - OBJECTIVES: Physical activity (PA) can provide numerous physical and psychological health gains, yet a low proportion of children in England are sufficiently active to accrue benefit. Analysing the correlates of PA from a socioecological perspective may help to identify factors that promote versus discourage PA. The purpose of the present study was to: (1) assess the relationships between a wide range of potential correlates and intensity-specific PA and (2) explore which correlates are associated with meeting government PA guidelines. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study on children aged 9-11 years from the South West of England (n=425; 183 males). OUTCOME MEASURES: A mixture of self-reported and objective measures (eg, body mass index (BMI), accelerometer-derived PA, self-reported sport participation, etc) were collected from child participants, parents and school teachers. After adjusting for covariates (ie, age, sex and accelerometer wear time), multilevel modelling techniques were employed to examine the relationships between potential correlates and light-intensity, moderate-intensity and vigorous-intensity PA, as measured with an ActiGraph GT3X+ accelerometer. Generalised linear mixed modelling was used to analyse the correlates associated with government recommended levels of PA. RESULTS: Computer use shared a negative association whereas parent support for PA showed a positive relationship with light-intensity PA. In terms of moderate-intensity PA, computer use and BMI z-score shared a negative association whereas positive relationships were found for sport participation, active transport and for outdoor time after school. Children at schools with 25%-49% of pupils attending school sport/PA clubs did more moderate intensity PA than those attending schools with lower participation rates. For vigorous-intensity PA, a negative relationship was observed for BMI z-score, and positive associations for self-efficacy, active transport, parent support and the presence of crossing guards on routes to school. Correlates associated with meeting the PA guidelines were BMI z-score (negative), sport participation, active transport and outdoor time after school (all positive). CONCLUSION: Results demonstrate that factors pertaining to the individual, home and school environment may play an important role in understanding the correlates of differing PA intensities in children. TRIAL REGISTRATION NUMBER: NCT01722500. PMID- 29431130 TI - Proactive approaches to identifying dementia and dementia risk; a qualitative study of public attitudes and preferences. AB - OBJECTIVES: The aim of this study was to critically explore the views of the public about the acceptability and feasibility of proactive approaches to earlier dementia diagnosis and also identification of people at high risk of dementia. DESIGN: Qualitative study using task group methodology and thematic data analysis. SETTING: Task groups were held either at the university (n=5) or at a carers' centre (n=1). PARTICIPANTS: A convenience sample of 31 of 54 participants identified by local non-statutory agencies took part in a task group. All were aged between 40 years and 80 years, 21 were women and 10men participated. RESULTS: Despite the use of task group methodology, participants expressed limited understandings of dementia and confusion between proactive approaches. Nevertheless, they highlighted a range of potential benefits and limitations of proactive approaches and the ethical issues raised. There was a preference to embed risk assessment within routine health checks, which focused on achieving a healthier lifestyle, rather than specifically on dementia. Participants emphasised the need to ensure informed consent prior to use of proactive approaches and to provide appropriate support. They also suggested alternative approaches that could potentially facilitate the early detection of dementia or reduce risk at a population level. CONCLUSIONS: As international policy on dementia shifts towards a prevention agenda there is growing interest in identifying those at risk of developing dementia. This study provides useful insights into the acceptability of the use of such proactive approaches among the public. The introduction of proactive approaches to dementia identification raises complex practical and ethical issues, particularly in the context of low public understanding of dementia. The importance of better quality information about dementia (and the likelihood of developing dementia) and provision of psychological support for those undergoing risk assessment were highlighted. PMID- 29431131 TI - What happens to patient experience when you want to see a doctor and you get to speak to a nurse? Observational study using data from the English General Practice Patient Survey. AB - OBJECTIVES: To examine patient consultation preferences for seeing or speaking to a general practitioner (GP) or nurse; to estimate associations between patient reported experiences and the type of consultation patients actually received (phone or face-to-face, GP or nurse). DESIGN: Secondary analysis of data from the 2013 to 2014 General Practice Patient Survey. SETTING AND PARTICIPANTS: 870 085 patients from 8005 English general practices. OUTCOMES: Patient ratings of communication and 'trust and confidence' with the clinician they saw. RESULTS: 77.7% of patients reported wanting to see or speak to a GP, while 14.5% reported asking to see or speak to a nurse the last time they tried to make an appointment (weighted percentages). Being unable to see or speak to the practitioner type of the patients' choice was associated with lower ratings of trust and confidence and patient-rated communication. Smaller differences were found if patients wanted a face-to-face consultation and received a phone consultation instead. The greatest difference was for patients who asked to see a GP and instead spoke to a nurse for whom the adjusted mean difference in confidence and trust compared with those who wanted to see a nurse and did see a nurse was -15.8 points (95% CI 17.6 to -14.0) for confidence and trust in the practitioner and -10.5 points (95% CI -11.7 to -9.3) for net communication score, both on a 0-100 scale. CONCLUSIONS: Patients' evaluation of their care is worse if they do not receive the type of consultation they expect, especially if they prefer a doctor but are unable to see one. New models of care should consider the potential unintended consequences for patient experience of the widespread introduction of multidisciplinary teams in general practice. PMID- 29431129 TI - Cohort profile: LIFEWORK, a prospective cohort study on occupational and environmental risk factors and health in the Netherlands. AB - PURPOSE: LIFEWORK is a large federated prospective cohort established in the Netherlands to quantify the health effects of occupational and environmental exposures. This cohort is also the Dutch contribution to the international Cohort Study of Mobile Phone Use and Health (COSMOS). In this paper, we describe the study design, ongoing data collection, baseline characteristics of participants and the repeatability of key questionnaire items. PARTICIPANTS: 88 466 participants were enrolled in three cohort studies in 2011-2012. Exposure information was collected by a harmonised core questionnaire, or modelled based on occupational and residential histories; domains include air pollution (eg, nitrogen dioxide (NO2), particulate matter with diameter <=2.5 um (PM2.5)), noise, electromagnetic fields (EMF), mobile phone use, shift work and occupational chemical exposures. Chronic and subacute health outcomes are assessed by self-report and through linkage with health registries. FINDINGS TO DATE: Participants had a median age of 51 years at baseline (range 19-87), and the majority are female (90%), with nurses being over-represented. Median exposure levels of NO2, PM2.5, EMF from base stations and noise at the participants' home addresses at baseline were 22.9 ug/m3, 16.6 ug/m3, 0.003 mWm2 and 53.1 dB, respectively. Twenty-two per cent of participants reported to have started using a mobile phone more than 10 years prior to baseline. Repeatability for self-reported exposures was moderate to high (weighted kappa range: 0.69-1) for a subset of participants (n=237) who completed the questionnaire twice. FUTURE PLANS: We are actively and passively observing participants; we plan to administer a follow-up questionnaire every 4-5 years-the first follow-up will be completed in 2018-and linkage to cause-of-death and cancer registries occurs on a (bi)annual basis. This prospective cohort offers a unique, large and rich resource for research on contemporary occupational and environmental health risks and will contribute to the large international COSMOS study on mobile phone use and health. PMID- 29431132 TI - Longitudinal changes in oculomotor function in young adults with mild traumatic brain injury in Sweden: an exploratory prospective observational study. AB - OBJECTIVES: To assess (1) whether visual disturbances can be demonstrated with objective measures more often in patients with mild traumatic brain injury (mTBI) than in orthopaedic controls and non-injured controls, (2) whether such objectively demonstrated disturbances change over time and (3) whether self reported visual symptoms after mTBI correlate with objectively measurable changes in visuomotor performance. DESIGN: A prospective, controlled, observational study, with assessments planned 7-10 and 75-100 days after injury. SETTING: Emergency department of a general hospital in Sweden. PARTICIPANTS: 15 patients with mTBI, 15 patients with minor orthopaedic injury, 15 non-injured controls, aged 18-40 years. OUTCOME MEASURES: Visual examination, including assessment of visual acuity, accommodation, eye alignment, saccades and stereoacuity. Symptom assessment using Convergence Insufficiency Symptoms Survey (CISS) and Rivermead PostConcussion Symptoms Questionnaire. RESULTS: Assessments were performed 4-13 and 81-322 days after injury (extended time frames for logistical reasons). No statistically significant difference was found between the mTBI and control groups regarding saccade performance and stereoacuity at any time point. The accommodative amplitude was significantly lower in the mTBI group compared with non-injured controls at baseline. 6 out of 13 patients with mTBI had accommodative insufficiency at follow-up. Near point of convergence in the mTBI group was receded at baseline and improved statistically significantly at follow up. At baseline, patients with mTBI had significantly higher CISS score than orthopaedic and non-injured controls. For patients with mTBI, the CISS score correlated with fusional vergence. CONCLUSION: There were some transient measurable visual changes regarding convergence in patients with mTBI during the subacute period after the injury. Our findings of persistence of accommodative insufficiency in a considerable proportion of patients with mTBI suggest that this visual function should not be overlooked in clinical assessment. PMID- 29431133 TI - An engaged research study to assess the effect of a 'real-world' dietary intervention on urinary bisphenol A (BPA) levels in teenagers. AB - OBJECTIVE: Bisphenol A (BPA) has been associated with adverse human health outcomes and exposure to this compound is near-ubiquitous in the Western world. We aimed to examine whether self-moderation of BPA exposure is possible by altering diet in a real-world setting. DESIGN: An Engaged Research dietary intervention study designed, implemented and analysed by healthy teenagers from six schools and undertaken in their own homes. PARTICIPANTS: A total of 94 students aged between 17 and 19 years from schools in the South West of the UK provided diet diaries and urine samples for analysis. INTERVENTION: Researcher participants designed a set of literature-informed guidelines for the reduction of dietary BPA to be followed for 7 days. MAIN OUTCOME MEASURES: Creatinine adjusted urinary BPA levels were taken before and after the intervention. Information on packaging and food/drink ingested was used to calculate a BPA risk score for anticipated exposure. A qualitative analysis was carried out to identify themes addressing long-term sustainability of the diet. RESULTS: BPA was detected in urine of 86% of participants at baseline at a median value of 1.22 ng/mL (IQR 1.99). No effect of the intervention diet on BPA levels was identified overall (P=0.25), but there was a positive association in those participants who showed a drop in urinary BPA concentration postintervention and their initial BPA level (P=0.003). Qualitative analysis identified themes around feelings of lifestyle restriction and the inadequacy of current labelling practices. CONCLUSIONS: We found no evidence in this self-administered intervention study that it was possible to moderate BPA exposure by diet in a real-world setting. Furthermore, our study participants indicated that they would be unlikely to sustain such a diet long term, due to the difficulty in identifying BPA-free foods. PMID- 29431134 TI - Smoking cessation support for regular smokers in Hungarian primary care: a nationwide representative cross-sectional study. AB - OBJECTIVES: Our study aimed to evaluate the effectiveness of general practitioners' (GPs') smoking cessation support (SCS). STUDY DESIGN: We carried out a cross-sectional study between February and April 2016. SETTING AND PARTICIPANT: A sample of 2904 regular smokers aged 18 years or older was selected randomly from 18 general medical practices involved in a national representative, general medical practice-based morbidity monitoring system. The GPs surveyed the selected adults and identified 708 regular smokers. MAIN OUTCOME MEASURES: Multivariate logistic regression models have been applied to evaluate the determinants (age, gender, education, smoking-related comorbidity, smoking intensity, intention to quit smoking and nicotine dependence) of provision of GP mediated SCS such as brief intervention, pharmacological and non-pharmacological programmatic support. RESULTS: According to the survey, 24.4% of the adults were regular smokers, 30% of them showed high nicotine dependence and 38.2% willing to quit smoking. Most of the smokers were not participated in SCS by GPs: brief intervention, programmatic non-pharmacological support and pharmacotherapy were provided for 25%, 7% and 2% of smokers, respectively. Low-nicotine-dependence individuals were less (OR 0.30, 95% CI 0.12 to 0.75), patients with intention to quit were more (OR 1.49, 95% CI 1.00 to 2.22) likely to receive a brief intervention. Vocational (OR 1.71, 95% CI 1.13 to 2.59) and high school education (OR 2.08, 95% CI 1.31 to 3.31), chronic obstructive pulmonary disease and cardiovascular diseases (OR 3.34, 95% CI 1.04 to 10.68; OR 3.91, 95% CI 2.33 to 6.54) increased the probability to receive support by GP. CONCLUSIONS: Although there are differences among smokers' subgroups, the SCS in Hungarian primary care is generally insufficient, compared with guidelines. Practically, the pharmacological support is not included in Hungarian GPs' practice. GPs should increase substantially the working time devoted to SCS, and the organisation of primary healthcare should support GPs in improving SCS services. PMID- 29431135 TI - Challenges of diagnosis and management of giant cell arteritis in general practice: a multimethods study. AB - BACKGROUND: In the UK, general practitioners (GPs) are usually the first medical contact for patients with suspected giant cell arteritis (GCA). While rare, it is critical not to miss, as delayed treatment can lead to significant complications including permanent visual loss. To date, little is known about the approach and challenges to diagnosis and management of GCA by GPs. OBJECTIVE: To investigate the diagnosis and management of patients with suspected GCA in UK general practice. DESIGN AND PARTICIPANTS: A multimethods approach was taken, comprising a postal survey of 5000 randomly selected UK GPs and semistructured telephone interviews of 24 GPs from across the UK. SETTING: UK general practice. RESULTS: 1249 questionnaires were returned. 879 responders (70%) indicated that they had diagnosed and managed a patient with GCA. A variety of clinical features were used to identify GCA. 21.9% suggested that they would exclude GCA as a diagnosis if headache was absent and around one-third do not routinely initiate glucocorticoid treatment prior to referral. Significant regional variations in referral pathways were reported. Thematic analysis of interview transcripts highlighted fears relating to a missed diagnosis of GCA and the non-specific nature of early GCA presentation. Accessing specialist care was highlighted as challenging by many GPs and that a national standard fast-track pathway is lacking to support this patient group. Additionally there were significant concerns regarding potential adverse effects relating to long-term treatment with glucocorticoids. CONCLUSION: GPs appear to over-rely on headache to identify GCA and marked geographical differences in management, with conflicting referral pathways and difficulties in accessing appropriate services exist in the UK. A national standard for fast-tracking patients with suspected GCA to relevant specialists would be beneficial to improve care and outcomes for patients with GCA. PMID- 29431137 TI - Coproduction of healthcare service with immigrant patients: protocol of a scoping review. AB - INTRODUCTION: Immigrant patients often meet barriers to patient-centred healthcare in their new host countries. Given the heterogeneity of patients from ethnic minorities, established strategies for patient centredness might not work in their case. The concept of coproduction provides a new perspective on how to collaboratively create the highest possible value for both the patient and the healthcare system. The concept acknowledges that all service is coproduced and directs attention to the relationship between patient and care provider. Coproduction is still a new concept in healthcare and its use with vulnerable groups of patients requires further study. This protocol outlines a scoping review to be conducted on the current knowledge on coproduction of service by immigrants and their service providers in the healthcare sector. METHODS AND ANALYSIS: We will use Joanna Briggs methodology for scoping reviews. The data will stem from the following databases: PubMed, Scopus, Ovid EMBASE, EBSCO CINAHL, EBSCO PsycINFO, Cochrane Library and Web of Science. We will also screen the websites of national authorities and research organisations for publications and review the literature lists of the identified articles for relevant references. We will include all types of literature on coproduction of healthcare or social service by immigrants and service providers, including their relationship with one another, communication and collaboration. Two reviewers will independently screen eligible publications and extract data using a checklist developed for this scoping review. ETHICS AND DISSEMINATION: The results of the study will provide an innovative perspective on the coproduction of value in healthcare service by immigrant patients and care providers. We will present the results at national and international conferences, seminars and other events with relevant stakeholders and immigrant patients, and publish them in a peer-reviewed journal. PMID- 29431136 TI - How patients' experiences of respiratory tract infections affect healthcare seeking and antibiotic use: insights from a cross-sectional survey in rural Anhui, China. AB - OBJECTIVE: To investigate the occurrence of reported respiratory tract infection (RTI) symptoms and their effects on use of self and professional care among patients in the community. DESIGN: A cross-sectional retrospective household survey. SETTING: 12 administrative villages from rural Anhui, China. PARTICIPANTS: 2160 rural adult residents aged >=18 years registered as rural residents and actually living in the sampled villages when this study was conducted. METHOD: The respondents were recruited using stratified-clustered randomised sampling. A structured questionnaire was deployed to solicit information about social demographics, symptoms of last RTI and healthcare seeking following the RTI. Descriptive analyses were performed to investigate the reported symptoms, and multivariate logistic regression models were developed to identify relationships between number of concurrent symptoms and healthcare seeking and antibiotics use. RESULTS: A total of 1968 residents completed the survey, resulting in a response rate of 91.1%. The number of concurrent symptoms showed a clear increasing trend with seeking help from clinics and being prescribed antibiotics. Multivariate regression revealed statistically significant associations between the following: (a) visiting clinics and education (OR=0.790), sore throat (OR=1.355), cough (OR=1.492), shortness of breath (OR=1.707) and fever (OR=2.142); (b) buying medicine from shops without prescription and education (OR=1.230) and cough (OR=1.452); (c) getting antibiotics at clinics and sore throat (OR=2.05) and earache and/or tinnitus (OR=4.884); and (d) obtaining antibiotics at medicine shops and productive cough (OR=1.971). CONCLUSIONS: Reported RTI symptoms play an important role in shaping both patient- and doctor-led responses. PMID- 29431138 TI - Is outpatient care benefit distribution of government healthcare subsidies equitable in rural ethnic minority areas of China? Results from cross-sectional studies in 2010 and 2013. AB - OBJECTIVES: Government healthcare subsidies for healthcare facilities play a significant role in providing more extensive healthcare access to patients, especially poor ones. However, equitable distribution of these subsidies continues to pose a challenge in rural ethnic minority areas of China. This study aimed to evaluate the benefits distribution of outpatient services across different socioeconomic populations in China's rural ethnic minority areas. SETTING: Inner Mongolia Autonomous Region, Xinjiang Autonomous Region and Qinghai Province. DESIGN: Two rounds of cross-sectional study. PARTICIPANTS: One thousand and seventy patients in 2010 and 907 patients in 2013, who sought outpatient services prior to completing the household surveys, were interviewed. METHODS: Benefits incidence analysis was performed to measure the benefits distribution of government healthcare subsidies across socioeconomic groups. The concentration index (CI) for outpatient care at different healthcare facility levels in rural ethnic minority areas was calculated. Two rounds of household surveys using multistage stratified samples were conducted. FINDINGS: The overall CI for outpatient care was -0.0146 (P>0.05) in 2010 and -0.0992 (P<0.01) in 2013. In 2010, the CI was -0.0537 (P<0.01), -0.0085 (P>0.05) and -0.0034 (P>0.05) at levels of village clinics (VCs), township health centres (THCs) and county hospitals (CHs), respectively. In 2013, the CI was -0.1353 (P<0.05), -0.0695 (P>0.05) and -0.1633 (P<0.01) at the levels of VCs, THCs and CHs, respectively. CONCLUSION: Implementation of the gatekeeper mechanism helped improve the benefits distribution of government healthcare subsidies in rural Chinese ethnic minority areas. Equitable distribution of government healthcare subsidies for VCs was improved by increasing financial input and ensuring the performance of primary healthcare facilities. Equitable distribution of subsidies for CHs was improved by policies that rationally guided patients' care-seeking behaviour. In addition, highly qualified physicians were also a key factor in ensuring equitable benefits distribution. PMID- 29431139 TI - The attitudes towards defensive medicine among physicians of obstetrics and gynaecology in China: a questionnaire survey in a national congress. AB - OBJECTIVE: The study aimed to determine prevalence, patterns and risk factors of defensive medicine by obstetricians and gynaecologists across China. DESIGN: This is a questionnaire survey by written and on-line interview for participants. PARTICIPANTS: Among 1804 registered physicians participating at the 2017 Congress of Chinese Obstetricians and Gynecologists Association in Chengdu City, Sichuan Province, China, from 17 to 20 August 2017, 1486 participants (82.4%) responded the survey. MAIN OUTCOME MEASURES: Participants' strongly disagreed/disagreed and strongly agreed/agreed options were compared to determine specific factors contributing to their preferences towards defensive medicine. RESULTS: In the whole cohort of 1486 participants, 903/1486 (60.8%), 283/1486 (19.0%) and 170/283 (60.1%) participants had experienced at least one medical dispute, lawsuit or loss of a lawsuit, respectively; and 1284 (86.4%) participants had witnessed their colleagues exposed to medical disputes, lawsuits or loss of a lawsuit. Generally, 62.9% of the participants strongly agreed or agreed with defensive medicine. Gender, administration duty, employment hospital, education status, subspecialty, exposure to any medical disputes, lawsuits or loss of a lawsuit, and colleagues' experiences were independent risk factors relevant to participants' preferences about defensive medicine in a multivariate model. Participants were more prone to accept or endorse defensive medicine if they were female physicians; without administrative duties; working in non-tertiary hospitals; with an undergraduate degree; with any exposure to medical disputes, lawsuits or loss of a lawsuit; or having witnessed colleagues' similar experiences. CONCLUSIONS: About two-thirds of Chinese physicians practising obstetrics and gynaecology in our survey agreed with the practice of defensive medicine, but they had diverse preferences and understanding of specific practices, harms of defensive medicine and physician's roles. PMID- 29431140 TI - Bike skills training for children with cerebral palsy: protocol for a randomised controlled trial. AB - INTRODUCTION: Two-wheel bike riding can be a goal for children with cerebral palsy (CP) and a means of participating in physical activity. It is possible for some children with CP to ride a two-wheel bike; however, currently far fewer can ride compared with their typically developing peers. Evidence supports training targeted towards goals of the child with CP and their family; yet there is little evidence to guide best-practice bike skills training. Task-specific training may lead to attainment of two-wheel bike-specific goals. This study aims to determine if a novel task-specific approach to training two-wheel bike skills is more effective than a parent-led home programme for attaining individualised two-wheel bike-specific goals in independently ambulant children with CP aged 6-15 years. METHODS AND ANALYSIS: Sixty eligible children with CP (Gross Motor Function Classification System levels I-II) aged 6-15 years with goals relating to riding a two-wheel bike will be randomised to either a novel task-specific centre-based group programme (intervention) or a parent-led home-based programme (comparison), both involving a 1-week intervention period. The primary outcome is goal attainment in the week following the intervention period (T1). Secondary outcomes include: goal attainment and participation in physical activity at 3 months postintervention (T2) and bike skills, attendance and involvement in bike riding, self-perception and functional skills at T1 and T2. Economic appraisal will involve cost-effectiveness and cost-utility analyses. Adherence of clinicians and parents to the intervention and comparison protocols will be assessed. Linear and logistic regression will be used to assess the effect of the intervention, adjusted for site as used in the randomisation process. ETHICS AND DISSEMINATION: This study was approved by the Human Research and Ethics Committees at The Royal Children's Hospital (#36209). Results will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03003026; Pre-results. PMID- 29431141 TI - Does tranexamic acid lead to changes in MRI measures of brain tissue health in patients with spontaneous intracerebral haemorrhage? Protocol for a MRI substudy nested within the double-blind randomised controlled TICH-2 trial. AB - OBJECTIVES: To test whether administration of the antifibrinolytic drug tranexamic acid (TXA) in patients with spontaneous intracerebral haemorrhage (SICH) leads to increased prevalence of diffusion-weighted MRI-defined hyperintense ischaemic lesions (primary hypothesis) or reduced perihaematomal oedema volume, perihaematomal diffusion restriction and residual MRI-defined SICH related tissue damage (secondary hypotheses). DESIGN: MRI substudy nested within the double-blind randomised controlled Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 trial (ISRCTN93732214). SETTING: International multicentre hospital-based study. PARTICIPANTS: Eligible adults consented and randomised in the TICH-2 trial who were also able to undergo MRI scanning. To address the primary hypothesis, a sample size of n=280 will allow detection of a 10% relative increase in prevalence of diffusion-weighted imaging (DWI) hyperintense lesions in the TXA group with 5% significance, 80% power and 5% imaging data rejection. INTERVENTIONS: TICH-2 MRI substudy participants will undergo MRI scanning using a standardised protocol at day ~5 and day ~90 after randomisation. Clinical assessments, randomisation to TXA or placebo and participant follow-up will be performed as per the TICH-2 trial protocol. CONCLUSION: The TICH-2 MRI substudy will test whether TXA increases the incidence of new DWI-defined ischaemic lesions or reduces perihaematomal oedema or final ICH lesion volume in the context of SICH. ETHICS AND DISSEMINATION: The TICH-2 trial obtained ethical approval from East Midlands - Nottingham 2 Research Ethics Committee (12/EM/0369) and an amendment to allow the TICH-2 MRI sub study was approved in April 2015 (amendment number SA02/15). All findings will be published in peer-reviewed journals. The primary outcome results will also be presented at a relevant scientific meeting. TRIAL REGISTRATION NUMBER: ISRCTN93732214; Pre results. PMID- 29431142 TI - Do EPs change their clinical behaviour in the hallway or when a companion is present? A cross-sectional survey. AB - OBJECTIVES: Our aim was to determine whether emergency physicians (EPs) felt their standard patient evaluation practice was modified by two non-private clinical encounters: hallway encounters and encounters during which a companion was present. METHODS: We administered an iteratively developed cross-sectional survey at an annual national professional meeting. We used logistic regression to compare relationships among non-private clinical encounters and predictors of interest. RESULTS: 409 EPs completed the survey. EPs deviated from standard history-taking when practising in a hallway location (78%) and when patients had a companion (84%). EPs altered their standard physical exam when practising in a hallway location (90%) and when patients had a companion (77%). EPs with at least a decade of experience were less likely to alter history-taking in the hallway (OR 0.55, 95% CI 0.31 to 0.99). Clinicians who frequently evaluated patients in the hallway reported delays or diagnostic error-related to altered history-taking (OR 2.34, 95% CI 1.33 to 4.11). The genitourinary system was the most common organ system linked to a delay or diagnostic error. Modifications in history taking were linked to delays or failure to diagnose suicidal ideation or self harm (25%), intimate partner violence (40%), child abuse (12%), human trafficking (8%), substance abuse (47%) and elder abuse (17%). CONCLUSIONS: Our study suggests that alterations in EP usual practice occurs when the doctor-patient dyad is disrupted by evaluation in a hallway or presence of a companion. Furthermore, these disruptions are associated with delays in care and failure to diagnosis medical, social and psychiatric conditions. PMID- 29431143 TI - Effects of prophylactic anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetic drugs: a systematic review and meta-analysis. AB - OBJECTIVES: To determine the effectiveness of prophylactic anticholinergic medications in reducing extrapyramidal symptoms in patients taking acute antiemetics with a dopamine D2 receptor antagonist effect. METHODS: Systematic searches of all published studies through March 2017 were identified from PubMed, Cochrane library, Embase, Web of Science and Scopus. Only randomised controlled trials of patients receiving dopamine D2 antagonist antiemetic therapy for acute migraine in which an anticholinergic or placebo was compared were included. Pooled ORs were calculated for incidence of extrapyramidal symptoms and sedation. RESULTS: Four placebo-controlled randomised controlled trials consisting of 737 patients met the inclusion criteria for our meta-analysis. The effect of diphenhydramine differed depending on the method of administration of the antiemetic. When the antiemetic was delivered as a 2 min antiemetic bolus, the odds of extrapyramidal symptoms were significantly reduced in the diphenhydramine group compared with placebo (OR 0.42; 95% CI 0.22 to 0.81; P=0.01). However, when the antiemetic was given as a 15 min infusion, there was no significant difference in extrapyramidal symptoms with or without diphenhydramine (OR 1.06; 95% CI 0.58 to 1.91; P=0.85). The lowest incidence of extrapyramidal symptoms was observed in patients receiving a 15 min antiemetic infusion without diphenhydramine prophylaxis (9.8%). In two trials including 351 patients that dichotomously reported sedation scales, diphenhydramine had significantly higher rates of sedation (31.6%vs19.2%, OR 2.01, 95% CI 1.21 to 3.33; P=0.007). CONCLUSION: Prophylactic diphenhydramine reduces extrapyramidal symptoms in patients receiving bolus antiemetic therapy with a dopamine D2 antagonist effect, but not when it is given as an infusion. Because of significantly greater sedation with diphenhydramine, the most effective strategy is to administer the D2 antagonist antiemetic as a 15 min infusion without prophylaxis. PMID- 29431144 TI - Paradigm shift? Purity, progress and the origins of first-episode psychosis. AB - First-episode psychosis has garnered significant attention and resources within mental health services in North America, Europe and Australia/New Zealand since the 1990s. Despite this widespread embrace, little scholarship exists that examines underlying concepts, ideologies and imagery embedded within the early intervention paradigm. In this paper, I offer a sociohistorical analysis of the emergence of first-episode psychosis and early intervention as entities in psychiatry, drawing on contemporary philosophical thought to explore various concepts embedded in them. Although scattered references to 'prodrome' and 'incipient cases' exist in the historic psychiatric literature, the notion of first-episode psychosis as a distinct chronological stage emerged in the late 1980s. This occurred in response to a desire for a homogeneous, medication-naive population within schizophrenia research. Thematically, concerns regarding 'purity' as well as notions of 'progress' can be read off of the body of work surrounding the creation of the term and its development into a clinical organising concept. Furthermore, examining the sociohistorical context of the term demonstrates its entanglement with the course of atypical antipsychotic drug development, the expansion of clinical rating scales and wider neoliberal biopolitics within healthcare. Within psychiatry, the early intervention model has been termed a 'paradigm shift,' with the promise that earlier interventions will translate into shorter durations of untreated illness, improved utilisation of services and better prognoses for recovery. While these are laudable goals, they are tied to assumptions about biomedical progress and idealisations of clinical populations that feminist and disability critiques problematise. PMID- 29431145 TI - Johne's disease: a successful eradication programme in a dairy goat herd. AB - This retrospective analysis and report describes the successful eradication and posteradication surveillance programme for Johne's disease (Mycobacterium avium subspecies paratuberculosis (MAP)) in a closed herd of dairy goats. In 1994, MAP's presence in the goat herd was first suspected through individual annual serological screening and then subsequently confirmed through faecal culture and histopathology in 1997 when implementation of a more aggressive programme of testing and eradication of the diseased animals began. This programme included frequent serological screening of all adult goats using ELISA and agar gel immunodiffusion assays. Faecal cultures for bacteria were performed on suspect or positive animals and for all goats found dead or euthanased, and tissues were submitted for histopathology and acid-fast staining. Additional disease eradication measures included maintaining a closed herd and minimising faecal oral transmission of MAP. Following a more aggressive testing regimen and euthanasia of goats with positive faecal culture, the herd was first considered free of MAP in 2003 and has remained free to the present day. PMID- 29431147 TI - The pathogenetic role of beta-cell mitochondria in type 2 diabetes. AB - Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic beta-cells. Type 2 diabetes evolves when beta-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to beta-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the beta-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on beta-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes. PMID- 29431146 TI - Does the addition of hyperbaric oxygen therapy to conventional treatment modalities influence the outcome of soldiers with idiopathic sudden sensorineural hearing loss? AB - BACKGROUND: Idiopathic sudden sensorineural hearing loss (ISSNHL) is defined as a 30-decibel (dB) loss in hearing over three contiguous frequencies within 3 days. The cause remains unknown, and there is currently no consensus in the literature as to how it is best treated. Conventional treatment in our unit comprises steroids, pentoxyphiline and dextran, with the potential addition of hyperbaric oxygen therapy (HBOT). METHODS: A prospective randomised trial was performed on all soldiers diagnosed with ISSNHL in our institution from 1 January 2007 to 31 December 2016. Participants were randomly allocated to one of two groups. Group A was treated with conventional treatment plus HBOT. Group B was treated with conventional treatment only. Data collection included age, gender, clinical symptoms, pure-tone audiometry results and treatment outcome. RESULTS: 60 participants were enrolled (53 male, 7 female) with ages ranging from 18 to 65 years (mean age of 30.3). No significant differences were observed in the baseline characteristics between the two groups, including gender, age, site, associated symptoms, duration of symptoms and severity of hearing loss. Hearing recovery using Siegel's criteria on days 8 and 13 showed no significant differences between treatment groups. However, the hearing recovery on day 180 was significantly better in those who received the conventional treatment plus HBOT (P<0.05). Additionally, no significant side effects were observed in either group. CONCLUSIONS: HBOT plus existing conventional treatment was associated with a better outcome than conventional treatment alone. We would recommend the addition of HBOT is recommended as a first-line treatment modality for all soldiers presenting with ISSNHL. PMID- 29431149 TI - Antiretroviral therapy suppresses rectal HIV-RNA shedding despite inflammation in MSM with rectal C. trachomatis and N. gonorrhoeae infections-a cross-sectional, single-center study. AB - OBJECTIVES: Rectal infections with Chlamydia trachomatis and/or Neisseria gonorrhoeae (CT/NG) are common in men who have sex with men (MSM) and are linked to HIV transmission. However, rectal CT/NG infections are often asymptomatic and it is not known how they contribute to HIV transmission. We assessed clinical and cytological signs of inflammation as well as rectal HIV-RNA in HIV-infected MSM with and without CT/NG infection. METHODS: 112 HIV-positive MSM with or without rectal symptoms and with or without antiretroviral therapy who underwent high resolution anoscopy (HRA) at the proctological outpatient centre of the University Hospital Essen, Germany, between November 2013 and February 2014 were included in this cross-sectional study. During the examination, rectal swabs for the assessment of CT/NG, HIV-RNA and inflammatory cells (granulocytes, lymphocytes, histiocytes) were collected. 110 patients were assessed according to the study protocol, and no imputation of missing data was performed. RESULTS: Rectal infections with CT or NG were detected in 17 participants, and 4 participants were coinfected. Only symptomatic CT/NG infections (8/17) showed signs of inflammation in HRA. Symptomatic CT/NG infections were also associated with the detection of lymphocytes and histiocytes in rectal cytology (both P<0.001). In contrast, asymptomatic CT/NG infections neither resulted in clinical nor cytological signs of inflammation. Rectal HIV-RNA was undetectable in all participants with rectal CT/NG infections who received combined antiretroviral therapy (ART) when plasma HIV-RNA was below the limit of detection (n=13). Besides rectal CT/NG infections, syphilis (n=4) and HPV-associated lesions (n=37) were frequently detected, and proctological symptoms were associated with simultaneous infection with >=2 STDs. CONCLUSIONS: Only symptomatic but not asymptomatic rectal infections with CT and/or NG were associated with clinical and cytological signs of inflammation. Rectal HIV shedding was not promoted by CT/NG infections in patients receiving ART with suppressed plasma HIV-RNA. TRIAL REGISTRATION NUMBER: UTN: U1111-1150-4804. German Clinical Trials Register (DRKS): DRKS00005468. PMID- 29431148 TI - Detection of Chlamydia trachomatis in rectal specimens in women and its association with anal intercourse: a systematic review and meta-analysis. AB - OBJECTIVES: Chlamydia trachomatis is the most commonly diagnosed bacterial STI. Lack of prevalence and risk factor data for rectal chlamydia in women has testing and treatment implications, as azithromycin (a first-line urogenital chlamydia treatment) may be less effective for rectal chlamydia. We conducted a systematic review of studies on women in high-income countries to estimate rectal chlamydia prevalence, concurrency with urogenital chlamydia and associations with reported anal intercourse (AI). DESIGN: Systematic review and four meta-analyses conducted using random-effects modelling. DATA SOURCES: Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO and the Cochrane Database were searched for articles published between January 1997 and October 2017. ELIGIBILITY CRITERIA: Studies reporting rectal chlamydia positivity in heterosexual women aged >=15 years old in high-income countries were included. Studies must have used nucleic acid amplification tests and reported both the total number of women tested for rectal chlamydia and the number of rectal chlamydia infections detected. Conference abstracts, case reports and studies with self-reported diagnoses were excluded. Data extracted included setting, rectal and urogenital chlamydia testing results, AI history, and demographics. RESULTS: Fourteen eligible studies were identified, all among diverse populations attending sexual health services. Among routine clinic-attending women, summary rectal chlamydia positivity was 6.0% (95% CI 3.2% to 8.9%); summary concurrent rectal chlamydia infection was 68.1% in those who tested positive for urogenital chlamydia (95% CI 56.6% to 79.6%); and of those who tested negative for urogenital chlamydia, 2.2% (95% CI 0% to 5.2%) were positive for rectal chlamydia. Reported AI was not associated with rectal chlamydia (summary risk ratio 0.90; 95% CI 0.75 to 1.10). CONCLUSIONS: High levels of rectal chlamydia infection have been shown in women with urogenital chlamydia infection. The absence of association between reported AI and rectal chlamydia suggests AI is not an adequate indicator for rectal testing. Further work is needed to determine policy and practice for routine rectal testing in women. PMID- 29431150 TI - Evidence for negative thermal expansion in the superconducting precursor phase SmFeAsO. AB - The fluorine-doped rare-earth iron oxypnictide series SmFeAsO1-x F x (0 [Formula: see text] 0.10) was investigated with high resolution powder x-ray scattering. In agreement with previous studies (Margadonna et al 2009 Phys. Rev. B. 79 014503), the parent compound SmFeAsO exhibits a tetragonal-to-orthorhombic structural distortion at [Formula: see text] = 130 K which is rapidly suppressed by [Formula: see text] 0.10 deep within the superconducting dome. The change in unit cell symmetry is followed by a previously unreported magnetoelastic distortion at 120 K. The temperature dependence of the thermal expansion coefficient [Formula: see text] reveals a rich phase diagram for SmFeAsO: (i) a global minimum at 125 K corresponds to the opening of a spin-density wave instability as measured by pump probe femtosecond spectroscopy (Mertelj et al 2010 Phys. Rev. B 81 224504) whilst (ii) a global maximum at 110 K corresponds to magnetic ordering of the Sm and Fe sublattices as measured by magnetic x-ray scattering (Nandi et al 2011 Phys. Rev. B 84 055419). At much lower temperatures than [Formula: see text], SmFeAsO exhibits a significant negative thermal expansion on the order of -40 ppm . K-1 in contrast to the behaviour of other rare-earth oxypnictides such as PrFeAsO (Kimber et al 2008 Phys. Rev. B 78 140503) and the actinide oxypnictide NpFeAsO (Klimczuk et al 2012 Phys. Rev. B 85 174506) where the onset of [Formula: see text] 0 only appears in the vicinity of magnetic ordering. Correlating this feature with the temperature and doping dependence of the resistivity and the unit cell parameters, we interpret the negative thermal expansion as being indicative of the possible condensation of itinerant electrons accompanying the opening of a SDW gap, consistent with transport measurements (Tropeano et al 2009 Supercond. Sci. Technol. 22 034004). PMID- 29431151 TI - Hydrodynamic shrinkage of liquid CO2 Taylor drops in a straight microchannel. AB - Hydrodynamic shrinkage of liquid CO2 drops in water under a Taylor flow regime is studied using a straight microchannel (length/width ~100). A general form of a mathematical model of the solvent-side mass transfer coefficient (k s) is developed first. Based on formulations of the surface area (A) and the volume (V) of a general Taylor drop in a rectangular microchannel, a specific form of k s is derived. Drop length and speed are experimentally measured at three specified positions of the straight channel, namely, immediately after drop generation (position 1), the midpoint of the channel (position 2) and the end of the channel (position 3). The reductions of drop length (L x , x = 1, 2, 3) from position 1 to 2 and down to 3 are used to quantify the drop shrinkage. Using the specific model, k s is calculated mainly based on L x and drop flowing time (t). Results show that smaller CO2 drops produced by lower flow rate ratios ([Formula: see text]) are generally characterized by higher (nearly three times) k s and Sherwood numbers than those produced by higher [Formula: see text], which is essentially attributed to the larger effective portion of the smaller drop contributing in the mass transfer under same levels of the flowing time and the surface-to-volume ratio (~104 m-1) of all drops. Based on calculated pressure drops of the segmented flow in microchannel, the Peng-Robinson equation of state and initial pressures of drops at the T-junction in experiments, overall pressure drop (DeltaP t) in the straight channel as well as the resulted drop volume change are quantified. DeltaP t from position 1-3 is by average 3.175 kPa with a ~1.6% standard error, which only leads to relative drop volume changes of 0.30/00 to 0.520/00. PMID- 29431152 TI - Franck Condon shift assessment in 2D MoS2. AB - Optical spectroscopy (OS) techniques are often coupled with first-principles density functional theoretical (DFT) calculations for determining the precise influence of defects on the electronic and structural properties of two dimensional (2D) transition metal dichalcogenides. Such calculations are carried out presuming there is little or no effect of vibrational transitions on the observed electronic spectrum. However, if the effect of change in vibrational energy (Franck Condon (FC) shift) associated with such a transition is large, it could possibly lead to a different origin for the observed peak. One such instance is the attribution of the 0.75 eV cathodoluminescence peak by Fabbri et al (2016 Nat. Commun. 7 13044) to an optical transition from an S vacancy level in the band gap, under the assumption that the FC shift is negligible. Here, by first principles constrained DFT calculations using hybrid HSE06 functional we show that this combined prediction of OS and DFT calculations is valid for 2D MoS2 since the FC shift associated with electronic transitions from a sulfur vacancy is indeed small ~28 meV. Based on our calculations we conclude that it is reasonable to make a direct connection between DFT calculations and optical spectroscopy techniques in this material, hence, establishing a one to one relation between defect related emission bands and electronic transitions from the defect levels. PMID- 29431153 TI - Zinc oxide decorated multi-walled carbon nanotubes: their bolometric properties. AB - We report the synthesis of MWNT/ZnO hybrid nanostructures. A simple, affordable, chemical procedure to functionalize MWNTs with ZnO nanoparticles was performed. A significant portion of the surface of MWNTs was covered with ZnO nanoparticles; these particles formed highly porous spherical nodules of 50-150 nm in diameter, sizes that are an order of magnitude larger than similar ZnO nanonodules reported in the literature. Hence, the self-assembled nanocomposite the ZnO exhibited a large surface-to-volume ratio, which is a very advantageous property for potential catalytic applications. The resultant MWNT/ZnO nanocomposites were characterized by x-ray diffraction, scanning and high-resolution transmission electron microscopy, and UV-vis and Raman spectroscopy. The temperature coefficient of resistance (TCR) of the nanocomposites was measured and reported. The average TCR value goes from -5.6%/K up to -18%/K, over temperature change intervals from 10 K to 1 K. Based on these TCR results, the nanocomposite MWNT/ZnO prepared in this work is a promising material, with potential application as a bolometric sensor. PMID- 29431154 TI - Helical Flow Component of Left Ventricular Assist Devices (LVADs) Outflow Improves Aortic Hemodynamic States. AB - BACKGROUND Although LVADs are confirmed to have strong effects on aortic hemodynamics, the precise mechanisms of the helical flow component of LVAD outflow are still unclear. MATERIAL AND METHODS To clarify these effects, 3 cases - normal case, flat flow case, and realistic flow case - were designed and studied by using the CFD approach. The normal case denoted the normal aorta without LVAD support, and the flat flow case represented the aorta with the outflow cannula. Similarly, the realistic flow case included the aortic model, the model of outflow cannula, and the model of LVAD. The velocity vector, blood streamline, distribution of wall shear stress (WSS), and the local normalized helicity (LNH) were calculated. RESULTS The results showed that the helical component of LVAD outflow significantly improved the aortic hemodynamics. Compared with the flat flow case, the helical flow eliminated the vortex near the outer wall of the aorta and improved the blood flow transport (normal case 0.1 m/s vs. flat flow case 0.14 m/s vs. realistic flow case 0.30 m/s) at the descending aorta. Moreover, the helical flow was confirmed to even the distribution of WSS, reduce the peak value of WSS (normal case 0.92 Pa vs. flat flow case 7.39 Pa vs. realistic flow case 5.2Pa), and maintain a more orderly WSS direction. CONCLUSIONS The helical flow component of LVAD outflow has significant advantages for improving aortic hemodynamic stability. Our study provides novel insights into LVAD optimization. PMID- 29431155 TI - Reconstructing Archaeological Networks with Structural Holes. AB - Model-based reconstruction is an approach to infer network structures where they cannot be observed. For archaeological networks, several models based on assumptions concerning distance among sites, site size, or costs and benefits have been proposed to infer missing ties. Since these assumptions are formulated at a dyadic level, they do not provide means to express dependencies among ties and therefore include less plausible network scenarios. In this paper we investigate the use of network models that explicitly incorporate tie dependence. In particular, we consider exponential random graph models, and show how they can be applied to reconstruct networks coherent with Burt's arguments on closure and structural holes (Burt 2001). The approach is illustrated on data from the Middle Bronze Age in the Aegean. PMID- 29431156 TI - Corrigendum to "Osteogenic Differentiation of hDPSCs on Biogenic Bone Apatite Thin Films". AB - [This corrects the article DOI: 10.1155/2017/3579283.]. PMID- 29431157 TI - Thrombolysis of a stroke patient with history of rtPA-associated angioedema. PMID- 29431158 TI - Erratum: A comparative evaluation of sealing ability of four root end filling materials using fluid filtration method: An in vitro study. AB - [This corrects the article on p. 307 in vol. 20, PMID: 29386776.]. PMID- 29431159 TI - Student-run clinics: The future of outpatient neurology practice? PMID- 29431160 TI - Neurologic attack and dynamic perfusion abnormality in neuronal intranuclear inclusion disease. PMID- 29431162 TI - Still, do no harm. PMID- 29431161 TI - Spontaneous periodic hypothermia in Parkinson disease with hypothalamic involvement. PMID- 29431163 TI - Powassan virus postencephalitic parkinsonism. PMID- 29431165 TI - "Think metabolic" in adults with diagnostic challenges: Biotinidase deficiency as a paradigm disorder. AB - Neurologists should consider the possibility of an inherited metabolic disorder in adults with neurologic symptoms that may or may not mimic those seen in affected children, such as in the case of biotinidase deficiency. Because many of these disorders are treatable, they must be included in the differential diagnosis. Technologies, such as specific biochemical analysis and whole exomic sequencing, can assist the clinician by leading to the appropriate diagnosis and treatment. Whole exomic sequencing can identify known and putative mutations in a patient's genome. The neurologist must "think metabolic" in sorting out complex and difficult cases. PMID- 29431164 TI - Recommendations for the detection and diagnosis of Niemann-Pick disease type C: An update. AB - Purpose of review: Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice. Recent findings: New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified. Summary: This publication provides expert recommendations for clinicians who may see patients presenting with the signs and symptoms of NP-C, including general practitioners, pediatricians, neurologists, and psychiatrists. PMID- 29431166 TI - Incorporating students into clinic may be associated with both improved clinical productivity and educational value. AB - Background: In this study, we aimed to evaluate ambulatory clinic responsibilities that neurology clerkship students perceive as having the highest educational value and to evaluate the association between a student's presence and level of responsibility and a preceptor's clinical and financial productivity during a clinic session. Methods: Physician preceptors (n = 43) and medical students (n = 67) in the Johns Hopkins Neurology clerkship from 2014 to 2015 were included. Students rated their experience and responsibilities in 291 neurology clinic sessions. Productivity metrics (e.g., relative value units [RVU]/clinic) were collected for each preceptor in the presence and absence of students. Results: A student's rating of a clinic as an effective learning experience increased with each additional patient the student interviewed (odds ratio [OR] 1.89, p < 0.001), presented (OR 1.86, p < 0.001), or documented (OR 2.00, p < 0.001). The mean RVU/session for preceptors also increased based on the number of patients interviewed (beta = 2.64, p = 0.026), presented (beta = 2.42, p = 0.047), and documented (beta = 2.70, p = 0.036) by students. On average, preceptor RVU/session increased by 42% (mean 5.6 +/- 1.2, p < 0.0001) when a student was present in clinic compared to sessions without students. In addition, preceptor invoices increased by 35% (mean 2.7 +/- 0.6, p < 0.0001) and charges by 39% (mean $929 +/- $210, p < 0.0001) when a student was present in clinic. Conclusions: This observational study suggests a mutual benefit to preceptor clinical productivity and student-perceived educational value when students have active responsibilities in neurology clinics. Despite concerns that students slow down preceptors in clinic, these results suggest that preceptors may have an overall boost in productivity, potentially by performing billable work while students independently see patients. PMID- 29431167 TI - Potential and pitfalls of email control as a burnout antidote. PMID- 29431169 TI - Comparing the cost-per-QALYs gained and cost-per-DALYs averted literatures. AB - Background: We examined the similarities and differences between studies using two common metrics used in cost-effectiveness analyses (CEAs): cost per quality adjusted life years (QALYs) gained and cost per disability-adjusted life year (DALY) averted. Methods: We used the Tufts Medical Center CEA Registry, which contains English-language cost-per-QALY gained studies, and Global Cost Effectiveness Analysis (GHCEA) Registry, which contains cost-per-DALY averted studies. We examined study characteristics including intervention type, sponsor, country, and primary disease, and also analysed the number of CEAs versus disease burden estimates for major diseases and conditions across three geographic regions. Results: We identified 6,438 cost-per-QALY and 543 cost-per-DALY studies published through 2016 and observed rapid growth in publication rates for both literatures. Cost-per-QALY studies were most likely to examine pharmaceuticals and interventions in high-income countries. Cost-per-DALY studies predominantly focused on infectious disease interventions and interventions in low and lower middle income countries. We found discrepancies in the number of published CEAs for certain diseases and conditions in certain regions, suggesting "under studied" areas (e.g., cardiovascular disease in Southeast Asia, East Asia, and Oceania and "overstudied" areas (e.g., HIV in Sub Saharan Africa) relative to disease burden in those regions. Conclusions: The number of cost-per QALY and cost-per-DALY analyses has grown rapidly with applications to diverse interventions and diseases. Discrepancies between the number of published studies and disease burden suggest funding opportunities for future cost effectiveness research. PMID- 29431168 TI - King-Devick Test identifies real-time concussion and asymptomatic concussion in youth athletes. AB - Background: Sports concussion has an annual incidence of approximately 3.8 million. Over half go unreported and a substantial number may be asymptomatic. A rapid, cost-effective, and reliable tool that facilitates diagnosis of concussion is needed. The King-Devick (K-D) test is a vision-based tool of rapid number naming for assessment of concussion. In this study, we evaluated the utility of the K-D test in real time for identification of symptomatic concussion in youth athletes and to determine if similar impairment (subclinical concussion) exists in youth athletes without an obvious head injury or symptoms. Methods: Youth hockey players underwent K-D testing preseason, postseason, and immediately after suspected concussion. Additional testing was performed in a subgroup of nonconcussed athletes immediately before and after a game to determine effects of fatigue on K-D scores. Results: Among 141 players tested, 20 had clinically diagnosed concussion. All 20 had immediate postconcussion K-D times >5 seconds from baseline (average 7.3 seconds) and all but 2 had worse postseason scores (46.4 seconds vs 52.4 seconds, p < 0.05, Wilcoxon signed rank test). Nonconcussed athletes saw minimal improvement postseason (43.9 seconds vs 42.1 seconds, p < 0.05) and 51 nonconcussed players assessed before and after a game revealed no significant time change as a result of fatigue. Conclusions: Rapid number naming using the K-D test accurately identifies real-time, symptomatic concussion in youth athletes. Scores in concussed players may remain abnormal over time. Athletes should undergo preseason and postseason K-D testing, with additional evaluation real time to inform the assessment of suspected concussion. Classification of Evidence: This study provides Class III evidence that the K-D test accurately identifies real-time concussions in youth athletes. PMID- 29431170 TI - Exenatide Prevents Diet-induced Hepatocellular Injury in A CEACAM1-Dependent Mechanism. AB - The Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) promotes insulin sensitivity by inducing insulin clearance and reducing de novo lipogenesis in the liver. Consistently, Cc1-/- mice with null deletion of Ceacam1 gene exhibit hyperinsulinemia and insulin resistance, in addition to steatohepatitis. They also exhibit early pericellular fibrosis. Redelivering Ceacam1 to the liver reverses the altered metabolism and histopathology of Cc1-/- mice. Exenatide, a long-acting glucagon-like peptide-1 receptor agonist, induces Ceacam1 transcription and consequently, reverses impaired insulin clearance and insulin resistance caused by high-fat intake. Additionally, it reverses fat accumulation in the liver. The current studies show that exenatide also restored the activities of alanine transaminase and aspartate aminotransferase, and reversed the inflammatory and oxidative stress response to high-fat diet in wild type, but not in Cc1-/- mice. Exenatide also prevented diet-induced activation of the TGFbeta/Smad2/Smad3 pro-fibrogenic pathways, and normalized the mRNA levels of pro-fibrogenic genes in wild-type, but not in Cc1-/- mice. Together, the data demonstrate that exenatide prevented diet-induced pro-fibrogenesis and hepatocellular injury in a CEACAM1-dependent mechanism. PMID- 29431171 TI - The upgoing thumb sign: An interobserver/intraobserver reliability study. AB - Background: The upgoing thumb sign as a subtle clinical finding of upper motor neuron involvement has been frequently reported in patients with TIAs and minor strokes. This study was designed to show the method of examination and interpretation and the interobserver/intraobserver reliability. Methods: The thumb sign was elicited in TIA/minor strokes or stroke mimics. After obtaining the participant's permission, the examinations were recorded. Two independent neurologists reviewed all patients for the possibility of an upgoing thumb sign. After 1 hour education about the definition of an upgoing thumb sign to a group of stroke fellows, nurse practitioners, and a research secretary, the videos were reviewed and the participants rated the thumb sign independently. The intraobserver reliability was assessed after 3 months by rating the same videos. Results: The interobserver reliability among 9 raters showed an overall agreement of 0.83 and fixed-marginal kappa of 0.66. The same videos were reviewed by the observers after 3 months with a similar level of agreement (percent of overall agreement 0.84, fixed-marginal kappa 0.66) and a substantial to almost perfect level of intraobserver concordance (mean 0.86; SD 0.08; median 0.90; interquartile range 25-75, 0.8, 0.95). Conclusions: The upgoing thumb sign is a subtle upper limb neurologic finding, with a high level of interobserver and intraobserver reliability. The test is easy to perform and can be interpreted accurately. PMID- 29431172 TI - Progression and effect of cognitive-behavioral changes in patients with amyotrophic lateral sclerosis. AB - Background: To prospectively evaluate the progression of cognitive-behavioral function in amyotrophic lateral sclerosis (ALS) and examine the association of cognitive-behavioral deficits with disease progression, patient quality of life (QOL), and caregiver burden. Methods: We evaluated cognitive-behavioral function using the Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen at enrollment and after 7 months in a cohort of patients with ALS. Paired t tests were used to evaluate the change in the 2 assessments. Linear regression and Kruskal-Wallis tests were applied to investigate how initial cognitive or behavioral status related to outcomes. Results: The mean test-retest interval was 6.8 months (SD 1.6). Cognitive status of the study population (n = 49) overall did not change over the study period (p = 0.06) despite progression of motor weakness (p < 0.001), though small subsets of the sample demonstrate cognitive change. Patients initially classified as behaviorally normal showed increased behavioral problems over time (t = -2.8, p = 0.009). Decline in cognitive (beta = -1.3, p = 0.03) and behavioral (beta = -0.76, p = 0.002) status predicted increasing caregiver burden. Behavioral abnormalities predicted decline in forced vital capacity and ALS Functional Rating Scale-Revised score (p = 0.008, 0.012) in the study population and patient QOL in the most severely affected group (t = 4.3, p = 0.003). Conclusions: Cognitive-behavioral change is a key aspect of disease heterogeneity in ALS. Executive function in ALS overall remains stable over 7 months as detected by an administered screening tool. However, patients may develop caregiver-reported behavioral symptoms in that time period. Screening for caregiver-reported symptoms has a particular utility in predicting future clinical decline, increased caregiver burden, and worsening patient QOL. PMID- 29431174 TI - Small fiber neuropathy presenting during the antecedent period of undifferentiated arthritis prior to rheumatoid arthritis. PMID- 29431173 TI - Segmental arterial mediolysis: A rare cause of rapidly progressive arterial dissections. PMID- 29431175 TI - Efficacy of rituximab as third-line therapy in combined central and peripheral demyelination. PMID- 29431176 TI - PhD Forum: Multimodal IoT and EMR based Smart Health Application for Asthma Management in Children. AB - According to a study done in 2014 by National Health Interview Survey around 6.3 million children in United States suffer from asthma [1]. Asthma remains one of the leading reasons for pediatric admissions to children's hospitals, and has a prevalence rate of approximately 10% in children and it leads to missed days from school and other societal costs. This occurs despite improved medications to control asthma symptoms. Asthma management is challenging as it involves understanding asthma causes and avoiding asthma triggers that are both multi factorial and individualistic in nature. It is almost impossible for doctors to constantly monitor each patient's health and environmental triggers. According to a recent article, the IoT device market in health-care will increase to a worth of $117 billion by the year 2020 [2]. The monitoring segment of IoT devices have predicted to increase $15 billion in 2017 [5]. The sales of smart watches, fitness and health trackers, are expected to account for more than 70% of all wearables sale worldwide in 2016 [6]. According to IBM, the volume of health-care data has reached to 150 exabytes in 2017 [7]. The data generated from these consumer graded devices is increasing day by day. This data collection has exacerbated the problem of understanding the data and making sense of it. PMID- 29431177 TI - Ataxia and autonomic dysfunction as presenting symptoms in late-onset Alexander disease. PMID- 29431178 TI - Improving email strategies to target stress and productivity in clinical practice. AB - Physician burnout is gaining increased attention in medicine and neurology and often relates to hours worked and insufficient time. One component of this is administrative burden, which relates to regulatory requirements and electronic health record tasks but may also involve increased time spent processing emails. Research in academic medical centers demonstrates that physicians face increasing inbox sizes related to mass distribution emails from various sources on top of emails required for patient care, research, and teaching. This commentary highlights the contribution of administrative tasks to physician burnout, research to date on email in medical contexts, and corporate strategies for reducing email burden that are applicable to neurology clinical practice. Increased productivity and decreased stress can be achieved by limiting the amount one accesses email, managing inbox size, and utilizing good email etiquette. Department and practice physician leaders have roles in decreasing email volume and modeling good practice. PMID- 29431179 TI - Transgender venous thrombosis. PMID- 29431180 TI - Rigidity of the magic pentagram game. AB - A game is rigid if a near-optimal score guarantees, under the sole assumption of the validity of quantum mechanics, that the players are using an approximately unique quantum strategy. Rigidity has a vital role in quantum cryptography as it permits a strictly classical user to trust behavior in the quantum realm. This property can be traced back as far as 1998 (Mayers and Yao) and has been proved for multiple classes of games. In this paper we prove ridigity for the magic pentagram game, a simple binary constraint satisfaction game involving two players, five clauses and ten variables. We show that all near-optimal strategies for the pentagram game are approximately equivalent to a unique strategy involving real Pauli measurements on three maximally-entangled qubit pairs. PMID- 29431181 TI - Characterizing performance improvement in primary care systems in Mesoamerica: A realist evaluation protocol. AB - Background. Improving performance of primary care systems in low- and middle income countries (LMICs) may be a necessary condition for achievement of universal health coverage in the age of Sustainable Development Goals. The Salud Mesoamerica Initiative (SMI), a large-scale, multi-country program that uses supply-side financial incentives directed at the central-level of governments, and continuous, external evaluation of public, health sector performance to induce improvements in primary care performance in eight LMICs. This study protocol seeks to explain whether and how these interventions generate program effects in El Salvador and Honduras. Methods. This study presents the protocol for a study that uses a realist evaluation approach to develop a preliminary program theory that hypothesizes the interactions between context, interventions and the mechanisms that trigger outcomes. The program theory was completed through a scoping review of relevant empirical, peer-reviewed and grey literature; a sense-making workshop with program stakeholders; and content analysis of key SMI documents. The study will use a multiple case-study design with embedded units with contrasting cases. We define as a case the two primary care systems of Honduras and El Salvador, each with different context characteristics. Data will be collected through in-depth interviews with program actors and stakeholders, documentary review, and non-participatory observation. Data analysis will use inductive and deductive approaches to identify causal patterns organized as 'context, mechanism, outcome' configurations. The findings will be triangulated with existing secondary, qualitative and quantitative data sources, and contrasted against relevant theoretical literature. The study will end with a refined program theory. Findings will be published following the guidelines generated by the Realist and Meta-narrative Evidence Syntheses study (RAMESES II). This study will be performed contemporaneously with SMI's mid-term stage of implementation. Of the methods described, the preliminary program theory has been completed. Data collection, analysis and synthesis remain to be completed. PMID- 29431183 TI - Transcriptomic definition of molecular subgroups of small round cell sarcomas. AB - Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups. VGLL2-fused tumours represented a more biologically and pathologically heterogeneous group. This study also refined the characteristics of some entities such as EWSR1-PATZ1 spindle cell sarcoma or FUS-NFATC2 bone tumours that are different from EWSR1-NFATC2 tumours and transcriptionally resemble CIC-fused tumour entities. We also describe a completely novel group of epithelioid and spindle-cell rhabdomyosarcomas characterized by EWSR1- or FUS-TFCP2 fusions. Finally, expression data identified some potentially new therapeutic targets or pathways. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29431182 TI - Comprehensive circular RNA profiling reveals the regulatory role of the circRNA 000911/miR-449a pathway in breast carcinogenesis. AB - Circular RNAs (circRNAs) are key regulators in the development and progression of human cancers; however their roles in breast tumorigenesis are not yet well understood. Thus, the present study aimed to investigate the expression profiles and potential modulatory effects of circRNAs on breast carcinogenesis. A human circRNA microarray analysis was performed to screen for abnormally expressed circRNAs in breast cancer tissue and circRNA-000911 was identified as a circRNA which was significantly downregulated in breast cancer cells. Mechanistic investigations suggested that the enhanced expression of circRNA-000911 suppressed cell proliferation, migration and invasion, and promoted the apoptosis of breast cancer cells. By using a biotin-labeled circRNA-000911 probe to perform RNA precipitation in breast cancer cells, we identified miR-449a as the circRNA 000911-associated microRNA. Gain- and loss-of-function assays indicated that miR 449a antagonized circRNA-000911 to regulate breast cancer progression. Subsequently, Notch1 was identified as the functional target of miR-449a, and the overexpression of circRNA-000911 in breast cancer elevated Notch1 expression. Furthermore, Cignal Signal Transduction Reporter Array and western blot analysis identified nuclear factor-kappaB (NF-kappaB) signaling as a functional target of the circRNA-000911/miR-449a pathway. On the whole, our findings indicate that circRNA-000911 plays an anti-oncogenic role in breast cancer and may thus serve as a promising therapeutic target for patients with breast cancer. Therefore, the overexpression of circRNA-000911 may provide a future direction which may aid in the development of a novel treatment strategy for breast cancer. PMID- 29431185 TI - How High Schools Become Empowering Communities: A Mixed-Method Explanatory Inquiry into Youth-Adult Partnership and School Engagement. AB - Educational reform efforts emphasize empowerment and engagement, but these concepts are rarely translated into policy or classroom practice. This inquiry explores how schools can become places where students take ownership over their own learning. Phase 1 of this inquiry, a survey of students from diverse high schools, examines pathways to school engagement. Results indicated that youth voice in decision-making, particularly when the experience is situated within supportive adult relationships and a sense of safety, significantly predicts emotional and cognitive engagement. Phase 2, a case study of an exemplary high school, sought to explain these pathways. Grounded in the theoretical perspectives of "empowered community settings" and "youth-adult partnership," analyses highlighted the importance of a shared belief system and core instructional activities that were student-centered, affirmative, and strength based. Within this context, the opportunity role structure allowed students to exercise voice in creating their own educational program. The relational environment offered partnership and safety for academic risk-taking. Teachers broke down traditional roles and power hierarchies in ways that helped students discover their own sources of engagement. The article identifies ways that community psychologists, as policy framers and as researchers, can help schools become places of empowerment and engagement. PMID- 29431184 TI - An ultrasensitive chemiluminescence immunoassay for fumonisin B1 detection in cereals based on gold-coated magnetic nanoparticles. AB - BACKGROUND: In the present study, a novel highly sensitive magnetic enzyme chemiluminescence immunoassay (MECLIA) was developed to detect fumonisin B1 (FB1 ) in cereal samples. The gold-coated magnetic nanoparticles (Fe3 O4 @Au, GoldMag) were used as solid phase carrier to develop a competitive CLIA for detecting FB1 , in which FB1 in samples would compete with FB1 -ovalbumin coated on the surface of Fe3 O4 @Au nanoparticles for binding with FB1 antibodies. Successively, horseradish peroxidase labeled goat anti-rabbit IgG (HRP-IgG) was conjugated with FB1 antibodies on the microplate. In substrate solution containing luminol and H2 O2 , HRP-IgG catalyzed luminol oxidation by H2 O2 , generating a high chemiluminescence signal. The FB1 immune GoldMag particles were characterized by Fourier transform infrared spectroscopy, scanning electron microscope and zeta potential analysis, etc. RESULTS: The concentrations and the reaction times of these immunoreagents were optimized to improve the performances of this method. The established method could detect as low as 0.027 ng mL-1 FB1 from 0.05 ng mL-1 to 25 ng mL-1 , demonstrating little cross-reaction (less than 2.4%) with other structurally related compounds. The average intrassay relative SD (RSD) (n = 6) was 3.4% and the average interassay RSD (n = 6) was 5.4%. This method was successfully applied for the determination of FB1 in corn and wheat and gave recoveries of between 98-110% and 91-105%, respectively. CONCLUSION: The results of the present study suggest that the MECLIA approach has potential application for high-throughput fumonisin screening in cereals. (c) 2018 Society of Chemical Industry. PMID- 29431186 TI - Trogocytosis of ligand-receptor complex and its intracellular transport in CD30 signalling. AB - BACKGROUND INFORMATION: CD30, which is characteristically expressed in classical Hodgkin lymphoma (cHL), is thought to transduce signals by ligation of trimerised CD30 ligand (CD30L) on the surface of surrounding cells and recruitment of downstream molecules. In this report, we propose a new mechanism for CD30 signalling by its ligand. We prepared two stable transformants, CHO cells expressing CD30L fused to mCherry and HeLa cells expressing CD30 fused to GFP. RESULTS: Co-culture of these cells triggered clustering of CD30 and CD30L at the cellular interface, formation of multiple CD30L-CD30 complexes, internalisation of these complexes with a portion of the plasma membrane into the HeLa cells, and intracellular transport to the lysosomal compartment. The internalisation process was significantly inhibited by actin polymerisation inhibitors. The CD30L-CD30 interaction was found to trigger active signalling processes, as measured by Ca2+ influx, and similar mechanisms were observed using cHL cell lines. CONCLUSIONS: These results suggest that CD30 extracts CD30L from CD30L-expressing cells by actin-mediated trogocytosis, resulting in the generation of signalosomes, intracellular signalling, lysosomal degradation and a subsequent refractory phase. We postulate that similar processes may operate in tumours endogenously expressing CD30. These observations thus provide new insights into our understanding of the biological roles of CD30 in normal and malignant cells and, in particular, in cHL. SIGNIFICANCE: This study suggests a novel model of CD30 signalling that provides new insights into the biological roles of CD30 and other members of this family in normal and malignant cells. PMID- 29431187 TI - Migration Factors in West African Immigrant Parents' Perceptions of Their Children's Neighborhood Safety. AB - Immigrants make up large proportions of many low-income neighborhoods, but have been largely ignored in the neighborhood safety literature. We examined perceived safety's association with migration using a six-item, child-specific measure of parents' perceptions of school-aged (5-12 years of age) children's safety in a sample of 93 West African immigrant parents in New York City. Aims of the study were (a) to identify pre-migration correlates (e.g., trauma in home countries), (b) to identify migration-related correlates (e.g., immigration status, time spent separated from children during migration), and (c) to identify pre migration and migration correlates that accounted for variance after controlling for non-migration-related correlates (e.g., neighborhood crime, parents' psychological distress). In a linear regression model, children's safety was associated with borough of residence, greater English ability, less emotional distress, less parenting difficulty, and a history of child separation. Parents' and children's gender, parents' immigration status, and the number of contacts in the U.S. pre-migration and pre-migration trauma were not associated with children's safety. That child separation was positively associated with safety perceptions suggests that the processes that facilitate parent-child separation might be reconceptualized as strengths for transnational families. Integrating migration-related factors into the discussion of neighborhood safety for immigrant populations allows for more nuanced views of immigrant families' well being in host countries. PMID- 29431188 TI - DJ-1 plays an obligatory role in the cardioprotection of delayed hypoxic preconditioning against hypoxia/reoxygenation-induced oxidative stress through maintaining mitochondrial complex I activity. AB - DJ-1 was recently reported to mediate the cardioprotection of delayed hypoxic preconditioning (DHP) by suppressing hypoxia/reoxygenation (H/R)-induced oxidative stress, but its mechanism against H/R-induced oxidative stress during DHP is not fully elucidated. Here, using the well-established cellular model of DHP, we again found that DHP significantly improved cell viability and reduced lactate dehydrogenase release with concurrently up-regulated DJ-1 protein expression in H9c2 cells subjected to H/R. Importantly, DHP efficiently improved mitochondrial complex I activity following H/R and attenuated H/R-induced mitochondrial reactive oxygen species (ROS) generation and subsequent oxidative stress, as demonstrated by a much smaller decrease in reduced glutathione/oxidized glutathione ratio and a much smaller increase in intracellular ROS and malondialdehyde contents than that observed for the H/R group. However, the aforementioned effects of DHP were antagonized by DJ-1 knockdown with short hairpin RNA but mimicked by DJ-1 overexpression. Intriguingly, pharmacological inhibition of mitochondria complex I with Rotenone attenuated all the protective effects caused by DHP and DJ-1 overexpression, including maintenance of mitochondria complex I and suppression of mitochondrial ROS generation and subsequent oxidative stress. Taken together, this work revealed that preserving mitochondrial complex I activity and subsequently inhibiting mitochondrial ROS generation could be a novel mechanism by which DJ-1 mediates the cardioprotection of DHP against H/R-induced oxidative stress damage. PMID- 29431189 TI - Molecular analysis of PALB2-associated breast cancers. AB - PALB2 is established as the most clinically important moderate to high penetrance breast cancer predisposition gene after BRCA1 and BRCA2. Mutations in classical familial cancer predisposition genes are presumed to be recessive at the cellular level and therefore a second inactivating somatic mutation is required in the tumour tissue. However, from the limited data that exist, PALB2 may be an example of a cancer predisposition gene that does not conform to Knudson's 'two hit' paradigm. We conducted genome-wide copy number analysis and targeted sequencing of PALB2 and other breast cancer driver genes in 15 invasive breast cancers from individuals carrying pathogenic germline mutations in PALB2. The majority of cancers showed clear evidence of bi-allelic inactivation of PALB2 (10/15) either as loss of heterozygosity involving the wild-type allele (six tumours) or as somatic point mutations (four tumours). All PALB2-null cancers had high homologous recombination deficiency (HRD) scores consistent with a homologous recombination repair deficiency. Interestingly, all but one of the PALB2 heterozygous cancers also had high HRD scores, suggesting that alternative mechanisms of PALB2 functional loss might be operating in these cancers. Our findings demonstrate that PALB2 does undergo bi-allelic inactivation in the majority of breast cancers from PALB2 germline mutation carriers. This feature has implications for the discovery of new moderate to high penetrance breast cancer predisposition genes as it supports using the existence of a 'second hit' and mutation signatures as important search criteria. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29431190 TI - "A joke a day keeps the doctor away?" Meta-analytical evidence of differential associations of habitual humor styles with mental health. AB - Humor and mental health are interconnected as is evidenced by a large number of studies. However, associations are only small and inconsistent as the operationalization of humor poses a methodological challenge. The Humor Styles Questionnaire (HSQ) differentiates four humor styles that might be beneficial or harmful to mental health. The aim of the present study was to meta-analytically aggregate studies using the HSQ to assess the associations of different humor styles with four areas of mental health (self-esteem, life satisfaction, optimism, depression). An extensive electronic database literature search identified 37 studies that reported correlations between the HSQ scales and the four areas of mental health in 45 independent samples (total N = 12,734). In total, 16 meta-analyses were conducted. Moderating effects of participant age, sex, and geographic region were examined via subgroup analyses and meta regression. Humor styles differed in terms of their associations with mental health. Health-promoting humor styles were overall positively correlated with mental health (small-to-medium effect sizes). Self-defeating humor was overall negatively correlated with mental health. Aggressive humor was overall unrelated with mental health. Moderator analyses suggested geographic differences (Eastern vs. Western samples) and sex differences for some of these associations. Fostering specific humor styles may be beneficial for mental health. In addition, observing the habitual use of humor styles might help therapists to develop a better understanding of their clients. Differences in the utilization and the correlates of humor styles in Eastern and Western societies, and sex differences, need to be addressed in future research. PMID- 29431191 TI - In vivo microdialysis with ultra performance liquid chromatography-mass spectrometry for analysis of tetramethylpyrazine and its interaction with borneol in rat brain and blood. AB - Tetramethylpyrazine (TMP) has been widely used in the treatment of ischemic cerebrovascular disease. However, the mechanism of TMP and how to increase its bioavailability need to be further explored. In our study, an in vivo microdialysis sampling technique coupled with ultra-performance liquid chromatography-mass spectrometry method was developed to investigate the pharmacokinetic properties of TMP and its interaction with different doses of borneol (BO) in rats. Linearity of TMP in brain and blood dialysates exhibited good linear relationships over the concentration range of 0.991-555.14 ng/mL. The specificity, linearity, accuracy, precision, matrix effect and stability were within acceptable ranges. The results demonstrated that BO had a marked impact on the pharmacokinetic properties of TMP. After co-administration, the areas under the concentration-time curve (AUC) of TMP in brain and blood were significantly increased. Meanwhile, the peak concentration of TMP in brain was also enhanced. The AUCBrain /AUCBlood of TMP, increased from 44% to 56 and 60.8% after co administration with BO (15 and 30 mg/kg). The pharmacodynamic results showed that TMP co-administration with BO enhanced the cerebral blood flow during the period of ischemia and reduced the infarct volume. Overall, it might be an effective way to treat stroke to use TMP co-administered with BO. PMID- 29431192 TI - Modeling Dewatered Domains in Multilayer Analytic Element Models. AB - This proposed technique allows sensible and numerically stable behavior in multilayer analytic element models when layers dewater. When saturated thickness approaches zero in an unconfined or fresh/salt interface domain, the domain transitions to a very thin confined domain with a minimum saturated thickness M. M is an adjustable input parameter, so you can make the horizontal flow in dewatered domains negligibly small by making the minimum saturated thickness very small. Vertical flows can pass through a dewatered domain, whether it is near the surface or at depth. For example, recharge may pass through a shallow dewatered layer to a deeper layer that is not dewatered. This approach is examined in detail in an example multilayer model of mine dewatering. PMID- 29431194 TI - Neuronal-like differentiated SH-SY5Y cells adaptation to a mild and transient H2 O2 -induced oxidative stress. AB - : Preconditioning (PC) is a cell adaptive response to oxidative stress and, with regard to neurons, can be considered as a neuroprotective strategy. The aim of the present study was to verify how neuronal-like differentiated SH-SY5Y cells adapt to a mild and transient H2 O2 -induced oxidative stress and, hence, whether may be considered as more sensitive cell model to study PC pathways. A first screening allowed to define H2 O2 concentrations for PC (10MUM-50MUM), applied before damage(100MUM H2 O2 ). Cell viability measured 24 hours after 100MUM H2 O2 -induced damage was ameliorated by 24-hour pre-exposure to low-concentration H2 O2 (10MUM-30MUM) with cell size as well restored. Markers for apoptosis (Bcl-2 and Bad), inflammation (iNOS), and redox system (MnSOD) were also determined, showing that, in cells pre-exposed to 10MUM H2 O2 and then submitted to 100MUM H2 O2 , Bcl-2 levels were higher, Bad and iNOS levels were lower than those observed in damaged cells, and MnSOD levels were unchanged. Such findings show that (1) neuronal-like differentiated SH-SY5Y cells are a suitable model to investigate PC response and more sensitive to the effect of a mild and transient H2 O2 -induced oxidative stress with respect to other neuronal cells; (2) 10MUM H2 O2 -induced PC is mediated by apoptotic and inflammatory pathways, unlike antioxidant system; (3) such neuroprotective strategy and underlying signals proven in neuronal-like differentiated SH-SY5Y cells may contribute to understand in vivo PC mechanisms and to define a window for pharmacological intervention, namely, related to ischemic brain damage. SIGNIFICANCE OF THE STUDY: Neuronal-like differentiated SH SY5Y cells are a suitable model to investigate PC, an endogenous neuroprotective response to a mild and transient H2 O2 -induced oxidative stress, elicited by 24 hour exposure to very low H2 O2 concentrations and mediated by both apoptotic and inflammatory pathways. This model reflects in vivo PC mechanisms occurring after brain trauma and provides novel information about pathways and time of protection useful for an appropriate pharmacological intervention. PMID- 29431196 TI - Cutting nature at its joints, but how and where? PMID- 29431195 TI - Parsing the guidelines on guidelines: Balancing sensibility and conflict of interest. PMID- 29431193 TI - Circulating tumor cells and survival in abiraterone- and enzalutamide-treated patients with castration-resistant prostate cancer. AB - BACKGROUND: The outcome to treatment administered to patients with metastatic castration-resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers guiding treatment decision making. OBJECTIVE: To investigate the prognostic value of circulating tumor cell (CTC) enumeration and dynamics, in the context of second-line endocrine therapies (ie, abiraterone acetate or enzalutamide), irrespective of prior systemic therapies. DESIGN, SETTINGS, AND PARTICIPANTS: In a prospective, multicentre study blood samples for CTC enumeration were collected from patients with mCRPC at baseline (n = 174). In patients who responded for minimally 10-12 weeks a follow-up sample was collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For baseline analysis, patients were stratified in <5 or >=5 CTCs/7.5 mL, whereas for the analysis of CTC dynamics at 10-12 weeks, in patients with stable, increasing or decreasing CTC counts. Progression-free survival (PFS), overall survival (OS), and PSA changes at 10-12 weeks were compared between groups. RESULTS: Patients demonstrating increasing CTCs on therapy had a shorter median PFS (4.03 vs 12.98 vs 13.67 months, HR 3.6, 95%CI 1.9-6.8; P < 0.0001) and OS (11.2 months vs not reached, HR 9.5, 95%CI 3.7-24; P < 0.0001), compared to patients with decreasing or stable CTCs. Multivariable Cox regression showed that prior chemotherapy (HR 4.1, 95%CI 1.9-8.9; P = 0.0003), a high baseline CTC count (HR 1.5, 95%CI 1.2 1.9; P = 0.002) and increasing CTCs at follow-up (HR 3.3, 95%CI 1.4-7.6; P = 0.005) were independent predictors of worse PFS. Previous chemotherapy (HR 7, 95%CI 1.9-25; P = 0.003), high baseline CTC counts (HR 2.2, 95%CI 1.4-3.7; P = 0.002) and increasing CTCs during therapy (HR 4.6, 95%CI 1.4-15; P = 0.01) were independently associated with shorter OS. >=30% and >=50% PSA responses less frequently occurred in patients with CTC inclines at 10-12 weeks on therapy (chi2 test: P < 0.01). CONCLUSIONS: CTC dynamics during therapy are associated with PSA response and provide independent clinical prognostication over PSA declines. Hence the study demonstrates the pharmacodynamic properties of CTCs. PMID- 29431197 TI - Efficacy and safety of antidepressant augmentation of continued antipsychotic treatment in patients with schizophrenia. AB - OBJECTIVE: To evaluate the efficacy and safety of antidepressant augmentation of antipsychotics in schizophrenia. METHODS: Systematic literature search (PubMed/MEDLINE/PsycINFO/Cochrane Library) from database inception until 10/10/2017 for randomized, double-blind, efficacy-focused trials comparing adjunctive antidepressants vs. placebo in schizophrenia. RESULTS: In a random effects meta-analysis (studies = 42, n = 1934, duration = 10.1 +/- 8.1 weeks), antidepressant augmentation outperformed placebo regarding total symptom reduction [standardized mean difference (SMD) = -0.37, 95% confidence interval (CI) = -0.57 to -0.17, P < 0.001], driven by negative (SMD = -0.25, 95% CI = 0.44-0.06, P = 0.010), but not positive (P = 0.190) or general (P = 0.089) symptom reduction. Superiority regarding negative symptoms was confirmed in studies augmenting first-generation antipsychotics (FGAs) (SMD = -0.42, 95% CI = 0.77, -0.07, P = 0.019), but not second-generation antipsychotics (P = 0.144). Uniquely, superiority in total symptom reduction by NaSSAs (SMD = -0.71, 95% CI = -1.21, -0.20, P = 0.006) was not driven by negative (P = 0.438), but by positive symptom reduction (SMD = -0.43, 95% CI = -0.77, -0.09, P = 0.012). Antidepressants did not improve depressive symptoms more than placebo (P = 0.185). Except for more dry mouth [risk ratio (RR) = 1.57, 95% CI = 1.04-2.36, P = 0.03], antidepressant augmentation was not associated with more adverse events or all-cause/specific-cause discontinuation. CONCLUSIONS: For schizophrenia patients on stable antipsychotic treatment, adjunctive antidepressants are effective for total and particularly negative symptom reduction. However, effects are small-to-medium, differ across antidepressants, and negative symptom improvement seems restricted to the augmentation of FGAs. PMID- 29431198 TI - Metabolomic analysis for the protective effects of mangiferin on sepsis-induced lung injury in mice. AB - This study aimed to investigate the efficacy of mangiferin, including its known antioxidant and anti-inflammatory effects on sepsis-induced lung injury induced by a classical cecal ligation and puncture (CLP) models in mouse using a metabolomics approach. A total of 24 mice were randomly divided into four groups: the sham group was given saline before sham operation. The CLP group received the CLP operation only. HMF and LMF groups were given mangiferin treatment of high dose and low dose of mangiferin, respectively, before the CLP operation. One week after treatment, the mice were sacrificed and their lungs were collected for metabolomics analysis. We developed ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry to perform lung metabolic profiling analysis. With the methods of principal component analysis and partial least squares discriminant analysis, 58 potential metabolites associated with amino acid metabolism, purine metabolism, lipid metabolism and energy regulation were observed to be increased or reduced in HMF and LMF groups compared with the CLP group. Conclusively, our results suggest that mangiferin plays a protective role in the moderation of sepsis-induced lung injury through reducing oxidative stress, regulating lipid metabolism and energy biosynthesis. PMID- 29431200 TI - GATA3 staining in primary cutaneous apocrine cribriform carcinoma: Usefulness to differentiate it from breast cancer metastasis. AB - BACKGROUND: Primary cutaneous apocrine cribriform carcinoma (PCACC) is a rare tumor, clinically appearing as a solitary nodule, mostly involving extremities of females and this lesion usually raises a differential diagnosis with metastatic cribriform carcinomas, especially breast cancer. OBJECTIVE: To study GATA3 expression in a series of 14 primary cutaneous cribriform carcinomas and to test its usefulness to differentiate this tumor from metastatic breast cancer. METHODS: We retrieved 14 cases with PCACC (each from a different patient) from the files of the authors. Cases were dated from 1994 to 2014. We also evaluated 6 cases of cutaneous breast cancer metastasis RESULTS: No PCACCs expressed GATA3. Breast cancer metastases expressed GATA3 in 100% of our studied cases. CONCLUSION: Even though GATA3 expression has been reported in many benign and malignant adnexal tumors (mostly of sebaceous, follicular, and apocrine differentiation), as well as in many other neoplasms, GATA3 staining to differentiate PCACC from skin breast cancer metastasis has a high negative predictive value. A positive GATA3 staining in this context should permit one to rule out PCACC with a high level of confidence. PMID- 29431199 TI - N-glycosylation by N-acetylglucosaminyltransferase V enhances the interaction of CD147/basigin with integrin beta1 and promotes HCC metastasis. AB - While the importance of protein N-glycosylation in cancer cell migration is well appreciated, the precise mechanisms by which N-acetylglucosaminyltransferase V (GnT-V) regulates cancer processes remain largely unknown. In the current study, we report that GnT-V-mediated N-glycosylation of CD147/basigin, a tumor associated glycoprotein that carries beta1,6-N-acetylglucosamine (beta1,6-GlcNAc) glycans, is upregulated during TGF-beta1-induced epithelial-to-mesenchymal transition (EMT), which correlates with tumor metastasis in patients with hepatocellular carcinoma (HCC). Interruption of beta1,6-GlcNAc glycan modification of CD147/basigin decreased matrix metalloproteinase (MMP) expression in HCC cell lines and affected the interaction of CD147/basigin with integrin beta1. These results reveal that beta1,6-branched glycans modulate the biological function of CD147/basigin in HCC metastasis. Moreover, we showed that the PI3K/Akt pathway regulates GnT-V expression and that inhibition of GnT-V-mediated N-glycosylation suppressed PI3K signaling. In summary, beta1,6-branched N glycosylation affects the biological function of CD147/basigin and these findings provide a novel approach for the development of therapeutic strategies targeting metastasis. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29431201 TI - The in-hospital burden of hidradenitis suppurativa in patients with inflammatory bowel disease: a decade nationwide analysis from 2004 to 2014. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that significantly affects the patient's quality of life. Multiple studies have shown a strong association between HS and inflammatory bowel disease (IBD). Our primary goal was to explore the in-hospital burden of HS on patients with IBD. Our secondary goal was to establish unique baseline characteristics and comorbidities of IBD patients with HS. METHODS: This was a retrospective cohort study using the National Inpatient Sample (NIS) database for the years 2004 through 2014. All patients with ICD-9 CM codes for any diagnosis of IBD and HS were included. The primary outcome was the medical and financial burden of HS on patients with IBD. Medical burden was measured by in-hospital morbidity and mortality, and financial burden was measured by resource utilization. RESULTS: A total of 3,079,332 admissions with IBD were recorded, of which 4369 had a concomitant diagnosis of HS. IBD-HS patients were significantly younger and mostly African-American females; they were more likely to be smokers, obese, and have diabetes mellitus, depression, and anemia. There was no mortality difference between the IBD-HS and IBD-only groups; nevertheless, there was a higher likelihood of developing sepsis in the IBD-HS cohort (4.9% vs. 2.6%; P < 0.001). Patients with IBD-HS had an increased hospital length of stay (5 vs. 4 days; P < 0.001) and higher total hospitalization costs ($13,272 vs. $12,237; P = 0.013). CONCLUSIONS: This large scale study strengthens the evidence that these two inflammatory conditions are truly associated and establishes their joint effect on overall morbidity, mortality, and resource utilization. PMID- 29431202 TI - The role and relevance of mast cells in urticaria. AB - This review presents evidence that the skin mast cell, in particular the MCTC subtype, is the primary effector cell in urticaria. Mast cells are located in the upper dermis, the ideal situation for wheal formation and sensory nerve stimulation. Increased numbers of mast cells are found in both lesional and non lesional skin in CSU and inducible urticaria. Mast cell degranulation in the area of wheals has been demonstrated repeatedly by light and electron microscopy. Histamine, PGD2 and tryptase are found in the venous blood draining wheal formation. The last 2 are specific for mast cells rather than basophils. Mast cell reactivity is increased in active urticaria by local inflammatory cytokines and neuropeptides. Mast cell cytokines and neuropeptides, particularly nerve growth factor, induce a Th2 type inflammation that is particularly obvious at the sites of whealing. In conclusion, autoimmunity, either of Type 1 viz. IgE antibodies to local autoallergens, or Type 2b, viz. IgG autoantibodies to IgE or its receptor, are considered to be the most frequent causes of CSU. In both cases, the mast cell is likely to be the axial cell in producing the wheals. PMID- 29431203 TI - Changing the threshold-Signals and mechanisms of mast cell priming. AB - Mast cells play a key role in allergy and other inflammatory diseases involving engagement of multivalent antigen with IgE bound to high-affinity IgE receptors (FcepsilonRIs). Aggregation of FcepsilonRIs on mast cells initiates a cascade of signaling events that eventually lead to degranulation, secretion of leukotrienes and prostaglandins, and cytokine and chemokine production contributing to the inflammatory response. Exposure to pro-inflammatory cytokines, chemokines, bacterial and viral products, as well as some other biological products and drugs, induces mast cell transition from the basal state into a primed one, which leads to enhanced response to IgE-antigen complexes. Mast cell priming changes the threshold for antigen-mediated activation by various mechanisms, depending on the priming agent used, which alone usually do not induce mast cell degranulation. In this review, we describe the priming processes induced in mast cells by various cytokines (stem cell factor, interleukins-4, -6 and -33), chemokines, other agents acting through G protein-coupled receptors (adenosine, prostaglandin E2 , sphingosine-1-phosphate, and beta-2-adrenergic receptor agonists), toll-like receptors, and various drugs affecting the cytoskeleton. We will review the current knowledge about the molecular mechanisms behind priming of mast cells leading to degranulation and cytokine production and discuss the biological effects of mast cell priming induced by several cytokines. PMID- 29431204 TI - Is it time for a new classification of mast cells? What do we know about mast cell heterogeneity? AB - Mast cells (MCs) are derived from committed precursors that leave the hematopoietic tissue, migrate in the blood, and colonize peripheral tissues where they terminally differentiate under microenvironment stimuli. They are distributed in almost all vascularized tissues where they act both as immune effectors and housekeeping cells, contributing to tissue homeostasis. Historically, MCs were classified into 2 subtypes, according to tryptic enzymes expression. However, MCs display a striking heterogeneity that reflects a complex interplay between different microenvironmental signals delivered by various tissues, and a differentiation program that decides their identity. Moreover, tissue-specific MCs show a trained memory, which contributes to shape their function in a specific microenvironment. In this review, we summarize the current state of our understanding of MC heterogeneity that reflects their different tissue experiences. We describe the discovery of unique cell molecules that can be used to distinguish specific MC subsets in vivo, and discuss how the improved ability to recognize these subsets provided new insights into the biology of MCs. These recent advances will be helpful for the understanding of the specific role of individual MC subsets in the control of tissue homeostasis, and in the regulation of pathological conditions such as infection, autoimmunity, and cancer. PMID- 29431205 TI - Non-IgE mediated mast cell activation. AB - Mast cells (MCs) are innate immune cells that are scattered in tissues throughout the organism being particularly abundant at sites exposed to the environment such as the skin and mucosal surfaces. Generally known for their role in IgE-mediated allergies, they have also important functions in the maintenance of tissue integrity by constantly sensing their microenvironment for signals by inflammatory triggers that can comprise infectious agents, toxins, hormones, alarmins, metabolic states, etc. When triggered their main function is to release a whole set of inflammatory mediators, cytokines, chemokines, and lipid products. This allows them to organize the ensuing innate immune and inflammatory response in tight coordination with resident tissue cells, other rapidly recruited immune effector cells as well as the endocrine and exocrine systems of the body. To complete these tasks, MCs are endowed with a large repertoire of receptors allowing them to respond to multiple stimuli or directly interact with other cells. Here we review some of the receptors expressed on MCs (ie, receptors for Immunoglobulins, pattern recognition receptors, nuclear receptors, receptors for alarmins, and a variety of other receptors) and discuss their functional implication in the immune and inflammatory response focusing on non-IgE-mediated activation mechanisms. PMID- 29431206 TI - Imaging of mast cells. AB - Mast cells are a part of the innate immune system implicated in allergic reactions and the regulation of host-pathogen interactions. The distribution, morphology and biochemical composition of mast cells has been studied in detail in vitro and on tissue sections both at the light microscopic and ultrastructural level. More recently, the development of fluorescent reporter strains and intravital imaging modalities has enabled first glimpses of the real-time behavior of mast cells in situ. In this review, we describe commonly used imaging approaches to study mast cells in cell culture as well as within normal and diseased tissues. We further describe the interrogation of mast cell function via imaging by providing a detailed description of mast cell-nerve plexus interactions in the intestinal tract. Together, visualizing mast cells has expanded our view of these cells in health and disease. PMID- 29431207 TI - Role of mast cells and basophils in pruritus. AB - To protect our body systems, there is a constant interactive conversation between the skin nervous and immune system. Important elements of this conversation in the skin include mast cells, basophils, and sensory nerve fibers. These cells employ a vast array of sensors that detect danger and react accordingly. This reaction, summarized as neurogenic inflammation, manifests at the conscious level as sensations including pain and itch. Here we provide a perspective on the blossoming knowledge that is illuminating connections between mast cells, basophils, and sensory nerve fibers in the mediation of itch. We discuss established mediators and receptors, in particular cytokine and neuropeptide pathways, upstream proteases, and proteinase-activated receptors, and the emerging role of mas-related G-protein-coupled receptors in itch. PMID- 29431208 TI - RBL cells as models for in vitro studies of mast cells and basophils. AB - Since their establishment in 1981, RBL-2H3 cells have been widely used as a mast cell (MC) model. Their ability to be easily grown in culture in large amounts, their responsiveness to FcepsilonRI-mediated triggers and the fact that they can be genetically manipulated, have provided advantages over primary MCs, in particular for molecular studies relying on genetic screening. Furthermore, the ability to generate clones that stably express proteins of interest, for example, a human receptor, have marked the RBL cells as an attractive MC model for drug screening. Indeed, 3 RBL reporter cell lines (RS-ATL8, NFAT-DsRed, and NPY-mRFP) have been generated providing useful models for drug and allergen screening. Similarly, RBL cells stably expressing the human MrgprX2 receptor provide a unique paradigm for analyzing ligand interactions and signaling pathways of the unique human receptor. Finally, transient co-transfections of RBL cells allow functional genomic analyses of MC secretion by combining library screening with simultaneous expression of a reporter for exocytosis. RBL cells thus comprise powerful tools for the study of intracellular membrane trafficking and exocytosis and the detection of allergens, vaccine safety studies and diagnosis of allergic sensitization. Their recent uses as an investigative tool are reviewed here. PMID- 29431209 TI - Biomarkers for evaluation of mast cell and basophil activation. AB - Mast cells and basophils play a pathogenetic role in allergic, inflammatory, and autoimmune disorders. These cells have different development, anatomical location and life span but share many similarities in mechanisms of activation and type of mediators. Mediators secreted by mast cells and basophils correlate with clinical severity in asthma, chronic urticaria, anaphylaxis, and other diseases. Therefore, effective biomarkers to measure mast cell and basophil activation in vivo could potentially have high diagnostic and prognostic values. An ideal biomarker should be specific for mast cells or basophils, easily and reproducibly detectable in blood or biological fluids and should be metabolically stable. Markers of mast cell and basophil include molecules secreted by stimulated cells and surface molecules expressed upon activation. Some markers, such as histamine and lipid mediators are common to mast cells and basophils whereas others, such as tryptase and other proteases, are relatively specific for mast cells. The best surface markers of activation expressed on mast cells and basophils are CD63 and CD203. While these mediators and surface molecules have been associated to a variety of diseases, none of them fulfills requirements for an optimal biomarker and search for better indicators of mast cell/basophil activation in vivo is ongoing. PMID- 29431210 TI - Corrigendum. PMID- 29431213 TI - What we know (and don't know) about the biology and functions of mast cells and basophils. PMID- 29431211 TI - The contribution of mast cells to bacterial and fungal infection immunity. AB - Mast cells are hematopoietic progenitor-derived, granule-containing immune cells that are widely distributed in tissues that interact with the external environment, such as the skin and mucosal tissues. It is well-known that mast cells are significantly involved in IgE-mediated allergic reactions, but because of their location, it has also been long hypothesized that mast cells can act as sentinel cells that sense pathogens and initiate protective immune responses. Using mast cell or mast cell protease-deficient murine models, recent studies by our groups and others indicate that mast cells have pleiotropic regulatory roles in immunological responses against pathogens. In this review, we discuss studies that demonstrate that mast cells can either promote host resistance to infections caused by bacteria and fungi or contribute to dysregulated immune responses that can increase host morbidity and mortality. Overall, these studies indicate that mast cells can influence innate immune responses against bacterial and fungal infections via multiple mechanisms. Importantly, the contribution of mast cells to infection outcomes depends in part on the infection model, including the genetic approach used to assess the influence of mast cells on host immunity, hence highlighting the complexity of mast cell biology in the context of innate immune responses. PMID- 29431214 TI - Human mast cells and basophils-How are they similar how are they different? AB - Mast cells and basophils are key contributors to allergies and other inflammatory diseases since they are the most prominent source of histamine as well as numerous additional inflammatory mediators which drive inflammatory responses. However, a closer understanding of their precise roles in allergies and other pathological conditions has been marred by the considerable heterogeneity that these cells display, not only between mast cells and basophils themselves but also across different tissue locations and species. While both cell types share the ability to rapidly degranulate and release histamine following high-affinity IgE receptor cross-linking, they differ markedly in their ability to either react to other stimuli, generate inflammatory eicosanoids or release immunomodulating cytokines and chemokines. Furthermore, these cells display considerable pharmacological heterogeneity which has stifled attempts to develop more effective anti-allergic therapies. Mast cell- and basophil-specific transcriptional profiling, at rest and after activation by innate and adaptive stimuli, may help to unravel the degree to which these cells differ and facilitate a clearer understanding of their biological functions and how these could be targeted by new therapies. PMID- 29431212 TI - Mast cells as sources of cytokines, chemokines, and growth factors. AB - Mast cells are hematopoietic cells that reside in virtually all vascularized tissues and that represent potential sources of a wide variety of biologically active secreted products, including diverse cytokines and growth factors. There is strong evidence for important non-redundant roles of mast cells in many types of innate or adaptive immune responses, including making important contributions to immediate and chronic IgE-associated allergic disorders and enhancing host resistance to certain venoms and parasites. However, mast cells have been proposed to influence many other biological processes, including responses to bacteria and virus, angiogenesis, wound healing, fibrosis, autoimmune and metabolic disorders, and cancer. The potential functions of mast cells in many of these settings is thought to reflect their ability to secrete, upon appropriate activation by a range of immune or non-immune stimuli, a broad spectrum of cytokines (including many chemokines) and growth factors, with potential autocrine, paracrine, local, and systemic effects. In this review, we summarize the evidence indicating which cytokines and growth factors can be produced by various populations of rodent and human mast cells in response to particular immune or non-immune stimuli, and comment on the proven or potential roles of such mast cell products in health and disease. PMID- 29431217 TI - The role of mast cells in autoinflammation. AB - The concept of autoinflammation was proposed to define a new class of immune disorders categorized by self-directed inflammation that is driven via activation of innate immune pathways. Within innate immunity, inflammasomes serve as intracellular signaling platforms to endogenous danger molecules and pathogens. Their key function is the cleavage of pro-interleukin-1beta (pro-IL-1beta) into its active form to promote inflammation and programmed cell death. A growing number of inflammasome sensors were described, among which NLR family pyrin domain containing 3 (NLRP3) is the best-studied sensor. Besides macrophages, monocytes, and other innate immune cells, mast cells (MCs) were shown to express functional inflammasomes too. Also, MCs are both, a source and target of IL 1beta. Here we review the functional relevance and role of MC inflammasomes and MC-derived IL-1beta in contributing to the inflammation at the skin, joints, and central nervous system in rare monogenic autoinflammatory conditions and also common inflammatory and degenerative diseases. PMID- 29431218 TI - The controversial role of mast cells in fibrosis. AB - Fibrosis is a medical condition characterized by an excessive deposition of extracellular matrix compounds such as collagen in tissues. Fibrotic lesions are present in many diseases and can affect all organs. The excessive extracellular matrix accumulation in these conditions can often have serious consequences and in many cases be life-threatening. A typical event seen in many fibrotic conditions is a profound accumulation of mast cells (MCs), suggesting that these cells can contribute to the pathology. Indeed, there is now substantialv evidence pointing to an important role of MCs in fibrotic disease. However, investigations from various clinical settings and different animal models have arrived at partly contradictory conclusions as to how MCs affect fibrosis, with many studies suggesting a detrimental role of MCs whereas others suggest that MCs can be protective. Here, we review the current knowledge of how MCs can affect fibrosis. PMID- 29431220 TI - Corrigendum. PMID- 29431219 TI - Morphological comparison of the ampullae of Lorenzini of three sympatric benthic rays. AB - This study investigated and compared the morphology of the electrosensory system of three species of benthic rays. Neotrygon trigonoides, Hemitrygon fluviorum and Maculabatis toshi inhabit similar habitats within Moreton Bay, Queensland, Australia. Like all elasmobranchs, they possess the ability to detect weak electrical fields using their ampullae of Lorenzini. Macroscopically, the ampullary organs of all three species are aggregated in three bilaterally paired clusters: the mandibular, hyoid and superficial ophthalmic clusters. The hyoid and superficial ophthalmic clusters of ampullae arise from both dorsal and ventral ampullary pores. The dorsal pores are typically larger than the ventral pores in all three species, except for the posterior ventral pores of the hyoid grouping. Ampullary canals arising from the hyoid cluster possessed a quasi sinusoidal shape, but otherwise appeared similar to the canals described for other elasmobranchs. Ultrastructure of the ampullae of Lorenzini of the three species was studied using a combination of light, confocal and electron microscopy. All possess ampullae of the alveolar type. In N. trigonoides and M. toshi, each ampullary canal terminates in three to five sensory chambers, each comprising several alveoli lined with receptor and supportive cells and eight to 11 sensory chambers in H. fluviorum. Receptor cells of all three species possess a similar organization to those of other elasmobranchs and were enveloped by large, apically nucleated supportive cells protruding well into the alveolar sacs. The luminally extended chassis of supportive cells protruding dramatically into the ampullary lumen had not previously been documented for any elasmobranch species. PMID- 29431221 TI - Human introduction or natural dispersion? Atlantic Ocean occurrence of the Indo Pacific whitetip reef shark Triaenodon obesus. AB - Occurrence of multiple whitetip reef sharks Triaenodon obesus in the Atlantic Ocean is reported for the first time from near a sunken ferry off the Parana coast in south-eastern Brazil. This occurrence is hypothesized to have been caused by either a human introduction or a remarkably long oceanic displacement. PMID- 29431222 TI - Saurogobio punctatus sp. nov., a new cyprinid gudgeon (Teleostei: Cypriniformes) from the Yangtze River, based on both morphological and molecular data. AB - A new cyprinid gudgeon, Saurogobio punctatus sp. nov., is described based on specimens collected from the Yangtze River, China. The new species can be distinguished from its congeners by differences in both morphology and the cytochrome b (cytb) gene sequence. Numerous minute blackish spots are scattered on dorsal and caudal fins in S. punctatus sp. nov. v. absent in the other seven valid Saurogobio species. The new species can be further distinguished from its congeners by the following unique combination of characters: a dorsal fin with eight branched rays; absence of scales in chest area before pectoral origin; upper and lower lips thick, covered with papillae; and a papillose mental pad approximately triangular. Morphologically, the new species most resembles the Chinese lizard gudgeon Saurogobio dabryi, but the new species lays yellowish adhesive eggs v. white pelagic eggs in S. dabryi. A phylogenetic analysis of all Saurogobio species based on cytb gene sequences indicated that S. punctatus sp. nov was distinctly separated from its congeners, with mean sequence divergence ranging from 12.6 to 21.0%. Therefore, molecular data further supported the distinctiveness of the new species. PMID- 29431223 TI - A rainbow trout Oncorhynchus mykiss strain with higher aerobic scope in normoxia also has superior tolerance of hypoxia. AB - This study compared parr from three strains of rainbow trout Oncorhynchus mykiss to examine intraspecific variation in metabolic traits, hypoxia tolerance and upper thermal tolerance in this species. At the strain level, variation in absolute aerobic scope (AAS), critical oxygen level (O2crit ), incipient lethal oxygen saturation (ILOS) and critical thermal maximum (CTmax ) generally exhibited consistent differences among the strains, suggesting the possibility of functional associations among these traits. This possibility was further supported at the individual level by a positive correlation between ILOS and O2crit and a negative correlation between O2crit and AAS. These results indicate that intraspecific differences in hypoxia tolerance among strains of O. mykiss may be primarily determined by differences in the ability to maintain oxygen uptake in hypoxia and that variation in aerobic scope in normoxia probably plays a role in determining the ability of these fish to sustain metabolism aerobically as water oxygen saturation is reduced. PMID- 29431216 TI - Mast cell-neural interactions contribute to pain and itch. AB - Mast cells are best recognized for their role in allergy and anaphylaxis, but increasing evidence supports their role in neurogenic inflammation leading to pain and itch. Mast cells act as a "power house" by releasing algogenic and pruritogenic mediators, which initiate a reciprocal communication with specific nociceptors on sensory nerve fibers. Consequently, nerve fibers release inflammatory and vasoactive neuropeptides, which in turn activate mast cells in a feedback mechanism, thus promoting a vicious cycle of mast cell and nociceptor activation leading to neurogenic inflammation and pain/pruritus. Mechanisms underlying mast cell differentiation, activation, and intercellular interactions with inflammatory, vascular, and neural systems are deeply influenced by their microenvironment, imparting enormous heterogeneity and complexity in understanding their contribution to pain and pruritus. Neurogenic inflammation is central to both pain and pruritus, but specific mediators released by mast cells to promote this process may vary depending upon their location, stimuli, underlying pathology, gender, and species. Therefore, in this review, we present the contribution of mast cells in pathological conditions, including distressing pruritus exacerbated by psychologic stress and experienced by the majority of patients with psoriasis and atopic dermatitis and in different pain syndromes due to mastocytosis, sickle cell disease, and cancer. PMID- 29431215 TI - Human eosinophils and mast cells: Birds of a feather flock together. AB - While the origin of the phrase "birds of a feather flock together" is unclear, it has been in use for centuries and is typically employed to describe the phenomenon that people with similar tastes or interests tend to seek each other out and congregate together. In this review, we have co-opted this phrase to compare innate immune cells of related origin, the eosinophil and mast cell, because they very often accumulate together in tissue sites under both homeostatic and inflammatory conditions. To highlight overlapping yet distinct features, their hematopoietic development, cell surface phenotype, mediator release profiles and roles in diseases have been compared and contrasted. What emerges is a sense that these two cell types often interact with each other and their tissue environment to provide synergistic contributions to a variety of normal and pathologic immune responses. PMID- 29431224 TI - A new species of Curimatopsis Steindachner (Characiformes: Curimatidae) from the Rio Nhamunda, Amazon basin. AB - A new species of Curimatopsis is described from the Rio Nhamunda, Amazon basin in northern Brazil. The new species is distinguished from congeners by the presence of a distinctive concentration of dark pigmentation over the entire lower lobe of the caudal fin, reticulate pattern of body pigmentation, lower jaw longer than and overlapping the anterior portion of the upper jaw, crescent-shaped posterior nostril and by morphometric and meristic data. Comments on the phylogenetic position of the new species within Curimatopsis are also provided. PMID- 29431225 TI - Highest catch of the vulnerable broadnose sevengill shark Notorynchus cepedianus in the south-west Atlantic. AB - An exceptional catch of 97 broadnose sevengill sharks Notorynchus cepedianus in Samborombon Bay, Argentina, in 2013 is described from a single overnight gillnet fishing operation. Sixty-five female and 32 male N. cepedianus, ranging in size between 105-201 and 112-190 cm LT , respectively, were recorded in this catch. Fishers' observations and published information suggest that this species aggregates in the area seasonally for feeding. PMID- 29431226 TI - Life-history traits of the leatherjacket Meuschenia scaber, a long-lived monacanthid. AB - The present study describes the age and growth of the leatherjacket Meuschenia scaber, a common Australasian monacanthid and valued by-catch of the inshore bottom trawl fishery in New Zealand. Age was determined from the sagittal otoliths of 651 individuals collected between July 2014 and March 2016 in the Hauraki Gulf of New Zealand. Otolith sections revealed alternating opaque and translucent zones and edge-type analysis demonstrated that these are deposited annually. Meuschenia scaber displayed rapid initial growth, with both males and females reaching maturity in 1-2 years and 50% of both sexes matured at 1.5 years. Maximum age differed substantially between the sexes, at 9.8 years for males and 17.1 years for females. Growth rate was similar between sexes, although males reached greater mass at age than females in the early part of the lifespan. The length-mass relationship differed significantly between the sexes, with males displaying negative allometric growth and females isometric growth. Female condition was highest in July, declined in August with the onset of spawning and showed a slight peak in January and February, immediately following the spawning season. This study substantially extends the maximum longevity recorded for monacanthids, although males had much shorter lifespans and higher mortality, than females. PMID- 29431227 TI - Parasitic copepods affect morphospace and diet of larvae of a temperate reef fish. AB - The effects of ectoparasites on larvae of the clingfish Gobiesox marmoratus were evaluated at the dietary and morphometric levels. The larvae and ectoparasites were collected by nearshore plankton samplings during October, November and December 2013 off El Quisco Bay, central Chile. The standardized abundance of total larvae and those ectoparasitized larvae (PL) was positively related and high parasite prevalence was found throughout the sampling period (up to 38%). Geometric morphometrics analyses indicate main changes in the shape through early ontogeny and subtle but significant variations between PL and non-parasitized larvae (NPL). Prey composition varied between PL and NPL; small size (<6 mm standard length, LS ) parasitized larval G. marmoratus ate mostly gastropod larvae, whereas small non-parasitized specimens ate mainly cirripede nauplii. All larger (>8 mm LS ), pre-settlement stages parasitized by Trifur and, or Caligus copepods had content in their gut, suggesting that ectoparasites did not diminish prey capture in host with larger size. Morphometric and dietary changes occurring during larval development were decoupled, both for PL and NPL. The maintenance of a slender, more hydrodynamic body through pelagic development and the ingestion of less-mobile prey in PL suggests non-lethal effects of ectoparasitism on rocky reef fish larvae. PMID- 29431228 TI - Efficacy of MAS063DP lotion vs 0.02% triamcinolone acetonide lotion in improving post-ablative fractional CO2 laser resurfacing wound healing: a split-face, triple-blinded, randomized, controlled trial. AB - Proven as effective acne scar treatment, ablative fractional carbon dioxide (AFCO2 ) laser requires post-laser wound healing care. MAS063DP is a multicomponent nonsteroidal anti-inflammatory moisturizer for effective post laser treatment. This study compares the efficacy of MAS063DP and 0.02% triamcinolone acetonide (TA) lotion for post-laser wound healing and complications. A split-face, triple-blinded, clinical study was performed in 16 patients, aged 20-50 years, receiving AFCO2 on both sides of the face, with MAS063DP on one side and 0.02% TA on the other side for 7 days twice daily. Digital photography, hemoglobin, and melanin index at baseline were obtained immediately after laser treatment and then at days 3, 5, 7, and 30. Erythema, edema, crusting, adverse effects, and post-inflammatory hyperpigmentation (PIH) were followed every visit. Sixteen patients, mean age 38.6 (8.4) years, with moderate-severe atrophic scar and skin phototype III-IV completed the study. Clinical improvement of edema, erythema, crusting, and hyperpigmentation was observed from day 3 to day 30 (P < 0.001), with no statistically significant difference in both groups. There was also no statistical difference of hemoglobin, melanin index, and texture at days 3, 5, 7, and 30. Melanin index at day 30 was significantly less than baseline in both MAS063DP and 0.02% TA. With PIH in 50% of cases, both treatments demonstrated good safety profiles and no serious adverse reactions. MAS063DP could be an effective treatment for post laser wound healing and complications, compatible to 0.02% TA. PMID- 29431229 TI - Utilization of health-care services by young children: The aftermath of the Turkish Health Transformation Program. AB - The Turkish Health Transformation Program, initiated in 2003, has identified achieving universal access to health care as 1 of its main tenets. To date, substantial progress has been made toward universal health coverage. Service utilization statistics display an upward trend. In this study, we use official and nationally representative microdata collected by the Turkish Health Research Surveys to examine young children's (ages 0-5) utilization of health services. Children in this age group deserve special attention because adverse health conditions in early childhood are known to have long-time consequences. Policy makers regularly monitor statistics such as infant mortality rate and under-5 mortality rate. We conduct logistic regression analyses to explain the probabilities of being taken to a health institution, to a dentist, and being included in the newborn screening program. We use a rich set of explanatory variables that represent the socioeconomic status (SES) of the child's household. Contrary to our expectations and to the goals of universal health coverage is SES indicators such as the insurance ownership of the parent matter for utilization. Decomposition analyses confirm these findings and reveal that the increase in utilization should have been higher than observed. Children from low SES households should be given special attention and that research efforts should focus on identifying the barriers that still hinder children's utilization of health-care services. PMID- 29431230 TI - Examining the association between exposure to mass media and health insurance enrolment in Ghana. AB - Although previous studies have explored the National Health Insurance Scheme (NHIS) in Ghana, very little attention is paid to the influence of mass media exposure on NHIS enrolment. Yet, understanding this linkage is important, particularly due to the critical role of mass media in disseminating health information and shaping people's health perceptions and choices. Using data from the 2014 Ghana Demographic and Health Survey, we employed logistic regression analysis to understand the relationship between NHIS enrolment and exposure to print media, radio, and television. Our findings indicate that women with more exposure to radio (OR = 1.23, P < 0.01) and television (OR = 1.24, P < 0.01) were more likely to enroll in the NHIS than those with no exposure. For men, more exposure to print media was associated with higher odds of enrolling in the NHIS (OR = 1.41, P < 0.01). In conclusion, all 3 types of media may be helpful in promoting NHIS enrolment in Ghana. However, given that the relationship between media exposure and enrolment in the NHIS was gendered, we recommend that policymakers should pay attention to these dynamics to ensure effective targeting in NHIS media campaigns for increased enrolment into the scheme. PMID- 29431231 TI - Defining Primary Care Shortage Areas: Do GIS-based Measures Yield Different Results? AB - PURPOSE: To examine whether geographic information systems (GIS)-based physician to-population ratios (PPRs) yield determinations of geographic primary care shortage areas that differ from those based on bounded-area PPRs like those used in the Health Professional Shortage Area (HPSA) designation process. METHODS: We used geocoded data on primary care physician (PCP) locations and census block population counts from 1 US state to construct 2 shortage area indicators. The first is a bounded-area shortage indicator defined without GIS methods; the second is a GIS-based measure that measures the populations' spatial proximity to PCP locations. We examined agreement and disagreement between bounded shortage areas and GIS-based shortage areas. FINDINGS: Bounded shortage area indicators and GIS-based shortage area indicators agree for the census blocks where the vast majority of our study populations reside. Specifically, 95% and 98% of the populations in our full and urban samples, respectively, reside in census blocks where the 2 indicators agree. Although agreement is generally high in rural areas (ie, 87% of the rural population reside in census blocks where the 2 indicators agree), agreement is significantly lower compared to urban areas. One source of disagreement suggests that bounded-area measures may "overlook" some shortages in rural areas; however, other aspects of the HPSA designation process likely mitigate this concern. Another source of disagreement arises from the border crossing problem, and it is more prevalent. CONCLUSIONS: The GIS-based PPRs we employed would yield shortage area determinations that are similar to those based on bounded-area PPRs defined for Primary Care Service Areas. Disagreement rates were lower than previous studies have found. PMID- 29431232 TI - Past, present, and future of a freshwater fish metapopulation in a threatened landscape. AB - It is well documented that hydropower plants can affect the dynamics of fish populations through landscape alterations and the creation of new barriers. Less emphasis has been placed on the examination of the genetic consequences for fish populations of the construction of dams. The relatively few studies that focus on genetics often do not consider colonization history and even fewer tend to use this information for conservation purposes. As a case study, we used a 3-pronged approach to study the influence of historical processes, contemporary landscape features, and potential future anthropogenic changes in landscape on the genetic diversity of a fish metapopulation. Our goal was to identify the metapopulation's main attributes, detect priority areas for conservation, and assess the consequences of the construction of hydropower plants for the persistence of the metapopulation. We used microsatellite markers and coalescent approaches to examine historical colonization processes, traditional population genetics, and simulations of future populations under alternate scenarios of population size reduction and gene flow. Historical gene flow appeared to have declined relatively recently and contemporary populations appeared highly susceptible to changes in landscape. Gene flow is critical for population persistence. We found that hydropower plants could lead to a rapid reduction in number of alleles and to population extirpation 50-80 years after their construction. More generally, our 3-pronged approach for the analyses of empirical genetic data can provide policy makers with information on the potential impacts of landscape changes and thus lead to more robust conservation efforts. PMID- 29431233 TI - Lactoferrin increases sperm membrane functionality of frozen equine semen. AB - During cryopreservation, sperm was submitted to an increase in reactive oxygen species generation. This work aimed to improve the quality of frozen equine sperm after the addition of antioxidants lactoferrin (Lf) and catalase (Cat) to a freezing extender. Semen from six stallions was frozen with the extenders: F1) control, INRA 82 freezing extender, F2) F1 + 500 MUg/ml Lf and F3) F1 + 200 IU/ml Cat. After thawing, sperm motility parameters, membrane functionality and integrity, and acrosome integrity and spontaneous acrosome-reacted sperm were evaluated with a computer-assisted sperm analysis, a hypoosmotic swelling test and epifluorescent microscopy, respectively. Nitrite, hydroperoxide and iron concentrations of frozen semen were measured with spectrophotometry. The percentage of functional membrane sperm treated with Lf was higher (50.7% +/- 11.6%) compared to that of the control (37.6% +/- 15.6%), while the iron (61.4 +/ 11.6 vs 73.3 +/- 13.8 mg/dl) and nitrite concentrations (16.3 +/- 7.1 vs 25.9 +/ 4.2 MUM/MUg protein) were lower, respectively (p < .05). Thus, it can be suggested that Lf protect stallion spermatozoon during freezing as it has increased the percentage of sperm with functional membrane and decreased the lipid oxidant agents. PMID- 29431234 TI - Barium titanate microparticles as potential carrier platform for lanthanide radionuclides for their use in the treatment of arthritis. AB - Since the inception of radiation synovectomy, a host of radioactive colloids and microparticles incorporating suitable therapeutic radionuclides have been proposed for the treatment of arthritis. The present article reports the synthesis and evaluation of barium titanate microparticles as an innovative and effective carrier platform for lanthanide radionuclides in the preparation of therapeutic agents for treatment of arthritis. The material was synthesized by mechanochemical route and characterized by X-ray diffraction, scanning electron microscopy, surface area, and particle size distribution analyses. Loading of lanthanide radionuclides (166 Ho, 153 Sm, 177 Lu, and 169 Er) on the microparticles was achieved in high yield (> 95%) resulting in the formulation of loaded particulates with excellent radiochemical purities (> 99%). Radiolanthanide-loaded microparticles exhibited excellent in vitro stability in human serum. In vitro diethylene triamine pentaacetic acid challenge study indicated fairly strong chemical association of lanthanides with barium titanate microparticles. Long-term biodistribution studies carried out after administration of 177 Lu-loaded microparticles into one of the knee joints of normal Wistar rats revealed near-complete retention of the formulation (> 96% of the administered radioactivity) within the joint cavity even 14 days post administration. The excellent localization of the loaded microparticles was further confirmed by sequential whole-body radio-luminescence imaging studies carried out using 166 Ho-loaded microparticles. PMID- 29431235 TI - Barriers to treatment adherence for individuals with latent tuberculosis infection: A systematic search and narrative synthesis of the literature. AB - OBJECTIVES: We investigated the rates of initiation and completion of treatment for latent TB infection (LTBI), factors explaining nonadherence and interventions to improve treatment adherence in countries with low TB incidence. DESIGN: A systematic search was performed in PubMed and Embase. All included articles were assessed for risk of bias. A narrative synthesis of the results was conducted. RESULTS: There were 54 studies included in this review. The proportion of people initiating treatment varied from 24% to 98% and the proportion of people completing treatment varied from 19% to 90%. The main barriers to adherence included the fear or experience of adverse effects, long duration of treatment, financial barriers, lack of transport to clinics (for patients), and insufficient resources for LTBI control. While interventions like peer counseling, incentives, and culturally specific case management have been used to improve adherence, the proportion of people who initiate and complete LTBI treatment still remains low. CONCLUSION: To further improve treatment and LTBI control and to fulfill the World Health Organization goal of eliminating TB in low-incidence countries, greater priority should be given to the use of treatment regimens involving shorter durations and fewer adverse effects, like the 3-month regimen of weekly rifapentine plus isoniazid, supported by innovative patient education and incentive strategies. PMID- 29431236 TI - Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure. AB - The influence of the solvent in nucleation of tolbutamide, a medium-sized, flexible and polymorphic organic molecule, has been explored by measuring nucleation induction times, estimating solvent-solute interaction enthalpies using molecular modelling and calorimetric data, probing interactions and clustering with spectroscopy, and modelling solvent-dependence of molecular conformation in solution. The nucleation driving force required to reach the same induction time is strongly solvent-dependent, increasing in the order: acetonitrile47 Gy (69% vs. 5%; P < 0.0001) and esophageal D5cm3 was >15 Gy (67% vs. 9%; P < 0.001). All 12 patients with esophagitis were managed with oral opioid analgesics. Nine patients with persistent symptoms received subsequent fluconazole for empiric fungal treatment and each had a decreased need for opioid analgesics within 2-5 days. CONCLUSION: Approximately one-third of patients with Ewing sarcoma of the thoracic region will develop acute esophagitis. An esophageal D5cm3 dose < 15 Gy and maximal esophageal dose < 47 Gy may keep the rate of acute esophagitis under 5%. However, the association with neutropenia and consistent response to antifungal therapy suggest chemotherapy-associated toxicity and an infectious component as part of the process. PMID- 29431251 TI - Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). AB - AIMS: Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM HF, using a variety of statistical approaches advocated for this type of analysis. METHODS AND RESULTS: In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67-0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71-0.89], the LWYY method (RR 0.78, 95% CI 0.68-0.90), and the joint frailty model (HR 0.75, 95% CI 0.66-0.86) (all P < 0.001). The effect of sacubitril/valsartan vs. enalapril on recurrent HF hospitalizations/CV death was similar. CONCLUSIONS: In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied. PMID- 29431252 TI - Factors associated with abandonment of therapy by children diagnosed with solid tumors in Peru. AB - BACKGROUND: Abandonment of treatment is a major cause of treatment failure and poor survival in children with cancer in low- and middle-income countries. The incidence of treatment abandonment in Peru has not been reported. The aim of this study was to examine the prevalence of and factors associated with treatment abandonment by pediatric patients with solid tumors in Peru. METHODS: We retrospectively reviewed the sociodemographic and clinical data of children referred between January 2012 and December 2014 to the two main tertiary centers for childhood cancer in Peru. The definition of treatment abandonment followed the International Society of Paediatric Oncology, Paediatric Oncology in Developing Countries, Abandonment of Treatment recommendation. RESULTS: Data from 1135 children diagnosed with malignant solid tumors were analyzed, of which 209 (18.4%) abandoned treatment. Bivariate logistic regression analysis showed significantly higher abandonment rates in children living outside the capital city, Lima (forest; odds ratio [OR] 3.25; P < 0.001), those living in a rural setting (OR 3.44; P < 0.001), and those whose parent(s) lacked formal employment (OR 4.39; P = 0.001). According to cancer diagnosis, children with retinoblastoma were more likely to abandon treatment compared to children with other solid tumors (OR 1.79; P = 0.02). In multivariate regression analyses, rural origin (OR 2.02; P = 0.001) and lack of formal parental employment (OR 2.88; P = 0.001) were independently predictive of abandonment. CONCLUSION: Treatment abandonment prevalence of solid tumors in Peru is high and closely related to sociodemographical factors. Treatment outcomes could be substantially improved by strategies that help prevent abandonment of therapy based on these results. PMID- 29431253 TI - Researching the decline in adolescent drinking: The need for a global and generational approach. AB - Adolescent alcohol consumption has been in decline across many high-income countries since the early to mid-2000s. This is a significant public health trend, with few documented examples from history where such a global downward shift in alcohol consumption has occurred primarily among the adolescent segment of the population. In this commentary we describe the nature and breadth of the trend; reflect on the environmental, social and policy factors that have been proffered; and argue that to adequately understand and support the maintenance of these trends, three important methodological considerations are needed for future research. Firstly, longitudinal panel and qualitative studies are needed to complement and inform continuing cross-sectional research. Secondly, a collaborative cross-cultural approach is needed to contextualise the international scale of the trend and thirdly, future research must be situated within a historical and generational perspective to understand declines in adolescent drinking in the context of a broader shift in adolescent behaviours. PMID- 29431254 TI - Guideline recommendations for cardiac resynchronization therapy evolve but does clinical practice match the pace? PMID- 29431255 TI - Short-term side effects and patient-reported outcomes of bleomycin sclerotherapy in vascular malformations. AB - BACKGROUND: Vascular malformations (VM) are congenital lesions that can be debilitating and cause significant aesthetic and functional limitations. The chemotherapeutic agent bleomycin has been utilized as a sclerosant, directly injected percutaneously into the VM. Unfortunately, little is known about the benefits and short-term side effects of bleomycin with intralesional injections. PROCEDURE: An IRB approved, retrospective chart review was performed on patients with VM who had been treated with intralesional bleomycin. Data included type of VM, number of treatments, total bleomycin dose per m2, and adverse effects. A questionnaire was administered to available patients to assess subjective outcomes and side effects. RESULTS: Forty-six patients were treated with 141 procedures of bleomycin sclerotherapy for VM. Patient ages ranged from 1 to 20 years (median age 10 years). The median cumulative bleomycin dose was 16.3 units/m2/person (range of 1.7-97.0 units/m2/person). Sixty-three percent of patients were reached for a questionnaire to assess short-term side effects. Ninety percent of patients surveyed were satisfied to very satisfied with the results from the procedure. About 24% of patients experienced transient nausea, vomiting and/or local hyperpigmentation. CONCLUSION: Bleomycin sclerotherapy can be an effective treatment of VM with repeat exposure with minor risk of short term side effects, however, long-term risks are of great concern. Further studies are required to assess systemic absorption and long-term risks. PMID- 29431256 TI - Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. AB - AIMS: We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid-range ejection fraction [HFmrEF; ejection fraction (EF) 40 49%]. METHODS AND RESULTS: In 7598 patients enrolled in the CHARM Programme (HF across the spectrum of EF), we assessed characteristics, outcomes and treatment effect of candesartan according to EF. Patients with HFmrEF (n = 1322, 17%) were similar to those with HF with reduced EF (HFrEF; n = 4323, 57%) with respect to some characteristics, and intermediate between HFrEF and HF with preserved EF (HFpEF; n = 1953, 26%) with respect to others. Over a mean follow-up of 2.9 years, the incidence rates for the primary outcome of cardiovascular death or HF hospitalization were 15.9, 8.5 and 8.9 per 100 patient-years in HFrEF, HFmrEF and HFpEF. In adjusted analyses, the rates of the primary outcome declined with increasing EF up to 50%. For treatment effect, the incidence rates for the primary outcome for candesartan vs. placebo were 14.4 vs. 17.5 per 100 patient years in HFrEF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75-0.91; P < 0.001], 7.4 vs. 9.7 per 100 patient-years in HFmrEF (HR 0.76, 95% CI 0.61-0.96; P = 0.02), and 8.6 vs. 9.1 per 100 patient-years in HFpEF (HR 0.95, 95% CI 0.79 1.14; P = 0.57). For recurrent HF hospitalization, the incidence rate ratios were 0.68 in HFrEF (95% CI 0.58-0.80; P < 0.001), 0.48 in HFmrEF (95% CI 0.33-0.70; P < 0.001), and 0.78 in HFpEF (95% CI 0.59-1.03; P = 0.08). With EF as a continuous spline variable, candesartan significantly reduced the primary outcome until EF well over 50% and recurrent HF hospitalizations until EF well over 60%. CONCLUSION: Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF. ClinicalTrials.gov: CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712. PMID- 29431257 TI - Editorial to the Special Issue: "Biochemistry of Protein-Protein and Protein Lipid Interactions: Applications to Biotechnology". PMID- 29431259 TI - The snow tire illusion: Different levels of perceptual assimilation across a single stimulus configuration. AB - While observing a specific traffic sign in the field, we noticed an apparent distortion of size and shape of the circle that contained the sign. This novel illusion manifests as a distortion of the horizontal compared to the vertical dimension of the sign. The illusion seems to be underlined by similar mechanisms to those in the Delboeuf illusion. The aim of our study was to determine the existence and magnitude of the snow tire illusion. We conducted two experiments using the method of constant stimuli. The first experiment was conducted on the standard sign, while in the second, the stimuli were rotated 90 degrees counterclockwise. Both experiments consisted of three conditions: the snow tire, the ellipse, and the simple circle (control) conditions. The data showed a robust illusion effect for both the standard and rotated sign compared to the control condition, with a large majority of participants experiencing the illusion. The snow tire illusion seems to be a combination of assimilation mechanisms of different magnitudes. The assimilation is larger for one dimension of the sign, thus producing the shape distortion. The illusion may be a manifestation of a thus far undocumented non-uniform effect of assimilation on perceived size and shape. PMID- 29431260 TI - A feasibility study of noninvasive ablation of ventricular tachycardia using high intensity focused ultrasound. AB - BACKGROUND: Current transcatheter ablation of ventricular tachycardia (VT) techniques is limited in part by its invasive nature and superficial depth of ablation lesions. OBJECTIVES: This study was aimed at evaluating the feasibility of targeted ablation of cardiac tissues using high-intensity focused ultrasound (HIFU) as a potential means for noninvasive ablation of VT. METHODS: Ablation of ventricular myocardium was performed in anesthetized closed-chest dogs using a HIFU therapeutic system that is currently used clinically for ablation of human solid tumors. Ventricular pacing using a bipolar catheter was performed at a rate slightly higher than intrinsic sinus rate to mimic VT. The myocardium at the tip of the pacing catheter was targeted for ablation. Ablation endpoint was loss of ventricular capture first and confirmed by electrical nonexcitation with 10-mA, 2 ms pulse-width unipolar stimulation. RESULTS: Optimal ablation energy was identified at 400 W for 2-4 seconds. In five separate experimental preparations, pacing could be terminated successfully during HIFU energy delivery, which was further confirmed by electrical nonexcitation. However, capture could be obtained at other nonablated locations using the same pacing catheter. Both transmural and localized lesions could be created in a controlled fashion without apparent injury to skin, lung, or pericardium on postmortem examination. CONCLUSION: This pilot study suggests that HIFU is potentially useful for noninvasive ablation of targeted, localized myocardial tissues, and it may be potentially applicable for VT ablation, particularly for those with intramyocardial/epicardial origins. PMID- 29431258 TI - Human cardiomyocyte calcium handling and transverse tubules in mid-stage of post myocardial-infarction heart failure. AB - AIMS: Cellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end-stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca2+ handling in post-myocardial-infarction (MI) patients at mid-stage of HF. METHODS AND RESULTS: Nine MI patients and eight control patients without MI (non-MI) were included. Biopsies were taken from the left ventricular myocardium and processed for further measurements with epifluorescence and confocal microscopy. Cardiomyocyte function was progressively impaired in MI cardiomyocytes compared with non-MI cardiomyocytes when increasing electrical stimulation towards frequencies that simulate heart rates during physical activity (2 Hz); at 3 Hz, we observed almost total breakdown of function in MI. Concurrently, we observed impaired Ca2+ handling with more spontaneous Ca2+ release events, increased diastolic Ca2+ , lower Ca2+ amplitude, and prolonged time to diastolic Ca2+ removal in MI (P < 0.01). Significantly reduced transverse-tubule density (-35%, P < 0.01) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase 2a (SERCA2a) function (-26%, P < 0.01) in MI cardiomyocytes may explain the findings. Reduced protein phosphorylation of phospholamban (PLB) serine-16 and threonine-17 in MI provides further mechanisms to the reduced function. CONCLUSIONS: Depressed cardiomyocyte contraction and relaxation were associated with impaired intracellular Ca2+ handling due to impaired SERCA2a activity caused by a combination of alteration in the PLB/SERCA2a ratio and chronic dephosphorylation of PLB as well as loss of transverse tubules, which disrupts normal intracellular Ca2+ homeostasis and handling. This is the first study that presents these mechanisms from viable and intact cardiomyocytes isolated from the left ventricle of human hearts at mid-stage of post-MI HF. PMID- 29431261 TI - Erratum. PMID- 29431266 TI - Lewis Base-Promoted Ring-Opening 1,3-Dioxygenation of Unactivated Cyclopropanes Using a Hypervalent Iodine Reagent. AB - A facile and effective system has been developed for the regio- and chemoselective ring-opening/electrophilic functionalization of cyclopropanes through C-C bond activation by [bis(trifluoroacetoxy)iodo]benzene with the aid of the Lewis basic promoter p-toluenesulfonamide. The p-toluenesulfonamide-promoted system works well for a wide range of cyclopropanes, resulting in the formation of 1,3-diol products in good yields and regioselectivity. PMID- 29431262 TI - The Japanese Society of Pathology Guidelines on the handling of pathological tissue samples for genomic research: Standard operating procedures based on empirical analyses. AB - Genome research using appropriately collected pathological tissue samples is expected to yield breakthroughs in the development of biomarkers and identification of therapeutic targets for diseases such as cancers. In this connection, the Japanese Society of Pathology (JSP) has developed "The JSP Guidelines on the Handling of Pathological Tissue Samples for Genomic Research" based on an abundance of data from empirical analyses of tissue samples collected and stored under various conditions. Tissue samples should be collected from appropriate sites within surgically resected specimens, without disturbing the features on which pathological diagnosis is based, while avoiding bleeding or necrotic foci. They should be collected as soon as possible after resection: at the latest within about 3 h of storage at 4 degrees C. Preferably, snap-frozen samples should be stored in liquid nitrogen (about -180 degrees C) until use. When intending to use genomic DNA extracted from formalin-fixed paraffin-embedded tissue, 10% neutral buffered formalin should be used. Insufficient fixation and overfixation must both be avoided. We hope that pathologists, clinicians, clinical laboratory technicians and biobank operators will come to master the handling of pathological tissue samples based on the standard operating procedures in these Guidelines to yield results that will assist in the realization of genomic medicine. PMID- 29431265 TI - Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells. AB - Cannabinoid 1 receptors (CB1Rs) are expressed in peripheral tissues, including islets of Langerhans, where their function(s) is under scrutiny. Using mouse beta cell lines, human islets and CB1R-null (CB1R-/- ) mice, we have now investigated the role of CB1Rs in modulating beta-cell function and glucose responsiveness. Synthetic CB1R agonists diminished GLP-1-mediated cAMP accumulation and insulin secretion as well as glucose-stimulated insulin secretion in mouse beta-cell lines and human islets. In addition, silencing CB1R in mouse beta cells resulted in an increased expression of pro-insulin, glucokinase (GCK) and glucose transporter 2 (GLUT2), but this increase was lost in beta cells lacking insulin receptor. Furthermore, CB1R-/- mice had increased pro-insulin, GCK and GLUT2 expression in beta cells. Our results suggest that CB1R signalling in pancreatic islets may be harnessed to improve beta-cell glucose responsiveness and preserve their function. Thus, our findings further support that blocking peripheral CB1Rs would be beneficial to beta-cell function in type 2 diabetes. PMID- 29431269 TI - MiR-129-5p inhibits glioma cell progression in vitro and in vivo by targeting TGIF2. AB - This study purposed to explore the correlation between miR-129-5p and TGIF2 and their impacts on glioma cell progression. Differentially expressed miRNA was screened through microarray analysis. MiR-129-5p expression levels in glioma tissues and cells were measured by qRT-PCR. CCK-8 assay, flow cytometer, transwell assay and wound-healing assay were employed to detect cell proliferation, apoptosis and cycle, invasiveness and migration, respectively. Dual-luciferase reporting assay was performed to confirm the targeted relationship between miR-129-5p and TGIF2. The effects of TGIF2 expression on cell biological functions were also investigated using the indicated methods. Tumour xenograft was applied to explore the impact of miR-129-5p on tumorigenesis in vivo. MiR-129-5p expression was down-regulated in both glioma tissues and glioma cells, while TGIF2 expression was aberrantly higher than normal level. Dual-luciferase reporter assay validated the targeting relation between miR-129 5p and TGIF2. Overexpression of miR-129-5p or down-regulation of TGIF2 inhibited the proliferation, invasion and migration capacity of glioma cells U87 and U251, and meanwhile blocked the cell cycle as well as induced cell apoptosis. MiR-129 5p overexpression repressed the tumour development in vivo. MiR-129-5p and TGIF2 had opposite biological functions in glioma cells. MiR-129-5p could inhibit glioma cell progression by targeting TGIF2, shining light for the development of target treatment for glioma. PMID- 29431272 TI - Prolonged uninterrupted sitting elevates postprandial hyperglycaemia proportional to degree of insulin resistance. AB - Prolonged uninterrupted sitting is related adversely to cardiometabolic risk markers and postprandial hyperglycaemia, relative to sitting interrupted by regular brief activity breaks. However, whether the magnitude of hyperglycaemic responses to prolonged sitting is dependent upon the underlying degree of insulin resistance remains unclear. Data were pooled from 3 randomized cross-over laboratory-based trials (n = 62) that examined the postprandial blood glucose- and insulin-lowering effects of prolonged sitting vs sitting interrupted by regular brief activity breaks in overweight/obese adults who had normal or impaired glucose metabolism (2 trials) or type 2 diabetes not treated by insulin (1 trial). Corrected for study effects, the magnitude of differences in postprandial glucose and insulin responses between the 2 conditions was significantly exacerbated with poorer baseline levels of fasting glucose, insulin and/or surrogate markers of beta-cell function and insulin resistance. This suggests that those with higher underlying levels of insulin resistance may derive greater metabolic benefits from regularly interrupting prolonged sitting than their healthier counterparts. If these findings can be replicated, they may have implications for future targeting and optimization of physical activity/sedentary behaviour interventions in the prevention and management of type 2 diabetes. PMID- 29431270 TI - Modelling the dopamine and noradrenergic cell loss that occurs in Parkinson's disease and the impact on hippocampal neurogenesis. AB - Key pathological features of Parkinson's Disease (PD) include the progressive degeneration of midbrain dopaminergic (DA) neurons and hindbrain noradrenergic (NA) neurons. The loss of DA neurons has been extensively studied and is the main cause of motor dysfunction. Importantly, however, there are a range of 'non movement' related features of PD including cognitive dysfunction, sleep disturbances and mood disorders. The origins for these non-motor symptoms are less clear, but a possible substrate for cognitive decline may be reduced adult hippocampal neurogenesis, which is reported to be impaired in PD. The mechanisms underlying reduced neurogenesis in PD are not well established. Here we tested the hypothesis that NA and DA depletion, as occurs in PD, impairs hippocampal neurogenesis. We used 6-hydroxydopamine or the immunotoxin dopamine-beta hydroxylase-saporin to selectively lesion DA or NA neurons, respectively, in adult Sprague Dawley rats and assessed hippocampal neurogenesis through phenotyping of cells birth-dated using 5-bromo-2'-deoxyuridine. The results showed no difference in proliferation or differentiation of newborn cells in the subgranular zone of the dentate gyrus after NA or DA lesions. This suggests that impairment of hippocampal neurogenesis in PD likely results from mechanisms independent of, or in addition to degeneration of DA and NA neurons. PMID- 29431273 TI - Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2): Emerging key players in epithelial integrity and cancer. AB - The growth, survival, and metabolic activities of multicellular organisms at the cellular level are regulated by intracellular signaling, systemic homeostasis and the pericellular microenvironment. Pericellular proteolysis has a crucial role in processing bioactive molecules in the microenvironment and thereby has profound effects on cellular functions. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and HAI-2 are type I transmembrane serine protease inhibitors expressed by most epithelial cells. They regulate the pericellular activities of circulating hepatocyte growth factor activator and cellular type II transmembrane serine proteases (TTSPs), proteases required for the activation of hepatocyte growth factor (HGF)/scatter factor (SF). Activated HGF/SF transduces pleiotropic signals through its receptor tyrosine kinase, MET (coded by the proto-oncogene MET), which are necessary for cellular migration, survival, growth and triggering stem cells for accelerated healing. HAI-1 and HAI-2 are also required for normal epithelial functions through regulation of TTSP-mediated activation of other proteases and protease-activated receptor 2, and also through suppressing excess degradation of epithelial junctional proteins. This review summarizes current knowledge regarding the mechanism of pericellular HGF/SF activation and highlights emerging roles of HAIs in epithelial development and integrity, as well as tumorigenesis and progression of transformed epithelial cells. PMID- 29431275 TI - Burst Spinal Cord Stimulation: Review of Preclinical Studies and Comments on Clinical Outcomes. AB - BACKGROUND: Burst spinal cord stimulation (SCS) technology uses a novel waveform that consists of closely packed high-frequency electrical impulses followed by a quiescent period. Within the growing field of neuromodulation, burst stimulation is unique in that it mimics the natural burst firing of the nervous system, in particular the thalamo-cingulate rhythmicity, resulting in modulation of the affective and attentional components of pain processing (e.g., medial thalamic pathways). STUDY DESIGN: A review of preclinical and clinical studies regarding burst SCS for various chronic pain states. METHODS: Available literature was reviewed on burst stimulation technology. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles. OUTCOME MEASURES: The primary outcome measure was to understand the mechanisms of action with regards to burst stimulation and to review clinical data on the indications of burst SCS for various chronic pain states. RESULTS: We present both mechanisms of action and review uses of burst stimulation for various pain states. CONCLUSIONS: Burst stimulation offers a novel pain reduction tool with the absence of uncomfortable paresthesia for failed back surgery syndrome, diabetic neuropathic pain, and anesthesia dolorosa. Preclinical models have emphasized that the potential mechanisms for burst therapy could be related to neural coding algorithms that mimic the natural nervous system firing patterns, resulting in effects on both the medial and lateral pain pathways. Other mechanisms include frequency dependent opioid release, modulation of the pain gate, and activation of electrical and chemical synapses. PMID- 29431274 TI - Differential contributions of Ca2+ -activated K+ channels and Na+ /K+ -ATPases to the generation of the slow afterhyperpolarization in CA1 pyramidal cells. AB - In many types of CNS neurons, repetitive spiking produces a slow afterhyperpolarization (sAHP), providing sustained, intrinsically generated negative feedback to neuronal excitation. Changes in the sAHP have been implicated in learning behaviors, in cognitive decline in aging, and in epileptogenesis. Despite its importance in brain function, the mechanisms generating the sAHP are still controversial. Here we have addressed the roles of M-type K+ current (IM ), Ca2+ -gated K+ currents (ICa(K) 's) and Na+ /K+ -ATPases (NKAs) current to sAHP generation in adult rat CA1 pyramidal cells maintained at near-physiological temperature (35 degrees C). No evidence for IM contribution to the sAHP was found in these neurons. Both ICa(K) 's and NKA current contributed to sAHP generation, the latter being the predominant generator of the sAHP, particularly when evoked with short trains of spikes. Of the different NKA isoenzymes, alpha1 -NKA played the key role, endowing the sAHP a steep voltage dependence. Thus normal and pathological changes in alpha1 -NKA expression or function may affect cognitive processes by modulating the inhibitory efficacy of the sAHP. PMID- 29431276 TI - Potential efficacy of a RNAi-based topical treatment for psoriasis. PMID- 29431277 TI - MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro. AB - Mutations in the methyl-CpG-binding protein-2 gene (MECP2) are commonly associated with Rett syndrome. However, it has long been appreciated that there exists a spectrum of neuropsychiatric phenotypes associated with MECP2 variants. The most frequent Rett missense mutations are located in either the methyl-CpG binding domain (MBD) or transcription repression domain (TRD). Clinical roles for mutations in other domains such as the intervening domain (ID) or AT-Hook domains have yet to be determined. Here, we report functional analysis of MECP2 missense mutations, located in AT-Hook1 within the ID, in a large Pakistani family with childhood onset cognitive decline and schizophrenia (SCZ), de novo in a girl with atypical Rett syndrome, and de novo in a woman with SCZ. We show that both p.Arg190His and p.Arg190Cys affect the ability of MeCP2 to bind to AT-rich DNA, also the brain-derived neurotrophic factor (BDNF) promoter, with the more drastic effects seen for p.Arg190Cys. Both mutations also affect nuclear chromatin clustering in vitro. These data support a possible molecular link between MECP2 AT-Hook1 mutations and psychosis. Given the ongoing large-scale whole exome and whole genome sequencing projects for psychiatric disorders, our findings suggest that rare missense variants in MECP2 be carefully evaluated for molecular consequences. PMID- 29431278 TI - Stable isotope fractionation of strontium in coccolithophore calcite: Influence of temperature and carbonate chemistry. AB - Marine calcifying eukaryotic phytoplankton (coccolithophores) is a major contributor to the pelagic production of CaCO3 and plays an important role in the biogeochemical cycles of C, Ca and other divalent cations present in the crystal structure of calcite. The geochemical signature of coccolithophore calcite is used as palaeoproxy to reconstruct past environmental conditions and to understand the underlying physiological mechanisms (vital effects) and precipitation kinetics. Here, we present the stable Sr isotope fractionation between seawater and calcite (Delta88/86 Sr) of laboratory cultured coccolithophores in individual dependence of temperature and seawater carbonate chemistry. Coccolithophores were cultured within a temperature and a pCO2 range from 10 to 25 degrees C and from 175 to 1,240 MUatm, respectively. Both environmental drivers induced a significant linear increase in coccolith stable Sr isotope fractionation. The temperature correlation at constant pCO2 for Emiliania huxleyi and Coccolithus braarudii is expressed as Delta88/86 Sr = 7.611 * 10-3 T + 0.0061. The relation of Delta88/86 Sr to pCO2 was tested in Emiliania huxleyi at 10 and 20 degrees C and resulted in Delta88/86 Sr = -5.394 * 10-5 pCO2 - 0.0920 and Delta88/86 Sr = -5.742 * 10-5 pCO2 - 0.1351, respectively. No consistent relationship was found between coccolith Delta88/86 Sr and cellular physiology impeding a direct application of fossil coccolith Delta88/86 Sr as coccolithophore productivity proxy. An overall significant correlation was detected between the elemental distribution coefficient (DSr ) and Delta88/86 Sr similar to inorganic calcite with a physiologically induced offset. Our observations indicate (i) that temperature and pCO2 induce specific effects on coccolith Delta88/86 Sr values and (ii) that strontium elemental ratios and stable isotope fractionation are mainly controlled by precipitation kinetics when embedded into the crystal lattice and subject to vital effects during the transmembrane transport from seawater to the site of calcification. These results provide an important step to develop a coccolith Delta88/86 Sr palaeoproxy complementing the existing toolbox of palaeoceanography. PMID- 29431279 TI - Strategic value-directed learning and memory in Alzheimer's disease and behavioural-variant frontotemporal dementia. AB - In healthy adults, the ability to prioritize learning of highly valued information is supported by executive functions and enhances subsequent memory retrieval for this information. In Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD), marked deficits are evident in learning and memory, presenting in the context of executive dysfunction. It is unclear whether these patients show a typical memory bias for higher valued stimuli. We administered a value-directed word-list learning task to AD (n = 10) and bvFTD (n = 21) patients and age-matched healthy controls (n = 22). Each word was assigned a low, medium or high point value, and participants were instructed to maximize the number of points earned across three learning trials. Participants' memory for the words was assessed on a delayed recall trial, followed by a recognition test for the words and corresponding point values. Relative to controls, both patient groups showed poorer overall learning, delayed recall and recognition. Despite these impairments, patients with AD preferentially recalled high-value words on learning trials and showed significant value-directed enhancement of recognition memory for the words and points. Conversely, bvFTD patients did not prioritize recall of high-value words during learning trials, and this reduced selectivity was related to inhibitory dysfunction. Nonetheless, bvFTD patients showed value-directed enhancement of recognition memory for the point values, suggesting a mismatch between memory of high-value information and the ability to apply this in a motivationally salient context. Our findings demonstrate that value-directed enhancement of memory may persist to some degree in patients with dementia, despite pronounced deficits in learning and memory. PMID- 29431280 TI - The effect on emergency department visits of raised alcohol minimum prices in Saskatchewan, Canada. AB - INTRODUCTION AND AIMS: The province of Saskatchewan, Canada introduced minimum prices graded by alcohol strength in April 2010. As previous research found this intervention significantly decreased alcohol consumption and alcohol-attributable morbidity, we aim to test the association between the intervention and the rate of emergency department (ED) visits in four alcohol-related injury categories [motor vehicle collisions (MVC), assaults, falls and total alcohol-related injuries]. DESIGN AND METHODS: Data on ED visits in the city of Regina were obtained from the Saskatchewan Ministry of Health. Auto-regressive integrated moving average time series models were used to test the immediate and lagged effects of the pricing intervention on rates of alcohol-related nighttime. ED visits and controlled for daytime rates of ED visits, economic variables, linear and seasonal trends, and auto-regressive and moving average effects. RESULTS: The implementation of an alcohol minimum pricing strategy in Saskatchewan was associated with decreased MVC-related ED visits for women aged 26 and over after a 6 month lag period (-39.4%, P < 0.001). There was no significant abrupt effect of this intervention on ED visits of four injury types in any of four gender-age categories; however, rates of ED visits among young males for MVCs and assaults decreased substantially during this study. DISCUSSION AND CONCLUSIONS: The minimum pricing policy change led to a lagged decrease in motor vehicle-collision related ED visits for women older than 25. Of note, there did not appear to be an instantaneous effect on the rate of alcohol-related injury ED visits immediately after the policy implementation nor lagged effects for other gender-age groups. PMID- 29431281 TI - Remodeling of dermal collagen in photoaged skin using low-dose 5-aminolevulinic acid photodynamic therapy occurs via the transforming growth factor-beta pathway. AB - 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) is known to be effective in the treatment of photoaged skin. However, the molecular mechanisms still remain elusive. Protoporphyrin IX (PpIX) fluorescence is primarily located in the epidermis while ALA-PDT affects the dermal collagen, presumably by an indirect mechanism. This study aimed to investigate the molecular communication in low dose ALA-PDT occurring between epidermal keratinocytes and dermal fibroblasts. Western blotting and enzyme-linked immunosorbent assays were performed to evaluate collagen expression and transforming growth factor-beta (TGF-beta) signaling in human keratinocytes and dermal fibroblasts. The impact on fibroblast proliferation was assessed by morphology and proliferating cell nuclear antigen immunofluorescence. Skin biopsies from mice were used to analyze the histological changes in dermal collagen and PpIX distribution. When fibroblasts were cocultured with keratinocytes treated with low-dose ALA-PDT, collagen synthesis and fibroblast proliferation were enhanced. Low-dose ALA-PDT stimulated TGF-beta1 expression in keratinocytes. Fibroblasts cocultured with low-dose ALA-PDT-treated keratinocytes also showed activation of the TGF-beta pathway. In vivo, PpIX fluorescence was densely distributed in photoaged mouse epidermis while collagen in the mouse dermis underwent remodeling. This study suggests that low-dose ALA PDT can stimulate keratinocytes to release TGF-beta1, activating the TGF-beta pathway in dermal fibroblasts to remodel collagen in the dermis. PMID- 29431282 TI - The structural invariance of the Temporal Experience of Pleasure Scale across time and culture. AB - The Temporal Experience of Pleasure Scale (TEPS) is a self-report instrument that assesses pleasure experience. Initial scale development and validation in the United States yielded a two-factor solution comprising anticipatory and consummatory pleasure. However, a four-factor model that further parsed anticipatory and consummatory pleasure experience into abstract and contextual components was a better model fit in China. In this study, we tested both models using confirmatory factor analysis in an American and a Chinese sample and examined the configural measurement invariance of both models across culture. We also examined the temporal stability of the four-factor model in the Chinese sample. The results indicated that the four-factor model of the TEPS was a better fit than the two-factor model in the Chinese sample. In contrast, both models fit the American sample, which also included many Asian American participants. The four-factor model fit both the Asian American and Chinese samples equally well. Finally, the four-factor model demonstrated good measurement and structural invariance across culture and time, suggesting that this model may be applicable in both cross-cultural and longitudinal studies. PMID- 29431283 TI - Predictive value of presuperior cavopulmonary anastomosis cardiac catheterization at increased altitude. AB - OBJECTIVE: Infants with single ventricle physiology typically undergo cardiac catheterization prior to superior cavopulmonary anastomosis (SCPA) to assess operative suitability. Predictors of poor outcome at sea level include elevated pulmonary artery pressure (mPAP), indexed pulmonary vascular resistance (PVRi), age <3 months, significant atrioventricular valve regurgitation, among others. Increased altitude has vasoconstrictive effects on the pulmonary vasculature, which may affect pre-SCPA hemodynamics and outcomes. The goal of this study was to determine the predictive value of pre-SCPA catheterization data with regard to reaching Fontan palliation at altitude. DESIGN: A retrospective review revealed 150 patients who underwent pre-SCPA catheterization over a 10-year period. Subjects were grouped by progression to Fontan vs aborted palliation, heart transplant or death. Statistics included t-tests, logistic regression and receiver operator characteristic (ROC) curve analysis. RESULTS: Independent predictors of failure to achieve Fontan operation at increased altitude include decreased ventricular function, increased mPAP, increased PVRi, and prolonged hospitalization, after adjusting for ventricular morphology and sex. CONCLUSIONS: Our data indicate that decreased ventricular function most strongly predicts failure to reach Fontan palliation. Additionally, mPAP and PVRi play an important role in determining outcomes at increased altitude. Prolonged hospitalization is likely a marker of increased medical complexity or more problematic physiology. PMID- 29431284 TI - Increased blood lactate is prevalent and identifies poor prognosis in patients with acute heart failure without overt peripheral hypoperfusion. AB - AIMS: Lactate is produced by anaerobic metabolism and may reflect inadequate tissue perfusion in conditions such as acute heart failure (AHF). We evaluated the prevalence and clinical significance of elevated blood lactate on admission in patients with AHF. METHODS AND RESULTS: We enrolled 237 patients with AHF (mean age 67 +/- 12 years; 70% men) presenting without overt clinical evidence of peripheral hypoperfusion ('warm haemodynamic profile'). Median (upper and lower quartiles) blood lactate on admission was 1.8 (1.5; 2.4) mmol/L; 103 (43%) patients had an elevated blood lactate (>=2 mmol/L). Patients with an elevated lactate had higher blood high-sensitivity troponin I [15.4 (8.5; 26.1) vs. 9.9 (4.3; 19.6) pg/mL], aspartate aminotransferase [28 (20; 44) vs 24 (19; 36) IU/L] and endothelin-1 (12.1 +/- 6.2 vs. 9.3 +/- 3.9 pg/mL) (all P < 0.05). In this group plasma concentration of neutrophil gelatinase-associated lipocalin increased during the first 48 h, whereas values fell for those with normal baseline lactate [1.9 (-3.2; 9.7) vs. -1.3 (-13.9; 5.6) MUg/dL; P < 0.05). One year mortality was higher amongst patients with an elevated blood lactate (36% vs. 21%; P < 0.05). After adjustment for other well-established prognostic variables, blood lactate on admission predicted poor outcome (hazard ratio 1.24, 95% confidence interval 1.08-1.41; P < 0.05). CONCLUSIONS: An elevated blood lactate on admission is common in AHF patients without overt clinical evidence of peripheral hypoperfusion and is associated with markers of organ dysfunction/damage and a worse prognosis. PMID- 29431285 TI - East Asia may have a better 1-year survival following an acute heart failure episode compared with Europe: results from an international observational cohort. PMID- 29431286 TI - Spectroscopic Evidence for Aminomethylene (H-C-NH2 )-The Simplest Amino Carbene. AB - Although N-heterocyclic carbenes have been well-studied, the simplest aminocarbene, aminomethylene H-C-NH2 , has not been spectroscopically identified to date. Herein we report the gas-phase preparation of aminomethylene by high vacuum flash pyrolysis of cyclopropylamine and subsequent trapping of the pyrolysate in an inert argon matrix at 12 K. Aminomethylene was characterized by matching matrix IR and UV/Vis spectroscopic data with ab initio coupled cluster computations. After UV irradiation of the matrix aminomethylene rearranges to its isomer methanimine (formaldimine) H2 C=NH. Based on our experimental results and computations aminomethylene has a singlet ground state with a reaction barrier of almost 46 kcal mol-1 to methanimine so that H-tunneling is excluded. PMID- 29431287 TI - Comparison of cardiopulmonary-based risk models with a clinical heart failure risk model. PMID- 29431288 TI - Heart-brain interactions in patients with heart failure, including takotsubo syndrome: a need to monitor autonomic sympathetic activity. PMID- 29431289 TI - Coupling of Bifunctional CoMn-Layered Double Hydroxide@Graphitic C3 N4 Nanohybrids towards Efficient Photoelectrochemical Overall Water Splitting. AB - The development of durable, low-cost, and efficient photo-/electrolysis for the oxygen and hydrogen evolution reactions (OER and HER) is important to fulfill increasing energy requirements. Herein, highly efficient and active photo /electrochemical catalysts, that is, CoMn-LDH@g-C3 N4 hybrids, have been synthesized successfully through a facile in situ co-precipitation method at room temperature. The CoMn-LDH@g-C3 N4 composite exhibits an obvious OER electrocatalytic performance with a current density of 40 mA cm-2 at an overpotential of 350 mV for water oxidation, which is 2.5 times higher than pure CoMn-LDH nanosheets. For HER, CoMn-LDH@g-C3 N4 (eta50 =-448 mV) requires a potential close to Pt/C (eta50 =-416 mV) to reach a current density of 50 mA cm2 . Furthermore, under visible-light irradiation, the photocurrent density of the CoMn-LDH@g-C3 N4 composite is 0.227 mA cm-2 , which is 2.1 and 3.8 time higher than pristine CoMn-LDH (0.108 mA cm-2 ) and g-C3 N4 (0.061 mA cm-2 ), respectively. The CoMn-LDH@g-C3 N4 composite delivers a current density of 10 mA cm-2 at 1.56 V and 100 mA cm-2 at 1.82 V for the overall water-splitting reaction. Therefore, this work establishes the first example of pure CoMn-LDH and CoMn-LDH@g-C3 N4 hybrids as electrochemical and photoelectrochemical water splitting systems for both OER and HER, which may open a pathway to develop and explore other LDH and g-C3 N4 nanosheets as efficient catalysts for renewable energy applications. PMID- 29431290 TI - In vitro photoacoustic spectroscopy of pulsatile blood flow: Probing the interrelationship between red blood cell aggregation and oxygen saturation. AB - We investigate the optical wavelength dependence in quantitative photoacoustic (QPA) assessment of red blood cell (RBC) aggregation and oxygen saturation (sO2 ) during pulsatile blood flow. Experimentally, the pulsatile flow was imaged with a 700 to 900 nm laser using the VevoLAZR. Theoretically, the photoacoustic (PA) signals were computed based on a Green's function integrated with a Monte Carlo simulation of radiant fluence. The pulsatile flow created periodic conditions of RBC aggregation/nonaggregation, altering the aggregate size, and, in turn, the sO2 . The dynamic range, DR (a metric of change in PA power) from 700 to 900 nm for nonaggregated RBCs, was 5 dB for both experiment and theory. A significant difference in the DR for aggregated RBCs was 1.5 dB between experiment and theory. Comparing the DR at different wavelengths, the DR from nonaggregated to aggregated RBCs at 700 nm was significantly smaller than that at 900 nm for both experiment (4.0 dB < 7.1 dB) and theory (5.3 dB < 9.0 dB). These results demonstrate that RBC aggregation simultaneously affects the absorber size and the absorption coefficient in photoacoustic imaging (PAI) of pulsatile blood flow. This investigation elucidates how QPA spectroscopy can be used for probing hemodynamics and oxygen transport by PAI of blood flow. PMID- 29431291 TI - Slow to heel: a literature review on the management of diabetic calcaneal ulceration. AB - The diabetic heel ulcer (DHU) represents a reconstructive challenge to clinicians and the multidisciplinary team alike. It is traditionally viewed as a condition that is inherently difficult to treat due to the intrinsic anatomical vulnerabilities of the heel. In addition to this, several factors are associated with poorer end outcomes - namely, that of major amputation. These include peripheral vascular disease, infection/osteomyelitis and the size of the ulcer itself. In light of the significant morbidity, economic burden and mortality seen in this cohort of patients, this review aims to explore current treatment modalities that have been undertaken. Literature in this field has mostly been confined to a handful of small case studies, some of which reflect novel, multimodal approaches, and promising results. Management with osteotomy, flap reconstruction and acellular dermal matrices, amongst other options, is covered within this review. PMID- 29431292 TI - Chikungunya: A rheumatologist's perspective. AB - Chikungunya (CHIK), a viral infection, is transmitted by Aedes mosquitoes. It is characterized by a phase of acute infection, which is sometimes followed by chronic rheumatisim in the form of arthralgia or myalgia that can last for months and even years. Several studies have been conducted to understand the mechanisms underlying inflammation associated with CHIK infection, persistence of viruses in monocytes-macrophages, and their relationship to the chronic symptoms. Chronic arthritis is one of the serious complications of CHIK infection, which is characterized by swelling and acute pain that poorly responds to treatment with analgesics. Such debilitating chronic joint pain mimics that of rheumatic arthritis and significantly compromises the quality of life. Diagnosis is primarily based on the initial viral detection using molecular methods or the use of virus culture, and on the basis of an immune response in the later stages. In the absence of published guidelines, physicians are often limited to prescribing analgesics and steroids for symptomatic care, as there is no accurate approach for the treatment and management of pain. This review aims to focus on the need for appropriate guidelines that will aid in developing suitable pharmacologic treatment to manage pain associated with post-CHIK chronic inflammatory rheumatism. PMID- 29431293 TI - IL-17A[G197G]-Association between NOx and gestational age in a South African birth cohort. AB - Interleukin (IL-)17A, plays a role in pathogenic defence, but is implicated in chronic inflammatory diseases, and has recently been associated with variable pregnancy outcomes. We investigated the role of maternal IL-17-[G197A]-specific effects of third-trimester IL-17 mRNA expression, NOx exposure levels and other variables on gestational age, in the Mother and Child in the Environment (MACE) birth cohort in South Africa. A total of 327 participants were genotyped for IL 17-[G197A] by polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP). Quantitative real-time PCR was used to quantitate IL-17-mRNA expression in whole blood. Multivariate linear regression analysis, stratified by IL-17-[G197A] genotype, was used to test for effects of NOx , IL17A/GAPDH, haemoglobin, body mass index, HIV-1 positivity, maternal education and income level on gestational age. Lower expression was associated with the IL-17-GG versus GA in the cohort and HIV-1-negative group (p = .0007, p = .0058), while no difference was observed in the HIV-1 positives. Elevated IL-17A expression was observed in the high NOx exposure groups, within IL-17[G197G] (p = .0004). IL 17[G197G] was associated with PTB (p < .0001), and the PTB group had lower IL-17A expression compared to the full-term group (p = .0002). IL-17 expression was associated with an increase in gestational age (p = .038), and NOx was associated with a decrease in gestational age in the IL-17[G197G] model (p = .046). PMID- 29431294 TI - Rapid tranquilization: An audit of Irish mental health nursing practice. AB - Rapid tranquillization is a pharmacological intervention sometimes employed in mental health care for the management of acute behavioural disturbance. It is a form of restrictive practice, which, along with seclusion and restraint, is a conventional and controversial intervention in the therapeutic management of risk in mental health settings. This study surveyed mental health nurses practice in rapid tranquillization. A self-report questionnaire was utilized which addressed aspects such as definitions of rapid tranquillization, presence of rapid tranquillization policy, types of incidents where it is used and postintervention monitoring. The results demonstrate that rapid tranquillization is an intervention used in the management of acute behavioural disturbance in various mental health settings in Ireland. Respondents showed a basic understanding of rapid tranquillization as an intervention; however, some areas reported not having a specific rapid tranquillization policy. There was some evidence of a variation in postrapid tranquillization monitoring of psychiatric/mental health and physical health. Service user debriefing following rapid tranquillization was reported to be common; however, the content of this was not elaborated on. In the light of variations in practice, specific training and the development of rapid tranquillization policies are recommended. PMID- 29431295 TI - From Anilines to Aryl Ethers: A Facile, Efficient, and Versatile Synthetic Method Employing Mild Conditions. AB - We have developed a simple and direct method for the synthesis of aryl ethers by reacting alcohols/phenols (ROH) with aryl ammonium salts (ArNMe3+ ), which are readily prepared from anilines (ArNR'2 , R'=H or Me). This reaction proceeds smoothly and rapidly (within a few hours) at room temperature in the presence of a commercially available base, such as KOt Bu or KHMDS, and has a broad substrate scope with respect to both ROH and ArNR'2 . It is scalable and compatible with a wide range of functional groups. PMID- 29431296 TI - Utility of incomplete right bundle branch block as an isolated ECG finding in children undergoing initial cardiac evaluation. AB - OBJECTIVE: This study evaluates the ability of experienced pediatric electrophysiologists (EPs) to reliably classify incomplete right bundle branch block (IRBBB) and assesses its clinical utility as an isolated ECG finding in a group of healthy outpatient children without prior cardiac evaluation. DESIGN: We performed a retrospective analysis of all electrocardiographic and echocardiographic records at Boston Children's Hospital between January 1, 2005, and December 31, 2014. Echocardiographic diagnoses were identified if registered between the date of the index electrocardiogram and the ensuing year. A selected subset of 473 ECGs was subsequently reanalyzed in a blinded manner by six pediatric EPs to determine the consistency with which the finding of IRBBB could be assigned. RESULTS: Of the 331 278 ECGs registered in the BCH database, 32 127 (9.7%) met inclusion criteria and were analyzed for the prevalence of isolated right bundle conduction disturbance findings. The mean age was 12.1 +/- 4.0 years, and the population was 49% male. Of the 32 127 ECGs, 72.5% were coded normal, 3.0% were coded IRBBB, and 0.5% were coded complete right bundle branch block (CRBBB). A total of 7.3% of patients coded as normal had an ensuing echocardiogram, compared to 12.5% coded IRBBB. Echo findings were recorded in 0.1% of normal and 0.2% of IRBBB. Patients with ASD-secundum type were no more likely to have isolated IRBBB on previous ECG than the general population (2.5% vs 3.0%). Analysis of inter-reader variability in ECG findings and conduction disturbance identification was high (range of IRBBB prevalence 1-20% among readers). Reinterpretation of ECGs using explicit diagnostic criteria did not demonstrate consistent discrimination of IRBBB and Normal ECGs. CONCLUSIONS: IRBBB is not uncommon in a healthy school age population and is observed to have high inter-reader variability. It was associated with increased use of echocardiographic exam but was not associated with increased rate of echocardiographic findings when compared with rates for normal ECGs. PMID- 29431297 TI - Lyme disease surveillance in the United States: Looking for ways to cut the Gordian knot. AB - Current surveillance methods have been useful to document geographic expansion of Lyme disease in the United States and to monitor the increasing incidence of this major public health problem. Nevertheless, these approaches are resource intensive, generate results that are difficult to compare across jurisdictions, and measure less than the total burden of disease. By adopting more efficient methods, resources could be diverted instead to education of at-risk populations and new approaches to prevention. In this special issue of Zoonoses and Public Health, seven articles are presented that either evaluate traditional Lyme disease surveillance methods or explore alternatives that have the potential to be less costly, more reliable, and sustainable. Twenty-five years have passed since Lyme disease became a notifiable condition - it is time to reevaluate the purpose and goals of national surveillance. PMID- 29431298 TI - Radiographic Measurements Following Surgery for Distal Radius Fractures in an Israeli Population. AB - BACKGROUND: Fractures of the distal radius are the most common fractures in the upper extremity, and their incidence is increasing with the aging of the population. Despite anatomical reduction of the bones, many patients complain of residual pain. A reason for this may be ligament injury not addressed during surgery or conservative treatment. Radiographic measurements may allow assessment of ligament integrity but they may be population specific and differ among races. OBJECTIVES: To assess radiographic wrist measurements in an Israeli population and to compare them to existing values. METHODS: Demographic data, previous diagnosis of osteoporosis, fracture classification, and radiologic measurements (radial height, radial inclination, ulnar variance, volar tilt, and d2/w2) were measured and compared. RESULTS: The study was comprised of 53 females and 27 males, mean age 64 years, with wrist radiographs following surgery. Of these, 13% were smokers and 38.5% had osteoporosis. According to the Arbeitsgemeinschaft fur Osteosynthesefragen classification system, most of the fractures were comminuted and intra-articular. The mean values for all measurements did not differ significantly from values in the literature. The average d2/w2 ratio (describing the radiocarpal ligaments) was 0.42, significantly differing from this measurement in normal wrists as described in the literature, but similar to a population following surgery (P = 0.002). CONCLUSIONS: Our population had more fragility fractures than other populations. Otherwise, our demographics and measurements did not differ from normal values described in the literature. This study supports the validity of any wrist radiographic study performed in our population. PMID- 29431299 TI - Clinical Knee Alignment among Adolescents and Association with Body Mass Index: A Large Prevalence Study. AB - BACKGROUND: Children and adolescents are commonly referred to an orthopedic surgeon to assess knee malalignment. OBJECTIVES: To assess the prevalence of genu varum and valgum among adolescents, and to identify correlates of these conditions. METHODS: A medical database of 47,588 candidates for military service presenting to the northern recruitment center during an 11 year period was analyzed to identify clinical knee alignment. Based on the standing skin surface intercondylar distance (ICD) or intermalleolar distance (IMD), the prevalence rates of genu varum (ICD >= 3 cm) and genu valgum (IMD >= 4 cm) were calculated. The association of gender, body mass index (BMI), and place of residence to knee alignment was studied. RESULTS: The rates of genu varum and valgum were 11.4% (5427) and 5.6% (2639), respectively. Genu varum was significantly more prevalent among males than females (16.2% vs. 4.4%, P < 0.001). It was also more prevalent among underweight subjects and less prevalent among overweight and obese subjects (P < 0.001). Genu valgum was significantly more prevalent among females than males (9.4% vs. 2.9%) and in overweight and obese subjects compared to those with normal BMI, while less prevalent in underweight subjects (P < 0.001). Multivariate analysis revealed that genu varum was independently positively associated with male gender, underweight, and living in a rural area. Genu valgum was independently positively associated with female gender, overweight, and obesity. CONCLUSIONS: This study establishes a modern benchmark for the cutoff and prevalence of genu varum and valgum as well as associations with gender and BMI. PMID- 29431300 TI - Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis in Adults: A Retrospective Analysis of 23 Patients in China. AB - BACKGROUND: Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease with poor prognosis despite intensive therapy. OBJECTIVES: To discuss the ideal therapy of EBV associated HLH for adults. METHODS: We retrospectively studied 23 adult patients with EBV-associated HLH at our institution between January 2000 and June 2015. The clinical characteristics, treatment, and prognosis of adult EBV-associated HLH were analyzed. The median age was 38 years (range 18-72). RESULTS: All patients were found to have high fever, thrombocytopenia, abnormal liver function, elevated ferritin, and lactate dehydrogenase. Leukopenia, anemia, coagulopathy, hypofibrinogenemia, and splenomegaly were found in more than 80% of patients. Ten patients were treated with HLH-2004 protocol. Eventually, 95.7% of patients died of EBV-associated HLH. Non-HLH-2004 treatment and bone marrow suppression may predict early relapse independently, and the poor performance status and high lactate dehydrogenase level can be poor prognostic factors. It was also validated in comprehensive analysis of published articles. CONCLUSIONS: Adult EBV-associated HLH occurs most often in people of Asian descent who are older than 35 years. These patients had a disappointing outcome despite intensive treatment, especially with high lactate dehydrogenase levels, poor performance status, and bone marrow suppression. HLH-2004 protocol has shown a glimmer of hope in the adult populations. PMID- 29431301 TI - Seroepidemiological Study of Epstein-Barr Virus in Different Population Groups in Croatia. AB - BACKGROUND: The Epstein-Barr virus (EBV) is one of the most common viruses found in humans, causing lifelong infection in up to 95% of the world population. OBJECTIVES: To analyze the seroprevalence of EBV infection in different population groups in Croatia. METHODS: During a 2 year period (2015-2016), a total of 2022 consecutive serum samples collected from Croatian residents were tested for the presence of EBV-specific viral capsid antigen (VCA) immunoglobulin M (IgM) and IgG antibodies using an enzyme-linked immunoassay. IgM/IgG-positive samples were further tested for IgG avidity. RESULTS: The overall prevalence of EBV IgG antibodies was 91.4%. Females had significantly higher IgG seroprevalence than males (93.1% vs. 89.9%, P = 0.008). According to age, IgG seropositivity increased progressively from 59.6% in children age < 9 years to 98.3% in 30-39 year olds, and remained stable thereafter (P < 0.001). The IgG seroprevalence differed significantly among groups: 68.1% in children/adolescents and 95.9% in adults; multiple sclerosis (100%), hemodialysis patients (97.7%), heart transplant recipients (93.8%), hematological malignancies (91.2%), and Crohn's disease (88.5%), P < 0.001. IgM antibodies were detected in 9% of participants. Using IgG avidity, recent primary EBV infection was documented in 83.8% of IgM positive subjects < 9 years old, 69.2% age 10-19, 33.3% age 20-29, and 3.6-4.2% > 40. All IgM positive participants > 40 years showed high IgG avidity. Logistic regression showed that age is associated with EBV IgG seropositivity. CONCLUSIONS: EBV is widespread in the Croatian population. Older age appears to be the main risk factor for EBV seropositivity. PMID- 29431302 TI - The New Test for Monitoring Infliximab Therapy: From Laboratory to Clinical Practice. AB - BACKGROUND: Biological agents for anti-tumor necrosis factor-alpha therapy have revolutionized treatments for autoimmune diseases; however, approximately 20% of rheumatology and 40% of gastroenterology patients do not respond to the therapy, or they show reduced drug efficacy because of anti-drug antibody (ADA) formation. OBJECTIVES: To evaluate laboratory tools for individual monitoring of infliximab therapy and the relationship between ADA and infliximab serum levels, ADA and clinical response, and ADA and autoantibodies. METHODS: Our study comprised patients treated with infliximab and affected by selected rheumatology and gastroenterology diseases. Sera were analyzed for infliximab, total-anti-drug antibodies (Total-ADA), and free-anti-drug antibodies (Free-ADA) serum levels and for the detection of specific autoantibodies. RESULTS: We analyzed 73 patients. Total-ADA were detected in 26 rheumatology and 21 gastroenterology patients. Serum infliximab levels were significantly lower in Total-ADA positive patients (P = 0.01 for rheumatology group, P = 0.02 for gastroenterology group). A lack of response was observed in 7 rheumatology and 15 gastroenterology samples. Total ADA serum levels were statistically significantly higher in patients with treatment failure in both groups (P = 0.01 and P = 0.001, respectively). There was no significant association between the presence of Total-ADA and other autoantibodies. Free-ADA were detected in only 27 rheumatology patients. Results showed a significant correlation with clinical outcome (P = 0.006). CONCLUSIONS: The correlation with clinical response suggests that the presence of ADA could interfere with efficacy of therapy. The tests for monitoring therapy may be an important tool to assist clinicians in early detection and prevention of therapy failure. PMID- 29431303 TI - Eosinophilic Fasciitis: A Single Center Experience of Seven Patients. AB - BACKGROUND: Eosinophilic fasciitis (EF) is a rare disease characterized by scleroderma-like skin, inflammation of deep muscle fascia, hypergammaglobulinemia, peripheral eosinophilia, and elevated erythrocyte sedimentation rate. OBJECTIVES: To present our experience in diagnosis and treatment of seven biopsy-proven EF patients in a large tertiary medical center. METHODS: We screened all patients who were admitted to our tertiary medical center and diagnosed with EF by tissue biopsies from January 2000 to January 2016. We analyzed relevant patient files regarding diagnosis, treatment, and outcome parameters. A comprehensive framework was presented based on the results of our observations and the corresponding literature. RESULTS: We identified seven patients (six males; one child). Mean age at diagnosis was 37.4 years (range 10-67 years). Underlying autoimmune disorders were observed in three patients (42.8 %). Disease anatomical distribution was noted in lower and upper limbs (85.7% and 57.1%, respectively) as well as neck and shoulders (14.3% each). Three patients (42.8%) had a history of initial misdiagnosis. The mean time period from first clinical presentation to histopathological diagnosis was 150.3 days (range 16-602 days). Treatment included oral glucocorticoids (71.4%), pulse methylprednisolone (14.2%), and methotrexate (42.8%). Recovery from symptoms related to EF was observed in six patients. CONCLUSIONS: Diagnosis of EF is primarily based on clinical and histopathological findings. As eradication of this disease can be expedited with early treatment, it is important to increase awareness in the medical community. PMID- 29431304 TI - Ketoacidosis in Newly Diagnosed Type 1 Diabetes in Children and Adolescents in Israel: Prevalence and Risk Factors. AB - BACKGROUND: Diabetic ketoacidosis (DKA) as the first presentation of type 1 diabetes mellitus (T1DM) is a serious complication that is preventable. OBJECTIVES: To identify risk factors for DKA at presentation of T1DM to delineate high-risk Israeli populations that could benefit from preventative measures. METHODS: Data for this multicenter retrospective study were collected from the medical files of three pediatric diabetes centers representing three districts in Israel. Inclusion criteria were diagnosis of T1DM, age at diagnosis <= 17 years, permanent residency in Israel, and documentation of the presence or absence of DKA at presentation. RESULTS: The study population included 607 patients of whom 438 met the inclusion criteria. The mean age at diagnosis was 9.1 +/- 4.5 years. DKA was present at diagnosis in 156/438 patients (35.6%). The incidence of DKA was different among the three diabetes centers (P = 0.04). The DKA group was significantly younger than the non-DKA group (8.4 +/- 4.5 vs. 9.5 +/- 4.4, respectively, P = 0.008). DKA was significantly associated with maternal origin (Ashkenazi Jewish origin [lower] vs. non-Ashkenazi, P = 0.04) and with paternal education level (academic [lower] vs. non-academic education, P = 0.04). Stepwise logistic regression showed that maternal Ashkenazi Jewish origin has a protective effect on DKA (odds ratio [OR] 0.4, 95% confidence interval [95%CI] 0.21-0.74, P = 0.004) and that younger age is an independent risk factor (OR 1.06, 95%CI 1.01 1.1, P = 0.02). CONCLUSIONS: A diabetes educational program targeting high-risk population groups may reduce the prevalence of DKA nationwide. PMID- 29431305 TI - The Epidemiological, Clinical, and Histopathological Characteristics of Lacrimal Gland Biopsies in a Tertiary Care Center in Israel. AB - BACKGROUND: The distribution of pathology and clinical characteristics of lacrimal gland diseases are different in different areas of the world. OBJECTIVES: To evaluate the incidence rate, patient characteristics, and indications for surgical intervention of lacrimal gland lesions in a tertiary care center in Israel. METHODS: All biopsied or surgically removed lacrimal gland lesions at the Goldschleger Eye Institute from 2009 to 2015 were identified. The following data were collected: age, gender, indications for surgical intervention, diagnosis, treatment, and prognosis. RESULTS: We evaluated 28 lacrimal gland biopsies from 26 patients (11 men, 15 women). Mean age at biopsy was 47.5 years old. The most common presenting symptoms were: eyelid swollenness (57.14%), ptosis (32.14%), and proptosis (10.71%). All patients underwent computed tomography and magnetic resonance imaging. In 28 cases, infiltrations of the lacrimal gland were found. In nine cases infiltration of muscles or orbital extension were found. The most common pathologies were non-specified inflammation (44.82%), lymphoma (20.68%), and immunoglobulin G4-related disease (10.34%). The treatment was diverse according to the patient diagnosis. Prognosis of lacrimal gland disease was good; however, in five patients the systemic disease progressed. CONCLUSIONS: Lesions of the lacrimal gland comprise a wide variety of pathological findings that require different treatment strategies. Lacrimal gland biopsies enable physicians to precisely recognize the pathology; therefore, it is important to consider this surgical method in any patient with lesions in the lacrimal gland. PMID- 29431306 TI - Knee Alignment and Its Significance: Is It Really Different in Various Population Groups? PMID- 29431307 TI - Epstein-Barr Virus: In Search of a Causal or a Casual Relationship Between the Virus and the Disease? PMID- 29431308 TI - Diagnostic and Clinical Significance of T Wave Inversion in Athletes. AB - BACKGROUND: Electrocardiography abnormalities are a common finding in athletes. To facilitate the differentiation of physiological adaptation versus pathological remodeling, a series of guidelines has emerged in the past decade that attempt to improve specificity while maintaining a high sensitivity. Recently, T wave inversion in the athletic population gained more attention, resulting in accelerated research leading to novel findings not yet integrated into clinical practice. We aim to simplify the knowledge to date and integrate it into one easy to use practical flowchart. PMID- 29431309 TI - Ankylosing Spondylitis Treatment after First Anti-TNF Drug Failure. PMID- 29431310 TI - Entrapment of Permanent Pacemaker Ventricular Lead in a Loop Formed by a Temporary Pacemaker Electrode. How to Untie a Tight Knot? PMID- 29431311 TI - A Case Report of Metastatic Primary Thyroid Leiomyosarcoma Treated with Pazopanib. PMID- 29431312 TI - Acute Myocardial Infarction in a Patient with Isolated Dextrocardia. PMID- 29431313 TI - Bilateral Frontal Hemorrhage Caused by Contrecoup Injury. PMID- 29431315 TI - [Features of fractional composition of polycyclic aromatic hydrocarbons and multielement contamination of soils of urban territories and their hygienic characteristics (on the example of soils of functional zones of Saint Petersburg)]. AB - This study is devoted to the investigation of quantitative and qualitative composition and distribution of polycyclic aromatic hydrocarbons (PAHs) in urban soils on the example of recreational, residential and industrial areas of Saint Petersburg (Russia). The evaluation of soil contamination levels with heavy metals and metalloids of the first and second classes of hazard is given as well. Total PAH content in soils of the studied area in most cases exceeds international soil quality guideline values (1 mg/kg), varying from 0.67 to 17.45 mg/kg. In most samples benzo[a] pyrene concentrations were found to be higher than MPC for this substance in soil. Calculated BaP-equivalents of PAHs indicate to the high carcinogenic risk for health, associated with soil contamination. Mean PAH concentrations in soil differ authentically between various types of functional zones and in the whole of the city. The significant positive correlation between soil organic content and PAH levels in soils was revealed in most samples. Calculated values of the total index of soil contamination (Zc) by heavy metals and metalloids were characterized by low values (47.28-121.14), that corresponds to the category of dangerous pollution (32 < Z < 128). PMID- 29431314 TI - [Evaluation of the content and migration of heavy metals in components of river ecosystems' of mining territories of the Republic of Bashkortostan]. AB - Exploration and development of mineral deposits in the Transurals of the Republic of Bashkortostan are accompanied by a comprehensive environmental impact. Ones of the most vulnerable elements of the landscape are the surface water bodies used for fishery purposes, recreation and household needs of the population. Extraction and processing of ores lead to the contamination of aquatic ecosystems by heavy metals (HM), which by passing into a pond, can actively be involved in the cycling of matter and migrate via food chains to the human under the consumption of fish products. Possessing by cumulative properties, HM can express mutagenic, teratogenic and carcinogenic properties. The aim of research was the study of the impact of mining facilities on the content of the priority HM in the components of river ecosystems in the Transurals of the Republic of Bashkortostan and the development of a complex of preventive measures on the improvement of the human environment. There was studied the content of Zn, Cu and Cd in the water, bottom sediments and phytomass of Elodea canadensis Michx. The measurements of mass concentrations of metals were performed by stripping voltammetry with the use of the STA device. The results showed that for the cross-sections there is typical the following descending series of elements in the river components: Zn > Cu > Cd. In water samples there is observed the exceedance of standards for water bodies of potable, cultural and community water use and fishery basins. The concentration of zinc varies in the range of 0.016-5.24 mg/dm; copper - 0.0024 0.095 mg/dm; cadmium - 0.0001-0.019 mg/dm. In bottom sediments, in general, the content of metals in comparison with control plots is increased to the tenfold value. The meaning of mobile forms of zinc in the ground varies in the range of 0.81-9.62 mg/kg; copper - 0.12-18.69 mg/kg; cadmium - 0.00013-0.092 mg/kg. The zinc concentration in above-ground phytomass of Elodea canadensis compared to control increases by 2-3.5 times, copper - 4-8 times, cadmium - 2-7 times. Univariate analysis of variance confirmed the accuracy of the impact of the degree of contamination on the accumulation of metals by Elodea canadensis. The results testify to the potential danger to health of water bodies of the region's population. PMID- 29431316 TI - [Premises to the transboundary environmental crisis in the water tract on the example of water tract of the Kuban-Manych]. AB - As a result, of the management of the irrigation system the most part of the runoff headwaters of the river Kuban was transferred to the arid plains of the Stavropol Territory, Rostov Region and Kalmykia Gravity Water via the water tract of the Kuban-Manych. This system was assumed to be supplied by pure mountain water. In fact, 3-4 class contaminated water currently passes to the water intake of the irrigation system (Nevinnomyssky channel). There is a tendency to the further deterioration in the quality of surface waters. It was determined that in the last decades in the catchment area of the upper reaches of the Kuban (Karachaevo-Cherkessia) the population was determined to increase sharply. As a result the discharge of industrial, agricultural, domestic and recreational waste into the river significantly increased. In that in catchment areas there is practically no infrastructure of the acquisition, processing and recycling of waste for the irrigation system. Intensive recreational and transport development of mountainous areas of Karachay-Cherkessia aggravates the situation and may lead to the need for deep water purification for subsequent consumption already in the vast territories of the Central Caucasus. Due to lack of the infrastructure for the water treatment in the upper reaches of the Kuban, it can lead to the serious systemic crisis. It is proposed to start to create in the catchment areas the cost-based system of recycling waste on the base of their processing by pyrolysis. PMID- 29431317 TI - [Monitoring of health of young students of northern territories residing in conditions of ecological trouble]. AB - In recent years, in sanitary science the interest in issues of young people has dramatically increased, that has been actualized by the necessity of a new objective assessment of the role of the youth in modern sanitary-ecological, sociocultural and economic processes. In this regard, a special interest is aroused by young students, the health of whom is determined largely by the condition of the habitat. So far complex assessment ofriskfactors in urbanized areas, prioritization of impacts, the establishment ofpriority impacts, the detection of informative territorial environmentally dependent indices ofpopulation health are presented to be important tasks in the solution of the regional challenges. The aim of this work was the assessment of the state of health of students of the Bratsk State University, residing in conditions of ecological trouble. In the territory of the city of Bratsk the environmental situation is characterized by long term multi-component air pollution with highly toxic vehicular and industrial emissions. In the work throughout the 4 years following-up there was executed an assessment of the physical development of students, there was determined structure and revealed the an increased level of morbidity rate of students of Bratsk state University in terms of educational space, which is characteristic for territories of ecological trouble in the city of Bratsk. Parameters of physical development of students in dynamics of training were established to be not liable to variation. It confirms the stability of the morphological signs as compared to functional ones. In the analysis of dynamics of indices of the harmonicity ofphysical development there was revealed a gain in the proportion of harmoniously developed students by the end of training. Physiometric indices of students to the fourth course of training were characterized by the increase offunctional capabilities of the respiratory system.The indices of the cardiovascular system performance had a tendency to the growth of the hypertensive response in boys and the increase in the number of people with normotensive response to physical stress by the end of training. To the IV course of training there was observed the increase in the number of young boys with stringency of mechanisms of adaptation to stress, whereas in young girls satisfactory adaptation was seen. PMID- 29431318 TI - [Influence of sociohygienic factors on the shaping of the nutritional status in children and teenagers]. AB - There was revealed the structure of deteriorations in the nutritional status of schoolchildren in the city: the most of students has normal nutritional status, but there was noted the high prevalence of excessive body weight and obesity among children and teenagers. Risk factors for development of deteriorations of the nutrition state were detected as follows: irrational food regimen, qualitative compartment offood, factors of educational environment, lifestyle. The main role in system of control of the nutritional status in children is referred to the correction of socio-hygienic factors which prove to be the priority ones in the shaping of the nutritional status in students. As the main condition determining the nutrition state of the up-to-date schoolchildren and the quality of their life in the whole the social cultural level of children and adolescents must be regarded as a result of the hygienic education and training in fundamentals of healthy lifestyle. Priority protective factors of the gain in the part of schoolchildren with normal nutritional status (optimalfood regimen, optimal dietary habits, sufficient level of physical activity) laidfrom the child age in conditions of the family, sufficient level of the physical activity and the implementation of the other element of hygienically expedient day regimen served as the base for the elaboration of the system of the control of nutritional status. Algorithm of the control of the nutritional status in the students of educational institutions includes the creation of healthcare educational environment, optimization of nutrition and physical activity, the shaping of the culture of healthy lifestyle, health-improving measures for children with disorders of nutritional status and their psychological pedagogical supports at the stage of the correction of the nutritional status, improvement of the medical service for the early detection of deviations of nutritional status with the estimation of the efficiency of the system ofpreventive and health improving measures. PMID- 29431319 TI - [Working conditions and functional state of the organism of mechaniciandrivers under the defoliation of the cotton-plants]. AB - In the article there are presented results of the study of the impact of working of mechanicians-drivers performing cotton-plant defoliation with a new import substituting low-toxic defoliant denoted as "Fandef-Alo" on a functional state of various systems of the organism. Working conditions and the character of labor processes under the execution of defoliation were revealed to give rise in adverse shifts of physiological responses of various systems of the organism in mechanician-drivers, and the noise and the overwork labor process elevate the probability for the risk of the occurrence of occupational diseases that is indicates to the need for measures for the making labor healthy. PMID- 29431320 TI - [Features of the lipid exchange in workers employed in aluminium productions]. AB - Aluminum production can be referred to the category of industries of the increased health hazard for the workers. During technological process of receiving aluminum the air of a working zone is polluted by a large number of harmful substances. Workers are exposed to the complex of toxicants possessing a polytropic impact on the body. The most significant consequences are violations of different types of metabolism in the organism, including lipid metabolism. The purpose of the study is the investigation of the state of lipid metabolism in persons working in the production of aluminum. The object of research was 108 male workers of aluminum production suffering from occupational pathology of airways. The group of comparison was consisted of 103 men, apparently healthy, not exposed to toxicants. There was determined the content of the total cholesterol (TC), high and low density lipoprotein cholesterol (HDLC and LDLC), triglycerides (TG), phospholipids (PL), atherogenic index (AI). Statistical processing was performed with the use of software "Statistica 6.0". There were established statistically significant differences of indices of lipid exchange in the persons occupied in aluminum production when related to the group of comparison. IA values in persons from the study group proved to be higher than in the comparison group, due to elevated levels of TC and LDLC. The TG and PL level was also higher. The values of IA, TC and TG in workers of aluminum production in more than 50% cases exceeded the reference values. The average concentration of HDL cholesterol in both groups did not differ, and was above the lower reference boundary. Established features of lipid metabolism in workers of aluminum allow us to suggest the distinction in mechanisms of developing proatherogenic disorders from previously established ones for workers exposed to other chemicals. One of the causes of the shaping of these disorders can be oxidative stress, which in turn serves as a response to the exposure of complex of toxic substances to workers. PMID- 29431321 TI - [Socio-economic aspects of epidemiology of helicobateriosis]. AB - There are considered special social and economic aspects of the epidemiology of Helicobacter pylori. These aspects acquired the particular importance for the last time due to the fact that the provision of the people with pure water has been becoming the focus of the attention of geopolitical and socio-economic interests in a number of countries. The availability ofpure drinking water serves a marker of the socio-economic state of the territory and the population living there. In Russia where different climatic conditions are deposited by considerable regional differences in the conditions of communal services caused both by various level of the socio-economic development of the territory, the supplementation with pure drinking water serves as the social determinant of the ecological conditions of the population's life. This particularly has impact on the unfeasible technical state of the water distribution systems, microorganism ecology of which can substantially affect public health. The performed by authors a specialized screening ofpresented at the official web site of the joint-stock company "Mosvodokanal" current data concerning the quality of drinking water consumed by 2500 Moscovites, tested for the Helicobacter pylori infection revealed no deviations from the sanitary standards in the water received by the consumers. Along with that, the comparison of the map documents of the distribution of the Helicobacter pylori infection in Moscow with the distribution of citizens' complaints of the decline of the quality of tap water has revealed a territorial fastening of the high values of the population infection rate of n^ylori and the urban sites with the greatest number of complaints. In the microbial ecology of water-distribution systems there are tightly aligned problems of their epidemiological safety, technical state and economic damage caused by corrosion as a result of microbiotic activity. In contrast to acute bacterial and viral infections which are deemed of the greatest importance when assessing the sanitary condition of water sources and water-distribution systems, the consequences of infection with H. pylori may not be manifestedfor a long time but some years later they may be manifested as serious chronic diseases (from gastritis to adenocarcinoma of the stomach and a wide range of extraintestinal pathologies), which causes great social and economic losses. Thus, the socio economic aspect of the epidemiology of helicobacteriosis includes at least two components: the technic - the maintenance of the feasible technic and sanitary state of the water distribution systems and the medico-social - expenditures for screening and treatment of infected patients. In total they are an inseparable part of the prevention of socially-important diseases in the public health system. PMID- 29431322 TI - [Cytogenetic status of the residents of the Gydansky Peninsula (Gydan)]. AB - The relevance of the study on the Gydansky Peninsula lies in poor knowledge and inaccessibility of the territory, planned intensive industrial development of the Gydansky Peninsula, in 2011 there were received licenses for the exploration of license areas at the peninsula up to 2031. Industrial development will inevitably lead to certain environmental shifts, emission of the harmful substances into biosphere, the accumulation of anthropogenic pollutants in soil and water sources. The proposed development of the territory of the Peninsula Gydan sets the task of assessment of the impact of gas and oil production in conditions of the far North on health, as well indigenous persons as employees recruited to this of the region. One of the informative approaches to the assessment of population health is the assessment of the cytogenetic status with the use of noninvasive analysis of buccal epithelium. The aim of the study is to determine the cytogenetic status of the inhabitants of the village of Antipayuta of the Yamal-Nenets Autonomous Okrug for the assessment of the impact of environmental factors on the health of the population at the present stage of the industrial development of the territory. Samples of buccal epithelium of 81 alien and indigenous people of the Yamal-Nenets Autonomous district were the object of the investigation. There was performed the analysis of indices of cells of buccal epithelium of the residents living in the village in comparison with the control group. The analysis of samples was performed on a Nikon Eclipse E100 microscope. For the assessment of the cytogenetic status of the individual there was used the proposed by Sycheva L. P. (2012-Index of accumulation of cytogenetic damages (Iac). It is shown that the frequency of occurrence of micronucleus and nuclear protrusions does not exceed the performance of the control group. The index of accumulation of cytogenetic damage for the population of the village is 0.78+/ 0.07% and corresponds to a low level. The analysis of indices of buccal epithelial cells of residents living in rural areas was performed in the comparison with the control group The prevalence rate of cells with micronuclei and protrusions were shown to account of 14.6% andfail to exceed indices in the control group. Accumulation index of cytogenetic damages for the village population is 0.78 +/- 0.07 % and corresponds to the low level. The amount of cells with micronuclei and protrusions in the current study is by 14.6% lower than the average of the control group. The intensity of proliferative processes and apoptosis in the comparison groups occurs evenly. PMID- 29431323 TI - [Hygienic estimation of the nutrition and the risk of morbidity associated with its violation]. AB - Among risk factors possessing a main importance in the shaping of theA public health the leading place is featured to the rational nutrition. Presented results testify to the absence of stable group in the adult population of Irkutsk who eats regularly, with a rational multiplicity and having all essential meal reception and the recommended food package. There was revealed the role of nutrition in shaping of morbidity rate in the adult population. The risk of circulatory diseases was established to account of 2.5 (95% CI 2.1-3.6), the infectious and parasitic diseases - 2.4 (95% CI 1.7-3.5), the endocrine system - 2,2 (95% CI 1.4-3.4), and urinary system - 2.3 (95% CI 1.7 to 3.0). PMID- 29431324 TI - [Actual problems of the microbiological safety of food products]. AB - Food-borne infectious diseases remain an actual problem of health care. In the Republic of Belarus the level of food-borne diseases persists to be stable, at the same time these diseases remain to be significant. Despite the insignificant number of nonconforming food samples the prevalence rates of food-borne acute infectious diseases of various etiology with dominantly food transmission pathway remain to be rather high. The mentioned fact determines the need for the development of approaches on the security of microbiological food safety based on the risk analysis. There are determined criteria for a hygienic assessment of the microbiological hazards (associated with the pathogen, food products and a consumer health state), there is presented the classification offood products in dependence on the grade of microbiological risk. There was performed the comparative analysis of requirements for the microbiological safety of food accepted in the Republic of Belarus and European Economic Union, in the European Union and at the international level, which testify to the presence of separate differences. Based on the international approaches there was substantiated the multilevel control system of management of microbiological risks, there is reported the characteristic of separate criteria. There are determined the directions of the improvement of the security of microbiological safety of food. PMID- 29431325 TI - [Study and methodology for research of the life quality in students]. AB - In this article there is reported a comparative analysis of methodological approaches to the assessment of the quality of life. There are present results of studies of quality of life of young students, performed with the use of compared methodological approaches (questionnaires) and allowing to construct the evaluation approach to the study of the quality of life in students. PMID- 29431326 TI - [Method of colored model radicals for assessment of oxidative equilibrium in biologic samples]. AB - The most specific method of the recording of the rate offree radical reactions is the method of electron paramagnetic resonance (EPR) spectroscopy, but it is rarely used in applied biology due to expensive equipment and complexity of the execution of measurements. However chemists have found a number of colored organic radicals which lose the coloring under transition into diamagnetic form. In the given paper there are presented results of our studies on the development of methods for the assessment of oxidant equilibrium in biological media with a use of stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) and cation-radicals of N,N-diethyl-p-phenylenediamine (DEPPD). We have developed the new modification of DPPH test, replacing methanol-based incubation medium by non-ionic detergent solution, compatible with native blood serum. Modified DPPH test conserved typical biphasic kinetics of the origin variant, had the similar sensitivity to model antioxidants (IC values 49, 38 and 13 mkMfor ascorbate, a-tocopherol and quercetine, correspondingly) and was applied in experiments on laboratory animals treated with nano- and ionic silver, carbon nanotubes, microfine coal and electrolytic dust. We have tried also the assay of serum lipid hydroperoxides based on Fe-initiated DEPPD oxidation (Alberti et al., 2000). The comparison of kinetics of DEPPD oxidation in model (HO/Fe) and biologic (rat serum/Fe) systems, before and after Fe addition, seems to be an evidence that ceruloplasmin (CP) was involved in the resulting process, but failed to determine its polynomial kinetics, at least for the rat serum and DEPPD excess. The use of CP monoclonal antibodies seems to be the best way for the clarification of the mechanism of this reaction. PMID- 29431327 TI - [Microscopic soil fungi - bioindicators organisms contaminated soil]. AB - In the paper there are considered methodological issues for the evaluation of soil biota in terms of oil pollution. Experimental studies have shown that under the exposure of a various levels of oil pollution meeting certain gradations of the state and optimal alteration in microbocenosis in sod-podzolic soils, there is occurred a transformation of structure of the complex of micromycetes and the accumulation of toxic species, hardly typical for podzolic soils - primarily represantatives of the genus Aspergillus (A.niger and A. versicolor), Paecilomyces (P.variotii Bainer), Trichoderma (T.hamatum), the genus of phytopathogens Fusarium (F.oxysporum), dermatophytes of genus Sporothrix (S. schenckii) and dark-colored melanin containing fungi of Dematiaceae family. Besides that there are presented data on the study of microbiocenosis of the urban soil, the urban soil differed from the zone soil, but shaped in similar landscape and climatic conditions, and therefore having a tendency to a similar response from the side of microorganisms inhabiting the soil. Isolated complex of soil microscopic fungi is described by many authors as a complex, characteristic for soils of megalopolises. This allowed authors of this work to suggest that in urban soils the gain in the occurrence of pathogenic species micromycetes also increases against a background of chronic, continuously renewed inflow of petroleum hydrocarbons from various sources of pollution. Because changes in the species composition of micromycetes occurred in accordance with the increasing load of oil, so far as microscopic soil fungi can be recommended as a bioindicator organisms for oil. In the article there is also provided information about the distinctive features of modern DNA identification method of soil microscopic fungi and accepted in our country methodology of isolation of micromycetes with the use of a nutrient Czapek medium. PMID- 29431328 TI - [The study of neurotoxicity of toluene in conditions of experimental modeling of prenatal hypoxic damage of the brain]. AB - There was executed the study of the impact of toluene on indices of behavior, cognitive capabilities and bioelectric activity of the brain in white rats with normal course of the period of antenatal development and against background ofprenatal hemic hypoxia Prenatal hypoxia was modeled in pregnant female rats by subcutaneous injection of sodium nitrite in a dose of 50 mg/kg at from the 10 to the 19 day of gestation. At the age of 3 months the males from the obtained offspring were exposed to inhalation exposure of toluene (150 ppm, 4 weeks). After exposure to toluene in animals there was evaluated the pattern of individual behavior, indices of cognitive capabilities and also bioelectric activity of the brain. There were revealed such common consistencies of transformations in the behavior of exposed to toluene animals with normal and impaired embryogenesis as disturbed motor activity, reduction of exploratory behavior and cognitive functions, impaired bioelectric potentials of the brain. Features of changes in behavior and EEG indices in toluene-exposed rats with prenatal hypoxia are characterized by inhibition of motor activity, increased anxiety and latency of main peaks of auditory and visual evoked potentials. Prenatal hypoxic damage of the central nervous system was shown to be an aggravating factor in toluene intoxication in rats. PMID- 29431329 TI - [Morphological comparative assessment of in vivo 2-week oral exposure of silver nanoparticles and silver sulfate on the mice liver]. AB - Currently the problem of the impact of nanoparticles and nanomaterials on human health remains to be poorly understood. As in our studies of the impact of silver nanoparticles on rats liver as well in works of other researchers there were investigated morphofunctional indices under peroral exposure. Although all researchers took different sizes, doses and concentrations of silver nanoparticles, various exposure time and different stabilizers, the same effects had been obtained, which, however, were occurred under both different doses and time of exposure. However, it was interesting to compare the impact of silver nanoparticles with reference substance - silver sulfate on the mice liver with the previously evaluated effect produced on the rats ' liver. By ourselves there was executed the morphological comparative evaluation of in vivo oral 2-weeks exposure of 4 concentrations (0.1; 5; 50 and 500 mg/l) of silver nanoparticles with size of 14 nm, stable arabian gum 1:7 by weight, and of 4 similar concentrations of silver sulfate on the liver of male mice SVAxS57V1/6 weighing 25-35g. 2 groups were considered as control: intact mice and mice received gum in water. Results of the exposure were assessed according to 10 morphological and functional indices. The impact of nanosilver was shown to initiate from its concentration of 50 mg/l and to express in the gain of the index of alteration of the cytoplasm of hepatocytes with the increasing in both severity of steatosis and the number of micronecroses, persisting at the same level at concentrations of 500 mg/l and with the elevation of the index of alteration of nuclei of hepatocytes, while the similar effect develops under the influence of silver sulfate at a concentration of 500 mg/l only. The remaining investigated morphofunctional indices did not differ significantly in all groups of mice. Unlike previously executed studies on rats, mice appeared to be sensitive to the effects of nano-silver more than to silver sulfate. PMID- 29431330 TI - [Hygienic and environmental problems of energy-saving illumination in urbanization of Crimea]. AB - The article considers the problems offloodlights pollution in the territory of Crimea due to the work of illumination led equipment of the key elements of the international transport artery "China-Europe". There was performed a qualitative assessment of characteristics of led floodlights pollution on the example of the sea surface of the transport crossing through the Kerch Strait. Ichthyologists and oceanographers were shown to estimate the amount of phytoplankton biomass based on sunlight illumination. The excess dose of blue light in the spectrum of led lighting was established to have an impact on phytoplankton greater than solar and lunar light, creating preconditions for the increase of biological mass of phytoplankton and consequently to the formation of the "stern stock". Arising from additional phytoplankton biomass can significantly influence on the schedule offish migration in waters of the Kerch Strait, the biomass of mosquitoes and midges, which are prey for amphibians and birds. The decline of the both light pollution and its negative impact on fauna andflora requires the development of semiconductor sources of white light with a biologically adequate spectrum in the framework of the "Lighting of the lighting equipment of Crimea". PMID- 29431331 TI - [Ecological hygienic assessment of soils quality in urban areas]. AB - Assessment of the soil quality is ofprime importance essential for the characterization of the ecological and hygienic condition of the territory, as the soil is the first link of the food chain, the source of secondary air and water pollution, as well as an integral index of ecological well-being of the environment. Herewith the qualitative analysis of soil complicated by the specifics of the soil genesis in the urban environment, in which an important role is played by manmade land bulk and alluvial soils; the inclusion of construction of material debris and household garbage in upper horizons; the growing up of the profile due to the perpetual introduction of different materials and intensive aeolian deposition. It is advisable to consider the currently neglected question of the study of soil vapor containing volatile chemicals. These pollutants penetrate into the building through cracks in the foundation and openings for utilities. Soil evaporation may accumulate in residential areas or in the soil under the building. Because of this, it is necessary to pay attention to the remediation of areas allocated for the built-up area, possessing a large-scale underground parking. Soil contamination is the result of significant anthropogenic impacts on the environment components. In general, about 89.1 million people (62.6% of the population of the country) live in terms of complex chemical load, determined by contamination offood, drinking water, air and soil. The list of microbiological and sanitary-chemical indices of the assessment of soils of urban areas may vary in dependence on the data obtained in pilot studies due to changes and additions to the assigned tasks. Timely forecast for the possibility of the usage of released lands of urban territories for the construction and the creation of new objects for different purposes should become the prevention of chronic non-infectious diseases in the population residing in urban areas. PMID- 29431333 TI - [Microbial communities in regions of arctic settlements]. AB - The composition and the structure of microbial communities in areas of Arctic settlements were studied. The main attention has been given to microscopic fungi. As result of observation of 5 Arctic regions 117 species of microscopic fungi are revealed in soils and anthropogenic substrates. The identification was carried out with the use ofmycological and molecular genetic methods. Most ofspecies belong to the Ascomycotina. Genus Penicillium is characterized by the most species diversity (24 species). Most offungi are destructors of various materials and potential human pathogens. Dominant species are revealed. The distribution of microorganisms in the living and working areas of polar stations, as well as the adjacent areas are described. Black-colored fungi adapted to unfavorable environment are often the dominated group of microorganisms on soils and anthropogenic substrates. The shaping of soil microbiota was shown to be related to the anthropogenic impact. Considerable similarity of microbial communities composition in the soil and man-made substrates is fixed. As result of mycological analysis of contaminated soils 76 species of microscopic fungi were observed, but 41 species of them (53.9%) were identified in the areas of Arctic polar stations on the man-made materials. These species include the representatives of the genera Alternaria, Aspergillus, Aureobasidium, Chaetomium, Cladosporium, Exophiala, Geomyces, Humicola, Penicillium, Mucor, Phoma, Rhodotorula, Trichoderma and Ulocladium. The obtained data show a significant similarity in species composition of contaminated soils and anthropogenic substrates. Human activity contributes to the distribution of cosmopolitan species, including opportunistic fungi, in the Arctic region. The high numbers of organotrophic bacteria were revealed in soil samples. Some species of microorganisms produce the organic acids in an external environment that promotes the erosion of materials. PMID- 29431332 TI - [Methodical issues of the monitoring for ammonium in indoors air]. AB - Introduction. To perform mass studies of the indoors air environment of the ammonium content the actual issues are the shortening of the sampling time and material costs for their implementation, reduction of adverse effects of ammonium with keeping of the objectivity of results. Aim. The elaboration of the method of short-term air sampling for indoors ammonium and comparative assessment ofdifferent methods of sampling in the course of modeling and field tests. Materials and Methods. Air sampling for ammonium was carried out according to the developed program and standard method, under the average daily 4-fold taking according to State Standards (GOST) 17.2.3.01-86 andRD 52.04.186-89. The evaluation of the significance of deviations of analysis results was carried out in accordance with GOST R ISO 5725-6-2002 and Recommendations of the Interstate Standardization RMG - 61-2003. Results. There were executed model and field tests of air sampling for ammonium according to the standard method and the program of short-term sampling. There were obtained significantly comparable results of ammonium content in the indoor air in the course of model and field tests. Conclusions. Sampling according to the developed program has a number of advantages, including: the shortening of sampling time, material costs, increasing in productivity in the analysis of indoor airfor the ammonium content. The execution oftest sampling according to the developed program allows to reduce the time of ammonium exposure to personnel carrying out the test sampling. PMID- 29431334 TI - [Biological and sanitary evaluation of Sibaisky quarry dumps of the Bashkortostan Republic]. AB - Dumps of quarries for the extraction of copper pyrite in Urals region of the Bashkortostan Republic are the problem object, which represents a main technogenic source of environmental pollution. Soils of Sibaisky quarry dumps are characterized by the elevated content of heavy metals relatively to maximum permissible concentrations and regional geochemical background. In sanitary hygienic evaluation of the pollution by studied technosols according to the total pollution index (Zc) it was revealed that according to the content of total forms studied technosols are referred to moderately hazard, while in regards of the same index concerning the content of the mobile forms technosols are referred to the category of hazardous. In this regard, in plant products grown in the area adjacent to the dumps, there was revealed an excess on cadmium. The biological activity of soils is very low, due to the low microbial community development. Soil formation in the dumps is almost not expressed, appearing in the formation of low-thick underdeveloped humus horizon with a little diversity of species and projective cover. Sanitary-hygienic situation in conditions in the quarry dump area is unfavorable, that does not allow newly formed soils to carry out environmental functions effectively PMID- 29431335 TI - Open-label study of ademetionine for the treatment of intrahepatic cholestasis associated with alcoholic liver disease. AB - BACKGROUND: The effect of oral and/or parenteral ademetionine (500 mg intravenous [IV] and tablet formulation) on clinical symptoms and biochemical markers of intrahepatic cholestasis (IHC) was investigated in subjects with alcoholic liver disease (ALD) and compensated liver function. METHODS: Prospective, multicenter, open-label study consisting of a screening period and an 8-week treatment period and performed in subjects (18-75 years) with compensated ALD and confirmed IHC. Subjects with a baseline serum conjugated bilirubin value above normal range were initially treated with IV ademetionine for two weeks (500-800 mg daily) and continued with oral ademetionine 1500 mg daily for a further six weeks. Subjects with a baseline serum conjugated bilirubin value within normal range were treated with oral ademetionine for eight weeks. RESULTS: A total of 72 subjects were treated; 41 initially with IV ademetionine and 31 with oral ademetionine. Clinical symptoms status improved from baseline to end of treatment with an increase in the proportion of subjects with no symptoms. Ademetionine showed significant improvements in primary efficacy parameters alkaline phosphatase (ALP) and gamma-glutamyltransferase (gammaGT) (P<0.0001). Although decreases of ALP were higher for subjects initially treated with IV ademetionine, these subjects also had higher baseline values. No safety concerns with ademetionine arose with respect to the severity or frequency of adverse events (AEs) during the treatment period, laboratory parameters, and vital signs. CONCLUSIONS: Administration of oral or IV/oral ademetionine step-therapy for 8 weeks to subjects with IHC due to ALD was safe and provided a significant improvement of disease burden. PMID- 29431337 TI - [Content of heavy metals and petroleum products in the soil on the territory of oilproducing areas of the Republic of Tatarstan]. AB - The paper presents data on the hygienic assessment of the content of heavy metals and petroleum products in the soil on the territory of oil-producing areas of the Republic of Tatarstan. The average total content of lead (10,1 mg/kg), cadmium (0.073 mg/kg), manganese (792.4 mg/kg), cobalt (14.2 mg/kg), chromium (87.6 mg/kg), nickel (65.2 mg/ kg), arsenic (8.0 mg/kg), copper (36.6 mg/kg) and zinc (521 mg/kg) in soil for agricultural purposes near objects oil production was shown not to exceed the established hygienic standards. Soil contamination with oil products leads to an increase in its toxicity and mutagenicity. Soil contamination with oil products at the level of as low as 30 mg/ kg leads to the gain in its toxicity (low toxicity) and mutagenicity (average) (specific gravity of germinated seeds was 70.7+/-0.67%, aberrations - 1.78+/-0.19%). PMID- 29431336 TI - [The importance of sanitary microbiological indices in the evaluation of epidemiological safety of water use in conditions of chemical contamination of water]. AB - The increasing chemicalization of production and life leads to the pollution of water bodies by chemicals, the effect of which on the micro - and macro - organisms is poorly understood. This section of the study in sanitary bacteriology is becoming ever more topical and is an important task of modern hygienic science. One of complicacies of the study of the problem is related with the fact that the presence of only experimental data fails to be sufficient, as the impact of any given chemical substance on different bacteria in the experiment does not mean that under natural conditions, similar results will be obtained. One reason for this may be the inhibitory effect of the given chemical on biological properties of bacteria, while in field conditions in the water several chemicals interacting with each other can exist. In this regard, the aim of the work was to assess the indicator value of sanitary and microbiological indices of epidemic hazard of water use in conditions of chemical pollution of surface water bodies. PMID- 29431338 TI - [Hygienic assessment of the impact of diesel fuel on the ordinary black soil microbiocenosis]. AB - The main sources of soil contamination by oil products in the Dnepropetrovsk region are oil depots, gas stations and all types of transport that use and transport oil. The diesel fuel was found to be the one of the priority multicomponent components of the petroleum products, so it there was occurred the necessity for the hygienic regulation of the oil component in order to monitor a multicomponent composition ofpetroleum products in the study of complex influence of environmental factors on health population. In the study of the effect of various concentrations of diesel fuel on the number of total bacterial count (TBC) as the threshold for general sanitary indicator of hazard, there was recommended the concentration of4000 mg/kg, which oppressed the vital activity of soil microorganisms by 50-27.3% for the first 2 weeks of the laboratory experiment. PMID- 29431339 TI - Validation of diagnostic methods for peritoneal carcinomatosis secondary to ovarian cancer. CT-scan, PET-CT or laparoscopy, what is the best? PMID- 29431340 TI - [Trends of change in demographic indices of population in the area of oil and gas deposits of the republic of Kazakhstan]. AB - According to assured resources of hydrocarbons the Republic of Kazakhstan (RK) is among ten largest oil countries in the world, trailing only some states of the Middle East, Latin America, as well Russia and the USA. Public health state is the one of most important indices of social development, the manifestation of the economic and sanitaryhygienic welfare, as well as national defense capability and cultural potential of the state. In relation with the intensive development of oil and gas fields the problems of environmental protection and healthcare of the population in these regions occur critically. Therefore, it causes keen interest both from the side of researches and practical health care workers. Rapid development of the oil and gas industry leads to changes in a medical and demographic situation of given regions that is related both with the natural migration of the population and other migratory processes. According to data of the Ministry of Energetics and natural resources of RK, the Karachaganak oil-gas condensate deposit is considered to be the one of the largest in the world. For the next 40 years, the field is becoming the stable financial donor of the country. Currently Karachaganak field is considered to be the one of the largest investment projects in Kazakhstan. The studied oil and gas condensate field is located in the Burlin district of West Kazakhstan region, which is 140 km far from the city of Uralsk and 160 km far from the city of Orenburg. The field was discovered in 1984. PMID- 29431341 TI - [Qualitative index of population health losses in the aral sea region]. AB - The article is devoted to the approbation of the modification of the method of the presentation of indices of medical and social losses of the population on an example of environmentally unfavorable Aral Sea region in Kazakhstan. The first step in improvement of the system ofpublic health care is the identification of the most important problems related with the assessment of the disease burden and the adjustment of data of such type in accordance national aims on the decline of medical and social losses in this problem area. So far according to the criteria for the determination of the boundary of ecological catastrophe area one of the indices is the steady gain in the mortality rate. Using the index "Years of Life Lost" (YLL) in medical statistics as a relatively new approach that continues to be improved and its development supposes the improvement in the quality of health statistics. We modified this method consisting in the determination of the coefficient of loss of years. In the given work after comprehensive analysis of the loss of years due to morbidity and mortality on the base of life tables the potential of lost years for the population was determined with bearing in mind of module tables and compared with the loss in years due to the health loss. So far there was declined the dimension of the comprehensive index, there was elevated its comparability with other indices, and the data interpretation has been optimized. Suggested modification can be used for a comprehensive assessment of health state in the execution of epidemiological studies and monitoring of medical and social situation in ecologically unfavorable regions. PMID- 29431342 TI - [Epidemiological and hygiene assessment of the health status of population in the area of the construction site of low-head water power development]. AB - Hydrotechnical facilities have significant environmental and health imyacts. Results of a hygienic assessment of the condition of environmental objects in the area of the yrojected Nizhny Novgorod low-head water ylant develoyment showed that the both air and water pollution level in decentralized water supply sources in Balakhna and Gorodets are lower than in the city of Nizhny Novgorod, and those of the water in the water supply network are higher than in the reference area. A cross-sectional study has revealed in the main grouf (Gorodets, Zavolzhye and Balakhna) the rate of morbidity of nervous system and cardiovascular diseases to be higher than in the reference group (Nizhny Novgorod), with cardiovascular diseases being the largest contributor to the overall grevalence rate in the groug under analysis; and digestive system diseases, in the reference group. The study has no revealed direct correlation between morbidity rate in children and adults and the studied factors. However, a direct relationship has been found between the prevalence rate of endocrine diseases in children and the quality of water in the water supply network in Balakhna District (p<0.007); also, there's a correlation between the morbidity rate of digestive diseases and air pollution and water quality in the water supply network (p<0.009). In the Gorodets District, the same situation has been revealed: the morbidity rate of endocrine diseases in children depends on quality of water from the water supply network (p<0.049); the prevalence rate of digestive diseases, on air pollution and water quality in the water supply network (p<0.048). In the same region in adults the prevalence rate of the nervous system diseases, digestive diseases and diseases of the skin and subcutaneous tissue depends on air pollution and pollution of water in the water supply network (p<0.011, p<0.01 and p<0.02, respectively). PMID- 29431343 TI - [Longitudinal sstudy of differences between functional state of the body in workers at the chrysotile asbestos plant]. AB - There were performed biochemical and cytological studies of blood in healthy workers of chrysotile asbestos plant in order to determine the functional state of the body, depending on the length of service and working conditions. Mentioned differences between the functional state of the organism were determined in the longitudinal study, under construction on schedule time series with the test group at specified intervals (every year for 7 years surveyed, the same group of healthy workers). The differences between the indices allow one to discriminate different levels of the functional state of the organism for the workers employed at processing complex with experience of 4 and 5 years, and for the employees in the mining and transport workshop with the experience of 5 and 6 years. As a result the work experience of 5 years is considered to be an occupational hazard for workers at processing complex, and 6 years of experience - as an occupational hazard for workers of mining and transport workshop. PMID- 29431344 TI - [Physiological and hygienic assessment of the impact of mobile phones with various radiation intensity on the functional state of brain of children and adolescents according to electroencephalographic data]. AB - To test the effect of mobile phones (MP) of various radiation intensities on the functional state of the brain in children and adolescents, a sham-controlled EEG study was conducted in a group of thirteen 6-13 years old children, including eight 6-10 years old children. The study showed that a 3-minute exposure to the MP causes the significant decline in alpha-band absolute power, which depends on the radiation intensity and the user's age. Different from sham, an EEG-effect of MP with the energy flux density (EFD) about 100 mW/cm2 was registered both in total, and in a younger (6-10 yr) group. Its bilateral character, more prominent in the hemisphere that is ipsilateral to MP, indicates that this intensity of the radiation influences not only the superficial cortical areas of the ipsilateral hemisphere, but also the deep structures of the brain. MP with the EFD less than 1 mW/cm2 differed from sham by EEG-effect only in the group of children who are 6 10 years old. Its local, ipsilateral character indicates to the superficial influence of such intensity of the radiation on the cortex of the ipsilateral hemisphere. The results show that for the regulation of MP-radiation it's necessary to consider age features of the brain's response. The high significance of the EFD, as an index in the assessment of the impact of MP on the EEG of children, is shown. Since almost all schoolchildren are the users of mobile phones, the situation with the valuation of MP-effects on children of various ages, requires hygienic solution. PMID- 29431345 TI - [Buccal micronucleus cytome assay in complex genetic-hygienic study of preschool children]. AB - There are presented results of the cytome analysis of epithelium of buccal mucosa in 167 children aged of 5-7 years, permanently residing in the city of Magnitogorsk and visiting municipal kindergartens. Frequencies of the main indices of genotoxic and toxic effects were: cells with micronuclei - 0.29+/-0.04 %, with protrusions ofnuclei - 1.47+/-0.17 %, with double nuclei -1.96+/-0.13 %, with two nuclei - 3,28+/-0,16 %, with perinuclear vacuole - 9.66+/-0.86 %, with pycnosis of nucleus - 4.60+/-0.31 per 1000 cells, with karyorrhexis - 0.86+/ 0.15per 1000 cells, with lysis of nucleus - 54.34+/-3.90 per 1000 cells, the condensed chromatin cells - 10.59+/-1.35 per 1000 cells. Most of these indices didn't differ from the same detected earlier in buccal epithelial cells from children of the same age in Moscow, except cells with perinuclear vacuole, which frequency in Moscow cohort was twice higher. Frequencies of cells with these anomalies were associated with the content of 19 out of 326 revealed components of contamination of the total-winter snow samples, taken on the territories of the kindergartens, which were visited by examined children. There was shown lack of differences from basic values of main indices previously establishedfor the children of the same age in Moscow, with the exception of cells with perinuclear vacuole, the rate of which in Moscow was twice higher. There were revealed confounding factors associated with test indices: gender of the child, the annual number of acute respiratory diseases, health group, income per one person in family, alcohol intake by parents. PMID- 29431346 TI - House of Delegates Year in Review. PMID- 29431347 TI - Bone dehiscences and fenestrations of the anterior mandibular facial bone wall: a retrospective cone beam computed tomography study. AB - BACKGROUND: To calculate the prevalence of dehiscences and fenestrations and measure the buccal alveolar bone width overlying healthy mandibular incisors and canines. METHODS: Cone beam computerized tomographies (CBCTs) from patients aged 18 to 30 years were selected from a private database. The thickness of buccal bone in the sagittal scan was measured perpendicular to the long axis of 6 teeth at two locations: at the crest level and at the mid-root level. A single calibrated examiner performed all measurements. Descriptive and inferential statistics were performed. RESULTS: A total of 100 CBCTs (600 teeth) were selected for the analysis. The overall prevalence of dehiscences and fenestrations was 89.16% and 5.16%, respectively. Dehiscences and fenestrations were shown to have a mean length of 6.78+/-1.90 mm and 4.89+/-1.74 mm, respectively. This result was similar between young and old subjects as well as between men and women. Bone width at the crest level was significantly thinner in women (0.71+/-0.13 mm), whereas men were found to have a statistically significant thicker bone at the mid-root level of tooth #33. Comparisons of bone width at the mid-root level among the 6 analyzed teeth showed no statistical difference. CONCLUSIONS: A high prevalence of dehiscences and sites with thin buccal bone were identified in correspondence of the lower anterior teeth by means of CBCT analysis. PMID- 29431348 TI - New technique for large mandibular and surrounding soft tissue reconstruction that uses an intraoral three-dimensional distractor for one step transport disc distraction osteogenesis. PMID- 29431349 TI - Vitamin D modulatory effect on cytokines expression by human gingival fibroblasts and periodontal ligament cells. AB - BACKGROUND: It has been demonstrated that vitamin D exerts several functions other than those implied in the bone homeostasis. It has been published the vitamin D can act on many cells and tissues behaving also as a modulatory factor in the immune responses. The aim of our study was to evaluate the effect of active vitamin D3 (VD) on the expression of pro-inflammatory and anti inflammatory cytokines (IL-6, IL-8, IL-10 and IL-12) in human gingival fibroblasts (hGF) and human periodontal ligament cells (hPDLc) triggered by Porphyromonas gingivalis and Streptococcus pyogenes. METHODS: Primary hGF and hPDLc pretreated or not by VD (10-8 mol/L) were exposed to P. gingivalis and S. pyogenes for 24 h. Production of IL-6, IL-8, IL-10 and IL-12 was evaluated by immunoenzymatic assay. mRNA of the same cytokines were evaluated by PCR. RESULTS: IL-6 secretion increased by 25.2% (+/-2.1) up to 51% (+/-3.3) in VD treated hGF and hPDLc exposed to P. gingivalis and S. pyogenes, compared to VD not treated cells. IL-8 secretion decreased approximately by 30% in VD-treated hGF and hPDLc compared to VD not-treated cells. IL-12 secretion decreased by 60%. On the contrary, anti-inflammatory cytokine IL-10 increased by approximately 200%. mRNA PCR confirmed these results. CONCLUSIONS: Within the limits of the study, the obtained results support the hypothesis of a modulatory role of VD on periodontal cells exposed to bacterial infection, reducing their inflammatory response and increasing the secretion of anti-inflammatory and modulatory cytokines. Consequently, it could be speculated that vitamin D assessment, and its possible implementation in deficiency cases, could play a role in periodontal treatment. PMID- 29431351 TI - Tying Together CDI, ICD-10, and Healthcare Data Analytics: How CDI Programs and ICD-10 Are Impacting Data Analytics-- and the Benefits Healthcare Organizations are Seeing. PMID- 29431350 TI - How to Break Into Analytics and Informatics. PMID- 29431352 TI - [Radiosensitivity of morphoenzymological structural elements of the jejunum mucous membrane in chronodynamics of the impact of electromagnetic fields impulses]. AB - Results of numerous researches have revealed that most sensitive to electromagnetic radiations are the nervous, endocrine and cardiovascular systems of an organism, however, the analysis of literary data confirms also the direct involvement of organs of the intestinal system in physiological, and not seldom, and the pathological program of the response of an organism to the action of extreme factors. In the experiment executed on white laboratory male rats by ourselves there was studied the grade of the radiosensitivity of morphoenzymological structural elements of jejunum mucous membrane after 5, 7 and 10 months of chronic influence of electromagnetic fields impulses with a density of induced currents 0.37; 0.7; 0.8; 2.7 kA/m and frequency of impulses 50, 100 and 500 in a week irrespective of their divisibility of ultrashort duration of 15 a 40 ns. Scientific value and novelty of results is concluded in revealed multiple linear relationships between indices of electromagneticfields (duration of the impact, density of induced currents, periodicity of impulses and the dynamics of the studied indices of a morphofunctional condition of a jejunum mucous membrane). Besides that, there was found the critical population to indices of electromagneticfields impulses parameters - the jejunum mast cells differing in hypersensitivity and dependence on duration of influence and density of induced currents revealed, at that their bioeffects were unidirectional. PMID- 29431353 TI - [Morphological structure of rat epiphysis exposed to electromagnetic radiation from communication devices]. AB - Pineal gland is one of the most important components of homeostasis - the supporting system of the body. It participates in the launch of stress responses, restriction of their development, prevention of adverse effects on the body. There was proved an impact of electromagnetic radiation on the epiphysis. However, morphological changes in the epiphysis under exposure to electromagnetic radiation of modern communication devices are studied not sufficiently. For the time present the population is daily exposed to electromagnetic radiation, including local irradiation on the brain. These date determined the task of this research - the study of the structure of rat pineal gland under the exposure to electromagnetic radiation from personal computers and mobile phones. These date determined the task of this research - the study of the structure of rat pineal gland under the exposure to electromagnetic radiation from personal computers and mobile phones. Performed transmission electron microscopy revealed signs of degeneration of dark and light pinealocytes. These signs were manifested in the development of a complex of general and specific morphological changes. There was revealed the appearance of signs of aging and depletion transmission electron microscopy both in light and dark pinealocytes. These signs were manifested in the accumulation of lipofuscin granules and electron-dense "brain sand", the disappearance of nucleoli, cytoplasm vacuolization and mitochondrial cristae enlightenment. PMID- 29431354 TI - Data Mining a Breach's Silver Lining: Analyze Breach Data to Improve Release of Information Performance in HIM. PMID- 29431355 TI - [The application of complex assessment of the health status of the population in tasks of the improvement of the socio-hygienic monitoring system]. AB - Improvement and unification of information and analytical technologies is the one of the priorities, the solution of which will provide the gain in the efficacy and appropriateness of management decisions, developed preventive and wellness measures. In the article there is explained the use of generalized indices of the real risk as criteria for the comprehensive assessment of the health state of the population at the regional and the municipal levels. The proposed criteria make it possible to increase the objectivity of the assessment of the health state in the sociohygienic monitoring system and in the implementation of the special studies of epidemiological type. There are presented results of a comprehensive assessment of the health state of the population in the cities of Rostov region for the ten-year period and according to socio-hygienic monitoring in 2014 year. In terms of twenty of markers characteristics ofpopulation health there were used indices of the total mortality and morbidity rate. There was executed the complex assessment of the cancer prevalence rate in the urban population on nine priority localizations of the malignant tumors, including stomach, colon, rectum, lungs, skin, mammary gland, corpus uteri, ovary and thyroid gland. There were identified territories of high and elevated real risk to health state of the population. There is presented the result of the application of mathematical modeling used for the assessment and prediction of the impact of environmental factors on the complex assessment of the health staty of the population. Results of research were used for the shaping of information and analytical materials in the Rostov region. PMID- 29431356 TI - [Methodical problems of monitoring of fine particulate matters in atmospheric air of residential areas]. AB - Inhalation of fine particulate matters (PM and PM ) poses a threat for the health of population. Purpose of the study the analysis of the monitoring of fine particulate matters in the atmospheric air of Saint-Petersburg and identification of the main problems of the monitoring. Research methods methods of scientific hypothetical deductive cognition, sanitary-statistical methods, general logical methods and approaches of researches: analysis, synthesis, abstracting, generalization, induction. Results. The article represents the analysis of the monitoring of fine particulate matters in the atmospheric air of Saint- Petersburg. Only 11 in automatic monitoring stations out of 22 there is carried out the control of fine particulate matters: in 7 - PM and PM, and in 4 - PM The average year concentrations were below MAC in all the stations. The maximum concentrations achieved 3 MAC, but the repeatance of cases of exceedence of concentrations more than MAC was very rare. On the average of the city concentrations of PM were decreased from 0,8 MAC in 2006 and 1,1 MAC in 2007 to 0,5 MAC in 2013-14. The executed analysis revealed main problems of the monitoring of fine particulate matters in the Russian Federation. They include the absence of the usage 1of the officially approved methods of controlling of PM and PM in the atmospheric air until March 1, 2016, lack of the modern equipment for measurement of fine particulate matters. Conclusions. Therefore, the state of the monitoring of fine particulate matters in the atmospheric air in the Russian Federation fails to be satisfactory. It is necessary to improve system of the monitoring, create modern Russian appliances, methods and means for measurement of fine particulate matters concentrations in the atmospheric air. PMID- 29431357 TI - Losing the Match Game: Study Reveals Gaps in HIM's Patient Identity Integrity Practices. PMID- 29431359 TI - Risk of Preterm Birth with Vaginal Progesterone in Twin Pregnancies. PMID- 29431360 TI - History and Physical Examination for Identifying Rotator Cuff Tears. PMID- 29431361 TI - Statins in Persons at Low Risk of Cardiovascular Disease. PMID- 29431362 TI - Puberty: Early and Delayed. PMID- 29431363 TI - Preventive Pediatric Health Care: Updated Recommendations from the AAP. PMID- 29431365 TI - Home Glucose Monitoring Offers No Benefit to Patients Not Using Insulin. PMID- 29431364 TI - Chronic Kidney Disease: Detection and Evaluation. AB - Chronic kidney disease affects 47 million people in the United States and is associated with significant health care costs, morbidity, and mortality. Because this disease can silently progress to advanced stages, early detection is critical for initiating timely interventions. Multiple guidelines recommend at least annual screening with serum creatinine, urine albumin/creatinine ratio, and urinalysis for patients with risk factors, particularly diabetes mellitus, hypertension, and a history of cardiovascular disease. The U.S. Preventive Services Task Force found insufficient evidence to assess the balance of benefits and harms of screening for chronic kidney disease in the general population, and the American College of Physicians recommends against screening asymptomatic adults without risk factors. Persistently elevated serum creatinine and albuminuria are diagnostic and prognostic hallmarks of chronic kidney disease. Lower levels of albuminuria are associated with adverse renal and cardiovascular outcomes. Serum cystatin C is a novel biomarker that is most useful when a false positive decreased estimated glomerular filtration rate calculated from serum creatinine is suspected. New guidelines incorporate albuminuria into the classification framework for chronic kidney disease and elaborate on identification of the disease, the frequency of follow-up, and recommendations for nephrology referral. Nephrology consultation is indicated for patients with an estimated glomerular filtration rate less than 30 mL per minute per 1.73 m2, persistent urine albumin/creatinine ratio greater than 300 mg per g or urine protein/creatinine ratio greater than 500 mg per g, or if there is evidence of a rapid loss of kidney function. A multidisciplinary approach between primary care physicians, nephrologists, and other subspecialists for implementing early interventions, providing education, and planning for advanced renal disease is key for effective management. PMID- 29431367 TI - In Hospitalized Patients with Influenza and an Infiltrate, Adding Clarithromycin and Naproxen to Oseltamivir Improves Outcomes. PMID- 29431366 TI - Hypnosis for Surgical Pain. PMID- 29431368 TI - Eye Changes After Recent International Travel. PMID- 29431369 TI - Gabapentinoids for Chronic Low Back Pain: Limited Evidence, More Harm Than Benefit. PMID- 29431372 TI - Pigmentation Disorders: Diagnosis and Management. AB - Pigmentation disorders are commonly diagnosed, evaluated, and treated in primary care practices. Typical hyperpigmentation disorders include postinflammatory hyperpigmentation, melasma, solar lentigines, ephelides (freckles), and cafe au lait macules. These conditions are generally benign but can be distressing to patients. Appropriate dermatologic history, skin examination, and skin biopsy, when appropriate, can help exclude melanoma and its precursors. In addition to addressing the underlying condition, hyperpigmentation is treated with topical agents, chemical peels, cryotherapy, light or laser therapy, or a combination of these methods. Cafe au lait macules are treated with surgical excision or laser therapy if treatment is desired. Hypopigmentation disorders include vitiligo, pityriasis alba, tinea versicolor, and postinflammatory hypopigmentation. Treatment of vitiligo depends on the distribution and extent of skin involvement, and includes topical corticosteroids and calcineurin inhibitors, ultraviolet A therapy (with or without psoralens), narrowband ultraviolet B therapy, and cosmetic coverage. Patients with stable, self-limited vitiligo may be candidates for surgical grafting techniques, whereas those with extensive disease may be candidates for depigmentation therapy to make skin tone appear more even. Other hypopigmentation disorders may improve or resolve with treatment of the underlying condition. PMID- 29431371 TI - Palpitations: Evaluation in the Primary Care Setting. AB - Palpitations are a common problem in the ambulatory primary care setting, and cardiac causes are the most concerning etiology. Psychiatric illness, adverse effects of prescription and over-the-counter medications, and substance use should also be considered. Distinguishing cardiac from noncardiac causes is important because of the risk of sudden death in those with an underlying cardiac etiology. A thorough history and physical examination, followed by targeted diagnostic testing, can distinguish cardiac conditions from other causes of palpitations. Persons with a history of cardiovascular disease, palpitations at work, or palpitations that affect sleep have an increased risk of a cardiac cause. A history of cardiac symptoms, a family history concerning for cardiac dysrhythmias, or abnormal physical examination or electrocardiography findings should prompt a more in-depth evaluation for heart disease. Ischemic symptoms may signal coronary heart disease and associated ventricular premature contractions that may warrant exercise stress testing. Exertional symptoms accompanied by elevated jugular venous pressure, rales, or lower extremity edema should raise concern for heart failure; imaging may be required to assess for functional and structural heart disease. PMID- 29431373 TI - Is "Precision Medicine" Ready to Use in Primary Care Practice? No: It Is Barely Ready for Testing. PMID- 29431374 TI - Is "Precision Medicine" Ready to Use in Primary Care Practice? Yes: It Offers Patients More Individualized Ways of Managing Their Health. PMID- 29431376 TI - Vision Screening in Children Aged 6 Months to 5 Years: Recommendation Statement. PMID- 29431375 TI - Statin Use for the Primary Prevention of Cardiovascular Disease in Adults. PMID- 29431377 TI - Effects of Contraceptives on Weight Gain or Loss. PMID- 29431378 TI - Acupuncture Is Ineffective for Treatment of Low Back Pain. PMID- 29431379 TI - Chronic Kidney Disease: What You Should Know. PMID- 29431380 TI - The AAFP Cognitive Care Kit: A Resource for Family Physicians. PMID- 29431381 TI - Erythematous Lesion on a Newborn's Scalp. PMID- 29431382 TI - Mite-Impermeable Covers Decrease Hospital Visits in Kids with Asthma. PMID- 29431383 TI - Behavioral Counseling to Promote a Healthful Diet and Physical Activity for Cardiovascular Disease Prevention in Adults Without Cardiovascular Risk Factors: Recommendation Statement. PMID- 29431384 TI - Cardiomyopathy: An Overview. AB - The definition and classification of cardiomyopathy have evolved considerably in recent years. Cardiomyopathy can be separated into primary (genetic, mixed, or acquired) and secondary categories, which result in varied phenotypes including dilated, hypertrophic, and restrictive patterns. Hypertrophic cardiomyopathy is the most common primary cardiomyopathy and can cause exertional dyspnea, presyncope, atypical chest pain, heart failure, and sudden cardiac death. Dilated cardiomyopathy can be genetic or acquired and typically presents with classic symptoms of heart failure with reduced ejection fraction. Restrictive cardiomyopathy is much less common and often associated with systemic disease. Family physicians should be alert for acquired variants of cardiomyopathy, including peripartum and stress-induced cardiomyopathy, as well as rare variants, such as arrhythmogenic right ventricular dysplasia and left ventricular noncompaction. In addition to history and physical examination, diagnosis of cardiomyopathy includes electrocardiography and echocardiography testing. Treatment may include appropriately staged therapy for heart failure, appropriate activity restriction, evaluation for implantable cardioverter-defibrillator placement, and consideration of heart transplantation in refractory cases. Genetic testing of families is an emerging modality with some potential to augment traditional screening performed by family physicians. PMID- 29431385 TI - Glucose Management in Hospitalized Patients. AB - Glucose management in hospitalized patients poses challenges to physicians, including identifying blood glucose targets, judicious use of oral diabetes mellitus medications, and implementing appropriate insulin regimens. Uncontrolled blood glucose levels can lead to deleterious effects on wound healing, increased risk of infection, and delays in surgical procedures or discharge from the hospital. Previously recommended strict blood glucose targets for hospitalized patients result in more cases of hypoglycemia without improvement in patient outcomes. The current target is 140 to 180 mg per dL. Use of oral diabetes medications, particularly metformin, in hospitalized patients is controversial. Multiple guidelines recommend stopping these medications at admission because of inpatient factors that can increase the risk of renal or hepatic failure. However, oral diabetes medications have important nonglycemic benefits and reduce the risk of widely fluctuating blood glucose levels. There is no proven risk of lactic acidosis from metformin in patients with normal kidney function, and it can be used safely in many hospitalized patients with diabetes. Insulin dosing depends on the patient's previous experience with insulin, baseline diabetes control, and renal function. Other considerations include the patient's current oral intake, comorbidities, and other medications. Many patients can be managed using only a basal insulin dose, whereas others benefit from additional short acting premeal doses. Historically, sliding scale insulin regimens have been used, but they have no proven benefit, increase the risk of hypoglycemia and large fluctuations in blood glucose levels, and are not recommended. Discharge planning is an important opportunity to address diabetes control, medication adherence, and outpatient follow-up. PMID- 29431386 TI - Gout: Diagnosis and Management. PMID- 29431387 TI - Herpes Zoster and Postherpetic Neuralgia: Prevention and Management. AB - Herpes zoster, or shingles, is caused by reactivation of varicella zoster virus, which causes chickenpox. There are an estimated 1 million cases in the Unites States annually, with an individual lifetime risk of 30%. Patients with conditions that decrease cell-mediated immunity are 20 to 100 times more likely to develop herpes zoster. Patients may present with malaise, headache, low-grade fever, and abnormal skin sensations for two to three days before the classic maculopapular rash appears. The rash is usually unilateral, confined to a single dermatome, and typically progresses to clear vesicles that become cloudy and crust over in seven to 10 days. Herpes zoster can be treated with acyclovir, valacyclovir, or famciclovir, ideally within 72 hours of the development of the rash. Postherpetic neuralgia is the most common complication, occurring in about one in five patients. It is defined as pain in a dermatomal distribution sustained for at least 90 days after acute herpes zoster. Treatment is focused on symptom control and includes topical lidocaine or capsaicin and oral gabapentin, pregabalin, or tricyclic antidepressants. The varicella zoster virus vaccine decreases the incidence of herpes zoster and is approved for adults 50 years and older. The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommends this vaccine for adults 60 years and older, except for certain immunosuppressed patients. PMID- 29431390 TI - Spondyloarthritis: NICE Releases Guidelines on Diagnosis and Treatment. PMID- 29431388 TI - Home Sleep Testing for Diagnosing Obstructive Sleep Apnea. PMID- 29431391 TI - Use of Mindfulness or Self-Hypnosis Provides Immediate Pain Relief to Hospitalized Patients. PMID- 29431393 TI - Treating Sleep Apnea with Positive Airway Pressure Does Not Reduce Adverse CV Outcomes or Mortality. PMID- 29431392 TI - Reslizumab (Cinqair) for Eosinophilic Asthma. PMID- 29431394 TI - Screening for Latent Tuberculosis Infection in Adults. PMID- 29431395 TI - YEARS Clinical Decision Tool Decreases CTA in Patients with Suspected Pulmonary Embolism. PMID- 29431397 TI - Antipsychotic Use in Patients with Dementia with Lewy Bodies. PMID- 29431396 TI - Lidocaine Patches Are No Better Than Placebo for Somatic Back Pain. PMID- 29431398 TI - Cardiomyopathy. PMID- 29431399 TI - USPSTF Recommendations: New and Updated in 2016. PMID- 29431400 TI - Acute Gout: ACP Provides Guideline on Diagnosis. PMID- 29431401 TI - Screening Tools for Unhealthy Alcohol Use. PMID- 29431402 TI - Topical Capsaicin for Treatment of Chronic Neuropathic Pain in Adults. PMID- 29431403 TI - Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. AB - Mild, asymptomatic elevations (less than five times the upper limit of normal) of alanine transaminase and aspartate transaminase levels are common in primary care. It is estimated that approximately 10% of the U.S. population has elevated transaminase levels. An approach based on the prevalence of diseases that cause asymptomatic transaminase elevations can help clinicians efficiently identify common and serious liver disease. The most common causes of elevated transaminase levels are nonalcoholic fatty liver disease and alcoholic liver disease. Uncommon causes include drug-induced liver injury, hepatitis B and C, and hereditary hemochromatosis. Rare causes include alpha1-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease. Extrahepatic sources, such as thyroid disorders, celiac sprue, hemolysis, and muscle disorders, are also associated with mildly elevated transaminase levels. The initial evaluation should include an assessment for metabolic syndrome and insulin resistance (i.e., waist circumference, blood pressure, fasting lipid level, and fasting glucose or A1C level); a complete blood count with platelets; measurement of serum albumin, iron, total iron binding capacity, and ferritin; and hepatitis C antibody and hepatitis B surface antigen testing. The nonalcoholic fatty liver disease fibrosis score and the alcoholic liver disease/nonalcoholic fatty liver disease index can be helpful in the evaluation of mildly elevated transaminase levels. If testing for common causes is consistent with nonalcoholic fatty liver disease and is otherwise unremarkable, a trial of lifestyle modification is appropriate. If the elevation persists, hepatic ultrasonography and further testing for uncommon causes should be considered. PMID- 29431404 TI - Hoarseness in Adults. AB - Hoarseness is a common presentation in primary care practices. Combined with other voice-related changes, it falls under the umbrella diagnosis of dysphonia. Hoarseness has a number of causes, ranging from simple inflammatory processes to less common psychiatric disorders to more serious systemic, neurologic, or cancerous conditions. Medication-induced hoarseness is common and should be considered. The initial evaluation begins with a targeted history and physical examination, while also looking for signs of potential systemic etiologies. Treatment should begin with voice rest, especially avoidance of whispering, and conservative management directed toward a presumptive cause. For example, proton pump inhibitors are appropriate for hoarseness due to reflux, and proper vocal hygiene is recommended for vocal abuse-related indications. In the absence of a clear indication, antibiotics, oral corticosteroids, and proton pump inhibitors should not be used for the empiric treatment of hoarseness. Direct visualization of the larynx and vocal folds, commonly mislabeled as vocal cords, should be performed within three months if an etiology has not been determined or if conservative management has been ineffective. Patients who experience symptoms lasting longer than two weeks and who have risk factors for dysplasia (e.g., tobacco use, heavy alcohol use, hemoptysis) may require earlier laryngoscopic evaluation. Voice therapy is effective for improving voice quality in patients with dysphonia if conservative measures are unsuccessful, and it can also be helpful for prophylaxis in high-risk individuals (e.g., vocalists, public speakers). Surgical management is indicated for laryngeal or vocal fold dysplasia or malignancy, airway obstruction, or benign pathology resistant to conservative treatment. PMID- 29431406 TI - Hypertrophic Cardiomyopathy: an Often Silent and Delayed Diagnosis. PMID- 29431405 TI - Hyperosmolar Hyperglycemic State. AB - Hyperosmolar hyperglycemic state is a life-threatening emergency manifested by marked elevation of blood glucose and hyperosmolarity with little or no ketosis. Although there are multiple precipitating causes, underlying infections are the most common. Other causes include certain medications, nonadherence to therapy, undiagnosed diabetes mellitus, substance abuse, and coexisting disease. In children and adolescents, hyperosmolar hyperglycemic state is often present when type 2 diabetes is diagnosed. Physical findings include profound dehydration and neurologic symptoms ranging from lethargy to coma. Treatment begins with intensive monitoring of the patient and laboratory values, especially glucose, sodium, and potassium levels. Vigorous correction of dehydration is critical, requiring an average of 9 L of 0.9% saline over 48 hours in adults. After urine output is established, potassium replacement should begin. Once dehydration is partially corrected, adults should receive an initial bolus of 0.1 units of intravenous insulin per kg of body weight, followed by a continuous infusion of 0.1 units per kg per hour (or a continuous infusion of 0.14 units per kg per hour without an initial bolus) until the blood glucose level decreases below 300 mg per dL. In children and adolescents, dehydration should be corrected at a rate of no more than 3 mOsm per hour to avoid cerebral edema. Identification and treatment of underlying and precipitating causes are necessary. PMID- 29431407 TI - Local Anesthesia for IUD Insertion or Endometrial Biopsy. PMID- 29431408 TI - Transdermal Estrogen and Progestogen Most Effective to Reduce Menopausal Vasomotor Symptoms. PMID- 29431410 TI - Oral Rehydration Solutions for the Treatment of Acute Watery Diarrhea. PMID- 29431411 TI - Concurrent Painless Weeping Nodule and Targetoid Lesion on the Hand. PMID- 29431413 TI - Elevated Liver Enzymes. PMID- 29431412 TI - Potential Benefits of L-Carnitine as Dietary Supplement. PMID- 29431415 TI - Stents for Stable Coronary Artery Disease. PMID- 29431416 TI - Pityriasis Rosea. PMID- 29431418 TI - Screening for Preeclampsia: Recommendation Statement. PMID- 29431419 TI - Refractive Index Tuning of Hybrid Materials for Highly Transmissive Luminescent Lanthanide Particle-Polymer Composites. AB - High-refractive-index ZrO2 nanoparticles were used to tailor the refractive index of a polymer matrix to match that of luminescent lanthanide-ion-doped (La0.92Yb0.075Er0.005F3) light-emitting particles, thereby reducing scattering losses to yield highly transparent emissive composites. Photopolymerization of blends of an amine-modified poly(ether acrylate) oligomer and tailored quantities of ZrO2 nanoparticles yielded optically transparent composites with tailored refractive indices between 1.49 and 1.69. By matching the refractive index of the matrix to that of La0.92Yb0.075Er0.005F3, composites with high transmittance (>85%) and low haze from the visible to infrared regions, bright 1530 nm optical emissions were achieved at solids loadings of La0.92Yb0.075Er0.005F3, ranging from 5 to 30 vol %. These optical results suggest that a hybrid matrix approach is a versatile strategy for the fabrication of functional luminescent optical composites of high transparency. PMID- 29431420 TI - MoS2 Nanoprobe for MicroRNA Quantification Based on Duplex-Specific Nuclease Signal Amplification. AB - MicroRNAs (miRNAs) play significant regulatory roles in physiologic and pathologic processes and are considered as important biomarkers for disease diagnostics and therapeutics. Simple, fast, sensitive, and selective detection of miRNAs, however, is challenged by their short length, low abundance, susceptibility to degradation, and homogenous sequence. Here, we report a novel design of nanoprobes for highly sensitive and selective detection of miRNAs based on MoS2-loaded molecular beacons (MBs) and duplex-specific nuclease (DSN) mediated signal amplification (DSNMSA). We show that MoS2 nanosheets not only exhibit high affinity toward MBs but also act as an efficient quencher for absorbed MBs. The strong fluorescence-quenching ability of MoS2 in combination with cyclic DSNMSA contributes to the superior sensitivity of our method, with a limit of detection 4 orders of magnitude lower than that of traditional hybridization methods. Moreover, the nanoprobes also show high selectivity for discriminating homogenous miRNA sequences with one-base differences because of the discrimination ability of MBs and DSN. Furthermore, we demonstrate that the MoS2-loaded MB nanoprobes can be utilized for multiplexed detection of miRNAs. Given its high sensitivity and specificity, as well as the multiplexed function; this novel method as an effective tool shows a great promise for simultaneous quantitative analysis of multiple miRNAs in biomedical research and clinical diagnosis. PMID- 29431421 TI - Synthetic Immunobiotics: A Future Success Story in Small Molecule-Based Immunotherapy? AB - Drug resistance to our current stock of antibiotics is projected to increase to levels that threaten our ability to reduce and eliminate bacterial infections, which is now considered one of the primary health care crises of the 21st century. Traditional antibiotic agents (e.g., penicillin) paved the way for massive advances in human health, but we need novel strategies to maintain the upper hand in the battle against pathogenic bacteria. Nontraditional strategies, such as targeted immunotherapies, could prove fruitful in complementing our antibiotic arsenal. PMID- 29431422 TI - Ruthenium-Tungsten Composite Catalyst for the Efficient and Contamination Resistant Electrochemical Evolution of Hydrogen. AB - A new catalyst, prepared by a simple physical mixing of ruthenium (Ru) and tungsten (W) powders, has been discovered to interact synergistically to enhance the electrochemical hydrogen evolution reaction (HER). In an aqueous 0.5 M H2SO4 electrolyte, this catalyst, which contained a miniscule loading of 2-5 nm sized Ru nanoparticles (5.6 MUg Ru per cm2 of geometric surface area of the working electrode), required an overpotential of only 85 mV to drive 10 mA/cm2 of H2 evolution. Interestingly, our catalyst also exhibited good immunity against deactivation during HER from ionic contaminants, such as Cu2+ (over 24 h). We unravel the mechanism of synergy between W and Ru for catalyzing H2 evolution using Cu underpotential deposition, photoelectron spectroscopy, and density functional theory (DFT) calculations. We found a decrease in the d-band and an increase in the electron work function of Ru in the mixed composite, which made it bind to H more weakly (more Pt-like). The H-adsorption energy on Ru deposited on W was found, by DFT, to be very close to that of Pt(111), explaining the improved HER activity. PMID- 29431423 TI - Osmosis-Driven Motion-Type Modulation of Biological Nanopores for Parallel Optical Nucleic Acid Sensing. AB - Recent developments in nanopore sequencing have inspired new concepts in precision medicine but limited in throughput. By optically encoding calcium flux from an array of nanopores, parallel measurements from hundreds of nanopores were reported, while lateral drifts of biological nanopores set obstacles for signal processing. In this paper, optical single-channel recording (oSCR) serves to track nanopores with high precision and a general principle of nanopore motion kinetics is quantitatively investigated. By finely adjusting the osmosis-oriented interactions between the lipid/substrate interfaces, motions of nanopores could be controllably restricted. Improved signal-to-noise ratio is observed from motion-restricted nanopores, which is experimentally demonstrated. To systematically evaluate oSCR with asymmetric salt concentrations, a finite element method simulation is established. oSCR with an array of immobilized nanopores suggests new strategies for sequencing DNA by microscopic imaging in high throughput and is widely applicable to the investigation of other transmembrane proteins. PMID- 29431424 TI - Gadolinium-Free Contrast Agents for Magnetic Resonance Imaging of the Central Nervous System. AB - We discuss how the recent revelation that gadolinium (Gd) from commercially available MRI contrast agents is irreversibly and cumulatively deposited in the central nervous system is driving innovation toward Gd-free contrast agents for neuroradiology. PMID- 29431426 TI - Strand Displacement Amplification Reaction on Quantum Dot-Encoded Silica Bead for Visual Detection of Multiplex MicroRNAs. AB - The combination of microbead array, isothermal amplification, and molecular signaling enables the continuous development of next-generation molecular diagnostic techniques. Herein we reported the implementation of nicking endonuclease-assisted strand displacement amplification reaction on quantum dots encoded microbead (Qbead), and demonstrated its feasibility for multiplexed miRNA assay in real sample. The Qbead featured with well-defined core-shell superstructure with dual-colored quantum dots loaded in silica core and shell, respectively, exhibiting remarkably high optical encoding stability. Specially designed stem-loop-structured probes were immobilized onto the Qbead for specific target recognition and amplification. In the presence of low abundance of miRNA target, the target triggered exponential amplification, producing a large quantity of stem-G-quadruplexes, which could be selectively signaled by a fluorescent G-quadruplex intercalator. In one-step operation, the Qbead-based isothermal amplification and signaling generated emissive "core-shell-satellite" superstructure, changing the Qbead emission-color. The target abundance-dependent emission-color changes of the Qbead allowed direct, visual detection of specific miRNA target. This visualization method achieved limit of detection at the subfemtomolar level with a linear dynamic range of 4.5 logs, and point-mutation discrimination capability for precise miRNA analyses. The array of three encoded Qbeads could simultaneously quantify three miRNA biomarkers in ~500 human hepatoma carcinoma cells. With the advancements in ease of operation, multiplexing, and visualization capabilities, the isothermal amplification-on Qbead assay could potentially enable the development of point-of-care diagnostics. PMID- 29431425 TI - Droplet Array-Based 3D Coculture System for High-Throughput Tumor Angiogenesis Assay. AB - Angiogenesis is critical for tumor progression and metastasis, and it progresses through orchestral multicellular interactions. Thus, there is urgent demand for high-throughput tumor angiogenesis assays for concurrent examination of multiple factors. For investigating tumor angiogenesis, we developed a microfluidic droplet array-based cell-coculture system comprising a two-layer polydimethylsiloxane chip featuring 6 * 9 paired-well arrays and an automated droplet-manipulation device. In each droplet-pair unit, tumor cells were cultured in 3D in one droplet by mixing cell suspensions with Matrigel, and in the other droplet, human umbilical vein endothelial cells (HUVECs) were cultured in 2D. Droplets were fused by a newly developed fusion method, and tumor angiogenesis was assayed by coculturing tumor cells and HUVECs in the fused droplet units. The 3D-cultured tumor cells formed aggregates harboring a hypoxic center-as observed in vivo-and secreted more vascular endothelial growth factor (VEGF) and more strongly induced HUVEC tubule formation than did 2D-cultured tumor cells. Our single array supported 54 assays in parallel. The angiogenic potentials of distinct tumor cells and their differential responses to antiangiogenesis agent, Fingolimod, could be investigated without mutual interference in a single array. Our droplet-based assay is convenient to evaluate multicellular interaction in high throughput in the context of tumor sprouting angiogenesis, and we envision that the assay can be extensively implementable for studying other cell-cell interactions. PMID- 29431428 TI - Crystal Structure and Band-Gap Engineering of a Semiconducting Coordination Polymer Consisting of Copper(I) Bromide and a Bridging Acceptor Ligand. AB - A new semiconducting 3D coordination polymer, [Cu2Br2(ttz)] n (1), with an acceptor bridging ligand, 1,2,4,5-tetrazine (ttz), was synthesized. The complex shows large absorption bands extending to the near-IR region, indicating a small band gap in the coordination polymer. This complex shows higher conductivity than those of [CuBr(pyz)] n (2), including pyrazine (pyz) with a higher lowest unoccupied molecular orbital level. We performed density functional theory band calculations using the VASP program to understand the electronic states and conducting paths of the coordination polymer. PMID- 29431427 TI - Chromis-1, a Ratiometric Fluorescent Probe Optimized for Two-Photon Microscopy Reveals Dynamic Changes in Labile Zn(II) in Differentiating Oligodendrocytes. AB - Despite the significant advantages of two-photon excitation microscopy (TPEM) over traditional confocal fluorescence microscopy in live-cell imaging applications, including reduced phototoxicity and photobleaching, increased depth penetration, and minimized autofluorescence, only a few metal ion-selective fluorescent probes have been designed and optimized specifically for this technique. Building upon a donor-acceptor fluorophore architecture, we developed a membrane-permeant, Zn(II)-selective fluorescent probe, chromis-1, that exhibits a balanced two-photon cross section between its free and Zn(II)-bound form and responds with a large spectral shift suitable for emission-ratiometric imaging. With a Kd of 1.5 nM and wide dynamic range, the probe is well suited for visualizing temporal changes in buffered Zn(II) levels in live cells as demonstrated with mouse fibroblast cell cultures. Moreover, given the importance of zinc in the physiology and pathophysiology of the brain, we employed chromis-1 to monitor cytoplasmic concentrations of labile Zn(II) in oligodendrocytes, an important cellular constituent of the brain, at different stages of development in cell culture. These studies revealed a decrease in probe saturation upon differentiation to mature oligodendrocytes, implying significant changes to cellular zinc homeostasis during maturation with an overall reduction in cellular zinc availability. Optimized for TPEM, chromis-1 is especially well-suited for exploring the role of labile zinc pools in live cells under a broad range of physiological and pathological conditions. PMID- 29431429 TI - Ru Nanoparticles-Loaded Covalent Organic Framework for Solvent-Free One-Pot Tandem Reactions in Air. AB - Condensation of benzene-1,3,5-tricarbohydrazide with benzene-1,4-dicarboxaldehyde generated a new covalent organic framework, COF-ASB (1), in which the organic units are held together via hydrazone linkage to form porous frameworks. COF-ASB (1) is highly crystalline and displays good chemical and thermal stability and is permanently porous. In addition, 1 can be an ideal support to load Ru nanoparticles (Ru NPs) to generate Ru@COF-ASB (2). The obtained composite material is able to highly promote one-pot tandem synthesis of imine products from benzyl alcohols and corresponding amines under solvent-free conditions in air. PMID- 29431430 TI - Quantum Chemical Study of the Water Exchange Mechanism of the Neptunyl(VI) and (V) Aqua Ions. AB - The water exchange reaction of the neptunyl(VI) and -(V) aqua ions was investigated with quantum chemical methods. Associative ( a) and dissociative ( d) exchange mechanisms were studied. The geometries and vibrational frequencies were computed with density functional theory (DFT) and multiconfiguration self consistent field (MCSCF) methods. The Gibbs activation energies (Delta G?) for a and d pathways were calculated with DFT and wave function theory (WFT), extended general multiconfiguration quasi-degenerate second-order perturbation theory (XGMC-QDPT2) including spin-orbit (SO) coupling at the SO configuration interaction (CI) level. The DFT-WFT agreement for Delta G? was poor for the investigated functionals except for LC-BOP-LRD. Due to ligand-field effects, Delta G? for the associatively activated exchange reaction of NpO2(OH2)52+ with a fdelta1 electron configuration is higher than for the actinyl(VI) aqua ions of U, Pu, and Am exhibiting f0, fdelta2, and fdelta2fphi1 electron configurations. PMID- 29431431 TI - Mn Self-Doping of Orthorhombic RMnO3 Perovskites: (R0.667Mn0.333)MnO3 with R = Er Lu. AB - Orthorhombic rare-earth trivalent manganites RMnO3 (R = Er-Lu) were self-doped with Mn to form (R0.667Mn0.333)MnO3 compositions, which were synthesized by a high-pressure, high-temperature method at 6 GPa and about 1670 K from R2O3 and Mn2O3. The average oxidation state of Mn is 3+ in (R0.667Mn0.333)MnO3. However, Mn enters the A site in the oxidation state of 2+, creating the average oxidation state of 3.333+ at the B site. The presence of Mn2+ was confirmed by hard X-ray photoelectron spectroscopy measurements. Crystal structures were studied by synchrotron powder X-ray diffraction. (R0.667Mn0.333)MnO3 crystallizes in space group Pnma with a = 5.50348(2) A, b = 7.37564(1) A, and c = 5.18686(1) A for (Lu0.667Mn0.333)MnO3 at 293 K, and they are isostructural with the parent RMnO3 manganites. Compared with RMnO3, (R0.667Mn0.333)MnO3 exhibits enhanced Neel temperatures of about TN1 = 106-110 K and ferrimagnetic or canted antiferromagnetic properties. Compounds with R = Er and Tm show additional magnetic transitions at about TN2 = 9-16 K. (Tm0.667Mn0.333)MnO3 exhibits a magnetization reversal or negative magnetization effect with a compensation temperature of about 16 K. PMID- 29431432 TI - Fe-N-Graphene Wrapped Al2O3/Pentlandite from Microalgae: High Fenton Catalytic Efficiency from Enhanced Fe3+ Reduction. AB - Efficient cycling of Fe3+/Fe2+ is a key step for the Fenton reaction. In this exploration, from microalgae, we have prepared a novel Fe-N-graphene wrapped Al2O3/pentlandite composite which showed high Fenton catalytic ability through accelerating of Fe3+ reduction. The catalyst exhibits high activity, good reusability along with stability, and wide adaptation for the organics degradation under neutral pH. High TON and H2O2 utilization efficiency have also reached by this catalyst. Characterization results disclose a unique structure that the layered Fe-N-graphene structure tightly covers on Al2O3/pentlandite particles. Mechanistic evidence suggests that the accelerated Fe3+/Fe2+ redox cycle originates from the enhanced electron transfer by the synergistic effect of Fe, Ni and Al in the catalyst, and it causes the low H2O2 consumption and high *OH generation rate. Moreover, organic radicals formed in the Fenton process also participate in the Fe3+ reduction, and this process may be accelerated by the N doped graphene through a quick electron transfer. These findings stimulate an approach with great potential to further extend the synthetic power and versatility of Fenton catalysis through N doped graphene in catalysts. PMID- 29431434 TI - Unexpected Magnetic Ordering on the Cr Substructure in UCr2Si2C and Structural Relationships in Quaternary U-Cr-Si-C Compounds. AB - Previous experimental and theoretical studies revealed that carbon insertion into the RCr2Si2 compounds drastically affects the magnetic behavior, since chromium does not carry any magnetic moment in RCr2Si2C (R = Y, La-Sm, Gd-Er) compounds in contrast to RCr2Si2 (R = Y, Sm, Gd-Lu, Th) compounds. In this study, we report on the unexpected magnetic ordering of chromium atoms in the isotype quaternary UCr2Si2C compound. While specific heat and magnetic measurements suggest a Pauli paramagnetic behavior, neutron powder diffraction reveals an antiferromagnetic ordering of the chromium substructure at high temperature ( TN > 300 K), while that of uranium remains nonmagnetically ordered down to 2 K. Its magnetic behavior, inverse in comparison to the RCr2Si2C carbides involving a magnetic lanthanide, is discussed in relation with the singularity of its crystal structure among the series. Moreover, the crystallographic structures and the structural stability of UCr2Si2C and of two other quaternary U-Cr-Si-C compounds (i.e., UCr3Si2C and U2Cr3Si2C3), based on the full occupancy of interstitial sites by carbon atoms, are discussed and compared to those of the related ternary intermetallics. Finally, the low-temperature form of UCr2Si2, corresponding to a displacive transformation around 210 K of the ThCr2Si2-type structure, is reinvestigated by considering a higher symmetry monoclinic unit cell ( C2/ m) instead of the previously reported triclinic cell ( P1). The antiferromagnetic ordering at low temperature ( TN = 30(2) K) of the uranium substructure is confirmed, and its magnetic structure is reanalyzed and discussed considering the monoclinic crystal structure. PMID- 29431435 TI - A New Ratiometric Lysosomal Copper(II) Fluorescent Probe To Map a Dynamic Metallome in Live Cells. AB - We synthesized a new ratiometric fluorescent Cu2+ probe, bearing a morpholine moiety for selective binding to lysosomes and two picolylamine arms for the specific chelation of divalent copper ions. The probe capability to detect lysosomal Cu2+ was demonstrated in human differentiated neuroblastoma cells by confocal microscopy. PMID- 29431433 TI - Supramolecular Assemblies for Transporting Proteins Across an Immiscible Solvent Interface. AB - Polymeric supramolecular assemblies that can effectively transport proteins across an incompatible solvent interface are described. We show that electrostatics and ligand-protein interactions can be used to selectively transport proteins from an aqueous phase to organic phase. These transported proteins have been shown to maintain their tertiary structure and function. This approach opens up new possibilities for application of supramolecular assemblies in sensing, diagnostics and catalysis. PMID- 29431436 TI - Relevance of Orbital Interactions and Pauli Repulsion in the Metal-Metal Bond of Coinage Metals. AB - The importance of relativity and dispersion in metallophilicity has been discussed in numerous studies. The existence of hybridization in the bonding between closed shell d10-d10 metal atoms has also been speculated, but the presence of attractive MO interaction in the metal-metal bond is still a matter of an ongoing debate. In this comparative study, a quantitative molecular orbital analysis and energy decomposition is carried out on the metallophilic interaction in atomic dimers (M+...M+) and molecular perpendicular [H3P-M-X]2 (where M = Cu, Ag, and Au; X = F, Cl, Br, and I). Our computational studies prove that besides the commonly accepted dispersive interactions, orbital interactions and Pauli repulsion also play a crucial role in the strength and length of the metal-metal bond. Although for M+...M+ the orbital interaction is larger than the Pauli repulsion, leading to a net attractive MO interaction, the bonding mechanism in perpendicular [H3P-M-X] dimers is different due to the larger separation between the donor and acceptor orbitals. Thus, Pauli repulsion is much larger, and two orbital, four-electron repulsion is dominant. PMID- 29431437 TI - Fast Oxidation of Porous Cu Induced by Nano-Twinning. AB - The fcc lattice of porous Cu prepared by dealloying Al2Cu with HCl aqueous solution exhibits a high density of twinning defects with an average domain size of about 3 nm along the ?111? directions. The high density of twinning was verified by X-ray diffraction and qualitatively interpreted by a structural model showing the 5% probability of twinning defect formation. Most of the twinning defects disappeared after annealing at 873 K for 24 h. Twinned Cu reveals much faster oxidation rate in comparison to that without (or with much fewer) twinning defects, as shown by X-ray diffraction and hydrogen differential scanning calorimetry. Using ab initio DFT calculations, we demonstrate that twinning defects in porous Cu are able to form nucleation centers for the growth of Cu2O. The geometry of the V-shaped edges on the twinned {211} surfaces is favorable for formation of the basic structural elements of Cu2O. The fast oxidation of porous Cu prepared by dealloying can thus be explained by the fast formation of the Cu2O nucleation centers and their high density. PMID- 29431439 TI - Marine Invertebrate Natural Products that Target Microtubules. AB - Marine natural products as secondary metabolites are a potential major source of new drugs for treating disease. In some cases, cytotoxic marine metabolites target the microtubules of the eukaryote cytoskeleton for reasons that will be discussed. This review covers the microtubule-targeting agents reported from sponges, corals, tunicates, and molluscs and the evidence that many of these secondary metabolites are produced by bacterial symbionts. The review finishes by discussing the directions for future development and production of clinically relevant amounts of these natural products and their analogues through aquaculture, chemical synthesis, and biosynthesis by bacterial symbionts. PMID- 29431440 TI - Synthesis of beta-Fluorovinyliodonium Salts by the Reaction of Alkynes with Hypervalent Iodine/HF Reagents. AB - The reaction of alkynes with PhIO and Py.HF followed by treatment with BF3.OEt2 gave beta-fluorovinyliodonium tetrafluoroborates in good to high yields. More conveniently, the reaction using PhI and Py.HF in the presence of m-CPBA also afforded beta-fluorovinyliodonium tetrafluoroborates in good yields. These methods have the advantages that beta-fluorovinyliodonium salts can be prepared without ArIF2. PMID- 29431438 TI - Applying Pose Clustering and MD Simulations To Eliminate False Positives in Molecular Docking. AB - In this work, we developed a computational protocol that employs multiple molecular docking experiments, followed by pose clustering, molecular dynamic simulations (10 ns), and energy rescoring to produce reliable 3D models of antibody-carbohydrate complexes. The protocol was applied to 10 antibody carbohydrate co-complexes and three unliganded (apo) antibodies. Pose clustering significantly reduced the number of potential poses. For each system, 15 or fewer clusters out of 100 initial poses were generated and chosen for further analysis. Molecular dynamics (MD) simulations allowed the docked poses to either converge or disperse, and rescoring increased the likelihood that the best-ranked pose was an acceptable pose. This approach is amenable to automation and can be a valuable aid in determining the structure of antibody-carbohydrate complexes provided there is no major side chain rearrangement or backbone conformational change in the H3 loop of the CDR regions. Further, the basic protocol of docking a small ligand to a known binding site, clustering the results, and performing MD with a suitable force field is applicable to any protein ligand system. PMID- 29431442 TI - Phase Cycling RT-TDDFT Simulation Protocol for Nonlinear XUV and X-ray Molecular Spectroscopy. AB - Real-time time-dependent density functional theory (RT-TDDFT) provides a practical algorithm for propagating a many-electron system driven by external laser fields. The fields are included nonperturbatively in the propagation, and the molecular reduced single-electron density operator and various spectroscopic and diffraction signals can be computed directly, avoiding the expensive calculation of many-body states. Nonlinear optical signals contain contributions of multiple pathways. A phase cycling protocol is implemented in order to separate these pathways. Simulations of XUV four-wave mixing signals in the CO molecule are compared with ab initio sum-over-states calculations. PMID- 29431441 TI - Synthesis of Delta20-Ginsenosides Rh4, (20E)-Rh3, Rg6, and Rk1: A General Approach To Access Dehydrated Ginsenosides. AB - Four representative Delta20-ginsenosides, namely, ginsenosides Rh4 (1), (20E)-Rh3 (2), Rg6 (3), and Rk1 (4) from Panax Ginseng, were chemically synthesized for the first time. Dehydration of the naturally occurring 20(S)-protopanaxatriol and 20(S)-protopanaxadiol provided all types of Delta20-sapogenins, which were separated due to a judicious choice of protecting groups. The Delta20-sapogenins were then directly glycosylated with glycosyl ortho-alkynylbenzoate donors under the catalysis of Ph3PAuNTf2 as key steps. The neutral conditions of the glycosylations were crucial to prevent the acid-labile Delta20,21 double bond from isomerization. PMID- 29431443 TI - Quantum Chemical and Statistical Rate Theory Studies of the Vinyl Hydroperoxides Formed in trans-2-Butene and 2,3-Dimethyl-2-butene Ozonolysis. AB - The vinyl hydroperoxide (VHP), the major isomerization product of the syn-alkyl Criegee intermediate (CI) formed in alkene ozonolysis, is a direct precursor of hydroxyl radical (OH), the most important oxidant in the troposphere. While simulations of CI reactivity have usually assumed the VHP to be a prompt and quantitative source of OH, recent quantum chemical studies have revealed subtleties in VHP reactivity such as a barrier to peroxy bond homolysis and a possible rearrangement to a hydroxycarbonyl. In this work, we use M06-L, Weizmann 1 Brueckner Doubles, and equation-of-motion spin-flip coupled-cluster theories to calculate a comprehensive reaction mechanism for the syn and anti conformers of the parent VHP formed in trans-2-butene ozonolysis and the 1-methyl VHP formed in 2,3-dimethyl-2-butene ozonolysis. We predict that for the parent VHP the anti homolysis transition structure (TS) is 3 kcal mol-1 lower in energy than the syn TS, but for the 1-methyl system, the syn TS is 2 kcal mol-1 lower in energy. Statistical rate theory simulations based on the quantum chemical data predict that the parent VHP preferentially decomposes to vinoxy and OH radicals under all tropospheric conditions, while the 1-methyl VHP preferentially decomposes to 1 methylvinoxy and OH radicals only close to 298 K; at 200 K, the 1-methyl VHP preferentially rearranges to hydroxyacetone. Lower temperatures and higher pressures favor the temporary accumulation of both the parent and the 1-methyl VHP. PMID- 29431444 TI - A Catalytic Enantioselective Iodocyclization Route to Dihydrooxazines. AB - The first catalytic enantioselective synthesis of 5,6-dihydro-4H-1,2-oxazines bearing an oxygen-containing quaternary stereogenic center has been developed through iodoetherification of gamma,delta-unsaturated oximes. This operationally straightforward reaction is catalyzed by Cinchona alkaloids-based bifunctional tertiary aminothiourea derivatives and furnishes the products generally in good to excellent yields and with moderate to high enantioselectivities (up to 97:3 er). PMID- 29431445 TI - Hydrolysis of Phosphonothioates with a Binaphthyl Group: P-Stereogenic O Binaphthyl Phosphonothioic Acids and Their Use as Optically Active Ligands and Chiral Discriminating Agents. AB - The hydrolysis of phosphonothioates with a binaphthyl group afforded the first example of O-(2'-hydroxy)binaphthyl phosphonothioic acids in good to high yields and >95:5 diastereoselectivity. The reaction proceeds via an axis-to-center chirality-transfer reaction. The ability of these acids to act as chiral molecular auxiliaries was demonstrated by using them as optically active ligands for the asymmetric ethylation of benzaldehyde and as a chiral discriminating agent for chiral aliphatic amines. PMID- 29431446 TI - Davis-Beirut Reaction: Alkoxide versus Hydroxide Addition to the Key o Nitrosoimine Intermediate. AB - Reaction options, alkoxide vs hydroxide vs amine addition to the key intermediate (o-nitrosoimine) generated in the Davis-Beirut reaction of an o-nitrobenzylamine substrate, are reported to explain the nucleophilic addition selectivity of this one-pot indazole-forming process. The hydroxide addition/deprotection pathway as well as the fate of the resulting o-nitrosobenzaldehyde were both uncovered with several o-nitrobenzylamine substrates, and design elements required for an efficient double Davis-Beirut reaction, inspired by new mechanistic insights, were defined. PMID- 29431447 TI - Synthesis of (+)-Disparlure via Enantioselective Iodolactonization. AB - The BINOL-amidine organic catalyst 1 was previously shown to promote highly efficient enantioselective halolactonization reactions of olefinic acids. As part of these studies, it was discovered that the enantioenriched iodolactones could be easily converted into enantioenriched cis-1,2-disubstituted epoxides. This halolactonization-epoxidation sequence was applied to the synthesis of (+) disparlure, which resulted in the shortest catalytic enantioselective synthesis to date, requiring only five steps and proceeding in 33% yield. PMID- 29431448 TI - Hupercumines A and B, Lycopodium Alkaloids from Huperzia cunninghamioides, Inhibiting Acetylcholinesterase. AB - A novel class of C38N4 Lycopodium alkaloid, hupercumine A (1), consisting of two octahydroquinolines, a decahydroquinoline, and a piperidine, and a new C27N3-type alkaloid, hupercumine B (2), were isolated from Huperzia cunninghamioides (Hayata) Holub. The structures and absolute configurations of 1 and 2 were elucidated on the basis of spectroscopic data, chemical means, and biogenetic point of view. Hupercumines A (1) and B (2) showed moderate inhibitory activity against acetylcholinesterase. PMID- 29431450 TI - Advanced NMR-Based Structural Investigation of Glucosinolates and Desulfoglucosinolates. AB - Glucosinolates (GLs) constitute a class of plant secondary metabolites that are characteristic of the order Brassicales. They each contain a common hydrophilic moiety connected to a mostly hydrophobic side chain whose constitution is the most frequent structural variant. Their transformations by myrosinases lead to intensively studied and highly reactive compounds of biological relevancy. In other respects, the enzymatic desulfation of GLs produces derivatives (DS-GLs) that are useful for GL analysis. A collection of 31 compounds, GLs and DS-GLs, representing 17 different side chains was established in order to report accurate descriptions of the molecules' 1H-, 13C-, and 15N-NMR parameters. The descriptions of the 1H-NMR spectra were achieved using the PERCH software, which accurately analyzed the complex coupling patterns that arose from strongly coupled nuclei. The chemical shift assignments were supported by 2D COSY, HSQC, and HMBC spectra. The impact of desulfation and the influence of the nature of the side chains on the chemical shift values are discussed. The results of the spectroscopic analysis and the 3D chemical-structure models of the studied molecules were grouped in structure-and-data-format (SDF) files. The NMR parameters were also collected in a simple text file, a spreadsheet file, and a relational database. PMID- 29431451 TI - Cationic Surfactant-Induced Formation of Uniform Gold Nanoparticle Clusters with High Efficiency of Photothermal Conversion under Near-Infrared Irradiation. AB - A novel and simple method for the fabrication of gold nanoparticle (AuNP) clusters was introduced for use as an efficient near-infrared (NIR) photothermal agent. Cationic surfactants were employed to assemble AuNPs into clusters, during which polyvinylpyrrolidone (PVP) was used to stabilize the AuNP clusters. Through this manner, AuNP clusters with a uniform shape and a narrow size distribution (55.4 +/- 5.0 nm by electron microscope) were successfully obtained. A mechanism for the formation of AuNP clusters was studied and proposed. Electrostatic interactions between AuNPs and cationic surfactants, hydrophobic interactions between hydrocarbon chains of cationic surfactants, and repulsive steric interactions of PVP were found to play an important role with regard to the formation mechanism. Photothermal effect in the NIR range of the AuNP clusters was demonstrated; results presented a highly efficient photothermal conversion (with a maximum eta of 65%) of the AuNP clusters. The clusters could be easily coated by a silica layer, enabling their biocompatibility and colloidal stability in physiological fluids. The easy-to-fabricate AuNP clusters showed high potential of use as an NIR photothermal agent for cancer therapy. PMID- 29431449 TI - Ni-Catalyzed Electrochemical Decarboxylative C-C Couplings in Batch and Continuous Flow. AB - An electrochemically driven, nickel-catalyzed reductive coupling of N hydroxyphthalimide esters with aryl halides is reported. The reaction proceeds under mild conditions in a divided electrochemical cell and employs a tertiary amine as the reductant. This decarboxylative C(sp3)-C(sp2) bond-forming transformation exhibits excellent substrate generality and functional group compatibility. An operationally simple continuous-flow version of this transformation using a commercial electrochemical flow reactor represents a robust and scalable synthesis of value added coupling process. PMID- 29431452 TI - Smoking by young women with restrained eating following a food prime in the context of an alternative distractor. AB - Female smokers with elevated dietary restraint (high restrainers) may smoke more than nonrestrained eaters after a disinhibiting food event. The current study aimed to determine whether high restrainers smoke merely to distract themselves from unplanned eating or whether the weight-control aspects of smoking play a role. Primary aims were to test the effect of restraint status and a food prime on smoking and eating behavior in the presence of an alternative distractor (a computer tablet) and to examine the role of expectancies. Utilizing a between subject design, female smokers (N = 128) were randomized to receive a milkshake prime (Prime condition) or not (No-Prime). They then received access to tempting foods, cigarettes, and the computer tablet. As expected, higher dietary restraint predicted shorter latency to smoke and craving to smoke but not latency to use the tablet. Additionally, a pattern of proximal expectancy subscales associated with weight/appetite control predicted cigarette consumption. Neither restraint nor expectancies interacted with condition to predict smoking behavior. Findings suggest that dietary restrainers attempt to prevent food consumption by turning to cigarettes, beyond preference for other salient distracting stimuli. Thus, smoking appears to function as more than simply a distractor from eating, and it is also associated with strong beliefs about weight and appetite control. Results offer implications for assessment and intervention among individuals presenting for smoking cessation treatment, particularly young adult women. Specifically, assessment of dietary restraint and expectancies related to weight and appetite aspects of smoking may be important to consider for tailored interventions. (PsycINFO Database Record PMID- 29431453 TI - Relations between facets and personality domains with impulsivity: New evidence using the DSM-5 Section III framework in patients with substance use disorders. AB - Section III of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition proposes an alternative diagnostic model for personality disorders based on the identification of pathological personality facets. Despite the existing evidence for the relationship between personality disorders and impulsivity in patients with substance use disorders, no study has yet been conducted within this framework. Thus, using a sample of 110 patients with substance use disorders, the present work aims to (a) analyze the relationship between the different personality facets and domains evaluated by the Personality Inventory for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PID 5) and impulsivity and (b) explore the relationships between severity of dependency and personality facets and dimensions of impulsivity. With respect to PID-5 domains, except for sensation-seeking, antagonism and disinhibition showed correlations higher than .30 with the following dimensions: urgency, premeditation, perseverance, sensation-seeking, and positive urgency (UPPS-P). The domains of detachment and psychoticism showed weaker correlations with different UPPS-P dimensions. The risk-taking PID-5 facet explains 49% variability of the sensation-seeking dimension of UPPS-P, whereas the impulsivity facet was significant on regression models computed with lack of premeditation, positive urgency, and negative urgency dimensions. Heroin and cocaine severity of dependence were moderately related to different personality facets. Lower relationships between alcohol and cannabis severity of dependence, impulsivity, and PID-5 facets were found. As a conclusion, the relationships between personality domains and impulsivity behave similarly to their five-factor equivalents for some dimensions but not for negative urgency, which might indicate the lack of specificity of this dimension of impulsivity on this type of patients. (PsycINFO Database Record PMID- 29431454 TI - A test of the psychometric characteristics of the BIS-Brief among three groups of youth. AB - The Barratt Impulsiveness Scale (BIS-11) is the most widely administered trait impulsiveness questionnaire. Recently a shorter, unidimensional version of the instrument was developed for adults (BIS-Brief). While psychometric characteristics of the BIS-Brief support its use among adults, it also may be more appropriate for youth samples than the complete BIS-11 because it less burdensome and omits items about activities not usually encountered by children and adolescents. This article describes a test of psychometric characteristics of the BIS-Brief among youth. To measure a sufficiently wide range of scores, analyses were conducted based on secondary data analysis of data sets pooled from 3 distinct youth cohorts aged 10-17: healthy controls (Control; n = 356); those who had a family history of substance use disorder (FH+; n = 302); and psychiatric inpatients (Patients; n = 322). Model fit for the BIS-Brief was good but varied somewhat depending on the respondent cohort. There was a strong correlation between test and re-test BIS-Brief both within a single day and at 6 months, and also a strong correlation between BIS-Brief and BIS-11 scores. Concurrent validity was supported by correlation with questionnaire measures, which tended to be more robustly associated with BIS-Brief than behavioral measures. Both BIS-Brief and BIS-11 forms were similarly associated with other convergent measures. In conclusion, the BIS-Brief is a shorter version of the BIS 11 that reduces participant burden and with psychometric properties that support its use among youth populations. (PsycINFO Database Record PMID- 29431455 TI - The efficacy of 90-minute versus 60-minute sessions of prolonged exposure for posttraumatic stress disorder: Design of a randomized controlled trial in active duty military personnel. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) can have devastating effects on multiple aspects of functioning. Thus, it is imperative to increase access to evidence-based treatment for PTSD. Prolonged Exposure therapy (PE) has extensive empirical support and is one of the first-line PTSD treatments included in civilian, veteran, and military clinical practice guidelines. However, the standard 90-min PE session format can constitute a significant barrier to its adoption in routine clinical care settings, which typically schedule 60-min appointment sessions. If the length of PE sessions could be reduced from 90 to 60 min without compromising treatment efficacy and efficiency, this would remove a major barrier to PE adoption. METHOD: This paper describes the rationale and methods of a randomized controlled noninferiority trial comparing 90-min versus 60-min PE sessions (including 40- vs. 20-min imaginal exposures, respectively) among 160 active duty military personnel with PTSD. The aims of this study are to: (1) examine the efficacy and efficiency (i.e., rate of symptom improvement) of 90- versus 60-min PE; (2) assess change in psychophysiological markers of treatment response across conditions; and (3) test mechanisms of change underlying the efficacy of PE. RESULTS/CONCLUSIONS: The results of this study will inform dissemination efforts in military, veteran, and civilian sectors. Further, identifying mechanisms of therapeutic change will answer important theoretical questions about how PE works, in order to refine and increase the efficacy and efficiency of PE to better meet the needs of individuals with PTSD. (PsycINFO Database Record PMID- 29431456 TI - Forensic psychology and correctional psychology: Distinct but related subfields of psychological science and practice. AB - This article delineates 2 separate but related subfields of psychological science and practice applicable across all major areas of the field (e.g., clinical, counseling, developmental, social, cognitive, community). Forensic and correctional psychology are related by their historical roots, involvement in the justice system, and the shared population of people they study and serve. The practical and ethical contexts of these subfields is distinct from other areas of psychology-and from one another-with important implications for ecologically valid research and ethically sound practice. Forensic psychology is a subfield of psychology in which basic and applied psychological science or scientifically oriented professional practice is applied to the law to help resolve legal, contractual, or administrative matters. Correctional psychology is a subfield of psychology in which basic and applied psychological science or scientifically oriented professional practice is applied to the justice system to inform the classification, treatment, and management of offenders to reduce risk and improve public safety. There has been and continues to be great interest in both subfields-especially the potential for forensic and correctional psychological science to help resolve practical issues and questions in legal and justice settings. This article traces the shared and separate developmental histories of these subfields, outlines their important distinctions and implications, and provides a common understanding and shared language for psychologists interested in applying their knowledge in forensic or correctional contexts. (PsycINFO Database Record PMID- 29431457 TI - Is memory better for objects than for separate single features? The temporal hypothesis. AB - Working memory, the system allowing for a simultaneous maintenance and processing of information, is typically conceived as a capacity limited system. A proposed method to transcend its standard maintenance capacity is to maintain multifeature objects, instead of isolated features. Several studies have shown that multifeature memory items are stored as objects instead of separate single features in working memory, this object-based maintenance being thought to result in an increase in the number of features that can be maintained. We present a series of 4 experiments that challenge the belief that object-based maintenance per se is at the origin of the better memory for features in case of multifeature item presentation. Instead, we propose an account based on the temporal parameters of the memory item's presentation, which explains memory performance in terms of the time available for encoding/consolidation per feature. (PsycINFO Database Record PMID- 29431458 TI - Differential emotional processing in concrete and abstract words. AB - Emotion (positive and negative) words are typically recognized faster than neutral words. Recent research suggests that emotional valence, while often treated as a unitary semantic property, may be differentially represented in concrete and abstract words. Studies that have explicitly examined the interaction of emotion and concreteness, however, have demonstrated inconsistent patterns of results. Moreover, these findings may be limited as certain key lexical variables (e.g., familiarity, age of acquisition) were not taken into account. We investigated the emotion-concreteness interaction in a large-scale, highly controlled lexical decision experiment. A 3 (Emotion: negative, neutral, positive) * 2 (Concreteness: abstract, concrete) design was used, with 45 items per condition and 127 participants. We found a significant interaction between emotion and concreteness. Although positive and negative valenced words were recognized faster than neutral words, this emotion advantage was significantly larger in concrete than in abstract words. We explored potential contributions of participant alexithymia level and item imageability to this interactive pattern. We found that only word imageability significantly modulated the emotion concreteness interaction. While both concrete and abstract emotion words are advantageously processed relative to comparable neutral words, the mechanisms of this facilitation are paradoxically more dependent on imageability in abstract words. (PsycINFO Database Record PMID- 29431459 TI - Feeling distressed from making decisions: Assessors' need to be right. AB - Our research posits that decision-making is particularly distressing for individuals with high assessment tendencies. Assessment involves truth concerns about making the "right" decision. We hypothesize that people with high assessment experience greater distress during decision-making because of their concerns about making a wrong decision. In four studies of chronic assessment conducted across four different decision contexts, we found assessment to be positively associated with distress, with this relation being mediated by concerns with being wrong. A meta-analysis of these results provided support for the robustness of this positive association. Finally, a fifth experimental study that induced assessment found the same association with distress. Moreover, an implicit measure of truth concerns mediated this positive association. Given the prevalence of decision-making activities in everyday life, our findings about how truth concerns can cause distress have important implications for the psychological well-being of assessment-oriented individuals. (PsycINFO Database Record PMID- 29431460 TI - Attentional and evaluative biases help people maintain relationships by avoiding infidelity. AB - Two longitudinal studies of 233 newlywed couples suggest that automatic attentional and evaluative biases regarding attractive relationship alternatives can help people maintain relationships by avoiding infidelity. Both studies assessed participants' tendency to automatically disengage attention from photos of attractive, opposite sex individuals; one study assessed participants' tendency to devalue those individuals by comparing their attractiveness evaluations to evaluations made by single people, and both studies assessed infidelity and relationship status multiple times for approximately three years. Several sources of devaluation emerged, but only participants' history of short term sex predicted both biases; having more short-term sexual partners was associated with being slower to disengage attention from attractive alternatives, and, among men, evaluating such individuals more positively. In turn, both processes exerted indirect effects on relationship dissolution by predicting infidelity; being 100 ms faster to disengage attention from attractive alternatives or rating them 2 scale points lower in attractiveness was associated with a decrease in the odds of infidelity of approximately 50%; the effect of devaluation on infidelity was stronger among participants who evidenced steeper declines in marital satisfaction. These associations emerged because unfaithful individuals took longer to disengage attention from attractive alternatives compared with other social targets and did not differ from singles in their evaluations of those alternatives. Among several other predictors of infidelity, partner attractiveness was associated with a decrease in the odds of infidelity among men but not women. These findings suggest a role for basic psychological processes in predicting infidelity, highlight the critical role of automatic processes in relationship functioning, and suggest novel ways to promote relationship success. (PsycINFO Database Record PMID- 29431461 TI - Effects of audio headings on learning. AB - Text-to-speech (TTS) programs often do a poor job of translating writing devices such as headings from visual into audio mode. Previous research studies have attempted to address this problem but these studies have mainly used heading detection tasks. The current study seeks to investigate (a) whether the presence of audio headings improves performance in natural learning tasks and (b) the type of heading rendering that is the most useful in natural learning tasks. Two experiments compared the effects of two types of rendering strategies on note taking and cued recall. Results from this study revealed that a prosodic rendering strategy was most useful to the listeners in natural learning tasks. (PsycINFO Database Record PMID- 29431462 TI - Investigating and explaining the effects of successive relearning on long-term retention. AB - Research on techniques for enhancing long-term retention has focused almost exclusively on single-session learning conditions. However, even the most potent initial learning manipulations typically do not yield retention levels sufficient for successful performance in many real-world contexts. In contrast, successive relearning (i.e., practicing to some level of mastery in multiple learning sessions) is a promising technique for enhancing long-term retention, but surprisingly few studies have been conducted to date. In two experiments, the advantage of successive relearning over single-session learning (i.e., relearning potency) was substantial, ds = 1.52 to 4.19. Additionally, the effects of initial lag on retention were sizable prior to relearning (ds = 1.07 to 1.87) but attenuated after relearning (ds = -.20 to .38; the extent to which relearning attenuates the effects of initial learning conditions is referred to as relearning override). To evaluate a possible explanation of these effects, we formally tested the relearning attenuatesdecay (RAD) model. The RAD model accurately accounted for relearning potency and relearning override effects (and several other secondary effects). We discuss the practical and theoretical implications of these findings and advocate that successive relearning is an important next frontier for educationally relevant memory research. (PsycINFO Database Record PMID- 29431463 TI - It can become 5 degrees C warmer: The extremity effect in climate forecasts. AB - Climate projections and other predictions are often described as outcomes that can happen, indicating possibilities that are imaginable, but uncertain. Whereas the meanings of other uncertainty terms have been extensively studied, the uses of modal verbs like can and will have rarely been examined. Participants in five experiments were shown graphs and verbal statements showing projections of future global warming, sea level rise, and other climate-related issues. All studies gave support for the extremity hypothesis, which states that people use can statements to describe the topmost values in a distribution of outcomes, regardless of their actual probabilities. Despite their extremity, outcomes that can happen are believed to have a substantial likelihood of occurrence. The extremity effect was replicated in 2 languages (Norwegian and English), and with several related terms (can, possible, could, and may). The combination of extremity and exaggerated likelihood conveyed by such statements could lead to serious miscommunications. (PsycINFO Database Record PMID- 29431464 TI - The effects of alcohol intoxication on young adult women's identification of risk for sexual assault: A systematic review. AB - Alcohol-related sexual assault among young adult women continues to present a public health concern. Social information-processing theory provides an organizing framework for understanding how alcohol intoxication can impair the processing of sexual assault risk cues and behavioral responding in sexual assault scenarios. The aim of the present article was to systematically review the extant research on the effects of alcohol intoxication on sexual assault risk information processing among young adult women. We selected relevant research through a systematic search of scientific databases, using key words related to young adult women, alcohol intoxication, and risk recognition, resulting in 14 independent research samples meeting all criteria. Studies used a variety of methods and dependent measures, precluding quantitative analysis of results. Thirteen of the 14 studies identified report at least partial support for intoxication impairing the attention to cues, interpretation of social information, or intended behavioral response in a hypothetical sexual assault scenario. Given some mixed findings, further research is warranted to identify contextual and individual differences related to risk detection and intended responding and to fully test other aspects of social information processing. Results have implications for improving alcohol-related sexual assault prevention programs by addressing the impact of alcohol intoxication on processing sexual assault risk information. (PsycINFO Database Record PMID- 29431465 TI - Unconscious conflict adaptation without feature-repetitions and response time carry-over. AB - Leading theories of cognition linked executive control to consciousness or awareness. Evidence from masked priming experiments questioned this link, but without addressing possible confounds. Responding to a target after a masked prime, participants are slower if prime and target present conflicting (incongruent) than nonconflicting (congruent) information. Crucially, congruence in the previous trial modulates this congruence effect, presenting a congruence sequence effect. This has been interpreted as conflict adaptation by executive control processes, but alternative explanations through trial-to-trial feature repetitions and response-time (RT) carry-over are possible. Here, we ruled out these alternative explanations by a mixed-model analysis of trials without trial to-trial feature-repetitions and still found a congruence-sequence effect-that is, evidence for conflict adaptation, in the absence of conflict awareness. There was also no evidence that the participants' awareness of their RTs played a role. These findings suggest that executive control can indeed operate in an awareness independent fashion. (PsycINFO Database Record PMID- 29431466 TI - Daphne striata Tratt. and D. mezereum L.: a study of anti-proliferative activity towards human cancer cells and antioxidant properties. AB - In this study, we investigated for the first time the anti-proliferative and antioxidant properties of D. mezereum and D. striata. The aerial parts were extracted by maceration with n-hexane, dichloromethane, and methanol. MPLC, GC, and GC-MS were used for the phytochemical study. The anti-proliferative activity was tested against MCF-7, A549, LNCaP, ACHN, and C32 cancer human cells. The antioxidant activity was measured by employing beta-carotene bleaching, ABTS, DPPH, and FRAP tests. The Relative Antioxidant Capacity Index (RACI) was applied from the perspective of statistics. D. mezereum dichloromethane extract showed a remarkable anti-proliferative with an IC50 of 6.08 MUg/mL against LNCaP cells. Experimental data indicate that Daphne species have interesting anti proliferative and antioxidant properties that deserve more investigations to develop novel antineoplastic drugs. PMID- 29431467 TI - Correlation Between Programmed Death Receptor-1 Expression in Tumor-Infiltrating Lymphocytes and Programmed Death Ligand-1 Expression in Non-Small Cell Lung Carcinoma. AB - CONTEXT.-: The interaction between programmed death ligand-1 (PD-L1) and programmed death receptor-1 (PD-1) on activated T cells sends an inhibitory signal that dampens the immune response. Tumors can express PD-L1 and evade the immune system. In advanced non-small cell lung carcinoma, expression of PD-1 in tumor-infiltrating lymphocytes (TILs) correlates with PD-L1 expression in tumor cells (TCs). However, this relationship has not been thoroughly explored in early disease. OBJECTIVE.-: To investigate the correlation of PD-1 and PD-L1 in non small cell lung carcinoma tumor samples, with emphasis on stage I disease. DESIGN.-: Whole tissue sections from non-small cell lung carcinoma tumors were retrospectively evaluated by immunohistochemistry for PD-1 and PD-L1 expression. The scoring was based on the percentage of cells positive for PD-1 in TILs and PD L1 in TCs and tumor-infiltrating immune cells (ICs). RESULTS.-: Expression of PD 1 in TILs was observed in 147 of 161 non-small cell lung carcinoma cases (91%). The majority of cases negative for PD-1 also lacked PD-L1 in TCs. The 68 cases with highest PD-1 expression in TILs included 33 (49%) with expression of PD-L1 in TCs and ICs. Strong correlations were observed in patients with elevated PD-1 expression in TILs and PD-L1 in TCs ( P = .01) and ICs ( P = .003). Expression of PD-1 also correlated with increased PD-L1 in TCs and ICs when the 2 were grouped together ( P < .001). Finally, stage I patients with negative PD-1 and PD-L1 expression showed trends toward increased disease-specific survival. CONCLUSIONS. : Expression of PD-1 in TILs correlates with PD-L1 expression in both TCs and ICs. Furthermore, negative expression of PD-1 and PD-L1 suggest trends toward disease-specific survival, even in early disease stages. PMID- 29431469 TI - Retraction of: Redox-Sensing Iron-Sulfur Cluster Regulators, by Crack JC, Le Brun NE. Antioxid Redox Signal [Epub ahead of print]; DOI: 10.1089/ars.2017.7369, 2017. PMID- 29431468 TI - Nipple-Invasive Primary Carcinomas: Clinical, Imaging, and Pathologic Features of Breast Carcinomas Originating in the Nipple. AB - Context Patients choosing to retain the nipple when undergoing therapeutic or prophylactic mastectomy are at risk for cancers arising at that site. Objective To identify cases of invasive carcinoma arising within the nipple and to investigate their clinical, imaging, biologic, and staging features. Design Carcinomas were identified by prospective review of surgical and consult cases at 4 hospitals. Results The 24 patients identified presented with symptoms related to the nipple. Mammography did not detect the cancer in most cases. Ten patients (42%) had skin changes from ductal carcinoma in situ involving nipple skin (Paget disease), with small foci of invasion into the dermis, and 6 of those 10 carcinomas (60%) stained positive for human epidermal growth factor receptor 2 (HER2). The remaining 14 patients (58%) presented with a nipple mass or with skin changes. These were larger invasive carcinomas of both ductal and lobular types. Only 2 of those 14 carcinomas (14%) were HER2+. Three of 15 patients (20%) undergoing lymph node biopsy had a single metastasis. No patients have had recurrent disease. Conclusions Rare, invasive, primary nipple carcinomas typically present as subtle nipple thickening or an exudative crust on the skin. Imaging studies are often nonrevealing. A variety of histologic and biologic types of carcinomas occur, similar to cancers arising deeper in the breast. Although the carcinomas invaded into the dermis, some with skin ulceration, the likelihood of lymph node metastasis was no higher than carcinomas of similar sizes. Patients who choose to preserve their nipple(s) should be aware of the possibility of breast cancer arising at that site and to bring any observed changes to the attention of their health care providers. PMID- 29431470 TI - Economic Evaluation of Safflower Yellow Injection for the Treatment of Patients with Stable Angina Pectoris in China: A Cost-Effectiveness Analysis. AB - OBJECTIVE: The purpose of this study was to evaluate the cost-effectiveness of Safflower Yellow Injection (SYI) plus conventional treatment (SYI group) versus conventional treatment only (conventional group) for the treatment of stable angina pectoris (SAP) patients in China. METHODS: A decision-tree model was constructed and the treatment impact was estimated for up to 1 year. The data, including treatment effectiveness, episodes of angina pectoris (AP)-associated hospitalization and its in-hospital mortality, mortality rate of heart diseases, and cost of hospitalization, were obtained from literature. The costs of medications were calculated based on their average bidding prices in China. The authors also conducted a doctor survey to obtain cost associated with death of cardiovascular events. Sensitivity analysis was performed to evaluate the robustness of the results. RESULTS: SAP patients in the SYI group (n = 1000) gained incremental 66.01 quality-adjusted life years (QALYs) at a cost of $250,294 compared with patients receiving conventional treatment, yielding an incremental cost-effectiveness ratio of $3,791/QALY, which was less than Chinese GDP per capita and is considered to be highly cost effective per WHO-recommended economic evaluation guidelines. Sensitivity analysis indicated that the results were robust with variations for all major parameters of the model. CONCLUSION: SYI combined with conventional treatment is a highly cost-effective therapy option compared with the conventional treatment for treatment of SAP in China. PMID- 29431472 TI - Cytoprotective and antioxidant effects of the red alga Alsidium corallinum against hydrogen peroxide-induced toxicity in rat cardiomyocytes. AB - CONTEXT: Sepsis is the manifestation of the immune and inflammatory responses to infection that may ultimately result in multiorgan failure. Many substances are involved in myocardial dysfunction in sepsis, including hydrogen peroxide. OBJECTIVE: This study evaluates the protective activity of the red alga Alsidium corallinum against hydrogen peroxide (H2O2)-induced toxicity in H9c2 cardiomyocytes. MATERIAL AND METHODS: The biological properties of A. corallinum were firstly investigated. Secondly, the H9c2 cells were pre-treated with alga extract, and then exposed to H2O2. RESULTS: Our results showed richness of the alga in antioxidant compounds, and its biological activities. H2O2 induced a morphological changes and decrease in H9c2 cell viability correlating with an increase in enzymatic and non-enzymatic antioxidants. Pre-treatment with A. corallinum, reduces toxicity and decreased the antioxidants status induced by H2O2. CONCLUSION: These findings indicated for the first time the protective effect of A. corallinum against H2O2-induced toxicity in H9c2 cells. PMID- 29431471 TI - Appetite Suppression and Altered Food Preferences Coincide with Changes in Appetite-Mediating Hormones During Energy Deficit at High Altitude, But Are Not Affected by Protein Intake. AB - Karl, J. Philip, Renee E. Cole, Claire E. Berryman, Graham Finlayson, Patrick N. Radcliffe, Matthew T. Kominsky, Nancy E. Murphy, John W. Carbone, Jennifer C. Rood, Andrew J. Young, and Stefan M. Pasiakos. Appetite suppression and altered food preferences coincide with changes in appetite-mediating hormones during energy deficit at high altitude, but are not affected by protein intake. High Alt Med Biol. 19:156-169, 2018.-Anorexia and unintentional body weight loss are common during high altitude (HA) sojourn, but underlying mechanisms are not fully characterized, and the impact of dietary macronutrient composition on appetite regulation at HA is unknown. This study aimed to determine the effects of a hypocaloric higher protein diet on perceived appetite and food preferences during HA sojourn and to examine longitudinal changes in perceived appetite, appetite mediating hormones, and food preferences during acclimatization and weight loss at HA. Following a 21-day level (SL) period, 17 unacclimatized males ascended to and resided at HA (4300 m) for 22 days. At HA, participants were randomized to consume measured standard-protein (1.0 g protein/kg/d) or higher protein (2.0 g/kg/d) hypocaloric diets (45% carbohydrate, 30% energy restriction) and engaged in prescribed physical activity to induce an estimated 40% energy deficit. Appetite, food preferences, and appetite-mediating hormones were measured at SL and at the beginning and end of HA. Diet composition had no effect on any outcome. Relative to SL, appetite was lower during acute HA (days 0 and 1), but not different after acclimatization and weight loss (HA day 18), and food preferences indicated an increased preference for sweet- and low-protein foods during acute HA, but for high-fat foods after acclimatization and weight loss. Insulin, leptin, and cholecystokinin concentrations were elevated during acute HA, but not after acclimatization and weight loss, whereas acylated ghrelin concentrations were suppressed throughout HA. Findings suggest that appetite suppression and altered food preferences coincide with changes in appetite mediating hormones during energy deficit at HA. Although dietary protein intake did not impact appetite, the possible incongruence with food preferences at HA warrants consideration when developing nutritional strategies for HA sojourn. PMID- 29431473 TI - Genetic Association of the Norepinephrine Transporter Gene G1287A Polymorphism with Risk of Schizophrenia: A Case-Control Study and Meta-Analysis. AB - BACKGROUND: The G1287A polymorphism (rs5569) in exon 9 of the norepinephrine transporter (NET) gene has been associated with schizophrenia in several populations. However, the results are conflicting. Moreover, few studies have investigated the relationship between the G1287A polymorphism and schizophrenia among the Chinese Han population. METHODS: A case-control study was designed to explore whether the G1287A genetic variant is related to schizophrenia in the Chinese Han population. The results from this study were then included in the performance of a meta-analysis to further analyze the association of the G1287A polymorphism with schizophrenia. RESULTS: No significant differences in the genotype and allele distributions of G1287A were found between Chinese Han patients with schizophrenia and control participants. Similarly, in gender specific analyses, no significant differences were found for G1287A genotype and allele distributions in either the male or the female case-control comparisons. Finally, the results of this meta-analysis also showed that the NET gene G1287A polymorphism was not associated with schizophrenia in the total population under allelic, recessive, dominant, or homozygous genetic models. CONCLUSION: Our case control study and meta-analysis suggest that the NET gene G1287A polymorphism may not be involved in the etiology of schizophrenia in the Chinese Han population. PMID- 29431475 TI - Increased Anxiety and Anhedonia in Female Rats Following Exposure to Altitude. AB - Sheth, Chandni, Hendrik Ombach, Paul Olson, Perry F. Renshaw, and Shami Kanekar. Increased anxiety and anhedonia in female rats following exposure to altitude. High Alt Med Biol. 19:81-90, 2018.-Anxiety disorders are chronic, highly prevalent conditions, often comorbid with depression. Both anxiety and depression form major risk factors for suicide. Living at altitude is associated with higher rates of depression and suicide, leading us to address whether anxiety disorders may also be amplified at altitude. Using a novel translational animal model, we previously showed that depression-like behavior increases with altitude of housing in female, but not male rats. We now use this model to examine the effects of altitude on both anxiety-like behavior and anhedonia, a core symptom of depression. After housing for a week at sea level, 4500 or 10,000 ft, rats were evaluated for anxiety in the open-field test or the elevated plus maze, and anhedonia in the sucrose preference test. Another group was tested at baseline. Anxiety-like behavior increased in females housed at altitude. In females, lower sucrose preference was seen in those housed at 10,000 ft versus those at sea level. Males showed no change in anxiety or anhedonia across groups. These data suggest that living at moderate-high altitude may pose a risk factor for those vulnerable to anxiety disorders, with the potential to be particularly detrimental to females at altitude. PMID- 29431474 TI - Maternal Carbamazepine Therapy and Unusual Adverse Effects in a Breastfed Infant. AB - BACKGROUND: Usually, no adverse effects are observed in breastfed infants whose mothers are treated with the anti-epileptic carbamazepine. In this article, we described unusual short-term adverse effects observed in a young infant after exposure to carbamazepine during pregnancy and lactation. CASE REPORT: A 40-day old female infant, born at term, was admitted to the Pediatric Clinic at University of Sassari, Italy, for recurrent regurgitations and vomiting. She was breastfed since birth and her mother was under chronic carbamazepine therapy. Gastroesophageal reflux was initially suspected; therefore, thickening of feeds and postural therapy were applied without any benefit. Subsequently, high levels of carbamazepine were detected in infant serum and in maternal breast milk. After an unsuccessful attempt to combine breastfeeding with formula feeding, the switch to exclusive formula feeding was made, with subsequent rapid resolution of symptoms and body weight increase. DISCUSSION AND CONCLUSIONS: The use of carbamazepine is considered compatible with breastfeeding, even if the potential risk of adverse reactions in breastfed infants exists. In this case, the discontinuation of breastfeeding resulted in the complete resolution of symptoms, suggesting a correlation between the observed manifestations in the infant and her exposure to maternal therapy. PMID- 29431476 TI - Design, synthesis and molecular modeling study for some new 2-substituted benzimidazoles as dual inhibitors for VEGFR-2 and c-Met. AB - AIM: Computer-aided drug design techniques were adopted to design three series of 2-substituted-5-nitrobenzimidazole derivatives hybridized with piperzine 5a,b, oxadiazole 7a,b, 9, 14a-c and triazolo-thiadiazole moieties 12a-d, as VEGFR-2/c Met kinase inhibitors. MATERIALS & METHODS: The designed compounds were synthesized adopting the chemical pathways outlined in schemes 1 and 2 to afford the desired three series followed by evaluating their inhibitory activities against VEGFR-2 and c-Met and in vitro anticancer activities. RESULT: Analogs bearing substituted phenyl ring attached to oxadiazole ring 14a showed the greatest inhibitory activities against non-small-cell lung cancer NCI-H522 and melanoma SK-MEL-2 with inhibition percent of 48.70 and 42.62, respectively. Moreover, unsubstituted phenoxymethyl derivative 12d exhibited promising inhibitory activity against VEGFR-2 and c-Met (35.88 and 88.48%), respectively. CONCLUSION: The above results revealed that 2-substituted-5-nitrobenzimidazole hybridized with various heterocyclic scaffolds could be a potential anticancer agent. PMID- 29431477 TI - Evaluation of give kids a boost: A school-based program to increase booster seat use among urban children in economically disadvantaged areas. AB - OBJECTIVE: This study evaluated the effectiveness of a series of 1-year multifaceted school-based programs aimed at increasing booster seat use among urban children 4-7 years of age in economically disadvantaged areas. METHODS: During 4 consecutive school years, 2011-2015, the Give Kids a Boost (GKB) program was implemented in a total of 8 schools with similar demographics in Dallas County. Observational surveys were conducted at project schools before project implementation (P0), 1-4 weeks after the completion of project implementation (P1), and 4-5 months later (P2). Changes in booster seat use for the 3 time periods were compared for the 8 project and 14 comparison schools that received no intervention using a nonrandomized trial process. The intervention included (1) train-the-trainer sessions with teachers and parents; (2) presentations about booster seat safety; (3) tailored communication to parents; (4) distribution of fact sheets/resources; (5) walk-around education; and (6) booster seat inspections. The association between the GKB intervention and proper booster seat use was determined initially using univariate analysis. The association was also estimated using a generalized linear mixed model predicting a binomial outcome (booster seat use) for those aged 4 to 7 years, adjusted for child-level variables (age, sex, race/ethnicity) and car-level variables (vehicle type). The model incorporated the effects of clustering by site and by collection date to account for the possibility of repeated sampling. RESULTS: In the 8 project schools, booster seat use for children 4-7 years of age increased an average of 20.9 percentage points between P0 and P1 (P0 = 4.8%, P1 = 25.7%; odds ratio [OR] = 6.9; 95% confidence interval [CI], 5.5, 8.7; P < .001) and remained at that level in the P2 time period (P2 = 25.7%; P < .001, for P0 vs. P2) in the univariate analysis. The 14 comparison schools had minimal change in booster seat use. The multivariable model showed that children at the project schools were significantly more likely to be properly restrained in a booster seat after the intervention (OR = 2.7; 95% CI, 2.2, 3.3) compared to the P0 time period and compared to the comparison schools. CONCLUSION: Despite study limitations, the GKB program was positively associated with an increase in proper booster seat use for children 4-7 years of age in school settings among diverse populations in economically disadvantaged areas. These increases persisted into the following school year in a majority of the project schools. The GKB model may be a replicable strategy to increase booster seat use among school-age children in similar urban settings. PMID- 29431478 TI - High-intensity interval training improves inflammatory and adipokine profiles in postmenopausal women with metabolic syndrome. AB - This study investigate the effects of high-intensity interval training (HIIT) on systemic levels of inflammatory and hormonal markers in postmenopausal women with metabolic syndrome (MS). Fifteen postmenopausal women with MS completed the training on treadmills. Functional, body composition parameters, maximal oxygen uptake (VO2max), and lipid profile were assessed before and after HIIT. Serum or plasma levels of cytokines and hormonal markers were measured along the intervention. The analysis of messenger RNA (mRNA) expression of these cytokines was performed in peripheral blood mononuclear cells (PBMC). VO2max and some anthropometric parameters were improved after HIIT, while decreased levels of proinflammatory markers and increased levels of interleukin-10 (IL-10) were also found. Adipokines were also modulated after 12 weeks or training. The mRNA expression of the studied genes was unchanged after HIIT. In conclusion, HIIT benefits inflammatory and hormonal axis on serum or plasma samples, without changes on PBMC of postmenopausal MS patients. PMID- 29431481 TI - Performing a digital rectal examination: considerations and interpretation. PMID- 29431480 TI - Identification of a Novel Nonsense ASPM Mutation in a Large Consanguineous Pakistani Family Using Targeted Next-Generation Sequencing. AB - AIMS: To identify the pathogenic mutation underlying microcephaly primary hereditary (MCPH) in a large consanguineous Pakistani family. METHODS: A five generation family with an autosomal recessive transmission of MCPH was recruited. Targeted next-generation DNA sequencing was carried out to analyze the genomic DNA sample from the proband with MCPH using a previously designed panel targeting 46 known microcephaly-causing genes. Sanger sequencing was performed to verify all identified variants. RESULTS: We found a novel homozygous nonsense mutation, c.7543C>T, in the ASPM gene. This mutation led to the substitution of an arginine with a stop codon at amino acid residue 2515 (p.Arg2515Ter). The mutation cosegregated with the MCPH phenotype in all affected and obligate carrier family members, but was not present in public databases (dbSNP147, Exome Variant Server, the 1000 Genomes Project, Exome Aggregation Consortium, Human Gene Mutation Database, and ClinVar) or 200 control individuals. The c.7543C>T mutation in ASPM may activate nonsense-mediated mRNA decay pathways and could underlie the pathogenesis of MCPH through a loss-of-function mechanism. CONCLUSIONS: The c.7543C>T (p.Arg2515Ter) mutation in ASPM is a novel pathogenic mutation for the typical MCPH phenotype in this family. PMID- 29431482 TI - How to run a bedside teaching session. PMID- 29431479 TI - The Habitability of Proxima Centauri b: Environmental States and Observational Discriminants. AB - Proxima Centauri b provides an unprecedented opportunity to understand the evolution and nature of terrestrial planets orbiting M dwarfs. Although Proxima Cen b orbits within its star's habitable zone, multiple plausible evolutionary paths could have generated different environments that may or may not be habitable. Here, we use 1-D coupled climate-photochemical models to generate self consistent atmospheres for several evolutionary scenarios, including high-O2, high-CO2, and more Earth-like atmospheres, with both oxic and anoxic compositions. We show that these modeled environments can be habitable or uninhabitable at Proxima Cen b's position in the habitable zone. We use radiative transfer models to generate synthetic spectra and thermal phase curves for these simulated environments, and use instrument models to explore our ability to discriminate between possible planetary states. These results are applicable not only to Proxima Cen b but to other terrestrial planets orbiting M dwarfs. Thermal phase curves may provide the first constraint on the existence of an atmosphere. We find that James Webb Space Telescope (JWST) observations longward of 10 MUm could characterize atmospheric heat transport and molecular composition. Detection of ocean glint is unlikely with JWST but may be within the reach of larger-aperture telescopes. Direct imaging spectra may detect O4 absorption, which is diagnostic of massive water loss and O2 retention, rather than a photosynthetic biosphere. Similarly, strong CO2 and CO bands at wavelengths shortward of 2.5 MUm would indicate a CO2-dominated atmosphere. If the planet is habitable and volatile-rich, direct imaging will be the best means of detecting habitability. Earth-like planets with microbial biospheres may be identified by the presence of CH4-which has a longer atmospheric lifetime under Proxima Centauri's incident UV-and either photosynthetically produced O2 or a hydrocarbon haze layer. Key Words: Planetary habitability and biosignatures-Planetary atmospheres-Exoplanets-Spectroscopic biosignatures-Planetary science-Proxima Centauri b. Astrobiology 18, 133-189. PMID- 29431483 TI - Catastrophic cerebral myelinolysis following extreme hyponatraemia. PMID- 29431484 TI - Striatal hand in a woman with Parkinson's disease. PMID- 29431485 TI - Trampoline park safety legislation: springtime in Cheshire. PMID- 29431486 TI - Reducing recurrent hospital admissions in patients with decompensated cirrhosis. AB - Recurrent admissions to hospital are a major issue for people living with decompensated cirrhosis, particularly those who develop chronic hepatic encephalopathy, a condition that leads to significantly impaired quality of life for patients and their family caregivers. Such patients have high health-care use costs but recent data have shown how the appropriate use of effective medical therapy can significantly reduce hospital admissions, length of stay and unplanned readmissions. Redesigning clinical services to optimize access to specialist care and improving the education and support of patients and their carers can further help to reduce the burden of this disease. PMID- 29431488 TI - The Perioperative Quality Improvement Programme: improving outcomesd. PMID- 29431489 TI - Systemic air embolism as a complication of percutaneous lung biopsy. PMID- 29431490 TI - Hypercapnia vs normocapnia in patients with acute respiratory distress syndrome PMID- 29431491 TI - Customizable pre-printed consent forms: a solution in light of the Montgomery ruling. AB - INTRODUCTION: This article presents an audit cycle supported quality improvement project addressing best practice in the consent process for lower limb arthroplasty which takes into account the new standard in surgical consent and the importance of material risks. METHODS: 50 consecutive total hip and total knee replacement consent forms over a 3-month period were reviewed for legibility and completeness. Following the introduction of a new, pre-printed but customizable consent form the review process was repeated. RESULTS: The introduction of a customizable, pre-printed consent form that can be adjusted to reflect the individualized material risks of each patient increased legibility, reduced inappropriate human error variation and abolished the use of abbreviations and medical jargon. CONCLUSIONS: When used as part of an extended consent process, the authors feel that the use of pre-printed but customizable consent forms improves legibility, completeness and consistency and also provides the ability to highlight those complications that are of particular importance for that patient to satisfy the new accepted standard in surgical consent. PMID- 29431493 TI - General Medical Council trainee survey: implications for hospital doctors. PMID- 29431492 TI - Carotid body paraganglioma: a rare pathology but not to be forgotten. PMID- 29431494 TI - Howard Florey: father of the antibiotic era. PMID- 29431495 TI - Using personalized teaching and learning to improve clinical performance. AB - The intention of personalized teaching and learning to improve clinical performance is the optimization of individual performance across a variety of tasks in different environments. Educational interventions need to have a focus on the assessment and feedback of both outcome and process of performance. An essential component of the assessment and feedback on the process of performance is how 'the will' and 'the skill' are dynamically adapted by the individual through self-regulated learning processes. Microanalysis can identify the key self-regulated learning processes and the findings used to inform self-regulated learning enhanced feedback for personalized teaching and learning. The experience of the authors in using self-regulated learning enhanced feedback for optimizing performance in prescribing by junior doctors is discussed. PMID- 29431496 TI - Penetrating neck injuries. AB - Penetrating neck injuries are becoming more common because of the increasing prevalence of knife and gun crimes. The immediate and long-term consequences of injury to the neck can be significant because of the close relationship of important anatomical structures in a confined space. Delayed recognition of major injury and inadequate treatment results in high morbidity and mortality. Developing a clear understanding of the underlying anatomy, common mechanisms of injury and principles of management will provide first responders, emergency doctors and trauma surgeons with confidence in appropriate evidence-based management. Early involvement of otolaryngologists or head and neck surgeons is advisable. Two cases of penetrating neck injury from the June 2017 London Bridge terror attack are discussed. PMID- 29431497 TI - Improving safety of care for older people. PMID- 29431499 TI - Clinical News. PMID- 29431498 TI - Assessment and management of adult spinal deformities. AB - Adult spinal deformity is a complex condition, increasing in prevalence, and occurring in a patient population in which it poses unique challenges. This review provides an overview of adult spinal deformity with a particular focus on its clinical evaluation, radiological assessment and classification, reviewing the current literature and amalgamating this with the authors' clinical experience. PMID- 29431500 TI - Diagnostic coronary angiography: past, present and future. PMID- 29431501 TI - Endometriosis: a rare cause of multiple lung nodules on imaging. PMID- 29431502 TI - Mesenteric ischaemia: an overview of diagnostic and therapeutic best practice. AB - Mesenteric ischaemia is relatively uncommon, but is an important diagnosis to remember as it can lead to significant morbidity and mortality. Improvements in clinical imaging technology have made rapid diagnosis and treatment possible, but this relies on awareness of the condition. This article summarizes current best practice in diagnosis and management of mesenteric ischaemia to guide the clinician. PMID- 29431503 TI - Performing a digital rectal examination: indications and examination. PMID- 29431504 TI - The Sister Mary Joseph nodule. PMID- 29431506 TI - In Briefs. PMID- 29431505 TI - An Initial Assessment of Secular Trends in Muscular Strength Among Children, Adolescents, and Adults Across the Lifespan: National Sample of Americans. AB - PURPOSE: Adequate muscular strength has important implications for morbidity and early mortality prevention. There are no data on the recent trends in muscular strength across lifespan, which was this study's purpose. DESIGN: Cross sectional. SETTING: 2011 to 2012 and 2013 to 2014 waves of the National Health and Nutrition Examination Survey across the United States. PARTICIPANTS: The analyzed sample included 12 295 participants aged 6 to 85 years. MEASURES: Muscular strength was assessed via a handgrip dynamometer. ANALYSIS: Adjusted Wald test. RESULTS: As expected, men (vs women) had greater grip strength, with grip strength declining as age increased. Central to the focus of this study, there were no changes in absolute or relative grip strength across the waves for any of the evaluated populations (considering age, gender, and race-ethnicity). CONCLUSION: These findings demonstrate that muscular grip strength, across all age, gender, and race-ethnicity populations in the United States, has not changed in the 2 successive 2-year time windows, contained over a 4-year period. PMID- 29431507 TI - High Amounts of Sitting, Low Cardiorespiratory Fitness, and Low Physical Activity Levels: 3 Key Ingredients in the Recipe for Influencing Metabolic Syndrome Prevalence. AB - PURPOSE: Limited research has evaluated the independent and additive associations of moderate-to-vigorous physical activity (MVPA), sedentary behavior (SB), and cardiorespiratory fitness (CRF) with metabolic syndrome, which was the purpose of this study. DESIGN: Cross-sectional. SETTING: National Health and Nutrition Examination Survey 2003 to 2004. SAMPLE: Three hundred seven adults aged 20 to 49 years. MEASURES: Moderate-to-vigorous physical activity and SB were assessed via accelerometer, whereas CRF was assessed via submaximal treadmill testing. Metabolic syndrome was assessed via the American Heart Association/National Heart, Lung, and Blood Institute guidelines. ANALYSIS: Multivariable logistic regression. RESULTS: A 10 min/d increase in MVPA was associated with a 45% reduced odds of metabolic syndrome (odds ratio [OR] = 0.55, 95% confidence interval [CI] = 0.40-0.76, P = .001), and a 10 mL/kg/min increase in CRF was associated with a 43% reduced odds of having metabolic syndrome (OR = 0.57, 95% CI = 0.37-0.87, P = .013). Additionally, a statistically significant combined association of MVPA, SB, and CRF with metabolic syndrome was present; individuals who had below-median SB and above-median MVPA and CRF had an 88% reduced odds of metabolic syndrome (OR = 0.12, 95% CI = 0.03-0.48, P = .005) when compared to those who had below-median MVPA and CRF and above-median SB. CONCLUSION: When considering MVPA, SB, and CRF, MVPA and CRF were both independently associated with metabolic syndrome (SB was not) among this young adult population and there was also evidence to support a combined association of all 3 parameters on metabolic syndrome. PMID- 29431509 TI - Reviewers List 2017. PMID- 29431508 TI - Head, Heart, and Feet in Exercise and Weight Management. AB - It has been argued that the willpower of our citizenry hasn't measurably changed during the decades in which our nation's waistlines have measurably expanded. I agree, and I'd also submit that a weakening of political willpower and a lack of moral courage among those of us called to leadership is the more disturbing culprit. A case needs to be made that what we know and believe as a profession is most readily measured by what we permit to happen. As you review the sum of the research in this special issue on activity, weight, and diabetes, I anticipate you will share my observation that the current action in health promotion is less about dieting, exercise prescriptions, and chronic condition management and more about the right mix of head, heart, and feet. That is, we are testing the interaction effects of education and attitudes against culture and environment and assessing how the interacting effects of these variables influence motivation and action. This special journal issue shows how great results are occurring in health promotion every day via education and culture change, and it will also bolster your courage to carry on with morality and heart. PMID- 29431510 TI - Accelerometer-Assessed Physical Activity and School Absenteeism Due to Illness or Injury Among Children and Adolescents: NHANES 2003 to 2006. AB - INTRODUCTION: To examine the association between objectively measured moderate to vigorous physical activity (MVPA) and total physical activity with school absenteeism due to illness or injury among children and adolescents. DESIGN: Cross-sectional study. SETTING: National Health and Nutrition Examination Survey 2003 to 2006. PARTICIPANTS: A total of 1249 children (aged 6-11 years) and 1747 adolescents (aged 12-17 years). MEASURES: School absenteeism was categorized as no/minimal school absenteeism (0-8 missed school days in the past 12 months), moderate absenteeism (9-17 missed days), or severe absenteeism (18+ missed days). Physical activity was objectively measured via accelerometry. ANALYSIS: Multinomial logistic regression. RESULTS: Children in the most active quartile had 89% reduced odds of severe absenteeism relative to the least active quartile (odds ratio [OR]: 0.11; 0.95% confidence interval [CI]: 0.02-0.48); results were similar for MVPA. For adolescents, those in the most active quartile for MVPA had a 41% reduced odds of having moderate (vs no/minimal) absenteeism (OR = 0.59; 95% CI: 0.35-0.99). For children, a multiplicative interaction effect of MVPA and poverty level on severe absenteeism was observed (OR = 0.98, P = .02). CONCLUSION: Higher levels of physical activity were associated with lower odds of severe school absenteeism. Such an observation is important, as school absenteeism strongly contributes to academic performance. Particular attention for promoting physical activity and closely monitoring school absenteeism among youth below the poverty level may be warranted. PMID- 29431511 TI - The Art of Health Promotion: Linking research to practice. PMID- 29431512 TI - Heparanase Is a Critical Regulator of Mitotic Spindles Required for Maintaining Chromosome Stability. AB - The mitotic spindle, assembled by microtubule organization center (MTOC), is a critical structure required for proper chromosome segregation during mitosis. Studies demonstrated that defects of mitotic spindle assembling would result in chromosome instability, associating with oncogenesis. In this study, we identified that heparanase (HPSE) was localized on MTOC in mitotic cells. Induced expression of HPSE in human airway epithelial cells promoted mitotic spindle formation, and silencing of HPSE expression disrupted the mitotic spindle formation, resulting in chromosome instability, including chromosome mis segregation and increased micronuclei formation. In conclusion, HPSE is an important protein in regulation of mitotic spindle and loss of HPSE function on MTOC associates with chromosome instability, indicating that loss of HPSE on MTOC may play critical roles in oncogenesis. PMID- 29431514 TI - Behavioural automaticity moderates and mediates the relationship of trait self control and physical activity behaviour. AB - OBJECTIVES: Trait self-control has been shown to be associated with physical activity behaviour. However, in contrast with the theoretical assumption underlying the strength model of self-control, self-control seems to be more important for automatic compared with controlled behaviours. It is argued that self-control might facilitate the formation of adaptive habits (behavioural automaticity) and therefore enhance health behaviour through an indirect effect. The credibility of this hypothesis was empirically assessed in a proof-of-concept study. METHODS: In a prospective design study with two laboratory sessions, participants (N = 124) completed standardised questionnaires assessing trait self control and behavioural automaticity as predictors (1st session) and actual physical activity behaviour (after one week) as the dependent variable (2nd session). RESULTS: The predictive power of self-control was stronger for participants with high behavioural automaticity compared with participants with low behavioural automaticity. Furthermore, automaticity mediated the relationship between self-control and behaviour. DISCUSSION: Behavioural automaticity appears to be a helpful construct for specifying the relationship between self-control and physical activity. Our results support the approach of effortless self control and self-control success, an extension of the strength model of self control which assumes that self-control is helpful in creating effective routines. In future studies, causal relationships should be examined using more robust and rigorous research designs. PMID- 29431513 TI - Safety and Feasibility of the OmniPod Hybrid Closed-Loop System in Adult, Adolescent, and Pediatric Patients with Type 1 Diabetes Using a Personalized Model Predictive Control Algorithm. AB - BACKGROUND: The safety and feasibility of the OmniPod personalized model predictive control (MPC) algorithm in adult, adolescent, and pediatric patients with type 1 diabetes were investigated. METHODS: This multicenter, observational trial included a 1-week outpatient sensor-augmented pump open-loop phase and a 36 h inpatient hybrid closed-loop (HCL) phase with announced meals ranging from 30 to 90 g of carbohydrates and limited physical activity. Patients aged 6-65 years with HbA1c between 6.0% and 10.0% were eligible. The investigational system included a modified version of OmniPod, the Dexcom G4 505 Share(r) AP System, and the personalized MPC algorithm running on a tablet computer. Primary endpoints included sensor glucose percentage of time in hypoglycemia <70 mg/dL and hyperglycemia >250 mg/dL. Additional glycemic targets were assessed. RESULTS: The percentage of time <70 mg/dL during the 36-h HCL phase was mean (standard deviation): 0.7 (1.7) in adults receiving 80% meal bolus (n = 24), and 0.7 (1.2) in adults (n = 10), 2.0 (2.4) in adolescents (n = 12), and 2.0 (2.6) in pediatrics (n = 12) receiving 100% meal bolus. The overall hypoglycemia rate was 0.49 events/24 h. The percentage of time >250 mg/dL was 8.0 (7.5), 3.6 (3.7), 4.9 (6.3), and 6.7 (5.6) in the study groups, respectively. Percentage of time in the target range of 70-180 mg/dL was 69.5 (14.4), 73.0 (15.0), 72.6 (15.5), and 70.1 (12.3), respectively. CONCLUSIONS: The OmniPod personalized MPC algorithm performed well and was safe during day and night use in adult, adolescent, and pediatric patients with type 1 diabetes. Longer term studies will assess the safety and performance of the algorithm under free living conditions with extended use. PMID- 29431515 TI - Different expression profiles of the lysyl oxidases and matrix metalloproteinases in human ACL fibroblasts after co-culture with synovial cells. AB - Purposes The anterior cruciate ligament (ACL) has poor functional healing response. The synovial tissue surrounding ACL ligament might be a major regulator of the microenvironment in the joint cavity after ACL injury, thus affecting the repair process. Using transwell co-culture, this study explored the direct influence of human synovial cells (HSCs) on ACL fibroblasts (ACLfs) by characterizing the differential expression of the lysyl oxidase family (LOXs) and matrix metalloproteinases (MMP-1, -2, -3), which facilitate extracellular matrix (ECM) repair and degradation, respectively. Methods The mRNA expression levels of LOXs and MMP-1, -2, -3 were analyzed by semi-quantitative PCR and quantitative real-time PCR. The protein expression levels of LOXs and MMP-1, -2, -3 were detected by western blot. Results We found that co-culture resulted in an increase in the mRNAs of LOXs in normal ACLfs and differentially regulated the expression of MMPs. Then we applied 12% mechanical stretch on ACLfs to induce injury and found the mRNA expression levels of LOXs in injured ACLfs were decreased in the co-culture group relative to the mono-culture group. Conversely, the mRNA expression levels of MMPs in injured ACLfs were promoted in the co culture group compared with the mono-culture group. At translational level, we found that LOXs were lower while MMPs were highly expressed in the co-culture group compared to the mono-culture group. Conclusions The co-culture of ACLfs and HSCs, which mimicked the cell-to-cell contact in a micro-environment, could contribute to protein modulators for wound healing, inferring the potential reason for the poor self-healing of injured ACL. PMID- 29431516 TI - Does a histologically inflamed resection margin increase postoperative complications in patients with Crohn's disease? AB - OBJECTIVES: Our study assessed whether the presence of histologically inflamed resection margins increased postoperative anastomotic complications in Crohn's disease (CD) patients. We also examined the influence of other risk factors for postoperative complications. MATERIALS AND METHODS: Presence of chronic inflammation and activity of inflammation was scored from the resection margin specimens of 70 patients undergoing surgery due to CD. Anastomotic complications were recorded with a one-month follow-up. We also analysed other risk factors for postoperative complications, such as patient age, previous surgeries, preoperative C-reactive protein, faecal calprotectin, albumin and haemoglobin levels, American Society of Anesthesiologists (ASA) classification, preoperative immunosuppressive medication, surgical approach and the presence of intraoperative fistula or abscess. RESULTS: In total, 46 patients (65.7%) had active inflammation in the bowel resection margin - 12 patients (17.1%) with mild, five patients (7.1%) with moderate and 29 patients (41.4%) with strong activity. We found 14 (20.0%) postoperative complications, of which three (4.6%) were anastomotic. The presence of active inflammation at the resection margin did not significantly influence the occurrence of postoperative anastomotic complications. None of the other risk factors examined significantly increased postoperative complications among our sample. CONCLUSIONS: After bowel-sparing surgery for CD, the frequency of histologically inflamed resection margins is high. However, postoperative complication rate remains low. The current practice with resection of only the most affected bowel segments for CD seems to be a safe choice. We still need further research concerning risk factors for postoperative complications in Crohn's patients. PMID- 29431518 TI - Effectiveness of omalizumab in adolescent and adult patients with chronic idiopathic/spontaneous urticaria: a systematic review of 'real-world' evidence. AB - INTRODUCTION: Chronic idiopathic/spontaneous urticaria (CIU/CSU) is a dermatological condition characterized by itchy wheals and/or angioedema of continuous or intermittent duration of >=6 weeks with a high burden of disease and impact on quality of life. Omalizumab is a recombinant humanized monoclonal antibody that inhibits the binding of IgE to high affinity receptors, and is approved for the CIU/CSU indication. The objective of this systematic review was to evaluate and synthesize the evidence on the real-world effectiveness of omalizumab in CIU/CSU in daily clinical practice. Areas covered: This review of 84 observational effectiveness studies covers treatments (dosing, medication use), clinical outcomes (treatment response, disease activity, quality of life), and safety. Expert opinion: The clinical outcomes observed across studies underscore the real-world effectiveness of omalizumab in the management of CIU/CSU. Continued treatment may assist patients showing an initial response to achieve a complete treatment response. Response rates are aligned with observed changes in disease activity, symptom experience, and quality of life, and this across subtypes of CIU/CSU. The positive therapeutic profile is complemented by a positive safety profile. The real-world evidence summarized here points convincingly at the high degree of effectiveness of omalizumab in the treatment of CIU/CSU in daily clinical practice. PMID- 29431517 TI - Informatics and machine learning to define the phenotype. AB - INTRODUCTION: For the past decade, the focus of complex disease research has been the genotype. From technological advancements to the development of analysis methods, great progress has been made. However, advances in our definition of the phenotype have remained stagnant. Phenotype characterization has recently emerged as an exciting area of informatics and machine learning. The copious amounts of diverse biomedical data that have been collected may be leveraged with data driven approaches to elucidate trait-related features and patterns. Areas covered: In this review, the authors discuss the phenotype in traditional genetic associations and the challenges this has imposed.Approaches for phenotype refinement that can aid in more accurate characterization of traits are also discussed. Further, the authors highlight promising machine learning approaches for establishing a phenotype and the challenges of electronic health record (EHR) derived data. Expert commentary: The authors hypothesize that through unsupervised machine learning, data-driven approaches can be used to define phenotypes rather than relying on expert clinician knowledge. Through the use of machine learning and an unbiased set of features extracted from clinical repositories, researchers will have the potential to further understand complex traits and identify patient subgroups. This knowledge may lead to more preventative and precise clinical care. PMID- 29431519 TI - Subcutaneous semaglutide (NN9535) for the treatment of type 2 diabetes. AB - INTRODUCTION: It is critical for individuals with type 2 diabetes mellitus (T2DM) to maintain optimal glycemia while avoiding hypoglycemia, control body weight, and reduce cardiovascular risk. The GLP-1 receptor agonists stimulate glucose dependent insulin release (low risk of hypoglycemia), inhibit glucagon secretion, slow gastric emptying and suppress appetite (weight loss). The new members of the class are available as once daily or weekly injections. Additionally, some members of the class have demonstrated reduced cardiovascular risk. Areas covered: This manuscript describes semaglutide - a new investigational long acting GLP-1 receptor agonist. The key trials from the clinical development process are reviewed and important end-points highlighted. Expert opinion: Once weekly semaglutide has shown superiority in reducing glycosylated hemoglobin and body weight in comparison with placebo and active comparators when used as monotherapy or in combination treatment. In addition, semaglutide improved markers of beta-cell function and have shown cardiovascular risk reduction similar to once daily liraglutide. Although, overall semaglutide safety was comparable to other GLP-1 receptor agonists (low risk of hypoglycemia and high frequency of gastrointestinal side effects), increase in retinopathy complications requires further investigation. PMID- 29431520 TI - Beneficial effects of acute trans-resveratrol supplementation in treated hypertensive patients with endothelial dysfunction. AB - Endothelial dysfunction is a surrogate marker of cardiovascular risk. Resveratrol is known to improve endothelial function in animals, however, clinical trials are limited. We hypothesized that the acute trans-resveratrol supplementation improves endothelial function in treated hypertensive patients with endothelial dysfunction. Twenty-four hypertensive patients between 45 and 65 years-old with baseline endothelial dysfunction were enrolled in a randomized, cross-over, double-blind, placebo-controlled trial. Individuals received either a single dose of trans-resveratrol (300 mg) or placebo and were crossed-over after a one-week washout period. Blood pressure (BP) measurements, aortic systolic blood pressure (SBP) and brachial flow-mediated dilation (FMD) were performed before and 1.5 hours after the intervention. FMD was significantly increased in women (4.2 +/- 0.5 vs 7.1 +/- 1.3%, p = 0.026) but not in men (4.4 +/- 0.9 vs 4.9 +/- 0.8%, p = 0.588) in the trans-resveratrol group. There was no statistical difference between baseline and final values of brachial BP and also no changes in aortic SBP. Patients with higher low-density lipoprotein (LDL) cholesterol had better FMD response to trans-resveratrol than patients with lower LDL cholesterol (7.4 +/- 1.2 vs 4.3 +/- 1.0%, p = 0.004). Our study demonstrated that the acute supplementation of trans-resveratrol promoted an improvement in endothelial function, especially in women and those with higher LDL-cholesterol, despite no changes in BP. List of Abbreviation: Aix: augmentation index; AP: augmentation pressure; BP: blood pressure; BMI: body Mass Index; CVD: cardiovascular disease; FMD: flow-mediated dilation; FRS: Framingham Risk Score; HDL: high-density lipoprotein; LDL: low-density lipoprotein; NO: nitric oxide; SPSS: Statistical Package for Social Sciences; ROS: reactive oxygen species; SBP: systolic blood pressure; TG: triglycerides. PMID- 29431522 TI - Posttraumatic stress disorder, emotional suppression and psychiatric co-morbidity in patients with chronic idiopathic urticaria: a moderated mediation analysis. AB - BACKGROUND: There is evidence suggesting that posttraumatic stress disorder (PTSD) symptom severity and CIU severity are linked and partially mediated by the high-anxious defense mechanism. What is unclear is whether emotional suppression, as a defense serving the opposite purpose for high-anxious defense, can also act as a mediator and whether this mediational effect is partly influenced by time since trauma and trauma type. AIMS: To investigate whether emotional suppression mediated the links between PTSD and CIU symptom severities, and PTSD and psychiatric co-morbid symptom severities. It then examined whether the mediating effect would be moderated by how long ago the trauma occurred and trauma type. METHODS: One hundred CIU patients were compared with 60 allergy patients. They completed questionnaires measuring PTSD, psychiatric co-morbidity and emotional suppression. RESULTS: Suppressing depression mediated the relationship between PTSD and psychiatric co-morbidity. How long ago the trauma occurred and trauma type moderated the mediational effect of suppressing depression. CONCLUSIONS: Following a past trauma, CIU patients may develop PTSD symptoms which influence their psychological well-being through using different levels of emotional suppression, especially suppressing depression. The levels depend on the severity of PTSD symptoms, trauma history and whether they experienced interpersonal traumas. PMID- 29431521 TI - Effect of Exercise Duration on Subsequent Appetite and Energy Intake in Obese Adolescent Girls. AB - There is a growing interest regarding the effect of exercise on appetite and energy intake in youth. While the role of exercise intensity has been a primary focus of study, the effect of exercise duration on subsequent food intake has not been fully examined in obese adolescents. On three separate mornings in a randomly assigned order, obese adolescent girls (n = 20) aged 12-15 years old were asked to perform a rest session (control, CON) or two cycling sessions for 20 (EX20) or 40 min (EX40) set at their ventilatory threshold. Absolute and relative energy intake were measured from an ad libitum lunch meal 30 min after rest or exercise and appetite feelings assessed using visual analogue scales throughout the day. Hunger, satiety, and prospective food consumption were not significantly different between conditions. Absolute energy intake (kcal) did not differ between conditions, while relative energy intake on EX40 (571 +/- 381 kcal) was significantly lower than during CON (702 +/- 320 kcal; p < .05) and EX20 (736 +/- 457 kcal; p < .05). Fat ingestion (in grams) was significantly lower on CON (7.8 +/- 3.2 g) compared with EX20 (10.3 +/- 4.6 g; p < .01). Protein intake (in grams) was higher on EX20 (37.0 +/- 16.6 g) compared with both CON (29.5 +/- 11.7 g; p < .01) and EX40 (33.1 +/- 10.9 g; p < .05). However, the percentage of total energy derived from each macronutrient was not different between conditions. Obese adolescent girls do not compensate for an acute bout of exercise set at their ventilatory threshold by increasing energy intake, regardless of the exercise duration. PMID- 29431523 TI - Molecular diagnosis of antimicrobial resistance in Escherichia coli. AB - INTRODUCTION: Antimicrobial resistance is a growing global public health threat. The complexities of antimicrobial resistance in gram-negative bacteria such as Escherichia coli pose significant diagnostic and therapeutic challenges. Molecular diagnostics are emerging in this field. Areas covered: The authors review the clinical importance of pathogenic E. coli and discuss the mechanisms of resistance to common antibiotics used to treat these infections. We review the literature on antimicrobial susceptibility testing and discuss the current state of phenotypic as well as molecular methodologies. Clinical vignettes are presented to highlight how molecular diagnostics may be used for patient care. Expert commentary: The future use of molecular diagnostics for detection of antimicrobial resistance will be tailored to the context, whether hospital epidemiology, infection control, antibiotic stewardship, or clinical care. Further clinical research is needed to understand how to best apply molecular diagnostics to these settings. PMID- 29431524 TI - What is the role of statins in the elderly population? PMID- 29431525 TI - Localized surface plasmon resonance based biosensing. AB - INTRODUCTION: Bioanalytical sensing based on the principle of localized surface plasmon resonance experiences is currently an extremely rapid development. Novel sensors with new kinds of plasmonic transducers and innovative concepts for the signal development as well as read-out principles were identified. This review will give an overview of the development of this field. Areas covered: The focus is primarily on types of transducers by preparation or dimension, factors for optimal sensing concepts and the critical view of the usability of these devices as innovative sensors for bioanalytical applications. Expert commentary: Plasmonic sensor devices offer a high potential for future biosensing given that limiting factors such as long-time stability of the transducers, the required high sensitivity and the cost-efficient production are addressed. For higher sensitivity, the design of the sensor in shape and material has to be combined with optimal enhancement strategies. Plasmonic nanoparticles from bottom-up synthesis with a post-synthetic processing show a high potential for cost efficient sensor production. Regarding the measurement principle, LSPRi offers a large potential for multiplex sensors and can provide a high-throughput as well as highly paralleled sensing. The main trends are expected towards optimal LSPR concepts which represent cost-efficient and robust point-of-care solutions, and the use of multiplexed devices for clinical applications. PMID- 29431526 TI - The potential role of statins in treating liver disease. AB - INTRODUCTION: Statins are commonly use for the management of dyslipidemia, worldwide. Various studies have demonstrated that statins offer significant reduction in the risk of cardiovascular morbidity and mortality. However, this class of drugs has been implicated in potential liver toxicity, thus has been considered as a 'forbidden-drug' in patients with increased liver enzymes. Areas covered: Studies have shown that statins might offer clinical benefits in the setting of viral hepatitis, progression of cirrhosis, and hepatocellular carcinoma. More importantly, this class of drugs was shown to ameliorate liver histological (in both imaging and biopsy studies) and functional alterations in patients with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. In addition, two large survival studies have demonstrated reduction in the risk for cardiovascular events with statin use in patients with elevated transaminase levels at baseline. Expert commentary: These benefits were of greater extent compared with patients with normal liver function tests at baseline. However, current international guidelines seem to neglect these findings and are not including statins in the management algorithm of patients with non-alcoholic fatty liver disease or steatohepatitis. Future randomized studies providing biopsy-proven benefits will establish the use of statins in the prevention of cardiovascular events and therapeutic algorithm of these patients. PMID- 29431527 TI - Role of cardiac electronic implantable device in the stratification and management of embolic risk of silent atrial fibrillation: are all atrial fibrillations created equal? AB - INTRODUCTION: Ischemic strokes may be associated with atrial fibrillation (AF). AF detection is critical in ischemic stroke survivors, often recommending a switch from antiplatelet therapy to oral anticoagulants for secondary prevention. Areas covered: Cardiac implantable electronic devices (CIED) with their long-term recording capability allows to document AF and to quantify the arrhythmia burden. Recent series in pacemaker and implantable cardioverter-defibrillator (ICD) recipients with no prior stroke showed that short episodes of AF increased stroke risk compared with those without AF recorded. Detection of AF by CIEDs represent a unique opportunity for promp prevention of embolic risk in silent AF. It will be attractive to identify AF before a stroke occurs. Expert commentary: The purpose of this article is to review the role of CIED to detect AF, to quantify the role of AF burden, and to guide primary and secondary stroke prevention. PMID- 29431528 TI - Targeting the exposome: does correcting vitamin D deficiency have potential to treat and prevent asthma? PMID- 29431529 TI - The relationship between sense of community belonging and self-rated mental health among Canadians with mental or substance use disorders. AB - BACKGROUND: One-third of Canadians meet the criteria for a mental or substance use disorder at some point in their lifetime. While prevention and treatment efforts have been focused on the individual, studies suggest the importance of incorporating social and community factors. AIMS: This study investigates the relationship between community belonging and self-rated mental health among Canadians with mental or substance use disorders. METHODS: The Canadian Community Health Survey-Mental Health (2012) is a nationally representative survey of Canadians aged 15 years and older (n = 25,113). The present analytic sample is comprised of respondents reporting a mental or substance use disorder in the previous 12 months (n = 2628). The relationship between community belonging and self-rated mental health is depicted with a multivariable multinomial logistic regression model. RESULTS: Self-rated mental health was reported as follows: poor or fair (38.1%); good (33.7%); and very good or excellent (28.2%). In the multivariable multinomial model, a positive relationship was observed. Those reporting very strong compared to very weak community belonging had an increased odds of better mental health. CONCLUSIONS: Findings indicate the importance of social and community-based interventions to effectively engage and retain individuals in services for the prevention and treatment of mental and substance use disorders. PMID- 29431530 TI - Does oophorectomy reduce breast cancer mortality for BRCA mutation carriers after breast cancer? PMID- 29431531 TI - Effect of Human Placental Extract Treatment on Random-Pattern Skin Flap Survival in Rats. AB - BACKGROUND: Human placental extract (HPE), prepared from the placentas of healthy, postpartum females, displays various physiological activities, including antioxidative properties. In this study, a dorsal skin flap model was used to investigate the effect of HPE on flap viability in rats. MATERIALS AND METHODS: Forty male Sprague-Dawley rats underwent random-pattern skin flap surgeries. The animals were randomly divided among a control group and three treatment groups (localized injection (LI), 10 mg/kg/d localized HPE injections; low-dose treatment (LT), 10 mg/kg/d systemic HPE injections; high-dose treatment (HT), 40 mg/kg/d systemic HPE injections). Surviving skin flap areas were measured 7 days after surgery and tissue samples were stained with hematoxylin and eosin; vascular endothelial growth factor expression was determined immunohistochemically. To evaluate the antioxidant and antiapoptotic effects of HPE, malondialdehyde, glutathione peroxidase, and caspase-3 levels were examined. RESULTS: Seven days after surgery, HPE-treated animals had significantly reduced necrotic areas, rats receiving the highest HPE dose demonstrated the greatest flap survival. In the HPE groups, the histopathological scores were lower than for the control group. Immunohistochemistry showed markedly more numerous vascular endothelial growth factor-positive cells in the HT group than in the C group. Malondialdehyde levels were significantly lower and glutathione peroxidase levels were higher in the HT group than in the C group. HPE treatment significantly inhibited apoptosis by lowering caspase-3 activity. CONCLUSIONS: HPE treatment yielded positive effects on flap survival, due to its antioxidant and antiapoptotic properties. These results suggest a new therapeutic approach for enhancing flap viability and accelerating wound repair. PMID- 29431532 TI - A 29-year analysis of acute peak salicylate concentrations in fatalities reported to United States poison centers. AB - BACKGROUND/OBJECTIVES: The threshold salicylate concentration commonly recommended to initiate extracorporeal elimination, in the absence of significant end-organ toxicity, is 100 mg/dL. Unfortunately, the grade of evidence to support this decision is low. Our primary aim is to describe highest reported salicylate concentrations in patients who died from acute salicylate ingestions. Our secondary aim is to determine if age or coingestants varied with highest reported salicylate concentration. METHODS: We analyzed acute salicylate fatalities reported to the National Poison Data System (NPDS) between 1 January 1986 and 31 December 2014. Included were patients who died during the index hospitalization and for which acute salicylate toxicity was the primary cause of death. We used descriptive statistics with standard deviations (SD) or 95% confidence intervals (CI) where appropriate. We created a general linear model that evaluated the association of age and coingestions with salicylate concentrations. We divided the patients into age quartiles to assess a possible interaction between age and salicylate concentration. RESULTS: We identified 602 acute salicylate fatalities that fit inclusion criteria. The mean peak reported fatal salicylate concentration across all age groups was 99.19 mg/dL (+/- 50.2 mg/dL). The median peak fatal salicylate concentration was 97.0 mg/dL. The oldest quartile had a lower mean concentration (age >57 years; 90.4 mg/dL) than the youngest quartile (age <30 years; 111.6 mg/dL, mean difference 21.2 mg/dL, 95%CI 6.1-36.3). Fatalities with a coingestant had a lower mean concentration of 91.5 mg/dL compared to 104.8 mg/dL among those ingesting salicylates alone (mean difference 13.4 mg/dL, 95%CI 21.4-5.3). Increasing age and the presence of any coingestions were negatively associated with fatal concentrations (estimates; 95%CI 0.41; 0.61 0.021 and -14.43; 22.45-6.42, respectively). When opioids were a coingestant, mean concentration was 72.8 (mean difference 32.1 95%CI 23.1-41.1). CONCLUSIONS: Using the current recommended hemodialysis threshold of 100 mg/dL, more than half of the patients would be deprived of this critical life-saving therapy. Additionally, increasing age and ingestion of other substances, especially opioids, are associated with lower peak fatal salicylate concentrations. A prospective, randomized controlled trial considering salicylate concentrations and other clinical factors may provide further guidance for hemodialysis. PMID- 29431533 TI - Bright-field in situ hybridization detects gene alterations and viral infections useful for personalized management of cancer patients. AB - INTRODUCTION: Bright-field in situ hybridization (ISH) methods detect gene alterations that may improve diagnostic precision and personalized management of cancer patients. Areas covered: This review focuses on some bright-field ISH techniques for detection of gene amplification or viral infection that have already been introduced in tumor pathology, research and diagnostic practice. Other emerging ISH methods, for the detection of translocation, mRNA and microRNA have recently been developed and need both an optimization and analytical validation. The review also deals with their clinical applications and implications on the management of cancer patients. Expert commentary: The technology of bright-field ISH applications has advanced significantly in the last decade. For example, an automated dual-color assay was developed as a clinical test for selecting cancer patients that are candidates for personalized therapy. Recently an emerging bright-field gene-protein assay has been developed. This method simultaneously detects the protein, gene and centromeric targets in the context of tissue morphology, and might be useful in assessing the HER2 status particularly in equivocal cases or samples with heterogeneous tumors. The application of bright-field ISH methods has become the gold standard for the detection of tumor-associated viral infection as diagnostic or prognostic factors. PMID- 29431534 TI - Organization of Dietary Control for Nutrition-Training Intervention Involving Periodized Carbohydrate Availability and Ketogenic Low-Carbohydrate High-Fat Diet. AB - The authors describe the implementation of a 3-week dietary intervention in elite race walkers at the Australian Institute of Sport, with a focus on the resources and strategies needed to accomplish a complex study of this scale. Interventions involved: traditional guidelines of high carbohydrate (CHO) availability for all training sessions; a periodized CHO diet which integrated sessions with low and high CHO availability within the same total CHO intake; and a ketogenic low-CHO high-fat diet. Seven-day menus and recipes were constructed for a communal eating setting to meet nutritional goals as well as individualized food preferences and special needs. Menus also included nutrition support before, during, and after exercise. Daily monitoring, via observation and food checklists, showed that energy and macronutrient targets were achieved. Diets were matched for energy (~14.8 MJ/d) and protein (~2.1 g.kg-1.day-1) and achieved desired differences for fat and CHO, with high CHO availability and periodized CHO availability: CHO = 8.5 g.kg-1.day-1, 60% energy, fat = 20% of energy and low-CHO high-fat diet: 0.5 g.kg-1.day-1 CHO, fat = 78% energy. There were no differences in micronutrient intake or density between the high CHO availability and periodized CHO availability diets; however, the micronutrient density of the low-CHO high-fat diet was significantly lower. Daily food costs per athlete were similar for each diet (~AU$ 27 +/- 10). Successful implementation and monitoring of dietary interventions in sports nutrition research of the scale of the present study require meticulous planning and the expertise of chefs and sports dietitians. Different approaches to sports nutrition support raise practical challenges around cost, micronutrient density, accommodation of special needs, and sustainability. PMID- 29431535 TI - Differences in the Postprandial Release of Appetite-Related Hormones Between Active and Inactive Men. AB - Active, as opposed to inactive, individuals are able to adjust their energy intake after preloads of different energy contents. The mechanisms responsible for this remain unknown. This study examined differences in plasma concentration of appetite-related hormones in response to breakfasts of different energy contents, between active and inactive men. Sixteen healthy nonobese (body mass index = 18.5-27 kg/m2) adult males (nine active and seven inactive) participated in this study. Participants were given a high-energy (570 kcal) or a low-energy (205 kcal) breakfast in a random order. Subjective feelings of appetite and plasma concentrations of active ghrelin, active glucagon-like peptide-1, total peptide YY (PYY), cholecystokinin, and insulin were measured in fasting and every 30 min up to 2.5 hr, in response to both breakfasts. Mixed analysis of variance (fat mass [in percentage] as a covariate) revealed a higher concentration of active ghrelin and lower concentration of glucagon-like peptide-1, and cholecystokinin after the low-energy breakfast (p < .001 for all). Postprandial concentration of PYY was greater after the high energy compared with the low energy, but for inactive participants only (p = .014). Active participants had lower postprandial concentrations of insulin than inactive participants (p < .001). Differences in postprandial insulin between breakfasts were significantly lower in active compared with inactive participants (p < .001). Physical activity seems to modulate the postprandial plasma concentration of insulin and PYY after the intake of breakfasts of different energy contents, and that may contribute, at least partially, to the differences in short-term appetite control between active and inactive individuals. PMID- 29431536 TI - Multiday Pomegranate Extract Supplementation Decreases Oxygen Uptake During Submaximal Cycling Exercise, but Cosupplementation With N-acetylcysteine Negates the Effect. AB - Pomegranate extract (POMx) has been suggested as an ergogenic aid due to its rich concentration of polyphenols, which are proposed to enhance nitric oxide bioavailability, thereby improving the efficiency of oxygen usage and, consequently, endurance exercise performance. Although acute POMx supplementation improves aerobic exercise performance in untrained individuals, trained athletes appear to require chronic supplementation for a similar effect. Furthermore, the combination of POMx with a thiol antioxidant may prove more effective than POMx alone, due to the protective effects of thiols on nitric oxide. Thus, this study hypothesized that multiday POMx supplementation would decrease the oxygen uptake (VO2) required by trained cyclists to perform submaximal exercise and increase performance during a time trial, and that thiol (N-acetylcysteine [NAC]) cosupplementation would enhance these effects. Eight cyclists completed four 8 day supplementation periods: POMx only, NAC only, POMx + NAC (BOTH), and placebo. Following supplementation, they performed submaximal cycling and a 5-min time trial, with VO2 and muscle oxygen saturation (SmO2) being recorded. A three-way (POMx * NAC * Intensity) repeated-measures analysis of variance with a Fisher's least significant difference post hoc assessment was performed for dependent variables (p <= .05). VO2 during submaximal exercise was reduced with POMx versus placebo (-2.6 ml.min-1.kg-1, p = .009) and BOTH (-2.5 ml.min-1.kg-1, p < .05) and increased with NAC (+1.9 ml.min-1.kg-1, p < .03), despite no main effect of treatment on SmO2 or performance. It appears that POMx's high polyphenol content reduced the VO2 required during submaximal exercise. However, NAC cosupplementation annulled this effect; thus, NAC may interact with nitric oxide to reduce its bioavailability. PMID- 29431537 TI - Workload, Fatigue, and Muscle Damage in an Under-20 Rugby Union Team Over an Intensified International Tournament. AB - PURPOSE: To examine the effects of an intensified tournament on workload, perceptual and neuromuscular fatigue, and muscle-damage responses in an international under-20 rugby union team. METHODS: Players were subdivided into a high-exposure group (HEG, n = 13) and a low-exposure group (LEG, n = 11) according to match-play exposure time. Measures monitored over the 19-d period included training session (n = 10) and match (n = 5) workload determined via global positioning systems and session rating of perceived exertion. Well-being scores, countermovement jump height performance, and blood creatine kinase concentrations were collected at various time points. RESULTS: Analysis of workload cumulated across the tournament entirety for training and match play combined showed that high-speed running distance was similar between groups, while a very likely larger session rating of perceived exertion load was reported in HEG vs LEG. In HEG, high-speed activity fluctuated across the 5 successive matches, albeit with no clear trend for a progressive decrease. No clear tendency for a progressive decrease in well-being scores prior to or following matches was observed in either group. In HEG, trivial to possibly small reductions in postmatch countermovement jump performance were observed, while unclear to most likely moderate increases in prematch blood creatine kinase concentrations occurred until prior to match 4. CONCLUSIONS: The magnitude of match-to-match changes in external workload, perceptual and neuromuscular fatigue, and muscle damage was generally unclear or small. These results suggest that irrespective of exposure time to match play players generally maintained performance and readiness to play across the intensified tournament. These findings support the need for holistic systematic player-monitoring programs. PMID- 29431538 TI - The Use of Microtechnology to Monitor Collision Performance in Professional Rugby Union. AB - PURPOSE: To determine if microtechnology-derived collision loads discriminate between collision performance and compare the physical and analytical components of collision performance between positional groups. METHODS: Thirty-seven professional male rugby union players participated in this study. Collision events from 11 competitive matches were coded using specific tackle and carry classifications based on the ball-carrier's collision outcome. Collisions were automatically detected using 10 Hz microtechnology units. Collision events were identified, coded (as tackle or carry), and timestamped at the collision contact point using game analysis software. Attacking and defensive performances of 1609 collision events were analyzed. RESULTS: Collision loads were significantly greater during dominant compared with neutral and passive collisions (P < .001; effect size [ES] = 0.53 and 0.80, respectively), tackles (P < .0001; ES = 0.60 and 0.56, respectively), and carries (P < .001; ES = 0.48 and 0.79, respectively). Overall, forwards reported a greater number and frequency of collisions but lower loads per collision and velocities at collision point than did backs. Microtechnology devices can also accurately, sensitively, and specifically identify collision events (93.3%, 93.8%, and 92.8%, respectively). CONCLUSION: Microtechnology is a valid means of discriminating between tackle and carry performance. Thus, microtechnology-derived collision load data can be utilized to track and monitor collision events in training and games. PMID- 29431539 TI - Male Flat Jockeys Do Not Display Deteriorations in Bone Density or Resting Metabolic Rate in Accordance With Race Riding Experience: Implications for RED-S. AB - Despite consistent reports of poor bone health in male jockeys, it is not yet known if this is a consequence of low energy availability or lack of an osteogenic stimulus. Given the rationale that low energy availability is a contributing factor in low bone health, we tested the hypothesis that both hip and lumbar bone mineral density (BMD) should progressively worsen in accordance with the years of riding. In a cross-sectional design, male apprentice (n = 17) and senior (n = 14) jockeys (matched for body mass and fat-free mass) were assessed for hip and lumbar spine BMD, as well as both measured and predicted resting metabolic rate (RMR). Despite differences (p < .05) in years of race riding (3.4 +/- 2 vs. 16.3 +/- 6.8), no differences were apparent (p > .05) in hip (-0.9 +/- 1.1 vs. -0.8 +/- 0.7) and lumbar Z-scores (-1.3 +/- 1.4 vs. -1.5 +/ 1) or measured RMR (1,459 +/- 160 vs. 1,500 +/- 165 kcal/day) between apprentices and senior jockeys, respectively. Additionally, years of race riding did not demonstrate any significant correlations (p > .05) with either hip or lumbar spine BMD. Measured RMR was also not different (p > .05) from predicted RMR in either apprentice (1,520 +/- 44 kcal/day) or senior jockeys (1,505 +/- 70 kcal/day). When considered with previously published data examining underreporting of energy intake and direct assessments of energy expenditure, we suggest that low BMD in jockeys is not due to low energy availability per se but rather the lack of an osteogenic stimulus associated with riding. PMID- 29431540 TI - Pharmacokinetic/pharmacodynamic drug evaluation of enzalutamide for treating prostate cancer. AB - INTRODUCTION: Enzalutamide is the first approved second-generation androgen receptor (AR) antagonist in the treatment of metastatic castration-resistant prostate cancer (mCRPC) with or without docetaxel-based chemotherapy. Over the past 5 years, a number of attempts were made to determine the efficacy of enzalutamide in the different clinical settings. Areas covered: A literature search was performed at the PubMed, Embase, and Web of Science database to collect the most relevant and impactful studies, including basic science investigations, clinical trials, and reviews. This article focuses on the pharmacology, efficacy, tolerability, and future perspective of enzalutamide. Expert opinion: The treatment paradigm of CRPC has been dramatically challenged of late. Enzalutamide are in wide use because of its favorable efficacy and safety, but primary or acquired resistance to the drug will eventually develop. Further studies are thus necessary to identify appropriate patients who can achieve apparent benefits from enzalutamide alone or in combination with other drugs. PMID- 29431541 TI - An update on the use of Raman spectroscopy in molecular cancer diagnostics: current challenges and further prospects. AB - INTRODUCTION: Cancer is responsible for an extraordinary burden of disease, affecting 90.5 million people worldwide in 2015. Outcomes for these patients are improved when the disease is diagnosed at an early, or even precancerous, stage. Raman spectroscopy is demonstrating results that show its ability to detect the molecular changes that are diagnostic of precancerous and cancerous tissue. This review highlights the new advances occurring in this domain. Areas covered: PubMed searches were undertaken to identify new research in the utilisation of Raman spectroscopy in cancer diagnostics. The areas in which Raman spectroscopy is showing promise are covered, including improving the accuracy of identifying precancerous changes, using the technology in real time, in vivo modalities, the search for a biomarker to aid potential screening and predicting the response of the cancer to the treatment regimen. Expert commentary: Many of the examples in this review are focused on Barrett's oesophagus and oesophageal adenocarcinoma as this is my area of expertise and perfectly exemplifies where Raman spectroscopy could be utilised in clinical practise. The authors discuss the areas where they believe current knowledge is lacking and how Raman spectroscopy could answer the dilemmas that are still faced in the management of cancer. PMID- 29431542 TI - Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters. AB - INTRODUCTION: The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known. Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies. Also, relevant pharmacodynamic considerations in obesity are discussed. Expert opinion: Over the last two decades, increased knowledge is generated on PK and PD in obesity. Future research should focus on filling in the knowledge gaps that remain, especially in connecting obesity-related physiological changes with changes in PK and/or PD and vice versa. Ultimately, this knowledge can be used to develop physiologically based PK and PD models on the basis of quantitative systems pharmacology principles. Moreover, efforts should focus on thorough prospective evaluation of developed model-based doses with subsequent implementation of these dosing recommendations in clinical practice. PMID- 29431543 TI - High flow nasal oxygen therapy utilization: 7-year experience at a community teaching hospital. AB - OBJECTIVE: To examine the use of high flow nasal cannula oxygen therapy (HFNC) between 2008 and 2014 in patients 18 years or older at a community teaching hospital. METHODS: Yearly utilization rates of HFNC, noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) were calculated among admissions with a set of cardiopulmonary diagnoses (heart failure, COPD, asthma or pneumonia). RESULTS: Among the 41,711 admissions with at least one of the above cardiopulmonary condition, HFNC was utilized in 1,128 or 27.0/1000; NIV was used in an average of 169/1000 and IMV in 231/1000. HFNC was accompanied by IMV or NIV 71.3% of the time. From 2008 to 2014 HFNC utilization increased an average of 17.5% annually; NIV increased by 10.2% annually while IMV's utilization increased by 1.6% annually. The highest rate of change in HFNC use was among admissions with pneumonia and those with COPD. CONCLUSION: HFNC utilization increased steadily over a 7-year period at our hospital. Frequently, HFNC therapy was used in combination with other ventilatory modes to support patients' respiration. Similar with other technologies in healthcare, the uptake of HFNC has preceded the evidence from robust clinical trials. PMID- 29431544 TI - Monitoring Training Load and Well-Being During the In-Season Phase in National Collegiate Athletic Association Division I Men's Basketball. AB - PURPOSE: To characterize the weekly training load (TL) and well-being of college basketball players during the in-season phase. METHODS: Ten (6 guards and 4 forwards) male basketball players (age 20.9 [0.9] y, stature 195.0 [8.2] cm, and body mass 91.3 [11.3] kg) from the same Division I National Collegiate Athletic Association team were recruited to participate in this study. Individualized training and game loads were assessed using the session rating of perceived exertion at the end of each training and game session, and well-being status was collected before each session. Weekly changes (%) in TL, acute-to-chronic workload ratio, and well-being were determined. Differences in TL and well-being between starting and bench players and between 1-game and 2-game weeks were calculated using magnitude-based statistics. RESULTS: Total weekly TL and acute to-chronic workload ratio demonstrated high week-to-week variation, with spikes up to 226% and 220%, respectively. Starting players experienced a higher (most likely negative) total weekly TL and similar (unclear) well-being status compared with bench players. Game scheduling influenced TL, with 1-game weeks demonstrating a higher (likely negative) total weekly TL and similar (most likely trivial) well-being status compared with 2-game weeks. CONCLUSIONS: These findings provide college basketball coaches information to optimize training strategies during the in-season phase. Basketball coaches should concurrently consider the number of weekly games and player status (starting vs bench player) when creating individualized periodization plans, with increases in TL potentially needed in bench players, especially in 2-game weeks. PMID- 29431545 TI - Oxidative and nitrative stress-related changes in human lens epithelial cells following exposure to X-rays. AB - PURPOSE: There is limited understanding of the mechanistic effects of ionizing radiation (IR) exposure in cataract formation. In this study, we explored the effects of IR on reactive oxygen/nitrogen species (ROS and RNS) generation in human lens epithelial (HLE) cells as an early key event to long-term damage. MATERIALS AND METHODS: HLE cell-line was exposed to X-rays at varied doses (0-5 Gy) and dose-rates. Cell lysates and supernatants were collected 20 h post exposure and analysed for viability, cell cycling and metabolites of ROS (p, m-, o-, tyrosines, 3-chlorotyrosine (cl-tyrosine), 8-hydroxy deoxyguanosine, (8-OH dG) and RNS (3-nitrotyrosine). RESULTS AND CONCLUSIONS: HLE cell-line exhibited a bi-phasic response in terms of cell viability, ROS and RNS profiles. At doses <0.5 Gy, ROS and RNS levels were lower than control and at higher doses (>0.5 Gy) a steady increase was observed in each metabolite. This response was observed irrespective of dose-rate. Among the associations tested, cl, p, m-tyrosine and 3 nitrotyrosine revealed changes (p < .05) at 5 Gy compared exclusively to 0.05 and 0.01 Gy. In addition, dose-rate related differences were observed. Overall, the data suggests that ROS and RNS are key events in radiation induced damage and this response is dependent on the dose and dose-rate of IR exposure. PMID- 29431546 TI - The Trainability of Adolescent Soccer Players to Brief Periodized Complex Training. AB - PURPOSE: To investigate the effect of a complex, short-term strength/power training protocol on performance and body composition of elite early adolescent soccer players. METHODS: Twenty-two players (14-15 y) were randomly assigned to (1) an experimental group (N = 12; participated in a 5-wk training protocol with traditional multijoint power resistance exercises, Olympic-style lifts, plyometric drills, and speed work; 4 times per week) or (2) a control group (N = 10). Strength and power performance (jumping, speed, change of direction, repeated sprint ability, endurance, isokinetic strength of knee flexors and extensors, maximal strength in various lifts, and speed-endurance) were evaluated pretraining and posttraining. RESULTS: Cessation of training for 5 weeks in the control group induced a marked performance deterioration (~5%-20%). Training not only prevented strength performance deterioration but also increased it (~2% 30%). Endurance and repeated sprint ability declined to a smaller extent in experimental group compared with control group (15% vs 7.5%). Isometric strength and body composition remained unaltered in both groups. CONCLUSIONS: Results demonstrate that (1) young players exhibit a high level of trainability of their strength/power performance (but not endurance) in response to a short-term complex training protocol during early adolescence, (2) Olympic-style lifts are characterized by increased safety in this age group and appear to be highly effective, (3) lifts incorporating a hip thrust result in increased strength of both knee extensors and flexors, (4) cessation of training for only 5 weeks results in marked deterioration of strength/power and endurance performance, and (5) improvement of strength/power performance may be related to neural-based adaptation as body composition remained unaffected. PMID- 29431547 TI - Feasibility of the rapid assessment of avoidable blindness with diabetic retinopathy module (RAAB+DR) in industrialised countries: challenges and lessons learned in Hungary. AB - PURPOSE: To present experiences gained during the planning, implementation, and practical performance of the rapid assessment of avoidable blindness with diabetic retinopathy module (RAAB+DR) in an established market economy. METHODS: A total of 3523 people aged 50 years or older were examined at their homes in 105 randomly selected clusters in Hungary. During the 4-month-long field work, five teams visited the clusters. Each team was composed of a senior ophthalmic resident or eye specialist, a nurse, an assistant, a driver, and a local guide. The local guides were found through local mayors of the towns or villages or other local leaders. RESULTS: Of all 105 clusters, 41% were completed in 1 day and 59% required a longer stay. The shortest daily examination time was 3.5 hours and the longest was 10 hours. Altogether, 7.6% of the enumeration areas needed revisit, mainly due to insufficient preparatory work and absence of the subjects. The best local guides were the local government workers, health visitors, and general practitioner (GP) nurses. Refusal of pupillary dilatation was relatively high and varied greatly among the study groups (7.7-43.8%). CONCLUSION: The performance of a RAAB+DR study in a well-industrialised country is difficult, but may be successful. The most critical factor for success is an excellent local guide who is able to achieve participation of the people. The results of the RAAB are a solid basis for the development of a national programme for universal eye health and to prepare active media campaigns. PMID- 29431548 TI - Impact of Energy Availability, Health, and Sex on Hemoglobin-Mass Responses Following Live-High-Train-High Altitude Training in Elite Female and Male Distance Athletes. AB - PURPOSE: The authors investigated the effects of sex, energy availability (EA), and health status on the change in hemoglobin mass (DeltaHbmass) in elite endurance athletes over ~3-4 wk of live-high-train-high altitude training in Flagstaff, AZ (2135 m; n = 27 women; n = 21 men; 27% 2016 Olympians). METHODS: Precamp and postcamp Hbmass (optimized carbon monoxide rebreathing method) and iron status were measured, EA was estimated via food and training logs, and a Low Energy Availability in Females Questionnaire (LEAFQ) and a general injury/illness questionnaire were completed. Hypoxic exposure (h) was calculated with low (<500 h), moderate (500-600 h), and high (>600 h) groupings. RESULTS: Absolute and relative percentage DeltaHbmass was significantly greater in women (6.2% [4.0%], P < .001) than men (3.2% [3.3%], P = .008). %DeltaHbmass showed a dose-response with hypoxic exposure (3.1% [3.8%] vs 4.9% [3.8%] vs 6.8% [3.7%], P = .013). Hbmasspre was significantly higher in eumenorrheic vs amenorrheic women (12.2 [1.0] vs 11.3 [0.5] g/kg, P = .004). Although statistically underpowered, %DeltaHbmass was significantly less in sick (n = 4, -0.5% [0.4%]) vs healthy (n = 44, 5.4% [3.8%], P < .001) athletes. There were no significant correlations between self-reported iron intake, sex hormones, or EA on Hbmass outcomes. However, there was a trend for a negative correlation between LEAFQ score and %DeltaHbmass (r = -.353, P = .07). CONCLUSIONS: The findings confirm the importance of baseline Hbmass and exposure to hypoxia on increases in Hbmass during altitude training, while emphasizing the importance of athlete health and indices of EA on an optimal baseline Hbmass and hematological response to hypoxia. PMID- 29431549 TI - Self-Paced Cycling Improves Cognition on Institutionalized Older Adults Without Known Cognitive Impairment: A 15-Month Randomized Controlled Trial. AB - This study aimed at identifying the effects of self-paced cycling on the cognitive and functional status and fall risk on institutionalized older adults without cognitive impairment. A total of 39 individuals were randomly assigned to an exercise group or to a control group. The exercise group participants cycled at their self-selected intensity at least for 15 min daily during 15 months. The control group participants performed recreational activities. The Mini-Mental State Examination, Fuld object memory evaluation, and symbol digit modality test were used for cognitive assessments. The Katz index, the timed "Up & Go" test, and the World Health Organization questionnaire were used to assess functional independence, mobility, and fall risk. Significant improvements were observed in the exercise group for global cognition and attention, visual scanning, and processing speed. Long-term self-paced cycling training seems to have a protective effect on cognitive status and attention, visual scanning, and processing speed in older institutionalized individuals. PMID- 29431550 TI - In silico analysis of anti-leukemia immune response and immune evasion in acute myeloid leukemia. PMID- 29431551 TI - Lead-interacting proteins and their implication in lead poisoning. AB - Lead is an important heavy metal used worldwide in several applications, especially in industry. People exposed to lead can develop a wide range of symptoms associated with lead poisoning. Many effects of lead poisoning are reported in the literature, showing a compromising of whole body health, with symptoms related to cardiovascular, immune, bone, reproductive, hematological, renal, gastrointestinal, and nervous system. However, the molecular lead targets as well as the pathways affected by lead poisoning are not completely described. The aim of this study was to construct a map of metabolic pathways impaired in lead poisoning by evaluating which biomolecules are directly affected by lead. Through manual literature curation, we identified proteins which physically interact with lead and subsequently determined the metabolic pathways those proteins are involved with. At total, we identified 23 proteins involved with heme synthesis, calcium metabolism, neurotransmission, among other biological systems, which helps to understand the wide range of lead-poisoning symptoms. PMID- 29431552 TI - Porcine interleukin-6 enhances the expression of CYP2C33 through a constitutive androstane receptor/retinoid X receptor-mediated pathway. AB - Cytochrome P450, which is expressed in humans and other animals, is a superfamily of drug-metabolizing enzymes that play important roles in the metabolism of endogenous and xenobiotic substrates via oxidation, peroxidation and reduction. Of endogenous substrates, interleukin (IL)-6 is a crucial cytokine involved in inflammation in the liver. The present study aims to elucidate the mechanisms through which IL-6 modulates cytochrome P450 expression. CYP2C33 expression was found to be increased in HepLi cells and primary porcine hepatocytes treated with IL-6 in a concentration-dependent manner. IL-6 treatment also increased the expression of the transcriptional regulators, constitutive androstane receptor (CAR) and pregnane X receptor. Overexpression of CAR promoted CYP2C33 expression at the mRNA and protein levels, whereas knockdown of CAR by small interfering RNA reduced CYP2C33 expression. Luciferase assays showed that IL-6 treatment of HepLi cells and primary porcine hepatocytes increased CYP2C33 promoter activity. Co immunoprecipitation and western blotting demonstrated that CAR and RXR could form heterodimers. IL-6 affects CYP2C33 expression through CAR/retinoid X receptor (RXR) heterodimers. PMID- 29431553 TI - Quantitative assessment of the sensitivity of dormant AML cells to the BAD mimetics ABT-199 and ABT-737. AB - Cells from patients with acute myeloid leukemia (AML) that remain dormant and protected by stromal cells may escape effects of chemotherapy. We modeled dormancy in vitro and investigated the ability of Bcl-2 inhibitors ABT-199 and ABT-737 to overcome chemoprotection of dormant cells. CD34-enriched primary AML cells with aberrant leukemia-associated phenotypes (LAPs) were cultured on stromal cells. The chemosensitivity of dormant (PKH26high), CD34+, LAP+ cells was ascertained by 5-colour flow cytometric counting after 12 d. The PKH26high, CD34+, LAP + subset retained clonogenic capacity. The dormant fraction was completely resistant to Ara-C (p = .007). However, ABT-199 and ABT-737 were able to reduce the dormant fraction by 84% and 80%, respectively, of their effects on proliferating counterparts. In conclusion, we have elaborated a system for quantifying chemosensitivity in LAP+ dormant leukemia cells, thought to contribute to disease relapse, and shown sensitivity of dormant LAP+ cells to ABT 199 and ABT-737 in this system. PMID- 29431554 TI - Development of an adverse outcome pathway for chemically induced hepatocellular carcinoma: case study of AFB1, a human carcinogen with a mutagenic mode of action. AB - Adverse outcome pathways (AOPs) are frameworks starting with a molecular initiating event (MIE), followed by key events (KEs) linked by KE relationships (KERs), ultimately resulting in a specific adverse outcome. Relevant data for the pathway and each KE/KER are evaluated to assess biological plausibility, weight of-evidence, and confidence. We aimed to describe an AOP relevant to chemicals directly inducing mutation in cancer critical gene(s), via the formation of chemical-specific pro-mutagenic DNA adduct(s), as an early critical step in tumor etiology. Such chemicals have mutagenic modes-of-action (MOA) for tumor induction. To assist with developing this AOP, Aflatoxin B1 (AFB1) was selected as a case study because it has a rich database and is considered to have a mutagenic MOA. AFB1 information was used to define specific KEs, KERs, and to inform development of a generic AOP for mutagen-induced hepatocellular carcinoma (HCC). In assessing the AFB1 information, it became clear that existing data are, in fact, not optimal and for some KEs/KERs, the definitive data are not available. In particular, while there is substantial information that AFB1 can induce mutations (based on a number of mutation assays), the definitive evidence the ability to induce mutation in the cancer critical gene(s) in the tumor target tissue - is not available. Thus, it is necessary to consider the patterns of results in the weight-of-evidence for KEs and KERs. It was important to determine whether there was sufficient evidence that AFB1 can induce the necessary critical mutations early in the carcinogenic process, which was the case. PMID- 29431555 TI - Current concepts in tumor imaging with whole-body MRI with diffusion imaging (WB MRI-DWI) in multiple myeloma and lymphoma. AB - Whole-body MRI (WB-MRI) with diffusion-weighted imaging (DWI) can now be used to stage and restage multiple myeloma (MM) and lymphoma. Magnetic resonance imaging (MRI) is the standard tool to detect BM involvement (BMI). The 2016 diagnostic criteria of the International Myeloma Working Group identify WB-MRI and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) as the most sensitive imaging techniques for detecting skeletal and extra skeletal MM invasion, respectively. Preliminary findings have also shown that WB MRI is better than CT and equal to PET/CT in staging aggressive lymphoma and Hodgkin lymphoma, whereas MRI is better for diagnosing BMI in patients with low grade lymphoma. Signal intensity (SI) and the apparent diffusion coefficient (ADC) are useful metrics to quantify the chemotherapy response in WB-MRI. PMID- 29431556 TI - The Fit Matters: Influence of Accelerometer Fitting and Training Drill Demands on Load Measures in Rugby League Players. AB - PURPOSE: To determine the relationship between drill type and accelerometer derived loads during various team-sport activities and examine the influence of unit fitting on these loads. METHODS: Sixteen rugby league players were fitted with microtechnology devices in either manufacturer vests or playing jerseys before completing standardized running, agility, and tackling drills. Two dimensional (2D) and 3-dimensional (3D) accelerometer loads (BodyLoadTM) per kilometer were compared across drills and fittings (ie, vest and jersey). RESULTS: When fitted in a vest, 2D BodyLoad was higher during tackling (21.5 [14.8] AU/km) than during running (9.5 [2.5] AU/km) and agility (10.3 [2.7] AU/km). Jersey fitting resulted in more than 2-fold higher BodyLoad during running (2D = 9.5 [2.7] vs 29.3 [14.8] AU/km, 3D = 48.5 [14.8] vs 111.5 [45.4] AU/km) and agility (2D = 10.3 [2.7] vs 21.0 [8.1] AU/km, 3D = 40.4 [13.6] vs 77.7 [26.8] AU/km) compared with a vest fitting. Jersey fitting also produced higher BodyLoad during tackling drills (2D = 21.5 [14.8] vs 27.8 [18.6] AU/km, 3D = 42.0 [21.4] vs 63.2 [33.1] AU/km). CONCLUSIONS: This study provides evidence supporting the construct validity of 2D BodyLoad for assessing collision/tackling load in rugby league training drills. Conversely, the large values obtained from 3D BodyLoad (which includes the vertical load vector) appear to mask small increases in load during tackling drills, rendering 3D BodyLoad insensitive to changes in contact load. Unit fitting has a large influence on accumulated accelerometer loads during all drills, which is likely related to greater incidental unit movement when units are fitted in jerseys. Therefore, it is recommended that athletes wear microtechnology units in manufacturer-provided vests to provide valid and reliable information. PMID- 29431557 TI - Four Square Step Test With Foam Is More Accurate Than Those Without Foam for Discriminating Between Older Adults With and Without Fall History. AB - OBJECTIVE: The aim was to compare the use of the four square step test (FSST) and the FSST with foam surface (FSST + foam) scores for discriminating between adults, faller older adults, and nonfaller older adults. METHODS: Fifty-four participants (18 for each group) were assessed using the FSST and FSST + foam. The area under the curve (AUC) of receiver operating characteristic curve was calculated and used to compare the accuracy of the tests. RESULTS: The FSST + foam was more accurate than FSST for discriminating between faller and nonfaller older adults (area under the curves were 0.765 and 0.725, respectively) and between nonfaller older adults and adults (area under the curves were 0.99 and 0.95, respectively). The cutoff score for discriminating between faller and nonfaller older adults was 11.21, with a sensitivity and specificity of 0.889 and 0.611, respectively. CONCLUSION: FSST + foam could be used as an alternative assessment for discriminating between adults, faller, and nonfaller older adults. PMID- 29431558 TI - Toxicity assessment of biological suspensions using the dielectric impedance spectroscopy technique. AB - PURPOSE: This article studies the variation of the electromagnetic parameters of a suspension of zebrafish (Danio rerio) embryos to assess its potential applications to toxicological and biomedical research areas. MATERIALS AND METHODS: For this purpose, the dielectric impedance spectroscopy technique is applied to a modified coaxial line enclosing the biological suspension to be characterized in the frequency range from 100 kHz to 100 MHz. The electrical parameters of the suspension under test were obtained by fitting the impedance spectra to the resulted from the simulation of the test fixture using finite elements (FE). RESULTS: Variation of the complex permittivity of the suspensions makes possible to identify viable and non-viable embryos after a toxic exposure, as well as different stages during the blastula period of embryonic development of the zebrafish. CONCLUSIONS: The approach presented here, combining experimental and simulation techniques, may provide a basis for a non-invasive method to assess toxicity in any biological suspension. PMID- 29431559 TI - The Effects of Filter Cutoff Frequency on Musculoskeletal Simulations of High Impact Movements. AB - Estimation of muscle forces through musculoskeletal simulation is important in understanding human movement and injury. Unmatched filter frequencies used to low pass filter marker and force platform data can create artifacts during inverse dynamics analysis, but their effects on muscle force calculations are unknown. The objective of this study was to determine the effects of filter cutoff frequency on simulation parameters and magnitudes of lower-extremity muscle and resultant joint contact forces during a high-impact maneuver. Eight participants performed a single-leg jump landing. Kinematics was captured with a 3D motion capture system, and ground reaction forces were recorded with a force platform. The marker and force platform data were filtered using 2 matched filter frequencies (10-10 Hz and 15-15 Hz) and 2 unmatched filter frequencies (10-50 Hz and 15-50 Hz). Musculoskeletal simulations using computed muscle control were performed in OpenSim. The results revealed significantly higher peak quadriceps (13%), hamstrings (48%), and gastrocnemius forces (69%) in the unmatched (10-50 Hz and 15-50 Hz) conditions than in the matched (10-10 Hz and 15-15 Hz) conditions (P < .05). Resultant joint contact forces and reserve (nonphysiologic) moments were similarly larger in the unmatched filter categories (P < .05). This study demonstrated that artifacts created from filtering with unmatched filter cutoffs result in altered muscle forces and dynamics that are not physiologic. PMID- 29431560 TI - Targeting the bone marrow microenvironment in acute leukemia. AB - Despite individual differences between certain leukemias, the overall survival rate in acute leukemia remains low at approximately 40%. Novel therapeutics, including targeted therapies like tyrosine kinase inhibitors, have been incorporated into treatment regimens, but most have failed at eradicating leukemic stem cells (LSCs). The causes of disease relapse, progression, and resistance to chemotherapy are as yet not entirely clear but thought to be linked to protection in the bone marrow microenvironment (BMM). In this review, we summarize current knowledge on the BMM in acute leukemias and examine the ongoing efforts to target the BMM, which include treatment strategies targeting (a) leukemia-BMM interactions, (b) leukemia-cell intrinsic pathways influenced by the BMM, and (c) direct BMM targeting strategies. It is likely that the future ploy against leukemia will involve these and other innovative strategies designed to eradicate the last remaining warrior - the LSC. PMID- 29431561 TI - Effects of Resistance Training of Peripheral Muscles Versus Respiratory Muscles in Older Adults With Sarcopenia Who are Institutionalized: A Randomized Controlled Trial. AB - This study compares the effects of two resistance training programs in peripheral and respiratory musculature on muscle mass and strength and physical performance and identifies the appropriate muscle mass parameter for assessing the intervention effects. Thirty-seven institutionalized older Spanish adults with sarcopenia were analyzed: control group (n = 17), respiratory muscle training group (n = 9), and peripheral muscle training group (n = 11). Measured outcomes were appendicular skeletal muscle mass (ASM/height2, ASM/weight, and ASM/BMI), isometric knee extension, arm flexion and handgrip strength, maximal inspiratory and expiratory pressures, and gait speed pre- and postintervention. Trained groups participated in a 12-week program and improved in maximum static inspiratory pressure, maximum static expiratory pressure, knee extension, and arm flexion (p < .05), whereas nonsignificant changes were found in gait speed and ASM indexes pre- and postintervention in the three groups. In conclusion, resistance training improved skeletal muscle strength in the studied population, and any ASM index was found to be appropriate for detecting changes after physical interventions. PMID- 29431562 TI - Ionizing radiation does not impair the mechanisms controlling genetic stability during T cell receptor gene rearrangement in mice. AB - PURPOSE: To determine whether low dose/low dose rate radiation-induced genetic instability may result from radiation-induced inactivation of mechanisms induced by the ATM-dependent DNA damage response checkpoint. To this end, we analysed the faithfulness of T cell receptor (TR) gene rearrangement by V(D)J recombination in DNA from mice exposed to a single dose of X-ray or chronically exposed to low dose rate gamma radiation. MATERIALS AND METHODS: Genomic DNA obtained from the blood or the thymus of wild type or Ogg1-deficient mice exposed to low (0.1) or intermediate/high (0.2-1 Gy) doses of radiation either by acute X-rays exposure or protracted exposure to low dose-rate gamma-radiation was used to analyse by PCR the presence of illegitimate TR gene rearrangements. RESULTS: Radiation exposure does not increase the onset of TR gene trans-rearrangements in irradiated mice. In mice where it happens, trans-rearrangements remain sporadic events in developing T lymphocytes. CONCLUSION: We concluded that low dose/low dose rate ionizing radiation (IR) exposure does not lead to widespread inactivation of ATM-dependent mechanisms, and therefore that the mechanisms enforcing genetic stability are not impaired by IR in developing lymphocytes and lymphocyte progenitors, including BM-derived hematopoietic stem cells, in low dose/low dose rate exposed mice. PMID- 29431563 TI - Changing role of bone marrow examination in the diagnosis of hematological malignancies. PMID- 29431565 TI - World Records in Half-Marathon Running by Sex and Age. AB - The relationship between age and elite marathon race times is well investigated, but little is known for half-marathon running. This study investigated the relationship between half-marathon race times and age in 1-year intervals by using the world single age records in half-marathon running and the sex difference in performance from 5 to 91 years in men and 5 to 93 years in women. We found a fourth-order polynomial relationship between age and race time for both women and men. Women achieve their best half-marathon race time earlier in life than men, 23.89 years compared with 28.13 years, but when using a nonlinear regression analysis, the age of the fastest race time does not differ between men and women, with 26.62 years in women and 26.80 years in men. Moreover, the sex difference in half-marathon running performance increased with advancing age. PMID- 29431564 TI - Transferring picture exchange requests to receptive identification for children with ASD. AB - The purpose of this study was to evaluate a procedure to transfer stimulus control from picture exchange requests to receptive identification. Three children with autism spectrum disorder (ASD) and absent receptive identification repertoires participated. An adapted alternating treatment design was used. During intervention, two high-preferred and two low-preferred targets were available during picture exchange requesting sessions. Participants requested primarily for one or both high-preferred targets. During receptive identification instructional sessions, one participant acquired one high-preferred target, one participant acquired all targets, and one participant demonstrated no improvements. Generalization to novel examples of targets was assessed pre- and post-intervention and programmed if necessary. One participant generalized his acquired high-preferred target without programming. Another participant generalized a high-preferred and a low-preferred target without programming, and acquired a high-preferred target with programming. Potential benefits of this intervention and suggestions for future research are presented. PMID- 29431566 TI - Levocarnitine for asparaginase-induced hepatic injury: a multi-institutional case series and review of the literature. AB - Asparaginase, an important treatment component for acute lymphoblastic leukemia (ALL), causes severe hepatotoxicity in some patients. Levocarnitine is a mitochondrial co-factor that can potentially ameliorate the mitochondrial toxicity of asparaginase. In this retrospective case series, we describe the clinical presentation and management of six pediatric and young adult patients (mean age 12.7, range 9-24 years) with ALL who developed Grade 3-4 hyperbilirubinemia following administration of asparaginase as part of induction/re-induction therapy. Five of these patients were treated with levocarnitine with subsequent improvement of hyperbilirubinemia, while one patient was given levocarnitine prophylactically during induction and developed Grade 3 hyperbilirubinemia, but did not require therapy adjustments or delays. Increased awareness in the pediatric oncology community regarding asparaginase associated hepatic toxicity and the potential role of levocarnitine in management is warranted. PMID- 29431567 TI - Deep spontaneous molecular remission in a patient with congenital acute myeloid leukemia expressing a novel MOZ-p300 fusion transcript. PMID- 29431568 TI - Characteristics of early acute respiratory distress syndrome in newly diagnosed acute myeloid leukemia. AB - Acute respiratory complications occur frequently during the early phase of acute myeloid leukemia (AML) but information on the most severe form, acute respiratory distress syndrome (ARDS), is lacking. We retrospectively analyzed 280 patients with newly diagnosed AML in order to describe the incidence, risk factors and early mortality associated with ARDS within 15 d. Univariate and then multivariate analysis were performed. ARDS developed in 9% of patients and was associated with 64% day-30 mortality. White blood cell count on admission was an independent risk factor for ARDS (OR = 1.007, 95% CI = 1.001-1.012, p = .012) with a moderate prediction ability (AUC 0.704, p = .001). Other variables were associated with ARDS in univariate but not in multivariate analysis: body mass index (p = .06), transfusions (p = .001) and sepsis (p < .0001). Leukemia specific complications and documented infections were the most frequent ARDS etiologies and were sometimes associated, with no clear distinctive temporal pattern. PMID- 29431569 TI - Selective effects of fenitrothion on murine splenic T-lymphocyte populations and cytokine/granzyme production. AB - The aim of this study was to investigate in vitro effects of fenitrothion (FNT) on mouse splenic lymphocytes. Here, naive mice had their spleens harvested and splenocytes isolated. After exposure to FNT for 48 hr: splenocyte viability was measured using a tetrazolium dye assay; cell phenotypes, i.e., B-cells (CD19+), T cells (CD3+), and T-cell subsets (CD4+ and CD8+), were quantified by flow cytometry; and, production of cytokines/granzyme-B was assessed via enzyme-linked immunosorbent assay. The ability for FNT to induce oxidative stress in the cells was evaluated by measuring hydroxyl radical (.OH) and malondialdehyde (MDA) production and changes in glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity. The results showed that FNT significantly inhibited splenocyte proliferation, and decreased production of interleukin (IL)-2, interferon gamma, IL-4, and granzyme B, but had no impact on IL-6 production. FNT also selectively decreased splenic T-cell levels but did not induce changes in CD19+ B-cells. Further, within the T-cell populations, percentages of CD3+, CD4+, and CD8+ T-cells (particularly CD8+ T-cells) were reduced. Lastly, FNT selectively increased MDA and .OH production and inhibited SOD and GSH-Px activities in the splenic lymphocytes. These findings suggest that, due to oxidative damage, FNT selectively inhibits splenic T-lymphocyte survival and cytokine/granzyme production in vitro. PMID- 29431570 TI - Levofloxacin-Loaded Nanoparticles Decrease Emergence of Fluoroquinolone Resistance in Escherichia coli. AB - Antimicrobial resistance is a major global health problem that is developed upon exposure of bacteria to antimicrobial agents, and, thus, reducing or eliminating the ability of the currently available antibacterial drugs to eradicate bacterial infections. The aim of the current study was to encapsulate levofloxacin (third generation fluoroquinolones) into chitosan (CS) nanoparticles, to evaluate the antibacterial potency of the nanosized drug, and to characterize the major genetic mutations associated with the exposure of bacteria to the levofloxacin loaded nanoparticle versus free levofloxacin. Three consecutive mutants were selected by stepwise exposure of one reference and two clinical Escherichia coli isolates to a series of progressively increasing concentrations of levofloxacin and the levofloxacin-loaded nanoparticles. Mutations in quinolone resistance determining region (QRDR) of gyrA and parC and regulators of AcrAB efflux pump (soxR, soxS and acrR) for all the selected-mutants were determined using polymerase chain reaction and sequencing. Mutants developed upon exposure to the nanosized drug had higher sensitivity to levofloxacin, compared with the levofloxacin-selected mutants. In addition, mutations in gyrA were observed in the levofloxacin first mutants, but in the nanosized levofloxacin second mutants. In the third mutants, an additional mutation in parC and mutations in the regulators were found only in levofloxacin-selected mutants. Loading of levofloxacin into the CS nanoparticles could increase the antibacterial activity of the drug and decrease the emergence of resistant mutants. To the best of our knowledge, this is the first study to explore the role of antimicrobial-loaded nanoparticles in the reduction of emergence of bacterial resistance. PMID- 29431571 TI - Cross-Cultural Adaptation of the Physician Orders for Life-Sustaining Treatment Form to Brazil. AB - BACKGROUND: The Physician Orders for Life-Sustaining Treatment (POLST) paradigm is considered one of the most important strategies to respect patients' values at the end of life in the United States. The cross-cultural adaptation of POLST entailed several methodological considerations, which may be informative for international researchers who may also consider bringing POLST to their countries as a means to promote care at the end of life that is consistent with patients' preferences. OBJECTIVE: To report the methods and outcome of the cross-cultural adaptation of the POLST form to Brazil. DESIGN: Cross-cultural adaptation study. SETTING/SUBJECTS: Twenty physicians and 10 patients at a university hospital participated in the pilot tests. RESULTS: The cross-cultural adaptation process included choosing which existing POLST form(s) to use as a source, deciding the intended reading level, which healthcare professionals should be allowed to sign the form, and consultation with attorneys, bioethicists, and members of the National POLST Paradigm Task Force. Pilot tests occurred in two stages using different approaches. First, 20 physicians were trained about POLST and asked for any unclear aspects related to the form. Second, trained investigators completed POLST forms after engaging in advance care planning conversations with 10 hospitalized patients or patients' surrogates. CONCLUSIONS: This report provides a basis for future cross-cultural adaptations of POLST to other countries. The authors hope such new adaptations will broaden the possibilities of research using POLST and also may promote wider provision of care at the end of life that is consistent with patients' preferences. PMID- 29431572 TI - MLK1 and MLK2 integrate gibberellins and circadian clock signaling to modulate plant growth. AB - The covalent histone modifications were associated with plant development. However, the function of histone modification factors involved in gibberellins (GAs) signaling pathway remains unclear. In recent study, we reported that histone modification factors MUT9p-LIKE KINASE1 (MLK1) and MLK2 coordinate GA and circadian clock signaling in hypocotyl elongation. MLK1 and MLK2 interact with the DELLA protein REPRESSOR OF ga1-3 (RGA), and antagonize the function of RGA to interact with CIRCADIAN CLOCK ASSOCIATED1 (CCA1), resulting in promoting hypocotyl elongation. In this addendum to the report, we presented and discussed the results related to the function of MLK1 and MLK2 in GA pathway. MLK1 and MLK2 interact with RGA, which is independent on 17-amino acid DELLA, TVHYNP, or Poly S/T/V motif, suggesting that MLK1 and MLK2 might have novel functions beyond the protein degradation. PMID- 29431573 TI - Top 10 Tips Palliative Care Clinicians Should Know About Radiation Oncology. AB - As palliative care (PC) moves upstream in the course of advanced illness, it is critical that PC providers have a broad understanding of curative and palliative treatments for serious diseases. Possessing a working knowledge of radiation therapy (RT), one of the three pillars of cancer care, is crucial to PC providers given RT's role in both the curative and palliative settings. This article provides PC providers with a primer on the vocabulary of RT; the team of people involved in the planning of RT; and common indications, benefits, and side effects of treatment. PMID- 29431574 TI - Dynamic Diffuse Optical Tomography for Monitoring Neoadjuvant Chemotherapy in Patients with Breast Cancer. AB - Purpose To identify dynamic optical imaging features that associate with the degree of pathologic response in patients with breast cancer during neoadjuvant chemotherapy (NAC). Materials and Methods Of 40 patients with breast cancer who participated in a longitudinal study between June 2011 and March 2016, 34 completed the study. There were 13 patients who obtained a pathologic complete response (pCR) and 21 patients who did not obtain a pCR. Imaging data from six subjects were excluded from the study because either the patients dropped out of the study before it was finished or there was an instrumentation malfunction. Two weeks into the treatment regimen, three-dimensional images of both breasts during a breath hold were acquired by using dynamic diffuse optical tomography. Features from the breath-hold traces were used to distinguish between response groups. Receiver operating characteristic (ROC) curves and sensitivity analysis were used to determine the degree of association with 5-month treatment outcome. Results An ROC curve analysis showed that this method could identify patients with a pCR with a positive predictive value of 70.6% (12 of 17), a negative predictive value of 94.1% (16 of 17), a sensitivity of 92.3% (12 of 13), a specificity of 76.2% (16 of 21), and an area under the ROC curve of 0.85. Conclusion Several dynamic optical imaging features obtained within 2 weeks of NAC initiation were identified that showed statistically significant differences between patients with pCR and patients without pCR as determined 5 months after treatment initiation. If confirmed in a larger cohort prospective study, these dynamic imaging features may be used to predict treatment outcome as early as 2 weeks after treatment initiation. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29431575 TI - Short interval overnight laser scanning suggest sub-circadian periodicity of tree turgor. AB - A recent study by Zlinszky et al., 1 uses high-resolution terrestrial laser scanning to investigate the variability of overnight movement of leaves and branches in vascular plants. This study finds among others that the investigated plants show periodic movements of around one centimetre in amplitude and 2-6 hour periodicity. Sub-circadian process dynamics of plants were so far not in focus of research, but here we compare the findings with other published cases of short term periodicity in leaf turgor, sap flow and especially trunk diameter. Several authors have noted overnight variations in these parameters within periods of several hours and in absence of environmental changes with similar dynamics. We revisit the unknown questions of short-term plant movement and make a suggestion for future research. PMID- 29431577 TI - What does "Diversity" Mean for Public Engagement in Science? A New Metric for Innovation Ecosystem Diversity. AB - Diversity is increasingly at stake in early 21st century. Diversity is often conceptualized across ethnicity, gender, socioeconomic status, sexual preference, and professional credentials, among other categories of difference. These are important and relevant considerations and yet, they are incomplete. Diversity also rests in the way we frame questions long before answers are sought. Such diversity in the framing (epistemology) of scientific and societal questions is important for they influence the types of data, results, and impacts produced by research. Errors in the framing of a research question, whether in technical science or social science, are known as type III errors, as opposed to the better known type I (false positives) and type II errors (false negatives). Kimball defined "error of the third kind" as giving the right answer to the wrong problem. Raiffa described the type III error as correctly solving the wrong problem. Type III errors are upstream or design flaws, often driven by unchecked human values and power, and can adversely impact an entire innovation ecosystem, waste money, time, careers, and precious resources by focusing on the wrong or incorrectly framed question and hypothesis. Decades may pass while technology experts, scientists, social scientists, funding agencies and management consultants continue to tackle questions that suffer from type III errors. We propose a new diversity metric, the Frame Diversity Index (FDI), based on the hitherto neglected diversities in knowledge framing. The FDI would be positively correlated with epistemological diversity and technological democracy, and inversely correlated with prevalence of type III errors in innovation ecosystems, consortia, and knowledge networks. We suggest that the FDI can usefully measure (and prevent) type III error risks in innovation ecosystems, and help broaden the concepts and practices of diversity and inclusion in science, technology, innovation and society. PMID- 29431576 TI - Serum Albumin Modulates the Bioactivity of Rosmarinic Acid. AB - Rosmarinic acid (RA) is a phenolic compound with biological activity. The objective of the present study was to investigate whether this compound kept its biological activity in the presence of proteins. For this purpose, bovine serum albumin (BSA) was used as a model protein, and the capacity of the RA to inhibit acetylcholinesterase (AChE) and affect antioxidant activity was evaluated in the absence and presence of BSA. A mixture of phenolic compounds containing RA, obtained from a medicinal plant was added to this study. The AChE inhibitory activity of RA was reduced by ~57% in the presence of BSA, while the antioxidant activity increased. These results lead to the investigation of the effect of RA on the BSA structure using Fourier transform infrared spectroscopy (FTIR). At 37 degrees C and higher temperatures, RA caused a decrease in the temperature modifications on the protein structure. Furthermore, FTIR and native-gel analysis revealed that protein aggregation/precipitation, induced by temperature, was reduced in the presence of RA. The novelty of the present work resides in the study of the enzyme inhibitory activity and antioxidant capacity of polyphenols, such as RA, in the presence of a protein. The findings highlight the need to consider the presence of proteins when assessing biological activities of polyphenols in vitro and that enzyme inhibitory activity may be decreased, while the antioxidant capacity remains or even increases. PMID- 29431578 TI - Patency of the arterial pedal-plantar arch in patients with chronic kidney disease or diabetes mellitus. AB - BACKGROUND: Patency of the pedal-plantar arch limits risk of amputation in peripheral artery disease (PAD). We examined patients without chronic kidney disease (CKD)/diabetes mellits (DM) [PAD-control], those with DM without CKD, and those with CKD without DM. METHOD: Uni- and multivariate logistic regression was used to assess association of CKD with loss of patency of the pedal-plantar arch and presence of tibial or peroneal vessel occlusion. Multivariate models adjusted for age, sex, hypertension, hyperlipidemia and smoking. RESULTS: A total of 419 patients were included [age 75.2 +/- 10.3 years, 288 (69%) male]. CKD nearly doubled the unadjusted odds ratio (OR) for loss of patency of the pedal-plantar arch. After adjustment, association remained significant for severe CKD [estimated glomerular filtration rate (eGFR) <= 29 ml/min compared with eGFR >= 60 ml/min, adjusted (adj.) OR 8.24 (95% confidence interval {CI} 0.99-68.36, p = 0.05)]. CKD was not related to risk of tibial or peroneal artery occlusion [PAD control versus CKD, adj. OR 1.09 (95% CI 0.49-2.44, p = 0.83)] in contrast to DM [PAD-control versus DM, adj. OR 2.41 (95% CI 1.23-4.72, p = 0.01), CKD versus DM, adj. OR 2.21 (95% CI 0.93-5.22); p = 0.07)]. CONCLUSIONS: Below the knee (BTK) vascular pattern differs in patients with either DM or CKD alone. Severe CKD is a risk factor for loss of patency of the pedal-plantar arch. PMID- 29431580 TI - What We Do: Key Activities of an Outpatient Palliative Care Team at an Academic Cancer Center. AB - BACKGROUND: Outpatient palliative care (PC) has been shown to positively impact quality of life and decrease healthcare utilization, but there are limited data describing what activities render these benefits. OBJECTIVE: Describe the topics addressed by an outpatient PC team during scheduled visits. DESIGN: Longitudinal cohort study. SETTING: The Symptom Management Service, an ambulatory PC program at an academic comprehensive cancer center. MEASUREMENT: Between March 23, 2015 and June 14, 2016, outpatient PC providers completed a checklist after each clinic visit, documenting topics covered during the visit. RESULTS: During the study period, 1243 visits were conducted for 577 unique patients. Symptom management was the topic most commonly addressed during initial visits (in 92% of visits), followed by an introduction of PC (69%), support for family caregivers (47%), and communication with other clinicians (38%). Providers also supported patients to understand their prognosis (28%), treatment options (36%), and to make care decisions (22%). Formal advance care planning activities occurred infrequently, however, including designation of a Durable Power of Attorney for Healthcare (26%), completion of an advance directive or Provider Orders for Life Sustaining Treatment form (10%), and discussing hospice (8%). Follow-up visits were dominated by symptom management (93%) and caregiver support (27%). CONCLUSIONS: Symptom management, support for family and caregivers, and care coordination are the most common activities that occurred during scheduled outpatient PC visits. These findings can guide developing PC practices, as well as clinicians who provide primary PC. PMID- 29431579 TI - Simultaneous biodegradation of bifenthrin and chlorpyrifos by Pseudomonas sp. CB2. AB - The degradation of bifenthrin (BF) and chlorpyrifos (CP), either together or individually, by a bacterial strain (CB2) isolated from activated sludge was investigated. Strain CB2 was identified as belonging to genus Pseudomonas based on the morphological, physiological, and biochemical characteristics and a homological analysis of the 16S rDNA sequence. Strain CB2 has the potential to degrade BF and CP, either individually or in a mixture. The optimum conditions for mixture degradation were as follows: OD600nm = 0.5; incubation temperature = 30 degrees C; pH = 7.0; BF-CP mixture (10 mg L-1 of each). Under these optimal conditions, the degradation rate constants (and half-lives) were 0.4308 d-1 (1.61 d) and 0.3377 d-1 (2.05 d) for individual BF and CP samples, respectively, and 0.3463 d-1 (2.00 d) and 0.2931 d-1 (2.36 d) for the BF-CP mixture. Major metabolites of BF and CP were 2-methyl-3-biphenylyl methanol and 3,5,6-trichloro 2-pyridinol, respectively. No metabolite bioaccumulation was observed. The ability of CB2 to efficiently degrade BF and CP, particularly in a mixture, may be useful in bioremediation efforts. PMID- 29431581 TI - A systematic review of propulsion from the flutter kick - What can we learn from the dolphin kick? AB - Propulsion, one of the most important factors in front crawl swimming performance, is generated from both the upper and lower limbs, yet little is known about the mechanisms of propulsion from the alternating movements of the lower limbs in the flutter kick (FK). The purpose of this systematic review was to review the literature relating to the mechanisms of propulsion from FK in front crawl. There was limited information about the mechanisms of propulsion in FK. Since movements of the lower limbs are similar between FK and the dolphin kick (DK), mechanisms of propulsion from DK were reviewed to better understand propulsion from FK. Recent evidence suggests that propulsion in DK is generated in conjunction with formation and shedding of vortices. Similar vortex structures have been observed in FK. Visualisation and simulation techniques, such as particle image velocimetry (PIV) and computational fluid dynamics (CFD), are non invasive tools that can effectively model water flow without impacting swimming technique. These technologies allow researchers to estimate the acceleration of water and, consequently, the propulsive reaction forces acting on the swimmer. Future research should use these technologies to investigate propulsion from FK. PMID- 29431582 TI - Soils impacted by PAHs: Would the stabilized organic matter be a green tool for the immobilization of these noxious compounds? AB - The objective of this study was to investigate the role of stabilized organic matter (vermicompost) and tropical soils in the sorption of naphthalene, anthracene and benzo[a]pyrene. The results obtained for the three compounds were extrapolated for the priority polycyclic aromatic hydrocarbons (PAHs) pollutants according to Environmental Protection Agency (US EPA). To evaluate the sorption process, high performance liquid chromatography was employed and the data was fitted by Freundlich isotherms. The results suggest that the sorption effect generally increases with the number of benzene rings of the PAHs, and that the persistence of PAHs in the environment is possibly related to the number of benzene rings in the PAH molecule. In addition, the pH of the vermicompost can strongly affect the adsorption process in this matrix. PMID- 29431584 TI - Horizon Scanning: How Will Metabolomics Applications Transform Food Science, Bioengineering, and Medical Innovation in the Current Era of Foodomics? AB - Food and engineering sciences have tended to neglect the importance of human nutrition sciences and clinical study of new molecules discovered by food engineering community, and vice versa. Yet, the value of systems thinking and use of omics technologies in food engineering are rapidly emerging. Foodomics is a new concept and practice to bring about "precision nutrition" and integrative bioengineering studies of food composition, quality, and safety, and applications to improve health of humans, animals, and other living organisms on the planet. Foodomics signals a three-way convergence among (1) food engineering; (2) omics systems science technologies such as proteomics, metabolomics, glycomics; and (3) medical/life sciences. This horizon scanning expert review aims to challenge the current practices in food sciences and bioengineering so as to adopt foodomics and systems thinking in foodstuff analysis, with a focus on possible applications of metabolomics. Among the omics biotechnologies, metabolomics is one of the prominent analytical platforms of interest to both food engineers and medical researchers engaged in nutritional sciences, precision medicine, and systems medicine diagnostics. Medical and omics system scientists, and bioengineering scholars can mutually learn from their respective professional expertise. Moving forward, establishment of "Foodomics Think Tanks" is one conceivable strategy to integrate medical and food sciences innovation at a systems scale. With its rich history in food sciences and tradition of interdisciplinary scholarship, the Silk Road countries offer notable potential for synthesis of diverse knowledge strands necessary to realize the prospects of foodomics from Asia and Middle East to Europe. PMID- 29431583 TI - Gut microbiota modify risk for dietary glycemia-induced age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of blindness world wide. Although the etiology of AMD is multifactorial, diet and nutrition have strong epidemiologic associations with disease onset and progression. Recent studies indicate a role for gut microbiota in development of AMD in mouse models and in some forms of human AMD. We previously found that consuming lower glycemia diets is associated with protection against AMD in humans and switching from higher to lower glycemia diets arrests AMD phenotypes in mice. Gut microbiota populations and circulating microbial cometabolites were altered in response to dietary carbohydrates, indicating a gut-retina axis. Here we explore additional gut microbiota-AMD interactions that point toward pathogenic roles for some gut microbiota families, including Ruminococcaceae and Lachnospiraceae, and individual members of Turicibacteraceae, Clostridiaceae, and Mogibacteriaceae. We also speculate on potential mechanisms by which gut microbiota influence AMD, with the objective of devising new AMD diagnoses and treatments. PMID- 29431585 TI - Calculation of 3D genome structures for comparison of chromosome conformation capture experiments with microscopy: An evaluation of single-cell Hi-C protocols. AB - Single-cell chromosome conformation capture approaches are revealing the extent of cell-to-cell variability in the organization and packaging of genomes. These single-cell methods, unlike their multi-cell counterparts, allow straightforward computation of realistic chromosome conformations that may be compared and combined with other, independent, techniques to study 3D structure. Here we discuss how single-cell Hi-C and subsequent 3D genome structure determination allows comparison with data from microscopy. We then carry out a systematic evaluation of recently published single-cell Hi-C datasets to establish a computational approach for the evaluation of single-cell Hi-C protocols. We show that the calculation of genome structures provides a useful tool for assessing the quality of single-cell Hi-C data because it requires a self-consistent network of interactions, relating to the underlying 3D conformation, with few errors, as well as sufficient longer-range cis- and trans-chromosomal contacts. PMID- 29431586 TI - Drain Failure in Intra-Abdominal Abscesses Associated with Appendicitis. AB - BACKGROUND: Previous studies have suggested that percutaneous drainage and interval appendectomy is an effective treatment for appendicitis with associated abscess. Few studies to date have analyzed risk factors for failed drain management. We hypothesized that older patients with more co-morbidities would be at higher risk for failing conservative treatment. METHODS: The 2010-2014 editions of the National Inpatient Sample (NIS) were queried for patients with diagnoses of peri-appendiceal abscesses. Minors and elective admissions were excluded. We identified patients who underwent percutaneous drainage and defined drain failure as undergoing a surgical operation after drainage but during the same inpatient visit to assess for factors associated with failure of drainage alone as a treatment. After univariable analysis, binomial logistic regression was used to assess for independent risk factors. Frequencies were analyzed by chi2 and continuous variables by Student's t-test. RESULTS: A total of 2,209 patients with appendiceal abscesses received drains; 561 patients (25.4%) failed conservative management and underwent operative intervention. On univariable analysis, patients who failed conservative management were younger, more likely to be Hispanic, have more inpatient diagnoses, and to have undergone drainage earlier in the hospital course. Multivariable regression demonstrated that the number of diagnoses, female sex, and Hispanic race were predictive of failure of drainage alone. Older age, West and Midwest census regions, and later drain placement were predictive of successful treatment with drainage alone. Failure was associated with more charges and longer hospital stay but not with a higher mortality rate. CONCLUSION: Approximately a quarter of patients will fail management of appendiceal abscess with percutaneous drain placement alone. Risk factors for failure are patient complexity, female sex, earlier drainage, and Hispanic race. Failure of drainage is associated with higher total charges and longer hospital stay; however, no change in the mortality rate was noted. PMID- 29431587 TI - Quality control of mRNAs at the entry of the nuclear pore: Cooperation in a complex molecular system. AB - Despite extensive research on how mRNAs are quality controlled prior to export into the cytoplasm, the exact underlying mechanisms are still under debate. Specifically, it is unclear how quality control proteins at the entry of the nuclear pore complex (NPC) distinguish normal and aberrant mRNAs. While some of the involved components are suggested to act as switches and recruit different factors to normal versus aberrant mRNAs, some experimental and computational evidence suggests that the combined effect of the regulated stochastic interactions between the involved components could potentially achieve an efficient quality control of mRNAs. In this review, we present a state-of-the-art portrait of the mRNA quality control research and discuss the current hypotheses proposed for dynamics of the cooperation between the involved components and how it leads to their shared goal: mRNA quality control prior to export into the cytoplasm. PMID- 29431589 TI - Development of a golf-specific load monitoring tool: Content validity and feasibility. AB - Athletes often record details of their training and competitions, supported by information such as environmental conditions, travel, as well as how they felt. However, it is not known how prevalent these practices are in golfers, or how valuable this process is perceived. The purpose of this study was to develop a golf-specific load monitoring tool (GLMT), and establish the content validity and feasibility of this tool amongst high-level golfers. In the first phase of development, 21 experts were surveyed to determine the suitability of items for inclusion in the GLMT. Of the 36 items, 21 received >78% agreement, a requirement to establish content validity and for inclusion in the GLMT. Total duration was the preferred metric for golf-specific activities, whilst rating of perceived exertion (RPE) was preferred for measuring physical training. In the second phase, feasibility of the tool was assessed by surveying 13 high-level male golfers following 28-days of daily GLMT use. All items included in the GLMT were deemed feasible to record, with all players participating in the feasibility study providing high to very high ratings. Golfers responded that they would consider using a load monitoring tool of this nature long term, provided it can be completed in less than five minutes per day. PMID- 29431590 TI - Antimicrobial prescribing in post-graduate training practices: a cross-sectional study of prescribing data in general practices in England. AB - Introduction Seventy-five percent of all antimicrobials are prescribed in primary care. There is a growing concern about inappropriate oral antimicrobial prescribing. Interventions to enhance antimicrobial stewardship are actively promoted through educational and other means. GP training practice status has been shown to influence patient care. This study seeks to study the influence of GP training practice status on antimicrobial prescribing. Methods A cross sectional analysis of practice antimicrobial prescribing data was conducted for the year 2015-2016 comparing training and non-training practices across England. Data for all practices and prescribing was obtained from NHS Digital. Univariate analyses were conducted on the two measures of antibiotic prescribing included in the study. Multivariable regression models were constructed to identify the predictors of antibiotic prescribing volumes and of broad spectrum antibiotic prescribing. Results GP training practice status was a significant predictor of overall antibiotic prescribing volume, B = -0.009 (95% confidence intervals, 0.012, -0.005), p < 0.001. GP training practices prescribed fewer antibiotics, representing a reduction of 6.2 centiles from the median. GP training practice status was also a significant predictor of broad spectrum antibiotic prescribing, B = -0.3 (95% confidence intervals, -0.04, -0.01), p = 0.001. GP training practices prescribed fewer broad spectrum antibiotics, representing a reduction from the median of 6.0 centiles. Discussion Training practices prescribe fewer antimicrobials overall and specifically fewer broad spectrum oral antimicrobials (quinolones and cephalosporins). There is a need for further research to understand the interplay between postgraduate GP training and reductions in antimicrobial prescribing. PMID- 29431591 TI - The Role of Cranial Temperature in Neuroprotection by Sodium Hydrogen Sulfide After Cardiac Arrest in Mice. AB - The hydrogen sulfide donor sodium hydrogen sulfide (NaHS) is recognized as a neuroprotective agent, which induces a hibernation-like metabolic state and hypothermia. However, it remains unclear whether it is the sulfide itself or the hypothermia induced by the sulfide that mediates treatment outcomes following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). We therefore tested whether NaHS improved outcomes following CA/CPR in mice maintained at 35.0 degrees C by active warming during recovery. Adult male mice were subjected to 8 minutes CA/CPR and randomly treated intraperitoneally with either implantation of miniosmotic pump with NaHS (50 MUmol/kg/day) for 3 days or vehicle 30 minutes after CPR. A normothermia group had cranial temperatures kept >35.0 degrees C for 6 hours with a heat pad, and a hypothermia group was allowed to spontaneous hypothermia at room temperature (26.0 degrees C). Behavioral testing and histological evaluation of neurons in the CA1 hippocampal region and striatum were performed on days 4 and 12 after CA/CPR. Both cranial and body temperature decreased following CA/CPR in the hypothermia group, and this was enhanced by NaHS treatment. In the active warming (normothermia) group, NaHS protected striatal neurons and improved long-term survival, which was comparable to the hypothermia groups. No differences were found in the CA1 region. Following CA/CPR, NaHS treatment decreased the heart rate, but not the mean arterial pressure. Our study demonstrated that post-CPR treatment with NaHS exerted neuroprotection in mice while maintaining a normal cranial temperature, indicating that NaHS-related neuroprotection is independent of the known protective effect of spontaneous hypothermia. PMID- 29431588 TI - Aptamers in HIV research diagnosis and therapy. AB - Aptamers are high affinity single-stranded nucleic acid or protein ligands which exhibit specificity and avidity comparable to, or exceeding that of antibodies and can be generated against most targets. The functionality of aptamers is based on their unique tertiary structure, complexity and their ability to attain unique binding pockets by folding. Aptamers are selected in vitro by a process called Systematic Evolution of Ligands by Exponential enrichment (SELEX). The Kd values for the selected aptamer are often in the picomolar to low nanomolar range. Stable and nontoxic aptamers could be selected for a wide range of ligands including small molecules to large proteins. Aptamers have shown tremendous potential and have found multipurpose application in the field of therapeutic, diagnostic, biosensor and bio-imaging. While their mechanism of action can be similar to that of monoclonal antibodies, aptamers provide additional advantages in terms of production cost, simpler regulatory approval and lower immunogenicity as they are synthesized chemically. Human immunodeficiency virus (HIV) is the primary cause of acquired immune deficiency syndrome (AIDS), which causes significant morbidity and mortality with a significant consequent decrease in the quality of patient's lives. While cART has led to good viral control, people living with HIV now suffer from non-HIV comorbidities due to viral protein expression that cannot be controlled by cART. Hence pathophysiological mechanisms that govern these comorbidities with a focus on therapies that neutralize these HIV effects gained increased attention. Recent advances in HIV/AIDS research have identified several molecular targets and for the development of therapeutic and diagnostic using aptamers against HIV/AIDS. This review presents recent advances in aptamers technology for potential application in HIV diagnostics and therapeutics towards improving the quality of life of people living with HIV. PMID- 29431592 TI - In-season changes in ventricular morphology and systolic function in adolescent female athletes. AB - PURPOSE: To evaluate the influence of physical maturity on the changes in ventricular morphology and function with sport training in female youth athletes. METHODS: Thirty-two female athletes (age 13-18 years) underwent height and weight measurement and 2-D echocardiographic evaluation immediately prior to, and following, a 20-week soccer season. Pre- and post-season left ventricular end diastolic diameter (LVEDD), end-diastolic volume (LVEDV), ejection fraction (LVEF), stroke volume (LVSV), mass (LVM), and posterior wall thickness (LVPWT), right ventricular end-diastolic diameter (RVEDD), end-diastolic area (RVEDA), and fractional area change (RVFAC), and interventricular septal thickness (IVST) were compared. In-season change in each variable was compared across pre-season hours of vigorous physical activity (0-1, 2-3, >3 hours). RESULTS: Significant increases were identified in LVEDV (51.3 +/- 10.4 v 56.4 +/- 9.6 ml/m2, p = 0.001) and RVEDA (10.5 +/- 1.9 v 11.3 +/- 2.5 cm2/m2, p = 0.040), but not LVEDD, LVM, LVPWT, LVSV, RVEDD, RVEDA, RVFAC, or IVST (p > 0.05 for all). In-season changes in echocardiographic variables did not differ across hours of pre-season vigorous physical activity (p > 0.05 for all). CONCLUSION: Among female adolescent soccer players, in-season training elicits changes in resting ventricular volume, but not wall thickness or systolic function. These adaptations do not appear to be influenced by pre-season physical activity level. PMID- 29431593 TI - Caffeine use in a Super Rugby game and its relationship to post-game sleep. AB - OBJECTIVE: To examine the relationship between regular game-related caffeine consumption on sleep after an evening Super Rugby game. METHODS: Twenty elite rugby union players wore a wrist-activity monitor to measure sleep for three days before, three days after and on the night of an evening Super Rugby game (19:00 21:00). Players ingested caffeine as they would normally (i.e. before and sometimes during a game) and saliva samples were collected before (17:00) and after (21:30) the game for caffeine concentration. RESULTS: Compared to the nights leading up to the game, on the night of the game, players went to bed 3 h later (23:08 +/- 66 min vs 02:11 +/- 114 min; p < .001) and had 1:30 hh:mm less sleep (5:54 +/- 2:59 vs 8:02 +/- 1:24 hh:mm; p < .05) and four players did not sleep after the game. Post-game caffeine saliva concentrations were greater than pre-game levels in 17 players (Pre-game 0.40 ug/mL vs Post-game 2.77 ug/mL; p < .001). The increase in caffeine saliva concentrations was moderately associated with an increase in sleep latency (p < .05), a decrease in sleep efficiency (p < .05), and a trend for a decrease in sleep duration (p = .06) on game night. CONCLUSION: Caffeine consumption before a Super Rugby game markedly increases post-game saliva caffeine levels. This may contribute to the observed 3.5 h delay in time at sleep onset and the 1.5 h reduction in sleep duration on the night of the game. This study highlights the need for a strategic approach to the use of caffeine within a Super Rugby team considering the potential effect on post-game sleep. PMID- 29431594 TI - Re: "Feasibility of a Miniature Esophageal Heat Exchange Device for Rapid Therapeutic Cooling in Newborns: Preliminary Investigations in a Piglet Model" by Dingley et al. (Ther Hypothermia Temp Manag 2018;8:36-44). PMID- 29431595 TI - Wheelchair Mobility Performance Enhancement by Changing Wheelchair Properties: What Is the Effect of Grip, Seat Height, and Mass? AB - PURPOSE: To provide insight on the effect of wheelchair settings on wheelchair mobility performance (WMP). METHODS: Twenty elite wheelchair basketball athletes of low (n = 10) and high classification (n = 10) were tested in a wheelchair basketball-directed field test. Athletes performed the test in their own wheelchairs, which were modified for 5 additional conditions regarding seat height (high-low), mass (central-distributed), and grip. The previously developed inertial-sensor-based WMP monitor was used to extract wheelchair kinematics in all conditions. RESULTS: Adding mass showed most effect on WMP, with a reduced average acceleration across all activities. Once distributed, additional mass also reduced maximal rotational speed and rotational acceleration. Elevating seat height had an effect on several performance aspects in sprinting and turning, whereas lowering seat height influenced performance minimally. Increased rim grip did not alter performance. No differences in response were evident between low- and high-classified athletes. CONCLUSIONS: The WMP monitor showed sensitivity to detect performance differences due to the small changes in wheelchair configuration. Distributed additional mass had the most effect on WMP, whereas additional grip had the least effect of conditions tested. Performance effects appear similar for both low- and high-classified athletes. Athletes, coaches, and wheelchair experts are provided with insight into the performance effect of key wheelchair settings, and they are offered a proven sensitive method to apply in sport practice, in their search for the best wheelchair-athlete combination. PMID- 29431596 TI - A modified F-test for hypothesis testing in large-scale data. AB - Nowadays, performing simultaneous hypothesis testing under small sample sizes in large-scale features has received unprecedented attention in practice. Traditional approaches are not appropriate for this purpose. Instead, a novel approach which is based on the null statistic is used in the literature. The null statistic approach, using the permutation samples of all features, permits the more accurate estimation of the [Formula: see text]-value for a target feature. However, the known methods, working based on the null statistic, cannot be applied to features with three or more levels. In the present study, an attempt is made to introduce a new permutation test statistic which can be modified to the null statistic approach when features have three or more levels. The robustness of the proposed test statistic and its performance in estimating the [Formula: see text]-value are demonstrated through conducting simulation studies and the analysis of two real datasets. PMID- 29431597 TI - Effect of movement velocity during resistance training on muscle-specific hypertrophy: A systematic review. AB - Currently, it is unclear whether manipulation of movement velocity during resistance exercise has an effect on hypertrophy of specific muscles. The purpose of this systematic review of literature was to investigate the effect of movement velocity during resistance training on muscle hypertrophy. Five electronic databases were searched using terms related to movement velocity and resistance training. Inclusion criteria were randomised and non-randomised comparative studies; published in English; included healthy adults; used dynamic resistance exercise interventions directly comparing fast training to slower movement velocity training; matched in prescribed intensity and volume; duration >=4 weeks; and measured muscle hypertrophy. A total of six studies were included involving 119 untrained participants. Hypertrophy of the quadriceps was examined in five studies and of the biceps brachii in two studies. Three studies found significantly greater increases in hypertrophy of the quadriceps for moderate slow compared to fast training. For the remaining studies examining the quadriceps, significant within-group increase in hypertrophy was found for only moderate-slow training in one study and for only fast training in the other study. The two studies that examined hypertrophy of the biceps brachii found greater increases for fast compared to moderate-slow training. Caution is required when interpreting the findings from this review due to the low number of studies, hence insufficient data. Future longitudinal randomised controlled studies in cohorts of healthy adults are required to confirm and extend our findings. PMID- 29431599 TI - Lithuanian dentists' knowledge, attitudes, and clinical practices regarding obstructive sleep apnea: A nationwide cross-sectional study. AB - OBJECTIVE: To investigate the knowledge, attitudes toward, and aspects of clinical practice regarding obstructive sleep apnea (OSA) among Lithuanian dentists. METHODS: A cross-sectional study was carried out during the period from December 2016 to March 2017. A survey instrument was designed and pilot tested prior to full-scale administration. Self-administered questionnaires, including a cover letter, were distributed to 550 dentists during continuing dental education programs. RESULTS: A total of 353 participants (64.2%) completed and returned the questionnaire. Increased years of experience were significantly associated with lesser knowledge about OSA (p < 0.05). However, there were no significant differences between general practitioners and specialists (p = 0.243). Most respondents indicated strong positive attitudes regarding OSA. The majority did not have any clinical experience regarding the management of OSA patients. DISCUSSION: Development of additional education and practical implementation strategies should be considered in order to overcome the examined barriers. PMID- 29431598 TI - Momordica charantia Administration Improves Insulin Secretion in Type 2 Diabetes Mellitus. AB - An improvement in parameters of glycemic control has been observed with Momordica charantia in patients with type 2 diabetes mellitus (T2DM). It is unknown whether this improvement is through a modification of insulin secretion, insulin sensitivity, or both. We hypothesized that M. charantia administration can improve insulin secretion and/or insulin sensitivity in patients with T2DM, without pharmacological treatment. The objective of the study was to evaluate the effect of M. charantia administration on insulin secretion and sensitivity. A randomized, double-blinded, placebo-controlled, clinical trial was carried out in 24 patients who received M. charantia (2000 mg/day) or placebo for 3 months. A 2 h oral glucose tolerance test (OGTT) was done before and after the intervention to calculate areas under the curve (AUC) of glucose and insulin, total insulin secretion (insulinogenic index), first phase of insulin secretion (Stumvoll index), and insulin sensitivity (Matsuda index). In the M. charantia group, there were significant decreases in weight, body mass index (BMI), fat percentage, waist circumference (WC), glycated hemoglobin A1c (A1C), 2-h glucose in OGTT, and AUC of glucose. A significant increase in insulin AUC (56,562 +/- 36,078 vs. 65,256 +/- 42,720 pmol/L/min, P = .043), in total insulin secretion (0.29 +/- 0.18 vs. 0.41 +/- 0.29, P = .028), and during the first phase of insulin secretion (557.8 +/- 645.6 vs. 1135.7 +/- 725.0, P = .043) was observed after M. charantia administration. Insulin sensitivity was not modified with any intervention. In conclusion, M. charantia administration reduced A1C, 2-h glucose, glucose AUC, weight, BMI, fat percentage, and WC, with an increment of insulin AUC, first phase and total insulin secretion. PMID- 29431600 TI - Subcritical water oxidation of propham by H2O2 using response surface methodology (RSM). AB - This study was conducted to investigate the degradation of propham, which is a compound that pollutes water and seriously threatens human health, by subcritical water oxidation and using H2O2 as an oxidising agent. The maximum total organic carbon removal rate of propham was obtained as 73.65% at 40 min of treatment time and 60 mM of H2O2 concentration and 373 K of temperature. In addition, response surface method based on the Box-Behnken design was applied to design the degradation experiments of propham for determination of the combined effects of process variables, namely temperature, concentration of oxidising agent and treatment time. The proposed quadratic model of propham degradation, which was examined with the analysis of variance, was used for navigating the design space. The R2 and adjusted R2 values of the model were determined as 0.9921 and 0.9819 respectively. It was shown that propham was effectively degraded, thus could be removed from the water by using an environmentally friendly method. PMID- 29431601 TI - Pain Management Among Culturally Diverse Older Adults. PMID- 29431603 TI - President's Message. PMID- 29431604 TI - Editorial: Sulfur-Containing Amino Acids in Cardiovascular and Neural Physiology, Pathophysiology and Pharmacology: An Overview and Update. PMID- 29431605 TI - Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae. AB - Extensively drug-resistant Klebsiella pneumoniae (XDR-KP) infections cause high mortality and are disseminating globally. Identifying the genetic basis underpinning resistance allows for rapid diagnosis and treatment. XDR isolates sourced from Greece and Brazil, including 19 polymyxin-resistant and five polymyxin-susceptible strains, were subjected to whole genome sequencing. Seventeen of the 19 polymyxin-resistant isolates harboured variations upstream or within mgrB. The most common mutation identified was an insertion at nucleotide position 75 in mgrB via an ISKpn26-like element in the ST258 lineage and ISKpn13 in one ST11 isolate. Three strains acquired an IS1 element upstream of mgrB and another strain had an ISKpn25 insertion at 133 bp. Other isolates had truncations (C28STOP, Q30STOP) or a missense mutation (D29E) affecting mgrB. Complementation assays revealed all mgrB perturbations contributed to resistance. Missense mutations in phoQ (T281M, G385C) were also found to facilitate resistance. Several variants in phoPQ co-segregating with the ISKpn26-like insertion were identified as potential partial suppressor mutations. Three ST258 samples were found to contain subpopulations with different resistance-conferring mutations, including the ISKpn26-like insertion colonizing with a novel mutation in pmrB (P158R), both confirmed via complementation assays. These findings highlight the broad spectrum of chromosomal modifications which can facilitate and regulate resistance against polymyxins in K. pneumoniae. PMID- 29431606 TI - Correction: Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor. PMID- 29431607 TI - Sorting out "non-canonical" autophagy. PMID- 29431608 TI - Adverse effects of opioids for non-cancer pain. PMID- 29431609 TI - FMT: colonoscopy or capsule? PMID- 29431611 TI - CVS effects of ? canagliflozin. PMID- 29431610 TI - Revised advice on switching between antiepileptic products. PMID- 29431612 TI - Testosterone therapy in hypogonadal men. PMID- 29431614 TI - Intensive weight management for remission of type 2 diabetes. PMID- 29431613 TI - MHRA: quinine QT-prolonging effects and drug interactions. PMID- 29431616 TI - Role of the pregnane X receptor in binge ethanol-induced steatosis and hepatotoxicity. AB - The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that defends against toxic agents. We have shown that PXR promotes chronic ethanol (EtOH)-induced steatosis. Therefore, we examined the role of PXR in binge EtOH-induced hepatotoxicity. Male wild type (WT) and Pxr-null mice were orally administered three binge doses of EtOH (4.5 g/kg, every 12 hours) and euthanized four hours after the final dose. Pxr-null mice displayed higher basal mRNA levels of hepatic lipogenic transcription factor sterol regulatory element binding protein 1c (Srebp-1c) and its target stearoyl-CoA desaturase 1 (Scd1) and the lipid peroxide detoxifying aldo-keto reductase 1b7 (Akr1b7) and higher protein levels of EtOH-metabolizing alcohol dehydrogenase 1 (ADH1). In both genotypes, binge EtOH-induced triglyceride accumulation was associated with inhibition of fatty acid beta-oxidation and upregulation of Srebp-1c- regulated lipogenic genes and hepatic CYP2E1 protein. Unexpectedly, gene expression of Cyp2b10, a constitutive androstane receptor target gene, implicated in EtOH hepatotoxicity, was PXR-dependent upregulated by binge EtOH. Also, PXR-dependent was the binge EtOH-induced inhibition of hepatic Akr1b8 mRNA, and protein levels of aldehyde dehydrogenase (ALDH) 1A1 and anti-apoptotic Bcl-2, but increased pro-apoptotic Bax protein expression, leading to increases in residual EtOH concentration and the cellular oxidative stress marker, malondialdehyde. In contrast, Pxr-null mice displayed increased Akr1b7 gene and ADH1 protein expression and hypertriglyceridemia following binge EtOH exposure. Taken together, this study demonstrates that PXR ablation prevents EtOH induced upregulation of Cyp2b10 and that PXR potentiates binge EtOH-induced oxidative stress and inhibition of EtOH catabolism, but protects against alcoholic hyperlipidemia. PMID- 29431615 TI - GLUT12 promotes prostate cancer cell growth and is regulated by androgens and CaMKK2 signaling. AB - Despite altered metabolism being an accepted hallmark of cancer, it is still not completely understood which signaling pathways regulate these processes. Given the central role of androgen receptor (AR) signaling in prostate cancer, we hypothesized that AR could promote prostate cancer cell growth in part through increasing glucose uptake via the expression of distinct glucose transporters. Here, we determined that AR directly increased the expression of SLC2A12, the gene that encodes the glucose transporter GLUT12. In support of these findings, gene signatures of AR activity correlated with SLC2A12 expression in multiple clinical cohorts. Functionally, GLUT12 was required for maximal androgen-mediated glucose uptake and cell growth in LNCaP and VCaP cells. Knockdown of GLUT12 also decreased the growth of C4-2, 22Rv1 and AR-negative PC-3 cells. This latter observation corresponded with a significant reduction in glucose uptake, indicating that additional signaling mechanisms could augment GLUT12 function in an AR-independent manner. Interestingly, GLUT12 trafficking to the plasma membrane was modulated by calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-5'-AMP-activated protein kinase (AMPK) signaling, a pathway we previously demonstrated to be a downstream effector of AR. Inhibition of CaMKK2 AMPK signaling decreased GLUT12 translocation to the plasma membrane by inhibiting the phosphorylation of TBC1D4, a known regulator of glucose transport. Further, AR increased TBC1D4 expression. Correspondingly, expression of TBC1D4 correlated with AR activity in prostate cancer patient samples. Taken together, these data demonstrate that prostate cancer cells can increase the functional levels of GLUT12 through multiple mechanisms to promote glucose uptake and subsequent cell growth. PMID- 29431618 TI - Induction Chemotherapy plus Concurrent Chemoradiotherapy in Endemic Nasopharyngeal Carcinoma: Individual Patient Data Pooled Analysis of Four Randomized Trials. AB - Purpose: Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC.Experimental Design: Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively.Results: Median follow-up was 5.0 years. The HR for PFS was 0.70 [95% confidence interval (CI), 0.56-0.86; P = 0.0009; 9.3% absolute benefit at 5 years] in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57-0.99; P = 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51-0.90; P = 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48-1.01; P = 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected.Conclusions: This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control. Clin Cancer Res; 24(8); 1824-33. (c)2018 AACR. PMID- 29431617 TI - Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma. AB - Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays antisecretory effects in animals and patients. Here, endogenous induction of AF protein or exogenous administration of AF peptide reduced IFP and increased drug uptake in GBM xenografts. AF inhibited cell volume regulation of GBM cells, an effect that was phenocopied in vitro by the sodium-potassium-chloride cotransporter 1 (SLC12A2/NKCC1) inhibitor bumetanide. As a result, AF induced apoptosis and increased survival in GBM models. In vitro, the ability of AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKCC1 knockdown. Next, AF's ability to sensitize GBM cells to the alkylating agent temozolomide, standard of care in GBM patients, was evaluated. Importantly, combination of AF induction and temozolomide treatment blocked regrowth in GBM xenografts. Thus, AF-mediated inhibition of cell volume regulation represents a novel strategy to increase drug uptake and improve outcome in GBM. Mol Cancer Res; 16(5); 777-90. (c)2018 AACR. PMID- 29431620 TI - Legitimacy in bioethics: challenging the orthodoxy. AB - Several prominent writers including Norman Daniels, James Sabin, Amy Gutmann, Dennis Thompson and Leonard Fleck advance a view of legitimacy according to which, roughly, policies are legitimate if and only if they result from democratic deliberation, which employs only public reasons that are publicised to stakeholders. Yet, the process described by this view contrasts with the actual processes involved in creating the Affordable Care Act (ACA) and in attempting to pass the Health Securities Act (HSA). Since the ACA seems to be legitimate, as the HSA would have been had it passed, there seem to be counterexamples to this view. In this essay, I clarify the concept of legitimacy as employed in bioethics discourse. I then use that clarification to develop these examples into a criticism of the orthodox view-that it implies that legitimacy requires counterintuitively large sacrifices of justice in cases where important advancement of healthcare rights depends on violations of publicity. Finally, I reply to three responses to this challenge: (1) that some revision to the orthodox view salvages its core commitments, (2) that its views of publicity and substantive considerations do not have the implications that I claim and (3) that arguments for it are strong enough to support even counterintuitive results. My arguments suggest a greater role for substantive considerations than the orthodox view allows. PMID- 29431619 TI - Prevalence of physical conditions and multimorbidity in a cohort of adults with intellectual disabilities with and without Down syndrome: cross-sectional study. AB - OBJECTIVES: To investigate the prevalence of multimorbidity in adults with intellectual disabilities with and without Down syndrome. DESIGN: Large, population-based cross-sectional study. SETTING: The geographical area of one Health Board, Scotland. PARTICIPANTS: All adults (aged 16+ years) known to general practitioners to have intellectual disabilities and adults receiving services provided or paid by intellectual disabilities health or social work services. 1023/1562 potential participants took part (65.5%); 562 (54.9%) men and 461 (45.1%) women, aged 43.9 years (16-83 years). 186 had Down syndrome and 837 did not. MAIN OUTCOME MEASURES: The prevalence of International Statistical Classification of Diseases, 10th revision, physical health conditions and multimorbidity detected at a comprehensive health assessment. RESULTS: The mean number of physical health conditions/participant was 11.04, and 98.7% had multimorbidity. The most prevalent conditions are painful and/or disabling and, in some cases, life threatening. The five most prevalent were visual impairment, obesity, epilepsy, constipation and ataxic/gait disorders. The pattern of multimorbidity differs from that seen in the general population and is spread across the entire adult life course. The extent of multimorbidity in the adults with Down syndrome was similar to that of the adults without Down syndrome, while the prevalence of individual conditions differed. CONCLUSIONS: This robustly designed study with a large population found an extremely high prevalence of multimorbidity in adults with intellectual disabilities across the entire adult life course. This increases complexity of medical management that secondary healthcare services and medical education are not yet geared towards, as these tend to focus on single conditions. This is in addition to complexity due to limitations in communication and understanding. As the physical conditions within their multimorbidity also differ from that seen in the older general population, urgent attention is needed to develop the care pathways and guidelines that are required to inform and so improve their healthcare. PMID- 29431621 TI - Haploidentical HSCT for hemoglobinopathies: improved outcomes with TCRalphabeta+/CD19+-depleted grafts. AB - We examined outcomes of haploidentical hematopoietic cell transplantation (haplo HCT) using T-cell receptor alphabeta+ (TCRalphabeta+)/CD19+-depleted grafts (TCR group, 14 patients) in children with hemoglobinopathies. Patients received a preparative regimen consisting of busulfan, thiotepa, cyclophosphamide, and antithymocyte globulin preceded by fludarabine, hydroxyurea, and azathioprine. The median follow-up among surviving patients was 3.9 years. The 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 84% and 69%, respectively. The incidence of graft failure was 14%. We compared outcomes to a historical group of 40 patients with hemoglobinopathies who received CD34+-selected grafts (CD34 group). The median follow-up of surviving patients for the CD34 group was 7.5 years. The 5-year probabilities of OS and DFS were 78% and 39%, respectively. The CD34 group had a significantly higher incidence of graft failure (45%) than the TCR group (14%) (P = .048). The incidences of grades 2 to 4 acute graft-versus-host disease (GVHD) in the TCR and CD34 groups were 28% and 29%, respectively, and 21% and 10% (P = .1), respectively, for extensive chronic GVHD. Viral reactivation was common in both groups. The overall incidence of posttransplant lymphoproliferative disorders for the entire group was 16%. Among all patients, 5 developed autoimmune hemolytic anemia or thrombocytopenia, with the overall cumulative incidence of 11%. The 2 groups showed suboptimal CD4+ recovery within the first 6 months of transplantation with no significant difference between groups. These data demonstrate that TCRalphabeta+/CD19+-depleted grafts are associated with a reduced incidence of graft failure, but delayed immune reconstitution and associated morbidity and mortality remain a significant challenge. PMID- 29431622 TI - C/EBPalpha overrides epigenetic reprogramming by oncogenic transcription factors in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease caused by recurrent mutations in the transcription regulatory machinery, resulting in abnormal growth and a block in differentiation. One type of recurrent mutations affects RUNX1, which is subject to mutations and translocations, the latter giving rise to fusion proteins with aberrant transcriptional activities. We recently compared the mechanism by which the products of the t(8;21) and the t(3;21) translocation RUNX1-ETO and RUNX1-EVI1 reprogram the epigenome. We demonstrated that a main component of the block in differentiation in both types of AML is direct repression of the gene encoding the myeloid regulator C/EBPalpha by both fusion proteins. Here, we examined at the global level whether C/EBPalpha is able to reverse aberrant chromatin programming in t(8;21) and t(3;21) AML. C/EBPalpha overexpression does not change oncoprotein expression or globally displace these proteins from their binding sites. Instead, it upregulates a core set of common target genes important for myeloid differentiation and represses genes regulating leukemia maintenance. This study, therefore, identifies common CEBPA-regulated pathways as targets for therapeutic intervention. PMID- 29431623 TI - Prevalence and risk factors for venous thromboembolism in children with sickle cell disease: an administrative database study. AB - A hypercoagulable state resulting in increased venous thromboembolism (VTE) has been described in adults with sickle cell disease (SCD), but similar data for children are lacking. The objective of this retrospective cohort study was to describe the rate of VTE and risk factors associated with VTE in children with SCD across tertiary-care children's hospitals in the United States between the years 2009 and 2015. We used the Pediatric Health Information System database to investigate all pediatric patients with SCD admitted to 1 of 48 participating institutions between 1 January 2009 and 30 September 2015. International Classification of Disease, Ninth Edition, Clinical Modification codes were used to identify index thromboembolic events and chronic medical conditions known to be associated with VTE. Billing codes were used to identify central venous line (CVL) placement and pharmaceutical billing codes to identify estrogen containing oral-contraceptive use. Logistic regression analysis was used to study the association among unique patient characteristics, VTE, and death. 10 454 eligible subjects with SCD were identified. Median age (+/-interquartile range) of study cohort was 10 (+/-11) years. 181 subjects (1.7%) developed an index venous thromboembolic event during the study period. Median age at VTE diagnosis was 15.9 (+/-7.4) years. On multivariable logistic regression analysis, CVL placement, chronic renal disease, history of stroke, female sex, length of hospitalization, intensive care unit utilization, and older age were associated with VTE. After adjusting for other variables, VTE was independently associated with death. In summary, VTE can occur in pediatric patients with SCD. CVL placement is a modifiable risk factor for VTE development. PMID- 29431627 TI - TSH, Thyroid Hormone, and PTC-Letter. PMID- 29431628 TI - TSH, Thyroid Hormone, and PTC-Response. PMID- 29431630 TI - Ethylene Signaling Modulates Cortical Microtubule Reassembly in Response to Salt Stress. AB - Regulation of cortical microtubule reorganization is essential for plant cell survival under high salinity conditions. In response to salt stress, microtubules undergo rapid depolymerization followed by reassembly to form a new microtubule network that promotes cell survival; however, the upstream regulatory mechanisms for this recovery response are largely unknown. In this study, we demonstrate that ethylene signaling facilitates salt stress-induced reassembly of cortical microtubules in Arabidopsis (Arabidopsis thaliana). Microtubule depolymerization was not affected under salt stress following the suppression of ethylene signaling with Ag+ or in ethylene-insensitive mutants, whereas microtubule reassembly was significantly inhibited. ETHYLENE-INSENSITIVE3, a key transcription factor in the ethylene signaling pathway, was shown to play a central role in microtubule reassembly under salt stress. In addition, we performed functional characterization of the microtubule-stabilizing protein WAVE DAMPENED2-LIKE5 (WDL5), which was found to promote ethylene-associated microtubule reassembly and plant salt stress tolerance. These findings indicate that ethylene signaling regulates microtubule reassembly by up-regulating WDL5 expression in response to salt stress, thereby implicating ethylene signaling in salt-stress tolerance in plants. PMID- 29431629 TI - Lipopolysaccharides Trigger Two Successive Bursts of Reactive Oxygen Species at Distinct Cellular Locations. AB - Lipopolysaccharides (LPS) are major components of the outer membrane of gram negative bacteria and are an important microbe-associated molecular pattern (MAMP) that triggers immune responses in plants and animals. A previous genetic screen in Arabidopsis (Arabidopsis thaliana) identified LIPOOLIGOSACCHARIDE SPECIFIC REDUCED ELICITATION (LORE), a B-type lectin S-domain receptor kinase, as a sensor of LPS. However, the LPS-activated LORE signaling pathway and associated immune responses remain largely unknown. In this study, we found that LPS trigger biphasic production of reactive oxygen species (ROS) in Arabidopsis. The first transient ROS burst was similar to that induced by another MAMP, flagellin, whereas the second long-lasting burst was induced only by LPS. The LPS-triggered second ROS burst was found to be conserved in a variety of plant species. Microscopic observation of the generation of ROS revealed that the LPS-triggered second ROS burst was largely associated with chloroplasts, and functional chloroplasts were indispensable for this response. The lipid A moiety, the most conserved portion of LPS, appears to be responsible for the second ROS burst. Surprisingly, the LPS- and lipid A-triggered second ROS burst was only partially dependent on LORE. Together, our findings provide insight on the LPS-triggered ROS production and the associated signaling pathway. PMID- 29431631 TI - Natural Variation Underlies Differences in ETHYLENE RESPONSE FACTOR17 Activity in Fruit Peel Degreening. AB - Through natural or human selection, many fleshy fruits have evolved vivid external or internal coloration, which often develops during ripening. Such developmental changes in color are associated with the biosynthesis of pigments as well as with degreening through chlorophyll degradation. Here, we demonstrated that natural variation in the coding region of the gene ETHYLENE RESPONSE FACTOR17 (ERF17) contributes to apple (Malus domestica) fruit peel degreening. Specifically, ERF17 mutant alleles with different serine (Ser) repeat insertions in the coding region exhibited enhanced transcriptional regulation activity in a dual-luciferase reporter assay when more Ser repeats were present. Notably, surface plasmon resonance analysis showed that the number of Ser repeats affected the binding activity of ERF17 to the promoter sequences of chlorophyll degradation-related genes. In addition, overexpression of ERF17 in evergreen apples altered the accumulation of chlorophyll. Furthermore, we demonstrated that ERF17 has been under selection since the origin of apple tree cultivation. Taken together, these results reveal allelic variation underlying an important fruit quality trait and a molecular genetic mechanism associated with apple domestication. PMID- 29431632 TI - Long-Term Clinical Comparison of Procedural End Points After Pulmonary Vein Isolation in Paroxysmal Atrial Fibrillation: Elimination of Nonpulmonary Vein Triggers Versus Noninducibility. AB - BACKGROUND: Pulmonary vein isolation (PVI) is effective for maintenance of sinus rhythm in 50% to 75% of patients with paroxysmal atrial fibrillation, and it is not uncommon for patients to require additional ablation after PVI. We prospectively evaluated the relative effectiveness of 2 post-PVI ablation strategies in paroxysmal atrial fibrillation. METHODS AND RESULTS: A total of 500 patients (mean age, 55.7+/-11.0 years; 74.6% male) were randomly assigned to undergo ablation by 2 different strategies after PVI: (1) elimination of non-PV triggers (group A, n=250) or (2) stepwise substrate modification including complex fractionated atrial electrogram or linear ablation until noninducibility of atrial tachyarrhythmia was achieved (group B, n=250). During a median follow up of 26.0 months, 75 (32.2%) patients experienced at least 1 episode of recurrent atrial tachyarrhythmia after the single procedure in group A compared with 105 (43.8%) patients in group B (P value in log-rank test of Kaplan-Meier analysis: 0.012). Competing risk analysis showed that the cumulative incidence of atrial tachycardia was significantly higher in group B compared with group A (P=0.007). With the exception of total ablation time, there were no significant differences in fluoroscopic time or procedure-related complications between the 2 groups. CONCLUSIONS: Elimination of triggers as an end point of ablation in patients with paroxysmal atrial fibrillation decreased long-term recurrence of atrial tachyarrhythmia compared with a noninducibility approach achieved by additional empirical ablation. The post-PVI trigger test is thus a better end point of ablation for paroxysmal atrial fibrillation. PMID- 29431633 TI - February 5th Question. PMID- 29431635 TI - Response to Letter to the Editor on "Anti-Psoriatic Drug Monomethylfumarate Increases Nuclear Factor Erythroid 2-Related Factor 2 Levels and Induces Aquaporin-3 mRNA and Protein Expression". PMID- 29431634 TI - A Comment on "Anti-Psoriatic Drug Monomethylfumarate Increases Nuclear Factor Erythroid 2-Related Factor 2 Levels and Induces Aquaporin-3 mRNA and Protein Expression". PMID- 29431636 TI - Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas. AB - Comprehensive genetic analyses have identified germline SDHB and FH gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an SDHx-like molecular profile in the absence of SDHx or FH mutations and identified a germline mutation in the SLC25A11 gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline SLC25A11 mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that SLC25A11 acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in SDHx- and FH-related tumors were observed both in tumors with mutated SLC25A11 and in Slc25a11Delta/Delta immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that SLC25A11 is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation.Significance: A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. Cancer Res; 78(8); 1914-22. (c)2018 AACR. PMID- 29431638 TI - S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNFalpha/TNFR1-Mediated Cell Survival to Cell Death. AB - TNFalpha is a prominent proinflammatory cytokine and a critical mediator for the development of many types of cancer such as breast, colon, prostate, cervical, skin, liver, and chronic lymphocytic leukemia. Binding of TNFalpha to TNFR1 can lead to divergent signaling pathways promoting predominantly NF-kappaB activation but also cell death. We report here that the nitric oxide (NO) donor glyceryl trinitrate (GTN) converts TNFalpha, generated from immune cells or cancer cells stimulated by chemotherapy, into a prodeath mediator in colon and mammary cancer cells. GTN-mediated S-nitrosylation of cIAP1 on cysteines 571 and 574 inhibited its E3 ubiquitin ligase activity, which in turn reduced Lys63-linked ubiquitination of RIP1 and initiated assembly of a death complex. These findings provide insights into how NO can harness advantageous aspects of inflammation in cancer and provide new therapeutic strategies.Significance: Combination of an NO donor with chemotherapeutic drug-induced TNFalpha represents a potentially valuable anticancer strategy. Cancer Res; 78(8); 1948-57. (c)2018 AACR. PMID- 29431637 TI - Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells. AB - Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated, including in non-small cell lung cancer (NSCLC). Here, we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo Snail-mediated transformation relied upon silencing of the tumor-suppressive RNA splicing regulatory protein ESRP1. In clinical specimens of NSCLC, ESRP1 loss was documented in Snail-expressing premalignant pulmonary lesions. Mechanistic investigations showed that Snail drives malignant progression in an ALDH+CD44+CD24- pulmonary stem cell subset in which ESRP1 and stemness-repressing microRNAs are inhibited. Collectively, our results show how ESRP1 loss is a critical event in lung carcinogenesis, and they identify new candidate directions for targeted therapy of NSCLC.Significance: This study defines a Snail-ESRP1 cancer axis that is crucial for human lung carcinogenesis, with implications for new intervention strategies and translational opportunities. Cancer Res; 78(8); 1986-99. (c)2018 AACR. PMID- 29431639 TI - CXCL12gamma Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes. AB - There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12gamma in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12gamma expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12gamma induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCalpha/NFkappaB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance in vivo Together, our results establish a significant function for CXCL12gamma in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.Significance: Expression of CXCL12gamma induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC. Cancer Res; 78(8); 2026-39. (c)2018 AACR. PMID- 29431641 TI - Sulforaphane metabolites cause apoptosis via microtubule disruption in cancer. AB - Sulforaphane (SFN) inhibited growth in many cancers, but its half-life is 2 h in circulation. However, its metabolites, sulforaphane-cysteine (SFN-Cys) and sulforaphane-N-acetyl-cysteine (SFN-NAC) had longer half-lives and decreased the cell viability in both dose- and time-dependent manners in human prostate cancer. Flow cytometry assay revealed that these two SFN metabolites induced apoptosis with the features such as vacuolization, disappeared nuclear envelope, nuclear agglutination and fragmentation via transmission electron microscopy observation. Western blot showed that the sustained phosphorylation of ERK1/2 mediated by SFN metabolites caused activation and upregulation of cleaved Caspase 3 and downregulation of alpha-tubulin. High expression of alpha-tubulin was demonstrated to be positively correlated with cancer pathological grading. Both co-immunoprecipitation and immunofluorescence staining implicated the interaction between SFN metabolite-induced phosphorylated ERK1/2 and alpha-tubulin, and Caspase 3 cleavage assay showed that alpha-tubulin might be the substrate for cleaved Caspase 3. More, the SFN metabolite-mediated reduction of alpha-tubulin increased the depolymerization and instability of microtubules by microtubule polymerization assay. Reversely, microtubule-associated protein Stathmin-1 phosphorylation was increased via phosphorylated ERK1/2 and total Stathmin-1 was reduced, which might promote over-stability of microtubules. Immunofluorescence staining also showed that SFN metabolites induced the 'nest-like' structures of microtubule distribution resulting from the disrupted and aggregated microtubules, and abnormal nuclear division, suggesting that the disturbance of spindle formation and mitosis turned up. Thus, SFN-Cys and SFN-NAC triggered the dynamic imbalance of microtubules, microtubule disruption leading to cell apoptosis. These findings provided a novel insight into the chemotherapy of human prostate cancer. PMID- 29431642 TI - Towards optimal personalized diet and vitamin supplementation in NET patients. PMID- 29431644 TI - Induction of microRNA-199 by Nitric Oxide in Endothelial Cells is Required for Nitrovasodilator Resistance via Targeting of Prostaglandin I2 Synthase. AB - Background -Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by nitrate tolerance, owing to the dysfunction of prostaglandin I2 synthase (PTGIS). Micro RNAs (miRNAs) repress target gene expression and are recognized as important epigenetic regulators of endothelial function. The aim of this study was to determine whether nitrates induce nitrovasodilator resistance via microRNA-dependent repression of PTGIS gene expression. Methods -Nitrovasodilator resistance was induced by nitroglycerin (GTN; 100 mg/kg/day, 3 days) infusion in Apoe-/- mice. The responses of aortic arteries to nitric oxide (NO) donors were assessed in organ chamber. The expressional levels of miR-199a/b were assayed by RT-qPCR or FISH. Results -In cultured HUVECs, NO donors induced miR-199a/b endogenous expression of and downregulated PTGIS gene expression, both of which were reversed by carboxyl-PTIO or silence of serum response factor. Evidence from computational and luciferase reporter gene analyses indicates that the seed sequence of 976-982 in 3'-UTR of PTGIS mRNA is a target of miR-199a/b. Gain-functions of miR-199a/b resulting from chemical mimics or adenovirus-mediated overexpression increased PTGIS mRNA degradation in HEK293 cells and HUVECs. Furthermore, GTN-decreased PTGIS gene expression was prevented by miR-199a/b antagomirs or was mirrored by the enforced expression of miR-199a/b in HUVECs. In Apoe-/- mice, GTN induced the ectopic expression of miR-199a/b in the carotid arterial endothelium, decreased PTGIS gene expression, and instigated nitrovasodilator resistance, all of which were abrogated by miR-199a/b antagomirs or LNA-anti-miR-199. Importantly, the effects of miR-199a/b inhibitions were abolished by adenovirus-mediated PTGIS deficiency. Moreover, the enforced expression of miR-199a/b in vivo repressed PTGIS gene expression and impaired the responses of aortic arteries to GTN/sodium nitroprusside/acetylcholine/cinaciguat/riociguat, whereas the exogenous expression of PTGIS gene prevented nitrovasodilator resistance in Apoe-/- mice subjected to GTN infusion or miR-199a/b overexpression. Finally, indomethacin, iloprost, and SQ29548 improved vasorelaxation in GTN-infused Apoe-/- mice, while U51605 induced nitrovasodilator resistance. In humans, the increased expressions of miR-199a/b were closely associated with nitrate tolerance. Conclusions -NO induced ectopic expression of miR-199a/b in endothelial cells is required for nitrovasodilator resistance via the repression of PTGIS gene expression. Clinically, miR-199a/b is a novel target for the treatment of nitrate tolerance. PMID- 29431643 TI - Epigenetic Dysregulation of the Dynamin-Related Protein 1 Binding Partners MiD49 and MiD51 Increases Mitotic Mitochondrial Fission and Promotes Pulmonary Arterial Hypertension: Mechanistic and Therapeutic Implications. AB - BACKGROUND: Mitotic fission is increased in pulmonary arterial hypertension (PAH), a hyperproliferative, apoptosis-resistant disease. The fission mediator dynamin-related protein 1 (Drp1) must complex with adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here, we examine the role of 2 recently discovered, poorly understood Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51), in normal vascular cells and explore their dysregulation in PAH. METHODS: Immunoblots of pulmonary artery smooth muscle cells (control, n=6; PAH, n=8) and immunohistochemistry of lung sections (control, n=6; PAH, n=6) were used to assess the expression of MiD49 and MiD51. The effects of manipulating MiDs on cell proliferation, cell cycle, and apoptosis were assessed in human and rodent PAH pulmonary artery smooth muscle cells with flow cytometry. Mitochondrial fission was studied by confocal imaging. A microRNA (miR) involved in the regulation of MiD expression was identified using microarray techniques and in silico analyses. The expression of circulatory miR was assessed with quantitative reverse transcription-polymerase chain reaction in healthy volunteers (HVs) versus patients with PAH from Sheffield, UK (plasma: HV, n=29, PAH, n=27; whole blood: HV, n=11, PAH, n=14) and then confirmed in a cohort from Beijing, China (plasma: HV, n=19, PAH, n=36; whole blood: HV, n=20, PAH, n=39). This work was replicated in monocrotaline and Sugen 5416-hypoxia, preclinical PAH models. Small interfering RNAs targeting MiDs or an miR mimic were nebulized to rats with monocrotaline-induced PAH (n=4-10). RESULTS: MiD expression is increased in PAH pulmonary artery smooth muscle cells, which accelerates Drp1-mediated mitotic fission, increases cell proliferation, and decreases apoptosis. Silencing MiDs (but not other Drp1 binding partners, fission 1 or mitochondrial fission factor) promotes mitochondrial fusion and causes G1-phase cell cycle arrest through extracellular signal-regulated kinases 1/2- and cyclin-dependent kinase 4 dependent mechanisms. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased miR-34a 3p expression. Circulatory miR-34a-3p expression is decreased in both patients with PAH and preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH. CONCLUSIONS: In health, MiDs regulate Drp1-mediated fission, whereas in disease, epigenetic upregulation of MiDs increases mitotic fission, which drives pathological proliferation and apoptosis resistance. The miR-34a-3p-MiD pathway offers new therapeutic targets for PAH. PMID- 29431645 TI - Subretinal Human Umbilical Tissue-Derived Cell Transplantation Preserves Retinal Synaptic Connectivity and Attenuates Muller Glial Reactivity. AB - Human umbilical tissue-derived cells (hUTC or palucorcel) are currently under clinical investigation for the treatment of geographic atrophy, a late stage of macular degeneration, but how hUTC transplantation mediates vision recovery is not fully elucidated. Subretinal administration of hUTC preserves visual function in the Royal College of Surgeons (RCS) rat, a genetic model of retinal degeneration caused by Mertk loss of function. hUTC secrete synaptogenic and neurotrophic factors that improve the health and connectivity of the neural retina. Therefore, we investigated the progression of synapse and photoreceptor loss and whether hUTC treatment preserves photoreceptors and synaptic connectivity in the RCS rats of both sexes. We found that RCS retinas display significant deficits in synaptic development already by postnatal day 21 (P21), before the onset of photoreceptor degeneration. Subretinal transplantation of hUTC at P21 is necessary to rescue visual function in RCS rats, and the therapeutic effect is enhanced with repeated injections. Synaptic development defects occurred concurrently with morphological changes in Muller glia, the major perisynaptic glia in the retina. hUTC transplantation strongly diminished Muller glia reactivity and specifically protected the alpha2delta-1-containing retinal synapses, which are responsive to thrombospondin family synaptogenic proteins secreted by Muller glia. Muller glial reactivity and reduced synaptogenesis observed in RCS retinas could be recapitulated by CRISPR/Cas9 mediated loss-of-Mertk in Muller glia in wild-type rats. Together, our results show that hUTC transplantation supports the health of retina at least in part by preserving the functions of Muller glial cells, revealing a previously unknown aspect of hUTC transplantation-based therapy.SIGNIFICANCE STATEMENT Despite the promising effects observed in clinical trials and preclinical studies, how subretinal human umbilical tissue-derived cell (hUTC) transplantation mediates vision improvements is not fully known. Using a rat model of retinal degeneration, the RCS rat (lacking Mertk), here we provide evidence that hUTC transplantation protects visual function and health by protecting photoreceptors and preserving retinal synaptic connectivity. Furthermore, we find that loss of Mertk function only in Muller glia is sufficient to impair synaptic development and cause activation of Muller glia. hUTC transplantation strongly attenuates the reactivity of Muller glia in RCS rats. These findings highlight novel cellular and molecular mechanisms within the neural retina, which underlie disease mechanisms and pinpoint Muller glia as a novel cellular target for hUTC transplantation. PMID- 29431647 TI - Neural Mechanisms for Adaptive Learned Avoidance of Mental Effort. AB - Humans tend to avoid mental effort. Previous studies have demonstrated this tendency using various demand-selection tasks; participants generally avoid options associated with higher cognitive demand. However, it remains unclear whether humans avoid mental effort adaptively in uncertain and non-stationary environments, and if so, what neural mechanisms underlie this learned avoidance and whether they remain the same irrespective of cognitive-demand types. We addressed these issues by developing novel demand-selection tasks where associations between choice options and cognitive-demand levels change over time, with two variations using mental arithmetic and spatial reasoning problems (29:4 and 18:2 males:females). Most participants showed avoidance, and their choices depended on the demand experienced on multiple preceding trials. We assumed that participants updated the expected cost of mental effort through experience, and fitted their choices by reinforcement learning models, comparing several possibilities. Model-based fMRI analyses revealed that activity in the dorsomedial and lateral frontal cortices was positively correlated with the trial by-trial expected cost for the chosen option commonly across the different types of cognitive demand, and also revealed a trend of negative correlation in the ventromedial prefrontal cortex. We further identified correlates of cost prediction-error at time of problem-presentation or answering the problem, the latter of which partially overlapped with or were proximal to the correlates of expected cost at time of choice-cue in the dorsomedial frontal cortex. These results suggest that humans adaptively learn to avoid mental effort, having neural mechanisms to represent expected cost and cost-prediction-error, and the same mechanisms operate for various types of cognitive demand.SIGNIFICANCE STATEMENTIn daily life, humans encounter various cognitive demands, and tend to avoid high-demand options. However, it remains unclear whether humans avoid mental effort adaptively under dynamically changing environments, and if so, what are the underlying neural mechanisms and whether they operate irrespective of cognitive-demand types. To address these issues, we developed novel tasks, where participants could learn to avoid high-demand options under uncertain and non stationary environments. Through model-based fMRI analyses, we found regions whose activity was correlated with the expected mental effort cost, or cost prediction-error, regardless of demand-type, with overlap or adjacence in the dorsomedial frontal cortex. This finding contributes to clarifying the mechanisms for cognitive-demand avoidance, and provides empirical building blocks for the emerging computational theory of mental effort. PMID- 29431646 TI - Basolateral Amygdala Inputs to the Medial Entorhinal Cortex Selectively Modulate the Consolidation of Spatial and Contextual Learning. AB - Although evidence suggests that the basolateral amygdala (BLA) and dorsal hippocampus (DH) work together to influence the consolidation of spatial/contextual learning, the circuit mechanism by which the BLA selectively modulates spatial/contextual memory consolidation is not clear. The medial entorhinal cortex (mEC) is a critical region in the hippocampus-based system for processing spatial information. As an efferent target of the BLA, the mEC is a candidate by which the BLA influences the consolidation of such learning. To address several questions regarding this issue, male Sprague Dawley rats received optogenetic manipulations of different BLA afferents immediately after training in different learning tasks. Optogenetic stimulation of the BLA-mEC pathway using ChR2(E123A) after spatial and cued-response Barnes maze training enhanced and impaired retention, respectively, whereas optical inhibition of the pathway using eNpHR3.0 produced trends in the opposite direction. Similar stimulation of the BLA-posterior dorsal striatum pathway had no effect. BLA-mEC stimulation also selectively enhanced retention for the contextual, but not foot shock, component of a modified contextual fear-conditioning procedure. In both sets of experiments, only stimulation using bursts of 8 Hz light pulses significantly enhanced retention, suggesting the importance of driving activity in this frequency range. An 8 Hz stimulation of the BLA-mEC pathway increased local field potential power in the same frequency range in the mEC and in the DH. Together, the present findings suggest that the BLA modulates the consolidation of spatial/contextual memory via projections to the mEC and that activity within the 8 Hz range is critical for this modulation.SIGNIFICANCE STATEMENT The mechanism by which the basolateral amygdala (BLA) influences the consolidation of spatial/contextual memory is unknown. Using an optogenetic approach with multiple behavioral procedures, we found that immediate posttraining 8 Hz stimulation of BLA projections to the medial entorhinal cortex (mEC) enhanced retention for spatial/contextual memory, impaired retention for cued-response memory, and had no effect on foot shock learning for contextual fear conditioning. Electrophysiological recordings confirmed that 8 Hz stimulation of this pathway increased activity in the 8 Hz range in the mEC and in the dorsal hippocampus, a region critical for spatial memory consolidation. This suggests that coordinated BLA activity with downstream regions in the 8 Hz activity range immediately after training is important for consolidation of multiple memory forms. PMID- 29431648 TI - The Role of Mesolimbic Circuitry in Buffering Election-Related Distress. AB - The 2016 U.S. presidential election yielded distress among many individuals who identify with historically marginalized groups. We used functional magnetic resonance imaging and psychological measures to test the hypotheses that neural response to reward, probing the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC), and social support would ameliorate the effects of election distress among those who felt negatively affected by the result. Within 4 months of the 2016 U.S. presidential election, we tested human participants who felt affected by the election result (n = 40, Mage = 21.9 years, 28 female) and control participants (n = 20, Mage = 20.25 years, 12 female) who did not feel affected by the election result. Election-related distress significantly differed between the groups, and distress accounted for over half of the relationship between discrimination experiences and depression symptoms among affected individuals. NAcc activation, connectivity between the NAcc and mPFC, and family support moderated the associations between election distress and depression symptoms. Prior work has primarily investigated mesolimbic circuitry in reward and motivation contexts, but our findings extend the relevance of functioning in this circuitry to ameliorating psychological manifestations of acute distress after shifts in political climate. These findings highlight the psychological effects of this important historic event and identify neurobiological and social mechanisms associated with individual differences in response to election distress.SIGNIFICANCE STATEMENT The 2016 U.S. presidential election was psychologically distressing for many individuals. In this study, election-related distress was linked to depression symptomology for affected individuals but not control individuals. However, among individuals distressed by the election, those with greater neural response to reward and higher family support were protected against these depressive symptoms. Previous research has examined how neural response to reward after a discrete event ameliorates clinical symptoms. The current study extends this knowledge by demonstrating that both the brain and social support may play influential roles in dampening affective responses to ongoing and anticipated distress related to political climate. Leveraging this finding to enact interventions that dampen continuous distress, political or otherwise, is a promising endeavor for future research. PMID- 29431649 TI - Sleep deprivation distinctly alters glutamate transporter 1 apposition and excitatory transmission to orexin and MCH neurons. AB - Glutamate transporter 1 (GLT1) is the main astrocytic transporter that shapes glutamatergic transmission in the brain. However, whether this transporter modulates sleep/wake regulatory neurons is unknown. Using quantitative immunohistochemical analysis, we assessed perisomatic GLT1 apposition with sleep/wake neurons in the male rat following 6-h sleep deprivation (SD) or following 6-h undisturbed conditions when animals were mostly asleep (Rest). We found that SD decreased perisomatic GLT1 apposition with wake-promoting orexin (ORX) neurons in the lateral hypothalamus (LH) compared to Rest. Reduced GLT1 apposition was associated with tonic presynaptic inhibition of excitatory transmission to these neurons due to the activation of group III metabotropic glutamate receptors, an effect mimicked by a GLT1 inhibitor in the Rest condition. In contrast, SD resulted in increased GLT1 apposition with sleep promoting melanin-concentrating hormone (MCH) neurons in the LH. Functionally, this decreased the postsynaptic response of MCH neurons to high frequency synaptic activation without changing presynaptic glutamate release. The changes in GLT1 apposition with ORX and MCH neurons were reversed after 3 h of sleep opportunity following 6-h SD. These SD effects were specific to orexin and MCH neurons, as no change in GLT1 apposition was seen in basal forebrain cholinergic or parvalbumin-positive GABA neurons. Thus, within a single hypothalamic area, GLT1 differentially regulates excitatory transmission to wake- and sleep promoting neurons depending on sleep history. These processes may constitute novel astrocyte-mediated homeostatic mechanisms controlling sleep/wake behavior.SIGNIFICANCE STATEMENTSleep/wake cycles are regulated by the alternate activation of sleep- and wake-promoting neurons. Whether and how astrocytes can regulate this reciprocal neuronal activity is unclear. Here we report that within the lateral hypothalamus, where functionally opposite wake-promoting orexin (ORX) neurons and sleep-promoting melanin-concentrating hormone (MCH) neurons co distribute, the glutamate transporter GLT1, mainly present on astrocytes, distinctly modulates excitatory transmission in a cell-type specific manner and according to sleep history. Specifically, GLT1 is reduced around the somata of ORX neurons while increased around MCH neurons following sleep deprivation, resulting in different forms of synaptic plasticity. Thus, astrocytes can fine tune the excitability of functionally discrete neurons via glutamate transport, which may represent novel regulatory mechanisms for sleep. PMID- 29431651 TI - Development of Cross-Orientation Suppression and Size Tuning and the Role of Experience. AB - Many sensory neural circuits exhibit response normalization, which occurs when the response of a neuron to a combination of multiple stimuli is less than the sum of the responses to the individual stimuli presented alone. In the visual cortex, normalization takes the forms of cross-orientation suppression and surround suppression. At the onset of visual experience, visual circuits are partially developed and exhibit some mature features such as orientation selectivity, but it is unknown whether cross-orientation suppression is present at the onset of visual experience or requires visual experience for its emergence. We characterized the development of normalization and its dependence on visual experience in female ferrets. Visual experience was varied across the following three conditions: typical rearing, dark rearing, and dark rearing with daily exposure to simple sinusoidal gratings (14-16 h total). Cross-orientation suppression and surround suppression were noted in the earliest observations, and did not vary considerably with experience. We also observed evidence of continued maturation of receptive field properties in the second month of visual experience: substantial length summation was observed only in the oldest animals (postnatal day 90); evoked firing rates were greatly increased in older animals; and direction selectivity required experience, but declined slightly in older animals. These results constrain the space of possible circuit implementations of these features.SIGNIFICANCE STATEMENT The development of the brain depends on both nature-factors that are independent of the experience of an individual animal-and nurture-factors that depend on experience. While orientation selectivity, one of the major response properties of neurons in visual cortex, is already present at the onset of visual experience, it is unknown whether response properties that depend on interactions among multiple stimuli develop without experience. We find that the properties of cross-orientation suppression and surround suppression are present at eye opening, and do not depend on visual experience. Our results are consistent with the idea that a majority of the basic properties of sensory neurons in primary visual cortex are derived independent of the experience of an individual animal. PMID- 29431650 TI - Protein Translation in the Nucleus Accumbens Is Dysregulated during Cocaine Withdrawal and Required for Expression of Incubation of Cocaine Craving. AB - Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies ("incubates") during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneurosomes prepared after >47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2alpha (eIF2alpha) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2alpha dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving.SIGNIFICANCE STATEMENT Cue-induced cocaine craving progressively intensifies (incubates) during withdrawal in both humans and rats. This may contribute to persistent vulnerability to relapse. We previously demonstrated a role for protein translation in synaptic adaptations in the NAc closely linked to incubation. Here, we tested the hypothesis that translation is dysregulated during cocaine withdrawal, and this contributes to incubated craving. Analysis of signaling pathways regulating translation suggested that translation is enhanced when "incubated" rats undergo a cue-induced seeking test. Furthermore, intra-NAc infusions of drugs that inhibit protein translation through different mechanisms reduced expression of incubated cue-induced cocaine seeking. These results demonstrate that the expression of incubation depends on an acute increase in translation that may result from dysregulation of several pathways. PMID- 29431652 TI - Dynamic flexibility in striatal-cortical circuits supports reinforcement learning. AB - Complex learned behaviors must involve the integrated action of distributed brain circuits. While the contributions of individual regions to learning have been extensively investigated, much less is known about how distributed brain networks orchestrate their activity over the course of learning. To address this gap, we used fMRI combined with tools from dynamic network neuroscience to obtain time resolved descriptions of network coordination during reinforcement learning in humans. We found that learning to associate visual cues with reward involves dynamic changes in network coupling between the striatum and distributed brain regions, including visual, orbitofrontal, and ventromedial prefrontal cortex (n=22, 13 females). Moreover, we found that this flexibility in striatal network coupling correlates with participants' learning rate and inverse temperature, two parameters derived from reinforcement learning models. Finally, we found that episodic learning, measured separately in the same participants at the same time, was related to dynamic connectivity in distinct brain networks. These results suggest that dynamic changes in striatal-centered networks provide a mechanism for information integration during reinforcement learning.SIGNIFICANCE STATEMENTLearning from the outcomes of actions - referred to as reinforcement learning - is an essential part of life. The roles of individual brain regions in reinforcement learning have been well characterized in terms of updating values for actions or cues. Missing from this account, however, is an understanding of how different brain areas interact during learning to integrate sensory and value information. Here we characterize flexible striatal-cortical network dynamics that relate to reinforcement learning behavior. PMID- 29431653 TI - Regulation of synapse development by Vgat deletion from ErbB4-positive interneurons. AB - GABA signaling has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA activity die prematurely. Here, we studied synapse development by ablating vesicular GABA transporter Vgat in in ErbB4-positive (ErbB4+) interneurons. We show that inhibitory axo-somatic synapses onto pyramidal neurons vary from one cortical layer to another; however, inhibitory synapses on axon initial segments (AISs) were similar across layers. On the other hand, PV-positive (PV+)/ErbB4+ interneurons and PV-only interneurons receive a higher number of inhibitory synapses from PV+ErbB4+ interneurons, compared with ErbB4-only interneurons. Notably, Vgat deletion from ErbB4+ interneurons reduced axo-somatic or axo-axonic synapses from PV+ErbB4+ interneurons onto excitatory neurons. This effect was associated with corresponding changes in neurotransmission. However, the Vgat mutation seemed to have little effect on inhibitory synapses onto PV+ and/or ErbB4+ interneurons. Interestingly, perineuronal nets (PNNs), extracellular matrix structures implicated in maturation, survival, protection and plasticity of PV+ interneurons, were increased in the cortex of ErbB4-Vgat-/- mice. No apparent difference was observed between males and females. These results demonstrate that Vgat of ErbB4+ interneurons is essential for the development of inhibitory synapses onto excitatory neurons and suggest a role of GABA in circuit assembly.SIGNIFICANCE STATEMENTGABA has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA die prematurely. To this end, we ablated Vgat in ErbB4+ interneurons in an inducible manner. We provide evidence that the formation of inhibitory as well as excitatory synapses onto excitatory neurons requires Vgat in interneurons. In particular, inhibitory axo-somatic and axo-axonic synapses are more vulnerable. Our results suggest a role of GABA in circuit assembly. PMID- 29431656 TI - Global Impact of 2017 American Heart Association/American College of Cardiology Hypertension Guidelines: A Perspective From Japan. PMID- 29431654 TI - Enhanced Operant Extinction and Prefrontal Excitability in a Mouse Model of Angelman Syndrome. AB - Angelman syndrome (AS), a neurodevelopmental disorder associated with intellectual disability, is caused by loss of maternal allele expression of UBE3A in neurons. Mouse models of AS faithfully recapitulate disease phenotypes across multiple domains, including behavior. Yet in AS, there has been only limited study of behaviors encoded by the prefrontal cortex, a region broadly involved in executive function and cognition. Because cognitive impairment is a core feature of AS, it is critical to develop behavioral readouts of prefrontal circuit function in AS mouse models. One such readout is behavioral extinction, which has been well described mechanistically and relies upon prefrontal circuits in rodents. Here we report exaggerated operant extinction in male AS model mice, concomitant with enhanced excitability in medial prefrontal neurons from male and female AS model mice. Abnormal behavior was specific to operant extinction, as two other prefrontally dependent tasks (cued fear extinction and visuospatial discrimination) were largely normal in AS model mice. Inducible deletion of Ube3a during adulthood was not sufficient to drive abnormal extinction, supporting the hypothesis that there is an early critical period for development of cognitive phenotypes in AS. This work represents the first formal experimental analysis of prefrontal circuit function in AS, and identifies operant extinction as a useful experimental paradigm for modeling cognitive aspects of AS in mice.SIGNIFICANCE STATEMENT Prefrontal cortex encodes "high-level" cognitive processes. Thus, understanding prefrontal function is critical in neurodevelopmental disorders where cognitive impairment is highly penetrant. Angelman syndrome is a neurodevelopmental disorder associated with speech and motor impairments, an outwardly happy demeanor, and intellectual disability. We describe a behavioral phenotype in a mouse model of Angelman syndrome and related abnormalities in prefrontal cortex function. We hypothesize that robust and reliable prefrontally encoded behavior may be used to model cognitive impairments in Angelman syndrome. PMID- 29431657 TI - Global Impact of 2017 American College of Cardiology/American Heart Association Hypertension Guidelines: A Perspective From China. PMID- 29431658 TI - Global Impact of 2017 American Heart Association/American College of Cardiology Hypertension Guidelines: A Perspective From India. PMID- 29431659 TI - Validation of DAPT Score (Dual Antiplatelet Therapy) in East Asian Patients. PMID- 29431655 TI - Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral and Type II at Central Nociceptor Terminals. AB - Systemic fentanyl induces hyperalgesic priming, long-lasting neuroplasticity in nociceptor function characterized by prolongation of inflammatory mediator hyperalgesia. To evaluate priming at both nociceptor terminals, we studied, in male Sprague Dawley rats, the effect of local administration of agents that reverse type I (protein translation) or type II [combination of Src and mitogen activated protein kinase (MAPK)] priming. At the central terminal, priming induced by systemic, intradermal, or intrathecal fentanyl was reversed by the combination of Src and MAPK inhibitors, but at the peripheral terminal, it was reversed by the protein translation inhibitor. Mu-opioid receptor (MOR) antisense prevented fentanyl hyperalgesia and priming. To determine whether type I and II priming occur in the same population of neurons, we used isolectin B4-saporin or [Sar9, Met(O2)11]-substance P-saporin to deplete nonpeptidergic or peptidergic nociceptors, respectively. Following intrathecal fentanyl, central terminal priming was prevented by both saporins, whereas that in peripheral terminal was not attenuated even by their combination. However, after intradermal fentanyl, priming in the peripheral terminal requires both peptidergic and nonpeptidergic nociceptors, whereas that in the central terminal is dependent only on peptidergic nociceptors. Pretreatment with dantrolene at either terminal prevented fentanyl-induced priming in both terminals, suggesting communication between central and peripheral terminals mediated by intracellular Ca2+ signaling. In vitro application of fentanyl increased cytoplasmic Ca2+ concentration in dorsal root ganglion neurons, which was prevented by pretreatment with dantrolene and naloxone. Therefore, acting at MOR in the nociceptor, fentanyl induces hyperalgesia and priming rapidly at both the central (type II) and peripheral (type I) terminal and this is mediated by Ca2+ signaling.SIGNIFICANCE STATEMENT Fentanyl, acting at the MU-opioid receptor (MOR), induces hyperalgesia and hyperalgesic priming at both the central and peripheral terminal of nociceptors and this is mediated by endoplasmic reticulum Ca2+ signaling. Priming in the central terminal is type II, whereas that in the peripheral terminal is type I. Our findings may provide useful information for the design of drugs with improved therapeutic profiles, selectively disrupting individual MOR signaling pathways, to maintain an adequate long-lasting control of pain. PMID- 29431660 TI - Survivor's Remorse: Is There an Increased Risk of Dementia After Surviving a Myocardial Infarction? PMID- 29431661 TI - Comparisons Between Ductal Stenting and Blalock-Taussig Shunts for Infants With Ductal-Dependent Pulmonary Circulation. PMID- 29431662 TI - Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing. AB - The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues. PMID- 29431664 TI - Midterm Safety and Performance of a Leadless Cardiac Pacemaker: 3-Year Follow-up to the LEADLESS Trial (Nanostim Safety and Performance Trial for a Leadless Cardiac Pacemaker System). PMID- 29431665 TI - Postoperative Complications Decrease Long-Term Survival After Thoracic Aneurysm Repair Despite Apparently Successful "Rescue" From Early Mortality. PMID- 29431666 TI - Letter by Koh Regarding Article, "Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label)". PMID- 29431668 TI - Letter by Jin-shan and Xue-bin Regarding Article, "Idiopathic Ventricular Fibrillation in a 29-Year-Old Man". PMID- 29431667 TI - Response by Kusters et al to Letter Regarding Article, "Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label)". PMID- 29431669 TI - Response by Beach et al to Letter Regarding Article, "Idiopathic Ventricular Fibrillation in a 29-Year-Old Man". PMID- 29431672 TI - ERK Inhibition: A New Front in the War against MAPK Pathway-Driven Cancers? AB - ERK inhibitors have enormous therapeutic potential against tumors that are BRAF mutant, BRAF-MEK inhibitor resistant, or RAS mutant. In this issue of Cancer Discovery, Sullivan and colleagues report on the first-in-human dose-escalation study of the ERK inhibitor ulixertinib, which they show to be well tolerated with clinical activity against a wide range of tumor types. Cancer Discov; 8(2); 140 2. (c)2018 AACR.See related article by Sullivan et al., p. 184. PMID- 29431673 TI - A Critical Need for Better Cancer Immunotherapy Models: Are Organotypic Tumor Spheroid Cultures the Answer? AB - Immunotherapy has transformed the therapeutic landscape of cancer, but the preclinical evaluation of combination approaches that will deepen and broaden its clinical benefit has lagged far behind due to the lack of expedient and easily accessible ex vivo human systems. In this issue, Jenkins and colleagues and Deng and colleagues report the use of organotypic cultures of tumors derived from mice and humans containing both tumor cells and cells from their local immune microenvironment to recapitulate the in vivo use of immune checkpoint inhibitors and extend the application of this system to therapeutic combinations of immune checkpoint blockade and molecularly targeted agents. Cancer Discov; 8(2); 143-5. (c)2018 AACR.See related article by Jenkins et al., p. 196See related article by Deng et al., p. 216. PMID- 29431674 TI - What's the FOX Got to Do with the KITten? Regulating the Lineage-Specific Transcriptional Landscape in GIST. AB - Transcriptional regulation of the KIT receptor tyrosine kinase, a master regulator in gastrointestinal stromal tumors (GIST) and their precursors, the interstitial cells of Cajal (ICC), is part of a positive feedback loop involving the transcription factor ETV1. A new study now shows that the forkhead box (FOX) family transcription factor FOXF1 not only is an upstream regulator of ETV1 and hence ICC/GIST lineage-specific gene transcription, but also functions as lineage specific pioneer factor with an active role in chromatin rearrangement to facilitate ETV1 binding and transcriptional activity. Cancer Discov; 8(2); 146-9. (c)2018 AACRSee related article by Ran et al., p. 234. PMID- 29431675 TI - Application of one-dimensional semiclassical transition state theory to the CH3OH + H ? CH2OH/CH3O + H2 reactions. AB - The rate constants of the two branches of H-abstractions from CH3OH by the H-atom and the corresponding reactions in the reverse direction are calculated using the one-dimensional semiclassical transition state theory (1D SCTST). In this method, only the reaction mode vibration of the transition state (TS) is treated anharmonically, while the remaining internal degrees of freedom are treated as they would have been in a standard TS theory calculation. A total of eight ab initio single-point energy calculations are performed in addition to the computational cost of a standard TS theory calculation. This allows a second order Richardson extrapolation method to be employed to improve the numerical estimation of the third- and fourth-order derivatives, which in turn are used in the calculation of the anharmonic constant. Hindered-rotor (HR) vibrations are identified in the equilibrium states of CH3OH and CH2OH, and the TSs of the reactions. The partition function of the HRs are calculated using both a simple harmonic oscillator model and a more sophisticated one-dimensional torsional eigenvalue summation (1D TES) method. The 1D TES method can be easily adapted in 1D SCTST computation. The resulting 1D SCTST with 1D TES rate constants show good agreement to previous theoretical and experimental works. The effects of the HR on rate constants for different reactions are also investigated.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431676 TI - Hamiltonian flow over saddles for exploring molecular phase space structures. AB - Despite using potential energy surfaces, multivariable functions on molecular configuration space, to comprehend chemical dynamics for decades, the real happenings in molecules occur in phase space, in which the states of a classical dynamical system are completely determined by the coordinates and their conjugate momenta. Theoretical and numerical results are presented, employing alanine dipeptide as a model system, to support the view that geometrical structures in phase space dictate the dynamics of molecules, the fingerprints of which are traced by following the Hamiltonian flow above saddles. By properly selecting initial conditions in alanine dipeptide, we have found internally free rotor trajectories the existence of which can only be justified in a phase space perspective.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431677 TI - High-accuracy water potential energy surface for the calculation of infrared spectra. AB - Transition intensities for small molecules such as water and CO2 can now be computed with such high accuracy that they are being used to systematically replace measurements in standard databases. These calculations use high-accuracy ab initio dipole moment surfaces and wave functions from spectroscopically determined potential energy surfaces (PESs). Here, an extra high-accuracy PES of the water molecule (H216O) is produced starting from an ab initio PES which is then refined to empirical rovibrational energy levels. Variational nuclear motion calculations using this PES reproduce the fitted energy levels with a standard deviation of 0.011 cm-1, approximately three times their stated uncertainty. The use of wave functions computed with this refined PES is found to improve the predicted transition intensities for selected (problematic) transitions. A new room temperature line list for H216O is presented. It is suggested that the associated set of line intensities is the most accurate available to date for this species.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431678 TI - Kinetics and dynamics of near-resonant vibrational energy transfer in gas ensembles of atmospheric interest. AB - This study of near-resonant, vibration-vibration (V-V) gas-phase energy transfer in diatomic molecules uses the theoretical/computational method, of Marsh & McCaffery (Marsh & McCaffery 2002 J. Chem. Phys.117, 503 (doi:10.1063/1.1489998)) The method uses the angular momentum (AM) theoretical formalism to compute quantum-state populations within the component molecules of large, non equilibrium, gas mixtures as the component species proceed to equilibration. Computed quantum-state populations are displayed in a number of formats that reveal the detailed mechanism of the near-resonant V-V process. Further, the evolution of quantum-state populations, for each species present, may be followed as the number of collision cycles increases, displaying the kinetics of evolution for each quantum state of the ensemble's molecules. These features are illustrated for ensembles containing vibrationally excited N2 in H2, O2 and N2 initially in their ground states.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431679 TI - Statistical mechanics of binary mixture adsorption in metal-organic frameworks in the osmotic ensemble. AB - Although crucial for designing separation processes little is known experimentally about multi-component adsorption isotherms in comparison with pure single components. Very few binary mixture adsorption isotherms are to be found in the literature and information about isotherms over a wide range of gas-phase composition and mechanical pressures and temperature is lacking. Here, we present a quasi-one-dimensional statistical mechanical model of binary mixture adsorption in metal-organic frameworks (MOFs) treated exactly by a transfer matrix method in the osmotic ensemble. The experimental parameter space may be very complex and investigations into multi-component mixture adsorption may be guided by theoretical insights. The approach successfully models breathing structural transitions induced by adsorption giving a good account of the shape of adsorption isotherms of CO2 and CH4 adsorption in MIL-53(Al). Binary mixture isotherms and co-adsorption-phase diagrams are also calculated and found to give a good description of the experimental trends in these properties and because of the wide model parameter range which reproduces this behaviour suggests that this is generic to MOFs. Finally, a study is made of the influence of mechanical pressure on the shape of CO2 and CH4 adsorption isotherms in MIL-53(Al). Quite modest mechanical pressures can induce significant changes to isotherm shapes in MOFs with implications for binary mixture separation processes.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431680 TI - Quantum chemical study of the structure, spectroscopy and reactivity of NO+.(H2O) n=1-5 clusters. AB - Quantum chemical methods including Moller-Plesset perturbation (MP2) theory and density functional theory (DFT) have been used to study the structure, spectroscopy and reactivity of NO+(H2O) n=1-5 clusters. MP2/6-311++G** calculations are shown to describe the structure and spectroscopy of the clusters well. DFT calculations with exchange-correlation functionals with a low fraction of Hartree-Fock exchange give a binding energy of NO+(H2O) that is too high and incorrectly predict the lowest energy structure of NO+(H2O)2, and this error may be associated with a delocalization of charge onto the water molecule directly binding to NO+ Ab initio molecular dynamics (AIMD) simulations were performed to study the NO+(H2O)5 [Formula: see text] H+(H2O)4 + HONO reaction to investigate the formation of HONO from NO+(H2O)5 Whether an intracluster reaction to form HONO is observed depends on the level of electronic structure theory used. Of note is that methods that accurately describe the relative energies of the product and reactant clusters did not show reactions on the timescales studied. This suggests that in the upper atmosphere the reaction may occur owing to the energy present in the NO+(H2O)5 complex following its formation.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431681 TI - Hartree-Fock implementation using a Laguerre-based wave function for the ground state and correlation energies of two-electron atoms. AB - An implementation of the Hartree-Fock (HF) method using a Laguerre-based wave function is described and used to accurately study the ground state of two electron atoms in the fixed nucleus approximation, and by comparison with fully correlated (FC) energies, used to determine accurate electron correlation energies. A variational parameter A is included in the wave function and is shown to rapidly increase the convergence of the energy. The one-electron integrals are solved by series solution and an analytical form is found for the two-electron integrals. This methodology is used to produce accurate wave functions, energies and expectation values for the helium isoelectronic sequence, including at low nuclear charge just prior to electron detachment. Additionally, the critical nuclear charge for binding two electrons within the HF approach is calculated and determined to be ZHFC=1.031 177 528.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431682 TI - Isomers and energy landscapes of micro-hydrated sulfite and chlorate clusters. AB - We present putative global minima for the micro-hydrated sulfite SO32-(H2O) N and chlorate ClO3-(H2O) N systems in the range 3<=N<=15 found using basin-hopping global structure optimization with an empirical potential. We present a structural analysis of the hydration of a large number of minimized structures for hydrated sulfite and chlorate clusters in the range 3<=N<=50. We show that sulfite is a significantly stronger net acceptor of hydrogen bonding within water clusters than chlorate, completely suppressing the appearance of hydroxyl groups pointing out from the cluster surface (dangling OH bonds), in low-energy clusters. We also present a qualitative analysis of a highly explored energy landscape in the region of the global minimum of the eight water hydrated sulfite and chlorate systems.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431683 TI - Interactions of C+(2PJ ) with rare gas atoms: incipient chemical interactions, potentials and transport coefficients. AB - Accurate interatomic potentials were calculated for the interaction of a singly charged carbon cation, C+, with a single rare gas atom, RG (RG = Ne-Xe). The RCCSD(T) method and basis sets of quadruple-zeta and quintuple-zeta quality were employed; each interaction energy was counterpoise corrected and extrapolated to the basis set limit. The lowest C+(2P) electronic term of the carbon cation was considered, and the interatomic potentials calculated for the diatomic terms that arise from these: 2Pi and 2Sigma+ Additionally, the interatomic potentials for the respective spin-orbit levels were calculated, and the effect on the spectroscopic parameters was examined. In doing this, anomalously large spin orbit splittings for RG = Ar-Xe were found, and this was investigated using multi reference configuration interaction calculations. The latter indicated a small amount of RG -> C+ electron transfer and this was used to rationalize the observations. This is taken as evidence of an incipient chemical interaction, which was also examined via contour plots, Birge-Sponer plots and various population analyses across the C+-RG series (RG = He-Xe), with the latter showing unexpected results. Trends in several spectroscopic parameters were examined as a function of the increasing atomic number of the RG atom. Finally, each set of RCCSD(T) potentials was employed, including spin-orbit coupling to calculate the transport coefficients for C+ in RG, and the results were compared with the limited available data.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431684 TI - Accessing the molecular frame through strong-field alignment of distributions of gas phase molecules. AB - A rationale for creating highly aligned distributions of molecules is that it enables vector properties referenced to molecule-fixed axes (the molecular frame) to be determined. In the present work, the degree of alignment that is necessary for this to be achieved in practice is explored. Alignment is commonly parametrized in experiments by a single parameter, [Formula: see text], which is insufficient to enable predictive calculations to be performed. Here, it is shown that, if the full distribution of molecular axes takes a Gaussian form, this single parameter can be used to determine the complete set of alignment moments needed to characterize the distribution. In order to demonstrate the degree of alignment that is required to approach the molecular frame, the alignment moments corresponding to a few chosen values of [Formula: see text] are used to project a model molecular frame photoelectron angular distribution into the laboratory frame. These calculations show that [Formula: see text] needs to approach 0.9 in order to avoid significant blurring to be caused by averaging.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431685 TI - Modern theoretical chemistry: the legacy of Prof. John N. Murrell. PMID- 29431686 TI - Dynamic simulations of many-body electrostatic self-assembly. AB - Two experimental studies relating to electrostatic self-assembly have been the subject of dynamic computer simulations, where the consequences of changing the charge and the dielectric constant of the materials concerned have been explored. One series of calculations relates to experiments on the assembly of polymer particles that have been subjected to tribocharging and the simulations successfully reproduce many of the observed patterns of behaviour. A second study explores events observed following collisions between single particles and small clusters composed of charged particles derived from a metal oxide composite. As before, observations recorded during the course of the experiments are reproduced by the calculations. One study in particular reveals how particle polarizability can influence the assembly process.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431687 TI - Cn (n=2-4): current status. AB - The major aspects of the C2, C3 and C4 elemental carbon clusters are surveyed. For C2, a brief analysis of its current status is presented. Regarding C3, the most recent results obtained in our group are reviewed with emphasis on modelling its potential energy surface which is particularly complicated due to the presence of multiple conical intersections. As for C4, the most stable isomeric forms of both triplet and singlet spin states and their possible interconversion pathways are examined afresh by means of accurate ab initio calculations. The main strategies for modelling the ground triplet C4 potential are also discussed. Starting from a truncated cluster expansion and a previously reported DMBE form for C3, an approximate four-body term is calibrated from the ab initio energies. The final six-dimensional global DMBE form so obtained reproduces all known topographical aspects while providing an accurate description of the C4 linear rhombic isomerization pathway. It is therefore commended for both spectroscopic and reaction dynamics studies.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431688 TI - Probing the rate-determining region of the potential energy surface for a prototypical ion-molecule reaction. AB - We report a joint experimental-theoretical study of the F- + HCl -> HF + Cl- reaction kinetics. The experimental measurement of the rate coefficient at several temperatures was made using the selected ion flow tube method. Theoretical rate coefficients are calculated using the quasi-classical trajectory method on a newly developed global potential energy surface, obtained by fitting a large number of high-level ab initio points with augmentation of long-range electrostatic terms. In addition to good agreement between experiment and theory, analyses suggest that the ion-molecule reaction rate is significantly affected by shorter-range interactions, in addition to the traditionally recognized ion dipole and ion-induced dipole terms. Furthermore, the statistical nature of the reaction is assessed by comparing the measured and calculated HF product vibrational state distributions to that predicted by the phase space theory.This article is part of the theme issue 'Modern theoretical chemistry'. PMID- 29431690 TI - ILDR2-Fc Is a Novel Regulator of Immune Homeostasis and Inducer of Antigen Specific Immune Tolerance. AB - ILDR2 is a member of the Ig superfamily, which is implicated in tricellular tight junctions, and has a putative role in pancreatic islet health and survival. We recently found a novel role for ILDR2 in delivering inhibitory signals to T cells. In this article, we show that short-term treatment with ILDR2-Fc results in long-term durable beneficial effects in the relapsing-remitting experimental autoimmune encephalomyelitis and NOD type 1 diabetes models. ILDR2-Fc also promotes transplant engraftment in a minor mismatch bone marrow transplantation model. ILDR2-Fc displays a unique mode of action, combining immunomodulation, regulation of immune homeostasis, and re-establishment of Ag-specific immune tolerance via regulatory T cell induction. These findings support the potential of ILDR-Fc to provide a promising therapeutic approach for the treatment of autoimmune diseases. PMID- 29431689 TI - Dysregulated Th1 Immune and Vascular Responses in Scrub Typhus Pathogenesis. AB - Scrub typhus is an emerging, insect-transmitted disease caused by Orientia tsutsugamushi, a Gram- and LPS-negative bacterium that replicates freely within professional phagocytes and endothelial cells. Scrub typhus is prevalent with high mortality rates, but information regarding its molecular pathogenesis, microbial virulence determinants, and key immune responses is limited. Improved animal models have recently been developed that respectively resemble the pathological features of self-limiting or severe scrub typhus in humans. Strong activation of Th1 and CD8, but not Th2 and regulatory T, immune responses, accompanied by altered angiopoietin/Tie2-related regulation, are hallmarks of lethal infection in murine models. This review, based primarily on recent advances from clinical and experimental studies, highlights tissue- and endothelial cell-specific biomarkers that are indicative of immune dysregulation. The potential roles of neutrophils and damage-associated molecular pattern molecules at late stages of disease are discussed in the context of vascular leakage, pulmonary and renal injury, and scrub typhus pathogenesis. PMID- 29431691 TI - Low-Dose Methotrexate Prevents Primary and Secondary Humoral Immune Responses and Induces Immune Tolerance to a Recombinant Immunotoxin. AB - Recombinant immunotoxins (RITs) are chimeric proteins being developed for cancer treatment. They are composed of an Ab fragment that targets a cancer Ag and a cytotoxic portion of Pseudomonas exotoxin A. They are effective for patients with hematologic malignancies with defective immunity, but their efficacy against solid tumors is limited by anti-drug Ab (ADA) responses in immune-competent patients. Pre-existing Abs or immune memory owing to previous toxin exposure represent additional hurdles because they induce rapid and strong ADA responses. Here, we evaluated the efficacy of methotrexate (MTX) to prevent ADA formation against the mesothelin-targeting RIT LMB-100 in naive mice and in mice with pre existing Abs. We found that low-dose MTX combined with LMB-100 completely suppressed the formation of ADAs in a dose- and frequency-dependent manner. Suppression of the immune response restored blood levels of LMB-100 and prevented its neutralization. Furthermore, combination of MTX with LMB-100 did not compromise the immune response against a second Ag given after stopping MTX, indicating specific immune tolerance. Adoptive transfer of splenocytes suppressed Ab responses to LMB-100 in recipient mice, indicating a durable immune tolerance. We conclude that combination of MTX and LMB-100 is effective at preventing immune responses in a durable, Ag-specific manner. We propose combining low-dose MTX in immune-competent cancer patients receiving RIT therapy to prevent immunogenicity. This approach could be applied to other immunogenic therapeutic agents and to proteins for which there is pre-existing immunity. PMID- 29431693 TI - An Antigen-Free, Plasmacytoid Dendritic Cell-Targeting Immunotherapy To Bolster Memory CD8+ T Cells in Nonhuman Primates. AB - The priming, boosting, and restoration of memory cytotoxic CD8+ T lymphocytes by vaccination or immunotherapy in vivo is an area of active research. Particularly, nucleic acid-based compounds have attracted attention due to their ability to elicit strong Ag-specific CTL responses as a vaccine adjuvant. Nucleic acid-based compounds have been shown to act as anticancer monotherapeutic agents even without coadministration of cancer Ag(s); however, so far they have lacked efficacy in clinical trials. We recently developed a second-generation TLR9 agonist, a humanized CpG DNA (K3) complexed with schizophyllan (SPG), K3-SPG, a nonagonistic Dectin-1 ligand. K3-SPG was previously shown to act as a potent monoimmunotherapeutic agent against established tumors in mice in vivo. In this study we extend the monoimmunotherapeutic potential of K3-SPG to a nonhuman primate model. K3-SPG activated monkey plasmacytoid dendritic cells to produce both IFN-alpha and IL-12/23 p40 in vitro and in vivo. A single injection s.c. or i.v. with K3-SPG significantly increased the frequencies of activated memory CD8+ T cells in circulation, including Ag-specific memory CTLs, in cynomolgus macaques. This increase did not occur in macaques injected with free CpG K3 or polyinosinic-polycytidylic acid. Injection of 2 mg K3-SPG induced mild systemic inflammation, however, levels of proinflammatory serum cytokines and circulating neutrophil influx were lower than those induced by the same dose of polyinosinic polycytidylic acid. Therefore, even in the absence of specific Ags, we show that K3-SPG has potent Ag-specific memory CTL response-boosting capabilities, highlighting its potential as a monoimmunotherapeutic agent for chronic infectious diseases and cancer. PMID- 29431692 TI - Development of Asthma in Inner-City Children: Possible Roles of MAIT Cells and Variation in the Home Environment. AB - Humans have populations of innate-like T lymphocytes with an invariant TCR alpha chain that recognize nonpeptide Ags, including invariant NKT (iNKT) cells and mucosal-associated invariant T (MAIT) cells. iNKT cell involvement in human asthma is controversial, whereas there has been little analysis of MAIT cells. Using peripheral blood cells from 110 participants from the Urban Environment and Childhood Asthma (URECA) birth cohort study, these cells were analyzed for number and function. We determined whether iNKT cell or MAIT cell frequency at 1 y is correlated with the cytokine polarization of mainstream CD4+ T cells and/or the development of asthma by age 7 y. Dust samples from 300 houses were tested for iNKT cell antigenic activity. Our results show that a higher MAIT cell frequency at 1 y of age was associated with a decreased risk of asthma by age 7 y. The frequency of MAIT cells was associated with increased production of IFN-gamma by activated CD4+ T cells from the URECA cohort. iNKT cell antigenic activity in bedroom dust samples was associated with higher endotoxin concentration and also with reduced risk of asthma. In conclusion, MAIT cell frequency at 1 y may reflect the tendency of the immune system toward Th1 responses and is associated with protection from asthma. Additionally, iNKT cell antigenic activity may be a marker of houses with increased microbial exposures and therefore also with protection from asthma. PMID- 29431695 TI - Advancing Cancer Screening with Liquid Biopsies. AB - A new liquid biopsy technique, CancerSEEK, that evaluates tumor mutations and cancer-linked proteins can detect 70% of cancers in patients who have one of eight tumor types. The technique can pinpoint the location of a tumor in 68% of cases. However, its sensitivity drops off at earlier disease stages. PMID- 29431694 TI - ILDR2 Is a Novel B7-like Protein That Negatively Regulates T Cell Responses. AB - The B7-like protein family members play critical immunomodulatory roles and constitute attractive targets for the development of novel therapies for human diseases. We identified Ig-like domain-containing receptor (ILDR)2 as a novel B7 like protein with robust T cell inhibitory activity, expressed in immune cells and in immune-privileged and inflamed tissues. A fusion protein, consisting of ILDR2 extracellular domain with an Fc fragment, that binds to a putative counterpart on activated T cells showed a beneficial effect in the collagen induced arthritis model and abrogated the production of proinflammatory cytokines and chemokines in autologous synovial-like cocultures of macrophages and cytokine stimulated T cells. Collectively, these findings point to ILDR2 as a novel negative regulator for T cells, with potential roles in the development of immune related diseases, including autoimmunity and cancer. PMID- 29431696 TI - E-cigarette Report Reveals Research Gaps. AB - In a comprehensive analysis of existing studies, the U.S. National Academies of Sciences, Engineering, and Medicine concluded that electronic cigarettes are addictive, though less toxic than conventional cigarettes. The report also identified key areas for future research, including smoking cessation, adolescent use, and long-term health effects. PMID- 29431697 TI - Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAFV600E Colorectal Cancer. AB - Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAFV600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivoIn vitro, the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome.Significance: We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in BRAFV600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 417-27. (c)2018 AACR.See related commentary by Janku, p. 389See related article by Corcoran et al., p. 428This article is highlighted in the In This Issue feature, p. 371. PMID- 29431700 TI - Influence of tidal volume and positive end-expiratory pressure on ventilation distribution and oxygenation during one-lung ventilation. AB - OBJECTIVE: The aim of the study was to explore the feasibility of titrating tidal volume (V T) and positive end-expiratory pressure (PEEP) during one-lung ventilation (OLV) based on ventilation distribution and oxygenation. APPROACH: Twenty-four consecutive patients requiring intubation with a double-lumen tube and subsequent OLV for thoracic surgical procedures were examined prospectively in lateral posture. Electrical impedance tomography (EIT), blood gases, respiratory mechanics were successfully measured in 21 patients at various combinations of V T (4 ml kg-1, 6 ml kg-1, 8 ml kg-1 body weight) and PEEP (0 cm H2O, 4 cm H2O, 8 cm H2O) during OLV. MAIN RESULTS: Low V T and low PEEP resulted in low global respiratory system compliance (C rs). Arterial partial pressure of O2 (PaO2) decreased with falling V T. Regional C rs measured with EIT showed high values at high V T and high PEEP in all but two patients. Regional C rs in mid and most dependent regions indicated tidal recruitment/derecruitment in eight patients at 8 ml kg-1 of V T and 4 cm H2O of PEEP; in four patients at 8 ml kg-1 and 0 cm H2O; in one patient at 6 ml kg-1 and 8 cm H2O. The changes in regional C rs induced by decreasing PEEP from 8 to 4 cm H2O were much smaller than those from 4 to 0 cm H2O. Ventilation distribution was most inhomogeneous with V T of 8 ml kg-1. All measures differed significantly among various V T and PEEP steps (p < 0.05). SIGNIFICANCE: By using EIT in combination with PaO2, it is feasible to titrate V T and PEEP at the bedside during OLV. PMID- 29431698 TI - MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia. AB - In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9 MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.Significance: Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML. Cancer Discov; 8(4); 478-97. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 371. PMID- 29431699 TI - Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer. AB - Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) +/- MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428-43. (c)2018 AACR.See related commentary by Janku, p. 389See related article by Hazar-Rethinam et al., p. 417This article is highlighted in the In This Issue feature, p. 371. PMID- 29431701 TI - Combined treatment of hydroxypropyl guar gum in oilfield fracturing wastewater by coagulation and the UV/H2O2/ferrioxalate complexes process. AB - Hydroxypropyl guar gum is considered to be a main component of oilfield fracturing wastewater (OFW). This work is intended to optimize the experimental conditions for the maximum oxidative degradation of hydroxypropyl guar gum by the coagulation and UV/H2O2/ferrioxalate complexes process. Optimal reaction conditions were proposed based on the chemical oxygen demand (COD) removal efficiency and UV_vis spectra analysis. The overall removal efficiency of COD reached 83.8% for a dilution ratio of raw wastewater of 1:2, pH of 4 and FeCl3 loading of 1,000 mg/L in the coagulation process; the dosage of H2O2 (30%,v/v) was 0.6% (v/v) and added in three steps, the n(H2O2)/n(Fe2+) was 2:1, n(Fe2+)/n(C2O42-) was 3:1 and pH was 4 in the UV/H2O2/ferrioxalate complexes process; pH was adjusted to 8.5-9 by NaOH and then cationic polyacrylamide (CPAM) of 2 mg/L was added in the neutralization and flocculation process. The decrease in COD during the coagulation process reduced the required H2O2 dosage and improved efficiency in the subsequent UV/H2O2/ferrioxalate complexes process. Furthermore, COD removal efficiency significantly increased by more than 13.4% with the introduction of oxalate compared with UV/Fenton. The UV_vis spectra analysis results indicated that the coagulation and UV/H2O2/ferrioxalate complexes process could efficiently remove the hydroxypropyl guar gum dissolved in OFW. An optimal combination of these parameters produced treated wastewater that met the GB8978-1996 Integrated Wastewater Discharge Standard level III emission standard. PMID- 29431702 TI - Understanding the effects of bulk mixing on the determination of the affinity index: consequences for process operation and design. AB - The main objective of this study is to demonstrate the importance of mixing conditions as a source of inconsistencies between half-saturation indices in comparable systems (e.g. conventional activated sludge, membrane bioreactor) when operated at different conditions or different scales. As proof-of-principle, an exemplary system consisting of the second vessel of a hybrid respirometer has been studied. The system has been modeled both using an integrated computational fluid dynamics (CFD)-biokinetic model (assumed to represent the physical system) and a tanks-in-series, completely stirred tank reactor biokinetic model (representing the applied model). The results show that different mixing conditions cause deviations in the half-saturation indices calculated when matching the applied model to the physical system performance. Additionally, sensor location has been shown to impact the calculation of half-saturation indices in the respirometric system. This will only become more pronounced at larger scales. Thus, mixing conditions clearly affect operation and design of wastewater treatment reactors operated at low substrate concentrations. Both operation and design can be improved with the development and application of integrated CFD-biokinetic or compartmental models. PMID- 29431703 TI - Solid-liquid separation of an effluent produced by a fixed media biofilm reactor. AB - An experimental study dedicated to the characterization of the settleability of solids produced in immersed fixed media biofilm reactors has been carried out. The influence of operating temperature (0.1 to 16 degrees C) and surface organic loading rate (OLR) (0.4 to 10 g of soluble carbonaceous BOD5 per m2 of media per day) on settleable solids quantities, particle size distributions (PSD) as well as flocs morphology was evaluated. Results have shown that the OLR has no statistically significant influence on the settleability of the suspended solids. However, the operating temperature was identified as a factor that significantly influences the settling potential. The highest operating temperatures (14-16 degrees C) were related to the worst settling performances. On the other hand, the best settling performances were observed at intermediate operating temperatures (around 10 degrees C). The latter conditions were also associated with the largest fractions of large particles (>100 MUm) in the effluent. Differences in PSD were found to be well correlated with settling performances. Part of the performance results variability which cannot be explained by differences in PSD can potentially be attributed to differences in flocs morphology (compactness). PMID- 29431704 TI - Brackish water desalination using electrodialysis: predictive mass transfer and concentration distribution model along the electrodialyzer. AB - This study employs theory and experimental data from a laboratory-scale electrodialyzer to predict sodium chloride (NaCl) mass transport and concentration distribution along the electrodialyzer as a function of feed concentration, feed flow rate, applied voltage, and pressure. Moreover, a model was developed to predict the ion removal as a function of driving forces through solving the complete Navier-Stokes, continuity, and steady state Nernst-Planck equations by the finite difference numerical method. The findings of the experiments confirmed that concentration distributions are nonlinear along both the dilute and concentrate compartments. The results also demonstrated that increases in pressure and feed flow rate have a negative effect on salt removal, linear and nonlinear for pressure and flow rate, respectively. In the investigated ranges, higher voltage increased salt removal at a constant feed concentration. PMID- 29431705 TI - Characterization of sludge properties for sewage treatment in a practical-scale down-flow hanging sponge reactor: oxygen consumption and removal of organic matter, ammonium, and sulfur. AB - The characteristics of sludge retained in a down-flow hanging sponge reactor were investigated to provide a better understanding of the sewage treatment process in the reactor. The organic removal and sulfur oxidation conditions were found to differ between the first layer and the following three layers. It was found that 63% and 59% of the organic matter was removed in the first layer, even though the hydraulic retention time was only 0.2 h. It is thought that the organic removal resulted from aerobic and anaerobic biodegradation on the sponge medium. The sulfate concentration increased 1.5-1.9-fold in the first layer, with almost no subsequent change in the second to fourth layers. It was shown that oxidation of sulfide in the influent was completed in the first layer. The result of the oxygen uptake rate test with an ammonium nitrogen substrate suggested that the ammonium oxidation rate was affected by the condition of dissolved oxygen (DO) or oxidation-reduction potential (ORP). PMID- 29431706 TI - Prediction of sludge bulking using the knowledge-leverage-based fuzzy neural network. AB - One of the most important steps and the main bottleneck of the activated sludge wastewater treatment process (WWTP) is the secondary clarification, where sludge bulking is still a widespread problem. In this paper, an intelligent method, based on a knowledge-leverage-based fuzzy neural network (KL-FNN), is developed to predict sludge bulking online. This proposed KL-FNN can make full use of the data and the existing knowledge from the operation of WWTP. Meanwhile, a transfer learning mechanism is applied to adjust the parameters of the proposed method to improve the predicting accuracy. Finally, this proposed method is applied to a real wastewater treatment plant for predicting the sludge bulking risk, and then for predicting the sludge bulking. The experimental results indicate that the proposed prediction method can be used as a tool to achieve better performance and adaptability than the existing methods in terms of predicting accuracy for sludge bulking. PMID- 29431707 TI - Fe3O4-CS-L: a magnetic core-shell nano adsorbent for highly efficient methyl orange adsorption. AB - A novel core-shell bio-adsorbent was fabricated by using biological materials for removing methyl orange (MO) from aqueous solution. The structure characteristics results of scanning electron microscopy (SEM), Fourier transform infrared spectrometry (FT-IR), thermo-gravimetric analysis (TGA), vibrating sample magnetometer (VSM), and Brunauer-Emmett-Teller (BET) shows that Fe3O4-CS-L has been successfully prepared. The effects of contact time, pH, temperature and initial concentration were explored. The results suggested pH was a negligible factor in adsorption progress. Kinetic studies showed that the experiment data followed pseudo-second-order model. Boyd mode suggested that external mass transfer showed a rather weak rate control for MO adsorption onto Fe3O4-CS-L. Equilibrium studies showed that isotherm data were the best described by Langmuir model. The maximum adsorption capacity of MO estimated to be 338.98 mg/g at 298 K. Moreover, the adsorption capacity of Fe3O4-CS-L can keep about 74% in the fifth adsorption-regeneration cycle. Thus, the Fe3O4-CS-L could be a kind of promising material for removing MO from wastewater. PMID- 29431708 TI - Adsorption of Methylene blue and Rhodamine B by using biochar derived from Pongamia glabra seed cover. AB - Biochar obtained through the pyrolysis of Pongamia glabra seed cover (PGSC) at 550 degrees C with a heating rate of 40 degrees C/min was characterized and its ability to adsorb the dyes Methylene blue (MB) and Rhodamine B (RB) from aqueous solutions was investigated. The effect of pH, temperature and initial concentration of the dyes on adsorption behavior were investigated. The equilibrium sorption data were analyzed by using Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich (D-R) isotherms. Equilibrium data were well fitted for D R isotherm in case of MB and Langmuir isotherm in case of RB dyes. The kinetics of dye adsorption on PGSC biochar was well described by applying pseudo-second order rate equations. The surface of adsorbent before and after the removal of dyes was characterized by using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) analysis. The study suggested that PGSC biochar could be used as a highly efficient adsorbent for the removal of synthetic dyes. PMID- 29431709 TI - Effect of Doppler flow meter position on discharge measurement in surcharged manholes. AB - Determining the proper installation location of flow meters is important for accurate measurement of discharge in sewer systems. In this study, flow field and flow regimes in two types of manholes under surcharged flow were investigated using a commercial computational fluid dynamics (CFD) code. The error in measuring the flow discharge using a Doppler flow meter (based on the velocity in a Doppler beam) was then estimated. The values of the corrective coefficient were obtained for the Doppler flow meter at different locations under various conditions. Suggestions for selecting installation positions are provided. PMID- 29431710 TI - Effect of salinity on medium- and low-pressure UV disinfection of Vibrio cholerae. AB - The problem of biological invasions attributed to ballast water release is an ongoing problem that threatens ecosystems and human health. Ultraviolet (UV) radiation has been increasingly used for ballast water treatment mainly due to the advantages of short contact time and minimized harmful disinfection by products. In this study, the impact of salinity on the inactivation of Vibrio cholerae (NCTC 7253) was examined, and comparison of inactivation level and disinfection kinetics after medium-pressure (MP) (1 kW) and low-pressure (LP) (10 W) UV irradiation was made. MP UV exposure resulted in higher inactivation efficacy against V. cholerae than LP UV exposure especially at lower UV doses (<=3 mJ cm-2) and salinity had a negative impact on both MP and LP UV disinfection, especially at higher UV doses (>=3 mJ cm-2 for MP and >=4 mJ cm-2 for LP). To understand the mechanisms of salinity effect on V. cholerae, the enzyme-linked immunosorbent assay (ELISA) was employed to determine the number of cyclobutane pyrimidine dimers (CPDs), one major type of DNA damage. No significant effects of salinity were found at the CPDs level except for 3% artificial seawater after LP UV exposure case. It is imperative that site specific conditions of salinity be taken into account in the design of UV reactors to treat V. cholerae and other species. PMID- 29431711 TI - Initial conditions of urban permeable surfaces in rainfall-runoff models using Horton's infiltration. AB - Infiltration is a key process controlling runoff, but varies depending on antecedent conditions. This study provides estimates on initial conditions for urban permeable surfaces via continuous simulation of the infiltration capacity using historical rain data. An analysis of historical rainfall records show that accumulated rainfall prior to large rain events does not depend on the return period of the event. Using an infiltration-runoff model we found that for a typical large rain storm, antecedent conditions in general lead to reduced infiltration capacity both for sandy and clayey soils and that there is substantial runoff for return periods above 1-10 years. PMID- 29431712 TI - Performance analysis and experimental study on rainfall water purification with an extensive green roof matrix layer in Shanghai, China. AB - Current research has validated the purification of rainwater by a substrate layer of green roofs to some extent, though the effects of the substrate layer on rainwater purification have not been adequately quantified. The present study set up nine extensive green roof experiment combinations based on the current conditions of precipitation characteristics observed in Shanghai, China. Different rain with pollutants were simulated, and the orthogonal design L9 (33) test was conducted to measure purification performance. The purification influences of the extensive green roof substrate layer were quantitatively analyzed in Shanghai to optimize the thickness, proportion of substrate, and sodium polyacrylate content. The experimental outcomes resulted in ammonium nitrogen (NH4+-N), lead (Pb), and zinc (Zn) removal of up to 93.87%, 98.81%, and 94.55% in the artificial rainfall, respectively, and NH4+-N, Pb, and Zn event mean concentration (EMC) was depressed to 0.263 mg/L, 0.002 mg/L and 0.018 mg/L, respectively, which were all well below the pollutant concentrations of artificial rainfall. With reference to the rainfall chemical characteristics of Shanghai, a combination of a 200 mm thickness, proportions of 1:1:2 of Loam: Perlite: Cocopeat and 2 g/L sodium polyacrylate content was suggested for the design of an extensive green roof substrate to purify NH4+-N, Pb and Zn. PMID- 29431713 TI - Anaerobic co-digestion of sludge and microalgae grown in municipal wastewater - a feasibility study. AB - In this study a natural mix of microalgae grown in wastewater of municipal character was co-digested with sewage sludge in mesophilic conditions, in both batch and semi-continuous modes. The semi-continuous experiment was divided into two periods with OLR1 (organic loading rate) of 2.4 kg volatile solids (VS) m-3 d 1 and HRT1 (hydraulic retention time) of 15 days, and OLR2 of 3.5 kg VS m-3 d-1 and HRT2 of 10 days, respectively. Results showed stable conditions during both periods. The methane yield was reduced when adding microalgae (from 200 +/- 25 NmL CH4 g VSin-1, to 168 +/- 22 NmL CH4 g VSin-1) but VS reduction was also decreased by 51%. This low digestibility was confirmed in the anaerobic batch test. However, adding microalgae improved the dewaterability of the digested sludge. The high heavy metals content in the microalgae resulted in a high heavy metals content in the digestate, making it more difficult to reuse the digestate as fertilizer on arable land. The heavy metals are thought to originate from the flue gas used as a CO2 source during the microalgae cultivation. Therefore the implementation of CO2 mitigation via algal cultivation requires careful consideration regarding the source of the CO2-rich gas. PMID- 29431714 TI - The ion-exchanger-loop-stripping process: ammonium recovery from sludge liquor using NaCl-treated clinoptilolite and simultaneous air stripping. AB - The technical feasibility of an ammonium recovery process ('ion-exchanger-loop stripping') for sludge liquor from municipal wastewater treatment plants is examined. The proposed process combines ion-exchange on natural zeolites with simultaneous air stripping of ammonia to produce an industrial NOx-removal agent. Column experiments with continuously recycled NH4Cl-solutions and a real sludge liquor sample were conducted to determine basic ion-exchange kinetics of the applied clinoptilolite. Mass balances of consecutive loading/regeneration cycles show the positive influence of NaCl-pretreatment as well as simultaneous air stripping on the NH4+-exchange capacities. Removal rates for NH4+ between 61.5 and 84.6% were achieved at NH4+-concentrations typical for sludge liquor (900 to 2,300 mg L-1). Zeolite loadings ranged from 5 to 8 mg NH4+ g-1 after 90 min of loading. Regeneration rates were between 42.9 and 49.7%, but increased to 64.8% with simultaneous air stripping. A minimal decrease in the ammonium removal rate was observed as a result of matrix effects in sludge liquor (e.g. flocculants, competing ions). Liquid analyses showed a considerable phosphate-reduction in the sludge liquor sample after ion-exchange due to potential struvite or apatite precipitation. The obtained results enable a detailed design, scale-up and further optimization of the ion-exchanger-loop-stripping process in future. PMID- 29431715 TI - Immobilization of halophilic yeast for effective removal of phenol in hypersaline conditions. AB - A halotolerant yeast strain of Candida sp. was purified for phenol biodegradation and was immobilized in alginate and nano-SiO2. The concentration of nanoscale SiO2 was optimized and phenol degradation performance with different initial phenol concentrations was evaluated. Three common kinetic models were used to correlate the experimental data. The effects of pH and salinity on phenol biodegradation were also investigated. It was found that 1.0% (w/v) was the optimal nano-SiO2 concentration and the immobilized cells had a better phenol removal performance compared to free cells. More than 99% of 600 mg l-1 phenol was removed by the immobilized strains within 48 h. The immobilized cells also showed highest phenol degradation rates when pH and salinity were 6.5 and 0%, respectively. The high removal efficiency of phenol in reusability tests indicated the promising application of the immobilized Candida strain in phenol degradation under hypersaline conditions over a long period. PMID- 29431716 TI - Effect of salinity variation on the autotrophic kinetics of the start-up of a membrane bioreactor and hybrid moving bed biofilm reactor-membrane bioreactor at low hydraulic retention time. AB - A membrane bioreactor (MBR) and a hybrid moving bed biofilm reactor-membrane bioreactor (hybrid MBBR-MBR) for municipal wastewater treatment were studied to determine the effect of salinity on nitrogen removal and autotrophic kinetics. The biological systems were analyzed during the start-up phase with a hydraulic retention time (HRT) of 6 h, total biomass concentration of 2,500 mg L-1 in the steady state, and electric conductivities of 1.05 mS cm-1 for MBR and hybrid MBBR MBR working under regular salinity and conductivity variations of 1.2-6.5 mS cm-1 for MBR and hybrid MBBR-MBR operating at variable salinity. The variable salinity affected the autotrophic biomass, which caused a reduction of the nitrogen degradation rate, an increase of time to remove ammonium from municipal wastewater and longer duration of the start-up phase for the MBR and hybrid MBBR MBR. PMID- 29431717 TI - Inter-stage thermophilic aerobic digestion may increase organic matter removal from wastewater sludge without decreasing biogas production. AB - Combining aerobic and anaerobic digestion in a two-stage system can improve the degradation of wastewater sludge over the use of either technology alone. But use of aerobic digestion as a pre-treatment before anaerobic digestion generally reduces methane production due to loss of substrate through oxidation. An inter stage configuration may avoid this reduction in methane production. Here, we evaluated the use of thermophilic aerobic digestion (TAD) as an inter-stage treatment for wastewater sludge using laboratory-scale semi-continuous reactors. A single anaerobic digester was compared to an inter-stage system, where a thermophilic aerobic digester (55 degrees C) was used between two mesophilic anaerobic digesters (37 degrees C). Both systems had retention times of approximately 30 days, and the comparison was based on measurements made over 97 days. Results showed that the inter-stage system provided better sludge destruction (52% volatile solids (VS) removal vs. 40% for the single-stage system, 44% chemical oxygen demand (COD) removal vs. 34%) without a decrease in total biogas production (methane yield per g VS added was 0.22-0.24 L g-1 for both systems). PMID- 29431718 TI - Biosorption of praseodymium (III) using Terminalia arjuna bark powder in batch systems: isotherm and kinetic studies. AB - The high demand for rare earth elements (REEs) used in various advanced materials implies demand for increased production of REEs or the recycling of solutions to recover the REEs they contain. In this study, the biosorption of Pr(III) from aqueous solution by bark powder of Terminalia arjuna was examined in a batch system as a function of metal concentration, biosorbent dosage, pH and contact time. Results showed that T. arjuna bark powder has a high affinity for adsorbing Pr(III): more than 90% at pH 6.63. The adsorption of Pr(III) by T. arjuna bark powder was investigated by the Langmuir, Freundlich, Temkin and Dubinin Radushkevich isotherm models. The kinetics of the biosorption process was tested with pseudo-first-order and pseudo-second-order models, and the results showed that the biosorption process was better fitted to the pseudo-second-order model. From Fourier transform infrared spectroscopy (FT-IR) analysis, it is confirmed that the biomolecules of T. arjuna bark powder are involved in the biosorption process of Pr(III) metal ions. PMID- 29431719 TI - Pesticide removal through wastewater and advanced treatment: full-scale sampling and bench-scale testing. AB - Dieldrin and DDx removal through wastewater treatment, ozonation, and microfiltration was assessed for a water reuse project for groundwater replenishment in Monterey, California, USA. Full-scale sampling was conducted at the wastewater treatment plant, and physical wastewater treatment processes, ozonation, and microfiltration were tested at the bench scale. Removals observed through wastewater treatment, ozonation, and microfiltration were 84%, 44% to 63%, and 97% to 98%, respectively, for dieldrin, and 93%, 36% to 48%, and 92% to 94% for DDx. These were sufficient to meet California Ocean Plan water quality objectives after wastewater treatment alone. Levels in the secondary effluent, ahead of ozonation, microfiltration, reverse osmosis and advanced oxidation in the advanced water purification facility, met drinking water standards. Removal of dieldrin and DDx through wastewater treatment occurred by physical treatment processes; removal through the full-scale wastewater treatment plant, which included biological and physical treatment processes, matched removal through the physical bench-scale wastewater treatment processes. Dieldrin and DDx removal correlated with removal of volatile suspended solids, suggesting that volatile suspended solids could be used as an indicator for pesticide removal through wastewater treatment. Dieldrin and DDx concentrations were highest in the solids contact process, where biomass is accumulated for carbon removal. PMID- 29431720 TI - Test of precoat filtration technology for treatment of swimming pool water. AB - The technical performance of a precoat filter was compared with that of a traditional sand filter. Particle concentration and size distribution were measured before and after the filtration of swimming pool water. Both the sand and precoat filters could reduce the particle concentration in the effluent. However, higher particle removal efficiency was generally observed for the precoat filter, especially for particles smaller than 10 MUm in diameter. Adding flocculant improved the removal efficiency of the sand filter, resulting in removal efficiencies comparable to those of the precoat filter. Three powders, i.e., two types of perlite (Harbolite(r) and Aquatec perlite) and cellulose fibers (Arbocel(r)), were tested for the precoat filter, but no significant difference in particle removal efficiency was observed among them. The maximum efficiency was reached within 30-40 min of filtration. The energy required for the pumps increased by approximately 35% over a period of 14 days. The energy consumption could be reduced by replacing the powder on the filter cloth. The sand filter was backwashed once a week, while the powder on the precoat filter was replaced every two weeks. Under these conditions, it was possible to reduce the water used for cleaning by 88% if the precoat filter was used instead of the sand filter. PMID- 29431721 TI - Variations of odorous VOCs detected by different assessors via gas chromatography coupled with mass spectrometry and olfactory detection port (ODP) system. AB - Odorous volatile organic compounds (VOCs) were analysed via a thermal desorption gas chromatograph coupled with a mass spectrometer and olfactory detection port (TD-GC-MS/ODP) to characterize odour emissions from a wastewater treatment plant (WWTP). Three trained ODP assessors, screened according to the European dynamic olfactometry standard (EN: 13725), were used for the olfactory analysis. Their sensitivity to n-butanol varied within the acceptable limits. VOC samples from the WWTP were collected onto Tenax TA sorbent tubes in triplicate and each assessor analysed one tube in the same sample desorbing and analysing conditions. Intensities of odours detected from ODP were scaled from 1 to 4. The ODP assessors used their own odour descriptors based on their own experience as well as referenced descriptors on published compost and wastewater odour wheels. The ODP assessors detected a total of 32 different odorous VOCs; however, the intensities assigned by each assessor to particular VOCs varied. Moreover, some odorous VOCs were not detected by all assessors. For example, geosmin was detected by only two assessors. The use of a TD-GC-MS/ODP system for the analysis of odorous VOCs is valuable when analysed by different assessors, allowing a range of responses to specific odorants in a populations to be investigated. PMID- 29431722 TI - Modification of UASB reactor by using CFD simulations for enhanced treatment of municipal sewage. AB - Up-flow anaerobic sludge blanket (UASB) has been in use since last few decades for the treatment of organic wastewaters. However, the performance of UASB reactor is quite low for treatment of low strength wastewaters (LSWs) due to less biogas production leading to poor mixing. In the present research work, a modification was done in the design of UASB to improve mixing of reactor liquid which is important to enhance the reactor performance. The modified UASB (MUASB) reactor was designed by providing a slanted baffle along the height of the reactor having an angle of 5.7 degrees with the vertical wall. A two-dimensional computational fluid dynamics (CFD) simulation of three phase gas-liquid-solid flow in MUASB reactor was performed and compared with conventional UASB reactor. The CFD study indicated better mixing in terms of vorticity magnitude in MUASB reactor as compared to conventional UASB, which was reflected in the reactor performance. The performance of MUASB was compared with conventional UASB reactor for the onsite treatment of domestic sewage as LSW. Around 16% higher total chemical oxygen demand removal efficiency was observed in MUASB reactor as compared to conventional UASB during this study. Therefore, this MUASB model demonstrates a qualitative relationship between mixing and performance during the treatment of LSW. From the study, it seems that MUASB holds promise for field applications. PMID- 29431723 TI - Release of hydrogen sulfide under intermittent flow conditions - the potential of simulation models. AB - For engineering purposes it is especially useful to be able to predict and control sewer corrosion rates and odor impacts as well as to design effective measures aiming to reduce effects related to hydrogen sulfide formation and release. Doing so, it is important to use modeling tools that are capable of assessing variations of dissolved oxygen, dissolved sulfide and hydrogen sulfide gas concentrations for a wide range of environmental scenarios. Two such models were assessed: AEROSEPT, an empirical formulation, and WATS, a conceptual and more complex approach. The models were applied to evaluate the effects of transitions between pressure mains and gravity sewers in the air-liquid mass transfer of hydrogen sulfide at the Ericeira sewer system in Portugal. This network is known to have odor and corrosion problems, especially during summer. Despite the unavoidable uncertainties due to the unsteady flow rate and the quantification of air velocity and turbulence, the simulation results obtained with both models have been shown to adequately predict the overall behavior of the system. PMID- 29431724 TI - Removal of crotamiton and its degradation intermediates from secondary effluent using TiO2-zeolite composites. AB - Crotamiton, a scabicide and antipruritic agent persistent during biological treatment processes, is frequently detected in secondary effluent. In this study, titanium dioxide (TiO2) and high-silica zeolite (HSZ-385) composites were synthesized and applied for the treatment of crotamiton in secondary effluent. Crotamiton was rapidly adsorbed by HSZ-385, and the adsorption performance of crotamiton in the secondary effluent was quite close to that in the test using ultrapure water. Even though the TiO2-zeolite composites showed lower adsorption rates than that of HSZ-385, similar crotamiton adsorption capacities were revealed using both test materials. The photocatalytic decomposition of crotamiton was significantly inhibited by the water matrix at low initial concentrations. The TiO2-zeolite composites rapidly adsorbed crotamiton from secondary effluent, and then the crotamiton was gradually decomposed under ultraviolet irradiation. Importantly, when using TiO2-zeolite composites, coexisting material in the secondary effluent did not markedly inhibit crotamiton removal at low initial crotamiton concentration. The behaviors of the main intermediates during treatment demonstrated that the main degradation intermediates of crotamiton were also captured by the composites. PMID- 29431725 TI - Energy consumption of agitators in activated sludge tanks - actual state and optimization potential. AB - Depending on design capacity, agitators consume about 5 to 20% of the total energy consumption of a wastewater treatment plant. Based on inhabitant-specific energy consumption (kWh PE120-1 a-1; PE120 is population equivalent, assuming 120 g chemical oxygen demand per PE per day), power density (W m-3) and volume specific energy consumption (Wh m-3 d-1) as evaluation indicators, this paper provides a sound contribution to understanding energy consumption and energy optimization potentials of agitators. Basically, there are two ways to optimize agitator operation: the reduction of the power density and the reduction of the daily operating time. Energy saving options range from continuous mixing with low power densities of 1 W m-3 to mixing by means of short, intense energy pulses (impulse aeration, impulse stirring). However, the following correlation applies: the shorter the duration of energy input, the higher the power density on the respective volume-specific energy consumption isoline. Under favourable conditions with respect to tank volume, tank geometry, aeration and agitator position, mixing energy can be reduced to 24 Wh m-3 d-1 and below. Additionally, it could be verified that power density of agitators stands in inverse relation to tank volume. PMID- 29431726 TI - Immobilization of laccase onto porous polyvinyl alcohol/halloysite hybrid beads for dye removal. AB - Laccase was immobilized in polyvinyl alcohol beads containing halloysite nanotubes (PVA/HNTs) to improve the stability and reusability of enzyme. The porous structure of PVA/HNTs beads facilitates the entrapment of enzyme and prevents the leaching of immobilized laccase as well. Halloysite nanotubes act as bridge to connect the adjacent pores, facilitating the electron transfer and enhancing the mechanical properties. PVA/HNTs beads have high laccase immobilization capacity (237.02 mg/g) and activity recovery yield (79.15%), indicating it can be used as potential support for laccase immobilization. Compared with free laccase, the immobilized laccase on hybrid beads exhibits enhanced pH tolerance (even at pH 8.0), good thermal stability (57.5% of the initial activity can be maintained at 75 degrees C), and excellent storage stability (81.17% of enzyme activity could be retained after storage at 4 degrees C for 5 weeks compared with that for free enzyme of 60%). Also, the removal efficiency for reactive blue can reach as high as 93.41% in the presence of redox mediator 2,2-azinobis(3-ethylbenzthiazoline-6-sulfonate), in which adsorption and degradation exist simultaneously. The remarkable pH tolerance, thermal and storage stability, and reuse ability imply potential application of porous PVA/HNTs immobilized enzyme in environmental fields. PMID- 29431727 TI - Using submersible fluorescence sensors to track the removal of organic matter in decentralized wastewater treatment systems (DEWATS) in real time. AB - Decentralized wastewater treatment systems (DEWATS) using anaerobic treatment are increasingly being considered for wastewater treatment with options for non potable water reuse at the community scale. One challenge for ensuring performance and reliability of DEWATS is the lack of suitable on-site sensors to monitor failure or contamination events. In this study, the aim was to use in situ fluorescence sensors to track the performance of a DEWATS, consisting of an anaerobic baffled reactor (ABR) coupled to anaerobic filter (AF) and constructed wetland (CW) treatment processes. A submersible in situ fluorometer equipped with tryptophan (TRP) and chromophoric dissolved organic matter (CDOM) sensors was deployed in each chamber of the ABR-AF-CW system, and results showed that TRP fluorescence was preferentially removed over CDOM fluorescence throughout the system. Significant relationships between TRP fluorescence and chemical oxygen demand (COD) also suggested that TRP fluorescence could be used as a surrogate for COD and soluble COD concentrations. Strong agreement between results obtained from the 1D in situ fluorometer and those obtained from a 3D benchtop fluorometer lends further support to the use of in situ fluorescence sensors to track DEWATS performance. PMID- 29431728 TI - Influence of vegetation type and temperature on the performance of constructed wetlands for nutrient removal. AB - In this study, the influence of vegetation type and environmental temperature on performance of constructed wetlands (CWs) was investigated. Results of vegetation types indicated that the removal of most nutrients in polyculture was greater than those in monoculture and unplanted control. The greatest removal percentages of NH4+-N, total nitrogen (TN) and total phosphorus (TP) in polyculture were 98.7%, 98.5%, and 92.6%, respectively. In experiments of different temperatures, the removal percentages of NH4+-N, NO3--N, TN and TP in all CWs tended to decrease with the decline of temperature. Especially, a sharp decline in the removal percentages of NO3--N (decreased by above 13.8%) and TN (decreased by above 7.9%) of all CWs was observed at low temperature (average temperature of 8.9 degrees C). Overall, the performance of CWs was obviously influenced by temperature, and the polyculture still showed best performance in the removal of nitrogen when the average temperature dropped to 19.8 degrees C. Additionally, the variations of urease activities in rhizosphere soil tended to decrease with the decreasing temperature. Overall, a substantial enhancement for nitrogen and TP removal in polyculture (Canna indica + Lythrum salicaria) was observed. In conclusion, CW cultivated with polyculture was a good strategy for enhancing nutrient removal when temperature was above 19.8 degrees C. PMID- 29431729 TI - Development of in-house lattice-Boltzmann simulator of bioreactors for wastewater treatment: basic concepts and initial results. AB - While computational modelling has increasingly supported wastewater bioreactor engineering, novel numerical techniques have been developed such as the lattice Boltzmann method (LBM). With vinasse treatment as case study, this work is a first step towards a comprehensive LBM simulator of a continuous-flow anaerobic packed-bed reactor. Extensions from typical models comprise one-dimensional (besides time) dependence, species transport via convection and diffusion, and imposition of either Dirichlet or Danckwerts condition at inlet. The LBM simulator proved to be operational when simulating the bioreactor at different hydraulic retention times (HRTs). Simulated profiles show that stepwise feeding concentrations are smoothed as they are transported towards the bioreactor exit while concentrations increase or decrease in response to generation or degradation kinetics. Good fitting was observed for concentrations of acetic acid (2.1 kg-COD/m3 for HRT = 24 h) and butyric acid (1.3 kg-COD/m3 for HRT = 16 h) at the exit whereas other concentrations were numerically simulated at proper order of magnitude. PMID- 29431730 TI - Flow-through electrosorption process for removal of 2,4-D pesticide from aqueous solutions onto activated carbon cloth fixed-bed electrodes. AB - Wastewater treatment systems have great importance in dealing with increasing environmental pollution. In this study, a specially designed and constructed flow through electrochemical cell was used to enhance the electrosorptive removal capacity of 2,4-Dichlorofenoxyacetic acid (2,4-D) pesticide from aqueous solutions onto high area activated carbon cloth (ACC) fixed-bed electrodes. The change in concentration of 2,4-D during the electrosorption process was followed by an online UV-Vis spectrophotometric system. Effects of operational parameters such as volumetric flow rate, applied potential and existence of Na2SO4 salt on electrosorption of 2,4-D were examined. Optimum values were found to be 10 mL.min 1 for volumetric flow rate and +900 mV for the applied potential to polarize ACC. Maximum capacity of 729 mg.gACC-1 has been achieved for removal of 2,4-D pesticides. PMID- 29431731 TI - Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity. AB - Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner. We found that iPSC-CMs recapitulated the clinical genotype-phenotype discordance in vitro. Importantly, iPSC-CMs derived from the severely affected LQT2 patients displayed prolonged action potentials compared with cells from mildly affected first-degree relatives. The iPSC-CMs derived from all patients with hERG R752W mutation displayed lower IKr amplitude. Interestingly, iPSC-CMs from severely affected mutation-positive individuals exhibited greater L-type Ca2+ current. Whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2, providing biologically plausible explanations for this variable expressivity. Genome editing to correct a REM2 variant reversed the enhanced L-type Ca2+ current and prolonged action potential observed in iPSC-CMs from severely affected individuals. Thus, our findings showcase the power of combining complementary physiological and genomic analyses to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. Furthermore, we propose that this strategy can be deployed to unravel myriad confounding pathologies displaying variable expressivity. PMID- 29431733 TI - Cardiovascular outcome trials of diabetes drugs: lessons learned. PMID- 29431732 TI - STAT3/p53 pathway activation disrupts IFN-beta-induced dormancy in tumor repopulating cells. AB - Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell intrinsic signaling pathways for entering into dormancy. Here, we show that IFN beta treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-beta signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-beta correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-beta provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities. PMID- 29431734 TI - Disruption of staphylococcal aggregation protects against lethal lung injury. AB - Infection by Staphylococcus aureus strain USA300 causes tissue injury, multiorgan failure, and high mortality. However, the mechanisms by which the bacteria adhere to, then stabilize on, mucosal surfaces before causing injury remain unclear. We addressed these issues through the first real-time determinations of USA300 alveolar interactions in live lungs. We found that within minutes, inhaled USA300 established stable, self-associated microaggregates in niches at curved, but not at flat, regions of the alveolar wall. The microaggregates released alpha hemolysin toxin, causing localized alveolar injury, as indicated by epithelial dye loss, mitochondrial depolarization, and cytosolic Ca2+ increase. Spread of cytosolic Ca2+ through intercellular gap junctions to adjoining, uninfected alveoli caused pulmonary edema. Systemic pretreatment with vancomycin, a USA300 cidal antibiotic, failed to protect mice infected with inhaled WT USA300. However, vancomycin pretreatment markedly abrogated mortality in mice infected with mutant USA300 that lacked the aggregation-promoting factor PhnD. We interpret USA300-induced mortality as having resulted from rapid bacterial aggregation in alveolar niches. These findings indicate, for the first time to our knowledge, that alveolar microanatomy is critical in promoting the aggregation and, hence, in causing USA300-induced alveolar injury. We propose that in addition to antibiotics, strategies for bacterial disaggregation may constitute novel therapy against USA300-induced lung injury. PMID- 29431735 TI - Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism. AB - The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel-Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin. In vitro and in vivo data indicated that Vhl-deficient osteoblasts displayed massively increased glucose uptake and glycolysis associated with upregulated HIF target gene expression, resembling the Warburg effect that typifies cancer cells. Overall, the glucose consumption by the skeleton was increased in the mutant mice, as revealed by 18F-FDG radioactive tracer experiments. Moreover, the glycemia levels correlated inversely with the level of skeletal glucose uptake, and pharmacological treatment with the glycolysis inhibitor dichloroacetate (DCA), which restored glucose metabolism in Vhl-deficient osteogenic cells in vitro, prevented the development of the systemic metabolic phenotype in the mutant mice. Altogether, these findings reveal a novel link between cellular glucose metabolism in osteoblasts and whole-body glucose homeostasis, controlled by local hypoxia signaling in the skeleton. PMID- 29431736 TI - Capturing the interactome of newly transcribed RNA. AB - We combine the labeling of newly transcribed RNAs with 5-ethynyluridine with the characterization of bound proteins. This approach, named capture of the newly transcribed RNA interactome using click chemistry (RICK), systematically captures proteins bound to a wide range of RNAs, including nascent RNAs and traditionally neglected nonpolyadenylated RNAs. RICK has identified mitotic regulators amongst other novel RNA-binding proteins with preferential affinity for nonpolyadenylated RNAs, revealed a link between metabolic enzymes/factors and nascent RNAs, and expanded the known RNA-bound proteome of mouse embryonic stem cells. RICK will facilitate an in-depth interrogation of the total RNA-bound proteome in different cells and systems. PMID- 29431737 TI - A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. AB - Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy. PMID- 29431738 TI - Nanopore sequencing and assembly of a human genome with ultra-long reads. AB - We report the sequencing and assembly of a reference genome for the human GM12878 Utah/Ceph cell line using the MinION (Oxford Nanopore Technologies) nanopore sequencer. 91.2 Gb of sequence data, representing ~30* theoretical coverage, were produced. Reference-based alignment enabled detection of large structural variants and epigenetic modifications. De novo assembly of nanopore reads alone yielded a contiguous assembly (NG50 ~3 Mb). We developed a protocol to generate ultra-long reads (N50 > 100 kb, read lengths up to 882 kb). Incorporating an additional 5* coverage of these ultra-long reads more than doubled the assembly contiguity (NG50 ~6.4 Mb). The final assembled genome was 2,867 million bases in size, covering 85.8% of the reference. Assembly accuracy, after incorporating complementary short-read sequencing data, exceeded 99.8%. Ultra-long reads enabled assembly and phasing of the 4-Mb major histocompatibility complex (MHC) locus in its entirety, measurement of telomere repeat length, and closure of gaps in the reference human genome assembly GRCh38. PMID- 29431739 TI - A highly specific SpCas9 variant is identified by in vivo screening in yeast. AB - Despite the utility of CRISPR-Cas9 nucleases for genome editing, the potential for off-target activity limits their application, especially for therapeutic purposes. We developed a yeast-based assay to identify optimized Streptococcus pyogenes Cas9 (SpCas9) variants that enables simultaneous evaluation of on- and off-target activity. We screened a library of SpCas9 variants carrying random mutations in the REC3 domain and identified mutations that increased editing accuracy while maintaining editing efficiency. We combined four beneficial mutations to generate evoCas9, a variant that has fidelity exceeding both wild type (79-fold improvement) and rationally designed Cas9 variants (fourfold average improvement), while maintaining near wild-type on-target editing efficiency (90% median residual activity). Evaluating evoCas9 on endogenous genomic loci, we demonstrated a substantially improved specificity and observed no off-target sites for four of the eight single guide RNAs (sgRNAs) tested. Finally, we showed that following long-term expression (40 d), evoCas9 strongly limited the nonspecific cleavage of a difficult-to-discriminate off-target site and fully abrogated the cleavage of two additional off-target sites. PMID- 29431740 TI - Deep learning improves prediction of CRISPR-Cpf1 guide RNA activity. AB - We present two algorithms to predict the activity of AsCpf1 guide RNAs. Indel frequencies for 15,000 target sequences were used in a deep-learning framework based on a convolutional neural network to train Seq-deepCpf1. We then incorporated chromatin accessibility information to create the better-performing DeepCpf1 algorithm for cell lines for which such information is available and show that both algorithms outperform previous machine learning algorithms on our own and published data sets. PMID- 29431742 TI - Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. AB - Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell type specificity of nuclear receptors remain poorly understood. Here we outline a role for a long noncoding RNA (lncRNA) in modulating the cell type-specific actions of liver X receptors (LXRs), sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux. Mice lacking the MeXis gene show reduced Abca1 expression in a tissue-selective manner. Furthermore, loss of MeXis in mouse bone marrow cells alters chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Mechanistic studies reveal that MeXis interacts with and guides promoter binding of the transcriptional coactivator DDX17. The identification of MeXis as a lncRNA modulator of LXR-dependent gene expression expands understanding of the mechanisms underlying cell type-selective actions of nuclear receptors in physiology and disease. PMID- 29431741 TI - Sugar release and growth of biofuel crops are improved by downregulation of pectin biosynthesis. AB - Cell walls in crops and trees have been engineered for production of biofuels and commodity chemicals, but engineered varieties often fail multi-year field trials and are not commercialized. We engineered reduced expression of a pectin biosynthesis gene (Galacturonosyltransferase 4, GAUT4) in switchgrass and poplar, and find that this improves biomass yields and sugar release from biomass processing. Both traits were maintained in a 3-year field trial of GAUT4 knockdown switchgrass, with up to sevenfold increased saccharification and ethanol production and sixfold increased biomass yield compared with control plants. We show that GAUT4 is an alpha-1,4-galacturonosyltransferase that synthesizes homogalacturonan (HG). Downregulation of GAUT4 reduces HG and rhamnogalacturonan II (RGII), reduces wall calcium and boron, and increases extractability of cell wall sugars. Decreased recalcitrance in biomass processing and increased growth are likely due to reduced HG and RGII cross-linking in the cell wall. PMID- 29431746 TI - Surface morphology and adlayer structure of Se on Rh(111). AB - The deposition of Se from SeO32- solutions was examined in the submonolayer regime by cyclic voltammetry, scanning tunneling microscopy and atomic force microscopy. Up to a coverage of ca. 0.5 (Se atoms to substrate atoms) a smooth adlayer is obtained with a 2 * ?3 structure. When the coverage is increased, at around 0.55 V further deposition is paralleled by a roughening starting at the monoatomic steps. The adsorbed Se is stable in the SeO32- free solution. For coverages below 0.25, separate domains for the Se covered regions and Se free regions were observed for potentials above 0.6 V. Since this is the potential of the spike corresponding to adsorption of OH at the clean Rh(111) surface in HClO4, we have to assume that Se and OH adsorb in separate domains. At lower potentials, where OH is desorbed, Se spreads over the complete surface which then appears completely smooth in the STM images. When the coverage is about 0.25 or above, the roughening is also observed in SeO32- free solution, demonstrating that the rough structures are not due to disordered deposition, but really due to a roughening by place exchange. PMID- 29431744 TI - A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration. AB - Deficits in Schwann cell-mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice. HDAC3 antagonizes the myelinogenic neuregulin-PI3K-AKT signaling axis. Moreover, genome wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann cell-specific deletion of either Hdac3 or Tead4 in mice resulted in an elevation of myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair. PMID- 29431747 TI - Ambient-air ozonolysis of triglycerides in aged fingerprint residues. AB - In forensic science, reconstructing the timing of events occurring during a criminal offense is of great importance. In some cases, the time when particular evidence was left on a crime scene is a critical matter. The ability to estimate the fingerprint age would raise the evidentiary value of fingerprints tremendously. For this purpose the most promising approach is the analysis of changes in the chemical compositions of fingerprint residues in the course of aging. The focus of our study is the identification of human specific compounds in fingerprint residues, characterized by a significant aging behavior that could analytically be used for the age determination of fingerprints in future. The first challenge is the sensitive detection of trace amounts of relevant human specific fingerprint compounds. Highly sensitive LC-MS methods were developed for the reliable structure identification of unsaturated triglycerides and their natural degradation products in order to proof the aging mechanism that takes place in fingerprint residues. Thus our results build the fundamental basis for further forensic method development and potential application in forensic investigation. Ozonolysis was found to be one of the major lipid degradation pathways in fingerprint residues in ambient air. High-resolution tandem mass spectrometry (HRMS2) was carried out to identify the ozonolysis products (TG48:0 monoozonide) formed under exposure to the highly reactive ozone in atmospheric air. The obtained products were confirmed by matrix assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). Despite several challenges and limitations in the age estimation of fingerprints, the identification of individual degradation products of specific unsaturated lipids in aged fingerprint samples represents a significant analytical progress, resulting in a strong increase in the validity of chemical analysis of fingerprints. PMID- 29431745 TI - DKK2 imparts tumor immunity evasion through beta-catenin-independent suppression of cytotoxic immune-cell activation. AB - Immunotherapy offers new options for cancer treatment, but efficacy varies across cancer types. Colorectal cancers (CRCs) are largely refractory to immune checkpoint blockade, which suggests the presence of yet uncharacterized immune suppressive mechanisms. Here we report that the loss of adenomatosis polyposis coli (APC) in intestinal tumor cells or of the tumor suppressor PTEN in melanoma cells upregulates the expression of Dickkopf-related protein 2 (DKK2), which, together with its receptor LRP5, provides an unconventional mechanism for tumor immune evasion. DKK2 secreted by tumor cells acts on cytotoxic lymphocytes, inhibiting STAT5 signaling by impeding STAT5 nuclear localization via LRP5, but independently of LRP6 and the Wnt-beta-catenin pathway. Genetic or antibody mediated ablation of DKK2 activates natural killer (NK) cells and CD8+ T cells in tumors, impedes tumor progression, and enhances the effects of PD-1 blockade. Thus, we have identified a previously unknown tumor immune-suppressive mechanism and immunotherapeutic targets particularly relevant for CRCs and a subset of melanomas. PMID- 29431748 TI - Effects of 1-hexanol on C12E10 micelles: a molecular simulations and light scattering study. AB - The micelles of the non-ionic C12E10 surfactant and 1-hexanol as an aqueous solution additives are studied toward the purpose of understanding the role of alcohol additives in tuning the characteristics of alkyl-ethoxylate micellar systems. Our dynamic light scattering and cloud point experiments show that the addition of hexanol induces a response similar to an increase of temperature. We associate the change with increased attraction between the micelles at low to moderate hexanol loadings and a potential increase of the aggregate size at a high hexanol-to-surfactant ratio. Detailed molecular dynamic simulation characterization shows that hexanol solubilizes to a micelle palisade layer when the hexanol-to-C12E10 ratio is less than or equal to 0.5 while swollen micelles, in which a part of hexanol forms an oil core, are present when the ratio increases above approximately 1.5. The simulations indicate that the surface of the micelles is rough. Formation of reverse hexanol structures akin to those found in bulk octanol is observed in the oil core. Molecular simulations associate the increase in attraction between micelles observed via the experiments with decreased chain density in the headgroup region. This density decrease is caused by hexanol molecules solubilized between neighbouring surfactants. Altogether, these findings provide detailed physical characterization of the effect of an archetypal solution additive, hexanol, on an alkyl ethoxylate micelle system. These findings could bear a significance in designing micellar and emulsion based systems with desired solution characteristics or properties for e.g. drug delivery, catalysis, or platforms for green chemistry reactions. PMID- 29431750 TI - The versatility of N,O-dialkylphosphoramidate stationary phase-separations in HILIC, highly aqueous RP LC conditions and purely aqueous mobile phase. AB - The chromatographic properties of N,O-dialkylphosphoramidate stationary phase with an octadecyl chain (Amino-P-C18) were studied. Based on the U-shape retention plots over the mobile phase composition for the particular tested compounds (nucleosides and nucleic bases) and solvent excess adsorption isotherms, the separations of the tested compounds were performed in various chromatographic conditions. The separations were performed via hydrophilic interaction liquid chromatography, in highly aqueous mobile phase as well as using pure water as a mobile phase. The obtained results confirm that the specific structure of the amino-P-C18 stationary phase allows solvation over a whole range of mobile phase compositions. The ability of this material to undergo chromatographic separation in extreme mobile phase compositions (hydrophilic interaction chromatography and purely aqueous systems) was also confirmed. Successful separation of test mixtures using pure water as a mobile phase is in accordance with the rules of "green chemistry". PMID- 29431743 TI - Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL 15 production in FLT3-ITD-mutant leukemia cells. AB - Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1 year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long term survival in six mouse models of FLT3-ITD+ AML. Sorafenib-related IL-15 production caused an increase in CD8+CD107a+IFN-gamma+ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD+ AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8+ T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD mutant AML relapse, an otherwise fatal complication after allo-HCT. PMID- 29431751 TI - Rapid flow in multilayer microfluidic paper-based analytical devices. AB - Microfluidic paper-based analytical devices (MUPADs) are a versatile and inexpensive point-of-care (POC) technology, but their widespread adoption has been limited by slow flow rates and the inability to carry out complex in field analytical measurements. In the present work, we investigate multilayer MUPADs as a means to generate enhanced flow rates within self-pumping paper devices. Through optical and electrochemical measurements, the fluid dynamics are investigated and compared to established flow theories within MUPADs. We demonstrate a ~145-fold increase in flow rate (velocity = 1.56 cm s-1, volumetric flow rate = 1.65 mL min-1, over 5.5 cm) through precise control of the channel height in a 2 layer paper device, as compared to archetypical 1 layer MUPAD designs. These design considerations are then applied to a self-pumping sequential injection device format, known as a three-dimensional paper network (3DPN). These 3DPN devices are characterized through flow injection analysis of a ferrocene complex and anodic stripping detection of cadmium, exhibiting a 5* enhancement in signal compared to stationary measurements. PMID- 29431752 TI - Transition metal free regio-selective C-H hydroxylation of chromanones towards the synthesis of hydroxyl-chromanones using PhI(OAc)2 as the oxidant. AB - The chromanone scaffold is considered as a privileged structure in drug discovery. Herein, we report a highly efficient PhI(OAc)2 mediated regioselective, direct C-H hydroxylation of chromanones. This method offers easy access to substituted 6-hydroxy chromanones in moderate to good isolated yields, thus paving the way for their pharmaceutical studies. PMID- 29431753 TI - Quantitative modeling of microalgae based sequestration of atmospheric CO2. AB - Marine microalgae have been identified as a considerable sink of atmospheric CO2. Since macroscopic ecosystems cannot be studied experimentally with the required microscopic spatial resolution, a novel modeling method is being presented to quantify this sequestration process. The presented modeling studies indicate that the fixation of carbon by microalgae is species-specific and depends on competition effects among multiple species. PMID- 29431754 TI - Palladium-catalyzed hydroformylation of terminal arylacetylenes with glyoxylic acid. AB - A simple, practical and governable palladium-catalyzed hydroformylation of terminal arylacetylenes has been disclosed. The reaction proceeds under syngas free conditions, using readily available glyoxylic acid as the formyl source, under mild conditions, giving rise to a broad range of alpha,beta-unsaturated aldehydes. PMID- 29431755 TI - Simplified determination of complex stoichiometry for colorimetric metal indicators by inkjet printing. AB - This paper presents the determination of complex binding stoichiometry for colorimetric metal indicators according to the Job plot method by means of an office inkjet printer in combination with digital colour analysis. In contrast to the conventional solution-based analysis involving manual preparation of many mixed solutions, the elaborated inkjet-based approach allows convenient automated mixing of metal salt and indicator solutions in various ratios on a paper substrate. Inkjet-deposited liquid volumes and mixing ratios were controlled by simple colour value setting on a PC. For this purpose, a custom printing colour profile has been elaborated to achieve a linear relationship between the software set CMYK (Cyan, Magenta, Yellow and Key plate (Black)) colour values and the amount of deposited ink. The inkjet-based Job plot analysis was validated against the solution-based conventional approach for binding stoichiometry determination of five known metal ion-indicator systems. Simple colour scanning and colour analysis of printed spots on filter paper gave accurate results for five different stoichiometries and colorimetric response patterns. This inkjet printing approach using a customized printing colour profile allows rapid, flexible and precise deposition and mixing of reagent solutions, and thus, is expected to be useful for wide application purposes, which require the controlled deposition of reagents on a substrate. PMID- 29431756 TI - Combining asymmetric PCR-based enzymatic amplification with silicon photonic microring resonators for the detection of lncRNAs from low input human RNA samples. AB - A method for quantifying biologically relevant long-non-coding RNAs by combining nucleic acid amplification via asymmetric polymerase chain reaction (PCR) with label-free PCR product detection using silicon photonic microring resonator arrays is described. This approach eliminates the need for fluorophores, which presents a limit for spectral multiplexing in conventional qPCR methods, and rather offers potential for much higher levels of plexity by spatially arraying capture probes. Here, we demonstrate the potential of this technique to detect two differentially expressed lncRNA transcripts and an internal control mRNA transcript in different commercial human tissue specimens, as well as in a glioblastoma cell line using only nanogram input amounts of total RNA. The obtained results were validated using single-plex RT-qPCR and found to be in good agreement, demonstrating the potential of this technique for lncRNA quantification applications. PMID- 29431757 TI - A self-assembled nanoprobe for long-term cancer cell nucleus-specific staining and two-photon breast cancer imaging. AB - Herein, a novel self-assembled nanoprobe for the long-term tracking of the nucleoli of cancer cells and for differentiating between clinical breast cancer tissues and para-carcinoma tissues has been developed. PMID- 29431758 TI - Cluster assemblies as superatomic solids: a first principles study of bonding & electronic structure. AB - The synthesis of cluster based materials poses an exciting challenge for experimental chemistry. The main advantage of these materials compared to conventional bulk compounds is the simple tunability of the chemical and physical characteristics of individual clusters. As a consequence, cluster assemblies can theoretically be used for the creation of designer materials exhibiting specifically desired properties. Since superatoms reveal a large intrinsic thermodynamic stability and often very interesting tunable electronic characteristics, they seem to be an excellent choice as building blocks for the bulk. Here, we present a detailed first principles analysis of carefully chosen superatomic cluster binary and bulk assemblies, in order to determine which forces control the attractive interaction in superatomic solids, and how the individual cluster properties affect these assemblies. This study uses the highly tunable and stable Au13(RS(AuSR)2)6 cluster with a variety of dopants as a model system, while the principles are likely transferable to other ligand protected systems with a straightforward superatomic electron count, such as aluminum or sodium clusters. Three different superatomic materials based on doped gold clusters, boranes and C60s are constructed and evaluated. Beyond the verification that superatoms can be used to create materials that reveal emergent atom-based solid like properties, various factors influencing superatomic materials, such as the EA, IP and relative sizes of the clusters, have been identified and critically evaluated. PMID- 29431759 TI - Structural dynamics upon photoexcitation-induced charge transfer in a dicopper(i) disulfide complex. AB - The structural dynamics of charge-transfer states of nitrogen-ligated copper complexes has been extensively investigated in recent years following the development of pump-probe X-ray techniques. In this study we extend this approach towards copper complexes with sulfur coordination and investigate the influence of charge transfer states on the structure of a dicopper(i) complex with coordination by bridging disulfide ligands and additionally tetramethylguanidine units [CuI2(NSSN)2]2+. In order to directly observe and refine the photoinduced structural changes in the solvated complex we applied picosecond pump-probe X-ray absorption spectroscopy (XAS) and wide-angle X-ray scattering (WAXS). Additionally, the ultrafast evolution of the electronic excited states was monitored by femtosecond transient absorption spectroscopy in the UV-Vis probe range. DFT calculations were used to predict molecular geometries and electronic structures of the ground and metal-to-ligand charge transfer states with singlet and triplet spin multiplicities, i.e. S0, 1MLCT and 3MLCT, respectively. Combining these techniques we elucidate the electronic and structural dynamics of the solvated complex upon photoexcitation to the MLCT states. In particular, femtosecond optical transient spectroscopy reveals three distinct timescales of 650 fs, 10 ps and >100 ps, which were assigned as internal conversion to the ground state (Sn -> S0), intersystem crossing 1MLCT -> 3MLCT, and subsequent relaxation of the triplet to the ground state, respectively. Experimental data collected using both X-ray techniques are in agreement with the DFT-predicted structure for the triplet state, where coordination bond lengths change and one of the S-S bridges is cleaved, causing the movement of two halves of the molecule relative to each other. Extended X-ray absorption fine structure spectroscopy resolves changes in Cu-ligand bond lengths with precision on the order of 0.01 A, whereas WAXS is sensitive to changes in the global shape related to relative movement of parts of the molecule. The results presented herein widen the knowledge on the electronic and structural dynamics of photoexcited copper-sulfur complexes and demonstrate the potential of combining the pump-probe X-ray absorption and scattering for studies on photoinduced structural dynamics in copper-based coordination complexes. PMID- 29431760 TI - Electrochemical initiation of electron-catalyzed phenanthridine synthesis by trifluoromethylation of isonitriles. AB - The electron-catalyzed formation of phenanthridines starting from isonitriles initiated by an electrochemical reduction of the Togni reagent is presented. The required number of faradays per mole of starting material and the respective yields clearly show the catalytic character of the electron in this reaction. The mechanism is supported by cyclic voltammetry experiments. PMID- 29431761 TI - Isothermal multiple displacement amplification of DNA templates in minimally buffered conditions using phi29 polymerase. AB - The isothermal amplification of DNA in minimally buffered conditions allows to perform and monitor nucleic acid amplification with minimal technological and operative requirements. We show in this work how phi29 can operate multiple displacement amplification in minimally buffered conditions producing, as a readout, pH shifts attaining subunits of pH. PMID- 29431762 TI - Synthesis of novel Au@Void@Nb2O5 core-shell nanocomposites with enhanced photocatalytic activity. AB - Nb2O5 as a semiconductor material has attracted significant attention in recent years due to its outstanding advantages. In this article, novel Au@Void@Nb2O5 core-shell nanocomposites have been fabricated through a facile sol-gel method. The construction process of this core-shell nanostructure has been presented in detail. The as-prepared core-shell nanostructure exhibits nanosphere morphology with Nb2O5 acting as the shell and Au nanoparticles acting as the core, which was proved using SEM and TEM. The noble metal Au core protected by the Nb2O5 shell promotes an interfacial charge-transfer process. The core-shell nanocomposites demonstrate excellent visible light absorption, as shown by the UV-Vis diffuse reflectance spectra. The as-prepared photocatalyst Au@Void@Nb2O5-2 calcined at 300 degrees C exhibits higher photocatalytic efficiency than Au@SiO2@Nb2O5-2-300 degrees C, Nb2O5 and P25, as evaluated by the degradation of rhodamine B (Rh B) under visible light. In the photodegradation process of the Rh B solution, holes (h+) play a more important role than hydroxyl radicals (OH) over the as-prepared photocatalyst, which was analyzed using active species trapping experiments and photoluminescence (PL) spectroscopy. Moreover, the photocatalyst Au@Void@Nb2O5-2 calcined at 300 degrees C exhibits excellent durability of its photocatalytic activity even after five successive cycles. This contribution gives a new perspective for designing and preparing novel metal-Nb2O5 nanostructure catalysts applied in environmental treatments. PMID- 29431763 TI - Simultaneous non-polar and polar lipid analysis by on-line combination of HILIC, RP and high resolution MS. AB - Given the chemical diversity of lipids and their biological relevance, suitable methods for lipid profiling and quantification are demanded to reduce sample complexity and analysis times. In this work, we present a novel on-line chromatographic method coupling hydrophilic interaction liquid chromatography (HILIC) dedicated to class-specific separation of polar lipid to reversed-phase chromatography (RP) for non-polar lipid analysis. More specifically, the void volume of the HILIC separation-consisting of non-polar lipids- is transferred to the orthogonal RP column enabling the on-line combination of HILIC with RP without any dilution in the second dimension. In this setup the orthogonal HILIC and RP separations were performed in parallel and the effluents of both columns were combined prior to high-resolution MS detection, offering the full separation space in one analytical run. Rapid separation for both polar and non-polar lipids within only 15 min (including reequilibration time) was enabled using sub-2 MUm particles and UHPLC. The method proved to be robust with excellent retention time stability (RSDs < 1%) and LODs in the fmol to pmol (absolute on column) range even in the presence of complex biological matrix such as human plasma. The presented high-resolution LC-MS/MS method leads to class-specific separation of polar lipids and separation of non-polar lipids which is lost in conventional HILIC separations. HILIC-RP-MS is a promising tool for targeted and untargeted lipidomics workflows as three interesting features are combined namely (1) the decreased run time of state of the art shotgun MS methods, (2) the elevated linear dynamic range inherent to chromatographic separation and (3) increased level of identification by separation of polar and non-polar lipid classes. PMID- 29431765 TI - Ultrastable actinide endohedral borospherenes. AB - Since the discovery of the first all-boron fullerenes B40-/0, metal-doped borospherenes have received extensive attention. So far, in spite of theoretical efforts on metalloborospherenes, the feasibility of actinide analogues remains minimally explored. Here we report a series of actinide borospherenes AnBn (An = U, Th; n = 36, 38, and 40) using DFT-PBE0 calculations. All the AnBn complexes are found to possess endohedral structures (An@Bn) as the global minima. In particular, U@B36 (C2h, 3Ag) and Th@B38 (D2h, 1Ag) exhibit nearly ideal endohedral borospherene structures. The C2h U@B36 and D2h Th@B38 complexes are predicted to be highly robust both thermodynamically and dynamically. In addition to the actinide size match to the cage, the covalent character of the metal-cage bonding in U@B36 and Th@B38 affords further stabilization. Bonding analysis indicates that U@B36 and Th@B38 can be qualified as 32-electron systems, and Th@B38 exhibits 3D aromaticity with sigma plus pi double delocalization bonding. The results demonstrate that doping with appropriate actinide atoms is promising to stabilize diverse borospherenes, and may provide routes for borospherene modification and functionalization. PMID- 29431766 TI - Glucuronic acid as a helix-inducing linker in short peptides. AB - A new strategy is demonstrated for making peptides helical, using a carbohydrate to bridge between sidechains at each end of a pentapeptide. CD and NMR spectra establish that both an alpha-helix and a 310-helix structure can form depending upon the bridge. PMID- 29431767 TI - Liquid crystal based sensing device using a smartphone. AB - Liquid crystal (LC) based optical sensors have been found to be very promising for detecting aqueous biological samples due to the ease of optical detection, their cost effectiveness and the removal of the need for labelling biological species with fluorescent dyes. To date, all LC based sensors are studied in laboratories using conventional polarizing optical microscopy (POM), and no attention has been paid towards the fabrication of portable LC sensing devices for use in commercial purposes. Here, we designed and fabricated a 3D printed portable, lightweight, and inexpensive sensing device using a smartphone to detect the optical signal of LC based sensors. The accuracy of the optical signal using the fabricated sensing device is similar to that obtained using conventional POM. The fabricated sensing device, using a smartphone, gives a novel and new platform to LC based sensors for practical applications in the industrial world and people's daily lives. PMID- 29431768 TI - Conformational preferences and isomerization upon excitation/ionization of 2 methoxypyridine and 2-N-methylaminopyridine. AB - Conformers from the rotations of the methyl group and the methoxy or methylamino group, namely staggered (s)/eclipsed (e)-cis/trans 2-methoxypyridine (2MOP) and 2 N-methylaminopyridine (2NMP), are studied using theoretical calculations in combination with one-color resonance-enhanced two-photon ionization (1C-R2PI) and mass-analyzed threshold ionization (MATI) spectroscopies. The calculations predict that, for cis 2MOP, trans 2MOP and trans 2NMP, only the s conformers are stable in the S0, S1 and D0 states. However, for cis 2NMP, the stable conformer is staggered in the S0 state but eclipsed in the S1 and D0 states, indicating an isomerization upon the excitation or ionization from the S0 state. This is experimentally supported by the 1C-R2PI and MATI spectra of 2NMP. Due to the relative instability, the number density of trans 2MOP is too low in the sample to be detected. All the bands in the 1C-R2PI and MATI spectra of 2MOP are assigned to s-cis 2MOP. The energy differences between cis and trans conformers are derived from excitation and ionization energies, indicating another conformational isomerization: stable trans 2NMP in the S0 and S1 states but stable cis 2NMP in the D0 state. For 2MOP, the so-called syn preference previously found for the S0 state is also observed in the S1 and D0 states. The conformational preference and isomerization are discussed with natural bond orbital calculations and reduced density gradient analysis. For 2MOP, the syn preferences are mainly caused by the exchange repulsion among several sigma orbitals of the OCH3 group and the pyridine ring. While the relative stabilities of the s and e conformers of cis 2MOP and cis 2NMP are simultaneously influenced by steric repulsion and orbital interactions. PMID- 29431770 TI - Predicting anisotropic thermal displacements for hydrogens from solid-state NMR: a study on hydrogen bonding in polymorphs of palmitic acid. AB - The hydrogen-bonding environments at the COOH moiety in eight polycrystalline polymorphs of palmitic acid are explored using solid-state NMR. Although most phases have no previously reported crystal structure, measured 13C chemical shift tensors for COOH moieties, combined with DFT modeling establish that all phases crystallize with a cyclic dimer (R22(8)) hydrogen bonding arrangement. Phases A2, Bm and Em have localized OH hydrogens while phase C has a dynamically disordered OH hydrogen. The phase designated As is a mix of five forms, including 27.4% of Bm and four novel phases not fully characterized here due to insufficient sample mass. For phases A2, Bm, Em, and C the anisotropic uncertainties in the COOH hydrogen atom positions are established using a Monte Carlo sampling scheme. Sampled points are retained or rejected at the +/-1sigma level based upon agreement of DFT computed 13COOH tensors with experimental values. The collection of retained hydrogen positions bear a remarkable resemblance to the anisotropic displacement parameters (i.e. thermal ellipsoids) from diffraction studies. We posit that this similarity is no mere coincidence and that the two are fundamentally related. The volumes of NMR-derived anisotropic displacement ellipsoids for phases with localized OH hydrogens are 4.1 times smaller than those derived from single crystal X-ray diffraction and 1.8 times smaller than the volume of benchmark single crystal neutron diffraction values. PMID- 29431771 TI - Unexpected differences in the reactivity between the phosphorus and arsenic derivatives [(CpBIGFe)2(MU,eta4:4-E4)] (E = P and As). AB - Different reaction pathways were determined between thermolysis and photolysis reactions of the butterfly complex [{CpBIGFe(CO)2}2(MU,eta1:1-As4)] (1b). The thermolysis leads to novel arsenic-rich compounds [(CpBIGFe)2(MU,eta4:4-As4)] (2b), [(CpBIGFe)3(MU3,eta4:4:4-As6)] (4) and [CpBIGFe(eta5-As5)] (5), whereas the photolysis of [{CpBIGFe(CO)2}2(MU,eta1:1-E4)] (1a: E = P; 1b: E = As) exclusively results in the decarbonylation products [(CpBIGFe)2(MU,eta4:4-P4)] (2a), 2b and [(CpBIGFe)(MU,eta4:1-As4)(CpBIGFe(CO)2)] (3). The E4 complexes 2a and 2b show unique structural differences in the solid state despite their related compositions. PMID- 29431772 TI - The reactivity of cyclopropyl cyanide in titan's atmosphere: a possible pre biotic mechanism. AB - Cyclopropyl cyanide and other simple nitriles detected in Titan's atmosphere could be precursors leading to the formation of organic macromolecules in the atmosphere of Saturn's largest satellite. Proposing a thermodynamically possible mechanism that explains their formation and supports experimental results represents a difficult challenge. Experiments done in the Atomic and Molecular Physics Laboratory at the University of Trento (AMPL) have studied the ion molecule reaction between cyclopropyl cyanide and its protonated form, with reaction products being characterized by mass spectrometry. In addition to the expected ion-molecule adduct stabilized by non-covalent long-range interactions, in this work we prove that another distinct species having the same mass to charge ratio (m/z) of 135 is also produced. Moreover, from a previous study of the neutral cyclopropyl cyanide potential energy surface (PES) which shows a partial biradical character it has been possible to characterize the formation through the bimolecular reaction of a new covalent cyclic organic molecule. Calculations have been carried out at the ab initio Moller-Plesset (MP2) level of theory, ensuring the connectivity of the stationary points by using the intrinsic reaction coordinate (IRC) procedure. In order to characterize the reaction transition state, multireference calculations were done using a complete active space involving six electrons and six molecular orbitals [CAS (6 e-, 6 m.o.)]. This study opens the possibility of exploring the formation of new organic molecules by gaseous phase ion-molecule interaction schemes, with such molecules having relevance in interstellar space and in astrobiology (and may be involved in prebiotic molecular evolution). PMID- 29431773 TI - A near-infrared fluorescent probe for sensitive detection and imaging of sulfane sulfur in living cells and in vivo. AB - Sulfane sulfur refers to ionized sulfur that is reversibly attached to other sulfur atoms in the form of 6-valence electrons (S0). Sulfane sulfur possesses stronger nucleophilicity and reducibility than hydrogen sulfide in a series of physiological reactions, which probably makes sulfane sulfur the actual signal molecule in cells. Herein, we designed and synthesized a near-infrared (NIR) fluorescent probe BD-diSH for sensitive detection and imaging of sulfane sulfur in living cells and in vivo. The probe BD-diSH is composed of two moieties: the fluorophore azo-BODIPY and the sulfane sulfur recognition unit, viz., 2-mercapto benzoate. BD-diSH displayed high sensitivity and selectivity towards sulfane sulfur. The mercapto group (-SH) of 2-mercapto benzoic acid can nucleophilically capture the sulfur atom of thiosulfoxide tautomers in sulfane sulfur to form SSH. The group -SSH will immediately induce intramolecular cyclization reaction and release the azo-BODIPY fluorophore to emit NIR fluorescence. The probe BD diSH was successfully applied to detect and image sulfane sulfur in the cytoplasm of the living cells. The results illustrated that the endogenous and exogenous sulfane sulfur level changed depending on different cell lines. BD-diSH was also capable of imaging the level changes of sulfane sulfur in mice. The above applications make our new probe a potential chemical tool for the study of physiological and pathological functions of sulfur sulfide in living cells and in vivo. PMID- 29431774 TI - Active droplet-array (ADA) microfluidics enables multiplexed complex bioassays for point of care testing. AB - We introduce a novel and versatile microfluidic technology that allows parallel and multi-step bioanalytical procedures to be simply implemented by switching reagent-containing droplet arrays among alternative interaction zones for intended mass or energy transport in a programmable manner. This enables multiplexed complex bioassays for point-of-care testing. PMID- 29431775 TI - Cascade covalent and coordination bond formation for Ti-based cage assembly: catalysis and coordination bifunctionality of TiCl4. AB - The metallosupramolecular Ti-based M4L4 cage of [Ti4O2L4Cl8] (L = 4 acetamidobenzoic acid) is synthesized via the one-pot solvothermal reaction of 4 aminobenzoic acid, acetic acid and TiCl4. The Ti(iv) ion functions as a Lewis acid catalyst for acylation condensation, and then coordinates with the resultant 4-acetamidobenzoic acid to afford Ti-based cage formation in a cascade fashion. PMID- 29431776 TI - Sumanene: an efficient pi-bowl for dihydrogen storage. AB - Density functional theory calculations at the M06L/6-311++G(d,p) level show that sumanene (Su), a polycyclic aromatic pi-bowl, and its anionic forms possess high dihydrogen binding affinity. The dihydrogen rich systems such as Su(H2)40, Su (H2)40, and Su2-(H2)40 show interaction energy (Eint) values of 51.7, 63.0 and 87.6 kcal mol-1, respectively. The ion-pair complexes of anionic, dianionic and trianionic sumanenes with K+ also have a significant H2 binding capacity with Eint values of 61.6 kcal mol-1 for Su-K+(H2)47, 77.1 kcal mol-1 for Su2 (K+)2(H2)51 and 132.6 kcal mol-1 for Su3-(K+)3(H2)51. The charge delocalization in the complex increases substantially with an increase in the amount of H2 adsorbed, which parallels with a declining trend in the magnitude of the molecular electrostatic potential (MESP) minimum (Vmin) for Su, Su-, Su2-, Su-K+, Su2-(K+)2, and Su3-(K+)3. Also, using quantum theory of atoms in molecules (QTAIM) analysis, sumaneneH2 noncovalent interactions and secondary dihydrogen interactions within the complex are established by locating bond critical points (bcp). The structured network of noncovalent bonds in the complex accounts for the stability of the complex. Further, by replacing K+ with lighter metals such as Li+ or Na+, a 66-74% increase in Eint is observed for anion-M+ and dianion (M+)2 ion pairs. Our results prove that sumanene systems possess significant dihydrogen binding affinity, which can be employed in developing efficient hydrogen storage systems. PMID- 29431778 TI - LiCs2La(BO3)2 and Li3K9La3(BO3)7: new mixed alkali metal lanthanum borates with three-dimensional open frameworks and short cut-off edges. AB - Two new mixed alkali metal lanthanum borates, LiCs2La(BO3)2 and Li3K9La3(BO3)7, were synthesized through a high-temperature solution method and millimeter-sized colorless crystals were obtained. The structures of LiCs2La(BO3)2 and Li3K9La3(BO3)7 have an intricate three-dimensional (3D) open framework with one dimensional (1D) infinite channels surrounded by cation polyhedra and isolated BO3 units. In particular, LiCs2La(BO3)2 exhibits a short cut-off edge <190 nm and a large experimental band gap of 6.20 eV, evidenced by diffuse reflection spectroscopy. Moreover, to better understand the relationship between the electronic structures and optical properties of LiCs2La(BO3)2, theoretical calculations using density functional theory were performed. The result indicated that LiCs2La(BO3)2 has a calculated birefringence of 0.036@1064 nm and the direct band gap is 4.54 eV. In addition, the effects of ion substitution on structural transition and the metal ion/boron ratio on dimensions of the B-O frameworks are also discussed in detail. PMID- 29431777 TI - Flammulina velutipes polysaccharides improve scopolamine-induced learning and memory impairment in mice by modulating gut microbiota composition. AB - Flammulina velutipes polysaccharides (FVP) have been proved to be effective in improving learning and memory impairment in mice. However, their underlying mechanism remains unclear. The aim of this study was to investigate the relationship between memory improvement and gut microbiota regulation of FVP. The results showed a significant decrease in the relative abundances of Clostridia and Bacilli but a significant increase in Bacteroidia, Erysipelotrichia and Actinobacteria in the FVP-treated group versus the control group. Fecal microbiota transplantation of mice with 'FVP microbiota' derived from FVP-fed mice resulted in improved learning and memory function compared to colonization with 'common microbiota' derived from control individuals. FVP and 'FVP microbiota' significantly increased the numbers of platform crossings and the swimming distance of mice in the probe test and decreased the escape latency and total swimming distance of mice in the hidden platform test. Moreover, FVP and 'FVP microbiota' regulated cytokines, such as IL-1beta, TNF-alpha, IL-6 and IL 10, suggesting a mechanism involving the suppression of neuroinflammation. This study indicated that the regulation of the gut microbiome may have a causal role in improving scopolamine-induced impairment of learning and memory. PMID- 29431779 TI - Cyclometalated N-heterocyclic carbene iridium(iii) complexes with naphthalimide chromophores: a novel class of phosphorescent heteroleptic compounds. AB - A series of cyclometalated N-heterocyclic carbene complexes of the general formula [Ir(C^N)2(C^C:)] has been prepared. Two sets of compounds were designed, those where (C^C:) represents a bidentate naphthalimide-substituted imidazolylidene ligand and (C^N) = ppy (3a), F2ppy (4a), bzq (5a) and those where (C^C:) represents a naphthalimide-substituted benzimidazolylidene ligand and (C^N) = ppy (3b), F2ppy (4b), bzq (5b). The naphthalimide-imidazole and naphthalimide-benzimidazole ligands 1a,b and the related imidazolium and benzimidazolium salts 2a,b were also prepared and fully characterized. The N heterocyclic carbene Ir(iii) complexes have been characterized by NMR spectroscopy, cyclic voltammetry and elemental analysis. Moreover, the molecular structures of one imidazolium salt and four Ir(iii) complexes were determined by single-crystal X-ray diffraction. The structures provide us with valuable information, most notably the orientation of the naphthalimide chromophore with respect to the N-heterocyclic carbene moiety. All compounds are luminescent at room temperature and in a frozen solvent at 77 K, exhibiting a broad emission band that extends beyond 700 nm. The presence of the naphthalimide moiety changes the character of the lowest excited state from 3MLCT to 3LC, as corroborated by DFT and TD-DFT calculations. Remarkably, replacing imidazole with a benzimidazole unit improves the quantum yields of these compounds by decreasing the knr values which is an important feature for optimized emission performance. These studies provide valuable insights about a novel class of N-heterocyclic carbene-based luminescent complexes containing organic chromophores and affording metal complexes emitting across the red-NIR range. PMID- 29431780 TI - Synthesis, structure and optoelectronic properties of hybrid iodobismuthate & iodoantimonate semiconducting materials. AB - The syntheses and structures of five iodobismuthate and nine iodoantimonate hybrid materials are presented. The 1,3-dimethyl-2-oxo-2,3-dihydropyrimidinium cation has been used to template the isostructural, one-dimensional [C6H9N2O][SbI4] (I) and [C6H9N2O][BiI4] (II), while 4-methylmorpholinium templates the compounds, [C5H12NO]4[Sb6I22] (III) and [C5H12NO]4[Bi4I16] (IV), both containing isolated iodopnictogenide cluster anions. Five iodoantimonate compounds, templated by piperazinium cation derivatives, have been synthesised; [C4H12N2][SbI4]2.4H2O (V), [C5H14N2][SbI4]2.3H2O (VI), two polymorphs of [C6H16N2][SbI4]2.2H2O (VII and VIII) and [C6H16N2][Sb4I16]0.5.H2O (IX), mainly adopting structures closely related to previously published 1D iodobismuthate hybrid materials. 1-Ethyl-2-methylbenzimidazolium cations, formed in situ in the reaction medium, template the isostructural 1D structures of [C10H13N2][SbI4] (X) and [C10H13N2][BiI4] (XI). 1,4-Diazabicyclo[2.2.2]octandiium (DABCOH2)2+ di cations are shown to template a hydrated iodoantimonate structure [C6H14N2]2[Sb4I16].2H2O (XII) containing [Sb4I16]4- complex anions and a mixed phase of two iodobismuthate materials; one phase contains, uniquely, a mixture of the complex anions [Bi2I10]4- and [BiI6]3- in the form [C6H14N2]10[Bi2I10]2[BiI6]4.(H2O)8 (XIII), and the second, [C6H14N2]2[Bi4I16].2H2O (XIV), contains discrete [Bi4I16]4- clusters. The stability and thermal decomposition routes of these phases have been determined using thermogravimetric analysis. UV-vis spectroscopy has been used to determine band gap energy estimates which are related, for a range of iodobismuthate and iodoantimonate materials, to their structural features and potential optoelectronic applications. PMID- 29431781 TI - Unravelling the mechanistic details of metal binding to mammalian metallothioneins from stoichiometric, kinetic, and binding affinity data. AB - Metallothioneins (MTs) are small, cysteine-rich proteins, found throughout Nature. Their ability to bind a number of different metals with a range of stoichiometric ratios means that this protein family is critically important for essential metal (Zn2+ and Cu+) homeostasis, metal storage, metal donation to nascent metalloenzymes as well as heavy metal detoxification. With its 20 cysteines, metallothionein is also considered to protect cells against oxidative stress. MT has been studied by a large number of researchers over the last 6 decades using a variety of spectroscopic techniques. The lack of distinguishing chromophores for the multitude of binding sites has made the evaluation of stoichiometric properties for different metals challenging. Initially, only 113Cd NMR spectroscopy could provide strong evidence for the proposed cluster formation of Cd-MT. The extraordinary development of electrospray ionization mass spectrometry (ESI-MS), where all coexisting species in solution are observed, revolutionized MT research. Prior to the use of ESI-MS data, a range of "magic numbers" representing metal-to-MT molar ratios were reported from optical spectroscopic studies. The availability of ESI mass spectral data led to (i) the confirmation of cluster formation, (ii) a conceptual understanding of the cooperativity involved in multiple metal binding events, (iii) the presence of domain specificity between regions of the protein and (iv) mechanistic details involving both binding affinities and rate constants. The kinetic experiments identified the presence of multiple individual binding sites, each with a unique rate constant and an analogous binding affinity. The almost linear trend in rate constants as a function of bound As3+ provided a unique insight that became a critical step in the complete understanding of the mechanistic details of the metalation of MT. To fully define the biological function of this sulfur-rich protein it is necessary to determine kinetic rate constants and binding affinities for the essential metals. Recently, Zn2+ competition experiments between both of the isolated fragments (alpha and beta) and the full-length protein (betaalpha-MT 1a) as well as Zn2+ competition between betaalpha-MT 1a and carbonic anhydrase were reported. From these data, the trend in binding affinities and the values of the Kf of the 7 bimolecular reactions involved in metalation were determined. From the analysis of ESI-MS data for Cu+ binding to betaalpha-MT 1a at different pH-values, a trend in the 20 binding affinities for the complete metalation mechanism was reported. This review details a personal view of the historical development of the determination of stoichiometry for metal binding, the structure of the binding sites, the rates of the metalation reactions and the underlying binding affinities for each metalation step. We have attempted to summarize the experimental developments that led to the publication in May 2017 of the experimental determination of the 20 binding constants for the 20 sequential bimolecular reactions for Cu+ binding to the 20 Cys of apoMT as a function of pH that show the appearance and disappearance of clusters. We report both published data and in a series of tables an assembly of stoichiometries, and equilibrium constants for Zn2+ and Cu+ for many different metallothioneins. PMID- 29431782 TI - A metal-organic framework derived hierarchical nickel-cobalt sulfide nanosheet array on Ni foam with enhanced electrochemical performance for supercapacitors. AB - Metal-organic frameworks (MOFs) have emerged as a new platform for the construction of various functional materials for energy related applications. Here, a facile MOF templating method is developed to fabricate a hierarchical nickel-cobalt sulfide nanosheet array on conductive Ni foam (Ni-Co-S/NF) as a binder-free electrode for supercapacitors. A uniform 2D Co-MOF nanowall array is first grown in situ on Ni foam in aqueous solution at room temperature, and then the Co-MOF nanowalls are converted into hierarchical Ni-Co-S nanoarchitectures via an etching and ion-exchange reaction with Ni(NO3)2, and a subsequent solvothermal sulfurization. Taking advantage of the compositional and structural merits of the hierarchical Ni-Co-S nanosheet array and conductive Ni foam, such as fast electron transportation, short ion diffusion path, abundant active sites and rich redox reactions, the obtained Ni-Co-S/NF electrode exhibits excellent electrochemical capacitive performance (1406.9 F g-1 at 0.5 A g-1, 53.9% retention at 10 A g-1 and 88.6% retention over 1000 cycles), which is superior to control CoS/NF. An asymmetric supercapacitor (ASC) assembled by using the as fabricated Ni-Co-S/NF as the positive electrode and activated carbon (AC) as the negative electrode delivers a high energy density of 24.8 W h kg-1 at a high power density of 849.5 W kg-1. Even when the power density is as high as 8.5 kW kg-1, the ASC still exhibits a high energy density of 12.5 W h kg-1. This facile synthetic strategy can also be extended to fabricate other hierarchical integrated electrodes for high-efficiency electrochemical energy conversion and storage devices. PMID- 29431783 TI - One-pot sustainable synthesis of magnetic MIL-100(Fe) with novel Fe3O4 morphology and its application in heterogeneous degradation. AB - A novel, rapid and simple method is described for the synthesis of magnetic MIL 100(Fe) with novel Fe3O4 morphology, which significantly improved the sustainability of conventional fabrication processes in several aspects. The magnetic MOFs were prepared (i) in one pot (instead of multiple steps), (ii) at room temperature (instead of temperatures over 150 degrees C), (iii) within a few hours with excellent yield (instead of in few days with low productivity) and (iv) in the absence of any corrosive inorganic acid and organic reagent. The materials were tested in the industrially demanded photocatalytic and photo Fenton degradation of sodium sulfadiazine. The degradation results indicated that the Fe3O4 nanorods could accelerate the catalytic efficiency. The catalyst would be of potential application due to its stable catalytic activity in repeated reaction cycles and no need for regeneration. Therefore, the MIL-100(Fe) and magnetic MIL-100(Fe) proposed in this study are ideal catalysts for the heterogeneous degradation of sodium sulfadiazine. PMID- 29431784 TI - Fabrication of Bi19S27I3 nanorod cluster films for enhanced photodetection performance. AB - Thin-film photodetectors built from one-dimensional nanostructures have attracted extensive attention due to their significance in basic scientific research and potential technological applications. It is still desirable to develop new materials with a wide response range for application in photodetectors. In this work, a Bi19S27I3 nanorod cluster film has been successfully fabricated on various rigid substrates by a facile solvothermal method. The component nanorods exhibit an oriented growth along the [001] direction. The UV-Vis-NIR absorption spectrum shows a continuous strong absorption spanning the whole visible light to near-infrared region and presents a direct band gap of 0.83 eV for the prepared Bi19S27I3 nanorod clusters. The spectral photoresponse of the Bi19S27I3-based photodetector device demonstrates a broad photoresponse ranging from ultraviolet to near infrared. The photocurrent results reveal that the photodetector exhibits a more sensitive response towards near-infrared light than visible light. Furthermore, the photodetector based on the Bi19S27I3 nanorod cluster film shows significantly enhanced photodetection performance compared to Bi19S27I3 nanorod powder. The photocurrent and on-off ratio of the prepared nanorod cluster film are respectively up to 400 times and several times higher than those of the powder sample. The on-off ratios are about 265 and 66 under NIR illumination and 48 and 11 under visible light for the film and powder samples, respectively. These results suggest a great potential application of the prepared Bi19S27I3 nanorod cluster film in optoelectronic devices. PMID- 29431785 TI - Dietary intake of glucono-delta-lactone attenuates skin inflammation and contributes to maintaining skin condition. AB - Skin properties are influenced by both external (e.g., ultraviolet [UV], chemicals, and bacteria) and internal factors (e.g., nutrition and hormones). Therefore, some dietary supplements are expected to improve skin conditions. Glucono-delta-lactone (GDL) is widely used as a food additive and is naturally present in wine, honey, and other foods. The aim of this study was to assess whether GDL improves skin condition and inflammation. In a double-blind, placebo controlled study, 40 healthy Japanese male volunteers were randomly assigned to either the GDL (2000 mg day-1) or placebo group. A significant difference was found in the rates of change in transepidermal water loss (TEWL) from the baseline to 6 months between the placebo and GDL groups (P < 0.05). Facial lightness (L*) significantly increased by 1.6% only in the GDL group at 6 months compared with the baseline. The value of the elasticity parameter, Ua/Uf, of dietary GDL significantly increased (6.2% at 2 months and 5.4% at 6 months). Besides these, dietary GDL suppressed UVB-induced erythema (a*) and pigmentation (L*). Dietary GDL has anti-inflammatory effects on the skin and prevents/improves skin disorders caused by seasonal change. PMID- 29431786 TI - A Suzuki-Miyaura method for labelling proliferating cells containing incorporated BrdU. AB - The 5-bromo-2'-deoxyuridine (BrdU) incorporation cell proliferation assay is the most commonly used method for assessing DNA replication. The current detection of BrdU in cells relies on antibody immunostaining, but has various limitations including low antibody specificity and poor tissue penetration. In this study, we utilised a Suzuki-Miyaura reaction to develop a chemical method to label cellular BrdU with fluorescent boronic acid probes. The coupling conditions were optimised for complex cellular environments, and the key observation was the need to use oxygen scavengers and zerovalent palladium to prevent side reactions and increase the rate of coupling. The reliability and specificity of the BrdU Suzuki-Miyaura labelling method were verified under various biological conditions. The applicability of the BrdU Suzuki-Miyaura labelling methodology was also investigated, and we show that labelling cellular BrdU is highly sensitive and reliable, which is comparable to the ideal performance of BrdU immunostaining. Moreover, the Suzuki-Miyaura reaction protocol provides high BrdU recognition specificity. Taken together, the BrdU Suzuki-Miyaura labelling protocol provides an attractive alternative to the more traditional cell proliferation assay. PMID- 29431787 TI - Lysozyme and DNA binding affinity of Pd(ii) and Pt(ii) complexes bearing charged N,N-pyridylbenzimidazole bidentate ligands. AB - New cisplatin analogue Pd(ii) and Pt(ii) complexes bearing charged pyridylbenzimidazole derivatives furnished with either an alkylated sulfonate or a phosphonium side chain were synthesized, fully characterized and tested for their antimicrobial and cytotoxic activities against noncancerous human embryonic kidney cells (HEK293). The interactions with CT-DNA were investigated using UV/vis spectroscopy. Assignment of the electronic transitions was performed with the aid of TDDFT. The complexes showed interesting antifungal activity against Candida albicans and Cryptococcus neoformans. The Pd(ii) complex conjugated with alkylated triphenylphosphonium exhibited higher cytotoxicity (CC50 = 8.932 MUg mL 1, equivalent to 12 nM) than the others. The reactivity towards hen egg white lysozyme (HEWL) was investigated by electrospray ionization mass spectrometry. The formation of DNA- and HEWL-adducts was achieved via the noncovalent and covalent interactions. PMID- 29431788 TI - Effect of ligand substitution on the SMM properties of three isostructural families of double-cubane Mn4Ln2 coordination clusters. AB - Three isostructural lanthanide series with a core of MnMnLn2 are reported. These three families have the formulae of [MnMnLn2(MU4-O)2(H2edte)2(piv)6(NO3)2] {no crystallization solvent, Ln = La, Ce, Pr, Nd, Eu (1-4, 6); solv = 3MeCN, Ln = Sm, Gd, Tb, Dy, Ho, Er, Tm, Yb, Y (5, 7-13)}, where H2edte = N,N,N',N'-tetrakis(2 hydroxyethyl)ethylenediamine and piv = pivalate; [MnMnLn2(MU4 O)2(H2edte)2(benz)6(NO3)2], where benz = benzoate, or [MnMnLn2(MU4 O)2(edteH2)2(benz)6(NO3)2].2MeCN {Ln = Gd, Tb, Dy (14-16); and [MnMnLn2(MU4 O)2(edteH2)2(piv)8].solv {solv = 4MeCN, Ln = La (17); solv = 2MeCN.tol.H2O, Ln = Pr, Nd, Sm, Tb (18-20, 22); solv = 2MeCN.H2O, Ln = Gd (21). These compounds crystallize in two different systems, namely, monoclinic in the space groups P21/n for 1-4, 6, and 14-16 and C2/c for 5, 7-13, 18-20, and 22 and triclinic in the space group P1[combining macron] for 17 and 21. The crystal structures of these compounds display a face-fused dicubane structure connected by different types of bridged oxygen atoms. Solid-state dc magnetic susceptibility characterization was carried out for 1-22, and fitting showed that MnIIIMnIII is antiferromagnetically (AF) coupled and MnIIMnIII, MnIILn and MnIIILn are weakly ferromagnetically coupled. In addition, ac measurements were carried out and showed that only 7, 15, and 22 for Tb, 8 and 16 for Dy, and 20 for Sm exhibited slow magnetization relaxation. In the case of 15, it was possible to determine the energy barrier of the slow-relaxation behavior by fitting peak temperatures to the Arrhenius law, which gave a value of Ueff = 21.2 K and a pre-exponential factor of tau0 = 4.0 * 10-9 s. PMID- 29431789 TI - Ethylene glycol-mediated rapid synthesis of carbon-coated ZnFe2O4 nanoflakes with long-term and high-rate performance for lithium-ion batteries. AB - Carbonaceous hybrid nanocomposites with a porous flaky structure hold great promise as high-performance electrodes for lithium-ion batteries (LIBs); yet large-scale synthesis is still a challenge. In this work, we successfully develop a novel carbon hybrid structure of carbon-coated ZnFe2O4 nanoflakes (ZnFe2O4@C NFs) through a fast ethylene glycol (EG)-mediated metal alkoxide method, refluxing at 200 degrees C in EG and a post-calcination at 500 degrees C in a N2 atmosphere. The organic components in the pre-synthesized ZnFe-alkoxide precursor (ZnFe2(OCH2CH2O)4) can be transferred into an amorphous carbon layer easily surrounding the crystalline ZnFe2O4 subunits during the annealing process. The flaky morphologies of the as-prepared ZnFe2O4@C hybrids are highly dependent on the refluxing temperature. Upon increasing the refluxing temperature from 140 degrees C to 200 degrees C, the sphere-like morphology of the ZnFe2O4@C composites gradually evolves into microflowers and separate nanoflakes. When used as an anode for LIBs, the hybrid ZnFe2O4@C NFs present excellent electrochemical performance with high discharge capacity, long-term cyclic stability and superior high-rate capability. Even after 1000 cycles at 0.5 A g-1, the hybrid ZnFe2O4@C NFs still deliver a stable reversible discharge capacity of 778.6 mA h g-1. PMID- 29431790 TI - Synthesis and magneto-structural studies on a new family of carbonato bridged 3d 4f complexes featuring a [CoLn(CO3)] (Ln = La, Gd, Tb, Dy and Ho) core: slow magnetic relaxation displayed by the cobalt(ii)-dysprosium(iii) analogue. AB - A new family of [3 + 3] hexanuclear 3d-4f complexes [(MU3-CO3){CoIILnIIIL(MU3 OH)(OH2)}3]-(ClO4).mC2H5OH.nH2O (1-5) [Ln = La (1), Gd (2), Tb (3), Dy (4), and Ho (5)] have been prepared in moderate to high yields (62-78%) following a self assembly reaction between the ligand 6,6',6''-(nitrilotris(methylene))tris-(2 methoxy-4-methylphenol) (H3L), Co(OAc)2.4H2O and the lanthanide ion precursors in the mandatory presence of tetrabutylammonium hydroxide. During the reaction, atmospheric carbon dioxide is fixed in the product molecule as a bridging carbonato ligand which connects all the three lanthanide centers of this molecular assembly through a rare eta2:eta2:eta2-MU3 mode of bridging as revealed from X-ray crystallography. The metal centers in all these compounds, except the GdIII analogue (2), are coupled in antiferromagnetic manner while the nature of coupling in the CoGd complex is ferromagnetic. DFT calculations revealed that this ferromagnetic interaction occurs most likely by the CoII-GdIII superexchange, mediated via the bridging oxygen atoms. Only the CoII-DyIII compound (4) displayed a slow relaxation of the magnetization at a very low temperature as established by AC susceptibility measurements. The data provides an estimation of the activation energy U/kB = 9.2 K and the relaxation time constant tau0 = 1.0 * 10-7 s. PMID- 29431791 TI - The disclosure of mesoscale behaviour of a 3d-SMM monolayer on Au(111) through a multilevel approach. AB - Here we present a computational study of a full- and a half-monolayer of a Fe4 single molecule magnet ([Fe4(L)2(dpm)6], where H3L = 2-hydroxymethyl-2 phenylpropane-1,3-diol and Hdpm = dipivaloylmethane, Fe4Ph) on an unreconstructed surface of Au(111). This has been possible through the application of an integrated approach, which allows the explicit inclusion of the packing effects in the classical dynamics to be used in a second step in periodic and non periodic high level DFT calculations. In this way we can obtain access to mesoscale geometrical data and verify how they can influence the magnetic properties of interest of the single Fe4 molecule. The proposed approach allows to overcome the ab initio state-of-the-art approaches used to study Single Molecule Magnets (SMMs), which are based on the study of one single adsorbed molecule and cannot represent effects on the scale of a monolayer. Indeed, we show here that it is possible to go beyond the computational limitations inherent to the use, for such complex systems, of accurate calculation techniques (e.g. ab initio molecular dynamics) without losing the level of accuracy necessary to gain new detailed insights, hardly reachable at the experimental level. Indeed, long range and edge effects on the Fe4 structures and their easy axis of magnetization orientations have been evidenced as their different contributions to the overall macroscopic behavior. PMID- 29431792 TI - Bringing upconversion down to the molecular scale. AB - After solid state and nanoparticles, discrete molecular and supramolecular systems displaying upconversion (UC) in solution have recently emerged in the literature. This frontier article intends to recall the roots of molecular UC and will try to draw perspectives to improve the actual state of the art. PMID- 29431793 TI - Hydrogen evolution reactions boosted by bridge bonds between electrocatalysts and electrodes. AB - The interfacial interactions between nanostructured electrode materials and electrodes play an important part in the performance enhancement of electrochemical energy devices. However, the mechanism of interfacial interactions, as well as its influence on device performance, still remains unclear and is rarely studied. In this work, a CoS2 nanobelt catalyst assembled on Ti foil (CoS2 nanobelts/Ti) is prepared through in situ chemical conversions and chosen as an example to probe the interfacial interactions between the CoS2 catalyst and the Ti electrode, and the correlation between the interfacial interaction and the hydrogen evolution reaction (HER) performance. By a series of characterization studies and analyses, we propose that interfacial bridge bonds (Ti-S-Co and Ti-O-Co) in a covalent form may exist in the CoS2 nanobelts/Ti as well as its precursor Co(OH)3 nanobelts growing on Ti foil, which is further supported by density functional theory (DFT) calculations. Moreover, as a binder free electrocatalytic electrode, the CoS2 nanobelts/Ti shows boosted HER performance, including higher catalytic activity, and lower overpotential and Tafel slope, compared to its counterpart transformed from a solution-produced precursor. The HER performance enhancement is ascribed to the existence of interfacial bridge bonds that not only strengthen the electrode-catalyst mechanical integrity, but also serve as efficient charge transfer channels between the electrode and the catalyst, thus ensuring a stable and fluent electron transfer for the HER. Furthermore, the DFT calculations reveal that the CoS2 nanobelts/Ti catalyst with interfacial covalent interactions can facilitate the adsorption of H+ ions/H2 molecules and the desorption of H2 molecules for an accelerated HER. This work provides a new insight into the interfacial interactions between electrodes and electrode materials in electrochemical devices, and paves the way for the rational design and construction of high performance electrochemical devices for practical energy applications. PMID- 29431794 TI - Direct C3-arylations of 2-indolylmethanols with tryptamines and tryptophols via an umpolung strategy. AB - A Bronsted acid-catalyzed direct C3-arylation of 2-indolylmethanols with tryptamines and tryptophols has been established, leading to a series of potentially bioactive 2,3'-biindole derivatives with a broad substrate scope and generally good yields (38 examples, up to 96% yield). In this process, the reactivity of the C3-position of 2-indolylmethanol is switched from nucleophilic to electrophilic, which can serve as an umpolung strategy in indole chemistry. This protocol not only provides a new strategy for accessing structurally diversified 2,3'-biindolyl frameworks, but also satisfies the requirement of green chemistry. PMID- 29431795 TI - Viable stretchable plasmonics based on unidirectional nanoprisms. AB - Well-defined ordered arrays of plasmonic nanostructures were fabricated on stretchable substrates and tunable plasmon-coupling-based sensing properties were comprehensively demonstrated upon extension and contraction. Regular nanoprism patterns consisting of Ag, Au and Ag/Au bilayers were constructed on the stretchable polydimethylsiloxane substrate. The nanoprisms had the same orientation over the entire substrate (3 * 3 cm2) via metal deposition on a single-crystal microparticle monolayer assembly. The plasmonic sensor based on the Ag/Au bilayer showed a 6-fold enhanced surface enhanced Raman scattering signal under 20% uniaxial extension, whereas a 3-fold increase was observed upon 6% contraction, compared with the Au nanoprism arrays. The sensory behaviors were corroborated by finite-difference time-domain simulation, demonstrating the tunable electromagnetic field enhancement effect via the localized surface plasmon resonance coupling. The advanced flexible plasmonic-coupling-based devices with tunable and quantifiable performance herein suggested are expected to unlock promising potential in practical bio-sensing, biotechnological applications and optical devices. PMID- 29431796 TI - A turn-on near-infrared fluorescence probe with aggregation-induced emission based on dibenzo[a,c]phenazine for detection of superoxide anions and its application in cell imaging. AB - A new turn-on near-infrared fluorescence probe (BDP) based on dibenzo[a,c]phenazine for superoxide anion detection with aggregation-induced emission properties as well as a desirable large Stokes shift was designed and synthesized. After BDP reacted with superoxide, the initial diphenyl-phosphinyl groups of BDP were cleaved, resulting in the production of the pyridinium modified fluorophore (BD) with near-infrared emission. The fluorescent sensor BDP has a high selectivity for superoxide anions over some other intracellular ROSs, reductants, metal ions and amino acids. When HepG2 cells undergo apoptosis and inflammation, BDP is a good probe to keep track of the endogenous superoxide anion level by confocal laser scanning microscopic imaging. PMID- 29431797 TI - Sustained consumption of cocoa-based dark chocolate enhances seizure-like events in the mouse hippocampus. AB - While the consumption of caffeine and cocoa has been associated with a variety of health benefits to humans, some authors have proposed that excessive caffeine intake may increase the frequency of epileptic seizures in humans and reduce the efficiency of antiepileptic drugs. Little is known, however, about the proconvulsant potential of the sustained, excessive intake of cocoa on hippocampal neural circuits. Using the mouse as an experimental model, we examined the effects of the chronic consumption of food enriched in cocoa-based dark chocolate on motor and mood-related behaviours as well as on the excitability properties of hippocampal neurons. Cocoa food enrichment did not affect body weights or mood-related behaviours but rather promoted general locomotion and improved motor coordination. However, ex vivo electrophysiological analysis revealed a significant enhancement in seizure-like population spike bursting at the neurogenic dentate gyrus, which was paralleled by a significant reduction in the levels of GABA-alpha1 receptors thus suggesting that an excessive dietary intake of cocoa-enriched food might alter some of the synaptic elements involved in epileptogenesis. These data invite further multidisciplinary research aiming to elucidate the potential deleterious effects of chocolate abuse on behaviour and brain hyperexcitability. PMID- 29431798 TI - Boron calixphyrin complexes: exploring the coordination chemistry of a BODIPY/porphyrin hybrid. AB - Boron complexes of calix[4]phyrins (1.1.1.1) were prepared by reacting the free base ligands with BF3.Et2O. The reaction conditions can be efficiently tailored to produce mono- or di-boron calixphyrins. Mono-BF2 calixphyrins with boron coordinating to either the dipyrrin, BF2[H(Calix)], or dipyrromethane, BF2[H(Calix)] and BF2[H2(Calix)]+, bonding sites were isolated. The dipyrromethane isomer, BF2[H(Calix)], isomerises into BF2[H(Calix)] which kinetic studies and DFT calculations indicate is an intramolecular process. Two isomers of B2OF2(Calix) were isolated, one isomer bonding via the dipyrrin sites with the FBOBF moiety in cisoid geometry, and the second isomer bonding via the dipyrromethane sites with the FBOBF moiety in transoid geometry. Although the cisoid/dipyrrin isomer was calculated to be most energetically favourable for B2OF2(Calix), the isolation of the transoid/dipyrromethane isomer is postulated to occur via the presumed intermediate (BF2)2(Calix), for which DFT indicated a preference for transoid/dipyrromethane geometry. PMID- 29431799 TI - A combined experimental and computational investigation on pyrene based D-pi-A dyes. AB - The geometry (twist vs. planar) of a dye is one of the most pivotal factors for determining intramolecular charge transfer (ICT), light harvesting and photovoltaic properties of dye-sensitized solar cells. In order to comprehend the role of dye geometry on the above properties, we have devised the pyrene based D pi-A dyes namely 2-cyano-3-(5-pyren-1-yl-furan-2-yl)-acrylic acid (PFCC) and 2 cyano-3-(5-pyren-1-ylethynyl-furan-2-yl)-acrylic acid (PEFCC). The synthesized pyrene dyes were well characterized by NMR and EI-MS spectrometry. In both the dyes, the donor (pyrene) and acceptor (cyanoacrylic acid) segments remained the same. The varied pi-spacers were furan and ethynyl furan. The influences of the ethynyl spacer on the energy levels, light absorption, dynamics of excited states and photovoltaic properties of the DSCs were systematically investigated via theoretical calculations and spectroscopic measurements. UV-visible absorption spectral measurements indicated that the introduction of the ethynyl spacer enhances the molar absorptivity of a dye (PEFCC) in the order of 2, but does not shift the absorption range, which is consistent with the results obtained from density functional theory (DFT) calculations. The theoretical analysis indicated that the charge transfer transition is mainly constituted of the HOMO to the LUMO that were found to be located on donor and acceptor segments, respectively, which is supportive for efficient charge separation and electron injection processes. TDDFT calculations highlighted that the LUMO of the PEFCC dye is more stabilized by the incorporation of the ethynyl group between the pyrene and furan moieties that aid to inject electrons efficiently into TiO2 thereby resulting in an enhanced power conversion efficiency of 2.47% when compared to the PFCC dye. Notably, the overall conversion efficiency of the PEFCC dye reached 60% with respect to that of an N719-based device (4.12%) fabricated under similar conditions. Transient absorption kinetic studies demonstrated that a slower charge recombination rate is an essential factor behind enhanced efficiencies in PEFCC based cells. PMID- 29431800 TI - Formate complexes of titanium(iv) supported by a triamido-amine ligand. AB - The terminal formate complex [(OCHO)Ti(N3N)] (3) containing the trianionic triamido-amine ligand (Me3SiNCH2CH2)3N3- (N3N) was prepared via salt metathesis of [ClTi(N3N)] (1) with sodium formate or alternatively by treatment of the alkyl complex [nBuTi(N3N)] (2) with ammonium formate [HNEt3][OCHO]. Deprotonation of 3 with potassium hexamethyldisilazide gave a polymeric helical chain of the oxo complex {K[OTi(N3N)]}n (4). Reaction of 2 with the trityl salt [Ph3C][B(3,5 Cl2C6H3)4] or the Bronsted acid [HNEt3][B(C6F5)4] gave [(Et2O)Ti(N3N)][BR4] (6[BR4].Et2O) with R = 3,5-Cl2C6H3 or C6F5. The diethyl ether ligand was easily replaced by other L-type donor ligands such as tetrahydrofuran, pyridine, and 4 dimethylaminopyridine to give 6[BR4].L with L = thf, py, and dmap. Reaction of 6[BR4].Et2O with a stoichiometric amount of CO2 gave the dimeric, dicationic bis(carbamate)-bridged complexes [Ti{N(CH2CH2NSiMe3)2(CH2CH2NSiMe3(MU-CO2 etaO:etaO'))}]2[BR4]2 (7[BR4]2) through insertion of one CO2 into one of the titanium-amido bonds. Addition of pyridine to 7[B(C6F5)4]2 formed the monomeric carbamate complex [(py)Ti{((O2C kappa2O,O')NSiMe3CH2CH2)N(CH2CH2NSiMe3)2}][B(C6F5)4] (8[B(C6F5)4].py). The cationic formate-bridged species [(Ti(N3N))2(MU-OCHO-etaO:etaO')][BR4] (10[BR4]) readily formed when the terminal formate complex 3 was reacted with the cationic 6[BR4]. The reactivity of triamido-amine stabilized titanium(iv) complexes is shown to differ considerably from that of related titanium tris(anilide) complexes. PMID- 29431802 TI - Two-color dark-field (TCDF) microscopy for metal nanoparticle imaging inside cells. AB - Noble metal nanoparticles (NPs) supporting localized surface plasmon resonances are widely used in the context of biotechnology as optical and absorption contrast agents with great potential applicability to both diagnostics and less invasive therapies. In this framework, it is crucial to have access to simple and reliable microscopy techniques to monitor the NPs that have internalized into cells. While dark field (DF) microscopy takes advantage of the enhanced NP scattering at their plasmon resonance, its use in cells is limited by the large scattering background from the internal cell compartments. Here, we report on a novel two-color dark field microscopy that addresses these limitations by significantly reducing the cell scattering contribution. We first present the technique and demonstrate its enhanced contrast, specificity and reliability for NP detection compared to a standard optical dark field. We then demonstrate its potential suitability in two different settings, namely wide-field parallel screening of circulating cells in microfluidic chips and high-resolution tracking of internalized NPs in cells. These proof of principle experiments show a promising capability of this approach with possible extension to other kinds of targeted systems like bacteria and vesicles. PMID- 29431801 TI - Integrated dual-modality microfluidic sensor for biomarker detection using lithographic plasmonic crystal. AB - This paper reports an integrated dual-modality microfluidic sensor chip, consisting of a patterned periodic array of nanoposts coated with gold (Au) and graphene oxide (GO), to detect target biomarker molecules in a limited sample volume. The device generates both electrochemical and surface plasmon resonance (SPR) signals from a single sensing area of Au-GO nanoposts. The Au-GO nanoposts are functionalized with specific receptor molecules, serving as a spatially well defined nanostructured working electrode for electrochemical sensing, as well as a nanostructured plasmonic crystal for SPR-based sensing via the excitation of surface plasmon polaritons. High sensitivity of the electrochemical measurement originates from the presence of the nanoposts on the surface of the working electrode where radial diffusion of redox species occurs. Complementarily, the SPR detection allows convenient tracking of dynamic antigen-antibody interactions, to describe the association and dissociation phases occurring at the sensor surface. The soft-lithographically formed nanoposts provide high reproducibility of the sensor response to epidermal growth factor receptor (ErbB2) molecules even at a femtomolar level. Sensitivities of the electrochemical measurements to ErbB2 are found to be 20.47 MUA MUM-1 cm-2 in a range from 1 fM to 0.1 MUM, and those of the SPR measurements to be 1.35 nm MUM-1 in a range from 10 pM to 1 nM, and 0.80 nm MUM-1 in a range from 1 nM to 0.1 MUM. The integrated dual-modality sensor offers higher sensitivity (through higher surface area and diffusions from nanoposts for electrochemical measurements), as well as the dynamic measurements of antigen-antibody bindings (through the SPR measurement), while operating simultaneously in a same sensing area using the same sample volume. PMID- 29431804 TI - Light-responsive polymers for microfluidic applications. AB - While the microfluidic device itself may be small, often the equipment required to control fluidics in the chip unit is large e.g. pumps, valves and mixing units, which can severely limit practical use and functional scalability. In addition, components associated with fluidic control of the device, more specifically the valves and pumps, contribute significantly to the overall unit cost. Here we sketch the problem of a gap between high end accurate, but expensive sensor platforms, versus less accurate, but widely employable hand-held low-cost devices. Recent research has shown that the integration of light responsive materials within microfluidic devices can provide the function of expensive fluidic components, and potentially enable sophisticated measurements to be made using much less expensive equipment. An overview of the most recent developments will be presented for valves, mixers, transport and sample handling inside microfluidic devices. PMID- 29431803 TI - Cretan tea (Origanum dictamnus L.) as a functional beverage: an investigation on antiglycative and carbonyl trapping activities. AB - Accumulation of advanced glycation end products (AGEs) in vivo is associated with many chronic disorders such as diabetes, renal failure, aging, and Alzheimer's disease. The aim of this study was to expand the knowledge about the functional properties of Origanum dictamnus L. beverage (Cretan tea) by an investigation about the inhibitory effects on the formation of AGEs and the capacity to trap dicarbonyl compounds. Dittany infusion was characterized for its polyphenolic composition by RP-HPLC-DAD-ESI/MSn and twenty compounds were detected. Its antiglycative property was evaluated by in vitro BSA-sugar (glucose, fructose, and ribose) and BSA-methylglyoxal (MGO) assays, tests for the formation of Amadori products and dicarbonyl compounds, and the direct glyoxal (GO) and MGO trapping capacity. The infusion showed the highest inhibitory effect on the formation of dicarbonyl compounds and AGEs (activity values range from 72-100%) and only a weak effect on the formation of Amadori products, indicating that the antiglycative action occurred primarily during the last two phases of the non enzymatic glycation reaction. These activities are partially correlated with the antioxidant/antiradical activity, as demonstrated by the scavenger capacity against the ABTS cation and DPPH stable radicals, and the reducing power. The registered high anti-AGE capacity could probably be ascribed to the dittany polyphenolic composition particularly rich in flavone derivatives. These findings support further investigations to study the feasibility of dittany as an antiglycative agent in food or cosmetic preparation. PMID- 29431805 TI - Silicon nanohybrid-based SERS chips armed with an internal standard for broad range, sensitive and reproducible simultaneous quantification of lead(ii) and mercury(ii) in real systems. AB - Lead ions (Pb2+) and mercury ions (Hg2+), the two commonly coexisting heavy metal ions, pose severe risks to environment and human health. To date, no surface enhanced Raman scattering (SERS) sensor has been reported for the simultaneous quantification of Pb2+ and Hg2+ in real systems. Herein, the first demonstration of SERS chips for simultaneous quantification of Pb2+ and Hg2+ in real systems is presented based on the combination of reproducible silicon nanohybrid substrates and a corrective internal standard (IS) sensing strategy. This chip was made of a silver nanoparticle-decorated silicon wafer via modification of the IS, i.e. 4 aminothiophenol, molecules. The as-prepared chip was further functionalized with Pb2+- and Hg2+- specific DNA strands capable of simultaneously detecting Pb2+ and Hg2+. Quantitatively, upon correction by the IS Raman signals, the broad dynamic ranges from 100 pM to 10 MUM for Pb2+ and from 1 nM to 10 MUM for Hg2+ were achieved, with the detection limit down to 19.8 ppt for Pb2+ and 168 ppt for Hg2+. For real applications, we further demonstrated that Pb2+ and Hg2+ spiked into industrial wastewater could be readily distinguished via the presented chip, and the relative standard deviation (RSD) value was less than ~15%. More significantly, the resulting SERS chip can be well coupled with a hand-held Raman instrument and can then be used for the qualitative analysis of both Pb2+ and Hg2+ in real systems in a portable manner. Our results suggest that this high quality SERS chip is a powerful tool for on-site detection of various heavy metal ions in real samples in the field of food safety and environment protection. PMID- 29431806 TI - A scalable process to produce lipid-based compartmented Janus nanoparticles with pharmaceutically approved excipients. AB - In the field of nanotechnologies, theranostic approaches and fixed-dose combination products require the development of innovative carriers able to co encapsulate several entities of interest. This communication describes the preparation and characterization of lipid-based Janus compartmented nanoparticles. They were successfully prepared using a scalable process with pharmaceutically approved excipients. The analysis of the microscopic structure and supramolecular organization demonstrated the formation of two physico chemically different compartments enabling the co-administration at once of both liposoluble and hydrosoluble active pharmaceutical ingredients. PMID- 29431808 TI - Grignard-mediated rearrangement of trifluoroacetyl from dihydroisoquinoline enamides to afford tertiary trifluoromethylcarbinols. AB - Treatment of the trifluoroacetyl enamides of dihydroisoquinolines 2 with diverse Grignard reagents afforded tertiary trifluoromethyl-carbinols 4 by facilitating the addition of tertiary carbinols to the beta-carbon of enamides 2. Based on the confirmed formation of vinylogous amides 3, the transformation likely proceeds via unique acyl group rearrangement to the beta-carbon of the enamide and subsequent nucleophilic addition of the Grignard reagent. Given the synthetic utility and novelty of this reaction, this work may open new avenues for the synthesis of pharmaceutically important tertiary trifluoromethylcarbinols on cyclic enamide systems. PMID- 29431807 TI - Multi-functional organosilane-polymerized carbon dot inverse opals. AB - This paper demonstrates multi-functional optical properties of organosilane polymerized carbon dot inverse opals, such as tricolor-fluorescence, fluorescence enhancement, multi-color micro-patterns for anti-fake applications and a thermally-induced blueshift of bandgaps. It is of significance for the design and fabrication of novel optical devices. PMID- 29431809 TI - Lanthanide-MOFs constructed from mixed dicarboxylate ligands as selective multi responsive luminescent sensors. AB - Five novel Ln-MOFs associated with the mixed ligands of 4-(pyridin-3-yloxy) phthalic acid (H2ppda) and terephthalic acid (H2bdc), namely, [Ln(ppda)(bdc)0.5(C2H5OH)(H2O)]n (Ln = Sm (1), Eu (2), Gd (3), Tb (4), and Dy (5)) were synthesized under the solvothermal conditions. Compounds 1-5 exhibit the isostructural 2D layered structures. The solid-state luminescence properties of compounds 1, 2, 4 and 5 were investigated in detail. It was found that compound 4 not only detected nitrobenzene derivatives-based explosives with high selectivity, sensitivity, and recyclability, but also served as an excellent selective sensing material for Fe3+ ion and Cr2O72- ion. In particular, it is worth noting that the detection limit of TNP can reach 3.0 * 10-8 M. It was found that the free oxygen atoms of the ether bond, which function as the Lewis basic sites in Ln-MOFs, might interact with metal ions. In addition, the sensing mechanisms of 4 for different analytes were explored further. PMID- 29431810 TI - Exploiting coumarin-6 as ancillary ligands in 1,10-phenanthroline Ir(iii) complexes: generating triplet photosensitisers with high upconversion capabilities. AB - A series of new Ir(iii) complexes incorporating 3-(2-benzothiazolyl)-7 (diethylamino)coumarin (coumarin 6) and ethynylpyrene (EP) functionalised 1,10 phenanthroline (phen) were developed. [Ir(iii)(coumarin 6)2(3-EP-phen)](PF6) (Ir 3) proved to be the most promising material in triplet photosensitising applications. Highly absorbing at lambda = 485 nm (epsilon = 1.31 * 105 M-1 cm 1), it exhibits high upconversion and singlet oxygen quantum yields (PhiUC = 27.5%, PhiDelta = 81.5%) and an exemplary upconversion capability (eta = 3.60 * 106 M-1 cm-1). PMID- 29431811 TI - Bimetallic CoNiSx nanocrystallites embedded in nitrogen-doped carbon anchored on reduced graphene oxide for high-performance supercapacitors. AB - Exploring high-performance and low-priced electrode materials for supercapacitors is important but remains challenging. In this work, a unique sandwich-like nanocomposite of reduced graphene oxide (rGO)-supported N-doped carbon embedded with ultrasmall CoNiSx nanocrystallites (rGO/CoNiSx/N-C nanocomposite) has been successfully designed and synthesized by a simple one-step carbonization/sulfurization treatment of the rGO/Co-Ni precursor. The intriguing structural/compositional/morphological advantages endow the as-synthesized rGO/CoNiSx/N-C nanocomposite with excellent electrochemical performance as an advanced electrode material for supercapacitors. Compared with the other two rGO/CoNiOx and rGO/CoNiSx nanocomposites, the rGO/CoNiSx/N-C nanocomposite exhibits much enhanced performance, including a high specific capacitance (1028.2 F g-1 at 1 A g-1), excellent rate capability (89.3% capacitance retention at 10 A g-1) and good cycling stability (93.6% capacitance retention over 2000 cycles). In addition, an asymmetric supercapacitor (ASC) device based on the rGO/CoNiSx/N C nanocomposite as the cathode and activated carbon (AC) as the anode is also fabricated, which can deliver a high energy density of 32.9 W h kg-1 at a power density of 229.2 W kg-1 with desirable cycling stability. These electrochemical results evidently indicate the great potential of the sandwich-like rGO/CoNiSx/N C nanocomposite for applications in high-performance supercapacitors. PMID- 29431812 TI - Two distinct mechanisms upon absorption of volatile organic compounds into siloxane polymers. AB - The response of polysiloxane materials to volatile organic compounds (VOCs) including benzene, toluene, ethylbenzene, and toluene (BTEX), as well as cyclohexane, acetone, methanol and isopropanol is studied using thin film large angle refractometry. Refractive index and thickness changes are measured to quantify the diffusion rate and partition coefficients associated with the absorption and desorption of VOC vapours into polydimethylsiloxane (PDMS) and polydiphenylsiloxane (PDPS) - PDMS copolymer films. Absorption of volatile solvent vapours into siloxane polymers is found to follow two distinct mechanisms with different absorption rates. These mechanisms are also associated with different excess volumes of mixing and may be accompanied by a polymer restructuring step. PMID- 29431813 TI - A gold nano-electrode for single ion channel recordings. AB - The artificial bilayer single channel recording technique is commonly used to observe the detailed physiological properties of various ion channel proteins. It permits easy control of the solution and membrane lipid composition, and is also compatible with pharmacological screening devices. However, its use is limited due to low measurement efficiency. Here, we developed a novel artificial bilayer single channel recording technique in which solubilized ion channel proteins immobilized on a gold nano-electrode are directly incorporated into a lipid bilayer at the same time as the bilayer is formed at the tip of it on coming in contact with an aqueous-oil interface. Using this technique, we measured the single channel currents of several types of channels including KcsA, MthK, hBK and P2X4. This technique requires only one action to simultaneously form the bilayers and reconstitute the channels into the membranes. This simplicity greatly increases the measurement efficiency and allows the technique to potentially be combined with high-throughput screening devices. PMID- 29431814 TI - Correction: The photocatalytic role of electrodeposited copper on pencil graphite. AB - Correction for 'The photocatalytic role of electrodeposited copper on pencil graphite' by Arathi P. J. et al., Phys. Chem. Chem. Phys., 2018, 20, 3430-3432. PMID- 29431815 TI - C(sp2)-H functionalization of aldehyde-derived hydrazones via a radical process. AB - This review is focused on the recent advances in the C(sp2)-H functionalization of aldehyde-derived hydrazones via a radical process. Diverse substituted hydrazones including N-heterocycles are afforded under mild conditions with excellent selectivities. In general, an aminyl radical as the key intermediate is involved during the reaction process, and a broad reaction scope with good functional group tolerance can be observed. In some cases, a photocatalyst under visible light irradiation is involved, which initiates the radical reaction. PMID- 29431816 TI - Environmental Science: Processes & Impacts in 2018. AB - 2017 was another successful year for Environmental Science: Processes & Impacts (ESPI); it saw the expansion of our Editorial team and publication of two excellent Themed Issues, all while maintaining our commitment to provide our authors with exceptional customer service and fast times to publication. Through this Editorial, we wish to reflect upon some of the highlights from 2017 and also take this opportunity to reveal further new additions to the ESPI team and our plans for 2018. PMID- 29431817 TI - Large deformation electrohydrodynamics of a Skalak elastic capsule in AC electric field. AB - The axisymmetric electrohydrodynamic deformation of an elastic capsule with a capacitive membrane obeying the Skalak law under a uniform AC electric field is investigated using analytical and boundary integral theory. The low capillary number (the ratio of destabilizing shear or electric force to the stabilizing elastic force) regime shows that time-averaged prolate and oblate spheroid deformations, and the time-periodic prolate-sphere, oblate-sphere breathing modes are commensurate with the time averaged-deformation. A novel prolate-oblate breathing mode is observed due to an interplay of finite membrane charging time and the field reversal of the AC field. The study, when extended to high capillary numbers, shows new breathing modes of cylinder-prolate, cylinder oblate, and biconcave-prolate deformation. These are the results of highly compressive normal Maxwell stress at the poles and are aided by a weak compressive equatorial stress, characteristic of a capacitive membrane. The findings of this work should form the basis for the understanding of more complex biological cells and synthetic capsules for industrial applications. PMID- 29431818 TI - All-natural and highly flame-resistant freeze-cast foams based on phosphorylated cellulose nanofibrils. AB - Pure cellulosic foams suffer from low thermal stability and high flammability, limiting their fields of application. Here, light-weight and flame-resistant nanostructured foams are produced by combining cellulose nanofibrils prepared from phosphorylated pulp fibers (P-CNF) with microfibrous sepiolite clay using the freeze-casting technique. The resultant nanocomposite foams show excellent flame-retardant properties such as self-extinguishing behavior and extremely low heat release rates in addition to high flame penetration resistance attributed mainly to the intrinsic charring ability of the phosphorylated fibrils and the capability of sepiolite to form heat-protective intumescent-like barrier on the surface of the material. Investigation of the chemical structure of the charred residue by FTIR and solid state NMR spectroscopy reveals the extensive graphitization of the carbohydrate as a result of dephosphorylation of the modified cellulose and further dehydration due to acidic catalytic effects. Originating from the nanoscale dimensions of sepiolite particles, their high specific surface area and stiffness as well as its close interaction with the phosphorylated fibrils, the incorporation of clay nanorods also significantly improves the mechanical strength and stiffness of the nanocomposite foams. The novel foams prepared in this study are expected to have great potential for application in sustainable building construction. PMID- 29431819 TI - What happens to the silver ions? - Silver thiocyanate nanoparticle formation in an artificial digestion. AB - An artificial digestion of silver nitrate is reported. It is shown that AgSCN nanoparticles emerge from ionic silver in saliva and remain present during the entire digestion process. The particles were characterized by infrared spectroscopy and small- and wide-angle X-ray scattering (SAXS/WAXS) regarding their composition and size distribution. PMID- 29431820 TI - Single crystal diamond membranes for nanoelectronics. AB - Single crystal, nanoscale diamond membranes are highly sought after for a variety of applications including nanophotonics, nanoelectronics and quantum information science. However, so far, the availability of conductive diamond membranes has remained an unreachable goal. In this work we present a complete nanofabrication methodology for engineering high aspect ratio, electrically active single crystal diamond membranes. The membranes have large lateral directions, exceeding ~500 * 500 MUm2 and are only several hundreds of nanometers thick. We further realize vertical single crystal p-n junctions made from the diamond membranes that exhibit onset voltages of ~10 V and a current of several mA. Moreover, we deterministically introduce optically active color centers into the membranes, and demonstrate for the first time a single crystal nanoscale diamond LED. The robust and scalable approach to engineer the electrically active single crystal diamond membranes offers new pathways for advanced nanophotonic, nanoelectronic and optomechanical devices employing diamond. PMID- 29431822 TI - Structural, electronic and adhesion characteristics of zinc/silica interfaces: ab initio study on zinc/beta-cristobalite. AB - The weak interaction between zinc and silica is responsible for a poor performance of anti-corrosive galvanic zinc coatings on modern advanced high strength steels. With the goal of identifying its microscopic origin, we report an extensive ab initio study on the structural, electronic, and adhesion characteristics of a variety of model zinc/beta-cristobalite interfaces, representative for different oxidation conditions. We show that the weakness of the zinc-silica interaction at non polar interfaces is driven by the presence of surface siloxane rings. These latter are drastically detrimental to interface adhesion when intact and their breaking is impeded by a large energy barrier. Conversely, the characteristics of polar interfaces are principally driven by the capacity of zinc to screen the surface compensating charges and to form O-Zn bonds. This screening is especially efficient in an oxygen-rich environment where the substrate-induced partial oxidation of the zinc deposit produces a considerable enhancement of interface adhesion. The identified microscopic mechanisms of interface interactions furnish precious guidelines towards practical attempts to improve adhesion. In particular, processes which enable breaking the surface siloxane rings are expected to noticeably reinforce the interaction at non-polar interfaces. PMID- 29431823 TI - Radiation-induced disorder in compressed lanthanide zirconates. AB - The effects of swift heavy ion irradiation-induced disordering on the behavior of lanthanide zirconate compounds (Ln2Zr2O7 where Ln = Sm, Er, or Nd) at high pressures are investigated. After irradiation with 2.2 GeV 197Au ions, the initial ordered pyrochlore structure (Fd3[combining macron]m) transformed to a defect-fluorite structure (Fm3[combining macron]m) in Sm2Zr2O7 and Nd2Zr2O7. For irradiated Er2Zr2O7, which has a defect-fluorite structure, ion irradiation induces local disordering by introducing Frenkel defects despite retention of the initial structure. When subjected to high pressures (>29 GPa) in the absence of irradiation, all of these compounds transform to a cotunnite-like (Pnma) phase, followed by sluggish amorphization with further compression. However, if these compounds are irradiated prior to compression, the high pressure cotunnite-like phase is not formed. Rather, they transform directly from their post-irradiation defect-fluorite structure to an amorphous structure upon compression (>25 GPa). Defects and disordering induced by swift heavy ion irradiation alter the transformation pathways by raising the energetic barriers for the transformation to the high pressure cotunnite-like phase, rendering it inaccessible. As a result, the high pressure stability field of the amorphous phase is expanded to lower pressures when irradiation is coupled with compression. The responses of materials in the lanthanide zirconate system to irradiation and compression, both individually and in tandem, are strongly influenced by the specific lanthanide composition, which governs the defect energetics at extreme conditions. PMID- 29431824 TI - Correction: Colchicine metallocenyl bioconjugates showing high antiproliferative activities against cancer cell lines. AB - Correction for 'Colchicine metallocenyl bioconjugates showing high antiproliferative activities against cancer cell lines' by Karolina Kowalczyk et al., Dalton Trans., 2017, 46, 17041-17052. PMID- 29431825 TI - Unequal coordination environment in complexes of the type [Au2Ag2(R)4(L)2]n. An immiscible solvent mixture as a key point in the control of ligand replacement. AB - Following an acid-base strategy, based on the reaction between gold(i) basic fragments and acid silver salts, it is possible to obtain heterometallic polymers of the general formula [Au2Ag2(R)4(L)2]n (R = C6Cl2F3; L = pyrimidine). Using this new heterometallic complex [Au2Ag2(C6Cl2F3)4(pym)2]n (1) as a starting material, and a good coordinating solvent such as acetonitrile, it is possible to modify the arrangement of the ligands connected to the silver centres and to obtain three different tetranuclear Au2Ag2 building blocks leading to the new polymer [Au6Ag6(C6Cl2F3)12(MU2-pym)2(NCMe)6]n (2). Both complexes display very intense luminescence emission. Structural, experimental and computational studies have been carried out in order to identify the origin of these properties and the factors that can affect them, such as, the presence of metallophilic interactions as well as different coordination environments for the metallic centres. PMID- 29431827 TI - Correction: Band gap modification and photoluminescence enhancement of graphene nanoribbon filled single-walled carbon nanotubes. AB - Correction for 'Band gap modification and photoluminescence enhancement of graphene nanoribbon filled single-walled carbon nanotubes' by A. I. Chernov et al., Nanoscale, 2018, DOI: 10.1039/c7nr07054c. PMID- 29431828 TI - Key factors in pincer ligand design. AB - Pincers, tridentate ligands that prefer a meridional geometry, are a rising class because of their distinctive combination of properties. They permit a good level of control on the nature of the coordination sphere by holding the donor groups in a predictable arrangement. Some groups, such as an aryl or a pyridine, that would normally be easily lost as monodentate ligands, become reliably coordinated, especially if they form the central donor unit of the three. Many pincer complexes show exceptional thermal stability, a property that is particularly prized in homogeneous catalysis where they can permit high temperature operation. The connectors between the three donor groups are often rigid, enforcing a strict mer geometry but flexible linkers permit fac binding and even fluxionality between the two forms. Rigid pincers can make good ligands for asymmetric catalysis-if the wingtip groups cannot easily rotate they may instead maintain a geometry in which suitable substituents project into the active site area of the catalyst where they help enantio-differentiation of the relevant transition states. Examples have been selected to illustrate these and other properties of this promising ligand class. PMID- 29431829 TI - Enhanced charge transfer and separation of hierarchical hydrogenated TiO2 nanothorns/carbon nanofibers composites decorated by NiS quantum dots for remarkable photocatalytic H2 production activity. AB - Hierarchical core/shell hydrogenated TiO2 (H-TiO2) nanothorns/carbon nanofibers (CNFs) composites were produced through a solvothermal method, followed by ordinal calcination and hydrogenation treatments using the prepared carbon nanofiber as electron-transporting substrate material. The hierarchical H TiO2/CNFs composites possess more exposed surface active sites and offer efficient charge transport paths. NiS quantum dots as excellent electron acceptors and cocatalysts were anchored on the hierarchical H-TiO2/CNFs composites by a wet chemical deposition method. The synergistic effects of the surface defects (oxygen vacancies), NiS cocatalyst, and carbon nanofibers greatly improve charge transfer and separation, increase the accessible surface area and surface donor density of the composites and also extend the photoresponse from the ultraviolet to the visible light region. By taking advantage of these features and because of its unique architecture, the optimal NiS quantum dots decorated H-TiO2/CNFs composite exhibited a remarkable solar-driven hydrogen generation rate (75.92 MUmol h-1, 30 mg-1) in the absence of a Pt cocatalyst under AM 1.5 irradiation, which is about 12.3 times that of TiO2/CNFs nanostructures. PMID- 29431830 TI - Sensors for measuring subcellular zinc pools. AB - Zinc homeostasis is essential for normal cellular function, and defects in this process are associated with a number of diseases including type 2 diabetes (T2D), neurological disorders and cardiovascular disease. Thus, variants in the SLC30A8 gene, encoding the vesicular/granular zinc transporter ZnT8, are associated with altered insulin release and increased T2D risk while the zinc importer ZIP12 is implicated in pulmonary hypertension. In light of these, and findings in other diseases, recent efforts have focused on the development of refined sensors for intracellular free zinc ions that can be targeted to subcellular regions including the cytosol, endoplasmic reticulum (ER), secretory granules, Golgi apparatus, nucleus and the mitochondria. Here, we discuss recent advances in Zn2+ probe engineering and their applications to the measurement of labile subcellular zinc pools in different cell types. PMID- 29431831 TI - Solvent-free and biocompatible multiphased organic-inorganic hybrid nanocomposites. AB - Biocompatible chemically cross-linked organic-inorganic (O-I) hybrid nanocomposites were developed using a new atoxic, simple and fast, solvent-free pathway. Poly(epsilon-caprolactone) (PCL) and poly(ethylene glycol) (PEG), which are both biocompatible, were used as the organic moieties (at different PCL/PEG ratios), while in situ synthesized polysilsesquioxanes made up the inorganic moiety. The O-I hybrid nanocomposites' molecular structures were characterized using solid-state 29Si NMR, TGA and ATR-IR. Results showed an unusually high condensation yield of approximately 90% and two distinct silsesquioxane structures. No traces of the remaining isocyanate groups were found. Advanced morphological characterization of the ternary O-I hybrids was performed using a combination of electron microscopy and X-ray scattering techniques such as SEM, TEM, ESI-TEM, WAXS and temperature-dependent SAXS. Results showed the occurrence of spherical nanoparticles, associated with polysilsesquioxane, and ordered network grains, associated with PCL and/or PEG chains cross-linked by silsesquioxane cages. As a consequence, a four-phased nanostructured morphology was proposed. In this model, PCL and PEG are undistinguishable, while polysilsesquioxane nanoparticles are uniformly distributed throughout a homogeneous cross-linked matrix, which shows gel-like behavior. Moreover, a mobile phase made up of unbound polymer chains occurs at the grain interface. PMID- 29431832 TI - Protected 5-(hydroxymethyl)uracil nucleotides bearing visible-light photocleavable groups as building blocks for polymerase synthesis of photocaged DNA. AB - Nucleosides, nucleotides and 2'-deoxyribonucleoside triphosphates (dNTPs) containing 5-(hydroxymethyl)uracil protected with photocleavable groups (2 nitrobenzyl-, 6-nitropiperonyl or 9-anthrylmethyl) were prepared and tested as building blocks for the polymerase synthesis of photocaged oligonucleotides and DNA. Photodeprotection (photorelease) reactions were studied in detail on model nucleoside monophosphates and their photoreaction quantum yields were determined. Photocaged dNTPs were then tested and used as substrates for DNA polymerases in primer extension or PCR. DNA probes containing photocaged or free 5 hydroxymethylU in the recognition sequence of restriction endonucleases were prepared and used for the study of photorelease of caged DNA by UV or visible light at different wavelengths. The nitropiperonyl-protected nucleotide was found to be a superior building block because the corresponding dNTP is a good substrate for DNA polymerases, and the protecting group is efficiently cleavable by irradiation by UV or visible light (up to 425 nm). PMID- 29431833 TI - Magnetic properties and structure of tetranuclear lanthanide complexes based on 8 hydroxylquinoline Schiff base derivative and beta-diketone coligand. AB - Five tetranuclear lanthanide complexes [Gd4(dbm)4(L)6(MU3-OH)2].5CH3CN (1), [Tb4(dbm)4(L)6(MU3-OH)2].2CH3CH2OH.4CH3CN (2), [Dy4(dbm)4(L)6(MU3 OH)2].4CH3CN.2H2O (3), [Ho4(dbm)4(L)6(MU3-OH)2].CH3CH2OH.4CH3CN.2H2O (4) and [Er4(dbm)4(L)6(MU3-OH)2] (5) are obtained from the reaction of 5-(4 pyridinecarboxaldehyde)amino-8-hydroxylquinoline (HL) and Ln(dbm)3.2H2O (dbm = 1,3-diphenyl-1,3-propanedione). Complexes 1-5 are isomorphous and crystallize in the monoclinic space group P21/c. The metal ions in 1-5 adopt an approximately square-antiprismatic coordination environment. Magnetic studies indicate that complex 1 features a magnetocaloric effect (MCE) with the magnetic entropy change of -DeltaSm(T) = 16.35 J kg-1 K-1 at 3 K for DeltaH = 7 T. Additionally, complex 3 displays single molecule magnet (SMM) behavior, exhibiting an effective energy barrier of the relaxation of magnetization Ueff/kB = 89.38 K and pre-exponential factor tau0 = 3.32 * 10-8 s. PMID- 29431834 TI - Highly selective sensing of Fe3+ by an anionic metal-organic framework containing uncoordinated nitrogen and carboxylate oxygen sites. AB - Fast and highly selective detection of trace amounts of metal ions has become one of the most urgent issues concerning public security and living systems. However, developing a highly efficient fluorescent sensor for metal ions still remains a great challenge. Metal-organic frameworks (MOFs) are a promising class of porous fluorescent sensors towards ion detection. Herein, the anionic MOF FJI-C8 based on the pi-conjugated aromatic ligand H6TDPAT (2,4,6-tris(3,5 dicarboxylphenylamino)-1,3,5-triazine) containing uncoordinated nitrogen and carboxylate oxygen atoms was chosen as highly efficient sensor for selective detection of Fe3+. Due to the strong interaction between Fe3+ and Lewis base sites (uncoordinated nitrogen and carboxylate oxygen atoms), the high overlap between the emission spectrum of the anionic FJI-C8 and the absorption spectrum of Fe3+, and the good overlap of the excitation spectrum of the host material FJI C8 with the absorption spectrum of Fe3+, FJI-C8 exhibited a high sensitivity (0.0233 mM of Fe3+) and extra selectivity (Ksv = 8245 M-1) for the rapid detection (less than 30 s) of Fe3+ with low usage (0.04 mg mL-1 of FJI-C8 suspension). To the best of our knowledge, this is the first example of a luminescent MOF chemosensor based on a trefoil ligand with the highest density of uncoordinated N and carboxylate O atoms for the highly selective detection of Fe3+. It is also crucial to note that this is a first time detection of Fe3+ using both FJI-C8 suspension and solid after filtration, and the results indicate that the detection of Fe3+ using the FJI-C8 suspension is better. This study will pave the way for designing luminescent MOF chemosensors for the detection of Fe3+ ion. PMID- 29431836 TI - A visible-light photocatalytic thiolation of aryl, heteroaryl and vinyl iodides. AB - The general catalytic synthesis of aryl and vinyl thioethers from readily available halides remains a challenge. Herein we report a unified method for the thiolation of aryl and vinyl iodides with dialkyl disulfides using visible light photoredox catalysis. A range of thioether products bearing diverse functional groups can be accessed in high yield and with excellent chemoselectivity. We demonstrate the versatility of this method through the expedient synthesis of a family of thioether-rich natural products. A detailed investigation of the photocatalytic mechanism is presented from both steady-state and time-resolved luminescent quenching as well as transient absorption spectroscopy experiments. PMID- 29431837 TI - Spin-state dependence of the structural and vibrational properties of solvated iron(ii) polypyridyl complexes from AIMD simulations: aqueous [Fe(bpy)3]Cl2, a case study. AB - The accurate description of transition metal complexes in liquid solutions is a challenging fundamental research problem, which must be tackled when it comes to understanding the role of the solvent in the photoinduced low-spin (LS) -> high spin (HS) transition in solvated Fe(ii) complexes. We report an in-depth ab initio molecular dynamics (AIMD) study of the spin-state dependence of the structural and vibrational properties of the prototypical [Fe(bpy)3]2+ (bpy = 2,2'-bipyridine) LS complex in water. The description achieved for the LS and HS solution structures of aqueous [Fe(bpy)3]2+ significantly improves on and actually supersedes the one from our previous AIMD study [Lawson Daku and Hauser, J. Phys. Chem. Lett., 2010, 1, 1830], thanks to substantially longer simulation times and the use of the dispersion-corrected BLYP-D3 functional in place of the standard BLYP functional. The present results confirm the ~0.19 A lengthening of the Fe-N bonds and the increased thermal fluctuation of the molecular edifice stemming from the weakening of the Fe-N bonds upon the LS -> HS change of states. Revisiting our previous finding on the solvation of [Fe(bpy)3]2+, they indicate that the number of water molecules in its first hydration shell actually increases from ~15 in the LS state to ~17 in the HS state. The vibration modes and associated vibrational density of states (VDOS) of [Fe(bpy)3]2+ have been determined from a generalized normal coordinate analysis. The VDOS of the Fe-N stretching and bending modes are located in the far-IR region. For LS [Fe(bpy)3]2+, the peak positions of the VDOS of the Fe-N stretching modes agree very well with the experimental Fe-N stretching frequencies. For HS [Fe(bpy)3]2+, the spanned frequency range encompasses the Fe-N stretching frequency range reported for HS polypyridine Fe(ii) complexes. The LS and HS IR spectra of the complex have also been calculated in the 0 <= [small nu, Greek, macron] <= 2500 cm-1 range from the dynamics of the Wannier function centers. The calculated LS IR spectrum matches available experimental data. The predicted HS-LS IR difference spectrum of aqueous [Fe(bpy)3]2+ shows mostly an increase in intensity upon the LS -> HS change of states. PMID- 29431839 TI - Correction: Challenge in optoelectronic duplex switches: a red emission large size single crystal and a unidirectional flexible thin film of a hybrid multifunctional material. AB - Correction for 'Challenge in optoelectronic duplex switches: a red emission large size single crystal and a unidirectional flexible thin film of a hybrid multifunctional material' by Xiao Zhu et al., Dalton Trans., 2018, DOI: 10.1039/c7dt04489e. PMID- 29431838 TI - Fabrication of a self-assembled and flexible SERS nanosensor for explosive detection at parts-per-quadrillion levels from fingerprints. AB - Apart from high sensitivity and selectivity of surface-enhanced Raman scattering (SERS)-based trace explosive detection, efficient sampling of explosive residue from real world surfaces is very important for homeland security applications. Herein, we demonstrate an entirely new SERS nanosensor fabrication approach. The SERS nanosensor was prepared by self-assembling chemically synthesized gold triangular nanoprisms (Au TNPs), which we show display strong electromagnetic field enhancements at the sharp tips and edges, onto a pressure-sensitive flexible adhesive film. Our SERS nanosensor provides excellent SERS activity (enhancement factor = ~6.0 * 106) and limit of detection (as low as 56 parts-per quadrillions) with high selectivity by chemometric analyses among three commonly military high explosives (TNT, RDX, and PETN). Furthermore, the SERS nanosensors present excellent reproducibility (<4.0% relative standard deviation at 1.0 MUM concentration) and unprecedentedly high stability with a "shelf life" of at least 5 months. Finally, TNT and PETN were analyzed and quantified by transferring solid explosive residues from fingerprints left on solid surfaces to the SERS nanosensor. Taken together, the demonstrated sensitivity, selectivity, and reliability of the measurements as well as with the excellent shelf life of our SERS nanosensors obviate the need for complicated sample processing steps required for other analytical techniques, and thus these nanosensors have tremendous potential not only in the field of measurement science but also for homeland security applications to combat acts of terror and military threats. PMID- 29431835 TI - Processing of oat: the impact on oat's cholesterol lowering effect. AB - Epidemiological and interventional studies have clearly demonstrated the beneficial impact of consuming oat and oat-based products on serum cholesterol and other markers of cardiovascular disease. The cholesterol-lowering effect of oat is thought to be associated with the beta-glucan it contains. However, not all food products containing beta-glucan seem to lead to the same health outcome. Overall, highly processed beta-glucan sources (where the oat tissue is highly disrupted) appear to be less effective at reducing serum cholesterol, but the reasons are not well understood. Therefore, the mechanisms involved still need further clarification. The purpose of this paper is to review current evidence of the cholesterol-lowering effect of oat in the context of the structure and complexity of the oat matrix. The possibility of a synergistic action and interaction between the oat constituents promoting hypocholesterolaemia is also discussed. A review of the literature suggested that for a similar dose of beta glucan, (1) liquid oat-based foods seem to give more consistent, but moderate reductions in cholesterol than semi-solid or solid foods where the results are more variable; (2) the quantity of beta-glucan and the molecular weight at expected consumption levels (~3 g day-1) play a role in cholesterol reduction; and (3) unrefined beta-glucan-rich oat-based foods (where some of the plant tissue remains intact) often appear more efficient at lowering cholesterol than purified beta-glucan added as an ingredient. PMID- 29431840 TI - Hierarchical carbon nanotube composite yarn muscles. AB - Hybrid smart actuators fabricated using composites of carbon fibers and shape memory polymers have been extensively studied in recent years. However, relatively slow shape recovery has combined with the reset of shape deformation during cycles to restrict their practical use. An electrothermally reversible actuator based on carbon nanotube (CNT) composite yarn containing CNT fiber and thermoplastic polyurethane (TPU) resin with excellent shape memory was investigated in this paper. The combination of CNT yarn and TPU resin considerably amplified the contraction and stability. Large tensile stroke was obtained within 5 s (~13.8%) while lifting a load that was ~1905 times as heavy as the actuator. The generated contractive stress reached more than 33 MPa (corresponding to 120 g of the load) at a weight-to-yarn mass ratio of 28 400, which was about 30 times more than the shape recovery stress of shape memory polymer. In terms of the stability study, the process of annealing and contraction training was introduced. In addition, the quantitative relationship between temperature and contraction was also rigorously explored, which facilitated a more accurate and controllable contractile stroke. Great potential applications ranging from soft robots, wearable intelligent devices, and biomimetic devices to self-deployable structures in the aerospace field are likely to benefit from the advantages of low density, fast response without hysteresis, super flexible structure, as well as stitchability and large-scale production. PMID- 29431841 TI - Photoredox generation of the trifluoromethyl radical from borate complexes via single electron reduction. AB - A method for the generation of the CF3 radical from CF3-substituted borate complexes bearing a pyridine-N-oxide ligand is described. Cleavage of the C-B bond occurs via single electron reduction by a Cu(i) photocatalyst activated by visible light. PMID- 29431842 TI - FePt/Co core/shell nanoparticle-based anisotropic nanocomposites and their exchange spring behavior. AB - Anisotropic exchange-coupled nanocomposites provide us a salient candidate for the new generation of permanent magnets owing to their huge predicted maximum energy product. However, previous research basically focused on thin films or bulk materials and the impact of easy-axis alignment on the exchange coupling behavior is not clear. Herein, strongly coupled FePt/Co core/shell nanoparticles with single-phase-like hysteresis loops were synthesized by the seed mediated method. Then, these nanoparticles were successfully aligned by the external magnetic field and fixed in an acrylic binder, so that FePt/Co core/shell nanoparticle-based anisotropic nanocomposites were obtained. The nanocomposites exhibited high degree of orientation as indicated by the increased remanence ratio from 0.62 for isotropic nanoparticles to 0.78 for anisotropic nanocomposites. However, a visible kink in the demagnetization curve was observed around the zero field, implying the exchange spring behavior. This result suggests that the aligned FePt cores impose a stronger overall dipolar field in Co shells and finally, force the Co shells to reverse at a low field before the switch of FePt cores. Our research extends the preparation methods of anisotropic hard/soft-phase nanocomposites and might be helpful for the design of high performance anisotropic exchange-coupled nanocomposites. PMID- 29431843 TI - Enhancement of metal-metal interactions inside a large-cavity synthetic host in water. AB - The encapsulation of a series of metal-terpyridyl complexes in cucurbit[10]uril (CB[10]) in water is described. A strong enhancement of metal-metal and pi-pi interactions is observed due to double confinement in the large cavity. Furthermore, a linear supramolecular polymer featuring host-enhanced metallophilic interactions in water can be prepared. PMID- 29431844 TI - Correction: Diversified polyoxovanadate derivatives obtained by copper(i) catalysed azide-alkyne cycloaddition reaction: their synthesis and structural characterization. AB - Correction for 'Diversified polyoxovanadate derivatives obtained by copper(i) catalysed azide-alkyne cycloaddition reaction: their synthesis and structural characterization' by Hongli Jia et al., Dalton Trans., 2018, 47, 577-584. PMID- 29431845 TI - Capacity fade in high energy silicon-graphite electrodes for lithium-ion batteries. AB - A silicon-graphite blended anode is paired with a high capacity LiFePO4 reference/counter electrode to track irreversibility and lithium inventory. The LiFePO4 electrode provides a reliable, flat potential for dQ dV-1 analysis of LixSi and LixC electrochemical reactions. We relate this electrochemistry to the morphological and physical changes taking place. PMID- 29431846 TI - Isolation and structural characterization of a titanacyclopropane as key intermediate in the double aryl Grignard addition to 2-(arylethynyl)pyridine derivatives. AB - A titanacyclopropane species, which is a key reaction intermediate in the Ti(OiPr)4-mediated double aryl Grignard addition to 1,2-di(pyridin-2-yl)ethyne and related alkynes, was isolated and fully characterized. Based on this observation a one-pot synthesis of diarylated 1,2-di(pyridin-2-yl)ethanes and 2 (1,2,2-triarylvinyl)-pyridines was developed, including the tetraarylation of V shaped 2,6-bis(arylethynyl)pyridines. PMID- 29431847 TI - Synthesis of polyfluoroarene-substituted benzofuran derivatives via cooperative Pd/Cu catalysis. AB - A cooperative Pd/Cu-catalyzed dual C-H bond activation of electron-deficient polyfluoroarenes with aryl halides is developed. This protocol provides a unique and strategically distinct access to a variety of polyfluoroarene-substituted benzofuran derivatives. This is the first example of the introduction of electron deficient arenes to a Catellani-type reaction. PMID- 29431848 TI - Unravelling Lawesson's reagent: the structure of monomeric (4 methoxyphenyl)phosphine disulfide. AB - We describe the isolation as well as IR and UV/Vis spectroscopic characterization of (4-methoxyphenyl)phosphine disulfide in argon matrices at 10 K. The title compound proved to be highly photolabile; irradiation with UV light (lambda = 334 nm) led to rearrangement to the equally unreported 3-(4-methoxyphenyl)-1,2,3 dithiaphosphirane. Photoreversion can be achieved upon irradiation at lambda = 465 nm. PMID- 29431849 TI - Medical treatment in the management of deep endometriosis infiltrating the proximal rectum and sigmoid colon: a comprehensive literature review. AB - A comprehensive literature review was performed to evaluate the effect of various hormonal therapies, in terms of variations of intestinal and pain complaints and of patient satisfaction with treatment, in women with symptomatic, non-severely sub-occlusive endometriosis infiltrating the proximal rectum and sigmoid colon. A MEDLINE search through PubMed from 2000 to 2018 was conducted to identify all original English language articles published on medical treatment for colorectal endometriosis. Additional reports were identified by systematically reviewing reference lists and using the "similar articles" function in PubMed. A total of 420 women with colorectal endometriosis treated with combined oral contraceptives, progestins, gonadotropin releasing-hormone (GnRH) agonists and aromatase inhibitors have been described in eight case series, two retrospective cohort studies and four case reports. Published data consistently suggest that several hormonal medications can control most symptoms associated with intestinal endometriosis, provided the relative bowel lumen stenosis is less than 60%. Patients with irritative-type symptoms appear to respond better than those with constipation. Overall, about two-thirds of women were satisfied with the treatment received, independently of the drug used. Progestins are the compound supported by the largest body of evidence. The addition of aromatase inhibitors or, alternatively, the use of GnRH agonists does not seem to be associated with better outcomes. Long-term treatment with a progestin should be proposed as an alternative to surgery to patients with non-severely sub-occlusive endometriosis infiltrating the proximal rectum and sigmoid colon who are not seeking conception. The final decision should be shared together with the woman, respecting her preferences and priorities. PMID- 29431850 TI - Improvement of off-axis SABR plan verification results by using adapted dose reconstruction algorithms for the Octavius 4D system. AB - PURPOSE: Stereotactic ablative body radiotherapy (SABR) for lung patients can be performed with volumetric-modulated arc therapy (VMAT) plans using off-axis target geometry to allow treatment in their CBCT verified position. For patient specific quality assurance measurements using the PTW Octavius 4D phantom (PTW, Freiburg, Germany) (OCT4D) in conjunction with an Octavius 1000SRS array (OCT1000) (PTW, Freiburg, Germany), repositioning the phantom off-axis is required to ensure the measurement area coincides with the tumor. The aim of this work is to quantify delivery errors using an array repositioned off-axis and evaluate new software which incorporates corrections for off-axis phantom measurements. METHODS: Dynamic conformal arcs and 25 lung SABR plans were created with the isocenter at the patient midline and the target volume off-axis. Measurements were acquired with an OCT4D phantom in conjunction with a 729 array (PTW, Freiburg, Germany) (OCT729) placed at isocenter. These plans were recalculated and delivered to both the OCT729 and OCT1000 arrays repositioned so that the high-dose region was at the center of the phantom. Comparisons were made using VeriSoft v7.0 (PTW, Freiburg, Germany) and the newly implemented version 7.1 with 2%/2 mm gamma criterion (10% threshold) and results correlated with off axis distance to the tumor. RESULTS: Average pass rates for VeriSoft v7.0 significantly reduced from 92.7 +/- 2.4% to 84.9 +/- 4.1% when the phantom was repositioned compared to the isocenter setup for the OCT729. The gamma pass rates significantly decreased the further the phantom was moved off-axis. Significantly higher pass rates were observed for the OCT1000 of 95.7 +/- 3.6% and a significant decrease in gamma pass rate with off-axis phantom distance was again observed. In contrast, even with phantom repositioning, the pass rates for analysis with VeriSoft v7.1 were 93.7 +/- 2.1% and 99.4 +/- 1.1% for OCT729 and OCT1000, respectively. No significant difference in gamma pass rate was observed with off-axis phantom position irrespective of array type with the new software. CONCLUSION: The errors in QA phantom measurements due to dose reconstruction at off-axis target geometry have been demonstrated for conformal arcs and clinical VMAT SABR plans. A novel software solution implemented by the vendor to allow accurate pass rates has been tested. This solution enables high-resolution arrays with small active detection areas to be used for quality assurance of SABR treatment plans in the off-axis treatment position. PMID- 29431851 TI - Stress-induced tRNA cleavage and tiRNA generation in rat neuronal PC12 cells. AB - Transfer RNA (tRNA) plays a role in stress response programs involved in various pathological conditions including neurological diseases. Under cell stress conditions, intracellular tRNA is cleaved by a specific ribonuclease, angiogenin, generating tRNA-derived fragments or tRNA-derived stress-induced RNA (tiRNA). Generated tiRNA contributes to the cell stress response and has potential cell protective effects. However, tiRNA generation under stress conditions in neuronal cells has not been fully elucidated. To examine angiogenin-mediated tiRNA generation in neuronal cells, we used the rat neuronal cell line, PC12, in combination with analysis of SYBR staining and immuno-northern blotting using anti-1-methyladenosine antibody, which specifically and sensitively detects tiRNA. Oxidative stress induced by arsenite and hydrogen peroxide caused tRNA cleavage and tiRNA generation in PC12 cells. We also demonstrated that oxygen glucose deprivation, which is an in vitro model of ischemic-reperfusion injury, induced tRNA cleavage and tiRNA generation. In these stress conditions, the amount of generated tiRNA was associated with the degree of morphological cell damage. Time course analysis indicated that generation of tiRNA was prior to severe cell damage and cell death. Angiogenin over-expression did not influence the amount of tiRNA in normal culture conditions; however, it significantly increased tiRNA generation induced by cell stress conditions. Our findings show that angiogenin-mediated tiRNA generation can be induced in neuronal cells by different cell stressors, including ischemia-reperfusion. Additionally, detection of tiRNA could be used as a potential cell damage marker in neuronal cells. Cover Image for this issue: doi: 10.1111/jnc.14191. PMID- 29431852 TI - Nicotine-Use/Smoking Is Associated with the Efficacy of Naltrexone in the Treatment of Alcohol Dependence. AB - BACKGROUND: The opioid antagonist naltrexone is not efficacious for every alcohol treatment seeker. However, various individual factors, such as genetic differences and nicotine-use/smoking status, have been suggested as predictors of naltrexone response. In a randomized clinical trial, we previously reported that nicotine-use/smoking status might be a stronger predictor of naltrexone efficacy than OPRM1 A118G single nucleotide polymorphism (SNP) genotype. In this report, we further characterize the nicotine-users in that trial, examine other drinking outcomes, examine the influence of smoking change on naltrexone effects on drinking, and validate the result in smokers with disialo carbohydrate-deficient transferrin (%dCDT) change as an independent biomarker of response. METHODS: Individuals (n = 146) meeting DSM-IV criteria for alcohol dependence who were genotyped for the OPRM1 A118G SNP and who did, or did not, use nicotine/cigarettes were randomized, in a balanced fashion, to naltrexone (50 mg/d) or placebo and provided medical management (MM) over a 16-week clinical trial. Alcohol use and smoking during the trial were assessed and analyzed. RESULTS: Nicotine-use/smoking status significantly interacted with medication in reducing percent heavy drinking days (PHDD) during the trial (p = 0.003), such that nicotine-users/smokers showed significantly lower PHDD on naltrexone versus placebo (p = 0.0001, Cohen's d = 0.89), while nonusers showed no significant difference between naltrexone and placebo (p = 0.95, Cohen's d = 0.02). Similar effects were shown for drinks per day and percent days drinking. The superiority of naltrexone over placebo on PHDD reduction in nicotine-users/smokers was confirmed with %dCDT (Cohen's d range 0.3 to 0.9 over the study). Naltrexone did not significantly change cigarette use in smokers, and change in use did not influence naltrexone's effect on PHDD. CONCLUSIONS: These data confirm past findings that naltrexone is more efficacious in those who use nicotine/cigarettes. Compared to previous work on the OPRM1 A118G SNP, it appears that nicotine-use might be a more salient predictor of naltrexone treatment response. While naltrexone did not change cigarette use during the study, and smoking change was not related to alcohol reduction, it should be noted that participants were not seeking smoking cessation and MM did not address this issue. PMID- 29431854 TI - Courses and Conferences. PMID- 29431853 TI - rs294775 is a cis-regulatory SNP for human UGT2B10. AB - UGT2B10 is an important metabolism enzyme in human body and its substrates include multiple amine-containing compounds, especially nicotine, tamoxifen and multiple antidepressants. Multiple common SNPs have been observed in its promoter region, but their role in expression regulation has never been investigated. In this preliminary study, we identified a novel cis-regulatory SNP, rs294775, for UGT2B10 by plasmid construction, mutagenesis, and luciferase assay, whose mechanism was also investigated. Our work provides a basis for further pharmacogenetics study. PMID- 29431856 TI - Cerebral embolization, silent cerebral infarction and neurocognitive decline after thoracic endovascular aortic repair. AB - BACKGROUND: Silent cerebral infarction is brain injury detected incidentally on imaging; it can be associated with cognitive decline and future stroke. This study investigated cerebral embolization, silent cerebral infarction and neurocognitive decline following thoracic endovascular aortic repair (TEVAR). METHODS: Patients undergoing elective or emergency TEVAR at Imperial College Healthcare NHS Trust and Guy's and St Thomas' NHS Foundation Trust between January 2012 and April 2015 were recruited. Aortic atheroma graded from 1 (normal) to 5 (mobile atheroma) was evaluated by preoperative CT. Patients underwent intraoperative transcranial Doppler imaging (TCD), preoperative and postoperative cerebral MRI, and neurocognitive assessment. RESULTS: Fifty-two patients underwent TEVAR. Higher rates of TCD-detected embolization were observed with greater aortic atheroma (median 207 for grade 4-5 versus 100 for grade 1-3; P = 0.042), more proximal landing zones (median 450 for zone 0-1 versus 72 for zone 3-4; P = 0.001), and during stent-graft deployment and contrast injection (P = 0.001). In univariable analysis, left subclavian artery bypass (beta coefficient 0.423, s.e. 132.62, P = 0.005), proximal landing zone 0-1 (beta coefficient 0.504, s.e. 170.57, P = 0.001) and arch hybrid procedure (beta coefficient 0.514, s.e. 182.96, P < 0.001) were predictors of cerebral emboli. Cerebral infarction was detected in 25 of 31 patients (81 per cent) who underwent MRI: 21 (68 per cent) silent and four (13 per cent) clinical strokes. Neurocognitive decline was seen in six of seven domains assessed in 15 patients with silent cerebral infarction, with age a significant predictor of decline. CONCLUSION: This study demonstrates a high rate of cerebral embolization and neurocognitive decline affecting patients following TEVAR. Brain injury after TEVAR is more common than previously recognized, with cerebral infarction in more than 80 per cent of patients. PMID- 29431855 TI - Metabolic Clusters and Outcomes in Older Adults: The Cardiovascular Health Study. AB - BACKGROUND/OBJECTIVES: Few studies have the requisite phenotypic information to define metabolic patterns that may inform our understanding of the pathophysiology and consequences of diabetes in older adults. We sought to characterize clusters of older adults on the basis of shared metabolic features. DESIGN: Population-based prospective cohort study. SETTING: Four U.S. Cardiovascular Health Study field centers. PARTICIPANTS: Individuals aged 65 and older taking no glucose-lowering agents (N = 2,231). MEASUREMENTS: K-means cluster analysis of 11 metabolic parameters (fasting and postload serum glucose and plasma insulin, fasting C-peptide, body mass index, C-reactive protein (CRP), estimated glomerular filtration rate (eGFR), albuminuria, carboxymethyl lysine (an advanced glycation end-product), procollagen III N-terminal propeptide (a fibrotic marker)) and their associations with incident cardiovascular disease, diabetes, disability, and mortality over 8 to 14.5 years of follow-up and with measures of subclinical cardiovascular disease. RESULTS: A 6-cluster solution provided robust differentiation into distinct, identifiable clusters. Cluster A (n = 739) had the lowest glucose and insulin and highest eGFR and the lowest rates of all outcomes. Cluster B (n = 419) had high glucose and insulin and intermediate rates of most outcomes. Cluster C (n = 118) had the highest insulin. Cluster D (n = 129) had the highest glucose with much lower insulin. Cluster E (n = 314) had the lowest eGFR and highest albuminuria. Cluster F (n = 512) had the highest CRP. Rates of CVD, mortality, and subclinical atherosclerosis were highest in clusters C, D, and E and were similar to rates in participants with treated diabetes. Incidence of disability was highest in Cluster C. CONCLUSION: Clustering according to metabolic parameters identifies distinct phenotypes that are strongly associated with clinical and functional outcomes, even at advanced age. PMID- 29431857 TI - Thorp responds to Darney and Henderson regarding the "Contributions and limits of epidemiology in societal controversy". PMID- 29431858 TI - A new computer-aided detection approach based on analysis of local and global mammographic feature asymmetry. AB - PURPOSE: This study aims to develop and test a new computer-aided detection (CAD) approach and scheme, assessing the likelihood of a subject harboring breast abnormalities. METHODS: The proposed scheme is based on the analysis of both local and global bilateral mammographic feature asymmetries. The level of local or global asymmetry is assessed by analyzing mammographic features extracted from the bilaterally matched regions of interest (ROIs), or from the entire breast, respectively. The selected local and global feature vectors are combined and classified using a maximum likelihood obtained from a naive Bayes classifier. This scheme was evaluated using a leave-one-case-out cross-validation method that was applied to 243 subjects from mini-MIAS and INbreast databases. In addition, the result is compared with a conventional unilateral (or single) image-based CAD scheme. RESULTS: Using a case-based evaluation approach and an area under curve (AUC) of the receiver operating characteristic (ROC) as a performance index, the new scheme yielded AUC = 0.79 +/- 0.07, an 8.2% increase compared with AUC = 0.73 +/- 0.08 obtained using the unilateral image-based CAD scheme. CONCLUSIONS: This work demonstrates that applying bilateral asymmetry analysis increases the discriminatory power of CAD schemes while optimizing the likelihood assessment of breast abnormalities presence. Therefore, the proposed CAD approach provides the radiologist with beneficial supplementary information and can indicate high-risk cases. PMID- 29431859 TI - Adverse childhood experiences and depressive symptomatology among pregnant women. AB - INTRODUCTION: Adverse childhood experiences (ACE) result in somatic and mental health disturbances. Their influence on antenatal depression is scarcely studied. This study examined the association between experience of ACE and antenatal depressive symptomatology. MATERIAL AND METHODS: 1257 women from 172 antenatal clinics in Sweden were surveyed during pregnancy and 1 year after delivery. Demographics, previous medical history and Edinburgh Postpartum Depression Scale (EPDS) were collected in pregnancy and postpartum and ACE 1 year postpartum. ACEs were partitioned into 10 categories. Statistical analyses used linear and logistic regression with EPDS score as main outcome measure. RESULTS: 736 (58.6%) women reported at least one ACE category and 88 women (7%) reported five or more ACE categories. An EPDS score of >=13, which qualifies for a probable depression diagnosis, was reported by 277 (23%) women. In simple regression analyses the EPDS score was positively associated with the number of ACEs, cigarette smoking before pregnancy, body mass index and psychiatric disorders, whereas education level was inversely associated. In a multiple regression analysis, ACEs, education level and psychiatric disorder remained associated to the EPDS score. Among women with an ACE score >=5, the odds ratio of having an EPDS score indicating probable depression was 4.2 (CI 2.5-7.0). CONCLUSIONS: ACE was commonly reported. ACE and depressive symptomatology in late pregnancy were strongly associated in a dose-response manner. Women with several ACEs had high odds of depressive symptomatology in late pregnancy and were more likely to report depressive symptoms both in late pregnancy and postpartum. PMID- 29431860 TI - Continuously infused amphotericin B deoxycholate for primary treatment of invasive fungal disease in acute myeloid leukaemia. AB - Continuous administration of amphotericin B deoxycholate over 24 hours (24 h-D AmB) is better tolerated than rapid infusions. However, toxicity and outcome have not been assessed in a homogenous patient population with acute myeloid leukaemia (AML). We retrospectively analysed renal function and outcome in all adult patients with AML undergoing intensive chemotherapy between 2007 and 2012 at our institution. We compared a patient group with exposure to 24 h-D-AmB to a patient group without exposure to 24 h-D-AmB. One hundred and eighty-one consecutive patients were analysed, 133 (73.5%) received at least 1 dose of 24 h-D-AmB, and 48 (26.5%) did not. Reasons for 24 h-D-AmB initiation were invasive fungal disease (IFD) in 63.5% and empirical treatment for febrile neutropenia in 36.5% of the cases. Most patients with IFD received an oral triazole drug at hospital discharge. Baseline characteristics were well matched. Amphotericin B deoxycholate over 24 hours was given for a median 7 days (interquartile range 3 13). Peak creatinine concentration was higher in the 24 h-D-AmB-group (104.5 vs. 76 MUmol/L, P < .001) but normalized within 1 month after therapy (65.5 vs. 65 MUmol/L, P = .979). In neither of the 2 groups, end-stage renal disease occurred. There was no difference in 60-day survival (90% vs. 90%) and 2-year survival (58% vs. 58%). Invasive fungal disease partial response or better was observed in 68% of the patients. We conclude that antifungal therapy with continuously infused amphotericin B deoxycholate is safe in patients with AML. An antiinfective strategy based on 24 h-D-AmB in first line followed by an oral triazole compound represents an economically attractive treatment option. PMID- 29431861 TI - Non-steroidal anti-inflammatory agents to induce regression and prevent the progression of cervical intraepithelial neoplasia. AB - BACKGROUND: This is an updated version of the original Cochrane review published in 2014, Issue 4. Cervical intraepithelial neoplasia (CIN) precedes the development of invasive carcinoma of the cervix. Current treatment of CIN is quite effective, but there is morbidity for the patient related to pain, bleeding, infection, cervical stenosis and premature birth in a subsequent pregnancy. Effective treatment with medications, rather than surgery, would be beneficial. OBJECTIVES: To evaluate the effectiveness and safety of non-steroidal anti-inflammatory agents (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, to induce regression and prevent the progression of CIN. SEARCH METHODS: Previously, we searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 11), MEDLINE (November, 2013) and Embase (November week 48, 2013). An updated search was performed in August 2017 for CENTRAL (2017, Issue 8), MEDLINE (July, week 3, 2017) and Embase (July week 31, 2017). Trial registries and journals were also searched as part of the update. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled trials of NSAIDs in the treatment of CIN. DATA COLLECTION AND ANALYSIS: Three review authors independently abstracted data and assessed risks of bias in accordance with Cochrane methodology. Outcome data were pooled using fixed-effect meta-analyses. MAIN RESULTS: In three RCTs, 171 women over the age of 18 years were randomised to receive celecoxib 400 mg daily for 14 to 18 weeks versus placebo (one study, 130 participants), celecoxib 200 mg twice daily by mouth for six months versus placebo (one study, 25 participants), or rofecoxib 25 mg once daily by mouth for three months versus placebo (one study, 16 participants). The study with rofecoxib was discontinued when the medicine was withdrawn from the market in 2004. The trials ran from June 2005 to April 2012, June 2002 to October 2003, and May to October 2004, respectively. We have chosen to include the data from the rofecoxib study as outcomes may be similar when other such NSAIDs are utilised.Partial or complete regression of CIN 2 or CIN 3 occurred in 31 out of 70 (44%) in the treatment arms and 19 of 62 (31%) in the placebo arms (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.93 to 2.27; P value 0.10), three studies, 132 participants; moderate-certainty evidence). Complete regression of CIN 2 or CIN 3 occurred in 15 of 62 (24%) of those receiving celecoxib versus 10 of 54 (19%) of those receiving placebo (RR 1.31, 95% CI 0.65 to 2.67; P value 0.45, two studies, 116 participants; moderate certainty evidence). Partial regression of CIN 2 or CIN 3 occurred in 14 of 62 (23%) of those receiving celecoxib versus 8 of 54 (15%) of those receiving placebo (RR 1.56, 95% CI 0.72 to 3.4; P value 0.26), two studies, 116 participants; moderate-certainty evidence).Progression to a higher grade of CIN, but not to invasive cancer, occurred in one of 12 (8%) of those receiving celecoxib and two of 13 (15%) receiving placebo (RR 0.54, 95% CI 0.05 to 5.24; P value 0.60, one study, 25 participants; very low-certainty evidence). Two studies reported no cases of progression to invasive cancer within the timeframe of the study. No toxicity was reported in the two original articles. The trial added in this update had one Grade 3 gastrointestinal adverse effect in the treatment arm, but otherwise had similar Grade 1 to 2 side effects between treatment and placebo groups. Although the studies were well-conducted and randomised, some risk of bias was detected in all studies. Furthermore, the duration of the studies was short, which may mask identifying progression to cancer.The addition of the trial in this update quadrupled the number of patients in the original review and was a well-designed multicentre trial thus, increasing the overall certainty of evidence from very low to moderate for this review. AUTHORS' CONCLUSIONS: There are currently no convincing data to support a benefit for NSAIDs in the treatment of CIN. With the addition of this new, larger randomised trial we would rate this as overall moderate-certainty evidence by the GRADE criteria. PMID- 29431862 TI - Comprehensive evaluation of broad-beam transmission of patient supports from three fluoroscopy-guided interventional systems. AB - PURPOSE: The purpose of the study was to measure, evaluate, and model the broad beam x-ray transmission of the patient supports from representative modern fluoroscopy-guided interventional systems, for patient skin dose calculation. METHODS: Broad-beam transmission was evaluated by varying incident angle, kVp, added copper (Cu) filter, and x-ray field size for three fluoroscopy systems: General Electric (GE) Innova 4100 with Omega V table and pad, Siemens Axiom Artis with Siemens tabletop "narrow" (CARD) table and pad, and Siemens Zeego with Trumpf TruSystem 7500 table and pad. Field size was measured on the table using a lead ruler for all setups in this study. Exposure rates were measured in service mode using a calibrated Radcal 10 * 6-60 ion chamber above the patient support at the assumed skin location. Broad-beam transmission factors were calculated by the ratio of air kerma rates measured with and without a patient support in the beam path. First, angle dependency was investigated on the GE system, with the chamber at isocenter, for angles of 0 degrees , 15 degrees , 30 degrees , and 40 degrees , for a variety of kVp, added Cu filters, and for two field sizes (small and large). Second, the broad-beam transmission factor at normal incidence was evaluated for all three fluoroscopes by varying kVp, added Cu filter, and field size (small, medium, and large). An analytical equation was created to fit the data as to maximize R2 and minimize maximum percentage difference across all measurements for each system. RESULTS: For all patient supports, broad-beam transmission factor increased with field size, kVp, and added Cu filtration and decreased with incident angle. Oblique incidence measurements show that the transmission decreased by about 1%, 3%, and 6% for incident angles of 15 degrees , 30 degrees , and 40 degrees , respectively. The broad-beam transmission factors at 0 degrees for the table and table plus pad ranged from 0.73 to 0.96 and from 0.59 to 0.89, respectively. The GE and Siemens transmission factors were comparable, while the Trumpf transmission factors were the lowest. The data were successfully fitted to a function of angle, field size, kVp, and added Cu filtration using nine parameters, with an average R2 value of 0.977 and maximum percentage difference of 4.08%. CONCLUSIONS: This study evaluated the broad-beam transmission for three representative fluoroscopy systems and their dependency on angle, kVp, added Cu filter, and field size. The comprehensive data provided for patient support transmission will facilitate accurate calculation of peak skin dose (PSD) and may potentially be integrated into real-time and retrospective dose monitoring with access to Radiation Dose Structured Reports (RDSR) and radiation event data. PMID- 29431863 TI - Evaluation of target coverage and margins adequacy during CyberKnife Lung Optimized Treatment. AB - PURPOSE: Evaluation of target coverage and verification of safety margins, in motion management strategies implemented by Lung Optimized Treatment (LOT) module in CyberKnife system. METHODS: Three fiducial-less motion management strategies provided by LOT can be selected according to tumor visibility in the X ray images acquired during treatment. In 2-view modality the tumor is visible in both X ray images and full motion tracking is performed. In 1-view modality the tumor is visible in a single X ray image, therefore, motion tracking is combined with an internal target volume (ITV)-based margin expansion. In 0-view modality the lesion is not visible, consequently the treatment relies entirely on an ITV-based approach. Data from 30 patients treated in 2-view modality were selected providing information on the three-dimensional tumor motion in correspondence to each X ray image. Treatments in 1-view and 0-view modalities were simulated by processing log files and planning volumes. Planning target volume (PTV) margins were defined according to the tracking modality: end-exhale clinical target volume (CTV) + 3 mm in 2-view and ITV + 5 mm in 0-view. In the 1-view scenario, the ITV encompasses only tumor motion along the non-visible direction. Then, non uniform ITV to PTV margins were applied: 3 mm and 5 mm in the visible and non visible direction, respectively. We defined the coverage of each voxel of the CTV as the percentage of X ray images where such voxel was included in the PTV. In 2 view modality coverage was calculated as the intersection between the CTV centred on the imaged target position and the PTV centred on the predicted target position, as recorded in log files. In 1-view modality, coverage was calculated as the intersection between the CTV centred on the imaged target position and the PTV centred on the projected predictor data. In 0-view modality coverage was calculated as the intersection between the CTV centred on the imaged target position and the non-moving PTV. Similar to dose-volume histogram, CTV coverage volume histograms (defined as CVH) were derived for each patient and treatment modality. The geometric coverages of the 90% and 95% of CTV volume (C90, C95, respectively) were evaluated. Patient-specific optimal margins (ensuring C95 >= 95%) were computed retrospectively. RESULTS: The median +/- interquartile-rage of C90 and C95 for upper lobe lesions was 99.1 +/- 0.6% and 99.0 +/- 3.1%, whereas they were 98.9 +/- 4.2% and 97.8 +/- 7.5% for lower and middle lobe tumors. In 2 view, 1-view and 0-view modality, adopted margins ensured C95 >= 95% in 70%, 85% and 63% of cases and C95 >= 90% in 90%, 88% and 83% of cases, respectively. In 2 view, 1-view and 0-view a reduction in margins still ensured C95 >= 95% in 33%, 78% and 59% of cases, respectively. CONCLUSIONS: CTV coverage analysis provided an a-posteriori evaluation of the treatment geometric accuracy and allowed a quantitative verification of the adequacy of the PTV margins applied in CyberKnife LOT treatments offering guidance in the selection of CTV margins. PMID- 29431865 TI - Refinement of MLC modeling improves commercial QA dosimetry system for SRS and SBRT patient-specific QA. AB - PURPOSE: Mobius 3D (M3D) provides a volumetric dose verification of the treatment planning system's calculated dose using an independent beam model and a collapsed cone convolution superposition algorithm. However, there is a lack of investigation into M3D's accuracy and effectiveness for stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT) quality assurance (QA). Here, we collaborated with the vendor to develop a revised M3D beam model for SRS/SBRT cases treated with a 6X flattening filter-free (FFF) beam and high-definition multiple leaf collimator (HDMLC) on an Edge linear accelerator. METHODS: Eighty SRS/SBRT cases, planned with AAA dose algorithm and validated with Gafchromic film, were compared to M3D dose calculations using 3D gamma analysis with 2%/2 mm gamma criteria and a 10% threshold. A revised beam model was developed by refining the HD-MLC model in M3D to improve small field dose calculation accuracy and beam profile agreement. All cases were reanalyzed using the revised beam model. The impact of heterogeneity corrections for lung cases was investigated by applying lung density overrides to five cases. RESULTS: For the standard and revised beam models, respectively, the mean gamma passing rates were 94.6% [standard deviation (SD): 6.1%] and 98.0% [SD: 1.7%] (for the overall patient), 88.2% [SD: 17.3%] and 93.8% [SD: 6.8%] (for the brain PTV), 71.4% [SD: 18.4%] and 81.5% [SD: 14.3%] (for the lung PTV), 83.3% [SD: 16.7%] and 67.9% [SD: 23.0%] (for the spine PTV), and 78.6% [SD: 14.0%] and 86.8% [SD: 12.5%] (for the PTV of all other sites). The lung PTV mean gamma passing rates improved from 74.1% [SD: 7.5%] to 89.3% [SD: 7.2%] with the lung density overridden. The revised beam model achieved an output factor within 3% of plastic scintillator measurements for 2 * 2 cm2 MLC field size, but larger discrepancies are still seen for smaller field sizes which necessitate further improvement of the beam model. CONCLUSION: Special attention needs to be paid to small field dosimetry, MLC modeling, and inhomogeneity corrections in the beam model for SRS/SBRT QA. The improvements noted in this study, and further collaborations between clinical physicists and the vendor to refine the M3D beam model could enable M3D to become a premier SRS/SBRT QA tool. PMID- 29431866 TI - Monocyte subsets and their phenotypes during treatment with BCR-ABL1 tyrosine kinase inhibitors for Philadelphia chromosome-positive leukemia. AB - BCR-ABL1 tyrosine kinase inhibitors (TKIs) are effective agents in the treatment of Philadelphia chromosome-positive leukemia. However, vascular events have developed in some patients receiving each TKI. The perturbation of circulating monocyte subsets and their expressions of chemokine and scavenger receptors are associated with the development of cardiovascular events. Here, we examined the subsets of circulating monocytes and their phenotypes in 51 patients treated with imatinib, nilotinib, and dasatinib, and 11 healthy subjects in our institute. Except for a negative association between the number of classical monocytes and imatinib treatment, the proportions and numbers of monocyte subsets were not significantly associated with TKI treatment. However, chemokine receptors, CCR2, CX3CR1 on classical monocytes, and scavenger receptor, CD204, on intermediate and non-classical monocytes were significantly associated with TKIs. These data demonstrated the relationships between alterations of chemokine and scavenger receptors on different monocyte subsets and the TKI treatments. PMID- 29431867 TI - Spatially fractionated (GRID) radiation therapy using proton pencil beam scanning (PBS): Feasibility study and clinical implementation. AB - PURPOSE: GRID therapy is an effective treatment for bulky tumors. Linear accelerator (Linac)-produced photon beams collimated through blocks or multileaf collimators (MLCs) are the most common methods used to deliver this therapy. Utilizing the newest proton delivery method of pencil beam scanning (PBS) can further improve the efficacy of GRID therapy. In this study, we developed a method of delivering GRID therapy using proton PBS, evaluated the dosimetry of this novel technique and applied this method in two clinical cases. MATERIALS/METHODS: In the feasibility study phase, a single PBS proton beam was optimized to heterogeneously irradiate a shallow 20 * 20 * 12 cm3 target volume centered at a 6 cm depth in a water phantom. The beam was constrained to have an identical spot pattern in all layers, creating a "beamlet" at each spot position. Another GRID treatment using PBS was also performed on a deep 15 * 15 * 8 cm3 target volume centered at a 14 cm depth in a water phantom. Dosimetric parameters of both PBS dose distributions were compared with typical photon GRID dose distributions. In the next phase, four patients have been treated at our center with this proton GRID technique. The planning, dosimetry, and measurements for two representative patients are reported. RESULTS: For the shallow phantom target, the depth-dose curve of the PBS plan was uniform within the target (variation < 5%) and dropped quickly beyond the target (50% at 12.9 cm and 0.5% at 14 cm). The lateral profiles of the PBS plan were comparable to those of photon GRID in terms of valley-to-peak ratios. For the deep phantom target, the PBS plan provided smaller valley-to-peak ratios than the photon GRID technique. Pretreatment dose verification QA showed close agreement between the measurements and the plan (pass rate > 95% with a gamma index criterion of 3%/3 mm). Patients tolerated the treatment well without significant skin toxicity (radiation dermatitis grade <= 1). CONCLUSIONS: Proton GRID therapy using a PBS delivery method was successfully developed and implemented clinically. Proton GRID therapy offers many advantages over photon GRID techniques. The use of protons provides a more uniform beamlet dose within the tumor and spares normal tissues located beyond the tumor. This new PBS method will also reduce the dose to proximal organs when treating a deep-seated tumor. PMID- 29431864 TI - Negative regulators that mediate ocular immune privilege. AB - The ocular microenvironment has adapted several negative regulators of inflammation to maintain immune privilege and health of the visual axis. Several constitutively produced negative regulators within the eye TGF-beta2, alpha melanocyte stimulating hormone (alpha-MSH), Fas ligand (FasL), and PD-L1 standout because of their capacity to influence multiple pathways of inflammation, and that they are part of promoting immune tolerance. These regulators demonstrate the capacity of immune privilege to prevent the activation of inflammation, and to suppress activation of effector immune cells even under conditions of ocular inflammation induced by endotoxin and autoimmune disease. In addition, these negative regulators promote and expand immune cells that mediate regulatory and tolerogenic immunity. This in turn makes the immune cells themselves negative regulators of inflammation. This provides for a greater understanding of immune privilege in that it includes both molecular and cellular negative regulators of inflammation. This would mean that potentially new approaches to the treatment of autoimmune disease can be developed through the use of molecules and cells as negative regulators of inflammation. PMID- 29431868 TI - Correction of T cell deficiency in ZAP-70 knock-out mice by simple intraperitoneal adoptive transfer of thymocytes. AB - The tyrosine kinase zeta chain-associated protein of 70 kDa (ZAP-70) plays a key role in T cell development and signalling. In the absence of ZAP-70, T cell development is arrested in the CD4+ CD8+ double-positive stage, thus ZAP-70 homozygous knockout (ZAP-70-/- ) mice have no mature T cells in their peripheral lymphoid organs and blood, causing severe immunodeficiency. We investigated the early kinetics and long-term effects of wild-type thymocyte transfer on T cell repopulation in ZAP-70-/- mice. We used a single intraperitoneal (i.p.) injection to deliver donor thymocytes to the recipients. Here, we show that after i.p. injection donor thymocytes leave the peritoneum through milky spots in the omentum and home to the thymus, where donor-originated CD4- CD8- double-negative thymocytes most probably restore T cell development and the disrupted thymic architecture. Subsequently, newly developed, donor-originated, single-positive alphabeta T cells appear in peripheral lymphoid organs, where they form organized T cell zones. The established chimerism was found to be stable, as donor originated cells were present in transferred ZAP-70-/- mice as late as 8 months after i.p. injection. We demonstrate that a simple i.p. injection of ZAP-70+/+ thymocytes is a feasible method for the long-term reconstitution of T cell development in ZAP-70-deficient mice. PMID- 29431869 TI - Separation of plasma-derived exosomes into CD3(+) and CD3(-) fractions allows for association of immune cell and tumour cell markers with disease activity in HNSCC patients. AB - Head and neck squamous cell carcinoma (HNSCC) is a highly immunosuppressive malignancy. Exosomes in HNSCC patients' plasma are enriched in inhibitory cargo and mediate immunosuppression. As these exosomes are products of various cells, the cellular origin of immunoregulatory proteins they carry is unknown. To test whether tumour- or T cell-derived exosomes in patients' plasma are immunosuppressive and impact upon disease activity, we separated CD3(-) from CD3(+) exosomes by immunocapture using anti-CD3 antibodies. The exosome protein cargo was evaluated for immunoregulatory proteins using on-bead flow cytometry. Tumour protein-enriched CD3(-) exosomes were CD44v3(+) . Surprisingly, mean levels of programmed death ligand 1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4) and cyclooxygenase-2 (COX-2) were similar in CD3(+) and CD3(-) exosomes, although the latter induced higher (P < 0.0025) ex-vivo apoptosis of CD8(+) T cells and greater (P < 0.005) conversion of CD4+ T cells to CD4(+) CD39(+) regulatory T cells (Treg ). CD3(+) and CD3(-) exosomes carrying high levels of immunosuppressive proteins were highly effective in mediating these functions. Exosomes of patients with Union for International Cancer Control (UICC) stages III/IV disease had higher levels of PD-L1 and COX-2 than stages I/II patients (P < 0.005). Patients with nodal involvement had exosomes with the higher inhibitory protein content than N0 patients (P < 0.03). CD3(+) and CD3(-) exosomes of HNSCC patients had higher PD-L1, COX-2 and CD15s levels than healthy donors' exosomes (P < 0.009), although levels of immunostimulatory OX40 or OX40L were not different. By isolating CD3(-) /CD44v3-enriched and CD3(+) exosomes from plasma, the cellular origins of immunoregulatory proteins they carry were identified. Association of exosome molecular profiles with disease progression supports the exosome potential as future cancer biomarkers. PMID- 29431870 TI - A quarter of patients with type 1 diabetes have co-existing non-islet autoimmunity: the findings of a UK population-based family study. AB - Individuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA) and gastric H+ /K+ -ATPase (ATPA) and their genetic associations in a well characterized population-based cohort of individuals with T1D from the Bart's Oxford family study for whom islet autoantibody prevalence data were already available. Autoantibodies in sera from 1072 patients (males/females 604/468; median age 11.8 years, median T1D duration 2.7 months) were measured by radioimmunoassays; HLA class II risk genotype was analysed in 973 (91%) using polymerase chain reaction with sequence specific primers (PCR-SSP). The prevalence of TGA (and/or history of CD), TPOA and ATPA in patients was 9.0, 9.6 and 8.2%, respectively; 3.1% had two or more autoantibodies. Females were at higher risk of multiple autoimmunity; TGA/CD were associated with younger age and TPOA with older age. ATPA were uncommon in patients under 5 years, and more common in older patients. Anti-glutamate decarboxylase autoantibodies were predictive of co-existing TPOA/ATPA. TGA/CD were associated with human leucocyte antigen (HLA) DR3-DQ2, with the DR3-DQ2/DR3-DQ2 genotype conferring the highest risk, followed by DR4-DQ8/DR4-DQ8. ATPA were associated with DR3-DQ2, DRB1*0404 (in males) and the DR3-DQ2/DR4-DQ8 genotype. TPOA were associated with the DR3 DQ2/DR3-DQ2 genotype. Almost one-quarter of patients diagnosed with T1D aged under 21 years have at least one other organ-specific autoantibody. HLA class II genetic profiling may be useful in identifying those at risk of multiple autoimmunity. PMID- 29431872 TI - Interventions to prevent hypothermia at birth in preterm and/or low birth weight infants. AB - BACKGROUND: Newborn admission temperature is a strong predictor of outcomes across all gestations. Hypothermia immediately after birth remains a worldwide issue and, if prolonged, is associated with harm. Keeping preterm infants warm is difficult even when recommended routine thermal care guidelines are followed in the delivery room. OBJECTIVES: To assess the efficacy and safety of interventions designed for prevention of hypothermia in preterm and/or low birth weight infants applied within 10 minutes after birth in the delivery room, compared with routine thermal care or any other single/combination of intervention(s) also designed for prevention of hypothermia in preterm and/or low birth weight infants applied within 10 minutes after birth in the delivery room. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 5), MEDLINE via PubMed (1966 to 30 June 2016), Embase (1980 to 30 June 2016), and CINAHL (1982 to 30 June 2016). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi randomised trials. SELECTION CRITERIA: Trials using randomised or quasi randomised allocations to test interventions designed to prevent hypothermia (apart from 'routine' thermal care) applied within 10 minutes after birth in the delivery room for infants at < 37 weeks' gestation and/or birth weight <= 2500 grams. DATA COLLECTION AND ANALYSIS: We used Cochrane Neonatal methods when performing data collection and analysis. MAIN RESULTS: Twenty-five studies across 15 comparison groups met the inclusion criteria, categorised as: barriers to heat loss (18 studies); external heat sources (three studies); and combinations of interventions (four studies).Barriers to heat loss Plastic wrap or bag versus routine carePlastic wraps improved core body temperature on admission to the neonatal intensive care unit (NICU) or up to two hours after birth (mean difference (MD) 0.58 degrees C, 95% confidence interval (CI) 0.50 to 0.66; 13 studies; 1633 infants), and fewer infants had hypothermia on admission to the NICU or up to two hours after birth (typical risk ratio (RR) 0.67, 95% CI 0.62 to 0.72; typical risk reduction (RD) -0.25, 95% CI -0.29 to -0.20; number needed to treat for an additional beneficial outcome (NNTB) 4, 95% CI 4 to 5; 10 studies; 1417 infants). Risk of hyperthermia on admission to the NICU or up to two hours after birth was increased in infants in the wrapped group (typical RR 3.91, 95% CI 2.05 to 7.44; typical RD 0.04, 95% CI 0.02 to 0.06; number needed to treat for an additional harmful outcome (NNTH) 25, 95% CI 17 to 50; 12 studies; 1523 infants), but overall, fewer infants receiving plastic wrap were outside the normothermic range (typical RR 0.75, 95% CI 0.69 to 0.81; typical RD -0.20, 95% CI -0.26 to -0.15; NNTH 5, 95% CI 4 to 7; five studies; 1048 infants).Evidence was insufficient to suggest that plastic wraps or bags significantly reduce risk of death during hospital stay or other major morbidities, with the exception of reducing risk of pulmonary haemorrhage.Evidence of practices regarding permutations on this general approach is still emerging and has been based on the findings of only one or two small studies.External heat sourcesEvidence is emerging on the efficacy of external heat sources, including skin-to-skin care (SSC) versus routine care (one study; 31 infants) and thermal mattress versus routine care (two studies; 126 infants).SSC was shown to be effective in reducing risk of hypothermia when compared with conventional incubator care for infants with birth weight >= 1200 and <= 2199 grams (RR 0.09, 95% CI 0.01 to 0.64; RD 0.56, 95% CI -0.84 to -0.27; NNTB 2, 95% CI 1 to 4). Thermal (transwarmer) mattress significantly kept infants <= 1500 grams warmer (MD 0.65 degrees C, 95% CI 0.36 to 0.94) and reduced the incidence of hypothermia on admission to the NICU, with no significant difference in hyperthermia risk.Combinations of interventionsTwo studies (77 infants) compared thermal mattresses versus plastic wraps or bags for infants at <= 28 weeks' gestation. Investigators reported no significant differences in core body temperature nor in the incidence of hypothermia, hyperthermia, or core body temperature outside the normothermic range on admission to the NICU.Two additional studies (119 infants) compared plastic bags and thermal mattresses versus plastic bags alone for infants at < 31 weeks' gestation. Meta-analysis of these two studies showed improvement in core body temperature on admission to the NICU or up to two hours after birth, but an increase in hyperthermia. Data show no significant difference in the risk of having a core body temperature outside the normothermic range on admission to the NICU nor in the risk of other reported morbidities. AUTHORS' CONCLUSIONS: Evidence of moderate quality shows that use of plastic wraps or bags compared with routine care led to higher temperatures on admission to NICUs with less hypothermia, particularly for extremely preterm infants. Thermal mattresses and SSC also reduced hypothermia risk when compared with routine care, but findings are based on two or fewer small studies. Caution must be taken to avoid iatrogenic hyperthermia, particularly when multiple interventions are used simultaneously. Limited evidence suggests benefit and no evidence of harm for most short-term morbidity outcomes known to be associated with hypothermia, including major brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotising enterocolitis, and nosocomial infection. Many observational studies have shown increased mortality among preterm hypothermic infants compared with those who maintain normothermia, yet evidence is insufficient to suggest that these interventions reduce risk of in-hospital mortality across all comparison groups. Hypothermia may be a marker for illness and poorer outcomes by association rather than by causality. Limitations of this review include small numbers of identified studies; small sample sizes; and variations in methods and definitions used for hypothermia, hyperthermia, normothermia, routine care, and morbidity, along with lack of power to detect effects on morbidity and mortality across most comparison groups. Future studies should: be adequately powered to detect rarer outcomes; apply standardised morbidity definitions; focus on longer-term outcomes, particularly neurodevelopmental outcomes. PMID- 29431873 TI - Blood-brain barrier and its function during inflammation and autoimmunity. AB - The blood-brain barrier (BBB) is an important physiologic barrier that separates CNS from soluble inflammatory mediators and effector immune cells from peripheral circulation. The optimum function of the BBB is necessary for the homeostasis, maintenance, and proper neuronal function. The clinical and experimental findings have shown that BBB dysfunction is an early hallmark of various neurologic disorders ranging from inflammatory autoimmune, neurodegenerative, and traumatic diseases to neuroinvasive infections. Significant progress has been made in the understanding of the regulation of BBB function under homeostatic and neuroinflammatory conditions. Several neurologic disease-modifying drugs have shown to improve the BBB function. However, they have a broad-acting immunomodulatory function and can increase the risk of life-threatening infections. The recent development of in vitro multicomponent 3-dimensional BBB models coupled with fluidics chamber as well as a cell-type specific reporter and knockout mice gave a new boost to our understanding of the dynamics of the BBB. In the review, we discuss the current understanding of BBB composition and recent findings that illustrate the critical regulatory elements of the BBB function under physiologic and inflammatory conditions, and also suggested the strategies to control BBB structure and function. PMID- 29431871 TI - Immunoassay methods used in clinical studies for the detection of anti-drug antibodies to adalimumab and infliximab. AB - We examined the assay formats used to detect anti-drug antibodies (ADA) in clinical studies of the anti-tumour necrosis factor (TNF) monoclonal antibodies adalimumab and infliximab in chronic inflammatory disease and their potential impact on pharmacokinetic and clinical outcomes. Using findings of a recent systematic literature review of the immunogenicity of 11 biological/biosimilar agents, we conducted an ancillary qualitative review of a subset of randomized controlled trials and observational studies of the monoclonal antibodies against anti-TNF factor adalimumab and infliximab. Among studies of adalimumab and infliximab, the immunoassay method used to detect antibodies was reported in 91 of 111 (82%) and 154 of 206 (75%) adalimumab and infliximab studies, respectively. In most adalimumab and infliximab studies, an enzyme-linked immunosorbent assay or radioimmunoassay was used [85 of 91 (93%) and 134 of 154 (87%), respectively]. ADA incidence varied widely among assays and inflammatory diseases (adalimumab, 0-87%; infliximab, 0-79%). Pharmacokinetic and clinical outcomes were only reported for ADA-positive patients in 38 of 91 (42%) and 61 of 154 (40%) adalimumab and infliximab studies, respectively. Regardless of assay format or biological used, ADA formation was associated with lower serum concentrations, reduced efficacy and elevated rates of infusion-related reactions. Consistent with previous recommendations to improve interpretation of immunogenicity data for biologicals, greater consistency in reporting of assay methods and clinical consequences of ADA formation may prove useful. Additional standardization in immunogenicity testing and reporting, application of modern, robust assays that satisfy current regulatory expectations and implementation of international standards for marketed products may help to improve our understanding of the impact of immunogenicity to biologics. PMID- 29431875 TI - Phytosynthesized silver nanoparticles as antiquorum sensing and antibiofilm agent against the nosocomial pathogen Serratia marcescens: an in vitro study. AB - AIM: Serratia marcescens is an important multidrug-resistant human pathogen. The pathogenicity of S. marcescens mainly depends on the quorum sensing (QS) mechanism, which regulates the virulence factors production and biofilm formation. Hence, targeting QS mechanism in S. marcescens will ultimately pave the way to combat its pathogenicity. Thus, the present study is intended to evaluate the efficacy of Vetiveria zizanioides root extract-mediated silver nanoparticles (AgNPs) as a potent anti-QS and antibiofilm agent against S. marcescens. METHODS AND RESULTS: The AgNPs were synthesized using V. zizanioides aqueous root extract and the physiochemical properties of V. zizanioides-based AgNPs (VzAgNPs) were evaluated using analytical techniques such as ultraviolet visible absorption spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, dynamic light scattering and scanning and transmission electron microscopic techniques. VzAgNPs were found to attenuate the QS-dependent virulence factors, namely prodigiosin, protease, lipase, exopolysaccharide productions and biofilm formation of S. marcescens, without inhibiting its growth. Further, the transcriptomic analysis confirmed the down-regulation of QS dependent genes, which encode for the production of virulence factors and biofilm formation. CONCLUSION: The current study confirms VzAgNPs as an ideal anti-QS and antibiofilm agent against S. marcescens. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first approach that validates the anti-QS and antibiofilm potential of phytosynthesized VzAgNPs against the nosocomial pathogen, S. marcescens. As VzAgNPs exhibits potent antivirulent activities, it could be used to treat hospital-acquired S. marcescens infections. PMID- 29431874 TI - Short-chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. OBJECTIVE: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t PA in airway epithelial cells via their known receptors GPR41 and GPR43. METHODS: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. RESULTS: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. CONCLUSIONS AND CLINICAL RELEVANCE: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth. PMID- 29431876 TI - Real-life long-term effectiveness of fingolimod in Swiss patients with relapsing remitting multiple sclerosis. AB - BACKGROUND AND PURPOSE: In 2011, fingolimod was approved in Switzerland for the treatment of relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to assess the effectiveness and retention of fingolimod in a real-life Swiss setting, in which patients can receive fingolimod as both first- and second-line treatment for RRMS. METHODS: This cross-sectional, observational study with retrospective data collection was performed at 19 sites that comprised both hospitals and office-based physicians across Switzerland. Sites were asked to document eligible patients in consecutive chronological order to avoid selection bias. Demographic and clinical data from 274 consenting adult patients with RRMS who had received treatment with fingolimod were analyzed. RESULTS: Mean treatment duration with fingolimod was 32 months. Under fingolimod, 77.7% of patients remained free from relapses and 90.3% did not experience disability progression. The proportion of patients who were free from any clinical disease activity, i.e. without relapses and disability progression, was 72.1%. A total of 28.5% of patients had been RRMS treatment-naive prior to fingolimod therapy. High long-term treatment retention rates ranging between 95.7% at 24 months and 87.8% at 36 months were observed. CONCLUSION: In this Swiss cohort of naive and pre treated subjects with RRMS, the majority of patients under fingolimod treatment showed freedom from relapses and disability progression. In addition, treatment retention rate over 2 and 3 years was high, irrespective of previous treatment. PMID- 29431877 TI - Viral activity and outcome of hepatitis B surface antigen-positive grafts in deceased liver transplantation. AB - Indications of liver transplantation are extensive, but deceased donation does not meet the demand. Hepatitis B surface antigen (HBsAg)-positive grafts used to be discarded in the past. The aim of this study was to examine viral activity and outcome of HBsAg-positive deceased grafts transplanted to HBsAg-positive recipients. Eleven HBsAg-positive deceased grafts were transplanted to HBsAg positive patients with acute liver failure (3 patients), hepatocellular carcinoma (6 patients) and repeatedly bleeding varices (2 patients). Postoperatively, hepatitis B virus (HBV) infection was treated by a combination of antiviral nucleoside and nucleotide analogues. HBV DNA and HBsAg were measured periodically. The median (interquartile) model of end-stage liver disease score for the recipients was 19 (16-32) with a range from 11 to 40. HBV DNA was detected in 6 patients with a range from 61 to 1083 IU/mL before transplantation. After transplantation, HBV DNA was detected in 4 patients in the first month and 2 patients in the 6th month and became undetectable for all patients at end of the first year. The quantitative HBsAg ranged from 0.86 to 241.1 IU/mL at 6 months and 0.34 to 238.5 IU/mL at 24 months (P = .135). Three of the patients died in the early phase, and the other patients were followed up for 40.0 +/- 19.2 months with normal liver function. In conclusion, HBsAg-positive deceased liver grafts function well with minimal viral activity under treatment of combined antiviral nucleoside and nucleotide analogues. Use of HBsAg-positive deceased grafts is feasible and increases the donor pool to rescue dying patients. PMID- 29431878 TI - Characteristics associated with outcome in patients with first-ever posterior fossa stroke. AB - BACKGROUND AND PURPOSE: Factors such as infarct volume, infarct location and symptom severity can considerably influence long-term outcome in posterior fossa strokes. The decision about therapy can sometimes be complicated by discrepancies between infarct volume and clinical severity. We aimed to evaluate imaging and clinical parameters possibly influencing long-term outcome in patients with first ever posterior fossa stroke. METHODS: Imaging was performed on a 3-T magnetic resonance imaging scanner. Sixty-one of 1795 patients from the observational 1000Plus and LOBI studies (NCT00715533 and NCT02077582, clinicaltrials.org) were enrolled, meeting the inclusion criteria of first-ever posterior fossa stroke and magnetic resonance imaging examination within 24 h after symptom onset. Infarcts were classified as belonging to a proximal, middle or distal territory location in the posterior fossa. Good outcome was defined as a modified Rankin scale score of <=1 at 3 months. RESULTS: The largest lesion volumes on diffusion-weighted imaging on day 0 and fluid attenuation inversion recovery (FLAIR) on day 6 were found in the middle territory location with a median volume of 0.4 mL on diffusion-weighted imaging and 1.0 mL on FLAIR on day 6 versus 0.1/0.3 mL in the proximal and 0.1/0.1 mL in the distal territory location of the posterior fossa, respectively. Parameters associated with poor outcome were older age (P = 0.005), higher National Institutes of Health Stroke Scale score on admission/discharge (P = 0.016; P = 0.001), larger lesion volumes on FLAIR on day 6 (P = 0.013) and dysphagia (P = 0.02). There was no significant association between infarct location and modified Rankin scale score on day 90. CONCLUSION: Infarct volume and clinical severity, but not infarct location, were the main contributors to poor long-term outcome in first-ever posterior fossa strokes. PMID- 29431879 TI - Life-stage-associated remodelling of lipid metabolism regulation in Atlantic salmon. AB - Atlantic salmon migrates from rivers to sea to feed, grow and develop gonads before returning to spawn in freshwater. The transition to marine habitats is associated with dramatic changes in the environment, including water salinity, exposure to pathogens and shift in dietary lipid availability. Many changes in physiology and metabolism occur across this life-stage transition, but little is known about the molecular nature of these changes. Here, we use a long-term feeding experiment to study transcriptional regulation of lipid metabolism in Atlantic salmon gut and liver in both fresh- and saltwater. We find that lipid metabolism becomes significantly less plastic to differences in dietary lipid composition when salmon transitions to saltwater and experiences increased dietary lipid availability. Expression of genes in liver relating to lipogenesis and lipid transport decreases overall and becomes less responsive to diet, while genes for lipid uptake in gut become more highly expressed. Finally, analyses of evolutionary consequences of the salmonid-specific whole-genome duplication on lipid metabolism reveal several pathways with significantly different (p < .05) duplicate retention or duplicate regulatory conservation. We also find a limited number of cases where the whole-genome duplication has resulted in an increased gene dosage. In conclusion, we find variable and pathway-specific effects of the salmonid genome duplication on lipid metabolism genes. A clear life-stage associated shift in lipid metabolism regulation is evident, and we hypothesize this to be, at least partly, driven by nondietary factors such as the preparatory remodelling of gene regulation and physiology prior to sea migration. PMID- 29431880 TI - Anthropogenic disturbance homogenizes seagrass fish communities. AB - Anthropogenic activities have led to the biotic homogenization of many ecological communities, yet in coastal systems this phenomenon remains understudied. In particular, activities that locally affect marine habitat-forming foundation species may perturb habitat and promote species with generalist, opportunistic traits, in turn affecting spatial patterns of biodiversity. Here, we quantified fish diversity in seagrass communities across 89 sites spanning 6 degrees latitude along the Pacific coast of Canada, to test the hypothesis that anthropogenic disturbances homogenize (i.e., lower beta-diversity) assemblages within coastal ecosystems. We test for patterns of biotic homogenization at sites within different anthropogenic disturbance categories (low, medium, and high) at two spatial scales (within and across regions) using both abundance- and incidence-based beta-diversity metrics. Our models provide clear evidence that fish communities in high anthropogenic disturbance seagrass areas are homogenized relative to those in low disturbance areas. These results were consistent across within-region comparisons using abundance- and incidence-based measures of beta diversity, and in across-region comparisons using incidence-based measures. Physical and biotic characteristics of seagrass meadows also influenced fish beta diversity. Biotic habitat characteristics including seagrass biomass and shoot density were more differentiated among high disturbance sites, potentially indicative of a perturbed environment. Indicator species and trait analyses revealed fishes associated with low disturbance sites had characteristics including stenotopy, lower swimming ability, and egg guarding behavior. Our study is the first to show biotic homogenization of fishes across seagrass meadows within areas of relatively high human impact. These results support the importance of targeting conservation efforts in low anthropogenic disturbance areas across land- and seascapes, as well as managing anthropogenic impacts in high activity areas. PMID- 29431881 TI - Faster-X evolution: Theory and evidence from Drosophila. AB - A faster rate of adaptive evolution of X-linked genes compared with autosomal genes can be caused by the fixation of recessive or partially recessive advantageous mutations, due to the full expression of X-linked mutations in hemizygous males. Other processes, including recombination rate and mutation rate differences between X chromosomes and autosomes, may also cause faster evolution of X-linked genes. We review population genetics theory concerning the expected relative values of variability and rates of evolution of X-linked and autosomal DNA sequences. The theoretical predictions are compared with data from population genomic studies of several species of Drosophila. We conclude that there is evidence for adaptive faster-X evolution of several classes of functionally significant nucleotides. We also find evidence for potential differences in mutation rates between X-linked and autosomal genes, due to differences in mutational bias towards GC to AT mutations. Many aspects of the data are consistent with the male hemizygosity model, although not all possible confounding factors can be excluded. PMID- 29431882 TI - Counterion-Induced Asymmetric Control in Ring-Opening of Azetidiniums: Facile Access to Chiral Amines. AB - Counterion-induced stereocontrol is a powerful tool in organic synthesis. However, such enantiocontrol on tetrahedral ammonium cations remains challenging. Described here is the first example of using chiral anion phase-transfer catalysis to achieve intermolecular ring-opening of azetidiniums with excellent enantioselectivity (up to 97 % ee). Precise control over the formation and reaction of the chiral ion pair as well as inhibition of the background reaction by the biphasic system is key to the success of the reaction. PMID- 29431883 TI - An Optical Sensor Array Discriminates Syrups and Honeys. AB - We report a cross-reactive sensor array, combining a two-component probe system based upon three viologen substituted boronic acids and a poly(aryleneethynylene) (PAE) and an additional number of simple PAEs alone. This combined system discriminates 27 different honeys in aqueous solution, according to patterns in fluorescence intensity modulation, using linear discriminant analysis for data processing. The fluorescence turn-on array detects saccharide composition, while the PAEs discriminate trace colored components in the honeys. PMID- 29431884 TI - Successes and optimism in deep brain stimulation for neurological disorders: ripe for a surgical time out? PMID- 29431886 TI - Impact of anemia on in-hospital complications after ischemic stroke. AB - BACKGROUND AND PURPOSE: In-hospital complications after stroke represent barriers to optimal recovery and are even potentially life-threatening. Anemia is common in stroke patients and is related to poor outcome after stroke. Less is known, however, of the association of anemia with complications. We aimed to investigate the impact of anemia on a series of in-hospital complications after ischemic stroke. METHODS: Consecutive patients with ischemic stroke within 7 days were included. Anemia on admission and its severity were defined according to World Health Organization criteria. Eight pre-specified complications, such as pneumonia, gastrointestinal bleeding (GIB) and hemorrhagic transformation, were recorded during hospitalization. RESULTS: A total of 2647 patients were included. Anemia was present in 648 patients (24.5%), and 883 patients (33.4%) experienced at least one complication. Patients with anemia were more likely to experience one or more complications, pneumonia, GIB and thromboembolism (all P < 0.001) than patients without anemia. After adjustment for the confounders, patients with anemia had an adjusted odds ratio for at least one complication of 1.539 [95% confidence interval (CI), 1.232-1.923], for pneumonia of 1.707 (95% CI, 1.345 2.167), for GIB of 2.245 (95% CI, 1.215-4.148) and for thromboembolism of 3.443 (95% CI, 1.668-7.108). The risk of at least one complication, pneumonia, GIB and thromboembolism increased with anemia severity (all P < 0.05). There was no significant association between anemia and urinary tract infection, hemorrhagic transformation, seizures and brain herniation. CONCLUSION: Anemia is an independent predictor of in-hospital complications following stroke, especially for pneumonia, GIB and thromboembolism. It remains to be studied whether prophylaxis and treatment of anemia would prevent in-hospital complications. PMID- 29431887 TI - Long-term organic carbon sequestration in tidal marsh sediments is dominated by old-aged allochthonous inputs in a macrotidal estuary. AB - Tidal marshes are vegetated coastal ecosystems that are often considered as hotspots of atmospheric CO2 sequestration. Although large amounts of organic carbon (OC) are indeed being deposited on tidal marshes, there is no direct link between high OC deposition rates and high OC sequestration rates due to two main reasons. First, the deposited OC may become rapidly decomposed once it is buried and, second, a significant part of preserved OC may be allochthonous OC that has been sequestered elsewhere. In this study we aimed to identify the mechanisms controlling long-term OC sequestration in tidal marsh sediments along an estuarine salinity gradient (Scheldt estuary, Belgium and the Netherlands). Analyses of deposited sediments have shown that OC deposited during tidal inundations is up to millennia old. This allochthonous OC is the main component of OC that is effectively preserved in these sediments, as indicated by the low radiocarbon content of buried OC. Furthermore, OC fractionation showed that autochthonous OC is decomposed on a decadal timescale in saltmarsh sediments, while in freshwater marsh sediments locally produced biomass is more efficiently preserved after burial. Our results show that long-term OC sequestration is decoupled from local biomass production in the studied tidal marsh sediments. This implies that OC sequestration rates are greatly overestimated when they are calculated based on short-term OC deposition rates, which are controlled by labile autochthonous OC inputs. Moreover, as allochthonous OC is not sequestered in-situ, it does not contribute to active atmospheric CO2 sequestration in these ecosystems. A correct assessment of the contribution of allochthonous OC to the total sedimentary OC stock in tidal marsh sediments as well as a correct understanding of the long-term fate of locally produced OC are both necessary to avoid overestimations of the rate of in-situ atmospheric CO2 sequestration in tidal marsh sediments. PMID- 29431885 TI - Important and specific role for basophils in acute allergic reactions. AB - IgE-mediated allergic reactions involve the activation of effector cells, predominantly through the high-affinity IgE receptor (FcepsilonRI) on mast cells and basophils. Although the mast cell is considered the major effector cell during acute allergic reactions, more recent studies indicate a potentially important and specific role for basophils and their migration which occurs rapidly upon allergen challenge in humans undergoing anaphylaxis. We review the evidence for a role of basophils in contributing to clinical symptoms of anaphylaxis and discuss the possibility that basophil trafficking during anaphylaxis might be a pathogenic (to target organs) or protective (preventing degranulation in circulation) response. Finally, we examine the potential role of basophils in asthma exacerbations. Understanding the factors that regulate basophil trafficking and activation might lead to new diagnostic and therapeutic strategies in anaphylaxis and asthma. PMID- 29431888 TI - Management of a stage-structured insect pest: an application of approximate optimization. AB - Ecological decision problems frequently require the optimization of a sequence of actions over time where actions may have both immediate and downstream effects. Dynamic programming can solve such problems only if the dimensionality is sufficiently low. Approximate dynamic programming (ADP) provides a suite of methods applicable to problems of arbitrary complexity at the expense of guaranteed optimality. The most easily generalized method is the look-ahead policy: a brute-force algorithm that identifies reasonable actions by constructing and solving a series of temporally truncated approximations of the full problem over a defined planning horizon. We develop and apply this approach to a pest management problem inspired by the Mediterranean fruit fly, Ceratitis capitata. The model aims to minimize the cumulative costs of management actions and medfly-induced losses over a single 16-week season. The medfly population is stage-structured and grows continuously while management decisions are made at discrete, weekly intervals. For each week, the model chooses between inaction, insecticide application, or one of six sterile insect release ratios. Look-ahead policy performance is evaluated over a range of planning horizons, two levels of crop susceptibility to medfly and three levels of pesticide persistence. In all cases, the actions proposed by the look-ahead policy are contrasted to those of a myopic policy that minimizes costs over only the current week. We find that look ahead policies always out-performed a myopic policy and decision quality is sensitive to the temporal distribution of costs relative to the planning horizon: it is beneficial to extend the planning horizon when it excludes pertinent costs. However, longer planning horizons may reduce decision quality when major costs are resolved imminently. ADP methods such as the look-ahead-policy-based approach developed here render questions intractable to dynamic programming amenable to inference but should be applied carefully as their flexibility comes at the expense of guaranteed optimality. However, given the complexity of many ecological management problems, the capacity to propose a strategy that is "good enough" using a more representative problem formulation may be preferable to an optimal strategy derived from a simplified model. PMID- 29431889 TI - Coagulation and inflammation in long-term cancer survivors: results from the adult population. AB - : Essentials The increase of cancer survival remains curtailed by cardiovascular mortality. We studied a large range of inflammatory and coagulation biomarkers in long-term cancer survivors. Cancer history has an important impact on mortality independent of cardiovascular risk factors. Fibrinogen and von Willebrand factor are potential biomarkers in survivors of increased mortality. SUMMARY: Background The advances in cancer treatment and detection of early cancer have resulted in a steady increase in the number of of cancer survivors over the years. However, because of the long-term toxic effects of chemotherapy and radiotherapy, the incidence of cardiovascular disease (CVD) is increasing in survivors. Objectives To investigate traditional cardiovascular risk factors (CVRFs), inflammation and the coagulation profile in long-term cancer survivors (cancer diagnosis >= 5 years) from a large adult population-based study sample. Methods The presence of cardiovascular risk factors (CVRFs) and laboratory markers were compared in individuals with (n = 723) and without (n = 13626) a long-term history of cancer from the Gutenberg Health Study. Data on coagulation factors, D-dimer and von Willebrand factor (VWF) activity were available for 4974 individuals (n = 244 cancer survivors). Results In multivariable regression models, a history of cancer was, independently of CVRFs and CVD, associated with higher fibrinogen levels (beta 6.99, 95% confidence interval [CI] 1.16-12.8), VWF activity (beta 5.08, 95% CI 0.02-10.1), and antithrombin activity (beta 1.85, 95% CI 0.44-3.27). Cancer survivors with CVD showed notably higher VWF activity than individuals with CVD without a history of cancer, with a difference in the means of 23.0 (7.9 38.1). Multivariate Cox regression analysis, adjusted for CVRFs, confirmed that a long-term history of cancer is associated with a 72% higher mortality. Increased mortality in cancer survivors was dependent on fibrinogen level and VWF activity level. Conclusion Cancer survivors showed a worse inflammation and coagulation profile than individuals without a history of cancer. Overall mortality in long term cancer survivors was increased independently of traditional CVRFs. These results underline the need to further investigate plasma biomarkers as complementary cardiovascular risk predictors in cancer survivors. PMID- 29431890 TI - Saccade frequency response to visual cues during gait in Parkinson's disease: the selective role of attention. AB - Gait impairment is a core feature of Parkinson's disease (PD) with implications for falls risk. Visual cues improve gait in PD, but the underlying mechanisms are unclear. Evidence suggests that attention and vision play an important role; however, the relative contribution from each is unclear. Measurement of visual exploration (specifically saccade frequency) during gait allows for real-time measurement of attention and vision. Understanding how visual cues influence visual exploration may allow inferences of the underlying mechanisms to response which could help to develop effective therapeutics. This study aimed to examine saccade frequency during gait in response to a visual cue in PD and older adults and investigate the roles of attention and vision in visual cue response in PD. A mobile eye-tracker measured saccade frequency during gait in 55 people with PD and 32 age-matched controls. Participants walked in a straight line with and without a visual cue (50 cm transverse lines) presented under single task and dual-task (concurrent digit span recall). Saccade frequency was reduced when walking in PD compared to controls; however, visual cues ameliorated saccadic deficit. Visual cues significantly increased saccade frequency in both PD and controls under both single task and dual-task. Attention rather than visual function was central to saccade frequency and gait response to visual cues in PD. In conclusion, this study highlights the impact of visual cues on visual exploration when walking and the important role of attention in PD. Understanding these complex features will help inform intervention development. PMID- 29431891 TI - Independent and cooperative regulation of staphylopine biosynthesis and trafficking by Fur and Zur. AB - Staphylococcus aureus expresses the Cnt system implicated in the active transport of trace metals by synthesizing (CntKLM) and exporting (CntE) staphylopine, a metallophore chelating metals and then taken up by an ABC-transporter (CntABCDF). This machinery is encoded in the cntKLMABCDFE operon, preceded by a non-coding region (PcntK) and containing an internal promoter region (PcntA). PcntK comprises a Fur box followed by a Zur box, a sRNA transcription start and a repeated region, while PcntA comprises a Fur box that overlaps a Zur box. We found that PcntK promoter activity is attenuated by the repeated sequence and strictly controlled by Fur or Zur binding to its respective target sequences. Interestingly, we discovered a cooperative regulation of the PcntA activity by both Fur and Zur binding to the Fur/Zur box, by identifying a tripartite complex with DNA. Repression of PcntA is less sensitive to metal concentration and therefore loosely repressed as compared to PcntK activity. Furthermore, the Cnt system is essential for the optimal import of zinc, thereby linking regulation and function of Cnt. Overall, our results highlight the need for fine and differential tuning of staphylopine biosynthesis and trafficking in order to efficiently respond to metal starvation and optimize metal recovery. PMID- 29431893 TI - Formation of a Highly Reactive Cobalt Nanocluster Crystal within a Highly Negatively Charged Porous Coordination Cage. AB - Earth-abundant first-row transition-metal nanoclusters (NCs) have been extensively investigated as catalysts. However, their catalytic activity is relatively low compared with noble metal NCs. Enhanced catalytic activity of cobalt NCs can be achieved by encapsulating Co NCs in soluble porous coordination cages (PCCs). Two cages, PCC-2a and 2b, possess almost identical cavity in shape and size, while PCC-2a has five times more net charges than PCC-2b. Co2+ cations were accumulated in PCC-2a and reduced to ultra-small Co NCs in situ, while for PCC-2b, only bulky Co particles were formed. As a result, Co NCs@PCC-2a accomplished the highest catalytic activity in the hydrolysis of ammonium borane among all the first-row transition-metals NCs. Based on these results, it is envisioned that confining in the charged porous coordination cage could be a novel route for the synthesis of ultra-small NCs with extraordinary properties. PMID- 29431894 TI - Sample Ripening through Nanophase Separation Influences the Performance of Dynamic Nuclear Polarization. AB - Mixtures of water and glycerol provide popular matrices for low-temperature spectroscopy of vitrified samples. However, they involve counterintuitive physicochemical properties, such as spontaneous nanoscopic phase separations (NPS) in solutions that appear macroscopically homogeneous. We demonstrate that such phenomena can substantially influence the efficiency of dynamic nuclear polarization (DNP) by factors up to 20 % by causing fluctuations in local concentrations of polarization agents (radicals). Thus, a spontaneous NPS of water/glycerol mixtures that takes place on time scales on the order of 30-60 min results in a confinement of polarization agents in nanoscopic water-rich vesicles, which in return affects the DNP. Such effects were found for three common polarization agents, TEMPOL, AMUPol and Trityl. PMID- 29431892 TI - Correlates of economic decisions in the dorsal and subgenual anterior cingulate cortices. AB - The anterior cingulate cortex can be divided into distinct ventral (subgenual, sgACC) and dorsal (dACC), portions. The role of dACC in value-based decision making is hotly debated, while the role of sgACC is poorly understood. We recorded neuronal activity in both regions in rhesus macaques performing a token gambling task. We find that both encode many of the same variables; including integrated offered values of gambles, primary as well as secondary reward outcomes, number of current tokens and anticipated rewards. Both regions exhibit memory traces for offer values and putative value comparison signals. Both regions use a consistent scheme to encode the value of the attended option. This result suggests that neurones do not appear to be specialized for specific offers (that is, neurones use an attentional as opposed to labelled line coding scheme). We also observed some differences between the two regions: (i) coding strengths in dACC were consistently greater than those in sgACC, (ii) neurones in sgACC responded especially to losses and in anticipation of primary rewards, while those in dACC showed more balanced responding and (iii) responses to the first offer were slightly faster in sgACC. These results indicate that sgACC and dACC have some functional overlap in economic choice, and are consistent with the idea, inspired by neuroanatomy, which sgACC may serve as input to dACC. PMID- 29431895 TI - Barium as Honorary Transition Metal in Action: Experimental and Theoretical Study of Ba(CO)+ and Ba(CO). AB - Ba(CO)+ and Ba(CO)- have been produced and isolated in a low-temperature neon matrix. The observed C-O stretching wavenumber for Ba(CO)+ of 1911.2 cm-1 is the most red-shifted value measured for any metal carbonyl cations, indicating strong pi backdonation of electron density from Ba+ to CO. Quantum chemical calculations indicate that Ba(CO)+ has a 2 Pi reference state, which correlates with the 2 D(5d1 ) excited state of Ba+ that comprises significant Ba+ (5dpi1 )->CO(pi* LUMO) backbonding, letting the Ba(CO)+ complex behave like a conventional transition-metal carbonyl. A bonding analysis shows that the pi backdonation in Ba(CO)+ is much stronger than the Ba+ (5dsigma /6s)<-CO(HOMO) sigma donation. The Ba+ cation in the 2 D(5d1 ) excited state is a donor rather than an acceptor. Covalent bonding in the radical anion Ba(CO)- takes place mainly through Ba(5dpi )<-CO- (pi* SOMO) pi donation and Ba(5dsigma /6s)<-CO- (HOMO) sigma donation. The most important valence functions at barium in Ba(CO)+ cation and Ba(CO)- anion are the 5d orbitals. PMID- 29431896 TI - On taking the STING out of immune activation. AB - Nearly a decade ago, an endoplasmic reticulum (ER) adaptor protein called stimulator of interferon genes (STING) was found to be critical in the induction of type I IFN production in response to DNA virus infection. STING functions by sensing cytoplasmic DNA and activates key transcription factors, including IFN regulatory factor (IRF)-3 and IRF7, to initiate type I IFN expression. Type I IFNs are vital in immunity against viral infections and can influence cancer cell proliferation, migration, and apoptosis. Several studies have shown that STING activation results in potent antitumor activity by generating strong tumor specific cytotoxic T-cell responses. Moreover, compared with wild-type, STING knockout mice show greater susceptibility to viral infections. In this review, we discuss the importance of STING signaling during the induction of immune responses, especially those associated with type I IFN in viral infections and tumor immunity. Furthermore, we highlight recent data that unravel how the STING signaling pathway can be negatively regulated. PMID- 29431897 TI - FNA biopsy in grading pancreatic neuroendocrine tumors: Methodological issues regarding diagnostic value. PMID- 29431898 TI - Asymptomatic yellowish papules on the upper arms. PMID- 29431899 TI - A technique for teaching and photodocumentation of direct endoscopic rigid oesophagoscopy. PMID- 29431901 TI - Effects of fibroblast-myocyte coupling on the sinoatrial node activity: A computational study. AB - While the sinoatrial node (SAN) is structurally heterogeneous, most computer simulations of electrical activity take into account SAN pacemaker cells only. Our aim was to investigate how fibroblasts affect the SAN activity. We simulated the rabbit sinoatrial node accounting for differences between central and peripheral pacemaker cells, and for fibroblast-myocyte electrical coupling. We have observed that only if fibroblast-myocyte coupling is taken into account, (1) action potential is initiated in the central part of the SAN (within 1.2 mm of the center of simulated tissue); otherwise, leading centers are located on the periphery; (2) few (1 to 6) leading centers initiate action potential in the SAN; otherwise, we observed more than 8 leading centers; (3) acetylcholine superfusion results in a shift of leading centers toward the SAN periphery; and (4) sinus pauses up to 1.9 second follow acetylcholine superfusion. We observed negligible effect of fibroblast-myocyte coupling on the period of SAN activation. We conclude that fibroblast-myocyte coupling may explain action potential initiation and propagation from the center of the SAN observed in experimental studies, while atrial load on the peripheral SAN fails to explain this fact. PMID- 29431902 TI - Long-distance alteration of lymphatic drainage in a melanoma patient after axillary lymph node dissection. PMID- 29431900 TI - Deciphering drought-induced metabolic responses and regulation in developing maize kernels. AB - Drought stress conditions decrease maize growth and yield, and aggravate preharvest aflatoxin contamination. While several studies have been performed on mature kernels responding to drought stress, the metabolic profiles of developing kernels are not as well characterized, particularly in germplasm with contrasting resistance to both drought and mycotoxin contamination. Here, following screening for drought tolerance, a drought-sensitive line, B73, and a drought-tolerant line, Lo964, were selected and stressed beginning at 14 days after pollination. Developing kernels were sampled 7 and 14 days after drought induction (DAI) from both stressed and irrigated plants. Comparative biochemical and metabolomic analyses profiled 409 differentially accumulated metabolites. Multivariate statistics and pathway analyses showed that drought stress induced an accumulation of simple sugars and polyunsaturated fatty acids and a decrease in amines, polyamines and dipeptides in B73. Conversely, sphingolipid, sterol, phenylpropanoid and dipeptide metabolites accumulated in Lo964 under drought stress. Drought stress also resulted in the greater accumulation of reactive oxygen species (ROS) and aflatoxin in kernels of B73 in comparison with Lo964 implying a correlation in their production. Overall, field drought treatments disordered a cascade of normal metabolic programming during development of maize kernels and subsequently caused oxidative stress. The glutathione and urea cycles along with the metabolism of carbohydrates and lipids for osmoprotection, membrane maintenance and antioxidant protection were central among the drought stress responses observed in developing kernels. These results also provide novel targets to enhance host drought tolerance and disease resistance through the use of biotechnologies such as transgenics and genome editing. PMID- 29431903 TI - Intimate Partner Violence, Sexual Autonomy and Postpartum STD Prevention Among Young Couples: A Mediation Analysis. AB - CONTEXT: The transition to parenthood is a stressful time for young couples and can put them at risk for acquiring STDs. Mechanisms underlying this risk particularly, intimate partner violence (IPV) and sexual autonomy-have not been well studied. METHODS: Between 2007 and 2011, a prospective cohort study of the relationships and health of pregnant adolescents and their male partners recruited 296 couples at four hospital-based obstetrics and gynecology clinics in the U.S. Northeast; participants were followed up six and 12 months after the birth. Structural equation modeling identified associations among IPV at baseline and six months, sexual autonomy at six months and STD acquisition at 12 months. Mediating effects of sexual autonomy were tested via bootstrapping. RESULTS: Females were aged 14-21, and male partners were 14 or older. For females, IPV victimization at baseline was positively associated with the likelihood of acquiring a postpartum STD (coefficient, 0.4); level of sexual autonomy was inversely associated with the likelihood of acquiring an STD and of having a male partner who acquired one by the 12-month follow-up (-0.4 for each). For males, IPV victimization at baseline was negatively correlated with a female partner's sexual autonomy (-0.3) and likelihood of acquiring an STD (-0.7); victimization at six months was positively related to a partner's sexual autonomy (0.2). Sexual autonomy did not mediate these relationships. CONCLUSIONS: Females' sexual autonomy appears to protect against postpartum STDs for both partners. Future research should explore the efficacy of IPV-informed approaches to improving women's sexual and reproductive health. PMID- 29431906 TI - Is manual acne therapy medically necessary? PMID- 29431905 TI - Reply to FNA biopsy in grading pancreatic neuroendocrine tumors: Methodological issues regarding diagnostic value. PMID- 29431904 TI - Atrial fibrillation and venous thromboembolism: evidence of bidirectionality in the Atherosclerosis Risk in Communities Study. AB - : Essentials Atrial fibrillation (AF) may increase risk of venous thromboembolism (VTE), and vice versa. Bidirectionality was assessed prospectively via data from 15 129 black and white individuals. AF was associated with greater risk of developing VTE, and VTE with greater risk of AF. Associations were strongest among blacks and in the first 6 months after initial diagnosis. SUMMARY: Background Atrial fibrillation (AF) and venous thromboembolism (VTE) frequently co-occur. These conditions have shared risk factors and are accompanied by coagulation abnormalities. Furthermore, mechanistic pathways may directly link the disorders. Objectives To test the hypothesis that individuals with incident AF are at greater risk of developing VTE, and those with VTE are at elevated risk of AF. We also tested whether associations were stronger in the first 6 months after the initial diagnosis, and explored race differences. Patients/Methods A total of 15 129 ARIC study participants (45-64 years, 55% female, 26% Black) were followed from 1987 to 2011 for incident AF and VTE (median follow-up 19.8 years). Multivariable-adjusted Cox regression was used, with AF and VTE modeled as time dependent exposures. Results Incident AF was associated with greater risk of subsequent incident VTE (hazard ratio [95% CI], 1.71 [1.32-2.22]); the association was stronger in Black people (2.30 [1.48-3.58]) and during the first 6 months after AF diagnosis (5.08 [3.08-8.38]). Similarly, incident VTE was associated with increased risk of incident AF (1.73 [1.34-2.24]), especially in Black people (2.40 [1.55-3.74]) and in the first 6 months after VTE diagnosis (4.50 [2.61-7.77]). Conclusions The occurrence of AF was associated with increased risk of incident VTE, and occurrence of VTE was associated with greater risk of incident AF. Associations were particularly strong among Black people and during the first 6 months after the initial diagnosis, although they remained elevated even after 6 months. These findings highlight patient populations that may be at increased risk of AF and VTE, and perhaps should be targeted with preventive strategies. PMID- 29431908 TI - Stereodivergent Hydroboration of Allenes. AB - Full details of a stereodivergent hydroboration of allenes are reported. While hydroboration of an allene with 9-BBN provided a thermodynamically stable (E) allylic alcohol after oxidative work-up, the reaction of an identical allene with HB(Sia)2 (disiamylborane) formed a (Z)-allylic alcohol as the kinetic product. The developed conditions allowed for the synthesis of trisubstituted olefins in a highly stereoselective fashion, which is known to be challenging. The method was also applied to the stereodivergent synthesis of structural motifs such as skipped dienes and allylbenzenes, which are often embedded in biologically active natural products. PMID- 29431907 TI - Simultaneous determination of 29 pharmaceuticals in fish muscle and plasma by ultrasonic extraction followed by SPE-UHPLC-MS/MS. AB - A confirmatory method for the simultaneous detection of 29 pharmaceuticals in fish muscle and plasma was developed by using solid-phase extraction combined with ultra-high performance liquid chromatography and tandem mass spectrometry. Fish samples were extracted with methanol and enriched using Oasis HLB solid phase extraction columns in one step. Twenty-nine target pharmaceuticals were quantified by the internal standard method and the calibration curves showed good linearity in a wide range with determination coefficients of greater than 0.913. The detection limits of the pharmaceuticals ranged from 0.01 to 2.00 MUg/kg (MUg/L). The applicability of the method was checked by precision and recovery experiments. The average recoveries of the 29 pharmaceuticals were between 61 and 111%, and all the relative standard deviations were below 25%. Our reported method has been demonstrated to be sensitive, convenient, rapid, and reliable for the simultaneous determination of 29 pharmaceuticals in fish muscle and plasma. Real sample determination showed that 25 and 9 of the 29 compounds were detected in fish muscle and plasma, respectively. PMID- 29431909 TI - Dermatologic surgery in children: an update on indication, anesthesia, analgesia and potential perioperative complications. AB - BACKGROUND: Children undergoing dermatosurgical procedures require, unlike adults, particular attention; the administration of various analgesics, anesthetics or sedatives requires a thorough knowledge of drug pharmacokinetics and pharmacodynamics. Furthermore, there are concerns that drugs used for sedation/general anesthesia may result in anesthetic/analgesic complications in children undergoing surgery, with a risk of impaired mental development. OBJECTIVES: Based on our clinical experience and a literature review, we illustrate the most commonly used analgesic, anesthetic and sedative drugs in pediatric dermatosurgery, and identify risk factors and complications following dermatosurgical procedures. RESULTS: Topical anesthetics can be used in children for superficial dermatologic procedures or prior to infiltration anesthesia. Maximum recommended doses based on body weight should be calculated in order to avoid overdosage of local anesthetics. General anesthesia in dermatosurgery is considered safe and has a low rate of side effects. However, caution is advised in children under the age of one due to potential long-term neurological side effects. NSAIDs and opioids play a significant role in analgesia for children. CONCLUSIONS: This article reviews currently available data on analgesia, anesthesia and complications that may arise in pediatric dermatosurgery. These data may be useful in optimizing the safety and quality of care and in improving parent counseling. PMID- 29431910 TI - Lipomatoses. AB - Lipomatoses are benign proliferations of adipose tissue, often with typical distribution patterns, which usually occur without clear causes. In contrast to circumscribed lipomas, they develop diffusely and symmetrically and are not surrounded by a fibrous pseudocapsule. The most common form is benign symmetric lipomatosis (BSL; Launois-Bensaude syndrome), of which four types are distinguished based on the distribution pattern of hyperplastic adipose tissue. The etiology and pathogenesis of the disease are still largely unknown, although some forms appear to have a hereditary basis or to be associated with increased alcohol consumption. In some cases, mitochondrial dysfunctions have been detected. Lipomatoses may be solitary, but may also be associated with other symptoms or illnesses (comorbidity). Effective drug therapies are not known, but surgical procedures can alleviate the symptoms. Lipomatosis dolorosa, which can be distinguished from BSL, occurs predominantly in middle-aged women and is characterized by proliferation of adipose tissue and severe pain in the affected areas. Various differential diagnoses and concomitant illnesses need to be considered, in particular depression. There are no evidence-based recommendations for therapy. Repetitive lidocaine infusions can achieve temporary improvement. Recurrence after surgical intervention is not uncommon, but long-term success is also possible. PMID- 29431911 TI - The YEARS algorithm for suspected pulmonary embolism: shorter visit time and reduced costs at the emergency department. AB - Essentials The YEARS algorithm was designed to simplify the diagnostic workup of suspected pulmonary embolism. We compared emergency ward turnaround time of YEARS and the conventional algorithm. YEARS was associated with a significantly shorter emergency department visit time of ~60 minutes. Treatment of pulmonary embolism was initiated 53 minutes earlier with the YEARS algorithm SUMMARY: Background Recently, the safety of the YEARS algorithm, designed to simplify the diagnostic work-up of pulmonary embolism (PE), was demonstrated. We hypothesize that by design, YEARS would be associated with a shorter diagnostic emergency department (ED) visit time due to simultaneous assessment of pre-test probability and D dimer level and reduction in number of CT scans. Aim To investigate whether implementation of the YEARS diagnostic algorithm is associated with a shorter ED visit time compared with the conventional algorithm and to evaluate the associated cost savings. Methods We selected consecutive outpatients with suspected PE from our hospital included in the YEARS study and ADJUST-PE study. Different time-points of the diagnostic process were extracted from the to-the minute accurate electronic patients' chart system of the ED. Further, the costs of the ED visits were estimated for both algorithms. Results All predefined diagnostic turnaround times were significantly shorter after implementation of YEARS: patients were discharged earlier from the ED; 54 min (95% CI, 37-70) for patients managed without computed tomography pulmonary angiography (CTPA) and 60 min (95% CI, 44-76) for the complete study population. Importantly, patients diagnosed with PE by CTPA received the first dose of anticoagulants 53 min (95% CI, 22-82) faster than those managed according to the conventional algorithm. Total costs were reduced by on average ?123 per visit. Conclusion YEARS was shown to be associated with a shorter ED visit time compared with the conventional diagnostic algorithm, leading to faster start of treatment in the case of confirmed PE and savings on ED resources. PMID- 29431912 TI - Polymorphism in dural arteriovenous fistula: matrix metalloproteinase-2-1306 C/T as a potential risk factor for sinus thrombosis. AB - : Essentials Sinus thrombosis may play a crucial role in development of dural arteriovenous fistula (DAVF). Little is known about the association between gene polymorphism and the development of DAVF. MMP-2-1306 C/T showed a higher prevalence rate in DAVF cases with sinus thrombosis. MMP-2-1306C/T polymorphism is likely a potential risk factor for sinus thrombosis in DAVF. SUMMARY: Background Dural arteriovenous fistula (DAVF) is a rare but important cerebrovascular disorder in adults. Little is known about the molecular genetic pathogenesis underlying DAVF development. Objectives To investigate the associations of gene polymorphisms and DAVF. Materials and Methods By the use of real-time PCR genotyping, seven single-nucleotide polymorphisms (SNPs) of angiogenesis-related genes were analyzed in 72 DAVF patients. Pertinent clinical and imaging data were subgrouped on the basis of location (cavernous sinus versus lateral sinus), lesions (single versus multiple), cerebral venous reflux (CVR) grading (Borden I versus Borden II/III), and sinus thrombosis (with versus without). Results We found that individuals carrying the polymorphic allele of matrix metalloproteinase (MMP)-2-1306 C/T (rs243865) had a significantly increased risk of sinus thrombosis in DAVF (odds ratio 6.2; 95% confidence interval 1.7-22.9). There was a weak difference in associations of tissue inhibitor of metalloproteinase (TIMP)-2 (rs2277698) gene polymorphism and DAVF patients subgrouped by CVR grading. Conclusions These preliminary results indicate that MMP-2-1306 C/T, but not MMP-9, TIMP-1, TIMP-2, and vascular endothelial growth factor A SNP variants, is a risk factor for the development of sinus thrombosis in DAVF patients. PMID- 29431913 TI - Ion-Selective Electrodes Based on Hydrophilic Ionophore-Modified Nanopores. AB - We report the synthesis and analytical application of the first Cu2+ -selective synthetic ion channel based on peptide-modified gold nanopores. A Cu2+ -binding peptide motif (Gly-Gly-His) along with two additional functional thiol derivatives inferring cation-permselectivity and hydrophobicity was self assembled on the surface of gold nanoporous membranes comprising of about 5 nm diameter pores. These membranes were used to construct ion-selective electrodes (ISEs) with extraordinary Cu2+ selectivities, approaching six orders of magnitude over certain ions. Since all constituents are immobilized to a supporting nanoporous membrane, their leaching, that is a ubiquitous problem of conventional ionophore-based ISEs was effectively suppressed. PMID- 29431915 TI - Issue Information-Declaration of Helsinki. PMID- 29431916 TI - Clinical relevance of smartphone apps for diabetes management: A global overview. AB - BACKGROUND: We assessed the number, proportion, and clinical relevance of diabetes self-management apps in major languages spoken by 10 countries with the highest number of people with diabetes. METHODS: China, India, USA, Brazil, Russian Federation, Mexico, Indonesia, Egypt, Japan, and Pakistan were identified as the 10 countries with the largest number of people with diabetes based on the latest NCD-RisC survey. Android and iOS apps in the 10 national languages were extracted with a search strategy. App titles and descriptions were systematically screened by trained reviewers, including apps specific for diabetes self management and excluding apps for health care providers, general well-being, health and product promotion, and traditional cure. Eighteen apps in the above languages were then downloaded based on availability and popularity and assessed for clinical relevance to diabetes self-management with reference to current clinical guidelines. RESULTS: The diabetes-related search terms identified 3374 Android and 4477 iOS apps, where 1019 Android and 1303 iOS apps were screened as being relevant for diabetes self-management. Chinese and English language apps constitute above 80% of the diabetes apps, have more downloads, and more comprehensive clinically relevant functions compared with other languages. None of the apps assessed met all criteria for information provision and app functionalities nor provided information cited from accredited sources. CONCLUSIONS: Our study showed that apps could play an important role in complementing multifaceted diabetes care, but should preferably be regulated, context specific, and more tailored to users' needs with clear guidance for patients and clinicians about the choices. PMID- 29431914 TI - Role of CD133 Molecule in Wnt Response and Renal Repair. AB - Renal repair after injury is dependent on clonal expansion of proliferation competent cells. In the human kidney, the expression of CD133 characterizes a population of resident scattered cells with resistance to damage and ability to proliferate. However, the biological function of the CD133 molecule is unknown. By RNA sequencing, we found that cells undergoing cisplatin damage lost the CD133 signature and acquired metanephric mesenchymal and regenerative genes such as SNAIL1, KLF4, SOX9, and WNT3. CD133 was reacquired in the recovery phase. In CD133-Kd cells, lack of CD133 limited cell proliferation after injury and was specifically correlated with deregulation of Wnt signaling and E-cadherin pathway. By immunoprecipitation, CD133 appeared to form a complex with E-cadherin and beta-catenin. In parallel, CD133-Kd cells showed lower beta-catenin levels in basal condition and after Wnt pathway activation and reduced TCF/LEF promoter activation in respect to CD133+ cells. Finally, the lack of CD133 impaired generation of nephrospheres while favoring senescence. These data indicate that CD133 may act as a permissive factor for beta-catenin signaling, preventing its degradation in the cytoplasm. Therefore, CD133 itself appears to play a functional role in renal tubular repair through maintenance of proliferative response and control of senescence. Stem Cells Translational Medicine 2018;7:283 294. PMID- 29431917 TI - Huge pedunculated tumor of the thigh. PMID- 29431918 TI - Examining the psychological and emotional mechanisms of mindfulness that reduce stress to enhance healthy behaviours. AB - Engagement in modifiable health behaviours plays a critical role in the development of chronic illnesses. Research suggests that mindfulness facilitates health-enhancing behaviour, yet the influence of mindfulness on different health behaviours and the mechanisms underlying this association are unclear. This study investigated a mediation model that explores psychological and emotional coping processes (reappraisal, suppression, and psychological flexibility) as mechanisms connecting mindfulness to reduced stress perceptions and reactions, which then predict physical activity, fruit and vegetable consumption, and sleep quality. Adults (n = 233) completed self-report measures via Amazon's Mechanical Turk and path modelling was used to test the model for direct, indirect, and total effects. Results revealed that greater mindfulness was indirectly associated with greater engagement in all 3 health behaviours through the proposed mediators, although the association with fruit and vegetable consumption was only trending in significance. Among the coping processes, psychological flexibility emerged as the strongest mechanism in the prediction of stress. Findings suggest that being more mindful may have downstream stress-reductive effects that enhance engagement in healthy behaviour, supporting mindfulness as a potential addition to behavioural health interventions. PMID- 29431920 TI - Observation of Various and Spontaneous Magnetic Skyrmionic Bubbles at Room Temperature in a Frustrated Kagome Magnet with Uniaxial Magnetic Anisotropy. PMID- 29431919 TI - Host-induced gene silencing of a regulator of G protein signalling gene (VdRGS1) confers resistance to Verticillium wilt in cotton. AB - Verticillium wilt (VW), caused by soil-borne fungi of the genus Verticillium, is a serious disease affecting a wide range of plants and leading to a constant and major challenge to agriculture worldwide. Cotton (Gossypium hirsutum) is the world's most important natural textile fibre and oil crop. VW of cotton is a highly devastating vascular disease; however, few resistant germplasms have been reported in cotton. An increasing number of studies have shown that RNA interference (RNAi)-based host-induced gene silencing (HIGS) is an effective strategy for improving plant resistance to pathogens by silencing genes essential for the pathogenicity of these pathogens. Here, we have identified and characterized multifunctional regulators of G protein signalling (RGS) in the Verticillium dahliae virulence strain, Vd8. Of eight VdRGS genes, VdRGS1 showed the most significant increase in expression in V. dahliae after treating with the roots of cotton seedlings. Based on the phenotype detection of VdRGS1 deletion and complementation mutants, we found that VdRGS1 played crucial roles in spore production, hyphal development, microsclerotia formation and pathogenicity. Tobacco rattle virus-mediated HIGS in cotton plants silenced VdRGS1 transcripts in invaded V. dahliae strains and enhanced broad-spectrum resistance to cotton VW. Our data demonstrate that VdRGS1 is a conserved and essential gene for V. dahliae virulence. HIGS of VdRGS1 provides effective control against V. dahliae infection and could obtain the durable disease resistance in cotton and in other VW-susceptible host crops by developing the stable transformants. PMID- 29431921 TI - A Bioinspired Multifunctional Heterogeneous Membrane with Ultrahigh Ionic Rectification and Highly Efficient Selective Ionic Gating. PMID- 29431922 TI - What the neighbors say. PMID- 29431923 TI - Open, open, open. PMID- 29431924 TI - Coding and Auditing Vendor Discovery Guide. PMID- 29431925 TI - [Analysis of the rationality of the water schedule in student-athletes of various specializations]. AB - The presented in the article the analysis of water schedule in student-athletes showed a low level of water consumption culture and the irrationality of the actual water schedule. According to the results of the survey revealed that 86.7% of boys-athletes and 67.2% of girls athletes were revealed to fail to keep a certain water schedule; 98.3% student-athletes are in a state of dehydration of the body. There are established correlations between the presence of dehydration of the body and symptoms such as fatigue and decreased performance (correlation coefficient 0.594, p = 0.01), the appearance of dryness in the morning on an empty stomach (correlation coefficient 0.512, p = 0.01). PMID- 29431926 TI - [The study of the frequency of buccal epithelium cells with nuclear in athletes in dependence on the place got in the competition]. AB - Cytogenetic homeostasis ofathletes involved in hand-to-hand armyfighting, depending on the outcome of the fight and the level of aggressiveness has been studied. Status of the genetic apparatus in athletes was evaluated in buccal epithelium with the use of micronucleus test, which is widely usedfor the determination of the influence of various factors on the genetic stability of the organism. Psychological testing of athletes was executed with the use of Spielberger's State-Trait Anger Expression Inventory scale, Bass-Darky questionnaire for the diagnostics of aggression and hostile reactions, Eysenck Personality Questionnaire test for the evaluation ofpsychic conditions and method of U.P. Ilyin and P.A. Kovalev for the identification of the propensity to conflictness and aggressiveness (positive and negative) as the personal characteristics. The place taken by the athlete on the competition was shown to have an impact on the frequency of buccal epithelium cells with nuclear abnormalities (micronuclei, perinuclear vacuoles, notches, protrusions "tongue" and "broken egg"). Losers have nuclear aberrations more than winners. At that in athletes with higher aggressiveness and its attendant psychological characteristics the influence of the outcome of the competition on the number of cells with aberrations core is more pronounced. PMID- 29431927 TI - [About unification of indices of the possibility of disease occurrence in risk assessment methodology and the determination of the probability of non carcinogenic effects in toxicological-hygienic, clinical and epidemiological studies and according to data about health-seeking behavior]. AB - In the methodology for the assessment of the risk the possibility of the disease occurrence under the impact of carcinogenic and non-carcinogenic substances is measured by different indices. This leads to the fact that within the single methodology there are used various scores for such similar index as the risk of the disease occurrence, as a result carcinogens and systemic toxicants happen to be inconsistent from this point of view. At the same time, unlike carcinogens risk indices for systemic toxicants do not allow to evaluate the number of possible diseases in the population during the corresponding period of time, because they contain no information about their probability. Obviously, from this point of view, the characteristics of carcinogenic risk have certain advantages. Therefore, noncarcinogenic risk should be assessed by the similar indices as carcinogenic ones. However, an obstacle to this is the fact that in toxicological hygienic, clinical and epidemiological studies, according to the results of which there is determined the risk for systemic toxicants, the impact of non-lethal levels of the exposure is established not in separate individuals, as for carcinogens, but according to mean-group values of indices of the state of the body as the identification of the nonspecific effect under relatively non high doses (concentrations) in the single person is fairly difficult. Such data do not allow to estimate the probability of the break of the effect. Also the data concerning seeking for the medical help, considering repeated medical resource utilization due to protract diseases or afflictions occurring repeatedly in a person several times for the considered period of time fail to be the estimation of the probability for the disease occurrence. For the obtaining of the possibility of unification of the carcinogenic and non-carcinogenic indices of risk in the paper there are presented methods for the determination of the probability of non-carcinogenic effects in toxicological-hygienic, clinical and epidemiological studies, as well as according to statistical data on the seeking for the medical help, taking into account the repeated appeals of the protract or re-emerging diseases. PMID- 29431928 TI - Reduce BA Risk Through Due Diligence and Documentation. PMID- 29431929 TI - [Evaluation of occupational risk for health of operators of petrochemical production and their physiological and hygienic stipulation]. AB - The modernization of the technological process in the petrochemical industry has reduced the degree of influence of adverse factors of the production environment, but not eliminated the adverse impact of industrial environmental factors on the health ofworkers. Factors failed to meet hygienic standards in the workplace of operators were shown to be are electromagnetic radiation, chemicals (ammonium, nitrogen dioxide), industrial lighting. In addition operators ' work is characterized by high intensity of the labor process. Therewithal the labor of operators is characterized by the high intensity of the working process. For the operators ofpetroleum industry there is typical the risk from the combined exposure of the complex of chemical substances and noise, this risk proves both to be both potentially dangerous and increase in dependence on doses offactors and length of service. The level of individual professional risk in 32% of the operators is high; risk group for the profession is defined as high. In most cases, in operators of both small and long experience there was established the decline in the functional state of the central nervous system, the predominance of sympathetic tone in the regulation of adaptive processes, reduced reactivity of the autonomic nervous system and the more the length of service among operators the more the number of cases with poor adaptation and its breakdown. PMID- 29431930 TI - Transitioning to a Data-Driven, Informatics-Oriented Department. PMID- 29431931 TI - Addressing Data, Information, and Record Quality Challenges Through Standards. PMID- 29431932 TI - [Hygienic regulation of neonicotinoids derivative in the soil]. AB - For the assurance of the safe regulations for the use in agriculture persistent in soil insecticide neonicotinoids derivative, studies have been executed to investigate its impact on the soil microbiocenosis and migration to the neighboring environment of the active ingredient of this pesticide and the preparation based on it. On the ground of obtained experimental data there were determined threshold doses for the following indices of the harmfulness: migration-water, translocation (transmission into plants) and general sanitary indices. There were established limiting indices of the harmfulness: translocation and migration-water indices. The maximum permissible concentration (MPC) of neonicotinoids derivative in the soil accounted for 0.5 mg/kg of the soil. This content of the pesticide in the soil prevents its accumulation in plants in concentrations exceeding the maximum permissible levels (MPLs), in food products, it fails both to give rise in its transition in groundwater above the MPL for water reservoirs and influence on the soil microbiocenosis and self purification processes. PMID- 29431933 TI - [Quantitative spatio-temporal assessment of pollutants in atmospheric air in the combustion of the fuel of road transport]. AB - In the paper there are presented results of the study of the number of compounds of metals and polycyclic aromatic hydrocarbons (PAH) emitted into the environment with exhaust gases of road transport. In the composition of the exhaust gases 11000 tons of heavy metal compounds and 49.8 tons of highly toxic of PAHs in the soil were established to annually be emitted into the ambient air of St. Petersburg. There was justified the application of the method of the emission inventory of pollutants into the atmosphere from the combustion of the fuel of vehicles. There was established the quantity of PAH and metals emitted to the environment in dependence on the intensity of the traffic flow. The implementation of results of the study will allow to improve the quality of the sanitary and epidemiological surveillance in the territories of the cities with the developed road transport industry. PMID- 29431934 TI - [Modern problems of maintenance of hygienic safety of drinking water consumption at the regional level]. AB - Problems of hygienic reliability of the drinking water use in regions of the Russian Federation are observed in the article. The optimization of the water use was shown must be based on the bearing in mind of regional peculiarities of the shaping of water quality of groundwater and surface sources of the water use, taking into account of the effectiveness of regional water protection programs, programs for water treatment, coordination of the activity of economic entities and oversight bodies in the management of water quality on the basis of socio hygienic monitoring. Regional problems requiring hygienic justification and accounting, include such issues as complex hydrological, hydrogeological, climatic and geographical conditions, pronouncement of the severity of anthropogenic pollution of sources of water supply, natural conditions of the shaping of water quality, efficiency of the water treatment. There is need in the improvement of the problems of the water quality monitoring, including with the use of computer technology, which allows to realize regional hygienic monitoring and spatial-temporal analysis of the water quality, to model the water quality management, to predict conditions of the water use by population in regions taking into account peculiarities of the current health situation. In the article there is shown the practicability of the so-called complex concept of multiple barriers suggesting the combined use of chemical oxidation and physical methods of the preparation of drinking water. It is required the further development of legislation for the protection of water bodies from pollution with the bigging up the status of sanitary protection zones; timely revision of the regulatory framework, establishing sanitary-epidemiological requirements to potable water and drinking water supply. The problem of the provision of the population with safe drinking water requires complex solution within the framework of the implementation of target programs adopted at the Federal and regional levels. PMID- 29431935 TI - The Information Governance Road Map: Approaching Mile Marker 4. PMID- 29431936 TI - [The possibility of provision of hygienically safe residing for the population in residential construction located closely to air transport enterprises]. AB - Operation of the modern heavy aircraft on the surrounding vast territory is associated with the appearance of high levels of sound pressure generated by the powerful engines, especially during takeoff and landing operations. Currently, the elimination or significant reduction of noise pollution on the environment technically does not yet have a radical solution and the possible reduction of the impact ofnoise pollution on the residents ofnearby settlements is achievedfor residents of building by the optimal location of the runway, changing in conditions for the takeoff and landing of aircrafts, the ordering of the regimen of the airport, the introduction of the package sufficiently effective anti-noise diverse - engineering, planning activities, in some cases, the creation ofprotective noise shield on the border of the residential area and the construction ofprotective awnings over the children's and sports fields with fencing shields converted in the direction of the runway. An example of a positive decision, taking into account the complexity and variety of aspects of the problem, it is possible to consider the development of the project plan of the new microdistrict "Eletsky" in the Soviet district of the city of Lipetsk, falling under the impact of aircraft noise of plying aircrafts of the military airfield. PMID- 29431937 TI - [Development of social and hygienic monitoring at the regional level]. AB - The system of the environment and health monitoring system has been introduced into the work of the State Sanitary and Epidemiological Service of the Lipetsk region in 1995. During this period, there was created a database for the collection of regional information on the quality and safety of the environment and public health. Methodology of the analysis is based on an assessment of the habitat on the total rank sanitary and hygiene index of the risk assessment to public health. The established relationships between adverse impacts of environmental factors on health are supported by statistical methods and are visualized in the form of cartograms. The results of multivariate analysis of the environment and the state of public health are summarized in the annual reports and 4 atlases "Sanitary-epidemiological situation in the Lipetsk region" being a good tool for the coordination of managerial decision-making basis for the development of legislative, administrative and regulatory guidance documents on public health. In recent years, in the region there are noted stable trends in the improvement of the quality of the environment, the health of the population and the demographic situation. PMID- 29431938 TI - Best Practices for Patient Matching at Patient Registration. PMID- 29431939 TI - Auditing ICD-10 Through the Lens of Education. PMID- 29431940 TI - [Hygienic analysis of factors affecting of the occurrence of sleep disorders prevalence rate]. AB - Aim: To evaluate the prevalence rate of sleep disorders in various age and professional groups of the population - residents of different regions of Russia and to estimate the relative role of environmental, work-related and life style factors in their progression. Materials and Methods: 6 groups of the population including more than 2500 adults and children - residents of areas with various levels of environmental pollution were examined with the use of the structured questionnaire. Working conditions of state employees and health care professionals were examined. Statistical analysis including the calculation of odds ratios for sleep disorders was performed Results: Disorders of the sleep maintenance among adults were found in 49% of men and 51% of women in Moscow; 49.3% of men and 26.7% of women in Voronezh. Air pollution and noise levels increased risks of insomnia by 10% and 20% respectively. In the city of Serpukhov (the Moscow Region) 78.7% of girls and 94.1% of boys estimated their sleep as deep and sound; in the Great Novgorod so did 69.2% girls and 66.0% boys. A trend (R=0.97) for the increasing of the prevalence rate of insomnia symptoms among children with the age was revealed. In working populations there was shown the positive correlation between the prevalence rate of sleep disorders and job environment, hardness of the work (r=0.28) and work-related stress (odds ratio = 1.8). Conclusion: Harmful environmental factors, life style, hardness of the work and work related stress are independent risk factors of chronic insomnia. PMID- 29431941 TI - [Model of the assessment of the risk of conditions of the work with the use of pesticides: results and development]. AB - There is implemented the development of the model of assessment of the risk from working conditions/ This model allows to solve the problem of the safe use of pesticides in agricultural production of the Russian Federation. The importance of the parallel assessment of the risk for the specific factor of the external exposure to operators (SF ex.) and absorbed dose (SF int.) is presented. Studies of more than 500 pesticides have shown the following correlation of the SF ex. and SF int.: in 8.3-37.5% cases SF ex. and SF int. were practically equal, in 44.8-85.7% cases SF ex. was higher up to by 10 times and in 8.3-26.3% cases SF int. is higher up to by 30 times. Introduction of the new evaluation criterion SF int. increases reliability of the risk assessment. PMID- 29431942 TI - [Risk-oriented model of the control of the level of electric magnetic fields of base stations of cellular communications]. AB - The purpose of this study was to give the description of harmful effects of the impact of electromagnetic radiations from base stations of cellular communication as the most common sources of radio frequencies of electromagnetic fields in the environment. The highest values of the energy flux density were measured on the roofs of houses where antennas are installed - more than 10 pW/cm. The lowest values were recorded in inside premises with expositions of 0.1-1 pW/cm. In the close location of the railway station to the base stations of the cellular communication there was seen a cumulative effect. There are proposed both new safe hygienic approaches to the control for the safety of the work of base station and protective measures. PMID- 29431943 TI - [Modern approaches to carrying out preventive examinations of workers of vibration-dangerous occupations]. AB - The article presents scientific evidence showing the relevance and importance of addressing the issues of improvement of methods and approaches to the implementation of routine inspections of the working population, particularly the workers of vibration-dangerous occupations; the studied interrelationships between the exposure dose of vibration and noise will allow to include these investigations in a program of regular medical examinations of employees to detect early changes in the body of workers exposed to the vibration-dangerous impact. PMID- 29431944 TI - [Responsiveness of peripheral blood neutrophils under exposure to industrial aerosols]. AB - There was made an evaluation of the functional state of peripheral blood neutrophils in 230 workers with dustbreathing risks (mine, metallurgical and machine-building works). There was noted the change in the responsiveness of neutrophils in dependence on both composition and the intensity of the exposure of industrial aerosols to the human body. There was followed the relation between the pathology of the respiratory system with the biochemical changes of granulocytes. These data can be used for the assessment of the nonspecific body resistance in the development of dust lung diseases. PMID- 29431945 TI - [Toxicological-hygienic justification of the acceptable daily intake of acetamiprid]. AB - Neonicotinoids are currently meaningful component of rotation schemes of insecticides of selective action in the system of integrated pest control, which have agricultural importance in many countries. The research results of the biological impact of acetamiprid (neonicotinoids) on the body of laboratory animals are given in the article. The study showed that the explored active substance is related to the moderately hazardous compounds (hazard category 3) in case of one-time per oral penetration. Acetamiprid has polytropic action in the case of chronic (12 months) oral entering the body of laboratory animals, it gives rise changes in functionality of the central nervous system, blood system, liver functioning. On the base of alterations of the studied indices there were established both the no-effect dose level (NOEL) and acceptable daily intake of acetamiprid for humans. PMID- 29431946 TI - [Features of immune response in chronic exposure to industrial aerosols]. AB - There are considered features of disorders of the immune response in chronic exposure to dust aerosols. The detected changes of indices of the immune status of employees of the dust dangerous occupations and patients with chronic dust pathology of the lungs were unidirectional in the character, which is probably caused by manifestations of nonspecific response of the immune system to the dust factor. The deterioration of cellular immunity, humoral immunity and cytokine profile predisposes to the occurrence of immunopathologic states, contributing to the development of caused by both worksite and occupation pathology. PMID- 29431947 TI - [Choice of informative laboratory biomarkers for the early identification of changes in neurohumoral regulation and carbohydrate exchange in workers of the mining and mechanical engineering industry]. AB - The diagnostic significance of hormones and integral indices of pituitary adrenal, pituitary-thyroid and pituitary-gonadal system and carbohydrate metabolism (ACTH (corticotropin), aldosterone, cortisol, TSH (thyroid-stimulating hormone), free triiodothyronine (fT3), free thyroxine (fT4), luteinizing hormone (LH), follicle-stimulating hormone (FSH), total and free testosterone, insulin, integral pituitary-adrenal index (IPAI), the pituitary-thyroid index (PTI), indices of carbohydrate metabolism (Caro and HOMA-IR) was studied for the early diagnostics of disorders of neurohumoral regulation in workers of mining and mechanical engineering industries. The most informative indices, permitting to identify disorders of carbohydrate metabolism are established to be indices of insulin resistance (index Caro and index NOMA-IR) and the determination of insulin in serum. For the identification of changes in pituitary adrenal, pituitary-thyroid and pituitary-gonadal system in patients with vibration disease, sensory-neural hearing loss, comorbidity indexes IGNI, ITI, concentrations of LH and total testosterone are of the most diagnostically significance. PMID- 29431948 TI - [Hygienic assessment of working conditions and health of the workers of mining and processing enterprises]. AB - In the article there are presented results of studies on the hygienic assessment of working conditions and health status of 1200 workers of mining and processing enterprises (MPE) developing deposits of iron ores of the Kursk Magnetic Anomaly: Lebedinskiy MPE, Mikhaylovskiy MPE, Stoylenskiy MPE. There were revealed the differences in the character and intensity of adverse occupational factors, there was made the quantitation of the occupational risk level to the health workers of MPE both factories and quarries. The structure of occupational diseases in MPE factories is formed by dust lung diseases and the occupational pathology of the organ of hearing. In the structure of professional pathology in quarries workers vibration disease (61.5%) prevails. The obtained results indicate to the need of the development of the system of measures for the reduction in general and occupational morbidity rate of workers, the creation of safe working conditions, improving the early diagnosis of occupational and common diseases at the stage of preliminary and periodic medical examinations. PMID- 29431949 TI - [Retrospective analysis of primary disability among employees of enterprises for the production of technical ceramics]. AB - On the example of588 disability cases registered in employees of the plant for the production of technical ceramics during the 1975-2014 the analysis of the dynamics of illness, gender and age structure of disability indices on the main Origlnarartlcie and auxiliary units of the enterprise was executed for the interval of 10 years periods. There were followed trends in the alteration of the structure of the disability caused by the socio-economic, hygienic and demographic factors. PMID- 29431950 TI - In brief: Severe hypersensitivity reactions with rolapitant IV emulsion (Varubi). PMID- 29431968 TI - Back to the Basics on ICD-10-PCS Spinal Fusion Coding. PMID- 29431967 TI - [Hygienic aspects of the occurrence of ecology-dependent diseases in children and adolescents of the Primorsky Krai]. AB - With the use of the methodology of the system approach there were obtained results of the evaluation of the occurrence of ecology-dependent diseases in children and adolescents in bioclimatic zones of the Primorsky Krai. Analysis of the prevalence of the main classes of ecologically dependent diseases according to the appealability (diseases of the respiratory system, diseases of digestive organs, diseases of blood and blood-forming organs, diseases of the circulatory system, diseases of the skin and subcutaneous tissue, diseases of the genitourinary system, neoplasms, congenital anomalies, infectious diseases) was performed with the use of official statistical report forms No. 12 (ICD-10) over the period of2000-2014. Informational Database of parameters of the environment was represented by the factor modules: 6 - sanitary, and 5-environmental ones). By means of the method of the regression analysis there was established the relationship between environmental factors and the prevalence of ecological dependent diseases, there were calculated values of the factor loads influencing on the indices of the morbidity rate in children and adolescents. The analysis of morbidity according to classes showed that during the study period, in the total there was a gain in the indicator ecologically dependent morbidity rate in children by 33.3%, in adolescents - by 35.3%. In the children and adolescent population there are prevalent diseases of the respiratory system - 67.3% and 52.45%, respectively; further in children and adolescent groups diseases of the digestive system - 9.45% and 17.08% take place; then in the children cohort are infectious diseases, and in adolescents - diseases of the genitourinary system. The level of ecologically dependent morbidity rate is determined by the complex impact of environmental and hygienic factors, with a predominance of sanitary hygienic component and related with it parameters of the environment of habitation, such as chemical pollution of urban areas (soil, air, water sources), nevertheless biotropic factors (temperature, humidity, fog, number of days with biologically active solar radiation) make a significant contribution. The revealed various degree of the response of children and adolescents through the prevalence rate level to the exposure of ecological and hygienic factors of environment should be taken into account in the development and carrying out medical-preventive measures. PMID- 29431969 TI - Study: Gender Pay Gap Evident in Health IT Industry. PMID- 29431970 TI - Effectiveness of ACL Injury Prevention Programs. PMID- 29431971 TI - Cancer Screening Recommendations from the ACS: A Summary of the 2017 Guidelines. PMID- 29431972 TI - Beta Blockers Compared with Other Drug Options for the Treatment of Hypertension. PMID- 29431973 TI - OnabotulinumtoxinA Injections for Urge Incontinence. PMID- 29431974 TI - Childhood Bullying: Implications for Physicians. AB - Childhood bullying is common and can lead to serious adverse physical and mental health effects for both the victim and the bully. In teenagers, risk factors for becoming a victim of bullying include being lesbian, gay, bisexual, or transgender; having a disability or medical condition such as asthma, diabetes mellitus, a skin condition, or food allergy; or being an outlier in weight and stature. An estimated 20% of youth have been bullied on school property, and 16% have been bullied electronically in the past year. Bullying can result in emotional distress, depression, anxiety, social isolation, low self-esteem, school avoidance/refusal, and substance abuse for the victim and the bully. Preventive measures include encouraging patients to find enjoyable activities that promote confidence and self-esteem, modeling how to treat others with kindness and respect, and encouraging patients to seek positive friendships. For those who feel concern or guilt about sharing their experiences, it may be useful to explain that revealing the bullying may not only help end the cycle for them but for others as well. Once bullying has been identified, family physicians have an important role in screening for its harmful effects, such as depression and anxiety. A comprehensive, multitiered approach involving families, schools, and community resources can help combat bullying. Family physicians are integral in recognizing children and adolescents who are affected by bullying-as victims, bullies, or bully- victims-so they can benefit from the intervention process. PMID- 29431975 TI - Clostridium difficile Infection: Prevention and Treatment. PMID- 29431976 TI - Correction. PMID- 29431977 TI - Hemorrhoids: Diagnosis and Treatment Options. AB - Many Americans between 45 and 65 years of age experience hemorrhoids. Hemorrhoidal size, thrombosis, and location (i.e., proximal or distal to the dentate line) determine the extent of pain or discomfort. The history and physical examination must assess for risk factors and clinical signs indicating more concerning disease processes. Internal hemorrhoids are traditionally graded from I to IV based on the extent of prolapse. Other factors such as degree of discomfort, bleeding, comorbidities, and patient preference should help determine the order in which treatments are pursued. Medical management (e.g., stool softeners, topical over-the-counter preparations, topical nitroglycerine), dietary modifications (e.g., increased fiber and water intake), and behavioral therapies (sitz baths) are the mainstays of initial therapy. If these are unsuccessful, office-based treatment of grades I to III internal hemorrhoids with rubber band ligation is the preferred next step because it has a lower failure rate than infrared photocoagulation. Open or closed (conventional) excisional hemorrhoidectomy leads to greater surgical success rates but also incurs more pain and a prolonged recovery than office-based procedures; therefore, hemorrhoidectomy should be reserved for recurrent or higher-grade disease. Closed hemorrhoidectomy with diathermic or ultrasonic cutting devices may decrease bleeding and pain. Stapled hemorrhoidopexy elevates grade III or IV hemorrhoids to their normal anatomic position by removing a band of proximal mucosal tissue; however, this procedure has several potential postoperative complications. Hemorrhoidal artery ligation may be useful in grade II or III hemorrhoids because patients may experience less pain and recover more quickly. Excision of thrombosed external hemorrhoids can greatly reduce pain if performed within the first two to three days of symptoms. PMID- 29431978 TI - Introducing AFP's Next Editor-in-Chief. PMID- 29431980 TI - Opioids for Acute Pain: Proceed with Caution. PMID- 29431981 TI - Injected Corticosteroids for Plantar Heel Pain. PMID- 29431982 TI - Diffuse Thick Scale on Both Hands. PMID- 29431983 TI - Effectiveness of Skin-to-Skin Care for Procedure-Related Pain in Newborns. PMID- 29431984 TI - AFP: What's Ahead. PMID- 29431985 TI - Tremor: Sorting Through the Differential Diagnosis. AB - Tremor is an involuntary, rhythmic, oscillatory movement of a body part. It is the most common movement disorder encountered in primary care. The diagnosis of tremor is based on clinical information obtained from the history and physical examination. The most common tremors in patients presenting to primary care physicians are enhanced physiologic tremor, essential tremor, and parkinsonian tremor. All persons have low-amplitude, high-frequency physiologic tremors at rest and during action that are not reported as symptomatic, but can be enhanced by anxiety, medication use, caffeine intake, or fatigue. Features consistent with psychogenic tremor are abrupt onset, spontaneous remission, changing tremor characteristics, and extinction with distraction. Other types of tremor include cerebellar, dystonic, and drug- or metabolic-induced. The first step in evaluating a patient with tremor is to categorize the tremor based on its activation condition, topographic distribution, and frequency. Resting tremors occur in a body part that is relaxed and completely supported against gravity. Action tremors occur with voluntary contraction of a muscle and can be further subdivided into postural, isometric, and kinetic tremors. The most common pathologic tremor is essential tremor, which affects 0.4% to 6% of the population. In one-half of cases, it is transmitted in an autosomal-dominant fashion. More than 70% of patients with Parkinson disease have tremor as the presenting feature. This tremor is typically unilateral, occurs at rest, and becomes less prominent with voluntary movement. If there is diagnostic uncertainty, single-photon emission computed tomography can be used to visualize the integrity of the dopaminergic pathways in the brain, and transcranial ultrasonography may be useful to diagnose Parkinson disease. PMID- 29431986 TI - Evidence Poses a Challenge to Imaging Standards in the Diagnosis of Pneumonia. PMID- 29431987 TI - Solid-Phase Synthesis and Antibacterial Activity of Cyclohexapeptide Wollamide B Analogs. AB - Herein we report the antibacterial structure-activity relationships of cyclic hexapeptide wollamide analogs derived from solid-phase library synthesis. Wollamide B, a cyclic hexapeptide natural product, has been previously found to have activity against Mycobacterium bovis. To further evaluate its antimycobacterial/antibacterial potential, 27 peptides including wollamides A/B, and desotamide B, were synthesized and subsequently tested against a panel of clinically significant bacterial pathogens. Biological evaluation revealed that the cyclic scaffold, amide functionality in position I, tryptophan residue in position V, and the original stereochemistry pattern of the core scaffold were key for antituberculosis and/or antibacterial activity. In addition, against M. tuberculosis and Gram-positive bacteria, residues in position II and/or VI greatly impacted antibacterial activity and selectivity. Wollamides A (3) and B (2) along with their corresponding II (l-Leu) analog 10 retained the most promising antituberculosis activity, with the lowest minimum inhibitory concentration (MIC) against virulent M. tuberculosis H37Rv (MIC = 1.56 MUg/mL), as well as desirable selectivity indices (>100). Importantly, the antimicrobial activities of wollamides A and B do not result from disruption of the bacterial membrane, warranting further investigation into their mechanism of action. PMID- 29431988 TI - Correction to Oral Nanomedicine Based on Multicomponent Microemulsions for Drug Resistant Breast Cancer Treatment. PMID- 29431989 TI - Folate-Conjugated Polyphosphoester with Reversible Cross-Linkage and Reduction Sensitivity for Drug Delivery. AB - To improve the therapeutic efficacy and circulation stability in vivo, we synthesized a new kind of drug delivery carrier based on folic acid conjugated polyphosphoester via the combined reactions of Michael addition polymerization and esterification. The produced amphiphilic polymer, abbreviated as P(EAEP-AP) LA-FA, could self-assemble into nanoparticles (NPs) with core-shell structure in water and reversible core cross-linked by lipoyl groups. Using the core cross linked FA-conjugated nanoparticles (CCL-FA NPs) to encapsulate hydrophobic anticancer drug doxorubicin (DOX), we studied the stability of NPs, in vitro drug release, cellular uptake, and targeting intracellular release compared with both un-cross-linked FA-conjugated nanoparticles (UCL-FA NPs) and core cross-linked nanoparticles without FA conjugation (CCL NPs). The results showed that under the condition of pH 7.4, the DOX-loaded CCL-FA NPs could maintain stable over 72 h, and only a little DOX release (~15%) was observed. However, under the reductive condition (pH 7.4 containing 10 mM GSH), the disulfide-cross-linked core would be broken up and resulted in 90% of DOX release at the same incubation period. The study of methyl thiazolyl tetrazolium (MTT) assay indicated that the DOX-loaded CCL-FA NPs exhibited higher cytotoxicity (IC50: 0.33 mg L-1) against HeLa cells than the DOX-loaded CCL NPs without FA. These results indicate that the core cross-linked FA-conjugated nanoparticles have unique stability and targetability. PMID- 29431990 TI - Bioorthogonally Applicable Fluorogenic Cyanine-Tetrazines for No-Wash Super Resolution Imaging. AB - The synthesis, fluorogenic characterization, and labeling application of four tetrazine-quenched cyanine probes with emission maxima in the red-far red range is reported. Fluorescence of the cyanine-cores is quenched via through-bond energy-transfer (TBET) exerted by a bioorthogonal tetrazine unit. Upon bioorthogonal labeling reaction with cyclooctyne tagged proteins, the quenching effect ceases, and thus the fluorescence reinstates, resulting in an increase in fluorescence intensity. As a rare example among indocyanines, one of our new probes was found suitable in STED-based super-resolution imaging. The applicability of this fluorogenic Tet-Cy3 probe was therefore further demonstrated in the bioorthogonal labeling of cytoskeletal protein, actin, with subsequent super-resolution microscopy (STED) imaging even under no-wash conditions. PMID- 29431991 TI - Selective Adsorption of Ethane over Ethylene in PCN-245: Impacts of Interpenetrated Adsorbent. AB - The separation of ethane from ethylene using cryogenic distillation is an energy intensive process in the industry. With lower energetic consumption, the adsorption technology provides the opportunities for developing the industry with economic sustainability. We report an iron-based metal-organic framework PCN-245 with interpenetrated structures as an ethane-selective adsorbent for ethylene/ethane separation. The material maintains stability up to 625 K, even after exposure to 80% humid atmosphere for 20 days. Adsorptive separation experiments on PCN-245 at 100 kPa and 298 K indicated that ethane and ethylene uptakes of PCN-245 were 3.27 and 2.39 mmol, respectively, and the selectivity of ethane over ethylene was up to 1.9. Metropolis Monte Carlo calculations suggested that the interpenetrated structure of PCN-245 created greater interaction affinity for ethane than ethylene through the crossing organic linkers, which is consistent with the experimental results. This work highlights the potential application of adsorbents with the interpenetrated structure for ethane separation from ethylene. PMID- 29431992 TI - Effect of Surface Modification on Water Adsorption and Interfacial Mechanics of Cellulose Nanocrystals. AB - With increasing environmental concerns about petrochemical-based materials, the development of high-performance polymer nanocomposites with sustainable filler phases has attracted significant attention. Cellulose nanocrystals (CNCs) are promising nanocomposite reinforcing agents due to their exceptional mechanical properties, low weight, and bioavailability. However, there are still numerous obstacles that prevent these materials from achieving optimal performance, including high water adsorption, poor nanoparticle dispersion, and filler properties that vary in response to moisture. Surface modification is an effective method to mitigate these shortcomings. We use computational approaches to obtain direct insight into the water adsorption and interfacial mechanics of modified CNC surfaces. Atomistic grand-canonical Monte Carlo simulations demonstrate how surface modification of sulfated Na-CNCs impacts water adsorption. We find that methyl(triphenyl)phosphonium (MePh3P+)-exchanged CNCs have lower water uptake than Na-CNCs, supporting experimental dynamic vapor sorption measurements. The adsorbed water molecules show orientational ordering when distributed around the cations. Steered molecular dynamics simulations quantify traction-separation behavior of CNC-CNC interfaces. We find that exchanging sodium for MePh3P+ effectively changes the surface hydrophilicity, which in turn directly impacts interfacial adhesion and traction-separation behavior. Our analysis provides guidelines for controlling moisture effects in cellulose nanocomposites and nanocellulose films through surface modifications. PMID- 29431993 TI - Synthesis and Characterization of Structurally Diverse Alkaline-Earth Salen Compounds for Subterranean Fluid Flow Tracking. AB - A family of magnesium and calcium salen-derivatives was synthesized and characterized for use as subterranean fluid flow monitors. For the Mg complexes, di- n-butyl magnesium ([Mg(Bu n)2]) was reacted with N, N'-ethylene bis(salicylideneimine) (H2-salen), N, N'-bis(salicylidene)-1,2-phenylenediamine (H2-saloPh), N, N'-bis(3,5-di- t-butylsalicylidene)-ethylenediamine (H2-salo-Bu t), or N, N'-bis(3,5-di- t-butylsalicylidene)-1,2-phenylenediamine (H2-saloPh-Bu t), and the products were identified by single-crystal X-ray diffraction as [(kappa3-(O,N,N'),MU-(O')saloPh)(MU-(O),(kappa2-(N,N'),MU-(O')saloPh)2(MU (O),kappa3-(N,N',O')saloPh')Mg4].2tol (1.2tol; saloPh' = an alkyl-modified saloPh derivative generated in situ), [(kappa4-(O,N,N',O')saloPh)Mg(py)2].py (2.py), [(kappa4-(O,N,N',O')salo-Bu t)Mg(py)2] (3), [(kappa4-(O,N,N',O')saloPh-Bu t)Mg(py)2].tol (4.tol), and [(kappa3-(O,N,N'),MU-(O')saloPh-Bu t)Mg]2 (5), where tol = toluene; py = pyridine. For the Ca species, a calcium amide was independently reacted with H2-salo-Bu t and H2-saloPh-Bu t to generate the crystallographcially characterized compounds: [(kappa4-(O,N,N',O')salo-Bu t)Ca(py)3] (6), [(kappa4-(O,N,N',O')saloPh-Bu t)Ca(py)3].py (7.py). The bulk powders of these compounds were further characterized by a number of analytical tools, where 2-7 were found to be distinguishable by Fourier transform infrared and resonance Raman spectroscopies. Structural properties obtained from quantum calculations of gas-phase analogues are in good agreement with the single-crystal results. The potential utility of these compounds as taggants for monitoring subterranean fluid flows was demonstrated through a series of experiments to evaluate their stability to high temperature and pressure, interaction with mineral surfaces, and elution behavior from a loaded proppant pack. PMID- 29431994 TI - Transformations of Phosphorus Speciation during (Hydro)thermal Treatments of Animal Manures. AB - Phosphorus (P) in animal manures is an important P pool for P recycling and reclamation. In recent years, thermochemical techniques have gained much interests for effective waste treatment and P recycling. This study comparatively characterized the transformation of P during two representative thermochemical treatments (pyrolysis and hydrothermal carbonization, HTC) of four animal manures (swine, chicken, beef, and dairy manures) by combining nuclear magnetic resonance spectroscopy, X-ray absorption spectroscopy, and sequential extraction. For both pyrolysis and HTC treatments, degradation of organic phosphate and crystallization of Ca phosphate minerals were observed and were highly dependent on treatment temperature. Extensive crystallization of Ca phosphate minerals occurred at temperatures above 450 degrees C during pyrolysis, compared to the lower temperature (175 and 225 degrees C) requirements during HTC. As a result, P was immobilized in the hydrochars and high temperature pyrochars, and was extracted primarily by HCl. Because Ca is the dominating P-complexing cation in all four manures, all manures showed similar P speciation and transformation behaviors during the treatments. Results from this work provided deeper insights into the thermochemical processes occurred during the pyrolysis and HTC treatments of biological wastes, as well as guidance for P reclamation and recycling from these wastes. PMID- 29431995 TI - Complement Activation by PEGylated Gold Nanoparticles. AB - Gold nanoparticles (AuNPs) are widely used in biomedical applications, but much less is known about their immunological properties, particularly their interaction with the complement system, a key component of innate immunity serving as an indicator of their biocompatibility. Using a library of different sized AuNPs (10, 20, 40, and 80 nm) passivated with polyethylene glycol (PEG) of different molecular weight ( Mw = 1, 2, 5, and 10 kDa), we demonstrated that citrate-capped AuNPs activated the whole complement system in a size-dependent manner, characterized by the formation of the end-point activation product, SC5b 9, in human serum. Although PEGylation of AuNPs mitigated, but did not abolish, the activation level, complement activation by PEGylated AuNPs was independent of both the core size of AuNPs and the molecular weight of PEG. The cellular uptake of both citrate-capped and PEGylated AuNPs by human U937 promonocytic cells which expresses complement receptors were highly correlated to the level of complement activation. Taken together, our results provided new insights on the innate complement activation by PEGylated AuNPs that are widely considered to be inert biocompatible nanomaterials. PMID- 29431996 TI - Combining the Transcorrelated Method with Full Configuration Interaction Quantum Monte Carlo: Application to the Homogeneous Electron Gas. AB - We suggest an efficient method to resolve electronic cusps in electronic structure calculations through the use of an effective transcorrelated Hamiltonian. This effective Hamiltonian takes a simple form for plane wave bases, containing up to two-body operators only, and its use incurs almost no additional computational overhead compared to that of the original Hamiltonian. We apply this method in combination with the full configuration interaction quantum Monte Carlo (FCIQMC) method to the homogeneous electron gas. As a projection technique, the non-Hermitian nature of the transcorrelated Hamiltonian does not cause complications or numerical difficulties for FCIQMC. The rate of convergence of the total energy to the complete basis set limit is improved from [Formula: see text] to [Formula: see text], where M is the total number of orbital basis functions. PMID- 29431997 TI - Iridium-Catalyzed Intramolecular Asymmetric Allylic Alkylation of Hydroxyquinolines: Simultaneous Weakening of the Aromaticity of Two Consecutive Aromatic Rings. AB - Intramolecular asymmetric allylic alkylation reactions of 5- and 7 hydroxyquinoline derivatives were realized by a chiral Ir/NHC catalyst. A series of functionalized cyclic enones were afforded in excellent yields (up to 99%) and high enantioselectivity (up to 97% ee). Theoretical computations revealed that the aromaticity of the two consecutive rings of hydroxyquinoline substrates is significantly weakened. A highly efficient formal synthesis of (-)-gephyrotoxin was accomplished based on this method. PMID- 29431998 TI - Mechanism and Rate-Determining Factors of Amide Bond Formation through Acyl Transfer of Mixed Carboxylic-Carbamic Anhydrides: A Computational Study. AB - Acyl transfer of in situ-generated mixed anhydrides is an important method for amide bond formation from short linkages with the easily removed byproduct CO2. To improve our understanding of the inherently difficult acyl transfer hindered by the large ring strain, a density functional theory study was performed. The calculations indicate that the amidation of activated alpha-aminoesters and N protected amino acids is more likely to proceed via the self-catalytic nucleophilic substitution of the two substrates and the subsequent 1,3-acyl transfer. By comparison, the mechanism involving 1,5-acyl transfer is less kinetically favored because of the slow homocoupling of activated alpha aminoesters. Furthermore, we found that the detailed mechanism of 1,3-acyl transfer on the mixed carboxylic-carbamic anhydrides depends on the catalysts. Strong acidic catalysts and bifunctional catalysts both lead to stepwise pathways, but their elementary steps are different. Basic catalysts cause a concerted C-N bond formation/decarboxylation pathway. The calculations successfully explain the reported performances of different Bronsted-type catalysts and substrates, which validates the proposed mechanism and reveals the dependence of the reaction rates on the acid-base property of catalysts and the acidity of substrates. PMID- 29431999 TI - Theoretical Insight into the Mechansim and Origin of Ligand-Controlled Regioselectivity in Homogenous Gold-Catalyzed Intramolecular Hydroarylation of Alkynes. AB - This work aims at understanding the mechanism and regioselectivity in ligand controlled gold-catalyzed divergent intramolecular hydroarylation of alkynes reported by Jiang et al. ( J. Am. Chem. Soc. 2016 , 138 , 5218 - 5221 ). Focusing on a representative alkyne, N-propargyl-N-tosylaniline, we conducted a detailed computational study on the ortho- and para-position hydroarylation of the alkyne catalyzed by gold(I) catalysts with different ligands. Both the ortho- and para position hydroarylation reactions are found to follow a similar three-stage mechanism: electrophilic cyclization, proton loss, and protiodeauration. The initial electrophilic cyclization was identified as the rate- and regiochemistry determining step. With the flexible electron-deficient phosphite ligand, the ortho-position cyclization is identified as the energetically more favorable pathway, while with the rigid electron-abundant phosphine (Xphos) ligand, the dominant pathway turns to the para-position cyclization. The theoretical results are in good agreement with the experimental observations. The pi-pi interaction between alkynyl phenyl and the directing acylamino group are found to be mainly responsible for the observed ortho-selectivity, while a combination of favorable noncovalent CH...pi interaction and steric repulsion between Xphos ligand and alkynyl group contributes to the observed exclusive para-selectivity. The present calculations provide deeper insight into the mechanism and origin of regioselectivity of the title reaction. PMID- 29432000 TI - C-H to C-N Cross-Coupling of Sulfonamides with Olefins. AB - Cross-coupling of nitrogen with hydrocarbons under fragment coupling conditions stands to significantly impact chemical synthesis. Herein, we disclose a C(sp3)-N fragment coupling reaction between terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/SOX (sulfoxide-oxazoline) catalyzed intermolecular allylic C-H amination. A range of (56) allylic amines are furnished in good yields (avg. 75%) and excellent regio- and stereoselectivity (avg. >20:1 linear:branched, >20:1 E: Z). Mechanistic studies reveal that the SOX ligand framework is effective at promoting functionalization by supporting cationic pi-allyl Pd. PMID- 29432001 TI - Light-Sensitive Alkoxyamines as Versatile Spatially- and Temporally- Controlled Precursors of Alkyl Radicals and Nitroxides. AB - The use of UV/visible light irradiation as a means to initiate organic syntheses is increasingly attractive due to the high spatial and temporal control conferred by photochemical processes. The aim of this work is thus to demonstrate that alkoxyamines bearing a chromophore on the alkyl moiety can provide a photoprotecting group for the sensitive nitroxide functionality, that is known to degrade through redox processes. The dissociation of various photosensitive alkoxyamines was studied from 223 to 298 K under UV/visible irradiation, depending on the nature of the chromophore. In each case a rapid (typically in less than 1 h) and near-quantitative dissociation was observed. As an illustration of the interest of this approach, a pyrene-based alkoxyamine was employed for the spatially controlled coupling of polymer chains onto Si wafers to produce micropatterned surfaces. PMID- 29432002 TI - Iridium(I)-Catalyzed Alkylation Reactions To Form alpha-Alkylated Ketones. AB - A highly effective and green procedure for the formation of alpha-alkylated ketones has been disclosed via the reaction of primary alcohols with secondary alcohols and ketones by using [IrCl(COD)(NHC)] complexes as a catalyst. Various alpha-alkylated ketones were obtained in high yields from the alkylation of alcohol with alcohol and ketone with alcohol through a borrowing hydrogen reaction by using 0.05-0.5 mol % iridium(I) and a catalytic amount of KOH (5-10 mol %) as the base under air atmosphere and within very short reaction times. PMID- 29432004 TI - Measuring Interfacial Polymerization Kinetics Using Microfluidic Interferometry. AB - A range of academic and industrial fields exploit interfacial polymerization in producing fibers, capsules, and films. Although widely used, measurements of reaction kinetics remain challenging and rarely reported, due to film thinness and reaction rapidity. Here, polyamide film formation is studied using microfluidic interferometry, measuring monomer concentration profiles near the interface during the reaction. Our results reveal that the reaction is initially controlled by a reaction-diffusion boundary layer within the organic phase, which allows the first measurements of the rate constant for this system. PMID- 29432003 TI - Syntheses of Molybdenum Oxo Alkylidene Complexes through Addition of Water to an Alkylidyne Complex. AB - Addition of one equiv of water to Mo(CAr)[OCMe(CF3)2]3(1,2-dimethoxyethane) (2, Ar = o-(OMe)C6H4) in the presence of PPhMe2 leads to formation of Mo(O)(CHAr)[OCMe(CF3)2]2(PPhMe2) (3(PPhMe2)) in 34% yield. Addition of one equiv of water alone to 2 produces the dimeric alkylidyne hydroxide complex, {Mo(CAr)[OCMe(CF3)2]2(MU-OH)}2(dme) (4(dme)) in which each bridging hydroxide proton points toward an oxygen atom in an arylmethoxy group. Addition of PMe3 to 4(dme) gives the alkylidene oxo complex, (3(PMe3)), an analogue of 3(PPhMe2) (95% conversion, 66% isolated). Treatment of 3(PMe3) with two equiv of HCl gave Mo(O)(CHAr)Cl2(PMe3) (5), which upon addition of LiO-2,6-(2,4,6-i-Pr3C6H2)2C6H3 (LiOHIPT) gave Mo(O)(CHAr)(OHIPT)Cl(PMe3) (6). Compound 6 in the presence of B(C6F5)3 will initiate the ring-opening metathesis polymerization of cyclooctene, 5,6-dicarbomethoxynorbornadiene (DCMNBD), and rac-5,6-dicarbomethoxynorbornene (DCMNBE), and the homocoupling of 1-decene to 9-octadecene. The poly(DCMNBD) has a cis,syndiotactic structure, whereas poly(DCMNBE) has a cis,syndiotactic,alt structure. X-ray structures were obtained for 3(PPhMe2), 4(dme), and 6. PMID- 29432005 TI - Several Pesticides Influence the Nutritional Content of Sweet Corn. AB - Herbicides are pesticides used to eradicate unwanted plants in both crop and non crop environments. These chemistries are toxic to weeds due to inhibition of key enzymes or disruption of essential biochemical processes required for weedy plants to survive. Crops can survive systemic herbicidal applications through various forms of detoxification, including metabolism that can be enhanced by safeners. Field studies were conducted near Louisville, Tennessee and Painter, Virginia to determine how the herbicides mesotrione, topramezone, nicosulfuron, and atrazine applied with or without the safener isoxadifen-ethyl would impact the nutritional quality of "Incredible" sweet corn ( Zea mays L. var. rugosa). Several herbicide treatments increased the uptake of the mineral elements phosphorus, magnesium, and manganese by 8-75%. All herbicide treatments increased protein content by 4-12%. Applied alone, nicosulfuron produced similar levels of saturated, monounsaturated, and polyunsaturated fatty acids when compared to the nontreated check, but when applied with isoxadifen-ethyl, fatty acids increased 8 to 44% relative to the check or control. Nicosulfuron plus isoxadifen-ethyl or topramezone or the combination of all three actives increased the concentrations of fructose and glucose (40-68%), whereas reducing levels of maltose or sucrose when compared to the nontreated check (-15 to -21%). Disruptions in biochemical pathways in plants due to the application of herbicides, safeners, or other pesticides have the potential to alter the nutrient quality, taste, and overall plant health associated with edible crops. PMID- 29432007 TI - Functional Role and Hierarchy of the Intermolecular Interactions in Binding of Protein Kinase Clients to the Hsp90-Cdc37 Chaperone: Structure-Based Network Modeling of Allosteric Regulation. AB - A fundamental role of the Hsp90-Cdc37 chaperone machinery in mediating conformational development and activation of diverse protein kinase clients is essential for signal transduction. Structural and biochemical studies have demonstrated that characterization of global conformational changes and allosteric interactions in the Hsp90-Cdc37-kinase complexes are central to our understanding of the mechanisms underlying kinase recruitment and processing by the Hsp90-Cdc37 chaperone. The recent cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex has provided a framework for dissecting regulatory principles underlying differentiation and recruitment of protein kinase clients to the chaperone machinery. In this work, we have characterized functional role and hierarchy of the intermolecular interactions in binding of protein kinase clients to the Hsp90-Cdc37 system. The network analysis revealed important relationships between structural stability, global centrality, and functional significance of regulatory hotspots in chaperone regulation and client recognition. A unique asymmetric topography of the intermolecular communities in the chaperone-kinase complex has quantified a central mediating role of Cdc37 in client recognition and allosteric regulation of the chaperone-kinase complex. Modeling of allosteric pathways in the chaperone complex has further clarified structural and energetic signatures of allosteric hotspots, particularly linking sites of post-translational modifications in Hsp90 with their role in allosteric interactions and client regulation. The results of this integrative computational study are compared with a wide range of structural, biochemical, and cell-based experiments, offering a robust network-centric model of allosteric regulation and client kinase recognition by the Hsp90-Cdc37 chaperone machine. PMID- 29432008 TI - Intermolecular Hydrogen Abstraction from Hydroxy Group and Alkyl by T1(pipi*) of 1-Chloro-4-nitronaphthalene. AB - Nanosecond transient absorption and theoretical calculations have been used to investigate the intermolecular hydrogen abstractions from alcohols and 1-naphthol by the lowest excited triplet (T1) of 1-chloro-4-nitronaphthalene upon excitation of the compound in organic solvents. The hydrogen abstraction of T1 from hydroxy group of 1-naphthol takes place through an electron transfer followed by a proton transfer through hydrogen bonding interaction with rate constants of ~109 M-1 s 1. Hydrogen-bonding is crucial in this process, indicated by the observation of a half reduction for T1 yield when increasing the concentration of 1-naphthol. The hydrogen abstraction in this way can be decelerated by increasing solvent polarity and hydrogen-bonding donor ability. The T1 of 1-chloro-4 nitronaphthalene can undergo one-step H atom abstraction from alkyl hydrogen in alcoholic solvents, with rate constants of ~104 M-1 s-1, and produce radical intermediates with the absorption maximum at 368 nm. DFT calculation results indicate both oxygens of the nitro group are active sites for hydrogen abstraction, and the difference of activation barriers for formation of two radical isomers is only 1.0 kcal/mol. PMID- 29432006 TI - Enantioselective Synthesis of Pyrroloindolines via Noncovalent Stabilization of Indole Radical Cations and Applications to the Synthesis of Alkaloid Natural Products. AB - While interest in the synthetic chemistry of radical cations continues to grow, controlling enantioselectivity in the reactions of these intermediates remains a challenge. Based on recent insights into the oxidation of tryptophan in enzymatic systems, we report a photocatalytic method for the generation of indole radical cations as hydrogen-bonded adducts with chiral phosphate anions. These noncovalent open-shell complexes can be intercepted by the stable nitroxyl radical TEMPO. to form alkoxyamine-substituted pyrroloindolines with high levels of enantioselectivity. Further elaboration of these optically enriched adducts can be achieved via a catalytic single-electron oxidation/mesolytic cleavage sequence to furnish transient carbocation intermediates that may be intercepted by a wide range of nucleophiles. Taken together, this two-step sequence provides a simple catalytic method to access a wide range of substituted pyrroloindolines in enantioenriched form via a standard experimental protocol from a common synthetic intermediate. The design, development, mechanistic study, and scope of this process are presented, as are applications of this method to the synthesis of several dimeric pyrroloindoline natural products. PMID- 29432009 TI - Interfacial Modification for High-Efficiency Vapor-Phase-Deposited Perovskite Solar Cells Based on a Metal Oxide Buffer Layer. AB - Vacuum deposition is one of the most technologically relevant techniques for the fabrication of perovskite solar cells. The most efficient vacuum-based devices rely on doped organic contacts, compromising the long-term stability of the system. Here, we introduce an inorganic electron-transporting material to obtain power conversion efficiencies matching the best performing vacuum-deposited devices, with open-circuit potential close to the thermodynamic limit. We analyze the leakage current reduction and the interfacial recombination improvement upon use of a thin (<10 nm) interlayer of C60, as well as a more favorable band alignment after a bias/ultraviolet light activation process. This work presents an alternative for organic contacts in highly efficient vacuum-deposited perovskite solar cells. PMID- 29432010 TI - Cybastacines A and B: Antibiotic Sesterterpenes from a Nostoc sp. Cyanobacterium. AB - Cybastacines A (1) and B (2) were discovered as a novel pentacyclic sesterterpenoid-alkaloid skeleton structure, with a guanidinium group. These molecules were isolated from a Nostoc sp. cyanobacterium collected in the Canary Islands. Their structures were elucidated primarily by a combination of spectroscopic analyses and X-ray diffraction. These compounds showed antibiotic activities against several clinically relevant bacterial strains. PMID- 29432011 TI - Surface-Assisted Alkane Polymerization: Investigation on Structure-Reactivity Relationship. AB - Surface-assisted polymerization of alkanes is a remarkable reaction for which the surface reconstruction of Au(110) is crucial. The surface of (1*2)-Au(110) precovered with molecules can be completely transformed into (1*3)-Au(110) by introducing branched methylidene groups on both sides of the aliphatic chain (18, 19-dimethylidenehexatriacontane) or locally shifted into (1*3)-Au(110) under exposure to low-energy electrons (beam energy from 3.5 to 33.6 eV, for alkane dotriacontane). Scanning tunneling microscopy investigations demonstrate that alkane chains adsorbed on (1*3)-Au(110) are more reactive than on (1*2)-Au(110), presenting a solid experimental proof for structure-reactivity relationships. This difference can be ascribed to the existence of an extra row of gold atoms in the groove of (1*3)-Au(110), providing active sites of Au atoms with lower coordination number. The experimental results are further confirmed by density functional theory simulations. PMID- 29432013 TI - Reply to "Comment on 'The Mayonnaise Effect'". PMID- 29432012 TI - Strain Engineering to Enhance the Electrooxidation Performance of Atomic-Layer Pt on Intermetallic Pt3Ga. AB - Strain engineering has been a powerful strategy to finely tune the catalytic properties of materials. We report a tensile-strained two-to-three atomic-layer Pt on intermetallic Pt3Ga (AL-Pt/Pt3Ga) as an active electrocatalyst for the methanol oxidation reaction (MOR). Atomic-resolution high-angle annular dark field scanning transmission electron microscopy characterization showed that the AL-Pt possessed a 3.2% tensile strain along the [001] direction while having a negligible strain along the [100]/[010] direction. For MOR, this tensile-strained AL-Pt electrocatalyst showed obviously higher specific activity (7.195 mA cm-2) and mass activity (1.094 mA/MUgPt) than those of its unstrained counterpart and commercial Pt/C catalysts. Density functional theory calculations demonstrated that the tensile-strained surface was more energetically favorable for MOR than the unstrained one, and the stronger binding of OH* on stretched AL-Pt enabled the easier removal of CO*. PMID- 29432014 TI - Origin of Radiation-Induced Darkening in Yb3+/Al3+/P5+-Doped Silica Glasses: Effect of the P/Al Ratio. AB - Yb3+/Al3+/P5+-co-doped silica glasses with different P/Al ratios were prepared using the sol-gel method combined with high-temperature sintering. The evolution of composition-dependent color centers caused by X-ray irradiation in these glasses was correlated with their structural changes, which are controlled by the P/Al ratio. Nuclear magnetic resonance (NMR) and Raman spectra have been used to characterize the glass network structure, and advanced pulse electron paramagnetic resonance (EPR) has been employed to study the local coordination atomic structures of Yb3+ ions in pristine glasses as a function of the P/Al ratio. Si- (Si-E'), Al- (Al-E', Al-ODC, AlOHC), P- (P1, P2, POHC), and Yb-related (Yb2+) color centers in irradiated glasses have been observed and explained by optical absorption and continuous wave-EPR spectroscopies. The formation mechanisms of these centers, the structural models of glasses, and the relationship between them were proposed. Direct evidence confirms that the formation of Yb2+ ions induced by radiation is highly dependent on the coordination environment of Yb3+ ions in glasses. In addition, the glass network structure significantly affects the generation of oxygen hole color centers (AlOHCs/POHCs) caused by radiation. These results are useful in understanding the microstructural origin and the suppression mechanism of the radiodarkening effect by phosphorus co-doping in Yb3+-doped silica fibers. PMID- 29432015 TI - Hydrogen Bonding Features in Cholinium-Based Protic Ionic Liquids from Molecular Dynamics Simulations. AB - We explore the structure of a series of protic Ionic Liquids based on the choline cation and amino acid anions. In the series, the length and the branching of the amino acid alkyl chain varies. Ab initio molecular dynamics, X-ray diffraction measurements, and infrared spectra have been used to provide a reliable picture of the short-range structure and of the short-time dynamic process that characterize the fluids. We have put special emphasis on the peculiar and complicated network of hydrogen bonds that stem from the amphoteric nature of the anion moiety. The use of ab initio molecular dynamics allows us to calculate the "exact" charge density of the system and hence to obtain fairly accurate infrared spectra that, in turn, have been used to assign the experimental ones. PMID- 29432016 TI - Time-Resolved Sum Frequency Generation Spectroscopy: A Quantitative Comparison Between Intensity and Phase-Resolved Spectroscopy. AB - Time-resolved and two-dimensional sum frequency generation (TR-SFG and 2D-SFG) spectroscopies are promising tools in the experimental study of molecular dynamics, specifically at interfaces. Most implementations of TR/2D-SFG spectroscopy rely on a pump-probe scheme, where an excitation pulse excites a fraction of interfacial molecules into the first excited state of a specific vibrational mode, and a subsequent SFG probe pair detects the time-dependent changes of the surface vibrational response. In steady state SFG spectroscopy, phase-resolved detection (also known as heterodyne-detection), as opposed to SFG intensity measurements, has been shown to be useful in unraveling the steady state response of interfacial vibrations. Here, we explore the merits of phase resolved TR/2D-SFG spectroscopy. This purely theoretical and numerical study reveals that, for a typical response from aqueous interfaces, the intensity 2D SFG measurements contain the same information content as phase-resolved 2D-SFG measurements. We specifically analyze the frequency-dependence of the bleach lifetime (reflecting vibrational relaxation), and the time-dependent slope of the on-diagonal features observed in a 2D spectra. We show that for different systems, the intensity-based and phase-resolved 2D-SFG measurements provide the same information and are quantitatively very similar. We investigate the effect of different lineshapes, anharmonicity, and nonresonant signal contributions, and show that none of these effects substantially change the conclusion that intensity-based and phase-resolved 2D-SFG measurements provide equivalent information. PMID- 29432017 TI - Unraveling the Growth of Hierarchical Quasi-2D/3D Perovskite and Carrier Dynamics. AB - The construction of hybrid perovskites (both two-dimensional (2D) and three dimensional (3D)) has attracted intensive research interest recently. Here, a facile, two-step consecutive deposition method was developed for the first time to grow a hierarchical quasi-2D/3D perovskite superstructure, with an oriented quasi-2D ((BA)2(MA)n-1PbnI3n+1) perovskite nanosheet (NS) perpendicularly aligned on 3D perovskites. The superstructures are found to be mixtures of multiple perovskite phases, with n = 2, 3, 4 and 3D perovskite; however, the n value was naturally increased from top to the bottom, which is distinct from many other works. We found that the concentration gradient, namely, the initial ratio and amount of BAI/MAI, collectively contributes to the spatially confined nucleation and growth of oriented quasi-2D superstructure perovskite on 3D perovskites. An efficient charge carrier transfer was demonstrated from small-n to large-n phases in this perovskite superstructure, indicating a different type of energy funnel from top to bottom. PMID- 29432018 TI - Cluster Crystals Stabilized by Hydrophobic and Electrostatic Interactions. AB - Cluster crystals are crystalline materials in which each site is occupied by multiple identical particles, atoms, colloids, or polymers. There are two classes of systems that make cluster crystals. One is composed of particles that interact via potentials that are bound at the origin and thus are able to penetrate each other. The other consists of non-interpenetrating particles whose interaction potential diverges at the origin. The goal of this work is to find which systems of the second class can make cluster crystals that are stable at room temperature. First, the general properties of the required potentials are established using an analytical model and Monte Carlo simulations. Next, we ask how such potentials can be constructed by combining hydrophobic attraction and electrostatic repulsion. A colloid model with a hard-sphere core and a repulsive wall is introduced to mimic the hydrophobic interaction. Charge is added to create long-range repulsion. A search in the parameter space of the colloid size, counterion type, and charge configuration uncovers several models for which effective colloid-colloid interaction, determined in explicit solvent as a potential of mean force, has the necessary shape. For the effective potential, cluster crystals are confirmed as low free-energy configurations in replica exchange molecular dynamics simulations, which also generate the respective transition temperature. The model that exhibits a transition above room temperature is further studied in explicit solvent. Simulations on a 10 ns time scale show that crystalline conformations are stable below the target temperature but disintegrate rapidly above it, supporting the idea that hydrophobic and electrostatic interactions are sufficient to induce an assembly of cluster crystals. Finally, we discuss which physical systems are good candidates for experimental observations of cluster crystals. PMID- 29432019 TI - Binding of Tolperisone Hydrochloride with Human Serum Albumin: Effects on the Conformation, Thermodynamics, and Activity of HSA. AB - Tolperisone hydrochloride (TH) has muscle relaxant activity and has been widely used for several years in clinical practice to treat pathologically high skeletal muscle tone (spasticity) and related pains. The current study was designed to explore the binding efficacy of TH with human serum albumin (HSA) using multispectrscopic, calorimetric approach, FRET, esterase-like activity, and a molecular docking method. A reduction in fluorescence emission at 340 nm of HSA was attributed to fluorescence quenching by TH via a static quenching type. Binding constants ( Kb) were evaluated at different temperatures, and obtained Kb values were ~104 M-1, which demonstrated moderately strong affinity of TH for HSA. A calculated negative Delta G degrees value indicated spontaneous binding of TH to HSA. Far-UV CD spectroscopy revealed that the alpha-helix content was increased after TH binding. The binding distance between donor and acceptor was calculated to be 2.11 nm based on Forster's resonance energy transfer theory. ITC results revealed TH interacted with HSA via hydrophobic interactions and hydrogen bonding. The thermal stability of HSA was studied using DSC, and results showed that in the presence of TH the structure of HSA was significantly more thermostable. The esterase-like activity of HSA showed fixed Vmax and increased Km suggesting that TH binds with HSA in a competitive manner. Furthermore, molecular docking results revealed TH binds in the cavity of HSA, that is, subdomain IIA (Sudlow site I), and that it hydrogen bonds with K199 and H242 of HSA. Binding studies of drugs with HSA are potentially useful for elucidating chemico-biological interactions that can be utilized in the drug design, pharmaceutical, pharmacology, and biochemistry fields. This extensive study provides additional insight of ligand binding and structural changes induced in HSA relevant to the biological activity of HSA in vivo. PMID- 29432020 TI - SABRE-Relay: A Versatile Route to Hyperpolarization. AB - Signal Amplification by Reversible Exchange (SABRE) is used to switch on the latent singlet spin order of para-hydrogen (p-H2) so that it can hyperpolarize a substrate (sub = nicotinamide, nicotinate, niacin, pyrimidine, and pyrazine). The substrate then reacts reversibly with [Pt(OTf)2(bis-diphenylphosphinopropane)] by displacing OTf- to form [Pt(OTf)(sub)(bis-diphenylphosphinopropane)]OTf. The 31P NMR signals of these metal complexes prove to be enhanced when the substrate possesses an accessible singlet state or long-lived Zeeman polarization. In the case of pyrazine, the corresponding 31P signal was 105 +/- 8 times larger than expected, which equated to an 8 h reduction in total scan time for an equivalent signal-to-noise ratio under normal acquisition conditions. Hence, p-H2 derived spin order is successfully relayed into a second metal complex via a suitable polarization carrier (sub). When fully developed, we expect this route involving a second catalyst to successfully hyperpolarize many classes of substrates that are not amenable to the original SABRE method. PMID- 29432021 TI - Computation of a Theoretical Membrane Phase Diagram and the Role of Phase in Lipid-Raft-Mediated Protein Organization. AB - Lipid phase heterogeneity in the plasma membrane is thought to be crucial for many aspects of cell signaling, but the physical basis of participating membrane domains such as "lipid rafts" remains controversial. Here we consider a lattice model yielding a phase diagram that includes several states proposed to be relevant for the cell membrane, including microemulsion-which can be related to membrane curvature-and Ising critical behavior. Using a neural-network-based machine learning approach, we compute the full phase diagram of this lattice model. We analyze selected regions of this phase diagram in the context of a signaling initiation event in mast cells: recruitment of the membrane-anchored tyrosine kinase Lyn to a cluster of transmembrane IgE-FcepsilonRI receptors. We find that model membrane systems in microemulsion and Ising critical states can mediate roughly equal levels of kinase recruitment (binding energy ~ -0.6 kB T), whereas a membrane near a tricritical point can mediate a much stronger kinase recruitment (-1.7 kB T). By comparing several models for lipid heterogeneity within a single theoretical framework, this work points to testable differences between existing models. We also suggest the tricritical point as a new possibility for the basis of membrane domains that facilitate preferential partitioning of signaling components. PMID- 29432022 TI - Strong Localization of Surface Plasmon Polaritons with Engineered Disorder. AB - In this work, we experimentally demonstrate for the first time strong localization of surface plasmon polaritons (SPPs) at visible regime in metallic nanogratings with short-range correlated disorder. By increasing the degree of disorder, the confinement of SPPs is significantly enhanced, and the effective SPP propagation length dramatically shrinks. Strong localization of SPPs eventually emerges at visible regime, which is verified by the exponentially decayed fields and the vanishing autocorrelation function of the SPPs. Physically, the short-range correlated disorder induces strong interference among multiple scattered SPPs and provides an adequate fluctuation to effective permittivity, which leads to the localization effect. Our study demonstrates a unique opportunity for disorder engineering to manipulate light on nanoscale and may achieve various applications in random nanolasing, solar energy, and strong light-matter interactions. PMID- 29432023 TI - Highly Surface-Active Ca(OH)2 Monolayer as a CO2 Capture Material. AB - Greenhouse gas emissions originating from fossil fuel combustion contribute significantly to global warming, and therefore the design of novel materials that efficiently capture CO2 can play a crucial role in solving this challenge. Here, we show that reducing the dimensionality of bulk crystalline portlandite results in a stable monolayer material, named portlandene, that is highly effective at capturing CO2. On the basis of theoretical analysis comprised of ab initio quantum mechanical calculations and force-field molecular dynamics simulations, we show that this single-layer phase is robust and maintains its stability even at high temperatures. The chemical activity of portlandene is seen to further increase upon defect engineering of its surface using vacancy sites. Defect containing portlandene is capable of separating CO and CO2 from a syngas (CO/CO2/H2) stream, yet is inert to water vapor. This selective behavior and the associated mechanisms have been elucidated by examining the electronic structure, local charge distribution, and bonding orbitals of portlandene. Additionally, unlike conventional CO2 capturing technologies, the regeneration process of portlandene does not require high temperature heat treatment because it can release the captured CO2 by application of a mild external electric field, making portlandene an ideal CO2 capturing material for both pre- and postcombustion processes. PMID- 29432024 TI - Evaluation of MUC1-Aptamer Functionalized Hybrid Nanoparticles for Targeted Delivery of miRNA-29b to Nonsmall Cell Lung Cancer. AB - The objective of this study was to evaluate the therapeutic efficacy and pharmacokinetic study of mucin1-aptamer functionalized miRNA-29b-loaded hybrid nanoparticles (MAFMILHNs) in lung tumor-bearing SCID mice. MAFMILHNs were manufactured using an isoelectric point based nanotechnology. They were then fully characterized for particle size, loading capacity, zeta potential, and encapsulation efficiency. The ability of MAFMILHNs to downregulate oncoprotein DNMT3B both at the cellular level and in vivo was monitored using Western blot, while the effect of the downregulation of DNMT3B on tumor growth was assessed using bioluminescence. Results indicate that the presence of MUC1-aptamer conjugated to the surface of the nanoparticles enhanced the selective delivery of miRNA-29b to tumor cells and tissues. Further, the downregulation of DNMT3B by MAFMILHNs resulted in the inhibition of tumor growth in mouse models. PMID- 29432025 TI - Charge Reversible and Mitochondria/Nucleus Dual Target Lipid Hybrid Nanoparticles To Enhance Antitumor Activity of Doxorubicin. AB - The experiment aims to increase antitumor activity while decreasing the systemic toxicity of doxorubicin (DOX). Charge reversible and mitochondria/nucleus dual target lipid hybrid nanoparticles (LNPs) was prepared. The in vitro experimental results indicated that LNPs released more amount of DOX in acidic environment and delivered more amount of DOX to the mitochondria and nucleus of tumor cells than did free DOX, which resulted in the reduction of mitochondrial membrane potential and the enhancement of cytotoxicity of LNPs on tumor cells. Furthermore, the in vivo experimental results indicated that LNPs delivered more DOX to tumor tissue and significantly prolonged the retention time of DOX in tumor tissue as compared with free DOX, which consequently resulted in the high antitumor activity and low systemic toxicity of LNPs on tumor-bearing nude mice. The above results indicated that charge reversible mitochondria/nucleus dual targeted lipid hybrid nanoparticles greatly enhanced therapeutic efficacy of DOX for treating lung cancer. PMID- 29432027 TI - The Validity and Clinical Utility of the Personality Inventory for DSM-5 Response Inconsistency Scale. AB - The Personality Inventory for DSM-5 (PID-5; Krueger, Derringer, Markon, Watson, & Skodol, 2012) is a self-report instrument designed to assess the personality traits of the alternative model of personality disorders (AMPD) in Section III of the DSM-5. Despite its relatively recent introduction to the field, the instrument is frequently and widely used. One criticism of this instrument is that it does not include validity scales to detect potentially invalidating response style, including noncredible over- and underreporting and inconsistent (random) responding. Keeley, Webb, Peterson, Roussin, and Flanagan (2016) constructed an inconsistency scale (the PID-5-INC) to assess random responding on PID-5 and proposed a number of potential cut scores that could be applied. In this study, we attempted to cross-validate the PID-5-INC, including whether the scale could detect randomly generated protocols and distinguish them from nonrandom protocols produced by two student and two clinical samples. The PID-5 INC successfully distinguished random from nonrandom protocols and the best cut scores were similar to those reported by Keeley et al. (2016). We also found that a relatively low amount of random responding compromised the psychometric validity of the PID-5 trait scales, which extended previous work on this instrument. PMID- 29432026 TI - Developmental Trajectories of Executive and Verbal Processes in Children with Phenylketonuria. AB - Phenylketonuria (PKU) is a hereditary disorder characterized by disrupted phenylalanine metabolism and cognitive impairment. However, the precise nature and developmental trajectory of this cognitive impairment remains unclear. The present study used a verbal fluency task to dissociate executive and verbal processes in children with PKU (n = 23; 7-18 years) and controls (n = 44; 7-19 years). Data were collected at three longitudinal timepoints over a three-year period, and the contributions of age, group, and their interaction to fluency performance were evaluated. Results indicated impairments in executive processes in children with PKU, which were exacerbated by declining metabolic control. PMID- 29432028 TI - Correction to: A Psychometric Review of the Personality Inventory for DSM-5 (PID 5): Current Status and Future Directions. PMID- 29432029 TI - Overdiagnosis of ADHD in boys: Stereotype impact on neuropsychological assessment. AB - There is vigorous debate regarding the possibility that ADHD is overdiagnosed in boys. We investigated the impact of the gender stereotype depicting boys as inattentive and impulsive on neuropsychological assessment (observation of psychology students and child's cognitive performance). In experiment 1, after the stereotype was activated, psychology students rated a "boy," a "girl," or a "child" on a behavioral assessment scale. In experiment 2, 103 children (boys and girls) completed neuropsychological tasks under stereotype threat or neutral conditions. The gender stereotype led psychology students to assess a child's behaviors more negatively if they thought the child was a boy. Boys' performance on one cognitive score declined following stereotype threat. Regression path analyses suggested moderation by stigma consciousness. Additionally, there were mediating and suppressing (through stereotype endorsement) effects. Our results suggest that the gender stereotype might contribute to the overdiagnosis of ADHD in boys. PMID- 29432030 TI - Pharmacological activities of mogrosides. PMID- 29432031 TI - Deferred diagnosis in children assessed for fetal alcohol spectrum disorder. AB - Early intervention for individuals with FASD is paramount, thus exploring factors that affect the diagnostic process is critical. This process can be complicated by challenges gathering background information, accurately evaluating higher level cognitive skills across ages, and teasing apart the impact of life adversities from the effects of prenatal alcohol exposure. This study is a retrospective file review of 154 children (44% female; mean age 8.4 years, range 1.0 to 16.9) deferred at their first FASD assessment, and 51 (43% female; mean 9.9 years, range 2.7 to 17.2) who returned for a second assessment. Data was collected from three Canadian FASD clinics to explore reasons for deferral, the clinical profile of deferred children, why some returning children were diagnosed while others were not, and changes between assessments. Results suggest that deferred children initially lacked evidence of abnormalities sufficient for a diagnosis, presented with areas of relative neurobehavioral strength and difficulty, and children eventually diagnosed with FASD showed significantly more impaired brain function (p < 0.001, etap2 = 0.547), postnatal risk (p = 0.021, etap2 = 0.121), and comorbidities (p = 0.038, etap2 = 0.085) than undiagnosed children. These findings provide important insights into the process of clinical assessment for FASD. PMID- 29432032 TI - Superdosing phytase reduces real-time gastric pH in broilers and weaned piglets. AB - 1. The current study was conducted to investigate the effect of high phytase doses on growth performance and real-time gastric pH measurements in broiler chickens and pigs. 2. In the first experiment, 576 male Ross 308 broilers were fed in two phases (0-21 and 21-42 d) with 4 treatment groups, with diets meeting nutrient requirements containing 0, 500, 1500 or 2500 FTU/kg phytase. In the second, 64 Landrace weaners were fed on diets meeting nutrient requirements with or without phytase (0 or 2500 FTU/kg) in two phases (0-21 and 21-42 d). Heidelberg pH capsules were administered to 7 broilers and approximately 13 pigs per treatment group, pre- and post-phase change, with readings monitored over several hours. 3. Addition of phytase into an adequate Ca and P diet had no significant effect on broiler performance although phytase tended (P < 0.07) to improve feed conversion in pigs over the entire experimental period. Real-time pH capsule readings in broilers demonstrated an increase (P < 0.05) in gizzard pH when phytase was dosed at 500 or 1500 FTU/kg, while higher doses of 2500 FTU/kg phytase lowered pH to a level comparable to control birds. Gastric pH increased (P < 0.01) when animals were exposed to dietary phase change, signifying a potential challenge period for nutrient digestibility. However, pigs fed 2500 FTU/kg were able to maintain gastric pH levels through diet phase change. In contrast, spear-tip probe measurements showed no treatment effect on gastric pH. 4. These findings demonstrate dietary manipulation of gastric pH and the value of real-time pH capsule technology as a means of determining phytase dose response. PMID- 29432033 TI - Effects of 17beta-Estradiol on Activity, Gene and Protein Expression of Superoxide Dismutases in Primary Cultured Human Lens Epithelial Cells. AB - PURPOSE: Protective effects of estradiol against H2O2-induced oxidative stress have been demonstrated in lens epithelial cells. The purpose of this study was to investigate the effects of 17beta-estradiol (E2) on the different superoxide dismutase (SOD) isoenzymes, SOD-1, SOD-2, and SOD-3, as well as estrogen receptors (ERs), ERalpha and ERbeta, in primary cultured human lens epithelial cells (HLECs). MATERIALS AND METHODS: HLECs were exposed to 0.1 uM or 1 uM E2 for 1.5 h and 24 h after which the effects were studied. Protein expression and immunolocalization of SOD-1, SOD-2, ERalpha, and ERbeta were studied with Western blot and immunocytochemistry. Total SOD activity was measured, and gene expression analyses were performed for SOD1, SOD2, and SOD3. RESULTS: Increased SOD activity was seen after 1.5 h exposure to both 0.1 uM and 1 uM E2. There were no significant changes in protein or gene expression of the different SODs. Immunolabeling of SOD-1 was evident in the cytosol and nucleus; whereas, SOD-2 was localized in the mitochondria. Both ERalpha and ERbeta were immunolocalized to the nucleus, and mitochondrial localization of ERbeta was evident by colocalization with MitoTracker. Both ERalpha and ERbeta showed altered protein expression levels after exposure to E2. CONCLUSIONS: The observed increase in SOD activity after exposure to E2 without accompanying increase in gene or protein expression supports a role for E2 in protection against oxidative stress mediated through non-genomic mechanisms. PMID- 29432034 TI - Cognitive functioning in chronic post-stroke aphasia. AB - There is a minimal amount of knowledge regarding the cognitive abilities of people with aphasia. We evaluated the performance of individuals with chronic aphasia (AP) and control participants without aphasia (CP) with left hemisphere stroke in a battery of nonverbal cognitive tests and its relationship with aphasia severity, comprehension abilities, and speech fluency in a prospective cross-sectional study. Cognitive evaluation comprised 10 nonverbal tests. Scores were converted to age and education adjusted standard scores. Forty-eight AP and 32 CP were included. AP average scores were below normal range in three tests: Camel and Cactus Test, immediate recall of 5 Objects Test and Spatial Span. The mean test scores were significantly lower in AP than in CP, except in four tests. Aphasia severity and verbal comprehension ability correlated significantly with semantic memory, constructive abilities and attention/processing speed tests. Subjects with nonfluent aphasia had lower scores than CP in memory, executive functions and attention tests, while subjects with fluent aphasia showed lower scores in memory tests only. On average half of the individuals with aphasia exhibit results within the normal range. Nonetheless, their performance was worse than that of controls, despite the fact that many tests do not correlate with the severity of language disorder. PMID- 29432035 TI - Examination of discrepancies between subjective and objective memory with latent factors of the geriatric depression scale. AB - OBJECTIVE: The purpose of the present study was to examine whether multiple constructs of depressive symptoms explained discrepancies between subjective (SM) and objective memory (OM) in older adulthood. METHOD: A sub-sample (Range: 65-98 years, N = 606) of the 2000 Wave Panel 3 of the Long Beach Longitudinal Study was used to explore underlying latent factors within the Geriatric Depression Scale (GDS). RESULTS: Four GDS factors were identified (Dysphoria, Vigor/Withdrawal, Cognitive Concerns, and Agitation); the factor solution was tested in a confirmatory factor analysis. Mechanisms of the GDS factors on SM and OM were tested by using structural equation modeling. Dysphoria negatively predicted OM, but not SM, suggesting that people who scored high in Dysphoria might not sense their memory failures although they obviously performed poorly in OM. Cognitive concerns negatively predicted SM, but not OM, suggesting that cognitive concerns were not influential for OM, but negatively affected one's evaluation of SM. CONCLUSION: The study results have clinical implications since such relationships can be concealed while assessing depressive symptoms as a single GDS factor. Thus, the patterns of the GDS factors, SM, and OM derived from this study can be very useful for clinicians who conduct assessments on depressive symptoms and memory failures. PMID- 29432036 TI - Effects of a meal feeding regimen and the availability of fresh alfalfa on growth performance and meat and bone quality of broiler genotypes. AB - 1. The aim of this study was to identify a feeding regimen that encourages good pasture use in slow (SG) and fast (FG) growing broiler genotypes under free-range management. 2. SG and FG birds fed on either an ad libitum (ADB) or a meal feeding (MEF) programme were given free outdoor access with or without fresh alfalfa from day 22 to 72 and from day 22 to 45, respectively. In two consecutive trials, 800 birds of each genotype were included in a factorial design using groups of 40 birds replicated 5 times. 3. Fresh alfalfa consumption did not improve growth performance and meat quality attributes, whereas the feeding regimen had significant implications. When compared with their ad libitum-fed counterparts, meal-fed birds showed a significantly lower body weight at a considerably lower feed consumption rate, leading to a more favourable feed conversion ratio (FCR) during the course of the experiment. 4. The MEF regimen with a strong feed limitation significantly increased crop and gizzard weight in both genotypes. In FG birds, water holding capacity, drip loss, cooking loss and pH 45 in the breast and thigh meat were adversely affected by MEF; however, feed restriction demonstrated benefits with significant decreases in muscle fat accumulation. In SG birds, decreases in protein and dry matter content of the breast and thigh muscle with meal feeding were conclusive. 5. In both genotypes, there was no treatment-related effect on meat yield, mineral composition of the meat or bone mechanical properties. 6. In conclusion, MEF, irrespective of alfalfa intake, may provide a viable method to decrease FCR; it may be able to contribute to the production of chickens with lean carcasses but it was not capable of improving overall meat quality. PMID- 29432038 TI - Work Requirements And Conscience Protections. AB - The Trump administration broke from its predecessors by authorizing Medicaid work requirements. It also proposed to dramatically broaden rights to refuse to provide treatments for religious and moral reasons. PMID- 29432039 TI - The IFS (INECO Frontal Screening) and level of education: Normative data. AB - Level of education is known to confound neuropsychological test performance. The INECO Frontal Screening (IFS) is an easy-to-use and brief measure of several domains of executive function, which has previously shown reliably clinical usefulness and superior psychometric performance when compared to other frontal screening instruments. However, previous studies with the IFS have been limited to participants with high levels of education, preventing its generalizability to populations with less than 12 years of formal education. This is crucial, as less than half of the Latin American population and a large percentage of immigrants in developed countries attain high school education. The aim of this study was to generate IFS normative data in a sample stratified by age and education levels. One hundred and sixty one healthy adults were assessed with the IFS as well as measures of global cognitive screening, namely, the Addenbrooke Cognitive Examination Revised and the Mini-Mental State Examination. Multiple lineal regression analysis showed significant effects for education and nonsignificant effects for age. A correction grid for IFS raw scores was developed and cut-off scores were calculated. The correction grid and cut-off scores may be useful in the interpretation of IFS scores in participants with low education. PMID- 29432040 TI - Protective roles of flavonoids and flavonoid-rich plant extracts against urolithiasis: A review. AB - In the urinary system, urolithiasis is the third prevalent disorder which causes severe pain in individuals. Urinary stones are composed of calcium oxalate (CaOx) and calcium phosphate in approximately 80% of patients. Although various drugs and surgery operations are used to treat the disease, side effects of drugs and the high recurrence after therapy in patients cannot be ignored. Flavonoids are a large group of plant polyphenols with presumed beneficial effects on several common diseases. Whereas, a very few have reached clinical use. The results of recent studies have shown that the plant flavonoids could effectively inhibit the formation of CaOx stones in vitro and in vivo, correlating with their diuretic, antioxidant, anti-inflammatory, antibacterial properties and other protective effects. Thus, the flavonoids or flavonoid-rich plant extracts endowed with anti urolithiasis activities and probable mechanisms of actions were reviewed. In addition, we also put forward some issues needed to be concerned in future investigations as well as offered prospects and challenges for developing the plant flavonoids into drugs for stone prevention. PMID- 29432037 TI - Applying a Cognitive Neuroscience Perspective to Disruptive Behavior Disorders: Implications for Schools. AB - A cognitive neuroscience perspective seeks to understand behavior, in this case disruptive behavior disorders (DBD), in terms of dysfunction in cognitive processes underpinned by neural processes. While this type of approach has clear implications for clinical mental health practice, it also has implications for school-based assessment and intervention with children and adolescents who have disruptive behavior and aggression. This review articulates a cognitive neuroscience account of DBD by discussing the neurocognitive dysfunction related to emotional empathy, threat sensitivity, reinforcement-based decision-making, and response inhibition. The potential implications for current and future classroom-based assessments and interventions for students with these deficits are discussed. PMID- 29432042 TI - Relationship between upper airway diseases, exhaled nitric oxide, and bronchial hyperresponsiveness to methacholine. AB - OBJECTIVE: The "united airway disease" concept is based on the bidirectional interaction between asthma and rhinitis. The aim of this study was to determine the relationship between upper airway diseases and bronchial hyperresponsiveness (BHR), as well as their association with the fractional concentration of exhaled nitric oxide (FeNO) and atopy in patients with persistent symptoms suggestive of asthma requiring methacholine challenge testing (MCT) to confirm asthma diagnosis. METHODS: A cross-sectional prospective study was carried out in adult patients with persistent asthma-like symptoms and negative bronchodilator testing. FeNO and MCT were performed in all patients. Asthma was confirmed based on the presence of suggestive symptoms and MCT results. Associated upper airway diseases included allergic rhinitis, nonallergic rhinitis, chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD). RESULTS: The study included 575 patients; asthma was confirmed in 32.3%, and FeNO values >= 50 ppb were found in 27% of the patients. Elevated FeNO was significantly associated to AERD. The prevalence of atopy in asthma patients was 86.6%. Atopy was present in 90.4% of patients with asthma and FeNO levels >= 50 ppb. A significant association was found between AERD, asthma, and FeNO >= 50 ppb. CONCLUSIONS: Patients with symptoms suggestive of asthma but negative bronchodilator testing are commonly seen in usual practice. In this population, the association of high FeNO levels and BHR to atopy, as well as to AERD, suggests the presence eosinophilic inflammation in both the upper and lower airways and supports the "one airway" hypothesis. PMID- 29432043 TI - Prehospital Application of Hemostatic Agents in Iraq and Afghanistan. AB - INTRODUCTION: Hemorrhage is the leading cause of death on the battlefield. Development of chitosan- and kaolin-based hemostatic agents has improved hemorrhage control options. Sparse data exists on the use of these agents in the prehospital, combat setting. We describe recent use of these agents and compare patients receiving hemostatic to the baseline population. METHODS: We used a series of emergency department (ED) procedure codes to identify patients within the Department of Defense Trauma Registry (DODTR) from January 2007 to August 2016. We only included patients for whom the DODTR specified the hemostatic agent utilized (chitosan or kaolin). We defined a serious injury by body region as an Abbreviated Injury Score (AIS) of 3 or greater. RESULTS: Our predefined search codes captured 28,222 patients. Of those, 258 (0.9%) patients had documented hemostatic use: 58 chitosan, 201 kaolin, and one subject received both. Patients undergoing hemostatic agent application were more likely to be injured by gunshot wound or explosive. Patients with hemostatic application had higher median composite Injury Severity Scores (10 vs. 9, p < 0.001), and higher AIS for the abdomen, extremity and superficial body regions with higher rates of blood product utilization. Proportions of patients suffering traumatic amputations and undergoing tourniquet application were higher in the hemostatic agent group than the baseline population (11.6% vs. 6.7%, p = 0.002 and 43.4% vs. 13.8%, p < 0.001, respectively). CONCLUSIONS: Hemostatic agents were infrequently utilized to manage traumatic hemorrhage during the recent conflicts in Afghanistan and Iraq. Hemostatic agent use was more frequent in casualties with gunshot wounds, traumatic amputations, concomitant tourniquet application, and greater blood product administration." PMID- 29432041 TI - Qualitative Evaluation of the Coach Training within a Community Paramedicine Care Transitions Intervention. AB - OBJECTIVE: The Care Transitions Intervention (CTI) has potential to improve the emergency department (ED)-to-home transition for older adults. Community paramedics may function as the CTI coaches; however, this requires the appropriate knowledge, skills, and attitudes, which they do not receive in traditional emergency medical services (EMS) education. This study aimed to define community paramedics' perceptions regarding their training needs to serve as CTI coaches supporting the ED-to-home transition. METHODS: This study forms part of an ongoing randomized controlled trial evaluating a community paramedic implemented CTI to enhance the ED-to-home transition. The community paramedics' training covered the following domains: the CTI program, geriatrics, effective coaching, ED discharge processes, and community paramedicine. Sixteen months after starting the study, we conducted audio-recorded semi-structured interviews with community paramedics at both study sites. After transcribing the interviews, team members independently coded the transcripts. Ensuing group analysis sessions led to the development of final codes and identifying common themes. Finally, we conducted member checking to confirm our interpretations of the interview data. RESULTS: We interviewed all 8 participating community paramedics. Participants consisted solely of non-Hispanic whites, included 5 women, and had a mean age of 43. Participants had extensive backgrounds in healthcare, primarily as EMS providers, but minimal experience with community paramedicine. All reported some prior geriatrics training. Four themes emerged from the interviews: (1) paramedics with positive attitudes and willingness to acquire the needed knowledge and skills will succeed as CTI coaches; (2) active rather than passive learning is preferred by paramedics; (3) the existing training could benefit from adjustments such as added content on mental health, dementia, and substance abuse issues, as well as content on coaching subjects with a range of illness severity; and (4) continuing education should address the paramedic coaches' evolving needs as they develop proficiency with the CTI. CONCLUSIONS: Paramedics as CTI coaches represent an untapped resource for supporting ED-to-home care transitions. Our results provide the necessary first step to make the community paramedic CTI coach more successful. These findings may apply to training for similar community paramedicine roles, but additional research must investigate this possibility. PMID- 29432044 TI - Linkage and Antiretroviral Therapy Within 72 Hours at a Federally Qualified Health Center in New Orleans. PMID- 29432046 TI - 2017 Acknowledgment of Reviewers. PMID- 29432045 TI - A Conditional Economic Incentive Fails to Improve Linkage to Care and Antiretroviral Therapy Initiation Among HIV-Positive Adults in Cape Town, South Africa. AB - Interventions to improve antiretroviral therapy (ART) access are urgently needed to maximize the multiple benefits from ART. This pilot study examined the effect of a conditional economic incentive on linkage to care and uptake of treatment following ART referral by a mobile health clinic. Between April 2015 and May 2016, 86 individuals (>=18 years old) referred for ART in a resource-limited setting were randomized (1:1) to a control group or to an incentive: R300 cash (~$23, or 3.5 days minimum wage in the domestic worker sector), conditional upon starting ART within 3 months. Outcome data were obtained from clinic records. The incentive effects on linkage to care (first clinic visit within 3 months) and ART initiation (treatment uptake within 3 months) were assessed using logistic regression. Overall, 67% linked to care and 42% initiated ART within 3 months after referral. No significant differences were found between the incentive and non-incentive group in terms of linkage to care [adjusted odds ratio (aOR): 0.70, 95% confidence interval (CI): 0.26-1.91] and initiation of ART (aOR: 0.67, 95% CI: 0.26-1.78). Ordinary least-squares regression analysis showed that incentivized individuals linked to care in fewer days (-7.9, 95% CI: -18.09 to 2.26) and started treatment in fewer days (-7.3, 95% CI: -27.01 to 12.38), but neither result was statistically significant. Our findings demonstrate poor treatment uptake by both the intervention and control participants and further highlight the challenge in achieving universal early treatment access. Further research is required to understand how economic incentives, which have been shown to have many benefits, can be applied to improve linkage to HIV care and treatment. PMID- 29432048 TI - Current Controversies Regarding Peer Review in Scholarly Journals. PMID- 29432047 TI - Community-Acquired Meningitis in HIV-Infected Patients in the United States. AB - We conducted a retrospective study of 549 adults admitted with community-acquired meningitis (CAM) to several hospitals in New Orleans, LA and Houston, TX between 1999 and 2014 to characterize the current epidemiology, clinical manifestations, cerebrospinal fluid (CSF) characteristics, and outcomes of CAM between HIV infected and uninfected patients and to identify risk factors for adverse outcomes in CAM. Bivariate analysis and logistic regression analysis were used to identify prognostic factors. A total of 1022 patients with CAM were screened. Only 549 (53.7%) subjects had an HIV test and were included in the study. Of those, 138 (25%) had HIV infection. HIV-infected patients presented with less meningeal symptoms (headache, neck stiffness, and Kernig sign), but with higher rates of hypoglycorrhachia, elevated CSF protein, and an abnormal cranial imaging (p < 0.05). More than 50% of all the patients had an unknown etiology. Cryptococcal meningitis was the most common identified etiology of CAM in HIV infected patients followed by neurosyphilis and varicella-zoster virus (VZV). Viral and bacterial etiologies were the most frequent etiologies in non-HIV infected patients. Streptococcus pneumoniae was the most common bacterial pathogen in both groups, but it was rare overall (2%). Adverse clinical outcomes were similar in both groups (27% vs. 24%). Logistic regression identified hypoglycorrhachia and an abnormal neurological examination as independent predictor factors of worse outcome in all patients with meningitis. Our results demonstrate that the etiology, clinical presentation, and CSF findings differ between HIV-infected and HIV-uninfected adults with CAM, but clinical outcomes are similar. PMID- 29432049 TI - Polybrominated diphenyl ethers (PBDEs) in car and house dust from Thailand: Implication for human exposure. AB - This study examines concentrations of tri- to hexa-bromodiphenylethers (BDEs 17, 28, 47, 49, 66, 85, 99, 100, 153 and 154; Sigma10PBDEs (polybrominated diphenyl ethers)) in car (n = 30) and house dust samples (n = 53) collected from different provinces in Thailand. The specific objectives of this study were: (i) to monitor levels of tri- to hexa-bromodiphenylethers (BDEs 17, 28, 47, 49, 66, 85, 99, 100, 153 and 154; Sigma10PBDEs) in vehicle and residential dust sampled from various provinces in Thailand; (ii) to compare PBDE concentrations with those detected for domestic and automobile dust in studies from other countries and (iii) to estimate exposure of the Thai population to the target PBDEs via dust ingestion. Levels of Sigma10PBDEs in vehicle and domestic dust were 0.68-38 and 0.59-260 ng g-1, respectively. BDEs 99 and 47 were the most abundant congeners in all automobile and residential dust samples. A t-test analysis indicated that Sigma10PBDE concentrations in dust samples from dwellings exceeded significantly those from cars (p = 0.001). Furthermore, contents in dust of all PBDEs studied, except for BDE-28, were significantly higher in homes than in vehicles (p = 0.000 0.004). Principal Component Analysis (PCA) demonstrated no differences in PBDE congener patterns between Thai house and automobile dust, but revealed some subtle differences in the congener pattern between household dust samples in Thailand and those reported previously for the United Kingdom. Estimated environmental exposure of Thai adults and children for BDE-99 via dust ingestion were well within a chronic oral reference dose (RfD) for BDE-99 (100 ng/kg bw/day) proposed by the United States Environmental Protection Agency (US EPA). PMID- 29432050 TI - Preventing Rescue Surgeries by Endoscopic Clipping: A Valuable Resource in the Surgeon's Toolbox. AB - AIM: Over-the-scope-clip (OTSC) System is a relatively new endoluminal intervention for gastrointestinal (GI) leaks, fistulas, and bleeding. Here, we present a single center experience with the device over the course of 4 years. METHODS: Retrospective chart review was conducted for patients who received endoscopic OTSC treatment. Primary outcome is the resolution of the original indication for clip placement. Secondary outcomes are complications and time to resolution. RESULTS: Forty-one patients underwent treatment with the OTSC system from 2011 to 2015 with average follow-up of 152 days. The average age is 53.7. The most common site of clip placement was in the stomach (44%). Clips were placed after surgical complication for 28 patients (68%), endoscopic complications for 8 patients (19%), and spontaneous presentation in 5 patients (12%). Technical success was achieved in all patients. Overall, 34 patients (83%) were successfully treated. Nine patients required multiple clips and three patients required additional treatment modalities after OTSC. Four patients used the OTSC as a bridging therapy to surgery. Using OTSC for palliation versus nonpalliative indications was associated with lower rates of treatment success (50% versus 86%, P = .028). Using OTSC for symptoms <6 months had higher rates of treatment success than those experiencing longer symptoms (88% versus 65%, P = .045). There were no major morbidities or mortalities directly associated with the OTSC system. Complications from clip use were pain in two patients (5%) and hematemesis in one patient (3%). CONCLUSIONS: The OTSC System can be a very successful treatment for iatrogenic or spontaneous GI leaks and bleeds. Treatment success is more likely in patients treated within 6 months of diagnosis and less likely to when used for palliation. It was also successfully used as bridging therapy in several patients. PMID- 29432051 TI - Immunogenicity and persistence of a prime-boost re-vaccination strategy for pneumococcal vaccines in patients with rheumatoid arthritis. AB - OBJECTIVES: Patients with rheumatoid arthritis (RA) are at an increased risk of Pneumococcal infections. Immunogenicity and persistence of a prime-boost revaccination strategy using 13-valent/23-valent anti-pneumococcal vaccines was evaluated in patients with RA treated by Methotrexate (MTX) and anti-TNF. METHOD: Twenty-four patients with RA received one dose of PCV13 (Prevenar13(r); Pfizer) followed two months later by one dose of PPV23 (Pneumovax(r), Merck). Concentrations of IgG specific for 7 serotypes common to both vaccines and 3 uncommon serotypes, included only in the PPV23 were measured by ELISA and Opsonophagocytic Assay (OPA) at baseline and after 4, 12 and 24 months post vaccine. RESULTS: Similar percentages of protection were found at 4 months (63% vs. 55%), 12 months (54% vs. 50%) and 24 months (52% vs. 55%) for the 7 common and 3 uncommon serotypes when antibody titers were assayed by ELISA. Based on functional antibody measurements by OPA, a decrease of protected patients was observed 24 months after vaccine with only 19% of patients protected compared to 29% at baseline. CONCLUSION: Although the combined pneumococcal revaccination strategy induces good protection in the short term in RA patients, this protection does not persist beyond two years with levels of functional antibody decreasing below pre-vaccine levels. We did not observe a higher efficacy of the conjugate vaccine compared to the polysaccharide vaccine. Our results clearly question the advantage of the prime-boost strategy as it highlight the possible hyporesponse induced by PPV23 against the immune response elicited by the primo injection of the PCV13 vaccine. PMID- 29432053 TI - Gapless Genome Assembly of the Potato and Tomato Early Blight Pathogen Alternaria solani. AB - The Alternaria genus consists of saprophytic fungi as well as plant-pathogenic species that have significant economic impact. To date, the genomes of multiple Alternaria species have been sequenced. These studies have yielded valuable data for molecular studies on Alternaria fungi. However, most of the current Alternaria genome assemblies are highly fragmented, thereby hampering the identification of genes that are involved in causing disease. Here, we report a gapless genome assembly of A. solani, the causal agent of early blight in tomato and potato. The genome assembly is a significant step toward a better understanding of pathogenicity of A. solani. PMID- 29432052 TI - Protective Effects of Enteral Nutrition Supplemented with Crassostrea hongkongensis Polysaccharides Against 5-Fluorouracil-Induced Intestinal Mucosal Damage in Rats. AB - Chemotherapeutics, including 5-fluorouracil (5-FU), often damage the intestinal mucosal barrier and cause intestinal mucositis (IM). Supplementation with immunoregulatory polysaccharides from Crassostrea hongkongensis has been shown to positively influence the effectiveness and toxicity of 5-FU. Therefore, we studied the effects of oyster polysaccharides on 5-FU-induced intestinal mucosal damage in rats. The C30-60% ethanol-precipitated fraction of polysaccharides promoted IEC-6 cell proliferation and exhibited a maximal effect at a 0.0195 mg/mL concentration. Moreover, treatment with C30-60% polysaccharide-based nutrition formula (OPNF) partially prevented the 5-FU-induced degenerative changes in the histology and ultrastructure of small intestinal mucosa. In addition, the endotoxin level of rats fed with 5-FU and OPNF decreased to the normal control level. Furthermore, the 5-FU-induced increase of proinflammatory cytokine interleukin (IL)-2 and the decrease of anti-inflammatory cytokine IL-10 level in the peripheral blood were significantly attenuated by OPNF administration. In conclusion, Oyster C30-60% polysaccharides can ameliorate 5-FU induced IM by partially preventing mucosal damage, reducing inflammation, and promoting immunity. PMID- 29432054 TI - Ocular Drug Distribution and Safety of a Noninvasive Ocular Drug Delivery System of Dexamethasone Sodium Phosphate in Rabbit. AB - PURPOSE: To determine the ocular toxicity, systemic exposure, and amounts of dexamethasone sodium phosphate (DSP) in ocular tissues after administration of DSP with the Visulex system (DSP-Visulex). METHODS: DSP-Visulex was applied onto healthy rabbit eyes. DSP concentrations (4%, 8%, 15%, and 25%) and treatment durations (5, 10, and 20 min) were evaluated for the amounts of DSP in the ocular tissues and in plasma after single administrations of DSP-Visulex. The drug in eye tissues and plasma was analyzed by high-performance liquid chromatography UV/VIS and by liquid chromatography-mass spectrometry, respectively. The safety and tolerability were ascertained based on clinical observations and histopathological examinations from repeat weekly DSP-Visulex treatments (4%, 8%, 15%, and 25% for 20 min) for 12 weeks. RESULTS: Significant amounts of DSP (ie, higher than 1 MUg/g) were found in the anterior chamber, retina-choroid, cornea, vitreous, conjunctiva, and sclera after single applications of DSP-Visulex. The DSP concentrations in the ocular tissues and in plasma increased with increased DSP concentrations in the Visulex applicator and with increased application times. Systemic DSP was rapidly detected. The plasma half-life was 2-3 h. Cmax was 148 and 1,844 ng/mL, and the area under the plasma drug concentration versus time curve (AUC) was 418 and 3,779 ng . h/mL for the low dose (4% DSP-Visulex for 5 min) and the high dose (15% DSP-Visulex for 20 min), respectively. Ocular findings over 12 weeks were mostly conjunctival injection and eye discharge. These were transient and mild. Histopathological examinations indicated the eyes to be normal. CONCLUSIONS: DSP can be administered safely and effectively into the rabbit eye with the Visulex system. Treatment duration and DSP concentration are important factors in achieving therapeutic levels. Repeat applications of DSP Visulex are safe and well tolerated for weekly administrations over 4-12 weeks. DSP-Visulex has clinical potential for the noninvasive treatment of ocular diseases. PMID- 29432055 TI - Minimally Invasive Pediatric Cholecystectomy: A Comparison of Robotic and Laparoscopic Single and Multiport Techniques. AB - BACKGROUND: Pediatric laparoscopic cholecystectomy is the current standard of care for gallbladder pathology. Single-incision and multiport procedures, as well as robotic and minimally invasive platforms, have been described; however, there is no head-to-head assessment of these interventions in the existing literature. The purpose of our study was to directly compare the minimally invasive cholecystectomy techniques of laparoscopic multiport (LMP), laparoscopic single incision (LSI), robotic multiport (RMP), and robotic single incision (RSI). MATERIALS AND METHODS: All cholecystectomies performed by a single surgeon at a tertiary-care center from 2010 to 2014 were retrospectively reviewed. Seventy-one subjects were included as follows: 30 LMP, 20 LSI, 11 RMP, and 10 RSI. Data were collected on patient characteristics, operative technique, operative times, medications, and postoperative course and analyzed using a Kruskal-Wallis test with a significance of P < .05. RESULTS: Operative times for LMP and RSI were similar and shortest of all groups, while LSI was the most time consuming (P = .04). Pain medication use, both narcotic and non-narcotic, was not statistically different with any operation type (P = .37 and .98, respectively). Postoperative length of stay was similar across all groups except for the RSI group which was significantly shorter (P = .04). CONCLUSIONS: RSI cholecystectomy has significantly shorter postoperative length of stay compared to other minimally invasive techniques. In addition, operative times for RSI are equivalent to the current standard LMP technique. PMID- 29432056 TI - Consumption of Soymilk Reduces Lipid Peroxidation But May Lower Micronutrient Status in Apparently Healthy Individuals. AB - Consumption of soy products is speculated to reduce the risk and progression of some disease conditions. The underlying mechanisms mediating this effect are uncertain, but the lowering of oxidative stress has been suggested. This study was aimed at investigating the effect of soymilk on antioxidant status and lipid peroxidation in apparently healthy individuals. Five hundred milliliters of soymilk was taken daily by each of 39 apparently healthy individuals for a period of 28 days. Two sets of blood samples (baseline and after 28 days of soymilk intake) were collected and assayed for total antioxidant capacity (TAC), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione S-transferase (GST), manganese (Mn) and zinc (Zn) levels, using standard methods. Consumption of soymilk significantly increased serum TAC and reduced serum MDA when compared with baseline values (P < .001, P < .001 respectively). The decrease in MDA concentration was significantly contributed by the women (P < .001). Mean serum Mn was also significantly reduced (P = .03) when compared with baseline values. There were no changes in serum Zn concentration and the activity of SOD enzyme. The serum GST activity was significantly increased in men (P = .02) and significantly reduced in women (P < .001) in comparison with their corresponding baseline values. Daily consumption of soymilk enhanced antioxidant status and this led to reduced lipid peroxidation. It also resulted in a significant reduction of Mn. The dietary use of soymilk as an adjuvant to supplement meals seems beneficial health wise. However, soymilk should be taken with caution as it could result in micronutrient deficiency. PMID- 29432057 TI - Associations between Sociodemographic Characteristics and Sexual Risk Behaviors among Methamphetamine-using Men who Have Sex with Men. AB - BACKGROUND: Methamphetamine-using men who have sex with men (MSM) exhibit elevated rates of HIV and STI prevalence, indicating increased engagement in sexual risk behaviors. OBJECTIVES: This analysis elucidates associations between participant sociodemographics (i.e., age, racial/ethnic identity, sexual identity, educational attainment, and HIV status) and sexual risk behaviors, particularly substance use before/during sex, and engagement in condomless anal intercourse (CAI) with casual, anonymous, and/or exchange male partners. METHODS: From March 2014 through January 2016, 286 methamphetamine-using MSM enrolled in a technology-based study to reduce methamphetamine use and HIV sexual risk behaviors. A robustly estimated generalized structural equation model employing the negative binomial family and log link function (n = 282) tested the simultaneous associations between participant sociodemographics and engagement in HIV sexual risk behaviors. RESULTS: Participants' racial/ethnic identity (chi2(6) = 43.5; p < 0.0001), HIV status (chi2(6) = 22.0; p = 0.0012), educational attainment level (chi2(6) = 13.8; p = 0.0322), and years of age (chi2(6) = 32.4; p < 0.0001) all influenced participants' engagement in substance use before/during sex and engagement in CAI. Methamphetamine (chi2(2) = 7.0; p = 0.0309) and marijuana (chi2(2) = 9.7; p = 0.0079) use before/during sex influenced participants' engagement in CAI with casual, anonymous, and exchange male partners. CONCLUSION: Results indicate the importance of intervention efforts focused on younger racial/ethnic minority MSM with fewer years of educational attainment, and provides evidence of the specific subpopulations of MSM at greatest risk of detrimental effects of illicit substance use. PMID- 29432058 TI - A framework for establishing connections in physiotherapy practice. AB - The therapeutic relationship between practitioner and patient is embedded in the clinical interaction. Research using self-report tools has illustrated that positively evaluated therapeutic relationships can have favorable impacts on patient satisfaction with services and clinical outcomes. However, little is known about how physiotherapists develop the connections, or positive attachments, that help establish the therapeutic relationship. This study aimed to identify the various ways that physiotherapists establish meaningful connections with their patients. Interpretive description, a qualitative methodology, was used to structure the inductive and iterative design. Eleven physiotherapists and 7 patients from private practice clinics participated in semi-structured interviews to describe their experiences of the therapeutic relationship. Textual data were analyzed using qualitative content analysis and constant comparison. The iterative data generation and analysis process resulted in a framework composed of three "ways" (i.e. categories) of establishing connections: (1) acknowledging the individual, (2) giving-of-self, and (3) using the body as a pivot point. Findings were supported by various rigor strategies including peer debrief and external audit. This framework demonstrates that establishing connections is a multi-faceted endeavor with personal and professional characteristics. The findings provide practical knowledge that can be used to guide clinicians, educators, and researchers in addressing the therapeutic relationship. PMID- 29432059 TI - Microbiome Special Issue: Food, Drugs, Diagnostics, and Built Environments. PMID- 29432060 TI - Interview with Colin Garvey, Rensselaer Polytechnic Institute. Artificial Intelligence and Systems Medicine Convergence. PMID- 29432061 TI - Atorvastatin Treatment Modulates the Gut Microbiota of the Hypercholesterolemic Patients. AB - Hypercholesterolemia is one of the most important risk factors for development of cardiovascular diseases. The composition of gut microbiota (total microbes residing in the gut) impacts on cholesterol and lipid metabolism. On the contrary, alterations in gut microbiota in response to hypercholesterolemia or drug treatment with atorvastatin (a cholesterol-lowering agent) are rarely investigated. We performed 16S rDNA amplicon sequencing to evaluate the gut bacterial community of 15 untreated hypercholesterolemic patients (HP) and 27 atorvastatin-treated hypercholesterolemic patients (At-HP) and compared with 19 healthy subjects (HS). In total, 18 different phyla were identified in the study groups. An increase in relative abundance of Proteobacteria was observed in the HP group compared with At-HP and HS groups. The atherosclerosis-associated genus Collinsella was found at relatively higher abundance in the HP group. The anti inflammation-associated bacteria (Faecalibacterium prausnitzii, Akkermansia muciniphila, and genus Oscillospira) were found in greater abundance, and proinflammatory species Desulfovibrio sp. was observed at decreased abundance in the drug-treated HP group compared with the untreated HP group. Relative abundances of the Bilophila wadsworthia and Bifidobacterium bifidum (bile acid associated species) were decreased in the At-HP group. The At-HP and HS clustered separately from HP in the principal coordinate analysis. Decreased bacterial diversity was observed in the atorvastatin-treated group. In conclusion, these data suggest that atorvastatin treatment of patients with hypercholesterolemia may selectively restore the relative abundance of several dominant and functionally important taxa that were disrupted in the HP. Further studies are required to investigate the putative modifying effects of hypocholesterolemic drugs on functionality of gut microbiota, and the potential downstream effects on human health. PMID- 29432062 TI - Visibility impacts at Class I areas near the Bakken oil and gas development. AB - : Oil and gas activities have occurred in the Bakken region of North Dakota and nearby states and provinces since the 1950s but began increasing rapidly around 2008 due to new extraction methods. Three receptor-based techniques were used to examine the potential impacts of oil and gas extraction activities on airborne particulate concentrations in Class I areas in and around the Bakken. This work was based on long-term measurements from the Interagency Monitoring of Protected Visual Environments (IMPROVE) monitoring network. Spatial and temporal patterns in measured concentrations were examined before and after 2008 to better characterize the influence of these activities. A multisite back-trajectory analysis and a receptor-based source apportionment model were used to estimate impacts. Findings suggest that recent Bakken oil and gas activities have led to an increase in regional fine (PM2.5-particles with aerodynamic diameters <2.5 um) soil and elemental carbon (EC) concentrations, as well as coarse mass (CM = PM10 PM2.5). Influences on sulfate and nitrate concentrations were harder to discern due to the concurrent decline in regional emissions of precursors to these species from coal-fired electric generating stations. Impacts were largest at sites in North Dakota and Montana that are closest to the most recent drilling activity. IMPLICATIONS: The increase in oil and gas activities in the Bakken region of North Dakota and surrounding areas has had a discernible impact on airborne particulate concentrations that impact visibility at protected sites in the region. However, the impact has been at least partially offset by a concurrent reduction in emissions from coal-fired electric generating stations. Continuing the recent reductions in flaring would likely be beneficial for the regional visual air quality. PMID- 29432063 TI - Approach to Pulmonary Hypertension: From CT to Clinical Diagnosis. AB - Pulmonary hypertension (PH) is a condition characterized by increased pressure in the pulmonary circulation. It may be idiopathic or arise in the setting of other clinical conditions. Patients with PH tend to present with nonspecific cardiovascular or respiratory symptoms. The clinical classification of PH was recently revised at the World Health Organization symposium in Nice, France, in 2013. That consensus statement provided an updated classification based on the shared hemodynamic characteristics and management of the different categories of PH. Some features seen at computed tomography (CT) can suggest a subtype or probable cause of PH that may facilitate placing the patient in the correct category. These features include findings in the pulmonary arteries (peripheral calcification, peripheral dilatation, eccentric filling defects, intra-arterial soft tissue), lung parenchyma (centrilobular nodules, mosaic attenuation, interlobular septal thickening, bronchiectasis, subpleural peripheral opacities, ground-glass opacities, diffuse nodules), heart (congenital lesions, left heart disease, valvular disease), and mediastinum (hypertrophied bronchial arteries). An approach based on identification of these CT features in patients with PH will allow the radiologist to play an important role in diagnosis and help guide the clinician in management of PH. (c)RSNA, 2018. PMID- 29432064 TI - An historical experiment: Los Angeles smog evolution observed by blimp. AB - : Observations of smog over the Los Angeles Basin (LAB) links high oxidant mixing ratios with poor visibility, sometimes <5 km. By the 1970s, investigators recognized that most of the aerosol affecting visibility was from gaseous oxidation products, sulfate, nitrate, and organic carbon. This led to the 1972 1973 Aerosol Characterization Experiment (ACHEX), which included observations at the ground and from aircraft. Part of ACHEX was the measurement of smog by blimp in a Lagrangian-like format. The experiment on September 6, 1973, demonstrated that a blimp could travel with the wind across the LAB, observing ozone (O3) and precursors, and particles of different size ranges. These included condensation nuclei (CN) concentrations dominated by particles of <= 0.1 um diameter and light scattering coefficient (bsc) representing mainly particles of 0.1-2.0 um diameter. The results indicated a pollutant variation similar to that measured at a fixed site. Ozone was produced in an air mass, reaching a maximum of ~400 ppb in the presence of nitrogen oxides (NOx) and nonmethane hydrocarbons (NMHCs), then declined. Although the photochemistry was developing, bsc grew with O3 mixing ratio to a quasi-steady state at ~9-10 * 10-4 m-1, decreasing in value much later with decease in O3. The light scattering coefficient was found to be positively associated with the O3 mixing ratio, whereas CN concentrations were negatively proportional to O3 mixing ratio. The blimp experiment was supported with aircraft vertical profiles and ground-level observations from a mobile laboratory. The blimp flight obtained combined gas and particle changes aloft that could not be obtained by ground or fixed-wing aircraft measurements alone. The experiment was partially successful in achieving a true Lagrangian characterization of smog chemistry in a constrained or defined "open" air mass. IMPLICATIONS: The Los Angeles experiment demonstrated the use of a blimp as a platform for measurement of air pollution traveling with an air mass across an urban area. The method added unique data showing the relationship between photochemical smog chemistry and aerosol dynamics in smog. The method offers an alternative to reliance on smog chamber and modeling observations to designing air quality management strategies for reactive pollutants. PMID- 29432065 TI - Correction to: "Effects of Aqua-Lymphatic Therapy on Lower Extremity Lymphedema: A Randomized Controlled Study" by G Ergin, D Karadibak, HO Sener, and B Gurpinar Lymphatic Research and Biology 2017; 15(3): 284-291 DOI: 10.1089/lrb.2017.0017. PMID- 29432066 TI - Evaluation of CT Changes in the Head and Neck After Cancer Treatment: Development of a Measurement Tool. AB - BACKGROUND: The late effect continuum of lymphedema and fibrosis (LEF) affects more than 70% of patients after treatment for head and neck cancer (HNC). LEF is associated with symptom burden and decreased function and quality of life. Although surveillance imaging is common posttreatment, objective assessment of soft tissues is not, likely due to the lack of objective evaluation methods and understanding of the significance of LEF. We undertook the development of a tool to measure LEF using CT scans in HNC patients. METHODS AND RESULTS: We developed a CT measurement tool assessing sites of soft tissue damage secondary to tumor, surgery, or radiation. The tool was applied to pre- and posttreatment CT scans for 10 HNC patients. The data were reviewed, and the initial tool was modified. Ten additional patients' scans were assessed using the revised tool. The tool was modified further after data review by an expert panel and was then applied to scans from all 20 patients. The final tool included 11 items as follows: grading of fat stranding at 6 sites (axial reconstruction images, scale 0-2), measurement of epiglottic thickness (sagittal images, scale mm), and measurement of prevertebral soft tissue thickness at C3 (sagittal images, scale mm). A total of 176 CT scans were evaluated from 20 patients (range 4-14 examinations/patient). Preliminary data demonstrated face validity. CONCLUSIONS: The final LEF assessment tool (CT-LEFAT) provides a standardized method for assessing critical sites that are involved by LEF. Studies to assess reliability and validity are ongoing. PMID- 29432067 TI - Community-Based Treatment for Chronic Edema: An Effective Service Model. AB - BACKGROUND: Chronic edema care is patchy and of variable quality internationally. This study was undertaken to develop and evaluate a system of care that would provide for patients within a geographical area of London (Wandsworth), United Kingdom. METHODS AND RESULTS: A prospective cohort design with intervention of a new service design following a 6-month baseline period. Patients were identified through health professionals. A stratified random sample was drawn from all patients and an implementation strategy developed. Clinical assessment combined with questionnaires evaluated clinical, patient, and health service outcomes at 6 month periods. In all, 312 patients were identified in community and acute services giving a crude ascertainment rate of 1.16 per 1000 population. The random sample of 107 was mostly female (82%) with mean (standard deviation) age of 72.9 (12.4) in men and 68.6 (15.0) years in women. Mean reductions in limb volume achieved statistical differences at 6-12 months after implementation (difference [d] = 115 mL, p = 0.0001). Incidence of cellulitis dropped from 41.5/100 patient years at baseline to zero at 6-12 months. Quality of life showed greatest improvements between baseline and 6 months postimplementation, the largest differences being in role physical (d = 32.7, p = 0.0001) and role emotion (d = 24.0, p < 0.0001). EuroQol increased following implementation by a mean score of 0.05 (p = 0.007). There was a reduction in 6 monthly healthcare costs from L50171 per 100 patients at baseline to L17618 between 6 and 12 months. CONCLUSIONS: This process of implementation improves health outcomes while reducing healthcare costs in patients with lymphedema. PMID- 29432070 TI - Growing Insights into Breast Cancer-Related Lymphedema. PMID- 29432071 TI - Neurocysticercosis: An unusual seizure etiology in a hematopoietic stem cell transplanted patient. PMID- 29432072 TI - The effect of 111In radionuclide distance and auger electron energy on direct induction of DNA double-strand breaks: a Monte Carlo study using Geant4 toolkit. AB - PURPOSE: In this study, the effect of 111In position and Auger electron energy on direct induction of DSBs was investigated. MATERIALS AND METHODS: The Geant4-DNA simulation toolkit was applied using a simple B-DNA form extracted from PDBlib library. First, the simulation was performed for electrons with energies of 111In and equal emission probabilities to find the most effective electron energies. Then, 111In Auger electrons' actual spectrum was considered and their contribution in DSB induction analysed. RESULTS: The results showed that the most effective electron energy is 183 eV, but due to the higher emission probability of 350 eV electrons, most of the DSBs were induced by the latter electrons. Also, it was observed that most of the DSBs are induced by electrons emitted within 4 nm of the central axis of the DNA and were mainly due to breaks with <4 base pairs distance in opposing strands. Whilst, when 111In atoms are very close to the DNA, 1.3 DSBs have been obtained per decay of 111In atoms. CONCLUSIONS: The results show that the most effective Auger electrons are the 350 eV electrons from 111In atoms with <4 nm distance from the central axis of the DNA which induce ~1.3 DSBs per decay when bound to the DNA. This value seems reasonable when compared with the reported experimental data. PMID- 29432073 TI - m-Health Policy Readiness and Enabling Factors: Comparisons of Sub-Saharan Africa and Organization for Economic Cooperation and Development Countries. AB - BACKGROUND: As an innovative solution to poor access to care in low- and middle income countries (LMICs), m-health has gained wide attention in the past decade. INTRODUCTION: Despite enthusiasm from the global health community, LMICs have not demonstrated high uptake of m-health promoting policies or public investment. MATERIALS AND METHODS: To benchmark the current status, this study compared m health policy readiness scores between sub-Saharan Africa and high-income Organization for Economic Cooperation and Development (OECD) countries using an independent two-sample t test. In addition, the enabling factors associated with m-health policy readiness were investigated using an ordinal logistic regression model. The study was based on the m-health policy readiness scores of 112 countries obtained from the World Health Organization Third Global Survey on e Health. RESULTS: The mean m-health policy readiness score for sub-Saharan Africa was statistically significantly lower than that for OECD countries (p = 0.02). The enabling factors significantly associated with m-health policy readiness included information and communication technology development index (odds ratio [OR] 1.57; 95% confidence interval [CI] 1.12-2.2), e-health education for health professionals (OR 4.43; 95% CI 1.60-12.27), and the location in sub-Saharan Africa (OR 3.47; 95% CI 1.06-11.34). DISCUSSION: The findings of our study suggest dual policy goals for m-health in sub-Saharan Africa. First, enhance technological and educational support for m-health. Second, pursue global collaboration for building m-health capacity led by sub-Saharan African countries with hands-on experience and knowledge. CONCLUSION: Globally, countries should take a systematic and collaborative approach in pursuing m-health policy with the focus on technological and educational support. PMID- 29432075 TI - Indian elderly women's experiences of food procurement and preparation. AB - The present study explored the experiences of Indian elderly women in meal preparation and food procurement. Ten elderly women aged 60-72 years residing in a metropolis were interviewed. Thematic analysis identified two overarching themes: "Meal preparation and food procurement are meaningful occupations" and "Meal preparation and food procurement change with age." The findings suggests that Indian elderly women valued their participation in these activities. They actively adopted alternative strategies and technologies to overcome the challenges experienced while performing these activities. The findings highlight the strong influence of family and financial aspects on the decisions of elderly women with regard to meal preparation and food procurement. The study findings provide salient information on personal and environmental factors that could guide interventions to promote and maintain Indian elderly women's participation in these meaningful occupations. PMID- 29432074 TI - An opioid overdose curriculum for medical residents: Impact on naloxone prescribing, knowledge, and attitudes. AB - BACKGROUND: Despite escalating opioid overdose death rates, addiction medicine is underrepresented in residency curricula. Providing naloxone to at-risk patients, relatives, and first responders reduces overdose deaths, but rates of naloxone prescribing remain low. The goal of this study is to examine the impact of a brief curricular intervention for internal medicine residents on naloxone prescribing rates, knowledge, and attitudes. METHODS: Internal medicine residents (N = 160) at an urban, tertiary care medical center received two 1-hour didactic sessions addressing overdose prevention, including intranasal naloxone. The number of naloxone prescriptions generated by residents was compared to faculty, who received no similar intervention, in the 3-month periods before and after the curriculum. Resident knowledge and attitudes, as assessed by pre- and post intervention surveys, were compared. RESULTS: The resident naloxone prescribing rate increased from 420 to 1270 per 100,000 inpatient discharges (P = .01) and from 0 to 370 per 100,000 ambulatory visits (P < .001) post-intervention. Similar increases were not observed among inpatient faculty, whose prescribing rate decreased from 1150 to 880 per 100,000 discharges (P = .08), or among outpatient faculty, whose rate increased from 30 to 180 per 100,000 ambulatory visits (P < .001) but was lower than the post-intervention resident rate (P = .01). Residents demonstrated high baseline knowledge about naloxone, but just 13% agreed that they were adequately trained to prescribe pre-intervention. Post-intervention, residents were more likely to agree that they were adequately trained to prescribe (Likert mean 2.5 vs. 3.9, P < .001), to agree that treating addiction is rewarding (Likert mean 2.9 vs. 3.3, P = .03), and to attain a perfect score on the knowledge composite (57% vs. 33%, P = .05). CONCLUSIONS: A brief curricular intervention improved resident knowledge and attitudes regarding intranasal naloxone for opioid overdose reversal and significantly increased prescribing rates. PMID- 29432076 TI - Neoadjuvant Chemotherapy Followed by Radical Surgery Versus Concomitant Chemotherapy and Radiotherapy in Patients With Stage IB2, IIA, or IIB Squamous Cervical Cancer: A Randomized Controlled Trial. AB - Purpose We compared the efficacy and toxicity of neoadjuvant chemotherapy followed by radical surgery versus standard cisplatin-based chemoradiation in patients with locally advanced squamous cervical cancer. Patients and Methods This was a single-center, phase III, randomized controlled trial ( ClinicalTrials.gov identifier: NCT00193739). Eligible patients were between 18 and 65 years old and had stage IB2, IIA, or IIB squamous cervical cancer. They were randomly assigned, after stratification by stage, to receive either three cycles of neoadjuvant chemotherapy using paclitaxel and carboplatin once every 3 weeks followed by radical hysterectomy or standard radiotherapy with concomitant cisplatin once every week for 5 weeks. Patients in the neoadjuvant group received postoperative adjuvant radiation or concomitant chemotherapy and radiotherapy, if indicated. The primary end point was disease-free survival (DFS), defined as survival without relapse or death related to cancer, and secondary end points included overall survival and toxicity. Results Between September 2003 and February 2015, 635 patients were randomly assigned, of whom 633 (316 patients in the neoadjuvant chemotherapy plus surgery group and 317 patients in the concomitant chemoradiation group) were included in the final analysis, with a median follow-up time of 58.5 months. The 5-year DFS in the neoadjuvant chemotherapy plus surgery group was 69.3% compared with 76.7% in the concomitant chemoradiation group (hazard ratio, 1.38; 95% CI, 1.02 to 1.87; P = .038), whereas the corresponding 5-year OS rates were 75.4% and 74.7%, respectively (hazard ratio, 1.025; 95% CI, 0.752 to 1.398; P = .87). The delayed toxicities at 24 months or later after treatment completion in the neoadjuvant chemotherapy plus surgery group versus the concomitant chemoradiation group were rectal (2.2% v 3.5%, respectively), bladder (1.6% v 3.5%, respectively), and vaginal (12.0% v 25.6%, respectively). Conclusion Cisplatin-based concomitant chemoradiation resulted in superior DFS compared with neoadjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer. PMID- 29432077 TI - Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. AB - Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post treatment specimens. Results In group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a >= 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8+ and T-bet+ cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX 2401 administration. Conclusion Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response. PMID- 29432079 TI - First-Line Treatment of Hormone-Sensitive Metastatic Prostate Cancer: Is There a Single Standard of Care? PMID- 29432078 TI - Endogenous Tumor Suppressor microRNA-193b: Therapeutic and Prognostic Value in Acute Myeloid Leukemia. AB - Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR 193b knockout mice in vitro and in vivo. Results miR-193b exerted important, endogenous, tumor-suppressive functions on the hematopoietic system. miR-193b-3p was downregulated in several cytogenetically defined subgroups of pediatric and adult AML, and low expression served as an independent indicator for poor prognosis in pediatric AML (risk ratio +/- standard error, -0.56 +/- 0.23; P = .016). miR-193b-3p expression improved the prognostic value of the European LeukemiaNet risk-group stratification or a 17-gene leukemic stemness score. In knockout mice, loss of miR-193b cooperated with Hoxa9/Meis1 during leukemogenesis, whereas restoring miR-193b expression impaired leukemic engraftment. Similarly, expression of miR-193b in AML blasts from patients diminished leukemic growth in vitro and in mouse xenografts. Mechanistically, miR 193b induced apoptosis and a G1/S-phase block in various human AML subgroups by targeting multiple factors of the KIT-RAS-RAF-MEK-ERK (MAPK) signaling cascade and the downstream cell cycle regulator CCND1. Conclusion The tumor-suppressive function is independent of patient age or genetics; therefore, restoring miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms. PMID- 29432080 TI - Team-based care: Views from community health center staff. AB - Community health centers (CHC) provide quality care for vulnerable patients, and a potentially contributing factor to this quality is the integration of a patient centered medical home (PCMH). PCMH relies on a team-based approach, a principle in which social workers are trained and research examines in primary care environments. Less is known about team-based care in CHCs. An exploratory qualitative study with 14 CHC staff was conducted to examine the current state of team-based care and secondarily, to examine the role of social workers. Content analysis revealed four themes central to team-based care. Implications for CHCs and social workers are discussed. PMID- 29432081 TI - Retention of student pharmacists' knowledge and skills regarding overdose management with naloxone. AB - BACKGROUND: Overdose education and naloxone training was recently implemented into the required curriculum of the College of Pharmacy at the University of Rhode Island. The objective of this study was to compare the retention of knowledge between student pharmacists who received a didactic lecture only and student pharmacists who received the same lecture plus a skills-based objective structured clinical examination (OSCE) with a standardized patient actor. METHODS: Students in their first professional year (P1) of the Doctor of Pharmacy program (n = 129) and students in their second professional year (P2) (n = 123) attended a required lecture on opioid overdose, including detailed naloxone training. P2 students were additionally required to participate in an OSCE assessment following the didactic lecture component. An anonymous, voluntary survey was offered to all students approximately 6 months later. A chi-square or Fisher's exact test was performed on the survey responses to assess any difference in the responses between the 2 groups. RESULTS: A total of 99 P1 students (76.7%) and 116 P2 students (94.3%) completed the survey. P1 students were found to be more knowledgeable regarding the duration of naloxone action and identification of risk factors for opioid overdose. P2 students were found to be more knowledgeable regarding nonmedical ways patients may obtain opioids and the correct order of emergency response during a suspected opioid overdose. CONCLUSIONS: P2 students did not demonstrate superior retention of information regarding naloxone and opioid use disorder on survey questions compared with P1 students. There was a trend towards P2 students feeling more confident in their ability to counsel patients for overdose prevention and reporting disagreement with the statement that "overdose prevention for people who use drugs is a waste of time and money" compared with the P1 students, but these did not reach statistical significance. Since the opioid crisis continues unabated, naloxone training using OSCE and didactic methods remain an ongoing required part of the pharmacy curriculum. PMID- 29432082 TI - Enhancing Meaning when Facing Later Life Losses. AB - OBJECTIVE: This article presents several client cases to illustrate psychotherapeutic interventions for helping older adults facing later life losses enhance their sense of meaning. METHODS: Cases are derived from the client population of a community mental health clinic which provides psychotherapy for low income, seriously mentally ill, culturally diverse older adults, many of whom experience serious medical illnesses. Over the course of 24 years in this setting, the primary author has observed various interventions which offer possibilities to provide hope and meaning for clients with severe problems. RESULTS: Interventions discussed with individual cases include utilizing life review and reminiscence therapies, helping in grappling with the ending of life, facilitating enhanced relationships, encouraging creative endeavors, enabling spiritual and religious practices, honoring wisdom and legacy leaving, and engaging in mindfulness practices. Each approach is reviewed with reference to empirical support, clinical utility, and treatment considerations. CONCLUSIONS: Helping older adults to find hope and meaning in their lives can be challenging. Specific interventions which target meaning-making may be adapted to fit each client's needs. CLINICAL IMPLICATIONS: Clinicians may focus on enhancing meaning as a core or adjunct aspect of treatment with older adult clients. Considerations for implementing interventions may depend on contextual factors relevant to each case. PMID- 29432083 TI - Driving and riding under the influence of recent marijuana use: Risk factors among a racially diverse sample of young adults. AB - Driving (DUIM) and riding (RUIM) with a driver under the influence of marijuana increases crash risk. This study assessed risk factors for DUIM and RUIM among ethnically diverse young adults. Randomly selected individuals were surveyed. Multivariable regression was used to assess risk factors associated with DUIM and RUIM. Participants (N = 335, response rate = 34.9%) were 33.7% White non Hispanic. Reported DUIM and RUIM was not statistically significant by race/ethnicity. Frequency of marijuana use was significantly associated with greater risk of DUIM. Peer marijuana use was associated with greater risk of RUIM. Public health efforts to target social norms around marijuana-impaired driving are warranted. PMID- 29432084 TI - The relationship between drug use settings, roles in the drug economy, and witnessing a drug overdose in Baltimore, Maryland. AB - BACKGROUND: There has been a dramatic increase in drug overdose deaths in the United States. In the current study, the authors examined factors associated with witnessing a drug overdose. METHODS: A sample of 450 substance users in Baltimore, Maryland, were recruited for a behavioral intervention and were administered a survey. Multinomial logistic regression models were used to compare participants who never witnessed a drug overdose with those who witnessed one in the prior 6 months and those who witnessed an overdose over 6 months ago. RESULTS: Most (58%) participants were male, 40% experienced homelessness in the prior 6 months, 63% reported a history of heroin injecting, 84% had snorted heroin, 75% reported witnessing a drug overdose, and 38% experienced an overdose. In multinomial logistic regression models, witnessing an overdose in the past 6 months was associated with number of different types of places where drugs were used (adjusted odds ratio [aOR] = 1.34), history of experiencing an overdose (aOR = 1.80), injecting heroin and/or speedball (aOR = 1.78), and snorting heroin (aOR = 1.54). Witnessing an overdose more than 6 months ago was associated with number of different places where drugs were used (aOR = 1.25), history of experiencing an overdose (aOR = 1.61), snorting heroin (aOR = 1.42), and injecting heroin or speedball (aOR = 1.47). CONCLUSIONS: These data suggest that people who engage in more public and frequent drug use, and hence are more likely to witness an overdose, should be targeted for interventions to prevent and treat drug overdose. PMID- 29432085 TI - Training peers to treat Ebola centre workers with anxiety and depression in Sierra Leone. AB - BACKGROUND: Following the 2014 Ebola virus disease (EVD) outbreak in West Africa, the UK Department for International Development funded South London and Maudsley National Health Service (NHS) to develop a psychological intervention that ex Ebola Treatment Centre (ETC) staff could be trained to deliver to their peers to improve mental health in Sierra Leone. AIM: The two key aims were to assess the feasibility of training a national team to deliver a cognitive behavioural therapy (CBT)-based group intervention, and to evaluate the effectiveness of the overall intervention within this population. METHODS: UK clinicians travelled to Sierra Leone to train a small team of ex-ETC staff in a three-phased CBT-based intervention. Standardised clinical measures, as well as bespoke measures, were applied with participants through the intervention to assess changes in mental health symptomology, and the effectiveness of the intervention. RESULTS: The results found improvements across all factors of mental health in the bespoke measure from phase 1 to phase 3. Additionally, the majority of standardised clinical measures showed improvements between phase 2 and the start of phase 3, and pre- and post-phase 3. CONCLUSION: Overall, the findings suggest that it is possible to train staff from ETCs to deliver effective CBT interventions to peers. The implications of these results are discussed, including suggestions for future research and clinical intervention implementation within this population. The limitations of this research are also addressed. PMID- 29432086 TI - Overcoming medication stigma in peer recovery: A new paradigm. AB - BACKGROUND: Treatment for opioid use disorder involving opioid-based pharmacotherapies is considered most effective when accompanied by psychosocial interventions. Peer-led support groups are widely available and have been described by many as fundamental to the recovery process. However, some individuals using medications face stigma in these settings, which can be contradictory and counterproductive to their recovery. METHODS: This paper describes the development of the "Ability, Inspiration and Motivation" or "AIM" group, an alternative peer support group that aims to remove medication stigma from peer recovery. Qualitative interviews with staff, peers, and clients of a community-based buprenorphine treatment program were used to establish the core components of the curriculum to support client needs. RESULTS: Staff, peers, and clients of the buprenorphine program indicated a need and desire to establish a peer recovery group that recognizes persons on medication as being in recovery and destigmatizes use of medication to treat opioid addiction. A respectful environment, holistic perspective on health, spirituality, sharing, and celebration were all established as necessary pillars of the AIM group curriculum. CONCLUSIONS: The community-based effort to establish and develop the AIM group demonstrates that combining the strengths of a peer support with evidence-based medication treatment is both possible and desirable. Shifting the culture of peer recovery groups to support the use of medications may have implications for improving treatment retention and should be considered as a potential strategy to reduce the burden of the opioid epidemic. PMID- 29432087 TI - MDMA (ecstasy/molly) use among African Americans: The perceived influence of hip hop/rap music. AB - Over the past two decades, the demographic profile of MDMA (ecstasy/molly) users has changed. In particular, African American MDMA use has risen in some cities. One explanation of this new trend is the drug's recent popularity (as molly) in hip-hop/rap (HHR) music. Several top rappers endorse the drug as a way to have fun or get women "loose." There are currently no studies, however, that investigate the extent to which African American MDMA users listen to HHR music or the influence that these pro-MDMA messages have on their use of the drug. To address this gap, the current study used survey data to (a) identify the extent to which HHR music is listened to by African American MDMA users and (b) assess the perceived influence of HHR music on their decision to begin using. Qualitative interview data are also presented to contextualize the influence of these messages on their use of MDMA. The findings of this study suggest that African American MDMA users are high consumers of HHR music and that pro-MDMA messages in HHR music are influencing their expectations of the drug and their decision to initiate use. These findings add to the limited amount of research on African American MDMA use and have the potential to inform future interventions. PMID- 29432088 TI - Module-based comprehensive approach for addressing heterogeneous mental health sequelae of violent loss survivors. AB - Significant strides have been made in the trauma and grief fields to address the unique needs of those who have lost a loved one to violent death. Several treatment techniques have been found to be effective for symptoms of trauma and grief that are prevalent among violent loss survivors including restorative retelling and cognitive behavioral strategies. Current interventions either are tailored for a specific mental health problem or are more universal in nature for grief related to violent loss. This paper presents an evidence-based and guided modular approach for responding to the myriad potential mental health needs of violent loss survivors. A comprehensive module-based structured intervention for violent loss survivors, which specifically targets several common mental health difficulties following traumatic loss, may offer clinicians a thorough and flexible approach guided by clinical assessment to address the distinctive and common issues violent loss survivors often face. PMID- 29432092 TI - Local and Global Feature Learning for Blind Quality Evaluation of Screen Content and Natural Scene Images. AB - The blind quality evaluation of screen content images (SCIs) and natural scene images (NSIs) has become an important, yet very challenging issue. In this paper, we present an effective blind quality evaluation technique for SCIs and NSIs based on a dictionary of learned local and global quality features. First, a local dictionary is constructed using local normalized image patches and conventional -means clustering. With this local dictionary, the learned local quality features can be obtained using a locality-constrained linear coding with max pooling. To extract the learned global quality features, the histogram representations of binary patterns are concatenated to form a global dictionary. The collaborative representation algorithm is used to efficiently code the learned global quality features of the distorted images using this dictionary. Finally, kernel-based support vector regression is used to integrate these features into an overall quality score. Extensive experiments involving the proposed evaluation technique demonstrate that in comparison with most relevant metrics, the proposed blind metric yields significantly higher consistency in line with subjective fidelity ratings. PMID- 29432093 TI - Deep Context-Sensitive Facial Landmark Detection With Tree-Structured Modeling. AB - Facial landmark detection is typically cast as a point-wise regression problem that focuses on how to build an effective image-to-point mapping function. In this paper, we propose an end-to-end deep learning approach for contextually discriminative feature construction together with effective facial structure modeling. The proposed learning approach is able to predict more contextually discriminative facial landmarks by capturing their associated contextual information. Moreover, we present a tree model to characterize human face structure and a structural loss function to measure the deformation cost between the ground-truth and predicted tree model, which are further incorporated into the proposed learning approach and jointly optimized within a unified framework. The presented tree model is able to well characterize the spatial layout patterns of facial landmarks for capturing the facial structure information. Experimental results demonstrate the effectiveness of the proposed approach against the state of-the-art over the MTFL and AFLW-full data sets. PMID- 29432091 TI - Influenza A(H7N9) Virus Antibody Responses in Survivors 1 Year after Infection, China, 2017. AB - Avian influenza A(H7N9) virus has caused 5 epidemic waves in China since its emergence in 2013. We investigated the dynamic changes of antibody response to this virus over 1 year postinfection in 25 patients in Suzhou City, Jiangsu Province, China, who had laboratory-confirmed infections during the fifth epidemic wave, October 1, 2016-February 14, 2017. Most survivors had relatively robust antibody responses that decreased but remained detectable at 1 year. Antibody response was variable; several survivors had low or undetectable antibody titers. Hemagglutination inhibition titer was >1:40 for <40% of the survivors. Measured in vitro in infected mice, hemagglutination inhibition titer predicted serum protective ability. Our findings provide a helpful serologic guideline for identifying subclinical infections and for developing effective vaccines and therapeutics to counter H7N9 virus infections. PMID- 29432094 TI - Kernel K-Means Sampling for Nystrom Approximation. AB - A fundamental problem in Nystrom-based kernel matrix approximation is the sampling method by which training set is built. In this paper, we suggest to use kernel -means sampling, which is shown in our works to minimize the upper bound of a matrix approximation error. We first propose a unified kernel matrix approximation framework, which is able to describe most existing Nystrom approximations under many popular kernels, including Gaussian kernel and polynomial kernel. We then show that, the matrix approximation error upper bound, in terms of the Frobenius norm, is equal to the -means error of data points in kernel space plus a constant. Thus, the -means centers of data in kernel space, or the kernel -means centers, are the optimal representative points with respect to the Frobenius norm error upper bound. Experimental results, with both Gaussian kernel and polynomial kernel, on real-world data sets and image segmentation tasks show the superiority of the proposed method over the state-of-the-art methods. PMID- 29432095 TI - Convolutional Sparse and Low-Rank Coding-Based Image Decomposition. AB - We propose novel convolutional sparse and low-rank coding-based methods for cartoon and texture decomposition. In our method, we first learn a set of generic filters that can efficiently represent cartoon-and texture-type images. Then, using these learned filters, we propose two optimization frameworks to decompose a given image into cartoon and texture components: convolutional sparse coding based image decomposition; and convolutional low-rank coding-based image decomposition. By working directly on the whole image, the proposed image separation algorithms do not need to divide the image into overlapping patches for leaning local dictionaries. The shift-invariance property is directly modeled into the objective function for learning filters. Extensive experiments show that the proposed methods perform favorably compared with state-of-the-art image separation methods. PMID- 29432096 TI - Video Summarization Via Multiview Representative Selection. AB - Video contents are inherently heterogeneous. To exploit different feature modalities in a diverse video collection for video summarization, we propose to formulate the task as a multiview representative selection problem. The goal is to select visual elements that are representative of a video consistently across different views (i.e., feature modalities). We present in this paper the multiview sparse dictionary selection with centroid co-regularization method, which optimizes the representative selection in each view, and enforces that the view-specific selections to be similar by regularizing them towards a consensus selection. We also introduce a diversity regularizer to favor a selection of diverse representatives. The problem can be efficiently solved by an alternating minimizing optimization with the fast iterative shrinkage thresholding algorithm. Experiments on synthetic data and benchmark video datasets validate the effectiveness of the proposed approach for video summarization, in comparison with other video summarization methods and representative selection methods such as K-medoids, sparse dictionary selection, and multiview clustering. PMID- 29432097 TI - Spatial and Angular Resolution Enhancement of Light Fields Using Convolutional Neural Networks. AB - Light field imaging extends the traditional photography by capturing both spatial and angular distribution of light, which enables new capabilities, including post capture refocusing, post-capture aperture control, and depth estimation from a single shot. Micro-lens array (MLA) based light field cameras offer a cost effective approach to capture light field. A major drawback of MLA based light field cameras is low spatial resolution, which is due to the fact that a single image sensor is shared to capture both spatial and angular information. In this paper, we present a learning based light field enhancement approach. Both spatial and angular resolution of captured light field is enhanced using convolutional neural networks. The proposed method is tested with real light field data captured with a Lytro light field camera, clearly demonstrating spatial and angular resolution improvement. PMID- 29432098 TI - Physics-Based Image Segmentation Using First Order Statistical Properties and Genetic Algorithm for Inductive Thermography Imaging. AB - Thermographic inspection has been widely applied to non-destructive testing and evaluation with the capabilities of rapid, contactless, and large surface area detection. Image segmentation is considered essential for identifying and sizing defects. To attain a high-level performance, specific physics-based models that describe defects generation and enable the precise extraction of target region are of crucial importance. In this paper, an effective genetic first-order statistical image segmentation algorithm is proposed for quantitative crack detection. The proposed method automatically extracts valuable spatial-temporal patterns from unsupervised feature extraction algorithm and avoids a range of issues associated with human intervention in laborious manual selection of specific thermal video frames for processing. An internal genetic functionality is built into the proposed algorithm to automatically control the segmentation threshold to render enhanced accuracy in sizing the cracks. Eddy current pulsed thermography will be implemented as a platform to demonstrate surface crack detection. Experimental tests and comparisons have been conducted to verify the efficacy of the proposed method. In addition, a global quantitative assessment index F-score has been adopted to objectively evaluate the performance of different segmentation algorithms. PMID- 29432099 TI - When Dijkstra Meets Vanishing Point: A Stereo Vision Approach for Road Detection. AB - In this paper, we propose a vanishing-point constrained Dijkstra road model for road detection in a stereo-vision paradigm. First, the stereo-camera is used to generate the u- and v-disparity maps of road image, from which the horizon can be extracted. With the horizon and ground region constraints, we can robustly locate the vanishing point of road region. Second, a weighted graph is constructed using all pixels of the image, and the detected vanishing point is treated as the source node of the graph. By computing a vanishing-point constrained Dijkstra minimum-cost map, where both disparity and gradient of gray image are used to calculate cost between two neighbor pixels, the problem of detecting road borders in image is transformed into that of finding two shortest paths that originate from the vanishing point to two pixels in the last row of image. The proposed approach has been implemented and tested over 2600 grayscale images of different road scenes in the KITTI data set. The experimental results demonstrate that this training-free approach can detect horizon, vanishing point, and road regions very accurately and robustly. It can achieve promising performance. PMID- 29432100 TI - Her2Net: A Deep Framework for Semantic Segmentation and Classification of Cell Membranes and Nuclei in Breast Cancer Evaluation. AB - We present an efficient deep learning framework for identifying, segmenting, and classifying cell membranes and nuclei from human epidermal growth factor receptor 2 (HER2)-stained breast cancer images with minimal user intervention. This is a long-standing issue for pathologists because the manual quantification of HER2 is error-prone, costly, and time-consuming. Hence, we propose a deep learning-based HER2 deep neural network (Her2Net) to solve this issue. The convolutional and deconvolutional parts of the proposed Her2Net framework consisted mainly of multiple convolution layers, max-pooling layers, spatial pyramid pooling layers, deconvolution layers, up-sampling layers, and trapezoidal long short-term memory (TLSTM). A fully connected layer and a softmax layer were also used for classification and error estimation. Finally, HER2 scores were calculated based on the classification results. The main contribution of our proposed Her2Net framework includes the implementation of TLSTM and a deep learning framework for cell membrane and nucleus detection, segmentation, and classification and HER2 scoring. Our proposed Her2Net achieved 96.64% precision, 96.79% recall, 96.71% F score, 93.08% negative predictive value, 98.33% accuracy, and a 6.84% false positive rate. Our results demonstrate the high accuracy and wide applicability of the proposed Her2Net in the context of HER2 scoring for breast cancer evaluation. PMID- 29432101 TI - Fast MPEG-CDVS Encoder With GPU-CPU Hybrid Computing. AB - The compact descriptors for visual search (CDVS) standard from ISO/IEC moving pictures experts group has succeeded in enabling the interoperability for efficient and effective image retrieval by standardizing the bitstream syntax of compact feature descriptors. However, the intensive computation of a CDVS encoder unfortunately hinders its widely deployment in industry for large-scale visual search. In this paper, we revisit the merits of low complexity design of CDVS core techniques and present a very fast CDVS encoder by leveraging the massive parallel execution resources of graphics processing unit (GPU). We elegantly shift the computation-intensive and parallel-friendly modules to the state-of-the arts GPU platforms, in which the thread block allocation as well as the memory access mechanism are jointly optimized to eliminate performance loss. In addition, those operations with heavy data dependence are allocated to CPU for resolving the extra but non-necessary computation burden for GPU. Furthermore, we have demonstrated the proposed fast CDVS encoder can work well with those convolution neural network approaches which enables to leverage the advantages of GPU platforms harmoniously, and yield significant performance improvements. Comprehensive experimental results over benchmarks are evaluated, which has shown that the fast CDVS encoder using GPU-CPU hybrid computing is promising for scalable visual search. PMID- 29432102 TI - Efficient Scalable Median Filtering Using Histogram-Based Operations. AB - Median filtering is a smoothing technique for noise removal in images. While there are various implementations of median filtering for a single-core CPU, there are few implementations for accelerators and multi-core systems. Many parallel implementations of median filtering use a sorting algorithm for rearranging the values within a filtering window and taking the median of the sorted value. While using sorting algorithms allows for simple parallel implementations, the cost of the sorting becomes prohibitive as the filtering windows grow. This makes such algorithms, sequential and parallel alike, inefficient. In this work, we introduce the first software parallel median filtering that is non-sorting-based. The new algorithm uses efficient histogram based operations. These reduce the computational requirements of the new algorithm while also accessing the image fewer times. We show an implementation of our algorithm for both the CPU and NVIDIA's CUDA supported graphics processing unit (GPU). The new algorithm is compared with several other leading CPU and GPU implementations. The CPU implementation has near perfect linear scaling with a speedup on a quad-core system. The GPU implementation is several orders of magnitude faster than the other GPU implementations for mid-size median filters. For small kernels, and , comparison-based approaches are preferable as fewer operations are required. Lastly, the new algorithm is open-source and can be found in the OpenCV library. PMID- 29432103 TI - Pixel Binning for High Dynamic Range Color Image Sensor Using Square Sampling Lattice. AB - We propose a new pixel binning scheme for color image sensors. We minimized distortion caused by binning by requiring that the superpixels lie on a square sampling lattice. The proposed binning schemes achieve the equivalent of 4.42 times signal strength improvement with the image resolution loss of 5 times, higher in noise performance and in resolution than the existing binning schemes. As a result, the proposed binning has considerably less artifacts and better noise performance compared with the existing binning schemes. In addition, we provide an extension to the proposed binning scheme for performing single-shot high dynamic range image acquisition. PMID- 29432104 TI - A Gaussian Mixture Model Representation of Endmember Variability in Hyperspectral Unmixing. AB - Hyperspectral unmixing while considering endmember variability is usually performed by the normal compositional model, where the endmembers for each pixel are assumed to be sampled from unimodal Gaussian distributions. However, in real applications, the distribution of a material is often not Gaussian. In this paper, we use Gaussian mixture models (GMM) to represent endmember variability. We show, given the GMM starting premise, that the distribution of the mixed pixel (under the linear mixing model) is also a GMM (and this is shown from two perspectives). The first perspective originates from random variable transformations and gives a conditional density function of the pixels given the abundances and GMM parameters. With proper smoothness and sparsity prior constraints on the abundances, the conditional density function leads to a standard maximum a posteriori (MAP ) problem which can be solved using generalized expectation maximization. The second perspective originates from marginalizing over the endmembers in the GMM, which provides us with a foundation to solve for the endmembers at each pixel. Hence, compared to the other distribution based methods, our model can not only estimate the abundances and distribution parameters, but also the distinct endmember set for each pixel. We tested the proposed GMM on several synthetic and real datasets, and showed its potential by comparing it to current popular methods. PMID- 29432105 TI - Learning a Continuous-Time Streaming Video QoE Model. AB - Over-the-top adaptive video streaming services are frequently impacted by fluctuating network conditions that can lead to rebuffering events (stalling events) and sudden bitrate changes. These events visually impact video consumers' quality of experience (QoE) and can lead to consumer churn. The development of models that can accurately predict viewers' instantaneous subjective QoE under such volatile network conditions could potentially enable the more efficient design of quality-control protocols for media-driven services, such as YouTube, Amazon, Netflix, and so on. However, most existing models only predict a single overall QoE score on a given video and are based on simple global video features, without accounting for relevant aspects of human perception and behavior. We have created a QoE evaluator, called the time-varying QoE Indexer, that accounts for interactions between stalling events, analyzes the spatial and temporal content of a video, predicts the perceptual video quality, models the state of the client side data buffer, and consequently predicts continuous-time quality scores that agree quite well with human opinion scores. The new QoE predictor also embeds the impact of relevant human cognitive factors, such as memory and recency, and their complex interactions with the video content being viewed. We evaluated the proposed model on three different video databases and attained standout QoE prediction performance. PMID- 29432106 TI - A Feasibility Study of Autism Behavioral Markers in Spontaneous Facial, Visual, and Hand Movement Response Data. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disability with atypical traits in behavioral and physiological responses. These atypical traits in individuals with ASD may be too subtle and subjective to measure visually using tedious methods of scoring. Alternatively, the use of intrusive sensors in the measurement of psychophysical responses in individuals with ASD may likely cause inhibition and bias. This paper proposes a novel experimental protocol for non intrusive sensing and analysis of facial expression, visual scanning, and eye hand coordination to investigate behavioral markers for ASD. An institutional review board approved pilot study is conducted to collect the response data from two groups of subjects (ASD and control) while they engage in the tasks of visualization, recognition, and manipulation. For the first time in the ASD literature, the facial action coding system is used to classify spontaneous facial responses. Statistical analyses reveal significantly (p <0.01) higher prevalence of smile expression for the group with ASD with the eye-gaze significantly averted (p<0.05) from viewing the face in the visual stimuli. This uncontrolled manifestation of smile without proper visual engagement suggests impairment in reciprocal social communication, e.g., social smile. The group with ASD also reveals poor correlation in eye-gaze and hand movement data suggesting deficits in motor coordination while performing a dynamic manipulation task. The simultaneous sensing and analysis of multimodal response data may provide useful quantitative insights into ASD to facilitate early detection of symptoms for effective intervention planning. PMID- 29432107 TI - A Distributed Classification Procedure for Automatic Sleep Stage Scoring Based on Instantaneous Electroencephalogram Phase and Envelope Features. AB - During the past decades, a great body of research has been devoted to automatic sleep stage scoring using the electroencephalogram (EEG). However, the results are not yet satisfactory to be used as a standard procedure in clinical studies. In this study, using recent developments in robust EEG phase extraction, a novel set of EEG-based features containing the Shannon entropy of the instantaneous analytical form envelope and frequencies of the EEG are proposed for sleep stage scoring. The proposed feature set is used to construct a distributed decision tree classifier, with binary K-nearest neighbor classifiers at each decision node. The decision-tree structure is designed by brute-force-search over various combinations of the proposed feature set. The performance of the proposed approach is evaluated over two available sleep EEG data sets acquired using single-channel EEG. The first set contains 20 healthy young subjects containing equal number of male and female, and the second one has been acquired from 140 adult subjects from both genders, with sleep disorder. The performance of the proposed method is tested versus state-of-the-art classifiers. The results demonstrate that the proposed method, resulted in overall accuracies of 88.97% and 83.17% over the two data sets, respectively. Considering the high performance and simplicity of the proposed scheme, the method can be of interest for clinical sleep disorder studies. PMID- 29432108 TI - Evidence of Variabilities in EEG Dynamics During Motor Imagery-Based Multiclass Brain-Computer Interface. AB - Inter-subject and inter-session variabilities pose a significant challenge in electroencephalogram (EEG)-based brain-computer interface (BCI) systems. Furthermore, high dimensional EEG montages introduce huge computational burden due to excessive number of channels involved. Two experimental, i.e., inter session and inter-subject, variabilities of EEG dynamics during motor imagery (MI) tasks are investigated in this paper. In particular, the effect on the performance of the BCIs due to day-to-day variability in EEG dynamics during the alterations in cognitive stages is explored. In addition, the inter-subject BCIs feasibility between cortically synchronized and desynchronized subject pairs on pairwise performance associativity is further examined. Moreover, the consequences of integrating spatial brain dynamics of varying the number of channels - from specific regions of the brain - are also discussed in case of both the contexts. The proposed approach is validated on real BCI data set containing EEG data from four classes of MI tasks, i.e., left/right hand, both feet, and tongue, subjected prior to a preprocessing of three different spatial filtering techniques. Experimental results have shown that a maximum classification accuracy of around 58% was achieved for the inter-subject experimental case, whereas a 31% deviation was noticed in the classification accuracies across two sessions during the inter-session experimental case. In conclusion, BCIs, without the subject-and session-specific calibration and with lesser number of channels employed, play a vital role while promoting a generic and efficient framework for plug and play use. PMID- 29432109 TI - Oscillatory TMS-EEG-Responses as a Measure of the Cortical Excitability Threshold. AB - Transcranial magnetic stimulation (TMS) is a non-invasive tool to perturb brain activity. In TMS studies, the stimulation intensity (SI) is commonly normalized to the resting motor threshold (rMT) that produces muscle responses in 50% of stimulations applied to the motor cortex (M1). Since rMT is influenced by spinal excitability and coil-to-cortex distance, responses recorded from the cortex, instead of a peripheral muscle, could provide a more accurate marker for cortical excitability. Combining TMS with electroencephalography (EEG) enables the measurement of brain-wide cortical reactivity to TMS. We quantified TMS-induced changes in oscillatory power and the phase of EEG with event-related spectral perturbation (ERSP) and inter-trial coherence (ITC). We studied the SI-dependency of ERSP and ITC responses by stimulating the dominant M1 of ten healthy volunteers using single-pulse TMS with 150 pulses at 60%, 80%, 100%, and 120% of rMT. We found SI-dependent ERSP and ITC responses in M1, most notably with the wide-band (8-70 Hz) early ITC responses averaged 20-60 ms after TMS. With approximately linear SI-dependence, the early ITC response was consistent between SIs (intraclass correlation = 0.78, ). Our results reveal the potential of oscillatory EEG responses, in place of rMT, as a measure of the cortical excitability threshold in M1. PMID- 29432110 TI - The Cochlear Implant EEG Artifact Recorded From an Artificial Brain for Complex Acoustic Stimuli. AB - : Electroencephalographic (EEG) recordings provide objective estimates of listeners' cortical processing of sounds and of the status of their speech perception system. For profoundly deaf listeners with cochlear implants (CIs), the applications of EEG are limited because the device adds electric artifacts to the recordings. This restricts the possibilities for the neural-based metrics of speech processing by CI users, for instance to gauge cortical reorganization due to individual's hearing loss history. This paper describes the characteristics of the CI artifact as recorded with an artificial head substitute, and reports how the artifact is affected by the properties of the acoustical input signal versus the settings of the device. METHODS: We created a brain substitute using agar that simulates the brain's conductivity, placed it in a human skull, and performed EEG recordings with CIs from three different manufacturers. As stimuli, we used simple and complex non-speech stimuli, as well as naturally produced continuous speech. We examined the effect of manipulating device settings in both controlled experimental CI configurations and real clinical maps. RESULTS: An increase in the magnitude of the stimulation current through the device settings increases also the magnitude of the artifact. The artifact recorded to speech is smaller in magnitude than for non-speech stimuli due to signal-inherent amplitude modulations. CONCLUSION: The CI EEG artifact for speech appears more difficult to detect than for simple stimuli. Since the artifact differs across CI users, due to their individual clinical maps, the method presented enables insight into the individual manifestations of the artifact. PMID- 29432111 TI - Toward Drowsiness Detection Using Non-hair-Bearing EEG-Based Brain-Computer Interfaces. AB - Drowsy driving is one of the major causes that lead to fatal accidents worldwide. For the past two decades, many studies have explored the feasibility and practicality of drowsiness detection using electroencephalogram (EEG)-based brain computer interface (BCI) systems. However, on the pathway of transitioning laboratory-oriented BCI into real-world environments, one chief challenge is to obtain high-quality EEG with convenience and long-term wearing comfort. Recently, acquiring EEG from non-hair-bearing (NHB) scalp areas has been proposed as an alternative solution to avoid many of the technical limitations resulted from the interference of hair between electrodes and the skin. Furthermore, our pilot study has shown that informative drowsiness-related EEG features are accessible from the NHB areas. This study extends the previous work to quantitatively evaluate the performance of drowsiness detection using cross-session validation with widely studied machine-learning classifiers. The offline results showed no significant difference between the accuracy of drowsiness detection using the NHB EEG and the whole-scalp EEG across all subjects ( ). The findings of this study demonstrate the efficacy and practicality of the NHB EEG for drowsiness detection and could catalyze explorations and developments of many other real-world BCI applications. PMID- 29432112 TI - The Development and Preliminary Test of a Powered Alternately Walking Exoskeleton With the Wheeled Foot for Paraplegic Patients. AB - Upright walking has both physical and social meanings for paraplegic patients. The main purpose of this paper is to reduce the automatic functioning of the powered exoskeleton and enable the user to fully control the walking procedure in real-time, aiming to further improve the engagement of the patient during rehabilitation training. For this prototype, a custom-made hub motor was placed at the bottom of the exoskeleton's foot, and a pair of crutches with the embedded wireless controller were utilized as the auxiliary device. The user could alternatively press the button of the crutch to control the movement of the leg and by repeating this procedure, the user could complete a continuous walking motion. For safety, an automatic brake and mechanical limitation for maximum step length were implemented. A gait analysis was performed to evaluate the exoskeleton's motion capability and corresponding response of user's major muscles. The kinematic results of this paper showed that this exoskeleton could assist the user to walk in a motion trend close to the normally walk, especially for ankle joint. The electromyography results indicated that this exoskeleton could decrease the loading burden of the user's lower limb while requiring more involvements of upper-limb muscles to maintain balance while walking. PMID- 29432113 TI - An In-Laboratory Validity and Reliability Tested System for Quantifying Hand-Arm Tremor in Motions. AB - Despite the advancement of the tremor assessment systems, the current technology still lacks a method that can objectively characterize tremors in relative segmental movements. This paper presents a measurement system, which quantifies multi-degrees-of-freedom coupled relative motions of hand-arm tremor, in terms of joint angular displacement. In-laboratory validity and reliability tests of the system algorithm to provide joint angular displacement was carried out by using the two-degrees-of-freedom tremor simulator with incremental rotary encoder systems installed. The statistical analyses show that the developed system has high validity results and comparable reliability performances using the rotary encoder system as the reference. In the clinical trials, the system was tested on 38 Parkinson's disease patients. The system readings were correlated with the observational tremor ratings of six trained medical doctors. The moderate to very high clinical correlations of the system readings in measuring rest, postural and task-specific tremors add merits to the degree of readiness of the developed tremor measurement system in a routine clinical setting and/or intervention trial for tremor amelioration. PMID- 29432114 TI - Synergistic Elbow Control for a Myoelectric Transhumeral Prosthesis. AB - This paper presents a control approach for a myoelectric transhumeral prostheses that supplements a typical two-site electromyograms (EMG) input with the inertial measurement of arm motion. The inertial measurement is employed to: 1) provide synergistic movement between the prosthetic elbow joint and intact upper arm and 2) to switch control between the myoelectric elbow and hand. In order to assess the prospective efficacy of the control method, experiments were conducted on six healthy subjects who performed a series of pick-and-place tasks within a virtual environment. The assessments compared the time required to complete the pick-and place tasks using the proposed coordinated control approach, with the time required using a sequential control approach (i.e., the conventional approach used in commercial devices). Subjects on average completed the pick-and-place tasks 34% faster with the coordinated control approach, relative to the conventional sequential EMG method, with no difference in compensatory torso motion. PMID- 29432115 TI - The Pediatric SmartShoe: Wearable Sensor System for Ambulatory Monitoring of Physical Activity and Gait. AB - Cerebral palsy (CP) is a group of nonprogressive neuro-developmental conditions occurring in early childhood that causes movement disorders and physical disability. Measuring activity levels and gait patterns is an important aspect of CP rehabilitation programs. Traditionally, such programs utilize commercially available laboratory systems, which cannot to be utilized in community living. In this study, a novel, shoe-based, wearable sensor system (pediatric SmartShoe) was tested on 11 healthy children and 10 children with CP to validate its use for monitoring of physical activity and gait. Novel data processing techniques were developed to remove the effect of orthotics on the sensor signals. Machine learning models were developed to automatically classify the activities of daily living. The temporal gait parameters estimated from the SmartShoe data were compared against reference measurements on a GAITRite mat. A leave-one-out cross validation method indicated a 95.3% average accuracy of activity classification (for sitting, standing, and walking) for children with CP and 96.2% for healthy children. Average relative errors in gait parameter estimation (gait cycle, stance, swing, and step time, % single support time on both lower extremities, along with cadence) ranged from 0.2% to 6.4% (standard deviation range = 1.4% 9.9%). These results suggest that the pediatric SmartShoe can accurately measure physical activity and gait of children with CP and can potentially be used for ambulatory monitoring. PMID- 29432116 TI - Improved Prosthetic Control Based on Myoelectric Pattern Recognition via Wavelet Based De-Noising. AB - Real-time inference of human motor volition has great potential for the intuitive control of robotic devices. Toward this end, myoelectric pattern recognition (MPR) has shown promise in the control of prosthetic limbs. Interfering noise and susceptibility to motion artifacts have hindered the use of MPR outside controlled environments, and thus represent an obstacle for clinical use. Advanced signal processing techniques have been previously proposed to improve the robustness of MPR systems. However, the investigation of such techniques have been limited to offline implementations with long time windows, which makes real time use unattainable. In this work, we present a novel algorithm using discrete and stationary wavelet transforms for MPR that can be executed in real-time. Our wavelet-based de-noising algorithm outperformed conventional band-pass filtering (up to 100 Hz) and improved real-time MPR in the presence of motion artifacts, as measured by the motion test. Improved signal-to-noise ratio was found not to be crucial in offline MPR, as machine learning algorithms can integrate high but consistent noise as part of the signal. However, varying interference is expected to occur in real life where signal processing algorithms, as the one introduced in this paper, would potentially have a positive impact. Furthermore implementation of these algorithms in a prosthetic embedded system is required to validate their feasibility and usability during activities of the daily living. PMID- 29432117 TI - Closed-Loop Continuous Hand Control via Chronic Recording of Regenerative Peripheral Nerve Interfaces. AB - Loss of the upper limb imposes a devastating interruption to everyday life. Full restoration of natural arm control requires the ability to simultaneously control multiple degrees of freedom of the prosthetic arm and maintain that control over an extended period of time. Current clinically available myoelectric prostheses do not provide simultaneous control or consistency for transradial amputees. To address this issue, we have implemented a standard Kalman filter for continuous hand control using intramuscular electromyography (EMG) from both regenerative peripheral nerve interfaces (RPNI) and an intact muscle within non-human primates. Seven RPNIs and one intact muscle were implanted with indwelling bipolar intramuscular electrodes in two rhesus macaques. Following recuperations, function-specific EMG signals were recorded and then fed through the Kalman filter during a hand-movement behavioral task to continuously predict the monkey's finger position. We were able to reconstruct continuous finger movement offline with an average correlation of and a root mean squared error (RMSE) of 0.12 between actual and predicted position from two macaques. This finger movement prediction was also performed in real time to enable closed-loop neural control of a virtual hand. Compared with physical hand control, neural control performance was slightly slower but maintained an average target hit success rate of 96.70%. Recalibration longevity measurements maintained consistent average correlation over time but had a significant change in RMSE ( ). Additionally, extracted single units varied in amplitude by a factor of +18.65% and -25.85% compared with its mean. This is the first demonstration of chronic indwelling electrodes being used for continuous position control via the Kalman filter. Combining these analyses with our novel peripheral nerve interface, we believe that this demonstrates an important step in providing patients with more naturalistic control of their prosthetic limbs. PMID- 29432118 TI - A Mixed Integer Linear Programming Approach to Electrical Stimulation Optimization Problems. AB - Electrical stimulation optimization is a challenging problem. Even when a single region is targeted for excitation, the problem remains a constrained multi objective optimization problem. The constrained nature of the problem results from safety concerns while its multi-objectives originate from the requirement that non-targeted regions should remain unaffected. In this paper, we propose a mixed integer linear programming formulation that can successfully address the challenges facing this problem. Moreover, the proposed framework can conclusively check the feasibility of the stimulation goals. This helps researchers to avoid wasting time trying to achieve goals that are impossible under a chosen stimulation setup. The superiority of the proposed framework over alternative methods is demonstrated through simulation examples. PMID- 29432119 TI - Anticoagulant Use Among Patients With End-Stage Renal Disease Undergoing Percutaneous Coronary Intervention: An Analysis From the National Cardiovascular Data Registry. AB - BACKGROUND: Patients with end-stage renal disease undergoing percutaneous coronary intervention (PCI) have largely been excluded from trials of antithrombotic therapies leaving little data to guide agent choice in this population. METHODS AND RESULTS: The National Cardiovascular Data Registry CathPCI Registry was used to identify patients with end-stage renal disease undergoing PCI who received monotherapy with either bivalirudin or unfractionated heparin (UFH) (n=71 675). In hospital bleeding and mortality were compared and adjusted using the CathPCI Registry logistic regression models with generalized estimating equations with UFH as the reference. Bivalirudin was used in 51.3% of patients versus 48.7% for UFH. The use of bivalirudin decreased over time, and in 2014, UFH became the most frequently used. Patients receiving UFH were more likely to have an acute coronary syndrome presentation (37.8% versus 27.4%) or have cardiogenic shock (3.74% versus 1.98%). The observed rates for in hospital bleeding (7.0% versus 9.5%; adjusted odds ratio,0.82; 95% confidence interval, 0.76-0.87) and mortality (2.6% versus 4.2%; adjusted odds ratio, 0.87; 95% confidence interval, 0.78-0.97) were lower for patients receiving bivalirudin compared with those receiving UFH. CONCLUSIONS: In patients with end-stage renal disease undergoing PCI, bivalirudin and UFH were used with similar frequency although the patterns of use changed over the enrollment period. Patients with end-stage renal disease undergoing PCI had a lower adjusted risk of in hospital outcomes with bivalirudin; however, given the observational nature of this analysis, a randomized trial is warranted. PMID- 29432120 TI - Coronary Artery Perforation Complicated by Pericardial Abscess Formation: A Clinical Dilemma. PMID- 29432121 TI - Xrn2 accelerates termination by RNA polymerase II, which is underpinned by CPSF73 activity. AB - Termination is a ubiquitous phase in every transcription cycle but is incompletely understood and a subject of debate. We used gene editing as a new approach to address its mechanism through engineered conditional depletion of the 5' -> 3' exonuclease Xrn2 or the polyadenylation signal (PAS) endonuclease CPSF73 (cleavage and polyadenylation specificity factor 73). The ability to rapidly control Xrn2 reveals a clear and general role for it in cotranscriptional degradation of 3' flanking region RNA and transcriptional termination. This defect is characterized genome-wide at high resolution using mammalian native elongating transcript sequencing (mNET-seq). An Xrn2 effect on termination requires prior RNA cleavage, and we provide evidence for this by showing that catalytically inactive CPSF73 cannot restore termination to cells lacking functional CPSF73. Notably, Xrn2 plays no significant role in either Histone or small nuclear RNA (snRNA) gene termination even though both RNA classes undergo 3' end cleavage. In sum, efficient termination on most protein-coding genes involves CPSF73-mediated RNA cleavage and cotranscriptional degradation of polymerase-associated RNA by Xrn2. However, as CPSF73 loss caused more extensive readthrough transcription than Xrn2 elimination, it likely plays a more underpinning role in termination. PMID- 29432122 TI - Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. AB - Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-1 tetramer composed of two p20 and two p10 subunits (p20/p10) as an active species. In this study, we report that in the cell, the dominant species of active caspase-1 dimers elicited by inflammasomes are in fact full-length p46 and a transient species, p33/p10. Further p33/p10 autoprocessing occurs with kinetics specified by inflammasome size and cell type, and this releases p20/p10 from the inflammasome, whereupon the tetramer becomes unstable in cells and protease activity is terminated. The inflammasome-caspase-1 complex thus functions as a holoenzyme that directs the location of caspase-1 activity but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses. PMID- 29432123 TI - Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production, Leading to Improved Insulin Sensitivity. AB - The activation of Kupffer cells (KCs) and monocyte-derived recruited macrophages (McMPhis) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Mice with diet-induced obesity (DIO mice) treated with chromogranin A peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of proinflammatory genes, increased expression of anti-inflammatory genes in McMPhis, and inhibition of the infiltration of McMPhis resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very proinflammatory in CST-KO NCD mice and produced glucose intolerance, we tested the effects of (sorted with FACS) F4/80+Ly6C- cells (representing KCs) and F4/80-Ly6C+ cells (representing McMPhis) on hepatic glucose production (HGP). Both basal HGP and glucagon-induced HGP were markedly increased in hepatocytes cocultured with KCs and McMPhis from NCD-fed CST-KO mice, and the effect was abrogated upon pretreatment of CST-KO macrophages with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function. PMID- 29432124 TI - CDKN2A/B T2D Genome-Wide Association Study Risk SNPs Impact Locus Gene Expression and Proliferation in Human Islets. AB - Genome-wide association studies link the CDKN2A/B locus with type 2 diabetes (T2D) risk, but mechanisms increasing risk remain unknown. The CDKN2A/B locus encodes cell cycle inhibitors p14, p15, and p16; MTAP; and ANRIL, a long noncoding RNA. The goal of this study was to determine whether CDKN2A/B T2D risk SNPs impact locus gene expression, insulin secretion, or beta-cell proliferation in human islets. Islets from donors without diabetes (n = 95) were tested for SNP genotype (rs10811661, rs2383208, rs564398, and rs10757283), gene expression (p14, p15, p16, MTAP, ANRIL, PCNA, KI67, and CCND2), insulin secretion (n = 61), and beta-cell proliferation (n = 47). Intriguingly, locus genes were coregulated in islets in two physically overlapping cassettes: p14-p16-ANRIL, which increased with age, and MTAP-p15, which did not. Risk alleles at rs10811661 and rs2383208 were differentially associated with expression of ANRIL, but not p14, p15, p16, or MTAP, in age-dependent fashion, such that younger homozygous risk donors had higher ANRIL expression, equivalent to older donor levels. We identified several risk SNP combinations that may impact locus gene expression, suggesting possible mechanisms by which SNPs impact locus biology. Risk allele carriers at ANRIL coding SNP rs564398 had reduced beta-cell proliferation index. In conclusion, CDKN2A/B locus SNPs may impact T2D risk by modulating islet gene expression and beta-cell proliferation. PMID- 29432126 TI - Physical Activity in Patients With Type 2 Diabetes: The Case for Objective Measurement in Routine Clinical Care. PMID- 29432125 TI - Clinical and Patient-Centered Outcomes in Obese Patients With Type 2 Diabetes 3 Years After Randomization to Roux-en-Y Gastric Bypass Surgery Versus Intensive Lifestyle Management: The SLIMM-T2D Study. AB - OBJECTIVE: To compare the effect of Roux-en-Y gastric bypass (RYGB) surgery versus intensive medical diabetes and weight management (IMWM) on clinical and patient-reported outcomes in obese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We prospectively randomized 38 obese patients with type 2 diabetes (15 male and 23 female, with mean +/- SD weight 104 +/- 16 kg, BMI 36.3 +/- 3.4 kg/m2, age 52 +/- 6 years, and HbA1c 8.5 +/- 1.3% [69 +/- 14 mmol/mol]) to laparoscopic RYGB (n = 19) or IMWM (n = 19). Changes in weight, HbA1c, cardiovascular risk factors (UKPDS risk engine), and self-reported health status (the 36-Item Short-Form [SF-36] survey, Impact of Weight on Quality of Life [IWQOL] instrument, and Problem Areas in Diabetes Survey [PAID]) were assessed. RESULTS: After 3 years, the RYGB group had greater weight loss (mean -24.9 kg [95% CI -29.5, -20.4] vs. -5.2 [-10.3, -0.2]; P < 0.001) and lowering of HbA1c ( 1.79% [-2.38, -1.20] vs. -0.39% [-1.06, 0.28] [-19.6 mmol/mol {95% CI -26.0, 13.1} vs. -4.3 {-11.6, 3.1}]; P < 0.001) compared with the IMWM group. Changes in cardiometabolic risk for coronary heart disease and stroke were all more favorable in RYGB versus IMWM (P < 0.05 to P < 0.01). IWQOL improved more after RYGB (P < 0.001), primarily due to subscales of physical function, self-esteem, and work performance. SF-36 and PAID scores improved in both groups, with no difference between treatments. A structural equation model demonstrated that improvement in overall quality of life was more strongly associated with weight loss than with improved HbA1c and was manifest by greater improvements in IWQOL than with either SF-36 or PAID. CONCLUSIONS: Three years after randomization to RYGB versus IMWM, surgery produced greater weight loss, lower HbA1c, reduced cardiovascular risk, and improvements in obesity-related quality of life in obese patients with type 2 diabetes. PMID- 29432127 TI - Coupled regulation by the juxtamembrane and sterile alpha motif (SAM) linker is a hallmark of ephrin tyrosine kinase evolution. AB - Ephrin (Eph) receptor tyrosine kinases have evolutionarily diverged from other tyrosine kinases to respond to specific activation and regulatory signals that require close coupling of kinase catalytic and regulatory functions. However, the evolutionary basis for such functional coupling is not fully understood. We employed an evolutionary systems approach involving statistical mining of large sequence and structural data sets to define the hallmarks of Eph kinase evolution and functional specialization. We found that some of the most distinguishing Eph specific residues structurally tether the flanking juxtamembrane and sterile alpha motif (SAM) linker regions to the kinase domain, and substitutions of these residues in EphA3 resulted in faster kinase activation. We report for the first time that the SAM domain linker is functionally coupled to the juxtamembrane through co-conserved residues in the kinase domain and that together these residues provide a structural framework for coupling catalytic and regulatory functions. The unique organization of Eph-specific tethering networks and the identification of other Eph-specific sequence features of unknown functions provide new hypotheses for future functional studies and new clues to disease mutations altering Eph kinase-specific functions. PMID- 29432128 TI - N-terminal Sumoylation of Centromeric Histone H3 Variant Cse4 Regulates Its Proteolysis To Prevent Mislocalization to Non-centromeric Chromatin. AB - Stringent regulation of cellular levels of evolutionarily conserved centromeric histone H3 variant (CENP-A in humans, CID in flies, Cse4 in yeast) prevents its mislocalization to non-centromeric chromatin. Overexpression and mislocalization of CENP-A has been observed in cancers and leads to aneuploidy in yeast, flies, and human cells. Ubiquitin-mediated proteolysis of Cse4 by E3 ligases such as Psh1 and Sumo-Targeted Ubiquitin Ligase (STUbL) Slx5 prevent mislocalization of Cse4. Previously, we identified Siz1 and Siz2 as the major E3 ligases for sumoylation of Cse4. In this study, we have identified lysine 65 (K65) in Cse4 as a site that regulates sumoylation and ubiquitin-mediated proteolysis of Cse4 by Slx5. Strains expressing cse4 K65R exhibit reduced levels of sumoylated and ubiquitinated Cse4 in vivo Furthermore, co-immunoprecipitation experiments reveal reduced interaction of cse4 K65R with Slx5, leading to increased stability and mislocalization of cse4 K65R under normal physiological conditions. Based on the increased stability of cse4 K65R in psh1? strains but not in slx5? strains, we conclude that Slx5 targets sumoylated Cse4 K65 for ubiquitination-mediated proteolysis independent of Psh1. In summary, we have identified and characterized the physiological role of Cse4 K65 in sumoylation, ubiquitin-mediated proteolysis, and localization of Cse4 for genome stability. PMID- 29432129 TI - Identification of Two Distinct Classes of the Human INO80 Complex Genome-Wide. AB - Chromatin remodeling and histone modifying enzymes play a critical role in shaping the regulatory output of a cell. Although much is known about these classes of proteins, identifying the mechanisms by which they coordinate gene expression programs remains an exciting topic of investigation. One factor that may contribute to the targeting and activity of chromatin regulators is local chromatin landscape. We leveraged genomic approaches and publically-available datasets to characterize the chromatin landscape at targets of the human INO80 chromatin remodeling complex (INO80-C). Our data revealed two classes of INO80-C targets with distinct chromatin signatures. The predominant INO80-C class was enriched for open chromatin, H3K27ac, and representative subunits from each of the three INO80-C modules (RUVBL1, RUVBL2, MCRS1, YY1). We named this class Canonical INO80. Notably, we identified an unexpected class of INO80-C targets that contained only the INO80 ATPase and harbored a repressive chromatin signature characterized by inaccessible chromatin, H3K27me3, and the methyltransferase EZH2. We named this class Non-Canonical INO80 (NC-INO80). Biochemical approaches indicated that INO80-C and the H3K27 acetyltransferase P300 physically interact, suggesting INO80-C and P300 may jointly coordinate chromatin accessibility at Canonical INO80 sites. No interaction was detected between INO80-C and EZH2, indicating INO80-C and EZH2 may engage in a separate form of regulatory crosstalk at NC-INO80 targets. Our data indicate that INO80-C is more compositionally heterogenous at its genomic targets than anticipated. Moreover, our data suggest there is an important link between INO80-C and histone modifying enzymes that may have consequences in developmental and pathological contexts. PMID- 29432130 TI - Combined Assessment of Stress Myocardial Perfusion Cardiovascular Magnetic Resonance and Flow Measurement in the Coronary Sinus Improves Prediction of Functionally Significant Coronary Stenosis Determined by Fractional Flow Reserve in Multivessel Disease. AB - BACKGROUND: Recent studies using stress-rest perfusion cardiovascular magnetic resonance (CMR) demonstrated a close correlation between myocardial ischemia and reduced fractional flow reserve (FFR). However, its diagnostic concordance may be reduced in patients with multivessel disease. We sought to evaluate the concordance of adenosine stress-rest perfusion CMR for predicting reduced FFR, and to determine the additive value of measuring global coronary flow reserve (CFR) in the coronary sinus in multivessel disease. METHODS AND RESULTS: Ninety six patients with angiographic luminal narrowing >50% underwent comprehensive CMR study and FFR measurements in 139 coronary vessels. FFR <0.80 was considered hemodynamically significant. Global CFR was quantified as the ratio of stress rest coronary sinus flow measured by phase-contrast cine CMR. In 25 patients with single-vessel disease, visual assessment of perfusion CMR yielded high diagnostic concordance for predicting flow-limiting stenosis, with the area under receiver operating characteristic curve of 0.93 on a per-patient basis. However, in 71 patients with multivessel disease, perfusion CMR underestimated flow-limiting stenosis, resulting in the reduced area under receiver operating characteristic curve of 0.74. When CFR of <2.0 measured in the coronary sinus was considered as global myocardial ischemia, combined assessment provided correct reclassifications in 7 patients with false-negative myocardial ischemia, and improved the diagnostic concordance to 92% sensitivity and 73% specificity with the area under receiver operating characteristic curve of 0.88 (95% confidence interval, 0.80%-0.97%, P=0.002). CONCLUSIONS: Visual analysis of stress-rest perfusion CMR has limited concordance with FFR in patients with multivessel disease. Multiparametric CMR integrating stress-rest perfusion CMR and flow measurement in the coronary sinus is useful for detecting reduced FFR in multivessel disease. PMID- 29432131 TI - T-Wave Abnormality as Electrocardiographic Signature of Myocardial Edema in Non ST-Elevation Acute Coronary Syndromes. AB - BACKGROUND: T-wave abnormalities are common during the acute phase of non-ST segment elevation acute coronary syndromes, but mechanisms underlying their occurrence are unclear. We hypothesized that T-wave abnormalities in the presentation of non-ST-segment elevation acute coronary syndromes correspond to the presence of myocardial edema. METHODS AND RESULTS: Secondary analysis of a previously enrolled prospective cohort of patients presenting with non-ST-segment elevation acute coronary syndromes was conducted. Twelve-lead electrocardiography (ECG) and cardiac magnetic resonance with T2-weighted imaging were acquired before invasive coronary angiography. ECGs were classified dichotomously (ie, ischemic versus normal/nonischemic) and nominally according to patterns of presentation: no ST- or T-wave abnormalities, isolated T-wave abnormality, isolated ST depression, ST depression+T-wave abnormality. Myocardial edema was determined by expert review of T2-weighted images. Of 86 subjects (65% male, 59.4 years), 36 showed normal/nonischemic ECG, 25 isolated T-wave abnormalities, 11 isolated ST depression, and 14 ST depression+T-wave abnormality. Of 30 edema negative subjects, 24 (80%) had normal/nonischemic ECGs. Isolated T-wave abnormality was significantly more prevalent in edema-positive versus edema negative subjects (41.1% versus 6.7%, P=0.001). By multivariate analysis, an ischemic ECG showed a strong association with myocardial edema (odds ratio 12.23, 95% confidence interval 3.65-40.94, P<0.0001). Among individual ECG profiles, isolated T-wave abnormality was the single strongest predictor of myocardial edema (odds ratio 23.84, 95% confidence interval 4.30-132, P<0.0001). Isolated T wave abnormality was highly specific (93%) but insensitive (43%) for detecting myocardial edema. CONCLUSIONS: T-wave abnormalities in the setting of non-ST segment elevation acute coronary syndromes are related to the presence of myocardial edema. High specificity of this ECG alteration identifies a change in ischemic myocardium associated with worse outcomes that is potentially reversible. PMID- 29432132 TI - Outcomes of Heart Failure Admissions Under Observation Versus Short Inpatient Stay. AB - BACKGROUND: Patients with heart failure (HF) are admitted either under observation (OBS) or inpatient stays; however, there is little data on whether this designation reflects the clinical status of a patient, with significant logistical and financial implications. We sought to compare the outcomes of patients with HF admitted OBS versus inpatient stay (<=2 days; INPT). METHODS AND RESULTS: From January 1, 2008 to September 30, 2015, our multisite health system saw 21 339 unique patients totaling 52 493 hospital admissions with a primary diagnosis of HF. Patients were excluded if they underwent cardiac surgery (n=611), heart transplantation (n=187), or left ventricular assist device insertion (n=198), or if they died during hospitalization (n=1839). Of the remaining 50 654 discharges, 2 groups were identified: INPT group and OBS group. Outcomes were HF readmission, all-cause readmission, and all-cause mortality within 1 year of discharge. Hazard ratios were computed using the Andersen-Gill method in the Cox proportional-hazards model. A total of 8709 admissions (17%) occurred in the INPT group and 2648 admissions (5%) occurred in the OBS group. HF readmission rate at 1 year was 55.3% in INPT versus 66.5% in OBS (hazard ratio, 0.75; 95% confidence interval, 0.71-0.80; P<0.01). All-cause readmission rate at 1 year was 70.7% in INPT versus 82.5% in OBS (hazard ratio, 0.74; 95% confidence interval, 0.70-0.78; P<0.01). All-cause mortality at 1 year occurred in 25.2% of INPT versus 24.2% of OBS (hazard ratio, 1.03; 95% confidence interval, 0.95-1.12; P=0.46). CONCLUSIONS: HF admissions designated INPTs were associated with lower readmission rates and equivalent mortality to those designated OBS. PMID- 29432133 TI - Programming Cardiac Resynchronization Therapy for Electrical Synchrony: Reaching Beyond Left Bundle Branch Block and Left Ventricular Activation Delay. AB - BACKGROUND: QRS narrowing following cardiac resynchronization therapy with biventricular (BiV) or left ventricular (LV) pacing is likely affected by patient specific conduction characteristics (PR, qLV, LV-paced propagation interval), making a universal programming strategy likely ineffective. We tested these factors using a novel, device-based algorithm (SyncAV) that automatically adjusts paced atrioventricular delay (default or programmable offset) according to intrinsic atrioventricular conduction. METHODS AND RESULTS: Seventy-five patients undergoing cardiac resynchronization therapy (age 66+/-11 years; 65% male; 32% with ischemic cardiomyopathy; LV ejection fraction 28+/-8%; QRS duration 162+/-16 ms) with intact atrioventricular conduction (PR interval 194+/-34, range 128-300 ms), left bundle branch block, and optimized LV lead position were studied at implant. QRS duration (QRSd) reduction was compared for the following pacing configurations: nominal simultaneous BiV (Mode I: paced/sensed atrioventricular delay=140/110 ms), BiV+SyncAV with 50 ms offset (Mode II), BiV+SyncAV with offset that minimized QRSd (Mode III), or LV-only pacing+SyncAV with 50 ms offset (Mode IV). The intrinsic QRSd (162+/-16 ms) was reduced to 142+/-17 ms (-11.8%) by Mode I, 136+/-14 ms (-15.6%) by Mode IV, and 132+/-13 ms (-17.8%) by Mode II. Mode III yielded the shortest overall QRSd (123+/-12 ms, -23.9% [P<0.001 versus all modes]) and was the only configuration without QRSd prolongation in any patient. QRS narrowing occurred regardless of QRSd, PR, or LV-paced intervals, or underlying ischemic disease. CONCLUSIONS: Post-implant electrical optimization in already well-selected patients with left bundle branch block and optimized LV lead position is facilitated by patient-tailored BiV pacing adjusted to intrinsic atrioventricular timing using an automatic device-based algorithm. PMID- 29432135 TI - Measuring Cardiovascular Health Over the Life Course: A Lesson From Economics. PMID- 29432134 TI - Cardiovascular Risk and the American Dream: Life Course Observations From the BHS (Bogalusa Heart Study). AB - BACKGROUND: Economic literature shows that a child's future earnings are predictably influenced by parental income, providing an index of "socioeconomic mobility," or the ability of a person to move towards a higher socioeconomic status from childhood to adulthood. We adapted this economic paradigm to examine cardiovascular risk mobility (CRM), or whether there is life course mobility in relative cardiovascular risk. METHODS AND RESULTS: Participants from the BHS (Bogalusa Heart Study) with 1 childhood and 1 adult visit from 1973 to 2016 (n=7624) were considered. We defined population-level CRM as the rank-rank slope (beta) from the regression of adult cardiovascular disease (CVD) risk percentile ranking onto childhood CVD risk percentile ranking (beta=0 represents complete mobility; beta=1 represents no mobility). After defining and measuring relative CRM, we assessed its correlation with absolute cardiovascular health using the American Heart Association's Ideal Cardiovascular Health metrics. Overall, there was substantial mobility, with black participants having marginally better CRM than whites (betablack=0.10 [95% confidence interval, 0.05-0.15]; betawhite=0.18 [95% confidence interval, 0.14-0.22]; P=0.01). Having high relative CVD risk at an earlier age significantly reduced CRM (betaage*slope=-0.02; 95% confidence interval, -0.03 to -0.01; P<0.001). Relative CRM was strongly correlated with life course changes in Ideal Cardiovascular Health sum (r=0.62; 95% confidence interval, 0.60-0.65). CONCLUSIONS: Results from this novel application of an economic mobility index to cardiovascular epidemiology indicated substantial CRM, supporting the paradigm that life course CVD risk is highly modifiable. High CRM implies that the children with the best relative CVD profiles may only maintain a slim advantage over their peers into adulthood. PMID- 29432136 TI - A review of risk perception measurement in tobacco control research. AB - OBJECTIVE: To describe the characteristics of risk perception measures used in tobacco control research and to evaluate whether these measures incorporate measurement suggestions put forward by risk perception measurement scholars. DATA SOURCES: Three databases (PubMed, PsycINFO and Web of Science) were searched in March 2015 for published English language peer-reviewed articles measuring tobacco risk perceptions (n=2557). The search string included terms related to tobacco products, perceptions and risk. STUDY SELECTION: Three coders independently coded abstracts for initial inclusion. In total, 441 articles met the initial inclusion criteria, and 100 were randomly selected for a full-text review. DATA EXTRACTION: A codebook was developed and tested through a training phase. Three coders independently coded the characteristics of each article (eg, population), multi-item measure (eg, validity) and item (eg, likelihood, affect, health outcome). Fifty-four articles, 33 measures and 239 items were coded. DATA SYNTHESIS: Twenty-one articles had a multi-item risk perception measure, and 12 articles had one risk perception item. Many of the items asked about general health outcomes (36%), did not specify the person for whom risk was being judged (44%; eg, self, average person) or did not specify the conditions of use (27%; eg, the product used, intensity of use). CONCLUSIONS: There is little consistency across risk perception measures in tobacco research. There may be value in developing and disseminating best practices for assessing tobacco risk perceptions. A set of risk perception consensus measures may also benefit researchers in the field to help them consistently apply measurement recommendations. PMID- 29432137 TI - Air Travel for Subjects Receiving Long-Term Oxygen Therapy. AB - BACKGROUND: Ambulatory oxygen (O2) is the recommended treatment for hypoxemia at rest or induced by exercise. Commercial aircraft often fly at altitudes of 30,000 feet; their cabins are pressurized to altitudes of 6,000-8,000 feet, with an equivalent FIO2 of 0.15. O2 supplementation, for those receiving baseline ambulatory O2, is paramount. METHODS: We gathered information on subjects' experience traveling with supplementary oxygen and reasons individuals receiving O2 do not travel. Subjects were identified using a home oxygen database. Data were gathered by postal questionnaire. The objective of this study was to gather information relevant to subjects' experience organizing travel with supplementary oxygen and their experience of traveling itself. RESULTS: Between 2013 and 2015, 512 patients were entered into the database: 277 were excluded (269 had died, 8 had incomplete records). We sent 235 questionnaires, and 50 responses were received (21% response rate). Of these, 11 (22%) were returned as the patient had died, 20 (40%) had not traveled by air, 11 (22%) had flown with O2, 4 (8%) no longer used O2, and 4 (8%) forms were incomplete. Of those who traveled with O2, 54% found it complicated to organize their trip, 72% found it complicated to access information, and 81% would fly again. Regarding those who had never flown with O2, 35% were unaware that O2 was available on commercial aircraft, 30% had no wish to travel, and 30% had worries regarding their health. CONCLUSIONS: Air travel is challenging; however, those who did travel reported a mainly positive experience. Increasing available information on options for travel should help individuals. PMID- 29432138 TI - Characteristics of Subjects Who Failed a 120-Minute Spontaneous Breathing Trial. AB - BACKGROUND: The objective of this work was to identify the unique characteristics of patients who experienced success in a 30-min spontaneous breathing trial (SBT) but failed at 120 min. METHODS: Patients who had received mechanical ventilation for >24 h were eligible for inclusion in this study. The SBT was performed by 7 cm H2O of pressure support with zero PEEP. After a successful 120-min SBT, weaning from mechanical ventilation was performed. Data were collected at 30 and 120 min or at the failure of the SBT. All patients who successfully completed a 30-min SBT were enrolled. RESULTS: We enrolled 352 subjects in this study. Of these, 311 subjects (88.4%) directly completed a 120-min SBT (success group), and 41 subjects (11.6%) passed the test for at least 30 min but failed before 120 min (failure group). In data collected before the SBT, presence of chronic cardiopulmonary disease, number of previous SBT attempts before 30-min SBT success, age, and PaCO2 were independently associated with 120-min SBT failure. A scale was developed that used these 4 variables. The failure rate was low in subjects with <=2 points (3%) but significantly higher in subjects with >2 points (46%). In data collected at the 30-min SBT, PaCO2 , rapid shallow breathing index, DeltaPaO2 /FIO2 , Deltabreathing frequency, and DeltapH were independently associated with 120-min SBT failure. These 5 variables were then used to develop another scale to predict SBT success. Similar to the previous score, the failure rate was low in subjects with <=2 points (1%) and significantly higher in subjects with >2 points (55%). CONCLUSIONS: This study highlights differences between subjects who completed a 120-min SBT and those who succeeded at 30 min but failed by 120 min. In subjects with a score >2 points, reflecting a greater risk of SBT failure, a 120-min SBT may be required. PMID- 29432139 TI - Crossover Evaluation of Compressors and Nebulizers Typically Used by Cystic Fibrosis Patients. AB - BACKGROUND: Compressor/nebulizer units are used to deliver inhaled medications to patients with cystic fibrosis. Practitioners and parents frequently replace either the compressor or the nebulizer with a similar component from a different brand. We hypothesized that these changes could affect the compressor/nebulizer flow-pressure and aerosol characteristics. METHODS: The following compressors were studied: Pari Vios, Pulmo-Aide model 5650D, and Inspiration Elite model HS456. The following nebulizers were studied: Pari LC Plus, Viox, and SideStream Plus. Units that underwent intense use were tested. The recommended compressor/nebulizer combinations by the manufacturers were compared to all other combinations. In-line measurements of maximal flow and pressure were done for all combinations. A Next Generation Impactor was used to determine particle-size characteristics of albuterol (2.5 mg/3 mL). A breathing simulator programmed to deliver an adult breathing pattern was used. Albuterol concentration was measured with spectrophotometry at 276 nm. The following variables were studied: maximal flow and pressure generated by the compressor/nebulizer, mass median aerodynamic diameter, percentage of drug mass contained in particles < 5 MUm, and inhaled mass in the respirable range. RESULTS: Replacing the nebulizer resulted in changes in the flow-pressure characteristics, particle size, and inhaled mass in the respirable range of the paired compressor/nebulizers. The changes were more pronounced when the nebulizer was replaced than when the compressor was changed. CONCLUSIONS: Our findings indicate that, in general, replacing the nebulizer or compressor with a different brand changes the flow-pressure and aerosol characteristics. Practitioners should be cautious when changing compressor/nebulizer pairs unless they are aware of the resulting impact on the flow-pressure and aerosol characteristics. PMID- 29432140 TI - Noise Exposure From High-Flow Nasal Cannula Oxygen Therapy: A Bench Study on Noise Reduction. AB - BACKGROUND: High-flow nasal cannula (HFNC) oxygen therapy produces noise at a level such that patients often complain. However, the noise level has not been measured digitally. METHODS: We evaluated 3 types of HFNCs without filters and 2 types with filters attached for noise reduction. Optiflow (with and without a filter), MaxVenturi (with and without a filter) and AIRVO2 (without a filter only) were positioned at the center of a hospital room. We measured the noise levels at the distance of 1 m from the equipment at various total flows (30, 40, 50, 60 L/min) and FIO2 (0.40, 0.60, and 0.90). RESULTS: Noise levels were increased with the AIRVO2 and MaxVenturi when total flow and FIO2 were increased. Noise levels decreased with the MaxVenturi when a filter was used. The noise level did not change with the Optiflow when total flow and FIO2 were increased. The noise level decreased in the groups with AIRVO2 and Optiflow compared with MaxVenturi without a filter. CONCLUSIONS: The findings in this study show that the noise level of HFNC/Venturi could be reduced by attaching an intake filter. However, the noise level of HFNC/blender and HFNC/turbine decreased in comparison with HFNC/Venturi without an intake filter. PMID- 29432142 TI - Co-translational control of protein complex formation: a fundamental pathway of cellular organization? AB - Analyses of proteomes from a large number of organisms throughout the domains of life highlight the key role played by multiprotein complexes for the implementation of cellular function. While the occurrence of multiprotein assemblies is ubiquitous, the understanding of pathways that dictate the formation of quaternary structure remains enigmatic. Interestingly, there are now well-established examples of protein complexes that are assembled co translationally in both prokaryotes and eukaryotes, and indications are that the phenomenon is widespread in cells. Here, we review complex assembly with an emphasis on co-translational pathways, which involve interactions of nascent chains with other nascent or mature partner proteins, respectively. In prokaryotes, such interactions are promoted by the polycistronic arrangement of mRNA and the associated co-translation of functionally related cell constituents in order to enhance otherwise diffusion-dependent processes. Beyond merely stochastic events, however, co-translational complex formation may be sensitive to subunit availability and allow for overall regulation of the assembly process. We speculate how co-translational pathways may constitute integral components of quality control systems to ensure the correct and complete formation of hundreds of heterogeneous assemblies in a single cell. Coupling of folding of intrinsically disordered domains with co-translational interaction of binding partners may furthermore enhance the efficiency and fidelity with which correct conformation is attained. Co-translational complex formation may constitute a fundamental pathway of cellular organization, with profound importance for health and disease. PMID- 29432141 TI - Structure and function of the cytochrome P450 peroxygenase enzymes. AB - The cytochromes P450 (P450s or CYPs) constitute a large heme enzyme superfamily, members of which catalyze the oxidative transformation of a wide range of organic substrates, and whose functions are crucial to xenobiotic metabolism and steroid transformation in humans and other organisms. The P450 peroxygenases are a subgroup of the P450s that have evolved in microbes to catalyze the oxidative metabolism of fatty acids, using hydrogen peroxide as an oxidant rather than NAD(P)H-driven redox partner systems typical of the vast majority of other characterized P450 enzymes. Early members of the peroxygenase (CYP152) family were shown to catalyze hydroxylation at the alpha and beta carbons of medium-to long-chain fatty acids. However, more recent studies on other CYP152 family P450s revealed the ability to oxidatively decarboxylate fatty acids, generating terminal alkenes with potential applications as drop-in biofuels. Other research has revealed their capacity to decarboxylate and to desaturate hydroxylated fatty acids to form novel products. Structural data have revealed a common active site motif for the binding of the substrate carboxylate group in the peroxygenases, and mechanistic and transient kinetic analyses have demonstrated the formation of reactive iron-oxo species (compounds I and II) that are ultimately responsible for hydroxylation and decarboxylation of fatty acids, respectively. This short review will focus on the biochemical properties of the P450 peroxygenases and on their biotechnological applications with respect to production of volatile alkenes as biofuels, as well as other fine chemicals. PMID- 29432143 TI - Protein phosphatases at the nuclear envelope. AB - The nuclear envelope (NE) is a unique topological structure formed by lipid membranes (Inner and Outer Membrane: IM and OM) interrupted by open channels (Nuclear Pore complexes). Besides its well-established structural role in providing a physical separation between the genome and the cytoplasm and regulating the exchanges between the two cellular compartments, it has become quite evident in recent years that the NE also represents a hub for localized signal transduction. Mechanical, stress, or mitogen signals reach the nucleus and trigger the activation of several pathways, many effectors of which are processed at the NE. Therefore, the concept of the NE acting just as a barrier needs to be expanded to embrace all the dynamic processes that are indeed associated with it. In this context, dynamic protein association and turnover coupled to reversible post-translational modifications of NE components can provide important clues on how this integrated cellular machinery functions as a whole. Reversible protein phosphorylation is the most used mechanism to control protein dynamics and association in cells. Keys to the reversibility of the system are protein phosphatases and the regulation of their activity in space and time. As the NE is clearly becoming an interesting compartment for the control and transduction of several signalling pathways, in this review we will focus on the role of Protein Phosphatases at the NE since the significance of this class of proteins in this context has been little explored. PMID- 29432144 TI - Single-channel recordings of RyR1 at microsecond resolution in CMOS-suspended membranes. AB - Single-channel recordings are widely used to explore functional properties of ion channels. Typically, such recordings are performed at bandwidths of less than 10 kHz because of signal-to-noise considerations, limiting the temporal resolution available for studying fast gating dynamics to greater than 100 us. Here we present experimental methods that directly integrate suspended lipid bilayers with high-bandwidth, low-noise transimpedance amplifiers based on complementary metal-oxide-semiconductor (CMOS) integrated circuits (IC) technology to achieve bandwidths in excess of 500 kHz and microsecond temporal resolution. We use this CMOS-integrated bilayer system to study the type 1 ryanodine receptor (RyR1), a Ca2+-activated intracellular Ca2+-release channel located on the sarcoplasmic reticulum. We are able to distinguish multiple closed states not evident with lower bandwidth recordings, suggesting the presence of an additional Ca2+ binding site, distinct from the site responsible for activation. An extended beta distribution analysis of our high-bandwidth data can be used to infer closed state flicker events as fast as 35 ns. These events are in the range of single file ion translocations. PMID- 29432145 TI - Diamond anvil cell behavior up to 4 Mbar. AB - The diamond anvil cell (DAC) is considered one of the dominant devices to generate ultrahigh static pressure. The development of the DAC technique has enabled researchers to explore rich high-pressure science in the multimegabar pressure range. Here, we investigated the behavior of the DAC up to 400 GPa, which is the accepted pressure limit of a conventional DAC. By using a submicrometer synchrotron X-ray beam, double cuppings of the beveled diamond anvils were observed experimentally. Details of pressure loading, distribution, gasket-thickness variation, and diamond anvil deformation were studied to understand the generation of ultrahigh pressures, which may improve the conventional DAC techniques. PMID- 29432146 TI - Bacteriocyte cell death in the pea aphid/Buchnera symbiotic system. AB - Symbiotic associations play a pivotal role in multicellular life by facilitating acquisition of new traits and expanding the ecological capabilities of organisms. In insects that are obligatorily dependent on intracellular bacterial symbionts, novel host cells (bacteriocytes) or organs (bacteriomes) have evolved for harboring beneficial microbial partners. The processes regulating the cellular life cycle of these endosymbiont-bearing cells, such as the cell-death mechanisms controlling their fate and elimination in response to host physiology, are fundamental questions in the biology of symbiosis. Here we report the discovery of a cell-death process involved in the degeneration of bacteriocytes in the hemipteran insect Acyrthosiphon pisum This process is activated progressively throughout aphid adulthood and exhibits morphological features distinct from known cell-death pathways. By combining electron microscopy, immunohistochemistry, and molecular analyses, we demonstrated that the initial event of bacteriocyte cell death is the cytoplasmic accumulation of nonautophagic vacuoles, followed by a sequence of cellular stress responses including the formation of autophagosomes in intervacuolar spaces, activation of reactive oxygen species, and Buchnera endosymbiont degradation by the lysosomal system. We showed that this multistep cell-death process originates from the endoplasmic reticulum, an organelle exhibiting a unique reticular network organization spread throughout the entire cytoplasm and surrounding Buchnera aphidicola endosymbionts. Our findings provide insights into the cellular and molecular processes that coordinate eukaryotic host and endosymbiont homeostasis and death in a symbiotic system and shed light on previously unknown aspects of bacteriocyte biological functioning. PMID- 29432147 TI - Global rise in emerging alien species results from increased accessibility of new source pools. AB - Our ability to predict the identity of future invasive alien species is largely based upon knowledge of prior invasion history. Emerging alien species-those never encountered as aliens before-therefore pose a significant challenge to biosecurity interventions worldwide. Understanding their temporal trends, origins, and the drivers of their spread is pivotal to improving prevention and risk assessment tools. Here, we use a database of 45,984 first records of 16,019 established alien species to investigate the temporal dynamics of occurrences of emerging alien species worldwide. Even after many centuries of invasions the rate of emergence of new alien species is still high: One-quarter of first records during 2000-2005 were of species that had not been previously recorded anywhere as alien, though with large variation across taxa. Model results show that the high proportion of emerging alien species cannot be solely explained by increases in well-known drivers such as the amount of imported commodities from historically important source regions. Instead, these dynamics reflect the incorporation of new regions into the pool of potential alien species, likely as a consequence of expanding trade networks and environmental change. This process compensates for the depletion of the historically important source species pool through successive invasions. We estimate that 1-16% of all species on Earth, depending on the taxonomic group, qualify as potential alien species. These results suggest that there remains a high proportion of emerging alien species we have yet to encounter, with future impacts that are difficult to predict. PMID- 29432150 TI - QnAs with Martin Head-Gordon. PMID- 29432149 TI - Assessment of the Legionnaires' disease outbreak in Flint, Michigan. AB - The 2014-2015 Legionnaires' disease (LD) outbreak in Genesee County, MI, and the outbreak resolution in 2016 coincided with changes in the source of drinking water to Flint's municipal water system. Following the switch in water supply from Detroit to Flint River water, the odds of a Flint resident presenting with LD increased 6.3-fold (95% CI: 2.5, 14.0). This risk subsided following boil water advisories, likely due to residents avoiding water, and returned to historically normal levels with the switch back in water supply. During the crisis, as the concentration of free chlorine in water delivered to Flint residents decreased, their risk of acquiring LD increased. When the average weekly chlorine level in a census tract was <0.5 mg/L or <0.2 mg/L, the odds of an LD case presenting from a Flint neighborhood increased by a factor of 2.9 (95% CI: 1.4, 6.3) or 3.9 (95% CI: 1.8, 8.7), respectively. During the switch, the risk of a Flint neighborhood having a case of LD increased by 80% per 1 mg/L decrease in free chlorine, as calculated from the extensive variation in chlorine observed. In communities adjacent to Flint, the probability of LD occurring increased with the flow of commuters into Flint. Together, the results support the hypothesis that a system-wide proliferation of legionellae was responsible for the LD outbreak in Genesee County, MI. PMID- 29432148 TI - 15N detection harnesses the slow relaxation property of nitrogen: Delivering enhanced resolution for intrinsically disordered proteins. AB - Studies over the past decade have highlighted the functional significance of intrinsically disordered proteins (IDPs). Due to conformational heterogeneity and inherent dynamics, structural studies of IDPs have relied mostly on NMR spectroscopy, despite IDPs having characteristics that make them challenging to study using traditional 1H-detected biomolecular NMR techniques. Here, we develop a suite of 3D 15N-detected experiments that take advantage of the slower transverse relaxation property of 15N nuclei, the associated narrower linewidth, and the greater chemical shift dispersion compared with those of 1H and 13C resonances. The six 3D experiments described here start with aliphatic 1H magnetization to take advantage of its higher initial polarization, and are broadly applicable for backbone assignment of proteins that are disordered, dynamic, or have unfavorable amide proton exchange rates. Using these experiments, backbone resonance assignments were completed for the unstructured regulatory domain (residues 131-294) of the human transcription factor nuclear factor of activated T cells (NFATC2), which includes 28 proline residues located in functionally important serine-proline (SP) repeats. The complete assignment of the NFATC2 regulatory domain enabled us to study phosphorylation of NFAT by kinase PKA and phosphorylation-dependent binding of chaperone protein 14-3-3 to NFAT, providing mechanistic insight on how 14-3-3 regulates NFAT nuclear translocation. PMID- 29432151 TI - Identification and paleoclimatic significance of magnetite nanoparticles in soils. AB - In the world-famous sediments of the Chinese Loess Plateau, fossil soils alternate with windblown dust layers to record monsoonal variations over the last ~3 My. The less-weathered, weakly magnetic dust layers reflect drier, colder glaciations. The fossil soils (paleosols) contain variable concentrations of nanoscale, strongly magnetic iron oxides, formed in situ during the wetter, warmer interglaciations. Mineralogical identification of the magnetic soil oxides is essential for deciphering these key paleoclimatic records. Formation of magnetite, a mixed Fe2+/Fe3+ ferrimagnet, has been linked to soil redox oscillations, and thence to paleorainfall. An opposite hypothesis states that magnetite can only form if the soil is water saturated for significant periods in order for Fe3+ to be reduced to Fe2+, and suggests instead the temperature dependent formation of maghemite, an Fe3+-oxide, much of which ages subsequently into hematite, typically aluminum substituted. This latter, oxidizing pathway would have been temperature, but not rainfall dependent. Here, through structural fingerprinting and scanning transmission electron microscopy and electron energy loss spectroscopy analysis, we prove that magnetite is the dominant soil-formed ferrite. Maghemite is present in lower concentrations, and shows no evidence of aluminum substitution, negating its proposed precursor role for the aluminum substituted hematite prevalent in the paleosols. Magnetite dominance demonstrates that magnetite formation occurs in well-drained, generally oxidizing soils, and that soil wetting/drying oscillations drive the degree of soil magnetic enhancement. The magnetic variations of the Chinese Loess Plateau paleosols thus record changes in monsoonal rainfall, over timescales of millions of years. PMID- 29432153 TI - Correction for Sanderman et al., Soil carbon debt of 12,000 years of human land use. PMID- 29432152 TI - Double abdomen in a short-germ insect: Zygotic control of axis formation revealed in the beetle Tribolium castaneum. AB - The distinction of anterior versus posterior is a crucial first step in animal embryogenesis. In the fly Drosophila, this axis is established by morphogenetic gradients contributed by the mother that regulate zygotic target genes. This principle has been considered to hold true for insects in general but is fundamentally different from vertebrates, where zygotic genes and Wnt signaling are required. We investigated symmetry breaking in the beetle Tribolium castaneum, which among insects represents the more ancestral short-germ embryogenesis. We found that maternal Tc-germ cell-less is required for anterior localization of maternal Tc-axin, which represses Wnt signaling and promotes expression of anterior zygotic genes. Both RNAi targeting Tc-germ cell-less or double RNAi knocking down the zygotic genes Tc-homeobrain and Tc-zen1 led to the formation of a second growth zone at the anterior, which resulted in double abdomen phenotypes. Conversely, interfering with two posterior factors, Tc-caudal and Wnt, caused double-anterior phenotypes. These findings reveal that maternal and zygotic mechanisms, including Wnt signaling, are required for establishing embryo polarity and induce the segmentation clock in a short-germ insect. PMID- 29432154 TI - 5-Azacytidine prevents relapse and produces long-term complete remissions in leukemia xenografts treated with Moxetumomab pasudotox. AB - Moxetumomab pasudotox (Moxe) is a chimeric protein composed of an anti-CD22 Fv fused to a portion of Pseudomonas exotoxin A and kills CD22-expressing leukemia cells. It is very active in hairy-cell leukemia, but many children with relapsed/refractory acute lymphoblastic leukemia (ALL) either respond transiently or are initially resistant. Resistance to Moxe in cultured cells is due to low expression of diphthamide genes (DPH), but only two of six ALL blast samples from resistant patients had low DPH expression. To develop a more clinically relevant model of resistance, we treated NSG mice bearing KOPN-8 or Reh cells with Moxe. More than 99.9% of the cancer cells were killed by Moxe, but relapse occurred from discrete bone marrow sites. The resistant cells would no longer grow in cell culture and showed major chromosomal changes and changes in phenotype with greatly decreased CD22. RNA deep sequencing of resistant KOPN-8 blasts revealed global changes in gene expression, indicating dedifferentiation toward less mature B cell precursors, and showed an up-regulation of myeloid genes. When Moxe was combined with 5-azacytidine, resistance was prevented and survival increased to over 5 months in the KOPN-8 model and greatly improved in the Reh model. We conclude that Moxe resistance in mice is due to a new mechanism that could not be observed using cultured cells and is prevented by treatment with 5-azacytidine. PMID- 29432155 TI - Circadian clock-dependent and -independent posttranscriptional regulation underlies temporal mRNA accumulation in mouse liver. AB - The mammalian circadian clock coordinates physiology with environmental cycles through the regulation of daily oscillations of gene expression. Thousands of transcripts exhibit rhythmic accumulations across mouse tissues, as determined by the balance of their synthesis and degradation. While diurnally rhythmic transcription regulation is well studied and often thought to be the main factor generating rhythmic mRNA accumulation, the extent of rhythmic posttranscriptional regulation is debated, and the kinetic parameters (e.g., half-lives), as well as the underlying regulators (e.g., mRNA-binding proteins) are relatively unexplored. Here, we developed a quantitative model for cyclic accumulations of pre-mRNA and mRNA from total RNA-seq data, and applied it to mouse liver. This allowed us to identify that about 20% of mRNA rhythms were driven by rhythmic mRNA degradation, and another 15% of mRNAs regulated by both rhythmic transcription and mRNA degradation. The method could also estimate mRNA half lives and processing times in intact mouse liver. We then showed that, depending on mRNA half-life, rhythmic mRNA degradation can either amplify or tune phases of mRNA rhythms. By comparing mRNA rhythms in wild-type and Bmal1-/- animals, we found that the rhythmic degradation of many transcripts did not depend on a functional BMAL1. Interestingly clock-dependent and -independent degradation rhythms peaked at distinct times of day. We further predicted mRNA-binding proteins (mRBPs) that were implicated in the posttranscriptional regulation of mRNAs, either through stabilizing or destabilizing activities. Together, our results demonstrate how posttranscriptional regulation temporally shapes rhythmic mRNA accumulation in mouse liver. PMID- 29432156 TI - Role of ubiquitylation of components of mitotic checkpoint complex in their dissociation from anaphase-promoting complex/cyclosome. AB - The mitotic checkpoint system ensures the fidelity of chromosome segregation in mitosis by preventing premature initiation of anaphase until correct bipolar attachment of chromosomes to the mitotic spindle is reached. It promotes the assembly of a mitotic checkpoint complex (MCC), composed of BubR1, Bub3, Cdc20, and Mad2, which inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase. When the checkpoint is satisfied, anaphase is initiated by the disassembly of MCC. Previous studies indicated that the dissociation of APC/C-bound MCC requires ubiquitylation and suggested that the target of ubiquitylation is the Cdc20 component of MCC. However, it remained unknown how ubiquitylation causes the release of MCC from APC/C and its disassembly and whether ubiquitylation of additional proteins is involved in this process. We find that ubiquitylation causes the dissociation of BubR1 from Cdc20 in MCC and suggest that this may lead to the release of MCC components from APC/C. BubR1 in MCC is ubiquitylated by APC/C, although to a lesser degree than Cdc20. The extent of BubR1 ubiquitylation was markedly increased in recombinant MCC that contained a lysine-less mutant of Cdc20. Mutation of lysine residues to arginines in the N terminal region of BubR1 partially inhibited its ubiquitylation and slowed down the release of MCC from APC/C, provided that Cdc20 ubiquitylation was also blocked. It is suggested that ubiquitylation of both Cdc20 and BubR1 may be involved in their dissociation from each other and in the release of MCC components from APC/C. PMID- 29432157 TI - Flexible usage and social function in primate vocalizations. AB - Vocalizations are a pervasive feature of nonhuman primate social life, yet we know surprisingly little about their function. We review studies supporting the hypothesis that many primate vocalizations function to facilitate social interactions by reducing uncertainty about the signaler's intentions and likely behavior. Such interactions help to establish and maintain the social bonds that increase reproductive success. Compared with humans, songbirds, and a few other mammals, primates have small vocal repertoires that show little acoustic modification during development. However, their ability to modify call usage is extensive and tuned to variation in the social context, including the historical relationship between caller and listener and the caller's assessment of how a listener is likely to respond. We suggest parallels between the decision to vocalize and neurophysiological studies of other, nonvocal social decisions between interacting monkeys. The selective factors driving the early stages of language evolution may have come from the need to make decisions about when and how to call within the context of social challenges. PMID- 29432158 TI - 16p11.2 transcription factor MAZ is a dosage-sensitive regulator of genitourinary development. AB - Genitourinary (GU) birth defects are among the most common yet least studied congenital malformations. Congenital anomalies of the kidney and urinary tract (CAKUTs) have high morbidity and mortality rates and account for ~30% of structural birth defects. Copy number variation (CNV) mapping revealed that 16p11.2 is a hotspot for GU development. The only gene covered collectively by all of the mapped GU-patient CNVs was MYC-associated zinc finger transcription factor (MAZ), and MAZ CNV frequency is enriched in nonsyndromic GU-abnormal patients. Knockdown of MAZ in HEK293 cells results in differential expression of several WNT morphogens required for normal GU development, including Wnt11 and Wnt4. MAZ knockdown also prevents efficient transition into S phase, affects transcription of cell-cycle regulators, and abrogates growth of human embryonic kidney cells. Murine Maz is ubiquitously expressed, and a CRISPR-Cas9 mouse model of Maz deletion results in perinatal lethality with survival rates dependent on Maz copy number. Homozygous loss of Maz results in high penetrance of CAKUTs, and Maz is haploinsufficient for normal bladder development. MAZ, once thought to be a simple housekeeping gene, encodes a dosage-sensitive transcription factor that regulates urogenital development and contributes to both nonsyndromic congenital malformations of the GU tract as well as the 16p11.2 phenotype. PMID- 29432160 TI - Role of a selecting ligand in shaping the murine gammadelta-TCR repertoire. AB - Unlike alphabeta-T lineage cells, where the role of ligand in intrathymic selection is well established, the role of ligand in the development of gammadelta-T cells remains controversial. Here we provide evidence for the role of a bona fide selecting ligand in shaping the gammadelta-T cell-receptor (TCR) repertoire. Reactivity of the gammadelta-TCR with the major histocompatibility complex (MHC) Class Ib ligands, H2-T10/22, is critically dependent upon the EGYEL motif in the complementarity determining region 3 (CDR3) of TCRdelta. In the absence of H2-T10/22 ligand, the commitment of H2-T10/22 reactive gammadelta-T cells to the gammadelta fate is diminished, and the specification of those gammadelta committed cells to the IFN-gamma or interleukin-17 effector fate is altered. Furthermore, those cells that do adopt the gammadelta fate and mature exhibit a profound alteration in the gammadeltaTCR repertoire, including depletion of the EGYEL motif and reductions in both CDR3delta length and charge. Taken together, these data suggest that ligand plays an important role in shaping the TCR repertoire of gammadelta-T cells. PMID- 29432161 TI - Control of chemoselectivity in asymmetric tandem reactions: Direct synthesis of chiral amines bearing nonadjacent stereocenters. AB - This paper describes the mechanistic insight-guided development of a catalyst system, employing a phenolic proton donor catalyst in addition to a cinchonium derived phase-transfer catalyst, to control the chemoselectivity of two distinct intermediates, thereby enabling the desired asymmetric tandem conjugate addition protonation pathway to dominate over a number of side-reaction pathways to provide a synthetic approach for the direct generation of optically active amines bearing two nonadjacent stereocenters. PMID- 29432159 TI - NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. AB - Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer's disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polbeta+/- mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polbeta+/- mice have a reduced cerebral NAD+/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polbeta+/- mice but had no impact on amyloid beta peptide (Abeta) accumulation. NR-treated 3xTgAD/Polbeta+/- mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polbeta+/- mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polbeta+/- mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD+ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD+ levels therefore have therapeutic potential for AD. PMID- 29432162 TI - Pressure-induced structural change in MgSiO3 glass at pressures near the Earth's core-mantle boundary. AB - Knowledge of the structure and properties of silicate magma under extreme pressure plays an important role in understanding the nature and evolution of Earth's deep interior. Here we report the structure of MgSiO3 glass, considered an analog of silicate melts, up to 111 GPa. The first (r1) and second (r2) neighbor distances in the pair distribution function change rapidly, with r1 increasing and r2 decreasing with pressure. At 53-62 GPa, the observed r1 and r2 distances are similar to the Si-O and Si-Si distances, respectively, of crystalline MgSiO3 akimotoite with edge-sharing SiO6 structural motifs. Above 62 GPa, r1 decreases, and r2 remains constant, with increasing pressure until 88 GPa. Above this pressure, r1 remains more or less constant, and r2 begins decreasing again. These observations suggest an ultrahigh-pressure structural change around 88 GPa. The structure above 88 GPa is interpreted as having the closest edge-shared SiO6 structural motifs similar to those of the crystalline postperovskite, with densely packed oxygen atoms. The pressure of the structural change is broadly consistent with or slightly lower than that of the bridgmanite to-postperovskite transition in crystalline MgSiO3 These results suggest that a structural change may occur in MgSiO3 melt under pressure conditions corresponding to the deep lower mantle. PMID- 29432163 TI - Wooden tools and fire technology in the early Neanderthal site of Poggetti Vecchi (Italy). AB - Excavations for the construction of thermal pools at Poggetti Vecchi (Grosseto, Tuscany, central Italy) exposed a series of wooden tools in an open-air stratified site referable to late Middle Pleistocene. The wooden artifacts were uncovered, together with stone tools and fossil bones, largely belonging to the straight-tusked elephant Paleoloxodon antiquus The site is radiometrically dated to around 171,000 y B.P., and hence correlated with the early marine isotope stage 6 [Benvenuti M, et al. (2017) Quat Res 88:327-344]. The sticks, all fragmentary, are made from boxwood (Buxus sempervirens) and were over 1 m long, rounded at one end and pointed at the other. They have been partially charred, possibly to lessen the labor of scraping boxwood, using a technique so far not documented at the time. The wooden artifacts have the size and features of multipurpose tools known as "digging sticks," which are quite commonly used by foragers. This discovery from Poggetti Vecchi provides evidence of the processing and use of wood by early Neanderthals, showing their ability to use fire in tool making from very tough wood. PMID- 29432164 TI - Correction for Murari et al., Climate change and agricultural suicides in India. PMID- 29432166 TI - Thymic involution and rising disease incidence with age. AB - For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ~16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor. PMID- 29432165 TI - Loss of function of a rice TPR-domain RNA-binding protein confers broad-spectrum disease resistance. AB - Crops carrying broad-spectrum resistance loci provide an effective strategy for controlling infectious disease because these loci typically confer resistance to diverse races of a pathogen or even multiple species of pathogens. Despite their importance, only a few crop broad-spectrum resistance loci have been reported. Here, we report the identification and characterization of the rice bsr-k1 (broad spectrum resistance Kitaake-1) mutant, which confers broad-spectrum resistance against Magnaporthe oryzae and Xanthomonas oryzae pv oryzae with no major penalty on key agronomic traits. Map-based cloning reveals that Bsr-k1 encodes a tetratricopeptide repeats (TPRs)-containing protein, which binds to mRNAs of multiple OsPAL (OsPAL1-7) genes and promotes their turnover. Loss of function of the Bsr-k1 gene leads to accumulation of OsPAL1-7 mRNAs in the bsr-k1 mutant. Furthermore, overexpression of OsPAL1 in wild-type rice TP309 confers resistance to M. oryzae, supporting the role of OsPAL1 Our discovery of the bsr-k1 allele constitutes a significant conceptual advancement and provides a valuable tool for breeding broad-spectrum resistant rice. PMID- 29432168 TI - Correction for Das, Unfounded assumptions in linking crop-damaging temperature and suicide in India. PMID- 29432169 TI - Maturity of nearby faults influences seismic hazard from hydraulic fracturing. AB - Understanding the causes of human-induced earthquakes is paramount to reducing societal risk. We investigated five cases of seismicity associated with hydraulic fracturing (HF) in Ohio since 2013 that, because of their isolation from other injection activities, provide an ideal setting for studying the relations between high-pressure injection and earthquakes. Our analysis revealed two distinct groups: (i) deeper earthquakes in the Precambrian basement, with larger magnitudes (M > 2), b-values < 1, and many post-shut-in earthquakes, versus (ii) shallower earthquakes in Paleozoic rocks ~400 m below HF, with smaller magnitudes (M < 1), b-values > 1.5, and few post-shut-in earthquakes. Based on geologic history, laboratory experiments, and fault modeling, we interpret the deep seismicity as slip on more mature faults in older crystalline rocks and the shallow seismicity as slip on immature faults in younger sedimentary rocks. This suggests that HF inducing deeper seismicity may pose higher seismic hazards. Wells inducing deeper seismicity produced more water than wells with shallow seismicity, indicating more extensive hydrologic connections outside the target formation, consistent with pore pressure diffusion influencing seismicity. However, for both groups, the 2 to 3 h between onset of HF and seismicity is too short for typical fluid pressure diffusion rates across distances of ~1 km and argues for poroelastic stress transfer also having a primary influence on seismicity. PMID- 29432170 TI - Mechanism of ubiquitin transfer promoted by TRAF6. AB - Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) plays a vital role in immune signal transduction pathways by acting as a ubiquitin ligase (E3) for Lys63-linked polyubiquitin chain synthesis. However, the detailed mechanism by which the TRAF6 RING dimer promotes ubiquitin transfer was unknown. Through structural modeling and biochemical analysis, we here show that the TRAF6 RING dimer employs a concerted allosteric mechanism using both subunits of the TRAF6 dimer to promote ubiquitin (Ub) transfer. In particular, we reveal the importance of the C-terminal extension of the TRAF6 RING domain that mediates trans interactions with the donor-Ub. By analyzing structures and models of E3s in complex with Ub-loaded ubiquitin-conjugating enzymes (E2s), we further highlight the roles of N-terminal and C-terminal extensions beyond the bona fide RING domains in promoting Ub transfer through engagement with a donor-Ub in cis and in trans, respectively. PMID- 29432172 TI - Geometrical control of dissipation during the spreading of liquids on soft solids. AB - Gel layers bound to a rigid substrate are used in cell culture to control differentiation and migration and to lower the friction and tailor the wetting of solids. Their thickness, often considered a negligible parameter, affects cell mechanosensing or the shape of sessile droplets. Here, we show that the adjustment of coating thickness provides control over energy dissipation during the spreading of flowing matter on a gel layer. We combine experiments and theory to provide an analytical description of both the statics and the dynamics of the contact line between the gel, the liquid, and the surrounding atmosphere. We extract from this analysis a hitherto-unknown scaling law that predicts the dynamic contact angle between the three phases as a function of the properties of the coating and the velocity of the contact line. Finally, we show that droplets moving on vertical substrates coated with gel layers having linear thickness gradients drift toward regions of higher energy dissipation. Thus, thickness control opens the opportunity to design a priori the path followed by large droplets moving on gel-coated substrates. Our study shows that thickness is another parameter, besides surface energy and substrate mechanics, to tune the dynamics of liquid spreading and wetting on a compliant coating, with potential applications in dew collection and free-surface flow control. PMID- 29432171 TI - Regulation of Arabidopsis brassinosteroid receptor BRI1 endocytosis and degradation by plant U-box PUB12/PUB13-mediated ubiquitination. AB - Plants largely rely on plasma membrane (PM)-resident receptor-like kinases (RLKs) to sense extracellular and intracellular stimuli and coordinate cell differentiation, growth, and immunity. Several RLKs have been shown to undergo internalization through the endocytic pathway with a poorly understood mechanism. Here, we show that endocytosis and protein abundance of the Arabidopsis brassinosteroid (BR) receptor, BR INSENSITIVE1 (BRI1), are regulated by plant U box (PUB) E3 ubiquitin ligase PUB12- and PUB13-mediated ubiquitination. BR perception promotes BRI1 ubiquitination and association with PUB12 and PUB13 through phosphorylation at serine 344 residue. Loss of PUB12 and PUB13 results in reduced BRI1 ubiquitination and internalization accompanied with a prolonged BRI1 PM-residence time, indicating that ubiquitination of BRI1 by PUB12 and PUB13 is a key step in BRI1 endocytosis. Our studies provide a molecular link between BRI1 ubiquitination and internalization and reveal a unique mechanism of E3 ligase substrate association regulated by phosphorylation. PMID- 29432167 TI - Phylogenetic classification of the world's tropical forests. AB - Knowledge about the biogeographic affinities of the world's tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world's tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern hemisphere forests. PMID- 29432173 TI - A posttranslational modification of the mitotic kinesin Eg5 that enhances its mechanochemical coupling and alters its mitotic function. AB - Numerous posttranslational modifications have been described in kinesins, but their consequences on motor mechanics are largely unknown. We investigated one of these-acetylation of lysine 146 in Eg5-by creating an acetylation mimetic lysine to glutamine substitution (K146Q). Lysine 146 is located in the alpha2 helix of the motor domain, where it makes an ionic bond with aspartate 91 on the neighboring alpha1 helix. Molecular dynamics simulations predict that disrupting this bond enhances catalytic site-neck linker coupling. We tested this using structural kinetics and single-molecule mechanics and found that the K146Q mutation increases motor performance under load and coupling of the neck linker to catalytic site. These changes convert Eg5 from a motor that dissociates from the microtubule at low load into one that is more tightly coupled and dissociation resistant-features shared by kinesin 1. These features combined with the increased propensity to stall predict that the K146Q Eg5 acetylation mimetic should act in the cell as a "brake" that slows spindle pole separation, and we have confirmed this by expressing this modified motor in mitotically active cells. Thus, our results illustrate how a posttranslational modification of a kinesin can be used to fine tune motor behavior to meet specific physiological needs. PMID- 29432174 TI - Naked mole rats can undergo developmental, oncogene-induced and DNA damage induced cellular senescence. AB - Cellular senescence is an important anticancer mechanism that restricts proliferation of damaged or premalignant cells. Cellular senescence also plays an important role in tissue remodeling during development. However, there is a trade off associated with cellular senescence as senescent cells contribute to aging pathologies. The naked mole rat (NMR) (Heterocephalus glaber) is the longest lived rodent that is resistant to a variety of age-related diseases. Remarkably, NMRs do not show aging phenotypes until very late stages of their lives. Here, we tested whether NMR cells undergo cellular senescence. We report that the NMR displays developmentally programmed cellular senescence in multiple tissues, including nail bed, skin dermis, hair follicle, and nasopharyngeal cavity. NMR cells also underwent cellular senescence when transfected with oncogenic Ras. In addition, cellular senescence was detected in NMR embryonic and skin fibroblasts subjected to gamma-irradiation (IR). However, NMR cells required a higher dose of IR for induction of cellular senescence, and NMR fibroblasts were resistant to IR induced apoptosis. Gene expression analyses of senescence-related changes demonstrated that, similar to mice, NMR cells up-regulated senescence-associated secretory phenotype genes but displayed more profound down-regulation of DNA metabolism, transcription, and translation than mouse cells. We conclude that the NMR displays the same types of cellular senescence found in a short-lived rodent. PMID- 29432176 TI - Detection of aneuploidy in patients with cancer through amplification of long interspersed nucleotide elements (LINEs). AB - Aneuploidy is a feature of most cancer cells, and a myriad of approaches have been developed to detect it in clinical samples. We previously described primers that could be used to amplify ~38,000 unique long interspersed nucleotide elements (LINEs) from throughout the genome. Here we have developed an approach to evaluate the sequencing data obtained from these amplicons. This approach, called Within-Sample AneupLoidy DetectiOn (WALDO), employs supervised machine learning to detect the small changes in multiple chromosome arms that are often present in cancers. We used WALDO to search for chromosome arm gains and losses in 1,677 tumors and in 1,522 liquid biopsies of blood from cancer patients or normal individuals. Aneuploidy was detected in 95% of cancer biopsies and in 22% of liquid biopsies. Using single-nucleotide polymorphisms within the amplified LINEs, WALDO concomitantly assesses allelic imbalances, microsatellite instability, and sample identification. WALDO can be used on samples containing only a few nanograms of DNA and as little as 1% neoplastic content and has a variety of applications in cancer diagnostics and forensic science. PMID- 29432175 TI - Uterine influences on conceptus development in fertility-classified animals. AB - A major unresolved issue is how the uterus influences infertility and subfertility in cattle. Serial embryo transfer was previously used to classify heifers as high-fertile (HF), subfertile (SF), or infertile (IF). To assess pregnancy loss, two in vivo-produced embryos were transferred into HF, SF, and IF heifers on day 7, and pregnancy outcome was assessed on day 17. Pregnancy rate was substantially higher in HF (71%) and SF (90%) than IF (20%) heifers. Elongating conceptuses were about twofold longer in HF than SF heifers. Transcriptional profiling detected relatively few differences in the endometrium of nonpregnant HF, SF, and IF heifers. In contrast, there was a substantial difference in the transcriptome response of the endometrium to pregnancy between HF and SF heifers. Considerable deficiencies in pregnancy-dependent biological pathways associated with extracellular matrix structure and organization as well as cell adhesion were found in the endometrium of SF animals. Distinct gene expression differences were also observed in conceptuses from HF and SF animals, with many of the genes decreased in SF conceptuses known to be embryonic lethal in mice due to defects in embryo and/or placental development. Analyses of biological pathways, key players, and ligand-receptor interactions based on transcriptome data divulged substantial evidence for dysregulation of conceptus endometrial interactions in SF animals. These results support the ideas that the uterus impacts conceptus survival and programs conceptus development, and ripple effects of dysregulated conceptus-endometrial interactions elicit loss of the postelongation conceptus in SF cattle during the implantation period of pregnancy. PMID- 29432177 TI - Fast and accurate quantum Monte Carlo for molecular crystals. AB - Computer simulation plays a central role in modern-day materials science. The utility of a given computational approach depends largely on the balance it provides between accuracy and computational cost. Molecular crystals are a class of materials of great technological importance which are challenging for even the most sophisticated ab initio electronic structure theories to accurately describe. This is partly because they are held together by a balance of weak intermolecular forces but also because the primitive cells of molecular crystals are often substantially larger than those of atomic solids. Here, we demonstrate that diffusion quantum Monte Carlo (DMC) delivers subchemical accuracy for a diverse set of molecular crystals at a surprisingly moderate computational cost. As such, we anticipate that DMC can play an important role in understanding and predicting the properties of a large number of molecular crystals, including those built from relatively large molecules which are far beyond reach of other high-accuracy methods. PMID- 29432178 TI - General amino acid control in fission yeast is regulated by a nonconserved transcription factor, with functions analogous to Gcn4/Atf4. AB - Eukaryotes respond to amino acid starvation by enhancing the translation of mRNAs encoding b-ZIP family transcription factors (GCN4 in Saccharomyces cerevisiae and ATF4 in mammals), which launch transcriptional programs to counter this stress. This pathway involves phosphorylation of the eIF2 translation factor by Gcn2 protein kinases and is regulated by upstream ORFs (uORFs) in the GCN4/ATF4 5' leaders. Here, we present evidence that the transcription factors that mediate this response are not evolutionarily conserved. Although cells of the fission yeast Schizosaccharomyces pombe respond transcriptionally to amino acid starvation, they lack clear Gcn4 and Atf4 orthologs. We used ribosome profiling to identify mediators of this response in S. pombe, looking for transcription factors that behave like GCN4 We discovered a transcription factor (Fil1) translationally induced by amino acid starvation in a 5' leader and Gcn2 dependent manner. Like Gcn4, Fil1 is required for the transcriptional response to amino acid starvation, and Gcn4 and Fil1 regulate similar genes. Despite their similarities in regulation, function, and targets, Fil1 and Gcn4 belong to different transcription factor families (GATA and b-ZIP, respectively). Thus, the same functions are performed by nonorthologous proteins under similar regulation. These results highlight the plasticity of transcriptional networks, which maintain conserved principles with nonconserved regulators. PMID- 29432179 TI - PARP-1-dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability. AB - Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl)ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases. In the absence of CIRBP, cells showed reduced gammaH2AX, Rad51, and 53BP1 foci formation. Moreover, CIRBP depleted cells exhibited impaired homologous recombination, impaired nonhomologous end-joining, increased micronuclei formation, and higher sensitivity to gamma irradiation, demonstrating the active involvement of CIRBP in DSB repair. Furthermore, CIRBP depleted cells exhibited defects in DNA damage induced chromatin association of the MRN complex (Mre11, Rad50, and NBS1) and ATM kinase. CIRBP depletion also reduced phosphorylation of a variety of ATM substrate proteins and thus impaired the DNA damage response. Taken together, these results reveal a previously unrecognized role for CIRBP in DSB repair. PMID- 29432180 TI - Piezo2 channel regulates RhoA and actin cytoskeleton to promote cell mechanobiological responses. AB - Actin polymerization and assembly into stress fibers (SFs) is central to many cellular processes. However, how SFs form in response to the mechanical interaction of cells with their environment is not fully understood. Here we have identified Piezo2 mechanosensitive cationic channel as a transducer of environmental physical cues into mechanobiological responses. Piezo2 is needed by brain metastatic cells from breast cancer (MDA-MB-231-BrM2) to probe their physical environment as they anchor and pull on their surroundings or when confronted with confined migration through narrow pores. Piezo2-mediated Ca2+ influx activates RhoA to control the formation and orientation of SFs and focal adhesions (FAs). A possible mechanism for the Piezo2-mediated activation of RhoA involves the recruitment of the Fyn kinase to the cell leading edge as well as calpain activation. Knockdown of Piezo2 in BrM2 cells alters SFs, FAs, and nuclear translocation of YAP; a phenotype rescued by overexpression of dominant positive RhoA or its downstream effector, mDia1. Consequently, hallmarks of cancer invasion and metastasis related to RhoA, actin cytoskeleton, and/or force transmission, such as migration, extracellular matrix degradation, and Serpin B2 secretion, were reduced in cells lacking Piezo2. PMID- 29432181 TI - Three classes of recurrent DNA break clusters in brain progenitors identified by 3D proximity-based break joining assay. AB - We recently discovered 27 recurrent DNA double-strand break (DSB) clusters (RDCs) in mouse neural stem/progenitor cells (NSPCs). Most RDCs occurred across long, late-replicating RDC genes and were found only after mild inhibition of DNA replication. RDC genes share intriguing characteristics, including encoding surface proteins that organize brain architecture and neuronal junctions, and are genetically implicated in neuropsychiatric disorders and/or cancers. RDC identification relies on high-throughput genome-wide translocation sequencing (HTGTS), which maps recurrent DSBs based on their translocation to "bait" DSBs in specific chromosomal locations. Cellular heterogeneity in 3D genome organization allowed unequivocal identification of RDCs on 14 different chromosomes using HTGTS baits on three mouse chromosomes. Additional candidate RDCs were also implicated, however, suggesting that some RDCs were missed. To more completely identify RDCs, we exploited our finding that joining of two DSBs occurs more frequently if they lie on the same cis chromosome. Thus, we used CRISPR/Cas9 to introduce specific DSBs into each mouse chromosome in NSPCs that were used as bait for HTGTS libraries. This analysis confirmed all 27 previously identified RDCs and identified many new ones. NSPC RDCs fall into three groups based on length, organization, transcription level, and replication timing of genes within them. While mostly less robust, the largest group of newly defined RDCs share many intriguing characteristics with the original 27. Our findings also revealed RDCs in NSPCs in the absence of induced replication stress, and support the idea that the latter treatment augments an already active endogenous process. PMID- 29432182 TI - A big data analysis of the relationship between future thinking and decision making. AB - We use big data methods to investigate how decision-making might depend on future sightedness (that is, on how far into the future people's thoughts about the future extend). In study 1, we establish a link between future thinking and decision-making at the population level in showing that US states with citizens having relatively far future sightedness, as reflected in their tweets, take fewer risks than citizens in states having relatively near future sightedness. In study 2, we analyze people's tweets to confirm a connection between future sightedness and decision-making at the individual level in showing that people with long future sightedness are more likely to choose larger future rewards over smaller immediate rewards. In study 3, we show that risk taking decreases with increases in future sightedness as reflected in people's tweets. The ability of future sightedness to predict decisions suggests that future sightedness is a relatively stable cognitive characteristic. This implication was supported in an analysis of tweets by over 38,000 people that showed that future sightedness has both state and trait characteristics (study 4). In study 5, we provide evidence for a potential mechanism by which future sightedness can affect decisions in showing that far future sightedness can make the future seem more connected to the present, as reflected in how people refer to the present, past, and future in their tweets over the course of several minutes. Our studies show how big data methods can be applied to naturalistic data to reveal underlying psychological properties and processes. PMID- 29432183 TI - Ancient duons may underpin spatial patterning of gene expression in C4 leaves. AB - If the highly efficient C4 photosynthesis pathway could be transferred to crops with the C3 pathway there could be yield gains of up to 50%. It has been proposed that the multiple metabolic and developmental modifications associated with C4 photosynthesis are underpinned by relatively few master regulators that have allowed the evolution of C4 photosynthesis more than 60 times in flowering plants. Here we identify a component of one such regulator that consists of a pair of cis-elements located in coding sequence of multiple genes that are preferentially expressed in bundle sheath cells of C4 leaves. These motifs represent duons as they play a dual role in coding for amino acids as well as controlling the spatial patterning of gene expression associated with the C4 leaf. They act to repress transcription of C4 photosynthesis genes in mesophyll cells. These duons are also present in the C3 model Arabidopsis thaliana, and, in fact, are conserved in all land plants and even some algae that use C3 photosynthesis. C4 photosynthesis therefore appears to have coopted an ancient regulatory code to generate the spatial patterning of gene expression that is a hallmark of C4 photosynthesis. This intragenic transcriptional regulatory sequence could be exploited in the engineering of efficient photosynthesis of crops. PMID- 29432184 TI - Profile of Natasha V. Raikhel. PMID- 29432185 TI - Lipid bilayer composition modulates the unfolding free energy of a knotted alpha helical membrane protein. AB - alpha-Helical membrane proteins have eluded investigation of their thermodynamic stability in lipid bilayers. Reversible denaturation curves have enabled some headway in determining unfolding free energies. However, these parameters have been limited to detergent micelles or lipid bicelles, which do not possess the same mechanical properties as lipid bilayers that comprise the basis of natural membranes. We establish reversible unfolding of the membrane transporter LeuT in lipid bilayers, enabling the comparison of apparent unfolding free energies in different lipid compositions. LeuT is a bacterial ortholog of neurotransmitter transporters and contains a knot within its 12-transmembrane helical structure. Urea is used as a denaturant for LeuT in proteoliposomes, resulting in the loss of up to 30% helical structure depending upon the lipid bilayer composition. Urea unfolding of LeuT in liposomes is reversible, with refolding in the bilayer recovering the original helical structure and transport activity. A linear dependence of the unfolding free energy on urea concentration enables the free energy to be extrapolated to zero denaturant. Increasing lipid headgroup charge or chain lateral pressure increases the thermodynamic stability of LeuT. The mechanical and charge properties of the bilayer also affect the ability of urea to denature the protein. Thus, we not only gain insight to the long-sought-after thermodynamic stability of an alpha-helical protein in a lipid bilayer but also provide a basis for studies of the folding of knotted proteins in a membrane environment. PMID- 29432186 TI - Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region. AB - A hallmark of B-cell immunity is the generation of a diverse repertoire of antibodies from a limited set of germline V(D)J genes. This repertoire is usually defined in terms of amino acid composition. However, variable domains may also acquire N-linked glycans, a process conditional on the introduction of consensus amino acid motifs (N-glycosylation sites) during somatic hypermutation. High levels of variable domain glycans have been associated with autoantibodies in rheumatoid arthritis, as well as certain follicular lymphomas. However, the role of these glycans in the humoral immune response remains poorly understood. Interestingly, studies have reported both positive and negative effects on antibody affinity. Our aim was to elucidate the role of variable domain glycans during antigen-specific antibody responses. By analyzing B-cell repertoires by next-generation sequencing, we demonstrate that N-glycosylation sites are introduced at positions in which glycans can affect antigen binding as a result of a specific clustering of progenitor glycosylation sites in the germline sequences of variable domain genes. By analyzing multiple human monoclonal and polyclonal (auto)antibody responses, we subsequently show that this process is subject to selection during antigen-specific antibody responses, skewed toward IgG4, and positively contributes to antigen binding. Together, these results highlight a physiological role for variable domain glycosylation as an additional layer of antibody diversification that modulates antigen binding. PMID- 29432187 TI - Global changes of H3K27me3 domains and Polycomb group protein distribution in the absence of recruiters Spps or Pho. AB - Polycomb group (PcG) proteins maintain the silenced state of key developmental genes in animals, but how these proteins are recruited to specific regions of the genome is still poorly understood. In Drosophila, PcG proteins are recruited to Polycomb response elements (PREs) that include combinations of sites for sequence specific DNA binding "PcG recruiters," including Pho, Cg, and Spps. To understand their roles in PcG recruitment, we compared Pho-, Cg-, and Spps-binding sites against H3K27me3 and key PcG proteins by ChIP-seq in wild-type and mutant third instar larvae. H3K27me3 in canonical Polycomb domains is decreased after the reduction of any recruiter. Reduction of Spps and Pho, but not Cg, causes the redistribution of H3K27me3 to heterochromatin. Regions with dramatically depleted H3K27me3 after Spps knockout are usually accompanied by decreased Pho binding, suggesting their cooperative binding. PcG recruiters, the PRC2 component E(z), and the PRC1 components Psc and Ph cobind thousands of active genes outside of H3K27me3 domains. This study demonstrates the importance of distinct PcG recruiters for the establishment of unique Polycomb domains. Different PcG recruiters can act both cooperatively and independently at specific PcG target genes, highlighting the complexity and diversity of PcG recruitment mechanisms. PMID- 29432189 TI - Profile of Nancy Ip. PMID- 29432190 TI - Accelerated wound healing in mice by on-site production and delivery of CXCL12 by transformed lactic acid bacteria. AB - Impaired wound closure is a growing medical problem associated with metabolic diseases and aging. Immune cells play important roles in wound healing by following instructions from the microenvironment. Here, we developed a technology to bioengineer the wound microenvironment and enhance healing abilities of the immune cells. This resulted in strongly accelerated wound healing and was achieved by transforming Lactobacilli with a plasmid encoding CXCL12. CXCL12 delivering bacteria administrated topically to wounds in mice efficiently enhanced wound closure by increasing proliferation of dermal cells and macrophages, and led to increased TGF-beta expression in macrophages. Bacteria produced lactic acid reduced the local pH, which inhibited the peptidase CD26 and consequently enhanced the availability of bioactive CXCL12. Importantly, treatment with CXCL12-delivering Lactobacilli also improved wound closure in mice with hyperglycemia or peripheral ischemia, conditions associated with chronic wounds, and in a human skin wound model. Further, initial safety studies demonstrated that the topically applied transformed bacteria exerted effects restricted to the wound, as neither bacteria nor the chemokine produced could be detected in systemic circulation. Development of drugs accelerating wound healing is limited by the proteolytic nature of wounds. Our technology overcomes this by on-site chemokine production and reduced degradation, which together ensure prolonged chemokine bioavailability that instructed local immune cells and enhanced wound healing. PMID- 29432191 TI - Divergent and parallel routes of biochemical adaptation in high-altitude passerine birds from the Qinghai-Tibet Plateau. AB - When different species experience similar selection pressures, the probability of evolving similar adaptive solutions may be influenced by legacies of evolutionary history, such as lineage-specific changes in genetic background. Here we test for adaptive convergence in hemoglobin (Hb) function among high-altitude passerine birds that are native to the Qinghai-Tibet Plateau, and we examine whether convergent increases in Hb-O2 affinity have a similar molecular basis in different species. We documented that high-altitude parid and aegithalid species from the Qinghai-Tibet Plateau have evolved derived increases in Hb-O2 affinity in comparison with their closest lowland relatives in East Asia. However, convergent increases in Hb-O2 affinity and convergence in underlying functional mechanisms were seldom attributable to the same amino acid substitutions in different species. Using ancestral protein resurrection and site-directed mutagenesis, we experimentally confirmed two cases in which parallel substitutions contributed to convergent increases in Hb-O2 affinity in codistributed high-altitude species. In one case involving the ground tit (Parus humilis) and gray-crested tit (Lophophanes dichrous), parallel amino acid replacements with affinity-enhancing effects were attributable to nonsynonymous substitutions at a CpG dinucleotide, suggesting a possible role for mutation bias in promoting recurrent changes at the same site. Overall, most altitude-related changes in Hb function were caused by divergent amino acid substitutions, and a select few were caused by parallel substitutions that produced similar phenotypic effects on the divergent genetic backgrounds of different species. PMID- 29432192 TI - Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm. AB - Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1alpha (MIP-1alpha) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease. PMID- 29432193 TI - Bayesian selection of misspecified models is overconfident and may cause spurious posterior probabilities for phylogenetic trees. AB - The Bayesian method is noted to produce spuriously high posterior probabilities for phylogenetic trees in analysis of large datasets, but the precise reasons for this overconfidence are unknown. In general, the performance of Bayesian selection of misspecified models is poorly understood, even though this is of great scientific interest since models are never true in real data analysis. Here we characterize the asymptotic behavior of Bayesian model selection and show that when the competing models are equally wrong, Bayesian model selection exhibits surprising and polarized behaviors in large datasets, supporting one model with full force while rejecting the others. If one model is slightly less wrong than the other, the less wrong model will eventually win when the amount of data increases, but the method may become overconfident before it becomes reliable. We suggest that this extreme behavior may be a major factor for the spuriously high posterior probabilities for evolutionary trees. The philosophical implications of our results to the application of Bayesian model selection to evaluate opposing scientific hypotheses are yet to be explored, as are the behaviors of non Bayesian methods in similar situations. PMID- 29432194 TI - Structurally modulated codelivery of siRNA and Argonaute 2 for enhanced RNA interference. AB - Small interfering RNA (siRNA) represents a promising class of inhibitors in both fundamental research and the clinic. Numerous delivery vehicles have been developed to facilitate siRNA delivery. Nevertheless, achieving highly potent RNA interference (RNAi) toward clinical translation requires efficient formation of RNA-induced gene-silencing complex (RISC) in the cytoplasm. Here we coencapsulate siRNA and the central RNAi effector protein Argonaute 2 (Ago2) via different delivery carriers as a platform to augment RNAi. The physical clustering between siRNA and Ago2 is found to be indispensable for enhanced RNAi. Moreover, by utilizing polyamines bearing the same backbone but distinct cationic side-group arrangements of ethylene diamine repeats as the delivery vehicles, we find that the molecular structure of these polyamines modulates the degree of siRNA/Ago2 mediated improvement of RNAi. We apply this strategy to silence the oncogene STAT3 and significantly prolong survival in mice challenged with melanoma. Our findings suggest a paradigm for RNAi via the synergistic coassembly of RNA with helper proteins. PMID- 29432196 TI - Layer-specific systolic and diastolic strain in hypertensive patients with and without mild diastolic dysfunction. AB - This study sought to examine layer-specific longitudinal and circumferential systolic and diastolic strain, strain rate (SR) and diastolic time intervals in hypertensive patients with and without diastolic dysfunction. Fifty-eight treated hypertensive patients were assigned to normal diastolic function (NDF, N = 39) or mild diastolic dysfunction (DD, N = 19) group. Layer-specific systolic and diastolic longitudinal and circumferential strains and SR were assessed. Results showed no between-group difference in left ventricular mass index (DD: 92.1 +/- 18.1 vs NDF: 88.4 +/- 16.3; P = 0.44). Patients with DD had a proportional reduction in longitudinal strain across the myocardium (endocardial for DD -13 +/ 4%; vs NDF -17 +/- 3, P < 0.01; epicardial for DD -10 +/- 3% vs NDF -13 +/- 3%, P < 0.01; global for DD: -12 +/- 3% vs NDF: -15 +/- 3, P = 0.01), and longitudinal mechanical diastolic impairments as evidenced by reduced longitudinal strain rate of early diastole (DD 0.7 +/- 0.2 L/s vs NDF 1.0 +/- 0.3 L/s, P < 0.01) and absence of a transmural gradient in the duration of diastolic strain (DD endocardial: 547 +/- 105 ms vs epicardial: 542 +/- 113 ms, P = 0.24; NDF endocardial: 566 +/- 86 ms vs epicardial: 553 +/- 77 ms, P = 0.03). Patients with DD also demonstrate a longer duration of early circumferential diastolic strain (231 +/- 71 ms vs 189 +/- 58 ms, P = 0.02). In conclusion, hypertensive patients with mild DD demonstrate a proportional reduction in longitudinal strain across the myocardium, as well as longitudinal mechanical diastolic impairment, and prolonging duration of circumferential mechanical relaxation. PMID- 29432195 TI - Capicua controls Toll/IL-1 signaling targets independently of RTK regulation. AB - The HMG-box protein Capicua (Cic) is a conserved transcriptional repressor that functions downstream of receptor tyrosine kinase (RTK) signaling pathways in a relatively simple switch: In the absence of signaling, Cic represses RTK responsive genes by binding to nearly invariant sites in DNA, whereas activation of RTK signaling down-regulates Cic activity, leading to derepression of its targets. This mechanism controls gene expression in both Drosophila and mammals, but whether Cic can also function via other regulatory mechanisms remains unknown. Here, we characterize an RTK-independent role of Cic in regulating spatially restricted expression of Toll/IL-1 signaling targets in Drosophila embryogenesis. We show that Cic represses those targets by binding to suboptimal DNA sites of lower affinity than its known consensus sites. This binding depends on Dorsal/NF-kappaB, which translocates into the nucleus upon Toll activation and binds next to the Cic sites. As a result, Cic binds to and represses Toll targets only in regions with nuclear Dorsal. These results reveal a mode of Cic regulation unrelated to the well-established RTK/Cic depression axis and implicate cooperative binding in conjunction with low-affinity binding sites as an important mechanism of enhancer regulation. Given that Cic plays a role in many developmental and pathological processes in mammals, our results raise the possibility that some of these Cic functions are independent of RTK regulation and may depend on cofactor-assisted DNA binding. PMID- 29432197 TI - EDUCATIONAL SERIES IN CONGENITAL HEART DISEASE: Echocardiographic assessment of left to right shunts: atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent arterial duct. AB - This review article will guide the reader through the basics of echocardiographic assessment of congenital left to right shunts in both paediatric and adult age groups. After reading this article, the reader will understand the pathology and clinical presentation of atrial septal defects (ASDs), ventricular septal defects (VSDs), atrioventricular septal defects (AVSDs) and patent arterial duct. Echocardiography is the mainstay in diagnosis and follow-up assessment of patients with congenital heart disease. This article will therefore describe the echocardiographic appearances of each lesion, and point the reader towards specific features to look for echocardiographically. PMID- 29432188 TI - Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis. AB - Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 * 10-14), two common variants, GCH1 (rs72713460, P = 4.36 * 10-5) and KCNJ15 (rs928771, P = 3.60 * 10-6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system. PMID- 29432198 TI - Impact of image quality on reliability of the measurements of left ventricular systolic function and global longitudinal strain in 2D echocardiography. AB - BACKGROUND: Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) play important roles in diagnosis and management of cardiac diseases. However, the issue of the accuracy and reliability of LVEF and GLS remains to be solved. Image quality is one of the most important factors affecting measurement variability. The aim of this study was to investigate whether improved image quality could reduce observer variability. METHODS: Two sets of three apical images were acquired using relatively old- and new generation ultrasound imaging systems (Vivid 7 and Vivid E95) in 308 subjects. Image quality was assessed by endocardial border delineation index (EBDI) using a 3-point scoring system. Three observers measured the LVEF and GLS, and these values and inter-observer variability were investigated. RESULTS: Image quality was significantly better with Vivid E95 (EBDI: 26.8 +/- 5.9) than that with Vivid 7 (22.8 +/- 6.3, P < 0.0001). Regarding the inter-observer variability of LVEF, the r-value, bias, 95% limit of agreement and intra-class correlation coefficient for Vivid 7 were comparable to those for Vivid E95. The % variabilities were significantly lower for Vivid E95 (5.3-6.5%) than those for Vivid 7 (6.5-7.5%). Regarding GLS, all observer variability parameters were better for Vivid E95 than for Vivid 7. Improvements in image quality yielded benefits to both LVEF and GLS measurement reliability. Multivariate analysis showed that image quality was indeed an important factor of observer variability in the measurement of LVEF and GLS. CONCLUSIONS: The new-generation ultrasound imaging system offers improved image quality and reduces inter-observer variability in the measurement of LVEF and GLS. PMID- 29432199 TI - Effect of a combination of flip and zooming stimuli on the performance of a visual brain-computer interface for spelling. AB - Brain-computer interface (BCI) systems can allow their users to communicate with the external world by recognizing intention directly from their brain activity without the assistance of the peripheral motor nervous system. The P300-speller is one of the most widely used visual BCI applications. In previous studies, a flip stimulus (rotating the background area of the character) that was based on apparent motion, suffered from less refractory effects. However, its performance was not improved significantly. In addition, a presentation paradigm that used a "zooming" action (changing the size of the symbol) has been shown to evoke relatively higher P300 amplitudes and obtain a better BCI performance. To extend this method of stimuli presentation within a BCI and, consequently, to improve BCI performance, we present a new paradigm combining both the flip stimulus with a zooming action. This new presentation modality allowed BCI users to focus their attention more easily. We investigated whether such an action could combine the advantages of both types of stimuli presentation to bring a significant improvement in performance compared to the conventional flip stimulus. The experimental results showed that the proposed paradigm could obtain significantly higher classification accuracies and bit rates than the conventional flip paradigm (p<0.01). PMID- 29432200 TI - Reliability and validity of lumbar disc height quantification methods using magnetic resonance images. AB - Disc height has been a focus of research on disc degeneration and low back pain (LBP). However, choosing an appropriate method to quantify disc height remains controversial. The aim of the present study was to determine the reliability and construct validity of disc height quantification methods. Repeated semi-automatic measurements of L4-5 and L5-S1 discs were obtained from 43 T2-weighted mid sagittal 3T magnetic resonance (MR) images of 22 subjects with LBP (43+/-13 years), blinded to prior measurements. Heights were calculated with area-based methods (using 60%, 80% and 100% of the disc width), and point-based methods (Hurxthal's, Dabbs' and combining the two). Intra-class correlation coefficients (ICC) and standard error of measurement (SEM) were estimated. Construct validity was assessed using correlation coefficients. Intra-rater ICC(3,1) of the area based disc height measurements ranged from 0.84 to 0.99 with an inter-rater ICC(2,1) of 0.99. Measurements with point-based methods had lower intra- and inter-rater reliability ranging between 0.76 and 0.96 and between 0.84 and 0.98, respectively. Inter-rater SEM varied between 0.2 and 0.3 mm for area-based methods and between 0.3 and 0.7 mm for point-based methods. Excluding Dabbs', high correlations (r>0.9) were observed between methods. Area-based height measurements using partial disc width demonstrated excellent reliability and construct validity and outperformed point-based methods. PMID- 29432201 TI - Bacterial contamination of reusable venipuncture tourniquets in tertiary-care hospital. PMID- 29432202 TI - Plasma midregional proadrenomedullin (MR-proADM) concentrations and their biological determinants in a reference population. AB - BACKGROUND: Midregional proadrenomedullin (MR-proADM) is emerging as a prognostic biomarker for detecting the failure of multiple organs. Establishment of scientifically robust reference intervals facilitates interpretation of laboratory test results. The objectives of this study were (i) to establish reliable reference intervals for plasma MR-proADM using a commercially available automated fluoroimmunoassay in apparently healthy individuals, and (ii) to identify biological determinants of MR-proADM concentrations. METHODS: A total of 506 questionnaire-identified apparently healthy adults were enrolled in a single center, cross-sectional study. A final reference group (n=172) was selected after exclusion of obese individuals, those with increased values of laboratory biomarkers indicating asymptomatic myocardial injury or dysfunction, ongoing inflammation, diabetes, dyslipidemia and renal dysfunction and outliers. RESULTS: The 2.5th and 97.5th percentile intervals for MR-proADM values in the reference group (90% confidence interval) were 0.21 (0.19-0.23) and 0.57 (0.55-0.59) nmol/L, respectively. Although older age, higher values of HbA1c, C-reactive protein, B-type natriuretic peptide and body mass index, together with a history of smoking and a decreased estimated glomerular filtration rate were significantly associated with increasing concentrations of MR-proADM in both univariate and multivariate analyses, magnitudes of these relationships were modest and did not substantially influence MR-proADM reference intervals. Sex dependent difference in MR-proADM reference intervals was not detected [0.19 (0.16-0.22)-0.56 (0.54-0.60) nmol/L in females vs. 0.22 (0.20-0.25)-0.58 (0.57 0.63) nmol/L in males]. CONCLUSIONS: Our study successfully established robust reference intervals for MR-proADM concentrations in plasma. Considering the negligible influence of potential biological determinants on plasma MR-proADM, we recommend the adoption of single reference intervals for adult population as a whole. PMID- 29432203 TI - Associations between health-related quality of life and body mass index in Portuguese adolescents: LabMed physical activity study. AB - Background In adolescence there are several biological and physiological changes associated with overweight and obesity. Objective The purpose of this study was to analyze the associations between health-related quality of life (HRQoL) and body mass index (BMI) in adolescents. Methods This is a cross-sectional analysis of 957 Portuguese adolescents (446 girls and 511 boys) aged 12-18 years. A series of variables were collected: (a) HRQoL was assessed using the KIDSCREEN-10 questionnaire; (b) socioeconomic status (SES) was measured using the Family Affluence Scale; (c) body composition (weigh, height) were measured and BMI was calculated and, (d) pubertal stage was assessed with Tanner stages; (e) the 20-m shuttle-run was used to estimate cardiorespiratory fitness. Regression models and mediation analysis were performed to assess the association between HRQoL and BMI. Results HRQoL was significantly higher in boys than girls (p < 0.05). The prevalence of overweight and obesity was 23.5% and 6.7% in girls, and 21.3% and 5% in boys, respectively. HRQoL was inversely and significantly associated with BMI in boys (B = -0.130; p < 0.05) and girls (B = -0.148; p < 0.05) after controlling for age, pubertal stage and SES. Cardiorespiratory fitness act as a full mediator variable on the relationship between BMI and HRQoL in adolescents (p < 0.05). Conclusion Our results suggest that cardiorespiratory fitness acted as a full mediator in the relationship between BMI and HRQoL, in adolescents. Public health policies targeting a wealthy weight and an improved physical fitness level could be a strategy of particular interest for improving the HRQoL of adolescents. PMID- 29432204 TI - Relationship between adaptation and self-esteem in addicted female prisoners in the south east of Iran. AB - Background Reduction of the adaptation and self-esteem can be the consequence of opium addiction and imprisonment. Drug use causes inappropriate behaviors in women, which are quite different from those in men. Social deviations, prostitution, high-risk sexual behaviors, abortion, divorce and imprisonment followed by loss of self-esteem are the consequences of women's addiction. The present study was conducted to assess the relationship between adaptation and self-esteem in addicted female prisoners. Methods In this descriptive analytical study, 130 addicted female prisoners were selected from a prison in the south east of Iran using census sampling. The data were collected by a demographic questionnaire, the Rosenberg's self-esteem scale and the bell adjustment inventory (BAI). Results According to the results, women's adaptation fell into the 'very unsatisfactory' range. The highest mean was related to the emotional dimension, while the lowest mean was in terms of the health dimension. In total, 96.4% of the participating women had low adaptation. The mean total self-esteem fell into the low range; in fact, 84.6% of the women had a low self-esteem. The results showed no significant relationships between adaptation and self-esteem in these women; however, self-esteem was significantly and inversely related to health and emotional adaptation. Conclusion The findings showed that the majority of the women had unsatisfactory adaptation as well as poor self-esteem. No significant relationships were observed between adaptation and self-esteem in the addicted female prisoners. PMID- 29432205 TI - Better informed is better decided: Addressing the risks of delaying childbearing for female higher educational students. AB - Objective Delayed childbearing has gradually started to become the norm for higher educational students, with possible increased future fertility risks and psychological distress as a consequence. What do female students expect from their general practitioners (GP) and other health care providers (HCPs) with regard to delaying childbearing? We also looked into indicators that can be used by HCPs to detect female university students who have issues regarding delayed childbearing. Methods Cross sectional study: A total of 398 female students (mean age 21.83; SD = 2.4) from at least three different universities completed the questionnaire (distributed through the Internet and at a students' health service). Potential predictors for having an issue regarding delayed childbearing were assessed with multivariate logistic regression. Results Thirteen percent of 398 female students experienced being childless as more or less problematic. Forty-nine percent thinks having children deserves more attention and 33% of the students expect attention from their GP regarding a possible desire to have children during contraceptive consultations. Four factors demonstrated significant associations with having an issue concerning delayed childbearing: age (these issues also occur in younger students), worrying about fertility, not opting for an abortion if pregnant and dissatisfaction with current contraceptive use. Conclusion HCPs should discuss delayed childbearing with female students, addressing both the decrease of fertility after a certain age (30), the limited range of fertility methods, and the possible negative physical and psychological consequences of postponement. These elements could be included into programmes of sexual and reproductive health training and into pre-conception care and pre conception education. PMID- 29432206 TI - Evaluation of hematological alterations after therapeutic use of dipyrone in healthy adults: a prospective study. AB - Background Dipyrone is a non-narcotic analgesic/antipyretic widely used in some countries but prohibited in others due to suspected risk of agranulocytosis. The primary goal of this study was to evaluate hematological alterations in healthy adult volunteers after treatment with dipyrone. Methods The study enrolled 30 healthy volunteers of both genders, aged 19-37 years. They received tablets containing 500 mg of dipyrone sodium to be used four times daily for 7 consecutive days. Before the first administration, arterial pressure was measured and blood was collected in order to evaluate hematological baseline parameters. On the 8th day after the beginning of treatment, the volunteers had their blood pressure assessed once more and underwent a second blood draw. Total and specific leukocyte counts, creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), erythrocytes, and platelets were quantitatively determined. Results No statistically significant difference was observed among total or specific leukocyte counts. Number of platelets, erythrocytes, hemoglobin, and hematocrit decreased after treatment. Diastolic pressure, mean arterial pressure (MAP), and urea concentration declined, while creatinine, AST, and ALT showed no significant alterations. It is noteworthy that, even for parameters that showed statistically significant changes, the highest and lowest values remained within the normal ranges. Conclusions Although dipyrone has historically been associated with agranulocytosis, leukocyte counts remained practically unchanged after oral administration of dipyrone. On the other hand, the present study adds evidence that dipyrone is able to produce statistically relevant decrease in number of platelets, erythrocytes, hemoglobin, and hematocrit in healthy adults, even after short-term treatment. PMID- 29432207 TI - Prevalence of comorbid conditions pre-existing and diagnosed at a tertiary care pediatric weight management clinic. AB - BACKGROUND: Childhood obesity places individuals at risk for a multitude of physical and mental health problems. The aim of this study was to assess the prevalence of obesity related comorbidities diagnosed prior to and after attending a tertiary care pediatric weight management clinic. METHODS: A cross sectional retrospective chart review of patients 2-17 years old seen in the weight management clinic at Alberta Children's Hospital from May 2012 to May 2014. RESULTS: A total of 199 patients were included in the review. Comorbidity prevalences were: hypertension 6 (3%), prediabetes 11 (5.5%), type 2 diabetes 3 (1.5%), dyslipidemia 105 (52.8%), non-alcoholic fatty liver disease 31 (15.6%), asthma 45 (22.6%), obstructive sleep apnea 21 (10.6%), and polycystic ovarian syndrome (PCOS) 9 (12% of females >=10 years at the first visit). Concerns related to depression and anxiety were present in 20 (10.1%) and 25 (12.6%) patients respectively. The majority of comorbidities were identified prior to joining the clinic. Conditions requiring more specialized tests, such as diabetes and PCOS, were more commonly identified after joining the clinic. CONCLUSIONS: These results give further insight into the prevalence of obesity-related comorbidities in overweight and obese children and adolescents, and demonstrate the importance of screening for these known comorbidities. It is important to have the resources and an experienced multi-disciplinary team to follow children and their families through treatment. PMID- 29432208 TI - Transcriptome profiling reveals an IAA-regulated response to adventitious root formation in lotus seedling. AB - Adventitious roots (ARs) of lotus (Nelumbonucifera Gaertn.) play a critical role in water and nutrient uptake. We found that exogenously applied 10-MUM indole-3 acetic acid (IAA) promoted the formation of ARs, while 150-MUM IAA significantly inhibited the emergence of ARs. However, little is known about these different responses to various concentrations of IAA at the molecular level. This study, therefore, examined the gene expression profiling in four libraries treated with 10- and 150-MUM IAA based on the high-throughout tag sequencing technique. Approximately 2.4*107 clean tags were obtained after the removal of low-quality tags from each library respectively, among which about 10% clean tags were unambiguous tag-mapped genes to the reference genes. We found that some genes involved in auxin metabolism showed a similar tendency for expression in the A/CK and C/CK libraries, while three genes were enhanced their expression only in the A/CK libraries. Two transcription factors including B3 domain-containing protein At2g36080-like and trihelix transcription factor were up-regulated for transcriptional level in the A/C libraries. The expressions of six important genes related to AR formation were significantly different in the A/CK and C/CK libraries. In summary, this study provides a comprehensive understanding of gene expression regulated by IAA involved in AR formation in lotus. PMID- 29432209 TI - The fabrication of highly conductive and flexible Ag patterning through baking Ag nanosphere-nanoplate hybrid ink at a low temperature of 100 degrees C. AB - With the aim of developing highly conductive ink for flexible electronics on heat sensitive substrates, Ag nanospheres and nanoplates were mixed to synthesize hybrid inks. Five kinds of hybrid ink and two types of pure ink were written to square shape on Epson photo paper using rollerball pens, and sintered at a low temperature (100 degrees C). The microstructure, electrical resistivity, surface porosity, hardness and flexibility of silver patterns were systematically investigated and compared. It was observed that the optimal mixing ratio of nanospheres and nanoplates was 1:1, which equipped the directly written pattern with excellent electrical and mechanical properties. The electrical resistivity was 0.103 MUOmega . m, only 6.5 times that of bulk silver. The enhancement compared to pure silver nanospheres or nanoplates based ink was due to the combined action of nanospheres and nanoplates. This demonstrates a valuable way to prepare Ag nanoink with good performance for printed/written electronics. PMID- 29432210 TI - Thermoelectric properties of Co4Sb12 with Bi2Te3 nanoinclusions. AB - The figure of merit (zT) of a thermoelectric material can be enhanced by incorporation of nanoinclusions into bulk material. The presence of bismuth telluride (Bi2Te3) nanoinclusions in Co4Sb12 leads to lower phonon thermal conductivity by introducing interfaces and defects; it enhances the average zT between 300-700 K. In the current study, Bi2Te3 nanoparticles were dispersed into bulk Co4Sb12 by ball-milling. The bulk was fabricated by spark plasma sintering. The presence of Bi2Te3 dispersion in Co4Sb12 was confirmed by x-ray diffraction, scanning electron microscopy, transmission electron microscopy and electron back scattered diffraction technique. Energy dispersive spectroscopy showed antimony (Sb) as an impurity phase for higher contents of Bi2Te3 in the sample. The Seebeck coefficient (S) and electrical conductivity (sigma) were measured in the temperature range of 350-673 K. The negative value of S indicates that most of the charge carriers were electrons. A decrease in S and increase in sigma with Bi2Te3 content are due to the increased carrier concentration, as confirmed by Hall measurement. The thermal conductivity, measured between 423-673 K, decreased due to the increased phonon scattering at interfaces. A maximum zT of 0.17 was achieved at 523 K and it did not vary much throughout the temperature range. The experimental results of composites were compared by using effective medium theories. PMID- 29432211 TI - Inkjet printing and electrical characterisation of DNA-templated cadmium sulphide nanowires. AB - Cadmium sulphide can be templated on lambda-DNA molecules to form an aqueous dispersion of CdS/lambda-DNA nanowires. Subsequent addition of ethylene glycol to 50% v/v is sufficient to formulate an ink suitable for printing using piezoelectric drop-on-demand technology. Printed droplet arrays show a coffee ring morphology of individual deposits by fluorescence and Raman microscopy, but upon increasing the number of layers of printed material by repeated printing over each droplet, the dry deposit approaches closer to a disc shape. It is also possible to print parallel tracks by reducing the droplet separation in the array until neighbouring droplets overlap before they dry. The droplets coalesce to form a strip of width roughly equal to the diameter of the droplets. Evaporation driven capillary flow sends the nanowires to the edges of the strip and when dry they form parallel tracks of CdS/lambda-DNA nanowire bundles. Both droplets and tracks were printed onto Pt-on-glass interdigitated microelectrodes (10 MUm width, 10 MUm gap). The current-voltage characteristics of these two-terminal devices were approximately ohmic, but with some hysteresis. The conductance increased with temperature as a simple activated process with activation energies of 0.57 +/- 0.02 eV (tracks) and 0.39 +/- 0.02 eV (droplets). The impedance spectra of the printed films were consistent with hopping between CdS grains. PMID- 29432212 TI - Tuning the electrical transport of type II Weyl semimetal WTe2 nanodevices by Mo doping. AB - We fabricated nanodevices from MoxW1-xTe2 (x = 0, 0.07, 0.35), and conducted a systematic comparative study of their electrical transport. Magnetoresistance measurements show that Mo doping can significantly suppress mobility and magnetoresistance. The results for the analysis of the two band model show that doping with Mo does not break the carrier balance. Through analysis of Shubnikov de Haas oscillations, we found that Mo doping also has a strong suppressive effect on the quantum oscillation of the sample, and the higher the ratio of Mo, the fewer pockets were observed in our experiments. Furthermore, the effective mass of electron and hole increases gradually with increasing Mo ratio, while the corresponding quantum mobility decreases rapidly. PMID- 29432214 TI - The association of proton pump inhibitors and chronic kidney disease: cause or confounding? AB - PURPOSE OF REVIEW: To discuss whether the recently described relationship between proton pump inhibitor (PPI) use and the risk of adverse kidney outcomes represents a causal relationship or is merely the result of confounding. RECENT FINDINGS: A wave of observational studies has described an association between PPI use and the risk of development of chronic kidney disease and its progression to end-stage renal disease. The results are generally robust and remarkably consistent across different studies. The application of modern pharmacoepidemiologic methods to estimate the effect of a putative unmeasured or unknown confounder or set of confounders on the relationship of PPI use and risk of adverse renal outcomes suggests that confounding is unlikely to explain away the reported association. SUMMARY: The constellation of evidence from all available studies suggests that PPI use is associated with increased risk of adverse kidney outcomes. Exercising vigilance in the use of PPI is warranted. PMID- 29432213 TI - Regulation of intestinal lipid and lipoprotein metabolism by the proglucagon derived peptides glucagon like peptide 1 and glucagon like peptide 2. AB - PURPOSE OF REVIEW: The intestine is highly efficient at absorbing and packaging dietary lipids onto the structural protein apoB48 for distribution throughout the body. Here, we summarize recent advances into understanding the physiological and pharmacological actions of the proglucagon-derived peptides: glucagon like peptide 1 (GLP-1) and glucagon like peptide 2 (GLP-2) on intestinal lipoprotein secretion. RECENT FINDINGS: Several recent studies have elucidated mechanisms underlying the paradoxical effects of GLP-1 and GLP-2 on intestinal production of triglyceride-rich lipoproteins (TRLs). Both gut-derived peptides are secreted on an equimolar basis in response to the same nutrient stimulus. Despite neither receptor demonstrating clear localization to enterocytes, a single injection of a GLP-1R agonist rapidly decreases delivery of intestinally packaged fatty acids into the plasma, while conversely GLP-2 receptor (GLP-2R) activation acutely increases TRL concentrations in plasma. SUMMARY: The regulation of TRL secretion is dependent on the coordination of many processes: fatty acid availability uptake, assembly onto the apoB48 polypeptide backbone, secretion and reuptake, which the hormonal, neural, inflammatory and metabolic milieu can all strongly influence. Understanding of how GLP-1 and GLP-2 receptor agonists control TRL production has clinical importance given that GLP1R agonists were recently demonstrated not only to provide glycemic control but also to prevent major adverse cardiovascular events in patients with T2DM and the success of GLP-2R agonists in treating short bowel disease. PMID- 29432215 TI - An update on predicting renal progression in IgA nephropathy. AB - PURPOSE OF REVIEW: Immunoglobulin A (IgA) nephropathy (IgAN) is a heterogeneous disease, and predicting individual patient risk of renal progression is challenging. Recent studies provide new evidence regarding the use of clinical, histologic, and biomarker predictors of renal outcome in IgAN. RECENT FINDINGS: A meta-analysis of clinical trials demonstrated that early change in proteinuria is a valid surrogate outcome measure for longer term decline in renal function, which supports the use of proteinuria to dynamically re-evaluate patient prognosis over time. The MEST histologic classification has been further validated in a large European cohort. An international multiethnic observational study demonstrated that crescents are independently associated with renal outcome, and as a result a crescent score (<25% versus >25% of glomeruli) has been added to MEST. Proteinuria, estimated glomerular filtration rate (GFR), and blood pressure at the time of biopsy can be used to accurately predict prognosis when combined with MEST, instead of using 2 years of follow-up data. Currently, no available risk prediction model that combines clinical and histologic predictors has been sufficiently validated for routine use. There are multiple biomarkers that have been studied in IgAN, however none have been externally validated and shown to improve prediction beyond clinical and histologic risk factors. SUMMARY: Proteinuria, estimated GFR, blood pressure, and the MEST-C score are the most readily available risk factors to predict renal prognosis in IgAN. Future research is required to develop and validate methods of integrating these risk factors together to accurately risk stratify individual patients, and provide the framework for evaluating biomarkers capable of further improving risk prediction. PMID- 29432216 TI - Glomerulogenesis and the role of endothelium. AB - PURPOSE OF REVIEW: Earlier works of the glomerulogenesis described morphological steps and protein expression during in-vivo and in-vitro kidney development. Recent technologies using cell-specific or conditional knock-out mice for several factors provide important knowledge about cross-talk signaling among resident cells as local events. Based on the recent advancement, this review revisits comprehensive morphological development of the glomerulus. RECENT FINDINGS: Interactions of presumptive podocyte vascular endothelial growth factor with vascular endothelial growth factor-2 on angioblasts initiate glomerular vascularization. In induced pluripotent stem cells or organoid-derived nephron formation, the lack of endothelium and mesangial cells under differentiated podocytes suggests the presence of another unknown mechanism for glomerular neovascularization. Mesangial cell migration is prerequisite for glomerular looping by interaction of endothelial platelet-derived grothe factor beta and mesangial platelet-derived growth factor receptor beta and requires the coreceptor neuropilin1. Development of the filtration barrier is promoted by cross-talk among resident cells and may need shear stress. The components of the glomerular basement membrane change during glomerulogenesis, and endothelium and podocytes produce laminin and type IV collagen alpha1 and alpha2, whereas type IV collagen alpha3, alpha4, alpha5 is derived only from podocytes. SUMMARY: Glomerulogenesis progresses by dynamic cellular migration/differentiation induced by cross-talk signaling in resident cells. Glomerular vasculogenesis and subsequent capillary development provide insight into glomerular regeneration and remodeling for medical application. PMID- 29432218 TI - Electroencephalography, magnetoencephalography and source localization: their value in epilepsy. AB - PURPOSE OF REVIEW: Source localization of cerebral activity using electroencephalography (EEG) or magnetoencephalography (MEG) can reveal noninvasively the generators of the abnormal signals recorded in epilepsy, such as interictal epileptic discharges (IEDs) and seizures. Here, we review recent progress showcasing the usefulness of these techniques in treating patients with drug-resistant epilepsy. RECENT FINDINGS: The source localization of IEDs by high density EEG and MEG has now been proved in large patient cohorts to be accurate and clinically relevant, with positive and negative predictive values rivaling those of structural MRI. Localizing seizure onsets is an emerging technique that seems to perform similarly well to the localization of interictal spikes, although there remain questions regarding the processing of signals for reliable results. The localization of somatosensory cortex using EEG/MEG is well established. The localization of language cortex is less reliable, although progress has been made regarding hemispheric lateralization. Source localization is also able to reveal how epilepsy alters the dynamics of neuronal activity in the large-scale networks that underlie cerebral function. SUMMARY: Given the high performance of EEG/MEG source localization, these tools should find a place similar to that of established techniques like MRI in the assessment of patients for epilepsy surgery. PMID- 29432219 TI - Calcitonin-gene-related peptide pathway mAbs and migraine prevention. AB - PURPOSE OF REVIEW: Monoclonal antibodies (mAbs) targeting the calcitonin-gene related peptide (CGRP) pathway have been developed for episodic and chronic migraine prevention, either through binding the CGRP ligand (eptinezumab, fremanezumab, galcanezumab) or the CGRP receptor (erenumab). We provide an update on published Phase 2 and Phase 3 trials, safety/tolerability data, pharmacokinetics and mechanism of action of these biologicals. RECENT FINDINGS: The efficacy data from Phase 2 trials are corroborated by those from published Phase 3 trials, with a multitude of publications expected in 2018. Review of safety data concluded there was no difference in total adverse events or main adverse events (including upper respiratory tract infection, nasopharyngitis, nausea, injection-site pain and back pain) between the mAbs and placebo injections except apparently for dizziness. The site of action of these mAbs is not fully elucidated but current insight is that their effect resides in the periphery; a contribution of central effect(s) can however not be excluded at present. SUMMARY: Although efficacy of all four drugs is modest over placebo in episodic and chronic migraine prevention and overall comparable with available oral preventive treatments, current tolerability and (short-term) safety data of this new treatment approach certainly promise a major step forward for migraine patients. PMID- 29432217 TI - Prematurity and future kidney health: the growing risk of chronic kidney disease. AB - PURPOSE OF REVIEW: The purpose of this review is to describe the role prematurity plays in the development of chronic kidney disease (CKD) and to discuss potential reasons for this association including decreased nephron mass, as well as postnatal insults such as neonatal acute kidney injury (nAKI). RECENT FINDINGS: New observational studies in humans and experimental studies in animal models have strengthened the association between prematurity, low birth weight and CKD. Growing evidence suggests increased susceptibility to CKD is caused by decreased nephron mass at birth. Beginning with a low nephron count may cause only subtle abnormalities during childhood, however may result in CKD, hypertension and albuminuria in adolescence or adulthood. Recent studies in premature infants reveal a high incidence of nAKI, which may also contribute to ongoing CKD risk. SUMMARY: Children born at low birth weights (both due to prematurity and/or intrauterine growth restriction) show increased risk of kidney dysfunction during adulthood. A better understanding of the modulators of nephron mass in premature infants as well as the effects of the extrauterine environment is essential. Additionally, improved awareness of at-risk infants is important as is early evaluation and detection of kidney dysfunction, allowing interventions to slow the progression to CKD. PMID- 29432220 TI - Severity scoring systems for pneumonia: current understanding and next steps. AB - PURPOSE OF REVIEW: To describe the current understanding and clinical applicability of severity scoring systems in pneumonia management. RECENT FINDINGS: Severity scores in community-acquired pneumonia are strong markers of mortality, but are not necessarily clinical decision-aid tools. The use of severity scores to support outpatient care in low-risk patients has moderate-to strong evidence available in the literature, mainly for the pneumonia severity index, and must be applied together with clinical judgment. It is not clear that severity scores are helpful to guide empiric antibiotic treatment. The inclusion of biomarkers and performance status might improve the predictive performance of the well known severity scores in community-acquired pneumonia. We should improve our methods for score evaluation and move toward the development of decision-aid tools. SUMMARY: The application of the available evidence favors the use of severity scoring systems to improve the delivery of care for pneumonia patients. The incorporation of new methodologies and the formulation of different questions other than mortality prediction might help the further development of severity scoring systems, and enhance their support to the clinical decision-making process for the pneumonia-management cascade. PMID- 29432222 TI - Immunotherapy for recurrent/metastatic head and neck cancer. AB - PURPOSE OF REVIEW: In the last decade, after cetuximab (anti-epidermal growth factor receptor), none of the novel investigated compounds has demonstrated benefit in head and neck squamous cell cancers (HNSCC), both in advanced and curative settings. Therefore, prognosis of recurrent/metastatic (R/M) HNSCC patients remains dismal, especially in platinum-refractory cohort. In the last few years, a new important class of drugs has affirmed its role. HNSCC, even if less 'immunogenic' than other malignancies (e.g. melanoma), was field of application of several new immune agents. To date, the most important data regard drugs acting on PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) axis that is a crucial checkpoint used by tumor for immune escape. Our purpose is to summarize the results of these PD-1/PD-L1 inhibitors, outlining some critical points and few practical suggestions. RECENT FINDINGS: Nivolumab was recently approved by main regulatory agencies as second-line treatment for platinum refractory R/M HNSCC. In the same setting, pembrolizumab was approved by FDA. Atezolizumab and durvalumab have already showed similar benefit in phase Ia and II studies, respectively. SUMMARY: Anti-PD1/PD-L1 agents are new effective therapies in R/M HNSCC. Their combination with conventional/novel compounds, as well as a better selection of responding patients, could lead to improve current results. PMID- 29432221 TI - Reducing morbidity and complications after major head and neck cancer surgery: the (future) role of enhanced recovery after surgery protocols. AB - PURPOSE OF REVIEW: To review the development and the benefits of enhanced recovery after surgery (ERAS) protocols in non-head and neck disciplines and to describe early implementation efforts in major head and neck surgeries. RECENT FINDINGS: Several groups have adopted ERAS protocols for major head and neck surgery and demonstrated its feasibility and effectiveness. SUMMARY: There is growing evidence that clinical and financial outcomes for patients undergoing major head and neck surgery rehabilitation can be significantly improved by standardizing preoperative, intraoperative, and postoperative treatment protocols. Current experience is limited to single centers. A future goal is to broaden the adoption of ERAS in head and neck surgical oncology to include national and international collaboration, data sharing, and learning. PMID- 29432223 TI - Management of Behcet's disease. AB - PURPOSE OF REVIEW: Current treatment modalities in Behcet's disease will be summarized in light of new studies published within the last 2 years. RECENT FINDINGS: There is an increasing interest in the treatment of refractory mucocutaneous symptoms of Behcet's disease, and results were quite promising with apremilast, anakinra, and ustekinumab. Data from large case series confirmed both the efficacy and safety of tumor necrosis factor-alpha inhibitors for the treatment of refractory major organ manifestations such as ocular, neurologic, vascular, and gastrointestinal involvement. In refractory ocular disease, long term results also confirmed the efficacy and safety of interferon-alpha. Interleukin-1 inhibitors and tocilizumab seem to be alternative options in patients with refractory ocular involvement. SUMMARY: Prospective and controlled studies for the management of major organ involvement in Behcet's disease are still limited. Data from primarily retrospective studies confirmed better outcomes of major organ involvement with tumor necrosis factor-alpha inhibitors and interferon-alpha. There were also acceptable results with interleukin-1 inhibitors for the management of refractory ocular disease, and with apremilast, anakinra, and ustekinumab for refractory mucocutaneous involvement. PMID- 29432224 TI - Extra-pulmonary diseases related to Mycoplasma pneumoniae in children: recent insights into the pathogenesis. AB - PURPOSE OF REVIEW: Providing an overview on Mycoplasma pneumoniae-related extra pulmonary diseases (MpEPDs) in children, who represent the preferred target population by those complications, and discussing the main pathogenic mechanisms implicated or potentially involved. RECENT FINDINGS: Recent evidences supported the fact that M. pneumoniae is more than an extra-cellular pathogen colonizing epithelial cells of the respiratory tract. It is able to penetrate the cell membrane of host cells and to invade the respiratory mucosa, leading to pronounced inflammatory responses and also spreading outside the respiratory system, to some extent. Thus, direct and indirect (immune-mediated) mechanisms have been described in M. pneumoniae infections, but the latter ones have been mainly implicated in MpEPDs, as reviewed here. Recently, interesting insights have been provided, especially as concern neurologic complications, and new potential mechanisms of disease have been emerging for autoimmunity. SUMMARY: The awareness of the occurrence of MpEPDs, showing very variable clinical expressions, could promote a correct diagnosis and an appropriate treatment. The knowledge of disease mechanisms in MpEPDs is largely incomplete, but recent advances from clinical studies and murine models might promote and direct future research. PMID- 29432225 TI - Nonsteroidal anti-inflammatory drugs and cancer pain. AB - PURPOSE OF REVIEW: This review aims to appraise the most recent evidence for the use of NSAIDS in cancer pain. RECENT FINDINGS: The Cochrane review reveals the paucity of high-quality evidence for the use of NSAIDS for cancer pain, highlighting methodological considerations for future research. There is limited evidence for the role of combined NSAIDs (celecoxib and diclofenac) alongside opioids for cancer pain. Recent retrospective data suggests NSAIDS may contribute to better pain control in hospitalized patients. In elderly patients in the last weeks of life, retrospective data shows a reduction in NSAID prescribing, without significant implications for pain relief. A recent systematic review looking at the increased risk of anastomotic leaks versus the survival benefits in cancer patients prescribed NSAIDs post oncological surgery was inconclusive. Considering the prescription of PPIs for gastroprotection, studies in the general population suggest potential risks of long-term use, including renal dysfunction and greater risk of fractures. Although current evidence for the anticancer properties of NSAIDS is based on retrospective cohort studies, there may be a role for aspirin and nonaspirin NSAIDs in reducing the risk of cancer. SUMMARY: Given the lack of quality evidence, NSAIDS should be prescribed on a case by case basis in discussion with the patient, with regular review of efficacy, whilst balancing the ongoing benefits and risks of continued use, taking into account the patient's likely prognosis. PMID- 29432226 TI - Combination treatment for male lower urinary tract symptoms with anticholinergic and alpha-blockers. AB - PURPOSE OF REVIEW: Although alpha-adrenergic antagonists (alpha-blockers) are effective for relieving voiding lower urinary tract symptoms (LUTS) in men, storage symptoms often persist. The aim of this manuscript is to evaluate the efficacy and safety of combination therapy with alpha-blockers and muscarinic receptor antagonists (anticholinergics). RECENT FINDINGS: High-quality evidence confirms that the addition of an anticholinergic improves micturition diary parameters, such as daytime and nocturnal frequency and urgency incontinence episodes, as well as total and storage subset scores on the International Prostate Symptom Score. Most studies demonstrate a statistically significant improvement over alpha-blocker monotherapy. Both, incidence of urinary retention and study withdrawal because of treatment-related adverse events with combination therapy, are low. Urodynamic indices, such as maximum flow rate and postvoid residual volume, are also minimally impacted by combination therapy. Outcomes on validated questionnaires and quality-of-life (QoL) indices also indicate a significant improvement. SUMMARY: The addition of an anticholinergic to an alpha blocker in men with storage and voiding LUTS is an effective practice in reducing both categories of symptoms. The addition of anticholinergic is associated with a low rate of urinary retention and the impact on efficient bladder emptying is minimal. Not unexpectedly, QoL is improved. PMID- 29432227 TI - The global epidemiology of adolescents living with HIV: time for more granular data to improve adolescent health outcomes. AB - PURPOSE OF REVIEW: The aim of this study was to summarize recent evidence on the global epidemiology of adolescents (age 10-19 years) living with HIV (ALHIV), the burden of HIV on the health of adolescents and HIV-associated mortality. RECENT FINDINGS: In 2016, there were an estimated 2.1 million (uncertainty bound 1.4-2.7 million) ALHIV; 770 000 younger (age 10-14 years) and 1.03 million older (age 15 19 years) ALHIV, 84% living in sub-Saharan Africa. The population of ALHIV is increasing, as more peri/postnatally infected ALHIV survive into older ages; an estimated 35% of older female ALHIV were peri/postnatally infected, compared with 57% of older male ALHIV. Although the numbers of younger ALHIV deaths are declining, deaths among older ALHIV have remained static since peaking in 2012. In 2015, HIV-associated mortality was the eighth leading cause of adolescent death globally and the fourth leading cause in African low and middle-income countries. SUMMARY: Needed investments into characterizing and improving adolescent HIV-related health outcomes include strengthening systems for nationally and globally disaggregated data by age, sex and mode of infection; collecting more granular data within routine programmes to identify structural, social and mental health challenges to accessing testing and care; and prioritizing viral load monitoring and adolescent-focused differentiated models of care. PMID- 29432228 TI - Growth and pubertal development in HIV-infected adolescents. AB - PURPOSE OF REVIEW: We present an overview of recent research in the inter-related areas of growth and pubertal development among adolescents with HIV. Growth deficits early in childhood can lead to delayed puberty, with subsequent effects on pubertal growth spurts and bone health. RECENT FINDINGS: Impaired growth remains a critical concern, particularly in low-resource settings, where stunting, wasting and underweight remain pervasive. Antiretroviral treatment (ART) initiation results in improved growth, with greatest growth recovery in the first years and more improvement in weight than in height. However, even years after ART initiation, growth deficits persist in low-resource settings (LRS), and adolescents appear at particularly increased risk. The high prevalence of stunting translates to delays in pubertal onset and sexual maturity. In contrast, HIV-infected adolescents in developed countries do not demonstrate persistent wasting, yet still have delayed pubertal development. Impaired growth increases the risk for mortality, virologic failure, and abnormal bone health, as well as increased depression and stigma. SUMMARY: Early initiation of ART across all age groups regardless of immunological status is essential for restoring growth. Coordination of ART initiation, nutritional supplementation programs, and concurrent prophylaxis is required to ameliorate growth deficits and pubertal delays, particularly in LRS. PMID- 29432229 TI - Reaching key adolescent populations. AB - PURPOSE OF REVIEW: Adolescents and young people who fit within key populations face some of the greatest barriers to HIV care, but are frequently overlooked. We review the recent literature on these young, vulnerable populations including HIV risk factors, barriers to care, and strategies for engagement. RECENT FINDINGS: Common risk factors include age, risky sexual practices, poor education, and high levels of alcohol and drug abuse. Barriers to care include limited data, criminalization, and high levels of stigma. Strategies to increase engagement include incorporating adolescents into biological and behavioral surveys and the use of social media. Digital innovations for HIV prevention and testing show promise, and pre-exposure prophylaxis may be acceptable. At a policy level, decriminalizing same-sex activity and commercial sex work are priorities. Differentiated models of care including HIV self-testing, after-hour services, community-based delivery, and multimonth dispensing of antiretroviral therapy, should be combined into holistic care. SUMMARY: There has been limited success in reaching these key adolescent populations largely because of criminalization and stigma. Accurate, generalizable data are needed to inform the development of innovative strategies for holistic care. PMID- 29432230 TI - Youth-friendly services and differentiated models of care are needed to improve outcomes for young people living with HIV. AB - PURPOSE OF REVIEW: Outcomes among young people living with HIV (YPLWH) remain disturbingly poor. We summarize recent research on youth-friendly services (YFS) and adolescent-specific differentiated care models, which may improve outcomes across the HIV care continuum for this vulnerable population. We further emphasize unique complexities that characterize the transition from childhood through adolescence to adulthood which must be considered when caring for YPLWH. RECENT FINDINGS: Studies suggest that YFS may improve outcomes in some but not all steps of the HIV care continuum. However, generalizability is compromised by the limited numbers of studies, frequent use of nonequivalent comparison groups, small sample sizes and/or short follow-up. Reproducibility and scale-up are further hindered by lack of insufficient details on operational aspects of YFS, an effective minimum package of YFS and contextual factors that may facilitate adoption of YFS. Differentiated models of care for YPLWH are in very early stages of development with positive preliminary outcomes, but most pilot models focus only on stable patients on antiretroviral therapy. SUMMARY: YFS and adolescent specific differentiated models of care are needed to improve health outcomes among YPLWH, but scale-up should be guided by rigorous research and address the unique complexities that characterize the vulnerable period of adolescence. PMID- 29432232 TI - LEARNING OBJECTIVES AND CORE COMPETENCIES. PMID- 29432234 TI - The Rebirth of Continuum, or: Out With the Gold, in With the New. PMID- 29432231 TI - Noncommunicable diseases in adolescents with perinatally acquired HIV-1 infection in high-income and low-income settings. AB - PURPOSE OF REVIEW: Perinatally HIV-infected adolescents may be at increased risk of noninfectious comorbidities later in life. This review summarizes recent advances in the understanding of noncommunicable diseases (NCD) among HIV infected adolescents in high-income and lower middle-income countries, and identifies key questions that remain unanswered. We review atherosclerotic vascular disease (AVD), chronic bone disease (CBD), chronic kidney disease (CKD), and chronic lung disease (CLD). RECENT FINDINGS: Persistent immune activation and inflammation underlie the pathogenesis of AVD, highlighting the importance of treatment adherence and maintenance of viral suppression, and the need to evaluate interventions to decrease risk. Tenofovir disoproxil fumarate (TDF) and trials of vitamin D supplementation have been the focus of recent studies of CBD with limited studies to date evaluating tenofovir alafenamide as an alternative to TDF for decreasing risk for bone and renal adverse effects among HIV-infected adolescents. Recent studies of CKD have focused primarily on estimating prevalence in different settings whereas studies of CLD are limited. SUMMARY: As perinatally HIV-infected children age into adolescence and adulthood with effective long-term ART, it is necessary to continue to evaluate their risks for noninfectious comorbidities and complications, understand mechanisms underlying their risks, and identify and evaluate interventions specifically in this population. PMID- 29432235 TI - Genetic Diagnostics for Neurologists. AB - PURPOSE OF REVIEW: This article puts advances in the field of neurogenetics into context and provides a quick review of the broad concepts necessary for current practice in neurology. RECENT FINDINGS: The exponential growth of genetic testing is due to its increased speed and decreasing cost, and it is now a routine part of the clinical care for a number of neurologic patients. In addition, phenotypic pleiotropy (mutations in the same gene causing very disparate phenotypes) and genetic heterogeneity (the same clinical phenotype resulting from mutations in different genes) are now known to exist in a number of conditions, adding an additional layer of complexity for genetic testing in these disorders. SUMMARY: Although the growing complexity of technical knowledge in the ordering and interpretation of genetic tests makes it necessary for neurologists to consult medical geneticists, limitations in the availability of such professionals often means neurologists will be on the front line dealing with suspected or confirmed neurogenetic conditions. The growing availability of broad genetic testing through chromosomal microarray and next-generation sequencing and the expanded phenotypic spectrum of many conditions has implications for genetic counseling and medical management. This article discusses the various forms of genetic variability and how to test for each of them. It also provides an update on the most common forms of neurologic presentations of genetic disease and a review of testing strategies. PMID- 29432236 TI - Testing for Inborn Errors of Metabolism. AB - PURPOSE OF REVIEW: This article provides an overview of genetic metabolic disorders that can be identified by metabolic tests readily available to neurologists, such as tests for ammonia, plasma amino acids, and urine organic acids. The limitations of these tests are also discussed, as they only screen for a subset of the many inborn errors of metabolism that exist. RECENT FINDINGS: Advances in next-generation sequencing and the emerging use of advanced metabolomic screening have made it possible to diagnose treatable inborn errors of metabolism that are not included in current newborn screening programs. Some of these inborn errors of metabolism are especially likely to present with nonspecific neurologic phenotypes, such as epilepsy, ataxia, or intellectual disability. However, cost may be a barrier to obtaining these newer tests. It is important to keep in mind that common metabolic testing may lead to treatable diagnoses. Resources are available to guide neurologists in diagnosing genetic metabolic conditions. SUMMARY: This article introduces the clinical presentations of treatable inborn errors of metabolism that are important for neurologists to consider in patients of all ages. Inborn errors of metabolism are rare, but they can present with neurologic symptoms. Newborns are now screened for many treatable metabolic disorders, but these screening tests may miss milder presentations of treatable inborn errors of metabolism that present later in life. These patients may present to adult neurologists who may be less likely to consider metabolic genetic testing. PMID- 29432237 TI - Hypoxic-Ischemic Encephalopathy and Other Neonatal Encephalopathies. AB - PURPOSE OF REVIEW: Neonatal encephalopathy is the most common condition in neonates encountered by child neurologists. The etiology is most often global hypoxia-ischemia due to failure of cerebral perfusion to the fetus caused by uterine, placental, or umbilical cord compromise prior to or during delivery. Other etiologies of neonatal encephalopathy include ischemic stroke and intracranial hemorrhage, infection, developmental anomalies, and inborn errors of metabolism. RECENT FINDINGS: Therapeutic hypothermia is standard of care for the treatment of neonatal encephalopathy presumed to be caused by hypoxia-ischemia. The number needed to treat is approximately 6 to 7 to prevent one child from either death or disability at age 18 to 22 months. EEG monitoring and MRI are important tools in determining the etiology of encephalopathy and prognosis of the infant. SUMMARY: Neonatal encephalopathy is a heterogeneous disorder that is characterized by alterations in mental status, hypotonia, seizures, and abnormalities in feeding and respiration. The most common cause of neonatal encephalopathy is hypoxic-ischemic encephalopathy, for which treatment with 72 hours of therapeutic hypothermia is associated with reduced death or disability. PMID- 29432238 TI - Nervous System Malformations. AB - PURPOSE OF REVIEW: This article provides an overview of the most common nervous system malformations and serves as a reference for the latest advances in diagnosis and treatment. RECENT FINDINGS: Major advances have occurred in recognizing the genetic basis of nervous system malformations. Environmental causes of nervous system malformations, such as perinatal infections including Zika virus, are also reviewed. Treatment for nervous system malformations begins prior to birth with prevention. Folic acid supplementation reduces the risk of neural tube defects and is an important part of health maintenance for pregnant women. Fetal surgery is now available for prenatal repair of myelomeningocele and has been demonstrated to improve outcomes. SUMMARY: Each type of nervous system malformation is relatively uncommon, but, collectively, they constitute a large population of neurologic patients. The diagnosis of nervous system malformations begins with radiographic characterization. Genetic studies, including chromosomal microarray, targeted gene sequencing, and next-generation sequencing, are increasingly important aspects of the assessment. A genetic diagnosis may identify an associated medical condition and is necessary for family planning. Treatment consists primarily of supportive therapies for developmental delays and epilepsy, but prenatal surgery for myelomeningocele offers a glimpse of future possibilities. Prognosis depends on multiple clinical factors, including the examination findings, imaging characteristics, and genetic results. Treatment is best conducted in a multidisciplinary setting with neurology, neurosurgery, developmental pediatrics, and genetics working together as a comprehensive team. PMID- 29432239 TI - Neurocutaneous Disorders. AB - PURPOSE OF REVIEW: This article presents an up-to-date summary of the genetic etiology, diagnostic criteria, clinical features, and current management recommendations for the most common neurocutaneous disorders encountered in clinical adult and pediatric neurology practices. RECENT FINDINGS: The phakomatoses are a phenotypically and genetically diverse group of multisystem disorders that primarily affect the skin and central nervous system. A greater understanding of the genetic and biological underpinnings of numerous neurocutaneous disorders has led to better clinical characterization, more refined diagnostic criteria, and improved treatments in neurofibromatosis type 1, Legius syndrome, neurofibromatosis type 2, Noonan syndrome with multiple lentigines, tuberous sclerosis complex, Sturge-Weber syndrome, and incontinentia pigmenti. SUMMARY: Neurologists require a basic knowledge of and familiarity with a wide variety of neurocutaneous disorders because of the frequent involvement of the central and peripheral nervous systems. A simple routine skin examination can often open a broad differential diagnosis and lead to improved patient care. PMID- 29432240 TI - Leukodystrophies. AB - PURPOSE OF REVIEW: The leukodystrophies, typically considered incurable neurodegenerative disorders, are often diagnosed after irreversible central and peripheral nervous system injury has occurred. Early recognition of these disorders is imperative to enable potential therapeutic interventions. This article provides a summary of the symptoms of and diagnostic evaluation for leukodystrophies, along with the currently available therapies and recent advances in management. RECENT FINDINGS: The leukodystrophies are a rapidly expanding field because of advances in neuroimaging and genetics; however, recognition of the clinical and biochemical features of a leukodystrophy is essential to accurately interpret an abnormal MRI or genetic result. Moreover, the initial symptoms of leukodystrophies may mimic other common pediatric disorders, leading to a delay in the recognition of a degenerative disorder. SUMMARY: This article will aid the clinician in recognizing the clinical features of leukodystrophies and providing accurate diagnosis and management. PMID- 29432241 TI - Evaluation and Acute Management of Ischemic Stroke in Infants and Children. AB - PURPOSE OF REVIEW: This article provides an overview of stroke in neonates, infants, and children. RECENT FINDINGS: Arterial ischemic stroke and cerebral venous sinus thrombosis are increasingly recognized in childhood as important causes of lifelong morbidity and mortality. Diagnosis of arterial ischemic stroke is frequently delayed, as acute neurologic deficits can be challenging to detect in the young child, and stroke is often not considered in the differential diagnosis. Neurologic sequelae following stroke are common, and strategies to minimize stroke size and optimize recovery are being developed. Recurrent arterial ischemic stroke is not uncommon, particularly in children with cerebral arteriopathy. Cerebral venous sinus thrombosis causes obstruction of venous outflow leading to venous infarcts. Complications include hemorrhagic conversion of infarcts and increased intracranial pressure. Without treatment, thrombus extension with increased symptoms is common. Robust guidelines of care that exist for adults do not exist for children, particularly for children with arterial ischemic stroke. SUMMARY: The approach to stroke in infants and children can be informed by clinical experience in pediatric stroke and cerebral venous sinus thrombosis, the extensive literature on pediatric thrombosis, and extrapolation from data from adult patients. PMID- 29432242 TI - Epileptic Encephalopathies. AB - PURPOSE OF REVIEW: This article reviews the manifestations and treatment of the epileptic encephalopathies, which are a heterogeneous group of disorders characterized by both seizures and neurocognitive impairment. RECENT FINDINGS: Next-generation (exome- and genome-based) sequencing technologies are revolutionizing the identification of single-gene causes of epileptic encephalopathy but have only had a modest impact on patient-specific treatment decisions. The treatment of most forms of epileptic encephalopathy remains a particularly challenging endeavor, with therapeutic decisions chiefly driven by the electroclinical syndrome classification. Most antiseizure drugs are ineffective in the treatment of these disorders, and treatments that are effective often entail significant risk and cost. SUMMARY: The epileptic encephalopathies continue to pose a major challenge in diagnosis and treatment, with most patients experiencing very poor outcomes, although a significant minority of patients respond to, or are even cured by, specific therapies. PMID- 29432243 TI - Epilepsy Syndromes in Childhood. AB - PURPOSE OF REVIEW: Epilepsy syndromes are an important clinical construct in pediatric epilepsy, as they encompass recognizable patterns seen in patients with epilepsies, whether of the more benign variety or associated with encephalopathy. RECENT FINDINGS: Syndromes may be organized by age of onset: neonatal, infantile, childhood, or adolescent. The assignment of a syndrome has specific implications for diagnosis, management, and prognostication. The 2010 revised classification of the epilepsies by the International League Against Epilepsy preserved the syndrome approach, while progress in genetics continues to advance our understanding of the pathophysiology and overlap of the epilepsy syndromes. SUMMARY: Given that mutations of the same gene may cause both encephalopathic and relatively benign epilepsies, an understanding of the pediatric epilepsy syndromes remains vital to patient care. PMID- 29432244 TI - Pediatric Sleep Disorders. AB - PURPOSE OF REVIEW: This article provides an overview of the clinical features, diagnosis, and treatment of insomnia, restless legs syndrome, periodic limb movements of sleep, parasomnias, narcolepsy, and sleep-related breathing disorders among children and adolescents. RECENT FINDINGS: Pediatric presentations of sleep disorders differ from adult presentations, making diagnosis challenging. Specific clinical syndromes, such as cataplexy in children with narcolepsy type 1, can have an altogether different presentation compared to adult-onset symptoms, contributing to diagnostic delays and potential misdiagnoses. More broadly, research shows strong associations between sleep and daytime cognition, mood, and behavior among children with and without neurologic conditions and thus suggests a need to identify and treat sleep problems to optimize daytime functioning. SUMMARY: Addressing sleep problems in children with neurologic conditions and neurodevelopmental disorders improves quality of life for patients and their families and, in many cases, reduces neurologic disease burden. PMID- 29432245 TI - Evaluation of the Child With Developmental Impairments. AB - PURPOSE OF REVIEW: This article discusses the diagnostic evaluation of intellectual developmental disorder, comprising global developmental delay and intellectual disability in children. RECENT FINDINGS: With a prevalence of 1% to 3% and substantial comorbidity, high lifetime costs, and emotional burden, intellectual developmental disorder is characterized by limitations in both intellectual functioning (IQ less than 70) and adaptive behavior starting before 18 years of age. Pinpointing the precise genetic cause is important, as it allows for accurate genetic counseling, avoidance of unnecessary testing, prognostication, and tailored management, which, for an increasing number of genetic conditions, targets the pathophysiology and improves outcomes. SUMMARY: The etiology of intellectual developmental disorder is heterogeneous, which mandates a structured approach that considers family situation, test costs, yield, and potential therapeutic tractability of the identified condition. Diagnosis of an underlying genetic cause is increasingly important with the advent of new treatments. Still, in many cases, the cause remains unknown, and research is needed to elucidate its complex molecular basis. PMID- 29432246 TI - Evaluation and Management of the Child With Autism Spectrum Disorder. AB - PURPOSE OF REVIEW: Autism spectrum disorder is a neurodevelopmental disorder defined by deficits in social communication and the presence of restricted and repetitive behaviors and interests. This article provides the tools to diagnose and manage patients with autism spectrum disorder. RECENT FINDINGS: Autism spectrum disorder is a heterogeneous condition with varying presentations, multiple etiologies, and a number of comorbidities that impact the course and management of the disorder. This article defines the core features of social communication deficits, including problems with social reciprocity, decreased nonverbal communication, and difficulties in developing and maintaining relationships. The second domain of repetitive behaviors and restricted interests, which includes the presence of stereotyped behaviors or speech, insistence on sameness and behavioral rigidity, intense or out of the ordinary interests, and unusual responses to sensory stimulation, is also delineated. Comorbidities commonly seen with autism spectrum disorder include medical, neurologic, and psychiatric conditions. Despite intense research efforts, the etiology of autism spectrum disorder remains unknown in most cases, but it is clear that a strong genetic component exists that interacts with various environmental risk factors. Current research is identifying overlapping neurobiological pathways that are involved in pathogenesis. Treatment involves intensive behavioral therapy and educational programming along with traditional ancillary services, such as speech/language, occupational, and physical therapies. Psychopharmacologic treatments are also used to target certain symptoms and comorbid conditions. SUMMARY: Neurologists can play an important role in diagnosing autism spectrum disorder according to clinical criteria through a comprehensive evaluation that includes a thorough medical and developmental history, behavioral and play observations, and a review of standardized cognitive and language evaluations. Neurologists are also responsible for investigating etiologies, recommending and advocating for appropriate behavioral and educational interventions, and identifying and often managing comorbidities. PMID- 29432247 TI - Transition From Pediatric to Adult Neurologic Care. AB - PURPOSE OF REVIEW: With advances in medical care, the number of youths surviving with medically complex conditions has been steadily increasing. Inadequate transition planning and execution can lead to gaps in care, unexpected emergency department visits, and an increase in health care costs and patient/caregiver anxiety. Many barriers that prevent adequate transition have been identified, including insufficient time or staff to provide transition services, inadequate reimbursement, resistance from patients and caregivers, and a dearth of accepting adult providers. RECENT FINDINGS: Transition is distinct from transfer of care. Transition is a planned multistage process, while transfer refers to a point in time where responsibility of care shifts from one provider to another. Key differences exist between the pediatric and adult models of care. A successful transition should empower the patient to understand and take responsibility in managing his or her condition; foster independent functioning to the extent that is possible; integrate educational, legal, and community resources in the care plan; and identify appropriate adult health care providers at the time of transfer. Different models have been proposed to streamline the transition process, with improvement in patients' knowledge of their condition, self efficacy, and confidence. SUMMARY: Neurologists have a key role in supporting their patients in the transition to adulthood. This article reviews basic tenets and provides tools to assist in navigating the complex transition process. These tenets are intended to improve quality of care and decrease clinician burden and remain an active area of research. PMID- 29432248 TI - Neurologic Complications in the Pediatric Intensive Care Unit. AB - PURPOSE OF REVIEW: All critical care is directed at maintaining brain health, but recognizing neurologic complications of critical illness in children is difficult, and limited data exist to guide practice. This article discusses an approach to the recognition and management of seizures, stroke, and cardiac arrest as complications of other critical illnesses in the pediatric intensive care unit. RECENT FINDINGS: Convulsive and nonconvulsive seizures occur frequently in children after cardiac arrest or traumatic brain injury and during extracorporeal membrane oxygenation. Seizures may add to neurologic morbidity, and continuous EEG monitoring is needed for up to 24 hours for detection. Hypothermia has not been shown to improve outcome after cardiac arrest in children, but targeted temperature management with controlled normothermia and prevention of fever is a mainstay of neuroprotection. SUMMARY: Much of brain directed pediatric critical care is empiric. Recognition of neurologic complications of critical illness requires multidisciplinary care, serial neurologic examinations, and an appreciation for the multiple risk factors for neurologic injury present in most patients in the pediatric intensive care unit. Through attention to the fundamentals of neuroprotection, including maintaining or restoring cerebral perfusion matched to the metabolic needs of the brain, combined with anticipatory planning, these complications can be prevented or the neurologic injury mitigated. PMID- 29432249 TI - Pediatric Traumatic Brain Injury and Concussion. AB - PURPOSE OF REVIEW: This article summarizes the impact and complications of mild traumatic brain injury and concussion in children and outlines the recent evidence for its assessment and early management. Useful evidence-based management strategies are provided for children who have a typical recovery following concussion as well as for those who have persistent postconcussion syndrome. Cases are used to demonstrate the commonly encountered pathologies of headache, cognitive issues, and mood disturbances following injury. RECENT FINDINGS: A clinical risk score using risk factors for poor recovery (eg, female sex, adolescence, previous migraine, and a high degree of acute symptoms) can be used to help the clinician plan follow-up in the community. Prolonged periods of physical and cognitive rest should be avoided. Multidisciplinary treatment plans are often required in the management of persistent postconcussion syndrome. SUMMARY: A paucity of research exists for the treatment of postconcussion syndrome. Current treatments target individual symptoms. PMID- 29432250 TI - How the International Classification of Diseases, Tenth Revision, Clinical Modification Affects Coding for Pediatric Diagnoses. AB - Accurate coding is important for proper reimbursement and documentation of care provided. Recent changes in disease classification systems have affected the coding for pediatric diagnoses. This article provides an overview of coding considerations for pediatric diagnoses, including coding for intellectual disabilities and congenital malformations. PMID- 29432255 TI - Solid organ transplantation of viral hepatitis C positive donor organs into viral hepatitis C negative recipients. AB - PURPOSE OF REVIEW: Strategies are needed to reduce waitlist mortality and increase transplantation rates. Advances in hepatitis C therapy has allowed the transplant community to look toward utilization of grafts from hepatitis C viremic donors to expand the organ pool. Use of such grafts for hepatitis C negative patients is being evaluated and debated, and early trial data are emerging. RECENT FINDINGS: Both hepatitis C antibody-positive/nucleic acid test negative and viremic donors are currently underutilized. Outcomes for viral hepatitis C (HCV) viremic transplant recipients are improving in the setting of direct-acting antiviral therapy. Optimization of graft utilization from HCV 'positive' donors and expansion to use of viremic donors for HCV-negative recipients will likely reduce waitlist mortality and result in net overall reduction in healthcare expenditures. SUMMARY: Herein, we provide a review of recent advancements relating to hepatitis C in solid organ transplant and outline future directions. A primary future focus will be data collection of outcomes of transplantation of grafts from HCV 'viremic' donors to nonviremic recipients in formal clinical trial protocols. PMID- 29432254 TI - Moving from the HIV Organ Policy Equity Act to HIV Organ Policy Equity in action: changing practice and challenging stigma. AB - PURPOSE OF REVIEW: The HIV Organ Policy Equity (HOPE) Act, signed in 2013, reversed the federal ban on HIV-to-HIV transplantation. In this review, we examine the progress in HOPE implementation, the current status of HIV-to-HIV transplantation, and remaining challenges. RECENT FINDINGS: Pursuant to the HOPE Act, the Department of Health and Human Services revised federal regulations to allow HIV-to-HIV transplants under research protocols adherent to criteria published by the National Institutes of Health. The first HIV-to-HIV kidney and liver transplants were performed at Johns Hopkins in March of 2016. Legal and practical challenges remain. Further efforts are needed to educate potential HIV+ donors and to support Organ Procurement Organizations. As of November 2017, there are 22 transplant centers approved to perform HIV-to-HIV transplants in 10 United Network for Organ Sharing regions. To date, 16 Organ Procurement Organizations in 22 states have evaluated HIV+ donors. The National Institutes of Health-funded HOPE in Action: A Multicenter Clinical Trial of HIV-to-HIV Deceased Donor (HIVDD) Kidney Transplantation Kidney Trial will launch at 19 transplant centers in December of 2017. A HOPE in Action Multicenter HIVDD Liver Trial is in development. SUMMARY: Significant progress toward full HOPE implementation has been made though barriers remain. Some challenges are unique to HIV-HIV transplantation, whereas others are amplifications of issues across the current transplant system. In addition to a public health benefit for all transplant candidates in the United States, partnership on the HOPE Act has the potential to address systemic challenges to national donation and transplantation. PMID- 29432256 TI - Portal vein thrombosis: yes or no on anticoagulation therapy. AB - PURPOSE OF REVIEW: To describe portal vein thrombosis (PVT) in the setting of cirrhosis especially in relation to its potential impact on liver transplantation. In addition, the safety and efficacy of anticoagulation is reviewed. RECENT FINDINGS: PVT in cirrhosis occurs in up to 26% of patients awaiting liver transplantation. Different studies have suggested that PVT impacts negatively post-liver transplantation survival, particularly in first year post liver transplantation and when PVT is complete involving the porto-mesenteric confluence and not allowing physiological anastomosis. Anticoagulation is effective in preventing PVT progression and may achieve partial or complete PVT recanalization. Its use in patients with cirrhosis seems not to be associated with increased bleeding risk. SUMMARY: The goal of anticoagulation is to prevent thrombus extension to the superior mesenteric vein and/or favor recanalization if previously affected, allowing physiological anastomosis during liver transplantation and therefore improving outcome. Low-molecular-weight heparin and vitamin K antagonist have a similar safety profile without specific data in favor of any of them. Treatment with direct anticoagulants cannot be recommended yet because of limited experience in cirrhosis. Transjugular intrahepatic portosystemic shunt could be an alternative particularly if thrombosis progresses despite satisfactory anticoagulation and/or when PVT is associated with severe portal hypertension complications. However, careful consideration of potential risks and benefits of anticoagulation is recommended until further studies are conducted. PMID- 29432257 TI - Progression of living liver donation worldwide. AB - PURPOSE OF REVIEW: Living donor liver transplantation (LDLT) has developed into a well tolerated and viable option when deceased donor transplantation is not available. Transplant and advanced hepatobiliary surgeons from around the world have performed living donor hepatectomies consistently for decades with acceptable donor outcomes. However, optimizing the preoperative workup, donor selection, operative technique, and perioperative care will improve these outcomes. This manuscript reviews recent worldwide literature for the living liver donor. RECENT FINDINGS: Overall, younger living donors produce better recipient outcomes but with careful selection donor over 55 years old may be used safely. Magnetic resonance is becoming the imaging of choice for living donor preoperative planning and its ability to predict steatosis may make predonation liver biopsy unnecessary. Programs with experience in LDLT and laparoscopic liver resection are making significant progress toward consistent use of the laparoscopic approach to living donor hepatectomy. Biliary, pulmonary, and infectious complications are the predictable complications with more serious complications and donor death being very rare. In a majority of cases, the donor's health-related quality of life and psychological well being are preserved. SUMMARY: These recent findings will allow us to better care for the living liver donor and enable LDLT continued progress. PMID- 29432258 TI - Overview of aldosterone-related genetic syndromes and recent advances. AB - PURPOSE OF REVIEW: Primary aldosteronism is the most common form of secondary hypertension. Early diagnosis and treatment are key to cure of hypertension and prevention of cardiovascular complications. Recent genetic discoveries have improved our understanding on the pathophysiology of aldosterone production and triggered the development of new diagnostic procedures and targeted treatments for primary aldosteronism. RECENT FINDINGS: Different inherited genetic abnormalities distinguish specific forms of familial hyperaldosteronism. Somatic mutations are found not only in aldosterone-producing adenoma (APA), leading to primary aldosteronism, but also in aldosterone producing cell clusters of normal and micronodules from image-negative adrenal glands. Genetic knowledge has allowed the discovery of surrogate biomarkers and specific pharmacological inhibitors. Ageing appears to be associated with dysregulated and relatively autonomous aldosterone production. SUMMARY: New biochemical markers and pharmacological approaches may allow preoperative identification of somatic mutation carriers and use of targeted treatments. PMID- 29432259 TI - Explicit Disability Bias in Peer Review. PMID- 29432260 TI - Cost-related Nonadherence to Medication Treatment Plans: Native Hawaiian and Pacific Islander National Health Interview Survey, 2014. AB - BACKGROUND: Adherence to medication treatment plans is important for chronic disease (CD) management. Cost-related nonadherence (CRN) puts patients at risk for complications. Native Hawaiians and Pacific Islanders (NHPI) suffer from high rates of CD and socioeconomic disparities that could increase CRN behaviors. OBJECTIVE: Examine factors related to CRN to medication treatment plans within an understudied population. RESEARCH DESIGN: Using 2014 NHPI-National Health Interview Survey data, we examined CRN among a nationally representative sample of NHPI adults. Bonferroni-adjusted Wald test and multivariable logistic regression were performed to examine associations among financial burden-related factors, CD status, and CRN. RESULTS: Across CD status, NHPI engaged in CRN behaviors had, on an average, increased levels of perceived financial stress, financial insecurity with health care, and food insecurity compared with adults in the total NHPI population. Regression analysis indicated perceived financial stress [adjusted odds ratio (AOR)=1.16; 95% confidence intervals (CI), 1.10 1.22], financial insecurity with health care (AOR=1.96; 95% CI, 1.32-2.90), and food insecurity (AOR=1.30; 95% CI, 1.06-1.61) all increase the odds of CRN among those with CD. We also found significant associations between perceived financial stress (AOR=1.15; 95% CI, 1.09-1.20), financial insecurity with health care (AOR=1.59; 95% CI, 1.19-2.12), and food insecurity (AOR=1.31; 95% CI, 1.04-1.65) and request for lower cost medication. CONCLUSIONS: This study demonstrated health-related and non-health-related financial burdens can influence CRN behaviors. It is important for health care providers to collect and use data about the social determinants of health to better inform their conversations about medication adherence and prevent CRN. PMID- 29432261 TI - An Outpatient Heart Failure Clinic Reduces 30-Day Readmission and Mortality Rates for Discharged Patients: Process and Preliminary Outcomes. AB - BACKGROUND: The first outpatient heart failure clinic (HFC) in Western New York was developed within a large private cardiology practice with the objective of reducing 30-day all-cause rehospitalization and inpatient mortality. PURPOSE: The aim of this study was to analyze the process and patient outcomes of this independent outpatient HFC. The specific aims were to (a) describe the outpatient care strategies employed and (b) determine whether the HFC reduced 30-day all cause rehospitalizations and inpatient mortality by comparing HFC data with census data. METHODS: This study used a retrospective chart analysis of 415 adults who had been enrolled in the target HFC after hospitalization for HF. Data were summarized using frequency comparisons and descriptive statistics. One sample chi-square tests were conducted to test the observed values in the study sample against census data. RESULTS: Patients in the HFC were less likely to experience a readmission to hospital within 30 days of discharge (69% reduction within the study period, p < .001). Patients were seen acutely after discharge, had multiple medication adjustments, and received ongoing telephonic follow-up. The HFC had statistically lower inpatient mortality rates (1.2% vs. 11.6% national average, p < .001), likely a result of the HFC care regimen and referrals for palliative care (17%). CONCLUSIONS: The results of this analysis highlight the importance of developing an outpatient HFC in collaboration with hospitals that is aimed at reducing 30-day all-cause readmissions and inpatient mortality, with referral to palliative care when indicated. PMID- 29432262 TI - Increased Radiation but No Benefits in Pedicle Screw Accuracy With Navigation versus a Freehand Technique in Scoliosis Surgery. AB - BACKGROUND: The clinical value of pedicle screws in spinal deformity surgery is well known; however, screw insertion is demanding and sometimes associated with complications. Navigation systems based on intraoperatively obtained three dimensional (3-D) images were developed to minimize pedicle screw misplacements. However, there is a lack of data confirming superiority of navigation above other techniques. There are also concerns regarding increased radiation used during the procedure. QUESTIONS/PURPOSES: The purposes of this study were (1) to compare accuracy of the two methods of pedicle screws placement: intraoperative 3-D image navigation versus a freehand technique in patients with idiopathic scoliosis; and (2) to assess the radiation dose received by patients with both methods. METHODS: Between 2014 and 2016, 49 patients underwent posterior spinal fusion with all pedicle screw constructs for idiopathic scoliosis performed by two surgeons. The study design involved alternating the use of the freehand technique and navigation to position pedicle screws in consecutive patients, forming groups of 27 patients with 451 navigated screws and 22 patients with 384 screws positioned freehand. The two groups did not differ in age, sex, or magnitude of deformity. Two observers not involved in the treatment evaluated the position of the screws. The pedicle breach was assessed on intraoperatively obtained 3-D O-arm(r) scans according to a grading system: Grade 0 = no pedicle wall violation; Grade 1 = perforation <= 2 mm; Grade 2 = 2 to 4 mm; and Grade 3 = perforation > 4 mm. Grades 0 and 1 were considered properly positioned and Grades 2 and 3 represented malposition. RESULTS: In terms of accuracy, we found no differences, with the numbers available, between the freehand and navigated groups in terms of the proportion of screws that were properly positioned (96% freehand and 96% in the navigation group, respectively; p = 0.518). Grade 3 pedicle screws were observed only in the freehand group and were all located in the upper thoracic spine. Patients undergoing navigated pedicle screw placement received a greater mean radiation dose than those whose screws were placed freehand (1071 +/- 447 mGy-cm versus 391 +/- 53 mGy-cm; mean difference, 680 mGy-cm; 95% confidence interval, 217-2053 mGy-cm; p < 0.001). CONCLUSIONS: In patients with moderate idiopathic scoliosis undergoing primary surgery, we did not observe benefits of pedicle screw placement with CT-based navigation, but the patients experienced greater exposure to radiation. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29432263 TI - Perioperative Inpatient Use of Selective Serotonin Reuptake Inhibitors Is Associated With a Reduced Risk of THA and TKA Revision. AB - BACKGROUND: Depression is common in the general population, and so it is likewise common among patients undergoing THA and TKA. Depression is associated with lower perioperative patient-reported outcomes and an increased risk of postoperative complications. Antidepressants are effective in managing symptoms of depression and may potentially contribute to better functional status and better clinical outcomes after THA and TKA. QUESTIONS/PURPOSES: We examined (1) whether perioperative depression is associated with all-cause revisions, revisions for aseptic loosening, revisions without infection, and periprosthetic joint infections (PJIs) in patients undergoing THA and TKA; and (2) whether perioperative antidepressant use reduces the risk of all-cause revisions, revisions for aseptic loosening, aseptic revisions, and PJIs in patients undergoing THA and TKA. METHODS: This was a retrospective study of adult patients (>= 18 years) who underwent 20,112 primary and revision THAs and TKAs from January 1, 2002, through December 31, 2009, at a large US tertiary care hospital. Data on patient and surgery characteristics and outcomes (dates and types of revisions, death) were ascertained through the institutional joint registry. Perioperative antidepressant use was assessed by searching the daily medication administration records beginning at admission and ending at discharge. A diagnosis of depression was present in 4466 (22%), and antidepressants were administered at the time of 5077 (25%) surgical procedures. Multivariable Cox proportional hazard models were used to estimate associations between antidepressant use and the risk of all-cause revisions, revisions for aseptic loosening, aseptic revisions, and PJIs. RESULTS: Depression was associated with an increased risk of all-cause revisions (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.42-2.02; p < 0.001) and PJIs (HR, 2.23; 95% CI, 1.53-3.17; p < 0.001). Overall, perioperative antidepressant use was not associated with the risk of revision or PJI, but selective serotonin reuptake inhibitor (SSRI) users had a lower risk of all-cause revisions (HR, 0.77; 95% CI, 0.61-0.96; p = 0.001) and aseptic revisions (HR, 0.72; 95% CI, 0.56-0.93; p = 0.013). CONCLUSIONS: The presence of a depression diagnosis confers an increased risk of revision and PJI among patients undergoing THA and TKA, yet the risk is lower within the subset of patients who received SSRIs during the perioperative period. Future longitudinal studies with detailed antidepressant medication histories are warranted to better understand the potential biologic effects of SSRI on the risk of revision in patients undergoing THA and TKA. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29432264 TI - Longitudinal Growth and pQCT Measures in Hutterite Children and Grandchildren Are Associated With Prevalence of Hip or Knee Replacement Resulting From Osteoarthritis in Parents and Grandparents. AB - BACKGROUND: Osteoarthritis (OA) is one of the leading causes of disability in the world. Several genes are associated with the development of OA, and previous studies have shown adult children of individuals with OA have higher areal bone mineral density (BMD). Because childhood is an important period of growth and bone development, and body composition is known to be associated with BMD, we speculated that there may be differences in growth and bone measures among young children with a genetic predisposition to OA. QUESTIONS/PURPOSES: (1) Do differences exist at baseline in anthropometric and peripheral quantitative CT (pQCT) measurements between children and grandchildren of individuals with OA and controls? (2) Do children and grandchildren of individuals with OA accrue bone longitudinally at a different rate than controls? METHODS: Longitudinal anthropometric (height, weight) and bone (cortical and trabecular volumetric BMD and cross-sectional area) measurements by pQCT were obtained at baseline and 18 and 36 months on children (n = 178) and grandchildren (n = 230) of 23 individuals with hip or knee arthroplasty resulting from OA and 23 sex-matched controls (16 females each). Grandchildren (age, 8-30 years) were further categorized as growing (premenarcheal or male < 14 years, n = 99) or mature (>= 2 years postmenarchal or males >= 18 years, n = 96). The remaining 35 grandchildren could not be categorized and were excluded. RESULTS: Mature granddaughters and grandsons of individuals with OA had greater trabecular volumetric BMD than controls (236 +/- 24 and 222 +/- 26 mg/cm, respectively, for granddaughters, difference of 14 [95% confidence interval {CI}, 1-28] mg/cm, p = 0.041 and 270 +/ 22 and 248 +/- 30 mg/cm, respectively, for grandsons, difference of 22 [95% CI, 1-42] mg/cm, p = 0.040). Greater trabecular volumetric BMD was observed in daughters of individuals with OA compared with daughters of controls (228 +/- 28 and 212 +/- 33 mg/cm, respectively, difference of 18 [95% CI, 3-30] mg/cm, respectively [p = 0.021]). Growing granddaughters and grandsons of controls had greater decreases in cortical volumetric BMD than grandchildren of individuals with OA (time-by-group [TG] based on mixed model [+/- standard error] -9.7 +/- 4.3 versus -0.8 +/- 4.4 mg/cm/year, respectively, for granddaughters, difference of 9.0 [95% CI, 2.4-15.5] mg/cm/year, p = 0.007 and -6.8 +/- 3.3 versus 4.5 +/- 3.4 mg/cm/year, respectively, for grandsons, difference of 11.3 [95% CI, 4.3 18.3] mg/cm/year, p = 0.002). Cortical volumetric BMD was maintained in sons of individuals with OA, but decreased in sons of controls (-0.0 +/- 1.5 versus -4.3 +/- 1.0 mg/cm/year, respectively, difference of 4.3 [95% CI, 0.7-7.8] mg/cm/year, p = 0.019 [TG]). There was a greater apparent decrease in cross-sectional area among daughters of individuals with OA than in controls (-4.6 +/- 0.9 versus -1.7 +/- 0.9 mm/year, respectively, difference of -2.9 [95% CI, -5.3 to -0.6] mm/year, p = 0.015 [TG]). CONCLUSIONS: Several anthropometric and bone differences exist between children and grandchildren of individuals with OA and controls. If these differences are confirmed in additional studies, it would be important to identify the mechanism so that preventive measures could be developed and implemented to slow or reduce OA development. CLINICAL RELEVANCE: Differences in growth and bone development may lead to increased loads on cartilage that may predispose offspring to the development of OA. If these differences are confirmed in additional studies, it would be important to identify the mechanism so that preventive measures could be developed and implemented to slow or reduce OA development. PMID- 29432265 TI - CORR Insights(r): Are Psychosocial Factors Associated With Patient-reported Outcome Measures in Patients With Rotator Cuff Tears? A Systematic Review. PMID- 29432266 TI - Looking for Holes in Sterile Wrapping: How Accurate Are We? AB - BACKGROUND: Defects in sterile surgical wrapping are identified by the presence of holes through which light can be seen. However, it is unknown how reliably the human eye can detect these defects. QUESTIONS/PURPOSES: The purpose of this study was to determine (1) how often holes in sterile packaging of various sizes could be detected; and (2) whether differences in lighting, experience level of the observer, or time spent inspecting the packaging were associated with improved likelihood of detection of holes in sterile packaging. METHODS: Thirty participants (10 surgical technicians, 13 operating room nurses, seven orthopaedic surgery residents) inspected sterile sheets for perforations under ambient operating room (OR) lighting and then again with a standard powered OR lamp in addition to ambient lighting. There were no additional criteria for eligibility other than willingness to participate. Each sheet contained one of nine defect sizes with four sheets allocated to each defect size. Ten wraps were controls with no defects. Participants were allowed as much time as necessary for inspection. RESULTS: Holes >= 2.5 mm were detected more often than holes <= 2 mm (87% [832 of 960] versus 7% [82 of 1200]; odds ratio, 88.6 [95% confidence interval, 66.2-118.6]; p < 0.001). There was no difference in detection accuracy between OR lamp and ambient lightning nor experience level. There was no correlation between inspection time and detection accuracy. CONCLUSIONS: Defects <= 2 mm were not reliably detected with respect to lighting, time, or level of experience. Future research is warranted to determine defect sizes that are clinically meaningful. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 29432267 TI - Effectiveness of Preoperative Antibiotics in Preventing Surgical Site Infection After Common Soft Tissue Procedures of the Hand. AB - BACKGROUND: Antibiotic prophylaxis is a common but controversial practice for clean soft tissue procedures of the hand, such as carpal tunnel release or trigger finger release. Previous studies report no substantial reduction in the risk of surgical site infection (SSI) after antibiotic prophylaxis, yet are limited in power by low sample sizes and low overall rates of postoperative infection. QUESTIONS/PURPOSES: Is there evidence that antibiotic prophylaxis decreases the risk of SSI after soft tissue hand surgery when using propensity score matching to control for potential confounding variables such as demographics, procedure type, medication use, existing comorbidities, and postoperative events? METHODS: This retrospective analysis used the Truven Health MarketScan databases, large, multistate commercial insurance claims databases corresponding to inpatient and outpatient services and outpatient drug claims made between January 2007 and December 2014. The database includes records for patients enrolled in health insurance plans from self-insured employers and other private payers. Current Procedural Terminology codes were used to identify patients who underwent carpal tunnel release, trigger finger release, ganglion and retinacular cyst excision, de Quervain's release, or soft tissue mass excision, and to assign patients to one of two cohorts based on whether they had received preoperative antibiotic prophylaxis. We identified 943,741 patients, of whom 426,755 (45%) were excluded after meeting one or more exclusion criteria: 357,500 (38%) did not have 12 months of consecutive insurance enrollment before surgery or 1 month of enrollment after surgery; 60,693 (6%) had concomitant bony, implant, or incision and drainage or debridement procedures; and 94,141 (10%) did not have complete data. In all, our initial cohort consisted of 516,986 patients, among whom 58,201 (11%) received antibiotic prophylaxis. Propensity scores were calculated and used to create cohorts matched on potential risk factors for SSI, including age, procedure type, recent use of steroids and immunosuppressive agents, diabetes, HIV/AIDs, tobacco use, obesity, rheumatoid arthritis, alcohol abuse, malnutrition, history of prior SSI, and local procedure volume. Multivariable logistic regression before and after propensity score matching was used to test whether antibiotic prophylaxis was associated with a decrease in the risk of SSI within 30 days after surgery. RESULTS: After controlling for patient demographics, hand procedure type, medication use, existing comorbidities (eg, diabetes, HIV/AIDs, tobacco use, obesity), and postoperative events through propensity score matching, we found that the risk of postoperative SSI was no different between patients who had received antibiotic prophylaxis and those who had not (odds ratio, 1.03; 95% CI, 0.93-1.13; p = 0.585). CONCLUSIONS: Antibiotic prophylaxis for common soft tissue procedures of the hand is not associated with reduction in postoperative infection risk. While our analysis cannot account for factors that are not captured in the billing process, this study nevertheless provides strong evidence against unnecessary use of antibiotics before these procedures, especially given the difficulty of conducting a randomized prospective study with a sample size large enough to detect the effect of prophylaxis on the low baseline risk of infection. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29432268 TI - What Injury Mechanism and Patterns of Ligament Status Are Associated With Isolated Coronoid, Isolated Radial Head, and Combined Fractures? PMID- 29432269 TI - CORR Insights(r): Floor Effect of PROMIS Depression CAT Associated With Hasty Completion in Orthopaedic Surgery Patients. PMID- 29432270 TI - What Is the Long-term Survival for Primary THA With Small-head Metal-on-metal Bearings? AB - BACKGROUND: Large-head metal-on-metal (MoM) bearing hip replacements have been shown to have a much higher rate of revision than other bearing surfaces. However, small-head (<= 32 mm) MoM bearing surfaces have been in use for many years with several reports of satisfactory mid- to long-term survivorship. It is unclear whether the long-term survival of small-head MoM devices will continue to be satisfactory or whether the same concerns seen with the large-head MoM devices will ultimately become more prevalent. QUESTIONS/PURPOSES: We analyzed a large national registry to ask: (1) What is the 15-year Kaplan-Meier survivorship of primary conventional THA using small-head (<= 32 mm) MoM bearing surfaces compared with large-head MoM bearing surfaces in primary THA? (2) Is there an increased rate of revision for adverse reaction to metal debris (ARMD) in this group of patients over time? METHODS: The Australian Orthopaedic Association National Joint Replacement Registry longitudinally maintains data on all primary and revision joint arthroplasties with nearly 100% capture. We analyzed all conventional primary THAs performed from Registry inception in September 1999 until December 31, 2015, in patients with a diagnosis of osteoarthritis and using MoM bearing surfaces <= 32 mm in diameter, defined as small-head MoM. The study group included 4838 primary THA with <= 32-mm MoM bearing surfaces. There were 2506 (51.8%) male patients and the median age of patients undergoing THA with a small-head MoM bearing surface was 64 years (range, 20-92 years of age). The outcome measure was the cumulative percent revision defined as the time to first revision using Kaplan-Meier estimates of survivorship at 15 years; reasons for revision and type of revision were also examined. We specifically investigated whether there was an increased risk of revision for ARMD in this MoM group compared with all other bearing surfaces. We compared these results with large head MoM THAs (femoral head size > 32 mm). RESULTS: The cumulative percent revision for small-head MoM designs at 15 years was 8.5% (95% confidence interval [CI], 7.3-9.9). The cumulative percent revision for large-head MoM at 14 years was 27.4% (95% CI, 24.8-30.2). Prostheses with a large-head MoM articulation have a higher rate of revision than small-head MoM bearing surfaces (hazard ratio after 6 years, 5.14; 95% CI, 4.1-6.5; p < 0.001). Over time, there was a gradual increase in the diagnosis of ARMD for small-head MoM and the cumulative incidence of revision for ARMD was 0.8% at 15 years. CONCLUSIONS: Despite survival that is substantially greater than that of large-head MoM THAs, there has been a marked decrease in the use of small-head MoM designs in our registry. Although the reasons for this are likely multifactorial, the increasing incidence of revisions for ARMD among small-head MoM THAs is concerning. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29432271 TI - CORR Insights(r): What Are the Complications, Survival, and Outcomes After Revision to Reverse Shoulder Arthroplasty in Patients Older Than 80 Years? PMID- 29432272 TI - Editorial Comment: Comprehensive Orthopaedic Care. PMID- 29432273 TI - CORR Insights(r): Is Physician Empathy Associated With Differences in Pain and Functional Limitations After a Hand Surgeon Visit? PMID- 29432274 TI - Letter to the Editor: What Injury Mechanism and Patterns of Ligament Status Are Associated With Isolated Coronoid, Isolated Radial Head, and Combined Fractures? PMID- 29432275 TI - CORR Insights(r): What Is the Clinical Importance of Incidental Findings on Staging CT Scans in Patients With Sarcoma? PMID- 29432276 TI - Neurogenic Pulmonary Edema and Stunned Myocardium in a Patient With Meningioma: A Heart-Brain Cross Talk. PMID- 29432277 TI - Patient, Surgeon, and Anesthesiologist Satisfaction: Who has the Priority? PMID- 29432278 TI - Acquired Central Hypoventilation Syndrome Unmasked by Propofol Sedation. PMID- 29432279 TI - 13C-Mixed Triglyceride Breath Test and Fecal Elastase as an Indirect Pancreatic Function Test in Cystic Fibrosis Infants. AB - BACKGROUND: The 'gold standard' test for the indirect determination of pancreatic function status in infants with cystic fibrosis (CF), the 72-hour fecal fat excretion test, is likely to become obsolete in the near future. Alternative indirect pancreatic function tests with sufficient sensitivity and specificity to determine pancreatic phenotype need further evaluation in CF infants. OBJECTIVE: Evaluation of the clinical utility of both the noninvasive, nonradioactive C mixed triglyceride (MTG) breath test and fecal elastase-1 (FE1) in comparison with the 72-hour fecal fat assessment in infants with CF. METHODS: C-MTG breath test and the monoclonal and polyclonal FE1 assessment in stool was compared with the 72-hour fecal fat assessment in 24 infants with CF. Oral pancreatic enzyme substitution (PERT; if already commenced) was stopped before the tests. RESULTS: Sensitivity rates between 82% and 100% for CF patients with pancreatic insufficiency assessed by both the C-MTG breath test and the FE1 tests proved to be high and promising. The C-MTG breath test (31%-38%) as well as both FE1 tests assessed by the monoclonal (46%-54%) and the polyclonal (45%) ELISA kits, however, showed unacceptably low-sensitivity rates for the detection of pancreatic-sufficient CF patients in the present study. CONCLUSIONS: The C-MTG breath test with nondispersive infrared spectroscopy (NDIRS) technique, as well as both FE1 tests, are not alternatives to the fecal fat balance test for the evaluation of pancreatic function in CF infants during the first year of life. PMID- 29432280 TI - Proteomics and Gastrointestinal Dynamic Models: 2 Possible Allies. PMID- 29432281 TI - Lymph node ratio as a prognostic factor in melanoma: results from European Organization for Research and Treatment of Cancer 18871, 18952, and 18991 studies. AB - The aim of this study was to assess the prognostic importance of lymph node ratio (LNR) in stage III melanoma after complete lymph nodal dissections. From European Organization for Research and Treatment of Cancer randomized trials 18871, 18952, and 18991, 2358 patients had full information on positive and examined lymph nodes (LNs) and were included. Cox proportional hazards models stratified by trial were used to assess the prognostic impact of LNR adjusted for confounders on melanoma-specific survival. Optimal cutoff values for LNR were calculated for each LN dissection site (axillary, inguinal, and neck). LNR (>= vs. <35%: hazard ratio=1.44, 95% confidence interval: 1.23-1.69) and number of positive LNs appeared to be of independent strong prognostic importance. Dissection sites impacted the optimal LNR cutoff: 35% for axillary, 40% for inguinal, and 50% for neck dissections. Combining these into one 'high versus low LNR' resulted in a highly significant multivariately adjusted hazard ratio of 1.48 (95% confidence interval: 1.26-1.74). In subgroup analyses, LNR was only significant in advanced disease (American Joint Committee on Cancer stage N2b, N3; IIIC). LNR was most significant for inguinal dissections, followed by axillary dissections, but seemed less useful in neck dissections. LNR is an independent significant prognostic factor in stage III melanoma patients. Our study showed higher than previously reported cutoffs that differed per dissection site. However, because of conflicting results compared with other studies and apparent limited prognostic impact confined to subgroups, the practical use of LNR seems limited. PMID- 29432282 TI - Phase I Study of Multiple Epitope Peptide Vaccination in Patients With Recurrent or Persistent Cervical Cancer. AB - Cancer immunotherapy has now been established as a leading standard therapeutic option in a subset of patients with cancer. In this study, we conducted a phase I dose-escalation trial using a mixture of 5 peptides to vaccinate cervical cancer patients with HLA-A*2402. The primary endpoints were safety and determination of a recommended vaccine dose, and the secondary endpoints were evaluations of immunologic responses and clinical efficacy. All patients had recurrent or persistent disease and had failed to respond to or were intolerant to prior standard chemotherapy. Peptides derived from forkhead box protein M1 (FOXM1), maternal embryonic leucine zipper kinase (MELK), Holliday junction-recognition protein, and vascular endothelial growth factor receptors 1 and 2 were administered to 9 patients in a 3 patient-cohort design, with doses of 0.5, 1, or 2 mg of each of the individual peptides in a mixture with incomplete Freund's adjuvant. The major adverse events were anemia and injection site reactions, which were seen in 77.8% (7/9) and 66.7% (6/9) of patients, respectively. Grade 3 anemia was observed in 1 patient. No dose-limiting toxicity of the vaccine was observed. Seven (78%) patients achieved stable disease, and the median progression-free survival was 3.3 months (102 d). Interferon-gamma enzyme-linked immunospot assays for each of the 5 antigens showed that 8 (89%) and 7 (78%) patients had high T-cell responses to FOXM1 and MELK, respectively. In conclusion, we demonstrated that this 5-peptide vaccine was tolerable, and that FOXM1 and MELK could be promising targets for immunotherapy in patients with cervical cancer. PMID- 29432283 TI - Nurse Educator Attitudes Toward People With Disabilities. AB - AIM: As educators strongly influence the attitudes of their students, the purpose of this study was to determine nurse educator attitudes toward people with disabilities. BACKGROUND: Inadequate education of health professionals is a known barrier to care for people with disability. Continuing calls for improved education of health professionals compel an assessment of nurse educator attitudes. METHOD: This was a cross-sectional, correlational web-based survey of nurse educators (n = 126). Nurse educator attitudes were analyzed using descriptive statistics, analysis of variance, and multiple regression analysis. RESULTS: Nurse educators held discriminatory attitudes toward people with disabilities, though most preferred a biopsychosocial model of disability. Forty four percent lacked knowledge of disability-related aims, objectives, or outcomes within the curriculum. CONCLUSION: To advance equity in health care, nurse educators must confront personal bias and teach competent care of people with disabilities. PMID- 29432284 TI - beta-Blockers in myocardial infarction and coronary artery disease with a preserved ejection fraction: recommendations, mechanisms, and concerns. AB - beta-Blockers are a recommended therapy in patients with acute myocardial infarction and coronary artery disease. beta-Blockers markedly and unequivocally reduce mortality in patients with myocardial infarction and coronary artery disease with heart failure and a reduced ejection fraction. However, the mortality effects of beta-blockers in patients with a preserved ejection fraction are not established even though they represent the majority of patients with coronary artery disease. In this review, we will assess the evidence basis of the recommendations for beta-blockers in the US guidelines and discuss emerging concerns about the use of beta-blockers and other heart rate-lowering medications in patients with a preserved ejection fraction that suggest that their long-term adverse outcomes may outweigh their antianginal benefits. PMID- 29432285 TI - A Well-Tolerated and Effective Antiepileptic Drug for Patients With Myasthenia Gravis at Last? AB - Antiepileptic drugs have been known to worsen myasthenia gravis (MG) symptoms, and therefore, in patients who suffer both conditions (myasthenia and epilepsy), treatment selection is difficult. We report 2 cases of patients with MG who were safely treated with lacosamide. Evidence about antiepileptic drug treatment and adverse effects in MG is reviewed. PMID- 29432287 TI - Allergy to Carbidopa. AB - BACKGROUND: D-Decarboxylase inhibitors, such as carbidopa or benserazide, have been used as adjunct therapy in Parkinson disease shortly after levodopa synthesis in the 1960s. These compounds increase intracerebral drug concentration and decrease adverse effects by blocking peripheral conversion to dopamine. Skin rash as part of an allergic reaction was previously described in subjects who were using levodopa in combination with carbidopa or benserazide; however, etiology was never clear. Allergic reactions to carbidopa have not previously been reported. METHODS: We report a case of a 77-year-old woman with a diagnosis of idiopathic Parkinson disease, who developed autonomic and dermatological signs: conjunctival injection, rhinorrhea, excessive sweating, hypertension, and pruritic generalized rash, among others, immediately after carbidopa/levodopa administration regardless of the manufacturer. Treatment with dexamethasone combined with chloropyramine hydrochloride resulted in complete resolution of the hypersensitivity reaction each time it presented. The autonomic and dermatological manifestations did not reappear after treatment was replaced with benserazide/levodopa. CONCLUSIONS: To the best of our knowledge, this is the first case report of an allergic reaction specific to carbidopa. Our case highlights the importance of identifying the source of a hypersensitivity drug response, whether it is caused by the active component or by the excipients. PMID- 29432286 TI - Effect of Concomitant Medications on the Safety and Efficacy of Extended-Release Carbidopa-Levodopa (IPX066) in Patients With Advanced Parkinson Disease: A Post Hoc Analysis. AB - OBJECTIVES: Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in "off" time, "on" time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). METHODS: ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR- and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures ("off" time and "on" time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. RESULTS AND CONCLUSIONS: Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in "off" time and "on" time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD LD formulation provides approximately an additional hour of "good" on time. PMID- 29432288 TI - Are Corticosteroid Injections Safe to Inject into Knees With Osteoarthritis?: What Are the Long-term Effects? PMID- 29432289 TI - Surgeon, Hospital, and Geographic Variation in Minimally Invasive Colectomy. AB - OBJECTIVE: To identify sources of variation in the use of minimally invasive surgery (MIS) for colectomy. BACKGROUND: MIS is associated with decreased analgesic use, shorter length of stay, and faster postoperative recovery. This study identified factors explaining variation in MIS use for colectomy. METHODS: The Statewide Planning and Research Cooperative System was queried for scheduled admissions in which a colectomy was performed for neoplastic, diverticular, or inflammatory bowel disease between 2008 and 2015. Mixed-effects analyses were performed assessing surgeon, hospital, and geographic variation and factors associated with an MIS approach. RESULTS: Among 45,714 colectomies, 68.1% were performed using an MIS approach. Wide variation in the rate of MIS was present across 1253 surgeons (median 50%, interquartile range 10.9%-84.2%, range 0.3% 99.7%). Calculating intraclass correlation coefficients after controlling for case-mix, 62.8% of the total variation in MIS usage was attributable to surgeon variation compared with 28.5% attributable to patient variation, 7% attributable to hospital variation, and 1.6% attributable to geographic variation. Surgeon years in practice since residency/fellowship completion explained 19.2% of the surgeon variation, surgeon volume explained 5.2%, hospital factors explained 0.1%, and patient factors explained 0%. CONCLUSIONS: Wide surgeon variation exists regarding an MIS approach for colectomy, and most of the total variation is attributable to individual surgeon practices-much of which is related to year of graduation. As increasing surgeon age is inversely proportional to the rate of MIS, patient referral and/or providing tailored training to older surgeons may be constructive targets in increasing the use of MIS and reducing healthcare utilization. PMID- 29432290 TI - Abstracts of Scientific Papers and Posters Presented at the Annual Meeting of the Association of Academic Physiatrists: Atlanta, Georgia; February 13-17, 2018. PMID- 29432291 TI - Long-term neurocognitive outcomes following surgery and anaesthesia in early life. AB - PURPOSE OF REVIEW: Repeated controversial and alarming statements of the potential dangers of anaesthetic agents on neurological outcomes in children continue to be issued based primarily on preclinical studies. This review assesses the current evidence of laboratory and clinical data and identifies areas of concerns. RECENT FINDINGS: Published animal and laboratory data consistently indicate that prolonged and excessive use of anaesthetic agents can lead to morphological changes and neurocognitive impairment in animals without a clear cut-off age or a superiority of one technique over another. Retrospective human studies and prospective clinical trials indicate that short exposures to anaesthesia and surgery are safe and have no effect on long-term neurological outcomes. Small and consistent continuing improvements in the perioperative period (aggregation of marginal gains) will impact on long-term neurological morbidity in humans. SUMMARY: It is biologically plausible that anaesthetic agents may induce structural changes during mammalian brain development and beyond. However, in the absence of alternatives the impact of the choice of anaesthetic drugs on long-term neurocognitive outcomes is almost certainly to be of limited relevance in humans. The underlying disease processes, surgical intervention, and trauma as well as other known perioperative factors more significantly affect these outcomes. PMID- 29432292 TI - Acute pain management in children: challenges and recent improvements. AB - PURPOSE OF REVIEW: The evidence regarding the efficacy of analgesics available to guide postoperative pain treatment in pediatric patients is limited. Opioid medications are very often an important component of pediatric postoperative pain treatment but have been associated with perioperative complications. We will focus on initiatives aiming to provide effective treatment minimizing the use of opioids and preventing the long-term consequences of pain. RECENT FINDINGS: Interpatient variability in postoperative pain is currently managed by applying protocols or by trial and error, thus often leading to patients being either undertreated or overtreated. Few evidence-based reports are available to guide the use of opioid medications in children, including the prescription of opioids after hospital discharge. Using combinations of nonopioid analgesics in a multimodal approach may limit the need for opioids, thus decreasing the risk of toxicity and dose-related side effects. There is a lack of adequate research in this field, and more specifically on identifying which patient is at higher risk of poor postoperative pain management. SUMMARY: Treatment options have evolved in recent years, including the combinations of multimodal regimens and regional anesthetic techniques. Using combinations of nonopioid analgesics in a multimodal approach may limit the need for opioids. PMID- 29432293 TI - Is spinal anaesthesia in young infants really safer and better than general anaesthesia? AB - PURPOSE OF REVIEW: Concerns regarding the potential neurotoxic effects of general anaesthesia have seen resurgence in awake spinal anaesthesia in neonates and infants. This review includes recently published data from a large prospective randomized controlled trial with view to determining if spinal anaesthesia is safer and better than general anaesthesia in this population. RECENT FINDINGS: Compared with general anaesthesia, spinal anaesthesia results in less haemodynamic instability and fewer early (<30 min) apnoeic episodes in neonates and infants undergoing inguinal herniorraphy; the overall incidence of apnoeas in the first 12 h postoperatively was similar. Neurodevelopmental outcome 2 years postoperatively was similar. An appreciable failure rate for spinal anaesthesia was confirmed. SUMMARY: Spinal anaesthesia represents a suitable alternative to general anaesthesia in neonates and infants undergoing minor surgery avoiding the need for endotracheal intubation and ventilation. Spinal anaesthesia has some advantages but a significant failure rat and has not been demonstrated to improve neurodevelopmental outcome. PMID- 29432294 TI - Intensive care practitioner: I forgot half the things I learned and the other half seems to be all wrong! PMID- 29432295 TI - Screening tools for paediatric malnutrition: are we there yet? AB - PURPOSE OF REVIEW: The development of nutritional screening tools has done much to raise the profile of nutrition and encourage healthcare practitioners to consider how to identify children at nutritional risk. However, the next challenge is to ensure nutritional screening accurately identifies those who have immediate and ongoing risk and therefore the potential to impact on it. RECENT FINDINGS: In this article, we review recent evidence which suggests that the large-scale use of these tools outside of a research setting is not always helpful. Most are highly sensitive but not particularly specific and therefore cases may be 'overdiagnosed' but also missed. It may therefore be time for nutritional screening to evolve into a process which is able to better consider the cause of risk and requirements for nutrition support with referral criteria, defined goals and outcome measures and exit criteria using a 'measure, plot, think, act' approach embedded into physician rounds. Key challenges relate to improving compliance around nutritional screening within the hospital setting and comparison of nutrition risk between centres, as well as an understanding of the barriers which prevent nutritional screening and assessment from occurring. SUMMARY: It remains to be elucidated as to whether returning to a process which embeds nutritional assessment within the medical review rather than relying on a 'nutrition score' from a screening tool is a more effective way in which to identifying those patients that are malnourished or at risk of malnutrition during their hospital stay. PMID- 29432296 TI - Gut microbiota: puppeteer of the host juvenile growth. AB - PURPOSE OF REVIEW: This review focuses on the recent discoveries about the impact of intestinal microbiota on mammalian host juvenile growth. RECENT FINDINGS: Intestinal microbiota is a powerful modulator of many facets of multicellular host's physiology. Recent results from human field studies and animal research have clearly shown that not only the nutrition, but also the intestinal microbiota impacts host postnatal growth kinetics. Absence of microbiome leads to stunted growth in mammalian gnotobiotic models and changes in the composition of the intestinal microbiota can impact the postnatal growth kinetics both positively and negatively under normal nutritional conditions as well as in undernutrition. Strikingly, specific bacterial strains are able to interact with GH/IGF-1 somatotropic axis activity, thus directly impacting host juvenile development. SUMMARY: Intestinal microbiota dictates the pace of host postnatal growth. This newly described role envisages that therapy with specific bacterial strains, together with re-nutritional strategies, might successfully alleviate the long-term sequelae of undernutrition during childhood in humans. PMID- 29432297 TI - Should fecal microbial transplantation be used in the ICU? AB - PURPOSE OF REVIEW: Maintaining gut barrier defenses, modulating immune responses, and supporting the role of commensal microbiota are major factors influencing outcome in critical illness. Of these, maintaining a commensal 'lifestyle' and preventing the emergence of a virulent pathobiome may be most important in reducing risk of infection and multiple organ failure. RECENT FINDINGS: The polymeric formulas utilized for enteral nutrition in the ICU are absorbed high in the gastrointestinal tract and may not reach the microbial burden in the cecum where their effect is most needed. The provision of a few select probiotic organisms may be insufficient to refaunate the gut and establish a 'recovery pattern,' propelling the patient toward health and homeostasis. Use of fecal microbial transplantation (FMT) appears to be a more successful strategy for replenishing the intestinal microbiome and maintaining its commensal phenotypic expression. SUMMARY: FMT has become an attractive option to mitigate multiple organ dysfunction in the ICU. This article discusses the physiology, rationale, early experience, and expectations for such therapy in the critically ill patient. PMID- 29432298 TI - Ventricular Assist Device Patients Have Different Clinical Outcomes and Altered Patterns of Bleeding with Intracranial Hemorrhage. AB - Intracranial hemorrhage (ICH) is one of the most feared complications of left ventricular assist device (LVAD) support. However, outcomes in this group have not been well described. We therefore sought to examine clinical outcomes in this patient population in comparison to those with heart failure (HF) and no LVAD, as well as those without HF or LVAD. The National Inpatient Sample database, years 2002-2012, was queried to classify patients into 3 groups: any ICH (group 1), any HF with any ICH (group 2), and any LVAD with any ICH (group 3). Clinical outcomes, hemorrhage type, neurosurgical intervention rates, and hospital factors were collected and analyzed. Group 1 consisted of 419,264 patients, group 2 had 41,186, and group 3 had 118 patients. Group 3 patients were more likely to be in large, academic medical centers, with longer length of stay and higher hospital charges. Inpatient mortality was highest in this group at 39%; however, 46.2% were ultimately discharged to home. Patients in group 3 were more likely to have a subarachnoid or intracerebral hemorrhage versus a subdural or epidural hemorrhage. Neurosurgical intervention rates did not differ between the groups. Although LVAD patients with ICH have worse clinical outcomes, the majority survived their event and nearly half were able to be discharged home. Left ventricular assist device patients also have a distinct pattern of bleeding with ICH. Additional study is required to understand risk factors for the development of ICH in this population and ideal management strategies. PMID- 29432299 TI - Comparative metaproteomics analysis shows altered fecal microbiota signatures in patients with major depressive disorder. AB - Major depressive disorder (MDD) is a highly prevalent and debilitating mental illness, which is associated with disorder of gut microbiota. However, few studies focusing on detection of the signatures of bacteria in feces of MDD patients using proteomics approach have been carried out. Here, a comparative metaproteomics analysis on the basis of an isobaric tag for relative and absolute quantification coupled with tandem mass spectrometry was carried out to explore the signature of gut microbiota in patients with MDD. Ten patients (age: 18-56 years, five women) who had MDD and a score over 20 on the Hamilton's Depression Scale and 10 healthy controls (age: 24-65 years, five women) group matched for sex, age, and BMI were enrolled. As a result, 279 significantly differentiated bacterial proteins (P<0.05) were detected and used for further bioinformatic analysis. According to phylogenetic analysis, statistically significant differences were observed for four phyla: Bacteroidetes, Proteobacteria, Firmicutes, Actinobacteria (P<0.05, for each). Abundances of 16 bacterial families were significantly different between the MDD and healthy controls (P<0.05). Furthermore, Cluster of Orthologous Groups analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that disordered metabolic pathways of bacterial proteins were mainly involved in glucose metabolism and amino acid metabolism. In conclusion, fecal microbiota signatures were altered significantly in MDD patients. Our findings provide a novel insight into the potential connection between gut microbiota and depression. PMID- 29432300 TI - Dopamine modulates striatal response to reward and punishment in patients with Parkinson's disease: a pharmacological challenge fMRI study. AB - It is well established that Parkinson's disease leads to impaired learning from reward and enhanced learning from punishment. The administration of dopaminergic medications reverses this learning pattern. However, few studies have investigated the neural underpinnings of these cognitive processes. In this study, using fMRI, we tested a group of Parkinson's disease patients on and off dopaminergic medications and matched healthy individuals. All individuals completed an fMRI cognitive task that dissociates feedback learning from reward versus punishment. The administration of dopaminergic medications attenuated blood oxygen level dependent (BOLD) responses to punishment in the bilateral putamen, in bilateral dorsolateral prefrontal cortex and the left premotor cortex. Further, the administration of dopaminergic medications resulted in a higher ratio of BOLD activity between reward and punishment trials in these brain areas. BOLD activity in these brain areas was significantly correlated with learning from punishment, but not from reward trials. Furthermore, the administration of dopaminergic medications altered BOLD activity in the right insula and ventromedial prefrontal cortex when Parkinson's disease patients were anticipating feedback. These findings are in agreement with a large body of literature indicating that Parkinson's disease is associated with enhanced learning from punishment. However, it was surprising that dopaminergic medications modulated punishment learning as opposed to reward learning, although reward learning has been directly linked to dopaminergic function. We argue that these results might be attributed to both a change in the balance between direct and indirect pathway activation in the basal ganglia as well as the differential activity of D1 versus D2 dopamine receptors. PMID- 29432301 TI - Adenovirus-delivered GFP-HO-1C[INCREMENT]23 attenuates blood-spinal cord barrier permeability after rat spinal cord contusion. AB - The blood-spinal cord barrier (BSCB) plays a key role in maintaining the microenvironment and is primarily composed of tight junction proteins and nonfenestrated capillary endothelial cells. After injury, BSCB damage results in increasing capillary permeability and release of inflammatory factors. Recent studies have reported that haem oxygenase-1 (HO-1) fragments lacking 23 amino acids at the C-terminus (HO-1C[INCREMENT]23) exert novel anti-inflammatory and antioxidative effects in vitro. However, no study has identified the role of HO 1C[INCREMENT]23 in vivo. We aimed to investigate the protective effects of HO 1C[INCREMENT]23 on the BSCB after spinal cord injury (SCI) in a rat model. Here, adenoviral HO-1C[INCREMENT]23 (Ad-GFP-HO-1C[INCREMENT]23) was intrathecally injected into the 10th thoracic spinal cord segment (T10) 7 days before SCI. In addition, nuclear and cytoplasmic extraction and immunofluorescence staining of HO-1 were used to examine the effect of Ad-GFP-HO-1C[INCREMENT]23 on HO-1 nuclear translocation. Evan's blue staining served as an index of capillary permeability and was detected by fluorescence microscopy at 633 nm. Western blotting was also performed to detect tight junction protein expression. The Basso, Beattie and Bresnahan score was used to evaluate kinematic functional recovery through the 28th day after SCI. In this study, the Ad-GFP-HO-1C[INCREMENT]23 group showed better kinematic functional recovery after SCI than the Ad-GFP and Vehicle groups, as well as smaller reductions in TJ proteins and capillary permeability compared with those in the Ad-GFP and Vehicle groups. These findings indicated that Ad-GFP-HO-1C[INCREMENT]23 might have a potential therapeutic effect that is mediated by its protection of BSCB integrity. PMID- 29432303 TI - Utility of Echocardiography as Screening for Late-onset Anthracycline-induced Cardiotoxicity in Pediatric Cancer Survivors: Observations from the First Decade After End of Therapy. AB - Current screening guidelines are available for anthracycline-induced cardiotoxicity. However, the utility of echocardiogram screening for late-onset anthracycline cardiotoxicity especially in the decade immediately after end of therapy is debatable. A retrospective chart review of patients seen in the Thriving after Cancer Clinic at Rady Children's Hospital January 2006 to December 2013 was performed. Treatment data, echocardiogram results, cardiology referral notes and cardiac medication data were abstracted from anthracycline-exposed survivors. Descriptive and univariate comparative statistics were performed. Of 368 patients (45% female, median 5.3 y old at diagnosis [range 0 to 18.3], median 5.0 y from end of therapy [EOT] [range 0 to 18.2]), a total of 4 patients (10 year cumulative incidence after EOT 1.3%; 95% confidence interval, 0.1%-19.7%) required cardiac medication for late-onset cardiotoxicity (>1 y after EOT). Those requiring medication for late-onset cardiotoxicity were exposed to more anthracyclines than survivors without cardiotoxicity (median, 360 mg/m [range, 300 to 375 mg/m] vs. 182 mg/m [range, 26 to 515 mg/m], P=0.009). None had neck or chest radiation. In this population, medication initiation for late-onset anthracycline cardiotoxicity was limited predominantly to the first 3 years after EOT, with the next >13 years after EOT. These findings add to the growing body of literature assessing current guidelines to inform improvements in screening practices of survivorship providers. PMID- 29432302 TI - Allogeneic Matched Related Donor Bone Marrow Transplantation for Pediatric Patients With Severe Aplastic Anemia Using "Low-dose" Cyclophosphamide, ATG Plus Fludarabine. AB - BACKGROUND: The combination of cyclophosphamide (CY) and antithymocyte globulin (ATG) has been used as a standard conditioning regimen for matched related donor transplantation in patients with severe aplastic anemia. PROCEDURE: To decrease the regimen-related toxicity while maintaining appropriate engraftment and survival rates, fludarabine (FLU) was added to the regimen. Four pediatric patients received matched related donor bone marrow transplantation with CY (50 mg/kg*2) (instead of the 50 mg/kg*4 standard dosing), equine ATG (30 mg/kg*3), with the addition of FLU (30 mg/m*4). Graft versus host disease (GvHD) prophylaxis included a calcineurin inhibitor and methotrexate. RESULTS: No grade 4 acute toxicities occurred during the first 30 days after transplant. All patients engrafted with normalization of peripheral blood counts and transfusion independence. One patient developed grade 1 to 2 acute GvHD, followed by chronic GvHD that resolved. With a median follow-up of 41.7 months, all 4 patients are alive and transfusion free, with complete donor chimerism. This combination of a low-dose CY/ATG+FLU regimen was overall very well tolerated and contributed toward a successful outcome including engraftment, chimerism, and survival. CONCLUSION: This small pilot study shows that this cytoreductive regimen could be considered as the standard of care for transplantation of pediatric patients with aplastic anemia from HLA-matched siblings. PMID- 29432304 TI - Anemia in Adolescents and Young Adult Patients With Congenital Heart Disease. AB - INTRODUCTION: Despite anemia in acquired heart disease being a common problem, little is known in patients with congenital heart disease (CHD). METHODS: In total, 544 consecutive stable noncyanotic CHD patients were studied to determine demographic, clinical, and analytic parameters. Anemia was defined as a condition in which hemoglobin concentration was <13 g/dL in male individuals and <12 g/dL in female individuals. RESULTS: In total, 49 (9%) CHD patients had anemia. Patients with complex anatomy had the highest prevalence of anemia (33%). The median hemoglobin concentration was 14.4 (13.5 to 15.6) mg/dL. Of the total anemic CHD patients, 21 of 49 (43%) were microcytic (mean corpuscular volume <84 fL) and 46 of 49 (94%) had a mean corpuscular volume under 95 fL. Oral anticoagulation, oral antiaggregation, diuretic treatment, and having valve prostheses or cardiovascular risk factors, such as arterial hypertension or diabetes mellitus, did not reach statistical significance between anemic and nonanemic CHD patients. Multivariate analyses determined as risk factors for anemia a worse New York Heart Association functional class (patients in class >II/IV) (odds ratio [OR], 8.37; 95% confidence interval [CI], 1.69-41.35), N terminal proB-type natriuretic peptide levels >125 pg/mL (OR, 7.90; 95% CI, 2.88 21.69), and apoferritn levels below 15 ng/mL (OR, 0.21; 95% CI, 0.09-0.50). The Kaplan-Meier survival analysis showed no significant differences in mortality between anemic and nonanemic CHD patients (P=0.143). CONCLUSIONS: The incidence of anemia in CHD patients is similar to that of the normal population and iron deficiency anemia accounts for most of the cases. There were no significant differences in mortality between CHD patients with and without anemia. PMID- 29432305 TI - Pediatric Bronchial Carcinoid Tumors: A Case Series and Review of the Literature. AB - Bronchial carcinoid tumor, while rare, remains the most common primary malignant lung tumor in children. We present a retrospective analysis of 7 patients with typical bronchial carcinoid tumors diagnosed at 2 pediatric tertiary care referral centers between 1990 and 2014. The most common presenting symptom was pneumonia, followed by respiratory distress. Somatostatin scans were performed in selected patients. All patients had negative resection margin following surgery and were alive without disease at last follow-up. Typical carcinoid tumors have a good prognosis following definitive surgical resection. A review of published literature on pediatric bronchial carcinoid tumors is provided. PMID- 29432306 TI - Parvovirus B19-associated Hemophagocytic Lymphohistiocytosis in a Patient With Glucose-6-phosphate Dehydrogenase Deficiency. AB - We report a case of a 12-year-old male with glucose-6-phosphate dehydrogenase deficiency presenting with clinical signs of sepsis and pancytopenia. Investigations revealed parvovirus B19 (PVB19)-associated hemophagocytic lymphohistiocytosis (HLH). The patient recovered fully and quickly with symptomatic treatment. Current evidence suggests that PVB19-associated HLH has a favorable prognosis. Mild undiagnosed cases of HLH may be the cause of pancytopenia in PVB19 infections. PMID- 29432307 TI - Extranodal Hodgkin Lymphoma of the Bone Marrow Without Lymphadenopathy and Unusual Cytogenetic Translocation. PMID- 29432308 TI - ABVD Without Radiation for Newly Diagnosed Pediatric and Young Adult Patients With Hodgkin Lymphoma: A Single Center Retrospective Analysis of 28 Consecutive Patients. AB - Hodgkin lymphoma (HL) is the most common malignancy affecting adolescents and young adults. Treatment with a combination of chemotherapy and radiation results in cure rates of >90%. However, radiation therapy causes significant late effects and avoiding radiation entirely for patients who respond to chemotherapy is an accepted strategy. Since 2011, 28 consecutive patients diagnosed with classic HL have been treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for 4 to 6 cycles. Patients who achieved a complete metabolic response (CMR) as assessed by [F] fluorodeoxyglucose positron emission tomography by the end of chemotherapy did not receive radiation. Among the 27 evaluable patients, 26/27 (96.2%) achieved a CMR with ABVD alone with 24/27 (88.9%) having achieved a CMR after 2 cycles. Event-free survival at 5 years is 90.5% and overall survival is 100% with a median follow-up time of 22.4 and 22.1 months, respectively. Treating pediatric and young adult HL patients with ABVD alone results in CMRs in >95% of patients. Patients who were refractory to ABVD or relapsed after treatment eventually achieved remission with a combination of standard and novel salvage therapies. This regimen demonstrates the feasibility of avoiding upfront radiation in newly diagnosed pediatric HL patients. PMID- 29432309 TI - Maternal Exposure to Pesticides, Paternal Occupation in the Army/Police Force, and CYP2D6*4 Polymorphism in the Etiology of Childhood Acute Leukemia. AB - Epidemiologic studies have suggested that parental occupations, pesticide use, environmental factors, and genetic polymorphism are involved in the etiology of childhood acute leukemia (CAL). In total, 116 cases of CAL and 162 controls were recruited and submitted to blood drawing to assess the presence of genetic polymorphisms. Parental occupations, pesticides exposure, and other potential determinants were investigated. Increased risk for CAL was associated with prenatal maternal use of insecticides/rodenticides (odds ratio [OR]=1.87; 95% confidence intervals [CI], 1.04-3.33), with subjects living <100 m from pesticide treated fields (OR=3.21; 95% CI, 1.37-7.53) and with a paternal occupation as traffic warden/policeman (OR=4.02; 95% CI, 1.63-9.87). Associations were found between CAL and genetic polymorphism of CYP2D6*4 for homozygous alleles (mutant type/mutant type: OR=6.39; 95% CI, 1.17-34.66). In conclusion, despite the small sample size, maternal prenatal exposure to pesticides, paternal occupation as a traffic warden/police officer, and CYP2D6*4 polymorphism could play a role in the etiology of CAL. PMID- 29432310 TI - A Congenital Case of Ependymoblastoma: A Rare and Aggressive Brain Tumor. AB - Congenital brain tumors are rare, representing <2% of all childhood brain tumors. Of these, ependymoblastoma is a profoundly aggressive embryonal brain tumor that is included in the diagnostic entity known as an embryonal tumor with multilayered rosettes. This report of a congenital ependymoblastoma diagnosed at birth aims to highlight how much remains unknown about embryonal tumor with multilayered rosettes and the devastating prognosis of this condition. Despite recent advancements made in identifying molecular targets for therapy, this tumor continues to have a high rate of recurrence with few successful treatment options, especially when diagnosed in the newborn period. PMID- 29432311 TI - A Rare Cause of Secondary Immunodeficiency: Generalized Lymphatic Anomaly. PMID- 29432312 TI - Survival Following Tumor Recurrence in Children With Medulloblastoma. AB - Medulloblastoma is the most common malignant brain tumor in children. Published survival rates for this tumor are ~70%; however, there is limited published information on outcome after disease recurrence. This was an observational study which included all persons under the age of 18 years diagnosed with medulloblastoma from 1990 to 2009 inclusive in Canada. Data collected included date of diagnosis, age at diagnosis, sex, stage, pathology, treatment, recurrence, and current status. Survival rates were determined. In total, 550 cases were ascertained meeting the study criteria. The overall survival rate at 1 year was 83.6%+/-1.7%, at 3 years 77.2%+/-1.9%, and at 5 years 72.5%+/-20%. The progression-free survival rates were 78%+/-1.9%, 70%+/-2.1%, and 69+/-2.1% at 1, 3, and 5 years from initial diagnosis. In total, 173 (31.2%) were reported to have had tumor recurrence and 23 (11.4%) of them were alive at the time of survey with an overall survival rate at 1 year of 38.3%+/-4%, at 2 years of 16.9%+/ 3.3%, and at 5 years of 12.4%+/-2.8%. Our data confirm that children with recurrent medulloblastoma have a poor prognosis, supporting the need for novel treatment approaches for this group. PMID- 29432313 TI - Cup-like Blasts in 2 Pediatric Patients With NPM-1-Positive Acute Myeloid Leukemia. AB - Cup-like phenotype is defined in some subtypes of acute myeloid leukemia (AML) and have been associated with NPM-1 and/or FLT3-ITD positivity in the presence of normal karyotype in >60% of patients. Herein we present two pediatric AML-M1 patients with cuplike nuclear morphology and NPM-1 positivity. Both patients were negative for FLT3-ITD mutation. NPM-1 mutation and FLT3-ITD mutation should be kept in mind in AML patients with cup-like blast morphology as these two mutations are important molecular markers for prognosis, risk group classification and also for response to treatment. PMID- 29432314 TI - Retroperitoneal Angiomatoid Fibrous Histiocytoma Presenting as a Recurrent Spontaneous Retroperitoneal Hemorrhage in a 9-Year-Old Boy. AB - Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that typically presents in children and young adults. Occurrence outside of the extremities and the head and neck region is exceedingly rare. We report the case of a 9-year-old boy who presented with recurrent retroperitoneal hemorrhage initially thought to be a manifestation of an underlying bleeding disorder. After comprehensive diagnostic work-up, including multiple negative biopsies, the patient underwent surgical resection of an extensively hemorrhagic intramuscular mass and to date remains well. Pathologic examination confirmed AFH with EWSR1 gene rearrangement. This first documented report of an AFH in a retroperitoneal location in a child highlights the diagnostic difficulties and clinical challenges of AFH arising in an atypical location. PMID- 29432316 TI - Pediatric Supracondylar Humerus Fractures: Does After-Hours Treatment Influence Outcomes? AB - OBJECTIVE: To compare the outcomes of pediatric supracondylar humerus fractures treated during daytime hours to those treated after-hours. DESIGN: Retrospective. SETTING: Academic Level I trauma center. PATIENTS/PARTICIPANTS: Two hundred ninety-eight pediatric patients treated with surgical reduction and fixation of closed supracondylar fractures were included. INTERVENTION: Seventy-seven patients underwent surgery during daytime hours (06:00-15:59 on weekdays). One hundred eighty-six patients underwent surgery after-hours (16:00-05:59 on weekdays and any surgery on weekends or holidays). MAIN OUTCOME MEASURES: Surgeon subspecialty, operative duration, and radiographic and clinical outcomes, including range of motion and carrying angle, were extracted from the patient medical records. RESULTS: There were no patient-related demographic differences between the daytime hours and after-hours groups. Daytime surgery was more likely to be performed by a pediatric orthopaedic surgeon than after-hours surgery. Fractures treated after-hours had more severe injury patterns. After-hours surgery was not independently associated with rate of open reduction, operative times, complications, achievement of functional range of motion, or radiographic alignment. A late-night surgery subgroup analysis demonstrated an increased rate of malunion in patients undergoing surgery between the hours of 23:00 and 05:59. CONCLUSIONS: There is no difference in the operative duration or outcomes after surgical treatment of pediatric supracondylar humerus fractures performed after hours when compared with daytime surgery. However, late-night surgery performed between 23:00 and 05:59 may be associated with a higher rate of malunion. Surgeons can use these data to make better-informed decisions about the timing of surgery in this patient population. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29432315 TI - Dexrazoxane Significantly Reduces Anthracycline-induced Cardiotoxicity in Pediatric Solid Tumor Patients: A Systematic Review. AB - Cardiotoxicity is a dose-limiting and potentially lethal complication of anthracycline administration. Previous studies failed to determine definitive toxic doses or cardioprotective factors. Current dosing strategies may utilize unnecessarily high anthracycline doses, such that survival benefit may not outweigh increased toxicity rates. A systematic review of randomized controlled trials and prospective/retrospective studies investigating anthracycline treatment in pediatric solid tumors was performed from PubMed/MEDLINE and Cochrane databases. Generalized linear models mapping survival, cardiotoxicity, and cardiotoxicity-free survival adjusted for male-to-female ratio, follow-up time, and concomitant chemotherapeutic drugs or cardioprotective agents (dexrazoxane) were generated using R. Survival rose linearly with increasing cumulative anthracycline dose whereas cardiotoxicity demonstrated exponential increases both without (dose, >200 mg/m) and with (dose, >400 mg/m) dexrazoxane. Maximum cardiotoxicity-free survival was 268.2 mg/m without and 431.8 mg/m with dexrazoxane. Despite increasing cardiotoxicity-free dose by >150 mg/m, dexrazoxane minimally improved projected survival (71.9% vs. 75.4%). Cardiotoxicity increased linearly as a function of follow-up time with rates doubling from 5 to 20 years, without evidence of plateau. On the basis of our model, current dosing regimens-doxorubicin doses >375 mg/m without dexrazoxane overvalue increased anthracycline administration and may contribute to devastating cardiotoxicity. The linear increase of cardiotoxicity without evidence of plateau confirms the necessity for lifelong cardiac monitoring. PMID- 29432317 TI - Outcomes of Early Surgical Intervention in Geriatric Proximal Femur Fractures Among Patients Receiving Direct Oral Anticoagulation. AB - OBJECTIVE: To evaluate the prehospital use of direct oral anticoagulant (DOAC) agents on the outcomes of early surgical fixation of a geriatric hip fracture. DESIGN: Case control study. SETTING: Two academic Level 1 trauma centers. INTERVENTION: Early (<48 h) surgical fixation of a geriatric proximal femur fracture. PATIENTS: Nineteen patients receiving Pradaxa (dabigatran), Eliquis (apixaban), or Xarelto (rivaroxaban) who underwent surgery between 2010 and 2015 and 74 control patients. MAIN OUTCOME MEASUREMENTS: Time to surgery, transfusion rates, changes in hemoglobin levels, postoperative complications, readmission rates, and survival out to 1 year. RESULTS: There were no differences in transfusions, changes in hemoglobin levels, wound complications, or survival at any time point. Patients on DOAC had a longer delay to reach the operating room (28.9 h v 21.4 h P = 0.03) and were more likely to undergo readmission within 30 days (21% vs. 5.3% P = 0.05). No readmissions occurred for a complication of the surgical site, bleeding, or a venous thromboembolic event. CONCLUSIONS: Geriatric patients with hip fractures receiving DOAC before admission did not demonstrate worse outcomes with early surgical intervention. The increased readmission rate in this population seems attributable to the underlying cardiac conditions for which the patients were receiving anticoagulation. These results suggest that the delay recommended for patients using a DOAC before elective procedures may be unwarranted in the surgically urgent setting of a hip fracture. Additional studies will be necessary for appropriate meta-analysis. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29432318 TI - Helical Blade or the Integrated Lag Screws: A Matched Pair Analysis of 100 Patients With Unstable Trochanteric Fractures. AB - OBJECTIVES: To compare the radiological and clinical results with PFNA-II and InterTan in the treatment of unstable trochanteric fractures in the elderly. DESIGN: Retrospective, multicenter, matched pair. SETTING: Three tertiary level trauma centers. PATIENTS: Hundred elderly patients who underwent intramedullary stabilization with either the PFNA-II or the InterTan for osteoporotic unstable trochanteric fractures. INTERVENTIONS: Fifty matched pairs consisting of OTA/AO A2 and A3 fractures were created from a cohort of 290 patients who underwent internal fixation for unstable trochanteric fractures with the PFNA-II or InterTan nails. OUTCOME MEASUREMENTS: Radiological assessment was performed to compare union rates, varus collapse, medial or lateral screw/blade migration, and cut-out. Functional outcome at 1 year was assessed and compared using Harris hip score, Timed Up and Go test, and the mobility score. RESULTS: Union rates, fracture reduction, neck shaft angle, and tip-apex distance were similar in both groups. The PFNA-II group had a significantly higher degree of lateral sliding of the helical blade (P < 0.001). The InterTan group had a better Harris hip score, mobility score, Timed Up and Go test scores, and abductor strength (P < 0.05) at 1 year. The incidence of varus collapse and medial blade migration were higher in the PFNA-II group (P > 0.05). The need for repeat surgery to address surgery related complications were significantly high in the PFNA-II group (P = 0.045). CONCLUSIONS: The InterTan may provide superior functional outcome and reduced complications than does the Proximal Femur Nail - Antirotation in elderly patients with unstable trochanteric fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29432319 TI - Are Variable-Angle Locking Screws Stable Enough to Prevent Calcaneal Articular Surface Collapse? A Biomechanical Study. AB - PURPOSE: To compare fixed- or variable-angle locking screws in calcaneal fracture plates using a sawbones biomechanical model. METHODS: Intra-articular calcaneal fractures were created in synthetic bones. Reduction and stabilization was performed with 3 different plates. In group A, a fixed-angle locking plate was used with screws fastened perpendicularly to the plate (3.5 LCP, DePuySynthes). In groups B and C (2.7 VA-LCP, DePuySynthes and 3.5 Aptus, Medartis, respectively), fracture fixation was performed using variable-angle locking plates. Biomechanical testing was conducted. Displacement of the subtalar articular surface, stiffness, maximum displacement, change in the angle of Gissane, and mode of failure under cyclic loading at 200 N, 600 N, and 1000 N (500 cycles each) were determined. RESULTS: No statistically significant difference of articular surface dislocation under cyclic loading was detected. The stiffness and maximum displacement did not reveal any disparity as well. The change in the angle of Gissane showed only minor displacement of the articular surface. CONCLUSION: In our study, the resistance of variable-angle locking plates against articular surface displacement was similar to fixed-angle locking screws. PMID- 29432320 TI - Segmental Tibia Fractures: An Analysis of Complication and Healing Rates. AB - OBJECTIVES: To determine the most commonly associated injuries, complications, and healing rates of patients sustaining segmental tibial shaft fractures. DESIGN: Retrospective review. SETTING: Two Level I trauma centers. PATIENTS: A total of 108 patients with segmental tibial shaft fractures were identified between 2005 and 2013. INTERVENTION: None. MAIN OUTCOME MEASURES: Demographics, injury characteristics, treatments, and complications. Categories were evaluated and analyzed based on frequency of occurrence. Time to union was assessed based on serial radiographs. RESULTS: A total of 108 patients met the inclusion criteria. All fractures were OTA/AO type 42C2. Seventy-three patients (68%) sustained open fractures. There were 34 patients (31%) who had compartment syndrome. The median Injury Severity Score was 27 (range 4-75). Ninety-five patients underwent reamed intramedullary nailing of the tibia, 4 underwent open reduction internal fixation, and 2 patients were definitively treated with external fixation. The median length of hospital stay was 11 days (range 3-48). Outcome data (time to union/delayed union/malunion) was available for 101 patients. The median time to union was 26 weeks (range 14-48). The delayed union rate was 40% (40/101) and the nonunion rate was 10% (10/101). CONCLUSION: Segmental tibial shaft fractures are often associated with severe polytrauma and are most often open fractures. Reamed intramedullary nailing after appropriate resuscitative and stabilization methods can result in excellent alignment and union in these fractures, with low nonunion and infection rates at 1 year. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29432321 TI - Evaluation of Intramedullary Fixation for Pediatric Femoral Shaft Fractures in Developing Countries. AB - OBJECTIVES: To report the clinical results after treatment of pediatric femoral shaft fractures with the SIGN Fracture Care International (SIGN) pediatric and standard fin nails. DESIGN: Retrospective review of prospectively collected data. SETTING: Sixteen global SIGN centers from 2003 to 2013. PATIENTS/PARTICIPANTS: One hundred twelve pediatric patients who sustained a diaphyseal pediatric femoral shaft fracture. INTERVENTION: Intramedullary fixation with the standard or pediatric SIGN nail. MAIN OUTCOME MEASUREMENTS: Main outcome measurements include clinical and radiographic healing and postoperative complications. RESULTS: The mean age of the pediatric fin patients was 9.4 years (4-15) and 11.2 years (4-18) for the standard fin patients. Painless weight bearing was achieved in 94.7% and 94.5% of the patients at the last follow-up. In total, 23 patients had repeat surgery for the removal of implant. Failure of implant with bending of the nail and/or a valgus or varus deformity (>10 degrees) was noted in 7/57 (12.3%) of the patients treated with the pediatric fin nail, of which 6/7 were >10 years old. Five of these 7 patients were classified as technical errors attributed to inadequate nail diameter, length, or initial malreduction. No complications were noted at any age in the standard fin nail group. CONCLUSIONS: In resource-poor settings, SIGN pediatric fin and standard fin nails seem to be an effective treatment option for femoral shaft fractures. In patients with larger canals, the surgeon should consider using the standard fin nail for improved stability and to minimize potential complications. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29432322 TI - Acute Compartment Syndrome: An Expert Survey of Orthopaedic Trauma Association Members. AB - OBJECTIVES: The goal of this study was to describe current opinions of orthopaedic trauma experts regarding acute compartment syndrome (ACS). DESIGN: Web-based survey. PARTICIPANTS: Active Orthopaedic Trauma Association (OTA) members. METHODS: A 25-item web-based questionnaire was advertised to active members of the OTA. Using a cross-sectional survey study design, we evaluated the perceived importance of ACS, as well as preferences in diagnosis and treatment. RESULTS: One hundred thirty-nine of 596 active OTA members (23%) completed the survey. ACS was believed to be clinically important and with severe sequelae, if missed. Responses indicated that diagnosis should be based on physical examination in an awake patient, and that intracompartmental pressure testing was valuable in the obtunded or unconscious patient. The diagnosis of ACS with monitoring should be made using the difference between diastolic blood pressure and intracompartmental pressure (DeltaP) of <=30 mm Hg. Once ACS is diagnosed, respondents indicated that fasciotomies should be performed as quickly as is reasonable (within 2 hours). The consensus for wound management was closure or skin grafting within 1-5 days later, and skin grafting was universally recommended if closure was delayed to >7 days. CONCLUSIONS: ACS is a challenging problem with poor outcomes if missed or inadequately treated. OTA members demonstrated agreement to many diagnostic and treatment choices for ACS. LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of the levels of evidence. PMID- 29432323 TI - Changes in Motor Coordination Induced by Local Fatigue during a Sprint Cycling Task. AB - PURPOSE: This study investigated how muscle coordination is adjusted in response to a decrease in the force-generating capacity of one muscle group during a sprint cycling task. METHODS: Fifteen participants were tested during a sprint before and after a fatigue electromyostimulation protocol was conducted on the quadriceps of one leg. Motor coordination was assessed by measuring myoelectrical activity, pedal force, and joint power. RESULTS: The decrease in force-generating capacity of the quadriceps (-28.0% +/- 6.8%) resulted in a decrease in positive knee extension power during the pedaling task (-34.4 +/- 30.6 W; P = 0.001). The activity of the main nonfatigued synergist and antagonist muscles (triceps surae, gluteus maximus and hamstrings) of the ipsilateral leg decreased, leading to a decrease in joint power at the hip (-30.1 +/- 37.8 W; P = 0.008) and ankle (-20.8 +/- 18.7 W; P = 0.001). However, both the net power around the knee and the ability to effectively orientate the pedal force were maintained during the extension by reducing the coactivation and the associated negative power produced by the hamstrings. Adaptations also occurred in flexion phases in both legs, exhibiting an increased power (+17.9 +/- 28.3 [P = 0.004] and +19.5 +/- 21.9 W [P = 0.026]), associated with an improvement in mechanical effectiveness. CONCLUSION: These results demonstrate that the nervous system readily adapts coordination in response to peripheral fatigue by (i) decreasing the activation of adjacent nonfatigued muscles to maintain an effective pedal force orientation (despite reducing pedal power) and (ii) increasing the neural drive to muscles involved in the flexion phases such that the decrease in total pedal power is limited. PMID- 29432324 TI - Classification of Intensity in Team Sport Activity. AB - PURPOSE: This study aimed to assess the efficacy of critical metabolic power derived from variable-speed movement for classifying intensity in team sport activity. METHODS: Elite male hockey players (n = 12) completed a series of time trials (100 yards, 400 yards, 1500 yards) and a 3-min all-out test to derive both critical speed (CS) and critical power (CP). Heart rate (HR), blood lactate, and rating of perceived exertion were measured during each protocol. Participants (n = 10) then played two competitive hockey matches. Time spent greater than 85% of maximum HR was compared with time spent above CS (from the time trials) and CP (from the 3-min test). RESULTS: Between protocols, there was a moderate and nonsignificant association for CS (r = 0.359, P = 0.252) and a very large association for CP (r = 0.754, P = 0.005); the association was very large for peak HR (r = 0.866, P < 0.001), large for blood lactate (r = 0.506, P = 0.093), and moderate for rating of perceived exertion (rho = 0.441, P = 0.152). Time trials produced higher CS (4.3 vs 2.0 m.s, P < 0.001) and CP (18.3 vs 10.5 W.kg, P < 0.001) values than did the 3-min test. In matches, there was a very large association between time spent above 85% of maximum HR and time spent above both CS (r = 0.719, P < 0.001) and CP (r = 0.867, P < 0.001). This relationship was stronger for CP compared with CS (Z = 3.29, P = 0.0007). CONCLUSIONS: Speed is not an appropriate parameter for the classification of team sport activity comprising continual changes in speed and direction; however, critical metabolic power derived from variable-speed activity seems useful for this purpose. PMID- 29432325 TI - Let the Pleasure Guide Your Resistance Training Intensity. AB - PURPOSE: The purpose of this study was to evaluate the feasibility and reliability of the Feeling Scale (FS) to self-regulate resistance training (RT) intensity. METHODS: Sixteen sedentary men (39.7 +/- 7.5 yr) performed 3 familiarization sessions, 2 one-repetition maximum (1RM) testing, and 16 RT sessions (four sessions for each FS descriptor; randomized). The FS descriptors were "very good" (FS + 5), "good" (FS + 3), "fairly good" (FS + 1), and "fairly bad" (FS - 1). Resistance exercises were leg press, chest press, knee extension, and seated biceps curl. Participants were instructed to select a load associated with the verbal/numerical descriptor of the FS to perform three sets of 10 repetitions. RESULTS: Participants lifted a significantly greater %1RM as the FS level decreased from FS + 5 to FS - 1 (P < 0.001). The mean %1RM values for the FS descriptors of +5, +3, +1, and -1, respectively, were as follows: leg press, 42.5% +/- 9.5%, 58.2% +/- 7.4%, 69.9% +/- 7.0%, and 80.7% +/- 5.4%; knee extensor, 37.4% +/- 9.6%, 54.5% +/- 9.3%, 65.3% +/- 8.7%, and 78.2% +/- 5.9%; chest press, 42.4% +/- 11.3%, 54.9% +/- 11.4%, 66.4% +/- 12.6%, and 78.2% +/- 13.5%; and biceps curl, 39.0% +/- 8.1%, 54.0% +/- 9.7%, 68.4% +/- 5.9%, and 83.2% +/- 3.0%. The interclass correlation coefficient over the four experimental sessions ranged from 0.73 to 0.99 for %1RM and from 0.77 to 0.99 for weight lifted, with a coefficient of variation of approximately 7%, 4%, 2%, and 2% for FS descriptors of +5, +3, +1, and -1, respectively. CONCLUSION: This study is the first to demonstrate that the FS can be used to self-regulate exercise intensity in RT. The lower the FS descriptor, the higher the weight lifted. In addition, the load self-selected for each FS descriptor was reliable across the four sessions. PMID- 29432326 TI - Exercise Improves Physical Activity and Comorbidities in Obese Adults with Asthma. AB - INTRODUCTION: Obese adults with asthma have an increased number of comorbidities and reduced daily life physical activity (DLPA), which may worsen asthma symptoms. Exercise is recommended to improve asthma outcomes; however, the benefits of exercise for psychosocial comorbidities and physical activity levels in obese adults with asthma have been poorly investigated. OBJECTIVE: This study aimed to assess the effects of exercise on DLPA, asthma symptoms, and psychosocial comorbidities in obese adults with asthma. METHODS: Fifty-five grade II obese adults with asthma were randomly assigned to either a weight loss program + exercise program (WL + E group, n = 28) or a weight loss program + sham (WL + S group, n = 27). The WL + E group incorporated aerobic and resistance muscle training into the weight loss program (nutrition and psychological therapies), whereas the WL + S group performed breathing and stretching exercises. DLPA, asthma symptoms, sleep quality, and anxiety and depression symptoms were quantified before and after treatment. RESULTS: After 3 months, the WL + E group presented a significant increase in daily step counts (3068 +/- 2325 vs 729 +/- 1118 steps per day) and the number of asthma symptom-free days (14.5 +/- 9.6 vs 8.6 +/- 11.4 d.month) compared with the WL + S group. The proportion of participants with improvements in depression symptoms (76.4% vs 16.6%) and a lower risk of developing obstructive sleep apnea (56.5% vs 16.3%) was greater in the WL + E group than that in the WL + S group (P < 0.05). Significant improvements in sleep efficiency (6.6% +/- 5.1% vs 1.3% +/- 4.7%) and latency ( 3.7 +/- 5.9 vs 0.2 +/- 5.6 min) were also observed in the WL + E group. CONCLUSIONS: Our results strongly suggest that exercise training plus a weight loss program improves DLPA, sleep efficiency, and depression and asthma symptoms in obese adults with asthma. PMID- 29432327 TI - Mixed-methods development of a new patient-reported outcome instrument for chronic low back pain: part 1-the Patient Assessment for Low Back Pain - Symptoms (PAL-S). AB - We describe the mixed-methods (qualitative and quantitative) development and preliminary validation of the Patient Assessment for Low Back Pain-Symptoms (PAL S), a patient-reported outcome measure for use in chronic low back pain (cLBP) clinical trials. Qualitative methods (concept elicitation and cognitive interviews) were used to identify and refine symptom concepts and quantitative methods (classical test theory and Rasch measurement theory) were used to evaluate item- and scale-level performance of the measure using an iterative approach. Patients with cLBP participated in concept elicitation interviews (N = 43), cognitive interviews (N = 38), and interview-based assessment of paper-to electronic mode equivalence (N = 8). A web-based sample of patients with self reported cLBP participated in quantitative studies to evaluate preliminary (N = 598) and revised (n = 401) drafts and a physician-diagnosed cohort of patients with cLBP (N = 45) participated in preliminary validation of the measure. The PAL S contained 14 items describing symptoms (overall pain, sharp, prickling, sensitive, tender, radiating, shocking, shooting, burning, squeezing, muscle spasms, throbbing, aching, and stiffness). Item-level performance, scale structure, and scoring seemed to be appropriate. One-week test-retest reproducibility was acceptable (intraclass correlation coefficient 0.81 [95% confidence interval, 0.61-0.91]). Convergent validity was demonstrated with total score and MOS-36 Bodily Pain (Pearson correlation -0.79), Neuropathic Pain Symptom Inventory (0.73), Roland-Morris Disability Questionnaire (0.67), and MOS 36 Physical Functioning (-0.65). Individual item scores and total score discriminated between numeric rating scale tertile groups and painDETECT categories. Respondent interpretation of paper and electronic administration modes was equivalent. The PAL-S has demonstrated content validity and is potentially useful to assess treatment benefit in cLBP clinical trials. PMID- 29432328 TI - Impact of Tourette Syndrome on School Measures in a Nationally Representative Sample. AB - OBJECTIVE: Children with Tourette syndrome (TS) are at risk for a variety of co occurring conditions and learning and school problems. The purpose of this study was to determine the impact of TS and co-occurring conditions on school measures. METHODS: Parent-reported data from the 2007-2008 and 2011-2012 National Survey of Children's Health were combined (n = 129,353 children aged 6-17 yrs). Parent report of health care provider diagnosis of TS; co-occurring mental, emotional, and behavioral conditions; learning and language conditions; and school measures were assessed. School measures included type of school, individual education plan (IEP), number of school days missed, school problems, doing well in school, doing homework, and repeating a grade. Children with TS were compared with those who never had TS on school measures accounting for co-occurring conditions. RESULTS: After adjusting for demographics, compared with children without TS, children currently with TS were more likely to have an IEP, have a parent contacted about school problems, and not complete homework. After further adjusting for co occurring conditions, only IEP status remained statistically significant. Compared with children with mild TS, children with moderate or severe TS were more likely to have an IEP, repeat a grade, encounter school problems, and not care about doing well in school. CONCLUSION: Tourette syndrome severity and co occurring conditions are associated with school challenges and educational service needs. Awareness among health care providers, teachers and parents of the potential challenges related to both TS and co-occurring conditions would help to best support the child's education. PMID- 29432330 TI - A Case of Acute Problem Gambling Associated With Agomelatine. PMID- 29432329 TI - A Review of Phytoestrogens and Their Association With Pelvic Floor Conditions. AB - INTRODUCTION: Urinary incontinence, pelvic organ prolapse, and fecal incontinence are pelvic floor disorders (PFDs) disproportionately experienced by postmenopausal women. Limited data exist suggesting that phytoestrogens may have an impact on the pathophysiology and symptom of PFDs. PURPOSE OF REVIEW: The aim of the study was to review the current literature addressing the role of phytoestrogens on PFDs, including the pathophysiology, symptom, treatment, and possible prevention. FINDINGS: Qualifying literature spans from 2003 to 2017 and included 14 studies ranging from in vitro, animal, and observational studies to randomized clinical trials. SUMMARY: Although the literature is limited, most studies on phytoestrogens and PFDs support associations with pathophysiologic mechanisms, symptoms, and treatment for urinary incontinence and pelvic organ prolapse, but not fecal incontinence. Less is known regarding the prevention of PFDs with phytoestrogen intake over time. Overall, the potential influence of phytoestrogens on PFDs is not well understood, and more research is needed. PMID- 29432331 TI - Evaluation of the Effect of Fluvoxamine in Patients With Schizophrenia Under Risperidone Treatment: A Clinical Trial. AB - PURPOSE/BACKGROUND: The effectiveness of selective-serotonin reuptake inhibitors in the improvement of schizophrenia is a controversial issue. The aim of this study was to evaluate the effect of fluvoxamine on the symptoms of schizophrenia including positive and negative symptoms, cognitive impairment, and quality of life. METHODS/PROCEDURES: This clinical trial was performed on 68 patients with chronic schizophrenia, treated with risperidone at 22 Bahman Hospital of Qazvin, Iran during 2015 to 2016. The patients were randomly divided into control and intervention groups (34 patients per group). The control group was treated with risperidone and biperiden, whereas the intervention group received fluvoxamine, besides risperidone, and biperiden. The participants completed the Wechsler Memory Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms (SANS), and the World Health Organization Quality of Life Scale, and the findings were statistically analyzed at baseline and postintervention (8 and 10 weeks). FINDINGS/RESULTS: The mean +/- SD Wechsler Memory Scale scores in the evaluated intervals (baseline, week 8, and week 10), respectively, were 70.58 +/- 11.51, 70.76 +/- 11.36, and 70.88 +/- 11.40 in the control group and 74.76 +/- 10.56, 77.76 +/- 10.56, and 77.76 +/- 10.73 in the intervention group (F = 126.73, P <= 0.001). The difference between the groups in terms of SANS and quality of life scores was significant in the specified intervals, SANS (F = 6.36, P = 0.004), and quality of life (F = 15.13, P <= 0.001). Nevertheless, no difference was observed in terms of Scale for the Assessment of Positive Symptoms scores (P > 0.05). IMPLICATIONS/CONCLUSIONS: The results indicated that risperidone augmentation with fluvoxamine could significantly improve cognitive impairments and negative symptoms among patients with schizophrenia. Moreover, this augmentation led to higher quality of life among these patients. PMID- 29432332 TI - Impacts of Educating for Equity Workshop on Addressing Social Barriers of Type 2 Diabetes With Indigenous Patients. AB - INTRODUCTION: Health education about Indigenous populations in Canada (First Nations, Inuit, and Metis people) is one approach to enable health services to mitigate health disparities faced by Indigenous peoples related to a history of colonization and ongoing social inequities. This evaluation of a continuing medical education workshop, to enhance family physicians' clinical approach by including social and cultural dimensions within diabetes management, was conducted to determine whether participation in the workshop improved self reported knowledge, skills, and confidence in working with Indigenous patients with type 2 diabetes. METHODS: The workshop, developed from rigorous national research with Indigenous patients, diabetes care physicians, and Indigenous health medical educators, was attended by 32 family physicians serving Indigenous populations on three sites in Northern Ontario. A same-day evaluation survey assessed participants' satisfaction with workshop content and delivery. Preworkshop and postworkshop surveys consisting of 5-point Likert and open-ended questions were administered 1 week before and 3 month after the workshop. Descriptive statistics and t test were performed to analyze Likert scale questions; thematic analysis was used to elicit and cluster themes from open ended responses. RESULTS: Participants reported high satisfaction with all aspects of the workshop. Reporting improved understanding of socioeconomic (P = .002), psychosocial, and cultural factors (P = .001), participants also described adapting their clinical approach to more actively incorporating social and cultural factors and focusing on patient-centered care. DISCUSSION: The workshop was effective in shifting physician's self-reported knowledge, attitudes, and skills resulting in clinical approach modifications within social, psychosocial, and cultural domains for their Indigenous patients with diabetes. PMID- 29432334 TI - Mechanisms of Glaucoma in Exfoliation Syndrome. AB - The most important characteristic of exfoliation syndrome (XFS) is that it involves a greater risk of developing glaucoma. In comparison with other forms of open-angle glaucoma, exfoliation glaucoma is more resistant to medical therapy and progresses faster. Possible pathologic mechanisms of glaucoma development in XFS comprise: (1) elevated intraocular pressure (IOP) caused by functional impairment of aqueous humor outflow due to deposition of exfoliation material in the trabecular meshwork and trabecular cell dysfunction, (2) XFS-associated connective tissue elastosis leading to structural and functional alterations of the lamina cribrosa which increases the vulnerability toward elevated IOP and development of glaucomatous optic neuropathy, (3) elevated IOP due to closure of the anterior chamber angle accompanied by forward displacement of the crystalline lens due to zonular weakness, (4) presumable primary functional impairment of retinal ganglion cells. In addition to the discovery of lysyl oxidase-like 1, further genetic associations have been identified and knowledge related to XFS etiology and pathophysiology has markedly increased over the past 10 years. Further cell biological investigations navigated by the molecular genetics underlying XFS will eventually lead to a better understanding of the complex mechanisms of exfoliation glaucoma. PMID- 29432335 TI - Extracellular Matrix Regulation and Dysregulation in Exfoliation Syndrome. AB - Several lines of evidence, such as ultrastructural signs for activated fibrillogenesis and excessive production of elastic microfibrillar components in the anterior segment of the eye and throughout the body, indicate that exfoliation syndrome (XFS) is an elastic microfibrillopathy, leading to the accumulation of an abnormal extracellular fibrillar material (XFM). The upregulation of elastic microfibrillar components is paralleled by the selective upregulation of the cross-linking enzyme lysyl oxidase-like 1 (LOXL1) in the early phase of the disease, suggesting that LOXL1 participates in the stabilization of newly synthesized elastic proteins and finally in the stable accumulation of XFM. Whereas the excessive production of elastic proteins rises from early to late XFS stages, possibly mediated by increasing fibrogenic stimuli in the aqueous humor, LOXL1 is downregulated in late stages of the disease by as yet unknown mechanisms, possibly leading to the well-documented elastotic matrix alterations characteristic of eyes with late stage XFS. Several studies indicate complex changes of the proteolytic balance in the anterior segment of XFS eyes, characterized primarily by decreased matrix metalloproteinase-2 activity, the major aqueous matrix metalloproteinase, potentially leading to a shift from appropriate matrix turnover to progressive matrix accumulation. In contrast, in nearly all tissues of the posterior segment, XFM seems to be absent and differential gene expression is confined to the lamina cribrosa, characterized by a stage-independent, primary, and XFS-specific downregulation of LOXL1 and elastic components in XFS eyes. Concomitant with this deficiency, the laminar elastic fiber network displays prominent ultrastructural alterations, which may lead to increased vulnerability to glaucomatous damage. Various growth factors, stress conditions, or dietary factors have been supposed to potentially influence the manifestation of the disease. However, in spite of increasing knowledge, the pathogenetic factors initiating the abnormal matrix process still remain elusive. Such information would be critical for our understanding of disease progression and would disclose new options for pharmaceutical intervention at the onset of the disease. PMID- 29432333 TI - Buprenorphine Treatment for Adolescents and Young Adults With Opioid Use Disorders: A Narrative Review. AB - : In the past decade, a new cohort of adolescents and young adults with opioid use disorders (OUD) has emerged. While medications and psychosocial treatments are available, few adolescents and young adults with OUD can access and remain in treatment. Effective, practical, and scalable treatment paradigms for this young population are needed. Buprenorphine is a medication with unique pharmacological and regulatory characteristics that make it a promising component of adolescent and young adult OUD treatment models. Three randomized controlled trials and multiple observational studies have evaluated the use of buprenorphine to treat this population. However, data from these studies have not been consolidated into an up-to-date summary that may be useful to clinicians. The objective of this narrative review is to inform clinical practice by summarizing results of primary and secondary analyses from randomized controlled clinical trials and observational studies that have evaluated the use of buprenorphine to treat adolescents and young adults with OUD. Based on results from these studies, we encourage the conceptualization of OUD among youth as a chronic medical condition requiring a long-term management strategy. This includes treatment with buprenorphine in conjunction with medication-prescribing protocols that do not necessarily require daily clinic attendance for observed medication adherence. However, more study of treatment delivery models, addressing such issues as medication adherence and intensity requirements, is needed to determine practices that optimize outcomes for youth. PMID- 29432336 TI - Limited Documentation and Treatment Quality of Glycemic Inpatient Care in Relation to Structural Deficits of Heterogeneous Insulin Charts at a Large University Hospital. AB - OBJECTIVES: Insulin charts represent a key component in the inpatient glycemic management process. The aim was to evaluate the quality of structure, documentation, and treatment of diabetic inpatient care to design a new standardized insulin chart for a large university hospital setting. METHODS: Historically grown blank insulin charts in use at 39 general wards were collected and evaluated for quality structure features. Documentation and treatment quality were evaluated in a consecutive snapshot audit of filled-in charts. The primary end point was the percentage of charts with any medication error. RESULTS: Overall, 20 different blank insulin charts with variable designs and significant structural deficits were identified. A medication error occurred in 55% of the 102 audited filled-in insulin charts, consisting of prescription and management errors in 48% and 16%, respectively. Charts of insulin-treated patients had more medication errors relative to patients treated with oral medication (P < 0.01). Chart design did support neither clinical authorization of individual insulin prescription (10%), nor insulin administration confirmed by nurses' signature (25%), nor treatment of hypoglycemia (0%), which resulted in a reduced documentation and treatment quality in clinical practice 7%, 30%, 25%, respectively. CONCLUSIONS: A multitude of charts with variable design characteristics and structural deficits were in use across the inpatient wards. More than half of the inpatients had a chart displaying a medication error. Lack of structure quality features of the charts had an impact on documentation and treatment quality. Based on identified deficits and international standards, a new insulin chart was developed to overcome these quality hurdles. PMID- 29432337 TI - Improving Patient Safety Culture: A Report of a Multifaceted Intervention. AB - OBJECTIVE: The aim of the study was to improve the safety culture at a Veterans Administration hospital using evidence-based approaches. METHODS: We implemented a patient safety summit with follow-up actions. We measured safety climate before and after the summit using the Agency for Healthcare Research and Quality (AHRQ) Hospital Survey of Patient Safety Culture with modifications and the Safety Attitudes Questionnaire (SAQ). The summit brought hospital leaders together to discuss patient safety topics and relate them to our hospital. At the summit's end, hospital workgroups collectively submitted Safety Culture Action forms, indicating their intended actions to improve safety culture. We analyzed all survey results using the chi test. We shared lessons learned. RESULTS: The hospital leadership started safety walk rounds. There were 107 hospital employees at the summit. Attendees submitted 53 Safety Culture Action forms. We received 232 AHRQ survey responses in 2014 and 116 in 2016, for response rates of approximately 11% and 8.9%, respectively. We received 140 SAQ responses (11%) from 1244 employees in 2016 and 242 responses (18%) from 1342 employees in 2017. The AHRQ survey results indicated that perception of teamwork within hospital units improved. The SAQ results indicated that employees' comfort with reporting errors and expressing disagreement with physicians improved, and employees' perceptions of leadership's safety efforts and the levels of staffing worsened. CONCLUSIONS: Although some aspects of safety culture improved after the summit and follow-up interventions, others did not. Future interventions should be targeted toward individual microsystems or units and measure safety climate perceptions for intervention recipients exclusively. PMID- 29432338 TI - Patient-Reported Experience in the Pediatric Emergency Department: What Matters Most? AB - INTRODUCTION: Although the Child Hospital Consumer Assessment of Healthcare Providers and Systems is a validated tool for the inpatient experience, it may not address features unique to the pediatric emergency department (PED). There is currently no publicly available validated patient-reported experience survey for the PED, and what matters most in this setting remains unknown. METHODS: Twelve semistructured interviews were conducted with a convenience sample of parents of children younger than 14 years at a Canadian PED. Data analysis was performed using inductive thematic analysis to identify aspects of patient-reported experiences that matter most to parents in the PED. RESULTS: Five themes were identified: (1) making waiting a positive experience, (2) taking the time to provide care, (3) forging a positive partnership, (4) speak up for safe care, and (5) making the environment feel safer. Parents highlighted that while waiting for care is not desirable, it is made more acceptable through the communication of wait time estimates and the presence of child activities in the waiting room. Furthermore, although interactions with providers are brief, parents emphasized the importance of creating an environment of partnership with open communication, taking the time to examine their child, and actively demonstrating the provision of safe, quality care. CONCLUSIONS: Results from this study suggest that a patient-reported experience survey in the PED may need to embed elements not currently captured in Child Hospital Consumer Assessment of Healthcare Providers and Systems, such as waiting room experience, comprehensiveness of health assessments, and observations of safety measures. Future studies can use these findings to develop a patient-reported experience survey for use in the PED. PMID- 29432339 TI - 18F-Choline PET/MR Can Detect and Delineate Local Recurrence After High-Intensity Focused Ultrasound Therapy of Prostate Cancer. AB - Restaging local recurrence after high-intensity focused ultra-sound (HIFU) is based on multiparametric MRI (mpMRI). However, postinterventional changes of the tissue, such as edema or hemorrhage, are limiting tumor detection on mpMRI. We present a case of a rising prostate-specific antigen values, negative mpMRI, and a Gleason score of 4+4 on template biopsy after HIFU. On F-choline PET/MR, high focal uptake was detected at the location of positive biopsy. Re-HIFU based on the fused F-choline PET/MR images was performed, followed by a recurrence-free period of 11 months. Thus, F-choline PET/MR could improve guiding retreatment in patients with recurrence after HIFU. PMID- 29432340 TI - Castleman's Disease of the Kidney Mimicking Renal Cell Carcinoma on FDG PET/CT. AB - Castleman's disease of the kidney is extremely rare. We present a case of Castleman's disease in the left kidney with multiple para-aortic enlarged lymph nodes. Both the renal lesion and para-aortic lymph nodes showed hypervascularity on enhanced CT and minimally increased FDG uptake on FDG PET/CT, mimicking renal cell carcinoma with para-aortic nodal metastases. This case suggests that Castleman's disease should be considered as a rare differential diagnosis in patients with a hypervascular and hypermetabolic renal lesion. PMID- 29432341 TI - Rare Case of Intratracheal Metastasis Detected on 68Ga-Prostate-Specific Membrane Antigen PET/CT Scan in a Case of Thyroglobulin Elevated Negative Iodine Scan Syndrome. AB - A 64-year-old woman underwent completion thyroidectomy with upper tracheal ring resection and right-sided neck dissection for papillary carcinoma of the thyroid infiltrating the trachea and was given I radioiodine treatment. Three years later, she presented with hemoptysis. On evaluation, she had increased serum thyroglobulin and negative iodine scan (TENIS). F-FDG PET/CT scan did not identify any site of disease. One year later, Ga-PSMA scan done revealed a moderate focal tracer-avid intratracheal soft tissue; biopsy revealed it to be metastatic papillary carcinoma of the thyroid. This case kindles the possibility of using Ga-PSMA PET/CT to reveal occult disease in cases of TENIS. PMID- 29432342 TI - Long-lasting Intense Bone Tracer Activity at the Sites of Collagen Injection. AB - Collagen injection has been used as dermal filler in plastic and cosmetic surgery. A technetium Tc methylene diphosphonate bone scintigraphy was performed in a 47-year-old woman as part of the breast cancer evaluation. The images showed intense methylene diphosphonate activity on both sides of the frontal head, where she received collagen injection 1 year prior. The activity was visualized again in all 3 follow-up bone scans over the subsequent 3 years. PMID- 29432343 TI - Clinical Impact of Radioguided Localization in the Treatment of Solitary Pulmonary Nodule: A 20-Year Retrospective Analysis. AB - PURPOSE: Incidental solitary pulmonary nodules (SPNs) have become an increasingly common CT finding worldwide. Although there are currently many imaging strategies for evaluating SPNs, the differential diagnosis and management of SPNs remains complex because of overlap between benign and malignant processes. Moreover, transbronchial or percutaneous CT-guided biopsies do not always allow definitive diagnoses. In such cases, video-assisted thoracic surgery (VATS) has become the preferred surgical procedure for diagnosis and, in selected cases, for treatment of indeterminate SPNs. The difficulties in localizing smaller, deeper, and ground glass nodules have been approached with different techniques. The aim of this study was to report 20 years of experience with radioguided thoracoscopic resection of SPNs at the Regional Centre of Nuclear Medicine of Pisa. METHODS: Three hundred ninety-five patients with SPNs less than 2 cm and deeper than 5 mm below the visceral pleura underwent CT-guided injection of a suspension composed of 0.1 to 0.2 mL Tc-labeled human albumin macroaggregates (Tc-MAA) and of 0.2 to 0.3 mL of nonionic contrast medium into or adjacent to the SPN. During VATS, the pulmonary area with the highest target/background ratio identified by an 11-mm diameter collimated thoracoscopic gamma probe was resected. RESULTS: From 1997 to 2016, approximately 395 patients with SPN underwent VATS wedge resection using the radioguided technique. Mean SPN size was 13 mm (range, 5-20 mm) with mean distance of 15 mm (range, 6-39 mm) from the visceral pleura. Mean VATS procedural time was 40 minutes (range, 20-90 minutes), with an average time of 3 minutes (range, 1-5 minutes) to localize the nodule. Neither mortality nor major perioperative complication was reported. The success rate of VATS with radioguidance in our series was 99%. Histological examination revealed 206 benign lesions (52%), 59 primary lung tumors (15%), and 130 metastatic nodules (33%). CONCLUSIONS: This study demonstrates that radioguided SPN localization by VATS is a feasible, safe, and rapid procedure with highly successful rate of SPN resection. PMID- 29432344 TI - Metaplastic Squamous Cell Carcinoma of Breast Demonstrated on 18F-FDG PET/CT. AB - A 32-year-old woman presented with 3 months' history of rapid enlargement of the left breast and superficial ulceration. Staging F-FDG PET/CT performed after admission demonstrated a hypermetabolic mass in the left breast, with smaller hypermetabolic areas in the left axillary and internal mammary lymph nodes, as well as in the sternum. Postoperatively, the mass was diagnosed as metaplastic squamous cell carcinoma of the breast. PMID- 29432345 TI - 18F-FDG PET/CT Findings in a Patient With IgG4-Related Sclerosing Mesenteritis. AB - A large mass in the abdomen was revealed by ultrasonography on a 68-year-old woman presenting with abdominal pain and weight loss. To exclude the malignancy, an F-FDG PET/CT was performed, which showed a solitary soft tissue mass with heterogeneous F-FDG avidity at the root of small bowel mesentery. Because of the elevation of inflammatory markers and serum IgG4 level, IgG4-related sclerosing mesenteritis was suspected, which was proved by the subsequent biopsy. The mass gradually shrunk and ultimately disappeared in 6 months after a low-dose steroid therapy. PMID- 29432346 TI - A Case Series of Molecular Imaging of Glucagonoma After Initial Therapy-68Ga DOTATATE PET/CT Reveals Similar Results as in Neuroendocrine Tumors of Other Origin in Follow-up and Re-evaluation. AB - Glucagonoma is an extremely rare, glucagon-secreting neuroendocrine tumor of the pancreas. Only sparse data are available about the characteristics of this tumor in somatostatin receptor imaging and only for the situation of initial diagnosis. We present a series of 3 glucagonoma patients who underwent at least 1 Ga DOTATATE PET/CT scan. All patients were diagnosed by either histology and/or elevated serum levels of glucagon. The presented cases suggest that somatostatin receptor-based imaging can probably be used for re-evaluation of disease status in patients with glucagonoma in a similar way as it is already established for neuroendocrine tumors of other origin. PMID- 29432347 TI - Lactate Level Versus Lactate Clearance for Predicting Mortality in Patients With Septic Shock Defined by Sepsis-3. AB - OBJECTIVES: This study aimed to compare the prognostic value of lactate level and lactate clearance at 6 hours after septic shock recognition. And, we performed it to determine lactate kinetics in the Sepsis-3 defined septic shock. DESIGN: This retrospective study was performed from a prospective septic shock registry. SETTINGS: This study was performed at single urban tertiary center. And, all patients were treated with protocol-driven resuscitation bundle therapy between 2010 and 2016. PATIENTS: We included septic shock patients who met the Sepsis-3 definition, which involves lactate levels greater than or equal to 2 mmol/L and vasopressor use. INTERVENTIONS: Serum lactate levels were measured at initial and 6 hours from septic shock recognition. MEASUREMENTS AND MAIN RESULTS: Lactate clearance was calculated as ([initial lactate - 6-hr lactate]/initial lactate) * 100. The prognostic value of measured lactate levels and lactate clearance for 28 day mortality was analyzed and compared with that of subsequent lactate levels greater than or equal to 2 mmol/L, greater than or equal to 3 mmol/L, and greater than or equal to 4 mmol/L and less than 10%, less than 20%, and less than 30% lactate clearance. A total of 1,060 septic shock patients by Sepsis-3, 265 patients died (28-d mortality: 25%). In survivor, groups had lower median 6-hour lactate level and higher lactate clearance than nonsurvivors (2.5 vs 4.6 mmol/L and 35.4% vs 14.8%; p < 0.01). Both lactate and lactate clearance were associated with mortality after adjusting for confounders (odd ratio, 1.27 [95% CI, 1.21 1.34] and 0.992 [95% CI, 0.989-0.995]), but lactate had a significantly higher prognostic value than lactate clearance (area under the curve, 0.70 vs 0.65; p < 0.01). The prognostic value of subsequent lactate levels (>= 2, >= 3, and >= 4 mmol/L) and lactate clearances (< 10%, < 20%, and < 30%) was not significantly differed. However, lactate levels of greater than or equal to 2 mmol/L had the greatest sensitivity (85.3%). CONCLUSIONS: Our findings indicate lactate and lactate clearance are both useful targets in patients with septic shock defined by Sepsis-3. Serum lactate level at 6-hour can be an easier and more effective tool for prognosis of septic shock patients who were treated with protocol-driven resuscitation bundle therapy. PMID- 29432348 TI - Trends of Incidence and Risk Factors of Ventilator-Associated Pneumonia in Elderly Patients Admitted to French ICUs Between 2007 and 2014. AB - OBJECTIVES: To assess trends and risk factors of ventilator-associated pneumonia according to age, particularly in the elderly admitted to French ICUs between 2007 and 2014. DESIGN: Multicenter, prospective French national Healthcare Associated Infection surveillance network of ICUs ("Reseau REA-Raisin"). SETTINGS: Two-hundred fifty six ICUs in 246 settings in France. PATIENTS: Included were all adult patients hospitalized greater than or equal to 48 hours in ICUs participating in the network. INTERVENTIONS: Ventilator-associated pneumonia surveillance over time. MEASUREMENTS AND MAIN RESULTS: Overall and multidrug-resistant organism-related ventilator-associated pneumonia incidence rates were expressed per 1,000 intubation days at risk. Age was stratified into three groups: young (18-64 yr old), old (65-74 yr old), and very old (75+ yr old). Age-stratified multivariate mixed-effects Poisson regressions were undertaken to assess trends of ventilator-associated pneumonia incidence over time, with center as the random effect. Ventilator-associated pneumonia risk factors were also evaluated. Of 206,223 patients, 134,510 were intubated: 47.8% were young, 22.3% were old, and 29.9% were very old. Ventilator-associated pneumonia incidence was lower in the very old group compared with the young group (14.51; 95% CI, 16.95-17.70 vs 17.32; 95% CI, 16.95-17.70, respectively, p < 0.001). Methicillin-resistant Staphylococcus aureus and third-generation cephalosporin-resistant Enterobacteriaceae were identified more frequently in very old patients (p < 0.001 and 0.014, respectively). Age-stratified models disclosed that adjusted ventilator-associated pneumonia incidence decreased selectively in the young and old groups over time (adjusted incidence rate ratios, 0.88; 95% CI, 0.82-0.94; p < 0.001 and adjusted incidence rate ratios, 0.95; 95% CI, 0.86-1.04; p = 0.28, respectively). Male gender and trauma were independently associated with ventilator-associated pneumonia in the three age groups, whereas antibiotics at admission was a protective factor. Scheduled surgical ICU and immunodeficiency were risk factors of ventilator-associated pneumonia in the old group (p = 0.003). CONCLUSIONS: Ventilator-associated pneumonia incidence is lower but did not decrease over time in very old patients compared with young patients. PMID- 29432351 TI - Holistic Interventions and the Issue of Evidence. PMID- 29432350 TI - An Exploratory Reanalysis of the Randomized Trial on Efficacy of Corticosteroids as Rescue Therapy for the Late Phase of Acute Respiratory Distress Syndrome. AB - OBJECTIVES: In the Acute Respiratory Distress Syndrome Network randomized controlled trial, methylprednisolone treatment was associated with increased return to mechanical ventilation with partial loss of early improvements. We hypothesize a causal relationship between protocol-driven rapid discontinuation of methylprednisolone post extubation and return to mechanical ventilation. To explore this possibility, we investigated the timing that events occurred in each treatment arm during active treatment intervention (efficacy) and after stopping therapy. DESIGN AND SETTINGS: Retrospective intention-to-treat analysis of multicenter randomized controlled trial. PATIENTS AND INTERVENTIONS: Patients were randomized to methylprednisolone (2 mg/kg/d) or placebo (89 vs 91). The target sample size was reduced post hoc and provided 80% power for an optimistic 50% mortality reduction. MEASUREMENTS AND MAIN RESULTS: Findings are reported as methylprednisolone versus placebo. By day 28, fewer patients died before achieving extubation (15.7% vs 25.3% and risk ratio, 0.62; 95% CI, 0.34-1.13), more achieved successful extubation (71.9% vs 49.5% and risk ratio, 1.45; CI, 1.14-1.85), time to successful extubation was shorter (hazard ratio, 2.05; CI, 1.42-2.96), and more were discharged alive from the ICU (65.2% vs 48.3%; risk ratio, 1.35; CI, 1.04-1.75). After treatment discontinuation, more methylprednisolone-treated patients returned to mechanical ventilation (26.6% vs 6.7%; risk ratio, 3.98; CI, 1.24-12.79)-consistent with reconstituted systemic inflammation in the presence of adrenal suppression. Participants returning to mechanical ventilation without reinstitution of methylprednisolone had increased risk of ventilator dependence and mortality. Despite loss of early benefits, methylprednisolone was associated with sizable and significant improvements in all secondary outcomes and reduction in serious complications (shock and severe infections). CONCLUSIONS: During active intervention, methylprednisolone was safe and effective in achieving disease resolution. Our findings support rapid glucocorticoid discontinuation post extubation as likely cause of disease relapse. Gradual tapering might be necessary to preserve the significant improvements achieved during methylprednisolone administration. PMID- 29432349 TI - The Impact of Acute Organ Dysfunction on Long-Term Survival in Sepsis. AB - OBJECTIVES: To estimate the impact of each of six types of acute organ dysfunction (hepatic, renal, coagulation, neurologic, cardiac, and respiratory) on long-term mortality after surviving sepsis hospitalization. DESIGN: Multicenter, retrospective study. SETTINGS: Twenty-one hospitals within an integrated healthcare delivery system in Northern California. PATIENTS: Thirty thousand one hundred sixty-three sepsis patients admitted through the emergency department between 2010 and 2013, with mortality follow-up through April 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute organ dysfunction was quantified using modified Sequential Organ Failure Assessment scores. The main outcome was long-term mortality among sepsis patients who survived hospitalization. The estimates of the impact of each type of acute organ dysfunction on long-term mortality were based on adjusted Cox proportional hazards models. Sensitivity analyses were conducted based on propensity score matching and adjusted logistic regression. Hospital mortality was 9.4% and mortality was 31.7% at 1 year. Median follow-up time among sepsis survivors was 797 days (interquartile range: 384-1,219 d). Acute neurologic (odds ratio, 1.86; p < 0.001), respiratory (odds ratio, 1.43; p < 0.001), and cardiac (odds ratio, 1.31; p < 0.001) dysfunction were most strongly associated with short-term hospital mortality, compared with sepsis patients without these organ dysfunctions. Evaluating only patients surviving their sepsis hospitalization, acute neurologic dysfunction was also most strongly associated with long-term mortality (odds ratio, 1.52; p < 0.001) corresponding to a marginal increase in predicted 1-year mortality of 6.0% for the presence of any neurologic dysfunction (p < 0.001). Liver dysfunction was also associated with long-term mortality in all models, whereas the association for other organ dysfunction subtypes was inconsistent between models. CONCLUSIONS: Acute sepsis-related neurologic dysfunction was the organ dysfunction most strongly associated with short- and long-term mortality and represents a key mediator of long-term adverse outcomes following sepsis. PMID- 29432352 TI - LETTER TO THE EDITOR. PMID- 29432353 TI - Practices in Human Dignity in Palliative Care: A Qualitative Study. AB - Respecting and valuing an individual's existential dignity forms the basis of nursing and medical practice and of nursing care. The objective of the study was to determine the approach to human dignity that nurses and physicians have while providing palliative care. This qualitative study was performed using a phenomenological research design. In-depth semistructured interviews were conducted in 9 nurses and 5 physicians with human dignity approach in palliative care. Following the qualitative Colaizzi method of analyzing the data, the statements made by the nurses and physicians during the interviews were grouped under 8 categories. Consistent with the questionnaire format, 8 themes and 43 subthemes of responses were determined describing the human dignity of the nurse and the physicians. The results of the study showed that in some of the decisions and practices of the nurses giving nursing care and physicians giving medical care to palliative care patients, while they displayed ethically sensitive behavior, on some points, they showed approaches that violated human dignity and showed lack of awareness of ethical, medical, and social responsibilities. PMID- 29432354 TI - A Conceptual Framework Encompassing the Psychoneuroimmunoendocrinological Influences of Listening to Music in Patients With Heart Failure. AB - Patients with heart failure have been traditionally treated with a pharmacology based approach, diet, exercise, and rehabilitation for reducing symptoms, hospitalizations, and mortality. We have developed a solid conceptual framework for music listening-based protocols, showing how music may have a broad range of positive effects on cardiovascular health through psychoneuroimmunoendocrinological pathways. PMID- 29432355 TI - A Window Toward the World: Older Adults' Experiences of Becoming in Health and Developing as Human Beings Through Interacting With Others Using Real Video Communication. AB - The population in the Nordic countries, as well as globally, is increasingly becoming older. Concurrently, with an increased aging population, there is an increase in poor health and loneliness among older adults. The aim of this study was to uncover, from a caring science perspective, community-living older adults' experiences of interacting with others via real video communication. The study uses a hermeneutical approach. The material consists of interviews with older adults regarding their experiences of using real video communication. The texts were interpreted through hermeneutical reading. Study participation and data storage and handling for research purposes were approved by the participants when they provided their informed consent. Ethical permission to conduct this study was granted by a research board. The findings uncovered that welfare technology offers a metaphor-a window toward the world-that comprises the overarching core theme "Being in a movement toward becoming a unity as a human being," and 3 main themes: "Alleviating suffering through beating involuntary solitude," "Being in the world as an equal and dignified human being," and "Dedicating new perspectives and meaning in life." Welfare technology seems to be an important means to improve the quality of life for older adults living at home. Welfare technology enables older people to be in contact with other people in an easy way. Further research is needed to uncover issues of welfare technology from different perspectives. PMID- 29432356 TI - Grieving With Humor: A Correlational Study on Sense of Humor and Professional Grief in Palliative Care Nurses. AB - The aim of this study was to explore the relationship between humor and professional grief. Findings confirm that these are not independent phenomena. Using humor as a coping mechanism emerged as a response to death-related work. Likewise, positive attitudes toward humor seem to alleviate the distress associated with end-of-life care. PMID- 29432357 TI - Perspectives of Oncology Nurses on Complementary and Alternative Medicine in Turkey: A Cross-Sectional Survey. AB - In Turkey, between 22.1% and 84.1% of patients with cancer use complementary and alternative medicine (CAM). However, few CAM-related studies have focused on the perspective of oncology nurses. This study aimed to determine the knowledge, attitudes, and practices of Turkish oncology nurses regarding CAM. A descriptive cross-sectional survey of 127 participants was conducted in Ankara, Turkey. A semistructured questionnaire including characteristics, knowledge, attitudes, and practices of oncology nurses toward CAM was administered to participants. We found that more than half of nurses (54.0%) surveyed had no information on CAM modalities. Most oncology nurses (81.1%) used audiovisual media sources to obtain CAM information. Many nurses (81.3%) reported not using any CAM in cancer care, and only 26.8% recommended CAM to patients. Most nurses used CAM to accelerate wound healing (19.7%) and to manage symptoms, including constipation and diarrhea (8.8%) and anxiety (7.9%). Music (52.8%), massage (49.6%), and exercise (48.8%) were stated to be beneficial. Important barriers to use CAM for patients with cancer involved a lack of knowledge (60.6%); needing physician approval to apply any CAM methods to patients (52.1%); legal and institutional issues (47.2%); and limited educational, training, or certificate programs (44.1%). There is a need for increased knowledge about CAM by oncology nurses, considering their vital role in symptom management of patients with cancer. This can be achieved through solving legal and institutional problems, structured and comprehensive education/training programs, and the integration of CAM therapy into cancer care guidelines. PMID- 29432359 TI - Risk Awareness, Harm Reduction, and Frontline Nurses on Alert. PMID- 29432358 TI - Therapeutic Lifestyle Considerations for Optimum Health. PMID- 29432360 TI - Periareolar Access for Minimally Invasive Cardiac Surgery: The Brazilian Technique. AB - The periareolar access has been the preferred technique used at our institution for minimally invasive cardiac surgery since 2006. The surgical approach consists of video-assisted minithoracotomy in the 4th right intercostal space, through a periareolar incision. Initially, the technique was restricted to minimally invasive mitral valve surgeries but, due to its feasibility and safety, was soon incorporated as an ideal access for other cardiac pathologies such as tricuspid valve disease, atrial septal defect, atrial fibrillation, and pacemaker leads endocarditis. The technique was performed in 214 patients, and it is associated with excellent aesthetic and functional results, with low morbimortality and no reoperations at long-term follow-up. Here, we describe and support the use of periareolar access as a routine surgical technique for correction of several cardiac pathologies, especially in women. PMID- 29432361 TI - Single-Port Thoracoscopic Pericardial Window Under Local Anesthesia. AB - There are numerous surgical approaches for the treatment of pericardial effusions but no clear consensus of best management. We present a 44-year-old woman with metastatic breast cancer presenting with a new 2-cm pericardial effusion on ultrasound. In light of the patient's palliative condition and the urgent need for chemotherapy, careful consideration was made for her surgical drainage of the pericardial effusion. Because of the patient's medical comorbidities, a general anesthetic was deemed not to be in the patient's best interest. Furthermore, the invasive subxiphoid or thoracotomy approach for a pericardial window would have risked delaying her much needed chemotherapy. A single-port thoracoscopic pericardial window was performed under light sedation, ventilating spontaneously on supplementary oxygen through nasal cannula only. The patient was positioned in a supine position, and a single 8-mm port was inserted into the left hemithorax at the 5th intercostal space, midaxillary line under local anesthetic, and a pericardial window made. This minimally invasive approach, without the need for intubation or ventilation, allowed for rapid relief of symptoms and discharge for the patient to begin her chemotherapy in a timely manner. By undergoing the procedure awake and through a single port, the patient was discharged after a short inpatient stay. This novel approach can be advocated for patients where a general anesthetic or invasive surgical procedure is not suitable in the treatment of their pericardial effusion. PMID- 29432362 TI - Left Axillary Artery Cannulation Facilitates Reoperative Total Aortic Arch Replacement. AB - Total aortic arch replacement remains a technically formidable procedure, particularly in patients with previous proximal aortic dissection repair. Our case discussion highlights a useful strategy for extracorporeal support and circulation management to facilitate total arch reconstruction in the reoperative setting, based on cannulation of the left axillary artery. Our preference is to use a left axillary artery approach to initiate cardiopulmonary bypass and to ultimately revascularize the left arm via an extra-anatomic graft. Our technique, as described, affords the option to initiate cardiopulmonary bypass before sternal re-entry, it reduces the risk of embolic complications and possible stroke, and it directly facilitates simple extra-anatomic debranching of the left subclavian artery, resulting in easier arch and great vessel reconstruction within the chest. PMID- 29432363 TI - Sternotomy Sparing Thoratec HeartMate 3 Implantation Via Bilateral Minithoracotomy. AB - A novel sternotomy sparing implantation technique for the Thoratec HeartMate 3 is described. Cannulation of the left ventricular apex is performed via a minithoracotomy in the left fourth or fifth intercostal space. The outflow graft is advanced through the pericardium to a second minithoracotomy in the right second intercostal space and then anastomosed to the ascending aorta. This approach was performed in three patients so far with no need for conversion. We did not observe any perioperative adverse events, such as bleeding or thromboembolic complications, as well as no short-term mortality. This technique is especially appealing in multimorbid and frail patients, future transplant candidates, and patients with impaired right ventricular function. PMID- 29432364 TI - Per-Ventricular Insertion of Melody Valve-in-Valve in the Neoaortic Position in a Single-Ventricle Patient. AB - Percutaneous therapies for congenital heart disease have been evolving rapidly despite limited investment from industry. The Melody transcatheter pulmonary valve (Medtronic, Inc, Minneapolis, MN USA) replacement therapy represents an important advancement in this arena. It has been approved in the United States for use in the pulmonary position, on a Humanitarian Device Exemption status. Off label use of the Melody transcatheter pulmonary valve has extended to the mitral, pulmonary, and aortic valves, especially in previously implanted valves with prosthetic valve degeneration. The single-ventricle patient poses additional challenges. However, there exists one report in the English literature of a patient undergoing Melody transcatheter neoaortic valve replacement after the patient developed severe neoaortic regurgitation after Fontan palliation. Here, we describe a patient with hypoplastic left heart syndrome, palliated with a Norwood modified Blalock-Taussig shunt, with a progressively regurgitant quadricusp neoaortic valve who underwent bioprosthetic valve replacement. There was early prosthetic valve degeneration after a year of bioprosthesis implantation. As he was declined for transplantation, he underwent successful per ventricular Melody valve-in-valve replacement. PMID- 29432365 TI - AAOS Appropriate Use Criteria: Management of Carpal Tunnel Syndrome. PMID- 29432366 TI - Systemic hemodynamic response to terlipressin predicts development of hepatorenal syndrome and survival in advanced cirrhosis. AB - BACKGROUND: The aim of this study was to predict the occurrence of hepatorenal syndrome (HRS) and death in patients with advanced cirrhosis and ascites. PATIENTS AND METHODS: We retrospectively evaluated 2-year data of 78 patients with cirrhosis and ascites (Child-Pugh B/C: 45/43). The mean arterial pressure (MAP) and cardiac output (CO) were measured in all patients just before administration of 2 mg of terlipressin and 30 min later. Systemic vascular resistance (SVR) was calculated as MAP/CO. DeltaMAP, and DeltaCO, and DeltaSVR were defined as the percentage change of MAP, CO, and SVR, respectively, after terlipressin injection. Plasma renin activity (PRA) and plasma aldosterone were evaluated at baseline. Two multivariate models were used: one excluding (model 1) and one including (model 2) the Model of End-stage Liver Disease score. RESULTS: Higher DeltaSVR, Model of End-stage Liver Disease score, and PRA were related independently to the severity of cirrhosis. Independent predictors of HRS at 12 and 24 months were DeltaSVR (models 1/2: P=0.008/0.01 and 0.01/0.02, respectively), DeltaCO (models 1/2: P=0.01/0.03 and 0.03/0.04, respectively), and PRA (models 1/2: P=0.04 and model 1: P=0.04, respectively). DeltaSVR at 12 and 24 months (models 1/2: P=0.005/0.01 and 0.01/0.03, respectively) and DeltaCO at 24 months (models 1/2: P=0.02/0.01, respectively) were related independently to survival. Patient groups with significantly higher probability of HRS and mortality were identified by certain cutoffs of DeltaSVR (20.6 and 22.8%, respectively) and DeltaCO (-10.6 and -11.8%, respectively). DeltaSVR and DeltaCO independently predicted survival in patients with the most advanced cirrhosis and infection-related survival. CONCLUSION: An increase in SVR by at least 20% and a decrease in CO at least 10% in response to terlipressin could predict HRS and mortality in patients with advanced cirrhosis. PMID- 29432367 TI - The possible relationship between Campylobacter spp./Arcobacter spp. and patients with ulcerative colitis. AB - BACKGROUND AND AIMS: The role of bacterial infection in the pathogenesis of ulcerative colitis (UC) is under investigation. This study aims to (i) determine the prevalence of Campylobacter spp. and Arcobacter spp. in patients with UC, (ii) identify the antibiotic susceptibility of isolated agents, and (iii) investigate the role of these microorganisms in the pathogenesis and/or activation of UC. PATIENTS AND METHODS: Eighty patients with UC and 40 healthy individuals were included in the study. Stool samples were used for cultural examination. Direct plating, membrane filtration, and enrichment methods were used for isolation. 16s rRNA sequence analysis was used for definitive identification of isolates that were identified phenotypically. RESULTS: In the UC group, 20 (25%) patients had proctitis, 40 (50%) patients had left-type involvement, and 20 (25%) patients had extensive involvement. Campylobacter spp. were isolated from four (5%) patients in the UC group and isolates were identified as C. curvus, C. concisus, C. sputorum, and C. jejuni. C. concisus and C. jejuni were found to be resistant to ciprofloxacin, levofloxacin, and trimethoprim-sulfamethoxazole. C. jejuni was also resistant to tetracycline. All samples were negative for Arcobacter spp. The samples from the control group neither showed the presence of Campylobacter spp. nor Arcobacter spp. CONCLUSION: Given the clinical, endoscopic, and bacteriological examination results, it is believed that Campylobacter spp. are agents that cause flare-up clinically by being superimposed on the primary disease, rather than agents that initiate the disease in patients with UC. Arcobacter spp., which are known to cause acute gastroenteritis, were not found to be associated with UC. PMID- 29432368 TI - Fecal Microbiota Differences According to the Risk of Advanced Colorectal Neoplasms. AB - GOALS AND BACKGROUND: This study aimed to compare differences in the fecal microbiota according to the risk of advanced colorectal neoplasia (ACN) based on a risk-score model in a large Korean cohort. STUDY: Stool samples were collected from 1122 health screening recipients: 404 enrolled in the average risk (AR) group, 514 in the moderate risk (MR) group, and 204 in the high risk (HR) group, in accordance with their risk of ACN. The fecal microbiota was characterized using pyrosequencing of the V3-V4 region of the 16S rRNA genes. RESULTS: The overall microbial diversity was significantly reduced with an increased risk of ACN [false discovery rate (FDR), P<0.001], and the composition was significantly different between the risk groups (Bonferroni corrected, P<0.05). On taxonomic comparison, 6 of 11 phyla and 39 of 88 genera were significantly different among the risk groups (all FDR P<0.05). These included under-representation of Bacteroides, Ruminococcus, and Bifidobacterium, and over-representation of Prevotella and Fusobacterium with an increased risk of ACN. In particular, we observed that the unknown genus of Ruminococcaceae were relatively abundant (16.2%) in the AR group and significantly depleted with an increased risk of ACN (13.5% in the HR group; FDR P<0.001). CONCLUSIONS: These findings support the hypothesis that the fecal microbiota is different according to the risk of ACN. An unknown genus of Ruminococcaceae, as novel potential butyrate producers, might have a possible role in colorectal tumorigenesis in the Korean population. PMID- 29432369 TI - Implementation of an Early Discharge Protocol and Chest Pain Clinic for Low-Risk Chest Pain in the Emergency Department. AB - BACKGROUND: Most of the patients presenting to emergency department with chest pain are at low risk of adverse events. Identifying high-risk patients can be challenging and resource intensive. METHODS: We created a protocol to assist early discharge of low-risk adults with chest pain from emergency department. Also a chest pain clinic (CPC) was started for cardiology follow-up within 72 hours. In a retrospective cohort study, primary outcome of major adverse cardiac events (MACEs) of death, myocardial infarction, or revascularization was compared between CPC patients and those hospitalized for observation. In addition, rate of observation admissions and MACE were compared in the pre- and postintervention periods using piecewise regression and multiple logistic regression, respectively. RESULTS: A total of 1422 patients were admitted for observation, and 290 were seen in CPC in the 1-year postintervention period. Thirty-day MACE was very low (0.7% in observation and 0.3% in CPC) postintervention. A total of 3637 patients were admitted for observation over the 2-year preintervention period. Thirty-day-adjusted MACE rate was not significantly different between pre and postintervention periods (0.4% vs. 0.6%, P = 0.3), also monthly observation admissions did not change significantly; however, utilization of stress testing (57.2% vs. 41.0%, P < 0.001) and cardiac catheterization (2.3% vs. 1.6%, P = 0.036) was reduced. CONCLUSION: Chest pain patients admitted for observation and risk stratification are at very low risk of 30-day MACE. An intervention based on a chest pain protocol and availability of early cardiology follow-up did not change the admission rate of these patients. This intervention was not associated with increased risk of adverse outcomes. PMID- 29432370 TI - Experiences of a One-hour Algorithm in Chest Pain Patients With a Nonelevated Troponin T at Presentation. AB - BACKGROUND: We aimed to evaluate the use of a 1-hour measurement of high sensitivity cardiac troponin T (hs-cTnT) in an emergency department (ED) population of chest pain patients with a nonelevated baseline hs-cTnT and to examine the prevalence of early dynamic changes in hs-cTnT and the association with admission rate, diagnosis, and outcome. METHODS: All patients with a chief complaint of chest pain presenting to the ED of Karolinska University Hospital, Solna, Sweden, from December 2014 to September 2015 who had a baseline hs-cTnT of <=14 ng/L and a second value obtained within >30 to <=90 minutes were followed for 30 days regarding admission, readmission, myocardial infarction (MI), and death. RESULTS: A total of 1091 patients were included. Dynamic 1-hour changes in hs-cTnT defined as an increase or decrease of >=3 ng/L occurred in 23 patients (2.1%). Fifteen patients (65.2%) in the dynamic group were admitted, compared with 148 patients (13.9%) in the nondynamic group (P < 0.001). Four of the admitted patients (26.7%) in the dynamic and 1 (0.7%) in the nondynamic group were diagnosed with an MI (P < 0.001). No death or MI occurred within 30 days among those discharged from the ED. CONCLUSIONS: Dynamic 1-hour changes in hs cTnT were uncommon but associated with a higher rate of admission and of MI in an unselected population of chest pain patients with a nonelevated hs-cTnT at presentation. Lack of dynamic changes makes MI highly unlikely, and a 1-hour measurement may facilitate an early rule out of MI but should be used together with clinical assessment. PMID- 29432371 TI - Clinical Outcomes of Transferred Versus Onsite Primary Percutaneous Coronary Intervention for Patients With STEMI: Time to Look Beyond Door to Balloon Time. AB - BACKGROUND: It is currently unknown if the delay due to practical aspects associated with transfer of patients from a non-percutaneous coronary intervention (PCI) facility to a primary PCI facility is associated with adverse outcomes. METHODS: We conducted a retrospective cohort study of all patients who presented with ST-segment elevation myocardial infarction (STEMI) and underwent primary PCI in 2 large regional STEMI centers in Massachusetts between January 2005 and June 2009. The cohort was divided into onsite patients who presented directly to the primary PCI center and transferred patients referred from another facility. The primary outcome was a composite of in-hospital major cardiovascular events (death, myocardial infarction, and stroke). Secondary outcomes were the individual components of the composite endpoint and bleeding complications. RESULTS: The cohort included a total of 1236 patients. Among them, 426 (34%) patients were transferred patients and 810 (66%) were onsite patients. The median door to balloon time was significantly higher at for transferred patients (124 vs. 71 minutes). There was no significant difference in primary composite endpoint between the 2 groups (onsite 3.8% vs. transfer 5.3%, odds ratio 1.50, 95% confidence interval 0.79-2.84; P = 0.21). Adjusted risk estimates did not show a statistical difference in all-cause bleeding rates between the groups (onsite 10.1% vs. transfer 7.3%, odds ratio 0.68, 95% confidence interval 0.41 1.14; P = 0.14). CONCLUSIONS: This study confirms that well-established and integrated regional STEMI programs provide equivalent care to transferred patients and onsite patients. Parameters beyond door to balloon times should be investigated for their contributions to improve patient outcomes. PMID- 29432372 TI - ECG-to-Decision Time Impact on 30-Day Mortality and Reperfusion Times for STEMI Care. AB - OBJECTIVES: Little data are published on the unique care performance metric of electrocardiogram-to-decision time (E2Decide) for primary percutaneous coronary intervention (PCI) treatment of ST-elevation myocardial infarction (STEMI). The objective of this study is to evaluate E2Decide time on mortality and delayed reperfusion. METHODS: This was a retrospective study of STEMI activations treated with primary PCI at 2 PCI-capable hospitals located in Duluth, Minnesota, and Fargo, North Dakota, originating in 3 different settings: (1) primary PCI-capable hospital emergency departments, (2) non-PCI facilities, and (3) in the field by emergency medical services. Analysis of variance, generalized linear modeling, and logistic regression models were used in this study. RESULTS: There were 289 (96 females) STEMI patients included in our analyses. Non significant differences were observed in E2Decide time between male and female patients (9.7 vs. 11.1 min, respectively). Generalized linear modeling revealed that only non-PCI facilities significantly affected E2Decide time [beta = 6.29; P = 0.007; 95% confidence interval (CI), 1.7-10.9] relative to PCI-capable hospitals. We found that E2Decide time was significantly associated with the metric decision-to-PCI, and that for every additional E2Decide minute, the decision-to-PCI increased by another 1.21 minutes (P < 0.001; 95% CI, 0.873-1.56). We also found a 20.3% increased odds of 30-day mortality for every 5-minute increase in E2Decide time (estimated odds ratio = 1.20; 95% CI, 1.04-1.38). CONCLUSIONS: We observed that a delay in E2Decide time was significantly associated with a subsequent delay in decision-to-PCI time. E2Decide time was significantly associated with increased odds in 30-day mortality. This study demonstrates the potential value of the metric E2Decide time. PMID- 29432373 TI - Contrast-Induced Nephropathy in STEMI Patients With and Without Chronic Kidney Disease. AB - INTRODUCTION: Contrast-induced nephropathy (CIN) following percutaneous coronary intervention (PCI) is associated with adverse outcomes; however, there are scarce data comparing clinical outcomes of post-PCI CIN in ST elevation myocardial infarction (STEMI) patients with and without chronic kidney disease (CKD). We sought to assess the incidence, clinical predictors, and short-term and long-term clinical outcomes of post-PCI CIN in STEMI patients with and without CKD. METHODS: We performed a retrospective observational cohort study involving 554 patients who underwent PCI for STEMI from February 2010 to November 2013. CKD was defined as estimated glomerular filtration rate <=60 mL/min and CIN as creatinine increase by >=25% or >=0.5 mg/dL from baseline within 72 hours after catheterization contrast exposure. RESULTS: In the entire population, CIN developed in 89 (16%) patients. The incidence of CIN was 19.7% (27/137) in CKD patients and 11.1% (62/417) in non-CKD patients, P < 0.05. Univariate analysis predictors of CIN were older age (65 vs. 60 years), diabetes (35% vs. 21%), peripheral artery disease (11% vs. 5%), cardiogenic shock (24% vs. 13%), hemodynamic support placement (34% vs. 14%), and Mehran score (9.4 +/- 7 vs. 5.4 +/- 5.2) with all P < 0.05. The predictors of CIN were the same across the CKD and non-CKD cohort with the exception of diabetes. In multivariate analysis, the strongest predictor of CIN in CKD patients was diabetes (odds ratio, 5.8; CI, 1.8 18.6); however, diabetes was not a predictor in the non-CKD population. In the non-CKD population, each single unit increase in the Mehran score was associated with a 1.1 times greater likelihood of CIN (odds ratio, 1.1; CI, 1.01-1.2). Patients with CIN had higher rates of inpatient mortality (14.6% vs. 2.8%), longer length of hospitalization (8 +/- 11 vs. 3.4 +/- 4.4 days), need for inpatient dialysis (11.2% vs. 0%), higher 30-day mortality (14.6% vs. 3.0%), and higher incidence of long-term serum creatinine >0.5 mg/dL from baseline (16.9% vs. 2.4%) with all P < 0.05. CONCLUSIONS: Overall, we found that CKD patients undergoing PCI for STEMI have a higher incidence of CIN than non-CKD patients. CIN confers worse short-term and long-term outcomes irrespective of baseline renal function. PMID- 29432374 TI - Development of an Outpatient Guideline for Optimal Anticoagulation Bridging in Patients With Durable Mechanical Circulatory Support. AB - Patients with durable mechanical circulatory support are at increased risk of thromboembolic and bleeding complications. Current guidelines recommend that these patients receive chronic anticoagulation with warfarin to maintain a target international normalized ratio (INR) as specified by device manufacturers. Limited data exist regarding management of subtherapeutic INRs in this setting. To standardize clinical practice at our institution, we assembled a multidisciplinary task force including members from various specialties to develop a guideline for managing subtherapeutic INRs that incorporates published data and expert opinion. In this article, we present our clinical practice guideline as a decision support tool to aid clinicians in developing a consistent strategy for managing subtherapeutic INRs and for safely bridging anticoagulation in patients receiving mechanical circulatory support. PMID- 29432375 TI - Positive Predictive Value of Noninvasive Stress Testing Is Poor in the Real World. AB - Abnormal noninvasive stress test (NIST) findings do not always correlate with angiographically significant (luminal obstruction >=50%) coronary artery disease. Positive predictive value (PPV) of NIST in the real clinical practice is not well known. The goal of this retrospective study was to determine the PPV of NIST and assess the factors affecting PPV in a US community hospital. This study included all consecutive patients (n = 355) who underwent invasive coronary angiography after a positive NIST within ~1-year duration at our institution. Three hundred twenty-four patients were included in the analysis after exclusion of 31 patients. Sixty percent of patients were female and mean age was 63.2 (SD 12.4). Myocardial perfusion imaging, echocardiogram (treadmill or dobutamine), and treadmill electrocardiogram were the tests of choice in 95% (n = 307), 4% (n = 14), and 1% (n = 3) of patients, respectively. Overall PPV of NIST was 36.4% (118/324). When patients were stratified by age (<50 years, 50-65 years, >=65 years), older age groups had significantly higher PPV (<0.001). When patients were grouped by body mass index (<25, 25-30, >=30), those in lower body mass index groups had higher PPV (P = 0.01). Stress echocardiogram had significantly higher PPV compared with myocardial perfusion imaging stress test (71% vs. 35%; P < 0.005). Stress test site (in-hospital vs. outpatient office) or specialty of interpreting physician did not significantly impact PPV. Multivariable logistic regression analysis revealed that older age, male sex, and total number of cardiac risk factors were significant determinants of higher PPV. Our single center study revealed that overall PPV of NIST is poor (36.4%), more notably in young, female, or obese patients. PMID- 29432376 TI - Complementary Diagnostic Value of Heart Type Fatty Acid-binding Protein in Early Detection of Acute Myocardial Infarction. AB - BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is a novel biomarker for myocardial injury. We compared the use of H-FABP with serum levels of cardiac troponin-T (cTnT) and creatine kinase-MB (CK-MB) in the diagnosis of patients suspicious to acute myocardial infarction (AMI). METHODS: From October 2013 to December 2014, 182 consecutive patients suspicious to acute coronary syndrome were enrolled in this study, who presented within the past 6 hours from the onset of symptoms. Venous blood samples were drawn at baseline to measure serum biochemistry, high-sensitive cardiac troponin T (hs-cTNT), creatine kinase-MB, and H-FABP, and the measurements were repeated after 8 hours. The patients were categorized into 3 groups based on the baseline and second measurements of cTnT and general characteristics, and changes of H-FABP levels were then compared between the groups. Sensitivity and specificity of H-FABP in predicting the presence of AMI was calculated. RESULTS: A total of 91 patients had AMI. Changes of H-FABP through time were also significantly different between the AMI and non AMI patients (P < 0.001). A cutoff point of 7.15 for H-FABP could predict AMI with a sensitivity of 51.5%, specificity of 96.3%, and diagnostic accuracy of 68.3%. The area under the receiver operating characteristic curve for H-FABP at 8 hours was 79.4% (95% confidence interval: 73.0-85.9; P < 0.001). Positive predictive value and negative predictive value for H-FABP were 85% and 60%, respectively. CONCLUSIONS: H-FABP can be used as an additional cardiac biomarker in the diagnosis of AMI. PMID- 29432377 TI - Two-year Follow-up of Patients With Unstable Angina/Non-ST Segment Elevation Myocardial Infarction Undergoing Early Invasive Strategy: Predictors of Normal or Near-Normal Coronary Angiography and Mortality. AB - BACKGROUND: Predictors of normal or near-normal coronary angiography (NONCAG) in patients with unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) and their importance regarding the prognosis are not understood. Accordingly, we determined these predictors as well as mortality risk factors at 2-year follow-up of UA/NSTEMI patients managed by the early invasive strategy. METHODS: We prospectively studied consecutive patients with UA/NSTEMI managed with the early invasive strategy at Tehran Heart Center, in 1-year period. Echocardiography was performed before coronary angiography (CAG) for all the patients. Baseline characteristics, laboratory parameters, echocardiographic findings, invasive treatment modalities, and survival status after 2 years of follow-up were collected. We identified the predictors of NONCAG in the first phase of the study and then the risk factors of mortality in the second phase. RESULTS: In the study period, 298 patients including 211 (71%) males, with the age of 59.31 +/- 10.72 years were enrolled. The following factors were predictors of NONCAG: the female sex (P < 0.001); negative family history of CAD (P = 0.028); Thrombolysis in Myocardial Infarction (TIMI) risk score (P < 0.001); and early transmitral flow velocity/mean mitral annular velocity (E/E'mean) (P = 0.003). The following items were significant protective factors against mortality: percutaneous coronary intervention (PCI) (P = 0.012), age (P = 0.001), and E/E'mean (P = 0.020). CONCLUSION: Patients' baseline characteristics as well as echocardiographic data could help in predicting those with NONCAG and PCI can be considered as the treatment of strategy with the most protection against mortality. PMID- 29432378 TI - Low perfusion pressure is associated with renal tubular injury in infants undergoing cardiac surgery with cardiopulmonary bypass: A secondary analysis of an observational study. AB - BACKGROUND: Earlier work on adults undergoing surgery with cardiopulmonary bypass suggests that there is a close relationship between the lower limit of the cerebral and renal autoregulation pressures. Although cerebral autoregulation during bypass in infants has been extensively investigated, the impact of bypass on kidney function is not well known. It is, nevertheless, acknowledged that the main pathophysiological process involved in cardiac surgery-related kidney damage is tubular injury, and that urine neutrophil gelatinase-associated lipocaline (uNGAL) is a reliable biomarker of injury. OBJECTIVE: To identify the most predictive bypass variable for the measurement of renal injury, its threshold value and the most predictive time below that threshold. DESIGN: Observational study linking electronically recorded bypass perfusion pressure and oxygen delivery rate with intra-operative uNGAL excretion. Variations in bypass variables were accounted for by their excursions below several thresholds. SETTING: French tertiary referral paediatric cardiac centre. PATIENTS: A total of 72 infants in whom uNGAL was measured within 1 h of bypass. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Renal injury, identified by a high creatinine normalised uNGAL concentration (>21.2 MUg mmol). RESULTS: At the end of bypass, 43.75% of infants had high uNGAL. A more than 40% pressure drop below the normal age standardised mean arterial pressure was associated with high uNGAL. Receiver operating curve [interquartile range] areas were 0.626 [0.501 to 0.752] for a more than 40% drop, and 0.679 [0.555 to 0.804] for a more than 50% drop. A more than 40% pressure drop for 19.5 min provided a 0.65 negative predictive value for high uNGAL, and a more than 50% pressure drop for 5.4 min provided a 0.67 negative predictive value. The link between uNGAL and oxygen delivery rate was negligible. CONCLUSION: Maintaining the perfusion pressure above 60% of the normal age-standardised mean arterial pressure may provide an effective renal protective strategy. TRIAL REGISTRATION: Registered on October 11, 2010, ClinicalTrials.gov Identifier: NCT01219998. PMID- 29432379 TI - Dexmedetomidine as a part of general anaesthesia for caesarean delivery in patients with pre-eclampsia: A randomised double-blinded trial. AB - BACKGROUND: During general anaesthesia, endotracheal intubation of patients with pre-eclampsia causes stimulation of the sympathetic nervous system and catecholamine release, which may lead to maternal and neonatal complications. OBJECTIVE: To attenuate both the stress response and the haemodynamic response to tracheal intubation in patients with pre-eclampsia. DESIGN: A randomised, double blind, controlled study. SETTING: Single University Hospital. PATIENTS: Sixty patients aged 18 to 45 years with pre-eclampsia receiving general anaesthesia for caesarean section. INTERVENTIONS: The patients were randomly allocated to three groups. Groups D1and D2 received an infusion of dexmedetomidine 1 MUg kg over the 10 min before induction of general anaesthesia, then 0.4 and 0.6 MUg kg h dexmedetomidine, respectively. Group C received equivalent volumes of 0.9% saline. MAIN OUTCOME MEASURES: The primary outcome was the effect of dexmedetomidine on mean arterial blood pressure measured before induction of general anaesthesia at 1 and 5 min after intubation, and then every 5 min until 10 min after extubation. The secondary outcomes were blood glucose and serum cortisol (measured before induction of general anaesthesia, and at 1 and 5 min after intubation), postoperative visual analogue pain scores, time to first request for analgesia, the total consumption of analgesia, Ramsay sedation score, maternal and placental vein blood serum levels of dexmedetomidine and neonatal Apgar score at 1 and 5 min. RESULTS: At all assessment times, the mean arterial pressures were significantly lower in the dexmedetomidine groups than in the control group. Compared with group C, the heart rate was significantly lower in both groups D1 and D2. In group D2, the heart rate was lower than in group D1. Serum glucose and cortisol were significantly higher in the controls than in either group D1 or D2. Group D2 patients were significantly more sedated on arrival in the recovery room followed by D1. Time to first analgesia was significantly longer in groups D2 and D1 than in group C, and the visual analogue pain scores were significantly lower in groups D1 and D2 than in group C at 1, 2, 3 and 5 h. Total morphine consumption was significantly lower in groups D1 and D2 than in the control group. There was no difference in Apgar scores across the three groups despite significantly higher dexmedetomidine concentrations in group D2 (both maternal and placental vein) than in group D1. CONCLUSION: Administration of dexmedetomidine in doses 0.4 and 0.6 MUg kg h was associated with haemodynamic and hormonal stability, without causing significant adverse neonatal outcome. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR201706002303170), (www.pactr.org). PMID- 29432380 TI - Low anaesthetic waste gas concentrations in postanaesthesia care unit: A prospective observational study. AB - BACKGROUND: Volatile anaesthetics are a potential hazard during occupational exposure, pregnancy or in individuals with existing disposition to malignant hyperthermia. Anaesthetic waste gas concentration in postanaesthesia care units (PACU) has rarely been investigated. OBJECTIVE(S): The current study aims to assess concentrations of volatile anaesthetics in relation to room size, number of patients and ventilator settings in different PACUs. DESIGN: A prospective observational study. SETTING: Two different PACUs of the Hannover Medical School (Hannover, Germany) were evaluated in this study. The rooms differed in dimensions, patient numbers and room ventilation settings. PATIENTS: During the observation period, sevoflurane anaesthesia was performed in 65 of 140 patients monitored in postanaesthesia unit one and in 42 of 70 patients monitored in postanaesthesia unit two. MAIN OUTCOME MEASURES: Absolute trace gas room concentrations of sevoflurane measured with a compact, closed gas loop high resolution ion mobility spectrometer. RESULTS: Traces of sevoflurane could be detected in 805 out of 970 samples. Maximum concentrations were 0.96 +/- 0.20 ppm in postanaesthesia unit one, 0.82 +/- 0.07 ppm in postanaesthesia unit two. Median concentration was 0.12 (0.34) ppm in postanaesthesia unit one and 0.11 (0.28) ppm in postanaesthesia unit two. CONCLUSION: Low trace amounts of sevoflurane were detected in both PACUs equipped with controlled air exchange systems. Occupational exposure limits were not exceeded. PMID- 29432381 TI - Systematic review of prehospital tourniquet use in civilian limb trauma. AB - BACKGROUND: Military enthusiasm for limb tourniquet use in combat casualty care has resulted in acceptance by the trauma community for use in the prehospital care of civilian limb injuries. To date, there has been no report synthesizing the published data on civilian tourniquet use. The objective of this systematic review was to compile and analyze the content and quality of published data on the civilian use of tourniquets in limb trauma. METHODS: The MEDLINE database was searched for studies on civilian limb tourniquet use in adults published between 2001 and 2017. Search terms were tourniquet, trauma, and injury. Military reports and case series lacking systematic data collection were excluded. Counts and percentages were aggregated and weighted for analysis. RESULTS: Reports were included from six regional trauma centers and one interregional collaboration (total of 572 cases). One national prehospital database report was included but analyzed separately (2,048 cases). All were retrospective cohort studies without prospective data collection. Three reports defined a primary outcome, two had a nontourniquet control group, and no two articles reported the same variables. Limb injury severity and characteristics were inconsistently and incompletely described across reports, as were tourniquet indications and effectiveness. Arterial injury was reported in two studies and was infrequent among cases of tourniquet use. Mortality was low, and limb-specific complications were infrequent but variably reported. CONCLUSION: The rapid increase in the civilian use of tourniquets for limb hemorrhage control has occurred without a large amount or high quality of data. Adoption of a multicenter registry with standardized data collection specific to limb trauma and tourniquet use can serve to improve the trauma community's understanding of the safety and effectiveness of tourniquet use in civilian trauma settings. LEVEL OF EVIDENCE: Systematic review, level IV. PMID- 29432382 TI - Association Between Macroscopic Tongue Ischemia and Enterocyte Injury and Poor Outcome in Patients With Septic Shock: A Preliminary Observational Study. AB - A correlation between sublingual and intestinal mucosa microcirculation, and ischemic necrosis of the tongue as a sign of poor prognosis has been reported. However, an association between tongue ischemia and intestinal health and subsequent outcome has never been studied. This preliminary prospective observational study evaluated the association between macroscopic tongue ischemia and enterocyte injury and poor outcome in patients with septic shock. In this study, 57 adults with septic shock on mechanical ventilators were enrolled. Macroscopic tongue ischemia upon intensive care unit (ICU) admission was assessed by two independent intensivists. We used intestinal fatty-acid binding protein (I FABP) as a biomarker of enterocyte injury and evaluated the association with tongue ischemia. Demographic variables, risk factor data, and 28-day mortality information were also collected. Compared with patients with normal tongues (n = 45), those with ischemic tongues (n = 12) had a significantly higher Acute Physiology and Chronic Health Evaluation II score (29.0 [25.0-34.0] vs. 36.5 [30.5-44.5], P = 0.017), lactate level (2.8 [2.0-5.0] vs. 9.3 [4.5-10.6], P = 0.002), and I-FABP level (1.9 [0.8-4.0] vs. 54.4 [19.5-159.3], P < 0.001) and the all-cause 28-day mortality was significantly higher (7% vs. 83%, P < 0.001). In conclusion, macroscopic tongue ischemia at ICU admission was associated with enterocyte injury and poor outcome in patients with septic shock. Although there is a disadvantage in that assessment of the tongue was subjective, tongue ischemia could be used to gauge the severity of intestinal injury and to estimate poor outcome in the clinical setting. PMID- 29432383 TI - Safety and Immunogenicity of Seven Dosing Regimens of the Candidate RTS,S/AS01E Malaria Vaccine Integrated Within an Expanded Program on Immunization Regimen: A Phase II, Single-Center, Open, Controlled Trial in Infants in Malawi. AB - BACKGROUND: In a phase III trial, the RTS,S/AS01 malaria vaccine produced lower anti-circumsporozoite (CS) antibody titers when co-administered with Expanded Programme on Immunization vaccines (0-, 1- and 2-month schedule) at 6 to 12 weeks compared with 5 to 17 months at first vaccination. Alternative infant immunization schedules within the Expanded Programme on Immunization were investigated. METHODS: This phase II, open, single-site (Blantyre, Malawi) trial was conducted in infants 1 to 7 days of age. Subjects were equally randomized across 7 groups to receive 3 doses of RTS,S/AS01E at time points that included <=7 days, 6, 10, 14 and 26 weeks, and 9 months. All RTS,S/AS01E groups plus a control group (without RTS,S/AS01E) received Bacillus Calmette-Guerin + oral poliovirus vaccine at <=7 days, diphtheria, tetanus, whole-cell pertussis, hepatitis B and Haemophilus influenzae type b vaccine + oral poliovirus vaccine at 6, 10, and 14 weeks and measles vaccine at 9 months; one RTS,S/AS01E group and the control additionally received hepatitis B vaccination at <=7 days. Serum anti CS antibody geometric mean concentration (GMC; enzyme-linked immunosorbent assay) and safety were assessed up to age 18 months. RESULTS: Of the 480 infants enrolled, 391 completed the study. No causally related serious adverse event was reported. A higher frequency of fever within 7 days of RTS,S/AS01E vaccination compared with control was observed. Compared with the standard 6-, 10-, 14-week schedule, anti-CS antibody GMC ratios post-dose 3 were significantly higher in the 10-, 14- and 26-week group only (ratio 1.80; 95% confidence interval, 1.24 2.60); RTS,S/AS01E vaccination at <=7 days and 10 and 14 weeks produced significantly lower anti-CS GMCs (ratio 0.59; 95% confidence interval, 0.38 0.92). CONCLUSIONS: Initiation of RTS,S/AS01E vaccination above 6 weeks of age tended to improve anti-CS antibody responses. Neonatal vaccination was well tolerated but produced a comparatively lower immune response. PMID- 29432384 TI - Antibiotic-resistant Gram-negative Blood Stream Infections in Children With Cancer: A Review of Epidemiology, Risk Factors, and Outcome. PMID- 29432385 TI - Economic Evaluation of Selective Neonatal Bacillus Calmette-Guerin Vaccination of High-risk Infants in Ireland. AB - BACKGROUND: In Western Europe, currently only Ireland and Portugal continue to provide universal neonatal bacillus Calmette-Guerin (BCG) vaccination programs, despite not being considered as high tuberculosis (TB) incidence countries. Other European countries only vaccinate infants considered at high risk of contracting TB. We evaluated the cost-effectiveness of selective BCG vaccination compared with strategies of universal and no vaccination. METHODS: An economic model was used to simulate a cohort from birth to life expectancy, taking the perspective of the publicly funded healthcare system. BCG protection was modeled to last 15 years. International vaccine efficacy data were combined with Irish epidemiologic and cost data. The model took into account long-term sequelae associated with TB meningitis and severe adverse reactions relating to the BCG vaccine. A fully probabilistic model was used to incorporate uncertainty across all parameters. RESULTS: At &OV0556;139,557 per quality-adjusted life year, selective vaccination was not cost-effective relative to a program of no vaccination. The incremental cost-effectiveness of universal vaccination was &OV0556;2.55 million per quality adjusted life year relative to selective vaccination. There was substantial uncertainty regarding the effectiveness of BCG vaccination. The cost effectiveness of selective vaccination could be substantially improved by reducing the cost of administering the vaccine. CONCLUSIONS: In the absence of changes to other aspects of TB control, a switch to selective vaccination will result in increased cases of childhood TB. Although not considered cost effective, selective vaccination may be preferable to no vaccination until other changes to TB control may be implemented to reduce the risk of TB in children. PMID- 29432386 TI - Validation of a Reversed-Phase Ultra-High-Performance Liquid Chromatographic Method With Photodiode Array Detection for the Determination of Voriconazole in Human Serum and Its Application to Therapeutic Drug Monitoring. AB - BACKGROUND: Voriconazole is a broad-spectrum triazole antifungal agent. It is widely used in the treatment of invasive fungal infections in immunocompromised patients. Because the pharmacokinetics of voriconazole demonstrates considerable variability, monitoring its serum levels plays an important role in optimizing therapies against many clinically relevant fungal pathogens. The aim of this study was to validate a simple and rapid U-HPLC-PDA method with minimal sample preparation for routine therapeutic drug monitoring (TDM) of voriconazole. METHODS: After protein precipitation with the internal standard solution (posaconazole 5.0 mg/L in acetonitrile), chromatographic separation was performed in 4 minutes using water and acetonitrile as mobile phases and an Acquity UPLC BEH HSS C18 column (2.1 * 100 mm, 1.7 um). The temperature was set at 45 degrees C and the flow rate was 0.4 mL/min. Photodiode array detection at 256 nm was used as detection system. The method was validated according international guidelines for linearity, accuracy, precision, selectivity, lower limit of quantitation, carry over, and stability under different conditions. RESULTS: All performance parameters were within acceptance criteria, demonstrating that the validated method is fit for purpose. After assay validation, 115 serum samples collected from 41 patients were analyzed to report the experience of the laboratory in TDM of voriconazole. Results showed a large variability in voriconazole trough levels, suggesting that this drug should be frequently measured in patients under treatment to enhance therapies efficacy and improve safety. CONCLUSIONS: In this study, a reproducible U-HPLC-PDA assay with a short analysis time, requiring only a small amount of serum, good accuracy and reproducibility was validated, which is suitable for routine TDM of voriconazole in serum. PMID- 29432387 TI - Quantification of Phosphatidylethanols in Whole Blood as a Proxy for Chronic Alcohol Consumption, Using Ultra Performance Convergence Chromatography Tandem Mass Spectrometry. AB - BACKGROUND: Detection of alcohol consumption after a longer period can be useful in certain patient groups. To monitor chronic alcohol consumption, a novel analytical method for the quantification of phosphatidylethanols (PEths) was developed and validated using ultra performance convergence chromatography-tandem mass spectrometry. METHODS: The main phosphatidylethanols like palmitoyl-2-oleoyl sn-glycero-3-phosphoethanol (POPEth), 1-palmitoyl-2-linoleoyl-sn-glycero-3 phosphoethanol, and 1,2-dioleoyl-sn-glycero-3-phosphoethanol were analyzed using a simple and fast sample preparation protocol followed by chromatographic separation using ultra performance convergence chromatography, a novel kind of supercritical fluid chromatography. Mass spectrometric detection was conducted by applying negative electrospray ionization and multiple reaction monitoring mode. Only 50 MUL of whole blood is needed for the simultaneous quantification of all 3 compounds within 5-minute run-to-run analysis time. POPEth-d5 was applied as internal standard. RESULTS: The method was validated according to the Food and Drug Administration guidelines. Correlation coefficients were higher than 0.995 for all 3 compounds. Intraday and interday inaccuracies were <15% for all analytes in the established linear range. Intraday and interday imprecision were <15% for all analytes. Lower limit of quantification for 1,2-dioleoyl-sn-glycero 3-phosphoethanol, palmitoyl-2-linoleoyl-sn-glycero-3-phosphoethanol, and POPEth are, respectively, 3, 6, and 6 mcg/L. Sample stability at -80 degrees C was 1 year. Extracts were stable for 1 day in the autosampler and 2 days at 2-8 degrees C in a closed Eppendorf tube. Samples were tested after 3 freeze-thaw cycles and considered stable. Patient samples have been analyzed with this new method. In a cohort of 248 pregnant women, 17 patients (6.9%) scored positive for PEth. CONCLUSIONS: The described method is suitable for the simultaneous quantitative analysis of the most abundant PEth homologues. Major advantages are low LLOQs, minimal sample volume and clean-up, and a short run time. The method is now available to monitor alcohol consumption in patients and has been incorporated in clinical practice and research. PMID- 29432388 TI - What's New in Shock, March 2018? PMID- 29432389 TI - Mini-Review: Perfluorocarbons, Oxygen Transport, and Microcirculation in Low Flow States: In Vivo and In Vitro Studies: Erratum. PMID- 29432390 TI - The game of politics. PMID- 29432391 TI - Management of delirium across an integrated health system. AB - Facilitating throughput with systems thinking. PMID- 29432392 TI - RESPONSE TO LETTER BY. PMID- 29432393 TI - Predicting Likelihood of Surgery Before First Visit in Patients With Back and Lower Extremity Symptoms: A Simple Mathematical Model Based on More Than 8,000 Patients. AB - STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: To create a data-driven triage system stratifying patients by likelihood of undergoing spinal surgery within 1 year of presentation. SUMMARY OF BACKGROUND DATA: Low back pain (LBP) and radicular lower extremity (LE) symptoms are common musculoskeletal problems. There is currently no standard data-derived triage process based on information that can be obtained before the initial physician patient encounter to direct patients to the optimal physician type. METHODS: We analyzed patient-reported data from 8006 patients with a chief complaint of low back pain and/or LE radicular symptoms who presented to surgeons at a large multidisciplinary spine center between September 1, 2005 and June 30, 2016. Univariate and multivariate analysis identified independent risk factors for undergoing spinal surgery within 1 year of initial visit. A model incorporating these risk factors was created using a random sample of 80% of the total patients in our cohort, and validated on the remaining 20%. RESULTS: The baseline 1-year surgery rate within our cohort was 39% for all patients and 42% for patients with LE symptoms. Those identified as high likelihood by the center's existing triage process had a surgery rate of 45%. The new triage scoring system proposed in this study was able to identify a high likelihood group in which 58% underwent surgery, which is a 46% higher surgery rate than in nontriaged patients and a 29% improvement from our institution's existing triage system. CONCLUSION: The data driven triage model and scoring system derived and validated in this study (Spine Surgery Likelihood-11), significantly improved existing processes in predicting the likelihood of undergoing spinal surgery within 1 year of initial presentation. This triage system will allow centers to more selectively screen for surgical candidates and more effectively direct patients to surgeons or nonoperative spine specialists. LEVEL OF EVIDENCE: 4. PMID- 29432395 TI - Utility of Supine Lateral Radiographs for Assessment of Lumbar Segmental Instability in Degenerative Lumbar Spondylolisthesis. AB - STUDY DESIGN: Retrospective chart review OBJECTIVE.: To determine whether supine lateral radiographs increase the amount of segmental instability visualized in single-level lumbar degenerative spondylolisthesis, when compared to traditional lateral flexion-extension radiographs. We hypothesized that supine radiographs increase the amount of segmental instability seen in single-level lumbar spondylolisthesis when compared to flexion-extension. SUMMARY OF BACKGROUND DATA: Accurate evaluation of segmental instability is critical to the management of lumbar spondylolisthesis. Standing flexion-extension lateral radiographs are routinely obtained, as it is believed to precipitate the forward-backward motion of the segment; however, recent studies with magnetic resonance imaging and computed tomography have shown that the relaxed supine position can facilitate the reduction of the anterolisthesed segment. Here, we show that inclusion of supine lateral radiographs increases the amount of segmental instability seen in single-level lumbar spondylolisthesis when compared to traditional lateral radiographs. METHODS: Supine lateral radiographs were added to the routine evaluation (standing neutral/flexion/extension lateral radiographs) of symptomatic degenerative spondylolisthesis at our institution. In this retrospective study, 59 patients were included. The amount of listhesis was measured and compared on each radiograph: standing neutral lateral ("neutral"), standing flexion lateral ("flexion"), standing extension lateral ("extension"), and supine lateral ("supine"). RESULTS: A total of 59 patients (51 women, 8 men), with a mean age of 63.0 years (+/-9.85 yr) were included. The mean mobility seen with flexion-extension was 5.53 +/- 4.11. The mean mobility seen with flexion supine was 7.83% +/- 4.67%. This difference was significant in paired t test (P = 0.00133), and independent of age and body mass index. Maximal mobility was seen between flexion and supine radiographs in 37 patients, between neutral and supine radiographs in 11 cases, and between traditional flexion-extension studies in 11 cases. CONCLUSION: Supine radiograph demonstrates more reduction in anterolisthesis than the extension radiograph. Incorporation of a supine lateral radiograph in place of extension radiograph can improve our understanding of segmental mobility when evaluating degenerative spondylolisthesis. LEVEL OF EVIDENCE: 3. PMID- 29432396 TI - Gathering tips from carers to support people with dementia: an adaptation of the TOP 5 program for community use. AB - AIM: Behavioral and psychological symptoms of dementia are often managed inappropriately with antipsychotic medicines. The TOP 5 program, which involves recording up to five relevant and meaningful tips that assist in personalizing care for the person with dementia, has been tested in the hospital setting and transitions of care in Australia, and has been found to be useful. Our study aimed to adapt the TOP 5 program as a strategy to support people with dementia in a primary care setting and to test the acceptability of our adapted TOP 5 program materials. METHODS: The adapted TOP 5 program materials were delivered as part of a larger intervention by the Australian Government Department of Veterans' Affair's Veterans' Medicines Advice & Therapeutic Education Services program to reduce inappropriate antipsychotic use in veterans with dementia. This study focuses on the acceptability of our adapted TOP 5 program materials for ascertaining carer or family members' advice about what actions might help to calm their relative when she or he is agitated. Educational materials relating to the resources for implementing the adapted TOP 5 program together with the one page survey response to evaluate acceptability of our adapted TOP 5 program materials were mailed to 4827 general practitioners (GPs), 8381 accredited pharmacists, and 2510 Residential Aged Care Facilities. RESULTS: We received survey response forms from 350 (7%) GPs, 366 (4%) pharmacists, and 196 (8%) residential aged care facilities. Although the response rate was low, 90% of respondents in all groups indicated they were very likely or moderately likely to assist family members and carers of patients with dementia to identify their top tips to personalize care. GPs who found the information useful more frequently indicated that they were likely to assist family members and carers in identifying their top tips. Approximately one-third of respondents reported they had received positive feedback from families regarding the helpfulness of sharing their practical tips for care of their loved one. Pharmacists indicated having the tips would assist them when undertaking medicines reviews. CONCLUSIONS: Our findings suggest that the TOP 5 program, or an adaptation of the TOP 5 program, such as ours, has potential to improve the health and care of people with dementia and their carers by using patient centerd nonpharmacological approaches and avoiding the unnecessary use of antipsychotics for behavioral and psychological symptoms of dementia. Longer-term follow-up would help to establish whether the apparent benefits persist. PMID- 29432394 TI - Outcomes Reported After Surgery for Cauda Equina Syndrome: A Systematic Literature Review. AB - STUDY DESIGN: This is a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. OBJECTIVE: To assess the outcomes reported in trials and observational studies of surgery for cauda equina syndrome (CES), and to inform the development of a core outcome set. SUMMARY OF BACKGROUND DATA: Scoping searches revealed that there were inconsistencies in which outcomes were reported and how they were measured in research studies for patients who had undergone surgery for CES. METHODS: Ovid Medline, Embase, CINAHL Plus, and trial registries were searched from January 1, 1990 to September 30, 2016 with the term "cauda equina syndrome." Inclusion and exclusion criteria were applied according to study design, diagnosis, procedure, publication date, language, and patient age. Data extracted included demographics, study design, the outcomes reported, and their definition. We also assessed variation in the use of terminology for each outcome domain. RESULTS: A total of 1873 articles were identified, of which 61 met the inclusion criteria. Of these, 737 outcomes reported verbatim were categorized into 20 core outcome domains and 12 subdomains with a range of 1 to 141 outcomes per outcome domain or subdomain. The most commonly reported outcomes were bladder function (70.5%), motor function (63.9%), and sensation (50.8%). Significant variation in the terms used for each outcome was documented, for example, bladder function outcome domain had 141 different terms. CONCLUSION: There is significant heterogeneity in outcomes reported for studies after surgery for CES patients. This indicates a clear need for the development of a core outcome set, which has been registered as number 824 on the COMET (Core Outcome Measure in Effectiveness Trials) database. LEVEL OF EVIDENCE: 1. PMID- 29432397 TI - Attitudes, knowledge and behaviors related to evidence-based practice in health professionals involved in pain management. AB - BACKGROUND: Healthcare professionals involved in pain management come from different disciplines, which may have different perspectives and training about evidence-based practice (EBP). A common concern for health professionals is pain management. Understanding how different professions involved in pain management view EBP forms the ideal context to study professional differences in EPP, and how this might influence pain management. PURPOSE: The purpose of this study was to compare different professions with respect to knowledge, attitudes and self reported behavior toward EBP. STUDY DESIGN: Cross-sectional study. METHODS: Physicians, nurses, occupational therapists, physical therapists and psychologists who were involved in pain management (n = 675) completed an online survey on a single occasion. The survey included demographic questions and the EBP-knowledge, attitude, behavior questionnaire (EBP-KABQ). This is a 27-item questionnaire that has been validated for use with different health professionals, and measures four constructs related to EBP (knowledge, attitude, behavior and outcome/decision). Differences between professionals were identified using a one-way between groups analysis of variance, with post-hoc testing (statistical significance was set at P value less than 0.05; clinical significance set at a mean difference of 10%). RESULTS: The score on three of the four subscales of the KABQ were statistically different across professions. In general, knowledge scores were high for all professions (83-87%). Nurses demonstrated statistically higher levels of EBP knowledge (87%) when compared with other groups (F = 4.79, P = 0.001), but the differences were not deemed clinically relevant. Behavior was the lowest subscale and the most variable across professions (37-56%). Physicians had statistically significant (F = 25.69; P = 0.001), and clinically relevant, higher behavior subscale scores (56%) when compared with other professional groups. Physicians (73%) also had higher outcome/decision subscale scores (F = 6.50; P = 0.001), but this was only marginally different from other professions (65-73%). The attitude subscale scores were low and were not different across professions (range 57-59%; F = 1.65, P = 0.16; NS). CONCLUSION: The current study indicates that physicians and allied health professionals have similar EBP attitudes and knowledge. All professional groups seem to have suboptimal implementation of EBP. The nature of medical decision-making, its evidentiary pool, or longer experience with EBP may contribute to greater implementation amongst physicians. PMID- 29432398 TI - Ranolazine treatment in the heterogeneous symptomatic stable coronary artery disease population. PMID- 29432399 TI - Cryoballoon vs. radiofrequency contact force ablation for paroxysmal atrial fibrillation: a propensity score analysis. AB - BACKGROUND: Radiofrequency and cryoballoon pulmonary vein isolation are common approaches for paroxysmal atrial fibrillation treatment, showing similar results in recent multicenter studies, including heterogeneous tools and protocols. The aim of this study is to compare prospectively in a single, high-volume center the outcome of paroxysmal atrial fibrillation ablation performed specifically by second-generation cryoballoon or contact force radiofrequency ablation. METHODS: Consecutive patients scheduled for paroxysmal atrial fibrillation transcatheter ablation have been included and prospectively followed up. Aiming to reduce potential bias deriving from baseline characteristics, a propensity score matching analysis has been performed to analyze safety and efficacy outcomes. RESULTS: Out of consecutive patients undergoing atrial fibrillation transcatheter ablation between January 2015 and December 2016, 46 patients approached by cryoablation were matched 1 : 1 by propensity score to a similar population treated by last-generation radiofrequency ablation. Freedom from atrial fibrillation after 12 months (76 vs. 78%, P = 0.804) and incidence of complications (4 vs. 6%, P = 0.168) did not differ between the two groups. Radiological exposure was higher for the cryoballoon group (11 vs. 4 min, P < 0.001), whereas procedural duration did not differ (P = 0.174). Aiming to assess the potential impact of a learning curve in patients undergoing cryoablation, the first-third of patients (n = 15) were compared with the remaining, reporting longer radiological exposure (P < 0.001), but similar safety and efficacy. CONCLUSION: In this propensity score analysis, last-generation cryoballoon and radiofrequency catheters for atrial fibrillation ablation present similar efficacy and safety. Cryoablation requires longer fluoroscopy exposure compared with radiofrequency, although this is reduced by increased experience. PMID- 29432400 TI - Treatment of coronary artery disease with a new-generation drug-coated balloon: final results of the Italian Elutax SV rEgistry-DCB-RISE. AB - AIMS: Drug-coated balloons (DCBs) are a recognized alternative to stents for the treatment of in-stent restenosis (ISR), and there is some initial clinical evidence about their efficacy for the treatment of small coronary vessels. Newer generation DCBs were developed to overcome the reduced deliverability of the previous generation, also warranting a more effective drug delivery to vessel wall. However, the vast majority of new-generation DCBs still lack of reliability due to paucity of clinical data. METHODS: Between 2012 and 2015, all patients treated with Elutax SV DCB (Aachen Resonance, Germany) at nine Italian centers were enrolled in this retrospective registry. Primary outcome was the occurrence of target-lesion revascularization (TLR) at the longest available follow-up. Secondary endpoints were procedural success and occurrence of device-oriented adverse cardiovascular events including cardiac death, target-vessel myocardial infarction, stroke, and TLR. A minimum 6-month clinical follow-up was required. RESULTS: We enrolled 544 consecutive patients treated at 583 sites. Fifty-three per cent of the patients had ISR, and the rest native vessel coronary artery disease. Procedural success occurred in 97.5%. At the longest available clinical follow-up (average 13.3 +/- 7.4 months), 5.9% of the patients suffered a TLR and 7.1% a device-oriented adverse cardiovascular event. We did not register cases of target-vessel abrupt occlusion. At multivariate analysis, severe calcification at the lesion site was the first determinant for the occurrence of TLR. CONCLUSION: This registry on the performance of a new-generation DCB shows an adequate profile of safety and efficacy at mid-term clinical follow-up. PMID- 29432401 TI - Long-term outcomes and predictors of recurrence after pulmonary vein isolation with multielectrode ablation catheter in patients with atrial fibrillation. AB - PURPOSE: Despite various techniques used in atrial fibrillation ablation, recurrence of atrial arrhythmias still constitutes a clinical problem. The aim of this study was to document the long-term outcomes of pulmonary vein isolation with a ring-shaped ablation catheter (PVAC). METHODS: All consecutive patients presenting with paroxysmal or persistent atrial fibrillation (pxAF or perAF, respectively) treated with PVAC (first generation) were enrolled. After standard follow-up during the first year, all patients were contacted for long-term follow up. In addition to the patient's medical history, 3-day Holter monitoring was performed. Endpoints were atrial fibrillation-related symptoms, ECG documentation of atrial fibrillation or other left atrial arrhythmias and reablation. RESULTS: In total, 125 patients (78% with pxAF) were enrolled. All but two pulmonary veins (0.4% of 485 pulmonary veins) could be successfully isolated. At 12 months, 83% of patients in the pxAF group and 53% of patients in the perAF group were free from symptoms. The mean long-term follow-up was 51 +/- 14 months. Regarding long term efficacy, 56% of patients in the pxAF group and 28% of patients in the perAF group were free from any recurrence at 72 months. Independent predictors of event free survival were perAF (hazard ratio 2.76, P = 0.001) and the existence of mild valvular disease (hazard ratio 2.69, P = 0.001). No significant complication due to PVAC occurred, especially no ischemic stroke. CONCLUSION: Long-term follow-up indicated for the first time in such a considerable cohort that pulmonary vein isolation with PVAC is a safe and very efficient method for treating pxAF - despite known microembolism issues. Patients with perAF receive less benefit from PVAC and ablation therapy should be reserved to pxAF. Significantly, even mild valvular disease was an independent predictor of atrial fibrillation recurrence. PMID- 29432402 TI - Performance Under Stress Conditions During Multidisciplinary Team Immersive Pediatric Simulations. AB - OBJECTIVES: The primary objective was to determine whether technical and nontechnical performances were in some way correlated during immersive simulation. Performance was measured among French Emergency Medical Service workers at an individual and a team level. Secondary objectives were to assess stress response through collection of physiologic markers (salivary cortisol, heart rate, the proportion derived by dividing the number of interval differences of successive normal-to-normal intervals > 50 ms by the total number of normal-to normal intervals [pNN50], low- and high-frequency ratio) and affective data (self reported stress, confidence, and dissatisfaction), and to correlate them to performance scores. DESIGN: Prospective observational study performed as part of a larger randomized controlled trial. SETTING: Medical simulation laboratory. SUBJECTS: Forty-eight participants distributed among 12 Emergency Medical System teams. INTERVENTIONS: Individual and team performance measures and individual stress response were assessed during a high-fidelity simulation. Technical performance was assessed by the intraosseous access performance scale and the Team Average Performance Assessment Scale; nontechnical performance by the Behavioral Assessment Tool for leaders, and the Clinical Teamwork Scale. Stress markers (salivary cortisol, heart rate, pNN50, low- and high-frequency ratio) were measured both before (T1) and after the session (T2). Participants self reported stress before and during the simulation, self-confidence, and perception of dissatisfaction with team performance, rated on a scale from 0 to 10. MEASUREMENTS AND MAIN RESULTS: Scores (out of 100 total points, mean +/- SD) were intraosseous equals to 65.6 +/- 14.4, Team Average Performance Assessment Scale equals to 44.6 +/- 18.1, Behavioral Assessment Tool equals to 49.5 +/- 22.0, Clinical Teamwork Scale equals to 50.3 +/- 18.5. There was a strong correlation between Behavioral Assessment Tool and Clinical Teamwork Scale (Rho = 0.97; p = 0.001), and Behavioral Assessment Tool and Team Average Performance Assessment Scale (Rho = 0.73; p = 0.02). From T1 to T2, all stress markers (salivary cortisol, heart rate, pNN50, and low- and high-frequency ratio) displayed an increase in stress level (p < 0.001 for all). Self-confidence was positively correlated with performance (Clinical Teamwork Scale: Rho = 0.47; p = 0.001, Team Average Performance Assessment Scale: Rho = 0.46; p = 0.001). Dissatisfaction was negatively correlated with performance (Rho = -0.49; p = 0.0008 with Behavioral Assessment Tool, Rho = -0.47; p = 0.001 with Clinical Teamwork Scale, Rho = 0.51; p = 0.0004 with Team Average Performance Assessment Scale). No correlation between stress response and performance was found. CONCLUSIONS: There was a positive correlation between leader (Behavioral Assessment Tool) and team (Clinical Teamwork Scale and Team Average Performance Assessment Scale) performances. These performance scores were positively correlated with self confidence and negatively correlated with dissatisfaction. PMID- 29432403 TI - Neutrophil Extracellular Traps in Children With Meningococcal Sepsis. AB - OBJECTIVES: Children with meningococcal sepsis are highly at risk for fulminant disease, multiple organ failure, and death. Recently, neutrophil extracellular traps levels have been indicated as a marker for severity in different kinds of sepsis. Our aim was to study the role of neutrophil extracellular traposis in meninogococcal sepsis in children. DESIGN: We measured myeloperoxidase-DNA, a marker for neutrophil extracellular traps, in serum of meningococcal sepsis patients upon admission to PICU, at 24 hours, and at 1 month and studied the association with clinical outcome. Subsequently, we tested whether Neisseria meningitidis, isolated from children with meningococcal sepsis, were able to induce neutrophil extracellular traposis, using confocal microscopy live imaging. SETTING: We used enzyme-linked immunosorbent assays to measure myeloperoxidase DNA in patient serum. We also included inflammatory markers that were previously measured in this group. PATIENTS: We included exclusively children with meningococcal sepsis. INTERVENTIONS: From each patient, serum was collected for analysis. MEASUREMENTS AND MAIN RESULTS: Myeloperoxidase-DNA levels at admission (n = 35; median, 0.21 AU/mL; interquartile range, 0.12-0.27) and at 24 hours (n = 39; median, 0.14 AU/mL; interquartile range, 0.09-0.25) were significantly higher than the myeloperoxidase-DNA levels after 1 month (controls: n = 36; median, 0.07 AU/mL; interquartile range, 0.05-0.09; p < 0.001). We did not observe a correlation between myeloperoxidase-DNA levels and mortality, cell-free DNA, or other inflammatory markers. In addition, N. meningitidis are fast and strong inducers of neutrophil extracellular traposis. CONCLUSIONS: Children admitted to PICU for meningococcal sepsis have higher neutrophil extracellular traps levels at admission and after 24 hours than controls. Neutrophil extracellular traps levels were not associated with outcome, cell-free DNA, or other inflammatory markers. These neutrophil extracellular traps may be induced by N. meningitidis, since these are strong neutrophil extracellular traposis inducers. PMID- 29432404 TI - Duration to Establish an Emergency Vascular Access and How to Accelerate It: A Simulation-Based Study Performed in Real-Life Neonatal Resuscitation Rooms. AB - OBJECTIVES: To compare the duration to establish an umbilical venous catheter and an intraosseous access in real hospital delivery rooms and as a secondary aim to assess delaying factors during establishment and to provide recommendations to accelerate vascular access in neonatal resuscitation. DESIGN: Retrospective analysis of audio-video recorded neonatal simulation training. SETTINGS: Simulation training events in exact replications of actual delivery/resuscitation rooms of 16 hospitals with different levels of care (Austria and Germany). Equipment was prepared the same way as for real clinical events. SUBJECTS: Medical teams of four to five persons with birth-related background (midwives, nurses, neonatologists, and anesthesiologists) in a realistic team composition. INTERVENTIONS: Audio-video recorded mannequin-based simulated resuscitation of an asphyxiated newborn including the establishment of either umbilical venous catheter or intraosseous access. MEASUREMENTS AND MAIN RESULTS: The duration of access establishment (time from decision to first flush/aspiration), preparation (decision to start of procedure), and the procedure itself (start to first flush/aspiration) was significantly longer for umbilical venous catheter than for intraosseous access (overall duration 199 vs 86 s). Delaying factors for umbilical venous catheter establishment were mainly due to the complex approach itself, the multitude of equipment required, and uncertainties about necessary hygiene standards. Challenges in intraosseous access establishment were handling of the unfamiliar material and absence of an intraosseous access kit in the resuscitation room. There was no significant difference between the required duration for access establishment between large centers and small hospitals, but a trend was observed that duration for umbilical venous catheter was longer in small hospitals than in centers. Duration for intraosseous access was similar in both hospital types. CONCLUSIONS: Vascular access establishment in neonatal resuscitation could be accelerated by infrastructural improvements and specific training of medical teams. In simulated in situ neonatal resuscitation, intraosseous access is faster to establish than umbilical venous catheter. Future studies are required to assess efficacy and safety of both approaches in real resuscitation settings. PMID- 29432405 TI - Interhospital Transport of Critically Ill Children to PICUs in the United Kingdom and Republic of Ireland: Analysis of an International Dataset. AB - OBJECTIVES: International data on characteristics and outcomes of children transported from general hospitals to PICUs are scarce. We aimed to 1) describe the development of a common transport dataset in the United Kingdom and Ireland and 2) analyze transport data from a recent 2-year period. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Specialist pediatric critical care transport teams and PICUs in the United Kingdom and Ireland. PATIENTS: Critically ill children less than 16 years old transported by pediatric critical care transport teams to PICUs in the United Kingdom and Ireland. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A common transport dataset was developed as part of the Paediatric Intensive Care Audit Network, and standardized data were collected from all PICUs and pediatric critical care transport teams from 2012. Anonymized data on transports (and linked PICU admissions) from a 2-year period (2014-2015) were analyzed to describe patient and transport characteristics, and in uni- and multivariate analyses, to study the association between key transport factors and PICU mortality. A total of 8,167 records were analyzed. Transported children were severely ill (median predicted mortality risk 4.4%) with around half being infants (4,226/8,167; 51.7%) and nearly half presenting with respiratory illnesses (3,619/8,167; 44.3%). The majority of transports were led by physicians (78.4%; consultants: 3,059/8,167, fellows: 3,344/8,167). The median time for a pediatric critical care transport team to arrive at the patient's bedside from referral was 85 minutes (interquartile range, 58-135 min). Adverse events occurred in 369 transports (4.5%). There were considerable variations in how transports were organized and delivered across pediatric critical care transport teams. In multivariate analyses, consultant team leader and transport from an intensive care area were associated with PICU mortality (p = 0.006). CONCLUSIONS: Variations exist in United Kingdom and Ireland services for critically ill children needing interhospital transport. Future studies should assess the impact of these variations on long-term patient outcomes taking into account treatment provided prior to transport. PMID- 29432406 TI - Examination of Utricular Response Using oVEMP and Unilateral Centrifugation Rotation Testing. AB - OBJECTIVES: Significant advancements have been made toward the clinical assessment of utricular function through ocular vestibular-evoked myogenic potentials (oVEMP) and unilateral centrifugation (UCF) testing. To date, no study has examined intrasubject relationships between these measures. The study hypothesis was that intrasubject responses from oVEMP and UCF testing would be correlated inasmuch as both tests have been reported to assess utricular function. DESIGN: UCF rotations and oVEMP testing were performed on healthy volunteers, aged 18 to 62 years. A within-subject study design compared and correlated UCF outcome measures of ocular counterroll, subjective visual vertical, and ocular counterroll-gravitational inertial acceleration slope against peak to peak oVEMP N1-P1 amplitude. RESULTS: Correlational analyses failed to reveal any significant relationships between oVEMP amplitude and UCF responses suggesting that these tests may be inciting different response properties within the utricular system. CONCLUSIONS: Various anatomical and physiological differences within the utricle, in addition to the fundamental differences in stimulus properties between the oVEMP and UCF tests, could explain the lack of significant correlations between these measures and suggest that oVEMP and UCF testing may be complimentary in their evaluation of the utricular system. These data reinforce the complexities of the utricular system and provide further insight into the difficulties encountered in its clinical assessment. PMID- 29432408 TI - A Randomized Trial Comparing Clinical Outcomes Between Zero-Profile and Traditional Multilevel Anterior Cervical Discectomy and Fusion Surgery for Cervical Myelopathy. AB - STUDY DESIGN: Prospective randomized study from a single center OBJECTIVE.: The purpose of this study was to compare outcomes between a zero-profile (ZP) anterior cervical discectomy and fusion (ACDF) construct to a traditional ACDF with anterior cervical plate (ACP) in the treatment of multilevel cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: Multilevel cervical spondylotic myelopathy can be treated by a variety of techniques, most commonly with corpectomy, ACDF, posterior cervical fusion, or a combination of the three. Examples in the literature of comparative effectiveness of different anterior approach types are few. METHODS: A total of 104 patients with multilevel cervical spondylotic myelopathy were randomized in equal proportion between treated with ACDF and ZP or ACDF with ACP. Clinical efficacy of two groups was evaluated preoperatively and at all postoperative time points through 2 years postoperative by the Japanese Orthopedic Association score and the neck disability index. Radiographic changes from baseline, including disc height and cervical lordosis, were evaluated at the same postoperative time points. Complications were assessed perioperatively and through 2 years postoperatively. RESULTS: The ZP and ACP ACDF groups demonstrated substantially equivalent Japanese Orthopaedic Association, neck disability index, disc height, and lordosis improvements from baseline, which were maintained through 2 years postoperatively. Complications occurred in 4% of ZP and 17% of ACP patients (P = 0.052), and zero (0%) ZP and four (8%) ACP patients reported hoarseness or dysphagia. CONCLUSION: ZP used in multilevel ACDF may obtain favorable clinical outcomes and a lower postoperative complication. LEVEL OF EVIDENCE: 2. PMID- 29432409 TI - TO THE EDITOR. PMID- 29432410 TI - Angiopoietin-Like 4 Attenuates Brain Edema and Neurological Deficits in a Mouse Model of Experimental Intracerebral Hemorrhage. AB - BACKGROUND Angiopoietin-like 4 (ANGPTL4) is neuroprotective when administered acutely for the treatment of cerebral ischemia. The aim of the present study was to evaluate the preventive effects of ANGPTL4 on the formation of brain edema and to determine whether it promotes the recovery of neurological function following intracerebral hemorrhage (ICH). MATERIAL AND METHODS Recombinant human ANGPTL4 (rhANGPTL4; 40 ug/kg) or a vehicle was administered intraperitoneally 5 min prior to bacterial collagenase-induced ICH in male C57/B6J mice. Behavioral tests were performed prior to ICH and at days 1, 3, 7, 14, 21, and 28 after ICH. Brain edema and hematoma volume were examined separately using the wet weight/dry weight method and hematoxylin-eosin staining. The integrity of the tight and adherens junctions was quantified via immunofluorescence. The ultrastructure of the blood brain barrier (BBB) was examined using transmission electron microscopy. Vascular endothelial (VE)-cadherin, claudin-5, Src, and phospho-Src in the ipsilateral and contralateral striatum were detected by Western blot analysis. RESULTS RhANGPTL4 reduced brain edema and hematoma volume and improved neurological functional recovery over the subsequent 4 weeks when compared with the control group. rhANGPTL4 significantly increased VE-cadherin and claudin-5-positive areas and relative amounts in the peri-hematoma region compared with the control group. In addition, ANGPTL4 significantly reduced the ratio of phospho-Src to Src. The significant reduction of Src kinase activity in the peri-hematoma region of ANGPTL-treated mice was paralleled by a decrease in vascular permeability and edema formation. CONCLUSIONS These results suggest that ANGPTL4 is a relevant target for vasculoprotection and cerebral protection during stroke. PMID- 29432411 TI - Electrical receptive fields of retinal ganglion cells: Influence of presynaptic neurons. AB - Implantable retinal stimulators activate surviving neurons to restore a sense of vision in people who have lost their photoreceptors through degenerative diseases. Complex spatial and temporal interactions occur in the retina during multi-electrode stimulation. Due to these complexities, most existing implants activate only a few electrodes at a time, limiting the repertoire of available stimulation patterns. Measuring the spatiotemporal interactions between electrodes and retinal cells, and incorporating them into a model may lead to improved stimulation algorithms that exploit the interactions. Here, we present a computational model that accurately predicts both the spatial and temporal nonlinear interactions of multi-electrode stimulation of rat retinal ganglion cells (RGCs). The model was verified using in vitro recordings of ON, OFF, and ON OFF RGCs in response to subretinal multi-electrode stimulation with biphasic pulses at three stimulation frequencies (10, 20, 30 Hz). The model gives an estimate of each cell's spatiotemporal electrical receptive fields (ERFs); i.e., the pattern of stimulation leading to excitation or suppression in the neuron. All cells had excitatory ERFs and many also had suppressive sub-regions of their ERFs. We show that the nonlinearities in observed responses arise largely from activation of presynaptic interneurons. When synaptic transmission was blocked, the number of sub-regions of the ERF was reduced, usually to a single excitatory ERF. This suggests that direct cell activation can be modeled accurately by a one dimensional model with linear interactions between electrodes, whereas indirect stimulation due to summated presynaptic responses is nonlinear. PMID- 29432412 TI - Hub connectivity, neuronal diversity, and gene expression in the Caenorhabditis elegans connectome. AB - Studies of nervous system connectivity, in a wide variety of species and at different scales of resolution, have identified several highly conserved motifs of network organization. One such motif is a heterogeneous distribution of connectivity across neural elements, such that some elements act as highly connected and functionally important network hubs. These brain network hubs are also densely interconnected, forming a so-called rich club. Recent work in mouse has identified a distinctive transcriptional signature of neural hubs, characterized by tightly coupled expression of oxidative metabolism genes, with similar genes characterizing macroscale inter-modular hub regions of the human cortex. Here, we sought to determine whether hubs of the neuronal C. elegans connectome also show tightly coupled gene expression. Using open data on the chemical and electrical connectivity of 279 C. elegans neurons, and binary gene expression data for each neuron across 948 genes, we computed a correlated gene expression score for each pair of neurons, providing a measure of their gene expression similarity. We demonstrate that connections between hub neurons are the most similar in their gene expression while connections between nonhubs are the least similar. Genes with the greatest contribution to this effect are involved in glutamatergic and cholinergic signaling, and other communication processes. We further show that coupled expression between hub neurons cannot be explained by their neuronal subtype (i.e., sensory, motor, or interneuron), separation distance, chemically secreted neurotransmitter, birth time, pairwise lineage distance, or their topological module affiliation. Instead, this coupling is intrinsically linked to the identity of most hubs as command interneurons, a specific class of interneurons that regulates locomotion. Our results suggest that neural hubs may possess a distinctive transcriptional signature, preserved across scales and species, that is related to the involvement of hubs in regulating the higher-order behaviors of a given organism. PMID- 29432413 TI - Comprehensive analysis of central carbon metabolism illuminates connections between nutrient availability, growth rate, and cell morphology in Escherichia coli. AB - Bacterial morphology is a complex trait that is highly sensitive to changes in the environment. For heterotrophic organisms, such as Escherichia coli, increases in nutrient levels are frequently accompanied by several-fold increases in both size and growth rate. Despite the dramatic nature of these changes, how alterations in nutrient availability translate into changes in growth and morphology remains a largely open question. To understand the signaling networks coupling nutrient availability with size and shape, we examined the impact of deletions in the entirety of non-essential central carbon metabolic genes on E. coli growth rate and cell size. Our data reveal the presence of multiple metabolic nodes that play important yet distinctive roles in dictating biosynthetic capacity and shaping cell morphology. Specifically, perturbations of acetyl-CoA metabolism impact cell size and division through changes in fatty acid synthesis. Additionally, we identify a genetic pathway linking glucose levels to cell width through the signaling molecule cyclic-AMP. Together our findings highlight a surprising diversity of factors and mechanisms contributing to growth potential and cell morphology, providing a foundation for further studies. PMID- 29432414 TI - EAT1 transcription factor, a non-cell-autonomous regulator of pollen production, activates meiotic small RNA biogenesis in rice anther tapetum. AB - The 24-nucleotides (nt) phased secondary small interfering RNA (phasiRNA) is a unique class of plant small RNAs abundantly expressed in monocot anthers at early meiosis. Previously, 44 intergenic regions were identified as the loci for longer precursor RNAs of 24-nt phasiRNAs (24-PHASs) in the rice genome. However, the regulatory mechanism that determines spatiotemporal expression of these RNAs has remained elusive. ETERNAL TAPETUM1 (EAT1) is a basic-helix-loop-helix (bHLH) transcription factor indispensable for induction of programmed cell death (PCD) in postmeiotic anther tapetum, the somatic nursery for pollen production. In this study, EAT1-dependent non-cell-autonomous regulation of male meiosis was evidenced from microscopic observation of the eat1 mutant, in which meiosis with aberrantly decondensed chromosomes was retarded but accomplished somehow, eventually resulting in abortive microspores due to an aberrant tapetal PCD. EAT1 protein accumulated in tapetal-cell nuclei at early meiosis and postmeiotic microspore stages. Meiotic EAT1 promoted transcription of 24-PHAS RNAs at 101 loci, and importantly, also activated DICER-LIKE5 (DCL5, previous DCL3b in rice) mRNA transcription that is required for processing of double-stranded 24-PHASs into 24-nt lengths. From the results of the chromatin-immunoprecipitation and transient expression analyses, another tapetum-expressing bHLH protein, TDR INTERACTING PROTEIN2 (TIP2), was suggested to be involved in meiotic small-RNA biogenesis. The transient assay also demonstrated that UNDEVELOPED TAPETUM1 (UDT1)/bHLH164 is a potential interacting partner of both EAT1 and TIP2 during early meiosis. This study indicates that EAT1 is one of key regulators triggering meiotic phasiRNA biogenesis in anther tapetum, and that other bHLH proteins, TIP2 and UDT1, also play some important roles in this process. Spatiotemporal expression control of these bHLH proteins is a clue to orchestrate precise meiosis progression and subsequent pollen production non-cell-autonomously. PMID- 29432415 TI - Same but not alike: Structure, flexibility and energetics of domains in multi domain proteins are influenced by the presence of other domains. AB - The majority of the proteins encoded in the genomes of eukaryotes contain more than one domain. Reasons for high prevalence of multi-domain proteins in various organisms have been attributed to higher stability and functional and folding advantages over single-domain proteins. Despite these advantages, many proteins are composed of only one domain while their homologous domains are part of multi domain proteins. In the study presented here, differences in the properties of protein domains in single-domain and multi-domain systems and their influence on functions are discussed. We studied 20 pairs of identical protein domains, which were crystallized in two forms (a) tethered to other proteins domains and (b) tethered to fewer protein domains than (a) or not tethered to any protein domain. Results suggest that tethering of domains in multi-domain proteins influences the structural, dynamic and energetic properties of the constituent protein domains. 50% of the protein domain pairs show significant structural deviations while 90% of the protein domain pairs show differences in dynamics and 12% of the residues show differences in the energetics. To gain further insights on the influence of tethering on the function of the domains, 4 pairs of homologous protein domains, where one of them is a full-length single-domain protein and the other protein domain is a part of a multi-domain protein, were studied. Analyses showed that identical and structurally equivalent functional residues show differential dynamics in homologous protein domains; though comparable dynamics between in silico generated chimera protein and multi-domain proteins were observed. From these observations, the differences observed in the functions of homologous proteins could be attributed to the presence of tethered domain. Overall, we conclude that tethered domains in multi-domain proteins not only provide stability or folding advantages but also influence pathways resulting in differences in function or regulatory properties. PMID- 29432416 TI - SOX2 regulates common and specific stem cell features in the CNS and endoderm derived organs. AB - Stem cells are defined by their capacities to self-renew and generate progeny of multiple lineages. The transcription factor SOX2 has key roles in the regulation of stem cell characteristics, but whether SOX2 achieves these functions through similar mechanisms in distinct stem cell populations is not known. To address this question, we performed RNA-seq and SOX2 ChIP-seq on embryonic mouse cortex, spinal cord, stomach and lung/esophagus. We demonstrate that, although SOX2 binds a similar motif in the different cell types, its target regions are primarily cell-type-specific and enriched for the distinct binding motifs of appropriately expressed interacting co-factors. Furthermore, cell-type-specific SOX2 binding in endodermal and neural cells is most often found around genes specifically expressed in the corresponding tissue. Consistent with this, we demonstrate that SOX2 target regions can act as cis-regulatory modules capable of directing reporter expression to appropriate tissues in a zebrafish reporter assay. In contrast, SOX2 binding sites found in both endodermal and neural tissues are associated with genes regulating general stem cell features, such as proliferation. Notably, we provide evidence that SOX2 regulates proliferation through conserved mechanisms and target genes in both germ layers examined. Together, these findings demonstrate how SOX2 simultaneously regulates cell-type specific, as well as core transcriptional programs in neural and endodermal stem cells. PMID- 29432417 TI - Heritable tumor cell division rate heterogeneity induces clonal dominance. AB - Tumors consist of a hierarchical population of cells that differ in their phenotype and genotype. This hierarchical organization of cells means that a few clones (i.e., cells and several generations of offspring) are abundant while most are rare, which is called clonal dominance. Such dominance also occurred in published in vitro iterated growth and passage experiments with tumor cells in which genetic barcodes were used for lineage tracing. A potential source for such heterogeneity is that dominant clones derive from cancer stem cells with an unlimited self-renewal capacity. Furthermore, ongoing evolution and selection within the growing population may also induce clonal dominance. To understand how clonal dominance developed in the iterated growth and passage experiments, we built a computational model that accurately simulates these experiments. The model simulations reproduced the clonal dominance that developed in in vitro iterated growth and passage experiments when the division rates vary between cells, due to a combination of initial variation and of ongoing mutational processes. In contrast, the experimental results can neither be reproduced with a model that considers random growth and passage, nor with a model based on cancer stem cells. Altogether, our model suggests that in vitro clonal dominance develops due to selection of fast-dividing clones. PMID- 29432418 TI - Spike and burst coding in thalamocortical relay cells. AB - Mammalian thalamocortical relay (TCR) neurons switch their firing activity between a tonic spiking and a bursting regime. In a combined experimental and computational study, we investigated the features in the input signal that single spikes and bursts in the output spike train represent and how this code is influenced by the membrane voltage state of the neuron. Identical frozen Gaussian noise current traces were injected into TCR neurons in rat brain slices as well as in a validated three-compartment TCR model cell. The resulting membrane voltage traces and spike trains were analyzed by calculating the coherence and impedance. Reverse correlation techniques gave the Event-Triggered Average (ETA) and the Event-Triggered Covariance (ETC). This demonstrated that the feature selectivity started relatively long before the events (up to 300 ms) and showed a clear distinction between spikes (selective for fluctuations) and bursts (selective for integration). The model cell was fine-tuned to mimic the frozen noise initiated spike and burst responses to within experimental accuracy, especially for the mixed mode regimes. The information content carried by the various types of events in the signal as well as by the whole signal was calculated. Bursts phase-lock to and transfer information at lower frequencies than single spikes. On depolarization the neuron transits smoothly from the predominantly bursting regime to a spiking regime, in which it is more sensitive to high-frequency fluctuations. The model was then used to elucidate properties that could not be assessed experimentally, in particular the role of two important subthreshold voltage-dependent currents: the low threshold activated calcium current (IT) and the cyclic nucleotide modulated h current (Ih). The ETAs of those currents and their underlying activation/inactivation states not only explained the state dependence of the firing regime but also the long-lasting concerted dynamic action of the two currents. Finally, the model was used to investigate the more realistic "high-conductance state", where fluctuations are caused by (synaptic) conductance changes instead of current injection. Under "standard" conditions bursts are difficult to initiate, given the high degree of inactivation of the T-type calcium current. Strong and/or precisely timed inhibitory currents were able to remove this inactivation. PMID- 29432419 TI - An efficient Bayesian meta-analysis approach for studying cross-phenotype genetic associations. AB - Simultaneous analysis of genetic associations with multiple phenotypes may reveal shared genetic susceptibility across traits (pleiotropy). For a locus exhibiting overall pleiotropy, it is important to identify which specific traits underlie this association. We propose a Bayesian meta-analysis approach (termed CPBayes) that uses summary-level data across multiple phenotypes to simultaneously measure the evidence of aggregate-level pleiotropic association and estimate an optimal subset of traits associated with the risk locus. This method uses a unified Bayesian statistical framework based on a spike and slab prior. CPBayes performs a fully Bayesian analysis by employing the Markov Chain Monte Carlo (MCMC) technique Gibbs sampling. It takes into account heterogeneity in the size and direction of the genetic effects across traits. It can be applied to both cohort data and separate studies of multiple traits having overlapping or non overlapping subjects. Simulations show that CPBayes can produce higher accuracy in the selection of associated traits underlying a pleiotropic signal than the subset-based meta-analysis ASSET. We used CPBayes to undertake a genome-wide pleiotropic association study of 22 traits in the large Kaiser GERA cohort and detected six independent pleiotropic loci associated with at least two phenotypes. This includes a locus at chromosomal region 1q24.2 which exhibits an association simultaneously with the risk of five different diseases: Dermatophytosis, Hemorrhoids, Iron Deficiency, Osteoporosis and Peripheral Vascular Disease. We provide an R-package 'CPBayes' implementing the proposed method. PMID- 29432420 TI - In vitro studies of Rickettsia-host cell interactions: Confocal laser scanning microscopy of Rickettsia helvetica-infected eukaryotic cell lines. AB - Rickettsia (R.) helvetica is the most prevalent rickettsia found in Ixodes ricinus ticks in Germany. Several studies reported antibodies against R. helvetica up to 12.5% in humans investigated, however, fulminant clinical cases are rare indicating a rather low pathogenicity compared to other rickettsiae. We investigated growth characteristics of R. helvetica isolate AS819 in two different eukaryotic cell lines with focus on ultra-structural changes of host cells during infection determined by confocal laser scanning microscopy. Further investigations included partially sequencing of rickA, sca4 and sca2 genes, which have been reported to encode proteins involved in cell-to-cell spread and virulence in some rickettsiae. R. helvetica grew constantly but slowly in both cell lines used. Confocal laser scanning microscopy revealed that the dissemination of R. helvetica AS819 in both cell lines was rather mediated by cell break-down and bacterial release than cell-to-cell spread. The cytoskeleton of both investigated eukaryotic cell lines was not altered. R. helvetica possesses rickA, but its expression is not sufficient to promote actin-based motility as demonstrated by confocal laser scanning microscopy. Hypothetical Sca2 and Sca4 proteins were deduced from nucleotide gene sequences but the predicted amino acid sequences were disrupted or truncated compared to other rickettsiae most likely resulting in non-functional proteins. Taken together, these results might give a first hint to the underlying causes of the reduced virulence and pathogenicity of R. helvetica. PMID- 29432422 TI - TopicalPdb: A database of topically delivered peptides. AB - TopicalPdb (http://crdd.osdd.net/raghava/topicalpdb/) is a repository of experimentally verified topically delivered peptides. Data was manually collected from research articles. The current release of TopicalPdb consists of 657 entries, which includes peptides delivered through the skin (462 entries), eye (173 entries), and nose (22 entries). Each entry provides comprehensive information related to these peptides like the source of origin, nature of peptide, length, N- and C-terminal modifications, mechanism of penetration, type of assays, cargo and biological properties of peptides, etc. In addition to natural peptides, TopicalPdb contains information of peptides having non-natural, chemically modified residues and D-amino acids. Besides this primary information, TopicalPdb stores predicted tertiary structures as well as peptide sequences in SMILE format. Tertiary structures of peptides were predicted using state-of-art method PEPstrMod. In order to assist users, a number of web-based tools have been integrated that includes keyword search, data browsing, similarity search and structural similarity. We believe that TopicalPdb is a unique database of its kind and it will be very useful in designing peptides for non-invasive topical delivery. PMID- 29432421 TI - The rate and potential relevance of new mutations in a colonizing plant lineage. AB - By following the evolution of populations that are initially genetically homogeneous, much can be learned about core biological principles. For example, it allows for detailed studies of the rate of emergence of de novo mutations and their change in frequency due to drift and selection. Unfortunately, in multicellular organisms with generation times of months or years, it is difficult to set up and carry out such experiments over many generations. An alternative is provided by "natural evolution experiments" that started from colonizations or invasions of new habitats by selfing lineages. With limited or missing gene flow from other lineages, new mutations and their effects can be easily detected. North America has been colonized in historic times by the plant Arabidopsis thaliana, and although multiple intercrossing lineages are found today, many of the individuals belong to a single lineage, HPG1. To determine in this lineage the rate of substitutions-the subset of mutations that survived natural selection and drift-, we have sequenced genomes from plants collected between 1863 and 2006. We identified 73 modern and 27 herbarium specimens that belonged to HPG1. Using the estimated substitution rate, we infer that the last common HPG1 ancestor lived in the early 17th century, when it was most likely introduced by chance from Europe. Mutations in coding regions are depleted in frequency compared to those in other portions of the genome, consistent with purifying selection. Nevertheless, a handful of mutations is found at high frequency in present-day populations. We link these to detectable phenotypic variance in traits of known ecological importance, life history and growth, which could reflect their adaptive value. Our work showcases how, by applying genomics methods to a combination of modern and historic samples from colonizing lineages, we can directly study new mutations and their potential evolutionary relevance. PMID- 29432423 TI - Estimation of the number of women of reproductive age in need of preventive chemotherapy for soil-transmitted helminth infections. AB - BACKGROUND: Soil-transmitted helminth infections are among the most common infections in developing countries. Globally, as many as 2 billion people are considered to be at risk for soil-transmitted-helminth (STH) infections. Preschool children (PSAC), school-age children (SAC) and women of reproductive age (WRA) are at high risk of STH-attributable morbidity and preventive chemotherapy (PC) for STH is recommended by the World health Organization (WHO). METHODOLOGY/PRINCIPAL FINDINGS: Over the last five years, PC coverage in PSAC and SAC has gradually increased, while coverage in WRA has lagged. Estimating the numbers of WRA in each endemic country would inform scale-up in this group. A two step process was used: 1) total numbers of girls and women between 15 and 49 years of age were obtained from the United Nations World Population Prospects 2015 database; and 2) the proportion in need of PC was obtained primarily from extrapolation from the WHO PC Databank. WRA were divided into four sub-groups reflecting different reproductive life stages, each having a potentially different interface with the health care system and, consequently, presenting different opportunities for intervention strategies. Worldwide, we estimated that 688 million WRA in 102 countries were in need of PC for STH in 2015. The South East Asia (49%) and Africa regions (26%) had the highest numbers. Adolescent girls accounted for 16%, while pregnant and lactating women each represented 10%. Over 25 million pregnant women alone were estimated living in areas where the prevalence of hookworm and T. trichiura infection was >= 20%. Approximately 20% of at-risk WRA had received deworming with albendazole through the Global Programme to Eliminate Filariasis. CONCLUSIONS/SIGNIFICANCE: To close current gaps in coverage, numbers of WRA in need of PC for STH are essential for operational strategies to control STH infection. PMID- 29432424 TI - Neonatal corticosteroid therapy affects growth patterns in early infancy. AB - OBJECTIVE: Although postnatal corticosteroid (CS) therapy has well established beneficial effects on pulmonary function, it may also result in growth restriction during treatment. The course of early childhood growth is believed to predict cardiovascular and metabolic diseases in adulthood. Therefore, we determined the effects of postnatal dexamethasone (DEX) or hydrocortisone (HC) treatment on patterns of postnatal growth until approximately four years of age. STUDY DESIGN: In an observational cohort study of children born prematurely (<32 weeks of gestation), we compared growth patterns for body weight, height, and head circumference from birth to age four years, of children who received DEX (boys: N = 30, girls: N = 14), HC (boys: N = 33, girls: N = 28) to a reference group that had not received postnatal CSs (boys: N = 52, girls: N = 53) using linear mixed-effects modeling. RESULTS: Growth velocity curves of CS-treated neonates showed a shift to the right, representing a delay in time. They had decreased absolute growth velocities during and shortly after treatment, followed by an increase in growth velocity thereafter. A shift to the right was also seen for the age at which maximal growth velocity of weight/height was reached in boys and girls. Fractional growth rates of weight, height, and head circumference were generally reduced in the CS-treated groups during the first two months of age, with catch-up growth in the following months. In DEX-treated infants these changes were more pronounced than in HC-treated infants. CONCLUSION: These data suggest that postnatal growth patterns of preterm born infants are affected by CS treatment, more by DEX than by HC. Effects were observed mainly on growth velocities. This observation may have impact on health in later life for those individuals treated with CSs in the neonatal period. A definitive conclusion would require a randomized trial of these therapies. PMID- 29432425 TI - Environmental impact of the largest petroleum terminal in SE Brazil: A multiproxy analysis based on sediment geochemistry and living benthic foraminifera. AB - The Dutos e Terminais do Centro Sul (DTCS) is one of the largest petroleum terminals of the South America located in the Sao Sebastiao Channel (SSC) on the southeastern Brazilian coast. The aims of this study were to compare the sediment quality near the DTCS with that of several sites in the SSC region including the Araca (AR) domestic sewage outfall and to assess the efficiency of the DTCS wastewater treatment plant. To achieve these goals, textural, geochemical, and living benthic foraminifera results were analyzed for the DTCS, AR, and SSC regions. Sediments in the DTCS area were silty with high concentrations of total organic carbon (1.7-2.4%), total nitrogen (0.2-0.3%), total sulfur (0.4-0.6%), and total (0.12-0.18%) and inorganic phosphorous (0.07-0.11%). These values were higher than those in sediments collected in the SSC and Araca regions. The sediments' concentrations of As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn in the SSC and AR regions were lower than their corresponding probable effect levels (PELs). However, sediments near the DTCS were enriched with As, Cu, and Ni, whose concentrations exceeded their corresponding threshold effect levels (TELs). Around the DTCS outfall diffusers, living foraminiferal densities and diversities were lower than those for the other areas studied. In the DTCS area, it was necessary to search 50 to 190 cm3 of sediment to find 100 live specimens. In the SSC and Araca areas, a maximum of 40 cm3 of sediment was enough to locate 100 live specimens. The lower density and diversity of living foraminifera around the DTCS than around the other areas illustrates the impact of the environmental stress caused by the presence of pollutants. These results indicate that the wastewater treatment plant efficiency is low and its discharge of pollutants from petrochemical waste liquids affects the benthic fauna around the DTCS in a potentially harmful manner. PMID- 29432426 TI - Single cell on-chip whole genome amplification via micropillar arrays for reduced amplification bias. AB - Single cell whole genome amplification is susceptible to amplification biases that impact the accuracy of single cell sequencing data. To address this, we have developed a microfluidic device for the isolation and purification of genomic DNA from individual cells. The device uses a micropillar array to physically capture single cells and its chromosomal DNA upon extraction. The extracted DNA is immobilized within the micropillar array in a way that allows isothermal amplification. In this system, whole genome amplification of the single cell is carried out under a continual fluid flow within the microfluidic channel. We have demonstrated the process for amplification of individual human cancer cell genomes from the HeLa cell line. By sampling select gene loci along the human genome and performing whole exome sequencing, we demonstrate improved genome coverage and reduced amplification bias compared to amplification of single cells deposited in wells by fluorescence activated cell sorting. PMID- 29432427 TI - Brain entropy and human intelligence: A resting-state fMRI study. AB - Human intelligence comprises comprehension of and reasoning about an infinitely variable external environment. A brain capable of large variability in neural configurations, or states, will more easily understand and predict variable external events. Entropy measures the variety of configurations possible within a system, and recently the concept of brain entropy has been defined as the number of neural states a given brain can access. This study investigates the relationship between human intelligence and brain entropy, to determine whether neural variability as reflected in neuroimaging signals carries information about intellectual ability. We hypothesize that intelligence will be positively associated with entropy in a sample of 892 healthy adults, using resting-state fMRI. Intelligence is measured with the Shipley Vocabulary and WASI Matrix Reasoning tests. Brain entropy was positively associated with intelligence. This relation was most strongly observed in the prefrontal cortex, inferior temporal lobes, and cerebellum. This relationship between high brain entropy and high intelligence indicates an essential role for entropy in brain functioning. It demonstrates that access to variable neural states predicts complex behavioral performance, and specifically shows that entropy derived from neuroimaging signals at rest carries information about intellectual capacity. Future work in this area may elucidate the links between brain entropy in both resting and active states and various forms of intelligence. This insight has the potential to provide predictive information about adaptive behavior and to delineate the subdivisions and nature of intelligence based on entropic patterns. PMID- 29432428 TI - PLAC1 as a serum biomarker for breast cancer. AB - Placental-specific protein 1 (PLAC1) is an X-linked trophoblast gene that is re expressed in several malignancies, including breast cancer, and is therefore a potential biomarker to follow disease onset and progression. Sera from 117 preoperative/pretreatment breast cancer patients and 51 control subjects, including those with fibrocystic disease, were analyzed for the presence of PLAC1 protein as well as its expression by IHC in tumor biopsies in a subset of subjects. Serum PLAC1 levels exceeded the mean plus one standard deviation (mean+SD) of the level in control subjects in 67% of subjects with ductal carcinoma in situ (DCIS), 67% with HER2+ tumors, 73% with triple-negative cancer and 73% with ER+/PR+ tumors. Greater sensitivity was achieved using the mean+2 SD of control PLAC1 serum values, where the false positive rate was 3% and was exceeded by 38%, 40%, 60% and 43% of subjects with DCIS, HER2+, TNBC and ER+/PR+/HER2- tumors. PLAC1 was detected in 97% of tumor biopsies, but did not correlate quantitatively with serum levels. There was no significant correlation of serum PLAC1 levels with race, age at diagnosis, body mass index (BMI) or the presence of metastatic disease. It remains to be determined whether PLAC1 serum levels can serve as a diagnostic biomarker for the presence or recurrence of disease post-surgery and/or therapy. PMID- 29432429 TI - Mental effort and discomfort: Testing the peak-end effect during a cognitively demanding task. AB - We applied the peak-end paradigm that was first introduced in the pain literature to examine the experience of effort and discomfort during a cognitively demanding working memory task. A total of 401 participants were asked to rate their effort and discomfort during and after the administration of a working memory task, which systematically varied task difficulty within participants and task duration between participants. Over the course of the task, participants reported a decrease in reported effort and an increase in reported discomfort. Peak and end real-time ratings were significant predictors of retrospective ratings for effort and discomfort; average and initial ratings predicted a small amount of additional variance. The regression analyses with effort and discomfort were largely consistent, with some exceptions. End discomfort significantly predicted willingness to do the task again, but not end effort. These findings highlight the ways in which the experience of effort and discomfort are integrally related, yet importantly separate, during a cognitively demanding task. PMID- 29432430 TI - Different physiological stages and breeding systems related to the variability of meat quality of indigenous Pantaneiro sheep. AB - This study configures a first report regarding the variability of meat quality of locally adapted Pantaneiro sheep depending on different physiological stages and breeding systems. Pantaneiro sheep are raised in Brazil under a tropical wetland ecosystem denominated Pantanal. Twenty-nine Pantaneiro sheep from different sex and physiological stages were sorted into three groups, simulating three of the most representative ovine meat products commercialized by South American industries: a) non castrated male lambs (n = 11); b) wethers (n = 9); c) cull ewes (n = 9). Animals from each physiological stage were submitted to different breeding systems, resembling farming strategies adopted in several developing countries of South America. The effect of physiological stages on the quality of meat was accessed using 16 variables measured in the longissimus thoracis et lumborum (LM) and the semimembranosus (SM) muscles. The variables were related to brightness, color, physical aspects, soluble and total collagen as well as chemical traits. The physiological stage was defined as a classification variable in order to proceed ANOVA tests and comparison of means (P<0.05). Multivariate analysis was used to identify patterns of similarity and differentiation between samples of different physiological stages (a, b, c). The results revealed that meat quality varies according to different physiological stages, especially between lambs (a) and cull ewes (c). As a consequence, the physiological stage at slaughter should be taken into consideration to cote the quality of meat from indigenous sheep raised in tropical regions. The results contribute towards sensorial evaluation and the characterization of potential food products derived from indigenous sheep bred under tropical climate in developing countries. PMID- 29432431 TI - Improving succinylation prediction accuracy by incorporating the secondary structure via helix, strand and coil, and evolutionary information from profile bigrams. AB - Post-translational modification refers to the biological mechanism involved in the enzymatic modification of proteins after being translated in the ribosome. This mechanism comprises a wide range of structural modifications, which bring dramatic variations to the biological function of proteins. One of the recently discovered modifications is succinylation. Although succinylation can be detected through mass spectrometry, its current experimental detection turns out to be a timely process unable to meet the exponential growth of sequenced proteins. Therefore, the implementation of fast and accurate computational methods has emerged as a feasible solution. This paper proposes a novel classification approach, which effectively incorporates the secondary structure and evolutionary information of proteins through profile bigrams for succinylation prediction. The proposed predictor, abbreviated as SSEvol-Suc, made use of the above features for training an AdaBoost classifier and consequently predicting succinylated lysine residues. When SSEvol-Suc was compared with four benchmark predictors, it outperformed them in metrics such as sensitivity (0.909), accuracy (0.875) and Matthews correlation coefficient (0.75). PMID- 29432432 TI - MicroRNA expression in benign breast tissue and risk of subsequent invasive breast cancer. AB - MicroRNAs are endogenous, small non-coding RNAs that control gene expression by directing their target mRNAs for degradation and/or posttranscriptional repression. Abnormal expression of microRNAs is thought to contribute to the development and progression of cancer. A history of benign breast disease (BBD) is associated with increased risk of subsequent breast cancer. However, no large scale study has examined the association between microRNA expression in BBD tissue and risk of subsequent invasive breast cancer (IBC). We conducted discovery and validation case-control studies nested in a cohort of 15,395 women diagnosed with BBD in a large health plan between 1971 and 2006 and followed to mid-2015. Cases were women with BBD who developed subsequent IBC; controls were matched 1:1 to cases on age, age at diagnosis of BBD, and duration of plan membership. The discovery stage (316 case-control pairs) entailed use of the Illumina MicroRNA Expression Profiling Assay (in duplicate) to identify breast cancer-associated microRNAs. MicroRNAs identified at this stage were ranked by the strength of the correlation between Illumina array and quantitative PCR results for 15 case-control pairs. The top ranked 14 microRNAs entered the validation stage (165 case-control pairs) which was conducted using quantitative PCR (in triplicate). In both stages, linear regression was used to evaluate the association between the mean expression level of each microRNA (response variable) and case-control status (independent variable); paired t-tests were also used in the validation stage. None of the 14 validation stage microRNAs was associated with breast cancer risk. The results of this study suggest that microRNA expression in benign breast tissue does not influence the risk of subsequent IBC. PMID- 29432433 TI - Psychometric properties of the PROMIS Physical Function item bank in patients receiving physical therapy. AB - OBJECTIVES: The Patient-Reported Outcomes Measurement Information System (PROMIS) is a universally applicable set of instruments, including item banks, short forms and computer adaptive tests (CATs), measuring patient-reported health across different patient populations. PROMIS CATs are highly efficient and the use in practice is considered feasible with little administration time, offering standardized and routine patient monitoring. Before an item bank can be used as CAT, the psychometric properties of the item bank have to be examined. Therefore, the objective was to assess the psychometric properties of the Dutch-Flemish PROMIS Physical Function item bank (DF-PROMIS-PF) in Dutch patients receiving physical therapy. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: 805 patients >18 years, who received any kind of physical therapy in primary care in the past year, completed the full DF-PROMIS-PF (121 items). METHODS: Unidimensionality was examined by Confirmatory Factor Analysis and local dependence and monotonicity were evaluated. A Graded Response Model was fitted. Construct validity was examined with correlations between DF-PROMIS-PF T-scores and scores on two legacy instruments (SF-36 Health Survey Physical Functioning scale [SF36-PF10] and the Health Assessment Questionnaire Disability-Index [HAQ DI]). Reliability (standard errors of theta) was assessed. RESULTS: The results for unidimensionality were mixed (scaled CFI = 0.924, TLI = 0.923, RMSEA = 0.045, 1th factor explained 61.5% of variance). Some local dependence was found (8.2% of item pairs). The item bank showed a broad coverage of the physical function construct (threshold-parameters range: -4.28-2.33) and good construct validity (correlation with SF36-PF10 = 0.84 and HAQ-DI = -0.85). Furthermore, the DF PROMIS-PF showed greater reliability over a broader score-range than the SF36 PF10 and HAQ-DI. CONCLUSIONS: The psychometric properties of the DF-PROMIS-PF item bank are sufficient. The DF-PROMIS-PF can now be used as short forms or CAT to measure the level of physical function of physiotherapy patients. PMID- 29432434 TI - Prevalence of trachoma in the Kayes region of Mali eight years after stopping mass drug administration. AB - BACKGROUND: In 2009, three years after stopping mass treatment with azithromycin, a trachoma impact survey in four health districts in the Kayes region of Mali found a prevalence of trachomatous inflammation-follicular (TF) among children aged 1 to 9 years of >5% and a trachomatous trichiasis (TT) prevalence within the general population (>=1-year-old) of <1%. As a result, the government's national trachoma program expanded trichiasis surgery and related activities required to achieve trachoma elimination. METHODOLOGY/PRINCIPAL FINDINGS: In 2015, to assess progress towards elimination, a follow-up impact survey was conducted in the Kayes, Kenieba, Nioro and Yelimane health districts. The survey used district level two-stage cluster random sampling methodology with 20 clusters of 30 households in each evaluation unit. Subjects were eligible for examination if they were >=1 year. TF and TT cases were identified and confirmed by experienced ophthalmologists. In total 14,159 people were enumerated and 11,620 (82%) were examined. TF prevalence (95% confidence interval (CI)) was 0.5% (0.3-1%) in Kayes, 0.8% (0.4-1.7%) in Kenieba, 0.2% (0-0.9%) in Nioro and 0.3% (0.1-1%) in Yelimane. TT prevalence (95% CI) was 0.04% (0-0.25%) in Kayes, 0.29% (0.11-0.6%) in Kenieba, 0.04% (0-0.25%) in Nioro and 0.07% (0-0.27%) in Yelimane. CONCLUSIONS/SIGNIFICANCE: Eight years after stopping MDA and intensifying trichiasis surgery outreach campaigns, all four districts reached the TF elimination threshold of <5% and three of four districts reached the TT elimination threshold of <0.1%. PMID- 29432435 TI - Exploring the role of voluntary disease schemes on UK farmer bio-security behaviours: Findings from the Norfolk-Suffolk Bovine Viral Diarrhoea control scheme. AB - The article describes the influence of a disease control scheme (the Norfolk Suffolk Bovine Viral Diarrhoea Disease (BVD) Eradication scheme) on farmers' bio security attitudes and behaviours. In 2010, a survey of 100 cattle farmers (53 scheme members vs. 47 out of scheme farmers) was undertaken among cattle farmers residing in Norfolk and Suffolk counties in the UK. A cross-sectional independent measures design was employed. The main analytical tool was content analysis. The following variables at the farmer-level were explored: the specific BVD control measures adopted, livestock disease priorities, motivation for scheme membership, wider knowledge acquisition, biosecurity behaviours employed and training course attendance. The findings suggest that participation in the BVD scheme improved farmers' perception of the scheme benefits and participation in training courses. However, no association was found between the taking part in the BVD scheme and livestock disease priorities or motivation for scheme participation, or knowledge about BVD bio-security measures employed. Equally importantly, scheme membership did appear to influence the importance accorded specific bio-security measures. Yet such ranking did not appear to reflect the actual behaviours undertaken. As such, disease control efforts alone while necessary, are insufficient. Rather, to enhance farmer bio-security behaviours significant effort must be made to address underlying attitudes to the specific disease threat involved. PMID- 29432436 TI - Change in hippocampal theta oscillation associated with multiple lever presses in a bimanual two-lever choice task for robot control in rats. AB - Hippocampal theta oscillations have been implicated in working memory and attentional process, which might be useful for the brain-machine interface (BMI). To further elucidate the properties of the hippocampal theta oscillations that can be used in BMI, we investigated hippocampal theta oscillations during a two lever choice task. During the task body-restrained rats were trained with a food reward to move an e-puck robot towards them by pressing the correct lever, ipsilateral to the robot several times, using the ipsilateral forelimb. The robot carried food and moved along a semicircle track set in front of the rat. We demonstrated that the power of hippocampal theta oscillations gradually increased during a 6-s preparatory period before the start of multiple lever pressing, irrespective of whether the correct lever choice or forelimb side were used. In addition, there was a significant difference in the theta power after the first choice, between correct and incorrect trials. During the correct trials the theta power was highest during the first lever-releasing period, whereas in the incorrect trials it occurred during the second correct lever-pressing period. We also analyzed the hippocampal theta oscillations at the termination of multiple lever pressing during the correct trials. Irrespective of whether the correct forelimb side was used, the power of hippocampal theta oscillations gradually decreased with the termination of multiple lever pressing. The frequency of theta oscillation also demonstrated an increase and decrease, before and after multiple lever pressing, respectively. There was a transient increase in frequency after the first lever press during the incorrect trials, while no such increase was observed during the correct trials. These results suggested that hippocampal theta oscillations reflect some aspects of preparatory and cognitive neural activities during the robot controlling task, which could be used for BMI. PMID- 29432437 TI - Experimental increase in baseline corticosterone level reduces oxidative damage and enhances innate immune response. AB - Glucocorticoid (GC) hormones are significant regulators of homeostasis. The physiological effects of GCs critically depend on the time of exposure (short vs. long) as well as on their circulating levels (baseline vs. stress-induced). Previous experiments, in which chronic and high elevation of GC levels was induced, indicate that GCs impair both the activity of the immune system and the oxidative balance. Nonetheless, our knowledge on how mildly elevated GC levels, a situation much more common in nature, might influence homeostasis is limited. Therefore, we studied whether an increase in GC level within the baseline range suppresses or enhances condition (body mass, hematocrit and coccidian infestation) and physiological state (humoral innate immune system activity and oxidative balance). We implanted captive house sparrows Passer domesticus with either 60 days release corticosterone (CORT) or control pellets. CORT-treated birds had elevated baseline CORT levels one week after the implantation, but following this CORT returned to its pre-treatment level and the experimental groups had similar CORT levels one and two months following the implantation. The mass of tail feathers grown during the initial phase of treatment was smaller in treated than in control birds. CORT implantation had a transient negative effect on body mass and hematocrit, but both of these traits resumed the pre-treatment values by one month post-treatment. CORT treatment lowered oxidative damage to lipids (malondialdehyde) and enhanced constitutive innate immunity at one week and one month post-implantation. Our findings suggest that a relatively short term (i.e. few days) elevation of baseline CORT might have a positive and stimulatory effect on animal physiology. PMID- 29432438 TI - Molecular adaptation in Rubisco: Discriminating between convergent evolution and positive selection using mechanistic and classical codon models. AB - Rubisco (Ribulose-1, 5-biphosphate carboxylase/oxygenase) is the most important enzyme on earth, catalyzing the first step of photosynthetic CO2 fixation. So, without it, there would be no storing of the sun's energy in plants. Molecular adaptation of Rubisco to C4 photosynthetic pathway has attracted a lot of attention. C4 plants, which comprise less than 5% of land plants, have evolved more efficient photosynthesis compared to C3 plants. Interestingly, a large number of independent transitions from C3 to C4 phenotype have occurred. Each time, the Rubisco enzyme has been subject to similar changes in selective pressure, thus providing an excellent model for convergent evolution at the molecular level. Molecular adaptation is often identified with positive selection and is typically characterized by an elevated ratio of non-synonymous to synonymous substitution rate (dN/dS). However, convergent adaptation is expected to leave a different molecular signature, taking the form of repeated transitions toward identical or similar amino acids. Here, we used a previously introduced codon-based differential-selection model to detect and quantify consistent patterns of convergent adaptation in Rubisco in eudicots. We further contrasted our results with those obtained by classical codon models based on the estimation of dN/dS. We found that the two classes of models tend to select distinct, although overlapping, sets of positions. This discrepancy in the results illustrates the conceptual difference between these models while emphasizing the need to better discriminate between qualitatively different selective regimes, by using a broader class of codon models than those currently considered in molecular evolutionary studies. PMID- 29432439 TI - Genetic association of -1562C>T polymorphism in the MMP9 gene with primary glaucoma in a north Indian population. AB - MMP (Matrix metalloproteinase) 9 is reported to affect glaucoma pathogenesis by altering intraocular pressure (IOP) through its role in remodeling the extracellular matrix (ECM) in the trabecular meshwork. A genetic variant at the promoter region in the MMP9 gene (-1562C>T) has a putative role in regulating its transcription rate and hence can affect genetic predisposition to primary glaucoma. The present study examined the association of -1562C>T promoter polymorphism in the MMP9 gene with Primary Open Angle Glaucoma (POAG) and Primary Angle Closure Glaucoma (PACG) in a north Indian population. A total of 729 subjects (POAG = 224, PACG = 138 and 367 controls) were recruited for the study. Genotyping for the promoter sequence variant was done with PCR-RFLP method. Genotypic and allelic frequency distribution of the POAG and PACG data sets were compared to that of controls by chi-square test and genetic association was tested under different genetic models as implemented under PLINK. Statistically significant difference was observed in the genotype frequencies between PACG cases and controls (p = 0.030). However, in the POAG cases, this difference was only borderline (p = 0.052). Genetic model analysis, under the dominant model revealed 1.6 and 1.4 fold increased susceptibility to PACG and POAG (p = 0.012, p = 0.032) respectively. A higher frequency of CT genotype was observed in PACG as well as POAG males as compared to female subjects. According to the dominant model, CT+TT genotype conferred 1.8 fold higher risk of developing PACG among male patients as compared to the control group (p = 0.048, OR = 1.87;1.00-3.50). Current findings suggest significant association of MMP9 -1562C>T polymorphism with primary glaucoma in the targeted north Indian population and warrant further replication of the findings in other populations. PMID- 29432440 TI - Why do people move? Enhancing human mobility prediction using local functions based on public records and SNS data. AB - The quality of life for people in urban regions can be improved by predicting urban human mobility and adjusting urban planning accordingly. In this study, we compared several possible variables to verify whether a gravity model (a human mobility prediction model borrowed from Newtonian mechanics) worked as well in inner-city regions as it did in intra-city regions. We reviewed the resident population, the number of employees, and the number of SNS posts as variables for generating mass values for an urban traffic gravity model. We also compared the straight-line distance, travel distance, and the impact of time as possible distance values. We defined the functions of urban regions on the basis of public records and SNS data to reflect the diverse social factors in urban regions. In this process, we conducted a dimension reduction method for the public record data and used a machine learning-based clustering algorithm for the SNS data. In doing so, we found that functional distance could be defined as the Euclidean distance between social function vectors in urban regions. Finally, we examined whether the functional distance was a variable that had a significant impact on urban human mobility. PMID- 29432441 TI - FAS promoter polymorphisms and serum sFas level are associated with increased risk of nerve damage in Bangladeshi patients with Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an autoimmune disorder of the peripheral nervous system triggered by molecular mimicry between pathogen lipopolysaccharides and host nerve gangliosides. Polymorphisms in the Fas receptor (FAS) and Fas ligand (FASL) genes may potentially alter the elimination of autoreactive immune cells and affect disease susceptibility or disease severity in GBS. We detected single nucleotide polymorphisms (SNPs) in FAS (-1377G/A and -670A/G) and FASL (-843C/T) in a prospective cohort of 300 patients with GBS and 300 healthy controls from the Bangladeshi population. Genotype distributions were not significantly different between patients with GBS and healthy controls. The FAS -670 AG heterozygous (P = 0.0005, OR = 2.5, 95% CI = 1.5-4.2) and GG homozygous (P = 0.0048, OR = 2.6, 95% CI = 1.3-5.0) genotypes were more common in patients with anti-GM1 antibodies than patients without anti-GM1 antibodies. The FAS -670 G allele was more prevalent in anti-GM1 antibody-positive than -negative patients (P = 0.0002, OR = 1.9, 95% CI = 1.4-2.7) and also in patients with the axonal subtype than demyelinating subtype (P < 0.0001, OR = 4.8, 95% CI = 2.3-10.1). The 1377G/-670G GG haplotype was significantly associated with the axonal subtype (P < 0.0001) and anti-ganglioside antibody-positivity (P = 0.0008) in GBS. Serum sFas (237.5 pg/mL vs. 159.5 pg/mL; P < 0.0001) and sFasL (225.1 pg/mL vs. 183.4 pg/mL; P = 0.0069) were elevated in patients with GBS compared to healthy controls, and among patients with high serum sFas was associated with severe GBS (P = 0.0406). In conclusion, this study indicates FAS-FASL promoter SNPs may promote the production of cross-reactive anti-ganglioside antibodies in GBS. PMID- 29432442 TI - The managed clearing: An overlooked land-cover type in urbanizing regions? AB - Urban ecosystem assessments increasingly rely on widely available map products, such as the U.S. Geological Service (USGS) National Land Cover Database (NLCD), and datasets that use generic classification schemes to detect and model large scale impacts of land-cover change. However, utilizing existing map products or schemes without identifying relevant urban class types such as semi-natural, yet managed land areas that account for differences in ecological functions due to their pervious surfaces may severely constrain assessments. To address this gap, we introduce the managed clearings land-cover type-semi-natural, vegetated land surfaces with varying degrees of management practices-for urbanizing landscapes. We explore the extent to which managed clearings are common and spatially distributed in three rapidly urbanizing areas of the Charlanta megaregion, USA. We visually interpreted and mapped fine-scale land cover with special attention to managed clearings using 2012 U.S. Department of Agriculture (USDA) National Agriculture Imagery Program (NAIP) images within 150 randomly selected 1-km2 blocks in the cities of Atlanta, Charlotte, and Raleigh, and compared our maps with National Land Cover Database (NLCD) data. We estimated the abundance of managed clearings relative to other land use and land cover types, and the proportion of land-cover types in the NLCD that are similar to managed clearings. Our study reveals that managed clearings are the most common land cover type in these cities, covering 28% of the total sampled land area- 6.2% higher than the total area of impervious surfaces. Managed clearings, when combined with forest cover, constitutes 69% of pervious surfaces in the sampled region. We observed variability in area estimates of managed clearings between the NAIP-derived and NLCD data. This suggests using high-resolution remote sensing imagery (e.g., NAIP) instead of modifying NLCD data for improved representation of spatial heterogeneity and mapping of managed clearings in urbanizing landscapes. Our findings also demonstrate the need to more carefully consider managed clearings and their critical ecological functions in landscape- to regional-scale studies of urbanizing ecosystems. PMID- 29432443 TI - Short term doxycycline treatment induces sustained improvement in myocardial infarction border zone contractility. AB - Decreased contractility in the non-ischemic border zone surrounding a MI is in part due to degradation of cardiomyocyte sarcomeric components by intracellular matrix metalloproteinase-2 (MMP-2). We recently reported that MMP-2 levels were increased in the border zone after a MI and that treatment with doxycycline for two weeks after MI was associated with normalization of MMP-2 levels and improvement in ex-vivo contractile protein developed force in the myocardial border zone. The purpose of the current study was to determine if there is a sustained effect of short term treatment with doxycycline (Dox) on border zone function in a large animal model of antero-apical myocardial infarction (MI). Antero-apical MI was created in 14 sheep. Seven sheep received doxycycline 0.8 mg/kg/hr IV for two weeks. Cardiac MRI was performed two weeks before, and then two and six weeks after MI. Two sheep died prior to MRI at six weeks from surgical/anesthesia-related causes. The remaining 12 sheep completed the protocol. Doxycycline induced a sustained reduction in intracellular MMP-2 by Western blot (3649+/-643 MI+Dox vs 9236+/-114 MI relative intensity; p = 0.0009), an improvement in ex-vivo contractility (65.3+/-2.0 MI+Dox vs 39.7+/-0.8 MI mN/mm2; p<0.0001) and an increase in ventricular wall thickness at end-systole 1.0 cm from the infarct edge (12.4+/-0.6 MI+Dox vs 10.0+/-0.5 MI mm; p = 0.0095). Administration of doxycycline for a limited two week period is associated with a sustained improvement in ex-vivo contractility and an increase in wall thickness at end-systole in the border zone six weeks after MI. These findings were associated with a reduction in intracellular MMP-2 activity. PMID- 29432444 TI - Agreement between self-reported and physically verified male circumcision status in Nyanza region, Kenya: Evidence from the TASCO study. AB - BACKGROUND: Self-reported male circumcision (MC) status is widely used to estimate community prevalence of circumcision, although its accuracy varies in different settings depending on the extent of misreporting. Despite this challenge, self-reported MC status remains essential because it is the most feasible method of collecting MC status data in community surveys. Therefore, its accuracy is an important determinant of the reliability of MC prevalence estimates based on such surveys. We measured the concurrence between self reported and physically verified MC status among men aged 25-39 years during a baseline household survey for a study to test strategies for enhancing MC uptake by older men in Nyanza region of Kenya. The objective was to determine the accuracy of self-reported MC status in communities where MC for HIV prevention is being rolled out. METHODS: Agreement between self-reported and physically verified MC status was measured among 4,232 men. A structured questionnaire was used to collect data on MC status followed by physical examination to verify the actual MC status whose outcome was recorded as fully circumcised (no foreskin), partially circumcised (foreskin is past corona sulcus but covers less than half of the glans) or uncircumcised (foreskin covers half or more of the glans). The sensitivity and specificity of self-reported MC status were calculated using physically verified MC status as the gold standard. RESULTS: Out of 4,232 men, 2,197 (51.9%) reported being circumcised, of whom 99.0% were confirmed to be fully circumcised on physical examination. Among 2,035 men who reported being uncircumcised, 93.7% (1,907/2,035) were confirmed uncircumcised on physical examination. Agreement between self-reported and physically verified MC status was almost perfect, kappa (k) = 98.6% (95% CI, 98.1%-99.1%. The sensitivity of self-reporting being circumcised was 99.6% (95% CI, 99.2-99.8) while specificity of self-reporting uncircumcised was 99.0% (95% CI, 98.4-99.4) and did not differ significantly by age group based on chi-square test. Rate of consenting to physical verification of MC status differed by client characteristics; unemployed men were more likely to consent to physical verification (odds ratio [OR] = 1.48, (95% CI, 1.30-1.69) compared to employed men and those with post-secondary education were less likely to consent to physical verification than those with primary education or less (odds ratio [OR] = 0.61, (95% CI, 0.51-0.74). CONCLUSIONS: In this Kenyan context, both sensitivity and specificity of self reported MC status was high; therefore, MC prevalence estimates based on self reported MC status should be deemed accurate and applicable for planning. However MC programs should assess accuracy of self-reported MC status periodically for any secular changes that may undermine its usefulness for estimating community MC prevalence in their unique settings. PMID- 29432445 TI - Promising effects of xanthine oxidase inhibition by allopurinol on autonomic heart regulation estimated by heart rate variability (HRV) analysis in rats exposed to hypoxia and hyperoxia. AB - BACKGROUND: It has long been suggested that reactive oxygen species (ROS) play a role in oxygen sensing via peripheral chemoreceptors, which would imply their involvement in chemoreflex activation and autonomic regulation of heart rate. We hypothesize that antioxidant affect neurogenic cardiovascular regulation through activation of chemoreflex which results in increased control of sympathetic mechanism regulating heart rhythm. Activity of xanthine oxidase (XO), which is among the major endogenous sources of ROS in the rat has been shown to increase during hypoxia promote oxidative stress. However, the mechanism of how XO inhibition affects neurogenic regulation of heart rhythm is still unclear. AIM: The study aimed to evaluate effects of allopurinol-driven inhibition of XO on autonomic heart regulation in rats exposed to hypoxia followed by hyperoxia, using heart rate variability (HRV) analysis. MATERIAL AND METHODS: 16 conscious male Wistar rats (350 g): control-untreated (N = 8) and pretreated with Allopurinol-XO inhibitor (5 mg/kg, followed by 50 mg/kg), administered intraperitoneally (N = 8), were exposed to controlled hypobaric hypoxia (1h) in order to activate chemoreflex. The treatment was followed by 1h hyperoxia (chemoreflex suppression). Time-series of 1024 RR-intervals were extracted from 4kHz ECG recording for heart rate variability (HRV) analysis in order to calculate the following time-domain parameters: mean RR interval (RRi), SDNN (standard deviation of all normal NN intervals), rMSSD (square root of the mean of the squares of differences between adjacent NN intervals), frequency-domain parameters (FFT method): TSP (total spectral power) as well as low and high frequency band powers (LF and HF). At the end of experiment we used rat plasma to evaluate enzymatic activity of XO and markers of oxidative stress: protein carbonyl group and 8-isoprostane concentrations. Enzymatic activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measures in erythrocyte lysates. RESULTS: Allopurinol reduced oxidative stress which was the result of hypoxia/hyperoxia, as shown by decreased 8-isoprostane plasma concentration. XO inhibition did not markedly influence HRV parameters in standard normoxia. However, during hypoxia, as well as hyperoxia, allopurinol administration resulted in a significant increase of autonomic control upon the heart as shown by increased SDNN and TSP, with an increased vagal contribution (increased rMSSD and HF), whereas sympathovagal indexes (LF/HF, SDNN/rMSSD) remained unchanged. CONCLUSIONS: Observed regulatory effects of XO inhibition did not confirm preliminary hypothesis which suggested that an antioxidant such as allopurinol might activate chemoreflex resulting in augmented sympathetic discharge to the heart. The HRV regulatory profile of XO inhibition observed during hypoxia as well as post-hypoxic hyperoxia corresponds to reported reduced risk of sudden cardiovascular events. Therefore our data provide a new argument for therapeutical use of allopurinol in hypoxic conditions. PMID- 29432446 TI - Utilization of Landsat-8 data for the estimation of carrot and maize crop water footprint under the arid climate of Saudi Arabia. AB - The crop Water Footprint (WF) can provide a comprehensive knowledge of the use of water through the demarcation of the amount of the water consumed by different crops. The WF has three components: green (WFg), blue (WFb) and grey (WFgr) water footprints. The WFg refers to the rainwater stored in the root zone soil layer and is mainly utilized for agricultural, horticultural and forestry production. The WFb, however, is the consumptive use of water from surface or groundwater resources and mainly deals with irrigated agriculture, industry, domestic water use, etc. While the WFgr is the amount of fresh water required to assimilate pollutants resulting from the use of fertilizers/agrochemicals. This study was conducted on six agricultural fields in the Eastern region of Saudi Arabia, during the period from December 2015 to December 2016, to investigate the spatiotemporal variation of the WF of silage maize and carrot crops. The WF of each crop was estimated in two ways, namely agro-meteorological (WFAgro) and remote sensing (WFRS) methods. The blue, green and grey components of WFAgro were computed with the use of weather station/Eddy covariance measurements and field recorded crop yield datasets. The WFRS estimated by applying surface energy balance principles on Landsat-8 imageries. However, due to non-availability of Landsat-8 data on the event of rainy days, this study was limited to blue component (WFRS-b). The WFAgro of silage maize was found to range from 3545 m3 t 1 to 4960 m3 t-1; on an average, the WFAgro-g, WFAgro-b, and WFAgro-gr are composed of < 1%, 77%, and 22%, respectively. In the case of carrot, the WFAgro ranged between 297 m3 t-1 and 502 m3 t-1. The WFAgro-g of carrot crop was estimated at <1%, while WFAgro-b and WFAgro-gr was 67% and 32%, respectively. The WFAgro-b is occupied as a major portion in WF of silage maize (77%) and carrot (68%) crops. This is due to the high crop water demand combined with a very erratic rainfall, the irrigation is totally provided using groundwater delivered by center pivot irrigation systems. On the other hand, the WFRS-b estimated using Landsat-8 data was varied from 276 (+/-73) m3 t-1 (carrot) and 2885 (+/-441) m3 t 1 (silage maize). The variation (RMSE) between WFRS-b and WFAgro-b was about 17% and 14% for silage maize and carrot crops, respectively. PMID- 29432447 TI - Beyond monetary benefits of restoring sight in Vietnam: Evaluating well-being gains from cataract surgery. AB - A more holistic understanding of the benefits of sight-restoring cataract surgery requires a focus that goes beyond income and employment, to include a wider array of well-being measures. The objective of this study is to examine the monetary and non-monetary benefits of cataract surgery on both patients as well as their caregivers in Vietnam. Participants were randomly recruited from a Ho-Chi-Minh City Hospital. A total of 82 cataract patients and 83 caregivers participated in the survey conducted for this study. Paired t-tests, Wilcoxon Signed Rank tests, and regression analysis are used to detect any statistically significant differences in various measures of well-being for patients and caregivers before and after surgery. There are statistically significant improvements in monetary and non-monetary measures of well-being for both patients and caregivers approximately three months after undergoing cataract surgery, compared with baseline assessments collected prior to surgery. Non-monetary measures of well being include self-assessments of overall health, mental health, hope, self efficacy, happiness and life satisfaction. For patients, the benefits included statistically significant improvements in earnings, mobility, self-care, the ability to undertake daily activities, self-assessed health and mental health, life satisfaction, hope, and self-efficacy (p<0.01). For caregivers, attendance at work improved alongside overall health, mental health, hope, self-efficacy, happiness and life satisfaction, three months post-surgery (p<0.01). Restoring sight has positive impacts for those suffering from cataracts and their caregivers. Sometimes the benefits are almost equal in their magnitude. The study has also demonstrated that many of these impacts are non-monetary in nature. It is clear that estimates of the rate of return to restoring sight that focus only on financial gains will underestimate the true returns to society of restoring sight from cataract surgeries. PMID- 29432449 TI - Naked aggression: Personality and portfolio manager performance. AB - We provide evidence that a personality trait, aggression, has a first-order effect on group financial decision making. In a laboratory experiment on group portfolio choice, highly aggressive subjects (measured by a standard psychology test) were much more likely to recommend risky investment strategies consistent with their own personal information, regardless of the information received by other group members. Outside of this group context, aggression had no effect on subject behavior. Thus, our aggression measure appears to capture an aggressive disposition, which seeks to dominate group decisions, rather than simply reflect risk attitudes or cognitive biases. PMID- 29432448 TI - Probing the role of intercalating protein sidechains for kink formation in DNA. AB - Protein binding can induce DNA kinks, which are for example important to enhance the specificity of the interaction and to facilitate the assembly of multi protein complexes. The respective proteins frequently exhibit amino acid sidechains that intercalate between the DNA base steps at the site of the kink. However, on a molecular level there is only little information available about the role of individual sidechains for kink formation. To unravel structural principles of protein-induced DNA kinking we have performed molecular dynamics (MD) simulations of five complexes that varied in their architecture, function, and identity of intercalated residues. Simulations were performed for the DNA complexes of wildtype proteins (Sac7d, Sox-4, CcpA, TFAM, TBP) and for mutants, in which the intercalating residues were individually or combined replaced by alanine. The work revealed that for systems with multiple intercalated residues, not all of them are necessarily required for kink formation. In some complexes (Sox-4, TBP), one of the residues proved to be essential for kink formation, whereas the second residue has only a very small effect on the magnitude of the kink. In other systems (e.g. Sac7d) each of the intercalated residues proved to be individually capable of conferring a strong kink suggesting a partially redundant role of the intercalating residues. Mutation of the key residues responsible for kinking either resulted in stable complexes with reduced kink angles or caused conformational instability as evidenced by a shift of the kink to an adjacent base step. Thus, MD simulations can help to identify the role of individual inserted residues for kinking, which is not readily apparent from an inspection of the static structures. This information might be helpful for understanding protein-DNA interactions in more detail and for designing proteins with altered DNA binding properties in the future. PMID- 29432450 TI - Endogenous overexpression of an active phosphorylated form of DNA polymerase beta under oxidative stress in Trypanosoma cruzi. AB - Trypanosoma cruzi is exposed during its life to exogenous and endogenous oxidative stress, leading to damage of several macromolecules such as DNA. There are many DNA repair pathways in the nucleus and mitochondria (kinetoplast), where specific protein complexes detect and eliminate damage to DNA. One group of these proteins is the DNA polymerases. In particular, Tc DNA polymerase beta participates in kinetoplast DNA replication and repair. However, the mechanisms which control its expression under oxidative stress are still unknown. Here we describe the effect of oxidative stress on the expression and function of Tc DNA polymerase beta To this end parasite cells (epimastigotes and trypomastigotes) were exposed to peroxide during short periods of time. Tc DNA polymerase beta which was associated physically with kinetoplast DNA, showed increased protein levels in response to peroxide damage in both parasite forms analyzed. Two forms of DNA polymerase beta were identified and overexpressed after peroxide treatment. One of them was phosphorylated and active in DNA synthesis after renaturation on polyacrylamide electrophoresis gel. This phosphorylated form showed 3-4-fold increase in both parasite forms. Our findings indicate that these increments in protein levels are not under transcriptional control because the level of Tc DNA polymerase beta mRNA is maintained or slightly decreased during the exposure to oxidative stress. We propose a mechanism where a DNA repair pathway activates a cascade leading to the increment of expression and phosphorylation of Tc DNA polymerase beta in response to oxidative damage, which is discussed in the context of what is known in other trypanosomes which lack transcriptional control. PMID- 29432451 TI - Microexon gene transcriptional profiles and evolution provide insights into blood processing by the Schistosoma japonicum esophagus. AB - BACKGROUND: Adult schistosomes have a well-developed alimentary tract comprising an oral sucker around the mouth, a short esophagus and a blind ending gut. The esophagus is not simply a muscular tube for conducting blood from the mouth to gut but is divided into compartments, surrounded by anterior and posterior glands, where processing of ingested blood is initiated. Self-cure of rhesus macaques from a Schistosoma japonicum infection appears to operate by blocking the secretory functions of these glands so that the worms cease feeding and slowly starve to death. Here we use subtractive RNASeq to characterise the genes encoding the principal secretory products of S. japonicum esophageal glands, preparatory to evaluating their relevance as targets of the self-cure process. METHODOLOGY/PRINCIPAL FINDINGS: The heads and a small portion of the rear end of male and female S. japonicum worms were separately enriched by microdissection, for mRNA isolation and library construction. The sequence reads were then assembled de novo using Trinity and those genes enriched more than eightfold in the head preparation were subjected to detailed bioinformatics analysis. Of the 62 genes selected from the male heads, more than one third comprised MEGs encoding secreted or membrane-anchored proteins. Database searching using conserved motifs revealed that the MEG-4 and MEG-8/9 families had counterparts in the bird schistosome Trichobilharzia regenti, indicating an ancient association with blood processing. A second group of MEGs, including a MEG-26 family, encoded short peptides with amphipathic properties that most likely interact with ingested host cell membranes to destabilise them. A number of lysosomal hydrolases, two protease inhibitors, a secreted VAL and a putative natterin complete the line-up. There was surprisingly little difference between expression patterns in males and females despite the latter processing much more blood. SIGNIFICANCE/CONCLUSIONS: The mixture of approximately 40 proteins specifically secreted by the esophageal glands is responsible for initiating blood processing in the adult worm esophagus. They comprise the potential targets for the self cure process in the rhesus macaque, and thus represent a completely new cohort of secreted proteins that can be investigated as vaccine candidates. PMID- 29432452 TI - A conserved Eph family receptor-binding motif on the gH/gL complex of Kaposi's sarcoma-associated herpesvirus and rhesus monkey rhadinovirus. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a human oncogenic virus associated with Kaposi's sarcoma and two B-cell malignancies. The rhesus monkey rhadinovirus (RRV) is a virus of nonhuman primates that is closely related to KSHV. Eph family receptor tyrosine kinases (Ephs) are cellular receptors for the gH/gL glycoprotein complexes of both KSHV and RRV. Through sequence analysis and mutational screens, we identified conserved residues in the N-terminal domain of KSHV and RRV glycoprotein H that are critical for Eph-binding in vitro. Homology based structural predictions of the KSHV and RRV gH/gL complexes based on the Epstein-Barr-Virus gH/gL crystal structure located these amino acids in a beta hairpin on gH, which is likely stabilized by gL and is optimally positioned for protein-protein interactions. Guided by these predictions, we generated recombinant RRV and KSHV strains mutated in the conserved motif as well as an RRV gL null mutant. Inhibition experiments using these mutants confirmed that disruption of the identified Eph-interaction motif or of gL expression resulted in complete detargeting from Ephs. However, all mutants were infectious on all cell types tested, exhibiting normal attachment but a reduction in infectivity of up to one log order of magnitude. While Eph-binding-negative RRV mutants were replication-competent on fibroblasts, their infectivity was comparatively more reduced on endothelial cells with a substantial subpopulation of endothelial cells remaining resistant to infection. Together, this provides evidence for a cell type-specific use of Ephs by RRV. Furthermore, our results demonstrate that gL is dispensable for infection by RRV. Its deletion caused a reduction in infectivity similar to that observed after mutation of Eph-binding residues in gH. Our findings would be compatible with an ability of KSHV and RRV to use other, less efficient entry mediators in lieu of Ephs, although these host factors may not be uniformly expressed by all cells. PMID- 29432453 TI - Clinical findings and prognosis of patients hospitalized for acute decompensated heart failure: Analysis of the influence of Chagas etiology and ventricular function. AB - AIMS: Explore the association between clinical findings and prognosis in patients with acute decompensated heart failure (ADHF) and analyze the influence of etiology on clinical presentation and prognosis. METHODS AND RESULTS: Prospective cohort of 500 patients admitted with ADHF from Aug/2013-Feb/2016; patients were predominantly male (61.8%), median age was 58 (IQ25-75% 47-66 years); etiology was dilated cardiomyopathy in 141 (28.2%), ischemic heart disease in 137 (27.4%), and Chagas heart disease in 113 (22.6%). Patients who died (154 [30.8%]) or underwent heart transplantation (53[10.6%]) were younger (56 years [IQ25-75% 45 64 vs 60 years, IQ25-75% 49-67], P = 0.032), more frequently admitted for cardiogenic shock (20.3% vs 6.8%, P<0.001), had longer duration of symptoms (14 days [IQ25-75% 4-32.8 vs 7.5 days, IQ25-75% 2-31], P = 0.004), had signs of congestion (90.8% vs 76.5%, P<0.001) and inadequate perfusion more frequently (45.9% vs 28%, P<0.001), and had lower blood pressure (90 [IQ25-75% 80-100 vs 100, IQ25-75% 90-120], P<0.001). In a logistic regression model analysis, systolic blood pressure (P<0.001, OR 0.97 [95%CI 0.96-0.98] per mmHg) and jugular distention (P = 0.004, OR 1.923 [95%CI 1.232-3.001]) were significant. Chagas patients were more frequently admitted for cardiogenic shock (15%) and syncope/arrhythmia (20.4%). Pulmonary congestion was rare among Chagas patients and blood pressure was lower. The rate of in-hospital death or heart transplant was higher among patients with Chagas (50.5%). CONCLUSIONS: A physical exam may identify patients at higher risk in a contemporaneous population. Our findings support specific therapies targeted at Chagas patients in the setting of ADHF. PMID- 29432454 TI - History dependence in insect flight decisions during odor tracking. AB - Natural decision-making often involves extended decision sequences in response to variable stimuli with complex structure. As an example, many animals follow odor plumes to locate food sources or mates, but turbulence breaks up the advected odor signal into intermittent filaments and puffs. This scenario provides an opportunity to ask how animals use sparse, instantaneous, and stochastic signal encounters to generate goal-oriented behavioral sequences. Here we examined the trajectories of flying fruit flies (Drosophila melanogaster) and mosquitoes (Aedes aegypti) navigating in controlled plumes of attractive odorants. While it is known that mean odor-triggered flight responses are dominated by upwind turns, individual responses are highly variable. We asked whether deviations from mean responses depended on specific features of odor encounters, and found that odor triggered turns were slightly but significantly modulated by two features of odor encounters. First, encounters with higher concentrations triggered stronger upwind turns. Second, encounters occurring later in a sequence triggered weaker upwind turns. To contextualize the latter history dependence theoretically, we examined trajectories simulated from three normative tracking strategies. We found that neither a purely reactive strategy nor a strategy in which the tracker learned the plume centerline over time captured the observed history dependence. In contrast, "infotaxis", in which flight decisions maximized expected information gain about source location, exhibited a history dependence aligned in sign with the data, though much larger in magnitude. These findings suggest that while true plume tracking is dominated by a reactive odor response it might also involve a history-dependent modulation of responses consistent with the accumulation of information about a source over multi-encounter timescales. This suggests that short-term memory processes modulating decision sequences may play a role in natural plume tracking. PMID- 29432455 TI - Vector-borne disease risk indexes in spatially structured populations. AB - There are economic and physical limitations when applying prevention and control strategies for urban vector borne diseases. Consequently, there are increasing concerns and interest in designing efficient strategies and regulations that health agencies can follow in order to reduce the imminent impact of viruses like Dengue, Zika and Chikungunya. That includes fumigation, abatization, reducing the hatcheries, picking up trash, information campaigns. A basic question that arise when designing control strategies is about which and where these ones should focus. In other words, one would like to know whether preventing the contagion or decrease vector population, and in which area of the city, is more efficient. In this work, we propose risk indexes based on the idea of secondary cases from patch to patch. Thus, they take into account human mobility and indicate which patch has more chance to be a corridor for the spread of the disease and which is more vulnerable, i.e. more likely to have cases?. They can also indicate the neighborhood where hatchery control will reduce more the number of potential cases. In order to illustrate the usefulness of these indexes, we run a set of numerical simulations in a mathematical model that takes into account the urban mobility and the differences in population density among the areas of a city. If we label by i a particular neighborhood, the transmission risk index (TRi) measures the potential secondary cases caused by a host in that neighborhood. The vector transmission risk index (VTRi) measures the potential secondary cases caused by a vector. Finally, the vulnerability risk index (VRi) measures the potential secondary cases in the neighborhood. Transmission indexes can be used to give geographical priority to some neighborhoods when applying prevention and control measures. On the other hand, the vulnerability index can be useful to implement monitoring campaigns or public health investment. PMID- 29432456 TI - GM1 ganglioside-independent intoxication by Cholera toxin. AB - Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors via its B subunit (CTB). We have recently shown that in addition to the previously described binding partner ganglioside GM1, CTB binds to fucosylated proteins. Using flow cytometric analysis of primary human jejunal epithelial cells and granulocytes, we now show that CTB binding correlates with expression of the fucosylated Lewis X (LeX) glycan. This binding is competitively blocked by fucosylated oligosaccharides and fucose-binding lectins. CTB binds the LeX glycan in vitro when this moiety is linked to proteins but not to ceramides, and this binding can be blocked by mAb to LeX. Inhibition of glycosphingolipid synthesis or sialylation in GM1-deficient C6 rat glioma cells results in sensitization to CT-mediated intoxication. Finally, CT gavage produces an intact diarrheal response in knockout mice lacking GM1 even after additional reduction of glycosphingolipids. Hence our results show that CT can induce toxicity in the absence of GM1 and support a role for host glycoproteins in CT intoxication. These findings open up new avenues for therapies to block CT action and for design of detoxified enterotoxin-based adjuvants. PMID- 29432457 TI - The spectrum of neurological disease associated with Zika and chikungunya viruses in adults in Rio de Janeiro, Brazil: A case series. AB - BACKGROUND: During 2015-16 Brazil experienced the largest epidemic of Zika virus ever reported. This arthropod-borne virus (arbovirus) has been linked to Guillain Barre syndrome (GBS) in adults but other neurological associations are uncertain. Chikungunya virus has caused outbreaks in Brazil since 2014 but associated neurological disease has rarely been reported here. We investigated adults with acute neurological disorders for Zika, chikungunya and dengue, another arbovirus circulating in Brazil. METHODS: We studied adults who had developed a new neurological condition following suspected Zika virus infection between 1st November 2015 and 1st June 2016. Cerebrospinal fluid (CSF), serum, and urine were tested for evidence of Zika, chikungunya, and dengue viruses. RESULTS: Of 35 patients studied, 22 had evidence of recent arboviral infection. Twelve had positive PCR or IgM for Zika, five of whom also had evidence for chikungunya, three for dengue, and one for all three viruses. Five of them presented with GBS; seven had presentations other than GBS, including meningoencephalitis, myelitis, radiculitis or combinations of these syndromes. Additionally, ten patients positive for chikungunya virus, two of whom also had evidence for dengue virus, presented with a similar range of neurological conditions. CONCLUSIONS: Zika virus is associated with a wide range of neurological manifestations, including central nervous system disease. Chikungunya virus appears to have an equally important association with neurological disease in Brazil, and many patients had dual infection. To understand fully the burden of Zika we must look beyond GBS, and also investigate for other co-circulating arboviruses, particularly chikungunya. PMID- 29432458 TI - Capability and opportunity in hot shooting performance: Evidence from top-scoring NBA leaders. AB - In basketball games, whenever players successfully shoot in streaks, they are expected to demonstrate heightened performance for a stretch of time. Streak shooting in basketball has been debated for more than three decades, but most studies have provided little significant statistical evidence and have labeled random subjective judgments the "hot hand fallacy." To obtain a broader perspective of the hot hand phenomenon and its accompanying influences on the court, this study uses field goal records and optical tracking data from the official NBA database for the entire 2015-2016 season to analyze top-scoring leaders' shooting performances. We first reflect on the meaning of "hot hand" and the "Matthew effect" in actual basketball competition. Second, this study employs statistical models to integrate three different shooting perspectives (field goal percentage, points scored, and attempts). This study's findings shed new light not only on the existence or nonexistence of streaks, but on the roles of capability and opportunity in NBA hot shooting. Furthermore, we show how hot shooting performances resulting from capability and opportunity lead to actual differences for teams. PMID- 29432459 TI - Use of count-based image reconstruction to evaluate the variability and repeatability of measured standardised uptake values. AB - Standardized uptake values (SUVs) are the most widely used quantitative imaging biomarkers in PET. It is important to evaluate the variability and repeatability of measured SUVs. Phantom studies seem to be essential for this purpose; however, repetitive phantom scanning is not recommended due to the decay of radioactivity. In this study, we performed count-based image reconstruction to avoid the influence of decay using two different PET/CT scanners. By adjusting the ratio of 18F-fluorodeoxyglucose solution to tap water, a NEMA IEC body phantom was set for SUVs of 4.0 inside six hot spheres. The PET data were obtained using two scanners (Aquiduo and Celesteion; Toshiba Medical Systems, Tochigi, Japan). We set the start time for image reconstruction when the total radioactivity in the phantom was 2.53 kBq/cc, and employed the counts of the first 2-min acquisition as the standard. To maintain the number of counts for each image, we set the acquisition time for image reconstruction depending on the decay of radioactivity. We obtained 50 images, and calculated the SUVmax and SUVpeak of all six spheres in each image. The average values of the SUVmax were used to calculate the recovery coefficients to compare those measured by the two different scanners. Bland Altman analyses of the SUVs measured by the two scanners were also performed. The measured SUVs using the two scanners exhibited a 10-30% difference, and the standard deviation (SD) of the measured SUVs was between 0.1-0.2. The Celesteion always exhibited higher values than the Aquiduo. The smaller sphere exhibited a larger SD, and the SUVpeak had a smaller SD than the SUVmax. The Bland-Altman analyses showed poor agreement between the SUVs measured by the two scanners. The recovery coefficient curves obtained from the two scanners were considerably different. The Celesteion exhibited higher recovery coefficients than the Aquiduo, especially at approximately 20-mm-diameter. Additionally, the curves were lower than those calculated from the standard 30-min acquisition images. We propound count-based image reconstruction to evaluate the variability and repeatability of measured SUVs. These results are also applicable for the standardization and harmonization of SUVs in multi-institutional studies. PMID- 29432460 TI - Negative interferences by calcium dobesilate in the detection of five serum analytes involving Trinder reaction-based assays. AB - Previously, we reported the strong negative interference of calcium dobesilate, a vasoprotective agent, in creatinine assays involving the Trinder reaction. It is hypothesized that a similar effect occurs in the detection of uric acid (UA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). The interferences of calcium dobesilate during the detection of the five serum analytes were investigated on automated systems/analysers, and the effects were compared among eight different assay systems for each analyte. A calcium dobesilate standard was added into two sets of the blank serum pools of each analyte at final concentrations of 0, 2, 4, 8, 16, 32, and 64 MUg/mL. The percentage deviation of each analyte value was calculated between each drug concentration and the drug free samples. The clinically acceptable error levels for UA, TC, TG, HDL-C, and LDL-C were defined as +/-4.87%, +/-4.1%, +/-9.57%, +/-5.61%, and +/-5.46%, respectively. The observed interference was concentration dependent for each analyte. In the presence of 16 MUg/mL calcium dobesilate, which was within the therapeutic range, all seven Trinder reaction-based UA assay systems, two TG assay systems, two HDL-C assay systems and one TC assay system exhibited negative drug interferences. Calcium dobesilate negatively interferes with the detection of UA, TG, TC, and HDL-C in assay systems based on the Trinder reaction. The effect was most significant in UA and TG detection. PMID- 29432461 TI - A smart all-in-one device to measure vital signs in admitted patients. AB - BACKGROUND: Vital sign measurements in hospitalized patients by nurses are time consuming and prone to operational errors. The Checkme, a smart all-in-one device capable of measuring vital signs, could improve daily patient monitoring by reducing measurement time, inter-observer variability, and incorrect inputs in the Electronic Health Record (EHR). We evaluated the accuracy of self measurements by patient using the Checkme in comparison with gold standard and nurse measurements. METHODS AND FINDINGS: This prospective comparative study was conducted at the Internal Medicine ward of an academic hospital in the Netherlands. Fifty non-critically ill patients were enrolled in the study. Time related measurement sessions were conducted on consecutive patients in a randomized order: vital sign measurement in duplicate by a well-trained investigator (gold standard), a Checkme measurement by the patient, and a routine vital sign measurement by a nurse. In 41 patients (82%), initial calibration of the Checkme was successful and results were eligible for analysis. In total, 69 sessions were conducted for these 41 patients. The temperature results recorded by the patient with the Checkme differed significantly from the gold standard core temperature measurements (mean difference 0.1 +/- 0.3). Obtained differences in vital signs and calculated Modified Early Warning Score (MEWS) were small and were in range with predefined accepted discrepancies. CONCLUSIONS: Patient calculated MEWS using the Checkme, nurse measurements, and gold standard measurements all correlated well, and the small differences observed between modalities would not have affected clinical decision making. Using the Checkme, patients in a general medical ward setting are able to measure their own vital signs easily and accurately by themselves. This could be time saving for nurses and prevent errors due to manually entering data in the EHR. PMID- 29432462 TI - Adaptability of the Saccharomyces cerevisiae yeasts to wine fermentation conditions relies on their strong ability to consume nitrogen. AB - Saccharomyces cerevisiae strains are genetically diverse, largely as a result of human efforts to develop strains specifically adapted to various fermentation processes. These adaptive pressures from various ecological niches have generated behavioral differences among these strains, particularly in terms of their nitrogen consumption capacities. In this work, we characterize this phenotype by the specific quantity of nitrogen consumed under oenological fermentation conditions using a new approach. Indeed, unlike previous studies, our experiments were conducted in an environment containing excess nitrogen, eliminating the nitrogen limitation/starvation factor that is generally observed in fermentation processes. Using these conditions, we evaluated differences in the nitrogen consumption capacities for a set of five strains from diverse origins. The strains presented extremely different phenotypes and variations in their capacities to take up nitrogen from a wine fermentation environment. These variations reflect the differences in the nitrogen uptake capacities between wine and non-wine strains. Finally, the strains differed in their ability to adapt to the nitrogen composition of the environment, leading to variations in the cellular stress states, fermentation performances and the activity of the nitrogen sensing signaling pathway. PMID- 29432463 TI - Beyond factor analysis: Multidimensionality and the Parkinson's Disease Sleep Scale-Revised. AB - Many studies have sought to describe the relationship between sleep disturbance and cognition in Parkinson's disease (PD). The Parkinson's Disease Sleep Scale (PDSS) and its variants (the Parkinson's disease Sleep Scale-Revised; PDSS-R, and the Parkinson's Disease Sleep Scale-2; PDSS-2) quantify a range of symptoms impacting sleep in only 15 items. However, data from these scales may be problematic as included items have considerable conceptual breadth, and there may be overlap in the constructs assessed. Multidimensional measurement models, accounting for the tendency for items to measure multiple constructs, may be useful more accurately to model variance than traditional confirmatory factor analysis. In the present study, we tested the hypothesis that a multidimensional model (a bifactor model) is more appropriate than traditional factor analysis for data generated by these types of scales, using data collected using the PDSS-R as an exemplar. 166 participants diagnosed with idiopathic PD participated in this study. Using PDSS-R data, we compared three models: a unidimensional model; a 3 factor model consisting of sub-factors measuring insomnia, motor symptoms and obstructive sleep apnoea (OSA) and REM sleep behaviour disorder (RBD) symptoms; and, a confirmatory bifactor model with both a general factor and the same three sub-factors. Only the confirmatory bifactor model achieved satisfactory model fit, suggesting that PDSS-R data are multidimensional. There were differential associations between factor scores and patient characteristics, suggesting that some PDSS-R items, but not others, are influenced by mood and personality in addition to sleep symptoms. Multidimensional measurement models may also be a helpful tool in the PDSS and the PDSS-2 scales and may improve the sensitivity of these instruments. PMID- 29432464 TI - A robust technique based on VLM and Frangi filter for retinal vessel extraction and denoising. AB - The exploration of retinal vessel structure is colossally important on account of numerous diseases including stroke, Diabetic Retinopathy (DR) and coronary heart diseases, which can damage the retinal vessel structure. The retinal vascular network is very hard to be extracted due to its spreading and diminishing geometry and contrast variation in an image. The proposed technique consists of unique parallel processes for denoising and extraction of blood vessels in retinal images. In the preprocessing section, an adaptive histogram equalization enhances dissimilarity between the vessels and the background and morphological top-hat filters are employed to eliminate macula and optic disc, etc. To remove local noise, the difference of images is computed from the top-hat filtered image and the high-boost filtered image. Frangi filter is applied at multi scale for the enhancement of vessels possessing diverse widths. Segmentation is performed by using improved Otsu thresholding on the high-boost filtered image and Frangi's enhanced image, separately. In the postprocessing steps, a Vessel Location Map (VLM) is extracted by using raster to vector transformation. Postprocessing steps are employed in a novel way to reject misclassified vessel pixels. The final segmented image is obtained by using pixel-by-pixel AND operation between VLM and Frangi output image. The method has been rigorously analyzed on the STARE, DRIVE and HRF datasets. PMID- 29432465 TI - Seasonal and diurnal patterns of soil respiration in an evergreen coniferous forest: Evidence from six years of observation with automatic chambers. AB - Soil respiration (Rs) plays a key role in the carbon balance of forest ecosystems. There is growing evidence that Rs is strongly correlated with canopy photosynthesis; however, how Rs is linked to aboveground attributes at various phenological stages, on the seasonal and diurnal scale, remains unclear. Using an automated closed dynamic chamber system, we assessed the seasonal and diurnal patterns of Rs in a temperate evergreen coniferous forest from 2005 to 2010. High frequency Rs rates followed seasonal soil temperature patterns but the relationship showed strong hysteresis. Predictions of Rs based on a temperature response model underestimated the observed values from June to July and overestimated those from August to September and from January to April. The observed Rs was higher in early summer than in late summer and autumn despite similar soil temperatures. At a diurnal scale, the Rs pattern showed a hysteresis loop with the soil temperature trend during the seasons of high biological activity (June to October). In July and August, Rs declined after the morning peak from 0800 to 1400 h, although soil temperatures continued to increase. During that period, figure-eight-shaped diurnal Rs patterns were observed, suggesting that a midday decline in root physiological activity may have occurred in early summer. In September and October, Rs was higher in the morning than in the night despite consistently high soil temperatures. We have characterised the magnitude and pattern of seasonal and diurnal Rs in an evergreen forest. We conclude that the temporal variability of Rs at high resolution is more related to seasons across the temperature dependence. PMID- 29432466 TI - Knockdown of L1CAM significantly reduces metastasis in a xenograft model of human melanoma: L1CAM is a potential target for anti-melanoma therapy. AB - Finding additional functional targets for combination therapy could improve the outcome for melanoma patients. In a spontaneous metastasis xenograft model of human melanoma a shRNA mediated knockdown of L1CAM more than sevenfold reduced the number of lung metastases after the induction of subcutaneous tumors for two human melanoma cell lines (MeWo, MV3). Whole genome expression arrays of the initially L1CAM high MeWo subcutaneous tumors revealed unchanged or downregulated genes involved in epithelial to mesenchymal transition (EMT) except an upregulation of Jagged 1, indicating a compensatory change in Notch signaling especially as Jagged 1 expression showed an increase in MeWo L1CAM metastases and Jagged 1 was expressed in metastases of the initially L1CAM low MV3 cells as well. Expression of 17 genes showed concordant regulation for L1CAM knockdown tumors of both cell lines. The changes in gene expression indicated changes in the EMT network of the melanoma cells and an increase in p53/p21 and p38 activity contributing to the reduced metastatic potential of the L1CAM knockdowns. Taken together, these data make L1CAM a highly interesting therapeutic target to prevent further metastatic spread in melanoma patients. PMID- 29432468 TI - Effects of manual hyperinflation, clinical practice versus expert recommendation, on displacement of mucus simulant: A laboratory study. AB - INTRODUCTION: Manual hyperinflation (MH), a maneuver applied in mechanically ventilated patients to facilitate secretion removal, has large variation in its performance. Effectiveness of MH is usually evaluated by its capacity to generate an expiratory flow bias. The aim of this study was to compare the effects of MH and its resulting flow bias-applied according to clinical practice versus according to expert recommendation on mucus movement in a lung model simulating a mechanically ventilated patient. METHODS: Twelve physiotherapists were asked to apply MH, using a self-inflating manual resuscitator, to a test lung as if to remove secretions under two conditions: according to their usual clinical practice (pre-instruction phase) and after verbal instruction to perform MH according to expert recommendation was given (post-instruction phase). Mucus simulant movement was measured with a photodensitometric technique. Peak inspiratory flow (PIF), peak inspiratory pressure (PIP), inspiratory time (TINSP), tidal volume (VT) and peak expiratory flow (PEF) were measured continuously. RESULTS: It was found that MH performed post-instruction delivered a smaller VT (643.1 +/- 57.8 ml) at a lower PIP (15.0 +/- 1.5 cmH2O), lower PIF (38.0 +/- 9.6 L/min), longer TINSP (1.84 +/-0.54 s) and lower PEF (65.4 +/- 6.7L/min) compared to MH pre-instruction. In the pre-instruction phase, MH resulted in a mean PIF/PEF ratio of 1.73 +/- 0.38 and mean PEF-PIF difference of 54.6 +/- 28.3 L/min, both out of the range for secretion removal. In the post instruction phase both indexes were in the adequate range. Consequently, the mucus simulant was moved outward when MH was applied according to expert recommendation and towards the test lung when it was applied according to clinical practice. CONCLUSIONS: Performance of MH during clinical practice with PIF higher than PEF was ineffective to clear secretion in a lung model simulating a mechanically ventilated patient. In order to remove secretion, MH should result in an adequate expiratory flow bias. PMID- 29432467 TI - A drift-diffusion checkpoint model predicts a highly variable and growth-factor sensitive portion of the cell cycle G1 phase. AB - Even among isogenic cells, the time to progress through the cell cycle, or the intermitotic time (IMT), is highly variable. This variability has been a topic of research for several decades and numerous mathematical models have been proposed to explain it. Previously, we developed a top-down, stochastic drift diffusion+threshold (DDT) model of a cell cycle checkpoint and showed that it can accurately describe experimentally-derived IMT distributions [Leander R, Allen EJ, Garbett SP, Tyson DR, Quaranta V. Derivation and experimental comparison of cell-division probability densities. J. Theor. Biol. 2014;358:129-135]. Here, we use the DDT modeling approach for both descriptive and predictive data analysis. We develop a custom numerical method for the reliable maximum likelihood estimation of model parameters in the absence of a priori knowledge about the number of detectable checkpoints. We employ this method to fit different variants of the DDT model (with one, two, and three checkpoints) to IMT data from multiple cell lines under different growth conditions and drug treatments. We find that a two-checkpoint model best describes the data, consistent with the notion that the cell cycle can be broadly separated into two steps: the commitment to divide and the process of cell division. The model predicts one part of the cell cycle to be highly variable and growth factor sensitive while the other is less variable and relatively refractory to growth factor signaling. Using experimental data that separates IMT into G1 vs. S, G2, and M phases, we show that the model-predicted growth-factor-sensitive part of the cell cycle corresponds to a portion of G1, consistent with previous studies suggesting that the commitment step is the primary source of IMT variability. These results demonstrate that a simple stochastic model, with just a handful of parameters, can provide fundamental insights into the biological underpinnings of cell cycle progression. PMID- 29432469 TI - Correction: Baroreflex sensitivity and outcomes following coronary surgery. AB - [This corrects the article DOI: 10.1371/journal.pone.0175008.]. PMID- 29432470 TI - Prevalence of actual uptake and willingness to use pre-exposure prophylaxis to prevent HIV acquisition among men who have sex with men in Hong Kong, China. AB - OBJECTIVES: This study was to investigate the prevalence of actual uptake of pre exposure prophylaxis (PrEP), willingness to use daily oral PrEP under two cost scenarios, and potential issues related to PrEP use among men who have sex with men (MSM) with HIV negative/unknown sero-status in Hong Kong, China. Factors associated with the two measures of willingness were also investigated. METHODS: 403 eligible MSM completed the anonymous venue-based face-to-face interview/telephone interview. RESULTS: Only 1% had ever used PrEP. After being briefed about some facts of PrEP, the prevalence of willingness to use daily oral PrEP was 7.7% if they could purchase PrEP at private hospitals/clinics at HK$8,000 (US$1,032)/month (market rate) and 45.2% if free PrEP was provided by public hospitals/clinics in Hong Kong (free PrEP). After adjusted for significant background variables, significant factors of these two measures of willingness included: (1) number of correct responses to knowledge on PrEP, (2) perceived risk of HIV infection in the next six months, and (3) constructs of the Theory of Planned Behavior: positive and negative attitudes toward PrEP, perceived their significant others would support them take PrEP (perceived subjective norm), perceived number of local MSM who were willing to take PrEP (perceived descriptive norm), and confidence in using PrEP under the two scenarios (perceived behavioral control). Among all participants, 9.7% and 25.1% would start and discontinue using PrEP without consulting doctors; 26.0% would not take PrEP daily if it was provided for free, and 42.4% would not take up HIV testing every 3 months after using PrEP. CONCLUSION: Different strategies should be considered for promoting PrEP at market rate and if free PrEP is made available. Future promotion should increase their knowledge about PrEP, modify their perceptions related to HIV and PrEP, and address some potential issues related to PrEP use. PMID- 29432471 TI - In vitro mouse spermatogenesis with an organ culture method in chemically defined medium. AB - We previously reported the successful induction and completion of mouse spermatogenesis by culturing neonatal testis tissues. The culture medium consisted of alpha-minimum essential medium (alpha-MEM), supplemented with Knockout serum replacement (KSR) or AlbuMAX, neither of which were defined chemically. In this study, we formulated a chemically defined medium (CDM) that can induce mouse spermatogenesis under organ culture conditions. It was found that bovine serum albumin (BSA) purified through three different procedures had different effects on spermatogenesis. We also confirmed that retinoic acid (RA) played crucial roles in the onset of spermatogonial differentiation and meiotic initiation. The added lipids exhibited weak promoting effects on spermatogenesis. Lastly, luteinizing hormone (LH), follicle stimulating hormone (FSH), triiodothyronine (T3), and testosterone (T) combined together promoted spermatogenesis until round spermatid production. The CDM, however, was not able to produce elongated spermatids. It was also unable to induce spermatogenesis from the very early neonatal period, before 2 days postpartum, leaving certain factors necessary for spermatogenic induction in mice unidentified. Nonetheless, the present study provided important basic information on testis organ culture and spermatogenesis in vitro. PMID- 29432472 TI - Use of viral load surveillance data to assess linkage to care for persons with HIV released from corrections. AB - Incarcerated people remain a priority group in efforts to control and reverse the HIV epidemic. Following release, social instability and reengagement in key transmission risk behaviors increase the risk of secondary transmission of HIV. Targeted programs have been developed to facilitate reengagement in care on reentry. Evaluation of the impact of these initiatives requires a systematic, confidential, framework for assessment of linkage to care for persons released from corrections. By linking HIV viral load surveillance data to corrections release data, the time to the first laboratory monitoring service in the community as well as the virologic status can be assessed. Using this method, we linked release data for sentenced individuals released from Massachusetts state correctional facilities in 2012 to HIV surveillance data from the Massachusetts HIV/AIDS Surveillance Program (MHASP) for the years 2012-2013. We identified 41 individuals with HIV released in 2012. Ninety-one percent had identified virologic assessments post release, 41% within 30 days. Thirty-three percent did not have a viral load assessed for more than 90 days and 31% had detectable virus at the time of their initial assessment. Persons with longer incarcerations (> 180 days) were more likely to have suppressed viral load at the time of follow-up (p = 0.05). This work demonstrates the important value of HIV laboratory surveillance data and correctional release data as a tool to assess linkage to care following release from corrections. We encourage jurisdictions to explore utilizing similar methodology to evaluate the effectiveness of the linkage to HIV care after release from incarceration. PMID- 29432473 TI - Setup in a clinical workflow and impact on radiotherapy routine of an in vivo dosimetry procedure with an electronic portal imaging device. AB - High conformal techniques such as intensity-modulated radiation therapy and volumetric-modulated arc therapy are widely used in overloaded radiotherapy departments. In vivo dosimetric screening is essential in this environment to avoid important dosimetric errors. This work examines the feasibility of introducing in vivo dosimetry (IVD) checks in a radiotherapy routine. The causes of dosimetric disagreements between delivered and planned treatments were identified and corrected during the course of treatment. The efficiency of the corrections performed and the added workload needed for the entire procedure were evaluated. The IVD procedure was based on an electronic portal imaging device. A total of 3682 IVD tests were performed for 147 patients who underwent head and neck, abdomen, pelvis, breast, and thorax radiotherapy treatments. Two types of indices were evaluated and used to determine if the IVD tests were within tolerance levels: the ratio R between the reconstructed and planned isocentre doses and a transit dosimetry based on the gamma-analysis of the electronic portal images. The causes of test outside tolerance level were investigated and corrected and IVD test was repeated during subsequent fraction. The time needed for each step of the IVD procedure was registered. Pelvis, abdomen, and head and neck treatments had 10% of tests out of tolerance whereas breast and thorax treatments accounted for up to 25%. The patient setup was the main cause of 90% of the IVD tests out of tolerance and the remaining 10% was due to patient morphological changes. An average time of 42 min per day was sufficient to monitor a daily workload of 60 patients in treatment. This work shows that IVD performed with an electronic portal imaging device is feasible in an overloaded department and enables the timely realignment of the treatment quality indices in order to achieve a patient's final treatment compliant with the one prescribed. PMID- 29432474 TI - Community knowledge, perceptions and attitudes regarding leprosy in rural Cameroon: The case of Ekondotiti and Mbonge health districts in the South-west Region. AB - BACKGROUND: Although leprosy is one of the oldest diseases known to humanity, it remains largely misunderstood. Misconceptions about leprosy lead to stigma towards people with the disease. This study aimed at exploring the knowledge, perceptions and attitudes regarding leprosy in rural Cameroon. METHODS: We carried out a cross-sectional community survey of 233 respondents aged 15-75 years, free from leprosy, and living in two rural health districts of the South west Region of Cameroon. A questionnaire designed to evaluate knowledge, perceptions and attitudes about leprosy was used. Binary logistic regression was used to determine independent predictors of negative attitudes. RESULTS: About 82% of respondents had heard about, and 64.4% knew someone with leprosy. Information on leprosy was mainly from community volunteers (40.6%), friends (38.0%), and the media (24%). Only 19.7% of respondents knew the cause of leprosy, and a considerable proportion linked it to a spell (25.3%), unclean blood (15.5%) and heredity (14.6%). About 72% knew that leprosy is curable and 86.3% would advise medical treatment. Attitudes towards leprosy patients were generally negative. Only 42% would shake hands, 32.6% would share the same plate, and 28.3% and 27% respectively, would allow their child to play or marry a person with leprosy. Furthermore, only 33.9% approved of participation of leprosy patients, and 42.9% of their employment. Independent predictors of negative attitudes were: the belief that leprosy is a curse; is caused by a germ; and having seen a leprosy patient. The negative attitudes were dampened by: the beliefs that leprosy is a punishment, is hereditary and is due to poor personal hygiene. CONCLUSION: An awareness intervention using community volunteers and the media, with information on the cause of leprosy, its clinical manifestations and curability, and sensitization messages correcting the misconceptions and beliefs regarding leprosy, could improve the community knowledge and attitudes towards leprosy. This would ultimately contribute to the reduction of leprosy burden in the community. PMID- 29432475 TI - High-Throughput Tabular Data Processor - Platform independent graphical tool for processing large data sets. AB - High-throughput technologies generate considerable amount of data which often requires bioinformatic expertise to analyze. Here we present High-Throughput Tabular Data Processor (HTDP), a platform independent Java program. HTDP works on any character-delimited column data (e.g. BED, GFF, GTF, PSL, WIG, VCF) from multiple text files and supports merging, filtering and converting of data that is produced in the course of high-throughput experiments. HTDP can also utilize itemized sets of conditions from external files for complex or repetitive filtering/merging tasks. The program is intended to aid global, real-time processing of large data sets using a graphical user interface (GUI). Therefore, no prior expertise in programming, regular expression, or command line usage is required of the user. Additionally, no a priori assumptions are imposed on the internal file composition. We demonstrate the flexibility and potential of HTDP in real-life research tasks including microarray and massively parallel sequencing, i.e. identification of disease predisposing variants in the next generation sequencing data as well as comprehensive concurrent analysis of microarray and sequencing results. We also show the utility of HTDP in technical tasks including data merge, reduction and filtering with external criteria files. HTDP was developed to address functionality that is missing or rudimentary in other GUI software for processing character-delimited column data from high throughput technologies. Flexibility, in terms of input file handling, provides long term potential functionality in high-throughput analysis pipelines, as the program is not limited by the currently existing applications and data formats. HTDP is available as the Open Source software (https://github.com/pmadanecki/htdp). PMID- 29432476 TI - The impact of infrared radiation in flight control in the Australian "firebeetle" Merimna atrata. AB - Infrared (IR) receptors are rare in insects and have only been found in the small group of so-called pyrophilous insects, which approach forest fires. In previous work the morphology of the IR receptors and the physiology of the inherent sensory cells have been investigated. It was shown that receptors are located on the thorax and the abdomen respectively and show an astounding diversity with respect to structure and the presumed transduction mechanism. What is completely missing, however, is any behavioral evidence for the function of the IR receptors in pyrophilous insects. Here we describe the responses of the Australian "firebeetle", Merimna atrata to IR radiation. Beetles in a restrained flight were laterally stimulated with IR radiation of an intensity 20% above a previously determined electrophysiological threshold of the IR organs (40 mW/cm2). After exposure, beetles always showed an avoidance response away from the IR source. Reversible ablation experiments showed that the abdominal IR receptors are essential for the observed behavior. Tests with weaker IR radiation (11.4 mW/cm2) also induced avoidance reactions in some beetles pointing to a lower threshold. In contrast, beetles were never attracted by the IR source. Our results suggest that the IR receptors in Merimna atrata serve as an early warning system preventing an accidental landing on a hot surface. We also tested if another fire specific stimulus, the view of a large smoke plume, influenced the flight. However, due to an unexpected insensitivity of the flying beetles to most visual stimuli results were ambiguous. PMID- 29432477 TI - Digital diagnosis and treatment of mandibular condylar fractures based on Extensible Neuro imaging Archive Toolkit (XNAT). AB - OBJECTIVES: The treatment of condylar fractures has long been controversial. In this paper, we established a database for accurate measurement, storage, management and analysis of patients' data, in order to help determine the best treatment plan. METHODS: First of all, the diagnosis and treatment database was established based on XNAT, including 339 cases of condylar fractures and their related information. Then image segmentation, registration and three-dimensional (3D) measurement were used to measure and analyze the condyle shapes. Statistical analysis was used to analyze the anatomical structure changes of condyle and the surrounding tissues at different stages before and after treatment. The processes of condylar fracture reestablishment at different stages were also dynamically monitored. Finally, based on all these information, the digital diagnosis and treatment plans for condylar fractures were developed. RESULTS: For the patients less than 18 years old with no significant dislocation, surgical treatment and conservative treatment were equally effective for intracapsular fracture, and had no significant difference for neck and basal fractures. For patients above 18 years old, there was no significant difference between the two treatment methods for intracapsular fractures; but for condylar neck and basal fractures, surgical treatment was better than conservative treatment. When condylar fracture shift angle was greater than 11 degrees, and mandibular ramus height reduction was greater than 4mm, the patients felt the strongest pain, and their mouths opening was severely restricted. There were 170 surgical cases with condylar fracture shift angel greater than 11 degrees, and 118 of them (69.4%) had good prognosis, 52 of them (30.6%) had complications such as limited mouth opening. There were 173 surgical cases with mandibular ramus height reduction more than 4mm, and 112 of them (64.7%) had good prognosis, 61 of them (35.3%) had complications such as limited mouth opening. CONCLUSIONS: The establishment of XNAT condylar fracture database is helpful for establishing a digital diagnosis and treatment workflow for mandibular condylar fractures, providing new theoretical foundation and application basis for diagnosis and treatment of condylar fractures. PMID- 29432478 TI - Correction: Apoptosis by [Pt(O,O'-acac)(gamma-acac)(DMS)] requires PKC-delta mediated p53 activation in malignant pleural mesothelioma. AB - [This corrects the article DOI: 10.1371/journal.pone.0181114.]. PMID- 29432479 TI - Quality science from quality measurement: The role of measurement type with respect to replication and effect size magnitude in psychological research. AB - The quality of psychological studies is currently a major concern. The Many Labs Project (MLP) and the Open-Science-Collaboration (OSC) have collected key data on replicability and statistical effect sizes. We build on this work by investigating the role played by three measurement types: ratings, proportions and unbounded (measures without conceptual upper limits, e.g. time). Both replicability and effect sizes are dependent on the amount of variability due to extraneous factors. We predicted that the role of such extraneous factors might depend on measurement type, and would be greatest for ratings, intermediate for proportions and least for unbounded. Our results support this conjecture. OSC replication rates for unbounded, 43% and proportion 40% combined are reliably higher than those for ratings at 20% (effect size, w = .20). MLP replication rates for the original studies are: proportion = .74, ratings = .40 (effect size w = .33). Original effect sizes (Cohen's d) are highest for: unbounded OSC cognitive = 1.45, OSC social = .90); next for proportions (OSC cognitive = 1.01, OSC social = .84, MLP = .82); and lowest for ratings (OSC social = .64, MLP = .31). These findings are of key importance to scientific methodology and design, even if the reasons for their occurrence are still at the level of conjecture. PMID- 29432480 TI - Influence of body variables in the development of metabolic syndrome-A long term follow-up study. AB - OBJECTIVES: The body variable associated with the diagnosis of Metabolic Syndrome (MetS) is an elevated waist circumference (WC), although a number of other variables have been suggested. Among these, an elevated waist-to-height ratio (WHtR), ie a value higher than 0.5, that may identify abnormality, independently from height. An elevated WHtR provided the best correlation with MetS in a prior study in a large Italian population. In order to assess the validity of this conclusion, a long-term follow-up study re-examined this population, also in order to detect possible associations with cardiovascular (CV) risk. METHODS AND RESULTS: 1,071 subjects with a complete follow-up of over 6 years were evaluated with a comparative assessment of the three anthropometric variables, namely WHtR, WC and body mass index (BMI). WHtR>= 0.5 had the highest sensitivity for the identification of MetS, both in males and females (94.1% and 86.7% respectively). WHtR was of reduced specificity, occurring, yet less frequently (17.7% in males and 30% in females), in patients without MetS. By contrast, enlarged WC occurred with a lower frequency in male patients who developed MetS (30.2%) whereas in females, frequency was higher than in males (69.3%). Finally, a BMI>= 25 kg/m2 had intermediate sensitivity and specificity regardless of gender. WC showed the highest odds ratio (2.62, 95%CI: 1.18-5.78) for the prediction of CV occurrence. CONCLUSION: The present study confirms WHtR as an excellent screening tool in identifying MetS carriers, but, different from reports in other countries, it shows a lower specificity in our population. PMID- 29432482 TI - Are carnivore digestive separation mechanisms revealed on structure-rich diets?: Faecal inconsistency in dogs (Canis familiaris) fed day old chicks. AB - Pronounced variations in faecal consistency have been described anecdotally for some carnivore species fed a structure-rich diet. Typically two faecal consistencies are distinguished, namely hard and firm versus liquid and viscous faeces. It is possible that a separation mechanism is operating in the carnivore digestive tract, as in many herbivore species. Six beagle dogs were fed two experimental diets in a cross-over design of 7 days. Test diets consisted of chunked day old chicks differing only in particle size (fine = 7.8 mm vs coarse = 13 mm) in order to vary dietary structure. Digestive retention time was measured using titanium oxide (TiO2) as marker. The total faecal output was scored for consistency and faecal fermentation profiles were evaluated through faecal short chain fatty acid (SCFA) and ammonia (NH3) analyses. A total of 181 faecal samples were collected. Dietary particle size did not affect faecal consistency, fermentative end products nor mean retention time (MRT). However, a faecal consistency dichotomy was observed with firm faeces (score 2-2.5) and soft faeces (score 4-4.5) being the most frequently occurring consistencies in an almost alternating pattern in every single dog. Firm and soft faeces differed distinctively in fermentative profiles. Although the structure difference between diets did not affect the faecal dichotomy, feeding whole prey provoked the occurrence of the latter which raises suspicion of a digestive separation mechanism in the canine digestive tract. Further faecal characterisation is however required in order to unravel the underlying mechanism. PMID- 29432481 TI - Viral microRNA effects on persistent infection of human lymphoid cells by polyomavirus SV40. AB - BACKGROUND: Polyomaviruses, including simian virus 40 (SV40), display evidence of lymphotropic properties. This study analyzed the nature of SV40-human lymphocyte interactions in established cell lines and in primary lymphocytes. The effects of viral microRNA and the structure of the viral regulatory region on SV40 persistence were examined. RESULTS: SV40 DNA was maintained in infected B cell and myeloid cell lines during cell growth for at least 28 days. Limiting dilution analysis showed that low amounts of SV40 DNA (~2 copies per cell) were retained over time. Infected B cells remained viable and able to proliferate. Genome copies of the SV40 microRNA-null mutant persisted at higher levels than the DNA of wild-type viruses. Complex viral regulatory regions produced modestly higher DNA levels than simple regulatory regions. Viral large T-antigen protein was detected at low frequency and at low levels in infected B cells. Following infection of primary lymphocytes, SV40 DNA was detected in CD19+ B cells and CD14+ monocytes, but not in CD3+ T cells. Rescue attempts using either lysates of SV40-infected B lymphocytes, coculture of live cells, or infectious center assays all showed that replication-competent SV40 could be recovered on rare occasions. SV40 infections altered the expression of several B cell surface markers, with more pronounced changes following infections with the microRNA-null mutant. CONCLUSION: These findings indicate that SV40 can establish persistent infections in human B lymphocytes. The cells retain low copy numbers of viral DNA; the infections are nonproductive and noncytolytic but can occasionally produce infectious virus. SV40 microRNA negatively regulates the degree of viral effects on B cells. SIGNIFICANCE: Lymphocytes may serve as viral reservoirs and may function to disseminate polyomaviruses to different tissues in a host. To our knowledge, this report is the first extensive analysis of viral microRNA effects on SV40 infection of human lymphocytes. PMID- 29432483 TI - Histamine as an emergent indoor contaminant: Accumulation and persistence in bed bug infested homes. AB - Histamine is used in bronchial and dermal provocation, but it is rarely considered an environmental risk factor in allergic disease. Because bed bugs defecate large amounts of histamine as a component of their aggregation pheromone, we sought to determine if histamine accumulates in household dust in bed bug infested homes, and the effects of bed bug eradication with spatial heat on histamine levels in dust. We collected dust in homes and analyzed for histamine before, and up to three months after bed bug eradication. Histamine levels in bed bug infested homes were remarkably high (mean = 54.6+/-18.9 MUg/100 mg of sieved household dust) and significantly higher than in control homes not infested with bed bugs (mean < 2.5+/-1.9 MUg/100 mg of sieved household dust). Heat treatments that eradicated the bed bug infestations failed to reduce histamine levels, even three months after treatment. We report a clear association between histamine levels in household dust and bed bug infestations. The high concentrations, persistence, and proximity to humans during sleep suggest that bed bug-produced histamine may represent an emergent contaminant and pose a serious health risk in the indoor environment. PMID- 29432485 TI - Correction: Epidemiological investigation into the prevalence of abnormal inter arm blood pressure differences among different ethnicities in Xinjiang, China. AB - [This corrects the article DOI: 10.1371/journal.pone.0188546.]. PMID- 29432484 TI - Submicroscopic placental infection by non-falciparum Plasmodium spp. AB - BACKGROUND: Among the Plasmodium species that infect humans, adverse effects of P. falciparum and P. vivax have been extensively studied and reported with respect to poor outcomes particularly in first time mothers and in pregnant women living in areas with unstable malaria transmission. Although, other non falciparum malaria infections during pregnancy have sometimes been reported, little is known about the dynamics of these infections during pregnancy. METHODS AND FINDINGS: Using a quantitative PCR approach, blood samples collected from Beninese pregnant women during the first antenatal visit (ANV) and at delivery including placental blood were screened for Plasmodium spp. Risk factors associated with Plasmodium spp. infection during pregnancy were assessed as well as the relationships with pregnancy outcomes. P. falciparum was the most prevalent Plasmodium species detected during pregnancy, irrespective either of parity, of age or of season during which the infection occurred. Although no P. vivax infections were detected in this cohort, P. malariae (9.2%) and P. ovale (5.8%) infections were observed in samples collected during the first ANV. These non-falciparum infections were also detected in maternal peripheral blood (1.3% for P. malariae and 1.2% for P. ovale) at delivery. Importantly, higher prevalence of P. malariae (5.5%) was observed in placental than peripheral blood while that of P. ovale was similar (1.8% in placental blood). Among the non falciparum infected pregnant women with paired peripheral and placental samples, P. malariae infections in the placental blood was significantly higher than in the peripheral blood, suggesting a possible affinity of P. malariae for the placenta. However, no assoctiation of non-falciparum infections and the pregnancy outcomes was observed. CONCLUSIONS: Overall this study provided insights into the molecular epidemiology of Plasmodium spp. infection during pregnancy, indicating placental infection by non-falciparum Plasmodium and the lack of association of these infections with adverse pregnancy outcomes. PMID- 29432486 TI - Fractal analysis of plaque border, a novel method for the quantification of atherosclerotic plaque contour irregularity, is associated with pro-atherogenic plasma lipid profile in subjects with non-obstructive carotid stenoses. AB - BACKGROUND AND AIMS: Plaque border irregularity is a known imaging characteristic of vulnerable plaques, but its evaluation heavily relies on subjective evaluation and operator expertise. Aim of the present work is to propose a novel fractal analysis based method for the quantification of atherosclerotic plaque border irregularity and assess its relation with cardiovascular risk factors. METHODS AND RESULTS: Forty-two asymptomatic subjects with carotid stenosis underwent ultrasound evaluation and assessment of cardiovascular risk factors. Total, low density lipoprotein (LDL), high-density lipoprotein (HDL) plasma cholesterol and triglycerides concentrations were measured for each subject. Fractal analysis was performed in all the carotid segments affected by atherosclerosis, i.e. 147 segments. The resulting fractal dimension (FD) is a measure of irregularity of plaque profile on long axis view of the plaque. FD in the severest stenosis (main plaque FD,mFD) was 1.136+/-0.039. Average FD per patient (global FD,gFD) was 1.145+/-0.039. FD was independent of other plaque characteristics. mFD significantly correlated with plasma HDL (r = -0.367,p = 0.02) and triglycerides to-HDL ratio (r = 0.480,p = 0.002). CONCLUSIONS: Fractal analysis is a novel, readily available, reproducible and inexpensive technique for the quantitative measurement of plaque irregularity. The correlation between low HDL levels and plaque FD suggests a role for HDL in the acquisition of morphologic features of plaque instability. Further studies are needed to validate the prognostic value of fractal analysis in carotid plaques evaluation. PMID- 29432488 TI - The impact of insecticide applications on the dynamics of resistance: The case of four Aedes aegypti populations from different Brazilian regions. AB - BACKGROUND: In the tropics, the utilization of insecticides is still an important strategy for controlling Aedes aegypti, the principle vector of dengue, chikungunya and Zika viruses. However, increasing insecticide resistance in Ae. aegypti populations might hinder insecticide efficacy on a long-term basis. It will be important to understand the dynamics and evolution of insecticide resistance by assessing its frequency and the mechanisms by which it occurs. METHODOLOGY/PRINCIPAL FINDINGS: The insecticide resistance status of four Brazilian Ae. aegypti populations was monitored. Quantitative bioassays with the major insecticides employed in the country was performed: the adulticide deltamethrin (a pyrethroid-PY) and the larvicides, temephos (an organophosphate) and diflubenzuron (a chitin synthesis inhibitor). Temephos resistance was detected in all populations although exhibiting a slight decrease over time probably due to the interruption of field use. All vector populations were susceptible to diflubenzuron, recently introduced in the country to control Ae. aegypti. Resistance against deltamethrin was extremely high in three populations. Molecular assays investigated substitutions in the voltage gated sodium channel (NaV), the PY target site, at positions 1011, 1016 and 1534. Elevated frequencies of substitutions Val1016Ile and Phe1534Cys related to high PY resistance levels were identified. Biochemical assays detected alterations in the activities of two detoxifying enzyme classes related to metabolic resistance, glutathion-S transferases and esterases. The results obtained were evaluated in the context of both recent insecticide use and the records of dengue incidence in each locality. CONCLUSIONS/SIGNIFICANCE: The four Ae. aegypti populations evaluated were resistant to the neurotoxic insecticides, temephos and deltamethrin. However, they were still susceptible to diflubenzuron. A probable correlation between adult insect resistance to PY and the domestic application of insecticides is discussed, pointing to the need for awareness measures regarding the correct utilization by citizens. This work aims to contribute to the efficient and rational management of Ae. aegypti control of both larvae and adults. PMID- 29432487 TI - Structural basis of mammalian glycan targeting by Vibrio cholerae cytolysin and biofilm proteins. AB - Vibrio cholerae is an aquatic gram-negative microbe responsible for cholera, a pandemic disease causing life-threatening diarrheal outbreaks in populations with limited access to health care. Like most pathogenic bacteria, V. cholerae secretes virulence factors to assist colonization of human hosts, several of which bind carbohydrate receptors found on cell-surfaces. Understanding how pathogenic virulence proteins specifically target host cells is important for the development of treatment strategies to fight bacterial infections. Vibrio cholerae cytolysin (VCC) is a secreted pore-forming toxin with a carboxy-terminal beta-prism domain that targets complex N-glycans found on mammalian cell-surface proteins. To investigate glycan selectivity, we studied the VCC beta-prism domain and two additional beta-prism domains found within the V. cholerae biofilm matrix protein RbmC. We show that the two RbmC beta-prism domains target a similar repertoire of complex N-glycan receptors as VCC and find through binding and modeling studies that a branched pentasaccharide core (GlcNAc2-Man3) represents the likely footprint interacting with these domains. To understand the structural basis of V. cholerae beta-prism selectivity, we solved high-resolution crystal structures of fragments of the pentasaccharide core bound to one RbmC beta-prism domain and conducted mutagenesis experiments on the VCC toxin. Our results highlight a common strategy for cell-targeting utilized by both toxin and biofilm matrix proteins in Vibrio cholerae and provide a structural framework for understanding the specificity for individual receptors. Our results suggest that a common strategy for disrupting carbohydrate interactions could affect multiple virulence factors produced by V. cholerae, as well as similar beta-prism domains found in other vibrio pathogens. PMID- 29432489 TI - Forecasting the spatial and seasonal dynamic of Aedes albopictus oviposition activity in Albania and Balkan countries. AB - The increasing spread of the Asian tiger mosquito, Aedes albopictus, in Europe and US raises public health concern due to the species competence to transmit several exotic human arboviruses, among which dengue, chikungunya and Zika, and urges the development of suitable modeling approach to forecast the spatial and temporal distribution of the mosquito. Here we developed a dynamical species distribution modeling approach forecasting Ae. albopictus eggs abundance at high spatial (0.01 degree WGS84) and temporal (weekly) resolution over 10 Balkan countries, using temperature times series of Modis data products and altitude as input predictors. The model was satisfactorily calibrated and validated over Albania based observed eggs abundance data weekly monitored during three years. For a given week of the year, eggs abundance was mainly predicted by the number of eggs and the mean temperature recorded in the preceding weeks. That is, results are in agreement with the biological cycle of the mosquito, reflecting the effect temperature on eggs spawning, maturation and hatching. The model, seeded by initial egg values derived from a second model, was then used to forecast the spatial and temporal distribution of eggs abundance over the selected Balkan countries, weekly in 2011, 2012 and 2013. The present study is a baseline to develop an easy-handling forecasting model able to provide information useful for promoting active surveillance and possibly prevention of Ae. albopictus colonization in presently non-infested areas in the Balkans as well as in other temperate regions. PMID- 29432491 TI - Clonal chromosomal and genomic instability during human multipotent mesenchymal stromal cells long-term culture. AB - BACKGROUND AIMS: Spontaneous mutagenesis often leads to appearance of genetic changes in cells. Although human multipotent mesenchymal stromal cells (hMSC) are considered as genetically stable, there is a risk of genomic and structural chromosome instability and, therefore, side effects of cell therapy associated with long-term effects. In this study, the karyotype, genetic variability and clone formation analyses have been carried out in the long-term culture MSC from human gingival mucosa. METHODS: The immunophenotype of MSC has been examined using flow cytofluorometry and short tandem repeat (STR) analysis has been carried out for authentication. The karyotype has been examined using GTG staining and mFISH, while the assessment of the aneuploidy 8 frequency has been performed using centromere specific chromosome FISH probes in interphase cells. RESULTS: The immunophenotype and STR loci combination did not change during the process of cultivation. From passage 23 the proliferative activity of cultured MSCs was significantly reduced. From passage 12 of cultivation, clones of cells with stable chromosome aberrations have been identified and the biggest of these (12%) are tetrasomy of chromosome 8. The random genetic and structural chromosomal aberrations and the spontaneous level of chromosomal aberrations in the hMSC long-term cultures were also described. CONCLUSIONS: The spectrum of spontaneous chromosomal aberrations in MSC long-term cultivation has been described. Clonal chromosomal aberrations have been identified. A clone of cells with tetrasomy 8 has been detected in passage 12 and has reached the maximum size by passage 18 before and decreased along with the reduction of proliferative activity of cell line by passage 26. At later passages, the MSC line exhibited a set of cells with structural variants of the karyotype with a preponderance of normal diploid cells. The results of our study strongly suggest a need for rigorous genetic analyses of the clone formation in cultured MSCs before use in medicine. PMID- 29432490 TI - Differential microstructural alterations in rat cerebral cortex in a model of chronic mild stress depression. AB - Chronic mild stress leads to depression in many cases and is linked to several debilitating diseases including mental disorders. Recently, neuronal tracing techniques, stereology, and immunohistochemistry have revealed persistent and significant microstructural alterations in the hippocampus, hypothalamus, prefrontal cortex, and amygdala, which form an interconnected system known as the stress circuit. Most studies have focused only on this circuit, however, some studies indicate that manipulation of sensory and motor systems may impact genesis and therapy of mood disorders and therefore these areas should not be neglected in the study of brain microstructure alterations in response to stress and depression. For this reason, we explore the microstructural alterations in different cortical regions in a chronic mild stress model of depression. The study employs ex-vivo diffusion MRI (d-MRI) to assess cortical microstructure in stressed (anhedonic and resilient) and control animals. MRI is followed by immunohistochemistry to substantiate the d-MRI findings. We find significantly lower extracellular diffusivity in auditory cortex (AC) of stress groups and a significantly higher fractional anisotropy in the resilient group. Neurite density was not found to be significantly higher in any cortical ROIs in the stress group compared to control, although axonal density is higher in the stress groups. We also report significant thinning of motor cortex (MC) in both stress groups. This is in agreement with recent clinical and preclinical studies on depression and similar disorders where significant microstructural and metabolic alterations were found in AC and MC. Our findings provide further evidence that the AC and MC are sensitive towards stress exposure and may extend our understanding of the microstructural effects of stress beyond the stress circuit of the brain. Progress in this field may provide new avenues of research to help in diagnosis and treatment intervention for depression and related disorders. PMID- 29432493 TI - Mediation analysis for logistic regression with interactions: Application of a surrogate marker in ophthalmology. AB - Mediation analysis is often based on fitting two models, one including and another excluding a potential mediator, and subsequently quantify the mediated effects by combining parameter estimates from these two models. Standard errors of such derived parameters may be approximated using the delta method. For a study evaluating a treatment effect on visual acuity, a binary outcome, we demonstrate how mediation analysis may conveniently be carried out by means of marginally fitted logistic regression models in combination with the delta method. Several metrics of mediation are estimated and results are compared to findings using existing methods. PMID- 29432494 TI - Correction: Heritable heading time variation in wheat lines with the same number of Ppd-B1 gene copies. AB - [This corrects the article DOI: 10.1371/journal.pone.0183745.]. PMID- 29432492 TI - Molecular epidemiology of fluoroquinolone resistant Salmonella in Africa: A systematic review and meta-analysis. AB - BACKGROUND: Wide-ranging evidence on the occurrence of fluoroquinolone (FQ) resistance genetic determinants in African Salmonella strains is not available. The main objectives of this study were to assess the heterogeneity, estimate pooled proportions and describe the preponderance of FQ-resistance determinants in typhoidal and non-typhoidal Salmonella (NTS) isolates of Africa. METHODS: Genetic and phenotypic data on 6103 Salmonella isolates were considered. Meta- and frequency analyses were performed depending on the number of studies by category, number of isolates and risks of bias. A random effects model was used to assess heterogeneity and estimate pooled proportions. Relative and cumulative frequencies were calculated to describe the overall preponderance of FQ resistance determinants in quinolone resistant isolates. RESULTS: The pooled proportion of gyrA mutants (Salmonella enterica serovar Typhi, Salmonella enterica serovar Typhimurium, and Salmonella enterica serovar Enteritidis) was estimated at 5.7% (95% Confidence interval (CI) = 2.6, 9.8; Tau squared (T2) = 0.1105), and was higher in S. Typhi than in S. Typhimurium (odds ratio (OR) = 3.3, 95%CI = 2, 5.7). The proportions of each of gyrB and parC mutants, and strains with Plasmid Mediated Quinolone Resistance genes (qnrA, qnrB and qnrS) were low (<= 0.3%). Overall, 23 mutant serotypes were identified, and most strains had mutations at codons encoding Ser83 and Asp87 of gyrA (82%, 95%CI = 78, 86). CONCLUSIONS: Mutations at gyrA appear to account for ciprofloxacin non susceptibility in most clinical Salmonella strains in Africa. The estimates could be harnessed to develop a mismatch-amplification mutation-assay for the detection of FQ-resistant strains in Africa. PMID- 29432495 TI - Rogue waves in the two dimensional nonlocal nonlinear Schrodinger equation and nonlocal Klein-Gordon equation. AB - In this paper, we investigate two types of nonlocal soliton equations with the parity-time (PT) symmetry, namely, a two dimensional nonlocal nonlinear Schrodinger (NLS) equation and a coupled nonlocal Klein-Gordon equation. Solitons and periodic line waves as exact solutions of these two nonlocal equations are derived by employing the Hirota's bilinear method. Like the nonlocal NLS equation, these solutions may have singularities. However, by suitable constraints of parameters, nonsingular breather solutions are generated. Besides, by taking a long wave limit of these obtained soliton solutions, rogue wave solutions and semi-rational solutions are derived. For the two dimensional NLS equation, rogue wave solutions are line rogue waves, which arise from a constant background with a line profile and then disappear into the same background. The semi-rational solutions shows intriguing dynamical behaviours: line rogue wave and line breather arise from a constant background together and then disappear into the constant background again uniformly. For the coupled nonlocal Klein Gordon equation, rogue waves are localized in both space and time, semi-rational solutions are composed of rogue waves, breathers and periodic line waves. These solutions are demonstrated analytically to exist for special classes of nonlocal equations relevant to optical waveguides. PMID- 29432496 TI - Correction: Long-term intra-individual reproducibility of heart rate dynamics during exercise and recovery in the UK Biobank cohort. AB - [This corrects the article DOI: 10.1371/journal.pone.0183732.]. PMID- 29432498 TI - Editorial. AB - no summary. PMID- 29432497 TI - Autologous T cells expressing the oncogenic transcription factor KLF6-SV1 prevent apoptosis of chronic lymphocytic leukemia cells. AB - Crosstalk between leukemic cells and the tumor microenvironment is of importance in chronic lymphocytic leukemia (CLL). T cells seem to sustain the survival of CLL cells by various mechanisms. The Kruppel-like family of transcription factors (KLFs) are identified as regulators of proliferation and cell death. In the present study, we analyzed the expression of the wild type (WT) gene KLF6 and the oncogenic splice variant 1 (KLF6-SV1) at the mRNA level in subsets of T cells from CLL patients (n = 29), multiple myeloma patients (n = 6) and normal donors (n = 10). RNA Silencing was used for wtKLF6 and KLF6-SV1. Tumor cell apoptosis was measured. A significant overexpression of wtKLF6 and KLF6-SV1 in T cells of CLL patients compared to normal donors and myeloma patients was noted (p<0.002). Western blot showed that both wtKLF6 and KLF6-SV1 were expressed in purified T cells from CLL patients. KLF6-SV1 siRNA transfection induced a significant down regulation of KLF6-SV1 in CLL T cells, which lost the capability to sustain the growth of leukemic cells. However, no such a significant effect was seen after wtKLF6 transfection of the autologous T cells. The results suggest that KLF6-SV1 may play a role in the regulation of survival CLL cells. PMID- 29432499 TI - Industry-corrupted psychiatric trials. AB - The goal of this paper is to expose the research misconduct of pharmaceutical industry sponsored clinical trials via three short case studies of corrupted psychiatric trials that were conducted in the United States. We discuss the common elements that enable the misrepresentation of clinical trial results including ghostwriting for medical journals, the role of key opinion leaders as co-conspirators with the pharmaceutical industry and the complicity of top medical journals in failing to uphold standards of science and peer review. We conclude that the corruption of industry-sponsored clinical trials is one of the major obstacles facing evidence-based medicine. PMID- 29432500 TI - Large animals as potential models of human mental and behavioral disorders. AB - Many animal models in different species have been developed for mental and behavioral disorders. This review presents large animals (dog, ovine, swine, horse) as potential models of this disorders. The article was based on the researches that were published in the peer-reviewed journals. Aliterature research was carried out using the PubMed database. The above issues were discussed in the several problem groups in accordance with the WHO International Statistical Classification of Diseases and Related Health Problems 10thRevision (ICD-10), in particular regarding: organic, including symptomatic, disorders; mental disorders (Alzheimer's disease and Huntington's disease, pernicious anemia and hepatic encephalopathy, epilepsy, Parkinson's disease, Creutzfeldt-Jakob disease); behavioral disorders due to psychoactive substance use (alcoholic intoxication, abuse of morphine); schizophrenia and other schizotypal disorders (puerperal psychosis); mood (affective) disorders (depressive episode); neurotic, stress-related and somatoform disorders (posttraumatic stress disorder, obsessive compulsive disorder); behavioral syndromes associated with physiological disturbances and physical factors (anxiety disorders, anorexia nervosa, narcolepsy); mental retardation (Cohen syndrome, Down syndrome, Hunter syndrome); behavioral and emotional disorders (attention deficit hyperactivity disorder). This data indicates many large animal disorders which can be models to examine the above human mental and behavioral disorders. PMID- 29432501 TI - Venlafaxine and sertraline does not affect the expression of genes regulating stress response in female MDD patients. AB - OBJECTIVES: The aim of this study was to analyze the expression of 3 genes involved in the regulation of HPA axis: GR, HSP90 and FKBP5, in patients with major depressive disorder (MDD) before antidepressant treatment and after 8 weeks of pharmacotherapy. Additionally, we analyzed the level of glucocorticoid receptor isoforms before and after treatment. METHODS: The study included 30 female patients (aged 18-60 years), with major depres- sive disorder diagnosed on the basis of the Structured Clinical Interview for DSM-IV (SCID). Antidepressant treatment included use of sertraline or venlafaxine. The assessment of patients' mental state (severity of depression) was checked by the Hamilton Depression Rating Scale (HDRS). After 8 weeks of treatment, the same clinical and molecular tests were performed. All of the patients underwent dexamethasone suppression test (DST). MRNA was isolated from the peripheral blood to evaluate the expression of the studied genes using real-time PCR with TaqMan probes. The concentration of GR isoforms (alpha and beta) in serum was also determined using ELISA. Statistical analysis was performed using Statistica v.12.0 software. RESULTS: The abnormal cortisol level was only seen in 20% of patients. Dysregulation on HPA axis was observed in 10% of patients. We observed significant clinical improvement after 8 weeks of pharmacotherapy in all patients. Almost the whole group of patients (except one patient) showed full remission of symptoms. We observed significant moderate correlation between cortisol level after DST before treatment and after 8 weeks of pharmacotherapy (r2 = 0.44). The results showed no significant difference in the expression of 3 analyzed genes compared before and after 8 weeks of therapy. The results of ELISA showed decreased level of alpha isoform after pharmacotherapy, independent of drug. CONCLUSIONS: The results showed no significant changes in the expression of genes involved in the stress axis activity during antidepressant therapy. PMID- 29432502 TI - Comparison of the effect of intravenous anesthetics used for anesthesia during electroconvulsive therapy on the hemodynamic safety and the course of ECT. AB - Electroconvulsive therapy (ECT) is the treatment method widely used in psychiatric disorders such as depression, bipolar disorder, schizophrenia and schizoaffective disorder. The advantage of ECT is therapeutic response that occurs significantly earlier than during pharmacotherapy. Initially ECTwas used without anesthesia. Then, in the 1950s procedures with general anesthesia were introduced to reduce the complications that may occur during a seizure caused by ECT, such as broken bones, teeth, tendon rupture, muscle damage. Currently, in general anesthesia for ECTseveral medications are used interchangeably: thiopental, propofol, etomidate and ketamine. In different resorts and different countries different anestethics are used, the choice is determined mainly by the experience of each resort and a kind of tradition. The authors provide an overview of objective data showing how various anesthetics affect the quality of ECT and the presence of any hemodynamic complications after ETC. Selection of articles included in this paper was made by searching Medline and PubMed databases using specific keywords: electroconvulsive therapy, general anesthesia, the risks and benefits of thiopental, ketamine, propofol and etomidate. The results of this review are inconclusive when it comes to the effect of intravenous anesthetics on the quality of the ECT treatment and side effects relating to respiratory and cardiovascular system. On this basis it is impossible to determine which of intravenous anesthetics is most advantageous from the point of view of the patient. To develop the optimum scheme of anesthesia for ECT, it is necessary to conduct further, methodologically correct studies. PMID- 29432503 TI - Therapeutic drug monitoring of atypical antipsychotics. AB - The paper presents an overview and analysis of the results of research on therapeutic ranges of concentrations and receptor occupancy, mainly D2 receptors, in the treatment with some atypical antipsychotic drugs. Amisulpride, aripiprazole, clozapine, quetiapine, olanzapine, risperidone, paliperidone, sertindole, and ziprasidone were taken into account. The benefits of therapeutic drug monitoring to optimize the effectiveness of treatment and avoid side effects or toxicity were shown. The safety of patients, with the possibility to use the lowest effective dose, is an undoubted profit of TDM. This helps to avoid overdosing resulting in adverse events (with particular emphasis on extrapyramidal symptoms and seizures).The need and desirability of TDM is due to the inter -and intraindividual differences in the pharmacokinetics of drugs, because only some of them have a close correlation between dose and plasma concentration. The plasma concentration correlates well with the occupancy of D2 receptors. The efficient and safe level is determined at 60-80%. Based on the knowledge of the indications for TDM and therapeutic concentration ranges, amisulpride, clozapine and olanzapine have the highest level of recommendation to use TDM. Therapeutic ranges of plasma concentrations of the analyzed drugs were determined to be 200-320 ng/ml for amisulpride, 150-210 ng/ml for aripiprazole, over 350-500 ng/ml for clozapine, 50-500 ng/ml for quetiapine, 20-40 ng/ml for olanzapine, 20-60 ng/ml for risperidone and paliperidone, 50-100 ng/ml for sertindole and 50-130 ng/ml for ziprasidone. PMID- 29432504 TI - A retrospective study of DRESS - drug reaction with eosinophilia and systemic symptoms. AB - OBJECTIVES: DRESS (drug reaction with eosinophilia and systemic syndrome) is qualified as hypersensitivity after drug reaction. This syndrome may occur due to any medication intake. There are three main groups of symptoms defining DRESS: skin lesions, hematological abnormalities and internal organ involvement. METHODS: A retrospective study was performed on a group of 261 patients with drug reactions hospitalized in the Clinic of Dermatology from 2004 until 2017. RESULTS: There were ten cases of DRESS of 261 hypersensitivity drug reactions observed in the Clinic. The drug which most frequently caused DRESS in the studied group was carbamazepine - six patients (60%). Lamotrigine was the cause of DRESS in two cases, oxycarbamazepine in one patient and dexketoprofen in one patient. The skin lesion was present in 100% patients. Mainly it was coalescing hemorrhagic rash accompanied by face edema. Eosinophilia was noticed in 80% of patients and the presence of atypical lymphocytes - in 40%. The main infiltrate organ was liver in 8 cases. CONCLUSIONS: DRESS diagnosis should be taken into consideration especially in patients treated eith antiepileptic drugs. Early diagnosis and drug discontinuation can contribute to preventing serious complications of DRESS. PMID- 29432505 TI - The use of EEG Biofeedback/Neurofeedback in psychiatric rehabilitation. AB - The aim of the systematic review was to evaluate the use of EEG Biofeedback/Neurofeedback in patients treated for mental disorders. The review covered publications analyzing influences and effects of therapy in patients receiving psychiatric treatment based on EEG Biofeedback/Neurofeedback. Selection of publications was made by searching PubMed and Scopus databases. 328 records concerning applications of the presented method were identified in total, including 84 records for patients diagnosed with mental disorders. The analysis of studies indicates that EEG Biofeedback/Neurofeedback is used for treatment of neurological, somatic and mental disorders. Its psychiatric applications for clinically diagnosed disorders include treatmentof depression, anorexia, dyslexia, dysgraphia, ADD, ADHD, schizophrenia, abuse of substances, neuroses, PTSD, and Alzheimer's disease. Research results imply that the neuromodulating effect of the therapy positively influences cognitive processes, mood, and anxiety levels. Positive effects of EEG Biofeedback confirm usefulness of this method as a main or auxiliary method in treatment of people with mental disorders. On the basis of conducted studies, it is worthwhile to consider inclusion of this method into the comprehensive neurorehabilitation activities. PMID- 29432506 TI - Eating habits and nutritional status of patients with affective disorders and schizophrenia. AB - OBJECTIVES: The aim of the study was to assess the nutritional value of the food intake in the group of men and women suffering from recurrent affective disorders and schizophrenia, and also to determine the relation between selected nutritional parameters with anthropometric indices defining the nutritional status of the subjects. METHODS: 219 persons participated in the study (61 patients with recurrent depressive disorders, 60 patients with schizophrenia and 98 healthy volunteers). A24-hour dietary recall was used in the quantitative assessment of the diet. Anthropometric and biochemical measurements as well as body composition analysis were used to assess the nutritional status. RESULTS: It was shown that women with depression and schizophrenia had a significantly higher content of both visceral adipose tissue and subcutaneous adipose tissue as compared with the control group. A diet with a higher content of energy from protein, a higher supply of calcium promoted a lower fat content in the bodies of women suffering from depression (no such relationship was observed in the group of men). In the group of patients with schizophrenia, a diet with a lower supply of energy promoted a lower BMI value, waist circumference, lower waist-hip ratio and a lower fat content in the body. CONCLUSIONS: An improper energy structure and an improper content of nutrients can, in the future, contribute to the development of many somatic diseases, thus leading to deterioration of life quality of subjects and preventing the maintenance of mental health. PMID- 29432507 TI - Application of phase angle for evaluation of the nutrition status of patients with anorexia nervosa. AB - The evaluation of the nutrition status of patients has been the subject of interest of many scientific disciplines. Any deviation from normal values is a serious clinical problem. There are multiple nutrition status evaluation methods used including diet history, scales and questionnaires, physical examination, anthropometric measurements, biochemical measurements, function tests, as well as bioelectric impedance analysis or adipometry. Phase angle, obtained by means of bioelectric impedance analysis, is another parameter that is being more and more frequently applied in nutrition status monitoring. It is proportional to body cell mass. Its direct correlation with the cellular nutrition status has been documented. High phase angle values signify well-being, while low phase angle values indicate poor condition of cells. The purpose of this paper was to review the current state of knowledge about the application of phase angle in evaluation and monitoring of the nutrition status of patients with anorexia nervosa on the basis of available literature. It was proven that the phase angle values in patients with anorexia nervosa are much lower compared to healthy people. Detailed observations showed phase angle value increase in the course of treatment. The relevance of the commonly used body mass index (BMI) has been questioned due to significant degree of generalization in the nutrition status evaluation. Thus, there is a need for new, objective parameters for nutrition status evaluation, which will assist in the treatment and monitoring of patients in a more meaningful and reliable way. The existing independent studies equivocally confirm the usefulness of phase angle in the evaluation of nutrition status of patients with anorexia nervosa and its broader application in clinical practice is only a matter of time. However, these are merely attempts and they have not yet found wider application in clinical practice in the treatment of anorexia nervosa. PMID- 29432508 TI - A Study on the relationship between orthorexia and vegetarianism using the BOT (Bratman Test for Orthorexia). AB - OBJECTIVES: The following article presents the relationship between vegetarianism and orthorexia nervosa (ON). Vegetarianism is an ideology and a way of life that aims at minimizing animal exploitation. A vegetarian diet excludes the consumption of meat together with other animal derived products. According to scientists, orthorexia nervosa is considered to be a new, yet unclassified eating disorder. It involves introducing dietary restrictions by individuals who feel a desire to improve their health status by healthy eating. METHODS: The study involved 2,611 participants, namely 1,346 vegetarians and 1,265 non-vegetarians. The research questionnaire consisted of general personal and anthropometric characteristics, the BOT(Bratman Test for Orthorexia) and questions evaluating the participants' attitude towards nutrition. RESULTS: Based on the obtained results, health food fanaticism is more specific to vegetarians than non vegetarians. The risk for orthorexia nervosa decreases with age and diet duration. The biggest number of health food fanatics was found in the group of lacto-vegetarians, a lower number among ovo-vegetarians and lacto-ovo vegetarians, and the smallest number was observed in the vegan group. Also, vegetarians were reported to have dietary consultations as frequently as non vegetarians. CONCLUSIONS: Very few studies can be found on the relationship between orthorexia nervosa and vegetarianism. Some scientists believe that vegetarians are particularly prone to orthorexia nervosa. In addition, it has been suggested by other researchers that vegetarianism can be used to mask eating disorders, as it allows these affected individuals to avoid certain products or situations related to food. The direction of cause and effect cannot be determined. PMID- 29432509 TI - Body image and depressive symptoms in person suffering from psoriasis. AB - OBJECTIVES: The purpose of the research study was specifying the relationship between severity of psoriasis and body image and self-reported depressive symptoms, taking into account the differences between the sexes. METHODS: The research study involved 54 psoriasis patients, including 30 men and 24 women aged from 19 to 82. The level of depressive symptoms was assessed using the Beck Depression Inventory, and body image - using the Multidimensional Body-Self Relations Questionnaire. The disease severity was objectively assessed using the Psoriasis Area and Severity Index. RESULTS: The female psoriasis patients were more critical of their appearance than the men (p< 0.01), and at the same time they were more appearance-oriented (p< 0.05). The men rated their fitness level (p< 0.01) and care for good physical condition (p< 0.01) higher than the women. The women showed less satisfaction with their body parts than the men (p< 0.01) and more fear of obesity (p< 0.05) and overweight (p< 0.05). No statistically significant differences were found between men and women with regard to general evaluation of body image and self-reported depressive symptoms. Moreover, it was established that in the case of both women and men there was a correlation between lowered mood and psoriasis severity (R = 0.416), as well as body image (R = - 0.282). In relation to individual scales, there was a statistically significant relationship between self-reported depressive symptoms and appearance evaluation (R = - 0.519), health evaluation (R = - 0.585), satisfaction with body parts (R = - 0.462), as well as appearance orientation (R = 0.425). CONCLUSIONS: Distortion of body image is correlated with self-reported depressive symptoms in psoriasis patients. PMID- 29432510 TI - Stigmatization feelings and depression symptoms in psoriasis patients. AB - OBJECTIVES: The objective of the study was to show the correlation between the feelings of stigmatization and depressive symptoms in psoriasis patients. The study has considered severity of feelings of stigmatization and depressive symptoms, as well as factors such as gender and skin lesions visibility. METHODS: The study involved 54 adult subjects suffering from psoriasis - 26 women and 28 men. The patients filled in the 33-item Feelings of Stigmatization Questionnaire and the Beck Depression Inventory. Moreover, the subjects were asked to mark the location of their psoriatic lesions on a schematic drawing. RESULTS: A correlation was found between feelings of stigmatization and depressive symptoms in the psoriasis patients. No differences between women and men were found with regard to depressive symptoms and feelings of stigmatization (except for the secretiveness aspect). It was found that location of skin lesions did not have an effect on occurrence of depressive symptoms and feelings of stigmatization (except for the shame and guilt aspect). CONCLUSIONS: It is still necessary to change the public attitude to patients with psoriasis. It is also very important to provide the patients with psychotherapeutic support aimed at enhancing their self-acceptance in order to overcome any feelings of stigmatization and to prevent them from depression. PMID- 29432511 TI - Trait and state anxiety in patients treated with intensive short-term group psychotherapy for neurotic and personality disorders. AB - OBJECTIVES: The study aimed to determine the severity of trait and state anxiety in patients treated for neurotic and personality disorders with intensive, short term group psychotherapy and to analyse the change of anxiety intensity in the course of treatment. METHODS: 116 patients (81 females and 35 males) participated in the study. The measurement of anxiety intensity was conducted with the State Trait Anxiety Inventory (STAI) at the beginning and at the end of treatment. RESULTS: The majority of patients (69% of the study group) demonstrated a high intensity of state anxiety at the beginning of the treatment with 47.4% being classified as very high. High intensity of trait anxiety was observed in 64.7% of participants (50.9% -very high). RCI (Reliable Change Index) and RCV (Reliable Change Value) indicated a significant change in state anxiety intensity in 62.1% of participants (48.3% - significant decrease, 13.8% increase). At the end of treatment more than a half of patients manifested medium and low intensity of both trait and state anxiety. CONCLUSIONS: At the beginning of psychotherapy the majority of patients demonstrated high intensity of both trait and state anxiety. In the course of therapy a considerable reduction of intensity of trait and state anxiety is observed. Significant deterioration in trait anxiety is observed in one out of every thirteen treated patients. Polish adaptation of STAI questionnaire is a useful tool for monitoring effectiveness of psychotherapy and may be successfully applied for screening and detailed diagnosis of neurotic and personality disorders. PMID- 29432512 TI - Theory of drives and emotions - from Sigmund Freud to Jaak Panksepp. AB - The article discusses the development of psychoanalytic theory in the direction of broadening the reflection on their own based on data derived from empirical studies other than clinical case study. Particularly noteworthy is the convergence that followed between neuroscience and psychoanalysis and the rise of the so-called neuropsychoanalysis. Consequently, this led to eject empirical hypotheses and begin research on defense mechanisms, self, memory, dreams, empathy, dynamic unconscious and emotional-motivational processes (theory of drives). Currently neuropsychoanalysis constituted itself as a discipline contained in itself three separate areas: the psychodynamic neuroscience, clinical neuropsychoanalysis and theory building. The article introduces the theory of Jaak Panksepp emotional systems as an example of anintegrated neurobiology of affect, behavioral biology, evolutionary psychology and psychoanalysis. The theory of emotional systems includes the description of the SEEKING system representing basic motivational system of the organism. Apart from a new perspective on the theory of drives described by Sigmund Freud, it offers the possibility to take into account the emotional and motivational systems within the understanding of mental disorders such as depression, addiction and psychosis, which is the core of psychoanalytic thinking. PMID- 29432513 TI - Report from the 9th International Congress of Cognitive Psychotherapy, Cluj Napoca, 28.06.-01.07.2017. PMID- 29432514 TI - Improving SNP prioritization and pleiotropic architecture estimation by incorporating prior knowledge using graph-GPA. AB - Summary: Integration of genetic studies for multiple phenotypes is a powerful approach to improving the identification of genetic variants associated with complex traits. Although it has been shown that leveraging shared genetic basis among phenotypes, namely pleiotropy, can increase statistical power to identify risk variants, it remains challenging to effectively integrate genome-wide association study (GWAS) datasets for a large number of phenotypes. We previously developed graph-GPA, a Bayesian hierarchical model that integrates multiple GWAS datasets to boost statistical power for the identification of risk variants and to estimate pleiotropic architecture within a unified framework. Here we propose a novel improvement of graph-GPA which incorporates external knowledge about phenotype-phenotype relationship to guide the estimation of genetic correlation and the association mapping. The application of graph-GPA to GWAS datasets for 12 complex diseases with a prior disease graph obtained from a text mining of biomedical literature illustrates its power to improve the identification of risk genetic variants and to facilitate understanding of genetic relationship among complex diseases. Availability and implementation: graph-GPA is implemented as an R package 'GGPA', which is publicly available at http://dongjunchung.github.io/GGPA/. DDNet, a web interface to query diseases of interest and download a prior disease graph obtained from a text mining of biomedical literature, is publicly available at http://www.chunglab.io/ddnet/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29432515 TI - Urinary Angiotensinogen Excretion Level Is Associated With Elevated Blood Pressure in the Normotensive General Population. AB - BACKGROUND: Inflammation, intrarenal renin-angiotensin system (RAS) activation, oxidative stress, and carbonyl stress have been postulated to play a fundamental role in controlling blood pressure. However, little is known about the association among renal RAS activation, carbonyl stress, and blood pressure elevation. METHODS: We evaluated the relationship between blood pressure elevation and either renal RAS activity or carbonyl stress in the general population (N = 355) in Japan. To minimize the effect of antihypertensive drug therapy, we divided participants into 3 groups (normotensive, hypertensive-with non-medication, and hypertensive-with-medication). Intrarenal RAS activity and carbonyl stress were indicated by the urinary angiotensinogen (AGT) and carbonyl compound excretion levels, respectively. RESULTS: The urinary AGT and carbonyl compound excretion levels were significantly associated with blood pressure. Using a stepwise multiple regression analysis, we found that the urinary AGT excretion levels were strongly associated with blood pressure elevation, compared with inflammation, oxidative stress, and carbonyl stress markers, in all groups. Urinary carbonyl compound excretion was significantly associated with blood pressure in only the hypertensive-without-medication group. Furthermore, blood pressure was significantly increased in these participants, and both the urinary AGT and carbonyl compound levels were high. The urinary AGT excretion levels were strongly associated with elevated blood pressure in normotensive people, and inappropriate renal RAS activity and carbonyl stress independently contributed to the development of hypertension. CONCLUSIONS: These findings suggest that RAS activation, particularly renal RAS activation exert a fundamental role in the pathogenesis of hypertension in the general population. PMID- 29432516 TI - Survey Estimates of Changes in Alcohol Use Patterns Following the 2012 Privatization of the Washington Liquor Monopoly. AB - Aims: The US state of Washington's 333 state-run liquor stores were privatized on 1 June 2012 and purchases began in ~1500 licensed stores of a variety of types. A regime of taxes and fees was implemented to replace the revenues generated by the state stores and, 1 year later, the beer tax was reduced by two thirds. This study evaluates the impact of these changes on total alcohol and spirits consumption in a retrospective pre-test design. Methods: The study sample consists of 2289 adults recruited in three cross-sectional surveys during 2014 and 2015. Retrospective typical past month quantity-frequency measures for before privatization drinking and current past month quantity-frequency measures were compared within subjects, for all alcohol and for spirits only. Results: No change in alcohol volume was seen across privatization while spirits volume was found to decrease, suggesting a shift from spirits to beer. This decline in spirits volume came from a reduction in drinking days while overall drinking days were found to increase. This was offset by a reduction in drinks per drinking day and in heavy occasions. Conclusions: These findings accurately mirror the overall flat trend in per capita alcohol sales but seem to exaggerate the very small shift towards beer seen in sales data. Effects of increased spirits availability appear to have been countered by increased spirits prices and a decreased beer tax, leading to a shift to beer consumption. Short summary: Survey-based analyses of alcohol use across Washington's spirits privatization, beer tax reduction and marijuana legalization found no change in alcohol volume, a reduction in spirits volume and a shift to more moderate drinking patterns. Reductions in drinking occurred among marijuana users and those with lower educational attainment reduced spirits volume. PMID- 29432517 TI - Spectral clustering based on learning similarity matrix. AB - Motivation: Single-cell RNA-sequencing (scRNA-seq) technology can generate genome wide expression data at the single-cell levels. One important objective in scRNA seq analysis is to cluster cells where each cluster consists of cells belonging to the same cell type based on gene expression patterns. Results: We introduce a novel spectral clustering framework that imposes sparse structures on a target matrix. Specifically, we utilize multiple doubly stochastic similarity matrices to learn a similarity matrix, motivated by the observation that each similarity matrix can be a different informative representation of the data. We impose a sparse structure on the target matrix followed by shrinking pairwise differences of the rows in the target matrix, motivated by the fact that the target matrix should have these structures in the ideal case. We solve the proposed non-convex problem iteratively using the ADMM algorithm and show the convergence of the algorithm. We evaluate the performance of the proposed clustering method on various simulated as well as real scRNA-seq data, and show that it can identify clusters accurately and robustly. Availability and implementation: The algorithm is implemented in MATLAB. The source code can be downloaded at https://github.com/ishspsy/project/tree/master/MPSSC. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29432518 TI - The effect of biannual medication reviews on the appropriateness of psychotropic drug use for neuropsychiatric symptoms in patients with dementia: a randomised controlled trial. AB - Objective: We studied the efficacy of biannual structured medication reviews to improve the appropriateness of psychotropic drug (PD) prescriptions for neuropsychiatric symptoms (NPS) in nursing home patients with dementia. Study Design and Setting: In this randomised controlled trial, the intervention encompassed a structured multidisciplinary medication review by physician, pharmacist and nurse. During this 18-month study, the patient's medical files were assessed every 6 months. The primary outcome was the appropriateness of PD prescriptions defined by the Appropriate Psychotropic drug use In Dementia (APID) index sum score, lower scores indicating more appropriate use. Results: At baseline, 380 patients were included, of which 222 were randomised to the intervention group. Compared to the control group, the APID index sum score in the intervention group improved significantly for all PD prescriptions (-5.28, P = 0.005). Conclusion: We advise the implementation of a structured, repeated medication review with the essential roles of pharmacist, physician and nurse, into daily practice. This work was supported and funded by the Netherlands Organisation for Health Research and Development (ZonMw). Netherlands Trial Register (NTR3569). PMID- 29432519 TI - The role of biomarkers and imaging in the clinical diagnosis of dementia. AB - Recognition of dementia relies on a good clinical history, supported by formal cognitive testing, but identifying the subtype of dementia may be wrong in 20% or more of cases. Accuracy may be improved by use of imaging and cerebrospinal fluid (CSF) biomarkers. Structural neuroimaging is recommended for most patients, not just to identify potentially reversible surgical pathology, but also to detect vascular changes and patterns of cerebral atrophy. Functional imaging can help to confirm neurodegeneration and to distinguish dementia subtypes when structural imaging has been inconclusive. Amyloid-positron emission tomography scans reflect neuritic plaque burden and identify the earliest pathological changes in Alzheimer's disease, but their value outside research settings is still uncertain. A combination of low CSF amyloid beta1-42 and high CSF total-tau or phospho-tau also has high predictive power for AD pathology, but diagnostic usefulness decreases with age because of the increased prevalence of AD-type pathology in non-demented people. The need to use biomarkers more routinely will become necessary as disease-modifying treatments become available and accurate subtype diagnosis will be required at an early (ideally pre-dementia) stage. Clinicians should be considering the resources and expertise that will soon be needed for optimal dementia diagnosis. PMID- 29432520 TI - CRootBox: a structural-functional modelling framework for root systems. AB - Background and Aims: Root architecture development determines the sites in soil where roots provide input of carbon and take up water and solutes. However, root architecture is difficult to determine experimentally when grown in opaque soil. Thus, root architecture models have been widely used and been further developed into functional-structural models that simulate the fate of water and solutes in the soil-root system. The root architecture model CRootBox presented here is a flexible framework to model root architecture and its interactions with static and dynamic soil environments. Methods: CRootBox is a C++-based root architecture model with Python binding, so that CRootBox can be included via a shared library into any Python code. Output formats include VTP, DGF, RSML and a plain text file containing coordinates of root nodes. Furthermore, a database of published root architecture parameters was created. The capabilities of CRootBox for the unconfined growth of single root systems, as well as the different parameter sets, are highlighted in a freely available web application. Key results: The capabilities of CRootBox are demonstrated through five different cases: (1) free growth of individual root systems; (2) growth of root systems in containers as a way to mimic experimental setups; (3) field-scale simulation; (4) root growth as affected by heterogeneous, static soil conditions; and (5) coupling CRootBox with code from the book Soil physics with Python to dynamically compute water flow in soil, root water uptake and water flow inside roots. Conclusions: CRootBox is a fast and flexible functional-structural root model that is based on state-of-the art computational science methods. Its aim is to facilitate modelling of root responses to environmental conditions as well as the impact of roots on soil. In the future, this approach will be extended to the above-ground part of the plant. PMID- 29432521 TI - Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. AB - Background: We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application. Patients and methods: We assessed a retrospective cohort of women from the Tubingen University Women's Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features. Results: Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB [89 (19.7%)], stage II [26 (5.8%)], and stage III/IV [61 (13.5%)]. ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression free (P = 0.001) and disease-specific (P = 0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, kappa 0.88. Discussion: We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials. PMID- 29432522 TI - WDL-RF: predicting bioactivities of ligand molecules acting with G protein coupled receptors by combining weighted deep learning and random forest. AB - Motivation: Precise assessment of ligand bioactivities (including IC50, EC50, Ki, Kd, etc.) is essential for virtual screening and lead compound identification. However, not all ligands have experimentally determined activities. In particular, many G protein-coupled receptors (GPCRs), which are the largest integral membrane protein family and represent targets of nearly 40% drugs on the market, lack published experimental data about ligand interactions. Computational methods with the ability to accurately predict the bioactivity of ligands can help efficiently address this problem. Results: We proposed a new method, WDL-RF, using weighted deep learning and random forest, to model the bioactivity of GPCR associated ligand molecules. The pipeline of our algorithm consists of two consecutive stages: (i) molecular fingerprint generation through a new weighted deep learning method, and (ii) bioactivity calculations with a random forest model; where one uniqueness of the approach is that the model allows end-to-end learning of prediction pipelines with input ligands being of arbitrary size. The method was tested on a set of twenty-six non-redundant GPCRs that have a high number of active ligands, each with 200-4000 ligand associations. The results from our benchmark show that WDL-RF can generate bioactivity predictions with an average root-mean square error 1.33 and correlation coefficient (r2) 0.80 compared to the experimental measurements, which are significantly more accurate than the control predictors with different molecular fingerprints and descriptors. In particular, data-driven molecular fingerprint features, as extracted from the weighted deep learning models, can help solve deficiencies stemming from the use of traditional hand-crafted features and significantly increase the efficiency of short molecular fingerprints in virtual screening. Availability and implementation: The WDL-RF web server, as well as source codes and datasets of WDL-RF, is freely available at https://zhanglab.ccmb.med.umich.edu/WDL-RF/ for academic purposes. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29432523 TI - Bipolar radiofrequency ablation: can we control parameters of return electrode? Author's reply. PMID- 29432524 TI - Reimplantation versus remodelling with ring annuloplasty: comparison of mid-term outcomes after valve-sparing aortic root replacement. AB - OBJECTIVES: Remodelling with extra-aortic ring annuloplasty has emerged as an alternative approach to root reimplantation. However, no studies have yet compared outcomes between procedures. The aim of this study was to compare mid term outcomes in patients undergoing reimplantation versus remodelling with extra aortic annuloplasty. METHODS: From 2001 to 2017, 142 patients underwent root remodelling with extra-aortic annuloplasty (n = 83, 48 +/- 13 years) or a reimplantation technique (n = 59, 48 +/- 12 years) at the Montreal Heart Institute. No differences were observed in the incidence of connective tissue disease (24% vs 29%, P = 0.9) or preoperative aortic insufficiency >=3 (37% vs 23%, P = 0.24). However, in the remodelling group, there were more bicuspid aortic valves (31% vs 9%; P < 0.01), and the mean preoperative aortic annulus diameter was larger (27.2 +/- 3.6 mm vs 25.6 +/- 2.4 mm; P = 0.01). The mean follow-up duration was 3.9 years (100% complete). RESULTS: There were no hospital deaths and 5 late deaths. At 5 years, overall survival was similar in both groups (100%, P = 0.98). Similarly, 5-year freedom from aortic valve reoperation was equivalent (97 +/- 2% in both groups, P = 0.95). Furthermore, 5-year survival free from aortic insufficiency >=2 or reoperation was 84 +/- 5% in the remodelling with annuloplasty group vs 83 +/- 6% in the reimplantation group (P = 0.62). The mean annular diameter was 24.3 +/- 0.5 mm at 5 years vs 23.6 +/- 0.3 mm at discharge in the remodelling group (P = 0.28) and 24.4 +/- 0.6 mm vs 23.2 +/- 0.3 mm, respectively, in the reimplantation group (P = 0.1). CONCLUSIONS: Despite a higher prevalence of bicuspid aortic valves and larger aortic annular diameters, mid-term outcomes after remodelling with extra-aortic annuloplasty and reimplantation are comparable. Extra-aortic ring annuloplasty is effective at stabilizing annular dimensions. PMID- 29432525 TI - Factors influencing the use of subcutaneous or transvenous implantable cardioverter-defibrillators: results of the European Heart Rhythm Association prospective survey. AB - The purpose of this European Heart Rhythm Association (EHRA) prospective snapshot survey is to provide an overview of the factors influencing patient selection for the implantation of a particular type of device: subcutaneous implantable cardioverter-defibrillator (S-ICD) or transvenous implantable cardioverter defibrillator (TV-ICD), across a broad range of tertiary European centres. A specially designed electronic questionnaire was sent via the internet to tertiary reference centres routinely implanting both TV-ICDs and S-ICDs. These centres were asked to prospectively include and fill-in this questionnaire for all consecutive patients implanted with an implantable cardioverter-defibrillator (ICD) (both TV-ICD and S-ICD) during an 8-week period of time. Questions concerned standards of care and policies used for patient management, focusing particularly on the reasons for choosing one or the other type of ICD for each patient. In total 20 centres participated at the survey and entered individual data from a total of 429 consecutive patients (men 76.3%). Indication of implantation was primary prevention for 73% of the patients. Implanted devices were distributed between cardiac resynchronisation therapy (CRT) ones with back up defibrillators (31.6%), single-chamber TV-ICD (29.5%), S-ICD (19.8%), and dual chamber TV-ICD (19.1%).The rate of S-ICD shows the current penetration of this treatment in everyday practice. Main reasons favouring the use of an S-ICD were young age (66.7%), anticipated (38.9%) or previous (9.3%) lead-related complications, and elevated risk (18.5%) or previous device infection (7.4%). Importantly, the choice for this device was also based on patient preference (16.7%) or active lifestyle (13%). The three most frequent reasons for the use of a transvenous device were the option of antitachycardia pacing (43.2%), and logically, the current or expected need for CRT (40%) or for permanent pacing (39.6%). This snapshot survey with individual patient data provides a contemporary insight into ICD implantation and management in the European electrophysiology tertiary centres. It also helps to better understand the reasons which condition the choice between a S-ICD and a traditional TV-ICD. Finally, it gives a picture of the distribution of various types of ICD, few years after the introduction of the S-ICD in the Europe. PMID- 29432526 TI - A Smartphone-Driven Thermometer Application for Real-time Population- and Individual-Level Influenza Surveillance. AB - Background: Smartphone-based sensors may enable real-time surveillance of infectious diseases at population and household levels. This study evaluates the use of data from commercially available "smart thermometers," connected to a mobile phone application, for surveillance of influenza-like illness (ILI). Methods: At a population level, we analyzed the correlation between thermometer recordings and Centers for Disease Control and Prevention-reported ILI activity nationally and by age group and region. We developed time-series models to forecast ILI activity in real time and up to 3 weeks in advance. We analyzed the ability of thermometer readings to track the duration of fevers and identify biphasic fever patterns. We also investigated potential transmission of febrile illness within households among device users. Results: Thermometer readings were highly correlated with national ILI activity (r > 0.95) and activity patterns across regions and age groups. Thermometer readings also significantly improved forecasts of ILI activity in real time and up to 3 weeks in advance. We found that fevers lasting between 3 and 6 days and biphasic fever episodes occurred more frequently during the influenza season. In addition, potential cases of in household transmission of febrile illness originated more frequently from children than adults. Conclusions: Smart thermometers represent a novel source of information for influenza surveillance and forecasting. Thermometer readings capture real-time ILI activity at a population level, and they can also be used to generate improved forecasts. Moreover, the widespread deployment of these smart thermometers may also allow for more rapid and efficient surveillance at the household level. PMID- 29432528 TI - Reply: False positive blood hCG test following Corifollitropin alfa injection. PMID- 29432529 TI - The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia. AB - Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. However, the pathological mechanisms driving neuronal atrophy in FTD remain poorly understood. Here we identify a conserved role for the novel pro apoptotic protein plenty of SH3s (POSH)/SH3 domain containing ring finger 1 in mediating neuropathology in Drosophila and mammalian models of charged multivesicular body protein 2B (CHMP2BIntron5) associated FTD. Aberrant, AKT dependent, accumulation of POSH was observed throughout the nervous system of both Drosophila and mice expressing CHMP2BIntron5. Knockdown of POSH was shown to be neuroprotective and sufficient to alleviate aberrant neuronal morphology, behavioral deficits and premature-lethality in Drosophila models, as well as dendritic collapse and cell death in CHMP2BIntron5expressing rat primary neurons. POSH knockdown also ameliorated elevated markers of Jun N-terminal kinase and apoptotic cascades in both Drosophila and mammalian models. This study provides the first characterization of POSH as a potential component of an FTD neuropathology, identifying a novel apoptotic pathway with relevance to the FTD spectrum. PMID- 29432527 TI - Advanced lesion symptom mapping analyses and implementation as BCBtoolkit. AB - Background: Patients with brain lesions provide a unique opportunity to understand the functioning of the human mind. However, even when focal, brain lesions have local and remote effects that impact functionally and structurally connected circuits. Similarly, function emerges from the interaction between brain areas rather than their sole activity. For instance, category fluency requires the associations between executive, semantic, and language production functions. Findings: Here, we provide, for the first time, a set of complementary solutions for measuring the impact of a given lesion on the neuronal circuits. Our methods, which were applied to 37 patients with a focal frontal brain lesions, revealed a large set of directly and indirectly disconnected brain regions that had significantly impacted category fluency performance. The directly disconnected regions corresponded to areas that are classically considered as functionally engaged in verbal fluency and categorization tasks. These regions were also organized into larger directly and indirectly disconnected functional networks, including the left ventral fronto-parietal network, whose cortical thickness correlated with performance on category fluency. Conclusions: The combination of structural and functional connectivity together with cortical thickness estimates reveal the remote effects of brain lesions, provide for the identification of the affected networks, and strengthen our understanding of their relationship with cognitive and behavioral measures. The methods presented are available and freely accessible in the BCBtoolkit as supplementary software [1]. PMID- 29432530 TI - Effects of withdrawing high-fiber ingredients before marketing on finishing pig growth performance, carcass characteristics, and intestinal weights. AB - Two experiments were conducted to determine the duration of high-fiber ingredient removal from finishing pig diets before marketing to restore carcass yield and carcass fat iodine value (IV), similar to pigs continuously fed a corn-soybean meal diet. In experiment 1, 288 pigs (initially 38.4 +/- 0.3 kg body weight [BW]) were used in an 88-d study and fed either a low-fiber corn-soybean meal diet from day 0 to 88 or a high-fiber diet containing 30% corn distillers dried grains with solubles and 19% wheat middlings until day 20, 15, 10, 5, or 0 before slaughter and switched to the low-fiber corn-soybean meal diet thereafter. Diets were not balanced for net energy. From day 0 to 88, pigs continuously fed the high-fiber diet tended to have increased average daily feed intake (P = 0.072) and decreased G:F and carcass yield (P = 0.001) compared with pigs fed the low-fiber corn soybean meal diet. Pigs continuously fed the high-fiber diet had greater (P < 0.010) IV of jowl, backfat, belly, and ham collar fat than those fed the low fiber corn-soybean meal diet throughout. As days of withdrawal increased, pigs previously fed the high-fiber diet had increased carcass yield (quadratic; P = 0.039). Pigs continuously fed the high-fiber diet had heavier (percentage of hot carcass weight [HCW]) full large intestines (P = 0.003) than pigs fed the corn soybean meal diet. Full large intestine weight decreased (linear; P = 0.018) as withdrawal time increased. Belly fat IV tended (linear; P = 0.080) to improve as withdrawal time increased. In experiment 2, a total of 1,089 pigs (initially 44.5 +/- 0.1 kg BW) were used in a 96-d study with the same dietary treatments as in experiment 1, except pigs were fed the high-fiber diet until day 24, 19, 14, 9, or 0 before slaughter and then switched to the corn-soybean meal diet. Pigs fed the high-fiber diet throughout had decreased average daily gain and G:F (P = 0.001) compared with those fed the low-fiber corn-soybean meal diet. For pigs initially fed the high-fiber diet and then switched to the low-fiber corn-soybean meal diet, G:F tended to improve (linear; P = 0.070) as withdrawal period increased. Pigs fed the high-fiber diet throughout had decreased HCW (P = 0.001) compared with those fed the low-fiber corn-soybean meal diet and HCW marginally increased (quadratic; P = 0.077) as withdrawal period increased. In summary, switching pigs from a high-fiber diet to a corn-soybean meal diet for up to 24 d before market increased carcass yield (experiment 1) or HCW (experiment 2) with the improvement most prominent during the first 5 to 9 d after withdrawal. PMID- 29432531 TI - Brain tissue plasticity: protein synthesis rates of the human brain. AB - All tissues undergo continuous reconditioning via the complex orchestration of changes in tissue protein synthesis and breakdown rates. Skeletal muscle tissue has been well studied in this regard, and has been shown to turnover at a rate of 1-2% per day in vivo in humans. Few data are available on protein synthesis rates of other tissues. Because of obvious limitations with regard to brain tissue sampling no study has ever measured brain protein synthesis rates in vivo in humans. Here, we applied stable isotope methodology to directly assess protein synthesis rates in neocortex and hippocampus tissue of six patients undergoing temporal lobectomy for drug-resistant temporal lobe epilepsy (Clinical trial registration: NTR5147). Protein synthesis rates of neocortex and hippocampus tissue averaged 0.17 +/- 0.01 and 0.13 +/- 0.01%/h, respectively. Brain tissue protein synthesis rates were 3-4-fold higher than skeletal muscle tissue protein synthesis rates (0.05 +/- 0.01%/h; P < 0.001). In conclusion, the protein turnover rate of the human brain is much higher than previously assumed. PMID- 29432532 TI - MiR-134, epigenetically silenced in gliomas, could mitigate the malignant phenotype by targeting KRAS. AB - Gliomas are characterized by a malignant phenotype with proliferation, cell cycle arrest and invasion. To explore the biological consequences of epigenetically regulated miRNAs, we performed a microarray-based screening (whose expression was affected by 5-AZA treatment) followed by bisulfite sequencing validation. We found that miR-134 as an epigenetically regulated suppressor gene with prognostic value in gliomas. MicroRNA-134 was downregulated in high-grade gliomas, especially in GBM samples. Functional studies in vitro and in vivo in mouse models showed that overexpression of miR-134 was sufficient to reduce cell cycle arrest, cell proliferation and invasion. Target analysis and functional assays correlated the malignant phenotype with miR-134 target gene KRAS, an established upstream regulator of ERK and AKT pathways. Overall, our results highlighted a role for miR-134 in explaining the malignant phenotype of gliomas and suggested its relevance as a target to develop for early diagnostics and therapy. PMID- 29432533 TI - CrossPlan: systematic planning of genetic crosses to validate mathematical models. AB - Motivation: Mathematical models of cellular processes can systematically predict the phenotypes of novel combinations of multi-gene mutations. Searching for informative predictions and prioritizing them for experimental validation is challenging since the number of possible combinations grows exponentially in the number of mutations. Moreover, keeping track of the crosses needed to make new mutants and planning sequences of experiments is unmanageable when the experimenter is deluged by hundreds of potentially informative predictions to test. Results: We present CrossPlan, a novel methodology for systematically planning genetic crosses to make a set of target mutants from a set of source mutants. We base our approach on a generic experimental workflow used in performing genetic crosses in budding yeast. We prove that the CrossPlan problem is NP-complete. We develop an integer-linear-program (ILP) to maximize the number of target mutants that we can make under certain experimental constraints. We apply our method to a comprehensive mathematical model of the protein regulatory network controlling cell division in budding yeast. We also extend our solution to incorporate other experimental conditions such as a delay factor that decides the availability of a mutant and genetic markers to confirm gene deletions. The experimental flow that underlies our work is quite generic and our ILP-based algorithm is easy to modify. Hence, our framework should be relevant in plant and animal systems as well. Availability and implementation: CrossPlan code is freely available under GNU General Public Licence v3.0 at https://github.com/Murali group/crossplan. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29432536 TI - Bipolar radiofrequency ablation: can we control parameters of return electrode? PMID- 29432535 TI - Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia. AB - Among the many types of neurons expressing protein kinase C (PKC) enzymes, cerebellar Purkinje neurons are particularly reliant on appropriate PKC activity for maintaining homeostasis. The importance of PKC enzymes in Purkinje neuron health is apparent as mutations in PRKCG (encoding PKCgamma) cause cerebellar ataxia. PRKCG has also been identified as an important node in ataxia gene networks more broadly, but the functional role of PKC in other forms of ataxia remains unexplored, and the mechanisms by which PKC isozymes regulate Purkinje neuron health are not well understood. Here, we investigated how PKC activity influences neurodegeneration in inherited ataxia. Using mouse models of spinocerebellar ataxia type 1 (SCA1) and 2 (SCA2) we identify an increase in PKC mediated substrate phosphorylation in two different forms of inherited cerebellar ataxia. Normalizing PKC substrate phosphorylation in SCA1 and SCA2 mice accelerates degeneration, suggesting that the increased activity observed in these models is neuroprotective. We also find that increased phosphorylation of PKC targets limits Purkinje neuron membrane excitability, suggesting that PKC activity may support Purkinje neuron health by moderating excitability. These data suggest a functional role for PKC enzymes in ataxia gene networks, and demonstrate that increased PKC activity is a protective modifier of degeneration in inherited cerebellar ataxia. PMID- 29432537 TI - The nerve of the spleen! Causing hypertension by placental growth factor. PMID- 29432539 TI - Submaximal exercise training, more than dietary selenium supplementation, improves antioxidant status and ameliorates exercise-induced oxidative damage to skeletal muscle in young equine athletes. AB - Exercise is associated with increased production of reactive oxygen species (ROS) as metabolism is upregulated to fuel muscle activity. If antioxidant systems become overwhelmed, ROS can negatively affect health and performance. Adaptation to exercise through regular training has been shown to improve defense against oxidative insult. Given selenium's role as an antioxidant, we hypothesized that increased Se intake would further enhance skeletal muscle adaptations to training. Quarter Horse yearlings (18 +/- 0.2 mo; 402 +/- 10 kg) were randomly assigned to receive either 0.1 or 0.3 mg Se/kg DM and placed in either an untrained or a trained (30 min walk-trot-canter, 4 d/wk) group for 14 wk. Phase 1 (wk 1 to 8) consisted of 4 treatments: trained and fed 0.1 mg Se/kg DM through wk 14 (CON-TR; n = 10), trained and fed 0.3 mg Se/kg DM through wk 14 (HIGH-TR; n = 10), untrained and fed 0.1 mg Se/kg DM through wk 14 (CON-UN; n = 5), or untrained and fed 0.3 mg Se/kg DM through wk 14 (HIGH-UN; n = 5). During Phase 2 (wk 9 to 14), dietary Se level in half of the trained horses was reversed, resulting in 6 treatments: CON-TR (n = 5), trained and fed 0.1 mg/kg Se in Phase 1 and then switched to 0.3 mg/kg Se for Phase 2 (ADD-TR; n = 5), trained and fed 0.3 mg/kg Se in Phase 1 and then switched to 0.1 mg/kg Se for Phase 2 (DROP-TR; n = 5), HIGH-TR (n = 5), CON-UN (n = 5), or HIGH-UN (n = 5). All horses underwent a 120-min submaximal exercise test (SET) at the end of Phase 1 (SET 1) and 2 (SET 2). Blood samples and biopsies from the middle gluteal muscle were collected before and after each phase of the study and in response to each SET and analyzed for markers of oxidative damage and antioxidant enzyme activity. In both phases, serum Se was higher (P < 0.0001) when horses received a diet with 0.3 than 0.1 mg Se/kg DM. Throughout the 14-wk study, resting activities of muscle glutathione peroxidase (GPx; P = 0.004) and superoxide dismutase (SOD; P = 0.06) were greater in trained horses than in untrained horses. In response to SET 1, serum creatine kinase (CK) activity was lower in trained horses than in untrained horses (P < 0.0001), indicating less muscle damage, but plasma lipid hydroperoxides (LPO) and muscle GPx and SOD activities were unaffected by training or Se. In response to SET 2, trained horses had greater muscle SOD activity (P = 0.0002) and lower serum CK activity (P = 0.003) and showed a trend for lower plasma LPO (P = 0.09) and muscle malondialdehyde (P = 0.09) than untrained horses. Muscle GPx activity did not change in response to SET 2 and was unaffected by training or Se. Results indicate that exercise training lessens muscle damage and improves antioxidant defense following an acute bout of prolonged exercise and was not further enhanced by feeding Se above the NRC requirement. PMID- 29432540 TI - Characterization of variability in pork carcass composition and primal quality,. AB - The objective was to characterize the factors and production practices that contribute to variation in pork composition and quality. It is possible the variation in pork quality traits, such as color, marbling, and tenderness, contributes to reduced customer confidence in the predictability of finished product quality and, therefore, pork products becoming less competitive for consumer dollars. Pigs raised in 8 different barns representing 2 seasons (hot and cold) and 2 production focuses (lean and quality) were used in this study. Pigs were marketed in 3 groups from each barn and marketing procedures followed commercial marketing procedures. Data were collected on a total of 7,684 pigs. The mivque0 option of the VARCOMP procedure in SAS was used to evaluate the proportion of variation each independent variable (season, production focus, marketing group, sex, and random variation) contributed to total variance. Random variation including inherent biological differences, as well as factors not controlled in this study, contributed the greatest proportion to total variation for each carcass composition and quality trait. Pig and other factors contributed to 93.5% of the variation in HCW, and marketing group, sex, season, and production focus accounted for 4.1, 1.4, 0.8, and 0.3%, respectively. Variation in percent carcass lean was attributed to production focus (36.4%), sex (15.8%), and season (10.2%). Pig and other factors contributed the greatest percentage of total variation (39.4%). Loin weight variation was attributed to production focus (21.4%), sex (5.4%), season (2.7%), marketing group (1.8%), and pig (68.7%). Belly weight variation was attributed to pig (88.9%), sex (4.1%), marketing group (3.8%), production focus (3.0%), and season (0.1%). Variation in ham weight was attributed to pig and other factors (93.9%), marketing group (2.8%), production focus (2.2%), and season (1.1%). Ultimate pH variation was attributed to pig (88.5%), season (6.2%), production focus (2.4%), marketing group (2.2%), and sex (0.7%). Aside from pig (71.9%), production focus (14.0%) was the next largest contributor to variation in iodine value followed by sex (13.2%) and marketing group (0.9%). Variation in carcass quality and composition could be accounted for, but the greatest percentage of variation was due to factors not accounted for in normal marketing practices. PMID- 29432541 TI - Reassessing Surgical Management of the Bony Vault in Rhinoplasty. AB - Level of Evidence 5: PMID- 29432543 TI - Genetic profiling of cell-free DNA from cerebrospinal fluid: opening the barrier to leptomeningeal metastasis in EGFR-mutant NSCLC. PMID- 29432538 TI - Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events. AB - Infertility affects ~7% of couples of reproductive age with little change in incidence in the last two decades. ART, as well as other interventions, have made major strides in correcting this condition. However, and in spite of advancements in the field, the age of the female partner remains a main factor for a successful outcome. A better understanding of the final stages of gamete maturation yielding an egg that can sustain embryo development and a pregnancy to term remains a major area for improvement in the field. This review will summarize the major cellular and molecular events unfolding at the oocyte-to embryo transition. We will provide an update on the most important processes/pathways currently understood as the basis of developmental competence, including the molecular processes involved in mRNA storage, its recruitment to the translational machinery, and its degradation. We will discuss the hypothesis that the translational programme of maternal mRNAs plays a key role in establishing developmental competence. These regulations are essential to assemble the machinery that is used to establish a totipotent zygote. This hypothesis further supports the view that embryogenesis begins during oogenesis. A better understanding of the events required for developmental competence will guide the development of novel strategies to monitor and improve the success rate of IVF. Using this information, it will be possible to develop new biomarkers that may be used to better predict oocyte quality and in selection of the best egg for IVF. PMID- 29432542 TI - Apicomplexan C-Mannosyltransferases Modify Thrombospondin Type I-containing Adhesins of the TRAP Family. AB - In many metazoan species, an unusual type of protein glycosylation, called C mannosylation, occurs on adhesive thrombospondin type 1 repeats (TSRs) and type I cytokine receptors. This modification has been shown to be catalyzed by the Caenorhabditis elegans DPY-19 protein and orthologues of the encoding gene were found in the genome of apicomplexan parasites. Lately, the micronemal adhesin thrombospondin-related anonymous protein (TRAP) was shown to be C-hexosylated in Plasmodium falciparum sporozoites. Here, we demonstrate that also the micronemal protein MIC2 secreted by Toxoplasma gondii tachyzoites is C-hexosylated. When expressed in a mammalian cell line deficient in C-mannosylation, P. falciparum and T. gondii Dpy19 homologs were able to modify TSR domains of the micronemal adhesins TRAP/MIC2 family involved in parasite motility and invasion. In vitro, the apicomplexan enzymes can transfer mannose to a WXXWXXC peptide but, in contrast to C. elegans or mammalian C-mannosyltransferases, are inactive on a short WXXW peptide. Since TSR domains are commonly found in apicomplexan surface proteins, C-mannosylation may be a common modification in this phylum. PMID- 29432544 TI - Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins. AB - Aims: Given the clinical impact of LMNA cardiomyopathies, understanding lamin function will fulfill a clinical need and will lead to advancement in the treatment of heart failure. A multidisciplinary approach combining cell biology, atomic force microscopy (AFM), and molecular modeling was used to analyse the biomechanical properties of human lamin A/C gene (LMNA) mutations (E161K, D192G, N195K) using an in vitro neonatal rat ventricular myocyte model. Methods and results: The severity of biomechanical defects due to the three LMNA mutations correlated with the severity of the clinical phenotype. AFM and molecular modeling identified distinctive biomechanical and structural changes, with increasing severity from E161K to N195K and D192G, respectively. Additionally, the biomechanical defects were rescued with a p38 MAPK inhibitor. Conclusions: AFM and molecular modeling were able to quantify distinct biomechanical and structural defects in LMNA mutations E161K, D192G, and N195K and correlate the defects with clinical phenotypic severity. Improvements in cellular biomechanical phenotype was demonstrated and may represent a mechanism of action for p38 MAPK inhibition therapy that is now being used in human clinical trials to treat laminopathies. PMID- 29432545 TI - Effect of castration method and analgesia on inflammation, behavior, growth performance, and carcass traits in feedlot cattle. AB - Our objective was to determine the effect of castration timing, method, and use of the analgesic meloxicam (MEL) on inflammation, behavior, performance, and carcass traits in feedlot cattle. This study was a randomized complete block design conducted over a 3-yr period. In total, 194 crossbred beef calves from a single ranch origin were randomized at birth to receive one of five treatments arranged as a 2 * 2 + 1 factorial: 1) bulls castrated within 48 h of birth (CON), 2) bulls surgically castrated on day 0 without MEL (SUR), 3) bulls surgically castrated on day 0 with MEL (SUR + MEL), 4) bulls band castrated on d 0 without MEL (BAN), and 5) bulls band castrated on day 0 with MEL (BAN + MEL). Upon feedlot arrival (day -11; average 287 +/- 2.03 d of age), animals were blocked by initial BW (224 +/- 4.5 kg) and assigned randomly to treatment pens in three consecutive years (n = 2 pens per treatment in each year). Oral MEL was administered at 1 mg/kg BW concurrent with applicable castration treatment on day 0. Data were analyzed using the MIXED and GLIMMIX procedures of SAS with pen (year) serving as experimental unit. From days 0 to 7, ADG was reduced (P = 0.01) for surgical (-0.42) compared to band (0.43 kg/d) castration. Conversely, ADG was increased for surgical (1.74) vs. band (1.46 kg/d) castration from days 14 to 32. There was also an overall (day 0 to final) improvement in ADG for MEL (P = 0.02), but no effect of castration method was observed (P = 0.81). The CON group had the greatest (P = 0.05) marbling score. Backfat thickness was increased (P = 0.01) for MEL. A treatment * day interaction (P = 0.04) existed for serum haptoglobin, with SUR having the greatest (P < 0.01) concentration on days 1 and 4. Meloxicam administered in the surgically castrated treatment reduced (P = 0.01) serum haptoglobin concentration on day 1. Relative to baseline, standing duration for surgical castration was increased 113 min (P < 0.01), while banding caused 6.7 more lying bouts (P < 0.01) immediately following castration on day 0. Step count was greatest for BAN, intermediate for CON, and least for surgical (P < 0.01). Results suggest that MEL mitigated the more pronounced inflammation observed for surgical castration, whereas behavior was differentially altered for castration method indicative of a divergent pain response. Castration, regardless of method, transiently reduced ADG, but MEL administration improved overall ADG for both methods. PMID- 29432546 TI - Dynamics of a geminivirus-encoded pre-coat protein and host RNA-dependent RNA polymerase 1 in regulating symptom recovery in tobacco. AB - RNA silencing is an integral part of the cellular defense mechanisms in plants that act against virus infection. However, the specific role of RNA silencing and the interplay between host and virus components during recovery from geminivirus infection remains unknown. Hence, in this study we aimed to examine the mechanism behind the host-specific recovery of Nicotiana tabacum infected with Tomato leaf curl Gujarat virus (ToLCGV). Unlike Tomato leaf curl New Delhi virus (ToLCNDV), ToLCGV infection resulted in symptom remission in N. tabacum, and we found that this was mainly due to cross-talk between the pre-coat protein (encoded by the AV2 ORF) of the virus and the host RNA-silencing component RNA-dependent RNA polymerase 1 (encoded by NtRDR1) of N. tabacum. Moreover, apart from the AV2 mutant, other mutants of ToLCNDV developed severe symptoms on a transgenic NtRDR1 overexpression line of N. benthamiana. In contrast, inoculation with ToLCGV resulted in symptom remission, which was due to enhanced methylation of the ToLCGV promoter. Our study reveals a novel 'arms race' in which the pre-coat protein of ToLCNDV selectively blocks the recovery process through inhibiting host-specific RDR1-mediated antiviral silencing in tobacco. PMID- 29432547 TI - Fsh-Pc-Sce complex mediates active transcription of Cubitus interruptus (Ci). AB - The Hedgehog (Hh) signaling pathway plays important roles in both embryonic development and adult tissue homeostasis. Such biological functions are mediated by the transcription factor Cubitus interruptus (Ci). Yet the transcriptional regulation of the effector Ci itself is poorly investigated. Through an RNAi based genetic screen, we identified that female sterile (1) homeotic (Fsh), a transcription co-activator, directly activates Ci transcription. Biochemistry assays demonstrated physical interactions among Fsh, Sex combs extra (Sce), and Polycomb (Pc). Functional assays further showed that both Pc and Sce are required for Ci expression, which is not likely mediated by the derepression of Engrailed (En), a repressor of Ci, in Pc or Sce mutant cells. Finally, we provide evidence showing that Pc/Sce facilitates the binding of Fsh at Ci locus and that the physical interaction between Fsh and Pc is essential for Fsh-mediated Ci transcription. Taken together, we not only uncover that Ci is transcriptionally regulated by Fsh-Pc-Sce complex but also provide evidence for the coordination between Fsh and PcG proteins in transcriptional regulation. PMID- 29432548 TI - Newly diagnosed glioblastoma: adverse socioeconomic factors correlate with delay in radiotherapy initiation and worse overall survival. AB - The optimal time for starting radiation in patients with glioblastoma (GBM) is controversial. We aimed to evaluate postoperative radiotherapy treatment patterns and the impact of timing of radiotherapy on survival outcomes in patients with GBM using a large, national hospital-based registry in the era of Stupp chemoradiation. We performed a retrospective cohort study using the National Cancer Data Base and identified adults with GBM diagnosed between 2010 and 2013 and treated with chemoradiation. We classified time from surgery/biopsy to radiation start into the following categories: <15 days, 15-21 days, 22-28 days, 29-35 days, 36-42 days and >42 days. We assessed the relation between time to radiation start and survival using Cox proportional hazards modeling adjusting for clinically relevant variables that were selected a priori. We used multivariate logistic modeling to determine factors independently associated with receipt of delayed radiation treatment. A total of 12 738 patients met our inclusion criteria after our cohort selection process. The majority of patients underwent either gross total (n = 5270, 41%) or subtotal (n = 4700, 37%) resection, while 2768 patients (22%) underwent biopsy only. Median time from definitive surgery or biopsy to initiation of radiation was 29 days (interquartile range 24-36 days). For patients who had biopsy or subtotal resection, earlier initiation of radiation did not appear to be associated with improved survival. However, among patients who underwent gross total resection, there appeared to be improved survival with early initiation of radiation. Patients who initiated radiation within 15-21 days of gross total resection had improved survival (hazard ratio 0.82, 95% confidence interval 0.69-0.98, P = 0.03) compared with patients who had delayed (>42 days after surgery) radiation. There was also a trend (P = 0.07 to 0.12) for improved survival for patients who initiated radiation within 22-35 days of gross total resection compared with patients who had delayed radiation. Patients who were black, had Medicaid or other government insurance or were not insured, and who lived in metropolitan areas or further away from the treating facility had higher odds of receiving radiation >35 days after gross total resection. Patients who lived in higher income areas had higher odds of receiving radiation within 35 days of a gross total resection. In a large cohort of patients with GBM treated with chemoradiation, our data suggest a survival benefit in initiating radiotherapy within 35 days after gross total resection. Further research is warranted to understand barriers to timely access to optimal therapy. PMID- 29432549 TI - Incidence, mortality and determinants of survival from cervical cancer in Northwest Russia: a registry-based cohort study. AB - Background: Cervical cancer is the third most common cancer among women. The evidence from Russia, however, is scarce. We studied the incidence of and mortality from cervical cancer in northwest Russia, and assessed determinants of survival among cervical cancer patients. Methods: This registry-based historical cohort study obtained data on all primary cases of cervical cancer in the Arkhangelsk region in 2000-2014 from the Arkhangelsk Regional Cancer Registry. One- and 5-y survival was calculated using life tables. Factors associated with survival were studied using Kaplan-Meier curves and Cox regression. Results: The incidence increased from 10.9 per 100 000 in 2000 to 20.9 per 100 000 in 2014, while mortality increased from 2.0 to 7.8 per 100 000 during the same period. One and 5-y survival was 77.4% (95% CI 75.4 to 79.4) and 60.0% (95% CI 54.6 to 61.5), respectively. Significant inverse association was observed between survival and stage of cancer. Patients with adenocarcinoma (HR=1.6, 95% CI 1.2 to 2.2), other histological types of cancer (HR=1.8, 95% CI 1.4 to 2.4) and those with undefined histologic type (HR=3.8, 95% CI 2.5 to 5.8) had shorter survival than patients with squamous cell carcinoma. Conclusions: Incidence of and mortality from cervical cancer in northwest Russia is considerably higher than in developed countries. Increased incidence in recent years may be attributed to increased screening. PMID- 29432551 TI - An Atypical Late Embryogenesis Abundant Protein OsLEA5 Plays a Positive Role in ABA-Induced Antioxidant Defense in Oryza sativa L. AB - OsLEA5 acts as a co-regulator of a transcriptional fact ZFP36 to enhance the expression and the activity of ascorbate peroxidase OsAPX1 to regulate seed germination in rice, but it it unknown whether OsLEA5 is also crucial in plant seedlings under stress conditions. To determine this, we generated OsLEA5 overexpression and knockdown rice plants. We found that overexpression of OsLEA5 in rice plants enhanced the tolerance to drought and salt stress; in contrast, an RNA interference (RNAi) mutant of OsLEA5 rice plants was more sensitive to drought and salinity. Further investigation found that various stimuli and ABA could induce OsLEA5 expression, and OsLEA5 acted downstream of ZFP36 to be involved in ABA-induced generation of hydrogen peroxide (H2O2), and the regulation of the expression and the activities of antioxidant defense enzymes in plants leaves, and OsLEA5 contributed to stabilize ZFP36. Additionally, OsLEA5 participates in the accumulation of ABA by up-regulating ABA biosynthesis genes and down-regulating ABA metabolism genes. Moreover, we found that two homologs of OsLEA5 (5C700, short for Os05g0526700; and 5C300, short for Os05g0584300) which were induced by ABA also interacted with ZFP36 separately; interestingly, the nuclear-located 5C700 could also act as a co-activator of ZFP36 to modulate OsAPX1, while 5C300 which was down-regulated by ABA induction acted as an ABA induced inhibitor of ZFP36 to regulate OsAPX1. Hence, our conclusion is that OsLEA5 participates in the ABA-mediated antioxidant defense to function in drought and salt stress response in rice, and the 5C subgroup of LEAs contribute by acting as co-regulators of the transcription factor ZFP36. PMID- 29432550 TI - Strategies for prediction and mitigation of radiation-induced liver toxicity. AB - Although well described in the 1960s, liver toxicity secondary to radiation therapy, commonly known as radiation-induced liver disease (RILD), remains a major challenge. RILD encompasses two distinct clinical entities, a 'classic' form, composed of anicteric hepatomegaly, ascites and elevated alkaline phosphatase; and a 'non-classic' form, with liver transaminases elevated to more than five times the reference value, or worsening of liver metabolic function represented as an increase of 2 or more points in the Child-Pugh score classification. The risk of occurrence of RILD has historically limited the applicability of radiation for the treatment of liver malignancies. With the development of 3D conformal radiation therapy, which allowed for partial organ irradiation based on computed tomography treatment planning, there has been a resurgence of interest in the use of liver irradiation. Since then, a large body of evidence regarding the liver tolerance to conventionally fractionated radiation has been produced, but severe liver toxicities has continued to be reported. More recently, improvements in diagnostic imaging, radiation treatment planning technology and delivery systems have prompted the development of stereotactic body radiotherapy (SBRT), by which high doses of radiation can be delivered with high target accuracy and a steep dose gradient at the tumor - normal tissue interface, offering an opportunity of decreasing toxicity rates while improving tumor control. Here, we present an overview of the role SBRT has played in the management of liver tumors, addressing the challenges and opportunities to reduce the incidence of RILD, such as adaptive approaches and machine-learning-based predictive models. PMID- 29432552 TI - Routine immunization in Pakistan: comparison of multiple data sources and identification of factors associated with vaccination. AB - Background: Within Pakistan, estimates of vaccination coverage with the pentavalent vaccine, oral polio vaccine (OPV) and measles vaccine (MV) in 2011 were reported to be 74%, 75% and 53%, respectively. These national estimates may mask regional variation. The reasons for this variation have not been explored. Methods: Data from the Multiple Indicator Cluster Surveys (MICS) for Balochistan and Punjab (2010-2011) are analysed to examine factors associated with receiving three or more doses of the pentavalent vaccine and one or more MVs using regression modelling. Pentavalent and OPV estimates from the MICS were compared to vaccine dose histories from surveillance for acute flaccid paralysis (AFP; poliomyelitis) to ascertain agreement. Results: Adjusted coverage of children 12 23 months of age were estimated to be 16.0%, 75.5% and 34.2% in Balochistan and 58.0%, 87.7% and 72.6% in Punjab for the pentavalent vaccine, OPV and MV, respectively. Maternal education, healthcare utilization and wealth were associated with receiving the pentavalent vaccine and the MV. There was a strong correlation of district estimates of vaccination coverage between AFP and MICS data, but AFP estimates of pentavalent coverage in Punjab were biased toward higher values. Conclusions: National estimates mask variation and estimates from individual surveys should be considered alongside other estimates. The development of strategies targeted towards poorly educated parents within low wealth quintiles that may not typically access healthcare could improve vaccination rates. PMID- 29432553 TI - Short-term heat stress altered metabolism and insulin signaling in skeletal muscle. AB - Heat-related complications continue to be a major health concern for humans and animals and lead to potentially life-threatening conditions. Heat stress (HS) alters metabolic parameters and may alter glucose metabolism and insulin signaling. Therefore, the purpose of this investigation was to determine the extent to which 12 h of HS-altered energetic metabolism in oxidative skeletal muscle. To address this, crossbred gilts (n = 8/group) were assigned to one of three environmental treatments for 12 h: thermoneutral (TN; 21 degrees C), HS (37 degrees C), or pair-fed to HS counterparts but housed in TN conditions (PFTN). Following treatment, animals were euthanized and the semitendinosus red (STR) was recovered. Despite increased relative protein abundance of the insulin receptor, insulin receptor substrate (IRS1) phosphorylation was increased (P = 0.0005) at S307, an inhibitory site, and phosphorylated protein kinase B (AKT) (S473) was decreased (P = 0.03) likely serving to impair insulin signaling following 12 h of HS. Further, HS increased phosphorylated protein kinase C (PKC) zeta/lambda (P = 0.02) and phosphorylated PKCdelta/theta protein abundance (P = 0.02), which are known to regulate inhibitory serine phosphorylation of IRS1 (S307). Sarcolemmal glucose transporter 4 (Glut4) was decreased (P = 0.04) in the membrane fraction of HS skeletal muscle suggesting diminished glucose uptake capacity. HS-mediated increases (P = 0.04) in mechanistic target of rapamycin (mTOR) were not accompanied by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). HS decreased (P = 0.0006) glycogen synthase (GS) and increased (P = 0.02) phosphorylated GS suggesting impaired glycogen synthesis. In addition, HS altered fatty acid metabolic signaling by increasing (P = 0.02) Acetyl-CoA carboxylase (ACC), decreasing (P = 0.005) phosphorylated ATP-citrate lyase (pATPCL) and fatty acid synthase (P = 0.01) (FAS). These data suggest that 12 h of HS blunted insulin signaling, decreased protein synthesis, and altered glycogen and fatty acid metabolism. PMID- 29432554 TI - Measuring care transitions in Sweden: validation of the care transitions measure. AB - Objective: To translate and assess the validity and reliability of the original American Care Transitions Measure, both the 15-item and the shortened 3-item versions, in a sample of people in transition from hospital to home within Sweden. Design: Translation of survey items, evaluation of psychometric properties. Setting: Ten surgical and medical wards at five hospitals in Sweden. Participants: Patients discharged from surgical and medical wards. Main outcome measure: Psychometric properties of the Swedish versions of the 15-item (CTM-15) and the 3-item (CTM-3) Care Transition Measure. Results: We compared the fit of nine models among a sample of 194 Swedish patients. Cronbach's alpha was 0.946 for CTM-15 and 0.74 for CTM-3. The model indices for CTM-15 and CTM-3 were strongly indicative of inferior goodness-of-fit between the hypothesized one factor model and the sample data. A multidimensional three-factor model revealed a better fit compared with CTM-15 and CTM-3 one factor models. The one-factor solution, representing 4 items (CTM-4), showed an acceptable fit of the data, and was far superior to the one-factor CTM-15 and CTM-3 and the three-factor multidimensional models. The Cronbach's alpha for CTM-4 was 0.85. Conclusions: CTM-15 with multidimensional three-factor model was a better model than both CTM 15 and CTM-3 one-factor models. CTM-4 is a valid and reliable measure of care transfer among patients in medical and surgical wards in Sweden. It seems the Swedish CTM is best represented by the short Swedish version (CTM-4) unidimensional construct. PMID- 29432555 TI - Gibberellins promote nodule organogenesis but inhibit the infection stages of nodulation. AB - Leguminous plant roots can form a symbiosis with soil-dwelling nitrogen-fixing rhizobia, leading to the formation of a new root organ, the nodule. Successful nodulation requires co-ordination of spatially separated events in the root, including infection in the root epidermis and nodule organogenesis deep in the root cortex. We show that the hormone gibberellin plays distinct roles in these epidermal and cortical programmes. We employed a unique set of genetic material in pea that includes severely gibberellin-deficient lines and della-deficient lines that enabled us to characterize all stages of infection and nodule development. We confirmed that gibberellin suppresses infection thread formation and show that it also promotes nodule organogenesis into nitrogen-fixing organs. In both cases, this is achieved through the action of DELLA proteins. This study therefore provides a mechanism to explain how both low and high gibberellin signalling can result in reduced nodule number and reveals a clear role for gibberellin in the maturation of nodules into nitrogen-fixing organs. We also demonstrate that gibberellin acts independently of ethylene in promoting nodule development. PMID- 29432556 TI - A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy. AB - Background: Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown. Methods: Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS). Results: PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 * 10-7 for rs9999820, all P < 10 5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 * 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways. Conclusions: The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation. PMID- 29432557 TI - Epigenetic modifiers as new immunomodulatory therapies in solid tumours. AB - Background: Immune therapies have revolutionized cancer treatment over the last few years by allowing improvements in overall survival. However, the majority of patients is still primary or secondary resistant to such therapies, and enhancing sensitivity to immune therapies is therefore crucial to improve patient outcome. Several recent lines of evidence suggest that epigenetic modifiers have intrinsic immunomodulatory properties, which could be of therapeutic interest. Material and methods: We reviewed preclinical evidence and clinical studies which describe or exploit immunomodulatory properties of epigenetic agents. Experimental approaches, clinical applicability and corresponding ongoing clinical trials are described. Results: Several epigenetic modifiers, such as histone deacetylase inhibitors, DNA methyl transferase inhibitors, bromodomain inhibitors, lysine specific histone demethylase 1 inhibitors and enhancer of zeste homolog 2 inhibitors, display intrinsic immunomodulatory properties. The latter can be achieved through the action of these drugs either on cancer cells (e.g. presentation and generation of neoantigens, induction of immunogenic cell death, modulation of cytokine secretion), on immune cells (e.g. linage, differentiation, activation status and antitumor capability), or on components of the microenvironment (e.g. regulatory T cells and macrophages). Several promising combinations, notably with immune checkpoint blockers or adoptive T-cell therapy, can be envisioned. Dedicated clinically relevant approaches for patient selection and trial design will be required to optimally develop such combinations. Conclusion: In an era where immune therapies are becoming a treatment backbone in many tumour types, epigenetic modifiers could play a crucial role in modulating tumours' immunogenicity and sensitivity to immune agents. Optimal trial design, including window of opportunity trials, will be key in the success of this approach, and clinical evaluation is ongoing. PMID- 29432558 TI - Models of epigenetic age capture patterns of DNA methylation in glioma associated with molecular subtype, survival, and recurrence. AB - Background: Models of epigenetic aging (epigenetic clocks) have been implicated as potentially useful markers for cancer risk and prognosis. Using 2 previously published methods for modeling epigenetic age, Horvath's clock and epiTOC, we investigated epigenetic aging patterns related to World Health Organization grade and molecular subtype as well as associations of epigenetic aging with glioma survival and recurrence. Methods: Epigenetic ages were calculated using Horvath's clock and epiTOC on 516 lower-grade glioma and 141 glioblastoma cases along with 136 nontumor (normal) brain samples. Associations of tumor epigenetic age with patient chronological age at diagnosis were assessed with correlation and linear regression, and associations were validated in an independent cohort of 203 gliomas. Contribution of epigenetic age to survival prediction was assessed using Cox proportional hazards modeling. Sixty-three samples from 18 patients with primary-recurrent glioma pairs were also analyzed and epigenetic age difference and rate of epigenetic aging of primary-recurrent tumors were correlated to time to recurrence. Results: Epigenetic ages of gliomas were near-universally accelerated using both Horvath's clock and epiTOC compared with normal tissue. The 2 independent models of epigenetic aging were highly associated with each other and exhibited distinct aging patterns reflective of molecular subtype. EpiTOC was found to be a significant independent predictor of survival. Epigenetic aging of gliomas between primary and recurrent tumors was found to be highly variable and not significantly associated with time to recurrence. Conclusions: We demonstrate that epigenetic aging reflects coherent modifications of the epigenome and can potentially provide additional prognostic power for gliomas. PMID- 29432559 TI - Glutamate Receptor Homolog3.4 is Involved in Regulation of Seed Germination Under Salt Stress in Arabidopsis. AB - Seed germination is sensitive to salt stress. ABA and Ca2+ are involved in the regulation of seed germination under salt stress. Ca2+ influx mediated by glutamate receptors (GLRs) plays important roles in many physiological processes in plants. Here, we investigated the correlation of GLRs, Ca2+ and ABA during seed germination in response to salt stress by using Arabidopsis thaliana wild type and T-DNA insertion knockout mutants of glutamate receptor homolog3.4. We demonstrated that atglr3.4-1 and atglr3.4-2 mutants were more sensitive to NaCl during seed germination and post-germination growth than wild-type plants. Treatments of wild-type seedlings with NaCl evoked a marked elevation in cytosolic Ca2+ activity ([Ca2+]cyt), and the elevation was inhibited by antagonists of GLRs, while the NaCl-induced elevation in [Ca2+]cyt was impaired in atglr3.4-1 and atglr3.4-2 mutants. Moreover, the mutants exhibited a lower expression of SOS3, SOS2 and SOS1, and greater accumulation of Na+ than wild-type seeds in the presence of NaCl. Mutation of AtGLR3.4 rendered the mutants more sensitive to ABA, while overexpression of AtGLR3.4 made the transgenic lines more tolerant to ABA in terms of seed germination. However, there was no difference in ABA content between atglr3.4 mutants and wild-type seeds, accompanied by lower expression of ABI3 and ABI4 in atglr3.4 mutants when challenged with NaCl. These results demonstrate that AtGLR3.4-mediated Ca2+ influx may be involved in the regulation of seed germination under salt stress by modulating Na+ accumulation through the SOS pathway. PMID- 29432560 TI - Nutrient composition and digestibility of energy and nutrients in wheat middlings and red dog fed to growing pigs. AB - This experiment was designed to determine nutrient composition and apparent total tract digestibility (ATTD) of GE, DM, OM, and NDF and the concentration of DE and ME in 10 sources of wheat middlings and in 1 source of red dog that were obtained from different flour mills in the United States. Twelve growing pigs (initial BW: 31.0 +/- 1.0 kg) were randomly allotted to a 12 * 8 Youden square design with 12 dietary treatments and eight 14 d periods. Pigs were individually housed in metabolism crates for total collection of feces and urine. A basal diet based on corn and soybean meal, and 11 diets containing corn, soybean meal, and 39.4% of one of the 10 sources of wheat middlings or of red dog were formulated. The ATTD of GE, DM, OM, and NDF in all diets was calculated using the direct procedure, and the ATTD of GE, DM, OM, and NDF in each source of wheat middlings or red dog was calculated by difference. Values for DE and ME were calculated as well. The average concentration of CP was 17.67% in wheat midlings and 17.0% in red dog, and the concentration of acid hydrolyzed ether extract (AEE) and total dietary fiber (TDF) was 2.44 and 13.90% in red dog, but 4.07 and 36.45% in wheat middlings. Red dog also contained more starch (42.98%) than wheat middlings (20.28%). Red dog had greater bulk density (498.5 g/L) and smaller particle size (146 um) compared with wheat middlings (315.1 g/L and 783 um). The average ATTD of GE, DM, OM, and NDF in wheat middlings (67.2%, 71.2%, 72.9%, and 53.0%, respectively) was less (P < 0.05) than in red dog (79.35%, 82.9%, 86.6%, and 58.7%, respectively). The average concentrations of DE and ME in wheat middlings were 2,990 and 2,893 kcal/kg DM, and these values were less (P < 0.05) than the DE and ME in red dog (3,408 and 3,292 kcal/kg DM). In conclusion, wheat middlings contains more fiber and less starch than red dog and the ATTD of GE and nutrients is greater in red dog than in wheat middlings. As a consequence, concentrations of DE and ME are greater in red dog than in wheat middlings. PMID- 29432561 TI - Sutureless pericardial marsupialization for the repair of congenital right pulmonary veins atresia. AB - We present a very rare case of isolated right pulmonary veins atresia in a 4-year old girl. As the presence of a pulsatile blind pulmonary venous confluence adjacent to the left atrium was demonstrated by preoperative right pulmonary arterial wedge angiography, we applied sutureless pericardial marsupialization for the repair of right pulmonary veins atresia. She is currently 8 years old without pulmonary veins stenosis. PMID- 29432562 TI - Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders. AB - Calcineurin is a calcium (Ca2+)/calmodulin-regulated protein phosphatase that mediates Ca2+-dependent signal transduction. Here, we report six heterozygous mutations in a gene encoding the alpha isoform of the calcineurin catalytic subunit (PPP3CA). Notably, mutations were observed in different functional domains: in addition to three catalytic domain mutations, two missense mutations were found in the auto-inhibitory (AI) domain. One additional frameshift insertion that caused premature termination was also identified. Detailed clinical evaluation of the six individuals revealed clinically unexpected consequences of the PPP3CA mutations. First, the catalytic domain mutations and frameshift mutation were consistently found in patients with nonsyndromic early onset epileptic encephalopathy. In contrast, the AI domain mutations were associated with multiple congenital abnormalities including craniofacial dysmorphism, arthrogryposis and short stature. In addition, one individual showed severe skeletal developmental defects, namely, severe craniosynostosis and gracile bones (severe bone slenderness and perinatal fractures). Using a yeast model system, we showed that the catalytic and AI domain mutations visibly result in decreased and increased calcineurin signaling, respectively. These findings indicate that different functional effects of PPP3CA mutations are associated with two distinct disorders and suggest that functional approaches using a simple cellular system provide a tool for resolving complex genotype-phenotype correlations. PMID- 29432563 TI - Traumatic injury induces stress granule formation and enhances motor dysfunctions in ALS/FTD models. AB - Traumatic brain injury (TBI) has been predicted to be a predisposing factor for amyotrophic lateral sclerosis (ALS) and other neurological disorders. Despite the importance of TBI in ALS progression, the underlying cellular and molecular mechanisms are still an enigma. Here, we examined the contribution of TBI as an extrinsic factor and investigated whether TBI influences the susceptibility of developing neurodegenerative symptoms. To evaluate the effects of TBI in vivo, we applied mild to severe trauma to Drosophila and found that TBI leads to the induction of stress granules (SGs) in the brain. The degree of SGs induction directly correlates with the level of trauma. Furthermore, we observed that the level of mortality is directly proportional to the number of traumatic hits. Interestingly, trauma-induced SGs are ubiquitin, p62 and TDP-43 positive, and persistently remain over time suggesting that SGs might be aggregates and exert toxicity in our fly models. Intriguingly, TBI on animals expressing ALS-linked genes increased mortality and locomotion dysfunction suggesting that mild trauma might aggravate neurodegenerative symptoms associated with ALS. Furthermore, we found elevated levels of high molecular weight ubiquitinated proteins and p62 in animals expressing ALS-causing genes with TBI, suggesting that TBI may lead to the defects in protein degradation pathways. Finally, we observed that genetic and pharmacological induction of autophagy enhanced the clearance of SGs and promoted survival of flies in vivo. Together, our study demonstrates that trauma can induce SG formation in vivo and might enhance neurodegenerative phenotypes in the fly models of ALS. PMID- 29432564 TI - Management of metastatic retroperitoneal sarcoma: a consensus approach from the Trans-Atlantic Retroperitoneal Sarcoma Working Group (TARPSWG). AB - Introduction: Retroperitoneal sarcoma (RPS) is a rare disease accounting for 0.1% 0.2% of all malignancies. Management of RPS is complex and requires multidisciplinary, tailored treatment strategies at all stages, but especially in the context of metastatic or multifocal recurrent disease. Due to the rarity and heterogeneity of this family of diseases, the literature to guide management is limited. Methods: The Trans-Atlantic Retroperitoneal Sarcoma Working Group (TARPSWG) is an international collaboration of sarcoma experts from all disciplines convened in an effort to overcome these limitations. The TARPSWG has compiled the available evidence surrounding metastatic and multifocally recurrent RPS along with expert opinion in an iterative process to generate a consensus document regarding the complex management of this disease. The objective of this document is to guide sarcoma specialists from all disciplines in the diagnosis and treatment of multifocal recurrent or metastatic RPS. Results: All aspects of patient assessment, diagnostic processes, local and systemic treatments, and palliation are reviewed in this document, and consensus recommendations provided accordingly. Recommendations were guided by available evidence, in conjunction with expert opinion where evidence was lacking. Conclusions: This consensus document combines the available literature regarding the management of multifocally recurrent or metastastic RPS with the practical expertise of high volume sarcoma centers from multiple countries. It is designed as a tool for decision making in the complex multidisciplinary management of this condition and is expected to standardize management across centers, thereby ensuring that patients receive the highest quality care. PMID- 29432566 TI - ECG spot diagnosis: acute pericarditis. PMID- 29432565 TI - An RNA-dependent mechanism for transient expression of bacterial translocation filaments. AB - The prokaryotic RNA chaperone Hfq mediates sRNA-mRNA interactions and plays a significant role in post-transcriptional regulation of the type III secretion (T3S) system produced by a range of Escherichia coli pathotypes. UV-crosslinking was used to map Hfq-binding under conditions that promote T3S and multiple interactions were identified within polycistronic transcripts produced from the locus of enterocyte effacement (LEE) that encodes the T3S system. The majority of Hfq binding was within the LEE5 and LEE4 operons, the latter encoding the translocon apparatus (SepL-EspADB) that is positively regulated by the RNA binding protein, CsrA. Using the identified Hfq-binding sites and a series of sRNA deletions, the sRNA Spot42 was shown to directly repress translation of LEE4 at the sepL 5' UTR. In silico and in vivo analyses of the sepL mRNA secondary structure combined with expression studies of truncates indicated that the unbound sepL mRNA is translationally inactive. Based on expression studies with site-directed mutants, an OFF-ON-OFF toggle model is proposed that results in transient translation of SepL and EspA filament assembly. Under this model, the nascent mRNA is translationally off, before being activated by CsrA, and then repressed by Hfq and Spot42. PMID- 29432567 TI - Bile Acid Sequestration by Cholestyramine Mitigates FGFR4 Inhibition-Induced ALT Elevation. AB - The FGF19- fibroblast growth factor receptor (FGFR4)-betaKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1, elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels. PMID- 29432568 TI - Cellulite: A Surgical Treatment Approach. AB - Background: Cellulite is one of the most common skin and subcutaneous tissue conditions, affecting predominantly the thighs and hips in postadolescent women. Its etiology is not well defined, and multiple available treatments show variable efficacy. Objectives: To describe a technique for treatment of cellulite of the gluteal region, thighs, and hips through superficial liposuction utilizing a special cannula, combined with subcutaneous autologous fat grafting. Methods: A retrospective review was performed of patients treated over 26 years at the Hospital Sao Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. Patients underwent pretreatment evaluation as to the extent of their cellulite, and pretreatment and posttreatment photographs were obtained for visual evaluation of the results. Results: Procedures were performed on 126 patients: 121 (96%) women and 5 (4%) men. The majority considered their results good or excellent. The complication rate was low, with the most common complications being ecchymosis, contour irregularities, partial recurrence of cellulite, seroma, and numbness. Conclusions: We describe an effective method for the treatment of cellulite. Whereas subcision techniques utilize a needle or microblade to cut fibrous septa, we utilize a special cannula; larger areas can be treated than with subcision. Fat grafting is utilized to correct depressions and improve skin quality, which are added benefits compared to traditional subcision. Considering the multiple available cellulite treatments and their limitations, and the high patient satisfaction rate we achieved, with a low recurrence and complication rate, this technique can be a safe and effective option for patients with cellulite. Level of Evidence 4: PMID- 29432570 TI - Insomnia-perchance a dream? Results from a NREM/REM sleep awakening study in good sleepers and patients with insomnia. AB - Study Objectives: Insomnia disorder (ID) is a frequent sleep disorder coupled with increased risks for somatic and mental illness. Although subjective complaints are severe, polysomnography (PSG) parameters show only modest differences between groups. Rapid eye movement (REM) sleep as the most aroused sleep state may be especially vulnerable to be perceived as wake. To directly assess possible differences, we determined auditory waking thresholds and sleep perception in patients with ID and healthy control participants (good sleeper controls [GSC]) in N2 and REM sleep. Methods: In case-control study, 27 patients with ID and 27 age- and gender-matched controls were included. Four consecutive nights were assessed in the sleep laboratory, with nights 3 and 4 each containing three awakenings either from stable N2 or REM sleep. Awakening thresholds in patients with ID did not differ from GSC, but decreased over the course of the night. Patients with ID indicated significantly more frequently than GSC having been awake when woken from REM sleep but not from N2 and were less sure when indicating they had been asleep. Additionally, participants with ID rated their REM sleep mentation as more emotionally negative compared with GSC. Conclusions: This study presents direct evidence that the subjective experience of insomnia might be specifically coupled to the REM sleep state. Assuming chronic hyperarousal as a central pathophysiologically relevant pathway for insomnia, this might become especially evident during REM sleep, thus reflecting a hybrid sleep state in insomnia being coupled with altered sleep perception. PMID- 29432569 TI - Sleep quality and adolescent default mode network connectivity. AB - Sleep suffers during adolescence and is related to academic, emotional and social behaviors. How this normative change relates to ongoing brain development remains unresolved. The default mode network (DMN), a large-scale brain network important for complex cognition and socioemotional processing, undergoes intra-network integration and inter-network segregation during adolescence. Using resting state functional connectivity and actigraphy over 14 days, we examined correlates of naturalistic individual differences in sleep duration and quality in the DMN at rest in 45 human adolescents (ages 14-18). Variation in sleep quality, but not duration, was related to weaker intrinsic DMN connectivity, such that those with worse quality sleep evinced weaker intra-network connectivity at rest. These novel findings suggest sleep quality, a relatively unexplored sleep index, is related to adolescent brain function in a network that contributes to behavioral maturation and undergoes development during adolescence. PMID- 29432572 TI - The Role of Cognitive Control in the Self-Regulation and Reinforcement of Smoking Behavior. AB - Cognitive control (CC) - the ability to regulate attention and memory - plays an important role in a variety of health behaviors, including smoking behavior. In this theoretical review of the literature, we propose a CC and smoking behavior framework that includes 1) the positive influence of CC on the self-regulation of smoking; 2) nicotine-induced improvements in CC that may indirectly reinforce smoking (including withdrawal reversal effects); and 3) the long-term effects of smoking on the brain that may result in reduced CC. Integration of these literatures suggests that CC contributes to both self-regulation (i.e., brake pedal) and nicotine-related reinforcement (i.e., gas pedal) amid the catastrophic effects of long-term smoking, which may reduce self-regulatory control over smoking while also enhancing indirect reinforcement. Supportive evidence and limitations of this approach will be presented, as well as ideas for future research directions that may more fully examine this multifaceted modeling of CC in relation to smoking behavior. PMID- 29432571 TI - Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo. AB - Small interfering RNA (siRNA)-based drugs require chemical modifications or formulation to promote stability, minimize innate immunity, and enable delivery to target tissues. Partially modified siRNAs (up to 70% of the nucleotides) provide significant stabilization in vitro and are commercially available; thus are commonly used to evaluate efficacy of bio-conjugates for in vivo delivery. In contrast, most clinically-advanced non-formulated compounds, using conjugation as a delivery strategy, are fully chemically modified (100% of nucleotides). Here, we compare partially and fully chemically modified siRNAs in conjugate mediated delivery. We show that fully modified siRNAs are retained at 100x greater levels in various tissues, independently of the nature of the conjugate or siRNA sequence, and support productive mRNA silencing. Thus, fully chemically stabilized siRNAs may provide a better platform to identify novel moieties (peptides, aptamers, small molecules) for targeted RNAi delivery. PMID- 29432573 TI - Selection, periodicity and potential function for Highly Iterative Palindrome-1 (HIP1) in cyanobacterial genomes. AB - Highly Iterated Palindrome 1 (HIP1, GCGATCGC) is hyper-abundant in most cyanobacterial genomes. In some cyanobacteria, average HIP1 abundance exceeds one motif per gene. Such high abundance suggests a significant role in cyanobacterial biology. However, 20 years of study have not revealed whether HIP1 has a function, much less what that function might be. We show that HIP1 is 15- to 300 fold over-represented in genomes analyzed. More importantly, HIP1 sites are conserved both within and between open reading frames, suggesting that their overabundance is maintained by selection rather than by continual replenishment by neutral processes, such as biased DNA repair. This evidence for selection suggests a functional role for HIP1. No evidence was found to support a functional role as a peptide or RNA motif or a role in the regulation of gene expression. Rather, we demonstrate that the distribution of HIP1 along cyanobacterial chromosomes is significantly periodic, with periods ranging from 10 to 90 kb, consistent in scale with periodicities reported for co-regulated, co expressed and evolutionarily correlated genes. The periodicity we observe is also comparable in scale to chromosomal interaction domains previously described in other bacteria. In this context, our findings imply HIP1 functions associated with chromosome and nucleoid structure. PMID- 29432574 TI - Inverted U-wave and myocardial ischemia. PMID- 29432575 TI - Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening. AB - Aims: More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities. Methods and results: DM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM + HC + HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure-volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained. Conclusions: The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction. PMID- 29432576 TI - Direct measurement of intercellular CO2 concentration in a gas-exchange system resolves overestimation using the standard method. AB - Intercellular CO2 concentration of leaves (Ci) is a critical parameter in photosynthesis. Nevertheless, uncertainties in calculating Ci arise as stomata close. Here, by modifying the assimilation chamber of a commercial gas-exchange equipment to directly measure Ci, we demonstrate overestimation of calculated Ci (i.e. Ci(c)) without stimulating stomatal closure. Gas exchange was measured on one side of the leaf while measured Ci (Ci(m)) was acquired simultaneously on the other side of the leaf in hypostomatous passion fruit (Passiflora edulis Sims) and amphistomatous sunflower (Helianthus annuus L.) and common bean (Phaseolus vulgaris L.). The adaxial surface showed comparable Ci(c) and Ci(m) in sunflower, whereas in common bean, where the adaxial surface has a low stomatal density, Ci(c) markedly differed from Ci(m) when the stomata remained open. However, the latter discrepancy disappeared when measuring the leaf flipped upside down so that the gas exchange was measured (i.e. Ci was calculated) on the abaxial side, which has a much higher stomatal density. The passion fruit showed the largest discrepancy on the astomatous side, indicating that the cuticle has a large impact on the calculation. Direct measurement of Ci is recommended as a more accurate estimate than the calculation when stomatal gas transport is restricted. Occurrence of overestimation and prospects for direct measurement are discussed. PMID- 29432577 TI - Sema3a plays a role in the pathogenesis of CHARGE syndrome. AB - CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome. First, Chd7 is enriched at the Sema3a promotor in neural crest cells and loss of function of Chd7 inhibits Sema3a expression. Second, using a Xenopus CHARGE model, we show that human SEMA3A rescues Chd7 loss of function. Third, to elucidate if SEMA3A mutations in addition to CHD7 mutations also contribute to the severity of the CHARGE phenotype, we screened 31 CHD7-positive patients and identified one patient with a heterozygous non synonymous SEMA3A variant, c.2002A>G (p.I668V). By analyzing protein expression and processing, we did not observe any differences of the p.I668V variant compared with wild-type SEMA3A, while a pathogenic SEMA3A variant p.R66W recently described in a patient with Kallmann syndrome did affect protein secretion. Furthermore, the p.I668V variant, but not the pathogenic p.R66W variant, rescues Chd7 loss of function in Xenopus, indicating that the p.I668V variant is likely benign. Thus, SEMA3A is part of an epigenetic loop that plays a role in the pathogenesis of CHARGE syndrome, however, it seems not to act as a common direct modifier. PMID- 29432578 TI - Physical activity and masculinity in rural men: a qualitative study of men recruited from churches. AB - The majority of rural US men fail to meet physical activity (PA) guidelines and are at risk for chronic diseases. This study sought to understand rural men's perceptions about PA and PA engagement and the influence of masculinity and social norms. From 2011 to 2014, 12 focus groups were conducted with men prior to a church-based health promotion intervention. Men were recruited from Illinois' rural, southernmost seven counties, where 40% of men report no exercise in the past 30 days. We used inductive content analysis methods to identify PA-related themes, and subsequently used elements of the Health, Illness, Men, and Masculinities framework as a lens to explore subthemes. We identified four themes: (i) knowledge of the positive impact of PA on health, (ii) perceptions of appropriate types of PA for men, (iii) the importance of purposeful PA and (iv) the desire to remain strong and active, particularly during aging. These findings can inform strategies for messaging and interventions to promote PA among rural men. Health promotion efforts should consider the intersections between rurality and masculinity as it relates to rural men's perceptions of PA, include information about purposeful PA and encourage them to engage in PA with a support person. PMID- 29432579 TI - Typical doses and dose rates in studies pertinent to radiation risk inference at low doses and low dose rates. AB - In order to quantify radiation risks at exposure scenarios relevant for radiation protection, often extrapolation of data obtained at high doses and high dose rates down to low doses and low dose rates is needed. Task Group TG91 on 'Radiation Risk Inference at Low-dose and Low-dose Rate Exposure for Radiological Protection Purposes' of the International Commission on Radiological Protection is currently reviewing the relevant cellular, animal and human studies that could be used for that purpose. This paper provides an overview of dose rates and doses typically used or present in those studies, and compares them with doses and dose rates typical of those received by the A-bomb survivors in Japan. PMID- 29432580 TI - Integrated regulation triggered by a cryophyte omega-3 desaturase gene confers multiple-stress tolerance in tobacco. AB - omega-3 fatty acid desaturases (FADs) are thought to contribute to plant stress tolerance mainly through linolenic acid (C18:3)-induced membrane stabilization, but a comprehensive analysis of their roles in stress adaptation is lacking. Here, we isolated a microsomal omega-3 FAD gene (CbFAD3) from a cryophyte (Chorispora bungeana) and elucidated its functions in stress tolerance. CbFAD3, exhibiting a high identity to Arabidopsis AtFAD3, was up-regulated by abiotic stresses. Its functionality was verified by heterogonous expression in yeast. Overexpression of CbFAD3 in tobacco constitutively increased C18:3 in both leaves and roots, which maintained the membrane fluidity, and enhanced plant tolerance to cold, drought, and salt stresses. Notably, the constitutively increased C18:3 induced a sustained activation of plasma membrane Ca2+-ATPase, thereby, changing the stress-induced Ca2+ signaling. The reactive oxygen species (ROS) scavenging system, which was positively correlated with the level of C18:3, was also activated in the transgenic lines. Microarray analysis showed that CbFAD3 overexpressing plants increased the expression of stress-responsive genes, most of which are affected by C18:3, Ca2+, or ROS. Together, CbFAD3 confers tolerance to multiple stresses in tobacco through the C18:3-induced integrated regulation of membrane, Ca2+, ROS, and stress-responsive genes. This is in contrast with previous observations that simply attribute stress tolerance to membrane stabilization. PMID- 29432581 TI - 14q32 and let-7 microRNAs regulate transcriptional networks in fetal and adult human erythroblasts. AB - In humans, fetal erythropoiesis takes place in the liver whereas adult erythropoiesis occurs in the bone marrow. Fetal and adult erythroid cells are not only produced at different sites, but are also distinguished by their respective transcriptional program. In particular, whereas fetal erythroid cells express gamma-globin chains to produce fetal hemoglobin (HbF), adult cells express beta globin chains to generate adult hemoglobin. Understanding the transcriptional regulation of the fetal-to-adult hemoglobin switch is clinically important as re activation of HbF production in adult erythroid cells would represent a promising therapy for the hemoglobin disorders sickle cell disease and beta-thalassemia. We used RNA-sequencing to measure global gene and microRNA (miRNA) expression in human erythroblasts derived ex vivo from fetal liver (n = 12 donors) and bone marrow (n = 12 donors) hematopoietic stem/progenitor cells. We identified 7829 transcripts and 402 miRNA that were differentially expressed (false discovery rate <5%). The miRNA expression patterns were replicated in an independent collection of human erythroblasts using a different technology. By combining gene and miRNA expression data, we developed transcriptional networks which show substantial differences between fetal and adult human erythroblasts. Our analyses highlighted the miRNAs at the imprinted 14q32 locus in fetal erythroblasts and the let-7 miRNA family in adult erythroblasts as key regulators of stage-specific erythroid transcriptional programs. Altogether, our results provide a comprehensive resource to prioritize genes that may modify clinical severity in red blood cell (RBC) disorders, or genes that might be implicated in erythropoiesis by genome-wide association studies of RBC traits. PMID- 29432582 TI - Structural rearrangements in the mitochondrial genome of Drosophila melanogaster induced by elevated levels of the replicative DNA helicase. AB - Pathological conditions impairing functions of mitochondria often lead to compensatory upregulation of the mitochondrial DNA (mtDNA) replisome machinery, and the replicative DNA helicase appears to be a key factor in regulating mtDNA copy number. Moreover, mtDNA helicase mutations have been associated with structural rearrangements of the mitochondrial genome. To evaluate the effects of elevated levels of the mtDNA helicase on the integrity and replication of the mitochondrial genome, we overexpressed the helicase in Drosophila melanogaster Schneider cells and analyzed the mtDNA by two-dimensional neutral agarose gel electrophoresis and electron microscopy. We found that elevation of mtDNA helicase levels increases the quantity of replication intermediates and alleviates pausing at the replication slow zones. Though we did not observe a concomitant alteration in mtDNA copy number, we observed deletions specific to the segment of repeated elements in the immediate vicinity of the origin of replication, and an accumulation of species characteristic of replication fork stalling. We also found elevated levels of RNA that are retained in the replication intermediates. Together, our results suggest that upregulation of mtDNA helicase promotes the process of mtDNA replication but also results in genome destabilization. PMID- 29432583 TI - The clinical utility of PGD with HLA matching: a collaborative multi-centre ESHRE study. AB - STUDY QUESTION: Has PGD-HLA been successful relative to diagnostic and clinical efficacy? SUMMARY ANSWER: The diagnostic efficacy of PGD-HLA protocols was found lower in this study in comparison to published PGD-HLA protocols and to that reported for general PGD by ESHRE (78.5 vs 94.1% and vs 92.6%, respectively), while the clinical efficacy has proven very difficult to assess due to inadequate follow-up of both the ART/PGD and HSCT procedure outcomes. WHAT IS KNOWN ALREADY: The first clinical cases for PGD-HLA were reported in 2001. It is now a well established procedure, with an increasing number of cycles performed every year. However, PGD-HLA is still offered by relatively few PGD centres, the currently available data is fragmented and most reports on PGD-HLA applications are limited in number and scope. Published systematic details on methodology, diagnostic results, overall ART success and haematopoietic stem cell transplantation (HSCT) outcomes are limited, precluding an evaluation of the true clinical utility of PGD-HLA cycles. STUDY DESIGN, SIZE, DURATION: This retrospective multi-centre cohort study aimed to investigate the diagnostic and clinical efficacy of the PGD HLA procedure and the aspects of PGD-HLA cycles influencing positive outcomes: birth of genetically suitable donor-baby (or babies) and HSCT. In April 2014, 32 PGD centres (Consortium members and non-members) with published/known PGD-HLA activity were invited to participate. Between February and September 2015, 14 centres submitted their data, through a custom-designed secure database, with unique login access for each centre. Data parameters covered all aspects of PGD HLA cycles (ART, embryology and genetic diagnosis), donor-babies born and HSCT. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 716 cycles submitted by 14 centres (performed between August 2001 and September 2015), the quality evaluation excluded 12 cycles, leaving 704, from 364 couples. The online database, based on REDCap, a free, secure, web-based data-capture application, was customized by Centre for Clinical Epidemiology and Outcomes Research (CLEO), Athens. Continuous variables are presented using mean, standard deviation, median and interquartile range, and categorical variables are presented as absolute and relative frequencies. MAIN RESULTS AND THE ROLE OF CHANCE: The data included 704 HLA-PGD cycles. Mean maternal age was 33.5 years. Most couples (81.3%) requested HLA typing with concurrent exclusion of a single monogenic disease (58.6% for beta thalassaemia). In 92.5% couples, both partners were fertile, with an average 1.93 HLA-PGD cycles/couple. Overall, 9751 oocytes were retrieved (13.9/cycle) and 5532 embryos were analysed (7.9/cycle). Most cycles involved fresh oocytes (94.9%) and Day 3 embryo biopsy (85.3%). In 97.5% of cycles, the genotyping method involved PCR only. Of 4343 embryos diagnosed (78.5% of analysed embryos), 677 were genetically suitable (15.4% of those analysed for HLA alone, 11.6% of those analysed for HLA with exclusion of monogenic disease). Of the 364 couples, 56.6% achieved an embryo transfer (ET) and 598 embryos were transferred in 382 cycles, leading to 164 HCG-positive pregnancies (pregnancy rate/ET 41.3%, pregnancy rate/initiated cycle 23.3%) and 136 babies born (live birth rate/ET 34.3%, live birth rate/initiated cycle 19.3%) to 113 couples. Data analysis identified the following limitations to the overall success of the HLA-PGD procedure: the age of the mother undergoing the treatment cycle, the number of oocytes collected per cycle and genetic chance. HSCT was reported for 57 cases, of which 64.9% involved combined umbilical cord-blood and bone marrow transplantation from the HLA identical sibling donor; 77.3% of transplants reported no complications. LIMITATIONS REASONS FOR CAUTION: The findings of the study may be limited as not all PGD centres with PGD-HLA experience participated. Reporting bias on completion of the online database may be another potential limitation. Furthermore, the study is based on retrospective data collection from centres with variable practices and strategies for ART, embryology and genetic diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: This is the first multi-centre study evaluating the clinical utility of PGD-HLA, indicating variations in practice and outcomes throughout 15 years and between centres. The study highlights parameters important for positive outcomes and provides important information for both scientists and couples interested in initiating a cycle. Above all, the study underlines the need for better collaboration between all specialists involved in the ART-PGD/HLA procedure, as well as the need for comprehensive and prospective long-term data collection, and encourages all specialists to aim to properly evaluate and follow-up all procedures, with the ultimate aim to promote best practice and encourage patient informed decision making. STUDY FUNDING/COMPETING INTEREST(S): The study wishes to acknowledge ESHRE for funding the customization of the REDCap database. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A. PMID- 29432584 TI - Fitness tradeoffs of antibiotic resistance in extra-intestinal pathogenic Escherichia coli. AB - Evolutionary trade-offs occur when selection on one trait has detrimental effects on other traits. In pathogenic microbes, it has been hypothesized that antibiotic resistance trades off with fitness in the absence of antibiotic. While studies of single resistance mutations support this hypothesis, it is unclear whether trade offs are maintained over time, due to compensatory evolution and broader effects of genetic background. Here, we leverage natural variation in 39 extra-intestinal clinical isolates of Escherichia coli to assess trade-offs between growth rates and resistance to fluoroquinolone and cephalosporin antibiotics. Whole genome sequencing identifies a broad range of clinically relevant resistance determinants in these strains. We find evidence for a negative correlation between growth rate and antibiotic resistance, consistent with a persistent trade off between resistance and growth. However, this relationship is sometimes weak, and depends on the environment in which growth rates are measured. Using in vitro selection experiments, we find that compensatory evolution in one environment does not guarantee compensation in other environments. Thus, even in the face of compensatory evolution and other genetic background effects, resistance may be broadly costly, supporting the use of drug restriction protocols to limit the spread of resistance. Furthermore, our study demonstrates the power of using natural variation to study evolutionary trade-offs in microbes. PMID- 29432585 TI - Quality of care and clinical outcomes of chronic obstructive pulmonary disease in patients with schizophrenia. A Danish nationwide study. AB - Objective: To examine the association between schizophrenia and the quality of care and clinical outcomes of chronic obstructive pulmonary disease (COPD). Design: A Danish nationwide population-based cohort study using comprehensive information from Danish registries between 2008 and 2013. Setting: Public Danish hospitals. Participants: 72 692 COPD patients with hospital contacts including 621 with schizophrenia. Intervention: COPD care. Main Outcome Measures: The quality of COPD care was defined as meeting guideline-recommended process performance measures of care. Potential predictors of COPD care among patients with schizophrenia included patient- (sex, age, alcohol or drug abuse, Global Assessment of Functioning score, duration of schizophrenia), provider- (quality of schizophrenia care), and system-related factors (contact-volume defined as hospital department and clinics' annual average contact volume of COPD patients). Clinical outcomes included 30-day all-cause readmission and 30-day all-cause mortality risk following an admission for exacerbation of COPD. Results: Compared to COPD patients without schizophrenia, COPD patients with schizophrenia had a lower chance of receiving treatment with long-acting muscarinic antagonists (LAMA) or long-acting beta2-agonists (LABA) (Relative risk (RR) 0.92, 95% CI: 0.87-0.98). Female sex was associated with a higher chance of receiving LAMA/LABA treatment among COPD patients with schizophrenia. COPD patients with schizophrenia had a higher risk of 30-day mortality (adjusted odds ratio (OR) 1.27, 95% CI: 1.01-1.59) but not a higher risk of readmission compared with COPD patients without schizophrenia. Conclusions: COPD patients with schizophrenia had a slightly lower chance of receiving LAMA/LABA treatment, but a substantially increased risk of death following admission for an exacerbation compared with patients without schizophrenia. PMID- 29432587 TI - Identifying Biomarkers for Risk of Premature Menopause Among Childhood Cancer Survivors May Lead to Targeted Interventions and Wellness Strategies. PMID- 29432586 TI - Effects of different starch source of starter on small intestinal growth and endogenous GLP-2 secretion in preweaned lambs. AB - The objective of this study was to investigate the effects of different sources of starch in starter feed on small intestinal growth and endogenous glucagon-like peptide 2 (GLP-2) secretion in preweaned lambs. Twenty-four 10-d-old lambs were divided into three groups that were treated with different iso-starch diets containing purified cassava starch (CS, n = 8), maize starch (MS, n = 8), and pea starch (PS, n = 8). At 56 d old, there was no significant difference in final body weight (BW) of lambs among the three groups. However, different starch source in starter significantly affected the average daily feed intake (ADFI) and average daily gain (ADG) of lambs among three groups. Compared with the CS and MS diets, the PS diet significantly increased the GLP-2 concentration in blood plasma (P < 0.001), the crypt depth of the jejunum (P = 0.006), and the villus height of the ileum (P = 0.039). Meanwhile, PS diet significantly increased the mRNA expression of proglucagon and the glucagon-like peptide 2 receptor (GLP-2R) in the jejunum and ileum (P < 0.001). Furthermore, the PS diet significantly upregulated the mRNA expression of cyclin D1 (P < 0.001), cyclin E (P = 0.006), and cyclin-dependent kinases 6 (CDK6) (P = 0.048) in the jejunum and cyclin A (P < 0.001), cyclin D1 (P < 0.001), and CDK6 (P = 0.002) in the ileum. Correlation analysis showed that endogenous GLP-2 secretion was positively related to the mRNA levels of cell cycle proteins in small intestinal mucosa. In summary, all results showed that PS in starter feed promoted small intestinal growth that may, in part, be related to cell cycle acceleration and endogenous GLP-2 secretion in preweaned lambs. These findings provide new insights into nutritional interventions that promote the development of small intestines in young ruminants. PMID- 29432588 TI - METHOD FOR OCCUPATIONAL SKIN DOSE ESTIMATION IN UPPER EXTREMITY 131I-MIBG CONTAMINATION. AB - This study examines upper extremity skin contamination of nuclear medicine and radiation safety staff during 131I-Metaiodobenzylguanidine (MIBG) therapy. Utilizing retrospective data, a methodology for performing a rapid assessment of the radiation dose to the skin of the upper extremities is presented. Using the skin contamination measurements and calculated skin dose for each contamination incident at our facility, a conversion factor (XE) was derived that estimates skin dose (DE) based on the initial contamination measurement. This methodology yields an estimate of the final skin dose accounting for radioactive decay, decontamination and other factors, such as skin sloughing. As a standard practice multiple time-point measurements from initial contamination to background should be used to calculate the total attributable skin dose. However, to provide an early projection of the expected skin dose, the dose can be reasonably estimated to be <0.10% mSv cpm-1 (10% mrem cpm-1) of the initial contamination measurement. PMID- 29432589 TI - Changing CHANGE: adaptations of an evidence-based telehealth cardiovascular disease risk reduction intervention. AB - Relatively few successful medication adherence interventions are translated into real-world clinical settings. The Prevention of Cardiovascular Outcomes in African Americans with Diabetes (CHANGE) intervention was originally conceived as a randomized controlled trial to improve cardiovascular disease-related medication adherence and health outcomes. The purpose of the study was to describe the translation of the CHANGE trial into two community-based clinical programs. CHANGE 2 was available to Medicaid patients with diabetes and hypertension whose primary care homes were part of a care management network in the Northern Piedmont region of North Carolina. CHANGE 3 was available to low income patients receiving care in three geographical areas with multiple chronic conditions at low or moderate risk for developing cardiovascular disease. Adaptations were made to ensure fit with available organizational resources and the patient population's health needs. Data available for evaluation are presented. For CHANGE 2, we evaluated improvement in A1c control using paired t test. For both studies, we describe feasibility measured by percentage of patients who completed the curriculum. CHANGE 2 involved 125 participants. CHANGE 3 had 127 participants. In CHANGE 2, 69 participants had A1c measurements at baseline and 12-month follow-up; A1c improved from 8.4 to 7.8 (p = .008). In CHANGE 3, interventionists completed 47% (n = 45) of calls to enroll participants at the 4-month encounter, and among those eligible for a 12-month call (n = 52), 21% of 12-month calls were completed with participants. In CHANGE 2, 40% of participants (n = 50) completed all 12 encounters. Thoughtful adaptation is critical to translate clinical trials into community-based clinic settings. Successful implementation of adapted evidence-based interventions may be feasible and can positively affect patients' disease control. PMID- 29432590 TI - Mycobacterium tuberculosis and HIV Coinfection Brings Fire and Fury to Macrophages. PMID- 29432591 TI - The 14-3-3 protein HbGF14a interacts with a RING zinc finger protein to regulate expression of the rubber transferase gene in Hevea brasiliensis. AB - Hevea brasiliensis is a key commercial source of natural rubber (cis 1,4 polyisoprene). In H. brasiliensis, rubber transferase is responsible for cis-1,4 polymerization of isoprene units from isopentenyl diphosphate and thus affects the yield of rubber. Little is known about the regulatory mechanisms of the rubber transferase gene at a molecular level. In this study we show that the 5'UTR intron of the promoter of the rubber transferase gene (HRT2) suppresses the expression of HRT2. A H. brasiliensis RING zinc finger protein (designated as HbRZFP1) was able to interact specifically with the HRT2 promoter to down regulate its transcription in vivo. A 14-3-3 protein (named as HbGF14a) was identified as interacting with HbRZFP1, both in yeast and in planta. Transient co expression of HbGF14a and HbRZFP1-encoding cDNAs resulted in HbRZFP1-mediated HRT2 transcription inhibition being relieved. HbGF14a repressed the protein-DNA binding of HbRZFP1 with the HRT2 promoter in yeast. We propose a regulatory mechanism by which the binding of HbGF14a to HbRZFP1 interferes with the interaction of HbRZFP1 with the HRT2 promoter, thereby repressing the protein-DNA binding between them. This study provides new insights into the role of HbGF14a in mediating expression of the rubber transferase gene in Hevea brasiliensis. PMID- 29432592 TI - Ultra-low-dose coronary artery calcium scoring using novel scoring thresholds for low tube voltage protocols-a pilot study. AB - Aims: To determine if tube-adapted thresholds for coronary artery calcium (CAC) scoring by computed tomography at 80 kilovolt-peak (kVp) tube voltage and 70-kVp yield comparable results to the standard 120-kVp protocol. Methods and results: We prospectively included 103 patients who underwent standard scanning with 120 kVp tube voltage and additional scans with 80 kVp and 70 kVp. Mean body mass index (BMI) was 27.9 +/- 5.1 kg/m2. For the lowered tube voltages, we applied novel kVp-adapted thresholds for calculation of CAC scores and compared them with standard 120-kVp scans using intraclass correlation and Bland-Altman (BA) analysis. Furthermore, risk-class (CAC score 0/1-10/11-100/101-400/>400) changes were assessed. Median CAC score from 120-kVp scans was 212 (interquartile range 25-901). Thirteen (12.6%) patients had zero CAC. Using the novel kVp-adapted thresholds, CAC scores derived from 80-kVp scans showed excellent correlation (r = 0.994, P < 0.001) with standard 120-kVp scans with BA limits of agreement of 235 (-39.5%) to 172 (28.9%). Similarly, for 70-kVp scans, correlation was excellent (r = 0.972, P < 0.001) but with broader limits of agreement of -476 ( 85.0%) to 270 (48.2%). Only 2 (2.8%) reclassifications were observed for the 80 kVp scans in patients with a BMI <30 kg/m2 (n = 71), and 2 (6.1%) for the 70-kVp scans in patients with a BMI <25 kg/m2 (n = 33). Mean effective radiation dose was 0.60 +/- 0.07 millisieverts (mSv), 0.19 +/- 0.02 mSv, and 0.12 +/- 0.01 mSv for the 120-kVp, 80-kVp, and 70-kVp scans, respectively. Conclusion: The present study suggests that CAC scoring with reduced peak tube voltage is accurate if kVp adapted thresholds for calculation of CAC scores are applied while offering a substantial further radiation dose reduction. PMID- 29432593 TI - Selective Difficulties in Lexical Retrieval and Nonverbal Executive Functioning in Children With HbSS Sickle Cell Disease. AB - Language deficits in multilingual children with sickle cell disease (SCD) are poorly understood. We tested the hypothesis that selective language deficits in this population could relate to an impaired frontal lobe functioning often associated with high-risk homozygous HbS disease (HbSS). In all, 32 children from immigrant communities with HbSS SCD aged 6 to 12 years (mean age = 9.03, n = 9 with silent infarcts) and 35 demographically matched healthy controls (mean age = 9.14) were tested on their naming skills, phonological and semantic fluency, attention, and selected executive functions (response inhibition and planning skills). Analyses of variance showed significant differences between patients and controls in inhibition and planning (p = .001 and .001), and phonological fluency (p = .004). The poorer performance in phonological fluency of the children with SCD was not associated with any visible brain damage to language areas. Hierarchical regression analyses showed that, whereas the control children's vocabulary knowledge explained their performance in the phonological fluency tasks, only inhibition skills accounted for variance in the performance of the children with SCD. These results suggest a selective impairment of verbal and nonverbal executive functioning (i.e., planning, inhibition, and phonological fluency) in children with SCD, with deficits possibly owing to frontal area hypoxia. PMID- 29432594 TI - Nuclear import of Cdc13 limits chromosomal capping. AB - Cdc13 is an essential protein involved in telomere maintenance and chromosome capping. Individual domain analyses on Cdc13 suggest the presence of four distinct OB-fold domains and one recruitment domain. However, it remained unclear how these sub-domains function in the context of the whole protein in vivo. Here, we use individual single domain deletions to address their roles in telomere capping. We find that the OB2 domain contains a nuclear localization signal that is essential for nuclear import of Cdc13 and therefore is required for chromosome capping. The karyopherin Msn5 is important for nuclear localization, and retention of Cdc13 in the nucleus also requires its binding to telomeres. Moreover, Cdc13 homodimerization occurs even if the protein is not bound to DNA and is in the cytoplasm. Hence, Cdc13 abundance in the nucleus and, in consequence, its capping function is strongly affected by nucleo-cytoplasmic transport as well as nuclear retention by DNA binding. PMID- 29432595 TI - Function and molecular regulation of DWARF1 as a C-24 reductase in brassinosteroid biosynthesis in Arabidopsis. AB - DWARF1 (DWF1) is a sterol C-24 reductase that catalyses the conversion of 24 methylenecholesterol (24-MCHR) to campesterol (CR) in Arabidopsis. A loss-of function mutant, dwf1, showed similar phenotypic abnormalities to brassinosteroid (BR)-deficient mutants. These abnormalities were reversed in the wild-type phenotype by exogenous application of castasterone (CS) and brassinolide (BL), but not dolichosterone (DS). Accumulation of DS and decreased CS were found in quantitative analysis of endogenous BRs in dwf1. The enzyme solution prepared from dwf1 was unable to convert 6-deoxoDS to 6-deoxoCS and DS to CS, as seen in either wild-type or 35S:DWF1 transgenic plants. This suggests that DWF1 has enzyme activity not only for a sterol C-24 reductase, but also for a BR C-24 reductase that catalyses C-24 reduction of 6-deoxoDS to 6-deoxoCS and of DS to CS in Arabidopsis. Overexpression of DWF1 in a BR-deficient mutant (det2 35S:DWF1) clearly rescued abnormalities found in det2, indicating that DWF1 functions in biosynthesis of active BRs in Arabidopsis. Expression of DWF1 is down-regulated by application of CS and BL and in a BR-dominant mutant, bes1-D. E-boxes in the putative promoter region of DWF1 directly bind to a BR transcription factor, BES1, implying that DWF1 expression is feedback-regulated by BR signaling via BES1. Overall, biosynthesis of 24-methylene BR is an alternative route for generating CS, which is mediated and regulated by DWF1 in Arabidopsis. PMID- 29432596 TI - High Turnover of Tissue Macrophages Contributes to Tuberculosis Reactivation in Simian Immunodeficiency Virus-Infected Rhesus Macaques. AB - Background: Tuberculosis (TB) and human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) profoundly affect the immune system and synergistically accelerate disease progression. It is believed that CD4+ T-cell depletion by HIV is the major cause of immunodeficiency and reactivation of latent TB. Previous studies demonstrated that blood monocyte turnover concurrent with tissue macrophage death from virus infection better predicted AIDS onset than CD4+ T-cell depletion in macaques infected with simian immunodeficiency virus (SIV). Methods: In this study, we describe the contribution of macrophages to the pathogenesis of Mycobacterium tuberculosis (Mtb)/SIV coinfection in a rhesus macaque model using in vivo BrdU labeling, immunostaining, flow cytometry, and confocal microscopy. Results: We found that increased monocyte and macrophage turnover and levels of SIV-infected lung macrophages correlated with TB reactivation. All Mtb/SIV-coinfected monkeys exhibited declines in CD4+ T cells regardless of reactivation or latency outcomes, negating lower CD4+ T-cell levels as a primary cause of Mtb reactivation. Conclusions: Results suggest that SIV related damage to macrophages contributes to Mtb reactivation during coinfection. This also supports strategies to target lung macrophages for the treatment of TB. PMID- 29432597 TI - Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma. AB - Background: Primary central nervous system lymphoma (PCNSL) represents a particular entity within non-Hodgkin lymphomas and is associated with poor outcome. The present study addresses the potential clinical relevance of chimeric transcripts in PCNSL discovered by using RNA sequencing (RNA-seq). Methods: Seventy-two immunocompetent and newly diagnosed PCNSL cases were included in the present study. Among them, 6 were analyzed by RNA-seq to detect new potential fusion transcripts. We confirmed the results in the remaining 66 PCNSL. The gene fusion was validated by fluorescence in situ hybridization (FISH) using formalin fixed paraffin-embedded (FFPE) samples. We assessed the biological and clinical impact of one new gene fusion. Results: We identified a novel recurrent gene fusion, E26 transformation-specific translocation variant 6-immunoglobulin heavy chain (ETV6-IgH). Overall, ETV6-IgH was found in 13 out of 72 PCNSL (18%). No fusion conserved an intact functional domain of ETV6, and ETV6 was significantly underexpressed at gene level, suggesting an ETV6 haploinsufficiency mechanism. The presence of the gene fusion was also validated by FISH in FFPE samples. Finally, PCNSL samples harboring ETV6-IgH showed a better prognosis in multivariate analysis, P = 0.03, hazard ratio = 0.33, 95% CI = 0.12-0.88. The overall survival at 5 years was 69% for PCNSL harboring ETV6-IgH versus 29% for samples without this gene fusion. Conclusions: ETV6-IgH is a new potential surrogate marker of PCNSL with favorable prognosis with ETV6 haploinsufficiency as a possible mechanism. The potential clinical impact of ETV6-IgH should be validated in larger prospective studies. PMID- 29432598 TI - Brainstem abscess successfully treated with stereotactic aspiration. PMID- 29432599 TI - Editorial: 40th Anniversary of UKEMS. PMID- 29432600 TI - Early-Life Parent-Child Relationships and Adult Children's Support of Unpartnered Parents in Later Life. AB - Objectives: The proportion of older adults who are unpartnered has increased significantly over the past 25 years. Unpartnered older adults often rely on their adult children for support. Most previous studies have focused on proximal factors associated with adult children's support of their parents, while few have examined distal factors, such as parent-child relationships formed during childhood. This study fills the gap by investigating the direct and indirect associations between early-life parent-child relationships and adult children's upward transfers to unpartnered parents. Method: Data came from two supplements to the Panel Study of Income Dynamics, in which respondents were asked about their relationships with mothers and fathers before age 17 and their transfers of time and money to parents in 2013. Path models were estimated for unpartnered mother-adult child dyads and father-adult child dyads separately. Results: For adult children of unpartnered mothers, psychological closeness has a direct, positive association with time transfer, while physical violence has an indirect association with time transfer through adult children's marital status. For adult children of unpartnered fathers, psychological closeness has neither a direct nor an indirect association with time or money transfer, but physical violence has a direct, negative association with time transfer. Discussion: Early-life parent child relationships play a pivotal role in influencing adult children's caregiving behavior, both directly and indirectly. Our findings suggest that by improving their relationships with children early in life, parents may be able to increase the amount of time transfer that they receive in late life. PMID- 29432601 TI - SURF-COPD: the recording of cardiovascular risk in patients with chronic lung disease. AB - Background: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic obstructive pulmonary disease (COPD) and such patients tend to carry a heavy burden of risk factors for CVD. There is little information on the documentation and management of CVD risk factors in COPD patients. Aim: To audit the recording and management of CVD risk factors in 200 COPD patients attending the respiratory out-patient clinics at two University teaching hospitals. Design: Retrospective analysis of hospital records. Results: While there was reasonable recording of a history of CVD risk factors such as hypertension and hyperlipidaemia, the actual recording of risk factor levels was poor-blood pressure and heart rate were recorded in less than half of subjects; lipids, waist circumference, HbA1c and height were essentially not recorded at all. Conclusions: Best practice guidelines and standard operating procedures for CVD risk factor recording and control require to be developed if the major cause of death in COPD subjects, CVD, is to be addressed. An outline for a standard operating procedure is presented in the Appendix. Serial audits will be required to assess the efficacy of such measures. PMID- 29432603 TI - In Vitro Screening for Seizure Liability Using Microelectrode Array Technology. AB - Drug-induced seizure liabilities produce significant compound attrition during drug discovery. Currently available in vitro cytotoxicity assays cannot predict all toxicity mechanisms due to the failure of these assays to predict sublethal target-specific electrophysiological liabilities. Identification of seizurogenic and other electrophysiological effects at early stages of the drug development process is important to ensure that safe candidate compounds can be developed while chemical design is taking place, long before these liabilities are discovered in costly preclinical in vivo studies. The development of a high throughput and reliable in vitro assay to screen compounds for seizure liabilities would de-risk compounds significantly earlier in the drug discovery process and with greater dependability. Here we describe a method for screening compounds that utilizes rat cortical neurons plated onto multiwell microelectrode array plates to identify compounds that cause neurophysiological disruptions. Changes in 12 electrophysiological parameters (spike train descriptors) were measured after application of known seizurogenic compounds and the response pattern was mapped relative to negative controls, vehicle control and neurotoxic controls. Twenty chemicals with a variety of therapeutic indications and targets, including GABAA antagonists, glycine receptor antagonists, ion channel blockers, muscarinic agonist, delta-opioid receptor agonist, dopaminergic D2/adrenergic receptor blocker and nonsteroidal anti-inflammatory drugs, were tested to assess this system. Sixteen of the seventeen seizurogenic/neurotoxic compounds tested positive for seizure liability or neurotoxicity, moreover, different endpoint response patterns for firing rate, burst characteristics and synchrony that distinguished the chemicals into groups relating to target and seizurogenic response emerged from the data. The negative and vehicle control compounds had no effect on neural activity. In conclusion, the multiwell microelectrode array platform using cryopreserved rat cortical neurons is a highly effective high throughput method for reliably screening seizure liabilities within an early de risking drug development paradigm. PMID- 29432602 TI - Modeling the Growth and Decline of Pathogen Effective Population Size Provides Insight into Epidemic Dynamics and Drivers of Antimicrobial Resistance. AB - Nonparametric population genetic modeling provides a simple and flexible approach for studying demographic history and epidemic dynamics using pathogen sequence data. Existing Bayesian approaches are premised on stochastic processes with stationary increments which may provide an unrealistic prior for epidemic histories which feature extended period of exponential growth or decline. We show that nonparametric models defined in terms of the growth rate of the effective population size can provide a more realistic prior for epidemic history. We propose a nonparametric autoregressive model on the growth rate as a prior for effective population size, which corresponds to the dynamics expected under many epidemic situations. We demonstrate the use of this model within a Bayesian phylodynamic inference framework. Our method correctly reconstructs trends of epidemic growth and decline from pathogen genealogies even when genealogical data are sparse and conventional skyline estimators erroneously predict stable population size. We also propose a regression approach for relating growth rates of pathogen effective population size and time-varying variables that may impact the replicative fitness of a pathogen. The model is applied to real data from rabies virus and Staphylococcus aureus epidemics. We find a close correspondence between the estimated growth rates of a lineage of methicillin-resistant S. aureus and population-level prescription rates of $?beta$-lactam antibiotics. The new models are implemented in an open source R package called skygrowth which is available at https://github.com/mrc-ide/skygrowth. PMID- 29432604 TI - Artificial light and biological responses of broiler chickens: dose-response. AB - Light intensity is an important aspect for broiler production. However, previous results do not provide a solid scientific basis for quantifying the response of broilers to light intensity. This study performed a meta-analysis to model the response of broilers to 0.1-200 lux of light intensity. Meta-analysis was used to integrate smaller studies and increase the statistical power over that of any single study and explore new hypotheses. The results indicated that light intensity <5 lux caused welfare concern (P < 0.05) and light intensity <1 lux induced productivity loss of broiler (P < 0.05), whereas greater level of light intensity >10 lux led to increased mortality (P < 0.01) and decreased uniformity (P < 0.05). Meta-regression showed that 30-200 lux light intensity was negatively related to BW (P = 0.047) and feed intake change (P = 0.054), whereas a quadratic relationship was observed between feed conversion ratio change and 50-180 lux light intensity (R2 = 0.95). In addition, the majority of carcass characteristics (abdominal fat weight and wing weight) and metabolic indicators (K+, Ca2+, and T3) were affected by light intensity >5 lux. To conclude, this meta-analysis based on published data quantitatively identified that 5 lux of light intensity during grow-out period should be the minimum level to maintain a well productivity and welfare of broiler chickens. PMID- 29432605 TI - An Enduring Health Risk of Childhood Adversity: Earlier, More Severe, and Longer Lasting Work Disability in Adult Life. AB - Objectives: Childhood adversity has been linked with adult health problems. We hypothesized that childhood adversity would also be associated with work limitations due to physical or nervous health problems, known as work disability. Method: With data from the Panel Study of Income Dynamics (PSID) (1968-2013; n=6,045; 82,374 transitions; 129,107 person-years) and the 2014 PSID Childhood Retrospective Circumstances Study, we estimated work disability transition probabilities with multinomial logistic Markov models. Four or more adversities defined a high level. Microsimulations quantified adult work disability patterns for African American and non-Hispanic white women and men, accounting for age, education, race, sex, diabetes, heart disease, obesity, and sedentary behavior. Results: Childhood adversity was significantly associated with work disability. Of African American women with high adversity, 10.2% had moderate work disability at age 30 versus 4.1% with no reported adversities; comparable results for severe work disability were 5.6% versus 1.9% (both p<0.01). Comparable results for whites were 11.3% versus 4.7%, and 3.5% versus 1.1% (p<0.01). The association of childhood adversity with work disability remained significant after adjusting for diabetes, heart disease, obesity, and sedentary behavior (p<0.05). Conclusions: Childhood adversity may increase work disability throughout adult life. PMID- 29432607 TI - Positive Psychology in Research with the Deaf Community: An Idea Whose Time Has Come. AB - The emergence of positive psychology as an approach to studying what makes life worth living has inspired a new wave of research. Studies have focused on the prevalence and degree of positive attributes, attitudes, and characteristics in the wider population. Increasingly, lessons learned from positive psychology have been applied to understanding the more diverse experiences of individuals belonging to various groups. Only recently, however, has positive psychology research incorporated a disability perspective, and very little research from a positive psychology stance has been conducted with deaf people. This article addresses the application of positive psychology constructs in the context of deaf communities and individuals who are deaf or hard of hearing. We argue that utilization of a positive psychology paradigm can broaden and enrich a collective understanding of deaf people, and suggest a different set of research questions. A positive psychology mindset encourages scholars to learn how people who are deaf or hard of hearing, and those within the larger deaf community1, may define and attain "the good life." PMID- 29432608 TI - Age-dependent increase in c-Jun N-terminal kinase-2 activity: does this help to understand Ca2+-calmodulin-dependent protein-kinase II-mediated atrial arrhythmogenesis in human atrial fibrillation? PMID- 29432609 TI - Impaired Cerebral Hemodynamics and Frailty in Patients with Cardiovascular Disease. AB - Background: Recent studies suggest that impaired cerebrovascular reactivity (CVR), a marker of cerebral microvascular damage, is associated with a higher risk of stroke, cognitive decline, and mortality. We tested whether abnormal cerebrovascular status is associated with late-life frailty among men with pre existing cardiovascular disease. Methods: A subset of 327 men (mean age at baseline 56.7 +/- 6.5 years) who previously participated in the Bezafibrate Infarction Prevention (BIP) trial (1990-1997) and then in the BIP Neurocognitive Study underwent a neurovascular evaluation 14.6 +/- 1.9 years after baseline (T1) and were evaluated for frailty 19.9 +/- 1.0 years after baseline (T2). CVR was measured at T1 using the breath-holding index and carotid large-vessel disease using ultrasound. Frailty status was measured at T2 according to the physical phenotype developed by Fried. Patients were categorized into CVR tertiles with cutoff points at <=0.57, 0.58-0.94, and >=0.95 and also as normal or impaired (<0.69) CVR. We assessed the change in the odds of being in the advanced rank of frailty status (normal, prefrail, and frail) using ordered logistic regression. Results: After adjustment, the estimated OR (95% confidence intervals) for increasing frailty in the lower tertile was 1.94 (1.09-3.46) and in the middle tertile 1.24 (0.70-2.19), compared with the higher CVR tertile. The estimated OR for increasing frailty for patients with impaired vs. normal CVR was 1.76 (1.11 2.80). Conclusions: These findings provide support that cerebral microvascular dysfunction among patients with pre-existing cardiovascular disease is related to prefrailty and frailty and suggest an added value of assessing the cerebral vascular functional status for identifying patients at-risk of developing frailty. PMID- 29432610 TI - Accelerometer Physical Activity is Associated with Greater Gray Matter Volumes in Older Adults without Dementia or Mild Cognitive Impairment. AB - Objectives: Physical activity (PA) is a modifiable health behavior that can protect against age-related gray matter atrophy and cognitive dysfunction. Current studies of PA and gray matter failed to utilize device measures of PA and do not focus on adults >80 years. Thus, the purpose of this secondary analysis was to examine cross-sectional associations between accelerometer lifestyle PA and (a) gray matter volumes and (b) cognitive function, controlling for demographics and health status. Method: Participants were 262 older adults without dementia or mild cognitive impairment from Rush Memory and Aging Project, an epidemiological cohort study. Participants wore an accelerometer to assess total daily lifestyle PA, and completed anatomical magnetic resonance imaging to assess gray matter volumes and a neurocognitive test battery to assess cognitive function. Results: Multivariate linear regression indicated that higher levels of total daily lifestyle PA was significantly related to larger gray matter volumes, F(2, 215) = 3.61, p = .027, including subcortical gray matter (beta = .17, p = .007) and total gray matter (beta = .11, p = .049), with no significant associations between lifestyle PA and cognitive function. Discussion: These findings may inform future lifestyle PA interventions in order to attenuate age related gray matter atrophy. PMID- 29432612 TI - Loss of job-related right to healthcare is associated with reduced quality and clinical outcomes of diabetic patients in Mexico. AB - Objectives: The Mexican Institute of Social Security (IMSS) provides a package of health, economic and social benefits to workers employed in private firms within the formal labour market and to their economic dependants. Affiliates have a right to these benefits only while they remain contracted, thus posing a risk for the continuity of healthcare. This study evaluates the association between the time (in days) without the right to healthcare due to job loss in the formal labour market and the quality of healthcare and clinical outcomes among IMSS affiliates with Type 2 diabetes mellitus (T2DM). Design: Retrospective cohort study 2013-2015. Setting: Six IMSS family medicine clinics (FMC) in Mexico City. Participants: T2DM patients (n = 27 217) affiliated with job-related health insurance and at least one consultation with a family doctor during 2013. Source of Information: IMSS affiliation department database and electronic health records and clinical laboratory databases. Main Outcome Measure(s): Quality of the processes (eight indicators) and outcomes (three indicators) of healthcare. Results: The results indicated that losing IMSS right to healthcare is frequent, occurring to one-third of T2DM patients during the follow-up period. The time without the right to healthcare in the observed period was of 120 days on average and was associated with a 43.2% loss of quality of care and a 19.2% reduction in clinical outcomes of T2DM. Conclusion: Policies aimed at ensuring access and continuity of care, regardless of job status, are critical for improving the quality of processes and outcomes of healthcare for diabetic patients. PMID- 29432611 TI - When the Whole is Not Greater than the Sum of the Parts: A Critical Review of Laboratory Bioassay Effects Testing for Insecticidal Protein Interactions. AB - Many studies have been conducted to investigate synergism among insecticidal proteins; however, a consensus on minimal data requirements and interpretation is lacking. While some have concluded that all additive predictive-type models should be abandoned, we advocate that additivity models can remain useful as assessment tools and that an appropriately designed interaction study will never systematically underestimate the existence of synergism, irrespective of which additivity model (or none at all) may be used. To generate the most meaningful synergy assessment datasets in support of safety assessments, we highlight two beneficial steps to follow: (i) select a testing model which is the most consistent with current knowledge regarding the action of the insecticidal proteins and (ii) avoid using bioassay methods which may result in excess response heterogeneity. We also outline other experimental design elements to consider, which may be crucial for conducting future studies of this type. A contrast of underlying testing assumptions associated with the additivity models is provided, along with a comprehensive review of interaction data for Cry1, Cry2, Cry3, Cry9, and Vip3A insecticidal proteins. Our review captures four recurrent findings: i) experiments reporting synergistic interactions are a minority, ii) the degree of synergism reported is low in magnitude, iii) reported interactions are sometimes equivocal/inconclusive due to unconfirmed model assumptions or other bioassay challenges, and iv) due to biological response variation many of the reported interactions may be artefactual. A brief overview of the positioning of interaction testing data in safety assessments of GM food crops is also provided. PMID- 29432613 TI - Circulating Dkk1 and TRAIL Are Associated With Cognitive Decline in Community Dwelling, Older Adults With Cognitive Concerns. AB - Background: Osteoporosis and Alzheimer's disease are common diseases of aging that would seem to be unrelated, but may be linked through the influence of bone derived signals on brain function. The aim of the current study is to investigate the relationship between circulating levels of bone-related biomarkers and cognition. Methods: The population included 103 community-dwelling older individuals with memory concerns but without cognitive impairment. A global cognition summary measure was collected at baseline and 6, 12, and 18 months post enrollment by converting raw scores from 19 cognitive function tests to z-scores and averaging. Baseline plasma concentrations of bone-related biomarkers, including undercarboxylated, carboxylated, and total osteocalcin, parathyroid hormone, C-terminal telopeptide of collagen 1 (CTX-1), procollagen type 1 amino terminal propeptide, osteoprotegrin, osteopontin, Dickkopf WNT signaling pathway inhibitor 1 (Dkk1), sclerostin, and amyloid beta peptides (Abeta40 and Abeta42), were measured. Results: Using sex, age, and education-adjusted mixed-effects models, we found that baseline levels of TNF-related apoptosis-inducing ligand (TRAIL; p < .001), Dkk1 (p = .014), and CTX-1 (p = .046) were related to the annual rate of change of global cognition over the 18 month follow-up. In cognitive domain-specific analysis, baseline TRAIL was found to be positively related to the annual rate of change in episodic (p < .001) and working memory (p = .016), and baseline Dkk1 was positively related to semantic memory (p = .027) and negatively related to working memory (p = .016). Conclusions: These results further confirm the link between bone and brain health and suggest that circulating levels of bone-related biomarkers may have diagnostic potential to predict worsening cognition. PMID- 29432614 TI - Identification of an (AC)n microsatellite in the Six1 gene promoter and its effect on production traits in Pietrain * Duroc * Landrace * Yorkshire pigs. AB - The Sine oculis homeobox 1 (Six1) gene is important for skeletal muscle growth and fiber specification; therefore, it is considered as a promising candidate gene that may influence porcine growth and meat quality traits. Nevertheless, the association of Six1 with these processes and the mechanisms regulating its expression remain unclear. The objectives of this study were to identify variant sites of Six1 in different pig breeds, conduct association analysis to evaluate the relationship between polymorphisms of these variants and porcine production traits in Pietrain * Duroc * Landrace * Yorkshire commercial pigs, and explore the potential regulatory mechanisms of Six1 affecting production traits. A total of 12 variants were identified, including 10 single- nucleotide variations (SNVs), 1 insertion- deletion (Indel), and 1 (AC)n microsatellite. Association analysis demonstrated that the SNV, g.1595A>G, was significantly associated with meat color (redness, a*); individuals with the G allele had greater a* values (P < 0.05). Moreover, our results demonstrated that the (AC)n polymorphism in the Six1 promoter was significantly associated with weaning weight (P < 0.05), carcass weight (P < 0.05), and thoracic and lumbar back fat (P < 0.01).In addition, we found that the (AC)n variant was closely related with Six1 expression levels and demonstrated this polymorphism on promoter activity by in vitro experiments. Overall, this study provides novel evidence for elucidating the effects of Six1 on porcine production traits as promising candidate and describes two variants with these traits, which are potential reference markers for pig molecular breeding. In addition, our data on the relationship between porcine Six1 expression and the polymorphic (AC)n microsatellite in its promoter may facilitate similar studies in other species. PMID- 29432617 TI - Outcomes following coronary artery bypass grafting with microsurgery in paediatric patients. AB - OBJECTIVES: Paediatric coronary artery bypass grafting is indicated in cases of clinically significant and symptomatic coronary stenosis, with frequent complications occurring in the perioperative period. To reduce complications and improve outcomes of these procedures, surgical microscopes have been used at our centre with the anastomosis performed by a microvascular surgeon. The purpose of this article is to report our institutional experience in all patients who have undergone paediatric coronary artery bypass grafting procedures with and without microvascular techniques. METHODS: Twenty-four patients who underwent coronary artery bypass grafting from January 2000 to May 2017 were retrospectively reviewed. RESULTS: Eighteen patients underwent bypass without microvascular involvement and 6 patients required the use of microsurgical techniques. Median age at the time of operation was 9.79 and 2.02 years for the 2 groups, respectively. The median weight at the time of operation was 41.2 and 10.75 kg for the 2 groups, respectively. Procedures were performed emergently in 4 patients. Three major anastomotic complications occurred requiring reoperation, although none occurred in the microvascular group. The median follow-up was 3.40 years and 5.25 years for the 2 groups, respectively. Three patients were symptomatic at last follow-up and 2 deaths occurred, all in the non-microvascular group. All grafts were patent in both groups. There were no statistically significant differences between preoperative and postoperative ejection fraction between the groups. CONCLUSIONS: Our results highlight the potential positive impact of collaboration between cardiac and microvascular surgeons during paediatric coronary artery bypass grafting procedures and the subsequent reduction in complications that may be expected. PMID- 29432616 TI - Autoregulation of mazEF expression underlies growth heterogeneity in bacterial populations. AB - The MazF toxin sequence-specifically cleaves single-stranded RNA upon various stressful conditions, and it is activated as a part of the mazEF toxin-antitoxin module in Escherichia coli. Although autoregulation of mazEF expression through the MazE antitoxin-dependent transcriptional repression has been biochemically characterized, less is known about post-transcriptional autoregulation, as well as how both of these autoregulatory features affect growth of single cells during conditions that promote MazF production. Here, we demonstrate post transcriptional autoregulation of mazF expression dynamics by MazF cleaving its own transcript. Single-cell analyses of bacterial populations during ectopic MazF production indicated that two-level autoregulation of mazEF expression influences cell-to-cell growth rate heterogeneity. The increase in growth rate heterogeneity is governed by the MazE antitoxin, and tuned by the MazF-dependent mazF mRNA cleavage. Also, both autoregulatory features grant rapid exit from the stress caused by mazF overexpression. Time-lapse microscopy revealed that MazF-mediated cleavage of mazF mRNA leads to increased temporal variability in length of individual cells during ectopic mazF overexpression, as explained by a stochastic model indicating that mazEF mRNA cleavage underlies temporal fluctuations in MazF levels during stress. PMID- 29432615 TI - Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium. AB - Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal Analysis Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities and, ultimately, improved outcomes for a patient population in need. PMID- 29432618 TI - A new practical and versatile mouse model of proneural glioblastoma. PMID- 29432619 TI - Attenuated accumulation of jasmonates modifies stomatal responses to water deficit. AB - To determine whether drought-induced root jasmonate [jasmonic acid (JA) and jasmonic acid-isoleucine (JA-Ile)] accumulation affected shoot responses to drying soil, near-isogenic wild-type (WT) tomato (Solanum lycopersicum cv. Castlemart) and the def-1 mutant (which fails to accumulate jasmonates during water deficit) were self- and reciprocally grafted. Rootstock hydraulic conductance was entirely rootstock dependent and significantly lower in def-1, yet def-1 scions maintained a higher leaf water potential as the soil dried due to their lower stomatal conductance (gs). Stomatal sensitivity to drying soil (the slope of gsversus soil water content) was low in def-1 self-grafts but was normalized by grafting onto WT rootstocks. Although soil drying increased 12-oxo phytodienoic acid (OPDA; a JA precursor and putative antitranspirant) concentrations in def-1 scions, foliar JA accumulation was negligible and foliar ABA accumulation reduced compared with WT scions. A WT rootstock increased drought-induced ABA and JA accumulation in def-1 scions, but decreased OPDA accumulation. Xylem-borne jasmonates were biologically active, since supplying exogenous JA via the transpiration stream to detached leaves decreased transpiration of WT seedlings but had the opposite effect in def-1. Thus foliar accumulation of both ABA and JA at WT levels is required for both maximum (well watered) gs and stomatal sensitivity to drying soil. PMID- 29432621 TI - Implementation of the Autovalidation Algorithm for Clinical Chemistry Testing in the Laboratory Information System. AB - Objective: Autovalidation algorithm should be properly designed with clearly defined criteria and any data that do not meet the criteria, must be reviewed and manually validated. The aim was to define the rules for autovalidation in our laboratory information system (LIS), and validate the algorithm prior to its implementation in routine laboratory work. Methods: Autovalidation was implemented for all routine serum biochemistry tests. The algorithm included analytical measurement ranges (AMR), delta check, critical values, serum indices and all preanalytical and analytical flags from the analyzer. Results: In the validation process 9805 samples were included, and 78.3% (7677) of all samples were autovalidated. The highest percentage of non-validated samples (54.9%) refers to those with at least one result outside the method linearity ranges (AMR criteria) while critical values were observed to be the least frequent criterion for stopping autovalidation (1.8%). Also, 38 samples were manually validated as they failed to meet the autovalidation criteria. Conclusion: Implementation of algorithm for autovalidation in our institution resulted in the redesign of the existing LIS. This model of the autovalidation algorithm significantly decreased the number of manually validated test results and can be used as a model for introducing autovalidation in other laboratory settings. PMID- 29432622 TI - Stopwatches and Click Boxes: The Intersection of Scientific Management and Family Medicine. PMID- 29432620 TI - Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide. AB - Background: Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Methods: Brain derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Results: Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. Conclusions: This study provides further evidence implicating low brain brain derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide. PMID- 29432623 TI - A Time-Motion Study of Primary Care Physicians' Work in the Electronic Health Record Era. AB - BACKGROUND AND OBJECTIVES: Electronic health records (EHRs) have had mixed effects on the workflow of ambulatory primary care. In this study, we update previous research on the time required to care for patients in primary care clinics with EHRs. METHODS: We directly observed family physician (FP) attendings, residents, and their ambulatory patients in 982 visits in clinics affiliated with 10 residencies of the Residency Research Network of Texas. The FPs were purposely chosen to reflect a diversity of patient care styles. We measured total visit time, previsit chart time, face-to-face time, non-face time, out-of-hours EHR work time, and total EHR work time. RESULTS: The mean (SD) visit length was 35.8 (16.6) minutes, not counting resident precepting time. The mean time components included 2.9 (3.8) minutes working in the EHR prior to entering the room, 16.5 (9.2) minutes of face-to-face time not working in the EHR, 2.0 (2.1) minutes working in the EHR in the room (which occurred in 73.4% of the visits), 7.5 (7.5) minutes of non-face time (mostly EHR time), and 6.9 (7.6) minutes of EHR work outside of normal clinic operational hours (which occurred in 64.6% of the visits). The total time and total EHR time varied only slightly between faculty physicians, third-year and second-year residents. Multivariable linear regression analysis revealed many factors associated with total visit time including patient, physician, and clinic infrastructure factors. CONCLUSIONS: Primary care physicians spent more time working in the EHR than they spent in face-to-face time with patients in clinic visits. PMID- 29432624 TI - Same Content, Different Methods: Comparing Lecture, Engaged Classroom, and Simulation. AB - BACKGROUND AND OBJECTIVES: There is a push to use classroom technology and active teaching methods to replace didactic lectures as the most prevalent format for resident education. This multisite collaborative cohort study involving nine residency programs across the United States compared a standard slide-based didactic lecture, a facilitated group discussion via an engaged classroom, and a high-fidelity, hands-on simulation scenario for teaching the topic of acute dyspnea. The primary outcome was knowledge retention at 2 to 4 weeks. METHODS: Each teaching method was assigned to three different residency programs in the collaborative according to local resources. Learning objectives were determined by faculty. Pre- and posttest questions were validated and utilized as a measurement of knowledge retention. Each site administered the pretest, taught the topic of acute dyspnea utilizing their assigned method, and administered a posttest 2 to 4 weeks later. Differences between the groups were compared using paired t-tests. RESULTS: A total of 146 residents completed the posttest, and scores increased from baseline across all groups. The average score increased 6% in the standard lecture group (n=47), 11% in the engaged classroom (n=53), and 9% in the simulation group (n=56). The differences in improvement between engaged classroom and simulation were not statistically significant. CONCLUSIONS: Compared to standard lecture, both engaged classroom and high-fidelity simulation were associated with a statistically significant improvement in knowledge retention. Knowledge retention after engaged classroom and high-fidelity simulation did not significantly differ. More research is necessary to determine if different teaching methods result in different levels of comfort and skill with actual patient care. PMID- 29432625 TI - Burnout and Resiliency Among Family Medicine Program Directors. AB - BACKGROUND AND OBJECTIVES: Nearly one-half (46%) of physicians report at least one symptom of burnout. Family medicine residency program directors may have similar and potentially unique levels of burnout as well as resiliency. The primary aims of this study were to examine burnout and resiliency among family medicine residency directors and characterize associated factors. METHODS: The questions used were part of a larger omnibus survey conducted by the Council of Academic Family Medicine (CAFM) Educational Research Alliance (CERA) in 2016. Program and director-specific characteristics were obtained. Symptoms of burnout were assessed using two single-item measures adapted from the full Maslach Burnout Inventory, and level of resiliency was assessed using the Brief Resilience Scale. RESULTS: The overall response rate for the survey was 53.7% (245/465). Symptoms of high emotional exhaustion or high depersonalization were reported in 27.3% and 15.8% of program directors, respectively. More than two thirds of program directors indicated that they associated themselves with characteristics of resiliency. Emotional exhaustion and depersonalization were significantly correlated with never having personal time, an unhealthy work-life balance, and the inability to stop thinking about work. The presence of financial stress was significantly correlated with higher levels of emotional exhaustion and depersonalization. In contrast, the level of resiliency reported was directly correlated with having a moderate to great amount of personal time, healthy work life balance, and ability to stop thinking about work, and negatively correlated with the presence of financial stress. CONCLUSIONS: Levels of emotional exhaustion, depersonalization, and resiliency are significantly related to personal characteristics of program directors rather than characteristics of their program. PMID- 29432626 TI - Satisfaction, Motivation, and Retention in Academic Faculty Incentive Compensation Systems: A CERA Survey. AB - BACKGROUND AND OBJECTIVES: The use of incentive compensation in academic family medicine has been a topic of interest for many years, yet little is known about the impact of these systems on individual faculty members. Better understanding is needed about the relationship of incentive compensation systems (ICSs) to ICS satisfaction, motivation, and retention among academic family medicine faculty. METHODS: The Council of Academic Family Medicine (CAFM) Educational Research Alliance (CERA) conducted a nationwide survey of its members in 2013. This study reports the results of the incentive compensation question subset of the larger omnibus survey. RESULTS: The overall response rate was 53%. The majority (70% [360/511]) of academic faculty reported that they are eligible for some type of incentive compensation. The faculty reported moderate satisfaction, with only 38% being satisfied or highly satisfied with their ICS. Overall mean motivation and intent to remain in their current position were similar. The percentage of total income available as an incentive explained less than 10% of the variance of those outcomes. Faculty perceptions of appropriateness of the measures, understanding of the measurement and reward systems, and perception of due process are all related to satisfaction with the ICS, motivation, and retention. CONCLUSIONS: ICSs are common in academic family medicine, yet most faculty do not find them to motivate their choice of activities or promote staying in their current position. Design and implementation are both important in promoting faculty satisfaction with the ICS, motivation, and retention. PMID- 29432627 TI - The Cost of Family Medicine Residency Training: Impacts of Federal and State Funding. AB - BACKGROUND AND OBJECTIVES: Numerous organizations are calling for the expansion of graduate medical education (GME) positions nationally. Developing new residency programs and expanding existing programs can only happen if financial resources are available to pay for the expenses of training beyond what can be generated in direct clinical income by the residents and faculty in the program. The goal of this study was to evaluate trended data regarding the finances of family medicine residency programs to identify what financial resources are needed to sustain graduate medical education programs. METHODS: A group of family medicine residency programs have shared their financial data since 2002 through a biennial survey of program revenues, expenses, and staffing. Data sets over 12 years were collected and analyzed, and results compared to analyze trends. RESULTS: Overall expenses increased 70.4% during this period. Centers for Medicare and Medicaid Services (CMS) GME revenue per resident increased by 15.7% for those programs receiving these monies. Overall, total revenue per resident, including clinical revenues, state funding, and any other revenue stream, increased 44.5% from 2006 to 2016. The median cost per resident among these programs, excluding federal GME funds, is currently $179,353; this amount has increased over the 12 years by 93.7%. CONCLUSIONS: For this study group of family medicine programs, data suggests a cost per resident per year, excluding federal and state GME funding streams, of about $180,000. This excess expense compared to revenue must be met by other agencies, whether from CMS, the Health Resources and Services Administration (HRSA), state expenditures or other sources, through stable long-term commitments to these funding mechanisms to ensure program viability for these essential family medicine programs in the future. PMID- 29432628 TI - The Relationship Between Preclinical Grading and USMLE Scores in US Allopathic Medical Schools. AB - BACKGROUND AND OBJECTIVES: Pass/fail preclinical grading is associated with improved student well-being. Studies do not demonstrate differences in United States Medical Licensing Examination (USMLE) scores after adopting pass/fail grading, but were conducted at unrepresentative, highly selective institutions, and average scores increased overall during the study periods. We investigated the effect of preclinical grading on USMLE scores across 96 US medical schools. METHODS: Preclinical grading systems were identified with the 2017 Association of American Medical Colleges Medical School Admissions Requirements. Median undergraduate grade point average (GPA) and Medical College Admission Test (MCAT) scores and average Step 1 and Step 2 clinical knowledge (CK) scores were available for 96 of 142 US medical schools on US News Grad Compass. Multiple linear regression was used to adjust for entering student characteristics, and one-tailed Student's t tests were used to test for noninferiority. Noninferiority margins were calculated using standard errors from the USMLE Score Interpretation Guidelines and average class size. RESULTS: Fifty-six (58.3%) of 96 schools use pass/fail preclinical grading. After adjusting for MCAT, pass/fail grading was not associated with significant differences in average Step 1 (P=0.98) or Step 2 CK (P=0.63). The 90% confidence interval of the effect of pass/fail grading on Step 1 (-1.27, 1.24) did not cross the noninferiority margin of -1.33 (P=0.043). The 90% confidence interval for Step 2 CK (-1.46, 0.81) also did not cross the noninferiority margin of -1.5 (P=0.044). CONCLUSIONS: Pass/fail preclinical grading is noninferior to tiered preclinical grading in terms of USMLE scores. PMID- 29432629 TI - Seven Years of Teaching Communication With the Patient-Centered Observation Form. AB - BACKGROUND AND OBJECTIVES: For years, family medicine has taught patient-centered communication through observations and observation checklists. We explored the utility of one checklist, the Patient-Centered Observation Form (PCOF), to teach and evaluate patient-centered communication in our family medicine residencies. METHODS: We conducted a mixed-method study of five University of Minnesota Family Medicine Residencies' seven years of experience teaching and evaluating residents' patient-centered communication skills. All programs have a behavioral health (BH) faculty-led observation curriculum that uses the PCOF to assess resident skills and give feedback. We conducted a BH faculty focus group and interviews, generated themes from the BH responses, and then queried family medicine (FM) faculty regarding these themes through an online survey. RESULTS: Ten BH faculty participated in the focus group/interviews, and 71% (25/35) of FM faculty completed the survey about themes derived from the BH interviews. The residencies complete between 1 to 11 observations per resident per year. Since implementation, four programs have continuously used the PCOF due to its versatility, design as a formative rather than summative feedback tool, and relative ease of use. BH faculty believe longitudinal observations with the PCOF resulted in improved resident patient-centered communication. Most importantly, all faculty described a shift in family medicine culture toward patient-centered communication. Time for observations and feedback is the primary curricular barrier. CONCLUSIONS: Our findings support the utility of the PCOF for teaching and evaluating patient-centered communication in family medicine training. PMID- 29432631 TI - fmCASES National Examination as a Pretest in a Family Medicine Clerkship. AB - BACKGROUND AND OBJECTIVES: Pretests have been shown to contribute to improved performance on standardized tests by serving to facilitate development of individualized study plans. fmCASES is an existing validated examination used widely in family medicine clerkships throughout the country. Our study aimed to determine if implementation of the fmCASES National Examination as a pretest decreased overall failure rates on the end-of-clerkship National Board of Medical Examiners (NBME) subject examination, and to assess if fmCASES pretest scores correlate with student NBME scores. METHODS: One hundred seventy-one and 160 clerkship medical students in different class years at a single institution served as the control and intervention groups, respectively. The intervention group took the fmCASES National Examination as a pretest at the beginning of the clerkship and received educational prescriptions based on the results. Chi-square analysis, Pearson correlation, and receiver operating curve analysis were used to evaluate the effectiveness and correlations for the intervention. RESULTS: Students completing an fmCASES National Examination as a pretest failed the end of-clerkship NBME exam at significantly lower rates than those students not taking the pretest. The overall failure rate for the intervention group was 8.1% compared to 17.5% for the control group (P=0.01). Higher pretest scores correlated with higher NBME examination scores (r=0.55, P<0.001). CONCLUSIONS: fmCASES National Examination is helpful as a formative assessment tool for students beginning their family medicine clerkship. This tool introduces students to course learning objectives, assists them in identifying content areas most in need of study, and can be used to help students design individualized study plans. PMID- 29432630 TI - Promoting Documentation of Suicidality in a Family Medicine Residency Clinic. AB - BACKGROUND AND OBJECTIVES: Careful assessment of depression and suicidality are important given their prevalence and consequences for quality of life. Our study evaluated the impact of an educational intervention in a family medicine residency clinic on rates of provider documentation regarding suicidality. METHODS: We offered two brief workshops to our clinic staff and created two standardized charting templates to empower and educate providers. One template used with the patient during the clinic visit elicited key factors (eg, plan, intent, barriers) and offered treatment plan options. The second template included supportive text and resources to include in the after-visit summary. A chart review was completed, examining 350 patient records in which the patient reported thoughts of death or suicide in the preceding 2 weeks on the Patient Health Questionnaire-9 ([PHQ-9], 150 over a 5-month baseline period, 150 in months 1 through 4 immediately following the workshops and template development, and 50 at follow-up months 7 through 8 following the intervention). We examined use of the templates and changes in rates of documentation of suicidality. RESULTS: Rates of provider documentation of suicidality for patients who had expressed suicidal ideation on the PHQ-9 increased significantly from 57% at baseline to 78% in the postintervention phase; the rise persisted at follow-up. Rates of use of the assessment template were 58% (postintervention) and 49% (follow-up). Anecdotal provider feedback reflected appreciation of the templates for assessing and documenting challenging issues. CONCLUSIONS: Brief educational interventions were associated with improved rates of provider documentation of suicidality. The longer-term impact of the workshops and templates warrant further investigation. PMID- 29432632 TI - Standardized Contraceptive Handout Facilitates Contraceptive Counseling. AB - BACKGROUND AND OBJECTIVES: Effective public provision of contraceptive services depends upon regular interventions at the primary care level. Recognizing the need to improve the frequency and quality of contraceptive counseling at a rural family medicine residency, this study sought to determine if the introduction of a simple teaching tool would lead to an increase in the rates of such counseling. METHODS: Resident physicians at a rural clinic provided contraceptive counseling to all eligible women, utilizing a simple educational table as a teaching aid. Rates of counseling were compared before, during, and after the intervention. RESULTS: A total of 3,606 patient encounters were included for analysis. Rates of contraceptive counseling in the preintervention period (n=832) and postintervention period (n=1,983) increased significantly (0.8% vs 5.2%, P<0.001). In addition, rates of counseling increased from the intervention phase (n=791) to the postintervention period (2.4% vs 5.2%, P<0.001). CONCLUSION: The introduction of educational tools may increase rates of contraceptive counseling without being an undue burden upon providers. PMID- 29432633 TI - I Couldn't Convince Mama. PMID- 29432634 TI - The Blue Canister. PMID- 29432639 TI - Black History Month: Progress, Imperfection, and Opportunities. PMID- 29432640 TI - Diamond burs versus curettes in root planing: a randomized clinical trial. AB - BACKGROUND: This study compares diamond burs and curettes by clinical, microbiological, biochemical and scanning electron microscopic parameters and treatment time data in the non-surgical periodontal treatment of patients with chronic periodontitis. METHODS: Two quadrants of each of the 12 patients received root planing with diamond burs, whereas the other two quadrants were treated with curettes. Clinical periodontal measurements were recorded at baseline and then 1, 3 and 6 months after completion of non-surgical periodontal treatment. Subgingival plaque and gingival crevicular fluid samples were obtained at baseline and 1-month control. Twenty-one hopeless teeth received root planing with diamond burs or curettes or no treatment and then extracted for microscopic evaluations. RESULTS: Clinical periodontal parameters improved similarly with both treatment modalities. Microbiological analyses revealed similar findings for the bacterial load (16S gene copy numbers) and ratio of each bacterium to the total bacterial count at baseline and 1-month control. Cytokine levels in the gingival crevicular fluid samples exhibited differences between the two treatments. Scanning electron microscopic analyses indicated that diamond burs were better in terms of calculus removal and loss of tooth substance indices but roughness index values were better for curettes. CONCLUSIONS: Diamond burs provide findings comparable with curettes in root planing. PMID- 29432641 TI - Magnetotactic bacteria used to generate electricity based on Faraday's law of electromagnetic induction. AB - : Magnetotactic bacteria (MTB) have the unique ability to produce magnetic particles surrounded by a biomembrane to form the magnetosome organelle. Therefore, MTB have novel physical and magnetic properties and have consequently been used in several biotechnological applications. The magnetic properties of these micro-organisms and their magnetosomes have, however, never been used for the generation of electricity as described in this letter. Comparisons were made between, firstly, the electricity generated from purified magnetosomes, MTB culture (bacterial cells with magnetosomes) and sterile, liquid growth medium (control). Secondly, the electricity generated by a dilution series of purified magnetosomes were compared. A statistically significant difference was found between the voltage measured from the purified magnetosomes (highest voltage), MTB culture (lower voltage) and liquid growth medium (lowest voltage). In the dilution series, the voltage measured increased as the magnetosome concentration increased, but only up to an optimum concentration (0.0376 mg ml-1 ). In this study, we have demonstrated that a significantly higher voltage than that of the control could be measured when MTB or purified magnetosomes were pumped through a solenoid by applying Faraday's law of electromagnetic induction. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides proof-of-concept of electromagnetic induction using magnetosomes or magnetotactic bacteria in an experimental setup based on the law of Faraday. The concept of using these bacteria or their biomineralized magnetic nanoparticles as a biological alternative in low voltage electricity generation has the potential to be further explored and developed. PMID- 29432642 TI - Classification of tongue cancer resection and treatment algorithm. AB - BACKGROUND AND OBJECTIVES: Reconstruction of tongue cancer defects is challenging due to the complex anatomy and physiology of the tongue. Here, we classify patterns of tongue tissue loss and describe a treatment algorithm for achieving good functional and oncologic outcomes. METHODS: We retrospectively reviewed 50 tongue squamous-cell carcinomas surgically treated between January 2010-June 2015. Cancer resection and tongue reconstruction were stratified according to the missing anatomical subunits. RESULTS: A type 1 defect is a unilateral and marginal defect, not crossing the midline, and not extending to the posterior third of the tongue. Type 2 involves the two-anterior-thirds of the mobile body, not crossing the midline, without posterior-third evolvement. Type 3 involves the two-anterior-thirds of the mobile body of the tongue with contralateral extension. Type 4 extends to the tongue base. Type 5 defect comprises any of the previous defects along with involvement of the floor of the mouth. Type 2 and 3 defects were the most common. Microvascular reconstruction was performed in 23 out of 50 patients. Complications included infection, partial necrosis, dehiscence, and microvascular thrombosis. CONCLUSIONS: Our classification system and treatment algorithm represent a reliable method of addressing management of tongue defects. PMID- 29432643 TI - Growth media and assay plate material can impact on the effectiveness of cationic biocides and antibiotics against different bacterial species. AB - : The effectiveness of several cationic disinfectants as well as colistin and polymyxin B were assessed under different growth conditions against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa strains. These conditions included different media (MH1, MH2, TSB and LB) and plate material (polypropylene and polystyrene). Results showed that Minimum inhibitory and bactericidal concentrations (MIC/MBC) values of colistin and polymyxin B were significantly lower on polypropylene plates when compared to polystyrene plates regardless of media used. There were also differences in MIC/MBC values to certain biocides e.g. chlorhexidine and octenidine particularly for S. aureus and E. coli strains, with polypropylene again showing lower values. Other biocides appear to be mostly unaffected by plate type. Whether biocide efficacy was altered by media composition was organism dependent with S. aureus and E. coli more affected than P. aeruginosa. Lower MIC values were more commonly associated with MH2 media and higher MIC values with TSB media for both polypropylene and polystyrene plates, although there were exceptions. Results obtained for standard strains were, in general, indicative for other S. aureus, E. coli and P. aeruginosa strains tested. This study demonstrates the importance of media composition and plate material on biocide effectiveness and highlights the need for optimized disinfectant testing methods. SIGNIFICANCE AND IMPACT OF THE STUDY: There are an increasing number of reports of bacterial strains that are multi drug resistant. The use of biocides as part of infection control is crucial in helping to combat the spread of these particular strains. Unlike for antibiotics, there are few standardized measuring techniques to understand if an isolate has become more resistant to biocides. This study demonstrates the importance of media composition and plate material on variation and reporting of susceptibility of several bacterial species to specific cationic biocides. It is a useful comparison study to highlight the need to standardize biocide susceptibility testing. PMID- 29432644 TI - A randomized, multinational, noninferiority, phase III trial to evaluate the safety and efficacy of BF-200 aminolaevulinic acid gel vs. methyl aminolaevulinate cream in the treatment of nonaggressive basal cell carcinoma with photodynamic therapy. AB - BACKGROUND: Basal cell carcinoma (BCC) represents the most common nonmelanoma skin cancer worldwide, affecting mainly adult, fair-skinned individuals. The World Health Organization distinguishes aggressive and nonaggressive forms, of which prototypical variants of the latter are primary nodular and superficial BCC. OBJECTIVES: To demonstrate noninferiority of BF-200 ALA (a nanoemulsion gel containing 5-aminolaevulinic acid) compared with MAL (a cream containing methyl aminolaevulinate) in the treatment of nonaggressive BCC with photodynamic therapy (PDT). Noninferiority of the primary efficacy variable (overall patient complete response 12 weeks after last PDT) would be declared if the mean response for BF 200 ALA was no worse than that for MAL, within a statistical margin of Delta = 15%. METHODS: The study was a randomized, phase III trial performed in Germany and the U.K. with ongoing 5-year follow-up. Of 281 randomized patients, 138 were treated with BF-200 ALA and 143 with MAL. Patients received two PDT sessions 1 week apart. Remaining lesions 12 weeks after the second PDT were retreated. Illumination was performed with a red light source (635 nm, 37 J cm-2 ). The results shown include clinical end points and patients' reassessment 12 months after the last PDT. The study was registered with EudraCT (number 2013-003241 42). RESULTS: Of the BF-200 ALA-treated patients, 93.4% were complete responders compared with 91.8% in the MAL group. The difference of means was 1.6, with a one sided 97.5% confidence interval of -6.5, establishing noninferiority (P < 0.0001). The results for secondary efficacy parameters were in line with the primary outcome. Recurrence rates 12 months after the last treatment were <= 10%. CONCLUSIONS: Treatment of nonaggressive BCC with BF-200 ALA-PDT is highly effective and well tolerated with proven noninferiority to MAL-PDT. It demonstrates low recurrence rates after 1 year of follow-up. PMID- 29432645 TI - Alcohol binge drinking in early pregnancy and the effect on fetal growth: a cohort study. AB - INTRODUCTION: Alcohol binge drinking is common in early pregnancy and is a well established risk factor for subsequent child health. Yet, very few studies have investigated the effect on fetal growth. Furthermore, it has been speculated that the timing of binge drinking may be a determining factor for neonatal growth. The objective of this study was to assess the potential effect of binge drinking and different drinking patterns (timing and number of binge drinking episodes) in early pregnancy on fetal growth estimated by birthweight and birth length. MATERIAL AND METHODS: From 1 March to 31 August 2000, 1836 pregnant Danish women from Aarhus University Hospital and Fredericia Hospital were included in the study and interviewed around the early second trimester about their drinking habits during their pregnancy. Information on anthropometric measures at birth was obtained from the Danish Medical Birth Registry. The potential effect of binge drinking and different drinking patterns was estimated using a multivariate general linear regression model adjusted for potential confounders that were selected a priori based on the currently available scientific literature. RESULTS: The women who reported any binge drinking gave birth to children with a reduction in birth length of -0.02 cm (95% CI -0.23 to 0.18) and an increase in birthweight of 0.2 g (95% CI -42.8 to 43.2). The number of binge episodes and the timing of these episodes were also not associated with fetal growth. CONCLUSIONS: The study suggests that binge drinking and different drinking patterns in early pregnancy do not affect fetal growth. PMID- 29432646 TI - High-level expression and characterization of a new kappa-carrageenase from marine bacterium Pedobacter hainanensis NJ-02. AB - : A novel kappa-carrageenase gene (CgkB) has been cloned from Pedobacter hainanensis NJ-02 and expressed heterologously in Escherichia coli BL21 (DE3). It consisted of 1935 bp and encoded 644 amino acid residues with a molecular weight of 71.61 kDa. The recombinant enzyme showed maximal activity of 2458 U mg-1 at 40 degrees C and pH 8.0. Additionally, it could retain more than 70% of its maximal activity after being incubated at pH of 5.5-10.0 below 40 degrees C. K+ and a broad range of NaCl can activate the enzyme. The Km and Vmax of CgkB was 2.4 mg ml-1 and 126 mmol mg-1 min-1 . The ESI-MS analysis of hydrolysates indicated that the enzyme can endolytically depolymerize the carrageenan into tetrasaccharides and hexasaccharides. The results indicated that the enzyme with high activity could be a valuable enzyme tool to produce carrageenan oligosaccharides with various activities. SIGNIFICANCE AND IMPACT OF THE STUDY: Enzymatic preparation of carrageenan oligosaccharides has drawn increased attention due to their various physiological activities. It is urgent to explore enzyme tools with higher activity and better stability. In this work, a novel kappa-carrageenase was identified and characterized from marine bacterium Pedobacter hainanensis NJ-02. The enzyme with high activity could be a valuable tool to produce carrageenan oligosaccharides with various activities. PMID- 29432647 TI - Efficient production of trans-4-Hydroxy-l-proline from glucose by metabolic engineering of recombinant Escherichia coli. AB - : Trans-4-Hydroxy-l-proline (trans-Hyp) is a valuable chiral building block for the synthesis of pharmaceutical intermediates. Bioconversion of l-proline using recombinant strain with proline-4-hydroxylase (P4H) is a preferred biocatalytic process in the economical production of trans-Hyp. In this study, a recombinant E. coli overexpressing hydroxylase (P4H), gamma-glutamyl kinase and glutamate semialdehyde dehydrogenase (ProBA) genes were constructed by knocking out the key genes in the metabolism. These key genes contained putA encoding proline dehydrogenase (PutA) in the l-proline metabolism and other catalytic enzyme genes, sucAB encoding alpha-ketoglutarate dehydrogenase (SucAB), aceAK encoding isocitratelyase (AceA) and isocitrate dehydrogenase kinase/phosphatase (AceK) in the TCA cycle. This recombinant strain coupled the synthetic pathway of trans-Hyp with TCA cycle of the host strain. It inhibited the consumption of l-proline completely and promoted the accumulation of 2-oxoglutarate (2-OG) as a co substrate, which realized the highest conversion of glucose to trans-Hyp. A fed batch strategy was designed, capable of producing 31.0 g l-1 trans-Hyp from glucose. It provided a theoretical basis for commercial conversion of glucose to trans-Hyp. SIGNIFICANCE AND IMPACT OF THE STUDY: Trans-4-Hydroxy-l-proline (trans Hyp) is a valuable chiral building block for the synthesis of pharmaceutical intermediates. Unsatisfactory microbial bioconversion resulted in a low yield of trans-Hyp. In this study, we blocked the unwanted blunting pathways of host strain and make the cell growth couple with the trans-Hyp synthesis from glucose. Finally, a recombinant Escherichia coli with short-cut and efficient trans-Hyp biosynthetic pathway was obtained. It provided a theoretical basis for commercial production of trans-Hyp. PMID- 29432648 TI - Pilocarpine and artificial saliva for the treatment of xerostomia and xerophthalmia in Sjogren syndrome: a double-blind randomized controlled trial. AB - BACKGROUND: Sjogren syndrome (SS) is associated with xerostomia and xerophthalmia. Pilocarpine has been shown to stimulate the secretion of saliva. OBJECTIVES: To investigate and compare the efficacy of pilocarpine and artificial saliva as symptomatic treatments for xerostomia and xerophthalmia in patients with SS. METHODS: A double-blind randomized controlled study was performed. A total of 72 patients with SS were assigned randomly to receive 10 drops of pilocarpine (5 mg) or 10 drops of artificial saliva orally, three times daily for 12 weeks. Whole saliva and tear flow were evaluated at baseline and periodically throughout the study to provide a global assessment of dryness and to report any adverse effects. RESULTS: Patients receiving pilocarpine had a statistically significant improvement in their salivary flow (P < 0.001), lacrimal flow (P < 0.001) and their subjective global assessment (P < 0.001), compared with patients who received artificial saliva. The most common side-effects were sialorrhoea and nausea. CONCLUSIONS: Pilocarpine is more effective than artificial saliva for enhancing salivary and lacrimal secretion in patients with SS. This is the first study to compare the efficacy of pilocarpine and artificial saliva for the treatment of xerostomia and xerophthalmia in SS. PMID- 29432649 TI - A review of clinical trial registry use in dermatology systematic reviews. PMID- 29432650 TI - Effects of ultrasonic removal of fractured files from the middle third of root canals on dentinal cracks: a micro-computed tomography study. AB - AIM: To evaluate the frequency of dentinal microcracks after ultrasonic removal of fractured files from the middle third of root canals using micro-computed tomography (micro-CT). METHODOLOGY: Eighteen bilaterally matched pairs of human mandibular incisors extracted for periodontal reasons were included. The matched pairs of teeth were then divided into a control group and an experimental group, with one member of each pair assigned to each group. In the control group, the canals were instrumented using the ProTaper Next (PTN) system. In the experimental group, size 20 K-files were fractured in the middle third of the root canals, followed by their ultrasonic removal. Subsequently, the canals were instrumented with the PTN system. All teeth were scanned using high-resolution micro-CT before (preoperative) and after (intraoperative) file removal and after (postoperative) root canal preparation. Pre-, intra-, and postoperative cross sectional images of the roots were screened to identify the presence of dentinal defects. Two experienced observers evaluated the images twice in a blinded manner. The incidence of dentinal microcracks was noted and statistically analysed using Fisher's exact and McNemar's tests (P = 0.05), with the root cross section and the tooth root as the units of analysis, respectively. RESULTS: All fractured files in the experimental group were removed successfully. New microcracks were detected in 0.56% (93/16 472) cross-sections (8/18 specimens) generated after file removal in the experimental group. These microcracks were detected 4-6 mm below the root canal orifice and exhibited a width and length of 12-36 MUm and 48-72 MUm, respectively. They did not disappear or propagate after canal preparation. No new dentinal microcracks were observed in the control group. There was a significant difference in the incidence of new microcracks between the two groups (P < 0.05). CONCLUSIONS: Ultrasonic removal of fractured files from root canals resulted in the formation of short microcracks in a small number of cross-sections in approximately half the specimens. Further studies are necessary to determine the cause and consequences of this finding. PMID- 29432651 TI - A 20-year historical prospective cohort study of root canal treatments. A Multilevel analysis. AB - AIM: To evaluate the number of healthy and functional root filled teeth of patients included in a recall programme for at least 20 years. METHODOLOGY: Teeth were root filled by a single specialist following manual canal instrumentation, lateral/vertical compaction of gutta-percha and restored with glass-ionomer cements and bonding system/composite resin. In a large percentage of teeth, a metal-ceramic crown was placed during follow-up. Patients included in the recall programme (n = 130) were blindly assessed both clinically and radiographically (every 2 years) to evaluate clinical symptoms and periapical status (PAI). The following variables were analysed: age, tooth location, tooth type, initial diagnosis, PAI, root filling length and coronal restoration type. Chi-square test and multilevel analysis were performed to detect variables associated with treatment functionality and disease/lesions (P < 0.05). A cumulative teeth survival curve was constructed by means of Kaplan-Meier using extractions as the end-point. RESULTS: At the 20-year recall, 72 patients (31 M, 41 F; mean age 57.7 +/- 8.29 years; 196 teeth) completed the follow-up. Thirty-six patients were excluded for medical complications or died before the end of the study. Drop-outs consisted of 22 patients (17%) who did not complete the follow-up. Single metal ceramic crowns were positioned after 4-6 months in 40% of teeth. Composite restorations were replaced with single metal-ceramic crowns during the follow-up in 53% of teeth after 8-19 years. Of 196 teeth, 155 were classified as Survived (79%), 128 of which (65%) were Healthy (PAI <= 2). Thirty-nine teeth (20%) were extracted for nonendodontic reasons. Twenty-nine teeth (15%) were classified as: re-exacerbation (11 teeth; 5.6%) or persistent asymptomatic lesions (18 teeth; 9%). Only two re-exacerbated teeth were extracted. Multilevel analysis confirmed the clinical relevance of tooth type (P = 0.001) on Survived and healthy teeth (P = 0.007). Tooth location (P = 0.0045) and initial diagnosis (P = 0.019) significantly affected only Healthy teeth. CONCLUSIONS: Root filled teeth were more frequently extracted for non-endodontic reasons rather than for endodontic disease. The majority of teeth with adequate root fillings, adequate restorations and included in a recall programme remained functional and healthy for more than 20 years. PMID- 29432652 TI - Osteonecrosis of the jaws: a 14-year retrospective survey of hospital admissions. AB - BACKGROUND: Osteonecrosis of the jaw (ONJ) is a serious complication of both radiation and antiresorptive therapies. This study aimed to determine how many patients have been treated for medication-related osteonecrosis of the jaws (MRONJ) and osteoradionecrosis (ORN), and whether the number of diagnoses has decreased over time with improved awareness and preventative measures. METHODS: Medical records at the Royal Brisbane and Women's Hospital, Gold Coast University Hospital and Robina Hospital were reviewed to identify patients diagnosed with MRONJ and ORN between January 2003 and May 2017. Data on patient demographics, year of admission and primary disease were analysed. RESULTS: Two hundred and thirty-eight patients were diagnosed with ONJ, of which 74.4% were ORN and 25.6% were MRONJ. Tongue (24.6%), floor of mouth (17.3%) and tonsillar (15.1%) squamous cell carcinomas were the most common primary diseases associated with ORN, with a strong male predominance (80%). Of patients diagnosed with MRONJ, 52.5% were taking low-dose antiresorptives for osteoporosis (44.2%), rheumatoid arthritis (4.6%) or Paget's disease (3.3%), while 47.5% were oncology patients receiving high-dose antiresorptives. CONCLUSIONS: The number of patients diagnosed with MRONJ and ORN has trended upwards since 2003. ORN affected three times more patients than MRONJ, and patients on low-dose antiresorptives accounted for over half of the MRONJ cases. PMID- 29432653 TI - The synergistic activities of the combination of tumour necrosis factor-alpha, interleukin-17A and interferon-gamma in epidermal keratinocytes. PMID- 29432654 TI - Eccrine sweat glands associate with the human hair follicle within a defined compartment of dermal white adipose tissue. AB - BACKGROUND: Eccrine sweat glands (ESGs) are critical for thermoregulation and are involved in wound healing. ESGs have traditionally been considered as separate skin appendages without connection to the pilosebaceous unit (PSU). However, recent preliminary evidence has encouraged the hypothesis that the PSU and ESG are more interconnected than previously thought. OBJECTIVES: To re-evaluate the morphology of human skin adnexa with an integrated three-dimensional (3D) perspective in order to explore the possible interconnections that the PSU and the ESG may form. METHODS: A systematic 3D reconstruction method of skin sections, direct visualization of human scalp follicular unit transplant grafts and a scalp strip ex vivo were used to validate and further explore the hypothesis. RESULTS: We demonstrate that the coiled portion of most ESGs is morphologically integrated into the PSU of human scalp skin and forms a structural unit that is embedded into a specific, hair follicle-associated region of dermal white adipose tissue (dWAT). This newly recognized unit is easily accessible and experimentally tractable by organ culture of follicular units and can be visualized intravitally. CONCLUSIONS: We propose a model of functional human skin anatomy in which ESGs are closely associated with the PSU and the dWAT to form a common homeostatic tissue environment, which may best be encapsulated in the term 'adnexal skin unit'. The challenge now is to dissect how each component of this superstructure of human skin functionally cooperates with and influences the other under physiological conditions, during regeneration and repair and in selected skin diseases. PMID- 29432655 TI - Effects of treatment for psoriasis on circulating levels of leptin, adiponectin and resistin: a systematic review and meta-analysis. AB - BACKGROUND: Metabolic syndrome, a risk factor of cardiovascular disease, is more common in patients with psoriasis than in the general population. Circulating adipokine concentrations are altered in patients with psoriasis and are suggested to represent the pathophysiological link between psoriatic lesions and metabolic alterations. OBJECTIVES: To perform a systematic review of the literature for studies that investigated possible differences in circulating levels of leptin, adiponectin or resistin in patients with psoriasis before and after any treatment intervention, and to meta-analyse the best evidence available. METHODS: A search was conducted in three databases (PubMed, Central and Embase). Eligible for the review were studies that assessed leptin, adiponectin or resistin concentrations in patients with psoriasis before and after any topical or systemic treatment. RESULTS: After treatment, blood concentrations of leptin were similar to those before treatment [standardized mean difference (SMD) 0.06, 95% confidence interval (CI) -0.09 to 0.20], with no heterogeneity among studies (I2 = 0%, P = 0.88). After treatment, blood concentrations of adiponectin were similar to those before treatment (SMD -0.14, 95% CI -0.34 to 0.05), with significant heterogeneity among studies (I2 = 36.8%, P = 0.032). After treatment, blood concentrations of resistin were significantly lower than those before treatment (SMD 0.50, 95% CI 0.20-0.79), with significant heterogeneity among studies (I2 = 61.4%, P < 0.001). CONCLUSIONS: There is no evidence that treatment for psoriasis modifies leptin and adiponectin concentrations. However, treatment intervention reduces resistin concentrations, a finding that is expected to be of clinical importance. PMID- 29432656 TI - Improving the efficacy of PET-CT imaging in head and neck cancer management and surveillance through the multidisciplinary team: A multicentre, retrospective cohort analysis of 51 patients. PMID- 29432657 TI - Clinical profile, antibiotic susceptibility pattern of bacterial isolates and factors associated with complications in culture-proven typhoid patients admitted to an urban hospital in Bangladesh. AB - OBJECTIVES: Typhoid fever is one of the major causes of morbidity and mortality in typhoid endemic countries like Bangladesh. However, data on the clinical and microbiological profile as well as factors associated with complications of typhoid in Bangladesh are scarce. We intended to characterise the clinical and microbiological profile of culture-proven typhoid fever and to identify factors associated with complications. METHODOLOGY: Retrospective analysis of clinical data from 431 patients with culture-confirmed typhoid fever admitted to Dhaka hospital of International Centre for Diarrhoeal Disease Research, Bangladesh, between January 2010 and December 2014. Clinical and microbiological profiles of the patients including age, sex, and duration of illness prior to hospital admission, haematological parameters and the antimicrobial resistance profile of the infecting isolate, duration of hospital stay and defervescence time were examined by logistic regression to identify the factors associated with complications. RESULT: About one of three patients were children under 5 years, and 21.5% of them were severely malnourished. During hospitalisation, 17.4% patients developed complications; mainly encephalopathy (6.7%), ileus (6.5%) and pneumonia (3.5%). Among culture-positive cases, 28.3% isolates showed multidrug resistant (MDR) and more than 90% of isolates were resistant to nalidixic acid and had intermediate sensitivity to ciprofloxacin. Five isolates were resistant to azithromycin; all isolates were sensitive to cefixime and ceftriaxone. Complication was independently associated with duration of fever before admission (adjusted odds ratio: 0.85; 95% CI: 0.074-0.97; P < 0.05), thrombocytopenia on admission (AOR: 2.84; 95% CI: 01.06-7.57; P < 0.05), duration of hospital stay (AOR: 1.34; 95% CI: 1.15-1.57; P < 0.01) and defervescence time (AOR: 0.83; 95% CI: 0.70-0.99; P < 0.05). CONCLUSION: The high prevalence of typhoid fever among under-five children and complications among hospitalised patients are matters of concern. Sensitivity of Salmonella Typhi to ceftriaxone and cefixime was better than to other conventional antibiotics. Shorter duration of fever and thrombocytopenia on admission can be considered as early signs of complications. PMID- 29432658 TI - Recent Progress in Chemistry of Multiple Helicenes. AB - The last decade has witnessed multiple helicenes arising as an interesting class of nonplanar polycyclic aromatics of inherent multihelicity. These molecules present esthetic structures and interesting properties not available to helicenes of single helicity. Herein an overview of multiple helicenes with respect to structures, stereochemical dynamics, synthesis, and applications is provided. Recently reported multiple helicenes are surveyed with an emphasis on molecular structures and stereochemistry of multiple carbohelicenes. After this survey, the synthesis of multiple helicenes through the Scholl reaction is discussed and recent applications of multiple helicenes in organic electronics are summarized. On the basis of these discussions, conclusions are reached on the current status of multiple helicenes and an outlook for this field is provided. PMID- 29432659 TI - Relationship between serum adipsin and the first phase of glucose-stimulated insulin secretion in individuals with different glucose tolerance. AB - AIMS/INTRODUCTION: To detect serum adipsin levels in individuals with different glucose tolerance, and investigate the relationship between adipsisn and the first phase of insulin secretion. MATERIALS AND METHODS: A total of 56 patients with newly diagnosed type 2 diabetes mellitus, 36 patients with impaired glucose tolerance (IGT) and 45 individuals with normal glucose tolerance were enrolled. Intravenous glucose tolerance tests were carried out to evaluate pancreatic beta cell function. The serum levels of adipsin, interleukin-1beta and high sensitivity C-reactive protein were assayed. RESULTS: Serum adipsin levels were significantly lower in the type 2 diabetes mellitus and the IGT patients than those in the normal glucose tolerance group (P < 0.05). The acute insulin response and area under the curve showed a progressive decrease in the normal glucose tolerance and IGT groups, and decreased to the lowest levels in the type 2 diabetes mellitus group (P < 0.05). Adipsin was found to be negatively correlated with waist-to-hip ratio, free fatty acid, fasting plasma glucose, 2-h postprandial plasma glucose, glycated hemoglobin, homeostasis model assessment of insulin resistance, interleukin-1beta and high-sensitivity C-reactive protein (P < 0.05 or P < 0.001), and positively correlated with homeostasis model assessment of beta-cell function, high-density lipoprotein cholesterol, the area under the curve of the first phase insulin secretion and acute insulin response (P < 0.05 or P < 0.001). Stepwise multiple regression analysis showed that homeostasis model assessment for beta-cell function and acute insulin response were independently related to adipsin (P < 0.05). CONCLUSIONS: Serum adipsin levels were lower in type 2 diabetes mellitus and IGT patients, and correlated with the first phase of insulin secretion. Adipsin might be involved in the pathology of type 2 diabetes mellitus. PMID- 29432660 TI - Recent gestational diabetes was associated with mothers stopping predominant breastfeeding earlier in a multi-ethnic population. AB - AIM: It has previously been shown that breastfeeding may reduce the risk of type 2 diabetes in mothers with recent gestational diabetes mellitus (GDM). This study compared the cessation of predominant breastfeeding in mothers with and without recent GDM in a multi-ethnic population. METHODS: From May 2008 to May 2010, healthy pregnant women attending antenatal care provided by community health services in Eastern Oslo, Norway were recruited. We included 616 women-58% non Western-and interviewed and examined them at a mean of 15 and 28 weeks of gestation and 14 weeks' postpartum. Cox regression models examined the association between GDM, as assessed by the 2013 World Health Organization criteria, and breastfeeding cessation. RESULTS: Overall, 190 of the 616 (31%) mothers had GDM and they ended predominant breastfeeding earlier than mothers without GDM, with an adjusted hazard ratio (aHR) of 1.33 and 95% confidence interval (95% CI) of 1.01-1.77. Mothers of South Asian origin ended predominant breastfeeding earlier than Western European mothers in the adjusted analysis (aHR 1.53, 95% CI: 1.04-2.25), but Middle Eastern mothers did not. CONCLUSION: Recent gestational diabetes was associated with earlier cessation of predominant breastfeeding in Western European and non-Western women. PMID- 29432661 TI - Is pulmonary vascular disease reversible with PPAR gamma agonists? AB - Severe angio-obliterative PAH remains a disease characterized by great morbidity and shortened survival. Unfortunately, the only currently available treatments for angio-obliterative changes are palliative in the form of pulmonary vasodilators evolving from the phosphodiesterase inhibitor sildenafil to endothelin receptor antagonist: Bosentan; while the only definitive treatment is lung transplantation which remains dependent on the availability of donors and the transplant policies which vary widely from a country to another. PPARs, especially the gamma isoform, are largely expressed in pulmonary artery endothelial cells and smooth muscle cells. They are also found on endothelial progenitor cells. Several previous studies have highlighted the role of PPAR gamma agonists in reversal of vascular remodeling especially in coronary, carotid and peripheral vascular disease atherosclerotic plaques. Experimental studies have also revealed that PPAR gamma activation affects many different pathways; thus, the effect of PPAR gamma is multifaceted, affecting almost every pathobiological pathway involved in the development of PAH simultaneously. We thereby hypothesize that PPAR gamma agonists may play a key role in reversing severe pulmonary angio-obliterative changes and promote microvascular regeneration which may substitute the need for heart-lung transplantation in such patients. PMID- 29432662 TI - Associations of overweight/obesity and socioeconomic status with hypertension prevalence across racial and ethnic groups. AB - Racial/ethnic disparities in the prevalence of diagnosed hypertension are persistent but may be partially explained by racial/ethnic differences in weight category and neighborhood socioeconomic status. The authors compared hypertension prevalence rates among 4 060 585 adults with overweight or obesity across 10 healthcare systems by weight category and neighborhood education level in geographically and racially diverse individuals. Data were obtained from electronic health records. Hypertension was defined as at least two outpatient visits or one inpatient hospitalization with a coded diagnosis. Logistic regression, adjusted for age, sex, and site, with two-way interactions between race/ethnicity and weight category or neighborhood education, was used to examine the association between hypertension and race/ethnicity, with whites as the reference. Results documented that odds ratios for hypertension prevalence were greater for blacks, American Indians/Alaskan Natives, Asians, and Native Hawaiians/other Pacific Islanders compared with whites and lower for Hispanics in similar weight categories and neighborhood education levels. Although two-way interactions were statistically significant, the magnitude of the odds of hypertension compared with whites did not substantially vary across weight or neighborhood education. Hypertension odds were almost double relative to whites for blacks and Native Hawaiians/other Pacific Islanders across most weight categories and all neighborhood education levels. Odds of hypertension were about 50% greater for Asians relative to whites across weight categories. Results suggest that other factors might be associated with racial/ethnic disparities in hypertension. More research is needed to understand the many factors that may contribute to variation in diagnosed hypertension across racial/ethnic groups with overweight or obesity. PMID- 29432663 TI - Transcutaneous bilirubinometry should be carried out in newborn infants at least seven hours after phototherapy finishes. PMID- 29432664 TI - The impact of cold ischemia time at the higher end of the KDPI spectrum: what is the risk? PMID- 29432665 TI - Post-transplant lymphoproliferative disorder prevention: new light on the horizon? PMID- 29432666 TI - Impact of rotavirus vaccination on rotavirus hospitalisation rates among a resource-limited rural population in Mbita, Western Kenya. AB - OBJECTIVES: A two-dose oral monovalent rotavirus vaccine (RV1) was introduced into the Kenyan National Immunization Program in July 2014. We assessed trends in hospitalisation for rotavirus-specific acute gastroenteritis (AGE) and strain distribution among children <5 years in a rural, resource-limited setting in Kenya before and after the nationwide implementation of the vaccine. METHODS: Data on rotavirus AGE and strain distribution were derived from a 5-year hospital based surveillance. We compared rotavirus-related hospitalisations and strain distribution in the 2-year post-vaccine period with the 3-year pre-vaccine baseline. Vaccine administrative data from the Unit of Vaccines and Immunization Services (UVIS) for Mbita sub-county were used to estimate rotavirus immunisation coverage in the study area. RESULTS: We observed a 48% (95% CI: 27-64%) overall decline in rotavirus-related hospitalisations among children aged <5 years in the post-vaccine period. Coverage with the last dose of rotavirus vaccine increased from 51% in year 1% to 72% in year 2 of the vaccine implementation. Concurrently, reductions in rotavirus hospitalisations increased from 40% in the first year to 53% in the second year of vaccine use. The reductions were most pronounced among the vaccine-eligible group, with the proportion of cases in this age group dropping to 14% in post-vaccine years from a high of 51% in the pre-vaccine period. A diversity of rotavirus strains circulated before the introduction of the vaccine with G1P[8] being the most dominant strain. G2P[4] replaced G1P[8] as the dominant strain after the vaccine was introduced. CONCLUSIONS: Rotavirus vaccination has resulted in a notable decline in hospital admissions for rotavirus infections in a rural resource-limited population in Kenya. This provides early evidence for continued use of rotavirus vaccines in routine childhood immunisations in Kenya. Our data also underscore the need for expanding coverage on second dose so as to maximise the impact of the vaccine. PMID- 29432667 TI - Highly Stable Aqueous Zinc-Ion Storage Using a Layered Calcium Vanadium Oxide Bronze Cathode. AB - Cost-effective aqueous rechargeable batteries are attractive alternatives to non aqueous cells for stationary grid energy storage. Among different aqueous cells, zinc-ion batteries (ZIBs), based on Zn2+ intercalation chemistry, stand out as they can employ high-capacity Zn metal as the anode material. Herein, we report a layered calcium vanadium oxide bronze as the cathode material for aqueous Zn batteries. For the storage of the Zn2+ ions in the aqueous electrolyte, we demonstrate that the calcium-based bronze structure can deliver a high capacity of 340 mA h g-1 at 0.2 C, good rate capability, and very long cycling life (96 % retention after 3000 cycles at 80 C). Further, we investigate the Zn2+ storage mechanism, and the corresponding electrochemical kinetics in this bronze cathode. Finally, we show that our Zn cell delivers an energy density of 267 W h kg-1 at a power density of 53.4 W kg-1 . PMID- 29432668 TI - Reply to: Correspondence regarding the impact of kidney transplantation on insulin sensitivity. PMID- 29432669 TI - Socio-economic gradients in prevalent tuberculosis in Zambia and the Western Cape of South Africa. AB - OBJECTIVE: To describe the associations between socio-economic position and prevalent tuberculosis in the 2010 ZAMSTAR Tuberculosis Prevalence Survey, one of the first large tuberculosis prevalence surveys in Southern Africa in the HIV era. METHODS: The main analyses used data on 34 446 individuals in Zambia and 30 017 individuals in South Africa with evaluable tuberculosis culture results. Logistic regression was used to estimate adjusted odds ratios for prevalent TB by two measures of socio-economic position: household wealth, derived from data on assets using principal components analysis, and individual educational attainment. Mediation analysis was used to evaluate potential mechanisms for the observed social gradients. RESULTS: The quartile with highest household wealth index in Zambia and South Africa had, respectively, 0.55 (95% CI 0.33-0.92) times and 0.70 (95% CI 0.54-0.93) times the adjusted odds of prevalent TB of the bottom quartile. College or university-educated individuals in Zambia and South Africa had, respectively, 0.25 (95% CI 0.12-0.54) and 0.42 (95% CI 0.25-0.70) times the adjusted odds of prevalent TB of individuals who had received only primary education. We found little evidence that these associations were mediated via several key proximal risk factors for TB, including HIV status. CONCLUSION: These data suggest that social determinants of TB remain important even in the context of generalised HIV epidemics. PMID- 29432670 TI - Formation of Multilayer Graphene Domains with Strong Sulfur-Carbon Interaction and Enhanced Sulfur Reduction Zones for Lithium-Sulfur Battery Cathodes. AB - A newly designed sulfur/graphene computational model emulates the electrochemical behavior of a Li-S battery cathode, promoting the S-C interaction through the edges of graphene sheets. A random mixture of eight-membered sulfur rings mixed with small graphene sheets is simulated at 64 wt %sulfur loading. Structural stabilization and sulfur reduction calculations are performed with classical reactive molecular dynamics. This methodology allowed the collective behavior of the sulfur and graphene structures to be accounted for. The sulfur encapsulation induces ring opening and the sulfur phase evolves into a distribution of small chain-like structures interacting with C through the graphene edges. This new arrangement of the sulfur phase not only leads to a less pronounced volume expansion during sulfur reduction but also to a different discharge voltage profile, in qualitative agreement with earlier reports on sulfur encapsulation in microporous carbon structures. The Li2 S phase grows around ensembles of parallel graphene nanosheets during sulfur reduction. No diffusion of sulfur or lithium between graphene nanosheets is observed, and extended Li2 S domains bridging the space between carbon ensembles are suppressed. The results emphasize the importance of morphology on the electrochemical performance of the composite material. The sulfur/graphene model outlined here provides new understanding of the graphene effects on the sulfur reduction behavior and the role that van der Waals interactions may play in promoting formation of multilayer graphene ensembles and small Li2 S domains during sulfur reduction. PMID- 29432671 TI - What Does the New Ontario Pharmacare Plan offer Children and Young Adults with Rare Disorders? AB - A publicly-funded pharmacare program (OHIP+) was announced in the 2017 Ontario budget for all children and young adults that will begin in January 2018 and cover drugs in the Ontario Public Drug Programs (OPDP) formulary. In this commentary, drugs indicated for rare disorders commonly occurring in childhood that were reviewed by the Common Drug Review (CDR) between 2004 and 2016 are examined to assess the Ontario reimbursement situation. OPDP reimburse few of these drugs and only about half of those covered are accessible with consistency and without onerous conditions. Providing reimbursement for rare disorder drugs that received a positive CDR recommendation would likely cost less than a quarter of OHIP+'s projected cost. Children who will benefit most from OHIP+ are those with common conditions whose parents do not presently have access to provincial or private insurance. Children with rare disorders deserve accessible provincial financial support for potentially life-transforming drugs. PMID- 29432672 TI - Development and Validation of an Index Score to Adjust for Healthy User Bias in Observational Studies. AB - BACKGROUND: Objectives: To develop a healthy user index to serve as a method of confounding adjustment in future observational studies of preventive therapies. METHODS: A large administrative database of patients with type 2 diabetes was split in half randomly, yielding derivation and validation cohorts. Influenza vaccination was used as a 'prototypical marker' of a healthy user. In our derivation cohort, we fitted a mixed effects logistic regression model, and a points-based system was used to construct the index. The healthy user index was then evaluated in the validation cohort. RESULTS: Overall, 13% had received the influenza vaccination. In the derivation cohort (n= 914 732), the healthy user index ranged from 0 to 91 with a mean of 41.6 (SD 12.9). When applied to the validation cohort (n= 913 231), the index ranged from 0 to 96 (mean 41.6, SD 12.9) and significantly predicted influenza vaccination with a c-statistic of 0.605, suggesting moderate discrimination ability. CONCLUSION: Our healthy user index combined age, sex and healthy behaviors to predict healthy users within administrative datasets. This index score may allow for better adjustment of healthy user bias in health services research; however, external validation is further required. Key Words: Administrative Data Uses, Bias, Biostatistical Methods, Observational Data. PMID- 29432673 TI - Anticounterfeiting Strategies of Local Drug Manufacturers in Lagos, Nigeria: Implications for Public Health. AB - BACKGROUND: Nigeria has been plagued by counterfeit and poor quality medicines with several studies indicating varying degree of prevalence. Thus, this study is aimed at determining the anticounterfeiting strategies employed by local drug manufacturers in Lagos-Nigeria. METHOD: The first phase was a descriptive study which involves the use of a self-administered closed ended structured questionnaire to assess the anticounterfeiting strategies employed by local manufacturers in Nigeria. The second phase was an experimental study which involves selection of two classes of most frequently faked drugs identified by the respondents in the first phase. The selected drugs were then subjected to spot checks using the truscan analysis deployed by NAFDAC to identify counterfeit medicine. Anticounterfeiting features on the samples were also examined. The data obtained from phase one were analyzed using SPSS and the data obtained from phase two were entered into the truscan data sheet and analyzed using Chi-squared and ANOVA. Results were considered to be significant at P-value <= 0.05. RESULTS: The outcome of the study showed that 83% and 78% of antimalarials drawn from the manufacturing sources and open market respectively passed the truscan spot checks. Similarly, 50% of antibiotics drawn from the two sampling sites passed the truscan checks. There was no significant difference (p >= 0.05) between the sampled antimalarials and antibiotics from the manufacturing sources and open market. CONCLUSION: The current rate of counterfeit medicines is relatively low. Strategies to encourage the use of combination of anticounterfeiting technologies by the manufacturers should be established. PMID- 29432674 TI - Shen-Kang protects against tacrolimus-induced renal injury. AB - Background/Aims: Evidence suggests that Shen-Kang (SK), a traditional Chinese herbal medicine, protects against various types of renal injury. In this study, we evaluated whether SK treatment confers renoprotection in a rat model of chronic tacrolimus (TAC) nephropathy. Methods: Rats were treated daily with TAC (1.5mg/kg, subcutaneously) and SK (450 mg/kg, intravenously) for 4 weeks. The effects of SK on TAC-induced renal injury were assessed by measuring renal function, urine albumin excretion, histopathology, inflammatory cell infiltration, expression of profibrotic (transforming growth factor beta1 [TGF beta1] and TGF-beta inducible gene-h3 [betaig-h3]) and proinflammatory cytokines, oxidative stress, and apoptotic cell death. Results: Administration of SK preserved glomerular integrity (fractional mesangial area and Wilms tumor 1 positive glomeruli), attenuated tubulointerstitial fibrosis, and reduced the number of ectodermal dysplasia 1-positive cells, and this was paralleled by improved urine albumin excretion and renal dysfunction. At the molecular level, SK treatment suppressed expression of TGF-beta1/Smad2/3, betaig-h3, and proinflammatory cytokines. Oxidative stress and apoptotic cell death were significantly decreased with SK treatment, and apoptosis-related genes were regulated toward cell survival (active caspase-3 and the B-cell lymphoma-2/Bcl2 associated X [Bcl-2/Bax] ratio). Conclusions: SK protects against TAC-induced renal injury. PMID- 29432675 TI - Linear Positional Isomer Sorting in Nonporous Adaptive Crystals of a Pillar[5]arene. AB - Here we show a new adsorptive separation approach using nonporous adaptive crystals of a pillar[5]arene. Desolvated perethylated pillar[5]arene crystals (EtP5alpha) with a nonporous character selectively adsorb 1-pentene (1-Pe) over its positional isomer 2-pentene (2-Pe), leading to a structural change from EtP5alpha to 1-Pe loaded structure (1-Pe@EtP5). The purity of 1-Pe reaches 98.7% in just one cycle and EtP5alpha can be reused without losing separation performance. PMID- 29432676 TI - Genistein: A Dual Inhibitor of Both Amyloid beta and Human Islet Amylin Peptides. AB - Abnormal misfolding and aggregation of amyloid peptides into amyloid fibrils are common and critical pathological events in many neurodegenerative diseases. Most inhibitors or drugs have been developed to prevent amyloid aggregation of a specific peptide, showing sequence-dependent inhibition mechanisms. It is more challenging to develop or discover inhibitors capable of preventing the aggregation of two or more different amyloid peptides. Genistein, a major phytoestrogen in soybean, has been widely used as an anti-inflammation and cerebrovascular drug due to its antioxidation and antiacetylcholinesterase effects. Herein, we examine the inhibitory effects of genistein on the aggregation of amyloid-beta (Abeta, associated with Alzheimer's disease) and human islet amylin (hIAPP, associated with type 2 diabetes) and Abeta- and hIAPP induced neurotoxicity using a combination of experimental and computational approaches. Collective experimental results from thioflavin T (ThT), atomic force microscopy (AFM), and circular dichroism (CD) demonstrate that genistein shows strong inhibition ability to prevent the conformational transition of both Abeta and hIAPP monomers to beta-sheet structures, thus reducing final amyloid fibrillization from Abeta and hIAPP monomer aggregation by 40-63%. Further 3-[4,5 dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and large unilamellar vesicle (LUV) assays show that genistein helps to increase cell viability, decrease cell apoptosis, and reduce cell membrane leakage, where the cell protection effect of genistein is likely correlated with its reduced membrane leakage. Comparative molecular dynamics (MD) simulations reveal that genistein prefers to bind the beta-sheet groove, a common structural motif of amyloid fibrils, of both Abeta and hIAPP oligomers to interfere with their self-aggregation. This work for the first time demonstrates genistein as a dual inhibitor of Abeta and hIAPP aggregation. Further structural optimization and refinement of genistein may generate a series of effective sequence-independent inhibitors against the aggregation and toxicity of different amyloid peptides. PMID- 29432677 TI - Multifunctional Biomaterial Coating Based on Bio-Inspired Polyphosphate and Lysozyme Supramolecular Nanofilm. AB - Current implant materials have widespread clinical applications together with some disadvantages, the majority of which are the ease with which infections are induced and difficulty in exhibiting biocompatibility. For the efficient improvement of their properties, the development of interface multifunctional modification in a simple, universal, and environmently benign approach becomes a critical challenge and has acquired the attention of numerous scientists. In this study, a lysozyme-polyphosphate composite coating was fabricated for titanium(Ti) based biomaterial to obtain a multifunctional surface. This coating was easily formed by sequentially soaking the substrate in reduced-lysozyme and polyphosphate solution. Such a composite coating has shown predominant antibacterial activity against Gram-negative bacteria ( E. coli) and improved cell adhesion, proliferation, and differentiation, which are much better than those of the pure substrate. This facile modification endows the biomaterial with anti-infective and potential bone-regenerative performance for clinical applications of biomaterial implants. PMID- 29432678 TI - Dynamics of the Interaction of RecG Protein with Stalled Replication Forks. AB - As a guardian of the bacterial genome, the RecG DNA helicase repairs DNA replication and rescues stalled replication. We applied atomic force microscopy (AFM) to directly visualize dynamics of RecG upon the interaction with replication fork substrates in the presence and absence of SSB using high-speed AFM. We directly visualized that RecG moves back and forth over dozens of base pairs in the presence of SSB. There is no RecG translocation in the absence of SSB. Computational modeling was performed to build models of Escherichia coli RecG in a free state and in complex with the fork. The simulations revealed the formation of complexes of RecG with the fork and identified conformational transitions that may be responsible for RecG remodeling that can facilitate RecG translocation along the DNA duplex. Such complexes do not form with the DNA duplex, which is in line with experimental data. Overall, our results provide mechanistic insights into the modes of interaction of RecG with the replication fork, suggesting a novel role of RecG in the repair of stalled DNA replication forks. PMID- 29432679 TI - Hypervalent Bonding in the OF(a4Sigma-), SF(a4Sigma-), SF5/SF6, and OSF4 Species. AB - Hypervalency has struggled the conventional wisdom of too many chemists for so many years. Numerous theories and bonding models have been introduced but the so called "hypervalency" mystery remains. We offer a simple and appealing explanation for the bonding mechanism of OF(a4Sigma-), SF(a4Sigma-), SF5/SF6, and OSF4 based solely on the fact that excited and/or ionic states of the constituent fragments may and actually do occur in the ground states of so many "every day" molecules. In particular, and through multireference methods, we have found that the bonding in all the studied species is ionic in nature, perhaps contrary to the present status of our chemical beliefs. Although the "atoms in molecules" hypothesis is certainly not the only way to explain the formation of the chemical bond, we strongly believe that it is the simplest and most economical conceptual principle that should guide our chemical thinking. PMID- 29432681 TI - Pharming for Genes in Neurotransmission: Combining Chemical and Genetic Approaches in Caenorhabditis elegans. AB - Synaptic transmission is central to nervous system function. Chemical and genetic screens are valuable approaches to probe synaptic mechanisms in living animals. The nematode Caenorhabditis elegans is a prime system to apply these methods to discover genes and dissect the cellular pathways underlying neurotransmission. Here, we review key approaches to understand neurotransmission and the action of psychiatric drugs in C. elegans. We start with early studies on cholinergic excitatory signaling at the neuromuscular junction, and move into mechanisms mediated by biogenic amines. Finally, we discuss emerging work toward understanding the mechanisms driving synaptic plasticity with a focus on regulation of protein translation. PMID- 29432680 TI - Unified Total Synthesis of Pyrroloazocine Indole Alkaloids Sheds Light on Their Biosynthetic Relationship. AB - The total synthesis of seven members of the lapidilectine and grandilodine family of alkaloids has been accomplished in racemic and enantiopure form without protection/deprotection of functional groups. The two key steps, an 8- endo-dig hydroarylation and a 6- exo-trig photoredox cyclization, were catalyzed using gold. A rationale for the formation of the cyclopropane ring of the lundurines is also provided. PMID- 29432682 TI - Kinetically Controlled Formation and Decomposition of Metastable [(BiSe)1+delta] m[TiSe2] m Compounds. AB - Preparing homologous series of compounds allows chemists to rapidly discover new compounds with predictable structure and properties. Synthesizing compounds within such a series involves navigating a free energy landscape defined by the interactions within and between constituent atoms. Historically, synthesis approaches are typically limited to forming only the most thermodynamically stable compound under the reaction conditions. Presented here is the synthesis, via self-assembly of designed precursors, of isocompositional incommensurate layered compounds [(BiSe)1+delta] m[TiSe2] m with m = 1, 2, and 3. The structure of the BiSe bilayer in the m = 1 compound is not that of the binary compound, and this is the first example of compounds where a BiSe layer thicker than a bilayer in heterostructures has been prepared. Specular and in-plane X-ray diffraction combined with high-resolution electron microscopy data was used to follow the formation of the compounds during low-temperature annealing and the subsequent decomposition of the m = 2 and 3 compounds into [(BiSe)1+delta]1[TiSe2]1 at elevated temperatures. These results show that the structure of the precursor can be used to control reaction kinetics, enabling the synthesis of kinetically stable compounds that are not accessible via traditional techniques. The data collected as a function of temperature and time enabled us to schematically construct the topology of the free energy landscape about the local free energy minima for each of the products. PMID- 29432683 TI - Isotope Fractionation in Biogas Allows Direct Microbial Community Stability Monitoring in Anaerobic Digestion. AB - Process monitoring of anaerobic digestion is typically based on operational parameters, such as pH and volatile fatty acid concentration, that are lagging on actual microbial community performance. In this study, 13C isotope fractionation in CH4 and CO2 in the biogas was used to monitor process stability of anaerobic digestion in response to salt stress. A gradual and pulsed increase in salt concentration resulted in a decrease in methane production. No clear shift in delta13CH4 was observed in response to the gradual increase in salt concentration, and delta13CO2 of the biogas showed only a clear shift after process failure, compared with the control. In contrast, both delta13CH4 and delta13CO2 in the biogas changed in response to the pulsed increase in salt concentration. This change preceded the decrease in methane production. A significantly different bacterial and archaeal community profile was observed between the DNA and RNA level, which was also reflected in a different relation with the delta13CH4 and delta13CO2 values. This shows that isotope fractionation in the biogas can predict process stability in anaerobic digestion, as it directly reflects shifts in the total and active microbial community, yet, due to its temporal character, further validation is needed. PMID- 29432684 TI - Highly Stretchable and Wearable Strain Sensor Based on Printable Carbon Nanotube Layers/Polydimethylsiloxane Composites with Adjustable Sensitivity. AB - Strain sensors that are capable of monitoring complex human motions with high accuracy are highly desirable for developing wearable electronics. This paper reports the fabrication of highly stretchable and sensitive multidirectional strain sensors with tunable strain gauge factors by employing a digitally controlled printer to incorporate carbon nanotube (CNT) layers into polydimethylsiloxane (PDMS) substrates. The fabricated sensors exhibit a high stretchability (up to 45%) and sensitivity with a gauge factor of 35.75. The gauge factors could be easily modulated by tuning the number of CNT printing cycles to accommodate diverse requirements. The cyclic loading-unloading test results revealed that the composite strain sensors exhibited excellent long-term durability. Particularly, in this work, for the first time, human-motion-induced strain was measured by a motion capture system and compared with the strain data obtained from the fabricated strain sensors. The deviation of strains measured by composite sensors is less than 20%, indicating the great accuracy of CNT/PDMS sensors to quantify the amount of motion-induced strain. Of significant importance is that due to the flexibility of the printing technique used, rosette type sensors were fabricated to simultaneously measure strains along multiple axes. These superior sensing capabilities of the fabricated CNT/PDMS strain sensors give them great application potential in motion-detecting systems. PMID- 29432685 TI - Tetracyanomethane under Pressure: Extended CN Polymers from Precursors with Built in sp3 Centers. AB - Tetracyanomethane, C(CN)4, is a tetrahedral molecule containing a central sp3 carbon that is coordinated by reactive nitrile groups that could potentially transform to an extended CN network with a significant fraction of sp3 carbon. High-purity C(CN)4 was synthesized, and its physiochemical behavior was studied using in situ synchrotron angle-dispersive powder X-ray diffraction (PXRD) and Raman and infrared (IR) spectroscopies in a diamond anvil cell (DAC) up to 21 GPa. The pressure dependence of the fundamental vibrational modes associated with the molecular solid was determined, and some low-frequency Raman modes are reported for the first time. Crystalline molecular C(CN)4 starts to polymerize above ~7 GPa and transforms into an interconnected disordered network, which is recoverable to ambient conditions. The results demonstrate feasibility for the pressure-induced polymerization of molecules with premeditated functionality. PMID- 29432686 TI - Single-Site Active Iron-Based Bifunctional Oxygen Catalyst for a Compressible and Rechargeable Zinc-Air Battery. AB - The exploitation of a high-efficient, low-cost, and stable non-noble-metal-based catalyst with oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) simultaneously, as air electrode material for a rechargeable zinc-air battery is significantly crucial. Meanwhile, the compressible flexibility of a battery is the prerequisite of wearable or/and portable electronics. Herein, we present a strategy via single-site dispersion of an Fe-Nx species on a two-dimensional (2D) highly graphitic porous nitrogen-doped carbon layer to implement superior catalytic activity toward ORR/OER (with a half-wave potential of 0.86 V for ORR and an overpotential of 390 mV at 10 mA.cm-2 for OER) in an alkaline medium. Furthermore, an elastic polyacrylamide hydrogel based electrolyte with the capability to retain great elasticity even under a highly corrosive alkaline environment is utilized to develop a solid-state compressible and rechargeable zinc-air battery. The creatively developed battery has a low charge-discharge voltage gap (0.78 V at 5 mA.cm-2) and large power density (118 mW.cm-2). It could be compressed up to 54% strain and bent up to 90 degrees without charge/discharge performance and output power degradation. Our results reveal that single-site dispersion of catalytic active sites on a porous support for a bifunctional oxygen catalyst as cathode integrating a specially designed elastic electrolyte is a feasible strategy for fabricating efficient compressible and rechargeable zinc-air batteries, which could enlighten the design and development of other functional electronic devices. PMID- 29432687 TI - Hexagonal Boron Nitride: The Thinnest Insulating Barrier to Microbial Corrosion. AB - We report the use of a single layer of two-dimensional hexagonal boron nitride (SL-hBN) as the thinnest insulating barrier to microbial corrosion induced by the sulfate-reducing bacteria Desulfovibrio alaskensis G20. We used electrochemical methods to assess the corrosion resistance of SL-hBN on copper against the effects of both the planktonic and sessile forms of the sulfate-reducing bacteria. Cyclic voltammetry results show that SL-hBN-Cu is effective in suppressing corrosion effects of the planktonic cells at potentials as high as 0.2 V ( vs Ag/AgCl). The peak anodic current for the SL-hBN coatings is ~36 times lower than that of bare Cu. Linear polarization resistance tests confirm that the SL-hBN coatings serve as a barrier against corrosive effects of the G20 biofilm when compared to bare Cu. The SL-hBN serves as an impermeable barrier to aggressive metabolites and offers ~91% corrosion inhibition efficiency, which is comparable to much thicker commercial coatings such as polyaniline. In addition to impermeability, the insulating nature of SL-hBN suppresses galvanic effects and improves its ability to combat microbial corrosion. PMID- 29432688 TI - Thermally Induced Structural Evolution of Silicon- and Oxygen-Containing Hydrogenated Amorphous Carbon: A Combined Spectroscopic and Molecular Dynamics Simulation Investigation. AB - Silicon- and oxygen-containing hydrogenated amorphous carbon (a-C:H:Si:O) coatings are amorphous thin-film materials composed of hydrogenated amorphous carbon (a-C:H), doped with silicon and oxygen. Compared to a-C:H, a-C:H:Si:O exhibits much lower susceptibility to oxidative degradation and higher thermal stability, making a-C:H:Si:O attractive for many applications. However, the physical mechanisms for this improved behavior are not understood. Here, the thermally induced structural evolution of a-C:H:Si:O was investigated in situ by X-ray photoelectron and absorption spectroscopy, as well as molecular dynamics (MD) simulations. The spectroscopy results indicate that upon high vacuum annealing, two thermally activated processes with a Gaussian distribution of activation energies with mean value E and standard deviation sigma take place in a-C:H:Si:O: (a) ordering and clustering of sp2 carbon ( E +/- sigma = 0.22 +/- 0.08 eV) and (b) conversion of sp3- to sp2-bonded carbon ( E +/- sigma = 3.0 +/- 1.1 eV). The experimental results are in qualitative agreement with the outcomes of MD simulations performed using a ReaxFF potential. The MD simulations also indicate that the higher thermal stability of a-C:H:Si:O compared to a-C:H (with similar fraction of sp2-bonded carbon and hydrogen content) derives from the significantly lower fraction of strained carbon-carbon sp3 bonds in a-C:H:Si:O compared to a-C:H, which are more likely to break at elevated temperatures. PMID- 29432689 TI - Influence of Parabens on Bacteria and Fungi Cellular Membranes: Studies in Model Two-Dimensional Lipid Systems. AB - Langmuir monolayers were used to study the influence of four commercially applied parabens on multicomponent systems composed of lipid species characteristic of the cellular membrane of microorganisms found in carbohydrates and proteins reaching products, including food and cosmetics. The aim of the undertaken studies was to shed new light on the problem of parabens' interactions with membrane lipids and their affinity for monolayers differing with regard to the composition, mutual lipid ratios, and physicochemical properties. The discussion is based on the pi-A isotherm characteristics, surface morphology observation performed with BAM, and analysis of the diffraction data collected for the periodically ordered lipid domains present in the investigated multicomponent films. Our studies revealed that the selected parabens are capable of surface film modification and that the magnitude of this effect increases with the number of methylene groups in the ester part of paraben molecules. We found that the strongest destructive effect was observed for model 1 (Staphylococcus aureus), a lower effect was observed for model 2 (Pseudomonas aeruginosa), and the lowest effect was observed for model 3 (Candida albicans). It was inferred that such a trend appears due to the composition of the artificial membranes, i.e., above all, in the presence or lack of sterol molecules and the content of negatively charged lipids. PMID- 29432690 TI - Sequential DNA Binding and Dimerization Processes of the Photosensory Protein EL222. AB - EL222 is a blue light sensor protein, which consists of a light-oxygen-voltage domain as a light sensor and a LuxR-type helix-turn-helix DNA-binding domain. The reaction dynamics of the protein-DNA binding were observed for the first time using the time-resolved transient grating method. The reaction scheme was determined, showing that photoexcited EL222 first binds DNA and the ground state EL222 monomer is subsequently associated with the complex. Rate constants on the millisecond scale were determined for these processes. In addition, binding rates for EL222 with three DNA sequences, with different binding affinities, were measured. Although EL222 binds nonspecific DNA sequences with affinities at least 5-fold lower than the target sequence affinity, the binding rates were almost the same as that for the target DNA. This observation indicates that the specific and nonspecific binding affinities are mainly controlled by differences in the dissociation of DNA binding. PMID- 29432691 TI - Monomeric and Dimeric 68Ga-Labeled Bombesin Analogues for Positron Emission Tomography (PET) Imaging of Tumors Expressing Gastrin-Releasing Peptide Receptors (GRPrs). AB - The GRPr, highly expressed in prostate PCa and breast cancer BCa, is a promising target for the development of new PET radiotracers. The chelator HBED-CC ( N, N' bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine- N, N'-diacetic acid) was coupled to the bombesin peptides: HBED-C-BN(2-14) 1, HBED-CC-PEG2-[d-Tyr6,beta Ala11,Thi13,Nle14]-BN(6-14) 2, HBED-CC-Y-[d-Phe6,Sta13,Leu14]-BN(6-14) (Y = 4 amino-1-carboxymethylpiperidine) 3, and HBED-CC-{PEG2-Y-[d-Phe6,Sta13,Leu14]-BN(6 14)}2 4 (homodimer). Compounds 1-4 presented high binding affinities for GRPr (T47D, 0.56-3.51 nM; PC-3, 2.12-4.68 nM). In PC-3 and T47D cells, agonists [68Ga]1 and [68Ga]2 were mainly internalized while antagonists [68Ga]3 and [68Ga]4 were surface bound. Cell-related radioactivity reached a maximum after 45 min, while tracer levels followed GRPr expression (PC-3 > T47D > LNCaP > MDA-MB 231). [68Ga]4 showed the highest cell-bound radioactivity (PC-3 and T47D). In vivo, tumor (PC-3) targeting for [68Ga]3 and [68Ga]4 increased over time, with dynamic MUPET showing clearer tumors images at later time points. [68Ga]3 and [68Ga]4 can be considered suitable PET tracers for imaging PCa and BCa expressing GRPr. PMID- 29432692 TI - Activation of Persulfate by Nanosized Zero-Valent Iron (NZVI): Mechanisms and Transformation Products of NZVI. AB - The mechanisms involved in the activation of persulfate by nanosized zero-valent iron (NZVI) were elucidated and the NZVI transformation products identified. Two distinct reaction stages, in terms of the kinetics and radical formation mechanism, were found when phenol was oxidized by the persulfate/NZVI system. In the initial stage, lasting 10 min, Fe0(s) was consumed rapidly and sulfate radicals were produced through activation by aqueous Fe2+. The second stage was governed by Fe catalyzed activation in the presence of aqueous Fe3+ and iron (oxyhydr)oxides in the NZVI shells. The second stage was 3 orders of magnitude slower than the initial stage. An electron balance showed that the sulfate radical yield per mole of persulfate was more than two times higher in the persulfate/NZVI system than in the persulfate/Fe2+ system. Radicals were believed to be produced more efficiently in the persulfate/NZVI system because aqueous Fe2+ was supplied slowly, preventing sulfate radicals being scavenged by excess aqueous Fe2+. In the second stage, the multilayered shell conducted electrons, and magnetite in the shell provided electrons for the activation of persulfate. Iron speciation analysis (including X-ray absorption spectroscopy) results indicated that a shrinking core/growing shell model explained NZVI transformation during the persulfate/NZVI process. PMID- 29432693 TI - Novel Supramolecular Nanoparticles Derived from Cucurbit[7]uril and Zwitterionic Surfactants. AB - Binding constants, log K ~ 6.6 M-1, and NMR characterization of the complexes formed by sulfobetaines and cucurbit[7]uril (CB7) support the electrostatic interaction as the major driving force. This very strong binding motif is cross linked by additional CB7 molecules, resulting in the formation of supramolecular nanoparticles (SNPs) with an average diameter of 172 nm and a negative surface potential. The time course evolution of the particle size and the surface potential suggests the very fast formation of an amorphous aggregate that absorbs an additional amount of sulfobetaine. These aggregates afford very stable (more than 2 weeks) nanoparticles in an aqueous dispersion. The reversibility of the sulfobetaine/CB7 host/guest complexes allows SNP disaggregation by adding a competitive guest as shown by treatment with tetraethylammonium chloride. The addition of this competitive cation triggers a SNP-to-micelle transition. The potential application of these nanoparticles as drug delivery vehicles was investigated by using carboxyfluorescein. These experiments revealed that upon externally induced disruption of the SNPs (by tetraethylammonium chloride) the fluorescent dye was trapped in micellar aggregates that can be further disrupted by cyclodextrin addition. PMID- 29432694 TI - Ultrafast Four-Dimensional Coherent Spectroscopy by Projection Reconstruction. AB - Multidimensional coherent spectroscopy provides insights into the vibronic structure and dynamics of complex systems. In general, the higher the dimensionality, the better the spectral discrimination and the more information that may be extracted about the system. A major impediment to widespread implementation of these methods, however, is that the acquisition time generally increases exponentially with dimensionality, prohibiting practical implementation. We demonstrate the use of nonuniform sampling based on the projection-slice theorem and inverse Radon transform within the context of a fifth-order, 4D technique (GAMERS) designed to correlate the vibrational contributions to different electronic states. Projection-reconstruction (PRO GAMERS) greatly reduces the data sampling requirements without sacrificing frequency resolution. The sensitivity of this technique is demonstrated to surpass conventional uniform sampling by orders of magnitude. The incorporation of projection-reconstruction into multidimensional coherent spectroscopy opens up the possibility to study the structure of complex chemical, biological, and physical systems with unprecedented detail. PMID- 29432695 TI - Single-Step In Situ Assembling Routes for the Shape Control of Polymer Nanoparticles. AB - Controlling shapes of polymer nanoparticles via single-step process is a challenge due to their amorphous chemical nature. Precise regulation of interfacial interactions, electrical charging and reaction dynamics during ongoing polymerization process provides an environment where uniform nucleation, growth and in situ assembling can be realized, and hence nanoparticles of complex shapes can be obtained. In this work, it is investigated how in situ assembling of the growing nanoparticles succeeds and specifically in different manners by using cationic, anionic, polyionic, and nonionic surface-active agents in a time dependent blended form. Micelle of molecular surfactants leads the spheres, but long chained polyelectrolytes support in situ assembling of growing spheres to form the nonspherical polymer nanoparticles in order to minimize the surface energy of a system. Similarly, a nonionic polymer promotes the movement of growing species in solution and allows tunable aggregation-based growth which produces more complexed nanoparticles. Furthermore, the application of acid, base and salt solution also contribute specific effect where unexpected size and shape of nanoparticles can be obtained. Overall, the roles of limited polarizability, solvation power, mobility, ionic strength, pH, and microfluidics for the synthesis of various shape-controlled polymer nanoparticles are presented here. PMID- 29432696 TI - Electrophile-Dependent Alkylations of Lithiated 4-Alkoxyalk-4-enenitriles. AB - Alkylations of acyclic, lithiated 4-alkoxyalk-4-enenitriles are highly diastereoselective with an unusual electrophile-dependent preference. Alkyl halides, sulfur, chlorine, and acyl cyanide electrophiles intercept a series of lithiated 4-alkoxyalk-4-enenitriles to install contiguous tertiary-quaternary stereocenters with high diastereoselectivity, whereas acylations with ester and carbonate electrophiles are modestly selective. The diastereoselectivity is consistent with electrophilic attack on the most accessible face of the lithated nitrile for most electrophiles except ester and carbonate electrophiles, which likely precoordinate the lithiated nitrile before acylation. Intercepting the lithiated 4-alkoxyalk-4-enenitriles with a range of electrophiles provide insight into the criteria for otherwise challenging diastereoselective alkylations and acylations of acyclic nitriles. PMID- 29432697 TI - The importance of increasing exercise capacity during cardiac rehabilitation in heart failure: Optimising training to optimise prognosis. PMID- 29432698 TI - Long-term depression induced by endogenous cannabinoids produces neuroprotection via astroglial CB1R after stroke in rodents. AB - Ischemia not only activates cell death pathways but also triggers endogenous protective mechanisms. However, it is largely unknown what is the essence of the endogenous neuroprotective mechanisms induced by preconditioning. In this study we demonstrated that systemic injection of JZL195, a selective inhibitor of eCB clearance enzymes, induces in vivo long-term depression at CA3-CA1 synapses and at PrL-NAc synapses produces neuroprotection. JZL195-elicited long-term depression is blocked by AM281, the antagonist of cannabinoid 1 receptor (CB1R) and is abolished in mice lacking cannabinoid CB1 receptor (CB1R) in astroglial cells, but is conserved in mice lacking CB1R in glutamatergic or GABAergic neurons. Blocking the glutamate NMDA receptor and the synaptic trafficking of glutamate AMPA receptor abolishes both long-term depression and neuroprotection induced by JZL195. Mice lacking CB1R in astroglia show decreased neuronal death following cerebral ischemia. Thus, an acute elevation of extracellular eCB following eCB clearance inhibition results in neuroprotection through long-term depression induction after sequential activation of astroglial CB1R and postsynaptic glutamate receptors. PMID- 29432699 TI - Population genomics of sorghum (Sorghum bicolor) across diverse agroclimatic zones of Niger. AB - Improving adaptation of staple crops in developing countries is important to ensure food security. In the West African country of Niger, the staple crop sorghum (Sorghum bicolor) is cultivated across diverse agroclimatic zones, but the genetic basis of local adaptation has not been described. The objectives of this study were to characterize the genomic diversity of sorghum from Niger and to identify genomic regions conferring local adaptation to agroclimatic zones and farmer preferences. We analyzed 516 Nigerien accessions for which local variety name, botanical race, and geographic origin were known. We discovered 144 299 single nucleotide polymorphisms (SNPs) using genotyping-by-sequencing (GBS). We performed discriminant analysis of principal components (DAPC), which identified six genetic groups, and performed a genome scan for loci with high discriminant loadings. The highest discriminant coefficients were on chromosome 9, near the putative ortholog of maize flowering time adaptation gene Vgt1. Next, we characterized differentiation among local varieties and used a genome scan of pairwise FST values to identify SNPs associated with specific local varieties. Comparison of varieties named for light- versus dark-grain identified differentiation near Tannin1, the major gene responsible for grain tannins. These findings could facilitate genomics-assisted breeding of locally adapted and farmer-preferred sorghum varieties for Niger. PMID- 29432700 TI - Relationship between diverticulosis and nonalcoholic fatty liver disease in elderly patients. AB - Objective To compare clinical and laboratory features of elderly patients with and without diverticulosis and assess factors related to hepatosteatosis. Method This retrospective case-control study analysed the clinical and laboratory data, colonoscopy and abdominal ultrasonography records of patients >65 years who underwent colonoscopies. Subjects were categorized according to the presence and absence of colonic diverticulosis. Univariate/multivariate logistic regression analyses were performed to evaluate the independent predictive factors of hepatosteatosis. Results A total of 355 patients were enrolled in the study: 169 had colonic diverticulosis; and 186 without colonic diverticulosis formed the control group. Age, sex and chronic disorders associated with the metabolic syndrome did not differ between the diverticulosis and control groups. The rate of hepatosteatosis was lower in patients with diverticulosis compared with the control group (27% versus 42%, respectively). Diabetes mellitus, hyperlipidaemia and hepatosteatosis were more common among patients aged <75 years. In the multivariate logistic regression analysis, diverticulosis remained an independent predictor of hepatosteatosis (odds ratio 0.529; 95% confidence interval 0.323, 0.866). Other independent predictive factors in the multivariate analysis were triglyceride and albumin. Conclusion Diverticulosis in the elderly was found to be a negative predictor of hepatosteatosis. Higher values of albumin and triglyceride in conjunction with the absence of diverticulosis may be suggestive of nonalcoholic fatty liver disease in the elderly. PMID- 29432701 TI - Plasticity of Light-induced Concurrent Glutamatergic and GABAergic Quantal Events in the Suprachiasmatic Nucleus. AB - Neurons in the suprachiasmatic nucleus (SCN) exhibit circadian variation in their neuronal activities. Here, we show that their input synapses undergo daily regulation. We discovered daily variation in the frequencies, but not the peak amplitudes, of miniature postsynaptic currents (mPSCs) for both glutamatergic and GABAergic synapses. In addition, the changes in the frequencies of mPSCs from glutamatergic and GABAergic synapses were antiphasic: An increase in the glutamatergic mPSC frequency and a decrease in the GABAergic mPSC frequency co occurred during the dark phase of the light-dark cycle. Through optogenetic stimulation of presynaptic glutamatergic axonal terminals, we demonstrated that the elicited quantal size glutamatergic PSC could evoke action potentials in postsynaptic SCN neurons with higher probability during the light phase than during the dark phase. To investigate whether the intrinsic clock or the light dark cycle mediates the daily rhythm of input synapses, we examined the mPSCs under light masking and skeleton photoperiod schemes. A prolonged light pulse (3 h) at the beginning of the subjective night suppressed the changes in mPSCs frequencies for both glutamatergic and GABAergic synapses; under the skeleton photoperiod, no significant differences were observed in mPSCs frequencies between the subjective day and night. Furthermore, we discovered that the plasticity of these concurrent quantal events occurred primarily in vasoactive intestinal peptide (VIP) neurons. This work provides evidence for light-dependent synaptic plasticity at glutamatergic and GABAergic input synapses of ventral SCN neurons. This concurrent synaptic plasticity could serve as one mechanism for regulating the responsiveness of SCN neurons to the wide range of light input over the day and night. PMID- 29432703 TI - Factors Influencing Southeastern U.S. Mothers' Participation in Baby-Friendly Practices: A Mixed-Methods Study. AB - BACKGROUND: Mothers in the southeastern United States, including rural-dwelling and African American mothers, have historically had low rates of breastfeeding; however, no studies have investigated these mothers' experiences of breastfeeding support processes associated with the Baby-Friendly Hospital Initiative. Research aim: This study aimed to determine factors influencing southeastern U.S. mothers' participation in Baby-Friendly practices and breastfeeding decisions. METHODS: Using a convergent parallel mixed-methods design, medical record review of mother infant dyads ( n = 234) provided data to determine if those who participated in more than half of the Ten Steps to Successful Breastfeeding had improved breastfeeding outcomes. Logistic regression was conducted to determine whether maternal demographic/clinical characteristics were predictive of Baby-Friendly practice participation. Qualitative methods included in-depth interviews ( n = 16). Directed content analysis was conducted to identify themes. Results of the analysis of the two data sets were triangulated to enhance understanding of mothers' barriers to and facilitators of participation in Baby-Friendly practices. RESULTS: Rural-dwelling and African American mothers had greater odds of nonparticipation in Baby-Friendly practices relative to other groups (odds ratios = 5 and 10, respectively; p <= .01). Mothers who received lactation consultation and had moderate (15-44 min) or completed (>= 45 min) skin-to-skin contact had greater odds of participation in Baby-Friendly practices (both odds ratios >= 17.5; p < .05). Directed content analysis revealed six themes: maternal desire to breastfeed, infant state, maternal state, milk supply concerns, provider support, and access to breastfeeding equipment and support services. CONCLUSION: Rural-dwelling African American mothers had limited knowledge of Baby Friendly practices; however, culturally tailored services could improve Baby Friendly practice participation and breastfeeding success. PMID- 29432704 TI - Clinicopathological features and comorbidities of cats with mild, moderate or severe hyperthyroidism: a radioiodine referral population. AB - OBJECTIVES: This study sought to explore the clinicopathological features and comorbidities of cats with mild, moderate and severe hyperthyroidism in a radioiodine referral population. METHODS: Medical records were reviewed, along with results of serum biochemistry, urinalysis, systolic blood pressure and diagnostic imaging performed at the time of radioiodine referral. Cats were grouped by total thyroxine (TT4) levels as mildly (TT4 60.1-124.9 nmol/l), moderately (TT4 125-250 nmol/l) or severely (TT4 >250 nmol/l) hyperthyroid at the time of diagnosis and referral. RESULTS: Thirty percent (42/140) of the cats were <10 years old at diagnosis. In 24.3% (34/140), hyperthyroidism was diagnosed incidentally. The time between diagnosis and referral for radioiodine was significantly longer in cats with severe hyperthyroidism at the time of referral ( P = 0.004). An increase in severity group between the time of diagnosis and referral occurred in 38.6% (54/140) of cats. At referral, 54.3% (25/46) of cats with mild, 66.7% (42/63) with moderate and 80.6% (25/31) with severe hyperthyroidism were unstable despite ongoing medical or dietary management. The prevalence of cardiac abnormalities was significantly increased in cats with severe hyperthyroidism ( P = 0.014) compared with those with mild or moderate hyperthyroidism. There was no significant difference in the likelihood of renal disease ( P = 0.708) or hypertension ( P = 0.328) between the groups. CONCLUSIONS AND RELEVANCE: Incidental diagnosis of hyperthyroidism occurs commonly, potentially owing to increased disease screening. Cats with severe hyperthyroidism at referral were more likely to be chronically hyperthyroid with a history of poor stabilisation. This subset of patients was significantly more likely to have cardiac abnormalities. Thyrotoxic cardiomyopathy may ultimately affect patient suitability for curative treatments (radioiodine or thyroidectomy) owing to higher anaesthetic risks and potential for decompensation into congestive heart failure with the stress of travel and hospitalisation. Curative therapy should be considered before the development of severe hyperthyroidism. PMID- 29432705 TI - Lay Patient Navigators' Perspectives of Barriers, Facilitators and Training Needs in Initiating Advance Care Planning Conversations With Older Patients With Cancer. AB - CONTEXT: Respecting Choices is an evidence-based model of facilitating advance care planning (ACP) conversations between health-care professionals and patients. However, the effectiveness of whether lay patient navigators can successfully initiate Respecting Choices ACP conversations is unknown. As part of a large demonstration project (Patient Care Connect [PCC]), a cohort of lay patient navigators underwent Respecting Choices training and were tasked to initiate ACP conversations with Medicare beneficiaries diagnosed with cancer. OBJECTIVES: This article explores PCC lay navigators' perceived barriers and facilitators in initiating Respecting Choices ACP conversations with older patients with cancer in order to inform implementation enhancements to lay navigator-facilitated ACP. METHODS: Twenty-six lay navigators from 11 PCC cancer centers in 4 states (Alabama, George, Tennessee, and Florida) completed in-depth, one-on-one semistructured interviews between June 2015 and August 2015. Data were analyzed using a thematic analysis approach. RESULTS: This evaluation identifies 3 levels patient, lay navigator, and organizational factors in addition to training needs that influence ACP implementation. Key facilitators included physician buy-in, patient readiness, and navigators' prior experience with end-of-life decision making. Lay navigators' perceived challenges to initiating ACP conversations included timing of the conversation and social and personal taboos about discussing dying. CONCLUSION: Our results suggest that further training and health system support are needed for lay navigators playing a vital role in improving the implementation of ACP among older patients with cancer. The lived expertise of lay navigators along with flexible longitudinal relationships with patients and caregivers may uniquely position this workforce to promote ACP. PMID- 29432706 TI - "People don't understand what goes on in here": A consensual qualitative research analysis of inmate-caregiver perspectives on prison-based end-of-life care. AB - BACKGROUND: The age demographic of the incarcerated is quickly shifting from young to old. Correctional facilities are responsible for navigating inmate access to healthcare; currently, there is no standardization for access to end-of life care. There is growing research support for prison-based end-of-life care programs that incorporate inmate peer caregivers as a way to meet the needs of the elderly and dying who are incarcerated. AIM: This project aims to (a) describe a prison-based end-of-life program utilizing inmate peer caregivers, (b) identify inmate-caregiver motivations for participation, and (c) analyze the role of building trust and meaningful relationships within the correctional end-of life care setting. DESIGN: A total of 22 semi-structured interviews were conducted with inmate-caregivers. Data were analyzed using Consensual Qualitative Research methodology. SETTING/PARTICIPANTS: All inmate-caregivers currently participating in the end-of-life peer care program at Briarcliff Correctional Facility were given the opportunity to participate. All participants were male, over the age of 18, and also incarcerated at Briarcliff Correctional Facility, a maximum security, state-level correctional facility. RESULTS: In total, five over arching and distinct domains emerged; this manuscript focuses on the following three: (a) program description, (b) motivation, and (c) connections with others. CONCLUSION: Findings suggest that inmate-caregivers believe they provide a unique and necessary adaptation to prison-based end-of-life care resulting in multilevel benefits. These additional perceived benefits go beyond a marginalized group gaining access to patient-centered end-of-life care and include potential inmate caregiver rehabilitation, correctional medical staff feeling supported, and correctional facilities meeting end-of-life care mandates. Additional research is imperative to work toward greater standardization of and access to end-of-life care for the incarcerated. PMID- 29432707 TI - Personalised and population healthcare for higher value. PMID- 29432708 TI - Diagnostic accuracy of the postexercise ankle-brachial index for detecting peripheral artery disease in suspected claudicants with and without diabetes. AB - The postexercise ankle-brachial index (ABI) is recommended in patients with normal resting ABI when peripheral artery disease (PAD) is suspected. The aims of this study were to determine the comparative diagnostic accuracy of the resting and postexercise ABI for detecting PAD, and, the effect of the presence of diabetes on these. Three methods of interpretation currently in use were also investigated: a reduction in postexercise ABI by >20% compared to resting ABI, an ABI value of <=0.90 postexercise, or a reduction in systolic ankle pressure of >30 mmHg postexercise. This retrospective study used colour duplex ultrasound (CDU) as the reference standard. In 278 limbs (whole group), the resting ABI had an overall area under the curve (AUC) of 0.71, with the postexercise ABI yielding a similar diagnostic accuracy of AUC 0.72. In the non-diabetes group ( n=171), the resting ABI had an overall AUC of 0.74 and the postexercise ABI had a similar AUC of 0.76. In the diabetes group ( n=107), overall accuracy was reduced compared to the non-diabetes group, with the resting ABI having an overall AUC of 0.65 and the postexercise ABI yielding a similar accuracy with an AUC of 0.64. The overall diagnostic accuracy of the postexercise ABI for diagnosing PAD was not greatly improved compared to resting ABI. Given the lower overall diagnostic accuracy in the diabetes group, both the resting and the postexercise ABI results in diabetes populations should be interpreted with caution. There is a risk of undiagnosed disease if relying on these results alone to determine lower limb vascular status. PMID- 29432709 TI - Neprilysin inhibition and endothelin-1 elevation: Focus on the kidney. AB - Increasing the degree of renin-angiotensin system (RAS) blockade by combining >=2 RAS blockers marginally increases efficacy, but results in more side effects. Hence, interference with other systems is currently being investigated, like potentiation of natriuretic peptides with neprilysin inhibitors. However, the neprilysin inhibitor thiorphan was recently found to increase endothelin-1 when administered to TGR(mREN2)27 (Ren2) rats on top of RAS blockade. Here we investigated whether this effect is thiorphan-specific, by comparing the neprilysin inhibitors thiorphan and sacubitril, administered by osmotic minipumps at a low or high dose for 7 days, in Ren2 rats. Plasma and urinary levels of endothelin-1, atrial and brain natriuretic peptide (ANP, BNP) and their second messenger cyclic guanosine 3'5' monophosphate (cGMP) were monitored. No significant differences were found in the plasma concentrations of endothelin-1, cGMP, ANP and BNP after treatment, although plasma ANP tended to be higher in the high-dose thiorphan treatment group and the low- and high-dose sacubitril treatment groups, compared with vehicle. Urinary endothelin-1 increased in the low-dose thiorphan and high-dose sacubitril groups, compared with baseline, although significance was reached for the former only. Urinary cGMP rose significantly in the high-dose sacubitril treatment group compared with baseline. Both urinary endothelin-1 and cGMP were significantly higher in the high-dose sacubitril group compared with the low-dose sacubitril group. In conclusion, endothelin-1 upregulation occurs with both thiorphan and sacubitril, and is particularly apparent in neprilysin-rich organs like the kidney. High renal neprilysin levels most likely also explain why sacubitril increased cGMP in urine only. PMID- 29432710 TI - Serum cystatin C is independently associated with aortic arterial stiffness in patients with type 2 diabetes. AB - BACKGROUND: Higher cystatin C levels are associated with an increased cardiovascular risk. We evaluated the association between serum cystatin C and aortic arterial stiffness in patients with type 2 diabetes mellitus (DM). METHODS: Fasting blood samples were collected from 170 patients with type 2 DM. Carotid-femoral pulse wave velocity (cfPWV) values > 10 m/s were used to define the high aortic arterial stiffness group. RESULTS: Sixty-seven patients with DM (39.4%) were defined as the high aortic arterial stiffness group. Patients with DM in the high aortic arterial stiffness group had older age (P = 0.003), higher systolic blood pressure (P < 0.001), diastolic blood pressure (P = 0.045), triglyceride (P = 0.046), blood urea nitrogen (P = 0.038), creatinine (P = 0.006), urine albumin-to-creatinine ratio (P = 0.004), and serum cystatin C (P < 0.001) levels but lower estimated glomerular filtration rate (P < 0.001). Multivariate logistic regression analysis showed that serum cystatin C level (each increase of 0.1 mg/l, odds ratio: 1.369, 95% confidence interval (CI): 1.049-1.787, P = 0.021) was still an independent predictor of aortic arterial stiffness in patients with DM. CONCLUSION: Serum cystatin C level positively correlated with aortic arterial stiffness among patients with type 2 DM. PMID- 29432711 TI - Seroprevalence of human cysticercosis in Jatai, Goias state, Brazil. AB - The Taenia solium cysticercosis affects millions of people worldwide and is considered a public health problem, especially in developing countries. The diagnosis of neurocysticercosis is complex and involves the analysis of epidemiological, clinical, neuroimaging, and immunological host data. Neurocysticercosis is endemic in Brazil, and is related to the cause of death mainly in the Southeast, South, and Central-West regions. The objective of this study was to determine the seroprevalence of cysticercosis in inhabitants of the city of Jatai, Goias, in the Central-West region of Brazil from April to August 2012. A total of 529 serum samples were analyzed by enzyme-linked immunosorbent assay for detecting IgG antibodies against T. solium larvae, and Western blotting was used for confirming the diagnosis through the recognition of at least two specific peptides from their serum antibodies. The 351/529 (66.3%) reactive samples were analyzed by enzyme-linked immunosorbent assay and Western blotting confirmed the diagnosis in 73 samples that recognized at least two of the following peptides specific IgG antibodies for cysticercosis: 18, 24, 28-32, 39 42, 47-52, 64-68, and 70kDa. The seroprevalence of cysticercosis was 13.8% (95% CI 5.9-21.7), demonstrating that the studied area is endemic to this disease. PMID- 29432712 TI - Expiratory Flow Limitation During Mechanical Ventilation. AB - Expiratory flow limitation (EFL) is present when the flow cannot rise despite an increase in the expiratory driving pressure. The mechanisms of EFL are debated but are believed to be related to the collapsibility of small airways. In patients who are mechanically ventilated, EFL can exist during tidal ventilation, representing an extreme situation in which lung volume cannot decrease, regardless of the expiratory driving forces. It is a key factor for the generation of auto- or intrinsic positive end-expiratory pressure (PEEP) and requires specific management such as positioning and adjustment of external PEEP. EFL can be responsible for causing dyspnea and patient-ventilator dyssynchrony, and it is influenced by the fluid status of the patient. EFL frequently affects patients with COPD, obesity, and heart failure, as well as patients with ARDS, especially at low PEEP. EFL is, however, most often unrecognized in the clinical setting despite being associated with complications of mechanical ventilation and poor outcomes such as postoperative pulmonary complications, extubation failure, and possibly airway injury in ARDS. Therefore, prompt recognition might help the management of patients being mechanically ventilated who have EFL and could potentially influence outcome. EFL can be suspected by using different means, and this review summarizes the methods to specifically detect EFL during mechanical ventilation. PMID- 29432713 TI - Probing the extended lipid anchorage with cytochrome c and liposomes containing diacylphosphatidylglycerol lipids. AB - Experiments investigating the adsorption and desorption of cytochrome c onto and from liposomes containing 50 mol% 1,2-diacylphosphatidylglycerol lipids [10:0, 12:0, 14:0, 16:0, 18:1(Delta9 cis)] with 1,2-dioleoyl-sn-glycero-3 phosphatidylcholine (DOPC) in pH 7.4 buffered solutions of low to moderate ionic strength are reported. Fluorescence experiments show that cytochrome c has a similar adsorption affinity for the five labeled 50 mol% PG liposome systems investigated. Fluorescence recovery experiments reveal the extent of cytochrome c desorption upon the addition of >10* excess of unlabeled 100% 1,2-dioleoyl-sn glycero-3-phosphatidylglycerol (DOPG) liposomes is dependent on the lipid's acyl chain length. The extent of desorption is also shown to be independent of temperature, albeit over a narrow range. The differences in the extent of cytochrome c desorption from liposomes containing PG lipids with different acyl chain lengths is attributed to the varying contribution of the binding motif involving the extended lipid anchorage in response to lipid packing stress. PMID- 29432714 TI - Suppressive effects of aryl-hydrocarbon receptor repressor on adipocyte differentiation in 3T3-L1 cells. AB - The aryl-hydrocarbon receptor repressor (AhRR) negatively regulates aryl hydrocarbon receptor (AhR) signaling via its inhibitory transactivation. AhR is well known to suppress adipocyte differentiation, but the function of AhRR during adipogenesis is unclear. The purpose of this study was to investigate the role of AhRR in adipocyte differentiation using 3T3-L1 cells. During the early phase of differentiation, AhRR expression was transiently induced, but throughout the entire differentiation process, low levels of AhR expression were maintained. AhRR knockdown significantly increased not only glycerol-3-phosphate dehydrogenase (GPDH) activity but also lipid accumulation inside the cells. AhRR overexpression clearly reduced GPDH activity and lipid accumulation, indicating that AhRR upregulation during the early stage of adipogenesis suppresses adipocyte differentiation. Since AhRR knockdown increases the expression and activity of peroxisome proliferator-activated receptor gamma (PPARgamma), AhRR negatively regulates PPARgamma during adipogenesis. In summary, similar to AhR, AhRR acts as an inhibitor of adipocyte differentiation. In addition to controlling the negative feedback loop of AhR, AhRR might be involved in other functions, especially in adipocyte differentiation processes. PMID- 29432715 TI - Attenuation of cryopreservation-induced oxidative stress by antioxidant: Impact of Coenzyme Q10 on the quality of post-thawed buck spermatozoa. AB - The aim of this study was to determine the quality of post-thawed buck spermatozoa by attenuation of cryopreservation-induced oxidative stress using CoQ10, a lipophilic antioxidant. Ejaculates at every sampling period were collected from four Mahabadi bucks, pooled and diluted in soybean lecithin-based extenders containing 0 (negative control, NC), 0.5 (CQ0.05), 1 (CQ1), and 1.5 (CQ1.5) MUM CoQ10 and 0.9% (v/v) DMSO (positive control, PC). The diluted semen was gradually cooled to 4 degrees C, then frozen and stored in liquid nitrogen. After thawing, total motility although was significantly higher in CQ1 (53.40 +/- 1.83) than control groups (43.60 +/- 1.83% and 42.20 +/- 1.83%; P < 0.05), but this parameter did not differ between CQ1 and CQ1.5. Sperm viability was significantly higher in CQ1 (54.20 +/- 2.03%) than that of control and CQ0.5. The CQ1 and CQ1.5 led to significantly higher the plasma membrane functionality compared to control groups. Sperm abnormality was significantly lower in CQ1 than that of NC. The results also showed that MDA level was significantly lower in CQ1 and CQ1.5 compared with control and CQ0.5. The CQ1 (59.43 +/- 3.93%) was significantly increased mitochondrial activity compared to control groups. Although a greater value for %DFI was found in NC (10.24 +/- 0.48%) and PC (9.77 +/- 0.48%) groups compared to others, it was lower in CQ1 group (4.26 +/- 0.48%). In conclusion, based on our research results, 1 MUM CoQ10 could protect buck spermatozoa from cryoinjury. PMID- 29432716 TI - Shoulder Point Fitting Method as a New Universal Tricuspid Annuloplasty. AB - Approximately half of all tricuspid valves consist of four or more leaflets; however, no previous reports have discussed how to implant an annuloplasty ring in these multi-leaflet valves. We herein define the shoulder point of the tricuspid annulus and the annuloplasty ring and advocate a simple and universal fitting method to avoid deforming the tricuspid valve after ring implantation. PMID- 29432717 TI - Reply. PMID- 29432718 TI - Natural History of Ground-Glass Lesions Among Patients With Previous Lung Cancer. AB - BACKGROUND: Among patients with previous lung cancer, the malignant potential of subsequent ground-glass opacities (GGOs) on computed tomography remains unknown, with a lack of consensus regarding surveillance and intervention. This study sought to describe the natural history of GGO in patients with a history of lung cancer. METHODS: A retrospective review was performed of 210 patients with a history of lung cancer and ensuing computed tomography evidence of pure or mixed GGOs between 2007 and 2013. Computed tomography reports were reviewed to determine the fate of the GGOs, by classifying all lesions as stable, resolved, or progressive over the course of the study. Multivariable analysis was performed to identify predictors of GGO progression and resolution. RESULTS: The mean follow-up time was 13 months. During this period, 55 (26%) patients' GGOs were stable, 131 (62%) resolved, and 24 (11%) progressed. Of the 24 GGOs that progressed, three were subsequently diagnosed as adenocarcinoma. Patients of black race (odds ratio [OR], 0.26) and other races besides white (OR, 0.89) had smaller odds of GGO resolution (p = 0.033), whereas patients with previous lung squamous cell carcinoma (OR, 5.16) or small cell carcinoma (OR, 5.36) were more likely to experience GGO resolution (p < 0.001). On multivariable analysis, only a history of adenocarcinoma was an independent predictor of GGO progression (OR, 6.9; p = 0.011). CONCLUSIONS: Among patients with a history of lung cancer, prior adenocarcinoma emerged as a predictor of GGO progression, whereas a history of squamous cell carcinoma or small cell carcinoma and white race were identified as predictors of GGO resolution. PMID- 29432719 TI - A systematic review of contraceptive continuation among women living with HIV. AB - BACKGROUND: Women living with HIV (WLHIV) experience high rates of unmet contraceptive need and unintended pregnancy. Contraceptive method-specific continuation rates and associated factors are critical for guiding providers tasked with both reproductive health (RH) and HIV care. We conducted this systematic review to determine whether contraceptive continuation rates differ between WLHIV and uninfected women and, for WLHIV, whether differences are impacted by method type, antiretroviral therapy use or other factors. METHODS: We searched Ovid MEDLINE, POPLINE and PubMed.gov for studies published between January 1, 2000, and August 31, 2016. Inclusion criteria comprised prospective data of WLHIV, nonbarrier method continuation as an outcome measure, and recorded method switching and/or discontinuation. RESULTS: Of 939 citations screened, 22 articles from 18 studies were eligible. For studies with comparator groups, data quality was moderate overall based on Grading of Recommendations, Assessment, Development and Evaluations and Newcastle-Ottawa Quality Assessment scales. Of four studies comparing women by HIV serostatus, two showed higher rates of contraceptive continuation among WLHIV versus uninfected women, while two others detected lower continuation rates for the same comparison. Generally, baseline method continuation exceeded 60% for studies with >12months of follow-up. Studies providing contraception had higher continuation rates than studies not providing contraception, while women allocated to contraceptive methods in trials had similar continuation rates to those choosing contraceptive methods. Across all studies, continuation rates differed by method and context, with the copper intrauterine device showing greatest variability between sites (51%-91% continuation rates at >=12months). Implant continuation rates were >=86%, though use was low relative to other methods and limited to few studes. CONCLUSIONS: Contraceptive continuation among WLHIV differs by method and context. More longitudinal studies with contraceptive continuation as a measured outcome following >=12months are needed to strengthen integration of RH and HIV care. PMID- 29432720 TI - Exosomes and regenerative medicine: state of the art and perspectives. AB - Exosomes have attracted the attention of the scientific community in recent years due to their widespread distribution, their possible functions as biomarkers of disease, and their great potential to be applied as therapeutic agents. Exosomes carry proteins and nucleic acids that can facilitate their uptake by distant target cells through endocytosis, such that exosomes could be targeted to a specific cell or cells to enhance or interfere with specific biological processes. This review will mainly focus on their roles in tissue repair and regenerative processes. Exosomal engineering and their potential applications in tissue regeneration are also reviewed here as an outlook for future research. PMID- 29432721 TI - Vastus Lateralis Motor Unit Firing Rate Is Higher in Women With Patellofemoral Pain. AB - OBJECTIVE: To compare neural drive, determined from motor unit firing rate, in the vastus medialis and lateralis in women with and without patellofemoral pain. DESIGN: Cross-sectional study. SETTING: University research laboratory. PARTICIPANTS: Women (N=56) 19 to 35 years of age, including 36 with patellofemoral pain and 20 controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants sustained an isometric knee extension contraction at 10% of their maximal voluntary effort for 70 seconds. Motor units (N=414) were identified using high-density surface electromyography. Average firing rate was calculated between 5 and 35 seconds after recruitment for each motor unit. Initial firing rate was the inverse of the first 3 motor unit interspike intervals. RESULTS: In control participants, vastus medialis motor units discharged at higher rates than vastus lateralis motor units (P=.001). This was not observed in women with patellofemoral pain (P=.78) because of a higher discharge rate of vastus lateralis compared with control participants (P=.002). No between-group differences were observed for vastus medialis (P=.93). Similar results were obtained for the initial motor unit firing rate. CONCLUSIONS: These findings suggest that women with patellofemoral pain have a higher neural drive to vastus lateralis but not vastus medialis, which may be a contributor of the altered patellar kinematics observed in some studies. The different neural drive may be an adaptation to patellofemoral pain, possibly to compensate for decreased quadriceps force production, or a precursor of patellofemoral pain. PMID- 29432722 TI - Clinical Assessment of Spasticity in People With Spinal Cord Damage: Recommendations From the Ability Network, an International Initiative. AB - A thorough assessment of the extent and severity of spasticity, and its effect on functioning, is central to the effective management of spasticity in persons with spinal cord damage (SCD). These individuals however do not always receive adequate assessment of their spasticity. Inadequate assessment compromises management when the effect of spasticity and/or need for intervention are not fully recognized. Assessment is also central to determining treatment efficacy. A barrier to spasticity assessment has been the lack of consensus on clinical and functional measures suitable for routine clinical practice. To extend on existing work, a working group of the Ability Network identified and consolidated information on possible measures, and then synthesized and formulated findings into practical recommendations for assessing spasticity and its effect on function in persons with SCD. Sixteen clinical and functional measures that have been used for this purpose were identified using a targeted literature review. These were mapped to the relevant domains of the International Classification of Functioning, Disability and Health to assess the breadth of their coverage; coverage of many domains was found to be lacking, suggesting a focus for future work. The advantages, disadvantages, and usefulness of the measures were assessed using a range of criteria, with a focus on usefulness and feasibility in routine clinical practice. Based on this evaluation, a selection of measures suitable for initial and follow-up assessments are recommended. The recommendations are intended to have broad applicability to a variety of health care settings where people with SCD are managed. PMID- 29432723 TI - Phos-tau peptide immunization of amyloid-tg-mice reduced non-mutant phos-tau pathology, improved cognition and reduced amyloid plaques. AB - Tau-immumotherapy has shown promising results in tangle/tauopathy-tg animal models. Here we immunized amyloid-mice (APPSwe/PSEN1dE9-tg, presenting amyloid plaques, not neurofibrillary-tangles) with phos-tau peptides, previously shown by us to have high efficacy in mutant-tau tauopathy-mice. These amyloid-mice allowed us to test the effect of the vaccine in a model of familial AD patients with mutant amyloid plaque pathology, where tau pathology - once develops - is of non mutant tau. Fourteen-month-old amyloid-mice were immunized with phos-tau peptides or vehicle. Eight weeks later, amelioration of cognitive impairment was noticed. Histological analysis revealed that the phos (non-mutant)-tau pathology (detected by us in these aged amyloid-mice while not in non-tg-mice), was lower in the phos tau immunized amyloid-mice than in the non-immunized mice. Interestingly, we detected a decrease in amyloid plaque pathology, probably associated with the increased microglial burden, which surrounded both tau and amyloid pathology. These results point to the added value of immunizing AD-mice with the phos-tau vaccine, targeting both tau and amyloid pathology, which may have clinical relevance. It also points to the multifaceted interplay between tau/amyloid pathologies. PMID- 29432725 TI - Energy Coupling Efficiency in the Type I ABC Transporter GlnPQ. AB - Solute transport via ATP binding cassette (ABC) importers involves receptor mediated substrate binding, which is followed by ATP-driven translocation of the substrate across the membrane. How these steps are exactly initiated and coupled, and how much ATP it takes to complete a full transport cycle, are subject of debate. Here, we reconstitute the ABC importer GlnPQ in nanodiscs and in proteoliposomes and determine substrate-(in)dependent ATP hydrolysis and transmembrane transport. We determined the conformational states of the substrate binding domains (SBDs) by single-molecule Forster resonance energy transfer measurements. We find that the basal ATPase activity (ATP hydrolysis in the absence of substrate) is mainly caused by the docking of the closed-unliganded state of the SBDs onto the transporter domain of GlnPQ and that, unlike glutamine, arginine binds both SBDs but does not trigger their closing. Furthermore, comparison of the ATPase activity in nanodiscs with glutamine transport in proteoliposomes shows that the stoichiometry of ATP per substrate is close to two. These findings help understand the mechanism of transport and the energy coupling efficiency in ABC transporters with covalently linked SBDs, which may aid our understanding of Type I ABC importers in general. PMID- 29432724 TI - Guanabenz promotes neuronal survival via enhancement of ATF4 and parkin expression in models of Parkinson disease. AB - Reduced function of parkin appears to be a central pathogenic event in Parkinson disease (PD). Increasing parkin levels enhances survival in models of PD-related neuronal death and is a promising therapeutic objective. Previously, we demonstrated that the transcription factor ATF4 promotes survival in response to PD-mimetic stressors by maintaining parkin levels. ATF4 translation is up regulated by phosphorylation of the translation initiation factor eIF2alpha. The small molecule guanabenz enhances eIF2alpha phosphorylation by blocking the function of GADD34, a regulatory protein that promotes eIF2alpha dephosphorylation. We tested the hypothesis that guanabenz, by inhibiting GADD34 and consequently increasing eIF2alpha phosphorylation and elevating ATF4, would improve survival in models of PD by up-regulating parkin. We found that GADD34 is strongly induced by 6-OHDA, and that GADD34 localization is dramatically altered in dopaminergic substantia nigra neurons in PD cases. We further demonstrated that guanabenz attenuates 6-hydroxydopamine (6-OHDA) induced cell death of differentiated PC12 cells and primary ventral midbrain dopaminergic neurons in culture, and of dopaminergic neurons in the substantia nigra of mice. In culture models, guanabenz also increases eIF2alpha phosphorylation and ATF4 and parkin levels in response to 6-OHDA. Furthermore, if either ATF4 or parkin is silenced, then the protective effect of guanabenz is lost. We also found similar results in a distinct model of neuronal death: primary cultures of cortical neurons treated with the topoisomerase I inhibitor camptothecin, in which guanabenz limited camptothecin-induced neuronal death in an ATF4- and parkin-dependent manner. In summary, our data suggest that guanabenz and other GADD34 inhibitors could be used as therapeutic agents to boost parkin levels and thereby slow neurodegeneration in PD and other neurodegenerative conditions. PMID- 29432726 TI - Co-expression of vasoactive intestinal peptide and protein gene product 9.5 surrounding the lumen of human Schlemm's canal. AB - Previous studies of aqueous humor outflow have focused primarily on resistance at the trabecular meshwork (TM), and little is known about the function of Schlemm's canal (SC). Here, we aimed to investigate whether SC is innervated by the peripheral nervous system. Ten eye specimens from eight donors were processed for histological analysis. CD31 was used to identify SC, after which we used protein gene product (PGP) 9.5 as a marker to detect nerve fibers around SC. We then characterized the nerves by double staining for PGP9.5 and sympathetic nerve markers, such as tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DbetaH), or the parasympathetic marker vasoactive intestinal peptide (VIP), as well as sensory nerve marker calcitonin gene-related peptide (CGRP) and vesicular glutamate transporter 2 (VGLUT2). Immunohistochemistry and immunofluorescence were also performed to detect the expression of gamma-epithelial Na+ channel (gamma-ENaC) in SC. We found that different markers were expressed in the anterior chamber angle, with the luminal surface of SC were only positive stained for PGP9.5, VIP, and gamma-ENaC. CGRP and VGLUT2 were expressed in TM and scleral spur (SS), whereas TH and DbetaH were absent in both TM and SC. Furthermore, PGP9.5 was co-expressed with VIP and gamma-ENaC in the region surrounding the SC as well as in SS. Our findings indicate that the peripheral nerves anatomically spread in the tissues around the SC and the local nerve fibers may be parasympathetic or sensory rather than sympathetic. PMID- 29432727 TI - Acute Pancreatitis and Pancreatic Cancer Risk: A Nationwide Matched-Cohort Study in Denmark. AB - BACKGROUND & AIMS: Acute pancreatitis may be a risk factor for pancreatic cancer; however, findings from studies on this association are conflicting. We investigated the association between acute pancreatitis and increased risk of pancreatic cancer. METHODS: We conducted a nationwide, population-based, matched cohort study of all patients admitted to a hospital in Denmark with a diagnosis of acute pancreatitis from January 1, 1980, through October 31, 2012. As many as 5 individuals from the general population without acute pancreatitis were matched for age and sex to each patient with acute pancreatitis. Pancreatic cancer risk was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), calculated using the Cox proportional hazards model. Cox models were stratified by age, sex, and year of pancreatitis diagnosis and adjusted for alcohol- and smoking-related conditions, and Charlson Comorbidity Index score. RESULTS: We included 41,669 patients diagnosed with incident acute pancreatitis and 208,340 comparison individuals. Patients with acute pancreatitis had an increased risk of pancreatic cancer compared with the age- and sex-matched general population throughout the follow-up period. The risk decreased over time but remained high after more than 5 years of follow-up (adjusted HR 2.02; 95% CI 1.57-2.61). Two- and 5-year absolute risks of pancreatic cancer among patients with acute pancreatitis were 0.70% (95% CI 0.62%-0.78%) and 0.87% (95% CI 0.78%-0.97), respectively. CONCLUSIONS: In a nationwide, population-based, matched cohort study, we observed an association between a diagnosis of acute pancreatitis and long-term risk of pancreatic cancer. PMID- 29432728 TI - Galectin-3 is essential for proper bone cell differentiation and activity, bone remodeling and biomechanical competence in mice. AB - OBJECTIVE: Galectin-3 is constitutively expressed in bone cells and was recently shown to modulate osteogenic transdifferentiation of vascular smooth muscle cells and atherosclerotic calcification. However, the role of galectin-3 in bone physiology is largely undefined. To address this issue, we analyzed (1) the skeletal features of 1-, 3- and 6-month-old galectin-3 null (Lgals3-/-) and wild type (WT) mice and (2) the differentiation and function of osteoblasts and osteoclasts derived from these animals. METHODS: Long bone phenotype, gene expression profile, and remodeling were investigated by micro-computed tomography, real time-PCR, static and dynamic histomorphometry, and assessment of biochemical markers of bone resorption and formation. Bone competence was also evaluated by biomechanical testing at 3 months. In vitro, the effects of galectin 3 deficiency on bone cell differentiation and function were investigated by assessing (a) gene expression of osteoblast markers, alkaline phosphatase activity, mineralization assay, and WNT/beta-catenin signaling (of which galectin 3 is a known regulator) in osteoblasts; and (b) tartrate-resistant acid phosphatase activity and bone resorption activity in osteoclasts. RESULTS: Lgals3 /- mice revealed a wide range of age-dependent alterations including lower bone formation and higher bone resorption, accelerated age-dependent trabecular bone loss (p < 0.01 vs. WT at 3 months) and reduced bone strength (p < 0.01 vs. WT at 3 months). These abnormalities were accompanied by a steady inflammatory state, as revealed by higher bone expression of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-6 (p < 0.001 vs. WT at 3 months), increased content of osteal macrophages (p < 0.01 vs. WT at 3 months), and reduced expression of markers of alternative (M2) macrophage activation. Lgals3-/- osteoblasts and osteoclasts showed impaired terminal differentiation, reduced mineralization capacity (p < 0.01 vs. WT cells) and resorption activity (p < 0.01 vs. WT cells). Mechanistically, impaired differentiation and function of Lgals3-/- osteoblasts was associated with altered WNT/beta-catenin signaling (p < 0.01 vs. WT cells). CONCLUSIONS: These data provide evidence for a contribution of galectin-3 to bone cell maturation and function, bone remodeling, and biomechanical competence, thus identifying galectin-3 as a promising therapeutic target for age-related disorders of bone remodeling. PMID- 29432729 TI - Functional characterization and quantitative expression analysis of two GnRH related peptide receptors in the mosquito, Aedes aegypti. AB - To cope with stressful events such as flight, organisms have evolved various regulatory mechanisms, often involving control by endocrine-derived factors. In insects, two stress-related factors include the gonadotropin-releasing hormone related peptides adipokinetic hormone (AKH) and corazonin (CRZ). AKH is a pleiotropic hormone best known as a substrate liberator of proteins, lipids, and carbohydrates. Although a universal function has not yet been elucidated, CRZ has been shown to have roles in pigmentation, ecdysis or act as a cardiostimulatory factor. While both these neuropeptides and their respective receptors (AKHR and CRZR) have been characterized in several organisms, details on their specific roles within the disease vector, Aedes aegypti, remain largely unexplored. Here, we obtained three A. aegypti AKHR transcript variants and further identified the A. aegypti CRZR receptor. Receptor expression using a heterologous functional assay revealed that these receptors exhibit a highly specific response for their native ligands. Developmental quantitative expression analysis of CRZR revealed enrichment during the pupal and adult stages. In adults, quantitative spatial expression analysis revealed CRZR transcript in a variety of organs including head, thoracic ganglia, primary reproductive organs (ovary and testis), as well as male carcass. This suggest CRZ may play a role in ecdysis, and neuronal expression of CRZR indicates a possible role for CRZ within the nervous system. Quantitative developmental expression analysis of AKHR identified significant transcript enrichment in early adult stages. AKHR transcript was observed in the head, thoracic ganglia, accessory reproductive tissues and the carcass of adult females, while it was detected in the abdominal ganglia and enriched significantly in the carcass of adult males, which supports the known function of AKH in energy metabolism. Collectively, given the enrichment of CRZR and AKHR in the primary and secondary sex organs, respectively, of adult mosquitoes, these neuropeptides may play a role in regulating mosquito reproductive biology. PMID- 29432730 TI - Prolyl isomerase Pin1 is required sperm production by promoting mitosis progression of spermatogonial stem cells. AB - A prolyl isomerase Pin1 deficient (Pin1-/-) male mice had severe testicular atrophy. We investigated the function of Pin1 in spermatogenesis by analyzing the Pin1-/- mice at reproductive age. Pin1-/- mice had lessalphaPLZF positive spermatogonia (undifferentiated spermatogonia) than wild type (WT). Nevertheless, the Pin1-/- testis contained approximately the same number of GFRalpha1 positive spermatogonia (SSCs in steady state) as the WT testis. Furthermore, degeneration of the spermatogenia appeared in seminiferous tubules of 10 months old Pin1-/- mouse testis, and abnormal shape GFRalpha1 positive spermatogonia were observed. In Pin1-/- spermatogonia, the ratio of the phospho-histone H3 positive cells (mitotic cells) in GFRalpha1-positive spermatogonia was higher than that of WT. These results suggest that Pin1 promotes the progression of the mitotic cell cycle of SSC in steady-state, which is required for the sperm production from SSCs. PMID- 29432731 TI - AntogomiR-451 protects human gastric epithelial cells from ethanol via activating AMPK signaling. AB - The prevention and treatment efficiency of ethanol-induced gastric epithelial injury are not satisfied. We have previously shown that AMP-activated protein kinase (AMPK) activation exerts a pro-survival function in human gastric epithelial cells (GECs). miroRNA-451 ("miR-451")'s inhibitor, antagomiR-451, can activate AMPK signaling. In the present study, we show that forced-expression of antagomiR-451 via a lentiviral vector depleted miR-451, leading to AMPK activation in established GES-1 cells and primary human GECs. AntagomiR-451 efficiently protected GES-1 cells and primary human GECs from ethanol-induced viability reduction and apoptosis. AMPK activation is required for antagomiR-451 induced GEC protection. AMPKalpha1 knockdown (by targeted-shRNAs) or knockout (by CRISPR-Cas-9 KO plasmid) blocked antagomiR-451-induced AMPK activation, and GEC protection against ethanol. Further experimental results show that antagomiR-451 significantly attenuated ethanol-induced reactive oxygen species (ROS) production, lipid peroxidation and DNA damage. Collectively, antagomiR-451 protects human GECs from ethanol via activating AMPK signaling. PMID- 29432732 TI - Long non-coding RNA 00312 downregulates cyclin B1 and inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo. AB - Long non-coding RNAs are dysregulated in human hepatocellular carcinoma (HCC). We tested the potential effect of long non-coding RNA 00312 ("Lnc00312") on human HCC cell behavior in vitro and in vivo. Forced-expression of Lnc00312 by a lentiviral vector induced proliferation inhibition and apoptosis in HepG2 cells and primary human HCC cells. Lnc00312 downregulated cyclin B1 and induced G2-M cell cycle arrest in HCC cells. Restoring cyclin B1 expression by a cyclin B1 cDNA construct inhibited Lnc00312-induced cytotoxicity against HCC cells. Conversely, siRNA-mediated knockdown of Lnc00312 increased cyclin B1 expression and promoted HepG2 cell proliferation. In vivo, the growth of HepG2 xenograft tumors in severe combined immunodeficient (SCID) mice was largely inhibited after expression of Lnc00312. Significantly, Lnc00312 is downregulated in human HCC tissues, which is negatively correlated with the tumor grade. Overall, Lnc00312 inhibits human HCC cell proliferation in vitro and in vivo. Cyclin B1 could be a key target protein of Lnc00312 in human HCC cells. PMID- 29432733 TI - DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation. AB - Rac1 is a member of the Rho family of small GTPases that regulates cytoskeletal reorganization, membrane polarization, cell migration and proliferation. Recently, a self-activating mutation of Rac1, Rac1P29S, has been identified as a recurrent somatic mutation frequently found in sun-exposed melanomas, which possesses increased inherent GDP/GTP exchange activity and cell transforming ability. However, the role of cellular Rac1-interacting proteins in the transforming potential of Rac1P29S remains unclear. We found that the catalytic domain of DOCK1, a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of a variety of cancers, can greatly accelerate the GDP/GTP exchange of Rac1P29S. Enforced expression of Rac1P29S induced matrix invasion and macropinocytosis in wild-type (WT) mouse embryonic fibroblasts (MEFs), but not in DOCK1-deficient MEFs. Consistently, a selective inhibitor of DOCK1 that blocks its GEF function suppressed the invasion and macropinocytosis in WT MEFs expressing Rac1P29S. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1P29S mutation and express DOCK1 endogenously. Genetic inactivation and pharmacological inhibition of DOCK1 suppressed their invasion and macropinocytosis. Taken together, these results indicate that DOCK1 is a critical regulator of the malignant phenotypes induced by Rac1P29S, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1P29S mutation. PMID- 29432734 TI - The anti-osteosarcoma cell activity by a mTORC1/2 dual inhibitor RES-529. AB - mTOR over-activation is important for human osteosarcoma (OS) tumorigenesis and progression. RES-529 is a mTORC1/2 dual inhibitor. Here, our results show that RES-529 inhibited viability, cell cycle progression and proliferation of the established (U2OS line) and primary human OS cells. RES-529 induced apoptosis activation in OS cells. It was yet non-cytotoxic to OB-6 osteoblastic cells and the primary human osteoblasts. RES-529 disrupted assembling of mTORC1 (mTOR Raptor association) and mTORC2 (mTOR-Rictor-mLST8 association) in human OS cells, blocking mTORC1/2 activation. Significantly, RES-529 induced reactive oxygen species (ROS) production and mitochondrial depolarization in U2OS cells as well. RES-529-induced anti-OS cell activity was more potent than other known Akt-mTOR inhibitors. In vivo, RES-529 intraperitoneal injection significantly inhibited U2OS xenograft tumor growth in severe combined immunodeficiency (SCID) mice. mTORC1/2 activation in RES-529-treated tumor tissues was largely inhibited. Collectively, the mTOR inhibitor RES-529 efficiently inhibits human OS cell growth in vitro and in vivo. PMID- 29432735 TI - Cellular toxicity driven by high-dose vitamin C on normal and cancer stem cells. AB - As a powerful antioxidant, vitamin C protects cells from oxidative damage by inhibiting production of free radicals. However, high levels of vitamin C shows cytotoxicity especially on cancerous cells through generating excessive ROS and blocking the energy homeostasis. Although the double-sided character of vitamin C has been extensively studied in many cell types, there is little research on the consequence of vitamin C treatment in stem cells. Here, we identified that high dose vitamin C shows cellular toxicity on proliferating NSPCs. We also demonstrated that undifferentiated NSPCs are more sensitive to vitamin C-driven DNA damage than differentiated cells, due to higher expression of Glut genes. Finally, we showed that high-dose vitamin C selectively induces DNA damage on cancer stem cells rather than differentiated tumor cells, raising a possibility that vitamin C may be used to target cancer stem cells. PMID- 29432736 TI - miR-223/Hsp70/JNK/JUN/miR-223 feedback loop modulates the chemoresistance of osteosarcoma to cisplatin. AB - Osteosarcoma (OS) is a primary bone malignancy with a five-year survival rate of 60%; the chemoresistance of OS still remains a huge challenge. Heat shock protein 70 (Hsp70), a member of HSP family, is overexpressed in OS cell lines and involved in the resistance of OS cell lines. In addition, miRNAs have been involved in the carcinogenesis and chemoresistance of OS; of them, miR-223 has been reported to be underexpressed and serve as a tumor suppressor in OS through targeting Hsp90B1, also a member of HSP family. Herein, online tools predicted that Hsp70 might be a direct target of miR-223. In the present study, miR-223 expression was down-regulated in OS tissues and cell lines; miR-223 overexpression enhanced the cellular effects of cisplatin (CDDP) on OS cell lines. Through binding to the HSPA1A 3'UTR, miR-223 could regulate Hsp70 protein levels and downstream JNK/JUN signaling pathway, thus modulating OS cell apoptosis through Hsp70 under CDDP stress. Finally, JUN, a downstream transcription factor of JNK signaling, could bind to the promoter region of miR 223 to promote its transcription. In summary, miR-223, Hsp70 and downstream JNK/JUN formed a feedback loop to modulate the chemoresistance of OS to CDDP. PMID- 29432737 TI - Activated STAT3 may participate in tumor progression through increasing CD133/survivin expression in early stage of colon cancer. AB - The activation of signal transducer and activator of transcription 3 (STAT3) by elevated interleukin (IL) levels has been reported to regulate tumorigenesis both in vitro and in vivo. However, the clinical implication of p-STAT3 expression in colon cancer is still controversial. In this study, we evaluated the effect of STAT3 inactivation on biologic behavior of primary (Caco-2) and metastatic colon cancer cells (LoVo and SNU407) and the relation of p-STAT3 expression with the invasion of colon tumor. In vitro study, the STAT3 inhibition by siRNA and stattic treatment significantly reduced colony formation and cell migration and decreased CD133 and survivin the expression compared with a control in all three cell lines. Furthermore, primary cancer cells exhibited a marked decrease in CD133 expression and increased apoptosis compared to metastatic cells after stattic treatment. The immunohistochemical assay using clinical samples of colonic tumors with various invasion depth showed that p-STAT3 expression was inversely associated with tumor invasion (p = 0.001, hazard ratio (HR) = 0.328, 95% confidence interval (95%CI): 0.170-0.632). In conclusion, p-STAT3 may participate in the progression of the early stage of colon cancer through the up regulation of CD133, which in turn induces survivin expression. However, the regulatory mechanism of these molecules in tumor progression in vivo is need to be more verified. PMID- 29432738 TI - Humanin promotes mitochondrial biogenesis in pancreatic MIN6 beta-cells. AB - Mitochondrial dysfunction is associated with beta-cell failure and insulin resistance in diabetes. Humanin is an endogenous cytoprotective peptide. In the current study, we aimed to define the effects of Humanin on mitochondrial biogenesis in pancreatic beta-cells. Our findings demonstrated that Humanin treatment significantly increased the expression of PGC-1alpha and its downstream target genes NRF1 and TFAM in MIN6 beta-cells. Notably, Humanin treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial mass, elevating mtDNA/nDNA ratio, and stimulating the expression of cytochrome B, which were suppressed by the specific AMPK inhibitor compound C. Indeed, Humanin treatment caused the phosphorylation of AMPK, which was involved in the induction of PGC-1alpha, NRF1, and TFAM by Humanin. Importantly, our findings indicate that Humanin treatment led to a possible functional gain of the mitochondria by increasing ATP levels and respiratory rate. Our findings provided a new insight into the molecular mechanisms of action by which Humanin improves pancreatic beta cell function via enhanced mitochondrial mass and performance. PMID- 29432739 TI - KSHV vPK inhibits Wnt signaling via preventing interactions between beta-catenin and TCF4. AB - Viral factors interact with host cellular proteins, leading to dysregulation of signaling pathways. The Wnt pathway is known to participate in embryonic development and oncogenesis under dysregulation conditions. A downstream factor of the Wnt signaling pathway, beta-catenin, activates T-cell factor (TCF) dependent transcription, which contributes to cell proliferation and tumorigenesis. In this study, we demonstrated that viral protein kinase (vPK) encoded by Kaposi's sarcoma-associated herpesvirus inhibits the Wnt signaling pathway without affecting nuclear localization and expression of beta-catenin. Coimmunoprecipitation and chromatin immunoprecipitation assays revealed that vPK interacts with beta-catenin, reducing the binding affinity on TCF binding regions as well as interactions of beta-catenin with TCF4. Overexpression of vPK led to reduced mRNA expression of cyclin D1, a well-known transcriptional product of Wnt signaling, suggesting that vPK effectively regulates the host signaling pathway through direct interactions with cellular proteins. PMID- 29432740 TI - Crystal structure of a substrate-binding protein from Rhodothermus marinus reveals a single alpha/beta-domain. AB - Substrate-binding proteins (SBPs) bind to specific ligands and are associated with membrane protein complexes for transport or signal transduction. Most SBPs recognize substrates by the hinge motion between two distinct alpha/beta domains. However, short SBP motifs are often observed in protein databases, which are located around methyl-accepting chemotaxis protein genes, but structural and functional studies have yet to be performed. Here, we report the crystal structure of an unusually small SBP from Rhodothermus marinus (named as RmSBP) at 1.9 A. This protein is composed of a single alpha/beta-domain, unlike general SBPs that have two distinct domains. RmSBP exhibits a high structural similarity to the C-terminal domain of the previously reported amino acid bound SBPs, while it does not contain an N-terminal domain for substrate recognition. As a result of the structural comparison analysis, RmSBP has a putative SBP that is different from the previously reported SBP. Our results provide insight into a new class of substrate recognition mechanism by the mini SBP protein. PMID- 29432741 TI - Dietary nitrate protects submandibular gland from hyposalivation in ovariectomized rats via suppressing cell apoptosis. AB - Xerostomia, a major oral symptom of menopause, is a subjective feeling of dry mouth associated with oral pain and difficulties in deglutition and speech, which significantly reduces patient's quality of life. Dietary nitrate, which can be converted to nitric oxide, has multiple physiological functions in the body, including antioxidant activity and vasodilatation; however, its protective effect against xerostomia remains poorly understood. The present study aimed to evaluate the effects of dietary nitrate on estrogen deficiency-induced xerostomia. We established an ovariectomized (OVX) rat model, which included five groups: sham operated, OVX, OVX + 0.4 mM nitrate, OVX + 2 mM nitrate, and OVX + 4 mM nitrate (n = 6). After ovariectomy, animals in the nitrate treatment groups received appropriate amounts of sodium nitrate dissolved in distilled water for 3 months. The results showed that nitrate treatment reduced body weight and water intake, and increased serum nitrate and nitrite levels. Furthermore, nitrate uptake increased saliva secretion as evidenced by saliva flow rates and aquaporin 5 expression, and alleviated histological lesions as evidenced by reduction of the fibrotic area and cell atrophy in the salivary glands. Although protective effects of nitrate against estrogen deficiency-induced xerostomia were observed at all doses, treatment with 2 mM nitrate was more effective than that with 0.4 mM and 4 mM nitrate. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase-3 expression analyses showed that nitrate also protected cells from apoptosis, possibly through upregulation of Cu-Zn superoxide dismutase (Cu-Zn SOD) known to inhibit oxidative stress-related apoptosis. Our findings indicate that nitrate could improve functional activity of the salivary glands in OVX rats by suppressing apoptosis and upregulating Cu-Zn SOD expression, suggesting that dietary nitrate may potentially prevent hyposalivation in menopausal women. PMID- 29432742 TI - Knockdown of ARL4C inhibits osteogenic differentiation of human adipose-derived stem cells through disruption of the Wnt signaling pathway. AB - ADP-ribosylation factor-like 4C (ARL4C) has been shown to play an important role in cholesterol secretion, microtubule dynamics, and cell morphological changes. However, its role in osteogenesis has not been explored. In this study, we found that ARL4C is downregulated during the osteogenic differentiation of human adipose derived stem cells (hASCs). Knockdown of ARL4C suppresses osteogenesis of hASCs in vitro and in vivo. We demonstrate that ARL4C knockdown likely attenuates osteogenesis of hASCs through inhibition of the Wnt signaling pathway. These results provide new insights into the mechanisms of osteogenic differentiation and provide a potential molecular target for bone tissue engineering. PMID- 29432744 TI - A microtubule-associated protein MAP1B binds to and regulates localization of a calcium-binding protein ALG-2. AB - MAP1B (microtubule-associated protein 1B) binds to microtubules and regulates microtubule dynamics. Previously, we showed calcium-dependent interaction between MAP1B and a calcium-binding protein ALG-2 (apoptosis-linked gene 2), which is involved in regulation of the protein secretion pathway. Although ALG-2 generally binds to proteins through two consensus binding motifs such as ABM-1 and ABM-2, the absence of these motifs in MAP1B suggests a unique binding mode between MAP1B and ALG-2. Here, we identified the region of mouse MAP1B responsible for binding to ALG-2, and found point mutations that abrogated binding of MAP1B to ALG-2. Furthermore, interaction between MAP1B and ALG-2 selectively prevented ALG-2 from binding to proteins with ABM-2 such as Sec31A, suggesting competition between MAP1B and ABM-2-containing proteins for binding to ALG-2. Consistently, in MAP1B knockout cells, co-localization of ALG-2 with Sec31A was increased. Moreover, overexpression of wild-type MAP1B, but not the MAP1B mutant defective in ALG-2 binding, altered localizations of ALG-2 and Sec31A into dispersed distributions, suggesting that MAP1B regulates localizations of ALG-2 and Sec31A in the cells. Finally, we found two cancer-associated mutations of human MAP1B located near ALG 2 binding sites. The introduction of the corresponding mutations in mouse MAP1B dramatically reduced the binding ability to ALG-2. Thus, these results suggest that MAP1B plays a role in regulation of ALG-2 and Sec31A localizations, and that dysregulation of calcium-dependent binding of ALG-2 to MAP1B might influence pathological conditions such as cancers. PMID- 29432743 TI - The inhibition of the effect and mechanism of vascular intimal hyperplasia in Tiam1 knockout mice. AB - T-Cell Lymphoma Invasion and Metastasis 1 (Tiam1) is a specific nucleotide exchange factor (GEF) that can activate Rho-like GTPase and Rac1 and regulate various cellular processes, including cell cycle progression and cell migration. The roles of Tiam1 in vascular intimal hyperplasia, especially in vascular smooth muscle cell proliferation and migration, are not fully understood. In this study, we investigated the effect of Tiam1 on vascular intimal hyperplasia in a carotid artery ligation model and human aortic smooth muscle cells (HASMCs). We found that the expression of Tiam1 was up-regulated in the neointima of carotid artery ligation mice and that Tiam1-/- mice following carotid artery ligation had less neointimal formation compared with wild type mice. Knockdown of Tiam1 by siRNA markedly attenuated PDGF-induced migration and proliferation in HASMCs by inhibiting the activation of Rac1. Therefore, these results suggest that Tiam1 is an important regulator of intima hyperplasia. It may regulate vascular intimal hyperplasia through the activation of Rac1. PMID- 29432745 TI - Potential testicular toxicity of gentamicin in adult rats. AB - Gentamycin is an aminoglycoside antibiotic commonly used against Gram-negative bacteria. This study was designed to investigate the testicular toxicity of gentamicin in adult rats. Gentamicin was given to rats at 0, 60, 80 or 100 mg/kg/day for 10 consecutive days. The absolute weight of testes reduced significantly in relation to the dose, while gentamicin at a dose of 60 mg/kg did not show any significant change in the relative testes weight. Sperm count and motility and daily sperm production decreased in a dose-related manner. Serum testosterone level was significantly decreased after gentamicin treatment in a dose-dependent manner. The activities of LDH-X was decreased while that of caspases-3 &-9 were significantly increased in a dose-related manner. H2O2 production and lipid peroxidation were significantly increased while the activities of SOD, CAT, GPX and GR, in addition to, the non-enzymatic GSH level were significantly decreased suggesting that gentamicin-induced oxidative stress. The biochemical findings were confirmed by histopathological examination of the testis. Atrophy, degeneration and loss of spermatogenesis were observed after gentamicin treatment. The findings of this study indicate that gentamicin induces oxidative stress associated with impairment of spermatogenesis, in addition to apoptosis. These data provide insight into the mode of action of gentamicin induced impairment of spermatogenesis in the rat testis. PMID- 29432746 TI - Chronic Hepatitis E in a Renal Transplant Recipient: The First Report of Genotype 4 Hepatitis E Virus Caused Chronic Infection in Organ Recipient. PMID- 29432747 TI - Multicystic Pancreas on Endoscopic Ultrasound Imaging: Worth Thinking Outside the 'Box' (Pancreas). PMID- 29432748 TI - A Rare Cause of Whole Gastrointestinal Duct Edema and Multiple Small Intestinal Polypoid Ulcers. PMID- 29432749 TI - Using Proactive Therapeutic Drug Monitoring of Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease: From an Old Concept to a Future Standard of Care? PMID- 29432750 TI - An Abdominal Mass. PMID- 29432751 TI - An efficient screening method for purifying and crystallizing membrane proteins using modified clear-native PAGE. AB - Membrane proteins, such as G-protein coupled receptors, control communication between cells and their environments and are indispensable for many cellular functions. Nevertheless, structural studies on membrane proteins lag behind those on water-soluble proteins, due to their low structural stability, making it difficult to obtain crystals for X-ray crystallography. Optimizing conditions to improve the stability of membrane proteins is essential for successful crystallization. However, the optimization usually requires large amounts of purified samples, and it is a time-consuming and trial-and-error process. Here, we report a rapid method for precrystallization screening of membrane proteins using Clear Native polyacrylamide gel electrophoresis (CN-PAGE) with the modified Coomassie Brilliant Blue G-250 (mCBB) stain that was reduced in sodium formate. A2A adenosine receptor (A2AAR) was selected as a target membrane protein, for which we previously obtained the crystal structure using an antibody, and was expressed as a red fluorescent protein fusion for in-gel fluorescence detection. The mCBB CN-PAGE method enabled the optimization of the solubilization, purification, and crystallization conditions of A2AAR using the solubilized membrane fraction expressing the protein without purification procedures. These data suggest the applicability of mCBB CN-PAGE technique to a wide variety of integral membrane proteins. PMID- 29432752 TI - Functional electrospun nanofibers-based electrochemiluminescence immunosensor for detection of the TSP53 using RuAg/SiO2NPs as signal enhancers. AB - A functional electrospun nanofibers-based electrochemiluminescence (ECL) immunosensor for detection of the tumor suppressor protein p53 (TSP53) at trace level using core-shell nanocomposite as signal enhancers is fabricated. The gold nanoparticles (AuNPs) were decorated on the surface of the electrospun carbon nanotubes (MWCNTs) doped chitosan (CTS) nanofibers (MWCNTs-CTS) by in-situ electrodeposition. The functional electrospun nanofibers (MWCNTs-CTS-AuNPs) was utilized as supporting scaffolds for TSP53 capture antibody (CAb) immobilization firstly. They can dramatically increase the amount and stability of CAb attachment, and efficiently enhance the sensitivity of detection. After a sandwich immunoreaction, TSP53 and Ru(bpy)32+/silver nanoparticles doped silica core-shell nanocomposite (RuAg/SiO2NPs)-labeled detection antibody (RuAg/SiO2NPs@DAb) captured onto the electrode surface. It was observed that the increase of response ECL signal was proportional to the TSP53 concentration in the range of 1 pg mL-1 to 1 ng mL-1. The detection limit was 0.5 pg mL-1, which is comparable or better than that in reported TSP53 assays. The immunosensor was successfully applied to determination of TSP53 in normal human cubital vein blood samples with good recovery, and the results are basically consistent with the TSP53 Kit (ELISA). Excellent sensitivity and selectivity make the developed ECL immunosensor a potential and simple tool for the detection of tumor biomarkers. PMID- 29432753 TI - Establishment of potent and specific synthetic substrate for dipeptidyl-peptidase 7. AB - Bacterial dipeptidyl-peptidase (DPP) 7 liberates a dipeptide with a preference for aliphatic and aromatic penultimate residues from the N-terminus. Although synthetic substrates are useful for activity measurements, those currently used are problematic, because they are more efficiently degraded by DPP5. We here aimed to develop a potent and specific substrate and found that the kcat/Km value for Phe-Met-methylcoumaryl-7-amide (MCA) (41.40 +/- 0.83 MUM-1 s-1) was highest compared to Met-Leu-, Leu-Leu-, and Phe-Leu-MCA (1.06-3.77 MUM-1 s-1). Its hydrolyzing activity was abrogated in a Porphyromonas gingivalis dpp7-knockout strain. Conclusively, we propose Phe-Met-MCA as an ideal synthetic substrate for DPP7. PMID- 29432754 TI - Optimizing research in symptomatic uterine fibroids with development of a computable phenotype for use with electronic health records. AB - BACKGROUND: Women with symptomatic uterine fibroids can report a myriad of symptoms, including pain, bleeding, infertility, and psychosocial sequelae. Optimizing fibroid research requires the ability to enroll populations of women with image-confirmed symptomatic uterine fibroids. OBJECTIVE: Our objective was to develop an electronic health record-based algorithm to identify women with symptomatic uterine fibroids for a comparative effectiveness study of medical or surgical treatments on quality-of-life measures. Using an iterative process and text-mining techniques, an effective computable phenotype algorithm, composed of demographics, and clinical and laboratory characteristics, was developed with reasonable performance. Such algorithms provide a feasible, efficient way to identify populations of women with symptomatic uterine fibroids for the conduct of large traditional or pragmatic trials and observational comparative effectiveness studies. Symptomatic uterine fibroids, due to menorrhagia, pelvic pain, bulk symptoms, or infertility, are a source of substantial morbidity for reproductive-age women. Comparing Treatment Options for Uterine Fibroids is a multisite registry study to compare the effectiveness of hormonal or surgical fibroid treatments on women's perceptions of their quality of life. Electronic health record-based algorithms are able to identify large numbers of women with fibroids, but additional work is needed to develop electronic health record algorithms that can identify women with symptomatic fibroids to optimize fibroid research. We sought to develop an efficient electronic health record-based algorithm that can identify women with symptomatic uterine fibroids in a large health care system for recruitment into large-scale observational and interventional research in fibroid management. STUDY DESIGN: We developed and assessed the accuracy of 3 algorithms to identify patients with symptomatic fibroids using an iterative approach. The data source was the Carolina Data Warehouse for Health, a repository for the health system's electronic health record data. In addition to International Classification of Diseases, Ninth Revision diagnosis and procedure codes and clinical characteristics, text data mining software was used to derive information from imaging reports to confirm the presence of uterine fibroids. Results of each algorithm were compared with expert manual review to calculate the positive predictive values for each algorithm. RESULTS: Algorithm 1 was composed of the following criteria: (1) age 18-54 years; (2) either >=1 International Classification of Diseases, Ninth Revision diagnosis codes for uterine fibroids or mention of fibroids using text mined key words in imaging records or documents; and (3) no International Classification of Diseases, Ninth Revision or Current Procedural Terminology codes for hysterectomy and no reported history of hysterectomy. The positive predictive value was 47% (95% confidence interval 39-56%). Algorithm 2 required >=2 International Classification of Diseases, Ninth Revision diagnosis codes for fibroids and positive text-mined key words and had a positive predictive value of 65% (95% confidence interval 50-79%). In algorithm 3, further refinements included >=2 International Classification of Diseases, Ninth Revision diagnosis codes for fibroids on separate outpatient visit dates, the exclusion of women who had a positive pregnancy test within 3 months of their fibroid-related visit, and exclusion of incidentally detected fibroids during prenatal or emergency department visits. Algorithm 3 achieved a positive predictive value of 76% (95% confidence interval 71-81%). CONCLUSION: An electronic health record-based algorithm is capable of identifying cases of symptomatic uterine fibroids with moderate positive predictive value and may be an efficient approach for large scale study recruitment. PMID- 29432756 TI - Region- and Cell-specific Aneuploidy in Brain Aging and Neurodegeneration. AB - Variations in genomic DNA content, or aneuploidy, are a well-recognized feature of normal human brain development. Whether changes in the levels of aneuploidy are a factor in Alzheimer's disease (AD) is less clear, as the data reported to date vary substantially in the levels of aneuploidy detected (0.7-11.5%), possibly due to methodological limitations, but also influenced by individual, regional and cellular heterogeneity as well as variations in cell subtypes. These issues have not been adequately addressed to date. While it is known that the DNA damage response increases with age, the limited human studies investigating aneuploidy in normal aging also show variable results, potentially due to susceptibility to age-related neurodegenerative processes. Neuronal aneuploidy has recently been reported in multiple brain regions in Lewy body disease, but similar genomic changes are not a feature of all synucleinopathies and aneuploidy does not appear to be related to alpha-synuclein aggregation. Rather, aneuploidy was associated with Alzheimer's pathology in the hippocampus and anterior cingulate cortex and neuronal degeneration in the substantia nigra. The association between Alzheimer's pathology and aneuploidy in regions with limited neurodegeneration is supported by a growing body of in vitro and in vivo data on aneuploidy and beta-amyloid and tau abnormalities. Large-scale studies using high resolution techniques alongside other sensitive and specific methodologies are now required to assess the true extent of cell- and region-specific aneuploidy in aging and neurodegeneration, and to determine any associations with pathologies. PMID- 29432755 TI - Pelvic muscles' mechanical response to strains in the absence and presence of pregnancy-induced adaptations in a rat model. AB - BACKGROUND: Maternal birth trauma to the pelvic floor muscles is thought to be consequent to mechanical demands placed on these muscles during fetal delivery that exceed muscle physiological limits. The above is consistent with studies of striated limb muscles that identify hyperelongation of sarcomeres, the functional muscle units, as the primary cause of mechanical muscle injury and resultant muscle dysfunction. However, pelvic floor muscles' mechanical response to strains have not been examined at a tissue level. Furthermore, we have previously demonstrated that during pregnancy, rat pelvic floor muscles acquire structural and functional adaptations in preparation for delivery, which likely protect against mechanical muscle injury by attenuating the strain effect. OBJECTIVE: We sought to determine the mechanical impact of parturition-related strains on pelvic floor muscles' microstructure, and test the hypothesis that pregnancy induced adaptations modulate muscle response to strains associated with vaginal delivery. STUDY DESIGN: Three-month-old Sprague-Dawley late-pregnant (N = 20) and nonpregnant (N = 22) rats underwent vaginal distention, replicating fetal crowning, with variable distention volumes. Age-matched uninjured pregnant and nonpregnant rats served as respective controls. After sacrifice, pelvic floor muscles, which include coccygeus, iliocaudalis, and pubocaudalis, were fixed in situ and harvested for fiber and sarcomere length measurements. To ascertain the extent of physiological strains during spontaneous vaginal delivery, analogous measurements were obtained in intrapartum rats (N = 4) sacrificed during fetal delivery. Data were compared with repeated measures and 2-way analysis of variance, followed by pairwise comparisons, with significance set at P < .05. RESULTS: Gross anatomic changes were observed in the pelvic floor muscles following vaginal distention, particularly in the entheseal region of pubocaudalis, which appeared translucent. The above appearance resulted from dramatic stretch of the myofibers, as indicated by significantly longer fiber length compared to controls. Stretch ratios, calculated as fiber length after vaginal distention divided by baseline fiber length, increased gradually with increasing distention volume. Paralleling these macroscopic changes, vaginal distention resulted in acute and progressive increase in sarcomere length with rising distention volume. The magnitude of strain effect varied by muscle, with the greatest sarcomere elongation observed in coccygeus, followed by pubocaudalis, and a smaller increase in iliocaudalis, observed only at higher distention volumes. The average fetal rat volume approximated 3 mL. Pelvic floor muscle sarcomere lengths in pregnant animals undergoing vaginal distention with 3 mL were similar to intrapartum sarcomere lengths in all muscles (P > .4), supporting the validity of our experimental approach. Vaginal distention resulted in dramatically longer sarcomere lengths in nonpregnant compared to pregnant animals, especially in coccygeus and pubocaudalis (P < .0001), indicating significant attenuation of sarcomere elongation in the presence of pregnancy induced adaptations in pelvic floor muscles. CONCLUSION: Delivery-related strains lead to acute sarcomere elongation, a well-established cause of mechanical injury in skeletal muscles. Sarcomere hyperelongation resultant from mechanical strains is attenuated by pregnancy-induced adaptations acquired by the pelvic floor muscles prior to parturition. PMID- 29432757 TI - A novel NMR-based assay to measure circulating concentrations of branched-chain amino acids: Elevation in subjects with type 2 diabetes mellitus and association with carotid intima media thickness. AB - OBJECTIVES: Plasma branched-chain amino acid (BCAA) levels, measured on nuclear magnetic resonance (NMR) metabolomics research platforms or by mass spectrometry, have been shown to be associated with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). We developed a new test for quantification of BCAA on a clinical NMR analyzer and used this test to determine the clinical correlates of BCAA in 2 independent cohorts. DESIGN AND METHODS: The performance of the NMR-based BCAA assay was evaluated. A method comparison study was performed with mass spectrometry (LC-MS/MS). Plasma BCAA were measured in the Insulin Resistance Atherosclerosis Study (IRAS, n = 1209; 376 T2DM subjects) and in a Groningen cohort (n = 123; 67 T2DM subjects). In addition, carotid intima media thickness (cIMT) was measured successfully in 119 subjects from the Groningen cohort. RESULTS: NMR-based BCAA assay results were linear over a range of concentrations. Coefficients of variation for inter- and intra-assay precision ranged from 1.8-6.0, 1.7-5.4, 4.4-9.1, and 8.8-21.3%, for total BCAA, valine, leucine, and isoleucine, respectively. BCAA quantified from the same samples using NMR and LC-MS/MS were highly correlated (R2 = 0.97, 0.95 and 0.90 for valine, leucine and isoleucine). In both cohorts total and individual BCAA were elevated in T2DM (P = 0.01 to <=0.001). Moreover, cIMT was associated with BCAA independent of age, sex, T2DM and metabolic syndrome (MetS) categorization or alternatively of individual MetS components. CONCLUSIONS: BCAA levels, measured by NMR in the clinical laboratory, are elevated in T2DM and may be associated with cIMT, a proxy of subclinical atherosclerosis. PMID- 29432758 TI - Paper spray mass spectrometry for the direct, semi-quantitative measurement of fentanyl and norfentanyl in complex matrices. AB - BACKGROUND: Fentanyl is a potent, synthetic opioid at the centre of an international health crisis that has seen thousands of fatal overdoses. Most analytical methods focus on the detection of fentanyl in blood and/or urine (i.e., post-drug use). Harm reduction (including pre-screening before drug use) may be an effective strategy against fentanyl overdoses. METHOD: Paper spray-mass spectrometry (PS-MS) is an inexpensive, direct sampling strategy where a small volume of sample (<10 MUL) is spotted onto a piece of paper that is then wetted and connected to high voltage. Ions are emitted from the paper and enter a mass spectrometer for sensitive and selective semi-quantitation using labeled internal standards. RESULTS: We present the use of PS-MS for the direct measurement of fentanyl and norfentanyl using a custom PS interface, demonstrating that paper tip position and quality can significantly affect quantitative results. Furthermore, we observe comparable calibrations for fentanyl and norfentanyl (0.5 to 600 ng/mL) across a variety of complex matrices (methanol, diluted urine, analgesic slurry). Detection limits for fentanyl are as low as 0.049 ng/mL (0.4 pg total material) in methanol, and 0.66 ng/mL (5.3 pg total material) spiked in an analgesic slurry (illicit substance simulation). PS-MS was compared with liquid chromatography-MS for the analyses of real urine samples, with satisfactory results. CONCLUSION: PS-MS shows potential as a sensitive and selective direct measurement strategy for use in fentanyl harm reduction strategies, and may also be used for pre-screening in advance of or in combination with more conventional (i.e., chromatographic) analyses. PMID- 29432759 TI - Bisphenol A exposure disturbs the bone metabolism: An evolving interest towards an old culprit. AB - Bisphenol A (BPA) (2,2,-bis (hydroxyphenyl) propane), a well-known endocrine disruptor (ED), is the exogenous chemical that mimic the natural endogenous hormone like oestrogen. Due to its extensive exposure to humans, BPA is considered to be a major toxicological agent for general population. Environmental exposure of BPA results in adverse health outcomes including bone loss. BPA disturbs the bone health by decreasing the plasma calcium level and inhibiting the calcitonin secretion. BPA also stimulated differentiation and induced apoptosis in human osteoblasts and osteoclasts. However, little is known about the underlying mechanisms of the untoward effect of BPA against bone metabolism. The present review gives an overview on the possible mechanisms of BPA towards bone loss. The previous literature shows that BPA exerts its toxic effect on bone cells by binding to the oestrogen related receptor-gamma (ERgamma), reducing the bone morphogenic protein-2 (BMP-2) and alkaline phosphatase (ALP) activities. BPA interrupts the bone metabolism via RANKL, apoptosis and Wnt/beta-catenin signaling pathways. It is, however, still debated on the exact underlying mechanism of BPA against bone health. We summarised the molecular evidences with possible mechanisms of BPA, an old environmental culprit, in bone loss and enlightened the underlying understanding of adverse action of BPA in the society. PMID- 29432760 TI - Toxic effects of fluoride on organisms. AB - Accumulation of excess fluoride in the environment poses serious health risks to plants, animals, and humans. This endangers human health, affects organism growth and development, and negatively impacts the food chain, thereby affecting ecological balance. In recent years, numerous studies focused on the molecular mechanisms associated with fluoride toxicity. These studies have demonstrated that fluoride can induce oxidative stress, regulate intracellular redox homeostasis, and lead to mitochondrial damage, endoplasmic reticulum stress and alter gene expression. This paper reviews the present research on the potential adverse effects of overdose fluoride on various organisms and aims to improve our understanding of fluoride toxicity. PMID- 29432761 TI - Application of the Quality by Design Approach to the Freezing Step of Freeze Drying: Building the Design Space. AB - The present work shows a rational method for the development of the freezing step of a freeze-drying cycle. The current approach to the selection of freezing conditions is still empirical and nonsystematic, thus resulting in poor robustness of control strategy. The final aim of this work is to fill this gap, describing a rational procedure, based on mathematical modeling, for properly choosing the freezing conditions. Mechanistic models are used for the prediction of temperature profiles during freezing and dimension of ice crystals being formed. Mathematical description of the drying phase of freeze-drying is also coupled with the results obtained by freezing models, thus providing a comprehensive characterization of the lyophilization process. In this framework, deep understanding of the phenomena involved is required, and according to the Quality by Design approach, this knowledge can be used to build the design space. The step-by-step procedure for building the design space for freezing is thus described, and examples of applications are provided. The calculated design space is validated upon experimental data, and we show that it allows easy control of the freezing process and fast selection of appropriate operating conditions. PMID- 29432762 TI - Synthesis of a Glibenclamide Cocrystal: Full Spectroscopic and Thermal Characterization. AB - A cocrystal of glibenclamide, an antidiabetic drug classified as type II compound according to the Biopharmaceutics Classification System, has been synthesized using tromethamine as coformer in 1:1 molar ratio, by slow solvent evaporation cocrystalization. The cocrystal obtained was characterized by X-ray powder diffraction, differential scanning calorimetry, Raman, mid infrared, and near infrared spectroscopy. The results consistently show the formation of a cocrystal between active pharmaceutical ingredients and conformer with the synthons corresponding to hydrogen bonding between hydrogen in amines of tromethamine and carbonyl and sulfonyl groups in glibenclamide. PMID- 29432763 TI - "Product on Stopper" in a Lyophilized Drug Product: Cosmetic Defect or a Product Quality Concern? AB - During manufacturing of a lyophilized drug product, operator errors in product handling during loading of product filled vials onto the lyophilizer can lead to a seemingly cosmetic defect which can impact certain critical quality attributes of finished product. In this study, filling of a formulated monoclonal antibody in vials was performed using a peristaltic pump filling unit, and subsequently, the product was lyophilized. After lyophilization, upon visual inspection, around 40% of vials had cosmetic defect with residual product around stopper of the vial and were categorized as "product on stopper" vials, whereas remaining 60% vials with no cosmetic defect were called "acceptable vials." Both groups of vials from 1 single batch were tested for critical quality attributes including protein concentration (ultraviolet absorbance at 280), residual moisture (Karl Fischer), sterility (membrane filtration), and container closure integrity (CCI) (blue dye ingress). Analysis of protein quality attributes such as aggregation, protein concentration, residual moisture showed no significant difference between vials with "product on stopper" and "acceptable vials." However, CCI of the "product on stopper" vials was compromised due to the presence of product around stopper of the vial. The results from this case study demonstrate the following 2 important findings: (1) that a seemingly cosmetic defect may impact product quality, compromising the integrity of the product and (2) that CCI test method can be used as an orthogonal method to sterility testing to evaluate sterility assurance of the product. The corrective action proposed to mitigate this defect is use of a larger sized vial that can potentially minimize this defect that arises because of product handling errors. PMID- 29432764 TI - Seasonality of honey bee (Apis mellifera) micronutrient supplementation and environmental limitation. AB - Honey bees (Apis mellifera) obtain micronutrients from floral resources and "dirty", or turbid, water. Past research suggests that honey bees drink dirty water to supplement the micronutrients in their floral diet, however, there is no research that directly investigates how floral micronutrient content varies with water preferences, or how micronutrients in honey bees themselves vary seasonally. In this study, we used chemical analyses (ICP-OES) to investigate seasonal variation of micronutrients in honey bee workers and floral resources in the field. We found that honey bees likely use mineralized water to supplement their floral diet and may be limited by availability of calcium and potassium. Our results also suggest that honey bees may seasonally seek specific micronutrients, perhaps in preparation for overwintering. PMID- 29432765 TI - Food consumption in ground beetles is limited under hypoxic conditions in response to ad libitum feeding, but not restricted feeding. AB - Habitats on land with low oxygen availability provide unique niches inhabited by numerous species. The occupation of such hypoxic niches by animals is hypothesized to come at a cost linked to the limitations of aerobic metabolism and thus energy budget but may also provide benefits through physical protection from predators and parasitoids or reduced competition for food. We investigated the effects of hypoxic conditions on standard metabolic rate (SMR) and specific dynamic action (SDA) in male Carabus nemoralis. SMR and SDA were determined under three manipulated oxygen availabilities: 7, 14 and 21% O2 and two feeding regimes: limited or ad libitum food consumption. In both hypoxic conditions, C. nemoralis was able to maintain SMR at levels similar to those in normoxia. When the meal size was limited, SDA duration did not differ among the oxygen availability conditions, but SDA was smaller under hypoxic conditions than at normoxic levels. The relative cost of digestion was significantly higher in normoxia than in hypoxia, but it did not affect net energy intake. In contrast, when offered a large meal to simulate ad libitum food conditions, beetles reduced their food consumption and net energy gain by 30% under hypoxia. Oxygen availability may influence the consumed prey size: the hypoxic condition did not limit net energy gain when the beetles fed on a small meal but did when they fed on a large meal. The results indicate that meal size is an important variable in determining differences in physiological costs and whole animal energy budgets at different concentrations of environmental oxygen levels. PMID- 29432766 TI - The thermal dependence of carbon stable isotope incorporation and trophic discrimination in the domestic cricket, Acheta domesticus. AB - Stable isotopes are valuable tools in physiological and ecological research, as they can be used to estimate diet, habitat use, and resource allocation. However, in most cases a priori knowledge of two key properties of stable isotopes is required, namely their rate of incorporation into the body (incorporation rate) and the change of isotope values between consumers and resources that arises during incorporation of the isotopes into the consumer's tissues (trophic discrimination). Previous studies have quantified these properties across species and tissue types, but little is known about how they vary with temperature, a key driver of many biological rates and times. Here, we explored for the first time how temperature affects both carbon incorporation rate and trophic discrimination via growth rates, using the domestic cricket, Acheta domesticus. We raised crickets at 16 degrees C, 21 degrees C, and 26 degrees C and showed that temperature increased carbon isotope incorporation rate, which was driven by both an increased growth rate and catabolism at higher temperatures. Trophic discrimination of carbon isotopes decreased at higher temperatures, which we attributed to either lower activation energies needed to synthesize non-essential amino acids at higher temperatures or the increased utilization of available resources of consumers at higher temperatures. Our results demonstrate that temperature is a key driver of both carbon isotope incorporation rate and trophic discrimination, via mechanisms that likely persist across all ectotherms. Experiments to determine incorporation rates and trophic discrimination factors in ectotherms must include temperature as a major factor, and natural variation in temperature might have significant effects on these isotopic properties that then can affect inferences made from isotope values. PMID- 29432767 TI - Suppress to feel and remember less: Neural correlates of explicit and implicit emotional suppression on perception and memory. AB - Available evidence suggests that emotion regulation can modulate both immediate (emotional experience) and long-term (episodic memory) effects of emotion, and that both explicit and implicit forms may be effective. However, neural mechanisms by which explicit and implicit emotional suppression affect these phenomena remain unclear, particularly regarding their effects on memory. In this study, participants rated the emotional content of negative and neutral images, following explicit (verbal instructions) or implicit (priming) induction of emotional suppression goals, during functional magnetic resonance imaging. Participants' memory for the images was tested one week later. Behaviorally, explicit suppression reduced emotional ratings of negative images, whereas both explicit and implicit suppression reduced subsequent memory. At the neural level, the engagement of explicit suppression was uniquely associated with decreased activity in the amygdala (AMY), during emotional ratings, and in the AMY and inferior frontal gyrus (IFG), during successful encoding. Although both explicit and implicit suppression diminished functional connectivity between these regions and the hippocampus (HC) linked to successful encoding, explicit suppression was uniquely associated with interference with AMY-HC interactions, which no longer predicted subsequent memory for the explicitly-suppressed items. Overall, these findings advance our understanding of the common and dissociable mechanisms of explicit and implicit emotional suppression on perception and memory, and suggest their impact on both bottom-up and top-down mechanisms involved in emotion cognition interactions. PMID- 29432768 TI - Reading and visual word recognition ability in semantic dementia is not predicted by semantic performance. AB - This paper describes longitudinal testing of two Semantic Dementia (SD) cases. It is common for patients with SD to present with deficits in reading aloud irregular words (i.e. surface dyslexia), and in lexical decision. Theorists from the connectionist tradition (e.g. Woollams et al., 2007) argue that in SD cases with concurrent surface dyslexia, the deterioration of irregular word reading and recognition performance is related to the extent of the deterioration of the semantic system. The Dual Route Cascaded model (DRC; Coltheart et al., 2001) makes no such prediction. We examined this issue using a battery of cognitive tests and two structural scans undertaken at different points in each cases time course. Across both cases, our behavioural testing found little evidence of a key putative link between semantic impairment and the decline of irregular word reading or lexical decision. In addition, our neuroimaging analyses suggested that it may be the emergence of atrophy to key neural regions both inside and outside the anterior temporal lobes that may best capture the emergence of impairments of irregular word reading, and implicated inferior temporal cortex in surface dyslexia. PMID- 29432769 TI - Self-construals moderate associations between trait creativity and social brain network. AB - Creativity is an adaptive way of thinking and plays a key role in problem solving. Recent brain imaging studies focused on structural and functional characteristics of the brain that are correlated with creativity. But whether and how the association between creativity and the brain is moderated by individuals' cultural traits remains unclear. We integrated functional magnetic resonance imaging (fMRI) and questionnaire measures (Williams creativity aptitude test) of trait creativity and self-construal (e.g., interdependence) in male adults to examine whether trait creativity is associated with neural activities underlying social cognition and whether and how the association is moderated by individuals' self-construals. We found that interdependence moderates the association between trait creativity and neural activities in the left superior temporal sulcus, right anterior insular, right temporal-parietal junction and right precentral gyrus engaged in reflection of one's own social attributes. Interdependence also moderates the association between trait creativity and neural activities in the left superior temporal sulcus and right posterior insular involved in reflection of a friend's social attributes. The link of trait creativity and the functional connectivity between the medial prefrontal cortex and postcentral gyri during reflection of a friend's social attributes is also moderated by interdependence. Participants with high and low creativity traits can be dissociated in a three dimension space defined by integration of interdependence and the brain activity underlying reflection of one's own and the friend's attributes. Our findings suggest that trait creativity is imprinted on the social brain and the link between trait creativity and the neural activities underlying the processing of self and others is moderated by a cultural trait. PMID- 29432770 TI - RNA-Seq analysis during the life cycle of Cryptosporidium parvum reveals significant differential gene expression between proliferating stages in the intestine and infectious sporozoites. AB - Cryptosporidium parvum is a major cause of diarrhoea in humans and animals. There are no vaccines and few drugs available to control C. parvum. In this study, we used RNA-Seq to compare gene expression in sporozoites and intracellular stages of C. parvum to identify genes likely to be important for successful completion of the parasite's life cycle and, thereby, possible targets for drugs or vaccines. We identified 3774 protein-encoding transcripts in C. parvum. Applying a stringent cut-off of eight fold for determination of differential expression, we identified 173 genes (26 coding for predicted secreted proteins) upregulated in sporozoites. On the other hand, expression of 1259 genes was upregulated in intestinal stages (merozoites/gamonts) with a gene ontology enrichment for 63 biological processes and upregulation of 117 genes in 23 metabolic pathways. There was no clear stage specificity of expression of AP2-domain containing transcription factors, although sporozoites had a relatively small repertoire of these important regulators. Our RNA-Seq analysis revealed a new calcium-dependent protein kinase, bringing the total number of known calcium-dependent protein kinases (CDPKs) in C. parvum to 11. One of these, CDPK1, was expressed in all stages, strengthening the notion that it is a valid drug target. By comparing parasites grown in vivo (which produce bona fide thick-walled oocysts) and in vitro (which are arrested in sexual development prior to oocyst generation) we were able to confirm that genes encoding oocyst wall proteins are expressed in gametocytes and that the proteins are stockpiled rather than generated de novo in zygotes. RNA-Seq analysis of C. parvum revealed genes expressed in a stage specific manner and others whose expression is required at all stages of development. The functional significance of these can now be addressed through recent advances in transgenics for C. parvum, and may lead to the identification of viable drug and vaccine targets. PMID- 29432772 TI - The effects of synbiotic supplementation on insulin resistance/sensitivity, lipid profile and total antioxidant capacity in women with gestational diabetes mellitus: A randomized double blind placebo controlled clinical trial. AB - AIMS: The role of gut microbiota in the management of diabetes is shown. In this randomized clinical trial we assessed the effects of synbiotic supplementation on insulin, lipid profile and antioxidative status among women with gestational diabetes mellitus (GDM). METHODS: Ninety pregnant women with GDM were randomly assigned into two groups to receive either a daily synbiotic capsule - consisting of L. acidophilus, L. plantarum, L. fermentum, L. gasseri (1.5-7.0 * 109-10 CFU/g) - with fructooligosaccharide (38.5 mg), or placebo for 6 weeks. Fasting plasma glucose (FPG), insulin, homeostasis model assessment-insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), high- and low density lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol (TC), triglycerides (TG), total antioxidant capacity (TAC), and systolic and diastolic blood pressure (SBP, DSP) were assessed before and after the intervention. RESULTS: No significant changes in FPG, insulin resistance/sensitivity, lipid profile and TAC indices were seen in synbiotic group compared to the placebo one (p > 0.05). Significant within group increases for HDL-C and TAC levels in synbiotic group were observed (p < 0.05). LDL-C showed significant increment in the placebo group compared to the baseline of the study (6.9 mg/dL, p < 0.05). Between group comparison showed significant decrease in SBP and DBP in synbiotic group compared to placebo (-2.5 vs. 8.6 mmHg, and -1.8 vs. 2.1 mmHg, p < 0.05). CONCLUSIONS: The results showed that, in women with GDM, synbiotic supplementation had no effect on FPG and insulin resistance/sensitivity indices. Lipid profile and TAC status may be affected by synbiotic supplementation. Synbiotic is effective in reducing of blood pressure in women with GDM. PMID- 29432773 TI - Identifying patterns of general practitioner service utilisation and their relationship with potentially preventable hospitalisations in people with diabetes: The utility of a cluster analysis approach. AB - AIMS: We aimed to characterise use of general practitioners (GP) simultaneously across multiple attributes in people with diabetes and examine its impact on diabetes related potentially preventable hospitalisations (PPHs). METHODS: Five years of panel data from 40,625 adults with diabetes were sourced from Western Australian administrative health records. Cluster analysis (CA) was used to group individuals with similar patterns of GP utilisation characterised by frequency and recency of services. The relationship between GP utilisation cluster and the risk of PPHs was examined using multivariable random-effects negative binomial regression. RESULTS: CA categorised GP utilisation into three clusters: moderate; high and very high usage, having distinct patient characteristics. After adjusting for potential confounders, the rate of PPHs was significantly lower across all GP usage clusters compared with those with no GP usage; IRR = 0.67 (95%CI: 0.62-0.71) among the moderate, IRR = 0.70 (95%CI 0.66-0.73) high and IRR = 0.76 (95%CI 0.72-0.80) very high GP usage clusters. CONCLUSIONS: Combination of temporal factors with measures of frequency of use of GP services revealed patterns of primary health care utilisation associated with different underlying patient characteristics. Incorporation of multiple attributes, that go beyond frequency-based approaches may better characterise the complex relationship between use of GP services and diabetes-related hospitalisation. PMID- 29432771 TI - The relationships between faecal egg counts and gut microbial composition in UK Thoroughbreds infected by cyathostomins. AB - A growing body of evidence, particularly in humans and rodents, supports the existence of a complex network of interactions occurring between gastrointestinal (GI) helminth parasites and the gut commensal bacteria, with substantial effects on both host immunity and metabolic potential. However, little is known of the fundamental biology of such interactions in other animal species; nonetheless, given the considerable economic losses associated with GI parasites, particularly in livestock and equines, as well as the global threat of emerging anthelmintic resistance, further explorations of the complexities of host-helminth-microbiota interactions in these species are needed. This study characterises the composition of the equine gut commensal flora associated with the presence, in faecal samples, of low (Clow) and high (Chigh) numbers of eggs of an important group of GI parasites (i.e. the cyathostomins), prior to and following anthelmintic treatment. High-throughput sequencing of bacterial 16S rRNA amplicons and associated bioinformatics and statistical analyses of sequence data revealed strong clustering according to faecal egg counts (P = 0.003). A trend towards increased populations of Methanomicrobia (class) and Dehalobacterium (genus) was observed in Clow in comparison with Chigh. Anthelmintic treatment in Chigh was associated with a significant reduction of the bacterial Phylum TM7 14 days post-ivermectin administration, as well as a transient expansion of Adlercreutzia spp. at 2 days post-treatment. This study provides a first known insight into the discovery of the intimate mechanisms governing host-parasite microbiota interactions in equines, and sets a basis for the development of novel, biology-based intervention strategies against equine GI helminths based on the manipulation of the commensal gut flora. PMID- 29432774 TI - Proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) controls immune synapse stability in human T cells. AB - BACKGROUND: Proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) is a cytosolic adaptor protein involved with T-cell activation, differentiation, and migration. On cognate T-cell contact, PSTPIP1 is recruited to surface expressed CD2, where it regulates F-actin remodeling. An immune synapse (IS) is thereby rapidly formed, consisting of T-cell receptor clusters surrounded by a ring of adhesion molecules, including CD2. OBJECTIVE: From genetic screening of patients with primary immunodeficiencies, we identified 2 mutations in PSTPIP1, R228C and T274M, which we further characterized in the primary patients' T cells. METHODS: F-actin dynamics were assessed in primary T cells from the patients and control subjects by using fluorescence-activated cell sorting. HEK293T and Jurkat cells were transfected with R228C, T274M, and wild-type PSTPIP1 to visualize F actin in IS formation. CD2-PSTPIP1 association was quantified through immunoprecipitation assays. RESULTS: The patients presented with immunodeficiency without signs of autoinflammation. The patient with the R228C mutation had expansion of mostly naive phenotype T cells and few memory T cells; the patient with the T274M mutation had 75% reduction in CD4 T cells that were predominantly of the memory subset. We observed F-actin polymerization defects in T cells from both patients with PSTPIP1, most notably the patient with the T274M mutation. Capping of CD2-containing membrane microdomains was disrupted. Analysis of IS formation using Jurkat T-cell transfectants revealed a reduction in F-actin accumulation at the IS, again especially in cells from the patient with the T274M PSTPIP1 mutation. T cells from the patient with the T274M mutation migrated spontaneously at increased speed, as assessed in a 3-dimensional collagen matrix, whereas T-cell receptor cross-linking induced a significantly diminished calcium flux. CONCLUSIONS: We propose that PSTPIP1 T-cell differentiation defects are caused by defective control of F-actin polymerization. A preactivated polymerized F-actin status, as seen in T cells from patients with the PSTPIP1 T274M mutation, appears particularly damaging. PSTPIP1 controls IS formation and cell adhesion through its function as an orchestrator of the F-actin cytoskeleton. PMID- 29432775 TI - Comparative transcriptome analysis of a Trichoplusia ni cell line reveals distinct host responses to intracellular and secreted protein products expressed by recombinant baculoviruses. AB - The baculovirus insect cell expression system has become a firmly established production platform in biotechnology. Various complex proteins, multi-subunit particles including veterinary and human vaccines are manufactured with this system on a commercial scale. Apart from baculovirus infected Spodoptera frugiperda (Sf9) cells, the Trichoplusia ni (HighFive) cell line is alternatively used as host organism. In this study, we explored the protein production capabilities of Tnms42 insect cells, a new derivative of HighFive, which is free of latent nodavirus infection. As a model system, a cytosolic (mCherry) and a secreted (hemagglutinin) protein were overexpressed in Tnms42 cells. The response of the host cells was followed in a time course experiment over the infection cycle by comparative transcriptome analysis (RNA-seq). As expected, the baculovirus infection per se had a massive impact on the host cell transcriptome, which was observed by the huge total number of differentially expressed transcripts (>14,000). Despite this severe overall cellular reaction, a specific response could be clearly attributed to the overexpression of secreted hemagglutinin, revealing limits in the secretory capacity of the host cell. About 400 significantly regulated transcripts were identified and assigned to biochemical pathways and gene ontology (GO) categories, all related to protein processing, folding and response to unfolded protein. The identification of relevant target genes will serve to design specific virus engineering concepts for improving the yield of proteins that are dependent on the secretory pathway. PMID- 29432776 TI - Establishment of Cre-mediated HBV recombinant cccDNA (rcccDNA) cell line for cccDNA biology and antiviral screening assays. AB - Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), existing in hepatocyte nuclei as a stable minichromosome, plays a central role in the life cycle of the virus and permits the persistence of infection. Despite being essential for HBV infection, little is known about the molecular mechanisms of cccDNA formation, regulation and degradation, and there is no therapeutic agents directly targeting cccDNA, fore mostly due to the lack of robust, reliable and quantifiable HBV cccDNA models. In this study, combined the Cre/loxP and sleeping beauty transposons system, we established HepG2-derived cell lines integrated with 2-60 copies of monomeric HBV genome flanked by loxP sites (HepG2-HBV/loxP). After Cre expression via adenoviral transduction, 3.3-kb recombinant cccDNA (rcccDNA) bearing a chimeric intron can be produced in the nuclei of these HepG2 HBV/loxP cells. The rcccDNA could be accurately quantified by quantitative PCR using specific primers and cccDNA pool generated in this model could be easily detected by Southern blotting using the digoxigenin probe system. We demonstrated that the rcccDNA was epigenetically organized as the natural minichromosome and served as the template supporting pgRNA transcription and viral replication. As the expression of HBV S antigen (HBsAg) is dependent on the newly generated cccDNA, HBsAg is the surrogate marker of cccDNA. Additionally, the efficacies of 3 classes of anti-HBV agents were evaluated in HepG2-HBV/loxP cells and antiviral activities with different mechanisms were confirmed. These data collectively suggested that HepG2-HBV/loxP cell system will be powerful platform for studying cccDNA related biological mechanisms and developing novel cccDNA targeting drugs. PMID- 29432777 TI - Multiple glycolytic enzymes are antigens also in biliary atresia. PMID- 29432778 TI - "Looking-at-nothing" during sequential sensorimotor actions: Long-term memory based eye scanning of remembered target locations. AB - Before acting humans saccade to a target object to extract relevant visual information. Even when acting on remembered objects, locations previously occupied by relevant objects are fixated during imagery and memory tasks - a phenomenon called "looking-at-nothing". While looking-at-nothing was robustly found in tasks encouraging declarative memory built-up, results are mixed in the case of procedural sensorimotor tasks. Eye-guidance to manual targets in complete darkness was observed in a task practiced for days beforehand, while investigations using only a single session did not find fixations to remembered action targets. Here, it is asked whether looking-at-nothing can be found in a single sensorimotor session and thus independent from sleep consolidation, and how it progresses when visual information is repeatedly unavailable. Eye movements were investigated in a computerized version of the trail making test. Participants clicked on numbered circles in ascending sequence. Fifty trials were performed with the same spatial arrangement of 9 visual targets to enable long term memory consolidation. During 50 consecutive trials, participants had to click the remembered target sequence on an empty screen. Participants scanned the visual targets and also the empty target locations sequentially with their eyes, however, the latter less precise than the former. Over the course of the memory trials, manual and oculomotor sequential target scanning became more similar to the visual trials. Results argue for robust looking-at-nothing during procedural sensorimotor tasks provided that long-term memory information is sufficient. PMID- 29432779 TI - The protective effect of alpha-lipoic acid against brain ischemia and reperfusion injury via mTOR signaling pathway in rats. AB - Alpha-lipoic Acid(ALA), an endogenous short-chain fatty acid, has been found inducing a protective effect against ischemia and reperfusion(I/R) injury. Recently, mTOR signaling pathway has been proved to involve in the mechanism of I/R injury. In our previous study, we determined that ALA could protect cerebral endothelial cells against I/R injury via mTOR signaling pathway. However, whether ALA can protect against brain I/R injury in vivo and its mechanisms is uncertain. In this study, we try to explore if the ALA treatment can protect against brain I/R injury and confirm the relationship between ALA and mTOR signaling pathway. ALA was administrated to the animals after dMCAo and reperfusion model established with or without rapamycin pre-treatment. The results showed the infarct size was obviously reduced after ALA treatment in acute stage, neurological functions were also improved distinctly. The mTOR signaling pathway was remarkably blocked after brain I/R injury while it could be activated through ALA treatment. However, rapamycin, can abolish the protective effects induced by ALA treatment in both acute and long-term phase. In conclusion, we demonstrate the protective effects induced by ALA treatment against the brain I/R injury in rats and mTOR signaling pathway is required for the protective effects of ALA against brain I/R injury. The results might contribute to the potential clinical application of ALA and provide a potential therapeutic target on ischemic stroke. PMID- 29432781 TI - Pleiotropy, the physiologic basis for biologic fields. AB - Biologic organisms act like fields. Hypothetically, pleiotropy results from the systematic re-purposing of genes over the course of the evolutionary history of the organism as pre-adaptations or exaptations. Mechanistically, pleiotropic genes are selected for during the process of evolution with reference to the First Principles of Physiology (FPP). Under stress conditions, pleiotropic genes will act as a functional network to cohesively maintain allostasis. There are strong homologies between Quantum Mechanics and the FPP. The homology between the Quantum states of the electron and cell may be due to the self-organizing principle that underlies both, hypothetically emanating from the Big Bang that formed the Universe some 13.8 billion years ago. The identification of the common origins and principles of physics and biology offers a cohesive explanation for origins and evolution of life. PMID- 29432780 TI - How mechanical forces shape the developing eye. AB - In the vertebrate embryo, the eyes develop from optic vesicles that grow laterally outward from the brain tube and contact the overlying surface ectoderm. Within the region of contact, each optic vesicle and the surface ectoderm thicken to form placodes, which then invaginate to create the optic cup and lens pit, respectively. Eventually, the optic cup becomes the retina, while the lens pit closes to form the lens vesicle. Here, we review current hypotheses for the physical mechanisms that create these structures and present novel three dimensional computer (finite-element) models to illustrate the plausibility and limitations of these hypotheses. Taken together, experimental and numerical results suggest that the driving forces for early eye morphogenesis are generated mainly by differential growth, actomyosin contraction, and regional apoptosis, with morphology mediated by physical constraints provided by adjacent tissues and extracellular matrix. While these studies offer new insight into the mechanics of eye development, future work is needed to better understand how these mechanisms are regulated to precisely control the shape of the eye. PMID- 29432782 TI - Subpopulations of extracellular vesicles and their therapeutic potential. AB - Extracellular vesicles (EVs), such as exosomes and microvesicles, have over the last 10-15 years been recognized to convey key messages in the molecular communication between cells. Indeed, EVs have the capacity to shuttle proteins, lipids, and nucleotides such as RNA between cells, leading to an array of functional changes in the recipient cells. Importantly, the EV secretome changes significantly in diseased cells and under conditions of cellular stress. More recently, it has become evident that the EV secretome is exceptionally diverse, with many different types of EVs being released by a single cell type, and these EVs can be described in terms of differences in density, molecular cargos, and morphology. This review will discuss the diversity of EVs, will introduce some suggestions for how to categorize them, and will propose how EVs and their subpopulations might be used for very different therapeutic purposes. PMID- 29432783 TI - Effect of target temperature management at 32-34 degrees C in cardiac arrest patients considering assessment by regional cerebral oxygen saturation: A multicenter retrospective cohort study. AB - AIM: Target temperature management (TTM) is used in comatose post-cardiac arrest patients, but the recommended temperature range is wide. This study aimed to assess the effectiveness of TTM at 32-34 degrees C while considering the degree of cerebral injury and cerebral circulation, as assessed by regional cerebral oxygen saturation (rSO2). METHODS: This is a secondary analysis of prospectively collected registry data from comatose patients who were transferred to 15 hospitals in Japan after out-of-hospital cardiac arrest (OHCA) from 2011 to 2013. The primary outcome was all-cause mortality at 90 days after OHCA, and the secondary outcome was favorable neurological outcomes as evaluated according to the Cerebral Performance Category. We monitored rSO2 noninvasively with near infrared spectroscopy, which could assess cerebral perfusion and the balance of oxygen delivery and uptake. RESULTS: We stratified 431 study patients into three groups according to rSO2 on hospital arrival: rSO2 <=40% (n = 296), rSO2 41-60% (n = 67), and rSO2 >=61% (n = 68). Propensity score analysis revealed that TTM at 32-34 degrees C decreased all-cause mortality in patients with rSO2 41-60% (average treatment effect on treated [ATT] by propensity score matching [PSM] 0.51, 95%CI -0.70 to -0.33; ATT by inverse probability of treatment weighting [IPW] -0.52, 95%CI -0.71 to -0.34), and increased favorable neurological outcomes in patients with rSO2 41-60% (ATT by PSM 0.50, 95%CI 0.32-0.68; ATT by IPW 0.52, 95%CI 0.35-0.69). CONCLUSION: TTM at 32-34 degrees C effectively decreased all cause mortality in comatose OHCA patients with rSO2 41-60% on hospital arrival in Japan. PMID- 29432784 TI - Cognitive and neuromodulation strategies for unhealthy eating and obesity: Systematic review and discussion of neurocognitive mechanisms. AB - We systematically reviewed research on cognitive training and neuromodulation interventions for reducing food craving/intake, unhealthy diet and weight, and discussed their mechanisms of action. We reviewed 50 studies involving six cognitive trainings: Approach and Attentional Bias Modification, Implementation Intentions, Response Inhibition, Episodic Future Thinking and Working Memory; and four neuromodulation approaches: Transcranial Magnetic Stimulation (TMS), transcranial Direct Current Stimulation (tDCS), Deep Brain Stimulation (DBS) and Neurofeedback. Response Inhibition and Implementation Intentions have shown to reduce unhealthy diet and weight in people with overweight/obesity. Attentional Bias Modification has shown promising results in healthy-weight participants. Brain stimulation of the Dorsolateral Prefrontal Cortex via tDCS and the Hypothalamus via DBS showed benefits for reducing food craving and weight in people with overweight/obesity. Studies quality was generally high, but most trials were short-term and many conducted in healthy-weight samples. Modification of cognitive control and motivational processes/circuits are common mechanisms of beneficial training and neuromodulation interventions, and thus a promising approach for overweight/obesity treatment. Longer duration trials in clinical populations are needed to confirm benefits. PMID- 29432785 TI - Expression of MDM2 and p16 in angiomyolipoma. AB - Angiomyolipoma (AML) arises primarily from the kidney but may grow into the retroperitoneal space mimicking a primary retroperitoneal tumor. Fine needle aspiration (FNA) and core needle biopsy of AML, particularly the fat-predominant variant, may be difficult to distinguish from retroperitoneal well-differentiated liposarcoma (WDLS) or lipoma. Commonly used immunomarkers, MDM2 and p16, have proven useful in diagnosing WDLS and dedifferentiated liposarcoma (DDLS), while HMB45 and Melan-A are melanocyte-related markers characteristically expressed in AML. In this study, we investigated the utility of MDM2 and p16 along with HMB45 and Melan-A immunohistochemical analysis in distinguishing AML from WDL/DDLS or lipoma. Immunohistochemically, AMLs demonstrated focal MDM2 expression (40% of cases) and focal/diffuse expression of p16 (60%). AMLs marked focally or diffusely with HMB45 (76% of cases) and Melan-A (96%). These latter two immunomarkers were not expressed in any of the WDLS/DDLSs or lipomas tested. WDLS/DDLSs showed focal/diffuse expression of MDM2 (91% of cases) and p16 (97%). While focal expression of MDM2 and p16 was observed in 14% and 67% of lipomas, respectively, no lipoma exhibited diffuse MDM2 positivity. In our hands, MDM2 expression by itself cannot exclude the diagnosis of AML or lipoma, and p16 alone is not helpful in separating AML and conventional lipoma from WDLS/DDLS. However, along with morphology, an immunohistochemical battery including HMB45, Melan-A, MDM2 and p16 are useful in distinguishing AML from WDLS/DDLS or lipoma. For equivocal cases, fluorescence in situ hybridization for MDM2 should be performed. PMID- 29432786 TI - Oleic acid induces the novel apolipoprotein O and reduces mitochondrial membrane potential in chicken and human hepatoma cells. AB - Non-alcoholic fatty liver disease (NAFLD) is marked by hepatic fat accumulation and reflects a spectrum of chronic liver diseases associated with obesity, impaired insulin sensitivity and dyslipidemia. Apolipoprotein O (ApoO) is a new member of the plasma apolipoprotein family that may play a role in lipid metabolism and electron transport activity of the mitochondrium. However, its physiological functions have not been elucidated yet. Based on our previous data in a non-mammalian experimental system [1], we hypothesized that hepatic expression of ApoO is tightly linked not only to diet-induced hepatosteatosis, but also to increased lipoprotein-production induced by, e.g., hormones and oxidative stress. To gain insight into a mammalian experimental system, we compared the effects of lipid loading on ApoO regulation in chicken hepatoma LMH cells with those in the human hepatoma cell line HepG2. Incubation of the cells with BSA-complexed oleic acid (OA-Alb) induced triglyceride accumulation, but did not affect cell viability. qPCR using specific primer pairs and Western blot analysis with in-house produced rabbit anti-ApoO antisera demonstrated significant increase in ApoO transcript and protein levels in both cell lines. ROS formation due to OA-Alb treatment was only slightly altered in LMH cells, indicating an intact antioxidant defense system of the cells. Oxidative stress applied by addition of H2O2 revealed induction of ApoO transcript and protein level in the same or even higher extent as monitored in the presence of OA-Alb. Upon treatment with estrogen for 24 h quantitative analysis of ApoO transcript and protein revealed increases of ApoO expression supporting the assumption that estrogen affects lipoprotein metabolism at various points. Furthermore, both cell lines showed a significant decrease of the mitochondrial membrane potential upon incubation with OA-Alb. Therefore, we assume that our findings support a role of ApoO as an effector of compromised mitochondrial function that likely accompanies the onset of non-alcoholic fatty liver disease. PMID- 29432787 TI - Possible involvement of monoamine neurons in the emotional abnormality in Kir6.2 deficient mice. AB - ATP-sensitive potassium (KATP) channels consist of two structurally different subunits: a pore-forming subunit of the Kir6.0-family (Kir6.1 or Kir6.2) and a regulatory sulfonylurea receptor subunit (SUR1, SUR2A or SUR2B). Although Kir6.2 is widely distributed in the brain, the mechanisms that underlie the impact of Kir6.2 on emotional behavior are not yet fully understood. To clarify the role of Kir6.2 in emotional behavior, in the present study, we investigated the behavioral characteristics of Kir6.2-knockout (Kir6.2-/-) mice. Kir6.2-/- mice showed impaired general behavior in a locomotor activity test and open field test. In addition, anxiety-like behavior was observed in the open field test, elevated plus-maze test and light-dark test. In particular, excessive anxiety like behavior was observed in female Kir6.2-/- mice. Moreover, we investigated whether Kir6.2 is expressed on monoamine neurons in the brain. Immunohistochemical studies showed that Kir6.2 was co-localized with tryptophan hydroxylase (TPH), a marker of serotonergic neurons, in dorsal raphe nuclei. Kir6.2 was also co-localized with tyrosine hydroxylase (TH), a marker of dopaminergic/noradrenergic neurons, in the ventral tegmental area and locus coeruleus. Next, we checked the protein levels of TH and TPH in the midbrain. Interestingly, TPH expression was significantly elevated in female Kir6.2-/- mice. These results suggest that Kir6.2 in monoamine neurons, especially serotonergic neurons, could play a key role in emotional behavior. PMID- 29432788 TI - Different perception levels of histamine-induced itch sensation in young adult mice. AB - Itch is an unpleasant sensation that evokes behavioral responses such as scratching the skin. Interestingly, it is conceived that the perception of itch sensation is influenced by age. Indeed, accumulating evidence supports the idea that even children or younger adults show distinctive itch sensation depending on age. This evidence implies the presence of a mechanism that regulates the perception of itch sensation in an age-dependent fashion. Therefore, the purpose of the present study was to investigate a putative mechanism for the age dependent perception of itch sensation by comparing histamine-induced scratching behaviors in 45-day old (D45) and 75-day old male "young adult" mice. The results indicated that, following histamine administration, the D75 mice spent a longer time scratching than D45 mice. However, the intensity of the calcium influx induced by histamine in primary culture of dorsal root ganglia (DRG) neurons was not different between D45 and D75 mice. Moreover, no apparent difference was observed in mRNA levels of a characteristic His-related receptor and ion channel. In contrast, the mRNA levels of Toll-Like Receptor 4 (TLR4) were increased approximately by two-fold in D75 DRG compared with D45 DRG. Additionally, D75 derived DRG neurons exhibited enhanced intracellular calcium increase by lipopolysaccharide (LPS, a TLR4 agonist) than those of D45 mice. Furthermore, intensities of calcium influx induced by histamine were significantly potentiated when co-treated with LPS in D75 DRG neurons, but not in those of D45 mice. Thus, it appears that D75 mice showed enhanced histamine-induced scratching behaviors not by increased expression levels of histamine-related genes, but probably due to augmented TLR4 expression in DRG neurons. Consequently, the current study found that different perception levels of histamine-induced itch sensation are present in different age groups of young adult mice. PMID- 29432789 TI - Behavioural incentive interventions for health behaviour change in young people (5-18 years old): A systematic review and meta-analysis. AB - Physical inactivity, an unhealthy diet, smoking, and alcohol consumption are key determinants of morbidity and mortality. These health behaviours often begin at a young age and track into adulthood, emphasising a need for interventions in children and young people. Previous research has demonstrated the potential effectiveness of behavioural incentive (BI) interventions in adults. However, little is known about their effectiveness in children and adolescents. Eight bibliographic databases were searched. Eligibility criteria included controlled trials using behavioural incentives (rewards provided contingent on successful performance of the target behaviour) as an intervention component for health behaviour change in children and adolescents. Intervention effects (standardised mean differences or odds ratios) were calculated and pooled by health behaviour, using a random effects model. Twenty-two studies were included (of n = 8392 identified), 19 of which were eligible for meta-analysis: physical activity (n = 8); healthier eating (n = 3); and smoking (n = 8). There was strong evidence that behavioural incentives may encourage healthier eating behaviours, some evidence that behavioural incentives were effective for encouraging physical activity behaviour, and limited evidence to support the use of behavioural incentives for smoking cessation and prevention in adolescents. Findings suggest that behavioural incentives may encourage uptake and initiation of healthy eating and physical activity in young people. However, this is a limited evidence base and a wide range of incentive designs have yet to be explored. Future research should further investigate the acceptability of these intervention approaches for young people. PMID- 29432790 TI - Neighborhood built environment and socioeconomic status in relation to physical activity, sedentary behavior, and weight status of adolescents. AB - INTRODUCTION: The study examined the association of neighborhood walkability to multiple activity-related outcomes and BMI among adolescents and evaluated socioeconomic status as an effect modifier. METHOD: Cross-sectional study, with adolescents recruited from neighborhoods that met criteria for a 2 * 2 matrix defined by high/low GIS-defined walkability and high/low median income. Adolescents aged 12-16 years (n = 928) were recruited from selected neighborhoods in Maryland and King County, Washington regions in 2009-2011. There were 50.4% girls, and 66.3% were non-Hispanic white, with no medical restrictions on physical activity (PA) or diets. Total PA and sedentary time was assessed by 7 days of accelerometer monitoring. Adolescents self-reported active transport, time spent on 6 sedentary behaviors, and height and weight, used to compute BMI percentiles. Mixed model linear and logistic regressions examined outcomes for association with walkability and income, adjusting for demographic covariates and clustering within block groups. RESULTS: Walkability was positively and significantly related to objectively-measured PA (p < .001) and more frequent walking for transportation (p < .001). Total self-reported sedentary time (p = .048) and TV time (p < .007) were negatively related to walkability. Time in vehicles was negatively related to walkability only among higher-income adolescents. CONCLUSIONS: Neighborhood walkability was strongly and consistently associated with adolescents' objectively-assessed total physical activity and reported active transportation. A novel finding was that adolescents living in walkable neighborhoods reported less television time and less time in vehicles. Most results were similar across income categories. Results strengthen the rationale for recommendations to improve walkability. PMID- 29432792 TI - Simulating the component counts of combinatorial structures. AB - This article describes and compares methods for simulating the component counts of random logarithmic combinatorial structures such as permutations and mappings. We exploit the Feller coupling for simulating permutations to provide a very fast method for simulating logarithmic assemblies more generally. For logarithmic multisets and selections, this approach is replaced by an acceptance/rejection method based on a particular conditioning relationship that represents the distribution of the combinatorial structure as that of independent random variables conditioned on a weighted sum. We show how to improve its acceptance rate. We illustrate the method by estimating the probability that a random mapping has no repeated component sizes, and establish the asymptotic distribution of the difference between the number of components and the number of distinct component sizes for a very general class of logarithmic structures. PMID- 29432791 TI - Functional, signalling and transcriptional differences of three distinct type I IFNs in a perciform fish, the mandarin fish Siniperca chuatsi. AB - Teleost fish are unique in having type I and type II interferons (IFNs) only, and the type I IFNs are classified into Group one and Group two based on the presence of two or four cysteines respectively, and are further classified into seven subgroups. In the present study, three distinct type I IFNs, IFNc, IFNd and IFNh, have been identified in the genome sequences of a perciform fish, the mandarin fish Siniperca chuatsi. These IFNs are induced following the stimulation of Polyinosinic polycytidylic acid (poly(I:C)) and Resiquimod (R848) either in vivo or in vitro. But, the infectious spleen and kidney necrosis virus (ISKNV) infection caused a delayed response of IFNs, which may be resulted from the viral inhibition of type I IFN production and related signalling. The three receptor subunits, cytokine receptor family B 1 (CRFB1), CRFB2 and CRFB5 are also expressed in a similar manner as observed for the IFNs, and IFNc, IFNd and IFNh use preferentially the receptor complex, CRFB2 and CRFB5, CRFB1 and CRFB5, CRFB1 and CRFB5 respectively for their effective signalling in the induction of IFN stimulated genes (ISGs). Moreover, the IFNs are able to induce their own expression, and also the IRF3 and IRF7 expression, leading to the amplification of IFN cascade. It is further revealed that these three IFNs are transcribed differently by IRF7 and IRF3. The composition, function, signalling and transcription of type I IFNs have been investigated in detail in a teleost fish. PMID- 29432793 TI - The impact of natural aging on computational and neural indices of perceptual decision making: A review. AB - It is well established that natural aging negatively impacts on a wide variety of cognitive functions and research has sought to identify core neural mechanisms that may account for these disparate changes. A central feature of any cognitive task is the requirement to translate sensory information into an appropriate action - a process commonly known as perceptual decision making. While computational, psychophysical, and neurophysiological research has made substantial progress in establishing the key computations and neural mechanisms underpinning decision making, it is only relatively recently that this knowledge has begun to be applied to research on aging. The purpose of this review is to provide an overview of this work which is beginning to offer new insights into the core psychological processes that mediate age-related cognitive decline in adults aged 65 years and over. Mathematical modelling studies have consistently reported that older adults display longer non-decisional processing times and implement more conservative decision policies than their younger counterparts. However, there are limits on what we can learn from behavioural modeling alone and neurophysiological analyses can play an essential role in empirically validating model predictions and in pinpointing the precise neural mechanisms that are impacted by aging. Although few studies to date have explicitly examined correspondences between computational models and neural data with respect to cognitive aging, neurophysiological studies have already highlighted age-related changes at multiple levels of the sensorimotor hierarchy that are likely to be consequential for decision making behaviour. Here, we provide an overview of this literature and suggest some future directions for the field. PMID- 29432795 TI - Growth differentiation factor 11 improves neurobehavioral recovery and stimulates angiogenesis in rats subjected to cerebral ischemia/reperfusion. AB - The recent suggestion that growth differentiation factor 11 (GDF11) acts as a rejuvenation factor has remained controversial. However, in addition to its role in aging, the relationship between GDF11 and cerebral ischemia is still an important area that needs more investigation. Here we examined effects of GDF11 on angiogenesis and recovery of neurological function in a rat model of stroke. Exogenous recombinant GDF11 (rGDF11) at different doses were directly injected into the tail vein in rats subjected to cerebral ischemia/reperfusion (I/R). Neurobehavioral tests were performed, the proliferation of endothelial cells (ECs) and GDF11 downstream signal activin-like kinase 5 (ALK5) were assessed, and functional microvessels were measured. Results showed that rGDF11 at a dosage of 0.1 mg/kg/day could effectively activate cerebral angiogenesis in vivo. In addition, rGDF11 improved the modified neurological severity scores and the adhesive removal somatosensory test, promoted proliferation of ECs, induced ALK5 and increased vascular surface area and the number of vascular branch points in the peri-infarct cerebral cortex after cerebral I/R. These effects were suppressed by blocking ALK5. Our novel findings shed new light on the role of GDF11. Our results strongly suggest that GDF11 improves neurofunctional recovery from cerebral I/R injury and that this effect is mediated partly through its proangiogenic effect in the peri-infarct cerebral cortex, which is associated with ALK5. Thus, GDF11/ALK5 may represent new therapeutic targets for aiding recovery from stroke. PMID- 29432796 TI - Opioid and alpha2 adrenergic mechanisms are activated by GABA agonists in the lateral parabrachial nucleus to induce sodium intake. AB - The activation of GABA, opioid or alpha2 adrenergic mechanisms in the lateral parabrachial nucleus (LPBN) facilitates hypertonic NaCl intake in rats. In the present study, we combined opioid or alpha2 adrenergic antagonists with GABA agonists into the LPBN in order to investigate if NaCl intake caused by GABAergic activation in normohydrated rats depends on opioid or alpha2-adrenergic mechanisms in this area. Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN were used. Bilateral injections of muscimol or baclofen (GABAA and GABAB agonists, respectively, 0.5 nmol/0.2 MUl) into the LPBN induced strong ingestion of 0.3 M NaCl (45.8 +/- 7.3 and 21.8 +/- 4.8 ml/240 min, respectively) and water intake (22.7 +/- 3.4 and 6.6 +/- 2.5 ml/240 min, respectively). Naloxone (opioid antagonist, 150 nmol/0.2 MUl) into the LPBN abolished 0.3 M NaCl and water intake to muscimol (2.0 +/- 0.6 and 0.9 +/- 0.2 ml/240 min, respectively) or baclofen (2.3 +/- 1.1 and 0.8 +/- 0.4 ml/240 min, respectively). RX 821002 (alpha2 adrenoceptor antagonist, 10 nmol/0.2 MUl) into the LPBN reduced 0.3 M NaCl intake induced by the injections of muscimol or baclofen (26.6 +/- 8.0 and 10.1 +/- 4.9 ml/240 min, respectively). RX 821002 reduced water intake induced by muscimol (7.7 +/- 2.9 ml/240 min), not by baclofen. The results suggest that sodium intake caused by gabaergic activation in the LPBN in normohydrated rats is totally dependent on the activation of opioid mechanisms and partially dependent on the activation of alpha2 adrenergic mechanisms in the LPBN. PMID- 29432797 TI - Ethological and multi-behavioral analysis of learning and memory performance in laboratory rodent models. AB - Behavioral studies using animal models have widely contributed to advancing our understanding of the neuroregulatory mechanisms of human cognitive states and disorders. A variety of behavioral tests and theoretical models have been developed that provide a standardized toolbox of behavioral test paradigms available to researchers, and thus allow rapid progress in studies of the molecular-genetic bases of behavior relevant to neurocognitive diseases. However, a growing effort to utilize standardized paradigms has overlooked the diverse behavioral characteristics of test rodents expressed in standardized test situations. This review describes two popular test paradigms for cognitive assessment in rodents: social recognition and fear conditioning tasks. An extensive assessment of observed behavior during testing indicates a need to further elucidate the sequential strategic processes employed by test animals in conjunction with the use of standardized test settings and dependent variables. The present study calls specific attention to the considerable but improvable problem of the appropriateness and applicability of these standardized test paradigms; it thereby unravels the essential contribution of multi-behavioral assessment to further advancing neuroscience research using rodent behavioral models. PMID- 29432794 TI - Different macaque models of cognitive aging exhibit task-dependent behavioral disparities. AB - Deficits in cognitive functions that rely on the integrity of the frontal and temporal lobes are characteristic of normative human aging. Due to similar aging phenotypes and homologous cortical organization between nonhuman primates and humans, several species of macaque monkeys are used as models to explore brain senescence. These macaque species are typically regarded as equivalent models of cognitive aging, yet no direct comparisons have been made to support this assumption. Here we used adult and aged rhesus and bonnet macaques (Macaca mulatta and Macaca radiata) to characterize the effect of age on acquisition and retention of information across delays in a battery of behavioral tasks that rely on prefrontal cortex and medial temporal lobe networks. The cognitive functions that were tested include visuospatial short-term memory, object recognition memory, and object-reward association memory. In general, bonnet macaques at all ages outperformed rhesus macaques on tasks thought to rely primarily on the prefrontal cortex, and were more resilient to age-related deficits in these behaviors. On the other hand, both species were comparably impaired by age on tasks thought to preferentially engage the medial temporal lobe. Together, these results suggest that rhesus and bonnet macaques are not equivalent models of cognitive aging and highlight the value of cross-species comparisons. These observations should enable improved design and interpretation of future experiments aimed at understanding changes in cognition across the lifespan. PMID- 29432798 TI - Development of a gold-nano particle based novel dot immunobinding assay for rapid and sensitive detection of Banana bunchy top virus. AB - An improved gold nanoparticle based Dot immunobinding assay (DIBA) was developed for the detection of Banana bunchy top virus (BBTV), that is more efficient, sensitive, rapid and simpler than conventional DIBA and ELISA. Instead of enzyme conjugates, gold nanoparticles were used as reporters owing to their unique optical properties. Antibody was raised against expressed recombinant coat protein of BBTV. The gold nanoparticles were conjugated to primary / detection antibody raised following immunization with recombinant coat protein, making it highly specific for the virus. Gold nanoparticle conjugated primary antibody (GCPab) based DIBA developed in this study has a detection efficiency comparable to ELISA. The results of using this assay format for detection of BBTV in banana plants from four geographical regions of India are also presented in this report. The test could detect the virus at sap dilution up-to 10-2. Using this improved DIBA, any lab with basic amenities can perform indexing on large numbers of samples. PMID- 29432800 TI - An overview of the emerging interface between cardiac metabolism, redox biology and the circadian clock. AB - At various biological levels, mammals must integrate with 24-hr rhythms in their environment. Daily fluctuations in stimuli/stressors of cardiac metabolism and oxidation-reduction (redox) status have been reported over the course of the day. It is therefore not surprising that the heart exhibits dramatic oscillations in various cellular processes over the course of the day, including transcription, translation, ion homeostasis, metabolism, and redox signaling. This temporal partitioning of cardiac processes is governed by a complex interplay between intracellular (e.g., circadian clocks) and extracellular (e.g., neurohumoral factors) influences, thus ensuring appropriate responses to daily stimuli/stresses. The purpose of the current article is to review knowledge regarding control of metabolism and redox biology in the heart over the course of the day, and to highlight whether disruption of these daily rhythms contribute towards cardiac dysfunction observed in various disease states. PMID- 29432799 TI - Mitochondrial protein S-nitrosation protects against ischemia reperfusion-induced denervation at neuromuscular junction in skeletal muscle. AB - Deterioration of neuromuscular junction (NMJ) integrity and function is causal to muscle atrophy and frailty, ultimately hindering quality of life and increasing the risk of death. In particular, NMJ is vulnerable to ischemia reperfusion (IR) injury when blood flow is restricted followed by restoration. However, little is known about the underlying mechanism(s) and hence the lack of effective interventions. New evidence suggests that mitochondrial oxidative stress plays a causal role in IR injury, which can be precluded by enhancing mitochondrial protein S-nitrosation (SNO). To elucidate the role of IR and mitochondrial protein SNO in skeletal muscle, we utilized a clinically relevant model and showed that IR resulted in significant muscle and motor nerve injuries with evidence of elevated muscle creatine kinase in the serum, denervation at NMJ, myofiber degeneration and regeneration, as well as muscle atrophy. Interestingly, we observed that neuromuscular transmission improved prior to muscle recovery, suggesting the importance of the motor nerve in muscle functional recovery. Injection of a mitochondria-targeted S-nitrosation enhancing agent, MitoSNO, into ischemic muscle prior to reperfusion reduced mitochondrial oxidative stress in the motor nerve and NMJ, attenuated denervation at NMJ, and resulted in accelerated functional recovery of the muscle. These findings demonstrate that enhancing mitochondrial protein SNO protects against IR-induced denervation at NMJ in skeletal muscle and accelerates functional regeneration. This could be an efficacious intervention for protecting neuromuscular injury under the condition of IR and other related pathological conditions. PMID- 29432801 TI - Leptospira interrogans infection leads to IL-1beta and IL-18 secretion from a human macrophage cell line through reactive oxygen species and cathepsin B mediated-NLRP3 inflammasome activation. AB - Leptospirosis is a worldwide zoonosis caused by spirochetes from the genus Leptospira. Although there is a large diversity of clinical signs and symptoms, a severe inflammatory response is common to all leptospirosis patients. The mechanism of IL-1beta secretion during Leptospira infection has been previously studied in mouse macrophages. However, the outcome of Leptospira infection is very different in human and murine macrophages, and the mechanisms responsible for IL-1beta secretion in human macrophages had not been investigated. This study therefore examines the effects of Leptospira interrogans infection on inflammasome activation and proinflammatory cytokine expression in human macrophages. Increased mRNA and protein expression of NLRP3 was observed by real time RT-PCR and flow cytometry at 1 h after co-cultivation. Enzyme-linked immunosorbent assay (ELISA) determination showed that IL-1beta and IL-18 are released in the culture supernatants at 1 h after cultivation. The inhibition assay showed that glybenclamide (a K+ efflux inhibitor that blocks NLRP3 inflammasome activation) and N-benzyloxycarbony-Val-Ala-Asp (O-methyl) fluoromethylketone (Z-VAD-FMK; a caspase-1 inhibitor) and NLRP3 depletion with siRNAs reduced the levels of IL-1beta and IL-18 release. Moreover, the levels of IL-1beta and IL-18 production decreased in CA-074 (a cathepsin B inhibitor) and NAC (an anti-oxidant) pretreated human macrophages, compared to untreated controls. This study suggests that L. interrogans infection leads to reactive oxygen species (ROS)- and cathepsin B-dependent NLRP3 inflammasome activation, which subsequently mediates caspase-1 activation and IL-1beta and IL-18 release. PMID- 29432802 TI - Task-dependent enhancement of facial expression and identity representations in human cortex. AB - What cortical mechanisms allow humans to easily discern the expression or identity of a face? Subjects detected changes in expression or identity of a stream of dynamic faces while we measured BOLD responses from topographically and functionally defined areas throughout the visual hierarchy. Responses in dorsal areas increased during the expression task, whereas responses in ventral areas increased during the identity task, consistent with previous studies. Similar to ventral areas, early visual areas showed increased activity during the identity task. If visual responses are weighted by perceptual mechanisms according to their magnitude, these increased responses would lead to improved attentional selection of the task-appropriate facial aspect. Alternatively, increased responses could be a signature of a sensitivity enhancement mechanism that improves representations of the attended facial aspect. Consistent with the latter sensitivity enhancement mechanism, attending to expression led to enhanced decoding of exemplars of expression both in early visual and dorsal areas relative to attending identity. Similarly, decoding identity exemplars when attending to identity was improved in dorsal and ventral areas. We conclude that attending to expression or identity of dynamic faces is associated with increased selectivity in representations consistent with sensitivity enhancement. PMID- 29432803 TI - Learning and memory is modulated by cannabidiol when administered during trace fear-conditioning. AB - Cannabidiol (CBD) is thought to have therapeutic potential for treating psychiatric conditions that affect cognitive aspects of learning and memory, including anxiety and post-traumatic stress disorder (PTSD). Studies have shown that CBD enhances extinction of fear memory when given after conditioning. This led us to hypothesize that CBD, if administered prior to fear conditioning, might modulate cognitive learning and memory processes in additional ways that would further guide its potential use for treating PTSD. Therefore, we designed a study to investigate effects of CBD on fear learning and memory when administered to mice prior to administering a trace fear conditioning protocol which imposes cognitive demands on the learning and memory process. We show that CBD-treated animals had increased levels of freezing during conditioning, enhanced generalized fear, inhibited cue-dependent memory extinction, slightly increased levels of freezing during an auditory-cued memory test, and increased contextual fear memory. Because synaptic plasticity is the fundamental mechanism of learning and memory, we also evaluated the impact of CBD on trace conditioning-dependent dendritic spine plasticity which occurred in the dorsal lateral amygdala and CA1 region of the ventral hippocampus. We showed that CBD mildly enhanced spine densities independent of conditioning, and inhibited conditioning-dependent spine increases in the hippocampi, but not the amygdala of fear conditioned animals. Overall, the memory-modulating effects of a single pre-conditioning dose of CBD, which we show here, demonstrate the need to more fully characterize its basic effects on memory, suggest caution when using it clinically as an anxiolytic, and point to a need for more research into its potential as a therapeutic for treating memory-loss disorders. PMID- 29432804 TI - Effects of long-term nitrate supplementation on carbohydrate metabolism, lipid profiles, oxidative stress, and inflammation in male obese type 2 diabetic rats. AB - PURPOSE: Supplementation with inorganic nitrate to boost the nitrate-nitrite nitric oxide (NO) pathway, may act as a potential therapeutic agent in diabetes. The aim of this study was to determine the effects of nitrate on carbohydrate metabolism, lipid profiles, oxidative stress, and inflammation in obese type 2 diabetic rats. METHODS: Male Wistar rats were divided into 4 groups: Control, control + nitrate, diabetes, and diabetes + nitrate. Diabetes was induced using a high-fat diet and low-dose of streptozotocin. Sodium nitrate (100 mg/L in drinking water) was administered simultaneously for two months. Serum levels of fasting glucose, insulin, and lipid profiles were measured every 2-weeks. Glycated hemoglobin (HbA1c) was measured monthly. Serum thiobarbituric reactive substances (TBARS) level and catalase activity were measured before and after treatment. At the end of the study, glucose, pyruvate, and insulin tolerance tests were done. Glucose-stimulated insulin secretion (GSIS) and insulin content from isolated pancreatic islets were also assessed; mRNA expression of iNOS as well as mRNA expression and protein levels of GLUT4 in insulin-sensitive tissues, and serum IL-1beta were determined. RESULTS: Nitrate supplementation in diabetic rats significantly improved glucose tolerance, lipid profiles, and catalase activity as well as decreased gluconeogenesis, fasting glucose, insulin, and IL 1beta; although it had no significant effect on GSIS, islet insulin content, HbA1c, and serum TBARS. Compared to the controls, in diabetic rats, mRNA expression and protein levels of GLUT4 were significantly lower in the soleus muscle (54% and 34%, respectively) and epididymal adipose tissue (67% and 41%, respectively). In diabetic rats, nitrate administration increased GLUT4 mRNA expression and protein levels in both soleus muscle (215% and 17%, respectively) and epididymal adipose tissue (344% and 22%, respectively). In diabetic rats, nitrate significantly decreased elevated iNOS mRNA expression in both the soleus muscle and epididymal adipose tissue. CONCLUSION: Chronic nitrate supplementation in obese type 2 diabetic rats improved glucose tolerance, insulin resistance, and dyslipidemia; these favorable effects were associated with increased mRNA and protein expression of GLUT4 and decreased mRNA expression of iNOS in insulin sensitive tissues, and with decreased gluconeogenesis, inflammation, and oxidative stress. PMID- 29432805 TI - Intracellular drug delivery: Potential usefulness of engineered Shiga toxin subunit B for targeted cancer therapy. AB - A treasure trove of intracellular cancer drug targets remains hidden behind cell membranes. However, engineered pathogen-derived toxins such as Shiga toxins can deliver small or macromolecular drugs to specific intracellular organelles. After binding to ganglioglobotriaosylceramide (Gb3, CD77), the non-toxic subunit B (StxB) of the Shiga-holotoxin is endocytosed and delivers its payload by a unique retrograde trafficking pathway via the endoplasmic reticulum to the cytosol. This review provides an overview of biomedical applications of StxB-based drug delivery systems in targeted cancer diagnosis and therapy. Biotechnological production of the Stx-material is discussed from the perspective of developing efficacious and safe therapeutics. PMID- 29432806 TI - Characterization of lipid metabolism genes and the influence of fatty acid supplementation in the hepatic lipid metabolism of dusky grouper (Epinephelus marginatus). AB - Dusky grouper is an important commercial fish species in many countries, but some factors such as overfishing has significantly reduced their natural stocks. Aquaculture emerges as a unique way to conserve this species, but very little biological information is available, limiting the production of this endangered species. To understand and generate more knowledge about this species, liver transcriptome sequencing and de novo assembly was performed for E. marginatus by Next Generation Sequencing (NGS). Sequences obtained were used as a tool to validate the presence of key genes relevant to lipid metabolism, and their expression was quantified by qPCR. Moreover, we investigated the influence of supplementing different dietary fatty acids on hepatic lipid metabolism. The results showed that the different fatty acids added to the diet dramatically changed the gene expression of some key enzymes associated with lipid metabolism as well as hepatic fatty acid profiles. Elongase 5 gene expression was shown to influence intermediate hepatic fatty acid elongation in all experimental groups. Hepatic triglycerides reflected the diet composition more than hepatic phospholipids, and were characterized mainly by the high percentage of 18:3n3 in animals fed with a linseed oil rich diet. Results for the saturated and monounsaturated fatty acids suggest a self-regulatory potential for retention and oxidation processes in liver, since in general the tissues did not directly reflect these fatty acid diet compositions. These results indicated that genes involved in lipid metabolism pathways might be potential biomarkers to assess lipid requirements in the formulated diet for this species. PMID- 29432807 TI - Systematic evaluation of common lubricants for optimal use in tablet formulation. AB - As an essential formulation component for large-scale tablet manufacturing, the lubricant preserves tooling by reducing die-wall friction. Unfortunately, lubrication also often results in adverse effects on tablet characteristics, such as prolonged disintegration, slowed dissolution, and reduced mechanical strength. Therefore, the choice of lubricant and its optimal concentration in a tablet formulation is a critical decision in tablet formulation development to attain low die-wall friction while minimizing negative impact on other tablet properties. Three commercially available tablet lubricants, i.e., magnesium stearate, sodium stearyl fumerate, and stearic acid, were systematically investigated in both plastic and brittle matrices to elucidate their effects on reducing die-wall friction, tablet strength, tablet hardness, tablet friability, and tablet disintegration kinetics. Clear understanding of the lubrication efficiency of commonly used lubricants as well as their impact on tablet characteristics would help future tablet formulation efforts. PMID- 29432808 TI - The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction. AB - BACKGROUND AND AIMS: Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co administration of the peripherally acting MU-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo. METHODS: In a double blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale. RESULTS: During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (-45.9 vs -38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01). CONCLUSIONS: In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process. PMID- 29432809 TI - Seizure progression and inflammatory mediators promote pericytosis and pericyte microglia clustering at the cerebrovasculature. AB - BACKGROUND: Cerebrovascular dysfunction and inflammation occur in epilepsy. Here we asked whether pericytes, a pivotal cellular component of brain capillaries, undergo pathological modifications during experimental epileptogenesis and in human epilepsy. We evaluated whether pro-inflammatory cytokines, present in the brain during seizures, contribute to pericyte morphological modifications. METHODS: In vivo, unilateral intra-hippocampal kainic acid (KA) injections were performed in NG2DsRed/C57BL6 mice to induce status epilepticus (SE), epileptogenesis, and spontaneous recurrent seizures (SRS). NG2DsRed mice were used to visualize pericytes during seizure progression. The effect triggered by recombinant IL-1beta, TNFalpha, or IL-6 on pericytes was evaluated in NG2DsRed hippocampal slices and in human-derived cell culture. Human brain specimens obtained from temporal lobe epilepsy (TLE) with or without sclerosis (HS) and focal cortical dysplasia (FCD-IIb) were evaluated for pericyte-microglial cerebrovascular assembly. RESULTS: A disarray of NG2DsRed+ pericyte soma and ramifications was found 72 h post-SE and 1 week post-SE (epileptogenesis) in the hippocampus. Pericyte modifications topographically overlapped with IBA1+ microglia clustering around the capillaries with cases of pericytes lodged within the microglial cells. Microglial clustering around the NG2DsRed pericytes lingered at SRS. Pericyte proliferation (Ki67+) occurred 72 h post-SE and during epileptogenesis and returned towards control levels at SRS. Human epileptic brain tissues showed pericyte-microglia assemblies with IBA1/HLA microglial cells outlining the capillary wall in TLE-HS and FCD-IIb specimens. Inflammatory mediators contributed to pericyte modifications, in particular IL-1beta elicited pericyte morphological changes and pericyte-microglia clustering in NG2DsRed hippocampal slices. Modifications also occurred when pro-inflammatory cytokines were added to an in vitro culture of pericytes. CONCLUSIONS: These results indicate the occurrence of pericytosis during seizures and introduce a pericyte microglial mediated mechanism of blood-brain barrier dysfunction in epilepsy. PMID- 29432811 TI - Rapamycin attenuates Th2-driven experimental allergic conjunctivitis. AB - Allergic conjunctivitis is mediated by eosinophilic infiltration and Th2 type immune responses. This study aims to elucidate the role of rapamycin, mTOR inhibitor, on OVA-induced experimental allergic conjunctivitis (EAC). Rapamycin administration intraperitoneally markedly reduced clinical signs, total and OVA specific IgE and IgG1/G2a ratio in serum, and conjunctival eosinophilic infiltration. Infiltrations of CD11c+ dendritic cells and CD4+ T cells, and the expressions of chemokines and adhesion molecules in the conjunctiva were attenuated in rapamycin-treated mice, as well as decreased Th1 and Th2 cytokines in the cervical lymph nodes compared to non-treated mice. The expression of mTOR signaling proteins was increased in EAC and reduced by rapamycin treatment. Topical application of rapamycin was also proved to show reduced clinical signs, eosinophil infiltration, and Th2 type immune responses comparable to those from intraperitoneal injection of rapamycin. These findings suggest the therapeutic implications of rapamycin in the attenuation of allergic conjunctivitis. PMID- 29432810 TI - Characterization of the role of global regulator FliA in the pathophysiology of Pseudomonas aeruginosa infection. AB - FliA is known to be a sigma factor that regulates bacterial flagella gene expression. Accumulating evidence suggests that FliA is involved in bacterial behavior other than motility. To elucidate the contribution of FliA to Pseudomonas aeruginosa pathophysiology, we analyzed the biological properties and gene expression profiles of a DeltafliA mutant. Transcriptome analysis results demonstrated that the expression levels of flagella biogenesis genes decreased dramatically in the mutant; consequently, the DeltafliA mutant failed to synthesize flagella and exhibited reduced motility. The DeltafliA mutant displayed stronger hemolytic and caseinolytic activities, as well as pyocyanin production. The expression of type 6 secretion system-II genes and interbacterial competition activity was decreased in the DeltafliA mutant. Direct evidence of fliA participation in virulence was obtained from analysis of hypervirulent strain B136-33. Adhesion to and cytotoxicity toward mammalian cells and penetration through cell layers were noted; furthermore, the colonization ability of the fliA::Tn5 mutant in the intestines of laboratory mice was compromised. Notably, the fliA-overexpressing strain displayed phenotypes similar to that of the fliA-defective strain, indicating that optimal FliA levels are critical to bacterial physiology. Our findings indicate that FliA plays diverse roles in P. aeruginosa, not only in flagella biosynthesis, but also in pathophysiology. PMID- 29432812 TI - A new pH-responsive peptide tag for protein purification. AB - This paper describes a new pH-responsive peptide tag that adds a protein reversible precipitation and redissolution character. This peptide tag is a part of a cell surface protein B (CspB) derived from Corynebacterium glutamicum. Proinsulin that genetically fused with a peptide of N-terminal 6, 17, 50, or 250 amino acid residues of CspB showed that the reversible precipitation and redissolution depended on the pH. The transition occurred within a physiological and narrow pH range. A CspB50 tag comprising 50 amino acid residues of N-terminal CspB was further evaluated as a representative using other pharmaceutical proteins. Below pH 6.8, almost all CspB50-Teriparatide fusion formed an aggregated state. Subsequent addition of alkali turned the cloudy protein solution transparent above pH 7.3, in which almost all the CspB50-Teriparatide fusion redissolved. The CspB50-Bivalirudin fusion showed a similar behavior with slightly different pH range. This tag is offering a new protein purification method based on liquid-solid separation which does not require an affinity ligand. This sharp response around neutral pH is useful as a pH-responsive tag for the purification of unstable proteins at a non-physiological pH. PMID- 29432814 TI - PI3K/AKT/mTOR activation and autophagy inhibition plays a key role in increased cholesterol during IL-17A mediated inflammatory response in psoriasis. AB - Psoriasis is an immune-mediated inflammatory disease of the skin. Previous studies including ours have shown that IL-17A plays a major role in its pathogenesis; however, its precise molecular mechanism of action is not well understood. Cytokines like TNF alpha and IL-23 are also important in mediating the disease and some studies have also reported autophagy as a novel mechanism by which cytokines controls the immune response. Herein, we investigated the effect of IL-17A on autophagy and reveal crosstalk between autophagy and cholesterol signaling in keratinocytes. Our results suggest that IL-17A stimulated keratinocytes activated PI3K/AKT/mTOR signaling and inhibited autophagy by simultaneously inhibiting autophagosome formation and enhancing autophagic flux. Western blotting was utilized to detect the expression of autophagic markers (LC3 and p62), PI3K, mTOR and AKT. Induction of autophagy by mTOR inhibitor rapamycin and/or starvation also inhibited the levels of IL-17A secreted IL-8, CCL20 and S100A7 in keratinocytes. Herein, we also observed that inhibition of autophagy by IL-17A was accompanied by enhanced cellular cholesterol levels which in turn regulated the autophagic flux. To investigate crosstalk between autophagy and cellular cholesterol, we used methyl-beta-cyclodextrin (MbetaCD), which disrupts detergent-insoluble microdomains (DIMs) by depleting cells of cholesterol and checked autophagy. Decreased expression of LC3-II in psoriatic lesional skin compared to non-lesional skin and induction of autophagy by anti-psoriatic drug methotrexate in keratinocytes further confirms the role of autophagy in psoriasis. Our findings suggest that modulators of autophagy and/or cholesterol levels may be developed, and also may lead to new therapeutic agents for psoriasis treatment. PMID- 29432815 TI - Targeting the RAS-dependent chemoresistance: The Warburg connection. AB - RAS protein family members (KRAS4A, KRAS4B, HRAS and NRAS) function as GDP-GTP regulated on-off switches, which regulate cytoplasmic-nuclear signaling networks ruling diverse normal cellular processes. Constitutive activating mutations in RAS genes are found in up to 30% of human cancers, and remarkably, the oncogenic Ras mutations and mutations in other components of Ras/MAPK signaling pathways seem to be mutually exclusive in most tumors, pointing out that deregulation of Ras-dependent signaling is an essential requirement for tumorigenesis. Up to 30% of solid tumors are known to have a mutated (abnormal) KRAS gene. Unfortunately, patients harboring mutated KRAS CRC are unlikely to benefit from anti-EGFR therapy. Moreover, it remains unclear that patients with KRAS wild-type CRC will definitely respond to such therapies. Although some clinically designed strategies to modulate KRAS aberrant activation have been designed, all attempts to target KRAS have failed in the clinical assays and K-RAS has been assumed to be invulnerable to chemotherapeutic attack. Recently, different encouraging publications reported that ascorbate may have a selective antitumoral effect on KRAS mutant cancer cells. In this review we aim to describe the prevalence and importance of KRAS mutation in cancer and associated problems for the clinical handling of patients harboring these tumors. We highlight the role of mutated KRAS in boosting and keeping the tumor associated aberrant cell metabolism stating that further in-depth studies on the molecular mechanism of ascorbate to bypass mutated KRAS-related metabolic alterations may constitute a new pathway to design novel molecules in order handle tumor resistance to anti EGFR-therapies. PMID- 29432813 TI - 4-PBA ameliorates cellular homeostasis in fibroblasts from osteogenesis imperfecta patients by enhancing autophagy and stimulating protein secretion. AB - The clinical phenotype in osteogenesis imperfecta (OI) is attributed to the dominant negative function of mutant type I collagen molecules in the extracellular matrix, by altering its structure and function. Intracellular retention of mutant collagen has also been reported, but its effect on cellular homeostasis is less characterized. Using OI patient fibroblasts carrying mutations in the alpha1(I) and alpha2(I) chains we demonstrate that retained collagen molecules are responsible for endoplasmic reticulum (ER) enlargement and activation of the unfolded protein response (UPR) mainly through the eukaryotic translation initiation factor 2 alpha kinase 3 (PERK) branch. Cells carrying alpha1(I) mutations upregulate autophagy, while cells with alpha2(I) mutations only occasionally activate the autodegradative response. Despite the autophagy activation to face stress conditions, apoptosis occurs in all mutant fibroblasts. To reduce cellular stress, mutant fibroblasts were treated with the FDA-approved chemical chaperone 4-phenylbutyric acid. The drug rescues cell death by modulating UPR activation thanks to both its chaperone and histone deacetylase inhibitor abilities. As chaperone it increases general cellular protein secretion in all patients' cells as well as collagen secretion in cells with the most C terminal mutation. As histone deacetylase inhibitor it enhances the expression of the autophagic gene Atg5 with a consequent stimulation of autophagy. These results demonstrate that the cellular response to ER stress can be a relevant target to ameliorate OI cell homeostasis. PMID- 29432816 TI - New weapons to penetrate the armor: Novel reagents and assays developed at the NCI RAS Initiative to enable discovery of RAS therapeutics. AB - Development of therapeutic strategies against RAS-driven cancers has been challenging due in part to a lack of understanding of the biology of the system and the ability to design appropriate assays and reagents for targeted drug discovery efforts. Recent developments in the field have opened up new avenues for exploration both through advances in the number and quality of reagents as well as the introduction of novel biochemical and cell-based assay technologies which can be used for high-throughput screening of compound libraries. The reagents and assays developed at the NCI RAS Initiative offer a suite of new weapons that could potentially be used to enable the next generation of RAS drug discovery efforts with the hope of finding novel therapeutics for a target once deemed undruggable. PMID- 29432817 TI - Carcinoma cuniculatum of the lip: A case report. AB - Carcinoma cuniculatum, a very well differentiated sub-type of epidermoid carcinoma, is a rare invasive tumor with a low risk of metastasis. It principally affects the lower limbs, notably the soles of the feet. Facial involvement is exceptional. A case of a patient with carcinoma cuniculatum of the lower lip is presented and diagnostic difficulties of head locations of this tumor, as well as their management are discussed. PMID- 29432818 TI - Differential time to positivity of central and peripheral blood cultures is inaccurate for the diagnosis of Staphylococcus aureus long-term catheter-related sepsis. AB - OBJECTIVES: Differential time to positivity of cultures of blood drawn simultaneously from central venous catheter and peripheral sites is widely used to diagnose catheter-related bloodstream infections without removing the catheter. However, the accuracy of this technique for some pathogens, such as Staphylococcus aureus, is debated in routine practice. METHODS: In a 320-bed reference cancer centre, the charts of patients with at least one blood culture positive for S. aureus among paired blood cultures drawn over a six-year period were studied retrospectively. Microbiological data were extracted from the prospectively compiled database of the microbiology unit. Data concerning the 149 patients included were reviewed retrospectively by independent physicians blinded to the absolute and differential times to positivity, in order to establish or refute the diagnosis of catheter-related sepsis. Due to missing data, 48 charts were excluded, so 101 cases were actually analysed. The diagnosis was established in 62 cases, refuted in 15 cases and inconclusive in the remaining 24 cases. RESULTS: For the 64 patients with both central and peripheral positive blood cultures, the differential positivity time was significantly greater for patients with catheter-related bloodstream infections due to S. aureus (P<0.02). However, because of the high number of false-negative cases, the classic cut-off limit of 120 min showed 100% specificity but only 42% sensitivity for the diagnosis of catheter-related bloodstream infection due to S. aureus. CONCLUSIONS: These results strongly suggest that despite its high specificity, the differential time to positivity may not be reliable to rule out catheter-related bloodstream infection due to S. aureus. PMID- 29432819 TI - Resistance patterns of Enterobacteriaceae in urines are similar in symptomatic and asymptomatic patients. AB - Antibiograms of urine cultures are being used to guide empiric treatment for urinary tract infections (UTIs). However, roughly 50% of urine cultures are from patients with asymptomatic bacteriuria (ABU). It is unclear whether Enterobacteriaceae in ABU patients have similar resistance patterns as UTI patients. Hence, we aimed to compare the antimicrobial resistance patterns in patients with ABU to patients with symptomatic UTI. We found no major differences in resistance patterns, and therefore empiric treatment choices can be guided by antibiograms that include ABU patients. PMID- 29432820 TI - Real-time polymerase chain reaction detection of Lichtheimia species in bandages associated with cutaneous mucormycosis in burn patients. AB - BACKGROUND: Cutaneous mucormycoses, mainly due to Lichtheimia (Absidia), have occurred on several occasions in the Burn Unit of the University Hospital of Lille, France. AIM: To investigate the potential vector role of non-sterile bandages used to hold in place sterile gauze used for wound dressing. METHODS: Mycological analysis by conventional culture, Mucorales real-time polymerase chain reaction (qPCR), and Lichtheimia species-specific qPCR were performed on eight crepe and six elasticized bandages that were sampled on two independent occasions in March 2014 and July 2016. Characteristics of the seven Lichtheimia mucormycoses which occurred in burn patients between November 2013 and July 2016 were also collected to assess the epidemiological relationship between potentially contaminated bandages and clinical infections. FINDINGS: One Lichtheimia corymbifera strain was isolated from a crepe bandage by culture, and Lichtheimia spp. qPCR was positive in six out of eight crepe and four out of six elasticized bandages. Using species-specific qPCR, Lichtheimia ramosa, Lichtheimia ornata, and L. corymbifera were identified in six out of ten, five out of ten, and four out of ten bandages, respectively. In patients with mucormycosis, L. ramosa and L. ornata were present in five and two cases, respectively. CONCLUSION: Our data support the utility of Mucorales qPCR for epidemiological investigations, the potential role of these bandages in cutaneous mucormycoses in burn patients in our centre, and, consequently, the need for sterile bandages for the dressing of extensive wounds. PMID- 29432821 TI - Bacteriology and cefuroxime resistance in endophthalmitis following cataract surgery before and after the introduction of prophylactic intracameral cefuroxime: a retrospective single-centre study. AB - BACKGROUND: Intracameral cefuroxime as prophylaxis against postoperative endophthalmitis (POE) following cataract surgery was introduced in 1996 at St Erik Eye Hospital. Soon after the introduction of intracameral cefuroxime, the rate of POE fell dramatically and a shift in the aetiology was noticed. AIM: To analyse bacteriology and susceptibility to cefuroxime before and after the introduction of intracameral cefuroxime. METHODS: All culture-proven cases of endophthalmitis at St Erik Eye Hospital after cataract surgery performed over a 20-year period were included in a retrospective observational study. FINDINGS: Sixty-two cases of endophthalmitis occurred in 34,390 (0.18%) cataract surgeries before the introduction of intracameral cefuroxime (Period 1), while 33 cases occurred in 75,144 (0.044%) operations after the introduction of intracameral cefuroxime (Period 2), showing a significant difference between the periods (P < 0.001). The incidence of coagulase-negative staphylococci (1/1400 vs 1/15,000; P < 0.001), Staphylococcus aureus (1/2000 vs 1/30,000; P < 0.001), streptococci other than enterococci (1/2500 vs 1/25,000; P < 0.001) and Propionibacterium acnes (1/16,000 vs 0/75,000; P = 0.04) fell sharply in Period 2. Cefuroxime sensitive strains became less frequent in Period 2 (P < 0.001). Enterococci became the predominant species, albeit not significantly (P = 0.13), whereas the rate of cefuroxime-resistant strains almost reached significance (P = 0.05) in Period 2. CONCLUSIONS: Intracameral cefuroxime leads to a reduction of the rate of endophthalmitis after cataract surgery, and brings about a shift in pathogens from cefuroxime-sensitive to cefuroxime-resistant organisms. PMID- 29432822 TI - Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects. AB - Macromolecular (pro)drugs hold much promise as broad-spectrum antiviral agents as either microbicides or carriers for intracellular delivery of antiviral drugs. Intriguing opportunity exists in combining the two modes of antiviral activity in the same polymer structure such that the same polymer acts as a microbicide and also serves to deliver the conjugated drug (ribavirin) into the cells. We explore this opportunity in detail and focus on the polymer backbone as a decisive constituent of such formulations. Fourteen polyanions (polycarboxylates, polyphosphates and polyphosphonates, and polysulfonates) were analyzed for blood pro/anti coagulation effects, albumin binding and albumin aggregation, inhibitory activity on polymerases, cytotoxicity, and anti-inflammatory activity in stimulated macrophages. Ribavirin containing monomers were designed to accommodate the synthesis of macromolecular prodrugs with disulfide-exchange triggered drug release. Kinetics of drug release was fast in all cases however enhanced hydrophobicity of the polymer significantly slowed release of ribavirin. Results of this study present a comprehensive view on polyanions as backbone for macromolecular prodrugs of ribavirin as broad-spectrum antiviral agents. PMID- 29432823 TI - Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation. AB - Existing oral antiretroviral (ARV) agents have been shown in human studies to exhibit limited lymph node penetration and lymphatic drug insufficiency. As lymph nodes are a reservoir of HIV, it is critical to deliver and sustain effective levels of ARV combinations in these tissues. To overcome lymph node drug insufficiency of oral combination ARV therapy (cART), we developed and reported a long-acting and lymphocyte-targeting injectable that contains three ARVs hydrophobic lopinavir (LPV) and ritonavir (RTV), and hydrophilic tenofovir (TFV) stabilized by lipid excipients in a nanosuspension. A single subcutaneous (SC) injection of this first-generation formulation of drug combination nanoparticles (DcNPs), named TLC-ART101, provided persistent ARV levels in macaque lymph node mononuclear cells (LNMCs) for at least 1 week, and in peripheral blood mononuclear cells (PBMCs) and plasma for at least 2 weeks, demonstrating long acting pharmacokinetics for all three drugs. In addition, the lymphocyte targeting properties of this formulation were demonstrated by the consistently higher intracellular drug concentrations in LNMCs and PBMCs versus those in plasma. To provide insights into the complex mechanisms of absorption and disposition of TLC-ART101, we constructed novel mechanism-based pharmacokinetic (MBPK) models. Based upon plasma PK data obtained after single administration of TLC-ART101 (DcNPs) and a solution formulation of free triple-ARVs, the models feature uptake from the SC injection site that respectively routes free and nanoparticle-associated ARVs via the blood vasculature and lymphatics, and their eventual distribution into and clearance from the systemic circulation. The models provided simultaneous description of the complex long-acting plasma and lymphatic PK profiles for all three ARVs in TLC-ART101. The long-acting PK characteristics of the three drugs in TLC-ART101 were likely due to a combination of mechanisms including: (1) DcNPs undergoing preferential lymphatic uptake from the subcutaneous space, (2) retention in nodes during lymphatic first-pass, (3) subsequent slow release of ARVs into blood circulation, and (4) limited extravasation of DcNP-associated ARVs that resulted in longer persistence in the circulation. PMID- 29432825 TI - Cerebrospinal fluid aspects of neonates with or without microcephaly born to mothers with gestational Zika virus clinical symptoms. PMID- 29432824 TI - Immune response to antigen adsorbed to aluminum hydroxide particles: Effects of co-adsorption of ALF or ALFQ adjuvant to the aluminum-antigen complex. AB - Aluminum salts have been used as vaccine adjuvants for >50 years, and they are currently present in at least 146 licensed vaccines worldwide. In this study we examined whether adsorption of Army Liposome Formulation (ALF) to an aluminum salt that already has an antigen adsorbed to it might result in improved immune potency of the aluminum-adsorbed antigen. ALF is composed of a family of anionic liposome-based adjuvants, in which the liposomes contain synthetic phospholipids having dimyristoyl fatty acyl groups, cholesterol and monophosphoryl lipid A (MPLA). For certain candidate vaccines, ALF has been added to aluminum hydroxide (AH) gel as a second adjuvant to form ALFA. Here we show that different methods of preparation of ALF changed the physical structures of both ALF and ALFA. Liposomes containing the saponin QS21 (ALFQ) have also been mixed with AH to form ALFQA as an effective combination. In this study, we first adsorbed one of two different antigens to AH, either tetanus toxoid conjugated to 34 copies of a hapten (MorHap), which has been used in a candidate heroin vaccine, or gp140 protein derived from the envelope protein of HIV-1. We then co-adsorbed ALF or ALFQ to the AH to form ALFA or ALFQA. In each case, the immune potency of the antigen adsorbed to AH was greatly increased by co-adsorbing either ALF or ALFQ to the AH. Based on IgG subtype and cytokine analysis by ELISPOT, ALFA induced predominately a Th2-type response and ALFQ and ALFQA each induced more balanced Th1/Th2 responses. PMID- 29432826 TI - Usefulness of beta-D-glucan for diagnosis and follow-up of invasive candidiasis in onco-haematological patients. AB - OBJECTIVES: Definitive diagnosis of invasive candidiasis (IC) may be difficult to achieve in patients with haematological malignancy (PHM). We aimed to evaluate the performance of BDG for the diagnosis and the follow-up of IC in PHM. PATIENTS AND METHODS: We retrospectively reviewed the serological data of BDG assay in adult and paediatric PHM, who developed candidemia or chronic disseminated candidiasis (CDC) through a 4-year period. Sensitivity and kinetics of BDG were determined for both clinical forms. RESULTS: In a panel of 3027 PHM, incidence rates of candidemia and CDC ranged between 0.74 and 0.77 and 0.30 and 0.44 according to the group of patients. At the time of diagnosis, 43.5% and 73% of cases of candidemia and CDC had a positive BDG assay, respectively. We found a significant correlation between the level of BDG at diagnosis and the outcome of candidemia (p = 0.022). In all cases of CDC, BDG negative results were obtained 2 to 6 months before recovery of the CT-scan lesions. CONCLUSIONS: BDG exhibits a low sensitivity to detect IC in PHM, but its kinetics correlates the clinical outcome. Additional studies are warranted in patients with CDC to evaluate the interest of monitoring BDG levels to anticipate the discontinuation of antifungal maintenance therapy. PMID- 29432827 TI - MicroRNA profile of silk gland reveals different silk yields of three silkworm strains. AB - Silk proteins are synthesized and secreted by the silk gland. The differential gene expression in it leads to different silk yield among various silkworm strains. As crucial factors, microRNAs (miRNAs) regulate protein synthesis at post-transcriptional level in silk gland. MiRNAs expression level in the silk gland of three silkworm strains (Jingsong, Lan10 and Dazao) was analyzed and 33 differentially expressed miRNAs (DEMs) were discovered between JingSong (JS) and Lan10 (L10), 60 DEMs between JS and Dazao, 54 DEMs between L10 and Dazao respectively. The DEMs target genes were predicted combing with two different methods and their functions were annotated according to gene ontology. Our previous studies showed that a batch of genes related to silk yield were identified in JS and L10 strains by comparative transcriptome and quantitative trait loci (QTL) method. Thirteen DEMs whose target genes are related to protein biosynthesis processes were screened by combining with these researches. Twelve DEMs potentially regulate nineteen genes which exist in our QTL results. Six common DEMs potentially regulate the genes in both of previous results. Finally, five DEMs were selected to verify their expression levels between JS and L10 by qRT-PCR, which showed similar difference as the results of small RNA-sequencing. MiRNAs in the silk gland may directly affect silk protein biosynthesis in different silkworm strains. In current work, we identified a batch of DEMs which potentially regulate the genes related to silk yield. Further functionally study of these miRNAs will contribute to improve varieties and boost the silk yield. Our research provides a basis for studying these miRNAs and their functions in silk production. PMID- 29432828 TI - Identification of two novel foot-and-mouth disease virus cytotoxic T lymphocyte epitopes that can bind six SLA-I proteins. AB - Currently available vaccines from inactivated foot-and-mouth disease virus (FMDV) only protect animals by inducing neutralizing antibodies. A vaccine that contains cytotoxic T lymphocytes (CTL) epitopes to induce strong CTL responses might protect animals more effectively. Herein, we used swine leukocyte antigen class I (SLAI) proteins derived from six different strains of domestic pigs to screen and identify shared FMDV CTL epitopes. Four potential FMDV CTL epitopes (Q01, Q02, AS3, and QA4) were confirmed by mass spectrometry. We also determined the antigenicity of these epitopes to elicit cell-mediated immunoresponse by the ELISPOT and CTL assays. Among the four peptides, Q01 and QA4 were found to bind all six SLA-I proteins with strong affinity and elicit significant activity of CTL (P < 0.01). We conclude that Q01 and QA4 peptides are novel shared epitopes that can be recognized by all six SLA-I molecules on representative CTLs. PMID- 29432829 TI - Vitamin D receptor gene methylation in hepatocellular carcinoma. AB - Worldwide, hepatocellular carcinoma (HCC) is the major subtype of primary liver cancers. HCC is typically diagnosed late in its course. With respect to cancer, the genomic actions of vitamin D are mediated through binding to the Vitamin D Receptor (VDR), which allows it to modulate the expression of genes in a cell-and tissue-specific manner. Epigenetics is a rapidly evolving field of genetic study applicable to HCC. Changes in DNA methylation patterns are thought to be early events in hepatocarcinogenesis. Curcumin has great potential as an epigenetic agent. Accordingly, the current study has been designed to study the methylation status of VDR gene promoter for the first time in HCC aiming to find its clinical significance and potential screening role in chronic Liver Disease (CLD). Additionally, we aimed to investigate, the effect of Curcumin on HCC cell line, aiming to discover new therapeutic targets through epigenetics. This study was conducted on 45 formalin-fixed, paraffin-embedded liver tissue blocks including 15 HCC samples (group A), 15 CLD samples (group B) and 15 apparently normal tissue taken from around benign lesions (group C). Methylation Specific Restriction Digestion and qPCR were done on all samples after DNA extraction. The percentage of VDR gene promoter methylation was significantly higher in the HCC group compared to both CLD and control groups (p < 0.01). VDR promoter methylation by (MS-qPCR) was decreased and the relative expression of VDR by (qRT PCR) was markedly increased in a dose-dependent fashion in cells grown in Curcumin-adequate medium. In conclusion, this study may open a new gate for the use of VDR promoter methylation as a potential biomarker in HCC. PMID- 29432830 TI - Functional polymorphisms of the neuropilin 1 gene are associated with the risk of tetralogy of Fallot in a Chinese Han population. AB - Tetralogy of Fallot (TOF) is one of the most severe forms of cyanotic congenital heart disease (CHD) and is also the most common. Previous genome-wide association study (GWAS) and replication studies have suggested that a polymorphism in the neuropilin 1 (NRP1) gene is significantly associated with the risk of TOF. To further confirm the association between the NRP1 polymorphism and the risk of TOF and to identify additional positive functional single-nucleotide polymorphisms (SNPs) for TOF risk, we systematically screened for functional polymorphisms throughout the regulatory and coding regions of the NRP1 gene. A total of 11 functional SNPs in 747 Chinese Han individuals, including 314 TOF patients and 433 healthy controls, were genotyped using the MassARRAY system and GeneScan. The results revealed that the allelic and genotypic frequencies of the NRP1 polymorphism rs2228638 were strongly associated with the risk of TOF (p = 0.002 and 0.001, respectively). To increase the robustness of rs2228638 as a TOF risk SNP, we conducted a meta-analysis that combined published studies and our current case-control study. The meta-analysis showed that the T allele of the NRP1 polymorphism rs2228638 was significantly associated with an increased risk of TOF in the combined population, which included European and Chinese Han individuals [combined p < 0.00001, odds ratio (OR) = 1.53, 95% confidence interval (95% CI) = 1.35-1.73]. In addition, the association analysis suggested for the first time that there is a strong association between the allele distribution of rs10080 and susceptibility to TOF (p = 0.001). Our data provide further evidence of the association between NRP1 polymorphisms and TOF risk, and suggest that rs2228638 may be an excellent marker for TOF risk in European and Chinese Han populations. PMID- 29432831 TI - PXR polymorphisms have impact on the clinical efficacy of clopidogrel in patients undergoing percutaneous coronary intervention. AB - BACKGROUNDS: Clopidogrel is widely used in Coronary Heart Disease (CHD) patients undergoing percutaneous coronary intervention (PCI) to prevent thrombotic events. However, clopidogrel response variability (CRV) may affect the patients' clinical outcomes. The current data have shown that genetic factors play an important role in CRV. The aim of this research is to investigate the association of pregnane X receptor (PXR, also called NR1I2) genetic polymorphisms with the clinical efficacy of clopidogrel in patients undergoing PCI. METHODS: A total of 384 patients undergoing PCI were recruited and treated with dual antiplatelet therapy (DAPT) for 12 months. The plasma concentration of clopidogrel carboxylic acid metabolites (CLPM) was measured by High Performance Liquid Chromatography (HPLC). The maximum aggregation rate (MAR) of platelet were measured by PL-11 analyzer. PXR genetic polymorphisms were determined by Sequenom MassArray system. The clinical outcomes were observed by readmission, outpatient and calling back interview within 12 months after PCI. RESULTS: Among all 384 patients, a total of 153 patients were occurred with major adverse cardiovascular events (MACE), 29 patients were occurred with bleeding events, the other patients had a favorable prognosis. The polymprphisms of PXR rs3814057A > C [OR(95%CI): 0.71(0.527-0.957), P = 0.024], rs3814058T > C [OR (95%CI): 1.395(1.034-1.883), P = 0.029] and rs6785049 A > G [OR(95%CI): 0.724 (0.535-0.979), P = 0.036] were significantly associated with MACE. The haplotype h1 (GCC) was associated with a higher risk of MACE [OR (95%CI): 1.385 (1.028-1.866), P = 0.031]. Whereas, the haplotype h2 (AAT) was associated with a lower risk of MACE [OR (95%CI): 0.711(0.525-0.962), P = 0.027]. CONCLUSIONS: The genotypes and haplotypes of PXR rs3814057, rs3814058 and rs6785049 have impact on the MACE in clopidogrel treated patients after PCI. PMID- 29432832 TI - New utilization of Polygonum multiflorum polysaccharide as macromolecular carrier of 5-fluorouracil for controlled release and immunoprotection. AB - WPMP-2 is an acid polysaccharide isolated from Polygonum multiflorum, which demonstrated excellent immunomodulatory activity. In order to reduce immunosuppression of 5-fluorouracil (5-Fu), WPMP-2 was utilized as a macromolecular carrier to conjugate the 5-Fu derivatives 5-fluorouracil-1-acetic acid (5-FUAC) through ester bond. The conjugate showed controlled drug release behaviour in vitro at 37 degrees C in phosphate buffer (pH7.4), and only 5-FUAC was detected in the media. The cytotoxicity test in vitro showed that the conjugate exhibited different cytotoxicity to HepG-2 and HT-29 cells. In addition, immunization study in vivo illustrated that the conjugate displayed immunoprotective effect by mitigating inhibition and damage effects of 5-Fu on secretion of cytokines, proliferation of splenocytes, and phagocytosis of peritoneal macrophages. It was indicated that the conjugation of 5-Fu and WPMP-2 could be a potential double effective drug delivery system. PMID- 29432833 TI - Structure of an entangled heteropolysaccharide from Pholidota chinensis Lindl and its antioxidant and anti-cancer properties. AB - A major polysaccharide PCP-I was isolated and purified from Pholidota chinensis Lindl. The physicochemical and structural properties of PCP-I were studied using high-performance size-exclusion chromatography (HPSEC), gas chromatography (GC), Fourier transform infrared spectroscopy (FTIR), periodate oxidation-smith degradation, methylation-GC-MS analysis, nuclear magnetic resonance (NMR) spectroscopy and transmission electron microscopy (TEM) analysis. PCP-I was homogeneous with molecular weight (Mw) of 249kDa and composed of xylose and fucose at a molar ratio of 2.45:1. The repeating structural units of PCP-I were >3)-alpha-D-Xylp-(1-> and ->4)-alpha-L-Fucp-(1->, the terminal fractions were T-D GalAp, and TEM further revealed that PCP-I was the entangled microstructure which was composed of four non-branched single chains. Compared with Vitamin C (Vc) and 5 fluorine urine (5-Fu), PCP-I showed scavenging effects of superoxide (EC50=1.09mg/mL) and hydroxyl (EC50=0.11mg/mL) radicals equivalent to Vc, and PCP I (IC50=69.54MUg/mL) also exhibited good anti-proliferation capability for human colon cancer cell line caco-2. PMID- 29432834 TI - Polymer blends used to develop felodipine-loaded hollow microspheres for improved oral bioavailability. AB - Felodipine (FD) has been widely used in anti-hypertensive treatment. However, it has extremely low aqueous solubility and poor bioavailability. To address these problems, FD hollow microspheres as multiple-unit dosage forms were synthesized by a solvent diffusion evaporation method. Particle size of the hollow microspheres, types of ethylcellulose (EC), amounts of EC, polyvinyl pyrrolidone (PVP) and FD were investigated based on an orthogonal experiment of three factors and three levels. In addition, the release kinetics in vitro and pharmacokinetics in beagle dogs of the optimized FD hollow microspheres was investigated and compared with Plendil (commercial FD sustained-release tablets) as a single-unit dosage form. Results showed that the optimal formulation was composed of EC10 cp:PVP:FD (0.9:0.16:0.36, w/w). The FD hollow microspheres were globular with a hollow structure and have high drug loading (17.69+/-0.44%) and floating rate (93.82+/-4.05%) in simulated human gastric fluid after 24h. Pharmacokinetic data showed that FD hollow microspheres exhibited sustained-release behavior and significantly improved relative bioavailability of FD compared with the control. Pharmacodynamic study showed that the FD hollow microspheres could effectively lower blood pressure. Therefore, these findings demonstrated that the hollow microspheres were an effective sustained-release delivery system for FD. PMID- 29432835 TI - Quercetin and iron metabolism: What we know and what we need to know. AB - Iron is a life-supporting micronutrient that is required in the human diet, and is essential for maintaining physiological homeostasis. Properly harnessing a redox-active metal such as iron is a great challenge for cells and organisms because an excess of highly reactive iron catalyzes the formation of reactive oxygen species and can lead to cell and tissue damage. Quercetin is a typical flavonoid that is commonly found in fruits and vegetables and has versatile biological effects. From a classical viewpoint, owing to its unique chemical characteristics, quercetin has long been associated with iron metabolism only in the context of its iron-chelating and ROS-scavenging activities. However, within the field of human iron biology, expanding concepts of the roles of quercetin are flourishing, and great strides are being made in understanding the interactions between quercetin and iron. This progress highlights the varied roles of quercetin in iron metabolism, which involve much more than iron chelation alone. A review of these studies provides an ideal context to summarize recent progress and discuss compelling evidence for therapeutic opportunities that could arise from a better understanding of the underlying mechanisms. PMID- 29432836 TI - Quercetin attenuates the hyperoxic lung injury in neonatal mice: Implications for Bronchopulmonary dysplasia (BPD). AB - Quercetin (QU) is one of the most common flavonoids that are present in a wide variety of fruits, vegetables, and beverages. This compound possesses potent anti inflammatory and anti-oxidant properties. Supplemental oxygen is routinely administered to premature infants with pulmonary insufficiency. However, hyperoxia is one of the major risk factors for the development of bronchopulmonary dysplasia (BPD), which is also termed chronic lung disease in premature infants. Currently, no preventive approaches have been reported against BPD. The treatment of BPD is notably limited to oxygen administration, ventilatory support, and steroids. Since QU has been shown to be effective in reducing inflammation and oxidative stress in various disease models, we hypothesized that the postnatal QU treatment of newborn mice will protect against hyperoxic lung injury by the upregulation of the phase I (CYP1A/B) and/or phase II, NADPH quinone reductase enzymes. Newborn C57BL/6J mice within 24 h of birth with the nursing dams were exposed to either 21% O2 (air) and/or 85% O2 (hyperoxia) for 7 days. The mice were treated, intraperitoneally (i.p.) once every other day with quercetin, at a concentration of 20 mg/kg, or saline alone from postnatal day (PND) 2-6. The mice were sacrificed on day 7, and lung and liver tissues were collected. The expression levels of CYP1A1, CYP1B1, NQO1 proteins and mRNA as well as the levels of MDA-protein adducts were analyzed in lung and liver tissues. The findings indicated that QU attenuated hyperoxia mediated lung injury by reducing inflammation and improving alveolarization with decreased number of neutrophil and macrophage infiltration. The attenuation of this lung injury correlated with the upregulation of CYP1A1/CYP1B1/NQO1 mRNA, proteins and the down regulation of NF-kB levels and MDA-protein adducts in lung and liver tissues. The present study demonstrated the potential therapeutic value of quercetin in the prevention and/or treatment of BPD. PMID- 29432837 TI - Vitamin K2, a menaquinone present in dairy products targets castration-resistant prostate cancer cell-line by activating apoptosis signaling. AB - The aim of this study was to evaluate the therapeutic effects of vitamin K2 (VK2) on castration-resistant prostate cancer (CRPC) and its anti-cancer mechanisms in a pre-clinical study using a VCaP cell line (ATCC(r) CRL-2876TM) which was established from a vertebral bone metastasis from a patient with hormone refractory prostate cancer. Our data showed that VK2 significantly inhibited CRPC VCaP cell proliferation in a dose-dependent manner at 48 h treatment in vitro. In addition, VK2 reduced the migration potential of VCaP cells and inhibited anchorage-independent growth of these cells. Our results also showed that VK2 induces apoptosis in VCaP cells. Furthermore, VK2 enforced growth arrest in VCaP cells by activating cellular senescence. Notably, VK2 treatment elevated the levels of reactive oxygen species in VCaP cells. Western blot analysis revealed that VK2 downregulated the expression of androgen receptor, BiP, survivin, while activating caspase-3 and -7, PARP-1 cleavage, p21 and DNA damage response marker, phospho-H2AX in VCaP cells. In conclusion, our study suggests that VK2 might be a potential anti-cancer agent for CRPC by specifically targeting key anti apoptotic, cell cycle progression and metastasis-promoting signaling molecules. PMID- 29432838 TI - Chemical composition and radical scavenging activity of Amygdalus pedunculata Pall leaves' essential oil. AB - The main objective of the current study was to investigate the components and radical scavenging activity of essential oil from Amygdalus pedunculata Pall leaves (APEO) extracted by an ultrasound-assisted method. Thirty-eight chemical components were identified in APEO using gas chromatography-mass spectrometry (GC MS). APEO primarily consisted of alcohols (36.82%), esters (28.81%), ketones (1.47%), alkanes (18.61%) and phenols (8.93%). The most abundant compound was n hexanol (33.49%). The antioxidant activity of APEO was characterized for 2,2 diphenyl-1-picrylhydrazyl (DPPH) radical, hydroxyl radical (OH.), hydrogen peroxide (H2O2), and superoxide anion radical (O2.-) scavenging and Fe3+ reduction, and the IC50 values were 2.32, 2.65, 2.42, 5.24 and 4.19 mg/mL, respectively. The IC50 values for H2O2 scavenging and Fe3+ reduction of APEO were less than those of ascorbic acid (Vc; 3.15 and 5.13 mg/mL). The results showed that APEO has a high radical scavenging activity. PMID- 29432840 TI - T-2 toxin-induced toxicity in neuroblastoma-2a cells involves the generation of reactive oxygen, mitochondrial dysfunction and inhibition of Nrf2/HO-1 pathway. AB - The molecular mechanisms of T-2 mycotoxin induced neurotoxicity remains enigmatic. In the present study we show that T-2 toxin induced neurotoxicity in mouse neuroblastoma2a (N2a) cells is both dose- and time-dependent and is associated with oxidative stress, mitochondrial dysfunction and apoptosis. T-2 toxin treatment of N2a cells at 10, 20, 40 and 80 ng/mL for 24 h significantly up regulated the mRNA expression of p53, Bax, and caspase-8 and down-regulated the expression of Nrf2 and HO-1 mRNA and protein expression. Activation of caspases 8, -9 and -3 was also evident in a concentration-dependent manner. Pre-treatment of the cells with the antioxidant N-acetyl-cysteine markedly suppressed T-2 toxin induced neurotoxicity and caspase activation. Conversely, pre-treatment of the cells with the Nrf2 inhibitor brusatol or the HO-1 inhibitor zinc protoporphyrin IX, enhanced T-2 toxin induced neurotoxicity and increased the activation of caspase-9 and -3. Taken together, these novel findings suggest that T-2 toxin induced neurotoxicity in N2a cells involves oxidative stress, mitochondrial dysfunction and apoptosis via the inhibition of the Nrf2/HO-1 and activation of p53 pathway. The present study highlights the potential of developing much needed pharmacological interventions to prevent T-2 toxin neurotoxicity. PMID- 29432839 TI - Protective effects of rosuvastatin and vitamin E against fipronil-mediated oxidative damage and apoptosis in rat liver and kidney. AB - Fipronil (FPN) is a phenylpyrazole insecticide that is extensively used in agriculture and veterinary applications. However, FPN is also a potent environmental toxicant to animals and humans. Therefore, the current study aimed to investigate the protective role of rosuvastatin (ROSU) and vitamin E (Vit E) against FPN-induced hepatorenal toxicity in albino rats. Seven groups with eight rats each were used for this purpose; these groups included the control vehicle group that received corn oil, the Vit E group (1000 mg/kg, orally), the ROSU group (10 mg/kg, orally), the FPN group (20 mg/kg, orally), the FPN-ROSU group, the FPN-Vit E group, and the FPN-Vit E-ROSU group. The results revealed that FPN significantly increased serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, cholesterol, urea, and creatinine. In addition, there were substantial increases in the liver and kidney contents of malondialdehyde and nitric oxide, along with significant decreases in glutathione, superoxide dismutase, catalase, and glutathione peroxidase. FPN also caused histological changes and increased the expression of caspase-3 in the liver and kidney tissues. However, administration of ROSU and Vit E alone or in combination ameliorated the FPN-induced oxidative damage and apoptosis, possibly through their antioxidant properties. PMID- 29432841 TI - Evaluation of 13-week repeated oral dose toxicity of Areca catechu in F344/N rats. AB - This study investigated the potential toxicity of the Areca catechu water extract after 13-week repeated oral administration at 0, 166.7, 500, and 1500 mg/kg/day in rats. During the study period, clinical signs, mortality, body weight, food consumption, water consumption, urinalysis, estrous cycle, sperm count and motility, ophthalmoscopy, hematology, serum biochemistry, gross pathology, organ weights, and histopathology were examined. At 1500 mg/kg/day, both sexes exhibited an increase in the incidence of abnormal clinical signs, which included, decreased body weight gain and food consumption, and increased urine bilirubin, ketone bodies, specific gravity, and protein and kidney weight. An increase in liver weight and estrous cycle alterations was observed in females. Serum biochemical and histopathological investigations revealed an increase in the levels of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, and the incidence of hepatic necrosis in females. At 500 mg/kg/day, an increase in the incidence of abnormal clinical signs including diarrhea and soiled perineal region, was observed in both sexes. No treatmentrelated effects were observed at 166.7 mg/kg/day. Under the present experimental conditions, the target organs were determined to be the liver, kidney, and female reproductive system in rats. The no-observedeffect level was considered to be 166.7 mg/kg/day in rats. PMID- 29432843 TI - The neuronal protection of a zinc-binding protein isolated from oyster. AB - Mitochondrial function is applied as oxidative stress and neuronal damage index. In this study, d-galactose was used to induce free radicals production and neuronal damage in HN-h cells, and the effect of novel 43 kDa protein isolated from oyster on anti-mitochondrial dysfunction and zinc-binding ability were evaluated. Crystal violet stain results indicated zinc-binding protein of oyster (ZPO) attenuated neuronal cell death induced by 100 mM of d-galactose on HN-h cells in a dose-dependent manner. ZPO alleviated mitochondrial inactivation, mitochondrial membrane potential decreasing, oxidative stress, and fusion/fission state in non-cytotoxic concentration of d-galactose (50 mM)-treated HN-h cells. ZPO treatment recovered metallathionein-3 (MT-3) decrease and inhibited beta- and gamma-secretase as well as amyloid beta (Abeta) accumulation in HN-h cells caused by d-galactose induction. These results suggest ZPO could avoid oxidative stress and is a functional protein for zinc concentration maintainability, which has potential for development of functional foods for neuronal protection. PMID- 29432844 TI - Pharmacogenomics signature: A novel strategy on the individual differences in drug response. AB - Patients exhibit a wide heterogeneity in their responses to a drug treatment due to variations in the molecular determinants underlying this heterogeneity. Pharmacogenomics approaches can be used to integrate information on drug responsiveness with alterations in molecular entities, often on a genome-wide scale. However, most of the studies involving pharmacogenomics of specific therapeutics are in their early stages and thus are not ready for clinical utilization. Genotyping studies tackle around a candidate gene approach using genes known to be important in the pharmacokinetics and pharmacodynamics of the administered drugs. However, this approach could miss potentially important genes that influence drug sensitivity through unknown mechanisms. The way to get around this limiting approach is sought after. Here, we introduce and propose a novel concept of pharmacogenomics signature (PGx-S) for elucidating holistically the effects of genetic polymorphisms upon individual variations in drug responses in an attempt to boost the pharmacovigilant capacities of drug responses. PMID- 29432842 TI - Diet with high content of advanced glycation end products induces systemic inflammation and weight gain in experimental mice: Protective role of curcumin and gallic acid. AB - The present study was aimed to investigate the effect of diet derived AGEs (dAGEs) on the circulatory levels of pro-inflammatory cytokines, chemokines and to evaluate the protective efficacy of natural anti-oxidants curcumin (CU) and gallic acid (GA) respectively against the dAGEs-induced systemic inflammation in experimental Swiss albino mice. The experimental mice were fed with dAGEs in the presence and absence of CU and GA for 6 months. The levels of 40 circulatory pro inflammatory cytokines and chemokines were evaluated using Proteome-Cytokine Array kit. In addition, serum levels of N-ECML, CRP and HbA1c were estimated by ELISA method. Among the sixteen pro- and anti-inflammatory cytokines analysed, five (IL-16, IL-1alpha, ICAM, TIMP-1 and C5a) were found to be highly expressed (3.5-fold) and eleven cytokines were moderately expressed (2-fold) in dAGEs fed mice. In case of chemokines, three (BLC, SDF-1 and MCP-1) were found to be highly expressed (4-fold) and ten showed moderate expression (2-fold) as compared with basal diet fed mice. Interestingly, CU or GA co-treatment normalized the levels of circulatory pro- and anti-inflammatory cytokines, chemokines, N-ECML, CRP and HbA1c levels. Together, the present study suggests that dAGEs are positively associated with the development of systemic inflammation in experimental mice. PMID- 29432845 TI - ADAM9 mediates the interleukin-6-induced Epithelial-Mesenchymal transition and metastasis through ROS production in hepatoma cells. AB - Interleukin (IL)-6 has been implicated in the invasion and metastasis of hepatocellular carcinoma (HCC). However, the molecular events that mediate this process are poorly understood. Here, we showed that IL-6 promoted the epithelial mesenchymal transition (EMT) in HCC cell lines, and upregulated a disintegrin and metalloprotease 9 (ADAM9) expression by activating the JNK signaling pathway. ADAM9 was upregulated in human HCCs which promoted HCC cell invasion and the EMT by interacting with NADPH oxidase 1 and inducing reactive oxygen species generation. Knockdown of ADAM9 inhibited the IL-6-induced EMT. Additionally, ADAM9 expression was positively correlated with IL-6 and Snail expression in human HCC specimens. Taken together, our results showed that ADAM9 is an important mediator of IL-6-induced HCC cell migration and invasion, and may provide a novel therapeutic target for HCC management. PMID- 29432846 TI - NF-kappaB in pancreatic cancer: Its key role in chemoresistance. AB - Pancreatic cancer is considered a lethal disease with a high mortality and an extremely low five-year survival rate. Chemotherapy plays a pivotal role in pancreatic cancer treatment both in an adjuvant setting after complete resection and in the case of unresectable metastatic disease. However, none of the available combination chemotherapy regimens has resulted in satisfactory survival outcomes. Recent studies have revealed that both constitutive and induced activation of nuclear factor kappa B (NF-kappaB) in pancreatic cancer cells are closely associated with cell proliferation, invasion, anti-apoptosis, inflammation, angiogenesis and chemotherapeutic resistance. Therefore, NF-kappaB inhibitors in combination with cytotoxic compounds have been reported as novel agents that improve chemotherapy sensitivity in pancreatic cancer. In this review, we outline recent developments in the understanding of the role of the NF kappaB signaling pathway and its associated genes in the progression of pancreatic cancer and highlight some potentially effective strategies for pancreatic cancer treatment. PMID- 29432847 TI - Ascitic fluid from advanced ovarian cancer patients compromises the activity of receptor tyrosine kinase inhibitors in 3D cell clusters of ovarian cancer cells. AB - Ovarian cancer patients in the advanced stages of the disease show clinical ascites, which is associated with a poor prognosis. There is limited understanding of the effect of ascitic fluid on ovarian cancer cells and their response to anticancer drugs. We investigated the antitumour effects of EGFR/Her 2 (canertinib) and c-Met (PHA665752) inhibitors in a 3D cell model of three ovarian cancer lines. Single and combined inhibitor treatments affected cell growth of OVCAR-5 and SKOV-3 cell lines but not OV-90 cell line. Growth reduction was correlated with the down expression of PCNA, EGFR, HER-2, c-MET, ERK and AKT and their phosphorylation status in cells in growth factor supplemented media. However, these effects were not re-producible in OVCAR-5 and SKOV-3 cell lines when they were exposed to ascitic fluid obtained from three ovarian cancer patients. Serum albumin and protein components in the ascitic fluids may reduce the cellular uptake of the inhibitors. PMID- 29432848 TI - Characterization of a recombinant Bacteroides fragilis sialidase expressed in Escherichia coli. AB - The human gut commensal Bacteroides fragilis produces sialidases that remove a terminal sialic acid from host-derived polysaccharides. Sialidase is considered to be involved in B. fragilis infection pathology. A native B. fragilis sialidase has been purified and characterized, and was shown to be post-translationally modified by glycosylation. However, the biochemical properties of recombinant B. fragilis sialidase expressed in a heterologous host remain uncharacterized. In this study, we examined the enzymatic properties of the 60-kDa sialidase NanH1 of B. fragilis YCH46, which was prepared as a recombinant protein (rNanH1) in Escherichia coli. In E. coli rNanH1 was expressed as inclusion bodies, which were separated from soluble proteins to allow solubilization of insoluble rNanH1 in a buffer containing 8 M urea and renaturation in refolding buffer containing 100 mM CaCl2 and 50 mM L-arginine. The specific activity of renatured rNanH1 measured using 4-methylumberiferyl-alpha-D-N-acetyl neuraminic acid as a substrate was 6.16 MUmol/min/mg. The optimal pH of rNanH1 ranged from 5.0 to 5.5. The specific activity of rNanH1 was enhanced in the presence of calcium ions. rNanH1 preferentially hydrolyzed the sialyl alpha2,8 linkage and cleaved sialic acids from mucin and serum proteins (e.g., fetuin and transferrin) but not from alpha1 acid glycoprotein, which is similar to the previously observed biochemical properties for a native sialidase purified from B. fragilis SBT3182. The results and methods described in this study will be useful for preparing and characterizing recombinant proteins for other B. fragilis sialidase isoenzymes. PMID- 29432849 TI - Cultivation of multiple genera of hydrogenotrophic methanogens from different environmental niches. AB - Six genera of hydrogenotrophic methanogens, namely Methanobrevibacter, Methanobacterium, Methanocorpusculum, Methanothermobacter, Methanoculleus, and Methanospirillum were cultivated from diverse environmental niches like rumen, feces, gut, and sediments using BY medium. We also report a putative novel genus and two novel species of methanogens isolated from termite, Indian star tortoise, and green iguana. PMID- 29432850 TI - Combining high-throughput sequencing and targeted loci data to infer the phylogeny of the "Adenocalymma-Neojobertia" clade (Bignonieae, Bignoniaceae). AB - Combining high-throughput sequencing data with amplicon sequences allows the reconstruction of robust phylogenies based on comprehensive sampling of characters and taxa. Here, we combine Next Generation Sequencing (NGS) and Sanger sequencing data to infer the phylogeny of the "Adenocalymma-Neojobertia" clade (Bignonieae, Bignoniaceae), a diverse lineage of Neotropical plants, using Maximum Likelihood and Bayesian approaches. We used NGS to obtain complete or nearly-complete plastomes of members of this clade, leading to a final dataset with 54 individuals, representing 44 members of ingroup and 10 outgroups. In addition, we obtained Sanger sequences of two plastid markers (ndhF and rpl32 trnL) for 44 individuals (43 ingroup and 1 outgroup) and the nuclear PepC for 64 individuals (63 ingroup and 1 outgroup). Our final dataset includes 87 individuals of members of the "Adenocalymma-Neojobertia" clade, representing 66 species (ca. 90% of the diversity), plus 11 outgroups. Plastid and nuclear datasets recovered congruent topologies and were combined. The combined analysis recovered a monophyletic "Adenocalymma-Neojobertia" clade and a paraphyletic Adenocalymma that also contained a monophyletic Neojobertia plus Pleonotoma albiflora. Relationships are strongly supported in all analyses, with most lineages within the "Adenocalymma-Neojobertia" clade receiving maximum posterior probabilities. Ancestral character state reconstructions using Bayesian approaches identified six morphological synapomorphies of clades namely, prophyll type, petiole and petiolule articulation, tendril ramification, inflorescence ramification, calyx shape, and fruit wings. Other characters such as habit, calyx cupular trichomes, corolla color, and corolla shape evolved multiple times. These characters are putatively related with the clade diversification and can be further explored in diversification studies. PMID- 29432851 TI - Filtering of target sequence capture individuals facilitates species tree construction in the plant subtribe Iochrominae (Solanaceae). AB - Advances in sequencing technology have made it possible to produce large multi locus datasets required for species tree analyses. One challenge with constructing high throughput sequencing datasets, however, is that missing information is propagated at different steps in the sequence preparation process. To date, species tree studies have focused on filtering and removing errors that occur at particular loci. Given the way that high throughput sequencing datasets are constructed, however, large amounts of error or ambiguity may also manifest across individuals. Here we use a novel tree-based multivariate clustering method to identify and remove individuals with low phylogenetic signal in a nuclear sequence capture dataset for the Iochrominae clade (Solanaceae). Our results suggest that the low quality tips are the result of the library preparation process (e.g. unequal pooling) rather than poor capture due to phylogenetic distance from the reference species. After implementing the clustering approach and removing low quality tips, we construct an Iochrominae species tree that resolves a number of unknown relationships. We propose this pipeline as a valuable tool for species tree reconstruction with phylogenomic datasets containing variable levels of missing data. PMID- 29432852 TI - Environmental manganese exposure and associations with memory, executive functions, and hyperactivity in Brazilian children. AB - Manganese (Mn) is an essential element, however high levels of Mn have been associated with lower neuropsychological performance and behavioral problems in children. We investigated the associations between hair Mn concentrations and neuropsychological and behavioral performances among children with long-term exposure to airborne Mn aged between 7 and 12 years. Neuropsychological performance included tests of: verbal memory, inhibitory control, cognitive flexibility, verbal fluency, and motor function. We used the Conners Abbreviated Rating Scale for teachers to assess students' behaviors of hyperactivity. Hair manganese (MnH) concentrations in children and exposure to airborne manganese from a ferro-manganese alloy plant were analyzed and correlated with tests scores. Multivariable linear models adjusting for potential confounders showed that elevated levels of MnH were associated with lower performance in verbal memory, as measured by the free recall after interference (beta = - 1.8; 95% CI: 3.4, - 0.2), which indicates susceptibility to interference, and Delayed Effect (beta = -2.0; 95% CI: -3.7, - 0.2), representing a loss of information over time. Additionally, we found patterns of effect modification by sex in three subtests measuring verbal memory: the free recall after interference score, Interference Effect, and Delayed Effect (all at p < 0.10). Overall, the results suggest that long-term airborne Mn exposure may be associated with lower performance in verbal memory, and hyperactivity behaviors. PMID- 29432853 TI - Neurobehavioral effects of 1,2-propanediol in zebrafish (Danio rerio). AB - The use of electronic cigarettes (e-cigarettes) is increasing despite insufficient information concerning their long-term effects, including the effects of maternal e-cigarette use on pre- and postnatal development. Our previous study demonstrated that developmental exposure to 1,2-propanediol (a principal component of e-cigarette liquid) affected early development of zebrafish, causing reduced growth, deformities, and hyperactive swimming behavior in larvae. The current study extends assessment of the developmental toxicity of 1,2-propanediol by examining additional long-term behavioral effects. We demonstrate that embryonic/larval exposure of zebrafish to 1,2-propanediol (0.625% or 1.25%) not only affected behavioral parameters in the larvae, but also caused persisting behavioral effects in adults after early developmental exposure. Additional parameters, including neural and vascular development in larvae, stress response in adults, and concentration of neurotransmitters dopamine and serotonin in adult brain were examined, in order to explain the behavioral differences. These additional assessments did not find 1,2-propanediol exposure to significantly affect Tg(Neurog1:GFP) or the transcript abundance of neural genes (Neurog1, Ascl1a, Elavl3, and Lef1). Vascular development was not found to be affected by 1,2-propanediol exposure, as inferred from experiments with Tg(Flk1:eGFP) zebrafish; however, transcript abundance of vascular genes (Flk1, Vegf, Tie-2, and Angpt1) was decreased. No statistically significant changes were noted for plasma cortisol or brain neurotransmitters in adult fish. Lastly, analysis of gene transcripts involved with 1,2-propanediol metabolism (Adh5, Aldh2.1, and Ldha) showed an increase in Adh5 transcript. This is the first study to demonstrate that developmental exposure to 1,2-propanediol has long-term neurobehavioral consequences in adult zebrafish, showing that e cigarettes contain substances potentially harmful to neurodevelopment. PMID- 29432854 TI - Color vision impairment with low-level methylmercury exposure of an Amazonian population - Brazil. AB - Land exploitation that follows deforestation and mining can result in soil erosion and the release of mercury to the waters of rivers in the Amazon Basin. Inorganic mercury is methylated by bacteria that are present in the environment and it serves as a source of human contamination through fish consumption in the form of methylmercury. Long-term exposure to low-level methylmercury in the riverside populations can lead to nervous system alterations, some of which are visual impairments such as loss of luminance contrast sensitivity, restricted visual fields and color vision defects. The present study sought to examine color vision in a group of adults living in the central Brazilian Amazon who were exposed to low-levels of methylmercury. Total Hg concentrations were measured from hair collected at the time of the testing. The D15d and FM100 color vision arrangement tests were applied in a population of 36 (22 males) and 42 (25 males), respectively. Controls were healthy volunteers from the cities of Sao Paulo for the D15d and Belem for the FM100. There was a statistically significant difference in performance between those who were exposed and controls for both tests (p < 0.01 and p < 0.0001, respectively, Mann-Whitney U test), meaning that adults living in this region of the Amazon made more mistakes on both tests when compared to controls. A linear regression was performed using Hg concentrations and test scores. Hg concentrations accounted for 7% and 2% of color D15d and FM100 arrangement test errors, respectively. Although other studies have previously found color vision impairment in the Amazon, they tested inhabitants on the east side of the Amazon, while this study was conducted in the central Amazon region and it is the first study in a population with no direct contact with the Hg source of contamination. These results suggest that long-term exposure to low-level methylmercury in riverside populations is more widely spread in the Amazon Basin than previously reported. This information is needed to implement public health policies that will ensure a safer environment for the Amazonian population. PMID- 29432855 TI - Suppression of lung inflammation by the methanol extract of Spilanthes acmella Murray is related to differential regulation of NF-kappaB and Nrf2. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Although Spilanthes acmella has been used to relieve inflammation, fever, pain, or infection in traditional Asian medicine, experimental evidence supporting these functions is scarce. Here, we examined an anti-inflammatory function and a possible underlying mechanism of S. acmella Murray (SAM). MATERIALS AND METHOD: The methanol extract of SAM was fingerprinted by HPLC. C57BL/6 mice were administered with a single intratracheal (i.t.) LPS and 2 h later with a single i.t. SAM. The effect of SAM on lung inflammation was assessed by histology, semi-quantitative RT-PCR, and MPO assay of lung tissue. The effects of SAM on a pro-inflammatory factor NF-kappaB and an anti inflammatory factor Nrf2 were analyzed by immunoblotting of nuclear proteins and by semi-quantitative RT-PCR analysis of mRNA of the genes governed by these transcription factors. V5-Nrf2 was precipitated by an anti-V5 antibody and the ubiquitinated V5-Nrf2 was revealed by immunoblotting of HA-tagged ubiquitin. RESULTS: The i.t. SAM robustly diminished a neutrophilic lung inflammation induced by i.t. LPS treatment of mice. In RAW 264.7 cells, SAM suppressed the nuclear localization of NF-kappaB and the expression of NF-kappaB-dependent cytokine genes. SAM increased the level of Nrf2 in the nucleus and the expression of Nrf2-dependent genes while suppressing ubiquitination of Nrf2. CONCLUSION: Our results suggest that SAM can suppress a neutrophilic inflammation in mouse lungs, which is associated with suppressed NF-kappaB and activated Nrf2. Our results provide experimental evidence supporting the anti-inflammatory function of S. acmella. PMID- 29432856 TI - Aqueous extracts from Uncaria tomentosa (Willd. ex Schult.) DC. reduce bronchial hyperresponsiveness and inflammation in a murine model of asthma. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria tomentosa (Willd. Ex Schult) DC is used by indigenous tribes in the Amazonian region of Central and South America to treat inflammation, allergies and asthma. The therapeutic properties of U. tomentosa have been attributed to the presence of tetracyclic and pentacyclic oxindole alkaloids and to phenolic acids. AIMS OF THE STUDY: To characterize aqueous bark extracts (ABE) and aqueous leaf extracts (ALE) of U. tomentosa and to compare their anti-inflammatory effects. MATERIALS AND METHODS: Constituents of the extracts were identified by ultra performance liquid chromatography-mass spectrometry. Anti-inflammatory activities were assessed in vitro by exposing lipopolysaccharide-stimulated macrophage cells (RAW264.7-Luc) to ABE, ALE and standard mitraphylline. In vivo assays were performed using a murine model of ovalbumin (OVA)-induced asthma. OVA-sensitized animals were treated with ABE or ALE while controls received dexamethasone or saline solution. Bronchial hyperresponsiveness, production of Th1 and Th2 cytokines, total and differential counts of inflammatory cells in the bronchoalveolar lavage (BAL) and lung tissue were determined. RESULTS: Mitraphylline, isomitraphylline, chlorogenic acid and quinic acid were detected in both extracts, while isorhyncophylline and rutin were detected only in ALE. ABE, ALE and mitraphylline inhibited the transcription of nuclear factor kappa-B in cell cultures, ALE and mitraphylline reduced the production of interleukin (IL)-6, and mitraphylline reduced production of tumor necrosis factor-alpha. Treatment with ABE and ALE at 50 and 200 mg kg-1, respectively, reduced respiratory elastance and tissue damping and elastance. ABE and ALE reduced the number of eosinophils in BAL, while ALE at 200 mg kg-1 reduced the levels of IL-4 and IL-5 in the lung homogenate. Peribronchial inflammation was significantly reduced by treatment with ABE and ALE at 50 and 100 mg kg-1 respectively. CONCLUSION: The results clarify for the first time the anti-inflammatory activity of U. tomentosa in a murine model of asthma. Although ABE and ALE exhibited distinct chemical compositions, both extracts inhibited the production of pro-inflammatory cytokines in vitro. In vivo assays revealed that ABE was more effective in treating asthmatic inflammation while ALE was more successful in controlling respiratory mechanics. Both extracts may have promising applications in the phytotherapy of allergic asthma. PMID- 29432857 TI - A joint frailty model provides for risk stratification of human immunodeficiency virus-infected patients based on unobserved heterogeneity. AB - OBJECTIVES: To investigate the association between recurrent AIDS-defining events and a semicompeting risk of death in patients with advanced, multidrug-resistant human immunodeficiency virus infection and to identify individuals at increased risk for these events using a joint frailty model. STUDY DESIGN AND SETTING: Three hundred sixty-eight patients with antiretroviral treatment failure in the Options in Management of Antiretrovirals Trial randomized to two antiretroviral treatment strategies using a 2 * 2 factorial design, intensive vs. standard and interruption vs. continuation, and followed for development of AIDS-defining events and death. RESULTS: Participants were heterogeneous for risk of AIDS defining events and death (P < 0.001), and AIDS-defining events were strongly associated with death (P < 0.001), irrespective of treatment. The frailty model was used to classify individuals into high- and low-risk groups based on unobserved heterogeneity. Low-risk individuals were unlikely to die (0%) or have an AIDS-defining event (<4%), whereas high-risk individuals had event rates approaching 70%. About one-third of high-risk individuals had accelerated mortality, all who died before experiencing an AIDS-defining event. High-risk was associated with being immunocompromised and higher predicted 5-year mortality. CONCLUSION: The joint frailty model permits classification of individuals into risk groups based on unobserved heterogeneity that may be identifiable based on observed covariates, providing advantages over the traditional Cox model. PMID- 29432858 TI - GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence. AB - OBJECTIVE: To provide guidance on how systematic review authors, guideline developers, and health technology assessment practitioners should approach the use of the risk of bias in nonrandomized studies of interventions (ROBINS-I) tool as a part of GRADE's certainty rating process. STUDY DESIGN AND SETTING: The study design and setting comprised iterative discussions, testing in systematic reviews, and presentation at GRADE working group meetings with feedback from the GRADE working group. RESULTS: We describe where to start the initial assessment of a body of evidence with the use of ROBINS-I and where one would anticipate the final rating would end up. The GRADE accounted for issues that mitigate concerns about confounding and selection bias by introducing the upgrading domains: large effects, dose-effect relations, and when plausible residual confounders or other biases increase certainty. They will need to be considered in an assessment of a body of evidence when using ROBINS-I. CONCLUSIONS: The use of ROBINS-I in GRADE assessments may allow for a better comparison of evidence from randomized controlled trials (RCTs) and nonrandomized studies (NRSs) because they are placed on a common metric for risk of bias. Challenges remain, including appropriate presentation of evidence from RCTs and NRSs for decision-making and how to optimally integrate RCTs and NRSs in an evidence assessment. PMID- 29432859 TI - Pragmatic trials revisited: applicability is about individualization. PMID- 29432860 TI - Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval. AB - OBJECTIVES: The aim of this study was to evaluate how often the European Medicines Agency (EMA) has authorized drugs based on nonrandomized studies and whether there is an association between treatment effects and EMA preference for further testing in randomized clinical trials (RCTs). STUDY DESIGN AND SETTING: We reviewed all initial marketing authorizations in the EMA database on human medicines between 1995 and 2015 and included authorizations granted without randomized data. We extracted data on treatment effects and EMA preference for further testing in RCTs. RESULTS: Of 723 drugs, 51 were authorized based on nonrandomized data. These 51 drugs were licensed for 71 indications. In the 51 drug-indication pairs with no preference for further RCT testing, effect estimates were large [odds ratio (OR): 12.0 (95% confidence interval {CI}: 8.1 17.9)] compared to effect estimates in the 20 drug-indication pairs for which future RCTs were preferred [OR: 4.3 (95% CI 2.8-6.6)], with a significant difference between effects (P = 0.0005). CONCLUSION: Nonrandomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on nonrandomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence. PMID- 29432861 TI - Is providing uncertainty intervals in treatment ranking helpful in a network meta analysis? PMID- 29432862 TI - Responsible Epidemiologic Research Practice: a guideline developed by a working group of the Netherlands Epidemiological Society. AB - OBJECTIVES: To develop a guideline on Responsible Epidemiologic Research Practice that will increase value and transparency, increase the accountability of the epidemiologists, and reduce research waste. SETTING: A working group of the Netherland Epidemiological Society was given the task of developing a guideline that would meet these objectives. Several publications about the need to prevent Detrimental Research Practices triggered this work. Among these were a series in the Lancet on research waste and a subsequent series on transparency in the Journal of Clinical Epidemiology. The reputation and trust in epidemiologic research is still high, and the Netherlands Epidemiological Society wishes to keep it that way. The guideline deals with how epidemiologic research should be conducted, archived, and disclosed. It does not deal with the more technical aspects, such as required sample size, choice of study design, and so forth. The guideline describes each step in the process of conducting an epidemiologic study, from the first idea to the ultimate publication and beyond. METHODS: The working group reviewed the literature on responsible research conduct, including the various existing codes of conduct. It applied the general principles from these codes to the elements of an epidemiologic study and formulated specific recommendations for each of these. Next step was to draft the guideline. Preceding the 2016 annual national epidemiology conference in Wageningen, a preconference was organized to discuss the draft guideline and to assess support. Support was clearly present, and the provided recommendations were incorporated into the draft guideline. In March 2017, a draft version of the guideline was sent to all 1,100 members of the society with the request to review and provide comments. All received responses were positive, and some minor additions were made. The Responsible Epidemiologic Research Practice guideline has now been approved by the board of the Netherlands Epidemiological Society. CONCLUSION: With the Responsible Epidemiologic Research Practice guideline, we hope to contribute to better research practices in epidemiology but perhaps also in adjacent disciplines. PMID- 29432863 TI - Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats. AB - : Neonatal handling (NH) of male rat pups strongly attenuates stress response and stress-induced persistent muscle hyperalgesia in adults. Because female sex is a well established risk factor for stress-induced chronic muscle pain, we explored whether NH provides resilience to stress-induced hyperalgesia in adult female rats. Rat pups underwent NH, or standard (control) care. Muscle mechanical nociceptive threshold was assessed before and after water avoidance (WA) stress, when they were adults. In contrast to male rats, NH produced only a modest protection against WA stress-induced muscle hyperalgesia in female rats. Gonadectomy completely abolished NH-induced resilience in male rats but produced only a small increase in this protective effect in female rats. The administration of the antiestrogen drug fulvestrant, in addition to gonadectomy, did not enhance the protective effect of NH in female rats. Finally, knockdown of the androgen receptor by intrathecal antisense treatment attenuated the protective effect of NH in intact male rats. Together, these data indicate that androgens play a key role in NH-induced resilience to WA stress-induced muscle hyperalgesia. PERSPECTIVE: NH induces androgen-dependent resilience to stress induced muscle pain. Therefore, androgens may contribute to sex differences observed in chronic musculoskeletal pain and its enhancement by stress. PMID- 29432864 TI - Intestinal granular cells of a cartilaginous fish, thornback ray Raja clavata: Morphological characterization and expression of different molecules. AB - This investigation aims to fill gaps in our understanding of the intestinal immune cells of elasmobranchs. Whole digestive tracts of fifteen thornback ray Raja clavata were provided by a trawl fleet from the Gulf of Asinara (Sardinia, western Mediterranean Sea). Histochemical, immunohistochemical and ultrastructural observations were conducted on the spiral intestine. Three types of granular cells were identified; type I in epithelium, types II and III in lamina propria-submucosa, with each of them containing cytoplasmic granules with different ultrastructural characteristics. Data on size and density of each granular cell type are provided. Immunostaining of intestinal sections showed the reactivity of the granular cells: type I cells were positive for lysozyme, mast cell tryptase and tumor necrosis factor-alpha based on antibody staining; type III cells were immune-reactive to anti-interleukin 6 antibody, whilst type II cells were negative to all the antibodies used. Comparison of each granular cell type with immune cells of teleosts or mammals and an hypothesis on their nature and function are reported. A potential role for granular cells in intestinal cellular immunity is also discussed with respect to type I and type III cells having similarities to Paneth cells and neutrophils, respectively. PMID- 29432865 TI - Functional characterization of purinergic P2Y2 and P2Y12 receptors involved in Japanese flounder (Paralichthys olivaceus) innate immune responses. AB - G-protein-coupled P2Y receptors activated by extracellular nucleotides play important roles under different physiological and pathophysiological conditions in mammals. To investigate the immunological relevance of P2Y receptors in fish, we identified and characterized the P2Y2 and P2Y12 receptors in Japanese flounder Paralichthys olivaceus. The P. olivaceus P2Y2 and P2Y12 receptors harbor seven transmembrane domains but share only 24% sequence identity. Real-time PCR analysis revealed the constitutive but unequal mRNA expression pattern of P2Y2R and P2Y12R in normal Japanese flounder tissues with the dominant expression of P2Y2R in head kidney and blood and P2Y12R in hepatopancreas. In addition, the expression of P2Y2 and P2Y12 receptors was markedly modulated by PAMPs stimulation and Edwardsiella tarda infection. Furthermore, blockage of P2Y12R potently increased ADP-activated pro-inflammatory cytokine IL-1beta gene expression in the head kidney macrophages (HKMs). Moreover, inhibition of P2Y2 and P2Y12 receptor activity with their respective potent antagonists significantly altered some of the LPS-induced pro-inflammatory cytokine gene expression in the HKMs. However, blockade of P2Y12R did not affect the poly(I:C) induced pro-inflammatory cytokine gene expression examined in the HKMs. Collectively, we have for the first time reported the role of purinergic P2Y2 and P2Y12 receptors in fish innate immunity. Our findings have also addressed the importance of extracellular ATP and its metabolites in fish innate immune responses. PMID- 29432867 TI - Release of large amounts of lipopolysaccharides from Pseudomonas aeruginosa cells reduces their susceptibility to colistin. AB - Pseudomonas aeruginosa is an important etiological agent of opportunistic infections. Injectable colistin is available as a last-line treatment option for multidrug-resistant P. aeruginosa infections. When cells were inoculated at a high number, colistin-susceptible P. aeruginosa grew on agar medium containing colistin at a concentration 10-fold higher than the minimum inhibitory concentration without acquiring colistin resistance. This study examined the responsible mechanism for growth in the presence of a high concentration of colistin. Cell wash fluid derived from P. aeruginosa efficiently reduced colistin antimicrobial activity. This reduction was mediated by lipopolysaccharide (LPS) in the wash fluid. Extracellular LPS inhibited colistin activity more effectively than cell-bound LPS in fixed cells. Cell wash fluids from Escherichia coli and Acinetobacter baumannii also reduced colistin activity; however, they were less potent than those from P. aeruginosa. The amount of LPS in cell wash fluid from P. aeruginosa was approximately 10-fold higher than that in fluid from E. coli or A. baumannii. In conclusion, cell-free LPS derived from bacterial cells inhibited the antimicrobial activity of colistin, and this effect was greatest for P. aeruginosa. Thus, large amounts of broken and dead cells of P. aeruginosa at infection foci will reduce the effectiveness of colistin, even against cells that have not yet acquired resistance. PMID- 29432866 TI - Expression and functional analysis of receptor-interacting serine/threonine kinase 2 (RIP2) in Japanese flounder (Paralichthys olivaceus). AB - Being a key adaptor protein in NOD1/2 and NF-kappaB signaling pathways, receptor interacting serine/threonine kinase 2 (RIP2) plays an important role in innate immune response in vertebrates. In this study, we identified and characterized the Paralichthys olivaceus RIP2 gene (PoRIP2). Phylogenetic, alignment, and genomic analysis of PoRIP2 were conducted to determine its conservation and evolutionary relationship with other RIP2 in vertebrates. qRT-PCR results showed that the expression of PoRIP2 was high in the spleen and head kidney. Meanwhile, embryonic development expression profile revealed that it was high in the early developmental stages and hatching stage. In vivo, we examined the expression pattern in different tissues after being challenged with Edwardsiella tarda. PoRIP2 was up-regulated in tissues at different time points. In vitro, the expression of PoRIP2 was also increased after treatment with Poly I:C, PGN, and E. tarda. Transfection and overexpression experiments indicated that PoRIP2 was located in the cytoplasm of the FG-9307 cell line. The pro-inflammatory cytokines, IL-1beta, IL-6, and IL-8, could be activated and up-regulated by PGN stimulation in PoRIP2 overexpressed cells. The inhibitory action was obvious in PoRIP2 overexpressed cells, and the quantity of E. tarda decreased. These findings highlight the important role of PoRIP2 in regulating innate immune in P. olivaceus. Our results indicated that PoRIP2 might be involved in immune response and the activation of the NF-kappaB signaling pathways. Our study can improve the knowledge on the immune system of fish and provide a theoretical basis for the study of prevention and treatment of fish diseases. PMID- 29432869 TI - Detection of ISEcp1-associated blaCTX-M-15-mediated resistance to colistin in KPC producing Klebsiella pneumoniae isolates. PMID- 29432868 TI - Repurposing niclosamide for intestinal decolonization of vancomycin-resistant enterococci. AB - Enterococci are commensal micro-organisms present in the gastrointestinal tract of humans. Although normally innocuous to the host, strains of enterococcus exhibiting resistance to vancomycin (VRE) have been associated with high rates of infection and mortality in immunocompromised patients. Decolonization of VRE represents a key strategy to curb infection in highly-susceptible patients. However, there is a dearth of decolonizing agents available clinically that are effective against VRE. The present study found that niclosamide, an anthelmintic drug, has potent antibacterial activity against clinical isolates of vancomycin resistant Enterococcus faecium (minimum inhibitory concentration 1-8 ug/mL). E. faecium mutants exhibiting resistance to niclosamide could not be isolated even after multiple (10) serial passages. Based upon these promising in-vitro results and the limited permeability of niclosamide across the gastrointestinal tract (when administered orally), niclosamide was evaluated in a VRE colonization reduction murine model. Remarkably, niclosamide outperformed linezolid, an antibiotic used clinically to treat VRE infections. Niclosamide was as effective as ramoplanin in reducing the burden of vancomycin-resistant E. faecium in the faeces, caecal content and ileal content of infected mice after only 8 days of treatment. Linezolid, in contrast, was unable to decrease the burden of VRE in the gastrointestinal tract of mice. The results obtained indicate that niclosamide warrants further evaluation as a novel decolonizing agent to suppress VRE infections. PMID- 29432870 TI - Risk Stratification for Erectile Dysfunction After Pelvic Fracture Urethral Injuries. AB - OBJECTIVE: To compare the frequency and severity of erectile dysfunction (ED) among pelvic fracture patients with and without urethral injuries and to identify potential risk factors for ED in the setting of pelvic fracture injury. MATERIALS AND METHODS: A retrospective review was conducted of male patients treated for pelvic fractures with and without urethral injuries at a Level 1 trauma center between 2005 and 2016. The International Index of Erectile Function (IIEF-5) questionnaire was administered to patients by telephone to assess post-injury ED. Additional questions about pre-injury ED, post-injury symptoms, and past medical history were reviewed. RESULTS: Fifty patients (42%, n = 118) responded to the IIEF-5 questionnaire: 29 with pelvic fractures alone and 21 with PFUIs. We observed a numerical increase in frequency of new onset ED in patients with pelvic fracture urethral injuries (PFUIs) (n = 12, 57%) compared with patients with pelvic fractures alone (n = 11, 38%) (P = .3). Patients with PFUIs reported lower IIEF-5 scores (ie worse ED) than patients with pelvic fractures alone (13 versus 18, P = .05). There were no significant differences in potential risk factors between the 2 groups on univariate analyses. CONCLUSION: ED was more severe following PFUI than pelvic fracture alone. We suspect that urethral injury is not the direct cause of ED, but rather a surrogate for extensive pelvic injury and risk for neurovascular injury. A larger prospective analysis is warranted to clarify this hypothesis and to further stratify risk factors for developing ED in pelvic fracture patients with and without urethral injuries. PMID- 29432871 TI - Tertiary Referral Hospital Experiences of Men Presenting With Painless Postcoital Gross Hematuria and a Suggestion for the Management Algorithm. AB - OBJECTIVE: To review the tertiary referral hospital experiences of men presenting with painless postcoital gross hematuria (PCGH) and suggest a management algorithm. MATERIALS AND METHODS: We reviewed clinical data from 19 male patients who first visited a clinic because of PCGH between 2009 and 2016. The patients were evaluated according to our tentative management algorithm for painless PCGH. First, a general workup for painless gross hematuria (GH) was performed. If the cause of the PCGH was not identified, a vascular workup of the pelvic vasculatures for PCGH was performed, including transrectal and penile ultrasonography with Doppler study. Pelvic angiography and subsequent angioembolization were recommended at the physician's discretion. RESULTS: The median age of the patients was 47 (range: 30-67) years. The tentative management algorithm led to no abnormal findings in 7 patients and identified urologic malignancies in 2 patients. Urethrocystoscopy revealed urethral hemangioma in 3 patients. Doppler ultrasonography revealed pelvic varicosities in 3 patients, complicated cyst of Cowper glands in 1 patient, and pelvic arteriovenous malformation in 3 patients. Pelvic angiography was recommended for the 3 patients with pelvic arteriovenous malformation, and 2 of those patients were successfully treated by angioembolization. CONCLUSION: The clinical approach to painless PCGH should be different from that of painless GH. Both the general and the vascular workup for the pelvic vasculatures for painless GH are mandatory for the evaluation of patients with painless PCGH. PMID- 29432872 TI - Varicocele Due to Post-traumatic Arteriovenous Fistula. AB - Varicocele consists of abnormally dilated and tortuous veins within the pampiniform plexus, usually in the left scrotum. We reported a rare case of right varicocele due to post-traumatic arteriovenous fistula successfully treated by percutaneous embolization. PMID- 29432874 TI - Re: Thompson et al.: Predictors of a Successful Urology Resident Using Medical Student Application Materials (Urology 2017;108:22-28). PMID- 29432873 TI - Characterization of Urothelial Cancer Circulating Tumor Cells with a Novel Selection-Free Method. AB - OBJECTIVE: To investigate circulating tumor cells (CTCs) as biomarkers of urothelial carcinoma (UC). To date, the majority of work on this topic has utilized the CellSearch test, which has limited sensitivity due to reliance on positive selection for the cell surface protein epithelial cell adhesion molecule (EpCAM). We used a novel selection-free method to enumerate and characterize CTCs across a range of UC stages. MATERIALS AND METHODS: Blood samples from 38 patients (9 controls, 8 nonmuscle invasive bladder cancer [NMIBC], 12 muscle invasive bladder cancer [MIBC], and 9 metastatic UC) were processed with the AccuCyte-CyteFinder system. Slides were stained for the white blood cell markers CD45 and CD66b and the epithelial markers EpCAM and pancytokeratin. CTCs were defined as any cytokeratin postive and white blood cell marker negative cell. Separately, the more restrictive CellSearch definition was applied, with the additional requirement of EpCAM positivity. The Kruskal-Wallis ANOVA test compared CTC counts by stage. RESULTS: Greater than or equal to 1 CTC was detected in 2 of 8 (25%) patients with NMIBC, 7 of 12 (58%) with MIBC, and 6of 9 (67%) with metastatic disease. No control had CTCs. Comparing CTC counts between groups, the only statistically significant comparison was between controls and patients with metastatic UC (P = .009). With EpCAM positivity as a CTC requirement, no CTCs were detected in any patient with NMIBC, and only 2 (17%) patients with MIBC had CTCs. CTCs tended to be larger in metastatic patients. CONCLUSION: CTCs were detected at all UC stages and exhibited phenotypic diversity of cell size and EpCAM expression. EpCAM negative CTCs that would be missed with the CellSearch test were detected in patients with NMIBC and patients with MIBC. PMID- 29432875 TI - New Tools to Measure Ejaculatory Latency-Arousal to Ejaculation Time Interval and Erection to Ejaculation Time Interval: A Pilot Study. AB - OBJECTIVE: The present study aimed to evaluate the proposed novel tools, namely, arousal to ejaculation time interval (AETI) and erection to ejaculation time interval (EETI), and to measure ejaculatory latency during different types of sexual encounters in a pilot study. MATERIALS AND METHODS: The study period was from September 2016 to December 2016. After obtaining informed consent and institutional review board approval, the medical practitioners without any comorbidity and who volunteered to participate were asked to report their self assessed AETI and EETI during a sexual activity. They were also asked to opine as to whether they consider themselves as normal ejaculators, delayed ejaculators, or premature ejaculators. Statistical data including mean, standard deviation, and P value were obtained. RESULTS: The sample size was 60 with a mean age of 48.9 +/- 10.8 years. A total of 48 participants reported themselves as normal. Their mean AETIs were 624.8 +/- 83.6 seconds, 700 +/- 79.1 seconds, and 420 +/- 57.7 seconds, and their mean EETIs were 355 +/- 82.6 seconds, 442.5 +/- 46.6 seconds, and 240 +/- 38.6 seconds during heterosexual vaginal intercourse, masturbation, and oral sex, respectively. Twelve participants reported premature ejaculation, and their mean AETIs were 122 +/- 11.6 seconds, 73.33 +/- 11.2 seconds, and 74 +/- 12.3 seconds, and their mean EETIs were 106.7 +/- 21.6 seconds, 70 +/- 13.7 seconds, and 60 +/- 11.8 seconds during heterosexual vaginal intercourse, masturbation, and oral sex, respectively. None of the participants reported themselves as delayed ejaculators. The differences between the means were statistically significant (P <=.0001). CONCLUSION: AETI and EETI can be used to measure ejaculatory latency in different types of sexual encounters. PMID- 29432876 TI - Effects of d-cycloserine on individual differences in relapse of fear. AB - The major weakness of psychological and pharmacological interventions for anxiety disorders is that the fear often returns. We examined whether DCS, which has attracted considerable attention as a potential pharmacological adjunct to therapy, reduces relapse, and whether individual differences in the rate of extinction modulates its effectiveness in reducing relapse. Experimentally-naive adult male rats received pairings of a white noise CS with a shock US, extinction to a criterion immediately followed by an injection of DCS or Saline, and then were tested for relapse of fear (renewal, spontaneous recovery, or reinstatement; in four separate experiments). The number of blocks to reach criteria in extinction was used to classify animals as "Fast" or "Slow" Extinguishers. We consistently found that while DCS reduced relapse in Fast Extinguishers, it had minimal effects on relapse in Slow Extinguishers. Importantly, the differences in the effect of DCS on Fast and Slow Extinguishers was not due to Fast Extinguishers being less susceptible to relapse as animals in both groups exhibited similar amounts of relapse when injected with saline. Relapse, of all three types tested, was consistently reduced by DCS, but only in the Fast Extinguishers. Such findings contribute to a growing literature identifying factors that could influence the efficacy of pharmacological adjuncts to exposure therapy. These results have important implications for the development of personalized treatment approaches, which recognize, and are tailored to, individual differences. PMID- 29432877 TI - The effects of vitamin D and probiotic co-supplementation on mental health parameters and metabolic status in type 2 diabetic patients with coronary heart disease: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: This study was carried out to evaluate the effects of vitamin D and probiotic co-supplementation on mental health parameters and metabolic status in diabetic people with coronary heart disease (CHD). METHODS: This randomized, double-blind, placebo-controlled trial was carried out among 60 diabetic people with CHD, aged 45-85 years old. Subjects were randomly allocated into two groups to receive either 50,000 IU vitamin D every 2 weeks plus 8 * 109 CFU/g probiotic of Lactocare Zisttakhmir Co (n = 30) or placebo (n = 30) for 12 weeks. Fasting blood samples were obtained at baseline and after the 12-week intervention to determine metabolic profiles. RESULTS: After the 12-week intervention, compared with the placebo, vitamin D and probiotic co-supplementation resulted in significant improvements in beck depression inventory total score (-2.8 +/- 3.8 vs. -0.9 +/- 2.1, P = 0.01), beck anxiety inventory scores (-2.1 +/- 2.3 vs. -0.8 +/- 1.4, P = 0.009) and general health questionnaire scores (-3.9 +/- 4.1 vs. 1.1 +/- 3.4, P = 0.005). Compared with the placebo, vitamin D and probiotic co supplementation resulted in significant reductions in serum insulin levels (-2.8 +/- 3.8 vs. +0.2 +/- 4.9 MUIU/mL, P = 0.009), homeostasis model of assessment estimated insulin resistance (-1.0 +/- 1.6 vs. -0.1 +/- 1.5, P = 0.02), and a significant increase in serum 25-OH-vitamin D (+11.8 +/- 5.9 vs. +0.1 +/- 1.4 ng/mL, P < 0.001), the quantitative insulin sensitivity check index (+0.03 +/- 0.04 vs. -0.001 +/- 0.01, P = 0.003) and serum HDL-cholesterol levels (+2.3 +/- 3.5 vs. -0.5 +/- 3.8 mg/dL, P = 0.004). In addition, changes in serum high sensitivity C-reactive protein (hs-CRP) (-950.0 +/- 1811.2 vs. +260.5 +/- 2298.2 ng/mL, P = 0.02), plasma nitric oxide (NO) (+1.7 +/- 4.0 vs. -1.4 +/- 6.7 MUmol/L, P = 0.03) and plasma total antioxidant capacity (TAC) (+12.6 +/- 41.6 vs. -116.9 +/- 324.2 mmol/L, P = 0.03) in the supplemented group were significantly different from the changes in these indicators in the placebo group. CONCLUSIONS: Overall, vitamin D and probiotic co-supplementation after 12 weeks among diabetic people with CHD had beneficial effects on mental health parameters, serum hs-CRP, plasma NO, TAC, glycemic control and HDL-cholesterol levels. CLINICAL TRIAL REGISTRATION NUMBER: http://www.irct.ir: IRCT2017073033941N4. PMID- 29432878 TI - Longitudinal associations between glucocorticoid receptor methylation and late life depression. AB - It has been suggested that hypothalamus-pituitary-adrenal (HPA) axis dysregulation plays a role in the etiology of depression. HPA axis function is mediated by glucocorticoid receptors (GRs), which are influenced by epigenetic mechanisms (DNA methylation). The association between the DNA methylation of the GR gene (nuclear receptor subfamily 3, group C, member 1; NR3C1) and late-life depression as well as the role of NR3C1 methylation in the prediction of the incidence of depression have not yet been investigated. Therefore, we examined the independent and longitudinal effects of the methylation of three CpG sites in exon 1F of NR3C1 on late-life depression using peripheral blood. In total, 732 Korean community residents aged >=65 years were assessed; 521 individuals in this group without depression at baseline were followed 2 years later. The Geriatric Mental State Schedule was used to identify depression, and demographic and clinical covariates were evaluated. The effects of NR3C1 methylation (the individual methylation status of three CpG sites and their average values) on current and follow-up depression were calculated using a multivariate logistic regression model. Higher NR3C1 methylation levels at CpG 2 and 3 and the average methylation value were independently associated with the prevalence of depression at baseline. Additionally, a higher NR3C1 methylation level at CpG 2 was associated with depression incidence 2 years later in this population. These findings suggest an association between the methylation of NR3C1 exon 1F, especially at CpG 2, and depression later in life. PMID- 29432879 TI - Human papilloma virus 16/18: Fabricator of trouble in oral squamous cell carcinoma. AB - AIM: To find out the association between Human Papilloma Virus (HPV) genotypes 16/18 in Pakistani patients with oral squamous cell carcinoma (OSCC). METHODS: DNA from oral rinse of 300 subjects was taken. The subjects included 100 cases with OSCC and 200 controls. Samples were analyzed by both conventional and real time PCR using "HPV consensus Gp5+/Gp6+ and HPV 16, 18 specific primers". RESULTS: Out of 300 persons, 74/300 (25%) were found to be infected with HPV: "46/100(46%) from cases and 74/200(14%) from controls". The distribution was: HPV16, 6/300 (8%): 4/100 (9%) from OSCC group and 2/200 (8%) from controls while HPV 18 was 9/300(12%): 5/100(11%) from cases and 4/200(16%) from controls. Out of 300 subjects, 26(35%) were infected by "both HPV 16/18 (23(50%) from cases and 3(12%) from controls". Persons who were infected with HPV 16&18 had higher chances to develop OSCC as compared to those who didn't have HPV 16/18 (AOR: 21.4, 95% CI: 5.73 - 80.8). CONCLUSION: The exposure to high risk strains of Human papilloma virus (16/18) in combination can be fabricotor of trouble (p<0.001, Adjusted odds ratio; 21.42) in OSCC. PMID- 29432880 TI - Prevalence of Hepatitis B virus and Hepatitis D virus Coinfection in Western Burkina Faso and molecular characterization of the detected virus strains. AB - OBJECTIVES: In this study, we monitored the seroprevalence of HBV-HDV co infection in different population groups in the Western part of Burkina Faso, and described the genetic diversity of the detected virus strains. METHODS: Between October 2013 and December 2014, venous blood samples were collected from different cohorts (blood donors, pregnant women, outpatients) in the western region of Burkina Faso. Samples were tested for HBsAg and total anti-HDV antibodies. Positive samples were further analysed for HBV-DNA and HDV-RNA. Genotyping of the detected virus strains was done by nucleotide sequencing and phylogenetic analyses. RESULTS: A total of 841 participants were included in this study. The mean age was 27.45 years (range: 7-89 years). HBsAg was found in 117 (13.9%) participants. Of the HBsAg positive samples, 4 (3.4%) were positive for total anti-HDV antibodies and negative for HDV RNA. Phylogenetic analyses based on the HBV complete genome (n=10) and S fragment sequences (n=35) showed that all strains belonged to genotype E. CONCLUSIONS: Our study showed a high HBsAg prevalence, but a low rate of HDV co-infection in HBsAg carriers from western Burkina Faso. The predominance of HBV genotype E in the country was confirmed. Our findings contribute to a better understanding of the burden of HBV and HDV infection in western Burkina Faso. PMID- 29432881 TI - The Hippocampus is a Critical Site Mediating Antidepressant-like Activity of Apelin-13 in Rats. AB - The peptide apelin and its receptor APJ are found to express in multiple brain regions, especially in the regions such as the hippocampus and hypothalamus that play important roles in stress and depression. The distribution of apelin and APJ suggests that the apelinergic signaling may be a key mediator in the development of stress-related depressive behavior. We recently demonstrated that intracerebroventricular (i.c.v) injection of apelin-13 exerts an antidepressant like activity in the rat forced swimming test (FST). However, the possible brain region mediating apelin-13's antidepressant-like activity remains unclear. In the present study, we determined whether the hippocampus and hypothalamus are the possible regions mediating antidepressant-like activity of apelin-13. We found that forced swimming exposure upregulated apelin and APJ protein expression levels in the hippocampus but not hypothalamus in rats. Further, intrahippocampal injection of apelin-13 exerted an antidepressant-like activity (as indicated by a decreased immobility behavior), and intrahippocampal infusion of APJ receptor antagonist F13A blocked the antidepressant-like activity produced by i.c.v injection of apelin-13 in the FST. Moreover, intrahypothalamic injection of apelin-13 did not affect the immobility behavior in the FST. These findings suggest that the hippocampus, but not hypothalamus, is a critical site mediating antidepressant-like activity of apelin-13 in rats. PMID- 29432882 TI - Congenital Deafness Reduces, But Does Not Eliminate Auditory Responsiveness in Cat Extrastriate Visual Cortex. AB - Congenital deafness not only affects the development of the auditory cortex, but also the interrelation between the visual and auditory system. For example, congenital deafness leads to visual modulation of the deaf auditory cortex in the form of cross-modal plasticity. Here we asked, whether congenital deafness additionally affects auditory modulation in the visual cortex. We demonstrate that auditory activity, which is normally present in the lateral suprasylvian visual areas in normal hearing cats, can also be elicited by electrical activation of the auditory system with cochlear implants. We then show that in adult congenitally deaf cats auditory activity in this region was reduced when tested with cochlear implant stimulation. However, the change in this area was small and auditory activity was not completely abolished despite years of congenital deafness. The results document that congenital deafness leads not only to changes in the auditory cortex but also affects auditory modulation of visual areas. However, the results further show a persistence of fundamental cortical sensory functional organization despite congenital deafness. PMID- 29432883 TI - Regulation of Phosphorylation of AMPA Glutamate Receptors by Muscarinic M4 Receptors in the Striatum In vivo. AB - The acetylcholine muscarinic 4 (M4) receptor is a principal muscarinic receptor subtype present in the striatum. Notably, Galphai/o-coupled M4 receptors and Galphas/Golf-coupled dopamine D1 receptors are coexpressed in striatonigral projection neurons and are thought to interact with each other to regulate neuronal excitability, although underlying molecular mechanisms are poorly understood. In this study, we investigated the role of M4 receptors in the regulation of phosphorylation of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptors in the rat normal and dopamine stimulated striatum in vivo. We found that a systemic injection of a M4 antagonist tropicamide increased AMPA receptor GluA1 subunit phosphorylation at a protein kinase A-dependent site (S845) in the striatum. The tropicamide-induced S845 phosphorylation was rapid, reversible, and dose-dependent and occurred in the two subdivisions of the striatum, i.e., the caudate putamen and nucleus accumbens. Coadministration of subthreshold doses of tropicamide and a D1 agonist SKF81297 induced a significant increase in S845 phosphorylation. Coadministered tropicamide and a dopamine psychostimulant amphetamine at their subthreshold doses also elevated S845 phosphorylation. Tropicamide alone or coinjected with SKF81297 or amphetamine had no effect on GluA1 phosphorylation at S831. Tropicamide did not affect GluA2 phosphorylation at S880. These results reveal a selective inhibitory linkage from M4 receptors to GluA1 in S845 phosphorylation in striatal neurons. Blockade of the M4-mediated inhibition significantly augments constitutive and dopamine-stimulated GluA1 S845 phosphorylation. PMID- 29432885 TI - Repetitive Brain Injury of Juvenile Mice Impairs Environmental Enrichment-Induced Modulation of REM Sleep in Adulthood. AB - Traumatic brain injuries (TBIs) are a common and costly ongoing public health concern. Injuries that occur during childhood development can have particularly profound and long-lasting effects. One common consequence and potential mediator of negative outcomes of TBI is sleep disruption which occurs in a substantial proportion of TBI patients. These individuals report greater incidences of insomnia and sleep fragmentation combined with a greater overall sleep requirement meaning that many patients are chronically sleep-deprived. We sought to develop an animal model of developmental TBI-induced sleep dysfunction. Specifically, we tested the hypothesis that early (postnatal day 21), repeated closed head injuries in Swiss-Webster mice, would impair basal and homeostatic sleep responses in adulthood. Further, we asked whether environmental enrichment (EE), a manipulation that improves functional recovery following TBI and has been shown to alter sleep physiology, would prevent TBI-induced sleep dysfunction and alter sleep-modulatory peptide expression. In contrast to our hypothesis, the mild, repeated head injury that we used did not significantly alter basal or homeostatic sleep responses in mice housed in standard laboratory conditions. Sham-injured mice housed in enriched environments exhibited enhanced rapid eye movement (REM) sleep and expression of the REM-promoting peptide pro-melanin concentrating hormone, an effect that was not apparent in TBI mice housed in enriched environments. Thus, TBI blocked the REM-enhancing effects of EE. This work has important implications for the management and rehabilitation of the TBI patient population. PMID- 29432884 TI - The Changing Sensory and Sympathetic Innervation of the Young, Adult and Aging Mouse Femur. AB - Although bone is continually being remodeled and ultimately declines with aging, little is known whether similar changes occur in the sensory and sympathetic nerve fibers that innervate bone. Here, immunohistochemistry and confocal microscopy were used to examine changes in the sensory and sympathetic nerve fibers that innervate the young (10 days post-partum), adult (3 months) and aging (24 months) C57Bl/6 mouse femur. In all three ages examined, the periosteum was the most densely innervated bone compartment. With aging, the total number of sensory and sympathetic nerve fibers clearly declines as the cambium layer of the periosteum dramatically thins. Yet even in the aging femur, there remains a dense sensory and sympathetic innervation of the periosteum. In cortical bone, sensory and sympathetic nerve fibers are largely confined to vascularized Haversian canals and while there is no significant decline in the density of sensory fibers, there was a 75% reduction in sympathetic nerve fibers in the aging vs. adult cortical bone. In contrast, in the bone marrow the overall density/unit area of both sensory and sympathetic nerve fibers appeared to remain largely unchanged across the lifespan. The preferential preservation of sensory nerve fibers suggests that even as bone itself undergoes a marked decline with age, the nociceptors that detect injury and signal skeletal pain remain relatively intact. PMID- 29432886 TI - On Information Metrics for Spatial Coding. AB - The hippocampal formation is involved in navigation, and its neuronal activity exhibits a variety of spatial correlates (e.g., place cells, grid cells). The quantification of the information encoded by spikes has been standard procedure to identify which cells have spatial correlates. For place cells, most of the established metrics derive from Shannon's mutual information (Shannon, 1948), and convey information rate in bits/s or bits/spike (Skaggs et al., 1993, 1996). Despite their widespread use, the performance of these metrics in relation to the original mutual information metric has never been investigated. In this work, using simulated and real data, we find that the current information metrics correlate less with the accuracy of spatial decoding than the original mutual information metric. We also find that the top informative cells may differ among metrics, and show a surrogate-based normalization that yields comparable spatial information estimates. Since different information metrics may identify different neuronal populations, we discuss current and alternative definitions of spatially informative cells, which affect the metric choice. PMID- 29432887 TI - Role of Brain Neuroinflammatory Factors on Hypertension in the Spontaneously Hypertensive Rat. AB - It is already widely known that the different brain areas involved in blood pressure control, are highly vulnerable to the deleterious effects of this condition. Of particular concern are hypertensive and neuroinflammatory-dependent injuries that by modifying blood flow account for artery structural and functional alterations. It was thus our intention to establish if expression changes of some key brain neuroinflammatory factors like caspase-1,3, NF-kB, IL 1beta and NLRP3, which are known to control blood pressure, are actively involved with inflammation regulatory events in a highly valuable spontaneously hypertensive rat (SHR) model. Indeed, notably increased (p < 0.001) caspase-1, NLRP3 and IL-1beta mRNA levels were detected in amygdalar plus hypothalamic areas of SHR. Contextually, similar up-regulated levels of these factors were also reported in brainstem nuclei with respect to the few hippocampal areas. This trend was supported by moderate increases (p < 0.05) of NLRP3 in amygdalar and brainstem sites, while notably greater expression differences of NF-kB protein were observed in hippocampal and hypothalamic areas of SHR. At the same time, moderately increased levels of iNOS were typical of all of the above brain areas with the exception of the consistently (p < 0.01) increased levels featured in the brainstem. Moreover, even immunohistochemical evaluations supplied notably and moderately increased cleaved caspase-3 cell levels in hippocampus and hypothalamus areas, respectively. Overall, evident hypertensive bouts correlated to neuroinflammatory events, especially in brain areas controlling blood pressure, tend to underlie the value of novel therapeutic approaches designed to improve brain blood flow and subsequently reduce hypertensive-dependent cerebral complications. PMID- 29432888 TI - Audit of Cardiac Surgery Outcomes for Low Birth Weight and Premature Infants. AB - The burden of disease associated with cardiac surgery in preterm and low birth weight infants is increasing. This retrospective study aimed to compare the mortality and morbidity of cardiac surgery in low birth weight and preterm infants with that of a case-matched normal population. This was a single-center audit of cardiac surgery interventions at a tertiary pediatric center in Melbourne, Australia. Subjects underwent intervention in the first 3 months of life and were preterm (<37 weeks' gestation) or <2500 g at birth. Subjects were case-matched with 2 controls of term gestation and appropriate birth weight with the same primary diagnosis and intervention. Principal outcomes were mortality and complications in the 6 months following intervention. A total of 513 participants were included for analysis in the 13-year study period. There was an increased risk of mortality (odds ratio 6.26; 95% confidence interval (3.19, 12.3)) and rate of complications (odds ratio 2.29; 95% confidence interval (1.38, 3.78)) in low birth weight and premature infants compared with the control population. Patients who did not survive were more likely to have required extracorporeal membrane oxygenation (relative risk [RR] 6.6, P < 0.001), developed postoperative sepsis (RR 2.6, P = 0.012), and undergone unplanned reintervention (RR 2.3, P < 0.001) compared with survivors. Preterm and low birth weight patients had twice the RR of developing complications and 6 times the risk of mortality in the 6 months following cardiac intervention compared with a matched population. Observed trends suggest delaying surgery in clinically stable infants beyond 35 weeks corrected gestational age and 2500-g weight may result in improved survival. PMID- 29432889 TI - Best Medical Treatment and Selective Stent-GraftRepair for Acute Type B Aortic Intramural Hematoma. AB - This study aimed to describe our experience with the management and the results of stent-graft (SG) repair of acute type B aortic intramural hematoma (B-IMH). Between January 2005 and July 2016, we identified 41 B-IMHs. Major end points were early and long-term survival, aortic remodeling, freedom from aortic-related mortality (ARM), and freedom from reintervention. Thirty-one (76%) patients eventually underwent SG repair: 16 (52%) cases in the acute phase, and 6 (19%) in the subacute (14-30 days) phase. Nine (29%) patients showed aortic lesion progression in the follow-up despite best medical treatment, and required SG repair in the chronic phase. The presence of ulcer-like projections at the admission computed tomography angiography was significantly higher in patients who eventually required SG repair (5% vs 36%, odds ratio: 4.08, P = .043). At 12 months, whereas ARM showed a trend in favor of SG (84% +/- 10 vs 100%; log-rank: P = .075), the freedom from aortic progression was significantly lower in the SG group (64% +/- 13 vs 94% +/- 5; log-rank: P = .002). Median follow-up was 31 months (range, 2-96; interquartile range, 11-62.5). Freedom from ARM and freedom from aortic reintervention was 92% +/- 5 (95% confidence interval: 75-98) at 12 months. Aortic remodeling was observed in 26 (84%) patients. No differences were noted between patients treated with SG in the acute and in the chronic phase. In our experience, B-IMH was associated with 47% aortic adverse event rate in the follow-up with best medical treatment alone. At mid-term, results of SG repair are encouraging. PMID- 29432890 TI - Risk Factors for Gastrostomy Tube Placement in Single Ventricle Patients Following The Norwood Procedure. AB - Neonates with single ventricle heart disease frequently experience poor oral feeding and inconsistent weight gain, often requiring gastrostomy tube (gtube) placement. We sought to identify risk factors for gtube placement in neonates following the Norwood procedure at our institution. We retrospectively reviewed multiple preoperative, operative, and postoperative variables in neonates <30 days with single ventricle heart disease following the Norwood procedure. Study outcomes included duration of mechanical ventilation, hospital length of stay (HLOS), and gtube requirement. Multivariable logistic regression was used to analyze for associated risk factors. Seventy-nine neonates were included in the study, of which 47 underwent gtube placement (59.5%). Multivariable regression analysis found vocal cord dysfunction (P = 0.001, odds ratio 1.1, 95% confidence interval 1.0-1.4) and longer duration of sedative or narcotic infusion (P = 0.01, odds ratio 1.1, 1.03-1.2) to be independently associated with the requirement for gtube among patients who underwent the Norwood procedure. There was a significant difference in HLOS (median 69 vs 33, P = 0.003) between the gtube and the no gtube groups. Univariate analysis comparing the era of surgery was performed and found a significant difference between the groups in terms of the number of gtubes placed (P = 0.02) and duration of sedative or narcotic infusion days (P = 0.038). Both were greater in the era from 2011 to 2015. In a single-institution analysis of neonates following the Norwood procedure, gtube requirement was independently associated with vocal cord dysfunction and longer duration of sedative or narcotic infusions. gtube placement was also associated with longer HLOS. PMID- 29432891 TI - Estimation of Achievable Oxygen Consumption Following Transfusion With Rejuvenated Red Blood Cells. AB - Erythrocyte storage induces a nonphysiological increase in hemoglobin-oxygen affinity (quantified by low p50, the oxygen tension at 50% hemoglobin saturation), which can be restored through biochemical rejuvenation. The objective was to mathematically model the impact of transfusing up to 3 standard allogeneic units or rejuvenated units on oxygen delivery (DO2) and oxygen consumption (VO2). Oxygen dissociation curves were generated from additive solution-1 red blood cell (RBC) leukoreduced units (n = 7) before and after rejuvenation following manufacturer's instructions. Two of these units were used to prepare standard or rejuvenated donor RBC and added to samples of fresh whole blood. These admixtures were used to construct an in vitro transfusion model of postoperative anemia and determine a linear equation for calculating the sample p50, which was subsequently used to calculate DO2 and VO2 after simulated transfusions. Whole blood-packed red blood cell unit admixture p50s could be predicted from a linear model including the p50 of its components, the mass fraction of the transfused component, and interaction terms (R2 = .99, P < 0.001). Transfusion with standard units slightly, but significantly, increased projected DO2 compared with rejuvenated units (P = 0.03), but rejuvenated units markedly increased projected VO2 (P = 0.03). Standard units did not significantly change VO2 relative to pre-transfusion levels (P > 0.1). Using high-p50, rejuvenated RBC in simulated transfusions greatly improved projected VO2, indicating the potential for increased end-organ oxygen availability compared with standard transfusion. Patient capacity to increase cardiac output after cardiac surgery may be limited. Transfusing high-p50 RBC in this setting may improve the perioperative care of these patients. PMID- 29432892 TI - Local dermal delivery of cyclosporin A, a hydrophobic and high molecular weight drug, using dissolving microneedles. AB - Dissolving microneedles (MN) containing cyclosporin A (CyA) were prepared for local delivery of CyA into the dermal layer. The efficacy of using MN to deliver CyA, an insoluble and high molecular weight drug, was observed and compared with oral administration of solubilized CyA. Microneedles containing CyA (CyA MN) were prepared using a closed, low-temperature molding process. The mechanical properties of CyA MN and phase separation were studied regarding the content of CyA. CyA MN were inserted into porcine skin for a predetermined time, and the dissolution and delivered amount of CyA were measured in vitro with an optical microscope and high-performance liquid chromatography (HPLC) analysis of the extracted CyA. A pharmacokinetic study of CyA MN was performed in vivo by administering 10% CyA MN, and the pharmacokinetic profile was compared with that of orally administered CyA. Pyramidal CyA MN (600 MUm long, 250 MUm wide) were prepared. CyA MN penetrated skin successfully with up to 50% CyA content. When 10% CyA MN were pressed into porcine skin for 60 min, 65% of MN length was dissolved and 34 +/- 6.5 MUg of CyA in MN was delivered into the skin. Under the same conditions with 10% CyA MN administered to rats, CyA MN showed Tmax of 8 h, Cmax of 15.9 ng/ml, and area under curve (AUC) of 686, compared to Tmax of 2 h, Cmax of 18.205 ng/ml, and AUC of 254 for oral administration of solubilized CyA. A therapeutic dose of CyA for treatment of psoriasis was delivered via MN into the skin layer without solubilization of CyA. Due to the hydrophobic properties and high molecular weight of CyA, the safety of CyA delivery was improved using dissolving microneedles because the slow systemic absorption and local treatment enabled CyA to remain in the skin for a longer time. Microneedles are an effective method with high bioavailability for local dermal delivery of insoluble drugs. PMID- 29432893 TI - Improvement of cognitive functions in response to a regular Nordic walking training in elderly women - A change dependent on the training experience. AB - Although regular physical activity is known to benefit health of aging populations, there are still many factors, which regulate exercise-induced adaptive changes. Among many vitamin D and myokines are under consideration. We, therefore, evaluated the influence of a single session of and regular Nordic Walking (NW) training combined with vitamin D supplementation on cognitive functions and muscle strength and some elements of the amino-acid profile. Thirty five healthy elderly women (68 +/- 5 years old) from health promotion programmes took part in the study. At baseline they were divided into two groups: women, who participated in NW training for the first time (Beginners Group: BG) and women, who continued regular NW training longer than four years (Advance Group: AG). All women had a similar concentration of vitamin D (above 20 ng.ml-1) at baseline. The 12 weeks of NW training was supported by supplementation of vitamin D3 (4000 IU/day). Muscle strength, serum concentrations of myokines (irisin and IL-6), brain derived neurotrophic factor (BDNF), inflammation marker, glucose, branched amino acids and tryptophan were all assessed at baseline, 1 h after the first single training session and adequately at the end of the training programme. In addition, iron and ferritin were measured. The concentration of vitamin D3 as well as psychological (Quality-of-Life Assessment, The Beck Depression Inventory 2) and cognitive evaluations (D2 test of attention, Trial Making Test A&B) were also performed before and after the 12-week training programme. Data were interpreted using magnitude-based inferences. According to data obtained in this study, regular NW training resulted in improvement of cognitive functions in aged women. These positive changes were accompanied by an increase of irisin and BDNF concentration (adjusted effect moderate and likely). Our data also revealed that observed reductions of glucose and tryptophan concentrations might have positively contributed to the amelioration of cognitive functions. Still, obtained results indicated that it was not the level vitamin D that modulated exercise-induced changes, but rather the long-lasting experience and being more advanced in training. PMID- 29432894 TI - Buckberg's blood cardioplegia for protection of adult and senile myocardium in a rat in vitro model of acute myocardial infarction. AB - BACKGROUND: In patients undergoing surgical myocardial revascularization for acute myocardial infarction, excellent myocardial protection can be achieved by blood cardioplegia. We investigated the influence of age on cardiac function, metabolism, and infarct size using Buckberg's blood cardioplegia (BCP). METHODS: The hearts of male Wistar rats ("adult", age 3 months, n = 8; "senile", age 24 months, n = 8) were excised and mounted on a blood-perfused isolated heart apparatus. An acute myocardial infarction was induced by coronary artery ligation for 30 min before aortic clamping and infusion of Buckberg's BCP. Throughout the experiment, functional parameters were recorded: coronary blood flow (normalized by heart weight), left ventricular peak developed pressure (LVpdP), and positive and negative derived left ventricular pressure over time (dLVPdtmax and dLVPdtmin). Oxygen consumption (MVO2) and lactate production of the hearts were calculated. The infarct size after 90 min of reperfusion (in % of the area at risk) was measured with triphenyl tetrazolium chloride staining of the myocardium. RESULTS: The baseline coronary flow normalized by heart weight was significantly lower in the senile hearts (1.6 +/- 0.4 ml/(min * g)) compared with the adult hearts (2.0 +/- 0.3 ml/(min * g); p = 0.04). After 90 min of aortic clamping, hemodynamic function of senile hearts recovered better than that of adult hearts: LVpdP (adult 57% of baseline [BL]; senile 88% BL; p = 0.044) and dLVPdtmax (adult 74% BL, senile 102% BL; p = 0.12). In contrast, myocardial infarct size was similar between the adult (26%) and senile (21%; p = 0.45) hearts, and coronary flow recovered to a similar extent (55% BL and 58% BL, respectively). During reperfusion, MVO2 (80% BL and 81% BL) and lactate production (1.2 and 1.3 MUmol/min) were similar in the two groups. CONCLUSION: After acute myocardial infarction in a rat model, hearts recovered function after reperfusion with Buckberg's BCP solution. Hearts from aged animals recovered better than those from younger animals. PMID- 29432895 TI - A cross-omics approach to investigate temporal gene expression regulation by 5 hydroxymethylcytosine via TBH-derived oxidative stress showed involvement of different regulatory kinases. AB - Regulation of DNA methylation plays a crucial role in biological processes and carcinogenesis. The formation of 5-hydroxymethylcytosine (5hmC) by oxidation of 5 methylcytosine (5mC) has been proposed as an intermediate of active demethylation. However, whether and how active demethylation is regulated by oxidative stress-related processes is not well understood. Here we investigated whether free oxygen radicals are capable of directly forming 5hmC and how this enhanced whole genome gene expression. We applied LC-MS/MS technology for the analysis of 5mC, 5hmC, 5-formylcytosine (5fC) and 5-hydroxymethyluracyl (5hmU) in HepG2 cells exposed to hydroxyl- and methyl radicals, formed by tert-butyl hydroperoxide (TBH) at multiple time points. We observed that TBH is able to induce a significant increase in 5hmC. A detailed evaluation of the hydroxymethylome using a combination of 5hmC-immunoprecipitation and microarrays resulted in the identification of highly dynamic modifications that appear to increase during prolonged oxidant exposure. Analyses of temporal gene expression changes in combination with network analysis revealed different subnetworks containing differentially expressed genes (DEGs) with differentially hydroxyl methylated regions (DhMRs) in different regulatory kinases enriched with serine threonine kinases. These serine-threonine kinases compromises MAPK14, RPSK6KA1, RIPK1, and PLK3 and were all previously identified as key-regulators in hepatocarcinogenesis and subject of study for chemotherapeutic interventions. PMID- 29432896 TI - Transcriptional response to organic compounds from diverse gasoline and biogasoline fuel emissions in human lung cells. AB - Modern vehicles equipped with Gasoline Direct Injection (GDI) engine have emerged as an important source of particulate emissions potentially harmful to human health. We collected and characterized gasoline exhaust particles (GEPs) produced by neat gasoline fuel (E0) and its blends with 15% ethanol (E15), 25% n-butanol (n-But25) and 25% isobutanol (i-But25). To study the toxic effects of organic compounds extracted from GEPs, we analyzed gene expression profiles in human lung BEAS-2B cells. Despite the lowest GEP mass, n-But25 extract contained the highest concentration of polycyclic aromatic hydrocarbons (PAHs), while i-But25 extract the lowest. Gene expression analysis identified activation of the DNA damage response and other subsequent events (cell cycle arrest, modulation of extracellular matrix, cell adhesion, inhibition of cholesterol biosynthesis) following 4 h exposure to all GEP extracts. The i-But25 extract induced the most distinctive gene expression pattern particularly after 24 h exposure. Whereas E0, E15 and n-But25 extract treatments resulted in persistent stress signaling including DNA damage response, MAPK signaling, oxidative stress, metabolism of PAHs or pro-inflammatory response, i-But25 induced changes related to the metabolism of the cellular nutrients required for cell recovery. Our results indicate that i-But25 extract possessed the weakest genotoxic potency possibly due to the low PAH content. PMID- 29432897 TI - Bleeding predictors in patients following venous thromboembolism treated with vitamin K antagonists: Association with increased number of single nucleotide polymorphisms. AB - INTRODUCTION: Single nucleotide polymorphisms (SNP) in genes encoding proteins involved in metabolism and action of vitamin K antagonists (VKA) affect anticoagulation stability. We investigated how those polymorphisms influence bleeding rates in patients following venous thromboembolism (VTE). MATERIALS AND METHODS: In 324 patients following unprovoked VTE, 143 (44%) on warfarin and 181 (56%) on acenocoumarol, we recorded bleeds within the preceding 24 months. We assessed eight SNP, including those in cytochrome P450 isoform 2C9 (CYP2C9) and isoform 4F2 (CYP4F2), vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX), apolipoprotein E (APOE) and multidrug resistance gene 1 (MDR1). RESULTS: Within 48 months before enrolment, bleeding events occurred in 80 (25%) patients, including 14 (4%) major bleeds. Patients with bleeds had 16.2% lower median time in therapeutic range (TTR) and were more often carriers of CYP2C9*3 variant (26 [33%] vs. 19 [8%], p < 0.001) compared with the remainder. Bleeding occurred more frequently in patients with >=4 SNP compared with the remainder (27 [34%] vs. 47 [19%], p = 0.009) with no intergroup differences of TTR. Number of SNP was one of the predictors of any bleeding. The regression model for major bleeding including factors such as CYP2C9*3 c. 1075 C, VKORC1 c. -1639 A and APOE c. 388 C showed good predictive ability (area under the curve - 0.79). CONCLUSIONS: In VTE patients on the maintenance treatment with VKA, bleeding episodes are associated with CYP2C9 gene variations and increased number of SNP of genes involved in the action and metabolism of VKA. PMID- 29432898 TI - Acarbose inhibits the proliferation and migration of vascular smooth muscle cells via targeting Ras signaling. AB - Atherosclerosis involves the proliferation and migration of vascular smooth muscle cells (VSMCs). The migration of VSMCs from the media into the intima and their subsequent proliferation are important processes in neointima formation in atherosclerosis and restenosis after percutaneous coronary interventions. Acarbose, an alpha-glucosidase inhibitor, has been demonstrated to not affect serum levels of glucose and decrease the progression of intima-media thickening in rabbits fed with a high cholesterol diet (HCD). We previously showed that increased Ras protein levels enhanced the migration of TNF-alpha treated A7r5 cells. The aim of this study was to determine the inhibitory effects of acarbose on Ras expression in A7r5 cells. Acarbose also inhibited the phosphorylation of focal adhesion kinase (FAK) and Akt, activities of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9, and protein expressions of small G proteins (Ras, Cdc42, RhoA, and Rac1) in a dose-dependent manner. We also found that acarbose could effectively inhibit the proliferation and migration of RasG12V A7r5 cells by blocking small G proteins and phosphoinositide-3-kinase (PI3K)/Akt signaling. These studies demonstrated that acarbose could theoretically decrease atherosclerosis by targeting Ras signaling. PMID- 29432899 TI - Non-canonical DNA structures: Comparative quantum mechanical study. AB - A study of relative thermodynamic stability of non-canonical DNA structures (triplexes, G-quadruplexes, i-motifs) for the first time was conducted on the basis of quantum chemical DFT/B3LYP/6-31++G (d) calculations. Results of the calculations completely reproduce the experimental data on stability of G quadruplexes comparatively Watson-Crick B-DNA. It was discovered that combinations of non-canonical DNA structures were energetically more favorable than separated nitrogenous bases. Supramolecular complexes of the non-canonical DNA structures (NSs) can be considered as a biological drug targets in gene regulation (for example in tumor therapy), in contrast to previous works, where NSs were studied independently. PMID- 29432901 TI - Nerve-Sparing Technique during Laparoscopic Radical Hysterectomy: Critical Steps. AB - STUDY OBJECTIVE: To show the feasibility and safety of nerve-preserving laparoscopic radical hysterectomy (type C1 Querleu-Morrow Classification [1]) for the treatment of early cervical cancer. DESIGN: A surgical video article (Canadian Task Force classification III). SETTING: A university hospital (University Hospital of Barcelona, Barcelona, Spain). PATIENTS: Nerve-preserving radical hysterectomy is performed in a patient with Federation Internationale de Gynecologie et d'Obstetrique stage 1B1 cervical cancer with deep stromal invasion. INTERVENTIONS: Three steps are fundamental for the removal of the cervix with a safe oncologic margin and preservation of the pelvic autonomic nerves [2]. 1. Step 1: for the correct preservation of the pelvic splanchnic nerves (ventral roots from spinal nerves S2-S4) and the inferior hypogastric plexus during the section of the paracervix, it is essential to identify the deep uterine vein. This vein will correspond with the inferior limit of the dissection. 2. Step 2: during the dissection of the uterosacral ligament and after dissecting the Okabayashi space, the inferior hypogastric nerve is isolated. This nerve runs 2 cm parallel below the uterosacral ligament in the peritoneal leaf of the broad ligament. 3. Step 3: during the section of the vesicouterine ligament, the lateral side must be preserved because it includes the medial and inferior vesical veins that drain to the deep uterine vein. CONCLUSION: Nerve-sparing laparoscopic radical hysterectomy is an attractive surgical approach for early-stage cervical cancer. Direct visualization of the pelvic autonomic nervous system (sympathetic and parasympathetic branches) innervating the bladder and rectum makes the nerve-sparing approach a safe and feasible procedure. PMID- 29432900 TI - Thermodynamic analysis of Kex2 activity: The acylation and deacylation steps are potassium- and substrate-dependent. AB - Kex2 is the prototype of a large family of eukaryotic subtilisin-related proprotein-processing proteases that cleave at sites containing pairs of basic residues. Here, we studied the effects of KCl on the individual rate constants of association, dissociation, acylation and deacylation and determined the thermodynamic parameters at each step of the Kex2 reaction. Potassium bound Kex2 with KD=20.3mM. The order in which potassium entered the reaction system modified the effect of activation or inhibition, which depended on the size of the substrate. A possible allosteric potassium binding site at the S6 subsite was involved in activation, and a distant site located between the catalytic domain and the P-domain was involved in inhibition. Potassium decreased the energetic barriers of almost all steps of catalysis. The acylation of Ac-PMYKR-AMC in the absence of potassium was the rate-limiting step. Therefore, for substrates containing a P1-Arg, the deacylation step is not necessarily the rate-limiting event, and other residues at the P' positions may participate in controlling the acylation and deacylation steps. Thus, it is reasonable to conclude that potassium is involved in the processing of the alpha-mating factor that promotes Ca2+ mobilization by activating a high-affinity Ca2+-influx system to increase the cytosolic [Ca2+], resulting in the activation of channels that are essential for the survival of Saccharomyces cerevisiae cells. PMID- 29432902 TI - Anterior Focal Adenomyosis and Bladder Deep Infiltrating Endometriosis: Is There a Link? AB - STUDY OBJECTIVE: To evaluate the association between bladder deep infiltrating endometriosis (DIE) and anterior focal adenomyosis of the outer myometrium (aFAOM) diagnosed by preoperative magnetic resonance imaging (MRI). DESIGN: An observational, cross-sectional study using prospectively collected data (Canadian Task Force classification II-2). SETTING: Single university tertiary referral center. PATIENTS: All nonpregnant women younger than 42 years who had undergone complete surgical exeresis of endometriotic lesions. For each patient a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding the surgery. Only women with preoperative standardized uterine MRI were retained for this study. INTERVENTIONS: Thirty-nine women with histologically proven bladder DIE and an available preoperative MRI were enrolled in the study. Patients were divided into 2 groups: women with aFAOM (aFAOM (+), n = 19) and women without aFAOM (aFAOM ( ), n = 20). Both groups were compared for general characteristics, medical history, MRI findings, and disease severity. MEASUREMENTS AND MAIN RESULTS: Nineteen patients (48.7%) with bladder DIE had aFAOM at preoperative MRI. The rate of associated diffuse adenomyosis was similar in the 2 groups (63.2% [n = 12] vs 73.7% [n = 14]; p = .48). The rate of an associated ovarian endometrioma (OMA) was significantly lower in the aFAOM (+) group (10.5% [n = 2] vs 40.0% [n = 8]; p = .03). There were fewer associated intestinal DIE lesions in the aFAOM (+) group compared with the aFAOM (-) group (26.3% vs 75.0%; p = .02), with lower involvement of the pouch of Douglas (26.3% vs 70%; p < .01). Total American Society for Reproductive Medicine score was significantly lower in the aFAOM (+) group (13.8 +/- 12.2 vs 62.2 +/- 46.2; p < .01). CONCLUSION: aFAOM is present in only half of women with bladder DIE and appears to be associated with lower associated posterior DIE. PMID- 29432903 TI - Use of the Limbs and Things Hysterectomy Model to Describe the Process for Establishing Validity. AB - STUDY OBJECTIVE: To demonstrate the process for establishing or refuting validity for the Limbs and Things hysterectomy model. DESIGN: Prospective study using Kane's framework for establishing validity (Canadian Task Force classification: II-2). SETTING: Total laparoscopic hysterectomy (TLH) assessments completed in the operating room (OR) and simulation at 3 academic medical centers. PARTICIPANTS: Obstetrics and gynecology residents (n = 26 postgraduate years 3 4), a gynecologic oncology fellow (postgraduate year 5), and a gynecology oncology attending. INTERVENTIONS: Participants were rated with the myTIPreport feedback application by nonblinded faculty in the OR after TLH. In-person, simulation-based assessments were provided by 2 faculty members blinded to experience level using myTIPreport and Global Operative Assessment of Laparoscopic Skills (GOALS). Videos of simulated TLHs were rated by 2 minimally invasive gynecology fellows. MEASUREMENTS AND MAIN RESULTS: OR scores for TLH steps were significantly higher than simulation assessments (p < .001) with "competent" marked more frequently in the OR. Number of robotic + conventional TLHs performed as primary surgeon was not significantly correlated with OR myTIPreport rating (Spearman r = .30, p = .14) but was significantly correlated with myTIPreport and GOALS in-person simulation ratings (Spearman r = .39-.58, p = .001-.04). Agreement between in-person simulation rater 1 and 2 myTIPreport assessments was 71.4% (weighted kappa, .68; 95% confidence interval, .45-.90), and intraclass correlation for the GOALS overall assessment was .71 (95% confidence interval, .46-.85), indicating substantial agreement. Blinded video reviews showed similar agreement (73.1%) between raters but less correlation with experience (Spearman r = .32-.42, p = .11-.03) than in-person reviews. Using area under the receiver operating characteristic curve, mean score for the individual components of GOALS that best differentiated myTIPreport noncompetent and competent levels of performance was 4.3. Feedback acceptability and model realism were rated highly. CONCLUSION: The scoring and generalization validity inferences for Limbs and Things and myTIPreport are supported when global assessments of performance are evaluated but not for individual components of the assessment instruments. PMID- 29432904 TI - Bowel Perforation after Global Endometrial Ablation. PMID- 29432905 TI - Transvaginal Single-Port Laparoscopy Pelvic Reconstruction with Y-Shaped Mesh. AB - STUDY OBJECTIVE: To demonstrate a new technique for pelvic reconstruction in patients with multiple-compartment pelvic organ prolapse (POP) using Y-shaped mesh via transvaginal single-port laparoscopy. DESIGN: Description and step-by step demonstration of the procedure using video and still images (Canadian Task Force classification III). SETTING: It is more and more prudent for pelvic floor reconstruction with mesh because of mesh-related complications. Learning from sacrocolpopexy with a lower rate of mesh erosion (3.5%), a new method of pelvic reconstruction via natural orifice transluminal endoscopic surgery is feasible. INTERVENTIONS: The patient was a 67-year-old woman with a Pelvic Organ Prolapse Quantification System (POP-Q) stage III anterior compartment, stage III middle compartment, and stage II posterior compartment. Institutional Review Board and Ethics Committee approval was obtained. Vaginal hysterectomy and preventative bilateral salpingo-oophorectomy were performed first. Under laparoscopy, the pelvic peritoneum on the right side was incised from the promontory to the vault. Once the rectovaginal septum was separated, a 2-cm "window" of the lower posterior vaginal wall was created. Then the Y-shaped mesh (ARTISYN; Ethicon, Somerville, NJ) was fixed to the posterior vaginal and the sacral promontory (S1). After the pelvic peritoneum was closed, a "window" of lower anterior vaginal wall was made, and the anterior mesh was sutured to the descending ramus of pubis. Finally, the vaginal roof was closed. The operation took roughly 2 hours, and total blood loss was approximately 40 mL. The patient recovered well. No relapse of prolapse, mesh erosion, or any other complications were observed at the 6-month follow-up. CONCLUSION: Transvaginal single-port laparoscopic pelvic reconstruction can be considered for patients with total POP. However, additional studies with larger numbers of patients are needed. PMID- 29432906 TI - Hepatitis B virus X protein and proinflammatory cytokines synergize to enhance TRAIL-induced apoptosis of renal tubular cells by upregulation of DR4. AB - Persistent infection with hepatitis B virus (HBV) may lead to HBV-associated glomerulonephritis (HBV-GN). Presence of HBV-DNA and -RNA in renal tubular epithelial cells (RTECs) suggests direct virus-induced injury. Increase in proinflammatory cytokines is also observed under these conditions. Apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays a significant role in the pathogenesis of HBV-infections. However, the effects of HBV X protein (HBx) on TRAIL-induced apoptosis of RTECs especially under certain inflammatory conditions remain obscure. Here, we show that HBx synergizes with proinflammatory cytokines to significantly increase TRAIL-induced apoptosis of RTECs. HBx markedly up-regulates death receptor-4 (DR4) expression by enhancing the activation of nuclear factor-kappa B (NF-kappaB) in the presence of proinflammatory cytokines. Dramatic increase in DR4 expression leads to the sensitization of RTECs to TRAIL-induced apoptosis. Furthermore, in patients with HBV-GN, DR4 expression in the kidneys is significantly elevated and is positively correlated with the HBx and proinflammatory cytokines expression. These findings provide a novel insight into the underlying mechanisms of renal tubule lesions induced by HBx in HBV-GN. PMID- 29432907 TI - Educational Text Messages Decreased Emergency Department Utilization Among Infant Caregivers: A Randomized Trial. AB - OBJECTIVE: To determine the feasibility and effectiveness of text messages as an educational tool to reduce the prevalence of nonurgent emergency department (ED) visits among a population with high levels of low health literacy. METHODS: This prospective, randomized experiment conducted in a large, urban, academic pediatric primary care practice enrolled 231 caregivers of infants into 2 groups: enhanced standard of care materials at well-child visits through 6 months (n = 99 completing), and enhanced standard of care and 4 text messages a week through 6 months (n = 108 completing). Use of the ED and visit urgency were compared between groups via chart review at 1 year of age. RESULTS: Of the 230 included in the analysis, 84.2% (n = 194 of 230) were racial or ethnic minorities, 69.7% (n = 142 of 204) reported yearly incomes of less than $20,000 per year, and 70.4% (n = 142 of 204) were identified as having likely or probable limited health literacy. Participants who received text messages had fewer visits to the ED in their first year (2.14 visits in the control group to 1.47 visits in the intervention group who received text messages; P < .05). CONCLUSIONS: Sending educational text messages to caregivers is effective in reducing the number of visits to the ED. Given the accessibility and small expense of sending text messages, these findings have direct implications on the cost of health care, in addition to improving continuity and quality of care for pediatric patients. PMID- 29432908 TI - Shared Decision Making for Children With Developmental Disorders: Recent Advances. PMID- 29432909 TI - Influence of Helicobacter pylori virulence factors CagA and VacA on pathogenesis of gastrointestinal disorders. AB - Helicobacter Pylori (H. pylori) is a gram-negative bacteria infecting numerous people all over the world. It has been established that H. pylori play an important role in pathogenesis of gastritis, peptic ulcer and gastric cancer. Pathogenic features of this bacterium are mainly attributes to the existence of pathogenic islands (PAI) genes. The most known genes in these islands are cytotoxin-associated gene A (CagA) and vacuolating cytotoxin gene (VacA). Most studies demonstrated various frequency of CagA and VacA in patient with peptic ulcer or gastritis in different countries. This variation in CagA and VacA frequency may be due to the capability of this bacterium to be genetically versatile and can alter the expression of these genes with geographic diversity. Although H. pylori infection is not usually associated with any clinical symptoms, but sometimes leads to inflammation in gastrointestinal system and resulted in peptic ulcer and gastric cancer. In this regard, this review will illustrate the importance of Helicobacter pylori in pathogenesis of gastrointestinal disorders with focusing on CagA and VacA virulence factors. PMID- 29432910 TI - Lactobacillus paracasei 28.4 reduces in vitro hyphae formation of Candida albicans and prevents the filamentation in an experimental model of Caenorhabditis elegans. AB - The objective of this study was to evaluate the influence of microbe-microbe interactions to identify a strain of Lactobacillus that could reduce the filamentation of Candida albicans ATCC 18804 using in vitro and in vivo models. Thus presenting a probiotic effect against the fungal pathogen. First, we analyzed the ability of 25 clinical isolates of Lactobacillus to reduce filamentation in C. albicans in vitro. We found that L. paracasei isolate 28.4 exhibited the greatest reduction of C. albicans hyphae (p = 0.0109). This reduction was confirmed by scanning electron microscopy analysis. The influence of C. albicans filamentation was found to be contributed through reduced gene expression of filament associated genes (TEC1 and UME6). In an in vivo study, prophylactic provisions with L. paracasei increased the survival of Caenorhabditis elegans worms infected with C. albicans (p = 0.0001) by 29%. Prolonged survival was accompanied by the prevention of cuticle rupture of 27% of the worms by filamentation of C. albicans, a phenotype that is characteristic of C. albicans killing of nematodes, compared to the control group. Lactobacillus paracasei isolate 28.4 reduced the filamentation of C. albicans in vitro by negatively regulating the TEC1 and UME6 genes that are essential for the production of hyphae. Prophylactic provision of Lactobacillus paracasei 28.4 protected C. elegans against candidiasis in vivo. L. paracasei 28.4 has the potential to be employed as an alternative method to control candidiasis. PMID- 29432911 TI - Tephrosin attenuates sepsis induced acute lung injury in rats by impeding expression of ICAM-1 and MIP-2. AB - Acute lung injury (ALI), a devastating form of respiratory infections, is characterized by increased edema, release of cytokines, weakened arterial oxygenation and infiltration of neutrophils and lymphocytes. The objective of the research envisaged was to reveal protective effects of tephrosin (TP) in ALI. In the present investigation, sepsis was triggered in rats by cecal ligation and puncture (CLP) method, and TP was administered intraperitonially. Five groups - Group A (control), Group B (Sham group) Group C (infected and untreated), and Group D and E (infected and treated with 25 and 50 mg/kg TP respectively) - of ten rats each, were used for the investigation. Evaluation parameters included measurement of arterial oxygenation, lung water content, protein determination, cytokine determination, neutrophil and lymphocyte count in the bronchoalveolar lavage fluid (BALF). As indicated by histopathological examination, the lung injury score was maximum in group C, but indicated reduction in group D and E. Intracellular adhesion molecule (ICAM)-1 and macrophage inflammatory protein-2 (MIP-2) are known to be important mediators responsible for ALI. Reduction in the ICAM-1 and MIP-2 expression was found to reduce after treatment with TP. In comparison to group D, group E reflected higher magnitude of ICAM-1 and MIP-2 suppression due to administration of higher TP dose. Compared to Group A and B, Group E indicated slightly higher expression of ICAM-1 and MIP-2. The research envisaged thus supports that TP attenuates ICAM-1 and MIP-2 expression in sepsis induced ALI rat model. PMID- 29432912 TI - In vitro evaluation of new 2-phenoxy-benzo[g][1,2,4]triazolo[1,5-a]quinazoline derivatives as antimicrobial agents. AB - Previously, seventeen 2-phenoxy-benzo[g][1,2,4]triazolo[1,5-a]quinazoline derivatives were prepared and characterized by physicochemical and spectral means. This study was conducted to evaluate their activities in vitro against five Gram-negative and five Gram-positive of clinically pathogenic bacterial strains and ten fungal strains. The antimicrobial activity was assessed, and the minimum inhibitory concentration values of the tested compounds were determined in MUg ml-1, using the diffusion agar technique. The bacterial strains used were Escherichia coli (ATCC 25922), Proteus mirabilis (ATCC 7002), Klebsiella oxytoca (ATCC 700324), Pseudomonas aeruginosa (ATCC 10145), Enterobacter cloacae (ATCC 13047D-5), Bacillus subtilis (NRRL B-543), Enterococcus faecalis (RCMB 0100154 2), Staphylococcus aureus (ATCC 29213), Staphylococcus epidermidis (ATCC 12228), and Streptococcus pyogenes (RCMB 0100174-2). Aspergillus fumigatus (RCMB 02568), Syncephalastrum racemosum (IMI 21178), Geotricum candidum (IMI 329542), Candida albicans (ATCC 10231), Aspergillus niger (IMI 130783), Cryptococcus neoformans (NRRL Y-1518), Candida tropicalis (RCMB 05239), Penicillium expansum (IMI 146655), Microsporum canis (RCMB 0834), and Trichophyton mentagrophytes (RCMB 0925) were used as the fungal strains. Ampicillin and gentamicin were used as reference antibacterial drugs and amphotericin B was used as the reference antifungal drug. The antimicrobial studies revealed that the tested compounds 6 8, 11, 12, and 14-16 showed the highest activities against the bacterial and fungal strains. The current study showed that some benzo[g]traizoloquinazolines displayed remarkable antimicrobial activity and could be used as template for further design of potent antimicrobial agent. PMID- 29432913 TI - Effects of fluconazole on the clinical outcome and immune response in fungal co infected tuberculosis patients. AB - With overuse of the broad-spectrum antibiotics, the pulmonary fungal infection increasingly becomes the most common complication associated with senile pulmonary tuberculosis (TB) and attracts intensive attentions from clinicians. Here we presented the retrospective analysis of impact of fluconazole treatment on the clinical outcome and immune response in fungal co-infected tuberculosis patients. A randomized, double-blind, placebo-controlled trial of fluconazole (100 mg per day for consecutive weeks) in fungal-positive senile tuberculosis patients was conducted in our hospital. Peripheral eosinophil counts were computed by the automatic hematology analyzer. The secretory inflammatory cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and chemokines chemokine C-X-C motif ligand (CXCL)9, CXCL10, CXCL11 were determined with enzyme-linked immunosorbent assay kits. The peripheral T helper 1 cells (Th1) and regulatory T cells (Treg) population were analyzed by flow cytometry. None of significant difference in respect to baseline TB score was observed between placebo and fluconazole groups. Administration of fluconazole significantly stimulated eosinophils population and secretion of inflammatory cytokines IFN-gamma and TNF-alpha. Simultaneously, the peripheral Th1% and chemokines including CXCL9, CSCL10, CXCL11 were markedly induced in response to fluconazole treatment. Fungal infection significantly affected host immunity during tuberculosis which was effectively reversed by fluconazole treatment. PMID- 29432915 TI - Measuring adolescent drinking-refusal self-efficacy: Development and validation of the Drinking Refusal Self-Efficacy Questionnaire-Shortened Adolescent version (DRSEQ-SRA). AB - BACKGROUND: This study aimed to develop and validate a shortened version of the Drinking Refusal Self-Efficacy Questionnaire-Revised Adolescent version (DRSEQ RA) using a large sample of adolescents. METHODS: Secondary school students (N = 2609, M = 14.52 years, SD = 0.94) completed the DRSEQ-RA (consisting of subscales: Social Pressure; Opportunistic; Emotional Relief) and the Alcohol Use Disorders Identification Test (AUDIT). These data were analysed using non parametric item response theory (NIRT) including Mokken scalability coefficients, and confirmatory factor analysis. RESULTS: Social Pressure subscale items were better able to distinguish between adolescents with lower or higher levels of drinking refusal self-efficacy, while the Opportunistic and Emotional Relief subscale items were able to distinguish adolescents with low drinking-refusal self-efficacy. The DRSEQ-RA was reduced from 19-items to a 9-item scale and retained the original three-factor structure. The reduced scale was named the Drinking Refusal Self-Efficacy Questionnaire-Shortened Revised Adolescent version (DRSEQ-SRA). The DRSEQ-RA and the DRSEQ-SRA have almost identical psychometric properties. They both demonstrated good fit to the data, each explained 18% of the variance in alcohol consumption, Adj. R2 = 0.18, p < .001 respectively. The DRSEQ-RA and the DRSEQ-SRA also have excellent scale and subscale internal reliability (alphas = 0.92-0.99). CONCLUSIONS: The DRSEQ-SRA is a short, 9-item, measure of adolescent drinking-refusal self-efficacy which demonstrates both reliability and validity. A significant advantage is brevity. The DRSEQ-SRA may be a valuable tool for identifying risk of adolescent drinking and prevention/treatment planning in settings where survey administration time is critical. PMID- 29432914 TI - Identification of the heme acquisition system in Vibrio vulnificus M2799. AB - Vibrio vulnificus, the causative agent of serious, often fatal, infections in humans, requires iron for its pathogenesis. As such, it obtains iron via both vulnibactin and heme-mediated iron-uptake systems. In this study, we identified the heme acquisition system in V. vulnificus M2799. The nucleotide sequences of the genes encoding heme receptors HupA and HvtA and the ATP-binding cassette (ABC) transport system proteins HupB, HupC, and HupD were determined, and then used in the construction of deletion mutants developed from a Deltaics strain, which could not synthesize vulnibactin. Growth experiments using these mutants indicated that HupA and HvtA are major and minor heme receptors, respectively. The expressions of two proteins were analyzed by the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Furthermore, complementation analyses confirmed that the HupBCD proteins are the only ABC transport system shared by both the HupA and HvtA receptors. This is the first genetic evidence that the HupBCD proteins are essential for heme acquisition by V. vulnificus. Further investigation showed that hupA, hvtA, and hupBCD are regulated by Fur. The qRT-PCR analysis of the heme receptor genes revealed that HupR, a LysR-family positive transcriptional activator, upregulates the expression of hupA, but not hvtA. In addition, ptrB was co-transcribed with hvtA, and PtrB had no influence on growth in low-iron CM9 medium supplemented with hemin, hemoglobin, or cytochrome C. PMID- 29432917 TI - Polyphenol extracts from dried sugarcane inhibit inflammatory mediators in an in vitro colon cancer model. AB - : Sugarcane is an important crop grown in tropical regions for sugar, and for ethanol production. Sugarcane is also a source of phytochemicals but its nutraceutical potential has been under-explored. We show that ethanol extracts of whole dried sugarcane (WDS) recovers a rich content of polyphenols, flavonoids and antioxidant activity that act on inflammatory mediator proteins. To investigate the mechanisms of this activity, we stimulated SW480 colon cancer cells with lipopolysaccharide, exposed cells to WDS and quantitated changes to the proteome and phosphoproteome using label-free mass spectrometry. The grape derived anti-inflammatory polyphenol, resveratrol (RSV) was used as a control. Using SWATH-MS we quantitated ~3000 proteins showing that WDS significantly altered the expression of the oxidative stress regulator SELH. WDS induced changes in protein expression predicted the involvement of NFkappaB pathway members. Reduced NFkappaB phosphorylation and IL-8 secretion confirmed this effect. In contrast, RSV was predicted to act primarily through modulation of the PI3K/AKT pathway. Phosphoproteomics studies indicate that WDS interfered in the phosphorylation of cell stress regulators c-Jun, EGFR, PKA, PKCbeta and SIRT1. Confirmed through pharmacological inhibition, kinase enrichment analysis presented C-Raf to modulate WDS activity. These results demonstrate the anti inflammatory utility of WSD and define aspects of its mechanisms of action. SIGNIFICANCE: Despite the increasing interest of nutraceuticals in health promotion, scientific evidence proving the molecular mechanisms involved is still lacking. This study investigated some of the mechanistic aspects of in vitro use of whole dried sugarcane extracts in the context of regulating cellular inflammation by using proteomics and phosphoproteomics strategies. We determined that WDS extracts regulate key inflammatory pathways including NFkappaB, while kinase enrichment analysis from phosphoproteomics demonstrated a role for C-Raf in controlling this mechanism. We demonstrated that the mechanism of WDS extracts on controlling inflammation differs from that of the polyphenol, resveratrol. The results presented herein contribute towards unravelling the activity of nutraceuticals extracted from sugarcane. PMID- 29432916 TI - E-cigarette advertising exposure in e-cigarette naive adolescents and subsequent e-cigarette use: A longitudinal cohort study. AB - OBJECTIVE: Electronic (E-) cigarettes are one of the most popular tobacco products used by adolescents today. This study examined whether exposure to advertisements in (1) social networking sites (Facebook, Twitter, YouTube, Pinterest/Google Plus), (2) traditional media (television/radio, magazines, billboards), or (3) retail stores (convenience stores, mall kiosks, tobacco shops) was associated with subsequent e-cigarette use in a longitudinal cohort of adolescents. METHODS: Data were drawn from longitudinal surveys conducted in fall 2013 (wave 1) and spring 2014 (wave 2) of a school-based cohort attending 3 high schools and 2 middle schools in Connecticut. Adolescents were asked about tobacco use behaviors and where they had recently seen e-cigarette advertising at wave 1. We used logistic regression to determine whether advertising exposure at wave 1 increased the odds of e-cigarette use by wave 2, controlling for demographics and cigarette smoking status at wave 1. RESULTS: Among those who have never used e cigarettes in wave 1 (n = 1742), 9.6% reported e-cigarette use at wave 2. Multivariate logistic regression demonstrated that exposure to e-cigarette advertising on Facebook (OR 2.12 = p < 0.02) at wave 1, but not other venues, significantly increased the odds of subsequent e-cigarette use wave 2. Age, white race, and cigarette smoking at wave 1 also was associated with e-cigarette use at wave 2. CONCLUSION: This study provides one of the first longitudinal examinations demonstrating that exposure to e-cigarette advertising on social networking sites among youth who had never used e-cigarettes increases the likelihood of subsequent e-cigarette use. PMID- 29432918 TI - Exploration of the platelet proteome in patients with early-stage cancer. AB - : Platelets play an important role in tumor growth and, at the same time, platelet characteristics are affected by cancer presence. Therefore, we investigated whether the platelet proteome harbors differentially expressed proteins associated with early-stage cancer. For this proof-of-concept study, patients with early-stage lung (n = 8) or head of pancreas cancer (n = 4) were included, as were healthy sex- and age-matched controls for both subgroups. Blood samples were collected from controls and from patients before surgery. Furthermore, from six of the patients, a second sample was collected two months after surgery. NanoLC-MS/MS-based proteomics of gel-fractionated platelet proteins was used for comparative spectral count analyses of patients to controls and before to after surgery samples. The total platelet proteome dataset included 4384 unique proteins of which 85 were significantly (criteria Fc > 1.5 and p < 0.05) changed in early-stage cancer compared to controls. In addition, the levels of 81 platelet proteins normalized after tumor resection. When filtering for the most discriminatory proteins, we identified seven promising platelet proteins associated with early-stage cancer. In conclusion, this pioneering study on the platelet proteome in cancer patients clearly identifies platelets as a new source of candidate protein biomarkers of early-stage cancer. BIOLOGICAL SIGNIFICANCE: Currently, most blood-based diagnostics/biomarker research is performed in serum or plasma, while the content of blood cells is usually neglected. It is known that especially blood platelets, which are the main circulating pool of many bioactive proteins, such as growth factors, chemokines, and cytokines, are a potentially rich source of biomarkers. The current study is the first to measure the effect of early-stage cancer on the platelet proteome of patients. Our study demonstrates that the platelet proteome of patients with early-stage lung or head of pancreas cancer differs considerably compared to that of healthy individuals of matched sex and age. In addition, the platelet proteome of cancer patients normalized after surgical resection of the tumor. Exploiting platelet proteome differences linked to both tumor presence and disease status, we were able to demonstrate that the platelet proteome can be mined for potential biomarkers of cancer. PMID- 29432919 TI - YAP1 is essential for osteoclastogenesis through a TEADs-dependent mechanism. AB - Yes-associated protein 1 (YAP1), the core effector of the Hippo signaling pathway, has been identified as a key regulator of tissue homeostasis and organ development by controlling cell proliferation and differentiation. Previous studies have shown that YAP1 regulates multiple steps during skeletal development and bone remodeling, including the self-renewal and differentiation of mesenchymal stem cells (MSCs). However, its role in osteoclastogenesis remains largely unknown. Here, we report that YAP1 is an essential regulator for osteoclast differentiation and activity. Both mRNA and protein levels of YAP1 were downregulated during RANKL-induced osteoclastogenesis. Short hairpin RNA mediated knockdown of YAP1 in bone marrow-derived macrophages (BMM) prevented the formation and function of multinucleated osteoclasts, and markedly abrogated the expression of osteoclast marker genes. Furthermore, the suppression of osteoclastogenesis and bone resorption activity were also observed in the BMM treated with verteporfin, a small molecule that inhibits the association of YAP1 with the transcriptional enhancer-associated domain (TEAD) family of transcription factors, the major partner of YAP1. Mechanistically, the interaction of YAP1/TEADs with AP-1 and cooperation on downstream gene transcription were confirmed, and RANKL-induced NF-kappaB signaling was also impaired in the YAP1-inhibited condition. Our results revealed the essential role of YAP1 and the YAP1-TEADs complex in regulating osteoclastogenesis and related gene expression. PMID- 29432920 TI - Bouveret's Syndrome. PMID- 29432921 TI - Complete Response of Diffuse Large B Cell Lymphoma After Direct-Acting Antiviral Therapy for Hepatitis C Virus. PMID- 29432923 TI - Peribiliary Cysts Presenting as Primary Sclerosing Cholangitis. PMID- 29432922 TI - Use of Appropriate Surveillance for Patients With Nondysplastic Barrett's Esophagus. AB - BACKGROUND & AIMS: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Guidelines recommend that patients with nondysplastic BE (NDBE) undergo surveillance endoscopy every 3-5 years. We aimed to identify factors associated with surveillance endoscopy of patients with NDBE and identify trends in appropriate surveillance endoscopy of NDBE at a large tertiary care center. METHODS: We performed a retrospective analysis of data from a Barrett's Esophagus Registry, identifying patients with NDBE who underwent endoscopy in 2002 or later. We identified patients with NDBE and collected data on length of BE segment, esophageal lesions, demographic features, medications, histology findings, comorbidities, development of EAC, and dates of follow-up endoscopies. We defined appropriate surveillance as 3-5 years between 2nd and 3rd endoscopies, over-utilizers as patients who had less than 3 years between their 2nd and 3rd endoscopies, under-utilizers as patients who had more than 5 years between their 2nd and 3rd endoscopies; and never-surveilled as patients who never received a 2nd endoscopy. The primary outcomes were effects of patient factors, year, and referring providers on appropriateness of surveillance intervals. RESULTS: We identified 477 patients with NDBE. Only 15.9% had appropriate surveillance; 37.9% were over-utilizers 15.7% were under-utilizers and 30.4% were never surveilled. Patients were less likely to be over-surveilled if their primary care physician referred them for their 3rd endoscopy instead of a gastroenterologist (adjusted odds ratio, 0.51; 95% CI, 0.27-0.95). Male patients or those with an increased number of comorbidities were more likely to be under-surveilled or never surveilled, whereas patients with long BE segment were more likely to be over surveilled. CONCLUSIONS: In a retrospective analysis of data from a registry of patients with BE, we found that less than 16% receive appropriate surveillance for NDBE. A primary care provider in the same health system as the endoscopy clinic reduced risk of over-surveillance. This could reflect better coordination of care between specialists and primary care providers. PMID- 29432924 TI - Evaluation of dicloran phototoxicity using primary cardiomyocyte culture from Crassostrea virginica. AB - Dicloran is a commonly used fungicide throughout the Southern and Western United States. Runoff of dicloran from agriculture systems to nearby waterbodies can accumulate in the organisms that inhabit those areas. Although severe damage of dicloran to ecological systems has not been reported, its toxicity has been modified by photodegradation. The objective of this study is to assess the changes of dicloran toxicities during photo exposure using a reliable in vitro biological model. In the present investigation, the photodegradation of dicloran in vitro showed over 90% of dicloran was degraded within 24h of UV exposure in water. Two major intermediate degradation products, 2-chloro-1,4-benzoquinone (CBQ) and 1,4-benzoquinone (BQ), were detected upon UV exposure of dicloran; however, they were rapidly degraded via photolysis. To estimate the impact of the phototoxicity of dicloran to aquatic organisms, we developed an in vitro cell culture system using the C. virginica cardiomyoctes (CvCMs) which were isolated from heart tissues and formed beating cell clusters. The CvCM clusters were treated with irradiated dicloran or the two intermediate standards, CBQ and BQ, and they showed up to 41% decrease in beating rates compared to control cell clusters. Expression levels of selected genes: def, hsp70, and cam, were upregulated in response to stimulations of UV irradiated dicloran and the two standard intermediates. The four-hour irradiated dicloran also resulted in more significant inhibition in the proliferation and small cardioactive peptide beta production of CvCMs than other treatment. Tested solutions of photolyzed dicloran showed elevated toxicities opposed to the standard intermediates, CBQ and BQ, suggesting additive toxicity of these dicloran products or toxicity due to other unidentified degradation products. Results of this study supported our hypothesis that the degradation of dicloran caused by photo irradiation results in an elevated toxicity which can be evaluated by the in vitro CvCM model. PMID- 29432925 TI - Applicability of common stomatal conductance models in maize under varying soil moisture conditions. AB - In the context of climate warming, the varying soil moisture caused by precipitation pattern change will affect the applicability of stomatal conductance models, thereby affecting the simulation accuracy of carbon-nitrogen water cycles in ecosystems. We studied the applicability of four common stomatal conductance models including Jarvis, Ball-Woodrow-Berry (BWB), Ball-Berry-Leuning (BBL) and unified stomatal optimization (USO) models based on summer maize leaf gas exchange data from a soil moisture consecutive decrease manipulation experiment. The results showed that the USO model performed best, followed by the BBL model, BWB model, and the Jarvis model performed worst under varying soil moisture conditions. The effects of soil moisture made a difference in the relative performance among the models. By introducing a water response function, the performance of the Jarvis, BWB, and USO models improved, which decreased the normalized root mean square error (NRMSE) by 15.7%, 16.6% and 3.9%, respectively; however, the performance of the BBL model was negative, which increased the NRMSE by 5.3%. It was observed that the models of Jarvis, BWB, BBL and USO were applicable within different ranges of soil relative water content (i.e., 55%-65%, 56%-67%, 37%-79% and 37%-95%, respectively) based on the 95% confidence limits. Moreover, introducing a water response function, the applicability of the Jarvis and BWB models improved. The USO model performed best with or without introducing the water response function and was applicable under varying soil moisture conditions. Our results provide a basis for selecting appropriate stomatal conductance models under drought conditions. PMID- 29432926 TI - Influence of a mixture of metals on PAHs biodegradation processes in soils. AB - In order to assess the effect of mixed pollutants, the influence of different concentration levels of a mixture of metals (Cr, Co, Pb, Mn, Ni, Cu, Zn) on the biodegradation of some PAHs (phenanthrene, fluoranthene, pyrene, benzo[b]fluoranthene and benzo[a]pyrene) in soil samples was evaluated. To do so, groups of microcosms of a natural soil from the region of Sabadell (Barcelona, Spain) were prepared as a reproduction of the native environment at laboratory scale, under controlled conditions. Mixtures of PAHs and metals were carefully selected, according to soil characterization and microbiological growth preliminary assays, and were added to microcosms. These microcosms were analyzed at various times, along two months, to obtain PAHs dissipation time-courses. A first-order kinetic modelling allowed obtaining different rate constants and DT50 values as a function of the metal levels introduced in microcosms. As a general observation, the higher the concentration of metals, the lower the biodegradation of PAHs of 3-4 rings (phenanthrene, fluoranthene and pyrene). On the other hand, no important effect on the biodegradation of higher molecular weight PAHs (benzo[b]fluoranthene and benzo[a]pyrene) was observed at the different concentration levels of metals tested. PMID- 29432927 TI - Organophosphate flame retardants and plasticizers in indoor dust, air and window wipes in newly built low-energy preschools. AB - The construction of extremely airtight and energy efficient low-energy buildings is achieved by using functional building materials, such as age-resistant plastics, insulation, adhesives, and sealants. Additives such as organophosphate flame retardants (OPFRs) can be added to some of these building materials as flame retardants and plasticizers. Some OPFRs are considered persistent, bioaccumulative and toxic. Therefore, in this pilot study, the occurrence and distribution of nine OPFRs were determined for dust, air, and window wipe samples collected in newly built low-energy preschools with and without environmental certifications. Tris(1,3-dichloroisopropyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP) were detected in all indoor dust samples at concentrations ranging from 0.014 to 10MUg/g and 0.0069 to 79MUg/g, respectively. Only six OPFRs (predominantly chlorinated OPFRs) were detected in the indoor air. All nine OPFRs were found on the window surfaces and the highest concentrations, which occurred in the reference preschool, were measured for 2-ethylhexyl diphenyl phosphate (EHDPP) (maximum concentration: 1500ng/m2). Interestingly, the OPFR levels in the environmental certified low-energy preschools were lower than those in the reference preschool and the non-certified low-energy preschool, probably attributed to the usage of environmental friendly and low-emitting building materials, interior decorations, and consumer products. PMID- 29432928 TI - Impact of the wood combustion in an open fireplace on the air quality of a living room: Estimation of the respirable fraction. AB - Presently, both in rural areas and in cities open fireplaces are still present and large quantities of wood are combusted every year. The present study aims to characterize aerosol size distribution, chemical composition and deposition in the human respiratory tract of particles emitted during the combustion of logs of oak in an open fireplace installed in the living room of a typical village house. CO2 and CO levels and aerosol size distribution have been continuously monitored and a PM10 sampler with two types of filters for chemical and microscopic analysis was also installed. The increment, between the operating periods and the indoor background, in the organic carbon and PM10 concentration due to the use of the fireplace is 15.7+/-0.6 (mean+/-standard deviation) and 58.5+/-6.2MUgm-3, respectively. The two main polluting processes during the operation of the fireplace are the ignition with the subsequent refueling and the final cleaning of the residual ashes. In both phases mean values around 1800 particles cm-3 with CMD of 0.15MUm were measured. However, while PM10 levels of 130+/-120MUgm-3 were estimated for the ignition stage, values of 200+/-200MUgm-3 were obtained during the final cleaning step. Assessment conducted according to ISO standard 7708:1995, demonstrated that a person who stays in a living room when an open fireplace is lit will inhale, on average, 217MUgm-3 and 283MUgm-3 during the ignition and the refueling stages, respectively. Subsequent refueling proved to be much less polluting. The ashes removal can also be very polluting and dangerous to health if there are hidden small incandescent embers among the ashes (estimated PM10 of 132MUgm-3), reaching a CO2 level of 1940ppm and a dangerous level of CO of 132ppm. PMID- 29432929 TI - High molecular weight components of natural organic matter preferentially adsorb onto nanoscale zero valent iron and magnetite. AB - Nanoscale zero valent iron particles (nano-Fe0) are attractive for in-situ groundwater remediation due to their high reactivity and ability to degrade many different classes of environmental contaminants. It is expected that adsorbed natural organic matter (NOM), which is heterogeneous and typically has a wide molecular weight (MW) distribution, will affect the reactivity and performance of nano-Fe0 as a remediation agent. However, the interaction of NOM with nano-Fe0 has not been well-studied. In this study, we used high performance size exclusion chromatography (HPSEC) to determine if there was preferential sorption of the high MW fraction of NOM onto nano-Fe0 that have a Fe0 core and a Fe-oxide shell (predominantly magnetite). Adsorption of two types of NOM, Suwannee River Humic Acid (SRHA) and Fulvic Acid (SRFA), to nano-Fe0 was compared to magnetite of similar size (nano-Fe3O4) to also assess the effect of the Fe0 core on adsorption of NOM. The results showed that the surface area normalized adsorbed mass (mg/m2) of both SRHA and SRFA onto nano-Fe0 is almost three times than that of nano Fe3O4. This is attributed to a greater number of reactive sites on nano-Fe0 compared to nano-Fe3O4, and indicates that the surface properties of nano-Fe0 are different that nano-Fe3O4 despite the shell of magnetite on nano-Fe0. The sorption capacity of both SRHA and SRFA onto nano-Fe0 were similar. However, the intermediate sized MW fractions (2-6 kDa) of SRHA were preferentially adsorbed onto the nano-Fe0 surface, whereas the large MW fractions (>3.5 kDa) of SRFA were preferentially adsorbed. These results suggest that NOM interaction with nano-Fe0 are a function of the MW distribution of the NOM in the system studied and indicate that the MW distributions of NOM should be taken into consideration when predicting the fate and performance of nano-Fe0 in environmental remediation. PMID- 29432930 TI - The intake of water containing a mix of pollutants at environmentally relevant concentrations leads to defensive response deficit in male C57Bl/6J mice. AB - Previous studies have individually confirmed the toxic effects from different pollutants on mammals. However, effects resulting from the exposure of these animals to multi-pollutant mixes have not been studied so far. Thus, the aim of the current study is to assess the effect from the chronic exposure (105days) of C57Bl/6J mice to a mix of pollutants on their response to potential predators. In order to do so, the following groups were formed: "control", "Mix 1* [compounds from 15 pollutants identified in surface waters at environmentally relevant concentration (ERC)]", "Mix 10*" and "Mix 25*" (concentrations 10 and 25 times higher than the ERC). From the 100th experimental day on, the animals were subjected to tests in order to investigate whether they showed locomotor, visual, olfactory and auditory changes, since these abilities are essential to their anti predatory behavior. Next, the animals' behavior towards potential predators (Felis catus and Pantherophis guttatus) was assessed. The herein collected data did not show defensive response from any of the experimental groups to the predatory stimulus provided by P. guttatus. However, the control animals, only, presented anti-predatory behavior when F. catus was introduced in the apparatus, fact that suggests defensive response deficit resulting from the treatments. Thus, the current study is pioneer in showing that the chronic intake of water containing a mix of pollutants (even at low concentrations) leads to behavioral disorders able to affect the survival and population dynamics of mammalian species at ecological level. PMID- 29432931 TI - Self-organizing maps for indications of airborne polychlorinated biphenyl (PCBs) and organochlorine pesticide (OCPs) dependence on spatial and meteorological parameters. AB - This paper investigates the relation of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in air samples with meteorological parameters (temperature, atmospheric pressure and relative humidity) using the Kohonen self organizing map (SOM). Both gas- and particle-adsorbed phase of 20 PCB congeners and 7 OCPs including the three new ones (alpha-HCH, beta-HCH, and gamma-HCH) listed in the Stockholm Convention were collected during a one-year period at urban locations in Zagreb (Croatia). Moving beyond existing studies, the SOM analysis showed that the meteorological characteristics of transient seasons such as spring had no influence on the dissimilarities in the behavior of PCBs and OCPs. Towards the identification of pollutant spatial patterns, the SOM did not isolate a clear phenomenon probably due to the absence of local pollution sources contributing to the elevated concentrations of these compounds. Overall, our results have shown that the SOM method, by recognizing significant differences among PCB and OCP seasonality, could be recommended in the analysis of pollutant distribution depending on temperature and atmospheric pressure. PMID- 29432932 TI - Gamma radiation induces dose-dependent oxidative stress and transcriptional alterations in the freshwater crustacean Daphnia magna. AB - Among aquatic organisms, invertebrate species such as the freshwater crustacean Daphnia magna are believed to be sensitive to gamma radiation, although information on responses at the individual, biochemical and molecular level is scarce. Following gamma radiation exposure, biological effects are attributed to the formation of free radicals, formation of reactive oxygen species (ROS) and subsequently oxidative damage to lipids, proteins and DNA in exposed organisms. Thus, in the present study, effects and modes of action (MoA) have been investigated in D. magna exposed to gamma radiation (dose rates: 0.41, 1.1, 4.3, 10.7, 42.9 and 106 mGy/h) after short-term exposure (24 and 48 h). Several individual, cellular and molecular endpoints were addressed, such as ROS formation, lipid peroxidation, DNA damage and global transcriptional changes. The results showed that oxidative stress is one of the main toxic effects in gamma radiation exposed D. magna, mediated by the dose-dependent increase in ROS formation and consequently oxidative damage to lipids and DNA over time. Global transcriptional analysis verified oxidative stress as one of the main MoA of gamma radiation at high dose rates, and identified a number of additional MoAs that may be of toxicological relevance. The present study confirmed that acute exposure to gamma radiation caused a range of cellular and molecular effects in D. magna exposed to intermediate dose rates, and highlights the need for assessing effects at longer and more environmentally relevant exposure durations in future studies. PMID- 29432933 TI - Arterial stiffening and thickening in patients with pseudoxanthoma elasticum. AB - BACKGROUND AND AIMS: Patients with pseudoxanthoma elasticum (PXE), a monogenetic calcification disease, are at high vascular risk. Although the precise arterial phenotype remains unestablished, it is hypothesized that PXE predominantly affects the medial arterial layer leading to arterial stiffening. We aimed to test this hypothesis by measuring arterial wall characteristics in PXE and comparisons with the general population and diabetes mellitus type 2 (DM2), a condition typically associated with mixed intimal and medial arterial disease. METHODS: Extensive arterial wall characterization was performed in 203 PXE patients involving intima-media thickness (IMT), pulse wave velocity (PWV) and pulse pressure (PP) measurements. IMT and PWV in PXE were compared with the general population using age, sex and mean arterial pressure corrected values for each PXE patient. IMT and PP were compared between PXE and DM2 independently of sex, age and systolic blood pressure, using data of DM2 patients (n = 1033) from the Second Manifestations of ARTerial disease (SMART) cohort. RESULTS: PXE patients had significantly higher IMT (mean difference 0.09 mm; 95% CI 0.07-0.12 mm) and PWV (mean difference 2.5 m/s; 95% CI 1.9-3.0 m/s) compared to the general population. IMT in PXE was lower compared to DM2 (0.72 mm; 95% CI 0.68-0.75 mm vs. 0.85 mm; 95% CI 0.83-0.87 mm, p-value<0.01), whereas PP in PXE was higher compared to DM2 (60 mmHg; 95% CI 59-62 vs. 57 mmHg; 95% CI 57-58 mmHg, p value<0.01). CONCLUSIONS: PXE patients have thicker arterial walls than the general population, but thinner arterial walls than DM2 patients at similar age. Arterial stiffening is more pronounced in PXE patients compared to DM2 patients. PMID- 29432934 TI - Alpha-1 antitrypsin deficiency: From the lung to the heart? AB - BACKGROUND AND AIMS: Alpha-1 antitrypsin (A1AT) is the most abundant serine protease inhibitor in human blood and exerts important anti-inflammatory and immune-modulatory effects. In combination with smoking or other long-term noxious exposures such as occupational dust and fumes, genetic A1AT deficiency can cause chronic obstructive pulmonary disease, a condition with elevated cardiovascular risk. The effects of A1AT deficiency on cardiovascular risk have hardly been studied today. METHODS: Using data from 2614 adults from the population-based SAPALDIA cohort, we tested associations of serum A1AT and SERPINA1 mutations with carotid intima-media thickness (CIMT, measured by B-mode ultrasonography) or self reported arterial hypertension or cardiovascular disease in multiple regression models using a Mendelian Randomization like analysis design. Mutations Pi-S and Pi-Z were coded as ordinal genotype score (MM, MS, MZ/SS, SZ and ZZ), according to their progressive biological impact. RESULTS: Serum A1AT concentration presented a u-shaped association with CIMT. At the lower end of the A1AT distribution, an analogous, linear association between SERPINA1 score and higher CIMT was observed, resulting in an estimated 1.2% (95%-confidence interval -0.1 2.5) increase in CIMT per unit (p = 0.060). Genotype score was significantly associated with arterial hypertension with an odds ratio (OR) of 1.2 (1.0-1.5) per unit (p = 0.028). The association with cardiovascular disease was not significant (OR 1.3 (0.9-1.9)). CONCLUSIONS: Our results support a possible causal relationship between genetic A1AT deficiency and increased cardiovascular risk, which needs to be better taken into account for the management of affected patients and first-degree relatives. PMID- 29432935 TI - Uric acid is associated with long-term adverse cardiovascular outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention. AB - BACKGROUND AND AIMS: Evidence links uric acid (UA) with the promotion of cardiovascular disease. We assessed the prognostic value of UA on long-term major adverse outcomes (MACE) in patients with acute coronary syndrome (ACS), undergoing percutaneous coronary intervention (PCI). METHODS: As primary endpoint, we assessed the association of UA (continuous and dichotomized) with MACE, including cardiovascular death, myocardial infarction (MI) and stroke, using Cox regression and propensity matching. As secondary endpoints, the influence of hyperuricemia (defined as UA levels > 6.0 mg/dl in women, and >7.0 mg/dl in men) was analysed separately for cardiovascular death, MI, and stroke. The incremental prognostic value of UA was tested using the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI). RESULTS: We included 1215 patients. Hyperuricemia was present in 356 (29.3%) patients. Mean follow-up was 5.5 years. UA (HR 1.091 [1.035-1.150]; p = 0.001) and hyperuricemia (HR 1.750 [1.388-2.207]; p < 0.001) were significantly associated with MACE. Results were consistent between Cox regression and propensity matched analysis. Patients with hyperuricemia had a 1.6-fold increased relative risk for cardiovascular death (p = 0.005) and a 1.5-fold increased risk for MI (p = 0.032). For stroke, hyperuricemia only constituted a confounder (HR 1.104; p = 0.970). The prognostic accuracy of an established risk prediction model was significantly increased by adding UA (continuous NRI p = 0.004; categorical NRI p = 0.029; IDI p = 0.002). CONCLUSIONS: Our data suggest an independent association of elevated UA with long-term MACE in ACS patients undergoing PCI. Whether lowering UA might be beneficial remains to be elucidated in large clinical trials. PMID- 29432936 TI - Preschoolers fast map and retain artifact functions as efficiently as artifact names, but artifact actions are the most easily learned. AB - To become skilled artifact users, children must learn the actions and functions associated with artifacts. We investigated preschoolers' ability to fast map an action, function and name associated with a novel artifact, and retain the new mapping long term following brief incidental exposure to the artifact being used. In Experiment 1, 3- and 5-year-olds (N = 144) were tested 1 week after two exposures to a novel action, function, and name. Participants performed well on comprehension tests of all three kinds of information. In Experiment 2, 3-year olds (N = 100) were exposed to these three kinds of information only once. Retention of the action-artifact link was above chance levels, whereas retention of function and the name was not. Finally, in Experiment 3, 4-year-olds (N = 128) performed well on an action production task 1 week after brief exposure. In contrast, their performance on a name production task immediately after exposure was poor. Our data suggest that preschoolers can retain function information about a novel artifact from minimal exposure, similar to their ability to learn an artifact name. Crucially, their ability to remember action-artifact mappings is markedly better than their ability to remember functions and names. PMID- 29432937 TI - Detection of VIM-2-, IMP-1- and NDM-1-producing multidrug-resistant Pseudomonas aeruginosa in Malaysia. AB - OBJECTIVES: The increasing incidence of carbapenem-resistant Pseudomonas aeruginosa along with the discovery of novel metallo-beta-lactamases (MBLs) is of concern. In this study, the isolation of MBL-producing P. aeruginosa clinical strains in Malaysia was investigated. METHODS: A total of 53 P. aeruginosa clinical strains were isolated from different patients in Sultanah Aminah Hospital (Johor Bahru, Malaysia) in 2015. Antimicrobial susceptibility testing was performed, and minimum inhibitory concentrations (MICs) of imipenem and meropenem were determined by Etest. Carbapenem-resistant strains were screened for MBL production by the imipenem-ethylene diamine tetra-acetic acid (IMP-EDTA) double-disk synergy test, MBL imipenem/imipenem-inhibitor (IP/IPI) Etest and PCR. Multilocus sequence typing (MLST) analysis was performed for genotyping of the isolates. RESULTS: Among the 53 clinical strains, 3 (5.7%) were identified as MBL producers. Multidrug resistance was observed in all three strains, and two were resistant to all of the antimicrobials tested. Sequencing analysis confirmed that the three strains harboured carbapenemase genes (blaIMP-1, blaVIM-2 and blaNDM-1 in one isolate each). These multidrug-resistant strains were identified as sequence type 235 (ST235) and ST308. CONCLUSIONS: The blaIMP-1 and blaNDM-1 genes have not previously been reported in Malaysian P. aeruginosa isolates. The emergence of imipenemase 1 (IMP-1)- and New Delhi metallo-beta-lactamase 1 (NDM 1)-producing P. aeruginosa in Malaysia maybe travel-associated. PMID- 29432938 TI - First report on antimicrobial resistance and molecular characterisation of Salmonella enterica serotype Typhi isolated from human specimens in Luanda, Angola. AB - OBJECTIVES: Typhoid fever is a common infection in Africa and, despite scarce surveillance reports, its incidence is commonly considered high by the Angolan health system. Drug-resistant Salmonella enterica serotype Typhi has emerged, making antimicrobial susceptibility testing essential to provide clinical guidance. This is the first report analysing the antimicrobial resistance patterns and population structure of the few S. enterica ser. Typhi isolated from patients with typhoid fever in Luanda, Angola. METHODS: Isolates were collected by the Angolan National Institute of Public Health between September 2013 and May 2014. Ten isolates were identified by the API 20E system and serotyping, and the genus was confirmed by PCR. All isolates were tested for antibiotic susceptibility, and the presence of resistance genes [blaCTX-M, blaSHV, blaTEM, blaOXA-1, several plasmid-borne genes encoding AmpC beta-lactamases, sul and qnr genes, dfrIa, dfrA12, aac(6')-Ib, cmlA and floR] were screened by PCR. Isolates were typed by PFGE and MLST. RESULTS: Several isolates were identified with resistance to trimethoprim/sulfamethoxazole (n=6), beta-lactams (n=5) and chloramphenicol (n=1) and reduced susceptibility to ciprofloxacin (n=2). PFGE revealed eight closely related restriction patterns, and MLST grouped these into three sequence types (ST1, ST2 and ST8), with ST2 being predominant. CONCLUSION: This first epidemiological report provides a preliminary description of S. enterica ser. Typhi strains circulating in Luanda and emphasises the need for continuous monitoring of this pathogen to provide information in order to implement better epidemiological strategies for the control of typhoid fever in Angola. PMID- 29432939 TI - Effect of elevated imipenem/cilastatin minimum inhibitory concentrations on patient outcomes in Gram-negative bloodstream infections. AB - OBJECTIVES: Carbapenem minimum inhibitory concentration (MICs) are known to predict outcomes for patients with Gram-negative bacteraemia. However, limited data exist on how MICs influence such outcomes when organisms are classified as carbapenem-resistant. The purpose of this study was to evaluate the effect of increasing imipenem/cilastatin MICs on mortality in patients with Gram-negative bloodstream infection (BSI). METHODS: Patients with an imipenem/cilastatin resistant (MIC>4mg/L) monomicrobial Gram-negative BSI were eligible for inclusion in the study and were assessed for baseline characteristics, organ function, microbiological data, timing and type of therapeutic treatment, and in-hospital mortality. RESULTS: A total of 62 patients with imipenem/cilastatin-resistant bacterial isolates (MIC>4mg/L) were retrospectively studied. Time to event analyses found no difference between patients who received carbapenem therapy and those who did not (P=0.10). After adjustment, patients receiving directed therapy were less likely to die (adjusted hazard ratio=0.35, 95% confidence interval 0.15 0.83; P<0.01), whereas higher modified Acute Physiology and Chronic Health Evaluation (APACHE) II score and days to positive culture were associated with non-survival. CONCLUSION: This study did not demonstrate a relationship between receipt of a carbapenem and mortality in patients with carbapenem-resistant Gram negative BSI. PMID- 29432940 TI - Modulation of incisor eruption in rats by sympathetic efferents. AB - INTRODUCTION: Intact neural supply is necessary for tooth eruption. Sympathetic denervation accelerates or decelerates the eruption rate depending on the tooth condition (intact or injured). The aim of this study is to reexamine the role of the sympathetic innervation, through the observation of the effects of pre or post ganglionic chemical sympathectomy on the eruption of intact rat incisors. MATERIALS AND METHODS: Different groups of rats were subjected to either ganglionic or peripheral chemical sympathectomy and the observed effects on incisor eruption were compared to those made on intact/sham groups or on rats subjected to inferior alveolar nerve (IAN) lesion. RESULTS: The total amount of eruption in control/naive rats, measured over a total period of 144 h, was 3 +/- 0.15 mm and decreased to 2.57 +/- 0.06 mm (n = 8; p < 0.01) or 2.8 +/- 0.10 mm (n = 8; p < 0.05) following treatment with guanethidine and hexamethonium, respectively. This amount decreased to 1.8 +/- 0.14 mm (p < 0.001 vs. control, n = 7; or p < 0.01 vs. sham, n = 5) in rats subjected to IAN lesion. CONCLUSION: Sympathectomy delayed tooth eruption. Blocking the sympathetic effectors with guanethidine exerted more potent effects than ganglionic block with hexamethonium. Intact sympathetic supply is required for tooth growth under normal conditions. PMID- 29432941 TI - Exploiting transcriptomic data for metabolic engineering: toward a systematic strain design. AB - Transcriptomics is now recognized as a primary tool for metabolic engineering as it can be used for identifying new strain designs by diagnosing current states of microbial cells. This review summarizes current application of transcriptomic data for strain design. Along with a few successful examples, limitations of conventionally used differentially expressed gene-based strain design approaches have been discussed, which have been major reasons why transcriptomic data are considerably underutilized. Recently, integrative network-based approaches interpreting transcriptomic data in the context of biological networks were invented to provide complimentary solutions for metabolic engineering by overcoming the limitations of conventional approaches. Here, we highlight recent pioneering studies in which integrative network-based methods have been used for providing novel strain designs. PMID- 29432942 TI - Improving Sperm Viability After Spinal Cord Injury Using Hyperbaric Therapy. AB - BACKGROUND: Infertility is one of many complications of spinal cord injury (SCI) in male patients, who are often at the peak of their reproductive life. This study evaluated effects of hyperbaric therapy (HT) on quality of sperm of rats with SCI and correlated the findings with histologic analysis of the testicles. METHODS: This experimental study comprised 18 rats that were submitted to SCI with a MASCIS Impactor and randomly allocated to either a HT or a control group. Testicular biopsies were performed on the first and 28th day of the study; 4 parameters were evaluated: concentration of sperm per mL, number of round cells per field, number of inflammatory cells per field (peroxidase [Endtz] test), and sperm viability (hypo-osmotic swelling test). RESULTS: There was no difference in sperm concentration between the HT group (P = 0.41) and control group (P = 0.74) during 28 days. From day 1 to day 28, sperm viability decreased twice as much in the control group (P = 0.001) compared with the HT group (P = 0.017). There was no difference between the groups in mean sperm concentration and number of round and inflammatory cells. On the first day, there was no difference in sperm viability between groups. There was a significantly higher (P = 0.001) percentage of viable sperm in the HT group (86.8 +/- 5.6) compared with the control group (48.8 +/- 21.8) on day 28. CONCLUSIONS: SCI increased the number of round and inflammatory cells and diminished sperm viability in both groups. HT promoted greater sperm viability in rats with SCI. PMID- 29432943 TI - Functional-Based Resection Does Not Worsen Quality of Life in Patients with a Diffuse Low-Grade Glioma Involving Eloquent Brain Regions: A Prospective Cohort Study. AB - OBJECTIVE: We assessed the impact of surgery on postoperative cognitive function and ability to work in adult patients with a diffuse low-grade glioma involving eloquent brain regions and having a functional-based maximal surgical resection using intraoperative corticosubcortical mapping under awake conditions. METHODS: We prospectively included 39 consecutive patients with diffuse isocitrate dehydrogenase-mutant low-grade glioma without preoperative and adjuvant oncologic treatment and assessed preoperative (mean, 24.1 +/- 21.2 days before surgery) and postoperative (mean, 14.6 +/- 13.2 months after surgery) cognitive evaluations and ability to work together with clinical, imaging, therapeutic, and follow-up characteristics before tumor progression. RESULTS: None of the 3 patients without preoperative cognitive deficit had postoperative worsening. We observed a significant inverse interaction between worsened postoperative cognitive function and extent of resection: 80.0%, 18.8%, and 16.7% of worsening after partial, subtotal, and total resection, respectively (P = 0.020). We observed an independent interaction between improved postoperative cognitive function and extent of resection: 20.0%, 43.7%, and 44.4% of improvement after partial, subtotal, and total resection, respectively (P = 0.022). Of the employed patients, 61.8% were unable to work preoperatively and 82.4% resumed their employment postoperatively (mean, 6.9 +/- 5.5 months). We observed an independent interaction between postoperative ability to work, similar or superior to preoperative work capacity and extent of resection (P < 0.001): 20.0%, 87.5%, and 100% ability to work after partial, subtotal resection, and total resection. CONCLUSIONS: The extent of the functional-based surgical resection and the residual tumor for diffuse low-grade gliomas involving eloquent brain regions correlate with postoperative cognitive outcomes and return to work rates. PMID- 29432944 TI - Expression of Matrix Metalloproteinase-9, Pituitary Tumor Transforming Gene, High Mobility Group A 2, and Ki-67 in Adrenocorticotropic Hormone-Secreting Pituitary Tumors and Their Association with Tumor Recurrence. AB - OBJECTIVE: Matrix metalloproteinase-9 (MMP-9), pituitary tumor transforming gene (PTTG), and high mobility group A 2 (HMGA2) play important roles in the tumorigenesis of adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors, but their associations with tumor recurrence after transsphenoidal adenomectomy remain unclear. The aim of the study was to investigate the immunohistochemical expression profiles of MMP-9, PTTG, HMGA2, and Ki-67 in recurrent and nonrecurrent ACTH-secreting pituitary tumors and to identify their associations with tumor behavior and recurrence status. METHODS: A retrospective study was performed including 55 patients with sporadic Cushing's disease with long-term remission after transsphenoidal adenomectomy. Fifty-five ACTH-secreting pituitary tumor specimens and 2 normal pituitary glands were collected. After an intensive follow-up (33-59 months, mean 41.8 months), patients were divided into 2 groups based on their recurrence status: the nonrecurrent group (n = 28) and the recurrent group (n = 27). The expression of MMP-9, PTTG, HMGA2, and Ki-67 in each sample was examined and quantified by immunohistochemistry. The association between MMP-9, PTTG, HMGA2, and Ki-67 expression and clinicopathologic characteristics and tumor recurrence were evaluated. RESULTS: There was a significantly increased expression of MMP-9 in the recurrent group compared with the nonrecurrent group (P = 0.022), and this was strongly associated with the recurrence-free interval (P = 0.007, correlation coefficient. = -0.354). PTTG, HMGA2, and Ki-67 expression were not significantly different between the recurrent group and the nonrecurrent group. No expression of MMP-9, PTTG, HMGA2, or Ki-67 was detected in the 2normal pituitary glands. CONCLUSIONS: ACTH secreting pituitary tumors with greater levels of MMP-9 were associated with a greater recurrence rate and a shorter recurrence-free interval. MMP-9 could be a valuable tool for predicting recurrence of ACTH-secreting pituitary tumors. PMID- 29432945 TI - Utility of 3-Dimensional-Printed Models in Enhancing the Learning Curve of Surgery of Tuberculum Sellae Meningioma. AB - OBJECTIVE: To investigate the value of 3-dimensional (3D)-printed models with pathologic entities in enhancing the learning curve of surgery of tuberculum sellae meningioma. METHODS: We printed 4 models of tuberculum sellae meningiomas based on radiologic data using a 3D printer. Participants were allocated to the 3D group and the atlas group. In the 3D group, participants learned surgery with the assistance of 3D models. In the atlas group, participants used only 2 dimensional materials to assist their learning. All participants undertook a pre test and post-test. The scores were used to identify the difference in learning efficiency between the 2 groups. RESULTS: A total of 42 new trainees were recruited, of whom 22 were in the 3D group and 20 in the atlas group. The baseline data were not significantly different. The difference of pre-test score was not significant, either. However, the post-test score was significantly greater in the 3D group (P = 0.005), and the change in score was also significantly greater in the 3D group (P < 0.001). In accordance with the objective test, the subjective survey through a questionnaire from participants in the 3D group showed that 3D models significantly promoted the learning curve of this kind of complex skull base surgery. CONCLUSIONS: 3D-printed models can assist in improving the learning curve of surgery of tuberculum sellae meningiomas. It particularly aids in memorization and spatial construction, improves understanding of surgical view, and arouses interest on the part of the trainee. We recommend using it in the education of complex skull base surgery. PMID- 29432946 TI - Postoperative Cerebral Infarction Risk Factors and Postoperative Management of Pediatric Patients with Moyamoya Disease. AB - OBJECTIVE: Although revascularization surgery for patients with moyamoya disease can effectively prevent ischemic events and thus improve the long-term clinical outcome, the incidence of postoperative ischemic complications affects patients' quality of life. This study aimed to clarify the risk factors associated with postoperative ischemic complications and to discuss the appropriate perioperative management. METHODS: Fifty-eight revascularization operations were performed in 37 children with moyamoya disease. Patients with moyamoya syndrome were excluded from this study. Magnetic resonance imaging was performed within 7 days after surgery. Postoperative cerebral infarction was defined as a diffusion-weighted imaging high-intensity lesion with or without symptoms. We usually use fentanyl and dexmedetomidine as postoperative analgesic and sedative drugs for patients with moyamoya disease. We used barbiturate coma therapy for pediatric patients with moyamoya disease who have all postoperative cerebral infarction risk factors. RESULTS: Postoperative ischemic complications were observed in 10.3% of the children with moyamoya disease (6 of 58). Preoperative cerebral infarctions (P = 0.0005), younger age (P = 0.038), higher Suzuki grade (P = 0.003), and posterior cerebral artery stenosis/occlusion (P = 0.003) were related to postoperative ischemic complications. Postoperative cerebral infarction occurred all pediatric patients using barbiturate coma therapy. CONCLUSIONS: The risk factors associated with postoperative ischemic complications for children with moyamoya disease are preoperative infarction, younger age, higher Suzuki grade, and posterior cerebral artery stenosis/occlusion. Barbiturate coma therapy for pediatric patients with moyamoya disease who have the previous risk factors is insufficient for prevention of postoperative cerebral infarction. More studies are needed to identify the appropriate perioperative management. PMID- 29432947 TI - Recent progress in the structural modification and pharmacological activities of ligustrazine derivatives. AB - Ligustrazine is a main active fraction of the traditional medicine known as Ligusticum chuanxiong hort, which has been used as clinical medication for cerebral thrombosis, coronary heart disease and stenocardia recently. The rapid metabolism and short half-life of ligustrazine seriously limits its application in clinical practice. Therefore, derivatives of ligustrazine are designed and synthesized in our and other labs, including piperazine, cinnamic acid, styrene, acylguanidine, amides, curcumin and triterpenes derivatives of ligustrazine. Most of these compounds present better pharmacodynamics activities and more favorable pharmacokinetic properties compared to the parent compound. Besides, some new biological activities of these compounds are discovered. Hence, this review continues the previous review of our group as well as aims to highlight recent prominent advances in this field in the past ten years. PMID- 29432948 TI - Phenylpyridine-2-ylguanidines and rigid mimetics as novel inhibitors of TNFalpha overproduction: Beneficial action in models of neuropathic pain and of acute lung inflammation. AB - 4-phenylpyridin-2-yl-guanidine (5b): a new inhibitor of the overproduction of pro inflammatory cytokines (TNFalpha and Il1beta) was identified from a high throughput screening of a chemical library on human peripheral blood mononuclear cells (PBMCs) after LPS stimulation. Derivatives, homologues and rigid mimetics of 5b were designed and synthesized, and their cytotoxicity and ability to inhibit TNFalpha overproduction were evaluated. Among them, compound 5b and its mimetic 12 (2-aminodihydroquinazoline) showed similar inhibitory activities, and were evaluated in vivo in models of lung inflammation and neuropathic pain in mice. In particular, compound 12 proved to be active (5 mg/kg, ip) in both models. PMID- 29432950 TI - Editorial. PMID- 29432949 TI - Synthesis and biological evaluation of carbamates derived from aminocombretastatin A-4 as vascular disrupting agents. AB - A series of twenty-six carbamates derived from aminocombretastatin A-4 (AmCA-4) were synthesized and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest, microtubule network organization, apoptosis and endothelial tubular structures in vitro. The anti-proliferative activity of the synthetic carbamates was measured on several human tumor cell lines (i.e. HT-29, MCF-7, HeLa, A-549, MDA-MB-231, HL-60) as well as on the endothelial cell line HMEC-1 and the non-tumor cell line HEK-293. The compounds showed anti-proliferative activity in the nanomolar range thereby exceeding by far the activity of combretastatin A-4 (CA-4) and, in some cases, the activity of AmCA-4. The most active compounds proved to be the carbamates bearing chloro, bromo or methoxy groups in the meta position of the phenyl ring. Moreover, all carbamates inhibited in vitro tubulin polymerization, in a similar manner to that of CA-4 and AmCA-4 by interacting with the colchicine binding site in tubulin. The synthetic carbamates proved as active as AmCA-4 in causing mitotic arrest, as assessed in A549 human lung cancer cells, and disruption of the microtubule cellular network. Some selected carbamates induced apoptosis at concentrations as low as 10 nM, being more active than AmCA-4. Finally, these selected carbamates displayed a vascular disrupting activity on endothelial cells in a dose-dependent manner. In conclusion, our data indicate that carbamates derived from aminocombretastatin A-4 represent interesting lead compounds for the design of vascular disrupting agents. PMID- 29432951 TI - Understanding protein adaptations can help us solve real problems. PMID- 29432953 TI - Axon guidance: Signaling pathways old and new across a variety of developmental contexts. PMID- 29432954 TI - Mechanistic insights and therapeutic opportunities of antimicrobial chemokines. AB - Chemokines are a family of small proteins best known for their ability to orchestrate immune cell trafficking and recruitment to sites of infection. Their role in promoting host defense is multiplied by a number of additional receptor dependent biological activities, and most, but not all, chemokines have been found to mediate direct antimicrobial effects against a broad range of microorganisms. The molecular mechanism(s) by which antimicrobial chemokines kill bacteria remains unknown; however, recent observations have expanded our fundamental understanding of chemokine-mediated bactericidal activity to reveal increasingly diverse and complex actions. In the current review, we present and consider mechanistic insights of chemokine-mediated antimicrobial activity against bacteria. We also discuss how contemporary advances are reshaping traditional paradigms and opening up new and innovative avenues of research with translational implications. Towards this end, we highlight a developing framework for leveraging chemokine-mediated bactericidal and immunomodulatory effects to advance pioneering therapeutic approaches for treating bacterial infections, including those caused by multidrug-resistant pathogens. PMID- 29432955 TI - The evolution, function and mechanisms of action for plant defensins. AB - Plant defensins are an extensive family of small cysteine rich proteins characterised by a conserved cysteine stabilised alpha beta protein fold which resembles the structure of insect and vertebrate defensins. However, secondary structure and disulphide topology indicates two independent superfamilies of defensins with similar structures that have arisen via an extreme case of convergent evolution. Defensins from plants and insects belong to the cis defensin superfamily whereas mammalian defensins belong to the trans-defensin superfamily. Plant defensins are produced by all species of plants and although the structure is highly conserved, the amino acid sequences are highly variable with the exception of the cysteine residues that form the stabilising disulphide bonds and a few other conserved residues. The majority of plant defensins are components of the plant innate immune system but others have evolved additional functions ranging from roles in sexual reproduction and development to metal tolerance. This review focuses on the antifungal mechanisms of plant defensins. The activity of plant defensins is not limited to plant pathogens and many of the described mechanisms have been elucidated using yeast models. These mechanisms are more complex than simple membrane permeabilisation induced by many small antimicrobial peptides. Common themes that run through the characterised mechanisms are interactions with specific lipids, production of reactive oxygen species and induction of cell wall stress. Links between sequence motifs and functions are highlighted where appropriate. The complexity of the interactions between plant defensins and fungi helps explain why this protein superfamily is ubiquitous in plant innate immunity. PMID- 29432952 TI - G.I. pros: Antimicrobial defense in the gastrointestinal tract. AB - The gastrointestinal tract is a complex environment in which the host immune system interacts with a diverse array of microorganisms, both symbiotic and pathogenic. As such, mobilizing a rapid and appropriate antimicrobial response depending on the nature of each stimulus is crucial for maintaining the balance between homeostasis and inflammation in the gut. Here we focus on the mechanisms by which intestinal antimicrobial peptides regulate microbial communities during dysbiosis and infection. We also discuss classes of bacterial peptides that contribute to reducing enteric pathogen outgrowth. This review aims to provide a comprehensive overview on the interplay of diverse antimicrobial responses with enteric pathogens and the gut microbiota. PMID- 29432956 TI - Special issue: Cell polarity and planar cell polarity proteins. PMID- 29432958 TI - Implementation of guidelines for early peanut introduction at a pediatric academic center. PMID- 29432959 TI - Impact of Adverse Event Solicitation on the Safety Profile of SQ House Dust Mite Sublingual Immunotherapy Tablet. AB - BACKGROUND: It has been recommended that sublingual immunotherapy (SLIT) safety be assessed using solicited adverse event (AE) collection methods. OBJECTIVES: The objectives of this study were to describe the impact on the safety profile of SQ house dust mite (HDM) SLIT-tablet (12 SQ-HDM dose) when prespecified local application site reactions were solicited versus unsolicited, and discuss ramifications of AE solicitation. METHODS: Subjects were randomized to daily 12 SQ-HDM or placebo for up to 52 weeks in 4 double-blinded, multicenter trials. In one trial (NCT01700192; N = 1272), subjects documented daily the presence or absence of 15 World Allergy Organization-defined local application site reactions using a structured questionnaire of closed-ended questions (solicited AEs). Subjects in the other trials were not asked about specific AEs (unsolicited AEs), and AE data were pooled (N = 1287). Analysis was limited to adults aged 18 to 65 years. RESULTS: Whether AEs were solicited or unsolicited, the most common AEs leading to study discontinuation with 12 SQ-HDM were throat irritation and oral pruritus. Approximately 95% of treatment-related AEs were mild to moderate. Placebo-subtracted frequencies of local application site reactions associated with 12 SQ-HDM were higher when solicited versus unsolicited (ie, throat irritation, 46% vs 13%, respectively; oral pruritus, 47% vs 17%; ear pruritus, 40% vs 4%; mouth swelling, 8% vs 2%; tongue ulceration, 10% vs 0%; mouth ulceration, 7% vs <1%). CONCLUSIONS: Qualitatively, the safety profile of 12 SQ HDM was similar when AEs were solicited versus unsolicited; hence, solicitation did not alter the safety profile. Higher observed frequencies of local application site reactions with AE solicitation may be partly due to suggestive reporting bias, as observed in placebo-treated subjects. PMID- 29432957 TI - Modulation of toll-like receptor signaling by antimicrobial peptides. AB - Antimicrobial peptides (AMPs) are typically thought of as molecular hole punchers that directly kill pathogens by membrane permeation. However, recent work has shown that AMPs are pleiotropic, multifunctional molecules that can strongly modulate immune responses. In this review, we provide a historical overview of the immunomodulatory properties of natural and synthetic antimicrobial peptides, with a special focus on human cathelicidin and defensins. We also summarize the various mechanisms of AMP immune modulation and outline key structural rules underlying the recently-discovered phenomenon of AMP-mediated Toll-like receptor (TLR) signaling. In particular, we describe several complementary studies demonstrating how AMPs self-assemble with nucleic acids to form nanocrystalline complexes that amplify TLR-mediated inflammation. In a broader scope, we discuss how this new conceptual framework allows for the prediction of immunomodulatory behavior in AMPs, how the discovery of hidden antimicrobial activity in known immune signaling proteins can inform these predictions, and how these findings reshape our understanding of AMPs in normal host defense and autoimmune disease. PMID- 29432960 TI - Use of ICS/LABA Combinations or LAMA Is Associated with a Lower Risk of Acute Exacerbation in Patients with Coexistent COPD and Asthma. AB - BACKGROUND: Based on current guidelines, more research is urgently needed to guide appropriate treatment for patients with asthma-chronic obstructive pulmonary disease (COPD) overlap. OBJECTIVE: The objective of this study was to investigate medication effects on acute exacerbation in patients with coexistent COPD and asthma. METHODS: Using Taiwan's National Health Insurance Research Database, we conducted a nationwide population-based study to evaluate medication effects in patients with COPD and asthma. Patients diagnosed with both asthma and COPD between 1997 and 2012 were enrolled as the COPD + asthma cohort. The primary endpoint was acute exacerbation. The definitions of COPD and asthma were validated. The validation study confirmed the accuracy of definitions of COPD (86.2% sensitivity) and asthma (92.0% sensitivity). RESULTS: The study included 251,398 patients with COPD + asthma and 514,522 patients with COPD alone, with a mean follow-up period of 9.85 years. After adjustment, hazard ratios (HRs) for long-acting muscarinic antagonist (LAMA) and inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) combinations were lower (time-dependent model, 1 year: LAMA, HR 0.51, 95% confidence interval [CI] 0.49-0.54; ICS/LABA combinations, HR 0.61, 95% CI 0.60-0.62; all P < .0001) than were those for LABAs or ICSs in patients with COPD and asthma. CONCLUSIONS: The use of LAMA or ICS/LABA combinations was associated with a lower risk of acute exacerbation in patients with COPD and asthma in this study. PMID- 29432961 TI - Conjunctivitis occurring in atopic dermatitis patients treated with dupilumab clinical characteristics and treatment. PMID- 29432962 TI - Application of a new vitamin D blood test on the Emirati population. AB - Research shows that immunoassay techniques are not the best choice for the estimation of vitamin D in human blood samples. The main reasons are that some immunoassays are not able to distinguish between 25-OHD3 and 25-OHD2 vitamin D metabolites. Furthermore, immunoassays cannot differentiate between 25OHD and inactive epimers of vitamin D. Vitamin D epimers and isobars have been known to overlap with the 25OHD signals and give false positives when tested. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) can differentiate between 25OHD3 and 25OHD2. Separating epimers and isobars (which have the same molecular weight) from vitamin D is achieved through chromatographic separation from actual 25OHD peaks, although this could also cause inaccuracies in vitamin D measurements. The main aim of this study was to develop and validate an improved LC-MS/MS method (using a Shimadzu 8060 system) that could accurately detect and quantitate up to 10 different metabolites of vitamin D, as well as differentiate the epimers and isobars. The secondary aim was to apply the developed LC-MS/MS method for the accurate measurement of blood vitamin D levels in the Emirati population. The Shimadzu 8060 system was run using positive ion electrospray ionization (ESI) in Dynamic Multiple Reaction Monitoring (DMRM) mode for quantification. The method involved blood sample collection from 80 Emirati volunteers, followed by serum extraction and liquid-liquid extraction. The chromatography column used for the analysis was an Ascentis Express F5. Precursor and product ions were detected using a Shimadzu 8060 LC-MS/MS system, and 10 metabolites of vitamin D were detected and quantified, including epimers and isobars. The method validation showed good sensitivity, recovery, linearity, precision, specificity, and accuracy. Furthermore, the data showed that vitamin D epimer 3-epi-25OHD and isobar 7-alpha-hydroxy-4-cholesten-3-one (7alphaC4) accounted for a significant portion of vitamin D results in the Emirati population. We report a more reliable, reproducible, and robust LC-MS/MS method for the accurate detection of 25OHD (vitamin D) in the Emirati population. The method has the capacity to detect and separate 10 metabolites of vitamin D as well as separate 25OHD from co-eluting epimers and isobars. The method has also been successfully implemented in gauging vitamin D deficiency in the Emirati population. Thus, this improved LC-MS/MS method could prove very useful in accurately estimating the levels of vitamin D in the Emirati population and in further clinical studies. PMID- 29432963 TI - Efficacy of different modes of vitamin D supplementation strategies in Saudi adolescents. AB - : Vitamin D deficiency is rampant in the Middle East, even in children and adolescents. This study was designed to investigate the effects of different vitamin D repletion strategies commonly used on serum vitamin D levels of Saudi adolescents. STUDY DESIGN: A 6-month multi-center, controlled, clinical study, involving 34 schools in the central region of Riyadh, Saudi Arabia. Different strategies of vitamin D supplementation were tested (200 ml fortified milk of different brands or vitamin D tablet (1,000IU). Anthropometrics were taken and fasting blood samples withdrawn at baseline and after intervention for the quantification of serum glucose, lipid profile and 25(OH) vitamin D. A significant increase in 25(OH)D level was observed in subjects supplemented with vitamin D tablet, milk brand 2 and milk brand 4, whereas subjects supplied with fortified milk brands 1 and 3 respectively, exhibited a significant decrease in 25(OH)D levels. Analysis of covariance showed that after adjusting for baseline 25(OH)D, age, gender and BMI, the mean 25(OH)D levels of children who were taking vitamin D tablet (9.1 +/- 0.8 nmol/l) and milk brand 4 were significantly higher (7.3 +/- 1.1 nmol/l) than children taking milk brand 2 (1.6 +/- 1.0 nmol/l). Subjects supplied with milk brands 1 and 2 exhibited a significant increase in total cholesterol level, while it dropped significantly in subjects taking milk brand 3, while no changes were observed in other groups. Different strategies in vitamin D supplementation used in this clinical study elicited varying degrees of improvement in serum 25(OH)D level. The observed outcomes were dependent on the strategy and gender in the Saudi adolescent population, with oral tablet supplementation being favored in boys. PMID- 29432964 TI - Partially methylated galactans containing different proportions of 3-O-methyl galactose from Pleurotus citrinopileatus. AB - Pleurotus citrinopileatus, popularly known as "golden oyster mushroom" have medicinal properties, which are attributed mainly to the presence of bioactive polysaccharides. In this work, two partially 3-O-methylated galactans were isolated from the fruiting bodies of this fungus, via successive aqueous extraction, followed by fractionation by freeze-thawing, and precipitation of soluble material with Fehling solution. The structural assignments were carried out using mono- and bidimensional NMR spectroscopy, monosaccharide composition, and methylation analyses. The polysaccharides were characterized as linear, partially 3-O-methylated (1 -> 6)-linked alpha-galactopyranans, containing only Gal and 3-O-Me-Gal, in 2:1 and 1:1 molar ratios, with molar masses of 37.6 * 103 g/mol and 28.5 * 103 g/mol, respectively. Similar structures have been described for other Pleurotus spp., but showing a lower content of 3-O-Me-Gal. PMID- 29432966 TI - Rapid oral desensitization protocol to abiraterone acetate. PMID- 29432965 TI - Repeatability of nasal allergen challenge results: Further validation of the allergic rhinitis clinical investigator collaborative protocols. AB - BACKGROUND: Nasal allergen challenge (NAC) models have been used to study allergic rhinitis and new therapies. Symptoms and biological samples can be evaluated at time points after allergen exposure. OBJECTIVE: To verify protocol repeatability and adequate interval between allergen exposures. METHODS: Ten ragweed allergic participants were exposed to incrementally increasing dosages of ragweed allergen intranasally until they achieved a total nasal symptom score (TNSS) of 8 of 12 and a peak nasal inspiratory flow (PNIF) of 50% reduction or more from baseline. Three weeks later, participants were challenged with a cumulative dose equal to the sum of all the allergen doses received at screening. TNSS and PNIF were recorded at regular intervals, including a 24-hour assessment. A subsequent visit was conducted after a further 3 weeks. Nasal secretion samples were collected for cytokine and eosinophil quantification. RESULTS: Nine participants completed all visits. TNSS and PNIF responses followed previous patterns, with an initial peak at 30 minutes followed by a gradual decline. Most participants reported similar patterns at both NAC visits, although some did not demonstrate the same phenotype at both visits. Some experienced a secondary symptom increase 24 hours after NAC. Eosinophil and cytokine sections followed a similar pattern at both NAC visits. CONCLUSION: NAC is an adequate method for modeling AR in humans, demonstrating appropriate repeatability of symptoms, nasal mucosal eosinophil, and cytokines. The 24-hour time point, previously not studied in our model, may be beneficial in evaluation of long-acting medications. This three-week interval NAC model will be beneficial for studies in which before and after treatment comparisons are desired. PMID- 29432967 TI - Lack of effect of Timothy grass pollen sublingual immunotherapy tablet on birch pollen-induced allergic rhinoconjunctivitis in an environmental exposure unit. AB - BACKGROUND: Timothy grass pollen allergen extract tablets (Grastek) are standardized sublingual immunotherapy tablets (SLIT-T) approved for the treatment of grass pollen-induced allergic rhinitis (AR) and conjunctivitis. Many grass allergic patients are also cosensitized to birch pollen. Whether Timothy grass SLIT-T can confer symptomatic benefits for birch pollen-induced AR symptoms is unknown. OBJECTIVE: To evaluate the treatment effect of Timothy grass SLIT-T for birch pollen-induced AR in participants sensitized to both grass and birch pollen using an environmental exposure unit (EEU). METHODS: This study was a phase 4, randomized, double-blind, placebo-controlled, parallel-group study that enrolled participants aged 18 to 65 years allergic to both timothy grass and birch pollen. After a baseline EEU birch pollen challenge, in which a minimum total nasal symptom score (TNSS) of 6 of 12 was required for enrollment, participants were randomized to receive Timothy grass SLIT-T or placebo taken once daily for 4 months. No confirmatory grass pollen challenge was performed. The primary end point was the change in TNSS averaged from assessments from hours 2 to 5 during the posttreatment birch pollen challenge compared with baseline. The secondary and exploratory end points included temporally identical changes in total ocular symptom score (TOSS), total rhinoconjunctivitis symptom score (TRSS), and individual symptom scores. RESULTS: The difference in TNSS reduction after 4 months of therapy between the Timothy grass SLIT-T and placebo group was not significant (P = .83). Reductions in TOSS (P = .19) and TRSS (P = .67) were also comparable between groups. Findings between groups for individual symptom scores were similar (all P > .40), except for watery eyes, in which symptom reduction was slightly better in the placebo arm (P = .01). Timothy grass SLIT-T was well tolerated, and no serious adverse effects occurred. CONCLUSION: A bystander effect of grass SLIT-T on birch pollen-induced AR symptoms was not detected. Symptomatic benefits of grass SLIT-T are likely allergen specific. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02394600. PMID- 29432968 TI - Learnings from a pragmatic pilot trial of text messaging for high-risk adolescents with asthma. PMID- 29432969 TI - Age-related prevalence of chronic rhinosinusitis and nasal polyps and their relationships with asthma onset. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a major disease condition with high morbidity and can influence lower airway disease status in adults. However, its associations with adult asthma onset and activity have not been examined in detail in a general adult population. OBJECTIVE: To investigate relationships between CRS with nasal polyps (CRSwNP) and asthma characteristics. METHODS: A cross-sectional data set of 17,506 adult participants (>=18 years old) in the Korean National Health and Nutrition Examination Survey from 2010 through 2012 was analyzed. CRS was defined using structured questionnaires according to the international guideline, and presence of nasal polyps was objectively assessed using nasal endoscopy. Presence of asthma and its onset and current activity were assessed using structured questionnaires. RESULTS: CRS was significantly related to asthma, but the relationships were distinct by CRS and asthma status. CRSwNP was significantly associated with adult-onset asthma (onset after 18 years of age) or late-onset asthma (onset after 40 years of age), whereas CRS without nasal polyps was related to childhood-onset asthma (onset before 18 years) or early-onset asthma (onset before 40 years) in adults. The 2 CRS subgroups showed significant associations with current asthma but not with past asthma. However, the comorbid asthma rate was lower than 10% among subjects with CRS. CONCLUSION: This study found distinct age-related patterns of CRSwNP and asthma and demonstrated their significant associations in a general population. However, the low prevalence of asthma in CRSwNP is in sharp contrast to findings in Western populations, which warrants further investigation for ethnic or regional differences in relationships between CRSwNP and asthma. PMID- 29432970 TI - High tie versus low tie of the inferior mesenteric artery in colorectal cancer: A meta-analysis. AB - BACKGROUND: Colorectal cancer surgery includes "high tie" and "low tie"of the inferior mesenteric artery(IMA). However, different ligation level is closely related to the blood supply of anastomosis, which may increase the leakage rate, and it is unclear which technique confers a lower anastomotic leakage rate(AL) and survival advantage. OBJECTIVE: To compare the effectiveness and impact of inferior mesenteric artery (IMA) high ligation versus IMA low ligation on anastomotic leakage, lymph nodes yield rates and 5-year survival. METHODS: A list of these studies, published in English from 1990 to 2017, was obtained independently by two reviewers from databases such as PubMed, Medline, ScienceDirect and Web of Science. Anastomotic leakage rate, the yield of lymph nodes and 5-year survival were compared using Review Manager 5.3. RESULTS: There was no significant difference in anastomotic leakage, number of lymph nodes retrieved and 5-year survival rate for both techniques. CONCLUSIONS: Neither the high tie nor the low tie strategy has an evidence in terms of anastomotic leakage rate, harvested lymph nodes, and the 5-year survival rate. Further RCT is needed. PMID- 29432971 TI - Assessing the costs of disposable and reusable supplies wasted during surgeries. AB - BACKGROUND: The management of disposable and reusable supplies might have an impact on the cost efficiency of the Operating Room (OR). This study aimed to evaluate the cost and reasons for wasted supplies in the OR during surgical procedures. METHODS: We conducted an observational and prospective study in a French university hospital. We assessed the cost of wasted supplies in the OR (defined by opened unused devices), the reasons for the wastage, and the circulator retrievals. At the end, we assessed the perception of surgeons and nurses relative to the supply wastage. RESULTS: Fifty routine procedures and five non-scheduled procedures were observed in digestive (n = 20), urologic (n = 20) and gynecologic surgery (n = 15). The median cost [IQR] of open unused devices was ?4.1 [0.5; 10.5] per procedure. Wasted supplies represented up to 20.1% of the total cost allocated to surgical supplies. Considering the 8000 surgical procedures performed in these three surgery departments, the potential annual cost savings were 100 000?. The most common reason of wastage was an anticipation of the surgeon's needs. The circulating nurse spent up to 26.3% of operative time outside of the OR, mainly attending to an additional demand from the surgeon (30%). Most of the survey respondents (68%) agreed that knowing supply prices would change their behavior. CONCLUSIONS: This study showed the OR is a major source of wasted hospital expenditure and an area wherein an intervention would have a significant impact. Reducing wasted supplies could improve the cost efficiency of the OR and also decrease its ecological impact. PMID- 29432972 TI - The effect of lymphadenectomy in advanced ovarian cancer according to residual tumor status: A population-based study. AB - BACKGROUND: We investigated the effect of lymphadenectomy on the survival outcomes of patients with advanced epithelial ovarian cancer in the Surveillance, Epidemiology, and End Results database according to residual disease status. METHODS: We evaluated 3048 patients with International Federation of Gynecology and Obstetrics stage-IIIC-IV epithelial ovarian cancer. We assessed the effect of lymphadenectomy stratified by residual disease size on cause-specific survival (CSS). RESULTS: A total of 1904 (62.5%) patients received lymphadenectomy, and 1355 (71.2%) patients had nodal metastases. Lymph-node status had no significant association with residual tumor size in the lymphadenectomy group. In multivariate analysis, lymphadenectomy was associated with a significantly better CSS and was an independent prognostic factor for CSS. Patients with >10 lymph nodes removed had better CSS compared with non-lymphadenectomy and 1-10 lymph nodes removed groups. Lymphadenectomy was associated with a significantly better CSS in patients with no gross residual tumor, but not in patients with residual tumor <=1 cm or >1 cm. CONCLUSIONS: Lymphadenectomy is significantly associated with a better survival outcome in patients advanced ovarian cancer, but its positive effect diminishes as residual tumor size increases. PMID- 29432973 TI - Using dual capture/recapture studies to estimate the population size of persons who inject drugs (PWID) in the city of Hai Phong, Vietnam. AB - BACKGROUND: Good estimates of key population sizes are critical for appropriating resources to prevent HIV infection. We conducted two capture/recapture studies to estimate the number of PWID currently in Hai Phong, Vietnam. METHODS: A 2014 respondent-driven sampling (RDS) survey served as one capture, and distribution of cigarette lighters at drug use "hotspots" in 2016 served as another "capture." A 2016 survey using RDS, conducted 1 week after lighter distribution, served as "recapture" for both captures. Recaptured participants in the two surveys were identified with a computerized fingerprint reader. Recaptured participants from the lighter distribution were asked to show their lighters. RESULTS: 1385 participants were included in the "recapture" survey. They were 94% male and had a median age of 39. All (100%) injected heroin, and HIV prevalence was 30%. 144 of the 603 participants in the 2014 survey and 152 of the 600 PWID who had received lighters were "recaptured" in the 2016 survey. After adjusting for police suppression of drug use hotspots and conducting sensitivity analyses, our best estimate of the population size from the lighter recapture was 4617 (95% CI: 4090-5143), and our best estimate from the 2014 survey recapture was 5220 (95% CI: 4568-5872). A combined best estimate of the PWID population in Hai Phong is 5000, range 4000-6000. CONCLUSIONS: The capture/recapture studies produced consistent estimates. Adding a lighter/token distribution to planned RDS surveys may provide an inexpensive method for estimating PWID population size. Analyses of the estimates should include contextual information about the local drug scene. PMID- 29432974 TI - Similarities and changes between 15- and 24-year survival and retention rates of patients in a large medical-affiliated methadone maintenance treatment (MMT) center. AB - BACKGROUND: Environmental and social trends and patients' characteristics may affect predictors for methadone maintenance treatment (MMT) outcome. METHODS: We have expanded our previous study of predictors for MMT outcome (from 619 to 890 patients) and the study period (from 15 to 24 years). Survival and retention in MMT since admission to the MMT clinic (6/1993-6/2016) and until death or study closure (6/2017) were compiled and analyzed. RESULTS: Of 890 patients ever admitted (10,146.9 person-years (py)), 237 passed away (116 while in MMT). The mortality rate did not differ between those who stayed or left (2.6 vs. 2.1 per 100 py, p = 0.1), but it was lower among those who stayed >=1 year during any admission (2.1 vs. 3.3 per 100 py, respectively, p = 0.004). Age <40 years, no hepatitis C or B, no HIV, and no benzodiazepine abuse after one year predicted longer survival (multivariate analyses). No opiate or benzodiazepine abuse after one year, methadone dose >=100 mg/d, no DSM-IV-TR Axis II diagnosis only, and no direct hospital referral predicted longer retention. Cocaine abuse predicted poor retention and survival among 271 patients admitted during the extended part of the study period. CONCLUSIONS: Predictors for retention (associated with MMT outcome) and mortality (associated with pre-treatment comorbidity) after 24 years were similar to those after 15 years. Cocaine abuse as a predictor of both poor retention and poor survival in the later period may reflect the escalating trend for cocaine abuse and should be studied if related to other unmonitored substances. PMID- 29432975 TI - Sequencing and analysis of the whole genome of Indian Gujarati male. AB - The article presents the analysis of whole genome sequence of a Gujarati Indian individual (IHGP01) that was sequenced at 23.05* coverage with a total of 74.93 Gb of sequence data generated using Illumina HiSeq 2000 platform. Variant analysis revealed over 3.9 million single nucleotide variants (SNVs) and about 393,000 small insertions and deletions (InDels) including novel variants. The known variants were analyzed for their health and disease relevance and pharmacogenomic profile. Mitochondrial and Y-chromosome haplogroup analysis clearly indicated arrival on the continent not more than 20,000-25,000 years ago, following the route out of Africa to central Europe, then into Asian continent and subsequent migration to West part of the Indian subcontinent. The current research has added 141,000 novel genetic variations to the human DNA database. Functional analysis and validation of these novel variations and revelation of their role in health and disease will add a newer dimension to understand people of this subcontinent. PMID- 29432976 TI - Epigenomic and genomic landscape of Drosophila melanogaster heterochromatic genes. AB - Heterochromatin is associated with transcriptional repression. In contrast, several genes in the pericentromeric regions of Drosophila melanogaster are dependent on this heterochromatic environment for their expression. Here we present a comprehensive analysis of the epigenetic landscape of heterochromatic genes across all the developmental stages of Drosophila using the available histone modification and expression data from modENCODE. We find that heterochromatic genes exhibit combinations of active and inactive histone marks that correspond to their level of expression during development. We also show that Nuclear Matrix Associated Regions (MARs) are prominently present in the intergenic regions of heterochromatic genes during embryonic stages suggesting their plausible role in pericentromeric genome organization. Taken together, our meta-analysis of the various genomic datasets suggest that the epigenomic and genomic landscape of the heterochromatic genes are distinct which could be contributing to their unusual regulatory features as opposed to the surrounding heterochromatin, which is repressive in nature. PMID- 29432977 TI - Unknown facet of next gen DNA sequencing history. PMID- 29432978 TI - Classification of pathogenic microbes using a minimal set of single nucleotide polymorphisms derived from whole genome sequences. AB - In a context specific manner, Intra-species genomic variation plays an important role in phenotypic diversity observed among pathogenic microbes. Efficient classification of these pathogens is important for diagnosis and treatment of several infectious diseases. NGS technologies have provided access to wealth of data that can be utilized to discover important markers for pathogen classification. In this paper, we described three different approaches (Jensen Shannon divergence, random forest and Shewhart control chart) for identification of a minimal set of SNPs that can be used for classification of organisms. These methods are generic and can be implemented for analysis of any organism. We have shown usefulness of these approaches for analysis of Mycobacterium tuberculosis and Escherichia coli isolates. We were able to identify a minimal set of 18 SNPs that can be used as molecular markers for phylogroup based classification and 8 SNPs for pathogroup based classification of E. coli. PMID- 29432979 TI - A novel multi-atlas strategy with dense deformation field reconstruction for abdominal and thoracic multi-organ segmentation from computed tomography. AB - Anatomical evaluation of multiple abdominal and thoracic organs is generally performed with computed tomography images. Owing to the large field-of-view of these images, automatic segmentation strategies are typically required, facilitating the clinical evaluation. Multi-atlas segmentation (MAS) strategies have been widely used with this process, requiring multiple alignments between the target image and the set of known datasets, and subsequently fusing the alignment results to obtain the final segmentation. Nonetheless, current MAS strategies apply a global alignment of a deformable object, per organ, subdividing the segmentation process into multiple ones and losing the spatial information among nearby organs. This paper presents a novel MAS approach. First, a coarse-to-fine method with multiple global alignments (one per organ) is used. To make the method spatially coherent, these individual organs' global transformations are then fused in one using a dense deformation field reconstruction strategy. Second, from the candidate segmentations obtained, the final segmentation is estimated through an organ-based label fusion approach. The proposed method is evaluated and compared against a conventional MAS strategy through the segmentation of twelve abdominal and thoracic organs from the VISCERAL Anatomy benchmark. Average Dice coefficients for the liver, spleen, lungs and kidneys are all higher than 90%, are around 85% for the aorta, trachea and sternum and 70% for the pancreas, urinary bladder and gallbladder. The novel MAS strategy, with dense deformation field reconstruction, shows competitive results against other state-of-the-art methods, proving its added value for the segmentation of abdominal and thoracic organs, mainly for highly variable organs. PMID- 29432980 TI - Impact of timeliness of adjuvant chemotherapy and radiotherapy on the outcomes of breast cancer; a pooled analysis of three clinical trials. AB - OBJECTIVE: To assess the impact of delay in initiation of adjuvant chemotherapy and/or radiotherapy on the outcomes of breast cancer patients referred for adjuvant treatment. METHODS: This is a pooled analysis of patient-level data of 3390 breast cancer patients referred for adjuvant chemotherapy in three clinical trials. Overall and relapse-free survivals were assessed according to "surgery to chemotherapy interval" through Kaplan-Meier analysis. Likewise, among patients who received adjuvant radiotherapy, relapse-free survival was assessed according to "surgery to radiotherapy interval" through Kaplan-Meier analysis. Univariate and Multivariate analysis of factors affecting overall and relapse-free survival was then conducted through Cox regression analysis. RESULTS: Kaplan-Meier analysis of overall survival according to surgery to chemotherapy interval ( 6 weeks) was conducted. When stratified by the hormone receptor status, the longer interval was associated with worse overall survival in hormone receptor negative patients (P = 0.006); while it was not associated with overall survival difference in hormone receptor-positive patients (P = 0.268). In multivariate Cox regression analysis, the test of interaction between "surgery to chemotherapy interval" and hormone receptor status was significant (P = 0.015). Moreover, when the multivariate analysis was restricted to hormone receptor-negative patients, longer surgery to chemotherapy interval was associated with worse overall survival among this subset of patients (P = 0.004). On the other hand, in multivariate analysis of factors affecting relapse-free survival, surgery to radiotherapy interval did not impact relapse-free survival (P = 0.439). CONCLUSION: Among hormone receptor-negative patients, delaying chemotherapy initiation beyond 6 weeks (after surgery) is associated with worse patient outcomes. Moreover, delaying radiotherapy initiation beyond surgery does not compromise outcomes in patients receiving long course adjuvant chemotherapy. PMID- 29432981 TI - Different response of human mortality to extreme temperatures (MoET) between rural and urban areas: A multi-scale study across China. AB - BACKGROUND: The environmental variation in mortality due to extreme temperatures has been well-documented by many studies. Mortality to extreme temperatures (MoET) was recognized to vary geographically, either by countries within a region or by areas within a country. However, so far, little attention has been paid to rural residents, with even lesser attention on the potential rural-urban differences. The aim of our study was to offer a quite comprehensive analysis on the differences in temperature-mortality relationship between rural and urban areas across China. METHOD: A distributed lag nonlinear model was built to describe the temperature-mortality relationship, based on the mortality data and meteorological variable of 75 communities in China from 2007 to 2012. Subsequently, a meta-analysis was applied to compare the differences in the temperature-mortality relationship between rural and urban areas at various levels. RESULTS: Distinct responses regarding MoET between rural and urban areas were observed at different spatial scales. At regional level, more U-shaped curves were observed for temperature-mortality relationships in urban areas, while more J-shaped curves were observed in rural areas. At national scale, we found that the cold effect was stronger in rural areas (RR: rural 1.69 vs. urban 1.51), while heat effect was stronger in urban areas (RR: rural 1.01 vs. urban 1.12). Moreover, the modifying influence of air pollution on temperature mortality relationship was found to be very limited. CONCLUSION: The difference in response of MoET between rural and urban areas was noticeable, cold effect is more significant in China both in rural and urban areas. Additionally, urban areas in southern China and rural areas in northern China suffered more from extreme temperature events. Our findings suggest that differences in rural-urban responses to MoET should be taken seriously when intervention measures for reducing the risks to residents' health were adopted. PMID- 29432982 TI - Deep phenotyping of patients with Tuberous Sclerosis Complex and no mutation identified in TSC1 and TSC2. AB - Tuberous Sclerosis Complex (TSC) is a multisystemic condition caused by mutations in TSC1 or TSC2, but a pathogenic variant is not identified in up to 10% of the patients. The aim of this study was to delineate the phenotype of pediatric and adult patients with a definite clinical diagnosis of TSC and no mutation identified in TSC1 or TSC2. We collected molecular and clinical data of 240 patients with TSC, assessing over 50 variables. We compared the phenotype of the homogeneous group of individuals with No Mutation Identified (NMI) with that of TSC patients with a TSC1 and TSC2 pathogenic variant. 9.17% of individuals were classified as NMI. They were diagnosed at an older age (p = 0.001), had more frequent normal cognition (p < 0.001) and less frequent epilepsy (p = 0.010), subependymal nodules (p = 0.022) and giant cell astrocytomas (p = 0.008) than patients with TSC2 pathogenic variants. NMI individuals showed more frequent bilateral and larger renal angiomyolipomas (p = 0.001; p = 0.003) and pulmonary involvement (trend) than patients with TSC1 pathogenic variants. Only one NMI individual had intellectual disability. None presented with a subependymal giant cell astrocytoma. Other medical problems not typical of TSC were found in 42.86%, without a recurrent pattern of abnormalities. Other TSC-associated neuropsychiatric disorders and drug-resistance in epilepsy were equally frequent in the three groups. This study provides a systematic clinical characterization of patients with TSC and facilitates the delineation of a distinctive phenotype indicative of NMI patients, with important implications for surveillance. PMID- 29432983 TI - In vitro methods for the evaluation of antimicrobial surface designs. AB - : Bacterial adhesion and subsequent biofilm formation on biomedical implants and devices are a major cause of their failure. As systemic antibiotic treatment is often ineffective, there is an urgent need for antimicrobial biomaterials and coatings. The term "antimicrobial" can encompass different mechanisms of action (here termed "antimicrobial surface designs"), such as antimicrobial-releasing, contact-killing or non-adhesivity. Biomaterials equipped with antimicrobial surface designs based on different mechanisms of action require different in vitro evaluation methods. Available industrial standard evaluation tests do not address the specific mechanisms of different antimicrobial surface designs and have therefore been modified over the past years, adding to the myriad of methods available in the literature to evaluate antimicrobial surface designs. The aim of this review is to categorize fourteen presently available methods including industrial standard tests for the in vitro evaluation of antimicrobial surface designs according to their suitability with respect to their antimicrobial mechanism of action. There is no single method or industrial test that allows to distinguish antimicrobial designs according to all three mechanisms identified here. However, critical consideration of each method clearly relates the different methods to a specific mechanism of antimicrobial action. It is anticipated that use of the provided table with the fourteen methods will avoid the use of wrong methods for evaluating new antimicrobial designs and therewith facilitate translation of novel antimicrobial biomaterials and coatings to clinical use. The need for more and better updated industrial standard tests is emphasized. STATEMENT OF SIGNIFICANCE: European COST-action TD1305, IPROMEDAI aims to provide better understanding of mechanisms of antimicrobial surface designs of biomaterial implants and devices. Current industrial evaluation standard tests do not sufficiently account for different, advanced antimicrobial surface designs, yet are urgently needed to obtain convincing in vitro data for approval of animal experiments and clinical trials. This review aims to provide an innovative and clear guide to choose appropriate evaluation methods for three distinctly different mechanisms of antimicrobial design: (1) antimicrobial releasing, (2) contact-killing and (3) non-adhesivity. Use of antimicrobial evaluation methods and definition of industrial standard tests, tailored toward the antimicrobial mechanism of the design, as identified here, fulfill a missing link in the translation of novel antimicrobial surface designs to clinical use. PMID- 29432984 TI - High strength, biodegradable and cytocompatible alpha tricalcium phosphate-iron composites for temporal reduction of bone fractures. AB - : In this work alpha tricalcium phosphate (alpha-TCP)/iron (Fe) composites were developed as a new family of biodegradable, load-bearing and cytocompatible materials. The composites with composition from pure ceramic to pure metallic samples were consolidated by pulsed electric current assisted sintering to minimise processing time and temperature while improving their mechanical performance. The mechanical strength of the composites was increased and controlled with the Fe content, passing from brittle to ductile failure. In particular, the addition of 25 vol% of Fe produced a ceramic matrix composite with elastic modulus much closer to cortical bone than that of titanium or biodegradable magnesium alloys and specific compressive strength above that of stainless steel, chromium-cobalt alloys and pure titanium, currently used in clinic for internal fracture fixation. All the composites studied exhibited higher degradation rate than their individual components, presenting values around 200 MUm/year, but also their compressive strength did not show a significant reduction in the period required for bone fracture consolidation. Composites showed preferential degradation of alpha-TCP areas rather than beta TCP areas, suggesting that alpha-TCP can produce composites with higher degradation rate. The composites were cytocompatible both in indirect and direct contact with bone cells. Osteoblast-like cells attached and spread on the surface of the composites, presenting proliferation rate similar to cells on tissue culture-grade polystyrene and they showed alkaline phosphatase activity. Therefore, this new family of composites is a potential alternative to produce implants for temporal reduction of bone fractures. STATEMENT OF SIGNIFICANCE: Biodegradable alpha-tricalcium phosphate/iron (alpha-TCP/Fe) composites are promising candidates for the fabrication of temporal osteosynthesis devices. Similar to biodegradable metals, these composites can avoid implant removal after bone fracture healing, particularly in young patients. In this work, alpha-TCP/Fe composites are studied for the first time in a wide range of compositions, showing not only higher degradation rate in vitro than pure components, but also good cytocompatibility and mechanical properties controllable with the Fe content. Ceramic matrix composites show high specific strength and low elastic modulus, thus better fulfilling the requirements for bone fractures fixation. A significant advance over previous works on the topic is the use of pulsed electric current assisted sintering together with alpha-TCP, convenient to improve the mechanical performance and degradation rate, respectively. PMID- 29432985 TI - A relatively mild phenotype associated with mutation of SCN8A. AB - Mutations in SCN8A gene have been described in relation to infantile onset epilepsy with movement disorders and developmental delay. Recently various authors have reported patients carrying autosomal dominant heterozygous SCN8A mutations and a milder phenotype expression. We discuss the case of a 6-year-old girl with a positive family history for epilepsy, early benign focal epilepsy, well controlled by Carbamazepine, upper limb tremor since birth, ataxia, slight motor delay and normal cognitive development. Neuroradiological study is normal, waking EEGs are normal, while epileptiform abnormalities on the vertex appear during sleep. The girl carries a de novo mutation of the SCN8A gene with nucleotide substitution of c.3943G > A (p.Val 1315 Met), located in the domain III S4/S5 intracellular linker. In literature two other cases with the same mutation have been reported, both patients have an epileptic encephalopathy. Our patient's milder phenotype could be caused by a modifier effect, possibly a mutation in another gene or a mosaicism. The detailed description of our case should contribute to enlarging the description of the clinical features of SCN8A mutations and to recommending the deepening of genetic investigations to. PMID- 29432986 TI - Premenstrual dysphoric disorder and suicide attempts as a correlation among women in reproductive age. AB - AIM: Women likely attempt suicide more than men and sex hormones or menstrual cycle may be associated with female suicide attempts. There are debates regarding the correlation of premenstrual dysphoric disorder (PMDD) and suicidal behaviors. The objective of this study was to examine if PMDD was associated with suicidal attempts as sex hormones are contributed in its pathogenesis. METHODS: As a case control study 120 fertile woman with regular menstrual cycles attempting suicide and admitted to a general hospital were compared with a matched control group of 120 women selected among those accompanying other patients in other wards. Psychiatric interview based on DSM-5 criteria was conducted for diagnosing PMDD. RESULTS: There was a significantly higher frequency of PMDD in suicide attempters than in the controls (P = 0.001); while no remarkable difference was seen in frequency of premenstrual syndrome (PMS) between the two groups (P = 0.294) and attempting suicide was not related to the menstrual cycle (P = 0.52). CONCLUSIONS: This study suggests that PMDD may be associated with suicidal attempts, however it is not related to menstrual cycle. No relationship was found between PMS and suicidal acts. PMID- 29432987 TI - 3D printed microchannel networks to direct vascularisation during endochondral bone repair. AB - Bone tissue engineering strategies that recapitulate the developmental process of endochondral ossification offer a promising route to bone repair. Clinical translation of such endochondral tissue engineering strategies will require overcoming a number of challenges, including the engineering of large and often anatomically complex cartilage grafts, as well as the persistence of core regions of avascular cartilage following their implantation into large bone defects. Here 3D printing technology is utilized to develop a versatile and scalable approach to guide vascularisation during endochondral bone repair. First, a sacrificial pluronic ink was used to 3D print interconnected microchannel networks in a mesenchymal stem cell (MSC) laden gelatin-methacryloyl (GelMA) hydrogel. These constructs (with and without microchannels) were next chondrogenically primed in vitro and then implanted into critically sized femoral bone defects in rats. The solid and microchanneled cartilage templates enhanced bone repair compared to untreated controls, with the solid cartilage templates (without microchannels) supporting the highest levels of total bone formation. However, the inclusion of 3D printed microchannels was found to promote osteoclast/immune cell invasion, hydrogel degradation, and vascularisation following implantation. In addition, the endochondral bone tissue engineering strategy was found to support comparable levels of bone healing to BMP-2 delivery, whilst promoting lower levels of heterotopic bone formation, with the microchanneled templates supporting the lowest levels of heterotopic bone formation. Taken together, these results demonstrate that 3D printed hypertrophic cartilage grafts represent a promising approach for the repair of complex bone fractures, particularly for larger defects where vascularisation will be a key challenge. PMID- 29432989 TI - Transmission and scanning electron microscopic observations on antennal apical pegs in the wasp species Pimplinae (Insecta: Hymenoptera). AB - Pimplinae are parasitoids belonging to the family Ichneumonidae that attack and develops inside hidden host; female wasps evolved a peculiar host recognition strategy, that involves the use of self-produced vibrations which are transmitted through the antennae on the substrate and perceived back as an echo using the leg subgenual organ. In this study we investigated, using both scanning and transmission electron microscopy, the antennal tips of a few Pimplinae. In all the investigated species, the antennal tips present peculiar apical pegs with different shape and number, often defining a flattened sole devoid of other antennal structures, such as sensilla. These pegs are present in both sexes with different number and development, are inserted on the antennal wall through an inflexible socket and present a cuticular shaft with cuticle of different thickness. We never found the presence of sensory neurons or glandular epithelium associated with these pegs. Because of their peculiar morphological features, we hypothesize for the antennal apical pegs a role in the context of host searching behavior (in the case of the female through the vibrational sounding strategy), as well as during mating behavior. PMID- 29432988 TI - Dual-responsive polyplexes with enhanced disassembly and endosomal escape for efficient delivery of siRNA. AB - Despite the extracellular barriers for siRNA delivery have been overcome by utilizing advanced nanoparticle delivery systems, the key intracellular barriers after internalization including efficient disassembly of siRNA and endosomal escape still remains challenging. To address the issues, we developed a unique pH and redox potential-responsive polyplex delivery system based on the copolymer of mPEG-b-PLA-PHis-ssPEI1.8 k, which is composed of a pH-responsive copolymer of PEG-b-PLA-PHis (Mw 5 k) and a branched PEI (Mw1.8 k) linked with redox cleavable disulfide bond. The copolymer showed excellent siRNA complexation and protection abilities against endogenous substances at the relatively low N/P ratio of 6. The siRNA release from the polyplexes (N/P 6) was markedly increased from 13.62% to 58.67% under conditions simulating the endosomal microenvironment. Fluorescence resonance energy transfer (FRET) test also indicated a higher disassembly extent of siRNA from the copolymer. The accelerated siRNA release from the polyplexes was markedly restrained when the N/P ratio was raised above 10 due to the increasing of electrostatic interactions. The efficient endosomal escape of siRNA after internalization was confirmed by confocal microscopy, which was attributed to the cleavaged PEI chains inducing membrane destabilization, the "proton sponge effect" of PHis and PEI as well as the relative small size of after disassembly. The enhanced disassembly and endosomal escape were elucidated as the leading cause for polyplexes (N/P 6) showed more efficient Bcl-2 silencing (85.45%) than those polyplexes with higher N/P ratios (N/P 10 and 15). In vivo results further demonstrated that polyplexes (N/P 6) delivery of siBcl-2 significantly inhibited the MCF-7 breast tumor growth as compared to its counterparts. The incorporation of convertible non-electrical interactions at a balance with electrostatic interactions in complexation siRNA has been demonstrated as an effective strategy to achieve efficient disassembly from stable polyplexes. Moreover, polyplexes equipped with the enhanced disassembly and endosomal escape provides a new potential way to tackle the intracellular delivery bottleneck for siRNA delivery. PMID- 29432990 TI - A new method using a Foley Catheter to locate the diverticulum in laparoscopic repair of uterine cesarean scar defects. AB - OBJECTIVE(S): To introduce a new method using a Foley catheter to locate the diverticulum in laparoscopic repair of uterine cesarean scar defect (CSD), and to evaluate the gynecological outcomes and prognosis of this new procedure. STUDY DESIGN: Twelve patients with abnormal uterine bleeding or future fertility requirements opted for the laparoscopic repair of CSD. Then we present a series of photographic images before and after placement of the Foley catheter, and their clinical data to evaluate this new surgical technique. RESULTS: All operations were completed successfully, and a CSD in the posterior lower uterine segment was first reported in our study. In each case, photographic images confirmed that the location, size and boundary of the CSD, and its relationship with the surrounding organs, were clearly marked after placement of the Foley catheter. Mean operation time was 88.2 min and mean blood loss was 25.4 ml; no complications were observed. Of the 12 patients, 8 cases experienced abnormal uterine bleeding. Following laparoscopic repair, 75% of our cases achieved complete remission while 25% showed significant improvement. CONCLUSION: Laparoscopic repair represents an effective approach for symptomatic women with CSD. The additional use of a Foley catheter is strongly recommended for identifying and locating the diverticulum, and marking its boundary in the laparoscopic repair of uterine CSD. PMID- 29432991 TI - Short-term effects on temporal judgement: Sequential drivers of interval bisection and reproduction. AB - Our prior experiences provide the background with which we judge subsequent events. In the time perception literature one common finding is that providing participants with a higher percentage of a particular interval can skew judgment; intervals will appear longer if the distribution of intervals contains more short experiences. However, changing the distribution of intervals that participants witness also changes the short-term, interval-to-interval, sequence that participants experience. In the experiment presented here, we kept the overall distribution of intervals constant while manipulating the immediately-prior experience of participants. In temporal bisection, this created a noted assimilation effect; participants judged intervals as shorter given an immediately preceding short interval. In interval reproduction, there was no effect of the immediately prior interval length unless the prior interval had a linked motor command. We thus proposed that the immediately prior interval provided a context by which a subsequent interval is judged. However, in the case of reproduction, where a subsequent interval is reproduced, rather than seen, the effects of contextualization are attenuated. PMID- 29432992 TI - Merging weighted SVMs for parallel incremental learning. AB - Parallel incremental learning is an effective approach for rapidly processing large scale data streams, where parallel and incremental learning are often treated as two separate problems and solved one after another. Incremental learning can be implemented by merging knowledge from incoming data and parallel learning can be performed by merging knowledge from simultaneous learners. We propose to simultaneously solve the two learning problems with a single process of knowledge merging, and we propose parallel incremental wESVM (weighted Extreme Support Vector Machine) to do so. Here, wESVM is reformulated such that knowledge from subsets of training data can be merged via simple matrix addition. As such, the proposed algorithm is able to conduct parallel incremental learning by merging knowledge over data slices arriving at each incremental stage. Both theoretical and experimental studies show the equivalence of the proposed algorithm to batch wESVM in terms of learning effectiveness. In particular, the algorithm demonstrates desired scalability and clear speed advantages to batch retraining. PMID- 29432993 TI - Oridonin inhibits oral cancer growth and PI3K/Akt signaling pathway. AB - Oridonin, a bioactive diterpenoid purified from Rabdosia rubescens, has been shown to possess anticancer capacity in several cancer types. However, its effects on oral squamous cell carcinoma (OSCC) cells remain unclear. This study aimed to investigate the anticancer ability of oridonin in OSCC cells, including proliferation, apoptosis and underlying mechanisms using the OSCC cell lines, UM1 and SCC25. The results showed that oridonin not only inhibited proliferation and clonal formation but also induced G2/M cell cycle arrest and apoptosis in UM1 and SCC25 cells in a dose-dependent manner. Western blot revealed that oridonin treatment increased the ratio of Bax/Bcl-2, and activated the cleavage of caspase 3, caspase-9 and PARP-1. Oridonin also induced G2/M phase arrest in OSCC cells via down-regulating the G2/M transition-related proteins such as cyclin B1 or up regulating cyclin D1, cyclin D3, P21, p-CDK1 and cyclin A2. In addition, oridonin treatment significantly inhibited the phosphorylation of PI3K and Akt and inhibited tumor growth of OSCC xenograft in nude mice. Taken together, these results suggested that oridonin possesses anti-oral cancer capacity via inhibiting the PI3K/Akt signaling and induce apoptosis and G2/M-phase arrest. Therefore, oridonin may be a potential anticancer drug for the treatment of oral cancer. PMID- 29432994 TI - SPC25 upregulation increases cancer stem cell properties in non-small cell lung adenocarcinoma cells and independently predicts poor survival. AB - In this study, we investigated the functional role and prognostic value of spindle pole body component 25 (SPC25) in non-small cell lung cancer (NSCLC). SPC25 expression profile in lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and normal lung tissues was examined by using data from the Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). LUAD A549 cells and LUSC H520 cells were used to investigate the influence of SPC25 on cancer stem cell (CSC) properties in terms of the proportion of CD133+ cells, tumorsphere formation and CSC markers, including CD133, ALDH1 and Sox2. Data mining was also performed in the Kaplan-Meier plotter and TCGA-NSCLC to assess the independent prognostic value of SPC25. Results showed SPC25 was significantly upregulated in LUAD and LUSC tissues compared with normal lung tissues. SPC25 overexpression significantly increased the CSC properties and invasion of A549 cells, but not H520 cells. In comparison, SPC25 knockdown impaired the CSC properties and invasion of A549 cells, but not H520 cells. Univariate and multivariate analysis confirmed that high SPC25 expression was an independent prognostic factor for poor overall survival (OS) (HR: 1.622, 95%CI: 1.207-2.178, p = .001) and recurrence-free survival (RFS) (HR: 1.726, 95%CI: 1.242-2.399, p = .001) in LUAD patients. However, no independent prognostic value of SPC25 was observed in LUSC patients even under the best cut-off model. Based on these findings, we infer that SPC25 upregulation can increase CSC properties in LUAD and independently predict poor survival in this histological subtype. PMID- 29432995 TI - Long noncoding RNA maternally expressed gene 3 knockdown alleviates lipopolysaccharide-induced inflammatory injury by up-regulation of miR-203 in ATDC5 cells. AB - BACKGROUND: Osteoarthritis (OA) is a common degenerative joint disease, which seriously impacts the health of elderly. However, there is no effective treatment for curing this disease until now. Numerous studies reported that long noncoding RNAs (lncRNAs) are closely related to the pathogenesis of OA. Therefore, the study aims to investigate the effect of maternally expressed gene 3 (MEG3) on lipopolysaccharide (LPS)-induced inflammatory injury of ATDC5 cells. METHODS: Different concentrations (0, 1, 5, and 10 MUg/ml) of LPS were used to induce ATDC5 cells injury. The specific expressing vectors were then transfected into ATDC5 cells to alter MEG3, Sirt1 and miR-203 expressions. Flow cytometry, luciferase reporter, qRT-PCR and western blot assays were used to detect cell viability, apoptosis, and the expressions of apoptosis-related proteins and pro inflammatory factors (IL-1beta, IL-6, IL-8 and TNF-alpha). Meanwhile, ELISA was used for analyzing the concentrations of inflammatory cytokines in culture supernatant. Besides, the key pathways of PI3K/AKT and NF-kappaB were examined by western blot. RESULTS: LPS decreased cell viability, increased cell apoptosis, promoted the release of pro-inflammatory factors, and down-regulated MEG3 expression, Moreover, MEG3 knockdown alleviated LPS-induced inflammatory injury. MEG3 acted as a competing endogenous RNAs (ceRNA) for miR-203, and MEG3 knockdown reduced inflammatory injury by regulating miR-203. Furthermore, miR-203 positively regulated Sirt1 expression, and Sirt1 alleviated LPS-induced inflammatory injury via mediating PI3K/AKT and NF-kappaB pathways. CONCLUSION: This study showed that MEG3 knockdown alleviated LPS-induced inflammatory injury in ATDC5 cells by regulating miR-203 expression. Hence, the findings may offer a potential treatment perspective of OA. PMID- 29432996 TI - LncRNA-LET inhibits cell viability, migration and EMT while induces apoptosis by up-regulation of TIMP2 in human granulosa-like tumor cell line KGN. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disease characterized by hyperandrogenism, irregular menses, and polycystic ovaries. Several long non-coding RNAs (lncRNAs) are aberrantly expressed in PCOS patients; however, little is known about the effects of the lncRNA-low expression in tumor (lncRNA-LET) on PCOS. We aimed to explore the effects of lncRNA-LET on human granulosa-like tumor cell line, KGN. METHODS: Expression of lncRNA-LET in normal IOSE80 cells and granulosa cells was determined by qRT-PCR. KGN cell viability, apoptosis and migration were measured by trypan blue exclusion method, flow cytometry assay and wound healing assay, respectively. TGF-beta1 was used to induce epithelial-mesenchymal transition (EMT) process. LncRNA-LET expression and mRNA expressions of TIMP2 and EMT-related proteins were measured by qRT-PCR. Western blot analysis was used to measure the protein expression of apoptosis related proteins, EMT-related proteins, TIMP2, and the proteins in the Wnt/beta catenin and Notch signaling pathways. RESULTS: lncRNA-LET was down-regulated in KGN cells, and its overexpression inhibited cell viability and migration, and promoted apoptosis in KGN cells. Overexpression of lncRNA-LET increased the expression of E-cadherin and decreased the expressions of N-cadherin and vimentin in KGN cells. These effects of lncRNA-LET on KGN cells were reversed by TIMP2 suppression. Overexpression of TIMP2 inhibited cell viability, migration and EMT process, and increased apoptosis by activating the Wnt/beta-catenin and Notch pathways. CONCLUSION: Overexpression of lncRNA-LET inhibits cell viability, migration and EMT process, and increases apoptosis in KGN cells by up-regulating the expression of TIMP2 and activating the Wnt/beta-catenin and notch signaling pathways. PMID- 29432997 TI - A comparative study of hand hygiene and alcohol-based hand rub use among Irish nursing and medical students. AB - BACKGROUND: In Ireland, the setting for this study, the national prevalence rate of health care-associated infection (HCAI) in acute-care facilities is 5.2%. Hand hygiene and in particular hand rubbing using alcohol-based hand rub (ABHR) is highly efficacious in preventing HCAI transmission. Yet, compliance among healthcare professionals is sub-optimal. Less is known about the practices of nursing and medical students and no study comparing practices among these groups in Ireland was found. Hence, the aim of this study was to provide insight into the current hand hygiene and hand rubbing practices of nursing and medical students in Ireland and, by doing so, contribute to the broader understanding of this topic. METHODS: This observational study employed a cross-sectional, self reported design. An electronically administered questionnaire was sent to all nursing and medical students from one university. Data were analysed using appropriate software. RESULTS: The response rate was 37% (323/872). Higher compliance with the World Health Organisation 'my five moments for hand hygiene' model was reported among nursing students (NS) than medical students (MS), with scope for improvement in both disciplines identified. Hand hygiene compliance was highest after body fluid exposure (99.5% NS, 91% MS) and lowest after touching a patient's surroundings (61.5% NS, 57.5% MS). Attitudes towards hand rubbing were largely positive in both disciplines. 16% of NS were not aware of the clinical contraindications to ABHR use, compared to 45% of MS. 9% of NS did not know when to use soap and water and when to use ABHR, compared to 36% of MS. In contrast, more medical students (46%) than nursing students (22%) were routinely using alcohol-based hand rub for decontamination of hands as recommended. CONCLUSIONS: Results suggest scope to review current hand hygiene curricula focusing on the knowledge gaps, the practice deficits and the barriers to ABHR usage identified. PMID- 29432998 TI - Prevalence of depression among nursing students: A systematic review and meta analysis. AB - OBJECTIVES: To examine the global prevalence of depression among nursing students and the variation in depression rates influenced by demographic and educational factors. BACKGROUND: Depression affects approximately 350 million people worldwide and is the world's leading cause of disability. Nursing students struggle to cope with not only stressors common in higher education institutions but also anxiety towards clinical placements. Evidence has suggested high prevalence of depression among them, but no reviews have been conducted to report a consolidated prevalence. DESIGN: Systematic review and meta-analysis. REVIEW METHODS AND DATA SOURCES: A search was conducted from November 2015 to January 2016 on CINAHL, EMBASE, Medline OVID, Medline ProQuest, PsycINFO, PubMed, ScienceDirect, and SCOPUS, using a combination of keywords "depression", "nursing students", "mood disorder", "affective disorder", 'undergraduate nursing', "nursing education", "nursing undergraduate", and "nursing diploma". RESULTS: A total of 27 cross-sectional studies were included. The sample comprised 8918 nursing students and the mean age ranged from 17.4 to 28.4 years. Among these studies, the proportion of female students ranged from 79.0% to 100.0%. A high pooled prevalence of depression of 34.0% was reported among nursing students. Significant differences in depression prevalence were noted for different subgroups of age, with a higher prevalence noted in younger students (41.0%), and for different geographical regions, with Asian nursing students experiencing a higher prevalence of depression (43.0%). No significant difference was noted between nursing and non-nursing students. CONCLUSION: The findings suggest a high prevalence of depression among nursing students. This serves as an impetus for educational reforms in nursing schools and proposes for further research to aid prospective nurses in safeguarding their psychological wellbeing. In the long run, it is imperative that competent nurses be nurtured to improve the standards of healthcare and patients' quality of life. PMID- 29432999 TI - Spatial optimization of cropping pattern for sustainable food and biofuel production with minimal downstream pollution. AB - Biofuel has emerged as a substantial source of energy in many countries. In order to avoid the 'food versus fuel competition', arising from grain-based ethanol production, the United States has passed regulations that require second generation or cellulosic biofeedstocks to be used for majority of the biofuel production by 2022. Agricultural residue, such as corn stover, is currently the largest source of cellulosic feedstock. However, increased harvesting of crops residue may lead to increased application of fertilizers in order to recover the soil nutrients lost from the residue removal. Alternatively, introduction of less fertilizer intensive perennial grasses such as switchgrass (Panicum virgatum L.) and Miscanthus (Miscanthus x giganteus Greef et Deu.) can be a viable source for biofuel production. Even though these grasses are shown to reduce nutrient loads to a great extent, high production cost have constrained their wide adoptability to be used as a viable feedstock. Nonetheless, there is an opportunity to optimize feedstock production to meet bioenergy demand while improving water quality. This study presents a multi-objective simulation optimization framework using Soil and Water Assessment Tool (SWAT) and Multi Algorithm Genetically Adaptive Method (AMALGAM) to develop optimal cropping pattern with minimum nutrient delivery and minimum biomass production cost. Computational time required for optimization was significantly reduced by loose coupling SWAT with an external in-stream solute transport model. Optimization was constrained by food security and biofuel production targets that ensured not more than 10% reduction in grain yield and at least 100 million gallons of ethanol production. A case study was carried out in St. Joseph River Watershed that covers 280,000 ha area in the Midwest U.S. Results of the study indicated that introduction of corn stover removal and perennial grass production reduce nitrate and total phosphorus loads without compromising on food and biofuel production. Optimization runs yielded an optimal cropping pattern with 32% of watershed area in stover removal, 15% in switchgrass and 2% in Miscanthus. The optimal scenario resulted in 14% reduction in nitrate and 22% reduction in total phosphorus from the baseline. This framework can be used as an effective tool to take decisions regarding environmentally and economically sustainable strategies to minimize the nutrient delivery at minimal biomass production cost, while simultaneously meeting food and biofuel production targets. PMID- 29433000 TI - Unrefined humic substances as a potential low-cost amendment for the management of acidic groundwater contamination. AB - The present study explores a novel application of Huma-K, a commercially available, unrefined humic substance, as a promising low-cost source of organic matter for in situ remediation of contaminated acidic groundwater plumes. This can be achieved by creating a humic-rich coating on the surface of minerals which can enhance the sorption of contaminants from groundwater. Huma-K was characterized by means of scanning electron microscopy equipped with energy dispersive spectroscopy, Fourier-transform infrared analysis, and potentiometric titrations. Batch experiments were performed to investigate the sorption desorption behavior of Huma-K and to evaluate what conditions (pH, contact time, and initial Huma-K concentration) affect these processes upon injection into aquifer sediments. As evidenced by potentiometric titrations, Huma-K possesses functional groups that have an acidic nature, with pK values in the range of 4-6 (carboxylic) and 9-10 (phenolic). Sorption, homogeneous precipitation, and surface-induced precipitation seem to be favored in the presence of sediment at pH 4, where there is less deprotonation of acidic functional groups. As the pH is increased, functional groups become negatively charged, leading to electrostatic repulsion and dissolution of Huma-K from sediment. Kinetic experiments indicate that Huma-K sorption is a slow-rate process, most likely governed by film diffusion. The enhanced sorption of Huma-K in acidic conditions suggests that it may be used to create a subsurface treatment zone in acidic aquifers for the sequestration of contaminants such as uranium. The treatment zone will persist as long as the pH does not increase sufficiently to cause soil-bound Huma-K to be released, remobilizing aqueous contaminants. PMID- 29433001 TI - A new insight into the dependence of relaxation time on frequency in viscoelastic surfactant solutions: From experimental to modeling study. AB - HYPOTHESIS: The relaxation time in viscoelastic surfactant solutions is a function of temperature, salt/surfactant concentrations, resting conditions, as well as shear frequency. The simplistic assumption of a single and constant relaxation time is not representative of all relaxation modes in these solutions especially at high frequencies. EXPERIMENTS: Steady-state and oscillatory measurements are carried out to study the effects of high temperature, concentration and resting condition on the rheology of surfactants/salt mixtures including a non-ionic and a zwitterionic/anionic surfactant system. Furthermore, a novel semi-empirical rheological model is deducted based on Cates theory.This model introduces, for the first time, a frequency-dependence for the continuous relaxation time spectrum. FINDINGS: At high temperatures, the non-ionic surfactant become more viscoelastic and the zwitterionic/anionic system loses its viscoelasticity. The addition of surfactant/salt improves the viscoelasticity of both systems, and, for the zwitterionic/anionic mixture, increasing the resting temperature improves its viscoelasticity. In addition, the proposed model significantly improves predictions of traditional Maxwell model for different viscoelastic surfactant solutions (using data from this study and the literature) for a considerable range of surfactant and salt combinations at a wide range of temperature. PMID- 29433002 TI - A new wave front shape-based approach for acoustic source localization in an anisotropic plate without knowing its material properties. AB - Estimating the location of an acoustic source in a structure is an important step towards passive structural health monitoring. Techniques for localizing an acoustic source in isotropic structures are well developed in the literature. Development of similar techniques for anisotropic structures, however, has gained attention only in the recent years and has a scope of further improvement. Most of the existing techniques for anisotropic structures either assume a straight line wave propagation path between the source and an ultrasonic sensor or require the material properties to be known. This study considers different shapes of the wave front generated during an acoustic event and develops a methodology to localize the acoustic source in an anisotropic plate from those wave front shapes. An elliptical wave front shape-based technique was developed first, followed by the development of a parametric curve-based technique for non elliptical wave front shapes. The source coordinates are obtained by minimizing an objective function. The proposed methodology does not assume a straight line wave propagation path and can predict the source location without any knowledge of the elastic properties of the material. A numerical study presented here illustrates how the proposed methodology can accurately estimate the source coordinates. PMID- 29433003 TI - Mixing of ultrasonic Lamb waves in thin plates with quadratic nonlinearity. AB - This paper investigates the propagation of Lamb waves in thin plates with quadratic nonlinearity by one-way mixing method using numerical simulations. It is shown that an A0-mode wave can be generated by a pair of S0 and A0 mode waves only when mixing condition is satisfied, and mixing wave signals are capable of locating the damage zone. Additionally, it is manifested that the acoustic nonlinear parameter increases linearly with quadratic nonlinearity but monotonously with the size of mixing zone. Furthermore, because of frequency deviation, the waveform of the mixing wave changes significantly from a regular diamond shape to toneburst trains. PMID- 29433004 TI - A facile photoelectrochemical sensor for high sensitive ROS and AA detection based on graphitic carbon nitride nanosheets. AB - Photoactive material is one of the main challenges for fabrication of sensitive and selective photoelectrochemical (PEC) sensor. Herein, a facile PEC sensor is constructed using graphitic carbon nitride nanosheets (g-C3N4 NSs) coated on the surface of ITO electrode, where electron donor properties of potassium ferrocyanide and ascorbic acid is utilized for the tracing of hydrogen peroxide (H2O2), hypochlorite (ClO-), and ascorbic acid (AA). Our designed PEC sensor exhibits a good linear range to H2O2 concentrations from 12.5 to 875 uM in pH = 7.4 and 2.5-400 uM in pH = 10, while that for AA is in the range from 0.25 to 100 uM in pH = 7.4, and with the same pH for ClO- concentrations in the range from 0.5 to 19 * 10-3% (V/V) in a bleach sample. Owing to the good responses towards the traces of H2O2, AA, and ClO-, our designed system may be used as H2O2, ClO-, and AA sensor for outdoor applications with high specificity, long-time stability and good reproducibility. PMID- 29433005 TI - Cytotoxic activity and structural features of Ru(II)/phosphine/amino acid complexes. AB - Thirteen new ruthenium amino acid complexes were synthesized and characterized. They were obtained by the reaction of alpha-amino acids (AA) with [RuCl2(P-P)(N N)], where P-P=1,4-bis(diphenylphosphino)butane (dppb) or 1,3 bis(diphenylphosphino)propane (dppp) and N-N=4,4'-dimethyl-2,2'-bipyridine (4' Mebipy), 5,5'-dimethyl-2,2'-bipyridine (5'-Mebipy) or 4,4'-Methoxy-2-2' bipyridine (4'-MeObipy). This afforded a family of complexes formulated as [Ru(AA H)(P-P)(N-N)]PF6, where AA=glycine (Gly), L-alanine (Ala), L-valine (Val), L tyrosine (Tyr), L-tryptophan (Trp), L-histidine (His) and L-methionine (Met). All compounds were characterized by elemental analysis, spectroscopic and electrochemical techniques. The [Ru(AA-H)(P-P)(N-N)]PF6 complexes are octahedral (the AA-H ligand binding involves N-amine and O-carboxylate), diamagnetic (low spin d6, S=0) and present bands due to electronic transitions in the visible region. 1H, 13C{1H} and 31P{1H} NMR spectra of the complexes indicate the presence of C2 symmetry, and the identification of diastereoisomers. In vitro cytotoxicity assays of the compounds and cisplatin were carried out using MDA-MB 231 (human breast) tumor cell line and a non-tumor breast cell line (MCF-10A). Most complexes present promising results with IC50 values comparable with the reference drug cisplatin and high selectivity indexes were found for the complexes containing L-Trp. The binding of two Ru-precursors of the type [RuCl2(dppb)(NN)] (N-N=4'-MeObipy or 4'-Mebipy) to the blood transporter protein human serum albumin (HSA) was evaluated by fluorescence and circular dichroism spectroscopy. Both complexes bind HSA, probably in the hydrophobic pocket near Trp214, and the Ru-complex containing 4'-MeObipy shows higher affinity for HSA than the 4'-Mebipy one. PMID- 29433006 TI - Strains in trussed spine interbody fusion implants are modulated by load and design. AB - Titanium cages with 3-D printed trussed open-space architectures may provide an opportunity to deliver targeted mechanical behavior in spine interbody fusion devices. The ability to control mechanical strain, at levels known to stimulate an osteogenic response, to the fusion site could lead to development of optimized therapeutic implants that improve clinical outcomes. In this study, cages of varying design (1.00 mm or 0.75 mm diameter struts) were mechanically characterized and compared for multiple compressive load magnitudes in order to determine what impact certain design variables had on localized strain. Each cage was instrumented with small fiducial sphere markers (88 total) at each strut vertex of the truss structure, which comprised of 260 individual struts. Cages were subjected to a 50 N control, 1000 N, or 2000 N compressive load between contoured loading platens in a simulated vertebral fusion condition, during which the cages were imaged using high-resolution micro-CT. The cage was analyzed as a mechanical truss structure, with each strut defined as the connection of two vertex fiducials. The deformation and strain of each strut was determined from 50 N control to 1000 N or 2000 N load by tracking the change in distance between each fiducial marker. As in a truss system, the number of struts in tension (positive strain) and compression (negative strain) were roughly equal, with increased loads resulting in a widened distribution (SD) compared with that at 50 N tare load indicating increased strain magnitudes. Strain distribution increased from 1000 N (+156 +/- 415 MUepsilon) to 2000 N (+180 +/- 605 MUepsilon) in 1.00 mm cages, which was similar to 0.75 mm cages (+132 +/- 622 MUepsilon) at 1000 N load. Strain amplitudes increased 42%, from 346MUepsilon at 1000 N to 492MUepsilon at 2000 N, for 1.00 mm cages. At 1000 N, strain amplitude in 0.75 mm cages (481MUepsilon) was higher by 39% than that in 1.00 mm cages. These amplitudes corresponded to the mechanobiological range of bone homeostasis+formation, with 63 +/- 2% (p < .05 vs other groups), 72 +/- 3%, and 73 +/- 1% of struts within that range for 1.00 mm at 1000 N, 1.00 mm at 2000 N, and 0.75 mm at 1000 N, respectively. The effective compressive modulus for both cage designs was also dependent on strut diameter, with modulus decreasing from 12.1 +/- 2.3 GPa (1.25 mm) to 9.2 +/- 7.5 GPa (1.00 mm) and 3.8 +/- 0.6 GPa (0.75 mm). This study extended past micro-scale mechanical characterization of trussed cages to compare the effects of design on cage mechanical behavior at moderate (1000 N) and strenuous (2000 N) load levels. The findings suggest that future cage designs may be modulated to target desired mechanical strain regimes at physiological loads. PMID- 29433007 TI - Biodegradation and mechanical behavior of an advanced bioceramic-containing Mg matrix composite synthesized through in-situ solid-state oxidation. AB - Recent studies have shown great potential of Mg matrix composites for biodegradable orthopedic devices. However, the poor structural integrity of these composites, which results in excessive localized corrosion and premature mechanical failure, has hindered their widespread applications. In this research, an in-situ Powder Metallurgy (PM) method was used to fabricate a novel biodegradable Mg-bredigite composite and to achieve enhanced chemical interfacial locking between the constituents by triggering a solid-state thermochemical reaction between Mg and bredigite particles. The reaction resulted in a highly densified and integrated microstructure, which prevented corrosion pits from propagating when the composite was immersed in a physiological solution. In addition, chemical interlocking between the constituents prohibited interparticle fracture and subsequent surface delamination during compression testing, enabling the composite to withstand larger plastic deformation before mechanical failure. Furthermore, the composite was proven to be biocompatible and capable of maintaining its ultimate compressive strength in the strength range of cortical bone after 25-day immersion in DMEM. The research provided the necessary information to guide further research towards the development of a next generation of biodegradable Mg matrix composites with enhanced chemical interlocking. PMID- 29433008 TI - Molecular characterization of the vitamin D receptor (VDR) gene in Holstein cows. AB - Vitamin D plays a vital role in calcium homeostasis, growth, and immunoregulation. Because little is known about the vitamin D receptor (VDR) gene in cattle, the aim of the present investigation was to present the molecular characterization of exons 5 and 6 of the VDR gene in Holstein cows. DNA extraction, genomic sequencing, phylogenetic analysis, synteny mapping and single nucleotide gene polymorphism analysis of the VDR gene were performed to assess blood samples collected from 50 clinically healthy Holstein cows. The results revealed the presence of a 450-base pair (bp) nucleotide sequence that resembled exons 5 and 6 with intron 5 enclosed between these exons. Sequence alignment and phylogenetic analysis revealed a close relationship between the sequenced VDR region and that found in Hereford cattle. A close association between this region and the corresponding region in small ruminants was also documented. Moreover, a single nucleotide polymorphism (SNP) that caused the replacement of a glutamate with an arginine in the deduced amino acid sequence was detected at position 7 of exon 5. In conclusion, Holstein and Hereford cattle differ with respect to exon 5 of the VDR gene. Phylogenetic analysis of the VDR gene based on nucleotide sequence produced different results from prior analyses based on amino acid sequence. PMID- 29433009 TI - Paternity tests in Mexico: Results obtained in 3005 cases. AB - National and international reports regarding the paternity testing activity scarcely include information from Mexico and other Latin American countries. Therefore, we report different results from the analysis of 3005 paternity cases analyzed during a period of five years in a Mexican paternity testing laboratory. Motherless tests were the most frequent (77.27%), followed by trio cases (20.70%); the remaining 2.04% included different cases of kinship reconstruction. The paternity exclusion rate was 29.58%, higher but into the range reported by the American Association of Blood Banks (average 24.12%). We detected 65 mutations, most of them involving one-step (93.8% and the remaining were two-step mutations (6.2%) thus, we were able to estimate the paternal mutation rate for 17 different STR loci: 0.0018 (95% CI 0.0005-0.0047). Five triallelic patterns and 12 suspected null alleles were detected during this period; however, re amplification of these samples with a different Human Identification (HID) kit confirmed the homozygous genotypes, which suggests that most of these exclusions actually are one-step mutations. HID kits with >=20 STRs detected more exclusions, diminishing the rate of inconclusive results with isolated exclusions (<3 loci), and leading to higher paternity indexes (PI). However, the Powerplex 21 kit (20 STRs) and Powerplex Fusion kit (22 STRs) offered similar PI (p = 0.379) and average number of exclusions (PE) (p = 0.339) when a daughter was involved in motherless tests. In brief, besides to report forensic parameters from paternity tests in Mexico, results describe improvements to solve motherless paternity tests using HID kits with >=20 STRs instead of one including 15 STRs. PMID- 29433010 TI - Age estimation by canines' pulp/tooth ratio in an Iranian population using digital panoramic radiography. AB - OBJECTIVE: Age estimation in adults is an important issue in forensic science. This study aimed to estimate the chronological age of Iranians by means of pulp/tooth area ratio (AR) of canines in digital panoramic radiographs. MATERIALS AND METHODS: The sample consisted of panoramic radiographs of 271 male and female subjects aged 16-64 years. The pulp/tooth area ratio (AR) of upper and lower canines was calculated by AutoCAD software. Data were subjected to correlation and regression analysis. RESULTS: There was a significant and inverse correlation between age and pulp/tooth area ratio of upper and lower canines (r=-0.794 for upper canine and r=-0.282 for lower canine; p-value<0.001). Linear regression equations were derived separately for upper, lower and both canines. The mean difference between actual and estimated age using upper canine was 6.07+/-1.7. CONCLUSION: The results showed that the pulp/tooth area ratios of canines are a reliable method for age estimation in Iranians. The pulp/tooth area ratio of upper canine was better correlated with chronological age than that of lower canine. PMID- 29433011 TI - Cling film plastic wrap: An innovation for dead body packaging, preservation and transportation by first responders as a replacement for cadaver body bag in large scale disasters. AB - Cadaver body bags are the conventional method to contain a human body or human remains, which includes the use for storage and transportation of the deceased at any crime scene or disaster scene. During disasters, most often than not, the first responders including the police will be equipped with cadaver body bags to do scene processing of human remains and collection of personal belongings at the disaster site. However, in an unanticipated large scale disasters involving hundreds and thousands of fatalities, cadaver body bags supplies may be scarce. The authors have therefore innovated the cling film plastic wrap as an alternative for the cadaver body bag used at the disaster site. The plastic wrap was tested on six different experimental subjects, i.e. both adult and child mannequins; body parts of the mannequin figure (arm and hand); a human adult subject and an unknown dead body. The strengths of the cling film plastic wrap are discussed in comparison with the cadaver body bag in the aspects of costing, weight, duration of the wrap, water and body fluid resistant properties, visibility and other advantages. An average savings of more than 5000% are noted for both adult body wrap and child body wrap compared to the cadaver body wrap. This simply means that the authors can either wrap 25 adult dead bodies or 80 children dead bodies with the cost of 1 cadaver body bag. The cling film plastic wrap has proven to have significant innovation impact for dead body management particularly by the first responders in large scale disasters. With proper handling of dead bodies, first responders can manage the dead with dignity and respect in an overwhelmed situation to facilitate the humanitarian victim identification process later. PMID- 29433012 TI - Talking about male body-based contraceptives: The counseling visit and the feminization of contraception. AB - In developed countries, women bear the primary, and sometimes exclusive, responsibility for preventing pregnancy in heterosexual sexual relations. This unequal burden is not an intrinsic fact; it is the consequence of broad social narratives and interpersonal negotiations. The contraceptive counseling visit is increasingly recognized as a site of the discursive production of normative ideas about reproduction, suggesting that clinicians themselves may contribute to the assignment of responsibility for contraceptive labor to women (i.e. the feminization of contraception). Scholars have not yet considered how providers talk to patients about methods that are male body-based (i.e. condoms, withdrawal, and vasectomy) and, as such, may disrupt the feminization of responsibility for contraception. Using transcripts of 101 contraceptive counseling visits recorded between 2009 and 2012 in the San Francisco Bay Area, I investigate how clinicians discuss male body-based methods with female patients. Drawing on a constructivist approach, I find that clinicians generally devalued male body-based methods in their counseling. They did so by, first, failing to discuss them as options for long-term contraception. Second, when they did discuss them, clinicians tended to emphasize aspects of the methods that were presumed "negative" (e.g. the lower efficacy of withdrawal and condoms) but not features that patients might view positively (e.g. the high efficacy of vasectomy or the lack of side effects with condoms and withdrawal). In aggregate, these discursive practices marginalize male body-based methods as contraceptive choices. As a practical effect, this may encourage women to choose a method that does not best meet their preferences. At a structural level, by devaluing methods that could undercut the unequal division of fertility work, these discursive patterns contribute to the feminization of responsibility for contraception and the retrenchment of the unequal gendered division of fertility work. PMID- 29433013 TI - Workplace assimilation and professional jurisdiction: How nurses learn to blur the nursing-medical boundary. AB - In theorising 'the system of professions', Andrew Abbott emphasised how jurisdictional boundaries in the workplace are far fuzzier than those specified in law. A key reason for this fuzziness is the process he characterised as 'workplace assimilation', involving on the job learning of a craft version of another profession's knowledge system. However, despite its centrality, workplace assimilation remains poorly elaborated in the scholarly literature. To address this shortcoming, this study explores the workplace assimilation of nurses in a Norwegian emergency primary care clinic. Using an ethnographic approach, the study shows how nurses learned to blur the nursing-medical boundary by (1) doing physician-like work; (2) interacting with their colleagues; (3) comparing their own clinical assessments to those of physicians (as codified in the patient record) and (4) using medical reference works to guide their clinical decision making. In detailing these aspects of workplace assimilation, the study illuminates how and why workers come to blur jurisdictional boundaries in the workplace. PMID- 29433014 TI - A thought in the park: The influence of naturalness and low-level visual features on expressed thoughts. AB - Prior research has shown that the physical characteristics of one's environment have wide ranging effects on affect and cognition. Other research has demonstrated that one's thoughts have impacts on mood and behavior, and in this three-part research program we investigated how physical features of the environment can alter thought content. In one study, we analyzed thousands of journal entries written by park visitors to examine how low-level and semantic visual features of the parks correlate with different thought topics. In a second study, we validated our ecological results by conducting an online study where participants were asked to write journal entries while imagining they were visiting a park, to ensure that results from Study 1 were not due to selection bias of park visitors. In the third study, we experimentally manipulated exposure to specific visual features to determine if they induced thinking about the same thought topics under more generalized conditions. Results from Study 3 demonstrated a potential causal role for perceived naturalness and high non straight edges on thinking about "Nature", with a significant positive interaction. Results also showed a potential causal effect of naturalness and non straight edges on thinking about topics related to "Spiritual & Life Journey", with perceived naturalness having a negative relationship and non-straight edges having a positive relationship. We also observed a significant positive interaction between non-straight edge density and naturalness in relation to "Spiritual & Life Journey". These results have implications for the design of the built environment to influence human reflection and well-being. PMID- 29433015 TI - Effect of strenuous exercise on mediators of inflammation in patients with coronary artery disease. AB - BACKGROUND: Coronary artery disease (CAD) is considered a low-grade inflammatory disease. We aimed to identify effects of short-term strenuous exercise on mediators of systemic inflammation, endothelial and platelet activation in patients with angiographically verified CAD. We hypothesized that a more pronounced inflammatory response would be present in patients with CAD than in those without CAD. METHODS: In subjects with symptoms indicative of stable CAD, an exercise stress test on a bicycle ergometer was performed. Venous blood samples, taken at rest and within 5 min after end of exercise, were analyzed for the following markers by ELISAs: TNF-alpha, IL-6, MCP-1, ICAM-1, VCAM-1, E selectin, P-selectin, CD40L and RANTES. All participants underwent conventional coronary angiography. CAD was defined as having any degree of atherosclerosis. RESULTS: A total of 110 patients were included, of whom 74 were found to have CAD. Mean exercise duration was 10:06 +/- 3:56 min with no significant difference between the two groups. All measured markers changed significantly during exercise (p <= 0.012). A significantly less pronounced increase in CD40L in the CAD group than in the no CAD group was observed (p = 0.050), however, after adjustment for hematocrit this difference was no longer significant. CONCLUSION: An instant inflammatory response was observed during short-term strenuous exercise in patients with symptoms of CAD. However, the exercise mediated response was not more pronounced in patients with CAD. PMID- 29433016 TI - Self-sampling with HPV mRNA analyses from vagina and urine compared with cervical samples. AB - BACKGROUND: In order to increase coverage in the organized cervical screening program, self-sampling with HPV analyses has been suggested. OBJECTIVES: The aim was to compare human papillomavirus (HPV) mRNA detection in vaginal and urine self-collected samples with clinician-taken cervical samples and the corresponding clinician-taken histological specimens. STUDY DESIGN: Self collected vaginal, urine and clinician-taken cervical samples were analyzed from 209 women with the Aptima mRNA assay (Hologic Inc, MA, USA). Cervical cytology, colposcopy, biopsy and/or the loop electrosurgical excision procedure (LEEP) were performed in every examination. RESULTS: The sensitivity of the HPV mRNA test in detecting high-grade squamous intraepithelial lesions (HSIL)/adenocarcinoma in situ (AIS)/cancer cases was as follows: for the vaginal self-samples 85.5% (95% CI; 75.0-92.8), the urinary samples 44.8% (95% CI; 32.6-57.4), and for routine cytology 81.7% (95% CI; 70.7-89.9). For the clinician-taken cervical HPV samples the sensitivity of the HPV mRNA test in detecting HSIL/AIS/cancer was 100.0% (95% CI; 94.9-100.0). The specificity of the HPV mRNA was similar for the clinician taken cervical HPV samples and the self-samples: 49.0% vs. 48.1%. The urinary HPV samples had a specificity of 61.9% and cytology had a specificity of 93.3%. CONCLUSION: The sensitivity of the Aptima HPV mRNA test in detecting HSIL/AIS/cancer from vaginal self-samples was similar to that of routine cytology. The Aptima HPV mRNA vaginal self-sampling analysis may serve as a complement in screening programs. PMID- 29433017 TI - Continuing global improvement in human papillomavirus DNA genotyping services: The 2013 and 2014 HPV LabNet international proficiency studies. AB - BACKGROUND: Accurate and internationally comparable human papillomavirus (HPV) DNA detection and typing services are essential for HPV vaccine research and surveillance. OBJECTIVES: This study assessed the proficiency of different HPV typing services offered routinely in laboratories worldwide. STUDY DESIGN: The HPV Laboratory Network (LabNet) has designed international proficiency panels that can be regularly issued. The HPV genotyping proficiency panels of 2013 and 2014 contained 43 and 41 coded samples, respectively, composed of purified plasmids of sixteen HPV types (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68a and 68b) and 3 extraction controls. Proficient typing was defined as detection in both single and multiple infections of 50 International Units of HPV 16 and HPV 18 and 500 genome equivalents for the other 14 HPV types, with at least 97% specificity. RESULTS: Ninety-six laboratories submitted 136 datasets in 2013 and 121 laboratories submitted 148 datasets in 2014. Thirty-four different HPV genotyping assays were used, notably Linear Array, HPV Direct Flow-chip, GenoFlow HPV array, Anyplex HPV 28, Inno-LiPa, and PGMY-CHUV assays. A trend towards increased sensitivity and specificity was observed. In 2013, 59 data sets (44%) were 100% proficient compared to 86 data sets (59%) in 2014. This is a definite improvement compared to the first proficiency panel, issued in 2008, when only 19 data sets (26%) were fully proficient. CONCLUSION: The regularly issued global proficiency program has documented an ongoing worldwide improvement in comparability and reliability of HPV genotyping services. PMID- 29433018 TI - Interaction between deca-BDE and hepatic deiodinase in a highly PBDE-exposed bird. AB - Studies have shown that debromination of the major component in the deca brominated diphenyl ether mixture (deca-BDE), BDE-209, occurs in vivo in birds. Recent work from our laboratory on breeding ring-billed gulls (Larus delawarensis) exposed to elevated PBDE concentrations in the densely-populated metropolis of Montreal (Canada) further suggests that BDE-209 debromination is potentially catalyzed by deiodinases in liver microsomes. The first objective of this study was to determine if type 1 deiodinase (D1) was involved in the in vitro debromination of BDE-209 in liver microsomes of ring-billed gulls. The second objective was to determine if there was an interaction between D1 and BDE 209 using an in vitro D1 activity assay. No depletion of BDE-209 was observed in gull liver microsomes. A significant 42% increase in total D1 activity was found in gull liver microsomes at the medium BDE-209 concentration (1.0 nM), although not at the low (0.5 nM) or high (2.5 nM) concentrations, suggesting potential non dose related interaction with D1. Moreover, no correlation was found between total D1 activity in liver microsomes and plasma thyroid hormone levels, although there was a negative relationship between plasma BDE-209 concentrations and FT3 levels. Results from this study suggest that debromination of BDE-209 did not occur using present in vitro assay conditions, although indicated potential interaction with D1 that may have implication on circulating thyroid hormone status. PMID- 29433019 TI - Exposure to bisphenols and parabens during pregnancy and relations to steroid changes. AB - BACKGROUND: The harmful effects of endocrine disrupting compounds (EDCs) on human health are generally well-known, and exposure during fetal development may have lasting effects. Fetal exposure to bisphenol A (BPA) has been recently relatively well-studied; however, less is known about alternatives such as bisphenol S (BPS), bisphenol F (BPF) and bisphenol AF (BPAF), which have started to appear in consumer products. Parabens are another widespread group of EDCs, with confirmed transplacental passage. The usage of many cosmetic, pharmaceutical and consumer products during the pregnancy that may contain parabens and bisphenols has led to the need for investigation. OBJECTIVES: To shed more light into the transplacental transport of BPA, its alternatives, and parabens, and to study their relation to fetal steroidogenesis. METHODS: BPA, BPS, BPF, BPAF, methylparaben, ethylparaben, propylparaben, butylparaben, benzylparaben and 15 steroids including estrogens, corticoids, androgens and immunomodulatory ones were determined in 27 maternal (37th week of pregnancy) and cord plasma samples using liquid chromatography - tandem mass spectrometry methods. RESULTS: In cord blood, significantly higher BPA levels (p=0.0455) were observed compared to maternal plasma. The results from multiple regression models showed that in cord blood, methylparaben (beta=-0.027, p=0.027), propylparaben (beta=-0.025, p=0.03) and the sum of all measured parabens (beta=-0.037, p=0.015) were inversely associated with testosterone levels. CONCLUSION: To the best of our knowledge, this is the first study reporting the simultaneous detection of BPA, alternative bisphenols, parabens and steroids in maternal and cord plasma. Our study confirmed the transplacental transport of BPA, with likely accumulation in the fetal compartment. The negative association of cord blood parabens and testosterone levels points to possible risks with respect to importance of testosterone for prenatal male development. PMID- 29433020 TI - Radio frequency radiation-related cancer: assessing causation in the occupational/military setting. AB - BACKGROUND AND AIM: We reexamine whether radio frequency radiation (RFR) in the occupational and military settings is a human carcinogen. METHODS: We extended an analysis of an already-reported case series of patients with cancer previously exposed to whole-body prolonged RFR, mainly from communication equipment and radar. We focused on hematolymphatic (HL) cancers. We used analysis by percentage frequency (PF) of a cancer type, which is the proportion of a specific cancer type relative to the total number of cancer cases. We also examined and analyzed the published data on three other cohort studies from similar military settings from different countries. RESULTS: The PF of HL cancers in the case series was very high, at 40% with only 23% expected for the series age and gender profile, confidence interval CI95%: 26-56%, p<0.01, 19 out of 47 patients had HL cancers. We also found high PF for multiple primaries. As for the three other cohort studies: In the Polish military sector, the PF of HL cancers was 36% in the exposed population as compared to 12% in the unexposed population, p<0.001. In a small group of employees exposed to RFR in Israeli defense industry, the PF of HL cancers was 60% versus 17% expected for the group age and gender profile, p<0.05. In Belgian radar battalions the HL PF was 8.3% versus 1.4% in the control battalions as shown in a causes of deaths study and HL cancer mortality rate ratio was 7.2 and statistically significant. Similar findings were reported on radio amateurs and Korean war technicians. Elevated risk ratios were previously reported in most of the above studies. CONCLUSIONS: The consistent association of RFR and highly elevated HL cancer risk in the four groups spread over three countries, operating different RFR equipment types and analyzed by different research protocols, suggests a cause-effect relationship between RFR and HL cancers in military/occupational settings. While complete measurements of RFR exposures were not available and rough exposure assessments from patients interviews and from partial exposure data were used instead, we have demonstrated increased HL cancers in occupational groups with relatively high RFR exposures. Our findings, combined with other studies, indicate that exposures incurred in the military settings evaluated here significantly increased the risk of HL cancers. Accordingly, the RFR military exposures in these occupations should be substantially reduced and further efforts should be undertaken to monitor and measure those exposures and to follow cohorts exposed to RFR for cancers and other health effects. Overall, the epidemiological studies on excess risk for HL and other cancers together with brain tumors in cellphone users and experimental studies on RFR and carcinogenicity make a coherent case for a cause-effect relationship and classifying RFR exposure as a human carcinogen (IARC group 1). PMID- 29433021 TI - Residential green space and birth outcomes in a coastal setting. AB - BACKGROUND: Residential green space may improve birth outcomes, with prior studies reporting higher birthweight among infants of women living in greener areas. However, results from studies evaluating associations between green space and preterm birth have been mixed. Further, the potential influence of residential proximity to water, or 'blue space', on health has not previously been evaluated. OBJECTIVES: To evaluate associations between green and blue space and birth outcomes in a coastal area of the northeastern United States. METHODS: Using residential surrounding greenness (measured by Normalized Difference Vegetation Index [NDVI]) and proximity to recreational facilities, coastline, and freshwater as measures of green and blue space, we examined associations with preterm birth (PTB), term birthweight, and term small for gestational age (SGA) among 61,640 births in Rhode Island. We evaluated incremental adjustment for socioeconomic and environmental metrics. RESULTS: In models adjusted for individual - and neighborhood-level markers of socioeconomic status (SES), an interquartile range (IQR) increase in NDVI was associated with a 12% higher (95% CI: 4, 20%) odds of PTB and, conversely, living within 500 m of a recreational facility was associated with a 7% lower (95% CI: 1, 13%) odds of PTB. These associations were eliminated after further adjustment for town of residence. NDVI was associated with higher birthweight (7.4 g, 95% CI: 0.4-14.4 g) and lower odds of SGA (OR = 0.92, 95% CI: 0.87-0.98) when adjusted for individual-level markers of SES, but not when further adjusted for neighborhood SES or town. Living within 500 m of a freshwater body was associated with a higher birthweight of 10.1 g (95% CI: 2.0, 18.2) in fully adjusted models. CONCLUSIONS: Findings from this study do not support the hypothesis that residential green space is associated with reduced risk of preterm birth or higher birthweight after adjustment for individual and contextual socioeconomic factors, but variation in results with incremental adjustment raises questions about the optimal degree of control for confounding by markers of SES. We found that living near a freshwater body was associated with higher birthweight. This result is novel and bears further investigation in other settings and populations. PMID- 29433023 TI - Characterization of trace metal removal products in vertical flow bioreactor substrates at the Mayer Ranch Passive Treatment System in the Tar Creek Superfund Site. AB - A passive treatment system (PTS), including two parallel vertical flow bioreactors (VFBR), was constructed in 2008 for the treatment of unabated net alkaline ferruginous mine drainage in the Tar Creek Superfund Site in northeastern Oklahoma. Water quality data collected since the PTS began operation indicate significant removal of trace metals in the VFBR. Results of a sequential extraction procedure (SEP) performed on substrate samples showed that the majority of Cd, Co, Fe, Ni, Pb, and Zn were retained in the refractory organic/sulfide fraction. Subsequent acid volatile sulfide/simultaneously extracted metals (AVS/SEM) analyses confirmed the retention of Cd, Fe, Pb, and Zn as sulfides, but Co and Ni results were less certain. The majority of trace metals were retained as insoluble products in the VFBR, while up to 20% of most of the trace metals were retained in soluble, bioavailable fractions. Nearly 70% of Mn was retained in the soluble and bioavailable exchangeable, carbonate, and labile organic fractions. PMID- 29433022 TI - The aldehyde dehydrogenase AldA contributes to the hypochlorite defense and is redox-controlled by protein S-bacillithiolation in Staphylococcus aureus. AB - Staphylococcus aureus produces bacillithiol (BSH) as major low molecular weight (LMW) thiol which functions in thiol-protection and redox-regulation by protein S bacillithiolation under hypochlorite stress. The aldehyde dehydrogenase AldA was identified as S-bacillithiolated at its active site Cys279 under NaOCl stress in S. aureus. Here, we have studied the expression, function, redox regulation and structural changes of AldA of S. aureus. Transcription of aldA was previously shown to be regulated by the alternative sigma factor SigmaB. Northern blot analysis revealed SigmaB-independent induction of aldA transcription under formaldehyde, methylglyoxal, diamide and NaOCl stress. Deletion of aldA resulted in a NaOCl-sensitive phenotype in survival assays, suggesting an important role of AldA in the NaOCl stress defense. Purified AldA showed broad substrate specificity for oxidation of several aldehydes, including formaldehyde, methylglyoxal, acetaldehyde and glycol aldehyde. Thus, AldA could be involved in detoxification of aldehyde substrates that are elevated under NaOCl stress. Kinetic activity assays revealed that AldA is irreversibly inhibited under H2O2 treatment in vitro due to overoxidation of Cys279 in the absence of BSH. Pre treatment of AldA with BSH prior to H2O2 exposure resulted in reversible AldA inactivation due to S-bacillithiolation as revealed by activity assays and BSH specific Western blot analysis. Using molecular docking and molecular dynamic simulation, we further show that BSH occupies two different positions in the AldA active site depending on the AldA activation state. In conclusion, we show here that AldA is an important target for S-bacillithiolation in S. aureus that is up regulated under NaOCl stress and functions in protection under hypochlorite stress. PMID- 29433024 TI - Effect of quorum quenching on biofouling and ammonia removal in membrane bioreactor under stressful conditions. AB - Quorum quenching (QQ) has been used to control biofouling in membrane bioreactors (MBRs), but the effect of QQ on the performance of MBR has not been systematically studied. This study investigated the effect of QQ on ammonia removal in MBR especially in some stressful conditions. The results showed that membrane fouling was effectively alleviated by QQ in all conditions. For the short HRT (3.94 h), the ammonia removal in QQ-MBR was fluctuating. In the presence of nitrification inhibitors (acetonitrile and allylthiourea) or at low temperature (10 degrees C), QQ induced much more significant suppression on nitrification in batch test and MBR. The number of the ammonia oxidizing bacteria (AOB) was not decreasing in these situations, which indicated that QQ only suppressed the activity of AOB. In all, comprehensive considerations should be taken into account when applying a QS tuning strategy to a bioreactor. PMID- 29433025 TI - Time-dependent disturbances of chloride salts on overall redox reaction and luminescence in Vibrio fischeri. AB - The redox state of NADH/NADPH balance (nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate) is crucial in cellular homeostasis. Recent studies reported that sodium halide ions (NaX, X = F-, Cl-, Br- and I-) stimulated NAD(P)H in Vibrio fischeri (VF). However, it remained unanswered whether this pattern applied in salts with other cations, e.g., K+, Mg2+ and Ca2+, whose aquatic concentrations were increased by anthropogenic activities and climate change. Currently, VF were incubated with chloride salts, including KCl, MgCl2 and CaCl2, and effects were measured in a time-dependent fashion. Both NADH and NADPH showed stimulation that increased over time, and the greatest maximum stimulation at 24 h was CaCl2 > MgCl2 > KCl. The changes of NADH/NADPH ratios over time in CaCl2, MgCl2 and KCl were descendent, ascendant and stable, respectively. Simultaneously, FMN:NAD(P)H reaction catalyst (luciferase, in the form of expression levels of lux A and lux B), adenosine triphosphate and the expression levels of its regulating gene adk were also stimulated. The luminescence showed even more significant stimulations than the overall redox reaction. Together with earlier reported effects of NaCl, the chloride salts commonly disturbed the redox state and influenced the adaption of organisms to challenging environments. PMID- 29433026 TI - Simultaneous removal of nitrate and phosphate from wastewater by siderite based autotrophic denitrification. AB - The potential of simultaneous removal of nitrate and phosphate from wastewater by a single anaerobic Fe(II) oxidizing denitrifiers (the strain PXL1) was assessed using siderite biofilters under different influent TOC concentrations and hydraulic retention times (HRTs) over a 160-day trial. Higher TOC concentrations promoted NO3- removal, while there was no significant influence on PO43- removal. Lowering down HRT from 10 h to 5 h did not significantly influence NO3- and PO43- removal. The NO3- removal performance and microbial community structure in the biofilters indicated that NO3- was reduced to N2 by both strain PXL1 and heterotrophic Acidovorax delafieldii. Iron content analysis of the used siderite along the biofilters showed that PO43- removal was improved by the bio-oxidation of Fe(II) in siderite to Fe(III) via the strain PXL1. The coexistence of the strain PXL1 and natural siderite in nitrate-contaminated aquifers provides a practical technology for in situ remediation of nutrient contaminated waterbodies. PMID- 29433027 TI - Hydrolysis, adsorption, and biodegradation of bensulfuron methyl under methanogenic conditions. AB - Bensulfuron methyl (BSM), one of the most widely used herbicides in paddy soils, is frequently detected in natural and artificial aquatic systems. However, BSM transformation under methanogenic conditions has not been given sufficient attention. In this study, BSM elimination and transformation by anaerobic enrichment cultures were investigated. The results showed that BSM can be mineralized to methane through hydrolysis, adsorption, and biodegradation under a methanogenic environment. The adsorption led to protein static quenching in the extracellular polymeric substances (EPSs) of the enrichment cultures. Specifically, BSM mainly reacted with the amine, amide, amino acid, and amino sugar functional groups in proteins. BSM hydrolysis and biodegradation occurred through the breakage of the sulfonylurea bridge and sulfonyl amide linkage. The cleavage of the sulfonylurea bridge occurred in both hydrolysis and biodegradation, while the cleavage of the sulfonyl amide linkage only occurred in hydrolysis. These results elucidated the complex transformation of BSM under methanogenic conditions, which will advance the studies on sulfonylurea herbicide biotransformation and hazard assessment in the environment. PMID- 29433028 TI - Oxalate enhanced degradation of Orange II in heterogeneous UV-Fenton system catalyzed by Fe3O4@gamma-Fe2O3 composite. AB - Oxalate enhanced mechanism of Fe3O4@gamma-Fe2O3 was developed to provide novel insight into catalytic process regulation of iron oxide catalysts in heterogeneous UV-Fenton system. And the iron oxide composite of Fe3O4@gamma-Fe2O3 was characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), fourier transform infrared (FTIR) spectroscopy and nitrogen adsorption desorption isotherms. The results showed that large amount of iron could be leached from catalyst in the presence of oxalate, which promoted the homogeneous UV-Fenton reactions in solution. Orange II degradation could be significantly enhanced with the increase of the ratio of homogeneous UV-Fenton process to heterogeneous UV-Fenton process. The optimum concentration of oxalate determined by experiment was 0.5 mM in oxalate enhanced heterogeneous UV-Fenton system. On this condition, the pseudo-first-order rate constant value of Orange II degradation was 0.314 min-1, which was 2.3 times as high as that in heterogeneous UV-Fenton system. The removal rates of color and TOC were 100% and 86.6% after 20 min and 120 min treatment, respectively. In addition, the iron ions in solution could be almost completely adsorbed back to the catalyst surface in later degradation stages of Orange II. During the recycle experiments, the results showed that the increase of pH in solution and the sorption of intermediates on the catalyst surface would hinder oxalate enhanced process and lead to a decrease of degradation rate of Orange II in oxalate enhanced heterogeneous UV-Fenton system. PMID- 29433030 TI - Modeling the interaction and toxicity of Cu-Cd mixture to wheat roots affected by humic acids, in terms of cell membrane surface characteristics. AB - Responses of wheat (Triticum aestivum L.) seedling roots to the mixtures of copper (Cu), cadmium (Cd) and humic acids (HA) were investigated using the solution culture experiments, focusing on the interaction patterns between multiple metals and their influences on root proton release. A concentration addition multiplication (CA) model was introduced into the modeling analysis. In comparison with metal ion activities in bulk-phase solutions, the incorporation of ion activities at the root cell membrane surfaces (CMs) (denoted as {Cu2+}0 and {Cd2+}0) into the CA model could significantly improve their correlation with RRE (relative root elongation) from 0.819 to 0.927. Modeling analysis indicated that the co-existence of {Cu2+}0 significantly enhanced the rhizotoxicity of {Cd2+}0, while no significant effect of {Cd2+}0 on the {Cu2+}0 rhizotoxicity. 10 mg/L HA stimulated the root elongation even under metal stress. Although high concentration of metal ions inhibited the root proton release rate (DeltaH+), both the low concentration of metal ions and HA treatments increased the values of DeltaH+. In HA-Cu-Cd mixtures, actions of metal ions on DeltaH+ values were varied intricately among treatments but well modeled by the CA model. We concluded from the CA models that the electrostatic effect is vitally important for explaining the effect of {Cu2+}0 on the rhizotoxicity of {Cd2+}0, while it plays no unique role in understanding the influence of {Cd2+}0 on the rhizotoxicity of {Cu2+}0. Thus our study provide a novel way for modeling multiple metals behaviors in the environment and understanding the mechanisms of ion interactions. PMID- 29433029 TI - Covalent binding of the organophosphate insecticide profenofos to tyrosine on alpha- and beta-tubulin proteins. AB - Organophosphorus (OP) compounds can bind covalently to many types of proteins and form protein adducts. These protein adducts can indicate the exposure to and neurotoxicity of OPs. In the present work, we studied adduction of tubulin with the OP insecticide profenofos in vitro and optimized the method for detection of adducted peptides. Porcine tubulin was incubated with profenofos and was then digested with trypsin, followed by mass spectrometric identification of the profenofos-modified tubulin and binding sites. With solvent-assisted digestion (80% acetonitrile in digestion solution), the protein was digested for peptide identification, especially for some peptides with low mass. The MALDI-TOF-MS and LC-ESI-TOF-MS analysis results showed that profenofos bound covalently to Tyr83 in porcine alpha-tubulin (TGTY*83R) and to Tyr281 in porcine beta-tubulin (GSQQY*281R) with a mass increase of 166.02 Da from the original peptide fragments of porcine tubulin proteins. Tyrosine adduct sites were also confirmed by MALDI-TOF/TOF-MS analysis. This result may partially explain the neurotoxicity of profenofos at low doses and prolonged periods of exposure. PMID- 29433031 TI - Peroxymonosulfate/base process in saline wastewater treatment: The fight between alkalinity and chloride ions. AB - Both Cl- and base can affect PMS activation to produce reactive chlorine or oxygen species, but the overall effects of chloride on this emerging PMS/base technology in saline wastewater treatment are unknown. Here effectiveness of PMS/base, PMS/Cl- and PMS/base/Cl- is compared with a gradient concentration of chloride and alkalinity, by probing the degradation of methylene blue (MB). Both PMS/base and PMS/Cl- systems can rapidly degrade MB due to the generation of singlet oxygen and reactive chlorine, respectively. Interestingly, dye degradation and adsorbable organic halides (AOX) formation are inhibited in the PMS/base/Cl- system as high concentrations of Cl- and base co-exist. Reaction of PMS with chloride diminishes the effective concentration of PMS by base activation, whereas in return high alkalinity decreases the oxidation capacity of reactive species. Therefore, this finding may have significant technical implications for evaluating the applicability of the emerging PMS/base technology and optimizing the conditions for AOX abatement in PMS-based processes. PMID- 29433032 TI - Seasonal variations of PCDD/Fs congeners in air, soil and eggs from a Polish small-scale farm. AB - The transfer of dioxin from the environment to the food is a problem in a consumers' health protection. The study aimed to determine the concentration of dioxins in free-range chicken eggs, air and soil samples, collected during 12 months on an individual small farm, located in Malopolska region, Poland. In the majority of analyzed eggs, the concentrations of dioxin exceeded several times the legal limit of 2.5 pg WHO-TEQ g-1fat. Seasonal changes in the PCDD/Fs congeners in egg, air and soil samples were studied. During the winter season, when the combustion processes of the solid fuel in domestic furnaces are intensive, the PM10 concentration in the Malopolska region exceeds the legal limit (50MUg/m3) even eight times. In this period, eggs, air and soil samples showed a higher share of PCDFs with a specific contribution of 2,3,7,8-TCDF. During the summer months, in the egg, air and soil samples, the share of PCDDs is higher with dominant OCDD and 1,2,3,4,6,7,8-HpCDDs, showing the effect of other combustion processes such as grass utilization or burning plastic wastes in controlled fires. In August, the month of the highest average air temperature and lowest rainfall amount, the highest toxicity of PCDD/Fs in eggs (9.52pgWHO-TEQ g 1fat) was found. Due to the similarity of the shares of PCDD/Fs congeners in total WHO-TEQ value we can take into account the influence of toxicity of PCDD/Fs in the air and soil on the toxicity in the eggs. PMID- 29433033 TI - Applying molecular modelling and experimental studies to develop molecularly imprinted polymer for domoic acid enrichment from both seawater and shellfish. AB - A highly selective sample cleanup method using molecularly imprinted polymers (MIP) was developed for the enrichment of domoic acid (DA, an amnesic shellfish toxin) from both seawater and shellfish samples. Molecular modelling was firstly applied to screening a suitable functional monomer and optimize the polymer preparation. Theoretical results were in a good agreement with those of the experimental studies. MIP was prepared by precipitation polymerization using 1, 3, 5-pentanetricarboxylic acid and 2-(Trifluoromethyl)acrylic acid as the template molecule and functional monomer, respectively. The morphology and molecular structure of MIP were revealed by scanning electron microscope (SEM) and fourier transform infrared spectroscopy (FTIR), respectively. The obtained MIP showed high affinity and selectivity for DA with binding site numbers of 0.875 mg g-1 and an average association constant of 0.219 L mg-1 evaluated by adsorption experiments. The developed molecularly imprinted solid-phase extraction (MISPE) column achieved satisfied adsorption rate (99.2%) and recovery (71.2%) with relative standard deviation (RSD) less than 1.0%, which is more stable and precise than the C18, SAX, and HLB columns. Finally, the determination method for DA in both seawater and shellfish samples was then successfully established and validated using MISPE coupled with high-performance liquid chromatography-ultraviolet detection (HPLC-UV). The method limit of detection was 20 MUg L-1 and 50 MUg kg-1 for seawater and shellfish, respectively. This study demonstrates that molecular modelling is a useful tool to screening functional monomer and optimize polymer preparation. It provides an innovative polymer for trace DA monitoring in both seawater and shellfish. PMID- 29433034 TI - Inter-semispinal plane block for cervical spine surgery. PMID- 29433035 TI - A modified anterior approach for ultrasound-guided maxillary nerve block and its application to the mandibular nerve block. PMID- 29433036 TI - Hemodynamic monitoring by the aortic velocity-time integral in supra sternal Doppler echocardiography and total cavo-pulmonary derivation in cesarean delivery. PMID- 29433037 TI - Appropriate use of the increment entropy for electrophysiological time series. AB - The increment entropy (IncrEn) is a new measure for quantifying the complexity of a time series. There are three critical parameters in the IncrEn calculation: N (length of the time series), m (dimensionality), and q (quantifying precision). However, the question of how to choose the most appropriate combination of IncrEn parameters for short datasets has not been extensively explored. The purpose of this research was to provide guidance on choosing suitable IncrEn parameters for short datasets by exploring the effects of varying the parameter values. We used simulated data, epileptic EEG data and cardiac interbeat (RR) data to investigate the effects of the parameters on the calculated IncrEn values. The results reveal that IncrEn is sensitive to changes in m, q and N for short datasets (N<=500). However, IncrEn reaches stability at a data length of N=1000 with m=2 and q=2, and for short datasets (N=100), it shows better relative consistency with 2<=m<=6 and 2<=q<=8 We suggest that the value of N should be no less than 100. To enable a clear distinction between different classes based on IncrEn, we recommend that m and q should take values between 2 and 4. With appropriate parameters, IncrEn enables the effective detection of complexity variations in physiological time series, suggesting that IncrEn should be useful for the analysis of physiological time series in clinical applications. PMID- 29433038 TI - Deep transfer learning for characterizing chondrocyte patterns in phase contrast X-Ray computed tomography images of the human patellar cartilage. AB - Phase contrast X-ray computed tomography (PCI-CT) has been demonstrated to be effective for visualization of the human cartilage matrix at micrometer resolution, thereby capturing osteoarthritis induced changes to chondrocyte organization. This study aims to systematically assess the efficacy of deep transfer learning methods for classifying between healthy and diseased tissue patterns. We extracted features from two different convolutional neural network architectures, CaffeNet and Inception-v3 for characterizing such patterns. These features were quantitatively evaluated in a classification task measured by the area (AUC) under the Receiver Operating Characteristic (ROC) curve as well as qualitative visualization through a dimension reduction approach t-Distributed Stochastic Neighbor Embedding (t-SNE). The best classification performance, for CaffeNet, was observed when using features from the last convolutional layer and the last fully connected layer (AUCs >0.91). Meanwhile, off-the-shelf features from Inception-v3 produced similar classification performance (AUC >0.95). Visualization of features from these layers further confirmed adequate characterization of chondrocyte patterns for reliably distinguishing between healthy and osteoarthritic tissue classes. Such techniques, can be potentially used for detecting the presence of osteoarthritis related changes in the human patellar cartilage. PMID- 29433039 TI - Design-based research in designing the model for educating simulation facilitators. AB - The purpose of this article is to introduce the concept of design-based research, its appropriateness in creating education-based models, and to describe the process of developing such a model. The model was designed as part of the Nurse Educator Simulation based learning project, funded by the EU's Lifelong Learning program (2013-1-DK1-LEO05-07053). The project partners were VIA University College, Denmark, the University of Huddersfield, UK and Metropolia University of Applied Sciences, Finland. As an outcome of the development process, "the NESTLED model for educating simulation facilitators" (NESTLED model) was generated. This article also illustrates five design principles that could be applied to other pedagogies. PMID- 29433040 TI - Pharmaceutical opioid overdose deaths and the presence of witnesses. AB - BACKGROUND: In the past two decades, rates of pharmaceutical opioid use and harms resulting from their use (including death) have risen. The present study identified a series of fatal opioid overdoses where there was evidence that witnesses had noted symptoms consistent with overdose, and examined associated contextual factors. METHODS: A retrospective review was undertaken utilising the Coroners Court of Victoria's Overdose Deaths Register for pharmaceutical opioid overdose deaths between 2011 and 2013. Information on the source of pharmaceutical opioids, co-contributing drugs, history of drug dependence, and mental illness was extracted and coded. RESULTS: Pharmaceutical opioids were involved in 587 deaths, and within these, 125 cases (21%) were witnessed. The majority of these witnessed deaths (77.6%) occurred at the deceased's residence, with the witness being a partner or unrelated acquaintance who did not realise the significance of what they were witnessing. The most common contributing pharmaceutical opioids were methadone (49.6%), codeine (32.0%), and oxycodone (19.2%), with the source more often prescribed than diverted. Co-contributing drugs were involved in 110 cases, with the most common being benzodiazepines. Evidence of current dependence and mental illness was found in 53.6% of cases. CONCLUSION: Most pharmaceutical opioid overdose deaths with a witness present occurred in the deceased's home, with symptoms of overdose being noted, but not acted upon. These findings support the trialling of education and/or naloxone to partners and family members of people who use pharmaceutical opioids in order to reduce overdose deaths. PMID- 29433041 TI - Synthesis and photoluminescence properties of europium(III) complexes sensitized with beta-diketonato and N, N-donors ancillary ligands. AB - Synthesis of three new europium(III) complexes with 1,3-[bis(4 methoxyphenyl)]propane-1,3-dionato (HBMPD) ligand and ancillary ligands such as 2,2'-biquinoline (biq) or neocuproine (neo) has been reported in this report. The synthesized complexes were characterized by IR (infrared), 1H and 13C NMR (nuclear magnetic resonance) spectroscopy, CHN (carbon, hydrogen and nitrogen) elemental analysis, XRD (X-ray diffraction), TGA (thermogravimetric analysis) and photoluminescence (PL) spectroscopy. The emission spectra of europium(III) complexes displayed both the low intensity 5D1-3->7F0-3 transitions in 410-560nm blue-green region and high intensity characteristic 5D0->7F0-3 transitions in 575 640nm orange-red region correspond to the emission of ancillary ligands and europium ion respectively, which can lead to white luminescence due to integration of blue, green and red color emissions. The photoluminescence investigations indicate that the absorbed energy of the HBMPD ligand transferred to the central europium(III) ion in an efficient manner, which clearly explained by antenna effect. The excellent results of thermal behavior and photophysical properties like luminescence spectra, CIE (Commission Internationale Eclairage) chromaticity coordinates, luminescence decay curves and high quantum efficiency of the complexes make them a promising component of the white light-emitting diodes in display devices. PMID- 29433042 TI - Synthesis of a single 1,8-naphthalimide fluorophore as a molecular logic lab for simultaneously detecting of Fe3+, Hg2+ and Cu2. AB - A novel fluorescence sensing 1,8-naphthalimide fluorophore is synthesized and investigated. The novel probe comprising two different binding moieties is capable to detect selectively Fe3+ over the other representative metal ions as well as a combination of biologically important cations such as Fe3+, Cu2+ and Hg2+ in the physiological range without an interfering effect of the pHs. Due to the remarkable fluorescence changes in the presence of Fe3+, Hg2+ and Cu2+ ions, INH and AND logic gates are executed and the system is able to act as a single output combinatorial logic circuit with three chemical inputs. PMID- 29433043 TI - Increased movement variability in one-leg hops about 20 years after treatment of anterior cruciate ligament injury. AB - BACKGROUND: Recent studies highlight the need for understanding movement control of adjacent joints when evaluating knee function following anterior cruciate ligament (ACL) injury. However, while short-term adaptations to lower-extremity joint coupling have been studied, little is known about any potential long-term adaptations in neuromuscular control displayed by ACL-injured individuals. The aim of our study was to determine whether coordination variability of the hip knee joint couplings during the one-leg hop is altered about 20 years after injury in two ACL-injured groups compared to healthy knee controls. METHODS: Seventy persons performed one leg hops ~23 years after ACL injury and following different treatments: 33 participants treated with physiotherapy in combination with ACL-reconstruction (ACLR); 37 participants with physiotherapy alone (ACLPT). They were compared to 33 matched controls. A vector coding procedure was used to create joint couplings for knee and hip angles on all the cardinal planes for the Take-off and Landing phases. The standard deviation of each coupling was computed as a measure of coordination variability. FINDINGS: Both the ACL groups differed significantly from controls on their injured side with ~50% higher knee abduction adduction/hip internal-external rotation variability during the Take-off phase; ~33% higher knee abduction-adduction/knee flexion-extension variability and greater knee abduction-adduction/hip flexion-extension variability (ACLR 50%; ACLPT 80%) during the Landing phase. There were no major differences between injured and non-injured sides in any group. INTERPRETATION: Increased variability in lower-extremity joint couplings has emerged as a conspicuous feature of ACL injured persons in the very long term compared to non-injured controls, independent of treatment. Further research of the processes leading to alterations in movement variability using longitudinal studies would facilitate better understanding of the functional adaptations leading to knee dysfunction in the short- and long-term after ACL injury. PMID- 29433044 TI - Spent coffee enhanced biomethane potential via an integrated hydrothermal carbonization-anaerobic digestion process. AB - This study reports the implications of using spent coffee hydrochar as substrate for anaerobic digestion (AD) processes. Three different spent coffee hydrochars produced at 180, 220 and 250 degrees C, 1 h residence time, were investigated for their biomethane potential in AD process inoculated with cow manure. Spent coffee hydrochars were characterized in terms of ultimate, proximate and higher heating value (HHV), and their theoretical bio-methane yield evaluated using Boyle-Buswell equation and compared to the experimental values. The results were then analyzed using the modified Gompertz equation to determine the main AD evolution parameters. Different hydrochar properties were related to AD process performances. AD of spent coffee hydrochars produced at 180 degrees C showed the highest biomethane production rate (46 mL CH4/gVS.d), a biomethane potential of 491 mL/gVS (AD lasting 25 days), and a biomethane gas daily composition of about 70%. PMID- 29433045 TI - High xylan recovery using two stage alkali pre-treatment process from high lignin biomass and its valorisation to xylooligosaccharides of low degree of polymerisation. AB - In the present work, xylan from arecanut husk was extracted using 2 stage alkaline pretreatment process. In first step, biomass was incubated in alkali at different temperatures (25 degrees C, 50 degrees C and 65 degrees C), alkali concentrations (5%, 10%, 15% and 20% w/v), and incubation periods (8 h, 16 h and 24 h) and evaluated for xylan recovery. It was observed that 40-52% of available xylan could be recovered using 10% alkali when incubated for 8-24 h at 65 degrees C. Subsequently, the alkali pretreatment operating conditions which provided good xylan recovery were processed further using hydrothermal treatment to extract more xylan. For maximum xylan recovery (>90%), best operating conditions were identified when biomass was treated under hydrothermal treatment (1, 1.5 and 2 h) with varying incubation periods (8, 16, 24 h) and alkali concentrations (5%, 10%) using full factorial design. Incubating arecanut husk with 10% w/v NaOH, at 65 degrees C for a period of 8 h, followed by hydrothermal treatment at 121 degrees C for 1 h helped recover >94% xylan. In the next step, enzymatic hydrolysis process was optimized to recover maximum XOS (Optimized condition: 50 degrees C, pH 4 and 10 U enzyme dose). The hydrolysate comprised of xylobiose: 25.0 +/- 1.2 g/100 g xylan (~71% of XOS), xylotriose: 9.2 +/- 0.65 g/100 g xylan (26.2% of XOS) and xylotetrose: 0.9 +/- 0.04 g/100 g xylan (2% of XOS). The developed process enables to reduce alkali consumption for high recovery of xylan from biomass with relatively higher lignin content for its valorisation into a potential prebiotic oligosaccharide. PMID- 29433046 TI - A comprehensive insight into the effects of microwave-H2O2 pretreatment on concentrated sewage sludge anaerobic digestion based on semi-continuous operation. AB - This study gave a comprehensive insight into the effects of microwave-H2O2 pretreatment on concentrated sludge anaerobic digestion (AD). Results showed that mixture of activated sludge and pretreated sludge at mass ratio of 1:1 was efficient for enhancing AD, methane production was increased from 215.51 mL/g VSadded to 258.38 mL/g VSadded. Pretreatment resulted in the change of sludge properties, such as solubilization of organic matters, decrease of viscosity. For concentrated sludge AD, the "pH buffer system" ensured the "inhibitory steady state" during start-up period, and significant archaeal community shift from Methanosaeta to Methanosarcina ensured the true steady-state operation. Pretreatment further increased the relative abundance of functional microbia such as Bacteroidales, Clostridiales and Methanosarcina, and resulted in the decrease of viscosity of digested sludge in reactors. Based on the CFD simulation, the flow velocity became greater than the control. These comprehensive effects might contribute to enhanced efficiency of concentrated sludge AD. PMID- 29433047 TI - Effect of tricarboxylic acid cycle regulator on carbon retention and organic component transformation during food waste composting. AB - Composting is an environment friendly method to recycling organic waste. However, with the increasing concern about greenhouse gases generated in global atmosphere, it is significant to reduce the emission of carbon dioxide (CO2). This study analyzes tricarboxylic acid (TCA) cycle regulators on the effect of reducing CO2 emission, and the relationship among organic component (OC) degradation and transformation and microorganism during composting. The results showed that adding adenosine tri-phosphate (ATP) and nicotinamide adenine dinucleotide (NADH) could enhance the transformation of OC and increase the diversity of microorganism community. Malonic acid (MA) as a competitive inhibitor could decrease the emission of CO2 by inhibiting the TCA cycle. A structural equation model was established to explore effects of different OC and microorganism on humic acid (HA) concentration during composting. Furthermore, added MA provided an environmental benefit in reducing the greenhouse gas emission for manufacture sustainable products. PMID- 29433048 TI - Effects of changes in temperature on treatment performance and energy recovery at mainstream anaerobic ceramic membrane bioreactor for food waste recycling wastewater treatment. AB - An anaerobic ceramic membrane bioreactor (AnCMBR) has been attracted as an alternative technology to co-manage various organic substrates. This AnCMBR study investigated process performance and microbial community structure at decreasing temperatures to evaluate the potential of AnCMBR treatment for co-managing domestic wastewater (DWW) and food waste-recycling wastewater (FRW). As a result, the water flux (>=6.9 LMH) and organic removal efficiency (>=98.0%) were maintained above 25 degrees C. The trend of methane production in the AnCMBR was similar except for at 15 degrees C. At 15 degrees C, the archaeal community structure did not shifted, whereas the bacterial community structure was changed. Various major archaeal species were identified as the mesophilic methanogens which unable to grow at 15 degrees C. Our results suggest that the AnCMBR can be applied to co-manage DWW and FRW above 20 degrees C. Future improvements including psychrophilic methanogen inoculation and process optimization would make co-manage DWW and FRW at lower temperature climates. PMID- 29433049 TI - Mechanical cell disruption of Parachlorella kessleri microalgae: Impact on lipid fraction composition. AB - Samples of nitrogen-starved Parachlorella kessleri containing intact cells (IC), cells ground by bead milling (BM), and cells subjected to high-pressure cell disruption (HPD), together with their supernatants after centrifugation, were compared for granulometry and lipid profiles. The effects of disruption on the lipid profile and organisation were evaluated. The quantity of lipids available for extraction increased with disruption, and up to 81% could be recovered in supernatants after centrifugation, but a marked reorganization occurred. The proportion of amphiphilic free fatty acids and lysophosphatidylcholine increased during disruption due to their release or owing to lipid degradation by enzymes or physical conditions. This effect was more marked in HPD than in BM. Lipids contained in the aqueous phase, after disruption and centrifugation, were enriched in unsaturated fatty acids, BM leading to larger droplets than HPD. The larger liquid lipid droplet would be easier to recover in the following downstream processing. PMID- 29433050 TI - Outdoor pilot-scale cultivation of Spirulina sp. LEB-18 in different geographic locations for evaluating its growth and chemical composition. AB - This study evaluated whether outdoor cultivation of Spirulina sp. in different geographical locations affected its growth and biomass quality, with respect to the chemical composition, volatile compound and heavy metal content, and thermal stability. The positive effect of solar radiation and temperature on biomass productivity in Spirulina sp. cultivated in the northeast was directly related to its improved nutritional characteristics, which occurred with an increase in protein, phycocyanin, and polyunsaturated fatty acid (mainly gamma-linolenic) content. The biomass produced in Northeast and South Brazil showed high thermal stability and had volatile compounds that could be used as biomarkers of Spirulina, and their parameters were within the limits of internationally recognized standards for food additives; hence, they have been considered safe foods. However, the growth of crops in south Brazil occurred at lower rates due to low temperatures and luminous intensities, indicative of the robustness of microalgae in relation to these parameters. PMID- 29433051 TI - Exploring optimal supplement strategy of medicinal herbs and tea extracts for bioelectricity generation in microbial fuel cells. AB - This first-attempt study used extracts of appropriate antioxidant abundant Camellia and non-Camellia tea and medicinal herbs as model ESs to stably intensify bioelectricity generation performance in microbial fuel cells (MFCs). As electron shuttles (ESs) could stimulate electron transport phenomena by significant reduction of electron transfer resistance, the efficiency of power generation for energy extraction in microbial fuel cells (MFCs) could be appreciably augmented. Using environmentally friendly natural bioresource as green bioresource of ESs is the most promising to sustainable practicability. As comparison of power-density profiles indicated, supplement of Camellia tea extracts would be the most appropriate, then followed non-Camellia Chrysanthemum tea and medicinal herbs. Antioxidant activities, total phenolic contents and power stimulating activities were all electrochemically associated. In particular, the extract of unfermented Camellia tea (i.e., green tea) was the most promising ESs to augment bioenergy extraction compared to other refreshing medicinal herb extracts. PMID- 29433052 TI - Association of red cell distribution width with clinical outcomes in myelodysplastic syndrome. AB - Studies showed red cell distribution width (RDW) can improve the detection of morphological changes in red blood cells and the understanding of their contribution to dyserythropoiesis in myelodysplastic syndrome (MDS). The purpose of the study was to evaluate dyserythropoiesis in MDS by RDW analysis and to explore the utility of RDW in clinical practice. We retrospectively analyzed laboratory and clinical data of 101 patients (59 patients was refractory anemia (RA) according to the French-American-British (FAB) classification). In patients with RA, RDW was showed weak inverse correlation with both hemoglobin concentration (Hb) (rs = -0.37, P = 0.0035) and mean corpuscular hemoglobin concentration (MCHC) (rs = -0.36, P = 0.0047). On the other hand, RDW was showed weak correlation with the number of ringed sideroblasts in bone marrow (rs = 0.31, P = 0.023). The increased RDW (>=15.0%) was associated with shorter overall survival (OS) (P = 0.0086). In patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-t), effect of RDW on OS was less evident. These results suggested that increased RDW might reflect dyserythropoiesis, associated with deregulated hemoglobin synthesis and iron metabolism in MDS. Furthermore, increased RDW may have potential to be a prognostic significance in RA. PMID- 29433053 TI - Differentiation of mixed soil-borne fungi in the genus level using infrared spectroscopy and multivariate analysis. AB - Early detection of soil-borne pathogens, which have a negative effect on almost all agricultural crops, is crucial for effective targeting with the most suitable antifungal agents and thus preventing and/or reducing their severity. They are responsible for severe diseases in various plants, leading in many cases to substantial economic losses. In this study, infrared (IR) spectroscopic method, which is known as sensitive, accurate and rapid, was used to discriminate between different fungi in a mixture was evaluated. Mixed and pure samples of Colletotrichum, Verticillium, Rhizoctonia, and Fusarium genera were measured using IR microscopy. Our spectral results showed that the best differentiation between pure and mixed fungi was obtained in the 675-1800 cm-1 wavenumber region. Principal components analysis (PCA), followed by linear discriminant analysis (LDA) as a linear classifier, was performed on the spectra of the measured classes. Our results showed that it is possible to differentiate between mixed calculated categories of phytopathogens with high success rates (~100%) when the mixing percentage range is narrow (40-60) in the genus level; when the mixing percentage range is wide (10-90), the success rate exceeded 85%. Also, in the measured mixed categories of phytopathogens it is possible to differentiate between the different categories with ~100% success rate. PMID- 29433054 TI - Hallmarks of cancer: The CRISPR generation. AB - The hallmarks of cancer were proposed as a logical framework to guide research efforts that aim to understand the molecular mechanisms and derive treatments for this highly complex disease. Recent technological advances, including comprehensive sequencing of different cancer subtypes, have illuminated how genetic and epigenetic alterations are associated with specific hallmarks of cancer. However, as these associations are purely descriptive, one particularly exciting development is the emergence of genome editing technologies, which enable rapid generation of precise genetic and epigenetic modifications to assess the consequences of these perturbations on the cancer phenotype. The most recently developed of these tools, the system of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), consists of an RNA-guided endonuclease that can be repurposed to edit both genome and epigenome with high specificity, and facilitates the functional interrogation of multiple loci in parallel. This system has the potential to dramatically accelerate progress in cancer research, whether by modelling the genesis and progression of cancer in vitro and in vivo, screening for novel therapeutic targets, conducting functional genomics/epigenomics, or generating targeted cancer therapies. Here, we discuss CRISPR research on each of the ten hallmarks of cancer, outline potential barriers for its clinical implementation and speculate on the advances it may allow in cancer research in the near future. PMID- 29433055 TI - Presurgical treatment with somatostatin analogues in growth hormone-secreting pituitary adenomas: A long-term single-center experience. AB - OBJECTIVE: Acromegalic patients with macro- or giant adenomas often had poor prognosis after surgery. Somatostatin analogues (SSAs) show high effectiveness in both tumor shrinkage and serum GH reduction. But the role of SSAs in pre-surgical treatment and the management among macro- and giant adenomas remains controversial. PATIENTS AND METHODS: A total of 100 acromegalic patients with macro- or giant adenomas that underwent surgery in our institution between January 2010 and December 2016 were enrolled in the current retrospective study. The relationships between several potential parameters and surgical outcomes were further analyzed. RESULTS: The overall long-term remission rate was 45% accompanied by gross total resection (GTR) rate of 44%. GTR (adjusted OR = 16.346; p = .001) and nadir GH level on OGTT 7 days after surgery (GH-7, adjusted OR = 0.660, p = .039) showed predictive significance for remission after surgery. Tumor size and invasiveness as well as cavernous sinus invasion were risk factors for residual tumor. For invasive macro- or giant adenomas, 6 of 15 patients achieved long-term remission with SSA pre-treatment whereas none of the 18 patients without any preoperative treatment was endocrine controlled. CONCLUSIONS: Acromegalic patients did not gain more benefits from SSAs pretreatment. But, pre-treatment with SSA could be recommended to patients with invasive macro- or giant adenomas for significant improvement in long-term remission. GTR and GH-7 could be significant predictors in postoperative management of macro- or giant adenomas. PMID- 29433056 TI - Optic nerve sheath diameter based on preoperative brain computed tomography and intracranial pressure are positively correlated in adults with hydrocephalus. AB - OBJECTIVE: The usefulness of optic nerve sheath diameter (ONSD) in predicting increased intracranial pressure (ICP) is not well established in adults with hydrocephalus. In this retrospective study, we evaluated the correlation between ONSD measured on brain computed tomography (CT) and ICP in adults with hydrocephalus. PATIENTS AND METHODS: ONSDs were measured on preoperative brain CT images from 64 adult patients with hydrocephalus who underwent extracranial ventricular drainage or a ventriculoperitoneal shunt in 2016. ICP was defined as ventricular fluid pressure. RESULTS: The ONSD measured on preoperative CT was greater in patients (n = 8) with a higher ICP (>20 mmHg, 5.8vs. 4.9 mm, P = 0.001). The ONSD was linearly correlated with ICP (r = 0.543, P < 0.001) and was predictive of increased ICP with an area under the receiver operating characteristic curve of 0.834. The optimal cut-off value of 5.3 mm ONSD yielded 88% sensitivity and 79% specificity. The inter-class coefficient of ONSD on preoperative CT was 0.882. The correlation between ONSD on preoperative CT and ICP was detected only in patients with communicating and non-communicating hydrocephalus (r = 0.437 and r = 0.585, P = 0.037 and P = 0.002, respectively). CONCLUSION: ONSD measured on preoperative brain CT was linearly correlated with ICP in adult patients with communicating and non-communicating hydrocephalus, and it was a predictor of increased ICP with good discrimination and high inter observer reliability. These results suggest that preoperative ONSD measurement on brain CT can be helpful to safely manage such patients by providing information about ICP. PMID- 29433057 TI - A solution for the rare type match problem when using the DIP-STR marker system. AB - The rare type match problem is an evaluative challenging situation in which the analysis of a DNA profile reveals the presence of (at least) one allele which is not contained in the reference database. This situation is challenging because an estimate for the frequency of occurrence of the profile in a given population needs sophisticated evaluative procedures. The rare type match problem is very common when the DIP-STR marker system, which has proven itself very useful for dealing with unbalanced DNA mixtures, is used, essentially due to the limited size of the available database. The object-oriented Bayesian network proposed in Cereda et al. [7] to assess the value of the evidence for general scenarios, was not designed to deal with this particular situation. In this paper, the model is extended and partially modified to be able to calculate the full Bayesian likelihood ratio in presence of any (observed and not yet observed) allele of a given profile. The method is based on the approach developed in Cereda [5] for Y STR data. Alternative solutions, such as the plug-in approximation and an empirical Bayesian methodology are also proposed and compared with the results obtained with the full Bayesian approach. PMID- 29433058 TI - Defining mtDNA origins and population stratification in Rio de Janeiro. AB - The genetic composition of the Brazilian population was shaped by interethnic admixture between autochthonous Native Americans, Europeans settlers and African slaves. This structure, characteristic of most American populations, implies the need for large population forensic databases to capture the high diversity that is usually associated with admixed populations. In the present work, we sequenced the control region of mitochondrial DNA from 205 non-related individuals living in the Rio de Janeiro metropolitan region. Overall high haplotype diversity (0.9994 +/- 0.0006) was observed, and pairwise comparisons showed a high proportion of haplotype pairs with more than one-point differences. When ignoring homopolymeric tracts, pairwise comparisons showed no differences 0.18% of the time, and differences in a single position were found with a frequency of 0.32%. A high percentage of African mtDNA was found (42%), with lineages showing a major South West origin. For the West Eurasian and Native American haplogroups (representing 32% and 26%, respectively) it was not possible to evaluate a clear geographic or linguistic affiliation. When grouping the mtDNA lineages according to their continental origin (Native American, European and African), differences were observed for the ancestry proportions estimated with autosomal ancestry informative markers, suggesting some level of genetic substructure. The results from this study are in accordance with historical data where admixture processes are confirmed with a strong maternal contribution of African maternal ancestry and a relevant contribution of Native American maternal ancestry. Moreover, the evidence for some degree of association between mtDNA and autosomal information should be considered when combining these types of markers in forensic analysis. PMID- 29433060 TI - Dual tumor-targeted multifunctional magnetic hyaluronic acid micelles for enhanced MR imaging and combined photothermal-chemotherapy. AB - Multifunctional polymeric micelles were developed as a promising dual tumor targeted drug delivery platform for magnetic resonance (MR) imaging and combined photothermal-chemotherapy. HA-C16 copolymers were synthesized via peptide formation process with subsequent co-encapsulation of therapeutic agent docetaxel (DTX) and superparamagnetic iron oxide nanoparticles (SPIONs) to form the multifunctional micelles. The micelles exhibited uniform nanosize and remarkable colloidal stability in aqueous solution. The sustained drug release behavior from HA micelles was observed over the test period. Moreover, the specific targeting capability based on CD44 recptor-mediated endocytosis and the enhanced targeting efficacy by in presence of external magnetic field were investigated. The clustered SPIONs within micelles exerted excellent contrast effect with high r2 relaxivity in MR phantom test. Furthermore, the multifunctional micelles could readily convert light to heat to hyperthermia temperature upon near infrared light irradition and induce photothermal ablation to breast cancer cells. The combined photothermal therapy with DTX-mediated chemotherapy of the developed multifunctional polymeric micells could generate a synergistic therapeutic effect. Based on these findings, the resulting multifunctional micelles may provide high potential for multimodality theragnosis of cancer. PMID- 29433059 TI - Resveratrol liposomes and lipid nanocarriers: Comparison of characteristics and inducing browning of white adipocytes. AB - Trans-resveratrol (R) has a potential to increase energy expenditure via inducing browning in white adipose tissue. However, its low levels of aqueous solubility, stability, and poor bioavailability limit its application. We have successfully synthesized biocompatible, and biodegradable R encapsulated lipid nanocarriers (R nano), and R encapsulated liposomes (R-lipo). The mean particle size of R-nano and R-lipo were 140 nm and 110 nm, respectively, and their polydispersity index values were less than 0.2. Nanoencapsulation significantly increased aqueous solubility and enhanced chemical stability of R, especially at 37 degrees C. R lipo had higher physical and chemical stability than R-nano while R-nano had more prolonged release than R-lipo. Both R-nano and R-lipo increased cellular R content in 3T3-L1 cells. Both R-nano and R-lipo dose-dependently induced uncoupling protein 1 (UCP1) mRNA expression and decreased white specific marker insulin growth factor binding protein 3 expression under isoproterenol (ISO) stimulated conditions. At the low dose (5 MUM), nanoencapsulated compared to native R enhanced UCP1 and beige marker CD137 expression under ISO-stimulated conditions. Compared to R-nano, R-lipo had better biological activity, possibly due to its higher physical and chemical stability at the room and body temperature. Taken together, our study demonstrates that nanoencapsulation increased R's aqueous solubility and stability, which led to enhanced browning of white adipocytes. Even though both R-lipo and R-nano increased R's browning activities, their differential characteristics need to be considered in obesity treatment. PMID- 29433061 TI - Specialization of the auditory system for the processing of bio-sonar information in the frequency domain: Mustached bats. AB - For echolocation, mustached bats emit velocity-sensitive orientation sounds (pulses) containing a constant-frequency component consisting of four harmonics (CF1-4). They show unique behavior called Doppler-shift compensation for Doppler shifted echoes and hunting behavior for frequency and amplitude modulated echoes from fluttering insects. Their peripheral auditory system is highly specialized for fine frequency analysis of CF2 (~61.0 kHz) and detecting echo CF2 from fluttering insects. In their central auditory system, lateral inhibition occurring at multiple levels sharpens V-shaped frequency-tuning curves at the periphery and creates sharp spindle-shaped tuning curves and amplitude tuning. The large CF2-tuned area of the auditory cortex systematically represents the frequency and amplitude of CF2 in a frequency-versus-amplitude map. "CF/CF" neurons are tuned to a specific combination of pulse CF1 and Doppler-shifted echo CF2 or 3. They are tuned to specific velocities. CF/CF neurons cluster in the CC ("C" stands for CF) and DIF (dorsal intrafossa) areas of the auditory cortex. The CC area has the velocity map for Doppler imaging. The DIF area is particularly for Dopper imaging of other bats approaching in cruising flight. To optimize the processing of behaviorally relevant sounds, cortico-cortical interactions and corticofugal feedback modulate the frequency tuning of cortical and sub-cortical auditory neurons and cochlear hair cells through a neural net consisting of positive feedback associated with lateral inhibition. PMID- 29433062 TI - Suppression of the vestibular short-latency evoked potential by electrical stimulation of the central vestibular system. AB - In an attempt to view the effects of the efferent vestibular system (EVS) on peripheral dynamic vestibular function, we have monitored the Vestibular short latency Evoked Potential (VsEP) evoked by pulses of bone conducted vibration during electrical stimulation of the EVS neurons near the floor of the fourth ventricle in the brainstem of anesthetized guinea pigs. Given the reported effects of EVS on primary afferent activity, we hypothesized that EVS stimulation would cause a slight reduction in the VsEP amplitude. Our results show a substantial (>50%) suppression of the VsEP, occurring immediately after a single EVS current pulse. The effect could not be blocked by cholinergic drugs which have been shown to block efferent-mediated vestibular effects. Shocks produced a short-latency P1-N1 response immediately after the electrical artifact which correlated closely to the VsEP suppression. Ultimately, we have identified that this suppression results from antidromic blockade of the afferent response (the VsEP). It would appear that this effect is unavoidable for EVS stimulation, as we found no other effects. PMID- 29433063 TI - Effects of tandospirone augmentation in major depressive disorder patients with high anxiety: A multicenter, randomized, parallel-controlled, open-label study. AB - BACKGROUND: High levels of anxiety symptoms are common in individuals with major depressive disorder (MDD). Adjunctive anxiolytics are widely used in such patients; however, only a few studies have examined the strategy using tandospirone. This study aimed to evaluate the efficacy and safety of adjunctive tandospirone in individuals with MDD and high level of anxiety symptoms. METHODS: A multicenter, randomized, parallel-controlled, open-label study was conducted to evaluate the efficacy and safety of tandospirone coupled with selective serotonin reuptake inhibitors (SSRIs) in patients with MDD and high level of anxiety symptoms. Two hundred and forty-five patients fulfilling the DSM-IV-TR criteria for MDD were randomly assigned to 6 weeks of either SSRIs and tandospirone or SSRIs alone treatment. The efficacy was measured by HAMA total scores, HAMD-17 total scores, and Clinical Global Impressions severity subscale (CGI-S) score. RESULTS: After a 6-week follow-up, two hundred and thirty patients completed this study. Tandospirone coupled with SSRIs significantly improved depressive and anxiety symptoms compared to monotherapy with SSRIs as assessed by HAMD-17 total score (P = 0.003), HAMA total score (P = 0.010), and CGI-S score at week 6 (P = 0.003). The incidence rate of treatment-emergent adverse events (TEAEs) was similar in both groups; the therapy was well-tolerated. CONCLUSIONS: Short-term tandospirone augmentation was effective and well-tolerated in this study. Addition of tandospirone may improve outcomes in MDD patients with high anxiety. PMID- 29433064 TI - Establishing and dissolving cohesion during the vertebrate cell cycle. AB - Replicated chromatids are held together from the time they emerge from the replication fork until their separation in anaphase. This process, known as cohesion, promotes faithful DNA repair by homologous recombination in interphase and ensures accurate chromosome segregation in mitosis. Identification of cohesin thirty years ago solved a long-standing question about the nature of the linkage keeping together the sister chromatids. Cohesin is an evolutionarily conserved complex composed of a heterodimer of the Structural Maintenance of Chromosomes (SMC) family of ATPases, Smc1 and Smc3, the kleisin subunit Rad21 and a Huntingtin/EF3/PP2A/Tor1 (HEAT) repeat domain-containing subunit named SA/STAG. In addition to mediating cohesion, cohesin plays a major role in genome organization. Cohesin functions rely on the ability of the complex to entrap DNA topologically and in a dynamic manner. Establishment of cohesion during S phase requires coordination with the DNA replication machinery and restricts the dynamic behaviour of at least a fraction of cohesin. Dissolution of cohesion in subsequent mitosis is regulated by multiple mechanisms that ensure that daughter cells receive the correct number of intact chromosomes. We here review recent progress on our understanding of how these processes are regulated in somatic vertebrate cells. PMID- 29433065 TI - miR-330-5p/Tim-3 axis regulates macrophage M2 polarization and insulin resistance in diabetes mice. AB - Obesity is associated with a state of low-grade inflammatory response in adipose tissue, and contributes to the development of type 2 diabetes. Immune cells such as macrophages can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. Therefore, adipose tissue promotes macrophage infiltration, resulting in local inflammation and insulin resistance. Tim-3 negatively regulates IFN-gamma secretion and influences the ability to induce T cell tolerance in diabetes. MicroRNA contributes to the development of immunological tolerance and involves in macrophage polarization. However, the potential of Tim-3 to regulate macrophage polarization and the related microRNA has not been reported. In this experiment, 8-week-old C57BL/6 mice were fed a high-fat diet for 8 weeks. The adipose tissue macrophages were isolated, miR-330 5p and Tim-3 levels, and M1/M2 polarization were analyzed. In addition, insulin tolerance tests was detected. The results demonstrated that miR-330-5p levels increased but Tim-3 levels decreased, leading to M1 polarization and insulin tolerance in diabetes mice. In addition, inhibition of miR-330-5p enhanced Tim-3 levels, leading to M2 polarization and insulin tolerance attenuation in diabetes mice. Furthermore, we detected the inverse relationship between miR-330-5p and Tim-3. We found that Tim-3 mRNA contained conserved miR-330-5p binding sites in its 3'UTR, and miR-330-5p could directly regulate Tim-3 expression through these 3'UTR sites. Our study demonstrated that miR-330-5p served as a regulator of the M2 polarization and miR-330-5p/Tim-3 axis potentially down-regulated insulin resistance in diabetes, probably through enhancing the M2 polarization of macrophage. PMID- 29433066 TI - Immuno-profiles of BALB/c mice inoculated with Salmonella vector delivering B cell mitogen hydroxyproline epimerase. AB - The enzyme 4-hydroxyproline 2-epimerase (PrpA) involves in modulation of host immunity and is also reported as a potent B-cell mitogen. Live attenuated Salmonella Typhimurium (ST) vector constitutively expressing heterologous Brucella abortus PrpA protein (ST-PrpA) was inoculated in BALB/c mice in order to investigate the influence of the enzyme, on safety aspects, humoral and cellular immunity as well as protective efficacies against wild type challenges. No aggravation of morbidity was observed upon mice inoculation of ST-PrpA. Immunized mice showed significantly quicker anti-Salmonella IgG responses as compared to ST only immunization. This finding is in congruency with the increase IL-4 production evident in in vitro pulsed mice splenocytes. Increase protection against Salmonella challenge was also observed. These findings suggest that PrpA can be used as a protein adjuvant in a live Salmonella delivery system, in order to increase humoral responses effectively without major interference on the cell mediated immunity. PMID- 29433067 TI - Rapid induction of expression by LPS is accompanied by favorable chromatin and rapid binding of c-Jun. AB - The response to infection is managed in mammals by a coordinated immune response. Innate responses are rapid and hard wired and have been demonstrated to be regulated at the level of chromatin accessibility. This study examined primary human monocyte responses to LPS as a model of innate responses to bacteria. We utilized inhibitors of chromatin modifying enzymes to understand the inter relationships of the chromatin complexes regulating transcription. Multiplex digital gene detection was utilized to quantitate changes in mRNA levels for genes induced by LPS. In the first 30 min, genes that were highly induced by LPS as a group exhibited minimal effect of the chemical inhibitors of chromatin modifications. At 60 min, the more highly expressed genes were markedly more inhibitable. The effects of the inhibitors were almost entirely concordant in spite of different mechanisms of action. Two focus groups of genes with either high LPS inducibility at 30 min or high LPS inducibility at 60 min (but not at 30 min) were further examined by ChIP assay. NFkappaB p65 binding was increased at the promoters of 30- and 60-min highly inducible genes equivalently. Binding of c Jun was increased after LPS in the 30-min inducible gene set but not the 60-min inducible gene set. H3K4me3 and H4ac were not detectably altered by LPS stimulation. Baseline H3K4me3 and H4ac were higher in the 30-min highly inducible gene set compared to the 60-min highly inducible gene set. NFkappaB and JNK inhibitors led to diminished H4ac after LPS. The effects of DRB and C646 were greater for LPS-induced IL6 transcription at 30 min and LPS-stimulated H4ac compared to TNF where transcription was largely unaffected by the inhibitors. In conclusion, genes with very rapidly induced expression after LPS exhibited more favorable chromatin characteristics at baseline and were less inhibitable than genes induced at the later time points. PMID- 29433068 TI - A simplified approach for evaluating sustained slow pathway conduction for diagnosis and treatment of atrioventricular nodal reentry tachycardia in children and adults. AB - PURPOSE: During incremental atrial pacing in patients with atrioventricular nodal reentrant tachycardia, the PR interval often exceeds the RR interval (PR > RR) during stable 1:1 AV conduction. However, the PR/RR ratio has never been evaluated in a large group of patients with pacing from the proximal coronary sinus and after isoproterenol challenge. Our study validates new site of pacing and easier method of identification of PR > RR. MATERIAL AND METHODS: A prospective protocol of incremental atrial pacing from the proximal coronary sinus was carried out in 398 patients (AVNRT-228 and control-170). The maximum stimulus to the Q wave interval (S-Q = PR), SS interval (S-S), and Q-Q (RR) interval were measured at baseline and 10 min after successful slow pathway ablation and after isoproterenol challenge (obligatory). RESULTS: The mean maximum PR/RR ratios at baseline were 1.17 +/- 0.24 and 0.82 +/- 0.13 (p < 0.00001) in the AVNRT and controls respectively. There were no PR/RR ratios >=1 at baseline and after isoproterenol challenge in 12.3% of the AVNRT group and in 95.9% of the control group (p < 0.0001). PR/RR ratios >=1 were absent in 98% of AVNRT cases after slow pathway ablation/modification in children and 99% of such cases in adults (P = NS). The diagnostic performance of PR/RR ratio evaluation before and after isoproterenol challenge had the highest diagnostic performance for AVNRT with PR/RR > = 1 (sensitivity: 88%, specificity: 96%, PPV-97%, NPV 85%). CONCLUSIONS: The PR/RR ratio is a simple tool for slow pathway substrate and AVNRT evaluation. Eliminating PR/RR ratios >=1 may serve as a surrogate endpoint for slow pathway ablation in children and adults with AVNRT. PMID- 29433069 TI - Perceptions of child protective services among pregnant or recently pregnant, opioid-using women in substance abuse treatment. AB - Pregnant, opioid-using women represent a challenge to healthcare providers attempting to engage them in prenatal and substance abuse services. Limited, primarily international research suggests that child welfare clients have mixed feelings about Child Protective Services (CPS) and that fear of CPS may present a barrier to care. Understanding how pregnant opioid-using women in substance abuse treatment perceive CPS may be useful in encouraging substance abuse treatment initiation. Participants were currently or recently (within past 12 months) pregnant women with current or recent (within past 12 months) abuse/dependence of pharmaceutical opioids at a drug treatment facility. Participants were recruited by treatment staff to participate in a comprehensive study across multiple domains. Data for this analysis were collected using semi-structured qualitative interviews. Transcribed data were thematically analyzed using in vivo and interpretive coding by three coders for purposes of inter-rater reliability. Following 2, two-hour meetings, consensus was reached on primary themes and sub themes. Two major themes and several sub-themes were identified: 1) Participants' feelings and attitudes about CPS (positive and negative); 2) Interaction-based perceptions of CPS' function and performance. Participants' feelings toward CPS were often conditioned by their experiences with individual caseworkers. While many pregnant, opioid-using women identify legitimate, and even useful features of CPS, fear of CPS can be a barrier to care. Making substance abuse treatment accessible to this population requires recognition of their complex feelings toward CPS, and coordination among CPS case workers and substance abuse treatment providers. PMID- 29433070 TI - Speed, speed variation and crash relationships for urban arterials. AB - Speed and speed variation are closely associated with traffic safety. There is, however, a dearth of research on this subject for the case of urban arterials in general, and in the context of developing nations. In downtown Shanghai, the traffic conditions in each direction are very different by time of day, and speed characteristics during peak hours are also greatly different from those during off-peak hours. Considering that traffic demand changes with time and in different directions, arterials in this study were divided into one-way segments by the direction of flow, and time of day was differentiated and controlled for. In terms of data collection, traditional fixed-based methods have been widely used in previous studies, but they fail to capture the spatio-temporal distributions of speed along a road. A new approach is introduced to estimate speed variation by integrating spatio-temporal speed fluctuation of a single vehicle with speed differences between vehicles using taxi-based high frequency GPS data. With this approach, this paper aims to comprehensively establish a relationship between mean speed, speed variation and traffic crashes for the purpose of formulating effective speed management measures, specifically using an urban dataset. From a total of 234 one-way road segments from eight arterials in Shanghai, mean speed, speed variation, geometric design features, traffic volume, and crash data were collected. Because the safety effects of mean speed and speed variation may vary at different segment lengths, arterials with similar signal spacing density were grouped together. To account for potential correlations among these segments, a hierarchical Poisson log-normal model with random effects was developed. Results show that a 1% increase in mean speed on urban arterials was associated with a 0.7% increase in total crashes, and larger speed variation was also associated with increased crash frequency. PMID- 29433071 TI - Applying crash data to injury claims - an investigation of determinant factors in severe motor vehicle accidents. AB - An extensive number of research studies have attempted to capture the factors that influence the severity of vehicle impacts. The high number of risks facing all traffic participants has led to a gradual increase in sophisticated data collection schemes linking crash characteristics to subsequent severity measures. This study serves as a departure from previous research by relating injuries suffered in road traffic accidents to expected trauma compensation payouts and deriving a quantitative cost function. Data from the National Highway Traffic Safety Administration's (NHTSA) Crash Injury Research (CIREN) database for the years 2005-2014 is combined with the Book of Quantum, an Irish governmental document that offers guidelines on the appropriate compensation to be awarded for injuries sustained in accidents. A multiple linear regression is carried out to identify the crash factors that significantly influence expected compensation costs and compared to ordered and multinomial logit models. The model offers encouraging results given the inherent variation expected in vehicular incidents and the subjectivity influencing compensation payout judgments, attaining an adjusted-R2 fit of 20.6% when uninfluential factors are removed. It is found that relative speed at time of impact and dark conditions increase the expected costs, while rear-end incidents, incident sustained in van-based trucks and incidents sustained while turning result in lower expected compensations. The number of airbags available in the vehicle is also a significant factor. The scalar-outcome approach used in this research offers an alternative methodology to the discrete outcome models that dominate traffic safety analyses. The results also raise queries on the future development of claims reserving (capital allocations earmarked for future expected claims payments) as advanced driver assistant systems (ADASs) seek to eradicate the most frequent types of crash factors upon which insurance mathematics base their assumptions. PMID- 29433072 TI - Pregnenolone-progesterone-allopregnanolone pathway as a potential therapeutic target in first-episode antipsychotic-naive patients with schizophrenia. AB - Neurosteroids are both endogenous and exogenous steroids that rapidly alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. They are originated from cholesterol and have important implications for schizophrenia (SZ) pathophysiology and treatment strategies. Specifically, pregnenolone (PREG), progesterone (PROG) and allopregnanolone (ALLO) exhibit similar psychotropic properties. Using enzyme immunoassay, we compared the neurosteroids in PREG downstream pathways in plasma between healthy controls (HC, n = 43) and first-episode antipsychotic-naive patients with SZ (FEAN-SZ, n = 53) before antipsychotic drug (APD) treatment. Comparisons were also made particularly along PREG-PROG-ALLO pathway in the same FEAN-SZ patients across multiple time points following initiation of treatment for 12 months (m). Firstly, at baseline, levels of PREG were significantly higher and those of ALLO were lower in FEAN-SZ than in HC, whereas PROG, cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not different. Consequently, the molar ratios of ALLO/PREG and ALLO/PROG in FEAN-SZ were significantly reduced. Secondly, in response to APD at 1 month, ALLO levels in FEAN-SZ were markedly elevated, whereas PREG and PROG levels decreased. Thirdly, among FEAN-SZ, lower levels of PROG (reflecting higher conversion to ALLO) at baseline may predict better therapeutic outcome after 1 month of APD treatment. These findings point to the perturbations of the PREG-PROG-ALLO pathway early in psychosis, and further study of this pathway may inform alternative and innovative therapeutic targets for SZ. PMID- 29433073 TI - Link between children's hair cortisol and psychopathology or quality of life moderated by childhood adversity risk. AB - The hypothalamus-pituitary-adrenal axis (HPAA) and its end product, the glucocorticoid cortisol, has been shown to be associated with psychopathology. Determining cortisol concentrations in hair (HCC) allows the investigation of long-term HPAA-activity. There is a significant scarcity of studies investigating the link between HCC and psychopathology and quality of life in child and adolescent samples. In addition, as the HPAA constitutes a feedback system enabling adaption to environmental demands, it is important to consider the socio environmental context that the children grow up in. We therefore investigated the associations between child HCC and psychopathology/quality of life and compared these links in two groups of five to 12-year-olds: children living with mothers who report experiences of early life maltreatment (ELM) (high-risk group) and children whose mothers did not report any ELM (low-risk group). We expected that, under conditions of a high-risk environment, elevated HPAA-functioning would be associated with low levels of psychopathology and high levels of quality of life in children. Under low-risk conditions, elevated HPAA-functioning would be associated with high levels of psychopathology and low levels of quality of life in children. For the complete sample of N = 130 children, three-months HCC did not significantly predict child psychopathology or quality of life. However, there was a significant moderating effect of group membership: In the high-risk group, high levels of HCC were significantly associated with high levels of self reported quality of life. In the low-risk group, there was no association between HCC and self-reported quality of life. For child psychopathology, in the low-risk group, high levels of HCC were significantly associated with high levels of teacher reported behavior problems, whereas in the high-risk group, the association did not reach significance. Our results underline the importance of accounting for the social environment children grow up in when investigating the link between HCC and child psychopathology and quality of life. PMID- 29433074 TI - The relationship between inflammatory state and quantity of affective episodes in bipolar disorder. AB - OBJECTIVES: Immunological/inflammatory processes have been proposed to play an important role in the pathophysiology of mood disorders, including bipolar disorder (BD). The present study aimed to examine the influence of immune activation, measured on the basis of inflammatory markers, on the course of illness, proxied by the number of affective episodes, in patients with BD. METHODS: We investigated the relationship between high-sensitive CRP (hsCRP) and Interleukin 6 (IL-6), two inflammatory markers and characteristics of course of illness (e.g. number of affective episodes, depressive and manic symptoms) amongst a group of 190 individuals with BD. RESULTS: Among females with BD, there was a positive correlation between levels of hsCRP and the number of manic and depressive episodes. Moreover, levels of hsCRP and IL-6 were positively correlated with current manic symptoms, as measured by Young-Mania-Rating-Scale. There were no significant correlations between levels of the foregoing inflammatory markers, and manic and depressive symptoms in male individuals with BD. Furthermore, compared to their untreated counterparts, female patients treated with lithium demonstrated higher levels of hsCRP and male patients treated with atypical antipsychotics lower levels of hsCRP, respectively. CONCLUSIONS: Our results are suggesting that the association between inflammatory state and affective response in patients with BD may be gender-dependent. A future research would be to evaluate whether or not these gender differences can be observed in other inflammatory pathways associated with BD. PMID- 29433075 TI - Glucocorticoid receptor gene methylation moderates the association of childhood trauma and cortisol stress reactivity. AB - Exposure to childhood trauma (CT) has been linked to sustained dysregulations of major stress response systems, including findings of both exaggerated and attenuated hypothalamus-pituitary-adrenal (HPA) axis activity. Likewise, CT constitutes a common risk factor for a broad range of psychiatric conditions that involve distinct neuroendocrine profiles. In this study, we investigated the role of epigenetic variability in a stress-related gene as a potential mediator or moderator of such differential trajectories in CT survivors. For this, we screened adult volunteers for CT and recruited a healthy sample of 98 exposed (67 with mild-moderate, 31 with moderate-severe exposure) and 102 control individuals, with an equal number of males and females in each group. DNA methylation (DNAM) levels of the glucocorticoid receptor exon 1F promoter (NR3C1 1F) at functionally relevant sites were analyzed via bisulfite pyrosequencing from whole blood samples. Participants were exposed to a laboratory stressor (Trier Social Stress Test) to assess salivary cortisol stress responses. The major finding of this study indicates that DNAM in a biologically relevant region of NR3C1-1F moderates the specific direction of HPA-axis dysregulation (hypo- vs. hyperreactivity) in adults exposed to moderate-severe CT. Those trauma survivors with increased NR3C1-1F DNAM displayed, on average, 10.4 nmol/l (62.3%) higher peak cortisol levels in response to the TSST compared to those with low DNAM. In contrast, unexposed and mildly-moderately exposed individuals displayed moderately sized cortisol stress responses irrespective of NR3C1-1F DNAM. Contrary to some prior work, however, our data provides no evidence for a direct association of CT and NR3C1-1F DNAM status. According to this study, epigenetic changes of NR3C1-1F may provide a more in-depth understanding of the highly variable neuroendocrine and pathological sequelae of CT. PMID- 29433076 TI - Monitoring cell line identity in collections of human induced pluripotent stem cells. AB - The ability to reprogram somatic cells into induced pluripotent stem cells (hiPSCs) has led to the generation of large collections of cell lines from thousands of individuals with specific phenotypes, many of which will be shared among different research groups as invaluable tools for biomedical research. As hiPSC-based research involves extensive culture of many cell lines, the issue periodic cell line identification is particularly important to ensure that cell line identity remains accurate. Here we analyzed the different commercially available genotyping methods considering ease of in-house genotyping, cost and informativeness, and applied one of them in our workflow for hiPSC generation. We show that the chosen STR method was able to establish a unique DNA profile for each of the 35 individuals/hiPSC lines at the examined sites, as well as identify two discrepancies resulting from inadvertently exchanged samples. Our results highlight the importance of hiPSC line genotyping by an in-house method that allows periodic cell line identification and demonstrate that STR is a useful approach to supplement less frequent karyotyping and epigenetic evaluations. PMID- 29433077 TI - Characterization and expression of DEC205 in the cDC1 and cDC2 subsets of porcine dendritic cells from spleen, tonsil, and submaxillary and mesenteric lymph nodes. AB - Conventional dendritic cells (cDCs) are divided into the following different subtypes: cDC1, which promotes a Th1 response, and cDC2, which stimulates a Th2 and Th17 response. These cells have not been characterized in porcine lymphoid tissues. DEC205 is a receptor that increases antigen presentation and allows DCs to cross-present antigens. The objectives of this work were to characterize cDCs subsets in the tonsil, submaxillary and mesenteric lymph nodes and spleen lymphoid tissues and to determine their expression of DEC205 by flow cytometry. The cDC1 (MHCIIhighCADM1highCD172a-/low) and cDC2 (MHCIIhighCADM1highCD172a+) phenotypes were confirmed by the expression of characteristic cDC1 and cDC2 transcripts (FLT3, XCR1 and FCER1alpha). Among all lymphoid tissues, the spleen had the highest frequency of total cDCs. The cDC1:cDC2 ratio showed that all lymph tissues had higher levels of cDC1 than levels of cDC2. DEC205+ cDCs were found in all analyzed tissues, albeit with different frequencies. Our research will facilitate the study on the function of these cells and the investigation of the strategies for DEC205 targeting and functional studies. PMID- 29433078 TI - Biofilms in 3D porous media: Delineating the influence of the pore network geometry, flow and mass transfer on biofilm development. AB - This study investigates the functional correspondence between porescale hydrodynamics, mass transfer, pore structure and biofilm morphology during progressive biofilm colonization of a porous medium. Hydrodynamics and the structure of both the porous medium and the biofilm are experimentally measured with 3D particle tracking velocimetry and micro X-ray Computed Tomography, respectively. The analysis focuses on data obtained in a clean porous medium after 36 h of biofilm growth. Registration of the particle tracking and X-ray data sets allows to delineate the interplay between porous medium geometry, hydrodynamic and mass transfer processes on the morphology of the developing biofilm. A local analysis revealed wide distributions of wall shear stresses and concentration boundary layer thicknesses. The spatial distribution of the biofilm patches uncovered that the wall shear stresses controlled the biofilm development. Neither external nor internal mass transfer limitations were noticeable in the considered system, consistent with the excess supply of nutrient and electron acceptors. The wall shear stress remained constant in the vicinity of the biofilm but increased substantially elsewhere. PMID- 29433079 TI - The growth of Scenedesmus quadricauda in RO concentrate and the impacts on refractory organic matter, Escherichia coli, and trace organic compounds. AB - This study achieves a better operational simplicity for the phycoremediation of reverse osmosis (RO) concentrate using Scenedesmus quadricauda microalgae. Under continuous illumination with CO2 supplementation, algal growth in the RO concentrate resulted in a conversion of polymeric organic matter (a mixture of humic substances and polysaccharides) to biodegradable fractions and their prompt removal along with inorganic nutrients (NO3- and PO43-). The algal-induced degradation of humic-like substances which are typically refractory to microbial decomposition was demonstrated in an indirect manner. In this study, we also investigated the effects of algal treatment on the growth of Escherichia coli and removal of trace organic compounds (TOrCs) from the RO concentrate. Our results indicate that algal treatment of the RO concentrate using aeration with 10% (v/v) CO2 under continuous illumination is highly feasible as a safe and inexpensive technology to remove non- or slowly-biodegradable organic matter, reduce enteric bacteria, and attenuate TOrCs in wastewater. However, the results should not be generalized, but critically discussed, due to limitations of using the synthetic RO concentrate in evaluating the performance of wastewater remediation with microalgae. PMID- 29433080 TI - The impact of loading approach and biological activity on NOM removal by ion exchange resins. AB - The present study investigated the impact of different loading approaches and microbial activity on the Natural Organic Matter (NOM) removal efficiency and capacity of ion exchange resins. Gaining further knowledge on the impact of loading approaches is of relevance because laboratory-scale multiple loading tests (MLTs) have been introduced as a simpler and faster alternative to column tests for predicting the performance of IEX, but only anecdotal evidence exists to support their ability to forecast contaminant removal and runtime until breakthrough of IEX systems. The overall trends observed for the removal and the time to breakthrough of organic material estimated using MLTs differed from those estimated using column tests. The results nonetheless suggest that MLTs could best be used as an effective tool to screen different ion exchange resins in terms of their ability to remove various contaminants of interest from different raw waters. The microbial activity was also observed to impact the removal and time to breakthrough. In the absence of regeneration, a microbial community rapidly established itself in ion exchange columns and contributed to the removal of organic material. Biological ion exchange (BIEX) removed more organic material and enabled operation beyond the point when the resin capacity would have otherwise been exhausted using conventional (i.e. in the absence of a microbial community) ion exchange. Furthermore, significantly greater removal of organic matter could be achieved with BIEX than biological activated carbon (BAC) (i.e. 56 +/- 7% vs. 15 +/- 5%, respectively) when operated at similar loading rates. The results suggest that for some raw waters, BIEX could replace BAC as the technology of choice for the removal of organic material. PMID- 29433081 TI - Uptake and effects of cerium(III) and cerium oxide nanoparticles to Chlamydomonas reinhardtii. AB - Cerium (Ce) and cerium oxide nanoparticles (CeO2 NP) are increasingly used in different applications. Upon their release into the aquatic environment, the exposure of aquatic organisms becomes likely. In this study, the uptake of CeO2 NP and Ce3+ into the wild type and cell wall free mutant of Chlamydomonas reinhardtii was examined upon short term exposure. Separation of CeO2 NP and Ce3+ not taken up or loosely bound to the cells was performed by washing algae with EDTA. Despite a concentration and time dependent increase of cellular Ce upon exposure to CeO2 NP with the maximal calculated Ce concentration corresponding to 1.1 CeO2 NP per cell, an internalization of CeO2 NP with a mean size of 140 nm in C. reinhardtii was excluded. In contrast, dissolved Ce3+ (1 and 10 MUM) was taken up both in the wild type and cell wall free mutant of C. reinhardtii, with a linear increase of cellular Ce within 1-2 h and maximal cellular Ce of 6.04 * 10 4 mol Lcell-1 (wild type) and 9.0 * 10-5 mol Lcell-1 (cell wall free mutant). Based on competition with Ca2+ for Ce3+ uptake, on the comparison of the wild type and the cell wall free mutant and on inhibition of photosynthetic yield, we suggest that no efficient uptake routes for Ce3+ are available in C. reinhardtii and that a fraction of the cellular Ce in the wild type strongly sorbs to the algal cell wall. PMID- 29433082 TI - Acute exposure to chlorpyrifos induces reversible changes in health parameters of Nile tilapia (Oreochromis niloticus). AB - Chlorpyrifos (CPF) is one of the most common insecticides found in freshwater ecosystems, and has been detected in agricultural and fishery products worldwide. This study focused on comprehensive panel of hematological, immunotoxic and pathology changes in Nile tilapia (Oreochromis niloticus) during and after exposure to CPF at 15 MUg/L (0.043 MUM) (1/10 LC50, group CPF1), or 75 MUg/L (0.21 MUM) (1/2 LC50, group CPF2) for 14 days, followed by 2 weeks recovery. Different endpoints were used to determine effects of CPF on fish health: hematological parameters; antioxidant levels in liver and gills; innate immune parameters; expression levels of pro-inflammatory cytokine genes at mRNA level in anterior kidney and spleen; and histopathological assessment of gills, liver, and kidney tissues. RBCs were significantly decreased in CPF1 group compared to other groups only at day 3. Blood packed cell volume (PCV) and mean corpuscular volume (MCV) showed significant increase at day 3 and 14 of CPF exposure. TLC (Total Leukocytic Counts), neutrophil counts were significantly increased in CPF exposed groups at days 3, 7, 14 compared to the control. While, lymphocytes counts were significantly increased at CPF1 group compared to other groups at day 14. Antioxidant enzyme activity in liver and gills showed significant increase of Malondialdehyde (MDA) and glutathione (GSH), and significant decrease in (catalase/CAT/, glutathione S-transferase/GST/, and superoxide dismutase/SOD/); in CPF exposed groups. Serum bactericidal and lysozyme activity was nominally and significantly decreased, respectively, and whole blood respiratory burst was significantly increased in CPF2 group. The cytokine expression levels showed complex changes in expression patterns. In kidney, cytokine interleukin-8 (IL-8) was significantly upregulated at day 1 in both exposed group. Interleukin-1beta (IL-1beta) and Tumor necrosis factor-alpha (TNFalpha) were significantly upregulated at day 1 in CPF1 group, and then IL-8 and TNFalpha downregulated at day 3 in same group. At day 7, only TNFalpha was up and downregulated in CPF1 and CPF2, respectively compared to control. All gene expression levels in spleen were upregulated on day 7 of exposure in the high exposed group. Histopathology showed dose-dependent changes in CPF treated groups, indicating gill, liver, and posterior kidney changes associated with oxidative stress damages. Following recovery period, all measured parameters showed varying degrees in their reversibility to the control level. These findings provide important insights about the acute toxic effects of CPF on fish and show potential to be used as biomarkers in further toxicological evaluation studies. PMID- 29433083 TI - Inhibition of phospholipases influences the metabolism of wound-induced benzylisoquinoline alkaloids in Papaver somniferum L. AB - Benzylisoquinoline alkaloids (BIAs) are important secondary plant metabolites and include medicinally relevant drugs, such as morphine or codeine. As the de novo synthesis of BIA backbones is (still) unfeasible, to date the opium poppy plant Papaver somniferum L. represents the main source of BIAs. The formation of BIAs is induced in poppy plants by stress conditions, such as wounding or salt treatment; however, the details about regulatory processes controlling BIA formation in opium poppy are not well studied. Environmental stresses, such as wounding or salinization, are transduced in plants by phospholipid-based signaling pathways, which involve different classes of phospholipases. Here we investigate whether pharmacological inhibition of phospholipase A2 (PLA2, inhibited by aristolochic acid (AA)) or phospholipase D (PLD; inhibited by 5 fluoro-2-indolyl des-chlorohalopemide (FIPI)) in poppy plants influences wound induced BIA accumulation and the expression of key biosynthetic genes. We show that inhibition of PLA2 results in increased morphinan biosynthesis concomitant with reduced production of BIAs of the papaverine branch, whereas inhibition of PLD results in increased production of BIAs of the noscapine branch. The data suggest that phospholipid-dependent signaling pathways contribute to the activation of morphine biosynthesis at the expense of the production of other BIAs in poppy plants. A better understanding of the effectors and the principles of regulation of alkaloid biosynthesis might be the basis for the future genetic modification of opium poppy to optimize BIA production. PMID- 29433084 TI - Drought tolerance of sugarcane is improved by previous exposure to water deficit. AB - Under field conditions, plants are exposed to cycles of dehydration and rehydration during their lifespan. In this study, we hypothesized that sugarcane plants previously exposed to cycles of water deficits will perform better than plants that have never faced water deficits when both are subjected to low water availability. Sugarcane plants were grown in a nutrient solution and exposed to one (1WD), two (2WD) or three (3WD) water deficit cycles. As the reference, plants were grown in a nutrient solution without adding polyethylene glycol. Under water deficits, leaf gas exchange was significantly reduced in 1WD and 2WD plants. However, 3WD plants showed similar CO2 assimilation and lower stomatal conductance compared to the reference plants, with increases in intrinsic water use efficiency. Abscisic acid concentrations were lower in 3WD plants than in 1WD plants. Our data revealed root H2O2 concentration as an important chemical signal, with the highest root H2O2 concentrations found in 3WD plants. These plants presented higher root dry matter and root:shoot ratios compared to the reference plants, as well as higher biomass production when water was available. Our data suggest that sugarcane plants were able to store information from previous stressful events, with plant performance improving under water deficits. In addition, our findings provide a new perspective for increasing drought tolerance in sugarcane plants under nursery conditions. PMID- 29433085 TI - Patterns of body image concerns in adolescence and early adulthood: A latent profile analysis. AB - The present study aimed at identifying latent profiles of body image concerns in adolescents and young adults. Subsequently, associations between these profiles and potentially harmful behaviors are examined. Self-report data of 758 male and female adolescents, aged 14 to 22 years, were analyzed. Participants provided demographic and anthropometric data and completed surveys on weight/shape and muscularity concern as well as on disturbed eating behaviors and dysfunctional exercise. Latent profile analyses of weight/shape concern and muscularity concern were performed separately for each gender. The analyses indicated three-class solutions in men and women. In both genders, the inconspicuous class, characterized by small amounts of weight/shape and muscularity concerns, was the largest one (86% in men, 68% in women). Whereas 10% of the men and 23% of the women were assigned to the borderline class, 4% of the men and 8% of the women formed the conspicuous class (marked weight/shape and muscularity concerns). Between genders, the degrees of muscularity concern differed in the borderline and inconspicuous classes, while the degrees of weight/shape concern differed in the inconspicuous class only. The comparable degrees of weight/shape and muscularity concerns in men and women in the affected classes underline the relevance of both aspects in both genders. Classes could be distinguished by harmful behaviors, like restrained eating or emotional exercise, proving the clinical significance of body image concerns. PMID- 29433086 TI - Potential roles for glucagon-like peptide-17-36 amide and cholecystokinin in anorectic response to the trichothecene mycotoxin T-2 toxin. AB - Anorexia is a hallmark of animal and human exposed to T-2 toxin, a most poisonous trichothecene mycotoxins contaminating various cereal grains including wheat, corn and barley. Although this adverse effect has been well characterized in several animal species, the underlying mechanisms are unclear. The goal for this study was to elucidate the roles of two gut satiety hormones, glucagon-like peptide-17-36 amide (GLP-1) and cholecystokinin (CCK) in T-2 toxin-evoked anorectic response using a mouse anorexia bioassay. Elevations of plasma GLP-1 and CCK significantly corresponded to anorexia induction by T-2 toxin. Direct administration of exogenous GLP-1 and CCK markedly evoked anorectic responses similar to T-2 toxin. The GLP-1 receptor (GLP-1R) antagonist Exendin9-39 dose dependently cause attenuation of both GLP-1- and T-2 toxin-induced anorectic responses. Pretreatment with the CCK1 receptor (CCK1R) antagonist SR 27897 and CCK2 receptor (CCK2R) antagonist L-365,260 attenuated anorexia induction by both CCK- and T-2 toxin in a dose dependent manner. Taken together, our findings suggest that both GLP-1 and CCK play contributory roles in T-2 toxin-induced anorexia. PMID- 29433087 TI - Chromium accumulation and biomarker responses in the Neotropical fish Prochilodus lineatus caged in a river under the influence of tannery activities. AB - In order to assess the effects of tannery effluents (TE) in organism health, juveniles of Prochilodus lineatus were submitted to in situ tests at four different river locations: site A - upstream of the tannery; site B - next to the tannery; and sites C and D - downstream of the tannery. After 96 h exposure in the river, samples of fish tissue, river water and sediment were collected in order to quantify chromium (Cr) concentrations. Tissue samples were used to assess the activity of ethoxyresorufin-O-deethylase (EROD) and glutathione S transferase (GST), the content of glutathione (GSH) and metallothionein (MT) and the occurrence of lipid peroxidation (LPO) and DNA damage. Higher Cr concentrations were detected in the water and sediments from site B and in the liver of fish confined at site B, compared to the other sites. Fish caged at site B demonstrated higher levels of liver MT and hepatic EROD activity in relation to fish caged at the other sites. Moreover, fish from site B presented increased liver and branchial GST activities, as well as more GSH in the liver, than fish from site A. There were no significant variations in the occurrence of LPO and DNA damage among fish caged at the different sites. Thus, TE increased Cr levels in the water, sediments, and fish livers and stimulated the synthesis of MT and GSH and the activities of EROD and GST. In conclusion, TE affect the quality of the river and promote changes in biochemical biomarkers and Cr accumulation in P. lineatus. PMID- 29433088 TI - Role of residence time on the transformation of Zn, Cu, Pb and Cd attached to road dust in different land uses. AB - The adsorption behaviour of metals deposited on road surfaces undergo changes during dry weather periods, with the bioavailability varying compared to the original species, prior to incorporation in stormwater runoff. This study investigated the role of antecedent dry days on the transformation characteristics of Zn, Cu, Pb and Cd attached to different geochemical forms of road dust, in order to predict potential stormwater quality impacts. The study outcomes showed that the exchangeable fraction generally decreased with the increase in antecedent dry days, but the reducible, oxidisable and residual fractions increased. This implies that there is a time-dependent transformation of weakly bound metals in road dust to more persistent chemical forms. The transformation rate of metals was found to be in the order of Pb > Cu > Zn > Cd. Significant changes in metal distribution among the geochemical fractions were observed up to seven dry days, suggesting that during the initial antecedent dry days, the transformations can be relatively more significant. Among the analysed metals, Cd present on road surfaces has a higher potential for being bioavailable during the antecedent dry days. PMID- 29433089 TI - Proposal of potent inhibitors for vitamin-D receptor based on ab initio fragment molecular orbital calculations. AB - Vitamin D plays an important role in the regulation of the calcium and phosphorus metabolism as well as in bone formation. These physiological actions caused by vitamin D are triggered by the specific binding of vitamin D to its receptor (VDR). Here we investigated the specific interactions and binding affinities between VDR and vitamin D derivatives, using ab initio fragment molecular orbital (FMO) calculations. The FMO results elucidate that relative position of the two hydroxyl groups of the derivatives is essential for the strong binding affinity between the derivative and Arg274 residue of VDR. It is therefore expected that novel potent ligands, which have a great binding affinity for VDR, are developed by adjusting the positions of the hydroxyl groups in the derivatives in such a way as these groups form strong hydrogen bonds with VDR residues. We proposed these novel derivatives and investigated their specific interactions with VDR at atomic and electronic levels to obtain a more potent ligand for VDR. PMID- 29433090 TI - A systematic review of approaches to modelling lower limb muscle forces during gait: Applicability to clinical gait analyses. AB - Computational methods to estimate muscle forces during walking are becoming more common in biomechanical research but not yet in clinical gait analysis. This systematic review aims to identify the current state-of-the-art, examine the differences between approaches, and consider applicability of the current approaches in clinical gait analysis. A systematic database search identified studies including estimated muscle force profiles of the lower limb during healthy walking. These were rated for quality and the muscle force profiles digitised for comparison. From 13.449 identified studies, 22 were finally included which used four modelling approaches: static optimisation, enhanced static optimisation, forward dynamics and EMG-driven. These used a range of different musculoskeletal models, muscle-tendon characteristics and cost functions. There is visually broad agreement between and within approaches about when muscles are active throughout the gait cycle. There remain, considerable differences (CV 7%-151%, range of timing of peak forces in gait cycle 1%-31%) in patterns and magnitudes of force between and within modelling approaches. The main source of this variability is not clear. Different musculoskeletal models, experimental protocols, and modelling approaches will clearly have an effect as will the variability of joint kinetics between healthy individuals. Limited validation of modelling approaches, particularly at the level of individual participants, makes it difficult to conclude if any of the approaches give consistently better estimates than others. While muscle force modelling has clear potential to enhance clinical gait analyses future research is needed to improve validation, accuracy and feasibility of implementation in clinical practice. PMID- 29433091 TI - The influence of lower limb impairments on RaceRunning performance in athletes with hypertonia, ataxia or athetosis. AB - OBJECTIVES: RaceRunning enables athletes with limited or no walking ability to propel themselves independently using a three-wheeled running bike that has a saddle and a chest plate for support but no pedals. For RaceRunning to be included as a Para athletics event, an evidence-based classification system is required. Therefore, the aim of this study was to assess the association between a range of impairment measures and RaceRunning performance. METHODS: The following impairment measures were recorded: lower limb muscle strength assessed using Manual Muscle Testing (MMT), selective voluntary motor control assessed using the Selective Control Assessment of the Lower Extremity (SCALE), spasticity recorded using both the Australian Spasticity Assessment Score (ASAS) and Modified Ashworth Scale (MAS), passive range of motion (ROM) of the lower extremities and the maximum static step length achieved on a stationary bike (MSSL). Associations between impairment measures and 100-meter race speed were assessed using Spearman's correlation coefficients. RESULTS: Sixteen male and fifteen female athletes (27 with cerebral palsy), aged 23 (SD = 7) years, Gross Motor Function Classification System levels ranging from II to V, participated. The MSSL averaged over both legs and the ASAS, MAS, SCALE, and MMT summed over all joints and both legs, significantly correlated with 100 m race performance (rho: 0.40-0.54). Passive knee extension was the only ROM measure that was significantly associated with race speed (rho = 0.48). CONCLUSION: These results suggest that lower limb spasticity, isometric leg strength, selective voluntary motor control and passive knee extension impact performance in RaceRunning athletes. This supports the potential use of these measures in a future evidence based classification system. PMID- 29433092 TI - Structure-based optimization of free fatty acid receptor 1 agonists bearing thiazole scaffold. AB - The free fatty acid receptor 1 (FFA1) plays an important role in amplifying insulin secretion in a glucose dependent manner. We have previously reported a series of FFA1 agonists with thiazole scaffold exemplified by compound 1, and identified a small hydrophobic subpocket partially occupied by the methyl group of compound 1. Herein, we describe further structure optimization to better fit the small hydrophobic subpocket by replacing the small methyl group with other hydrophobic substituents. All of these efforts resulted in the identification of compound 6, a potent FFA1 agonist (EC50 = 39.7 nM) with desired ligand efficiency (0.24) and ligand lipophilicity efficiency (4.7). Moreover, lead compound 6 exhibited a greater potential for decreasing the hyperglycemia levels than compound 1 during an oral glucose tolerance test. In summary, compound 6 is a promising FFA1 agonist for further investigation, and the structure-based study promoted our understanding for the binding pocket of FFA1. PMID- 29433093 TI - Use of plasma exchange in pediatric severe sepsis in children's hospitals. AB - Pediatric severe sepsis (PSS) is an important cause of death in children. Mortality increases in those with sepsis and multiple organ dysfunction syndrome (MODS). Plasma exchange (PE) has been used as an adjuvant therapy in sepsis, with trials demonstrating variable success. This observational retrospective cohort study aimed to characterize patient demographics, PE use, mortality and resource utilization in septic children from 43 children's hospitals from 2004 to 2012. Of 49,153 PSS cases, 1.8% utilized PE. Utilization increased to 4.8% in those with sepsis and MODS. Comorbidities affected 72-74% of patients. PE patients noted a longer hospitalization than PSS patients (39 vs 17 days). Overall mortality was 14.1% in PSS, increasing to 32.1% in PSS patients receiving PE. Mortality was 22% and 44.4% in PE patients without and with MODS respectively. Mortality decreased over the study period in both PE subgroups. In conclusion, PE utilization in PSS remained stable throughout the study period while PSS mortality decreased over time. Children utilizing PE had a higher associated mortality, but also greater comorbidities and MODS prevalence, likely representing a predilection towards use in more critically ill patients. These data can provide demographic and outcome results to inform future PE trials in sepsis. PMID- 29433094 TI - Fingolimod reduces the clinical expression of active demyelinating lesions in MS. AB - BACKGROUND: Fingolimod is a modulator of Central and peripheral sphingosine pathways, which is currently approved for treatment of Multiple Sclerosis (MS). In animal models it reduces inflammation, but it is also able to potentiate glutamatergic transmission and synaptic plasticity. We aimed to explore whether Fingolimod is able to modify the clinical expression of new demyelinating lesions with respect to IFNbeta-1a in relapsing remitting MS (RRMS) patients suboptimal responders to IFNbeta-1a. METHODS: 103 patients with RRMS switching for inefficacy from IFNbeta-1a to Fingolimod and treated for at least 12 months were included. Annualised Relapse Rate (ARR), EDSS and the number of new brain and spinal gadolinium enhancing (Gd +) and T2 lesions were retrospectively assessed in the whole group during each treatment period. The likelihood of co-occurrence of new Gd + lesions and clinical relapses during IFNbeta-1a and Fingolimod treatment was analysed. RESULTS: The mean duration of treatment with IFNbeta-1a and Fingolimod was 3.14 (SD 1.6) and 3.22 years (SD 1.1) respectively. Significant reduction of ARR (p < .001), total number of Gd + and T2 lesions (p < .001) was found switching from IFNbeta-1a to Fingolimod. Gd + lesions occurring during treatment with Fingolimod were more likely to be asymptomatic compared with IFNbeta-1a (88% vs 30.9%, p = < .025). CONCLUSION: Fingolimod reduces clinical and radiological inflammation in MS. Additionally, it limits the clinical expression of new Gd + lesions, possibly reducing local inflammatory processes and improving brain network plasticity in patients with suboptimal response to IFNbeta-1a. PMID- 29433095 TI - Early relapse after RTX initiation in a patient with NMO/MS overlap syndrome: How long to conclude to a failure treatment? AB - BACKGROUND: We report a dramatic clinical and radiological worsening within two months after rituximab initiation in a patient with NeuroMyelitis Optica/Multiple Sclerosis (NMO/MS) overlap syndrome. METHODS: Case study. RESULTS: A 45-year-old Caucasian woman with NMO/MS overlap syndrome experienced a severe myelitis nine weeks after first rituximab infusion, with extensive new gadolinium-enhanced spinal cord lesions. CONCLUSION: This case report illustrates the limits of MS and NMO-Spectrum Disorder classification and challenges the criteria of therapeutic failure within the 6 months after rituximab initiation. PMID- 29433096 TI - Quantification and pharmacokinetics of alpinetin in rat plasma by UHPLC-MS/MS using protein precipitation coupled with dilution approach to eliminate matrix effects. AB - Alpinetin, a bioactive flavonoid, has attracted great attention due to its diverse therapeutic effects, namely anti-oxidant, anti-tumor and anti inflammatory effects with low systemic toxicity. Various determination methods have been developed in quality control and plant chemistry areas. However, quantification and pharmacokinetics of alpinetin in biological matrix have not been studied. In the present research, a sensitive, efficient and reliable ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) method for the determination of alpinetin in rat plasma was developed and validated. Plasma samples were processed with protein precipitation (PP) followed by a 5-fold acetonitrile/water (50:50, v/v) dilution to significantly decrease matrix effect which exited in one step PP method. Determination of alpinetin was conducted using positive electrospray ionization tandem mass spectrometry in multiple reaction monitoring mode. Results demonstrated that the method was precise (3.3%-12.3%), accurate (-5.8% to 10.8%) and linear in the range of 1-1000 ng/mL. The new developed method was subsequently applied to a pharmacokinetic research of alpinetin following oral and intravenous dosing to healthy Sprague Dawley rats. Alpinetin was demonstrated rapid absorption after oral administration with an absolute bioavailability of ~15.1% and extensive distribution after dosing. PMID- 29433098 TI - Thermoluminescence properties of 30Y2O3.30P2O5.40SiO2 vitroceramics in mixed neutron-gamma fields. AB - Powders of the 30Y2O3.30P2O5.40SiO2 vitroceramic were irradiated with broad spectrum d+Be (Eneutron = 0-14.5 MeV) and quasi-monoenergetic d+D neutrons (Eneutron = 12.4 +/- 0.22 MeV). The absorbed dose of d+Be neutrons was Dn = 2.52 +/- 8% Gy with Dgamma = 0.22 +/- 14% Gy accompanied gamma absorbed dose. The absorbed dose of d+D neutrons was Dn = 1.43 +/- 8% Gy with Dgamma = 0.21 +/- 14% Gy gamma absorbed dose. The thermoluminescence (TL) induced in the vitroceramics was studied. Both the gamma and neutron component contributed to the TL signals. The relative neutron sensitivities were [(TLn/TLgamma)/(Dn/Dgamma)]d+Be = 0.04 +/ 60% and [(TLn/TLgamma)/(Dn/Dgamma)]d+D = 0.11 +/- 43%. PMID- 29433097 TI - Validation and implementation of liquid chromatographic-mass spectrometric (LC MS) methods for the quantification of tenofovir prodrugs. AB - BACKGROUND: The nucleotide reverse transcriptase inhibitor tenofovir (TFV) is widely administered in a disoproxil prodrug form (tenofovir disoproxil fumarate, TDF) for HIV management and prevention. Recently, novel prodrugs tenofovir alafenamide fumarate (TAF) and hexadecyloxypropyl tenofovir (CMX157) have been pursued for HIV treatment while minimizing adverse effects associated with systemic TFV exposure. Dynamic and sensitive bioanalytical tools are required to characterize the pharmacokinetics of these prodrugs in systemic circulation. Two parallel methods have been developed, one to combinatorially quantify TAF and TFV, and a second method for CMX157 quantification, in plasma. METHODS: K2EDTA plasma was spiked with TAF and TFV, or CMX157. Following the addition of isotopically labeled internal standards and sample extraction via solid phase extraction (TAF and TFV) or protein precipitation (CMX157), samples were subjected to liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis. For TAF and TFV, separation occurred using a Zorbax Eclipse Plus C18 Narrow Bore RR, 2.1 * 50 mm, 3.5 MUm column and analytes were detected on an API5000 mass analyzer; CMX157 was separated using a Kinetex C8, 2.1 * 50 mm, 2.6 MUm column and quantified using an API4500 mass spectrometer. Methods were validated according to FDA Bioanalytical Method Validation guidelines. RESULTS: Analytical methods: were optimized for the multiplexed monitoring of TAF and TFV, and CMX157 in plasma. The lower limits of quantification (LLOQs) for TAF, TFV, and CMX157 were 0.03, 1.0, and 0.25 ng/mL, respectively. Calibration curves were generated via weighted linear regression of standards. Intra- and inter-assay precision and accuracy studies demonstrated %CVs <= 14.4% and %DEVs <= +/- 7.95%, respectively. Stability and matrix effects studies were also performed. All results were acceptable and in accordance with the recommended guidelines for bioanalytical methods. Assays were also applied to quantify in vivo concentrations of prodrugs and TFV in a preclinical study post-rectal administration. CONCLUSIONS: Sensitive, specific, and dynamic LC-MS/MS assays have been developed and validated for the multiplexed quantification TAF and TFV, as well as an independent assay for CMX157 quantification, in plasma. The described methods meet sufficient throughput criteria to support large research trials. PMID- 29433099 TI - Environmental risk assessment of the emerging EDCs contaminants from rural soil and aqueous sources: Analytical and modelling approaches. AB - The emerging endocrine disrupting chemicals posed high risk and much uncertainty to eco-environment and human health. An analytical method, developed for the simultaneous determination of five steroid estrogens in groundwater and soil based upon solid phase extraction and gas chromatography-mass spectrometry, was applied to investigate the distribution of estrone and 17beta-estradiol around Shenyang City with particular focus on penetrating from surface to groundwater in this study. Mean concentrations of the estrone and 17beta-estradiol were 55.1 ng L-1 and 56.1 ng L-1 in groundwater, 32.5 ng g-1 and 23.1 ng g-1 in soil, respectively. The distribution of estrone and 17beta-estradiol were similar in groundwater, the concentration in the west of the site center was relatively low, and the surroundings were relatively high. The concentration of estrone was changed less, but 17beta-estradiol was significantly increased in silt and silty sand layers in vadose zone profiles. Both estrone and 17beta-estradiol concentrations changed abruptly at the interface of layers. Incorporating the temporal and spatial evolution of physical-chemical-biological environmental parameters at the sites, sorption and biodegradation were suggested the controlling roles in the fate and transport of SEs in the soil-groundwater system. The Ecological risk quotients values of both soil and groundwater indicated a very high ecological risk associated with SEs, but the non carcinogenic harm quotients did not exceed the acceptable level of non carcinogenic human health risk. PMID- 29433100 TI - Microbe mediated arsenic release from iron minerals and arsenic methylation in rhizosphere controls arsenic fate in soil-rice system after straw incorporation. AB - Arsenic (As) contamination is a global problem. Straw incorporation is widely performed in As contaminated paddy fields. To understand how straw and straw biochar incorporation affect As transformation and translocation in the soil microbe-rice system, a pot experiment was carried out with different dosages of rice straw and straw biochar application. Results showed that both straw biochar and straw application significantly increased As mobility. Straw biochar mobilized As mainly through increasing soil pH and DOM content. Straw incorporation mainly through enhancing As release from iron (Fe) minerals and arsenate (As(V)) reduction to arsenite (As(III)). Straw biochar didn't significantly affect As methylation, while straw incorporation significantly enhanced As methylation, elevated dimethylarsenate (DMA) concentration in soil porewater and increased As volatilization. Straw biochar didn't significantly change total As accumulation in rice grains, but decreased As(III) accumulation by silicon (Si) inhibition. Straw incorporation significantly increased DMA, but decreased As(III) concentration in rice grains. After biochar application, dissolved As was significantly positively correlated with the abundance of Bacillus, indicating that Bacillus might be involved in As release, and As(III) concentration in polished grains was negatively correlated with Si concentration. The significant positive correlation between dissolved As with Fe and the abundance of iron-reducing bacteria suggested the coupling of As and Fe reduction mediated by iron-reducing bacteria. The significant positive correlation between DMA in rice grains and the abundance of methanogenic bacteria indicated that methanogenic bacteria could be involved in As methylation after straw application. The results of this study would advance the understanding how rice straw incorporation affects As fate in soil-microbe-rice system, and provide some guidance to straw incorporation in As contaminated paddy soil. This study also revealed a wealth of microorganisms in the soil environment that dominate As mobility and transformation after straw incorporation. PMID- 29433102 TI - Microplastics in oysters Saccostrea cucullata along the Pearl River Estuary, China. AB - As a transitional zone between riverine and marine environments, an estuary plays an important role for the sources, accumulation and transport of microplastics. Although estuarine environments are hotspots of microplastic pollution, the correlation between microplastic pollution and aquatic organisms is less known. Here we investigated microplastic pollution in wild oysters Saccostrea cucullata from 11 sampling sites along the Pearl River Estuary in South China. The microplastic abundances in oysters ranged from 1.4 to 7.0 items per individual or from 1.5 to 7.2 items per gram tissue wet weight, which were positively related to those in surrounding waters. The oysters near urban areas contained significantly more microplastics than those near rural areas. Fibers accounted for 69.4% of the total microplastics in oysters. Microplastic sizes varied from 20 to 5000 MUm and 83.9% of which were less than 100 MUm. Light color microplastics were significantly more common than dark color ones. Based on the results, oysters are recommended as a biomonitor for the microplastic pollution in estuaries. PMID- 29433101 TI - Polychlorinated biphenyl (PCB) contamination in Galveston Bay, Texas: Comparing concentrations and profiles in sediments, passive samplers, and fish. AB - The industrialized portion of the Houston Ship Channel (HSC) is heavily contaminated with anthropogenic contaminants, most prominent of which are the polychlorinated biphenyls (PCBs). This contamination has driven adaptive evolution in a keystone species for Galveston Bay, the Gulf killifish (Fundulus grandis). We investigated the geographical extent of PCB impacts by sampling 12 sites, ranging from the heavily industrialized upper portion of the HSC to Galveston Island. At each site, PCB concentrations and profiles were determined in three environmental compartments: sediment, water (polyethylene passive samplers), and fish tissue (resident Gulf killifish). We observed a steep gradient of PCB contamination, ranging from 4.00 to 100,000 ng/g organic carbon in sediment, 290-110,000 ng/g lipid in fish, and 4.5-2300 ng/g polyethylene in passive samplers. The PCB congener profiles in Gulf killifish at the most heavily contaminated sites were shifted toward the higher chlorinated PCBs and were highly similar to the sediment contamination profiles. In addition, while magnitude of total PCB concentrations in sediment and total fish contamination levels were highly correlated between sites, the relative PCB congener profiles in fish and passive samplers were more alike. This strong correlation, along with a lack of dependency of biota-sediment accumulation factors with total contamination rates, confirm the likely non-migratory nature of Gulf killifish and suggest their contamination levels are a good site-specific indicator of contamination in the Galveston Bay area. The spatial gradient of PCB contamination in Galveston Bay was evident in all three matrices studied and was observed effectively using Gulf killifish contamination as an environmentally relevant bioindicator of localized contamination in this environment. PMID- 29433103 TI - Exposure to organophosphate flame retardants of hotel room attendants in Wuhan City, China. AB - Indoor environments provide sources of exposure to organophosphate flame retardants (PFRs), which are artificially synthesized fire-protecting agents used as additives in interior products. As public spaces, hotels are required to meet stricter fire-precaution criteria. As such, room attendants may be exposed to higher levels of PFRs. Our goal was to characterize the exposure of hotel room attendants to PFRs by measuring metabolites in their urine and the corresponding parent PFRs in dust and hand-wipes collected from 27 hotels located in Wuhan City, China. The exposure of the attendants was found to be omnipresent: urinary metabolites of PFRs, such as DPHP (diphenyl phosphate), BDCIPP (bis(1,3-dichloro 2-propyl) phosphate), and DoCP (di-o-cresyl phosphate) & DpCP (di-p-cresyl phosphate) were detected with high frequency (87%, 79% and 87%, respectively). We observed that metabolites in post-shift urine were consistently present at higher levels than those in the first morning voids (p < 0.05 for BDCIPP and DPHP). Regarding external exposure, 10 PFRs were determined in both dust samples and hand-wipes, with TCIPP (tris(2-chloroisopropyl) phosphate) being the most abundant compound in both matrices. The levels of PFRs in hand-wipes and dust samples were not correlated. PFRs in dust and their corresponding urinary metabolites were not significantly correlated, while a moderate significant correlation of TDCIPP (tris(1,3-dichloro-2-propyl) phosphate) in hand-wipes and its urinary metabolite, BDCIPP, was observed in both morning void samples (p = 0.01) and post-shift urine (p = 0.002). Moreover, we found that participants from high-rise buildings (defined as > 7 stories) had significantly higher BDCIPP and DPHP concentrations than those from low-rise buildings. A possible reason is that high-rise buildings may use high-grade fireproof building materials to meet stricter fire restrictions. Overall, these results indicate that PFRs exposure in hotels is a contributor to the personal exposure of hotel room attendants. PMID- 29433104 TI - Stable isotope fractionation during uptake and translocation of cadmium by tolerant Ricinus communis and hyperaccumulator Solanum nigrum as influenced by EDTA. AB - The isotopic fractionation could contribute to understanding the Cd accumulation mechanisms in plant species. However, there are few of systematical investigations with regards to the Cd isotope fractionation in hyperaccumulator plants. The Cd tolerant Ricinus communis and hyperaccumulator Solanum nigrum were cultivated in nutrient solutions with varying Cd and EDTA concentrations. Cd isotope ratios were determined in the solution, root, stem and leaf. The two investigated plants were systematically enriched in light isotopes relative to their solutions (Delta114/110Cdplant-solution = -0.640/00 to -0.290/00 for R. communis and -0.840/00 to -0.310/00 for S. nigrum). Cd isotopes were markedly fractionated among the plant tissues. For both plant species, an enrichment in light Cd isotopes from solution to root was noted, followed by a slight depletion in light Cd isotopes from root to shoot. Noticeably, the chelation process has caused lighter Cd isotope enrichment in the root of R. communis and S. nigrum. Further, the good fits between ?114/110Cdroot-plant and ln Froot (or between ?114/110Cdshoot-plant and ln Fshoot) indicate that Cd isotopic signatures can be used to study Cd transportation during the metabolic process of plants. This study suggests that knowledge of the Cd isotope ratios could also provide new tool for identifying the Cd-avoiding crop cultivars. PMID- 29433105 TI - Microplastic pollution in the surface waters of Italian Subalpine Lakes. AB - Plastic debris incidence in marine environment was already highlighted in the early 1970s. Over the last decade, microplastic pollution in the environment has received increasing attention and is now an emerging research area. Many studies have focused on quantifying microplastic abundance in the marine environment, while there are relatively few data on microplastic occurrence in freshwater environment. Recent studies have reported high concentrations of microplastics in lakes and rivers, although the understanding of several factors influencing source, transport and fate is still limited. This study compares different lakes and the common factors, which could influence the occurrence and distribution of microplastics. The three subalpine lakes monitored include Lake Maggiore, Iseo and Garda. The selected sampling transects reflect the hydrologic conditions, the morphometric characteristics of these lakes, and other factors influencing the release of plastics debris in lakes. Particles of microplastics (<5 mm) were found in all sampled surfaces. The particles collected were classified depending on their number, shape and composition. The shape distribution showed the dominating occurrence of fragments (73.7%). The chemical composition of all examined samples clearly shows dominating presence of polyethylene (45%), polystyrene (18%) and polypropylene (15%). The results provide significant relations among the different contribution of direct and diffuse sources to the quantity of microplastics, highlighting the importance of understanding the spatial distribution dynamics of microplastics within a lake system that acts as a sink and source of plastic particles. PMID- 29433106 TI - Environmentally relevant microplastic exposure affects sediment-dwelling bivalves. AB - Most microplastics are expected to sink and end up in marine sediments. However, very little is known concerning their potential impact on sediment-dwelling organisms. We studied the long-term impact of microplastic exposure on two sediment-dwelling bivalve species. Ennucula tenuis and Abra nitida were exposed to polyethylene microparticles at three concentrations (1; 10 and 25 mg/kg of sediment) for four weeks. Three size classes (4-6; 20-25 and 125-500 MUm) were used to study the influence of size on microplastic ecotoxicity. Microplastic exposure did not affect survival, condition index or burrowing behaviour in either bivalve species. However, significant changes in energy reserves were observed. No changes were observed in protein, carbohydrate or lipid contents in E. tenuis, with the exception of a decrease in lipid content for one condition. However, total energy decreased in a dose-dependent manner for bivalves exposed to the largest particles. To the contrary, no significant changes in total energy were observed for A. nitida, although a significant decrease of protein content was observed for individuals exposed to the largest particles, at all concentrations. Concentration and particle size significantly influenced microplastic impacts on bivalves, the largest particles and higher concentrations leading to more severe effects. Several hypotheses are presented to explain the observed modulation of energy reserves, including the influence of microplastic size and concentration. Our results suggest that long-term exposure to microplastics at environmentally relevant concentrations can impact marine benthic biota. PMID- 29433107 TI - Alcohol withdrawal hallucinations in the general population, an epidemiological study. AB - Hallucinations are sometimes encountered in the course of alcohol withdrawal; however, both the factors predisposing to alcohol withdrawal hallucinations (AWH) and the implications of AWH with respect to the mechanisms of hallucinations remain unclear. To clarify these issues, we used data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) to investigate the demographic correlates, alcohol-use clinical patterns, and psychiatric comorbidities in two groups: drinkers with and without a history of AWH. We estimated the odds ratios for studied factors and used logistic regression analyses to compare the two groups. We found that over 2% of drinkers reported AWH (758 of a sample of 34,533 subjects). Alcohol tolerance and withdrawal seizures were highly associated with AWH, and exposure to alcohol during brain development was associated with a 10-fold increase in AWH compared to exposure during adulthood. African Americans, Native Americans, and unmarried subjects, as well as subjects with lower levels of education and lower levels of income were more likely to experience AWH. Furthermore, those with a history of AWH had higher odds ratios for most psychiatric illnesses than those without such history yet of anxiety disorders, only panic was associated with AWH. These associations suggest that higher levels of education and of standard of living could protect against AWH; while social isolation, hypervigilance, exposure to alcohol during brain development, and long and severe exposure to alcohol could predispose to AWH. PMID- 29433108 TI - Survey on the use of mental health services and help-seeking behaviors in a community population in Northwestern China. AB - There is little research into the patterns of mental health services use, related factors, and barriers in help-seeking behaviors among the community population in northwestern China. We conducted a community-based survey among the general population in Xi'an City with the stratified two-stage systematic selection scheme using the World Health Organization Composite International Diagnostic Interview version 3.0 computer-assisted personal interview (CIDI-CAPI 3.0). We interviewed 2447 individuals aged 16 years or older. The lifetime prevalence estimate of mental disorders was 21%. However, the lifetime use rate of mental health services of the 2447 responding subjects was 2.45% and 4.67% among those subjects who reported a mental disorder. Several variables were associated with lower use of mental health services: rural residence and divorced or unmarried. Among the group with mental disorders, 15/21 sought help from non-mental health specialty services such as a general physician (13/21). The high prevalence rate of mental disorders but low rate of mental health services use raises a significant public health issue in northwestern China. Reduction in the resource gap and encouraging people to seek treatment remain a challenge to the mental health services system. PMID- 29433110 TI - Intraspecific variability of ciprofloxacin accumulation, tolerance, and metabolism in Chinese flowering cabbage (Brassica parachinensis). AB - To investigate the mechanism of genotype differences in ciprofloxacin (CIP) accumulation, this study was designed to compare the tolerance and metabolic responses to CIP exposure between low (Cutai) and high (Sijiu) CIP-accumulation cultivars of Brassica parachinensis. Decreases in biomass and chlorophyll content were significantly greater (p < 0.05) and toxicities were more severe within cell ultrastructures of Cutai compared to Sijiu. A sequential growth test also revealed that Sijiu was more tolerant to CIP stress compared to Cutai. Meanwhile, significantly higher (p < 0.05) root parameters and higher areas of the stele and xylem may be responsible for the increased uptake and transport of CIP in Sijiu. Ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) analysis revealed that CIP was metabolized to three major metabolites by the hydroxylation and breakdown of the piperazinyl substituent in the CIP molecule. The enhanced metabolic transformation of CIP in Sijiu indicated a more efficient capacity to detoxify, which in turn favored an increased accumulation of CIP in this cultivar. Thus, the present study demonstrated that the stronger tolerance and metabolism of Sijiu to CIP were responsible for its high CIP accumulation, suggesting an evolutionary mechanism for adaptation to environmental stress. PMID- 29433109 TI - Pathogenesis of aortic wall complications in Marfan syndrome. AB - BACKGROUND: Patients with Marfan (MFS) syndrome and patients with a bicuspid aortic valve (BAV) are more prone to develop aortic dilation and dissection compared to persons with a tricuspid aortic valve (TAV). To elucidate potential common as well as distinct pathways of clinical relevance, we compared the histopathological substrates of aortic pathology. PATIENT AND METHODS: Ascending aortic wall specimen were divided in five groups: BAV (n=36) and TAV (n=23) without and with dilation and non-dilated MFS (n=8). We performed routine histology to study aortic wall features based on the aortic consensus statement. Immunohistological markers for vascular smooth muscle cell (VSMC) maturation, and expression of fibrillin-1 were additionally investigated for the underlying pathogenesis. RESULTS: On basis of the routine histology the aorta in MFS was similar to the aorta in dilated TAVs (overall medial degeneration, elastic fiber fragmentation, loss and disorganization, , and VSMC nuclei loss). The other markers aided in clustering the MFS and BAV patients with a significantly lower fibrillin-1 expression as compared to the TAVs (p<0.05), a lower level of differentiated VSMC markers (p<0.05) and elastic fiber thinning. CONCLUSIONS: Pathogenesis of aortopathy in MFS overlaps with mechanisms seen in BAV and TAV, leading to a so called double hit hypothesis for aortic complications in MFS. The ascending aortic wall in MFS is immature with undifferentiated VSMCs and low levels of fibrillin-1. The immature media becomes even more vulnerable for aortopathy due to other degenerative features which develop probably as a direct consequence of the fibrillin-1 mutation. PMID- 29433111 TI - [Acute Flaccid Myelitis]. AB - Acute flaccid myelitis (AFM) is a newly defined, rare, but clinically distinct syndrome of acute flaccid paralysis with spinal motor neuron involvement of unknown etiology. Clusters of AFM coincided with a nationwide outbreak of enterovirus D68 (EV-D68) in the United States during autumn to winter of 2014 and in Japan during the autumn of 2015. Although EV-D68 was detected in only 20% of the AFM patients, mainly from respiratory specimens without apparent viral detection from blood and cerebrospinal fluid (CSF) samples, strong temporal associations were noted. Core symptoms of AFM are focal limb weakness and cranial nerve dysfunction with acute onset, although limb paralysis varied in type and severity. Most patients showed extensive longitudinal spinal involvement on magnetic resonance imaging, pleocytosis in CSF, and abnormal motor conduction and/or F-waves in neurophysiological investigations in the acute phase which was within two weeks after onset. Immunomodulation therapy consisting of high-dose intravenous immunoglobulin or pulse methylprednisolone did not improve prognosis. Only about 10% of the patients showed complete recovery of limb weakness, but others had variable residual weakness at follow-up. With no effective treatment identified in the acute stage, studies are required to elucidate the pathophysiology and pathomechanisms of AFM and to develop both preventive measures and novel therapeutic interventions. PMID- 29433112 TI - [Zika Virus and Guillain-Barre Syndrome]. AB - Recent studies revealed an association between Zika virus infection and a variety of neurological disorders, including microcephaly, meningoencephalitis, myelitis, and Guillain-Barre syndrome (GBS). Following the first report of a patient diagnosed with GBS after Zika virus infection in December 2013, the number of GBS patients significantly increased in endemic countries, such as French-Polynesia and Latin American countries. Electrophysiological studies suggested that patients suffering from GBS associated with Zika virus infection manifest acute inflammatory demyelinating polyneuropathy (AIDP), rather than acute motor axonal neuropathy (AMAN). Causative autoantibodies, such as the anti-ganglioside antibodies in AMAN associated with Campylobacter jejuni infection, have not been identified in GBS associated with Zika virus infection. However, a recent study revealed a high level of peptide sharing between Zika virus polyprotein and human proteins related to myelin, demyelination, and axonal neuropathies. Additionally, another study reported significant peptide overlap between Zika virus and Cytomegalovirus, which is also related to microcephaly and AIDP. Further reserch is needed to elucidate the pathogenesis of GBS associated with Zika virus infection. PMID- 29433114 TI - [Hepatitis C Virus-Induced Cryoglobulinemic Vasculitis]. AB - Cryoglobulins are produced by the over-stimulated immune system of patients with hepatitis C virus (HCV). HCV-induced cryoglobulinemic vasculitis primarily affects small-sized vessels of systemic organs. The most common symptoms are purpura, joint pain, and peripheral neuropathy or Raynaud phenomenon. The blood tests of patients with HCV may exhibit raised erythrocyte sedimentation rate and C-reactive protein levels, positive rheumatoid factor and cryoglobulins, and decreased complement levels. Therapeutic options for HCV-induced cryoglobulinemic vasculitis, include anti-virals, Rituximab, steroids, immunosuppressant drugs, and plasma exchange. PMID- 29433113 TI - [Hand-Foot-and-Mouth Disease, Aseptic Meningitis, and Encephalitis Caused by Enterovirus]. AB - Enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), and CV-A6 are the major causative agents of Hand-foot-and-mouth disease (HFMD). These viruses belong to the species Enterovirus A of the genus Enterovirus of the family Picornaviridae. These viruses can also cause aseptic meningitis (AM), encephalitis and/or paralysis. EV-A71 is one of the main infectious agents related to severe encephalitis. Between 1997 and 2013, East and Southeast Asia experienced large encephalitis outbreaks caused by EV-A71 infections, which ranged from severe to lethal. In Japan, national surveillance for HFMD has been conducted since 1982 by monitoring both the notifications of HFMD patients and the causative agents. Even though EV-A71 and CV-A16 are the two major causative agents of HFMD, CV-A6 has been reported to cause atypical HFMD in Japan, since 2011. Both CV-A6 and CV-A16 also cause encephalitis: however, the reported numbers of encephalitis caused by CV-A6 and CV-A16 have been far fewer than those caused by EV-A71. Vaccines against EV-A71 have become available in some Asian countries, such as in China, but as of 2017 they remain unavailable in Japan, likely due to the sparsity of fatal cases. This article summarizes the complications of HFMD on the central nervous system, as well as its epidemiology, clinical manifestations, and treatment. Moreover, the article reviews the history of HFMD and discusses the experimental results of research aimed at the prevention, grading, sample collection, diagnosis, and treatment of severe EV-A71 infections. PMID- 29433115 TI - [New Diagnostic Criteria for Parkinson's Disease: MDS-PD Criteria]. AB - The International Parkinson and Movement Disorder Society offered standard diagnostic criteria for Parkinson's disease (PD) in 2015. These diagnostic criteria provided systematization of the diagnostic process and detailed explanations of parkinsonism, absolute exclusion criteria, red flags, and supportive criteria. The presence of parkinsonism was a core feature of the criteria. Clear instructions for defining the motor features were described. With regard to the novel aspects, non-motor manifestations (hyposmia, autonomic dysfunction, psychiatric dysfunction, and sleep dysfunction) and ancillary diagnostic tests (olfactory test, cardiac MIBG scintigraphy, and presynaptic dopaminergic imaging) were incorporated. Absolute exclusion criteria comprised 9 features that have the potential to exclude PD with greater than 97% sensitivity. The presence of dementia during the early stage of the illness was not classified as an exclusion criterion. The 10 red flags that indicate another cause of parkinsonism but can also be observed in pathologically proven PD were listed. Red flags were counterbalanced by supportive criteria to allow diagnosis of PD. These 4 supportive criteria were highly specific for a diagnosis of PD. With regard to the level of certainty, clinically established PD and clinically probable PD were described. In this review, we summarize the main points of the MDS-PD criteria and discuss the utility and limitations. PMID- 29433116 TI - [MR-Guided Focused Ultrasound]. AB - Since the middle of the 20th century and in order to treat neurological diseases, clinicians have proposed the use of ultrasound, instead of skin incision or trepanation, when performing intracranial thermocoagulation. However, focusing ultrasound intracranially with high precision was technically difficult until recent technological developments. Specifically, advancements in ultrasound phased-array transducers have eliminated the need for a craniotomy, and progress in magnetic resonance (MR) imaging has allowed the real-time measurement of intracranial temperature. Both of the above have enabled the use of MR-guided focused ultrasound as a treatment for refractory essential tremor. Studies focusing on the long-term effects of this treatment are under way. Given that it is less invasive than previous methods, this procedure could be indicated for the treatment of other neurological diseases, including Parkinson's disease, brain tumors, dystonia, and epilepsy. PMID- 29433117 TI - [Non-cirrhotic Portal-systemic Encephalopathy with Total Aphasia and Right Hemiplegia Following Transient Right Hemiparesis: A Case Report]. AB - A 77-year-old right-handed woman without any liver diseases was admitted to our hospital because of transient right hemiparesis. She developed total aphasia with right hemiplegia on the third hospital day. We suspected that she had a cerebral infarction following a transient ischemic attack. However, brain diffusion weighted images revealed no abnormal-intensity lesions, and cerebral angiography showed patent arteries. Additionally, her serum ammonia level was elevated. Theta waves without triphasic waves were detected by electroencephalogram. T1-weighted magnetic resonance brain images revealed high-intensity signals in the bilateral globus pallidus. Enhanced abdominal computed tomography showed a portal-systemic shunt from the splenic and inferior mesenteric veins into the left renal vein via the left ovarian vein. The administration of branched-chain amino acids and lactulose improved her clinical symptoms. We confirmed the diagnosis of non-cirrhotic portal-systemic encephalopathy (NCPSE), therefore balloon-occluded retrograde transvenous obliteration of the shunt vessel was performed. The recognition of NCPSE on the examination of a suspected stroke patient is important, as patients with NCPSE can present as stroke mimics. (Received June 26, 2017; Accepted August 22, 2017; Published February 1, 2018). PMID- 29433118 TI - [Trigeminal Herpes Zoster Presenting with High-intensity Signals for the Spinal Trigeminal Nucleus and Tract on Diffusion-weighted Image: A Case Report of Stroke Mimic]. AB - A 50-year-old woman was admitted to our hospital with dysesthesia on the right upper portion of her face and a headache. Diffusion-weighted brain magnetic resonance imaging (MRI) revealed high-intensity signals in the dorsolateral portion of the medulla oblongata. She was diagnosed with lateral medullary infarction and was intravenously treated with sodium ozagrel. On the second day of hospitalization, she had nausea and vomiting and showed nystagmus to all directions, suggesting damage to the vestibular nucleus. These manifestations coincided with partial symptoms of lateral medullary syndrome. On the third day of hospitalization, a rash appeared on the region of skin innervated by the first and second branches of the right trigeminal nerve. A reevaluation of the MRI findings indicated the presence of a lesion of the right spinal trigeminal nucleus and tract. She was treated with acyclovir for 14 days, and was discharged without any residual symptoms. Varicella zoster virus-DNA was detected in her cerebrospinal fluid. This disease mimics the presentation of a stroke and is important for differential diagnosis. (Received August 1, 2017; Accepted September 14, 2017; Published February 1, 2018). PMID- 29433119 TI - Rhotics and Palatalization: An Acoustic Examination of Upper and Lower Sorbian. AB - Two of the major problems with rhotics are: (1) rhotics, unlike most other classes, are highly resistant to secondary palatalization, and (2) acoustic cues for rhotics as a class have been elusive. This study examines the acoustics of Upper and Lower Sorbian rhotics. Dynamic measures of the F1-F3 and F2-F1 were recorded and compared using SSANOVAs. The results indicate there is a striking delay in achievement of F2 for both the palatalized rhotics, while F2, F1, and F2 F1 are similar for all the rhotics tested here. The results suggest an inherent articulatory conflict between rhotics and secondary palatalization. The delay in the F2 increase indicates a delay in the palatalization gesture. This is likely due to conflicting constraints on the tongue dorsum. There was also an overlap in the F2 and F2-F1 for both the uvular and alveolar rhotics. This suggests a strong acoustic cue to rhotic classhood is found in the F2 signal. The overall formant similarities in frequency and trajectory also suggest a strong similarity in the vocal tract shapes between uvular and alveolar rhotics. PMID- 29433120 TI - AGE-RAGE Interaction Does Not Explain the Clinical Improvements after Therapeutic Fasting in Osteoarthritis. AB - BACKGROUND: Therapeutic fasting improves joint pain in patients with osteoarthritis (OA), but the underlying mechanisms are unknown. Interactions of advanced glycation end products (AGEs) and their receptors (RAGE) play a role in OA pathogenesis. This study aimed to investigate whether the benefits of fasting in OA can be explained by changes in AGEs or RAGE. PATIENTS AND METHODS: 37 patients with OA underwent fasting for 8 days. Serum levels of an AGE (N-epsilon (carboxymethyl)-lysine; CML) and the soluble RAGE (sRAGE) as well as clinical outcome parameters such pain characteristics (measured by visual analogue scale; VAS), joint function (determined by the Western Ontario and McMaster Universities Arthritis Index; WOMAC), and quality of life (via the 36-Item Short-Form Health Survey (SF-36) questionnaire) were assessed. The variables were measured at baseline, the end of fasting, and at follow-up at 4 weeks. RESULTS: The CML levels did not significantly change from baseline to the end of intervention (Delta = -25.6 +/- 92.2 ng/ml; p = 0.10). In contrast, the sRAGE levels (Delta = 182.7 +/- 171.4 ng/ml; p < 0.0001) and the sRAGE/CML ratio (Delta = -0.4 +/- 0.6; p < 0.001) significantly decreased, but they returned to baseline levels 4 weeks after the end of fasting. The scores for pain, WOMAC, and the physical subscale of the SF-36 significantly improved during fasting. There was no correlation between the clinical outcomes and changes in serum levels of CML, sRAGE, or the sRAGE/CML ratio. CONCLUSIONS: Fasting resulted in a significant but non-sustained reduction of sRAGE levels and the sRAGE/CML ratio in OA, while the CML levels did not change. Improvement in clinical endpoints of OA does not correlate with changes in CML or sRAGE. PMID- 29433121 TI - Explaining Coronal Reduction: Prosodic Structure and Articulatory Posture. AB - Consonant reduction is often treated as an allophonic process at the phonological planning level, with one production target (allophone) being substituted for another. We propose that, alternatively, reduction can be the result of an online process driven by prosodically conditioned durational variability and an invariant production target. We show that this approach can account for patterns of coronal stop (/t/, /d/, and /n/) production in both American English and Spanish. Contrary to effort-driven theories of reduction, we show that reduction does notdepend on changes to gestural stiffness. Moreover, we demonstrate how differences between and within a language in the particular articulatory postures used to produce different coronal stops automatically lead to reduction to what have normally been considered distinct allophones - coronal approximants ([d]) and flaps ([r]). In this way, our approach allows us to understand different outcomes of coronal stop reduction as the dynamic interaction of a single process (durationally driven undershoot) and variable spatial targets. We show that these patterns are reflected across a wide variety of languages, and show how alternative outcomes of reduction may fit within the same general framework. PMID- 29433122 TI - Tongue-Palate Contact Timing during /s/ and /z/ in English. AB - Although numerous studies have investigated supraglottal strategies for signalling voicing in fricatives, there is still no agreement about the precise characteristics of tongue-to-palate contact timing during voiced as opposed to voiceless fricatives. In this study we use electropalatography (EPG) to investigate articulatory and coarticulatory characteristics of tongue-to-palate contact timing during /s/ and /z/ in English. Five typically speaking participants, speakers of Southern British English, produced 500 trochaic words containing the intervocalic alveolar fricatives /s/ or /z/. The time between the start of the frication and the maximum contact at the place of articulation was expressed as a percentage of each fricative's total duration (time to target, TT).This measure was used to analyse articulatory and coarticulatory timing during /s/ and /z/. Data for absolute timing were also presented. The results showed that the time between the start of the frication and the maximum contact point was longer for /s/ than for /z/. This difference was consistent across speakers but was not significant for all of them. The results of the coarticulatory effects showed that the influence of vowel context on TT values for /s/ and /z/ did not differ significantly, but there was a tendency for /z/ to be more resistant to coarticulation effects than /s/. PMID- 29433124 TI - Thalamic Deep Brain Stimulation Salvages Failed Focused Ultrasound Thalamotomy for Essential Tremor: A Case Report. AB - BACKGROUND: A recent randomized controlled trial investigating unilateral MRI guided focused ultrasound (FUS) for essential tremor demonstrated efficacy. The long-term durability of this thalamotomy, however, is unknown. Furthermore, the feasibility of stimulating a previously lesioned target such as the thalamic nucleus ventralis intermedius (Vim) is poorly understood. We report a case of tremor recurrence, following an initially successful FUS thalamotomy, in which Vim-DBS was subsequently utilized to regain tremor control. METHODS: An 81-year old right-handed female with medically refractory essential tremor (a Clinical Rating Scale for Tremor [CRST] value of 73) underwent left-sided FUS thalamotomy with initial abolition of right-upper extremity tremor. By the 6-month follow-up, there was complete recurrence of tremor (a CRST value of 76). The patient subsequently underwent left-sided Vim-DBS. RESULTS: Vim-DBS provided clinical improvement with a CRST value of 42 at the 3-month follow-up; the patient continues to do clinically well at the 6-month follow-up. This result mirrors previous reported cases of stimulation following radiofrequency and gamma-knife lesioning. Our literature review highlights several reasons for the waning of clinical benefit seen with lesional procedures. CONCLUSION: This case demonstrates that thalamic DBS can salvage a failed FUS thalamotomy and also the feasibility of stimulating a previously lesioned target. PMID- 29433123 TI - Endobronchial Treatment for Bronchial Carcinoid: Patient Selection and Predictors of Outcome. AB - BACKGROUND: Traditionally, surgical resection is the preferred treatment for typical carcinoids and atypical carcinoids located in the lungs. Recently however, several studies have shown excellent long-term outcome after endobronchial treatment of carcinoid tumors located in the central airways. This study investigates clinical and radiological features as predictors of successful endobronchial treatment in patients with a bronchial carcinoid tumor. OBJECTIVES: To identify clinical and radiological features predictive of successful endobronchial treatment in patients with bronchial carcinoid. METHODS: This analysis was performed in a cohort of patients with typical and atypical bronchial carcinoid referred for endobronchial treatment. Several patient characteristics, radiological features, and histological grade (typical or atypical carcinoid) were tested as predictors of successful endobronchial treatment. RESULTS: One hundred and twenty-five patients with a diagnosis of bronchial carcinoid underwent endobronchial treatment. On multivariate analysis, a tumor diameter <15 mm (odds ratio 0.09; 95% confidence interval 0.02-0.5; p = <0.01) and purely intraluminal growth on computer tomography (CT scan) (odds ratio, 9.1; 95% confidence interval 1.8-45.8; p = <0.01) were predictive of radical endobronchial treatment. The success rate for intraluminal tumors with a diameter <20 mm was 72%. CONCLUSIONS: Purely intraluminal disease and tumor diameter on CT scan seem to be independent predictors for successful endobronchial treatment in patients with bronchial carcinoid. Based on these data, patients with purely intraluminal carcinoid tumors with a diameter <20 mm on CT scan are good candidates for endobronchial treatment, regardless of histological grade. In contrast, all patients with a tumor diameter >=20 mm should be directly referred for surgery. PMID- 29433125 TI - Meridional overturning circulation conveys fast acidification to the deep Atlantic Ocean. AB - Since the Industrial Revolution, the North Atlantic Ocean has been accumulating anthropogenic carbon dioxide (CO2) and experiencing ocean acidification, that is, an increase in the concentration of hydrogen ions (a reduction in pH) and a reduction in the concentration of carbonate ions. The latter causes the 'aragonite saturation horizon'-below which waters are undersaturated with respect to a particular calcium carbonate, aragonite-to move to shallower depths (to shoal), exposing corals to corrosive waters. Here we use a database analysis to show that the present rate of supply of acidified waters to the deep Atlantic could cause the aragonite saturation horizon to shoal by 1,000-1,700 metres in the subpolar North Atlantic within the next three decades. We find that, during 1991-2016, a decrease in the concentration of carbonate ions in the Irminger Sea caused the aragonite saturation horizon to shoal by about 10-15 metres per year, and the volume of aragonite-saturated waters to reduce concomitantly. Our determination of the transport of the excess of carbonate over aragonite saturation (xc[CO32-])-an indicator of the availability of aragonite to organisms by the Atlantic meridional overturning circulation shows that the present-day transport of carbonate ions towards the deep ocean is about 44 per cent lower than it was in preindustrial times. We infer that a doubling of atmospheric anthropogenic CO2 levels-which could occur within three decades according to a 'business-as-usual scenario' for climate change-could reduce the transport of xc[CO32-] by 64-79 per cent of that in preindustrial times, which could severely endanger cold-water coral habitats. The Atlantic meridional overturning circulation would also export this acidified deep water southwards, spreading corrosive waters to the world ocean. PMID- 29433127 TI - ? PMID- 29433126 TI - MEK drives BRAF activation through allosteric control of KSR proteins. AB - RAF family kinases have prominent roles in cancer. Their activation is dependent on dimerization of their kinase domains, which has emerged as a hindrance for drug development. In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK). Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. Although GTP-bound RAS can modulate the dimerization of RAF isoforms by engaging their RAS-binding domains, KSR1 and KSR2 lack an RAS-binding domain and therefore the regulatory principles underlying their dimerization with other RAF family members remain unknown. Here we show that the selective heterodimerization of BRAF with KSR1 is specified by direct contacts between the amino-terminal regulatory regions of each protein, comprising in part a novel domain called BRS in BRAF and the coiled coil-sterile alpha motif (CC-SAM) domain in KSR1. We also discovered that MEK binding to the kinase domain of KSR1 asymmetrically drives BRAF-KSR1 heterodimerization, resulting in the concomitant stimulation of BRAF catalytic activity towards free MEK molecules. These findings demonstrate that KSR-MEK complexes allosterically activate BRAF through the action of N-terminal regulatory region and kinase domain contacts and challenge the accepted role of KSR as a scaffold for MEK recruitment to RAF. PMID- 29433128 TI - [The new National Immunization Program 2017-2019 and the Essential Care Levels: what is going to change?] AB - Italy is witnessing relevant challenges in the field of prevention and control of vaccine-preventable diseases. The worrying and growing phenomenon of "vaccine hesitancy" has contributed to the reduction of vaccination coverage, undermining goals reached thanks to vaccines introduction. The new Italian National Immunization Plan (NIP) 2017-2019 and the update of the list of Essential Care Levels (LEA), approved in the current year, extend the vaccination offer based on the latest scientific evidence with the introduction of new vaccines and the enlargement of target population. The decree-law containing urgent measures in immunization field issued in June 2017 represents a tool to achieve the goals reported in global and national immunization plans. Among others it has increased mandatory vaccinations from 4 to 10 and has made them compulsory for pre-school admission. Following the global and European vaccination goals, the priorities identified by the Italian NIP are to: maintain the polio-free status; pursue the elimination of measles and congenital rubella; ensure an active and free of charge vaccination offer, the access to services and the availability of vaccines; target hard to reach populations with low vaccination coverage; develop an institutional communication plan on vaccinations. Regarding the vaccination offer, the main novelties introduced by the NIP 2017-2019 include the introduction of: vaccines against N. meningitidis B, rotavirus and varicella in newborns; tetravalent meningococcal vaccine (ACWY135) and a booster dose of anti polio in adolescents; pneumococcal vaccines (PCV13 + PPV23) and anti-Zoster in subjects aged sixty-five. Furthermore, the NIP 2017-2019 establishes to extend HPV vaccination to male adolescents. The cost of new vaccinations, funded by the National Health System, is about 100 million euros in 2017 but, thanks to the new vaccination schedule, it is estimated that approximately 200 million euros will be saved because of the annual reduction of direct costs of vaccine-preventable diseases. Furthermore, the NIP tries to act against the growing public skepticism in vaccines, proposing solutions to counteract the fall in vaccination coverage by promoting a culture of vaccination and the empowerment of both health workers and general population. In this perspective, the NIP proposes to promote institutional communication campaigns, based on transparency, conveying information about vaccines risks and benefits and the ethical and social value of vaccinations. It is further proposed to strengthen the training of healthcare professionals, jointly with disciplinary actions against physicians who do not recommend vaccinations. Particular attention is also placed on the implementation of vaccines registries for the homogenization of data recording that allows to evaluate and to monitor vaccine policies. The update of LEA, which include a list of services provided by SSN, has adopted the innovations of the NIP and overcomes the criticism of regional inequalities in vaccination offer guaranteeing the same offer all over the Italian country. In conclusion, the NIP 2017-2019 and the new LEA are fully integrated into the current epidemiological and cultural scenario. They envisage a supply of evidence-based vaccinations, ensuring a free, equal and uniform vaccination offer on a national scale and striving for the promotion of a culture of vaccination. PMID- 29433129 TI - [Routine vaccination strategies, reactive vaccination, and pandemic preparedness and response]. AB - Vaccines represent the most important public health tools. In order to ensure the success of an effective and safe vaccine, it is important to implement adequate immunization strategies. Routine strategies, based on children immunization schedules, represent the most commonly utilized approach. Reactive immunization strategies may also be used and be effective especially in response to an outbreak; these strategies include both mass vaccination and ring vaccination, which relies on the identification and immunization of case contacts. A specific role is played by pandemic plan, in which the use of a vaccine may be either proactive, when specific population targets are immunized before the occurrence of an epidemic, or reactive. In conclusion, to successfully control vaccine preventable diseases, it is important to implement adequate vaccination strategies, taking into account the availability of the vaccine, the characteristics of the micro-organism, and epidemic dynamics. PMID- 29433130 TI - [The elimination of measles and rubella in Italy]. AB - Despite the WHO target for measles and rubella elimination in 2015, outbreaks still occur in all WHO Regions. After a description of the epidemiological situation of measles and rubella worldwide and especially in Europe, this paper aims to provide a detailed analysis of the current epidemiological context of Italy. The surge in the number of measles cases since the beginning of 2017, together with vaccination coverage still far from the 95% target, requires priority actions to be taken to achieve the elimination goals. Alongside the recently approved decree reintroducing compulsory vaccinations for school admissions, further measures are needed and should include the increase in the commitment of the 21 Regions; the implementation of supplemental immunization activities; improving the communication skills of health care workers; ensuring an effective communication with citizens; the enhancement of the surveillance network. PMID- 29433131 TI - [Vaccination in childhood: how to protect the "unprotectable"?] AB - The failure of immunization coverage is the primary reason for the transmission and the spread of the diseases in young infants not eligible for vaccination because of age and in immunocompromised individuals. In both these categories measles, pertussis and varicella could be devastating. Pertussis, measles and varicella in the first year of life are responsible to the ED admission, the hospitalization and, exceptionally, the death. The only way to protect very young infants and immunocompromised individuals is to obtain the adequate coverage in all the population. PMID- 29433132 TI - [The economic value of vaccinations: a systematic review of Italian economic evaluations and HTA reports]. AB - INTRODUCTION: Decision-making in healthcare should rely on evidence-based approaches able to make possible a transparent and robust assessment of all the aspects related to health technologies. One of the assessment elements is represented by the efficiency that is the specific objective of economic evaluations and also of Health Technology Assessment (HTA). The collection and synthesis of evidence is the first indispensable step in order to foster a proper convey of scientific knowledge to the decision-makers. This work, carried out within a broader project on the transfer of evidence from the scientific to the decision making world, is aimed to release an overview of economic evaluations and HTA on vaccines conducted in Italy. The project was carried out within the activities of the ISPOR Italy-Rome Chapter. METHODS: A systematic review of Italian economic evaluations and HTA performed on vaccines and published up to May 2015 was carried out. PubMed, Scopus and the NIHR HTA databases were queried and a hand-search was performed on key journals in the field (Global & Regional Health Technology Assessment; PharmacoEconomics Italian Research Articles; Giornale italiano di HTA; Politiche Sanitarie; HTA Focus - Pills of Clinical Governance; Pillole di Farmacoeconomia; Giornale Italiano di Farmacoeconomia e Farmacoutilizzazione; IJPH; Quaderni dell'IJPH). Studies were considered eligible if showing the results of a full economic evaluations and if performed in Italy. RESULTS: The literature search yielded 10 HTA reports and 33 economic evaluations. Among the latter, 20 (60,6%) were cost-effectiveness analyses. Ten studies (23,3%) assessed the vaccination against S. pneumoniae figuring out that it is cost-effectiveness and even costsaving in cases of newborns and subjects at risk. Nine studies (20,9%) addressed influenza vaccination and demonstrated its dominance on non-vaccination in the elderly. Eight studies (18,6%) evaluated the HPV vaccines concluding that they are cost-effective. Five studies (11,6%) devoted to anti-rotavirus vaccination showing its dominance on non-vaccination, in particular from the society perspective. Vaccination against pertussis, hepatitis B, chicken pox, measles, rubella, mumps were eventually shown cost saving. The vaccine against Neisseria meningitidis was considered potentially cost-effective. CONCLUSION: The Italian scientific evidence on efficiency of vaccination is broad and allows concluding that vaccinations are value for money interventions. PMID- 29433133 TI - [Vaccines: benefits have been forgotten]. AB - The increased use of vaccination has led to a significant decrease or even to the disappearance of serious infectious diseases. Currently, vaccines are often evaluated by their potential side effects while ignoring the benefits. This happens because of memory loss. The memory of the damage caused by vaccine preventable diseases has been lost. This paper illustrates the epidemiology of the major vaccine-preventable diseases and the risk of reintroduction of many pathologies in case the vaccine coverage continues to decrease. PMID- 29433134 TI - [An effective clinical leadrship to strenghten the immunization policies in Italy]. AB - Effective governance for health is a prerequisite for implementing a transformation in healthcare. Any change, in order to be fully implemented, requires a strong and transparent leadership. The recent drop in vaccine cover has led our National Health Service to implement a number of changes in health prevention and immunization strategies that make vaccination an optimal paradigm of how healthcare leadership should not remain the focus of few scientists and public health specialists, but it should be more and more widespread at all levels. In fact, as in other areas of health, the implementation of a national evidence-based planning through efficient organization and management is not sufficient to ensure good results, but it is necessary that the whole system - institutions, policy makers, healthcare professionals, media and citizens themselves - is actively involved in driving change, promoting ethical, economic and social value of vaccinations. PMID- 29433135 TI - [Training on vaccination for health care professionals]. AB - Vaccinations in Italy show a downward trend since 2013 due to an evergrowing mistrust of the population with regard to vaccination that has resulted in lesser adherence to vaccination programs. The main cause of the reduction is due to a tendency observed in recent years, even at the international level, known as 'vaccine hesitancy'. A growing number of studies on vaccine hesitancy show that causes vary by country, population, vaccine, and context influences, but in all cases emerges the importance of health care professionals in patients decision about vaccine. The new Piano Nazionale della Prevenzione Vaccinale 2017-2019 (PNPV - Italian National Plan on Vaccine Prevention) underlines the need to invest for healthcare professionals in technical and scientific training not only about vaccination and vaccination strategies, but also on communication skills. Training interventions are also considered important for achieving another PNPV goal that is to "support, at all levels, the sense of responsibility of healthcare workers [.....].". The training of health care staff is therefore recognized as a key aspect for the consolidation of national vaccination policies. It is intended to improve and standardize SSN's performance, skills and quality and to provide the essential tools to be able to respond adequately the growing demand for correct and exhaustive information from patients. Therefore, it is important to invest in strategies to improve technical, scientific and communication knowledges on vaccinations, adapting them to specific political, social and cultural contexts, in order to reinforce the sense of trust with citizens and to pursue the success of public health strategies to increase vaccine coverage. PMID- 29433136 TI - [Audit as a tool to improve the efficiency of the immunization services: the experience of a Local Health Authority in Rome]. AB - INTRODUCTION: The Italian Ministry of Health has launched an alert about the reduction in vaccine coverage (VC), which decreased below 95% since 2014 for many paediatric vaccines, oppositely from the National Prevention Plan 2014-18 and the National Immunization Plan 2017-2019. Even though the growing vaccine hesitancy attracts the attention of the media in the last few years, the organization of an easily accessible and efficient supply network remains a crucial imperative for ensuring satisfactory and uniform vaccine coverage. Taking into consideration some critical issues identified within the vaccination centres of the Local Health Authority (ASL) RM/A, the local health management decided to improve the VC in deep collaboration with all the health professionals. The amelioration process includes the following actions: verifying the current situation, analysing the main concerns, evaluating the possible solution, and activating those already deemed feasible. This paper aims to describe in details the methodology used in the audit and to present the results and actions undertaken following this amelioration process. METHODS: In the ASL RM/A, which counts 550.000 inhabitants, all the 5 vaccination centres started from 2014 to carry out at least one 30-hour audit each year in order to improve VC. The audits are structured according to the four steps defined by the Ministry of Health to address systematically the critical points identified, by implementing the improvement actions proposed by the audit team to the health management. The audits, accredited under the ECM for the medical and nursing personnel, started in February 2014 and the last edition of the program was completed in December 2016. RESULTS: During 20 meetings the audit "Centri Vaccinali" involved 11 professionals from 5 vaccine centres, who acknowledged being highly satisfied with the audit, which has been recognized as a valuable tool for improving their work. Following the activities performed in the VC improvement programme, throughout the 3-years period an in-depth review of the most relevant procedures implemented daily by the involved experts was conducted. Moreover, the share of goals and deadlines among the various professionals has leaded to a positive and fruitful collaboration of all experts working in the vaccination centres. This was achieved without creating an additional burden deriving from the improvement process activities. The analysis conducted after two years from the start of the programme has shown not just a significant improvement in vaccine coverage, but also an important increase in the number of vaccine sessions and in the total number of administered vaccines. CONCLUSIONS: Throughout the described process of improvement, the collaboration among health care professionals was significantly improved and immunization strategies were identified and shared among the centres. The audit demonstrated to be an effective methodology for facilitating the accessibility and usage of vaccination centres by the citizen/user as well as by the healthcare providers. It showed a quick and significant improvement that, by promoting accountability and transparency, will ensure greater efficacy and safety of vaccine services. PMID- 29433137 TI - ["The Invisibles" project, meeting and collaboration of Public Health and volunteering. The influenza vaccination experience to promote the health of the socially vulnerable and economically disadvantaged population]. AB - Migration and the current European socioeconomic conditions necessitate an evaluation/assessment, as detailed as possible, of the spread of seasonal infectious diseases in order to reduce inequalities in the healthcare system. The "Scuola di Formazione in Medicina Generale" of Lazio, in collaboration with the Community of Sant'Egidio of Rome, organized an influenza/flu vaccination campaign for homeless people, migrants and the poor in order to check their health conditions and prevent the spread of the most common infectious diseases. People were asked to fill in an anamnestic form, including personal details (name, surname, gender, date of birth and nationality) so that they could be classified according to specific health risks; they were also asked to give a short account of their medical history. During the clinical examination, the general conditions of the patients were evaluated, and some parameters, such as blood pressure, heart rate and oxygen saturation, were reported on the form. At the end of the interview, the participants were immunized with an influenza trivalent vaccine. Vulnerability and the risk of chronic and disabling diseases were assessed on the basis of anamnestic data, such as blood pressure, in order to evaluate the actual need for immunization. The 486 forms, collected and validated, revealed an average age of 37, and an average blood pressure of 129/82 mmHg. By dividing the participants into 4 groups based on their continent of origin (Europe, Asia, Africa, America), it became evident that the majority of them came from Europe (227), while a smaller number came from the other three continents. From the observation of the collected data, it can be stated that vaccinations are the principal weapon against the spread of seasonal infectious diseases in those categories of patients considered vulnerable because of their disadvantaged socioeconomic and sanitary conditions. The MMG (general practitioner), in collaboration with voluntary organizations, plays a central role in the management of these types of patients. PMID- 29433138 TI - [Alert for meningitis in Palermo? Successful strategies to counteract the impact of mass media]. AB - Following two invasive meningococcal disease cases among twenties, general population overloaded vaccination Units of the Palermo's District during summer 2016. Sicilian Health Authorities adopted several public health strategies including: a) active meningococcal vaccination free of charge for people from 18 up to 30 years of age, b) information in crowded places and rapid communication by media. An increase in anti-meningococcal vaccination doses administered (+868%) as well as in anti-dTp and HPV vaccination (+41% and +8%, respectively) due to a further catch-up was observed. PMID- 29433139 TI - [A health promotion campaign to improve flu vaccination adherence among medical residents in an Italian Teaching Hospital]. AB - INTRODUCTION: In Italy annual flu vaccination for health care workers is recommended but coverage is usually unsatisfying. The compliance is even worse among medical residents (MRs) both in literature, both in our experience: in the flu season 2014/ 15 only 0.6% of MRs enrolled at the Universita Cattolica del Sacro Cuore (UCSC) were vaccinated. For this reason, during the influenza season 2015/16, the Institute of Public Health of the UCSC, in collaboration with the Health Management of the "Agostino Gemelli" Teaching Hospital (FPG) and with the directive board of the Medical Specialization Schools (SSM) present at the University has tested several strategies to improve awareness and adherence to flu vaccination campaign by its staff. This study aims to analyze the impact of the strategies used during the 2015/16 campaign on flu vaccination coverage among MRs of an important Italian Teaching Hospital. METHODS: The study was conducted among MRs enrolled at the UCSC - FPG in 2015/16. The data was collected by the Occupational Medicine which, during the influenza seasons, immunize MRs against influenza free of charge. For each variable - vaccination, area of specialization (surgical, medical, clinical services), typology of SSM - was measured the absolute and percentage frequency. In order to compare the flu vaccination coverage between seasons 2014/15 and 2015/16 and between areas of specialization in 2015/16 chi-square test was used (statistical significance level of 0.05). The data were analyzed using STATA Software. RESULTS: Were included in the analysis 42 SSM with a total of 1041 MRs. During the vaccination campaign 2015/16, flu vaccine was administered to 99 MRs (9.5%), 8.9% more than in the previous season (p<0.001). There is also a significant difference in vaccine coverage between surgical, medical and clinical services areas in 2015/16 (p <0.001). The highest vaccination coverage was recorded among MRs of Hematology and Urology (54.5%). However, no one MRs had undergone flu vaccination in about 40% of SSM. CONCLUSIONS: Seasonal flu vaccination among HCWs is important to protect patients as well as them self and their family members. Considering that MRs represent the next generation of HCWs, they should be sensitized about the importance of preventing the spread of influenza in hospital population, becoming an active part of the necessary cultural change. This study highlights a first and promising, although insufficient, increase in flu vaccination coverage among MRs enrolled at the UCSC - FPG after introducing simple strategies to promote vaccination itself and, more generally, positive and proactive behaviors. The study summarizes the results in the short term, but it is well known that cultural changes require time and constancy. Therefore, it will be useful to monitor the improvement over time and extend the assessment to all health care professionals. PMID- 29433140 TI - [Colour duplex sonography and "Power-Duplex" in Perforator Surgery - Improvement of patients safety by efficient planning]. AB - INTRODUCTION: There are many techniques to identify vessels in perforator surgery, each with specific disadvantages. Handheld Dopplers are easy to use, but inaccurate with respect to the exact localisation of the perforator. Angio-CT is invasive, time consuming, and expensive. In contrast, duplex sonography is a reliable, easy-to-use and availabe alternative for pre-, intra-, and postoperative visualisation of vessels. Power Doppler further increases sensitivity and allows visualisation of vessels smaller than 0.5 mm in diameter. MATERIAL AND METHODS: The use of duplex sonography and power Doppler in preoperative planning is illustrated in photographs that show how to identify the course of the septal vessel in free ALT flaps, to ensure that there are competent recipient vessels and to plan pedicled perforator flaps. In all 33 free flaps (21 ALT, 5 DIEAP, 4 FCI, 2 MSAP, 1 tib. post. perf. flap) for lower leg and breast reconstruction and 19 pedicled perforator flaps at the trunk and the extremities were harvested with this technique and used to cover post traumatic and tumour defects. RESULTS: The detection accuracy of duplex sonography was 100 % with reference to the perforator being found within 0.5 cm of the duplexed point and the correct detection of the vessel course (septal vs. intramuscular). No flap loss was observed in this series. This is a non-invasive, reliable, and inexpensive, but time consuming and investigator-dependent technique. DISCUSSION: By direct visualisation of the arteries and veins, the exact localisation of fascia penetration can be detected and flaps can then be better designed. Perforators can be centred in the flaps. The course of perforators can be visualised - especially in ALT flaps - and time consuming dissections through muscle can be avoided. PMID- 29433141 TI - Synthesis and Molecular Docking Studies of (E)-4-(Substituted-benzylideneamino) 2H-Chromen-2-one Derivatives: Entry to New Carbonic Anhydrase Class Of Inhibitors. AB - The present article illustrated the synthesis and characterization of a novel series of (E)-4-(substituted-benzylideneamino)-2H-chromen-2-one derivatives 4A 4J: in good to excellent yields. The target compounds were synthesized by refluxing 4-aminocoumarin with aromatic aldehydes in ethanol. The structural confirmation was achieved by spectroscopic techniques such as (1H, 13C-NMR and FT IR) and elemental analysis. The synthesized compounds were evaluated for carbonic anhydrase II (CA-II) inhibition and free radical scavenging activity. All the compounds showed CA-II inhibition in the micro molar range. The compound 4C: exhibited higher potential in the series with IC50=0.0928+/-0.00545 uM (standard Acetazolamide IC50=0.997+/-0.0586 uM). Pharmacological investigations showed that the synthesized compounds 4A-4J: obey Lipinsk's rule. Compound 4C: elicited drug likeness and showed drug score value of 0.05. Molecular docking analysis showed that compound 4C: interacts with Asn66 and Gln91 amino acid residues. Graphical Abstract. PMID- 29433142 TI - PPAR-alpha Agonist Improves Hyperglycemia-Induced Oxidative Stress in Pancreatic Cells by Potentiating Antioxidant Defense System. AB - BACKGROUND: Diabetes-induced oxidative stress has an essential role in pancreatic cells dysfunction. The present study aimed to evaluate whether peroxisome proliferator activated receptor- alpha (PPAR-alpha) induction by fenofibrate counterbalances oxidative stress in pancreatic cells. METHODS: In this in vivo study, male Wistar rats were randomly divided into four groups as normal, normal treated, diabetic and diabetic treated groups (n=6 in each group). Diabetes was induced by a single intravenous injection of streptozotocin (45 mg/kg). Treated animals received fenofibrate for 8 weeks (80 mg/kg/day) orally. At the end of the 8th week, rats were sacrificed and blood samples and pancreas tissues were collected. Then, the content of malondialdehyde (MDA), nitrate (Nox) and glutathione (GLT) and enzymatic activities of catalase (CAT) and superoxide dismutase (SOD) were assessed. D ata were analyzed using two-way ANOVA. RESULTS: Diabetes deteriorated anti-oxidant defense capacity in pancreatic cells by reducing SOD and CAT activities and induced oxidative stress as reflected by increased MDA content and free radicals production (Nox content). Treatment by fenofibrate increased SOD and CAT activities and improved oxidative stress by decreasing pancreatic MDA and Nox levels. CONCLUSION: Uncontrolled hyperglycemia weakens anti-oxidant defense capacity in pancreatic cells and contributes to oxidative stress. PPAR-alpha induction by fenofibrate can restore anti-oxidant defense systems and improve diabetes-induced oxidative stress. PMID- 29433143 TI - Pyrrolopyrimidine, A Multifaceted Scaffold in Cancer Targeted Therapy. AB - Pyrrolopyrimidine derivatives represent a class of biologically active heterocyclic compounds which can serve as promising scaffolds that display remarkable biological activities, such as anti-inflammatory, antimicrobial, antiviral and anticancer. In the last few years, several pyrrolopyrimidine derivatives have been approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Due to their inimitable antioxidant and anti-tumor properties, researchers were inspired to develop novel derivatives for the treatment of different types of cancer. The present review summarizes recent literature up to 2017 on the most recent development in the medicinal chemistry of pyrrolopyrimidine derivatives and their potential as anticancer therapeutics, especially compounds acting as kinase inhibitors. PMID- 29433145 TI - Effect of Cord Blood Magnesium Level at Birth on Non-neurologic Neonatal Outcomes. AB - OBJECTIVE: We examined the effects of magnesium sulfate on non-neurologic neonatal outcomes with respect to cord blood magnesium level. STUDY DESIGN: We conducted a secondary analysis of the Maternal-Fetal Medicine Units Beneficial Effects of Antenatal Magnesium (MFMU BEAM) trial comparing the upper and lower quintiles of cord blood magnesium level. Outcomes included cerebral palsy (CP), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and assessments of mental and motor disability. Logistic regression was used to estimate adjusted odds ratios (aORs) of each outcome, controlling for gestational age (GA), birth weight, and treatment group (TG). RESULTS: A total of 1,254 women of the 2,444 included in the BEAM trial had cord blood magnesium levels recorded. GA and birth weight were lower and TG was more common in the upper quintile cohort (p < 0.001). Neonates in the upper quintile were more likely to have severe NEC (OR, 2.41, 95% confidence interval [CI]: 1.11-5.24), ROP (OR, 1.65, 95% CI: 1.05-2.59), and BPD (OR, 1.70, 95% CI: 1.04-2.73). Adjustment for covariates demonstrated no difference in the NEC, ROP, and BPD rates, although there was a decrease in rates of mental disability index < 70 which was not seen in the unadjusted analysis (aOR, 0.49, 95% CI: 0.25 0.99). CONCLUSION: Higher cord blood magnesium levels do not appear to have adverse non-neurologic effects on the neonate and may demonstrate improvement in neurologic outcomes. PMID- 29433144 TI - Smith-Lemli-Opitz Mutations in Unexplained Stillbirths. AB - OBJECTIVE: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive syndrome caused by a defect in cholesterol biosynthesis with mutations in 7 dehydrocholesterol reductase (DHCR7). A total of 3% of Caucasians carry DHCR7 mutations, theoretically resulting in a homozygote frequency of 1/4000. However, SLOS occurs in only 1/20,000 to 60,000 live births. Our objective was to assess DHCR7 mutations in unexplained stillbirths. STUDY DESIGN: Prospective, multicenter, population-based case-control study of all stillbirths and a representative sample of live births enrolled in five geographic areas. Cases with stillbirth due to obstetric complications, infection, or aneuploidy, and those with poor quality deoxyribonucleic acid (DNA) were excluded. DNA was extracted from placental tissue stored at -80 degrees C, and exons 3 to 9 of the DCHR7 gene were amplified, purified, and subjected to bidirectional sequencing to identify mutations. RESULTS: One-hundred forty four stillbirths were unexplained and had adequate DNA for analysis. Nine stillbirths of 139 (6.5%) had a single mutation in one allele in coding exons 3 to 9 of DHCR7 (Table 1). One case (0.7%) was a compound heterozygote for mutations in exons 3 to 9 of DHCR7; this fetus had no clinical or histologic features of SLOS. CONCLUSION: We detected SLOS mutations in only 0.7% of stillbirths. This does not support a strong association between unrecognized DHCR7 mutations and stillbirth. PMID- 29433146 TI - Reconstruction of Tragus and External Auditory Meatus using Remnant Auricle during Microtia Reconstruction. AB - This article investigates an effective method with which to reconstruct the tragus and external auditory meatus for microtia reconstruction. The external ear was reconstructed using a delayed postauricular skin flap in patients with congenital microtia. After the first stage of delaying the postauricular skin flap and the second stage of otoplasty with ear framework fabricated from autogenous rib cartilage draping with the delayed skin flap, the third stage involved tragus and external auditory meatus canaloplasty. After designing the remnant auricle flap, the lower part was trimmed and the tragus was reconstructed. The upper part was trimmed into a thin skin flap, which was rotated and used to cover the hollowed wound posterosuperior to the tragus so as to mimic the external auditory meatus. If remnant wounds were present, skin grafting was conducted. In total, 121 patients with congenital microtia were treated from March 2010 to March 2016. The reconstructed tragus and external auditory meatus were well formed, and all wounds healed well. No severe complications such as flap necrosis occurred. Six months postoperatively, the morphology of the reconstructed tragus and external auditory meatus was good. Overall, the patients and their families were satisfied. The use of remnant auricle to reconstruct the tragus and external auditory meatus is an effective auricular reconstruction technique. PMID- 29433147 TI - Balloon-assisted endoscopy facilitates endoscopic submucosal dissection of difficult superficial proximal colon tumors. AB - BACKGROUND: Colorectal endoscopic submucosal dissection (ESD) can be technically difficult in some situations, such as paradoxical movement of the proximal colon. The double-balloon endoscope provides stable endoscopic maneuvering, even in the small intestine. The aim of this study was to assess the outcomes of balloon assisted endoscopic submucosal dissection (BAESD) of colonoscopically difficult superficial proximal colon tumors. METHODS: We retrospectively reviewed the records of patients who underwent BAESD of superficial proximal colon tumors where colonoscopic difficulties were encountered, from January 2011 to September 2016. Difficulties were defined as a previous incomplete colonoscopy using a conventional colonoscope or unstable endoscopic maneuverability around the tumor with a conventional colonoscope. A propensity score model was used as a secondary analysis to compare outcomes of the BAESD group with those of a non-BAESD group. RESULTS: BAESD was performed on 63 tumors in 63 patients. En bloc resection was achieved for 62 tumors (98 %) and an R0 resection was achieved for 55 tumors (87 %). Propensity score matching analysis created 59 matched pairs from the BAESD and non-BAESD groups. There were no statistically significant differences between the two groups in en bloc resection (100 % vs. 100 %; P > 0.99), R0 resection (90 % vs. 93 %; P = 0.74), perforation (0 % vs. 2 %; P > 0.99) or postoperative bleeding (3 % vs. 0 %; P = 0.50). CONCLUSION: Balloon-assisted endoscopy achieved safe and reliable ESD of colonoscopically difficult superficial proximal colon tumors. PMID- 29433148 TI - International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. AB - This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH) for providing haemostasis-related guidance documents for clinical laboratories. This inaugural coagulation ICSH document was developed by an ad hoc committee, comprised of international clinical and laboratory direct acting oral anticoagulant (DOAC) experts. The committee developed consensus recommendations for laboratory measurement of DOACs (dabigatran, rivaroxaban, apixaban and edoxaban), which would be germane for laboratories assessing DOAC anticoagulation. This guidance document addresses all phases of laboratory DOAC measurements, including pre-analytical (e.g. preferred time sample collection, preferred sample type, sample stability), analytical (gold standard method, screening and quantifying methods) and post analytical (e.g. reporting units, quality assurance). The committee addressed the use and limitations of screening tests such as prothrombin time, activated partial thromboplastin time as well as viscoelastic measurements of clotting blood and point of care methods. Additionally, the committee provided recommendations for the proper validation or verification of performance of laboratory assays prior to implementation for clinical use, and external quality assurance to provide continuous assessment of testing and reporting method. PMID- 29433149 TI - Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach. AB - OBJECTIVE: To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels. METHODS: Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3). RESULTS: Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%). CONCLUSIONS: Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users. PMID- 29433150 TI - CX3CR1/CX3CL1 Axis Mediates Platelet-Leukocyte Adhesion to Arterial Endothelium in Younger Patients with a History of Idiopathic Deep Vein Thrombosis. AB - Mechanisms linking deep vein thrombosis (DVT) and subclinical atherosclerosis and risk of cardiovascular events are poorly understood. The aim of this study was to investigate the potential impact of CX3CR1/CX3CL1 axis in DVT-associated endothelial dysfunction. The study included 22 patients (age: 37.5 +/- 8.2 years) with a history of idiopathic DVT and without known cardiovascular risk factors and 23 aged-matched control subjects (age: 34 +/- 7.8 years). Flow cytometry was used to evaluate peripheral markers of platelet activation, leukocyte immunophenotypes and CX3CR1/CX3CL1 expression in both groups. A flow chamber assay was employed to measure leukocyte arrest under dynamic conditions. Platelet activation and the percentage of circulating CX3CR1-expressing platelets, CX3CR1 expressing platelet-bound monocytes and CD8+ lymphocytes were higher in patients with DVT than in controls. Additionally, patients with DVT had increased plasma levels of CX3CL1, soluble P-selectin and platelet factor 4/CXCL4. Interestingly, this correlated with enhanced platelet-leukocyte interaction and leukocyte adhesion to TNFalpha-stimulated arterial endothelial cells, which was partly dependent on endothelial CX3CL1 upregulation and increased CX3CR1 expression on platelets, monocytes and lymphocytes. In conclusion, increased CX3CR1 expression on circulating platelets may constitute a prognostic marker for long-term adverse cardiovascular events in patients with DVT. Blockade of CX3CL1/CX3CR1 axis may represent a new therapeutic strategy for the prevention of cardiovascular comorbidities associated with DVT. PMID- 29433151 TI - Anticoagulants Resumption after Warfarin-Related Intracerebral Haemorrhage: The Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy). AB - Whether to resume antithrombotic treatment after oral anticoagulant-related intracerebral haemorrhage (OAC-ICH) is debatable. In this study, we aimed at investigating long-term outcome associated with OAC resumption after warfarin related ICH, in comparison with secondary prevention strategies with platelet inhibitors or antithrombotic discontinuation. Participants were patients who sustained an incident ICH during warfarin treatment (2002-2014) included in the Multicenter Study on Cerebral Hemorrhage in Italy. Primary end-point was a composite of ischemic stroke/systemic embolism (SE) and all-cause mortality. Secondary end-points were ischemic stroke/SE, all-cause mortality and major recurrent bleeding. We computed individual propensity score (PS) as the probability that a patient resumes OACs or other agents given his pre-treatment variables, and performed Cox multivariable analysis using Inverse Probability of Treatment Weighting (IPTW) procedure. A total of 244 patients qualified for the analysis. Unlike antiplatelet agents, OAC resumption was associated with a lower rate of the primary end-point (weighted hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.45), as well as of overall mortality (weighted HR, 0.17; 95% CI, 0.06-0.45) and ischemic stroke/SE (weighted HR, 0.19; 95% CI, 0.06-0.60) with no significant increase of major bleeding in comparison with patients receiving no antithrombotics. In the subgroup of patients with atrial fibrillation, OACs resumption was also associated with a reduction of the primary end-point (weighted HR, 0.22; 95% CI, 0.09-0.54), and the secondary end-point ischemic stroke/SE (weighted HR, 0.09; 95% CI, 0.02-0.40). In conclusion, in patients who have an ICH while receiving warfarin, resuming anticoagulation results in a favorable trade-off between bleeding susceptibility and thromboembolic risk. PMID- 29433152 TI - [Not Available]. PMID- 29433153 TI - [Diagnosis Coding in German Medical Practices: A Retrospective Study Using Routine Data]. AB - OBJECTIVES: Primary care physicians and specialists deal with a wide range of diseases. The diagnoses are coded by using the annual version of the International Statistical Classification of Diseases and Related Health Problems, 10th revised version, German modification (ICD-10-GM). The aim of this study was to describe the current spectrum of documented diagnoses by physicians. Based on the underlying conditions, a broad variety of ICD-10-GM codes could be expected, which in many cases would not be coded to the final character (terminal). METHODS: 22,287,583 data sets of 900 medical practices of 13 various physician groups were included in this retrospective study. The data originate from the regions Brandenburg and North Rhine and the accounting period October 2014 - September 2015. The normalized Gini coefficient was applied as a measure for inequality. RESULTS: 97.6 % of the total data set were coded to the final character using the ICD-10-GM. ENT physicians used the highest rate of terminal codes (99.6 %), whereas orthopedists and cardiologists used the lowest rate (94.0 %). The broadest variety of different ICD-10-GM codes was used by primary care physicians (71.1 % of all possible terminal codes), the smallest variety was used by ophthalmologists (22.9 %). The lowest inequality of using ICD-10-GM codes could be detected for primary care physicians (Gini coefficient: 0.56), the highest inequality could be shown for ophthalmologists (Gini coefficient: 0.93). CONCLUSIONS: The specialists mainly use a circumscribed set of ICD-10-GM codes, whereas primary care physicians not only use a broad variety of different ICD-10 GM codes, but very often code them to their final character. This indicates a high quality of coding. PMID- 29433154 TI - Quality of Life and Functional Outcomes after Multiligament Knee Reconstruction. AB - We aimed to determine factors that affect the quality of life of patients undergoing a standardized surgical and postoperative management protocol for knee dislocations. A total of 31 patients (33 knees) were included in this study. We contacted patients at a minimum of 12 months postoperatively (mean: 38 months; range, 12-111 months) and administered the previously validated Multiligament Quality of Life questionnaire (ML-QOL), 2000 International Knee Documentation Committee Subjective Knee Form (IKDC), and Lysholm Knee Scoring Scale. We performed independent two-sample t-tests and age-adjusted multivariable linear regression analysis to examine the difference in these scores. Patients who underwent previous knee ligament surgery had significantly worse mean ML-QOL scores relative to patients who did not undergo previous knee ligament surgery (114.3 versus 80.4; p = 0.004) (higher score indicates worse quality of life). All other differences in the ML-QOL scores were not statistically significant. IKDC and Lysholm scores did not differ significantly with regards to the studied variables. Among patients with no previous knee ligament surgery, patients undergoing surgery within 3 weeks of injury had significantly worse mean ML-QOL scores relative to patients undergoing surgery greater than 3 weeks after their injury (98.7 versus 74.7; p = 0.042) and patients with Schenck classification of III or IV had significantly worse mean ML-QOL scores relative to patient with a Schenck classification of I or II (88.7 versus 62.9; p = 0.015). We found that patients with a previous history of knee ligament surgery had a significantly worse quality of life relative to those with no history of knee ligament surgery. This is a level III, retrospective cohort study. PMID- 29433155 TI - Nutraceuticals: opening the debate for a regulatory framework. AB - Currently, nutraceuticals do not have a specific definition distinct from those of other food-derived categories, such as food supplements, herbal products, pre- and probiotics, functional foods, and fortified foods. Many studies have led to an understanding of the potential mechanisms of action of pharmaceutically active components contained in food that may improve health and reduce the risk of pathological conditions while enhancing overall well-being. Nevertheless, there is a lack of clear information and, often, the claimed health benefits may not be properly substantiated by safety and efficacy information or in vitro and in vivo data, which can induce false expectations and miss the target for a product to be effective, as claimed. An officially shared and accepted definition of nutraceuticals is still missing, as nutraceuticals are mostly referred to as pharma-foods, a powerful toolbox to be used beyond the diet but before the drugs to prevent and treat pathological conditions, such as in subjects who may not yet be eligible for conventional pharmaceutical therapy. Hence, it is of utmost importance to have a proper and unequivocal definition of nutraceuticals and shared regulations. It also seems wise to assess the safety, mechanism of action and efficacy of nutraceuticals with clinical data. A growing demand exists for nutraceuticals, which seem to reside in the grey area between pharmaceuticals and food. Nonetheless, given specific legislation from different countries, nutraceuticals are experiencing challenges with safety and health claim substantiation. PMID- 29433156 TI - Enhancement of oral bioavailability of magnolol by encapsulation in mixed micelles containing pluronic F127 and L61. AB - OBJECTIVES: We aimed to prepare novel magnolol-loaded mixed micelles (MAG-M) by pluronic F127 and L61 to overcome the challenges of magnolol's poor solubility and then further improve its oral bioavailability. METHODS: Magnolol-loaded mixed micelles containing pluronic F127 and L61 were prepared by an organic solvent evaporation method. Physicochemical, transport experiment across Caco-2 cell monolayers and pharmacokinetic studies were performed to characterize MAG-M and to determine the final improvement of the oral bioavailability. KEY FINDINGS: The MAG-M solution was transparent and colourless with average size, polydispersity index and zeta potential of 228.0 +/- 2.1 nm, 0.298 +/- 0.012 and -0.89 +/- 0.02 mV. The micelle solution has a higher EE% and DL% of 81.57 +/- 1.49% and 27.58 +/ 0.53%, respectively. TEM result showed that the morphology of MAG-M was homogeneous and spherical shape. The dilution stability of MAG-M was no significant change in particle size and entrapment efficiency. MAG was demonstrated a sustained-release behaviour after encapsulated in micelles. MAG permeability across a Caco-2 cell monolayer was enhanced, and the pharmacokinetics study of MAG-M showed a 2.83-fold increase in relative oral bioavailability compared with raw MAG. CONCLUSIONS: The mixed micelles containing pluronic F127 and L61 as drug delivery system provided a well strategy for resolving the poor solubility and bioavailability problems of MAG. PMID- 29433158 TI - Corrigendum for Spaak et al. (2017) DOI: 10.1111/ele.12828. PMID- 29433157 TI - New innovations for 2018 and beyond. PMID- 29433159 TI - Prognostic Utility of Histological Growth Patterns of Colorectal Lung Oligometastasis. AB - BACKGROUND: Patients with resectable colorectal lung oligometastasis (CLOM) demonstrate a heterogeneous oncological outcome. However, the parameters for predicting tumor aggressiveness have not yet been fully investigated in CLOM. This study was performed to determine the prognostic value of histological growth patterns in patients who underwent surgery for CLOM. METHODS: The study included 92 patients who were diagnosed with CLOM among the first resection cases. CLOMs grow according to three histological patterns: aerogenous, pushing, and desmoplastic patterns. The growth patterns were evaluated on archival hematoxylin and eosin-stained tissue sections. RESULTS: The aerogenous pattern was found in 29.4% (n=27) of patients, the pushing pattern in 34.7% (n=32), the desmoplastic pattern in 6.5% (n=6), and a mix of two growth patterns in 29.4% (n=27). The size of the aerogenous pattern was significantly smaller than that of metastases with other patterns (p=.033). Kaplan-Meier analysis demonstrated that patients showing an aerogenous pattern appeared to have a poorer prognosis, which was calculated from the time of diagnosis of the CLOM (p=.044). The 5-year survival rate from the diagnosis of colorectal cancer tended to be lower in patients with an aerogenous pattern than in those who had a non-aerogenous pattern; however, the difference was marginally significant (p=.051). In the multivariate Cox analysis, the aerogenous pattern appeared as an independent predictor of poor overall survival (hazard ratio, 3.122; 95% confidence interval, 1.196 to 8.145; p=.020). CONCLUSIONS: These results suggest that the growth patterns may play a part as a histology-based prognostic parameter for patients with CLOM. PMID- 29433160 TI - Relationship Between Diet and Tinnitus: Korea National Health and Nutrition Examination Survey. AB - OBJECTIVES: This study aimed to analyze the association between nutritional intake and tinnitus prevalence by evaluating a large cross-sectional cohort. METHODS: Data from the Korea National Health and Nutrition Examination Survey collected between 2013 and 2015 were analyzed. The study population consisted of 7,621 individuals aged 40 to 80 years with complete tinnitus-related data. Individuals with inadequate responses to tinnitus history, noise exposure in the work place, or subjective hearing loss were excluded. Prevalence of tinnitus and tinnitus-related annoyance, and nutrition intake were measured using this questionnaire, and associations between tinnitus and nutritional data were evaluated by binary logistic regression analysis. RESULTS: Subjective tinnitus was reported by 1,435 individuals with subjective normal hearing (18.8%). Prevalence of tinnitus increased with age. However, among individuals with tinnitus, the proportion of individuals with tinnitus-related annoyance was similar across age groups. Older age, female sex, lower body mass index (BMI), and less vitamin B2 intake were significantly associated with tinnitus (P<0.001, P=0.002, P=0.041, P=0.013, respectively). Vitamin B2 intake was significantly less in individuals with tinnitus who were middle-aged (ages 51-55 and 56-60 years, P=0.012 and P=0.020, respectively). Less intake of water, protein, and vitamin B3 were associated with tinnitus-related annoyance (P=0.038, P=0.009, and P=0.005, respectively). Prevalence of annoyance was significantly associated with less water intake in younger ages (age 45-55 years) but with less protein and vitamin B3 intake in older ages (age 66-80 years). CONCLUSION: Reduced intake of vitamin B2 and B3, water, and protein may be associated with tinnitus and tinnitus-related annoyance, and further studies regarding the importance of adequate nutritional intake in the tinnitus management need to be performed. PMID- 29433161 TI - The Allele 2 of the VNTR Polymorphism in the Gene That Encodes a Natural Inhibitor of IL-1beta, IL-1RA Is Favorably Associated With Chronic Otitis Media. AB - OBJECTIVES: Chronic otitis media (COM) is followed by irreversible tissue damage and destruction of the middle ear structures, with the possibility of complications under the maintenance of inflammation. Inflammatory mediators such as cytokines play a crucial role in the initial stage of inflammation. The aim of this study was to evaluate the association of the polymorphisms in two innate immunity/inflammation cascade genes from interleukin-1 (IL-1) gene cluster with COM with regard to cholesteatoma. METHODS: In the cross-sectional case-control study, DNA samples were collected from 189 patients with COM and 119 controls from a population of Serbia. The +3953 C/T (rs1143634), TaqI polymorphism in interleukin-1 beta (IL-1beta) gene and 86 bp variable number tandem repeat (VNTR, rs2234663) polymorphism in the IL-1 receptor antagonist (IL-1RA) gene were analyzed by polymerase chain reaction. RESULTS: The IL-1beta TaqI polymorphism was not significantly different in patients compared with the control group. The significant difference between patients and controls was observed for both, genotype and allele frequencies of IL-1RA VNTR polymorphism (chi-square P<0.01). We found that carriers of IL-1RA allele 2 (odds ratio, 0.47; 95% confidence interval, 0.29 to 0.76; P=0.004) have a favorable association with COM, using multivariate logistic analysis that included both polymorphisms, age and sex. The IL-1RA allele frequency distribution was significantly different with regard to cholesteatoma. CONCLUSION: The carriers of allele 2 of VNTR IL-1RA polymorphism had a decreased odds ratio for COM, which is in agreement with findings in other inflammatory disease and its previous association with higher IL-1RA levels. Possible down-regulation of IL-1 mediated proinflammatory signaling pathways via IL-1RA in COM as well as results of our study should be further investigated and replicated. PMID- 29433162 TI - Examining the Methodology of the Transfusion Requirements in Cardiac Surgery-III (TRICS-III) Trial: Third Time's a Charm? PMID- 29433163 TI - Letter to the Editor Regarding "Aneurysm Clip Compression Technique in the Surgery of Aneurysms With Hard/Calcified Neck". PMID- 29433164 TI - Predicting Short-Term Outcome After Surgery for Primary Spinal Tumors Based on Patient Frailty; Methodologic Issues. PMID- 29433165 TI - Considerations in Meta-Analysis Regarding Complications of Cortical Bone Trajectory versus Traditional Pedicle Screw Fixation. PMID- 29433166 TI - Neurosurgery Elective for Preclinical Medical Students: 6-Year Follow-up. PMID- 29433167 TI - In Reply to "Neurosurgery Elective for Preclinical Medical Students: 6-Year Follow-up". PMID- 29433168 TI - Cisternostomy: Surgical Alternative for Patients with Refractory Posttraumatic Intracranial Hypertension. PMID- 29433169 TI - In Reply to "Cisternostomy: Surgical Alternative for Patients with Refractory Posttraumatic Intracranial Hypertension". PMID- 29433170 TI - In challenging the Myth of the Right Nondominant Hemisphere, Don't Go Too Far, Please. PMID- 29433171 TI - In Reply to "In challenging the Myth of the Right Nondominant Hemisphere, Don't Go Too Far, Please". PMID- 29433172 TI - Further Investigation About the Expression of SST, GAD2, and PVALB in Medulloblastoma. PMID- 29433173 TI - Further Investigation About Copy Number Variations and Methylation of AURKA, KIF4A, and NUSAP1 in Glioblastoma. PMID- 29433174 TI - Craniovertebral Junction Instability-An Overview. PMID- 29433175 TI - The Alar Ligaments: A Cadaveric and Radiologic Comparison Study. AB - OBJECTIVE: A precise anatomical description of the alar ligaments is important to better understand their biomechanical and pathologic implications. Although there are several studies regarding their anatomy, the literature is inconsistent. To our knowledge, there are no reports that compare cadaveric morphologic findings with computed tomography (CT) images of the alar ligaments. METHODS: Eight sides from 4 fresh-frozen cadaveric specimens were used in this study. After routine dissection of the craniocervical junction, the alar ligaments were exposed. We carried out measurements of the alar ligaments, their position within the craniovertebral junction, and their relation to the dens and adjacent structures. Fine-cut CT of the specimens was performed, and the measurements were later compared with the original cadaveric dissections. RESULTS: Alar ligaments were attached to the upper half of the lateral surface of the dens and ran laterally to its insertion just medial to the occipital condyle. The ligaments were found to have an ovoid cross-sectional area with a nearly horizontal caudocranial trajectory and comparable diameters in both anteroposterior and superoinferior directions between the CT and cadaveric measurements. CONCLUSIONS: There were small but not statistically significant differences in the measurements between the cadaver specimens and the CT images. There was however, a strong correlation between the proximal and distal insertions, as well as the orientation of the fibers, that suggests CT images can be an appropriate approach to the study of the anatomical and 3-dimensional features of the alar ligaments. PMID- 29433176 TI - The Decreasing Prevalence of the Arcuate Foramen. AB - BACKGROUND: The arcuate foramen (AF), or ponticulus posticus, is an anatomic variant of the first cervical vertebra that consists of a complete or partial osseous bridge over the groove for the vertebral artery and extends from the posterior aspect of the superior articular facet to the superior lateral border of the posterior arch. The AF has been associated with clinical symptoms, such as headache, migraine, neck pain, shoulder pain, arm pain, and vertebral artery dissection. We aimed to test whether the prevalence of the AF has decreased in the modern human population over the past centuries as a result of reduction in inbreeding and endogamy. METHODS: Possible reduction in the prevalence of the AF was assessed by comparing a 17th century rural sample (n = 108) with a 20th century modern urban sample (n = 192). RESULTS: When comparing the 17th and the 20th century samples, we found a statistically significant (P = 0.003) reduction of 14.5% (95% confidence interval 4.5-24.5) in the prevalence of the AF. CONCLUSIONS: Prevalence of the AF has been decreasing over the past centuries. PMID- 29433177 TI - Trabecular Anatomy of the Axis Vertebra: A Study of Shaded Volume-Rendered Computed Tomography Images. AB - BACKGROUND: To date, trabecular morphology studies have been conducted on thin section computed tomography (CT) scans of cadaveric bone. Here we describe the trabecular anatomy of the axis vertebra as revealed by an innovative imaging tool. METHODS: Ten patients who underwent thin-slice CT scans for suspected cervical spine injury were prospectively subjected to shaded volume-rendered 3 dimensional reconstruction of the images. The trabecular anatomy thus depicted was recreated, and the mechanical vectors were deduced independently by a senior radiologist and spine surgeon and then matched. The clinical implications were postulated. RESULTS: The most striking trabeculae are the vertical compression trabeculae connecting the C1 facet to the C3 body. The center of the body of C2 has a space with sparse trabeculae; similarly, the pars interarticularis also has a clear void. The dens contain predominantly tensile trabeculae that are retained even in older patients. Midline remnants of the odontoid body synchondrosis persist even into late adulthood. CONCLUSIONS: Shaded volume-rendered imaging appears to be an excellent tool for studying the trabecular anatomy of cancellous bone. The weight-bearing trabeculae run from the C1-2 facet to the C3 body; the inferior facet contributes little to weight-bearing. PMID- 29433178 TI - Radiological Evaluation of 510 Cases of Basilar Invagination with Evidence of Atlantoaxial Instability (Group A Basilar Invagination). AB - OBJECTIVE: To evaluate the musculoskeletal and soft tissue neural alterations in cases with group A basilar invagination. METHODS: Between January 2007 and August 2016, 510 patients with group A basilar invagination were surgically treated. The radiologic images of these patients were reviewed retrospectively. The patients were divided into 4 groups: group A1, comprising 60 patients with syringomyelia; group A2, comprising 354 patients with "external syrinx," marked by excessive cerebrospinal fluid (CSF) in the extramedullary space; group A3, comprising 51 patients with both syringomyelia and external syrinx; and group A4, comprising 45 patients with no abnormality of CSF cavitation in the spinal canal. RESULTS: A number of musculoskeletal and neural parameters, including the extent of basilar invagination, degree of angulation of the odontoid process, and facet malalignment, were evaluated in each of the 4 groups. The degree of basilar invagination was 6-27.4 mm (average, 15.85 mm) in group A1, 4.3-24.5 mm (average, 12.56 mm) in group A2, 5.6-17.6 mm (average 10.8 mm) in group A3, and 5.2-17.3 mm (average, 11.74 mm) in group A4. The angle of inclination of the odontoid process was 61.1-90.7 degrees (average, 71.4 degrees) in group A1, 30.5-79.8 degrees (average, 60.05 degrees) in group A2, 68.5-78.3 degrees (average, 73.4 degrees) in group A3, and 62.2-87.4 degrees (average, 71.2 degrees) in group A4. CONCLUSIONS: The nature of bone malformations directly influences the presence or absence of external syrinx and syringomyelia. PMID- 29433179 TI - Walk the Line. The Surgical Highways to the Craniovertebral Junction in Endoscopic Approaches: A Historical Perspective. AB - BACKGROUND: We compiled a comprehensive literature review on the anatomic and clinical results of endoscopic approaches to the craniocervical junction (CVJ) to better contribute to identify the best strategy. METHODS: An updated literature review was performed in the PubMed, OVID, and Google Scholar medical databases, using the terms "Craniovertebral junction," "Transoral approach," "Transnasal approach," "Transcervical approach," "Endoscopic endonasal approach," "Endoscopic transoral approach," "Endoscopic transcervical approach." Clinical series, anatomic studies, and comparative studies were reviewed. RESULTS: Pure endonasal and cervical endoscopic approaches still have some disadvantages, including the learning curve and the deeper surgical field. Endoscopically assisted transoral surgery with 30 degrees endoscopes represents an emerging option to standard microsurgical techniques for transoral approaches to the anterior CVJ. This approach should be considered as complementary rather than an alternative to the traditional microsurgical transoral-transpharyngeal approach. CONCLUSIONS: The transoral approach with sparing of the soft palate still remains the gold standard compared with the pure transnasal and transcervical approaches because of the wider working channel provided by the former technique. The transnasal endoscopic approach alone appears to be superior when the CVJ lesion exceeds the upper limit of the inferior third of the clivus. PMID- 29433180 TI - Atlantoaxial Fixation for Odontoid Fracture: Analysis of 124 Surgically Treated Cases. AB - OBJECTIVE: The authors analyze 124 cases with fracture of odontoid process. All patients were surgically treated by posterior atlantoaxial fixation. METHODS: There were 96 male and 28 female patients. The ages of the patients ranged from 12 to 80 years. Apart from Anderson and D'Alonzo type I (6 cases), type II (93 cases) and type III (25 cases), three sub-types of odontoid fractures were included in the classification. In type A (118 cases), there was vertical compression fracture that resulted in malalignment of the fractured odontoid process segments. Type B (49 cases) resulted when the fracture resulted in malalignment of the facets of atlas and axis. Type C (25 cases) included cases in which the fracture line involved the facet of axis. Fractures were divided into acute type when the injury was less than 3 months old (50 cases), delayed type when the injury was between 3 months to one year (34 cases) and chronic type when the injury was more than 1 year in duration (40 cases). All patients were treated with posterior atlantoaxial fixation with the techniques described in 1994 and 2004. Follow-up period ranged from 6 to 156 months (average 72 months). RESULTS: All patients improved in symptoms after surgery. There were no significant postoperative complications. CONCLUSIONS: Posterior atlantoaxial stabilization forms a safe surgical strategy for all kinds of odontoid fractures. Additional characteristics of odontoid fractures further subclassified them and assisted in surgical decision-making and in formulating the surgical strategy. PMID- 29433181 TI - Craniovertebral Junction Transoral Approach: Predictive Factors of Complications. AB - BACKGROUND: The transoral approach provides the most direct exposure to extradural lesions of the ventral craniovertebral junction. The morbidity and mortality from this approach greatly limits its use because they are still feared and debated. Using univariable and multivariable logistic regression analyses, this study aims to identify the factors associated with short-term complications in patients undergoing the transoral approach. METHODS: A consecutive cohort analysis of prospectively collected data in several neurosurgery spine departments evaluated 143 consecutive patients who had undergone craniovertebral junction transoral approach surgery. The mean age at the time of surgery was 45.1 +/- 19.1 years. The study analyzed the comorbidities, the operative procedure, and postoperative morbidity and mortality. RESULTS: Seventeen patients (11.9%) had a postoperative complication in the first month. In our univariable analysis: age, smoking, tumor etiology, preoperative posterior fixation, posterior bone graft, preoperative external lumbar shunt, and the transoral approach pathway were significantly associated with postoperative mortality and morbidity. In our multivariable analyses, preoperative external lumbar shunt was significantly associated with complication risks (odds ratio [OR] 6.7; 95% confidence interval [CI] 2.1-21.7, P < 0.001), whereas preoperative posterior fixation (OR 0.28; 95% CI 0.08-1.1, P < 0.04) and posterior bone graft (OR 0.14; 95% CI 0.03-0.6, P < 0.008) were significantly associated with lower complication risks. CONCLUSIONS: To reduce complications, it is essential to be aware of and to manage these preoperative risk factors. In such manner, we insinuate that postoperative complications depend on the surgeon's familiarity with the transoral approach. PMID- 29433183 TI - Quality of Life After Craniovertebral Junction Meningioma Resection: Shaping the Real Neurologic and Functional Expectancies About These Surgeries in a Contemporary Large Multicenter Experience. AB - OBJECTIVE: Craniovertebral junction (CVJ) meningiomas are one of the most surgically complex conditions in neuro-oncologic surgery. The aim of this work is to correlate our data with clinical outcome to outline factors leading to a worse functional prognosis. METHODS: We analyzed sex, age, clinical presentation, topography, surgical approach, Simpson grade resection, postoperative lower cranial nerve deficits, consistency, histology, site of origin, presence of a capsule, and radiologic and clinical follow-up at 1, 6, and 12 months of 61 patients affected by CVJ meningiomas, operated on in our institution from 1992 to 2014. RESULTS: 78.7% of patients were women (mean age, 52.85 years); the onset symptom was pain in 65.5% of cases. The mean preoperative Nurick grade of the sample was 3.78; the most frequent histologic type was endotheliomatous (42.8%). We treated 22 patients with a posterior median approach (5 with lateral and 17 with posterolateral axial topography); in 39 cases (30 anterolateral and 9 anterior) we performed a posterolateral approach. Gross total removal was achieved in 85.2% of cases. We recorded a final follow-up step overall neurologic improvement in the cohort (average preoperative Nurick grade, 3.81, and at 12 months, 2.13). Twenty-nine patients presented with lower cranial nerve deficit (permanent or transient) and no statistically significant association was found between surgical approach and temporary or permanent postoperative complications. CONCLUSIONS: We selected, in our experience, some predictors of worse outcome: preoperative sphincter impairment, absence of a capsule, cranial site of origin, a poor preoperative functional status, and firm consistency of the tumor. PMID- 29433182 TI - Extraspinal-Interdural Surgical Approach for C2 Neurinomas-Report of an Experience with 50 Cases. AB - OBJECTIVE: We report our experience with surgery in 50 patients with C2 neurinomas. The anatomic subtleties of these discrete forms of tumors and their surgical implications are analyzed. METHODS: During the period 2006-2016, we operated on 50 patients with 55 C2 neurinomas. Type A tumors were located within the spinal canal, type B tumors were located in the lateral gutter, and type C tumors had a paraspinal extension. By working within the dural confines of the tumor and appropriately angulating the microscope, the entire tumor bulk extending into 1 or all 3 compartments was resected. Follow-up duration ranged from 3 months to 10 years (mean 68 months). RESULTS: This series included 36 male and 14 female patients. Age range of patients was 14-70 years (mean age 36 years). Progressive symptoms of myelopathy were present in 41 patients. There were 16 type A + B tumors, 27 type B tumors, 10 type B + C tumors, and 2 type A + B + C tumors. All patients experienced symptom improvement after surgery and were able to resume their normal lifestyle. CONCLUSIONS: C2 neurinomas arise in the region of the C2 ganglion, and despite the fact that some achieve a large size, they remain confined within the dura. Radical tumor resection can be achieved by working within the layers of the dural cover. Bone removal and opening of spinal dura for tumor exposure and resection can be avoided. PMID- 29433184 TI - Transoral Versus Transnasal Approach for Craniovertebral Junction Pathologies: Never Say Never. AB - OBJECTIVE: For many years, the microsurgical transoral approach (TOA) has been accepted as the "gold standard" for the surgical treatment of a variety of congenital, developmental, and acquired pathologies affecting the craniovertebral junction. In the present study, we try to investigate both experimental and clinical fronts of such a challenging surgery, starting from the updated literature experience. TOA is actually presented as an "old-fashioned" surgical technique dealing with possible bacterial contamination, the need of postoperative nose gastric tube feeding for a week, the possible nasopharyngeal incompetence, and the postoperative tongue swelling. Otherwise, the endoscopic endonasal approach (EEA) appears strongly supported by the modern literature as the true "minimally invasive" procedure. METHODS: Our clinical experience deals with 23 anterior procedures in paediatric and adult patients (17 TOA and 6 EEA). We further report on our experimental cadaver laboratory study of 12 subjects. RESULTS: All the patients of TOA group but one were discharged after posterior procedures within two weeks and improved or remained unchanged after surgery and during the follow-up. No mayor complications occurred in TOA group. In EEA group two patients died for cerebrospinal fluid infection, for disease progression and for heart attack. CONCLUSION: Our and other available data suggest that no clear superiority of EEA over endoscopic TOA can be assessed so far; on the other hand, EEA can produce complications similar to TOA in craniovertebral junction surgery. PMID- 29433185 TI - C1-2 and C2-3 Instability in the Presence of Hypoplastic Posterior Elements of C2 Vertebra: Report of 2 Cases. AB - BACKGROUND: We present 2 cases involving a previously unreported clinical situation in which basilar invagination, atlantoaxial instability, and C2-3 instability were associated with a bifid posterior arch of the axis bone. CASE DESCRIPTIONS: Two young males presented with limb weakness, spasticity, and paresthesias. Both patients had altered voice quality, with reduced and thin volume, and difficulty sleeping supine. Radiologic imaging showed an absence of the posterior elements of the C2 vertebrae. The C3 spinous process mimicked the C2 spinous process in shape and size. C1-2 and C2-3 posterior fixations were performed. CONCLUSIONS: C1-2 and C2-3 fixation resulted in firm fixation of the region and a remarkable clinical recovery. The most significant features were an immediate postoperative improvement in voice quality and the ability to sleep comfortably in the supine position. PMID- 29433187 TI - Sentence Structure. PMID- 29433186 TI - Traumatic Atlantoaxial Spondyloptosis Associated with Displaced Odontoid Fracture: Complete Reduction via Posterior Approach Using "Joint Remodeling" Technique. AB - BACKGROUND: Atlantoaxial spondyloptosis (AAS), which is defined as complete displacement of facets of atlas anterior to the facets of axis such that there is no contact between the 2 articulating surfaces, is an extremely rare manifestation of atlantoaxial instability. The reason for an extreme rarity of traumatic AAS is probably the severity of injury in traumatic AAS that is usually incompatible to life. It represents the most severe form of atlantoaxial dislocation, and complete reduction in such a case presents a real technical challenge because of the interlocking of C1-C2 facets. Cranial traction fails to achieve reduction in such cases. CASE DESCRIPTION: In this report, we describe a case of traumatic odontoid fracture associated with AAS and discuss our technique of complete reduction of deformity via posterior approach. An 11-year-old child presented to us 4 months after a road traffic accident with progressive spastic quadriparesis. On evaluation, displaced type II odontoid fracture with AAS was detected. The patient underwent surgery via posterior approach. The techniques of "joint manipulation" and "joint remodeling" were used to achieve complete reduction of spondyloptosis. Postoperative imaging showed complete reduction of deformity. The patient also improved neurologically after surgery. CONCLUSION: This case report aims to present the ability of "joint manipulation" and "joint remodeling" techniques in achieving excellent reduction in even one of the most difficult post-traumatic deformities that affect the craniovertebral junction. PMID- 29433188 TI - Physicochemical and microstructural characterization of gum tragacanth added whey protein based films. AB - Edible films of gum tragacanth (GT) with whey protein were fabricated to see how the incorporation of GT influenced whey protein based film properties. Whey protein isolate (WPI) was replaced with GT at different ratios as 0.5, 1, 1.5 and 2% of WPI. Optical, mechanical, permeability and microstructural properties, as well as moisture sorption and solubility behavior of films were measured. The findings indicated that combination of WPI and GT in film formulation led to less strength, more flexible, less soluble films with lower permeability to water and with higher opacity. The results suggested that the addition of GT to WPI could lead to obtain modified WPI based edible films with desirable properties. PMID- 29433189 TI - Changes in polyphenol composition and bioactivity of the native Chilean white strawberry (Fragaria chiloensis spp. chiloensis f. chiloensis) after in vitro gastrointestinal digestion. AB - The Chilean white strawberry (Fragaria chiloensis spp. chiloensis f. chiloensis) is a semi-domesticated strawberry with high polyphenol content and antioxidant activity occurring in southern Chile. The aim of this work was to compare the composition and bioactivity of the polyphenol-enriched fruit extract (PEE) before and after simulated gastrointestinal digestion (GID). Results show a decrease by >50% in the total phenolic (TP) content at the end of the GID, compared to the non-digested PEE. A reduction in the antioxidant capacity of the PEEs was observed after GID by means of DPPH, FRAP, TEAC and anion superoxide assays. After simulated GID the PEE significantly inhibited alpha-glucosidase with an IC50 value of 3.13MUg/mL. The inhibition of pancreatic lipase was reduced by 95% after GID. All the PEEs did not show inhibitory effect towards alpha-amylase throughout the GID. In the same way, the PEEs did not significantly protect human gastric adenocarcinoma (AGS) cells against H2O2-induced stress. Thirty eight compounds were tentatively identified in the non-digested PEE. The compounds that were more affected by the simulated GID were simple phenolics. After the GID, only 33 and 25 compounds were detected, in the gastric and intestinal steps, respectively. These results evidence the changes elicited by GID on the bioactivity and polyphenolic composition of the white strawberry. PMID- 29433190 TI - Peptidome profiles and bioactivity elucidation of buffalo-milk dairy products after gastrointestinal digestion. AB - Buffalo milk is highly appreciated for its nutritive properties and highly employed in dairy products, despite this the release of bioactive peptides has not been investigated thoroughly. The aim of this work was to characterize in detail the bioaccesible peptides from buffalo-milk dairy products. Six products were subjected to in vitro simulated gastrointestinal digestion and then analyzed by LC-HRMS. The identified peptides were 165 in Yoghurt, 152 in Scamorza, 146 in Mozzarella, 136 in Grana and Ricotta, 120 in Ice Cream samples, belonging to both buffalo caseins (alphas1-, beta-, k-CN) and whey proteins (alpha-LA, beta-LG). The identified peptide sequences were subjected to a database driven bioactivity search. Results highlighted a wide range of potential bioactive peptides, including antihypertensive, immunomodulatory, antimicrobial, antidiabetic, anticancer and antioxidant activity. These data evidence the content of healthy peptides released from buffalo-milk dairy products and suggest that the specific technological process influence their bioaccessibility. PMID- 29433191 TI - Enhanced arginine biosynthesis and lower proteolytic profile as indicators of Saccharomyces cerevisiae stress in stationary phase during fermentation of high sugar grape must: A proteomic evidence. AB - A strain of Saccharomyces (S) cerevisiae (ISE19), which displayed an initial good adaptation to a high sugar medium with increased acetate and glycerol production but weak overall growth/fermentation performances, was selected during the alcoholic fermentation of Cortese grape must. To obtain insights into the metabolic changes that occur in the must during growth in particular conditions (high ethanol, high residual sugars and low nitrogen availability) leading to a sluggish fermentation or even fermentation arrest, comparative in-gel proteomic analyses were performed on cells grown in media containing 200g/L and 260g/L of glucose, respectively, while the YAN (Yeast Assimilable Nitrogen) concentration was maintained as it was. Two post-translationally different arginine synthases (pIs 5.6 and 5.8) were found in higher abundances in the high glucose-grown cells, together with an increased abundance of a glycosyltransferase involved in cell-wall mannans synthesis, and of two regulatory proteins (K7_Bmh1p and K7_Bmh2p) that control membrane transport. In parallel, a proteinase K-like proteolytic enzyme and three other protein fragments (Indolepyruvate decarboxylase 1, Fba1p and Eno1p) were present in lower abundances in the high glucose condition, where oxidative stress and cell cycle involved enzymes were also found to be less abundant. The overall results suggest that in stationary phase stress conditions, leading to stuck fermentation, S. cerevisiae ISE19 decreases cell replication, oxidative stress responses and proteolytic activity, while induces other metabolic modifications that are mainly based on cell-wall renewal, regulation of the solute transport across the cell membrane and de novo arginine synthesis. PMID- 29433192 TI - Various approaches in EPR identification of gamma-irradiated plant foodstuffs: A review. AB - Irradiation of food in the world is becoming a preferred method for their sterilization and extending their shelf life. For the purpose of trade with regard to the rights of consumers is necessary marking of irradiated foodstuffs, and the use of appropriate methods for unambiguous identification of radiation treatment. One-third of the current standards of the European Union to identify irradiated foods use the method of the Electron Paramagnetic Resonance (EPR) spectroscopy. On the other hand the current standards for irradiated foods of plant origin have some weaknesses that led to the development of new methodologies for the identification of irradiated food. New approaches for EPR identification of radiation treatment of herbs and spices when the specific signal is absent or disappeared after irradiation are discussed. Direct EPR measurements of dried fruits and vegetables and different pretreatments for fresh samples are reviewed. PMID- 29433193 TI - Effect of slightly acidic electrolyzed water on bioactive compounds and morphology of broccoli sprouts. AB - The producers of broccoli sprouts have become increasingly interested in improving their sulforaphane content. This study has evaluated the effects of slightly acidic electrolyzed water (SAEW) with different available chlorine concentrations (ACC) on broccoli sprouts: their content of some bioactive compounds such as glucosinolates, their morphology, and their total bacterial counts. The results have shown that SAEW might affect the content of sulforaphane by influencing the content of glucosinolates and the activity of myrosinase. SAEW inhibited the growth of broccoli sprouts: their fresh weight decreased as the available chlorine concentration (ACC) of the SAEW increased, but the different solutions did not affect their dry weight. The number of microorganisms on the broccoli sprout decreased by 1.71logCFU/g after using the SAEW with ACC value of 50mg/L treatment compared with tap water treatment. Overall, although SAEW adversely affected the morphology of broccoli sprouts, with a suitable ACC it can be a useful tool for enhancing the amount of secondary metabolites and reducing the microbial counts on broccoli sprouts intended for fresh consumption as a functional food. PMID- 29433194 TI - UPLC/QTOF/MS profiling of two Psidium species and the in-vivo hepatoprotective activity of their nano-formulated liposomes. AB - Liver diseases are major health problem in Egypt influencing lifestyle and economy. The demand for nutraceutical hepatoprotective agents is crucial to ameliorate the side effects of synthetic drugs. The present study aims to evaluate antioxidant and hepatoprotective activities of extracts of Psidium guajava L. and Psidium cattleianum Sabine leaves and their nano-formulated liposomes against paracetamol-induced liver damage in rats. Secondary metabolites profile of P. guajava and P. cattleianum leaves was investigated using UPLC-PDA ESI-qTOF-MSn. The nano-liposomes containing Psidium extracts were prepared using thin film hydration method. Biochemical analysis was based on monitoring serum levels of AST, ALT, ALP and total bilirubin. The liver homogenate was used for determination of GSH and MDA. Histopathological alterations were also studied. Metabolic profiling revealed qualitative differences between the two investigated species providing a comprehensive map for the metabolites present in P. guajava and P. cattleianum leaves cultivated in Egypt. The identified metabolites belong to different phytochemical classes; polyphenolics, flavonoids, triterpenes and meroterpenoids. Significant hepatoprotective effects were observed as evident from the decreased levels of AST, ALT, ALP, MDA and total bilirubin as well as restoration of decreased GSH level in the two studied Psidium extracts (250, 500mg/kg b. wt) and their respective nano-liposomes (500mg/kg b. wt), when compared to the diseased group. Nano-liposomes of Psidium guajava leaves (500mg/kg b. wt) greatly restored the normal architecture of the liver in the histopathological study, as regards to standard silymarin. The present study verified the effectiveness of Psidium guajava and Psidium cattleianum leaves extracts and their nano-liposomes in ameliorating the paracetamol-induced hepatotoxicity in rats. PMID- 29433195 TI - Biological properties and pharmacological potential of plant exudates. AB - Exudates released from plants, consist of complex mixtures of organic and inorganic molecules that have been used in traditional medicine from several years. They may vary among genera, species or within a genus and mainly include latex, sap, gums, resins, seed or root exudates. Plant exudates are known to possess several biological activities including, antimicrobial, anti inflammatory, antioxidant, wound healing and anti-nociceptive. Exudates oozed out from plants have also been used as ingredients in medicines, food, perfumes and cosmetics. The present review provides brief overview about the exudates released from plants, their biological properties and beneficial effects for human beings. Due to the presence of various compounds, different methodologies and procedures have been employed for their collection and analyses. Literature studies suggest that plant exudates have extensive therapeutic potential for curing diseases with minimal toxic effects. This aspect could be taken into account in prospective studies regarding the search of new products derived from plant exudates with pharmaceutical value. PMID- 29433196 TI - Trait anxiety and self-concept among children and adolescents with food neophobia. AB - Food problems in children and adolescents often have a detrimental effect on the emotional and psychological wellbeing of their parents. However, the impact of such problems on the psychological wellbeing of children and adolescents themselves has been less widely studied. The purpose of this study was to determine whether children and adolescents with food neophobia differed in trait anxiety and dimensions of self-concept from their neophilic and their average peers. A community sample of 831 participants (368 males and 463 females) between the ages of 8 and 16 were classified into six groups based on scores obtained on the Spanish Child Food Neophobia Scale (i.e., neophobic, average, and neophilic) and their age (i.e., children vs. adolescents). Compared with their neophilic peers, children with food neophobia showed higher levels of trait anxiety and a poorer social, physical, and academic self-concept. Among adolescents similar results were observed for trait anxiety and physical self-concept, but instead of social and academic self-concept it was family self-concept which distinguished between neophobic and neophilic participants. These results suggest that food neophobia is associated with trait anxiety and with some dimensions of self concept. This highlights the need to ascertain the threshold between 'normal' and 'problematic' eating behaviors, since the fact that a behavior is to some extent usual does not imply that it is harmless. PMID- 29433197 TI - Corrigendum to "Dehydration of jambolan [Syzygium cumini (L.)] juice during foam mat drying: Quantitative and qualitative changes of the phenolic compounds" [Food Research International 102 (2017) 32-42]. PMID- 29433198 TI - Sensory and volatile profiles of monofloral honeys produced by native stingless bees of the brazilian semiarid region. AB - Monofloral honeys produced by stingless bees M. subnitida Ducke and M. scutellaris Latrelle in typical flowering of the Brazilian semi-arid Ziziphus juazeiro Mart (juazeiro), Croton heliotropiifolius Kunth (velame branco) and Mimosa arenosa willd Poir (jurema branca) were characterized in relation to volatile and sensorial profile. It identified 11 sensory descriptors and 96 volatile compounds. It was noticed a strong effect of flowering in sensorial profile and volatile of honeys. Juazeiro honey stood out with a higher characteristic aroma, taste sweet, caramel flavor and levels of aromatic aldehydes; jurema honey has been described with herb and beeswax aroma and the presence of sulfur compounds and ketones; volatile acids associated with acid taste, medicinal taste and clove aroma characterized the velame branco honey. These results demonstrate that the knowledge of the sensory and aroma profile of these honeys can contribute to characterization of its floral and geographical identity. PMID- 29433199 TI - Degradation kinetics and antioxidant capacity of anthocyanins in air-impingement jet dried purple potato slices. AB - We investigated the types, degradation kinetics, and antioxidant capacities of anthocyanins in purple potato slices subjected to air-impingement jet drying (AIJD) at different drying temperatures (50, 65, and 80 degrees C). Petunidin-3-p coumaroylrutinoside-5-glucoside was the predominant anthocyanin in AIJD-treated purple potato and was positively correlated with antioxidant capacity. Anthocyanin concentration decreased with drying time, and anthocyanin degradation followed first-order reaction kinetics. At high drying temperatures, anthocyanin degradation had higher degradation rates and shorter half-life than at low drying temperatures. Thermodynamic results revealed that the degradation of anthocyanins is a non-spontaneous, endothermic reaction and that the transition state has lower structural freedom than the reactant. AIJD at 65 degrees C contributed to the highest anthocyanin content and antioxidant capacity. PMID- 29433200 TI - Relationship between nano/micro structure and physical properties of TiO2-sodium caseinate composite films. AB - Films obtained by casting, starting from conventional emulsions (CE), nanoemulsions (NE) or their gels, which led to different structures, with the aim of explore the relationship between structure and physical properties, were prepared. Sodium caseinate was used as the matrix, glycerol as plasticizer, glucono-delta-lactone as acidulant to form the gels, and TiO2 nanoparticles as reinforcement to improve physical behavior. Structural characterization was performed by SAXS and WAXS (Small and Wide Angle X-ray Scattering, respectively), combined with confocal and scanning electron microscopy. The results demonstrate that the incorporation of the lipid phase does not notably modify the mechanical properties of the films compared to solution films. Films from NE were more stable against oil release than those from CE. Incorporation of TiO2 improved mechanical properties as measured by dynamical mechanical analysis (DMA) and uniaxial tensile tests. TiO2 macroscopic spatial distribution homogeneity and the nanostructure character of NE films were confirmed by mapping the q-dependent scattering intensity in scanning SAXS experiments. SAXS microscopies indicated a higher intrinsic homogeneity of NE films compared to CE films, independently of the TiO2 load. NE-films containing structures with smaller and more homogeneously distributed building blocks showed greater potential for food applications than the films prepared from sodium caseinate solutions, which are the best known films. PMID- 29433201 TI - Pickering emulsions stabilized by media-milled starch particles. AB - A simple, organic solvent-free media-milling process was applied to modify the structure and morphology of maize starch granules. During the milling process, the sizes of starch granules reduced dramatically while their crystalline structure was largely damaged as verified by differential scanning calorimetry and X-ray diffraction. The surface hydrophobicity of milled starch was also characterized by contact angle measurement. These media-milled starch suspensions with different starch concentrations (i.e., 2.4%, 7.2% and 10.0%) were used as stabilizers to form Pickering emulsions. The droplet sizes of the Pickering emulsions prepared in this study ranged from approximately 10MUm to 900MUm depending on the milling time and the initial starch concentration. The droplet sizes decreased with prolonged milling time and increased initial starch concentration. Milled starch particles of around 100nm anchored at the emulsion interfaces were observed by cryo-scanning electron microscopy. Although some emulsions creamed immediately after homogenization, most emulsions exhibited stability against coalescence during the long-term storage of 6months. The emulsions also exhibited benign stability against a wide range of pH, ionic strength and temperature conditions. This research provides a new green approach to form food-grade emulsions to deliver active food ingredients. PMID- 29433202 TI - Effect of malondialdehyde modification on the binding of aroma compounds to soy protein isolates. AB - The interactions of soy protein isolate (SPI) and flavor compounds (hexanal, trans-2-hexenal, 1-octen-3-ol, trans-2-octenal, nonanal, and trans-2-nonenal) were investigated. The influence of SPI structure modified by malondialdehyde (MDA) and flavor compound structure on the interactions were determined by using headspace solid-phase microextraction (SPME) and gas chromatography (GC) combined with mass spectrometry (MS). The binding of native SPI to the flavor compounds decreased in the order trans-2-nonenal>nonanal>trans-2-octenal>trans-2 hexenal>hexanal>1-octen-3-ol. It might be attributed to that aldehydes are more hydrophobic than alcohols. The former is more conducive to hydrophobic binding with the SPI. Furthermore, the aldehydes, in particular trans-s-undecenal, could also react covalently. The effect of MDA modification on protein-flavor interactions depended on the structure of the flavor compound. Upon low concentration of MDA (<=1mM), the binding of all six flavors to SPI increased. However, a further increase in the extent of MDA (>=2.5mM), more soluble and even insoluble aggregates formed, which reduced the binding of hexanal and nonanal to SPI. The other four flavors with double bond revealed little changes in binding (trans-2-octenal, and trans-2-nonenal) or even an increase in binding (trans-2 hexenal, and 1-octen-3-ol). The results suggested that hydrophobic interactions were weakened upon high extent of oxidation, whereas covalent interactions were enhanced. PMID- 29433203 TI - Physicochemical and nutraceutical properties of moringa (Moringa oleifera) leaves and their effects in an in vivo AOM/DSS-induced colorectal carcinogenesis model. AB - Moringa (Moringa oleifera) is a plant that has generated great interest in recent years because of its attributed medicinal properties. The aim of this study was to characterize the bioactive compounds of moringa leaves (MO) and evaluate their effect on a colorectal carcinogenesis model. Twenty-four male CD-1 mice were divided into 4 groups: Group 1 fed with basal diet (negative control/NC); Group 2 received AOM/DSS (positive control); Groups 3 and 4 were fed with basal diet supplemented with moringa leaves (2.5% w/w and 5% w/w, respectively) for 12weeks. Moringa leaves exhibited a high content of dietary fiber (~18.75%) and insoluble dietary fiber (2.29%). There were identified 9 phenolic compounds whereas the chlorogenic and rho-coumaric acid showed the higher contents (44.23-63.34MUg/g and 180.45-707.42MUg/g, respectively). Moringa leaves decreased the activity of harmful fecal enzymes (beta-glucosidase, beta-glucuronidase, tryptophanase and urease up to 40%, 43%, 103% and 266%, respectively) as well tumors incidence in male CD1-mice (~50% with 5% w/v of moringa dose). These findings suggest that the bioactive compounds of moringa such as total dietary fiber and phenolic compounds may have chemopreventive capacity. This is the first study of the suppressive effect of moringa leaves in an in vivo model of AOM/DSS-induced colorectal carcinogenesis. PMID- 29433204 TI - Protection of color and chemical degradation of anthocyanin from purple corn (Zea mays L.) by zinc ions and alginate through chemical interaction in a beverage model. AB - Anthocyanin-rich purple corn pericarp water extract (PCW) has the potential to be used as a natural pigment in beverages. However, it has a limited shelf-life in aqueous solutions. The aim was to evaluate the effect of zinc ion (Zn2+) and alginate on color and chemical stability of anthocyanins from colored corn (PCW) in a beverage model for 12weeks. PCW was incorporated to Kool-Aid(r) InvisibleTM along with ZnCl2 and/or alginate. Individual ANC were quantified through HPLC, and color stability was evaluated through the CIE-L*a*b* color system. Complexation between PCW and Zn/alginate was evaluated with fluorescence spectroscopy. The combination of Zn and alginate was the most effective treatment improving the half-life of total ANC concentration (10.4weeks), cyanidin-3-O glucoside (7.5weeks) and chroma (18.4weeks), compared to only PCW (6.6, 4.5 and 12.7weeks, respectively). Zn and alginate had bimolecular quenching constants (Zn kq: 3.4*1011 M-1S-1 and AA kq: 1.0*1012 M-1S-1) suggesting that fluorescence quenching was binding rather than collisional. Results suggested that Zn/alginate interacted with ANC from purple corn slowing its chemical degradation. PMID- 29433205 TI - Effect of preliminary stresses on the resistance of Escherichia coli and Staphylococcus aureus toward non-thermal plasma (NTP) challenge. AB - As the development of hurdle technology, cross-protection of various stresses for pathogens posed the potential risk to food safety and public health. This study tried to explore various preliminary stresses including acidity, osmosis, oxidation, heat and cold on the resistance of microbial cells toward the non thermal plasma (NTP) exposure. The results indicated that short-term (4h) exposure of Staphylococcus aureus and Escherichia coli to acidity, osmosis, oxidation, heat and cold stresses did not lead to the resistance to the subsequent NTP treatment. On the contrary, acidity, osmosis and heat preadaptation increased the vulnerability of E. coli cells to NTP treatment. After exposing S. aureus to osmosis, oxidation, heat and cold stress for longer period (24h), the reduction level showed significantly (P<0.05) higher. Interestingly, long-term (24h) preliminary exposure of acidic stress exhibited protective effect for S. aureus against the following NTP exposure with less damage in cell membrane integrity, membrane potential and intracellular enzyme activity. It might be due to the protein production for oxidative stress response during preliminary acidic adaptation. In general, the obtained result helped to grasp better understanding of the microbial stress response to NTP treatment and provided insight for the future research in order to accelerate the development of NTP technology in food industry. PMID- 29433206 TI - Lycopene-rich extract from red guava (Psidium guajava L.) displays cytotoxic effect against human breast adenocarcinoma cell line MCF-7 via an apoptotic-like pathway. AB - This study investigated a lycopene-rich extract from red guava (LEG) for its chemical composition using spectrophotometry, mass spectrometry, attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR), and computational studies. The cytotoxic activity of LEG and the underlying mechanism was studied in human breast adenocarcinoma cells (MCF-7), murine fibroblast cells (NIH-3T3), BALB/c murine peritoneal macrophages, and sheep blood erythrocytes by evaluating the cell viability with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and flow cytometry. Spectrophotometry analysis showed that LEG contained 20% of lycopene per extract dry weight. Experimental and theoretical ATR-FTIR suggests the presence of lycopene, whereas MS/MS spectra obtained after fragmentation of the molecular ion [M]+* of 536.4364 show fragment ions at m/z 269.2259, 375.3034, 444.3788, and 467.3658, corroborating the presence of lycopene mostly related to all-trans configuration. Treatment with LEG (1600 to 6.25MUg/mL) for 24 and 72h significantly affected the viability of MCF-7 cells (mean half maximal inhibitory concentration [IC50]=29.85 and 5.964MUg/mL, respectively) but not NIH-3T3 cells (IC50=1579 and 911.5MUg/mL, respectively). Furthermore LEG at concentrations from 800 to 6.25MUg/mL presented low cytotoxicity against BALB/c peritoneal macrophages (IC50>=800MUg/mL) and no hemolytic activity. LEG (400 and 800MUg/mL) caused reduction in the cell proliferation and induced cell cycle arrest, DNA fragmentation, modifications in the mitochondrial membrane potential, and morphologic changes related to granularity and size in MCF-7 cells; however, it failed to cause any significant damage to the cell membrane or display necrosis or traditional apoptosis. In conclusion, LEG was able to induce cytostatic and cytotoxic effects on breast cancer cells probably via induction of an apoptotic-like pathway. PMID- 29433207 TI - Universal mini COI barcode for the identification of fish species in processed products. AB - Species substitution, the use of a low value fish in place of a high value fish, is the biggest problem in international trade and the leading cause of fraud in the fisheries arena sector. Current DNA barcoding systems have partly solved this problem but also failed in many instances to amplify PCR targets from highly processed products because of the degradation of a longer barcode marker (~650bp). In the present study, a novel mini barcode marker (295bp) was developed to discriminate fish species in raw and processed states forms. The barcode primers were cross-tested against 33 fish species and 15 other animal species and found to be universal for all the tested fish varieties. When 20 commercial fish products of five different categories were screened, all commercial fish sample yielded positive bands for the novel fish barcode. PCR product was sequenced to retrieve the species IDs that reflected 55% (11/20) of Malaysian fish products were mislabeled. PMID- 29433208 TI - Evaluation of the use of multiflora bee pollen on the volatile compounds and sensorial profile of Palomino fino and Riesling white young wines. AB - This study investigates the impact of bee pollen on volatile compounds, odour activity values and sensory profiles in Palomino fino and Riesling young white wines. Commercial bee pollen was added to grape must using six different doses (0 (control), 0.1, 0.25, 1, 5, 10 and 20g/L) and fermented under controlled conditions. Volatile compounds were determined with GC and GC-MS chromatography and sensorial analysis using a qualified panel of tasters. Bee pollen produces an increase in volatile compounds depending on the grape variety and the dose applied. It also increases the synthesis of higher alcohols, methanol, esters, acetaldehyde and terpenes, reducing alcohols and fatty acids. Wines with low doses (0.1 and 0.25g/L) showed the higher OAV values (fruity and floral) and scores in overall judgment for the sensory evaluation. High pollen doses decrease fruity character and could result in deviations affecting the sensorial quality. PMID- 29433209 TI - Effect of hop beta-acids as dietary supplement for broiler chickens on meat composition and redox stability. AB - Addition of beta-acids extracted from hop at different levels (0, 30mgkg-1, 60mgkg-1, 240mgkg-1) to the diet of broiler chickens demonstrated significant effects on the average concentration of polar metabolites and fatty acids of relevance for meat quality. The largest metabolic differences between control group and chicken fed different levels of beta-acids were achieved using 30mgkg-1 of supplement. As determined by EPR spin-trapping, increased redox stability was also obtained for meat from chicken fed 30mgkg-1 of beta-acids which also had highest level of endogenous antioxidants, especially anserine, carnosine, NADH and PUFAs. Diet and storage period were found to affect protein oxidation and myosin and actin were recognized as the main targets of protein oxidation. Myofibrillar proteins from chicken fed hop beta-acids showed to be less susceptible to oxidation. A moderated level of hop beta-acids as dietary supplement accordingly improve the overall redox stability, protecting myofibrillar proteins and fatty acids against oxidation and improve the nutritional properties of meat from broiler chickens. PMID- 29433210 TI - Delineation of salts, ripening and gentle heating effects on molecular structure of Cantal-type cheese by Mid-infrared spectroscopy. AB - In this study, five Cantal-type cheeses with different salts (NaCl and KCl) and two ripening times (5 and 15days) were analyzed for their physicochemical characteristics, their structure at a molecular level and their rheological properties during heating (20 to 60 degrees C). The analysis of the molecular structure of cheeses was investigated by MIR spectroscopy coupled with ICA (Independent Components Analysis) and rheological properties by small-amplitude oscillatory rheology. ICA on physicochemical characteristics showed a good discrimination of the cheeses as a function of their chemical characteristics and ripening time. ICA applied to MIR spectra gave Independent Components (ICs) that were attributed to the molecular characteristics of protein, water and fat. Signal proportions of each IC depicted information regarding changes in those ICs with salts, heating and ripening. In addition, similar fat melting temperatures were obtained, regardless the technique used (oscillatory rheology and MIR) for all cheeses. This study demonstrated that MIR spectroscopy coupled with ICA is a promising tool to monitor and characterize modification of cheeses at a molecular level depending on temperature, salt content, and ripening time. PMID- 29433211 TI - Effects of cooking and food matrix on estimated mineral bioavailability in Mloukhiya, a Mediterranean dish based on jute leaves and meat. AB - Traditional Mediterranean plant-based dishes could allow tackling malnutrition while preserving the cultural heritage. To determine the effect of the cooking method on mineral bioavailability, the content in minerals and chelators of Mloukhiya, a Mediterranean dish based on jute leaves (Corchorus olitorius) that contains also meat, was monitored during the whole cooking process. Mineral bioaccessibility was assessed by measuring in vitro dialyzability. Model equation was also used to estimate mineral bioavailability. Comparison of Mloukhiya samples collected at different cooking time points showed that the dish total mineral content did not change despite the exchanges between sauce and meat during cooking. However, iron bioavailability decreased, because 58% of heme iron was degraded after 5h of cooking and non-heme iron showed poor bioaccessibility (1.2%), mainly due to its high content of phenolic compounds. The bioaccessibility of other minerals (zinc, calcium, magnesium and potassium) was high, indicating that the food matrix had no or little effect. The mineral bioavailability values predicted by using mathematical models were of the same order of magnitude as the bioaccessibility values. PMID- 29433212 TI - Application of microencapsulation for the safe delivery of green tea polyphenols in food systems: Review and recent advances. AB - Green tea has been associated with the prevention and reduction of a wide range of severe health conditions such as cancer, immune, and cardiovascular diseases. The health benefits associated with green tea consumption have been predominantly attributed to green tea polyphenols. The functional properties of green tea polyphenols are mainly anti-oxidative, antimutagenic, anticarcinogenic, anti microbial, etc. These excellent properties have recently gained considerable attention in the food industry. However, their application is limited by their sensitivity to factors like temperature, light, pH, oxygen, etc. More, studies have reported the occurrence of unpleasant taste and color transfer during food processing. Lastly, the production of functional food requires to maintain the stability, bioactivity, and bioavailability of the active compounds. To tackle these obstacles, technological approaches like microencapsulation have been developed and applied for the formulation of green tea-enriched food products. The present review discusses the novelty in microencapsulation techniques for the safe delivery of green tea polyphenols in food matrices. After a literature on the green tea polyphenols composition, and their health attributes, the encapsulation methods and the coating materials are presented. The application of green tea encapsulates in food matrices as well as their effect on food functional and sensory properties are also discussed. PMID- 29433213 TI - Two-step rating-based 'double-faced applicability' test for sensory analysis of spread products as an alternative to descriptive analysis with trained panel. AB - Descriptive analysis with a trained sensory panel has thus far been the most well defined methodology to characterize various products. However, in practical terms, intensive training in descriptive analysis has been recognized as a serious defect. To overcome this limitation, various novel rapid sensory profiling methodologies have been suggested in the literature. Among these, attribute-based methodologies such as check-all-that-apply (CATA) questions showed results comparable to those of conventional sensory descriptive analysis. Kim, Hopkinson, van Hout, and Lee (2017a, 2017b) have proposed a novel attribute based methodology termed the two-step rating-based 'double-faced applicability' test with a novel output measure of applicability magnitude (d'A) for measuring consumers' product usage experience throughout various product usage stages. In this paper, the potential of the two-step rating-based 'double-faced applicability' test with d'A was investigated as an alternative to conventional sensory descriptive analysis in terms of sensory characterization and product discrimination. Twelve commercial spread products were evaluated using both conventional sensory descriptive analysis with a trained sensory panel and two step rating-based 'double-faced applicability' test with an untrained sensory panel. The results demonstrated that the 'double-faced applicability' test can be used to provide a direct measure of the applicability magnitude of sensory attributes of the samples tested in terms of d'A for sensory characterization of individual samples and multiple sample comparisons. This suggests that when the appropriate list of attributes to be used in the questionnaire is already available, the two-step rating-based 'double-faced applicability' test with d'A can be used as a more efficient alternative to conventional descriptive analysis, without requiring any intensive training process. PMID- 29433214 TI - Postharvest dehydration induces variable changes in the primary metabolism of grape berries. AB - Postharvest dehydration causes changes in texture, color, taste and nutritional value of food due to the high temperatures and long drying times required. In grape berries, a gradual dehydration process is normally utilized for raisin production and for making special wines. Here we applied a raisin industry mimicking dehydration process for eleven days at 50 degrees C to intact berry clusters from cv. Semillon plants, and a set of molecular, cellular and biochemical analyses were performed to study the impact of postharvest dehydration in the primary metabolism. Transcriptional analyses by real time qPCR showed that several aquaporins (VvTIP1;2 and VvSIP1) and sugar transporters (VvHT1, VvSWEET11, VvSWEET15, VvTMT1, VvSUC12) genes were strongly upregulated. Moreover, the study of key enzymes of osmolytes metabolism, including mannitol dehydrogenase (VvMTD) and sorbitol dehydrogenase (VvSDH), at gene expression and protein activity level, together with the transcriptional analysis of the polyol transporter gene VvPLT1, showed an enhanced polyol biosynthesis capacity, which was supported by the detection of sorbitol in dehydrated grapes only. The metabolism of organic acids was also modulated, by the induction of transcriptional and biochemical activity modifications in malate dehydrogenases and malic enzymes that led to organic acid degradation, as demonstrated by HPLC analysis. Taken together, this study showed that primary metabolism of harvested berries was severely influenced in response to dehydration treatments towards lower organic acid and higher sorbitol concentrations, while sugar transporter and aquaporin genes were significantly upregulated. PMID- 29433215 TI - Composition and bioaccessibility of elements in green seaweeds from fish pond aquaculture. AB - The elemental composition of five species of green seaweeds (Chaetomorpha linum, Rhizoclonium riparium, Ulva intestinalis, Ulva lactuca, Ulva prolifera) grown in fish pond aquaculture systems were studied. The elemental bioaccessibility in these species was also investigated through the application of an innovative in vitro digestive model of the human gastrointestinal tract. It was observed that R. riparium had the highest levels of Mn, Sr, Cd, Sn, and I and that U. lactuca had the highest Ni and Cu concentrations. The daily amounts of dried green seaweed required for achieving specific dietary intakes were calculated, namely: 7g of dried U. lactuca (for meeting Cu Recommended Daily Allowance, RDA); 173g of dried U. lactuca (Zn RDA); 78g of dried C. linum (Se RDA); 41g of dried C. linum (Mo RDA); and 0.5g of dried R. riparium (I Dietary Reference Intake, DRI). Concerning elemental bioaccessibility, Mn and Cu had the highest values, always above 50%, I values were in the lower range, between 14 and 31%. The elemental bioaccessibility range of R. riparium (31-100%) was higher than the ranges for other species, particularly C. linum (0-56%). The bioaccessibility results entailed higher quantities of dried seaweed for reaching dietary intakes: 10g of dried U. lactuca (Cu RDA); 290g of dried R. riparium (Zn RDA); and 2g of dried R. riparium (I DRI). Accordingly, R. riparium is a very rich I source. This study showed the importance of taking into account bioaccessibility results in estimating dietary intakes. PMID- 29433216 TI - Effect of altitude on biochemical composition and quality of green arabica coffee beans can be affected by shade and postharvest processing method. AB - Although various studies have assessed altitude, shade and postharvest processing effects on biochemical content and quality of coffee beans, data on their interactions are scarce. The individual and interactive effects of these factors on the caffeine, chlorogenic acids (CGA) and sucrose contents as well as physical and sensory qualities of green coffee beans from large plantations in southwestern Ethiopia were evaluated. Caffeine and CGA contents decreased with increasing altitude; they respectively declined 0.12 and 1.23gkg-1 100m-1. Sucrose content increased with altitude; however, the altitude effect was significant for wet-processed beans (3.02gkg-1 100m-1), but not for dry-processed beans (0.36g kg-1 100m-1). Similarly, sucrose content increased with altitude with much stronger effect for coffee grown without shade (2.11gkg-1 100m-1) compared to coffee grown under shade (0.93gkg-1 100m-1). Acidity increased with altitude when coffee was grown under shade (0.22 points 100m-1), but no significant altitude effect was observed on coffee grown without shade. Beans grown without shade showed a higher physical quality score for dry (37.2) than for wet processing (29.1). These results generally underline the complex interaction effects between altitude and shade or postharvest processing on biochemical composition and quality of green arabica coffee beans. PMID- 29433217 TI - Comparison of chemical, color stability, and phenolic composition from pericarp of nine colored corn unique varieties in a beverage model. AB - The objective was to compare the chemical stability and color of nine unique anthocyanin-rich colored corn varieties named/coded as V1, V2, V3... V9. Extracts were added to a beverage model and stored at 4 degrees C, 22 degrees C, or 32 degrees C for 12weeks. After 12 weeks of storage at 32 degrees C, variety V6 [high condensed form (CF), high cyanidin-3-O-glucoside (C3G)] had the longest anthocyanin half-life, based on the quantification by HPLC. V3 [high pelargonidin (Pg), high acylated form (C3-mal)] and V5 (high CF, high C3G, high C3-mal) had the most favorable hue. V5 and V6 had some of the smallest changes in color over time. These findings suggest that an abundance of condensed forms with C3G in corn extracts could contribute to the improved stability. Beverage storage parameters also influenced color parameters; low temperatures and low pH enhanced color and anthocyanin stability. The most promising corn varieties for future experiments are V3, V5, and V6 based on color retention. PMID- 29433218 TI - Application of high-throughput pyrosequencing in the analysis of microbiota of food commodities procured from small and large retail outlets in a U.S. metropolitan area - A pilot study. AB - With the advent of high-throughput sequencing technologies, it is possible to comprehensively analyze the microbial community of foods without culturing them in the laboratory. The estimation of all microbes inhabiting a food commodity (food microbiota) therefore may shed light on the microbial quality and safety of foods. In this study, we utilized high-throughput pyrosequencing of 16S rRNA genes as well as traditional microbiological methods to evaluate the bacterial diversity and the predicted metabolic pathways associated with the bacterial communities of selected foods (romaine lettuce, cabbage, deli meat, and chicken legs, total 200 samples) procured from small and large retail outlets located in Memphis-Shelby County, Tennessee, USA. For high-throughput sequencing, microbial genomic DNA was directly extracted from the food products and subjected to genetic sequencing. Aerobic plate count of all food samples was also performed. Foods from small stores (such as corner stores) were found to contain higher bacterial counts as compared to large stores (such as supermarkets). High throughput pyrosequencing in tandem with bioinformatics analyses revealed a comprehensive picture of the bacterial ecology of foods at different taxonomic levels. Firmicutes and Proteobacteria were the most abundant phyla across all products. At the genus level, Enterobacter and Pantoea in vegetables, and Bacillus and Aeromonas in animal products were found to be the most abundant. The bacterial predicted metabolic pathways such as inosine-5'-phosphate biosynthesis I, methylglyoxal (MG) degradation pathways, urea cycle, dTDP-l-rhamnose biosynthesis I, and mevalonate pathway I differed in foods procured from small stores as compared to large groceries or supermarkets. The results from this study revealed that the bacterial ecology (both in terms of numbers and types of bacteria) of food commodities might differ based on the vending outlet type (large vs. small) of retail stores. The overall estimation bacterial communities in foods by high-throughput sequencing method may be useful to identify potential taxa responsible for food spoilage. Moreover, the data from pyrosequencing of 16S rRNA genes can also be applied to infer major metabolic pathways in bacteria inhabiting different foods. This may reflect the role of these pathways in food bacteria interaction and adaptation. PMID- 29433219 TI - A novel non-destructive manner for quantitative determination of plumpness of live Eriocheir sinensis using low-field nuclear magnetic resonance. AB - The present study investigated the quantitative and non-destructive determination of Eriocheir sinensis' plumpness during four mature stages using low field nuclear magnetic resonance (LF-1H NMR). Normalized lipid volume of live E. sinensis was calculated from Sept to Dec using 3D LF-1H nuclear magnetic imaging (MRI) and the validity of proposed technique was compared and verified with traditional Soxhlet extraction and live dissection method, respectively. The results showed the plumpness of female E. sinensis was higher than that of male ones from Sept to Dec and the highest plumpness of male and female E. sinensis reached 99,436.44 and 109,207.15mm3 in Oct. The normalized lipid volume of live male and female E. sinensis had a positive correlation with lipid content. This proposed method with short assay time, favorable selectivity, and accuracy demonstrated its application potential in grading regulation and quality evaluation of live E. sinensis. PMID- 29433220 TI - Coriander (Coriandrum sativum): A promising functional food toward the well being. AB - Coriandrum sativum (C. sativum) or coriander is one of the most popularly used spices in culinary worldwide, and its medicinal values has been recognized since ancient time. C. sativum contains bioactive phytochemicals that are accounted for a wide range of biological activities including antioxidant, anticancer, neuroprotective, anxiolytic, anticonvulsant, analgesic, migraine-relieving, hypolipidemic, hypoglycemic, hypotensive, antimicrobial, and antiinflammatory activities. The major compound, linalool, abundantly found in seeds is remarked for its abilities to modulate many key pathogenesis pathways of diseases. Apart from the modulating effects, the potent antioxidant property of the C. sativum provides a key mechanism behind its protective effects against neurodegenerative diseases, cancer, and metabolic syndrome. This review shed light on comprehensive aspects regarding the therapeutic values of the C. sativum, which indicate its significance of being a promising functional food for promoting the well-being in the era of aging and lifestyle-related diseases. PMID- 29433221 TI - Colonic fermentation of polyphenolics from Sea buckthorn (Hippophae rhamnoides) berries: Assessment of effects on microbial diversity by Principal Component Analysis. AB - The present study investigates the stability of polyphenolic in Sea buckthorn berries juice (SBJ) during different phases of digestion and its effect on colonic microbial diversity. At each stage, the Total polyphenolic content (TPC), Total antioxidant activity (TAA) and polyphenolic profile was determined. A 1.64 and 2.20 folds increase in TPC with 4.88 and 9.61 folds increase in TAA were observed during gastric and small intestine digestion (p<0.05) with the release of quercetin from food matrix. The digestion resulted in deformation of intact crystalline structure as indicated by scanning electron micrographs. The colonic fermentation resulted in an increase in quercetin, caffeic acid with decrease in rutin and chlorogenic acid after 36h of fermentation (p<0.05). The Shannon diversity index (H) of beneficial groups including Lactic acid bacteria (LAB), Bacteroides/Prevotella and Bifidobacteria was increased by 35%, 71% and 17%, respectively (p<0.05). The PCA analysis indicated that the presence and digestion of polyphenolics promote the proliferation of Bacteroides/Prevotella group as well as Lactic acid bacteria and Bifidobacteria. The results suggest that SBJ is good source of prebiotic substrate in terms of the proliferation of beneficial gut microbiota. PMID- 29433222 TI - Segregation of Tetragenococcus halophilus and Zygosaccharomyces rouxii using W1/O/W2 double emulsion for use in mixed culture fermentation. AB - Antagonism in mixed culture fermentation can result in undesirable metabolic activity and negatively affect the fermentation process. Water-oil-water (W1/O/W2) double emulsions (DE) could be utilized in fermentation for segregating multiple species and controlling their release and activity. Zygosaccharomyces rouxii and Tetragenococcus halophilus, two predominant microbial species in soy sauce fermentation, were incorporated in the internal W1 and external W2 phase of a W1/O/W2, respectively. The suitability of DE for controlling T. halophilus and Z. rouxii in soy sauce fermentation was studied in relation to emulsion stability and microbial release profile. The effects of varying concentrations of Z. rouxii cells (5 and 7logCFU/mL) and glucose (0%, 6%, 12%, 30% w/v) in the W2 phase were investigated. DE stability was determined by monitoring encapsulation stability (%), oil globule size, and microstructure with fluorescence and optical microscopy. Furthermore, the effect of DE on the interaction between T. halophilus and Z. rouxii was studied in Tryptic Soy Broth containing 10% w/v NaCl and 12% w/v glucose and physicochemical changes (glucose, ethanol, lactic acid, and acetic acid) were monitored. DE destabilization resulted in cell release which was proportional to the glucose concentration in W2. Encapsulated Z. rouxii presented higher survival during storage (~3 log). The application of DE affected microbial cells growth and physiology, which led to the elimination of antagonism. These results demonstrate the potential use of DE as a delivery system of mixed starter cultures in food fermentation, where multiple species are required to act sequentially in a controlled manner. PMID- 29433223 TI - Grape and wine amino acid composition from Carignan noir grapevines growing under rainfed conditions in the Maule Valley, Chile: Effects of location and rootstock. AB - Nitrogen compounds play a key role on grape and wine quality. Their composition in grapes depends mainly on variety, viticultural management, and terroir, and affects fermentation kinetics and the volatile compound formation. The aim of this work was to study grape and wine amino acid composition of ungrafted or grafted onto cv. Pais Carignan grapevines growing under rainfed conditions in ten sites of the Maule Valley (Chile). The results showed that proline was the most abundant amino acid in grapes and wines. In general, Carignan noir grapevines grafted over Pais showed lower grape amino acid content respect to ungrafted vines. Cool night index (CI) was inversely correlated to several amino acids, showing that their plant synthesis or accumulation increased with lower minimum temperatures during the last month before harvest. Truquilemu (Tru) and Cienaga de Name (Cdn) sites showed the highest concentration for several amino acids and total amino acid content in grapes, which led to a faster alcoholic fermentation. PMID- 29433224 TI - Structure characteristics for intestinal uptake of flavonoids in Caco-2 cells. AB - Flavonoids are a large group of polyphenols and widely distributed in plant foods. Flavonoids exhibit various biological activities, such as anti-cancer, antioxidant and anti-inflammatory while poor oral bioavailability has been considered as a major hurdle in their use as functional foods. Cellular uptake and efflux of flavonoid implicates their bioavailability. To investigate the cellular uptake and efflux of flavonoids, 27 flavonoids were measured for their cellular uptake in Caco-2 cells with (CUV) and without (CU) the inhibitor of P glycoprotein (P-gp) verapamil. Then, a quantitative structure-absorption relationship (QSAR) model containing 21 compounds as training set was obtained from their corresponding CU. The model showed good robustness and predictivity with a high cross-validation coefficient (Q2) value of 0.809 and Log of the octanol/water partition coefficient (SlogP) and atomic charge on carbon 5 (QC5) were related to flavonoid uptake. The CUV of some flavonoids were significantly (p<0.05 or p<0.01) higher than their CU, suggesting that specific flavonoids are pumped out by P-gp. The structure-affinity relationship of flavonoids as substrates of P-gp was determined with the presence of 4'-OCH3, 3'-OCH3 and the absence of 3'-OH, 3-OH and 4'-OH favorable for the affinity of flavonoids. These results provide valuable information for screening flavonoids with good absorption and low affinity with transporters. PMID- 29433225 TI - Metabolite profiling of green, green/red, and red lettuce cultivars: Variation in health beneficial compounds and antioxidant potential. AB - Salad vegetables, commonly consumed at baby-leaf stages, are the most appropriate and emerging dietary source of antioxidant compounds. Screening and identification of nutrient-rich cultivars can be potentially useful to obtain a nutrient-dense diet. Thus, in this study, we explored the genetic potential of baby leaves of 23 diverse lettuce cultivars for the health-beneficial metabolites. The results showed that the composition and contents of the studied metabolites in lettuces varied significantly between cultivars and were principally dependent on leaf color. All red-leaf cultivars were rich in carotenoids, cyanidin, polyunsaturated fatty acids (PUFAs, primarily in the form of alpha-linolenic and linoleic acid,) total phenolic contents (TPC), and antioxidant potential. Among carotenoids, all-E-lutein was found in highest amount, followed by all-E-violaxanthin and all-E-lactucaxanthin, accounting for an average of 30%, 28% and 15% of total carotenoids, respectively. The content of total folate was recorded in the range of 6.51 (cv. Caesar Green) to 9.73MUg/g (DW) (cv. Asia Heuk Romaine). The principal component analysis (PCA) showed that the cyanidin and other phenolic compounds are the most potent scavengers of ABTS and DPPH radicals. The overall results suggested that all red-leaf lettuce cultivars have a distinct profile of phytoconstituents, which can be used as a nutrient-dense food. PMID- 29433226 TI - Physicochemical characteristics, ATR-FTIR molecular interactions and in vitro starch and protein digestion of thermally-treated whole pulse flours. AB - Hydrothermal treatments, annealing (ANN) and heat moisture treatment (HMT) were applied to four whole pulse flours (black bean, broad bean, chickpea and lentil) with the aim to increase their slow digestible (SDS) and resistant starch (RS) fractions. In order to assess differences in their molecular interactions, they were analyzed and compared by ATR-FTIR before and after in vitro digestion. Both hydrothermal treatments promoted changes on starch granular architecture, being reflected on their thermal and pasting properties, that where positively correlated with their amylose and protein contents (R=0.96, P<0.01). Overall, the proposed hydrothermal treatments increased their SDS and RS fractions, but they had different effect on their in vitro protein digestion. The ATR-FTIR analysis of cooked flours before and after digestion showed that thermal treatments promoted new physical interactions at molecular scale between starch and proteins, that were correlated with the amount of RS fraction. The outcomes of this study could help to understand the slow digestion properties and possible interactions of the flour components in these four pulses. PMID- 29433227 TI - Thap Maeo bananas: Fast ripening and full ethylene perception at low doses. AB - Brazil is a major producer and consumer of various banana types. Thap Maeo is a promising cultivar for the market due to its resistance to Black and Yellow Sigatoka disease. However, a lack of information and postharvest technologies concerning Thap Maeo physiology seems to be a significant problem limiting its expansion in the market. Thus, this study aims to establish Thap Maeo fruit's physical, biochemical, and physiological aspects, defining the best ethylene dosage for treatment considering fruit ripening parameters. Bananas were harvested and monitored during both natural and ethylene-induced ripening processes. Assessments of pulp firmness, peel color and endogenous ethylene production showed different profiles between ethylene-treated and non-treated fruits, whereas the ethylene responses concerning the carbohydrates and hormones profiles, as well as the ethylene receptors expression, were observed in all ethylene-treated fruits, even applying low concentrations of the hormone. It thus indicated the high ethylene-sensitivity of Thap Maeo cultivar. Such postharvest behaviors reverberate in lower ethylene requirements for treatment, which was established at 10MULL-1. Ethylene-inducible changes in fruit volatile compounds throughout ripening are also discussed. PMID- 29433228 TI - Steam pressure treatment of defective Coffea canephora beans improves the volatile profile and sensory acceptance of roasted coffee blends. AB - Between 15 and 20% of Brazilian coffee production corresponds to defective beans (PVA), which decreases the quality of the coffee brew. Steam treatment has been reported as an alternative to improve the volatile profile and cup quality of coffee. The aim of this study was to propose a steam treatment of defective Coffea canephora beans to improve the volatile profile of the roasted coffee. The sensory impacts of adding steamed coffee (SC) in Coffea arabica blends were evaluated. The steam treatments studied modified the volatile profile of roasted SCs, increasing the contents of acetoin, benzyl alcohol, maltol, 2,6 dimethylpyrazine, 2-furfurylthiol, and 5-methylfurfural and decreasing the contents of 4-ethylguaiacol, isovaleric acid, methional, 2,3-diethyl-5 methylpyrazine, and 3-methoxy-3-methylpyrazine. Among the evaluated parameters, the best condition to maximized the content of the volatiles with a potential positive impact and minimize those with a potential negative impact was 5bar/16min (SC 5). The thresholds of consumer rejection and of detection indicate that up to 30% SC 5 can be added to a high cup quality Coffea arabica coffee without perception or rejection of the coffee brew. A blend of 30% of SC 5 and 70% of Coffea arabica was well accepted. PMID- 29433229 TI - In vitro chemopreventive properties of peptides released from quinoa (Chenopodium quinoa Willd.) protein under simulated gastrointestinal digestion. AB - Because of the continuous and direct interaction between the digestive tract and foods, dietary compounds represent an interesting source of chemopreventive agents for gastrointestinal health. In this study, the influence of a standardized static in vitro gastrointestinal digestion model on the release of peptides with chemopreventive potential from quinoa protein was investigated. Gastroduodenal digests and fractions collected by ultrafiltration were evaluated for their in plate oxygen radical absorbance capacity and in vitro colon cancer cell viability inhibitory activity. Highest effects were observed in the digests obtained during the intestinal phase, with fraction containing peptides <5kDa as the main responsible for the antioxidant activity and peptides >5kDa showing the greatest anti-cancer effects. Seventeen potential bioactive peptides derived from quinoa proteins have been identified. These proteins might be utilized as new ingredients in the development of functional foods or nutraceuticals with the aim of reducing oxidative stress-associated diseases, including cancer. PMID- 29433230 TI - In vitro digestion behavior of water-in-oil-in-water emulsions with gelled oil water inner phases. AB - Double emulsions may be able to protect and release in a controlled manner bioactive compounds during digestion of food matrices. It was hypothesized that the physical state and solid content in the inner phases of water-in-oil-in-water (W1/O/W2) emulsions may affect the overall stability and the release behavior of bioactives during in vitro digestion. Therefore, hydrophobic (phytosterols or Vitamin D3) and hydrophilic (Vitamin B12) molecules were incorporated in double emulsions prepared either with a liquid (soybean oil - SO) or oil-fat gel (soybean oil+trimyristin - STO) lipid phase and liquid internal aqueous phase. In addition, the impact of a gelled inner aqueous phase was studied, using high methoxyl pectin. W1/O/W2 emulsions were prepared with polyglycerol polyricinoleate (PGPR) and sodium caseinate as emulsifiers. After the 30min in vitro gastric stage, all double emulsions showed no significant change in size. Lipid crystals were visible in the STO emulsions. Fat crystallization, and the formation of an oil fat gel, led to coalescence of the inner aqueous droplets. The inner aqueous droplets were no longer visible by confocal microscopy after the initial stages of 2h in vitro duodenal digestion. Fat crystals and droplets of non-spherical shape were also noted in the STO double emulsions up to 25min of in vitro duodenal stage. Overall, the STO emulsions had a higher extent of free fatty acid release and consequent bioactive transfer compared to the SO emulsions. The presence of the medium chain fatty acids (from trimyristin), in addition to the surface-to-core distribution of the hydrophobic bioactives within the oil droplet were key factors in lipid digestibility and bioactive release. The STO and SO samples did not differ in terms of the release of the hydrophilic molecule, vitamin B12, over time. On the other hand, there was a significant increase in the stability of the inner water phase, after gastric digestion, when this phase was gelled with high methoxyl pectin. This work demonstrated that the physical properties of the different internal phases of W1/O/W2 influenced lipid digestion and bioactive transfer kinetics during in vitro digestion. PMID- 29433231 TI - Volatile profile of elderberry juice: Effect of lactic acid fermentation using L. plantarum, L. rhamnosus and L. casei strains. AB - In this study we explored, for the first time, the lactic acid fermentation of elderberry juice (EJ). A total of 15 strains isolated from dairy and plant matrices, belonging to L. plantarum, L. rhamnosus and L. casei, were used for fermentations. The volatile profile of started and unstarted EJ was characterized by HS-SPME/GC-MS technique after 48h of fermentation and 12days of storage at 4 degrees C. All L. plantarum and L. rhamnosus strains exhibited a good capacity of growth while not all L. casei strains showed the same ability. The aromatic profile of fermented juices was characterized by the presence of 82 volatile compounds pertaining to different classes: alcohols, terpenes and norisoprenoids, organic acids, ketones and esters. Elderberry juice fermented with L. plantarum strains showed an increase of total volatile compounds after 48h while the juices fermented with L. rhamnosus and L. casei exhibited a larger increase after the storage. The highest concentration of total volatile compounds were observed in EJ fermented with L. plantarum 285 isolated from dairy product. Ketones increased in all fermented juices both after fermentation and storage and the most concentrated were acetoin and diacetyl. The organic acids were also affected by lactic acid fermentation and the most abundant acids detected in fermented juices were acetic acid and isovaleric acid. Hexanol, 3-hexen-1-ol (Z) and 2-hexen-1-ol (E) were positively influenced during dairy lactic acid bacteria strains fermentation. The most represented esters were ethyl acetate, methyl isovalerate, isoamyl isovalerate and methyl salicylate, all correlated with fruit notes. Among terpenes and norisoprenoids, beta-damascenone resulted the main representative with its typical note of elderberry. Furthermore, coupling obtained data with multivariate statistical analyses, as Principal Component Analysis (PCA) and Classification Trees (CT), it was possible to relate the characteristic volatile profile of samples with the different species and strains applied in this study. PMID- 29433232 TI - Non-triglyceride components modulate the fat crystal network of palm kernel oil and coconut oil. AB - PKO and CNO are composed of 97-98% triacylglycerols and 2-3% minor non triglyceride components (FFA, DAG and MAG). Triglycerides were separated from minor components by chromatographic method. The lipid composition, thermal properties, polymorphism, isothermal crystallization behavior, nanostructure and microstructure of PKO, PKO-TAG, CNO and CNO-TAG were evaluated. Removal of minor components had no effect on lipid composition and equilibrium solid fat contents. However, presence of minor components did increase the slip melting point and promoted the onset of crystallization from DSC crystallization profiles. The thickness of the nanoscale crystals increased with no polymorphic transformation after removing the minor components. Crystallization kinetics revealed that minor components decreased crystal growth rate with higher t1/2. Sharp changes in the values of the Avrami constant k and exponent n were observed for all fats around 10 degrees C. Increases in n around 10 degrees C indicated a change from one dimensional to multi-dimensional growth. From the results of polarized light micrographs, the transformation from the coarser crystal structure to tiny crystal structure occurred in microstructure networks at the action of minor components. PMID- 29433233 TI - Preparation and characterization of microparticles of beta cyclodextrin/glutathione and chitosan/glutathione obtained by spray-drying. AB - Reduced glutathione (GSH) is an efficient antioxidant on limitation of browning, of the loss of aromas and off-flavor formation in white wines. The encapsulation of GSH in a polymer system to be added in white wines may prolong its antioxidant action. The aim of this work was to prepare and characterize spray-dried microparticles using beta-cyclodextrin (beta-CD) or chitosan as polymers for encapsulation of GSH for its addition to wine to prevent oxidation. The microparticles obtained after the drying process were characterized regarding morphology, chemical interaction between GSH and polymers, thermal stability, microstructure, encapsulation efficiency and in vitro GSH release. SEM showed spherical microparticles, with wrinkled surfaces for beta-CD/GSH and smooth surfaces for chitosan/GSH. A wide distribution of particle size was observed. In general, beta-CD/GSH showed an average diameter smaller than the chitosan/GSH microparticles. FT-IR showed a possible interaction between GSH and both polymers. DSC and DRX showed that encapsulation process produced a marked decrease in GSH crystallinity. The encapsulation efficiency was 25.0% for chitosan/GSH and 62.4% for beta-CD/GSH microparticles. The GSH release profiles from microparticles showed that beta-CD can control the release behaviors of GSH better than chitosan in a model wine. Cumulative release data were fitted to an empirical equation to compute diffusional exponent (n), which indicates a trend the non-Fickian release of GSH. PMID- 29433234 TI - Effect of xanthan gum on lipid digestion and bioaccessibility of beta-carotene loaded rice starch-based filled hydrogels. AB - The aim of this study was to examine the effects of xanthan gum on the lipid digestibility, rheological properties, and beta-carotene bioaccessibility of rice starch-based filled hydrogels. beta-Carotene was solubilized within lipid droplets of emulsion that were then entrapped within rice starch hydrogels fabricated with different concentrations of xanthan gum. At a low concentration of xanthan gum (<0.5wt%), the viscous characteristics of the filled starch hydrogels increased. Furthermore, these hydrogels had a slower rate of lipid digestion than the beta-carotene-loaded emulsion. As the concentration of xanthan gum was increased (to 1.0wt% and 2.0wt%), the filled starch hydrogels became more elastic gel-like than those without xanthan gum, and also had the fastest rate and highest final extent of lipid digestion. The addition of xanthan gum to the filled starch hydrogel lowered the bioaccessibility of beta-carotene to varying degrees, depending on the xanthan gum concentration. The results obtained from this study can be useful in designing gel-like food products fortified with lipophilic nutraceuticals. PMID- 29433235 TI - Encapsulation and stabilization of beta-carotene by amylose inclusion complexes. AB - In the present study, we report a novel composition based on amylose (or starch) inclusion complex with an amphiphilic material as an effective encapsulation platform technology to incorporate guests of interest. Specifically, the encapsulation of beta-carotene in amylose-surfactant and amylose/starch-ascorbyl palmitate (AscP) inclusion complexes was investigated. Surfactants of different hydrophilicity/lipophilicity were selected to cover a broad range of HLB values. The formation of the inclusion complexes was characterized by X-ray diffraction and differential scanning calorimetry. The ability of amylose-surfactant system to encapsulate beta-carotene was dependent on the HLB value of the surfactants, instead of their ability to induce inclusion complexation. The incorporation of beta-carotene hindered amylose-surfactant inclusion complex formation, whereas no significant effect was observed on structural and thermal properties of starch AscP inclusion complex in the presence of beta-carotene. The X-ray diffraction pattern of amylose-AscP-beta-carotene showed that beta-carotene molecules did not crystallize into a separated phase and thus were suggested to be homogeneously immobilized within the polycrystalline amylose-AscP inclusion complexes. During a storage period of six weeks at 20 and 30 degrees C, the stability of beta carotene was improved by encapsulation in starch-AscP inclusion complexes compared with that in physical mixtures of the three components. PMID- 29433236 TI - A simple approach for rapid detection and quantification of adulterants in stingless bees (Heterotrigona itama) honey. AB - In this study, we propose an easy approach by combining the Fourier transform infrared and attenuated total reflectance (FTIR-ATR) spectroscopy together with chemometrics analysis for rapid detection and accurate quantification of five adulterants such as fructose, glucose, sucrose, corn syrup and cane sugar in stingless bees (Heterotrigona itama) honey harvested in Malaysia. Adulterants were classified using principal component analysis and soft independent modeling class analogy, where the first derivative of the spectra in the wavenumber range of 1180-750cm-1 was utilized. The protocol could satisfactorily discriminate the stingless bees honey samples that were adulterated with the concentrations of corn syrup above 8% (w/w) and cane sugar over 2% (w/w). Feasibility of integrating FTIR-ATR with chemometrics for precise quantification of the five adulterants was affirmed using partial least square regression (PLSR) analysis. The study found that optimal PLSR analysis achieved standard error of calibrations and standard error of predictions within an acceptable range of 0.686-1.087% and 0.581-1.489%, respectively, indicating good predictive capability. Hence, the method developed here for detecting and quantifying adulteration in H. itama honey samples is accurate and rapid, requiring only 7 8min to complete as compared to 3h for the standard method, AOAC method 998.12. PMID- 29433237 TI - Relationship between composition and bioactivity of persimmon and kiwifruit. AB - Fruits are foods that contain plenty of vitamins, minerals and some bioactive phytochemicals like polyphenols. Thus, fruits may exert different functional properties on human health, some of which are directly related to their antioxidant capacity like cancer or atherosclerosis. Owing to globalization, consumers have a wide repertory of fruits throughout the year. Among them, tropical and subtropical fruits are steadily expanding, as well as the studies about them. In this sense, this timely review focused on the nutritional value and chemical composition of persimmon and kiwifruit, two tropical fruits with a protective role on different chronic diseases. Thus, this review focused mainly on the presence of bioactive compounds such as polyphenols, tannins, carotenoids, vitamin C and the different functional properties (i.e. antioxidant capacity, antithrombotic activity, decrease of plasmatic lipids, etc.) arising from the presence of such biologically active molecules. Finally, the effects of genotype and ripening stage on antioxidant capacity and the content of bioactive compounds in persimmon and kiwifruit are also discussed. PMID- 29433238 TI - Disinfection efficacy over yeast biofilms of juice processing industries. AB - Membrane separation systems represent a hot - spot for biofilm formation in juice industries. Sodium hypochlorite (NaOCl) has been traditionally the disinfectant of choice; however, its effectiveness over well-established biofilms is limited. In this work the study of biofilm formation on ultrafiltration membranes was proposed. The effectiveness of cleaning and disinfection procedures commonly used in juice industry was tested on the removal and killing of cells. The species used (Rhodotorula mucilaginosa, Candida krusei, Candida kefyr and Candida tropicalis) were isolated from ultrafiltration modules of a clarified apple juice industry. Industrial concentrations of NaOCl (200mgCL?L-1) showed to be effective against planktonic cultures with >4 log reductions, whereas their overall efficiency against adhered cells was smaller. Recovery of viable cell counts to initial numbers was evidenced regardless of the time of colonization. The topography of the surface showed to have an impact on the efficiency of the disinfectant, presenting membranes smaller log reductions than stainless steel (~1.09-1.53logCFU). At 200mgCl?L-1 only membrane's cross flow recovery was reached with no long-term effect over the attached cells. The overall results demonstrated the recalcitrance of these biofilms to typical cleaning and disinfection process which may confer them with a selective advantage. PMID- 29433239 TI - Physical properties and stability evaluation of fish oil-in-water emulsions stabilized using thiol-modified beta-lactoglobulin fibrils-chitosan complex. AB - Fish oil-in-water emulsions containing fish oil, thiol-modified beta lactoglobulin (beta-LG) fibrils, chitosan and maltodextrin were fabricated using a high-energy method. The results showed that chitosan coating induced charge reversal; denoting successful biopolymers complexation. A significantly (p<0.05) larger droplet size and lower polydispersity index value, attributed to the thicker chitosan coating at the oil-water interface, were observed. At high chitosan concentrations, the cationic nature of chitosan strengthened the electrostatic repulsion between the droplets, thus conferring high oxidative stability and low turbidity loss rate to the emulsions. The apparent viscosity of emulsions stabilized using thiol-modified beta-LG fibrils-chitosan complex was higher than those stabilized using beta-LG fibrils alone, resulting in the former's higher creaming stability. Under thermal treatments (63 degrees C and 100 degrees C), emulsions stabilized using thiol-modified beta-LG fibrils chitosan complex possessed higher heat stability as indicated by the consistent droplet sizes observed. Chitosan provided a thicker protective layer that protected the oil droplets against high temperature. Bridging flocculation occurred at low chitosan concentration (0.1%, w/w), as revealed through microscopic observations which indicated the presence of large flocs. All in all, this work provided us with a better understanding of the application of protein fibrils-polysaccharide complex to produce stable emulsion. PMID- 29433240 TI - A GC-MS based metabolomics approach to determine the effect of salinity on Kimchi. AB - GC-MS datasets coupled with multivariate statistical analysis were used to investigate metabolic changes in Kimchi during fermentation and metabolic differences in Kimchi added with various amounts (0, 1.25, 2.5, and 5%) of salts. PCA score plot obtained after 1day of fermentation were clearly distinguishable by different salinity groups, implying that early fermentation speed varied according to Kimchi salinity. PLS-DA score plot from data obtained on the 50th day of fermentation also showed a clear separation, indicating metabolites of Kimchi were different according to salinity. Concentrations of lactic acid, acetic acid, and xylitol were the highest in Kimchi with 5% salinity while concentration of fumaric acid was the highest in Kimchi with 0% salinity. Rarefaction curves showed that numbers of operational taxonomic units (OTUs) in Kimchi with 5% salinity were higher than those in Kimchi with 0% salinity, implying that Kimchi with 5% salinity had more bacterial diversities. This study highlights the applicability of GC-MS based metabolomics for evaluating fermentative characteristics of Kimchi with different salinities. PMID- 29433241 TI - Physicochemical characteristics of complexes between amylose and garlic bioactive components generated by milling activating method. AB - Complexes of amylose (Am) with garlic bioactive components (GBCs) were prepared by milling activating treatment of Am and garlic paste (GP) together. The complex, produced by milling for 2.5h with the garlic (dry basis)/Am ratio of 1:5 (w/w) and water content of 25% (w/w) exhibited significantly higher allicin content (0.49mg/g of complex) than others. The scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transforms infrared (FT-IR), differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), high performance liquid chromatography (HPLC), and gas chromatography-mass spectrometry (GC-MS) techniques were used complex characterization. XRD results indicated that the Am and garlic bioactive components formed the V-type structure. FT-IR and DSC analysis further confirmed the formation of the Am-GBCs complex, and its thermal stability was improved in comparison with garlic powder. According to GC-MS results, all organosulfur compounds (OSCs) in fresh garlic were better retained to Am-GBCs complex. Therefore, the Am-GBCs complexes can have important applications as stable natural flavor compound systems. PMID- 29433242 TI - Changes in extra-virgin olive oil added with Lycium barbarum L. carotenoids during frying: Chemical analyses and metabolomic approach. AB - In this work, an Italian extra-virgin olive oil (EVOO) sample and the same sample added with a carotenoid-rich nutraceutical extract from Lycium barbarum L. (EVOOCar) were subjected to a frying process to comparatively assess chemical and physical changes and heat stability. Oxidation progress was monitored by measuring oil quality changes such as peroxide value, free acidity, K232, K268, and fatty acid composition as well as minor compound content, phenols, alpha tocopherol, and carotenoids. An UHPLC/QTOF-MS metabolomics approach discriminated the two oil samples based on their chemical changes during frying, identifying also the phenolic classes most exposed to statistically significant variations. Partial least square discriminant analysis and volcano analysis were applied together to identify the most significant markers allowing group separation. The decrease in total phenolic content was lower in EVOOCar than in EVOO during frying. Monounsaturated and polyunsaturated fatty acids showed a significant percentage loss, 3.7% and 17.2%, respectively, in EVOO after 180min frying at 180 degrees C, while they remained constant or slightly changed in EVOOCar. Zeaxanthin added to the oil rapidly decreased during the frying process. These findings showed that the addition of a carotenoid extract from L. barbarum can help to improve the oxidative stability of extra-virgin olive oil. PMID- 29433243 TI - The potential applications of mushrooms against some facets of atherosclerosis: A review. AB - Atherosclerosis is a complex pathology that involves several factors in its development, like oxidative stress, inflammation, hyperlipidemia, platelet aggregation and thrombus formation. Several drugs and therapeutic approaches have been developed to handle these aspects of atherosclerosis. However, some of these treatments can be costly and have undesirable side effects. Many constituents of mushrooms have been shown to have potential anti-atherosclerotic effects in several in vitro and in vivo studies. Recently, the possible mechanisms in which they exert these effects have also been elucidated. In this review, some of the research focusing on mushrooms and their potential anti-atherosclerotic effects are examined. Many mushroom species exhibited anti-oxidative, anti-inflammatory and hypolipidemic effects that can potentially attenuate the progression of atherosclerosis, either through their isolated compounds or use of crude extracts. More studies are focused on the effect that mushrooms have on gene expressions that are involved in oxidative stress, inflammation, and hyperlipidemia. These studies could provide us with a better understanding on the mechanisms in which the consumption of mushrooms could exert their possible anti atherosclerotic effects. Further research needs to be done to uncover other possible mechanisms that are affected by mushroom use. PMID- 29433244 TI - Identification of enzyme origin in dough improvers: DNA-based and proteomic approaches. AB - Enzymatic dough improvers (DIs) are increasingly used as baking co-adjuvants. Herein, an array of techniques, including Western blotting, PCR, electrophoresis based and shotgun proteomics, was addressed to identify the enzymes in six commercial DI preparations. In particular, this work sought to exclude the possible undeclared use of amylolytic enzymes from porcine (or other animal origin) pancreas in DIs. PCR-amplified mitochondrial cytochrome b (mt cyt b) gene region and porcine pancreatic alpha-amylase were the targets of DNA-based and protein methods, respectively, both assuring a limit of detection lower than 0.5 0.1% (w/w). Aspergillum oryzae alpha-amylase and Hordeum vulgare (barley) beta amylase were the most represented enzymes in all DI samples. Although one sample was PCR-positive, none among the DIs contained porcine pancreatic enzymes. Comparative gas chromatographic analysis of fatty acids suggested that the porcine contamination might arise from hard fats of porcine origin (lard), emphasizing the need of performing analyses at the protein level when the targets are enzymes or proteins. PMID- 29433245 TI - Evaluation of radical scavenging activity, intestinal cell viability and antifungal activity of Brazilian propolis by-product. AB - Propolis is a natural adhesive resinous compound produced by honeybees to protect hives from bacteria and fungi, being extremely expensive for food industry. During propolis production, a resinous by-product is formed. This resinous waste is currently undervalued and underexploited. Accordingly, in this study the proximate physical and chemical quality, as well as the antioxidant activity, radical scavenging activity and cell viability of this by-product were evaluated and compared with propolis in order to boost new applications in food and pharmaceutical industries. The results revealed that the by-product meets the physical and chemical quality standards expected and showed that the propolis waste contains similar amounts of total phenolic content (TPC) and total flavonoid content (TFC) to propolis. Also, a good scavenging activity against reactive oxygen and nitrogen species (ROS and RNS, respectively) determined by the assays of superoxide anion radical (O2-), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), nitric oxide (NO) and peroxyl radical (ROO) were determined. Linear positive correlations were established between the TPC of both samples and the antioxidant activity evaluated by three different methods (DPPH, ABTS and FRAP assays). The extracts were also screened for cell viability assays in two different intestinal cell lines (HT29-MTX and Caco-2), showing a viability concentration-dependent. Similarly, the Artemia salina assay, used to assess toxicity, demonstrated the concentration influence on results. Finally, the antifungal activity against ATCC species of Candida was demonstrated. These results suggest that propolis by-product can be used as a new rich source of bioactive compounds for different areas, such as food or pharmaceutical. PMID- 29433246 TI - Bubbles in noodle dough: Characterization by X-ray microtomography. AB - Bubbles, found in a huge variety of food products, are known to afford desirable quality attributes, especially those related to texture, mouthfeel and taste. However, the presence of bubbles and their effects on wheat flour noodles is an aspect that has been, until now, largely overlooked, despite the positive and negative connotations of bubbly inclusions on Asian noodle quality. X-rays from a synchrotron source (Biomedical Imaging and Therapy facility at the Canadian Light Source) were used to rapidly and non-destructively acquire tomographic images of noodle dough. Appropriate image analysis protocols were used to determine the bubble size distribution, the orientation of bubbles, and their position within the dough sheet. The effect of processing (one or multiple lamination steps) on bubble properties in the dough that was subsequently sheeted (gradual elongation and reduction in thickness) was investigated. Bubble size distributions, well captured by lognormal distribution function, showed that the lamination process induced bubble entrapment and reduction in bubble size. Bubbles were found to be flat, elongated and oriented in the sheeting direction, this effect being less for doughs laminated ten times (90 degrees rotations between lamination steps). Interestingly, a gradient in concentration of bubbles within the dough sheet was found from the noodle core to the sheet edges. Aging effects were also apparent. This first non-destructive study of bubbles in wheat-flour noodle dough provides a more complete knowledge of the dough sheet's internal structure, and how it originates via processing, and this has repercussions on the overall quality of Asian noodles. PMID- 29433247 TI - Effect of different buffer systems on the xanthine oxidase inhibitory activity of tuna (Katsuwonus pelamis) protein hydrolysate. AB - This study systematically explored the effect of HEPES, Tris and sodium phosphate (PB) buffers on the xanthine oxidase (XO) inhibitory activity of tuna protein hydrolysate (TPH, containing over 90% of constituents with molecular weight below 5kDa). The greatest XO inhibition by TPH was observed in HEPES buffer. The optimal HEPES concentration was 100mmol/L. Tryptophan fluorescence and circular dichroism measurements revealed the comparable stability of XO and TPH in the three buffers. The buffers did not alter the majority of XO or TPH structure but induced slight modifications to specific domains (e.g. Trp residues on alpha helices) and certain rearrangements (e.g. XO unfolding or refolding). HEPES buffer exerted stronger interactions with XO or TPH, causing a lower alpha helical content in XO and consequently a lower XO catalytic activity but greater XO inhibition, compared to Tris and PB buffers. PMID- 29433248 TI - A preliminary exploration of the potential of Eugenia uvalha Cambess juice intake to counter oxidative stress. AB - PURPOSE: The ability of foods to aid in the prevention of chronic metabolic diseases, has recently become an area of increased interest. In addition, there is growing interest in exploring the benefits of consuming underutilized fruits as alternatives to commercially available fruits. Eugenia uvalha Cambess (uvaia) is a native fruit of Brazil with great market and phytotherapy potential. The present study was conducted to investigate the effects of uvaia juice (UJ) on the levels of protein carbonyls (PCO) and antioxidant enzymes in the livers of rats fed a high-fat diet. METHODS: Thirty-two female rats were randomly assigned to four groups. The rats were fed either a standard diet (group C) or a high-fat diet (group HF). In addition, groups CUJ and HFUJ were treated with UJ (2mL/day) administered via gavage for 8weeks. RESULTS: In our study, UJ displayed high antioxidant activity (135.14+/-9.74 GAE/100g). Administration of UJ caused a significantly reduced concentration of rat liver PCO (47.4%), which was associated with a 29% increase in catalase activity. A significant increase in the concentration of oxidized glutathione (GSSG) (15.04+/-5.08nmol/ml) and a reduction in the reduced glutathione/oxidized glutathione ratio (GSH/GSSG) (11.30+/-2.68) were found in the HF group, whilst these changes were not observed in the HFUJ group (a result similar to that of group C). CONCLUSIONS: Our results demonstrate that UJ decreases oxidative damage by improving antioxidant efficiency and attenuating oxidative damage to proteins. PMID- 29433249 TI - Emulsions as delivery systems for gamma and delta tocotrienols: Formation, properties and simulated gastrointestinal fate. AB - Tocotrienols have been reported to have stronger bioactivities than tocopherols, and may therefore be suitable as a potent source of vitamin E in functional foods, supplements, and pharmaceuticals. However, their inclusion into new products is hindered by their low water-solubility and oral bioavailability. Oil in-water emulsions (O/W) could provide an adequate delivery system for these bioactive compounds. Tocotrienols were tested in bulk oil and within O/W conventional emulsions (>10MUm) and nanoemulsions (<350nm). The emulsions were prepared with medium chain triglycerides (MCT) as an oil phase (5 to 40% wt) and quillaja saponins as a natural surfactant. The gastrointestinal fate of the emulsion-based delivery systems was investigated using a simulated gastrointestinal tract (GIT). The physical properties of the emulsions (color, apparent viscosity) were affected with increased droplet concentration. The lipid phase composition (emulsion type and particle size) had a pronounced impact on the microstructure of the emulsions in different regions of the GIT. At simulated small intestine conditions, the rate of lipid digestion and tocotrienol bioaccessibility decreased in the following order: nanoemulsions>emulsions>bulk oil. These results suggest that emulsions containing small lipid droplets are particularly suitable for delivering tocotrienols. PMID- 29433250 TI - Edible flowers as sources of phenolic compounds with bioactive potential. AB - The edible flowers are widely used, but there is still a lot to be done in relation to its bioactive potential and its correlation with the presence of phenolic compounds. The aim of this study was determined the individual phenolic profile in the hydromethanolic extracts and infusion preparations of four different flower samples (Dahlia mignon, Rosa damascena 'Alexandria' and R. gallica 'Francesa' draft in R. canina, Calendula officinalis L., and Centaurea cyanus L.) and their bioactive potential (antioxidant, antiproliferative, and antibacterial capacity). All the studied flowers presented different profiles regarding their phenolic composition and revealed biological potential. The bioactive potential of the studied flowers was moderate, the hydromethanolic extracts of rose petals showed the best results for antioxidant and antibacterial assays, while the antiproliferative properties were only present in some of the tested cell lines, for the hydromethanolic extracts, in which dahlia and rose showed the best results. These results demonstrate that edible flowers can be used as a source of phenolic compounds with bioactive potential, which can be applied in the food sector, as foods and as sources natural ingredients. PMID- 29433251 TI - Ethyl acetate fraction from Hibiscus sabdariffa L. attenuates diabetes-associated cognitive impairment in mice. AB - The ameliorating effects of the ethyl acetate fraction from Hibiscus sabdariffa L. (EFHS)2 against diabetes mellitus (DM)3 and DM-induced cognitive impairment were investigated on streptozotocin (STZ)4-induced DM mice. The EFHS groups showed improved hyperglycemia and glucose tolerance compared to the STZ group. Furthermore, their liver and kidney function and lipid metabolic imbalance in the blood serum were effectively recovered. The EFHS groups significantly ameliorated STZ-induced cognitive impairment in Y-maze, passive avoidance, and Morris water maze (MWM)5 tests. The EFHS groups showed significant improvement in the antioxidant and cholinergic systems of the brain tissue. In addition, EFHS had an excellent ameliorating effect on protein expression levels from the tau hyperphosphorylation pathways, such as phospho-c-Jun N-terminal kinases (p-JNK),6 phospho-tau (p-tau),7 and cleaved poly (ADP-ribose) polymerase (c-PARP).8 The main compounds of EFHS were identified as various phenolic compounds, including hibiscus acid, caffeoylquinic acid (CQA)9 isomers, and quercetin derivates. Therefore, EFHS containing various physiologically active materials can potentially be used for improving DM-induced cognitive impairment via its antioxidant activity, improvement of the cholinergic system, and hyperphosphorylation tau signaling. PMID- 29433252 TI - Effect of free and microencapsulated Lactococcus lactis on composition and rheological properties of Manchego-type cheeses during ripening. AB - This study aimed at determining the composition and rheology changes during the ripening (60days) of Manchego-type cheeses prepared with Lactococcus lactis subsp. lactis and Lactococcus lactis subsp. cremoris in the free status and microencapsulated in gellan gum. The composition indicated that microencapsulation had a greater influence than the period of ripening since discrepancies were statistically significant (p<0.05) regarding the levels of protein, moisture, total solids and pH between the two cheeses both at the beginning and end of the ripening. Both cheeses presented predominantly elastic characteristics (G'>G"). The moduli and the viscosity significantly increased with the presence of microcapsules and, ripening time. Conversely, the recovery percentages on the creep curve decreased in both cheeses with an increase in ripening as a result of the degradation of proteins. The retarded time ranged between 2.32*10-2 and 2.38*10-2s and the Jo values were 29 times higher than the Ji values in the studied cheeses, indicating the loss of elasticity of the cheeses as they ripen. PMID- 29433253 TI - beta-Carotene degradation kinetics as affected by fat crystal network and solid/liquid ratio. AB - The aim of this research was to study beta-carotene degradation kinetics into lipid systems containing different fat crystal networks in the presence of increasing liquid oil amounts. To this purpose, fat blends containing liquid saturated medium chain triacylglycerols (MCT) with increasing content of saturated monoglycerides (MG), tripalmitin (PPP) and tristearin (SSS) were added with 0.6mg/g beta-carotene. The fat crystal networks formed in the fat blends were characterized by using polarized light microscopy and synchrotron X-ray diffraction (XRD). In addition, beta-carotene degradation was monitored during storage in the dark at 20 degrees C. Results highlighted that fat crystallization could differently affect beta-carotene stability. In bulk SSS and PPP, beta carotene degradation proceeded at comparable rate, whereas when the saturated liquid oil MCT is included in the fat network, the rate of oxidation slightly decreased. Interestingly, the oxidation rate was not significantly affected by the solid/liquid ratio of the systems. A completely different behavior was observed in MG containing systems: the rate of beta-carotene oxidation was in every case significantly lower than that observed in SSS and PPP containing samples. Also in this case, the MG protective effect was independent on its content in the fat mixtures. PMID- 29433254 TI - Characterization of volatile profile from ten different varieties of Chinese jujubes by HS-SPME/GC-MS coupled with E-nose. AB - Volatile profile of ten different varieties of fresh jujubes was characterized by HS-SPME/GC-MS (headspace solid phase micro-extraction combined with gas chromatography-mass spectrometry) and E-nose (electronic nose). GC-MS results showed that a total of 51 aroma compounds were identified in jujubes, hexanoic acid, hexanal, (E)-2-hexenal, (Z)-2-heptenal, benzaldehyde and (E)-2-nonenal were the main aroma components with contributions that over 70%. Differentiation of jujube varieties was conducted by cluster analysis of GC-MS data and principal component analysis & linear discriminant analysis of E-nose data. Both results showed that jujubes could be mainly divided into two groups: group A (JZ, PDDZ, JSXZ and LWZZ) and group B (BZ, YZ, MZ, XZ and DZ). There were significant differences in contents of alcohols, acids and aromatic compounds between group A and B. GC-MS coupled with E-nose could be a fast and accurate method to identify the general flavor difference in different varieties of jujubes. PMID- 29433255 TI - Characterization of key aroma compounds in Gujinggong Chinese Baijiu by gas chromatography-olfactometry, quantitative measurements, and sensory evaluation. AB - One of famous Chinese Baijiu, Gujinggong (GJG) that is produced in Anhui province, belongs to the famous Luzhou-aroma type of Baijiu in regards of its unique flavor characteristics. However, its key aroma-impact volatiles have not been clearly characterized. In this study, a total of 60 aroma compounds of GJG were identified by GC-O and GC-MS, and 35 of them were further recognized as important aroma compounds owing to their OAVs>=1 and sensory evaluation. As a result, its aroma profile was successfully simulated by reconstitution of those 35 and other 11 aroma compounds based on their measured concentrations in the GJG. Moreover, omission test was applied to investigate the effects of the important aroma compounds on the whole aroma profile of GJG. In this context, 9 aroma compounds were confirmed as the key aroma compounds of GJG. PMID- 29433256 TI - Oak wood extracts applied to the grapevine. An alternative to obtain quality Garnacha wines. AB - Stomata in leaves regulate gas interchange and transpiration in the grapevine and through these pores both the penetration of aqueous solutions with nutrients as well as the excretion of products take place. The aim of this work was to study the influence of spraying the vineyard with toasted and untoasted oak extracts on the volatile composition and on the organoleptic quality of wine made from Garnacha grapes. The results were compared with a Garnacha control wine obtained with grapes sprayed with distilled water. The absorption of the compounds from the oak wood extracts was irregular and some of these compounds were modified by the yeast during fermentation so as to prevent fermentation problems. This was observed particularly in the case of furfural which were transformed into furfuryl alcohol by yeast in order to avoid irreversible cellular damage. On applying a discriminant analysis to the concentration of volatile compounds in the wines, the three treatments (control, toasted and untoasted oak extracts) were differentiate. The wine obtained from grapes treated with toasted oak extract showed a more intense wood aroma after 18months of bottle aging than the other wines. Likewise, spicy aromas were found to be more intense in the samples treated with some type of oak wood extracts. PMID- 29433257 TI - Incorporation of bentonite clay in cassava starch films for the reduction of water vapor permeability. AB - Complete factorial planning 23 was applied to identify the influence of the cassava starch(A), glycerol(B) and modified clay(C) content on the water vapor permeability(WVP) of the cassava starch films with the addition of bentonite clay as a filler, its surface was modified by ion exchange from cetyltrimethyl ammonium bromide. The films were characterized by X-ray diffraction(XRD), fourier transform by infrared radiation(FTIR), atomic force microscopy(AFM) and scanning electron microscopy(SEM). The factorial analysis suggested a mathematical model thats predicting the optimal condition of the minimization of WVP. The influence of each individual factor and interaction in the WVP was investigated by Pareto graph, response surface and the optimization was established by the desirability function. The sequence of the degree of statistical significance of the investigated effects on the WVP observed in the Pareto graph was C>B>A>BC>AC. Interactions AB, BC and AC showed that the modified clay was the factor of greater significance. PMID- 29433258 TI - HPLC-DAD-APCI/ESI-MSn analysis of carotenoids and alpha-tocopherol in Costa Rican Acrocomia aculeata fruits of varying maturity stages. AB - Carotenoids and tocopherols were characterised in the meso- and exocarp of wild growing Costa Rican Acrocomia aculeata fruits. Comprehensive profiling of these lipophilic micronutrients in fruits of three varying maturity stages was conducted for the first time. A method for the simultaneous extraction and quantitation of carotenoids and alpha-tocopherol was developed and validated. Detailed HPLC-DAD-APCI/ESI-MSn analyses enabled the identification of alpha tocopherol and 25 carotenoids. The latter comprised antheraxanthin, beta carotene, lutein, luteoxanthin, neoxanthin, phytoene, phytofluene, violaxanthin, zeaxanthin, and several (Z)-isomers of the aforementioned compounds. Quantitation by HPLC-DAD/FLD revealed total carotenoid concentrations of 872+/-178 and 3075+/ 407MUg/100g fresh weight in the meso- and exocarp of fully ripe fruits, respectively. In both fruit fractions, progressing maturation resulted in the accumulation of phytoene, phytofluene, (all-E)-zeaxanthin, (all-E) antheraxanthin, and (all-E)-violaxanthin. Carotenoid profiling was supported by multivariate data analysis. Carotenoid precursors and xanthophyll cycle pigments characterised Macauba fruits of full maturity. PMID- 29433259 TI - Chemical and sensory differences between high price and low price extra virgin olive oils. AB - The aim of the study was to identify new potential chemical markers of extra virgin olive oil (EVOO) quality by using a multicomponent analysis approach. Sixty-six EVOOs were purchased from the Italian market and classified according to their price as low price EVOOs (LEVOOs) and high price EVOOs (HEVOOs) costing 3.60-5.90euro/L and 7.49-29.80euro/L respectively. Sensory and chemical parameters strictly related to olive oil quality have been investigated, like volatile substances, polar phenolic substances, antioxidant activity, fatty acid composition, and alpha-tocopherol. Significant differences in terms of chemical composition and sensory features have been highlighted between the two EVOOs classes investigated, proving a generally lower level of quality of LEVOOs, clearly showed also by means of principal component analysis. Among the most interesting outcomes, R ratio (free tyrosol and hydroxytyrosol over total free and bound forms), measuring the extent of secoiridoids hydrolysis, resulted to be significantly higher in LEVOOs than in HEVOOs. Other key differences were found in the volatile substances composition, in the stearic acid percentage and in p coumaric acid content. PMID- 29433260 TI - Hydroxytyrosol: Bioavailability, toxicity, and clinical applications. AB - Many beneficial properties have been attributed to the Mediterranean diet. Over the years, researchers have attempted to learn which foods and which food components are responsible for good health. One of these components is hydroxytyrosol, an important phenolic compound present in olive oil. Hydroxytyrosol is a molecule of high interest to the pharmaceutical industry due to its anti-inflammatory and antimicrobial qualities its role against cardiovascular diseases and metabolic syndrome and for its neuroprotection, antitumour, and chemo modulation effects. The interest in this molecule has led to wide research on its biological activities, its beneficial effects in humans and how to synthetize new molecules from hydroxytyrosol. This review describes the vast range of information about hydroxytyrosol, focusing on its involvement in biological mechanisms and modulation effects on different pathologies. This review also serves to highlight the role of hydroxytyrosol as a nutraceutical and as a potential therapeutic agent. PMID- 29433261 TI - Spoilage potential of brettanomyces bruxellensis strains isolated from Italian wines. AB - Brettanomyces bruxellensis is an important wine spoilage agent. In this study a population of Brettanomyces strains isolated from Italian wines was thoroughly investigated to evaluate adaptability to wine conditions and spoilage potential. The presumptive isolates of Brettanomyces were identified at species level with 26S rRNA gene sequencing and species-specific PCR, and subsequently subjected to analysis of intra-species variability through the study of intron splice sites (ISS-PCR). Although, some strains were tracked in wines from different regions, extensive genetic biodiversity was observed within the B. bruxellensis population investigated. All strains were evaluated for their growth ability in the presence of ethanol, high sugar content, low pH, different temperatures and sulphur dioxide, using optical density and flow cytometry measurement. The ability of yeasts to produce ethyl phenols in red wines with different chemical compositions was evaluated by means of high performance liquid chromatography with electrochemical detection (HPLC-ECD). The results highlighted wide variability in B. bruxellensis in response to wine limiting factors and in terms of the accumulation of ethyl phenols. As regards this last aspect, the differences found among strains were closely related to chemical composition of wine and strain resistance to environmental stress factors, making a priori evaluation of risk of wine alteration quite difficult. These results suggest that strategies for the control of Brettanomyces should be tailored on the basis of strain distribution and wine characteristics. PMID- 29433262 TI - The influence of pH and enzyme cross-linking on protein delivery properties of WPI-beet pectin complexes. AB - The incorporation of bioactive proteins and peptides into food is associated with the loss of bioactivity due to deactivation in complex food matrices and in digestion systems. In this study, two different types of protein carriers, i.e. biopolymer complexation and complex coacervation were fabricated using whey protein isolation (WPI, 6wt%) and beet pectin (BP, 1.25 and 1.00wt%) at pH5.5 and 3.5, respectively. The release of the encapsulated FITC-BSA, a model bioactive protein, in both carriers in the absence and presence of laccase was investigated at both pH7.0 and 4.0. Release of FITC-BSA from both lyophilized WPI-beet pectin biopolymer complexation and complex coacervation were biphasic with an initial burst release followed by a slower release phase. The addition of laccase in biopolymer complexation increased the loading efficiency from 44.95% to 52.15% and slowed down the burst release of FITC-BSA but did change the biphasic release pattern. Laccase-cross linked WPI (6wt%)-BP (1wt%) complex coacervation had highest FITC-BSA loading efficiency (96.90%). The release of the embedded FITC BSA in this carrier at both pH4 and 7 was in a gradual manner and the profile can be fit to zero order kinetics over the 72h study period suggesting enzymatically reinforced complex coacervation between the protein and the negatively charged beet pectin can restrain the burst release of FITC-BSA. These results indicate that laccase cross-linked WPI-beet pectin complex coacervation can be a good carrier system for delivering hydrophilic bioactive proteins or peptides successfully with enhanced loading parameters and sustained release profiles. PMID- 29433263 TI - Novel diagnostic tools for Asian (Apis cerana) and European (Apis mellifera) honey authentication. AB - Honey can be produced by different species of honeybees, with two being of economic importance due to their use in apiculture, namely Apis mellifera (known as European honeybee) and Apis cerana (known as Asian honeybee). Due to the decline of the wild populations of the Asian honeybee, this honey generally attains much higher market value, being prone to adulteration. This work aims at proposing new tools, based on the use of molecular markers, for the entomological authentication of honey. To this end, new species-specific primers were designed targeting the tRNAleu-cox2 intergenic region and allowing the detection of A. cerana DNA by qualitative polymerase chain reaction (PCR). Additionally, a novel real-time PCR method with high resolution melting analysis was developed to target the 16S rRNA gene of both bee species, allowing their discrimination in different clusters. The proposed methodologies were further applied with success in the authentication of Asian and European honey samples by the identification of honeybee DNA, demonstrating the usefulness of these simple and cost-effective new approaches. PMID- 29433264 TI - Dairy curd coagulated by a plant extract of Calotropis procera: Role of fat structure on the chemical and textural characteristics. AB - Milk is often subjected to technological treatments which have impacts on the structure of milk constituents and the characteristics of rennet curds. In this paper, the influence of the dairy fat structure on the biochemical and textural characteristics of curds coagulated by an extract of Calotropis procera leaves was studied. Standardized milks were reconstituted with the same contents in protein (35g.kg-1) and fat (35g.kg-1) but with different structures of fat i.e. homogenized anhydrous milk fat (HAMF), homogenized cream (HC) and non-homogenized cream (NHC). As expected, the size distributions of fat globules in the different milks were different. After their coagulations by the plant extract, the physico chemical characteristics of the curds and respective wheys were determined. No difference was observed in the coagulation time between the three milks but the whey removed more quickly from HAMF and HC curds than NHC-curd. The biochemical analyses of curds revealed a lower content in dry matter and fat in the NHC-curd compared to HAMF- and HC-curds. Otherwise, the NHC-whey exhibited the highest amount of fat. Observations by confocal microscopy showed that the fat globules were homogenously distributed and well trapped in the protein networks of HAMF- and HC-curds. In the NHC-curd, the fat globules were located in whey pockets, with less connectivity with the protein network. The textural analysis showed that the NHC-curd was more elastic, soft and adhesive than HAMF- and HC-curds. Homogenization significantly reduced the loss of fat during cheese manufacturing and conferred specific textural characteristics to the curds coagulated by an extract of Calotropis procera. PMID- 29433265 TI - Effect of high-pressure treatment on taste and metabolite profiles of ducks with two different vinasse-curing processes. AB - The effect of high-pressure (HP) (0.1, 150 and 300MPa, 15min) on taste profiles of vinasse-cured ducks was investigated; the metabolite profiles were determined using 1H NMR. HP at 150MPa increased the taste intensity of products compared with the controls, while HP at 300MPa did not further improve their taste compared with 150MPa treated samples. The metabonome of vinasse-cured ducks was dominated by 27 metabolites. HP increased amino acids, glucose, alkaloids and organic acids, but decreased inosine monophosphate and its derivatives, compared with the controls. The increments of metabolites in vinasse-dry-cured duck were higher than those in vinasse-wet-cured duck. The change of metabolites could be related to the enzyme activity, the degradations of proteins, sugars and nucleotides, and the permeation from vinasse-curing agents to duck meat. These findings suggest that 150MPa treatment was effective to improve the taste of vinasse-cured duck. PMID- 29433266 TI - Flavor profiling of apple ciders from the UK and Scandinavian region. AB - The aim of this study was to characterize the flavor profiles of 14 commercial apple ciders from the United Kingdom and Scandinavian region. The flavor properties were established by sensory profiling and analysis of volatile and non volatile components, including titratable acidity, pH, residual sugars and organic acids. A total of 72 volatile compounds were identified in the 14 apple ciders using dynamic headspace sampling (DHS) coupled to gas chromatography-mass spectrometry (GC/MS). The main volatile compounds found in apple ciders were esters and higher alcohols, followed by aldehydes and fatty acids. Sensory characterizations of the aroma and taste of apple ciders were carried out by a trained sensory panel using descriptive analysis with 23 sensory attributes. The attributes apple, cooked apple, yeasty, sweet and sour were the most predominant sensory descriptors used to describe the similarities and differences in the samples. Principal component analysis (PCA) showed that floral and fruity (fresh apple, banana and pear) odors were highly associated with sweet taste and opposed to the more complex aroma attributes (yeasty, lactic, chemical, mouldy, black pepper and earthy) and sour taste. Most of the UK apple ciders were characterized by these complex odors and taste notes sour, astringent and bitter, whereas ciders from the Scandinavian region had diverse sensory profiles. Partial least squares regression (PLS) based on the sensory and chemical data was able to cluster the ciders according to differences in production methods (oak-aged or spontaneous fermentation; controlled malolactic fermentation; industrial production with flavor modifications). Moreover, this study also suggested that ciders with marked levels of acetate esters were characterized by cooked/fresh apple, citrus and tropical fruit odors. PMID- 29433267 TI - Using Check-All-That-Apply (CATA) method for determining product temperature dependent sensory-attribute variations: A case study of cooked rice. AB - Temperatures of most hot or cold meal items change over the period of consumption, possibly influencing sensory perception of those items. Unlike temporal variations in sensory attributes, product temperature-induced variations have not received much attention. Using a Check-All-That-Apply (CATA) method, this study aimed to characterize variations in sensory attributes over a wide range of temperatures at which hot or cold foods and beverages may be consumed. Cooked milled rice, typically consumed at temperatures between 70 and 30 degrees C in many rice-eating countries, was used as a target sample in this study. Two brands of long-grain milled rice were cooked and randomly presented at 70, 60, 50, 40, and 30 degrees C. Thirty-five CATA terms for cooked milled rice were generated. Eighty-eight untrained panelists were asked to quickly select all the CATA terms that they considered appropriate to characterize sensory attributes of cooked rice samples presented at each temperature. Proportions of selection by panelists for 13 attributes significantly differed among the five temperature conditions. "Product temperature-dependent sensory-attribute variations" differed with two brands of milled rice grains. Such variations in sensory attributes, resulted from both product temperature and rice brand, were more pronounced among panelists who more frequently consumed rice. In conclusion, the CATA method can be useful for characterizing "product temperature-dependent sensory attribute variations" in cooked milled-rice samples. Further study is needed to examine whether the CATA method is also effective in capturing "product temperature dependent sensory-attribute variations" in other hot or cold foods and beverages. PMID- 29433268 TI - Dynamic correlations between microbiota succession and flavor development involved in the ripening of Kazak artisanal cheese. AB - Cheese is a typical handcrafted fermented food in Kazak minority from the Uighur Autonomy Region in China. The ripening process of the cheese is crucial for quality and flavor. The aim of this study was to gain a deeper knowledge on the bacterial and fungal community diversity at different time points during the post ripening of the cheese and to understand the relationship between bacterial and fungal profiles and the chemical components including amino acids, fatty acids and volatile compounds related the cheese flavor. Cheese samples were collected from days 5, 10, 15, 20 and 30 after the starting point of post-ripening. The bacterial and fungal compositions were analyzed with next generation sequencing targeting the 16S rDNA loci for bacteria and ITS loci for fungi. The amino acids contents were analyzed by reversed phase high performance liquid chromatography combined with UV detection. The fatty acids and the volatile components were analyzed by Solid Phase Micro Extraction followed by Gas Chromatography/Mass spectrometry. We found that Lactobacillus, Streptococcus, Kluyveromyces and Torulaspora were the dominant cheese's population. Bidirectional orthogonal partial least squares (O2PLS) based correlation analysis between microbiota succession and flavor dynamics showed that bacteria made more contributions to flavor formation than fungi. Eight bacteria genera and seven fungi genera were determined as functional core microbiota for the flavor production based on their dominance and functionality in microbial community. This study provided a comprehensive picture of the dynamic changes of microbiota profiles through the post-ripening process. The elucidation of the causal relationship between microbiota and the flavor components has advanced our understanding of the mechanism underlying the cheese development. PMID- 29433269 TI - Genetic relatedness, antimicrobial resistance and biofilm formation of Salmonella isolated from naturally contaminated poultry and their processing environment in northern Malaysia. AB - We investigated the genetic relatedness, antibiotic resistance and biofilm producing ability of 114 strains of Salmonella, belonged to three serotypes (Corvallis, Brancaster and Albany), isolated from naturally contaminated poultry and their environment in wet markets and smale-scale processing plant from northern Malaysia. Pulsed-field gel electrophoresis revealed that Salmonella strains isolated from various wet markets were clonally related, suggesting the widespread dissemination of these three serotypes in northern Malaysia. All except one strain of Salmonella were resistant to more than two classes of antibiotics, hence regarded as multidrug resistant (MDR). Resistance to sulphonamide (96.5%), ampicillin (89.5%), tetracycline (85.1%), chloramphenicol (75.4%), trimethoprim (68.4%), trimethoprim-sulfamethoxazole (67.5%), streptomycin (58.8%) and nalidixic acid (44.4%) were observed. Resistance determinants, floR, cmlA, tetA, tetB, tetG, temB, blaPSE-1, sul1, sul2, qnrA, qnrS, strA and aadA were detected by PCR among MDR Salmonella strains. Seventy six strains (66.7%) harboured class-I integrons. The gene cassettes identified were dfrA1, dfrA12, aadA2 and an open reading frame orfC with unknown function. All Salmonella strains produced biofilm and 69.3% of them were strong biofilm producers. Our findings suggested that most likely, persistent Salmonella colonises various sites in the processing environment by producing biofilm, which leads to their widespread dissemination in wet markets located in northern Malaysia. PMID- 29433270 TI - Comprehensive characterization of phenolic and other polar compounds in the seed and seed coat of avocado by HPLC-DAD-ESI-QTOF-MS. AB - Avocado seed and seed coat are important by-products from avocado industrialization, with important functional properties. The aim of the present study was to determine the phenolic profile and other polar compounds of avocado seed and seed coat using accelerated solvent extraction (ASE) and liquid chromatography coupled to Ultra-High-Definition Accurate-Mass Q-TOF. In this research 84 compounds were identified, within eight subclass group, among these 45 phenolic compounds were identified for first time in avocado seed. Condensed tannins, phenolic acids and flavonoids were the most representative groups in both samples. As far as we are concerned, this is the first time that avocado seed coat has been studied regarding its phenolic compounds using such a powerful instrumental technique. In addition, the radical-scavenging activities were analysed in order to estimate the antioxidant potential of extracts. These results point out that avocado seed and seed coat constitute a source of bioactive ingredients for its use in the food, cosmetic or pharmaceutical sector. PMID- 29433271 TI - Evolution of food antioxidants as a core topic of food science for a century. AB - Antioxidants are among the most studied topics both in the area of food science and nutrition. Antioxidants were firstly used as just a food preservative, then it was realized that they inhibited the oxidation processes not only in foods but also in human metabolism. Then, they gained the spotlight with their important roles both in foods and in human body. Consequently, significant number of research articles focusing on the antioxidant content of different foods, analytical methods for better estimation and measurement of the antioxidant capacity of foods have been publishing for years. In addition, there is a growing interest among the food scientists in improving the knowledge on the physiological effects of antioxidants in the human body. This review provides a historical overview about antioxidants covering their occurrence and roles in various foods, analytical methods for the determination of their antioxidant capacity, and their physiological effects. PMID- 29433272 TI - Capturing consumer perception of vegetable freshness in a simulated real-life taste situation. AB - Consumer testing in re-created purchase or consumption contexts may produce results with a higher external validity than laboratory testing and be a valid alternative to consumer testing in real-life contexts. Hence, the present study evaluates the utility of a novel immersive approach in sensory consumer testing. An immersive multisensory room was designed to reproduce consumption conditions close to real life, with large wall screen projections, audio and olfactory stimuli and furniture consistent with the video scenario. Overall liking and perceived freshness of two vegetable products (salad tomato and wild rocket) at different storage time were evaluated by a group of volunteers, regular consumers of the products. Evaluations were performed both in a immersive environment setting - the scenario was the dining room of a holiday farm overlooking a patio and the countryside - and in a traditional sensory lab setting, as a control. The magnitude of liking was higher when evaluations were performed in the immersive environment setting than in the traditional lab setting. However, the discrimination efficacy for freshness and liking of stored and un-stored vegetables was reduced in the immersive environment with respect to the control lab. Additional research, aimed at exploring other products and other consumption or purchase immersive scenarios, will further clarify whether these findings are product-dependent or determined by the contingent immersive situation. PMID- 29433273 TI - Transport of cellular water during drying: An understanding of cell rupturing mechanism in apple tissue. AB - The cellular structure of food tissue is complex, and it is difficult to understand the morphological changes during drying. Three different cellular environments, namely intracellular space, intercellular space, and cell wall in food tissue contain a different proportion of water. It is crucial to understand the moisture migration mechanisms from different cellular environments during drying for improving energy efficiency and for ensuring better quality dried foods. Due to the lack of sufficient understanding of transport mechanisms of different types of water, existing mathematical models for food drying have been developed without considering these components separately. Therefore, the main aim of the present work is to investigate the transport mechanisms of cellular water during drying. Experiments were performed using 1H NMR T2 relaxometry to investigate the proportion of different types of water at various stages of drying, taking apple as a sample. It was found that intercellular water migrates from intracellular region to the intercellular spaces mainly through rupturing of the cell membranes during drying of apple tissue. The cell membrane ruptures take place at various stages of drying rather than collapsing at one time. Interestingly, the trends of rupturing the cell membranes follow mostly a uniform pattern as rupturing takes places almost at a regular interval. The results were compared with the rupturing mechanism in the low porous material (potato) reported in authors' previous study. It was also observed that most of the cell membranes of potato tissue rupture at middle stages of drying while apple tissues rapture mostly uniformly. The penetration rate of heat energy with the pressure gradient between intracellular and intercellular environments are the predominant factors that cause the rupturing the cell membranes. PMID- 29433274 TI - The effects of microfluidization on rheological and textural properties of gluten free corn breads. AB - This study presents the potential of microfluidization as a value adding process to corn gluten meal (CGM), which is often used as animal feed and is underutilized in food industry. In this study, we aimed to improve water holding ability of corn gluten and to investigate possibility of using this zein-rich byproduct as the main ingredient in gluten-free bread formulations. For this reason, microfluidization as a milling process for CGM, and its effects on rheological and textural properties of gluten-free bread formulations were investigated. In addition, the effects of pH modification and hydrocolloids were analyzed. Microfluidization led to a higher surface area by disintegrating the large CGM molecules, and the structure became compatible to be used in gluten free bread formulations by overcoming hydrophobic nature. However, structural deformations were detected with pH modifications. The linear viscoelastic region of dough was observed at strains lower than 0.5%. For all formulations, elastic moduli (G') were higher than viscous moduli (G") indicating solid-like behavior. The addition of HPMC and guar resulted in higher moduli values. Microfluidization and pH modifications provided brighter color by revealing lutein and zeaxanthin due to decreased particle size. Texture profile showed that microfluidization and hydrocolloids decreased hardness, increased springiness and cohesiveness, which are desired characteristics for bread. Lastly, the addition of hydrocolloids led to an increase in specific volume by providing gas retention within the structure. HPMC provided 1.23-1.62 times bigger samples than control samples while it was only 1.02-1.12 times bigger for samples with guar according to specific volume analysis. PMID- 29433275 TI - Influence of carcass weight on meat quality of commercial feedlot steers with similar feedlot, slaughter and post-mortem management. AB - The effects of beef carcass weight on muscle pH/temperature profile and selected meat quality attributes were evaluated. Twenty-six carcasses from light (<=260kg, n=15) and heavy (>=290kg, n=11) feedlot steers were randomly allocated and stimulated with low voltage electrical stimulation (LVES) for 30s at 7min post mortem (pm). Quality evaluations were carried out on samples from the Longissimus et lumborum (LL) muscle from the left side of each carcass. Heavier carcasses showed faster pH decline and slower (P<0.05) temperature decline at 45min, 3, 6, 12 and 24h pm. Heavier carcasses passed through the heat shortening window (i.e. at pH6, temperature was >35 degrees C) but there was no sign of sarcomere shortening in any carcass. Significantly lower (P<0.05) shear force values were recorded in the heavier carcasses at 3days pm but at 14days pm, heavier carcasses had numerically lower but not significantly different shear force. Heavier carcasses produced numerically higher but not significant (P>0.05) drip loss at 3 and 14days pm as well as higher L* (meat lightness) (P<0.05) and C* (chroma) (P<0.05) values early (2days) pm. However, at 14days pm, there were no significant differences between the light and heavy carcasses in terms of L* and C*. No significant difference was observed between heavy and light carcasses in terms of H* at 2 and 14days pm. The study showed that heavier carcasses which favor slaughter house pricing can be produced and processed alongside lighter carcasses without significant detrimental effects on meat quality by using low voltage electrical stimulation (LVES). PMID- 29433276 TI - Interfacial activity and emulsifying behaviour of inclusion complexes between helical polysaccharides and flavouring molecules resulting from non-covalent interactions. AB - This study deals with the fabrication of inclusion complexes starting from a cross coupling of seven helical polysaccharides (host) and six flavouring agents (guest). Neither of the substrates is considered as an emulsifier when studied alone. Due to a complexation mechanism, the presence of intermolecular hydrogen bonds between substrates was highlighted by infra-red spectroscopy and 13C NMR. In addition, depending on the polysaccharide used, the guest molecule could be preferentially located either inside or in the interstitial spaces of the helix. In a comparison between raw substrates, the inclusion complexes obtained presented the unique interfacial activity of decreasing surface tension values (gamma) and, in some cases, their behaviour in water was similar to that of regular emulsifiers due to the presence of a critical aggregation concentration (CAC). Substrate concentrations and the ratios between them were the main parameters investigated in this study, which focused on the two inclusion complexes: vanillin/amylose and vanillin/iota-carrageenan. The first decreased gamma values by as much as 53mN/m with a double transition, whereas the second could cause gamma fall to 36mN/m with a regular break. In addition, these systems were able to stabilize foams for up to 60min, which confirmed their unique emulsifying properties. PMID- 29433277 TI - Composition of black soldier fly prepupae and systematic approaches for extraction and fractionation of proteins, lipids and chitin. AB - Black soldier fly (BSF, Hermetia illucens) constitutes an economic way to convert residual biomasses into a valuable source of biomolecules, such as proteins, lipids and chitin. The present investigation was undertaken to evaluate the feasibility of applying different extraction protocols, either chemical extractions or enzymatic assisted extraction, to recover pure fat, protein and chitin fractions. First, exact proximate composition, total amino acids, fatty acids profile, and N-acetylglucosamine content of the prepupae samples were determined. BSF prepupae biomass contained, expressed on dry weight, 32% proteins, 37% lipids, 19% minerals, 9% chitin. The lipid fraction was easily recovered by organic solvents, while the most challenging issue was the separation of protein from chitin. The best separation was obtained by alkali extraction of proteins (96% of protein recovered) albeit with loss in their integrity as indicated by the measurement of the degree of hydrolysis with the o phthaldialdehyde method. To avoid protein damage in alkali media, a stepwise protein extraction adopting milder conditions was also explored based on Osborne fractionation method, allowing the recovery of >85% of BSF high purity and high quality proteins, and the obtainment of chitin-enriched fraction as well. The possibility of using an enzymatic assisted extraction of proteins was also explored, obtaining a maximum nitrogen solubilisation in the best case (with Bacillus licheniformis protease) of about 60%. In this latter case, the chitin fraction obtained also had a significant residual protein content. PMID- 29433278 TI - Interactions and phase behaviors in mixed solutions of kappa-carrageenan and myofibrillar protein extracted from Alaska Pollock surimi. AB - In the present work, we provide insight into electrostatic interactions and phase behaviors in mixtures of myofibrillar protein (MP) and kappa-carrageenan (KC) of various pHs (8.0-3.0) and biopolymer weight ratios [R, from 1:1 to 20:1; total concentration=0.05% (w/w)] through turbidimetric analysis, dynamic light scattering (DLS) and zeta potential analysis, and optical microscopy. At R=1: 1, critical pH values (i.e., pHc, pHPhi1, and pHPhi2), which indicate phase transitions interrelated to the formation of soluble or insoluble MP-KC complexes, were observed at pH7.6, 6.8, and 3.6, respectively. As the ratio increased, the pHmax shifted from 4.9 to 5.8. A similar trend was observed for the isoelectric point of MP-KC mixtures, as determined by zeta potential measurements. The maximum interaction indicated by the highest turbidity occurred at pHmax=5.3, at a ratio of 5:1, whereas pHc remained constant during acidification. The changes in electrostatic interactions and transformations of phase behaviors accompanying the complex formation and disassociation processes were further supported by particle size distribution analysis and optical microscopic observations of MP-KC mixtures (R=1:1) at different pH values. This work fills the previous lack of studies on phase behaviors of surimi protein and colloidal polysaccharide in liquid system, and lay the foundation to provide a new way to solve problems of interactions between protein and polysaccharide during the processing of surimi products. PMID- 29433279 TI - Characterization of aroma-active compounds in Chinese quince (Pseudocydonia sinensis Schneid) by aroma dilution analyses. AB - Aroma-active compounds in the peel and pulp of Chinese quince fruits were extracted by high-vacuum distillation (HVD) and headspace solid-phase microextraction (HS-SPME) methods and identified by gas chromatography olfactometry (GC-O) combined with aroma dilution analyses. Ethyl 2 methylpropanoate, ethyl (E)-2-butenoate, ethyl 2-methylbutanoate, methional, (Z) 3-hexenyl acetate, beta-ionone, ethyl nonanoate, and gamma-decalactone were detected as the potent aroma-active compounds (log3FD factors>=5) in the peel of Chinese quince, while hexanal, (Z)-3-hexenal, and (Z)-3-hexenol, which have a green odor note, were potent aroma-active compounds with high log3FD factors (>=3) in the pulp of Chinese quince. In particular, ethyl propanoate, ethyl (E)-2 butenoate, and (Z)-3-hexenyl acetate-which had sweet and fruity aroma notes with relatively high FD factors-were detected in the samples extracted by HS-SPME. PMID- 29433280 TI - Contribution of specific amino acid and secondary structure to the antioxidant property of corn gluten proteins. AB - The composition, structure, and proper positioning of amino acid in a peptide are closely related to its antioxidant activity. In this study, we purified antioxidant peptides from corn protein hydrolysates (CPH) and identified novel antioxidant peptides from fraction CPH2-III as Ala-Gly-Ile/Leu-Pro-Met (AGI/LPM; 487.62Da) and His-Ala-Ile/Leu-Gly-Ala (HAI/LGA; 467.53Da). AGLPM and HALGA exhibited better oxygen radical absorbance capacities than AGIPM and HAIGA did (P<0.05), as assessed using HepG2 cells with the cellular antioxidant activity assay (CAA) and electron spin resonance (ESR) spectroscopy. Finally, the secondary structure was determined using circular dichroism (CD). ESR showed that the AGLPM and HALGA peptides had the strongest abilities to scavenge hydroxyl radicals, by 79.41+/-1.41% and 75.16+/-2.26%, respectively. Thus, corn gluten meal could be used as a potential source of antioxidant peptides for food applications. Additionally, the amino acid Leu compared with Ile may be a critical factor contributing to strong antioxidant activity than the Ile in the peptide sequence (not C-terminus or N-terminus) and CD showed that the lower alpha-helix and random coil are the main causes. PMID- 29433281 TI - Inactivation kinetics, structural, and morphological modification of mango soluble acid invertase by high pressure processing combined with mild temperatures. AB - The activity, structure and morphology of mango soluble acid invertase (SAI) were investigated after high pressure processing (HPP) combined with mild temperature at 50-600MPa and 40-50 degrees C. The activity of mango SAI was efficiently reduced by HPP at 50MPa/45 and 50 degrees C, or 600MPa/40, 45 and 50 degrees C, while it was increased by 10-30% after HPP at 50-200MPa/40 degrees C. Significant antagonistic effect of pressure and temperature on the activity of SAI was observed at 50-400MPa/50 degrees C. The secondary structure of SAI was not influenced by HPP. However, its tertiary structure was modified by HPP, and severer modification occurred with higher pressure, higher temperature, and longer treatment time. Results of atomic force microscope suggested that HPP at 400MPa/50 degrees C for 2.5min induced dissociation of SAI, and HPP at 600MPa/50 degrees C for 30min resulted aggregation of SAI. PMID- 29433282 TI - High isostatic pressure and thermal processing of acai fruit (Euterpe oleracea Martius): Effect on pulp color and inactivation of peroxidase and polyphenol oxidase. AB - The present study evaluated the effect of high isostatic pressure (HIP) on the activity of peroxidase (POD) and polyphenol oxidase (PPO) from acai. Acai pulp was submitted to several combinations of pressure (400, 500, 600MPa), temperature (25 and 65 degrees C) for 5 and 15min. The combined effect of HIP technology and high temperatures (690MPa by 2 and 5min at 80 degrees C) was also investigated and compared to the conventional thermal treatment (85 degrees C/1min). POD and PPO enzyme activity and instrumental color were examined after processing and after 24h of refrigerated storage. Results showed stability of POD for all pressures at 25 degrees C, which proved to be heat-resistant and baro-resistant at 65 degrees C. For PPO, the inactivation at 65 degrees C was 71.7% for 600MPa after 15min. In general, the increase in temperature from 25 degrees C to 65 degrees C reduced the PPO relative activity with no changes in color. Although the thermal treatment and the HIP (690MPa) along with high temperature (80 degrees C) reduced the PPO relative activity, and relevant darkening was observed in the processed samples. Thus, it can be concluded that POD is more baro resistant than PPO in acai pulp subjected to the same HIP processing conditions and processing at 600MPa/65 degrees C for 5min may be an effective alternative for thermal pasteurization treatments. PMID- 29433283 TI - Potential application of lipid organogels for food industry. AB - Controversial issues regarding the role of trans fatty acids in food have led to progressive changes in the legislation of several countries to include more information for consumers. In response, the industries decided to gradually replace trans fat in various products with the development of fatty bases of equivalent functionality and economic viability to partially hydrogenated fats, causing, however, a substantial increase in the content of saturated fatty acids in foods. Today, the lipid science aims to define alternatives to a problem that is widely discussed by health organizations worldwide: limit the saturated fat content in food available to the population. In this context, organogels have been indicated as a viable alternative to obtain semi-solid fats with reduced content of saturated fatty acids and compatible properties for food application. The objective of this review was to present the studies that address the lipid organogels as an alternative for food application. PMID- 29433284 TI - Stability of the potent antioxidant peptide SNAAC identified from Spanish dry cured ham. AB - Antioxidant peptides positively regulate oxidative stress in the human body as well as delay, retard or prevent protein and lipid oxidation in food products. Spanish dry-cured ham has been reported as a good source of bioactive peptides, being SNAAC the most active antioxidant peptide identified to date. In this work, the stability of this peptide against in vitro digestion, heat treatments and different salt concentrations was evaluated using three methods for measuring antioxidant activity: beta-carotene bleaching assay, ABTS radical scavenging capacity and ORAC assay. The results evidenced a marked decrease in the antioxidant activity of SNAAC after gastrointestinal digestion, and the MALDI-ToF MS analysis revealed the degradation of the peptide after the process, the generation of the fragment SNAA and the presence of a peptide dimer throughout the in vitro digestion. On the other hand, the peptide SNAAC showed good heat stability after exposure to different temperatures (50 degrees C, 72 degrees C, and 90 degrees C), but its antioxidant activity evaluated by ORAC assay decreased substantially when exposed to 100 degrees C as compared with the control at 37 degrees C. SNAAC remained stable in the presence of salt at concentrations ranging from 0 to 8% NaCl as well as it was able to inhibit about 40% of lipid oxidation in an emulsion system. These results reported the stability of the antioxidant peptide SNAAC to several conditions used in meat industry for the processing of dry-cured hams and ham-derived products and its effectiveness to partially prevent the lipid oxidation in these products. However, some strategies would be needed in order to increase the stability of the peptide during gastrointestinal digestion and thus improve its bioavailability to be used as functional food ingredient. PMID- 29433285 TI - Sampling methods for the study of volatile profile of PDO wine vinegars. A comparison using multivariate data analysis. AB - High-quality wine vinegars have been registered in Spain under protected designation of origin (PDO): "Vinagre de Jerez", "Vinagre de Condado de Huelva" and "Vinagre de Montilla-Moriles". The raw material, production and aging processes determine their quality and their aromatic composition. Vinegar volatile profile is usually analyzed by gas chromatography-mass spectrometry (GC MS), being necessary a previous extraction step. Thus, three different sampling methods (Headspace solid phase microextraction "HS-SPME", Headspace stir bar sorptive extraction "HSSE" and Dynamic headspace extraction "DHS") were studied for the analysis of the volatile composition of Spanish PDO wine vinegars. Multivariate curve resolution (MCR) was used to solve chromatographic problems, improving the results obtained. Principal component analysis (PCA) showed that not all the sampling methods were equally suitable for the characterization and differentiation between PDOs and categories, being HSSE the technique that made able the best vinegar characterization. PMID- 29433286 TI - Expression of genes associated with stress conditions by Listeria monocytogenes in interaction with nisin producer Lactococcus lactis. AB - The use of nisin producers in foods is considered a mitigation strategy to control foodborne pathogens growth, such as Listeria monocytogenes, due to the production of this bacteriocin in situ. However, when the bacteriocin does not reach an adequate concentration, the target bacteria can develop a cross-response to different stress conditions in food, such as acid, thermal and osmotic. This study aimed to evaluate the interaction of a nisin-producing strain of Lactococcus lactis DY-13 and L. monocytogenes in BHI and skim milk, and its influence on general (sigB), acid (gadD2), thermal (groEL) and osmotic (gbu) stress-related genes of the pathogen. L. monocytogenes populations decreased approximately 2log in BHI and 1log in milk after 24h in co-culture with the nisin producer L. lactis, coherent with the increasing expression of nisK. Expression of stress-related genes by L. monocytogenes presented lower oscillation in BHI than in milk, indicating its better ability to survive in milk, despite the higher nisin production. Stress-related genes presented a varied expression by L. monocytogenes in the tested conditions: sigB expression remained stable or reduced over time; gadD2 presented high expression in milk; groEL presented low expression in BHI when compared to milk, trending to decrease overtime; gbu expression in milk after 24h was lower than in BHI. The presented study demonstrated the growth of a nisin producer L. lactis can affect the expression of stress-related genes by L. monocytogenes, and understating these mechanisms is crucial to enhance the conservation methods employed in foods. PMID- 29433287 TI - Experimental study of physical and rheological properties of grape juice using different temperatures and concentrations. Part II: Merlot. AB - The effect of the temperature and concentration on rheological behavior of Merlot juice concentrates was assessed using a rheometer over a wide range of temperature (1-66 degrees C) and concentrations (13.6-45.0Brix) at shear rates of 0.84-212.1 1/s. The Ostwald-De Waele was the best rheological model fitted the data (R2=0.99967 and relative error=7.99%). The consistency levels were significantly reduced with the increase of temperature and increased with the increase of the concentrations, ranging from 0.1766 (13.6Brix at 66 degrees C) to 19.1140Pa.sn (45.0Brix at 1 degrees C). The flow behavior index presented no up or downward pattern when the temperatures were compared. The flow activation energy ranged from 13.95 (45.0Brix) to 24.88KJ/mol (21.0Brix) with a R2=0.9822 and 0.9812, respectively. Density and specific heat were influenced by both temperature and concentration; however, thermal conductivity was only influenced by concentration and temperature in two cases (13.6 and 29.0Brix). The data showed the potential use of Merlot juice concentrates as wine chaptalization agent in winemaking. PMID- 29433288 TI - Impact of oil droplet concentration on the optical, rheological, and stability characteristics of O/W emulsions stabilized with plant-based surfactant: Potential application as non-dairy creamers. AB - The development of plant-based foods and beverages is becoming increasingly popular because of growing consumer concerns about perceived ethical, health, and environmental issues. The current study examined the influence of oil droplet concentration on the physicochemical properties of oil-in-water (O/W) emulsions stabilized with a plant-based surfactant. Emulsions were utilized as model creamers, which consisted of medium chain triglycerides (MCT) as the oil phase and quillaja saponin as a plant-based surfactant. The optical, rheological and stability properties of these model creamers were measured at varied oil content from 0 to 15%, at a constant surfactant-to-oil ratio (1:15). The model creamers had an appearance similar to that of commercial non-dairy creamers, and their whiteness increased with increasing droplet concentration due to enhanced light scattering: L* from 77 to 91 for creamer and L* from 5 to 55 for white coffee. The quillaja saponin-coated lipid droplets were stable to aggregation and gravitational separation when added to hot acidic coffee solutions (85 degrees C, pH4.9), which was attributed to strong steric and electrostatic repulsions. The apparent viscosity of the model creamers increased with increasing droplet concentration due to increased frictional losses associated with the presence of the droplets. This study provides valuable information into the impact of oil content on the physicochemical properties of liquid creamers using plant based surfactants, which is important for the formulation of healthier products. PMID- 29433289 TI - Migration of antioxidants from polylactic acid films, a parameter estimation approach: Part I - A model including convective mass transfer coefficient. AB - A two-step solution based on the boundary conditions of Crank's equations for mass transfer in a film was developed. Three driving factors, the diffusion (D), partition (Kp,f) and convective mass transfer coefficients (h), govern the sorption and/or desorption kinetics of migrants from polymer films. These three parameters were simultaneously estimated. They provide in-depth insight into the physics of a migration process. The first step was used to find the combination of D, Kp,f and h that minimized the sums of squared errors (SSE) between the predicted and actual results. In step 2, an ordinary least square (OLS) estimation was performed by using the proposed analytical solution containing D, Kp,f and h. Three selected migration studies of PLA/antioxidant-based films were used to demonstrate the use of this two-step solution. Additional parameter estimation approaches such as sequential and bootstrap were also performed to acquire a better knowledge about the kinetics of migration. The proposed model successfully provided the initial guesses for D, Kp,f and h. The h value was determined without performing a specific experiment for it. By determining h together with D, under or overestimation issues pertaining to a migration process can be avoided since these two parameters are correlated. PMID- 29433290 TI - Salmonella, Escherichia coli and Enterobacteriaceae in the peanut supply chain: From farm to table. AB - Due to recent foodborne outbreaks, peanuts have been considered a potential risk for Salmonella transmission. For this reason, the aim of this study was to determine the prevalence and contamination load of Salmonella, Escherichia coli and Enterobacteriaceae throughout the peanut supply chain in Brazil. Samples of peanuts and peanut-containing processed products from post-harvest (n=129), secondary processing (n=185) and retail market (n=100) were analyzed. The results showed high Enterobacteriaceae counts in the post-harvest samples. At the end of the secondary processing, 16% of the samples remained contaminated by this group of microorganisms. Six peanut samples from primary production and one sample of peanut butter were tested positive for E. coli while Salmonella was detected in nine samples (2.2%): six from post-harvest, two from the initial stage of the secondary processing and one from retail. The Salmonella counts ranged between 0.004 and 0.092MPN/g and five serotypes were identified (Muenster, Miami, Javiana, Oranienburg, Glostrup). The results demonstrated a high prevalence of Enterobacteriaceae and low prevalence of E. coli throughout the peanut supply chain. Furthermore, it was verified that peanuts may become contaminated by Salmonella during different stages of the supply chain, especially at post harvest. PMID- 29433291 TI - Stability of lime essential oil microparticles produced with protein-carbohydrate blends. AB - The objective of this work was to analyze the influence of maltodextrin equivalent dextrose on the lime essential oil reconstitution, storage, release and protection properties. Four treatments were evaluated: whey protein concentrate (WPC), and blends of maltodextrin with dextrose equivalents of 5 (WM5), 10 (WM10) and 20 (WM20). The reconstitution and storage properties of the microparticles (solubility, wettability and density), water kinetics adsorption, sorption isotherms, thermogravimetric properties, controlled release and degradation kinetics of encapsulated lime essential oil were studied to measure the quality of the encapsulated materials. The results of the study indicated that the DE degree influences the characteristics of reconstitution, storage, controlled release and degradation characteristics of encapsulated bioactive compounds. The increase in dextrose equivalent improves microparticle solubility, wettability and density, mainly due to the size of the maltodextrin molecules. The adsorption kinetics and sorption isotherm curves confirmed the increase in the hygroscopicity of maltodextrins with higher degrees of polymerization. The size of the maltodextrin chains influenced the release and protection of the encapsulated lime essential oil. Finally, the maltodextrin polymerization degree can be considered a parameter that will influence the physicochemical properties of microencapsulated food. PMID- 29433292 TI - Inhibitory activity of phenolic-rich pistachio green hull extract-enriched pasta on key type 2 diabetes relevant enzymes and glycemic index. AB - Phenolic compounds as agro-industrial by-products have been associated with health benefits since they exhibit high antioxidant activity and anti-diabetic properties. In this study, polyphenol-rich extract from pistachio green hull (PGH) was evaluated for antioxidant activity and its ability to inhibit alpha amylase and alpha-glucosidase activity in vitro. The effect of PGH extract powder on in vitro starch digestibility was also evaluated. The results showed that PGH had stronger antioxidant activity than Trolox. The inhibitory effect of PGH extract against alpha-amylase from porcine pancreas was dose dependent and the IC50 value was ~174MUgGAE/mL. The crude PGH extract was eight times more potent on baker yeast alpha-glucosidase activity (IC50~6MUgGAE/mL) when compared to acarbose, whereas the IC50 value of PGH extract against rat intestinal maltase activity obtained ~2.6mgGAE/mL. The non-tannin fraction of PGH extract was more effective against alpha-glucosidase than tannin fraction whereas the alpha amylase inhibitor was concentrated in the tannin fraction. In vitro starch digestibility and glycemic index (GI) of pasta sample supplemented with PGH extract powder (1.5%) was significantly lower than the control pasta. The IC50 value of PGH extract obtained from cooked pasta against alpha-amylase and alpha glucosidase was increased. These results have important implications for the processing of PGH for food industry application and therefore could comply with glucose control diets. PMID- 29433293 TI - Thermal and non-thermal preservation techniques of tiger nuts' beverage "horchata de chufa". Implications for food safety, nutritional and quality properties. AB - "Horchata de chufa" is a traditional Spanish beverage produced from tiger nuts (Cyperus esculentus L.). Due to its richness in nutritional compounds, it is highly perishable and its conservation by pasteurization and/or adding preservatives is required. Although efficient, conventional thermal treatment for pasteurization induces changes in the nutritional and sensory properties. Replacing conventional pasteurization by non-thermal technologies such as pulsed electric fields, ultraviolet, and high pressure, combined with moderate temperatures (<40 degrees C) allows a reduction of energy consumption, along with the preservation of the most thermo-sensitive molecules. Accordingly, this review deals with the description of the most relevant non-thermal technologies applied to preserve "horchata" beverage in order to extend the shelf life and inactivate pathogenic microorganisms as well as to preserve the nutritional and quality properties of this food beverage. PMID- 29433294 TI - Bayesian modeling of two- and three-species bacterial competition in milk. AB - Listeria monocytogenes is a well-known food-borne pathogen and is among the bacteria best adapted to grow at low temperatures. Psychrotrophic spoilage microorganisms present in milk and milk products are primarily in the genus Pseudomonas, and their numbers increase during cold storage leading to deterioration and/or spoilage. The nature of the competition in two- or three species bacterial systems with L. monocytogenes, L. innocua, and P. fluorescens in skimmed milk at 7 or 14 degrees C was studied. The Baranyi growth model was used to estimate the growth rate and the maximum population density of the three microorganisms for each strain in single cultures or in two- or three-strains co cultures. The highest Listeria populations were achieved by pure cultures, decreasing in co-culture with P. fluorescens at both temperatures. A modified deterministic logistic model was applied which includes inhibition functions for single cultures, and two- or three-species cultures. A subsequent Bayesian approach was applied for modelling the bacterial interactions. There was not a direct correlation between the growth rate of P. fluorescens and its inhibitory effect on Listeria species. The use of some species from the natural food microflora to inhibit pathogen growth may be an important tool to enhance the safety of refrigerated foods such as milk and dairy products. PMID- 29433295 TI - Enhancing the physicochemical stability of beta-carotene solid lipid nanoparticle (SLNP) using whey protein isolate. AB - beta-Carotene is a nutraceutical that acts as a coloring agent and as pro-vitamin A, but its incorporation into foods is limited because of its hydrophobicity and low chemical stability. The aim of this study was to improve the physicochemical stability of beta-carotene by encapsulating into solid lipid nanoparticles (SLNPs) containing palmitic acid and corn oil, stabilized using whey protein isolate (WPI). The palmitic acid crystals covered the surface of the oil droplets and formed a solid shell to protect the encapsulated beta-carotene. Corn oil decreased the exclusion of beta-carotene from the solid lipid matrix to the surface of SLNPs. WPI increased the colloidal stability of the system, and improved beta-carotene oxidative stability. The rate of color fading due to beta carotene degradation increased with increasing temperature and was faster at lower pH. Lower ionic strengths had a slight impact on beta-carotene degradation, while higher ionic strengths accelerated beta-carotene breakdown. PMID- 29433296 TI - What is lost in translation: A cross-cultural study to compare the concept of nuttiness and its perception in soymilk among Korean, Chinese, and Western groups. AB - Cross-cultural communication of "nuttiness" can be problematic because the underlying conceptual elements and words used to describe its features may be largely culture-dependent. The present study was conducted to understand similarities and dissimilarities in the concept of nuttiness and its actual perception in our model food system, soymilk, among similar (Korean and Chinese) and dissimilar (Western) food cultures. In total, 110 Koreans, 103 Chinese, and 93 English-speaking, Western consumers were recruited. Subjects were asked to provide a definition of nuttiness and generate examples of nutty and non-nutty foods. They also rated the intensity of the nuttiness of 8 soymilk samples. Sensory profiles of 8 soymilk samples were obtained using 9 trained panelists. Data from the definition task were processed through textual analysis. To identify sensory drivers, consumer ratings of perceived nuttiness intensity in soymilk were projected onto a sensory space constructed from the descriptive profiles of nuttiness. We found significant association between culture and usage of specific words (chi270, 0.05=155.8, p<0.001). For example, whereas the concept of nuttiness in the Korean group involved sensory experiences evoked by sesame, roasted, proteic, or fatty foods, in Westerners, it was more nut-oriented. In contrast, the Chinese group associated nuttiness with general characteristics and hedonic dimensions such as good and comfort, rather than with specific foods. However, sensory drivers of nuttiness in soymilk were consistent across cultures. We found that although the abstract definition of nuttiness clearly demonstrated cross-cultural differences, sensory perception of nuttiness was almost identical across all groups. This suggests that cultural background influences verbalization of one's perception, but not the actual perception itself. PMID- 29433297 TI - Preservative effect of Camellia sinensis (L.) Kuntze seed extract in soy sauce and its mutagenicity. AB - The purpose of this study was to investigate the applicability of green tea seed (GTS) extract as a natural preservative in food. Food preservative ability and mutagenicity studies of GTS extract and identification of antimicrobial compounds from GTS extract were carried out. The GTS extract showed only anti-yeast activity against Candida albicans with MIC value of 938MUg/mL and Zygosaccharomyces rouxii with a MIC of 469MUg/mL. The active compounds were identified as theasaponin E1 (1), assamsaponin A (2), and assamsaponin B (3). And GTS extracts didn't show mutagenicity because there were no dose-dependent changes in colonies of Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli WP2uvrA regardless of the metabolic activation system. And GTS extract also showed a potent food preservation affect which eliminated all yeast below the MIC value in application test at soy sauce. Overall, these results indicate that GTS extract could be a safe and effective food preservative with anti-yeast activity. PMID- 29433298 TI - Chemical composition and inhibitory activities on dipeptidyl peptidase IV and pancreatic lipase of two underutilized species from the Brazilian Savannah: Oxalis cordata A.St.-Hil. and Xylopia aromatica (Lam.) Mart. AB - Brazil has the greatest vegetal biodiversity in the world, but products derived from native species are not optimally utilized. Oxalis cordata and Xylopia aromatica are two underutilized species whose leaves and fruits, respectively, have been used as food in the 19th century. In this study, we used chemical and in vitro assays to evaluate the potential of these species as functional foods. The inhibitory activity on pancreatic lipase and DPP-IV were evaluated using the crude extracts and fractions ethyl acetate, butanol and water of these two species. For polyphenols determination, samples were prepared with different solvents and these were analysed by chromatographic and spectroscopic methods. Finally, fatty acids profile was determinated by gas chromatography. The crude extract (IC50=0.84mg/ml), ethyl acetate extract (IC50=0.88mg/ml) an aqueous fraction (IC50=0.63mg/ml) of C. cordata were inhibitory on pancreatic lipase but inactive against dipeptidyl peptidase IV (DPP-IV). Extracts from X. aromatica were inactive against the lipase pancreatic enzyme, but a butanolic fraction inhibited DPP-IV (IC50=0.71+/-0.05mg/ml). The phenolic acids orientin/isorientin, chlorogenic acid (0.32g/100g) and the flavonoid derivatives rutin (0.27g/100g), quercetin and luteolin were observed in all products. Additionally, fatty acid quantification showed that oleic (7.5g/100g) and linoleic acid (6.5g/100g) were predominant in X. aromatica fruit. This study confirms the potential for the use of both plants as functional foods due to their nutritional value, biological activity and important phytochemical content. PMID- 29433299 TI - Cocoplum (Chrysobalanus icaco L.) decreases doxorubicin-induced DNA damage and downregulates Gadd45a, Il-1beta, and Tnf-alpha in vivo. AB - DNA damage and inflammation are promising targets in disease prevention studies. Since these pathways have shown to be modulated by dietary components, investigating the molecular effects of food becomes relevant. This study aimed at investigating the protective effects of cocoplum (Chrysobalanus icaco L.) against doxorubicin (DXR)-induced damage. Rats were treated with cocoplum (100, 200 or 400mg/kg/day) for 14days, associated or not with DXR (15mg/kg b.w.). Tissue targeted comet assay and the oxidative stress parameters oxidized/reduced glutathione and catalase were investigated in liver, kidney, and heart. The expressions of DNA damage/repair (Gadd45a, Parp1, Xrcc2) and proinflammatory genes (Il-1beta, Il-6, Nf-kappab, Tnf-alpha) were performed by real-time quantitative PCR. Cocoplum decreased DNA damage and the expressions of Gadd45a, Il-1beta, and Tnf-alpha induced by DXR. These findings demonstrate that cocoplum fruits possess antigenotoxic and anti-inflammatory effects against DXR-induced damage and encourage other in vivo/clinical studies with this fruit. PMID- 29433300 TI - Treatment rate for HCV in the direct-acting antivirals era in HIV co-infected patients: data from an Italian cohort. AB - BACKGROUND: New direct antiviral agents (DAA) are now effective in hepatitis C virus (HCV) infection; persons living with human immunodeficiency virus (HIV) (PLWH) were undertreated. Aim of this study was to describe the management of HCV treatment in a HIV/HCV cohort during a 16 years period. METHODS: An electronic review of all HIV patients with >1 clinic check from the year 2000 was made. Demographic, virologic and treatment data were collected. RESULTS: From 2000 to 2015 a total of 2352 PLWH were enrolled; 776 (33%) resulted positive at HCV antibodies, and were mostly genotype 1 and 3. 279/579 (48.2%) were treated, and 170 (29.3% of total, 60.9% of treated) obtained a SVR. Treatment rate for HCV had a significant increase in the 2015 (20.6%, P<0.05 when compared with previous years). SVR rate was significantly improved in the 2015 (P<0.05 when compared with each single previous year). At univariate analysis among the different year group there were significant differences in term of HCV RNA positive patients (P<0.001), number of treated (total) and naive patients (P<0.001 in each of cases), SVR rate (P<0.001), mortality rate (P=0.003). HCV-Ab positive patients with HCV-RNA not detectable (cured) increased during years. At 2015, 50.4% of the HCV-Ab positive patients resulted to be HCV-RNA negative. CONCLUSIONS: In the DAA's era a significant increase in the number of treatments was observed. SVR rate was significantly higher. Treatment rate still remains quite low. More than a half of our population of HCV co-infected patients results to be cured for HCV. PMID- 29433301 TI - Prevalence of Fructose Malabsorption in Patients With Irritable Bowel Syndrome After Excluding Small Intestinal Bacterial Overgrowth. AB - Background/Aims: Fructose malabsorption (FM) mimics symptoms of irritable bowel syndrome (IBS), and its prevalence has increased. Diagnosing FM in IBS is challenging because of its overlap with small intestinal bacterial overgrowth (SIBO). We assessed the prevalence of FM by comparing patients with IBS with asymptomatic control individuals after excluding SIBO using the glucose hydrogen breath test (HBT). Methods: Patients diagnosed with IBS and asymptomatic control individuals were enrolled prospectively. Dietary habits were assessed with the Food Frequency Questionnaire. After excluding SIBO, participants underwent HBTs with both 15 g and 25 g of fructose. Results: Thirty-five patients with IBS and 35 age- and sex-matched asymptomatic control individuals were enrolled. The 15-g fructose HBT yielded positive results in 7 of the 35 (20.0%) patients with IBS and in 2 of 35 (5.7%) controls (P = 0.070). The 25-g fructose HBT was positive in 16 of the 35 (45.7%) patients with IBS and in 8 of the 35 (22.9%) controls (P = 0.040). Analysis of the Food Frequency Questionnaire responses showed no significant differences between the 2 groups in dietary intake, although patients with IBS showed a significantly higher mean fiber intake than controls (21.24 +/- 11.35 g vs 15.87 +/- 7.07 g, respectively, P = 0.040). Conclusions: The 25-g fructose HBT identified FM in a significantly higher percentage of SIBO-negative patients with IBS than in asymptomatic control individuals, suggesting that FM may correlate with IBS. Education regarding dietary control of foods containing fructose may be useful for the management of patients with IBS. PMID- 29433302 TI - DNA Encountering Terbium(III): A Smart "Chemical Nose/Tongue" for Large-Scale Time-Gated Luminescent and Lifetime-Based Sensing. AB - Recent years have witnessed the rapid development of pattern-based sensors due to their potential to detect and differentiate a wealth of analytes with only few probes. However, no one has found or used the combination of DNA and terbium(III) (Tb) as a pattern recognition system for large-scale mix-and-measure assays. Here we report for the first time that DNA-sensitized Tb (DNA/Tb), as a label-free and versatile "chemical nose/tongue", can be employed for wide-scale time-gated luminescent (TGL) monitoring of metal ions covering nearly the entire periodic table in a cost-effective fashion. A series of guanine/thymine (G/T)-rich DNA ligands was screened to sensitize the luminescence of Tb (referring to the antenna effect) as smart pattern responders to metal ions in solution, and metal ion-DNA interactions can differentially alter the antenna effect of DNA toward Tb as pattern signals. Our results show that as few as 3 DNA/Tb label-free sensors could successfully discriminate 49 analytes, including alkali-metal ions, alkaline-earth-metal ions, transition/post-transition metal ions, and lanthanide ions. A blind test with 49 metals further confirmed the discriminating power of DNA/Tb sensors. Moreover, the lifetime-based pattern recognition application using DNA/Tb sensors was also demonstrated. This DNA/Tb pattern recognition strategy could be extended to construct a series of "chemical noses/tongues" for monitoring various biochemical species by using different responsive DNA ligands, thus promising a versatile and powerful tool for a sensing application and investigation of DNA-involving molecular interactions. PMID- 29433303 TI - Ligand-to-Ligand Interactions That Direct Formation of D2-Symmetrical Alternating Circular Helicate. AB - This work demonstrates that ligand-to-ligand interactions between achiral bis beta-diketonate (BTP) and chiral bis(4-phenyl-2-oxazolinyl)pyridine [( R)- or ( S)-Ph-Pybox] are successfully directed to the fabrication of a D2-symmetrical alternating circular helicate with the general formula [( R)- or ( S)-Ph Pybox]4(LnIII)4(BTP)6. The lanthanide(III) LnIII assemblies (LnIII4- RRRR and LnIII4- SSSS) have a nanometer-size squarelike grid (interatomic distances > 10 A). X-ray structure analysis revealed that the circular helicate contains two double helicate LnIII2L2 units, where both show ( M)-helicity for LnIII4- RRRR and ( P)-helicity for LnIII4- SSSS, where pi-pi stacking interaction is present between the side arm of ( R)-Ph-Pybox (Ph1) and the adjacent BTP ligand around the EuIII metal center ( dpipi = 3.636 A: the diketonate plane...Ph1 distance). The newly obtained circular lanthanide(III) helicate exists as single and homochiral diastereomers in solution (LnIII4- RRRR and LnIII4- SSSS), exhibiting circularly dichroism (CD) and circularly polarized luminescence (CPL). Conversely, the circular helicate favors the heterochiral arrangement (i.e., LnIII4- RRRR/LnIII4- SSSS). PMID- 29433304 TI - Three-Dimensional Network Architecture with Hybrid Nanocarbon Composites Supporting Few-Layer MoS2 for Lithium and Sodium Storage. AB - The exploration of anode materials for lithium ion batteries (LIBs) or sodium ion batteries (SIBs) represents a grand technological challenge to meet the continuously increased demand for the high-performance energy storage market. Here we report a facile and reliable synthetic strategy for in situ growth of few layer MoS2 nanosheets on reduced graphene oxide (rGO) cross-linked hollow carbon spheres (HCS) with formation of three-dimensional (3D) network nanohybrids (MoS2 rGO/HCS). Systematic electrochemical studies demonstrate, as an anode of LIBs, the as-developed MoS2-rGO/HCS can deliver a reversible capacity of 1145 mAh g-1 after 100 cycles at 0.1 A g-1 and a revisible capacity of 753 mAh g-1 over 1000 cycles at 2 A g-1. For SIBs, the as-developed MoS2-rGO/HCS can also maintain a reversible capacity of 443 mAh g-1 at 1 A g-1 after 500 cycles. The excellent electrochemical performance can be attributed to the 3D porous structures, in which the few-layer MoS2 nanosheets with expanded interlayers can provide shortened ion diffusion paths and improved Li+/Na+ diffusion mobility, and the hollow porous carbon spheres and the outside graphene network are able to improve the conductivity and maintain the structural integrity. PMID- 29433305 TI - Self-Template Synthesis of Co-Se-S-O Hierarchical Nanotubes as Efficient Electrocatalysts for Oxygen Evolution under Alkaline and Neutral Conditions. AB - We develop a facile self-template synthetic method to construct hierarchical Co Se-S-O (CoSe xS2- x@Co(OH)2) nanotubes on a carbon cloth as a self-standing electrode for electrocatalytic oxygen evolution reaction (OER). In the synthetic process, separate selenization and sulfurization on the Co(OH)F precursor in different solvents have played an important role in constructing CoSe xS2- x (Co Se-S) hierarchical nanotubes, which was further transformed into the nanotube like Co-Se-S-O via an in situ electrochemical oxidation process. The Co-Se-S-O obtained by the Kirkendall effect through two stepwise anion-exchange reactions represents the first quaternary Co-Se-S-O nanotube array, which dramatically enhances its surface area and conductivity. Further, it only requires low overpotentials of 230 and 480 mV to achieve a 10 mA cm-2 current density. The OER performance of Co-Se-S-O is much more efficient than that of its monochalcogenide counterparts, as well as the commercial benchmark catalyst IrO2. PMID- 29433306 TI - Seeded Mineralization Leads to Hierarchical CaCO3 Thin Coatings on Fibers for Oil/Water Separation Applications. AB - Like their biogenic counterparts, synthetic minerals with hierarchical architectures should exhibit multiple structural functions, which nicely bridge the boundaries between engineering and functional materials. Nevertheless, design of bioinspired mineralization approaches to thin coatings with distinct micro/nanotextures remains challenging in the realm of materials chemistry. Herein, a general morphosynthetic method based on seeded mineralization was extended to achieve prismatic-type thin CaCO3 coatings on fibrous substrates for oil/water separation applications. Distinct micro/nanotextures of the overlayers could be obtained in mineralization processes in the presence of different soluble (bio)macromolecules. These hierarchical thin coatings therefore exhibit multiple structural functions including underwater superoleophobicity, ultralow adhesion force of oil in water, and comparable stiffness/strength to the prismatic-type biominerals found in mollusk shells. Moreover, this controllable approach could proceed on fibrous substrates to obtain robust thin coatings, so that a modified nylon mesh could be employed for oil/water separation driven by gravity. Our bioinspired approach based on seeded mineralization opens the door for the deposition of hierarchical mineralized thin coatings exhibiting multiple structural functions on planar and fibrous substrates. This bottom-up strategy could be readily extended for the syntheses of advanced thin coatings with a broad spectrum of engineering and functional constituents. PMID- 29433307 TI - Role of Hepatic Organic Anion Transporter 2 in the Pharmacokinetics of R- and S Warfarin: In Vitro Studies and Mechanistic Evaluation. AB - Interindividual variability in warfarin dose requirement demands personalized medicine approaches to balance its therapeutic benefits (anticoagulation) and bleeding risk. Cytochrome P450 2C9 ( CYP2C9) genotype-guided warfarin dosing is recommended in the clinic, given the more potent S-warfarin is primarily metabolized by CYP2C9. However, only about 20-30% of interpatient variability in S-warfarin clearance is associated with CYP2C9 genotype. We evaluated the role of hepatic uptake in the clearance of R- and S-warfarin. Using stably transfected HEK293 cells, both enantiomers were found to be substrates of organic anion transporter (OAT)2 with a Michaelis-Menten constant ( Km) of ~7-12 MUM but did not show substrate affinity for other major hepatic uptake transporters. Uptake of both enantiomers by primary human hepatocytes was saturable ( Km ~ 7-10 MUM) and inhibitable by OAT2 inhibitors (e.g., ketoprofen) but not by OATP1B1/1B3 inhibitors (e.g., cyclosporine). To further evaluate the potential role of hepatic uptake in R- and S-warfarin pharmacokinetics, mechanistic modeling and simulations were conducted. A "bottom-up" PBPK model, developed assuming that OAT2-CYPs interplay, well recovered clinical pharmacokinetics, drug-drug interactions, and CYP2C9 pharmacogenomics of R- and S-warfarin. Clinical data were not available to directly verify the impact of OAT2 modulation on warfarin pharmacokinetics; however, the bottom-up PBPK model simulations suggested a proportional change in clearance of both warfarin enantiomers with inhibition of OAT2 activity. These results suggest that variable hepatic OAT2 function, in conjunction with CYP2C, may contribute to the high population variability in warfarin pharmacokinetics and possibly anticoagulation end points and thus warrant further clinical investigation. PMID- 29433308 TI - Aqueous Zinc Compounds as Residual Antimicrobial Agents for Textiles. AB - Textiles, especially those worn by patients and medical professionals, serve as vectors for proliferating pathogens. Upstream manufacturing techniques and end user practices, such as transition-metal embedment in textile fibers or alcohol based disinfectants, can mitigate pathogen growth, but both techniques have their shortcomings. Fiber embedment requires complete replacement of all fabrics in a facility, and the effects of embedded nanoparticles on human health remain unknown. Alcohol-based, end-user disinfectants are short-lived because they quickly volatilize. In this work, common zinc salts are explored as an end-user residual antimicrobial agent. Zinc salts show cost-effective and long-lasting antimicrobial efficacy when solution-deposited on common textiles, such as nylon, polyester, and cotton. Unlike common alcohol-based disinfectants, these zinc salt treated textiles mitigate microbial growth for more than 30 days and withstand commercial drying. Polyester fabrics treated with ZnO and ZnCl2 were further explored because of their commercial ubiquity and likelihood for rapid commercialization. ZnCl2-treated textiles were found to retain their antimicrobial coating through abrasive testing, whereas ZnO-treated textiles did not. Scanning electron microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry analyses suggest that ZnCl2 likely hydrolyzes and reacts with portions of the polyester fiber, chemically attaching to the fiber, whereas colloidal ZnO simply sediments and binds with weaker physical interactions. PMID- 29433309 TI - NLS-Cholic Acid Conjugation to IL-5Ralpha-Specific Antibody Improves Cellular Accumulation and In Vivo Tumor-Targeting Properties in a Bladder Cancer Model. AB - Receptor-mediated internalization followed by trafficking and degradation of antibody-conjugates (ACs) via the endosomal-lysosomal pathway is the major mechanism for delivering molecular payloads inside target tumor cells. Although a mainstay for delivering payloads with clinically approved ACs in cancer treatment and imaging, tumor cells are often able to decrease intracellular payload concentrations and thereby reduce the effectiveness of the desired application. Thus, increasing payload intracellular accumulation has become a focus of attention for designing next-generation ACs. We developed a composite compound (ChAcNLS) that enables ACs to escape endosome entrapment and route to the nucleus resulting in the increased intracellular accumulation as an interleukin-5 receptor alpha-subunit (IL-5Ralpha)-targeted agent for muscle invasive bladder cancer (MIBC). We constructed 64Cu-A14-ChAcNLS, 64Cu-A14-NLS, and 64Cu-A14 and evaluated their performance by employing mechanistic studies for endosome escape coupled to nuclear routing and determining whether this delivery system results in improved 64Cu cellular accumulation. ACs consisting of ~20 ChAcNLS or NLS moieties per 64Cu-A14 were prepared in good yield, high monomer content, and maintaining high affinity for IL-5Ralpha. Confocal microscopy analysis demonstrated ChAcNLS mediated efficient endosome escape and nuclear localization. 64Cu-A14-ChAcNLS increased 64Cu cellular accumulation in HT-1376 and HT-B9 cells relative to 64Cu-A14 and 64Cu-A14-NLS. In addition, we tested 64Cu-A14-ChAcNLS in vivo to evaluate its tissue distribution properties and, ultimately, tumor uptake and targeting. A model of human IL-5Ralpha MIBC was developed by implanting NOD/SCID mice with subcutaneous HT-1376 or HT-B9MIBC tumors, which grow containing high and low IL-5Ralpha-positive tumor cell densities, respectively. ACs were intravenously injected, and daily blood sampling, biodistribution at 48 and 96 h, and positron emission tomography (PET) at 24 and 48 h were performed. Region of interest (ROI) analysis was also performed on reconstructed PET images. Pharmacokinetic analysis and biodistribution studies showed that 64Cu-A14-ChAcNLS had faster clearance rates from the blood and healthy organs relative to 64Cu A14. However, 64Cu-A14-ChAcNLS maintained comparable tumor accumulation relative to 64Cu-A14. This resulted in 64Cu-A14-ChAcNLS having superior tumor/normal tissue ratios at both 48 and 96 h biodistribution time points. Visualization of AC distribution by PET and ROI analysis confirmed that 64Cu-A14-ChAcNLS had improved targeting of MIBC tumor relative to 64Cu-A14. In addition, 64Cu-A14 modified with only NLS had poor tumor targeting. This was a result of poor tumor uptake due to extremely rapid clearance. Thus, the overall findings in this model of human IL-5Ralpha-positive MIBC describe an endosome escape-nuclear localization cholic-acid-linked peptide that substantially enhances AC cellular accumulation and tumor targeting. PMID- 29433310 TI - Quantifying the Average Number of Nucleic Acid Therapeutics per Nanocarrier by Single Particle Tracking Microscopy. AB - Nucleic acid biopharmaceuticals are being investigated as potential therapeutics. They need to be incorporated into a biocompatible carrier so as to overcome several biological barriers. Rational development of suitable nanocarriers requires high-quality characterization techniques. While size, concentration, and stability can be very well measured these days, even in complex biological fluids, a method to accurately quantify the number of nucleic acid therapeutics encapsulated in nanocarriers is still missing. Here we present a method, based on concentration measurements with single particle tracking microscopy, with which it is possible to directly measure the number of plasmid DNA molecules per nanoparticle, referred to as the plasmid/NP ratio. Using DOTAP/DOPE liposomes as a model carrier, we demonstrate the usefulness of the method by investigating the influence of various experimental factors on the plasmid/NP ratio. We find that the plasmid/NP ratio is inversely proportional with the size of the pDNA and that the plasmid/NP decreases when lipoplexes are prepared at lower concentrations of pDNA and nanocarrier, with values ranging from 6.5 to 3 plasmid/NP. Furthermore, the effect of pre- and post-PEGylation of lipoplexes was examined, finding that pre-PEGylation results in a decreased plasmid/NP ratio, while post-PEGylation did not alter the plasmid/NP ratio. These proof-of-concept experiments show that single particle tracking offers an extension of the nanoparticle characterization toolbox and is expected to aid in the efficient development of nanoformulations for nucleic acid-based therapies. PMID- 29433312 TI - Human Telomeric G-Quadruplex Selective Fluoro-Isoquinolines Induce Apoptosis in Cancer Cells. AB - Small molecules that stabilize G-quadruplex structures in telomeres can prevent telomerase enzyme mediated telomere lengthening and subsequently lead to cell death. We herein report two fluoro-isoquinoline derivatives IQ1 and IQ2 as selective ligands for human telomeric G-quadruplex DNA. IQ1 and IQ2 containing different triazolyl side chains have been synthesized by Cu (I) catalyzed azide alkyne cycloaddition. Fluorescence Resonance Energy Transfer (FRET) melting assay and fluorescence binding titrations indicate that both these ligands exhibit binding preference for telomeric G-quadruplex DNA ( h-TELO) over other promoter DNA quadruplexes and duplex DNA. However, ligand IQ1, containing pyrrolidine side chains, is capable of discriminating among quadruplexes by showing higher affinity toward h-TELO quadruplex DNA. On the contrary, IQ2, containing benzamide side chains, interacts with all the investigated quadruplexes. NMR analysis suggests that IQ1 interacts strongly with the external G-quartets of h-TELO. Biological studies reveal that IQ1 is more potent than IQ2 in inhibiting telomerase activity by selectively interacting with telomeric DNA G-quadruplex. Moreover, a dual luciferase reporter assay indicates that IQ1 is unable to reduce the cellular expression of c-MYC and BCL2 at transcriptional level. Significantly, IQ1 mostly stains the nucleus, induces cell cycle arrest in G0/G1 phase, triggers apoptotic response in cancer cells, and activates caspases 3/7. PMID- 29433311 TI - Determination of Grayanotoxins from Rhododendron brachycarpum in Dietary Supplements and Homemade Wine by Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry. AB - A sensitive and specific high-performance liquid chromatography-quadrupole time of-flight-mass spectrometry (LC-QTOF-MS) method combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the determination of grayanotoxins I and III in dietary supplements and homemade wine. Grayanotoxins I and III were successfully extracted using solid-phase extraction cartridges, characterized by LC-QTOF-MS, and quantitated by LC-MS/MS. The LC-MS/MS calibration curves were linear over concentrations of 10-100 ng/mL (grayanotoxin I) and 20-400 ng/mL (grayanotoxin III). Grayanotoxins I and III were found in 51 foodstuffs, with quantitative determinations revealing total toxin concentrations of 18.4-101 000 ng/mL (grayanotoxin I) and 15.3-56 000 ng/mL (grayanotoxin III). The potential of the validated method was demonstrated by successful quantitative analysis of grayanotoxins I and III in dietary supplements and homemade wine; the method appears suitable for the routine detection of grayanotoxins I and III from Rhododendron brachycarpum. PMID- 29433313 TI - Grain Boundaries Act as Solid Walls for Charge Carrier Diffusion in Large Crystal MAPI Thin Films. AB - Micro- and nanocrystalline methylammonium lead iodide (MAPI)-based thin-film solar cells today reach power conversion efficiencies of over 20%. We investigate the impact of grain boundaries on charge carrier transport in large crystal MAPI thin films using time-resolved photoluminescence (PL) microscopy and numerical model calculations. Crystal sizes in the range of several tens of micrometers allow for the spatially and time resolved study of boundary effects. Whereas long ranged diffusive charge carrier transport is observed within single crystals, no detectable diffusive transport occurs across grain boundaries. The observed PL transients are found to crucially depend on the microscopic geometry of the crystal and the point of observation. In particular, spatially restricted diffusion of charge carriers leads to slower PL decay near crystal edges as compared to the crystal center. In contrast to many reports in the literature, our experimental results show no quenching or additional loss channels due to grain boundaries for the studied material, which thus do not negatively affect the performance of the derived thin-film devices. PMID- 29433314 TI - Proximity Hybridization-Regulated Immunoassay for Cell Surface Protein and Protein-Overexpressing Cancer Cells via Electrochemiluminescence. AB - A simple electrochemiluminescence (ECL) immunoassay based on a proximity hybridization-regulated strategy was developed for highly sensitive and specific detection of cell surface protein and protein-overexpressing cancer cells. A biosensor was fabricated by self-assembling a thiolated capture ss-DNA3 (partially hybridize with ss-DNA1 and ss-DNA2) and blocking with 6-mercapto-1 hexanol on a gold electrode surface. Target protein was simultaneously bound by two ss-DNA-tagged antibody probes (DNA1-Ab1 and DNA2-Ab2), while DNA1 and DNA2 were brought in sufficient proximity and hybridized with capture DNA3 on the surface of the biosensor. After ECL signal reagent Ru(phen)32+ was intercalated into the hybridized ds-DNAs, ECL measurement was performed in the coreactant solution. A "signal on" proximity hybridization-regulated ECL immunoassay for alpha-fetoprotein (AFP) was developed. The ECL intensity increased with the increase of AFP concentration in the range of 0.05-20.0 ng/mL with a detection limit of 6.2 pg/mL. Moreover, the developed ECL method was successfully used to detect AFP-overexpressing cancer cells (MCF-7 cancer cells as model) with a detection limit of 620 cells/mL (~60 MCF-7 cells in 100 MUL of cell suspension) and discriminate AFP expression on different types of the living cell surface. This work for the first time reports a proximity hybridization-regulated ECL immunoassay for the detection of the cell surface protein on a living cell surface with good specificity and sensitivity. This simple, specific, and sensitive strategy is greatly promising for the detection of proteins and specific cells. PMID- 29433315 TI - Factors Controlling Drug Release in Cross-linked Poly(valerolactone) Based Matrices. AB - There is keen interest in the development of biocompatible and biodegradable implantable delivery systems (IDDS) that provide sustained drug release for prolonged periods in humans. These systems have the potential to enhance therapeutic outcomes, reduce systemic toxicity, and improve patient compliance. Herein, we report the preparation and physicochemical characterization of cross linked polymeric matrices from poly(valerolactone)- co-poly(allyl-delta valerolactone) (PVL- co-PAVL) copolymers for use in drug delivery. A series of well-defined PVL- co-PAVL copolymers (PDI < 1.5) that vary in terms of MW and AVL content were prepared by ring opening polymerization catalyzed by 1,5,7 triazabicyclo[4.4.0]dec-5-ene. A subsequent cross-linking reaction using 1,6 hexanedithiol led to solid cylindrical amorphous or semicrystalline matrices as potential IDDS. High loading levels (up to 20% (w/w)) of several model drugs that vary in physicochemical properties, including paclitaxel, triamcinolone acetonide and hexacetonide, curcumin, and acetaminophen, were achieved using a postloading method in organic solvent. Drug-IDDS interactions were evaluated via the group contribution method and X-ray diffraction as well as calorimetric, spectroscopic, and microscopic techniques. Results indicate superior drug-matrix compatibility for drugs bearing phenyl groups. In vitro release studies under distinct sink conditions highlight the key factors (i.e., state and loading level of drug, solubility of drug in external media, and composition of release media) that impact drug release. PMID- 29433316 TI - In Situ Target Engagement Studies in Adherent Cells. AB - A prerequisite for successful drugs is effective binding of the desired target protein in the complex environment of a living system. Drug-target engagement has typically been difficult to monitor in physiologically relevant models, and with current methods, especially, while maintaining spatial information. One recent technique for quantifying drug-target engagement is the cellular thermal shift assay (CETSA), in which ligand-induced protein stabilization is measured after a heat challenge. Here, we describe a CETSA protocol in live A431 cells for p38alpha (MAPK14), where remaining soluble protein is detected in situ, using high-content imaging in 384-well, microtiter plates. We validate this assay concept using a number of known p38alpha inhibitors and further demonstrate the potential of this technology for chemical probe and drug discovery purposes by performing a small pilot screen for novel p38alpha binders. Importantly, this protocol creates a workflow that is amenable to adherent cells in their native state and yields spatially resolved target engagement information measurable at the single-cell level. PMID- 29433317 TI - Bioconjugation through Mesitylene Thiol Alkylation. AB - The design and generation of complex multifunctional macromolecular structures by bioconjugation is a hot topic due to increasing interest in conjugates with therapeutic applications. In this regard, the development of efficient, selective, and safe conjugation methods is a major objective. In this report, we describe the use of the bis(bromomethyl)benzene scaffold as a linker for bioconjugation with special emphasis on antibody conjugation. We first performed the monothioalkylation of 1,3,5-tris(bromomethyl)benzene, which rendered the reactive dibromotrimethylbenzyl derivatives to be used in thiol bis-alkylation. Next, we introduced into the linker either a bis(Cys)-containing peptide or anti CD4 and -CD13 monoclonal antibodies, previously subjected to partial reduction of disulfide bonds. Mass spectrometry, UV-vis spectra, and SDS-PAGE experiments revealed that this bis-alkylating agent for bioconjugation preserved both antibody integrity and antibody-antigen binding affinity, as assessed by flow cytometry. Taken together, our results show that the mesitylene scaffold is a suitable linker for thiol-based bioconjugation reactions. This linker could be applicable in the near future for the preparation of antibody drug conjugates. PMID- 29433318 TI - First Time Determination of Important Catalyst Sodium Methoxide Used in Biodiesel by Colorimetric Method. AB - A simple and selective spectrophotometric method has been developed for the first time for the determination of sodium methoxide in methanol solution in the presence of sodium hydroxide. The developed method involves the formation of a pink species by the reaction between sodium methoxide and alpha-santonin. The pink compound formed shows absorbance maximum at 513 nm. N, N-Dimethylformamide and methanol were used as solvents, and the reaction was performed at different temperatures and 25 degrees C was selected for further experiments. The pink compound formed was dried and then was studied using FTIR and mass spectrometry. The calibration curve was constructed from 0.10 to 0.30% (m/v) sodium methoxide in methanol, and the standard deviation is 0.010%. Similarly, the relative standard deviations of 28%, 26%, and 24% solutions of sodium methoxide were obtained in the range of 0.4 to 1.9%. The correlation coefficient of the analytical curve r = 0.9997; the limit of detection, LOD, is ca. 1.1 * 10-3 % w/w; and the limit of quantification, LOQ, is ca. 3.2 * 10-3 % w/w. The results of analysis were validated statistically. PMID- 29433319 TI - Theoretical Analysis of Carrier Ion Diffusion in Superconcentrated Electrolyte Solutions for Sodium-Ion Batteries. AB - Superconcentrated electrolyte solutions are receiving increasing attention as a novel class of liquid electrolyte for secondary batteries because of their unusual and favorable characteristics, which arise from a unique solution structure with a very small number of free solvent molecules. The present theoretical study investigates the concentration dependence of the structural and dynamical properties of these electrolyte solutions for Na-ion batteries using large-scale quantum molecular dynamics simulations. Microscopic analysis of the dynamical properties of Na+ ions reveals that ligand (solvent/anion) exchange reactions, an alternative diffusion pathway for Na+ ions, are responsible for carrier ion diffusion in the superconcentrated conditions. PMID- 29433320 TI - In-plane Anisotropy of Quantum Transport in Artificial Two-dimensional Au Lattices. AB - We report an experimental observation and direct control of quantum transport in artificial two-dimensional Au lattices. Combining the advanced techniques of low temperature deposition and newly developed double-probe scanning tunneling spectroscopy, we display a two-dimensional carrier transport and demonstrate a strong in-plane transport modulation in the two-dimensional Au lattices. In well ordered Au lattices, we observe the carrier transport behavior manifesting as a band-like feature with an energy gap. Furthermore, controlled structural modification performed by constructing coupled "stadiums" enables a transition of system dynamics in the lattices, which in turn establishes tunable resonant transport throughout a wide energy range. Our findings open the possibility of the construction and transport engineering of artificial lattices by the geometrical arrangement of scatterers and quantum chaotic dynamics. PMID- 29433321 TI - Structural Characterization of Self-Assembling Hybrid Nanoparticles for Bisphosphonate Delivery in Tumors. AB - Hybrid self-assembling nanoparticles (hsaNPs) encapsulating bisphosphonates (BPs) recently showed very promising results in preclinic experiments for the treatment of brain tumor. However, the poor knowledge on the architecture of hybrid nanovectors is certainly one of the main reasons hampering further clinical and industrial development of these technologies. Here we propose to combine different techniques, that is, small angle neutron scattering (SANS) and X-ray Sscattering (SAXS), with cryo-electron transmission microscopy (cryo-TEM) to study the architecture of the final hsaNPs as well as of the four components before the assembling process. Data analysis based on SANS and SAXS experiments suggested a multiple compartment architecture of the final product, consisting of two bilayers sourrounding a core. Structures consisting of two shells surrounding an internal core were also observed in the cryo-TEM analysis. Such high resolution insight, also combined with size distribution and zeta potential of the NPs, provides exhaustive characterization of hsaNPs encapsulating BPs, and it is aimed at supporting further their clinical and industrial development. PMID- 29433322 TI - Comparison of Four Quantitative Techniques for Monitoring Microalgae Disruption by Low-Frequency Ultrasound and Acoustic Energy Efficiency. AB - Ultrasound has been regarded as an environmental friendly technology to utilize microalgae biomass and control algal blooms. In this study, four quantitative techniques, including cell counting, optical density of algal suspension, pigments release, and protein release, were performed on three species of microalgae ( M. aeruginosa, C. pyrenoidosa, and C. reinhardtii) to develop effective techniques for rapid monitoring of cell disruption and to optimize the acoustic energy efficiency. Results showed optical density of algal suspensions was not an optimal indicator to monitor cell disruption, although it is a common technique for determining cell concentration in microbial cultures. Instead, an accurate and reliable technique was to determine the release of intracellular pigments (absorbance peaks of supernatant) for indicating cell rupture. The protein released during sonication could also be a useful indicator if it is the component of interest. A fitted power functional model showed a strong relationship between cell disruption and energy consumption ( R2 > 0.87). This model could provide an effective approach to directly compare the energy efficiency of ultrasound in different systems or with varying microalgae species. This study provides valuable information for microalgae utilization and the treatment of algal blooms by ultrasound, so as to achieve energy conservation and environmental safety. PMID- 29433323 TI - Standardization of steroid tests and implications for the endocrine community: Author's reply. PMID- 29433324 TI - Letter in response to: John W Honour. Standardization of steroid tests and implications for the endocrine community. Annals of Clinical Biochemistry, Vol. 54(6) 618-630. PMID- 29433325 TI - Comment on: Standardization of steroid tests and implications for the endocrine community. PMID- 29433326 TI - Comment on: Standardization of steroid tests and implications for the endocrine community. PMID- 29433327 TI - Redox Signaling from and to Peroxisomes: Progress, Challenges, and Prospects. AB - SIGNIFICANCE: Peroxisomes are organelles that are best known for their role in cellular lipid and hydrogen peroxide (H2O2) metabolism. Emerging evidence suggests that these organelles serve as guardians and modulators of cellular redox balance, and that alterations in their redox metabolism may contribute to aging and the development of chronic diseases such as neurodegeneration, diabetes, and cancer. Recent Advances: H2O2 is an important signaling messenger that controls many cellular processes by modulating protein activity through cysteine oxidation. Somewhat surprisingly, the potential involvement of peroxisomes in H2O2-mediated signaling processes has been overlooked for a long time. However, recent advances in the development of live-cell approaches to monitor and modulate spatiotemporal fluxes in redox species at the subcellular level have opened up new avenues for research in redox biology and boosted interest in the concept of peroxisomes as redox signaling platforms. CRITICAL ISSUES: This review first introduces the reader to what is known about the role of peroxisomes in cellular H2O2 production and clearance, with a focus on mammalian cells. Next, it briefly describes the benefits and drawbacks of current strategies used to investigate the complex interplay between peroxisome metabolism and cellular redox state. Furthermore, it integrates and critically evaluates literature dealing with the interrelationship between peroxisomal redox metabolism, cell signaling, and human disease. FUTURE DIRECTIONS: As the precise molecular mechanisms underlying many of these associations are still poorly understood, a key focus for future research should be the identification of primary targets for peroxisome-derived H2O2. PMID- 29433328 TI - Adult Children Living With Aging Parents: The Association Between Income and Parental Affect. AB - This study examined the moderating effect of parental income on the association between parent-child coresidence and parental affect. Secondary analysis was conducted with data from the ORANJ BOWL panel, a representative sample of adults in New Jersey, aged 50 to 74 years ( N = 5,688). Results indicated that income had a significant moderating effect on the association between the adult child's residential status and parents' positive and negative affect. Among parents with coresident adult children, an observed decline in positive affect and rise in negative affect were amplified as parental income level increased, suggesting differential strains on parental well-being across income levels. PMID- 29433330 TI - Endothelial Nanomechanics in the Context of Endothelial (Dys)function and Inflammation. AB - SIGNIFICANCE: Stiffness of endothelial cells is closely linked to the function of the vasculature as it regulates the release of vasoactive substances such as nitric oxide (NO) and reactive oxygen species. The outer layer of endothelial cells, consisting of the glycocalyx above and the cortical zone beneath the plasma membrane, is a vulnerable compartment able to adapt its nanomechanical properties to any changes of forces exerted by the adjacent blood stream. Sustained stiffening of this layer contributes to the development of endothelial dysfunction and vascular pathologies. Recent Advances: The development of specific techniques to quantify the mechanical properties of cells enables the detailed investigation of the mechanistic link between structure and function of cells. CRITICAL ISSUES: Challenging the mechanical stiffness of cells, for instance, by inflammatory mediators can lead to the development of endothelial dysfunction. Prevention of sustained stiffening of the outer layer of endothelial cells in turn improves endothelial function. FUTURE DIRECTIONS: The mechanical properties of cells can be used as critical marker and test system for the proper function of the vascular system. Pharmacological substances, which are able to improve endothelial nanomechanics and function, could take a new importance in the prevention and treatment of vascular diseases. Thus, detailed knowledge acquisition about the structure/function relationship of endothelial cells and the underlying signaling pathways should be promoted. Antioxid. Redox Signal. 00, 000-000. PMID- 29433329 TI - Combined Burst Wave Lithotripsy and Ultrasonic Propulsion for Improved Urinary Stone Fragmentation. AB - PURPOSE: Burst wave lithotripsy (BWL) is a new technology in development to fragment urinary stones. Ultrasonic propulsion (UP) is a separate technology under investigation for displacing stones. We measure the effect of propulsion pulses on stone fragmentation from BWL. MATERIALS AND METHODS: Two artificial stone models (crystalline calcite, BegoStone plaster) and human calcium oxalate monohydrate (COM) stones measuring 5 to 8 mm were subjected to ultrasound exposures in a polyvinyl chloride tissue phantom within a water bath. Stones were exposed to BWL with and without propulsion pulses interleaved for set time intervals depending on stone type. Fragmentation was measured as a fraction of the initial stone mass fragmented to pieces smaller than 2 mm. RESULTS: BegoStone model comminution improved from 6% to 35% (p < 0.001) between BWL and BWL with interleaved propulsion in a 10-minute exposure. Propulsion alone did not fragment stones, whereas addition of propulsion after BWL slightly improved BegoStone model comminution from 6% to 11% (p < 0.001). BegoStone model fragmentation increased with rate of propulsion pulses. Calcite stone fragmentation improved from 24% to 39% in 5 minutes (p = 0.047) and COM stones improved from 17% to 36% (p = 0.01) with interleaved propulsion. CONCLUSIONS: BWL with UP improved stone fragmentation compared with BWL alone in vitro. The improvement was greatest when propulsion pulses are interleaved with BWL treatment and when propulsion pulses are applied at a higher rate. Thus, UP may be a useful adjunct to enhance fragmentation in lithotripsy in vivo. PMID- 29433331 TI - Pseudoaneurysm formation and rupture after stereotactic radiotherapy for cerebral arteriovenous malformation: a case report and review of literature. AB - We report a rare delayed complication of de novo pseudoaneurysm formation and rupture after stereotactic radiotherapy for cerebral arteriovenous malformation. The patient presented with intracerebral haemorrhage due to rupture of a pseudoaneurysm in the previously irradiated field, which was excised for histological examination. The literature was reviewed for similar cases. PMID- 29433332 TI - Generation of high-yield insulin producing cells from human-induced pluripotent stem cells on polyethersulfone nanofibrous scaffold. AB - Transplantation of islet is a promising method in treatment of patients with type 1 diabetes mellitus (T1DM), however, is limited by islet shortage. The aim of this study was to prepare a polyethersulfone (PES) nanofibrous scaffolds to evaluate the pancreatic differentiation of human induced pluripotent stem cells (hiPSCs). The differentiation process in tissue culture dishes and PES scaffolds was evaluated at mRNA and protein level by RT-qPCR and immunofluorescence assay, respectively. The functionality of differentiated cells was determined by insulin and C-peptide release in response to glucose challenges. The results of this study showed that cells cultured on PES nanofibrous scaffolds exhibit more pancreatic beta-cell characteristics as they express more pancreatic tissue specific genes and proteins. Furthermore, the immunoassay showed that differentiated cells in both culture plates and PES scaffolds groups are functional and secrete C-peptide and insulin in response to glucose challenges. Altogether, the results of this study demonstrated that PES nanofibrous scaffold could provide the microenvironment that promotes the differentiation of induced pluripotent stem cells (iPSCs) into insulin producing cells. PMID- 29433333 TI - Growth performance, duodenal morphology and the caecal microbial population in female broiler chickens fed glycine-fortified low protein diets under heat stress conditions. AB - 1. This study was undertaken to examine the effect of feeding glycine (Gly) fortified low protein (LP) diets on the growth performance, duodenal morphology and caecal microbial populations of broiler chickens raised under unheated, cyclic or constant heat stress environmental conditions. 2. From d 1 to 21 (starter phase), an equivalent number of birds were fed either a normal protein (NP) diet or a LP diet fortified with Gly. From d 22 to 42 (grower phase), an equivalent number of birds from each starter diet were distributed to one of the following dietary groups: (i) an NP diet during the starter and grower phases (NPNP), (ii) an NP diet during the starter phase and a LP diet during the grower phase (NPLP), (iii) an LP diet during the starter phase and an NP diet during the grower phase (LPNP) or (iv) LP diets during both phases (LPLP). 3. Commencing from d 22, an equivalent number of birds from each dietary group were exposed to (i) 23 +/- 1 degrees C throughout (unheated), (ii) 34 +/- 1 degrees C for 7 h each day from 10:00 to 17:00 (cyclic heat) or (iii) 34 +/- 1 degrees C throughout (constant heat). 4. Feeding the LP diet during the starter phase resulted in feed intake (FI), weight gain (WG), feed conversion ratios (FCR) and energy efficiency ratios (EER) similar to those for the NP diet. The birds fed the LP diet had a significantly higher protein efficiency ratio (PER) compared with the birds fed the NP diet. 5. During the grower phase, there were significant diet * temperature interactions for F, WG, FCR, PER, EER, villus height, crypt depth and caecal Clostridia. The birds fed the NPLP and LPLP diets had lower FI, WG and EER, higher FCR, shorter villus height and crypt depth and higher caecal Clostridia compared with the birds fed LPNP and NPNP diets under constant heat stress. However, feeding birds the NPLP and LPLP diets resulted in FI, WG, EER, FCR, morphology parameters and caecal Clostridia equivalent to the birds fed LPNP and NPNP diets, as well as improved PER, under unheated and cyclic heat stress conditions. 6. In conclusion, our results indicate that Gly-fortified LP diets can be fed to broilers under normal and acute heat stress environmental conditions without any adverse effects on performance. However, the use of such LP diets can be detrimental to broilers under chronic heat stress conditions. PMID- 29433335 TI - Relationship between the prognostic value of ventilatory efficiency and age in patients with heart failure. AB - Background Ventilatory efficiency decreases with age. This study aimed to investigate the prognostic significance and cut-off value of the minute ventilation/carbon dioxide production (VE/VCO2) slope according to age in patients with heart failure. Methods and results We analysed 1501 patients with heart failure from our observational cohort who performed maximal symptom-limited cardiopulmonary exercise testing and separated them into three age groups (<=55 years, 56-70 years and >=71 years) in total and according to the three ejection fraction categories defined by European Society of Cardiology guidelines. The endpoint was set as heart failure events, hospitalisation for heart failure or death from heart failure. The VE/VCO2 slope increased with age. During the median follow-up period of 4 years, 141 heart failure (9%) events occurred. In total, univariate Cox analyses showed that the VE/VCO2 slope (cont.) was significantly related to heart failure events, while on multivariate analysis, the prognostic significance of the VE/VCO2 slope (cont.) was poor, accompanied by a significant interaction with age ( P < 0.0001). The cut-off value of the VE/VCO2 slope increased with the increase in age in not only the total but also the sub ejection fraction categories. Multivariate analyses with a stepwise method adjusted for estimated glomerular filtration rate, peak oxygen consumption, atrial fibrillation and brain natriuretic peptide, showed that the predictive value of the binary VE/VCO2 slope separated by the cut-off value varied according to age. There was a tendency for the prognostic significance to increase with age irrespective of ejection fraction. Conclusion The prognostic significance and cut off value of the VE/VCO2 slope may increase with advancing age. PMID- 29433336 TI - Dumbell atypical teratoid/rhabdoid tumour (AT/RT) of the cervical spine. AB - Spinal Atypical Teratoid/Rhabdoid Tumour (AT/RT) is a highly malignant tumour, and its prognosis is dismal especially for very young patients. In this article, we present the case of a teenage boy with AT/RT in the cervical spine and its multimodality management. A review of the literature on ATRT of the spine is also presented. PMID- 29433338 TI - Regulating cellular stress responses: an emerging strategy for rational metallodrug design. PMID- 29433337 TI - Development of a pre-operative scoring system for predicting risk of post operative paediatric cerebellar mutism syndrome. AB - BACKGROUND: Despite previous identification of pre-operative clinical and radiological predictors of post-operative paediatric cerebellar mutism syndrome (CMS), a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. The aim of the project is to develop a simple imaging-based pre-operative risk scoring scheme to stratify patients in terms of post-operative CMS risk. METHODS: Pre-operative radiological features were recorded for a retrospectively assembled cohort of 89 posterior fossa tumour patients from two major UK treatment centers (age 2-23yrs; gender 28 M, 61 F; diagnosis: 38 pilocytic astrocytoma, 32 medulloblastoma, 12 ependymoma, 1 high grade glioma, 1 pilomyxoid astrocytoma, 1 atypical teratoid rhabdoid tumour, 1 hemangioma, 1 neurilemmoma, 2 oligodendroglioma). Twenty-six (29%) developed post operative CMS. Based upon results from univariate analysis and C4.5 decision tree, stepwise logistic regression was used to develop the optimal model and generate risk scores. RESULTS: Univariate analysis identified five significant risk factors and C4.5 decision tree analysis identified six predictors. Variables included in the final model are MRI primary location, bilateral middle cerebellar peduncle involvement (invasion and/or compression), dentate nucleus invasion and age at imaging >12.4 years. This model has an accuracy of 88.8% (79/89). Using risk score cut-off of 203 and 238, respectively, allowed discrimination into low (38/89, predicted CMS probability <3%), intermediate (17/89, predicted CMS probability 3-52%) and high-risk (34/89, predicted CMS probability >=52%). CONCLUSIONS: A risk stratification model for post-operative paediatric CMS could flag patients at increased or reduced risk pre-operatively which may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme will be proposed for use during the surgical consenting process. PMID- 29433339 TI - Deconstructing trait anxiety: a network perspective. AB - BACKGROUND AND OBJECTIVES: For decades, the dominant paradigm in trait anxiety research has regarded the construct as signifying the underlying cause of the thoughts, feelings, and behaviors that supposedly reflect its presence. Recently, a network theory of personality has appeared. According to this perspective, trait anxiety is a formative construct emerging from interactions among its constitutive features (e.g., thought, feelings, behaviors); it is not a latent cause of these features. DESIGN: In this study, we characterized trait anxiety as a network system of interacting elements. METHODS: To do so, we estimated a graphical gaussian model via the computation of a regularized partial correlation network in an unselected sample (N = 611). We also implemented modularity-based community detection analysis to test whether the features of trait anxiety cohere as a single network system. RESULTS: We find that trait anxiety can indeed be conceptualized as a single, coherent network system of interacting elements. CONCLUSIONS: This radically new approach to visualizing trait anxiety may offer an especially informative view of the interplay between its constitutive features. As prior research has implicated trait anxiety as a risk factor for the development of anxiety-related psychopathology, our findings also set the scene for novel research directions. PMID- 29433340 TI - Worry and rumination: do they prolong physiological and affective recovery from stress? AB - BACKGROUND: Anxiety and depression have been linked to repetitive negative self regulation styles in the form of worry and rumination respectively. Following predictions of the metacognitive model [Wells, A., & Matthews, G. (1994). Attention and emotion: A clinical perspective. Hove: Erlbaum], the current study compared the effect on recovery from stress of three strategies: worry, rumination, and distraction using a stress exposure paradigm. It was predicted that worry and/or rumination would be associated with delayed recovery on physiological and/or self-report indices when compared to distraction. METHOD: Fifty-four participants were randomly assigned to one of the self-regulation conditions and then completed a modified version of the Trier Social Stress Test [TSST; Kirschbaum, C., Pirke, K. M., & Hellhammer, D. H. (1993). The "TSST" - A tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology, 28, 76-81. doi: 10.1159/000119004 ]. Skin conductance and negative affect (NA) measurements were obtained at six different time points. RESULTS: Skin conductance indicated a prolonged recovery in the rumination condition when compared with the distraction condition. Individuals in the worry condition reported an immediate-delayed recovery from stress marked by higher NA scores in comparison to the distraction condition. CONCLUSIONS: These findings may provide important insights into the effects of different forms of repetitive negative thinking on physiological and psychological recovery from stress. The different response patterns observed are discussed within the context of the metacognitive model. PMID- 29433341 TI - Planting Seeds to Grow Healthy Children: Strategic Community Partnerships. AB - More than one third of U.S adults are considered obese, and childhood obesity has more than doubled in the past 30 years. Food security can influence obesity, in particular, within inner cities where access to healthy food is often limited. The use of a mobile food truck program (with refrigeration) was implemented in two large inner cities in Connecticut as part of an initiative aimed at helping low-income families with young children gain access to healthy food and nutrition education. Collaborating with community child care centers was used. The experiences of the families who participated in the program were assessed via focus groups. Main ideas derived from the focus groups were participant satisfaction with money saving suggestions, ideas for how to make healthier choices, and excitement about opportunities to receive foods that they would not normally buy. This innovative mobile food truck program demonstrated the value of strategic community partnerships to influence health. PMID- 29433342 TI - Promoting Resilience: Breaking the Intergenerational Cycle of Adverse Childhood Experiences. AB - Adverse childhood experiences (ACEs), including trauma exposure, parent mental health problems, and family dysfunction, put children at risk for disrupted brain development and increased risk for later health problems and mortality. These negative effects may be prevented by resilience promoting environments that include protective caregiving relationships. We sought to understand (1) parents' experiences of ACEs, (2) the perceived impact on parenting, (3) protective factors that buffer ACEs potential negative impact, and (4) supports and services that can reduce the number and severity of ACEs and promote resilience among children exposed to early adversity. We conducted in-depth qualitative interviews with 11 low-income, urban parents of young children who had experienced ACEs. Interviews were analyzed for emergent themes and shared with parents from the community to ensure relevance and proper interpretation. Themes from these interviews describe the potential intergenerational cycle of ACEs and key factors that can break that cycle, including parent aspirations to make children's lives better and parent nurturance and support. Parents' suggestions for intervention are also presented. Our findings illuminate protective factors and family strengths that are important to build upon when developing and implementing interventions to promote resilience among parents and children exposed to early adversity. This study benefits from highly ecologically valid data obtained from low-socioeconomic status, racial/ethnic minority parents through one-on-one in depth interviews and interpreted with the aid of community stakeholders through a community-based participatory research approach. PMID- 29433343 TI - Cardiac-Specific Expression of DeltaH2-R15 Mini-Dystrophin Normalized All Electrocardiogram Abnormalities and the End-Diastolic Volume in a 23-Month-Old Mouse Model of Duchenne Dilated Cardiomyopathy. AB - Heart disease is a major health threat for Duchenne/Becker muscular dystrophy patients and carriers. Expression of a 6-8 kb mini-dystrophin gene in the heart holds promise to change the disease course dramatically. However, the mini dystrophin gene cannot be easily studied with adeno-associated virus (AAV) gene delivery because the size of the minigene exceeds AAV packaging capacity. Cardiac protection of the DeltaH2-R19 minigene was previously studied using the cardiac specific transgenic approach. Although this minigene fully normalized skeletal muscle force, it only partially corrected electrocardiogram and heart hemodynamics in dystrophin-null mdx mice that had moderate cardiomyopathy. This study evaluated the DeltaH2-R15 minigene using the same transgenic approach in mdx mice that had more severe cardiomyopathy. In contrast to the DeltaH2-R19 minigene, the DeltaH2-R15 minigene carries dystrophin spectrin-like repeats 16 to 19 (R16-19), a region that has been suggested to protect the heart in clinical studies. Cardiac expression of the DeltaH2-R15 minigene normalized all aberrant electrocardiogram changes and improved hemodynamics. Importantly, it corrected the end-diastolic volume, an important diastolic parameter not rescued by DeltaH2 R19 mini-dystrophin. It is concluded that that DeltaH2-R15 mini-dystrophin is a superior candidate gene for heart protection. This finding has important implications in the design of the mini/micro-dystrophin gene for Duchenne cardiomyopathy therapy. PMID- 29433344 TI - Association of cardiovascular risk factors on myocardial perfusion and fibrosis in asymptomatic individuals: cardiac magnetic resonance study. AB - Background Myocardial perfusion reserve index (MPRI) and extracellular volume fraction (ECV) on cardiac magnetic resonance (CMR) are known to quantify coronary microvascular dysfunction and myocardial fibrosis, respectively. Purpose To demonstrate that cardiovascular risk factors such as hypertension, diabetes, hyperlipidemia, and smoking are correlated with MPRI and ECV on CMR in asymptomatic individuals. Material and Methods Between October 2013 and July 2014, 196 individuals underwent CMR. After excluding those with chest pain, arrhythmia, and obstructive coronary artery disease, participants were divided into five groups: those without risk factor (n = 26) and those with one (n = 43), two (n = 35), three (n = 24), or four (n = 6) risk factors. MPRI and ECV were obtained on perfusion CMR and pre- and post-T1 mapping, respectively. Results A total of 134 asymptomatic individuals (109 men, 25 women; mean age = 54.4 +/- 7.08 years; body mass index [BMI] = 24.96 +/- 2.76 kg/m2; Framingham risk score [FRS] = 7.71 +/- 5.21) were included. The Jonckheere-Terpstra test demonstrated trends of increasing BMI, FRS, and left ventricular mass index (all P values < 0.001), but decreasing MPRI ( P = 0.001) with increasing numbers of risk factors. Stepwise multiple linear regression demonstrated that an increasing number of cardiovascular risk factors was an independent predictor of MPRI ( P = 0.001). However, there was no significant association between the number of risk factors and ECV ( P = 0.99). Conclusion We demonstrated that an increasing number of cardiovascular risk factors is significantly associated with reduced MPRI, but not with ECV on CMR. PMID- 29433345 TI - Computed tomography densitometric study of anti-angiogenic effect of regorafenib in colorectal cancer liver metastasis. AB - AIM: Regorafenib induces radiological changes in liver metastasis among patients with metastatic colorectal cancer (mCRC). The standard criteria used to evaluate solid tumor response (Response Evaluation Criteria in Solid Tumors) may be limited in assessing response to biologic agents with anti-angiogenic action. PATIENTS & METHODS: A total of 67 hepatic lesions in 32 selected patients were analyzed to evaluate tumor attenuation as measured by Hounsfield unit (HU) and size changes. RESULTS: Following two cycles of regorafenib, tumor HU values decreased in the in 73.1% (49/67) of lesions (average HU changes -25.6%) while tumor size increased in 64.2% (43/67) of them (average size changes +25.4%). CONCLUSION: The computed tomography density changes evaluation may be an additional tool, in combination with tumor sizing, to evaluate tumor response in patients treated with regorafenib. PMID- 29433346 TI - Mannosylated solid lipid nanoparticles for the selective delivery of rifampicin to macrophages. AB - Tuberculosis (TB) is still a devastating disease and more people have died of TB than any other infectious diseases throughout the history. The current therapy consists of a multidrug combination in a long-term treatment, being associated with the appearance of several adverse effects. Thus, solid lipid nanoparticles (SLNs) were developed using mannose as a lectin receptor ligand conjugate for macrophage targeting and to increase the therapeutic index of rifampicin (RIF). The developed SLNs were studied in terms of diameter, polydispersity index, zeta potential, encapsulation efficiency (EE) and loading capacity (LC). Morphology, in vitro drug release and differential scanning calorimetry studies, macrophage uptake studies, cell viability and storage stability studies were also performed. The diameter of the SLNs obtained was within the range of 160-250 nm and drug EE was above 75%. The biocompatibility of M-SLNs was verified and the internalization in macrophages was improved with the mannosylation. The overall results suggested that the developed mannosylated formulations are safe and a promising tool for TB therapy targeted for macrophages. PMID- 29433347 TI - Neuroimaging utilization and findings in headache outpatients: Significance of red and yellow flags. AB - Background Neuroimaging for headache commonly exceeds published guideline recommendations and may be overutilized. Methods We conducted a retrospective cross-sectional study of all outpatient community patients at Mayo Clinic Rochester who underwent a neuroimaging study for a headache indication in 2015. We assessed the neuroimaging utilization pattern, clinical application of red flags, and concordance with neuroimaging guidelines. Results We identified 190 outpatients who underwent 304 neuroimaging studies for headache. The median age was 46.5 years (range 18-91 years), 65% were female, and most reported no prior history of headache (n = 97, 51%). A minority of patients had prior brain imaging studies (n = 44, 23%) and neurological consultations for headache (n = 29, 15%). Few studies were ordered after consultation with a neurologist (n = 14, 7%). Seventy-seven percent of patients were documented to have a "red flag" justifying the imaging study. Abnormal neuroimaging findings were found in 3.1% of patients with warning flags (5/161); carotid dissection (n = 3) and reversible cerebral vasoconstrictive syndrome (n = 2). An estimated 35% of patients were imaged against guidelines. Conclusions The prevalence of serious causes of headache in a community practice was low despite the presence of a documented red flag symptom. Inadequate understanding or application of red flags may be contributing to recommendations to image patients against current guidelines. Interventions to reduce unnecessary neuroimaging of patients with headache need to be designed and implemented. PMID- 29433348 TI - Affection, Deception, and Evolution: Deceptive Affectionate Messages as Mate Retention Behaviors. AB - This study explored how partner mate value (PMV) and factors indicative of the relational climate (i.e., commitment and satisfaction) might affect individuals' tendency to use deceptive affectionate messages (DAMs). Participants ( N = 203) responded to a survey including measures regarding these variables. Contrary to predictions, PMV and the tendency to engage in DAMs were significantly and negatively associated with one another. Analyses further indicated that commitment significantly moderated the negative association between PMV and DAMs. The present study also provided evidence that when commitment to the relationship is low, satisfaction mediates the negative association between PMV and DAMs. PMID- 29433349 TI - Radiation-induced enteropathy - how a low-FODMAP diet might help. PMID- 29433350 TI - A review of post-caesarean infectious morbidity: how to prevent and treat. AB - Post-caesarean infectious complications result in significant maternal morbidity and mortality as well as increased readmissions and increased health care cost worldwide. This review provides a discussion of several risk factors that have been identified which predispose women to post-surgical infection. We also provide an overview of strategies for infection prevention including antibiotics, surgical techniques and negative pressure wound therapy. Criteria for diagnosis of wound infection are provided, as well as appropriate treatment regimens. Given the impact of maternal post caesarean infection, it is important for women's health care providers to understand how to prevent these infections, as well as recognise and treat them. PMID- 29433351 TI - Transcatheter pulmonary valve implantation: will it replace surgical pulmonary valve replacement? AB - INTRODUCTION: Right ventricular outflow tract (RVOT) dysfunction is a common hemodynamic challenge for adults with congenital heart disease (ACHD), including patients with repaired tetralogy of Fallot (TOF), truncus arteriosus (TA), and those who have undergone the Ross procedure for congenital aortic stenosis and the Rastelli repair for transposition of great vessels. Pulmonary valve replacement (PVR) has become one of the most common procedures performed for ACHD patients. Areas covered: Given the advances in transcatheter technology, we conducted a detailed review of the available studies addressing the indications for PVR, historical background, evolving technology, procedural aspects, and the future direction, with an emphasis on ACHD patients. Expert commentary: Transcatheter pulmonary valve implantation (TPVI) is widely accepted as an alternative to surgery to address RVOT dysfunction. However, current technology may not be able to adequately address a subset of patients with complex RVOT morphology. As the technology continues to evolve, new percutaneous valves will allow practitioners to apply the transcatheter approach in such patients. We expect that with the advancement in transcatheter technology, novel devices will be added to the TPVI armamentarium, making the transcatheter approach a feasible alternative for the majority of patients with RVOT dysfunction in the near future. PMID- 29433352 TI - Buprenorphine alone or with naloxone: Which is safer? AB - To address concerns regarding the intravenous diversion of buprenorphine, a combined buprenorphine-naloxone (BUP-NLX) preparation was developed. The aim of this study is to compare health outcomes in opioid dependent patients treated with BUP and BUP-NLX. All patients treated with BUP and/or BUP-NLX in Western Australia between 2001 and 2010 were included in the study ( N = 3455). Patients were identified via State prescribing records and matched against the State mortality, hospital, and emergency department records. Rates of health events were examined and compared using Cox Proportional Hazard Models and Generalized Estimating Equations. While on treatment there was no significant difference between mortality rates in the two groups, mortality rates following the cessation of treatment were significantly higher in patients treated with BUP-NLX (adjusted hazard ratio: 1.59). Rates of hospitalization were significantly elevated in BUP-NLX patients (adjusted odds ratio: 1.17) compared with BUP treated patients; however, rates of hospitalization with a skin/subcutaneous diagnosis were significantly lower in BUP-NLX treated patients (adjusted odds ratio: 0.65). Off-treatment rates of both all-cause hospital admissions (adjusted odds ratio: 1.53) and hospital admissions with an opioid poisoning diagnosis (adjusted odds ratio: 1.59) were significantly elevated in BUP-NLX treated patients compared with BUP treated patients. The addition of naloxone does not appear to improve the safety profile of buprenorphine. PMID- 29433353 TI - Prenatal diagnosis of double trisomy 48, XXX, +18; case report. PMID- 29433354 TI - The use of medial, wider vertical compression sutures to reduce uterine blood flow for effaced uterine isthmus: a case report. PMID- 29433355 TI - What would be missed in the first trimester if nuchal translucency measurement is replaced by cell free DNA foetal aneuploidy screening? AB - The aim of this study was to evaluate which chromosomal abnormalities in our cohort of foetuses with increased nuchal translucency (NT) in the first trimester of pregnancy could be detected by cell free (cf)DNA screening as well. There were 775 singleton pregnancies referred for cytogenetic testing due to an increased NT (>=3.0 mm). Chromosome aberrations were investigated using karyotyping or chromosomal microarray analysis (CMA). Karyotyping had been chosen for foetal cytogenetic testing by 446 patients, and CMA by 329 patients. Common aneuploidies (trisomies 21, 18, 13 and sex aneuploidies) were detected in 2.2% (99/446) and 1.8% (59/329) cases, respectively. In 329 with CMA testing, clinically significant copy number variations (CNVs) other than common aneuploidies were detected in 2.7% cases; among these, five had a pathogenic microscopic CNV, which could have been detected by karyotyping. There were four cases (1.2%) having a pathogenic submicroscopic CNV, which could have been missed by karyotyping. The total CMA detection rate (23.4%) was not statistically different from that (24.2%) by karyotyping (p > .05). The percentage of chromosomal aberrations, which cfDNA screening would miss in patients with increased NT in the first trimester, might be the same as in those with normal NT. Impact statement What is already known about this topic? First trimester NT is a powerful marker for screening for common aneuploidies. cfDNA screening is more accurate than any standard screening with NT. The need of NT in the era of prenatal screening using cfDNA is debated. What does this study add? An increased NT did not identify any additional aneuploidies that were detected by cfDNA screening. What are the implications of these findings for clinical practice and/or further research? The percentage of chromosomal aberrations which cfDNA screening would miss in patients with increased NT might be the same as in those with normal NT. PMID- 29433356 TI - Complex maternal congenital anomalies - a rare presentation and delivery through a supra-umbilical abdominal incision. PMID- 29433358 TI - Correction to: Ma et al., Controlled synthesis and size effects of multifunctional mesoporous silica nanosystem for precise cancer therapy. PMID- 29433357 TI - Transferrin and octaarginine modified dual-functional liposomes with improved cancer cell targeting and enhanced intracellular delivery for the treatment of ovarian cancer. AB - Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to enhance the delivery of therapeutics to tumors. Among many approaches for active tumor-targeting, arginine-rich cell penetrating peptides (AR-CPP) and ligands specific to target over-expressed receptors on cancer-cell surfaces, are popular. Earlier, we showed that the attachment of an AR-CPP octaarginine (R8) to the surface of DOXIL(r) (Doxorubicin encapsulated PEGylated liposomes) improved cytoplasmic and nuclear DOX delivery that enhanced the cytotoxic effect in vitro and improved therapeutic efficacy in vivo. Here, we report on DOX-loaded liposomes, surface-modified with, R8 and transferrin (Tf) (Dual DOX-L), to improve targeting of A2780 ovarian carcinoma cells via the over expressed transferrin receptors (TfRs) with R8-mediated intracellular DOX delivery. Flow cytometry analysis with fluorescently labeled DualL (without DOX) showed two-fold higher cancer-cell association than other treatments after 4 h treatment. Blocking entry pathways of R8 (macropinocytosis) and Tf (receptor mediated endocytosis, RME) resulted in a decreased cancer-cell association of DualL. Confocal microscopy confirmed involvement of both entry pathways and cytoplasmic liposome accumulation with nuclear DOX delivery for Dual DOX-L. Dual DOX-L exhibited enhanced cytotoxicity in vitro and was most effective in controlling tumor growth in vivo in an A2780 ovarian xenograft model compared to other treatments. A pilot biodistribution study showed improved DOX accumulation in tumors after Dual DOX-L treatment. All results collectively presented a clear advantage of the R8 and Tf combination to elevate the therapeutic potential of DOX-L by exploiting TfR over-expression imparting specificity followed by endosomal escape and intracellular delivery via R8. PMID- 29433360 TI - AMPK/Nrf2 signaling is involved in the anti-neuroinflammatory action of Petatewalide B from Petasites japonicus against lipopolysaccharides in microglia. AB - OBJECTIVES: Abnormal microglia secrete neuroinflammatory factors that play a pivotal role in neurodegenerative-disorder development. Thus, regulating abnormal microglia-activation could be a promising therapeutic strategy. The purposes of this study included investigating the effect of Petatewalide B on lipopolysaccharide- (LPS-) stimulated microglia and exploring the role of the AMPK/Nrf2- (adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2) signaling pathway in the anti-neuroinflammatory function of Petatewalide B. METHODS: We divided the microglia into four groups: a control group, a Petatewalide B-treated group, an LPS-treated group, and an LPS and Petatewalide B-treated group. The four groups of microglia were experimented with, using the NO, ELISA, and promoter assays, and western blotting was conducted to determine LPS-stimulated neuroinflammatory responses. RESULTS: We found that pretreatment with Petatewalide B strongly alleviates interleukin- (IL ) 1beta, IL-6, and tumor-necrosis-factor-alpha (TNF-alpha) production, and suppresses iNOS and nitric oxide (NO) overexpression in LPS-stimulated microglia. The AMPK/Nrf2-signaling pathway is important for inducing anti-neuroinflammatory responses. Mechanistic studies report that Petatewalide B increases nuclear-Nrf2 translocation, and heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) expression in a dose-dependent manner. Furthermore, Petatewalide B significantly up-regulates HO-1 and NQO1 by specifically improving antioxidant response-elements-transcription activity. We then investigated whether Nrf2/HO 1/NQO1 contribute to the anti-neuroinflammatory properties of Petatewalide B. Nrf2, HO-1, and NQO1 small-integrating-ribonucleic-acids (siRNAs) significantly blocked Petatewalide B-attenuated iNOS-promoter-activity in LPS-stimulated microglia. Furthermore, Petatewalide B also up-regulated AMPK-phosphorylation in a dose-dependent manner. We next evaluated whether blocking AMPK-phosphorylation using an inhibitor (compound C) would critically affect anti-neuroinflammatory responses. We found that the AMPK-phosphorylation is associated with nuclear-Nrf2 translocation and elevated HO-1 and NQO1 expression levels. Our data also showed that AMPK-inhibitor pretreatment significantly reverses Petatewalide B-attenuated iNOS-promoter-activity in LPS-stimulated microglia. CONCLUSIONS: Our findings provide the possible mechanism of the anti-neuroinflammatory properties of Petatewalide B that result from beneficial responses in the AMPK/Nrf2-signaling pathway. PMID- 29433361 TI - Takotsubo cardiomyopathy associated with buprenorphine precipitated withdrawal. PMID- 29433359 TI - Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models. AB - : Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is caused by genetics, environmental factors and aging, with few treatments currently available. Apoptosis and macroautophagy/autophagy play critical roles in PD pathogenesis; as such, modulating their balance is a potential treatment strategy. BCL2 (B cell leukemia/lymphoma 2) is a key molecule regulating this balance. Piperlongumine (PLG) is an alkaloid extracted from Piper longum L. that has antiinflammatory and anticancer effects. The present study investigated the protective effects of PLG in rotenone-induced PD cell and mouse models. We found that PLG administration (2 and 4 mg/kg) for 4 wk attenuated motor deficits in mice and prevented the loss of dopaminergic neurons in the substantia nigra induced by oral administration of rotenone (10 mg/kg) for 6 wk. PLG improved cell viability and enhanced mitochondrial function in primary neurons and SK-N-SH cells. These protective effects were exerted via inhibition of apoptosis and induction of autophagy through enhancement of BCL2 phosphorylation at Ser70. These results demonstrate that PLG exerts therapeutic effects in a rotenone-induced PD models by restoring the balance between apoptosis and autophagy. ABBREVIATIONS: 6-OHDA, 6 hydroxydopamine; ACTB, actin, beta; BafA1, bafilomycin A1; BAK1, BCL2 antagonist/killer 1; BAX, BCL2-associated X protein; BCL2, B cell leukemia/lymphoma2; BECN1, Beclin 1, autophagy related; CoQ10, coenzyme Q10; COX4I1/COX IV, cytochrome c oxidase subunit 4I1; CsA, cyclosporine A; ED50, 50% effective dose; FITC, fluorescein isothiocyanate; GFP, green fluorescent protein; HPLC, high-performance liquid chromatography; JC-1, tetraethylbenz imidazolylcarbocyanine iodide; LC3, microtubule-associated protein 1 light chain3; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LDH, lactate dehydrogenase; l-dopa, 3, 4-dihydroxyphenyl-l-alanine; MAPK8/JNK1, mitogen activated protein kinase 8; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mRFP, monomeric red fluorescent protein; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MTT, 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NFE2L2/NRF2, nuclear factor, erythroid derived 2, like 2; PD, Parkinson disease; PLG, piperlongumine; pNA, p-nitroanilide; PI, propidium iodide; PtdIns3K, phosphatidylinositol 3 kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PTX, paclitaxel; Rap, rapamycin; SQSTM1/p62, sequestosome 1; TH, tyrosine hydroxylase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; WIPI2, WD repeat domain, phosphoinositide interacting 2; ZFYVE1/DFCP1, zinc finger, FYVE domain containing 1. PMID- 29433362 TI - The ICF has made a difference to functioning and disability measurement and statistics. AB - AIMS: Fifteen years after the publication of the International Classification of Functioning, Disability and Health (ICF), we investigated: How ICF applications align with ICF aims, contents and principles, and how the ICF has been used to improve measurement of functioning and related statistics. METHODS: In a scoping review, we investigated research published 2001-2015 relating to measurement and statistics for evidence of: a change in thinking; alignment of applications with ICF specifications and philosophy; and the emergence of new knowledge. RESULTS: The ICF is used in diverse applications, settings and countries, with processes largely aligned with the ICF and intended to improve measurement and statistics: new national surveys, information systems and ICF-based instruments; and international efforts to improve disability data. Knowledge is growing about the components and interactions of the ICF model, the diverse effects of the environment on functioning, and the meaning and measurement of participation. CONCLUSION: The ICF provides specificity and a common language in the complex world of functioning and disability and is stimulating new thinking, new applications in measurement and statistics, and the assembling of new knowledge. Nevertheless, the field needs to mature. Identified gaps suggest ways to improve measurement and statistics to underpin policies, services and outcomes. Implications for Rehabilitation The ICF offers a conceptualization of functioning and disability that can underpin assessment and documentation in rehabilitation, with a growing body of experience to draw on for guidance. Experience with the ICF reminds practitioners to consider all the domains of participation, the effect of the environment on participation and the importance of involving clients/patients in assessment and service planning. Understanding the variability of functioning within everyday environments and designing interventions for removing barriers in various environments is a vital part of rehabilitation planning. PMID- 29433363 TI - To 'douche' or not to 'douche': hygiene habits may have detrimental effects on vaginal microbiota. AB - The importance of a healthy vaginal micro-flora is indisputable. Therefore, intravaginal practices, such as vaginal douching (VD), may inhibit or lower the colonisation of beneficial Lactobacilli strains. Although the results of disrupted vaginal microbiota have been widely reported in the literature, direct microbicidal effects of products used for VD have been rarely studied. Moreover, there are certain studies advocating the beneficial effects of VD. This in vitro study was designed to provide more evidence to help health care givers in disseminating the knowledge that VD might have detrimental effects on vaginal microbiota. Three commercially available VD products (A, B and C) were examined for their minimal inhibiting concentrations (MICs) against Lactobacilli strains. Although the MICs of product A (ranging from 0.19% to 0.09%, p < .05) were proven to be lower than the other two, all the products were potentially able to inhibit the growth of Lactobacilli strains effectively, and hence should be used with caution. Impact statement What is already known on this subject? The importance of vaginal microbiota has long been reported for the maintenance of health. The lack of a healthy vaginal ecosystem may lead to various diseases including pelvic inflammatory disease, bacterial vaginosis, sexually transmitted diseases, etc. Moreover, studies also stress that lack of beneficial bacteria may lead to miscarriages, premature delivery, ectopic pregnancy and cervical cancer. Despite a huge amount of data regarding the importance of vaginal microbiota, studies confirm that women still utilise VD for various reasons. Whilst the detrimental effect of VD have been widely reported in the literature; there are a few publications advocating the potential benefits of VD. Educational efforts are reported to lessen this practice. What do the results of this study add? In this in vitro study we aimed to substantiate the bactericidal potential of three commercially available products. There are studies about the clinical outcomes of VD, but a limited number of in vitro studies exist. Our results represent a direct measure of how potentially destructive VD is. What are the implications of these findings for clinical practice and/or further research? This information can be used for educational purposes, enhancing the efforts provided by health care givers used to lessen VD practice. PMID- 29433364 TI - Surgical management of superior petrosal sinus dural arteriovenous fistulae with dominant internal carotid artery supply. AB - Background While technological advances have improved the efficacy of endovascular techniques for tentorial dural arteriovenous fistulae (DAVF), superior petrosal sinus (SPS) DAVF with dominant internal carotid artery (ICA) supply frequently require surgical intervention to achieve a definitive cure. Methods To compare the angiographic and clinical outcomes of endovascular and surgical interventions in patients with SPS DAVF, the records of all patients with tentorial DAVF from August 2010 to November 2015 were reviewed. Results Within this cohort, eight patients with nine SPS DAVF were eligible for evaluation. Five DAVF were initially treated with endovascular embolization, while four underwent surgical occlusion without embolization. Of the SPS DAVF treated with embolization, two (40%) remained occluded on follow-up, while the remaining three (60%) persisted/recurred and required surgical intervention for definitive closure. Of the four SPS DAVF treated with primary surgical occlusion, all four (100%) remained closed on follow-up. In addition, of the three SPS DAVF that persisted/recurred following embolization and required subsequent surgical closure, all three (100%) remained occluded on follow-up. Two (100%) SPS DAVF that were successfully treated with embolization had major or minor external carotid artery supply, while the three (100%) persistent lesions had major ICA supply via the meningohypophyseal trunk (MHT). Three (75%) of the four SPS DAVF treated with primary surgical occlusion had dominant MHT supply. Conclusion Complete endovascular closure of SPS DAVF with dominant ICA supply via the MHT may be difficult to achieve, while upfront surgical intervention is associated with a high rate of complete occlusion. PMID- 29433365 TI - Treatment outcomes in cerebral artery dissection and literature review. AB - Methods Patients with cerebral artery dissections were reviewed in a hospital setting from 2008 to 2015. Clinical presentations, lesion locations, treatment modalities, functional outcomes, and mortality were reviewed. Parent artery occlusion was the first choice for surgery or endovascular treatment of a hemorrhagic dissecting cerebral artery. Endovascular or surgical reconstructive treatment was indicated in patients whose parent artery could not be occluded. Favorable functional outcomes were determined using modified Rankin Scale (mRS) scores of 0-2. Results In total, 61 patients with cerebral artery dissections were admitted to the hospital. Seven (11.5%) had traumatic dissections. All traumatic dissections were located in the internal carotid arteries. Overall favorable outcome rate was about 57% (4/7). Spontaneous cerebral artery dissections were found in 54 patients. No difference in favorable outcomes was observed between parent vessel occlusion and selective occlusion with parent vessel preservation (or vessel reconstruction) (70% and 63%, respectively, p = 1.000). Patients who presented with spontaneous dissection without intracranial hemorrhage had more favorable outcomes than those with intracranial hemorrhage (79% and 52%, respectively, p = 0.045). The mortality rate of patients with spontaneous dissection was 7.4%. Conclusions Most of the traumatic dissections were located on the internal carotid arteries and spontaneous dissections were commonly located on vertebral arteries. Nonhemorrhagic spontaneous cerebral dissections had better functional outcomes after treatment. Endovascular and surgical management were effective treatments by parent vessel occlusion or reconstructions. PMID- 29433366 TI - Mode of birth in twins: data and reflections. AB - Our primary objective was to compare neonatal and maternal outcomes in women with twin pregnancies, beyond 32 weeks, having a planned vaginal birth or a planned caesarean section (CS). This was a retrospective cohort study from a single tertiary centre over nine years. 534 sets of twins >=32 + 0 weeks of gestation were included. 401 sets were planned vaginally and 133 sets were planned by CS. We compared a composite adverse perinatal outcome (perinatal mortality or serious neonatal morbidity; five minute APGAR score <=4, neurological abnormality and need for intubation) and a composite maternal adverse outcome (major haemorrhage, trauma or infection) between the groups. There were no significant differences. Given the similarity of these results with several other larger studies of twin birth, we sought to look at reasons why there is still a rising rate of CS for twin births. We further make suggestions for keeping this rate to a sensible minimum. Impact statement What is already known on this subject? The largest randomised controlled study comparing planned vaginal birth with planned CSs for lower risk twins between 32 and 39 weeks of gestation, showed no added safety from planned CS. However, in most of the Western countries this conclusion has failed to increase the number of planned vaginal births for lower risk twins. What do the results of this study add? This observational study from a single tertiary centre provides external validation of the twin trial results in a practical day-to-day setting. It also provides insights as to how planned vaginal birth can be developed and maintained, with a key focus on safety and maternal participation in decision making. It does focus on consent and providing accurate data. What are the implications of these findings for clinical practice and/or further research? There are good grounds to encourage vaginal birth for low-risk twin pregnancies. The trend of rising caesarean rates in low-risk twin pregnancies worldwide will erode important skills for the conduct of vaginal births without any clear benefit for mothers or babies. The current situation demands careful thought about implementing innovative training opportunities for younger obstetricians. Finally, we need intelligent responses to many non evidence-based factors which can drive clinical practice. PMID- 29433367 TI - Experimental animal models for rheumatoid arthritis. AB - Rheumatoid Arthritis (RA) is an autoimmune systemic disorder of unknown etiology and is characterized by chronic inflammation and synovial infiltration of immune cells. RA is associated with decreased life expectancy and quality of life. The research on RA is greatly simplified by animal models that help us to investigate the complex system involving inflammation, immunological tolerance and autoimmunity. The animal models of RA with a proven track record of predictability for efficacy in humans include: collagen type II induced arthritis in rats as well as mice, adjuvant induced arthritis in rats and antigen induced arthritis in several species. The development of novel treatments for RA requires the interplay between clinical observations and studies in animal models. However, each model features a different mechanism driving the disease expression; the benefits of each should be evaluated carefully in making the appropriate choice for the scientific problem to be investigated. In this review article, we focus on animal models of arthritis induced in various species along with the genetic models. The review also discussed the similarity and dissimilarities with respect to human RA. PMID- 29433368 TI - Teaching childbirth with high-fidelity simulation. Is it better observing the scenario during the briefing session? AB - The design of optimal courses for obstetric undergraduate teaching is a relevant question. This study evaluates two different designs of simulator-based learning activity on childbirth with regard to respect to the patient, obstetric manoeuvres, interpretation of cardiotocography tracings (CTG) and infection prevention. This randomised experimental study which differs in the content of their briefing sessions consisted of two groups of undergraduate students, who performed two simulator-based learning activities on childbirth. The first briefing session included the observations of a properly performed scenario according to Spanish clinical practice guidelines on care in normal childbirth by the teachers whereas the second group did not include the observations of a properly performed scenario, and the students observed it only after the simulation process. The group that observed a properly performed scenario after the simulation obtained worse grades during the simulation, but better grades during the debriefing and evaluation. Simulator use in childbirth may be more fruitful when the medical students observe correct performance at the completion of the scenario compared to that at the start of the scenario. Impact statement What is already known on this subject? There is a scarcity of literature about the design of optimal high-fidelity simulation training in childbirth. It is known that preparing simulator-based learning activities is a complex process. Simulator-based learning includes the following steps: briefing, simulation, debriefing and evaluation. The most important part of high-fidelity simulations is the debriefing. A good briefing and simulation are of high relevance in order to have a fruitful debriefing session. What do the results of this study add? Our study describes a full simulator-based learning activity on childbirth that can be reproduced in similar facilities. The findings of this study add that high fidelity simulation training in childbirth is favoured by a short briefing session and an abrupt start to the scenario, rather than a long briefing session that includes direct instruction in the scenario. What are the implications of these findings for clinical practice and/or further research? The findings of this study reveal what to include in the briefing of simulator-based learning activities on childbirth. These findings have implications in medical teaching and in medical practice. PMID- 29433369 TI - Postpartum thromboprophylaxis in a multireligious cohort: a retrospective review of indications and uptake. AB - Strategies to prevent mortality from obstetric venous thromboembolism begin with identification, risk stratification and subsequently, implementation of prophylactic measures. We sought to identify the burden of pharmacologic thromboprophylaxis in postpartum women, including the main clinical indications and its uptake in a multireligious population, with Islam as the official religion. A total of 2514 deliveries between 1st January to 31st December 2016, across three centres in Malaysia were reviewed retrospectively from hospital based registries. 770 (30.62%) patients fulfilled the criteria for thromboprophylaxis based on the revised 2015 criteria proposed by the Royal College of Obstetricians and Gynaecologists. A combination of age, parity, BMI, caesarean section and preterm births were the main indications. One out of the five patients who delivered vaginally required thromboprophylaxis. In our setting with a sizable Muslim population, low molecular weight heparin was the thromboprophylaxis of choice in more than two-third of the patients. The information obtained from this study allows better local resource planning. Impact statement What is already known on this subject: Risk factors for venous thromboembolism in pregnancy and puerperium are largely drawn from registries due to the rarity of the index event. Up to 7% of women require antenatal thromboprophylaxis based on the criteria proposed by the Royal College of Obstetrician and Gynaecologists in 2009. What do the results of this study add: Using the RCOG guideline revised in 2015, a significant proportion of women delivering vaginally would require postnatal thromboprophylaxis based on age, parity and BMI. When either age or parity, both with relatively low odds ratio for thrombosis were omitted, a substantial proportion of women would not achieve the threshold for prophylaxis. Despite a sizable Muslim population in the country, the uptake of low molecular weight heparin was relatively high. What are the implications of these findings for clinical practice and/or future research: Cost-benefit studies should consider the adjusted odds ratio of individual indications on a VTE event. While uptake and acceptability is high, prospective studies on medication adherence is equally pertinent. PMID- 29433370 TI - Vitamin D deficiency in pregnant women and newborns in Lagos, Nigeria. AB - We aimed to determine the prevalence of Vitamin D deficiency among pregnant women and their newborns in order to make recommendations for Vitamin D supplementation, if necessary. It was a cross-sectional study carried out over a period of 12 months. Information such as use of Vitamin D supplements, number of daytime hours spent outdoors and dressing style was obtained from 166 pregnant women in Lagos, Nigeria; maternal and cord blood 25(OH)D concentration was determined using ELISA. The prevalence of Vitamin D deficiency (<20 ng/mL) in the mothers and newborns was 4.8% and 29.5%, respectively, while insufficiency (21-29 ng/mL) was 28.3% and 46.1%, respectively. Vitamin D supplement use during pregnancy, daytime outdoor exposure and mothers' dressing style were significantly associated with maternal serum 25(OH)D concentration (p < .05). Our study showed that despite a sunny environment like ours, inadequate serum 25(OH)D concentration is still considerable among pregnant women and their newborns and suggests a need for Vitamin D supplementation in pregnant women. Impact Statement What is already known on this subject? Vitamin D is an essential vitamin that plays a major role in maintaining pregnancy and ensuring adequate skeletal formation in the foetus. Studies have shown that there is high Vitamin D deficiency in pregnant women in the temperate regions of the world and thus Vitamin D supplements are being offered to these pregnant women. Studies have also shown that the foetal/neonatal serum Vitamin D level is a reflection of the maternal level. What the results of this study add? The results of this study adds that there may be some factors preventing adequate delivery of Vitamin D from the maternal circulation to the foetal circulation, because despite a low prevalence of Vitamin D deficiency in the mothers, their neonates had a high deficiency rate. What the implications are of these findings for clinical practice and/or further research? The implications of these findings are; further research is warranted in order to find what could be causing a reduced delivery of Vitamin D from the mothers to their foetuses, so as to prevent it if possible. Second, these findings suggest that our pregnant women should still receive a form of Vitamin D supplements, so as to raise their serum Vitamin D to a level which would guarantee optimal foetal concentration. PMID- 29433371 TI - Pregnancy complicated by systemic lupus erythematosus and its outcome over 10 years. AB - The aim was to study the feto-maternal outcome of pregnancies complicated by systemic lupus erythematosus (SLE). Analysis of a prospectively-maintained database of 73 patients (June 2006-March 2016) was done. Diagnosis of SLE was made by ACR(American College of Rheumatology)-criteria. Protocol scans and blood tests were done and patients with active disease were followed biweekly for 28 weeks, and weekly thereafter. Mean age + SD was 29 +/- 4.9. SLE was diagnosed before conception in 86% of patients. A total of 33% had active disease status during pregnancy and out of them 58% had a flare of SLE, compared to 26% who were in remission (p = .008). SLE activity had no effect on the rate of foetal demise (p = .57). Overall pregnancy loss was 14% with no maternal mortality. The incidence of SLE flare during pregnancy was significantly higher in patients who had active disease. But the incidence of foetal demise was not affected by disease activity. Impact Statement What is already known on this subject: SLE is one of the most common immunological disorders associated with pregnancy. Both SLE and pregnancy tend to influence each other due to complex interaction. The opinion seems to be divided regarding influence of pregnancy on SLE flare in world literature. What the results of this study add: Our data suggests a significantly greater incidence of SLE flare during pregnancy in patients with active disease, than in those in remission. What the implications are of these findings for clinical practice and/or further research: Though the majority of these flares were not major and did not require hospitalisation, these patients usually have a bad obstetric history. However, with multidisciplinary involvement, SLE activity in our series was not an independent predictor of a poor pregnancy outcome. PMID- 29433372 TI - Characterization of innate immune viral sensors in patients following allogeneic hematopoietic stem cell transplantation. AB - Viral infection is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplant (HSCT), with up to one in four deaths directly linked to viral disease. Whilst awaiting lymphocyte reconstitution post-HSCT, the innate antiviral immune response is the first line of defense against invading viruses. Several novel innate viral-sensing pathways have recently been characterized, but their physiological importance in humans is poorly understood. We analyzed a panel of innate viral-sensor genes in HSCT patients, and assessed whether differences in innate antiviral responses could account for variation in susceptibility to viral infections. Expression levels of innate viral sensors in HSCT patients with active viral infections, HSCT patients without active infections and healthy volunteers were highly homogenous. Although IFN-alpha expression was up-regulated in actively infected patients relative to controls, a corresponding up-regulation of innate viral sensor expression was not observed. IFN-alpha stimulation of patient PBMCs in vitro showed intact IFN-alpha signaling, but actively infected patients' PBMCs had reduced up-regulation of innate viral sensors. We show that the aberrant IFN-alpha responses in HSCT patients were not due to calcineurin inhibition. Our data therefore raises the possibility of an intrinsic defect in innate viral sensor up-regulation in HSCT patients following viral infection. PMID- 29433373 TI - Expression of angiogenic factors in sclerosing stromal tumours of the ovary. AB - Sclerosing stromal tumours (SSTs) are rare benign tumours and are generally observed in individuals in their teens to 20 s. Many cases are suspected as malignant tumours pre-operatively, owing to their high vascularity on diagnostic imaging. Herein, we aimed to evaluate the expressions of various angiogenic factors in SSTs. The expressions of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF) were examined by immunohistochemical staining. Upon immunohistochemistry, overexpressions of VEGF, bFGF, and HGF in the ovarian stroma were observed in SSTs. In the normal ovary, the expressions were strong around the vessels and weak in the stroma of the ovary, while a Sertoli-Leydig cell tumour showed weak staining with VEGF, locally strong staining with bFGF and negative staining with HGF. This is the first report about angiogenic factors such as bFGF, and HGF in SST. Impact statement What is already known on this subject? Sclerosing stromal tumour (SST) is a rare benign tumour with high vascularity. The high vascularity of SSTs are reported to be related to the overexpression of vascular endothelial growth factor (VEGF). But there is no study on the expressions of other angiogenic factors in SST. What do the results this study add? In the immunohistochemical analysis, VEGF, bFGF and HGF were found to be widely stained in SSTs. This results suggest the possibility that the high vascularity seen on diagnostic imaging, and the many small vessels observed microscopically may be related to the expressions of VEGF, bFGF and HGF in SSTs. What are the implications of these findings for clinical practice and/or further research? Our results suggest the possibility that the combined expression pattern of VEGF, bFGF, and HGF may be used as marker of SSTs. PMID- 29433374 TI - Objective evaluation of binaural summation through acoustic reflex measures. AB - OBJECTIVE: A previous study [Rawool, V. W. (2016). Auditory processing deficits: Assessment and intervention. New York, NY: Thieme Medical Publishers, Inc., pp. 186-187] demonstrated objective assessment of binaural summation through right contralateral acoustic reflex thresholds (ARTs) in women. The current project examined if previous findings could be generalised to men and to the left ear. DESIGN: Cross-sectional. STUDY SAMPLE: Sixty individuals participated in the study. Left and right contralateral ARTs were obtained in two conditions. In the alternated condition, the probe tone presentation was alternated with the presentation of the reflex activating clicks. In the simultaneous condition, the probe tone and the clicks were presented simultaneously. Binaural summation was calculated by subtracting the ARTs obtained in the simultaneous condition from the ARTs obtained in the alternated condition. RESULTS: MANOVA on ARTs revealed no significant gender or ear effects. The ARTs were significantly lower/better in the simultaneous condition compared to the alternated condition. CONCLUSIONS: Binaural summation was 4 dB or higher in 88% of the ears and 6 dB or higher in 76% of ears. Stimulation of six out of the total 120 (0.5%) ears resulted in worse thresholds in the simultaneous condition compared with the alternating condition, suggesting binaural interference. PMID- 29433375 TI - CXCR4 Antagonist AMD3100 Promotes Mesenchymal Stem Cell Mobilization in Rats Preconditioned with the Hypoxia-Mimicking Agent Cobalt Chloride. AB - Mobilization of mesenchymal stem cells (MSCs) is an attractive strategy for cell therapy. Our previous study demonstrated that MSCs can be mobilized in circulating blood by short-term hypoxia, and hypoxia-inducible factor-1alpha is essential for MSC mobilization. In the present study, the effect of the hypoxia mimicking agent CoCl2 was examined on MSC mobilization. The results indicated that the frequency of circulating MSCs increased slightly by administration of CoCl2. However, the mobilization efficiency was low. Considering the critical role of stromal cell-derived factor-1alpha (SDF-1)/CXCR4 axis in the regulation of MSC migration, the effects of granulocyte colony-stimulating factor (G-CSF) and the CXCR4 antagonist AMD3100 were investigated on MSC mobilization. The experiments were notably demonstrated in animals preconditioned with CoCl2. The frequency of colony-forming unit fibroblast and the proportion of CD45-CD90+ cells did not significantly increase in the peripheral blood of rats treated with G-CSF and/or AMD3100 alone. The concomitant administration of G-CSF with CoCl2 could not stimulate the release of MSCs. However, AMD3100 dramatically increased MSC mobilization efficiency in rats pretreated with CoCl2. Furthermore, we identified and compared the multilineage differentiation capacities of MSCs derived from bone marrow (BM-MSCs) and mobilized peripheral blood (PB-MSCs). The results indicated that PB-MSCs exhibited higher osteogenic potential and lower adipogenic differentiation as compared with BM-MSCs. The findings may inform studies investigating mechanisms of the regulation of MSC mobilization and can aid in the development of clinically useful therapeutic agents. PMID- 29433376 TI - Pomegranate supplementation improves cognitive and functional recovery following ischemic stroke: A randomized trial. AB - OBJECTIVES: We tested whether supplementing with pomegranate polyphenols can enhance cognitive/functional recovery after stroke. METHODS: In this parallel, block-randomized clinical trial, we administered commercially-available pomegranate polyphenol or placebo pills twice per day for one week to adult inpatients in a comprehensive rehabilitation setting starting approximately 2 weeks after stroke. Pills contained 1 g of polyphenols derived from whole pomegranate, equivalent to levels in approximately 8 oz of juice. Placebo pills were similar to the pomegranate pills except that they contained only lactose. Of the 163 patients that were screened, 22 were eligible and 16 were randomized (8 per group). We excluded one subject per group from the neuropsychological analyses since they were lost to follow-up, but we included all subjects in the analysis of functional data since outcome data were available. Clinicians and subjects were blinded to group assignment. Neuropsychological testing (primary outcome: Repeatable Battery for the Assessment of Neuropsychological Status) and functional independence scores were used to determine changes in cognitive and functional ability. RESULTS: Pomegranate-treated subjects demonstrated more neuropsychological and functional improvement and spent less time in the hospital than placebo controls. DISCUSSION: Pomegranate polyphenols enhanced cognitive and functional recovery after stroke, justifying pursuing larger clinical trials. PMID- 29433379 TI - Work-related musculoskeletal discomfort among heavy truck drivers. AB - BACKGROUND: Heavy truck drivers are exposed to various psychological, psychosocial and physiological factors, some of which can cause musculoskeletal discomfort in different body regions. PURPOSE: This study aims to investigate the correlation between different factors of musculoskeletal discomfort in heavy truck drivers. METHODS: A cross-sectional study design was applied. A total of 384 participants were interviewed using an updated version of the Nordic musculoskeletal questionnaire. While hypothesis testing was used to assess the association of different factors in musculoskeletal discomfort, logistic regression was applied to explore different correlations among questions of the survey. RESULTS: The results demonstrate that hours of exposure to vibration were associated with discomfort in the neck and shoulders (p < 0.001). This relationship was not statistically significant in the lower back area (p = 0.300). Additionally, 19 equations, their correlations and their odds ratios were formulated with Nagelkerke R2 > 0.05. CONCLUSION: Fifty-seven percent of the drivers were suffering from discomfort in their lower back region. Moreover, seat comfort was found to be highly correlated with discomfort in the neck, shoulder and upper back areas. Additionally, with aging the likelihood of experiencing discomfort in the neck, upper back and knees is increased. PMID- 29433378 TI - Image of the month: cyst of the canal of Nuck. PMID- 29433380 TI - Acute abdominal pain due to internal herniation of the sigmoid colon, fallopian tube and left ovary, a rare presentation of Allen Masters syndrome. AB - In 1955, Allen and Masters describe a painful syndrome which associates traumatic delivery to laceration found on the posterior leaf of the broad ligament. Herniation through this defect is a rare entity, accounted for about 4-7% of all internal hernias. Normally, it involves the small bowel. The authors present the case of a multiparous woman admitted at emergency for constipation and abdominal pain. The CT scan showed an extremely rare case of internal hernia of the sigmoid colon, fallopian tube and left ovary through a large defect of the broad ligament. The patient underwent a full laparoscopic surgery that allowed the reduction of the hernia and the suture of the defect with very good outcome. PMID- 29433382 TI - Corrigendum. PMID- 29433381 TI - Collateral circulation between angiosomes in the feet of diabetic patients. AB - Objectives The main factor in the healing of foot ulcers in diabetic patients is adequate perfusion. There is no consensus on whether direct or indirect revascularization is more effective in leg revascularization. At the centre of that debate, there is a disagreement about whether collateral circulation is sufficient or not. Our aim is to evaluate collateral circulation activity between angiosomes in the feet of diabetic patients by evaluating the level of occlusion in leg arteries and comparing the angiosome regions that have necrosis. Methods The study included 61 patients. All had undergone CT angiography to the lower extremity prior to any revascularization of the leg arteries between September 2014 and September 2016. Stenosis was evaluated on the anterior tibial artery, the posterior tibial artery and the peroneal artery up to the level of the ankle. The opening of the vessel wall at the narrowest part of the vessel was determined as a percentage. The areas with necrosis were determined according to the angiosomes of the posterior tibial artery, anterior tibial artery and peroneal artery vessels. Results Necrosis of the foot was most common in the posterior tibial artery angiosome. Necrosis in the posterior tibial artery angiosome was independent of the level of posterior tibial artery occlusion; however, it was associated with the occlusion of the anterior tibial artery ( p < 0.05). It was found that anterior tibial artery occlusion over 15% resulted in necrosis in the posterior tibial artery angiosome. Conclusions Collateral circulation between the anterior tibial artery and posterior tibial artery is active and there is almost always occlusion in the posterior tibial artery branches. The posterior tibial artery angiosome is fed by the collateral arteries of the anterior tibial artery even if there is no occlusion of posterior tibial artery at the level of the leg, so indirect revascularization on the anterior tibial artery is sufficient to provide foot circulation. PMID- 29433383 TI - Mycobacterium tuberculosis H37Rv infection regulates alternative splicing in Macrophages. AB - OBJECTIVE: The objective of this study was to evaluate the expression of genes encoding SR proteinsand alternative splicing of IL4 and TLR4 in Mycobacterium tuberculosis (M. tb) H37Rv-infected macrophages. MATERIALS AND METHODS: THP-1 cells were induced to differentiate into macrophages with 200 nM PMA, and H37Rv strains were used for macrophage infection. After RNA extraction, qRT-PCR was performed to evaluate the expression of many SR proteins as well as the alternative splicing of IL4 and TLR4. RESULTS: IL4 and TLR4 play significant roles in host immunity to tuberculosis. The level of IL-4 splice variants in THP 1 cells increased after M. tb H37Rv infection. Three splice variants of TLR4 were detected in M. tb-infected THP-1 cells, when compared with uninfected controls; the expression level of these splicing variants in M. tb-infected THP-1 cell was down-regulated. Since SR proteins are RNA-binding proteins that regulate RNA splicing, the expression of SR proteins was examined, and SRSF2 and SRSF3 were significantly down-regulated. In addition, splicing factors SRp75 and SF3a were also significantly down-regulated post M. tb infection. CONCLUSION: Our findings indicate that alternative splicing may be involved in host gene regulation post M. tb infection of macrophage cells. PMID- 29433384 TI - Region specific knock-out reveals distinct roles of chromatin modifiers in adult neurogenic niches. AB - Histone methyltransferases (HMTs) are present in heterogeneous cell populations within the adult brain including neurogenic niches. Yet the question remains whether loss of HMTs and the resulting changes in histone methylation alter cell fate in a region-specific manner. We utilized stereotaxic injection of Cre recombinant protein into the adult neurogenic niches, the subventricular zone (SVZ) adjacent to the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus. We confirmed that Cre protein was enzymatically active in vivo and recombination events were restricted to the vicinity of injection areas. In this study, we focus on using Cre mediated recombination in mice harboring floxed HMT: enhancer of zeste homolog 2 (EZH2) or suppressor of variegation homolog (Suv4 20h). Injectable Cre protein successfully knocked out either EZH2 or Suv4-20h, allowing assessment of long-term effects in a region-specific fashion. We performed meso-scale imaging and flow cytometry for phenotype analysis and unbiased quantification. We demonstrated that regional loss of EZH2 affects the differentiation paradigm of neural stem progenitor cells as well as the maintenance of stem cell population. We further demonstrated that regional loss of Suv4-20h influences the cell cycle but does not affect stem cell differentiation patterns. Therefore, Cre protein mediated knock-out a given HMT unravel their distinguishable and important roles in adult neurogenic niches. This Cre protein-based approach offers tightly-controlled knockouts in multiple cell types simultaneously for studying diverse regulatory mechanisms and is optimal for region-specific manipulation within complex, heterogeneous brain architectures. PMID- 29433386 TI - Sexual risk behaviors following circumcision among HIV-positive men in Rakai, Uganda. AB - OBJECTIVE: To determine whether circumcision of HIV-positive men is associated with increased subsequent sexual risk behaviors which may place their female partners at risk. METHODS: Newly circumcised and uncircumcised HIV-positive men in the Rakai Community Cohort Study were followed from baseline (July 2013 January 2015) to determine trend in sexual risk behaviors and association of circumcision with subsequent sexual risk behaviors at follow up (February 2015 September 2016). Risk behaviors included sexual activity, alcohol before sex, transactional sex, multiple sex partners, casual sex partners, and inconsistent condom use with casual partners. The association was evaluated using modified Poisson regression, and sensitivity analyses were performed after multiple imputation with chained equations for missing data. RESULTS: We identified 538 eligible men, of whom 113(21.0%) were circumcised at baseline and 425(79.0%) were uncircumcised. Men in fishing communities were more likely to be circumcised (p = 0.032) as well as those exposed to targeted HIV messaging (p < 0.001). Overall, 188(34.9%) men were lost to follow up and most were uncircumcised (p = 0.020). Among those followed up, behaviors remained largely unchanged with no differences by circumcision status. Transactional sex appeared to be associated with circumcision in unadjusted analyses (PR = 1.58, 95%CI = 1.01,2.48; p = 0.045, p = 0.05) and adjusted analyses (adj.PR = 1.54, 95%CI = 1.06,2.23; p = 0.022). However, the association was no longer significant in sensitivity analyses after accounting for loss to follow up (adj.PR = 1.43, 95%CI = 0.98,2.08; p = 0.066). No association with circumcision was observed for other sexual risk behaviors. CONCLUSION: We found no association between circumcision of HIV-positive men and subsequent sexual risk behavior. PMID- 29433385 TI - Intravenous lidocaine as adjuvant to general anesthesia in renal surgery. AB - The role of intraoperative intravenous lidocaine infusion has been previously evaluated for pain relief, inflammatory response, and post-operative recovery, particularly in abdominal surgery. The present study is a randomized double blinded trial in which we evaluated whether IV lidocaine infusion reduces isoflurane requirement, intraoperative remifentanil consumption and time to post operative recovery in non-laparoscopic renal surgery. Sixty patients scheduled to undergo elective non-laparoscopic renal surgery under general anesthesia were enrolled to receive either systemic lidocaine infusion (group L: bolus 1.5 mg/kg followed by a continuous infusion at the rate of 2 mg/kg/hr until skin closure) or normal saline (0.9% NaCl solution) (Group C). The depth of anesthesia was monitored using the Bispectral Index Scale (BIS), which is based on measurement of the patient's cerebral electrical activity. Primary outcome of the study was End-tidal of isoflurane concentration (Et-Iso) at BIS values of 40-60. Secondary outcomes include remifentanil consumption during the operation and time to extubation. Et-Iso was significantly lower in group L than in group C (0.63% +/- 0.10% vs 0.92% +/- 0.11%, p < 10-3). Mean remifentanil consumption of was significantly lower in group L than in group C (0.13 +/- 0.04 ug/kg/min vs 0.18 +/- 0.04 ug/kg/min, p < 10-3). Thus, IV lidocaine infusion permits a reduction of 31% in isoflurane concentration requirement and 27% in the intraoperative remifentanil need. In addition, recovery from anesthesia and extubation time was shorter in group L (5.8 +/- 1.8 min vs 7.9 +/- 2.0 min, p < 10-3). By reducing significantly isoflurane and remifentanil requirements during renal surgery, intravenous lidocaine could provide effective strategy to limit volatile agent and intraoperative opioids consumption especially in low and middle income countries. PMID- 29433387 TI - Pharmacological Effects of Scutellarin, An Active Component of Genus Scutellaria and Erigeron: A Systematic Review. AB - Flavonoid compound scutellarin (Scu) is quite frequently met in the plant kingdom, particularly in the genus Scutellaria (Lamiaceae) and Erigeron (Asteraceae). The extract of the herb of Erigeron breviscapus, containing this component in high amount, has been used for many years in traditional Chinese medicine. In recent years, studies have made great progress on the usefulness of Scu for treating various diseases by testing its mechanism of action. They support the traditional use of Scu rich plant in heart and cerebral ischemia. Scu can potentially be applied in Alzheimer's disease, Helicobacter pylori infection, vascular complications of diabetes and as an inhibitor of certain carcinomas. Various methods were designed to improve its isolation from plant material, solubility, absorption and bioavailability. On the basis of recent studies, it is suggested that Scu could be a promising candidate for new natural drug and deserves particular attention in further research and development. PMID- 29433389 TI - Phytotherapeutic Activities of Sanguisorba officinalis and its Chemical Constituents: A Review. AB - Sanguisorba officinalis Linne (S. officinalis, Rosaceae) has been used as a medicinal plant for the treatment of burns, hematemesis, melena, intestinal infections, and dermatitis for a long time in China, Korea, and Japan. The therapeutic efficacy of this herb is intimately associated with its anti-oxidant, anti-inflammatory, antiviral, antifungal, hemostatic, and anticancer activities. Its root contains triterpenoid saponins (zigyuglycoside I: C[Formula: see text]H[Formula: see text]O[Formula: see text] and ziyuglycoside II: C[Formula: see text]H[Formula: see text]O8) and tannins (sanguiin H-6: C[Formula: see text]H[Formula: see text]O[Formula: see text]). It has been recently revealed that these active constituents of S. officinalis possess antiwrinkle properties without cytotoxicity. They also have anticancer effects by inducing apoptosis and cell cycle arrest. Moreover, they can inhibit proliferative tumorigenesis. The underlying mechanism involved in the pharmacological actions of these active constituents is mainly related to p38 MAPK signaling. Although various studies have reported its therapeutic activities and major chemical components, review articles that extensively organize various properties of S. officinalis and its major constituents are still scarce. Taken together, the objective of this paper is to provide overall pharmacological and phytochemical profiles of S. officinalis and its constituents (including ziyuglycoside I, ziyuglycoside II, and sanguiin H-6), and their potential roles in clinical applications for the treatment of inflammatory diseases, bleeding disorders, and cancer. PMID- 29433388 TI - Eucalyptus globulus Inhibits Inflammasome-Activated Pro-Inflammatory Responses and Ameliorate Monosodium Urate-Induced Peritonitis in Murine Experimental Model. AB - Eucalyptus globulus Labill. (E. globulus, Myrtaceae) is used in Europe as a traditional folk remedy for inflammation-related disorders such as arthritis, diabetes, asthma, and gout. We investigated this study to evaluate the protective effects of E. globulus extract (EG) on inflammatory responses, and provide scientific and mechanistic evidence in in vitro and in vivo experimental models. LPS-stimulated murine bone marrow-derived macrophages (BMDMs) were used to study the regulatory effect of EG on inflammasome activation in vitro. Monosodium urate (MSU)-induced peritonitis was used to study the effect of EG in an in vivo murine model. EG suppressed IL-[Formula: see text] secretion via the regulation of apoptosis-associated speck-like proteins containing a CARD (ASC) oligomerization and caspase-1 maturation, leading to the inhibition of inflammasome activation. In the in vivo study, EG suppressed the MSU-induced peritonitis by attenuating interleukin (IL)-1[Formula: see text], providing scientific support for its traditional use in the treatment of inflammation-related disorders. PMID- 29433390 TI - Ethnomedicine, Phytochemistry and Pharmacology of Smilax glabra: An Important Traditional Chinese Medicine. AB - Smilax glabra (SG) Roxb., a well-known traditional Chinese medicine, has been extensively used worldwide for its marked pharmacological activities for treating syphilitic poisoned sores, limb hypertonicity, morbid leucorrhea, eczema pruritus, strangury due to heat, carbuncle toxin, and many other human ailments. Approximately 200 chemical compounds have been isolated from SG Roxb., and the major components have been determined to be flavonoids and flavonoid glycosides, phenolic acids, and steroids. Among these active compounds, the effects of astilbin, which is used as a quality control marker to determine the quality of SG Roxb., have been widely investigated. Based on in vivo and in vitro studies, the primary active components of SG Roxb. possess various pharmacological activities, such as cytotoxic, anti-inflammatory and immune-modulatory effects, anti-oxidant, hepatoprotective, antiviral, antibacterial, and cardiovascular system protective activities. However, an extensive study to determine the relationship between the chemical compositions and pharmacological effects of SG Roxb. has not been conducted and is worth of our study. Improving the means of utilizing the effects of SG is crucial. The present paper reviews the ethnopharmacology, phytochemistry, and pharmacology of SG Roxb. and assesses its ethnopharmacological use in order to explore its therapeutic potential for future research. PMID- 29433391 TI - p-Coumaric Acid, a Major Active Compound of Bambusae Caulis in Taeniam, Suppresses Cigarette Smoke-Induced Pulmonary Inflammation. AB - [Formula: see text]-coumaric acid ([Formula: see text]-CA) is a common compound found in medicinal herbs, including Bambusae Caulis in Taeniam (BC). It has been used to treat various diseases in China and Korea. Our previous study demonstrated that BC inhibits pulmonary and intestinal inflammation. In the present study, we used cigarette smoke (CS) to induce lung inflammation in vivo, and investigated the anti-inflammatory effects of [Formula: see text]-CA on CS induced inflammatory mice model. Mice were treated with BC and [Formula: see text]-CA via oral injection 2[Formula: see text]h before CS exposure. The body weight and the inflammatory cells in the bronchoalveolar lavage fluid were measured. The levels of relative inflammatory factors were confirmed by enzyme linked immunosorbent assay. The lung histological changes were examined by hematoxylin and eosin staining. Also, the protein level of nuclear factor [Formula: see text]B (NF-[Formula: see text]B) was evaluated by Western blotting. Our results indicated that BC and [Formula: see text]-CA inhibited CS-induced lung inflammation by regulating pro-inflammatory productions such as cytokines, chemokine, protease and NF-[Formula: see text]B. Consequently, these data demonstrated that [Formula: see text]-CA inhibited pulmonary inflammation by suppressing NF-[Formula: see text]B activity, through which pro-inflammatory mediators were regulated. Therefore, [Formula: see text]-CA, which was shown to be a major component of BC, can be considered as a strong therapeutic candidate for treating pulmonary inflammatory diseases. PMID- 29433392 TI - The Protective Effects of Gardenia jasminoides (Fructus Gardenia) on Amyloid-beta Induced Mouse Cognitive Impairment and Neurotoxicity. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. Although the exact causes of AD have not yet been fully elucidated, cholinergic dysfunction, mitochondrial damage, oxidative stress and neuroinflammation have been recognized as influential factors. Current drugs that are designed to address only a single target are unable to mitigate or prevent the progression of this complicated disease, so new disease-modifying drugs are urgently needed. Chinese herbs with thousand years of effective usage might be a good source for potential drugs. Gardenia jasminoides J. Ellis (Fructus Gardenia) is a common traditional Chinese medicine with tranquilizing effects, which is an important component of widely-used traditional Chinese medicine for dementia. GJ 4 is crocin richments extracted from Gardenia jasminoides J. Ellis. In our study, we attempted to observe the effects of GJ-4 on learning and memory injury induced by amyloid-[Formula: see text] 25-35 (A[Formula: see text] injection in mice. Treatment with GJ-4 dose-dependently enhanced the memory and cognition ability of A[Formula: see text]-injected mice. Preliminary mechanistic studies revealed the protective effect of GJ-4 was related to its protection of neurons and cholinergic dysfunction. The mechanistic results also indicated that GJ-4 could enhance antioxidant capacity and attenuate neuroinflammation. Our results implied that GJ-4 might be a promising drug to improve cognitive and memory impairment, with multiple targets. PMID- 29433393 TI - Epimedium koreanum Ameliorates Oxidative Stress-Mediated Liver Injury by Activating Nuclear Factor Erythroid 2-Related Factor 2. AB - Oxidative stress induced by reactive oxygen species is the main cause of various liver diseases. This study investigated the hepatoprotective effect of Epimedium koreanum Nakai water extract (EKE) against arachidonic acid (AA)[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells and carbon tetrachloride (CCl4-)-mediated acute liver injury in mice. Pretreatment with EKE (30 and 100[Formula: see text][Formula: see text]g/mL) significantly inhibited AA[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells by preventing changes in the expression of cleaved caspase-3 and poly(ADP-ribose) polymerase. EKE attenuated hydrogen peroxide production, glutathione depletion, and mitochondrial membrane dysfunction. EKE also increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), transactivated anti-oxidant response element harboring luciferase activity, and induced the expression of anti-oxidant genes. Furthermore, the cytoprotective effect of EKE against AA[Formula: see text][Formula: see text][Formula: see text]iron was blocked in Nrf2 knockout cells. Ultra-performance liquid chromatography analysis showed that EKE contained icariin, icaritin, and quercetin; icaritin and quercetin were both found to protect HepG2 cells from AA[Formula: see text][Formula: see text][Formula: see text]iron via Nrf2 activation. In a CCl4-induced mouse model of liver injury, pretreatment with EKE (300[Formula: see text]mg/kg) for four consecutive days ameliorated CCl4-mediated increases in serum aspartate aminotransferase activity, histological activity index, hepatic parenchyma degeneration, and inflammatory cell infiltration. EKE also decreased the number of nitrotyrosine-, 4 hydroxynonenal-, cleaved caspase-3-, and cleaved poly(ADP-ribose) polymerase positive cells in hepatic tissues. These results suggest EKE is a promising candidate for the prevention or treatment of oxidative stress-related liver diseases via Nrf2 activation. PMID- 29433394 TI - Ethyl Acetate Fraction from Dendropanax morbifera Leaves Increases T Cell Growth by Upregulating NF-AT-Mediated IL-2 Secretion. AB - Dendropanax morbifera Leveille (Araliaceae) is an endemic species that grows in Southwestern Korea and has been used as a folk medicine. Several studies reported that D. morbifera leaves have diverse therapeutic potentials. We found that the water extract of D. morbifera leaves increased the growth of EL-4 T cells. The water extract was divided into five fractions: [Formula: see text]-hexane, chloroform, ethyl acetate, [Formula: see text]-butanol, and water layers. The ethyl acetate (W-EA) fraction showed a more significant effect than the other fractions on the growth of EL-4 T cells, splenocytes, and isolated murine CD4[Formula: see text] T cells. We evaluated the W-EA fraction for its immunomodulatory effects focusing on T cell functions. First, we tested the effect of the W-EA fraction on the regulation of interleukin-2 (IL-2), a potent T cell growth factor. The W-EA fraction significantly increased IL-2 secretion in EL-4 T cells activated with phorbol 12-myristate 13-acetate (PMA) and ionomycin (Io). In addition, the W-EA fraction increased interferon-gamma (IFN-[Formula: see text] production in isolated murine splenocytes activated with Concanavalin A (ConA). Next, we examined the effect of the W-EA fraction on the regulation of transcriptional factors related to IL-2 production in T cells. The W-EA fraction significantly increased PMA/Io-induced promoter activity of a nuclear factor of activated T cells (NF-AT) in EL-4 T cells, but did not show any significant effects on the promoters of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-[Formula: see text]B). These results indicate that the W-EA fraction from water extract of D. morbifera leaves enhances IL-2 production at the transcriptional levels via the up-regulation of NF-AT in PMA/Io-activated EL 4 T cells. PMID- 29433395 TI - Chicoric Acid Improves Heart and Blood Responses to Hypobaric Hypoxia in Tibetan Yaks. AB - Yak is a wild bovine species living on the Qinghai Tibet Plateau that demonstrates good adaptability to the hypoxic environment. Chicoric acid, a natural phenolic compound, is known as having anti-oxidant, antiviral, anti inflammatory and analgesic properties. However, its effect on hypoxia adaptability of yak is still unclear. In this study 40 yaks were selected that were of similar age, parity and weight, and divided into the control group and experimental groups 1, 2, 3, randomly. Results showed that chicoric acid significantly improved RBC, HGB, and WBC. There are significantly beneficial effects to increasing total protein contents ([Formula: see text]): all treatments increased HDL-C contents, and supplementations 100[Formula: see text]mg/h significantly decreased the content of TG on the 60th day ([Formula: see text]). Contents of the serum related enzymes like ALP, GOP and GPT showed varying degrees of change, but no significant differences and the indexes of anti oxidant capacity (T-AOC and GSH-Px) were significantly improved ([Formula: see text]), but MDA was decreased ([Formula: see text]) under the action of the chicoric acid. Hypoxia-inducible factor in serum such as HIF-2[Formula: see text], EPO, ROS, Fe[Formula: see text] and Tf are all significantly decreased ([Formula: see text]). The myocardial mitochondrial parameters mtDNA, UCP2, PGC1 [Formula: see text], NRF1 and mitochondrial complexes were altered remarkably. Some indicators of glucose metabolism presented variation trends. Taken together, chicoric acid has shown a positive effect on the adaptive ability of yak in high altitude, hypoxic environment in plateau areas. Our findings reported a new potential means to enhance immunity and inflammatory response and improve the anti-oxidant capacity. PMID- 29433396 TI - Variations in the vascular and biliary structures of the liver: a comprehensive anatomical study. AB - PURPOSE: Vascular structures of the liver and the bile ducts are crucial during liver transplantation or liver resection surgery. Here, we report on variations in the vascular structures and bile ducts of 200 patients. MATERIALS AND METHODS: We reviewed magnetic resonance cholangiopancreatographic and multiple-detector computed tomographic data. RESULTS: Michels type 1 was detected in 54% of the patients. The other most common variations were, respectively, Michels type 5 (13%) and type 2 (11%). Unclassified variations were defined as Michels type 11; 5% of patients were in this group. Type 1 variations in the hepatic portal vein were detected in 76% of our study group. Other common variations were type 2 (9%) and type 3 (8.5%). The left and intermediate hepatic veins united to become a single vein and then joined the inferior vena cava in 64% of the patients. The right, intermediate, and left hepatic veins joined the inferior vena cava separately in 36% of the patients. Type A, which represents the classic anatomy of the bile duct, was observed in 51.5% of our patients. Type C1 and type B were detected in 15% and 12% of patients, respectively. CONCLUSIONS: We describe vascular and biliary variations in the livers of our patients. PMID- 29433397 TI - Hemophagocytic lymphohistiocytosis in an HIV-positive patient with concomitant disseminated histoplasmosis. AB - A 46-year-old Dominican man, known to have HIV, presented with constitutional symptoms of two week's duration. The patient was found to have cytopenias, significantly elevated ferritin level and lymphadenopathy. Biopsies and laboratory studies met the criteria for hemophagocytic lymphohistiocytosis (HLH). A concomitant diagnosis of histoplasmosis was confirmed as the trigger for HLH and treatment resulted in clinical improvement and resolution of symptoms. PMID- 29433399 TI - Death caused by appendicular knotting and small-bowel strangulation in a child: A case report and review. AB - Acute appendicitis is one of the most common surgical emergencies in paediatrics. However, acute appendicitis in early infancy is an uncommon condition. Furthermore, strangulation of the small intestine through appendicular knotting is described as very unusual in the literature and is generally not well diagnosed in the clinical context. This article reports the case of a 23-month old girl who entered the emergency department with a three-day history of abdominal symptoms and who died in less than 24 hours without receiving surgical intervention. The case turned judicial at the request of the parents who claimed lack of clarity in the diagnosis. A medico-legal autopsy was ordered to clarify the cause and manner of death. The autopsy documented herniation, strangulation and torsion of a 70 cm segment of the jejunum/ileum through an appendicular knot caused by the attachment of the distal end of the inflamed appendage to the ileum. The case is relevant because it is the first case of death by appendicular knot and strangulation of small bowel in an infant reported in the literature. The importance of autopsy to clarify the clinical diagnosis is noted. PMID- 29433400 TI - Roles for Autophagy Proteins in Immunity and Host Defense. AB - There is a clear link between defects in autophagy and the development of autoimmune and chronic inflammatory diseases, raising interest in better understanding the roles of autophagy within the immune system. In addition, autophagy has been implicated in the immune response to infection by pathogenic microbes. As such, there are efforts currently underway to develop modulators of autophagy as a therapeutic strategy for the treatment of the autoimmune, inflammatory, and infectious diseases. In this review, we discuss the numerous roles for autophagy in immunity and how these activities are linked to disease. We highlight how autophagy affects pathogen clearance, phagocytosis, pattern recognition receptor signaling, inflammation, antigen presentation, cell death, and immune cell development and maintenance. With these diverse and extensive immune-related functions for autophagy in mind, we finish by considering the possible implications of targeting autophagy as a therapeutic strategy. PMID- 29433401 TI - Amdoparvovirus Infection in Red Pandas ( Ailurus fulgens). AB - Aleutian mink disease virus is the type species in the genus Amdoparvovirus, and in mink and other Mustelidae can cause either subclinical disease or fatal chronic immune stimulation and immune complex disease. The authors describe a novel amdoparvovirus in the endangered red panda ( Ailurus fulgens), discovered using viral metagenomics. The authors analyzed the prevalence, tissue distribution, and disease association by PCR, in situ hybridization, electron microscopy, and histology in a group of 6 red pandas from a single zoological collection. The study incorporates a fecal shedding survey and analysis of tissues from 4 necropsied animals over a 12-year span. The tentatively named red panda amdoparvovirus (RpAPV) was detected in the feces and/or tissues of all animals tested. At necropsy of 1 geriatric animal, infection was associated with pyogranulomatous peritonitis, pancreatitis, and myocarditis. Other animals had detectable low-level viral nucleic acid in lymph nodes and both oral and intestinal epithelium at the time of necropsy. Full-length genome sequences of RpAPV strains from 2 animals had 12% sequence divergence, demonstrating genetic diversity even among in-contact animals. RpAPV is a persistent infection in this cohort of red pandas, and has variable clinical expression. PMID- 29433402 TI - The effect of low-dose ovarian stimulation with HMG plus progesterone on pregnancy outcome in women with history of recurrent pregnancy loss and secondary infertility: a retrospective cohort study. AB - We assessed the outcome of pregnancy in women with a history of recurrent pregnancy loss (RPL) following treatment with low-dose human menopausal gonadotropin (HMG)+progesterone or progesterone alone. This single-center retrospective cohort study included data from women diagnosed with RPL and treated between February 2005 and December 2012 with one cycle of HMG + progesterone or progesterone alone. Primary endpoint was the rate of ongoing pregnancies and losses by treatment, age (<38 vs. >=38 years) and in the subgroup with unexplained RPL. Of 169 RPL patients, 35.5% (n = 60) received HMG + progesterone and 64.5% (n = 109) progesterone alone. Compared to progesterone alone, HMG + progesterone led to a lower, although not significant, frequency of losses (3.3% vs. 11.9%, p = .09) and a twofold higher rate of ongoing pregnancies (41.7% vs. 19.3%, p = .002). Similar results were obtained in the subgroup of patients with unexplained RPL (ongoing pregnancies: 48.1% upon HMG + progesterone vs. 21.3% upon progesterone, p = .03; losses: 0% vs. 8.5%, respectively, p = .29) and in those <38 years (ongoing pregnancies: 47.4% vs. 18.8%, respectively, p = .003; losses: 5.3% vs. 10.9% respectively, p = .47). These findings suggest that HMG in women with RPL may reduce the rate of miscarriages and increase that of live births regardless of RPL cause and in women aged <38 years. PMID- 29433403 TI - The essential role of G protein-coupled receptor (GPCR) signaling in regulating T cell immunity. AB - AIM: The aim of this paper is to clarify the critical role of GPCR signaling in T cell immunity. METHODS: The G protein-coupled receptors (GPCRs) are the most common targets in current pharmaceutical industry, and represent the largest and most versatile family of cell surface communicating molecules. GPCRs can be activated by a diverse array of ligands including neurotransmitters, chemokines as well as sensory stimuli. Therefore, GPCRs are involved in many key cellular and physiological processes, such as sense of light, taste and smell, neurotransmission, metabolism, endocrine and exocrine secretion. In recent years, GPCRs have been found to play an important role in immune system. T cell is an important type of immune cell, which plays a central role in cell-mediated immunity. A variety of GPCRs and their signaling mediators (RGS proteins, GRKs and beta-arrestin) have been found to express in T cells and involved T cell mediated immunity. We will summarize the role of GPCR signaling and their regulatory molecules in T cell activation, homeostasis and function in this article. RESULTS: GPCR signaling plays an important role in T cell activation, homeostasis and function. CONCLUSION: GPCR signaling is critical in regulating T cell immunity. PMID- 29433404 TI - The characteristics of hypoactive sexual desire disorder in Korean women who visited a community-based gynaecology hospital for sexual dysfunction. AB - This cross-sectional study analysed the characteristics of HSDD (hypoactive sexual desire disorder) in Korean women. Two hundred and seventeen women seen for sexual dysfunction were assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Revised (DMS IV-TR) and the Female Sexual Function Index (FSFI). A diagnosis of HSDD was more common in women in their 40 s (56%), who had previously undergone surgery for a feeling of 'wide vagina'. Both too much or too little sexual activity caused HSDD. Longer physical contact and sexual foreplay duration lessened the prevalence of HSDD. We concluded that special attention should be paid to women in their 40 s, particularly those with a history of vaginal surgery as they are at risk of HSDD. Potential treatment options should include couple counselling about the optimal frequency and duration of sexual activity, as well as treatment specific to the disorders identified by the FSFI. Impact statement What is already known on this subject: Many socio-medical factors affect the prevalence of HSDD (Hypoactive sexual desire disorder). Age, cultural factors, relationship status, education, religion, employment, mental distress, depression, medications, menopausal status, multiple psychiatric disorders and a variety of medical conditions impact on sexual function. What do the results of this study add: A history of wide vaginal surgery (perineoplasty, vaginal rogation rejuvenation, or anterior vaginal introitoplasty) affects the incidence of HSDD (and have not been evaluated before). Both too much or too little sexual activity were found to have caused HSDD. A longer physical contact and duration of sexual foreplay lessened the prevalence of HSDD. What are the implications of these findings for clinical practice and/or further research: We concluded that special attention should be paid to women in their 40 s; particularly those with a history of wide vaginal surgery, as they are at risk of HSDD. Potential treatment options should include couple counselling about the optimal frequency and duration of sexual activity, as well as treatment specific to the disorders identified by the FSFI. PMID- 29433405 TI - Gender, migration and perceptions of HIV risk in Mexico. AB - This study examines the role that duty plays in men's and women's perceptions of HIV-related risk in Mexico, and how gender and migration influence these perceptions. We draw on qualitative data from the 2014 Study of Health and Migration in Mexico (SHMM), which included 24 in-depth interviews with migrant men and non-migrant women living in a medium-sized city in Guanajuato, Mexico. While men report migrating out of responsibility to provide for their families, this sense of duty also had implications for their sexual health behaviours. Duty permeates how residents in this migrant-sending community described their perceptions of HIV risk, with men and women drawing consistently on three aspects of duty: fidelity, gendered sexual expectations, and the burden of HIV prevention. We argue that a strong sense of duty can prompt gender role expansion for migrant men and limit gender role expansion for non-migrant women. PMID- 29433406 TI - Chest wall metastasis of endometrial cancer: case report and review of the literature. AB - INTRODUCTION: Endometrial cancer is the fourth most common female cancer and also distant metastases to the chest wall associated with these tumors are seen less common. Surgical treatment options for metastases of endometrial cancer are limited. CASE: A 57-year-old patient who underwent total abdominal hysterectomy + bilateral salpingo oophorectomy and received adjuvant chemotherapy for endometrioid-type adenocarcinoma of the endometrium and tuba is presented. The patient initially presented with pleural effusion 8 years ago and the tumor was detected while during etiologic screening. The patient had no problems after adjuvant chemotherapy and had been living in another city when she presented with a mass on the chest wall measuring 20 * 15 * 12 cm 8 years after the initial diagnosis and distant organ metastasis due to the first surgery was detected. The mass was first thought to be a sarcoma and the tru-cut biopsy revealed a metastatic lesion that was immunohistochemically similar to the first surgical specimen. The mass was resected with a wide radical excision and 'no touch' technique. The patient was then discharged with no postoperative complications. CONCLUSION: Here in, a case with a distant organ metastasis due to an endometrioid-type adenocarcinoma is presented accompanied by literature data. PMID- 29433407 TI - Bayesian hierarchical methods for meta-analysis combining randomized-controlled and single-arm studies. AB - Meta-analysis of interventions usually relies on randomized controlled trials. However, when the dominant source of information comes from single-arm studies, or when the results from randomized controlled trials lack generalization due to strict inclusion and exclusion criteria, it is vital to synthesize both sources of evidence. One challenge of synthesizing both sources is that single-arm studies are usually less reliable than randomized controlled trials due to selection bias and confounding factors. In this paper, we propose a Bayesian hierarchical framework for the purpose of bias reduction and efficiency gain. Under this framework, three methods are proposed: bivariate generalized linear mixed effects models, hierarchical power prior model and hierarchical commensurate prior model. Design difference and potential biases are considered in all models, within which the hierarchical power prior and hierarchical commensurate prior models further offer to downweight single-arm studies flexibly. The hierarchical commensurate prior model is recommended as the primary method for evidence synthesis because of its accuracy and robustness. We illustrate our methods by applying all models to two motivating datasets and evaluate their performance through simulation studies. We finish with a discussion of the advantages and limitations of our methods, as well as directions for future research in this area. PMID- 29433408 TI - Blunt Injury of the Innominate Artery: What Surprises to Expect? A Case Report. AB - Injuries of the supra-aortic trunk after blunt chest trauma are rare. This is a case report of a blunt traumatic lesion of the innominate artery (IA) origin that exhibited aortic arch involvement with a focus on imaging and treatment. A 41 year-old fisherman presented an IA injury secondary to a high-impact blunt chest trauma. Upon physical examination, vital signs were stable and upper extremity pulses were present. In addition to several bone fractures (costal ribs, clavicle, scapula, temporal, maxillary, and sphenoid), computed tomography angiography revealed dissection/pseudoaneurysm of the IA sparing the bifurcation. The patient underwent emergent angiography, which confirmed that the IA dissection was not ruptured, but it was unclear whether there was a pseudoaneurysm at the origin of the IA or aortic arch involvement. The patient was considered for open surgery. An ascending aorta-to-IA bypass was achieved by the off-pump beating heart approach. The IA stump was carefully observed, but oversewing was not possible due to the extension of the intimal-medial lesions into the artic arch. An on-pump intervention was then required for aortic angioplasty with a pericardial patch that was reinforced by Gel Seal. The postoperative course was uneventful. The patient was discharged without any complications. Conventional surgery provides good results and should remain in the armamentarium for the treatment of traumatic lesions at the IA origin, particularly if aortic arch involvement cannot be ruled out, to ensure a truly patient-tailored approach. PMID- 29433409 TI - Endovascular Management of SVC Syndrome due to Fibrosing Mediastinitis-A Feasibility and Safety Analysis. AB - PURPOSE: To assess the outcomes of endovascular management for superior vena cava (SVC) syndrome secondary to fibrosing mediastinitis (FM). METHODS: Between January 2004 and December 2016, 10 consecutive patients with endovascularly managed SVC syndrome secondary to FM were identified in an institutional database. Venograms were performed to assess the severity and location of the lesion and allow measurement for stent selection. Standard stenting and angioplasty techniques were utilized to establish luminal patency. The safety, feasibility, clinical success, and the primary and secondary patency were evaluated. Kaplan-Meier survival analysis was used to determine median duration of stent patency. A log-rank test was used to test differences in prior stent use. RESULTS: Our cohort was predominantly female (7/10) with an average age of 42.2 years. Of the 10 patients, 3 had undergone endovascular stenting at an outside institution prior to referral to our institution due to new, recurrent, or worsening symptoms. All patients underwent venography demonstrating stenosis (8/10) or occlusion (2/10) at initial presentation. Stenting or angioplasty was technically successful in 9 (90.0%) patients. Eight of 10 patients had primary stenting, while 1 achieved vascular patency and symptom resolution with angioplasty alone. Median duration of primary patency was 31.3 months (95% confidence interval: 5.9-103). Six (54.5%) patients required secondary revision procedures. Median duration of secondary patency was 6.1 months, with 25% of revisions occurring by 4 months and 75% occurring by 20.9 months. All treated patients (9/9) reported symptomatic relief at 1-month follow-up, establishing a clinical success rate of 100%. There were no 30-day adverse effects related to the procedure. CONCLUSION: This study demonstrates that endovascular therapy is a safe and feasible approach for managing FM-related SVC syndrome. PMID- 29433411 TI - Spinal accessory nerve repair using a direct nerve transfer from the upper trunk: results with 2 years follow-up. AB - : Spinal accessory nerve grafting requires identification of both nerve stumps in the scar tissue, which is sometimes difficult. We propose a direct nerve transfer using a fascicle from the posterior division of the upper trunk. We retrospectively reviewed 11 patients with trapezius palsy due to an iatrogenic injury of the spinal accessory nerve in nine cases. The mean age was 38 years (range 21-59). Preoperatively, patients showed shoulder weakness and limited range of motion. At a mean follow-up of 25 months, active shoulder abduction improvement averaged 57 degrees . Trapezius muscle strength graded M4 or M5 in 10 cases and M3 in one case. No deltoid or triceps impairment was reported. Scapula kinematics was considered normal in seven patients. This technique gave satisfactory functional results and may be an alternative to spinal accessory nerve grafting for the management of trapezius palsies if direct repair is not feasible. LEVEL OF EVIDENCE: IV. PMID- 29433410 TI - Snorkel Technique for Inferior Mesenteric Artery During Endovascular Repair of Abdominal Aortic Aneurysm. AB - PURPOSE: The snorkel technique is commonly used to preserve renal arteries in juxta renal aneurysm during endovascular repair. Herein, we present a patient who underwent bifurcated endograft implantation with snorkel technique for inferior mesenteric artery (IMA) in order to preserve the major source of bowel circulation. CASE REPORT: A 69-year-old male patient was diagnosed with abdominal aortic aneurysm. His history revealed that he had bowel resection due to a car accident 30 years ago. In addition, he was given relaparotomy 4 times due to intestinal complications. Computed tomography showed fusiform aneurysm with a maximal diameter of 60 mm and chronical occlusion of the superior mesenteric artery. Inferior mesenteric artery was found to be hypertrophic. During EVAR, 6 mm * 10 cm covered VIABAHN Endoprosthesis (Gore Medical) was implanted to the IMA over a 0.018 guidewire via puncture of the left axillary artery. Initially, the main body of the aortic stent-graft (Gore C3, size 23-14-16) was implanted to the infra renal segment of the aorta (below the renal arteries and the orifice using VIABAHN) via the right femoral artery. Next, the contralateral leg (Gore, 14-12 00) was implanted. Computed tomography was examined at 1- and 32-month postoperatively, and no endoleak or patency of IMA stent was detected. CONCLUSION: In this case of IMA-dependent circulation of the intestinal system, the protection of IMA via snorkel technique was successful. PMID- 29433412 TI - Modified Littler flap for sensory reconstruction of large thumb pulp defects. AB - : The Littler flap has been widely used to repair large pulp defects of the thumb; however, several complications have occurred frequently. In order to reduce these issues, the modified Littler flap innervated by the dorsal branch of the proper digital nerve and the proper digital nerve from the ulnar aspect of the middle finger or the radial aspect of the ring finger were devised in 16 consecutive cases. At the donor site, the defect of the proper digital nerve was repaired with a nerve graft from the proximal portion of the ipsilateral dorsal branch of the proper digital nerve. At the final follow-up, the scores for the static two-point discrimination test, Semmes-Weinstein monofilament test and total active motions in both recipient and donor fingers were nearly normal. This modified Littler flap provides a simple and reliable alternative for treatment of large defects of the thumb pulp with low donor-site morbidity. LEVEL OF EVIDENCE: IV. PMID- 29433414 TI - Unraveling the Mechanobiology of Extracellular Matrix. AB - Cells need to be anchored to extracellular matrix (ECM) to survive, yet the role of ECM in guiding developmental processes, tissue homeostasis, and aging has long been underestimated. How ECM orchestrates the deterioration of healthy to pathological tissues, including fibrosis and cancer, also remains poorly understood. Inquiring how alterations in ECM fiber tension might drive these processes is timely, as mechanobiology is a rapidly growing field, and many novel mechanisms behind the mechanical forces that can regulate protein, cell, and tissue functions have recently been deciphered. The goal of this article is to review how forces can switch protein functions, and thus cell signaling, and thereby inspire new approaches to exploit the mechanobiology of ECM in regenerative medicine as well as for diagnostic and therapeutic applications. Some of the mechanochemical switching concepts described here for ECM proteins are more general and apply to intracellular proteins as well. PMID- 29433413 TI - The Work of Titin Protein Folding as a Major Driver in Muscle Contraction. AB - Single-molecule atomic force microscopy and magnetic tweezers experiments have demonstrated that titin immunoglobulin (Ig) domains are capable of folding against a pulling force, generating mechanical work that exceeds that produced by a myosin motor. We hypothesize that upon muscle activation, formation of actomyosin cross bridges reduces the force on titin, causing entropic recoil of the titin polymer and triggering the folding of the titin Ig domains. In the physiological force range of 4-15 pN under which titin operates in muscle, the folding contraction of a single Ig domain can generate 200% of the work of entropic recoil and occurs at forces that exceed the maximum stalling force of single myosin motors. Thus, titin operates like a mechanical battery, storing elastic energy efficiently by unfolding Ig domains and delivering the charge back by folding when the motors are activated during a contraction. We advance the hypothesis that titin folding and myosin activation act as inextricable partners during muscle contraction. PMID- 29433415 TI - Mechanical Protein Unfolding and Degradation. AB - AAA+ proteolytic machines use energy from ATP hydrolysis to degrade damaged, misfolded, or unneeded proteins. Protein degradation occurs within a barrel shaped self-compartmentalized peptidase. Before protein substrates can enter this peptidase, they must be unfolded and then translocated through the axial pore of an AAA+ ring hexamer. An unstructured region of the protein substrate is initially engaged in the axial pore, and conformational changes in the ring, powered by ATP hydrolysis, generate a mechanical force that pulls on and denatures the substrate. The same conformational changes in the hexameric ring then mediate mechanical translocation of the unfolded polypeptide into the peptidase chamber. For the bacterial ClpXP and ClpAP AAA+ proteases, the mechanical activities of protein unfolding and translocation have been directly visualized by single-molecule optical trapping. These studies in combination with structural and biochemical experiments illuminate many principles that underlie this universal mechanism of ATP-fueled protein unfolding and subsequent destruction. PMID- 29433417 TI - Clinical Findings and Neurologic Outcome in Neonatal Encephalopathy With White Matter Injury Accompanied by Rotavirus. AB - Our objective was to elucidate the clinical characteristics and neurodevelopmental outcomes in neonatal encephalopathy with characteristic white matter injury as compared with other injury patterns on magnetic resonance diffusion-weighted imaging. We conducted a retrospective study comparing clinical and laboratory findings, and neurologic outcomes between 17 newborns with diffuse lesions in the periventricular white matter and white matter tract (group I) and 22 newborns with other patterns (group II). Stool samples indicated that 16 neonates (94.1%) in group I were rotavirus-positive, whereas none in group II had rotavirus infection. Significantly lower calcium levels were found in group I than in group II ( P < .001). Moreover, a more favorable neurodevelopmental outcome was observed in group I than in group II. This study suggests that characteristic white matter injury in neonatal encephalopathy may be related to decreased calcium levels induced by rotavirus, and may have a better neurodevelopmental prognosis than other causes. PMID- 29433418 TI - Evaluation of the Utility of a Dietary Therapy Second Opinion Clinic. AB - Fine-tuning ketogenic diets to achieve better seizure control may influence families to seek second opinions. Since 2009, Johns Hopkins Hospital has provided second opinions for children followed at other ketogenic diet centers. We retrospectively reviewed 65 consecutive children seen in this clinic; parents were also sent a 2-page survey. The mean age was 6.6 years and dietary therapy had been used a median 9 months. Seizure reduction >50% was achieved in 65%, including 35% with >90% reduction. Parent questions included how to improve seizure control (65%), ideal diet duration (18%), and confirmation of the plan (11%). The most common recommendations were anticonvulsant reduction (43%), adding oral citrates/calcium/vitamins (38%), and carnitine supplementation (31%). Diet discontinuation was more frequently suggested in those children with <50% seizure reduction (60% vs 20%, P = .001). Recommendations were successful in 78%, and the visit was reported as useful by 88%. PMID- 29433419 TI - Changes in Tactile Function During Intensive Bimanual Training in Children With Unilateral Spastic Cerebral Palsy. AB - Recently, an intensive bimanual intervention using sensory enriched materials resulted in improved tactile function in children with unilateral spastic cerebral palsy (USCP), raising the question of whether the observed tactile function improvement was due to the sensory enriched environment or the bimanual intervention per se. The present study investigates whether a bimanual intensive intervention improves tactile function. Nineteen children with USCP received 90 hours of bimanual training without enriched environment. Primary outcomes: Manual Form Perception Test/MFPT, Grating Orientation Task/GOT. Children were assessed before, after the training, and at the 4-month follow-up. Significant improvements were observed in MFPT for the more affected hand ( P = .015). Larger stereognosis/MFPT improvements correlated with poorer baseline motor function. Intensive bimanual training alone was sufficient to improve stereognosis, though no improvement in GOT was observed. Present and previously published findings suggest that environmental tactile enrichment incorporated into a bimanual motor training may be needed to improve spatial discrimination/GOT in children with USCP. PMID- 29433421 TI - The distribution of three candidate cold-resistant SNPs in six minorities in North China. AB - BACKGROUND: Heilongjiang Province located in northeast China is a multi-ethnic region with people who have lived in cold conditions for several generations. Fatty acids are important to people with cold resistance. CPT1A encodes a protein that imports long-chain fatty acids into the mitochondria for fatty-acid oxidation. FADS is an essential enzyme for the synthesis of long-chain polyunsaturated fatty acids. RESULTS: In the present study, we investigated the distributions of three cold resistance-related SNPs (rs80356779 G > A in CPT1A, rs7115739 T > G in FADS3 and rs174570 C > T in FADS2) from six populations that included 1093 individuals who have lived in Heilongjiang Province for at least three generations. The frequencies of rs174570 and rs7115739 were different in our six north minorities compared to the Chinese Dai in Xishuangbanna (CDX) in southern China. All the SNPs in Hezhen were significantly different from other five studied populations. In addition, the genetic distribution of rs174570 in Daur was significantly different from Manchu and Korea, and the frequency of rs7115739 in Ewenki was significantly different from the other populations. The results also showed that the frequencies of the three SNPs in the six minorities were different from those of Greenlandic Inuit and Siberian population. CONCLUSIONS: Our results showed the distributions of the three cold resistance related SNPs from six populations that included 1093 individuals in northern China. Distributions of the allele frequencies for the cold resistance-related SNPs in northern China were statistically different from those in southern China. These data help to establish the DNA genome database for the six populations and fully preserve existing minority genetic information. PMID- 29433420 TI - Liver proteome response of pre-harvest Atlantic salmon following exposure to elevated temperature. AB - BACKGROUND: Atlantic salmon production in Tasmania (Southern Australia) occurs near the upper limits of the species thermal tolerance. Summer water temperatures can average over 19 degrees C over several weeks and have negative effects on performance and health. Liver tissue exerts important metabolic functions in thermal adaptation. With the aim of identifying mechanisms underlying liver plasticity in response to chronic elevated temperature in Atlantic salmon, label free shotgun proteomics was used to explore quantitative protein changes after 43 days of exposure to elevated temperature. RESULTS: A total of 276 proteins were differentially (adjusted p-value < 0.05) expressed between the control (15 degrees C) and elevated (21 degrees C) temperature treatments. As identified by Ingenuity Pathway Analysis (IPA), transcription and translation mechanisms, protein degradation via the proteasome, and cytoskeletal components were down regulated at elevated temperature. In contrast, an up-regulated response was identified for NRF2-mediated oxidative stress, endoplasmic reticulum stress, and amino acid degradation. The proteome response was paralleled by reduced fish condition factor and hepato-somatic index at elevated temperature. CONCLUSIONS: The present study provides new evidence of the interplay among different cellular machineries in a scenario of heat-induced energy deficit and oxidative stress, and refines present understanding of how Atlantic salmon cope with chronic exposure to temperature near the upper limits of thermal tolerance. PMID- 29433422 TI - The effect of noise exposure on insulin sensitivity in mice may be mediated by the JNK/IRS1 pathway. AB - BACKGROUND: Epidemiological studies have suggested that noise exposure may increase the risk of type 2 diabetes mellitus (T2DM), and experimental studies have demonstrated that noise exposure can induce insulin resistance in rodents. The aim of the present study was to explore noise-induced processes underlying impaired insulin sensitivity in mice. METHODS: Male ICR mice were randomly divided into four groups: a control group without noise exposure and three noise groups exposed to white noise at a 95-dB sound pressure level for 4 h/day for 1, 10, or 20 days (N1D, N10D, and N20D, respectively). Systemic insulin sensitivity was evaluated at 1 day, 1 week, and 1 month post-noise exposure (1DPN, 1WPN, and 1MPN) via insulin tolerance tests (ITTs). Several insulin-related processes, including the phosphorylation of Akt, IRS1, and JNK in the animals' skeletal muscles, were examined using standard immunoblots. Biomarkers of inflammation (circulating levels of TNF-alpha and IL-6) and oxidative stress (SOD and CAT activities and MDA levels in skeletal muscles) were measured via chemical analyses. RESULTS: The data obtained in this study showed the following: (1) The impairment of systemic insulin sensitivity was transient in the N1D group but prolonged in the N10D and N20D groups. (2) Noise exposure led to enhanced JNK phosphorylation and IRS1 serine phosphorylation as well as reduced Akt phosphorylation in skeletal muscles in response to exogenous insulin stimulation. (3) Plasma levels of TNF-alpha and IL-6, CAT activity, and MDA concentrations in skeletal muscles were elevated after 20 days of noise exposure. CONCLUSIONS: Impaired insulin sensitivity in noise-exposed mice might be mediated by an enhancement of the JNK/IRS1 pathway. Inflammation and oxidative stress might contribute to insulin resistance after chronic noise exposure. PMID- 29433423 TI - MicroRNA-17-5p aggravates lipopolysaccharide-induced injury in nasal epithelial cells by targeting Smad7. AB - BACKGROUND: Globally, rhinitis is one of the most common chronic disorders. Despite availability of drugs to manage the symptomatology of rhinitis, researchers still focus on identification of novel molecular targets for better management. MicroRNAs are implicated in many biological and pathological processes. However, the role of miR-17-5p in rhinitis remains unexplored. This study aimed to explore the role of miR-17-5p in lipopolysaccharide (LPS)-induced injury of nasal epithelial RPMI2650 cells and to elucidate the possible underlying molecular mechanism. RESULTS: LPS damaged RPMI2650 cells by inhibiting cell proliferation, promoting apoptosis, and stimulating the release of inflammatory cytokines. miR-17-5p expression was significantly increased in RPMI2650 cells following treatment with LPS. Furthermore, it was found that overexpression of miR-17-5p led to aggravation of LPS-induced injury. miR-17-5p negatively regulated expression of Smad7; overexpression of Smad7 protected the RPMI2650 cells by inactivating NF-kappaB and Wnt/beta catenin pathways and vice versa. CONCLUSIONS: Overexpression of miR-17-5p aggravated LPS-induced damage of RPMI2650 cells. Expression of Smad7 was negatively regulated by miR-17-5p; Smad7 expression inactivated NF-kappaB and Wnt/beta catenin pathways. PMID- 29433424 TI - Molecular dynamics simulations revealed structural differences among WRKY domain DNA interaction in barley (Hordeum vulgare). AB - BACKGROUND: The WRKY transcription factors are a class of DNA-binding proteins involved in diverse plant processes play critical roles in response to abiotic and biotic stresses. Genome-wide divergence analysis of WRKY gene family in Hordeum vulgare provided a framework for molecular evolution and functional roles. So far, the crystal structure of WRKY from barley has not been resolved; moreover, knowledge of the three-dimensional structure of WRKY domain is pre requisites for exploring the protein-DNA recognition mechanisms. Homology modelling based approach was used to generate structures for WRKY DNA binding domain (DBD) and its variants using AtWRKY1 as a template. Finally, the stability and conformational changes of the generated model in unbound and bound form was examined through atomistic molecular dynamics (MD) simulations for 100 ns time period. RESULTS: In this study, we investigated the comparative binding pattern of WRKY domain and its variants with W-box cis-regulatory element using molecular docking and dynamics (MD) simulations assays. The atomic insight into WRKY domain exhibited significant variation in the intermolecular hydrogen bonding pattern, leading to the structural anomalies in the variant type and differences in the DNA-binding specificities. Based on the MD analysis, residual contribution and interaction contour, wild-type WRKY (HvWRKY46) were found to interact with DNA through highly conserved heptapeptide in the pre- and post-MD simulated complexes, whereas heptapeptide interaction with DNA was missing in variants (I and II) in post-MD complexes. Consequently, through principal component analysis, wild-type WRKY was also found to be more stable by obscuring a reduced conformational space than the variant I (HvWRKY34). Lastly, high binding free energy for wild-type and variant II allowed us to conclude that wild-type WRKY DNA complex was more stable relative to variants I. CONCLUSIONS: The results of our study revealed complete dynamic and structural information about WRKY domain DNA interactions. However, no structure base information reported to date for WRKY variants and their mechanism of interaction with DNA. Our findings highlighted the importance of selecting a sequence to generate newer transgenic plants that would be increasingly tolerance to stress conditions. PMID- 29433425 TI - Antigenic cartography of H1N1 influenza viruses using sequence-based antigenic distance calculation. AB - BACKGROUND: The ease at which influenza virus sequence data can be used to estimate antigenic relationships between strains and the existence of databases containing sequence data for hundreds of thousands influenza strains make sequence-based antigenic distance estimates an attractive approach to researchers. Antigenic mismatch between circulating strains and vaccine strains results in significantly decreased vaccine effectiveness. Furthermore, antigenic relatedness between the vaccine strain and the strains an individual was originally primed with can affect the cross-reactivity of the antibody response. Thus, understanding the antigenic relationships between influenza viruses that have circulated is important to both vaccinologists and immunologists. RESULTS: Here we develop a method of mapping antigenic relationships between influenza virus stains using a sequence-based antigenic distance approach (SBM). We used a modified version of the p-all-epitope sequence-based antigenic distance calculation, which determines the antigenic relatedness between strains using influenza hemagglutinin (HA) genetic coding sequence data and provide experimental validation of the p-all-epitope calculation. We calculated the antigenic distance between 4838 H1N1 viruses isolated from infected humans between 1918 and 2016. We demonstrate, for the first time, that sequence-based antigenic distances of H1N1 Influenza viruses can be accurately represented in 2 dimenstional antigenic cartography using classic multidimensional scaling. Additionally, the model correctly predicted decreases in cross-reactive antibody levels with 87% accuracy and was highly reproducible with even when small numbers of sequences were used. CONCLUSION: This work provides a highly accurate and precise bioinformatics tool that can be used to assess immune risk as well as design optimized vaccination strategies. SBM accurately estimated the antigenic relationship between strains using HA sequence data. Antigenic maps of H1N1 virus strains reveal that strains cluster antigenically similar to what has been reported for H3N2 viruses. Furthermore, we demonstrated that genetic variation differs across antigenic sites and discuss the implications. PMID- 29433426 TI - Older adults' perceptions and informational needs regarding frailty. AB - BACKGROUND: Frailty has been recognized as an important medical syndrome in older adults. Growing literature supports the clinical application of frailty but US older adults' perceptions of frailty have not been explored. We aim to examine perceptions and informational needs about frailty among older adults. METHODS: This was a qualitative study involving focus groups of community-dwelling older adults with diverse age and frailty status. We explored participants' beliefs and knowledge about frailty and informational needs about frailty as a medical syndrome. RESULTS: The participants' mean age was 76.3. Of the 29 participants, 21 (72%) were female, and 21 (72%) were white. We identified three major themes: 1) Older adults' perceptions of frailty differed from the definition used in medical literature; they often perceived a psychological component to being frailty and some were skeptical of the syndromic definition based on multiple symptoms. 2) Compared to participants who were non-frail or pre-frail, participants who were frail were more receptive to discussing their frailty status with clinicians; 3) Participants wanted know about how to treat or prevent frailty and the risks associated with being frail. Many participants felt that these information can be conveyed without necessarily using the specific term "frail", which they perceived to have a negative connotation. CONCLUSIONS: Older adults, especially those who are frail, may be interested to discuss frailty as a medical syndrome. However, negative perceptions are associated with the term "frail" and may be a barrier to clinical application of frailty. Further research is needed to understand acceptable ways for communicating about frailty in clinical practice. PMID- 29433427 TI - MethCNA: a database for integrating genomic and epigenomic data in human cancer. AB - BACKGROUND: The integration of DNA methylation and copy number alteration data promises to provide valuable insight into the underlying molecular mechanisms responsible for cancer initiation and progression. However, the generation and processing of these datasets are costly and time-consuming if carried out separately. The Illumina Infinium HumanMethylation450 BeadChip, initially designed for the evaluation of DNA methylation levels, allows copy number variant calling using bioinformatics tools. RESULTS: A substantial amount of Infinium HumanMethylation450 data across various cancer types has been accumulated in recent years and is a valuable resource for large-scale data analysis. Here we present MethCNA, a comprehensive database for genomic and epigenomic data integration in human cancer. In the current release, MethCNA contains about 10,000 tumor samples representing 37 cancer types. All raw array data were collected from The Cancer Genome Atlas and NCBI Gene Expression Omnibus database and analyzed using a pipeline that integrated multiple computational resources and tools. The normalized copy number aberration data and DNA methylation alterations were obtained. We provide a user-friendly web-interface for data mining and visualization. CONCLUSIONS: The Illumina Infinium HumanMethylation450 BeadChip enables the interrogation and integration of both genomic and epigenomic data from exactly the same DNA specimen, and thus can aid in distinguishing driver from passenger mutations in cancer. We expect MethCNA will enable researchers to explore DNA methylation and copy number alteration patterns, identify key oncogenic drivers in cancer, and assist in the development of targeted therapies. MethCNA is publicly available online at http://cgma.scu.edu.cn/MethCNA . PMID- 29433428 TI - Comparison of hepatitis E virus seroprevalence between HBsAg-positive population and healthy controls in Shandong province, China. AB - BACKGROUND: Persons with chronic hepatitis B (CHB) infection were reported to suffer severe disease after hepatitis E virus (HEV) superinfection, but the studies regarding HEV seroprevalence in this population were limited. A recent study in Vietnam found higher HEV seroprevalence among CHB patients compared with healthy controls. METHODS: A community-based case-control study was conducted in two counties of Shandong province, China, where hepatitis E incidence was at the highest (Rushan) and lowest (Zhangqiu) in the province based on data from routine public health surveillance. Four townships were selected randomly from each county and all residents in these townships were tested for hepatitis B surface antigen (HBsAg). Those tested positive for HBsAg (CHB group) and the 1:1 age and sex-matched HBsAg-negative residents (control group) were included. Anti-HEV IgM and IgG were tested and positive rates of IgG and IgM were compared between the CHB group and the control group. RESULTS: In total, 2048 CHB participants and 2054 controls were included in the study. In the CHB group, HEV IgG seroprevalence was 9.16% (95% CI: 7.47-11.09) in Zhangqiue and 38.06% (95% CI: 35.07-41.19) in Rushan (P < 0.001); the corresponding rates of IgM were 0.1% (95% CI: 0.002-0.54) and 1.57% (95% CI: 0.90-2.53), respectively (P < 0.001). HEV IgG seroprevalence was similar between CHB group and the control group in both counties (P = 0.21, P = 0.47, respectively) and the same results were found for the positive rate of IgM (P = 0.103, P = 0.262, respectively). Multivariable analysis showed the status of HBsAg was not independently associated with the status of anti-HEV IgG in either Zhangqiu or Rushan [P = 0.187, OR = 1.23(95% CI: 0.90, 1.68); P = 0.609, OR = 1.05 (95% CI: 0.87, 1.26)]. CONCLUSIONS: The seroprevalence of HEV varies greatly in different geographic areas, but the seroprevalence is similar between populations with and without CHB. CHB patients residing in high HEV endemic areas might be at higher risk for HBV-HEV superinfection. PMID- 29433429 TI - The management of children with bronchiolitis in the Australasian hospital setting: development of a clinical practice guideline. AB - BACKGROUND: Bronchiolitis is the commonest respiratory infection in children less than 12 months and cause of hospitalisation in infants under 6 months of age in Australasia. Unfortunately there is substantial variation in management, despite high levels of supporting evidence. This paper reports on the process, strengths and challenges of the hybrid approach used to develop the first Australasian management guideline relevant to the local population. METHOD: An adaption of the nine steps recommended by the National Health and Medical Research Council (NHMRC) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology were utilised. Following establishment of the Guideline Development Committee (GDC), we identified the population, intervention, comparator, outcomes and time of interest (PICOt) questions, undertook a systematic literature search and graded the evidence and recommendations using the NHMRC and GRADE processes. Using Nominal Group Techniques (NGT), consensus was sought in formulating the clinical practice recommendations and practice points. Key health professional bodies were consulted to ensure relevance in the Australasian emergency and ward settings. RESULTS: From 33 PICOT questions, clinical recommendations for practice that were deemed relevant to the Australasian population were identified. Specific considerations for the management of Australian and New Zealand indigenous infants in relation to the use of azithromycin and risk factors for more serious illness are included. Using NGT, consensus demonstrated by a median Likert score > 8 for all recommendations was achieved. The guideline presents clinical guidance, followed by the key recommendations and evidence review behind each recommendation. CONCLUSION: Developing evidence-based clinical guidelines is a complex process with considerable challenges. Challenges included having committee members located over two countries and five time zones, large volume of literature and variation of member's knowledge of grading of evidence and recommendations. The GRADE and NHMRC processes provided a systematic and transparent approach ensuring a final structure including bedside interface, and a descriptive summary of the evidence base and tables for each key statement. Involvement of stakeholders who will ultimately be end-users as members of the GDC provided valuable knowledge. Lessons learnt during this guideline development process provide valuable insight for those planning development of evidence-based guidelines. PMID- 29433431 TI - Correction to: Multiple Score Comparison: a network meta-analysis approach to comparison and external validation of prognostic scores. AB - CORRECTION: Following publication of the original article [1], a member of the writing group reported that his name is misspelt. The paper should appear in Pubmed under "Ter Riet G", bot as "Riet GT". PMID- 29433430 TI - SESOTHO trial ("Switch Either near Suppression Or THOusand") - switch to second line versus WHO-guided standard of care for unsuppressed patients on first-line ART with viremia below 1000 copies/mL: protocol of a multicenter, parallel-group, open-label, randomized clinical trial in Lesotho, Southern Africa. AB - BACKGROUND: The World Health Organization (WHO) recommends viral load (VL) measurement as the preferred monitoring strategy for HIV-infected individuals on antiretroviral therapy (ART) in resource-limited settings. The new WHO guidelines 2016 continue to define virologic failure as two consecutive VL >=1000 copies/mL (at least 3 months apart) despite good adherence, triggering switch to second line therapy. However, the threshold of 1000 copies/mL for defining virologic failure is based on low-quality evidence. Observational studies have shown that individuals with low-level viremia (measurable but below 1000 copies/mL) are at increased risk for accumulation of resistance mutations and subsequent virologic failure. The SESOTHO trial assesses a lower threshold for switch to second-line ART in patients with sustained unsuppressed VL. METHODS: In this multicenter, parallel-group, open-label, randomized controlled trial conducted in Lesotho, patients on first-line ART with two consecutive unsuppressed VL measurements >=100 copies/mL, where the second VL is between 100 and 999 copies/mL, will either be switched to second-line ART immediately (intervention group) or not be switched (standard of care, according to WHO guidelines). The primary endpoint is viral resuppression (VL < 50 copies/mL) 9 months after randomization. We will enrol 80 patients, giving us 90% power to detect a difference of 35% in viral resuppression between the groups (assuming two-sided 5% alpha error). For our primary analysis, we will use a modified intention-to-treat set, with those lost to care, death, or crossed over considered failure to resuppress, and using logistic regression models adjusted for the prespecified stratification variables. DISCUSSION: The SESOTHO trial challenges the current WHO guidelines, assessing an alternative, lower VL threshold for patients with unsuppressed VL on first-line ART. This trial will provide data to inform future WHO guidelines on VL thresholds to recommend switch to second-line ART. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03088241 ), registered May 05, 2017. PMID- 29433432 TI - Predictors of breast cancer cell types and their prognostic power in breast cancer patients. AB - BACKGROUND: Comprehensive understanding of intratumor heterogeneity requires identification of molecular markers, which are capable of differentiating different subpopulations and which also have clinical significance. One important tool that has been addressing this issue is single cell RNA-Sequencing (scRNASeq) that allows the quantification of expression profiles of transcripts in individual cells in a population of cancer cells. Using the expression profiles from scRNASeq, current studies conduct analysis to group cells into different subpopulations using clustering algorithms. In this study, we explore scRNASeq cancer data from a different perspective. We focus on scRNASeq data originating from cancer cells pertaining to a particular cancer type, where the cell type or the subpopulation to which each cell belongs is known. We investigate if the "cell type" of a cancer cell can be predicted based on the expression profiles of a small set of transcripts. RESULTS: We outline a predictive analytics pipeline to accurately predict 6 breast cancer cell types using single cell gene expression profiles. Instead of building predictive models using the complete human transcripts, the pipeline first eliminates predictors with low expression and low variance. A multinomial penalized logistic regression further reduces the size of the predictors to only 308, out of which 34 are long non-coding RNAs. Tuning of predictive models shows support vector machines and neural networks as the most accurate models achieving close to 98% prediction accuracies. We also find that mixture of protein coding genes and long non-coding RNAs are better predictors compared to when the two sets of transcripts are treated separately. A signature risk score originating from 65 protein coding genes and 5 lncRNA predictors is associated with prognostic survival of TCGA breast cancer patients. This association was maintained when the risk scores were generated using 65 PCGs and 5 lncRNA separately. We further show that predictors restricted to a particular cell type serve as better prognostic markers for the respective patient subtype. CONCLUSION: Our results show that in general, the breast cancer cell type predictors are also associated with patient survivability and hence have clinical significance. PMID- 29433433 TI - Epicardial adipose tissue is related to arterial stiffness and inflammation in patients with cardiovascular disease and type 2 diabetes. AB - BACKGROUND: Epicardial adipose tissue (EAT) is an emerging cardio-metabolic risk factor and has been shown to correlate with adverse cardiovascular (CV) outcome; however the underlying pathophysiology of this link is not well understood. The aim of this study was to evaluate the relationship between EAT and a comprehensive panel of cardiovascular risk biomarkers and pulse wave velocity (PWV) and indexed left ventricular mass (LVMI) in a cohort of patients with cardiovascular disease (CVD) and diabetes compared to controls. METHODS: One hundred forty-five participants (mean age 63.9 +/- 8.1 years; 61% male) were evaluated. All patients underwent cardiovascular magnetic resonance (CMR) examination and PWV. EAT measurements from CMR were performed on the 4-chamber view. Blood samples were taken and a range of CV biomarkers was evaluated. RESULTS: EAT measurements were significantly higher in the groups with CVD, with or without T2DM compared to patients without CVD or T2DM (group 1 EAT 15.9 +/- 5.5 cm2 vs. group 4 EAT 11.8 +/- 4.1 cm2, p = 0.001; group 3 EAT 15.1 +/- 4.3 cm2 vs. group 4 EAT 11.8 +/- 4.1 cm2, p = 0.024). EAT was independently associated with IL-6 (beta 0.2, p = 0.019). When added to clinical variables, both EAT (beta 0.16, p = 0.035) and IL-6 (beta 0.26, p = 0.003) were independently associated with PWV. EAT was significantly associated with LVMI in a univariable analysis but not when added to significant clinical variables. CONCLUSIONS: In patients with cardio-metabolic disease, EAT was independently associated with PWV. EAT may be associated with CVD risk due to an increase in systemic vascular inflammation. Whether targeting EAT may reduce inflammation and/or cardiovascular risk should be evaluated in prospective studies. PMID- 29433434 TI - Sequence variation and functional analysis of a FRIGIDA orthologue (BnaA3.FRI) in Brassica napus. AB - BACKGROUND: Allelic variation at the FRIGIDA (FRI) locus is a major contributor to natural variation of flowering time and vernalization requirement in Arabidopsis thaliana. Dominant FRI inhibits flowering by activating the expression of the MADS box transcriptional repressor FLOWERING LOCUS C (FLC), which represses flowering prior to vernalization. Four FRI orthologues had been identified in the domesticated amphidiploid Brassica napus. Linkage and association studies had revealed that one of the FRI orthologues, BnaA3.FRI, contributes to flowering time variation and crop type differentiation. RESULTS: Sequence analyses indicated that three out of the four BnaFRI paralogues, BnaA3.FRI, BnaA10.FRI and BnaC3.FRI, contained a large number of polymorphic sites. Haplotype analysis in a panel of 174 B. napus accessions using PCR markers showed that all the three paralogues had a biased distribution of haplotypes in winter type oilseed rape (P < 0.01). Association analysis indicated that only BnaA3.FRI contributes to flowering time variation in B. napus. In addition, transgenic functional complementation demonstrated that mutations in the coding sequence of BnaA3.FRI lead to weak alleles, and subsequently to flowering time variation. CONCLUSION: This study for the first time provides a molecular basis for flowering time control by BnaA3.FRI in B. napus, and will facilitate predictive oilseed rape breeding to select varieties with favorable flowering time and better adaption to latitude and seasonal shifts due to changing climate. PMID- 29433435 TI - Growth and metabolic characteristics of oleaginous microalgal isolates from Nilgiri biosphere Reserve of India. AB - BACKGROUND: Renewable energy for sustainable development is a subject of a worldwide debate since continuous utilization of non-renewable energy sources has a drastic impact on the environment and economy; a search for alternative energy resources is indispensable. Microalgae are promising and potential alternate energy resources for biodiesel production. Thus, our efforts were focused on surveying the natural diversity of microalgae for the production of biodiesel. The present study aimed at identification, isolation, and characterization of oleaginous microalgae from shola forests of Nilgiri Biosphere Reserve (NBR), the biodiversity hot spot of India, where the microalgal diversity has not yet been systematically investigated. RESULTS: Overall the higher biomass yield, higher lipid accumulation and thermotolerance observed in the isolated microalgal strains have been found to be the desirable traits for the efficient biodiesel production. Species composition and diversity analysis yielded ten potential microalgal isolates belonging to Chlorophyceae and Cyanophyceae classes. The chlorophytes exhibited higher growth rate, maximum biomass yield, and higher lipid accumulation than Cyanophyceae. Among the chlorophytes, the best performing strains were identified and represented by Acutodesmus dissociatus (TGA1), Chlorella sp. (TGA2), Chlamydomonadales sp. (TGA3) and Hindakia tetrachotoma (PGA1). The Chlamydomonadales sp. recorded with the highest growth rate, lipid accumulation and biomass yield of 0.28 +/- 0.03 day-1 (MUexp), 29.7 +/- 0.69% and 134.17 +/- 16.87 mg L-1 day-1, respectively. It was also found to grow well at various temperatures, viz., 25 degrees C, 35 degrees C, and 45 degrees C, indicating its suitability for open pond cultivation. The fatty acid methyl ester (FAME) analysis of stationary phase cultures of selected four algal strains by tandem mass spectrograph showed C16:0, C18:1 and C18:3 as dominant fatty acids suitable for biodiesel production. All the three strains except for Hindakia tetrachotoma (PGA1) recorded higher carbohydrate content and were considered as potential feed stocks for biodiesel production through hydrothermal liquefaction technology (HTL). CONCLUSIONS: In conclusion, the present investigation is a first systematic study on the microalgal diversity of soil and water samples from selected sites of NBR. The study resulted in isolation and characterization of ten potent oleaginous microalgae and found four cultures as promising feed stocks for biodiesel production. Of the four microalgae, Chlamydomonadales sp. (TGA3) was found to be significantly thermo-tolerant and can be considered as promising feedstock for biodiesel production. PMID- 29433436 TI - Poor quality data challenges conclusion and decision making: timely analysis of measles confirmed and suspected cases line list in Southern Nations Nationalities and People's Region, Ethiopia. AB - BACKGROUND: Measles is one of the leading causes of death among young children even though a safe and cost-effective vaccine is available. Timely analysis of measles surveillance data is crucial for epidemic control and can show disease control program status. Therefore, this study aimed to show vaccination status and delay in seeking health care using surveillance data. METHODS: A retrospective study was carried out in Southern Nations Nationalities and People's Region (SNNPR), Ethiopia. We reviewed 2132 records from measles surveillance line list data from July 2013 to January 2014. Descriptive statistics were performed using SPSS 20 for Windows. RESULTS: From a total of 2132 confirmed and suspected measles cases, 1319 (61.9%), had at least one dose of measles containing vaccine; the rest 398 (18.7%) and 415 (19.5%) were unvaccinated and had unknown status respectively. About two fifth, 846 (39.7%), cases visited health facilities within 48 h of onset of clinical signs/symptoms with a median of 2.0 days, IQR (1.0, 3.0). CONCLUSION: Majority of the measles cases were vaccinated with at least one dose of measles containing vaccine and vaccination data or vaccine potency at lower level was unclear. Delay in seeking healthcare was noted as only about two fifth of cases visited health facilities within 48 h of clinical manifestation. Vaccination and surveillance data quality and factors associated with delay in seeking health care should be investigated. PMID- 29433437 TI - Genomic insights into Staphylococcus equorum KS1039 as a potential starter culture for the fermentation of high-salt foods. AB - BACKGROUND: Our previous comparative genomic analysis of Staphylococcus equorum KS1039 with five S. equorum strains illuminated the genomic basis of its safety and salt tolerance. However, a comprehensive picture of the cellular components and metabolic pathways involved in the degradation of macromolecules and development of sensory properties has not been obtained for S. equorum. Therefore, in this study, we examined the general metabolism of S. equorum based on information obtained from published complete genome sequences of six S. equorum strains isolated from different niches. Additionally, the utility of strain KS1039 as a starter culture for high-salt food fermentations was examined. RESULTS: All six S. equorum strains contained genes involved in glycolysis, the tricarboxylic acid cycle, and amino acid metabolic pathways, as well as color development. Moreover, the strains had the potential to produce acetoin, butanediol, and branched chain fatty acids, all of which are important flavor compounds. None of the strains contained decarboxylase genes, which are required for histamine and tyramine production. Strain KS1039 contained bacteriocin and CRISPR/Cas gene clusters, and experimental results suggested that these genes were functional in vitro. CONCLUSIONS: The comparative genomic analysis carried out herein provides important information on the usefulness of S. equorum KS1039 as a starter culture for the fermentation of high-salt foods in terms of safety, salt tolerance, bacteriocin production, and foreign plasmid restriction. PMID- 29433438 TI - Protective effect of hydrogen-rich saline on pressure overload-induced cardiac hypertrophyin rats: possible role of JAK-STAT signaling. AB - BACKGROUND: Molecular hydrogen has been shown to have antioxidant effect and have been used to prevent oxidative stress-related diseases. The goal of this study was to explore if hydrogen-rich saline (HRS) plays a cardioprotective effect on abdominal aortic constriction (AAC) induced cardiac hypertrophy in rats. 60adult Sprague-Dawley rats received surgically the AAC for 6-week. After the surgery, the rats were randomly divided into 4 groups (15 for each):1: sham-operated (sham); 2: AAC-model; 3: AAC + Low HRS (LHRS); and 4: AAC + High HRS (HHRS). The rats in sham and AAC-model groups were treated with normal saline intraperitoneally, while rats in LHRS and HHRS groups were intraperitoneally treated with 3 or 6 mL/kg HRS daily, respectively, for 6-week. RESULTS: The ratios of HW/BW and LVW/BW were shown in an order of Model > LHRS > HHRS > SHAM groups. The cardiac hypertrophy was also manifested with increased expressions of atrial natriuretic peptide (ANP), brain natriuretic peptides (BNP) and fibrosis of cardiac tissues in AAC-model group, which could likewise be restrained in LHRS and HHRS groups. Moreover, the JAK-STAT (Janus Kinase-Signal transducers and activators of transcription) signaling molecule expressions were decreased with HRS treatment. CONCLUSIONS: Our results showed a protective effect of HRS on pressure overload-induced cardiac hypertrophy in rats, which may be associated to a decreasing in JAK-STAT signaling pathway. PMID- 29433439 TI - Legionella effector AnkX interacts with host nuclear protein PLEKHN1. AB - BACKGROUND: The intracellular bacterial pathogen Legionella pneumophila proliferates in human alveolar macrophages, resulting in a severe pneumonia termed Legionnaires' disease. Throughout the course of infection, L. pneumophila remains enclosed in a specialized membrane compartment that evades fusion with lysosomes. The pathogen delivers over 300 effector proteins into the host cell, altering host pathways in a manner that sets the stage for efficient pathogen replication. The L. pneumophila effector protein AnkX targets host Rab GTPases and functions in preventing fusion of the Legionella-containing vacuole with lysosomes. However, the current understanding of AnkX's interaction with host proteins and the means through which it exerts its cellular function is limited. RESULTS: Here, we investigated the protein interaction network of AnkX by using the nucleic acid programmable protein array (NAPPA), a high-density platform comprising 10,000 unique human ORFs. This approach facilitated the discovery of PLEKHN1 as a novel interaction partner of AnkX. We confirmed this interaction through multiple independent in vitro pull-down, co-immunoprecipitation, and cell based assays. Structured illumination microscopy revealed that endogenous PLEKHN1 is found in the nucleus and on vesicular compartments, whereas ectopically produced AnkX co-localized with lipid rafts at the plasma membrane. In mammalian cells, HaloTag-AnkX co-localized with endogenous PLEKHN1 on vesicular compartments. A central fragment of AnkX (amino acids 491-809), containing eight ankyrin repeats, extensively co-localized with endogenous PLEKHN1, indicating that this region may harbor a new function. Further, we found that PLEKHN1 associated with multiple proteins involved in the inflammatory response. CONCLUSIONS: Altogether, our study provides evidence that in addition to Rab GTPases, the L. pneumophila effector AnkX targets nuclear host proteins and suggests that AnkX may have novel functions related to manipulating the inflammatory response. PMID- 29433440 TI - Whole genome analysis of hypervirulent Klebsiella pneumoniae isolates from community and hospital acquired bloodstream infection. AB - BACKGROUND: Hypervirulent K. pneumoniae (hvKp) causes severe community acquired infections, predominantly in Asia. Though initially isolated from liver abscesses, they are now prevalent among invasive infections such as bacteraemia. There have been no studies reported till date on the prevalence and characterisation of hvKp in India. The objective of this study is to characterise the hypervirulent strains isolated from bacteraemic patients for determination of various virulence genes and resistance genes and also to investigate the difference between healthcare associated and community acquired hvKp with respect to clinical profile, antibiogram, clinical outcome and molecular epidemiology. RESULTS: Seven isolates that were susceptible to all of the first and second line antimicrobials and phenotypically identified by positive string test were included in the study. They were then confirmed genotypically by presence of rmpA and rmpA2 by PCR. Among the study isolates, four were from patients with healthcare associated infections; none were fatal. All patients with community acquired infection possessed chronic liver disease with fatal outcome. Genes encoding for siderophores such as aerobactin, enterobactin, yersiniabactin, allantoin metabolism and iron uptake were identified by whole genome sequencing. Five isolates belonged to K1 capsular type including one K. quasipneumoniae. None belonged to K2 capsular type. Four isolates belonged to the international clone ST23 among which three were health-care associated and possessed increased virulence genes. Two novel sequence types were identified in the study; K. pneumoniae belonging to ST2319 and K. quasipneumoniae belonging to ST2320. Seventh isolate belonged to ST420. CONCLUSION: This is the first report on whole genome analysis of hypervirulent K. pneumoniae from India. The novel sequence types described in this study indicate that these strains are evolving and hvKp is now spread across various clonal types. Studies to monitor the prevalence of hvKp is needed since there is a potential for the community acquired isolates to develop multidrug resistance in hospital environment and may pose a major challenge for clinical management. PMID- 29433441 TI - Ambulance use is not associated with patient acuity after road traffic collisions: a cross-sectional study from Addis Ababa, Ethiopia. AB - BACKGROUND: Africa accounts for one sixth of global road traffic deaths-most in the pre-hospital setting. Ambulance transport is expensive relative to other modes of pre-hospital transport, but has advantages in time-sensitive, high acuity scenarios. Many countries, including Ethiopia, are expanding ambulance fleets, but clinical characteristics of patients using ambulances remain ill defined. METHODS: This is a cross-sectional study of 662 road traffic collisions (RTC) patients arriving to a single trauma referral center in Addis Ababa, Ethiopia, over 7 months. Emergency Department triage records were used to abstract clinical and arrival characteristics, including acuity. The outcome of interest was ambulance arrival. Secondary outcomes of interest were inter facility referral and referral communication. Descriptive and multivariable statistics were computed to identify factors independently associated with outcomes. RESULTS: Over half of patients arrived with either high (13.1%) or moderate (42.2%) acuity. Over half (59.0%) arrived by ambulance, and nearly two thirds (65.9%) were referred. Among referred patients, inter-facility communication was poor (57.7%). Patients with high acuity were most likely to be referred (aOR 2.20, 95%CI 1.16-4.17), but were not more likely to receive ambulance transport (aOR 1.56, 95%CI 0.86-2.84) or inter-facility referral communication (aOR 0.98, 95%CI 0.49-1.94) than those with low acuity. Nearly half (40.2%) of all patients were referred by ambulance despite having low acuity. CONCLUSIONS: Despite ambulance expansion in Addis Ababa, ambulance use among RTC patients remains heavily concentrated among those with low-acuity. Inter-facility referral appears a primary contributor to low-acuity ambulance use. In other contexts, similar routine ambulance monitoring may help identify low-value utilization. Regional guidelines may help direct ambulance use where most valuable, and warrant further evaluation. PMID- 29433442 TI - Is problem alcohol use being detected and treated in Irish general practice? AB - BACKGROUND: The pattern of alcohol consumption in Ireland has serious societal and health consequences. General practice is well placed to screen for problem alcohol use and to carry out brief interventions. The aims of this study were to investigate the prevalence of documentation of problem alcohol use in patient records in Irish general practice, and to describe the documentation of its diagnosis and treatment. METHODS: General practitioners (GPs) affiliated with an Irish medical school were invited to participate in the study. One hundred patients were randomly selected from each participating practice using the practice software and the clinical records were reviewed for evidence of problem alcohol use. The following was recorded: patient demographics, whether problem alcohol use was documented, whether they had an intervention, a psychotropic medication or if a referral was made. Descriptive statistics and an estimate of the prevalence were calculated using SPSS and SAS software. RESULTS: Seventy one percent of the practices participated (n = 40), generating a sample of 3, 845 active patients. Only 57 patients (1.5%, 95% confidence interval 1 to 2%) were identified as having problem alcohol use in the previous two years. 29 (51%) of those with documented problem alcohol use were referred to other specialist services. 28 (49%) received a psychological intervention. 40 (70%) were prescribed psychotropic medications. CONCLUSION: This is the first large scale study of patient records in general practice in Ireland looking at documentation of screening and treatment of problem alcohol use. It highlights the current lack of documentation of alcohol problems and the need to re-inforce positive attitudes among GPs in relation to preventive work. PMID- 29433443 TI - Molecular epidemiological investigations of plague in Eastern Province of Zambia. AB - BACKGROUND: Plague is a flea-borne zoonotic and invasive disease caused by a gram negative coccobacillus bacterium called Yersinia pestis. Plague has caused three devastating pandemics globally namely: the Justinian, Black Death and Oriental plague. The disease in the Eastern Province of Zambia has been reported in Nyimba and Sinda Districts in the past 15 years. The aim of this study was to investigate the molecular epidemiology of plague in the two affected districts. Polymerase Chain Reaction (PCR), targeting Plasminogen activator gene (pla gene) of Y. pestis, was performed on suspected human bubo aspirates (n = 7), rodents (n = 216), shrews (n = 27) and fleas (n = 1494). Of these, one positive sample from each source or host was subjected to sequencing followed by phylogenetic analysis. RESULTS: The plasminogen activator gene (pla gene) of Y. pestis was detected in 42.8% bubo aspirates, 6.9% rodents, 3.7% shrew and 0.8% fleas. The fleas were from pigs (n = 4), goats (n = 5) and rodents (n = 3). The sequencing and phylogenetic analysis suggested that the pla gene of Y. pestis in Nyimba and Sinda was similar and the isolates demonstrated a high degree of evolutionary relationship with Antiqua strains from the Republic of Congo and Kenya. CONCLUSION: It can be concluded that pla gene of Y. pestis was present in various hosts in the two districts and the strains circulating in each district were similar and resembles those in the Republic of Congo and Kenya. PMID- 29433444 TI - A novel short L-arginine responsive protein-coding gene (laoB) antiparallel overlapping to a CadC-like transcriptional regulator in Escherichia coli O157:H7 Sakai originated by overprinting. AB - BACKGROUND: Due to the DNA triplet code, it is possible that the sequences of two or more protein-coding genes overlap to a large degree. However, such non-trivial overlaps are usually excluded by genome annotation pipelines and, thus, only a few overlapping gene pairs have been described in bacteria. In contrast, transcriptome and translatome sequencing reveals many signals originated from the antisense strand of annotated genes, of which we analyzed an example gene pair in more detail. RESULTS: A small open reading frame of Escherichia coli O157:H7 strain Sakai (EHEC), designated laoB (L-arginine responsive overlapping gene), is embedded in reading frame -2 in the antisense strand of ECs5115, encoding a CadC like transcriptional regulator. This overlapping gene shows evidence of transcription and translation in Luria-Bertani (LB) and brain-heart infusion (BHI) medium based on RNA sequencing (RNAseq) and ribosomal-footprint sequencing (RIBOseq). The transcriptional start site is 289 base pairs (bp) upstream of the start codon and transcription termination is 155 bp downstream of the stop codon. Overexpression of LaoB fused to an enhanced green fluorescent protein (EGFP) reporter was possible. The sequence upstream of the transcriptional start site displayed strong promoter activity under different conditions, whereas promoter activity was significantly decreased in the presence of L-arginine. A strand specific translationally arrested mutant of laoB provided a significant growth advantage in competitive growth experiments in the presence of L-arginine compared to the wild type, which returned to wild type level after complementation of laoB in trans. A phylostratigraphic analysis indicated that the novel gene is restricted to the Escherichia/Shigella clade and might have originated recently by overprinting leading to the expression of part of the antisense strand of ECs5115. CONCLUSIONS: Here, we present evidence of a novel small protein-coding gene laoB encoded in the antisense frame -2 of the annotated gene ECs5115. Clearly, laoB is evolutionarily young and it originated in the Escherichia/Shigella clade by overprinting, a process which may cause the de novo evolution of bacterial genes like laoB. PMID- 29433445 TI - Comparative genomic analysis reveals the evolution and environmental adaptation strategies of vibrios. AB - BACKGROUND: Vibrios are among the most diverse and ecologically important marine bacteria, which have evolved many characteristics and lifestyles to occupy various niches. The relationship between genome features and environmental adaptation strategies is an essential part for understanding the ecological functions of vibrios in the marine system. The advent of complete genome sequencing technology has provided an important method of examining the genetic characteristics of vibrios on the genomic level. RESULTS: Two Vibrio genomes were sequenced and found to occupy many unique orthologues families which absent from the previously genes pool of the complete genomes of vibrios. Comparative genomics analysis found vibrios encompass a steady core-genome and tremendous pan genome with substantial gene gain and horizontal gene transfer events in the evolutionary history. Evolutionary analysis based on the core-genome tree suggested that V. fischeri emerged ~ 385 million years ago, along with the occurrence of cephalopods and the flourish of fish. The relatively large genomes, the high number of 16S rRNA gene copies, and the presence of R-M systems and CRISPR system help vibrios live in various marine environments. Chitin-degrading related genes are carried in nearly all the Vibrio genomes. The number of chitinase genes in vibrios has been extremely expanded compared to which in the most recent ancestor of the genus. The chitinase A genes were estimated to have evolved along with the genus, and have undergone significant purifying selective force to conserve the ancestral state. CONCLUSIONS: Vibrios have experienced extremely genome expansion events during their evolutionary history, allowing them to develop various functions to spread globally. Despite their close phylogenetic relationships, vibrios were found to have a tremendous pan-genome with a steady core-genome, which indicates the highly plastic genome of the genus. Additionally, the existence of various chitin-degrading related genes and the expansion of chitinase A in the genus demonstrate the importance of the chitin utilization for vibrios. Defensive systems in the Vibrio genomes may protect them from the invasion of external DNA. These genomic features investigated here provide a better knowledge of how the evolutionary process has forged Vibrio genomes to occupy various niches. PMID- 29433446 TI - Homocysteine is a bystander for ST-segment elevation myocardial infarction: a case-control study. AB - BACKGROUND: Homocysteine has been long considered a risk factor for atherosclerosis. However, cardiovascular events cannot be reduced through homocysteine lowering by B vitamin supplements. Although several association studies have reported an elevation of serum homocysteine levels in cardiovascular diseases, the relationship of homocysteine with ST-segment elevation myocardial infarction (STEMI) is not well established. METHODS: We prospectively enrolled STEMI patients who were consecutively admitted to an intensive care unit following coronary intervention in a single medical center in Taiwan. Control subjects were individuals who presented to the outpatient or emergency department with acute chest pain but subsequently revealed patent coronary arteries by coronary arteriography. The association between serum homocysteine levels and STEMI was investigated. A culture system using human coronary artery endothelial cells was also established to examine the toxic effects of homocysteine at the cellular level. RESULTS: Patients with chest pain were divided into two groups. The STEMI group included 56 patients who underwent a primary percutaneous coronary intervention. The control group included 17 subjects with patent coronary arteries. There was no difference in serum homocysteine levels (8.4 +/- 2.2 vs. 7.6 +/- 1.9 MUmol/L, p = 0.142). When stratifying STEMI patients by the Killip classification into higher (Killip III-IV) and lower (Killip I-II) grades, CRP (3.3 +/- 4.1 vs. 1.4 +/- 2.3 mg/L, p = 0.032), peak creatine kinase (3796 +/- 2163 vs. 2305 +/- 1822 IU/L, p = 0.023), and SYNTAX scores (20.4 +/- 11.1 vs. 14.8 +/- 7.6, p = 0.033) were significantly higher in the higher grades, while serum homocysteine levels were similar. Homocysteine was not correlated with WBCs, CRP, or the SYNTAX score in STEMI patients. In a culture system, homocysteine at even a supraphysiological level of 100 MUmol/L did not reduce the cell viability of human coronary artery endothelial cells. CONCLUSIONS: Homocysteine was not elevated in STEMI patients regardless of Killip severity, suggesting that homocysteine is a bystander instead of a causative factor of STEMI. Our study therefore supports the current notion that homocysteine-lowering strategies are not essential in preventing cardiovascular disease. PMID- 29433447 TI - Comparative assessment of the quality of commercial black and green tea using microbiology analyses. AB - BACKGROUND: Drinking tea constitutes a tradition which is deeply rooted in the culture of several countries. Moreover, in recent years, tea consumption is growing all over the world. Improper herbal tea storage (long periods, humid environments) represents a relevant health hazard for consumers because of the growth of bacteria and molds. RESULTS: This study analyzed 32 samples of commercially available black and green teas - purchased from southern Italy markets and online-shops - and the monitoring of microbiological quality of the tea bag content was performed. Evaluations were conducted with the aim of characterizing pathogens indicated by the European and American guidelines (total bacterial count, fungi and Escherichia coli) and on the research of Pseudomonas spp. and Clostridium perfringens. The presence of ochratoxin A in tea matrix leaves and infusions was further assessed, using a validated and accredited HPLC FLD method. Microbial loads, for over 80% samples, ranged from 1.0 * 102 to 2.8 * 105 CFU/g tea: most of identified microorganisms were classified as Bacillaceae. The utilization of rapid detection and identification methods (PCR and sequencing), allowed the characterization of strains of Pseudomonas psychrotolerans, Staphylococcus warneri, Pantoea gaviniae and the isolation of one strain of Clostridium perfringens, whose ability to produce toxins can result in harmful outcomes for consumers. Fungi were isolated from 70% samples: the most prevalent molds were Aspergillus niger strains, followed by Aspergillus tubingensis. Ochratoxin A was detected in 22 of 32 tea solid samples investigated: concentrations resulted over the indicated limits for food products for 50% samples. CONCLUSIONS: Results obtained demonstrated the need to develop targeted regulations for the safety of herbal teas. PMID- 29433448 TI - The role of facial pattern variation for species recognition in red-fronted lemurs (Eulemur rufifrons). AB - BACKGROUND: Species recognition, i.e., the ability to distinguish conspecifics from heterospecifics, plays an essential role in reproduction. The role of facial cues for species recognition has been investigated in several non-human primate species except for lemurs. We therefore investigated the role of facial cues for species recognition in wild red-fronted lemurs (Eulemur rufifrons) at Kirindy Forest. We presented adult red-fronted lemurs pictures of male faces from five species including red-fronted lemurs, three closely related species, white fronted lemurs (E. albifrons), brown lemurs (E. fulvus), rufous brown lemurs (E. rufus), and genetically more distant red-bellied lemurs (E. rubriventer), occurring in allopatry with the study population. We predicted that red-fronted lemurs respond stronger to conspecific than to heterospecific pictures and that females show stronger responses than males. In addition, if genetic drift has played a role in the evolution of facial color patterns in the members of this genus, we predicted that responses of red-fronted lemurs correlate negatively with the genetic distance to the different species stimuli. RESULTS: Red-fronted lemurs looked significantly longer at pictures of their own species than at those of heterospecifics. Females spent less time looking at pictures of white-fronted, brown and red-bellied lemurs than males did, but not to pictures of red-bellied lemurs and a control stimulus. Individuals also exhibited sniffing behavior while looking at visual stimuli, and the time spent sniffing was significantly longer for pictures of conspecifics compared to those of heterospecifics. Moreover, the time spent looking and sniffing towards the pictures correlated negatively with the genetic distance between their own species and the species presented as stimulus. CONCLUSIONS: We conclude that red-fronted lemurs have the ability for species recognition using visual facial cues, which may allow them to avoid costly interbreeding. If so, sexual selection might have influenced the evolution of facial patterns in eulemurs. Since responses also correlated with genetic distance, our findings suggest a potential role of genetic drift as well as sexual selection in influencing the evolution of facial variation in eulemurs. Because study subjects looked and sniffed towards the presented pictures, red fronted lemurs might have the ability for multi-modal species recognition. PMID- 29433449 TI - The use of public performance reporting by general practitioners: a study of perceptions and referral behaviours. AB - BACKGROUND: Public performance reporting (PPR) of hospital data aims to improve quality of care in hospitals and to inform consumer choice. In Australia, general practitioners (GPs) are gatekeepers to secondary care with patients requiring their referral for non-emergency access. Despite their intermediary role, GPs have been generally overlooked as potential users of PPR of hospital data, with the majority of the PPR research focussing on consumers, surgeons and hospitals. METHODS: We examined the use of PPR of hospital data by GPs when referring patients to hospitals. Semi-structured interviews were conducted with 40 GPs, recruited via the Victorian Primary Care Practice-Based Research Network and GP teaching practices in Victoria, Australia. The interviews were recorded, transcribed and analysed thematically. RESULTS: We found that the majority of GPs did not use PPR when referring patients to hospitals. Instead, they relied mostly on informal sources of information such as their own or patients' previous experiences. Barriers that prevented GPs' use of PPR in their decision making included: lack of awareness and accessibility; perceived lack of data credibility; restrictive geographical catchments for certain hospitals; limited choices of public hospitals in regional and rural areas; and no mandatory PPR for private hospitals. CONCLUSIONS: Our findings suggest that lack of PPR awareness prevented GPs from using it in their referral practice. As gatekeepers to secondary care, GPs are in a position to guide patients in their treatment decisions and referrals using available PPR data. We suggest that there needs to be greater involvement by GPs in the development of hospital performance and quality indicators in Australia if GPs are to make greater use of them. The indicators require further development before GPs perceive them as valid, credible, and of use for informing their referral practices. PMID- 29433450 TI - Pathogen recognition by NK cells amplifies the pro-inflammatory cytokine production of monocyte-derived DC via IFN-gamma. AB - BACKGROUND: Besides their prominent role in the elimination of infected or malignantly transformed cells, natural killer (NK) cells serve as modulators of adaptive immune responses. Enhancing bidirectional crosstalk between NK cells and dendritic cells (DC) is considered a promising tool to potentiate cancer vaccines. We investigated to what extent direct sensing of viral and bacterial motifs by NK cells contributes to the response of inflammatory DC against the same pathogenic stimulus. RESULTS: We demonstrated that sensing of bacterial and viral PAMPs by NK cells contributes to DC cytokine production via NK cell-derived soluble factors. This enhancement of DC cytokine production was dependent on the pattern recognition receptor (PRR) agonist but also on the cytokine environment in which NK cells recognized the pathogen, indicating the importance of accessory cell activation for this mechanism. We showed in blocking experiments that NK cell-mediated amplification of DC cytokine secretion is dependent on NK cell derived IFN-gamma irrespective of the PRR that is sensed by the NK cell. CONCLUSIONS: These findings illustrate the importance of bidirectional interaction between different PRR-expressing immune cells, which can have implications on the selection of adjuvants for vaccination strategies. PMID- 29433451 TI - NBS1 rs2735383 polymorphism is associated with an increased risk of laryngeal carcinoma. AB - BACKGROUND: Nijmegen breakage syndrome 1 (NBS1), as a key protein in the DNA double-strand breaks (DSBs) repair pathway, plays an important role in maintaining genomic stability. Although single nucleotide polymorphisms (SNPs) in NBS1 have frequently been studied in multiple cancers, the relationships of two functional NBS1 polymorphisms (rs2735383 and rs1805794) with laryngeal carcinoma are yet unclear. Therefore, in the present study, we performed a case-control study including 342 cases and 345 controls to analyze the associations between two polymorphisms of NBS1 and the risk of laryngeal carcinoma. METHODS: We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to determine the genotypes of the functional SNPs in NBS1 gene. RESULTS: In comparison with the homozygous rs2735383GG genotype, the CC genotype was significantly associated with an increased risk of laryngeal carcinoma (adjusted OR = 1.884, 95%CI = 1.215-2.921). The rs2735383C variant genotypes (GC + CC) conferred a 1.410-fold increased risk of laryngeal carcinoma (adjusted OR = 1.410, 95%CI = 1.004-1.980). Furthermore, when compared to rs2735383GG genotype in laryngeal carcinoma tissues, the combined GC and CC genotypes exerted a significantly lower mRNA level of NBS1 (P = 0.003). In contrast, no significant association was found between rs1805794G > C polymorphism and cancer risk (adjusted OR = 1.074, 95%CI = 0.759-1.518 for GC; adjusted OR = 1.100, 95%CI = 0.678-1.787 for CC; adjusted OR = 1.079, 95%CI = 0.774-1.505 for GC + CC). CONCLUSIONS: These findings indicate that rs2735383G > C polymorphism in NBS1 may play a crucial role in the development of laryngeal carcinoma. PMID- 29433452 TI - Association between migraine and suicidal behavior among Ethiopian adults. AB - BACKGROUND: Despite the significant impact of migraine on patients and societies, few studies in low- and middle-income countries (LMICs) have investigated the association between migraine and suicidal behavior. The objective of our study is to examine the extent to which migraines are associated with suicidal behavior (including suicidal ideation, plans, and attempts) in a well-characterized study of urban dwelling Ethiopian adults. METHODS: We enrolled 1060 outpatient adults attending St. Paul hospital in Addis Ababa, Ethiopia. Standardized questionnaires were used to collect data on socio-demographics, and lifestyle characteristics. Migraine classification was based on the International Classification of Headache Disorders-2 diagnostic criteria. The Composite International Diagnostic Interview (CIDI) was used to assess depression and suicidal behaviors (i.e. ideation, plans and attempts). Multivariable logistic regression models were used to estimate adjusted odds ratio (AOR) and 95% confidence intervals (95% CIs). RESULTS: The prevalence of suicidal behavior was 15.1%, with a higher suicidal behavior among those who had migraines (61.9%). After adjusting for confounders including substance use and socio-demographic factors, migraine was associated with a 2.7 fold increased odds of suicidal behavior (AOR = 2.7; 95% CI 1.88-3.89). When stratified by their history of depression in the past year, migraine without depression was significantly associated with suicidal behavior (AOR: 2.27, 95% Cl: 1.49-3.46). The odds of suicidal behavior did not reach statistical significance in migraineurs with depression (AOR: 1.64, 95% CI: 0.40-6.69). CONCLUSION: Our study indicates that migraine is associated with increased odds of suicidal behavior in this population. Given the serious public health implications this has, attention should be given to the treatment and management of migraine at a community level. PMID- 29433453 TI - Male BRCA mutation carriers: clinical characteristics and cancer spectrum. AB - BACKGROUND: Mutations in BRCA1 and BRCA2 (BRCA1/2) genes are associated with an increased risk of breast and ovarian cancers in women. The cancer characteristics of men with BRCA1/2 mutations are less well studied. This study describes the unique cancer characteristics of male BRCA1/2 mutation carriers at our institution. METHODS: We performed a retrospective chart review on male patients who were seen between January 2004 and December 2014 and tested positive for a BRCA1/2 mutation. We evaluated clinical characteristics, pathology findings, treatment selection and survival. RESULTS: A total of 102 male patients were identified who tested positive for a BRCA1/2 deleterious mutation. Of these 102 patients, 33 (32%) had a diagnosis of cancer. Of these 33 patients with cancer, the majority (20 patients) were found to carry a BRCA2 mutation. Median age of cancer diagnosis was 65 years (Range: 35-75 years). Of the 33 patients diagnosed with cancer, 8 had two or more cancers, including 1 patient who had 4 cancers. Prostate cancer was the most commonly diagnosed cancer, seen in 13 patients, 11 of whom were BRCA2 positive. These cancers tended to have higher Gleason scores and elevated PSA levels. The majority of these prostate cancer patients were alive and disease free at a median follow-up of 7.4 years. Male breast cancer was the second most common cancer seen in 9 patients, all of whom were BRCA2 positive. The majority of these cancers were high grade, hormone receptor positive and associated with lymph node metastases. There were no breast cancer related deaths. Other cancers included bladder cancer, pancreatic cancer, melanoma and other skin cancers. CONCLUSIONS: This study describes the cancer characteristics and outcomes of male BRCA1/2 mutation carriers. A third of male BRCA1/2 mutation carriers had a diagnosis of cancer. A significant number of patients (mostly BRCA2 mutation positive) developed multiple cancers, which may have important implications for cancer screening and prevention. Despite having high grade histology and advanced stage at diagnosis, male BRCA1/2 mutation carriers with breast and prostate cancer demonstrated a favorable 5-year survival. PMID- 29433454 TI - Hepatitis B/C in the countries of the EU/EEA: a systematic review of the prevalence among at-risk groups. AB - BACKGROUND: In 2016, the World Health Organisation set a goal to eliminate viral hepatitis by 2030. Robust epidemiological information underpins all efforts to achieve elimination and this systematic review provides estimates of HBsAg and anti-HCV prevalence in the European Union/European Economic Area (EU/EEA) among three at-risk populations: people in prison, men who have sex with men (MSM), and people who inject drugs (PWID). METHODS: Estimates of the prevalence among the three risk groups included in our study were derived from multiple sources. A systematic search of literature published during 2005-2015 was conducted without linguistic restrictions to identify studies among people in prison and HIV negative/HIV sero-status unknown MSM. National surveillance focal points were contacted to validate the search results. Studies were assessed for risk of bias and high quality estimates were pooled at country level. PWID data were extracted from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) repository. RESULTS: Despite gaps, we report 68 single study/pooled HBsAg/anti HCV prevalence estimates covering 23/31 EU/EEA countries, 42 of which were of intermediate/high prevalence using the WHO endemicity threshold (of >=2%). This includes 20 of the 23 estimates among PWID, 20 of the 28 high quality estimates among people in prison, and four of the 17 estimates among MSM. In general terms, the highest HBsAg prevalence was found among people in prison (range of 0.3% - 25.2%) followed by PWID (0.5% - 6.1%) and MSM (0.0% - 1.4%). The highest prevalence of anti-HCV was also found among people in prison (4.3% - 86.3%) and PWID (13.8% - 84.3%) followed by MSM (0.0% - 4.7%). CONCLUSIONS: Our results suggest prioritisation of PWID and the prison population as the key populations for HBV/HCV screening and treatment given their dynamic interaction and high prevalence. The findings of this study do not seem to strongly support the continued classification of MSM as a high risk group for chronic hepatitis B infection. However, we still consider MSM a key population for targeted action given the emerging evidence of viral hepatitis transmission within this risk group together with the complex interaction of HBV/HCV and HIV. PMID- 29433455 TI - Elevated blood pressure among primary school children in Dar es salaam, Tanzania: prevalence and risk factors. AB - BACKGROUND: Whilst the burden of non-communicable diseases is increasing in developing countries, little data is available on blood pressure among Tanzanian children. This study aimed at determining the blood pressure profiles and risk factors associated with elevated blood pressure among primary school children in Dar es Salaam, Tanzania. METHODS: We conducted a cross sectional survey among 446 children aged 6-17 years from 9 randomly selected primary schools in Dar es Salaam. We measured blood pressure using a standardized digital blood pressure measuring machine (Omron Digital HEM-907, Tokyo, Japan). We used an average of the three blood pressure readings for analysis. Elevated blood pressure was defined as average systolic or diastolic blood pressure >= 90th percentile for age, gender and height. RESULTS: The proportion of children with elevated blood pressure was 15.2% (pre-hypertension 4.4% and hypertension 10.8%). No significant gender differences were observed in the prevalence of elevated BP. Increasing age and overweight/obese children were significantly associated with elevated BP (p = 0.0029 and p < 0.0001) respectively. Similar associations were observed for age and overweight/obesity with hypertension. (p = 0.0506 and p < 0.0001) respectively. In multivariate analysis, age above 10 years (adjusted RR = 3.63, 95% CI = 1.03-7.82) was significantly and independently associated with elevated BP in this population of school age children. CONCLUSIONS: We observed a higher proportion of elevated BP in this population of school age children. Older age and overweight/obesity were associated with elevated BP. Assessment of BP and BMI should be incorporated in school health program in Tanzania to identify those at risk so that appropriate interventions can be instituted before development of associated complications. PMID- 29433457 TI - An infant formula containing dairy lipids increased red blood cell membrane Omega 3 fatty acids in 4 month-old healthy newborns: a randomized controlled trial. AB - BACKGROUND: When breastfeeding is not possible, infants are fed formulas (IF) in which lipids are usually of plant origin. However, the use of dairy fat in combination with plant oils enables a lipid profile closer to breast milk in terms of fatty acid (FA) composition, triglyceride structure, polar lipids and cholesterol contents. The objective of this study was to determine the effect of an IF containing a mix of dairy fat and plant oils on Omega-3 FA content in red blood cells (RBC). METHODS: This study was a monocentric, double-blind, controlled, randomized trial. Healthy term infants were fed formulas containing a mix of dairy fat and plant oils (D), plant oils (P) or plant oils supplemented with ARA and DHA (PDHA). Breastfed infants were enrolled as a reference group (BF). FA in RBC phosphatidylethanolamine was evaluated after 4 months and FA in whole blood were evaluated at enrollment and after 4 months by gas chromatography. Differences between groups were assessed using an analysis of covariance with sex and gestational age as covariates. RESULTS: Seventy IF-fed and nineteen BF infants completed the protocol. At 4 months, RBC total Omega-3 FA levels in infants fed formula D were significantly higher than in group P and similar to those in groups PDHA and BF. RBC DHA levels in group D were also higher than in group P but lower than in groups PDHA and BF. RBC n-3 DPA levels in group D were higher than in groups P, PDHA and BF. A decrease in proportions of Omega-3 FA in whole blood was observed in all groups. CONCLUSIONS: A formula containing a mix of dairy lipids and plant oils increased the endogenous conversion of Omega-3 long-chain FA from precursor, leading to higher total Omega 3, DPA and DHA status in RBC than a plant oil-based formula. Modifying lipid quality in IF by adding dairy lipids should be considered as an interesting method to improve Omega-3 FA status. TRIAL REGISTRATION: Identifier NCT01611649 , retrospectively registered on May 25, 2012. PMID- 29433458 TI - Ecological study of road traffic injuries in the eastern Mediterranean region: country economic level, road user category and gender perspectives. AB - BACKGROUND: The Eastern Mediterranean region has the second highest number of road traffic injury mortality rates after the African region based on 2013 data, with road traffic injuries accounting for 27% of the total injury mortality in the region. Globally the number of road traffic deaths has plateaued despite an increase in motorization, but it is uncertain whether this applies to the Region. This study investigated the regional trends in both road traffic injury mortality and morbidity and examined country-based differences considering on income level, categories of road users, and gender distribution. METHODS: Register-based ecological study linking data from Global Burden of Disease Study with the United Nations Statistics Division for population and World Bank definition for country income level. Road traffic injury mortality rates and disability-adjusted life years were compiled for all ages at country level in 1995, 2005, 2015 and combined for a regional average (n = 22) and a global average (n = 122). The data were stratified by country economic level, road user category and gender. RESULTS: Road traffic injury mortality rates in the Region were higher than the global average for all three reference years but suggest a downward trend. In 2015 mortality rates were more than twice as high in low and high income countries compared to global income averages and motor vehicle occupants had a 3 fold greater mortality than the global average. Severe injuries decreased by more than half for high/middle income countries but remained high for low income countries; three times higher for males than females. CONCLUSION: Despite a potential downward trend, inequalities in road traffic injury mortality and morbidity burden remain high in the Eastern Mediterranean region. Action needs to be intensified and targeted to implement and enforce safety measures that prevent and mitigate severe motor vehicle crashes in high income countries especially and invest in efforts to promote public, active transport for vulnerable road users in the resource poor countries of the Region. PMID- 29433456 TI - Exome sequencing of primary breast cancers with paired metastatic lesions reveals metastasis-enriched mutations in the A-kinase anchoring protein family (AKAPs). AB - BACKGROUND: Tumor heterogeneity in breast cancer tumors is today widely recognized. Most of the available knowledge in genetic variation however, relates to the primary tumor while metastatic lesions are much less studied. Many studies have revealed marked alterations of standard prognostic and predictive factors during tumor progression. Characterization of paired primary- and metastatic tissues should therefore be fundamental in order to understand mechanisms of tumor progression, clonal relationship to tumor evolution as well as the therapeutic aspects of systemic disease. METHODS: We performed full exome sequencing of primary breast cancers and their metastases in a cohort of ten patients and further confirmed our findings in an additional cohort of 20 patients with paired primary and metastatic tumors. Furthermore, we used gene expression from the metastatic lesions and a primary breast cancer data set to study the gene expression of the AKAP gene family. RESULTS: We report that somatic mutations in A-kinase anchoring proteins are enriched in metastatic lesions. The frequency of mutation in the AKAP gene family was 10% in the primary tumors and 40% in metastatic lesions. Several copy number variations, including deletions in regions containing AKAP genes were detected and showed consistent patterns in both investigated cohorts. In a second cohort containing 20 patients with paired primary and metastatic lesions, AKAP mutations showed an increasing variant allele frequency after multiple relapses. Furthermore, gene expression profiles from the metastatic lesions (n = 120) revealed differential expression patterns of AKAPs relative to the tumor PAM50 intrinsic subtype, which were most apparent in the basal-like subtype. This pattern was confirmed in primary tumors from TCGA (n = 522) and in a third independent cohort (n = 182). CONCLUSION: Several studies from primary cancers have reported individual AKAP genes to be associated with cancer risk and metastatic relapses as well as direct involvement in cellular invasion and migration processes. Our findings reveal an enrichment of mutations in AKAP genes in metastatic breast cancers and suggest the involvement of AKAPs in the metastatic process. In addition, we report an AKAP gene expression pattern that consistently follows the tumor intrinsic subtype, further suggesting AKAP family members as relevant players in breast cancer biology. PMID- 29433459 TI - Assessment of peripheral blood lymphocyte subsets in children with iron deficiency anemia. AB - BACKGROUND: Iron plays an important role in body defense and essential for normal immune system development where its deficiency may result in an inadequate immune response. We aimed to assess the lymphocyte subsets in childhood iron deficiency anemia (IDA) with their laboratory correlations. METHODS: Fifty IDA (< 18 years) and 25 age and sex-matched healthy children were enrolled and a complete history was obtained and clinical examination was performed. Complete blood count, serum iron, total iron binding capacity and serum ferritin, were performed. Flow cytometric determination of peripheral blood CD3+, CD4+, CD8+ T-lymphocytes and CD19+ B-lymphocytes and CD4/CD8 ratio were done. RESULTS: Patients had significantly lower hemoglobin, Serum iron, ferritin levels and higher lymphocytic count in patients compared with controls (p = 0.001, 0.03, 0.001, 0.001 respectively). CD3 count and percentage were significantly lower in IDA patients compared to controls (p = 0.007 and 0.005 respectively). There was a Significant reduction in the CD4 count, percentage and CD4/CD8 ratio in patients compared with controls (p = 0.001, 0.001 and 0.005 respectively) while there was no significant difference regarding CD8 count and percentage. No significant difference between the two studied groups regarding either CD19 count or percentage (p = 0.28 and 0.18 respectively) were found. CONCLUSIONS: IDA is associated with impaired cell-mediated immune response specifically T-cell mediated immunity. PMID- 29433460 TI - Suicide rates in China, 2004-2014: comparing data from two sample-based mortality surveillance systems. AB - BACKGROUND: The decreasing suicide rate in China has been regarded as a major contributor to the decline of global suicide rate in the past decade. However, previous estimations on China's suicide rates might not be accurate, since often they were based on the data from the Ministry of Health's Vital Registration ("MOH-VR") System, which is biased towards the better-off population. This study aims to compare suicide data extracted from the MOH-VR System with a more representative mortality surveillance system, namely the Center for Disease Control and Prevention's Disease Surveillance Points ("CDC-DSP") System, and update China's national and subnational suicide rates in the period of 2004-2014. METHODS: The CDC-DSP data are obtained from the National Cause-of-Death Surveillance Dataset (2004-2014) and the MOH-VR data are from the Chinese Health Statistics Yearbooks (2005-2012) and the China Health and Family Planning Statistics Yearbooks (2013-2015). First, a negative binomial regression model was used to test the associations between the source of data (CDC-DSP/MOH-VR) and suicide rates in 2004-2014. Joinpoint regression analyses and Kitagawa's decomposition method are then applied to analyze the trends of the crude suicide rates. RESULTS: Both systems indicated China's suicide rates decreased over the study period. However, before the two systems merged in 2013, the CDC-DSP System reported significantly higher national suicide rates (IRR = 1.18, 95% Confidence Interval [CI]: 1.13-1.24) and rural suicide rates (IRR = 1.29, 95% CI: 1.21-1.38) than the MOH-VR System. The CDC-DSP System also showed significant reversing points in 2011 (95% CI: 2006-2012) and 2006 (95% CI: 2006-2008) on the rural and urban suicide trends. Moreover, the suicide rates in the east and central urban regions were reversed in 2011 and 2008. CONCLUSIONS: The biased MOH-VR System underestimated China's national and rural suicide rates. Although not widely appreciated in the field of suicide research, the CDC-DSP System provides more accurate estimations on China's suicide rates and is recommended for future studies to monitor the reversing trends of suicide rates in China's more developed areas. PMID- 29433461 TI - Community perspectives on persistent transmission of lymphatic filariasis in three hotspot districts in Ghana after 15 rounds of mass drug administration: a qualitative assessment. AB - BACKGROUND: The Global Program for the Elimination of Lymphatic Filariasis (GPELF) started operation in 2000 and aimed at eliminating the disease by the year 2020, following 5-6 rounds of effective annual Mass Drug Administration (MDA). The MDA programme took off in Ghana in 2001 and has interrupted transmission in many areas while it has persisted in some areas after 10 or more rounds of MDA. This study was to appreciate community members' perspectives on MDA after over 15 years of implementation. Findings will inform strategies to mobilise community members to participate fully in MDA to enhance the disease elimination process. METHODS: This was a qualitative study, employing key informant in-depth-interviews. Respondents were selected based on their recognition by community members as opinion leaders and persons who were knowledgeable about the topic of interest in the community. A snowball sampling technique was used to select respondents. RESULTS: Respondents were well informed about the MDA with most of them saying, it has been implemented for over 12 years. They were aware that the MDA was for the treatment/control of LF (elephantiasis). It came to light that MDA compliance was affected by five related barriers. These are; Medication, Personal, Health system, Disease and Social structure related barriers. Adverse effects of the drugs and the fact that many people perceived that they were not susceptibility to the infection have grossly affected the ingestion of the drugs. CONCLUSION: There is a need for community mobilization and promotional activities to explain the expected adverse reactions associated with the drugs to the people. Also the importance of why every qualified person in the community must comply with MDA must be emphasized. PMID- 29433462 TI - Early-onset neonatal hyperkalemia associated with maternal hypermagnesemia: a case report. AB - BACKGROUND: Neonatal nonoliguric hyperkalemia (NOHK) is a metabolic abnormality that occurs in extremely premature neonates at approximately 24 h after birth and is mainly due to the immature functioning of the sodium (Na+)/potassium (K+) pump. Magnesium sulfate is frequently used in obstetrical practice to prevent preterm labor and to treat preeclampsia; this medication can also cause hypermagnesemia and hyperkalemia by a mechanism that is different from that of NOHK. Herein, we report the first case of very early-onset neonatal hyperkalemia induced by maternal hypermagnesemia. CASE PRESENTATION: A neonate born at 32 weeks of gestation developed hyperkalemia (K+ 6.4 mmol/L) 2 h after birth. The neonate's blood potassium concentration reached 7.0 mmol/L 4 h after birth, despite good urine output. The neonate and his mother had severe hypermagnesemia caused by intravenous infusion of magnesium sulfate given for tocolysis due to pre-term labor. CONCLUSION: The early-onset hyperkalemia may have been caused by the accumulation of potassium ions transported through the placenta, the shift of potassium ions from the intracellular to the extracellular space in the infant due to the malfunctioning of the Na+/K+ pump and the inhibition of renal distal tube potassium ion secretion, there is a possibility that these mechanisms were induced by maternal and fetal hypermagnesemia after maternal magnesium sulfate administration. Because neonatal hyperkalemia poses a significant risk for the development of life-threatening cardiac arrhythmia, this case highlights the necessity of maternal blood magnesium monitoring during magnesium sulfate administration and neonatal blood potassium monitoring when there is severe maternal hypermagnesemia at delivery. PMID- 29433463 TI - Scedosporium apiospermum infectious scleritis following posterior subtenon triamcinolone acetonide injection: a case report and literature review. AB - BACKGROUND: Ubiquitous fungi of the Scedosporium apiospermum species complex (SASC) cause various opportunistic infections. Posterior subtenon triamcinolone acetonide (STTA) injection is a standard therapy for intraocular inflammation and macular edema. We report a case of Scedosporium apiospermum infectious scleritis after a posterior STTA injection. CASE PRESENTATION: A 75-year-old man received a posterior STTA injection to treat macular edema in his left eye. After 3 months, he complained of ocular pain and hyperemia in his left eye. Examination showed a subtenon abscess in the site corresponding with the STTA injection. After incising the abscess, the smear revealed numerous conidia-like structures. Although we suspected fungal infection and started topical voriconazole (VRCZ) and levofloxacin, the inflammation of the eye worsened. Fungal culture revealed filamentous fungus growth. Subsequently, we added systemic VRCZ and performed surgical debridement of the infected sclera and Tenon's capsule. Pathology of the sclera showed fungal hyphae. The antifungal susceptibility test revealed low minimum inhibitory concentrations for micafungin, VRCZ and miconazole (0.06, 0.25 and 0.5 MUg/mL, respectively). After 2 months, the ciliary injection subsided and VRCZ therapy was stopped. However, subtenon abscess recurred 1 month after discontinuation of topical VRCZ. Surgical debridement and topical VRCZ were resumed, with the eye finally improving after 5 months of management. The fungal species was identified as Scedosporium apiospermum sensu stricto morphologically and by DNA sequencing. CONCLUSIONS: This case was successfully treated by topical and systemic VRCZ and repeated surgical debridement. Infectious scleritis caused by SASC rarely develops after posterior STTA. SASC can produce conidia in the enclosed subtenon space. Late-onset infectious scleritis after a posterior STTA injection suggests the presence of a fungal infection, including SASC, thereby requiring extensive and prolonged medical and surgical treatment. PMID- 29433464 TI - The accuracy of parent-reported height and weight for 6-12 year old U.S. children. AB - BACKGROUND: Previous studies have examined correlations between BMI calculated using parent-reported and directly-measured child height and weight. The objective of this study was to validate correction factors for parent-reported child measurements. METHODS: Concordance between parent-reported and investigator measured child height, weight, and BMI (kg/m2) among participants in the Neighborhood Impact on Kids Study (n = 616) was examined using the Lin coefficient, where a value of +/-1.0 indicates perfect concordance and a value of zero denotes non-concordance. A correction model for parent-reported height, weight, and BMI based on commonly collected demographic information was developed using 75% of the sample. This model was used to estimate corrected measures for the remaining 25% of the sample and measured concordance between correct parent reported and investigator-measured values. Accuracy of corrected values in classifying children as overweight/obese was assessed by sensitivity and specificity. RESULTS: Concordance between parent-reported and measured height, weight and BMI was low (0.007, - 0.039, and - 0.005 respectively). Concordance in the corrected test samples improved to 0.752 for height, 0.616 for weight, and 0.227 for BMI. Sensitivity of corrected parent-reported measures for predicting overweight and obesity among children in the test sample decreased from 42.8 to 25.6% while specificity improved from 79.5 to 88.6%. CONCLUSIONS: Correction factors improved concordance for height and weight but did not improve the sensitivity of parent-reported measures for measuring child overweight and obesity. Future research should be conducted using larger and more nationally representative samples that allow researchers to fully explore demographic variance in correction coefficients. PMID- 29433465 TI - Strengthening health data on a rare and heterogeneous disease: sarcoma incidence and histological subtypes in Germany. AB - BACKGROUND: The population-based incidence of sarcoma and its histological subtypes in Germany is unknown. Up-to-date information on a disease with an incidence comparable to other cancer entities is of high public health relevance. The aim of this study was to determine this incidence and to detect significant changes in incidence trends using data from German epidemiological cancer registries. METHODS: Pooled data from the German Centre for Cancer Registry Data with a primary diagnosis occurring in 2013 were used. To date, this is the latest data on cancer incidence available for Germany. All German cancer registries with sufficient completeness were included (10 out of 11), covering a population of 70.0 million people, representing 87% of the German population. All malignant sarcomas according to the RARECARE Project and the WHO classification 2002 were considered for analysis and, above all, gastrointestinal stromal tumours (GIST) of uncertain behaviour. Sensitivity analysis was performed excluding certain histologies. RESULTS: The analysis included 3404 cases in men and 3442 cases in women diagnosed in 2013. The age adjusted sarcoma incidence (European standard) was 7.4 (men) and 6.6 (women) per 100,000 inhabitants. About 70% of sarcomas were soft tissue sarcomas, about 22% GIST, and about 9% bone sarcomas. The most common histological subtypes besides GIST were fibrosarcomas (14%) and liposarcomas (12%) in men and complex mixed and stromal neoplasms (22%), non-uterine leiomysarcomas (10%) and fibrosarcomas (9%) in women. Considering the trend for the years of diagnosis 2004 to 2013, there was a significant increase in incidence for GIST while the incidence of soft tissue sarcomas (only men) as well as of bone sarcoma stayed constant over time. As to soft tissue sarcoma in women, the incidence stayed constant up to the year 2009 and significantly decreased afterwards. CONCLUSION: This study is the first detailed analysis of a German wide population-based sarcoma incidence showing results comparable to the incidence detected in the RARECARE Project. PMID- 29433466 TI - Problem drinking among Flemish students: beverage type, early drinking onset and negative personal & social consequences. AB - BACKGROUND: Although alcohol is socially accepted in most Western societies, studies are clear about its associated negative consequences, especially among university and college students. Studies on the relationship between alcohol related consequences and both beverage type and drinking onset, however, are scarce, especially in a European context. The aim of this research was, therefore, twofold: (1) What is the relationship between beverage type and the negative consequences experienced by students? and (2) Are these consequences determined by early drinking onset? We will examine these questions within the context of a wide range of alcohol-related consequences. METHODS: The analyses are based on data collected by the inter-university project 'Head in the clouds?', measuring alcohol use among students in Flanders (Belgium). In total, a large dataset consisting of information from 19,253 anonymously participating students was available. Negative consequences were measured using a shortened version of the Core Alcohol and Drug Survey (CADS_D). Data were analysed using negative binomial regression. RESULTS: Results vary depending on the type of alcohol-related consequences: Personal negative consequences occur frequently among daily beer drinkers. However, a high rate of social negative consequences was recorded for both daily beer drinkers and daily spirits drinkers. Finally, early drinking onset was significantly associated with both personal and social negative consequences, and this association was especially strong between beer and spirits drinking onset and social negative consequences. CONCLUSIONS: Numerous negative consequences, both personal and social, are related to frequent beer and spirits drinking. Our findings indicate a close association between drinking beer and personal negative consequences as well as between drinking beer and/or spirits and social negative consequences. Similarly, early drinking onset has a major influence on the rates of both personal and social negative consequences. The earlier students started drinking, the more negative consequences they experienced during college or university. Several (policy) interventions are discussed. This study is the first to incorporate detailed information on both beverage type and drinking onset, and its associated negative consequences, as measured by the CADS_D, in a large student population. PMID- 29433467 TI - Effect of tendon vibration during wide-pulse neuromuscular electrical stimulation (NMES) on muscle force production in people with spinal cord injury (SCI). AB - BACKGROUND: Neuromuscular electrical stimulation (NMES) is commonly used in skeletal muscles in people with spinal cord injury (SCI) with the aim of increasing muscle recruitment and thus muscle force production. NMES has been conventionally used in clinical practice as functional electrical stimulation (FES), using low levels of evoked force that cannot optimally stimulate muscular strength and mass improvements, and thus trigger musculoskeletal changes in paralysed muscles. The use of high intensity intermittent NMES training using wide-pulse width and moderate-intensity as a strength training tool could be a promising method to increase muscle force production in people with SCI. However, this type of protocol has not been clinically adopted because it may generate rapid muscle fatigue and thus prevent the performance of repeated high-intensity muscular contractions in paralysed muscles. Moreover, superimposing patellar tendon vibration onto the wide-pulse width NMES has been shown to elicit further increases in impulse or, at least, reduce the rate of fatigue in repeated contractions in able-bodied populations, but there is a lack of evidence to support this argument in people with SCI. METHODS: Nine people with SCI received two NMES protocols with and without superimposing patellar tendon vibration on different days (i.e. STIM and STIM+vib), which consisted of repeated 30 Hz trains of 58 wide-pulse width (1000 MUs) symmetric biphasic pulses (0.033-s inter-pulse interval; 2 s stimulation train; 2-s inter-train interval) being delivered to the dominant quadriceps femoris. Starting torque was 20% of maximal doublet-twitch torque and stimulations continued until torque declined to 50% of the starting torque. Total knee extensor impulse was calculated as the primary outcome variable. RESULTS: Total knee extensor impulse increased in four subjects when patellar tendon vibration was imposed (59.2 +/- 15.8%) but decreased in five subjects (- 31.3 +/- 25.7%). However, there were no statistically significant differences between these sub-groups or between conditions when the data were pooled. CONCLUSIONS: Based on the present results there is insufficient evidence to conclude that patellar tendon vibration provides a clear benefit to muscle force production or delays muscle fatigue during wide-pulse width, moderate intensity NMES in people with SCI. TRIAL REGISTRATION: ACTRN12618000022268 . Date: 11/01/2018. Retrospectively registered. PMID- 29433469 TI - Combination of anti-PD-1 therapy and stereotactic radiosurgery for a gastric cancer patient with brain metastasis: a case report. AB - BACKGROUND: Brain metastases from gastric cancer are difficult to treat and their prognosis is poor. Despite various possible treatments, the survival rate of such patients is still unsatisfactory; therefore, new treatment modalities or combinations of therapies need to be explored. CASE PRESENTATION: We herein discuss a case of a 38-year-old man initially diagnosed with a gastric cancer brain metastasis. At first, only stereotactic radiosurgery (SRS) was performed, but it was not effective. After the brain and systemic metastases progressed, SRS and anti-PD-1 therapy were administered in combination, and the brain and intra abdominal metastatic lesions responded satisfactorily. CONCLUSION: The combination of anti-PD-1 therapy and SRS could be effective against gastric cancer with brain metastases. PMID- 29433468 TI - Suicide and deliberate self-harm in Pakistan: a scoping review. AB - BACKGROUND: Suicide is a major global public health problem with more than 800,000 incidents worldwide annually. Seventy-five percent of the global suicides occur in low and middle-income countries (LMICs). Pakistan is a LMIC where information on suicidal behavior is limited. The aim of the review is to map available literature on determinants, risk factors and other variables of suicidal behavior in Pakistan. METHOD: This study was based on Arksey and O'Malley's methodological framework of scoping review, combining peer reviewed publications with grey literature. Ten databases including Applied Social Sciences Index and Abstracts (ASSIA), Cochrane Trials Register (CRG), Cumulative Index to Nursing and Allied Health (CINAHL), National Library of Medicine Gateway (NLMG), ExcerptaMedica (EMBASE), National Library of Medicine's MEDLINE (PUBMED), PSYCHINFO, Social Science Citation Index and Science Citation Index (SCI) and Pakmedinet.com were searched from the beginning of their time frames until December 2016 using a combination of key terms. The inclusion criteria included studies of various study designs covering different aspects of suicidal behavior in English language. RESULTS: Six hundred and twenty three articles were initially retrieved from all ten databases. Two independent reviewers screened the titles and abstracts for relevance. One hundred and eighteen articles were read in full, out of which 11 were excluded because they did not fit the eligibility criteria. One hundred and ten articles, including two student theses and one report, were included in the final review. Most studies were descriptive in nature, with only three that used a case-control design. Majority of the studies were from urban areas, and addressed determinants rather than risk factors. Gender differences and age were predominantly reported, with more males committing suicide. Suicidal behavior was more common among individuals younger than 30 years of age. The three most common methods for suicides were hanging, poisoning and use of firearms. Mental illness as a risk factor for suicides was mentioned in only three studies. CONCLUSIONS: This review is the first attempt to synthesize available literature on suicidal behavior in Pakistan. The evidence is limited, and calls for more robust analytical research designs, along with a focus on risk factors. PMID- 29433470 TI - An investigation of physical and mental health consequences among Chinese parents who lost their only child. AB - BACKGROUND: The term "loss-of-only-child family" means that the only child in a family passed away or is disabled due to an accident or other events. The parents who cannot conceive or do not adopt another child, are known as Shidu parents in China. This study compares the physical and mental health of Shidu parents with those parents who have not experienced such loss. METHODS: The target group is comprised of parents being Shidu for more than 1 year (N = 95) and the control group is comprised of parents with a living child (N = 97) from the same area as the Shidu parents. Socio-demographic information and physical health outcomes were collected by the adapted questionnaires. PCL-C (PTSD Checklist-Civilian Version), CES-D (Center for Epidemiological Studies Depression Scale) and GHQ-12 (General Health Questionnaire) were applied to evaluate the parents' physical and mental status. RESULTS: Shidu parents have a higher risk of developing PTSD and depression, and suffer more severe psychiatric disorders compared to parents with a living child. The rate of PTSD in the Shidu group was up to 32.6% and the scores of PCL-C are much higher than the control group. The physical status of Shidu parents were much worse than that of the control group, characterized by higher morbidity of chronic diseases and more hospital visits. CONCLUSIONS: Shidu parents have more severe mental health problems and a higher rate of chronic diseases than parents who have a living child. Loss of the only child is the most traumatic event for the parents, which is a serious and unique problem in Chinese society that deserves attention. More studies and support are desired to improve the physical and mental health of Shidu parents. PMID- 29433471 TI - Mortality estimates among adult patients with severe acute respiratory infections from two sentinel hospitals in southern Arizona, United States, 2010-2014. AB - BACKGROUND: From October 2010 through February 2016, Arizona conducted surveillance for severe acute respiratory infections (SARI) among adults hospitalized in the Arizona-Mexico border region. There are few accurate mortality estimates in SARI patients, particularly in adults >= 65 years old. The purpose of this study was to generate mortality estimates among SARI patients that include deaths occurring shortly after hospital discharge and identify risk factors for mortality. METHODS: Patients admitted to two sentinel hospitals between 2010 and 2014 who met the SARI case definition were enrolled. Demographic data were used to link SARI patients to Arizona death certificates. Mortality within 30 days after the date of admission was calculated and risk factors were identified using logistic regression models. RESULTS: Among 258 SARI patients, 47% were females, 51% were white, non-Hispanic and 39% were Hispanic. The median age was 63 years (range, 19 to 97 years) and 80% had one or more pre-existing health condition; 9% died in hospital. Mortality increased to 12% (30/258, 30% increase) when electronic vital records and a 30-day post-hospitalization time frame were used. Being age >= 65 years (OR = 4.0; 95% CI: 1.6-9.9) and having an intensive care unit admission (OR = 7.4; 95% CI: 3.0-17.9) were independently associated with mortality. CONCLUSION: The use of electronic vital records increased SARI-associated mortality estimates by 30%. These findings may help guide prevention and treatment measures, particularly in high-risk persons in this highly fluid border population. PMID- 29433472 TI - Factors associated with developing a fear of falling in subjects with primary open-angle glaucoma. AB - BACKGROUND: To investigate the relationship between clinical risk factors, including visual field (VF) defects and visual acuity, and a fear of falling, among patients with primary open-angle glaucoma (POAG). METHODS: All participants answered the following question at a baseline ophthalmic examination: Are you afraid of falling? The same question was then answered every 12 months for 3 years. A binocular integrated visual field was calculated by merging a patient's monocular Humphrey field analyzer VFs, using the 'best sensitivity' method. The means of total deviation values in the whole, superior peripheral, superior central, inferior central, and inferior peripheral VFs were calculated. The relationship between these mean VF measurements, and various clinical factors, against patients' baseline fear of falling and future fear of falling was analyzed using multiple logistic regression. RESULTS: Among 392 POAG subjects, 342 patients (87.2%) responded to the fear of falling question at least twice in the 3 years study period. The optimal regression model for patients' baseline fear of falling included age, gender, mean of total deviation values in the inferior peripheral VF and number of previous falls. The optimal regression equation for future fear of falling included age, gender, mean of total deviation values in the inferior peripheral VF and number of previous falls. CONCLUSION: Defects in the inferior peripheral VF area are significantly related to the development of a fear of falling. PMID- 29433473 TI - Prevalence, risk awareness and health beliefs of behavioural risk factors for cardiovascular disease among university students in nine ASEAN countries. AB - BACKGROUND: Understanding behavioural risk factors of cardiovascular disease (CVD) is of great importance for CVD prevention and control. The aim of the study was to investigate the prevalence, risk awareness and health beliefs of behavioural risk factors of cardiovascular disease among university students in Association of Southeast Asian Nations (ASEAN) member states. METHODS: In a cross sectional survey 8806 (37.5% male and 62.5% female) university students (Mean age 20.6, SD = 2.0) from nine ASEAN countries responded to an anonymous questionnaire. RESULTS: Results indicate that across all nine countries, among men and women, 27.5% and 16.9%, respectively, were overweight or obese, 39.0% and 53.0% engaged in low physical activity, 6.9% and 2.5% were current tobacco users, 10.1% and 4.2% had engaged in binge drinking in the past month and 62.7% and 58.2%, respectively, did not avoid eating fat and cholesterol. After adjusting for socio-demographic factors, health status and health benefits, poor risk awareness was associated with tobacco use and binge drinking, and after adjusting for socio-demographic factors, health status and risk awareness, poorer health benefits beliefs predicted overweight, low physical activity, tobacco use, binge drinking and non-avoidance of fat and cholesterol. CONCLUSION: The study found a high prevalence of behavioural risk factors of CVD. Results may inform health promotion strategies among university students in ASEAN. PMID- 29433474 TI - Real-life feasibility of home-based pulmonary rehabilitation in chemotherapy treated patients with thoracic cancers: a pilot study. AB - BACKGROUND: Patients with advanced lung cancer (LC) or malignant pleural mesothelioma (MPM) exhibit limitation of exercise capacities and alteration of quality of life (QoL) induced by cancer and its treatment. Few studies assessed pulmonary rehabilitation (PR) in these chemotherapy-treated patients, and none evaluated a home-based PR program. METHODS: In this prospective uncontrolled observational pilot study, patients treated by chemotherapy for LC or MPM were screened for a home-based PR program combining exercise training with global cares including therapeutic education and psychosocial management. Feasibility and safety were evaluated by attendance and adherence to PR program. Various exercise tolerance tests, including 6-min walk test (6MWT) and 6-min stepper test (6MST), were performed before and after PR associated with, QoL and psychological assessment (VSRQ and HAD, respectively). RESULTS: 243 patients were considered eligible but only 71 (60.6 +/- 8.8 years) started a PR and 47 completed the program. Refusals to participate were mostly related to lack of motivation whereas withdrawals to PR were related to cancer-related medical issues. No adverse event related to PR was observed. Baseline 6MWT distance was associated with performance status (r = - 0.45, p = 0.001) and mMRC dyspnea scale (r = - 0.49, p < 0.001) but not with lung cancer stage. Post-PR reassessment showed 6MWT stability and 6MST improvement in patients who completed the program. Daily physical activity (p = 0.007) and anxiety (p = 0.02) scores were significantly improved. CONCLUSIONS: Home-based PR was feasible and safe in patients with advanced LC or MPM. Exercise capacities stability in patients who completed the PR program suggests that PR might be beneficial. Further studies are warranted to confirm and to improve the potential value of PR in these patients. PMID- 29433475 TI - Benefits of starting hypothermia treatment within 6 h vs. 6-12 h in newborns with moderate neonatal hypoxic-ischemic encephalopathy. AB - BACKGROUND: It has been suggested that mild hypothermia treatment of hypoxia ischemic encephalopathy (HIE) should start within 6 h after HIE, but many children are admitted to the hospital > 6 h, particularly in developing areas. We aimed to determine whether hypothermia treatment could remain effective within 12 h after birth. METHODS: According to their admission, 152 newborns were enrolled in the < 6 h and 6-12 h after HIE groups. All newborns received conventional treatment combined with mild head hypothermia therapy, according to our routine clinical practice. Some newborns only received conventional treatment (lacking informed consent). All newborns received amplitude-integrated electroencephalography (aEEG) monitoring for 4 h and neuron-specific enolase (NSE) measurement before and after 3 days of therapy. RESULTS: Compared to the conventional treatment, hypothermia significantly improved the aEEG scores and NSE values in all newborns of the < 6-h group. In the 6-12-h group, the aEEG scores (F = 5.67, P < 0.05) and NSE values (F = 4.98, P < 0.05) were only improved in newborns with moderate HIE. Hypothermia treatment seems to have no effect in newborns with severe HIE after 6 h (P > 0.05). Hypothermia improved the rates of neonatal death and 18-month disability (all P < 0.01). CONCLUSIONS: In newborns with moderate HIE, starting hypothermia therapy < 6 h and 6-12 h after HIE showed curative effects. In those with severe HIE, only starting hypothermia therapy within 6 h showed curative effects. PMID- 29433476 TI - TRPV4 regulates migration and tube formation of human retinal capillary endothelial cells. AB - BACKGROUND: Ca2+ entry plays an important role in modulating endothelial cell migration and tube formation. Transient receptor potential cation channel subfamily V member 4 (TRPV4) is a Ca2+-permeable channel that is widely expressed in endothelial cells. It has been reported that TRPV4 is expressed in HRCECs and regulates Ca2+ entry. However, the function of TRPV4 in human retinal capillary endothelial cells (HRCECs) remains unknown. METHODS: In this study we used western blot and immunostaining assay to verify TRPV4 expression in HRCECs. And then we pretreated HRCECs with HC067047 and transfected with specific shRNA of TRPV4. The functional presence of TrpV4 was determined by using fluorescence, migration and tube formation assay in TrpV4 knockdown cells or control cells. RESULTS: Using western blot and immunostaining, we confirmed TRPV4 expression in HRCECs. Moreover, inhibition of TRPV4 using the specific inhibitor HC067047 and the knockdown of TRPV4 with shRNA significantly suppressed tube formation and migration by HRCECs. CONCLUSIONS: TRPV4 is essential for HRCEC migration and tube formation, and maybe a potential therapeutic target for retinal vascular diseases. PMID- 29433477 TI - Prevalence and causes of blindness, visual impairment among different ethnical minority groups in Xinjiang Uygur autonomous region, China. AB - BACKGROUND: The aim of this cross-sectional study is to ascertain the prevalence and causes of blindness, visual impairment, uptake of cataract surgery among different ethnic groups in Xinjiang Uygur Autonomous Region, China. METHODS: Four thousand one hundred fifty people at 50 years and above from different minority ethnic groups were randomly selected for an eye examination. The four trained eye teams collected data using tumbling E visual chart, torch, portable slit lamp and direct ophthalmoscope in 2015. The World Health Organization's definition of blindness and visual impairment (VI) was used to classify patients in each ethnic group. Data were analyzed by different minority groups and were compared with Han Chinese. RESULTS: 3977 (95.8%) out of 4150 people were examined. The prevalence of blindness from the study population was 1.7% (95% confidence interval: 1.3 2.2%).There was no significant difference in prevalence of blindness between Han Chinese and people of Khazak and other minority ethnic groups, nor, between male and female. Cataract was the leading course (65.5%) of blindness and uncorrected refractive error was the most common cause of VI (36.3%) followed by myopic retinopathy. The most common barrier to cataract surgery was lack of awareness of service availability. CONCLUSIONS: This study documented a low blindness prevalence among people aged 50 years and over comparing to prevalence identified through studies of other regions in China. It still indicates blindness and un operated cataract as the significant public health issue, with no evidence of eye health inequalities, but some inequities in accessing to cataract surgery amongst ethnic minority groups in Xinjiang. PMID- 29433478 TI - Case report of severe myocarditis in an immunocompromised child with Respiratory Syncytial Virus infection. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection is common and may be severe among patients with preexisting cardiac anomalies, but direct involvement of myocardial damage is not common in those patients. Additionally, myocardial involvement has been rarely described among immune compromised children. CASE PRESENTATION: A 4-year-old girl with acute lymphoblastic leukemia who received maintenance chemotherapy in an outpatient clinic developed systemic inflammatory response syndrome. RSV infection was confirmed by a positive rapid antigen test and serological assay. Subsequently, she was diagnosed with severe myocarditis caused by RSV infection, which was diagnosed by abnormal findings of cardiac echography and ECG and elevated biomarkers for myocardial damage. Then, she was treated in the intensive care unit for 13 days. High amounts of RSV type B RNA was detected in tracheal aspirates and serum sample. CONCLUSION: This case report emphasizes that RSV infection may be associated with myocarditis in immunocompromised children receiving maintenance chemotherapy. PMID- 29433479 TI - Tinnitus services in the United Kingdom: a survey of patient experiences. AB - BACKGROUND: Tinnitus service provision in the United Kingdom has been investigated from the healthcare provider's perspective demonstrating considerable regional variation particularly regarding availability of psychological treatments. An audiological-based tinnitus service, however, was reportedly available for all tinnitus patients in the UK. The aim of the current study was to define and evaluate nationwide tinnitus healthcare services from the patients' viewpoint. METHODS: Secondary analyses were performed on data from a 33 item questionnaire provided by the British Tinnitus Association. The questionnaire had been distributed via email and social media. RESULTS: Responses from 937 participants who had or had previously experienced tinnitus were analysed. All but one person had at some time consulted their GP. About one in five received medication in primary care. The majority were referred to secondary care, generally an ENT surgeon or audiovestibular physician; some were referred directly to audiological services. In secondary care the majority underwent audiometric testing and over half underwent MRI scanning. Drugs were prescribed less frequently in secondary care. About one third of patients were referred onwards from diagnostic services in secondary care to receive therapeutic interventions for tinnitus. Therapy was generally delivered by an audiologist or hearing therapist. Just under two fifths of people discharged from secondary care returned to their GP, with most returning within one year. Over a third of this group were re-referred to secondary care. Few patients saw a psychologist (2.6%) though some psychological treatments were delivered by appropriately trained audiologists. Negative counselling from healthcare professionals in both primary and secondary care settings was reported. CONCLUSIONS: Although the UK has developed a national service for patients with tinnitus many people find it difficult to access, being blocked at the primary care level or after secondary care diagnostic services. Many of those discharged from secondary care return to their GP within a short space of time and are re-referred to secondary care creating an unsatisfactory and expensive revolving-door pattern of healthcare. Despite psychological treatment modalities having the best evidence base for successful tinnitus management, only a minority of tinnitus patients ever get to meet a psychologist. PMID- 29433480 TI - Ultrasonographic findings in cows with left displacement of abomasum, before and after reposition surgery. AB - BACKGROUND: The natural incidence of left displacement of abomasum (LDA) in dairy cows was high. The diagnosis of LDA usually relies on characteristic physical exam findings but that transabdominal ultrasound is a useful technique that has been applied to the diagnosis of gastrointestinal diseases of dairy cows in equivocal cases. METHODS: Forty dairy cows with LDA were clinically and ultrasonographically examined to determine the position and the echogenic property of the abomasum. The cows were examined ultrasonographically on the left side, from the 9th intercostal space (ICS) to the 12th ICS as well as the ventral left abdomen before and after reposition surgery. RESULTS: The vital signs were within normal range in most of the cows and the 'pinging' were clearly heard in 37 cows. The abomasal gas cap was visualized from the 9th to 12th ICS in 37 cows and characterized by reverberation artifacts. The abomasal ingesta appeared as homogeneous hypoechoic fluid with scattered hyperechoic foci and were mainly visible in the median region and ventral region of the 9th to 11th ICS in 35 cows. The pyloric canal was detected from the ventral left abdomen wall in 30 cows and appeared as a loop with hypoechogenic wall and echogenic luminal contents in cross section. CONCLUSION: These typical ultrasonograms, including reverberation artifacts, homogenous hypoechoic structures, are important diagnostic feature in ultrasonography of LDA. Furthermore, the circular acoustic image structure of the pyloric canal is an important characteristic of LDA, so it can be used as an important diagnostic basis of LDA. PMID- 29433481 TI - Impact of treatment strategy and physical performance on future knee-related self efficacy in individuals with ACL injury. AB - BACKGROUND: In people with anterior cruciate ligament (ACL) injury, high self efficacy facilitates recovery, indicated by improved muscle function, reduced knee symptoms and increased physical activity. Impact of treatment on future self efficacy is however not well investigated. The aims of the study were to 1) investigate knee-related self-efficacy 6 years after acute ACL injury in patients treated with exercise therapy alone or in combination with either early or the option of delayed ACL reconstruction (ACLR), and 2) to investigate associations between single-leg physical performance at various time points after ACL injury and knee self-efficacy at 6 years after injury. METHODS: Participants (n = 121) originated from the KANON-study (ISRCTN84752559), a treatment RCT including active adults with acute ACL injury treated with structured exercise therapy combined with early or the option of delayed ACLR. In this ancillary study, participants with knee self-efficacy data at 6 years (n = 89) were analyzed as treated; exercise therapy alone (n = 20), exercise therapy plus early ACLR (n = 46), and exercise therapy plus delayed ACLR (n = 23). The participants performed physical performance tests (hop, strength and balance) at the end the of exercise therapy (mean 10 (SD 6) months), and at 5 years, and rated their knee self efficacy using Knee Self-Efficacy Scale (K-SES) questionnaire (0 to 10, worst to best) at 6 years. RESULTS: Median K-SES score for the total group (n = 89) was 7.8 (IQR 5.9-9.0). There were no differences between treatment groups in K-SES scores at 6 years nor in physical performance at any time point (p >= 0.097). Worse knee flexion strength LSI (rsp = 0.341, p = 0.042) at the end of the exercise therapy, and worse LSI for single-leg hop test (rsp = 0.310, p = 0.005) at the end of the exercise therapy and at 5 years, correlated moderately with worse knee-related self-efficacy at 6 years. Low associations were observed between the remaining physical performance tests and K-SES scores (rsp <= 0.265, p >= 0.045). CONCLUSION: Knee-related self-efficacy at 6 years after ACL injury did not differ between those treated with ACLR, performed early or as a delayed procedure, or exercise therapy alone. Good physical performance at the end of the exercise therapy, and at 5 years, appears to have a positive, yet small, impact on future knee-related self-efficacy. PMID- 29433482 TI - Cholesterol of lipid rafts is a key determinant for entry and post-entry control of porcine rotavirus infection. AB - BACKGROUND: Lipid rafts are major structural components in plasma membranes that play critical roles in many biological processes including virus infection. However, few reports have described the relationship between lipid rafts and porcine rotavirus (PRV) infection. In this study, we investigated whether or not the locally high concentrations (3-5 fold) of cholesterol present in lipid rafts are required for PRV infection, and further examined which stages of the infection process are most affected. RESULTS: When cellular cholesterol was depleted by methyl-beta-cyclodextrin (MbetaCD), PRV infectivity significantly declined in a dose-dependent manner. This inhibition was partially reversed upon reintroduction of cholesterol into the system. This was corroborated by the co localization of PRV with a recombinant, GPI-anchored green fluorescent protein, which functioned as a marker for membranous regions high in cholesterol and indicative of lipid rafts. Changes in virus titer and western blot analyses indicated that depletion of cellular cholesterol with MbetaCD had no apparent effect on PRV adsorption; however, depletion of cholesterol significantly restricted entry and post-entry of PRV into the cell. Both points of inhibition were restored to near normal levels by the addition of exogenous cholesterol. CONCLUSIONS: We conclude from these studies that membrane-based cholesterol and in particular that localized to lipid rafts, is an indispensable biomolecule for PRV infection, and that cholesterol-based control of the infection process takes place during entry and immediately post-entry into the cell. PMID- 29433483 TI - Control of Staphylococcus aureus in dairy herds in a region with raw milk cheese production: farmers' attitudes, knowledge, behaviour and belief in self-efficacy. AB - BACKGROUND: Contagious mastitis is an important disease in dairy cattle, and the causative agent S. aureus can also impair raw milk cheese quality. In a confined region in eastern Switzerland attitude, knowledge and behaviour towards S. aureus und S. aureus control was assessed in 90 dairy farmers with communal alpine pasturing including raw milk cheese production with the aid of a questionnaire. RESULTS: Forty-three out of 90 questionnaires were returned (48% return rate). Farmers perceived reproductive problems as most important in their dairy herds followed by respiratory disease and diarrhoea in young stock. Most frequently stated as important motivating factors to participate in S. aureus control were "avoiding negative news about cheese quality in the press" followed by "I want to be proud of my somatic cell counts again". Most frequently chosen and identified as important constraining factors were "I fear that the authorities dictate and the farmers are not heard" followed by "costs to control S. aureus are too high because of premature culling" and "I am afraid to be forced to cull genetically valuable cows". Farmers with an experience of a S. aureus problem in their dairy herds had a significantly better knowledge about contagiosity and clinical manifestation of different S. aureus genotypes than farmers with no self-reported experience of a S. aureus problem. Veterinarians were indicated as the most important experts, farmers seek advice in case of mastitis and most farmers suggested subsidising bacteriological milk analysis as an incentive to motivate farmers towards S. aureus control. CONCLUSION: According to the results an improved knowledge transfer on S. aureus to dairy producers and an integrative approach to a S. aureus control program with subsidising milk analysis will be most promising to improve the S. aureus situation in this confinded region of eastern Switzerland. Veterinarians should cover a key role in consulting farmers during the control program. PMID- 29433484 TI - Small scale migration along the interoceanic highway in Madre de Dios, Peru: an exploration of community perceptions and dynamics due to migration. AB - BACKGROUND: Madre de Dios, a southern state in the Peruvian Amazon basin, has experienced rapid development as well as an influx of migrants since the construction of the Interoceanic Highway (IOH) connecting Brazil, Bolivia, and the Peruvian coast. We explored perceptions of migration and development in up to eight communities along the IOH in Madre de Dios following construction of the highway. METHODS: We conducted a multiple methods study involving focus group (FG) discussions and interviews with key informants (KIs) in eight communities in Madre de Dios. The data was used to develop and apply a survey on demographics, financial, personal, social, human, and physical capital in four communities between February 2014 and March 2015. RESULTS: We conducted 12 FGs and 34 KI interviews. A total of 522 people participated in the survey. Comparing migrants (those who had moved to the area after construction of the IOH) and non-migrants, we found no difference in food security or access to health services. The majority (67.6%) of respondents from both groups reported that illness was their primary threat to well-being. Non-migrants owned more land than migrants (p < 0.001), were more likely to have piped water directly in their home (p = 0.046), and were more likely to participate in community groups (p = 0.012). Looking at perceptions about migrants, KIs and FGs discussed both positive perceptions of migrants (increased cultural exchange and new technology) and negative perceptions (increased drugs and alcohol in their communities and a lack of investment in the community). Both migrants and non-migrants reported trusting the local government more than the national government. CONCLUSIONS: Although we hypothesized that migrants would have decreased access to food, water, health services, and land relative to non-migrants, our results show that the only significant differences were in land ownership and water access. Efforts to improve community infrastructure should be carried out at the local level and focus on improving issues reported by both groups, such as potable water, sewage, and increased access to health services. Furthermore, an emphasis on community cohesion, ensuring land rights, and increasing long-term job opportunities should help ease tensions between migrants and non-migrants. PMID- 29433485 TI - Safety and efficacy of platelet-rich plasma in treatment of carpal tunnel syndrome; a randomized controlled trial. AB - BACKGROUND: Carpal tunnel syndrome is the most common peripheral entrapment neuropathy, for which conservative treatments are the first measures taken. However, these measures are not usually sufficient. Recently major attention has been drawn to platelet-rich plasma for its possible effects on axon regeneration and neurological recovery. Although few studies have evaluated the effects of this treatment in carpal tunnel syndrome, further investigation is required to reach concrete conclusion. METHODS: In this randomized controlled trial, women referring to the physical medicine and rehabilitation clinic at Shahid Modarres Hospital during 2016 with a diagnosis of mild and moderate idiopathic carpal tunnel syndrome were chosen. They were randomly assigned to two groups: (i) a control group using only a wrist splint, and (ii) a platelet-rich plasma group that received wrist splints along with a single local injection of platelet-rich plasma. The outcome measures were assessed via Visual Analogue Scale, the Boston Carpal Tunnel Syndrome Questionnaire and electrophysiological findings including the peak latency of sensory nerve action potential and the onset latency of the compound muscle action potential. RESULTS: A total of 41 women were included (20 wrists as control group) and (21 wrists as platelet-rich plasma group). Before treatment there were no significant differences between the two groups except for the median peak latency of sensory nerve action potential which was significantly higher among the patients in the platelet-rich plasma group (p = 0.03). All the measured variables significantly decreased in both groups after 10 weeks of treatment except for the median onset latency of the compound muscle action potential (p = 0.472). Finally, the changes in neither of the evaluated outcome measures were found to significantly differ between the two groups, even when the analyses were adjusted for age of the patients. CONCLUSION: The findings of this study showed that in a relatively short period of time after treatment, a single injection of platelet-rich plasma in the wrist does not significantly add to the effects of conservative treatment with wrist splints, in regards to the women pain and symptom severity, functional status and electrophysiological parameters. TRIAL REGISTRATION: The trial has been retrospectively registered with an ID: IRCT2017041513442N13 (Date of registration: 2017-06-19). PMID- 29433486 TI - Information about management of chronic drug therapies prescribed at hospital discharge: does it affect patients' knowledge and self-confidence? AB - BACKGROUND: Hospital stay represents the opportunity for a change of therapy, about which patients may not know indications, contraindications, and mode of administration, which may lead to dosing errors, drug interactions, side effects, etc. It is therefore vital to communicate appropriate information to the discharged patient with a new prescription drug. The purpose of the study was to evaluate: 1) how communication about new chronic therapies is managed at hospital discharge and what kind of information is provided to patients; 2) to what extent patients are aware and confident in the management of these medications; 3) whether the way communication is provided affects patients' awareness and self confidence in the management of these therapies. METHODS: Participants were adult patients who were prescribed at least one new chronic medication at hospital discharge. A telephone interview after hospital discharge was performed to assess whether or not hospital healthcare personnel had given information about prescribed therapies and which aspects of therapies had been object of information. RESULTS: Five hundred thirty patients were interviewed. 67.7% reported having received counseling by the hospital physician, while 32.3% by discharge form. Basic information on treatment was provided to the great majority of patients, whereas only few patients reported to have been informed about eventual side effects and related behavior in case of side effects. CONCLUSIONS: Several aspects of patients' knowledge and self-confidence on long term medications prescribed at hospital discharge need to be improved and the way communication is provided has a crucial role in the empowerment of patients in the management of these medications. PMID- 29433487 TI - Development and validation of a questionnaire to evaluate the factors influencing training transfer among nursing professionals. AB - BACKGROUND: Most organizations invest in people for training to improve human capital and maximize profitability. Yet it is reported in industry and nursing as well that training effectiveness is constrained because of inadequate transfer of training and the underlying reasons for the transfer problem remain unknown. And there is lack of tool to measure transfer problem. METHODS: The purpose of this study was to develop and validate a questionnaire to evaluate the scores of factors influencing training transfer (FITT) among nursing professionals. The questionnaire was developed by item generation through interview with nurses and literature review. The FITT was validated in terms of content validity through expert reviews. Psychometric properties of the final instrument were assessed in a sample of 960 nurses with training experiences. RESULTS: The content validity of the instrument were as follows: the IR was 0.8095. 51 items on the 63-item scale had I-CVIs of 1.0 and the remaining 12 items had I-CVIs of 0.88. The S CVI/UA was 0.976 and the S-CVI/Ave was 0.977. For the exploratory step, principal axis factoring (PAF) was selected for this study. Parallel analysis was used to decide the number of factors to extract and oblimin rotation method was used. Exploratory factor analysis identified a five-factor solution including 53 items, accounting for 68.23% of the total variance. The confirmatory factor analysis showed some support for this five-factor model. The findings demonstrate high internal consistency (Cronbach's alpha = .965). CONCLUSIONS: This study indicates that the FITT is a valid and reliable instrument for assessing the factors influencing training transfer among nursing professionals. The FITT can be used to assess individual perceptions of catalysts and barriers to the transfer of training among nursing professionals, which can help promote training transfer and training effectiveness in the workplace. PMID- 29433488 TI - Prevalence of dysmenorrhea among University students in Northern Ghana; its impact and management strategies. AB - BACKGROUND: The period of menstruation is an eventful one for a significant number of post-pubescent females as they experience lower abdominal pains referred to as dysmenorrhea. This study conducted among female students of the Tamale campus of the University for Development Studies assessed the prevalence of dysmenorrhea, its impact on the students and treatment methods applied. METHODS: A cross-sectional study using a self-administered questionnaire was used to obtain data from 293 randomly selected female students. Data was analyzed using Graph Pad 5.01. Association between different variables was tested. RESULTS: The prevalence rate of dysmenorrhea was 83.6% with more than half describing their pain which lasts less than 3 days as moderate. This dysmenorrhea during menstruation affects the daily activities of up to 61.2% of respondents. Lower chronological age (chi2 = 8.28; df = 2; p = 0.016) and gynecological age (chi2 = 10.09; df = 2; p = 0.006) were the factors that were significantly associated with the presence of dysmenorrhea. Chronological and gynecological ages, age at menarche, menstrual duration or flow level do not influence the severity of dysmenorrhea but irregular menstrual flow is significantly associated with severe dysmenorrhea (chi2 = 10.54; df = 2; p = 0.005). Only 16.3% ever reported their dysmenorrhea to the hospital but increasing pain level is significantly associated with respondents visiting a hospital (chi2 = 65.61; df = 2; p < 0.0001) or use an allopathic medication (chi2 = 32.77; df = 2; p < 0.0001). Paracetamol preparation was the most common medication used notwithstanding the severity of the pain. CONCLUSIONS: There is high prevalence of dysmenorrhea among the female students of the Tamale campus of the University for Development studies which negatively affects the daily activity of majority of them. Although, bed rest was the most common treatment method practised, paracetamol preparation was the most common allopathic drug used in self- management of their dysmenorrhea. PMID- 29433489 TI - Predictors of inappropriate and excessive use of reliever medications in asthma: a 16-year population-based study. AB - BACKGROUND: Understanding factors associated with the inappropriate or excessive use of short-acting beta agonists (SABA) can help develop better policies. METHODS: We used British Columbian (BC)'s administrative health data (1997-2014) to create a retrospective cohort of asthma patients aged between 14 and 55 years. The primary and secondary outcomes were, respectively, inappropriate and excessive use of SABA based on a previously validated definition. Exposures were categorised into groups comprising socio-demographic variables, indicators of type and quality of asthma care, and burden of comorbid conditions. RESULTS: 343,520 individuals (56.3% female, average age 30.5) satisfied the asthma case definition, contributing 2.6 million person-years. 7.3% of person-years were categorised as inappropriate SABA use and 0.9% as excessive use. Several factors were associated with lower likelihood of inappropriate use, including female sex, higher socio-economic status, higher continuity of care, having received pulmonary function test in the previous year, visited a specialist in the previous year, and the use of inhaled corticosteroids in the previous year. An asthma-related outpatient visit to a general practitioner in the previous year was associated with a higher likelihood of inappropriate SABA use. Similar associations were found for excessive SABA use with the exception that visit to respirologist and the use of systemic corticosteroids were associated with increased likelihood of excessive use. CONCLUSIONS: Despite proven safety issues, inappropriate SABA use is still prevalent. Several factors belonging to patients' characteristics and type/quality of care were associated with inappropriate use of SABAs and can be used to risk-stratify patients for targeted attempts to reduce this preventable cause of adverse asthma outcomes. PMID- 29433491 TI - Barriers to delivering mental health services in Georgia with an economic and financial focus: informing policy and acting on evidence. AB - BACKGROUND: Whilst there is recognition that the global burden of disease associated with mental health disorders is significant, the economic resources available, especially in Low and Middle Income Countries, are particularly scarce. Identifying the economic (system) and financial (individual) barriers to delivering mental health services and assessing the opportunities for reform can support the development of strategies for change. METHODS: A mixed methods study was developed, which engaged with a range of stakeholders from mental health services, including key informants, service managers, healthcare professional and patients and their care-takers. Data generated from interviews and focus groups were analysed using an existing framework that outlines a range of economic and financial barriers to improving mental health practice. In addition, the study utilised health financing and programmatic data. RESULTS: The analysis identified a variety of local economic barriers, including: the inhibition of the diversification of the mental health workforce and services due to inflexible resources; the variable and limited provision of services across the country; and the absence of mechanisms to assess the delivery and quality of existing services. The main financial barriers identified were related to out-of pocket payments for purchasing high quality medications and transportation to access mental health services. CONCLUSIONS: Whilst scarcity of financial resources exists in Georgia, as in many other countries, there are clear opportunities to improve the effectiveness of the current mental health programme. Addressing system-wide barriers could enable the delivery of services that aim to meet the needs of patients. The use of existing data to assess the implementation of the mental health programme offers opportunities to benchmark and improve services and to support the appropriate commissioning and reconfiguration of services. PMID- 29433490 TI - Citral induced apoptosis in MDA-MB-231 spheroid cells. AB - BACKGROUND: Breast cancer remains a leading cause of death in women worldwide. Although breast cancer therapies have greatly advanced in recent years, many patients still develop tumour recurrence and metastasis, and eventually succumb to the disease due to chemoresistance. Citral has been reported to show cytotoxic effect on various cancer cell lines. However, the potential of citral to specifically target the drug resistant breast cancer cells has not yet been tested, which was the focus of our current study. METHODS: The cytotoxic activity of citral was first tested on MDA-MB-231 cells in vitro by MTT assay. Subsequently, spheroids of MDA-MB-231 breast cancer cells were developed and treated with citral at different concentrations. Doxorubicin, cisplatin and tamoxifen were used as positive controls to evaluate the drug resistance phenotype of MDA-MB-231 spheroids. In addition, apoptosis study was performed using AnnexinV/7AAD flowcytometry. Aldefluor assay was also carried out to examine whether citral could inhibit the ALDH-positive population, while the potential mechanism of the effect of citral was carried out by using quantitative real time- PCR followed by western blotting analysis. RESULTS: Citral was able to inhibit the growth of the MDA-MB-231 spheroids when compared to a monolayer culture of MDA-MB-231 cells at a lower IC50 value. To confirm the inhibition of spheroid self-renewal capacity, the primary spheroids were then cultured to additional passages in the absence of citral. A significant reduction in the number of secondary spheroids were formed, suggesting the reduction of self renewal capacity of these aldehyde dehydrogenase positive (ALDH+) drug resistant spheroids. Moreover, the AnnexinV/7AAD results demonstrated that citral induced both early and late apoptotic changes in a dose-dependent manner compared to the vehicle control. Furthermore, citral treated spheroids showed lower cell renewal capacity compared to the vehicle control spheroids in the mammosphere formation assay. Gene expression studies using quantitative real time PCR and Western blotting assays showed that citral was able to suppress the self-renewal capacity of spheroids and downregulate the Wnt/beta-catenin pathway. CONCLUSION: The results suggest that citral could be a potential new agent which can eliminate drug-resistant breast cancer cells in a spheroid model via inducing apoptosis. PMID- 29433492 TI - Listening to their voices: understanding rural women's perceptions of good delivery care at the Mibilizi District Hospital in Rwanda. AB - BACKGROUND: Poor quality maternity care may lead to increased maternal dissatisfaction, and subsequent decreased utilization of health services or both. In a responsive health system, determining suitable delivery care, in the mother's opinion, may lead to an improved quality of services and the mother's satisfaction. In Rwanda, there is still limited knowledge and inadequate research regarding patient satisfaction and preferences, especially for women's perceptions and needs during childbirth. This study captures rural women's perception of good delivery care to understand aspects of care they consider important during childbirth. METHODS: This qualitative study was conducted in the Mibilizi District Hospital catchment area located 350 km from the capital, Kigali, in the Western Province of Rwanda. It includes 25 in-depth interviews with purposively sampled rural mothers who had delivered in the hospital and five hospital midwives. Content analysis was performed manually. RESULTS: With regard to interpersonal relations at the health facility, the women agreed on the need for respectful treatment in areas of sufficient privacy and had distinct preferences for the gender of the birth attendant, or husband's presence during delivery. The women make a great effort to deliver in a health care facility and therefore, they expect to be assisted in a professional and safe manner. These expectations can be met on a personal level, but at times are counteracted by structural deficiencies and staff shortages. CONCLUSIONS: In gathering rural women's perceptions of good delivery care, this study reveals what mothers in remote areas in Rwanda consider important during child birth. The women's expectations, suggestions, and needs can enhance providers' awareness of the women's priorities during childbirth and serve as a guidepost for health services to increase the quality, acceptability and uptake of maternal health services. PMID- 29433493 TI - Protocol for the Individual Placement and Support (IPS) in Pain Trial: A randomized controlled trial investigating the effectiveness of IPS for patients with chronic pain. AB - BACKGROUND: Work disability involves large costs to the society as well as to the individual. Work disability is common among people with chronic pain conditions, yet few effective interventions exist. Individual Placement and Support (IPS) is an evidence-based work rehabilitation model originally developed to help people with severe mental illness obtain and maintain employment. The effectiveness of IPS for patients with severe mental illness is well documented, but the model has never before been tested for patients with chronic pain. METHODS/DESIGN: The aim of the IPS in Pain trial is to investigate the effectiveness of IPS as an integrated part of the interdisciplinary treatment for patients with chronic pain in a hospital outpatient clinic. The study is a randomized controlled trial comparing pain treatment with integrated IPS to treatment as usual in unemployed patients suffering from various chronic pain conditions. The primary outcome of the study is labor market participation during 12 months after enrollment, and secondary outcomes include physical and mental health and well-being, collected at baseline, 6, and 12 months. Finally, there will be an additional long-term follow-up for the primary outcome, which will be collected through a brief phone interview at 24 months. DISCUSSION: The IPS in Pain trial will be the first report of the effectiveness of the IPS model of supported employment applied in an outpatient setting for chronic pain patients. It will thus provide important information about the effectiveness of repurposing IPS to a new patient group in great need of job support. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02697656 . Registered January 15th, 2016. PMID- 29433494 TI - Incidental finding of large pneumothorax on Cardiac MR scan. AB - BACKGROUND: We believe this is the first case report of a pneumothorax being identified using cardiac magnetic resonance imaging. This case also illustrates the haemodynamic effect a large pneumothorax can have on right ventricular filling in diastole. CASE PRESENTATION: A 26-year-old attended for an interval follow up Cardiac Magnetic Resonance (CMR) of his thoracic aorta after a thoracic co-arctation repair aged 3. He was found to have an incidental large pneumothorax by the reporting cardiology fellow which was confirmed by the on-call radiologist. The pneumothorax was most notable for its compression of the right ventricle in diastole. Although the patient had worrying features on CMR imaging, he remained clinically stable and a conservative approach to management saw the pneumothorax resolve after a 3 week period. CONCLUSIONS: Pneumothoraces are important, potentially life threatening conditions. Although very rarely identified on MR imaging, radiographers and reporting doctors should be aware of their key features. This case serves to identify not only the abnormal lung parenchymal features but also the striking compressional effect of the pneumothorax on the right ventricle in diastole. Indeed we believe this is the first case report of a pneumothorax identified on CMR imaging. PMID- 29433495 TI - Presentation of laboratory test results in patient portals: influence of interface design on risk interpretation and visual search behaviour. AB - BACKGROUND: Patient portals are considered valuable instruments for self management of long term conditions, however, there are concerns over how patients might interpret and act on the clinical information they access. We hypothesized that visual cues improve patients' abilities to correctly interpret laboratory test results presented through patient portals. We also assessed, by applying eye tracking methods, the relationship between risk interpretation and visual search behaviour. METHODS: We conducted a controlled study with 20 kidney transplant patients. Participants viewed three different graphical presentations in each of low, medium, and high risk clinical scenarios composed of results for 28 laboratory tests. After viewing each clinical scenario, patients were asked how they would have acted in real life if the results were their own, as a proxy of their risk interpretation. They could choose between: 1) Calling their doctor immediately (high interpreted risk); 2) Trying to arrange an appointment within the next 4 weeks (medium interpreted risk); 3) Waiting for the next appointment in 3 months (low interpreted risk). For each presentation, we assessed accuracy of patients' risk interpretation, and employed eye tracking to assess and compare visual search behaviour. RESULTS: Misinterpretation of risk was common, with 65% of participants underestimating the need for action across all presentations at least once. Participants found it particularly difficult to interpret medium risk clinical scenarios. Participants who consistently understood when action was needed showed a higher visual search efficiency, suggesting a better strategy to cope with information overload that helped them to focus on the laboratory tests most relevant to their condition. CONCLUSIONS: This study confirms patients' difficulties in interpreting laboratories test results, with many patients underestimating the need for action, even when abnormal values were highlighted or grouped together. Our findings raise patient safety concerns and may limit the potential of patient portals to actively involve patients in their own healthcare. PMID- 29433496 TI - Benefit in liver transplantation: a survey among medical staff, patients, medical students and non-medical university staff and students. AB - BACKGROUND: The allocation of any scarce health care resource, especially a lifesaving resource, can create profound ethical and legal challenges. Liver transplant allocation currently is based upon urgency, a sickest-first approach, and does not utilize capacity to benefit. While urgency can be described reasonably well with the MELD system, benefit encompasses multiple dimensions of patients' well-being. Currently, the balance between both principles is ill defined. METHODS: This survey with 502 participants examines how urgency and benefit are weighted by different stakeholders (medical staff, patients on the liver transplant list or already transplanted, medical students and non-medical university staff and students). RESULTS: Liver transplant patients favored the sickest-first allocation, although all other groups tended to favor benefit. Criteria of a successful transplantation were a minimum survival of at least 1 year and recovery of functional status to being ambulatory and capable of all self-care (ECOG 2). An individual delisting decision was accepted when the 1-year survival probability would fall below 50%. Benefit was found to be a critical variable that may also trigger the willingness to donate organs. CONCLUSIONS: The strong interest of stakeholder for successful liver transplants is inadequately translated into current allocation rules. PMID- 29433497 TI - A painful experience of limited understanding: healthcare professionals' experiences with palliative care of people with severe dementia in Norwegian nursing homes. AB - BACKGROUND: People dying with dementia have significant healthcare needs, and palliative care, with its focus on comfort and quality of life, should be made available to these patients. The aim of this study was to explore and increase knowledge of healthcare professionals' experiences with palliative care to people with severe dementia in nursing homes. METHODS: To describe the phenomenon under investigation, we used a phenomenological research approach grounded in the philosophy of Husserl. Data were collected using in-depth interviews with 20 healthcare professionals from four Norwegian nursing homes. RESULTS: The general meaning structure of the healthcare professionals' experiences with providing palliative care to people with severe dementia is painfulness, due to their limited understanding of patients' individual modes of expression. The painfulness is illustrated by the following themes: challenges related to "reading" the patients' suffering, coming up short despite occasional success, handing the patients over to strangers, and disagreeing on the patients' best interests. The healthcare professionals struggled to understand patients by "reading" their suffering. Occasionally, they succeeded and were able to calm the patients, but they often had the feeling of coming up short in situations related to pain relief and coping with behavioural symptoms, such as aggression and rejection of care. They also found it painful when the weakest patients were moved from the sheltered unit to a somatic long-term unit and were handed over to strangers who did not know the patients' ways of expression. Although the healthcare professionals emphasized the importance of good collaboration with the patients' relatives to ensure the best possible palliative care, they frequently found themselves in difficult situations when they disagreed with the family on the patients' best interests. CONCLUSIONS: We found healthcare professionals' experiences of providing palliative care to people with severe dementia to be painful. To be able to understand the patients better, long-term familiarity and knowledge of how to "read" and observe patients with severe dementia are necessary. Openness in cooperation with the patients' relatives and with the professional team may increase healthcare professionals' understanding of the patients' situations and hence improve the quality of care. PMID- 29433498 TI - What does an enabling environment for infant and young child nutrition look like at implementation level? Perspectives from a multi-stakeholder process in the Breede Valley Sub-District, Western Cape, South Africa. AB - BACKGROUND: Breede Valley is a sub-district of the Cape Winelands district, Western Cape Province, South Africa. The administrative capital of the district is situated in the semi-rural town Worcester. Findings of a baseline survey in Worcester revealed poor infant feeding practices and childhood under- and overnutrition, with particular concern over high levels of stunting and low dietary diversity. Maternal overweight and obesity was high. These characteristics made the site suitable to study multi-sectoral arrangements for infant and young child nutrition (IYCN). The purpose of this study was to explore elements of an enabling environment with key stakeholders aimed at improving IYCN at implementation level. METHODS: Focus group discussions and interviews were conducted with representatives from two vulnerable communities; local and district government; higher education institutions; business; and the media in the Breede Valley. Audio recordings were transcribed and data were analysed with the Atlas.TI software programme. RESULTS: The participants viewed knowledge and evidence about the first 1000 days of life as important to address IYCN. The impact of early, optimal nutrition on health and intellectual development resonated with them. The IYCN narrative in the Breede Valley could therefore be framed around nutrition's development impact in a well-structured advocacy campaign. Participants felt that capacity and resources were constrained by many competing agendas spreading public resources thinly, leaving limited scope for promotion and prevention activities. "People" were viewed as a resource, and building partnerships and relationships, could bridge some shortfalls in capacity. Conversations about politics and governance elicited strong opinions about what should be done through direct intervention, policy formulation and legislation. A lead government agency could not be identified for taking the IYCN agenda forward, due to its complexity. Participants proposed it should be referred to a local, informal, inter-governmental body where directors and senior managers meet to address issues of cross-cutting importance. CONCLUSION: The study illustrated that knowledge and evidence; politics and governance; and capacity and resources, elements of the international definition of an enabling environment, also apply at implementation level. In addition, our findings indicated that a people-centred approach is critical in shaping the enabling environment at this level. PMID- 29433499 TI - Healthcare workers' beliefs, motivations and behaviours affecting adequate provision of sexual and reproductive healthcare services to adolescents in Cape Town, South Africa: a qualitative study. AB - BACKGROUND: Adolescents' sexual and reproductive healthcare (SRH) needs have been prioritized globally, and they have the rights to access and utilize SRH services for their needs. However, adolescents under-utilize SRH services, especially in sub-Saharan Africa. Many factors play a role in the under-utilization of SRH services by adolescents, such as the attitude and behaviour of healthcare workers. The aim of this study therefore, was to explore and gain an in-depth understanding of healthcare workers' beliefs, motivations and behaviours affecting adequate provision of these services to adolescents in South Africa. METHODS: Twenty-four healthcare workers in public SRH services in Cape Town, South Africa participated in this qualitative study through focus group discussions. To fulfill the aims of this study, nine focus group discussions were conducted among the SRH nurses. RESULTS: SRH nurses indicated that they are experiencing challenges with the concept and practice of termination of pregnancy. They explained that this practice contradicted their opposing beliefs and values. Some nurses felt that they had insufficient SRH skills, which hinder their provision of adequate SRH services to adolescents, while others described constraints within the health system such as not enough time to provide the necessary care. They also explained having limited access to schools where they can provide SRH education and pregnancy prevention services in the surrounding area. CONCLUSIONS: Nurses are faced with numerous challenges when providing SRH services to adolescents. Providing the nurses with training programmes that emphasize value clarification may help them to separate their personal beliefs and norms from the workplace practice. This may help them to focus on the needs of the adolescent in a way that is beneficial to them. At the health systems level, issues such as clinic operating hours need to be structured such that the time pressure and constraints upon the nurse is relieved. PMID- 29433500 TI - Effects of local treatment with and without sensorimotor and balance exercise in individuals with neck pain: protocol for a randomized controlled trial. AB - BACKGROUND: Impaired cervical joint position sense and balance are associated with neck pain. Specific therapeutic exercise and manual therapy are effective for improving neck pain and functional ability but their effects on joint position sense and balance impairments remain uncertain. Changes in the joint position sense and balance may need to be addressed specifically. The primary objective is to investigate the most effective interventions to improve impaired cervical joint position sense and balance in individuals with neck pain. The secondary objective is to assess the effectiveness of the interventions on pain intensity and disability, pain location, dizziness symptoms, cervical range of motion, gait speed, functional ability, treatment satisfaction and quality of life. METHODS: A 2 * 2 factorial, single blind RCT with immediate, short- and long-term follow-ups. One hundred and sixty eight participants with neck pain with impaired joint position sense and balance will be recruited into the trial. Participants will be randomly allocated to one of four intervention groups: i) local neck treatment, ii) local treatment plus tailored sensorimotor exercises, iii) local treatment plus balance exercises, and iv) local treatment plus sensorimotor and balance exercises. Participants receive two treatments for 6 weeks. Primary outcomes are postural sway and cervical joint position error. Secondary outcomes include gait speed, dizziness intensity, neck pain intensity, neck disability, pain extent and location, cervical range of motion, functional ability, perceived benefit, and quality of life. Assessment will be measured at baseline, immediately after treatment and at 3, 6, 12 month-follow ups. DISCUSSION: Neck pain is one of the major causes of disability. Effective treatment must address not only the symptoms but the dysfunctions associated with neck pain. This trial will evaluate the effectiveness of interventions for individuals with neck pain with impaired cervical joint position sense and balance. This trial will impact on clinical practice by providing evidence towards optimal and efficient management. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03149302 ). May 10, 2017. PMID- 29433502 TI - "I always tried to forget about the condition and pretend I was healed": coping with cervical cancer in rural Ghana. AB - BACKGROUND: Cervical cancer is a very common disease among women in Ghana and in the world as a whole. However, there is a dearth of information on the mechanisms cervical cancer patients adopt to cope with the condition in Ghana. This study sought to explore the strategies adopted by cervical cancer patients in rural Ghana to cope with the disease. METHODS: In-depth interviews were conducted to collect qualitative data from cervical cancer patients in a health facility in the Volta Region of Ghana. Data processing was done using the R software package for Qualitative Data Analysis (RQDA) and a thematic approach was used to analyse and present the results. RESULTS: The results show that cervical cancer patients adopted personal and psychological strategies such as sexual abstinence, personal hygiene, and disease denial to cope with the condition. Respondents also described social, financial and non-material support services they received from family members and the church as critical resources, which helped them to manage the conditions of the disease. Respondents also reported that faith healing, herbal and orthodox medicines helped them to manage the symptoms of the disease. CONCLUSIONS: Cervical cancer patients used a variety of coping strategies to manage the disease. Yet, it will be essential for interventions to focus on strengthening knowledge about the disease. This study underscores the need for financial, social and material support as well as an encouragement of the use of health services among cervical cancer patients. PMID- 29433501 TI - International core outcome set for clinical trials of medication review in multi morbid older patients with polypharmacy. AB - BACKGROUND: Comparisons of clinical trial findings in systematic reviews can be hindered by the heterogeneity of the outcomes reported. Moreover, the outcomes that matter most to patients might be underreported. A core outcome set can address these issues, as it defines a minimum set of outcomes that should be reported in all clinical trials in a particular area of research. The objective in this study was to develop a core outcome set for clinical trials of medication review in multi-morbid older patients with polypharmacy. METHODS: Firstly, eligible outcomes were identified through a systematic review of trials of medication review in older patients (>=65 years) and interviews with 15 older patients. Secondly, an international three-round Delphi survey in four countries involving patients, healthcare professionals, and experts was conducted to validate outcomes to be included in the core outcome set. Consensus meetings were conducted to validate the results. RESULTS: Of the 164 participants invited to take part in the Delphi survey, 150 completed Round 1, including 55 patients or family caregivers, 55 healthcare professionals, and 40 experts. A total of 129 participants completed all three rounds. Sixty-four eligible outcomes were extracted from 47 articles, 32 clinical trial protocols, and patient interviews. Thirty outcomes were removed and one added after Round 1, 18 outcomes were removed after Round 2, and seven after Round 3. Results were discussed during consensus meetings. Consensus was reached on seven outcomes, which constitute the core outcome set: drug-related hospital admissions; drug overuse; drug underuse; potentially inappropriate medications; clinically significant drug-drug interactions; health-related quality of life; pain relief. CONCLUSIONS: We developed a core outcome set of seven outcomes which should be used in future trials of medication review in multi-morbid older patients with polypharmacy. PMID- 29433503 TI - Correction to: Strengthening medical training programmes by focusing on professional transitions: a national bridging programme to prepare medical school graduates for their role as medical interns in Botswana. AB - Following publication of the original article [1], one of the authors reported that prior to publication her surname had changed from 'Kerlen' to 'van der Kruk', but that this change had not been incorporated in the final version. PMID- 29433504 TI - Successful treatment of methotrexate intolerance in juvenile idiopathic arthritis using eye movement desensitization and reprocessing - treatment protocol and preliminary results. AB - BACKGROUND: Methotrexate (MTX), commonly used in juvenile idiopathic arthritis (JIA), frequently has to be discontinued due to intolerance with anticipatory and associative gastrointestinal adverse effects. Eye Movement Desensitization and Reprocessing (EMDR) is a psychological method where dysfunctional experiences and memories are reprocessed by recall combined with bilateral eye movements. The objective of this study was to assess efficacy of EMDR for treatment of MTX intolerance in JIA patients. METHODS: We performed an open prospective study on consecutive JIA patients with MTX intolerance. Intolerance was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire prior to treatment, directly after treatment and after four months. Health-related quality of life was determined using the PedsQL prior to and four months after treatment. Patients were treated according to an institutional EMDR protocol with 8 sessions over two weeks. Changes in MISS and PedsQL were analyzed using non-parametric statistics. RESULTS: Eighteen patients with MTX intolerance (median MISS at inclusion 16.5, IQR = 11.75-20.25) were included. Directly after treatment, MTX intolerance symptoms were significantly improved (median MISS 1 (IQR = 0-2). After four months, median MISS score was at 6.5 (IQR = 2.75-12.25, p = 0.001), with 9/18 patients showing MISS scores >=6. Median PedsQL after 4 months improved significantly from 77.6% to 85.3% (p = 0.008). CONCLUSION: MTX intolerance in children with JIA was effectively treated using an EMDR protocol, with lasting effect over a period of 4 months. EMDR treatment can potentially increase quality of life of affected patients and enable continued MTX treatment. PMID- 29433505 TI - Why nutrition education is inadequate in the medical curriculum: a qualitative study of students' perspectives on barriers and strategies. AB - BACKGROUND: The provision of nutrition care by doctors is important in promoting healthy dietary habits, and such interventions can lead to reductions in disease morbidity, mortality, and medical costs. However, medical students and doctors report inadequate nutrition education and preparedness during their training at school. Previous studies investigating the inadequacy of nutrition education have not sufficiently evaluated the perspectives of students. In this study, students' perspectives on doctors' role in nutrition care, perceived barriers, and strategies to improve nutrition educational experiences are explored. METHODS: A total of 23 undergraduate clinical level medical students at the 5th to final year in the School of Medicine and Health Sciences of the University for Development Studies in Ghana were purposefully selected to participate in semi structured individual interviews. Students expressed their opinions and experiences regarding the inadequacy of nutrition education in the curriculum. Each interview was audio-recorded and later transcribed verbatim. Using the constant comparison method, key themes were identified from the data and analysis was done simultaneously with data collection. RESULTS: Students opined that doctors have an important role to play in providing nutrition care to their patients. However, they felt their nutrition education was inadequate due to lack of priority for nutrition education, lack of faculty to provide nutrition education, poor application of nutrition science to clinical practice and poor collaboration with nutrition professionals. Students opined that their nutrition educational experiences will be improved if the following strategies were implemented: adoption of innovative teaching and learning strategies, early and comprehensive incorporation of nutrition as a theme throughout the curriculum, increasing awareness on the importance of nutrition education, reviewing and revision of the curriculum to incorporate nutrition, and involving nutrition/dietician specialists in medical education. CONCLUSION: Though students considered nutrition care as an important role for doctors they felt incapacitated by non-prioritisation of nutrition education, lack of faculty for teaching of nutrition education, poor application of nutrition science and poor collaboration with nutrition professionals. Incorporation of nutrition as a theme in medical education, improving collaboration, advocacy and creating enabling environments for nutrition education could address some of the barriers to nutrition education. PMID- 29433506 TI - A randomized controlled trial of an intervention delivered by mobile phone app instant messaging to increase the acceptability of effective contraception among young people in Tajikistan. AB - BACKGROUND: Unintended pregnancy is associated with poorer health outcomes for women and their families. In Tajikistan, around 26% of married 15-24 year old women have an unmet need for contraception. There is some evidence that interventions delivered by mobile phone can affect contraceptive-related behaviour and knowledge. We developed an intervention delivered by mobile phone app instant messaging to improve acceptability of effective contraceptive methods among young people in Tajikistan. METHODS: This was a randomized controlled trial among Tajik people aged 16-24. Participants allocated to the intervention arm had access to an app plus intervention messages. Participants allocated to the control arm had access to the app plus control messages. The primary outcome was acceptability of at least one method of effective contraception at 4 months. Secondary outcomes were use of effective contraception at 4 months and during the study, acceptability of individual methods, service uptake, unintended pregnancy and induced abortion. Process outcomes were knowledge, perceived norms, personal agency and intention. Outcomes were analysed using logistic and linear regression. We conducted a pre-specified subgroup analysis and a post-hoc analysis of change in acceptability from baseline to follow-up. RESULTS: Five hundred and seventy-three participants were enrolled. Intervention content was included on the app, causing contamination. Four hundred and seventy-two (82%) completed follow-up for the primary outcome. There was no evidence of a difference in acceptability of effective contraception between the groups (66% in the intervention arm vs 64% in the control arm, adjusted OR 1.21, 95% CI .80 1.83, p = 0.36). There were no differences in the secondary or process outcomes between groups. There was some evidence that the effect of the intervention was greater among women compared to men (interaction test p = 0.03). There was an increase in acceptability of effective contraception from baseline to follow-up (2% to 65%, p < 0.001). CONCLUSIONS: The whole intervention delivered by instant messaging provided no additional benefit over a portion of the intervention delivered by app pages. The important increase in contraceptive acceptability from baseline to follow-up suggests that the intervention content included on the app may influence attitudes. Further research is needed to establish the effect of the intervention on attitudes towards and use of effective contraception among married/sexually active young people. TRIAL REGISTRATION: Clinicaltrial.gov NCT02905513 . Date of registration: 14 September 2016. PMID- 29433507 TI - Sudden spleen rupture in a Plasmodium vivax-infected patient undergoing malaria treatment. AB - BACKGROUND: Splenomegaly is one of the most common features of malaria. However, spontaneous splenic rupture, although unusual, represents a severe complication often leading to death. It is mostly seen in acute infection and primary attack, and it is most commonly associated with Plasmodium vivax. Here, a case of spontaneous splenic rupture diagnosed with a portable ultrasound apparatus shortly after starting treatment and with recurrent parasitaemia after splenectomy, is reported. CASE DESCRIPTION: In November 2015, a 45-year-old Brazilian man presented to the hospital in Manaus with fever, headache and myalgia. He was diagnosed with P. vivax malaria and, after a normal G6PD test, he started treatment with chloroquine and primaquine and was discharged. Two days later, he went back to the hospital with abdominal pain, dyspnea, dry cough, pallor, oliguria and fever. Using a portable ultrasound, he was diagnosed of rupture of the spleen, which was removed by emergency surgery. After this episode, he suffered two more malaria episodes with high parasitaemia at approximately 2-month intervals. DNA from different portions of the spleen was extracted and a qualitative PCR was performed to detect P. vivax. CONCLUSIONS: The splenic rupture suffered by this patient occurred 2 days after starting the treatment. Having a portable ultrasound apparatus may have saved the patient's life, as it revealed a haemorrhage needing an urgent surgery. Parasites were detected by PCR in the extracted spleen. This patient suffered two more vivax malaria diagnosed episodes in spite of receiving and completing treatment with chloroquine and primaquine for each clinical attack. Splenic rupture during acute malaria is uncommon, but it is likely underdiagnosed and underreported, because the lack of means and equipment hinders diagnostic confirmation, especially in endemic areas. PMID- 29433508 TI - Research priority-setting: reproductive health in the occupied Palestinian territory. AB - BACKGROUND: Occupied Palestinian territory (oPt) is an authority with limited resources. Therefore, research conducted in such a setting should be prioritized and coordinated to follow a national research agenda. This study aims to produce a research agenda for reproductive health in the oPt that can be utilized by reproductive health stakeholders and contribute to the development of policy based evidence to guide health practice. METHODS: In the current study, we followed research prioritization methods developed by the World Health Organization-Child Health and Nutrition Research Initiative. Research questions were obtained from reproductive health experts in the oPt. The questions were then grouped into thematic areas which were prioritized by the reproductive health experts. Scores were calculated and sorted to define the top priority research areas. RESULTS: A total of 232 research questions were prioritized by 30 reproductive health experts. Health system issues were the most addressed in the top 50 research questions. They included questions on the quality of services and health professionals' knowledge and continuous professional training. Adolescents' sexual and reproductive health and gender-based violence were rarely mentioned in the top 50 questions. The number of questions related to safe motherhood was around 50% followed by questions related to health system. Questions related to elderly women and menopause as well as reproductive system cancers were also within the top 50 ranked questions. CONCLUSIONS: Priority research areas in reproductive health were identified for the oPt, which should be utilized by researchers with a focus on the high priority areas. Policy makers and funders should coordinate their efforts to ensure the production of research with value to the Palestinian context, in the most efficient way possible. PMID- 29433509 TI - Prognostic indicators in the World Health Organization's algorithm for seriously ill HIV-infected inpatients with suspected tuberculosis. AB - BACKGROUND: Criteria for the 2007 WHO algorithm for diagnosing tuberculosis among HIV-infected seriously ill patients are the presence of one or more danger signs (respiratory rate > 30/min, heart rate > 120/min, temperature > 39 degrees C, and being unable to walk unaided) and cough >= 14 days. Determining predictors of poor outcomes among HIV-infected inpatients presenting with WHO danger signs could result in improved treatment and diagnostic algorithms. METHODS: We conducted a prospective cohort study of inpatients presenting with any duration of cough and WHO danger signs to two regional hospitals in Cape Town, South Africa. The primary outcome was all-cause mortality up to 56 days post-discharge, and the secondary outcome a composite of any one of: hospital admission for > 7 days, died in hospital, transfer to a tertiary level or tuberculosis hospital. We first assessed the WHO danger signs as predictors of poor outcomes, then assessed the added value of other variables selected a priori for their ability to predict mortality in common respiratory opportunistic infections (CD4 count, body mass index (BMI), being on antiretroviral therapy (ART), hypotension, and confusion) by comparing the receiver operating characteristic (ROC) area under the curve (AUC) of the two multivariate models. RESULTS: 484 participants were enrolled, median age 36, 66% women, 53% had tuberculosis confirmed on culture. The 56-day mortality was 13.2%. Inability to walk unaided, low BMI, low CD4 count, and being on ART were independently associated with poor outcomes. The multivariate model of the WHO danger signs showed a ROC AUC of 0.649 (95% CI 0.582-0.717) for predicting 56-day mortality, which improved to ROC AUC of 0.740 (95% CI 0.681 0.800; p = 0.004 for comparison between the two ROC AUCs) with the multivariate model including the a priori selected variables. Findings were similar in sub analyses of participants with culture-positive tuberculosis and with cough duration >= 14 days. CONCLUSION: The study design prevented a rigorous evaluation of the prognostic value of the WHO danger signs. Our prognostic model could result in improved algorithms, but needs to be validated. PMID- 29433510 TI - Review and critical appraisal of studies mapping from quality of life or clinical measures to EQ-5D: an online database and application of the MAPS statement. AB - BACKGROUND: The Health Economics Research Centre (HERC) Database of Mapping Studies was established in 2013, based on a systematic review of studies developing mapping algorithms predicting EQ-5D. The Mapping onto Preference-based measures reporting Standards (MAPS) statement was published in 2015 to improve reporting of mapping studies. We aimed to update the systematic review and assess the extent to which recently-published studies mapping condition-specific quality of life or clinical measures to the EQ-5D follow the guidelines published in the MAPS Reporting Statement. METHODS: A published systematic review was updated using the original inclusion criteria to include studies published by December 2016. We included studies reporting novel algorithms mapping from any clinical measure or patient-reported quality of life measure to either the EQ-5D-3L or EQ 5D-5L. Titles and abstracts of all identified studies and the full text of papers published in 2016 were assessed against the MAPS checklist. RESULTS: The systematic review identified 144 mapping studies reporting 190 algorithms mapping from 110 different source instruments to EQ-5D. Of the 17 studies published in 2016, nine (53%) had titles that followed the MAPS statement guidance, although only two (12%) had abstracts that fully addressed all MAPS items. When the full text of these papers was assessed against the complete MAPS checklist, only two studies (12%) were found to fulfil or partly fulfil all criteria. Of the 141 papers (across all years) that included abstracts, the items on the MAPS statement checklist that were fulfilled by the largest number of studies comprised having a structured abstract (95%) and describing target instruments (91%) and source instruments (88%). CONCLUSIONS: The number of published mapping studies continues to increase. Our updated database provides a convenient way to identify mapping studies for use in cost-utility analysis. Most recent studies do not fully address all items on the MAPS checklist. PMID- 29433511 TI - Histamine upregulates the expression of histamine receptors and increases the neuroprotective effect of astrocytes. AB - BACKGROUND: Astrocytes have attracted increasing attention over recent decades for their role in neuroinflammation. Histamine, a major aminergic brain neurotransmitter, has an important influence on the main activities of astrocytes, such as ion homeostasis, energy metabolism, and neurotransmitter clearance. However, little is known about the impact of histamine on astrocyte immunomodulatory function. METHODS: The expression of all known histamine receptor subtypes was examined in primary astrocytes. Then, primary astrocytes were pretreated with selective histamine receptor antagonists and stimulated with histamine. Cellular activation, proinflammatory cytokine production, and expression of neurotrophic factors were assessed. RESULTS: Astrocytes could constitutively express three histamine receptors (H1R, H2R, and H3R), and these three histamine receptors could be selectively upregulated to varying degrees upon histamine treatment. Histamine also dose-dependently stimulated astrocyte activation and subsequent production of glial cell-derived neurotrophic factor (GDNF), whereas it suppressed the secretion of the proinflammatory factors tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). The effects of histamine were completely abolished by either an H1R or H3R antagonist, while an H2R antagonist attenuated the effects partly. CONCLUSIONS: The present study identified the expression of H1R, H2R, and H3R on astrocytes. We also demonstrated that negative regulation of astrocytic TNF-alpha and IL-1beta production and the enhancement of astrocytic GDNF stimulated by histamine were receptor-mediated processes in which all three of the expressed histamine receptors (H1R, H2R, and H3R) were involved. These findings may further clarify the involvement and mechanism of astrocyte activation in neuroinflammation. PMID- 29433512 TI - Coupling the recombineering to Cre-lox system enables simplified large-scale genome deletion in Lactobacillus casei. AB - BACKGROUND: Lactobacillus casei is widely used in the dairy and pharmaceutical industries and a promising candidate for use as cell factories. Recently, genome sequencing and functional genomics provide the possibility for reducing L. casei genome. However, it was still limited by the inefficient and laborious genome deletion methods. RESULTS: Here, we proposed a genome minimization strategy based on LCABL_13040-50-60 recombineering and Cre-lox site-specific recombination system in L. casei. The LCABL_13040-50-60 recombineering system was used to introduce two lox sites (lox66 and lox71) into 5' and 3' ends of the targeted region. Subsequently, the targeted region was excised by Cre recombinase. The robustness of the strategy was demonstrated by single-deletion of a nonessential ~ 39.3 kb or an important ~ 12.8 kb region and simultaneous deletion of two non continuous genome regions (5.2 and 6.6 kb) with 100% efficiency. Furthermore, a cyclical application of this strategy generated a double-deletion mutant of which 1.68% of the chromosome was sequentially excised. Moreover, biological features (including growth rate, electroporation efficiency, cell morphology or heterologous protein productivity) of these mutants were characterized. CONCLUSIONS: To our knowledge, this strategy is the first instance of sequential deletion of large-scale genome regions in L. casei. We expected this efficient and inexpensive tool can help for rapid genome streamlining and generation restructured L. casei strains used as cell factories. PMID- 29433514 TI - Loss of skeletal muscle mass during neoadjuvant treatments correlates with worse prognosis in esophageal cancer: a retrospective cohort study. AB - BACKGROUND: Nutritional deficits, cachexia, and sarcopenia are extremely common in esophageal cancer. The aim of this article was to assess the effect of loss of skeletal muscle mass during neoadjuvant treatment on the prognosis of esophageal cancer patients. METHODS: Esophageal cancer patients (N = 115) undergoing neoadjuvant therapy and surgery between 2010 and 2014 were identified from our surgery database and retrospectively analyzed. Computed tomography imaging of the total cross-sectional muscle tissue measured at the third lumbar level defined the skeletal muscle index, which defined sarcopenia (SMI < 52.4 cm2/m2 for men and < 38.5 cm2/m2 for women). Images were collected before and after neoadjuvant treatments. RESULTS: Sarcopenia in preoperative imaging was prevalent in 92 patients (80%). Median overall survival was 900 days (interquartile range 334 1447) with no difference between sarcopenic (median = 900) and non-sarcopenic (median = 914) groups (p = 0.872). Complication rates did not differ (26.1% vs 32.6%, p = 0.725). A 2.98% decrease in skeletal muscle index during neoadjuvant treatment correlated with poor 2-year survival (log-rank p = 0.04). CONCLUSION: Loss of skeletal muscle tissue during neoadjuvant treatment correlates with worse overall survival. PMID- 29433513 TI - Epidemiological trends of sepsis in the twenty-first century (2000-2013): an analysis of incidence, mortality, and associated costs in Spain. AB - BACKGROUND: Sepsis has represented a substantial health care and economic burden worldwide during the previous several decades. Our aim was to analyze the epidemiological trends of hospital admissions, deaths, hospital resource expenditures, and associated costs related to sepsis during the twenty-first century in Spain. METHODS: We performed a retrospective study of all sepsis related hospitalizations in Spanish public hospitals from 2000 to 2013. Data were obtained from records in the Minimum Basic Data Set. The outcome variables were sepsis, death, length of hospital stay (LOHS), and sepsis-associated costs. The study period was divided into three calendar periods (2000-2004, 2005-2009, and 2010-2013). RESULTS: Overall, 2,646,445 patients with sepsis were included, 485,685 of whom had died (18.4%). The incidence of sepsis (events per 1000 population) increased from 3.30 (2000-2004) to 4.28 (2005-2009) to 4.45 (2010 2013) (p < 0.001). The mortality rates from sepsis (deaths per 10,000 population) increased from 6.34 (2000-2004) to 7.88 (2005-2009) to 7.89 (2010-2013) (p < 0.001). The case fatality rate (CFR) or proportion of patients with sepsis who died decreased from 19.1% (2000-2004) to 18.4% (2005-2009) to 17.9% (2010-2013) (p < 0.001). The LOHS (days) decreased from 15.9 (2000-2004) to 15.7 (2005-2009) to 14.5 (2010-2013) (p < 0.001). Total and per patient hospital costs increased from 2000 to 2011, and then decreased by the impact of the economic crisis. CONCLUSIONS: Sepsis has caused an increasing burden in terms of hospital admission, deaths, and costs in the Spanish public health system during the twenty-first century, but the incidence and mortality seemed to stabilize in 2010 2013. Moreover, there was a significant decrease in LOHS in 2010-2013 and a decline in hospital costs after 2011. PMID- 29433515 TI - Control of glycemia and blood pressure in British adults with diabetes mellitus and subsequent therapy choices: a comparison across health states. AB - BACKGROUND: To examine the intensity of glycemic and blood pressure control in British adults with diabetes mellitus and whether control levels or treatment deintensification rates differ across health states. METHODS: Retrospective cohort study using primary care electronic medical records (the United Kingdom Health Improvement Network Database) for adults with diabetes diagnosed at least 6 months before the index HbA1C and systolic blood pressure (SBP) measurements (to give their primary care physicians time to achieve treatment goals). We used prescribing records for 6 months pre/post the index measurements to determine who had therapy subsequently deintensified (based on "glycemic therapy score" and "antihypertensive therapy score" derived from number and dosage of medications). RESULTS: Of 292,170 individuals with diabetes, HbA1C < 6% or SBP < 120 mmHg after at least 6 months of management was less common in otherwise fit patients (15.0 and 12.7%) than in those who were mildly frail (16.6 and 13.2%) or moderately severely frail (20.2 and 17.0%, both p < 0.0001). In the next 6 months, only 44.7% of those with HbA1C < 6% had glycemic therapy reduced (44.4% of fit, 47.1% of mildly frail, and 41.5% of moderate-severely frail patients) and 39.8% of those with SBP < 120 had their antihypertensives decreased (39.3% of fit, 43.0% of mildly frail, and 46.7% of moderate-severely frail patients). On the other hand, more individuals exhibited higher than recommended levels for HbA1C or SBP after the first 6 months of therapy (37.3, 33.4, and 31.3% of fit, mildly frail, and moderately-severely frail patients had HbA1C > 7.5% and 46.6, 51.4, and 48.5% had SBP > 140 mmHg). The proportions of patients with HbA1C or SBP out of recommended treatment ranges changed little 6 months later despite frequent (median 14 per year) primary care visits. CONCLUSIONS: Glycemic and hypertensive control exhibited statistically significant but small magnitude differences across frailty states. Medication deintensification was uncommon, even in frail patients below SBP and HbA1C targets. SBP levels were more likely to be outside recommended treatment ranges than glycemic levels. Trial registration As this study is a retrospective secondary analysis of electronic medical record data and not a health care intervention trial it was not registered. PMID- 29433516 TI - A technical review and evaluation of implantable sensors for hearing devices. AB - Most commercially available cochlear implants and hearing aids use microphones as sensors for capturing the external sound field. These microphones are in general located in an external element, which is also responsible for processing the sound signal. However, the presence of the external element is the cause of several problems such as discomfort, impossibility of being used during physical activities and sleeping, and social stigma. These limitations have driven studies with the goal of developing totally implantable hearing devices, and the design of an implantable sensor has been one of the main challenges to be overcome. Different designs of implantable sensors can be found in the literature and in some commercial implantable hearing aids, including different transduction mechanisms (capacitive, piezoelectric, electromagnetic, etc), configurations microphones, accelerometers, force sensor, etc) and locations (subcutaneous or middle ear). In this work, a detailed technical review of such designs is presented and a general classification is proposed. The technical characteristics of each sensors are presented and discussed in view of the main requirements for an implantable sensor for hearing devices, including sensitivity, internal noise, frequency bandwidth and energy consumption. The feasibility of implantation of each sensor is also evaluated and compared. PMID- 29433517 TI - Quality of life of patients with first-time AMI: a descriptive study. AB - BACKGROUND: Outcomes following acute myocardial infarction (AMI) may result in death, increased morbidity, and change in quality of life (QOL). This study explores health-related QOL of first-time patients following AMI. METHODS: This cross-sectional study used a sample of patients with first-time AMI experienced between April 2011 and March 2015 at a tertiary health institution. Recruited patients belonged to different post-AMI periods: 2-10 weeks, 5-22 months, and > 22 months to 4 years post AMI. Inclusion criteria were not confused and communicating freely. Exclusion criteria were non-contactable, refusing to participate, and deceased. One-on-one interviews were conducted using the validated and pre-tested Quality of Life after Myocardial Infarction (QLMI) questionnaire. QOL of patients after AMI was evaluated at each period. Descriptive, Mann-Whitney U, Kruskal-Wallis, and regression analyses were conducted using SPSS version 24. RESULTS: A total of 534 participant interviews (overall response rate 65.4%) were conducted. Interviewees were predominantly male (67%), aged 51-65 years (45%), Indo-Trinidadian (81.2%), NSTEMI (64.4%), and hypertensive (72.4%). Overall QOL improved over time and in all domains: Emotional, Physical, and Social. Lower QOL was found among women, patients with NSTEMI, and diabetics in all domains; in patients with hypertension and renal disease in the Physical and Social domains only; and in patients with ischaemic heart disease (IHD) in the Physical domain only. Self-reported stress and lack of exercise were associated with lower QOL while drinking alcohol and eating out were related to better QOL. Hypercholesterolemia, smoking, and ethnicity showed no association with QOL. Declining QOL in the Physical domain with age was also found. The leading components of QOL were self-confidence and social exclusion (early post AMI), lack of self-confidence (intermediate post AMI), and tearfulness (late post AMI). CONCLUSIONS: QOL in AMI survivors improves over time. Female gender, NSTEMI, diabetes, hypertension, renal disease, stress, and lack of exercise were associated with lower QOL while hypercholesterolemia, smoking, and ethnicity showed no association with QOL. Cardiac rehabilitation and psychological support may enhance earlier increased QOL among survivors, particularly among vulnerable groups. PMID- 29433518 TI - Optimization and scale up of microfluidic nanolipomer production method for preclinical and potential clinical trials. AB - BACKGROUND: The process of optimization and fabrication of nanoparticle synthesis for preclinical studies can be challenging and time consuming. Traditional small scale laboratory synthesis techniques suffer from batch to batch variability. Additionally, the parameters used in the original formulation must be re optimized due to differences in fabrication techniques for clinical production. Several low flow microfluidic synthesis processes have been reported in recent years for developing nanoparticles that are a hybrid between polymeric nanoparticles and liposomes. However, use of high flow microfluidic synthetic techniques has not been described for this type of nanoparticle system, which we will term as nanolipomer. In this manuscript, we describe the successful optimization and functional assessment of nanolipomers fabricated using a microfluidic synthesis method under high flow parameters. RESULTS: The optimal total flow rate for synthesis of these nanolipomers was found to be 12 ml/min and flow rate ratio 1:1 (organic phase: aqueous phase). The PLGA polymer concentration of 10 mg/ml and a DSPE-PEG lipid concentration of 10% w/v provided optimal size, PDI and stability. Drug loading and encapsulation of a representative hydrophobic small molecule drug, curcumin, was optimized and found that high encapsulation efficiency of 58.8% and drug loading of 4.4% was achieved at 7.5% w/w initial concentration of curcumin/PLGA polymer. The final size and polydispersity index of the optimized nanolipomer was 102.11 nm and 0.126, respectively. Functional assessment of uptake of the nanolipomers in C4-2B prostate cancer cells showed uptake at 1 h and increased uptake at 24 h. The nanolipomer was more effective in the cell viability assay compared to free drug. Finally, assessment of in vivo retention in mice of these nanolipomers revealed retention for up to 2 h and were completely cleared at 24 h. CONCLUSIONS: In this study, we have demonstrated that a nanolipomer formulation can be successfully synthesized and easily scaled up through a high flow microfluidic system with optimal characteristics. The process of developing nanolipomers using this methodology is significant as the same optimized parameters used for small batches could be translated into manufacturing large scale batches for clinical trials through parallel flow systems. PMID- 29433519 TI - Factors influencing turnover intention among primary care doctors: a cross sectional study in Chongqing, China. AB - BACKGROUND: The intention to leave a job, known as turnover intention, among primary care doctors has a significant impact on primary health care service delivery. We investigated primary care doctors' turnover intention and analysed associated factors involved in primary health facilities in Chongqing, China. METHODS: A total of 440 doctors were interviewed, they were selected using a multi-stage stratified random sampling method. The survey instrument was a self administered questionnaire which assessed socio-demographic and work-related characteristics, job satisfaction and turnover intention. The data were analysed using chi2 test, one-way analysis of variance, exploratory factor analysis and linear regression analysis. RESULTS: Our study found that 42.3% of the primary care doctors we sampled in Chongqing, China, intended to resign. Location, age, job title, doctor's position level, work pressure and job satisfaction were associated with turnover intention. Job satisfaction included both employment related job satisfaction (including "your chance of promotion", "your rate of pay" and two other items) and satisfaction with the job itself (including "the freedom to choose your own method of working", "your job safety" and two other items). CONCLUSIONS: Improving job satisfaction, in terms of salary, promotion and job safety, is crucial for reducing turnover intention among primary care doctors. Therefore, we suggest that the government increase its financial investment in primary care facilities, especially in less-developed areas, and reform incentive mechanisms to improve the job satisfaction of primary care doctors. The government should consider policies such as establishing a social pension programme for village-level doctors and providing more opportunities for job promotion among primary care doctors, especially township-level doctors. Attention should also be paid to the impact of rapid urbanization, which could lead to increased workload or increased opportunities for career development, thus affecting primary care doctors' turnover intention. PMID- 29433521 TI - Adopting clinical genomics: a systematic review of genomic literacy among physicians in cancer care. AB - BACKGROUND: This article investigates the genomic knowledge of oncology care physicians in the adoption of clinical genomics. We apply Rogers' knowledge framework from his diffusion of innovation theory to identify three types of knowledge in the process of translation and adoption: awareness, how-to, and principles knowledge. The objectives of this systematic review are to: (1) examine the level of knowledge among physicians in clinical cancer genomics, and (2) identify potential interventions or strategies for development of genomic education for oncology practice. METHODS: We follow the PRIMSA statement protocol and conduct a search of five relevant electronic databases. Our review focuses on: (1) genomic knowledge of oncogenomics or genomic services in oncology practices among physicians, and (2) interventions or strategies to provide genomic education of oncogenomics for physicians. RESULTS: We include twenty-one studies in our analysis. Nine focus on interventions to provide genomic education for cancer care. Overall, physicians' knowledge of oncogenomics among the three types is limited. The genomic literacy of physicians vary by their provider specialty, location, years of practice, and the type of genomic services. The three distinctions of knowledge offer a sophisticated and helpful tool to design effective strategies and interventions to provide genomic education for cancer treatment. In the nine educational intervention studies, the main intervention outcomes are changes in awareness, referral rates, genomic confidence, and genomic knowledge. CONCLUSION: Rogers' diffusion of innovation model allows us to differentiate three types of knowledge in the development and adoption of clinical genomics. This analytical lens can inform potential avenues to design more effective strategies and interventions to provide genomic education for oncology practice. We identified and synthesized a dearth of high quality studies that can inform the most effective educational outcomes of these interventions. Future research should attend to improving applications of genomic services in clinical practices, along with organizational change engendered by genomics in oncology practice. PMID- 29433520 TI - Intermittent hypoxia promotes melanoma lung metastasis via oxidative stress and inflammation responses in a mouse model of obstructive sleep apnea. AB - BACKGROUND: Recently, increased tumor incidence and cancer-related mortality have been reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), the hallmark feature of OSA, contributes to the metastasis of tumors. However, the molecular mechanisms by which tumor metastasis is accelerated by OSA-like IH remain to be elucidated. METHODS: C57BL/6 J male mice were subjected to intravenous injection of B16F10 melanoma cells before receiving IH treatment. Then, the animals were randomly distributed into three groups (n = 8 each): normoxia (N) group, IH group, and antioxidant tempol group (IHT, exposed to IH after treatment with tempol). After the mice were sacrificed, the number and weight of lung metastatic colonies were assessed. The lung tissues with tumor metastasis were analyzed for markers of oxidative stress and inflammation and for HIF-1alpha using western blotting and real-time PCR (qRT-PCR). The level of reactive oxygen species (ROS) in B16F10 cell was also assessed after N, IH and IH with tempol treatments. RESULTS: Compared with normoxia, IH significantly increased the number and weight of mouse lung metastatic colonies. Treatment of B16F10 cells with IH significantly enhanced ROS generation. Lung tissues with tumor metastasis provided evidence of increased oxidative stress, as assessed by p22phox and SOD mRNA levels and the NRF2 protein level, as well as increased inflammation, as assessed by TNF-alpha and IL-6 mRNA levels and the NF-kappaB P65 protein level. HIF-1alpha protein levels were increased in response to IH treatment. Tempol, an important antioxidant, ameliorated IH-induced melanoma lung metastasis in mice and reduced oxidative stress and inflammation responses. CONCLUSIONS: These results support the hypothesis that oxidative stress and inflammation responses play an important role in the pathogenesis of OSA-like IH induced melanoma lung metastasis in mice. Antioxidant intervention provides a novel strategy for the prevention and treatment of cancer in OSA populations. PMID- 29433522 TI - ROS responsive resveratrol delivery from LDLR peptide conjugated PLA-coated mesoporous silica nanoparticles across the blood-brain barrier. AB - BACKGROUND: Oxidative stress acts as a trigger in the course of neurodegenerative diseases and neural injuries. An antioxidant-based therapy can be effective to ameliorate the deleterious effects of oxidative stress. Resveratrol (RSV) has been shown to be effective at removing excess reactive oxygen species (ROS) or reactive nitrogen species generation in the central nervous system (CNS), but the delivery of RSV into the brain through systemic administration is inefficient. Here, we have developed a RSV delivery vehicle based on polylactic acid (PLA) coated mesoporous silica nanoparticles (MSNPs), conjugated with a ligand peptide of low-density lipoprotein receptor (LDLR) to enhance their transcytosis across the blood-brain barrier (BBB). RESULTS: Resveratrol was loaded into MSNPs (average diameter 200 nm, pore size 4 nm) at 16 MUg/mg (w/w). As a gatekeeper, the PLA coating prevented the RSV burst release, while ROS was shown to trigger the drug release by accelerating PLA degradation. An in vitro BBB model with a co culture of rat brain microvascular endothelial cells (RBECs) and microglia cells using Transwell chambers was established to assess the RSV delivery across BBB. The conjugation of LDLR ligand peptides markedly enhanced the migration of MSNPs across the RBECs monolayer. RSV could be released and effectively reduce the activation of the microglia cells stimulated by phorbol-myristate-acetate or lipopolysaccharide. CONCLUSIONS: These ROS responsive LDLR peptides conjugated PLA-coated MSNPs have great potential for oxidative stress therapy in CNS. PMID- 29433523 TI - A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis. AB - Growing data point to the overlap between psychosis and pathological processes associated with immunological dysregulation as well as inflammation. Notably, the recent discovery of antibodies against synaptic and neuronal cell membrane proteins such as anti-N-methyl-D-aspartate receptor provides more direct evidence of the etiological connection between autoimmunity and subsequent hazard of psychosis. Here, we advocate the use of term "autoimmune psychosis," as this term suggests that autoimmune disorders can masquerade as drug-resistant primary psychosis, and this subtype of psychosis has anatomical and immunological footprints in the brain, despite the frequent absence of structural abnormalities on conventional brain MRI. Furthermore, this term might serve as a reminder not to overlook appropriate neurological workup such as neuroimaging and EEG testing, as well as CSF analysis, for cases with acute or subacute atypical onset of neuropsychiatric presentations including those dominated by acute psychotic symptoms. We propose etiologically and serologically oriented subclassification as well as multi-modal diagnostic approach to address some of the challenges inherent to early diagnosis of patients presenting with atypical and refractory new-onset psychotic symptoms of autoimmune origin. This is particularly relevant to the diagnosis of seronegative but probable autoimmune psychosis (SPAP) that might masquerade as antipsychotic drug-resistant primary psychotic disorder. This distinction is therapeutically important as autoimmune-related psychotic symptomatology can frequently respond well to timely treatment with proper immune modulatory therapies. PMID- 29433524 TI - Measuring replication competent HIV-1: advances and challenges in defining the latent reservoir. AB - Antiretroviral therapy cannot cure HIV-1 infection due to the persistence of a small number of latently infected cells harboring replication-competent proviruses. Measuring persistent HIV-1 is challenging, as it consists of a mosaic population of defective and intact proviruses that can shift from a state of latency to active HIV-1 transcription. Due to this complexity, most of the current assays detect multiple categories of persistent HIV-1, leading to an overestimate of the true size of the latent reservoir. Here, we review the development of the viral outgrowth assay, the gold-standard quantification of replication-competent proviruses, and discuss the insights provided by full length HIV-1 genome sequencing methods, which allowed us to unravel the composition of the proviral landscape. In this review, we provide a dissection of what defines HIV-1 persistence and we examine the unmet needs to measure the efficacy of interventions aimed at eliminating the HIV-1 reservoir. PMID- 29433525 TI - Assessment of clinical effect and treatment quality of immediate-release carvedilol-IR versus SLOW release carvedilol-SR in Heart Failure patients (SLOW HF): study protocol for a randomized controlled trial. AB - BACKGROUND: Carvedilol is a non-selective, third-generation beta-blocker and is one of the cornerstones for treatment for patients with heart failure and reduced ejection fraction (HFrEF). However, due to its short half-life, immediate-release carvedilol (IR) needs to be prescribed twice a day. Recently, slow-release carvedilol (SR) has been developed. The aim of this study is to evaluate whether carvedilol-SR is non-inferior to standard carvedilol-IR in terms of its clinical efficacy in patients with HFrEF. METHODS/DESIGN: Patients with stable HFrEF will be randomly assigned in a 1:1 ratio to the carvedilol-SR group (160 patients) and the carvedilol-IR group (160 patients). Patients aged >= 20 years, with a left ventricular ejection fraction <= 40%, N-terminal pro B-natriuretic peptide (NT proBNP) >= 125 pg/ml or BNP >= 35 pg/ml, who are clinically stable and have no evidence of congestion or volume retention, will be eligible. After randomization, patients will be followed up for 6 months. The primary endpoint is the change in NT-proBNP level from baseline to the study end. The secondary endpoints include the proportion of patients with NT-proBNP increment > 10% from baseline, composite of all-cause mortality and readmission, mortality rate, readmission rate, changes in blood pressure, quality of life, and drug compliance. DISCUSSIONS: The SLOW-HF trial is a prospective, randomized, open label, phase-IV, multicenter study to evaluate the therapeutic efficacy of carvedilol-SR compared to carvedilol-IR in HFrEF patients. If carvedilol-SR proves to be non-inferior to carvedilol-IR, a once-daily prescription of carvedilol may be recommended for patients with HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03209180 . Registered on 6 July 2017. PMID- 29433526 TI - Small dense low density lipoprotein-cholesterol and cholesterol ratios to predict arterial stiffness progression in normotensive subjects over a 5-year period. AB - BACKGROUND: Small dense low density lipoprotein-cholesterol (sdLDL-C), cholesterol ratios and carotid-femoral pulse wave velocity (cf-PWV) impart risk for all-cause morbidity and mortality independently of conventional cardiovascular disease (CVD) risk factors. This study was designed to identify feasible indicators for predicting arterial stiffness progression. METHODS: We followed up 816 normotensive participants without diabetes or CVD for nearly 5.0 years. Cholesterol parameters, ratios and other clinical and laboratory data were collected at baseline. cf-PWV were measured at baseline and the end of follow-up. RESULTS: PWV progression subjects had higher levels of PWV parameters, sdLDL-C and TG/HDL-C ratio. sdLDL-C and TG/HDL-C were significantly correlated with all PWV parameters. Multiple regression models showed that sdLDL-C was closely associated with follow-up PWV (beta = 0.222, p < 0.001) and ?PWV (beta = 0.275, p < 0.001). TG/HDL-C was only one cholesterol ratios that associated with all PWV parameters. sdLDL-C (OR = 2.070, 95%CI: 1.162 to 3.688, p = 0.014) and TG/HDL-C (OR = 1.355, 95%CI: 1.136 to 1.617, p = 0.001) could significantly determine the progression of PWV after correction for covariates. High sd-LDL-C quantiles subjects were more likely to develop arterial stiffness progression than low quantiles (Tertiles 3 vs Tertiles1, RR = 2.867, 95%CI: 1.106 to 7.434, p = 0.03). CONCLUSION: We founded that sdLDL-C and TG/HDL-C ratio can independently predict arterial stiffness progression in normotensive subjects, and high level sdLDL-C and TG/HDL-C ratio were associated with a higher risk of arterial stiffness. PMID- 29433527 TI - Functional status and annual hospitalization in multimorbid and non-multimorbid older adults: a cross-sectional study in Southern China. AB - BACKGROUND: Hospitalization over the last one year, an indicator of health service utilization, is an important and costly resource in older adult care. However, data on the relationship between functional status and annual hospitalization among older Chinese people are sparse, particularly for those with and without multimorbidity. In this study,we aimed to examine the association between functional status and annual hospitalization among community dwelling older adults in Southern China, and to explore the independent contributions of socio-demographic variables, lifestyle and health-related factors and functional status to hospitalization in multimorbid and non multimorbid groups. METHODS: This cross-sectional, community-based survey, studied 2603 older adults aged 60 years and above. Functional status was assessed by Functional Independence Measure (FIM). The outcome variable was any hospitalization over the last one year (annual hospitalization). Clustered logistic regression was used to analyze the independent contributions of FIM domains to annual hospitalization. RESULTS: Only in the multimorbid group, did the risk of annual hospitalization decrease significantly with increasing FIM score in walk domain (adjusted OR = 0.80 per SD increase, 95% CI = 0.70-0.91, P = 0.001) and its independent contribution accounted for 24.62%, more than that of socio-demographic variables (18.46%). However, among individuals without multimorbidity, there were no significant associations between FIM domains and annual hospitalization; thus, no independent contribution to the risk of hospitalization was observed. CONCLUSIONS: There exist some degree of correlation between functional status and annual hospitalization among older adults in Southern China, which might be due to the presence of multimorbidity with advanced age. PMID- 29433528 TI - Effect of socioeconomic inequalities on cholecystectomy outcomes: a 10-year population-based analysis. AB - BACKGROUND: Although numerous epidemiological studies on cholecystectomy have been conducted worldwide, only a few have considered the effect of socioeconomic inequalities on cholecystectomy outcomes. Specifically, few studies have focused on the low-income population (LIP). METHODS: A nationwide prospective study based on the Taiwan National Health Insurance dataset was conducted during 2003-2012. The International Classification of ICD-9-CM procedure codes 51.2 and 51.21-51.24 were identified as the inclusion criteria for cholecystectomy. Temporal trends were analyzed using a joinpoint regression, and the hierarchical linear modeling (HLM) method was used as an analytical strategy to evaluate the group-level and individual-level factors. Interactions between age, gender and SES were also tested in HLM model. RESULTS: Analyses were conducted on 225,558 patients. The incidence rates were 167.81 (95% CI: 159.78-175.83) per 100,000 individuals per year for the LIP and 123.24 (95% CI: 116.37-130.12) per 100,000 individuals per year for the general population (GP). After cholecystectomy, LIP patients showed higher rates of 30-day mortality, in-hospital complications, and readmission for complications, but a lower rate of routine discharge than GP patients. The hospital costs and length of stay for LIP patients were higher than those for GP patients. The multilevel analysis using HLM revealed that adverse socioeconomic status significantly negatively affects the outcomes of patients undergoing cholecystectomy. Additionally, male sex, advanced age, and high Charlson Comorbidity Index (CCI) scores were associated with higher rates of in-hospital complications and 30-day mortality. We also observed that the 30-day mortality rates for patients who underwent cholecystectomy in regional hospitals and district hospitals were significantly higher than those of patients receiving care in a medical center. CONCLUSION: Patients with a disadvantaged finance status appeared to be more vulnerable to cholecystectomy surgery. This result suggested that further interventions in the health care system are necessary to reduce this disparity. PMID- 29433529 TI - Independent prognostic impact of preoperative serum carcinoembryonic antigen and cancer antigen 15-3 levels for early breast cancer subtypes. AB - BACKGROUND: Although the prognosis for operable breast cancers is reportedly worse if serum carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels are above normal, the usefulness of this prognosis is limited due to the low sensitivity and specificity; in addition, the optimal cutoff levels remain unknown. METHODS: A total of 1076 patients who were operated for breast cancers (test set = 608, validation set = 468) without evidence of metastasis were recruited, and their baseline and postoperative serum CEA and CA15-3 levels were analyzed. The optimal cutoff values of CEA and CA15-3 for disease-free survival (DFS) were 3.2 ng/mL and 13.3 U/mL, respectively, based on receiver operating characteristic curve and area under the curve analyses. RESULTS: The DFS of patients with high CEA levels (CEA-high: n = 191, 5-year DFS 70.6%) was significantly worse (p < 0.0001) than that of CEA-low patients (n = 885, 5-year DFS 87.2%). There was a significant difference in DFS (p < 0.0001) between CA15-3 high and CA15-3-low patients (n = 314 and n = 762, respectively; 5-year DFS 71.8 vs. 89.3%). Significant associations between DFS and CA15-3 levels were observed irrespective of the subtypes. Multivariable analysis indicated that tumor size, lymph node metastasis, tumor grade, and CEA (p = 0.0474) and CA15-3 (p < 0.0001) levels were independent prognostic factors (hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.005-2.245 for CEA; HR 2.088, 95% CI 1.457-2.901 for CA15-3). CONCLUSIONS: These findings suggest that CEA and CA15-3 levels might be useful for predicting the prognosis of patients with operable early breast cancer irrespective of the subtype. Serum levels at baseline may reflect tumor characteristics for metastatic potential even when these levels are within the normal ranges. PMID- 29433530 TI - Correlation between lumbar intervertebral disc height and lumbar spine sagittal alignment among asymptomatic Asian young adults. AB - BACKGROUND: To investigate the distribution and characteristics of the lumbar intervertebral disc height (IDH) in asymptomatic Asian population and to determine whether the lumbar IDH is related to the lumbar spine sagittal alignment. METHODS: A cohort of 169 cases of asymptomatic volunteers was enrolled from January 2014 to July 2016. All participants underwent magnetic resonance imaging of the lumbar spine and panoramic radiography of the spine. Panoramic radiographs of the spine were taken to evaluate pelvic incidence (PI), sacral slope (SS), and pelvic tilt (PT) using Surgimap(r) software. Roussouly classification was utilized to categorize all subjects according to the four subtypes of sagittal alignment. The IDH was measured on the MRI mid-saggital section of the vertebral body. The relationships between lumbar IDH and spine pelvic parameters were also assessed using the Spearman correlation analysis. RESULTS: The reference value ranges of IDH in asymptomatic Asian volunteers between L1/2, L2/3, L3/4, L4/5, and L5/S1 were (6.25, 10.99), (6.97, 12.08), (7.42, 13.3), (7.76, 14.57),and (7.11, 13.12) mm, respectively. Based on the above reference value, the high lumbar intervertebral space is defined as more than 14 mm. According to the Roussouly Classification, there are 33 cases in type I, 48 in type II, 66 in type III, and 22 in type IV. According to the definition of the high IDH, there are two cases in type I, three in type II, nine in type III, and eight in type IV. The results indicated that people in the Roussouly III and IV subtypes had greater values for IDH compared to those of Roussouly I and II subtypes, and the spinopelvic parameters were partly correlated with IDH in different subtypes. In addition, levels L4-L5 showed the highest IDH for all four groups followed by the L3-L4 and L5-S1 levels, and the value of L3-L4 is equivalent to that of L5-S1. All type groups showed moderate and positive correlations between the PI and IDH except the level of L1-L2 in type IV. CONCLUSIONS: The IDH may influence the lumbar spine sagittal alignment in asymptomatic Asian adults. Moreover, pre-operative evaluation of IDH is useful for selection of optimal cage size and reconstruction of spinal alignment. PMID- 29433531 TI - Histopathologic characteristics of biopsies from dogs undergoing surgery with concurrent gross splenic and hepatic masses: 125 cases (2012-2016). AB - OBJECTIVE: To investigate the histopathologic characteristics of concurrent splenic and liver masses in dogs undergoing splenectomy and liver mass biopsy/resection. Medical records of 125 client-owned dogs found to have splenic mass or masses and a liver mass or masses during surgery were examined. Signalment (age, sex, breed), body weight, and results of histopathology were recorded for all dogs. RESULTS: Twenty-seven percent (34/125) of the dogs in this study had no evidence of malignancy in either the liver or the spleen. Sixty of 125 dogs (48.0%) had malignancy in the spleen and liver, and 56 (56/60, 93.3%) of those dogs had the same malignancy in both organs. Signalment was similar to that in other reports of splenic pathology. In this clinical population of dogs, 27% of dogs with concurrent gross splenic and liver masses discovered intraoperatively had benign lesions in both locations and therefore had a favorable prognosis. PMID- 29433532 TI - Is there a difference in bleeding after left ventricular assist device implant: centrifugal versus axial? AB - BACKGROUND: Continuous-flow left ventricular assist devices (CF-LVAD) have become the standard of care for patients with end stage heart failure. Device reliability has increased, bringing the potential for VAD, compared to transplant, into debate. However, complications continue to limit VADs as first line therapy. Bleeding is a major morbidity. A debate exists as to the difference in bleeding profile between the major centrifugal and axial flow devices. We hypothesized that there would be similar adverse bleeding event profiles between the 2 major CF-LVADs. METHODS: We retrospectively investigated isolated CF LVADs performed at our institution between July 2010 and July 2015: HeartMateII (HMII, n = 105) and HeartWare (HVAD, n = 34). We reviewed demographic, perioperative and short- and long-term outcomes. RESULTS: There was no significant difference in demographics or comorbidities. There was a low incidence of gastrointestinal (GI) bleed 3.9% in HMII and 2.9% in HVAD (p = 0.78). Preoperatively, the cohorts did not differ in coagulation measures (p = 0.95). Within the post-operative period, there was no difference in product transfusion: red blood cells (p = 0.10), fresh frozen plasma (p = 0.19), and platelets (p = 0.89). Post-operatively, a higher but not significantly different number of HMII patients returned to the operating room for bleeding (n = 27) compared to HVAD (n = 6, p = 0.35). There was no difference in rates of stroke (p = 0.65), re-intubation (p = 0.60), driveline infection (p = 0.05), and GI bleeding (p = 0.31). The patients had equivalent ICU LOS (p = 0.86) and index hospitalization LOS (p = 0.59). CONCLUSION: We found no difference in the rate of bleeding complications between the current commercially available axial and centrifugal flow devices. PMID- 29433533 TI - Simple descriptive missing data indicators in longitudinal studies with attrition, intermittent missing data and a high number of follow-ups. AB - OBJECTIVE: Missing data in longitudinal studies may constitute a source of bias. We suggest three simple missing data indicators for the initial phase of getting an overview of the missingness pattern in a dataset with a high number of follow ups. Possible use of the indicators is exemplified in two datasets allowing wave nonresponse; a Norwegian dataset of 420 subjects examined at 21 occasions during 6.5 years and a Dutch dataset of 350 subjects with ten repeated measurements over a period of 35 years. RESULTS: The indicators Last response (the timing of last response), Retention (the number of responded follow-ups), and Dispersion (the evenness of the distribution of responses) are introduced. The proposed indicators reveal different aspects of the missing data pattern, and may give the researcher a better insight into the pattern of missingness in a study with several follow-ups, as a starting point for analyzing possible bias. Although the indicators are positively correlated to each other, potential predictors of missingness can have a different relationship with different indicators leading to a better understanding of the missing data mechanism in longitudinal studies. These indictors may be useful descriptive tools when starting to look into a longitudinal dataset with many follow-ups. PMID- 29433534 TI - Identification of a novel autoantibody against self-vimentin specific in secondary Sjogren's syndrome. AB - BACKGROUND: Sjogren's syndrome (SS) is a primary autoimmune disease (pSS) or secondarily associated with other autoimmune diseases (sSS). The mechanisms underlying immune dysregulation in this syndrome remain unknown, and clinically it is difficult to diagnose owing to a lack of specific biomarkers. METHODS: We extracted immunoglobulins (Igs) from the sera of patients with sSS associated with rheumatoid arthritis (RA) and used them to screen a phage display library of peptides with random sequences. RESULTS: Our results show that an sSS-specific peptide, designated 3S-P, was recognized by sera of 68.2% (60 of 88) patients with sSS, 66.2% of patients with RA-sSS, and 76.5% of patients with systemic lupus erythematosus (SLE)-sSS. The anti-3S-P antibody was scarcely found in patients with pSS (1.8%), RA (1.3%), SLE (4.2%), ankylosing spondylitis (0%), and gout (3.3%), as well as in healthy donors (2%). The 3S-P-binding Igs (antibodies) were used to identify antigens from salivary glands and synovial tissues from patients with sSS. A putative target autoantigen expressed in the synovium and salivary gland recognized by anti-3S-P antibody was identified as self-vimentin. CONCLUSIONS: This novel autoantibody is highly specific in the diagnosis of sSS, and the underlying molecular mechanism of the disease might be epitope spreading involved with vimentin. PMID- 29433535 TI - Crack cocaine users views regarding treatment with contingency management in Brazil. AB - BACKGROUND: Contingency management (CM) has recently shown efficacy in promoting abstinence and retention in treatment among crack cocaine users in Brazil. However, partially because of unawareness and resistance among health care providers, CM has not been widely employed. The objective of this study was to conduct a secondary analysis in order to evaluate how CM participants perceive their treatment experience. METHODS: Twenty-seven crack cocaine users, previously assigned to 12 weeks of CM treatment, were assessed with a structured questionnaire designed to assess their personal opinion of, difficulty in understanding, and acceptance of the CM intervention, as well as their opinion regarding its impact on their treatment responses. RESULTS: Descriptive analyses showed that 92.6% of the participants found it very easy to understand the CM protocol. All participants reported liking their CM experience quite a bit. For the perceived effects of CM on their treatment response, 81.5% of the participants stated that CM helped them considerably, the mean score for the impact of CM on treatment response (out of a maximum of 10) being 9 (SD = 1.5). When asked if they believed CM could help other people with crack cocaine dependence, 92.6% of the participants stated that CM could help such people a lot and 7.4% stated that it could help them a little. CONCLUSIONS: From the perspective of the patients, CM was easily assimilated, easily accepted, and had a direct positive effect on treatment response. These findings provide additional support for the incorporation of CM into substance abuse treatment services in Brazil. PMID- 29433537 TI - Effect of Mobile-health on maternal health care service utilization in Eastern Ethiopia: study protocol for a randomized controlled trial. AB - BACKGROUND: Globally, the rapid development of mobile technology has created new ways of addressing public health challenges and shifted the paradigm of health care access and delivery. The primary aim of this study is to examine the effectiveness of Mobile-health on maternal health care service utilization in Eastern Ethiopia. METHODS/DESIGN: Through, a cluster-randomized controlled trial, 640 participants will be selected based on their districts and respective health centers as the unit of randomization. All pregnant mothers who fulfill the inclusion criteria will be allocated to a mobile-phone-based intervention and existing standard of care or control with a 1:1 allocation ratio. The intervention consists of a series of 24 voice messages which will be sent every 2 weeks from the date of enrollment until the close-out time. The control group will receive existing standard of care without voice messages. Data related to outcome variables will be assessed at three phases of the data collection periods. The primary outcome measures will be the proportion of antenatal care visits and institutional delivery, whereas the secondary outcome measures will consist of the proportion of postnatal care visits and pregnancy outcomes. Risk ratios will be used to a measure the effect of intervention on the outcomes which will be estimated with 95% confidence interval and all the analyses will be done with consideration of clustering effect. DISCUSSIONS: This study should generate evidence on the effectiveness of mobile-phone-based voice messages for the early initiation of maternal health care service use and its uptake. It has been carefully designed with the assumption of obtaining higher levels of maternal health care service use among the treatment group as compared to the control. TRIAL REGISTRATION: Pan African Clinical Trial Registry, www.panctr.org , ID: PACTR201704002216259 . Registered on 28 April 2017. PMID- 29433536 TI - Salinomycin, as an autophagy modulator-- a new avenue to anticancer: a review. AB - Since Salinomycin (Sal) emerged its ability to target breast cancer stem cells in 2009, numerous experiments have been carried out to test Sal's anticancer effects. What deserve to be mentioned is that Sal can efficiently induce proliferation inhibition, cell death and metastasis suppression against human cancers from different origins both in vivo and in vitro without causing serious side effects as the conventional chemotherapeutical drugs on the body. There may be novel cell death pathways involving the anticancer effects of Sal except the conventional pathways, such as autophagic pathway. This review is focused on how autophagy involves the effects of Sal, trying to describe clearly and systematically why autophagy plays a vital role in predominant anticancer effects of Sal, including its distinctive characteristic. Based on recent advances, we present evidence that a dual role of Sal involving in autophagy may account for its unique anticancer effects - the preference for cancer cells. Further researches are required to confirm the authenticity of this suppose in order to develop an ideal anticancer drug. PMID- 29433538 TI - microRNA-193a stimulates pancreatic cancer cell repopulation and metastasis through modulating TGF-beta2/TGF-betaRIII signalings. AB - BACKGROUND: Pancreatic cancer characterizes high recurrence and poor prognosis. In clinical practice, radiotherapy is widely used for pancreatic cancer treatment. However, the outcome remains undesirable due to tumor repopulation and following recurrence and metastasis after radiation. So, it is highly needed to explore the underlying molecular mechanisms and accordingly develop therapeutic strategies. Our previous studies revealed that dying cells from chemoradiation could stimulate repopulation of surviving pancreatic cancer cells. However, we still knew little how dying cells provoke pancreatic cancer cell repopulation. We herein would explore the significance of TGF-beta2 changes and investigate the modulation of microRNA-193a (miR-193a), and identify their contributions to pancreatic cancer repopulation and metastasis. METHODS: In vitro and in vivo repopulation models were established to mimic the biological processes of pancreatic cancer after radiation. Western blot, real-time PCR and dual luciferase reporter assays were accordingly used to detect miR-193a and TGF beta2/TGF-betaRIII signalings at the level of molecular, cellular and experimental animal model, respectively. Flow cytometry analysis, wound healing and transwell assay, vascular endothelial cell penetration experiment, and bioluminescence imaging were employed to assessthe biological behaviors of pancreatic cancer after different treatments. Patient-derived tumor xenograft (PDX) mice models were established to evaluate the therapeutic potential of miR 193a antagonist on pancreatic cancer repopulation and metastasis after radiation. RESULTS: miR-193a was highly expressed in the irradiated pancreatic cancer dying cells, accordingly elevated the level of miR-193a in surviving cells, and further promoted pancreatic cancer repopulation and metastasis in vitro and in vivo. miR 193a accelerated pancreatic cancer cell cycle and stimulated cell proliferation and repopulation through inhibiting TGF-beta2/TGF-betaRIII/SMADs/E2F6/c-Myc signaling, and even destroyed normal intercellular junctions and promoted metastasis via repressing TGF-beta2/TGF-betaRIII/ARHGEF15/ABL2 pathway. Knockdown of miR-193a or restoration of TGF-beta2/TGF-betaRIII signaling in pancreatic cancer cells was found to block pancreatic cancer repopulation and metastasis after radiation. In PDX models, the treatment in combination with miR-193a antagonist and radiation was found to dramatically inhibit pancreatic cancer cell repopulation and metastasis, and further improved the survival after radiation. CONCLUSIONS: Our findings demonstrated that miR-193a stimulated pancreatic cancer cell repopulation and metastasis through modulating TGF-beta2/TGF-betaRIII signalings, and miR-193a might be a potential therapeutic target for pancreatic cancer repopulation and metastasis. PMID- 29433539 TI - Prognostic impact of presumed breast or ovarian cancer among patients with unfavorable-subset cancer of unknown primary site. AB - BACKGROUND: The clinical utility and prognostic impact of presumed primary breast or ovarian cancer among patients with an unfavorable subset of cancer of unknown primary site (CUP) remains unclear. We aimed to evaluate the clinical relevance of the presumed primary site of CUP and the clinical outcome of site-specific therapy based on such presumptions. METHODS: Patients referred to our center who were diagnosed with unfavorable-subset CUP and treated between April 2007 and March 2015 were enrolled in this study. Data were collected retrospectively from the hospital database and electronic medical records. Presumptive primary breast or ovarian cancer was based on histological and immunohistochemical analyses and metastatic patterns. The outcomes of patients with unfavorable-subset CUP with a putative primary site in the breast or ovary (P-CUP) and of patients with unfavorable-subset CUP, but without P-CUP (U-CUP), were assessed. RESULTS: A total of 780 patients were referred to our hospital with malignancy of unknown origin. Of these, 409 patients were diagnosed with CUP and 344 patients with unfavorable-subset CUP. Following clinicopathological examination, 40 (11.6%) of the 344 patients had P-CUP and the remaining 303 (88.3%) patients had U-CUP. In total, 136 patients received chemotherapy (22 with P-CUP and 114 with U-CUP). Among the 22 patients with P-CUP, three received hormonal therapy for breast cancer, and 19 received chemotherapy based on the presumed primary organ (breast, 4; ovaries, 15). Conventional platinum-based chemotherapy was administered to 105 patients with U-CUP and non-platinum drug treatment to nine patients. The objective response rates were 61.1% (95% confidence interval [CI]: 38.6-83.6) and 41.1% (95% CI: 31.8-50.4) for patients with P-CUP and U-CUP, respectively. The median overall survival durations were 50.0 months and 16.9 months (log-rank: P = 0.002) for patients with P-CUP and U-CUP, respectively. P-CUP was identified as an independent predictor of good prognosis according to multivariate analysis. CONCLUSIONS: Patients with P-CUP had higher response rates and a better prognosis compared with patients with U-CUP. It might thus be reasonable to classify this subset as a new category of CUP with a favorable prognosis. PMID- 29433540 TI - Response to: "Monosodium urate crystal deposition associated with the progress of radiographic grade at the sacroiliac joint in axial SpA: a dual-energy CT study". PMID- 29433541 TI - Circular RNAs: a new frontier for cancer diagnosis and therapy. AB - In recent years, circular RNAs (circRNAs) have attracted considerable attention because they play a significant role in many fields of cancer biology. Additionally, it has become increasingly clear that circRNAs have the potential to make contributions to the successful application of individualized cancer medicine. This brief review introduces circRNAs by describing their potential as a biomarker and therapeutic target and discussing the possible strategies to target them. This review also presents the challenges that are encountered by circRNAs for their definitive entry into clinical practice. Clearly, our understanding of circRNAs helps to add a new dimension to the molecular structure of cancer and will provide many new opportunities for cancer treatment. PMID- 29433542 TI - SMURF1 facilitates estrogen receptor alpha signaling in breast cancer cells. AB - BACKGROUND: Estrogen receptor alpha (ER alpha) is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. ER alpha positive breast cancer can be well controlled by ER alpha modulators, such as tamoxifen. However, tamoxifen resistance is commonly observed by altered ER alpha signaling. Thus, further understanding of the molecular mechanisms, which regulates ER alpha signaling, is important to improve breast cancer therapy. METHODS: SMURF1 and ER alpha protein expression levels were measured by western blot, while the ER alpha target genes were measured by real-time PCR. WST-1 assay was used to measure cell viability; the xeno-graft tumor model were used for in vivo study. RNA sequencing was analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling was accomplished with luciferase assays, real-time RT-PCR and Western blotting. Protein stability assay and ubiquitin assay was used to detect ER alpha protein degradation. Immuno-precipitation based assays were used to detect the interaction domain between ER alpha and SMURF1. The ubiquitin-based Immuno-precipitation based assays were used to detect the specific ubiquitination manner happened on ER alpha. RESULTS: Here, we identify the E3 ligase SMURF1 facilitates ER alpha signaling. We show that depletion SMURF1 decreases ER alpha positive cell proliferation in vitro and in vivo. SMURF1 depletion based RNA-sequence data shows SMURF1 is necessary for ER alpha target gene expression in the transcriptomic scale. Immunoprecipitation indicates that SMURF1 associates with the N-terminal of ER alpha in the cytoplasm via its HECT domain. SMURF1 increases ER alpha stability, possibly by inhibiting K48 specific poly-ubiquitination process on ER alpha protein. Interestingly, SMURF1 expression could be induced via estradiol treatment. CONCLUSIONS: Our study reveals a novel positive feedback between SMURF1 and ER alpha signaling in supporting breast cancer growth. Targeting SMURF1 could be one promising strategy for ER alpha positive breast cancer treatment. PMID- 29433543 TI - Engaging policy-makers, health system managers, and policy analysts in the knowledge synthesis process: a scoping review. AB - BACKGROUND: It is unclear how to engage a wide range of knowledge users in research. We aimed to map the evidence on engaging knowledge users with an emphasis on policy-makers, health system managers, and policy analysts in the knowledge synthesis process through a scoping review. METHODS: We used the Joanna Briggs Institute guidance for scoping reviews. Nine electronic databases (e.g., MEDLINE), two grey literature sources (e.g., OpenSIGLE), and reference lists of relevant systematic reviews were searched from 1996 to August 2016. We included any type of study describing strategies, barriers and facilitators, or assessing the impact of engaging policy-makers, health system managers, and policy analysts in the knowledge synthesis process. Screening and data abstraction were conducted by two reviewers independently with a third reviewer resolving discrepancies. Frequency and thematic analyses were conducted. RESULTS: After screening 8395 titles and abstracts followed by 394 full-texts, 84 unique documents and 7 companion reports fulfilled our eligibility criteria. All 84 documents were published in the last 10 years, and half were prepared in North America. The most common type of knowledge synthesis with knowledge user engagement was a systematic review (36%). The knowledge synthesis most commonly addressed an issue at the level of national healthcare system (48%) and focused on health services delivery (17%) in high-income countries (86%). Policy-makers were the most common (64%) knowledge users, followed by healthcare professionals (49%) and government agencies as well as patients and caregivers (34%). Knowledge users were engaged in conceptualization and design (49%), literature search and data collection (52%), data synthesis and interpretation (71%), and knowledge dissemination and application (44%). Knowledge users were most commonly engaged as key informants through meetings and workshops as well as surveys, focus groups, and interviews either in-person or by telephone and emails. Knowledge user content expertise/awareness was a common facilitator (18%), while lack of time or opportunity to participate was a common barrier (12%). CONCLUSIONS: Knowledge users were most commonly engaged during the data synthesis and interpretation phases of the knowledge synthesis conduct. Researchers should document and evaluate knowledge user engagement in knowledge synthesis. REGISTRATION DETAILS: Open Science Framework ( https://osf.io/4dy53/ ). PMID- 29433544 TI - Scaffolds for the repair of bone defects in clinical studies: a systematic review. AB - BACKGROUND: This systematic review aims to summarize the clinical studies on the use of scaffolds in the repair of bony defects. METHODS: The relevant articles were searched through PubMed database. The following keywords and search terms were used: "scaffolds," "patient," "clinic," "bone repair," "bone regeneration," "repairing bone defect," "repair of bone," "osteanagenesis," "osteanaphysis," and "osteoanagenesis." The articles were screened according to inclusion and exclusion criteria, performed by two reviewers. RESULTS: A total of 373 articles were obtained using PubMed database. After screening, 20 articles were identified as relevant for the purpose of this systematic review. We collected the data of biological scaffolds and synthetic scaffolds. There are eight clinical studies of biological scaffolds included collagen, gelatin, and cellular scaffolds for bone healing. In addition, 12 clinical studies of synthetic scaffolds on HAp, TCP, bonelike, and their complex scaffolds for repairing bone defects were involved in this systematic review. CONCLUSIONS: There are a lot of clinical evidences showed that application of scaffolds had a good ability to facilitate bone repair and osteogenesis. However, the ideal and reliable guidelines are insufficiently applied and the number and quality of studies in this field remain to be improved. PMID- 29433545 TI - The effectiveness of ICT-based neurocognitive and psychosocial rehabilitation programmes in people with mild dementia and mild cognitive impairment using GRADIOR and ehcoBUTLER: study protocol for a randomised controlled trial. AB - BACKGROUND: Cognitive rehabilitation is a highly individualised, non pharmacological intervention for people with mild cognitive impairment (MCI) and dementia, which in recent years has also been developed for various IT platforms. METHODS: In this study, we aim to evaluate the effectiveness of the cognitive rehabilitation software GRADIOR in a multi-centre, single-blinded randomised controlled trial with people with MCI and mild dementia. A total of 400 people with MCI and mild dementia will be randomly allocated to one of four groups. This trial will compare the cognitive rehabilitation treatment using the GRADIOR programme with a psychosocial stimulation intervention (PSS) using the ehcoBUTLER platform, with a combined treatment consisting of GRADIOR and ehcoBUTLER, and with a group receiving treatment as usual during a period of 1 year. DISCUSSION: The outcomes of this clinical trial will be to determine any relevant changes in cognition, mood, quality of life, activities of daily living and quality of patient-carer relationship after 4 months and 1 year of intervention in a cross sectional group comparison. Participants will be followed-up for 1 year to investigate potential long-term effects of the conducted treatments. TRIAL REGISTRATION: Current Controlled Trials ISRCTN, ID: 15742788 . Registered on 12 June 2017. PMID- 29433546 TI - A unique role for galectin-9 in angiogenesis and inflammatory arthritis. AB - BACKGROUND: Galectin-9 (Gal-9) is a mammalian lectin secreted by endothelial cells that is highly expressed in rheumatoid arthritis synovial tissues and synovial fluid. Roles have been proposed for galectins in the regulation of inflammation and angiogenesis. Therefore, we examined the contribution of Gal-9 to angiogenesis and inflammation in arthritis. METHODS: To determine the role of Gal-9 in angiogenesis, we performed human dermal microvascular endothelial cell (HMVEC) chemotaxis, Matrigel tube formation, and mouse Matrigel plug angiogenesis assays. We also examined the role of signaling molecules in Gal-9-induced angiogenesis by using signaling inhibitors and small interfering RNA (siRNA). We performed monocyte (MN) migration assays in a modified Boyden chamber and assessed the arthritogenicity of Gal-9 by injecting Gal-9 into mouse knees. RESULTS: Gal-9 significantly increased HMVEC migration, which was decreased by inhibitors of extracellular signal-regulating kinases 1/2 (Erk1/2), p38, Janus kinase (Jnk), and phosphatidylinositol 3-kinase. Gal-9 HMVEC-induced tube formation was reduced by Erk1/2, p38, and Jnk inhibitors, and this was confirmed by siRNA knockdown. In mouse Matrigel plug assays, plugs containing Gal-9 induced significantly higher angiogenesis, which was attenuated by a Jnk inhibitor. Gal-9 also induced MN migration, and there was a marked increase in MN ingress when C57BL/6 mouse knees were injected with Gal-9 compared with the control, pointing to a proinflammatory role for Gal-9. CONCLUSIONS: Gal-9 mediates angiogenesis, increases MN migration in vitro, and induces acute inflammatory arthritis in mice, suggesting a novel role for Gal-9 in angiogenesis, joint inflammation, and possibly other inflammatory diseases. PMID- 29433547 TI - Finite-size effects in transcript sequencing count distribution: its power-law correction necessarily precedes downstream normalization and comparative analysis. AB - BACKGROUND: Though earlier works on modelling transcript abundance from vertebrates to lower eukaroytes have specifically singled out the Zip's law, the observed distributions often deviate from a single power-law slope. In hindsight, while power-laws of critical phenomena are derived asymptotically under the conditions of infinite observations, real world observations are finite where the finite-size effects will set in to force a power-law distribution into an exponential decay and consequently, manifests as a curvature (i.e., varying exponent values) in a log-log plot. If transcript abundance is truly power-law distributed, the varying exponent signifies changing mathematical moments (e.g., mean, variance) and creates heteroskedasticity which compromises statistical rigor in analysis. The impact of this deviation from the asymptotic power-law on sequencing count data has never truly been examined and quantified. RESULTS: The anecdotal description of transcript abundance being almost Zipf's law-like distributed can be conceptualized as the imperfect mathematical rendition of the Pareto power-law distribution when subjected to the finite-size effects in the real world; This is regardless of the advancement in sequencing technology since sampling is finite in practice. Our conceptualization agrees well with our empirical analysis of two modern day NGS (Next-generation sequencing) datasets: an in-house generated dilution miRNA study of two gastric cancer cell lines (NUGC3 and AGS) and a publicly available spike-in miRNA data; Firstly, the finite size effects causes the deviations of sequencing count data from Zipf's law and issues of reproducibility in sequencing experiments. Secondly, it manifests as heteroskedasticity among experimental replicates to bring about statistical woes. Surprisingly, a straightforward power-law correction that restores the distribution distortion to a single exponent value can dramatically reduce data heteroskedasticity to invoke an instant increase in signal-to-noise ratio by 50% and the statistical/detection sensitivity by as high as 30% regardless of the downstream mapping and normalization methods. Most importantly, the power-law correction improves concordance in significant calls among different normalization methods of a data series averagely by 22%. When presented with a higher sequence depth (4 times difference), the improvement in concordance is asymmetrical (32% for the higher sequencing depth instance versus 13% for the lower instance) and demonstrates that the simple power-law correction can increase significant detection with higher sequencing depths. Finally, the correction dramatically enhances the statistical conclusions and eludes the metastasis potential of the NUGC3 cell line against AGS of our dilution analysis. CONCLUSIONS: The finite-size effects due to undersampling generally plagues transcript count data with reproducibility issues but can be minimized through a simple power-law correction of the count distribution. This distribution correction has direct implication on the biological interpretation of the study and the rigor of the scientific findings. REVIEWERS: This article was reviewed by Oliviero Carugo, Thomas Dandekar and Sandor Pongor. PMID- 29433548 TI - Analytic validity of DecisionDx-Melanoma, a gene expression profile test for determining metastatic risk in melanoma patients. AB - BACKGROUND: The DecisionDx-Melanoma test provides prognostic information for patients with cutaneous melanoma (CM). Using formalin-fixed paraffin-embedded primary tumor tissue, the RT-PCR-based test classifies patients into a low- (Class 1) or high-risk (Class 2) category for recurrence based on expression of 31 genes. The current study was designed to assess the analytical validity of this test. METHODS: Inter-assay, inter-instrument, and inter-operator studies were performed to evaluate reliability of the 31-gene expression test results, sample stability and reagent stability. From March 2013 through June 2016, the gene expression test was performed on 8244 CM tumors. De-identified data from Pathology Reports were used to assess technical success. RESULTS: Robust sample and reagent stability was observed. Inter-assay concordance on 168 specimens run on 2 consecutive days was 99% and matched probability scores were significantly correlated (R2 = 0.96). Inter-instrument concordance was 95%, and probability scores had a correlation R2 of 0.99 (p < 0.001). From 8244 CM specimens submitted since 2013, 85% (7023) fulfilled pre-specified tumor content parameters. In these samples with sufficient tumor requirements, the technical success of the test was 98%. CONCLUSION: DecisionDx-Melanoma is a robust gene expression profile test that demonstrates strong reproducibility between experiments and has high technical reliability on clinical samples. PMID- 29433549 TI - Thinking BIG rheumatology: how to make functional genomics data work for you. AB - High-throughput sequencing assays have become an increasingly common part of biological research across multiple fields. Even as the resulting sequences pile up in public databases, it is not always obvious how to make use of these data sets. Functional genomics offers approaches to integrate these "big" data into our understanding of rheumatic diseases. This review aims to provide a primer on thinking about big data from functional genomics in the context of rheumatology, using examples from the field's literature as well as the author's own work to illustrate the execution of functional genomics research. Study design is crucial to ensure the right samples are used to address the question of interest. In addition, sequencing assays produce a variety of data types, from gene expression to 3D chromatin structure and single-cell technologies, that can be integrated into a model of the underlying gene regulatory networks. The best approach for this analysis uses the scientific process: bioinformatic methods should be used in an iterative, hypothesis-driven manner to uncover the disease mechanism. Finally, the future of functional genomics will see big data fully integrated into rheumatology, leading to computationally trained researchers and interactive databases. The goal of this review is not to provide a manual, but to enhance the familiarity of readers with functional genomic approaches and provide a better sense of the challenges and possibilities. PMID- 29433550 TI - FOLR1 increases sensitivity to cisplatin treatment in ovarian cancer cells. AB - BACKGROUND: Whether there is a mechanistic link between FOLR1 and response to cisplatin has not been extensively examined. In this study, we determine the expression of FOLR1 in ovarian cancer and examine if FOLR1 levels influence response to cisplatin. RESULTS: (1) FOLR1 protein expression was lowest in normal ovarian tissue, higher in benign ovarian tumors, and highest in malignant tumors (P < 0.01). (2) FOLR1 expression was decreased in platinum drug-resistant ovarian tumors compared to sensitive tumors (P < 0.01). Consistent with this, FOLR1 expression in tumors progressing following cisplatin treatment was lower than levels in tumors in remission (P < 0.01). (3) FOLR1 was successfully overexpressed at both the mRNA and protein levels following transfection in SKOV3 cells. (4) SKOV3 cells with FOLR1 overexpression were the most sensitive to cisplatin treatment (IC50 = 3.60 MUg/ml) and exhibited the highest inhibition rates in the presence of the drug (P < 0.05). (5) The rate of apoptosis of SKOV3 cells increased with cisplatin treatment in a dose- and time-dependent manner (P < 0.05). Cisplatin also induced S phase arrest in a concentration-dependent manner (P < 0.05). Apoptosis and S phase proportion were significantly altered by FOLR1 overexpression (P < 0.05). CONCLUSION: FOLR1 may be a useful biomarker for ovarian cancer, and it may be useful as a therapeutic application to improve sensitivity to cisplatin treatment. PMID- 29433551 TI - Characterization of subgroup J avian Leukosis virus isolated from Chinese indigenous chickens. AB - BACKGROUND: In spite of the purification of the laying hens and broilers of avian leukosis virus (ALV) has made remarkable achievements, the infection of ALV was still serious in Chinese indigenous chickens. METHODS: In order to assess the epidemic state of avian leukosis virus in indigenous chickens in China, 10 novel strains of ALV subgroup J (ALV-J), named JS16JH01 to JS16JH10, were isolated and identified by virus isolation and immunofluorescence antibody assays from a Chinese local breed farm with a sporadic incidence of tumors. To understand their virological characteristics further, the proviral genome of ENV-LTR was sequenced and compared with the reference strains. RESULTS: The homology of the gp85 gene between the ten ALV-J strains and NX0101 was in the range from 89.7-94.8% at the nuclear acid level. In addition, their gp85 genes were quite varied, with identities of 92-98% with themselves at the nuclear acid level. There were several snp and indel sites in the amino acid sequence of gp85 genes after comparison with other reference strains of ALV. Interestingly, a novel insertion in the gp85 region was found in two strains, JS16JH01 and JS16JH07, compared with NX0101 and HPRS-103. DISCUSSION: At present, owing to the large-scale purification of ALV in China, laying hens and broiler chickens with ALV infection are rarely detected, but ALVs are still frequently detected in the local chickens, which suggests that more efforts should be applied to the purification of ALV from indigenous chickens. PMID- 29433553 TI - The predictive role of pelvic magnetic resonance in the follow up of spontaneous or induced puberty in turner syndrome. AB - Puberty is a critical age for patients with Turner syndrome (TS): infertility is reported to be linked to karyotype and spontaneous puberty and menarche occur in approximately 30% of patients, especially in mosaicism. However, it is not always predictable considering hormonal pattern and pelvic transabdominal ultrasound scan (US).The aim of the study is to compare the accuracy of Magnetic Resonance Imaging (MRI) and US to evaluate uterine and gonads volume, to visualize the presence of follicles and to predict spontaneous puberty and menarche in girls with TS. In a retrospective study, we evaluated 19 TS patients (age: 9-16 years), who underwent transabdominal pelvic US and pelvic MRI as required by parents. We correlated pelvic imaging with karyotype, hormonal data and pubertal outcome, and we compared US resolution to MRI.MRI revealed a higher accuracy in the study of uterus and ovaries, and permitted to measure ovaries not visualized by US. Ovarian volume, the presence of follicles and the occurrence of spontaneous puberty were not related to the karyotype; spontaneous puberty started in one patient with a karyotype 45,X and in two patients with mosaicism (45,X/46,XX; 47,XXX/45, X). Ovarian follicles were relieved by MRI in patients with a spontaneous menarche and the persistence of menstrual cycles correlated with an ovarian volume corresponding to Tanner stage 3-4. We stress the role of MRI in the follow-up of TS adolescents, guide in the choice of the timing of treatment. PMID- 29433552 TI - Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward. AB - Recently, the US Food and Drug Administration (FDA) approved the first chimeric antigen receptor T cell (CAR-T) therapy for the treatment CD19-positive B cell acute lymphoblastic leukemia. While CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies, whether it can benefit solid tumor patients to the same extent is still uncertain. Even though hundreds of clinical trials are undergoing exploring a variety of tumor-associated antigens (TAA), no such antigen with comparable properties like CD19 has yet been identified regarding solid tumors CAR-T immunotherapy. Inefficient T cell trafficking, immunosuppressive tumor microenvironment, suboptimal antigen recognition specificity, and lack of safety control are currently considered as the main obstacles in solid tumor CAR-T therapy. Here, we reviewed the solid tumor CAR-T clinical trials, emphasizing the studies with published results. We further discussed the challenges that CAR-T is facing for solid tumor treatment and proposed potential strategies to improve the efficacy of CAR-T as promising immunotherapy. PMID- 29433554 TI - The Populus holobiont: dissecting the effects of plant niches and genotype on the microbiome. AB - BACKGROUND: Microorganisms serve important functions within numerous eukaryotic host organisms. An understanding of the variation in the plant niche-level microbiome, from rhizosphere soils to plant canopies, is imperative to gain a better understanding of how both the structural and functional processes of microbiomes impact the health of the overall plant holobiome. Using Populus trees as a model ecosystem, we characterized the archaeal/bacterial and fungal microbiome across 30 different tissue-level niches within replicated Populus deltoides and hybrid Populus trichocarpa * deltoides individuals using 16S and ITS2 rRNA gene analyses. RESULTS: Our analyses indicate that archaeal/bacterial and fungal microbiomes varied primarily across broader plant habitat classes (leaves, stems, roots, soils) regardless of plant genotype, except for fungal communities within leaf niches, which were greatly impacted by the host genotype. Differences between tree genotypes are evident in the elevated presence of two potential fungal pathogens, Marssonina brunnea and Septoria sp., on hybrid P. trichocarpa * deltoides trees which may in turn be contributing to divergence in overall microbiome composition. Archaeal/bacterial diversity increased from leaves, to stem, to root, and to soil habitats, whereas fungal diversity was the greatest in stems and soils. CONCLUSIONS: This study provides a holistic understanding of microbiome structure within a bioenergy relevant plant host, one of the most complete niche-level analyses of any plant. As such, it constitutes a detailed atlas or map for further hypothesis testing on the significance of individual microbial taxa within specific niches and habitats of Populus and a baseline for comparisons to other plant species. PMID- 29433556 TI - Treatment of glioblastoma with herbal medicines. AB - BACKGROUND: In the latest years, a lot of research studies regarding the usage of active agents from plants in the treatment of tumors have been published, but there is no data about successful usage of herbal remedies in the treatment of glioblastoma in humans. METHODS: The phytotherapy involved five types of herbal medicine which the subjects took in the form of tea, each type once a day at regular intervals. Three patients took herbal medicine along with standard oncological treatment, while two patients applied for phytotherapy after completing medical treatment. The composition of herbal medicine was modified when necessary, which depended on the results of the control scans using the nuclear magnetic resonance technique and/or computed tomography. RESULTS: Forty eight months after the introduction of phytotherapy, there were no clinical or radiological signs of the disease, in three patients; in one patient, the tumor was reduced and his condition was stable, and one patient lived for 48 months in spite of a large primary tumor and a massive recurrence, which developed after the treatment had been completed. CONCLUSIONS: The results achieved in patients in whom tumor regression occurred exclusively through the use of phytotherapy deserve special attention. In order to treat glioblastoma more effectively, it is necessary to develop innovative therapeutic strategies and medicines that should not be limited only to the field of conventional medicine. The results presented in this research paper are encouraging and serve as a good basis for further research on the possibilities of phytotherapy in the treatment of glioblastoma. PMID- 29433555 TI - SF3B1 deficiency impairs human erythropoiesis via activation of p53 pathway: implications for understanding of ineffective erythropoiesis in MDS. AB - BACKGROUND: SF3B1 is a core component of splicing machinery. Mutations in SF3B1 are frequently found in myelodysplastic syndromes (MDS), particularly in patients with refractory anemia with ringed sideroblasts (RARS), characterized by isolated anemia. SF3B1 mutations have been implicated in the pathophysiology of RARS; however, the physiological function of SF3B1 in erythropoiesis remains unknown. METHODS: shRNA-mediated approach was used to knockdown SF3B1 in human CD34+ cells. The effects of SF3B1 knockdown on human erythroid cell differentiation, cell cycle, and apoptosis were assessed by flow cytometry. RNA-seq, qRT-PCR, and western blot analyses were used to define the mechanisms of phenotypes following knockdown of SF3B1. RESULTS: We document that SF3B1 knockdown in human CD34+ cells leads to increased apoptosis and cell cycle arrest of early-stage erythroid cells and generation of abnormally nucleated late-stage erythroblasts. RNA-seq analysis of SF3B1-knockdown erythroid progenitor CFU-E cells revealed altered splicing of an E3 ligase Makorin Ring Finger Protein 1 (MKRN1) and subsequent activation of p53 pathway. Importantly, ectopic expression of MKRN1 rescued SF3B1 knockdown-induced alterations. Decreased expression of genes involved in mitosis/cytokinesis pathway including polo-like kinase 1 (PLK1) was noted in SF3B1-knockdown polychromatic and orthochromatic erythroblasts comparing to control cells. Pharmacologic inhibition of PLK1 also led to generation of abnormally nucleated erythroblasts. CONCLUSIONS: These findings enabled us to identify novel roles for SF3B1 in human erythropoiesis and provided new insights into its role in regulating normal erythropoiesis. Furthermore, these findings have implications for improved understanding of ineffective erythropoiesis in MDS patients with SF3B1 mutations. PMID- 29433557 TI - Metastatic uveal melanoma showing durable response to anti-CTLA-4 and anti-PD-1 combination therapy after experiencing progression on anti-PD-1 therapy alone. AB - BACKGROUND: Uveal melanoma accounts for 85% of the ocular melanomas and has an increased risk of hematogenous spread, most commonly to the liver. After curative intent therapy like surgery and radiation, fifty percent of patients present with distant metastasis. Metastatic uveal melanoma (MUM) does not harbor typically targetable mutations, e.g., BRAF as in cutaneous melanoma. As a result, there is no proven therapy for MUM. Various chemotherapy and immunotherapy regimens have been tried and only partial response (PR) is the best that has been achieved in most of the cases. Here, we present a case of MUM treated with combination immune checkpoint therapy (ipilimumab and nivolumab) following the progression with single-agent nivolumab and demonstrating a durable response without recurrence more than 22 months from the last treatment. CASE PRESENTATION: A 72-year-old Caucasian man presented with ciliary body melanoma of the left eye and underwent curative-intent enucleation but six months later developed diffuse hepatic metastases. He initially was treated with nivolumab 3 mg/kg every two weeks for four cycles but restaging scan showed a significant progression of the disease with increasing LDH. With the FDA approval for the combination of nivolumab 1mg/kg with Ipilimumab 3 mg/kg every three weeks for metastatic melanoma, this combination was given for four cycles with continuous rise in LDH to 993 unit/L (110-220 unit/L) until finishing cycle four of the treatment. Three weeks later, maintainence nivolumab 3mg/kg was initiated but two weeks later, he developed grade 4 liver toxicity with ALT 1565 unit/L (0-55 unit/L). A presumptive diagnosis of autoimmune hepatitis was made, nivolumab was stopped and oral prednisone 1mg/kg was started with quick resolution of elevated transaminases. Restaging abdominal MRI one month after the first and last dose of maintenance nivolumab showed PR and continuous shrinkage of the metastatic lesions with no hypermetabolic activity even on PET/CT. He is 22 months' post-treatment and continues to do well without any evidence of active disease. CONCLUSION: Although, limited response has been shown to single agent immune checkpoint inhibitors and chemotherapy, our patient showed durable response with anti-CTLA-4 and anti-PD-1 combination therapy in MUM. PMID- 29433558 TI - Comparison of screening strategies for prevalent vertebral fractures in South Korea: vertebral fracture assessment vs. spine radiography. AB - BACKGROUND: Vertebral Fracture Assessment (VFA) is a useful tool to detect the vertebral fracture (VF) with low cost and radiation exposure. We aimed to compare screening strategies including VFA and spine radiography (X-ray) for detecting VF in terms of clinical effectiveness, cost and radiation exposure. METHODS: Three screening strategies: 1) X-ray following VFA, 2) VFA only, and 3) X-ray only were compared using a Markov model based on administrative data from South Korea in a population aged >=50 years. We compared the incidence of new VFs, cost effectiveness of reducing new VFs and radiation exposure in each strategy. RESULTS: The incidence of new VFs was reduced in all screening strategies compared to no screening: 29.4% for women and 12.5% for men in both X-ray following the VFA and VFA only strategies and 35% for women and 17.5% for men in the X-ray only strategy. The X-ray following VFA strategy had the lowest cost, followed by the X-ray only, and VFA only strategies. The radiation doses for X ray only were 2,647-2,989 MUSv and 3,253-3,398 MUSv higher than in the X-ray following VFA and VFA only strategies. The new VF prevention effect was greater in women, and more prominent in older people (women >= 70, men >= 80) than people >= 50 years. CONCLUSIONS: The X-ray following VFA strategy is a cost-effective option for screening prevalent VF to prevent new VF in people aged >=50 years due to its high effectiveness, lowest cost, and least radiation exposure. PMID- 29433559 TI - CXCR7 participates in CXCL12-mediated migration and homing of leukemic and normal hematopoietic cells. AB - CXCR4 was the first receptor identified for CXCL12, but a second receptor, CXCR7, has also been described and its function in hematopoietic cells remains unknown. By inhibition of CXCR4 and/or CXCR7, we showed that CXCR7 participates in normal CD34+ and U937 cell migration and prevents downregulation of CXCR4 by CXCL12 stimulation. In addition, CXCR7 contributes to homing of acute myeloid leukemia and normal progenitor cells to the bone marrow and spleen of NOD/SCID mice. In summary, this study shows an essential role of CXCR7, together with CXCR4, in the control of normal and malignant hematopoietic cell migration and homing induced by CXCL12. PMID- 29433560 TI - An international survey on hypoglycemia among insulin-treated type I and type II diabetes patients: Turkey cohort of the non-interventional IO HAT study. AB - BACKGROUND: Limited real-world data are currently available on hypoglycemia in diabetes patients. The International Operations Hypoglycemia Assessment Tool (IO HAT) study was designed to estimate hypoglycemia in insulin-treated type I (T1DM) and type II (T2DM) diabetes mellitus patients from 9 countries. The data from Turkey cohort are presented here. METHODS: A non-interventional study to determine the hypoglycemia incidence, retrospectively and prospectively, in Turkish T1DM and T2DM patients using a 2-part self-assessment questionnaire. RESULTS: Overall, 2348 patients were enrolled in the Turkey cohort (T1DM = 306 patients, T2DM = 2042 patients). In T1DM patients, 96.8% patients reported hypoglycemic events (Incidence rate [IR]: 68.6 events per patient-year [ppy]), prospectively, while 74.0% patients reported hypoglycemic events (IR: 51.7 events ppy), retrospectively. In T2DM patients, 95.9% patients (IR: 28.3 events ppy) reported hypoglycemic events, prospectively, while 53.6% patients (IR: 23.0 events ppy) reported hypoglycemic events, retrospectively. Nearly all patients reported hypoglycemia during the prospective period. CONCLUSIONS: This is a first patient-reported dataset on hypoglycemia in Turkish, insulin-treated diabetes patients. A high incidence of patient-reported hypoglycemia confirms that hypoglycemia remains under-estimated. Hypoglycemia increased healthcare utilization impacting patients' quality of life. Hypoglycemia remains a common side effect with insulin-treatment and strategies to optimize therapy and reduce hypoglycemia occurrence in diabetes patients are required. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02306681 (Date of registration: 12 Nov 2014; retrospectively registered). PMID- 29433561 TI - Pregnancy outcome in a pregnant patient with idiopathic Pulmonary Arterial Hypertension: a case report and review of the literature. AB - BACKGROUND: Idiopathic pulmonary arterial hypertension is a rare and progressive condition which is aggravated by the physiologic changes during pregnancy. Because of high mortality rate, most physicians recommend early termination of pregnancy in patients with idiopathic pulmonary arterial hypertension. CASE PRESENTATION: Here we describe a case of a 30-year-old primigravida Caucasian housewife with functional class 1 idiopathic pulmonary arterial hypertension and a positive vasoreactive response to adenosine who had a full-term non-complicated delivery. Right-sided heart catheterization before the pregnancy showed severe pulmonary hypertension with mean pulmonary arterial pressure of 60 mmHg, and pulmonary vascular resistance of 12.2 WU. Vasoreactivity was positive after infusion of 200 MUg/kg per minute adenosine. During pregnancy, she did not receive medication other than prophylactic enoxaparin. She had an elective cesarean section under general anesthesia at 39 weeks of gestation without complication and delivered a healthy baby. After delivery, her hemodynamic status was stable. One month postpartum, she was in a stable clinical condition in functional class 1. CONCLUSIONS: In pregnant patients with pulmonary arterial hypertension, decreased mortality has been observed over recent years particularly in patients with well-controlled pulmonary pressure and a positive vasoreactivity test. PMID- 29433562 TI - The impact of insulin pump therapy to oxidative stress in patients with diabetic nephropathy. AB - BACKGROUND: The oxidative stress resulting from increased production of ROS plays a crucial role in the development of diabetic complications. We aim to explore the relationships between oxidative stress, diabetic nephropathy (DN) and short term insulin pump intensive therapy (insulin therapy). METHODS: Levels of 8 hydroxy-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), glutathione (GSH), superoxide dismutase (SOD) and Interleukin-6 (IL-6) were estimated before and after 2 weeks of insulin therapy in normal group (NC) and type 2 diabetic (DM) with normal albuminuria (NA), microalbuminuria (MA) and clinical albuminuria (CA). RESULTS: In DM group, levels of 8-OHdG and 3-NT were higher than those in NC group (P < 0.05); GSH and SOD were lower (P < 0.05). And their levels changed with urine albumin-creatinine ratio (P < 0.05). After insulin therapy, these derangements were significantly ameliorated and the changes in NA and MA groups were more significant than CA group (P < 0.05). Correlation analysis showed glycated hemoglobin, the course of disease, the HOME-IR and fasting plasma glucose were positively correlated with 8-OHdG and 3-NT, but negatively correlated with GSH and SOD. CONCLUSIONS: The oxidative stress gradually increased with the magnitude of DN, and insulin pump intensive therapy can significantly ameliorate the derangements in the early stage of DN. Trial registration NCT03174821. PMID- 29433563 TI - Therapeutic effect of human umbilical cord-derived mesenchymal stem cells on injured rat endometrium during its chronic phase. AB - BACKGROUND: Repair deficiency after endometrial injury is an important reason for intra-uterine adhesions, amenorrhea, and infertility in females. Bone marrow derived mesenchymal stem cell (BMSC) transplantation is effective in repairing the damaged endometrium. However, the possibility of using umbilical cord-derived MSCs (UC-MSCs) to treat endometrial injury is rarely reported. METHODS: Ethanol (95%) was injected into rat uterus to establish a model of endometrial injury. UC MSCs were injected through the tail vein, either as a single, twice, or thrice administration. Functional restoration of the uterus was assessed by testing embryo implantation rates. Endometrial morphological alteration was observed by hematoxylin and eosin staining. Endometrial fibrosis, markers of epithelial and stromal cells of endometrium, cell proliferation and angiogenesis, and inflammatory factors were detected using immunohistochemistry, Western blotting, and quantitative reverse-transcription polymerase chain reaction. RESULTS: Endometrial morphology and embryo implantation rates were significantly improved on day 8 of transplantation among single-, twice-, or thrice-administered rats. Moreover, UC-MSCs could alleviate fibrosis in general, and reduced the expression of fibrosis markers, alpha-smooth muscle actin (alpha-SMA) and transforming growth factor (TGF)-beta. The cell proliferation marker Ki-67 had a positive expression in the injured endometrium after UC-MSC transplantation. The endometrial stromal marker vimentin and epithelial marker cytokeratin-19 (CK-19) expressions were visibly increased. The expression of vascular markers CD31, vascular endothelial growth factor (VEGF)A, and matrix metalloprotein (MMP)9 was generally upregulated. Proinflammatory factors interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2 were significantly downregulated in the rats administered UC-MSCs twice and thrice. CONCLUSIONS: UC MSC transplantation contributed to the repair of endometrial injury and restoration of fertility, likely through the suppression of excessive fibrosis and inflammation, and enhancement of endometrial cell proliferation and vascular remodeling. PMID- 29433564 TI - High-dose thiotepa-related neurotoxicity and the role of tramadol in children. AB - BACKGROUND: Serious neurological adverse events (NAE) have occurred during treatment with high-dose thiotepa regimens of children with high-risk solid tumours. The objective was to assess the incidence of NAE related to high-dose thiotepa and to identify potential contributing factors that could exacerbate the occurrence of this neurotoxicity. METHODS: From May 1987 to March 2011, children with solid tumours treated with high-dose thiotepa were retrospectively identified. Each NAE detected led to an independent case analysis. Potential contributing factors were pre-specified and univariate/multivariable analyses were performed. RESULTS: Three hundred seven courses of thiotepa (251 patients) were identified. The total dose per treatment ranged from 600 to 900 mg/m2. 81 NAE (26%) were identified. 46 NAE were related to high-dose thiotepa during the first course (18.3%) and 11 during the second course (19.6%). The symptoms appeared in a median time of 2 days after the introduction of thiotepa. Central and peripheral symptoms were headaches, tremors, confusion, seizures, cerebellar syndrome, and coma. High-dose thiotepa was reintroduced in 18 cases and symptoms reappeared in 5 children. For 3 patients who had seizures during the first course, premedication with clonazepam for the second course has prevented recurrence of NAE. As contributing factors, brain tumour and tramadol treatment increased the risk of thiotepa-related neurotoxicity by 2 to 6 times respectively. CONCLUSIONS: The incidence of neurotoxicity was 18.3%. Brain tumours and tramadol treatment are risk factors to consider when using high-dose thiotepa. The outcome of patients was favourable without sequelae in all cases and rechallenge with thiotepa was possible. PMID- 29433565 TI - Genetic determinants of sporadic breast cancer in Sri Lankan women. AB - BACKGROUND: While a range of common genetic variants have been identified to be associated with risk of sporadic breast cancer in several Western studies, little is known about their role in South Asian populations. Our objective was to examine the association between common genetic variants in breast cancer related genes and risk of breast cancer in a cohort of Sri Lankan women. METHODS: A case control study of 350 postmenopausal women with breast cancer and 350 healthy postmenopausal women was conducted. Genotyping using the iPLEX GOLD assay was done for 56 haplotype-tagging single nucleotide polymorphisms (SNPs) in 36 breast cancer related genes. Testing for association was done using an additive genetic model. Odds ratios and 95% confidence intervals were calculated using adjusted logistic regression models. RESULTS: Four SNPs [rs3218550 (XRCC2), rs6917 (PHB), rs1801516 (ATM), and rs13689 (CDH1)] were significantly associated with risk of breast cancer. The rs3218550 T allele and rs6917 A allele increased breast cancer risk by 1.5-fold and 1.4-fold, respectively. The CTC haplotype defined by the SNPs rs3218552|rs3218550|rs3218536 on chromosome 7 (P = 0.0088) and the CA haplotype defined by the SNPs rs1049620|rs6917 on chromosome 17 (P = 0.0067) were significantly associated with increased risk of breast cancer. The rs1801516 A allele and the rs13689 C allele decreased breast cancer risk by 0.6-fold and 0.7 fold, respectively. CONCLUSIONS: These findings suggest that common genetic polymorphisms in the XRCC2, PHB, CDH1 and ATM genes are associated with risk of breast cancer among Sri Lankan postmenopausal women. The exact biological mechanisms of how these variants regulate overall breast cancer risk need further evaluation using functional studies. PMID- 29433566 TI - Differences in gene expression profile between vocal cord Leukoplakia and normal larynx mucosa by gene chip. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) play an important role in tumorigenesis. Vocal cord leukoplakia is a precancerous lesion in otolaryngological practice. Till now, the expression patterns and functions of lncRNAs in vocal cord leukoplakia have not been well understood. In this study, we used microarrays to investigate the aberrantly expressed lncRNAs and mRNAs in vocal cord leukoplakia and adjacent non-neoplastic tissues. METHODS: Gene Ontology and pathway analyses were performed to determine the significant function and pathways of the differentially expressed mRNAs. qRT-PCR was performed to further validate the expression of selected lncRNAs and mRNAs in vocal cord leukoplakia. RESULTS: Our study identified 170 differentially expressed lncRNAs and 99 differentially expressed mRNAs, including 142 up regulated lncRNAs and 28 down-regulated lncRNAs, and 54 up-regulated mRNAs and 45 down-regulated mRNAs. Among these, XLOC_000605 and DLX6-AS1 were the most aberrantly expressed lncRNAs. Furthermore, we identified an antisense lncRNA (LOC100506801), an enhancer-like lncRNA (AK057351) and three long intergenetic noncoding RNAs including XLOC_008001, XLOC_011989 and XLOC_007341. CONCLUSIONS: Our results revealed that many lncRNAs were differentially expressed between vocal cord leukoplakia tissues and normal tissue, suggesting that they may play a key role in vocal cord leukoplakia tumorigenesis. PMID- 29433567 TI - Laryngeal recurrence sites in patients previously treated with transoral laser microsurgery for squamous cell carcinoma. AB - BACKGROUND: The laryngeal framework provides a natural barrier preventing tumour spread to extralaryngeal structures. Transoral laser microsurgery (TLM) for laryngeal squamous cell carcinoma (SCC) may violate these boundaries, altering the pathways of tumor spread for potential recurrences. Our project objective is to describe laryngeal SCC recurrence patterns and overall survival in patients requiring total laryngectomy (TL) after TLM. METHODS: Patients undergoing TLM for laryngeal SCC requiring salvage TL were identified from a prospective CO2 laser database containing all patients undergoing TLM for head and neck malignancies at the QEII Health Sciences Center in Halifax, Nova Scotia between March 2002 - May 2014. Surgical pathology reports were analyzed for tumor characteristics, extent of recurrence and invasion of local structures. Kaplan-Meier analyses were performed to evaluate overall survival, disease specific survival (DSS) and locoregional control. RESULTS: Fifteen patients were identified from the database as receiving salvage TL for recurrent disease after initial TLM resection for laryngeal SCC. Final pathology reports demonstrated that 67% (10/15) of patients had thyroid cartilage involvement while 53% (9/15) of patients had cricoid cartilage involvement on salvage TL pathology. 33% (5/15) of patients had perineural invasion and 27% (4/15) had lymphovascular invasion. Mean and median follow-up times were 36.7 months and 26.8 months respectively (range 3.9-112.6). The Kaplan-Meier estimate for overall survival at 36 months was 40% post TL with a standard error (SE) of 13.6%. DSS was 47% (SE 14.2%), and locoregional control was 55% (SE 14.5%) post TL. CONCLUSIONS: Laryngeal recurrence sites following TLM seem to be consistent with historical data at known laryngeal sites of vulnerability. Treatment with TLM does not predispose patients to a lower rate of locoregional control and overall survival after total laryngectomy and salvage outcomes are consistent with literature values. PMID- 29433568 TI - The peopling of the last Green Sahara revealed by high-coverage resequencing of trans-Saharan patrilineages. AB - BACKGROUND: Little is known about the peopling of the Sahara during the Holocene climatic optimum, when the desert was replaced by a fertile environment. RESULTS: In order to investigate the role of the last Green Sahara in the peopling of Africa, we deep-sequence the whole non-repetitive portion of the Y chromosome in 104 males selected as representative of haplogroups which are currently found to the north and to the south of the Sahara. We identify 5,966 mutations, from which we extract 142 informative markers then genotyped in about 8,000 subjects from 145 African, Eurasian and African American populations. We find that the coalescence age of the trans-Saharan haplogroups dates back to the last Green Sahara, while most northern African or sub-Saharan clades expanded locally in the subsequent arid phase. CONCLUSIONS: Our findings suggest that the Green Sahara promoted human movements and demographic expansions, possibly linked to the adoption of pastoralism. Comparing our results with previously reported genome wide data, we also find evidence for a sex-biased sub-Saharan contribution to northern Africans, suggesting that historical events such as the trans-Saharan slave trade mainly contributed to the mtDNA and autosomal gene pool, whereas the northern African paternal gene pool was mainly shaped by more ancient events. PMID- 29433569 TI - MH84 improves mitochondrial dysfunction in a mouse model of early Alzheimer's disease. AB - BACKGROUND: Current approved drugs for Alzheimer's disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARgamma) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AbetaPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AbetaPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD. METHODS: Three-month-old Thy-1 AbetaPPSL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AbetaPPwt and HEK293-AbetaPPsw cells. Soluble Abeta1-40 and Abeta1-42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively. RESULTS: MH84 reduced cerebral levels of the beta-secretase-related C99 peptide and of Abeta40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARgamma coactivator-1alpha (PGC-1alpha) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence. CONCLUSIONS: MH84 modulates beta-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1alpha dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD. PMID- 29433570 TI - Role of ATP-sensitive potassium channels on hypoxic pulmonary vasoconstriction in endotoxemia. AB - BACKGROUND: ATP-regulated potassium channels (KATP) regulate pulmonary vascular tone and are involved in hypoxic pulmonary vasoconstriction (HPV). In patients with inflammation like sepsis or ARDS, HPV is impaired, resulting in a ventilation-perfusion mismatch and hypoxia. Since increase of vascular KATP channel Kir6.1 has been reported in animal models of endotoxemia, we studied the expression and physiological effects of Kir6.1 in murine endotoxemic lungs. We hypothesized that inhibition of overexpressed Kir6.1 increases HPV in endotoxemia. METHODS: Mice (C57BL/6; n = 55) with (n = 27) and without (n = 28) endotoxemia (35 mg/kg LPS i.p. for 18 h) were analyzed for Kir6.1 gene as well as protein expression and HPV was examined in isolated perfused mouse lungs with and without selective inhibition of Kir6.1 with PNU-37883A. Pulmonary artery pressure (PAP) and pressure-flow curves during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation were obtained. HPV was quantified as the increase in perfusion pressure in response to hypoxic ventilation in mmHg of baseline perfusion pressure (DeltaPAP) in the presence and absence of PNU-37883A. RESULTS: Endotoxemia increases pulmonary Kir6.1 gene (+ 2.8 +/- 0.3-fold) and protein expression (+ 2.1 +/- 0.3-fold). Hypoxia increases HPV in lungs of control animals, while endotoxemia decreases HPV (?PAP control: 9.2 +/- 0.9 mmHg vs. LPS: 3.0 +/- 0.7 mmHg, p < 0.05, means +/- SEM). Inhibition of Kir6.1 with 1 MUM PNU 37883A increases HPV in endotoxemia, while not increasing HPV in controls (?PAP PNU control: 9.3 +/- 0.7 mmHg vs. PNU LPS: 8.3 +/- 0.9 mmHg, p < 0.05, means +/- SEM). CONCLUSION: Endotoxemia increases pulmonary Kir6.1 gene and protein expression. Inhibition of Kir6.1 augments HPV in murine endotoxemic lungs. PMID- 29433571 TI - Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients. AB - BACKGROUND: Immune checkpoint therapy has dramatically changed the landscape of cancer therapy, providing an efficacious and durable therapeutic option for patients with advanced-stage disease. However, dermatologic toxicities are a well recognized side effect in patients receiving this therapy. A spectrum of immune related adverse events (irAEs) involving the skin can occur and include immunobullous disorders, lichenoid dermatitis, and vitiligo. Granulomatous/sarcoid-like lesions are now being recognized with the current class of checkpoint inhibitors (CPIs) that involve the dermis, the subcutaneous tissue (panniculitis), and lymph nodes. CASE PRESENTATION: We report 3 patients who developed granulomatous/sarcoid-like lesions while being treated with immune checkpoint therapy for advanced-stage melanoma, and we provide a comprehensive review of the literature in which similar cases are described. To date, 26 patients (including the 3 from this report) have been described with a median age of 57 years who developed granulomatous/sarcoid-like lesions associated with CPIs (median onset 6 months), of which 77% of patients had melanoma as primary tumor. To manage this adverse side effect, therapy was withheld in 38% of patients and 44% of the patients were treated with systemic steroids and 8% patients with localized therapy (one patient with intralesional triamcinolone). 96% of patients demonstrated either resolution or improvement of granulomatous/sarcoid-like lesions associated with CPIs irrespective of medical intervention. Therapeutic response, stable disease, or remission of primary malignancy was observed in 71% of reported patients who developed granulomatous/sarcoid-like lesions associated with CPIs over a median follow-up of 11.5 months since initiation of treatment. CONCLUSIONS: The development of granulomatous/sarcoid-like lesions associated with CPIs is a recognized manifestation with the current class of immune checkpoint therapy that may clinically and radiographically mimic disease recurrence. Awareness of this type of toxicity is important for appropriate management and possible measurement of therapeutic response in a subset of patients who manifest this type of immune-mediated reaction. PMID- 29433572 TI - Evaluation of a multicomponent pathway to address inpatient delirium on a neurosciences ward. AB - BACKGROUND: Delirium is a frequent and detrimental complication of inpatient hospitalization. Multicomponent intervention in selected groups has been shown to prevent and treat delirium, though little data exists on the effect of intervention in neurological patients. We studied the efficacy of a multicomponent delirium care pathway implemented on a largely neurology and neurosurgery hospital ward among unselected patients. METHODS: We incorporated a multicomponent delirium care pathway into the workflow of a university hospital for patients older than 50 years. The pathway involved risk-stratification for development of delirium, delirium screening, and non-pharmacologic behavioral prevention and intervention. We then retrospectively reviewed admissions before and after implementation of the care pathway. Our primary endpoint was incidence of delirium; secondary endpoints included delirium days, length of stay, restraint use, readmission rates, and discharge disposition. RESULTS: Seven hundred ninety eight admissions from before the delirium care pathway went into effect and 797 admissions from afterwards were reviewed. Baseline characteristics between groups were similar. Delirium incidence between the two groups did not change (7.0% before vs 7.2% after, p = 0.89). Length of stay among delirious patients significantly decreased after implementation of the delirium care pathway (9.60 before vs 7.06 after, beta = - 0.16, adjusted p-value = 0.001). CONCLUSION: Implementation of a delirium care pathway on a neurosciences ward was not associated with changes in the rate of delirium development, though length of stay among delirious patients decreased. In a largely neurologic population, multicomponent intervention to prevent and treat delirium may not change delirium incidence, but may be effective in mitigating delirium complications. PMID- 29433574 TI - Association between diet quality, dietary patterns and cardiometabolic health in Australian adults: a cross-sectional study. AB - BACKGROUND: Diet quality indices score dietary intakes against recommendations, whereas dietary patterns consider the pattern and combination of dietary intakes. Studies evaluating both methodologies in relation to cardiometabolic health in a nationally representative sample are limited. The aim of the present study was to investigate the relationship between diet quality, dietary patterns and markers of cardiometabolic health in Australian adults. METHODS: Dietary data, using two 24-h dietary recalls, were collected from adults in the cross-sectional Australian Health Survey 2011-2013 (n = 2121; 46.4 (SE 0.48) years). Diet quality was estimated using the Dietary Guideline Index (DGI). Dietary patterns (DPs), derived using reduced rank regression, were estimated using fiber density, SFA: PUFA and total sugars intake as intermediate markers. Multi-variable adjusted linear regression analyses were used to examine associations between diet quality and DPs and blood biomarkers, body mass index, waist circumference, diastolic and systolic blood pressure and an overall cardiometabolic risk score. RESULTS: DGI was associated with lower glucose (coef - 0.009, SE 0.004; P-trend = 0.033), body mass index (coef - 0.017, SE 0.007; P-trend = 0.019) and waist circumference (coef - 0.014, SE 0.005; P-trend = 0.008). Two dietary patterns were derived: dietary pattern-1 was characterized by higher intakes of pome fruit and wholegrain bread, while dietary pattern-2 was characterized by higher intakes of added sugars and tropical fruit. Dietary pattern-1 was associated with lower body mass index (coef - 0.028, SE 0.007; P-trend< 0.001) and waist circumference (coef - 0.017, SE 0.005; P-trend = 0.001). There was a trend towards lower cardiometabolic risk score. Dietary pattern-2 was associated with lower HDL cholesterol (coef - 0.026, SE 0.012; P-trend = 0.028). There was a trend towards lower diastolic blood pressure. No associations with other markers were observed. CONCLUSIONS: Better diet quality and healthier dietary patterns were primarily associated with favorable anthropometric markers of cardiometabolic health. Findings support the need for comparison of whole-diet based methodologies that take into consideration the interactions between foods and nutrients. Longitudinal studies are warranted to better understand causal relationships between diet and cardiometabolic health. PMID- 29433573 TI - Design of the Growth hormone deficiency and Efficacy of Treatment (GET) score and non-interventional proof of concept study. AB - BACKGROUND: The adverse effects of growth hormone (GH) deficiency (GHD) in adults (AGHD) on metabolism and health-related quality of life (HRQoL) can be improved with GH substitution. This investigation aimed to design a score summarising the features of GHD and evaluate its ability to measure the effect of GH substitution in AGHD. METHODS: The Growth hormone deficiency and Efficacy of Treatment (GET) score (0-100 points) assessed (weighting): HRQoL (40%), disease-related days off work (10%), bone mineral density (20%), waist circumference (10%), low-density lipoprotein cholesterol (10%) and body fat mass (10%). A prospective, non interventional, multicentre proof-of-concept study investigated whether the score could distinguish between untreated and GH-treated patients with AGHD. A 10-point difference in GET score during a 2-year study period was expected based on pre existing knowledge of the effect of GH substitution in AGHD. RESULTS: Of 106 patients eligible for analysis, 22 were untreated GHD controls (9 females, mean +/- SD age 52 +/- 17 years; 13 males, 57 +/- 13 years) and 84 were GH-treated (31 females, age 45 +/- 13 years, GH dose 0.30 +/- 0.16 mg/day; 53 males, age 49 +/- 15 years, GH dose 0.25 +/- 0.10 mg/day). Follow-up was 706 +/- 258 days in females and 653 +/- 242 days in males. The GET score differed between the untreated control and treated groups with a least squares mean difference of + 10.01 +/- 4.01 (p = 0.0145). CONCLUSIONS: The GET score appeared to be a suitable integrative instrument to summarise the clinical features of GHD and measure the effects of GH substitution in adults. Exercise capacity and muscle strength/body muscle mass could be included in the GET score. TRIAL REGISTRATION: NCT number: NCT00934063 . Date of registration: 02 July 2009. PMID- 29433575 TI - Uses and importance of wild fungi: traditional knowledge from the Tshopo province in the Democratic Republic of the Congo. AB - BACKGROUND: Wild mushrooms constitute an important non-timber forest product that provides diverse substances and services, especially food and income for local communities from many parts of the world. This study presents original ethnomycological documentation from the dense rainforests of the Democratic Republic of the Congo. METHODS: Ethnomycological surveys were made within local communities near the biosphere reserve of Yangambi and the Yoko forest reserve. The interviews involved 160 informants from six different ethnic communities (Bakumu, Turumbu, Topoke, Lokele, Ngelema, and Ngando). Specific reported use (RU), the relative importance (RI), and the cultural significance (CS) of wild edible fungi were calculated using quantitative data from enquiries. RESULTS: The people from Tshopo use 73 species of wild mushrooms either for food (68 species), as medicine (9 species), in a recreational context (2 species), or related to myths and beliefs (7 species). Women are more involved in harvesting and are the main holders of cultural aspects related to fungi. The results show that knowledge of useful mushrooms differs between ethnic groups. The Ngando people have the highest ethnomycological expertise, which is expressed in their extensive cultural and practical use of fungi. Pleurotus tuber-regium is the most important species (MCSI = 1.9 and p value < 2.2e-16) as it is being used for food, as a medicine, and more. Daldinia eschscholtzii is the most important (MUI = 0.86 and p value < 2.2e-16) for medicinal applications, while Schizophyllum commune, Auricularia cornea, A. delicata, Marasmius buzungolo, and Lentinus squarrosulus are mostly appreciated for food. The latter five species are all wood-decaying saprotrophs. CONCLUSION: Despite the presence of edible ectomycorrhizal taxa in the dense rainforests of Tshopo, local people only seem to have an interest in saprotrophic taxa. Some mushroom pickers deliberately cut down host trees to promote the development of saprotrophic taxa. Inducing forest degradation is considered beneficial as it promotes the development of saprotrophic taxa. The domestication of locally appreciated saprotrophic lignicolous fungi is proposed as a mitigating measure against fellings. PMID- 29433576 TI - Barriers and facilitators to the implementation of a paediatric palliative care team. AB - BACKGROUND: Over the last decade, paediatric palliative care teams (PPCTs) have been introduced to support children with life-limiting diseases and their families and to ensure continuity, coordination and quality of paediatric palliative care (PPC). However, implementing a PPCT into an organisation is a challenge. The objective of this study was to identify barriers and facilitators reported by healthcare professionals (HCPs) in primary, secondary or tertiary care for implementing a newly initiated multidisciplinary PPCT to bridge the gap between hospital and home. METHODS: The Measurement Instrument for Determinants of Innovations (MIDI) was used to assess responses of 71 HCPs providing PPC to one or more of the 129 children included in a pilot study of a PPCT based at a university children's hospital. The MIDI (29 items) assessed barriers and facilitators to implementing the PPCT by using a 5-point scale (completely disagree to completely agree) and additional open-ended questions. Items to which >=20% of participants responded with 'totally disagree/disagree' and >=80% responded with 'agree/totally agree' were considered as barriers and facilitators, respectively. A general inductive approach was used for open-ended questions. RESULTS: Reported barriers to implementing a PPCT were related to the HCP's own organisation (e.g., no working arrangements related to use of the intervention [PPCT] registered, other organisational changes such as merger going on). Reported facilitators were mainly related to the intervention (correctness, simplicity, observability and relevancy) and the user scale (positive outcome expectations, patient satisfaction) and only once to the organisation scale (information accessibility). Additionally, HCPs expressed the need for clarity about tasks of the PPCT and reported having made a transition from feeling threatened by the PPCT to satisfaction about the PPCT. CONCLUSION: Positive experiences with the PPCT are a major facilitator for implementing a PPCT. Tailored organisational strategies such as working arrangements by management, concrete information about the PPCT itself and the type of support provided by the PPCT should be clearly communicated to involved HCPs to increase awareness about benefits of the PPCT and ensure a successful implementation. New PPCTs need protection and resources in their initial year to develop into experienced and qualified PPCTs. PMID- 29433577 TI - Gaps and strategies in developing health research capacity: experience from the Nigeria Implementation Science Alliance. AB - BACKGROUND: Despite being disproportionately burdened by preventable diseases than more advanced countries, low- and middle-income countries (LMICs) continue to trail behind other parts of the world in the number, quality and impact of scholarly activities by their health researchers. Our strategy at the Nigerian Implementation Science Alliance (NISA) is to utilise innovative platforms that catalyse collaboration, enhance communication between different stakeholders, and promote the uptake of evidence-based interventions in improving healthcare delivery. This article reports on findings from a structured group exercise conducted at the 2016 NISA Conference to identify (1) gaps in developing research capacity and (2) potential strategies to address these gaps. METHODS: A 1-hour structured group exercise was conducted with 15 groups of 2-9 individuals (n = 94) to brainstorm gaps for implementation, strategies to address gaps and to rank their top 3 in each category. Qualitative thematic analysis was used. First, duplicate responses were merged and analyses identified emerging themes. Each of the gaps and strategies identified were categorised as falling into the purview of policy-makers, researchers, implementing partners or multiple groups. RESULTS: Participating stakeholders identified 98 gaps and 91 strategies related to increasing research capacity in Nigeria. A total of 45 gaps and an equal number of strategies were ranked; 39 gaps and 43 strategies were then analysed, from which 8 recurring themes emerged for gaps (lack of sufficient funding, poor research focus in education, inadequate mentorship and training, inadequate research infrastructure, lack of collaboration between researchers, research policy dissonance, lack of motivation for research, lack of leadership buy-in for research) and 7 themes emerged for strategies (increased funding for research, improved research education, improved mentorship and training, improved infrastructure for research, increased collaboration between academic/research institutions, greater engagement between researchers and policy-makers, greater leadership buy-in for research). CONCLUSIONS: The gaps and strategies identified in this study represent pathways judged to be important in increasing research and implementation science capacity in Nigeria. The inclusion of perspectives and involvement of stakeholders who play different roles in policy, research and implementation activities makes these findings comprehensive, relevant and actionable, not only in Nigeria but in other similar LMICs. PMID- 29433578 TI - Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension - study protocol for a randomized controlled trial. AB - BACKGROUND: Resistant hypertension is characterized when the blood pressure (BP) remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses, preferably including a diuretic. Identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether acting on the control of intravascular volume or sodium balance, or acting on the effects of the renin-angiotensin-aldosterone system (RAAS) on the kidney. METHODS/DESIGN: This is a randomized, open-label, clinical trial is designed to compare sequential nephron blockade and its contribution to the intravascular volume component with dual blockade of the RAAS plus bisoprolol and the importance of serum renin in maintaining BP levels. The trial has two arms: sequential nephron blockade versus dual blockade of the RAAS (with an angiotensin converting enzyme (ACE) inhibitor plus a beta-blocker) both added-on to a thiazide diuretic, a calcium-channel blocker and an angiotensin receptor-1 blocker (ARB). Sequential nephron blockade consists in a progressive increase in sodium depletion using a thiazide diuretic, an aldosterone-receptor blocker, furosemide and, finally, amiloride. On the other hand, the dual blockade of the RAAS consists of the progressive addition of an ACE inhibitor until the maximum dose and then the administration of a beta-blocker until the maximum dose. The primary outcomes will be reductions in the systolic BP, diastolic BP, mean BP and pulse pressure (PP) after 20 weeks of treatment. The secondary outcomes will evaluate treatment safety and tolerability, biochemical changes, evaluation of renal function and recognition of hypotension (ambulatory BP monitoring (ABPM)). The sample size was calculated assuming an alpha error of 5% to reject the null hypothesis with a statistical power of 80% giving a total of 40 individuals per group. DISCUSSION: In recent years, the cost of resistant hypertension (RH) treatment has increased. Thus, identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of intravascular volume or sodium balance, or by acting on the effects of the RAAS on the kidney. TRIAL REGISTRATION: Sequential Nephron Blockade vs. Dual Blockade Renin-angiotensin System + Bisoprolol in Resistant Arterial Hypertension (ResHypOT). ClinicalTrials.gov, ID: NCT02832973 . Registered on 14 July 2016. First received: 12 June 2016. Last updated: 18 July 2016. PMID- 29433579 TI - The role of fibrinolysis inhibition in engineered vascular networks derived from endothelial cells and adipose-derived stem cells. AB - BACKGROUND: Co-cultures of endothelial cells with mesenchymal stem cells currently represent one of the most promising approaches in providing oxygen and nutrient supply for microvascular tissue engineering. Still, to translate this model into clinics several in vitro parameters including growth medium and scaffold degradation need to be fine-tuned. METHODS: We recently described the co culture of adipose-derived stem cells with endothelial cells in fibrin, resulting in capillary formation in vitro as well as their perfusion in vivo. Here, we aimed to further characterise microvascular tube formation in fibrin by determining the role of scaffold degradation, thrombin concentration and culture conditions on vascularisation. RESULTS: We observed that inhibition of cell mediated fibrin degradation by the commonly used inhibitor aprotinin resulted in impaired vascular network formation. Aprotinin had no effect on laminin and collagen type IV deposition or formation of tube-like structures in scaffold-free co-culture, indicating that poor vascularisation of fibrin clots is primarily caused by inhibition of plasminogen-driven fibrinolysis. Co-culture in plasminogen- and factor XIII-depleted fibrin did not result in different vascular network density compared to controls. Furthermore, we demonstrate that thrombin negatively affects vascular network density at high concentrations. However, only transient activation of incorporated endothelial cells by thrombin could be observed, thus excluding a long-term inflammatory response in tissue-engineered micro-capillaries. Finally, we show that vascularisation of fibrin scaffolds in basal medium is undermined because of increased fibrinolytic activity leading to scaffold destabilisation without aprotinin. CONCLUSIONS: Taken together, our data reveal a critical role of fibrinolysis inhibition in in vitro cell-mediated vascularisation of fibrin scaffolds. PMID- 29433581 TI - Modification in aortic arch replacement surgery. AB - OBJECTIVE: We modified the conventional aortic arch replacement procedure to avoid circulation arrest and a prolonged extracorporeal circulation time, especially in cases of acute aortic dissection. We herein present our experience with a modified branch-first approach to acute aortic dissection, with anastomosis of the supra aortic vessels prior to commencing cardiopulmonary bypass. METHODS: Since 2012, 41 patients (aortic dissection, 36; arch aneurysm, 5) have undergone the modified procedure. Procedurally, the implanted graft was used as a landing zone for second-stage endovascular stent-graft deployment intended to manage the residual descending dissection. Antegrade and retrograde systemic perfusion was instituted during cardioplegic arrest. The brain was actively perfused via the graft throughout the procedure. RESULTS: Arch replacement surgery could generally be completed within approximately 4 h. During a 2-year period of aortic dissection or arch aneurysm treatment, only four anastomoses were required during the first stage of operation: two in the aorta, and one each in the innominate and left common carotid arteries. No patient died of surgical causes, and no stent grafts were deployed into the false lumen, a characteristic of procedures using traditionally antegrade deployment. CONCLUSION: We recommend that our procedure for acute aortic dissection be performed in two stages (graft replacement first and stent graft deployment second), particularly for patients underwent preoperative hypotesion. If malperfusion syndrome still exists after graft replacement, stent graft should be deployed in one stage. The arch aneurysm can be treated in one stage because there is no concern about false lumen deployment. PMID- 29433580 TI - Dietary patterns and physical activity in the metabolically (un)healthy obese: the Dutch Lifelines cohort study. AB - BACKGROUND: Diversity in the reported prevalence of metabolically healthy obesity (MHO), suggests that modifiable factors may be at play. We evaluated differences in dietary patterns and physical activity between MHO and metabolically unhealthy obesity (MUO). METHODS: Cross-sectional data of 9270 obese individuals (30-69 years) of the Lifelines Cohort Study was used. MHO was defined as obesity and no metabolic syndrome risk factors and no cardiovascular disease history. MUO was defined as obesity and >=2 metabolic syndrome risk factors. Sex-specific associations of dietary patterns (identified by principal component analysis) and physical activity with MHO were assessed by multivariable logistic regression (reference group: MUO). Analyses were adjusted for multiple covariates. RESULTS: Among 3442 men and 5828 women, 10.2% and 24.4% had MHO and 56.9% and 35.3% MUO, respectively. We generated four obesity-specific dietary patterns. Two were related to MHO, and in women only. In the highest quartile (Q) of 'bread, potatoes and sweet snacks' pattern, odds ratio (OR) (95% CI) for MHO was 0.52 (0.39-0.70). For the healthier pattern 'fruit, vegetables and fish', an OR of 1.36 (1.09-1.71) in Q3 and 1.55 (1.21-1.97) in Q4 was found for MHO. For physical activity, there was a positive association between moderate physical activity and vigorous physical activity in the highest tertile and MHO in women and men, respectively (OR 1.19 (1.01-1.41) and OR 2.02 (1.50-2.71)). CONCLUSION: The healthier diet -characterized by 'fruit, vegetables and fish'- and moderate physical activity in women, and vigorous physical activity in men may be related to MHO. The (refined) carbohydrate-rich 'bread, potatoes and sweet snacks' dietary pattern was found to counteract MHO in women. PMID- 29433582 TI - The frequency of Klebsiella pneumonia encoding genes for CTX-M, TEM-1 and SHV-1 extended-spectrum beta lactamases enzymes isolated from urinary tract infection. AB - BACKGROUND: The extended- spectrum beta-lactamase producing bacteria are widely spread worldwide. The productions of these enzymes cause bacterial resistance to a wide range of antibiotics. The aim of this study was to investigated the frequency of K. pneumonia encoding genes for CTX-M, TEM-1 and SHV-1 extended spectrum beta lactamases enzymes isolated from urinary tract infection. METHODS: This study is cross-sectional study. All K. pneumonia isolates from urine samples, which had grown on media culture more than 105 were delivered to the medical microbiology laboratory. K. pneumonia susceptibility of 198 samples were confirmed by disk diffusion. The gene frequency of genes was determined using PCR, and analyzed using SPSS version 21 software. FINDING: Most of the K. pneumonia isolated from urine producing beta-lactamase were resistant to cotrimoxazole (53.2%) followed by cefotaxime (50%), ceftazidime, ceftriaxone (40.3%), nalidixic acid (17.8%), amikacin and imipenem (1.6%) and meropenem (0%) respectively. Out of the 198 confirmed isolates of K. pneumonia, 62 cases (31.3%) have the gene phenotype of broad spectrum beta-lactamase enzymes and highest frequency of gene phenotype was related to the SHV-1 gene (85.5%). Then in the terms of abundance from highest to lowest CTXM-3 (56.5%), CTXM-1 (27.4%), TEM-1 (16.1%) and CTXM-2 (8.1%), were respectively. CONCLUSION: This study showed that K. pneumonia isolated from urine producing beta-lactamase were resistance to a wide range of antibiotics. Due to the increasing resistance of most antibiotics, control and supervision in the use of antibiotics and identification of broad spectrum beta-lactamase enzymes by phenotypic methods appears to be essential. PMID- 29433584 TI - Ipilimumab induced digital vasculitis. AB - BACKGROUND: Immune check point inhibitors (ICIs) have emerged as a new therapeutic paradigm for a variety of malignancies including metastatic melanoma. As the use of ICIs expand, immune-mediated adverse events are becoming a common occurrence. CASE PRESENTATION: We describe the first reported patient with small vessel vasculitis, manifested by digital ischemia, following treatment with high dose Ipilimumab for resected stage IIIB/C melanoma. This patient received high dose steroids, five-day intravenous (IV) Epoprostenol protocol, botulinum toxin injections, and Rituximab 375 mg/m2 weekly for four cycles. With this treatment regimen, the digital ischemia did not progress proximally, but she did require multiple distal digit amputations about six months after the onset of her symptoms. CONCLUSIONS: Prompt identification and management of immune related adverse events (IRAEs) are critical to optimal patient management. This patient's vasculitis did not reverse, but was likely halted and stabilized with multiple immunosuppressive medications. PMID- 29433583 TI - Mid-term survivorship of cruciate-retaining versus posterior-stabilized total knee arthroplasty using modular mini-keel tibial implants. AB - BACKGROUND: Reports of diverse outcomes in modular mini-keel tibial componentry for total knee arthroplasty (TKA) have raised concerns about early aseptic loosening. Cruciate-retaining (CR) prostheses, using mini-keel implants, have yet to be reported and compared to posterior-stabilizing (PS) designs. METHODS: A retrospective, case-matched study of 91 consecutive TKAs (n = 46 CR; n = 45 PS prostheses), using modular mini-keel tibial componentry with a 45-mm drop down stem extension, was conducted. The Knee Society Score functional survey, radiographic analysis including alignment and periprosthetic radiolucency, TKA prosthesis longevity, and surgical complications were reported and compared between CR and PS groups. RESULTS: The Knee Society Score at 5-year follow-up averaged 81.67 +/- 11.97 and 80.12 +/- 14.16 in the CR and PS groups, respectively (p = 0.29). The femorotibial angle averaged 5.85 degrees +/- 2.62 degrees and 5.85 degrees +/- 3.27 degrees valgus in the CR and PS groups, respectively (p = 0.60). The average tibial component angle was 0.46 degrees +/- 1.6 degrees and 0.61 degrees +/- 1.3 degrees varus in the CR and PS groups, respectively (p = 0.30); posterior inclination averaged 2.28 degrees +/- 2.36 degrees and 1.93 degrees +/- 2.72 degrees in the CR and PS groups, respectively (p = 0.51). Radiolucency was noted in 17 zones of the CR group and in 9 zones of the PS group (p = 0.24). Three TKAs required further surgery: one locking plate fixation for a periprosthetic tibial fracture (PS group) and two revision TKAs (one CR infection and one PS fracture). CONCLUSION: Modular mini keel tibial components showed good reliability and results with both CR and PS prostheses in minimally invasive surgery TKA. PMID- 29433585 TI - Characterization and validation of potential therapeutic targets based on the molecular signature of patient-derived xenografts in gastric cancer. AB - BACKGROUND: Patient-derived xenograft (PDX) models with definite molecular signature are attractive preclinical models for development of novel targeted drugs. Here, we profiled and explored potential therapeutic targets based on characterized PDX models for advanced gastric cancer (AGC). METHODS: The genomic variation and molecular profile of 50 PDX models from AGC patients were analyzed by targeted next-generation sequencing, in situ hybridization, and immunohistochemistry. The antitumor activities of several targeted drugs were investigated in the PDX models. Furthermore, response biomarkers were explored. RESULTS: Each PDX model had individual histopathological and molecular features, and recurrent alterations in the MAPK, ErbB, VEGF, mTOR, and cell cycle signaling pathways were major events in these PDX models. Several potential drug targets, such as EGFR, MET, and CCNE1, were selected and validated in this study. Volitinib demonstrated strong antitumor activity in PDX models with MET and phosphorylated MET (pMET) overexpression. The EGFR monoclonal antibodies BK011 and cetuximab inhibited tumor growth in a PDX model with EGFR amplification. Afatinib inhibited tumor growth in the PDX models with EGFR amplification, EGFR overexpression, or HER2 amplification. Apatinib was more sensitive in the PDX models with high microvessel density. The CDK1/2/9 inhibitor AZD5438 had superior anti-tumor activity in two models with higher copy number of CCNE1. CONCLUSIONS: PDX models with defined molecular signature are useful for preclinical studies with targeted drugs, and the results should be validated in larger studies with PDX models or in clinical trials. PMID- 29433586 TI - A case report of clonidine induced syncope: a review of central actions of an old cardiovascular drug. AB - BACKGROUND: Clonidine is an imidazoline sympatholytic, acting on both alpha2 adrenergic and imidazoline receptors in the brainstem to induce antihypertensive and negative chronotropic effects in the vasculature and heart respectively. CASE PRESENTATION: A 69-year-old gentleman with hypertension presented to the emergency department after multiple syncopal episodes over the past 12 months. Electrocardiogram demonstrated sinus bradycardia with a heart rate of 42 beats per minute. It was hypothesized that the antihypertensive agent clonidine was responsible for inducing symptomatic bradycardia. Clonidine was thus gradually tapered and then discontinued over five days restoring normal sinus rhythm rates while avoiding hypertensive rebound related to sympathetic surge. His heart rate and blood pressure remained within normal limits after the clonidine taper and subsequent adjustments to his other hypertensive medications and he was discharged. CONCLUSIONS: While clonidine has fallen out of favor for its indication as an antihypertensive, it remains a viable option for the use of opioid withdrawal, chronic pain, and smoking cessation, necessitating the appropriate clinical and pharmacological competencies for a physician to prescribe. A discussion of the clinical effects of clonidine brainstem receptor activation follows. PMID- 29433587 TI - Vitamin D status and intake of lactating Inuit women living in the Canadian Arctic. AB - OBJECTIVE: To determine the prevalence and correlates of healthy vitamin D status in lactating Inuit women living in remote regions of the Arctic. DESIGN: Cross sectional. SETTING: Households were selected randomly in thirty-six communities of Nunavut, Nunatsiavut and Inuvialuit Settlement Region. Dietary intake was assessed using a 24 h recall and an FFQ. Anthropometric measurements, household living conditions, supplement use and health status were assessed. In fasting samples, serum 25-hydroxyvitaimn D (25(OH)D) was measured using a chemiluminescent assay (LIAISON; Diasorin Inc.). SUBJECTS: Lactating Inuit women participating in the 2007-2008 International Polar Year Inuit Health Survey conducted in the months of August to October. RESULTS: Among participants (n 34), 8.8, 26.5 and 50.0 % had 25(OH)D concentrations at or above 75, 50 and 40 nmol/l, respectively. More than one-third of participants did not consume traditional foods during the previous day and only 11.3 % of total energy intake was derived from traditional foods. Only 14.7 % of the sample consumed the daily number of milk servings recommended by Canada's Food Guide (two servings) for First Nations, Inuit and Metis. Using multivariable logistic regression to examine 25(OH)D>=40 nmol/l, only higher body fat was inversely correlated with 25(OH)D concentration. CONCLUSIONS: The present study is the first to assess simultaneously vitamin D status and other known factors that affect it among lactating Inuit women living in remote communities in the Arctic. Healthy maternal vitamin D status was observed in 25 % of participants during the late summer and early autumn. This requires further assessment in a larger sample spanning more seasons. PMID- 29433588 TI - Ontogeny of behavioral traits in commercial sows. AB - As the number of gestating sows reared in group housing increases, a better understanding of behavioral traits needed to negotiate these more complex social interactions promises to increase animal welfare and productivity. However, little is known about different behavioral strategies or coping styles in sows, and even less is understood about their ontogeny. To study the development of coping styles in adult gestating sows, 36 sows from the same sire line and same commercial maternal genetics were followed from birth through their second parity. Each animal was observed in a battery of stress-related behavioral tests at 5 weeks, and 3 months of age as well as 24 h postpartum as a parity 1 sow, and during introduction to subsequent gestation period in group housing. The tests at different ages included response to handling, open field exploration, human interaction, litter handling and social interactions with conspecifics. Many of the observed behaviors were correlated during the same period of the animal's life and provided the motivation for a principal component analysis by age. Using principal component analysis, multiple traits were determined at each age point; at 5 weeks old: active, non-exploratory and cautious explained 82.5% of the variance; at 3 months of age: active, non-exploratory and low fear of humans explained 87.7% of the variance; and as primiparous sows: active, aggressive/dominant and submissive explained 82.0% of the variance. Several individual juvenile behaviors were associated with adult behavioral traits. For instance, the response to handling at 5 weeks was significantly predictive (beta=0.4; P<0.05) of the aggressive/dominant trait of parity 1 sows. Taken together results presented here suggest that early behavioral responses of prepuberal gilts during specific instances of elevated environmental or social stress can predict future behavioral response as gestating sows. PMID- 29433589 TI - Cassava whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) in East African farming landscapes: a review of the factors determining abundance. AB - Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) is a pest species complex that causes widespread damage to cassava, a staple food crop for millions of households in East Africa. Species in the complex cause direct feeding damage to cassava and are the vectors of multiple plant viruses. Whilst significant work has gone into developing virus-resistant cassava cultivars, there has been little research effort aimed at understanding the ecology of these insect vectors. Here we assess critically the knowledge base relating to factors that may lead to high population densities of sub-Saharan African (SSA) B. tabaci species in cassava production landscapes of East Africa. We focus first on empirical studies that have examined biotic or abiotic factors that may lead to high populations. We then identify knowledge gaps that need to be filled to deliver sustainable management solutions. We found that whilst many hypotheses have been put forward to explain the increases in abundance witnessed since the early 1990s, there are little published data and these tend to have been collected in a piecemeal manner. The most critical knowledge gaps identified were: (i) understanding how cassava cultivars and alternative host plants impact population dynamics and natural enemies; (ii) the impact of natural enemies in terms of reducing the frequency of outbreaks and (iii) the use and management of insecticides to delay the development of resistance. In addition, there are several fundamental methodologies that need to be developed and deployed in East Africa to address some of the more challenging knowledge gaps. PMID- 29433590 TI - The role of nutritional labelling and signposting from a European perspective. AB - The past half-century has been characterised by major technological developments and massive societal change, which have profoundly changed how food is produced, processed, sold and consumed. These days we are faced with a huge choice of pre packaged foods when we shop in modern supermarkets and we can buy seasonal food all year round, in and out of season. For decades now, the need to guide choice has been recognised, and retailers and many manufacturers have provided increasing amounts of on-pack information and signposting, and more recently UK retailers have led the way in championing front-of-pack information provision, to supplement the standard back-of-pack nutrient composition table. From a European perspective, the present paper summarises developments in nutrition labelling information and signposting, the legislation that controls on-pack declarations, and research conducted to assess whether or not the information is used, understood and supports healthier choices. It also considers whether more could be done to influence behaviour change positively, giving examples of approaches identified in the research. PMID- 29433591 TI - Paediatric abstract publication rates for the American Society of Echocardiography Meeting. AB - BACKGROUND: Abstract presentations of scientific information at meetings are important for broadcasting new information. Publication of these studies should be the final goal, but minimal data exist documenting publication rates, especially for paediatric sub-speciality meetings. The goal of this study was to document the manuscript publication rate for paediatric cardiac echocardiography abstracts and to determine whether there were differences between abstracts that were published versus not published. METHODS: Paediatric cardiac echocardiography abstracts presented from 2007 to 2011 at the American Society of Echocardiography Meetings were reviewed. Characteristics of the abstracts were noted. A Medline/Pubmed search was performed using keywords, first author, and senior author criteria to determine publication. Fisher's exact tests or chi2 tests were used for analysis. RESULTS: A total of 194 abstracts were reviewed. In all, 27 abstracts were oral presentations and 167 were poster presentations. A total of 124 abstracts were prospective studies and 70 were retrospective studies; 11 abstracts were basic science studies and 183 were clinical studies. Altogether, 25 abstracts dealt with three-dimensional echocardiography, 15 with fetal echocardiography, 56 with deformation analysis, 79 with standard transthoracic echocardiography, and 19 were in the other category. A total of 73 abstracts were subsequently published - with a 37.6% publication rate - 2.1+/-1.7 years after initial presentation. There were no significant differences in publication rates based on the above-noted variables. CONCLUSION: A paediatric cardiac echocardiography abstract publication rate of 37.6% is comparable to previous published publication rates for other meetings. No differences in variables analysed were noted between published versus unpublished abstracts. PMID- 29433592 TI - Ethnic cartography and politics in Vienna, 1918-1945. AB - In Vienna, the close of the First World War and the period of the peace negotiations in Paris saw an enormous boom of ethnic-geographic research approaches and ethnic map-making. This process continued with the appointment of the Viennese geographer Hugo Hassinger (1877-1952) to the chair of human geography at the University of Vienna in 1931 and intensified with the establishment of the South East German Research Association and the National Socialist takeover in March 1938. But did the initiatives to create ethnic maps originate with politicians and authorities, or did they come from the scientists themselves? This article argues that scientists embarked upon ethnic geographies on their own initiative. Although political institutions used scientists and their resources for their own, political ends (ethnographic maps served as an important source for the National Socialists in their operations for ethnic consolidation), scientists also mobilized resources from the political sphere for career and disciplinary purposes. PMID- 29433593 TI - Education, practical training and professional development for public health practitioners: a scoping review of the literature and insights for sustainable food system capacity-building. AB - OBJECTIVE: Noting the upstream positioning of sustainable food systems (SFS) to multiple global crises, the present review described examples of emerging and promising practices to support SFS-oriented education, practical training (PT) and continuing professional development (CPD) among trainees and public health practitioners (PHP). A secondary objective was to compile the evidence into practical considerations for educators, supervising practitioners and professional associations. DESIGN: A scoping review of the literature published between 2007 and 2017 was conducted in May 2017 using four databases: CINAHL, MEDLINE, Scopus and HSSA, along with bibliography hand-searching and expert consultation. Articles were screened for relevance and specificity by independent raters. RESULTS: Nineteen articles were included for analysis. Two-thirds of the articles related to dietitians and public health nutritionists. Emerging practices included curriculum-based considerations, incorporation of 'sustainability' within professional competencies and self-reflection related to SFS. Descriptions of SFS-related education, PT and CPD practices appeared largely in the literature from developed countries. Articles converged on the need for ecosystems, food systems and sustainability considerations within and across practice to support current and future practitioners. CONCLUSIONS: There is growing interest in SFS but guidance to support educators and preceptors is lacking. Updates to dietary guidelines to reflect issues of sustainability are a timely prompt to examine the education, training and development needs of trainees and PHP. Practical examples of emerging practices can empower PHP to promote SFS in all areas of practice. More research is needed to address identified gaps in the literature and to improve SFS-specific education, PT and CPD. PMID- 29433594 TI - The effectiveness of self-regulation in limiting the advertising of unhealthy foods and beverages on children's preferred websites in Canada. AB - OBJECTIVE: To assess the effectiveness of the self-regulatory Canadian Children's Food and Beverage Advertising Initiative (CAI) in limiting advertising of unhealthy foods and beverages on children's preferred websites in Canada.Design/Setting/SubjectsSyndicated Internet advertising exposure data were used to identify the ten most popular websites for children (aged 2-11 years) and determine the frequency of food/beverage banner and pop-up ads on these websites from June 2015 to May 2016. Nutrition information for advertised products was collected and their nutrient content per 100 g was calculated. Nutritional quality of all food/beverage ads was assessed using the Pan American Health Organization (PAHO) and UK Nutrient Profile Models (NPM). Nutritional quality of CAI and non-CAI company ads was compared using chi 2 analyses and independent t tests. RESULTS: About 54 million food/beverage ads were viewed on children's preferred websites from June 2015 to May 2016. Most (93.4 %) product ads were categorized as excessive in fat, Na or free sugars as per the PAHO NPM and 73.8 % were deemed less healthy according to the UK NPM. CAI-company ads were 2.2 times more likely (OR; 99 % CI) to be excessive in at least one nutrient (2.2; 2.1, 2.2, P<0.001) and 2.5 times more likely to be deemed less healthy (2.5; 2.5, 2.5, P<0.001) than non-CAI ads. On average, CAI-company product ads also contained (mean difference; 99 % CI) more energy (141; 141.1, 141.4 kcal, P<0.001, r=0.55), sugar (18.2; 18.2, 18.2 g, P<0.001, r=0.68) and Na (70.0; 69.7, 70.0 mg, P<0.001, r=0.23) per 100 g serving than non-CAI ads. CONCLUSIONS: The CAI is not limiting unhealthy food and beverage advertising on children's preferred websites in Canada. Mandatory regulations are needed. PMID- 29433595 TI - Management practices associated with reproductive performance in Holstein cows on large commercial dairy farms. AB - As a result of the increase in herd size and the intensification of production, the complexity of reproductive management has been growing in dairy herds. The aim of our study was to examine the associations of management practices and reproductive performance in Holstein cows on large commercial dairy farms. Management practices applied to cows were surveyed between 22 May and 6 November 2015 in 34 large Holstein-Friesian dairy herds in Hungary. Individual data of 23 784 cows that calved between 1 January 2014 and 31 December 2014 in the surveyed herds were gathered. Associations between the management practices and the reproductive parameters were analyzed by mixed effects models. Regarding heat abatement we found that ventilation with sprinklers was associated with the shortest breeding interval (P0.05) results to lack of heat stress protection. It was also revealed, that lack of a well-established voluntary waiting period (VWP) or a VWP shorter than 50 days was associated with less days to first service (P<0.01), shorter breeding interval (P<0.01) and calving to conception interval (P<0.05), as well as higher odds of carrying a calf by 200 days in milk (P<0.01) compared with those using a VWP of at least 50 days. Those farms that applied transrectal ultrasonography were more likely to use ventilation with sprinklers (P<0.05), hormonal synchronization (P<0.01) and to perform early pregnancy diagnosis followed by pregnancy recheck (P<0.05). The application of transrectal ultrasonography with one of the aforementioned practices was associated with reduced days to first service (P<0.05), shorter breeding interval (P<0.05) and higher odds of pregnancy at 200 days in milk (P<0.05). Our study highlights the management practices most closely related to improved reproductive performance, which are, therefore, suggested to be applied on dairy farms, considering the local circumstances of the individual farms. PMID- 29433596 TI - A Review of State Public Health Emergency Declarations in Peru: 2014-2016. AB - Peru has different legal mechanisms of emergency, one of which is the Public Health Emergency that is applicable when: there is high-risk for, or the existence of an outbreak, epidemic, or pandemic; the occurrence of cases of a disease classified as eliminated or eradicated; the occurrence of emerging or re emerging infectious diseases with high epidemic potential; the occurrence of rapid disseminated epidemics that simultaneously affect more than one department; as well as the existence of an event that affects the continuity of health services. From July 2014 to December 2016, 23 Public Health Emergencies were declared, out of which 57% were in the high-risk or existence of epidemics, 30% were due to some natural or anthropic events that generate a sudden decrease in the operative capacity of health services, and 13% were due to the existence of a rapid spreading epidemic that could affect more than one department in the country. The risk or occurrence of epidemiological outbreaks, mainly of Dengue, was the main cause of emergency declaration. One-hundred and forty million US dollars were allocated to implement the action plans that were part of the declaration, of which 72% was used to keep the operational capacity of health services and 28% to vector and epidemiological control measures. Bambaren C , Alatrista MdS . A review of state public health emergency declarations in Peru: 2014-2016. Prehosp Disaster Med. 2018;33(2):197-200. PMID- 29433597 TI - Laboratory Abnormalities in Polyneuropathy and Electrophysiological Correlations. AB - To study the frequency of laboratory test abnormalities, and electrophysiological correlations, we performed a retrospective chart review of 226 patients with polyneuropathy. The frequency of laboratory test abnormalities, and correlations with electrophysiological findings were explored. Abnormal glucose handling tests were the most common findings (54%), followed by paraproteinemia (21%) and anemia (21%). The frequencies of paraproteinemia and anemia in our cohort were significantly higher than previously reported. In addition, several laboratory abnormalities correlated with electrophysiological findings of median neuropathy at the wrist, expanding current knowledge about the deleterious effects of various metabolic and hematologic derangements at this site. PMID- 29433598 TI - Early, regular breast-milk pumping may lead to early breast-milk feeding cessation. AB - OBJECTIVE: To estimate the effect of early, regular breast-milk pumping on time to breast-milk feeding (BMF) and exclusive BMF cessation, for working and non working women. DESIGN: Using the Infant Feeding Practices Survey II (IFPS II), we estimated weighted hazard ratios (HR) for the effect of regular pumping (participant defined) compared with non-regular/not pumping, reported at month 2, on both time to BMF cessation (to 12 months) and time to exclusive BMF cessation (to 6 months), using inverse probability weights to control confounding. SETTING: USA, 2005-2007. SUBJECTS: BMF (n 1624) and exclusively BMF (n 971) IFPS II participants at month 2. RESULTS: The weighted HR for time to BMF cessation was 1.62 (95 % CI 1.47, 1.78) and for time to exclusive BMF cessation was 1.14 (95 % CI 1.03, 1.25). Among non-working women, the weighted HR for time to BMF cessation was 2.05 (95 % CI 1.84, 2.28) and for time to exclusive BMF cessation was 1.10 (95 % CI 0.98, 1.22). Among working women, the weighted HR for time to BMF cessation was 0.90 (95 % CI 0.75, 1.07) and for time to exclusive BMF cessation was 1.14 (95 % CI 0.96, 1.36). CONCLUSIONS: Overall, regular pumpers were more likely to stop BMF and exclusive BMF than non-regular/non-pumpers. Non working regular pumpers were more likely than non-regular/non-pumpers to stop BMF. There was no effect among working women. Early, regular pumpers may need specialized support to maintain BMF. PMID- 29433599 TI - Knowledge of nutrition and physical activity in apparently healthy Indian adults. AB - OBJECTIVE: To assess knowledge of nutrition and physical activity; examine associations of knowledge with sociodemographic and anthropometric parameters; and evaluate the relationship between knowledge and practice in adults. DESIGN: In a cross-sectional design, 720 adults were selected using random sampling. Data on anthropometry, body fat, diet, physical activity, and nutrition and physical activity knowledge were collected using standardized questionnaires. Tertiles were used to categorize nutrition knowledge (NK) and physical activity knowledge (PK).SettingsSubjects selected through routine health checks from hospitals, housing societies and residential areas. SUBJECTS: A total of 720 adults (361 men) aged 35-50 years participated. RESULTS: Mean age was 42.7 (sd 9.4) years and mean BMI was 25.8 (sd 5.0) kg/m2. Mean energy intake was 64 %, protein was 68 % and fat was 144 % of the RDA. Mean NK and PK scores were 10.2 (sd 2.9) and 6.5 (sd 1.7), respectively, and were similar across genders (P>0.05). Individuals with higher education exhibited significantly higher NK and PK. Individuals with high fat had significantly higher NK and PK (P<0.05) than participants with normal fat percentage. Overweight and obese individuals had significantly higher PK (P<0.05). Multivariate regression modelling indicated that NK was positively associated with dietary intakes of leafy vegetables, salads and sprouts but negatively associated with fruit intake. BMI, television and reading time were positively associated with PK, even after adjusting for sociodemographic status. CONCLUSIONS: There is a need for increased efforts towards developing health education programmes focusing on transforming nutrition and physical activity knowledge into practice and adherence to guidelines. PMID- 29433600 TI - Development and preliminary testing of the Brief Developmental Assessment: an early recognition tool for children with heart disease. AB - : Introduction Neurodevelopmental abnormalities are common in children with CHD and are the highest-priority concerns for parents and professionals following cardiac surgery in childhood. There is no additional routine monitoring of development for children with CHD in the United Kingdom; hence, neurodevelopmental concerns may be detected late, precluding early referral and intervention. METHODS: An early recognition tool - the "Brief Developmental Assessment" - was developed using quality improvement methodology involving several iterations and rounds of pilot testing. Our requirements were for a tool covering important developmental domains and practicable for use within inpatient and outpatient settings by paediatric cardiac health professionals who are non developmental specialists, without specialised equipment and which involved direct observation, as well as parental report. RESULTS: Items were included in the tool based on existing developmental measures, covering the domains of gross and fine motor skills, daily living skills, communication, socialisation, and general understanding. Items were developed for five age bands - 0-16 weeks, 17 34 weeks, 35-60 weeks, 15 months-2.9 years, and 3-4.9 years - and the final versions included a traffic light scoring system for identifying children with possible delay in any or all domains. Preliminary testing indicated excellent inter-rater reliability, an ability to detect children with a diagnosis known to be associated with developmental delay, and largely acceptable internal reliability. CONCLUSION: We report the evolution and preliminary testing of an early recognition tool for assessing the development of children with heart disease; this was encouraging and sufficiently good to support further validation in a larger study. PMID- 29433601 TI - Successful resection of giant right atrial appendage aneurysm to cure chaotic atrial tachycardia in a child: case report. AB - Right atrial appendage aneurysm is an extremely rare congenital malformation with unknown aetiology. The most common potential complication is atrial arrhythmias including atrial flutter, atrial fibrillation, and atrial tachycardia. These arrhythmias are usually refractory to medication therapy. Radiofrequency catheter ablation has poor efficacy with low success rate and high recurrence rate. Aneurysm resection is the recommended treatment with satisfactory efficacy. We report a child with chaotic atrial tachycardia due to giant right atrial appendage aneurysm who was successfully treated by aneurysm resection. PMID- 29433603 TI - Is Distance to the Nearest Registered Public Automated Defibrillator Associated with the Probability of Bystander Shock for Victims of Out-of-Hospital Cardiac Arrest? AB - : Introduction Rapid access to defibrillation is a key element in the management of out-of-hospital cardiac arrests (OHCAs). Public automated external defibrillators (PAEDs) are becoming increasingly available, but little information exists regarding the relation between the proximity to the arrest and their usage in urban areas. METHODS: This study is a retrospective, observational, cross-sectional analysis of non-traumatic OHCA during a 24-month period in the greater Montreal area (Quebec, Canada). Using logistic regression, bystander shock odds are described with regards to distance from the OHCA scene to the nearest PAED, adjusted for prehospital care arrival delay and time of day, and stratifying for type of location. RESULTS: Out of a total of 2,443 OHCA victims identified, 77 (3%) received bystander PAED shock, 622 (26%) occurred out of-home, and 743 (30%) occurred during business hours. When controlling for time (business hours versus other hours) and minimum response delay for prehospital care arrival, a marginal negative association was found between bystander shock and distance to the nearest PAED in logged meters (aOR=0.80; CI, 0.64-0.99) for out-of-home cardiac arrests. No significant association was found between distance and bystander shock for at-home arrests. Out-of-home victims had significantly higher odds of receiving bystander shock up to 175 meters of distance to a PAED inclusively (aOR=2.52; CI, 1.07-5.89). CONCLUSION: For out-of home cardiac arrests, proximity to a PAED was associated with bystander shock in the greater Montreal area. Strategies aiming to increase accessibility and use of these life-saving devices could further expand this advantage by assisting bystanders in rapidly locating nearby PAEDs. Neves Briard J , de Montigny L , Ross D , de Champlain F , Segal E . Is distance to the nearest registered public automated defibrillator associated with the probability of bystander shock for victims of out-of-hospital cardiac arrest? Prehosp Disaster Med. 2018;33(2):153 159. PMID- 29433604 TI - Unchaining people with mental disorders: medication is not the solution. AB - Chaining of people with mental disorders, and their incarceration and abuse in prisons or mental hospitals, is an affront to psychiatry and humanity. Although mental healthcare always needs attention to cultural and social contexts, this must never be at the cost of allowing human rights violations to go unchallenged. A rights-based approach must enforce well-established international human rights conventions, and scale-up comprehensive community services around the needs and preferences of people affected by mental disorders. Declaration of interest None. PMID- 29433605 TI - Chaining, culture and values: ethical issues in research in middle- and low income countries. AB - A paper in this month's British Journal of Psychiatry reports on research from Ghana where some participants were exposed to chaining, which raises ethical concerns. Strict boundaries need to exist between researchers and cruel, inhuman or degrading treatment. Nevertheless, there may be things we can learn from other cultures about our own values. Declaration of interest None. PMID- 29433606 TI - Routine outcome measurement: recovery, quality of life and co-production. AB - Patient-reported outcome measures (PROMs) are self-rated, but may not take in other aspects of the patient's perspective, such as the inclusion of domains that reflect service-user priorities. The clinician's view still has priority, although this situation has shifted in recent years. The Recovering Quality of Life (ReQoL) offers an advance in this area. Declaration of interest None. PMID- 29433607 TI - Developmental coordination disorder, psychopathology and IQ in 22q11.2 deletion syndrome. AB - BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of neurodevelopmental disorder, however, the links between developmental coordination disorder (DCD), intellectual function and psychiatric disorder remain unexplored. Aims To establish the prevalence of indicative DCD in children with 22q11.2DS and examine associations with IQ, neurocognition and psychopathology. METHOD: Neurocognitive assessments and psychiatric interviews of 70 children with 22q11.2DS (mean age 11.2, s.d. = 2.2) and 32 control siblings (mean age 11.5, s.d. = 2.1) were carried out in their homes. Nine children with 22q11.2DS and indicative DCD were subsequently assessed in an occupational therapy clinic. RESULTS: Indicative DCD was found in 57 (81.4%) children with 22q11.2DS compared with 2 (6.3%) control siblings (odds ratio (OR) = 36.7, P < 0.001). Eight of nine (89%) children with indicative DCD met DSM-5 criteria for DCD. Poorer coordination was associated with increased numbers of anxiety, (P < 0.001), attention-deficit hyperactivity disorder (ADHD) (P < 0.001) and autism spectrum disorder (ASD) symptoms (P < 0.001) in children with 22q11.2DS. Furthermore, 100% of children with 22q11.2DS and ADHD had indicative DCD (20 of 20), as did 90% of children with anxiety disorder (17 of 19) and 96% of children who screened positive for ASD (22 of 23). The Developmental Coordination Disorder Questionnaire score was related to sustained attention (P = 0.006), even after history of epileptic fits (P = 0.006) and heart problems (P = 0.009) was taken into account. CONCLUSIONS: Clinicians should be aware of the high risk of coordination difficulties in children with 22q11.2DS and its association with risk of mental disorder and specific neurocognitive deficits. Declaration of interest None. PMID- 29433608 TI - Brain-stem serotonin transporter availability in maternal uniparental disomy and deletion Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is a rare condition because of the deletion of paternal chromosomal material (del PWS), or a maternal uniparental disomy (mUPD PWS), at 15q11-13. Affective psychosis is more prevalent in mUPD PWS. We investigated the relationship between the two PWS genetic variants and brain-stem serotonin transporter (5-HTT) availability in adult humans. Mean brain-stem 5-HTT availability determined by [123I]-beta-CIT single photon emission tomography was lower in eight adults with mUPD PWS compared with nine adults with del PWS (mean difference -0.93, t = -2.85, P = 0.014). Our findings confirm an association between PWS genotype and brain-stem 5-HTT availability, implicating a maternally expressed/paternally imprinted gene, that is likely to account for the difference in psychiatric phenotypes between the PWS variants. Declaration of interest None. PMID- 29433609 TI - Undetected post-traumatic stress disorder in secondary-care mental health services: systematic review. AB - BACKGROUND: Comorbid post-traumatic stress disorder (PTSD) is associated with poorer outcomes of other disorders, but is treatable. Aims To estimate the frequency of clinically undetected PTSD in secondary care. METHOD: A systematic review of studies that screened for PTSD and reported on PTSD documentation in clinical records. Frequency of undetected PTSD was estimated, and reasons for heterogeneity explored. RESULTS: The median proportion of participants with undetected PTSD (29 studies) was 28.6% (interquartile range 18.2-38.6%). There was substantial heterogeneity, with studies conducted in the USA and those with the highest proportions of in-patients and patients with psychotic disorder reporting higher frequencies of undetected PTSD. CONCLUSIONS: Undetected PTSD is common in secondary care, even if the true value is at the lower limit of the estimates reported here. Trials examining the impact of routine screening for PTSD are required to determine whether such programmes should be standard procedure for all mental health services. Declaration of interest None. PMID- 29433611 TI - Recovering Quality of Life (ReQoL): a new generic self-reported outcome measure for use with people experiencing mental health difficulties. AB - BACKGROUND: Outcome measures for mental health services need to adopt a service user recovery focus. Aims To develop and validate a 10- and 20-item self-report recovery-focused quality of life outcome measure named Recovering Quality of Life (ReQoL). METHOD: Qualitative methods for item development and initial testing, and quantitative methods for item reduction and scale construction were used. Data from >6500 service users were factor analysed and item response theory models employed to inform item selection. The measures were tested for reliability, validity and responsiveness. RESULTS: ReQoL-10 and ReQoL-20 contain positively and negatively worded items covering seven themes: activity, hope, belonging and relationships, self-perception, well-being, autonomy, and physical health. Both versions achieved acceptable internal consistency, test-retest reliability (>0.85), known-group differences, convergence with related measures, and were responsive over time (standardised response mean (SRM) > 0.4). They performed marginally better than the Short Warwick-Edinburgh Mental Well-being Scale and markedly better than the EQ-5D. CONCLUSIONS: Both versions are appropriate for measuring service-user recovery-focused quality of life outcomes. Declaration of interest M.B. and J.Co. were members of the research group that developed the Clinical Outcomes in Routine Evaluation (CORE) outcome measures. PMID- 29433610 TI - Accuracy of the Whooley questions and the Edinburgh Postnatal Depression Scale in identifying depression and other mental disorders in early pregnancy. AB - BACKGROUND: There is limited evidence on the prevalence and identification of antenatal mental disorders. Aims To investigate the prevalence of mental disorders in early pregnancy and the diagnostic accuracy of depression-screening (Whooley) questions compared with the Edinburgh Postnatal Depression Scale (EPDS), against the Structured Clinical Interview DSM-IV-TR. METHOD: Cross sectional survey of women responding to Whooley questions asked at their first antenatal appointment. Women responding positively and a random sample of women responding negatively were invited to participate. RESULTS: Population prevalence was 27% (95% CI 22-32): 11% (95% CI 8-14) depression; 15% (95% CI 11-19) anxiety disorders; 2% (95% CI 1-4) obsessive-compulsive disorder; 0.8% (95% CI 0-1) post traumatic stress disorder; 2% (95% CI 0.4-3) eating disorders; 0.3% (95% CI 0.1 1) bipolar disorder I, 0.3% (95% CI 0.1-1%) bipolar disorder II; 0.7% (95% CI 0 1) borderline personality disorder. For identification of depression, likelihood ratios were 8.2 (Whooley) and 9.8 (EPDS). Diagnostic accuracy was similar in identifying any disorder (likelihood ratios 5.8 and 6). CONCLUSIONS: Endorsement of Whooley questions in pregnancy indicates the need for a clinical assessment of diagnosis and could be implemented when maternity professionals have been appropriately trained on how to ask the questions sensitively, in settings where a clear referral and care pathway is available. Declaration of interest L.M.H. chaired the National Institute for Health and Care Excellence CG192 guidelines development group on antenatal and postnatal mental health in 2012-2014. PMID- 29433612 TI - Effect of electroconvulsive therapy on hippocampal and amygdala volumes: systematic review and meta-analysis. AB - BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for depression, although the underlying mechanisms remain unclear. Animal studies have shown that electroconvulsive shock induced neuroplastic changes in the hippocampus. Aims To summarise volumetric magnetic resonance imaging studies investigating the effects of ECT on limbic brain structures. METHOD: A systematic review and meta-analysis was conducted to assess volumetric changes of each side of the hippocampus and amygdala before and after ECT. Standardised mean difference (SMD) was calculated. RESULTS: A total of 8 studies (n = 193) were selected for our analyses. Both right and left hippocampal and amygdala volumes increased after ECT. Meta-regression analyses revealed that age, percentage of those responding and percentage of those in remission were negatively associated with volume increases in the left hippocampus. CONCLUSIONS: ECT increased brain volume in the limbic structures. The clinical relevance of volume increase needs further investigation. Declaration of interest None. PMID- 29433613 TI - Joining psychiatric care and faith healing in a prayer camp in Ghana: randomised trial. AB - BACKGROUND: Care of people with serious mental illness in prayer camps in low income countries generates human rights concerns and ethical challenges for outcome researchers. Aims To ethically evaluate joining traditional faith healing with psychiatric care including medications (Clinical trials.gov identifier NCT02593734). METHOD: Residents of a Ghana prayer camp were randomly assigned to receive either indicated medication for schizophrenia or mood disorders along with usual prayer camp activities (prayers, chain restraints and fasting) (n = 71); or the prayer camp activities alone (n = 68). Masked psychologists assessed Brief Psychiatric Rating Scale (BPRS) outcomes at 2, 4 and 6 weeks. Researchers discouraged use of chaining, but chaining decisions remained under the control of prayer camp staff. RESULTS: Total BPRS symptoms were significantly lower in the experimental group (P = 0.003, effect size -0.48). There was no significant difference in days in chains. CONCLUSIONS: Joining psychiatric and prayer camp care brought symptom benefits but, in the short-run, did not significantly reduce days spent in chains. Declaration of interest None. PMID- 29433614 TI - Hope or hype in the treatment of schizophrenia - what's the role of the physician? AB - According to the experience of people with schizophrenia, their psychiatrists' attitude towards the outcome of their illness is lacking in hope, which directly affects mutual faith in treatment. Here we discuss the scientific basis of hope and show its instrumental role in optimising the best treatment strategies for schizophrenia. Declaration of interest R.A.B has received honoraria for educational input and non-financial support from Ache; honoraria for educational input from Lundbeck; grants, honoraria for educational input and non-financial support from Janssen; all outside the submitted work. G.E.M.G. has received honoraria for educational input and non-financial support from Janssen outside the submitted work. G.M. reports support from Janssen-Cilag, outside the submitted work, and is an employee at Janssen-Cilag. S.S. has received grants and honoraria for educational input from EnVivo Pharmaceuticals, Takeda, AbbVie and Janssen Pharmaceuticals, outside the submitted work. PMID- 29433615 TI - A haplotype of the dopamine transporter gene modulates regional homogeneity, gray matter volume, and visual memory in children with attention-deficit/hyperactivity disorder. AB - BACKGROUND: The dopamine transporter gene (DAT1) and visual memory deficits have been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). This study aimed to examine whether a DAT1 haplotype affected functional and structural brain alterations in children with ADHD and whether those alterations were associated with visual memory. METHOD: We recruited a total of 37 drug-naive children with ADHD (17 with the DAT1 rs27048 (C)/rs429699 (T) haplotype and 20 without the CT haplotype) and 37 typically developing children (17 with the CT haplotype and 20 without the CT haplotype). Visual memory was assessed by the pattern recognition memory (PRM) and spatial recognition memory (SRM) tasks. We analyzed functional and structural brain architecture with regional homogeneity (ReHo) and gray matter volume (GMV). RESULTS: The CT haplotype was associated with decreased ReHo in the left superior occipital gyrus, cuneus, and precuneus; and decreased GMV in the left superior occipital gyrus, cuneus, and precuneus, and in the right angular gyrus. Significant interactions of ADHD and the CT haplotype were found in the right postcentral gyrus for ReHo and in the right supplementary motor area for GMV. For the ADHD-CT group, we found negative correlations of total correct responses in PRM and SRM and positive correlations of mean latency of correct responses in PRM with the GMV in the left superior occipital gyrus, cuneus, and precuneus. CONCLUSIONS: Our findings suggest that the DAT1-related GMV alterations in the posterior cortical regions may contribute to visual memory performance in children with ADHD. PMID- 29433616 TI - A New Method for Environmental Flow Assessment Based on Basin Geology: Application to the Ebro Basin. AB - The determination of environmental flows is one of the commonest practical actions implemented on European rivers to promote their good ecological status. In Mediterranean rivers, groundwater inflows are a decisive factor in streamflow maintenance. This work examines the relationship between the lithological composition of the Ebro basin (Spain) and dry-season flows, in order to establish a model that can assist in the calculation of environmental flow rates. The explanatory variable used in the proposed model is easy to calculate and is sufficiently powerful to take into account all the required characteristics. The model has a high coefficient of determination, indicating that it is accurate for the intended purpose. The advantage of this method is that it requires very little data and provides a simple estimate of environmental flow. The results of this research also contribute to knowledge of the variables that influence low flow periods on rivers in the Ebro basin. PMID- 29433617 TI - Centrate Pretreatment Process (CPT) Sidestream Deammonification Startup- Operational Challenge. AB - In May 2015, Alexandria Renew Enterprises (AlexRenew), a 204,412 m3/d advanced resource recovery facility, started up a centrate pretreatment (CPT) system. This system utilizes the sidestream deammonification process (DEMON(r)) to remove nitrogen in the centrate produced from dewatering anaerobically-digested sludge. During the startup period, the ammonia and total nitrogen removal rates averaged 89 percent and 78 percent, respectively. The CPT system startup encountered a number of operational issues including centrate quality, nitrite control, excess polymer and micronutrient deficiency etc. These challenges were identified and addressed primarily through operational and process control measures. The CPT process reached 100% plant centrate production (0.5 kg N/m3/d) after 18 months of startup period. This paper summarized major challenges during the startup phase of the CPT system from an operational standpoint, documented our approaches and learnings to tackle each problem and shed some light on future improvement. PMID- 29433620 TI - Effects of various glutamine concentrations on gene expression and steviol glycosides accumulation in Stevia rebaudiana Bertoni. AB - Stevia rebaudiana Bertoni is one of the most important biologically sourced and low-calorie sweeteners that contains a lots of Steviol glycosides. Tissue culture is the best method for propagation of stevia and micro nutrients can affect both morphological traits and steviol glycosides production. In the present study, we investigated the effect of different concentrations of glutamine (10, 20, 30 and 40 g/l) on expression of UGT74G1 and UGT76G1 genes and stevioside and rebaudioside A accumulation in the leaves of stevia under in vitro conditions. The highest level of expression for UGT74G1 (1.000 Total lab unit) was seen at plants grown in MS media without glutamine and the highest gene expression level for UGT76G1 (1.321 Total lab unit) was observed at plants grown in 2% glutamine. Based on HPLC results, the highest amount of stevioside (22.74) was accumulated in plants which were under 3% glutamine treatment and the lowest production level of stevioside (16.19) was resulted under MS (0 glutamine) medium. The highest rebaudioside A (12.19) accumulation was observed under 2% glutamine treatment and the lowest accumulation of rebaudioside A (8.41) was seen at plants grown in MS medium. PMID- 29433621 TI - Effect of Stevia rebaudiana Bertoni extract on sexual dysfunction in Streptozotocin-induced diabetic male rats. AB - Stevia rebaudiana Bertoni has been used locally as a non-calorie sweetener in medicine and diabetic diet which claimed to have aphrodisiac properties, although no scientific data of this function have been reported. The aim of this study was to investigate the effect of S. rebaudiana extract on sexual dysfunction, testosterone levels and number of Leydig cells in Streptozotocin (STZ)-induced diabetic male rats. A total of 28 diabetic male rats were randomly divided into 4 groups: diabetic group without any extract and 3 extract groups (5, 50 and 100 mg/kg). Seven normal control rats were treated with vehicle mount latency and frequency of (ML, MF), intromission latency and frequency (IL, IF), ejaculation latency and frequency of (EL, EF), the mount latency post ejaculation (MPE), the intromission latency post ejaculation (ILE), the intromission frequency post ejaculation (IFE) were recorded during 30 min on days 0, 14, 28. The serum testosterone levels, blood glucose, sex organs weight, number of leydig cells and histology of testicular tissue were measured. The stevia group (5 mg/kg) had a significant (p<0.05) increase in EF and IF. The number of Leydig cells in the diabetic group were significantly (p<0.05) reduced compared to the normal group and diabetic groups with extract (5 and 50 mg/kg). The serum testosterone levels and other sexual behaviors did not show any significant differences. The low- dose stevia extract with attention to antioxidant, vasodilator and anti-diabetic properties can be aphrodisiac in STZ- induced diabetic male rats. PMID- 29433622 TI - Effect of nitrogen sources on gene expression of Stevia rebaudiana (Bertoni) under in vitro conditions. AB - Stevia rebaudiana (Bertoni) is a non-caloric sweetener belonging to Asteraceae family. Stevia compounds such as steviol glycosides (SGs) are 200 times sweeter than sugar. Stevioside and rebaudioside A are the two major steviol glycosides. Nitrogen is an essential element for plant growth and development. In this study the effects of nitrogen influenced by different concentrations of NH4NO3 (0, 825 and 1650 mg/l) and KNO3 (0, 950 and 1900 mg/l) is examined in MS medium. To analysis the UGT74G1 and UGT76G1 genes expression, involved in the synthesis of SGs, RT-qPCR technique was performed. Data showed that there were significant differences between all media. The shoot length, seedlings dry weight and leaf fresh weight of stevia increased with applying NH4NO3 along with KNO3. The highest expression of UGT74G1 gene, was observed in plantlets grown on MS medium with 0 mg/l NH4NO3 and 950 mg/l KNO3 (1.291 total lab unit) but the highest expression of UGT76G1 gene, was observed in plantlets grown on MS medium added by 1650 mg/l NH4NO3 +950 mg/l KNO3 (1.08 total lab unit). Moreover, the lowest value of UGT74G1 gene expression were revealed in MS medium added by 1650 mg/l NH4NO3 +0 mg/l KNO3 (0.80 total lab unit) and the lowest values of UGT76G1 gene expression seen in MS medium with 0 mg/l NH4NO3 +950 mg/l KNO3 (0.85 total lab unit) concentrations. The results of this study could be valuable in stevia breeding programs through glycosides biosynthesis pathways. PMID- 29433623 TI - Effects of life cycle and leaves location on gene expression and glycoside biosynthesis pathway in Stevia rebaudiana Bertoni. AB - Stevia rebaudiana Bertoni is One of the most important biologically sourced and low-calorie sweeteners that known as "Sweet Weed". It contains steviol glycosides that they are about 200-300 times sweeter than sucrose. Tissue culture is the best method with high efficiency that can overcome to problems of traditional methods, and it is the most useful tools for studying stress tolerance mechanisms under in vitro conditions to obtain drought tolerance. In the present research, we investigated the impact of life cycle, leaves location and the harvesting time on expression of UGT74G1 and UGT76G1 as well as steviol glycosides accumulation. The highest gene expression of both UGT74G1 and UGT76G1 (207.677 and 208.396 Total Lab unit, respectively) was observed in young leaves in the second vegetative year. Also, the highest amount of stevioside accumulation (13.04) was due to the old leaves in vegetative stage which had significant differences with other effects whereas the lowest accumulation (7.47) was seen at young leaves at vegetative stage. Interestingly, the highest level of rebaudioside a production (15.74) was occurred at the young leaves at vegetative stage. There was significant differences between life cycle and leaves location on steviol glycoside production in stevia. PMID- 29433624 TI - Investigation of different concentrations of MS media effects on gene expression and steviol glycosides accumulation in Stevia rebaudiana Bertoni. AB - Stevia rebaudiana Bertoni is one of two species that contains steviol glycosides. Among steviol glycosides that extracted from leaves, stevioside and rebaudioside A are the two major and the sweetest glycosides that are about 200-300 times sweeter than sucrose with zero calories. The best method for stevia propagation is tissue culture. So, for investigation of nutrients in medium, we studied the effect of different concentrations of MS media (MS, 0.5 MS, 0.25 MS, 0 MS) on morphological traits, UGT74G1 and UGT76G1 genes expression and accumulation of steviol glycosides in stevia leaves. The best growth rate (0.472 mm/d) has occurred in plants grown in MS media. Also, the highest gene expression of UGT74G1 gene (1.000 Total lab unit) was seen under MS treatment. However, the highest expression level of UGT76G1 gene (1.701 Total lab unit) was observed at plants grown in 0 MS. The highest amount of both Stevioside and Rebaudioside A (14.23 and 8.12, respectively) were accumulated in plants under MS treatment. Obviously, dilution of MS media associated with decreasing in both expression of the intended genes and accumulation of steviol glycosides. PMID- 29433625 TI - Effects of different concentrations of mannitol on gene expression in Stevia rebaudiana Bertoni. AB - Stevia rebaudiana Bertoni is one of the most important herbal sweetener plants from Asteracea family that have a lot of Steviol glycosides. Among different methods, tissue culture is the best way with high efficiency that is useful for studying stress tolerance mechanisms to obtain drought tolerance of stevia. For this purpose, different concentrations of mannitol (0, 10, 20, 30, 40, 50 mg/l) were used as various treatments in the culture medium of stevia. According to the results, the highest level of UGT85C2 gene expression (1.181 Total lab unit) was seen in plants grown under 30 mg/l mannitol treatment and the lowest level of this gene expression (0.603 Total lab unit) was observed under 40 mg/l mannitol treatment. However, the highest level of KO gene expression (1.323 Total lab unit) was observed under 20 mg/l mannitol. It shows stevia growth is affected by osmotic stress. Water deficiency has a negative impact on Stevia. However, the expression of genes had increased by particular mannitol concentrations. Actually, stevia can survive under various abiotic stresses. PMID- 29433626 TI - Metal oxides as a biostimulator for upregulation of genes involved in the biosynthesis of Rebaudioside- A. AB - Stevia rebaudiana Bertoni is a kind of perennial medicinal plant with sweetening properties which belongs to Asteraceae family. Its leaves with fundamental glycoside compounds consist of both a sugar part and a non-sugar sector. One of the glycoside compounds is Rebaudioside- A which has a greater importance in business. This experiment was conducted to evaluate the effects of Ag2O, CrO3, PbO, Fe2O3, BaO and TiO2 on the expression pattern of these genes in the Stevia rebaudiana. Rebaudioside- A biosynthesis was repeated 3 times with concentrations of 50, 100 and 200uM. Also, the results of the study pertaining to the expression pattern of these genes showed that metal oxides have led to an increase in the expression of the regulatory genes involved in biosynthesis of Rebaudioside- A. According to the expression profile, it was found that its effect on DXR, HDS, HDR, IDI and CPPS genes is more than other genes. The peak HPLC indicated for stevioside and Rebaudioside- A represents an increase in the production of this active ingredient under the influence of all treatments. In general, the expression profile of these genes and the results of HPLC show that whatever going to the end of the pathway of production of Rebaudioside- A, the activity of the enzymes increases under the influence of these treatments, and eventually a greater amount of Rebaudioside- A will be produced. This process shows that metal oxides will have a significant effect on the biosynthesis of Rebaudioside- A. PMID- 29433627 TI - The Effects of different nitrogen doses on antioxidant and antimicrobial activity of Stevia (Stevia rebaudiana Bert.). AB - In this study, the efficiency of the different nitrogen doses (0, 5, 10, 15 and 20 kg ha-1) on biological activity levels (antioxidant and antimicrobial activity) of Stevia rebaudiana Bert. was investigated. In addition, methanol extracts were obtained by maceration method from different doses of fertilizer applied stevia. The components in methanol extracts of plants were determined by gas chromatography-mass spectrometry (GC-MS) method. Antimicrobial activities of stevia extracts were investigated by microdilution method. The antioxidant activity evaluated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, ferric thiocyanate (FTC), thiobarbituric acid (TBA), reducing power, total phenol content (TPC), and total flavonoid content (TFC) methods. According to the results, the fertilizer doses effects on antimicrobial activity of stevia were not made much difference. But in antioxidant activity, there were some variations in the activity-dependent on fertilizer amount. PMID- 29433628 TI - Callus induction and somatic embryogenesis in Stevia rebaudiana Bertoni as a medicinal plant. AB - Stevia rebaudiana (Bert.) from Asteraceae family is a useful medicinal plant that prevents and cures diabetes, blood pressure, weight gain and tooth decay. Due to self-incompatibility in stevia, somatic embryo investigation for artificial seed production is valuable in this plant. In order to evaluate the callus induction characteristics in stevia, a factorial experiment was laid out based on a completely randomized design with three replications. The factors included ten hormone combinations and control, two kinds of media (MS and B5) and two types of explants (leaf and internode). Callus induction characters including the percentage of callus formation, days to callus induction, fresh and dry callus weight were recorded. Analysis of variance showed significant differences (p<0.01) among hormone combinations, media and explant types as well as their interactions. The best treatment for callus induction with minimum time to callus formation was 1 mg/l NAA+1 mg/l BAP. The highest fresh and dry callus weight were obtained on B5 medium supplemented by 1 mg/l 2,4-D+1 mg/l BAP (in leaf explant) and 0.25 mg/l 2,4-D+ 0.1 mg/l BAP (in internode explant). These results can be used in suspension culture. To induce somatic embryogenesis in suspension culture, six hormone treatments were investigated. The highest somatic embryogenesis percentage was obtained in MS medium supplemented by 2 mg/l 2,4-D+ 0.5 mg/l NAA+0.5 mg/l BAP. PMID- 29433630 TI - An exploration of the experiences of Australian Grey Nomads travelling with chronic conditions. AB - Internationally, the population is ageing and people are living well, longer. In Australia, extended travelling has gained popularity among older Grey Nomads due to time and opportunity post retirement. However, there is limited research available focusing on older Australians' health while travelling. This paper reports the qualitative phase of a larger mixed-method project that explores the experience of Australian Grey Nomads travelling with chronic conditions. Eight Grey Nomads participated in telephone interviews. Data were analysed using inductive thematic analysis. Two themes emerged, namely: continuity of care while travelling and experts on the road. Participants described encountering a fragmented health system, with challenges regarding finding health services; a lack of shared medical records; and difficulties accessing regular medications. Despite these challenges, participants demonstrated health preparedness, an ability to accommodate health on the road, and were all travelling for their health. This study highlights key systems issues that challenge health care while travelling, and identifies opportunities for both usual practices and rural health services to enhance the care provided to this group. PMID- 29433629 TI - Effect of decapitation and exogenous application of gibberellic acid (GA3) and cytokinin (CK) on some physiological characteristics of stevia. AB - Stevia (Stevia rebaudiana B.) has auxiliary buds that often remain dormant for a long time and sometimes remain dormant until the plants change at the reproductive stage. This study was designed out to investigate whether decapitation and exogenous application of plant growth regulators enhance the productivity of stevia through breaking the apical dominance and increasing physiological characteristics. Experiment was carried out as a factorial in randomized complete block design with three replications. Factors were consisted two agricultural practices (Decapitation and No-decapitation) and eight foliar spray including without spray as control, water spray, GA3 (300, 600 and 900 um) and CK (100, 200 and 400 um). The results of the present investigation indicated a positive response on number of branches and leaves, leaves and stem fresh weight and total dry weight, in both harvests not only from the decapitation of apical buds but also from foliar application of CK (400 uM). Thus, it can be concluded that the decapitation practices in conjunction with foliar application of CK (400 uM) could be used to increase the dry-leaf yield of stevia. However, further studies are required to standardize the dose of CK (400 uM) to improve the yield and quality of stevia. PMID- 29433632 TI - ? PMID- 29433631 TI - AMPK signaling to acetyl-CoA carboxylase is required for fasting- and cold induced appetite but not thermogenesis. AB - AMP-activated protein kinase (AMPK) is a known regulator of whole-body energy homeostasis, but the downstream AMPK substrates mediating these effects are not entirely clear. AMPK inhibits fatty acid synthesis and promotes fatty acid oxidation by phosphorylation of acetyl-CoA carboxylase (ACC) 1 at Ser79 and ACC2 at Ser212. Using mice with Ser79Ala/Ser212Ala knock-in mutations (ACC DKI) we find that inhibition of ACC phosphorylation leads to reduced appetite in response to fasting or cold exposure. At sub-thermoneutral temperatures, ACC DKI mice maintain normal energy expenditure and thermogenesis, but fail to increase appetite and lose weight. We demonstrate that the ACC DKI phenotype can be mimicked in wild type mice using a ghrelin receptor antagonist and that ACC DKI mice have impaired orexigenic responses to ghrelin, indicating ACC DKI mice have a ghrelin signaling defect. These data suggest that therapeutic strategies aimed at inhibiting ACC phosphorylation may suppress appetite following metabolic stress. PMID- 29433633 TI - [Atopic dermatitis of the adult: clinical presentation, complications and comorbidities]. AB - Atopic dermatitis (DA) is a chronic inflammatory skin disease. Its incidence and prevalence is increasing, especially in industrialized countries. The prevalence of AD in adults is estimated at 1-3 % of the general population and can present as adult-onset AD, or as infantile/childhood AD that persists, or recurs in adulthood. There are no specific diagnostic criteria for adult AD. Diagnosis may be also complicated by the fact that the clinical manifestations sometimes differ from pediatric AD. Moreover, many recent studies have identified adult AD as a systemic disease. Due to its chronicity and comorbidities, Adult AD has a major impact on quality of life and working abilities of affected patients. With the emergence of new treatments, we should see more and more adult AD in the future, a better knowledge of its characteristics is therefore required. PMID- 29433634 TI - [Burden of atopic dermatitis in adults]. AB - Atopic dermatitis may have a very important impact on adults. Visible lesions, but especially near-permanent pruritus or sometimes pain for decades, necessarily have consequences on all aspects of everyday life, including sleep, and professional, social, family and emotional life. Financial consequences are also possible. Poorly known, stigmatisation can be real. Treatments can be very demanding. Thus, the quality of life can be greatly altered and atopic dermatitis could be a heavy burden. The psychological consequences can be major. Co morbidity appears more and more as a major problem. Patients can therefore be caught in an infernal circle, consequences of the disease aggravating the disease. The best way out is probably to have very effective and well-tolerated treatments. PMID- 29433635 TI - [Current and upcoming treatments of adult atopic dermatitis]. AB - The treatment of atopic dermatitis in adults is based on the use of topical steroids and emollients. When AD is resistant to a well-conducted topical treatment, phototherapy or systemic treatments can be used: ciclosporin, methotrexate, azathioprine or mycophenolate mofetil. The therapeutic landscape of adult AD is about to change and even be revolutionized by the imminent arrival of new treatments: topical phosphodiesterase 4 inhibitors, topical or systemic JAK inhibitors, anti-IL-4 and/or antiIL-13 biotherapies (dupilumab, tralokinumab, lebrikizumab), anti-IL-31 (nemolizumab), anti-TSLP. PMID- 29433636 TI - [Epidemiology of atopic dermatitis]. AB - Atopic dermatitis (AD) is a chronic pruriginous skin disease which usually begins during early life (before the age of 2 years). Recently, the persistence of the disease in adulthood has been clearly established at least in a subset of patients, with frequent moderate to severe forms. The exact prevalence of the disease varies according to the study design and its estimate remains difficult mainly because of the lack of consensual diagnostic tools easily usable in population studies. Finally, the disease has a major impact in terms of public health and identification of risk factors for persistence at age adult is therefore of prime importance. PMID- 29433637 TI - [Atopic dermatitis physiopathology]. AB - Our understanding of the physiopathology of atopic dermatitis has much improved over the recent years. Epidermal barrier alterations are integrated into 2 theories called inside out and outside in. They are related to complex immune abnormalities. Understanding their mechanism makes it possible to foresee new therapeutics. Moreover, environmental biodiversity, the diversity of cutaneous microbiota and genetic predispositions in atopic dermatitis lead to a new, more comprehensive theory, " the biodiversity theory ", integrating epigenetics. PMID- 29433638 TI - The Chinese garden of genetics -celebrating 40th anniversary of Genetics Society of China. PMID- 29433639 TI - [Editorial Board: New members from Francophone space]. PMID- 29433640 TI - [La Societe francaise du cancer strengthens its information and education activity]. PMID- 29433641 TI - In search of the "metabolic footprint" in cardiovascular disease. PMID- 29433642 TI - Tennis elbow: associated psychological factors. AB - BACKGROUND: The etiology of tennis elbow is multifactorial. Overuse of the wrist extensors along with anatomic factors, such as flexibility problems, aging, and poor blood circulation, may play a role. This study investigated whether patients with tennis elbow have a different psychological profile compared with healthy controls. METHODS: Patients with clinical signs of tennis elbow, consulting at the Ghent University Hospital between September 2015 and January 2017, were offered a paper-and-pencil questionnaire about Big Five personality traits, perfectionism, anxiety, depression, work satisfaction, and working conditions. Healthy controls in the same risk group were offered the same questionnaires. RESULTS: We recruited 69 patients (35 men, 34 women) and 100 controls (44 men, 56 women). Tennis elbow patients scored significantly lower on the personality traits extraversion and agreeableness. Men, in particular, scored significantly higher on perfectionism and were more likely to develop an anxiety disorder or a depression. Concerning work, patients indicated a significantly higher workload (especially men) and a significantly lower autonomy (especially women). Female patients also indicated less contact with colleagues. However, work satisfaction was relatively high in both groups. CONCLUSION: The results suggest that there is a relationship between complaints related to tennis elbow and psychological characteristics. PMID- 29433643 TI - Prevalence and clinical outcomes of heterotopic ossification after ulnar collateral ligament reconstruction. AB - BACKGROUND: Ulnar collateral ligament (UCL) reconstruction has become increasingly popular in elite athletes. However, the prevalence of heterotopic ossification (HO) formation after UCL reconstruction has not yet been reported. We sought to determine the prevalence of HO formation after UCL reconstruction and the clinical outcomes following HO treatment. MATERIALS AND METHODS: From October 2005 to April 2014, 179 patients underwent primary UCL reconstruction. Of the 179 patients, 161 with a minimum of 2 years of follow-up were retrospectively reviewed to evaluate HO formation and clinical outcomes. RESULTS: Among 161 patients, HO was detected in 8 cases (5%). Of these 8 patients, 2 were asymptomatic and another 2 complained about transient ulnar neuropathy. The remaining 4 patients had pain; 2 were treated with open excision, and 1 underwent arthroscopic excision. The odds of HO in patients in whom transient ulnar neuropathy develops after UCL reconstruction are 6 times higher than those without transient ulnar neuropathy (odds ratio, 5.957; 95% confidence level, P = .04). Of the 8 patients, 7 returned to the same level or a higher level of competition. HO was found, on average, 5 months (range, 3-9 months) after UCL reconstruction. CONCLUSION: The prevalence of HO formation was approximately 5% after UCL reconstruction and increased with transient ulnar neuropathy. After UCL reconstruction, the surgeon should carefully observe HO formation, especially in the early stages after the operation. With appropriate treatment, the clinical outcomes of HO treatment after UCL reconstruction are favorable. PMID- 29433644 TI - What happens to patients when we do not repair their cuff tears? Five-year rotator cuff quality-of-life index outcomes following nonoperative treatment of patients with full-thickness rotator cuff tears. AB - BACKGROUND: The purpose of this study was to examine 5-year outcomes in a prospective cohort of patients previously enrolled in a nonoperative rotator cuff tear treatment program. METHODS: Patients with chronic (>3 months), full thickness rotator cuff tears (demonstrated on imaging) who were referred to 1 of 2 senior shoulder surgeons were enrolled in the study between October 2008 and September 2010. They participated in a comprehensive, nonoperative, home-based treatment program. After 3 months, the outcome in these patients was defined as "successful" or "failed." Patients in the successful group were essentially asymptomatic and did not require surgery. Patients in the failed group were symptomatic and consented to undergo surgical repair. All patients were followed up at 1 year, 2 years, and 5 or more years. RESULTS: At 5 or more years, all patients were contacted for follow-up; the response rate was 84%. Approximately 75% of patients remained successfully treated with nonoperative treatment at 5 years and reported a mean rotator cuff quality-of-life index score of 83 of 100 (SD, 16). Furthermore, between 2 and 5 years, only 3 patients who had previously been defined as having a successful outcome became more symptomatic and underwent surgical rotator cuff repair. Those in whom nonoperative treatment had failed and who underwent surgical repair had a mean rotator cuff quality-of-life index score of 89 (SD, 11) at 5-year follow-up. The operative and nonoperative groups at 5 year follow-up were not significantly different (P = .11). CONCLUSION: Nonoperative treatment is an effective and lasting option for many patients with a chronic, full-thickness rotator cuff tear. While some clinicians may argue that nonoperative treatment delays inevitable surgical repair, our study shows that patients can do very well over time. PMID- 29433645 TI - Difficulty in decision making in the treatment of displaced proximal humerus fractures: the effect of uncertainty on surgical outcomes. AB - BACKGROUND: Decision making in the management of proximal humerus fractures can be difficult in situations in which the surgeon is uncertain of the ideal treatment. METHODS: Two shoulder surgeons operatively treated 476 proximal humerus fractures from 1998-2014 with open reduction-internal fixation (ORIF), hemiarthroplasty, or reverse shoulder arthroplasty. Operative treatment was stratified by year to determine the evolution of technological influences on treatment over time. To evaluate the effect of uncertainty, 274 clinical vignettes were created for all patients with 1 year of follow-up or more and reviewed by 3 fellowship-trained shoulder surgeons to determine the type of treatment for each case. To evaluate the effect of certainty, range of motion for each patient with unanimous agreement on treatment was analyzed. RESULTS: ORIF treatment increased from 40% to 62% after release of the proximal humerus locking plate. Introduction of the fracture stem in 2011 increased reverse shoulder arthroplasty for fractures from 8.8% to 44.3%. Unanimous agreement on either operative or nonoperative treatment occurred 70.5% of the time. Only 63.5% of patients received the actual treatment selected (P = .001). Patients for whom unanimous agreement matched actual treatment in the ORIF treatment group showed improvement of forward elevation (144 degrees vs 123 degrees , P = .005) and abduction (129 degrees vs 103 degrees , P = .002). CONCLUSION: Successful management of displaced proximal humerus fractures requires both technical and decision-making abilities. The difficulty in making these decisions is reflected by the agreement of experienced shoulder surgeons only 63.5% of the time regarding the treatment performed. When uncertainty occurs, patients may have reduced outcomes as seen in the ORIF treatment group. PMID- 29433646 TI - Outcomes of Trabecular Metal-backed glenoid components in anatomic total shoulder arthroplasty. AB - BACKGROUND: As glenoid failure is one of the primary causes of failure of anatomic total shoulder arthroplasty (TSA), Trabecular Metal-backed glenoid components have become popular. This study reports implant survival and clinical outcomes of patients who received a Trabecular Metal-backed glenoid component during primary anatomic TSA. METHODS: Patients who underwent TSA with a Trabecular Metal-backed glenoid component by a single surgeon were identified and reviewed for clinical, radiographic, and patient-reported outcome measures with a minimum of 2 years' follow-up. RESULTS: Of 47 patients identified, radiographic and clinical follow-up was available on 36 patients (77%). Average age was 66.36 years (range, 50-85 years), and the average follow-up 41 months (range, 24-66 months). Three patients showed signs of osteolysis, 4 had radiographic evidence of metal debris, and 1 patient had a catastrophic failure after a fall. Of the 47 TSAs, 5 (11%) were revised to a reverse TSA for subscapularis failure and pain. Visual analog scale for pain scores improved by an average of 4.4. At final follow-up, the average Single Assessment Numeric Evaluation score was 72.4; Penn satisfaction score, 7.5; Penn score, 70.35; and American Shoulder and Elbow Surgeons score, 69.23. Outcome scores were similar in the 7 patients with osteolysis or metal debris compared to those without. CONCLUSION: Trabecular Metal-backed glenoids had a 25% rate of radiographic metal debris and osteolysis at a minimum 2-year follow-up in this series with one catastrophic failure. This implant should be used with caution, and patients followed closely. PMID- 29433647 TI - The success of return to sport after ulnar collateral ligament injury in baseball: a systematic review and meta-analysis. AB - BACKGROUND: Ulnar collateral ligament injury (UCLI) has significantly increased in overhead sports during the past 2 decades. Differences in return to sport (RTS) and RTS at previous level (RTSP) after UCLI have not been differentiated. METHODS: A computer-assisted literature search of PubMed, CINAHL, Embase, and SportDiscus databases using keywords related to RTS for UCLI was implemented. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for study methodology. Quality assessment was conducted using a modified Downs and Black scale. RESULTS: A total of 22 retrospective, level 3b or 4, studies (n = 2289) qualified for analysis. Overall RTS proportion was 90% (95% confidence interval [CI], 86%-94%) and overall RTSP proportion was 79% (95% CI, 75%-84%), both with significant heterogeneity (P < .001, I2 = 74%-84%). RTS and RTSP proportions were 89% (95% CI, 83%-94%) and 78% (95% CI, 72%-83%) for Major League Baseball players, 91% (95% CI, 77%-99%) and 67% (95% CI, 52%-81%) for Minor League Baseball players, 95% (95% CI, 75%-100%) and 92% (95% CI, 82%-98%) for collegiate players, and 93% (95% CI, 81%-100%) and 83% (95% CI, 77%-89%) for high school players, respectively. Increased earned run average, walks, and hits per inning pitched, decreased innings pitched, and decreased fastball velocity were found after UCLI. CONCLUSION: Low-level, high-bias evidence demonstrates overall RTS proportion is higher than RTSP, regardless of treatment type for UCLI. Although RTS proportions remained consistent across various levels of play, RTSP proportions were lower in professional players, particularly Minor League Baseball compared with collegiate and high school players. Pitching performance significantly decreased postoperatively in most studies. PMID- 29433648 TI - Engaging Osborne-Cotterill lesion with Mason 4 radial head elbow dislocation fracture: a case report of biomechanical importance and operative treatment. PMID- 29433649 TI - Letter to the Editor regarding Hackl et al: "Rare implant-specific complications of the MoPyC radial head prosthesis". PMID- 29433650 TI - Metaviromics: a tectonic shift in understanding virus evolution. PMID- 29433651 TI - Chief editor's 2017 annual report. PMID- 29433652 TI - Local research in Africa: a glimpse at possibilities in Niger. PMID- 29433653 TI - Exploring the broader consequences of diarrhoeal diseases on child health. PMID- 29433654 TI - Monitoring tools for child development: an opportunity for action. PMID- 29433655 TI - Limited access to CVD medicines in low-income and middle-income countries: poverty is at the heart of the matter. PMID- 29433656 TI - Making waves: can radio reduce child mortality? PMID- 29433657 TI - Swedish development assistance for health: critical questions to ask going forward. PMID- 29433658 TI - Developmental origins of health and disease in Africa-influencing early life. PMID- 29433659 TI - Advancing neuropsychiatric genetics training and collaboration in Africa. PMID- 29433660 TI - Contribution of perinatal conditions to cerebral palsy in Uganda. PMID- 29433661 TI - Infant formula in Iraq: part of the problem and not a simple solution. PMID- 29433663 TI - Vaccination to reduce antimicrobial resistance. PMID- 29433662 TI - Infant formula in Iraq: part of the problem and not a simple solution - Authors' reply. PMID- 29433664 TI - A socioeconomic lens on understanding early childhood linear growth faltering. PMID- 29433666 TI - Similarities and differences in child development from birth to age 3 years by sex and across four countries: a cross-sectional, observational study. AB - BACKGROUND: Knowledge about typical development is of fundamental importance for understanding and promoting child health and development. We aimed to ascertain when healthy children in four culturally and linguistically different countries attain developmental milestones and to identify similarities and differences across sexes and countries. METHODS: In this cross-sectional, observational study, we recruited children aged 0-42 months and their caregivers between March 3, 2011, and May 18, 2015, at 22 health clinics in Argentina, India, South Africa, and Turkey. We obtained a healthy subsample, which excluded children with a low birthweight, perinatal complications, chronic illness, undernutrition, or anaemia, and children with missing health data. Using the Guide for Monitoring Child Development, caregivers described their child's development in seven domains: expressive and receptive language, gross and fine motor, play, relating, and self-help. Clinicians examining the children also completed a checklist about the child's health status. We used logit and probit regression models based on the lowest deviance information criterion to generate Bayesian point estimates and 95% credible intervals for the 50th percentile ages of attainment of 106 milestones. We assessed the significance of differences between sexes and countries using predefined criteria and regions of practical equivalence. FINDINGS: Of 10 246 children recruited, 4949 children (48.3%) were included in the healthy subsample. For the 106 milestones assessed, the median age of attainment was equivalent for 102 (96%) milestones across sexes and 81 (76%) milestones across the four countries. Across countries, median ages of attainment were equivalent for all play milestones, 20 (77%) of 26 expressive language milestones, ten (67%) of 15 receptive language milestones, nine (82%) of 11 fine motor milestones, 14 (88%) of 16 gross motor milestones, and eight (73%) of 11 relating milestones. However, across the four countries the median age of attainment was equivalent for only two (22%) of nine milestones in the self-help domain. INTERPRETATION: The ages of attainment of developmental milestones in healthy children, and the similarities and differences across sexes and country samples might aid the development of international tools to guide policy, service delivery, and intervention research, particularly in low-income and middle-income countries. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development. PMID- 29433665 TI - Global disability-adjusted life-year estimates of long-term health burden and undernutrition attributable to diarrhoeal diseases in children younger than 5 years. AB - BACKGROUND: Diarrhoea is a leading cause of death and illness globally among children younger than 5 years. Mortality and short-term morbidity cause substantial burden of disease but probably underestimate the true effect of diarrhoea on population health. This underestimation is because diarrhoeal diseases can negatively affect early childhood growth, probably through enteric dysfunction and impaired uptake of macronutrients and micronutrients. We attempt to quantify the long-term sequelae associated with childhood growth impairment due to diarrhoea. METHODS: We used the Global Burden of Diseases, Injuries, and Risk Factors Study framework and leveraged existing estimates of diarrhoea incidence, childhood undernutrition, and infectious disease burden to estimate the effect of diarrhoeal diseases on physical growth, including weight and height, and subsequent disease among children younger than 5 years. The burden of diarrhoea was measured in disability-adjusted life-years (DALYs), a composite metric of mortality and morbidity. We hypothesised that diarrhoea is negatively associated with three common markers of growth: weight-for-age, weight-for height, and height-for-age Z-scores. On the basis of these undernutrition exposures, we applied a counterfactual approach to quantify the relative risk of infectious disease (subsequent diarrhoea, lower respiratory infection, and measles) and protein energy malnutrition morbidity and mortality per day of diarrhoea and quantified the burden of diarrhoeal disease due to these outcomes caused by undernutrition. FINDINGS: Diarrhoea episodes are significantly associated with childhood growth faltering. We found that each day of diarrhoea was associated with height-for-age Z-score (-0.0033 [95% CI -0.0024 to -0.0041]; p=4.43 * 10-14), weight-for-age Z-score (-0.0077 [-0.0058 to -0.0097]; p=3.19 * 10-15), and weight-for-height Z-score (-0.0096 [-0.0067 to -0.0125]; p=7.78 * 10 11). After addition of the DALYs due to the long-term sequelae as a consequence of undernutrition, the burden of diarrhoeal diseases increased by 39.0% (95% uncertainty interval [UI] 33.0-46.6) and was responsible for 55 778 000 DALYs (95% UI 49 125 400-62 396 200) among children younger than 5 years in 2016. Among the 15 652 300 DALYs (95% UI 12 951 300-18 806 100) associated with undernutrition due to diarrhoeal episodes, more than 84.7% are due to increased risk of infectious disease, whereas the remaining 15.3% of long-term DALYs are due to increased prevalence of protein energy malnutrition. The burden of diarrhoea has decreased substantially since 1990, but progress has been greater in long-term (78.7% reduction [95% UI 69.3-85.5]) than in acute (70.4% reduction [95% UI 61.7-76.5]) DALYs. INTERPRETATION: Diarrhoea represents an even larger burden of disease than was estimated in the Global Burden of Disease Study. In order to adequately address the burden of its long-term sequelae, a renewed emphasis on controlling the risk of diarrhoea incidence may be required. This renewed effort can help further prevent the potential lifelong cost on child health, growth, and overall potential. FUNDING: Bill & Melinda Gates Foundation. PMID- 29433668 TI - Effect of a mass radio campaign on family behaviours and child survival in Burkina Faso: a repeated cross-sectional, cluster-randomised trial. AB - BACKGROUND: Media campaigns can potentially reach a large audience at relatively low cost but, to our knowledge, no randomised controlled trials have assessed their effect on a health outcome in a low-income country. We aimed to assess the effect of a radio campaign addressing family behaviours on all-cause post neonatal under-5 child mortality in rural Burkina Faso. METHODS: In this repeated cross-sectional, cluster randomised trial, clusters (distinct geographical areas in rural Burkina Faso with at least 40 000 inhabitants) were selected by Development Media International based on their high radio listenership (>60% of women listening to the radio in the past week) and minimum distances between radio stations to exclude population-level contamination. Clusters were randomly allocated to receive the intervention (a comprehensive radio campaign) or control group (no radio media campaign). Household surveys were performed at baseline (from December, 2011, to February, 2012), midline (in November, 2013, and after 20 months of campaigning), and endline (from November, 2014, to March, 2015, after 32 months of campaigning). Primary analyses were done on an intention-to treat basis, based on cluster-level summaries and adjusted for imbalances between groups at baseline. The primary outcome was all-cause post-neonatal under-5 child mortality. The trial was designed to detect a 20% reduction in the primary outcome with a power of 80%. Routine data from health facilities were also analysed for evidence of changes in use and these data had high statistical power. The indicators measured were new antenatal care attendances, facility deliveries, and under-5 consultations. This trial is registered with ClinicalTrial.gov, number NCT01517230. FINDINGS: The intervention ran from March, 2012, to January, 2015. 14 clusters were selected and randomly assigned to the intervention group (n=7) or the control group (n=7). The average number of villages included per cluster was 34 in the control group and 29 in the intervention group. 2269 (82%) of 2784 women in the intervention group reported recognising the campaign's radio spots at endline. Post-neonatal under-5 child mortality decreased from 93.3 to 58.5 per 1000 livebirths in the control group and from 125.1 to 85.1 per 1000 livebirths in the intervention group. There was no evidence of an intervention effect (risk ratio 1.00, 95% CI 0.82-1.22; p>0.999). In the first year of the intervention, under-5 consultations increased from 68 681 to 83 022 in the control group and from 79 852 to 111 758 in the intervention group. The intervention effect using interrupted time-series analysis was 35% (95% CI 20-51; p<0.0001). New antenatal care attendances decreased from 13 129 to 12 997 in the control group and increased from 19 658 to 20 202 in the intervention group in the first year (intervention effect 6%, 95% CI 2-10; p=0.004). Deliveries in health facilities decreased from 10 598 to 10 533 in the control group and increased from 12 155 to 12 902 in the intervention group in the first year (intervention effect 7%, 95% CI 2-11; p=0.004). INTERPRETATION: A comprehensive radio campaign had no detectable effect on child mortality. Substantial decreases in child mortality were observed in both groups over the intervention period, reducing our ability to detect an effect. This, nevertheless, represents the first randomised controlled trial to show that mass media alone can change health-seeking behaviours. FUNDING: Wellcome Trust and Planet Wheeler Foundation. PMID- 29433667 TI - Inequalities in the use of secondary prevention of cardiovascular disease by socioeconomic status: evidence from the PURE observational study. AB - BACKGROUND: There is little evidence on the use of secondary prevention medicines for cardiovascular disease by socioeconomic groups in countries at different levels of economic development. METHODS: We assessed use of antiplatelet, cholesterol, and blood-pressure-lowering drugs in 8492 individuals with self reported cardiovascular disease from 21 countries enrolled in the Prospective Urban Rural Epidemiology (PURE) study. Defining one or more drugs as a minimal level of secondary prevention, wealth-related inequality was measured using the Wagstaff concentration index, scaled from -1 (pro-poor) to 1 (pro-rich), standardised by age and sex. Correlations between inequalities and national health-related indicators were estimated. FINDINGS: The proportion of patients with cardiovascular disease on three medications ranged from 0% in South Africa (95% CI 0-1.7), Tanzania (0-3.6), and Zimbabwe (0-5.1), to 49.3% in Canada (44.4 54.3). Proportions receiving at least one drug varied from 2.0% (95% CI 0.5-6.9) in Tanzania to 91.4% (86.6-94.6) in Sweden. There was significant (p<0.05) pro rich inequality in Saudi Arabia, China, Colombia, India, Pakistan, and Zimbabwe. Pro-poor distributions were observed in Sweden, Brazil, Chile, Poland, and the occupied Palestinian territory. The strongest predictors of inequality were public expenditure on health and overall use of secondary prevention medicines. INTERPRETATION: Use of medication for secondary prevention of cardiovascular disease is alarmingly low. In many countries with the lowest use, pro-rich inequality is greatest. Policies associated with an equal or pro-poor distribution include free medications and community health programmes to support adherence to medications. FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments). PMID- 29433669 TI - Behavioral and electroencephalographic evaluation of the anticonvulsive activity of Moringa oleifera leaf non-polar extracts and one metabolite in PTZ-induced seizures. AB - BACKGORUND: Moringa oleifera Lamarck is a species that has long been used in high demand in folk medicine, including for the treatment of epilepsy. Nevertheless, scientific studies demonstrating its anticonvulsant properties and the nature of the bioactive constituents are lacking. HYPOTHESIS/AIM: The aim of this study was to evaluate the anticonvulsant activities of the Moringa oleifera leaves in non polar vs. polar extracts using behavioral and electroencephalographic (EEG) analyses in rodents. METHODS: First, PTZ (80 mg/kg, i.p.)-induced tonic-clonic seizures were assayed via a dose-response (100, 200 and 300 mg/kg, i.p.) evaluation in mice. Then, a dosage of the extracts (100 or 300 mg/kg) and one metabolite (30 mg/kg, i.p.) was selected to evaluate its effect on PTZ (35 mg/kg, i.p.)-induced EEG paroxystic activities in rats compared to the effects of ethosuximide (reference anticonvulsant drug, 100 mg/kg, i.p.). Latent onset of the first paroxystic spike, first seizure and frequency as well as seizure severity, were determined using Racine's scale. RESULTS: Moringa oleifera ethanol and hexane extracts produced a delay in the seizure latency in mice and rats; this effect was improved in the presence of the hexane extract containing the active metabolite hexadecanoic acid. The anticonvulsant effects were corroborated in the spectral analysis by the potency of the EEG due to a reduction in the spike frequency and amplitude, as well as in the duration and severity of the seizures. The effects of the hexane extract resembled those observed in the reference antiepileptic drug ethosuximide. CONCLUSION: Moringa oleifera leaves possess anticonvulsant activities due to the complementary of the non-polar and polar constituents. However, the non-polar constituents appear to exert an important influence via the partial participation of fatty acids, providing evidence of the effects of this plant in epilepsy therapy. PMID- 29433670 TI - Genistein induced anticancer effects on pancreatic cancer cell lines involves mitochondrial apoptosis, G0/G1cell cycle arrest and regulation of STAT3 signalling pathway. AB - BACKGROUND: Genistein is a natural flavonoid that has been reported to exhibit anticancer effects against different types of cancers which include, but are not limited to, breast and oral squamous cell carcinoma. PURPOSE: The present study was designed to evaluate the anticancer effects of the natural flavonoid genistein against pancreatic cancer cell lines and to explore the underlying mechanism. METHODS: Antiproliferative activity was investigated by MTT assay. Apoptosis was detected by DAPI and annexin V/PI staining. DNA damage was assessed by comet assay. Reactive oxygen species (ROS) and reduction of mitochondrial membrane potential (MMP) were determined by flow cytometry. Cell migration was examined by wound healing assay. Protien expressions were determined by western blotting. RESULTS: Antiproliferative assay revealed that genistein reduced the cell viability of pancreatic cancer cells in a dose dependent manner with an IC50 of 20 and 25 uM against Mia-PaCa2 and PANC-1 cancer cell lines respectively. However, its antiproliferative effects were less pronounced against non-cancerous pancreatic ductal epithelial cell line (H6C7) as evident from the IC50 of 120 uM. Genistein induced significant morphological changes in pancreatic cancer cells and triggered cell cycle arrest in G0/G1 phase. DAPI staining and flow cytometric analysis revealed that genistein induced apoptosis in a dose dependent manner through generation of substantial amounts of ROS and reduction of MMP. However, treatment of the pancreatic cancer with genistein and ascorbic acid could abrogate the effects of genistein on cell viability. Protien expression analysis revealed that genistein upregulated cytosolic cytochrome c, Bax, cleaved Caspase 3 and cleaved caspase-9 expressions with concomitant downregulation of Bcl-2 expression. Moreover, genistein inhibited the phosphorylation of signal transducer and activator of transcription STAT3 proteins and downregulated the expression of survivin, cyclin D1 and ALDH1A1 in Mia-PaCa2 cells in a dose dependent manner. Interestingly, genistein could inhibit the cell migration potential of the Mia-PaCa2 cells which was further associated with the downregulation of metalloproteinases (MPP-2 and MPP-9). CONCLUSION: Taken together, we propose that genistein exerts anticancer activity in pancreatic cancer cells through induction of ROS mediated mitochondrial apoptosis, cell cycle arrest and regulation of STAT3 and may therefore prove beneficial in the management of pancreatic cancers cancer. PMID- 29433671 TI - Phytochemical-induced reactive oxygen species and endoplasmic reticulum stress mediated apoptosis and differentiation in malignant melanoma cells. AB - BACKGROUND: Phytochemicals are derived from plants, vegetables and daily products and exert chemopreventive effects. Malignant melanoma is highly metastatic, and melanoma patients can develop chemotherapeutic resistance against conventional melanoma therapies. METHODS: In the present study, we investigated the anti cancer effect of the phytochemicals kaempferol (Kaem), genistein (Gen), and 3'3 diindolylmethane (DIM) on melanoma cell viability. We also evaluated the altered expression of cell cycle-related genes. We verified the production of intracellular reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress at both the protein and cellular level using a western blot, TUNEL assay, and Dihydrodichlorofluorescein diacetate (DCF-DA) assay. RESULTS: Treatment of A375SM melanoma cells with phytochemicals resulted in inhibition of cell growth. Treatment with phytochemicals increased the gene expression of p21 and decreased the gene expression of cyclin E and/or cyclin B. The three phytochemicals activated the ROS-p38-p53 apoptotic pathway by increasing the level of phosphorylated p38 MAPK and p53, and they activated the ER stress-mediated apoptotic pathway by increasing the level of phosphorylated eIF2alpha and C/EBP homologous protein (CHOP). Both the ROS-p38-p53 and ER stress-mediated pathway induced the mitochondrial apoptotic pathway by attenuating Bcl-2 expression and upregulating BAX. Detection of morphological changes demonstrated that Kaem and Gen can induce differentiation in A375SM cell line. CONCLUSION: These results indicate that phytochemicals are potentially useful in treatments for melanoma due to their ability to inhibit melanoma cell growth and division via the ROS and ER stress pathway. PMID- 29433672 TI - Protective role of beta-patchoulene from Pogostemon cablin against indomethacin induced gastric ulcer in rats: Involvement of anti-inflammation and angiogenesis. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are most widely used as effective anti-inflammatory agents. However, their clinical application brings about inevasible gastrointestinal side effects. Pogostemon cablin is a traditional herbal medicine used for the treatment of gastrointestinal diseases in China. One of its representative components, the tricyclic triterpenoid beta patchoulone (beta-PAE) has demonstrated great anti-inflammatory activity and gastroprotective effect against ethanol-induced gastric injury, but its protective effect against gastric ulcer induced by indomethacin is still unknown. PURPOSE: To assess the protective effect of beta-PAE against ulcer produced by indomethacin and reveal the underlying pharmacological mechanism. STUDY DESIGN: We used an indomethacin-induced gastric ulcer model of rats in vivo. METHODS: Gastroprotective activity of beta-PAE (10, 20, 40 mg/kg, i.g.) was estimated via indomethacin-induced gastric ulcer model in rats. Histopathological and histochemical assessment of ulcerated tissues were performed. Protein and mRNA expression were determined by Elisa, Western blotting and qRT-PCR. RESULTS: beta PAE could inhibit ulcer formation. Histopathological and histochemical assessment macroscopically demonstrated that beta-PAE alleviates indomethacin-induced gastric ulceration in dose-dependent manner. After administration of beta-PAE, elevated tumor necrosis factor -alpha level was significantly decreased and the phosphorylation of JNK and IkappaB was markedly inhibited. beta-PAE suppressed the levels of E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule and monocyte chemoattractant protein 1, as well as myeloperoxidase. Meanwhile, beta-PAE increased cyclooxygenase enzyme activities (COX-1 and COX-2) to enhance the production of prostaglandin E2. Proangiogenic protein, vascular endothelial growth factor and its receptor fms-like tyrosine kinase-1 mRNA expression were promoted while anti-angiogenic protein, endostatin 1 and its receptor ETAR mRNA expression were decreased. CONCLUSION: beta-PAE may provide gastroprotection in indomethacin-induced gastric ulcer in rats by reducing inflammatory response and improving angiogenesis. PMID- 29433673 TI - Codonopsis lanceolata extract prevents hypertension in rats. AB - BACKGROUND: Codonopsis lanceolata, a plant with antioxidant, anti-cancer, anti inflammatory and blood lipid improving effects, has been widely used as a therapeutic agent in traditional medicine. PURPOSE: The present study investigated the ability of an ethanol extract of Codonopsis lanceolata (ECL) to prevent hypertension in hypertensive rats. METHODS: Rats were orally administered daily doses of 0 mg/kg, 200 mg/kg and 400 mg/kg ECL for 3 weeks. As a positive control, rats were orally administered 10 mg/kg/day nifedipine. Hypertension was induced by immobilization stress for 2 h/day and by administration of 0.8 mg/kg/day nicotine for 3 weeks, followed by injection of 3 mg/kg nicotine on the day of sacrifice. Blood pressure and heart rate were measured using a volume pressure recording system. Vasoconstriction and vasodilation of aortic cross sections were measured with a physiological recorder. Neutrophil counts in bronchoalveolar lavage fluid were estimated with an automated cell counter. RESULTS: Treatment with both dosages of ECL significantly reduced systolic blood pressure (SBP) in hypertensive rats. Both doses of ECL tended to increase ACh- and SNP-induced vascular relaxation in hypertensive rats. Treatment with 200 mg/kg ECL significantly reduced neutrophil in hypertensive rats. CONCLUSIONS: These results suggest that ECL is effective in reducing SBP and inflammation in hypertensive conditions. PMID- 29433674 TI - Protective effect of dietary Alchemilla mollis on UVB-irradiated premature skin aging through regulation of transcription factor NFATc1 and Nrf2/ARE pathways. AB - BACKGROUND: Alchemilla mollis (lady's mantle) is a common ingredient in skin care products. However, the protective mechanism of A. mollis against skin problems has not been elucidated. PURPOSE: This study was to investigate the effects of A. mollis ethanolic extract (AM) on UVB-irradiated normal human dermal fibroblasts (NHDF) and hairless mice. METHODS: The in vitro anti-photoaging effect of AM was performed in NHDFs. The antioxidant activities were assessed through DPPH, ABTS, and reactive oxygen species (ROS) assays. Matrix metalloproteinase 1 (MMP-1), IL 6, procollagen type I, and transforming growth factor-beta1 (TGF-beta1) were measured by kits. The protein levels of p-c-Jun, p-c-Fos, Nrf2, NQO-1, HO-1, nuclear NFATc1 and cytosolic p-NFATc1 were evaluated by western blotting. In in vivo, H&E and Masson's trichrome staining were carried out. Skin texture was analyzed using the roughness parameters. The expression of MMP-1, procollagen type I, TGF-beta1 and elastin were measured by western blot. RESULTS: AM included gallic acid as an active constituent. AM exhibited a strong antioxidant effect by inhibiting DPPH and ABTS free radicals, as well as ROS production. It was also found to upregulate transforming growth factor beta1, type I procollagen and elastin expression, and to downregulate matrix metalloproteinase-1 and interleukin-6 expression in AM-treated NHDFs under UVB irradiation. These effects were attributed to AP-1 and Nrf2/ARE signaling pathways. Significantly, it was demonstrated that AM regulated the UVB-induced NFATc1 dephosphorylation in nucleus. Based on dietary data, AM was effective for the prevention of wrinkle formation, skin thickening, water loss, and erythema in UVB-exposed mouse skin. CONCLUSION: Our data indicate that A. mollis provides protection from UVB exposure in both hairless mice skin in vivo and NHDFs in vitro. AM might therefore be useful as a cosmetic material and functional food for the prevention of UVB-induced human skin photoaging. PMID- 29433675 TI - Plant natural product plumbagin presents potent inhibitory effect on human cytochrome P450 2J2 enzyme. AB - BACKGROUND: Cytochrome P450 2J2 (CYP2J2) is not only highly expressed in many kinds of human tumors, but also promotes tumor cell growth via regulating the metabolism of arachidonic acids. CYP2J2 inhibitors can significantly reduce proliferation, migration and promote apoptosis of tumor cells by inhibiting epoxyeicosatrienoic acids (EETs) biosynthesis. Therefore screening CYP2J2 inhibitors is a significant way for the development of anti-cancer drug. PURPOSE: The aim of this study was to identify a new CYP2J2 inhibitor from fifty natural compounds obtained from plants. STUDY DESIGN: CYP2J2 inhibitor was screened from a natural compounds library and further the inhibitory manner and mechanism were evaluated. Its cytotoxicity against HepG2 and SMMC-7721 cell lines was also estimated. METHODS: The inhibitory effect was evaluated in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant CYP2J2 (rCYP2J2), using astemizole as a probe substrate and inhibitory mechanism was illustrated through molecular docking. The cytotoxicity was detected using SRB. RESULTS: In all candidates, plumbagin showed the strongest inhibitory effect on the CYP2J2 mediated astemizole O-demethylation activity. Further study revealed that plumbagin potently inhibited CYP2J2 activity with IC50 value at 3.82 uM, 3.37 uM and 1.17 uM in RLMs, HLMs and rCYP2J2, respectively. Enzyme kinetic studies showed that plumbagin was a mixed-type inhibitor of CYP2J2 in HLMs and rCYP2J2 with Ki value of 1.88 uM and 0.92 uM, respectively. Docking data presented that plumbagin interacted with CYP2J2 mainly through GLU 222 and ALA 223. Moreover, plumbagin showed strongly cytotoxic effects on hepatoma cell lines, such as HepG2 and SMMC-7721, with lower toxicity on rat primary hepatocytes. Plumbagin had no effect on the protein expression of CYP2J2 in HepG2 and SMMC-7721, while down regulated the mRNA level of anti-apoptosis protein Bcl-2. CONCLUSION: This study found out a new CYP2J2 inhibitor plumbagin from fifty natural compounds. Plumbagin presented a potential of anti-cancer pharmacological activity. PMID- 29433676 TI - Bioactive phytochemicals that regulate the cellular processes involved in diabetic nephropathy. AB - BACKGROUND: Owing to the multiple causative factors, the current advances in medication for diabetic nephropathy (DN) do not appear to have improved therapies for patients. Furthermore, use of multiple synthetic medications has shown various adverse effects and ultimately leads to deterioration of the condition. Medicinal plants and their bioactive constituents are considered to be safer and more effective than synthetic medicines against various chronic diseases. Therefore, the use of natural products in the management of DN has been suggested. In this article, we review medicinal plants and their specific bioactive phytochemicals that regulate the various cellular processes involved in the initiation of DN. A wide range of literature on phytochemicals and medicinal plants that may ameliorate DN was explored from the online available English works in various electronic databases, including Embase, Google Scholar, PubMed, Scopus, and Science Direct. RESULTS: Medicinal plants possess various bioactive constituents, which may slow or ameliorate the progression of DN and improve renal function through the targeting of multiple pathological causes via different pathways, including p38MAPK, JNK, ERK, TGF-beta, RhoA, NF-kappaB, Wnt, JAK-STAT, AMPK, mTOR, Akt, and TXNIP. Depletion or inhibition of these accelerating factors may provide a significant treatment for DN. CONCLUSION: Based on various experimental studies, traditional herbs and their bioactive constituents regulate the cellular processes involved in the initiation of DN owing to their significant pharmacological activities; however, the efficacy in animal models and humans has not yet been explored. Therefore, studies should be performed to evaluate the nephroprotective effects of medicinal plants in preclinical animal models and in humans. PMID- 29433677 TI - A hybrid of coumarin and phenylsulfonylfuroxan induces caspase-dependent apoptosis and cytoprotective autophagy in lung adenocarcinoma cells. AB - BACKGROUND: Lung adenocarcinoma is the most primary histologic subtype of non small cell lung cancer (NSCLC). Compound 8b, a novel coumarin derivative with phenylsulfonylfuroxan group, shows significant antiproliferation activity against lung adenocarcinoma cell with low toxicity. PURPOSE: This study aims to uncover the potential of compound 8b in relation to apoptosis as well as autophagy induction in lung adenocarcinoma cells. STUDY DESIGN: The cytotoxicity and apoptosis of A549 and H1299 cells induced by compound 8b were detected by MTT, microscope and western blot analysis. Autophagy was determined by TEM, confocal microscopy and western blot analysis. Akt/mTOR and Erk signaling pathway were also examined by western blot analysis. RESULTS: First, significant growth inhibition and caspase-dependent apoptosis were observed in compound 8b-treated A549 and H1299 cells. Then, we confirmed compound 8b-induced autophagy by autophagosomes formation, upregulated expression of autophagy-related protein LC3 II and autophagic flux. Importantly, abolishing autophagy using inhibitors and ATG5 siRNA enhanced the cytotoxicity of compound 8b, indicating the cytoprotective role of autophagy in lung adenocarcinoma. Further mechanistic investigations suggested that Akt/mTOR and Erk signaling pathways contributed to autophagy induction by compound 8b. CONCLUSION: This results demonstrate that compound 8b induces caspase-dependent apoptosis as well as cytoprotective autophagy in lung adenocarcinoma cells, which may provide scientific evidence for developing this furoxan-based NO-releasing coumarin derivative as a potential anti-lung adenocarcinoma therapeutic agents. PMID- 29433678 TI - Wogonin exacerbates the cytotoxic effect of oxaliplatin by inducing nitrosative stress and autophagy in human gastric cancer cells. AB - BACKGROUND: Gastric cancer remains one of the leading cause of death in the world. Drug combinations are potential approaches to provide more efficient treatments that minimize side effects. PURPOSE: We investigated the pharmacological effects of the combination of wogonin with oxaliplatin on gastric cancer cells in vitro and in vivo. METHODS AND RESULTS: In the present study, we found that wogonin enhanced the cytotoxicity of oxaliplatin; the drug combination resulted in strong synergistic inhibition of the cell viability in BGC-823 cells and in a zebrafish xenograft model. Interestingly, the combined treatment of wogonin and oxaliplatin modulated the expression of phospho-JNK (Thr183/Tyr185), phospho-ULK1 (Ser555) and the formation of LC3II. Confocal imaging data consistently showed that wogonin exacerbates the oxaliplatin-induced dissipation of the mitochondrial membrane potential (DeltaPsim) and formation of peroxynitrite in BGC-823 cells. Moreover, wogonin allows a reduction in oxaliplatin dose when they are combined; therefore, it is a relevant strategy for reducing the side effects of oxaliplatin while achieving the same response. CONCLUSION: These results suggest that wogonin can be a potential therapeutic candidate for enhancing the efficacy of oxaliplatin in gastric cancer treatment. PMID- 29433679 TI - Metabolic changes after licorice consumption: A systematic review with meta analysis and trial sequential analysis of clinical trials. AB - BACKGROUND: Licorice, also known as liquorice, refers to the root of Glycyrrhiza glabra L., a product widely available in the market in the form of licorice flavonoid oil (LFO), which is a concentrate of licorice flavonoids, being a dietary ingredient for functional foods with potential benefits for overweight subjects. PURPOSE: To summarize the results of the numerous clinical trials, and to clarify the metabolic changes after licorice consumption, through a systematic review with meta-analysis and Trial Sequential Analysis (TSA) of clinical trials. METHODS: This review was designed according to the PRISMA (Preferred Reported Items for Systematic Reviews and Meta-Analysis) recommendations. Several electronic databases were searched to identify the clinical trials. A meta analysis approach was then developed to statistically analyze the results, followed by TSA and meta-regression analyses. RESULTS: A total 26 clinical trials were considered for the quantitative synthesis of the data, totalizing 985 patients enrolled. Overall, it was possible to verify that the licorice consumption significantly reduces the body weight (WMD: -0.433 kg; 95% CI: -0.683 to -0.183; p-value = 0.001) and consequently the body mass index (BMI) of patients (WMD: -0.150 kg/m2; 95% CI: -0.241 to -0.058; p-value = 0.001). Another result with statistical significance was the increase in the diastolic blood pressure (DBP) (1.737 mmHg; 95% CI: 0.835 to 2.621; p-value < 0.0001) observed for the group subjected to licorice consumption, which is related to the hypernatremia also caused by licorice. CONCLUSION: The present meta-analysis demonstrated the positive effects of licorice consumption on the reduction of body weight and BMI of patients. However, the results also show the increase in blood pressure of patients associated with the hypernatremia caused by licorice. Consequently, licorice consumption should be avoided by hypertensive patients. PMID- 29433680 TI - Cyclocommunol induces apoptosis in human oral squamous cell carcinoma partially through a Mcl-1-dependent mechanism. AB - BACKGROUND: Crude extract of breadfruit has been reported to have antitumor activity against various cancer cell lines with unknown mechanism. PURPOSE: This study aims to investigate the proapoptotic effect of cyclocommunol (CYC), a prenylflavonoid from breadfruit, in two oral squamous cell carcinoma (OSCC) cell lines, SCC2095 and Ca922. METHODS: The antiproliferative effects of CYC were assessed by MTT assays and PI/annexin V analysis. SCC2095 cells were transiently transfected with Mcl-1 plasmid in overexpression experiment. Other methods used to investigate the mechanism of CYC included Western blotting, acridine orange staining and confocal microscopic visualization. RESULTS: Our results showed that CYC suppressed the viability of SCC2095 and Ca922 with IC50 values at 48 h of 4.2 and 5.0 uM, respectively. This decrease in viability occurred in a caspase dependent apoptotic manner. In addition, CYC down-regulated the phosphorylation/expression of Akt/mTOR and Mcl-1, accompanied by reactive oxygen species generation, and autophagy induction. Notably, overexpression of Mcl-1 using Mcl-1-tag-myc partially rescued CYC-mediated caspase-3 activation, PARP cleavage, and cytotoxicity. In summary, our study demonstrated the proapoptotic activity of CYC on OSCC, partially through down-regulation of Mcl-1. CONCLUSION: CYC from breadfruit has translational value as a proapoptotic agent for OSCC. PMID- 29433681 TI - Zerumbone targets the CXCR4-RhoA and PI3K-mTOR signaling axis to reduce motility and proliferation of oral cancer cells. AB - BACKGROUND: The CXCR4-RhoA and PI3K-mTOR signaling pathways play crucial roles in the dissemination and tumorigenesis of oral squamous cell carcinoma (OSCC). Activation of these pathways have made them promising molecular targets in the treatment of OSCC. Zerumbone, a bioactive monocyclic sesquiterpene isolated from the rhizomes of tropical ginger, Zingiber zerumbet (L.) Roscoe ex Sm. has displayed promising anticancer properties with the ability to modulate multiple molecular targets involved in carcinogenesis. While the anticancer activities of zerumbone have been well explored across different types of cancer, the molecular mechanism of action of zerumbone in OSCC remains largely unknown. PURPOSE: Here, we investigated whether OSCC cells were sensitive towards zerumbone treatment and further determined the molecular pathways involved in the mechanism of action. METHODS: Cytotoxicity, anti-proliferative, anti-migratory and anti-invasive effects of zerumbone were tested on a panel of OSCC cell lines. The mechanism of action of zerumbone was investigated by analysing the effects on the CXCR4-RhoA and PI3K-mTOR pathways by western blotting. RESULTS: Our panel of OSCC cells was broadly sensitive towards zerumbone with IC50 values of less than 5 uM whereas normal keratinocyte cells were less responsive with IC50 values of more than 25 uM. Representative OSCC cells revealed that zerumbone inhibited OSCC proliferation and induced cell cycle arrest and apoptosis. In addition, zerumbone treatment inhibited migration and invasion of OSCC cells, with concurrent suppression of endogenous CXCR4 protein expression in a time and dose-dependent manner. RhoA-pull down assay showed reduction in the expression of RhoA-GTP, suggesting the inactivation of RhoA by zerumbone. In association with this, zerumbone also inhibited the PI3K-mTOR pathway through the inactivation of Akt and S6 proteins. CONCLUSION: We provide evidence that zerumbone could inhibit the activation of CXCR4-RhoA and PI3K-mTOR signaling pathways leading to the reduced cell viability of OSCC cells. Our results suggest that zerumbone is a promising phytoagent for development of new therapeutics for OSCC treatment. PMID- 29433682 TI - A randomised double-blind placebo-controlled pilot trial of a combined extract of sage, rosemary and melissa, traditional herbal medicines, on the enhancement of memory in normal healthy subjects, including influence of age. AB - OBJECTIVE: To evaluate for the first time the effects of a combination of sage, rosemary and melissa (Salvia officinalis L., Rosmarinus officinalis L. and Melissa officinalis L.; SRM), traditional European medicines, on verbal recall in normal healthy subjects. To devise a suitable study design for assessing the clinical efficacy of traditional herbal medicines for memory and brain function. METHODS: Forty-four normal healthy subjects (mean age 61 +/- 9.26y SD; m/f 6/38) participated in this study. A double-blind, randomised, placebo-controlled pilot study was performed with subjects randomised into an active and placebo group. The study consisted of a single 2-week term ethanol extract of SRM that was chemically-characterised using high resolution LC-UV-MS/MS analysis. Immediate and delayed word recall were used to assess memory after taking SRM or placebo (ethanol extract of Myrrhis odorata (L.) Scop.). In addition analysis was performed with subjects divided into younger and older subgroups (<= 62 years mean age n = 26: SRM n = 10, Placebo n = 16; >= 63 years n = 19: SRM n = 13, Placebo n = 6). RESULTS: Overall there were no significant differences between treatment and placebo change from baseline for immediate or delayed word recall. However subgroup analysis showed significant improvements to delayed word recall in the under 63 year age group (p < 0.0123) with Cohen's effect size d = 0.92. No adverse effects were observed. CONCLUSION: This pilot study indicates that an oral preparation of SRM at the selected dose and for the period of administration is more effective than a placebo in supported verbal episodic memory in healthy subjects under 63 years of age. Short- and long- term supplementation with SRM extract merits more robust investigation as an adjunctive treatment for patients with Alzheimer's disease and in the general ageing population. The study design proved a simple cost effective trial protocol to test the efficacy of herbal medicines on verbal episodic memory, with future studies including broader cognitive assessment. PMID- 29433683 TI - Phytochemical profile of Orthosiphon aristatus extracts after storage: Rosmarinic acid and other caffeic acid derivatives. AB - BACKGROUND: Orthosiphon aristatus (Blume) Miq. is a medicinal herb which is traditionally used for the treatment of diabetes and kidney diseases in South East Asia. Previous studies reported higher concentration of antioxidative phytochemicals, especially rosmarinic acid (ester of caffeic acid) and other caffeic acid derivatives in this plant extract than the other herbs such as rosemary and sage which are usually used as raw materials to produce rosmarinic acid supplement in the market. PURPOSE: The phytochemical profile of O. aristatus was investigated at different storage durations for quality comparison. METHODS: The phytochemicals were extracted from the leaves and stems of O. aristatus using a reflux reactor. The extracts were examined for total phenolic and flavonoid contents, as well as their antioxidant capacities, in terms of radical scavenging, metal chelating and reducing power. The phytochemical profiles were also analyzed by unsupervised principal component analysis and hierarchical cluster analysis, in relation to the factor of storage at 4 degrees C for 5 weeks. RESULTS: The leaf extract was likely to have more phytochemicals than stem extract, particularly caffeic acid derivatives including glycosylated and alkylated caffeic acids. This explains higher ratio of total phenolic content to total flavonoid content with higher antioxidant capacities for the leaf extracts. Rosmarinic acid dimer and salvianolic acid B appeared to be the major constituents, possibly contributing to the previously reported pharmacological properties. However, the phytochemical profiles were found changing, even though the extracts were stored in the refrigerator (4 degrees C). The change was significantly observed at the fifth week based on the statistical pattern recognition technique. CONCLUSION: O. aristatus could be a promising source of rosmarinic acid and its dimer, as well as salvianolic acid B with remarkably antioxidant properties. The phytochemical profile was at least stable for a month stored at 4 degrees C. It is likely to be a good choice of herbal tea with comparable radical scavenging activity, but lower caffeine content than other tea samples. PMID- 29433684 TI - Short and long term modulation of tissue minerals concentrations following oral administration of black cumin (Nigella sativa L.) seed oil to laboratory rats. AB - BACKGROUND: Nigella sativa, or commonly called black cumin is a small herb of family Ranunculaceae is a well-known medicinal plant but its effects on tissue mineral concentrations of animal bodies is unknown. PURPOSE: To study the effect of oral administration of fixed oil of black cumin seeds on tissues mineral content using laboratory rats as experimental model. STUDY DESIGN: Experimental animals were exposed to two oral doses of seed oil (60 and 120 ml kg-1 body weight). Short- and long term experiments lasted 24 h and 60 days respectively, with three replicates each. METHODS: Oil extracted from black cumin seeds was subjected to GC-MS to identify chemical components. Following the wet digestion in nitric acid, samples of whole blood and organs of rats were subjected to atomic absorption spectrophotometry for determination of elements concentrations. Data were compared statistically at p < .05. RESULTS: Compared to control, Cr, Mn, Ni, Cu, Zn showed decrease, whereas Co, Na, Mg and K demonstrated increase, but Ca showed both increase and decrease in most of the tissues upon short term exposure to low and high doses of black cumin oil. During long term exposure, Cr, Fe, Mn, Cu exhibited decrease; Co, Na, Mg and Ca concentrations demonstrated an upregulation, whereas Ni and Zn showed increase and decrease in most of the tissues. Comparison of short term with long term experiments at low dose revealed increases in Fe, Zn, Cu, Mg, K and Ca, a decrease in Cr, Mn, Ni and Cu in most tissues, but both increase and decrease in Na. At high dose, an increase occurred in Fe, Ni, Zn, K, Ca, Mg, a decrease in Cr, while both increase and decrease in Cu, Co and Na concentrations. CONCLUSION: Our study demonstrates that oral administration of black cumin seeds oil to laboratory rats significantly alters tissue trace elements and electrolytes concentrations. The study appears beneficial but indicates modulatory role of black cumin oil as regards mineral metabolism with far reaching implications in health and disease. PMID- 29433685 TI - Cholinesterase-inhibitory effect and in silico analysis of alkaloids from bulbs of Hieronymiella species. AB - BACKGROUND: In Argentina, the Amaryllidaceae family (59 species) comprises a wide variety of genera, only a few species have been investigated as a potential source of cholinesterases inhibitors to treat Alzheimer disease (AD). PURPOSE: To study the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of the basic dichloromethane extracts (E) from Hieronymiella aurea, H. caletensis, H. clidanthoides, H. marginata, and H. speciosa species, as well as the isolated compounds from these plant extracts. STUDY DESIGN AND METHODS: AChE and BChE inhibitory activities were evaluated with the Ellman's spectrophotometric method. The alkaloids composition from the E was obtained by gas chromatography-mass spectrometry (GC-MS). The E were successively chromatographed on a silica gel column and permeated on Sephadex LH-20 column to afford the main alkaloids identified by means of spectroscopic data. Additionally, an in silico study was carried out. RESULTS: Nine known alkaloids were isolated from the E of five Hieronymiella species. Galanthamine was identified in all the species by GC-MS standing out H. caletensis with a relative abundance of 9.79% of the total ion current. Strong AChE (IC50 = 1.84 - 15.40 ug/ml) and moderate BChE (IC50 = 23.74 - 136.40 ug/ml) inhibitory activities were displayed by the extracts. Among the isolated alkaloids, only sanguinine and chlidanthine (galanthamine-type alkaloids) demonstrated inhibitory activity toward both enzymes. The QTAIM study suggests that sanguinine has the strongest affinity towards AChE, attributed to an additional interaction with Ser200 as well as stronger molecular interactions Glu199 and His440.These results allowed us to differentiate the molecular behavior in the active site among alkaloids possessing different in vitro inhibitory activities. CONCLUSION: Hieronymiella species growing in Argentina represent a rich and widespread source of galanthamine and others AChE and BChE inhibitors alkaloids. Additionally, the new trend towards the use of natural extracts as pharmaceuticals rather than pure drugs opens a pathway for the development of a phytomedicine derived from extracts of Hieronymiella spp. PMID- 29433686 TI - Gastrodia elata alleviates mutant huntingtin aggregation through mitochondrial function and biogenesis mediation. AB - BACKGROUND: According to the Compendium of Materia Medica, Gastrodia elata (GE) Blume is a top-grade herbal medicine frequently used to treat dizziness, headaches, tetanus, and epilepsy, suggesting that it affects neurological functions. Although studies have supported its effects in preventing diverse neurodegenerations such as Huntington's disease (HD), its mechanisms require further investigation. PURPOSE: To investigate the ability of the molecular mechanism of GE to prevent mutant huntingtin (mHTT) protein aggregation by focusing on mitochondrial function and biogenesis, which have been proposed as the therapeutic targets of HD. STUDY DESIGN/METHODS: mHtt overexpression in pheochromocytoma (PC12) cells was used as an in vitro cell model of HD. A retardation assay was applied to measure protein aggregation during Htt expression. Cotransfection with transcriptional genes was used to test their relationships with HTT aggregates by monitoring with a confocal laser scanning microscope. Western blot analysis was used to estimate protein expression under different drug treatments or when cotransfected with other related genes. RESULTS: Mutant, abnormal Htt overexpression resulted in significant protein aggregation in PC12 cells. GE dose-dependently attenuated mHTT aggregates and increased cyclic-AMP response element-binding protein (CREB) phosphorylation. Adenosine A2A-R receptor (A2A-R) antagonist counteracted these phenomena. CREB overexpression significantly attenuated mHTT aggregation. GE increased the promoter activity and expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha). Furthermore, wild-type PGC-1alpha but not mutant PGC-1alpha overexpression attenuated mHTT aggregates. CONCLUSION: GE attenuated mHtt aggregation by mediating mitochondrial function and biogenesis through the A2A-R/PKA/CREB/PGC-1alpha-dependent pathway. PMID- 29433687 TI - Effects of a fixed herbal drug combination (Ze 185) to an experimental acute stress setting in healthy men - An explorative randomized placebo-controlled double-blind study. AB - BACKGROUND: Considering the negative effects of stress on health, there is a growing interest in stress-reducing interventions. The present study examines the effects of a fixed combination of valerian, passion flower, lemon balm, and butterbur extracts (Ze 185) on biological and affective responses to a standardized psychosocial stress paradigm. PURPOSE: The aim of the present study was to investigate the efficacy of Ze 185 on cortisol and anxiety stress responses to acute psychosocial stress in healthy subjects. STUDY DESIGN: This study was a randomized, placebo-controlled, double blind study with 3 parallel groups. METHODS: 72 healthy male participants were randomized to 3 groups (Ze 185, placebo or no treatment) during 4 days prior to a standardized psychosocial stress paradigm. Principle outcomes were salivary cortisol and self-reported anxiety responses to stress assessed at the fourth day. RESULTS: The stress paradigm induced significant and large cortisol and self-reported anxiety responses. Groups did not differ significantly in their salivary cortisol response to stress, but participants in the Ze 185 condition showed significantly attenuated responses in self-reported anxiety in comparison to placebo (F(3, 41) = 3.33, p = 0.03) and no treatment (F(3, 43) = 2.77, p = 0.05). CONCLUSION: The results show that Ze 185 significantly attenuated the subjective emotional stress response during an acute stress situation, without affecting biological stress responses. Given that a circumscribed biological stress response is to be considered as an adaptive mechanism, Ze 185 reduces self-reported anxiety response to stress without affecting assumingly adaptive biological stress responses. PMID- 29433688 TI - Synergism of prenylflavonoids from Morus alba root bark against clinical MRSA isolates. AB - BACKGROUND: Clinical methicillin-resistant Staphylococcus aureus (MRSA) is a thorny problem in current anti-infective therapeutics and a challenge of new drug development. Plant prenylflavonoids possess anti-MRSA activity, but few of the prenylflavonoids have been reported the synergistic anti-MRSA effect when they are used in combination with conventional antibacterial agents. PURPOSE: This study deals with anti-MRSA activity of four prenylflavonoids from the root bark of Morus alba and their synergism with 11 conventional antibacterial agents. METHODS: Chromatographic methods and spectral analysis were used to isolate and identify the prenylflavonoids. The antibacterial activity and synergism were assessed by the broth microdilution method, checkerboard dilution test, and time kill curve assay, respectively. RESULTS: Four prenylflavonoids, i.e., cyclocommunol (Cy, 1), morusinol (Ml, 2), morusin (Mi, 3) and kuwanon E (Ku, 4), were isolated from Morus alba bark ethanol extract. Compounds 1, 3 and 4 showed high antimicrobial activity on both methicillin-susceptible S. aureus (MSSA) and MRSA strains with MICs/MBCs at 4-16/32-64 and 4-32/16-128 ug/ml, respectively. Ml (2) was not active. Compound 2 showed synergy with amikacin (AK) and streptomycin (SM) against all the ten MRSA isolates. Ml (2) and Ku (4) also showed synergy with ciprofloxacin (CI), etimicin (EM) and vancomycin (VA) against 7-9 isolates. The fractional inhibitory concentration indices (FICIs) ranged 0.09-1.00 and the dose reduction indices (DRIs) of these antibacterial agents ranged 2-128. Cy (1) and Mi (3) showed synergy with the tested antibacterial agents against only 1-3 MRSA isolates except VA. Furthermore, the MRSA resistance could be reversed in the combinations of AK with Cy, Ml, Mi and Ku; EM with Mi and Ku; and SM with Ml by the criteria of MIC interpretive standards for Staphylococcus spp. of CLSI. All the combinations showed only indifference in the 1 * MIC time-killing experiments. The prenylated substitutions play an important role in the activity of the compounds used alone and combined with the tested antibacterials. CONCLUSIONS: The study revealed for the first time the anti-MRSA synergism of prenylflavonoids 1-4 with eleven antibacterial agents and the reversal of MRSA resistance to aminoglycosides, especially amikacin. The results might be valuable for the development of new antibacterial drugs and synergists against MRSA infection. PMID- 29433689 TI - Open Access: Is There a Predator at the Door? PMID- 29433690 TI - The recognition of prescribing by nurses, a battle that is about to be won. PMID- 29433691 TI - ? AB - Antibiotics are involved act directly or indirectly on the intestinal microbiota. The consequences of changing microbiota equilibrium are an increased risk of developing certain pathologies and the emergence of resistant bacteria. In view of the new information accumulated in recent years, a more reasonable use of antibiotics in neonatology is all the more justified. In this sense, the forthcoming publication of new recommendations for the care of early neonatal bacterial infections seems to be a good initiative. PMID- 29433692 TI - ? AB - In the era of intrapartum chemoprophylaxis to reduce GBS, rates of early onset bacterial infection have declined in term newborns. New guidelines have been written in order to adapt our current practices to this epidemiological evolution and limit excessive exams and antibiotic administrations. The main point of these new guidelines consists in a clinical systematic surveillance in maternity for well appearing newborns instead of the current empiric antibiotic treatment. Advised biological exams are also detailed. PMID- 29433693 TI - ? AB - Pharmacokinetic and pharmacodynamics (PK/PD) data on antimicrobial agents enable physicians to optimize their use in clinical practice. Neonates exhibit a large inter-individual variability in antibiotic levels due to immaturity and maturational changes in the first weeks of life. This variability explains the large therapeutic margins needed to ensure an optimal efficacy of antibiotics. These pharmacokinetic characteristics have to be taken into account when treating neonatal sepsis, along with pharmacodynamics targets for each antibiotic and notably minimal inhibitory concentration for usual causes of neonatal bacterial infections (group B streptococcus and Escherichia coli). This paper presents PK/PD data of antimicrobial agents mainly used in neonatology (beta-lactamines and aminoglycosides) to help physicians to rationalize their use of antibiotics. PMID- 29433694 TI - ? AB - All newborns superior to 34 weeks of gestationnal age (GA) are concerned by these guidelines of the French Society of Neonatology and the French Society of Pediatrics. Only newborns at risk of Early-Onset Neonatal Bacterial Infection who are clinically symptomatic have to be treated with probabilistic antibiotherapy treatment. The antibiotic combination of choice is amoxicillin + gentamicin. The two exceptions that justify dual therapy with Cefotaxime and Gentamicin are the bacteriological documentation of Escherichia coli and/or the presence of clinical signs of severity. The continuation or not of the antibiotic treatment relies on the reevaluation of the clinical examination, the bacteriological culture results (blood culture and eventual Cerebro-Spinal-Fluid (CSF) culture) after 36-48 hours of treatment. Antibiotic treatment is continued for 7 days in case of positive blood culture, with amoxicillin alone if then bacterial species implicated are group B Streptococcus (GBS) or Listeria monocytogenes, with Cefotaxime alone in case of E.coli even if the strains are susceptible to aminopenicillins. In case of meningitis due to GBS or L. monocytogenes antibiotherapy is continued for 14 days with amoxicillin alone and 21 days of cefotaxime alone in case of E. coli meningitis. Specialist advice should be sought for other bacteria or extended spectrum beat-lactamase-producing E. coli. and the absence of bacteriological documentation, according to the clinical evolution and the inflammatory parameters, it can be decided to continue or not the antibiotherapy. PMID- 29433695 TI - ? AB - Zikavirus (ZV) is a flavivirus transmitted by Aedes mosquitoes' bites. Sexual transmission is possible. Common ZV infection is asymptomatic or associates flu like signs. Guillain-Barre syndrome following ZV infection is rare. Foetal infection, during the first trimester of pregnancy especially, can lead to severe neurological troubles. Diagnosis relies on blood and urine RT-PCR during the acute phase, and serology later in the disease. ELISA assays false positives are reported among patients infected with another flavivirus, whereas sero neutralization is more specific. Treatment is symptomatic. Several vaccines are in the pipeline. PMID- 29433696 TI - ? AB - Rational use of antibiotic has become a national and international health priority to fight against the emergence of multiresistant bacteria. Neonates are particularly exposed to antibiotic treatments because of their high susceptibility to severe infection and the lack of specificity of sepsis signs that make diagnosis difficult. This population is also particularly susceptible to microbiota disruption due to antibiotic treatment. Implementation of antibiotic stewardship in neonate is then an urgent need. According to a literature review, principles of antibiotic stewardship implementation in neonate are based on: (i) a multidisciplinary team comprising infectious disease specialists and aware of neonatal specificities (diagnosis, bacterial epidemiology, pharmacology) ; (ii) clear and easy-to-evaluate goals discussed a priori with neonatologists ; (iii) short-term assessment of the impact on antibiotic consumption and antimicrobial resistance ; (iv) enablement of the healthcare professionals within the ward to enhance the sustainability and (v) support from the institution. PMID- 29433697 TI - Where Does Your State Stand on Shackling of Pregnant Incarcerated Women? AB - Pregnant incarcerated women have been identified as a particularly high-risk group and among the most vulnerable women in the United States. The use of shackling or restraints poses health risks to pregnant women and their fetuses. Currently, only 22 states have legislation prohibiting or limiting the shackling of pregnant women. Here we provide an overview of the potential negative health outcomes that can result from shackling pregnant women, especially during labor and birth, and suggest strategies for nurses who wish to promote optimal health care for incarcerated women and to advocate for anti-shackling legislation in their states. PMID- 29433698 TI - Barriers to and Interventions that Increase Nurses' and Parents' Compliance With Safe Sleep Recommendations for Preterm Infants. AB - The purpose of this integrative review was to identify interventions that increase compliance of nurses and of parents with safe sleep recommendations for premature infants. Ten studies were included in the final sample, including three studies with a prospective descriptive design, five quality improvement initiatives with an interventional research design, one secondary analysis, and one retrospective medical chart review. Study samples included neonatal nurses and parents of premature infants in NICUs and transitional care nurseries in Massachusetts, Missouri, New York, North Carolina, Ohio, Pennsylvania, and Texas. Sample sizes ranged from 5 to 259 NICU parents and 86 to 658 neonatal nurses. The categories of interventions we identified include identifying barriers to compliance, changing hospital policy, and providing safe sleep education for nurses and parents. We conclude that hospitals should have current, evidence based safe sleep policies with clear transition guidelines for premature infants and that consistent and comprehensive nursing and parental education related to safe sleep should include current American Academy of Pediatrics recommendations and should address potential barriers to compliance. PMID- 29433699 TI - The Health Care Experiences of Lesbian Women Becoming Mothers. AB - As modern family composition shifts-for many, away from a heteronormative nuclear family-so, too, must the health care that families receive. Lesbian women and their families face particular difficulties with maternity care in the United States and internationally, because many care providers lack an understanding of this population's specific health care needs. In this article, I examine the challenges faced by lesbian women during the transition period to new motherhood and recommend improvements that can be made by individual providers and the health care system as a whole to better provide culturally competent health care for this population. PMID- 29433700 TI - A Literature Review of Cervical Cancer Screening in Transgender Men. AB - Most female-to-male (FTM) transgender men retain their cervixes and need comprehensive sexual health care, including cervical cancer screening. According to the literature, FTM individuals obtain cervical cancer screening less frequently and are less likely to be up to date on their Pap tests compared with cisgender women. Misinformation related to human papillomavirus and cervical cancer risk was noted for health care providers and FTM individuals. Absence of transgender-specific guidelines or trained health care providers presents barriers to cervical cancer screening for FTM individuals, and further research is indicated to develop comprehensive guidelines unique to the needs and experiences of this population. PMID- 29433701 TI - Intention and Initiation of Breastfeeding Among Women Who Are Incarcerated. AB - The Baby-Friendly Hospital Initiative recommends that all mothers be shown how to breastfeed, even when mothers and newborns are separated. Most incarcerated women are separated from their infants after the postpartum hospital stay, creating barriers to breastfeeding. We examined breastfeeding among a sample of women participating in a prison-based pregnancy program. Quantitative data indicated that women who discussed breastfeeding with their doulas were more likely to initiate breastfeeding. Three qualitative themes were identified: Benefits of Breastfeeding, Barriers to Breastfeeding, and Role of the Doula. We identified incongruence between the expected standard of breastfeeding support and the care incarcerated women received. Findings suggest that prison-based doula care might be an effective intervention for supporting breastfeeding among incarcerated women and highlight the importance of education for perinatal nurses about breastfeeding support of incarcerated women. PMID- 29433702 TI - Educating Nurses to Screen and Intervene for Intimate Partner Violence During Pregnancy. AB - Intimate partner violence (IPV) is a problem affecting women and families across the nation, and it has been associated with adverse pregnancy and birth outcomes. Here we describe how our team implemented an evidence-based protocol for the screening of pregnant women for IPV and case management for those experiencing violence. This protocol was implemented on an antepartum triage unit where nurses were educated on IPV, methods for screening pregnant women, and a brief intervention. Education included an online module and a live session with role playing exercises. Test scores indicated a significant increase in nurses' knowledge after completion of the module, and the overall educational program was rated as excellent by program participants. As part of the project, the Abuse Assessment Screen and the Danger Assessment-5-two instruments with predictive validity-were incorporated into the electronic health record. PMID- 29433704 TI - Becoming a Discerning User of Health-Related Mobile Apps. PMID- 29433705 TI - Continuous Labor Support for Every Woman. PMID- 29433703 TI - Low-Dose Aspirin for the Prevention of Preeclampsia. AB - Preeclampsia is a hypertensive disorder specific to pregnancy that remains a significant cause of maternal and neonatal morbidity and mortality. Identification of women who are most at risk for preeclampsia is imprecise. Because of the potential negative health consequences of preeclampsia for women and newborns and the lack of effective screening mechanisms preventing preeclampsia is an important component of prenatal care. Researchers have documented that low-dose aspirin, taken daily after the first trimester, can decrease the development of preeclampsia and reduce the incidence of preterm birth and birth of small-for-gestational-age infants. This column includes an overview of low-dose aspirin in pregnancy and a review of current recommendations from leading national organizations. PMID- 29433706 TI - A Breastfeeding Journey Through the Eyes of a Midwife Mother. PMID- 29433707 TI - Flexible Bronchoscopy. AB - Flexible bronchoscopy has changed the course of pulmonary medicine. As technology advances, the role of the flexible bronchoscope for both diagnostic and therapeutic indications is continually expanding. This article reviews the historical development of the flexible bronchoscopy, fundamental uses of the flexible bronchoscope as a tool to examine the central airways and obtain diagnostic tissue, and the indications, complications, and contraindications to flexible bronchoscopy. PMID- 29433708 TI - Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Diagnosis and Staging of Lung Cancer. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) is fundamental to the diagnosis of lung cancer, as many patients present with more advanced stages of lung cancer, with enlarged hilar and mediastinal lymph nodes. It also represents a way to sample pulmonary masses directly to make the diagnosis, whereby no other accessible tissue is present and the mass sits adjacent to a large central airway. Very importantly also, EBUS TBNA is the widely accepted first procedure in lung cancer staging. A combined procedure of EUS TBNA can be performed to improve diagnostic accuracy. PMID- 29433709 TI - State-of-the-Art Modalities for Peripheral Lung Nodule Biopsy. AB - Lung nodules are being increasingly detected, particularly with lung cancer screening with low-dose computed tomography. Although the vast majority of lung nodules are benign, many often require tissue diagnosis. Several modalities to obtain diagnostic tissue from peripheral lung nodules are available. Bronchoscopic modalities such as radial ultrasound and electromagnetic navigational bronchoscopy are becoming increasingly used because of their superior safety profile and improving diagnostic yield. Although these modalities continue to become more advanced, newer and complementary technologies appear promising. PMID- 29433710 TI - Endobronchial Ablative Therapies. AB - Endobronchial ablative therapies, such as mechanical debulking, laser therapy, electrocautery, argon plasma coagulation, cryotherapy, brachytherapy, photodynamic therapy, microdebrider bronchoscopy, resector balloon deobstruction, and intratumoral chemotherapy, are performed through a rigid or flexible bronchoscope in palliating or curing symptomatic malignant and benign airway lesions to improve symptoms, quality of life, and survival. Technical factors together with patient- and lesion-specific features determine the therapy of choice, as each therapy is different in capacity, limitation, and complications. In this article, indications, contraindications, and complications of endobronchial ablative therapies as well as practical issues related to their rational and cost-effective use are reviewed. PMID- 29433711 TI - The Art of Rigid Bronchoscopy and Airway Stenting. AB - Interventional pulmonology has grown significantly over the last 2 decades and is now seen as an essential component in thoracic oncology care. The rigid bronchoscope occupies a central role in this specialty and offers many important advantages over the flexible scope when performing therapeutic procedures on central airways. Although stenting practices have evolved, it is generally accepted that stents offer an important treatment option for selected patients with benign and malignant airway diseases. This article discusses rigid bronchoscopy and stenting, future challenges, complications of the procedure and stents, and future directions. PMID- 29433712 TI - Bronchoscopic Lung Volume Reduction. AB - Since the publication of the National Emphysema Treatment Trial study, lung volume reduction (LVR) has been considered a therapeutic alternative for patients with advanced obstructive lung disease. The high complication rate of surgical LVR has led to the development of bronchoscopic LVR (BLVR). Of the currently available BLVR alternatives, coils and unidirectional endobronchial valves lead the list. The choice of each device depends on emphysema characteristics and presence of collateral ventilation. Evaluation of these patients at centers with expertise in interventional pulmonology and management of BLVR is strongly recommended. PMID- 29433713 TI - Pulmonologist's Road Map to Mediastinal Lymph Node Imaging. AB - Mediastinal lymph node station maps are intended to facilitate nodal staging in patients with non-small cell lung cancer. These maps have been revised over time and the International Association for Study of Lung Cancer (IASLC) map is the latest rendition. This article illustrates the imaging appearance of each of the IASLC map mediastinal lymph node stations, overviews some of the mediastinal lymph node sampling techniques, and discusses common pitfalls of the IASLC map. It also reviews mediastinal anatomic variants and pathologic features that may simulate lymphadenopathy. PMID- 29433714 TI - Malignant Pleural Effusion: From Diagnostics to Therapeutics. AB - Malignant pleural effusion is a common complication of cancer and denotes a poor prognosis. It usually presents with dyspnea and a unilateral large pleural effusion. Thoracic computed tomography scans and ultrasound are helpful in distinguishing malignant from benign effusions. Pleural fluid cytology is diagnostic in about 60% of cases. In cytology-negative disease, pleural biopsies are helpful. Current management is palliative. Previously, first-line treatment for recurrent symptomatic malignant pleural effusion was chest drain insertion and talc pleurodesis, with indwelling pleural catheter insertion reserved for patients with trapped lung or failed talc pleurodesis. However, catheter insertion is an increasingly acceptable first-line treatment. PMID- 29433716 TI - Percutaneous Dilational Tracheostomy. AB - Tracheostomy tubes can be inserted surgically or percutaneously via percutaneous dilational tracheostomy (PDT). Tracheostomy is performed for upper airway obstruction, though more often to allow prolonged mechanical ventilation in place of endotracheal tubes. Preparation, performance, and postoperative management for PDT are best provided by a multidisciplinary team. Although PDT is a safe procedure in the hands of experienced operators, both early and late complications can arise. Caution must also be taken during early tracheostomy tube exchange given that immaturity of the stomal tract can risk loss of the airway. PMID- 29433715 TI - Intracavitary Therapeutics for Pleural Malignancies. AB - Pleural malignancies remain a serious therapeutic challenge, and are frequently refractory to standard treatment; however, they have the advantage of occurring in an enclosed cavity readily accessible for examination, biopsy, and serial sampling. Novel therapeutics can be administered via intracavitary delivery to maximize efficacy by targeting the site of involvement and potentially mitigating the adverse effects of systemic therapies. The easy accessibility of the pleural space lends itself well to repeated sampling and analysis to determine efficacy and toxicity of a given treatment paradigm. These factors support the rationale for delivery of novel therapeutics directly into the pleural space. PMID- 29433717 TI - Tracheobronchomalacia and Excessive Dynamic Airway Collapse. AB - Tracheobronchomalacia (TBM) and excessive dynamic airway collapse (EDAC) are more frequently being recognized as the etiology of multiple types of respiratory complaints from chronic cough to exertional syncope to recurrent infections. Identification of these conditions requires a high suspicion, as well as a thorough history and physical examination. Dynamic computed tomography imaging and bronchoscopic evaluation are integral in achieving an accurate diagnosis. Once recognized, treatment ranges from addressing underlying contributing conditions to surgical stabilization of the airway. Referral to an institution familiar with the evaluation and treatment of TBM/EDAC is essential for the appropriate management of these conditions. PMID- 29433718 TI - Pediatric Interventional Pulmonology. AB - Although controversy over the role of flexible versus rigid bronchoscopy for airway foreign body management persists, the effort should focus on prevention of aspiration of foreign bodies instead. This article discusses several recent advances in the bronchoscopic management of congenital tracheal stenosis, pediatric airway stenting, and the use of different types of lasers in children. The lack of randomized clinical trials leaves pediatric interventional bronchoscopic procedures without much national or international standards or guidelines. The number of published data in the form of cases reports and case series remains modest. More bronchoscopists should be trained in this growing field to overcome these limitations. PMID- 29433719 TI - The Business of Bronchoscopy: How to Set up an Interventional Pulmonology Program. AB - Interventional pulmonology has advanced rapidly over the last decade and continues to evolve with new medical advances and changes in the health care landscape. Establishing and developing a new interventional pulmonology program entails careful planning, including a needs assessment, a business plan with financial and marketing considerations, and outcomes monitoring. Addressing these aspects will provide a framework to ensure the success of a new interventional pulmonology program that can provide valuable services to the local practice and community. PMID- 29433721 TI - Bronchial Thermoplasty: A Nonpharmacologic Therapy for Severe Asthma. AB - Bronchial thermoplasty is an innovative treatment for patients with severe asthma and chronic airflow obstruction with an established long-term efficacy and safety profile. This review focuses on the role of bronchial thermoplasty in severe asthma, its mechanism of action, appropriate patient selection, current evidence, and recent developments of this therapy. PMID- 29433720 TI - Bronchoscopic Therapies for Peripheral Lung Malignancies. AB - Current advances in guided bronchoscopy methods permit minimally invasive access to essentially any area of the lungs. This provides a potential means to treat patients with localized lung malignancies who might not otherwise tolerate conventional treatment, which commonly relies on surgical resection. Ablation methods have long been used for bronchoscopic treatment of central airway malignancies and percutaneous treatment of peripheral lung cancer. This article reviews ablation technologies being adapted for use with guided bronchoscopy and the current state of investigation for the treatment of peripheral lung malignancies. PMID- 29433722 TI - Advances in Interventional Pulmonology. AB - Much has changed since the last review of interventional pulmonology (IP) published in this Clinics series. The rate of development of new techniques and their complexities require IP physicians to be constantly maintaining and updating their skill set. International agreed training pathways help ensure that the interventionalists of the present and future have the required knowledge of anatomy, manual dexterity, and clinical judgment to keep up with the continuing advances that are constantly expanding IP's diagnostic and therapeutic boundaries. IP remains one of the most desirable subspecialities in pulmonology, and the technologic advances make the future an exciting one. PMID- 29433723 TI - Reviewing Lung Cancer Screening: The Who, Where, When, Why, and How. AB - Lung cancer screening with annual low-dose computed tomography (CT) decreases lung cancer mortality in high-risk patients, as defined by smoking history (> 30 pack-years) and age (55-74 years). Risks to screening include overdiagnosis, anxiety about indeterminate nodules, and radiation exposure. To be effective, lung cancer screening must combine individualized risk assessment, shared decision-making, smoking cessation, structured reporting, high quality and multi specialty cancer care, and reliable follow-up; a multidisciplinary approach is crucial. Specialty organizations have outlined both the components of high quality lung cancer screening programs and the proposed metrics that programs should track. Long-term outcomes of lung cancer screening in the general population, further refinement of who to screen, and use of biomarkers for early cancer detection are ongoing research questions. PMID- 29433724 TI - Early Lung Cancer Detection. AB - Lung cancer is the most common cause of cancer deaths worldwide. A major reason for poor prognosis is that patients are usually diagnosed at an advanced stage and thus there are limited options for curative treatment at the time of diagnosis. Early detection may improve lung cancer survival, as demonstrated in computed tomography screening studies. New and innovative bronchoscopic methods have been developed for the early diagnosis of lung cancer. High-precision bronchoscopic imaging technology, such as optical biopsy, may potentially replace traditional biopsy techniques. This article reviews the advanced technologies for detection of early lung cancer. PMID- 29433725 TI - Palliative Care and Interventional Pulmonology. AB - Since pulmonary pathologies, such as lung cancer and chronic obstructive pulmonary disease (COPD), are some of the leading causes of morbidity and mortality around the world, pulmonologists are likely to encounter patients with unmet palliative care needs. This article focuses on the symptoms and complications encountered by patients with terminal pulmonary conditions, briefly describes the non-interventional palliative strategies, and then discusses more advanced therapies available in the realm of interventional pulmonology. Most of the literature discussed here is derived from patients with lung cancer and COPD. PMID- 29433726 TI - Sedation in Bronchoscopy: A Review. AB - Bronchoscopy has long been used as a diagnostic and therapeutic tool in medicine, with a wide range of appropriate sedative options. Flexible bronchoscopy is generally performed with sedation, and the choice of sedative is generally left to the practice pattern of the performing bronchoscopist. The concept of sedation is complex, with varying degrees of consciousness. A literature search was conducted on MEDLINE from 1969 to 2016, and appropriate data were reviewed. Randomized, controlled trials and prospective cohort studies were considered of highest impact. This article is a comprehensive review of existing data regarding sedation during bronchoscopy. PMID- 29433727 TI - Point-of-Care Ultrasound in the Intensive Care Unit. AB - Spreading beyond the realm of tertiary academic medical centers, point-of-care ultrasound in the intensive care unit is an important diagnostic tool. The real time feedback garnered can lead to critical and clinically relevant changes in management and decrease potential complications. Bedside ultrasound evaluation in the intensive care setting with a small, portable equipment is well-suited for placement of central lines, lumbar puncture, thoracentesis or other bedside ICU procedures and in the evaluation of cardiac activity, pleural and abdominal cavity and the overall fluid volume. Formalized curriculums centering on point-of care ultrasound are emerging that will enhance its applicability and relevance. PMID- 29433728 TI - Bronchoscopy Education: An Experiential Learning Theory Perspective. AB - Bronchoscopy programs implementing the experiential learning model address different learning styles. Problem-based learning improves knowledge retention, critical decision making, and communication. These modalities are preferred by learners and contribute to their engagement, in turn leading to durable learning. Follow-up after live events is warranted through spaced education strategies. The objectives of this article are to (1) summarize and illustrate the implementation of experiential learning theory for bronchoscopy courses, (2) discuss the flipped classroom model and problem-based learning, (3) illustrate bronchoscopy checklists implementation in simulation, and (4) discuss the importance of feedback and spaced learning for bronchoscopy education programs. PMID- 29433729 TI - Revolution in Respiratory Medicine. PMID- 29433730 TI - HAPPY NEW CAREER!! PMID- 29433731 TI - Relation of Increased Epicardial Fat After Fontan Palliation to Cardiac Output and Systemic Ventricular Ejection Fraction. AB - Epicardial fat produces multiple proinflammatory cytokines and is associated with adverse cardiovascular events. Inflammation and resultant endothelial dysfunction may play a role in progressive myocardial dysfunction among adults with single ventricle physiology after Fontan palliation, but the potential impact of increased epicardial fat volume (EFV) has not been studied. This study sought to determine if there is greater EFV in Fontan patients compared with a group of repaired tetralogy of Fallot (rTOF) patients. We retrospectively measured EFV manually on cardiac magnetic resonance imaging in Fontan patients, >=15 years, and 1:1 age, sex, and body mass index-matched patients with rTOF. EFV was indexed to body surface area. A random subset of studies was re-measured to assess intra- and interobserver reliability. Fontan patients (n = 63, median age 21.6 years, 51% male, mean body mass index 24.2 +/- 5.6 kg/m2) had a larger indexed EFV compared with matched rTOF patients (75.3 +/- 29.2 ml/m2 vs 60.0 +/- 19.9 ml/m2, p = 0.001). In Fontan patients, indexed EFV was inversely correlated with ventricular ejection fraction (r = -0.26, p = 0.04) and cardiac index (r = -0.33, p = 0.01). Intra- and interobserver reliabilities of the indexed EFV measurements in both groups were excellent (intraclass correlation coefficient ranges from 0.93 to 0.97). In conclusion, indexed EFV is higher in Fontan patients compared with patients with rTOF and is associated with lower ventricular ejection fraction and cardiac index. Increased EFV could play a role in the failing Fontan circulation, but longitudinal studies are necessary to establish any causative role. PMID- 29433732 TI - Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan: Role of Angiotensin II Receptor Type 1-Independent Activation of Endothelial Function. AB - Marfan syndrome (MFS) is a genetic disorder that frequently leads to aortic root dissection and aneurysm. Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS associated aortic root dilation, casting doubts about optimal therapy. To study the deleterious role of normal ATR1 signaling in aortic root widening, we generated MFS mice lacking ATR1a expression in an attempt to preserve protective ATR2 signaling. Despite being hypotensive and resistant to AngII vasopressor effects, MFS/ATR1a-null mice showed unabated aortic root enlargement and remained fully responsive to losartan, confirming that blood pressure lowering is of minor therapeutic value in MFS and that losartan's antiremodeling properties may be ATR1 independent. Having shown that MFS causes endothelial dysfunction and that losartan can activate endothelial function in mice and patients, we found that nitric oxide synthase (NOS) inhibition renders losartan therapeutically inactive, whereas multiple transgenic and pharmacologic models of endothelial NOS activation block aortic root dilation by correcting extracellular signal regulated kinase signaling. In vitro, losartan can increase endothelial NO release in the absence of AngII and correct MFS NO levels in vivo. Our data suggest that increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in MFS. PMID- 29433733 TI - DAF-16: FOXO in the Context of C. elegans. AB - In Caenorhabditis elegans, there is a single FOXO transcription factor homolog, encoded by the gene, daf-16. As a central regulator for multiple signaling pathways, DAF-16 integrates these signals which results in modulation of several biological processes including longevity, development, fat storage, stress resistance, innate immunity, and reproduction. Using C. elegans allows for studies of FOXO in the context of the whole animal. Therefore, manipulating levels or the activity of daf-16 results in phenotypic changes. Genetic and molecular analysis revealed that similar to other systems, DAF-16 is the downstream target of the conserved insulin/IGF-1 signaling (IIS) pathway; a PI 3 kinase/AKT signaling cascade that ultimately controls the regulation of DAF-16 nuclear localization. In this chapter, I will focus on understanding how a single gene daf-16 can incorporate signals from multiple upstream pathways and in turn modulate different phenotypes as well as the study of FOXO in the context of a whole organism. PMID- 29433735 TI - Regulation of Hepatic Glucose Metabolism by FoxO Proteins, an Integrated Approach. AB - FoxO proteins are ancient targets of insulin action and play an important role in mediating effects of insulin on gene expression and metabolism. Regulation of FoxO function in the liver is critical for the ability of insulin to maintain glucose homeostasis and suppress hepatic glucose production (HGP), and dysregulation of FoxO function is thought to contribute to the pathogenesis of diabetes mellitus. Signaling by the insulin/PI3 kinase/Akt pathway suppresses FoxO function, and FoxO proteins also are regulated by counterregulatory factors and sirtuin deacetylases which increase their activity. FoxO proteins promote gluconeogenic gene expression; however, effects of FoxO proteins on glycolytic, lipogenic, and lipid catabolic pathways also are important in mediating the effects of FoxOs on HGP. Recent studies indicate that hepatic FoxO proteins also exert important effects on extrahepatic tissues, including white and brown fat, that contribute to the regulation of HGP and systemic glucose utilization. Together, these observations indicate that FoxO proteins contribute to the regulation of systemic and hepatic glucose metabolism as part of a larger complex system engaged in the maintenance of metabolic homeostasis and the adaptation to changes in nutrient availability. PMID- 29433734 TI - FOXO in Neural Cells and Diseases of the Nervous System. AB - The evolutionarily conserved FOXO family of transcription factors has emerged as a significant arbiter of neural cell fate and function in mammals. From the neural stem cell (NSC) state through mature neurons under both physiological and pathological conditions, they have been found to modulate neural cell survival, stress responses, lineage commitment, and neuronal signaling. Lineage-specific FOXO knockout mice have provided an invaluable tool for the dissection of FOXO biology in the nervous system. Within the NSC compartments of the brain, FOXOs are required for the maintenance of NSC quiescence and for the clearance of reactive oxygen species. Within mature neurons, FOXO transcriptional activity is essential for the prevention of age-dependent axonal degeneration. Acutely, FOXO3 has been found to cause axonal degeneration upon withdrawal of neurotrophic factors. In more active neural signaling, FOXO6 promotes increased dendritic spine density of hippocampal neurons and is required for the consolidation of memories. In addition to the central nervous system (CNS), FOXOs also influence the functionality of the peripheral nervous system (PNS). FOXO1 knockout within the PNS results in a reduction of sympathetic tone and decreased levels of brain derived norepinephrine and lower energy expenditure. FOXO3 knockout mice have impaired hearing which may be due to defects in synapse localization within the ear. Given the scope of FOXO activities in both the CNS and PNS, it will be of interest to study FOXOs within the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. From within the nervous system, FOXOs may also regulate important parameters such as whole-body metabolism, motor function, and catecholamine production, making FOXOs key players in physiologic homeostasis. PMID- 29433736 TI - The Role of FoxOs in Bone Health and Disease. AB - Recent studies with murine models of cell-specific loss- or gain-of-function of FoxOs have provided novel insights into the function and signaling of these transcription factors on the skeleton. They have revealed that FoxO actions in chondrocytes are critical for normal skeletal development, and FoxO actions in cells of the osteoclast or osteoblast lineage greatly influence bone resorption and formation and, consequently, bone mass. FoxOs also act in osteoblast progenitors to inhibit Wnt signaling and bone formation. Additionally, FoxOs decrease bone resorption via direct antioxidant effects on osteoclasts and upregulation of the antiosteoclastogenic cytokine OPG in cells of the osteoblast lineage. Deacetylation of FoxOs by the NAD-dependent histone deacetylase Sirt1 in both osteoblasts and osteoclasts stimulates bone formation and inhibits bone resorption, making Sirt1 activators promising therapeutic agents for diseases of low bone mass. In this chapter, we review these advances and discuss their implications for the pathogenesis and treatment of estrogen deficiency-, Type 1 diabetes-, and age-related osteoporosis. PMID- 29433737 TI - Regulation of FOXO Factors in Mammalian Cells. AB - Forkhead box O (FOXO) transcription factors are central regulators of cellular homeostasis. FOXOs respond to a wide range of external stimuli, including growth factor signaling, oxidative stress, genotoxic stress, and nutrient deprivation. These signaling inputs regulate FOXOs through a number of posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and methylation. Covalent modifications can affect localization, DNA binding, and interactions with other cofactors in the cell. FOXOs integrate the various modifications to regulate cell type-specific gene expression programs that are essential for metabolic homeostasis, redox balance, and the stress response. Together, these functions are critical for coordinating a response to environmental fluctuations in order to maintain cellular homeostasis during development and to support healthy aging. PMID- 29433738 TI - FOXO3 and Exceptional Longevity: Insights From Hydra to Humans. AB - Aging is a complex, multifactorial process with significant plasticity. While several biological pathways appear to influence aging, few genes have been identified that are both evolutionarily conserved and have a strong impact on aging and age-related phenotypes. The FoxO3 gene (FOXO3), and its homologs in model organisms, appears especially important, forming a key gene in the insulin/insulin-like growth factor-signaling pathway, and influencing life span across diverse species. We highlight some of the key findings that are associated with FoxO3 protein, its gene and homologs in relation to lifespan in different species, and the insights these findings might provide about the molecular, cellular, and physiological processes that modulate aging and longevity in humans. PMID- 29433739 TI - Stem Cells Seen Through the FOXO Lens: An Evolving Paradigm. AB - Stem cells self-renew and differentiate to generate all tissues and cells in the body. Stem cell health promotes adaptive responses to tissue damage or loss and is essential for tissue regeneration with age. In the past decade, the evolutionarily conserved transcription factors FOXO with known functions in promoting healthy aging have emerged as key regulators of stem cell homeostasis in various tissues, including blood, neural, and muscle stem cells. Aberrant FOXO functions have been implicated in a variety of disorders including neurodegenerative, blood, cancer, and diabetes some of which are fostered by abnormal stem cell function. As discussed in this chapter, at least in some stem cells FOXO regulatory mechanisms and applied functions follow a complex set of rules distinct from that operating in progenitor cell populations and in cultured cell lines. Elucidating the exact nature of FOXO properties in stem cells will be critical for identifying and targeting aberrant FOXO-mediated mechanisms that promote stem cell-derived disease specifically with age. PMID- 29433740 TI - FOXOs Maintaining the Equilibrium for Better or for Worse. AB - A paradigm shift is emerging within the FOXO field and accumulating evidence indicates that we need to reappreciate the role of FOXOs, at least in cancer development. Here, we discuss the possibility that FOXOs are both tumor suppressors as well as promoters of tumor progression. This is mostly dependent on the biological context. Critical to this dichotomous role is the notion that FOXOs are central in preserving cellular homeostasis in redox control, genomic stability, and protein turnover. From this perspective, a paradoxical role in both suppressing and enhancing tumor progression can be reconciled. As many small molecules targeting the PI3K pathway are developed by big pharmaceutical companies and/or are in clinical trial, we will discuss what the consequences may be for the context-dependent role of FOXOs in tumor development in treatment options based on active PI3K signaling in tumors. PMID- 29433741 TI - Preface. PMID- 29433742 TI - Is Corneal Arcus Independently Associated With Incident Cardiovascular Disease in Asians? PMID- 29433744 TI - Chemotherapy-induced response of liver hemangiomas in a patient with a germ cell tumor: a case report. AB - Liver hemangiomas are the most common benign primary tumors of the liver. Due to their high prevalence, incidental finding of hemangiomas during radiological workup of oncologic patients is not uncommon. We present the case of a patient diagnosed of an ovarian immature teratoma and hepatic lesions with typical radiological appearance of hemangiomas that decreased in size during adjuvant chemotherapy with BEP regimen (cisplatin, etoposide and bleomycin). Chemotherapy induced shrinkage of hepatic hemangiomas can mimic the response of liver metastases to chemotherapy and may induce erroneous interpretations. The purpose of this report is to describe a chemotherapy-induced response of liver hemangiomas, especially when BEP combination is used. To date this observation has been barely reported in the literature and, to our knowledge, this is the first documented case of chemotherapy-induced response of liver hemangiomas in a patient diagnosed of an ovarian immature teratoma. PMID- 29433743 TI - Use of Donors Predisposed by Corneal Collagen Cross-linking in Penetrating Keratoplasty for Treating Patients With Keratoconus. PMID- 29433745 TI - The impact factor and RADIOLOGIA. PMID- 29433746 TI - ? PMID- 29433747 TI - Clinical, Social, and Genetic Factors Associated with Obesity at 12 Months of Age. AB - OBJECTIVE: To examine genomic, social, and clinical risk factors of >=85 weight for length percentile (WFLP) at 12 months. STUDY DESIGN: Children in this study had whole-genome sequencing, and clinical and social data were collected. WFLPs at 12 months of age were grouped as follows: (1) <85th, (2) >=85th to <95th, (3) >=95th to <99th, and (4) >=99th. Whole-genome sequencing data were used to analyze rare and common variants, and association of clinical and social factors was examined. RESULTS: A total of 690 children were included; WFLPs were 422 (61.2%) <85th, 112 (16.2%) >=85th-<95th, 89 (12.9%) >=95th-<99th, and 67 (9.7%) >=99th. Family-related risk factors associated with greater WFLP were greater paternal body mass index, WFLP >=99th OR 1.10 (1.03-1.16), and greater than recommended weight gain in pregnancy, WFLP >=85th-<95th OR 1.90 (1.09-3.26). More breast milk at 6 months was protective factor: WFLP >=85th-<95th, OR 0.98 (0.97 0.99), WFLP >=95th-<99th OR 0.98 (0.97-0.99), and WFLP >=99th OR 0.98 (0.96 0.99). Although none of the variants reached genome-wide significance, there was a trend toward increased prevalence of genetic variants within or near genes previously associated with obesity in children with WFLP >=99th. CONCLUSION: This cross-sectional study identified several modifiable factors, including increased weight gain in pregnancy and decreased breast milk at 6 months, associated with greater WFLP at 12 months. Strong genetic factors were not identified. PMID- 29433748 TI - Discussion of "Uptake and impact of synoptic reporting in a community care setting". PMID- 29433749 TI - Discussion of "Sarcopenia is not associated with morbidity, mortality, or recurrence after esophagectomy for cancer". PMID- 29433750 TI - Children's explicit assessments of reliability influence their willingness to learn novel labels. AB - This study examined how explicitly evaluating another person's performance influences 3.5-year-old children's willingness to learn from that person. Children interacted with a speaker who presented a series of familiar objects and labeled them either accurately or inaccurately. After establishing reliability, the speaker taught nonsense labels for two additional familiar objects. Half of the children were asked to explicitly judge whether the speaker was reliable before the novel labels were presented; half were asked to do so at the end of the experiment. Children who were given an opportunity to verbally assess the speaker's accuracy prior to label learning were more likely than those evaluating afterward to avoid learning from the previously inaccurate labeler. These findings show that explicitly evaluating their knowledge can reduce children's willingness to learn words from an unreliable source, expanding on prior research showing influences of explicit evaluations on children's problem solving. PMID- 29433751 TI - Corrigendum to 'Scavengers for bacteria: Rainbow trout have two functional variants of MARCO that bind to gram-negative and -positive bacteria' [Dev and Comp Imm (2017) 95-105]. PMID- 29433752 TI - Irradiation of rainbow trout at early life stages results in a proteomic legacy in adult gills. Part B; the effect of a second radiation dose, after one year, on the proteomic responses in the irradiated and non-irradiated bystander fish. AB - This study extends the investigation of the legacy effects of exposure to a single radiation dose at one of four early life stages, in adult rainbow trout (Part A), by examining the effects of a second identical dose after one year; i.e. egg 48 h after fertilisation (48 h egg) + 1 year, eyed egg + 1 year, yolk sac larvae (YSL) + 1 year and first feeder + 1 year. This included the induction of a bystander effect in non-irradiated trout which had swam with the irradiated fish. The second radiation dose negated any beneficial proteomic responses following early life stage irradiation only, particularly irradiation of 48 h eggs and eyed eggs (Part A). Instead the responses after early life stage + 1 year irradiation are consistently associated with tumorigenesis, cancer progression, or are otherwise damaging: upregulation of alpha-globin 1 (YSL + 1 year and first feeders + 1 year) and downregulation of histone H1, type II keratin, malate dehydrogenase 2-2, Na/K ATPase alpha subunit isoform 1b, nucleoside diphosphate kinase (48 h egg + 1 year), electron transfer flavoprotein subunit alpha (eyed egg + 1 year), 60 S ribosomal protein L30 (YSL + 1 year) and haemoglobin subunit beta-4 (first feeder + 1 year). Most significantly the second radiation dose also negated the overwhelmingly beneficial bystander effect proteomic responses induced by trout irradiated at an early life stage only (Part A). Instead the bystander effect proteomic changes induced by trout irradiated at an early life stage and again at 1 year have been associated with uncertain, with respect to tumorigenesis, or detrimental effects; upregulation of alpha-globin 1 (YSL + 1 year and first feeder + 1 year) and downregulation of malate dehydrogenase 2-2, nucleoside diphosphate kinase (48 h egg + 1 year), transferrin precursor (eyed egg + 1 year), 60 S ribosomal protein L30 (YSL + 1 year) and serine / threonine-protein phosphatase 2 A 65 kDa (first feeder + 1 year). This difference between the bystander effect induced proteomic changes following early life stage irradiation only and early life stage + 1 year irradiation may indicate a fundamental change in the non-targeted effects of radiation following multiple exposure to radiation. PMID- 29433753 TI - A glutathione-responsive sulfur dioxide polymer prodrug as a nanocarrier for combating drug-resistance in cancer chemotherapy. AB - Multidrug resistance (MDR) in cancer remains a significant challenge for curing cancer by chemotherapy. In this work, a kind of glutathione (GSH)-responsive polymer prodrug of SO2 was designed and synthesized, which presented synergistic effect with doxorubicin (DOX) for combating MCF-7 ADR human breast cancer cell. Firstly, a small molecular prodrug of SO2, N-(3-azidopropyl)-2,4 dinitrobenzenesulfonamide (AP-DNs), was chemically conjugated onto the side chain of methoxy poly (ethylene glycol)-block-poly (gamma-propargyl-l-glutamate) (mPEG PPLG) block copolymer to generate an amphiphilic polymer prodrug of SO2, mPEG-PLG (DNs). The obtained mPEG-PLG (DNs) prodrug could self-assemble into micelles in aqueous media and release SO2 rapidly in response to thiol compounds. Then, DOX was loaded into mPEG-PLG (DNs) nanoparticles with ultrahigh drug-loading efficiency (97.3%). In vitro drug release tests indicated that the DOX-loaded nanoparticles could simultaneously release SO2 and DOX by GSH triggering. Moreover, the effective cellular uptake of the DOX-loaded nanoparticles and subsequent intracellular release of SO2 and DOX were verified by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) analyses. The released SO2 could promote the reactive oxygen species (ROS) level in tumor cells, which thereby resulted in oxidative damages of cancer cells, together with restoration of MCF-7 ADR cells sensitivity to DOX. As a result, the released DOX and SO2 showed synergistic therapeutic effect against MCF-7 ADR cells. In vivo antitumor evaluation further indicated that, compared with free DOX, the DOX-loaded nanoparticles exhibited better antitumor effect in a MCF-7 ADR-xenografted nude mice model while had lower system toxicity. Overall, we demonstrated, for the first time, that a SO2 polymer prodrug, acting as a stimuli-responsive nanocarrier to codeliver DOX, can efficiently inhibit the proliferation of MDR tumor cells, which may offer a new weapon for combating MDR in cancer therapy. PMID- 29433754 TI - Noncovalent tagging of siRNA with steroids for transmembrane delivery. AB - Short interfering RNA (siRNA) has broad applications in biology and medicine, and holds tremendous potential to become a new class of therapeutics for many diseases. As a highly anionic macrobiomolecule, its cytosolic delivery, however, has been a major roadblock in translation. Here, we report the development of small, bifunctional chemical tags capable of transporting siRNA directly into the cytosol. The bifunctional tags consist of a siRNA-binding moiety that interacts with siRNA non-covalently, and a steroid domain that readily fuses with the mammalian cell membrane. In contrast to the conventional covalently conjugated siRNA-steroid that enters cells largely via endocytosis which substantially limits siRNA bioavailability, the non-covalently tagged siRNA is cell membrane permeant, avoiding the endocytic pathway. This new methodology enables effective RNA interference (RNAi) without the need of cationic transfection or endosomolytic agents, opening a new avenue for intracellular delivery of native biologics. PMID- 29433755 TI - Vitamin/mineral and micronutrient status in patients with classical phenylketonuria. AB - BACKGROUND & AIMS: Strict low-phenylalanine diet is associated with an increased risk of developing micronutrient deficiencies in patients with phenylketonuria (PKU). The primary objective of this single-center, case-control study was to assess the nutritional parameters of patients with PKU on strict low phenylalanine diet without vitamin and mineral supplementation compared to a healthy control group. Secondary objective was to identify the adequacy of vitamin/mineral supplementation in phenylalanine-free (Phe-free) amino acid formulas. METHODS: A total of 112 age- and sex-matched patients with PKU and 36 controls who did not take vitamin or mineral supplementation at least for the last 6 months were enrolled in the study. Biochemical and hematological markers including hemoglobin, serum vitamin B12, folic acid, iron, ferritin, transferrin saturation, copper, prealbumin, albumin, total protein, phosphorus, calcium, 25 hydroxy vitamin D, zinc, vitamin A and vitamin E levels were screened from fasting morning blood samples. RESULTS: One hundred and twelve patients with classical PKU (53 females, 47.3%) and 36 healthy controls (18 females, 50.0%) were enrolled in the study. The mean age of patients with PKU was 136.8 +/- 82.1 months (18-377). Median serum vitamin B12 level of patients with PKU was found to be higher than the control group (p = 0.002). Vitamin B12 deficiency was 15.2% and 30.6% in patients with PKU and healthy controls, respectively (p = 0.040). Mean serum folic acid level was higher in patients with PKU than the control group (p < 0.0001). In 55.4% of patients with PKU, and 2.8% of the control group, serum folic acid level was above the reference range (p < 0.0001). The frequency of ferritin and prealbumin values above the reference range was found to be higher in patients with PKU compared to the control group (44.4% vs 16.9%, p = 0.001; 38.8% vs 22.1%, p = 0.020, respectively). 25-Hydroxy vitamin D deficiency was detected in 53.6% and 47.2% of patients with PKU and the control group, respectively. Mean serum copper level was higher in the well-controlled (114.3 +/ 26.7 MUg/dL) group than the poorly controlled group (101.0 +/- 29.1 MUg/dL) (p = 0.022). CONCLUSIONS: Phe-free amino acid formulas provide adequate vitamin A and zinc levels in patients with PKU, and result in excess folic acid, vitamin B12, copper and vitamin E values that are higher than required levels. Our results demonstrate a high percentage of vitamin D deficiency in patients with classical PKU and also in healthy controls in Turkey. PMID- 29433757 TI - [Proposals for home care of the XXI century]. PMID- 29433756 TI - Tritium and radiocarbon levels in the Rhone river delta and along the French Mediterranean coastline. AB - The Rhone is characterised by a heavy concentration of nuclear-based industries including nuclear power stations and nuclear sites housing civilian and military facilities. Here, we report the results of a four-year survey (2010-2013) of tritium and radiocarbon levels in a variety of matrices within the Rhone delta and along the French Mediterranean coastline. The aim of the study is to create a spatial reference framework of environmental levels of these two radionuclides, which are the most prevalent in radioactive effluents from nuclear power stations. Although both tritium and radiocarbon levels in the samples analysed are very low and can only be detected using ultra-sensitive analytical techniques, they clearly show the influence of the tritium and radiocarbon discharges carried by the Rhone plume along the Mediterranean coast. The tritium content of suspended matter and sediments of the Rhone is a special case, which shows elevated tritium values not seen in other French rivers with similar nuclear facilities. The north-south spatial distribution of this tritium anomaly shows that these trace values are at their highest in the upper Rhone, close to the Swiss border and upstream of Creys Malville, the northernmost nuclear power station on the Rhone. This points to a legacy of past tritium releases by the watchmaking industry. A dedicated study would be needed to clearly identify the source and the exact nature of this contamination. PMID- 29433758 TI - [Validity of adjusted morbidity groups with respect to clinical risk groups in the field of primary care]. AB - OBJECTIVE: To compare the performance in terms of goodness of fit and explanatory power of 2morbidity groupers in primary care (PC): adjusted morbidity groups (AMG) and clinical risk groups (CRG). DESIGN: Cross-sectional study. LOCATION: PC in the Catalan Institute for the Health (CIH), Catalonia, Spain. PARTICIPANTS: Population allocated in primary care centers of the CIH for the year 2014. MAIN MEASUREMENTS: Three indicators of interest are analyzed such as urgent hospitalization, number of visits and spending in pharmacy. A stratified analysis by centers is applied adjusting generalized lineal models from the variables age, sex and morbidity grouping to explain each one of the 3variables of interest. The statistical measures to analyze the performance of the different models applied are the Akaike index, the Bayes index and the pseudo-variability explained by deviance change. RESULTS: The results show that in the area of the primary care the explanatory power of the AMGs is higher to that offered by the CRGs, especially for the case of the visits and the pharmacy. CONCLUSIONS: The performance of GMAs in the area of the CIH PC is higher than that shown by the CRGs. PMID- 29433759 TI - Why the history of public consultation matters for contemporary health policy. AB - Contemporary policy debates construct public involvement in England's National Health Service as "new," or as a practice dating back only as far as the 1990s. This article argues that the longer historical contexts of such consultative practice matter, and it explores various and shifting manifestations of "consultation" in the NHS from the foundation of the Service in 1948. In doing so, it first demonstrates that consultation has always been a part of the theory and practice of postwar health policy. Thinking about consultation as "new" presents such practice as unnecessary or transient, and may function as part of a damaging political vision of public affection for the NHS as a barrier to reform. Second, the article asserts that public interest in shaping NHS practice and policy has never been fully satisfied by official consultative mechanisms. "The public" is not a homogeneous group, but rather composed of various groups, communities, and individuals with rich perspectives and histories to share, having experienced the NHS as patients, friends, supporters, staff, and volunteers. Policy-makers should approach diverse publics as partners, and should meaningfully listen to protests around NHS reform, which often reflect public investment in the NHS, as well as valid concerns about how particular communities will be able to access health care. While the political will for such engagement has varied over time, individual politicians and local-level health agencies can make a difference by supporting, engaging with, and funding organizations which represent and empower a diverse range of communities: such groups have always, and will continue to play, a significant role in shaping NHS debate and care. PMID- 29433761 TI - What Aspect(s) of Genetics do You Think Most Excites Students in Your Classes? PMID- 29433760 TI - Corrigendum to "Pup exposure facilitates retrieving behavior via the oxytocin neural system in female mice" [Psychoneuroendocrinology 79 (2017) 20-30]. PMID- 29433762 TI - What Genetic Concept(s) Do You Think Are the Hardest for the Students to Grasp? PMID- 29433763 TI - Linking commonly used hand therapy outcome measures to individual areas of the International Classification of Functioning: A systematic review. AB - STUDY DESIGN: Systematic review. INTRODUCTION: Identifying outcome measures that correspond to the International Classification of Functioning (ICF) provides insight into selecting appropriate outcome tools in hand therapy practice. PURPOSE OF THE STUDY: The objective of this study is to systematically review patient-reported outcome measures commonly used in hand therapy to determine the extent to which the content represents the biopsychosocial view of the ICF. METHODS: A comprehensive literature search was conducted. Studies that met inclusion criteria were identified, and outcome measures were extracted. The meaningful concept was determined for each item on the measure and linked to the most specific ICF category. Summary linkage calculations were completed. RESULTS: Eleven patient-reported outcomes were identified from 43 included studies. Activity and participation had the highest content coverage followed by body functions. There was linking to personal factors and not defined-disability and mental health. Environmental factors were not represented in any of the included outcome measures. The core set representation of unique codes ranged from 8.55% to 18.80% (mean: 11.97%) for the Comprehensive ICF Core Set for Hand Conditions and from 30.43% to 47.83% (mean: 31.40%) for the Brief ICF Core Set for Hand Conditions. The percent representation of the Comprehensive ICF Core Set for Hand Conditions for unique disability ranged from 21.62% to 43.24% (mean: 20.33%) and from 62.50% to 87.50% (mean: 72.22%) for the Brief ICF Core Set for Hand Conditions. DISCUSSION: None of the included measures represent all categories of the ICF Core Sets for Hand Conditions. CONCLUSION: Utilizing the most recent refinement rules for the linking process, this study provides comparisons of measures along with clarity of content coverage for the most commonly used tools in the practice of hand therapy. PMID- 29433764 TI - Cold intolerance after nerve injury. AB - Cold intolerance after nerve injury can be severe and has been associated with high levels of pain and disability. This article provides an overview of the assessment and nonoperative management of cold-induced symptoms after peripheral nerve injury. A comprehensive evaluation should include both objective measures such as skin temperatures and subjective tools to assess the patient's perspective and impact of the symptoms. Management of the patient with cold intolerance remains challenging and should include adaptive strategies, warming interventions, and desensitization conditioning programs to minimize cold-induced pain and hyperresponses. PMID- 29433765 TI - A reconceptualization of the pain numeric rating scale: Anchors and clinically important differences. PMID- 29433766 TI - Root migration pattern after third molar coronectomy: a long-term analysis. AB - Coronectomy was introduced as a treatment for impacted lower third molars at high risk of inferior alveolar nerve damage. Root migration is considered one of the common surgical complications of this procedure. This study aimed to investigate the long-term behaviour of retained root(s) after coronectomy. This was a prospective study, with 3-5 years of follow-up, of patients who underwent lower third molar coronectomy. Panoramic radiographs were taken preoperatively and at 1 week, 6, 12, 24, 36, and 60 months postoperative. Root migration patterns were recorded. Factors including age, sex, type and pattern of impaction, and root form were analyzed with respect to the root migration rate. A total of 356 coronectomies were performed in 254 patients. Most root migration was found to occur within 6 months (91.1%) and 12 months (61.4%) postoperative. From 24 months onwards, less than 5% migrated further. Age was found to be a factor affecting root migration: migration decreased with increasing age (by 0.203mm less per year increase in age). Other factors investigated were found to be unrelated. Therefore, adequate preoperative warning should be given to young patients considering coronectomy as treatment for impacted lower third molars. However, it should also be noted that the incidence of root exposure leading to re-operation is low. PMID- 29433767 TI - Alloplastic temporomandibular joint replacement systems: a systematic review of their history. AB - This systematic review provides an overview of the historical evolution of the prosthetic temporomandibular joint and addresses the challenges and complications faced by engineers and surgeons, in an effort to shed light on why only a few systems remain available. A better understanding of the history of temporomandibular joint prostheses might also provide insights into the origin of the negative public opinion of the prosthesis, which is based on outdated information. A computerized search using the PubMed Central, ScienceDirect, Wiley Online, Ovid, and Cochrane Library databases was performed following the PRISMA guidelines. Out of 7122 articles identified, 41 met the inclusion criteria for this systematic review. Although several historical reviews have been published previously, none has covered such an extensive time period or has described all designs. Furthermore, besides providing a historical overview, this review discusses the rationale behind the evolution in design and biomaterials, which have largely contributed to the outcomes of the prosthetic systems. PMID- 29433768 TI - Ginger polyphenols attenuate cyclosporine-induced disturbances in kidney function: Potential application in adjuvant transplant therapy. AB - Cyclosporine (CYA), a common immuno-suppressant drug that is used in organ transplants, is associated with nephrotoxic effects. Scientific exploration of natural products of plant origin should be considered; especially, in a world with increasing prevalence of kidney diseases. Effects of ginger polyphenols (GP) in Wistar rats with CYA-induced perturbations in electrolyte balance and kidney function was determined. Fifty Wistar rats were recruited for this study such that graded doses of GP were administered following CYA-induced kidney injury and comparisons were made against control and toxic groups at p < 0.05. Distilled water, CYA (50 mg/kg p.o. for 10 days) and GP (100, 200 and 400 mg/kg p.o. for 21 days) were administered to the rats at 0.2 ml/100 g. CYA administration induced kidney injury as characterized by significant deleterious alterations in plasma and urine levels of creatinine, urea, Na+ and K+ electrolyte balance as well as creatinine clearance. Also, there was a significant derangement in feeding pattern and relative kidney weight. Using GSH and SOD as antioxidant indicators, there was significant disturbance of the anti-oxidant system while histopathological results showed evidence of interstitial vacuolations with atrophic glomeruli. These conditions were significantly attenuated (p < 0.05) following administration of graded doses of GP. It was, therefore, concluded that GP could potentially be a therapeutic choice for patients with CYA-induced kidney injury. PMID- 29433769 TI - Endoscopic submucosal dissection as treatment for early gastric cancer: Experience at two centers in Lima, Peru. AB - INTRODUCTION AND AIMS: The aim of the present study was to evaluate the feasibility of endoscopic submucosal dissection (ESD) and determine the clinical and pathologic characteristics of early gastric cancers and premalignant lesions treated with that technique at the Hospital Nacional of the Department of Health and a private clinic in Lima, Peru. MATERIAL AND METHODS: A descriptive study of all pre-malignant and malignant gastric lesions treated with ESD at the Gastroenterology Service of the Hospital Arzobispo Loayza and the Clinica Angloamericana was conducted within the time frame of January 2012 and January 2017. RESULTS: A total of 13 lesions were resected through ESD: 8 adenocarcinomas (61.53%), 3 adenomas with high-grade dysplasia (23%), and 2 adenomas with low grade dysplasia (15.38%). Twelve lesions (92.3%) were located in the lower third of the stomach. Slightly elevated lesions (Paris classification IIa) (4 lesions, 30.76%) and mixed slightly elevated lesions with a depressed component (IIa+IIc) (4 lesions, 30.76%) predominated. The mean size of the resected specimens was 35mm. Complete resection of all lesions was achieved in 11 cases (84.6%) and en bloc resection was carried out in 11 cases (84.6%). Resection was curative in 6 cases (75%), from the total of 8 resected adenocarcinomas. One case of perforation was the only complication reported (7.6%) and it was surgically resolved. CONCLUSIONS: The feasibility and efficacy of ESD for the treatment of early gastric cancer was demonstrated at two healthcare centers in Lima, Peru. The complication rate was similar to that reported in the international medical literature. PMID- 29433770 TI - Acid folic and pregnancy: A mandatory supplementation. AB - Neural tube defects (NTD) occur in 0.5 to 2 per 1000 pregnancies with various handicaps for the affected child. It is now well established that folic acid deficiency (absolute or relative) is a predisposing factor to this type of malformation. Several randomized controlled trials showed that high-dose folic acid (4mg) is an essential factor for prevention of neural tube defects recurrence and significantly prevents the first occurrence of neural tube defects with a lower dose (0.4mg). Other etiologies can favor the occurrence of NTD such as MTHFR polymorphism, some antiepileptic therapies, obesity and pregestational mellitus diabetes. Necessity of a preconception folic acid supplementation or at least folate nutritional status evaluation should be known for all of us including patients and public. PMID- 29433771 TI - Extremophiles for microbial-electrochemistry applications: A critical review. AB - Extremophiles, notably archaea and bacteria, offer a good platform for treating industrial waste streams that were previously perceived as hostile to the model organisms in microbial electrochemical systems (MESs). Here we present a critical overview of the fundamental and applied biology aspects of halophiles and thermophiles in MESs. The current study suggests that extremophiles enable the MES operations under a seemingly harsh conditions imposed by the physical (pressure, radiation, and temperature) and geochemical extremes (oxygen levels, pH, and salinity). We highlight a need to identify the underpinning mechanisms that define the exceptional electrocatalytic performance of extremophiles in MESs. PMID- 29433772 TI - Effect of support material pore size on the filtration behavior of dynamic membrane bioreactor. AB - The effect of support material pore size on the filtration behaviors during start up and stabilized stages in the dynamic membrane bioreactors (DMBR) was studied. Before the dynamic membrane (DM) was formed, the turbidity at 50-MUm could be more than 250 NTU, while it was less than 40 and 10 NTU at 25- and 10-MUm, respectively. After the DM was formed, the stabilized stage lasted for 61 days with low transmembrane pressure <0.6 kPa and the 5-, 10-, and 25-MUm filters had similar effluent turbidity (<1 NTU) and chemical oxygen demand. However, their averaged flux was 66.4, 25.1, and 3.5 L.m-2.h-1, respectively, suggesting that the 25-MUm filter had significantly lower filtration resistance. Consequently, to avoid unallowable high effluent turbidity during start-up or after membrane cleaning and to achieve high flux with low pressure filtration, a mesh size of ~25 MUm is more suitable for DMBR. PMID- 29433773 TI - Introduction to the special issue on Balanced diets in food systems: emerging trends and challenges for human health and wellbeing. PMID- 29433774 TI - Phenolics and essential mineral profile of organic acid pretreated unripe banana flour. AB - Banana fruit (Musa spp) though rich in essential minerals, has also been implicated for the presence of phytochemicals which nonetheless beneficial, can also act as mineral inhibitors when in forms such as phenolic compounds, phytates and tannins. This study assayed the essential macro and trace minerals as well as phenolic compounds present in unripe banana flour (UBF) obtained from the pulp of four different cultivars. Unripe banana flour was processed by oven drying in a forced air oven dryer at 70 degrees C upon pretreatment with ascorbic, citric and lactic acid. Organic acid pretreatment was done separately on each unripe banana cultivar at concentrations of 10, 15 and 20g/L. Phenolic compounds were profiled using liquid chromatography mass spectrometry electrospray ion (LC-MS-ESI) while essential minerals were determined using inductively coupled plasma atomic emission spectroscopy (ICP-AES) and mass spectroscopy (ICP-MS) respectively. Results of LC-MS-ESI assay of phenolics revealed the presence of flavonoids: epicatechin and myricetin 3-O-rhamnosyl-glucoside in varying concentrations in UBF. Essential mineral profile indicated that Zinc had the least occurrence of 3.55mg/kg (p<0.05), while potassium was the most abundant mineral at 14746.73mg/kg in UBF of all four banana cultivars. Correlation between phenolic compounds and essential minerals using Pearson's Correlation Coefficient test revealed weak and inverse association between flavonoids and most macro and trace minerals present in UBF samples. Organic acid pretreatment thus exhibited little effect on phenolics and essential minerals of UBF samples, though, inhibitory influence of phenolic compounds was recorded on essential minerals. PMID- 29433775 TI - Some physical and functional properties of finger millet (Eleusine coracana) obtained in sub-Saharan Africa. AB - The study determined the physical properties of finger millet (FM) (Eluesine coracana) grains and the functional properties of FM flour. Physical properties such as colour attributes, sample weight, bulk density, true density, porosity, surface area, sample volume, aspect ratio, sphericity, dimensional properties and moisture content of grain cultivars were determined. Water absorption capacity (WAC), bulk density (BD), dispersibility, viscosity and micro-structure of FM flours were also evaluated. Data collected were analyzed using SPSS statistical software version 23.0. Results showed that milky cream cultivar was significantly higher (p<0.05) than other samples in sample weight, bulk density, true density, aspect ratio and sphericity. However, pearl millet, used as a control, was significantly different from FM flour on all dimensional properties. Moisture content of milky cream showed higher significant difference for both grains and flours as compared to brown and black grain/flours. Milky cream cultivar was significantly different in L*, b*, C*, H* values, WAC, BD and dispersibility for both FM grains and flours. Data showed that brown flour was significantly higher in viscosity than in milky and black flours. Microstructure results revealed that starch granules of raw FM flours had oval/spherical and smooth surface. The study is important for agricultural and food engineers, designers, scientists and processors in the design of equipment for FM grain processing. Results are likely to be useful in assessing the quality of grains used to fortify FM flour. PMID- 29433776 TI - Enhancement of antioxidant activity and physicochemical properties of yogurt enriched with concentrated strawberry pulp obtained by block freeze concentration. AB - Strawberry juice was concentrated using block freeze concentration process. The concentrate was used to produce two yogurts with different concentrations of cryoconcentrated strawberry pulp (15% and 30%). Total lactic acid bacteria count, physicochemical and rheological properties was evaluated during storage (7days) for all yogurts. Also, the beverages produced were compared with two commercial trademarks. It was observed that the total lactic acid bacteria count remained higher than 108CFU.mL-1 during the storage time for all beverages studied. The viscosity of the yogurts decreased when the ratio of strawberry cryoconcentrate was increased. The Power Law model was successfully applied to describe the flow of the yogurts, which had a thixotropic behaviour. The incorporation of the cryoconcentrated strawberry pulp in the yogurt resulted in a product with 3-fold more anthocyanins content and antioxidant activity. The enrichment of natural yogurt with strawberry cryoconcentrated pulp proved to be effective in the production of a beverage with higher nutritional characteristics. PMID- 29433777 TI - Lipid metabolism potential and mechanism of CPe-III from chickpea (Cicer arietinum L.). AB - The effects of CPe-III on hyperlipidemic mice were investigated, along with molecular docking and dynamics analyses between CPe-III and CETP. This study was conducted in order to explore the lipid metabolism potential and mechanism of CPe III. CPe-III significantly (P<0.05) reduced serum total cholesterol, triglyceride and hepatic triglyceride levels and increased serum superoxide dismutase activity. CPe-III reversed liver changes induced by a high-fat diet and significantly (P<0.05) reduced kidney and epididymal fat indices. The activities of hepatic lipase and lipoprotein lipase, as well as fecal fat excretion, were significantly (P<0.05) enhanced. Furthermore, CPe-III was found to bind in the cavity of CETP, forming four stable hydrogen bonds. Hydrophobic interactions were the main driving force during binding. This study demonstrates that CPe-III improves dyslipidemia in mice. The binding of CPe-III to CETP demonstrates that CPe-III blocks cholesterol transport. These results indicate that CPe-III may be useful as an adjuvant element for hyperlipidemia and atherosclerosis therapies. PMID- 29433778 TI - Novel meat-enriched foods for older consumers. AB - Red meat enriched versions of bread, spaghetti, yoghurt, ice cream and chocolate were prototyped and assessed for some of their physical, chemical and microbiological properties, as well as sensory appeal. The protein content of the products were significantly increased and their colour went darker with meat enrichment (p<0.05). Bread volume and spaghetti tensile strength increased and ice cream meltability and yoghurt apparent viscosity decreased with meat enrichment (p<0.05). The overall acceptability/liking of bread, flavoured ice cream and spaghetti were not affected (p>0.05) but that of non-flavoured ice cream and yoghurt went down (p<0.05) with meat enrichment. 75% of the 940 panellist who ate the meat-enriched chocolates either loved or slightly-liked them. The outcome of the present study would assist in making the nutrition of meat available in a wider range of product categories, helping the meat industry stretch its established business models, and encouraging further development of novel food choices for elderly and other groups of consumers. PMID- 29433779 TI - Healthy diets with reduced environmental impact? - The greenhouse gas emissions of various diets adhering to the Dutch food based dietary guidelines. AB - OBJECTIVE: To determine the differences in environmental impact and nutrient content of the current Dutch diet and four healthy diets aimed at lowering greenhouse gas (GHG) emissions. METHODS: GHG emissions (as proxy for environmental impact) and nutrient content of the current Dutch diet and four diets adhering to the Dutch food based dietary guidelines (Wheel of Five), were compared in a scenario study. Scenarios included a healthy diet with or without meat, and the same diets in which only foods with relatively low GHG emissions are chosen. For the current diet, data from the Dutch National Food Consumption Survey 2007-2010 were used. GHG emissions (in kg CO2-equivalents) were based on life cycle assessments. Results are reported for men and women aged 19-30years and 31-50years. RESULTS: The effect on GHG emissions of changing the current Dutch diet to a diet according to the Wheel of Five (corresponding with the current diet as close as possible), ranged from -13% for men aged 31-50years to +5% for women aged 19-30years. Replacing meat in this diet and/or consuming only foods with relatively low GHG emissions resulted in average GHG emission reductions varying from 28-46%. In the scenarios in which only foods with relatively low GHG emissions are consumed, fewer dietary reference intakes (DRIs) were met than in the other healthy diet scenarios. However, in all healthy diet scenarios the number of DRIs being met was equal to or higher than that in the current diet. CONCLUSIONS: Diets adhering to food based dietary guidelines did not substantially reduce GHG emissions compared to the current Dutch diet, when these diets stayed as close to the current diet as possible. Omitting meat from these healthy diets or consuming only foods with relatively low associated GHG emissions both resulted in GHG emission reductions of around a third. These findings may be used to expand food based dietary guidelines with information on how to reduce the environmental impact of healthy diets. PMID- 29433780 TI - Nutritional enhancement of sheep meat fatty acid profile for human health and wellbeing. AB - Dietary fatty acids (FA) consumed by sheep, like other ruminants, can undergo biohydrogenation resulting in high proportions of saturated FA (SFA) in meat. Biohydrogenation is typically less extensive in sheep than cattle, and consequently, sheep meat can contain higher proportions of omega (n)-3 polyunsaturated FA (PUFA), and PUFA biohydrogenation intermediates (PUFA-BHI) including conjugated linoleic acid (CLA) and trans-monounsaturated FAs (t-MUFA). Sheep meat is also noted for having characteristically higher contents of branched chain FA (BCFA). From a human health and wellness perspective, some SFA and trans-MUFA have been found to negatively affect blood lipid profiles, and are associated with increased risk of cardiovascular disease (CVD). On the other hand, n-3 PUFA, BCFA and some PUFA-BHI may have many potential beneficial effects on human health and wellbeing. In particular, vaccenic acid (VA), rumenic acid (RA) and BCFA may have potential for protecting against cancer and inflammatory disorders among other human health benefits. Several innovative strategies have been evaluated for their potential to enrich sheep meat with FA which may have human health benefits. To this end, dietary manipulation has been found to be the most effective strategy of improving the FA profile of sheep meat. However, there is a missing link between the FA profile of sheep meat, human consumption patterns of sheep FA and chronic diseases. The current review provides an overview of the nutritional strategies used to enhance the FA profile of sheep meat for human consumption. PMID- 29433781 TI - Emerging trends in European food, diets and food industry. AB - Understanding how an adequate food security may be determined, how nutritional intakes evolve over time and are influenced by global dynamics are few of the questions scholars are trying to answer. In addition, a great interest is devoted to the changes in consumers' preferences and expectations as well as to the analysis of food innovations and their impact on the global market. We review the recent and emerging trends in food supply chains of selected sectors (fruits and vegetables, meat, and seafood), and deepen on emerging trends in the food industry. By presenting the evidence provided by the literature and emphasizing the unresolved research questions, we offer a critical view of future directions that should be followed by research agenda. PMID- 29433782 TI - Keystones affecting sub-Saharan Africa's prospects for achieving food security through balanced diets. AB - Socio-economic dynamics determine the transition from diets characterized by the risk of famine, to those characterized by the risk of diet-related non communicable disease (DR-NCD). This transition is of particular concern in Sub Saharan Africa (SSA) in which key socio-economic interactions that influence diet include economic growth and rapid urbanization; inequality and a growing middle class; and obesogenic food environments and an increasing prevalence of DR-NCD. In each case, countries in SSA are among those experiencing the most rapid change in the world. These interactions, styled as 'keystones', affect the functioning of other components of the food system and the diets that result. Data from the wealthiest quartile of countries in SSA suggest that these keystones may be increasing the risk of DR-NCD, widening inequalities in health outcomes due to unbalanced diets. To address this, new consumer and government capabilities that address these keystones are required. Food sensitive urban planning, supporting food literacy and fiscal management of consumption are examples. PMID- 29433783 TI - Targeting the pains of food insecurity and malnutrition among internally displaced persons with nutrient synergy and analgesics in organ meat. AB - Living with pain is one of the distressing effects of food insecurity and malnutrition among millions of internally displaced persons (IDPs) worldwide. Vulnerability to emotional pain, metabolic imbalance, chronic illnesses and non communicable diseases by IDPs are associated with stressed livelihood and restricted access to balanced diets in their camps. Tackling the complexity of issues related to internal displacement is challenging as 45% are globally trapped in protracted conditions. In this review, a diet-based intervention is proposed considering the potential benefits of nutrient synergy and analgesic constituents in organ meat. Providing an affordable, value added and well packaged nutrient dense diet is suggested to meet daily protein and micronutrient requirements from organ meat. Also, unlocking health-promoting bioactive substances and analgesics in restructured organ meat product is proposed as personalized dietary remedy to exert opioid bioactivity in food matrix. Exploiting the nutrient synergy of this animal by-product will not only improve the nutritional status or wellbeing but also raise the composite score of dietary diversity or food security index among IDPs by 2030. PMID- 29433784 TI - Do cancer patients change their diet in the e-health information era? A review of the literature and a survey as a proposal for the Italian population. AB - In recent years, there has been an explosion in the amount of available information on cancer in parallel with an ever-increasing number of cancer survivors. Cancer patients and long-term survivors are known to be more sensitive to health-related information and dietary changes could represent a potential consequence of this huge availability of messages. In our review about dietary changes after cancer diagnosis, we found that this topic is particularly investigated among the breast cancer population. The literature examined show that breast cancer patients modify their eating habits after diagnosis in a percentage that varies between approximately 30% and 60%. The most reported changes were an increased consumption of fruit and vegetables, a decrease in the consumption of red meat, fats and sugary foods. Patients who reported changes were more likely to be younger, with higher educational levels and with a longer period of time since their diagnosis of cancer. It also emerged that cancer patients are often more likely to use supplements. This topic has not been investigated in cancer patients in Italy, therefore, we propose an approach to explore it with a structured questionnaire: The "ECHO SURVEY - Eating habits CHanges in Oncologic patients". PMID- 29433785 TI - Serum selenium levels, the selenoprotein glutathione peroxidase and vascular protection: The SABPA study. AB - Selenium is an important co-factor for the optimal functioning of the antioxidant enzyme, glutathione peroxidase (GPx). Studies investigating the associations of selenium with blood pressure (BP) and hemodynamic measures are sparse. This study investigated whether 24h blood pressure, vascular resistance, arterial compliance and arterial stiffness relate to both serum selenium and GPx activity. In this cross-sectional study selenium levels, GPx activity, ambulatory blood pressure and arterial stiffness of 200 black and 209 white school teachers from South Africa were measured. Serum selenium levels were significantly lower in black compared to white teachers (p<0.001), independent of sex. One in 10 black men and one in five black women were selenium deficient (<8MUg/100ml). Only in white men inverse independent associations of 24h systolic BP (beta=-0.19; p=0.039) and 24h diastolic BP (beta=-0.21; p=0.029) with selenium were found. In the same group, an inverse association between carotid-dorsalis pedis pulse wave velocity (cd PWV) and GPx activity (beta=-0.23; p=0.017) were also found. To conclude, lower serum selenium levels in black populations from the same geographical region as their white counterparts may impact on the loss of the vasculoprotective effects of selenium and selenoproteins such as GPx. PMID- 29433786 TI - Incorporating orange-fleshed sweet potato into the food system as a strategy for improved nutrition: The context of South Africa. AB - Orange-fleshed sweet potato (OFSP) is considered the single most successful example of biofortification of a staple crop, and presents a feasible option to address vitamin A deficiency. Though initially promoted as part of a crop-based approach focusing on production and consumption at household level, it evolved into small-scale commercial production, predominantly in Sub-Saharan Africa. This paper reviews OFSP initiatives in relation to the South African food environment and food supply systems, also identifying opportunities for scaling out OFSP in a situation where sweet potato is not eaten as a staple. Current per capita consumption of sweet potato is low; the focus is thus on increasing consumption of OFSP, rather than replacing cream-fleshed varieties. For the major OFSP variety, Bophelo, 66g consumption can be sufficient to meet the recommended daily allowance for 1-3year old children (300MURE vitamin A). Despite a national Vitamin A supplementation programme and fortified staple foods in South Africa, 43.6% of children under 5years of age were reported to be vitamin A deficient in 2012, indicating a stronger need to promote the consumption of Vitamin A-rich foods, such as OFSP. To increase availability of and access to OFSP, all aspects of the food supply system need to be considered, including agricultural production, trade, food transformation and food retail and provisioning. Currently, small-scale commercial OFSP producers in South Africa prefer to deliver their produce to local informal markets. To enter the formal market, small-scale producers often have difficulties to meet the high standards of the retailers' centralised procurement system in terms of food quality, quantity and safety. Large retailers may have the power to increase the demand of OFSP, not just by improving availability but also by developing marketing strategies to raise awareness of the health benefits of OFSP. However, currently the largest scope for scaling out is through a number of public sector programmes such as the National School Nutrition Programme, Community Nutrition and Development Centres, Small-holder Farmer programmes and Agriparks. Though the major approach is focused on unprocessed, boiled OFSP, there are unexploited opportunities for processing of OFSP. However, the nutritional quality of products should be a main consideration within the context of the co-existence of undernutrition, overnutrition and micronutrient deficiencies in the country. PMID- 29433787 TI - Fruits and vegetables, as a source of nutritional compounds and phytochemicals: Changes in bioactive compounds during lactic fermentation. AB - Nutritional recommendations emphasize fruit and vegetable consumption. This is related to health-benefits associated with bioactive nutritive molecules (nutrients, vitamins, minerals, fibers, ...) as well as non-nutritive phytochemicals (phenolic compounds, flavonoids, bioactive peptides, ...) content of these types of foods. Fermented fruit or vegetable products are part of various diets worldwide. Lactic acid bacteria (LAB) fermentation is common among the various fermentation processes used. It produces changes in both profile and types of bioactive compounds. Molecules such as bioactive peptides, short chain fatty acids or polysaccharides are generated while sugar content or anti nutritional compounds are decreased and phenolic compounds are converted to molecules with added biological value. These transformations, associated with prebiotic and/or probiotic potential supply as well as improvement of food components bioaccessibility and bioavailability, result in modifications of health-related properties. Lastly, interactions between ingested fermented food, intestinal microbiota and their correlations to metabolomics profiles and health represent an important perspective deserving to be further explored. PMID- 29433788 TI - Gender differences in trends for heroin use and nonmedical prescription opioid use, 2007-2014. AB - BACKGROUND: Trends in the current opioid epidemic in the United States show that use of heroin is increasing while nonmedical use of prescription opioids is slowing. Understanding gender differences in these trends is essential to efforts to address the opioid epidemic. This study compared gender difference in trends in heroin and nonmedical prescription opioid use in the U.S. between 2007 and 2014. METHODS: Data from the National Survey on Drug Use and Health (NSDUH) were used to trace prevalence and to estimate risk for heroin and nonmedical prescription opioid use in the last year for women and men. RESULTS: Prevalence rates in the total sample (N = 447,188) indicate a notable increase in heroin use and a steady decline in the nonmedical use of prescription opioids between 2007 and 2014 for both women and men. Women are increasing heroin use at a faster rate than men but decreasing nonmedical prescription opioid use at a slower rate than men. Overall, risk factors for both heroin use and nonmedical prescription opioid use are similar to other illicit substances, but the magnitude of associations indicates that women may be at greater risk for the nonmedical use of prescription opioids than for the use of heroin. CONCLUSIONS: Trend analyses reveal a linear increase in heroin use and a quadratic decline in nonmedical prescription opioid use at the population level. The differential rates of change between men and women in use of both opioids highlight the need for comprehensive, gender-sensitive approaches to prevention and treatment for both heroin and nonmedical prescription opioid use. Future research should continue to explore gender differences in treatment access, including access to medication assisted treatments and treatments integrated with health and social services, especially for women. PMID- 29433789 TI - Letter to the Editor regarding the paper by N. Azzam et al. 'Germline polymorphisms on RET proto-oncogene involved in medullary thyroid carcinoma in a Druze family'. PMID- 29433790 TI - Response to Letter to the Editor, 'Pharmacokinetics partly explains the relationship between CEA level and survival of colorectal cancer patients treated with ramucirumab,' by Ibrahim et al. PMID- 29433791 TI - Long-term liver disease in methylmalonic and propionic acidemias. AB - BACKGROUND AND OBJECTIVES: Patients affected with methylmalonic acidemia (MMA) and propionic acidemia (PA) exhibit diverse long-term complications and poor outcome. Liver disease is not a reported complication. The aim of this study was to characterize and extensively evaluate long-term liver involvement in MMA and PA patients. PATIENTS AND METHODS: We first describe four patients who had severe liver involvement during the course of their disease. Histology showed fibrosis and/or cirrhosis in 3 patients. Such liver involvement led us to retrospectively collect liver (clinical, laboratory and ultrasound) data of MMA (N = 12) or PA patients (N = 16) from 2003 to 2016. RESULTS: Alpha-fetoprotein (alphaFP) levels were increased in 8/16 and 3/12 PA and MMA patients, respectively, and tended to increase with age. Moderate and recurrent increase of GGT was observed in 4/16 PA patients and 4/12 MMA patients. Abnormal liver ultrasound with either hepatomegaly and/or hyperechoic liver was observed in 7/9 PA patients and 3/9 MMA patients. CONCLUSIONS: These data demonstrate that approximately half of the patients affected by MMA or PA had signs of liver abnormalities. The increase of alphaFP with age suggests progressive toxicity, which might be due to the metabolites accumulated in PA and MMA. These metabolites (e.g., methylmalonic acid and propionic acid derivatives) have previously been reported to have mitochondrial toxicity; this toxicity is confirmed by the results of histological and biochemical mitochondrial analyses of the liver in two of our MMA patients. In contrast to the moderate clinical, laboratory or ultrasound expression, severe pathological expression was found for three of the 4 patients who underwent liver biopsy, ranging from fibrosis to cirrhosis. These results emphasize the need for detailed liver function evaluation in organic aciduria patients, including liver biopsy when liver disease is suspected. TAKE HOME MESSAGE: MMA and PA patients exhibit long-term liver abnormalities. PMID- 29433792 TI - Clinical characteristics of influenza virus-induced lower respiratory infection during the 2015 to 2016 season. AB - BACKGROUND: Influenza A(H1N1)pdm09 virus infections often manifest severe respiratory symptoms, particularly in patients with a past history of allergic disease. Most of these findings were reported during the 2009 pandemic. The purpose of this study was to detail the clinical characteristics of influenza virus-induced lower respiratory infection (LRI) during the A(H1N1)pdm09 predominant 2015-2016 season. METHODS: We retrospectively reviewed the clinical characteristics of influenza-induced LRI cases in children admitted to a tertiary children's hospital. Molecular diagnostic evaluation was performed on samples obtained from the most severe cases. RESULTS: We identified 66 patients with influenza-associated hospitalization and included 21 patients with influenza virus-induced LRI for analyses. Twelve patients (57%) were admitted to the pediatric intensive care unit, seven (33%) required mechanical ventilation, and three (14%) required extracorporeal membrane oxygenation. Plastic bronchitis (PB) was identified in six patients (29%), among whom a past medical history of asthma or food allergy were noted in all six patients. A past history of allergic disease was more common among patients with, than among those without, PB (p = 0.009). A(H1N1)pdm09 was detected from all the PB cases, and phylogenetic analyses of the hemagglutinin and neuraminidase genes demonstrated that this virus belonged to subclades 6B.1 and 6B.2. In the six PB cases, we found one patient with H275Y mutation in neuraminidase. CONCLUSION: Allergic disease was a risk factor for developing PB due to influenza A(H1N1)pdm09 infection during the 2015-16 season. PMID- 29433793 TI - Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. AB - Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss or mutations in SMN1. According to age of onset, achieved motor abilities, and life span, SMA patients are classified into type I (never sit), II (never walk unaided) or III (achieve independent walking abilities). SMN2, the highly homologous copy of SMN1, is considered the most important phenotypic modifier of the disease. Determination of SMN2 copy number is essential to establish careful genotype-phenotype correlations, predict disease evolution, and to stratify patients for clinical trials. We have determined SMN2 copy numbers in 625 unrelated Spanish SMA patients with loss or mutation of both copies of SMN1 and a clear assignation of the SMA type by clinical criteria. Furthermore, we compiled data from relevant worldwide reports that link SMN2 copy number with SMA severity published from 1999 to date (2834 patients with different ethnic and geographic backgrounds). Altogether, we have assembled a database with a total of 3459 patients to delineate more universal prognostic rules regarding the influence of SMN2 copy number on SMA phenotype. This issue is crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatments. PMID- 29433794 TI - Clinically variable nemaline myopathy in a three-generation family caused by mutation of the skeletal muscle alpha-actin gene. AB - We present here a Finnish nemaline myopathy family with a dominant mutation in the skeletal muscle alpha-actin gene, p.(Glu85Lys), segregating in three generations. The index patient, a 5-year-old boy, had the typical form of nemaline myopathy with congenital muscle weakness and motor milestones delayed but reached, while his mother never had sought medical attention for her very mild muscle weakness, and his maternal grandmother had been misdiagnosed as having myotonic dystrophy. This illustrates the clinical variability in nemaline myopathy. PMID- 29433795 TI - The utility of magnetic resonance imaging in the diagnosis and management of pediatric benign ovarian lesions. AB - BACKGROUND: The utility of magnetic resonance imaging (MRI) in the diagnosis and management of pediatric ovarian lesions has not been well defined. METHODS: A retrospective review of all girls who underwent MRI evaluation of ovarian masses during the period 2009-2015 was performed. The accuracy of MRI was evaluated by comparing results with surgical findings, pathology reports, and subsequent imaging. The influence of the MRI on the treatment plan was specifically explored. RESULTS: Eighteen girls, 12-17years of age, underwent 27 MRIs, subsequent to ultrasound identification of ovarian lesions. Of 9 neoplastic lesions diagnosed on MRI, 8 (89%) were confirmed by surgical and pathological findings. Of 18 functional lesions, 17 (94.4%) were confirmed pathologically or by resolution on subsequent imaging. Twenty MRI exams (74%) directly influenced the treatment plan, by leading to appropriate operative intervention in 9 and appropriate observation in 11. The extent of ovarian resection was guided by MRI findings in 8 of 9 (89%) neoplastic lesions. For characterizing lesions as neoplastic, the sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of MRI were 89%, 94%, 94%, 89%, and 93% respectively. CONCLUSIONS: MRI can differentiate functional from neoplastic pediatric ovarian masses, and guide ovarian resection in appropriate cases. LEVEL OF STUDY: II. PMID- 29433796 TI - Which Came First, the Chicken or the Egg?-Clinical Dilemmas in Managing Postoperative Bleeding and Decision-making for Re-exploration After Cardiac Surgery. PMID- 29433797 TI - Higher Transaminase Levels in the Postoperative Period After Orthotopic Heart Transplantation Are Associated With Worse Survival. AB - OBJECTIVE: Preoperative liver function in heart failure patients is associated with extensive functional, structural, and hemodynamic abnormalities. The authors hypothesized that perioperative liver dysfunction is associated with worse 2-year survival after orthotopic heart transplantation. DESIGN: Retrospective study. SETTING: Single-center, university hospital. PARTICIPANTS: The study comprised 209 consecutive patients undergoing heart transplantation. INTERVENTIONS: No interventions. MEASUREMENTS AND MAIN RESULTS: Hepatobiliary markers, hemodynamic parameters, echocardiographic parameters, the need for mechanical cardiac support, demographic parameters, and United Network for Organ Sharing and Model for End-Stage Liver Disease (MELD) scores were investigated. Fifty-five patients (26.3%) died, and the mean survival time was 3.61 years after transplantation. In multivariate Cox regression analysis, in addition to the preoperative modified MELD score, the 4th quartiles of the maximum aspartate transaminase (AST) and alanine transaminase levels on the 4th through 7th postoperative days were independently associated with mortality (odds ratio [OR] 2.46, 95% confidence interval [CI] 1.09-5.55; p = 0.031 and OR 2.41, 95% CI 1.13-5.18; p = 0.024, respectively). By expressing the transaminase values as the multiplier of the sex specific top normal value, the maximum AST and alanine transaminase levels (OR 1.02, 95% CI 1.01-1.02; p < 0.001 and OR 1.02, 95% CI 1.01-1.03; p = 0.001, respectively) were linked to worse survival. Among the postdischarge parameters, the modified MELD score (OR 1.17, 95% CI 1.09-1.27; p < 0.001) and the AST level were associated with postdischarge mortality (OR 1.002, 95% CI 1.001-1.003; p < 0.001 as a continuous variable; OR 1.07, 95% CI 1.05-1.10; p < 0.001, expressed as the multiplier of the sex-specific normal value, respectively). CONCLUSIONS: The severity of postoperative liver dysfunction negatively influences survival after heart transplantation, and liver function should be closely assessed in these patients. PMID- 29433798 TI - Screening for Abdominal Aortic Aneurysm During Transthoracic Echocardiography: A Systematic Review and Meta-analysis. AB - BACKGROUND: Screening for abdominal aortic aneurysm (AAA) during transthoracic echocardiography (TTE) may be an effective targeted screening strategy. OBJECTIVE: The aim was to assess the feasibility of AAA screening during TTE and to estimate the prevalence of AAA in patients undergoing TTE. METHODS: Electronic bibliographic sources were interrogated using a combination of free text and controlled vocabulary searches to identify studies reporting on AAA screening during TTE. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards. Fixed effect or random effects models were used to calculate pooled prevalence estimates. RESULTS: Twenty observational cohort studies were identified reporting a total of 43,341 participants (23,291 men and 20,050 women). Hypertension was reported in 41% (95% CI 38-43), hypercholesterolemia in 31% (95% CI 29-32), diabetes mellitus in 20% (95% CI 19-22), and tobacco use in 37% (95% CI 35-38). The aorta was visualised in 86% (95% CI 84-88) of the screened population. The pooled prevalence of AAA in the entire screened population was 0.033 (95% CI 0.024-0.044). The pooled prevalence of AAA in men was 0.046 (95% CI 0.032-0.065) and in women it was 0.014 (95% CI 0.008-0.022). The mean age of participants in whom an AAA was detected ranged across the studies from 66 to 85 years. The mean diameter of the aneurysm identified ranged across the studies from 35 mm to 45 mm. Clinical outcomes in participants with a detected AAA were poorly reported. CONCLUSIONS: Screening for AAA during TTE may identify a population group with a high risk of AAA in whom targeted screening may be beneficial. Further research is required to investigate the cost-effectiveness and clinical benefits of AAA screening in this setting. PMID- 29433799 TI - International survey among orthopaedic trauma surgeons: Lack of a definition of fracture-related infection. AB - INTRODUCTION: Fracture-related infection (FRI) is one of the most challenging musculoskeletal complications in orthopaedic-trauma surgery. Although the orthopaedic community has developed and adopted a consensus definition of prosthetic joint infections (PJI), it still remains unclear how the trauma surgery community defines FRI in daily clinical practice or in performing clinical research studies. The central aim of this study was to survey the opinions of a global network of trauma surgeons on the definitions and criteria they routinely use, and their opinion on the need for a unified definition of FRI. The secondary aims were to survey their opinion on the utility of currently used definitions that may be at least partially applicable for FRI, and finally their opinion on the important clinical parameters that should be considered as diagnostic criteria for FRI. METHODS: An 11-item questionnaire was developed to cover the above-mentioned aims. The questionnaire was administered by SurveyMonkey and was sent via blast email to all registered users of AO Trauma (Davos, Switzerland). RESULTS: Out of the 26'563 recipients who opened the email, 2'327 (8.8%) completed the questionnaire. Nearly 90% of respondents agreed that a consensus-derived definition for FRI is required and 66% of the surgeons also agreed that PJI and FRI are not equal with respect to diagnosis, treatment and outcome. Furthermore, "positive cultures from microbiology testing", "elevation of CRP", "purulent drainage" and "local clinical signs of infection" were voted the most important diagnostic parameters for FRI. CONCLUSION: This international survey infers the need for a consensus definition of FRI and provides insight into the clinical parameters seen by an international community of trauma surgeons as being critical for defining FRI. PMID- 29433800 TI - Inequalities in the risk of disability due to traffic injuries in the Spanish adult population, 2009-2010. AB - BACKGROUND: Although traffic injuries (TIs) are an important cause of disability the related factors are little known. We aimed to estimate the differences in risk of TI-related disability according to individual characteristics that might generate health inequalities. METHODS: Cross-sectional study using a representative Spanish population sample drawn from the European Health Interview Survey 2009/2010. We calculated traffic crashes in the preceding year which resulted in injuries. Disability was measured using the Global Activity Limitation Indicator and four indicators of limitations (sensory, physical functional, self-care and domestic activities). Principal socio-demographic and behavioural/lifestyle variables were studied. We used multivariate logistic regression to estimate the risk (ORs) of TI-related disability in the sample as whole and disability-related factors in persons who had experienced TIs. RESULTS: Persons with TIs had a higher risk of global disability (OR = 1.61; 95%CI:1.17 2.20), physical functional limitations (OR = 1.96; 95%CI:1.33-2.89) and self-care limitations (OR = 1.73; 95%CI:0.98-3.05). Among persons with TIs, GALI-related risk was higher in women (OR = 3.06, p = 0.002) and persons aged over 30 years (OR31-45years = 6.81, p < 0.001; OR46-64years = 5.96, p = 0.011; OR>64years = 4.54, p = 0.047). Lower risk was observed among persons with a higher educational level (OR = 0.22, p = 0.003). The risk of disability among persons with TIs who consumed illegal drugs was OR = 3.9 (p = 0.023). CONCLUSIONS: Traffic injuries in the preceding year are associated with higher risk of disability, which is unevenly distributed. Individual (women and persons over 30 years), socio economic (lower educational level) and behavioural (illegal drug use) factors are involved. Actions aimed at changing the unequal risk among vulnerable subgroups and providing health, social and protective services should be implemented. PMID- 29433801 TI - Risk factors of fixation failure in basicervical femoral neck fracture: Which device is optimal for fixation? AB - BACKGROUND: Basicervical femur neck fracture (FNF) is a rare type of fracture, and is associated with increased risk of fixation failure due to its inherent instability. The purpose of this study was (1) to investigate the incidence of fixation failure and (2) to determine risk factors for fixation failure in basicervical FNF after internal fixation. METHODS: To identify basicervical FNF with a minimum of 12 months follow-up, we retrospectively reviewed records of 3217 patients who underwent hip fracture surgery from May 2003 to March 2016. Among the identified 77 patients with basicervical FNF, 69 patients were followed up for at least 12 months. We evaluated the rate of collapse of fracture site and reoperation due to fixation failure. We performed a multivariable analysis to determine risk factors associated with fracture site collapse and fixation failure. RESULTS: Among the 69 patients with basicervical FNF, 17 (24.6%) showed collapse of fracture site, and 6 (8.6%) underwent conversion to arthroplasty because of fixation failure. In the multivariable analysis, use of extramedullary plating with a sliding hip screw was an independent significant risk factor for both collapse of fracture site (odds ratio 6.84; 95% confidence interval 1.91 24.5, p = 0.003) and fixation failure (odds ratio 12.2; 95% confidence interval 1.08-137.7, p = 0.042). CONCLUSIONS: Basicervical FNF treated with extramedullary plate with a sliding hip screw is more likely to fail than that treated with intramedullary nail with a helical blade. Our results suggested that intramedullary nail with a helical blade is more recommended for basicervical FNF compared with extramedullary plate with a sliding hip screw. LEVEL OF EVIDENCE: III, Retrospective cohort study. PMID- 29433802 TI - Chest ultrasonography for the emergency diagnosis of traumatic pneumothorax and haemothorax: A systematic review and meta-analysis. AB - OBJECTIVE: To assess the accuracy of the chest ultrasonography for the emergency diagnosis of traumatic pneumothorax and haemothorax in adults. STUDY DESIGN: Systematic review and meta-analysis. METHODS: PubMed, EMBASE, Scopus, Web of Science and LILACS (up to 2016) were systematically searched for prospective studies on the diagnostic accuracy of ultrasonography for pneumothorax and haemothorax in adult trauma patients. The references of other systematic reviews and the included studies were checked for further articles. The characteristics and results of the studies were extracted using a standardised form, and their methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Primary analysis was performed considering each hemithorax as an independent unit, while secondary analysis considered each patient. The global diagnostic accuracy of the chest ultrasonography was estimated using the Rutter-Gatsonis hierarchical summary ROC method. Moreover, Reitsma's bivariate model was used to estimate the sensitivity, specificity, positive likelihood ratio (LR + ) and negative likelihood ratio (LR-) of each sonographic sign. This review was previously registered (PROSPERO CRD42016048085). RESULTS: Nineteen studies were included in the review, 17 assessing pneumothorax and 5 assessing haemothorax. The reference standard was always chest tomography, alone or in parallel with chest radiography and observation of the chest tube. The overall methodological quality of the studies was low. The diagnostic accuracy of chest ultrasonography had an area under the curve (AUC) of 0.979 for pneumothorax (Fig). The absence of lung sliding and comet-tail artefacts was the most reported sonographic sign of pneumothorax, with a sensitivity of 0.81 (95% confidence interval [95%CI], 0.71-0.88), specificity of 0.98 (95%CI, 0.97-0.99), LR+ of 67.9 (95%CI, 26.3-148) and LR- of 0.18 (95%CI, 0.11-0.29). An echo-poor or anechoic area in the pleural space was the only sonographic sign for haemothorax, with a sensitivity of 0.60 (95%CI, 0.31-0.86), specificity of 0.98 (95%CI, 0.94-0.99), LR+ of 37.5 (95%CI, 5.26-207.5), LR- of 0.40 (95%CI, 0.17-0.72) and AUC of 0.953. CONCLUSION: Notwithstanding the limitations of the included studies, this systematic review and meta-analysis suggested that chest ultrasonography is an accurate tool for the diagnostic assessment of traumatic pneumothorax and haemothorax in adults. PMID- 29433803 TI - Latent human papillomavirus type 16 infection is widespread in patients with oropharyngeal cancers. PMID- 29433804 TI - Stereotactic Breast Biopsy With Benign Results Does Not Negatively Affect Future Screening Adherence. AB - PURPOSE: To evaluate whether false-positive stereotactic vacuum-assisted breast biopsy (SVAB) affects subsequent mammographic screening adherence. MATERIALS AND METHODS: This Institutional Review Board-approved, HIPAA-compliant retrospective review of women with SVAB was performed between 2012 and 2014. Patient age, clinical history, biopsy pathology, and first postbiopsy screening mammogram were reviewed. Statistical analyses were performed using Fisher's exact, Mann-Whitney, and chi2 tests. RESULTS: There were 913 SVABs performed in 2012 to 2014 for imaging detected lesions; of these, malignant or high-risk lesions or biopsies resulting in a recommendation of surgical excision were excluded, leaving 395 SVABs yielding benign pathology in 395 women. Findings were matched with a control population consisting of 45,126 women who had a BI-RADS 1 or 2 screening mammogram and did not undergo breast biopsy. In all, 191 of 395 (48.4%) women with a biopsy with benign results and 22,668 of 45,126 (50.2%) women without biopsy returned for annual follow-up >9 months and <=18 months after the index examination (P = .479). In addition, 57 of 395 (14.4%) women with a biopsy with benign results and 3,336 of 45,126 (7.4%) women without biopsy returned for annual follow-up >18 months after the index examination (P < .001). Older women, women with personal history of breast cancer, and women with postbiopsy complication after benign SVAB were more likely to return for screening (P = .026, P = .028, and P = .026, respectively). CONCLUSION: The findings in our study suggest that SVABs with benign results do not negatively impact screening mammography adherence. The previously described "harms" of false-positive mammography and biopsy may be exaggerated. PMID- 29433805 TI - Proactive multi-modality treatment of Pancreatic Neuroendocrine Tumours (PNETs): Potential survival benefits. AB - BACKGROUND/OBJECTIVES: Primary and metastatic pancreatic neuroendocrine tumours (PNET) can be treated with combination of surgery, locoregional and systemic therapy. Survival benefits from individual treatments have been well reported, however, the combined outcome from multimodal treatments are not well described in the literature. We report outcomes in a cohort of PNET patients treated with proactive, multimodality therapy. METHODS: 106 patients were identified from a single tertiary referral centre prospective database. Outcomes of treatment were studied, with the primary end point being death from any cause. RESULTS: Median follow-up was 71 months and overall 5-year survival of 62%. In patients with stage I-III disease (51 patients) estimated 5-year survival was 90%. Median survival in patients with stage IV disease was 51 months with an estimated 5-year survival of 40% in this group. A total of 80 patients (75%) had surgery of which 16% suffered complications requiring intervention. There was no perioperative mortality. CONCLUSIONS: This study demonstrates that proactive multimodal treatment is safe and may confer a survival benefit to patients in this cohort compared to historical data. PMID- 29433806 TI - Non-VMAT2 inhibitor treatments for the treatment of tardive dyskinesia. AB - Although VMAT2-inhibitors are now established as first-line treatment for tardive dyskinesia, not all patients respond to, or tolerate them. Numerous other agents have been adopted to treat tardive dyskinesia, but with variable results and generally lower quality methodologic reports. Amantadine is the most promising but benzodiazepines, branched chain neutral amino acids, Vitamin B6, several nutraceuticals, and botulinum toxin injections might help some patients. In all cases, better placebo controlled trials are needed before definitive recommendations can be made. PMID- 29433807 TI - Deep brain stimulation for tardive syndromes: Systematic review and meta analysis. AB - Among the broad entity of tardive syndromes, tardive dystonia and classical tardive dyskinesia sometimes require advanced treatments like deep brain stimulation of the globus pallidus internum (Gpi-DBS) or the subthalamic nucleus (STN-DBS). This systematic review has analyzed the currently available literature reporting cases with either tardive dystonia or dyskinesia treated with DBS. The key words for the literature search included all tardive syndromes and "deep brain stimulation." Thirty-four level VI studies and one level II study with 117 patients were included. Level I studies were not identified. Only four of the patients had tardive dyskinesia. All the others had tardive dystonia. The majority had Gpi-DBS (n = 109). Patients had a mean age of 47.4 (+/- SD 14.7) years. The duration of follow-up was 25.6 months +/- 26.2. The Abnormal Involuntary Movement Scale was reported in 51 patients with an improvement of 62 +/- 15% and the Burke-Fahn-Marsden scale was reported in 67 cases with an improvement of 76 +/- 21%. Reported adverse events were surgery-related in 7 patients, stimulation-induced in 12, and psychiatric in 3 patients. These reports thus suggest favorable effects of DBS and it seems to be relatively safe. DBS can be considered for patients with severe, medication-resistant symptoms. Controlled and randomized studies with blinded outcomes are needed. PMID- 29433808 TI - VMAT2 inhibitors for the treatment of tardive dyskinesia. AB - Tardive dyskinesia (TD) is an often disabling hyperkinetic movement disorder caused by exposure to dopamine receptor blocking agents. Although initially thought to most commonly occur with typical antipsychotics, the incidence is likely similar with atypical antipsychotics and antiemetics such as metoclopramide. Increased prescribing of these agents as well as low rates of remission have contributed to a rising prevalence of TD. Although this condition was described nearly 60 years ago, it is only within the past year that two novel therapeutic agents were FDA approved. Characterization of the VMAT2 inhibitor tetrabenazine, which was identified as a therapeutic agent for TD in older clinical trials, has yielded two distinct pharmacologic strategies to optimize response. The first strategy, used to create deutetrabenazine, employed deuterization of tetrabenazine to stabilize the pharmacokinetics and eliminate high peak plasma levels. The second strategy was the creation of a prodrug, valbenazine, for the two most active isoforms of tetrabenazine that also resulted in more stable pharmacokinetics and eliminated peak plasma levels. Both agents have been demonstrated to be effective and safe for the treatment of TD in multicenter, controlled trials and their development has led to a resurgence of interest in the characterization and treatment of this movement disorder. PMID- 29433809 TI - Future directions in tardive dyskinesia research. AB - Tardive dyskinesia (TD) research is at a crossroads because of renewed interest in this syndrome following the successful development and regulatory approval of two novel vesicular monoamine transport 2 (VMAT2) inhibitors. Despite these clinical advances, significant lacunae exist in the knowledge base of TD pathophysiology, prognosis, and epidemiology. Moreover, conflicting definitions of TD as either a syndrome that encompasses a broad array of related phenomena or as a specific subset of tardive syndromes are an impediment to both clinical and basic science research, and to educational efforts targeting nonspecialist clinicians. A unique opportunity is thus presented by the enhanced focus on TD to resolve fundamental issues with regards to nomenclature and clinical criteria, thereby facilitating more sophisticated surveillance and genetic and epidemiological research into tardive movement disorders related to dopamine receptor blocking agents. The widespread use of newer antipsychotics portends that TD will remain a persistent public health issue. This article will present one view of research avenues to be explored for this neuropsychiatric condition, including those that may yield immediate therapeutic benefits by extending expert knowledge into routine clinical care situations. PMID- 29433810 TI - The nosology of tardive syndromes. AB - Since the original description of side effects of neuroleptics, different terminologies and definitions for tardive dyskinesia (TD) and tardive syndrome (TS) have been used by different authors, and often these two terms have been used interchangeably. This paper proposes a nosology designed to define and clarify various terms and phenomenologies within the TS spectrum. We propose to use the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements, as well as to the analogous repetitive movements that can appear in the limbs, trunk, or pelvis. The repetitive, relatively rhythmic nature of the movements is the common denominator of this phenomenologic category. The term tardive syndrome refers to the spectrum of all persistent hyperkinetic, hypokinetic and sensory phenomenologies resulting from chronic dopamine receptor blocking agents (DRBA) exposure. Thus, TS is an umbrella term. When dystonia is the main feature of TS it is considered to be tardive dystonia (TDyst). Retrocollis appears to be the predominant form of cervical dystonia in this condition. Cranial dystonias, particularly oromandibular dystonia, are also common forms of TDyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. It is a sensory phenomenon and a common and disabling form of TS. Unlike acute akathisia, tardive akathisia tends to occur late and persists after the drug is withdrawn. In tardive tourettism, the patient exhibits the features of Tourette syndrome with complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior. Tardive tremor differs from the resting tremor seen in drug-induced parkinsonism in that it is mainly a postural and kinetic greater than resting tremor. Tardive pain has been reported in association with chronic use of DRBA's. The pain involved the mouth, tongue and the genital region. The patients tended to obsess over the pain and usually had some other form of motor tardive syndrome, either tardive dyskinesia, tardive akathisia or tardive dystonia. The term tardive parkinsonism has been proposed for those drug induced parkinsonism patients who have persistent symptoms following discontinuation of the DRBA. However, there is a strong possibility that the DRBA may have simply unmasked subclinical parkinsonism or that there is coincident Parkinson disease developing during the period the patient is taking the DRBA. PMID- 29433811 TI - Tardive dyskinesia: Epidemiology. AB - The term tardive syndrome (TS) encompasses a few different phenomenologic conditions, some of which occur in isolation and others in association with each other. This, along with the unusual confound for a drug side effect, in which increased use of the drug improves the problem, and the need for most patients to continue taking the offending drug, makes understanding the epidemiology difficult and unreliable. While the change from the "first generation" to the "second generation" of antipsychotic drugs is generally believed to have reduced the incidence of TS, prospective research studies have not supported that contention. Published reports have found point prevalences of 13% with second generation antipsychotics and 32% with first, yet others have found no differences. One study found increasing rates of TS with a 68% prevalence by 25 years, while another found a decreased prevalence over time, due presumably to masking effects of the antipsychotic drugs. Regardless of the possible differences, it is clear that TS remains a significant and common problem associated with almost all antipsychotic drugs. There have also been scattered reports of TS caused by drugs not known to inhibit dopamine receptors. These are reviewed and were found to be often of dubious reliability. PMID- 29433812 TI - The care of patients assessed as not in need of emergency ambulance care - Registered nurses' lived experiences. AB - AIM: The aim of this study was to describe the care of patients assessed as not in need of emergency ambulance care, from Registered Nurse's lived experiences. BACKGROUND: Non-emergency patients in need of ambulance care are described as vulnerable and patients in ambulance care have earlier been found to be dependent on the Registered Nurse. However, little is known about the care of non-emergency patients in the ambulance setting, from the perspective of Registered Nurses. METHODS: A reflective lifeworld research design was chosen. Five Registered Nurses with experience of ambulance care were individually interviewed. RESULTS: The result reveals the essence of the phenomenon as a desire to provide good care in an on-going struggle between one's own and others' expectations. Three meaning constituents emerged in the description; Being in a struggle between different expectations, Being in a questioned professional role, and Being in lack of support and formal directives. CONCLUSION: Registered Nurses' care for patients assessed as not in need of emergency ambulance care, is a complex struggle between different expectations. This may be related to the encounter between the nurse's and the patient's lifeworld. PMID- 29433813 TI - Praziquantel Interaction with Mammalian Targets in the Spotlight. AB - Chan et al. recently demonstrated that the antischistosomal drug praziquantel has a potent and specific interaction with human 5-HT2B receptors, and that the drug also elicits contraction of mouse mesenteric vasculature apparently mediated by the same receptor subtype We consider what this might mean about the drug's molecular therapeutic targets in both the worm and the host. PMID- 29433814 TI - Acute symptomatic seizures in term neonates: Etiologies and treatments. AB - Acute symptomatic seizures caused by either diffuse or focal perinatal hypoxic ischemic insults and intracranial hemorrhage in term newborns make up the large majority of all neonatal seizures. Acute seizures are one of the most common neurological disorders in term newborns who require admission to the neonatal intensive care unit. Despite elucidation of seizure pathogenesis in this population using animal models, treatment is limited by a lack of good evidence based guidelines because of a paucity of rigorously conducted clinical trials or prospective studies in human newborns. A result of this knowledge gap is that management, particularly drug choice, is guided by clinical experience rather than by data informing drug efficacy and safety. This review summarizes the common etiologies and pathogenesis of acute symptomatic seizures, and the current data informing their treatment, including potential novel drugs, together with a suggested treatment algorithm. PMID- 29433815 TI - Prognostic significance of HPV status in the re-irradiation of recurrent and second primary cancers of the head and neck. AB - PURPOSE: To evaluate the prognostic significance of human papillomavirus (HPV) status among patients treated by salvage radiation therapy for local-regional recurrences and second primary cancers of the head and neck arising in a previously irradiated field. METHODS AND MATERIALS: The medical records of 54 consecutive patients who underwent re-irradiation for squamous cell carcinoma of the head and neck occurring in a previously irradiated field were reviewed. Only patients with biopsy-proven evidence of recurrent disease that had previously been treated with doses of radiation therapy of at least 60 Gy were included. Determination of HPV status at the time of recurrence was performed by p16 immunohistochemistry. The median age at re-irradiation was 58.5 years (range, 27.9 to 81.5 years). Thirty patients (55.5%) were lifelong never-smokers. The Kaplan Meier method was used to calculate overall survival, progression-free survival, and local-regional control, and distant metastasis-free survival with comparisons between groups performed using the log-rank test. RESULTS: HPV status among tumors that were re-irradiated was as follows: 16 positive (29.7%); 7 negative (12.9%); 31 unknown (57.4%). The median overall survival in the entire cohort was 11.7 months (range, 8 to 27 months), with the 1-year and 2-year estimates of overall survival being 47.2% and 38.4%, respectively. A statistical trend was identified favoring patients with HPV-positive cancers with respect to the endpoints of overall survival (p = 0.06) and progression-free survival (p = 0.08) after re-irradiation when compared to the HPV-negative/unknown population. There was no significant difference in distant control between the two cohorts (p = 0.40). CONCLUSIONS: The favorable prognostic significance of HPV seemingly extends to patients treated by re-irradiation suggesting that this biomarker may be useful in risk stratification in this setting. PMID- 29433816 TI - Rickettsial infection in ticks (Acari: Ixodidae) from reptiles in the Colombian Caribbean. AB - Although more reptiles are illegally traded in Colombia than any other group of animals, for both local and international markets, little is known about ticks associated with reptiles or pathogens associated with these ticks. In this study, ticks were collected from reptiles in Magdalena, Cesar and La Guajira regions in northern Colombia, and identified morphologically using taxonomic keys and molecularly by sequencing of the COI gene. In addition, Rickettsia spp. were detected by PCR amplifying the gltA, 16S rRNA, and sca1 genes. Ticks were identified as Amblyomma dissimile, representing the first record for this species in 17 of the 26 species of reptiles sampled. Additionally, our data expand the distribution range for this tick in Colombia. Rickettsia spp. DNA was detected in 18 ticks (3.6%) from 16 reptiles. Sequence analyses indicated that most of the Rickettsia were members of the R. monacensis clade, most closely related to Rickettsia sp. strain Colombianensi. We detected one tick infected with a Rickettsia with 99% identity to R. bellii. PMID- 29433817 TI - Detection of Rickettsia massiliae/Bar29 and Rickettsia conorii in red foxes (Vulpes vulpes) and their Rhipicephalus sanguineus complex ticks. AB - To determine the prevalence of exposure to Rickettsia massiliae/Bar29 and Rickettsia conorii in wild red foxes, we collected blood samples and ticks from 135 foxes shot in different game reserve areas in Catalonia. To detect SFG rickettsia in Rhipicephalus sanguineus complex ticks collected from the foxes, we used real-time polymerase chain reaction (PCR) to screen for ompA gene and a tick borne bacteria flow chip technique based on multiplex PCR. Serum samples were positive for antibodies against spotted fever group (SFG) rickettsiae in 68 (50.3%). Molecular techniques identified R. massiliae in 107 ticks, R. aeschlimannii in 3 ticks, and R. slovaca in one tick; no R. conorii was identified in any of the ticks analyzed. We conclude that red foxes can carry ticks with SFG rickettsia. PMID- 29433819 TI - Medulloblastoma: A turning point from fundamental advances to improved survival and decreased sequelae. PMID- 29433818 TI - Spinal adhesive arachnoiditis following the rupture of an Adamkiewicz aneurysm: Literature review and a case illustration. AB - BACKGROUND: The rupture of an isolated spinal aneurysm is an exceptional occurrence. It might be responsible for a spinal subarachnoid haemorrhage (SSAH) that in rare cases can be complicated by arachnoiditis. Among the former the adhesive type is the most severe leading to the formation of a cyst and/or a syrinx. PATIENTS AND METHODS: The literature review was performed via a PubMed search using the following keywords. Adhesive arachnoiditis; spinal subarachnoid haemorrhage; spinal arachnoiditis; spinal arachnoid cyst; arachnoid cyst .Thesearch yielded 24 articles. Given the fact that only a few studies had been reported on the subject, we decided to include all studies regarding adhesive arachnoiditis after SAH leading to a descriptive literature review. Furthermore, a case illustration of a 57 year old man harbouring this type of rare pathology is described. RESULTS: Twenty-four case reports were found regarding spinal adhesive arachnoiditis (SAA) following SSAH. Posterior cerebral circulation bleeding (66.7%) most often occurred followed by spinal (9.1%) and anterior cerebral circulation (9.1%) respectively. The mean time between the haemorrhage and the SAA onset was 10 months. A higher predominance of symptomatic thoracic SAA was found. Including the present case, 80% of patients had a laminectomy, 72% had a micro adhesiolysis, and 56% a shunt placement. Cervical and upper thoracic involvement appeared to have a better outcome. CONCLUSION: Although most authors suggested surgical treatment, the long-term outcome remains unclear. Early stage diagnosis and management of this rare and disabling pathology may lead to a better outcome. Larger co-operative studies remain essential to obtain a better understanding of such a rare and complex disease. PMID- 29433820 TI - Surface enhanced Raman spectroscopy in microchip electrophoresis. AB - Coupling microchip capillary electrophoresis to surface enhanced Raman spectroscopy (MCE-SERS) combines the high separation power of capillary electrophoresis with the capability to obtain vibrational fingerprint spectra for compound identification. Raman spectroscopy is a structurally descriptive and label-free detection method which is particularly suited for chemical analysis because it is non-destructive and allows the identification of analytes. However, it suffers from poor sensitivity and sometimes even requires acquisition times far longer than the typical peak width of electrophoretic separations. The Raman intensity can be drastically improved if the analyte is brought into close proximity to nanostructured metal surfaces or colloids due to the surface enhancement effect. This paper presents a novel approach in the field of MCE-SERS on-line coupling. The key element of the developed glass microfluidic device is a dosing structure which consists of two side channels joining the MCE channel symmetrically after the electrophoretic separation of the analytes. The dosing channel supplies silver nanoparticles (Ag-NPs), to the separated electrophoretic zones which facilitates an on-the-fly recording of SERS-spectra of the separated compounds. The functionality of the MCE-SERS chip was evaluated by the analysis of a rhodamine model mixture within 90 s achieving RSD of migration times below 1.5%. The approach was successfully applied for the analysis of the food additive riboflavin in a barbecue sauce. PMID- 29433821 TI - A method for screening active components from Chinese herbs by cell membrane chromatography-offline-high performance liquid chromatography/mass spectrometry and an online statistical tool for data processing. AB - Cell membrane chromatography (CMC) has been successfully applied to screen bioactive compounds from Chinese herbs for many years, and some offline and online two-dimensional (2D) CMC-high performance liquid chromatography (HPLC) hyphenated systems have been established to perform screening assays. However, the requirement of sample preparation steps for the second-dimensional analysis in offline systems and the need for an interface device and technical expertise in the online system limit their extensive use. In the present study, an offline 2D CMC-HPLC analysis combined with the XCMS (various forms of chromatography coupled to mass spectrometry) Online statistical tool for data processing was established. First, our previously reported online 2D screening system was used to analyze three Chinese herbs that were reported to have potential anti inflammatory effects, and two binding components were identified. By contrast, the proposed offline 2D screening method with XCMS Online analysis was applied, and three more ingredients were discovered in addition to the two compounds revealed by the online system. Then, cross-validation of the three compounds was performed, and they were confirmed to be included in the online data as well, but were not identified there because of their low concentrations and lack of credible statistical approaches. Last, pharmacological experiments showed that these five ingredients could inhibit IL-6 release and IL-6 gene expression on LPS induced RAW cells in a dose-dependent manner. Compared with previous 2D CMC screening systems, this newly developed offline 2D method needs no sample preparation steps for the second-dimensional analysis, and it is sensitive, efficient, and convenient. It will be applicable in identifying active components from Chinese herbs and practical in discovery of lead compounds derived from herbs. PMID- 29433822 TI - Tetrafluoroterephthalonitrile-crosslinked beta-cyclodextrin polymers for efficient extraction and recovery of organic micropollutants from water. AB - In this study, we evaluated the performance of a novel tetrafluoroterephthalonitrile-crosslinked beta-cyclodextrin polymer (TFN-CDP) as a solid-phase extraction (SPE) material for the recovery of up to 189 diverse organic micropollutants (MPs) from water. The optimized extraction procedure requires loading of water samples adjusted to a pH of 3 onto 500 mg of TFN-CDP packed into an SPE cartridge. Under these conditions, 88.7% of the MPs have average extraction efficiencies greater than 80%. The optimized recovery procedure requires elution with 15 mL of methanol amended with 15 mg of calcium chloride. Under these conditions, 58.4% of the MPs have average absolute recoveries between 80% and 120%. We compared the performance of the optimized SPE method for TFN-CDP with a previously optimized SPE method employing hydrophilic lipophilic balance (HLB) adsorbents in nanopure water and in wastewater-impacted surface water. The data indicate that the optimized TFN-CDP method performs as well as or better than the optimized HLB-based SPE method. These findings represent an important step forward in the development of sustainable and inexpensive materials for the extraction and recovery of organic MPs from water. PMID- 29433823 TI - Porphyrin-based magnetic nanocomposites for efficient extraction of polycyclic aromatic hydrocarbons from water samples. AB - Stable and reusable porphyrin-based magnetic nanocomposites were successfully synthesized for efficient extraction of polycyclic aromatic hydrocarbons (PAHs) from environmental water samples. Meso-Tetra (4-carboxyphenyl) porphyrin (TCPP), a kind of porphyrin, can connect the copolymer after amidation and was linked to Fe3O4@SiO2 magnetic nanospheres via cross-coupling. Several characteristic techniques such as field emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectrometry, vibrating sample magnetometry and a tensiometer were used to characterize the as synthesized materials. The structure of the copolymer was similar to that of graphene, possessing sp2-conjugated carbon rings, but with an appropriate amount of delocalized pi-electrons giving rise to the higher extraction efficiency for heavy PAHs without sacrificing the performance in the extraction of light PAHs. Six extraction parameters, including the TCPP:Fe3O4@SiO2 (m:m) ratio, the amount of adsorbents, the type of desorption solvent, the desorption solvent volume, the adsorption time and the desorption time, were investigated. After the optimization of extraction conditions, a comparison of the extraction efficiency of Fe3O4@SiO2-TCPP and Fe3O4@SiO2@GO was carried out. The adsorption mechanism of TCPP to PAHs was studied by first-principles density functional theory (DFT) calculations. Combining experimental and calculated results, it was shown that the pi-pi stacking interaction was the main adsorption mechanism of TCPP for PAHs and that the amount of delocalized pi-electrons plays an important role in the elution process. Under the optimal conditions, Fe3O4@SiO2-porphyrin showed good precision in intra-day (<8.9%) and inter-day (<13.0%) detection, low method detection limits (2-10 ng L-1), and wide linearity (10-10000 ng L-1). The method was applied to simultaneous analysis of 15 PAHs with acceptable recoveries, which were 71.1%-106.0% for ground water samples and 73.7%-107.1% for Yangtze River water samples, respectively. PMID- 29433824 TI - Screening program in ovarian cancer: A logical step in clinical management? A meta-analysis. AB - OBJECTIVE: Treatment of ovarian cancer (OC) is a challenge and its poor prognosis still remains a problem of major importance. Due to the lack of early and specific symptoms, the vast majority of women are diagnosed with an advanced stage disease. The aim of this meta-analysis is to evaluate the impact of OC screening program in asymptomatic women on clinical outcomes. METHODS AND MATERIAL: A systematic literature electronic search was conducted in Pubmed, Medline, Scopus, and ClinicalTrials.gov databases. Articles were selected with a systematic approach. Clinical trials concerning screening strategy compared with usual care in asymptomatic OC women were considered, without any restrictions on the publication date. Trials were eligible if participants were asymptomatic and postmenopausal women. Outcomes included OC diagnosis and disease specific mortality. The pooled relative risk (RR) was calculated using a fixed-effects model. RESULTS: Overall, 3 randomized controlled trials met inclusion criteria, totaling 353,590 asymptomatic women. In total 177,188 women were assigned to screening program, and 176,402 women were assigned to usual care. The risk of OC diagnosis, both overall and at an early stage, was higher in screening group (RR = 1.07, 95% CI: 0.98-1.18; and RR = 1.30, 95% CI: 1.14-1.49, respectively). The RR for disease specific mortality was 0.96 (95% CI: 0.85-1.10). CONCLUSION: Our results suggest the possible benefit of OC screening program in term of early stage diagnosis and reduced specific OC mortality. Further studies of environmental or constitutional factors may lead to the identification of patient populations that could benefit from a screening program. PMID- 29433825 TI - Risk factors for prostate cancer: A multifactorial case-control study. AB - Prostate cancer is the third most commonly diagnosed cancer among Pakistani men. It is a multifactorial disease involving genetics together with environmental factors. Countries where men have greater dietary fat intake showed increased prostate cancer mortality rates. A population based case-control study was conducted to evaluate various prostate cancer risk factors. Study subjects were 896 prostate cancer cases (2010-2015) and 900 age matched controls. Odds ratio (OR) and 95% CI were used to estimate the association between different risk factors and prostate cancer. P values for different factors were computed by t test, chi-square test, and Fisher exact test. Results showed significant association of increased age (OR = 10.6; CI: 7.92-14.31; P = 0.0001; Z = 15.7) and smoking (P = 0.05) with risk of disease. Consistent evidence suggested that fruits (P = 0.0001), vegetables (P = 0.0007), and diabetes mellitus (OR = 0.84; CI: 0.72-0.97; P = 0.02; Z = 2.28) were significantly associated with decreased prostate cancer risk. Comparison of education, marital status, occupation, intake of meat (<100 grams/week, 101-250 grams/week, >250 grams/week), number of cigarettes smoked per day, smoking duration, and family history of disease among cases and controls were not associated (P > 0.05) with risk of prostate cancer. Most of the prostate cancer patients were at stage IV with a Gleason score ranging from 7-9 and had undergone surgery. This epidemiological study illustrated that age and smoking were potential risk factors for prostate cancer in Pakistani men. Furthermore, phytonutrients can reduce its risk to a greater extent. Prospective studies with detailed analysis and greater sample size are required to explore more accurate findings. PMID- 29433826 TI - Cancer cervix: Establishing an evidence-based strategy, an experience of a tertiary care centre in India. AB - Carcinoma cervix is a common cancer among Indian women. Evidence based management is essential for best practice in treatment of carcinoma cervix for its effective control. The current imaging system like CT, MRI and PET CT scans have contributed in identifying the patients for optimal treatment and delivering treatment accurately. For stages IB2 to IV, concurrent chemoradiation is advocated with improvement in overall survival proven with randomized trials. Brachytherapy is an integral part in the radiation treatment. Imaged-guided brachytherapy using MRI is desirable, however less expensive imaging modalities such as CT and ultrasonography has been evaluated. In special situation such as for HIV positive patients and patients with neuroendocrine tumors have role of radiotherapy. For further improvement in control of cancer, it is required to integrate basic research to answer clinically relevant questions. PMID- 29433827 TI - Adipocytokines and breast cancer. AB - A substantial number of studies have revealed that a growing list of cancers might be influenced by obesity. In this regard, one of the most prominent and well-characterized cancers is breast cancer, the leading cause of cancer death among women. Obesity is associated with an increased risk for the occurrence and development of breast cancer particular in postmenopausal women. Moreover, the relationship between adiposity and breast cancer risk is complex, with associations that differ depending on when body size is assessed (eg, premenopausal vs postmenopausal obesity) and when breast cancer is diagnosed (ie, premenopausal vs postmenopausal disease). Obesity is mainly due to excessive fat accumulation in the regional tissue. Adipocytes in obese individuals produce endocrine, inflammatory, and angiogenic factors to affect adjacent breast cancer cells. Adipocytokines, are biologically active polypeptides that are produced either exclusively or substantially by adipocytes, play a critical and complex role, and act by endocrine, paracrine, and autocrine pathways in the malignant progression of breast cancer. Furthermore, the increased levels of leptin, resistin, and decreased adiponectin secretion are directly associated with breast cancer development. And there are also many studies indicating that adipocytokines could mediate the survival, growth, invasion, and metastasis of breast cancer cells by different cellular and molecular mechanisms to reduce the survival time and prompt the malignancy. In present review, we discuss the correlations between several adipocytokines and breast cancer cells in obesity as well as the underlying signaling pathways to provide the novel ideas for the prevention and treatment of breast cancer. PMID- 29433828 TI - Patient-Centered Care in Renal Medicine: Five Strategies to Meet the Challenge. AB - There is growing interest in patient-centered care, defined by the Institute of Medicine as "care that is respectful of and responsive to individual patient preferences, needs, and values." Although generally accepted as uncontroversial, the notion of "centering" care on our patients is in fact quite revolutionary. Because medical teaching, research, and practice have traditionally been organized around diseases and organ systems rather than patients, making care more patient centered would require no less than a paradigm shift in how we practice medicine. This would call for a frameshift in how we envision our role as health care providers and fundamental changes to the health care delivery systems in which we practice. Although individual providers may have limited power to change health systems (at least in the short term), there are some simple strategies within our reach that can help make our care more patient centered. These include a willingness to listen, make time, go beyond our job description, re-imagine what it means to provide "good" care, and see value in relationship building. Although putting these practices to work in the complex, specialized, and fragmented health systems in which many of us operate may be challenging, I would argue that this is a "beautiful challenge" with potentially far-reaching benefits for both patients and providers. PMID- 29433829 TI - Acute mesenteric ischemia: A critical role for the radiologist. AB - Acute mesenteric ischemia is defined as an inadequate blood supply to the gastrointestinal tract resulting in ischemic and inflammatory injury that may progress to necrosis of the bowel wall. Prognosis is poor with a mortality rate greater than 95% without treatment, dropping to around 70% when surgical treatment is performed. Contrast-enhanced computed tomography (CT) has become the cornerstone of the diagnosis by showing features of vascular disorders (occlusion and/or insufficient blood supply) and features of intestinal ischemic injury. CT should be performed as rapidly as possible. Imaging-based patient management is required, and multimodal and multidisciplinary management should be introduced. The treatment involves multidisciplinary management by gastroenterologists, vascular and digestive surgeons, cardiologists, intensivists, and diagnostic and interventional radiologists. Based on our experience at a dedicated mesenteric stroke center, this article gives an overview of the diagnosis of acute mesenteric ischemia. The goal of this review is to improve the understanding of the imaging-based diagnosis to further improve the management of this life threatening condition. PMID- 29433830 TI - Combined transarterial and transvenous embolization of a ruptured utero-ovarian arteriovenous malformation with ethylene vinyl alcohol copolymer (Onyx(r)). PMID- 29433831 TI - Endovascular aortic arch repair using customs made branched stent graft under three-dimensional image fusion guidance. PMID- 29433832 TI - Microbes are off the menu: Defective macrophage phagocytosis in COPD. AB - In this issue of the Biomedical Journal, we learn about the pathophysiology of chronic obstructive pulmonary disease and how defective macrophage phagocytosis may lead to the build up of microbes and pollutants in inflamed lungs. We also focus on new findings that may take us a step closer to full automation in diagnostic bacteriology laboratories. Finally, we highlight the anti-tumor properties of microalgae and the application of algorithms to predict human emotion from electrocardiogram. PMID- 29433834 TI - Gasdermin: A new player to the inflammasome game. AB - Pyroptosis is a lytic type of programmed cell death that was traditionally associated with the involvement of inflammatory caspases, such as caspase-1. These inflammatory caspases are activated within multi-protein complexes called inflammasomes that are assembled in response to invading pathogens and/or danger signals. Pyroptotic cell death was suggested to evolve via the formation of pores in the plasma membrane, but the exact mechanism underlying the formation of these pores remained unclear. Recently, gasdermin D, a member of the gasdermin protein family was identified as a caspase substrate and essential effector of pyroptosis, being identified as the protagonist of membrane pore formation. Gasdermins have emerged as a family of new class of cell death inducers, but many questions remain unanswered. Here, we present an overview of recent work being done in the area of programmed cell death and the latest evidence regarding the role and participation of gasdermin D as an effector of pyroptosis. PMID- 29433833 TI - Macrophage phagocytosis cracking the defect code in COPD. AB - In the normal non-diseased lung, various macrophage populations maintain homeostasis and sterility by ingesting and clearing inhaled particulates, pathogens and apoptotic cells from the local environment. This process of phagocytosis leads to the degradation of the internalized material, coordinated induction of gene expression, antigen presentation and cytokine production, implicating phagocytosis as a central regulator of innate immunity. Phagocytosis is extremely efficient and any perturbation of this function is deleterious. In inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD), despite their increased numbers, macrophages demonstrate significantly reduced phagocytic capacity of bacteria and apoptotic cells. This defect could play a role in dysbiosis of the lung microbiome contributing to disease pathophysiology. In this review, we will discuss lung macrophages, describe phagocytosis and its related downstream processes and the reported phagocytosis defects in COPD. Finally, we will briefly examine current strategies that focus on restoring the phagocytic capabilities of lung macrophages that may have utility in COPD. PMID- 29433835 TI - Towards automated detection, semi-quantification and identification of microbial growth in clinical bacteriology: A proof of concept. AB - BACKGROUND: Automation in microbiology laboratories impacts management, workflow, productivity and quality. Further improvements will be driven by the development of intelligent image analysis allowing automated detection of microbial growth, release of sterile samples, identification and quantification of bacterial colonies and reading of AST disk diffusion assays. We investigated the potential benefit of intelligent imaging analysis by developing algorithms allowing automated detection, semi-quantification and identification of bacterial colonies. METHODS: Defined monomicrobial and clinical urine samples were inoculated by the BD KiestraTM InoqulATM BT module. Image acquisition of plates was performed with the BD KiestraTM ImagA BT digital imaging module using the BD KiestraTM OptisTM imaging software. The algorithms were developed and trained using defined data sets and their performance evaluated on both defined and clinical samples. RESULTS: The detection algorithms exhibited 97.1% sensitivity and 93.6% specificity for microbial growth detection. Moreover, quantification accuracy of 80.2% and of 98.6% when accepting a 1 log tolerance was obtained with both defined monomicrobial and clinical urine samples, despite the presence of multiple species in the clinical samples. Automated identification accuracy of microbial colonies growing on chromogenic agar from defined isolates or clinical urine samples ranged from 98.3% to 99.7%, depending on the bacterial species tested. CONCLUSION: The development of intelligent algorithm represents a major innovation that has the potential to significantly increase laboratory quality and productivity while reducing turn-around-times. Further development and validation with larger numbers of defined and clinical samples should be performed before transferring intelligent imaging analysis into diagnostic laboratories. PMID- 29433836 TI - Multiresolution image registration for multimodal brain images and fusion for better neurosurgical planning. AB - BACKGROUND: Imaging modalities in medicine gives complementary information. Inadequacy in clinical information made single imaging modality insufficient. There is a need for computer-based system that permits rapid acquisition of digital medical images and performs multi-modality registration, segmentation and three-dimensional planning of minimally invasive neurosurgical procedures. In this regard proposed article presents multimodal brain image registration and fusion for better neurosurgical planning. METHODS: In proposed work brain data is acquired from Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) modalities. CT and MRI images are pre-processed and given for image registration. BSpline deformable registration and multiresolution image registration is performed on the CT and MRI sequence. CT is fixed image and MRI is moving image for registration. Later end result is fusion of CT and registered MRI sequences. RESULTS: BSpline deformable registration is performed on the slices gave promising results but on the sequences noise have been introduced in the resultant image because of multimodal and multiresolution input images. Then multiresolution registration technique is performed on the CT and MRI sequence of the brain which gave promising results. CONCLUSION: The end resultant fused images are validated by the radiologists and mutual information measure is used to validate registration results. It is found that CT and MRI sequence with more number of slices gave promising results. Few cases with deformation during misregistrations recorded with low mutual information of about 0.3 and which is not acceptable and few recorded with 0.6 and above mutual information during registration gives promising results. PMID- 29433837 TI - Effect of Enzymatic pre-treatment of microalgae extracts on their anti-tumor activity. AB - BACKGROUND: There is an increasing need to find natural bioactive compounds for pharmaceutical applications, because they have less harmful side effects compared to their chemical alternatives. Microalgae (MA) have been identified as a promising source for these bioactive compounds, and this work aimed to evaluate the anti-proliferative effects of semi-purified protein extracted from MA against several tumor cell lines. METHODS: Tested samples comprised MA cell extracts treated with cellulase and lysozyme, prior to extraction. The effect of dialysis, required to remove unnecessary small molecules, was also tested. The anti-cancer efficacies of the dialyzed and undialyzed extracts were determined by measuring cell viability after treating four human cancer cell lines, specifically A549 (human lung carcinoma), MCF-7 (human breast adenocarcinoma), MDA MB-435 (human melanoma), and LNCap (human prostate cancer cells derived from a metastatic site in the lymph node). This was compared to the effects of the agents on the human BPH-1 cell line (benign human prostate epithelial cells). The t-test was used to statistically analyze the results and determine the significance. RESULTS: Against LNCap and A549 cells, the performance of cellulase-treated extracts was better (with p-values < 0.05, as compared to the control) than that of lysozyme treated preparations (with p-values mainly > 0.05, as compared to the control); however, they had similar effects against the other two tumor cell lines (with p values mainly < 0.05, as compared to the control). Moreover, based on their effect on BPH-1 cells, extracts from lysozyme-treated MA cells were determined to be safer against the benign prostate hyperplasia cells, BPH-1 (with p-values mainly > 0.05, as compared to the control). After dialysis, the performance of MA extracts from lysozyme-treated cells was enhanced significantly (with p-values dropping to < 0.05, as compared to the control). CONCLUSIONS: The results of this work provide important information and could provide the foundation for further research to incorporate MA constituents into pharmaceutical anti-cancer therapeutic formulations. PMID- 29433838 TI - Preliminary Asian experience of using perampanel in clinical practice. AB - BACKGROUND: To analyze the efficacy and safety of perampanel over a 3-month period in a sample of Asian people with epilepsy. METHODS: The efficacy and safety of perampanel as an adjunctive therapy for patients with epilepsy were retrospectively reviewed and analyzed. Patients were categorized according to seizure type, concomitant antiepileptic drug usage, and perampanel dosage. RESULTS: A total of 210 patients were included in the study and 131 patients completed 3 months of perampanel treatment. The average dosage of perampanel was 5.31 mg/day, and the 50% responder rate (>=50% seizure frequency reduction) in all patients was 45.8%, with a 27.5% seizure-free rate. For focal seizures, focal to bilateral tonic-clonic seizures, and primary generalized seizures, the 50% responder rates were respectively 29.4%, 49.5%, and 36.4%. In total, 39.5% of patients experienced adverse events within 3 months of observation period, and the rate of drug withdrawal due to adverse events was 8.6%. Dizziness, ataxia, irritability/aggression were the most common adverse events. CONCLUSIONS: The efficacy and safety of perampanel in a real-world setting with Asian patients is comparable to that in clinical trials that have included fewer Asian patients. PMID- 29433839 TI - An accurate emotion recognition system using ECG and GSR signals and matching pursuit method. AB - BACKGROUND: The purpose of the current study was to examine the effectiveness of Matching Pursuit (MP) algorithm in emotion recognition. METHODS: Electrocardiogram (ECG) and galvanic skin responses (GSR) of 11 healthy students were collected while subjects were listening to emotional music clips. Applying three dictionaries, including two wavelet packet dictionaries (Coiflet, and Daubechies) and discrete cosine transform, MP coefficients were extracted from ECG and GSR signals. Next, some statistical indices were calculated from the MP coefficients. Then, three dimensionality reduction methods, including Principal Component Analysis (PCA), Linear Discriminant Analysis, and Kernel PCA were applied. The dimensionality reduced features were fed into the Probabilistic Neural Network in subject-dependent and subject-independent modes. Emotion classes were described by a two-dimensional emotion space, including four quadrants of valence and arousal plane, valence based, and arousal based emotional states. RESULTS: Using PCA, the highest recognition rate of 100% was achieved for sigma = 0.01 in all classification schemes. In addition, the classification performance of ECG features was evidently better than that of GSR features. Similar results were obtained for subject-dependent emotion classification mode. CONCLUSIONS: An accurate emotion recognition system was proposed using MP algorithm and wavelet dictionaries. PMID- 29433840 TI - Thrombotic microangiopathy and accelerated hypertension after treatment with interferon beta. PMID- 29433841 TI - Relationship between acute kidney injury and serum procalcitonin (PCT) concentration in critically ill patients with influenza infection. AB - INTRODUCTION: Serum procalcitonin (PCT) concentration could be increased in patients with renal dysfunction in the absence of bacterial infection. OBJECTIVE: To determine the interactions among serum renal biomarkers of acute kidney injury (AKI) and serum PCT concentration, in patients admitted to the intensive care unit (ICU) due to lung influenza infection. DESIGN: Secondary analysis of a prospective multicentre observational study. SETTING: 148 Spanish ICUs. PATIENTS: ICU patients admitted with influenza infection without bacterial co-infection. Clinical, laboratory and hemodynamic variables were recorded. AKI was classified as AKI I or II based on creatinine (Cr) concentrations (>=1.60-2.50mg/dL and Cr>=2.51-3.99mg/dL, respectively). Patients with chronic renal disease, receiving renal replacement treatment or with Cr>4mg/dL were excluded. Spearman's correlation, simple and multiple linear regression analysis were performed. INTERVENTIONS: None. RESULTS: Out of 663 patients included in the study, 52 (8.2%) and 10 (1.6%) developed AKI I and II, respectively. Patients with AKI were significantly older, had more comorbid conditions and were more severally ill. PCT concentrations were higher in patients with AKI (2.62 [0.60-10.0]ng/mL vs. 0.40 [0.13-1.20]ng/mL, p=0.002). Weak correlations between Cr/PCT (rho=0.18) and Urea (U)/PCT (rho=0.19) were identified. Simple linear regression showed poor interaction between Cr/U and PCT concentrations (Cr R2=0.03 and U R2=0.018). Similar results were observed during multiple linear regression analysis (Cr R2=0.046 and U R2=0.013). CONCLUSIONS: Although PCT concentrations were slightly higher in patients with AKI, high PCT concentrations are not explained by AKI and could be warning sign of a potential bacterial infection. PMID- 29433842 TI - Audit of cataract surgery in Cadiz: visual outcomes and complications. AB - OBJECTIVE: To publish the outcomes and complications of age-related cataract surgery in Cadiz (Spain). Due to the lack of national audits, a comparison was made between the results obtained here and those of the most recent European audit, EUREQUO (2013), and the British audit RCOphth NOD (2015). METHODS: A prospective, longitudinal, before-after study of 312 patients undergoing cataract surgery in the University Hospitals of Puerta del Mar and Puerto Real (Cadiz), in 2013-14. Outcome measurements included sociodemographic characteristics, visual acuity (VA), symptoms secondary to cataract, ocular comorbidity, waiting time, expertise of surgeon (consultant vs. trainee), rate and type of surgical complications. RESULTS: The median age at surgery was 73.92+/-7.31. Almost all (98.3%) of patients at consultation had a VA >=0.60logMAR, with a mean pre surgical VA of 1.01logMAR (0.92-1.10). There was a 6.7% complication rate, with 3.8% posterior capsule ruptures and 2.8% corneal decompensations. No cases of endophthalmitis occurred. The mean post-operative VA was 0.28logMAR (0.22-0.33). More than three-quarters (78.8%) of cases achieved a post-operative VA <=0.3logMAR, and 27.6% of cases achieved a VA <=0.0logMAR. CONCLUSIONS: Our success rate was inferior to the EUREQUO and RCOphth NOD studies, with the percentage of patients acquiring a postoperative VA <=0.3logMAR being 98% and 89%, respectively. However, the populations were not comparable. It is hoped that this study will encourage other public hospitals in Spain to undertake audits and share their results, in order to provide a tool for constructive criticism and quality improvement initiatives. PMID- 29433843 TI - Biological alterations affecting risk of adult psychopathology following childhood trauma: A review of sex differences. AB - Childhood trauma exposure is a significant public health problem. While adult mental health consequences of such experiences are well documented, sex differences in both prevalence and severity are less understood. Sex-based differences in biological circuitry and physiological trauma responses are proposed to potentiate the differential risk for pathogenesis of mental health disorders among adults. This paper will provide a contextualized summary of neuroendocrine, neuroimaging, and behavioral epigenetic studies on biological sex differences contributing to internalizing psychopathology, specifically posttraumatic stress disorder and depression, among adults with a history of childhood abuse. This review concludes with a discussion of implications for trauma interventions and sex-based biopsychological research in violence prevention. PMID- 29433845 TI - Self-Perceived Health and Sleep Quality of Community Older Adults after Acupunch Exercises. AB - OBJECTIVES: To test the long-term effects of the 12-month Healthy Beat Acupunch (HBA) exercise program on the self-perceived health and sleep quality of older adults in community care centers, and to compare the effects of two delivery methods: instructor-led HBA for the first 6 months and DVD-guided HBA for another 6 months. DESIGN: Cluster-randomized controlled trial. SETTING: Eight community care centers. PARTICIPANTS: In total, 232 participants were recruited from eight community care centers, and cluster-randomized to the experimental (4 centers, N = 113) and control (4 centers, N = 119) groups. INTERVENTION: The experimental group received the instructor-led HBA program 3 times weekly for the first 6 months, followed by the DVD-guided HBA program for another 6 months. MEASUREMENTS: Self-perceived health and sleep quality were assessed using the Short Form Health Survey and the Pittsburgh Sleep Quality Index, respectively, at baseline and every 3 months for 1 year. RESULTS: The experimental group reported more favorable self-perceived physical and mental health, higher subjective sleep quality, and less daytime dysfunction than did the control group. Effect sizes of physical health and sleep quality increased from the instructor-led stage to the DVD-guided stage; the effect size of physical health showed the most significant change, increasing from 0.38 in the instructor-led stage to 0.55 in the DVD guided stage. CONCLUSIONS: The exercise program consisting of the instructor-led class, followed by the DVD-guided class, was an effective and feasible longitudinal program for older adults in community care centers. PMID- 29433844 TI - Glycogen synthase kinase-3beta activity and cognitive functioning in patients with bipolar I disorder. AB - Cognitive deficits are common in patients with bipolar disorder (BD) in remission and may be associated with glycogen synthase kinase-3 (GSK-3) activity, which is inhibited by lithium. GSK-3 may be a relevant treatment target for interventions tailored at cognitive disturbances in BD but the relation between GSK-3 activity, cognition and lithium treatment is unknown. We therefore investigated the possible association between GSK-3 activity and cognition and whether lithium treatment moderates this association in patients with BD. In a prospective 6-12 month follow-up study, GSK- 3beta activity in peripheral blood mononuclear cells was measured concurrently with cognitive performance assessed using a comprehensive test battery in 27 patients with BD-I in early and late remission following a manic or mixed episode. The GSK-3beta activity, measured as serine-9 phosphorylated GSK-3beta (pGSK-3beta) and the GSK-3beta ratio (serine-9-pGSK 3beta /total GSK-3beta), was negatively associated with sustained attention (p = 0.009 and p = 0.042, respectively), but not with other cognitive domains or global cognition. A crossover interaction between lithium treatment and the GSK activity was observed, indicating that lower pGSK-3beta levels (p = 0.015) and GSK ratio (p = 0.010) were associated with better global cognition in lithium users whereas the opposite association was observed in non-lithium treated patients. Findings were not statistically significant after Bonferroni correction. In conclusion, cognitive functioning may be associated with GSK-3 activity in patients with BD-I and lithium treatment may modulate this relationship. Future studies in larger sample sizes are warranted to confirm these associations. PMID- 29433846 TI - The Thick of It: Freely Wandering in Academic Medicine. PMID- 29433847 TI - Erratum to "Molecular mechanism of action of oxazolinoanthracyclines in cells derived from human solid tumors. Part 2" [Toxicol. in Vitro 46 (2018) 323-334]. PMID- 29433848 TI - Stop the toasts: the Global Fund's disturbing new partnership. PMID- 29433849 TI - Lenvatinib: can a non-inferiority trial change clinical practice? PMID- 29433851 TI - Systemic Medication Associations with Presumed Advanced or Uncontrolled Primary Open-Angle Glaucoma. AB - PURPOSE: To identify associations between systemic medications and primary open angle glaucoma (POAG) requiring a procedure using United States insurance claims data in a hypothesis-generating study. DESIGN: Database study. PARTICIPANTS: In total, 6130 POAG cases (defined as patients with POAG undergoing a glaucoma procedure) were matched to 30 650 controls (defined as patients undergoing cataract surgery but without a coded glaucoma diagnosis, procedure, or medication) by age, gender, and region of residence. METHODS: Participant prescription drug use was calculated for the 5-year period before the glaucoma procedure or cataract surgery. Separately for individual generic drugs and drug classes, logistic regression was used to assess the association with POAG status. This was done across all generic drugs and drug classes that were prescribed in at least 1% of cases and controls. Analyses were adjusted for age, sex, region of residence, employment status, insurance plan type, and the total number of drugs prescribed. MAIN OUTCOME MEASURES: Odds ratio (OR) and 95% confidence intervals (CIs) for the association between each drug or drug class and POAG. RESULTS: The median age of participants was 72 years, and 52% were women. We tested for associations of POAG with 423 drug classes and 1763 generic drugs, resulting in a total of 2186 statistical tests and a Bonferroni-adjusted significance threshold of P < 2.3 * 10-5. Selective serotonin reuptake inhibitors (SSRIs) were strongly associated with a reduced risk of POAG (OR, 0.70; 95% CI, 0.64-0.76; P = 1.0 * 10 15); the most significant drug in this class was citalopram (OR, 0.66; 95% CI, 0.57-0.77; P = 1.2 * 10-7). Calcium channel blockers were strongly associated with an increased risk of POAG (OR, 1.26; 95% CI, 1.18-1.35; P = 1.8 * 10-11); the most significant drug in this class was amlodipine (OR, 1.27; 95% CI, 1.18 1.37; P = 5.9 * 10-10). CONCLUSIONS: We present data documenting potential associations of SSRIs and calcium channel blockers with POAG requiring a procedure. Further research may be indicated to better evaluate any associates of serotonin metabolism or calcium channels in glaucoma, or establish whether the associations are due to variations in the patterns for prescribing these drugs. PMID- 29433850 TI - Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. AB - BACKGROUND: In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor alpha, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. METHODS: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight >=60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1.08. The trial is registered with ClinicalTrials.gov, number NCT01761266. FINDINGS: Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13.6 months (95% CI 12.1-14.9) was non-inferior to sorafenib (12.3 months, 10.4-13.9; hazard ratio 0.92, 95% CI 0.79-1.06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. INTERPRETATION: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed. FUNDING: Eisai Inc. PMID- 29433852 TI - Integrating Macular Ganglion Cell Inner Plexiform Layer and Parapapillary Retinal Nerve Fiber Layer Measurements to Detect Glaucoma Progression. AB - PURPOSE: To investigate the temporal relationship among progressive macular ganglion cell inner plexiform layer (GCIPL) thinning, progressive parapapillary retinal nerve fiber layer (RNFL) thinning, and visual field (VF) progression in patients with primary open-angle glaucoma (POAG). DESIGN: Prospective study. PARTICIPANTS: One hundred thirty-six POAG patients (231 eyes) followed up for >=5 years. METHODS: OCT imaging of the macular GCIPL and parapapillary RNFL and perimetry were performed at ~ 4-month intervals. Progressive GCIPL and RNFL thinning were determined by Guided Progression Analysis (GPA) of serial GCIPL and RNFL thickness maps. The specificities of GPA were calculated from the proportions of eyes with progressive GCIPL or RNFL thinning in 67 eyes of 36 healthy individuals followed up for >=5 years. Visual field progression (likely or possible) was determined by the Early Manifest Glaucoma Trial criteria. MAIN OUTCOME MEASURES: Hazard ratios for VF progression, progressive RNFL thinning, and progressive GCIPL thinning, as determined by time-varying Cox models. RESULTS: GPA detected 57 eyes (24.7%) with progressive GCIPL thinning and 66 eyes (28.6%) with progressive RNFL thinning at a specificity of 95.5% and 91.0%, respectively. Thirty-five eyes (15.2%) demonstrated progressive RNFL and GCIPL thinning, whereas 53 eyes (22.9%) demonstrated progressive RNFL or GCIPL thinning. Eyes with progressive GCIPL thinning had a higher risk for progressive RNFL thinning (HR, 5.27; 95% confidence interval [CI], 2.89-9.62), whereas eyes with progressive RNFL thinning were also at a higher risk for progressive GCIPL thinning (HR, 2.99; 95% CI, 1.48-6.02), after adjusting for baseline covariates. The HRs for likely and possible VF progression were 3.48 (95% CI, 1.51-8.01) and 2.74 (95% CI, 1.26-5.98), respectively, on detection of progressive GCIPL thinning and 3.66 (95% CI, 1.68-7.97) and 2.54 (95% CI, 1.23-5.21), respectively, on detection of progressive RNFL thinning after adjusting for baseline covariates. Eyes with VF progression were not at risk of progressive RNFL or GCIPL thinning (P >= 0.493). CONCLUSIONS: Progressive macular GCIPL thinning and progressive parapapillary RNFL thinning are mutually predictive. Because progressive RNFL thinning and progressive GCIPL thinning are both indicative of VF progression, integrating macular GCIPL and parapapillary RNFL measurements is relevant to facilitate early detection of disease deterioration in glaucoma patients. PMID- 29433853 TI - Identifying the low risk patient in surgical intensive and intermediate care units using continuous monitoring. AB - BACKGROUND: Continuous predictive monitoring has been employed successfully to predict subclinical adverse events. Should low values on these models, however, reassure us that a patient will not have an adverse outcome? Negative predictive values of such models could help predict safe patient discharge. The goal of this study was to validate the negative predictive value of an ensemble model for critical illness (using previously developed models for respiratory instability, hemorrhage, and sepsis) based on bedside monitoring data in the intensive care units and intermediate care unit. METHODS: We calculated the relative risk of 3 critical illnesses for all patients every 15 minutes (n= 124,588) for 2,924 patients downgraded from the surgical intensive care units and intermediate care unit between May 2014 to May 2016. We constructed an ensemble model to estimate at the time of intensive care units or intermediate care unit discharge the probability of favorable outcome after downgrade. RESULTS: Outputs form the ensemble model stratified patients by risk of favorable and bad outcomes in both intensive care units/intermediate care unit; area under the receiver operating characteristic curve = .639/.629 respectively for favorable outcomes and .645/.641 for adverse events. These performance characteristics are commensurate with published models for predicting readmission. The ensemble model remained a statistically significant predictor after adjusting for hospital duration of stay and admitting service. The rate of favorable outcome in the highest and lowest deciles in the intensive care units were 76.2% and 27.3% (2.8-fold decrease) and 88.3% and 33.2% in the intermediate care unit (2.7-fold decrease), respectively. CONCLUSION: An ensemble model for critical illness predicts favorable outcome after downgrade and safe patient discharge (hospital stay <7 days, no readmission, upgrade, or death). PMID- 29433854 TI - [Dermatophytosis due to Trichophyton violaceum at the parasitology-mycology laboratory of the military hospital of Meknes (about twelve cases)]. AB - INTRODUCTION: Trichophyton violaceum is an anthropophilic dermatophyte, common in Mediterranean and African countries, which causes particularly trichophytic tinea in school-aged children. The objective of this work is to study the clinical and epidemiological profile of T. violaceum infections. MATERIAL AND METHODS: This is a descriptive retrospective study of a series of twelve cases of T. violaceum dermatophytosis diagnosed among patients referred to our laboratory for suspicion of dermatomycosis during a period from January 2011 to December 2016. The diagnosis was based on the positivity of direct examination and culture, and the identification of our strains on the macroscopic and microscopic characteristics of the colonies. RESULTS: The mean age at diagnosis was 8.6 years with a sex ratio of 2. Tinea capitis (TC) was the most frequent clinical aspect (75 %), followed by onychomycosis (25 %). Among the TC, trichophytic tinea was predominant (66.7 %). Besides, we observed a case of pustulo-inflammatory tinea. Direct examination was positive and showed an endothrix pilar parasitism in all cases. DISCUSSION: The clinical expression of dermatophyties to T. violaceum is polymorphous. The TC is the most frequent as reported in the literature. However, kerion and onychomycoses of feet were rarely described in association with this dermatophyte, hence the importance of the mycological examination allowing to support the diagnosis of a misleading clinical lesion. PMID- 29433855 TI - Recent progress in tissue optical clearing for spectroscopic application. AB - This paper aims to review recent progress in optical clearing of the skin and over naturally turbid biological tissues and blood using this technique in vivo and in vitro with multiphoton microscopy, confocal Raman microscopy, confocal microscopy, NIR spectroscopy, optical coherence tomography, and laser speckle contrast imaging. Basic principles of the technique, its safety, advantages and limitations are discussed. The application of optical clearing agent on a tissue allows for controlling the optical properties of tissue. Optical clearing-induced reduction of tissue scattering significantly facilitates the observation of deep located tissue regions, at the same time improving the resolution and image contrast for a variety of optical imaging methods suitable for clinical applications, such as diagnostics and laser treatment of skin diseases, mucosal tumor imaging, laser disruption of pathological abnormalities, etc. PMID- 29433856 TI - Studying anti-oxidative properties of inclusion complexes of alpha-lipoic acid with gamma-cyclodextrin in single living fission yeast by confocal Raman microspectroscopy. AB - alpha-lipoic acid (ALA) is an essential cofactor for many enzyme complexes in aerobic metabolism, especially in mitochondria of eukaryotic cells where respiration takes place. It also has excellent anti-oxidative properties. The acid has two stereo-isomers, R- and S- lipoic acid (R-LA and S-LA), but only the R-LA has biological significance and is exclusively produced in our body. A mutant strain of fission yeast, Deltadps1, cannot synthesize coenzyme Q10, which is essential during yeast respiration, leading to oxidative stress. Therefore, it shows growth delay in the minimal medium. We studied anti-oxidant properties of ALA in its free form and their inclusion complexes with gamma-cyclodextrin using this mutant yeast model. Both free forms R- and S-LA as well as 1:1 inclusion complexes with gamma-cyclodextrin recovered growth of Deltadps1 depending on the concentration and form. However, it has no effect on the growth of wild type fission yeast strain at all. Raman microspectroscopy was employed to understand the anti-oxidant property at the molecular level. A sensitive Raman band at 1602cm-1 was monitored with and without addition of ALAs. It was found that 0.5mM and 1.0mM concentrations of ALAs had similar effect in both free and inclusion forms. At 2.5mM ALAs, free forms inhibited the growth while inclusion complexes helped in recovered. 5.0mM ALA showed inhibitory effect irrespective of form. Our results suggest that the Raman band at 1602cm-1 is a good measure of oxidative stress in fission yeast. PMID- 29433857 TI - Handling of uncertainty due to interference fringe in FT-NIR transmittance spectroscopy - Performance comparison of interference elimination techniques using glucose-water system. AB - The applicability of two elimination techniques for interferences occurring in measurements with cells of short pathlength using Fourier transform near-infrared (FT-NIR) spectroscopy was evaluated. Due to the growing interest in the field of vibrational spectroscopy in aqueous biological fluids (e.g. glucose in blood), aqueous solutions of d-(+)-glucose were prepared and split into a calibration set and an independent validation set. All samples were measured with two FT-NIR spectrometers at various spectral resolutions. Moving average smoothing (MAS) and fast Fourier transform filter (FFT filter) were applied to the interference affected FT-NIR spectra in order to eliminate the interference pattern. After data pre-treatment, partial least squares regression (PLSR) models using different NIR regions were constructed using untreated (interference affected) spectra and spectra treated with MAS and FFT filter. The prediction of the independent validation set revealed information about the performance of the utilized interference elimination techniques, as well as the different NIR regions. The results showed that the combination band of water at approx. 5200 cm 1 is of great importance since its performance was superior to the one of the so called first overtone of water at approx. 6800 cm-1. Furthermore, this work demonstrated that MAS and FFT filter are fast and easy-to-use techniques for the elimination of interference fringes in FT-NIR transmittance spectroscopy. PMID- 29433858 TI - Hearing Loss in Type 2 Diabetes in Association with Diabetic Neuropathy. AB - BACKGROUND: Reports assessing hearing abnormalities in diabetes are debated. We aimed to evaluated auditory alterations and their possible associations with vascular and neurological dysfunction in 160 Type 2 diabetes mellitus individuals and 100 age and sex-matched healthy controls. METHODS: Participants underwent pure tone audiometry (PTA). Associations with demographic, metabolic and neuropathic variables were assessed. RESULTS: Compared with healthy controls, diabetic patients had higher mean hearing thresholds at each frequency, with statistical significance at 2-8 kHz (p <0.05). Prevalence of hearing loss in diabetics was 67.5% (108/160), including high-frequency (72.22%, 78/108), and low/mid- and high-frequency (27.78%, 30/108). The mild hearing loss was predominant in diabetics with high-frequency impairment (52.56%), while the moderate/severe hearing loss was high in individuals with both low-and high frequency hearing loss (80.00%). Multiple logistic regression analysis of PTA parameters showed that higher Semmes Weinstein Monofilament (OR 1.24, 95% CI 1.02 1.52), Michigan Neuropathy Screening Instrument score (OR 1.38, 95% CI 1.14 1.68), and vibration perception threshold (OR 1.19, 95% CI 1.05-1.34) were independent risk factors for hearing impairment in diabetics after adjusting for potential covariates. CONCLUSIONS: These findings suggest that hearing loss is common in T2DM subjects, with predominantly high frequency involved. Diabetic neuropathic factors may explain the underlying mechanism of the association between diabetes and hearing loss. PMID- 29433859 TI - Effect of endoscopic failure on the results of internal surgical drainage in pancreatic pseudocyst. AB - BACKGROUND: The treatment of pancreatic pseudocysts has evolved during the past two decades. Endoscopic treatment (ET) has gradually become used as a first-line management even though it showed no significant superiority to surgical internal drainages (SIDs) in a recent randomized trial. The objective of the present work was to analyze the effect of ET failure on the results of SID in the global management of pancreatic pseudocysts. METHODS: A multicenter retrospective study (Clichy, Bordeaux, Nantes, and Rennes) was conducted between January 2000 and December 2012. The main criteria were as follows: (i) major postoperative complications (MPCs) (Clavien >= 3) and (ii) treatment failure in the first 12 mo. All factors that may affect these two parameters were tested in univariate and multivariate analyses, when necessary. RESULTS: One hundred nineteen patients, with a median age of 52 y (22-83) underwent SID, including 45 procedures (37.8%) performed after ET failure. Mortality and overall morbidity rates were 1.7% and 30.2%, respectively. Eighteen patients (15.1%) presented an MPC. Multivariate analysis revealed that failure of ET (odds ratio 3.04, confidence interval [1.04 to 9.5], P = 0.046) and BMI <=20 (odds ratio 4.5, confidence interval [1.50; 15.5], P = 0.010) were independent risk factors of MPCs. The success of SID was 92.5% in the first year. In univariate analysis, the occurrence of an MPC was the only factor linked to the failure of SID (P = 0.029). CONCLUSIONS: Performing an SID after ET failure is associated with an increased risk of MPC. Close postoperative monitoring is recommended for these patients. PMID- 29433860 TI - Surgical deserts in California: an analysis of access to surgical care. AB - BACKGROUND: Areas of minimal access to surgical care, often called "surgical deserts", are of particular concern when considering the need for urgent surgical and anesthesia care. We hypothesized that California would have an appropriate workforce density but that physicians would be concentrated in urban areas, and surgical deserts would exist in rural counties. METHODS: We used a benchmark of six general surgeons, six orthopedists, and eight anesthesiologists per 100,000 people per county to define a "desert". The number and location of these providers were obtained from the Medical Board of California for 2015. ArcGIS, version 10.3, was used to geocode the data and were analyzed in Redivis. RESULTS: There were a total of 3268 general surgeons, 3188 orthopedists, and 5995 anesthesiologists in California in 2015, yielding a state surgeon-to-population ratio of 7.2, 6.7, and 10.2 per 100,000 people, respectively; however, there was wide geographic variability. Of the 58 counties in California, 18 (31%) have a general surgery desert, 27 (47%) have an orthopedic desert, and 22 (38%) have an anesthesiology desert. These counties account for 15%, 25%, and 13% of the state population, respectively. Five, seven, and nine counties, respectively, have none in the corresponding specialty. CONCLUSIONS: Overall, California has an adequate ratio of surgical and anesthesia providers to population. However, because of their uneven distribution, significant surgical care deserts exist. Limited access to surgical and anesthesia providers may negatively impact patient outcome in these counties. PMID- 29433861 TI - Metabolic profile of children with extrahepatic portal vein obstruction undergoing meso-Rex bypass. AB - BACKGROUND: Extrahepatic portal vein obstruction (EHPVO) in children is often associated with growth restriction, which improves after the restoration of portal venous flow with a meso-Rex bypass, but the physiologic mechanism is unknown. The purpose of this study was to investigate the mechanism of growth delay in children with EHPVO by detailing the metabolic and nutritional profile before and after meso-Rex bypass. METHODS: Twenty consecutive children with EHPVO were prospectively studied before and 1 year after meso-Rex bypass. Caloric balance was determined by investigating caloric intake via a calorie count, total energy expenditure via a doubly labeled water isotope assay and stool caloric loss by bomb calorimetry. Laboratory markers of nutrition and growth hormone resistance were tested. RESULTS: Fifteen of the 20 children underwent successful meso-Rex bypass at a median age of 4.3 years. Prealbumin level was abnormally low (14.6 +/- 3.0 mg/dL) at surgery but improved (17.0 +/- 4.3 mg/dL) 1 year later (P = 0.026). Mean insulin-like growth factor 1 (IGF-1) level at baseline was 1.57 standard deviations below normal. IGF-1 levels increased from 88.3 +/- 38.9 to 117.3 +/- 54.5 ng/mL in the year after surgery (P = 0.047). Caloric intake divided by basal metabolic rate (1.90 +/- 0.61), total energy expenditure (97.2 +/- 15.0% of expected), and stool caloric losses (3.7 +/- 1.8% of caloric intake) were all normal at baseline. CONCLUSIONS: Children with EHPVO suffer from malnutrition and growth hormone resistance, which may explain their well established finding of growth restriction. Prealbumin and IGF-1 levels improve after a successful meso-Rex bypass. PMID- 29433863 TI - Aspiration for acute pilonidal abscess-a cohort study. AB - BACKGROUND: The traditional open incision and drainage of a pilonidal abscess is associated with slow healing and delayed return to normal daily activities. The aim of this study is to assess safety, effectiveness, and patient satisfaction of aspiration followed by antibiotics for a pilonidal abscess. MATERIAL AND METHODS: All patients presenting with an acute pilonidal abscess during the period December 2010 and December 2014 in York Hospital, UK, were treated with bedside aspiration under local anesthetic, followed by oral cefalexin and metronidazole for 7 days. Patients with immunosuppression, diabetes, overlying skin necrosis, and perforation were excluded. Complications of the procedure were prospectively recorded. Long-term outcomes and overall patients' satisfaction were assessed with the use of mailed questionnaires and Visual Analogue Scales (VAS) (0 = not satisfied at all, 10 = very satisfied). RESULTS: One hundred sixty-nine patients presented with an acute pilonidal abscess and a total of 100 patients were treated with aspiration and antibiotics. There were 50 women (50%) and the median (interquartile range [IQR]) age of the cohort was 24 (14) years. Eleven patients had a history of a previous pilonidal procedure. Seven patients were treated successfully with a reaspiration. Overall, 10 patients required incision and drainage after a median (IQR) follow-up time of 29 (47) months. Fifty-six patients returned completed questionnaires. The median (IQR) of the VAS for the overall satisfaction of the procedure was 9 (5). CONCLUSIONS: Aspiration of a pilonidal abscess in selected patients is effective in 83%, and it is associated with high overall satisfaction rates. PMID- 29433862 TI - Three dimensionally printed bioactive ceramic scaffold osseoconduction across critical-sized mandibular defects. AB - BACKGROUND: Vascularized bone tissue transfer, commonly used to reconstruct large mandibular defects, is challenged by long operative times, extended hospital stay, donor-site morbidity, and resulting health care. 3D-printed osseoconductive tissue-engineered scaffolds may provide an alternative solution for reconstruction of significant mandibular defects. This pilot study presents a novel 3D-printed bioactive ceramic scaffold with osseoconductive properties to treat segmental mandibular defects in a rabbit model. METHODS: Full-thickness mandibulectomy defects (12 mm) were created at the mandibular body of eight adult rabbits and replaced by 3D-printed ceramic scaffold made of 100% beta-tricalcium phosphate, fit to defect based on computed tomography imaging. After 8 weeks, animals were euthanized, the mandibles were retrieved, and bone regeneration was assessed. Bone growth was qualitatively assessed with histology and backscatter scanning electron microscopy, quantified both histologically and with micro computed tomography and advanced 3D image reconstruction software, and compared to unoperated mandible sections (UMSs). RESULTS: Histology quantified scaffold with newly formed bone area occupancy at 54.3 +/- 11.7%, compared to UMS baseline bone area occupancy at 55.8 +/- 4.4%, and bone area occupancy as a function of scaffold free space at 52.8 +/- 13.9%. 3D volume occupancy quantified newly formed bone volume occupancy was 36.3 +/- 5.9%, compared to UMS baseline bone volume occupancy at 33.4 +/- 3.8%, and bone volume occupancy as a function of scaffold free space at 38.0 +/- 15.4%. CONCLUSIONS: 3D-printed bioactive ceramic scaffolds can restore critical mandibular segmental defects to levels similar to native bone after 8 weeks in an adult rabbit, critical sized, mandibular defect model. PMID- 29433864 TI - Leukoreduction of packed red blood cells attenuates proinflammatory properties of storage-derived microvesicles. AB - BACKGROUND: Leukoreduction prior to packed red blood cell (pRBC) storage is not a universally accepted practice. Our laboratory has previously shown that microvesicles (MVs) accumulate in pRBC units during storage and play an important role in lung injury after resuscitation. Currently, the effect of leukoreduction on MV formation in stored pRBC units is unknown. In the present study, we investigated the hypothesis that leukoreduction of pRBC units prior to storage would attenuate the production of MVs and decrease pulmonary inflammation after hemorrhage and resuscitation. METHODS: Leukoreduced and nonleukoreduced pRBC units were prepared from human donors and C57/Bl6 mice and stored for up to 42 d and 14 d, respectively. At intervals during storage, MVs were isolated from pRBC units, quantified and characterized based on size, morphology, and levels of proinflammatory cytokines. In additional experiments, mice underwent controlled hemorrhage followed by resuscitation with normal saline (NS) with or without equal numbers of MVs isolated from leukoreduced or nonleukoreduced stored mouse pRBC. Histologic lung sections were evaluated for the presence of tissue edema and inflammatory cells. RESULTS: For both human and mouse pRBCs, the number of MVs significantly increased throughout the storage period. There were significantly fewer MVs present in leukoreduced units. The average MV size significantly increased over time and was similar between groups. Levels of interleukin 1alpha (IL-1alpha), regulated on activation, normal T cell expressed and secreted (RANTES), and macrophage-derived chemokine (MDC) were lower in MVs from leukoreduced pRBC units as compared with MVs from nonleukoreduced units. Hemorrhaged mice resuscitated with NS with the addition of MV from leukoreduced pRBC demonstrated significantly less pulmonary edema and inflammatory cell recruitment as compared to those resuscitated with NS with the addition of MV from nonleukoreduced pRBC. CONCLUSIONS: Prestorage leukoreduction of pRBC units reduces the formation and proinflammatory properties of MV, which in turn decreases lung injury secondary to MV from stored pRBC units after hemorrhage and resuscitation. PMID- 29433865 TI - Electricity and generator availability in LMIC hospitals: improving access to safe surgery. AB - BACKGROUND: Access to reliable energy has been identified as a global priority and codified within United Nations Sustainable Goal 7 and the Electrify Africa Act of 2015. Reliable hospital access to electricity is necessary to provide safe surgical care. The current state of electrical availability in hospitals in low- and middle-income countries (LMICs) throughout the world is not well known. This study aimed to review the surgical capacity literature and document the availability of electricity and generators. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search for surgical capacity assessments in LMICs in MEDLINE, PubMed, and World Health Organization Global Health Library was performed. Data regarding electricity and generator availability were extracted. Estimated percentages for individual countries were calculated. RESULTS: Of 76 articles identified, 21 reported electricity availability, totaling 528 hospitals. Continuous electricity availability at hospitals providing surgical care was 312/528 (59.1%). Generator availability was 309/427 (72.4%). Estimated continuous electricity availability ranged from 0% (Sierra Leone and Malawi) to 100% (Iran); estimated generator availability was 14% (Somalia) to 97.6% (Iran). CONCLUSIONS: Less than two-thirds of hospitals providing surgical care in 21 LMICs have a continuous electricity source or have an available generator. Efforts are needed to improve electricity infrastructure at hospitals to assure safe surgical care. Future research should look at the effect of energy availability on surgical care and patient outcomes and novel methods of powering surgical equipment. PMID- 29433866 TI - Management of nonparasitic splenic cysts in children. AB - BACKGROUND: The management of nonparasitic splenic cysts in children is unclear. Options include observation, cystectomy, partial or total splenectomy and percutaneous aspiration with and without sclerotherapy. The aim of this study is to assess the outcomes of these interventions at a children's hospital. MATERIALS AND METHODS: A retrospective review of patients aged <18 y with splenic cysts over 7 y was performed. Demographics, mode of intervention, and outcome data were collected. RESULTS: Forty-two patients were identified and their initial management was as follows: 32 patients were observed and 10 underwent intervention (four aspiration and sclerotherapy and six resection). Age (y) was higher for intervention patients than observation patients (P = 0.004), as was the cyst size (P < 0.001). Incidental finding was the most common presentation in observation patients (n = 30; 94%) and abdominal pain for intervention groups: aspiration and sclerotherapy (n = 3; 75%) and resection (n = 5; 83%). Two patients failed observation and required aspiration and sclerotherapy due to persistence of symptoms or size increase. Median number of aspiration with and without sclerotherapy interventions was three (range 1-5). All six patients had persistence, with two requiring surgical resection due to symptomatic persistence. Surgical procedures included laparoscopic cystectomy (n = 3), laparoscopic partial (n = 2) or complete splenectomy (n = 1), and/or open splenectomy (n = 2). One laparoscopic cystectomy patient had persistence but the other two had no follow-up imaging. Partial and total splenectomy patients had no recurrence and/or persistence. CONCLUSIONS: Observation is an appropriate management strategy for small asymptomatic splenic cysts. Aspiration with and without sclerotherapy and laparoscopic cystectomy are associated with higher rates of recurrence; thus, partial splenectomy may provide the best balance of recurrence and spleen preservation. PMID- 29433867 TI - Research during general surgery residency: a Web-based review of opportunities, structure and outputs. AB - BACKGROUND: Academic research is an integral part of general surgery training. Despite the recent research curriculum requirements of the Accreditation Council for Graduate Medical Education, there is perceived lack of research structure for residents. The aim of this study was to identify research opportunities, structure, and academic outputs during general surgical United States (US) residency. METHODS: A Web-based review of all accredited general surgery US residency programs was undertaken. Individual websites were reviewed for resident research duration, type, and structure. Research outputs, departmental projects, and availability of faculty supervisors were also identified. RESULTS: Data were available for 242 general surgery residency programs of which 137 (56.6%) offer dedicated research years, ranging from 1 to 4 years, and 30 (12.4%) programs mandate such time as required. One hundred forty-two (58.7%) programs mentioned opportunities in clinical research, 129 (53.3%) in basic sciences, 29 (12.0%) in health services and outcomes-based research, and 15 (6.2%) in education. Advanced degrees were mentioned by 38 (15.7%) programs, the majority being Master of Public Health, Master of Business Administration, or Doctor of Philosophy. Nineteen (7.9%) programs mentioned research structure, mostly qualitative in description. Thirty-four (14.0%) programs provided examples of resident presentations or publications, and 25 (10.3%) mentioned a resident research day. One hundred ninety-nine (82.2%) programs offered a list of faculty supervisors and 129 (53.3%) listed examples of department research projects. CONCLUSIONS: Although research opportunities are ample within surgical US residency training, programs should consider the opportunity to offer varied types of research, with the potential to pursue an advanced degree. Finally, guidelines should be developed with regard to resident research structure, process, and outcomes. PMID- 29433868 TI - Critical intestinal cells originate from the host in enteroid-derived tissue engineered intestine. AB - BACKGROUND: Enteroid-derived tissue-engineered intestine (TEI) contains intestinal subepithelial myofibroblasts (ISEMFs) and smooth muscle cells (SMCs). However, these cell types are not present in the donor enteroids. We sought to determine the origin of these cell types and to quantify their importance in TEI development. MATERIALS AND METHODS: Crypts from pan-EGFP or LGR5-EGFP mice were used for enteroid culture and subsequent implantation for the production of TEI. TEI from pan-EGFP enteroids was labeled for smooth muscle alpha actin (SMA) to identify ISEMFs and SMCs and green fluorescent protein (GFP) to identify cells from pan-EGFP enteroids. Fluorescence in situ hybridization (FISH) for the Y chromosome was applied to TEI from male LGR5-EGFP enteroids implanted into female nonobese diabetic/severe combined immunodeficiency mice. To identify chemotactic effects of intestinal epithelium on ISEMFs, a Boyden chamber assay was performed. RESULTS: Immunofluorescence of TEI from pan-EGFP enteroids revealed GFP-positive epithelium with surrounding SMA positivity and no colocalization of the two. FISH of TEI from male LGR5-EGFP enteroids implanted into female nonobese diabetic/severe combined immunodeficiency mice revealed that only the epithelium was Y chromosome positive. Chemotactic assays demonstrated increased ISEMF migration in the presence of enteroids (983 +/- 133) compared to that in the presence of either Matrigel alone (357 +/- 36) or media alone (339 +/- 24; P <= 0.05). CONCLUSIONS: Lack of GFP/SMA colocalization suggests that ISEMFs and SMCs are derived from host animals. This was confirmed by FISH which identified only epithelial cells as being male. All other cell types originated from host animals. The mechanism by which these cells are recruited is unknown; however, Boyden chamber assays indicate a direct chemotactic effect of intestinal epithelium on ISEMFs. PMID- 29433869 TI - Trends in laparoscopic colorectal surgery over time from 2005-2014 using the NSQIP database. AB - BACKGROUND: Laparoscopy, originally pioneered by gynecologists, was first adopted by general surgeons in the late 1980s. Since then, laparoscopy has been adopted in the surgical specialties and colorectal surgery for treatment of benign and malignant disease. Formal laparoscopic training became a required component of surgery residency programs as validated by the Fundamentals of Laparoscopic Surgery curriculum; however, some surgeons may be more apprehensive of widespread adoption of minimally invasive techniques. Although an overall increase in the use of laparoscopy in colorectal surgery is anticipated over a 10-year period, it is unknown if a similar increase will be seen in higher risk or more acutely ill patients. METHODS: Using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database from 2005-2014, colorectal procedures were identified by Current Procedural Terminology codes and categorized to open or laparoscopic surgery. The proportion of colorectal surgeries performed laparoscopically was calculated for each year. Separate descriptive statistics was performed and categorized by age and body mass index (BMI). American Society of Anesthesiology (ASA) classification and emergency case status variables were added to the project to help assess complexity of cases. RESULTS: During the 10-year study period, the number of colorectal cases increased from 3114 in 2005 to 51,611 in 2014 as more hospitals joined NSQIP. A total of 277,376 colorectal cases were identified; of which, 114,359 (41.2%) were performed laparoscopically. The use of laparoscopy gradually increased each year, from 22.7% in 2005 to 49.8% in 2014. Laparoscopic procedures were most commonly performed in the youngest age group (18-49 years), overweight and obese patients (BMI 25-34.9), and in ASA class 1-2 patients. Over the 10-year period, there was a noted increase in the use of laparoscopy in every age, BMI, and ASA category, except ASA 5. The percent of emergency cases receiving laparoscopic surgery also doubled from 5.5% in 2005 to 11.5% in 2014. CONCLUSIONS: Over a 10-year period, there was a gradual increase in the use of laparoscopy in colorectal surgery. Further, there was a consistent increase of laparoscopic surgery in all age groups, including the elderly, in all BMI classes, including the obese and morbidly obese, and in most ASA classes, including ASA 3-4, as well as in emergency surgeries. These trends suggest that minimally invasive colorectal surgery appears to be widely adopted and performed on more complex or higher risk patients. PMID- 29433870 TI - Parecoxib's effects on anastomotic and abdominal wound healing: a randomized Controlled trial. AB - BACKGROUND: Current evidence regarding the effects of selective cyclooxygenase inhibitors on gastrointestinal anastomoses is controversial. An experimental randomized control study was conducted in our institution to histopathologically evaluate the consequences of parecoxib, on intestinal and abdominal wound healing. METHODS: Twenty-four adult Wistar rats underwent laparotomy, ascending colon transection, and hand-sewn anastomosis. They were randomized to receive either parecoxib (0.5 mg/kg twice daily) or 0.9% normal saline by intraperitoneal injection postoperatively. Animals were euthanatized either on the third or the seventh postoperative day. Semiquantitative methods were used to evaluate both intestinal and abdominal wounds for inflammatory cell composition, angiogenesis, fibroblasts, granular tissue, collagen deposition, epithelization, and presence of necrosis, exudate, and abscess formation. Results are presented as (parecoxib: median [IQR] versus control: median [IQR], P-value). RESULTS: No macroscopic anastomotic leakage or wound dehiscence was observed. Intestinal anastomoses in the parecoxib group, showed significantly decreased epithelization (2 [1] versus 3 [1], [P = 0.004]) and collagen deposition (2 [0] versus 3 [1], [P = 0.041]). No difference was observed in angiogenesis (3 [1] versus 2.5 [1], [P = 0.158]). Abdominal wall specimens appeared to demonstrate decreased epithelization (2 [2] versus 4 [0.5], [P = 0.0004]) in the treatment group. No difference between the two groups was identified regarding collagen deposition (2.5 [1] versus 2 [0.5], [P = 0.280]) and angiogenesis (2.5 [1] versus 2 [1], [P = 0.633]). Necrosis was significantly more present in the parecoxib group in both specimen types, (3.5 [1] versus 2.5 [1], [P = 0.017]) and (3 [1] versus 1 [0.5], [P < 0.0001]). CONCLUSIONS: The present study shows that despite the absence of clinical adverse effects, parecoxib can impair anastomotic and abdominal wound healing on a histopathological level. PMID- 29433871 TI - Rotational gluteal flap versus modified Limberg flap in treatment of sacrococcygeal pilonidal disease. AB - BACKGROUND: Sacrococcygeal pilonidal disease (SPND) is a common surgical condition with a multitude of surgical treatments. The aim of this study was to compare the outcome of modified Limberg flap (MLF) and that of rotational gluteal flap (RGF) in treatment of SPND. MATERIALS AND METHODS: This was a retrospective case-controlled study involving adult patients of both genders who were treated with either MLF or RGF for SPND. The main outcomes of the study were the recurrence of SPND, complications, operation time, hospital stay, time of healing, time to return to daily activities, and cosmetic outcomes. RESULTS: A total of 189 (143 males) patients with a mean age of 23.5 y were included. Ninety five patients were treated with RGF (cases), and 94 were treated with MLF (controls). Both the groups were matched regarding age, gender, body mass index, and disease severity. The operation time of RGF was longer than that of MLF (P < 0.0001). No significant difference in recurrence was noted between RGF and MLF (3.1% versus 7.4%, P = 0.21). RGF had lower complication rate than MLF (17.9% versus 40.4%; P = 0.001). Time to return to work was similar in both the groups. RGF conferred significantly better cosmetic outcomes than MLF. CONCLUSIONS: Both RGF and MLF achieved comparable, low recurrence rates. Although the operation time of RGF was significantly longer than that of MLF, the RGF had shorter healing time; lower complication rate, particularly seroma formation; and better cosmetic appearance. PMID- 29433872 TI - Activated prothrombin complex concentrate for warfarin reversal in traumatic intracranial hemorrhage. AB - BACKGROUND: Patients with traumatic intracranial hemorrhage (TIH) anticoagulated with warfarin are at an increased risk of mortality. Fresh frozen plasma (FFP) and vitamin K have been the standard treatment for warfarin reversal; however, guidelines now recommend the use of prothrombin complex concentrate (PCC) for warfarin reversal in patients with life-threatening bleeding. Our protocol uses one vial (~1000 units) of activated PCC (aPCC) for warfarin reversal, regardless of the weight or presenting international normalized ratio (INR). The purpose of this study was to determine the safety and efficacy of using fixed, low-dose aPCC for warfarin reversal in patients with TIH. METHODS: This was a retrospective chart review that included patients with an Abbreviated Injury Scale Head score of >=3, TIH, and initial INR >= 1.5 on warfarin. Patients aged <18 years and those with no repeat INR were excluded. The primary outcome was to compare the percentage of patients with INR <= 1.4 after receiving aPCC versus FFP within 24 hours. RESULTS: Eighty-nine patients were in the FFP group and 31 patients in the aPCC group. The INR was reversed more effectively in the aPCC group compared with the FFP group (90.3% versus 69.7%, P = 0.029). The median time (hours) to reversal was also significantly shorter in the aPCC group compared with the FFP group (3.75 versus 6.75, P = 0.003). However, there was no difference in mortality (35.5% aPCC versus 22.2% control, P = 0.162) or incidences of thrombosis. CONCLUSION: Fixed, low-dose aPCC is safe and more effective at reversing the effects of warfarin than FFP in patients with TIH. PMID- 29433873 TI - Impact of repeated abdominal surgery on wound healing and myeloid cell dynamics. AB - BACKGROUND: Even though wound dehiscence is a surgical complication, under certain medical conditions, repetition of the laparotomy (LT) (relaparotomy) can become inevitable. In addition to the risks associated with this surgical operation, relaparotomy can interfere with the tissue healing and contribute to the development of chronic wounds. METHODS: In an experimental relaparotomy wounding model, this study investigated the impact of repeated surgery on wound healing and on the immune cells of myeloid origin. RESULTS: The first repeat of the LT triggered fibrosis and marginally interfered with the wound healing; however, the second operation completely abrogated the healing process. Splenomegaly was observed as an indicator of the chronic inflammation and the systemic effect of repeated laparotomies. In the blood stream, the spleen, and the liver, these repeated surgeries exhibited a major impact on the CD11b+Ly6C+Ly6G- monocytes. On the other hand, especially, whespecially the second relaparotomy resulted in a massive purging of neutrophil granulocytes into the circulation. These CD11b+Ly6C+Ly6G+ neutrophils that were disseminated on repeated abdominal laparotomies had a proinflammatory character that positively influenced T cell proliferation and displayed a high capacity for production of reactive oxygen species. CONCLUSIONS: The repetition of abdominal LT not only interferes with the wound healing but also contributes to the development of imperfectly healing wounds which have systemic impact on immune compartments. PMID- 29433874 TI - Acellular derivatives of mesenchymal stem cells prevent peritoneal adhesions in an animal model. AB - BACKGROUND: Peritoneal adhesions are nonanatomical connections that bind organs to the abdominal wall or among them. They arise after peritoneal injury, which triggers an inflammatory response followed by a healing process that leads to fibrotic tissue formation. Mesenchymal stem cells and their secretion products, also referred to as acellular derivatives (ACDs), have anti-inflammatory, fibrinolytic, and antifibrogenic properties. The aim of this study was to determine the effect of intraoperative administration of ACD on the appearance, severity, and progression of peritoneal adhesions, in an animal model. MATERIALS AND METHODS: Cecal erosions were mechanically induced in adult mice. Before closure, the vehicle, ACD, or Seprafilm was administered. Seven days later, the presence and grade of peritoneal adhesions were assessed macroscopically. One, 3, and 7 d after intervention, molecular and cellular markers of inflammation, fibrinolysis, and fibrogenesis were evaluated both locally and systemically. RESULTS: ACDs avoided the appearance of clinically relevant peritoneal adhesions. The vehicle had no effect, and Seprafilm reduced them inconsistently. The antiadhesive effect of ACD was associated with an early reduction of proinflammatory cytokine (tumor necrosis factor-alpha and interferon-gamma) secretion and leukocyte (polymorphonuclears, mononuclears, and macrophages) infiltration. High levels of D-dimer, low fibrin deposits, low myofibroblasts infiltration, and less fibrosis were also observed. CONCLUSIONS: ACD administered at the end of abdominal surgeries prevents the formation of peritoneal adhesions due to the modulation of inflammatory, fibrinolytic, and fibrogenic processes. PMID- 29433875 TI - Alterations in cancer stem-cell marker CD44 expression predict oncologic outcome in soft-tissue sarcomas. AB - BACKGROUND: Cancer stem cells (CSCs) have been shown to resist chemotherapy and promote metastasis after cytotoxic therapies. We sought to determine if the expression of CSC markers (aldehyde dehydrogenase [ALDH], CD44, and epidermal growth factor receptor [EGFR]) predicted outcomes in soft-tissue sarcoma (STS) patients. METHODS: We queried an institutional database of 23 STS patients and evaluated immunohistochemical expression of CSC markers ALDH, CD44, and EGFR. The Cancer Genome Atlas (TCGA) was also queried for STS clinical and genomic data. Disease-specific (DSS) and overall survival (OS) were assessed by univariate and Kaplan-Meier analysis. RESULTS: Of the 23 institutional patients, the majority was female, had high-grade tumors and had extremity tumors. With a median follow up of 27 months, nine patients (39%) experienced distant recurrence, and four (17%) died of disease. Mean H-scores at diagnosis (+/-standard error of the mean) for CD44, ALDH1, and EGFR were 169 +/- 27, 77 +/- 15, and 144 +/- 23, respectively. On univariate analysis, there was a trend for increased CD44 score to predict both worse DSS and OS (hazard ratio = 1.01, 95% confidence interval 1 1.02, P = 0.056), whereas ALDH and EGFR scores did not. Analysis of 74 TCGA STS cases with complete clinical and genomic data revealed that CD44 copy number alterations predicted worse DSS (9.89 months versus 72.5 months, P = 0.007) and a trend for worse OS (14.03 months versus 38.6 months, P = 0.12), whereas ALDH1 and EGFR copy number alteration did not. Multivariate analysis of the combined data sets was consistent with worse DSS among patients with higher CD44 expression. CONCLUSIONS: Institutional and national TCGA data show the association of elevated baseline CD44 expression with worse STS outcomes. Further study of CD44 as a possible novel STS biomarker appears indicated. PMID- 29433876 TI - Autogenous hepatic tissue transplantation into the omentum in a novel ectopic liver regeneration murine model. AB - BACKGROUND: Liver regeneration involves hyperplasia and hypertrophy of hepatic cells. The capacity of macroscopic liver tissue to regenerate in ectopic sites is unknown. We aim to develop a novel in vivo model of ectopic liver survivability and regeneration and assess its functionality. METHODS: Adult male Sprague-Dawley rats (n = 23) were divided into four groups: (1) single-stage (SS) group, wedge liver resection was performed, and the parenchyma was directly implanted into the omentum; (2) double-stage (DS) group, omentum pedicle was transposed over the left hepatic lobe followed by wedge liver resection along with omental flap; (3) Biogel + DS group, rats received intraperitoneal injection of inert polymer particles prior to DS; (4) Biogel + DS + portal vein ligation (PVL) group, Biogel + DS rats underwent subsequent PVL. Hepatobiliary iminodiacetic acid scintigraphy assessed bile excretion from ectopic hepatic implants. RESULTS: Histologically, the scores of necrosis (P < 0.001) and fibrosis (P = 0.004) were significantly improved in rats undergoing DS procedure (groups 2, 3, and 4) compared with the SS group. Biogel rats (Biogel + DS and Biogel + DS + PVL) demonstrated statistically increased scores of bile duct neoformation (P = 0.002) compared to those without the particles (SS and DS). Scintigraphy demonstrated similar uptake of radiotracer by ectopic hepatic implants in groups 2, 3, and 4. CONCLUSIONS: Omental transposition provided adequate microcirculation for proliferation of ectopic hepatic cells after liver resection. Inert polymers enhanced the regeneration by promoting differentiation of new bile ducts. The ectopic hepatic implants showed preserved function on scintigraphy. This model provides insights into the capacity of liver parenchyma to regenerate in ectopic sites and the potential as therapeutic target for cell therapy in end-stage liver disease. PMID- 29433877 TI - Self-inflicted gunshot wounds: readmission patterns. AB - BACKGROUND: Self-inflicted gunshot wounds (SI-GSWs) are often fatal, but roughly 20% of individuals survive. What happens to survivors after the initial hospitalization is unknown. We hypothesized that the SI-GSW survivors are frequently readmitted and that the pattern of readmission is different from that of the survivors of non-GSW self-harm (SH). METHODS: We conducted a retrospective cohort analysis using the 2013 and 2014 Nationwide Readmission Database. Patients with any diagnosis indicating deliberate SH in the first 6 months of the year were included. This group was divided into those who had SI-GSW as their mechanism and those who did not. Weighted numbers are reported. RESULTS: A total of 1987 patients were admitted for SI-GSW in the study period. Many (n = 506, 26%) experienced at least one readmission in 6 months. When compared with non-GSW SH patients, readmission rates were not statistically different (26% versus 26%, P = 0.60). However, readmissions for repeat SH were lower for the SI-GSW cohort (3% versus 7%, P = 0.004). Readmission for the SI-GSW cohort less frequently had a primary diagnosis of psychiatric illness (28% versus 57%, P < 0.001). In multivariate analysis, there was no difference in odds ratios (OR) of all-cause readmission between the two groups. SI-GSW was associated with a lower OR of repeat SH readmission compared with non-GSW SH (OR 0.65, P = 0.039). CONCLUSIONS: Readmissions after an SI-GSW are frequent, highlighting the burden of this injury beyond the index hospitalization. There are differences in readmission patterns for SI-GSW patients versus non-GSW SH patients, and this suggests that prevention and follow-up strategies may differ between the two groups. PMID- 29433878 TI - The effect of resident involvement on bariatric surgical outcomes: an ACS-NSQIP analysis. AB - BACKGROUND: Surgical residency training programs in the United States are modeled on the principle of graduated responsibility. Residents are given greater responsibility and autonomy in the operating room and during perioperative care as they gain surgical skills and progress through their training. The impact of this method of surgical training on patient outcomes remains unknown. The purpose of this study is to compare early patient morbidity and mortality after bariatric surgery in cases with and without resident participation using the American College of Surgeons National Surgical Quality Improvement Program database. METHODS: All patients undergoing bariatric surgery from 2006 through 2010 were identified within the American College of Surgeons National Surgical Quality Improvement Program database. These patients were divided into three groups based on resident involvement in their surgery (no resident, senior-level resident, and junior-level resident). The effect of resident involvement and postgraduate year level on 30-d morbidity and mortality was investigated using composite outcomes, including cardiac events (acute myocardial infarction or cardiac arrest requiring cardiopulmonary resuscitation), pulmonary events (pneumonia, prolonged intubation, or unplanned reintubation), wound (superficial surgical site infection, deep surgical site infection, organ-space infection, or dehiscence), septic events (sepsis and septic shock), clotting events (pulmonary embolism and deep venous thrombosis), and renal events (urinary tract infection and acute kidney injury requiring dialysis). Length of hospital stay, unplanned return to the operating room, and 30-d mortality were also investigated. RESULTS: A total of 19,616 patients underwent bariatric surgery from the year 2006 through 2010; 8960 (45.7%) procedures were performed with resident involvement, with 5406 (36.7%) of these cases involving a senior-level resident. Operations involving a senior-level resident were more likely to experience postoperative cardiac events (P < 0.006), pulmonary events (P = 0.03), wound events (P = 0.01), septic events (P < 0.002), renal events (P <= 0.01), prolonged operative time (P < 0.0001), and a prolonged length of hospital stay (P < 0.0001) than those that involved either no resident or a junior-level resident. CONCLUSIONS: Although bariatric operations involving senior-level residents have more statistically significant morbidity outcomes, these morbidity outcomes are related more to perioperative care rather than intraoperative resident involvement. This suggests that more emphasis on perioperative progressive responsibility may be needed to match operative oversight. PMID- 29433879 TI - Expression of neuropeptide Y and its receptors Y1 and Y2 in pancreatic intraepithelial neoplasia and invasive pancreatic cancer in a transgenic mouse model and human samples of pancreatic cancer. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is among the most dismal of human malignancies. Neuropeptides have shown to be implicated in angiogenesis, tumor growth, and formation of distant metastases in various solid tumors. In the present study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the impact of neuropeptide Y (NPY) and its receptors 1 (Y1) and 2 (Y2) in preneoplastic lesions and pancreatic cancer as a potential target with antiproliferative properties. In addition, human PDAC tissue was analyzed. MATERIALS AND METHODS: By interbreeding conditional LsL-Trp53R172H,LsL-KrasG12D and Pdx1-Cre strains, we obtained LsL-KrasG12D;LsL-Trp53R172H;Pdx1-Cre(KPC), LsL KrasG12D;Pdx1-Cre(KP) and control mice (n = 8 each). Mice were then followed in a longitudinal study for 3 to 6 mo. Pancreata were analyzed in regard to pancreatic intraepithelial neoplasia (PanIN) lesions and invasive carcinoma. Corresponding sections were then assessed by immunohistochemistry and quantitative polymerase chain reaction for NPY, Y1 and Y2 expression in murine and human samples. RESULTS: NPY and Y1 expressions were detected in human and murine pancreatic samples, but expression levels were similar in neoplastic and non-neoplastic tissue. Y2 revealed a significant increase of expression in the transgenic mouse model in PanIN lesions and pancreatic cancer compared to control. This holds also true for human samples of pancreatic cancer. Immunohistochemistry of Y2 in murine and human samples of PanINs and pancreatic carcinoma revealed an increased expression in PanIN lesions and pancreatic cancer. CONCLUSIONS: Y2 is strongly overexpressed in pancreatic cancer and may modulate angiogenesis. PMID- 29433880 TI - Reconstruction among patients undergoing mastectomy: the effect of surgical deserts. AB - BACKGROUND: Surgical deserts (SDs) are defined as the geographic maldistribution of general surgeons of six or less per 100,000 population in underserved/rural counties. Disparities have been reported in breast cancer outcomes; however, the effect of SDs remains unknown. We sought to examine the effect of SDs on breast reconstruction (BR) after mastectomy and the differences between patients in both the cohorts. METHODS: Using the Nationwide Inpatient Sample database years 2007 2011, we identified International Classification of Diseases 9th edition codes for breast cancer, mastectomy, and BR in California. SDs were identified using the American College of Surgeons Health Policy Research Institute workforce atlas. Data included patient demographics and socioeconomic status, and the primary outcome was the rates of BR. RESULTS: A total of 9325 mastectomy patients, with or without BR, were identified. Of this, 12.8% patients were in SDs, whereas 87.2% patients were in nonsurgical deserts (NSDs). Overall, 35.8% of patients received BR, whereas 64.2% did not. Of the patients in SDs, only 14% received BR, whereas in NSDs, 39% received BR. On multivariate analysis, SD patients were significantly less likely to receive BR than NSD patients (odds ratio [95% confidence interval], 0.29 [0.24-0.35]; P < 0.001). SDs had higher rates of low household income, Medicare insurance, and comorbidities. NSDs had higher rates of high household income, Health Maintenance Organization/private insurance, and lower rates of comorbidities. CONCLUSIONS: Patients in SDs are significantly less likely to receive BR. This disparity may be magnified because of differences in demographics and income levels, and decreased access to reconstructive surgeons. Interventions aimed at decreasing disparities caused by SDs are needed. PMID- 29433881 TI - Removal notice for Liver autotransplantation and retrohepatic vena cava reconstruction for alveolar echinococcosis [JSR 210 (2017) 169-176]. PMID- 29433882 TI - Comparison of precision and speed in laparoscopic and robot-assisted surgical task performance. AB - BACKGROUND: Robotic platforms have the potential advantage of providing additional dexterity and precision to surgeons while performing complex laparoscopic tasks, especially for those in training. Few quantitative evaluations of surgical task performance comparing laparoscopic and robotic platforms among surgeons of varying experience levels have been done. We compared measures of quality and efficiency of Fundamentals of Laparoscopic Surgery task performance on these platforms in novices and experienced laparoscopic and robotic surgeons. METHODS: Fourteen novices, 12 expert laparoscopic surgeons (>100 laparoscopic procedures performed, no robotics experience), and five expert robotic surgeons (>25 robotic procedures performed) performed three Fundamentals of Laparoscopic Surgery tasks on both laparoscopic and robotic platforms: peg transfer (PT), pattern cutting (PC), and intracorporeal suturing. All tasks were repeated three times by each subject on each platform in a randomized order. Mean completion times and mean errors per trial (EPT) were calculated for each task on both platforms. Results were compared using Student's t-test (P < 0.05 considered statistically significant). RESULTS: Among novices, greater errors were noted during laparoscopic PC (Lap 2.21 versus Robot 0.88 EPT, P < 0.001). Among expert laparoscopists, greater errors were noted during laparoscopic PT compared with robotic (PT: Lap 0.14 versus Robot 0.00 EPT, P = 0.04). Among expert robotic surgeons, greater errors were noted during laparoscopic PC compared with robotic (Lap 0.80 versus Robot 0.13 EPT, P = 0.02). Among expert laparoscopists, task performance was slower on the robotic platform compared with laparoscopy. In comparisons of expert laparoscopists performing tasks on the laparoscopic platform and expert robotic surgeons performing tasks on the robotic platform, expert robotic surgeons demonstrated fewer errors during the PC task (P = 0.009). CONCLUSIONS: Robotic assistance provided a reduction in errors at all experience levels for some laparoscopic tasks, but no benefit in the speed of task performance. Robotic assistance may provide some benefit in precision of surgical task performance. PMID- 29433883 TI - Maturation of effect size during enrollment of prospective randomized trials. AB - BACKGROUND: Randomized clinical trials are powered by calculating the minimum sample size required to achieve statistical significance, given an estimated effect size (ES). The ES is the raw difference between two treatment arms. ES quantifies the actual magnitude of clinical differences between cohorts and is usually reflective of the true meaning of the trial, regardless of statistical significance. Under a fixed protocol, we hypothesize that the ES may be attained at a smaller sample than predesigned. To investigate patterns of ES during enrollment, we analyzed completed trials that were completed at our institution. METHODS: Outcomes of 11 prospective randomized clinical trials from our institution were reviewed. ES was calculated at intervals throughout each trial to determine at which point a steady clinical difference was achieved between treatment cohorts. RESULTS: ES stabilized at a median of 64% enrollment. All patients were needed to meet the precise ES in our smallest study, indicating the need for full enrollment in smaller studies. Otherwise, 50% of our trials required between 48% and 76% of patient enrollment to meet ES. In comparing clinical outcomes, 9 of 12 found a final difference that was nearly identical to the difference that could have been determined much earlier. Categorical outcomes met stabilized ES at 51% enrollment and continuous outcomes at 68%. CONCLUSIONS: ES and final clinical outcomes were achieved before the completion of enrollment for most of our studies. This suggests that clinical differences detected by randomization may not necessarily require the robust sample size often needed to establish statistical significance. This is particularly relevant in fixed protocol interventional trials of homogenous populations. PMID- 29433884 TI - Squamous differentiation in papillary thyroid carcinoma: a rare feature of aggressive disease. AB - BACKGROUND: Papillary thyroid carcinoma with squamous differentiation (PTC-SD) is a poorly understood pathologic finding of unknown clinical significance. Selected case reports have suggested that PTC-SD is an aggressive tumor with a poor prognosis. Here we present the largest case series of PTC-SD reported in the United States. MATERIALS AND METHODS: The cancer registry at our tertiary care referral center was reviewed to identify all patients from 1995-2015 who had been diagnosed with PTC-SD on initial total thyroidectomy or lymph node dissection for recurrent disease. All cases were reviewed by an endocrine pathologist to confirm the diagnosis. Patient demographic, pathology, and outcomes data were collected and reviewed. RESULTS: During the study period, ten patients were diagnosed with PTC-SD, six in the primary tumor at the time of initial surgery, and four in lymph node metastases during surgery for recurrent disease. The median age at diagnosis was 56 y and half of the patients were male. Aggressive features such as multifocality (67%), extrathyroidal extension (67%), positive margin (89%), lymph node metastases (80%), and extranodal extension (60%) were far more prominent than is typically seen in classic PTC. Long-term follow-up (median 56.5 mo) demonstrated high rates of locoregional recurrence (60%), pulmonary metastases (30%), and mortality (10%). CONCLUSIONS: Squamous differentiation is a rare finding in PTC that is associated with aggressive pathologic features and poor long-term outcomes. This phenomenon may represent a step in progression toward dedifferentiation; thus, patients with PTC-SD should have close, life-long surveillance and should be treated according to evidence-based guidelines for high-risk thyroid cancers. PMID- 29433885 TI - Can flow cytometry reinvent the sentinel lymph node concept in gastric cancer patients? AB - BACKGROUND: The focused sentinel lymph node (SLN) concept we proposed previously relied on real time-quantitative polymerase chain reaction (RT-qPCR) to detect tumor cells, which is too elaborate for intraoperative use. Therefore, we evaluated flow cytometry for intraoperative detection of tumor cells in SLNs. METHODS: Sixty-five consecutive gastric cancer patients were included. SLN analysis was carried out for a single SLN from each patient, using the molecular methods of RT-qPCR (first 30 patients) and flow cytometry (final 35 patients). All LNs underwent hematoxylin and eosin staining and immunohistochemical examination. RESULTS: Extraction of the SLN from a high-risk station was an important determinant for accurate prediction of LN metastases. For RT-qPCR, the sensitivity and specificity of detection were 72.7% and 81.8%, respectively, and for flow cytometry, 36.8% and 100%, respectively. When only high-risk SLNs were analyzed and specimens with <10% viability of leukocytes were excluded, the sensitivity and specificity of flow cytometry were 60% and 100%, respectively. Multivariate analysis identified significant predictors for LN metastases as the molecular method of SLN analysis (P = 0.021; 95% confidence interval [CI]: 1.304 24.284) and lymphovascular invasion (P = 0.002; 95% CI: 2.142-28.555). In subgroup analysis of high-risk SLNs, only RT-qPCR was a significant predictor for LN metastases (P = 0.016; 95% CI: 1.581-91.084). CONCLUSIONS: Flow cytometry of high-risk SLNs, excluding specimens with low cell viability is a rapid, cost effective, widely obtainable, and highly specific method for SLN metastases detection although it lacks the necessary sensitivity. Therefore, it cannot be recommended as a stand-alone method for the detection of LN metastases during operations. PMID- 29433886 TI - Expanding the donor lung pool: how many donations after circulatory death organs are we missing? AB - BACKGROUND: The number of patients with end-stage pulmonary disease awaiting lung transplantation is at an all-time high, while the supply of available organs remains stagnant. Utilizing donation after circulatory death (DCD) donors may help to address the supply-demand mismatch. The objective of this study is to determine the potential donor pool expansion with increased procurement of DCD organs from patients who die at hospitals. MATERIAL AND METHODS: The charts of all patients who died at a single, rural, quaternary-care institution between August 2014 and June 2015 were reviewed for lung transplant candidacy. Inclusion criteria were age <65 y, absence of cancer and lung pathology, and cause of death other than respiratory or sepsis. RESULTS: A total of 857 patients died within a 1-year period and were stratified by age: pediatric <15 y (n = 32, 4%), young 15 64 y (n = 328, 38%), and old >65 y (n = 497, 58%). Those without cancer totaled 778 (90.8%) and 512 (59%) did not have lung pathology. This leaves 85 patients qualifying for DCD lung donation (pediatric n = 10, young n = 75, and old n = 0). Potential donors were significantly more likely to have clear chest X-rays (24.3% versus 10.0%, P < 0.0001) and higher mean PaO2/FiO2 (342.1 versus 197.9, P < 0.0001) compared with ineligible patients. CONCLUSIONS: A significant number of DCD lungs are available every year from patients who die within hospitals. We estimate the use of suitable DCD lungs could potentially result in a significant increase in the number of lungs available for transplantation. PMID- 29433887 TI - A cadaveric procedural anatomy simulation course improves video-based assessment of operative performance. AB - BACKGROUND: Inadequate anatomic knowledge has been cited as a major contributor to declining surgical resident operative competence. We analyzed the impact of a comprehensive, procedurally oriented cadaveric procedural anatomy dissection laboratory on the operative performance of surgery residents, hypothesizing that trainees' performance of surgical procedures would improve after such a dissection course. MATERIALS AND METHODS: Midlevel general surgery residents (n = 9) participated in an 8 wk, 16-h surgery faculty-led procedurally oriented cadaver simulation course. Both before and after completion of the course, residents participated in a practical examination, in which they were randomized to perform one of nine Surgical Council on Resident Education-designated "essential" procedures. The procedures were recorded using wearable video technology. Videos were deidentified before evaluation by six faculty raters blinded to examinee and whether performances occurred before or after an examinee had taken the course. Raters used the validated Operative Performance Rating System and Objective Structured Assessment of Technical Skill scales. RESULTS: After the course residents had higher procedure-specific scores (median, 4.0 versus 2.4, P < 0.0001), instrument-handling (4.0 versus 3.0, P = 0.006), respect for tissue (4.0 versus 3.0, P = 0.0004), time and motion (3.0 versus 2.0, P = 0.0007), operation flow (3.0 versus 2.0, P = 0.0005), procedural knowledge (4.0 versus 2.0, P = 0.0001), and overall performance scores (4.0 versus 2.0, P < 0.0001). Operative Performance Rating System and Objective Structured Assessment of Technical Skill scales averaged by number of items in each were also higher (3.2 versus 2.0, P = 0.0002 and 3.1 versus 2.2, P = 0.002, respectively). CONCLUSIONS: A cadaveric procedural anatomy simulation course covering a broad range of open general surgery procedures was associated with significant improvements in trainees' operative performance. PMID- 29433888 TI - Trauma registry implementation in low- and middle-income countries: challenges and opportunities. AB - BACKGROUND: Trauma registries are an essential part of trauma quality improvement programs aimed at decreasing morbidity and mortality in high-income countries. In low- and middle-income countries (LMICs), where the burden of injury is disproportionately high, hospitals have faced challenges in adapting trauma registry models implemented in high-income countries. We analyze the barriers to trauma registry implementation in LMICs to inform development of sustainable models in resource-constrained settings. MATERIALS AND METHODS: A structured review of published literature was performed. Relevant abstracts were identified using the PubMed, Embase, and CINAHL databases. The search terms included were: "implement registry," "trauma registry," "wounds and injuries," and "injury registry" combined with "Africa," "Asia," "low and middle income countries," "LMIC," and "developing countries." Articles describing challenges of trauma registry implementation were reviewed in full and details were abstracted. RESULTS: Twenty-eight articles addressed challenges of implementing trauma registries. Data quality (18), lack of resources (6), insufficient prehospital care (3), and difficulty with administrative duties and hospital organization (2) were reported as the most significant barriers to successful implementation. Solutions to the identified barriers were proposed by 15 articles. All 28 studies acknowledged that the presence of at least one local trauma registry improved injury surveillance and promoted better patient outcomes. CONCLUSIONS: Many LMICs face unique challenges to implementation that must be overcome to create sustainable trauma databases. Understanding these barriers and taking steps to evaluate the effectiveness of proposed solutions may further improve trauma care to address the high burden in these settings. PMID- 29433889 TI - Psychiatric disease in surgically treated colorectal cancer patients. AB - BACKGROUND: Underlying psychiatric conditions may affect outcomes of surgical treatment for colorectal cancer (CRC) because of complex clinical presentation and treatment considerations. We hypothesized that patients with psychiatric illness (PSYCH) would have evidence of advanced disease at presentation, as manifested by higher rates of colorectal surgery performed in the presence of obstruction, perforation, and/or peritonitis (OPP-surgery). MATERIALS AND METHODS: Using data from the 2007-2011 National Inpatient Sample, we identified patients with a diagnosis of CRC undergoing colorectal surgery. In addition to somatic comorbid conditions flagged in the National Inpatient Sample, we used the Clinical Classification Software to identify patients with PSYCH, including schizophrenia, delirium/dementia, developmental disorders, alcohol/substance abuse, and other psychiatric conditions. Our study outcome was OPP-surgery. In addition to descriptive analysis, we conducted multivariable logistic regression analysis to analyze the independent association between each of the PSYCH conditions and OPP-surgery, after adjusting for patient demographics and somatic comorbidities. RESULTS: Our study population included 591,561 patients with CRC and undergoing colorectal cancer surgery, of whom 60.6% were aged 65 years or older, 49.4% were women, and 6.3% had five or more comorbid conditions. Then, 17.9% presented with PSYCH. The percent of patients undergoing OPP-surgery was 13.9% in the study population but was significantly higher for patients with schizophrenia (19.3%), delirium and dementia (18.5%), developmental disorders (19.7%), and alcohol/substance abuse (19.5%). In multivariable analysis, schizophrenia, delirium/dementia, and alcohol/substance abuse were each independently associated with increased rates of OPP-surgery. CONCLUSIONS: Patients with PSYCH may have obstacles in receiving optimal care for CRC. Those with PSYCH diagnoses had significantly higher rates of OPP-surgery. Additional evaluation is required to further characterize the clinical implications of advanced disease presentation for patients with PSYCH diagnoses and colorectal cancer. PMID- 29433890 TI - An ad hoc three dimensionally printed tool facilitates intraesophageal suturing in experimental surgery. AB - BACKGROUND: Three-dimensional printing (3DP) has become popular for development of anatomic models, preoperative planning, and production of tailored implants. A novel laparoscopic, transgastric procedure for distal esophageal mucosectomy was developed. During this procedure, a space holder had to be introduced into the distal esophagus for exposure during suturing. The production process and evaluation of a 3DP space holder are described herein. MATERIALS AND METHODS: Computer-aided design software was used to develop models printed from polylactic acid. The prototype was adapted after testing in a cadaveric model. Subsequently, the device was evaluated in a nonsurvival porcine model. A mucosal purse-string suture was placed as orally as possible in the esophagus, in the intervention group with and in the control group without use of the tool (n = 8 each). The distance of the stitches from the Z-line was measured. The variability of stitches indicated the suture quality. RESULTS: The median maximum distance from the Z-line to purse-string suture was larger in the intervention group (5.0 [3.3 6.4] versus 2.4 [2.0-4.1] cm; P = 0.013). The time taken to place the sutures was shorter in the control group (P < 0.001). Stitch variance tended to be greater in the intervention group (2.3 [0.9-2.5] versus 0.7 [0.2-0.4] cm; P = 0.051). The time required for design and production of a tailored tool was less than 24 h. CONCLUSIONS: 3DP in experimental surgery enables rapid production, permits repeated adaptation until a tailored tool is obtained, and ensures independence from industrial partners. With the aid of the space holder more orally located esophageal lesions came within reach. PMID- 29433891 TI - Survival after radiation for stage I and II non-small cell lung cancer with positive margins. AB - BACKGROUND: There is limited data guiding treatment for positive margins following lobectomy for early-stage non-small cell lung cancer (NSCLC). Using data from the National Cancer Data Base, we sought to determine whether radiation therapy following lobectomy for stage I or II NSCLC was associated with improved overall survival in patients with positive margins. METHODS: Patients who underwent lobectomy without induction therapy for stage I or II NSCLC (1998-2006) with positive resection margins were selected. Patients were stratified by administration of radiation therapy following surgery, and overall survival was estimated using the Kaplan-Meier method. The association between radiation therapy and survival was adjusted for nonrandom treatment selection using Cox proportional hazards regression modeling. RESULTS: Positive margins were recorded in 1934 of 49,563 (3.9%) patients who underwent lobectomy for stage I or II NSCLC. Positive margin status was associated with significantly worse 5-year survival (34.5% versus 57.2%, P < 0.001). After selection of patients with positive margins and known radiation status and exclusion of patients who had upstaged disease or received radiation therapy for palliative indications, radiation therapy was used in 579 of 1579 patients (38.2%) but was not associated with a significant difference in the likelihood of death during subsequent follow up (hazard ratio: 1.10, 95% confidence interval: 0.90, 1.35). CONCLUSIONS: Positive margins following lobectomy for stage I or II NSCLC are associated with reduced 5-year survival. Postsurgical radiation is not strongly associated with an improvement in overall survival among these patients. PMID- 29433892 TI - Communication Practices of Mammography Facilities and Timely Follow-up of a Screening Mammogram with a BI-RADS 0 Assessment. AB - RATIONALE AND OBJECTIVES: The objective of this study was to evaluate the association of communication practices with timely follow-up of screening mammograms read as Breast Imaging Reporting and Data Systems (BI-RADS) 0 in the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. MATERIALS AND METHODS: A radiology facility survey was conducted in 2015 with responses linked to screening mammograms obtained in 2011 2014. We considered timely follow-up to be within 15 days of the screening mammogram. Generalized estimating equation models were used to evaluate the association between modes of communication with patients and providers and timely follow-up, adjusting for PROSPR site, patient age, and race and ethnicity. RESULTS: The analysis included 34,680 mammography examinations with a BI-RADS 0 assessment among 28 facilities. Across facilities, 85.6% of examinations had a follow-up within 15 days. Patients in a facility where routine practice was to contact the patient by phone if follow-up imaging was recommended were more likely to have timely follow-up (odds ratio [OR] 4.63, 95% confidence interval [CI] 2.76-7.76), whereas standard use of mail was associated with reduced timely follow-up (OR 0.47, 95% CI 0.30-0.75). Facilities that had standard use of electronic medical records to report the need for follow-up imaging to a provider had less timely follow-up (OR 0.56, 95% CI 0.35-0.90). Facilities that routinely contacted patients by mail if they missed a follow-up imaging visit were more likely to have timely follow-up (OR 1.65, 95% CI 1.02-2.69). CONCLUSIONS: Our findings support the value of telephone communication to patients in relation to timely follow-up. Future research is needed to evaluate the role of communication in completing the breast cancer screening episode. PMID- 29433894 TI - Engineering a Strong Bond between Stem Cells and Biotechnology. PMID- 29433893 TI - State of the Journal: CMGH's Progress, Prospects, and Impact Factor. PMID- 29433895 TI - Selected serum acute-phase proteins in peripartum sows and evaluation of their diagnostic usefulness. AB - Lactation impairment in sows is a frequent and significant clinical problem. Due to a complex aetiopathogenesis, early diagnosis of postpartum dysgalactia syndrome (PDS) is difficult and so far has usually been based on physical examination performed in the first days after farrowing. To date no data have been provided on the diagnostic usefulness of acute phase proteins (APP) in early diagnosis of peripartum disorders, including lactation disorders in sows. This study aimed at measuring the serum concentration of selected APP (C-reactive protein (CRP), haptoglobin (Hp), serum amyloid A (SAA) and pig major acute phase protein (Pig-MAP)) in sows with physiological and pathological course of the peripartum period and at evaluating the possibility of utilising the studied markers in the early diagnosis of lactation disorders. Also, the correlation between the studied APP serum concentration and production parameters was assessed. To the best of the authors' knowledge, the present study is the first such performed on sows. The experiment was conducted on 139 sows divided into three experimental groups based on the course of peripartum period: HEALTHY (n = 58) - clinically healthy sows, PDS (n = 45) - sows with milk production disorders, and OTHERS (n = 36) - sows which had experienced difficult parturitions, inflammations not connected with mammary glands (abscesses, hooves infections), or lameness. Thirteen serum samples from each sow were analysed, samples being taken on days -28 (-30 to -25), -14 (-16 to -11), -7 (-8 to -6), 5, -3, -1, 0 (parturition day), +1, +3, +5, +7, +14 and +28 (prior to or post farrowing). In order to measure the level of serum APP, commercial, quantitative ELISA tests were used. The results of the study indicate that the diagnosis made on the basis of the assessment of SAA levels on day 7 before the farrowing was not statistically different from the diagnosis made on the basis of the physical examination in the first days after the farrowing, that is the so-called "gold standard". The achieved results indicate that SAA may be a useful early marker of lactation impairments in sows, which allows detection of which sows are susceptible to lactation disorders with high probability even as early as one week before parturition. PMID- 29433896 TI - Generating tissue-resident macrophages from pluripotent stem cells: Lessons learned from microglia. AB - Over the past decades, the importance of the immune system in a broad scope of pathologies, has drawn attention towards tissue-resident macrophages, such as microglia in the brain. To enable the study of for instance microglia, it is crucial to recreate in vitro (and in vivo) assays. However, very fast loss of tissue-specific features of primary tissue resident macrophages, including microglia, upon in vitro culture has complicated such studies. Moreover, limited knowledge of macrophage developmental pathways and the role of local 'niche factors', has hampered the generation of tissue-resident macrophages from pluripotent stem cells (PSC). Recent data on the ontogeny of tissue-resident macrophages, combined with bulk and single cell RNAseq studies have identified the distinct origins and gene profile of microglia compared to other myeloid cells. As a result, over the past years, protocols have been published to create hPSC-derived microglia-'like' cells, as these cells are considered potential new therapeutic targets for therapies to treat neurodegenerative diseases. In this review we will provide an overview of different approaches taken to generate human microglia in vitro, taking into account their origin, and resemblance to their in vivo counterpart. Finally, we will discuss cell-extrinsic (culture conditions) and intrinsic factors (transcriptional machinery and epigenetics) that we believe can improve future differentiation protocols of tissue-resident macrophages from stem cells. PMID- 29433897 TI - High-cell-density cultivations to increase MVA virus production. AB - Increasing the yield and the productivity in cell culture-based vaccine manufacturing using high-cell-density (HCD) cultivations faces a number of challenges. For example, medium consumption should be low to obtain a very high concentration of viable host cells in an economical way but must be balanced against the requirement that accumulation of toxic metabolites and limitation of nutrients have to be avoided. HCD cultivations should also be optimized to avoid unwanted induction of apoptosis or autophagy during the early phase of virus infection. To realize the full potential of HCD cultivations, a rational analysis of the cultivation conditions of the appropriate host cell line together with the optimal infection conditions for the chosen viral vaccine strain needs to be performed for each particular manufacturing process. We here illustrate our strategy for production of the modified vaccinia Ankara (MVA) virus isolate MVA CR19 in the avian suspension cell line AGE1.CR.pIX at HCD. As a first step we demonstrate that the adjustment of the perfusion rate strictly based on the measured cell concentration and the glucose consumption rate of cells enables optimal growth in a 0.8 L bioreactor equipped with an ATF2 system. Concentrations up to 57 * 106 cells/mL (before infection) were obtained with a viability exceeding 95%, and a maximum specific cell growth rate of 0.019 h-1 (doubling time = 36.5 h). However, not only the cell-specific MVA-CR19 virus yield but also the volumetric productivity was reduced compared to infections at conventional cell-density (CCD). To facilitate optimization of the virus propagation phase at HCD, a larger set of feeding strategies was analyzed in small-scale cultivations using shake flasks. Densities up to 63 * 106 cells/mL were obtained at the end of the cell growth phase applying a discontinuous perfusion mode (semi-perfusion) with the same cell-specific perfusion rate as in the bioreactor (0.060 nL/(cell d)). At this cell concentration, a medium exchange at time of infection was required to obtain expected virus yields during the first 24 h after infection. Applying an additional fed-batch feeding strategy during the whole virus replication phase resulted in a faster virus titer increase during the first 36 h after infection. In contrast, a semi-continuous virus harvest scheme improved virus accumulation and recovery at a rather later stage of infection. Overall, a combination of both fed-batch and medium exchange strategies resulted in similar cell-specific virus yields as those obtained for CCD processes but 10-fold higher MVA-CR19 titers, and four times higher volumetric productivity. PMID- 29433898 TI - Construction and evaluation of Bordetella pertussis live attenuated vaccine strain BPZE1 producing Fim3. AB - Pertussis or whooping cough is currently the most prevalent vaccine-preventable childhood disease despite >85% global vaccination coverage. In recent years incidence has greatly increased in several high-income countries that have switched from the first-generation, whole-cell vaccine to the newer acellular vaccines, calling for improved vaccination strategies with better vaccines. We have developed a live attenuated pertussis vaccine candidate, called BPZE1, which is currently in clinical development. Unlike other pertussis vaccines, BPZE1 has been shown to provide strong protection against infection by the causative agent of pertussis, Bordetella pertussis, in non-human primates. BPZE1 is a derivative of the B. pertussis strain Tohama I, which produces serotype 2 (Fim2) but not serotype 3 fimbriae (Fim3). As immune responses to fimbriae are likely to contribute to protection, we constructed a BPZE1 derivative, called BPZE1f3, that produces both serotypes of fimbriae. Whereas nasal vaccination of mice with BPZE1 induced antibodies to Fim2 but not to Fim3, vaccination with BPZE1f3 elicited antibodies to both Fim2 and Fim3 at approximately the same level. In mice, both BPZE1 and BPZE1f3 provided equal levels of protection against clinical isolates that either produce Fim2 alone, both Fim2 and Fim3, or no fimbriae. However, vaccination with BPZE1f3 provided significantly stronger protection against Fim3 only producing B. pertussis than vaccination with BPZE1, indicating that immune responses to fimbriae contribute to serotype-specific protection against B. pertussis infection. PMID- 29433899 TI - Improving human papilloma virus vaccination rates throughout military treatment facilities. AB - OBJECTIVES: The four objectives of this study were to (1) educate military healthcare providers on HPV disease and vaccine, (2) assess short term recall of information presented at educational sessions, (3) assess provider comfort level with the vaccine, and (4) assess improvement in HPV vaccination rates. METHODS: Standardized interactive educational sessions were conducted at military primary care clinics with pre- and post-educational quizzes administered before and immediately following the sessions. Provider attitudes were assessed using Likert scale questionnaires. Vaccination rates in children and young adolescents ages 11 18 at one of the participating regions that had a champion and started a Quality Improvement (QI) project were assessed at baseline, at 3-months and at 6-months post sessions. RESULTS: 200 providers were reached at 48 primary care clinics during May 2014 through October 2015 with 200 quizzes and Likert scale questionnaires returned. There was increase in knowledge following the educational sessions as revealed in the pre- and post- test scores [t(57) = 5.04, p < 0.001]. There was a significant overall increase in comfort in answering patients' and parents' questions about HPV vaccine [p = 0.003]. There was a significant increase in the number of vaccines given at all the clinics 3 months after the educational sessions at the region who had a champion dedicated to monitoring vaccine rates and ensuring implementation efforts [p = 0.01] and started a QI project. This increase was not sustained at 6-months [p = 0.324]. CONCLUSIONS: Improvement in provider short term knowledge recall and comfort level in answering parents' questions was seen. We found that educational sessions can improve HPV vaccination rates in military clinics that have a vaccine champion for up to 3-months. Further research into the effects of having clinic vaccine champions is critical. PMID- 29433900 TI - Volatility and partitioning of Cd and Pb during sewage sludge thermal conversion. AB - In this paper, the thermal characteristics of sewage sludge and the transformation behavior of Pb and Cd during the thermal conversion process were addressed. The incineration process and pyrolysis process of the sewage sludge were investigated by thermogravimetric analysis. The results indicated that the thermal conversion process of the sewage sludge could be divided into three stages and the presence of oxygen could accelerate the decomposition of the sewage sludge. Furthermore, the effects of thermal conditions on the concentration ratio of Cd and Pb and their species partitioning in the residual char and ash were investigated. For the pyrolysis process, the maximum concentration ratio of Cd reached 41.64% at 500 degrees C and the lowest one 2.92% at 700 degrees C. Contrary, the concentration ratio of Pb remained above 93% as the temperature increased. Thus, the suitable temperature for the sewage sludge pyrolysis was below 500 degrees C. For the incineration process, the incineration temperature had great influence on the concentration ratio of Cd and Pb. When the incineration temperature increased from 700 degrees C to 900 degrees C, the concentration ratio of Cd decreased drastically from 99.32% to 10.96%. The maximum concentration ratio for Pb (95.31%) was reached at 800 degrees C. Besides, the lowest concentration ratio of Cd and Pb were obtained at a residence time of 30 min. The partitioning analyses of the Cd and Pb contained in the ash showed that the residence time had little effect on the partitioning of Cd and Pb, and the residual fractions of Cd and Pb were both above 90%. It was concluded that Cd and Pb were properly stabilized in the ash. Thus, Cd and Pb in the ash were difficult to be released into the environment and to cause secondary pollution. PMID- 29433901 TI - Mechanochemical pre-treatment for viable recycling of plastic waste containing haloorganics. AB - Chemical recycling technologies are the most promising for a waste-to energy/material recovery of plastic waste. However, 30% of such waste cannot be treated in this way due to the presence of halogenated organic compounds, which are often utilized as flame retardants. In fact, high quantities of hydrogen halides and dioxin would form. In order to enabling such huge amount of plastic waste as viable feedstock for recycling, an investigation on mechanochemical pre treatment by high energy ball milling is carried out on polypropylene containing decabromodiphenyl ether. Results demonstrate that co-milling with zero valent iron and quartz sand ensures complete debromination and mineralization of the flame retardant. Furthermore, a comparative experiment demonstrates that the mechanochemical debromination kinetics is roughly proportional to the polymer-to haloorganics mass ratio. PMID- 29433902 TI - Safety and Efficacy of PD-1/PD-L1 Inhibitors in Treatment-Naive and Chemotherapy Refractory Patients With Non-Small-Cell Lung Cancer: A Systematic Review and Meta Analysis. AB - INTRODUCTION: Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors show significant clinical activity in non-small-cell lung carcinoma (NSCLC). However, there is a relative lack of data on comparative efficacy of these drugs in the first-line setting versus chemotherapy-treated patients. We compared the efficacy and toxicity of these drugs in these 2 distinct groups of patients. MATERIALS AND METHODS: Electronic databases (PubMed-Medline, EMBASE, Scopus) and major conference proceedings were systematically searched for all phase I to III clinical trials in NSCLC using PD-1/PD-L1 inhibitors. Objective response rate (ORR) and progression-free survival (PFS) data were collected and combined using DerSimonian and Laird random effects model meta-analysis. The I2 statistic was used to assess heterogeneity. RESULTS: Seventeen distinct trials (8 with treatment-naive patients [n = 937]; 14 with chemotherapy-treated patients [n = 3620]; 5 with separate treatment-naive and previously treated arms) were included. Treatment-naive patients had a statistically significant higher ORR (30.2%; 95% confidence interval [CI], 22.70-38.2) than patients previously treated with chemotherapy (ORR, 20.1%; 95% CI, 17.5-22.9; P = .02). No significant differences in PFS were observed between the 2 groups. Treatment naive patients had statistically significant higher rates of all grade pneumonitis compared with previously treated patients (4.9%; 95% CI, 3.4-6.7 vs. 3.0%; 95% CI, 2.0-4.1; P = .04); however, no significant differences in any other immune-related adverse events were observed. CONCLUSION: PD-1/PD-L1 inhibitor therapy for advanced NSCLC has a significantly higher ORR and a higher rate of immune-mediated pneumonitis when used in the first-line setting compared with chemotherapy treated patients. PMID- 29433903 TI - How to win space in medical journals: Bits and tips. PMID- 29433904 TI - Hospital mortality scores are unduly influenced by changes in the number of admissions. PMID- 29433905 TI - Quality of life, compliance, safety and effectiveness in fit older metastatic colorectal patients with cancer treated in first-line with chemotherapy plus cetuximab: A restrospective analysis from the ObservEr study. AB - OBJECTIVES: The influence of age (<70 years and >=70 years) was retrospectively studied on the quality of life (QoL), incidence of side effects (including skin reactions) and efficacy of chemotherapy plus cetuximab in patients with KRAS wild type (WT) metastatic colorectal cancer (mCRC). METHODS: 225 patients of the Observed study (PS 0-1) were retrieved based on age (< 70 and >=70 years) and evaluated through EORTC QLQ-C30 and DLQI questionnaires. RESULTS: The two patient groups (141 < 70 and 84 >= 70 years, respectively) were balanced with no differences in any of the clinical and pathological characteristics considered. Both groups underwent similar type of first-line chemotherapy plus cetuximab, treatment duration and compliance. Cetuximab therapy caused similar incidence of side effects and impact on QoL in older and younger patients. No difference was observed in progression free survival (PFS) and in disease control rates between the two patient populations. Median overall survival (OS) was higher in patients <70 (27 months, 95% CI: 22.7-31.27) than in patients >=70 (19 months, 95% CI: 14.65-23.35) (p = 0.002), which is likely due to higher proportions of metastatic resection (27.0% vs 8.3%; p = 0.001) and utilization of second-line therapy in younger group (58.9% vs 42.9%; p = 0.028). CONCLUSION: The current data suggest that fit older patients with mCRC can be safely treated with a cetuximab-based therapy, as QoL and safety profile do not seem to be affected by age. In addition, age did not impact the choice of chemotherapy to be associated to cetuximab and treatment compliance. PMID- 29433906 TI - Membrane lipid environment: Potential modulation of chemokine receptor function. AB - Migration of leukocytes is typically mediated by G protein-coupled receptors (GPCRs) upon activation by specific ligands that range from small peptides, chemokines to a variety of lipidic molecules. The heptahelical receptors are highly dynamic structures and the signaling efficiency largely depends on the discrete contact with the ligand. In addition, several allosteric modulators of receptor activity have been reported, which do not induce migration by themselves. Another important mechanism modulating the activity of GPCRs is their local environment. Not only the membrane lipid composition influences the activity, but also direct binding of lipids, in particular cholesterol, was shown to alter receptor signaling properties. Recent findings indicate that also chemokine receptor activity is modulated by membrane lipids. In this short review we discuss this new paradigm and potential consequences for chemokine-induced migration. PMID- 29433907 TI - In vitro nuclear receptor inhibition and cytotoxicity of hydraulic fracturing chemicals and their binary mixtures. AB - The widespread use of hydraulic fracturing (HF) in oil and gas extraction operations has led to concern over environmental risks posed by chemicals used in HF fluids. Here we employed a suite of stable luciferase reporter gene assays to investigate the potential for selected HF chemicals or geogenics to activate or antagonise nuclear receptor signalling. We screened three biocides (bronopol [BP], glutaraldehyde [GA], and tetrakis(hydroxymethyl)phosphonium sulfate [THPS]), a surfactant (2-butoxyethanol), a friction reducer (polyacrylamide), and a coal seam geogenic (o-cresol) for their potential to act as agonists or antagonists of the estrogen receptor, androgen receptor, progesterone receptor (PR), glucocorticoid receptor or peroxisome proliferator-activated receptor gamma (PPARgamma). None of the chemicals induced luciferase activity in any of assays used in the study. In antagonistic mode, BP, GA and THPS caused reductions in luciferase activity in the reporter assays at higher concentrations (50-100 MUM), while at low concentrations (2-10 MUM) GA and THPS enhanced luciferase activity in some assays relative to controls. None of the other tested chemicals exhibited antagonism in the selected assays. In most cases, altered receptor signalling only occurred at concentrations exhibiting cytotoxicity. However, PPARgamma activity, and to a lesser extent PR activity, were inhibited by THPS at sub cytotoxic concentrations. The majority of binary combinations tested exhibited significantly less-than-additive cytotoxicity, and none of the combinations exhibited synergistic cytotoxicity. In summary, the results of the present study indicate that the selected chemicals are not likely to function as direct agonists of the nuclear receptors tested, and only one chemical, THPS was an apparent partial antagonist of two nuclear receptors. PMID- 29433908 TI - Pro-fibrotic phenotype of human skin fibroblasts induced by periostin via modulating TGF-beta signaling. AB - BACKGROUND: Periostin is a matricellular protein that belongs to a class of extracellular matrix (ECM)-related molecules defined by their ability to modulate cell-matrix interactions. We previously reported an elevated level of circulating periostin in patients with systemic sclerosis (SSc) and its association with the severity of skin sclerosis. OBJECTIVE: To examine the role of periostin in transforming growth factor (TGF)-beta signaling involved in fibrosis. METHODS: Levels of periostin were examined in skin and lung fibroblasts obtained from SSc patients. Levels of ECM proteins and pro-fibrotic factors were evaluated in periostin-expressing human skin fibroblasts in the presence or absence of TGF beta. Effects of periostin on the Smad proteins were also evaluated following stimulation with TGF-beta by immunoblotting, immunofluorescence staining, and RNA interference. RESULTS: Periostin was strongly expressed in skin and lung fibroblasts from SSc patients. Although recombinant periostin alone did not affect ECM protein levels, TGF-beta and recombinant periostin treatment or periostin overexpression in skin fibroblasts significantly enhanced the production of ECM proteins. Overexpression of periostin in the presence of TGF beta also augmented expressions of alpha-smooth muscle actin and early growth response-1 but decreased the level and activity of matrix metalloproteinase 1. Interestingly, the level of Smad 7, a TGF-beta-inducible inhibitor of TGF-beta signaling, was reduced in periostin-expressing fibroblasts but increased in periostin-silenced fibroblasts. In addition, Smad 7 reduction induced by periostin was partially inhibited in integrin alphaV-silenced fibroblasts. CONCLUSION: Periostin contributes to fibrosis by enhancing TGF-beta signaling via Smad 7 inhibition, which may lead to ECM deposition and periostin generation. PMID- 29433909 TI - Heat shock protein 90 inhibitor enhances apoptosis by inhibiting the AKT pathway in thermal-stimulated SK-MEL-2 human melanoma cell line. AB - BACKGROUND: Heat shock proteins (Hsps) are chaperone proteins, which are upregulated after various stresses. Hsp90 inhibitors have been investigated as adjuvant therapies for the treatment of melanoma. Thermal ablation could be a treatment option for surgically unresectable melanoma or congenital nevomelanocytic nevi, however, there is a limitation such as the possibility of recurrence. OBJECTIVE: We evaluated apoptosis in a melanoma cell line treated with the Hsp90 inhibitor 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17 DMAG), in hyperthermic conditions. METHODS: SK-MEL-2 cells were stimulated at 43 degrees C for 1 h and treated with 0, 0.1 and 1 MUM 17-DMAG. We evaluated the cell viability using MTT and apoptosis with HSP 90 inhibitor. We studied the protein expression of AKT, phospho-AKT, ERK, phospho-ERK, MAPK, and phospho-MAPK, caspase 3,7,9, and anti-poly (ADP-ribose) polymerase. RESULTS: 17-DMAG significantly inhibited the proliferation of the SK-MEL-2 cells at 37 degrees C (0.1 MUM: 44.47% and 1 MUM: 61.23%) and 43 degrees C (0.1 MUM: 49.21% and 1 MUM: 63.60%), suggesting synergism between thermal stimulation and 17-DMAG. 17-DMAG treatment increased the frequency of apoptotic cell populations to 2.17% (0.1 MUM) and 3.05% (1 MUM) in 37 degrees C controls, and 4.40% (0.1 MUM) and 4.97% (1 MUM) in the group stimulated at 43 degrees C. AKT phosphorylation were activated by thermal stimulation and inhibited by 17-DMAG. CONCLUSION: Hsp90 inhibitor treatment may be clinically applicable to enhance the apoptosis of melanoma cells in hyperthermic condition. PMID- 29433910 TI - Effect of the coexistence of sodium caseinate and Tween 20 as stabilizers of food emulsions at acidic pH. AB - In the present investigation the properties of edible nanoemulsions were studied. Sodium caseinate represents a good candidate for food emulsion preparations thanks to its surface-active properties and because it is perceived as a natural product by consumers. Nevertheless, it is very sensitive to acidic pH close to its isoelectric point and, if used as emulsion stabilizer, this aspect can negatively affect the emulsion stability. In order to prevent this drawback, sodium caseinate was used in combination with a non-ionic surfactant (Tween 20) as emulsifier of oil/water nanoemulsions. For these reasons, nanoemulsions stabilized by Tween 20, sodium caseinate and by a blend of the two emulsifiers were studied and compared according to their response to pH variations. Nanoemulsions were characterized for size of the dispersed phase with variation of time and temperature, for their rheological properties, for surface charge as a function of pH and for protein fluorescence. Noticeably, it was ascertained that, at pH close to caseinate isoelectric point, emulsions stabilized with the blend of caseinate and Tween 20 were more stable, compared with emulsions stabilized only with sodium caseinate. Such behavior was explained according to the composition of the emulsifiers at the oil/water interface where, at acidic pH, the presence of Tween 20 ensured the steric stabilization thus improving the role of sodium caseinate as emulsion stabilizer. PMID- 29433911 TI - The impact of deuteration on natural and synthetic lipids: A neutron diffraction study. AB - The structural investigation of cellular membranes requires access to model systems where the molecular complexity is representative of the cellular environment and that allow for the exploitation of structural techniques. Neutron scattering, and in particular neutron diffraction can provide unique and detailed information on the structure of lipid membranes. However, deuterated samples are desirable to fully exploit this powerful method. Recently, the extraction of lipids from microorganisms grown in deuterated media was demonstrated to be both an attracting route to obtain complex lipid mixtures resembling the composition of natural membranes, and to producing deuterated molecules in a very convenient way. A full characterization of these deuterated extracts is hence pivotal for their use in building up model membrane systems. Here we report the structural characterization of lipid extracts obtained from Pichia pastoris by means of neutron diffraction measurements. In particular, we compare the structure of membranes extracted from yeast cells grown in a standard culture medium and in a corresponding deuterated culture medium. The results show that the different molecular composition of the deuterated and protiated lipid extracts induce different structural organization of the lipid membranes. In addition, we compare these membranes composed of extracted yeast lipids with stacked bilayers prepared from synthetic lipid mixtures. PMID- 29433912 TI - Factors influencing ED care of young children at-risk for clinically important traumatic brain injury. AB - OBJECTIVES: Care decisions for young children presenting to the emergency department (ED) with head injury are often challenging (e.g. whether to obtain neuroimaging). We sought to identify factors associated with acute management of children at-risk for clinically important traumatic brain injury (ciTBI) and describe symptom management. METHODS: Observational evaluation of children, ages 0-4years, presenting to a pediatric ED following minor head injury. Children with >=1 risk element per the Pediatric Emergency Care Academic Research Network's decision rule were deemed "at-risk" for ciTBI. Clinician surveys regarding their initial clinical management were used to identify three care groups. Nonparametric tests analyzed group differences and logistic regression investigated associations of putative high-risk factors with neuroimaging. RESULTS: Of 104 children enrolled: (i) 30 underwent neuroimaging, (ii) 59 were observed, and (iii) 15 were discharged following the clinician's initial patient exam. Children with a non-frontal scalp hematoma were more likely to receive immediate neuroimaging and children not acting like themselves per caregiver report were more likely to be initially observed, relative to the other care groups (p<=0.01). Among high-risk factors, altered mental status (OR 5.12, 95% CI 1.8-21.1), presence of >=3 risk elements of the decision rule (OR 3.5, 95% CI 1.2 10.6), unclear skull fracture on exam (OR 31.3, 95% CI 5.4-593.8), and age<3months (OR 5.3, 95% CI 1.5-21.9) were associated with neuroimaging. No child had ciTBI. TBI symptoms (e.g. vomiting) were infrequently treated. CONCLUSIONS: ED management varied for young children with similar risk stratification. Investigation of how age in concert with specific risk factors influences medical decision making would advance evidenced-based care. PMID- 29433913 TI - The effect of application of a distal tourniquet on ultrasound guided radial artery cannulation in adult patients. PMID- 29433914 TI - Is it possible to recover from traumatic brain injury and a Glasgow coma scale score of 3 at emergency department presentation? AB - INTRODUCTION: A Glasgow Coma Scale (GCS) score of 3 on presentation in patients with traumatic brain injury (TBI) portends a poor prognosis. Consequently, there is often a tendency to treat these patients less aggressively because of low expectations for a good outcome. METHODS AND RESULTS: We performed a retrospective review of patients with TBI and a GCS score of 3. Patients were divided into 2 groups based on Glasgow Outcome Scale (GOS): Group 1 (GOS=1-3) and Group 2 (GOS=4-5). A total of 62 patients were included. The overall mortality rate was 80.6%. At 6-month, 9 patients (14.5%) achieved a GOS 4-5. Compared to Group 2 (n=9), Group 1 (n=53) had higher average APACHE IV score (104+/-19 vs 89+/-27, p=0.04), more patients with bilateral fixed pupils (59% vs 22%, p=0.04), and higher ICP burden (50+/-34 vs 0+/-0, p=0.0001). Using the CRASH calculator, the estimated mortality at 14days was 66% compared to actual mortality of 81%; difference of 15%, (p=0.05), and the estimated GOS 1-3 was 85.5% compared to actual of 85.5%, (p=1.0). CONCLUSIONS: 14.5% of patients with TBI and a GCS of 3 at presentation achieved a good outcome at 6months, and 6.9% of patients with GCS of 3 and bilateral fixed pupils on presentation to the ED achieved a good outcome at 6months. PMID- 29433916 TI - High dose of whey protein after resistance exercise promotes 45 S preribosomal RNA synthesis in older men. PMID- 29433915 TI - A novel assay provides sensitive measurement of physiologically relevant changes in albumin permeability in isolated human and rodent glomeruli. AB - Increased urinary albumin excretion is a key feature of glomerular disease but has limitations as a measure of glomerular permeability. Here we describe a novel assay to measure the apparent albumin permeability of single capillaries in glomeruli, isolated from perfused kidneys cleared of red blood cells. The rate of decline of the albumin concentration within the capillary lumen was quantified using confocal microscopy and used to calculate apparent permeability. The assay was extensively validated and provided robust, reproducible estimates of glomerular albumin permeability. These values were comparable with previous in vivo data, showing this assay could be applied to human as well as rodent glomeruli. To confirm this, we showed that targeted endothelial glycocalyx disruption resulted in increased glomerular albumin permeability in mice. Furthermore, incubation with plasma from patients with post-transplant recurrence of nephrotic syndrome increased albumin permeability in rat glomeruli compared to remission plasma. Finally, in glomeruli isolated from rats with early diabetes there was a significant increase in albumin permeability and loss of endothelial glycocalyx, both of which were ameliorated by angiopoietin-1. Thus, a glomerular permeability assay, producing physiologically relevant values with sufficient sensitivity to measure changes in glomerular permeability and independent of tubular function, was developed and validated. This assay significantly advances the ability to study biology and disease in rodent and human glomeruli. PMID- 29433918 TI - Comparison of clinical characteristics of patients with follicular thyroid carcinoma and Hurthle cell carcinoma. AB - INTRODUCTION: Hurthle cell carcinoma (HCC) is an uncommon thyroid cancer historically considered to be a variant of follicular thyroid carcinoma (FTC). The aim of this study was to assess the differences between these groups in terms of clinical factors and prognoses. PATIENTS AND METHODS: A total of 230 patients (153 with FTC and 77 with HCC) with a median follow-up of 13.4 years were studied. The different characteristics were compared using SPSS version 20 statistical software. RESULTS: Patients with HCC were older (57.3+/-13.8 years vs. 44.6+/-15.2 years; P<.001). More advanced TNM stages were also seen in patients with HCC and a greater trend to distant metastases were also seen in patients with HCC (7.8% vs. 2.7%, P=.078). The persistence/recurrence rate at the end of follow-up was higher in patients with HCC (13% vs. 3.9%, P=.011). However, in a multivariate analysis, only age (hazard ratio [HR] 1.10, confidence interval [CI] 1.04-1.17; P=.001), size (HR 1.43, CI 1.05-1.94; P=.021), and histological subtype (HR 9.79, CI 2.35-40.81; P=.002), but not presence of HCC, were significantly associated to prognosis. CONCLUSION: HCC is diagnosed in older patients and in more advanced stages as compared to FTC. However, when age, size, and histological subtype are similar, disease-free survival is also similar in both groups. PMID- 29433917 TI - Independent validation of a new reirradiation risk score (RRRS) for glioma patients predicting post-recurrence survival: A multicenter DKTK/ROG analysis. AB - BACKGROUND AND PURPOSE: Reirradiation (reRT) is a valid option with considerable efficacy in patients with recurrent high-grade glioma, but it is still not known which patients might be optimal candidates for a second course of irradiation. This study validated a newly developed prognostic score independently in an external patient cohort. MATERIAL AND METHODS: The reRT risk score (RRRS) is based on a linear combination of initial histology, clinical performance status, and age derived from a multivariable model of 353 patients. This score can predict post-recurrence survival (PRS) after reRT. The validation dataset consisted of 212 patients. RESULTS: The RRRS differentiates three prognostic groups. Discrimination and calibration were maintained in the validation group. Median PRS times in the development cohort for the good/intermediate/poor risk categories were 14.2, 9.1, and 5.3 months, respectively. The respective groups within the validation cohort displayed median PRS times of 13.8, 8.8, and 3.8 months, respectively. Uno's C for development data was 0.64 (CI: 0.60-0.69) and for validation data 0.63 (CI: 0.58-0.68). CONCLUSIONS: The RRRS has been successfully validated in an independent patient cohort. This linear combination of three easily determined clinicopathological factors allows for a reliable classification of patients and may be used as stratification factor for future trials. PMID- 29433919 TI - Gene Expression Dominance in Allopolyploids: Hypotheses and Models. AB - The classical example of nonadditive contributions of the two parents to allopolyploids is nucleolar dominance, which entails silencing of one parental set of ribosomal RNA genes. This has been observed for many other loci. The prevailing explanation for this genome-wide expression disparity is that the two merged genomes differ in their transposable element (TE) complement and in their level of TE-mediated repression of gene expression. Alternatively, and not exclusively, gene expression dominance may arise from mismatches between trans effectors and their targets. Here, we explore quantitative models of regulatory mismatches leading to gene expression dominance. We also suggest that, when pairs of merged genomes are similar from one allopolyploidization event to another, gene-level and genome dominance patterns should also be similar. PMID- 29433920 TI - Corrigendum to "Transient gestational exposure to drinking water containing excess hexavalent chromium modifies insulin signaling in liver and skeletal muscle of rat progeny" [Chem. Biol. Interact. 277 (2017) 119-128]. PMID- 29433921 TI - Modified perceptual training in sport: A new classification framework. AB - OBJECTIVES: To overview a framework that provides a theoretically-grounded approach to predicting the types of modified perceptual training tasks that will stimulate transfer of improved perceptual skills to sport performance environments. Modified perceptual training (MPT) collectively describes on- or off-field sports training tasks that are specifically designed to develop visual and perceptual-cognitive skill. Traditional training approaches in sport include sports vision training and perceptual-cognitive training, while recently, new technologies have enabled a broad range of additional MPT tools to become available to coaches and athletes. DESIGN: Short literature review and opinion article. METHODS: Literature in the fields of sports vision training and perceptual-cognitive training are summarised and contrasted. A selection of emerging MPT technologies are then overviewed. This leads to the identification of three interacting factors of MPT task design that may influence the task's capacity to transfer improved training performance to actual competition: (i) the targeted perceptual function, (ii) stimulus correspondence, and (iii) response correspondence, which are assimilated with key tenets of representative learning design. RESULTS: These three theoretically-grounded differences are adopted to support and justify the structure of the Modified Perceptual Training Framework which sets out predictions for future research to test in order to clarify the transfer effect of MPT tools. CONCLUSIONS: The application of the Modified Perceptual Training Framework may assist in future testing, design and selection of beneficial training tools in sport and as such, is predicted to have significant impact in empirical and practical settings. PMID- 29433922 TI - Effects of five-membered ring amino acid incorporation into peptides for coiled coil formation. AB - A five-membered ring amino acid (Ac5c), the peptides of which exhibit a preference for helical secondary structures, was introduced into peptides for the purpose of designing coiled coil peptides with high binding affinities. We prepared five types of peptides containing Ac5c with different numbers or at different positions. The incorporation of Ac5c into peptides enhanced their alpha helicities; however, in contrast to our expectations, it did not result in stable coiled coil formation. The structures of side chains in hydrophobic amino acids, not alpha-helicities appeared to be important for stable hydrophobic interactions between peptides. Although we were unable to develop coiled coil peptides with high binding affinities, the present results will be useful for designing novel coiled coil peptides. PMID- 29433923 TI - Substitution of terminal amide with 1H-1,2,3-triazole: Identification of unexpected class of potent antibacterial agents. AB - 3-Methoxybenzamide (3-MBA) derivatives have been identified as novel class of potent antibacterial agents targeting the bacterial cell division protein FtsZ. As one of isosteres for the amide group, 1,2,3-triazole can mimic the topological and electronic features of the amide, which has gained increasing attention in drug discovery. Based on these considerations, we prepared a series of 1H-1,2,3 triazole-containing 3-MBA analogues via isosteric replacement of the terminal amide with triazole, which had increased antibacterial activity. This study demonstrated the possibility of developing the 1H-1,2,3-triazole group as a terminal amide-mimetic element which was capable of both keeping and modulating amide-related bioactivity. Surprisingly, a different action mode of these new 1H 1,2,3-triazole-containing analogues was observed, which could open new opportunities for the development of antibacterial agents. PMID- 29433924 TI - Synthesis and cytotoxicity of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A. AB - A series of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A were designed and synthesized in 7 steps. Most compounds exhibited comparable cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780) to natural product ceratamine A. Compound 1k, bearing methoxy group at C-14, C-15 and C-16, showed the best in vitro cytotoxicity, which was better than ceratamine A. The structure and activity relationships study showed that the benzyloxymethyl group on N-3 played an important role on the cytotoxicity. PMID- 29433925 TI - Synthesis, antimicrobial activity and acid dissociation constants of methyl 5,5 diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives. AB - In this study, a series of polysubstituted methyl 5,5-diphenyl-1-(thiazol-2 yl)pyrrolidine-2-carboxylate derivatives were designed and synthesized by the cyclization reaction of methyl 1-(benzoylcarbamothioyl)-5,5-diphenylpyrrolidine-2 carboxylates and 2-bromo-1-(4-substituted phenyl)ethanones in 70-96% yield. The starting pyrrolidine derivatives were synthesized via a 1,3-dipolar cycloaddition reaction in 83-88% yield. The stereochemistry of one of these methyl 5,5-diphenyl 1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives was characterized by a single crystal X-ray diffraction study and the acid dissociation constants of these compounds were determined. An antimicrobial screening was performed against different bacterial and fungal strains and against the M. tuberculosis H37Rv strain. Interesting antibacterial activity was observed for two compounds against the A. baumannii strain with MIC values of 31.25 ug/mL (Ampicillin: 125 ug/mL) and against the M. tuberculosis H37Rv strain with MIC values of 0.98-1.96 ug/mL (Isoniazid: 0.98 ug/mL, Ethambutol: 1.96 ug/mL). Therefore, these structures can be considered as good starting points for the development of new powerful antimycobacterial agents. PMID- 29433926 TI - Effect of temperature modulations on TEMPO-mediated regioselective oxidation of unprotected carbohydrates and nucleosides. AB - Regioselective oxidation of unprotected and partially protected oligosaccharides is a much sought-after goal. Herein, we report a notable improvement in the efficiency of TEMPO-catalyzed oxidation by modulating the temperature of the reaction. Mono-, di-, and tri-saccharides are oxidized regioselectively in yields of 75 to 92%. The present method is simple to implement and is also applicable for selective oxidations of other mono- and poly-hydroxy compounds including unprotected and partially protected nucleosides. PMID- 29433927 TI - Novel nicotinamide analog as inhibitor of nicotinamide N-methyltransferase. AB - Nicotinamide N-methyltransferase (NNMT) has been linked to obesity and diabetes. We have identified a novel nicotinamide (NA) analog, compound 12 that inhibited NNMT enzymatic activity and reduced the formation of 1-methyl-nicotinamide (MNA), the primary metabolite of NA by ~80% at 2 h when dosed in mice orally at 50 mg/kg. PMID- 29433928 TI - Pharmacology and in vivo efficacy of pyridine-pyrimidine amides that inhibit microtubule polymerization. AB - Microtubule-targeting agents are important tools in cancer treatment. Generating novel microtubule targeting agents with novel pharmacology could dramatically expand the utility of this class of drugs. Here we characterize the pharmacology of recently described small molecule microtubule polymerization inhibitors. Pharmacokinetic experiments show oral bioavailability through gastric absorption. In vitro assays designed to predict absorption, distribution, metabolism, and excretion (ADME) and safety reveal a scaffold that is metabolically stable, evades P-glycoprotein, does not inhibit CYP enzymes, occurs as a significant free fraction in serum, and has exceptionally high cellular permeability. Together with in vivo efficacy models, pharmacology supports further development as a treatment for solid tumors. PMID- 29433929 TI - A novel peptide shows excellent anti-HIV-1 potency as a gp41 fusion inhibitor. AB - Fusion inhibitors of HIV prevent the virus from entering into the target cell via the interaction with gp41, which stops the process of spatial rearrangement of the viral envelope protein. A series of peptides have been designed and screened to obtain a highly potent novel sequence. Among them, CT105 possesses the most potent anti-viral ability at low nanomolar IC50 values against a panel of HIV-1 pseudoviruses from A, B, C and A1/D subtypes, whereas T20 shows much weaker potency. CT105 also shows excellent inhibitory activity at 260 pico molar IC50 against HIV-1 replication. As a fusion inhibitor, CT105 has a strong ability to interrupt gp41 core formation. The terminal half-life of CT105 possesses 1.72 fold longer than that of T20 as determined by developing an indirect competitive ELISA method. The results suggest that this artificial peptide CT105 could be a favorable architype for further optimization and modification. PMID- 29433930 TI - Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors. AB - The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub micromolar antiviral activity. PMID- 29433931 TI - Corrigendum to "1-Thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives as antitumor agents" [Bioorg. Med. Chem. Lett. 27 (2017) 4471-4477]. PMID- 29433932 TI - Racial and Ethnic Disparities in Hospital Mortality among Ischemic Stroke Patients in Hawaii. AB - BACKGROUND: We evaluated disparities in in-hospital mortality rates among whites, Native Hawaiians and other Pacific Islanders (NHOPI), Filipinos, and other Asian groups in Hawaii who were hospitalized for acute ischemic stroke. MATERIALS AND METHODS: Using a statewide hospital claims database, we performed a retrospective study including sequential acute ischemic stroke patients between 2010 and 2015. We compared in-hospital mortality rates among whites, NHOPI, Filipinos, other Asian groups excluding Filipinos, and other races (Blacks, Hispanics, Native Americans, mixed race). RESULTS: A total of 13,030 patient discharges were included in this study. The mean (+/-SD) age in years at the time of stroke was 63.5 +/- 14.3 for NHOPI, 69.6 +/- 14.4 for Filipinos, 67.8 +/- 14.2 for other race, 71.4 +/- 13.8 for whites, and 76.1 +/- 13.5 for other Asians (P < .001). NHOPI patients had higher rates of diabetes (48.8%), obesity (18.4%), and tobacco use (31.3%) compared with patients in other racial-ethnic categories. Filipino patients had the highest rate of hemorrhagic transformation (9.7%). Age-adjusted stroke mortality rates were highest among Filipinos (15.9%; 95% confidence interval [CI] = 14.3%-17.6%), followed by other Asian groups (15.1%; 95% CI = 14.0%-16.2%), NHOPI (14.8%; 95% CI = 12.8%-16.8%), other race (14.4%; 95% CI = 11.3%-17.4%), and lowest among whites (12.8%; 11.5%-14.2%). After adjusting for other confounding variables, Filipinos had higher mortality (odds ratio = 1.22, 95% CI = 1.03-1.45), whereas other Asian groups, NHOPI, and other race patients had mortality rates that were similar to whites. CONCLUSION: In Hawaii, Filipino ethnicity is an independent risk factor for higher in-hospital stroke mortality compared with whites. PMID- 29433933 TI - Five-Year Case Fatality Following First-Ever Stroke in the Mashhad Stroke Incidence Study: A Population-Based Study of Stroke in the Middle East. AB - BACKGROUND AND PURPOSE: Despite recent declines in stroke mortality in high income countries, the incidence and mortality of stroke have increased in many low- and middle-income countries. Population-based information on stroke in such countries is a research priority to address this rising trend. This study was designed to evaluate 5-year stroke mortality and its associated factors. METHODS: During a 12-month period beginning from November 2006, 624 patients with first ever stroke (FES) living in Mashhad, Iran, were recruited and followed longitudinally. Kaplan-Meier analyses were used to determine the cumulative risk of death. Prognostic variables associated with death were assessed using a Cox proportional hazard, backward logistic regression model. RESULTS: The 5-year cumulative risk of death was 53.8% for women and 60.5% for men (log rank = .1). The most frequent causes of death were stroke (41.2%), myocardial infarction/vascular diseases (16.4%), and pneumonia (14.2%). In multivariable Cox proportional hazard analysis, male gender (hazard ratio [HR]: 1.29, 95% confidence interval [CI]: 1.01-1.64), age (HR: 1.04, 95% CI: 1.03-1.05, per 1 year increase), National Institute of Health Stroke Scale score at admission (HR: 1.11, 95% CI: 1.09-1.12, per 1-point increase), atrial fibrillation (HR: 1.78, CI: 1.24-2.54), and education < 12 years (HR: 1.61, 95% CI: 1.08-2.4) were associated with greater 5-year case fatality. CONCLUSIONS: Long-term case fatality following stroke in Iran is greater than that observed in many high income countries. Targeting strategies to reduce the poor outcome following stroke, such as treating AF, is likely to reduce this disparate outcome. PMID- 29433934 TI - Evidence-Based Review Of Pharmacotherapy For Acute Agitation. Part 2: Safety. AB - BACKGROUND: The management of acute agitation in the emergency department often requires the administration of rapid-acting antipsychotic agents. However, there are few comparative studies and little guidance regarding the risks associated with use of such drugs in the acute setting. OBJECTIVE: This structured evidence based review compared the safety of antipsychotic pharmacotherapies for acute agitation using data from randomized controlled trials identified by a literature search of the PubMed database. RESULTS: Based on findings from 34 blinded, randomized controlled trials, common acute adverse effects of second-generation antipsychotics and haloperidol were headache, dizziness, insomnia, and somnolence. There were some differences in incidence of extrapyramidal symptoms (EPS), degree of sedation, and acute QTc prolongations between agents. CONCLUSIONS: The results of this review demonstrate the improved safety (particularly regarding EPS and over-sedation) of certain newer-generation antipsychotic agents compared with haloperidol and benzodiazepines for the treatment of acutely agitated patients. The risk of prolonged QT interval and torsade de pointes needs to be considered with haloperidol and some of the second generation antipsychotics. PMID- 29433935 TI - Gene Therapy for Adenosine Deaminase Deficiency: A Comprehensive Evaluation of Short- and Medium-Term Safety. AB - Loss of adenosine deaminase activity leads to severe combined immunodeficiency (ADA-SCID); production and function of T, B, and natural killer (NK) cells are impaired. Gene therapy (GT) with an autologous CD34+-enriched cell fraction that contains CD34+ cells transduced with a retroviral vector encoding the human ADA cDNA sequence leads to immune reconstitution in most patients. Here, we report short- and medium-term safety analyses from 18 patients enrolled as part of single-arm, open-label studies or compassionate use programs. Survival was 100% with a median of 6.9 years follow-up (range, 2.3 to 13.4 years). Adverse events were mostly grade 1 or grade 2 and were reported by all 18 patients following GT. Thirty-nine serious adverse events (SAEs) were reported by 15 of 18 patients; no SAEs were considered related to GT. The most common adverse events reported post GT include upper respiratory tract infection, gastroenteritis, rhinitis, bronchitis, oral candidiasis, cough, neutropenia, diarrhea, and pyrexia. Incidence rates for all of these events were highest during pre-treatment, treatment, and/or 3-month follow-up and then declined over medium-term follow-up. GT did not impact the incidence of neurologic/hearing impairments. No event indicative of leukemic transformation was reported. PMID- 29433936 TI - microRNA-219 Reduces Viral Load and Pathologic Changes in Theiler's Virus-Induced Demyelinating Disease. AB - Analysis of microRNA (miR) expression in the central nervous system white matter of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) revealed a significant reduction of miR-219, a critical regulator of myelin assembly and repair. Restoration of miR-219 expression by intranasal administration of a synthetic miR-219 mimic before disease onset ameliorates clinical disease, reduces neurogliosis, and partially recovers motor and sensorimotor function by negatively regulating proinflammatory cytokines and virus RNA replication. Moreover, RNA sequencing of host lesions showed that miR 219 significantly downregulated two genes essential for the biosynthetic cholesterol pathway, Cyp51 (lanosterol 14-alpha-demethylase) and Srebf1 (sterol regulatory element-binding protein-1), and reduced cholesterol biosynthesis in infected mice and rat CG-4 glial precursor cells in culture. The change in cholesterol biosynthesis had both anti-inflammatory and anti-viral effects. Because RNA viruses hijack endoplasmic reticulum double-layered membranes to provide a platform for RNA virus replication and are dependent on endogenous pools of cholesterol, miR-219 interference with cholesterol biosynthesis interfered virus RNA replication. These findings demonstrate that miR-219 inhibits TMEV-induced demyelinating disease through its anti-inflammatory and anti-viral properties. PMID- 29433937 TI - Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy. AB - We report a global adeno-associated virus (AAV)9-based gene therapy protocol to deliver therapeutic galactosylceramidase (GALC), a lysosomal enzyme that is deficient in Krabbe's disease. When globally administered via intrathecal, intracranial, and intravenous injections to newborn mice affected with GALC deficiency (twitcher mice), this approach largely surpassed prior published benchmarks of survival and metabolic correction, showing long-term protection of demyelination, neuroinflammation, and motor function. Bone marrow transplantation, performed in this protocol without immunosuppressive preconditioning, added minimal benefits to the AAV9 gene therapy. Contrasting with other proposed pre-clinical therapies, these results demonstrate that achieving nearly complete correction of GALC's metabolic deficiencies across the entire nervous system via gene therapy can have a significant improvement to behavioral deficits, pathophysiological changes, and survival. These results are an important consideration for determining the safest and most effective manner for adapting gene therapy to treat this leukodystrophy in the clinic. PMID- 29433938 TI - B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors. AB - Growing evidence links the aggressiveness of non-Hodgkin's lymphoma, especially the activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCLs) to Toll-like receptor 9 (TLR9)/MyD88 and STAT3 transcription factor signaling. Here, we describe a dual-function molecule consisting of a clinically relevant TLR9 agonist (CpG7909) and a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). The CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells. We further demonstrated that injections (i.v.) of CpG-STAT3dODN inhibited growth of human OCI-Ly3 lymphoma in immunodeficient mice. Moreover, systemic CpG-STAT3dODN administration induced complete regression of the syngeneic A20 lymphoma, resulting in long-term survival of immunocompetent mice. Both TLR9 stimulation and concurrent STAT3 inhibition were critical for immune-mediated therapeutic effects, since neither CpG7909 alone nor CpG7909 co-injected with unconjugated STAT3dODN extended mouse survival. The CpG-STAT3dODN induced expression of genes critical to antigen processing/presentation and Th1 cell activation while suppressing survival signaling. These effects resulted in the generation of lymphoma cell-specific CD8/CD4-dependent T cell immunity protecting mice from tumor rechallenge. Our results suggest that CpG-STAT3dODN as a systemic/local monotherapy or in combination with PD1 blockade can provide an opportunity for treating patients with B cell NHL. PMID- 29433939 TI - Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency. AB - We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi dose, systemic administration for treatment of single-gene inherited metabolic diseases. PMID- 29433940 TI - N-glycan sialylation in a silkworm-baculovirus expression system. AB - A silkworm-baculovirus system is particularly effective for producing recombinant proteins, including glycoproteins. However, N-glycan structures in silkworm differ from those in mammals. Glycoproteins in silkworm are secreted as pauci mannose type N-glycans without sialic acid or galactose residues. Sialic acid on N-glycans plays important roles in protein functions. Therefore, we developed pathways for galactosylation and sialylation in silkworm. Sialylated N-glycans on proteins were successfully produced in silkworm by co-expressing galactosyltransferase and sialyltransferase and providing an external supply of a sialylation-related substrate. alpha2,3/alpha2,6 Sialylation to N-glycans was controlled by changing the type of sialyltransferase expressed in silkworm. Furthermore, the co-expression of N-acetylglucosaminyltransferase II facilitated the formation of additional di-sialylated N-glycan structures. Our results provide new information on the control of N-glycosylation in silkworm. PMID- 29433941 TI - Selection of the Best of 2017 on Percutaneous Treatment of Chronic Occlusions. PMID- 29433942 TI - Fontan-associated Liver Disease. AB - Fontan-associated liver disease refers to the disturbance in the liver secondary to hemodynamic changes and systemic venous congestion following Fontan surgery. Although the natural history of this disease has not yet been established, patients with more advanced liver injury develop the complications of portal hypertension, such as ascites, variceal haemorrhage, or encephalopathy. Moreover, patients with Fontan surgery may have an increased risk of hepatocellular carcinoma. Periodic liver monitoring is essential to prevent this disease and provide early treatment of liver complications. PMID- 29433943 TI - Selection of the Best of 2017 on Cardiac Pacing: Magnetic Resonance in Patients With Pacemaker and Implantable Defibrillator. PMID- 29433944 TI - Inflammasome, Inflammation, and Tissue Homeostasis. AB - Organismal fitness demands proper response to neutralize the threat from infection or injury. At the mammalian intestinal epithelium barrier, the inflammasome coordinates an elaborate tissue repair response marked by the induction of antimicrobial peptides, wound-healing cytokines, and reparative proliferation of epithelial stem cells. The inflammasome in myeloid and intestinal epithelial compartments exerts these effects in part through maintenance of a healthy microbiota. Disease-associated mutations and elevated expression of certain inflammasome sensors have been identified. In many cases, inhibition of inflammasome activity has dramatic effects on disease outcome in mouse models of experimental colitis. Here, we discuss recent studies on the role of distinct inflammasome sensors in intestinal homeostasis and how this knowledge may be translated into a therapeutic setting. PMID- 29433945 TI - Re: Spontaneous hemoperitoneum in pregnancy (SHiP) and endometriosis - A systematic review of the recent literature. PMID- 29433946 TI - Definition and diagnosis of asthma-COPD overlap (ACO). AB - It is now widely recognized that asthma and COPD can coexist as asthma-COPD overlap (ACO), but the preliminary attempts at providing universal guidelines for the diagnosis of ACO still need to be improved. We believe that a case can be made for devising guidelines for the diagnosis of this increasingly common disease that are specific to Japan. In this paper, we present our consensus-based description of ACO which we believe is realistic for use in our country. In addition, we cite the scientific evidence for our own "objective" features used to develop the criteria for COPD and asthma diagnosis. We acknowledge that they will need to be validated and updated over time, but hope the results will encourage further research on the characteristics and treatment of this commonly encountered clinical problem. PMID- 29433947 TI - Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy. AB - Glutamic acid decarboxylase (GAD) antibody-associated encephalitis causes both acute seizures and chronic epilepsy with predominantly temporal lobe onset. This condition is challenging in diagnosis and management, and the incidence of GAD antibody (Ab)-related epilepsy could be much higher than commonly believed. Imaging and CSF evidence of inflammation along with typical clinical presentations, such as adult onset temporal lobe epilepsy (TLE) with unexplained etiology, should prompt testing for the diagnostic antibodies. High serum GAD Ab titer (>=2000U/mL or >=20nmol/L) and evidence of intrathecal anti-GAD Ab synthesis support the diagnosis. Unlike other immune-mediated epilepsies, antiglutamic acid decarboxylase 65 (GAD65) antibody-mediated epilepsy is often poorly responsive to antiepileptic drugs (AEDs) and only moderately responsive to immune therapy with steroids, intravenous immunoglobulin (IVIG), or plasma exchange (PLEX). Long-term treatment with more aggressive immunosuppressants such as rituximab (RTX) and/or cyclophosphamide is often necessary and may be more effective than current immunosuppressive approaches. The aim of this review is to review the physiology, pathology, clinical presentation, related ancillary tests, and management of GAD Ab-associated autoimmune epilepsy by searching the keywords and to promote the recognition and the initiation of proper therapy for this condition. PMID- 29433948 TI - Adherence barriers in pediatric epilepsy: From toddlers to young adults. AB - OBJECTIVE: The objectives of this study were to examine the continuity of adherence barriers across stages of development in pediatric epilepsy and to assess the differential influence of barriers on several important clinical outcomes from early childhood to young adulthood, including adherence, seizures, and health-related quality of life (HRQOL). METHOD: A developmentally representative sample of youth 2-25years with epilepsy was obtained by combining data from five different studies. A total of 269 caregivers and 77 adolescents and young adults were included in this investigation. Participants completed measures of adherence barriers and HRQOL. An electronic monitoring system was used to assess adherence to the primary antiepileptic drug over 30days. The prevalence of individual barriers across development and their relative importance as predictors of clinical outcomes were examined. RESULTS: Adherence barriers are characterized by both continuity and discontinuity from early childhood to early adulthood. Barriers such as disliking the taste of medication, parent forgetfulness, and refusal to take medications were significantly more salient during certain developmental periods. No significant differences across age groups were found for other barriers, including difficulty getting to the pharmacy and embarrassment. Certain adherence barriers, such as running out of medications, were more important to particular clinical outcomes despite being low prevalence. Adherence barriers differentially predicted adherence, seizure control, and HRQOL based on developmental stage. CONCLUSION: Routine assessment of adherence barriers is imperative from toddlerhood to young adulthood given that the prevalence of barriers and their relative influence on important health outcomes vary by developmental stage. Adherence intervention efforts should be targeted, developmentally tailored, and focused on those barriers that are most predictive of poor outcomes for a given developmental period. PMID- 29433949 TI - Patient versus neurologist preferences: A discrete choice experiment for antiepileptic drug therapies. AB - OBJECTIVE: This assessment was conducted to quantify and compare patient and neurologist preferences regarding antiepileptic drug (AED) attributes for treating epilepsy. METHODS: Patients with epilepsy (>=18years, treated with AEDs) and neurologists were recruited from nationally representative US panels to complete an online survey that included a discrete choice experiment (DCE). Participants chose between two hypothetical AEDs, characterized by six attributes in the DCE, which included 1) level of seizure control/reduction; 2) dosing frequency, 3) diminished coordination and balance, 4) psychiatric issues, 5) diminished energy level, and 6) dietary restrictions. The Sawtooth Software Choice-Based Conjoint (CBC) System for CBC Analysis was used to estimate treatment attribute ranking and weighting. RESULTS: Of the 720 respondents (518 patients and 202 neurologists), both patients and neurologists ranked seizure control as the most important attribute (rank 1) and dietary restrictions as the least important attribute (rank 6). However, seizure control had a significantly greater weighting in neurologists' decision-making than among patients (45% vs 32%, p<0.005). On the other hand, patients considered the risks of psychiatric adverse effects (19% vs 15%), diminished coordination and balance (16% vs 10%), and fatigue or diminished energy (13% vs 11%) as significantly more important (p<0.05) than did neurologists. CONCLUSION: Patients and neurologists had similar preference ranking order, with seizure reduction being ranked the most important attribute. However, neurologist treatment preferences were significantly more influenced by seizure reduction while patient preferences were significantly more influenced by adverse effects that may impact their quality of life. Understanding how patient and neurologist perspectives differ should encourage dialog to communicate the potential risks and benefits of AED therapy and assist in the shared decision-making process. PMID- 29433950 TI - Implementation and evaluation of a therapeutic patient education programme during a clinical trial in Yaounde, Cameroon - Trial ANRS-12286/MOBIDIP. AB - OBJECTIVES: High adherence is needed to maintain antiretroviral therapy efficacy. Few attempts at therapeutic patient education (TPE) have been made in sub-Saharan Africa. We describe patients' achievements before intervention and identified needs, TPE programme implementation and evaluation, and patients' satisfaction. METHODS: The TPE programme was proposed to patients in the ANRS-12286/MOBIDIP trial. Beforehand, a directory of competences to manage HIV infection was designed. Patients' HIV-related knowledge and skills assessment was realised, leading to an educational contract. Evaluation was performed using a standardised collection form and a satisfaction survey. RESULTS: Of 154 patients, 146 underwent TPE. During a median of 1.8 years, 47% of patients had >=3 consultations. Educational assessment revealed limited knowledge about HIV disease. Conversely, patients had frequently managed issues of adherence or disclosure. A median of 12 objectives were considered per patient, and 75% were attained. Objectives from the cognitive domain were less frequently attained. Patients appeared satisfied with the intervention: more emphasis was placed on psycho-affective aspects or experience-sharing than on the acquisition of knowledge. CONCLUSION: Active listening, know-how and a space for discussion appear more important for patients than knowledge on disease or treatments. PRACTICE IMPLICATIONS: In HIV care, the directory of learning objectives should be revised to include more objectives concerning practical skills for disease management. PMID- 29433951 TI - [Frontal fibrosing alopecia: A case report]. PMID- 29433952 TI - Recent Intimate Partner Violence and Housing Instability Among Women Veterans. AB - INTRODUCTION: Women Veterans are at increased risk of both housing instability and intimate partner violence compared with their non-Veteran counterparts. The objectives of the present study were (1) to assess the relationship between women Veterans' experience of intimate partner violence and various indicators of housing instability, and (2) to assess what correlates help to explain experiences of housing instability among women Veterans who experienced past-year intimate partner violence. METHODS: Data were collected from U.S. Department of Veterans Affairs electronic medical records for 8,427 women Veterans who were screened for past-year intimate partner violence between April 2014 and April 2016 at 13 Veterans Affairs' facilities. Logistic regressions performed during 2017 assessed the relationship between past-year intimate partner violence and housing instability. RESULTS: A total of 8.4% of the sample screened positive for intimate partner violence and 11.3% for housing instability. Controlling for age and race, a positive intimate partner violence screen increased odds of housing instability by a factor of 3. Women Veterans with past-year intimate partner violence were more likely to have an indicator of housing instability if they identified as African American, had screened positive for military sexual trauma, or had a substance use disorder; receiving compensation for a disability incurred during military service and being married were protective. CONCLUSIONS: For women Veterans, intimate partner violence interventions should assess for both physical and psychological housing needs, and housing interventions should coordinate with intimate partner violence programs to address common barriers to resources. PMID- 29433953 TI - Affordable Care Act Impact on Medicaid Coverage of Smoking-Cessation Treatments. AB - INTRODUCTION: Four sections of the Affordable Care Act address the expansion of Medicaid coverage for recommended smoking-cessation treatments for: (1) pregnant women (Section 4107), (2) all enrollees through a financial incentive (1% Federal Medical Assistance Percentage increase) to offer comprehensive coverage (Section 4106), (3) all enrollees through Medicaid formulary requirements (Section 2502), and (4) Medicaid expansion enrollees (Section 2001). The purpose of this study is to document changes in Medicaid coverage for smoking-cessation treatments since the passage of the Affordable Care Act and to assess how implementation has differentially affected Medicaid coverage policies for: pregnant women, enrollees in traditional Medicaid, and Medicaid expansion enrollees. METHODS: From January through June 2017, data were collected and analyzed from 51 Medicaid programs (50 states plus the District of Columbia) through a web-based survey and review of benefits documents to assess coverage policies for smoking-cessation treatments. RESULTS: Forty-seven Medicaid programs have increased coverage for smoking cessation treatments post-implementation of the Affordable Care Act by adopting one or more of the four smoking-cessation treatment provisions. Coverage for pregnant women increased in 37 states, coverage for newly eligible expansion enrollees increased in 32 states, and 15 states added coverage and/or removed copayments in order to apply for a 1% increase in the Federal Medical Assistance Percentage. Coverage for all recommended pharmacotherapy and group and individual counseling increased from seven states in 2009 to 28 states in 2017. CONCLUSIONS: The Affordable Care Act was successful in improving and expanding state Medicaid coverage of effective smoking-cessation treatments. Many programs are not fully compliant with the law, and additional guidance and clarification from the Centers for Medicare and Medicaid Services may be needed. PMID- 29433954 TI - BMI and Central Obesity With Falls Among Community-Dwelling Older Adults. AB - INTRODUCTION: This study examined the associations of BMI category and central obesity status, with falls among community-dwelling older adults in the U.S. METHODS: Data were drawn from the 2012 and 2014 U.S. Health and Retirement Study, a nationally representative longitudinal panel study funded by the National Institute of Aging. The study participants were U.S. community-dwelling older adults aged >=65 years (N=3,383). Multiple logistic regression and Poisson regression analyses examined the associations of BMI category and central obesity (waist circumference >102 cm in men and >88 cm in women) with experiencing a fall and fall injury, after adjusting for all other covariates. A prospective analysis was conducted in which independent variables from 2012 were examined in relation to dependent variables measured in the same participants in 2014. RESULTS: Overall, 35.2% of older adults experienced at least one fall in the past 2 years. Compared with those who were not, centrally obese older adults were more likely to experience a fall (AOR=1.37, 95% CI=1.01, 1.85) and fall more frequently (incidence rate ratio=1.15, 95% CI=1.03, 1.29). Fallers in the obese BMI category were less likely than normal-weight fallers to experience a fall injury (AOR=0.56, 95% CI=0.35, 0.91). CONCLUSIONS: These findings suggest that (1) central obesity be measured when assessing older adults' fall risk and (2) specific community prevention strategies for centrally obese older adults be developed to better prevent falls and fall-related injuries. PMID- 29433955 TI - Awareness of Cardiovascular Risk Factors in U.S. Young Adults Aged 18-39 Years. AB - INTRODUCTION: Young adults with hyperlipidemia, hypertension, and diabetes are at increased risk of developing heart disease later in life. Despite emphasis on early screening, little is known about awareness of these risk factors in young adulthood. METHODS: Data from the nationally representative cross-sectional National Health and Nutrition Examination Survey 2011-2014 were analyzed in 2017 to estimate the prevalence of self-reported awareness of hypercholesterolemia, hypertension, and diabetes in U.S. young adults aged 18-39 years (n=11,083). Prevalence estimates were weighted to population estimates using survey procedures, and predictors of awareness were identified using weighted logistic regression. RESULTS: Among U.S. young adults, the prevalence of hypercholesterolemia, hypertension, and diabetes was 8.8% (SE=0.4%); 7.3% (SE=0.3%); and 2.6% (SE=0.2%), respectively. The prevalence of borderline high cholesterol, blood pressure, and blood glucose were substantially higher (21.6% [SE= 0.6%]; 26.9% [SE=0.7%]; and 18.9% [SE=0.6%], respectively). Awareness was low for hypercholesterolemia (56.9% [SE=2.4%]) and moderate for hypertension and diabetes (62.7% [SE=2.4%] and 70.0% [SE=2.7%]); <25% of young adults with borderline levels of these risk factors were aware of their risk. Correlates of risk factor awareness included older age, insurance status, family income above the poverty line, U.S. origin, having a usual source of health care, and the presence of comorbid conditions. CONCLUSIONS: Despite the high prevalence of cardiovascular risk factors in U.S. young adults, awareness remains less than ideal. Interventions that target access may increase awareness and facilitate achieving treatment goals in young adults. PMID- 29433956 TI - HIV Pre-exposure Prophylaxis Program Implementation Using Intervention Mapping. AB - INTRODUCTION: HIV pre-exposure prophylaxis has been proven to be an effective tool in HIV prevention. However, numerous barriers still exist in pre-exposure prophylaxis implementation. METHODS: The framework of Intervention Mapping was used from August 2016 to October 2017 to describe the process of adoption, implementation, and maintenance of an HIV prevention program from 2012 through 2017 in Houston, Texas, that is nested within a county health system HIV clinic. Using the tasks outlined in the Intervention Mapping framework, potential program implementers were identified, outcomes and performance objectives established, matrices of change objectives created, and methods and practical applications formed. RESULTS: Results include the formation of three matrices that document program outcomes, change agents involved in the process, and the determinants needed to facilitate program adoption, implementation, and maintenance. Key features that facilitated successful program adoption and implementation were obtaining leadership buy-in, leveraging existing resources, systematic evaluation of operations, ongoing education for both clinical and nonclinical staff, and attention to emergent issues during launch. CONCLUSIONS: The utilization of Intervention Mapping to delineate the program planning steps can provide a model for pre-exposure prophylaxis implementation in other settings. PMID- 29433957 TI - Liposuction-assisted four pedicle-based breast reduction (LAFPBR): A new safer technique of breast reduction for elderly patients. AB - As older people increasingly care for their body image and remain active longer, the demand for reduction mammaplasty is increasing in this population. Only a few studies of reduction mammaplasty have specifically focussed on the outcomes in elderly women. We developed a new breast reduction technique: the Liposuction Assisted Four Pedicle-Based Breast Reduction (LAFPBR) that is especially indicated for elderly patients. The aim of this paper was to describe the LAFPBR technique and to determine whether it could be considered a safer option for elderly patients compared to the superomedial pedicle (SMP) technique. A retrospective study included sixty-two women aged 60 years and over who underwent bilateral breast reduction mammaplasty. Thirty-one patients underwent LAFPBR and 31 patients were operated using the SMP technique. Complications and patient satisfaction in both groups were analysed. Patient satisfaction was measured using a validated questionnaire: the client satisfaction questionnaire 8 (CSQ-8). The LAFPBR technique required less operating time, and avoided significant blood loss. Six minor complications were observed in SMP patients. No LAFPBR women developed a procedure-related complication. Patient satisfaction was high with a mean score of 29.65 in LAFPBR patients and 28.68 in SMP patients. The LAFPBR is an easy procedure that appears safer than SMP and results in a high satisfaction rate in elderly women. PMID- 29433958 TI - An ontology-driven clinical decision support system (IDDAP) for infectious disease diagnosis and antibiotic prescription. AB - BACKGROUND: The available antibiotic decision-making systems were developed from a physician's perspective. However, because infectious diseases are common, many patients desire access to knowledge via a search engine. Although the use of antibiotics should, in principle, be subject to a doctor's advice, many patients take them without authorization, and some people cannot easily or rapidly consult a doctor. In such cases, a reliable antibiotic prescription support system is needed. METHODS AND RESULTS: This study describes the construction and optimization of the sensitivity and specificity of a decision support system named IDDAP, which is based on ontologies for infectious disease diagnosis and antibiotic therapy. The ontology for this system was constructed by collecting existing ontologies associated with infectious diseases, syndromes, bacteria and drugs into the ontology's hierarchical conceptual schema. First, IDDAP identifies a potential infectious disease based on a patient's self-described disease state. Then, the system searches for and proposes an appropriate antibiotic therapy specifically adapted to the patient based on factors such as the patient's body temperature, infection sites, symptoms/signs, complications, antibacterial spectrum, contraindications, drug-drug interactions between the proposed therapy and previously prescribed medication, and the route of therapy administration. The constructed domain ontology contains 1,267,004 classes, 7,608,725 axioms, and 1,266,993 members of "SubClassOf" that pertain to infectious diseases, bacteria, syndromes, anti-bacterial drugs and other relevant components. The system includes 507 infectious diseases and their therapy methods in combination with 332 different infection sites, 936 relevant symptoms of the digestive, reproductive, neurological and other systems, 371 types of complications, 838,407 types of bacteria, 341 types of antibiotics, 1504 pairs of reaction rates (antibacterial spectrum) between antibiotics and bacteria, 431 pairs of drug interaction relationships and 86 pairs of antibiotic-specific population contraindicated relationships. Compared with the existing infectious disease relevant ontologies in the field of knowledge comprehension, this ontology is more complete. Analysis of IDDAP's performance in terms of classifiers based on receiver operating characteristic (ROC) curve results (89.91%) revealed IDDAP's advantages when combined with our ontology. CONCLUSIONS AND SIGNIFICANCE: This study attempted to bridge the patient/caregiver gap by building a sophisticated application that uses artificial intelligence and machine learning computational techniques to perform data-driven decision-making at the point of primary care. The first level of decision-making is conducted by the IDDAP and provides the patient with a first-line therapy. Patients can then make a subjective judgment, and if any questions arise, should consult a physician for subsequent decisions, particularly in complicated cases or in cases in which the necessary information is not yet available in the knowledge base. PMID- 29433959 TI - The effect of ethanol extract of Glycyrrhiza uralensis on the voltage-gated sodium channel subtype 1.4. AB - To investigate the inhibitory effect of Glycyrrhiza uralensis (G. uralensis) and its monomeric compounds on Nav1.4 voltage-gated sodium channels (VGSCs) and analyze the relationship between the content of its marker compounds and the inhibitory rate. Based on this study, we found that 4 mg/ml ethanol extract of G. uralensis at 30%, 50%, 70% and 90% (v/v) exhibited 77.00 +/- 0.03%, 34.75 +/- 0.09%, 100.00 +/- 0.01% and 2.00 +/- 0.01% inhibitory rates on INav1.4 respectively, and 8 mg/ml ethanol extract of G. uralensis at 30%, 50%, 70% and 90% (v/v) exhibited 99.00 +/- 0.01%, 97.10 +/- 0.02%, 100.00 +/- 0.01% and 17.00 +/- 0.04% inhibitory rates on INav1.4 respectively. Isoliquiritigenin, echinatin, liquiritin and glycyrrhizic acid exhibited higher inhibitory rates of 39.98 +/- 4.55%, 33.20 +/- 1.61%, 22.62 +/- 0.30% and 20.54 +/- 4.82% respectively. However, liquiritigenin, formononetin, neoisoliquiritin and glycyrrhetinic acid exhibited lower inhibitory rates of less than 20%. Further, liquiritin apioside, isoliquiritin and neoliquiritin exhibited almost no effect on INav1.4. These findings showed that glycyrrhizic acid reached a maximum concentration of 49.15 MUg/ml, while echinatin had the lowest concentration. The ethanol extract of G. uralensis has significant inhibitory effects on Nav1.4 VGSCs. This may be an important mechanism in the treatment of gastrocnemius spasm and could guide further research regarding material basis and mechanism of the treatment of gastrocnemius spasm with peony and licorice decoction. PMID- 29433960 TI - Identifying the causes of the changes in the prevalence patterns of diabetes in older U.S. adults: A new trend partitioning approach. AB - AIMS: To identify how efforts to control the diabetes epidemic and the resulting changes in diabetes mellitus, type II (T2D) incidence and survival have affected the time-trend of T2D prevalence. METHODS: A newly developed method of trend decomposition was applied to a 5% sample of Medicare administrative claims filed between 1991 and 2012. RESULTS: Age-adjusted prevalence of T2D for adults age 65+ increased at an average annual percentage change of 2.31% between 1992 and 2012. Primary contributors to this trend were (in order of magnitude): improved survival at all ages, increased prevalence of T2D prior to age of Medicare eligibility, decreased incidence of T2D after age of Medicare eligibility. CONCLUSIONS: Health services supported by the Medicare system, coupled with improvements in medical technology and T2D awareness efforts provide effective care for individuals age 65 and older. However, policy maker attention should be shifted to the prevention of T2D in younger age groups to control the increase in prevalence observed prior to Medicare eligibility. PMID- 29433961 TI - Immunology of the Uterine and Vaginal Mucosae. AB - Along with the maintenance of symbiotic mutualism with commensal microbes and protection against invasive infections common to all mucosal barrier tissues, female reproductive tissues have additional, unique tasks that include dynamic cyclic cellular turnover in menstruation and immunological tolerance to genetically foreign fetal antigens in pregnancy. Here we review current knowledge on distinct features of the immune cells in female reproductive tissue with regard to antimicrobial host defense and adaptations to accommodate the fetus during pregnancy. Outstanding areas for future research to obtain new functional insights on this enigmatic mucosal barrier are also highlighted. PMID- 29433962 TI - Does Intrathecal Morphine in Spinal Anesthesia Have a Role in Modern Multimodal Analgesia for Primary Total Joint Arthroplasty? AB - BACKGROUND: Intrathecal morphine (ITM) combined with bupivacaine spinal anesthesia can improve postoperative pain, but has potential side effects of postoperative nausea/vomiting (PONV) and pruritus. With the use of multimodal analgesia and regional anesthetic techniques, postoperative pain control has improved significantly to a point where ITM may be avoided in total joint arthroplasty (TJA). METHODS: We performed a retrospective study of primary TJA patients who underwent a standardized multimodal recovery pathway and received bupivacaine neuraxial anesthesia with ITM vs bupivacaine neuraxial anesthesia alone (control). RESULTS: In total, 598 patients were identified (131 controls, 467 ITMs) with similar demographics. On postoperative day 0 (POD 0), ITM patients had significantly lower mean visual analog scale scores (1.5 +/- 1.6 vs 2.5 +/- 1.9, P < .001) and consumed less oral morphine equivalents (10.5 +/- 25.4 vs 16.8 +/- 27.2, P = .013). ITM patients walked further compared to controls by POD 1 (133.6 +/- 159.6 vs 97.3 +/- 141 m, P = .028) and were less likely to develop PONV during their entire hospital stay (38.5% vs 48.6%, P = .043). No significant differences were seen for total morphine equivalents consumption, rate of discharge to care facility, length of stay, and 90-day readmission rates. CONCLUSION: ITM was associated with improved POD 0 pain scores and less initial oral/intravenous opioid consumption, which likely contributes to the subsequent improved mobilization and lower rates of PONV. In the setting of a modern regional anesthesia and multimodal analgesia recovery plan for TJA, ITM can still be considered for its benefits. PMID- 29433963 TI - Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group. AB - BACKGROUND: Despite the high incidence of metastatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. We aimed to evaluate the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer. METHODS: We did a multicentre, open-label, randomised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0-3. Eligible patients were randomly assigned (1:1) by an online randomisation system based on the minimisation method to receive metronomic oral cyclophosphamide 50 mg per day plus trastuzumab and pertuzumab, or trastuzumab and pertuzumab alone. Trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks. Patients were stratified by hormone receptor positivity, previous HER2 treatment, and baseline geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A difference of 10% or greater between the two groups was sought. Efficacy analyses were by intention to treat; safety was assessed in all patients who received at least one dose of study treatment. In case of progression, all patients were offered trastuzumab emtansine. This trial is registered with ClinicalTrials.gov, number NCT01597414, and is completed. FINDINGS: Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screening G8 score (<=14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated progression free survival at 6 months was 46.2% (95% CI 30.2-60.7) with trastuzumab and pertuzumab versus 73.4% (56.6-84.6) with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (hazard ratio [HR] 0.65 [95% CI 0.37-1.12], p=0.12). At a median follow-up of 20.7 months (IQR 12.5-30.4), the median progression-free survival was 5.6 months (95% CI 3.6-16.8) with trastuzumab and pertuzumab versus 12.7 months (6.7-24.8) with the addition of metronomic oral cyclophosphamide. The most frequent grade 3-4 adverse events were hypertension (in six [15%] of 39 patients in the trastuzumab and pertuzumab group vs five [12%] of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group), diarrhoea (four [10%] vs five [12%]), dyspnoea (two [5%] vs four [10%]), fatigue (three [8%] vs two [5%]), pain (two [5%] vs two [5%]), and a thromboembolic event (0 [0%] vs four [10%]). Severe cardiac toxicities were occasionally observed in both groups. In the trastuzumab and pertuzumab group four patients died without progression, due to cardiac arrest during treatment (n=1), peritoneal infection (n=1), respiratory failure (n=1), and sudden death without a specified cause (n=1). In the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group, one patient died from heart failure. INTERPRETATION: Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or supersede the need for taxane chemotherapy in this population. FUNDING: F Hoffmann-La Roche. PMID- 29433964 TI - Clinical trials in older, less fit populations: an unmet need? PMID- 29433965 TI - HIV preexposure prophylaxis: An essential, safe and effective prevention tool for sexual health. AB - Preexposure prophylaxis of HIV with antiretroviral drugs is a prevention tool available in France since 2016, combined with the prevention methods already used (condoms, post-exposure treatment, rapid treatment of diagnosed HIV infections, etc.). It is targeted at populations at high risk of HIV infection, especially men who have sex with men, for whom traditional prevention methods are insufficient. We collected clinical research data, which resulted in the launch of preexposure prophylaxis in the United States and then elsewhere in the world, safety, tolerability and cost data, as well as ongoing research data (new molecules/methods of administration). We also provided an update of its use in France. PMID- 29433966 TI - Temporal changes in liver stiffness after Fontan operation: Results of serial magnetic resonance elastography. AB - BACKGROUND: The relationship between temporal progression of magnetic resonance elastography derived liver stiffness (MRE-LS) and progression of Fontan associated liver disease (FALD) is unknown. To assess this relationship, we hypothesized that progression of MRE-LS correlated with progression FALD severity and clinical outcomes. METHODS: Retrospective review of Fontan patients who had >1 liver MRE, 2010-2016. Annual change in MRE-LS was the quotient of the difference between baseline and subsequent MRE-LS, and the interval between scans. RESULTS: 22 patients were enrolled; median age 29(19-38) years, 14 (64%) males and 10 (46%) with atriopulmonary Fontan. Baseline and subsequent MRE-LS values were 5.4 +/- 1.1 kPa and 5.8 +/- 0.9 kPa" for clarity, interval between scans was 25 +/- 5 months, and annual change in MRE-LS was 0.3 +/- 0.2 kPa. Temporal change in MRE-LS correlated with temporal changes in model for end-stage liver disease (MELD) score (r = 0.84, p < 0.001) and model for end-stage liver disease excluding international normalized ratio (MELD-XI) score (r = 0.75, p = 0.001). The study cohort was divided into 2 groups using the mean annual change in MRE-LS as the cut point. Groups A and B comprised of patients with annual increase in MRE-LS >=0.3 kPa (n = 6) and <0.3 kPa (n = 16) respectively. Composite adverse event endpoint (death, heart-liver transplant listing, palliative care, hospitalization, paracentesis) was more common in Group A (4 of 6, 67%) compared to Group B (3 of 16, 19%), p = 0.13 although this did not reach statistical significance due to small sample size. CONCLUSIONS: Progression of MRE-LS correlated with clinical deterioration as measured by worsening liver disease severity scores and the occurrence of adverse events. PMID- 29433967 TI - Role of myocardial collagen degradation and fibrosis in right ventricle dysfunction in transposition of the great arteries after atrial switch. AB - BACKGROUND: Heart failure is a serious event in patients with transposition of the great arteries (D-TGA) after atrial redirection surgery. We aimed to determine the association between myocardial fibrosis and systolic and diastolic systemic right ventricle (sRV) dysfunction. METHODS: Diastolic and systolic function of sRV was prospectively assessed using echocardiography and cardiac magnetic resonance imaging (CMR) in 48 patients with atrially switched D-TGA and 26 healthy subjects. Diastolic function of the subaortic ventricle was assessed by echocardiography Doppler and DTI. In CMR, ejection fraction of sRV and wall stress defined as the product of the systolic blood pressure and volume/mass ratio were assessed. Fibrosis extent within sRV myocardium was evaluated using gadolinium-enhanced magnetic resonance and serum collagen turnover biomarkers. RESULTS: Late gadolinium enhancement (LGE) was found in 35% of D-TGA patients, and the collagen degradation biomarker pro-MMP1:TIMP1 ratio was significantly increased in D-TGA patients compared to healthy subjects (1.0 * 10-2vs. 2.5 * 10 2, p = 0.04). Increase in sRV wall stress was significantly associated with LGE (p = 0.01) and pro-MMP1:TIMP1 ratio (r = 0.77, p < 0.01). After adjustment for age, sex, BMI, blood pressure and cardiac treatment, pro-MMP1:TIMP1 ratio was the strongest determinant of sRVEF (R2 = 0.85, p < 0.01). Pro-MMP1:TIMP1 ratio was also significantly correlated with the early diastolic filling parameter E/E' (r = 0.53, p = 0.02), but this was not anymore the case after adjustment. CONCLUSIONS: Diastolic and systolic sRV dysfunction is related to myocardial collagen degradation and fibrosis. Research in medical therapies that reduce systemic sRV afterload and limit collagen degradation is warranted in this setting. PMID- 29433968 TI - Dynamic stress computed tomography myocardial perfusion for detecting myocardial ischemia: A systematic review and meta-analysis. AB - BACKGROUND: Comparing to SPECT and MRI, with higher temporal and spatial resolution and development of radiation dose reduction, myocardial computed tomography perfusion has emerged as a potential method for evaluation of hemodynamic myocardial ischemia. This meta-analysis systematically analyzed the performance of dynamic CT myocardial perfusion (DCTMP) to diagnose myocardial ischemia (MI) with clinically established reference methods [MR/SPECT/PET perfusion and fractional flow reserve (FFR)] as the reference standard. METHODS: We searched PubMed, Embase and web of science databases for all published studies that evaluated the accuracy of DCTMP to diagnose MI met our inclusion criteria. An exact binomial rendition of the bivariate mixed-effects regression model with test type as a random-effects covariate was performed to synthesize the available data. RESULTS: The search revealed 13 eligible studies including 482 patients. The pooled sensitivity and specificity of myocardial blood flow (MBF) were 0.83 (95% CI: 0.80 to 0.86) and 0.90 (95% CI: 0.88 to 0.91) at the segment level, 0.85 (95% CI: 0.80 to 0.88) and 0.81 (95% CI: 0.78 to 0.84) at the artery level, and 0.93 (95% CI: 0.82 to 0.98) and 0.82 (95% CI: 0.70 to 0.91), at the patient level, respectively. The high area under the sROC curves of MBF were 0.944 at segment level, 0.911 at vessel level and 0.949 at patient level, respectively. CONCLUSIONS: DCTMP has a high diagnostic accuracy in detecting myocardial ischemia and it may increase significantly at segment level in combined use of coronary CTA. PMID- 29433969 TI - Shift work is associated with reduced heart rate variability among men but not women. AB - BACKGROUND: Imbalance in the autonomic nervous system due to a disrupted circadian rhythm may be a cause of shift work-related cardiovascular diseases. OBJECTIVE: We aimed to determine the association between shift work and cardiac autonomic activity in blue-collar workers. METHODS: The study included 665 blue collar workers aged 18-68 years in different occupations from two Danish cohort studies. Time and frequency domain parameters of heart rate variability (HRV) were measured during sleep using the Actiheart monitor, and used as markers of cardiac autonomic function. Multiple linear regression analyses were used to investigate differences in HRV between day and shift workers. RESULTS: Shift workers had no significantly different HRV parameters than day workers, except for a lower VLF (B: 0.21; 95% CI: -0.36-0.05). The lower VLF was only present among non-night shift workers (p < 0.05) and not among night shift workers (p > 0.05). Results differed significantly by gender (p for interaction < 0.10): among men, shift work was negatively associated with RMSSD (B: -7.83; 95% CI: -14.28 1.38), SDNN (B: -7.0; 95% CI: -12.27-1.78), VLF (B: -0.27; 95% CI: -0.46-0.09) and Total Power (B: -0.61; 95% CI: -1.20-0.03), while among women, shift work was only associated with the LF/HF ratio (B: -0.29; 95% CI: -0.54-0.03). CONCLUSION: Shift work was particularly associated with lower HRV during sleep among men. This indicates that shift work causes imbalance in the autonomic nervous system among men, which might increase their risk of cardiovascular diseases. PMID- 29433970 TI - An evidence-based scoring system for prioritizing mosaic aneuploid embryos following preimplantation genetic screening. AB - The aim of this study was to devise an evidence-based scoring system for prioritizing mosaic aneuploid embryos for transfer. A retrospective analysis was performed of all sequential cytogenetic and molecular results on chorionic villi samples (n = 72,472) and products of conception (n = 3806) analysed at a single centre. The likelihood that a mosaic aneuploidy detected in chorionic villi samples will involve the fetus, the incidence of clinically significant fetal uniparental disomy in the presence of a mosaic in chorionic villi and the chance of the mosaicism culminating in miscarriage were used to generate a scoring system for prioritizing mosaic aneuploid embryos detected by preimplantation genetic screening. A composite score was obtained for each individual mosaic aneuploidy after assignment of an individual risk score based on the incidence/likelihood of each adverse outcome. A final additional score was assigned to viable full or mosaic aneuploidies with a well-defined phenotype. The higher the composite score the lower the priority for embryo transfer. In conclusion, due to the paucity of prospective studies on the actual transfer of mosaic aneuploid embryos, we suggest using this evidence-based scoring system to provide a useful tool for clinicians, embryologists and patients. PMID- 29433971 TI - Large-scale Sequencing of Testicular Germ Cell Tumour (TGCT) Cases Excludes Major TGCT Predisposition Gene. AB - : Testicular germ cell tumour (TGCT), the most common cancer in young men, has a significant heritable basis that has long raised questions as to the existence of underlying major high-penetrance susceptibility gene(s). To determine the contribution of rare gene mutations to the inherited risk of TGCT, we analysed germline whole-exome data for 919 TGCT cases and 1609 cancer-free controls. We compared frequencies between TGCT cases and controls of rare (<1%) and low frequency (1-5%) coding variants (1) individually and (2) collapsed at the gene level via burden testing (T1, disruptive; T2, all deleterious; and T3, all nonsynonymous) using Fisher's exact test with Bonferroni correction of significance thresholds. No individual variant or individual gene showed a significant association with TGCT after correction for multiple testing. In the largest whole-exome sequencing study of testicular cancer reported to date, our findings do not support the existence of a major high-penetrance TGCT susceptibility gene (of odds ratio >10 and allele frequency [combined]>0.01%). Owing to its power, this study cannot exclude the existence of susceptibility genes responsible for occasional TGCT families or of rare mutations that confer very modest relative risks. In concert with findings from genome-wide association studies, our data support the notion that inherited susceptibility is largely polygenic with substantial contribution from common variation. PATIENT SUMMARY: In the largest study of its kind, we sequenced ~20 000 genes in 919 men with testicular germ cell tumour (TGCT) and 1609 TGCT-free individuals and found no evidence of a single major gene underlying predisposition to TGCT (in the manner of BRCA1 for breast cancer). Instead, familial risk of TGCT is likely to be due to varying dosages of hundreds of minor genetic factors. PMID- 29433972 TI - Re: Adjuvant Sunitinib in High-risk Renal-cell Carcinoma After Nephrectomy. PMID- 29433973 TI - Role of Surveillance Biopsy with No Cancer as a Prognostic Marker for Reclassification: Results from the Canary Prostate Active Surveillance Study. AB - BACKGROUND: Many patients who are on active surveillance (AS) for prostate cancer will have surveillance prostate needle biopsies (PNBs) without any cancer evident. OBJECTIVE: To define the association between negative surveillance PNBs and risk of reclassification on AS. DESIGN, SETTING, AND PARTICIPANTS: All men were enrolled in the Canary Prostate Active Surveillance Study (PASS) between 2008 and 2016. Men were included if they had Gleason <=3+4 prostate cancer and <34% core involvement ratio at diagnosis. Men were prescribed surveillance PNBs at 12 and 24 mo after diagnosis and then every 24 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Reclassification was defined as an increase in Gleason grade and/or an increase in the ratio of biopsy cores to cancer to >=34%. PNB outcomes were defined as follows: (1) no cancer on biopsy, (2) cancer without reclassification, or (3) reclassification. Kaplan-Meier and Cox proportional hazard models were performed to assess the risk of reclassification. RESULTS AND LIMITATIONS: A total of 657 men met inclusion criteria. On first surveillance PNB, 214 (32%) had no cancer, 282 (43%) had cancer but no reclassification, and 161 (25%) reclassified. Among those who did not reclassify, 313 had a second PNB. On second PNB, 120 (38%) had no cancer, 139 (44%) had cancer but no reclassification, and 54 (17%) reclassified. In a multivariable analysis, significant predictors of decreased future reclassification after the first PNB were no cancer on PNB (hazard ratio [HR]=0.50, p=0.008), lower serum prostate specific antigen, larger prostate size, and lower body mass index. A finding of no cancer on the second PNB was also associated with significantly decreased future reclassification in a multivariable analysis (HR=0.15, p=0.003), regardless of the first PNB result. The major limitation of this study is a relatively small number of patients with long-term follow-up. CONCLUSIONS: Men who have a surveillance PNB with no evidence of cancer are significantly less likely to reclassify on AS in the PASS cohort. These findings have implications for tailoring AS protocols. PATIENT SUMMARY: Men on active surveillance for prostate cancer who have a biopsy showing no cancer are at a decreased risk of having worse disease in the future. This may have an impact on how frequently biopsies are required to be performed in the future. PMID- 29433974 TI - Re: Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. PMID- 29433976 TI - Rate of deficit accumulation in home care users with intellectual and developmental disabilities. AB - PURPOSE: To identify factors associated with the rate of deficit accumulation in a population of adults with intellectual and developmental disabilities (IDD). METHODS: A longitudinal analysis of administratively held clinical data collected at routine home care assessments across Ontario (Canada) using the Resident Assessment Instrument for Home Care (RAI-HC) was conducted using a cohort comprised of 5074 adults with IDD 18-99 years of age who had at least two home care assessments between April 1, 2003 and March 31, 2015. Rates of deficit accumulation were calculated across variables of interest. Incidence rate ratios and 95% confidence intervals are presented. Negative binomial regression models using a generalized estimating equation (GEE) approach were developed. RESULTS: Increasing age, Down syndrome, and living in a group home were significant predictors of deficit accumulation. Rates of deficit accumulation tended to be higher among prefrail and frail individuals; however, impaired cognition and impairment in activities of daily living were associated with slower deficit accumulation. The relationship between provision of nursing and therapy services and deficit accumulation is unclear. CONCLUSIONS: Frailty should be monitored among adults with IDD starting at age 40 years, those with Down syndrome, and those who live in group homes. PMID- 29433977 TI - High neighborhood incarceration rate is associated with cardiometabolic disease in nonincarcerated black individuals. AB - PURPOSE: To examine the association between residence in neighborhoods with high rates of incarceration and cardiometabolic disease among nonincarcerated individuals. METHODS: We used data from two community cohort studies (n = 1368) in Atlanta, Georgia-META-Health and Predictive Health (2005-2012)-to assess the association between neighborhood incarceration rate and cardiometabolic disease, adjusting for individual-level and neighborhood-level factors. We also examined the interaction between race and neighborhood incarceration rate. RESULTS: Individuals living in neighborhoods with high incarceration rates were more likely to have dyslipidemia (odds ratio [OR] = 1.47; 95% confidence interval [CI] = 1.03-2.09) and metabolic syndrome (OR = 1.67; 95% CI = 1.07-2.59) in fully adjusted models. Interactions between race and neighborhood incarceration rate were significant; black individuals living in neighborhoods with high incarceration rates were more likely to have hypertension (OR = 1.59; 95% CI = 1.01-2.49), dyslipidemia (OR = 1.77; 95% CI = 1.12-2.80), and metabolic syndrome (OR = 1.80; 95% CI = 1.09-2.99). CONCLUSIONS: Black individuals living in neighborhoods with high rates of incarceration have worse cardiometabolic health profiles. Criminal justice reform may help reduce race-specific health disparities in the United States. PMID- 29433975 TI - Refined Analysis of Prostate-specific Antigen Kinetics to Predict Prostate Cancer Active Surveillance Outcomes. AB - BACKGROUND: For men on active surveillance for prostate cancer, utility of prostate-specific antigen (PSA) kinetics (PSAk) in predicting pathologic reclassification remains controversial. OBJECTIVE: To develop prediction methods for utilizing serial PSA and evaluate frequency of collection. DESIGN, SETTING, AND PARTICIPANTS: Data were collected from men enrolled in the multicenter Canary Prostate Active Surveillance Study, for whom PSA data were measured and biopsies performed on prespecified schedules. We developed a PSAk parameter based on a linear mixed-effect model (LMEM) that accounted for serial PSA levels. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of diagnostic PSA and/or PSAk with time to reclassification (increase in cancer grade and/or volume) was evaluated using multivariable Cox proportional hazards models. RESULTS AND LIMITATIONS: A total of 851 men met the study criteria; 255 (30%) had a reclassification event within 5 yr. Median follow-up was 3.7 yr. After adjusting for prostate size, time since diagnosis, biopsy parameters, and diagnostic PSA, PSAk was a significant predictor of reclassification (hazard ratio for each 0.10 increase in PSAk=1.6 [95% confidence interval 1.2-2.1, p<0.001]). The PSAk model improved stratification of risk prediction for the top and bottom deciles of risk over a model without PSAk. Model performance was essentially identical using PSA data measured every 6 mo to those measured every 3 mo. The major limitation is the reliability of reclassification as an end point, although it drives most treatment decisions. CONCLUSIONS: PSAk calculated using an LMEM statistically significantly predicts biopsy reclassification. Models that use repeat PSA measurements outperform a model incorporating only diagnostic PSA. Model performance is similar using PSA assessed every 3 or 6 mo. If validated, these results should inform optimal incorporation of PSA trends into active surveillance protocols and risk calculators. PATIENT SUMMARY: In this report, we looked at whether repeat prostate-specific antigen (PSA) measurements, or PSA kinetics, improve prediction of biopsy outcomes in men using active surveillance to manage localized prostate cancer. We found that in a large multicenter active surveillance cohort, PSA kinetics improves the prediction of surveillance biopsy outcome. PMID- 29433978 TI - Deconstructing a disparity: explaining excess preterm birth among U.S.-born black women. AB - PURPOSE: To determine components of excess preterm birth (PTB) rates for U.S. born black women relative to both foreign-born black women and U.S.-born white women attributable to differences in observed sociodemographic, behavioral, and medical risk factors. METHODS: Using the 2013 U.S. natality files, we used Oaxaca Blinder decomposition on the absolute scale to estimate the contribution of the group differences in the prevalence of PTB predictors between U.S.- and foreign born black women and U.S.-born black and U.S.-born white women. RESULTS: U.S. born blacks had a 3.2 (95% confidence interval: 3.0-3.5) and 4.4 (95% confidence interval: 4.3-4.5) percentage point higher risk of PTB than foreign-born blacks and U.S.-born whites, respectively. The variables in the models explained between 18% and 27% of the PTB disparities. Differences in paternal acknowledgment (about 12%), maternal hypertension (about 7%-11%), and maternal education (about 6%-10%) explained the largest proportion of these disparities. CONCLUSIONS: Programs and policies that address both distal and proximate factors, including the social determinants of health and the prevention and management of hypertension, may reduce the higher rates of PTB among U.S.-born black women compared to foreign born black women and U.S.-born white women. PMID- 29433979 TI - Marrow Hypocellularity, But Not Residual Blast Count or Receipt of Reinduction Chemotherapy, Is Prognostic on Day-14 Assessment in Acute Myeloid Leukemia Patients With Morphologic Residual Disease. AB - BACKGROUND: Induction chemotherapy for acute myeloid leukemia (AML) is based on the "7+3" cytarabine/anthracycline regimen. A nonhypocellular day 14 (D14) bone marrow sample with a blast count > 5% to 10% is suggestive of residual leukemia, for which a second course of induction chemotherapy has been recommended. Although the prognostic value of D14 bone marrow findings has been established, its use as a decision point is controversial because the benefit of repeat induction has been questioned. PATIENTS AND METHODS: In the present single-center retrospective study of 113 patients with newly diagnosed AML, we evaluated the role of cellularity on the clinical outcomes of patients with residual morphologic leukemia (blasts >= 5%). Among 64 patients with D14 bone marrow samples, 31 had residual morphologic leukemia. RESULTS: The complete remission (CR) rates were greater for the hypocellular (11 of 16) than for the nonhypocellular (4 of 15) patients (P = .03). The median overall survival (OS) for the hypocellular D14 patients was longer than that for the nonhypocellular patients (17 vs. 8 months; P = .02). No significant difference between the receipt of reinduction therapy and CR or OS was found on logistic or survival model analysis. The specificity for residual leukemia on D14 bone marrow samples was better for cellularity >= 20% and blasts >= 20% than for blasts >= 5%. CONCLUSION: The results of our study have shown that patients with < 20% cellularity and < 20% blasts on the D14 bone marrow assessment should continue observation until recovery rather than receive additional immediate therapy. PMID- 29433980 TI - Fatty infiltration and muscle atrophy of the rotator cuff in stemless total shoulder arthroplasty: a prospective cohort study. AB - BACKGROUND: The influence of preoperative rotator cuff fatty infiltration (FI) and muscle atrophy (MA) on the postoperative outcome of total shoulder arthroplasty (TSA) has only rarely been investigated and reported in the literature. We hypothesized that more FI and MA would be associated with a worse postoperative functional outcome. METHODS: This prospective cohort study included 63 patients (31 female and 32 male patients; mean age, 71 years [range, 53-89 years; standard deviation, 7 years]) with primary osteoarthritis of the shoulder operated on with anatomic stemless TSA. Preoperatively and at 3 months and 1 year after the operation, the functional outcome (QuickDASH [short version of Disabilities of the Arm, Shoulder and Hand questionnaire] score) and range of motion (ROM) (goniometer) and strength (dynamometer) for abduction at the scapular plane and for external rotation were measured. The degree of preoperative FI and MA was evaluated using computed tomography scans according to the Goutallier classification and Warner classification, respectively, for the supraspinatus and infraspinatus. RESULTS: We found clinically and statistically significant improvements in functional outcome, strength, and ROM at both 3 months and 1 year of follow-up compared with those preoperatively. The Pearson correlation coefficient (r) showed significant correlations between preoperative supraspinatus and infraspinatus FI and MA and preoperative and 1-year postoperative shoulder abduction and external rotation strength but not ROM. However, we found no influence of the rotator cuff FI and MA on the functional outcome after TSA. CONCLUSION: We demonstrated a significant correlation between rotator cuff FI and MA and strength but not ROM of the shoulder joint. PMID- 29433982 TI - Bimolecular Fluorescence Complementation of Alpha-synuclein Demonstrates its Oligomerization with Dopaminergic Phenotype in Mice. AB - Alpha-synuclein (alphaSyn) is encoded by the first causal gene identified in Parkinson's disease (PD) and is the main component of Lewy bodies, a pathological hallmark of PD. aSyn-based animal models have contributed to our understanding of PD pathophysiology and to the development of therapeutics. Overexpression of human wildtype alphaSyn by viral vectors in rodents recapitulates the loss of dopaminergic neurons from the substantia nigra, another defining pathological feature of the disease. The development of a rat model exhibiting bimolecular fluorescence complementation (BiFC) of alphaSyn by recombinant adeno-associated virus facilitates detection of the toxic alphaSyn oligomers species. We report here neurochemical, neuropathological and behavioral characterization of BiFC of alphaSyn in mice. Overexpression and oligomerization of alphaSyn through BiFC is detected by conjugated fluorescence. Reduced striatal dopamine and loss of nigral dopaminergic neurons are accompanied neuroinflammation and abnormal motor activities. Our mouse model may provide a valuable tool to study the role of alphaSyn in PD and to explore therapeutic approaches. PMID- 29433981 TI - The cost of Alzheimer's disease in China and re-estimation of costs worldwide. AB - INTRODUCTION: The socioeconomic costs of Alzheimer's disease (AD) in China and its impact on global economic burden remain uncertain. METHODS: We collected data from 3098 patients with AD in 81 representative centers across China and estimated AD costs for individual patient and total patients in China in 2015. Based on this data, we re-estimated the worldwide costs of AD. RESULTS: The annual socioeconomic cost per patient was US $19,144.36, and total costs were US $167.74 billion in 2015. The annual total costs are predicted to reach US $507.49 billion in 2030 and US $1.89 trillion in 2050. Based on our results, the global estimates of costs for dementia were US $957.56 billion in 2015, and will be US $2.54 trillion in 2030, and US $9.12 trillion in 2050, much more than the predictions by the World Alzheimer Report 2015. DISCUSSION: China bears a heavy burden of AD costs, which greatly change the estimates of AD cost worldwide. PMID- 29433984 TI - COPD exacerbations: transforming outcomes through research. PMID- 29433985 TI - Non-replication of neurophysiological predictors of non-response to rTMS in depression and neurophysiological data-sharing proposal. PMID- 29433983 TI - Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis. AB - Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p=0.0407) and overall survival (hazard ratio of 2.23, p=0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing. PMID- 29433986 TI - Surgical and Oncological Outcomes in Patients After Vascularised Flap Reconstruction for Locoregionally Advanced Penile Cancer. AB - BACKGROUND: Treatment of locoregionally advanced penile squamous cell carcinoma (LAPSCC) is challenging. The exact role (in terms of oncological benefit) of extensive surgery is not well established. Moreover, surgery invariably leads to large defects requiring reconstructive surgery. Rectus abdominis myocutaneous (RAM) and abdominal advancement flaps have an independent and constant blood supply, are easily harvested, and provide substantial skin coverage and soft tissue. OBJECTIVE: To determine the surgical and oncological outcomes in patients with LAPSCC undergoing surgical resection with RAM flaps. DESIGN, SETTING, AND PARTICIPANTS: From 2002 to 2016, a multi-institutional database identified 15 LAPSCC patients undergoing flap reconstructions. INTERVENTION: Local surgical resection with RAM or abdominal advancement flap reconstruction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Perioperative and pathologic data were collected. Postoperative complications were identified using the Clavien-Dindo classification for surgical complications. RESULTS AND LIMITATIONS: Fifteen patients (median age 61 yr) were treated, ten with curative intent. Thirteen patients received induction chemotherapy. Thirteen of the 15 patients (87%) experienced wound complications, including five Clavien-Dindo grade III complications. In 11/15 patients (73%), the disease recurred (median recurrence free interval 106 d). The majority of recurrences (91%) were locoregional, and in four cases the patient also had lesions in distant organs. Ten of the 15 patients (67%) died of their disease. The overall median follow-up interval was 10.5 mo. The study was limited by its retrospective design, the absence of quality-of-life measurements, and the cohort size. CONCLUSIONS: The results of this study show that surgical resection with reconstruction is associated with a risk of perioperative complications, including high-grade Clavien-Dindo complications. With a cure rate of 27%, surgery must be carefully considered and there is a need for alternative treatments. Lack of robust quality-of-life-data is also a serious shortcoming in the decision process for this patient category. PATIENT SUMMARY: Surgery in locoregionally advanced penile cancer has a low cure rate. Reconstruction of defects is surgically feasible, albeit with a high risk of complications. Furthermore, decision-making lacks robust data on quality of life after surgery. PMID- 29433987 TI - Poor Follow-up After Elevated Prostate-specific Antigen Tests: A Population-based Cohort Study. AB - BACKGROUND: Although prostate-specific antigen (PSA) testing is common, little is known about the pattern of retesting by either PSA values or subsequent prostate biopsies. Poor follow-up of high PSA values may lead to delayed diagnosis. OBJECTIVE: To estimate the probabilities of follow-up (including retesting, prostate biopsies, diagnosis, and cause-specific death) for men undergoing prostate cancer testing at a population level. DESIGN, SETTING, AND PARTICIPANTS: Cohort study design for men living in Stockholm with no previous diagnosis of prostate cancer between 2003 and 2015. Men were linked to the national health and population registries in Sweden. We report follow-up for men aged 50-79 yr at 2003 or at their index PSA test. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: State probabilities with 95% confidence intervals (CIs) were calculated using multistate Markov models. RESULTS AND LIMITATIONS: Among men not previously diagnosed with prostate cancer with an initial PSA value of >=10ng/ml, the proportions at 1 yr with no subsequent testing or only elevated PSA test values >3ng/ml were 21.7% (95% CI: 19.5, 23.9), 25.2% (95% CI: 23.9, 26.6), and 47.7% (95% CI: 46.2, 49.1) for those aged 50-59, 60-69, and 70-79 yr, respectively. No significant changes were noticed when stratifying by comorbidities. Limitations include the lack of detail from patient medical charts. This detail would have allowed for more accurate assessment of appropriate clinical follow-up. CONCLUSIONS: Regardless of medical history, a large proportion of men with PSA>=10ng/ml were not followed appropriately at 1 yr after the index PSA test. This may partially explain why opportunistic testing is not as effective as screening within trials to reduce prostate cancer mortality. PATIENT SUMMARY: For men aged 50-69 yr, who undertake a prostate-specific antigen (PSA) test, a PSA level of >10ng/ml should prompt further investigation. However, we found that one out of 10 of these men did not receive repeat testing within 1 yr of the initial test. This may partially explain why opportunistic prostate cancer testing is less effective than screening trials. PMID- 29433988 TI - Effectiveness and Harms of Using Kidneys with Small Renal Tumors from Deceased or Living Donors as a Source of Renal Transplantation: A Systematic Review. AB - CONTEXT: Kidney transplantation is the best treatment for patients with end-stage renal disease. Incidence of small renal masses (SRMs), which most frequently are renal cell carcinomas (RCCs), is highest in patients aged >60 yr. The increasing age of donors can lead to the diagnosis of a higher number of SRMs when assessing the patient for transplantation, and so can theoretically decrease the number of kidneys suitable for transplantation. Aiming to increase the pool of kidneys suitable for transplantation, a number of studies have reported their experience using kidneys with SRMs for transplantation. OBJECTIVE: To systematically review all available evidence on the effectiveness and harm of using kidneys with SRMs as a source of transplantation. EVIDENCE ACQUISITION: A computerized bibliographic search of the Medline, Embase, and Cochrane databases was performed for all studies reporting outcomes of adult renal transplantation using kidneys with SRMs. EVIDENCE SYNTHESIS: Nineteen studies enrolling 109 patients were included and synthesized narratively. The mean recipient age was 44.2 yr, and kidneys used were retrieved from living donors in 86% (94/109) of cases. Tumor excision was performed ex vivo in all cases except for two. The vast majority of excised tumors were RCCs (88/109 patients), and clear-cell subtype was most common. The mean tumor size was 2cm (range 0.5-6.0cm) and tumor grade was G1-G2 in 93% (75/81) of patients. With a mean follow-up of 39.9 mo, overall survival rates at 1, 3, and 5 yr were 97.7%, 95.4%, and 92%, respectively, and the mean graft survival rates 99.2%, 95%, and 95.6%, respectively. Only one local relapse occurred 9 yr after transplantation, which was managed conservatively. Functional outcomes, although infrequently reported, appear to be similar to those of conventional transplants, with 1.6% of these patients needing reoperation. CONCLUSIONS: The current literature, although with low-level evidence, suggests that kidneys with excised SRMs are an acceptable source of transplantation without compromising oncological outcomes and with similar functional outcomes to other donor kidneys. PATIENT SUMMARY: Renal transplantation using a kidney with a small renal mass does not appear to increase the risk of cancer recurrence and can be a good option for selected patients after appropriate counseling and allocation. PMID- 29433989 TI - Downregulation of long non-coding RNA ENSG00000241684 is associated with poor prognosis in advanced clear cell renal cell carcinoma. AB - OBJECTIVE: In order to identify potential novel biomarkers of advanced clear cell renal cell carcinoma (ccRCC), we re-evaluated published long non-coding RNA (lncRNA) expression profiling data. MATERIALS AND METHODS: The lncRNA expression profiles in ccRCC microarray dataset GSE47352 were analyzed and an independent cohort of 61 clinical samples including 21 advanced and 40 localized ccRCC patients was used to confirm the most statistically significant lncRNAs by real time PCR. Next, the relationships between the selected lncRNAs and ccRCC patients' clinicopathological features were investigated. The effects of LncRNAs on the invasion and proliferation of renal carcinoma cells were also investigated. RESULTS: The PCR results in a cohort of 21 advanced ccRCC and 40 localized ccRCC tissues were used for confirmation of the selected lncRNAs which were statistically most significant. The PCR results showed that the expression of three LncRNA (ENSG00000241684, ENSG00000231721 and NEAT1) were significantly downregulated in advanced ccRCC. Kaplan-Meier analysis revealed that reduced expression of LncRNA ENSG00000241684 and NEAT1 were significantly associated with poor overall survival. The univariate and multivariate Cox regression indicated LncRNA ENSG00000241684 had significant hazard ratios for predicting clinical outcome. LncRNA ENSG00000241684 expression was negatively correlated with pTNM stage. Overexpression of ENSG00000241684 significantly impaired cell proliferation and reduced the invasion ability in 786-O and ACHN cells. CONCLUSION: lncRNAs are involved in renal carcinogenesis and decreased lncRNA ENSG00000241684 expression may be an independent adverse prognostic factor in advanced ccRCC patients. PMID- 29433990 TI - Follow-up after curative treatment for oral squamous cell carcinoma. A critical appraisal of the guidelines and a review of the literature. AB - The oral cavity is the commonest subsite of head and neck squamous cell carcinoma (HNSCC). Because of the rising incidence and increasing survival, more patients will be enrolled in a routine follow-up program. This review gives an overview of the evidence and guideline recommendations concerning follow-up after oral squamous cell carcinoma (OSCC). There is limited evidence concerning the effectiveness of follow-up after OSCC. This lack of evidence is reflected in a variation in guideline recommendations with respect to test interval and duration (i.e. for 3-5 years or lifelong). Most studies on the value of routine follow-up after curative treatment include all HNSCC subsites. The available literature shows, that these subsites have a different timing of recurrence and a different risk of second primary tumors at different locations. This leaves no rationale for applying the same follow-up program to each of the HNSCC subsites. There is agreement in the literature that OSCC follow-up can either be discontinued after two or three years or should be lifelong based on the risk of second primary tumors. Many authors advocate a personalized follow-up regimen that is based on the risk of new disease rather than a one-size-fits-all surveillance program. The literature is conflicting about the survival benefits of asymptomatic detection of new disease for HNSCC. To aid the development of evidence-based follow-up advise after OSCC, future research should focus on risk stratification, the value of symptom-free detection of recurrences and the active role that patients might play in determining their own follow-up regimen. PMID- 29433991 TI - Changes in volume, clinical practice and outcome after reorganisation of oesophago-gastric cancer care in England: A longitudinal observational study. AB - AIM: The centralisation of oesophago-gastric (O-G) cancer services in England was recommended in 2001, partly because of evidence for a volume-outcome effect for patients having surgery. This study investigated the changes in surgical services for O-G cancer and postoperative mortality since centralisation. METHODS: Patients with O-G cancer who had an oesophageal or gastric resection between April 2003 and March 2014 were identified in the national Hospital Episodes Statistics database. We derived information on the number of NHS trusts performing surgery, their surgical volume, and the number of consultants operating. Postoperative mortality was measured at 30 days, 90 days and 1 year. Logistic regression was used to examine how surgical outcomes were related to patient characteristics and organisational variables. RESULTS: During this period, 29 205 patients underwent an oesophagectomy or gastrectomy. The number of NHS trusts performing surgery decreased from 113 in 2003-04 to 43 in 2013-14, and the median annual surgical volume in NHS trusts rose from 21 to 55 patients. The annual 30 day, 90 day and 1 year mortality decreased from 7.4%, 11.3% and 29.7% in 2003-04 to 2.5%, 4.6% and 19.8% in 2013-14, respectively. There was no evidence that high-risk patients were not undergoing surgery. Changes in NHS trust volume explained only a small proportion of the observed fall in mortality. CONCLUSION: Centralisation of surgical services for O-G cancer in England has resulted in lower postoperative mortality. This cannot be explained by increased volume alone. PMID- 29433992 TI - Changes in Statin Prescription Patterns in Patients Admitted to an Australian Geriatric Subacute Unit. AB - BACKGROUND: Assessment of demographic and clinical factors influencing the decision of statin discontinuation in the elderly population admitted to subacute geriatric unit. The aim of this study is to assess the clinical factors impacting the decision-making process of statin discontinuation in the elderly. METHODS: We retrospectively assessed changes in statin discontinuation and prescription among patients (>=60 years old) discharged from a geriatric evaluation and management unit by reviewing hospital digital medical records at Western Health - The Williamstown Hospital over a 12-month period from 4 February 2012 until 4 February 2013 inclusive. The main outcome of the study was to determine the independent predictors of statin discontinuation using logistic regression analysis. RESULTS: Of the studied population, 46% were already prescribed statins prior to their admission. Statins were discontinued in 17.5% of patients at discharge. Predictors of statin de-prescription included octogenarian status, primary prevention indication, poor functional recovery, residential care facility discharge destination and lower cognitive function. The presence of previous cardiovascular disease history and the burden of comorbidities were not predictors of statin discontinuation. CONCLUSIONS: We observed that factors that conveyed poor prognosis such as advanced age, poor functional recovery, worse cognitive function, being discharged to a residential care facility as well as primary prevention indication for statin prescription are predictors of statin discontinuation in the geriatric unit. PMID- 29433993 TI - Scar acceptance after pediatric urologic surgery. AB - INTRODUCTION: Patients undergo pediatric urologic surgery as infants and young children. OBJECTIVE: The purpose of the study was to evaluate the evolution of surgical scars over several years in order to inform parents and surgeons on the true cosmetic impact of pediatric surgery and evaluate patient scar satisfaction. STUDY DESIGN: This was a cross-sectional study where patients who have undergone urologic surgery at a young age are evaluated years later for scar satisfaction via an abbreviated validated questionnaire. Scar length currently was measured and compared with immediate postoperative scar length to assess for growth. RESULTS: Eighty-two children were evaluated with a median age (interquartile range) at the time of surgery and at the time of the study of 1 year (0.6-3 years) and 7 years (3-11 years), respectively. Pyeloplasty (48.8%), ureteral reimplantation/ureterocele reconstruction (41.5%) and other (9.8%) surgical techniques were included. No bother was reported in 84.0% of families. Surgical approach (robotic/laparoscopic vs. open) did not influence whether families reported very pleased/pleased versus neutral/somewhat bothered attitudes (p = 0.094). At time of surgery median scar length for all open surgical approaches (N = 65) was 4 cm (IQR 4-4.5 cm) and at time of the study scars were 6 cm (IQR 5-8 cm). For laparoscopic incisions, median length at time of surgery was 0.8 cm (IQR 0.8-1.1 cm) and at a mean follow up time of 2.3 years median scar length was 1.1 cm (IQR 1-1.5 cm). By race, Asian experienced the lowest percent change in scar length 0.3%, then Caucasian 0.8%, Latino 1.4% and self-described other ethnicity 2.0%. DISCUSSION: As predicted, scars grow in length over time in either open or minimally surgical approaches. Depending on patient race, scar growth varied. Regardless, survey results did not vary based on surgical approach, type of surgery or race of survey taker Summary figure. CONCLUSIONS: The majority of families are pleased with overall scar appearance after undergoing major pediatric urologic surgery. Scars tend to grow in length overtime with less growth noted in Asian children and flank incisions. PMID- 29433994 TI - Ubiquinone, ubiquinol, 4-hydroxybenzoic acid... What 'coenzyme Q10' should we care about in multiple system atrophy? PMID- 29433995 TI - Precision nutrition for prevention and management of type 2 diabetes. AB - Precision nutrition aims to prevent and manage chronic diseases by tailoring dietary interventions or recommendations to one or a combination of an individual's genetic background, metabolic profile, and environmental exposures. Recent advances in genomics, metabolomics, and gut microbiome technologies have offered opportunities as well as challenges in the use of precision nutrition to prevent and manage type 2 diabetes. Nutrigenomics studies have identified genetic variants that influence intake and metabolism of specific nutrients and predict individuals' variability in response to dietary interventions. Metabolomics has revealed metabolomic fingerprints of food and nutrient consumption and uncovered new metabolic pathways that are potentially modified by diet. Dietary interventions have been successful in altering abundance, composition, and activity of gut microbiota that are relevant for food metabolism and glycaemic control. In addition, mobile apps and wearable devices facilitate real-time assessment of dietary intake and provide feedback which can improve glycaemic control and diabetes management. By integrating these technologies with big data analytics, precision nutrition has the potential to provide personalised nutrition guidance for more effective prevention and management of type 2 diabetes. Despite these technological advances, much research is needed before precision nutrition can be widely used in clinical and public health settings. Currently, the field of precision nutrition faces challenges including a lack of robust and reproducible results, the high cost of omics technologies, and methodological issues in study design as well as high-dimensional data analyses and interpretation. Evidence is needed to support the efficacy, cost effectiveness, and additional benefits of precision nutrition beyond traditional nutrition intervention approaches. Therefore, we should manage unrealistically high expectations and balance the emerging field of precision nutrition with public health nutrition strategies to improve diet quality and prevent type 2 diabetes and its complications. PMID- 29433996 TI - Gelatin Thoracic Paravertebral Teaching Model for Placement of a Continuous Infusion Catheter in the Extrathoracic Paravertebral Space. AB - OBJECTIVE: Our aim was to develop an ultrasound-guided training curriculum for continuous infusion catheter placement in the paravertebral space and to create a gelatin thoracic spine-rib model for use in this training. We sought to create a model that was inexpensive and reusable such that multiple participants could use one model during training. DESIGN: The model was prepared by embedding a firm foam thoracic spine replica with bilateral attached ribs into an opaque gelatin mixture. Once solidified, a preselected area was excised on each side, such that the model could be easily refilled with new gelatin blocks for use by each participant. This allowed for multiple participants to use the same model while eliminating confusion with prior tract marks. SETTING: The Marcia and Eugene Applebaum Simulation Learning Institute, Beaumont Hospital, Royal Oak, MI; a private nonprofit tertiary care hospital associated with the OUWB School of Medicine, Rochester, MI. PARTICIPANTS: Fifty-two medical students and general surgery residents underwent a 30-minute didactic session on ultrasound technique for catheter placement followed by practice on the gelatin model. RESULTS: The texture and echogenicity of the model were subjectively comparable to those of tissue in vivo and the osseous elements of the spine in the model were clearly identified using ultrasound. The exchangeable catheter placement area provided an efficient and effective method to test accurate performance in catheter placement by multiple users. Participants increased their confidence in the use of ultrasound for this procedure. CONCLUSIONS: To date, this is the first gelatin thoracic spine-rib model that has been used to teach ultrasound-guided catheter insertion into the paravertebral space, with removable testing areas that can be used by multiple users. This model can provide an inexpensive training tool that can be used in a surgical simulation setting. PMID- 29433997 TI - In vitro activities of carbapenems in combination with amikacin, colistin, or fosfomycin against carbapenem-resistant Acinetobacter baumannii clinical isolates. AB - Carbapenem-resistant Acinetobacter baumannii clinical isolates (n=23) were investigated for carbapenem resistance mechanisms and in vitro activities of carbapenems in combination with amikacin, colistin, or fosfomycin. Major carbapenem resistance mechanism was OXA-23 production. The vast majority of these isolates were OXA-23-producing A. baumannii ST195 and ST542, followed by novel STs, ST1417, and ST1423. The interuption of carO by a novel insertion sequence, ISAba40, was found in two isolates. The combinations of imipenem and fosfomycin, meropenem and amikacin, imipenem and amikacin, and imipenem and colistin were synergistic against carbapenem-resistant A. baumannii by 65.2%, 46.2%, 30.8%, and 17.4%, respectively. Surprisingly, the combination of imipenem and fosfomycin was the most effective in this study against A. baumannii, which is intrinsically resistant to fosfomycin. Imipenem and fosfomycin inhibit cell wall synthesis; therefore, fosfomycin may be an adjuvant and enhance the inhibition of cell wall synthesis of carbapenem-resistant A. baumannii when combined with imipenem. PMID- 29433998 TI - Are pathogenic intestinal bacteria present in stool specimens from patients with chronic heart failure? AB - It has been reported that patients with chronic heart failure exhibit an intestinal overgrowth of primary gut bacterial pathogens, such as Shigella spp., Salmonella spp., Campylobacter spp., and Yersinia enterocolitica. We failed to reproduce these findings in a cohort of 39 patients admitted to the hospital with decompensated heart failure by means of conventional stool bacterial cultures and a multiplexed polymerase chain reaction assay. PMID- 29433999 TI - Evaluation of a human adenovirus viral load assay using the Altona RealStar(r) PCR test. AB - This study evaluated the performance of the Altona Diagnostics RealStar(r) Adenovirus Research Use Only (RUO) real-time PCR reagents for HAdV quantitation in plasma samples from immunodeficient patients. The assay was linear from 2.30 9.17 log10 copies/mL (coefficient of determination; R2=0.998) with limits of detection and quantification of 2.19 log10 and 2.30 log10 copies/mL (>95% positivity rate), respectively. Assay precision was highly reproducible with coefficients of variance ranging from 0% to 4.7%. A comparison of 66 matched samples showed good agreement (R2=0.845) between the Altona and the reference laboratory assay, with an average negative bias (-0.24 log10 copies/mL). Genotyping analysis demonstrated that HAdV species B and C accounted for 77% of the positive samples. A significant (>=0.9 log10) difference in quantitation between both tests was found for three HAdV types (HAdV types A12, B14 and F41). In conclusion, the Altona RealStar(r) test is a reliable and sensitive assay for HAdV DNA quantitation. PMID- 29434000 TI - Impact of inter-genotypic recombination and probe cross-reactivity on the performance of the Abbott RealTime HCV Genotype II assay for hepatitis C genotyping. AB - The Abbott RealTime HCV Genotype II assay (Abbott-RT-HCV assay) is a real-time PCR based genotyping method for hepatitis C virus (HCV). This study measured the impact of inter-genotypic recombination and probe cross-reactivity on the performance of the Abbott-RT-HCV assay. 517 samples were genotyped using the Abbott-RT-HCV assay over a one-year period, 34 (6.6%) were identified as HCV genotype 1 without further subtype designation raising the possibility of inaccurate genotyping. These samples were subjected to confirmatory sequencing. 27 of these 34 (79%) samples were genotype 1b while five (15%) were genotype 6. One HCV isolate was an inter-genotypic 1a/4o recombinant. This is a novel natural HCV recombinant that has never been reported. Inter-genotypic recombination and probe cross-reactivity can affect the accuracy of the Abbott-RT-HCV assay, both of which have significant implications on antiviral regimen choice. Confirmatory sequencing of ambiguous results is crucial for accurate genotyping. PMID- 29434001 TI - Validation and implementation of PlanovaTM BioEX virus filters in the manufacture of a new liquid intravenous immunoglobulin in China. AB - There is a continuous need to improve the viral safety of plasma products, and we here report the development and optimization of a manufacturing-scale virus removal nanofiltration step for intravenous immunoglobulin (IVIG) using the recently introduced PlanovaTM BioEX filter. IVIG throughput was examined for various operating parameters: transmembrane pressure, temperature, protein concentration, and prefiltration methods. The developed procedure was based on filtering undiluted process solution (50.0 g/l IVIG) under constant transmembrane pressure filtration at 294 kPa and 25 degrees C following prefiltration with a 0.1 MUm MILLEX VV filter. The recovery of IgG was approximately 98%, and no substantial changes in biochemical characteristics were observed before and after nanofiltration in scaled-up production. A viral clearance validation study with parvovirus under worst-case conditions performed at the National Institutes for Food and Drug Control of China (NIFDC) showed PPV logarithmic reduction value (LRV) > 4. Improved viral safety of IVIG can be assured by implementing a Planova BioEX nanofiltration step to ensure effective parvovirus clearance under conditions providing excellent protein recovery and no detectable impact on product biochemical properties. This plasma-derived IVIG product is the first to be certified for parvovirus safety by the NIFDC in China. PMID- 29434002 TI - Young Driver Compliance With Graduated Driver Licensing Restrictions Before and After Implementation of a Decal Provision. AB - PURPOSE: In May 2010, New Jersey implemented the first-in-the-nation decal provision to increase intermediate drivers' compliance with Graduated Driver Licensing restrictions and ultimately reduce young driver crashes. We previously found that the provision was associated with a 9.5% decline in crash rates. This study evaluates whether the decal provision was associated with an increase in compliance with passenger and nighttime restrictions. METHODS: We analyzed New Jersey driver licensing and crash data from 2008 through 2012. We used the quasi induced exposure method to estimate prevalence of noncompliance among 20,593 nonresponsible 17- to 20-year-old intermediate drivers involved in crashes. Multivariate log-binomial regression models compared the monthly prevalence of noncompliance with restrictions pre and post implementation, adjusted for age, sex, season, and area income and population density. Analyses were conducted in 2016-2017. RESULTS: Overall estimated noncompliance with the nighttime restriction was 1.75% before and 1.71% after the decal provision (p = .83). Noncompliance with the passenger restriction was 8.68% before and 8.31% after (p = .35). Introduction of the decal provision was not associated with a change in noncompliance rates. CONCLUSIONS: Compliance rates among New Jersey intermediate drivers were high both before and after the decal provision. Findings do not suggest that the decline in crash rates following implementation was because of increased compliance with nighttime or passenger driving restrictions. Additional research is needed to understand mechanisms by which decal provisions may reduce young driver crashes. PMID- 29434003 TI - Effect of the Online Game Shutdown Policy on Internet Use, Internet Addiction, and Sleeping Hours in Korean Adolescents. AB - PURPOSE: Internet addiction has emerged as a major public health problem worldwide. In November 2011, the South Korean government implemented an online game shutdown policy, lasting from 12:00 to 6:00 am, as a means of preventing Internet addiction in adolescents aged 15 or below. This study analyzed the effect of this shutdown policy on adolescent Internet use, addiction, and sleeping hours. METHODS: We analyzed data collected from the Korea Youth Risk Behavior Web-based Survey from 2011 to 2015. Respondents were divided into two groups by age: aged 15 or below (male = 76,048, female = 66,281) and aged 16 or above (male = 52,568, female = 49,060). A difference-in-difference analysis was used to evaluate the effect of this shutdown policy. RESULTS: In 2012, which is immediately following policy enforcement, daily amount of Internet use (in minutes) decreased more in adolescents affected by the policy (i.e., the aged 15 or below group). However, it steadily increased in 2013, 2014, 2015, and showed no meaningful long-term improvements 4 years after policy implementation (-3.648 minutes in 2012 [p = .001], -3.204 minutes in 2013 [p = .011], -1.140 minutes in 2014 [p = .384], and 2.190 minutes in 2015 [p = .107]). The shutdown policy did not alter Internet addiction or sleeping hours. Interestingly, female adolescents, adolescents with low academic performance, and adolescents with low exercise levels exhibited comparatively stronger and longer lasting initial declines in Internet usage. CONCLUSIONS: The shutdown policy had practically insignificant effects in reducing Internet use for target adolescents. Thus, policymakers aiming to reduce or prevent Internet addiction should use different strategies. PMID- 29434004 TI - A Systematic Review of Adolescent Girl Program Implementation in Low- and Middle Income Countries: Evidence Gaps and Insights. AB - Increasing attention to adolescent girls has generated an abundance of programs and a growing body of research on adolescent girls in low- and middle-income countries. Despite this, questions remain about what implementation approaches in program design are most effective, hindering efficient resource allocation, program scale-up, and replication across settings. To address these questions, we conducted a systematic review to identify lessons learned and gaps in the evidence base. We searched four electronic databases to identify studies published between 1990 and 2014 that evaluated health, social, and/or economic development programs targeting adolescent girls in low- and middle-income countries. Seventy-seven (77) studies meeting specified criteria were identified, of which 19 presented results that allowed conclusions relevant to implementation science. Studies examining the following questions were assessed: To what extent, if any, do multicomponent interventions (as opposed to single-component interventions) improve outcomes for girls? What is the added value of involving actors in addition to the girl herself such as parents, guardians, husbands (i.e., multilevel interventions)? What is the threshold proportion of girls who need to participate in a program to bring about normative and behavior changes at the community level? Is a greater level of program exposure associated with greater programmatic benefit for girls? Can supplemental "booster" activities extend the benefits of a program after it ends? We found evidence to support associations between multicomponent (vs. single component) programs, and longer program exposure (vs. less program exposure), with more favorable outcomes for girls, although both conclusions include methodological limitations. Overall, few studies assessed boosters or program saturation, and evidence on multilevel versus single-level programs was inconclusive. Few studies assessed implementation science questions by design, exposing large gaps in the evidence base. We call for future research to explicitly test such implementation science questions to inform more effective use of resources and to improve outcomes for girls. PMID- 29434005 TI - Exogenous human herpesvirus 6 reinfection after tumor-infiltrating T-lymphocyte therapy. AB - Exogenous human herpes virus 6 (HHV-6) reinfection has never been reported in patients receiving tumor-infiltrating T lymphocytes therapy. We report an unusual case of HHV-6 infection following infusion of HHV-6 infected autologous T lymphocytes. HHV-6 infection could interfere with the tumor antigen immune recognition and the efficacy of immunotherapy. PMID- 29434006 TI - MSC-exosome: A novel cell-free therapy for cutaneous regeneration. AB - Cutaneous regeneration is a dynamic and complex process that requires a series of coordinated interactions involving epidermal cells, dermal cells, growth factors, the extracellular matrix (ECM), nerves and blood vessels at a damaged site. Mesenchymal stromal cells (MSCs) have been reported to participate in all afore mentioned stages. Exosomes are one of the key secretory products of MSCs, resembling the effect of parental MSCs. They can shuttle various proteins, messenger RNA (mRNA) and microRNAs (miRNAs) to modulate the activity of recipient cells, and play important roles in cutaneous wound healing. Compared with MSCs, exosomes are more convenient to store and transport. Moreover, they avoid many risks associated with cell transplantation. Therefore, MSC-exosome-mediated therapy may be more safe and efficient. In this review, we summarize the latest studies and observations on the role of MSC-exosome in the acute and chronic wound model and provide a comprehensive understanding of the role of exosomes in wound healing. This review can assist investigators in exploring new therapeutic strategies for enhancing the efficacy of MSC-exosome for cutaneous repair and regeneration. PMID- 29434007 TI - MSCs-cells with many sides. AB - The field of mesenchymal stromal cell (MSC) biology and clinical cellular therapy has grown exponentially over the last few decades. With discovery of multiple tissue specific sources of stromal cells, invariably being termed MSCs, and their increasing clinical application, there is a need to further delineate the true definition of a mesenchymal stromal cell and to recognise the inherit differences between cell sources; both their potential and limitations. In this review, we discuss the importance of considering every stromal cell source as an independent entity and the need to critically evaluate and appreciate the true phenotype of these cells and their safety when considering their use in novel cell therapies. PMID- 29434008 TI - Specific learning difficulties in healthcare education: The meaning in the nomenclature. PMID- 29434009 TI - From the Editor. PMID- 29434010 TI - National Prevalence of Self-Reported Coronary Heart Disease and Chronic Stable Angina Pectoris: Factor Analysis of the Underlying Cardiometabolic Risk Factors in the SuRFNCD-2011. AB - BACKGROUND: Coronary heart disease (CHD) is one of the most common causes of mortality worldwide. The national prevalence remains unclear in most of the developing countries. OBJECTIVE: This study sought to estimate national prevalence of self-reported CHD and chronic stable angina pectoris in the general adult population of Iran using data from the fourth round of the Surveillance of Risk Factors of Non-Communicable Diseases (SuRFNCD-2011) survey. METHODS: The analysis comprised data of 11,867 civilian, nonhospitalized and noninstitutionalized residents ages 6 to 70 years of age. The calculated prevalence of self-reported CHD and chronic stable angina pectoris were extrapolated to the Iranian adult population who were >20 years old using the complex sample analysis. The factor analysis was performed for clustering of the associated cardiometabolic risk factors among people ages >40 years of age. RESULTS: The estimated national prevalence of self-reported CHD and chronic stable angina pectoris were 5.3% (95% confidence interval: 4.6 to 5.9) and 7.7% (95% confidence interval: 4.6 to 8.7), respectively. Higher prevalence of these conditions were observed among the older people, urban residents, and women. Factor analysis generated 4 distinct factors that were mainly indicators of dyslipidemia, hypertension, central obesity, hyperglycemia, and tobacco smoking. The factor incorporating hypertension was a significant correlate of self reported CHD. CONCLUSIONS: We report concerning prevalence of self-reported CHD and chronic stable angina pectoris in the adult population of Iran. The constellation of raised systolic and diastolic blood pressures was significantly predictive of the presence of self-reported CHD. PMID- 29434011 TI - A Multidimensional Tool Based on the eHealth Literacy Framework: Development and Initial Validity Testing of the eHealth Literacy Questionnaire (eHLQ). AB - BACKGROUND: For people to be able to access, understand, and benefit from the increasing digitalization of health services, it is critical that services are provided in a way that meets the user's needs, resources, and competence. OBJECTIVE: The objective of the study was to develop a questionnaire that captures the 7-dimensional eHealth Literacy Framework (eHLF). METHODS: Draft items were created in parallel in English and Danish. The items were generated from 450 statements collected during the conceptual development of eHLF. In all, 57 items (7 to 9 items per scale) were generated and adjusted after cognitive testing. Items were tested in 475 people recruited from settings in which the scale was intended to be used (community and health care settings) and including people with a range of chronic conditions. Measurement properties were assessed using approaches from item response theory (IRT) and classical test theory (CTT) such as confirmatory factor analysis (CFA) and reliability using composite scale reliability (CSR); potential bias due to age and sex was evaluated using differential item functioning (DIF). RESULTS: CFA confirmed the presence of the 7 a priori dimensions of eHLF. Following item analysis, a 35-item 7-scale questionnaire was constructed, covering (1) using technology to process health information (5 items, CSR=.84), (2) understanding of health concepts and language (5 items, CSR=.75), (3) ability to actively engage with digital services (5 items, CSR=.86), (4) feel safe and in control (5 items, CSR=.87), (5) motivated to engage with digital services (5 items, CSR=.84), (6) access to digital services that work (6 items, CSR=.77), and (7) digital services that suit individual needs (4 items, CSR=.85). A 7-factor CFA model, using small-variance priors for cross-loadings and residual correlations, had a satisfactory fit (posterior productive P value: .27, 95% CI for the difference between the observed and replicated chi-square values: -63.7 to 133.8). The CFA showed that all items loaded strongly on their respective factors. The IRT analysis showed that no items were found to have disordered thresholds. For most scales, discriminant validity was acceptable; however, 2 pairs of dimensions were highly correlated; dimensions 1 and 5 (r=.95), and dimensions 6 and 7 (r=.96). All dimensions were retained because of strong content differentiation and potential causal relationships between these dimensions. There is no evidence of DIF. CONCLUSIONS: The eHealth Literacy Questionnaire (eHLQ) is a multidimensional tool based on a well-defined a priori eHLF framework with robust properties. It has satisfactory evidence of construct validity and reliable measurement across a broad range of concepts (using both CTT and IRT traditions) in various groups. It is designed to be used to understand and evaluate people's interaction with digital health services. PMID- 29434012 TI - Reducing Sedentary Time for Obese Older Adults: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Older adults have high rates of obesity and are prone to chronic health conditions. These conditions are in part due to high rates of sedentary time (ST). As such, reducing ST could be an innovative strategy for improving health outcomes among obese older adults. To test this theory, we developed a novel, technology-enhanced intervention to reduce sitting time (I-STAND) and pilot tested it to assess the feasibility, acceptability, and preliminary effects of the intervention on ST and biometric outcomes. OBJECTIVE: The current paper aims to describe the rationale, design, and methods of the I-STAND sitting reduction pilot trial. METHODS: Older adults with obesity (n=60) were recruited from a large health care system and randomized to receive I-STAND or a healthy living intervention. I-STAND combined personal coaching with a technology enhanced intervention (Jawbone UP band) to cue breaks from sitting. Participants completed self-report and biometric assessments at baseline and 3 months. Additional qualitative results were collected from a subset of I-STAND participants (n=22) to further inform the feasibility and acceptability of the interventions. The primary outcome was total hours of daily sitting time measured by the activPAL device. Secondary outcomes included sit-to-stand transitions, bouts of sitting longer than 30 minutes, physical function, blood pressure, fasting glucose, cholesterol, and depressive symptoms. RESULTS: Study enrollment has ended and data processing is underway. CONCLUSIONS: Data from randomized trials on sitting reduction are needed to inform novel approaches to health promotion among older adults with obesity. Our trial will help fill this gap. The methods used in our study can guide future research on using technology-based devices to assess or prompt sedentary behavior reduction, or those interested in behavioral interventions targeting obese older adults with novel approaches. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02692560; https://clinicaltrials.gov/ct2/show/NCT02692560 (Archived by WebCite at http://www.webcitation.org/6wppLTWAl). PMID- 29434013 TI - Web-Based Communication Strategies Designed to Improve Intention to Minimize Risk for Colorectal Cancer: Randomized Controlled Trial. AB - BACKGROUND: People seek information on the Web for managing their colorectal cancer (CRC) risk but retrieve much personally irrelevant material. Targeting information pertinent to this cohort via a frequently asked question (FAQ) format could improve outcomes. OBJECTIVE: We identified and prioritized colorectal cancer information for men and women aged 35 to 74 years (study 1) and built a website containing FAQs ordered by age and gender. In study 2, we conducted a randomized controlled trial (RCT) to test whether targeted FAQs were more influential on intention to act on CRC risk than the same information accessed via a generic topic list. Secondary analyses compared preference for information delivery, usability, relevance, and likelihood of recommendation of FAQ and LIST websites. METHODS: Study 1 determined the colorectal cancer information needs of Australians (N=600) by sex and age group (35-49, 50-59, 60-74) through a Web based survey. Free-text responses were categorized as FAQs: the top 5 issues within each of the 6 cohorts were identified. Study 2 (N=240) compared the impact of presentation as targeted FAQ links to information with links presented as a generic list (LIST) and a CONTROL (no information) condition. We also tested preference for presentation of access to information as FAQ or LIST by adding a CHOICE condition (a self-selected choice of FAQs or a list of information topics). RESULTS: Study 1 showed considerable consistency in information priorities among all 6 cohorts with 2 main concerns: treatment of CRC and risk factors. Some differences included a focus on general risk factors, excluding diet and lifestyle, in the younger cohort, and on the existence of a test for CRC in the older cohorts. Study 2 demonstrated that, although respondents preferred information access ordered by FAQs over a list, presentation in this format had limited impact on readiness to act on colorectal cancer risk compared with the list or a no-information control (P=.06). Both FAQ and LIST were evaluated as equally usable. Those aged 35 to 49 years rated the information less relevant to them and others in their age group, and information ordered by FAQs was rated, across all age groups and both sexes, as less relevant to people outside the age group targeted within the FAQs. CONCLUSIONS: FAQs are preferred over a list as a strategy for presenting access to information about CRC. They may improve intention to act on risk, although further research is required. Future research should aim to identify better the characteristics of information content and presentation that optimize perceived relevance and fully engage the target audience. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12618000137291; https://www.anzctr.org. au/Trial/Registration/TrialReview.aspx?id=374129 (Archived by WebCite at http://www.webcitation.org/6x2Mr6rPC). PMID- 29434014 TI - How Can Social Media Lead to Co-Production (Co-Delivery) of New Services for the Elderly Population? A Qualitative Study. AB - BACKGROUND: The future of health care services in the European Union faces the triple challenges of aging, fiscal restriction, and inclusion. Co-production offers ways to manage informal care resources to help them cater for the growing needs of elderly people. Social media (SM) is seen as a critical enabler for co production. OBJECTIVE: The objective of this study was to investigate how SM private Facebook groups, forums, Twitter, and blogging-acts as an enabler of co production in health and care by facilitating its four underlying principles: equality, diversity, accessibility, and reciprocity. METHODS: We used normalization process theory as our theoretical framework to design this study. We conducted a qualitative study and collected data through 20 semistructured interviews and observation of the activities of 10 online groups and individuals. We then used thematic analysis and drew on principles of co-production (equality, diversity, accessibility, and reciprocity) as a deductive coding framework to analyze our findings. RESULTS: Our findings point to distinct patterns of feature use by different people involved in care of elderly people. This diversity makes possible the principles of co-production by offering equality among users, enabling diversity of use, making experiences accessible, and encouraging reciprocity in the sharing of knowledge and mutual support. We also identified that explication of common resources may lead to new forms of competition and conflicts. These conflicts require better management to enhance the coordination of the common pool of resources. CONCLUSIONS: SM uses afford new forms of organizing and collective engagement between patients, carers, and professionals, which leads to change in health and care communication and coordination. PMID- 29434015 TI - Trust in Health Information Sources: Survey Analysis of Variation by Sociodemographic and Tobacco Use Status in Oklahoma. AB - BACKGROUND: Modern technology (ie, websites and social media) has significantly changed social mores in health information access and delivery. Although mass media campaigns for health intervention have proven effective and cost-effective in changing health behavior at a population scale, this is best studied in traditional media sources (ie, radio and television). Digital health interventions are options that use short message service/text messaging, social media, and internet technology. Although exposure to these products is becoming ubiquitous, electronic health information is novel, incompletely disseminated, and frequently inaccurate, which decreases public trust. Previous research has shown that audience trust in health care providers significantly moderates health outcomes, demographics significantly influence audience trust in electronic media, and preexisting health behaviors such as smoking status significantly moderate audience receptivity to traditional mass media. Therefore, modern health educators must assess audience trust in all sources, both media (traditional and digital) and interpersonal, to balance pros and cons before structuring multicomponent community health interventions. OBJECTIVE: We aimed to explore current trust and moderators of trust in health information sources given recent changes in digital health information access and delivery to inform design of future health interventions in Oklahoma. METHODS: We conducted phone surveys of a cross-sectional sample of 1001 Oklahoma adults (age 18-65 years) in spring 2015 to assess trust in seven media sources: traditional (television and radio), electronic (online and social media), and interpersonal (providers, insurers, and family/friends). We also gathered information on known moderators of trust (sociodemographics and tobacco use status). We modeled log odds of a participant rating a source as "trustworthy" (SAS PROC SURVEYLOGISTIC), with subanalysis for confounders (sociodemographics and tobacco use). RESULTS: Oklahomans showed the highest trust in interpersonal sources: 81% (808/994) reported providers were trustworthy, 55% (550/999) for friends and family, and 48% (485/998) for health insurers. For media sources, 24% of participants (232/989) rated the internet as trustworthy, followed by 21% of participants for television (225/998), 18% for radio (199/988), and only 11% for social media (110/991). Despite this low self reported trust in social media, 40% (406/991) of participants reported using social media for tobacco-related health information. Trust in health providers did not vary by subpopulation, but sociodemographic variables (gender, income, and education) and tobacco use status significantly moderated trust in other sources. Women were on the whole more trusting than men, trust in media decreased with income, and trust in friends and family decreased with education. CONCLUSIONS: Health education interventions should incorporate digital media, particularly when targeting low-income populations. Utilizing health care providers in social media settings could leverage high-trust and low-cost features of providers and social media, respectively. PMID- 29434016 TI - Increasing Physical Activity Amongst Overweight and Obese Cancer Survivors Using an Alexa-Based Intelligent Agent for Patient Coaching: Protocol for the Physical Activity by Technology Help (PATH) Trial. AB - BACKGROUND: Physical activity has established health benefits, but motivation and adherence remain challenging. OBJECTIVE: We designed and launched a three-arm randomized trial to test artificial intelligence technology solutions to increase daily physical activity in cancer survivors. METHODS: A single-center, three-arm randomized clinical trial with an allocation ration of 1:1:1: (A) control, in which participants are provided written materials about the benefits of physical activity; (B) text intervention, where participants receive daily motivation from a fully automated, data-driven algorithmic text message via mobile phone (Coachtext); and (C) Voice Assist intervention, where participants are provided with an in-home on demand autonomous Intelligent Agent using data driven Interactive Digital Voice Assist on the Amazon Alexa/Echo (MyCoach). RESULTS: The study runs for 5 weeks: a one-week run-in to establish baseline, followed by 4 weeks of intervention. Data for study outcomes is collected automatically through a wearable sensor, and data are transferred in real-time to the study server. The recruitment goal is 42 participants, 14 in each arm. Electronic health records are used to prescreen candidates, with 39 participants recruited to date. DISCUSSION: This study aims to investigate the effects of different types of intelligent technology solutions on promoting physical activity in cancer survivors. This innovative approach can easily be expanded and customized to other interventions. Early lessons from our initial participants are helping us develop additional advanced solutions to improve health outcomes. TRIAL REGISTRATION: Retrospectively registered on July 10, 2017 at ClinicalTrials.gov: NCT03212079; https://clinicaltrials.gov/ct2/show/NCT03212079 (Archived by WebCite at http://www.webcitation.org/6wgvqjTji). PMID- 29434017 TI - Health Information Obtained From the Internet and Changes in Medical Decision Making: Questionnaire Development and Cross-Sectional Survey. AB - BACKGROUND: The increasing utilization of the internet has provided a better opportunity for people to search online for health information, which was not easily available to them in the past. Studies reported that searching on the internet for health information may potentially influence an individual's decision making to change her health-seeking behaviors. OBJECTIVE: The objectives of this study were to (1) develop and validate 2 questionnaires to estimate the strategies of problem-solving in medicine and utilization of online health information, (2) determine the association between searching online for health information and utilization of online health information, and (3) determine the association between online medical help-seeking and utilization of online health information. METHODS: The Problem Solving in Medicine and Online Health Information Utilization questionnaires were developed and implemented in this study. We conducted confirmatory factor analysis to examine the structure of the factor loadings and intercorrelations for all the items and dimensions. We employed Pearson correlation coefficients for examining the correlations between each dimension of the Problem Solving in Medicine questionnaire and each dimension of the Online Health Information Utilization questionnaire. Furthermore, we conducted structure equation modeling for examining the possible linkage between each of the 6 dimensions of the Problem Solving in Medicine questionnaire and each of the 3 dimensions of the Online Health Information Utilization questionnaire. RESULTS: A total of 457 patients participated in this study. Pearson correlation coefficients ranged from .12 to .41, all with statistical significance, implying that each dimension of the Problem Solving in Medicine questionnaire was significantly associated with each dimension of the Online Health Information Utilization questionnaire. Patients with the strategy of online health information search for solving medical problems positively predicted changes in medical decision making (P=.01), consulting with others (P<.001), and promoting self-efficacy on deliberating the online health information (P<.001) based on the online health information they obtained. CONCLUSIONS: Present health care professionals have a responsibility to acknowledge that patients' medical decision making may be changed based on additional online health information. Health care professionals should assist patients' medical decision making by initiating as much dialogue with patients as possible, providing credible and convincing health information to patients, and guiding patients where to look for accurate, comprehensive, and understandable online health information. By doing so, patients will avoid becoming overwhelmed with extraneous and often conflicting health information. Educational interventions to promote health information seekers' ability to identify, locate, obtain, read, understand, evaluate, and effectively use online health information are highly encouraged. PMID- 29434018 TI - Medical YouTube Videos and Methods of Evaluation: Literature Review. AB - BACKGROUND: Online medical education has relevance to public health literacy and physician efficacy, yet it requires a certain standard of reliability. While the internet has the potential to be a viable medical education tool, the viewer must be able to discern which information is reliable. OBJECTIVE: Our aim was to perform a literature review to determine and compare the various methods used when analyzing YouTube videos for patient education efficacy, information accuracy, and quality. METHODS: In November 2016, a comprehensive search within PubMed and Embase resulted in 37 included studies. RESULTS: The review revealed that each video evaluation study first established search terms, exclusion criteria, and methods to analyze the videos in a consistent manner. The majority of the evaluators devised a scoring system, but variations were innumerable within each study's methods. CONCLUSIONS: In comparing the 37 studies, we found that overall, common steps were taken to evaluate the content. However, a concrete set of methods did not exist. This is notable since many patients turn to the internet for medical information yet lack the tools to evaluate the advice being given. There was, however, a common aim of discovering what health-related content the public is accessing, and how credible that material is. PMID- 29434019 TI - Haematohidrosis treated with propranolol: a case report. PMID- 29434021 TI - End of life care for infants, children and young people with life-limiting conditions: planning and management: the NICE guideline 2016. PMID- 29434020 TI - Children and young people's versus parents' responses in an English national inpatient survey. AB - OBJECTIVE: Despite growing interest in children and young people's (CYP) perspectives on healthcare, they continue to be excluded from many patient experience surveys. This study investigated the feasibility of, and additional information gained by, measuring CYP experiences of a recent hospital admission. DESIGN: Cross-sectional analysis of national survey data. SETTING: Inpatients aged 8-15 years in eligible National Health Service hospitals, July-September 2014. PARTICIPANTS: 6204 parents/carers completed the parent section of the survey. The CYP section of the survey was completed by CYP themselves (n=3592), parents (n=849) or jointly (n=1763). MAIN OUTCOME MEASURES: Pain relief, involvement, quality of staff communication, perceived safety, ward environment, overall experience. ANALYSES: Single-measures intraclass correlations (ICCs) were used to assess the concordance between CYP and parent responses about the same inpatient episode. Multilevel logistic regression models, adjusted for individual characteristics, were used to compare the odds of positive responses when the CYP section of the survey was completed by parents, by CYP themselves or jointly. RESULTS: The CYP section of the survey was completed independently by 57.8% of CYP. Agreement between CYP and parent responses was reasonably good for pain relief (ICC=0.61 (95% CI 0.58 to 0.63)) and overall experience (ICC=0.70 (95% CI 0.68 to 0.72)), but much lower for questions comparing professionals' communication with CYP and with their parents (ICC range=0.28 (95% CI 0.24 to 0.32) to 0.51 (95% CI 0.47 to 0.54)). In the regression models, CYP were significantly less likely than parents to report feeling safe (adjusted OR (AOR)=0.54 (95% CI 0.38 to 0.76)), involvement in decisions (AOR=0.66 (95% CI 0.46 to 0.94)) or adequate privacy (AOR=0.68 (95% CI 0.52 to 0.89)). CONCLUSIONS: Including CYP (8-15 years) in patient experience surveys is feasible and enhances what is known from parents' responses. PMID- 29434022 TI - Fifteen-minute consultation: The child with an incidental finding of elevated aminotransferases. AB - It is not unusual to encounter abnormal liver enzyme levels on routine blood tests. When the abnormal elevation in aminotransferases persist, they require prompt and appropriate investigations as liver diseases in children are often insidious in onset and clinically silent. This article aims to provide (1) an explanation to the aetiologies of elevated aminotransferases; (2) an investigational approach to these children and (3) an insight into further investigations performed at a liver centre. PMID- 29434023 TI - Cerebellar ataxia as a first manifestation of Creutzfeldt-Jakob disease in two cousins. PMID- 29434024 TI - Socioeconomic deprivation, mortality and health of within-city migrants: a population cohort study. AB - BACKGROUND: Evidence linking selective migration (the situation where people in good health move from deprived to affluent areas, whilst people in poor health move in the opposite direction) within local areas to mortality is inconclusive. METHODS: Mortality in within-city migrants was examined using a Sheffield population cohort, adjusted for moves to care homes. The cohort comprised 310 894 people aged 25+ years in 2001 followed up for 9.18 years, with 42 252 (13.6%) deaths. Information on pre-existing medical conditions, socioeconomic indicators and smoking was available from a sample survey. RESULTS: Relative risks (95% CI) of mortality in migrants from deprived to affluent areas were lower compared with people remaining in deprived areas; 0.53 (0.42 to 0.65), 0.70 (0.61 to 0.80), 0.76 (0.68 to 0.86), 0.93 (0.88 to 1.00) and 0.98 (0.93 to 1.03) in the 25-44, 45 64, 65-74, 75-84 and 85+ year age bands, respectively. They also had lower prevalence ORs (95% CI) for bronchitis (0.59 (0.39 to 0.89)), asthma (0.70 (0.53 to 0.93)), depression (0.59 (0.38 to 0.94)), and were less likely to receive benefits (0.60 (0.47 to 0.76)) and less likely to smoke (0.66 (0.51 to 0.85)).Conversely, mortality relative risks in migrants from affluent to deprived areas were higher compared with people remaining in affluent areas; 1.71 (1.37 to 2.12), 1.59 (1.40 to 1.82), 1.44 (1.26 to 1.63), 1.18 (1.10 to 1.27) and 1.04 (1.00 to 1.09) in the corresponding age groups. They also had higher prevalence odds ratios for long-term illness (2.37 (1.71 to 3.29)), asthma (1.71 (1.25 to 2.35)), diabetes (3.03 (1.70 to 5.41)), depression (2.71 (1.74 to 4.21)), were more likely to receive benefits (2.25 (1.65 to 3.07)) and more likely to smoke (1.51 (1.12 to 2.05)). CONCLUSIONS: People moving from deprived to affluent areas had lower mortality and better health, and vice versa, especially in the younger age groups. This study provides strong evidence linking selective migration within local areas to mortality. PMID- 29434025 TI - Physical activity and trajectories in cognitive function: English Longitudinal Study of Ageing. AB - BACKGROUND: There are limited data on physical activity in relation to trajectories in cognitive function. The aim was to examine the association of physical activity with trajectories in cognitive function, measured from repeated assessments over 10 years. METHODS: We conducted a 10-year follow-up of 10 652 (aged 65+/-10.1 years) men and women from the English Longitudinal Study of Ageing, a cohort of community dwelling older adults. Self-reported physical activity was assessed at baseline and neuropsychological tests of memory and executive function were administered at regular 2-year intervals. Data from six repeated measurements of memory over 10 years and five repeated measurements of executive function over 8 years were used. RESULTS: The multivariable models revealed relatively small baseline differences in cognitive function by physical activity status in both men and women. Over the 10-year follow-up, physically inactive women experienced a greater decline in their memory (-0.20 recalled words, 95% CI -0.29 to -0.11, per study wave) and in executive function ability ( 0.33 named animals; -0.54 to -0.13, per study wave) in comparison with the vigorously active reference group. In men, there were no differences in memory ( 0.08 recalled words, 95% CI -0.18 to 0.01, per study wave), but small differences in executive function (-0.23 named animals; -0.46 to -0.01, per study wave) between inactive and vigorously active. CONCLUSION: Physical activity was associated with preservation of memory and executive function over 10 years follow-up. The results were, however, more pronounced in women. PMID- 29434028 TI - Effects of thyroid hormones on thermogenesis and energy partitioning. AB - Thyroid hormones (TH) are of central importance for thermogenesis, energy homeostasis and metabolism. Here, we will discuss these aspects by focussing on the physiological aspects of TH-dependent regulation in response to cold exposure and fasting, which will be compared to alterations in primary hyperthyroidism and hypothyroidism. In particular, we will summarise current knowledge on regional thyroid hormone status in the central nervous system (CNS) and in peripheral cells. In contrast to hyperthyroidism and hypothyroidism, where parallel changes are observed, local alterations in the CNS differ to peripheral compartments when induced by cold exposure or fasting. Cold exposure is associated with low hypothalamic TH concentrations but increased TH levels in the periphery. Fasting results in a reversed TH pattern. Primary hypothyroidism and hyperthyroidism disrupt these fine-tuned adaptive mechanisms and both, the hypothalamus and the periphery, will have the same TH status. These important mechanisms need to be considered when discussing thyroid hormone replacement and other therapeutical interventions to modulate TH status. PMID- 29434026 TI - Identification of early indicators of altered metabolism in normal development using a rodent model system. AB - Although the existence of a close relationship between the early maternal developmental environment, fetal size at birth and the risk of developing disease in adulthood has been suggested, most studies, however, employed experimentally induced intrauterine growth restriction as a model to link this with later adult disease. Because embryonic size variation also occurs under normal growth and differentiation, elucidating the molecular mechanisms underlying these changes and their relevance to later adult disease risk becomes important. The birth weight of rat pups vary according to the uterine horn positions. Using birth weight as a marker, we compared two groups of rat pups - lower birth weight (LBW, 5th to 25th percentile) and average birth weight (ABW, 50th to 75th percentile) - using morphological, biochemical and molecular biology, and genetic techniques. Our results show that insulin metabolism, Pi3k/Akt and Ppargamma signaling and the genes regulating growth and metabolism are significantly different in these groups. Methylation at the promoter of the InsII (Ins2) gene and DNA methyltransferase 1 in LBW pups are both increased. Additionally, the Dnmt1 repressor complex, which includes Hdac1, Rb (Rb1) and E2f1, was also upregulated in LBW pups. We conclude that the Dnmt1 repressor complex, which regulates the restriction point of the cell cycle, retards the rate at which cells traverse the G1 or G0 phase of the cell cycle in LBW pups, thereby slowing down growth. This regulatory mechanism mediated by Dnmt1 might contribute to the production of small-size pups and altered physiology and pathology in adult life. PMID- 29434027 TI - Genome sequencing identifies somatic BRAF duplication c.1794_1796dupTAC;p.Thr599dup in pediatric patient with low-grade ganglioglioma. AB - Gangliogliomas (WHO grade I) are rare tumors affecting the central nervous system and are most frequently observed in children. Next-generation sequencing of tumors is being utilized at an increasing rate in both research and clinical settings to characterize the genetic factors that drive tumorigenesis. Here, we report a rare BRAF somatic mutation (NM_004333.4:c.1794_1796dupTAC; p.Thr599dup) in the tumor genome from a pediatric patient in her late teens, who was initially diagnosed with low-grade ganglioglioma at age 13. This duplication of 3 nt introduces a second threonine residue at amino acid 599 of the BRAF protein. Based on previous studies, this variant is likely to increase kinase activity, similar to the well-characterized BRAF p.Val600Glu (V600E) pathogenic variant. In addition, although the p.T599dup somatic mutation has been documented rarely in human cancers, the variant has not been previously reported in ganglioglioma. The identification of this variant presents an opportunity to consider targeted therapy (e.g., BRAF inhibitor) for this patient. PMID- 29434029 TI - De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination. AB - Myelination calls for a remarkable surge in cell metabolism to facilitate lipid and membrane production. Endogenous fatty acid (FA) synthesis represents a potentially critical process in myelinating glia. Using genetically modified mice, we show that Schwann cell (SC) intrinsic activity of the enzyme essential for de novo FA synthesis, fatty acid synthase (FASN), is crucial for precise lipid composition of peripheral nerves and fundamental for the correct onset of myelination and proper myelin growth. Upon FASN depletion in SCs, epineurial adipocytes undergo lipolysis, suggestive of a compensatory role. Mechanistically, we found that a lack of FASN in SCs leads to an impairment of the peroxisome proliferator-activated receptor (PPAR) gamma-regulated transcriptional program. In agreement, defects in myelination of FASN-deficient SCs could be ameliorated by treatment with the PPARgamma agonist rosiglitazone ex vivo and in vivo. Our results reveal that FASN-driven de novo FA synthesis in SCs is mandatory for myelination and identify lipogenic activation of the PPARgamma transcriptional network as a putative downstream functional mediator. PMID- 29434030 TI - Src-mediated phosphorylation converts FHL1 from tumor suppressor to tumor promoter. AB - FHL1 has been recognized for a long time as a tumor suppressor protein that associates with both the actin cytoskeleton and the transcriptional machinery. We present in this study a paradigm that phosphorylated FHL1 functions as an oncogenic protein by promoting tumor cell proliferation. The cytosolic tyrosine kinase Src interacts with and phosphorylates FHL1 at Y149 and Y272, which switches FHL1 from a tumor suppressor to a cell growth accelerator. Phosphorylated FHL1 translocates into the nucleus, where it binds to the transcription factor BCLAF1 and promotes tumor cell growth. Importantly, the phosphorylation of FHL1 is increased in tissues from lung adenocarcinoma patients despite the down-regulation of total FHL1 expression. Kindlin-2 was found to interact with FHL1 and recruit FHL1 to focal adhesions. Kindlin-2 competes with Src for binding to FHL1 and suppresses Src-mediated FHL1 phosphorylation. Collectively, we demonstrate that FHL1 can either suppress or promote tumor cell growth depending on the status of the sites for phosphorylation by Src. PMID- 29434031 TI - A Survey of Virus Recombination Uncovers Canonical Features of Artificial Chimeras Generated During Deep Sequencing Library Preparation. AB - Chimeric reads can be generated by in vitro recombination during the preparation of high-throughput sequencing libraries. Our attempt to detect biological recombination between the genomes of dengue virus (DENV; +ssRNA genome) and its mosquito host using the Illumina Nextera sequencing library preparation kit revealed that most, if not all, detected host-virus chimeras were artificial. Indeed, these chimeras were not more frequent than with control RNA from another species (a pillbug), which was never in contact with DENV RNA prior to the library preparation. The proportion of chimera types merely reflected those of the three species among sequencing reads. Chimeras were frequently characterized by the presence of 1-20 bp microhomology between recombining fragments. Within species chimeras mostly involved fragments in opposite orientations and located less than 100 bp from each other in the parental genome. We found similar features in published datasets using two other viruses: Ebola virus (EBOV; -ssRNA genome) and a herpesvirus (dsDNA genome), both produced with the Illumina Nextera protocol. These canonical features suggest that artificial chimeras are generated by intra-molecular template switching of the DNA polymerase during the PCR step of the Nextera protocol. Finally, a published Illumina dataset using the Flock House virus (FHV; +ssRNA genome) generated with a protocol preventing artificial recombination revealed the presence of 1-10 bp microhomology motifs in FHV-FHV chimeras, but very few recombining fragments were in opposite orientations. Our analysis uncovered sequence features characterizing recombination breakpoints in short-read sequencing datasets, which can be helpful to evaluate the presence and extent of artificial recombination. PMID- 29434032 TI - Selection on Expected Maximum Haploid Breeding Values Can Increase Genetic Gain in Recurrent Genomic Selection. AB - Genomic selection (GS) offers the possibility to estimate the effects of genome wide molecular markers, which can be used to calculate genomic estimated breeding values (GEBVs) for individuals without phenotypes. GEBVs can serve as a selection criterion in recurrent GS, maximizing single-cycle but not necessarily long-term genetic gain. As simple genome-wide sums, GEBVs do not take into account other genomic information, such as the map positions of loci and linkage phases of alleles. Therefore, we herein propose a novel selection criterion called expected maximum haploid breeding value (EMBV). EMBV predicts the expected performance of the best among a limited number of gametes that a candidate contributes to the next generation, if selected. We used simulations to examine the performance of EMBV in comparison with GEBV as well as the recently proposed criterion optimal haploid value (OHV) and weighted GS. We considered different population sizes, numbers of selected candidates, chromosome numbers and levels of dominant gene action. Criterion EMBV outperformed GEBV after about 5 selection cycles, achieved higher long-term genetic gain and maintained higher diversity in the population. The other selection criteria showed the potential to surpass both GEBV and EMBV in advanced cycles of the breeding program, but yielded substantially lower genetic gain in early to intermediate cycles, which makes them unattractive for practical breeding. Moreover, they were largely inferior in scenarios with dominant gene action. Overall, EMBV shows high potential to be a promising alternative selection criterion to GEBV for recurrent genomic selection. PMID- 29434033 TI - PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia. AB - Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ~10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRBC843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment. PMID- 29434034 TI - Influence of alternative husbandry systems on postmortem findings and prevalence of important bacteria and parasites in layers monitored from end of rearing until slaughter. AB - In the present study 66 layer flocks housed in different alternative husbandry systems were monitored from placement of birds on the farm until slaughter to evaluate a possible influence on the occurrence of selected non-infectious as well as infectious diseases. Postmortems were performed and the occurrence of extraintestinal Escherichia coli and Gallibacterium anatis was investigated. No specific postmortem findings were seen in pullets. Non-infectious diseases were mainly found in layers. Most prominent postmortem findings in layers were reproductive tract lesions and the presence of intestinal helminths. From each flock E coli and from approximately 65 per centof the flocks G anatis were isolated. No significant differences were seen in regard to the housing system, but the prevalence of G anatis increased with the age of birds. The majority of reproductive tract lesions could be associated with E coli alone or G anatis co infections. The prevalence of Ascaridia galli and Heterakis gallinarum was not influenced by the housing system, but significantly increased with age. Cestodes were present in six flocks. Histomonosis was detected twice. Dermanyssus gallinae was found in 5 pullet and 20 layer flocks. Additional investigations were performed on demand. Again, reproductive tract lesions were the most prominent postmortem findings. In one flock each histomonosis or erysipelas was diagnosed, respectively. Severe affection by D gallinae was found once. Necrotic enteritis was seen in two layer flocks. PMID- 29434036 TI - Damaging de novo mutations diminish motor skills in children on the autism spectrum. AB - In individuals with autism spectrum disorder (ASD), de novo mutations have previously been shown to be significantly correlated with lower IQ but not with the core characteristics of ASD: deficits in social communication and interaction and restricted interests and repetitive patterns of behavior. We extend these findings by demonstrating in the Simons Simplex Collection that damaging de novo mutations in ASD individuals are also significantly and convincingly correlated with measures of impaired motor skills. This correlation is not explained by a correlation between IQ and motor skills. We find that IQ and motor skills are distinctly associated with damaging mutations and, in particular, that motor skills are a more sensitive indicator of mutational severity than is IQ, as judged by mutational type and target gene. We use this finding to propose a combined classification of phenotypic severity: mild (little impairment of either), moderate (impairment mainly to motor skills), and severe (impairment of both IQ and motor skills). PMID- 29434035 TI - Molecular dynamics correctly models the unusual major conformation of the GAGU RNA internal loop and with NMR reveals an unusual minor conformation. AB - The RNA "GAGU" duplex, (5'GACGAGUGUCA)2, contains the internal loop (5'-GAGU-3')2 , which has two conformations in solution as determined by NMR spectroscopy. The major conformation has a loop structure consisting of trans-Watson Crick/Hoogsteen GG pairs, A residues stacked on each other, U residues bulged outside the helix, and all sugars with a C2'-endo conformation. This differs markedly from the internal loops, (5'-GAGC-3')2, (5'-AAGU-3')2, and (5'-UAGG 3')2, which all have cis-Watson-Crick/Watson-Crick AG "imino" pairs flanked by cis-Watson-Crick/Watson-Crick canonical pairs resulting in maximal hydrogen bonding. Here, molecular dynamics was used to test whether the Amber force field (ff99 + bsc0 + OL3) approximates molecular interactions well enough to keep stable the unexpected conformation of the GAGU major duplex structure and the NMR structures of the duplexes containing (5'-GAGC-3')2, (5'-AAGU-3')2, and (5'-UAGG 3')2 internal loops. One-microsecond simulations were repeated four times for each of the duplexes starting in their NMR conformations. With the exception of (5'-UAGG-3')2, equivalent simulations were also run starting with alternative conformations. Results indicate that the Amber force field keeps the NMR conformations of the duplexes stable for at least 1 usec. They also demonstrate an unexpected minor conformation for the (5'-GAGU-3')2 loop that is consistent with newly measured NMR spectra of duplexes with natural and modified nucleotides. Thus, unrestrained simulations led to the determination of the previously unknown minor conformation. The stability of the native (5'-GAGU-3')2 internal loop as compared to other loops can be explained by changes in hydrogen bonding and stacking as the flanking bases are changed. PMID- 29434037 TI - Changes in the flagellar bundling time account for variations in swimming behavior of flagellated bacteria in viscous media. AB - Although the motility of the flagellated bacteria, Escherichia coli, has been widely studied, the effect of viscosity on swimming speed remains controversial. The swimming mode of wild-type E. coli is often idealized as a run-and-tumble sequence in which periods of swimming at a constant speed are randomly interrupted by a sudden change of direction at a very low speed. Using a tracking microscope, we follow cells for extended periods of time in Newtonian liquids of varying viscosity and find that the swimming behavior of a single cell can exhibit a variety of behaviors, including run and tumble and "slow random walk" in which the cells move at a relatively low speed. Although the characteristic swimming speed varies between individuals and in different polymer solutions, we find that the skewness of the speed distribution is solely a function of viscosity and can be used, in concert with the measured average swimming speed, to determine the effective running speed of each cell. We hypothesize that differences in the swimming behavior observed in solutions of different viscosity are due to changes in the flagellar bundling time, which increases as the viscosity rises, due to the lower rotation rate of the flagellar motor. A numerical simulation and the use of resistive force theory provide support for this hypothesis. PMID- 29434038 TI - Poldip2 is an oxygen-sensitive protein that controls PDH and alphaKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer. AB - Although the addition of the prosthetic group lipoate is essential to the activity of critical mitochondrial catabolic enzymes, its regulation is unknown. Here, we show that lipoylation of the pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase (alphaKDH) complexes is a dynamically regulated process that is inhibited under hypoxia and in cancer cells to restrain mitochondrial respiration. Mechanistically, we found that the polymerase-delta interacting protein 2 (Poldip2), a nuclear-encoded mitochondrial protein of unknown function, controls the lipoylation of the pyruvate and alpha-KDH dihydrolipoamide acetyltransferase subunits by a mechanism that involves regulation of the caseinolytic peptidase (Clp)-protease complex and degradation of the lipoate-activating enzyme Ac-CoA synthetase medium-chain family member 1 (ACSM1). ACSM1 is required for the utilization of lipoic acid derived from a salvage pathway, an unacknowledged lipoylation mechanism. In Poldip2-deficient cells, reduced lipoylation represses mitochondrial function and induces the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) by loss of substrate inhibition of prolyl-4-hydroxylases (PHDs). HIF-1alpha-mediated retrograde signaling results in a metabolic reprogramming that resembles hypoxic and cancer cell adaptation. Indeed, we observe that Poldip2 expression is down regulated by hypoxia in a variety of cell types and basally repressed in triple negative cancer cells, leading to inhibition of lipoylation of the pyruvate and alpha-KDH complexes and mitochondrial dysfunction. Increasing mitochondrial lipoylation by forced expression of Poldip2 increases respiration and reduces the growth rate of cancer cells. Our work unveils a regulatory mechanism of catabolic enzymes required for metabolic plasticity and highlights the role of Poldip2 as key during hypoxia and cancer cell metabolic adaptation. PMID- 29434039 TI - Molecular model of the mitochondrial genome segregation machinery in Trypanosoma brucei. AB - In almost all eukaryotes, mitochondria maintain their own genome. Despite the discovery more than 50 y ago, still very little is known about how the genome is correctly segregated during cell division. The protozoan parasite Trypanosoma brucei contains a single mitochondrion with a singular genome, the kinetoplast DNA (kDNA). Electron microscopy studies revealed the tripartite attachment complex (TAC) to physically connect the kDNA to the basal body of the flagellum and to ensure correct segregation of the mitochondrial genome via the basal bodies movement, during the cell cycle. Using superresolution microscopy, we precisely localize each of the currently known TAC components. We demonstrate that the TAC is assembled in a hierarchical order from the base of the flagellum toward the mitochondrial genome and that the assembly is not dependent on the kDNA itself. Based on the biochemical analysis, the TAC consists of several nonoverlapping subcomplexes, suggesting an overall size of the TAC exceeding 2.8 mDa. We furthermore demonstrate that the TAC is required for correct mitochondrial organelle positioning but not for organelle biogenesis or segregation. PMID- 29434040 TI - Elucidating the structural basis for differing enzyme inhibitor potency by cryo EM. AB - Histidine biosynthesis is an essential process in plants and microorganisms, making it an attractive target for the development of herbicides and antibacterial agents. Imidazoleglycerol-phosphate dehydratase (IGPD), a key enzyme within this pathway, has been biochemically characterized in both Saccharomyces cerevisiae (Sc_IGPD) and Arabidopsis thaliana (At_IGPD). The plant enzyme, having been the focus of in-depth structural analysis as part of an inhibitor development program, has revealed details about the reaction mechanism of IGPD, whereas the yeast enzyme has proven intractable to crystallography studies. The structure-activity relationship of potent triazole-phosphonate inhibitors of IGPD has been determined in both homologs, revealing that the lead inhibitor (C348) is an order of magnitude more potent against Sc_IGPD than At_IGPD; however, the molecular basis of this difference has not been established. Here we have used single-particle electron microscopy (EM) to study structural differences between the At and Sc_IGPD homologs, which could influence the difference in inhibitor potency. The resulting EM maps at ~3 A are sufficient to de novo build the protein structure and identify the inhibitor binding site, which has been validated against the crystal structure of the At_IGPD/C348 complex. The structure of Sc_IGPD reveals that a 24-amino acid insertion forms an extended loop region on the enzyme surface that lies adjacent to the active site, forming interactions with the substrate/inhibitor binding loop that may influence inhibitor potency. Overall, this study provides insights into the IGPD family and demonstrates the power of using an EM approach to study inhibitor binding. PMID- 29434042 TI - Maximizing the information learned from finite data selects a simple model. AB - We use the language of uninformative Bayesian prior choice to study the selection of appropriately simple effective models. We advocate for the prior which maximizes the mutual information between parameters and predictions, learning as much as possible from limited data. When many parameters are poorly constrained by the available data, we find that this prior puts weight only on boundaries of the parameter space. Thus, it selects a lower-dimensional effective theory in a principled way, ignoring irrelevant parameter directions. In the limit where there are sufficient data to tightly constrain any number of parameters, this reduces to the Jeffreys prior. However, we argue that this limit is pathological when applied to the hyperribbon parameter manifolds generic in science, because it leads to dramatic dependence on effects invisible to experiment. PMID- 29434043 TI - Personal bests as reference points. AB - Personal bests act as reference points. Examining 133 million chess games, we find that players exert effort to set new personal best ratings and quit once they have done so. Although specific and difficult goals have been shown to inspire greater motivation than vague pronouncements to "do your best," doing one's best can be a specific and difficult goal-and, as we show, motivates in a manner predicted by loss aversion. PMID- 29434041 TI - Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers. AB - Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication. CFI-400945 is a highly selective PLK4 inhibitor that deregulates centriole duplication, causing mitotic defects and death of aneuploid cancers. Prior work was substantially extended by showing CFI-400945 causes polyploidy, growth inhibition, and apoptotic death of murine and human lung cancer cells, despite expression of mutated KRAS or p53. Analysis of DNA content by propidium iodide (PI) staining revealed cells with >4N DNA content (polyploidy) markedly increased after CFI-400945 treatment. Centrosome numbers and mitotic spindles were scored. CFI-400945 treatment produced supernumerary centrosomes and mitotic defects in lung cancer cells. In vivo antineoplastic activity of CFI-400945 was established in mice with syngeneic lung cancer xenografts. Lung tumor growth was significantly inhibited at well-tolerated dosages. Phosphohistone H3 staining of resected lung cancers following CFI-400945 treatment confirmed the presence of aberrant mitosis. PLK4 expression profiles in human lung cancers were explored using The Cancer Genome Atlas (TCGA) and RNA in situ hybridization (RNA ISH) of microarrays containing normal and malignant lung tissues. PLK4 expression was significantly higher in the malignant versus normal lung and conferred an unfavorable survival (P < 0.05). Intriguingly, cyclin dependent kinase 2 (CDK2) antagonism cooperated with PLK4 inhibition. Taken together, PLK4 inhibition alone or as part of a combination regimen is a promising way to combat lung cancer. PMID- 29434044 TI - Reply to Bennett et al.: IJROBP study is consistent with our findings and offers insights on author preferences. PMID- 29434046 TI - Joseph J. Kieber. PMID- 29434045 TI - Radiation oncology authors and reviewers prefer double-blind peer review. PMID- 29434047 TI - Reference percentiles of FEV1 for the Canadian cystic fibrosis population: comparisons across time and countries. AB - BACKGROUND: Forced expiratory volume in 1 s (FEV1) indicates lung health in cystic fibrosis (CF). FEV1 is commonly communicated as a per cent predicted of a healthy individual sharing the same age, sex, race and height. CF-specific reference equations are complementary and calibrate a patient's FEV1 to that of their CF peers. OBJECTIVES: (1) To derive Canadian CF-specific FEV1 reference percentiles (FEV1%iles), (2) characterize how they have changed over time and (3) compare the Canadian FEV1%iles to those for USA and European CF populations. METHOD: CF FEV1%iles are calculated using the Canadian CF Registry and quantile regression. RESULTS: The Canadian FEV1%iles demonstrated better lung function in more recent time periods within Canada, especially below the 50% percentile and in males. When compared to USA and European FEV1%iles for the same time period, Canadian FEV1%iles were higher. CONCLUSION: CF-specific FEV1%iles can provide useful information about changes in lung health. An online calculator (available at cfpercentile. RESEARCH: sickkids.ca) makes these FEV1%iles accessible. PMID- 29434048 TI - Hospital end-of-life care in haematological malignancies. AB - OBJECTIVE: To investigate patterns of care during the last months of life of hospitalised patients who died from different haematological malignancies. METHODS: Nationwide register-based study, including all hospitalised adults >=20 years who died from haematological malignancies in France in 2010-2013. Outcomes included use of invasive cancer treatments and referral to palliative care. Percentages are adjusted for sex and age using direct standardisation. RESULTS: Of 46 629 inpatients who died with haematological malignancies, 24.5% received chemotherapy during the last month before death, 48.5% received blood transfusion, 12.3% were under invasive ventilation and 18.1% died in intensive care units. We found important variations between haematological malignancies. The use of chemotherapy during the last month of life varied from 8.6% among patients with chronic myeloid leukaemia up to 30.1% among those with non Hodgkin's lymphoma (P<0.001). Invasive ventilation was used in 10.2% of patients with acute leukaemia but in 19.0% of patients with Hodgkin's lymphoma (P<0.001). Palliative status was reported 30 days before death in only 14.8% of patients, and at time of death in 46.9% of cases. Overall, 5.5% of haematology patients died in palliative care units. CONCLUSION: A high proportion of patients who died from haematological malignancies receive specific treatments near the end of life. There is a need for a better and earlier integration of the palliative care approach in the standard practice of haematology. However, substantial variation according to the type of haematological malignancy suggests that the patients should not be considered as one homogeneous group. Implementation of palliative care should account for differences across haematological malignancies. PMID- 29434049 TI - Opinion: Valuation, liquidity price, and stability of cryptocurrencies. PMID- 29434053 TI - A Model Mechanism-Based Explanation of an In Vitro-In Vivo Disconnect for Improving Extrapolation and Translation. AB - An improved understanding of in vivo-to-in vitro hepatocyte changes is crucial to interpreting in vitro data correctly and further improving hepatocyte-based in vitro-to-in vivo extrapolations to human targets. We demonstrate using virtual experiments as a means of helping to untangle plausible causes of inaccurate extrapolations. We start with virtual mice that use biomimetic software livers. Previously, using these mice, we discovered model mechanisms that enabled achieving quantitative validation targets while also providing plausible causal explanations for temporal characteristics of acetaminophen hepatotoxicity. We isolated virtual hepatocytes, created a virtual culture, and then conducted dose response experiments in both culture and mice. We expected to see differences between the two dose-response curves but were somewhat surprised that they crossed because it evidenced that simulated acetaminophen metabolism and toxicity are different for virtual culture and mouse contexts even though individual hepatocyte mechanisms were unchanged. Differences in dose-response curves provide a virtual example of an in vivo-to-in vitro disconnect. We use detailed results of experiments to explain this disconnect. Individual hepatocytes contribute differently to system-level phenomena. In liver, hepatocytes are exposed to acetaminophen sequentially. Relative production of the reactive acetaminophen metabolite is largest (smallest) in pericentral (periportal) hepatocytes. Because that sequential exposure is absent in culture, hepatocytes from different lobular locations do not respond the same. A virtual culture-to-mouse translation can stand as a scientifically challengeable hypothesis explaining an in vivo-to-in vitro disconnect. It provides a framework to develop more reliable interpretations of in vitro observations, which then may be used to improve extrapolations. PMID- 29434052 TI - In Vitro and In Vivo Antitumor and Anti-Inflammatory Capabilities of the Novel GSK3 and CDK9 Inhibitor ABC1183. AB - Glycogen synthase kinase-3s (GSK3alpha and GSK3beta) are constitutively active protein kinases that target over 100 substrates, incorporate into numerous protein complexes, and regulate such vital cellular functions as proliferation, apoptosis, and inflammation. Cyclin-dependent kinase 9 (CDK9) regulates RNA production as a component of positive transcription elongation factor b and promotes expression of oncogenic and inflammatory genes. Simultaneous inhibition of these signaling nodes is a promising approach for drug discovery, although previous compounds exhibit limited selectivity and clinical efficacy. The novel diaminothiazole ABC1183 is a selective GSK3alpha/beta and CDK9 inhibitor and is growth-inhibitory against a broad panel of cancer cell lines. ABC1183 treatment decreases cell survival through G2/M arrest and modulates oncogenic signaling through changes in GSK3, glycogen synthase, and beta-catenin phosphorylation and MCL1 expression. Oral administration, which demonstrates no organ or hematologic toxicity, suppresses tumor growth and inflammation-driven gastrointestinal disease symptoms, owing in part to downregulation of tumor necrosis factor alpha and interleukin-6 proinflammatory cytokines. Therefore, ABC1183 is strategically poised to effectively mitigate multiple clinically relevant diseases. PMID- 29434051 TI - Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study. AB - OBJECTIVE: To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD. METHODS: GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer's disease (AD) and 10 healthy controls (HCs) of similar age. RESULTS: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98). CONCLUSIONS: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD. PMID- 29434054 TI - Influence of antifertility agents Dutasteride and Nifedipine on CatSper gene level in epididymis during sperm maturation in BALB/c mice. AB - Calcium (Ca2+) signaling is critical for successful fertilization. In spermatozoa, capacitation, hyperactivation of motility and the acrosome reaction are all mediated by increases in intracellular Ca2+ through CatSper (sperm specific cation channel). The CatSper channel complex contains four pore-forming alpha subunits (CatSper1-4) and five accessory subunits called beta, delta, epsilon, gamma and zeta. Genetic deletion of any of the four CatSper genes in mice results in loss of hyperactivated motility and male infertility. Despite their vital role in male fertility, almost very little is known about influence of antifertility agents on CatSper gene expression in epididymis and epididymal spermatozoa. Therefore, we performed quantitative real-time qPCR analysis for CatSper expression in the epididymis and epididymal sperm of BALB/c mice after treatment with Dutasteride (DS), a dual 5-alpha reductase inhibitor and Nifedipine (NF) a calcium channel blocker as positive control. We observed that treatment with antifertility agents Dutasteride and Nifedipine induced significant decreases in the caput and cauda epididymal sperm counts, motility and fertility which could partly be attributed to alteration in the normal morphology of the sperm associated with downregulation/upregulation of CatSper mRNAs in epididymis and epididymal spermatozoa of male BALB/c mice. These can be explained on the basis of interference with mechanisms affecting calcium ion signaling resulting in changes in intracellular calcium required for sperm activity, finally affecting sperm maturation and fertility of male BALB/c mice. These studies provide some novel avenues for developing new male contraceptives in future. PMID- 29434055 TI - Assessing metabolic rate and indoor air quality with passive environmental sensors. AB - The present work introduces the use of environmental sensors to assess indoor air quality (IAQ) in combination with human biometrics. The sensor array included temperature, relative humidity, carbon dioxide, and noise monitors. The array was used in a classroom as well as in a vehicle cabin to assess the carbon dioxide production rate of individuals in a closed ventilation environment. Analysis of carbon dioxide production allowed for the quantification of the average metabolic rate of the group of individuals in the classroom, and for one individual in the vehicle cabin. These results yielded a mere 5% difference from the values assessed using commercial metabolic rate instruments, and averaged values from epidemiological studies. The results presented in this work verify the feasibility of determining an individual's metabolic rate using passive environmental sensors; these same sensors are able to provide a metric of IAQ that helps characterize the safety of the environment in which the individual is present. PMID- 29434056 TI - Workplace stress: A neglected aspect of mental health wellbeing. PMID- 29434057 TI - Post-marketing safety signals: Challenges in regulatory decisions, communication & impact evaluation in developing countries. PMID- 29434059 TI - Certification & validation of biosafety level-2 & biosafety level-3 laboratories in Indian settings & common issues. AB - With increasing awareness regarding biorisk management worldwide, many biosafety laboratories are being setup in India. It is important for the facility users, project managers and the executing agencies to understand the process of validation and certification of such biosafety laboratories. There are some international guidelines available, but there are no national guidelines or reference standards available in India on certification and validation of biosafety laboratories. There is no accredited government/private agency available in India to undertake validation and certification of biosafety laboratories. Therefore, the reliance is mostly on indigenous experience, talent and expertise available, which is in short supply. This article elucidates the process of certification and validation of biosafety laboratories in a concise manner for the understanding of the concerned users and suggests the important parameters and criteria that should be considered and addressed during the laboratory certification and validation process. PMID- 29434058 TI - Improving accuracy of breast cancer biomarker testing in India. AB - There is a global mandate even in countries with low resources to improve the accuracy of testing biomarkers in breast cancer viz. oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2neu) given their critical impact in the management of patients. The steps taken include compulsory participation in an external quality assurance (EQA) programme, centralized testing, and regular performance audits for laboratories. This review addresses the status of ER/PR and HER2neu testing in India and possible reasons for the delay in development of guidelines and mandate for testing in the country. The chief cause of erroneous ER and PR testing in India continues to be easily correctable issues such as fixation and antigen retrieval, while for HER2neu testing, it is the use of low-cost non-validated antibodies and interpretative errors. These deficiencies can however, be rectified by (i) distributing the accountability and responsibility to surgeons and oncologist, (ii) certification of centres for testing in oncology, and (iii) initiation of a national EQA system (EQAS) programme that will help with economical solutions and identifying the centres of excellence and instill a system for reprimand of poorly performing laboratories. PMID- 29434060 TI - Impact of regulatory spin of pioglitazone on prescription of antidiabetic drugs among physicians in India: A multicentre questionnaire-based observational study. AB - Background & objectives: Pioglitazone was suspended for manufacture and sale by the Indian drug regulator in June 2013 due to its association with urinary bladder carcinoma, which was revoked within a short period (July 2013). The present questionnaire-based nationwide study was conducted to assess its impact on prescribing behaviour of physicians in India. Methods: Between December 2013 and March 2014, a validated questionnaire was administered to physicians practicing diabetes across 25 centres in India. Seven hundred and forty questionnaires fulfilling the minimum quality criteria were included in the final analysis. Results: Four hundred and sixteen (56.2%) physicians prescribed pioglitazone. Of these, 281 used it in less than the recommended dose of 15 mg/day. Most physicians (94.3%) were aware of recent regulatory events. However, only 333 (44.8%) changed their prescribing pattern. Seventeen of the 416 (4.1%) physicians who prescribed pioglitazone admitted having come across at least one type 2 diabetes mellitus patient (T2DM) who had urinary bladder carcinoma, and of these 13 said that it was in patients who took pioglitazone for a duration of more than two years. Only 7.8 per cent of physicians (n=58) categorically advocated banning pioglitazone, and the rest opined for its continuation or generating more evidence before decision could be taken regarding its use in T2DM. Interpretation & conclusions: Majority of the physicians though were aware of the regulatory changes with regard to pioglitazone, but their prescribing patterns were not changed for this drug. However, it was being used at lower than the recommended dose. There is a need for generating more evidence through improved pharmacovigilance activities and large-scale population-based prospective studies regarding the safety issues of pioglitazone, so as to make effectual risk-benefit analysis for its continual use in T2DM. PMID- 29434061 TI - Immediate neonatal outcomes of preterm infants born to mothers with preterm pre labour rupture of membranes. AB - Background & objectives: With the use of early and appropriate use of antibiotics, outcomes have improved in the mother-infant dyads exposed to preterm pre-labour rupture of membranes (PPROM). This study was undertaken to evaluate immediate neonatal outcomes in infants born before 33 completed weeks of gestation to mothers with PPROM versus without PPROM. Methods: During the study period from January 2013 to December 2013, a total of 182 mother-infant dyads were prospectively included in the study. Among the enrolled, 69 were in the PPROM group and 113 in the control group (no PPROM). Mother-infant dyads in PPROM group were covered with antibiotics. The primary outcome was the combined adverse neonatal outcome consisting of sepsis, necrotizing enterocolitis >Stage II or pneumonia or oxygen at day 28 or cystic periventricular leucomalacia or mortality before discharge. Results: Baseline maternal and neonatal variables were comparable across the two groups, except for higher incidence of singletons, maternal pregnancy-induced hypertension (PIH) in the control group and higher proportion of males, complete steroid coverage and oligohydramnios in the PPROM group. The proportion of infants with combined adverse neonatal outcome was similar between the two groups [odds ratio (OR): 1.43; 95% confidence interval (CI): 0.77-2.6]. Both the groups were comparable for most other neonatal morbidities and outcomes, except screen-positive sepsis (OR: 3.7; 95% CI: 1.17 11.5) which was higher in PPROM group. Interpretation & conclusions: Mothers with PPROM and their newborns when treated with timely and appropriate antibiotics had neonatal outcomes similar to those not exposed to PPROM. PMID- 29434062 TI - Glucose tolerance & insulin secretion & sensitivity characteristics in Indian children with cystic fibrosis: A pilot study. AB - Background & objectives: Cystic fibrosis (CF) is a life-limiting genetic condition resulting in chronic respiratory infections, pancreatic enzyme insufficiency and associated complications. This pilot study was undertaken to assess the glucose tolerance and insulin secretion and sensitivity among Indian children with CF. Methods: Children with CF under regular follow up at the Paediatric Pulmonology Clinic of a tertiary care hospital in New Delhi, India, were enrolled. Children who had a history of acute exacerbation or intake of systemic steroids within the last two weeks were excluded. Anthropometry, pulmonary function and disease severity (Shwachman) score were assessed. Fasting venous sample was drawn to assess glucose, insulin, haemoglobin and calcium. Oral glucose tolerance test was performed, and blood glucose and insulin were assessed at 30, 60, 90 and 120 min. Insulin secretion and sensitivity indices were calculated. Results: Twenty nine patients with a mean age of 11.2+/-4.1 yr were enrolled. Stunting, thinness, anaemia and hypocalcaemia were present in 31.0, 13.8, 37.0 and 48.3 per cent of the patients, respectively. Abnormal glucose tolerance (AGT) was present in 21.4 per cent. Insulin secretion was similar in individuals with AGT and normal glucose tolerance (NGT), but insulin sensitivity index was lower (0.12+/-0.02 vs 0.15+/-0.01, P<0.001) and homeostatic model assessment of insulin resistance higher [1.63 (0.53-1.76) vs 0.83 (0.28-4.43), P<0.05] in individuals with AGT compared to NGT. Interpretation & conclusions: AGT was observed in 21.4 per cent of children with CF. The CF patients with AGT had significantly lower insulin sensitivity compared to patients with NGT. Future multicentric studies with a large sample should be conducted to assess insulin secretion and sensitivity indices in CF patients compared to healthy controls. PMID- 29434063 TI - Mutations in OTOF, CLDN14 & SLC26A4 genes as major causes of hearing impairment in Dhadkai village, Jammu & Kashmir, India. AB - Background & objectives: A high incidence of hearing impairment is reported from the village of Dhadkai in the State of Jammu and Kashmir, India. Prevalence of endogamy in this community suggested a common genetic basis for the disorder. A genetic study was undertaken to ascertain the basis for the high incidence of hearing impairment in this region. Methods: In a two-step approach to identify the causative mutation/s, a whole-genome-based linkage analysis of an extended family of 45 members was carried out, which included 23 affected and 22 unaffected members. Mutational analysis for the candidate deafness genes helped reveal causative mutations in the family. In addition, seven deafness-causing genes, Cx26, SLC26A4, CLDN14, TMPRSS3, TMC1, TMIE and USH1C, were analyzed in smaller families with hearing impairment. Results: In the 45-member extended family, the critical chromosomal region mapped to 2p24-p22.The c.2122C>T (p.R708X) mutation in OTOF in 2p24-p22was identified as being the causal change. Linkage to 2p24-p22 locus was not observed in a particular branch of this extended family. Analysis of seven known deafness-causing genes in this branch revealed a mutation, c.254T>A (p.V85D), in CLDN14. Among seven small families unrelated to the 45-member extended family, hearing loss was attributable to p.R708X in OTOF in three families and to p.V85D in CLDN14 in one family; a new mutation c.1668T>A (p.Y556X) SLC26A4 was identified in two families and the causative change could not be identified in one family. Interpretation & conclusions: This study suggested considerable genetic heterogeneity in the causation of hearing loss in Dhadkai. Recessive mutations were observed in at least three genes causing hearing loss: OTOF (p.R708X), SLC26A4 (p.Y556X) and CLDN14 (p.V85D). Mutation p.R708X appeared to be the major cause of hearing impairment in Dhadkai. PMID- 29434064 TI - Cervical length measurement in nulliparous women at term by ultrasound & its relationship to spontaneous onset of labour. AB - Background & objectives: Data on serial cervical length (CL) measurements in pregnancy at term to predict spontaneous labour onset are scarce and conflicting. This study was conducted to observe CL changes preceding spontaneous onset of labour, by serial transvaginal sonography (TVS) and transabdominal sonography (TAS), in nulliparous Indian women near term. Methods: Only nulliparous women with a singleton foetus in cephalic presentation and who confirmed their gestational age were recruited. Sonographic CL measurements were taken at weekly intervals from 36 wk gestation onwards by a single ultrasonologist. Transabdominal and transvaginal measurements were undertaken using the suitable transducer probes with the women in the supine position. Results: A total of 104 women with spontaneous onset of labour were evaluated. There was substantial variation in CL measurements, both by TVS and by TAS, from 36 to 40 wk gestation, although the two sets of measurements correlated closely. Mean CL changed significantly over the last three weeks before delivery. However, only one-third of the women showed CL change of >5 mm per week in the last three weeks. There was poor correlation between gestational age at delivery and the last measured CL, either by TVS or TAS. Length >3.1 mm, measured by TVS at 38 wk gestation, predicted post-dated pregnancy to a limited extent. Interpretation & conclusions: Inter-individual variations in CL and in CL changes were large. Thus, it was not practical to predict spontaneous onset of labour by sonographic CL measurement near term. Post-dated pregnancy may be predicted with limited success. Further studies should explore other parameters, in addition to CL. PMID- 29434065 TI - Identification of a single nucleotide polymorphism indicative of high risk in acute myocardial infarction. AB - Background & objectives: Acute myocardial infarction (AMI) is a major health concern in India. The aim of the study was to identify single nucleotide polymorphisms (SNPs) associated with AMI in patients using dedicated chip and validating the identified SNPs on custom-designed chips using high-throughput microarray analysis. Methods: In pilot phase, 48 AMI patients and 48 healthy controls were screened for SNPs using human CVD55K BeadChip with 48,472 SNP probes on Illumina high-throughput microarray platform. The identified SNPs were validated by genotyping additional 160 patients and 179 controls using custom made Illumina VeraCode GoldenGate Genotyping Assay. Analysis was carried out using PLINK software. Results: From the pilot phase, 98 SNPs present on 94 genes were identified with increased risk of AMI (odds ratio of 1.84-8.85, P=0.04861 0.003337). Five of these SNPs demonstrated association with AMI in the validation phase (P=0.05). Among these, one SNP rs9978223 on interferon gamma receptor 2 [IFNGR2, interferon (IFN)-gamma transducer 1] gene showed a significant association (P=0.00021) with AMI below Bonferroni corrected P value (P=0.00061). IFNGR2 is the second subunit of the receptor for IFN-gamma, an important cytokine in inflammatory reactions. Interpretation & conclusions: The study identified an SNP rs9978223 on IFNGR2 gene, associated with increased risk in AMI patient from India. PMID- 29434066 TI - Perioperative antimicrobial therapy in preventing infectious complications following pancreatoduodenectomy. AB - Background & objectives: Infectious complications have been reported to occur in up to 45 per cent of patients, following pancreatoduodenectomy (PD). The incidence of perioperative infectious and overall complications is higher in patients undergoing preoperative invasive endoscopic procedures. The aim of the study was to compare the role of a carbapenem administered as three-once daily perioperative doses on infectious complications in patients at high risk for these complications versus those at low risk. Methods: A retrospective study with some secondary data collected from records was carried out on the data from a prospectively maintained surgical database of patients undergoing PD for pancreatic and periampullary lesions at a tertiary referral care centre, between June 2011 and May 2013. Patients were divided into two groups for comparison based on whether they underwent at least one preoperative endoscopic interventional procedure before PD (high-risk - intervention and low-risk - no intervention). All patients were administered three-once daily doses of ertapenem (1 g). Results: A total of 135 patients in two groups were comparable in terms of demographic and nutritional, surgical and histopathological factors. No significant difference between the two groups in terms of the overall morbidity (38.7 vs 35.7%), infectious complications (9.7 vs 4.8%), mortality (2.2 vs 2.4%) and mean post-operative hospital stay (9.2 vs 8.9 days) was observed. Interpretation & conclusions: Perioperative three-day course of once-daily administered ertapenem resulted in a non-significant difference in infectious and overall complications in high-risk patients undergoing PD as compared to the low risk group. PMID- 29434067 TI - Inhibition of coxsackievirus infection in cardiomyocytes by small dsRNA targeting its cognate coxsackievirus adenovirus receptor. AB - Background & objectives: Coxsackievirus B (CVB), a member of human Enterovirus group, is the most common cause of viral myocarditis. Coxsackievirus adenovirus receptor (CAR) is identified as a key determinant for the entry of CVB in the target cells. Thus, blockade of receptor by RNA interference (RNAi) may inhibit the entry and pathogenesis of CVB in cardiac cells. The present study was aimed to determine the effect of CAR small dsRNA (siRNA) on coxsackieviral load and CAR expression in coxsackievirus-infected cardiomyocytes. Methods: Transfection efficiency in rat cardiomyocytes (H9c2) was determined by the fluorescent microscopy and flow cytometry. CAR siRNA dose was optimized based on cell viability and relative CAR messenger RNA (mRNA) expression. Cardiomyocytes were transfected with CAR siRNA followed by infection with 100 multiplicity of infection of CVB, which were harvested after 24, 48 and 72 h post-infection (p.i.). RNA was extracted for relative CAR mRNA expression. Cells were freeze thawed thrice for estimating coxsackieviral load. Results: The efficiency of transfection was optimized to be >80 per cent and CAR siRNA dose of 60 pmol was standardized. The knockdown of CAR by siRNA decreased its expression twice the expression in normal cardiomyocytes after 24 h p.i. of CVB. The treatment with CAR siRNA resulted in significant two log reduction of CVB load in cardiomyocytes infected with CVB at 24 h p.i. and retained till 72 h p.i. Interpretation & conclusions: The inhibition of CAR by siRNA was found to be effective against CVB in cardiomyocytes. However, this treatment strategy has to be evaluated in vivo to develop a new treatment strategy for patients suffering with viral myocarditis. PMID- 29434068 TI - Molecular characterization of human Dirofilaria isolates from Kerala. AB - Background & objectives: Human dirofilariosis is a well-recognized zoonosis caused by several species of the genus Dirofilaria. The disease is prevalent among canines and human beings in Kerala. The objective of the present study was to confirm the human Dirofilaria isolates by molecular characterization. Methods: The worms or segments obtained from human sources were subjected to diagnostic polymerase chain reaction (PCR) targeting the cytochrome oxidase subunit 1 (COI) and 5S ribosomal RNA (rRNA) genes of Dirofilaria repens. The amplicons were sequenced and analyzed. Results: The filariid nematodes recovered from ocular as well as subcutaneous tissue of human origin were identified as D. repens based on PCR targeting COI as well as 5S rRNA genes. The phylogenetic analysis of the COI gene nucleotide sequence obtained in the present study showed that D. repens shared the closest evolutionary relationship with D. honkongensis. Interpretation & conclusions: Molecular identification of D. repens isolated from human source assumes significance from the point of zoonotic threat of this mosquito-borne nematode. Phylogenetic analysis revealed a close evolutionary relationship with Asian isolate of D. honkongensis. Timely detection and treatment of infection in dogs, together with mosquito control, should be an integral part of the control strategy of this disease. PMID- 29434069 TI - Vaginal lactobacilli profile in pregnant women with normal & abnormal vaginal flora. AB - Background & objectives: Lactobacilli species that are better adapted to vaginal environment of women may colonize better and offer protection against vaginal pathogenic bacteria. In this study, the distribution of common Lactobacillus species was investigated in pregnant women. Methods: Sixty seven pregnant women were included in the study and vaginal samples were collected for Gram staining. Women were classified as normal vaginal flora, intermediate flora and bacterial vaginosis (BV) based on Nugent's score. Vaginal samples were also collected for the identification of Lactobacillus spp. by multiplex polymerase chain reaction (PCR) profiling of 16S rDNA amplification method. Results: Lactobacillus crispatus (100%) was the most predominant Lactobacillus spp. present in pregnant women with normal flora, followed by L. iners (77%), L. jensenii (74%) and L. helveticus (60%). While, L. iners was commonly present across groups in women with normal, intermediate or BV flora, L. crispatus, L. jensenii and L. helveticus decreased significantly as the vaginal flora changed to intermediate and BV. In women with BV, except L. iners other species of lactobacilli was less frequently prevalent. Species such as L. rhamnosus, L. fermentum, L. paracasei and L. casei were not detected in any vaginal sample. Interpretation & conclusions: L. crispatus, L. jensinii and L. helveticus were predominant species in women with normal flora. L. crispatus alone or in combination with L. jensinii and L. helveticus may be evaluated for probiotic properties for the prevention and treatment of BV. PMID- 29434070 TI - Direct identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) from positive blood culture bottles: An opportunity to customize growth conditions for fastidious organisms causing bloodstream infections. AB - Culture-negative bacteraemia has been an enigmatic entity with respect to its aetiological agents. In an attempt to actively identify those positive blood cultures that escape isolation and detection on routine workflow, an additional step of MALDI-TOF MS (matrix-assisted laser desorption ionization-time of flight mass spectrometry) based detection was carried out directly from the flagged blood culture bottles. Blood samples from 200 blood culture bottles that beeped positive with automated (BACTEC) system and showed no growth of organism on routine culture media, were subjected to analysis by MALDI-TOF MS. Forty seven of the 200 (23.5%) bacterial aetiology could be established by bottle-based method. Based on these results, growth on culture medium could be achieved for the isolates by providing special growth conditions to the fastidious organisms. Direct identification by MALDI-TOF MS from BACTEC-positive bottles provided an opportunity to isolate those fastidious organisms that failed to grow on routine culture medium by providing them with necessary alterations in growth environment. PMID- 29434071 TI - Serosurvey of Malsoor virus among Rousettus leschenaulti bat & human population residing nearby Robber's cave, Mahabaleshwar, Maharashtra, India. PMID- 29434072 TI - Osseous sarcoidosis with lupus pernio. PMID- 29434073 TI - Placental growth factor (PlGF) is linked to inflammation and metabolic disorders in mice with diet-induced obesity. AB - Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) sub-family, plays a major role in angiogenesis and vasculogenesis. Previous study demonstrated that PlGF-overexpressing transgenic (Tg) mice had gestational loss. In addition, PlGF secretion was up-regulated in isolated T lymphocytes (T-cell) upon CD3/CD28 stimulation, suggesting that PlGF could be a regulator of T-cell differentiation and development. T-cells are well known to play a critical role in obesity-induced inflammation. Therefore, to verify the possible link of diet-induced obesity (DIO) with inflammation and related metabolic disorders, such as insulin resistance, we fed high-fat diet (HFD) to Tg mice for 16 weeks. Adiposity and glucose intolerance significantly increase in Tg mice fed a HFD (Tg HFD) compared to wild-type (WT) mice fed HFD (WT HFD). In addition, macrophage infiltrations were significantly higher in the epididymal white adipose tissue (EWAT), liver, and pancreatic islets of Tg HFD mice compared to WT HFD mice. In the in vitro study, we showed that isolated CD4+ T-cells from Tg mice further differentiate into type 1 (Th1) and type 17 (Th17) helper T-cells via CD3/CD28 stimulation. Furthermore, we observed that the pro-inflammatory cytokines IL-6, IL-17, and TNFalpha, are remarkably increased in Tg mice compared to WT mice. These findings demonstrate that PlGF overexpression in T-cells might lead to inflammatory T-cell differentiation and accumulation in adipose tissue (AT) or metabolism-related tissues, contributing to the development of systemic metabolic disorders. Thus, PlGF may provide an effective therapeutic target in the management of obesity-induced inflammation and related metabolic disorders. PMID- 29434075 TI - A Missense Mutation in GJA8 Encoding Connexin 50 in a Chinese Pedigree with Autosomal Dominant Congenital Cataract. AB - Congenital cataract is leading cause of visual impairment and blindness in children worldwide. Approximately one-third of congenital cataract cases are familial, whose genetic etiology can be distinguished by targeted exome sequencing. Here, a three-generation congenital cataract pedigree was recruited, and physical and ophthalmologic examinations were taken. Targeted exome sequencing of 139 cataract-related genes was performed on the proband III:1. Sanger sequencing was used to validate the presence of variation identified via exome sequencing in family members and 200 controls. Conservative and functional prediction was performed with bioinformatic tools. We, thus, found a heterozygous missense mutation c.10T>A (p.W4R) in gap junction protein alpha 8 (GJA8) in the patients. However, this mutation was not present in normal family members and 200 unrelated controls. The GJA8 gene encodes a gap junction protein, connexin 50 (Cx50), in lens fibers that provide channels for exchange of ions and small molecules between adjacent cells. Conservative and functional prediction suggests that the W-to-R substitution at codon 4 may impair the function of the human Cx50 protein. Accordingly, we analyzed the distribution of Flag-tagged mutant Cx50 protein in HeLa cervical cancer cells. Immunofluorescent staining showed that the W-to-R substitution impaired Cx50 trafficking to the plasma membrane to form the gap junction. In conclusion, c.10T>A (p.W4R) in GJA8 is the newly identified genetic cause of familial congenital cataract. The W-to-R substitution near the amino-terminus may alter the localization of mutant Cx50, thereby impairing gap junction formation, which is the molecular pathogenic mechanism of this mutation. PMID- 29434074 TI - Validation of simple indexes for nonalcoholic fatty liver disease in western China: a retrospective cross-sectional study. AB - Various noninvasive algorithms have been developed for predicting the presence of nonalcoholic fatty liver disease (NAFLD). The evaluation of the indexes' diagnostic performance has been reported in Europe and Asia over the past decade; however, external validation of them in China is rare. This study was aimed to evaluate various indexes for NAFLD in western China. It was a retrospective cross sectional study, using data from a large-scale health check-up project at Sichuan provincial hospital. Receiver operating characteristic (ROC) curves of eight indexes, including the fatty liver index (FLI), the hepatic steatosis index, lipid accumulation product and etc., were developed to predict ultrasonographic NAFLD. There were 13,122 subjects in this study (2,692 NAFLD patients and 10,430 non-NAFLD participants). The area under ROC curve of FLI for predicting NAFLD was 0.880 (95% confidence interval, 0.874-0.886), which was significantly higher than other seven indexes. Accuracy, sensitivity and specificity of FLI for NAFLD were good (cut-off value = 30, 0.782, 0.832, 0.770 and cut- off value = 60, 0.838, 0.443, 0.940, respectively). Furthermore, FLI also presented advantages in expenditure and accessibility, compared with other indexes. It supports FLI as an easily accessible index for physicians and a reliable predictor for NAFLD screening in western China. PMID- 29434076 TI - Differences in Gut Microbiota Profiles between Autoimmune Pancreatitis and Chronic Pancreatitis. AB - Host-derived factors alter gut microenvironment, and changes in gut microbiota also affect biological functions of host. Alterations of gut microbiota have been reported in a wide variety of diseases, but the whole picture of alterations in pancreatic diseases remains to be clarified. In particular, the gut microbiota may be affected by malnutrition or impaired exocrine pancreas function that is associated with pancreatic diseases. We here conducted comprehensive analysis of gut microbiota in patients with type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of the systemic IgG4-related disease, and chronic pancreatitis (CP). The two diseases were selected, because altered immune reactions in AIP and/or long-standing malnutrition in CP may influence the gut microbiota. Fecal samples were obtained from 12 patients with AIP before the steroid therapy and 8 patients with CP. Metagenome DNA was extracted, and microbiota was analyzed by next generation sequencing. Gut microbiota profiles were different between patients with AIP and those with CP; namely, the proportions of Bacteroides, Streptococcus and Clostridium species were higher in patients with CP. The reasons for the increased proportion of these bacterial species remain unknown, but may reflect malabsorption and/or decreased pancreatic enzymes, both of which are associated with CP. Incidentally, the identified Streptococcus species are oral cavity inhabitants and also known as pathogens for endocarditis. Despite the small sample size, this study has shown the differences in gut microbiota profiles between AIP and CP. Comprehensive analysis of the gut microbiota may be useful for the differential diagnosis of pancreatic diseases. PMID- 29434077 TI - Low Proportion of Dietary Plant Protein among Athletes with Premenstrual Syndrome Related Performance Impairment. AB - Premenstrual syndrome (PMS) is psychosomatic disorder that are limited to the late luteal phase in the menstrual cycle. PMS could impair athletic performance. To investigate associations between proportions of dietary plant and animal protein and PMS-related impairment of athletic performance, we surveyed 135 female athletes aged 18-23 years attending Kindai University. Participants belonged to authorized university clubs, all of which have high rankings in Japanese university sports. Participants completed self-administered questionnaires on diet history, demographics, and PMS-related impairment of athletic performance. Total protein, animal protein, and plant protein intake were examined, and the proportion of dietary plant protein was calculated for each participant. We divided athletes into two groups: those without PMS-related impairment of athletic performance (n = 117) and those with PMS-related performance impairment (n = 18). A t-test was used to compare mean values and multivariable adjusted mean values between groups; adjustment variables were energy intake, body mass index, and daily training duration. Total protein intake was not significantly different between the groups. However, athletes whose performance was affected by PMS reported higher intake of animal protein (mean 50.6 g) than athletes whose performance was unaffected by PMS (mean 34.9 g). Plant protein intake was lower among athletes with PMS-related impairment (mean 25.4 g) than among athletes without impairment (mean 26.9 g). The proportion of dietary plant protein was lower among athletes with PMS-related impairment (39.3%) than those without impairment (45.9%). A low proportion of dietary plant protein may cause PMS-related athletic impairment among athletes. PMID- 29434078 TI - Fas-associated protein factor 1 is involved in meiotic resumption in mouse oocytes. AB - Fas-associated protein factor 1 (FAF1) is a Fas-associated protein that functions in multiple cellular processes. Previous research showed that mutations in Faf1 led to the lethality of cleavage stage embryos in a mouse model. The aim of the present study was to analyze the expression pattern, localization, and function of FAF1 in meiotic resumption of mouse oocytes. FAF1 was exclusively expressed in oocytes at various follicular stages within the ovary and was predominantly localized in the cytoplasm of growing oocytes. Furthermore, Faf1 mRNA and protein were persistently present during oocyte maturation and Faf1 mRNA levels were similar in the germinal vesicle (GV), GV breakdown (GVBD), and metaphase II (MII) stages of oocytes. Moreover, knockdown of Faf1 in GV-stage oocytes led to a significantly decreased rate of GVBD. To our knowledge, these results provide the first evidence regarding a novel function of FAF1 in meiotic resumption in mouse oocytes. PMID- 29434079 TI - Strength, functionality and beauty of university buildings in earthquake-prone countries. AB - Strength, functionality and beauty are the three qualities identifying well designed architecture. For buildings in earthquake-prone countries such as Japan, emphasis on seismic safety frequently leads to the sacrifice of functionality and beauty. Therefore, it is important to develop new structural technologies that can ensure the seismic performance of a building without hampering the pursuit of functionality and beauty. The moment-resisting frame structures widely used for buildings in Japan are likely to experience weak-story collapse. Pin-supported walls, which can effectively enhance the structural story-by-story integrity of a building, were introduced to prevent such an unfavorable failure pattern in the seismic retrofit of an eleven-story building on a university campus in Tokyo, while also greatly aesthetically enhancing the facade of the building. The slight damage observed and monitoring records of the retrofitted building during the 2011 Tohoku earthquake in Japan demonstrate that the pin-supported walls worked as intended, protecting the building and guaranteeing the safety of its occupants during the earthquake. PMID- 29434081 TI - Inorganic scintillating materials and scintillation detectors. AB - Scintillation materials and detectors that are used in many applications, such as medical imaging, security, oil-logging, high energy physics and non-destructive inspection, are reviewed. The fundamental physics understood today is explained, and common scintillators and scintillation detectors are introduced. The properties explained here are light yield, energy non-proportionality, emission wavelength, energy resolution, decay time, effective atomic number and timing resolution. For further understanding, the emission mechanisms of scintillator materials are also introduced. Furthermore, unresolved problems in scintillation phenomenon are considered, and my recent interpretations are discussed. These topics include positive hysteresis, the co-doping of non-luminescent ions, the introduction of an aimed impurity phase, the excitation density effect and the complementary relationship between scintillators and storage phosphors. PMID- 29434080 TI - Exploring peptide hormones in plants: identification of four peptide hormone receptor pairs and two post-translational modification enzymes. AB - The identification of hormones and their receptors in multicellular organisms is one of the most exciting research areas and has lead to breakthroughs in understanding how their growth and development are regulated. In particular, peptide hormones offer advantages as cell-to-cell signals in that they can be synthesized rapidly and have the greatest diversity in their structure and function. Peptides often undergo post-translational modifications and proteolytic processing to generate small oligopeptide hormones. In plants, such small post translationally modified peptides constitute the largest group of peptide hormones. We initially explored this type of peptide hormone using bioassay guided fractionation and later by in silico gene screening coupled with biochemical peptide detection, which led to the identification of four types of novel peptide hormones in plants. We also identified specific receptors for these peptides and transferases required for their post-translational modification. This review summarizes how we discovered these peptide hormone-receptor pairs and post-translational modification enzymes, and how these molecules function in plant growth, development and environmental adaptation. PMID- 29434082 TI - Vibration-based monitoring for performance evaluation of flexible civil structures in Japan. AB - The vibration-based monitoring of flexible civil structures and performance evaluation from this monitoring are reviewed, with an emphasis on research and practice in Japan and the author's experiences. Some new findings and unexpected vibrations from the monitoring of real bridges and buildings are reported to emphasize the importance of monitoring. Future developments and applications of vibration-based monitoring to civil infrastructure management are also described. Many examples are taken from the author's past 30 years' experience of research on bridge dynamics. PMID- 29434083 TI - Survey of awareness about hazardous chemicals of residents living near chemical plants in South Korea. AB - With economic growth, the use of chemicals has continually increased, resulting in an increase of chemical accidents. Chemical accidents pose a life threat and can lead to many health problems among the residents living in close proximity to chemical plants. This study aimed to investigate the awareness of the residents living near chemical plants about hazardous chemicals, as well as to survey the awareness of workers who do not directly handle chemicals at chemical plants (WNHCs). To this end, a questionnaire survey was conducted among a total of 600 residents and 160 WNHCs. The questionnaire was composed of three items: awareness of chemical risk, awareness of countermeasures in chemical accidents, and imperious necessity of PPE (personal protective equipment). Statistical analysis of the data was performed with the Statistical Package for Social Sciences (SPSS) version 18.0. The results show that the government needs to complement the notification system of chemical risk for residents who live close to chemical plants. The highest priority of PPE which residents want to prepare for chemical accidents was respiratory protective equipment (RPE). They responded that, if necessary to purchase PPE, they could bear a portion of the expenses (up to US $30). This study provides basic data for the development of programs and policies on chemical safety relevant for the residents living in close proximity to chemical plants in South Korea. PMID- 29434085 TI - Increasing Research Opportunities in Asia Amidst Dramatically Changing Epidemiologic Patterns. PMID- 29434084 TI - Comprehensive Assessment of Risk Factors of Cause-Specific Infant Deaths in Japan. AB - BACKGROUND: Public attention is given to infants with socially high risks of child abuse and neglect, while clinical attention is provided to infants with a biologically high risk of diseases. However, few studies have systematically evaluated how biological or social factors cross over and affect cause-specific infant mortality. METHODS: We linked birth data with death data from the Japanese national vital statistics database for all infants born from 2003-2010. Using multivariate logistic regression, we examined the association between biological and social factors and infant mortality due to medical causes (internal causes), abuse (intentional external causes), and accidents (unintentional external causes). RESULTS: Of 8,941,501 births, 23,400 (0.26%) infants died by 1 year of age, with 21,884 (93.5%) due to internal causes, 175 (0.75%) due to intentional external causes, and 1,194 (5.1%) due to unintentional external causes. Infants with high social risk (teenage mothers, non-Japanese mothers, single mothers, unemployed household, four or more children in the household, or birth outside of health care facility) had higher risk of death by intentional, unintentional, and internal causes. Infant born with small for gestational age and preterm had higher risks of deaths by internal and unintentional causes, but not by intentional causes. CONCLUSIONS: Both biological as well as social factors were associated with infant deaths due to internal and external causes. Interdisciplinary support from both public health and clinical-care professionals is needed for infants with high social or biological risk to prevent disease and injury. PMID- 29434086 TI - [Competence of public health nursing related to home visits by novice public health nurses in Yamagata]. PMID- 29434087 TI - [A nationwide survey of PPSV23 vaccine coverage rates and their related factors among the elderly in Japan, 2016]. PMID- 29434088 TI - [Ethics education in Japanese public health nursing educational institutions]. PMID- 29434089 TI - [Utilization of evacuation surveillance for the Kanto-Tohoku Heavy Rainfall Disaster]. PMID- 29434090 TI - Determinants and Long-Term Outcomes of Percutaneous Coronary Interventions vs. Surgery for Multivessel Disease According to Clinical Presentation. AB - BACKGROUND: The long-term outcome of percutaneous coronary intervention (PCI) vs. coronary artery bypass graft (CABG), particularly for patients with non-ST elevation acute coronary syndrome (NSTE-ACS), remains controversial.Methods and Results:We retrospectively analyzed 2,827 patients (stable coronary artery disease [SCAD], n=1,601; NSTE-ACS, n=1,226) who underwent either PCI (n=1,732) or CABG (n=1,095). The 8-year composite of cardiac death and myocardial infarction (MI) was compared between PCI and CABG before and after propensity matching. For patients with NSTE-ACS, PCI was performed more frequently for those with higher Thrombolysis in Myocardial Infarction risk score and 3-vessel disease, and PCI led to significantly higher 8-year composite of cardiac death and MI than CABG (14.1% vs. 5.9%, hazard ratio [HR]=2.22, 95% confidence interval [CI]=1.37-3.58, P=0.001). There was a significant interaction between clinical presentation and revascularization strategy (P-interaction=0.001). However, after matching, the benefit of CABG vs. PCI was attenuated in patients with NSTE-ACS, whereas it was pronounced in those with SCAD. Interactions between clinical presentation and revascularization strategy were not observed (P-interaction=0.574). CONCLUSIONS: Although the determinants of PCI vs. CABG in real-world clinical practice differ according to the clinical presentation, a significant interaction between clinical presentation and revascularization strategy was not noted for long-term outcomes. The revascularization strategy for patients with NSTE-ACS can be based on the criteria applied to patients with SCAD. PMID- 29434091 TI - Risk of Cardiovascular Disease After Earthquake Disaster. PMID- 29434092 TI - Water Diffusion in the Brain of Chronic Hypoperfusion Model Mice: A Study Considering the Effect of Blood Flow. AB - PURPOSE: Chronic cerebral hypoperfusion model mice were created by unilateral common carotid artery occlusion (UCCAO) surgery, which does not cause cerebral infarction, but which does cause long-term reduction in cerebral blood flow (CBF) to the occluded side. Cognitive dysfunction in this mouse model has been demonstrated in behavioral experiments, but neuron density change was not found in a previous positron emission tomography (PET) study. As a next step, in this study we investigated the injury of neuronal fibers in chronic cerebral hypoperfusion model mice using diffusion tensor imaging (DTI). METHODS: In diffusion-weighted imaging (DWI), not only the diffusion of water but also the capillary flow in the voxel, i.e., intravoxel incoherent motion (IVIM), contributes to the signal. Thus, we used DTI to evaluate DWI signal changes in the brains of chronic hypoperfusion model mice at 4 weeks after UCCAO while monitoring the possible influence of CBF change using arterial spin-labeling (ASL) MRI. RESULTS: Simple t-tests indicated that there were significant differences in CBF between the control and occluded sides of the brain, but there was no significant difference for the mean diffusivity (MD) or fractional anisotropy (FA). However, as Pearson correlation analysis showed that MD was strongly correlated with CBF, analysis-of-covariance (ANCOVA) was then performed using CBF as a covariate and a significant difference in MD between the contra- and ipsilateral sides was found. Performing a similar procedure for the FA found no significant differences. CONCLUSION: The results suggest the injury of neuronal fibers due to chronic hypoperfusion. It is also suggested that CBF related signal changes should be considered when DWI-based information is used for pathological diagnosis. PMID- 29434094 TI - Nano-Materials for Bioimaging. PMID- 29434093 TI - Peripubertal exposure to the neonicotinoid pesticide dinotefuran affects dopaminergic neurons and causes hyperactivity in male mice. AB - Although neonicotinoid pesticides are expected to have harmful influence on mammals, there is little animal experimental data to support the effect and mechanisms. Since acetylcholine causes the release of dopamine, neonicotinoids may confer a risk of developmental disorders via a disturbance in the monoamine systems. Male mice were peripubertally administered dinotefuran (DIN) referring to no observed effect level (NOEL) and performed behavioral and immunohistological analyses. In an open field test, the total locomotor activity was increased in a dose-dependent manner. The immunoreactivity of tyrosine hydroxylase in the substantia nigra was increased in DIN-exposed mice. These results suggest that exposure to DIN in peripubertal male mice causes hyperactivity and a disturbance of dopaminergic signaling. PMID- 29434095 TI - Simple Formation of Cell Arrays Embedded in Hydrogel Sheets and Cubes. AB - Arrays with cell aggregations and single-cell arrays embedded in hydrogel sheets were fabricated by negative dielectrophoretic (n-DEP) cell-manipulation techniques and hydrogel gelation. Cells suspended randomly in a prepolymer solution were rapidly manipulated to form an island-like organization of cells through the repulsive force of n-DEP by using a DEP device consisting of grid electrodes. The cell patterns were retained by irradiating ultraviolet (UV) light so as to urge gelation. Moreover, control of the optical transparency of the grid electrode allows for the fabrication of cubes with single cells and cell aggregation. PMID- 29434096 TI - A Graphene Quantum Dots-Enzyme Hybrid System for the Fluorescence Assay of Alkaline Phosphatase Activity and Inhibitor Screening. AB - A graphene quantum dots (GQDs) and horse radish peroxidase (HRP) hybrid system was designed for the sensing of alkaline phosphatase (ALP) activity and inhibitor screening. We found that the photoluminescence (PL) intensity of GQDs could be quenched efficiently in the presence of phenol, H2O2 and HRP. Moreover, ALP could hydrolyze disodium phenyl phosphate (DPP) to produce phenol, and also could result in the photoluminescence quenching of GQDs. The decrease in the PL intensity was linear to the activity of ALP in the concentration range of 0.02 - 0.8 U/L, with a detection limit of 0.008 U/L. The proposed GQDs/HRP hybrid system was successfully applied to ALP determination in human serum samples. The inhibition study was further analyzed, and Na3VO4 (as an ALP inhibitor) showed a clear inhibition effect. The results suggest that the GQDs/HRP hybrid system has good potential applications for the assay of ALP activity and inhibitors screening in related biochemical fields. PMID- 29434097 TI - Three-dimensional Representation Method Using Pressure, Time, and Number of Theoretical Plates to Analyze Separation Conditions in HPLC Columns. AB - There has been considerable discussion of the speed performance of HPLC separation, especially regarding the relationship between theoretical plates and hold-up time. The fundamental discussion focuses on the optimal velocity, u0,opt, which gives a minimal height equivalent to a theoretical plate of the van Deemter plot. On the other hand, Desmet's method, using the kinetic performance limit (KPL), calculates the highest performance with a constant pressure drop, without focusing solely on the optimal velocity. In this paper, a precise method based on the KPL is proposed, to understand how increasing pressure enhances both theoretical plates and hold-up time. A three-dimensional representation method that combines the pressure drop with two axes of time and theoretical plates will be useful for discussing the effect of pressure in pressure-driven chromatography. Using three dimensions, the methods based on u0,opt and the KPL can be combined, because u0,opt can be visualized three-dimensionally, including the neighbor of u0,opt; and the question of whether the KPL is an asymptotic or effective limit can be investigated. Three performances of high resolution, high speed, and low pressure can be understood on different packing supports at a glance. PMID- 29434098 TI - Promotion Effect of Streptothricin on a Glucose Oxidase Enzymatic Reaction and Its Application to a Colorimetric Assay. AB - Previously, we reported that epsilon-poly-L-lysine (25 - 35 residues) significantly promoted a glucose oxidase enzymatic (GOx) reaction using ferricyanide ion as the oxidant, and that the effect was due to the formation of a polyion complex between anionic GOx and protonated (polycationic) epsilon-poly L-lysine. Here, we show that streptothricins (STs), which have an L-beta-lysine oligomer (1 - 7 residues) and possess only several positive charges at most, also effectively promote the GOx enzymatic reaction. Interestingly, the promotion effect increased with the size of the lysine oligomer of STs, suggesting that the ionic valence is a key factor determining the degree of the promotion effect. The GOx enzymatic reaction is accompanied by a color change due to the reduction of yellow ferricyanide ion to a colorless reductant. A more distinctive color change can be achieved by the addition of Fe(III) ions due to the formation of Prussian blue. Thus, the promotion effect allowed for colorimetric detection of STs at the 1 mg/L level. The detection method was simple and easy to carry out, and would become a helpful tool for the detection of STs. PMID- 29434099 TI - A Thioflavin T-induced G-Quadruplex Fluorescent Biosensor for Target DNA Detection. AB - The detection of disease-related DNA is of great significance for early and accurate diagnosis and therapy. In this work, we successfully achieved the sensitive detection of target DNA based on a thioflavin T (ThT)-induced G quadruplex fluorescent biosensor. ThT, a water-soluble fluorescent dye, can induce G-rich sequences to form G-quadruplexes and obtain an obviously enhanced fluorescence. In this work, it was employed to construct a biosensor for the detection of HIV. When the target HIV existed, the hairpin DNA probes would be opened in succession and release the completely exposed G-rich sequence to combine with ThT. The simple and rapid biosensor performed satisfactory selectivity; it also exhibited sensitivity with a detection limit of 2.4 nM. With good performance in human serum, we believe that this optical biosensor has the potential to be applied to the practical detection of target DNA. PMID- 29434100 TI - Electrochemical Determination of Chromium(VI) in River Water with Gold Nanoparticles-Graphene Nanocomposites Modified Electrodes. AB - In this study, nanocomposites of ligand-free gold nanoparticles that are anchored onto the graphene surface (Graphene/AuNPs) were synthesized by a sonochemical method in a single reaction step. A highly sensitive amperometric sensor using Graphene/AuNPs is proposed for the determination of trace hexavalent chromium Cr(VI) in environmental water samples. Compared with a gold electrode, a glassy carbon electrode and a AuNPs modified glassy carbon electrode, the Graphene/AuNPs modified glassy carbon electrode exhibits the highest electrocatalytic activity and stability towards the reduction of Cr(VI), based on the results by cyclic voltammetry and electrochemical AC impedance studies. This study shows that the Graphene/AuNPs-based sensor can detect Cr(VI) with a low detection limit of 10 nM (~0.5 MUg/L), a wide dynamic range of 0 to 20 MUM (R = 0.999) and very good selectivity and reproducibility. The electrode is applied to the determination of Cr(VI) in river samples with satisfactory recovery values. PMID- 29434101 TI - Microfluidic Analysis with Front-Face Fluorometric Detection for the Determination of Total Inorganic Iodine in Drinking Water. AB - A microfluidic method with front-face fluorometric detection was developed for the determination of total inorganic iodine in drinking water. A polydimethylsiloxane (PDMS) microfluidic device was employed in conjunction with the Sandell-Kolthoff reaction, in which iodide catalyzed the redox reaction between Ce(IV) and As(III). Direct alignment of an optical fiber attached to a spectrofluorometer was used as a convenient detector for remote front-face fluorometric detection. Trace inorganic iodine (IO3- and I-) present naturally in drinking water was measured by on-line conversion of iodate to iodide for determination of total inorganic iodine. On-line conversion efficiency of iodate to iodide using the microfluidic device was investigated. Excellent conversion efficiency of 93 - 103% (%RSD = 1.6 - 11%) was obtained. Inorganic iodine concentrations in drinking water samples were measured, and the results obtained were in good agreement with those obtained by an ICP-MS method. Spiked sample recoveries were in the range of 86%(+/-5) - 128%(+/-8) (n = 12). Interference of various anions and cations were investigated with tolerance limit concentrations ranging from 10-6 to 2.5 M depending on the type of ions. The developed method is simple and convenient, and it is a green method for iodine analysis, as it greatly reduces the amount of toxic reagent consumed with reagent volumes in the microfluidic scale. PMID- 29434102 TI - A "Dual-acceptor Channel" Membraneless Gas-diffusion Unit for Simultaneous Determination of Ethanol and Acetaldehyde in Liquors Using Reverse Flow Injection. AB - A new design of membraneless gas-diffusion unit with dual acceptor channels for separation, collection and simultaneous determination of two volatile analytes in liquid sample is presented. The unit is comprised of three parallel channels in a closed module. A sample is aspirated into the central channel and two kinds of reagents are introduced into the other two channels. Two analytes are isolated from the sample matrix by diffusion into head-space and absorbed into the specific reagents. Non-absorbed vapor is released by opening the programmable controlled lid. The unit was applied to liquors for measurement of ethanol and acetaldehyde using reverse flow injection. Dichromate and nitroprusside were exploited as reagents for colorimetric detection of ethanol and acetaldehyde, respectively. Good linearity ranges (r2 >0.99) with high precision (RSD <2%) and high accuracy (recovery: 90 - 105%) were achieved. The results were compared to the results by GC-FID and no significant difference was observed by paired t-test (95% confidence). PMID- 29434103 TI - A Simple and Highly Sensitive Quantitation of Eicosanoids in Biological Samples Using Nano-flow Liquid Chromatography/Mass Spectrometry. AB - A simple sample preparation method for eicosanoid was developed by the combination of deproteinization and nanoLC-ESI-MS/MS. Eicosanoids are a group of bioactive lipid mediators, present in trace amounts in the body. Therefore, an analytical method for eicosanoids requires superior sensitivity. The method described in this report, which takes advantage of the highly sensitive power of nanoLC-ESI-MS/MS, enabled a simplification of the sample-preparation process. Eicosanoid extraction was performed just by homogenization in methanol with subsequent phospholipid removal, and then the liquid phase was directly subjected to nanoLC-ESI-MS/MS analysis without a condensation process. The quantitation range achieved 0.01 - 100 ng/mL for thromboxane B2, and 0.05 - 100 ng/mL for prostaglandin E2, prostaglandin D2, prostaglandin F2, leukotriene B4, 6-keto prostaglandin F1alpha and 11-dehydro thromboxane B2. Rat brain sample analyses demonstrated the feasibility of the quantification of those seven eicosanoids from biological samples. PMID- 29434104 TI - Detection of Paracetamol in Water and Urea in Artificial Urine with Gold Nanoparticle@Al Foil Cost-efficient SERS Substrate. AB - We demonstrated that a cost-efficient, easy to prepare, hybrid SERS substrate gold nanoparticles (AuNPs) on untreated Al foil (AlF) can effectively detect pharmaceuticals, such as paracetamol and clinical biomarkers, like urea in artificial urine. The limit of detection (LOD) for paracetamol on AuNPs on AlF is superior (0.1 vs. 1 mM ) to the LOD reported for SERS detection of paracetamol in the literature. For SERS detection of urea in urine, AuNPs on both Al foil and Au film performed much better than AuNPs on glass, in terms of the concentration range, linearity and LOD. However, assay on AuNPs on AlF showed a better semi logarithmic trendline with R2 = 0.98 than an assay on AuNPs on Au film with R2 = 0.94. They have comparable sensitivity with LOD 0.024 and 0.017 M, respectively. The limit of quantification (LOQ) of the former is 0.026 M, which makes it sufficient for the quantification of urea in urine at both normal and pathophysiological (0.03 - 0.15 M) concentration. PMID- 29434105 TI - Application of a Lithium-ion Selective Metallacrown to Extraction Spectrophotometric Determination of Lithium in Saline Water. AB - The solvent-extraction behavior of Li+ and Na+ with a Li+ selective metallacrown, [{Ru(eta6-3,5-dimethylanisole)(2,3-pyridinediolate)}3], was investigated in the presence of organic dye anions, 3',3",5',5"-tetrabromophenolphthalein ethyl ester ([TBPE]-), 2,6-dichloroindophenolate, and picrate ([pic]-). Each alkali metal ion was extracted as a 1:1:1 ternary complex of the metal ion, metallacrown, and anion. The Li+/Na+ extraction selectivity is anion dependent and highest with [pic]-. Therefore, we devised an extraction-spectrophotometric determination method for Li+ in saline water based on the extraction of Li+ using the metallacrown and [pic]- for high selectivity and subsequent replacement of [pic]- in the extracted species with [TBPE]- for high sensitivity. When applying this to artificial seawater samples containing known concentrations of Li+, a linear relationship was observed between the absorbance at 571 nm of the organic phase and the Li+ concentration in the samples. By this method, the determination of Li+ at the sub-ppm level in natural seawater is possible. PMID- 29434106 TI - A New Microfluidic Polymer Chip with an Embedded Cationic Surfactant Ion selective Optode as a Detector for the Determination of Cationic Surfactants. AB - A new microfluidic polymer chip with an embedded cationic surfactant (CS) ion selective optode (CS-optode) as a detector of flow-injection analysis (FIA) for the determination of CSs was developed. The optode sensing membrane is based on a poly(vinyl chloride) membrane plasticized with 2-nitrophenyl octyl ether containing tetrabromophenolphthalein ethyl ester. Under the optimal flow conditions of the FIA system, the CS-optode showed a good linear relationship between the peak heights in the absorbance, and the concentrations of CS in a concentration range from 50 to 400 MUmol dm-3. The sample throughput of the present system for the determination of a CS ion (300 MUmol dm-3 zephiramine) was ca. 11 samples h-1. The proposed FIA system was applied to determine the level of CS in dental rinses. PMID- 29434107 TI - Determination of Aqueous Formic and Acetic Acids by Purge-and-Trap Analysis with a Needle-Type Extraction Device and Gas Chromatography Barrier Discharge Ionization Detector. AB - A purge-and-trap method using a needle-type extraction device and a gas chromatography-barrier discharge ionization detector for the analysis of formic (FA) and acetic acids (AA) in aqueous samples is presented. An activated carbon based adsorbent, Carboxen 1000, was employed as the extraction medium for the needle-type extraction device. The sampling time was 5 min for collecting headspace gas in a glass vial, including 10 mL of an aqueous sample. The detection limits for FA and AA with a headspace sampling volume of 100 mL were 3.3 and 2.0 mg L-1, respectively. Since the proposed method was based on purge and-trap collection, it was suitable for the determination of aqueous FA and AA in complex matrices with simple and rapid sample preparation steps. The proposed method was applied to the determination of FA and AA in fruit juice samples and FA generated by the electrochemical reduction of carbon dioxide. PMID- 29434108 TI - Rapid HPLC Analytical Method Development for Herbal Medicine Formulae Based on Retention Rules Acquired from the Constituting Herbs. AB - Herbal medicine (HM) formulae are the combinations of two or more types of constituting herbs. This study has proposed a novel approach to efficiently develop HPLC methods for HM formulae, which take advantage of the mutual retention rules between HM formulae and their constituting herbs. An HM formula composed of two herbs, Radix Salviae Miltiorrhizae and Rhizoma Chuanxiong, was taken as a case study. Based on design of experiments and stepwise multiple linear regression, models relating the analytical parameters to the chromatographic parameters were built (correlation coefficients >0.9870) for chemical compounds in the two herbs. These models representing the retention rules were utilized to predict the elution profile of the formula. The analytical parameters were numerically optimized to ensure adequate separation of the analytes. In validation experiments, satisfactory separations were achieved without any pre-experiments on the formula. The approach can significantly increase the HPLC method development efficiency for HM formulae. PMID- 29434109 TI - Moment Analysis of Mass Transfer Kinetics in Micellar Electrokinetic Chromatography Systems. AB - Moment equations were developed for quantitatively studying the separation characteristics of micellar electrokinetic chromatography (MEKC). They explain how the first absolute and second central moments of elution peaks are correlated with some fundamental parameters of the partition equilibrium and mass transfer kinetics in MEKC systems. In order to discuss the influence of the mass transfer kinetics on peak broadening, the moment equations were used to analyze the separation behavior in MEKC systems. Separation conditions were chosen on the basis of practical MEKC experiments previously conducted. It was quantitatively clarified that both the solute permeation at the interfacial boundary of surfactant micelles and axial diffusion of solute molecules in a capillary had a predominant contribution to the spreading of the elution peaks in MEKC systems. This is a preliminary study for the analytical determination of rate constants concerning solute permeation at the interface of surfactant micelles from elution peak profiles measured by MEKC. In addition, it was also indicated that the experimental conditions of MEKC systems could be controlled so that the interfacial solute permeation would have a predominant role for the band broadening. For example, the contribution of the interfacial permeation was about 33 times larger than that of the axial diffusion of solute molecules under the MEKC conditions in a previous study. This means that the rate constants could appropriately be determined for the interfacial solute permeation. PMID- 29434110 TI - Detection and Quantification of 4-Methylimidazole in Cola by Matrix-assisted Laser Desorption Ionization Mass Spectrometry with Fe2O3 Nanoparticles on Zeolite. AB - Food additives generally used in carbonated drinks, such as 4-methylimidazole (4MI), caffeine (Caf?), citric acid (CA), and aspartame (Apm), were measured by matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) using nanometer-sized particles of iron oxide (Fe2O3 NPs). The quantification of 4MI in Coca Cola (C-cola) was carried out. In order to improve the reproducibility of the peak intensities, Fe2O3 NPs loaded on ZSM5 zeolite were used as the matrix for quantification. By using 2-ethylimidazole (2EI) as the internal standard, the amount of 4MI in C-cola was determined to range from 88 to 65 MUg/355 mL. The results agree with the published value (approx. 72 MUg/355 mL). It was found that MALDI using Fe2O3 was applicable to the quantification of 4MI in C-cola. PMID- 29434111 TI - A Simple and Robust Method for Determination of Alkylmercury in Seawater and Industrial Wastewater by Phenylation Pretreatment Combined with GC-MS. AB - For determination of methylmercury (MeHg) and ethylmercury (EtHg) in seawater and industrial wastewater, a simple and robust analytical method was developed based on phenylation and solvent extraction followed by GC-MS measurement. Alkylmercury compounds were directly phenylated with sodium tetraphenylborate in water and extracted into toluene. The method detection limits obtained for MeHg and EtHg in pure water were 53.3 and 33.5 ng Hg L-1, respectively, which are almost 10 times lower than the environmental quality standards for water pollution in Japan (EQSJ): 0.5 MUg Hg L-1. The recoveries of alkylmercury compounds from seawater and four kinds of industrial wastewater except for EtHg from treated wastewater of an optic lens factory were satisfactory (>90%) at 1- or 4-fold concentrations of the EQSJ. Contrarily, the low recovery of EtHg from the treated wastewater (75.4 +/- 4.7%) was found to be caused by the rapid decomposition of EtHg into inorganic mercury. PMID- 29434112 TI - Temperature-variable NMR Study of the keto-enol Tautomerism of Phenylpyruvic Acid. AB - The keto-enol tautomerism of phenylpyruvic acid (PPA) has been studied by temperature-variable 9.4 T nuclear magnetic resonance (NMR) spectroscopy. It was found that PPA favored its existence in the enol form in dimethyl sulfoxide (DMSO) solvent, 93.5% of the enol and 6.5% of the keto tautomer was present in DMSO at room temperature. Increasing the temperature increased the percentage of the keto form. The experimental thermodynamic parameters for the tautomerism were successfully obtained from the spectral data. PMID- 29434113 TI - Implementation of Tube Radial Distribution Chromatography by Using a Commercially Available HPLC System. AB - Tube radial distribution chromatography based on tube radial distribution flow, or annular flow, in an open-tubular capillary has been reported. The chromatographic system requires specific instruments and treatments for microfluidic flow in the capillary tube. In this study, we have developed a new model of tube radial distribution chromatography, which is comprised of a commercially available HPLC system without any packed separation columns. Separation is performed in an open-tubular pipe (100-MUm inner diameter and 350 cm length; temperature, 5 degrees C) connected between the pump and the detector in the HPLC system. An analyte solution is introduced with a sample injector (2 MUL volume) and a ternary water/acetonitrile/ethyl acetate mixed solution (volume ratio of 3:8:2) is delivered as an eluent solution into the pipe at a flow rate of 10-MUL min-1. Fused silica and stainless pipes can separate 1-naphthol and 2,6 naphthalenedisulfonic acid, but a polyetheretherketone pipe cannot. The obtained data provides an important clue to practical developments in separation science. PMID- 29434114 TI - Droplet-counting Microtitration System for Precise On-site Analysis. AB - A new microtitration system based on the counting of titrant droplets has been developed for precise on-site analysis. The dropping rate was controlled by inserting a capillary tube as a flow resistance in a laboratory-made micropipette. The error of titration was 3% in a simulated titration with 20 droplets. The pre-addition of a titrant was proposed for precise titration within an error of 0.5%. The analytical performances were evaluated for chelate titration, redox titration and acid-base titration. PMID- 29434116 TI - Bactericidal and virucidal efficacies of potassium monopersulfate and its application for inactivating avian influenza virus on virus-spiked clothes. AB - An acidic agent, potassium monopersulfate (PMPS), was evaluated for bactericidal and virucidal effects against Salmonella Infantis (SI), Escherichia coli, rifampicin-resistant Salmonella Infantis (SI-rif), Newcastle disease virus (NDV), and avian influenza virus (AIV), in the absence or presence of organic materials. In addition, inactivation activity toward a virus on virus-spiked clothes was also examined. PMPS could inactivate SI, E. coli, and SI-rif even in the presence of organic materials under various concentrations and exposure/contact time conditions. PMPS could also inactivate NDV and AIV. In addition, PMPS could inactivate AIV on a virus-spiked rayon sheet. In conclusion, the present study showed that PMPS has good antimicrobial properties against SI, E. coli, SI-rif, NDV, and AIV when used at the optimal dosage and exposure timing. These results suggest that PMPS could be used as an alternative disinfectant for biosecurity enhancement in animal farms or hospitals. PMID- 29434117 TI - Prevalence and characteristics of extended-spectrum beta-lactamase-producing Escherichia coli in domestic and imported chicken meats in Japan. AB - The purpose of this study was to investigate the prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESBL-Ec) in retail chicken meats in Japan. Fifty-six domestic and 50 imported (Brazil, n=36; United States, n=8; Thailand, n=6) chicken meat samples were analyzed. The 162 ESBL-Ec included 111 from 43 (77%) domestic samples and 51 from 26 (52%) Brazilian samples. Fifty three and 30 of 111 and 51 ESBL-Ec from domestic and Brazilian chickens, respectively, were selected for ESBL genotyping. The blaCTX-M (91%), blaTEM (36%) and blaSHV (15%) genes were detected in ESBL-Ec isolated from domestic chickens, whereas blaCTX-M (100%) and blaTEM (20%) were detected in ESBL-Ec isolated from imported chickens. Among the blaCTX-M group, blaCTX-M-2 (45%) and blaCTX-M-1 (34%) were prevalent in domestic chicken isolates, whereas blaCTX-M-2 (53%) and blaCTX-M-8 (43%) were prevalent in imported chicken isolates. Domestic chicken isolates were mostly resistant to tetracycline (83%), followed by streptomycin (70%) and nalidixic acid (62%). Imported chicken isolates were resistant to streptomycin (77%), followed by nalidixic acid (63%) and tetracycline (57%). Notably, extensive multidrug resistance was detected in 60% (32/53) and 70% (21/30) ESBL-Ec from domestic and imported chickens, respectively. Virulence genes associated with diarrheagenic and extra-intestinal pathogenic E. coli were detected in ESBL-Ec isolated from domestic and imported chickens. These data suggest that ESBL-Ec in retail chicken meats could be a potential reservoir for antimicrobial resistance determinants and that some are potentially harmful to humans. PMID- 29434118 TI - The Significant Antitumor Activity of Nivolumab in Lung Adenocarcinoma with Choriocarcinomatous Features. AB - We report the case of a 60-year-old Japanese man with a metastatic brain tumor that caused ataxia. As a consequence of resection of a cerebellar tumor, the tumor was diagnosed as a poorly differentiated adenocarcinoma with choriocarcinomatous features. The patient underwent bronchoscopy, leading to a diagnosis of the same histology as the brain tumor. After the administration of first-line chemotherapy and maintenance therapy due to progressive disease, he was given nivolumab and obtained a partial response; however, 11-months later, computed tomography showed tumor progression. Our experience suggests that nivolumab has strong activity, even in patients with a rare form of lung cancer. PMID- 29434119 TI - Helicobacter pylori-negative Advanced Gastric Cancer with Massive Eosinophilia. AB - The incidence of Helicobacter pylori-negative gastric cancer is very low. A 60 year-old man was referred to Tokai University Hospital from a local clinic because of eosinophilia. The laboratory data revealed prominent eosinophilia, with a white blood cell count of 7,900 /MUL and increased eosinophil granulocyte level of 1,659 /MUL. After an examination for secondary eosinophilia, esophagogastroduodenoscopy showed an enlarged gastric fold in the corpus, suggesting type 4 gastric cancer. Repeated esophagogastroduodenoscopy (EGD) and a re-biopsy demonstrated poorly differentiated adenocarcinoma and signet ring cell carcinoma. The patient was negative for Helicobacter pylori infection according to the serum anti-Helicobacter pylori antibody, culture and histopathological findings. PMID- 29434121 TI - Rapid Destructive Coxopathy. PMID- 29434120 TI - Ventricular Septal Perforation: A Rare but Life-Threatening Complication Associated with Takotsubo Syndrome. AB - A 71-year-old woman was admitted with dyspnea. An electrocardiogram revealed ST segment elevation, and echocardiography showed akinesis in the left ventricular apex with hyperkinesis of the base. Coronary angiography revealed no stenosis, and left ventriculography indicated ballooning of the left ventricular apex and apical ventricular septal perforation. We diagnosed the patient with Takotsubo syndrome complicated by ventricular septal perforation, which was surgically repaired. Although ventricular septal perforation is recognized as a life threatening complication after acute myocardial infarction, it can also occur after Takotsubo syndrome. The early recognition and management of this condition can help prevent morbidity and mortality. PMID- 29434123 TI - Visible Liver from Huge Gastric Penetration. PMID- 29434122 TI - Spinocerebellar Ataxia Type 31 with Blepharospasm. AB - A 58-year-old man consulted our hospital due to a 2-year history of dysarthria and a 1-month history of blepharospasm. In addition to the ataxic dysarthria and blepharospasm, a neurological examination demonstrated slight ataxia of the trunk and lower limbs. Brain MRI demonstrated atrophy of the upper portion of the cerebellar vermis. Gene analysis established a diagnosis of spinocerebellar ataxia type 31 (SCA31). Single photon emission computed tomography (SPECT) with the three-dimensional stereotaxic ROI template (3DSRT) software program demonstrated hyperperfusion in the lenticular nucleus and thalamus. Although the association between SCA31 and blepharospasm in our patient remains unclear, we considered that this combination might be more than coincidental. PMID- 29434125 TI - Comment on: Clinical Characteristics of Severe Erosive Esophagitis among Patients with Erosive Esophagitis: A Case-control Study. PMID- 29434124 TI - The Usefulness and Limitations of Point-of-care Cardiac Troponin Measurement in the Emergency Department. AB - Objective This study was carried out to examine the usefulness of point-of-care (POC) cardiac troponin in diagnosing acute coronary syndrome (ACS) and to understand the limitations of a POC cardiac troponin I/T-based diagnoses. Methods Patients whose cardiac troponin levels were measured in the emergency department using a POC system (AQT System; Radiometer, Tokyo, Japan) between January and December 2016 were retrospectively examined (N=1,449). Patients who were < 20 years of age or who were admitted with cardiopulmonary arrest were excluded. The sensitivity and specificity of the POC cardiac troponin levels for the diagnosis of ACS were determined. Result One hundred and twenty of 1,449 total patients had ACS (acute myocardial infarction, n=88; unstable angina n=32). On comparing the receiver operating characteristic (ROC) curves, the area under the curve (AUC) values for POC cardiac troponin I and cardiac troponin T were 0.833 and 0.786, respectively. The sensitivity and specificity of POC cardiac troponin I when using the 99th percentile (0.023 ng/mL) as the diagnostic cut-off value were 69.0% and 88.1%, respectively. The sensitivity of POC cardiac troponin I (99th percentile) was higher in the patients sampled > 3 hours after symptom onset (83.3%) than in those sampled <= 3 hours after symptom onset (58.8%, p < 0.01). Conclusion When sampled > 3 hours after the onset of symptoms, the POC cardiac troponin I level is considered to be suitable for use in diagnosing ACS. However, when sampled <= 3 hours after the onset of symptoms, careful interpretation of POC cardiac troponins is therefore required to rule out ACS. PMID- 29434126 TI - Heart Failure with Hyperthyroidism Demonstrating Discrepancy between the Clinical Course and B-type Natriuretic Peptide Levels. AB - A 35-year-old Japanese man was emergently admitted to our hospital with chief complaints of palpitation and dyspnea. He has been treated for Basedow's disease. He was diagnosed with acute decompensated heart failure, atrial fibrillation and thyrotoxicosis. We started anti-thyroid agents and a treatment for heart failure with beta blockers and diuretics under anti-coagulation therapy. His B-type natriuretic peptide levels remained high, although the heart failure had been compensated and the heart rate was well controlled while hyperthyroidism still existed. We should bear in mind that a discrepancy can exist between the clinical course and the B-type natriuretic peptide level in heart failure patients complicated with hyperthyroidism. PMID- 29434127 TI - Platelet Satellitism. PMID- 29434129 TI - Thoracoscopic Images of Primary Pleural Melanoma. PMID- 29434128 TI - Late-onset Cerebrotendinous Xanthomatosis with a Novel Mutation in the CYP27A1 Gene. AB - Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn disruption in bile acid synthesis characterized by severe systemic xanthomas, cataracts and neurological injuries occurring before adolescence without elevation of the serum cholesterol or triglyceride levels. CTX is caused by a deficiency of the mitochondrial enzyme sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. We herein report a 50-year-old Japanese woman with late-onset CTX who had no relevant symptoms before the development of bilateral Achilles tendon xanthomas in middle age. A genetic analysis revealed a compound heterozygous mutation in the CYP27A1 gene with a previously known missense mutation (NM_000784.3:c.1421 G>A) and a novel frame shift mutation of NM_000784.3:c.1342_1343insCACC. PMID- 29434130 TI - Quetiapine-related Acute Kidney Injury Requiring Transient Continuous Hemodiafiltration. AB - A 73-year-old man, with congestive heart failure due to combined valvar disease, underwent curative surgery. Although the surgery was successful, his clinical course was eventful because of pulmonary complications, and he began to deteriorate mentally. Quetiapine was prescribed, which appeared to effectively settle his mental status. Following the administration of quetiapine, however, he developed acute kidney injury (AKI) that required continuous hemodiafiltration. Subsequent to discontinuation of quetiapine, his renal function gradually improved. Atypical antipsychotic drugs, including quetiapine, are frequently used to treat delirium in elderly patients in the intensive-care setting. This case highlights a potential risk of quetiapine-related AKI. PMID- 29434131 TI - The Palliative Effect of Endoscopic Uncovered Self-expandable Metallic Stent Placement Versus Gastrojejunostomy on Malignant Gastric Outlet Obstruction: A Pilot Study with a Retrospective Chart Review in Saga, Japan. AB - Objective Endoscopic self-expandable metallic stent (SEMS) placement and gastrojejunostomy (GJY) are palliative treatments for malignant gastric outlet obstruction (GOO). The aim of the present study was to compare the palliative effects of these treatments and identify predictors of a poor oral intake after treatment. Methods and Patients In total, 65 patients with GOO at multiple centers in Saga, Japan, were evaluated. Thirty-eight patients underwent SEMS placement, and 27 underwent GJY from January 2010 to December 2016. The characteristics and outcomes of the two groups were compared to detect predictors of treatment failure. Results No significant differences in the technical success, clinical success, post-treatment total protein, hospital discharge, duration from eating disability to death, or post-treatment overall survival were present between the SEMS and GJY groups. More patients in the GJY group than in the SEMS group received chemotherapy (51.4% vs. 26.3%, respectively; p=0.042). The period from treatment to the first meal was longer in the GJY group than in the SEMS group (4.5 vs. 3.0 days, respectively; p=0.013). The present study did not identify any risk factors for failure of SEMS placement. Although the stent length tended to be associated with a poor prognosis, the correlation was not statistically significant (odds ratio: 0.60, 95% confidence interval: 0.36-1.01, p=0.053). Conclusion Patients with GOO started meals more promptly after SEMS than after GJY, but the clinical outcomes were not markedly different between the SEMS and GJY groups. These findings suggest that endoscopic uncovered SEMS placement might be a feasible palliative treatment for GOO. PMID- 29434132 TI - Usefulness of Cutting Balloon Angioplasty Prior to Stenting with Intravascular Ultrasound Imaging Guidance for Spontaneous Multi-vessel Coronary Artery Dissection Including the Left Main Coronary Artery. AB - We report a case of percutaneous coronary intervention for spontaneous multi vessel coronary artery dissection including the left main coronary artery. This case suggests that intracoronary imaging is useful for understanding the complex anatomy and for choosing the appropriate management for effective revascularization. Furthermore, cutting balloon angioplasty prior to stenting is useful for preventing the longitudinal extension of the intramural hematoma and avoiding unnecessary stent implantation. PMID- 29434133 TI - Mantle Cell Lymphoma with a Single Protruding Lesion as the Cause of Intussusception. AB - Mantle cell lymphoma (MCL) is a malignant lymphoma of the gastrointestinal tract that mostly presents as multiple lymphomatous polyposis (MLP); however, MLP with intussusception is rarely reported in MCL. Furthermore, a single protruding lesion with intussusception has never been reported in primary small intestinal MCL. A 70-year-old man presented with pain in the right lower abdomen. Computed tomography and colonoscopy revealed ileocecal intussusception. Ileocecal resection was performed. Histology and immunohistochemistry of the resected specimen showed MCL with a single protruding lesion. The patient was successfully treated with surgery alone and remains in complete remission at the three-year follow-up. PMID- 29434134 TI - A Rare Case of Lupus Nephritis Presenting as Thrombotic Microangiopathy with Diffuse Pseudotubulization Possibly Caused by Atypical Hemolytic Uremic Syndrome. AB - A 31-year-old woman was admitted to our hospital for thrombotic microangiopathy (TMA). She was diagnosed with systemic lupus erythematosus (SLE) and class V lupus nephritis. She had no aggravated SLE activity, Shiga toxin positivity, ADAMTS13 abnormality, or other causes of secondary TMA. Plasma exchange partially improved TMA, and eculizumab was introduced for suspected atypical hemolytic uremic syndrome (aHUS), as eculizumab was effective in suppressing the TMA activity. A kidney biopsy revealed diffusely organized crescents (pseudotubulization) with glomerular and arteriolar endothelial injury and subepithelial immune deposits. Thus, this was a rare case of lupus nephritis presenting as TMA with pseudotubulization possibly caused by aHUS. PMID- 29434135 TI - Multiple Synchronous Sporadic Gastrointestinal Stromal Tumors in the Stomach and Jejunum. AB - A 77-year-old patient was admitted to our hospital for the further examination of melena. A computed tomography scan detected two submucosal tumors (SMTs) in the stomach and jejunum. Double-balloon endoscopy revealed the presence of a delle on the jejunal SMT, suggesting that the SMT was the origin of the gastrointestinal bleeding. Both tumors were surgically resected and subsequently diagnosed via histology as gastrointestinal stromal tumors (GISTs). Furthermore, the two GISTs had different mutations in the c-kit gene, suggesting that they were derived from different clonal origins. This report depicts an extremely rare case of multiple synchronous sporadic GISTs in the stomach and jejunum. PMID- 29434136 TI - Recurrent Drug-induced Liver Injury Caused by the Incidental Readministration of a Kampo Formula Containing Scutellariae Radix. AB - A 67-year-old woman experiencing coughing visited a clinic and was prescribed drugs, including shosaikoto extract, for 4 days. She subsequently suffered from liver injury, but her condition improved after the discontinuation of all medications. Approximately 1 year later, she experienced fatigue, consulted another clinic, and received saikokeishikankyoto extract for 21 days. She subsequently suffered liver injury again. Both shosaikoto and saikokeishikankyoto contain Scutellariae Radix. This case is thought to be one of recurrent drug induced liver injury caused by the incidental readministration of a Kampo formula containing Scutellariae Radix. An awareness of adverse drug events caused by Kampo formulas, especially those containing Scutellariae Radix, is essential. PMID- 29434137 TI - Ipsiversive Ocular Torsion, Skew Deviation, and Hearing Loss as Initial Signs of Anterior Inferior Cerebellar Artery Infarction. AB - A 67-year-old man with hypertension and type 2 diabetes mellitus was admitted to our hospital because of left hearing loss and vertical diplopia. A neurological examination showed ocular torsion, skew deviation, and sensorineural hearing loss in the left ear. Brainstem and cerebellar neurological signs were not observed. Left middle cerebellar peduncle infarction was evident on magnetic resonance imaging. He was treated with antiplatelet, however, the infarct progressed after this administration. Ocular tilt reaction (OTR) involves the triad of ocular torsion, skew deviation, and head tilt. Ipsiversive OTR components associated with hearing loss can be early diagnostic signs of anterior inferior cerebellar artery infarction. PMID- 29434138 TI - Amyotrophic Lateral Sclerosis after Receiving the Human Papilloma Virus Vaccine: A Case Report of a 15-year-old Girl. AB - We herein report a 15-year-old girl who developed rapid progressive muscle weakness soon after the third injection of a bivalent human papilloma virus (HPV) vaccine. Although immunotherapies were performed for possible vaccine-related disorders, she died of respiratory failure 14 months after the onset of the disease. A genetic analysis identified a heterozygous p.P525L mutation of the fused in sarcoma (FUS) gene, and a histopathological analysis was also consistent with FUS-associated amyotrophic lateral sclerosis (ALS) without any evidence of neuroinflammation. We concluded the diagnosis to be FUS-ALS, although we cannot completely rule out the possibility that the vaccination worked as a trigger. PMID- 29434139 TI - Regional Negative Pressure Pulmonary Edema with Pulmonary Thromboembolism. PMID- 29434140 TI - Preoperative Detection of Tumor Seeding after Endoscopic Ultrasonography-guided Fine Needle Aspiration for Pancreatic Cancer. PMID- 29434141 TI - Takayasu Arteritis Coexisting with Sclerosing Osteomyelitis. AB - We report a rare case of a 27-year-old woman with Takayasu arteritis (TAK) complicated by diffuse sclerosing osteomyelitis. She first presented with sclerosing osteomyelitis of the right mandible without evidence of arteritis in the carotid arteries. Eight months later, she complained of left neck pain, and imaging studies revealed the presence of arteritis in the left carotid artery. She was diagnosed with TAK, and immunosuppressive treatment was initiated, which was effective for both the arteritis and the osteomyelitis. Osteomyelitis is an important complication of TAK and bone scintigraphy is useful for its detection. PMID- 29434142 TI - The Author's Reply: Comment on: Clinical Characteristics of Severe Erosive Esophagitis among Patients with Erosive Esophagitis: A Case-control Study. PMID- 29434144 TI - MRI Cannot Detect Calcification for the Diagnosis of Fahr's Syndrome. PMID- 29434143 TI - The Safety and Efficacy of Treatment with Nab-paclitaxel and Carboplatin for Patients with Advanced Squamous Non-small Cell Lung Cancer Concurrent with Idiopathic Interstitial Pneumonias. AB - Objective Although lung squamous cell carcinoma (SCC) accounts for 20-30% of lung cancer cases, new treatment options are limited. The CA031 study showed that nanoparticle albumin-bound-paclitaxel (nab-PTX) plus carboplatin produced a significantly higher overall response rate (41%) than solvent-based paclitaxel plus carboplatin in patients with lung SCC. However, the safety and efficacy of combination chemotherapy of nab-PTX and carboplatin has not yet been established for patients with concurrent lung SCC and idiopathic interstitial pneumonias (IIPs). The aim of this study was to assess the safety and efficacy profiles of nab-PTX and carboplatin in patients with lung SCC and concurrent IIPs. Methods Eight patients with inoperable-stage lung SCC and IIPs were treated with nab-PTX plus carboplatin in a first-line setting between June 2013 and December 2016. One of the eight was a woman, and the median age was 77 (range=72-80) years. Their clinical outcomes, including chemotherapy-associated acute exacerbation of IIPs, were retrospectively investigated. Results The overall response rate was 50%, the median progression-free survival time was 5.6 months, and the median overall survival time was 8.1 months. No patients experienced chemotherapy-related exacerbation of IIPs in the first-line treatment with nab-PTX plus carboplatin. However, IIPs worsened in two of four patients who received second-line chemotherapy. Conclusion Combination chemotherapy of nab-PTX and carboplatin may be an effective and safe treatment option for patients with inoperable lung SCC with IIPs. To confirm this, a large-scale prospective study is needed. PMID- 29434145 TI - Relapsed Myasthenia Gravis after Nivolumab Treatment. AB - Nivolumab is a newly introduced promising therapy for treating lung cancer that restores the anti-tumor immunity by disrupting programmed cell death-1-mediated immuno-suppressive signaling. Although "new-onset" autoimmune diseases are well known immune-related adverse events, whether or not nivolumab exacerbates "pre existing" autoimmune disease remains unclear. We herein report a patient with "pre-existing" myasthenia gravis in whom nivolumab was administered that flared up after the treatment with nivolumab. Regardless of the disease stability, nivolumab has the potential to exacerbate an autoimmune disease, and we must pay close attention to each patient's medical history before administering this agent. PMID- 29434146 TI - Eosinophilic Gastroenteritis in Which Obstructive Jaundice Developed due to Invagination of the Duodenal Wall. AB - A 63-year-old woman was admitted with epigastric pain, eosinophilia, and elevated hepatobiliary enzyme levels. An upper gastrointestinal endoscopic examination showed that the mucosa of the gastroduodenal wall was edematous. Eosinophilic gastroenteritis (EGE) was diagnosed based on eosinophilic infiltration of the gastroduodenal mucosa. Computed tomography showed invagination of the duodenal wall into the common bile duct. The invagination of the duodenal wall improved after conservative therapy, while bile duct drainage was impossible due to the narrowing of the duodenal lumen. EGE was successfully treated without recurrence with steroids and antiallergic therapy. We herein report a rare case of EGE with obstructive jaundice. PMID- 29434147 TI - What Is the Impact of Mildly Altered Consciousness on Acute Hypoxemic Respiratory Failure with Non-invasive Ventilation? AB - Objective A severely altered level of consciousness (ALC) is considered to be a possible contraindication to non-invasive ventilation (NIV). We investigated the association between mild ALC and NIV failure in patients with hypoxemic respiratory failure. Methods A retrospective study was conducted by reviewing the medical charts of patients with de novo hypoxemic respiratory failure who received NIV treatment. The clinical background and the outcomes of patients with and without ALC were compared. Patients Patients who were admitted to our hospital for acute hypoxemic respiratory failure between July 2011 and May 2015 were included in the present study. Results Sixty-six of the 148 patients had ALC. In comparison to the patients without ALC, the patients with ALC were older (median: 72 vs. 78 years, p=0.02), had a higher Acute Physiology and Chronic Health Evaluation II score (18 vs. 19, p=0.02), and received a higher level of inspiratory pressure (8 cmH2O vs. 8, p<0.01). The median Glasgow Coma Scale score of the patients with ALC was 14 (interquartile range, 11-14). There were no significant differences between the groups in the rates of NIV failure (24% vs. 30%, p=0.4) and in-hospital mortality (13% vs. 16%, p=0.3). Conclusion NIV may be successfully applied to treat acute hypoxemic respiratory failure with mild ALC. NIV may be performed, with careful attention to the appropriate timing for intubation. PMID- 29434148 TI - Pseudogout Attack after Pegfilgrastim Administration in Anaplastic Large Cell Lymphoma. AB - A 67-year-old man with relapsed anaplastic large cell lymphoma received salvage chemotherapy, and pegfilgrastim was used to prevent febrile neutropenia. On day 18 of chemotherapy, he developed a pseudogout attack. Although the first symptoms improved, another pseudogout attack occurred when he received the second course of chemotherapy and pegfilgrastim. Filgrastim was then used for the third course of chemotherapy, and a pseudogout attack did not occur. The serum granulocyte stimulating factor (G-CSF) level was extremely elevated only when pegfilgrastim was used, suggesting a relationship between pseudogout and G-CSF. Pseudogout should be recognized as an adverse effect of pegfilgrastim. PMID- 29434150 TI - Bilateral Hydronephrotic Bladder Metastasis from Lung Cancer. PMID- 29434149 TI - Pancytopenia and Myelodysplastic Changes in Aceruloplasminemia: A Case with a Novel Pathogenic Variant in the Ceruloplasmin Gene. AB - A 72-year-old Japanese woman suffered from mild pancytopenia 3 years before her initial hospitalization. On admission, the levels of trace elements, particularly copper, and ceruloplasmin were significantly decreased in her blood serum. Abdominal lymphadenopathy and bone marrow dysplasia were detected. Hemosiderin deposition was observed in her lymph nodes and bone marrow, and magnetic resonance imaging suggested its deposition in various organs. A novel missense pathogenic variant (c.T1670G) was detected in the ceruloplasmin gene, resulting in an amino acid change (p.M557R). When copper deficiency is accompanied by cytopenia and dysplasia in a patient, it is worthwhile to consider a differential diagnosis of aceruloplasminemia. PMID- 29434151 TI - Primary Central Nervous System Post-transplant Lymphoproliferative Disorder Diagnosed by Peripheral Facial Nerve Palsy. AB - Although primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) causes various symptoms depending on the tumor region, there has been no previous report of PCNS-PTLD in the cerebellopontine angle that was diagnosed due to peripheral facial nerve palsy. We herein report a case involving a 62-year-old man with PCNS-PTLD in the cerebellopontine angle who was diagnosed due to peripheral facial nerve palsy. The reduction of immunosuppressive therapy, whole-brain radiotherapy, intrathecal chemotherapy, and rituximab were effective in treating this patient. Physicians should therefore be mindful that PCNS-PTLD can cause peripheral facial nerve palsy in renal transplant recipients. PMID- 29434152 TI - Whipple's Disease with Long-term Endoscopic Follow-up. AB - A 72-year-old man presented with anorexia and 15-kg weight loss over 3 years. Endoscopy revealed yellow, shaggy mucosa alternating with erythematous, eroded mucosa in the duodenum. Biopsy specimens showed massive infiltration of periodic acid-Schiff-positive macrophages in the lamina propria, consistent with Whipple's disease. The patient was treated with intravenous ceftriaxone for four weeks, followed by oral trimethoprim-sulfamethoxazole. His condition improved, and he gradually gained weight. Although the endoscopic findings improved with continuous trimethoprim-sulfamethoxazole administration, macrophage infiltration of the duodenal mucosa persisted. However, the patient has been symptom-free for eight years. PMID- 29434153 TI - Risk Factors for Chest Pain and Fever in Patients Undergoing Pleurodesis with OK 432. AB - Objective In Japan, pleurodesis is often performed using OK-432. However, OK-432 may cause severe chest pain and fever. The risk factors for these complications are unclear. The aim of this study was to identify the risk factors for chest pain and fever caused by pleurodesis with OK-432. Methods The clinical data of 94 patients who underwent pleurodesis with OK-432 were retrospectively analyzed. Patients who developed chest pain (indicated by a record of rescue pain medication) and/or fever (a recorded temperature of >38 degrees C) were identified. A logistic regression analysis was performed to determine the risk factors for these complications. Results Rescue medication for chest pain was required by 43.6% of the patients and 40.4% developed pyrexia after pleurodesis with OK-432. The univariate analysis showed that the likelihood of requiring rescue medication for chest pain was significantly increased in patients of <70 years of age (p=0.028) and in those who were not premedicated with a nonsteroidal anti-inflammatory drug (NSAID; p=0.003). Age <70 years (adjusted odds ratio 2.97, 95% confidence interval 1.10-8.00, p=0.031) and a lack of premedication with an NSAID (adjusted odds ratio 4.21, 95% confidence interval 1.47-12.04, p=0.007) remained significant factors in a multivariate analysis. The absence of NSAID premedication was the only statistically significant risk factor for fever in the univariate analysis (p=0.034). The multivariate analysis revealed no significant risk factors for fever. Conclusion The results of the present study suggest that premedication with an NSAID might be useful for preventing the chest pain caused by pleurodesis with OK-432. Furthermore, caution is advised when managing chest pain in adults of <70 years of age. Prospective studies should be performed to further investigate this issue. PMID- 29434154 TI - The Clinical Features of Ischemic Stroke Patients for Whom Smoking Was Considered the Sole Risk Factor for Ischemic Stroke. AB - Objective The purpose of this study was to clarify the clinical features of ischemic patients for whom cigarette smoking was the sole risk factor for ischemic stroke. Methods Among the 1,329 patients (male, n=833; female, n=496) with acute ischemic stroke who were admitted to our hospital between April 2005 and September 2016, 346 (26%) were smokers [male, n=308 (36.9%); female, 38 (7.6%)]. In 42 (3.1%; male, n=41; female, n=1) cases, cigarette smoking was considered to be the sole risk factor for ischemic stroke. Data regarding gender, age, the clinical type of ischemic stroke, the National Institutes of Health Stroke Scale (NIHSS) score at the admission, the modified Rankin scale (mRS) scores before the onset and at discharge, the progression of symptoms, and the recurrence of infarction were investigated. Results The mean age of the 42 patients was 63.2+/-12.4 years (range, 26-86 years). The clinical types of ischemic stroke included atherothrombosis (n=19), lacunar (n=17), other type (n=2) and undetermined type (n=4). The median NIHSS score at the time of admission for ischemic stroke was 2 (interquartile range: IQR 1-4.25). The median mRS scores before the onset and at the discharge were 0 (IQR 0-0) and 1 (IQR 0 2), respectively. One patient had symptoms of progression; no patients had recurrence of infarction. Conclusion Our findings suggest that cigarette smoking alone may induce ischemic stroke; moreover, patients for whom smoking was the sole risk factor for ischemic stroke showed milder symptoms in comparison to patients with other risk factors; however, ischemic stroke was induced from youth. Since cigarette smoking has detrimental effects on the central nervous system, we suggest that people be encouraged to quit smoking in order to maintain good health. PMID- 29434155 TI - Hyperplasia of Lymphoid Follicles and Lymphangiectasia in the Parietal Pleura in Bucillamine-induced Yellow Nail Syndrome. AB - Yellow nail syndrome (YNS) pleurisy is often difficult to control, and pathological examinations have rarely been reported. We herein report a case of bucillamine-induced YNS in which histopathology of the parietal pleura revealed hyperplasia of the lymphoid follicles and lymphangiectasia. Even after the discontinuation of bucillamine, the pleurisy and lymphedema showed no change. Based on the histopathological findings showing similarity to rheumatoid pleurisy, we administered corticosteroid treatments, and both the pleurisy and lymphedema improved. The findings in the present case suggest that, in bucillamine-induced YNS, pleurisy may be related to inflammation caused by rheumatoid arthritis in addition to abnormalities in lymphatic vessels. PMID- 29434156 TI - Isolated Follicle-stimulating Hormone Deficiency Coincidentally Diagnosed by Hematospermia. PMID- 29434157 TI - Suspected Hepatically Localized Granulomatosis with Polyangiitis. AB - The patient was a 72-year-old woman whose alkaline phosphatase levels had been elevated since she was 56 years old. Liver biopsies obtained when the patient was 64 and 66 years of age led to a suspicion of cholangitis caused by vasculitis. Furthermore, proteinase-3 anti-neutrophil cytoplasmic antibody positivity led to a suspicion of granulomatosis with polyangiitis, but subjective symptoms and disorders in other organs were absent, so this suspicion was not confirmed. Cholangitis caused by vasculitis rarely occurs without vasculitis in other organs. We herein report this case in which we obtained distinctive laparoscopic and imaging findings that raised suspicions of liver circulatory failure. PMID- 29434158 TI - Can Trainees Safely Perform Endoscopic Treatments for Common Bile Duct Stones? A Single-center Retrospective Study. AB - Objective There are no reports on whether or not trainees can safely carry out endoscopic procedures for the removal of common bile duct (CBD) stones. The aim of this study was to investigate the efficacy and safety of endoscopic treatments for CBD stones by trainees. Methods Endoscopic retrograde cholangiopancreatography (ERCP) was performed in 1,016 consecutive patients at our institution during the 6-year study period. The endoscopically treated patients with CBD stones were included in this study. Physicians who had experienced >=300 ERCP procedures were defined as experts, while those who had experienced <300 procedures were defined as trainees. The trainees were replaced by an expert when they could not achieve the established criteria. Patients were divided into the following three groups to retrospectively examine the patients' backgrounds, details of endoscopic treatments, and intra-/post-operative complications: Group A, completed by trainees under supervision of an expert; B, treated by an expert who switched in for a trainee in the middle of the procedure; and C, completed by an expert. Results A total of 325 patients with CBD stones underwent endoscopic treatments. The number included in Groups A, B, and C was 176, 102, and 47, respectively. The bile duct catheter insertion successes rates for Groups A, B, and C were 99.0%, 97.1%, and 100% (p=0.09), and the complete stone removal rates were 94.2%, 94.8%, and 100%, respectively (p=0.07), showing no significant difference among the three groups. Furthermore, the frequency of intra-/post-operative complications was not significantly different among the three groups (p=0.48, p=0.12, respectively). Conclusion This study showed that trainees could safely perform endoscopic procedures in accordance with our facility's criteria during ERCP. PMID- 29434159 TI - Successful Application of Edoxaban in the Treatment of Venous Thromboembolism Recurrence in a Patient with Non-small Cell Lung Cancer after Tumor Shrinkage. AB - This report describes the case of a 66-year-old man with non-small cell lung cancer and venous thromboembolism (VTE). Unfractionated heparin (UFH) was initially used to control VTE before chemotherapy. However, switching UFH to warfarin or edoxaban, a novel oral anticoagulant (NOAC), failed. Chemotherapy was then administered to control the tumor which was thought to have been the main cause of VTE, which had been treated by UFH. After tumor shrinkage was achieved by chemotherapy, we were able to successfully switch from UFH to edoxaban. Controlling the tumor size and activity enabled the use of edoxaban as maintenance therapy for VTE. PMID- 29434160 TI - The Relationship between Bladder, Periarterial and Somatic Neuropathy in Diabetes. AB - Objective Diabetes commonly affects the bladder nerves. However, the relationship among bladder, periarterial and somatic neuropathy in diabetes is not well known. In the present study we investigated these relationships. Methods A total of 110 diabetic subjects were enrolled in the study. All were referred for screening for diabetic neuropathy, irrespective of their symptoms. The patients included 61 men and 49 women; the mean age was 59.3 years (31-85 years); the mean disease duration was 14.0 years (5-30 years); and the mean HbA1c value was 10.1% (5.1 16.3%). We performed a nerve conduction study (NCS, A-alpha/beta and B fiber), ultrasound-based measurement of the post-void residual (PVR) volume (abnormal, >50 mL, mainly A-delta/C fiber) and postural blood pressure measurement (abnormal, >-20 mmHg, A-delta/C fiber). Fisher's exact probability test and Student's t-test were used to analyze the significance of differences. Results NCS abnormality, an abnormal PVR volume, and postural hypotension were noted in 74, 19, and 36 of the subjects, respectively. There were clear relationships between NCS and an abnormal PVR volume (p<0.05), postural hypotension and an abnormal PVR volume (p<0.05), or NCS and postural hypotension (p<0.01). There were also subjects who had NCS abnormality alone, a high PVR volume alone or postural hypotension alone. An abnormal PVR volume was not associated with the HbA1c value, but was clearly related to the duration of diabetes (p<0.05). Conclusion Bladder dysfunction was correlated with somatic and periarterial neuropathy. On the other hand, 16% of the cases of bladder dysfunction occurred in patients without somatic or periarterial neuropathy; thus, the regular measurement of the PVR volume is necessary. PMID- 29434161 TI - The Role of Endoscopic Ultrasound-guided Drainage for Autoimmune Pancreatitis associated Pancreatic Cysts: A Report of Five Cases and a Literature Review. AB - Objective Autoimmune pancreatitis (AIP) has been recognized as a benign disease, which that shows a prompt response to corticosteroid treatment (CST). It was previously believed to not be associated with cyst formation; however, a few cases of AIP-associated pancreatic cyst (PC) have been reported. Some cases were reported to have been effectively treated by CST, while others were refractory to CST. Many of the patients received interventional treatment. Until now, there has been no consensus on the therapeutic strategies for AIP-associated PC. The aim of the present study is to describe a therapeutic strategy for this condition. Methods We conducted a retrospective study of 5 cases of AIP-associated PC that were treated by endoscopic ultrasonography-guided pancreatic fluid collection drainage (ESPD) or CST at Tokyo Medical University Hospital between March 2012 and October 2016, analyzed the therapeutic outcomes, and performed a literature review. Results The initial treatments included CST (n=2) and ESPD (n=3). All of the PCs disappeared after treatment In 1 of the patients who received CST case and 3 of the patients who received ESPD; however, the PC did not disappear in one of the patients who received CST (corticosteroid maintenance therapy), even after the dose of corticosteroids was increased; ESPD was eventually performed and the PC disappeared. There were no procedure-related complaints. Conclusion We propose that CST be administered as the first-line treatment for AIP-associated PC, particularly in cases of PC without a history of CST. However, ESPD can be applied to treat cases of corticosteroid refractory PC. PMID- 29434162 TI - Bradycardia Is a Specific Phenotype of Catecholaminergic Polymorphic Ventricular Tachycardia Induced by RYR2 Mutations. AB - Objective Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited disease characterized by ventricular arrhythmias induced by physical exercise or emotional stress. The major cause of CPVT is mutations in RYR2, which encodes the cardiac ryanodine receptor channel. Recent advances in sequencing technology have yielded incidental findings of RYR2 variants in other cardiac diseases. Analyzing the characteristics of RYR2 variants related to CPVT will be useful for differentiation from those related to other cardiac diseases. We examined the phenotypic characteristics of patients with RYR2 variants. Methods Seventy-nine probands carrying RYR2 variants whose diagnoses were either CPVT (n=68) or long QT syndrome (LQTS; n=11) were enrolled. We compared the characteristics of the electrocardiogram (ECG) and the location of the RYR2 mutations-N-terminal (NT), central region (CR) or C-terminal (CT)-between the two patient groups. Results Using the ECGs available from 53 probands before beta blocker therapies, we analyzed the heart rates (HRs). CPVT probands showed bradycardia more frequently (25/44; 57%) than LQTS probands (1/9; 11%; p=0.024). In CPVT patients, 20 mutations were located in NT, 25 in CR and 23 in CT. In LQTS patients, 5 mutations were located in NT, 2 in CR and 4 in CT. There were no significant differences in the locations of the RYR2 mutations between the phenotypes. Conclusion Bradycardia was highly correlated with the phenotype of CPVT. When a clinically-diagnosed LQTS patient with bradycardia carries an RYR2 mutation, we should be careful to avoid making a misdiagnosis, as the patient may actually have CPVT. PMID- 29434163 TI - Combined Assessment of the Red Cell Distribution Width and B-type Natriuretic Peptide: A More Useful Prognostic Marker of Cardiovascular Mortality in Heart Failure Patients. AB - Objective An increased red cell distribution width (RDW) has been reported to be associated with adverse outcomes in patients with heart failure (HF). This study aimed to evaluate the prognostic power of the combined measurement of RDW and B type natriuretic peptide (BNP) concentrations in patients with HF. Methods and Results We retrospectively studied 116 patients (mean age, 63.7+/-14.3 years) who were admitted for the treatment of HF. Data including demographic information, vital signs, and laboratory and echocardiographic measurements at admission were collected from medical records. The observational period was defined as the number of days from hospitalization, and the study endpoint was defined as cardiovascular death. The mean RDW and BNP concentration at admission were 14.5+/ 2.0% and 626+/-593 pg/mL, respectively. During a median observation period of 1,046 days, 22 patients died of cardiovascular disease. A univariate Cox proportional hazard analysis revealed that both RDW [hazard ratio (HR) 1.252, p = 0.0391] and BNP (HR 1.001, p = 0.0445) were significant prognostic indices for cardiovascular death. A receiver operating characteristic curve analysis revealed that the optimal cut-off RDW and BNP values for cardiovascular death were 14.9% and 686 pg/mL, respectively. The Kaplan-Meier survival curve revealed that the survival rate of patients with both RDW >= 14.9% and BNP >= 686 pg/mL showed the poorest prognosis in comparison to the patients in the other groups. Conclusion The combined assessment of the RDW and BNP concentrations may be useful for predicting mortality in patients with HF. PMID- 29434164 TI - Nivolumab Induces Sustained Liver Injury in a Patient with Malignant Melanoma. AB - A 42-year-old man was diagnosed with cStage IIIb malignant melanoma and underwent resection. After interferon-beta therapy, 18-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) showed multiple lung metastases, and he received nivolumab (2 mg/kg) every 3 weeks, resulting in a total of 17 cycles. After treatment, 18F-FDG PET/CT showed a significant decrease in the size of the metastases, but he had a Grade 4 alanine aminotransferase (ALT) elevation. Liver histology revealed drug-induced liver damage. Therefore, we performed steroid half-pulse therapy followed by oral methylprednisolone, but his ALT level did not completely recover to the normal range even after five months. We herein report a case with specific, sustained liver injury induced by nivolumab as an immune-related adverse events. PMID- 29434165 TI - Pneumatosis Intestinalis. PMID- 29434166 TI - Diabetes Mellitus Induces Hyperreactivity of 5-Hydroxytryptamine (5-HT)-Induced Constriction in Human Internal Thoracic Artery and Is Associated with Increase in the Membrane Protein Level of 5-HT2A Receptor. AB - Studies indicate that 5-hydroxytryptamine (5-HT) released from activated platelets in coronary artery bypass grafting (CABG) induces 5-HT2A receptor mediated graft spasm. We previously reported that 5-HT-induced constriction of human endothelium-denuded saphenous vein (SV) was significantly augmented in patients with diabetes mellitus (DM) than in patients without DM (non-DM), without changes in the levels of the membrane-bound 5-HT2A receptor of their smooth muscle cells. Although the internal thoracic artery (ITA) is the key graft conduit for CABG, the effect of DM on the ITA graft spasm is still unclear. Therefore, in this study, we investigated the effect of DM on 5-HT-induced vasoconstriction and the level of membrane-bound 5-HT2A receptor in ITA grafts. 5 HT-induced constriction of the isolated human endothelial-denuded ITA was significantly higher in patients with DM than in patients without DM. In addition, the level of the 5-HT2A receptor in the membrane fraction of human ITA smooth muscle cells was significantly higher in patients with DM than in those without DM. These results demonstrate that DM is a risk factor for CABG in both venous and arterial conduits, and that it differentially affects the level of the membrane-bound 5-HT2A receptor in the venous and arterial smooth muscle cells. PMID- 29434167 TI - History of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis and Acute Pancreatitis as Risk Factors for Post-ERCP Pancreatitis. AB - BACKGROUND: Previous pancreatitis is a definite patient-related risk factor for pancreatitis after endoscopic retrograde cholangiopancreatography (post-ERCP pancreatitis: PEP). However, the effects of differences in the history of PEP and acute pancreatitis on the occurrence of PEP have not been fully investigated. We examined the relationship between previous PEP or previous acute pancreatitis and procedural factors associated with PEP. METHODS: Clinical data on 1,334 consecutive patients undergoing ERCP between April 2006 and June 2010 were collected. A multivariate logistic regression analysis was conducted to assess the relationship between PEP and the cannulation time (<15 min vs. >=15 min) or total procedure time (<30 min vs. >=30 min) according to previous pancreatitis (previous PEP: pPEP or previous acute pancreatitis: pAP), with adjustments for clinical characteristics. RESULTS: Longer cannulation times (>=15 min) correlated with the occurrence of PEP in the pPEP group (OR=2.97; 95% CI=1.10 to 8.43, P=0.03) and in patients without previous pancreatitis (non-preP group) (OR=2.43; 95% CI=1.41 to 4.14, P= 0.002), but not in the pAP group (OR=2.78; 95% CI=0.50 to 22.42, P= 0.25). In contrast, longer procedure times correlated with the occurrence of PEP in the pAP group (OR=3.93; 95% CI=1.11 to 16.5, P= 0.03), but not in the pPEP group (OR=2.79; 95% CI=0.92 to 9.18, P= 0.068) or non-preP group (OR=0.71; 95% CI=0.39 to 1.24, P= 0.23). CONCLUSIONS: A higher risk of PEP with previous PEP was associated with longer cannulation times, whereas a higher risk of PEP with previous acute pancreatitis was associated with longer procedure times. PMID- 29434168 TI - Compatibility and Stability of Nab-Paclitaxel in Combination with Other Drugs. AB - Albumin-bound paclitaxel (Abraxane(r), nab-paclitaxel) is not recommended to be administered concurrently or sequentially with other drugs due to concern for instability. The need to administer drugs separately increases infusion time. We evaluated the compatibility and stability of solutions containing nab-paclitaxel and other drugs, including gemcitabine hydrochloride, carboplatin, dexamethasone sodium phosphate, granisetron hydrochloride, and palonosetron hydrochloride. We visually examined changes in appearance, pH, and concentration of the mixed solutions of nab-paclitaxel and other drugs for up to 24 h. Concentration was measured using high-performance liquid chromatography (HPLC). The appearance and pH of the mixed solutions did not change for up to 24 h. The change in concentration up to 24 h was within 2%. The chromatogram did not change until 8 h. The results showed that the physical compatibility and chemical stability of nab-paclitaxel were not influenced when it was combined with other drugs until 8 h. This study suggests that nab-paclitaxel could be administered in a mixture or sequentially with other drugs to reduce administration time. PMID- 29434169 TI - Different Patterns in Abdominal Stab Wound in the Self-Inflicted and Assaulted Patients: An Observational Analysis of Single Center Experience. AB - Patterns of penetrating abdominal stab wounds (ASW) may be different according to the mechanism of injury. The purpose of this study was to review and characterize penetrating abdominal stab wounds in self-inflicted wound patients and assaulted patients. We retrospectively analyzed patients with ASW who were admitted to our emergency department from 2007 to 2015. The patients were divided into two groups: self-inflicted wound group and assaulted group. There were 46 stabbing cases in 45 different patients (25 males, 21 females; average age 47 y, range 21 to 85 y). Thirty-three patients were in the self-inflicted wound group and 13 patients were in the assaulted group. Although injury sites were concentrated around the periumbilical and epigastric regions in the self-inflicted wound group, the left lateral abdomen was a favorite site in the assaulted group. The peritoneum was violated in the 17 patients in the self-inflicted wound group and 11 patients in the assaulted group. Both the self-inflicted wound group and assaulted group included patients with previous psychological disorders (28 and 5 patients, respectively). The mean Revised Trauma Score, Probability of Survival, Injury Severity Score and the Acute Physiology and Chronic Health Evaluation II scores were not significantly different between the groups although the Injury Severity Score tended to be higher in the assaulted group. The rate of the peritoneal violation was significantly higher in the assaulted group than in the self-inflicted wound group. We also should be aware of more likelihood of patients with psychological disorders among those with assault wounds. PMID- 29434170 TI - Role of SIRPalpha in Homeostatic Regulation of T Cells and Fibroblastic Reticular Cells in the Spleen. AB - Signal regulatory protein alpha (SIRPalpha), is an immunoglobulin superfamily protein that is predominantly expressed in macrophages and dendritic cells (DCs), especially CD4+ conventional DCs (cDCs). In this study, we demonstrated that, in addition to the reduced number of CD4+ cDCs, the number of T cells was significantly decreased in the spleen of Sirpa-/- mice, in which full-length of SIRPalpha protein was systemically ablated. The size of the T cell zone was markedly reduced in the spleen of Sirpa-/- mice. In addition, Sirpa-/- mice revealed a marked reduction of CCL19, CCL21, and IL-7 expression, which are thought to be important for homeostasis of T cells in the spleen. Consistently, the abundance of fibroblastic reticular cells (FRCs), a subset of stromal cells in the T cell zone, was markedly reduced in the spleen of Sirpa-/- mice compared with Sirpaf/f mice. Moreover, we demonstrated that the mRNA expression of Lymphotoxin (LT) alpha, LTbeta, and LIGHT was significantly reduced in the spleen of Sirpa-/- mice. These data thus suggest that SIRPalpha is essential for steady state homeostasis of T cells and FRCs in the spleen. PMID- 29434171 TI - Association between Intra-Circuit Activated Clotting Time and Incidence of Bleeding Complications during Continuous Renal Replacement Therapy using Nafamostat Mesilate: a Retrospective Pilot Observational Study. AB - It has been proposed that anticoagulant activity during continuous renal replacement therapy with nafamostat mesilate can be monitored by using intra circuit activated clotting time. However, it is still unclear whether activated clotting time would be useful for this purpose. We conducted a retrospective study and included 76 patients who required continuous renal replacement therapy using nafamostat mesilate. We obtained information for pre- and post-filter activated clotting times and bleeding complications. We calculated time-weighted average activated clotting time. We divided the patients into three activated clotting time groups (low, middle, high) according to the tertiles of pre- and post-filter activated clotting times. Regarding post-filter time-weighted average activated clotting time, the incidence of bleeding complications in the high activated clotting time group was significantly higher than those in the low and middle activated clotting time groups (p=0.04). The incidences of bleeding complications were not significantly different among the three groups according to pre-filter time-weighted average activated clotting time (p=0.35). In sensitive analysis, the duration on continuous renal replacement therapy without bleeding complications was significantly longer for filters with post-tw ACT<262 than for those with post-tw ACT>=262 (p=0.03). This result suggested that post filter time-weighted average activated clotting time might be a good predictor of bleeding complications during continuous renal replacement therapy with nafamostat mesilate. Further study is required to refute or confirm our findings. PMID- 29434172 TI - New, Improved Version of the mCOP-PCR Screening System for Detection of Spinal Muscular Atrophy Gene (SMN1) Deletion. AB - BACKGROUND: Spinal muscular atrophy (SMA) is a frequent autosomal recessive disorder, characterized by lower motor neuron loss in the spinal cord. More than 95% of SMA patients show homozygous survival motor neuron 1 (SMN1) deletion. We previously developed a screening system for SMN1 deletion based on a modified competitive oligonucleotide priming-PCR (mCOP-PCR) technique. However, non specific amplification products were observed with mCOP-PCR, which might lead to erroneous interpretation of the screening results. AIM: To establish an improved version of the mCOP-PCR screening system without non-specific amplification. METHODS: DNA samples were assayed using a new version of the mCOP-PCR screening system. DNA samples had already been genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP), showing the presence or absence of SMN1 exon 7. The new mCOP-PCR method contained a targeted pre-amplification step of the region, including an SMN1-specific nucleotide, prior to the mCOP-PCR step. mCOP-PCR products were electrophoresed on agarose gels. RESULTS: No non-specific amplification products were detected in electrophoresis gels with the new mCOP PCR screening system. CONCLUSION: An additional targeted pre-amplification step eliminated non-specific amplification from mCOP-PCR screening. PMID- 29434173 TI - Gender Effects on the Clinical Phenotype in Japanese Patients with Spinal Muscular Atrophy. AB - BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a mutation in SMN1. SMA is classified into three subtypes (types 1, 2, 3) based on achieved motor milestones. Although NAIP and SMN2 are widely accepted as SMA modifying factors, gender-related modifying factors or gender effects on the clinical phenotype are still controversial. METHODS: A total of 122 Japanese patients with SMA, of which SMN1 was homozygously deleted, were analyzed from the perspective of the achieved motor milestone, NAIP status and SMN2 copy number. RESULTS: A predominance of male patients was observed in SMA type 3 (the walker group) without NAIP-deletion or with high SMN2 copy number (3 or 4 copies). CONCLUSION: We suggest the presence of gender-related modifiers on disease severity in SMA patients. The modifiers may contribute only in the presence of NAIP and a high copy number of SMN2. PMID- 29434175 TI - Can Hybrid Educational Activities of Team and Problem Based Learning Program be Effective for Japanese Medical Students? AB - BACKGROUND: The purpose of this study is to investigate the medical students'perceptions of the Hybrid Educational Activities between team based learning (TBL) and problem based learning (PBL) Program (HEATAPP), a novel educational program that combines characteristics of PBL and TBL. METHODS: A five day HEATAPP on infectious diseases was provided to 4th year medical students at Kobe University School of Medicine, Kobe, Japan. After the program, a focus group discussion was held among 6 medical students who participated in HEATAPP. We qualitatively analyzed the recorded data to delineate the effectiveness of, and the perceptions on, HEATAPP. RESULTS: Some students considered HEATAPP being effective as an active learning, and in developing questions. However, some students found active learning difficult to execute, since they were so familiar with passive learning such as lectures and examinations. They also found it difficult to identify important points by reading authentic textbooks on given issues, particularly English textbooks. CONCLUSIONS: Even though active learning and group discussion are underscored as important in medicine, some Japanese medical students may be reluctant to shift towards these since they are so used to passive learning since childhood. English language is another barrier to active learning. The introduction of active learning in the earlier stages of education might be an effective solution. Teachers at medical schools in Japan should be mindful of the students'potentially negative attitudes towards active learning, which is claimed to be successful in western countries. PMID- 29434174 TI - Macrophages Highly Express Carbonic Anhydrase 2 and Play a Significant Role in Demineralization of the Ectopic Calcification. AB - Vascular calcification is an important risk factor for cardiovascular disease, and is closely associated with all-cause mortality. Recently, it has been revealed that vascular calcification is not a passive precipitation of circulating minerals, but is a process actively regulated through machinery similar to bone formation. During the bone remodeling, osteoclasts execute the bone resorption by releasing hydrogen ions to dissolve minerals; however, molecular mechanisms underlying decalcification of ectopically calcified lesions remain largely unknown. Here, we identified a significant role of macrophages in decalcifying the ectopic calcification. Since carbonic anhydrase-2 (CA2) is critically involved in synthesizing hydrogen ions, we investigated its expression in various cells, and found that macrophages highly express CA2. We established a cell free assay system in which ectopic calcification is quantitatively analyzed in vitro, and using this assay system, we revealed that macrophages efficiently decalcify the ectopic calcification. Interestingly, M1 polarized macrophages showed reduced CA2 expression, whereas treatment with inflammatory cytokines and vasoactive peptides decreased CA2 expression in macrophages. Of note, treatment with angiotensin II significantly reduced the decalcification capacity in macrophages in association with reduced CA2 expression. Furthermore, overexpression of CA2 enhanced decalcification capacity in C2C12 myoblast cells. Together, we unveiled a potential role of macrophages in decalcifying the ectopic calcification, and identified that CA2 is critically involved in the cellular decalcification capacity. Activating cellular CA2 has a therapeutic potential in the treatment of ectopic calcification, especially in regressing vascular calcification. PMID- 29434176 TI - Associations Between CagA, VacA, and the Clinical Outcomes of Helicobacter Pylori Infections in Okinawa, Japan. AB - Helicobacter pylori, which is involved in the pathogenesis of gastroduodenal disease, produces CagA and VacA as major virulence factors. CagA is classified into East Asian and Western types based on the number and sequences of its Glu Pro-Ile-Tyr-Ala motifs. The vacA gene has three polymorphic regions: the signal (s), intermediate (i), and middle (m) regions. The lowest gastric cancer mortality rate is seen in Okinawa. On the Japanese mainland (Honshu), most H. pylori produce s1/m1-VacA, which exhibits strong toxicity, and East Asian-type CagA. However, the H. pylori detected in Okinawa produces s1/m2-VacA, which exhibits weak toxicity, or s2/m2-VacA, which is non-toxic, and Western-type CagA. Studies about the i-region of vacA have been performed around the world, but there have been few such studies in Japan. Therefore, the aim of this study was to assess the relationships between the clinical outcomes of H. pylori infections in Okinawa, vacA (especially the i-region genotype), and cagA. H. pylori strains that were collected from patients with gastric cancer or gastric ulcers in Okinawa only produced the i1-type VacA virulence factor. The vacuolating cytotoxin activity of i1-type VacA was stronger than that of i2-type VacA, suggesting that the i-region genotype of vacA is closely associated with vacuolating cytotoxin activity. These results indicate that the i-region genotype of vacA is a useful marker of both H. pylori virulence and the clinical outcomes of H. pylori infections in Okinawa, Japan. PMID- 29434177 TI - The Role of Electrophysiological Severity Scales for Decision-making with Regard to Surgery in Idiopathic Carpal Tunnel Syndrome. AB - The distribution of electrophysiological severity of carpal tunnel syndrome (CTS) in an outpatient setting and whether electrophysiological severity could be an objective tool for decision-making regarding choice of surgery were investigated. During conservative treatment, 1079 outpatients with idiopathic CTS were classified according to the electrophysiological severity scale (Stage 1-5). The results were provided to the patients and explained, but they were not indicated a treatment protocol intentionally. We recommended surgery to those outpatients who presented with difficulty in pinching due to severe thenar atrophy and/ or showing poor response to conservative treatment. However, the decision-making of surgical or nonsurgical treatment remained with patients. In the distribution of severity stages, Stage 4 was the most common (34%). Two hands were not classifiable. Surgery was chosen in 443 of 1077 hands (41.1%): The operation selection rate increased with severity of the stage and the patients with Stage 5 showed the greatest preference among Stage 1-5 (p<0.0001). This was shown in both female and male groups in gender analysis, and in both <= 69 y.o. and >=70 y.o. groups in the age analysis. There was no significant difference between female and male hands, and <= 69 y.o. and >=70 y.o. hands. Among varied reasons for the decision-making process for surgical treatment in CTS, electrophysiological severity scale plays an important role as an objective tool without being influenced by subjective elements; gender and age. PMID- 29434178 TI - A Case Series of Fibro-Osseous Lesions of the Jaws. AB - The aim of this case series was to reveal the difficulties in diagnosing fibro osseous lesions with radiological and histopathological examinations and quantify the potential risk of infection to fibro-osseous legions. To analyze the concordance between radiological and histopathological diagnoses, this retrospective case series included patients who were clinically diagnosed with fibro-osseous lesions via radiological findings and excluded the patients who did not undergo histopathological examinations. This study also included the patients in whom histopathological results confirmed fibro-osseous legions when preoperative radiological diagnosis did not include fibro-osseous legions. Eleven patients (three men, eight women; median age 24.5 years, range 15-57 years) were enrolled. Although radiological diagnoses of fibrous dysplasia (FD) corresponded with histopathological diagnoses in seven patients, mismatches between radiological findings and histopathological results were found in three patients. In one patient, suspected diagnosis with radiological examinations was malignant lymphoma or FD. In two patients, the histopathological differentiation between FD and ossifying fibroma (OF) was difficult. One patient had lesion recurrence which was suspected to be OF with surgical findings and postoperative course after the initial surgery. In three patients, infections of FD were found. Preoperative diagnosis of OF with radiographic feature of unilocular radiolucency is difficult. In cases in which histopathological differentiation between FD and OF is difficult, operative findings should be used because OF is often found to be well-encapsulated and easily enucleated. Bone in FD showing mixed radiolucent radiopaque may be vulnerable to infection. PMID- 29434179 TI - SMA Diagnosis: Detection of SMN1 Deletion with Real-Time mCOP-PCR System Using Fresh Blood DNA. AB - BACKGROUND: Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders. The symptoms are caused by defects of lower motor neurons in the spinal cord. More than 95% of SMA patients are homozygous for survival motor neuron 1 (SMN1) deletion. We previously developed a screening system for SMN1 deletion based on a modified competitive oligonucleotide priming-PCR (mCOP-PCR) technique using dried blood spot (DBS) on filter paper. This system is convenient for mass screening in the large population and/or first-tier diagnostic method of the patients in the remote areas. However, this system was still time-consuming and effort-taking, because it required pre-amplification procedure to avoid non specific amplification and gel-electrophoresis to detect the presence or absence of SMN1 deletion. When the fresh blood samples are used instead of DBS, or when the gel-electrophoresis is replaced by real-time PCR, we may have a simpler and more rapid diagnostic method for SMA. AIM: To establish a simpler and more rapid diagnostic method of SMN1 deletion using fresh blood DNA. METHODS: DNA samples extracted from fresh blood and stored at 4 C for 1 month. The samples were assayed using a real-time mCOP-PCR system without pre-amplification procedures. DNA samples had already been genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP), showing the presence or absence of SMN1 exon 7. The DNA samples were directly subjected to the mCOP-PCR step. The amplification of mCOP PCR was monitored in a real-time PCR apparatus. RESULTS: The genotyping results of the real-time mCOP-PCR system using fresh blood DNA were completely matched with those of PCR-RFLP. In this real-time mCOP-PCR system using fresh blood-DNA, it took only four hours from extraction of DNA to detection of the presence or absence of SMN1 deletion, while it took more than 12 hours in PCR-RFLP. CONCLUSION: Our real-time mCOP-PCR system using fresh blood DNA was rapid and accurate, suggesting it may be useful for the first-tier diagnostic method of SMA. PMID- 29434180 TI - Evaluation of a Small Animal Irradiation System for Animal Experiments Using EBT3 Model GAFCHROMICTM Film. AB - In cancer research, small animal models, for example, mice, rats, or rabbits, facilitate the in-depth study of biological processes and the effects of radiation treatment that can lead to breakthrough discoveries. However, the physical quality of small animal irradiation systems has not been previously evaluated. In this study, we evaluate the quality of a small animal irradiation system using GAFCHROMICTM film and a Tough Water Phantom. The profiles and percentage depth dose curves for several irradiation conditions were measured to evaluate the quality of the irradiation system. The symmetry ratios when the table was rotated were 1.1 (no filter), 1.0 (0.5 mm Al filter), 1.0 (1.0 mm Al filter), 1.1 (2 mm Al filter), and 1.0 (filter consisting of 0.5 mm Al combined with 0.1 mm Cu). The results of measuring the percentage depth dose curve showed that the relative doses were 17.5% (10 mm depth), 12.4% (20 mm depth), 9.5% (30 mm depth), and 7.4% (40 mm filter) with no filters inserted, 78.0% (10 mm depth), 61.1% (20 mm depth), 46.9% (30 mm depth), and 35.3% (40 mm depth) when a 1.0 mm Al filter was inserted, and 94.4% (10 mm depth), 81.7% (20 mm depth), 68.1% (30 mm depth), and 54.7% (40 mm depth) when a filter consisting of 1.0 mm Al combined with 0.2 mm Cu was inserted. These physical assessments seem to be necessary especially in vivo experiments because those increase reliability of data obtained from small animal irradiation systems. PMID- 29434181 TI - Efficacy of Hepatitis B Vaccination among Children in Special Region of Yogyakarta, Indonesia: Evaluation of Humoral and Cellular Immunity. AB - Hepatitis B remains a global burden, with estimated 15 to 40 percents of infected individuals eventually suffer from liver cirrhosis, liver failure, and hepatocellular carcinoma. Vaccination aims to form anti-HBs antibody with protective titer to prevent infection. CD4 T cell lymphocytes are known to play a major role in establishing immunity after vaccination. This study aimed to investigate protective titer rate among Indonesian children in Special Region of Yogyakarta following hepatitis B vaccination and correlation between anti-HBs titer and CD4 count. This is a cross-sectional study with 52 subjects between 8 months to 5 years of age in Bungas Community Health Service, Special Region of Yogyakarta, Indonesia. Anti-HBs titer was examined using enzyme immunoassay and CD4 count was examined using immunocytochemistry method. Of 52 subjects, median anti-HBs titer was 72.965 IU/L (interquartile range 360.98), mean CD4 count was 49.73% +/- 29.75. Protective level of antibody was found in 73.1% of subjects. Correlation test was conducted and no correlation was found between anti-HBs titer and CD4 count (r=-0.104, p=0.464). Age was found to have a weak negative correlation with anti-HBs titer (r=-0.367, p=0.007). We found high rate of protective titer among children in Special Region of Yogyakarta who have completed hepatitis B vaccination series. No correlation was established between anti-HBs titer and CD4 count. PMID- 29434182 TI - Corilagin Attenuates Allergy and Anaphylactic Reaction by Inhibiting Degranulation of Mast Cells. AB - BACKGROUND This study evaluated the anti-allergic activity of corilagin and also postulates the possible mechanism of its action. MATERIAL AND METHODS Corilagin was given orally at dose of 10, 20, and 40 mg/kg/day. All the animals (guinea pigs, rats, and mice) were sensitized for allergy such as eosinophilia and leukocytosis induced by milk; degranulation of mast cell by compound 48/80; and passive and active anaphylaxis. Moreover, the antagonistic effect was determined by estimating the effect of corilagin on contraction of guinea pig tracheal chain and ileum induced by Ach and histamine, respectively. RESULTS There was a significant decrease in the leukocyte and eosinophil counts in the corilagin treated group compared to the negative control group. Treatment with corilagin significantly protects the degranulation of mast cells, and it also has significant anti-muscarinic and antihistaminic activity by reducing the muscle contraction induced by Acetylcholine (Ach) and histamine in guinea pig tracheal chain and ileum. CONCLUSIONS Corilagin possess anti-anaphylactic and anti allergic activity by inhibiting the release of mediators from mast cells and by decreasing the serum concentration of immunoglobulin E (IgE). PMID- 29434183 TI - Plasmacytoid Urothelial Carcinoma of Ureter with Retroperitoneal Metastasis: A Case Report. AB - BACKGROUND Plasmacytoid is a rare histological variant of urothelial carcinoma (UC). Since the first reported case of plasmacytoid urothelial carcinoma (PUC), in 1991, only about 100 cases have since been reported, with most cases involving the bladder. Urothelial carcinomas of the upper urinary tract represent only 5% of urothelial cancers. To the best of our knowledge, there has only been 1 reported case of PUC of the ureter. PUC is a highly aggressive disease, with a poor prognosis. We present a rare biopsy-proven case of PUC of the ureter with retroperitoneal metastasis. CASE REPORT A 60-year-old man came into the hospital with complaints of a 5-day history of generalized abdominal pain, nausea, and vomiting, with no associated urinary symptoms prior to admission. CT demonstrated small bowel obstruction (SBO) and obstructive uropathy due to a right ureteric mass. Exploratory laparotomy, small bowel resection, gastrostomy tube placement, and umbilical hernia repair were all done. Histology and immunohistochemistry were compatible with plasmacytoid variant of urothelial cancer. He underwent a cystouretoscopy and a right ureteral stent placement with a right ureteroscopy. Final CT abdomen/pelvis revealed recurrent SBO before the ileocecal valve, possibly due to carcinomatosis. Ileocecal resection with end ileostomy placement was done. Systemic treatment will begin as an outpatient. CONCLUSIONS PUC arising from the ureter is rare, and retroperitoneal metastatic disease has not been reported previously. Here, we compare the clinical manifestations of the more common PUC of the bladder with our case. From this we are able to learn more about the disease and its presentation. PMID- 29434184 TI - Cyclosporin A Aggravates Calcification of Vascular Smooth Muscle Cells Under High Glucose Conditions with a Calcifying Medium. AB - BACKGROUND Vascular calcification (VC) progresses substantially even after kidney transplantation, and is a predictor of morbidity and mortality. However, the effect of cyclosporin A (CsA) on VC has not been reported in diabetic kidney transplant patients. In this study, we evaluated the effect of CsA on the VC of mouse vascular smooth muscle cells (VSMCs) under high glucose (HG). MATERIAL AND METHODS To demonstrate the effect of CsA (1.0 umol/L) and HG (30 mM) in the induction of the VC of the VSMCs, we determined alkaline phosphatase (ALP) activity, microscopic morphology of calcification, the expressions of the calcification and inflammation-related genes, and the intracellular calcium concentrations in VSMCs. RESULTS Calcification was observed 14 days after exposure to a calcifying medium (sodium phosphate monobasic and dibasic mixture). On microscopic morphology, CsA alone did not induce calcification under HG conditions, but clearly increased calcification under HG with a calcifying medium. ALP activity increased under HG with CsA or a calcifying medium compared to HG conditions alone. CsA increased ALP activity under low glucose (LG, 5.5 mM) with a calcifying medium, but markedly increased under HG with a calcifying medium. CsA significantly increased the mRNA expressions of the calcification markers (core binding factor-alpha 1, bone morphologic proteins 2) as well as those of the inflammatory marker (interleukin 6), under HG with a calcifying medium. Intracellular calcium concentrations were unchanged in CsA alone but significantly increased with the presence of a calcifying medium under both LG and HG conditions. CONCLUSIONS Considering the effect of CsA on VC, the vascular adverse effects of CsA need to be verified in diabetic transplant patients in the future. PMID- 29434185 TI - Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat. AB - Treatments for osteoarthritis (OA) are designed to restore chondrocyte function and inhibit cell apoptosis. Previous studies have shown that activation of the glucagon-like peptide-1 receptor (GLP-1R) leads to anti-inflammatory and anti apoptotic effects. However, the role of GLP-1R in the pathological process of OA is unclear. In present work, we aimed to demonstrate the potential effect of GLP 1R on chondrocytes and elucidate its underlying mechanisms. We found that activation of GLP-1R with liraglutide could protect chondrocytes against endoplasmic reticulum stress and apoptosis induced by interleukin (IL)-1beta or triglycerides (TGs). These effects were partially attenuated by GLP-1R small interfering RNA treatment. Moreover, inhibiting PI3K/Akt signaling abolished the protective effects of GLP-1R by increase the apoptosis activity and ER stress. Activating GLP-1R suppressed the nuclear factor kappa-B pathway, decreased the release of inflammatory mediators (IL-6, tumor necrosis factor alpha), and reduced matrix catabolism in TG-treated chondrocytes; these effects were abolished by GLP-1R knockdown. In the end, liraglutide attenuated rat cartilage degeneration in an OA model of knee joints in vivo. Our results indicate that GLP 1R is a therapeutic target for the treatment of OA, and that liraglutide could be a therapeutic candidate for this clinical application. PMID- 29434186 TI - Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulation. AB - Preconditioning (PC) is a phenomenon wherein a mild insult induces resistance to a later, severe injury. Although PC has been extensively studied in several neurological disorders, no studies have been performed in amyotrophic lateral sclerosis (ALS). Here we hypothesize that a sub-toxic acute exposure to the cycad neurotoxin beta-methylamino-L-alanine (L-BMAA) is able to delay ALS progression in SOD1 G93A mice and that NCX3, a membrane transporter able to handle the deregulation of ionic homeostasis occurring during ALS, takes part to this neuroprotective effect. Preconditioning effect was examined on disease onset and duration, motor functions, and motor neurons in terms of functional declines and severity of histological damage in male and female mice. Our findings demonstrate that a sub-toxic dose of L-BMAA works as preconditioning stimulus and is able to delay ALS onset and to prolong ALS mice survival. Interestingly, preconditioning prevented NCX3 downregulation in SOD1 G93A mice spinal cord, leading to an increased number of motor neurons associated to a reduced astrogliosis, and reduced the denervation of neuromuscular junctions observed in SOD1 G93A mice. These protective effects were mitigated in ncx3+/- mice. This study established for the first time an animal model of preconditioning in ALS and candidates NCX3 as a new therapeutic target. PMID- 29434187 TI - Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple negative breast cancer cells. AB - Glutamine plays an important role in the metabolism of tumor cells through its contribution to redox homeostasis, bioenergetics, synthesis of macromolecules, and signaling. Triple-negative breast cancers (TNBC) are highly metastatic and associated with poor prognosis. TNBC cells show a marked dependence on extracellular glutamine for growth. Herein we demonstrate that TNBC cells are markedly sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon glutamine deprivation. Upregulation of pro apoptotic TRAIL receptor 2 (TRAIL-R2/DR5) and downregulation of FLICE-inhibitory protein (FLIP) are observed in glutamine-deprived TNBC cells. Activation of the amino-acid-sensing kinase general control nonderepressible 2 (GCN2) upon glutamine deprivation is responsible for TRAIL-R2 upregulation through a signaling pathway involving ATF4 and CHOP transcription factors. In contrast, FLIP downregulation in glutamine-deprived TNBC occurs by a GCN2-independent mechanism. Importantly, silencing FLIP expression by RNA interference results in a marked sensitization of TNBC cells to TRAIL-induced apoptosis. In addition, pharmacological or genetic inhibition of transaminases increases TRAIL-R2 expression and downregulates FLIP levels, sensitizing TNBC cells to TRAIL. Interestingly, treatment with L-asparaginase markedly sensitizes TNBC cells to TRAIL through its glutaminase activity. Overall, our findings suggest that targeting the glutamine addiction phenotype of TNBC can be regarded as a potential antitumoral target in combination with agonists of proapoptotic TRAIL receptors. PMID- 29434188 TI - Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder in which genetic and environmental factors synergistically lead to loss of midbrain dopamine (DA) neurons. Mutation of leucine-rich repeated kinase2 (Lrrk2) genes is responsible for the majority of inherited familial cases of PD and can also be found in sporadic cases. The pathophysiological role of this kinase has to be fully understood yet. Hyperactivation of Lrrk2 kinase domain might represent a predisposing factor for both enhanced striatal glutamatergic release and mitochondrial vulnerability to environmental factors that are observed in PD. To investigate possible alterations of striatal susceptibility to mitochondrial dysfunction, we performed electrophysiological recordings from the nucleus striatum of a G2019S Lrrk2 mouse model of PD, as well as molecular and morphological analyses of G2019S Lrrk2-expressing SH-SY5Y neuroblastoma cells. In G2019S mice, we found reduced striatal DA levels, according to the hypothesis of alteration of dopaminergic transmission, and increased loss of field potential induced by the mitochondrial complex I inhibitor rotenone. This detrimental effect is reversed by the D2 DA receptor agonist quinpirole via the inhibition of the cAMP/PKA intracellular pathway. Analysis of mitochondrial functions in G2019S Lrrk2-expressing SH-SY5Y cells revealed strong rotenone-induced oxidative stress characterized by reduced Ca2+ buffering capability and ATP synthesis, production of reactive oxygen species, and increased mitochondrial fragmentation. Importantly, quinpirole was able to prevent all these changes. We suggest that the G2019S-Lrrk2 mutation is a predisposing factor for enhanced striatal susceptibility to mitochondrial dysfunction induced by exposure to mitochondrial environmental toxins and that the D2 receptor stimulation is neuroprotective on mitochondrial function, via the inhibition of cAMP/PKA intracellular pathway. We suggest new possible neuroprotective strategies for patients carrying this genetic alteration based on drugs specifically targeting Lrrk2 kinase domain and mitochondrial functionality. PMID- 29434189 TI - Ablation of protein phosphatase 5 (PP5) leads to enhanced both bone and cartilage development in mice. AB - This study aimed to investigate the role of protein phosphatase 5 (PP5) on bone and cartilage development using both in vivo and in vitro approaches. Six- to 8 week- old male PP5 knockout mice (KO) and their wild-type (WT) littermate controls were randomly selected for this study, and their body weights and bone (femur) lengths were measured. Micro-computed tomography scanning (Micro-CT) was performed to determine femoral bone density and micro-architecture. Mesenchymal stem cells (MSCs) isolated from bone marrow were used to examine the effects of PP5 on osteogenesis in vitro. Whole-mount Alcian blue and Alizarin red staining were used to detect cartilage formation in newborn vertebrae, limbs, and feet. Hematoxylin and eosin (H&E) staining was performed to determine growth plate thickness. Real-time PCR analysis, western blotting, and immunohistochemistry were used to detect the expression of genes and proteins in bone marrow-derived MSCs as well as in bone and cartilage tissues. The results showed PP5 KO mice exhibited significantly reduced body weight and shorter femur length compared to WT controls. The KO mice also had significantly higher volumetric bone mineral density (BMD), trabecular bone volume, and cortical thickness in the femur. The deficiency of PP5 significantly enhanced the formation of cartilage in vertebrae, limbs, and feet. In addition, KO mice possessed a wider distal femur growth plates containing significantly more chondrocytes than WT mice. Furthermore, higher expressions of several cartilage-specific genes were observed in the articular cartilage of PP5 KO mice. Immunohistochemical labeling of growth plates demonstrated that phospho-PPARgamma, Runx1, and Runx2 levels were considerably higher in the KO mice. In conclusion, PP5 is a significant negative regulator on the regulation of bone and cartilage development. PMID- 29434190 TI - MiR-22 suppresses epithelial-mesenchymal transition in bladder cancer by inhibiting Snail and MAPK1/Slug/vimentin feedback loop. AB - MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of bladder cancer (BCa). MiR-22 was previously reported to act as a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in BCa remain unclear. Here, we find that miR 22 is frequently downregulated in BCa tissues compared with adjacent non cancerous tissues. Overexpression of miR-22 significantly inhibits proliferation, migration, and invasion of BCa cells both in vitro and in vivo. Importantly, miR 22 is found to suppress cell proliferation/apoptosis by directly targeting MAPK1 (mitogen-activated protein kinase 1, ERK2) and inhibit cell motility by targeting both MAPK1 and Snail. Further statistical analysis shows that low-expression of MAPK1 or Snail is an independent prognostic factor for a better overall survival in patients with BCa (n = 401). Importantly, we describe an important regenerative feedback loop among vimentin, Slug and MAPK1 in BCa cells. MAPK1 induced Slug expression upregulates vimentin. Vimentin in turn activates MAPK1. By inhibiting Snail and MAPK1/Slug/vimentin feedback loop, miR-22 suppresses epithelial-mesenchymal transition (EMT) of BCa cells in vitro as well as in vivo. Taken together, this study reveals that miR-22 is critical to the proliferation, apoptosis and EMT progression in BCa cells. Targeting the pathway described here may be a novel approach for inhibiting proliferation and metastasis of BCa. PMID- 29434191 TI - Actin nucleator Spire 1 is a regulator of ectoplasmic specialization in the testis. AB - Germ cell differentiation during the epithelial cycle of spermatogenesis is accompanied by extensive remodeling at the Sertoli cell-cell and Sertoli cell spermatid interface to accommodate the transport of preleptotene spermatocytes and developing spermatids across the blood-testis barrier (BTB) and the adluminal compartment of the seminiferous epithelium, respectively. The unique cell junction in the testis is the actin-rich ectoplasmic specialization (ES) designated basal ES at the Sertoli cell-cell interface, and the apical ES at the Sertoli-spermatid interface. Since ES dynamics (i.e., disassembly, reassembly and stabilization) are supported by actin microfilaments, which rapidly converts between their bundled and unbundled/branched configuration to confer plasticity to the ES, it is logical to speculate that actin nucleation proteins play a crucial role to ES dynamics. Herein, we reported findings that Spire 1, an actin nucleator known to polymerize actins into long stretches of linear microfilaments in cells, is an important regulator of ES dynamics. Its knockdown by RNAi in Sertoli cells cultured in vitro was found to impede the Sertoli cell tight junction (TJ)-permeability barrier through changes in the organization of F-actin across Sertoli cell cytosol. Unexpectedly, Spire 1 knockdown also perturbed microtubule (MT) organization in Sertoli cells cultured in vitro. Biochemical studies using cultured Sertoli cells and specific F-actin vs. MT polymerization assays supported the notion that a transient loss of Spire 1 by RNAi disrupted Sertoli cell actin and MT polymerization and bundling activities. These findings in vitro were reproduced in studies in vivo by RNAi using Spire 1-specific siRNA duplexes to transfect testes with Polyplus in vivo-jetPEI as a transfection medium with high transfection efficiency. Spire 1 knockdown in the testis led to gross disruption of F-actin and MT organization across the seminiferous epithelium, thereby impeding the transport of spermatids and phagosomes across the epithelium and perturbing spermatogenesis. In summary, Spire 1 is an ES regulator to support germ cell development during spermatogenesis. PMID- 29434192 TI - Final results of a phase 1b study of the safety and efficacy of the PI3Kdelta inhibitor acalisib (GS-9820) in relapsed/refractory lymphoid malignancies. PMID- 29434193 TI - Absolute marine gravimetry with matter-wave interferometry. AB - Measuring gravity from an aircraft or a ship is essential in geodesy, geophysics, mineral and hydrocarbon exploration, and navigation. Today, only relative sensors are available for onboard gravimetry. This is a major drawback because of the calibration and drift estimation procedures which lead to important operational constraints. Atom interferometry is a promising technology to obtain onboard absolute gravimeter. But, despite high performances obtained in static condition, no precise measurements were reported in dynamic. Here, we present absolute gravity measurements from a ship with a sensor based on atom interferometry. Despite rough sea conditions, we obtained precision below 10-5 m s-2. The atom gravimeter was also compared with a commercial spring gravimeter and showed better performances. This demonstration opens the way to the next generation of inertial sensors (accelerometer, gyroscope) based on atom interferometry which should provide high-precision absolute measurements from a moving platform. PMID- 29434194 TI - Publisher Correction: Sumatran tiger survival threatened by deforestation despite increasing densities in parks. AB - In the original version of the Article, reference 18 was incorrectly numbered as reference 30, and references 19 to 30 were incorrectly numbered as 18 to 29. These errors have now been corrected in the PDF and HTML versions of the manuscript. PMID- 29434195 TI - Glacigenic sedimentation pulses triggered post-glacial gas hydrate dissociation. AB - Large amounts of methane are stored in continental margins as gas hydrates. They are stable under high pressure and low, but react sensitively to environmental changes. Bottom water temperature and sea level changes were considered as main contributors to gas hydrate dynamics after the last glaciation. However, here we show with numerical simulations that pulses of increased sedimentation dominantly controlled hydrate stability during the end of the last glaciation offshore mid Norway. Sedimentation pulses triggered widespread gas hydrate dissociation and explains the formation of ubiquitous blowout pipes in water depths of 600 to 800 m. Maximum gas hydrate dissociation correlates spatially and temporally with the formation or reactivation of pockmarks, which is constrained by radiocarbon dating of Isorropodon nyeggaensis bivalve shells. Our results highlight that rapid changes of sedimentation can have a strong impact on gas hydrate systems affecting fluid flow and gas seepage activity, slope stability and the carbon cycle. PMID- 29434196 TI - A human endothelial cell-based recycling assay for screening of FcRn targeted molecules. AB - Albumin and IgG have remarkably long serum half-lives due to pH-dependent FcRn mediated cellular recycling that rescues both ligands from intracellular degradation. Furthermore, increase in half-lives of IgG and albumin-based therapeutics has the potential to improve their efficacies, but there is a great need for robust methods for screening of relative FcRn-dependent recycling ability. Here, we report on a novel human endothelial cell-based recycling assay (HERA) that can be used for such pre-clinical screening. In HERA, rescue from degradation depends on FcRn, and engineered ligands are recycled in a manner that correlates with their half-lives in human FcRn transgenic mice. Thus, HERA is a novel cellular assay that can be used to predict how FcRn-binding proteins are rescued from intracellular degradation. PMID- 29434197 TI - BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis. AB - Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-beta-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3'-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b 5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anticancer drugs. PMID- 29434198 TI - Resonance Raman signature of intertube excitons in compositionally-defined carbon nanotube bundles. AB - Electronic interactions in low-dimensional nanomaterial heterostructures can lead to novel optical responses arising from exciton delocalization over the constituent materials. Similar phenomena have been suggested to arise between closely interacting semiconducting carbon nanotubes of identical structure. Such behavior in carbon nanotubes has potential to generate new exciton physics, impact exciton transport mechanisms in nanotube networks, and place nanotubes as one-dimensional models for such behaviors in systems of higher dimensionality. Here we use resonance Raman spectroscopy to probe intertube interactions in (6,5) chirality-enriched bundles. Raman excitation profiles for the radial breathing mode and G-mode display a previously unobserved sharp resonance feature. We show the feature is evidence for creation of intertube excitons and is identified as a Fano resonance arising from the interaction between intratube and intertube excitons. The universality of the model suggests that similar Raman excitation profile features may be observed for interlayer exciton resonances in 2D multilayered systems. PMID- 29434199 TI - Single-cell full-length total RNA sequencing uncovers dynamics of recursive splicing and enhancer RNAs. AB - Total RNA sequencing has been used to reveal poly(A) and non-poly(A) RNA expression, RNA processing and enhancer activity. To date, no method for full length total RNA sequencing of single cells has been developed despite the potential of this technology for single-cell biology. Here we describe random displacement amplification sequencing (RamDA-seq), the first full-length total RNA-sequencing method for single cells. Compared with other methods, RamDA-seq shows high sensitivity to non-poly(A) RNA and near-complete full-length transcript coverage. Using RamDA-seq with differentiation time course samples of mouse embryonic stem cells, we reveal hundreds of dynamically regulated non poly(A) transcripts, including histone transcripts and long noncoding RNA Neat1. Moreover, RamDA-seq profiles recursive splicing in >300-kb introns. RamDA-seq also detects enhancer RNAs and their cell type-specific activity in single cells. Taken together, we demonstrate that RamDA-seq could help investigate the dynamics of gene expression, RNA-processing events and transcriptional regulation in single cells. PMID- 29434200 TI - Sustained micellar delivery via inducible transitions in nanostructure morphology. AB - Nanocarrier administration has primarily been restricted to intermittent bolus injections with limited available options for sustained delivery in vivo. Here, we demonstrate that cylinder-to-sphere transitions of self-assembled filomicelle (FM) scaffolds can be employed for sustained delivery of monodisperse micellar nanocarriers with improved bioresorptive capacity and modularity for customization. Modular assembly of FMs from diverse block copolymer (BCP) chemistries allows in situ gelation into hydrogel scaffolds following subcutaneous injection into mice. Upon photo-oxidation or physiological oxidation, molecular payloads within FMs transfer to micellar vehicles during the morphological transition, as verified in vitro by electron microscopy and in vivo by flow cytometry. FMs composed of multiple distinct BCP fluorescent conjugates permit multimodal analysis of the scaffold's non-inflammatory bioresorption and micellar delivery to immune cell populations for one month. These scaffolds exhibit highly efficient bioresorption wherein all components participate in retention and transport of therapeutics, presenting previously unexplored mechanisms for controlled nanocarrier delivery. PMID- 29434201 TI - Advances in the diagnosis and treatment of Clostridium difficile infections. AB - Clostridium difficile is a leading cause of antibiotic-associated diarrhea worldwide. The diagnosis of C. difficile infection (CDI) requires both clinical manifestations and a positive laboratory test for C. difficile and/or its toxins. While antibiotic therapy is the treatment of choice for CDI, there are relatively few classes of effective antibiotics currently available. Therefore, the development of novel antibiotics and/or alternative treatment strategies for CDI has received a great deal of attention in recent years. A number of emerging agents such as cadazolid, surotomycin, ridinilazole, and bezlotoxumab have demonstrated activity against C. difficile; some of these have been approved for limited clinical use and some are in clinical trials. In addition, other approaches such as early and accurate diagnosis of CDI as well as disease prevention are important for clinical management. While the toxigenic culture and the cell cytotoxicity neutralization assay are still recognized as the gold standard for the diagnosis of CDI, new diagnostic approaches such as nucleic acid amplification methods have become available. In this review, we will discuss both current and emerging diagnostic and therapeutic modalities for CDI. PMID- 29434202 TI - Rac1 is a novel therapeutic target in mantle cell lymphoma. PMID- 29434203 TI - Plasma density limits for hole boring by intense laser pulses. AB - High-power lasers in the relativistic intensity regime with multi-picosecond pulse durations are available in many laboratories around the world. Laser pulses at these intensities reach giga-bar level radiation pressures, which can push the plasma critical surface where laser light is reflected. This process is referred to as the laser hole boring (HB), which is critical for plasma heating, hence essential for laser-based applications. Here we derive the limit density for HB, which is the maximum plasma density the laser can reach, as a function of laser intensity. The time scale for when the laser pulse reaches the limit density is also derived. These theories are confirmed by a series of particle-in-cell simulations. After reaching the limit density, the plasma starts to blowout back toward the laser, and is accompanied by copious superthermal electrons; therefore, the electron energy can be determined by varying the laser pulse length. PMID- 29434204 TI - A new high-resolution 3-D quantitative method for analysing small morphological features: an example using a Cambrian trilobite. AB - Taphonomic processes play an important role in the preservation of small morphological features such as granulation or pits. However, the assessment of these features may face the issue of the small size of the specimens and, sometimes, the destructiveness of these analyses, which makes impossible carrying them out in singular specimen, such as holotypes or lectotypes. This paper takes a new approach to analysing small-morphological features, by using an optical surface roughness (OSR) meter to create a high-resolution three-dimensional digital-elevation model (DEM). This non-destructive technique allows analysing quantitatively the DEM using geometric morphometric methods (GMM). We created a number of DEMs from three populations putatively belonging to the same species of trilobite (Oryctocephalus indicus) that present the same cranidial outline, but differ in the presence or absence of the second and third transglabellar furrows. Profile analysis of the DEMs demonstrate that all three populations show similar preservation variation in the glabellar furrows and lobes. The GMM shows that all populations exhibit the same range of variation. Differences in preservation are a consequence of different degrees of cementation and rates of dissolution. Fast cementation enhances the preservation of glabellar furrows and lobes, while fast dissolution hampers preservation of the same structures. PMID- 29434205 TI - Identification of novel PANDAR protein interaction partners involved in splicing regulation. AB - Interactions of long non-coding RNAs (lncRNA) with proteins play important roles in the regulation of many cellular processes. PANDAR (Promotor of CDKN1A Antisense DNA damage Activated RNA) is a lncRNA that is transcribed in a p53 dependent manner from the CDKN1A promoter and is involved in the regulation of proliferation and senescence. Overexpression of PANDAR has been observed in several tumor species and correlated with a poor prognosis for patient survival rate. Depending on the cellular state, PANDAR is known to interact with proteins such as the nuclear transcription factor Y subunit A (NF-YA) and the scaffold attachment factor A (SAF-A). However, a comprehensive analysis of the PANDAR interactome was missing so far. Therefore, we applied peptide nucleic acid (PNA) based pull-downs combined with quantitative mass spectrometry to identify new protein binding partners. We confirmed potential candidates like U2AF65 and PTBP1, known to be involved in RNA processing. Furthermore, we observed that overexpression of PANDAR leads to a reduced level of the short pro-apoptotic BCL X splice variant (BCL-XS) which is regulated by PTBP1. Simultaneous overexpression of PTBP1 was able to rescue this effect. Overall, our data suggest a role for PANDAR in the regulation of splicing events via its interaction partner PTBP1. PMID- 29434206 TI - Dynamically tunable band stop filter enabled by the metal-graphene metamaterials. AB - Dynamically tunable band stop filter based on metal-graphene metamaterials is proposed and numerically investigated at mid-infrared frequencies. The proposed filter is constructed by unit cells with simple gold strips on the stack of monolayer graphene and the substrate of BaF2. A stable modulation depth up to 23.26 dB can be achieved. Due to the cooperative effect of the "bright-bright" elements, the amount of the gold strips in each unit cell determines the number of the stop-bands, providing a simple and flexible approach to develop multispectral devices. Further investigations illustrate that the location of the stop bands not only can be adjusted by varying the length of gold strips, but also can be dynamically controlled by tuning the Fermi energy level of graphene, and deep modulation is acquired through designing the carrier mobility. With the sensitivity as high as 2393 nm/RIU of the resonances to the varieties of surrounding medium, the structure is also enabled to be an index based sensor. The results will benefit the on plane or integrated micro-structure research with simple structure and flexible tunability, and can be applied in multi-band stop filters, sensors and other graphene-based multispectral devices. PMID- 29434207 TI - Jasmonic acid ameliorates alkaline stress by improving growth performance, ascorbate glutathione cycle and glyoxylase system in maize seedlings. AB - Environmental pollution by alkaline salts, such as Na2CO3, is a permanent problem in agriculture. Here, we examined the putative role of jasmonic acid (JA) in improving Na2CO3-stress tolerance in maize seedlings. Pretreatment of maize seedlings with JA was found to significantly mitigate the toxic effects of excessive Na2CO3 on photosynthesis- and plant growth-related parameters. The JA induced improved tolerance could be attributed to decreased Na uptake and Na2CO3 induced oxidative damage by lowering the accumulation of reactive oxygen species and malondialdehyde. JA counteracted the salt-induced increase in proline and glutathione content, and significantly improved ascorbic acid content and redox status. The major antioxidant enzyme activities were largely stimulated by JA pretreatment in maize plants exposed to excessive alkaline salts. Additionally, increased activities of glyoxalases I and II were correlated with reduced levels of methylglyoxal in JA-pretreated alkaline-stressed maize plants. These results indicated that modifying the endogenous Na+ and K+ contents by JA pretreatment improved alkaline tolerance in maize plants by inhibiting Na uptake and regulating the antioxidant and glyoxalase systems, thereby demonstrating the important role of JA in mitigating heavy metal toxicity. Our findings may be useful in the development of alkali stress tolerant crops by genetic engineering of JA biosynthesis. PMID- 29434208 TI - Cognition, emotion and reward networks associated with sex differences for romantic appraisals. AB - Romantic love is a cross-culturally universal phenomenon that serves as a commitment device for motivating pair bonding in human beings. Women and men may experience different feelings when viewing the same warm, romantic scenes. To determine which brain systems may be involved in romance perception and examine possible sex differences, we scanned 16 women and 16 men who were intensely in love, using functional MRI. Participants were required to rate the romance level of 60 pictures showing romantic events that may frequently occur during romantic relationship formation. The results showed that greater brain activation was found for men in the insula, PCC (posterior cingulate cortex), and prefrontal gyrus compared with women, primarily under the High-romance condition. In addition, enhanced functional connectivity between the brain regions involved in the High-romance condition in contrast to the Low-romance condition was only found for men. These data suggest that men and women differ in the processing of romantic information and that it may be more effortful for men to perceive and evaluate romance degree. PMID- 29434209 TI - Long term Follow-up of Transvaginal Anatomical Implant of Mesh in Pelvic organ prolapse. AB - Transvaginal mesh (TVM) is a minimally invasive but effective treatment for pelvic organ prolapse (POP). However, mesh exposure is a common and problematic complication after TVM. This study assessed the safety and long-term outcomes of TVM. A retrospective review was performed on the medical records of 175 consecutive patients who underwent TVM with the anatomical implant technique for pelvic organ prolapse at our center from April 2007 to December 2012. All operations were performed using TVM with the anatomical implant technique. Intraoperative variables, postoperative complications, and TVM outcomes were assessed. In average of 8 years (ranging from 4 to 10 years), the objective cure ratio reached 99.4%; and the subjective success rate of the TVM operation was 91.4%. Only 2 cases (1.1%) were identified as having mesh exposure. The reoperation rate was 4.0% (95% CI, 1.1-6.9%). No patients abstained from sex due to the operation or postoperative discomfort. Our anatomical implant technique for correcting POP is feasible in TVM procedures, which lead to favourable subjective and objective outcomes with the lowest rates of mesh exposure (1.1%) in published data. Therefore, performing TVM operations with the appropriate technique could consider to be permitted. PMID- 29434210 TI - Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet induced obesity in adulthood. AB - The nutritional environment to which animals are exposed in early life can lead to epigenetic changes in the genome that influence the risk of obesity in later life. Here, we demonstrate that the fibroblast growth factor-21 gene (Fgf21) is subject to peroxisome proliferator-activated receptor (PPAR) alpha-dependent DNA demethylation in the liver during the postnatal period. Reductions in Fgf21 methylation can be enhanced via pharmacologic activation of PPARalpha during the suckling period. We also reveal that the DNA methylation status of Fgf21, once established in early life, is relatively stable and persists into adulthood. Reduced DNA methylation is associated with enhanced induction of hepatic FGF21 expression after PPARalpha activation, which may partly explain the attenuation of diet-induced obesity in adulthood. We propose that Fgf21 methylation represents a form of epigenetic memory that persists into adulthood, and it may have a role in the developmental programming of obesity. PMID- 29434211 TI - A cold-inducible RNA-binding protein (CIRP)-derived peptide attenuates inflammation and organ injury in septic mice. AB - Cold-inducible RNA-binding protein (CIRP) is a novel sepsis inflammatory mediator and C23 is a putative CIRP competitive inhibitor. Therefore, we hypothesized that C23 can ameliorate sepsis-associated injury to the lungs and kidneys. First, we confirmed that C23 dose-dependently inhibited TNF-alpha release, IkappaBalpha degradation, and NF-kappaB nuclear translocation in macrophages stimulated with CIRP. Next, we observed that male C57BL/6 mice treated with C23 (8 mg/kg BW) at 2 h after cecal ligation and puncture (CLP) had lower serum levels of LDH, ALT, IL 6, TNF-alpha, and IL-1beta (reduced by >=39%) at 20 h after CLP compared with mice treated with vehicle. C23-treated mice also had improved lung histology, less TUNEL-positive cells, lower serum levels of creatinine (34%) and BUN (26%), and lower kidney expression of NGAL (50%) and KIM-1 (86%). C23-treated mice also had reduced lung and kidney levels of IL-6, TNF-alpha, and IL-1beta. E-selectin and ICAM-1 mRNA was significantly lower in C23-treated mice. The 10-day survival after CLP of vehicle-treated mice was 55%, while that of C23-treated mice was 85%. In summary, C23 decreased systemic, lung, and kidney injury and inflammation, and improved the survival rate after CLP, suggesting that it may be developed as a new treatment for sepsis. PMID- 29434212 TI - CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. AB - CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 is often overexpressed in human cancers. However, clinically applicable cancer therapeutic strategies based on CARM1 expression remain to be explored. Here, we report that EZH2 inhibition is effective in CARM1-expressing epithelial ovarian cancer. Inhibition of EZH2 activity using a clinically applicable small molecule inhibitor significantly suppresses the growth of CARM1-expressing, but not CARM1-deficient, ovarian tumors in two xenograft models and improves the survival of mice bearing CARM1 expressing ovarian tumors. The observed selectivity correlates with reactivation of EZH2 target tumor suppressor genes in a CARM1-dependent manner. Mechanistically, CARM1 promotes EZH2-mediated silencing of EZH2/BAF155 target tumor suppressor genes by methylating BAF155, which leads to the displacement of BAF155 by EZH2. Together, these results indicate that pharmacological inhibition of EZH2 represents a novel therapeutic strategy for CARM1-expressing cancers. PMID- 29434213 TI - Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival. AB - Metabolic reprogramming is pivotal to sustain cancer growth and progression. As such dietary restriction therapy represents a promising approach to starve and treat cancers. Nonetheless, tumors are dynamic and heterogeneous populations of cells with metabolic activities modulated by spatial and temporal contexts. Autophagy is a major pathway controlling cell metabolism. It can downregulate cell metabolism, leading to cancer cell quiescence, survival, and chemoresistance. To understand treatment dynamics and provide rationales for better future therapeutic strategies, we investigated whether and how autophagy is involved in the chemo-cytotoxicity and -resistance using two commonly used human glioblastoma (GBM) cell lines U87 and U251 together with primary cancer cells from the GBM patients. Our results suggest that autophagy mediates chemoresistance through reprogramming cancer cell metabolism and promoting quiescence and survival. Further unbiased transcriptome profiling identified a number of clinically relevant pathways and genes, strongly correlated with TCGA data. Our analyses have not only reported many well-known tumor players, but also uncovered a number of genes that were not previously implicated in cancers and/or GBM. The known functions of these genes are highly suggestive. It would be of high interest to investigate their potential involvement in GBM tumorigenesis, progression, and/or drug resistance. Taken together, our results suggest that autophagy inhibition could be a viable approach to aid GBM chemotherapy and combat drug resistance. PMID- 29434214 TI - Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy. AB - Inflammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 inflammasome activation is a newly identified amplifying step in the pathogenesis of myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1beta, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 inflammasome activation and IL-1beta secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory effect of MSC on NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of the anti oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1beta-positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive effect of MSC on inflammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fibrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 inflammasome activation. PMID- 29434215 TI - Author Correction: Remora cranial vein morphology and its functional implications for attachment. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29434217 TI - IL-23 and IL-27 Levels in Serum are Associated with the Process and the Recovery of Guillain-Barre Syndrome. AB - IL-23 and IL-27 are believed to be involved in the pathogenesis of Guillain-Barre syndrome (GBS). However, changes in these cytokines during the dynamic pathological and recovery processes of GBS are not well described. In the present study, plasma was collected from 83 patients with various stages of GBS, 70 patients with central nervous system demyelinating diseases,70 patients with other neurological diseases (OND) and 70 age- and sex-matched healthy volunteers. Serum levels of IL-23, IL-27, and Campylobacter jejuni (CJ) IgM were assessed using enzyme linked immunosorbent assay (ELISA). We found that serum IL-23 levels of patients during the acute phase of GBS were significantly higher followed by a decreasing trend during the recovery phase of the disease. Serum IL-27 levels significantly increased during the acute phase of GBS, and gradually increased during the recovery phase. Interestingly, both the severity and subtype of GBS were closely associated with the two cytokines. IL-23 levels were positively correlated with IL-27 levels, prognosis, and other clinical parameters. Our findings confirm that IL-23 may show pro-inflammatory effects, especially at the early stage of GBS. IL-27 appears to have a dual role in GBS, with initial pro inflammatory effects, followed by anti-inflammatory properties during recovery. PMID- 29434216 TI - A large-scale RNA interference screen identifies genes that regulate autophagy at different stages. AB - Dysregulated autophagy is central to the pathogenesis and therapeutic development of cancer. However, how autophagy is regulated in cancer is not well understood and genes that modulate cancer autophagy are not fully defined. To gain more insights into autophagy regulation in cancer, we performed a large-scale RNA interference screen in K562 human chronic myeloid leukemia cells using monodansylcadaverine staining, an autophagy-detecting approach equivalent to immunoblotting of the autophagy marker LC3B or fluorescence microscopy of GFP LC3B. By coupling monodansylcadaverine staining with fluorescence-activated cell sorting, we successfully isolated autophagic K562 cells where we identified 336 short hairpin RNAs. After candidate validation using Cyto-ID fluorescence spectrophotometry, LC3B immunoblotting, and quantitative RT-PCR, 82 genes were identified as autophagy-regulating genes. 20 genes have been reported previously and the remaining 62 candidates are novel autophagy mediators. Bioinformatic analyses revealed that most candidate genes were involved in molecular pathways regulating autophagy, rather than directly participating in the autophagy process. Further autophagy flux assays revealed that 57 autophagy-regulating genes suppressed autophagy initiation, whereas 21 candidates promoted autophagy maturation. Our RNA interference screen identifies identified genes that regulate autophagy at different stages, which helps decode autophagy regulation in cancer and offers novel avenues to develop autophagy-related therapies for cancer. PMID- 29434218 TI - Association of cytosolic sialidase Neu2 with plasma membrane enhances Fas mediated apoptosis by impairing PI3K-Akt/mTOR-mediated pathway in pancreatic cancer cells. AB - Modulation of sialylation by sialyltransferases and sialidases plays essential role in carcinogenesis. There are few reports on sialyltransferase, however, the contribution of cytosolic sialidase (Neu2) remains unexplored in pancreatic ductal adenocarcinoma (PDAC). We observed lower expression of Neu2 in different PDAC cells, patient tissues, and a significant strong association with clinicopathological characteristics. Neu2 overexpression guided drug-resistant MIAPaCa2 and AsPC1 cells toward apoptosis as evidenced by decreased Bcl2/Bax ratio, activation of caspase-3/caspase-6/caspase-8, PARP reduction, reduced CDK2/CDK4/CDK6, and cyclin-B1/cyclin-E with unaffected caspase-9. Neu2 overexpressed cells exhibited higher expression of Fas/CD95-death receptor, FasL, FADD, and Bid cleavage confirming extrinsic pathway-mediated apoptosis. alpha2,6 linked sialylation of Fas helps cancer cells to survive, which is a substrate for Neu2. Therefore, their removal should enhance Fas-mediated apoptosis. Neu2 overexpressed cells indeed showed increased enzyme activity even on membrane. Interestingly, this membrane-bound Neu2 exhibited enhanced association with Fas causing its desialylation and activation as corroborated by decreased association of Fas with alpha2,6-sialic acid-binding lectin. Additionally, enhanced cytosolic Neu2 inhibited the expression of several growth factor-mediated signaling molecules involved in PI3K/Akt-mTOR pathway probably through desialylation which in turn also causes Fas activation. Furthermore, Neu2-overexpressed cells exhibited reduced cell migration, invasion with decreased VEGF, VEGFR, and MMP9 levels. To the best of our knowledge, this is the first report of cytosolic Neu2 on membrane, its association with Fas, enhanced desialylation, activation, and Fas-mediated apoptosis. Taken together, our study ascertains a novel concept by which the function of Fas/CD95 could be modulated indicating a critical role of upstream Neu2 as a promising target for inducing apoptosis in pancreatic cancer. PMID- 29434219 TI - Nemopilema nomurai jellyfish venom exerts an anti-metastatic effect by inhibiting Smad- and NF-kappaB-mediated epithelial-mesenchymal transition in HepG2 cells. AB - Epithelial-mesenchymal transition (EMT) is a key initial step in metastasis for malignant cancer cells to obtain invasive and motile properties. Inhibiting EMT has become a new strategy for cancer therapy. In our previous in vivo study, Nemopilema nomurai jellyfish venom (NnV) -treated HepG2 xenograft mice group showed that E-cadherin expression was strongly detected compared with non-treated groups. Therefore, this study aimed to determine whether NnV could inhibit the invasive and migratory abilities of HepG2 human hepatocellular carcinoma cells and to examine its effect on EMT. Our results revealed that transforming growth factor (TGF)-beta1 induced cell morphological changes and downregulated E cadherin and beta-catenin expression, but upregulated N-cadherin and vimentin expression through the Smad and NF-kappaB pathways in HepG2 cells. Treatment of TGF-beta1-stimulated HepG2 cells with NnV reversed the EMT-related marker expression, thereby inhibiting cell migration and invasion. NnV also significantly suppressed the activation of p-Smad3, Smad4, and p-NF-kappaB in a dose-dependent manner. These data indicated that NnV can significantly suppress cell migration and invasion by inhibiting EMT in HepG2 cells, and therefore might be a promising target for hepatocellular carcinoma therapeutics. PMID- 29434221 TI - Blue mussel shell shape plasticity and natural environments: a quantitative approach. AB - Shape variability represents an important direct response of organisms to selective environments. Here, we use a combination of geometric morphometrics and generalised additive mixed models (GAMMs) to identify spatial patterns of natural shell shape variation in the North Atlantic and Arctic blue mussels, Mytilus edulis and M. trossulus, with environmental gradients of temperature, salinity and food availability across 3980 km of coastlines. New statistical methods and multiple study systems at various geographical scales allowed the uncoupling of the developmental and genetic contributions to shell shape and made it possible to identify general relationships between blue mussel shape variation and environment that are independent of age and species influences. We find salinity had the strongest effect on the latitudinal patterns of Mytilus shape, producing shells that were more elongated, narrower and with more parallel dorsoventral margins at lower salinities. Temperature and food supply, however, were the main drivers of mussel shape heterogeneity. Our findings revealed similar shell shape responses in Mytilus to less favourable environmental conditions across the different geographical scales analysed. Our results show how shell shape plasticity represents a powerful indicator to understand the alterations of blue mussel communities in rapidly changing environments. PMID- 29434220 TI - The plant-specific histone residue Phe41 is important for genome-wide H3.1 distribution. AB - The dynamic incorporation of histone variants influences chromatin structure and many biological processes. In Arabidopsis, the canonical variant H3.1 differs from H3.3 in four residues, one of which (H3.1Phe41) is unique and conserved in plants. However, its evolutionary significance remains unclear. Here, we show that Phe41 first appeared in H3.1 in ferns and became stable during land plant evolution. Unlike H3.1, which is specifically enriched in silent regions, H3.1F41Y variants gain ectopic accumulation at actively transcribed regions. Reciprocal tail and core domain swap experiments between H3.1 and H3.3 show that the H3.1 core, while necessary, is insufficient to restrict H3.1 to silent regions. We conclude that the vascular-plant-specific Phe41 is critical for H3.1 genomic distribution and may act collaboratively with the H3.1 core to regulate deposition patterns. This study reveals that Phe41 may have evolved to provide additional regulation of histone deposition in plants. PMID- 29434222 TI - A secondary RET mutation in the activation loop conferring resistance to vandetanib. AB - Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects. PMID- 29434223 TI - Phylogenetic and environmental components of inter-specific variability in the antioxidant defense system in freshwater anomurans Aegla (Crustacea, Decapoda). AB - The antioxidant defense system (ADS) protects organisms against the potential oxidative stress induced by environmental features, underlying processes of habitat diversification. The anomurans Aegla constitute the most threatened freshwater decapods of South America, occupying pristine habitats with narrow distribution. Using phylogenetic comparative methods, we addressed: Is the variability of habitat physicochemical parameters and tissue ADS phylogenetically structured? How do environmental features correlate with ADS? How do they vary among species? Several physicochemical parameters of water, as well as metals in sediments, were measured in ten aeglid species' habitats. Additionally, metal accumulation and ADS parameters [metallothionein-like proteins (MTLP), antioxidant capacity against peroxyl radicals (ACAP), and glutathione system (GSH GSSG)] were evaluated in hepatopancreas. Water conductivity and pH showed phylogenetic signal, while all other physicochemical traits demonstrated plastic variability. Metals were present at natural concentrations, which are corroborated by the relative stable GSH/GSSG ratio, and by their absence of correlation with bioaccumulation levels and MTLP, both phylogenetically structured. However, metal variability across species' niches is associated with ACAP, a potential biomarker tool. Thus, the physiological sensitivity of aeglids is environmentally driven but also phylogenetically constrained, unraveling the importance of systematic framework for cross-species investigations and future monitoring strategies of these conspicuous freshwater animals. PMID- 29434224 TI - Rapid one-step biotinylation of biological and non-biological surfaces. AB - We describe a rapid one-step method to biotinylate virtually any biological or non-biological surface. Contacting a solution of biotin-spacer-lipid constructs with a surface will form a coating within seconds on non-biological surfaces or within minutes on most biological membranes including membrane viruses. The resultant biotinylated surface can then be used to interact with avidinylated conjugates, beads, vesicles, surfaces or cells. PMID- 29434225 TI - Mechanical stretch-induced osteogenic differentiation of human jaw bone marrow mesenchymal stem cells (hJBMMSCs) via inhibition of the NF-kappaB pathway. AB - Severe malocclusion can contribute to several serious dental and physical conditions, such as digestive difficulties, periodontal disease, and severe tooth decay. Orthodontic treatment is mainly used to treat malocclusion. Forces in orthodontic tooth results in bone resorption on the pressure side and bone deposition on the tension side. Osteoblasts have been considered as the key component in bone regeneration on the tension side. However, the underlying mechanisms remain unclear. In this study, we focus on how mechanical stretch regulates the osteogenesis during orthodontic treatment. Human jaw bone marrow mesenchymal stem cells (hJBMMSCs) were isolated from healthy adult donors and cultured in regular medium (control) or osteogenic medium (OS). Under OS culture, hJBMMSCs presented osteogenic differentiation potentials, as evidenced by increased mineralization, enhanced calcium deposition, and upregulated expression of osteogenesis markers (ALP, osterix, and Runx). What's more, the OS-induced osteogenesis of hJBMMSCs is associated with the dephosphorylation of IKK, activation of IKBalpha, and phosphorylation/nucleic accumulation of P65, which all indicated the inhibition of NF-kappaB activity. Overexpressing P65 in hJBMMSCs, which could constantly activate NF-kappaB, prevented the osteogenic differentiation in the OS. After that, we applied the Flexcell tension system, which could cause mechanical stretch on cultured hJBMMSCs to mimic the tension forces during tooth movement. Mechanical stretch resulted in 3.5-fold increase of ALP activity and 2.4-fold increase of calcium deposition after 7 days and 21 days treatment, respectively. The expression levels of ALP, Run*2, and Osterix were also significantly upregulated. In the meantime, applying mechanical stretch on OS-cultured hJBMMSCs also dramatically promoted the OS-induced osteogenesis. Both OS and mechanical stretch downregulated NF-kappaB activity. By overexpressing P65 in hJBMMSCs, neither OS nor mechanical stretch could induce their osteogenesis. These results indicated that, like OS induction, mechanical stretch-facilitated osteogenesis of hJBMMSCs by inhibiting NF-kappaB in the noninflammatory environments. PMID- 29434226 TI - Detection of multi-tomato leaf diseases (late blight, target and bacterial spots) in different stages by using a spectral-based sensor. AB - Several diseases have threatened tomato production in Florida, resulting in large losses, especially in fresh markets. In this study, a high-resolution portable spectral sensor was used to investigate the feasibility of detecting multi diseased tomato leaves in different stages, including early or asymptomatic stages. One healthy leaf and three diseased tomato leaves (late blight, target and bacterial spots) were defined into four stages (healthy, asymptomatic, early stage and late stage) and collected from a field. Fifty-seven spectral vegetation indices (SVIs) were calculated in accordance with methods published in previous studies and established in this study. Principal component analysis was conducted to evaluate SVIs. Results revealed six principal components (PCs) whose eigenvalues were greater than 1. SVIs with weight coefficients ranking from 1 to 30 in each selected PC were applied to a K-nearest neighbour for classification. Amongst the examined leaves, the healthy ones had the highest accuracy (100%) and the lowest error rate (0) because of their uniform tissues. Late stage leaves could be distinguished more easily than the two other disease categories caused by similar symptoms on the multi-diseased leaves. Further work may incorporate the proposed technique into an image system that can be operated to monitor multi diseased tomato plants in fields. PMID- 29434228 TI - Ultrahigh Oxygen Reduction Reaction Electrocatalytic Activity and Stability over Hierarchical Nanoporous N-doped Carbon. AB - Hierarchical nanoporous N-doped carbon ZNC-1000 was prepared by facile pyrolysis of well-designed nanosized ZIF-8 precursor with optimized reaction temperature and time. It possesses large surface areas leading to sufficient exposed electrochemical active sites. Meanwhile, its moderate graphitization degree and suitable nanosized hierarchical porosity distributions would lead to the sufficient interaction between O2 and the electrocatalyst surface which would benefit the transports of electrons and the electrolyte ions for ORR. As an electrocatalyst for oxygen reduction reaction, the ZNC-1000 presents a better catalytic property than the commercial Pt/C with 6/1 mV positive shifts for onset/half-wave potentials and 1.567 mA cm-2 larger for limiting current density respectively. The stability of ZNC-1000 is also much better than that of Pt/C with negative shifts of 0/-2 mV (vs 5/31 mV) for onset/half-wave potentials and 6.0% vs 29.2% loss of limiting current density after 5000 cycles of accelerated durability test, as well as the relative current of 87.5% vs 40.2% retention after 30,000 s continuous chronoamperometric operation. PMID- 29434227 TI - The NLRP3 Inflammasome May Contribute to Pathologic Neovascularization in the Advanced Stages of Diabetic Retinopathy. AB - Diabetic retinopathy (DR) is a retinal microvascular disease characterized by inflammatory and angiogenic pathways. In this study, we evaluated NLRP3 inflammasome in a double transgenic mouse model, Akimba (Ins2 Akita xVEGF+/-), which demonstrates hyperglycemia, vascular hyperpermeability and neovascularization seen in the proliferative DR. Retinal structural integrity, vascular leakage and function were examined by fundus photography, fluorescein angiography, optical coherence tomography, retinal flat mounts, laser speckle flowgraphy (LSFG), and electroretinography in Akimba and its parental strains, Akita (Ins2 Akita ) and Kimba (trVEGF029) mice. Inflammatory mechanisms involving NLRP3 inflammasome were investigated using real time-PCR, immunohistochemistry, ELISA and western blots. We observed an increased vascular leakage, reduced retinal thickness, and function in Akimba retina. Also, Akimba retina depicts decreased relative flow volume measured by LSFG. Most importantly, high levels of IL-1beta along with increased NLRP3, ASC, and Caspase-1 at mRNA and protein levels were observed in Akimba retina. However, the in vivo functional role remains undefined. In conclusion, increased activation of macroglia (GFAP), microglia (Iba-1 and OX-42) and perivascular macrophages (F4/80 and CD14) together with pro-inflammatory (IL-1beta and IL-6) and pro-angiogenic markers (PECAM-1, ICAM-1, VEGF, Flt-1, and Flk-1), suggested a critical role for NLRP3 inflammasome in the Akimba mouse model depicting advanced stages of DR pathogenesis. PMID- 29434229 TI - Determination of hemodynamic risk for vascular disease in planar artery bifurcations. AB - Understanding hemodynamics in blood circulation is crucial in order to unveil the mechanisms underlying the formation of stenosis and atherosclerosis. In fact, there are experimental evidences pointing out to the existence of some given vessel configurations that are more likely to develop the above mentioned pathologies. Along this manuscript, we performed an exhaustive investigation in a simplified model aiming to characterize by means of physical quantities those regions and configurations in vessel bifurcations that are more likely to develop such pathologies. The two-fold analysis is based, on the one hand, on numerical simulations (via CFD) and, on the other hand, on experiments realized in an ad hoc designed polydimethylsiloxane (PDMS) channel with the appropriate parameters and appropriate fluid flows. The results obtained demonstrate that low velocity regions and low shear stress zones are located in the outer walls of bifurcations. In fact, we found that there is a critical range of bifurcation angles that is more likely to vascular disease than the others in correspondence with some experimental evidence. The effect of the inflow velocity on this critical range is also analyzed. PMID- 29434230 TI - Comparing the similarity and difference of three influenza surveillance systems in China. AB - Three main surveillance systems (laboratory-confirmed, influenza-like illness (ILI) and nationwide Notifiable Infectious Diseases Reporting Information System (NIDRIS)) have been used for influenza surveillance in China. However, it is unclear which surveillance system is more reliable in developing influenza early warning system based on surveillance data. This study aims to evaluate the similarity and difference of the three surveillance systems and provide practical knowledge for improving the effectiveness of influenza surveillance. Weekly influenza data for the three systems were obtained from March 2010 to February 2015. Spearman correlation and time series seasonal decomposition were used to assess the relationship between the three surveillance systems and to explore seasonal patterns and characteristics of influenza epidemics in Gansu, China. Our results showed influenza epidemics appeared a single-peak around January in all three surveillance systems. Time series seasonal decomposition analysis demonstrated a similar seasonal pattern in the three systems, while long-term trends were observed to be different. Our research suggested that a combination of the NIDRIS together with ILI and laboratory-confirmed surveillance is an informative, comprehensive way to monitor influenza transmission in Gansu, China. These results will provide a useful information for developing influenza early warning systems based on influenza surveillance data. PMID- 29434231 TI - Graphene based room temperature flexible nanocomposites from permanently cross linked networks. AB - Graphene based room temperature flexible nanocomposites were prepared using epoxy thermosets for the first time. Flexible behavior was induced into the epoxy thermosets by introducing charge transfer complexes between functional groups within cross linked epoxy and room temperature ionic liquid ions. The graphene nanoplatelets were found to be highly dispersed in the epoxy matrix due to ionic liquid cation-pi interactions. It was observed that incorporation of small amounts of graphene into the epoxy matrix significantly enhanced the mechanical properties of the epoxy. In particular, a 0.6 wt% addition increased the tensile strength and Young's modulus by 125% and 21% respectively. The electrical resistance of nanocomposites was found to be increased with graphene loading indicating the level of self-organization between the ILs and the graphene sheets in the matrix of the composite. The graphene nanocomposites were flexible and behave like ductile thermoplastics at room temperature. This study demonstrates the use of ionic liquid as a compatible agent to induce flexibility in inherently brittle thermoset materials and improve the dispersion of graphene to create high performance nanocomposite materials. PMID- 29434232 TI - A Preferential Attachment Paradox: How Preferential Attachment Combines with Growth to Produce Networks with Log-normal In-degree Distributions. AB - Every network scientist knows that preferential attachment combines with growth to produce networks with power-law in-degree distributions. How, then, is it possible for the network of American Physical Society journal collection citations to enjoy a log-normal citation distribution when it was found to have grown in accordance with preferential attachment? This anomalous result, which we exalt as the preferential attachment paradox, has remained unexplained since the physicist Sidney Redner first made light of it over a decade ago. Here we propose a resolution. The chief source of the mischief, we contend, lies in Redner having relied on a measurement procedure bereft of the accuracy required to distinguish preferential attachment from another form of attachment that is consistent with a log-normal in-degree distribution. There was a high-accuracy measurement procedure in use at the time, but it would have have been difficult to use it to shed light on the paradox, due to the presence of a systematic error inducing design flaw. In recent years the design flaw had been recognised and corrected. We show that the bringing of the newly corrected measurement procedure to bear on the data leads to a resolution of the paradox. PMID- 29434233 TI - Absence of warmth permits epigenetic memory of winter in Arabidopsis. AB - Plants integrate widely fluctuating temperatures to monitor seasonal progression. Here, we investigate the temperature signals in field conditions that result in vernalisation, the mechanism by which flowering is aligned with spring. We find that multiple, distinct aspects of the temperature profile contribute to vernalisation. In autumn, transient cold temperatures promote transcriptional shutdown of Arabidopsis FLOWERING LOCUS C (FLC), independently of factors conferring epigenetic memory. As winter continues, expression of VERNALIZATION INSENSITIVE3 (VIN3), a factor needed for epigenetic silencing, is upregulated by at least two independent thermosensory processes. One integrates long-term cold temperatures, while the other requires the absence of daily temperatures above 15 degrees C. The lack of spikes of high temperature, not just prolonged cold, is thus the major driver for vernalisation. Monitoring of peak daily temperature is an effective mechanism to judge seasonal progression, but is likely to have deleterious consequences for vernalisation as the climate becomes more variable. PMID- 29434234 TI - Altered aspects of anxiety-related behavior in kisspeptin receptor-deleted male mice. AB - The roles of kisspeptin signaling outside the hypothalamus in the brain are unknown. We examined here the impact of Kiss1r-deletion on hippocampus-related behaviors of anxiety and spatial learning in adult male mice using two mouse models. In the first, global Kiss1r-null and control mice were gonadectomized (GDX KISS1R-KO). In the second, KISS1R signalling was rescued selectively in gonadotropin-releasing hormone neurons to generate Kiss1r-null mice with normal testosterone levels (intact KISS1R-KO). Intact KISS1R-KO rescue mice were found to spend twice as much time in the open arms of the elevated plus maze (EPM) compared to controls (P < 0.01). GDX KISS1R-KO mice showed a similar but less pronounced trend. No differences were detected between intact KISS1R-KO mice and controls in the open field test (OFT), although a marked reduction in time spent in the centre quadrant was observed for all GDX mice (P < 0.001). No effects of KISS1R deletion or gonadectomy were detected in the Morris water maze. These observations demonstrate that KISS1R signalling impacts upon anxiogenic neural circuits operative in the EPM, while gonadal steroids appear important for anxiety behaviour observed in the OFT. The potential anxiogenic role of kisspeptin may need to be considered in the development of kisspeptin analogs for the clinic. PMID- 29434235 TI - Peridotite weathering is the missing ingredient of Earth's continental crust composition. AB - The chemical composition of the continental crust cannot be adequately explained by current models for its formation, because it is too rich in Ni and Cr compared to that which can be generated by any of the proposed mechanisms. Estimates of the crust composition are derived from average sediment, while crustal growth is ascribed to amalgamation of differentiated magmatic rocks at continental margins. Here we show that chemical weathering of Ni- and Cr-rich, undifferentiated ultramafic rock equivalent to ~1.3 wt% of today's continental crust compensates for low Ni and Cr in formation models of the continental crust. Ultramafic rock weathering produces a residual that is enriched in Ni and also silica. In the light of potentially large volumes of ultramafic rock and high atmospheric CO2 concentrations during the Archean, chemical weathering must therefore have played a major role in forming compositionally evolved components of the early Earth's crust. PMID- 29434236 TI - The drought-tolerant Solanum pennellii regulates leaf water loss and induces genes involved in amino acid and ethylene/jasmonate metabolism under dehydration. AB - Breeding for drought-tolerant crops is a pressing issue due to the increasing frequency and duration of droughts caused by climate change. Although important sources of variation for drought tolerance exist in wild relatives, the mechanisms and the key genes controlling tolerance in tomato are little known. The aim of this study is to determine the drought response of the tomato wild relative Solanum pennellii (Sp) compared with the cultivated tomato Solanum lycopersicum (Sl). The paper investigates the physiological and molecular responses in leaves of Sp and Sl plants without stress and moderate drought stress. Significant physiological differences between species were found, with Sp leaves showing greater ability to avoid water loss and oxidative damage. Leaf transcriptomic analysis carried out when leaves did not as yet show visual dehydration symptoms revealed important constitutive expression differences between Sp and Sl species. Genes linked to different physiological and metabolic processes were induced by drought in Sp, especially those involved in N assimilation, GOGAT/GS cycle and GABA-shunt. Up-regulation in Sp of genes linked to JA/ET biosynthesis and signaling pathways was also observed. In sum, genes involved in the amino acid metabolism together with genes linked to ET/JA seem to be key actors in the drought tolerance of the wild tomato species. PMID- 29434237 TI - Unraveling the efficiency-limiting morphological issues of the perylene diimide based non-fullerene organic solar cells. AB - Herein we report a comparative morphological analysis of the perylene diimide (PDI)- and fullerene-based organic solar cells (OSCs) to identify the factors responsible for low performance of PDI-based devices. A PDI derivative, bis-PDI, and a fullerene derivative, PC70BM, are mixed with an efficient polymer donor, PffBT4T-2OD. The large disparity in power conversion efficiencies (PCEs) of OSCs composed of PffBT4T-2OD:bis-PDI (PCE = 5.18%) and PffBT4T-2OD:PC70BM (PCE = 10.19%) observed are attributed to differences in the nanostructural motif of bulk heterojunction (BHJ) morphologies of these blend systems. The X-ray scattering and surface energy characterizations revealed that the structurally dissimilar bis-PDI and PC70BM molecules determine the variation in blend film morphologies, and in particular, the molecular packing features of the donor PffBT4T-2OD polymer. In addition, high-resolution transmission electron microscopy (HRTEM) images explore the BHJ morphologies and presence of longer polymer fibrils in PffBT4T-2OD:bis-PDI system, justifying the unbalanced charge transport and high hole mobility. The low performance of PffBT4T-2OD:bis-PDI devices was further investigated by studying charge carrier recombination dynamics by using light-intensity-dependent and transient photovoltage (TPV) experiments. Furthermore, the temperature-dependent experiments showed the photovoltaic properties, including charge recombination losses, are strongly affected by energetic disorder present in bis-PDI-based system. PMID- 29434239 TI - Trigger mechanism for the abrupt loss of energetic ions in magnetically confined plasmas. AB - Interaction between a quasi-stable stationary MHD mode and a tongue-shaped deformation is observed in the toroidal plasma with energetic particle driven MHD bursts. The quasi-stable stationary 1/1 MHD mode with interchange parity appears near the resonant rational surface of q = 1 between MHD bursts. The tongue-shaped deformation rapidly appears at the non-resonant non-rational surface as a localized large plasma displacement and then collapses (tongue event). It curbs the stationary 1/1 MHD mode and then triggers the collapse of energetic particle and magnetic field reconnection. The rotating 1/1 MHD mode with tearing parity at the q = 1 resonant surface, namely, the MHD burst, is excited after the tongue event. PMID- 29434238 TI - Non-equivalent antigen presenting capabilities of dendritic cells and macrophages in generating brain-infiltrating CD8 + T cell responses. AB - The contribution of antigen-presenting cell (APC) types in generating CD8+ T cell responses in the central nervous system (CNS) is not fully defined, limiting the development of vaccines and understanding of immune-mediated neuropathology. Here, we generate a transgenic mouse that enables cell-specific deletion of the H 2Kb MHC class I molecule. By deleting H-2Kb on dendritic cells and macrophages, we compare the effect of each APC in three distinct models of neuroinflammation: picornavirus infection, experimental cerebral malaria, and a syngeneic glioma. Dendritic cells and macrophages both activate CD8+ T cell responses in response to these CNS immunological challenges. However, the extent to which each of these APCs contributes to CD8+ T cell priming varies. These findings reveal distinct functions for dendritic cells and macrophages in generating CD8+ T cell responses to neurological disease. PMID- 29434240 TI - Improved therapeutic potential of tapentadol employing cationic exchange resins as carriers in neuropathic pain: evidence from pharmacokinetic and pharmacodynamics study. AB - Current investigation was endeavoured to overcome problem of poor palatability and bioavailability of centrally acting analgesic, tapentadol (TAP) by formulating controlled release drug-resin complexes (DRCs). The technology encompassed in preparation of DRCs involved chemisorption of TAP to weak cationic resins (KyronT-134 and Tulsion335) by batch method. Various formulation variables like drug-resin ratio, pH, resin activation and swelling time were optimized to achieve maximum drug loading in DRCs. FT-IR, DSC, pXRD, in vitro release study under bio-relevant condition of mouth and in vivo sensory taste evaluation established formation of taste masked DRC whereas dissolution study assured prolonged drug release behaviour of optimized DRC. Among DRCs, TAP-KyronT-134 complex exhibited higher drug loading (80.89 +/- 4.56%), stability and prolonged release profile (10 h) without any detectable amount of drug release under salivary conditions. Pharmacokinetic studies in wistar rats revealed increased Tmax (2.67-fold), MRT (1.94-fold), elimination half-life (2.79-fold) and relative oral bioavailability (2.62-fold) of TAP on oral administration of optimized formulation compared to TAP solution. Furthermore, pharmacodynamics study confessed higher potential of DRC in attenuating chronic injury induced tactile allodynia for prolonged duration. In conclusion, the method developed is easily scalable and holds potential for commercialization with an evidence of obtaining more efficacious neuropathic pain management therapy. PMID- 29434241 TI - Streptomyces sp metabolite(s) promotes Bax mediated intrinsic apoptosis and autophagy involving inhibition of mTOR pathway in cervical cancer cell lines. AB - In cervical cancer, the association between HPV infection and dysregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR pathway) places mTOR as an attractive therapeutic target. The failure of current treatment modalities in advanced stages of this cancer and drawbacks of already available mTOR inhibitors demand for novel drug candidates. In the present study we identified the presence of a mTOR inhibitor in an active fraction of the ethyl acetate extract of Streptomyces sp OA293. The metabolites(s) in the active fraction completely inhibited mTORC1 and thereby suppressed activation of both of its downstream targets, 4E-BP1 and P70S6k, in cervical cancer cells. In addition, it also stalled Akt activation via inhibition of mTORC2. The mechanism of mTOR inhibition detailed in our study overcomes significant drawbacks of well known mTOR inhibitors such as rapamycin and rapalogs. The active fraction induced autophagy and Bax mediated apoptosis suggesting that mTOR inhibition resulted in programmed cell death of cancer cells. The molecular weight determination of the components in active fraction confirmed the absence of any previously known natural mTOR inhibitor. This is the first report of complete mTOR complex inhibition by a product derived from microbial source. PMID- 29434242 TI - Opinion formation in multiplex networks with general initial distributions. AB - We study opinion dynamics over multiplex networks where agents interact with bounded confidence. Namely, two neighbouring individuals exchange opinions and compromise if their opinions do not differ by more than a given threshold. In literature, agents are generally assumed to have a homogeneous confidence bound. Here, we study analytically and numerically opinion evolution over structured networks characterised by multiple layers with respective confidence thresholds and general initial opinion distributions. Through rigorous probability analysis, we show analytically the critical thresholds at which a phase transition takes place in the long-term consensus behaviour, over multiplex networks with some regularity conditions. Our results reveal the quantitative relation between the critical threshold and initial distribution. Further, our numerical simulations illustrate the consensus behaviour of the agents in network topologies including lattices and, small-world and scale-free networks, as well as for structure dependent convergence parameters accommodating node heterogeneity. We find that the critical thresholds for consensus tend to agree with the predicted upper bounds in Theorems 4 and 5 in this paper. Finally, our results indicate that multiplexity hinders consensus formation when the initial opinion configuration is within a bounded range and, provide insight into information diffusion and social dynamics in multiplex systems modeled by networks. PMID- 29434243 TI - Isolation and Expansion of Multipotent Progenitors from Human Trabecular Meshwork. AB - To expand multi-potent progenitors from human trabecular meshwork (TM), we have created a new optimized method on two-dimensional (2D) followed by three dimensional (3D) Matrigel in modified embryonic stem cell medium supplemented with 5% fetal bovine serum (MESCM + 5% FBS). The expanded TM cells were small cuboidal cells expressing TM markers such as AQP1, MGP, CHI3L1, and AnkG, embryonic stem cell (ESC) markers such as Oct4, Sox2, Nanog, and ABCG2, and neural crest (NC) markers such as p75NTR, FOXD3, Sox9, Sox10, and MSX1. Although expanded cells lost expression of these markers after passage, the cells regained the markers when Passage 2 cells were seeded on 3D Matrigel through activation of canonical BMP signaling. Such restored progenitors could differentiate into corneal endothelial cells, adipocytes, and chondrocytes but not keratocytes or osteocytes. Therefore, we have concluded that human TM harbors multipotent progenitors that can be effectively isolated and expanded using 2D Matrigel in MESCM + 5% FBS. This unique in vitro model system can be used to understand how TM is altered in glaucoma and whether such TM progenitor cells might one day be used for treating glaucoma or corneal endothelial dysfunction. PMID- 29434244 TI - Characterization of Retinal Ganglion Cell and Optic Nerve Phenotypes Caused by Sustained Intracranial Pressure Elevation in Mice. AB - Elevated intracranial pressure (ICP) can result in multiple neurologic sequelae including vision loss. Inducible models of ICP elevation are lacking in model organisms, which limits our understanding of the mechanism by which increased ICP impacts the visual system. We adapted a mouse model for the sustained elevation of ICP and tested the hypothesis that elevated ICP impacts the optic nerve and retinal ganglion cells (RGCs). ICP was elevated and maintained for 2 weeks, and resulted in multiple anatomic changes that are consistent with human disease including papilledema, loss of physiologic cupping, and engorgement of the optic nerve head. Elevated ICP caused a loss of RGC somas in the retina and RGC axons within the optic nerve, as well as a reduction in both RGC electrical function and contrast sensitivity. Elevated ICP also caused increased hypoxia-inducible factor (HIF)-1 alpha expression in the ganglion cell layer. These experiments confirm that sustained ICP elevation can be achieved in mice and causes phenotypes that preferentially impact RGCs and are similar to those seen in human disease. With this model, it is possible to model human diseases of elevated ICP such as Idiopathic Intracranial Hypertension and Spaceflight Associated Neuro ocular Syndrome. PMID- 29434245 TI - Galectin-3 Plays an Important Role in Preterm Birth Caused by Dental Infection of Porphyromonas gingivalis. AB - Dental infection is risk for preterm birth (PTB) through unclear mechanisms. We established a dental infection-induced PTB mouse model, in which Porphyromonas gingivalis (P.g.) induced PTB by 2 days. We analysed pathogenic factors contributing to PTB and their effects on trophoblasts in vitro. TNF-alpha, IL-8, and COX-2 were upregulated in P.g.-infected placenta. Galectin-3 (Gal-3), an immune regulator, was significantly upregulated in placenta, amniotic fluid, and serum. In vitro, P.g.-lipopolysaccharide (P.g.-LPS) increased TNF-alpha and Gal-3 in trophoblasts via NF-kappaB/MAPK signalling. Gal-3 inhibition significantly downregulated P.g.-LPS-induced TNF-alpha production. TNF-alpha upregulated Gal-3. Gal-3 also increased cytokines and Gal-3 through NF-kappaB/MAPK signalling. Moreover, Gal-3 suppressed CD-66a expression at the maternal-foetal interface. Co stimulation with Gal-3 and P.g.-LPS upregulated cytokine levels, while Gal-3 plus Aggregatibacter actinomycetemcomitans (A.a.)- or Escherichia coli (E. coli)-LPS treatment downregulated them, indicating the critical role of Gal-3 especially in P.g. dental infection-induced PTB. P.g.-dental infection induced PTB, which was associated with Gal-3-dependent cytokine production. New therapies and/or diagnostic systems targeting Gal-3 may reduce PTB. PMID- 29434246 TI - High throughput protease profiling comprehensively defines active site specificity for thrombin and ADAMTS13. AB - We have combined random 6 amino acid substrate phage display with high throughput sequencing to comprehensively define the active site specificity of the serine protease thrombin and the metalloprotease ADAMTS13. The substrate motif for thrombin was determined by >6,700 cleaved peptides, and was highly concordant with previous studies. In contrast, ADAMTS13 cleaved only 96 peptides (out of >107 sequences), with no apparent consensus motif. However, when the hexapeptide library was substituted into the P3-P3' interval of VWF73, an exosite-engaging substrate of ADAMTS13, 1670 unique peptides were cleaved. ADAMTS13 exhibited a general preference for aliphatic amino acids throughout the P3-P3' interval, except at P2 where Arg was tolerated. The cleaved peptides assembled into a motif dominated by P3 Leu, and bulky aliphatic residues at P1 and P1'. Overall, the P3 P2' amino acid sequence of von Willebrand Factor appears optimally evolved for ADAMTS13 recognition. These data confirm the critical role of exosite engagement for substrates to gain access to the active site of ADAMTS13, and define the substrate recognition motif for ADAMTS13. Combining substrate phage display with high throughput sequencing is a powerful approach for comprehensively defining the active site specificity of proteases. PMID- 29434248 TI - Modulation of small GTPase activity by NME proteins. AB - NME proteins are reported to influence signal transduction activity of small GTPases from the Ras superfamily by diverse mechanisms in addition to their generic NDP kinase activity, which replenishes the cytoplasmic pool of GTP. Comprehensive evidence shows that NME proteins modulate the activity of Ras GTPases, in particular members of the Rho family, via binding to their major activators GEFs. Direct interaction between several NMEs and Ras GTPases were also indicated in vitro and in vivo. These modes of regulation are mainly independent of the NME's kinase activity. NMEs also modulate the Ras-mediated signal transduction by interfering with the formation of a Ras signaling complex at the plasma membrane. In several examples, NMEs were proposed to perform the role of GAP proteins by promoting hydrolysis of the bound GTP, but this activity still requires additional verification. Early suggestions that NMEs can activate small GTPases by direct phosphorylation of the bound GDP, or by high-rate loading of GTP onto a closely apposed GTPase, were largely dismissed. In this review article, we survey and put into perspective published examples of identified and hypothetical mechanisms of Ras signaling modulation by NME proteins. We also point out involvement of NMEs in the transcriptional regulation of components of Ras GTPases-mediated signal transduction pathways, and reciprocal regulation of NME function by small GTPases, particularly related to NME's binding to membranes. PMID- 29434247 TI - Comparison of statistical methods for calculating life expectancy after spinal cord injury. AB - STUDY DESIGN: Retrospective observational. OBJECTIVES: To compare results of several different methods for calculating life expectancy in the same sample of people with spinal cord injury (SCI), and critically assess their advantages and disadvantages. SETTING: Two spinal centres in Great Britain. METHODS: Survival status of persons with traumatic SCI injured between 1943 and 2010 with follow-up to 2015 was determined. Standardised mortality ratios (SMRs) were calculated using age at injury and current (attained) age, and compared. Life expectancy was then estimated using the SMR methods and compared with the results of a method based on multivariate logistic regression of a person-year dataset. Life expectancy estimates calculated by applying SMRs based on current age to general population period (current) and cohort (projected) life tables were also compared. RESULTS: The estimated life expectancies were significantly higher when the SMRs were based on age at injury. They were also higher when a general population cohort life table was used, particularly for younger ages. With the exception of the ventilator-dependent group, the life expectancy estimates derived from logistic regression were slightly lower than those derived from SMRs based on current age and a general population period life table. CONCLUSIONS: The multivariate logistic regression of person-years method offers several advantages compared to the SMR method for calculating life expectancy after SCI, the main ones being: greater statistical power and precision with smaller sample sizes, the ability to include more predictive factors and to distinguish the otherwise confounded effects of current age, time post-injury, and calendar time. PMID- 29434249 TI - Tuning of heat and charge transport by Majorana fermions. AB - We investigate theoretically thermal and electrical conductances for the system consisting of a quantum dot (QD) connected both to a pair of Majorana fermions residing at the edges of a Kitaev wire and two metallic leads. We demonstrate that both quantities reveal pronounced resonances, whose positions can be controlled by tuning of an asymmetry of the couplings of the QD and a pair of MFs. Similar behavior is revealed for the thermopower, Wiedemann-Franz law and dimensionless thermoelectric figure of merit. The considered geometry can thus be used as a tuner of heat and charge transport assisted by MFs. PMID- 29434250 TI - DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives. AB - Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20 mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS. PMID- 29434251 TI - Transcriptome analysis in tissue sectors with contrasting crocins accumulation provides novel insights into apocarotenoid biosynthesis and regulation during chromoplast biogenesis. AB - Crocins, the red soluble apocarotenoids of saffron, accumulate in the flowers of Crocus species in a developmental and tissue-specific manner. In Crocus sieberi, crocins accumulate in stigmas but also in a distinct yellow tepal sector, which we demonstrate contains chromoplast converted from amyloplasts. Secondary metabolites were analysed by LC-DAD-HRMS, revealing the progressive accumulation of crocetin and crocins in the yellow sector, which were also localized in situ by Raman microspectroscopy. To understand the underlying mechanisms of crocin biosynthesis, we sequenced the C. sieberi tepal transcriptome of two differentially pigmented sectors (yellow and white) at two developmental stages (6 and 8) by Illumina sequencing. A total of 154 million high-quality reads were generated and assembled into 248,099 transcripts. Differentially expressed gene analysis resulted in the identification of several potential candidate genes involved in crocin metabolism and regulation. The results provide a first profile of the molecular events related to the dynamics of crocetin and crocin accumulation during tepal development, and present new information concerning apocarotenoid biosynthesis regulators and their accumulation in Crocus. Further, reveals genes that were previously unknown to affect crocin formation, which could be used to improve crocin accumulation in Crocus plants and the commercial quality of saffron spice. PMID- 29434252 TI - Adaptable surfactant-mediated method for the preparation of anisotropic metal chalcogenide nanomaterials. AB - The hot injection synthesis of nanomaterials is a highly diverse and fundamental field of chemical research, which has shown much success in the bottom up approach to nanomaterial design. Here we report a synthetic strategy for the production of anisotropic metal chalcogenide nanomaterials of different compositions and shapes, using an optimised hot injection approach. Its unique advantage compared to other hot injection routes is that it employs one chemical to act as many agents: high boiling point, viscous solvent, reducing agent, and surface coordinating ligand. It has been employed to produce a range of nanomaterials, such as CuS, Bi2S3, Cu2-xSe, FeSe2, and Bi4Se3, among others, with various structures including nanoplates and nanosheets. Overall, this article will highlight the excellent versatility of the method, which can be tuned to produce many different materials and shapes. In addition, due to the nature of the synthesis, 2D nanomaterial products are produced as monolayers without the need for exfoliation; a significant achievement towards future development of these materials. PMID- 29434253 TI - Association between maternal HIV disclosure and risk factors for perinatal transmission. AB - OBJECTIVE: To determine whether maternal disclosure of HIV serostatus is associated with uptake of perinatal HIV transmission prevention interventions. STUDY DESIGN: Retrospective cohort study of women living with HIV enrolled in a perinatal HIV clinic. Women who disclosed their HIV serostatus to sexual partner(s) prior to delivery were compared to non-disclosers. Multivariable logistic regression was performed. RESULTS: Of 209 women, 71.3% (N = 149) disclosed. Non-disclosers were more likely to attend <10 prenatal visits, demonstrated worse antiretroviral therapy adherence, required more time to achieve virologic suppression, and were less likely to have an undetectable viral load. On multivariable analyses, disclosure status did not remain associated with these factors. However, compared to non-disclosers, disclosers had lower odds of preterm delivery (OR: 0.43, 95% CI: 0.19-0.94) and greater odds of postpartum visit attendance (aOR: 5.10, 95% CI: 1.65-15.72). CONCLUSIONS: Non-disclosure of HIV status to sexual partner(s) during pregnancy may be a risk factor for preterm birth and poorer postpartum visit attendance. PMID- 29434254 TI - Implementation of a pilot program of Reach Out and Read(r) in the neonatal intensive care unit: a quality improvement initiative. AB - OBJECTIVE: Language exposure is important for neurodevelopment, but is sparse in the neonatal intensive care unit (NICU). STUDY DESIGN: We introduced Reach Out and Read (ROR) in the NICU as a quality improvement initiative to increase language exposure. Measures included availability of books, accessibility of parents, and enrollment of infants, percent infants read to by their parents, and data from parental surveys. RESULT: 98 infants were included (40 before, 58 after). We obtained books in the mother's language for 95% of infants, 82% eligible infants were enrolled, and 70% read to their infants (mean of 0.45 +/- 0.35 times/day). Surveyed parents enjoyed reading, noted positive effect(s), and intended to read post-discharge. CONCLUSION: We launched a well-received pilot ROR program in the NICU and reached our goal of >=50% infants being read to by their parents. Further study is needed to assess the impact of reading in the NICU on parents and infants. PMID- 29434255 TI - RIPK1-dependent cell death: a novel target of the Aurora kinase inhibitor Tozasertib (VX-680). AB - The Aurora kinase family (Aurora A, B and C) are crucial regulators of several mitotic events, including cytokinesis. Increased expression of these kinases is associated with tumorigenesis and several compounds targeting Aurora kinase are under evaluation in clinical trials (a.o. AT9283, AZD1152, Danusertib, MLN8054). Here, we demonstrate that the pan-Aurora kinase inhibitor Tozasertib (VX-680 and MK-0457) not only causes cytokinesis defects through Aurora kinase inhibition, but is also a potent inhibitor of necroptosis, a cell death process regulated and executed by the RIPK1, RIPK3 and MLKL signalling axis. Tozasertib's potency to inhibit RIPK1-dependent necroptosis and to block cytokinesis in cells is in the same concentration range, with an IC50 of 1.06 uM and 0.554 uM, respectively. A structure activity relationship (SAR) analysis of 67 Tozasertib analogues, modified at 4 different positions, allowed the identification of analogues that showed increased specificity for either cytokinesis inhibition or for necroptosis inhibition, reflecting more specific inhibition of Aurora kinase or RIPK1, respectively. These results also suggested that RIPK1 and Aurora kinases are functionally non-interacting targets of Tozasertib and its analogues. Indeed, more specific Aurora kinase inhibitors did not show any effect in necroptosis and Necrostatin-1s treatment did not result in cytokinesis defects, demonstrating that both cellular processes are not interrelated. Finally, Tozasertib inhibited recombinant human RIPK1, human Aurora A and human Aurora B kinase activity, but not RIPK3. The potency ranking of the newly derived Tozasertib analogues and their specificity profile, as observed in cellular assays, coincide with ADP-Glo recombinant kinase activity assays. Overall, we show that Tozasertib not only targets Aurora kinases but also RIPK1 independently, and that we could generate analogues with increased selectivity to RIPK1 or Aurora kinases, respectively. PMID- 29434256 TI - Mathematical modeling of the impact of cytokine response of acute myeloid leukemia cells on patient prognosis. AB - Acute myeloid leukemia (AML) is a heterogeneous disease. One reason for the heterogeneity may originate from inter-individual differences in the responses of leukemic cells to endogenous cytokines. On the basis of mathematical modeling, computer simulations and patient data, we have provided evidence that cytokine independent leukemic cell proliferation may be linked to early relapses and poor overall survival. Depending whether the model of cytokine-dependent or cytokine independent leukemic cell proliferation fits to the clinical data, patients can be assigned to two groups that differ significantly with respect to overall survival. The modeling approach further enables us to identify parameter constellations that can explain unexpected responses of some patients to external cytokines such as blast crisis or remission without chemotherapy. PMID- 29434257 TI - Broadband imaging with one planar diffractive lens. AB - We demonstrate imaging over the visible band using a single planar diffractive lens. This is enabled via multi-level diffractive optics that is designed to focus over a broad wavelength range, which we refer to as an achromatic diffractive lens (ADL). We designed, fabricated and characterized two ADLs with numerical apertures of 0.05 and 0.18. Diffraction-limited focusing is demonstrated for the NA = 0.05 lens with measured focusing efficiency of over 40% across the entire visible spectrum (450 nm to 750 nm). We characterized the lenses with a monochromatic and a color CMOS sensor, and demonstrated video imaging under natural sunlight and other broadband illumination conditions. We use rigorous electromagnetic simulations to emphasize that ADLs can achieve high NA (0.9) and large operating bandwidth (300 nm in the visible spectrum), a combination of metrics that have so far eluded other flat-lens technologies such as metalenses. These planar diffractive lenses can be cost-effectively manufactured over large areas and thereby, can enable the wide adoption of flat, low-cost lenses for a variety of imaging applications. PMID- 29434258 TI - Rationally designed synthetic protein hydrogels with predictable mechanical properties. AB - Designing synthetic protein hydrogels with tailored mechanical properties similar to naturally occurring tissues is an eternal pursuit in tissue engineering and stem cell and cancer research. However, it remains challenging to correlate the mechanical properties of protein hydrogels with the nanomechanics of individual building blocks. Here we use single-molecule force spectroscopy, protein engineering and theoretical modeling to prove that the mechanical properties of protein hydrogels are predictable based on the mechanical hierarchy of the cross linkers and the load-bearing modules at the molecular level. These findings provide a framework for rationally designing protein hydrogels with independently tunable elasticity, extensibility, toughness and self-healing. Using this principle, we demonstrate the engineering of self-healable muscle-mimicking hydrogels that can significantly dissipate energy through protein unfolding. We expect that this principle can be generalized for the construction of protein hydrogels with customized mechanical properties for biomedical applications. PMID- 29434259 TI - Three-dimensional ultrastructural analysis of the interface between an implanted demineralised dentin matrix and the surrounding newly formed bone. AB - Previous investigators have reported that transplanted demineralised dentin matrix (DDM) influences bone formation in vivo. However, the specific mechanism of how dentinal tubules contribute to bone formation has not been determined with regard to DDM transplantation therapy. In this study, we ultrastructurally investigated how DDM contacted the surrounding newly formed bone using a scanning electron microscopy (SEM) three-dimensional reconstruction method that is based on focused ion beam slicing and SEM (FIB/SEM). A pulverised and processed DDM derived from human teeth was implanted into rat calvarial bone defects, and a series of X-ray computed tomographic images were obtained over 12 weeks. Implants with surrounding new bone were removed and histologically examined using FIB/SEM. After obtaining objective block-face images, the target boundary face was reconstructed three-dimensionally. The osteocytes of the new bone tissue surrounding the DDM formed a network connected by their cellular processes and formed bone tissue. It is also interesting that the cellular processes of the osteocytes extended into the dentinal tubules, and that bone tissue with canaliculi had formed and filled the DDM surface. PMID- 29434261 TI - 2D MoS2 as an efficient protective layer for lithium metal anodes in high performance Li-S batteries. AB - Among the candidates to replace Li-ion batteries, Li-S cells are an attractive option as their energy density is about five times higher (~2,600 Wh kg-1). The success of Li-S cells depends in large part on the utilization of metallic Li as anode material. Metallic lithium, however, is prone to grow parasitic dendrites and is highly reactive to several electrolytes; moreover, Li-S cells with metallic Li are also susceptible to polysulfides dissolution. Here, we show that ~10-nm-thick two-dimensional (2D) MoS2 can act as a protective layer for Li-metal anodes, greatly improving the performances of Li-S batteries. In particular, we observe stable Li electrodeposition and the suppression of dendrite nucleation sites. The deposition and dissolution process of a symmetric MoS2-coated Li-metal cell operates at a current density of 10 mA cm-2 with low voltage hysteresis and a threefold improvement in cycle life compared with using bare Li-metal. In a Li S full-cell configuration, using the MoS2-coated Li as anode and a 3D carbon nanotube-sulfur cathode, we obtain a specific energy density of ~589 Wh kg-1 and a Coulombic efficiency of ~98% for over 1,200 cycles at 0.5 C. Our approach could lead to the realization of high energy density and safe Li-metal-based batteries. PMID- 29434262 TI - Revolving supramolecular chiral structures powered by light in nanomotor-doped liquid crystals. AB - Molecular machines operated by light have been recently shown to be able to produce oriented motion at the molecular scale1,2 as well as do macroscopic work when embedded in supramolecular structures3-5. However, any supramolecular movement irremediably ceases as soon as the concentration of the interconverting molecular motors or switches reaches a photo-stationary state6,7. To circumvent this limitation, researchers have typically relied on establishing oscillating illumination conditions-either by modulating the source intensity8,9 or by using bespoke illumination arrangements10-13. In contrast, here we report a supramolecular system in which the emergence of oscillating patterns is encoded at the molecular level. Our system comprises chiral liquid crystal structures that revolve continuously when illuminated, under the action of embedded light driven molecular motors. The rotation at the supramolecular level is sustained by the diffusion of the motors away from a localized illumination area. Above a critical irradiation power, we observe a spontaneous symmetry breaking that dictates the directionality of the supramolecular rotation. The interplay between the twist of the supramolecular structure and the diffusion 14 of the chiral molecular motors creates continuous, regular and unidirectional rotation of the liquid crystal structure under non-equilibrium conditions. PMID- 29434260 TI - Circulating exosomal microRNAs reveal the mechanism of Fructus Meliae Toosendan induced liver injury in mice. AB - The toxicological mechanisms of liver injury caused by most traditional Chinese medicine (TCM) remain largely unknown. Due to the unique features, exosomal microRNAs (miRNAs) are currently attracting major interests to provide further insights into toxicological mechanisms. Thus, taking Fructus Meliae Toosendan as an example of hepatoxic TCM, this study aimed to elucidate its hepatotoxicity mechanisms through profiling miRNAs in circulating exosomes of Fructus Meliae Toosendan water extract (FMT)-exposed mice. Biological pathway analysis of the 64 differentially expressed exosomal miRNAs (DEMs) showed that hepatic dysfunction induced by FMT likely related to apoptosis, mitochondrial dysfunction, and cell cycle dysregulation. Integrated analysis of serum exosomal DEMs and hepatic differentially expressed mRNAs further enriched oxidative stress and apoptosis related pathways. In vitro validation studies for omics results suggested that FMT-induced DNA damage was mediated by generating intracellular reactive oxygen species, leading to cell apoptosis through p53-dependent mitochondrial damage and S-phase arrest. Nrf2-mediated antioxidant response was activated to protect liver cells. Moreover, serum exosomal miR-370-3p, the most down-regulated miRNA involving in these pathways, might be the momentous event in aggravating cytotoxic effect of FMT by elevating p21 and Cyclin E. In conclusion, circulating exosomal miRNAs profiling could contribute to deepen the understanding of TCM induced hepatotoxicity. PMID- 29434263 TI - Continuously revolving patterns. PMID- 29434264 TI - Urban stormwater runoff negatively impacts lateral line development in larval zebrafish and salmon embryos. AB - After a storm, water often runs off of impervious urban surfaces directly into aquatic ecosystems. This stormwater runoff is a cocktail of toxicants that have serious effects on the ecological integrity of aquatic habitats. Zebrafish that develop in stormwater runoff suffer from cardiovascular toxicity and impaired growth, but the effects of stormwater on fish sensory systems are not understood. Our study investigated the effect of stormwater on hair cells of the lateral line in larval zebrafish and coho salmon. Our results showed that although toxicants in stormwater did not kill zebrafish hair cells, these cells did experience damage. Zebrafish developing in stormwater also experienced impaired growth, fewer neuromasts in the lateral line, and fewer hair cells per neuromast. A similar reduction in neuromast number was observed in coho salmon reared in stormwater. Bioretention treatment, intended to filter out harmful constituents of stormwater, rescued the lateral line defects in zebrafish but not in coho salmon, suggesting that not all of the harmful constituents were removed by the filtration media and that salmonids are particularly sensitive to aquatic toxicants. Collectively, these data demonstrate that sub-lethal exposure to stormwater runoff negatively impacts a fish sensory system, which may have consequences for organismal fitness. PMID- 29434265 TI - Phonon-driven spin-Floquet magneto-valleytronics in MoS2. AB - Two-dimensional materials equipped with strong spin-orbit coupling can display novel electronic, spintronic, and topological properties originating from the breaking of time or inversion symmetry. A lot of interest has focused on the valley degrees of freedom that can be used to encode binary information. By performing ab initio time-dependent density functional simulation on MoS2, here we show that the spin is not only locked to the valley momenta but strongly coupled to the optical E" phonon that lifts the lattice mirror symmetry. Once the phonon is pumped so as to break time-reversal symmetry, the resulting Floquet spectra of the phonon-dressed spins carry a net out-of-plane magnetization (~0.024MUB for single-phonon quantum) even though the original system is non magnetic. This dichroic magnetic response of the valley states is general for all 2H semiconducting transition-metal dichalcogenides and can be probed and controlled by infrared coherent laser excitation. PMID- 29434266 TI - Future global productivity will be affected by plant trait response to climate. AB - Plant traits are both responsive to local climate and strong predictors of primary productivity. We hypothesized that future climate change might promote a shift in global plant traits resulting in changes in Gross Primary Productivity (GPP). We characterized the relationship between key plant traits, namely Specific Leaf Area (SLA), height, and seed mass, and local climate and primary productivity. We found that by 2070, tropical and arid ecosystems will be more suitable for plants with relatively lower canopy height, SLA and seed mass, while far northern latitudes will favor woody and taller plants than at present. Using a network of tower eddy covariance CO2 flux measurements and the extrapolated plant trait maps, we estimated the global distribution of annual GPP under current and projected future plant community distribution. We predict that annual GPP in northern biomes (>=45 degrees N) will increase by 31% (+8.1 +/- 0.5 Pg C), but this will be offset by a 17.9% GPP decline in the tropics (-11.8 +/- 0.84 Pg C). These findings suggest that regional climate changes will affect plant trait distributions, which may in turn affect global productivity patterns. PMID- 29434267 TI - Early Changes of Articular Cartilage and Subchondral Bone in The DMM Mouse Model of Osteoarthritis. AB - To examine the early changes of articular cartilage and subchondral bone in the DMM mouse model of osteoarthritis, mice were subjected to DMM or SHAM surgery and sacrificed at 2-, 5- and 10-week post-surgery. Catwalk gait analyses, Micro Computed Tomography, Toluidine Blue, Picrosirius Red and Tartrate-Resistant Acid Phosphatase (TRAP) staining were used to investigate gait patterns, joint morphology, subchondral bone, cartilage, collagen organization and osteoclasts activity, respectively. Results showed OA progressed over 10-week time-course. Gait disparity occurred only at 10-week post-surgery. Osteophyte formed at 2-week post-surgery. BMDs of DMM showed no statistical differences comparing to SHAM at 2 weeks, but BV/TV is much higher in DMM mice. Increased BMD was clearly found at 5- and 10-week post-surgery in DMM mice. TRAP staining showed increased osteoclast activity at the site of osteophyte formation of DMM joints at 5- and 10-week time points. These results showed that subchondral bone turnover might occurred earlier than 2 weeks in this mouse DMM model. Gait disparity only occurred at later stage of OA in DMM mice. Notably, patella dislocation could occur in some of the DMM mice and cause a different pattern of OA in affected knee. PMID- 29434268 TI - Correspondence: Reply to 'Chimpanzee helping is real, not a byproduct'. PMID- 29434269 TI - Archaeology and ichnology at Gombore II-2, Melka Kunture, Ethiopia: everyday life of a mixed-age hominin group 700,000 years ago. AB - We report the occurrence at 0.7 million years (Ma) of an ichnological assemblage at Gombore II-2, which is one of several archaeological sites at Melka Kunture in the upper Awash Valley of Ethiopia, 2000 m asl. Adults and children potentially as young as 12 months old left tracks in a silty substrate on the shore of a body of water where ungulates, as well as other mammals and birds, congregated. Furthermore, the same layers contain a rich archaeological and palaeontological record, confirming that knapping was taking place in situ and that stone tools were used for butchering hippo carcasses at the site. The site gives direct information on hominin landscape use at 0.7 Ma and may provide fresh perspective on the childhood of our ancestors. PMID- 29434270 TI - Expression and replication of virus-like circular DNA in human cells. AB - The consumption of bovine milk and meat is considered a risk factor for colon- and breast cancer formation, and milk consumption has also been implicated in an increased risk for developing Multiple Sclerosis (MS). A number of highly related virus-like DNAs have been recently isolated from bovine milk and sera and from a brain sample of a MS patient. As a genetic activity of these Acinetobacter related bovine milk and meat factors (BMMFs) is unknown in eukaryotes, we analyzed their expression and replication potential in human HEK293TT cells. While all analyzed BMMFs show transcriptional activity, the MS brain isolate MSBI1.176, sharing homology with a transmissible spongiform encephalopathy associated DNA molecule, is transcribed at highest levels. We show expression of a replication-associated protein (Rep), which is highly conserved among all BMMFs, and serological tests indicate a human anti-Rep immune response. While the cow milk isolate CMI1.252 is replication-competent in HEK293TT cells, replication of MSBI1.176 is complemented by CMI1.252, pointing at an interplay during the establishment of persistence in human cells. Transcriptome profiling upon BMMF expression identified host cellular gene expression changes related to cell cycle progression and cell viability control, indicating potential pathways for a pathogenic involvement of BMMFs. PMID- 29434271 TI - Adherence and quality of life in adults and children during 3-years of SLIT treatment with Grazax-a real life study. AB - Respiratory allergic disease represents a global health problem, 30% of the population suffers from allergic rhinoconjunctivitis and 20% suffer from asthma. Allergy immunotherapy induce immunological tolerance and thereby modify the response to allergens and sublingual immunotherapy (SLIT) offers the possibility of home administration of allergen therapy, but adherence is more uncertain. The aim of the study was to investigate the adherence with GRAZAX in adults and children >= 5 years during three consecutive years of treatment. This was a non interventional, prospective, observational, multi-center, open-label study to investigate adherence, quality of life, safety and tolerability of GRAZAX in adult and pediatric patients in a real-life setting. During the 3-years study period estimation of adherence was done regularly. Quality of life as well as symptom score was also assessed. In total, 399 patients (236 adults and 163 children) were included in the study. At baseline, 100% suffered from moderate severe eyes and nose symptoms, and 31% had asthma in the grass pollen season. Overall, 55% completed a 3-years treatment period, whereas 37% stopped before end of study and 8% were lost to follow up. After 3 years, the adherence rate decreased from 98.2% (first month), 93.7% (first year), 93.2% (second year) and 88.9% (third year) and adverse events were the main reason for pre-term termination. The study suggests a good adherence to treatment in a real life setting among the patients finalizing 3-years SLIT therapy. The treatment was effective both on symptoms and HRQL. PMID- 29434272 TI - Modified Inguinal Microscope-Assisted Varicocelectomy under Local Anesthesia: A Non-randomised Controlled Study of 3565 Cases. AB - Varicocele is a common abnormality, but the conventional microsurgical subinguinal varicocelectomy (CMSV) has some disadvantages. We invented Modified Inguinal Microscope-Assisted Varicocelectomy (MIMV) under local anesthesia. This study aims to evaluate MIMV by comparing it to CMSV in operating duration, time to return to normal activity, postoperative complications, achievement of natural pregnancy and improvement of semen quality for patients with infertility, pain score for those with scrotal pain, and so on. We enrolled 3089 patients who underwent MIMV and 476 who underwent CMSV in our hospital. Both the operating duration and the time to return to normal activity of MIMV was shorter than that of CMSV (P < 0.001). The recurrence rate (P < 0.001) and injury rate of vas deferens (P = 0.011) after MIMV were lower than that after CMSV. Moreover, patients with MIMV showed higher degree of satisfaction with the surgery experience and outcome than those with CMSV (P < 0.001). However, no statistical difference was found between the two groups in scores of pain due to surgery, postoperative varicose veins diameters, reflux duration, and the postoperative complications of wound infection, hydrocele, atrophy of testis, epididymitis, and scrotal hematoma. In summary, MIMV is a promising varicocelectomy and could be applied more in clinical practice. PMID- 29434273 TI - Giant and tunable optical torque for micro-motors by increased force arm and resonantly enhanced force. AB - Micro-motors driven by light field have attracted much attentions for their potential applications. In order to drive the rotation of a micro-motor, structured optical beams with orbital angular momentum, spin angular momentum, anisotropic medium, and/or inhomogeneous intensity distribution should be used. Even though, it is still challenge to increase the optical torques (OT) in a flexible and controllable way in case of moderate incident power. In this paper, a new scheme achieving giant optical torque is proposed by increasing both the force arm and the force amplitude with the assistance of a ring resonator. In this case, the optical torque doesn't act on the target directly by the incident beam, but is transmitted to it by rotating the ring resonator connected with it. Using the finite-difference in time-domain method, we calculate the optical torque and find that both the direction and the amplitude of the torque can be tuned flexibly by modifying the frequency, or the relative phases of the sources. More importantly, the optical torque obtained here by linearly polarized beams can be 3 orders larger than those obtained using the structured beams. This opt mechanical-resonator based optical torque engineering system may find potential applications in optical driven micro-machines. PMID- 29434274 TI - Carbon storage in China's terrestrial ecosystems: A synthesis. AB - It is important to accurately estimate terrestrial ecosystem carbon (C) storage. However, the spatial patterns of C storage and the driving factors remain unclear, owing to lack of data. Here, we collected data from literature published between 2004 and 2014 on C storage in China's terrestrial ecosystems, to explore variation in C storage across different ecosystems and evaluate factors that influence them. We estimated that total C storage was 99.15 +/- 8.71 PgC, with 14.60 +/- 3.24 PgC in vegetation C (Veg-C) and 84.55 +/- 8.09 PgC in soil organic C (SOC) storage. Furthermore, C storage in forest, grassland, wetland, shrub, and cropland ecosystems (excluding vegetation) was 34.08 +/- 5.43, 25.69 +/- 4.71, 3.62 +/- 0.80, 7.42 +/- 1.92, and 15.17 +/- 2.20 PgC, respectively. In addition to soil nutrients and texture, climate was the main factor regulating the spatial patterns of C storage. Climate influenced the spatial patterns of Veg-C and SOC density via different approaches, Veg-C was mainly positively influenced by mean annual precipitation (MAP), whereas SOC was negatively dependent on mean annual temperature (MAT). This systematic estimate of C storage in China provides new insights about how climate constrains C sequestration, demonstrating the contrasting effects of MAP and MAT on Veg-C and SOC; thus, these parameters should be incorporated into future land management and C sequestration strategies. PMID- 29434275 TI - Quantification of glioblastoma mass effect by lateral ventricle displacement. AB - Mass effect has demonstrated prognostic significance for glioblastoma, but is poorly quantified. Here we define and characterize a novel neuroimaging parameter, lateral ventricle displacement (LVd), which quantifies mass effect in glioblastoma patients. LVd is defined as the magnitude of displacement from the center of mass of the lateral ventricle volume in glioblastoma patients relative to that a normal reference brain. Pre-operative MR images from 214 glioblastoma patients from The Cancer Imaging Archive (TCIA) were segmented using iterative probabilistic voxel labeling (IPVL). LVd, contrast enhancing volumes (CEV) and FLAIR hyper-intensity volumes (FHV) were determined. Associations with patient survival and tumor genomics were investigated using data from The Cancer Genome Atlas (TCGA). Glioblastoma patients had significantly higher LVd relative to patients without brain tumors. The variance of LVd was not explained by tumor volume, as defined by CEV or FLAIR. LVd was robustly associated with glioblastoma survival in Cox models which accounted for both age and Karnofsky's Performance Scale (KPS) (p = 0.006). Glioblastomas with higher LVd demonstrated increased expression of genes associated with tumor proliferation and decreased expression of genes associated with tumor invasion. Our results suggest LVd is a quantitative measure of glioblastoma mass effect and a prognostic imaging biomarker. PMID- 29434277 TI - Three-dimensional (3D) tetra-culture brain on chip platform for organophosphate toxicity screening. AB - Organophosphate-based compounds (OPs) represent a significant threat to warfighters (nerve agents) and civilian populations (pesticides). There is a pressing need to develop in vitro brain models that correlate to the in vivo brain to rapidly study OPs for neurotoxicity. Here we report on a microfluidic based three-dimensional, four-cell tissue construct consisting of 1) a blood brain barrier that has dynamic flow and membrane-free culture of the endothelial layer, and 2) an extracellular matrix (ECM)-embedded tissue construct with neuroblastoma, microglia, and astrocytes. We demonstrated this platform's utility by measuring OP effects on barrier integrity, acetylcholinesterase (AChE) inhibition, viability and residual OP concentration with four model OPs. The results show that the OPs penetrate the blood brain barrier (BBB) and rapidly inhibit AChE activity, and that in vitro toxicity was correlated with available in vivo data. This paper demonstrates the potential utility of a membrane-free tetra-cultured brain on chip that can be scaled to high throughput as a cost effective alternative method to animal testing. PMID- 29434276 TI - The Extracellular Domain of Pollen Receptor Kinase 3 is structurally similar to the SERK family of co-receptors. AB - During reproduction in flowering plants, the male gametophyte delivers an immotile male gamete to the female gametophyte in the pistil by formation of pollen tubes. In Arabidopsis thaliana, two synergid cells situated on either side of the egg cell produce cysteine-rich chemoattractant peptide LURE that guides the pollen tube to the female gametophyte for sexual reproduction. Recently, in Arabidopsis thaliana, Pollen Receptor Kinase 3 (PRK3), along with PRK1, PRK6, and PRK8, have been predicted to be the receptors responsible for sensing LURE. These receptors belong to the Leucine Rich Repeat Receptor Like Kinases (LRR-RLKs), the largest family of receptor kinases found in Arabidopsis thaliana. How PRKs regulate the growth and development of the pollen tube remains elusive. In order to better understand the PRK-mediated signaling mechanism in pollen tube growth and guidance, we have determined the crystal structure of the extracellular domain (ecd) of PRK3 at 2.5 A, which resembles the SERK family of plant co receptors. The structure of ecdPRK3 is composed of a conserved surface that coincides with the conserved receptor-binding surface of the SERK family of co receptors. Our structural analyses of PRK3 have provided a template for future functional studies of the PRK family of LRR-RLK receptors in the regulation of pollen tube development. PMID- 29434278 TI - Communication in necrophagous Diptera larvae: interspecific effect of cues left behind by maggots and implications in their aggregation. AB - Necrophagous Calliphoridae breed in vertebrate carrion. Their larvae aggregate and form large masses of individuals. These aggregated larvae can reach adulthood faster than scattered larvae, increasing their chances of survival. Furthermore, the gathering of larvae of different species suggests possible interspecific aggregation vectors. In this context, the effect of larval ground-left cues on larvae of Calliphora vomitoria and Lucilia sericata was studied. We used video tracking to follow larvae placed in binary choice tests. We observed (1) a preference of both species for a side marked by conspecific or heterospecific larvae compared to an unmarked side, (2) a preference of L. sericata larvae for a conspecific-marked side compared to a heterospecific-marked side but only at high concentration of cues and (3) a preference of both species for the side marked by the greater number of larvae. These results demonstrate that larvae leave a mark locally which is retentive, has an interspecific range, has an effect proportional to its intensity and whose strength varies depending on the emitting species. According to the self-organization theory, this mark could enhance larval gathering and promote interspecific aggregations. While not yet demonstrated, an interspecific Allee effect could explain the interspecific association of necrophagous calliphorid larvae. PMID- 29434280 TI - Identification and Documentation of Auricle Defects using Three-dimensional Optical Measurements. AB - Auricle defects are important and common occurrences in forensic medicine. The accurate measurement and assessment of auricle defects is key to identifying and evaluating injury, and the currently available methods are known to be labor intensive and inaccurate. In this paper, we introduce an identification and documentation of auricle defects solution, which consists of an optical three dimensional (3D) method and an effective algorithm to calculate the maximum projection area and identify auricle defects. In this study, three separate examiners measured 40 auricles of 20 adults using 3D optical measurement and two other commonly used methods to investigate the validity and representative reliability of 3D optical measurement for auricle defect identification. Based on the statistical analysis, the 3D measurement method is valid and showed a better reliability than the reference methods. We also present a representative auricle defect identification case using the proposed 3D optical measurement method. The study concludes that the optical 3D measurement method is a reliable and effective tool for auricle defect identification. PMID- 29434281 TI - Atomic-state diagnostics and optimization in cold-atom experiments. AB - We report on the creation, observation and optimization of superposition states of cold atoms. In our experiments, rubidium atoms are prepared in a magneto optical trap and later, after switching off the trapping fields, Faraday rotation of a weak probe beam is used to characterize atomic states prepared by application of appropriate light pulses and external magnetic fields. We discuss the signatures of polarization and alignment of atomic spin states and identify main factors responsible for deterioration of the atomic number and their coherence and present means for their optimization, like relaxation in the dark with the strobed probing. These results may be used for controlled preparation of cold atom samples and in situ magnetometry of static and transient fields. PMID- 29434279 TI - Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma. AB - Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2. PRN371 effectively suppresses NKTL cell proliferation and induces apoptosis through abrogation of the JAK3-STAT signaling. Moreover, the activity of PRN371 has a more durable inhibition on JAK3 compared to tofacitinib in vitro, leading to significant tumor growth inhibition in a NKTL xenograft model harboring JAK3 activating mutation. These findings provide a novel therapeutic approach for the treatment of NKTL. PMID- 29434282 TI - Murine hematopoietic stem cell reconstitution potential is maintained by osteopontin during aging. AB - In adult mammals, hematopoietic stem cells (HSCs) reside in the bone marrow and are in part regulated by the bone marrow microenvironment, called the stem cell niche. We have previously identified the bone marrow morphogen osteopontin (OPN), which is abundantly present in the bone marrow extracellular matrix, as a negative regulator of the size of the HSC pool under physiological conditions. Here, we study the impact of OPN on HSC function during aging using an OPN knockout mouse model. We show that during aging OPN deficiency is associated with an increase in lymphocytes and a decline in erythrocytes in peripheral blood. In a bone marrow transplantation setting, aged OPN-deficient stem cells show reduced reconstitution ability likely due to insufficient differentiation of HSCs into more mature cells. In serial bone marrow transplantation, aged OPN-/- bone marrow cells fail to adequately reconstitute red blood cells and platelets, resulting in severe anemia and thrombocytopenia as well as premature deaths of recipient mice. Thus, OPN has different effects on HSCs in aged and young animals and is particularly important to maintain stem cell function in aging mice. PMID- 29434283 TI - The wavelength of the incident light determines the primary charge separation pathway in Photosystem II. AB - Charge separation is a key component of the reactions cascade of photosynthesis, by which solar energy is converted to chemical energy. From this photochemical reaction, two radicals of opposite charge are formed, a highly reducing anion and a highly oxidising cation. We have previously proposed that the cation after far red light excitation is located on a component different from PD1, which is the location of the primary electron hole after visible light excitation. Here, we attempt to provide further insight into the location of the primary charge separation upon far-red light excitation of PS II, using the EPR signal of the spin polarized 3P680 as a probe. We demonstrate that, under far-red light illumination, the spin polarized 3P680 is not formed, despite the primary charge separation still occurring at these conditions. We propose that this is because under far-red light excitation, the primary electron hole is localized on ChlD1, rather than on PD1. The fact that identical samples have demonstrated charge separation upon both far-red and visible light excitation supports our hypothesis that two pathways for primary charge separation exist in parallel in PS II reaction centres. These pathways are excited and activated dependent of the wavelength applied. PMID- 29434284 TI - Prognostic interaction between bone marrow morphology and SF3B1 and ASXL1 mutations in myelodysplastic syndromes with ring sideroblasts. PMID- 29434285 TI - Generation of a Dual-Target, Safe, Inexpensive Microbicide that Protects Against HIV-1 and HSV-2 Disease. AB - HSV-2 infection is a significant health problem and a major co-morbidity factor for HIV-1 acquisition, increasing risk of infection 2-4 fold. Condom based prevention strategies for HSV-2 and HIV-1 have not been effective at stopping the HIV-1 pandemic, indicating that alternative prevention strategies need to be investigated. We have previously developed an inexpensive HIV-1 specific microbicide that utilizes the S-layer mediated display capabilities of Caulobacter crescentus, and have shown that recombinant C. crescentus displaying HIV entry blocking proteins are able to provide significant protection from HIV-1 infection in vitro. Here we demonstrate that recombinant C. crescentus are safe for topical application and describe 5 new recombinant C. crescentus that provide protection from HIV-1 infection in vitro. Further, we demonstrate protection from disease following intravaginal infection with HSV-2 in a murine model using C. crescentus expressing the anti-viral lectins Cyanovirin-N and Griffithsin, as well as alpha-1-antitrypsin and indolicidin. Interestingly, C. crescentus alone significantly reduced HSV-2 replication in vaginal lavage fluid. Protection from HSV-2 disease was strongly associated with early cytokine production in the vaginal tract. Our data support the potential for a dual-target microbicide that can protect against both HIV-1 and HSV-2, which could have an enormous impact on public health. PMID- 29434286 TI - Protactinium and the intersection of actinide and transition metal chemistry. AB - The role of the 5f and 6d orbitals in the chemistry of the actinide elements has been of considerable interest since their discovery and synthesis. Relativistic effects cause the energetics of the 5f and 6d orbitals to change as the actinide series is traversed left to right imparting a rich and complex chemistry. The 5f and 6d atomic states cross in energy at protactinium (Pa), making it a potential intersection between transition metal and actinide chemistries. Herein, we report the synthesis of a Pa-peroxo cluster, A6(Pa4O(O2)6F12) [A = Rb, Cs, (CH3)4N], formed in pursuit of an actinide polyoxometalate. Quantum chemical calculations at the density functional theory level demonstrate equal 5f and 6d orbital participation in the chemistry of Pa and increasing 5f orbital participation for the heavier actinides. Periodic changes in orbital character to the bonding in the early actinides highlights the influence of the 5f orbitals in their reactivity and chemical structure. PMID- 29434287 TI - Angiotensin II Type 1 Receptor-associated Protein Inhibits Angiotensin II-induced Insulin Resistance with Suppression of Oxidative Stress in Skeletal Muscle Tissue. AB - Enhancement of AT1 receptor-associated protein (ATRAP) in adipose tissue improves high fat diet (HFD)-induced visceral obesity and insulin resistance, and suppresses adipose oxidative stress. However, HFD loading is not a direct stimulatory factor for AT1 receptor. In the present study, we investigated the effect of chronic, low-dose angiotensin II (Ang II) stimulation on glucose and lipid metabolism in mice and functional role of ATRAP. ATRAP expression was higher in adipose tissue (5-10-fold) and skeletal muscle tissue (approximately 1.6-fold) in ATRAP transgenic (TG) mice compared with wild-type (WT) mice. After Ang II infusion, insulin sensitivity was impaired in WT mice, but this response was suppressed in TG mice. Unexpectedly, Ang II infusion did not affect the adipose tissue profile in WT or TG mice. However, in skeletal muscle tissue, Ang II stimulus caused an increase in oxidative stress and activation of p38 MAPK, resulting in a decrease in glucose transporter type 4 expression in WT mice. These responses were suppressed in TG mice. Our study suggests that Ang II induced insulin resistance is suppressed by increased ATRAP expression in skeletal muscle tissue. Hyperactivity of AT1 receptor could be related to formation of insulin resistance related to metabolic syndrome. PMID- 29434288 TI - Stem cell transplantation for T-cell lymphomas in Taiwan. AB - T-cell lymphomas are generally aggressive malignancies with poor prognosis. There are no standard treatment guidelines for T-cell lymphomas, and the timing of stem cell transplantation (SCT) is not well known. In this study, we investigated the outcomes of Taiwanese patients with T-cell lymphomas after SCT. We retrospectively analyzed 131 patients with T-cell lymphomas receiving SCT (autologous: 90, allogeneic: 41) from 2009 to 2014. More autologous SCT recipients were ALCL or in complete remission, and more allogeneic recipients had advanced disease. 56 patients who were sensitive to chemotherapy underwent SCT as upfront setting. The 2-year PFS and OS rates were 67.0 and 64.5%, respectively. Regarding disease status before transplantation, patients with CR1 had the best outcomes. Among different subtypes, patients with natural killer/T-cell lymphomas showed the worst outcomes, with 2-year OS rate of 23.5%. The OS rates for the other three major subtypes were as follows: 72.9% for ALCL; 75.0% for AITL; and 51.4% for PTCL-NOS. For more rare subtypes, such as ATLL and SPTCL, data from our study show that SCT can be beneficial. We concluded that upfront autologous SCT is feasible and effective for patients with low PIT, and disease status at transplant is the strong predictor of outcome. PMID- 29434289 TI - Use of split peripheral blood stem cell harvests in myeloma identifies functional preservation of progenitor cells cryopreserved for several years and demonstrates no functional damage to the bone marrow microenvironment. PMID- 29434291 TI - Correspondence: Chimpanzee helping is real, not a byproduct. PMID- 29434290 TI - Induction of differentiation of intrahepatic cholangiocarcinoma cells to functional hepatocytes using an organoid culture system. AB - Intrahepatic cholangiocarcinoma (IHCC) is a highly aggressive malignancy with a poor prognosis. It is thought to originate from cholangiocytes, which are the component cells of intrahepatic bile ducts. However, as patients with viral hepatitis often develop IHCC, it has been suggested that transformed hepatocytes may play a role in IHCC development. To investigate whether IHCC cells can be converted to functional hepatocytes, we established organoids derived from human IHCC and cultured them under conditions suitable for hepatocyte differentiation. IHCC organoids after hepatocyte differentiation acquired functions of mature hepatocytes such as albumin secretion, bile acid production and increased CYP3A4 activity. Studies using a mouse model of IHCC indicate that Wnt3a derived from macrophages recruited upon inflammation in the liver may promote the malignant transformation of hepatocytes to IHCC cells. The results of the present study support the recently proposed hypothesis that IHCC cells are derived from hepatocytes. PMID- 29434292 TI - Conductive Atomic Force Microscope Study of Bipolar and Threshold Resistive Switching in 2D Hexagonal Boron Nitride Films. AB - This study investigates the resistive switching characteristics and underlying mechanism in 2D layered hexagonal boron nitride (h-BN) dielectric films using conductive atomic force microscopy. A combination of bipolar and threshold resistive switching is observed consistently on multi-layer h-BN/Cu stacks in the low power regime with current compliance (I comp ) of less than 100 nA. Standard random telegraph noise signatures were observed in the low resistance state (LRS), similar to the trends in oxygen vacancy-based RRAM devices. While h-BN appears to be a good candidate in terms of switching performance and endurance, it performs poorly in terms of retention lifetime due to the self-recovery of LRS state (similar to recovery of soft breakdown in oxide-based dielectrics) that is consistently observed at all locations without requiring any change in the voltage polarity for I comp ~1-100 nA. PMID- 29434293 TI - Luminescence resonance energy transfer between genetically encoded donor and acceptor for protein-protein interaction studies in the molecular chaperone HSP70/HSP90 complexes. AB - Complex patterns of protein-protein interactions (PPInts) are involved in almost all cellular processes. This has stimulated the development of a wide range of methods to characterize PPInts in detail. Methods with fluorescence resonance energy transfer can be technically challenging and suffer from several limitations, which could be overcome by switching to luminescence resonance energy transfer (LRET) with lanthanide ions such as Tb3+. With LRET, energy transfer between PPInt partners works over a larger distance and with less topological constraints; moreover, the long-lived luminescence of lanthanides allows one to bypass the short-lived background fluorescence. We have developed a novel LRET method to investigate PPInts between partners expressed as fusion proteins with genetically encoded donor and acceptor moieties. Upon UV excitation of a tryptophan within a lanthanide binding peptide, the Tb3+ luminescence is harnessed to excite either a green or a red fluorescent protein. We demonstrate the usefulness of the LRET assay by applying it to analyze the interactions of the molecular chaperones HSP70 and HSP90 with their common co-chaperone HOP/Sti1. We recapitulate the previously described interaction specificities between the HSP70/HSP90 C-termini and tetratricopeptide repeat domains of HOP/Sti1 and demonstrate the impact of single point mutants on domain-domain interactions. PMID- 29434294 TI - Residential energy use emissions dominate health impacts from exposure to ambient particulate matter in India. AB - Exposure to ambient fine particulate matter (PM2.5) is a leading contributor to diseases in India. Previous studies analysing emission source attributions were restricted by coarse model resolution and limited PM2.5 observations. We use a regional model informed by new observations to make the first high-resolution study of the sector-specific disease burden from ambient PM2.5 exposure in India. Observed annual mean PM2.5 concentrations exceed 100 MUg m-3 and are well simulated by the model. We calculate that the emissions from residential energy use dominate (52%) population-weighted annual mean PM2.5 concentrations, and are attributed to 511,000 (95UI: 340,000-697,000) premature mortalities annually. However, removing residential energy use emissions would avert only 256,000 (95UI: 162,000-340,000), due to the non-linear exposure-response relationship causing health effects to saturate at high PM2.5 concentrations. Consequently, large reductions in emissions will be required to reduce the health burden from ambient PM2.5 exposure in India. PMID- 29434295 TI - Vaccination Against Lawsonia intracellularis Decreases Shedding of Salmonella enterica serovar Typhimurium in Co-Infected Pigs and Alters the Gut Microbiome. AB - Salmonella enterica serovar Typhimurium continues to be a major cause of foodborne illness worldwide and pork can serve as a source of infection. Co infection of S. enterica with Lawsonia intracellularis, a common intestinal pathogen of swine, has been found as risk factor for increased S. enterica shedding. The objective of this study was to investigate if vaccination against L. intracellularis could lead to decreased S. Typhimurium shedding. To test this hypothesis, pigs were challenged with either S. Typhimurium or S. Typhimurium and L. intracellularis, with and without L. intracellularis vaccination (n = 9 per group). A non-challenged group served as a negative control. Vaccination decreased the shedding of S. Typhimurium in co-infected animals by 2.12 log10 organisms per gram of feces at 7 days post infection. Analysis of the microbiome showed that vaccination led to changes in the abundance of Clostridium species, including Clostridium butyricum, in addition to other compositional changes that may explain the protection mediated against S. Typhimurium. These results indicate that vaccination against L. intracellularis in co-infected herds may provide a new tool to increase food safety by helping to prevent S. enterica without the need for antibiotics. PMID- 29434296 TI - Highly flexible transparent electrodes based on mesh-patterned rigid indium tin oxide. AB - We developed highly bendable transparent indium tin oxide (ITO) electrodes with a mesh pattern for use in flexible electronic devices. The mesh patterns lowered tensile stress and hindered propagation of cracks. Simulations using the finite element method confirmed that the mesh patterns decreased tensile stress by over 10% because of the escaped strain to the flexible film when the electrodes were bent. The proposed patterned ITO electrodes were simply fabricated by photolithography and wet etching. The resistance increase ratio of a mesh patterned ITO electrode after bending 1000 times was at least two orders of magnitude lower than that of a planar ITO electrode. In addition, crack propagation was stopped by the mesh pattern of the patterned ITO electrode. A mesh-patterned ITO electrode was used in a liquid-based organic light-emitting diode (OLED). The OLED displayed the same current density-voltage-luminance (J-V L) curves before and after bending 100 times. These results indicate that the developed mesh-patterned ITO electrodes are attractive for use in flexible electronic devices. PMID- 29434297 TI - Future changes in coastal upwelling ecosystems with global warming: The case of the California Current System. AB - Coastal upwelling ecosystems are among the most productive ecosystems in the world, meaning that their response to climate change is of critical importance. Our understanding of climate change impacts on marine ecosystems is largely limited to the open ocean, mainly because coastal upwelling is poorly reproduced by current earth system models. Here, a high-resolution model is used to examine the response of nutrients and plankton dynamics to future climate change in the California Current System (CCS). The results show increased upwelling intensity associated with stronger alongshore winds in the coastal region, and enhanced upper-ocean stratification in both the CCS and open ocean. Warming of the open ocean forces isotherms downwards, where they make contact with water masses with higher nutrient concentrations, thereby enhancing the nutrient flux to the deep source waters of the CCS. Increased winds and eddy activity further facilitate upward nutrient transport to the euphotic zone. However, the plankton community exhibits a complex and nonlinear response to increased nutrient input, as the food web dynamics tend to interact differently. This analysis highlights the difficulty in understanding how the marine ecosystem responds to a future warming climate, given to range of relevant processes operating at different scales. PMID- 29434298 TI - Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice. AB - Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo process of formation remains unknown. Synuclein, a component of LBs, is the defining characteristic of Parkinson's disease (PD). Here, we characterize dopamine (DA) neuron-specific autophagy deficient mice and provide in vivo evidence for LB formation. Synuclein deposition is preceded by p62 and resulted in the formation of inclusions containing synuclein and p62. The number and size of these inclusions were gradually increased in neurites rather than soma with aging. These inclusions may facilitate peripheral failures. As a result, DA neuron loss and motor dysfunction including the hindlimb defect were observed in 120-week-old mice. P62 aggregates derived from an autophagic defect might serve as "seeds" and can potentially be cause of LB formation. PMID- 29434299 TI - Quantitative Morphometry for Osteochondral Tissues Using Second Harmonic Generation Microscopy and Image Texture Information. AB - Osteoarthritis (OA) is a chronic joint disorder involving degeneration of articular cartilage and subchondral bone in joints. We previously established a second harmonic generation (SHG) imaging technique for evaluating degenerative changes to articular cartilage in an OA mouse model. SHG imaging, an optical label-free technique, enabled observation of collagen fibrils, and characterized critical changes in the collagenous patterns of the joints. However, it still remains to be determined how morphological changes in the organization of tissue collagen fibrils should be quantified. In this study, we addressed this issue by employing an approach based on texture analysis. Image texture analysis using the gray level co-occurrence matrix was explored to extract image features. We investigated an image patch-based strategy, in which texture features were extracted on individual patches derived from original images to capture local structural patterns in them. We verified that this analysis enables discrimination of cartilaginous and osseous tissues in mouse joints. Moreover, we applied this method to OA cartilage pathology assessment, and observed improvements in the performance results compared with those obtained using an existing feature descriptor. The proposed approach can be applied to a wide range of conditions associated with collagen remodeling and diseases of cartilage and bone. PMID- 29434300 TI - Partitioning the regional and local drivers of phylogenetic and functional diversity along temperate elevational gradients on an East Asian peninsula. AB - Species-centric approaches to biodiversity in ecological research are limited in their ability to reflect the evolutionary history and functional diversity of community assembly. Recently, the introduction of alternative facets of biodiversity, such as phylogenetic and functional diversity, has shed light on this problem and improved our understanding of the processes underlying biodiversity patterns. Here, we investigated the phylogenetic and functional diversity patterns of alpha, beta and gamma components in woody plant assemblages along regional and local elevational gradients in South Korea. Although the patterns of phylogenetic and functional diversity varied along regional and local elevational transects, the main drivers were partitioned into two categories: regional area or climate for phylogenetic diversity, depending on whether the transect was at a regional or local scale; and habitat heterogeneity for functional diversity, which was derived in elevational bands. Moreover, environmental distance was more important than was geographic distance for phylogenetic and functional beta diversity between paired elevational bands. These results support the hypothesis that niche-based deterministic processes such as environmental filtering and competitive exclusion are fundamental in structuring woody plant assemblages along temperate elevational gradients regardless of scale (regional vs. local) in our study areas. PMID- 29434301 TI - Advancing behavioural genomics by considering timescale. AB - Animal behavioural traits often covary with gene expression, pointing towards a genomic constraint on organismal responses to environmental cues. This pattern highlights a gap in our understanding of the time course of environmentally responsive gene expression, and moreover, how these dynamics are regulated. Advances in behavioural genomics explore how gene expression dynamics are correlated with behavioural traits that range from stable to highly labile. We consider the idea that certain genomic regulatory mechanisms may predict the timescale of an environmental effect on behaviour. This temporally minded approach could inform both organismal and evolutionary questions ranging from the remediation of early life social trauma to understanding the evolution of trait plasticity. PMID- 29434304 TI - A perfect match. PMID- 29434303 TI - Cell-geometry-dependent changes in plasma membrane order direct stem cell signalling and fate. AB - Cell size and shape affect cellular processes such as cell survival, growth and differentiation1-4, thus establishing cell geometry as a fundamental regulator of cell physiology. The contributions of the cytoskeleton, specifically actomyosin tension, to these effects have been described, but the exact biophysical mechanisms that translate changes in cell geometry to changes in cell behaviour remain mostly unresolved. Using a variety of innovative materials techniques, we demonstrate that the nanostructure and lipid assembly within the cell plasma membrane are regulated by cell geometry in a ligand-independent manner. These biophysical changes trigger signalling events involving the serine/threonine kinase Akt/protein kinase B (PKB) that direct cell-geometry-dependent mesenchymal stem cell differentiation. Our study defines a central regulatory role by plasma membrane ordered lipid raft microdomains in modulating stem cell differentiation with potential translational applications. PMID- 29434305 TI - X-ray electron density investigation of chemical bonding in van der Waals materials. AB - Van der Waals (vdW) solids have attracted great attention ever since the discovery of graphene, with the essential feature being the weak chemical bonding across the vdW gap. The nature of these weak interactions is decisive for many extraordinary properties, but it is a strong challenge for current theory to accurately model long-range electron correlations. Here we use synchrotron X-ray diffraction data to precisely determine the electron density in the archetypal vdW solid, TiS2, and compare the results with density functional theory calculations. Quantitative agreement is observed for the chemical bonding description in the covalent TiS2 slabs, but significant differences are identified for the interactions across the gap, with experiment revealing more electron deformation than theory. The present data provide an experimental benchmark for testing theoretical models of weak chemical bonding. PMID- 29434302 TI - Retinal progenitor cells release extracellular vesicles containing developmental transcription factors, microRNA and membrane proteins. AB - A range of cell types, including embryonic stem cells, neurons and astrocytes have been shown to release extracellular vesicles (EVs) containing molecular cargo. Across cell types, EVs facilitate transfer of mRNA, microRNA and proteins between cells. Here we describe the release kinetics and content of EVs from mouse retinal progenitor cells (mRPCs). Interestingly, mRPC derived EVs contain mRNA, miRNA and proteins associated with multipotency and retinal development. Transcripts enclosed in mRPC EVs, include the transcription factors Pax6, Hes1, and Sox2, a mitotic chromosome stabilizer Ki67, and the neural intermediate filaments Nestin and GFAP. Proteomic analysis of EV content revealed retinogenic growth factors and morphogen proteins. mRPC EVs were shown to transfer GFP mRNA between cell populations. Finally, analysis of EV mediated functional cargo delivery, using the Cre-loxP recombination system, revealed transfer and uptake of Cre+ EVs, which were then internalized by target mRPCs activating responder loxP GFP expression. In summary, the data supports a paradigm of EV genetic material encapsulation and transfer within RPC populations. RPC EV transfer may influence recipient RPC transcriptional and post-transcriptional regulation, representing a novel mechanism of differentiation and fate determination during retinal development. PMID- 29434306 TI - Correlation of surface site formation to nanoisland growth in the electrochemical roughening of Pt(111). AB - Platinum plays a central role in a variety of electrochemical devices and its practical use depends on the prevention of electrode degradation. However, understanding the underlying atomic processes under conditions of repeated oxidation and reduction inducing irreversible surface structure changes has proved challenging. Here, we examine the correlation between the evolution of the electrochemical signal of Pt(111) and its surface roughening by simultaneously performing cyclic voltammetry and in situ electrochemical scanning tunnelling microscopy (EC-STM). We identify a 'nucleation and early growth' regime of nanoisland formation, and a 'late growth' regime after island coalescence, which continues up to at least 170 cycles. The correlation analysis shows that each step site that is created in the 'late growth' regime contributes equally strongly to both the electrochemical and the roughness evolution. In contrast, in the 'nucleation and early growth' regime, created step sites contribute to the roughness, but not to the electrochemical signal. PMID- 29434307 TI - Solid-state electron spin lifetime limited by phononic vacuum modes. AB - Longitudinal relaxation is the process by which an excited spin ensemble decays into its thermal equilibrium with the environment. In solid-state spin systems, relaxation into the phonon bath usually dominates over the coupling to the electromagnetic vacuum1-9. In the quantum limit, the spin lifetime is determined by phononic vacuum fluctuations 10 . However, this limit was not observed in previous studies due to thermal phonon contributions11-13 or phonon-bottleneck processes10, 14,15. Here we use a dispersive detection scheme16,17 based on cavity quantum electrodynamics18-21 to observe this quantum limit of spin relaxation of the negatively charged nitrogen vacancy (NV-) centre 22 in diamond. Diamond possesses high thermal conductivity even at low temperatures 23 , which eliminates phonon-bottleneck processes. We observe exceptionally long longitudinal relaxation times T1 of up to 8 h. To understand the fundamental mechanism of spin-phonon coupling in this system we develop a theoretical model and calculate the relaxation time ab initio. The calculations confirm that the low phononic density of states at the NV- transition frequency enables the spin polarization to survive over macroscopic timescales. PMID- 29434308 TI - Illuminating interlayer interactions. PMID- 29434309 TI - Mixed matrix formulations with MOF molecular sieving for key energy-intensive separations. AB - Membrane-based separations can improve energy efficiency and reduce the environmental impacts associated with traditional approaches. Nevertheless, many challenges must be overcome to design membranes that can replace conventional gas separation processes. Here, we report on the incorporation of engineered submicrometre-sized metal-organic framework (MOF) crystals into polymers to form hybrid materials that successfully translate the excellent molecular sieving properties of face-centred cubic (fcu)-MOFs into the resultant membranes. We demonstrate, simultaneously, exceptionally enhanced separation performance in hybrid membranes for two challenging and economically important applications: the removal of CO2 and H2S from natural gas and the separation of butane isomers. Notably, the membrane molecular sieving properties demonstrate that the deliberately regulated and contracted MOF pore-aperture size can discriminate between molecular pairs. The improved performance results from precise control of the linkers delimiting the triangular window, which is the sole entrance to the fcu-MOF pore. This rational-design hybrid approach provides a general toolbox for enhancing the transport properties of advanced membranes bearing molecular sieve fillers with sub-nanometre-sized pore-apertures. PMID- 29434310 TI - Recombinant IFN-gamma from the bank vole Myodes glareolus: a novel tool for research on rodent reservoirs of zoonotic pathogens. AB - Rodent species like Myodes glareolus and Microtus spp. are natural reservoirs for many zoonotic pathogens causing human diseases and are gaining increasing interest in the field of eco-immunology as candidate animal models. Despite their importance the lack of immunological reagents has hampered research in these animal species. Here we report the recombinant production and functional characterization of IFN-gamma, a central mediator of host's innate and adaptive immune responses, from the bank vole M. glareolus. Soluble dimeric recMgIFN-gamma was purified in high yield from Escherichia coli. Its activity on M. glareolus and Microtus arvalis kidney cell lines was assessed by immunofluorescent detection of nuclear translocation and phosphorylation of the transcription factor STAT1. RecMgIFN-gamma also induced expression of an IFN-gamma-regulated innate immunity gene. Inhibition of vesicular stomatitis virus replication in vole cells upon recMgIFN-gamma treatment provided further evidence of its biological activity. Finally, we established a recMgIFN-gamma-responsive bank vole reporter cell line that allows the sensitive titration of the cytokine activity via a bioluminescence reporter assay. Taken together, we report valuable tools for future investigations on the immune response against zoonotic pathogens in their natural animal hosts, which might foster the development of novel animal models. PMID- 29434311 TI - Directed Differentiation of Adult Liver Derived Mesenchymal Like Stem Cells into Functional Hepatocytes. AB - Shortage of functional hepatocytes hampers drug safety testing and therapeutic applications because mature hepatocytes cannot be expanded and maintain functions in vitro. Recent studies have reported that liver progenitor cells can originate from mature hepatocytes in vivo. Derivation of proliferating progenitor cells from mature hepatocytes, and re-differentiation into functional hepatocytes in vitro has not been successful. Here we report the derivation of novel mesenchymal like stem cells (arHMSCs) from adult rat hepatocytes. Immunofluorescence and flow cytometry characterization of arHMSCs found expression of mesenchymal markers CD29, CD44, CD90, vimentin and alpha smooth muscle actin. These arHMSCs proliferated in vitro for 4 passages yielding 104 fold increase in cell number in 28 days, and differentiated into hepatocyte-like cells (arHMSC-H). The arHMSC-H expressed significantly higher level of hepatocyte-specific markers (200 fold for albumin and 6 fold for Cyp450 enzymes) than arHMSCs. The arHMSC-H also demonstrated dose response curves similar to primary hepatocytes for 3 of the 6 paradigm hepatotoxicants tested, demonstrating utility in drug safety testing applications. PMID- 29434312 TI - Circadian clocks of both plants and pollinators influence flower seeking behavior of the pollinator hawkmoth Manduca sexta. AB - Most plant-pollinator interactions occur during specific periods during the day. To facilitate these interactions, many flowers are known to display their attractive qualities, such as scent emission and petal opening, in a daily rhythmic fashion. However, less is known about how the internal timing mechanisms (the circadian clocks) of plants and animals influence their daily interactions. We examine the role of the circadian clock in modulating the interaction between Petunia and one of its pollinators, the hawkmoth Manduca sexta. We find that desynchronization of the Petunia circadian clock affects moth visitation preference for Petunia flowers. Similarly, moths with circadian time aligned to plants show stronger flower-foraging activities than moths that lack this alignment. Moth locomotor activity is circadian clock-regulated, although it is also strongly repressed by light. Moths show a time-dependent burst increase in flight activity during subjective night. In addition, moth antennal responsiveness to the floral scent compounds exhibits a 24-hour rhythm in both continuous light and dark conditions. This study highlights the importance of the circadian clocks in both plants and animals as a crucial factor in initiating specialized plant-pollinator relationships. PMID- 29434313 TI - Distributions of phytoplankton carbohydrate, protein and lipid in the world oceans from satellite ocean colour. AB - Energy value of phytoplankton regulates the growth of higher trophic species, affecting the tropic balance and sustainability of marine food webs. Therefore, developing our capability to estimate and monitor, on a global scale, the concentrations of macromolecules that determine phytoplankton energy value, would be invaluable. Reported here are the first estimates of carbohydrate, protein, lipid, and overall energy value of phytoplankton in the world oceans, using ocean colour data from satellites. The estimates are based on a novel bio-optical method that utilises satellite-derived bio-optical fingerprints of living phytoplankton combined with allometric relationships between phytoplankton cells and cellular macromolecular contents. The annually averaged phytoplankton energy value, per cubic metre of sub-surface ocean, varied from less than 0.1 kJ in subtropical gyres, to 0.5-1.0 kJ in parts of the equatorial, northern and southern latitudes, and rising to >10 kJ in certain coastal and optically complex waters. The annually averaged global stocks of carbohydrate, protein and lipid were 0.044, 0.17 and 0.108 gigatonnes, respectively, with monthly stocks highest in September and lowest in June, over 1997-2013. The fractional contributions of phytoplankton size classes e.g., picoplankton, nanoplankton and microplankton to surface concentrations and global stocks of macromolecules varied considerably across marine biomes classified as Longhurst provinces. Among these provinces, the highest annually averaged surface concentrations of carbohydrate, protein, and lipid were in North-East Atlantic Coastal Shelves, whereas, the lowest concentration of carbohydrate or lipid were in North Atlantic Tropical Gyral, and that of protein was in North Pacific Subtropical Gyre West. The regional accuracy of the estimates and their sensitivity to satellite inputs are quantified from the bio-optical model, which show promise for possible operational monitoring of phytoplankton energy value from satellite ocean colour. Adequate in situ measurements of macromolecules and improved retrievals of inherent optical properties from high-resolution satellite images, would be required to validate these estimates at local sites, and to further improve their accuracy in the world oceans. PMID- 29434314 TI - Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota. AB - Gut microbiota-related metabolites are potential clinical biomarkers for cardiovascular disease (CVD). Circulating succinate, a metabolite produced by both microbiota and the host, is increased in hypertension, ischemic heart disease, and type 2 diabetes. We aimed to analyze systemic levels of succinate in obesity, a major risk factor for CVD, and its relationship with gut microbiome. We explored the association of circulating succinate with specific metagenomic signatures in cross-sectional and prospective cohorts of Caucasian Spanish subjects. Obesity was associated with elevated levels of circulating succinate concomitant with impaired glucose metabolism. This increase was associated with specific changes in gut microbiota related to succinate metabolism: a higher relative abundance of succinate-producing Prevotellaceae (P) and Veillonellaceae (V), and a lower relative abundance of succinate-consuming Odoribacteraceae (O) and Clostridaceae (C) in obese individuals, with the (P + V/O + C) ratio being a main determinant of plasma succinate. Weight loss intervention decreased (P + V/O + C) ratio coincident with the reduction in circulating succinate. In the spontaneous evolution after good dietary advice, alterations in circulating succinate levels were linked to specific metagenomic signatures associated with carbohydrate metabolism and energy production with independence of body weight change. Our data support the importance of microbe-microbe interactions for the metabolite signature of gut microbiome and uncover succinate as a potential microbiota-derived metabolite related to CVD risk. PMID- 29434316 TI - Prepregnancy weight excess and cessation of exclusive breastfeeding: a systematic review and meta-analysis. AB - Recent studies have identified a relationship between maternal body mass index during prepregnancy (BMI) and exclusive breastfeeding (EBF), which is less common among mothers with higher BMI. The purpose of this literature review is to provide a pooled effect for the association between maternal excess weight during prepregnancy and cessation of exclusive breastfeeding. A systematic review was performed using articles present in six databases (PubMed, Scopus, Web off Science, Science direct, CINAHL and LILACS) published till February 2017. Studies investigating the association between excess maternal weight during prepregnancy and cessation of exclusive breastfeeding were included in the review. A meta analysis using random effects to obtain a pooled effect of the studied association was conducted only with studies reporting odds ratio (OR) or available data for the calculation. Univariate meta-regression was performed to evaluate possible sources of heterogeneity. Egger's tests were also performed to verify possible publication bias. From the 6889 studies identified, 102 were read in full and 17 were included in the meta-analysis, providing 28 estimates for the association. Overall, a positive association was observed between maternal excess weight during prepregnancy and cessation of exclusive breastfeeding (ES: 1.60 (95% CI: 1.47, 1.74), I2: 93.2%). According to the used independent variables, no sources of heterogeneity were identified between studies Bias in publication was found. Maternal excess weight during prepregnancy was associated with cessation of exclusive breastfeeding. A standardized measure for exclusive breastfeeding is still needed for estimating its duration, in addition to further studies in developing countries to understand what could explain the heterogeneity of the findings. PMID- 29434315 TI - Association of gut microbial communities with plasma lipopolysaccharide-binding protein (LBP) in premenopausal women. AB - The mechanisms by which obesity increases cancer risk are unclear, but some lines of evidence suggest that gut microbial communities (GMC) may contribute to chronic inflammation in obese individuals through raised systemic levels of lipopolysaccharides (LPS). We evaluated associations of the GMC in stool with plasma LPS-binding protein (LBP, a measure of LPS) and C-reactive protein (CRP) concentrations in 110 premenopausal women in the United States. Diet was assessed using 3-day food records and GMCs were evaluated using pyrosequencing of the 16S rRNA gene. OTUs were identified at 97% sequence similarity. Taxonomic classification and functional genes were imputed from 16S rRNA genes, and alpha and beta diversity were assessed using the Shannon index and MRPP, respectively. Multivariable linear regression analysis was used to assess the relation between LBP, specific bacterial genera identified with indicator species analysis, and CRP. Dietary fat intake, particularly saturated fat, and CRP were positively associated with increased LBP. GMC beta diversity, but not alpha diversity, was statistically significantly different between groups using unweighted Unifrac. Several taxa, particularly those in the Clostridia class, were more prevalent in women with low LBP, while Bacteroides were more prevalent in those with high LBP. Genes associated with gram-negative cell wall material synthesis were also associated with LBP and CRP. In contrast, Phascolarctobacterium was associated with lower concentrations of LBP and CRP. We found distinct differences between tertiles of LBP regarding the diversity and composition of the microbiome, as well as differences in functional genes that potentially activate LBP. PMID- 29434317 TI - Prevalence and impact of low body mass index on outcomes in patients with adolescent idiopathic scoliosis: a systematic review. AB - Comparatively lower body mass index (BMI) has been reported in patients with adolescent idiopathic scoliosis (AIS)-a feature which may be an unrecognised symptom, or an organic consequence of the condition. The primary aim of this systematic review is to investigate the relationship between low BMI and AIS. A secondary aim is to investigate the effect of low BMI on outcomes of postsurgical correction in this patient group. The Cochrane Library, PubMed, SCOPUS, Web of Science and Ovid MEDLINE databases were searched up to December 2016 for relevant studies that reported prevalence of low preoperative BMI in patients with AIS and/or compared BMI between patients with AIS and healthy controls, as well as those that examined the relationship between low BMI and postoperative outcomes. Forty-five eligible studies were identified from the search strategy. Mean differences (MDs) were used with 95% confidence intervals (CI) in a random effects model to compare BMI in patients with AIS and controls in a pooled analysis of data from nine eligible studies (n = 3747 patients). In the meta analysis, BMI of patients in the AIS group was significantly lower than those in the control group (MD -1.19, 95% CI -1.78 to -0.60). Low BMI in AIS can impact postoperative outcomes, including increased risk of ileus. This review demonstrates that patients with AIS are significantly more likely to have a low BMI compared to the general population. We advocate that closer attention be paid to AIS patients with low BMI both pre- and postsurgical correction. PMID- 29434318 TI - Exploring the association between serum 25-hydroxyvitamin D and serum lipids-more than confounding? AB - BACKGROUND/OBJECTIVES: In observational, but not interventional, studies there are strong associations between serum 25-hydroxyvitamin D (25(OH)D) and serum lipids. The purpose of the present study was to examine potential causes of this association. SUBJECTS/METHODS: A total of 17,411 subjects participating in the seventh survey of the Tromso Study were included in the cross-sectional study; 5384 subjects who participated in both the sixth and seventh survey were included in the longitudinal study; 2365 subjects who participated in both the fourth and seventh survey were included in the genetic study; and 479 subjects with impaired glucose tolerance were included in the vitamin D binding protein (DBP) analyses. RESULTS: For serum 25(OH)D, there were strong and positive associations with LDL , HDL-, and total-cholesterol, and a negative association with triglycerides that remained after adjustment for gender, age, BMI, diet, supplements, and lifestyle factors. These associations were seen in winter as well as summer. Except for serum cholesterol, change of season for blood sampling did not affect lipid levels. However, when analyzing separately, subjects with low or no intake of vitamin D supplements, fish oil and fat fish, only the association between 25(OH)D and HDL-cholesterol remained significant. Serum DBP or single-nucleotide polymorphisms related to 25(OH)D had no relation to lipid levels. CONCLUSIONS: The associations between 25(OH)D and lipids (except for HDL-cholesterol) can be explained by known confounding factors. However, for HDL-cholesterol, the cause of the association with 25(OH)D still remains unknown. PMID- 29434319 TI - Maternal vegetable intake in early pregnancy and wheeze in offspring at the age of 2 years. AB - BACKGROUND/OBJECTIVES: Vegetable intake during childhood may reduce the risk of subsequent asthma. We verified the effect of maternal intake during pregnancy on asthma risk in offspring, which has rarely been studied. SUBJECTS/METHODS: In a hospital-based birth cohort study conducted in Tokyo, we administered a food frequency questionnaire at two periods during the respondents' pregnancy: early and mid to late periods. In addition, a questionnaire including the International Study of Asthma and Allergies in Childhood questionnaire was conducted when the offspring were 2 years old. Multivariate Poisson regression adjusting for maternal baseline demographics was used to elucidate the association between maternal vegetable intake and the incidence of wheeze in the offspring. RESULTS: Among 310 singletons, 82 (26.5%) experienced wheeze at 2 years of age. Women with the highest intake of cruciferous, and folate-rich vegetables during early pregnancy reported a significantly lower prevalence of wheeze in their child at 2 years of age in comparison with those who reported the lowest intake (adjusted risk ratio: 0.48 and 0.47, 95% confidence interval: 0.26-0.89, and 0.25-0.87, respectively). In trend analysis, a higher maternal intake of cruciferous, folate rich vegetables, and total vegetables during early pregnancy was less likely to be associated with wheeze in the offspring at 2 years old (p for trend: 0.038, <0.001, and 0.028, respectively). Maternal vegetable intake during mid to late pregnancy was not associated with wheeze in the offspring. CONCLUSIONS: Maternal vegetable intake during early pregnancy may have a protective effect against asthma in offspring at 2 years of age. PMID- 29434320 TI - Host-guest complexes of imazalil with cucurbit[8]uril and beta-cyclodextrin and their effect on plant pathogenic fungi. AB - We report the control of imazalil (IMZ) antifungal activity utilizing its non covalent assembly with beta-cyclodextrins (beta-CD) and cucurbit[8]uril (CB8) macrocycles, as well as its stimuli-responsive disassembly with cadaverine. The NMR results are consistent with inclusion of a single IMZ molecule inside the cavities of either CB8 from its aromatic site or beta-CD from its aliphatic end. Efficient complex formation with both host molecules and controlled released upon the addition of cadaverine is supported by NMR measurements. The stimuli responsiveness of the same host-guest assemblies with cadaverine was validated against seven economically important plant pathogenic fungi which cause agriculturally important plant diseases across the globe. While loading the drug into macrocycles cavities suppressed its activity, subsequent adding of cadaverine efficiently restored it up. The results in the present paper enable researchers working in the area of mycology and plant pathology to inhibit or reduce the fungal growth on demand in order to control these economically important plant pathogenic fungi. PMID- 29434321 TI - The promotion function of Berberine for osteogenic differentiation of human periodontal ligament stem cells via ERK-FOS pathway mediated by EGFR. AB - Coptidis Rhizoma binds to the membrane receptors on hPDLSC/CMC, and the active ingredient Berberine (BER) that can be extracted from it may promote the proliferation and osteogenesis of periodontal ligament stem cells (hPDLSC). The membrane receptor that binds with BER on the cell surface of hPDLSC, the mechanism of direct interaction between BER and hPDLSC, and the related signal pathway are not yet clear. In this research, EGFR was screened as the affinity membrane receptor between BER and hPDLSC, through retention on CMC, competition with BER and by using a molecular docking simulation score. At the same time, the MAPK PCR Array was selected to screen the target genes that changed when hPDLSC was simulated by BER. In conclusion, BER may bind to EGFR on the cell membrane of hPDLSC so the intracellular ERK signalling pathways activate, and nuclear-related genes of FOS change, resulting in the effect of osteogenesis on PDLSC. PMID- 29434322 TI - Genome-wide investigation of pentatricopeptide repeat gene family in poplar and their expression analysis in response to biotic and abiotic stresses. AB - Pentatricopeptide repeat (PPR) proteins, which are characterized by tandem 30-40 amino acid sequence motifs, constitute of a large gene family in plants. Some PPR proteins have been identified to play important roles in organellar RNA metabolism and organ development in Arabidopsis and rice. However, functions of PPR genes in woody species remain largely unknown. Here, we identified and characterized a total of 626 PPR genes containing PPR motifs in the Populus trichocarpa genome. A comprehensive genome-wide analysis of the poplar PPR gene family was performed, including chromosomal location, phylogenetic relationships and gene duplication. Genome-wide transcriptomic analysis showed that 154 of the PtrPPR genes were induced by biotic and abiotic treatments, including Marssonina brunnea, salicylic acid (SA), methyl jasmonate (MeJA), mechanical wounding, cold and salinity stress. Quantitative RT-PCR analysis further investigated the expression profiles of 11 PtrPPR genes under different stresses. Our results contribute to a comprehensive understanding the roles of PPR proteins and provided an insight for improving the stress tolerance in poplar. PMID- 29434323 TI - CD44 variant inhibits insulin secretion in pancreatic beta cells by attenuating LAT1-mediated amino acid uptake. AB - CD44 variant (CD44v) contributes to cancer stemness by stabilizing the xCT subunit of system xc(-) and thereby promoting its glutamate-cystine antiporter activity. CD44 has also been implicated in autoimmune insulitis and inflammation in diabetic islets, but whether CD44v regulates insulin secretion has remained unclear. Here we show that CD44v inhibits insulin secretion by attenuating amino acid transport mediated by the L-type amino acid transporter LAT1. CD44v expression level was inversely related to insulin content in islets of normal and diabetic model mice. Knockdown of CD44 increased insulin secretion, the intracellular insulin level, and the transport of neutral amino acids mediated by LAT1 in Min6 cells. Attenuation of the uptake of neutral amino acids with a LAT inhibitor reduced insulin secretion and insulin content in Min6 cells, whereas overexpression of LAT1 increased insulin secretion. Moreover, inhibition of LAT1 prevented the increase in insulin secretion and content induced by CD44 depletion in Min6 cells. Our results thus implicate CD44v in the regulation of insulin secretion and reveal that amino acid transport is rate limiting for such secretion. They further suggest that amino acid transport mediated by LAT1 is a potential therapeutic target for diabetes. PMID- 29434324 TI - The utility of a network-based clustering method for dimension reduction of imaging and non-imaging biomarkers predictive of Alzheimer's disease. AB - While the identification of biomarkers for Alzheimer's disease (AD) is critical, emphasis must also be placed on defining the relationship between these and other indicators. To this end, we propose a network-based radial basis function-sparse partial least squares (RBF-sPLS) approach to analyze structural magnetic resonance imaging (sMRI) data of the brain. This intermediate phenotype for AD represents a more objective approach for exploring biomarkers in the blood and cerebrospinal fluid. The proposed method has two unique features for effective biomarker selection. The first is that applying RBF to sMRI data can reduce the dimensions without excluding information. The second is that the network analysis considers the relationship among the biomarkers, while applied to non-imaging data. As a result, the output can be interpreted as clusters of related biomarkers. In addition, it is possible to estimate the parameters between the sMRI data and biomarkers while simultaneously selecting the related brain regions and biomarkers. When applied to real data, this technique identified not only the hippocampus and traditional biomarkers, such as amyloid beta, as predictive of AD, but also numerous other regions and biomarkers. PMID- 29434325 TI - CellCycleTRACER accounts for cell cycle and volume in mass cytometry data. AB - Recent studies have shown that cell cycle and cell volume are confounding factors when studying biological phenomena in single cells. Here we present a combined experimental and computational method, CellCycleTRACER, to account for these factors in mass cytometry data. CellCycleTRACER is applied to mass cytometry data collected on three different cell types during a TNFalpha stimulation time course. CellCycleTRACER reveals signaling relationships and cell heterogeneity that were otherwise masked. PMID- 29434326 TI - Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. AB - Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide 1 . In the absence of new therapies, mortality rates due to untreatable infections are predicted to rise more than tenfold by 2050. Natural products (NPs) made by cultured bacteria have been a major source of clinically useful antibiotics. In spite of decades of productivity, the use of bacteria in the search for new antibiotics was largely abandoned due to high rediscovery rates2,3. As only a fraction of bacterial diversity is regularly cultivated in the laboratory and just a fraction of the chemistries encoded by cultured bacteria are detected in fermentation experiments, most bacterial NPs remain hidden in the global microbiome. In an effort to access these hidden NPs, we have developed a culture-independent NP discovery platform that involves sequencing, bioinformatic analysis and heterologous expression of biosynthetic gene clusters captured on DNA extracted from environmental samples. Here, we describe the application of this platform to the discovery of the malacidins, a distinctive class of antibiotics that are commonly encoded in soil microbiomes but have never been reported in culture-based NP discovery efforts. The malacidins are active against multidrug-resistant pathogens, sterilize methicillin-resistant Staphylococcus aureus skin infections in an animal wound model and did not select for resistance under our laboratory conditions. PMID- 29434327 TI - Iterative feedback bio-printing-derived cell-laden hydrogel scaffolds with optimal geometrical fidelity and cellular controllability. AB - For three-dimensional bio-printed cell-laden hydrogel tissue constructs, the well designed internal porous geometry is tailored to obtain the desired structural and cellular properties. However, significant differences often exist between the designed and as-printed scaffolds because of the inherent characteristics of hydrogels and cells. In this study, an iterative feedback bio-printing (IFBP) approach based on optical coherence tomography (OCT) for the fabrication of cell laden hydrogel scaffolds with optimal geometrical fidelity and cellular controllability was proposed. A custom-made swept-source OCT (SS-OCT) system was applied to characterize the printed scaffolds quantitatively. Based on the obtained empirical linear formula from the first experimental feedback loop, we defined the most appropriate design constraints and optimized the printing process to improve the geometrical fidelity. The effectiveness of IFBP was verified from the second run using gelatin/alginate hydrogel scaffolds laden with C3A cells. The mismatch of the morphological parameters greatly decreased from 40% to within 7%, which significantly optimized the cell viability, proliferation, and morphology, as well as the representative expression of hepatocyte markers, including CYP3A4 and albumin, of the printed cell-laden hydrogel scaffolds. The demonstrated protocol paves the way for the mass fabrication of cell-laden hydrogel scaffolds, engineered tissues, and scaled-up applications of the 3D bio-printing technique. PMID- 29434328 TI - Plastic roles of phenylalanine and tyrosine residues of TLS/FUS in complex formation with the G-quadruplexes of telomeric DNA and TERRA. AB - The length of a telomere is regulated via elongation and shortening processes. Telomeric DNA and telomeric repeat-containing RNA (TERRA), which both contain G rich repeated sequences, form G-quadruplex structures. Previously, translocated in liposarcoma (TLS) protein, also known as fused in sarcoma (FUS) protein, was found to form a ternary complex with the G-quadruplex structures of telomeric DNA and TERRA. We then showed that the third RGG motif of TLS, the RGG3 domain, is responsible for the complex formation. However, the structural basis for their binding remains obscure. Here, NMR-based binding assaying revealed the interactions in the binary and ternary complexes of RGG3 with telomeric DNA or/and TERRA. In the ternary complex, tyrosine bound exclusively to TERRA, while phenylalanine bound exclusively to telomeric DNA. Thus, tyrosine and phenylalanine each play a central role in the recognition of TERRA and telomeric DNA, respectively. Surprisingly in the binary complexes, RGG3 used both tyrosine and phenylalanine residues to bind to either TERRA or telomeric DNA. We propose that the plastic roles of tyrosine and phenylalanine are important for RGG3 to efficiently form the ternary complex, and thereby regulate the telomere shortening. PMID- 29434329 TI - Mountain rock glaciers contain globally significant water stores. AB - Glacier- and snowpack-derived meltwaters are threatened by climate change. Features such as rock glaciers (RGs) are climatically more resilient than glaciers and potentially contain hydrologically valuable ice volumes. However, while the distribution and hydrological significance of glaciers is well studied, RGs have received comparatively little attention. Here, we present the first near global RG database (RGDB) through an analysis of current inventories and this contains >73,000 RGs. Using the RGDB, we identify key data-deficient regions as research priorities (e.g., Central Asia). We provide the first approximation of near-global RG water volume equivalent and this is 83.72 +/- 16.74 Gt. Excluding the Antarctic and Subantarctic, Greenland Periphery, and regions lacking data, we estimate a near-global RG to glacier water volume equivalent ratio of 1:456. Significant RG water stores occur in arid and semi-arid regions (e.g., South Asia East, 1:57). These results represent a first-order approximation. Uncertainty in the water storage estimates includes errors within the RGDB, inherent flaws in the meta-analysis methodology, and RG thickness estimation. Here, only errors associated with the assumption of RG ice content are quantified and overall uncertainty is likely larger than that quantified. We suggest that RG water stores will become increasingly important under future climate warming. PMID- 29434330 TI - Carbonate chemistry of an in-situ free-ocean CO2 enrichment experiment (antFOCE) in comparison to short term variation in Antarctic coastal waters. AB - Free-ocean CO2 enrichment (FOCE) experiments have been deployed in marine ecosystems to manipulate carbonate system conditions to those predicted in future oceans. We investigated whether the pH/carbonate chemistry of extremely cold polar waters can be manipulated in an ecologically relevant way, to represent conditions under future atmospheric CO2 levels, in an in-situ FOCE experiment in Antarctica. We examined spatial and temporal variation in local ambient carbonate chemistry at hourly intervals at two sites between December and February and compared these with experimental conditions. We successfully maintained a mean pH offset in acidified benthic chambers of -0.38 (+/-0.07) from ambient for approximately 8 weeks. Local diel and seasonal fluctuations in ambient pH were duplicated in the FOCE system. Large temporal variability in acidified chambers resulted from system stoppages. The mean pH, Omegaarag and fCO2 values in the acidified chambers were 7.688 +/- 0.079, 0.62 +/- 0.13 and 912 +/- 150 uatm, respectively. Variation in ambient pH appeared to be mainly driven by salinity and biological production and ranged from 8.019 to 8.192 with significant spatio temporal variation. This experiment demonstrates the utility of FOCE systems to create conditions expected in future oceans that represent ecologically relevant variation, even under polar conditions. PMID- 29434331 TI - Prevalence of Depression in the Community from 30 Countries between 1994 and 2014. AB - The prevalence of depression may be affected by changes in psychiatric practices and the availability of online mental health information in the past two decades. This study aimed to evaluate the aggregate prevalence of depression in communities from different countries between 1994 and 2014 and to explore the variations in prevalence stratified by geographical, methodological and socio economic factors. A total of 90 studies were identified and met the inclusion criteria (n = 1,112,573 adults) with 68 studies on single point prevalence, 9 studies on one-year prevalence, and 13 studies on lifetime prevalence of depression. A random-effects model meta-analysis that was performed to calculate the aggregate point, one-year and lifetime prevalence of depression calculated prevalences of 12.9%, 7.2% and 10.8% respectively. Point prevalence of depression was significantly higher in women (14.4%), countries with a medium human development index (HDI) (29.2%), studies published from 2004 to 2014 (15.4%) and when using self-reporting instruments (17.3%) to assess depression. Heterogeneity was identified by meta-regression and subgroup analysis, and response rate, percentage of women and year of publication, respectively, were determined contribute to depression prevalence. This meta-analysis allows benchmarking of the prevalence of depression during the era when online health information emerged, facilitating future comparisons. PMID- 29434332 TI - The p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts. AB - NFkappaB activation and regulated cell death are important in tissue homeostasis, inflammation and pathogenesis. Here we show the role of the p55TNFR-IKK2l-Ripk3 axis in the regulation of synovial fibroblast homeostasis and pathogenesis in TNF mediated mouse models of arthritis. Mesenchymal-specific p55TNFR triggering is indispensable for arthritis in acute and chronic TNF-dependent models. IKK2 in joint mesenchymal cells is necessary for the development of cartilage destruction and bone erosion; however, in its absence synovitis still develops. IKK2 deletion affects arthritic and antiapoptotic gene expression leading to hypersensitization of synovial fibroblasts to TNF/Ripk1-mediated death via district mechanisms, depending on acute or chronic TNF signals. Moreover, Ripk3 is dispensable for TNF mediated arthritis, yet it is required for synovitis in mice with mesenchymal specific IKK2 deletion. These results demonstrate that p55TNFR-IKK2-Ripk3 signalling orchestrates arthritogenic and death responses in synovial fibroblasts, suggesting that therapeutic manipulation of this pathway in arthritis may require combinatorial blockade of both IKK2 and Ripk3 signals. PMID- 29434334 TI - Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. PMID- 29434333 TI - Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. AB - Immunotherapies have revolutionized medical oncology following the remarkable and, in some cases, unprecedented outcomes observed in certain groups of patients with cancer. Combination with other therapeutic modalities, including anti angiogenic agents, is one of the many strategies currently under investigation to improve the response rates and duration of immunotherapies. Such a strategy might seem counterintuitive given that anti-angiogenic agents can increase tumour hypoxia and reduce the number of blood vessels within tumours. Herein, we review the additional effects mediated by drugs targeting VEGF-dependent signalling and other pathways, such as those mediated by angiopoietin 2 or HGF, which might increase the efficacy of immunotherapies. In addition, we discuss the seldom considered possibility that immunotherapies, and immune-checkpoint inhibitors in particular, might increase the efficacy of anti-angiogenic or other types of antivascular therapies and/or promote changes in the tumour vasculature. In short, we propose that interactions between both therapeutic modalities could be considered a 'two-way street'. PMID- 29434335 TI - Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. PMID- 29434336 TI - Comparative transcriptomics provides novel insights into the mechanisms of selenium tolerance in the hyperaccumulator plant Cardamine hupingshanensis. AB - Selenium (Se) is an essential mineral element for animals and humans. Cardamine hupingshanensis (Brassicaceae), found in the Wuling mountain area of China, has been identified as a novel Se hyperaccumulator plant. However, the mechanism for selenium tolerance in Cardamine plants remains unknown. In this study, two cDNA libraries were constructed from seedlings of C. hupingshanensis treated with selenite. Approximately 100 million clean sequencing reads were de novo assembled into 48,989 unigenes, of which 39,579 and 33,510 were expressed in the roots and leaves, respectively. Biological pathways and candidate genes involved in selenium tolerance mechanisms were identified. Differential expression analysis identified 25 genes located in four pathways that were significantly responsive to selenite in C. hupingshanensis seedlings. The results of RNA sequencing (RNA Seq) and quantitative real-time PCR (RT-qPCR) confirmed that storage function, oxidation, transamination and selenation play very important roles in the selenium tolerance in C. hupingshanensis. Furthermore, a different degradation pathway synthesizing malformed or deformed selenoproteins increased selenium tolerance at different selenite concentrations. This study provides novel insights into the mechanisms of selenium tolerance in a hyperaccumulator plant, and should serve as a rich gene resource for C. hupingshanensis. PMID- 29434337 TI - Detection of genetic purging and predictive value of purging parameters estimated in pedigreed populations. AB - The consequences of inbreeding for fitness are important in evolutionary and conservation biology, but can critically depend on genetic purging. However, estimating purging has proven elusive. Using PURGd software, we assess the performance of the Inbreeding-Purging (IP) model and of ancestral inbreeding (Fa) models to detect purging in simulated pedigreed populations, and to estimate parameters that allow reliably predicting the evolution of fitness under inbreeding. The power to detect purging in a single small population of size N is low for both models during the first few generations of inbreeding (t ~ N/2), but increases for longer periods of slower inbreeding and is, on average, larger for the IP model. The ancestral inbreeding approach overestimates the rate of inbreeding depression during long inbreeding periods, and produces joint estimates of the effects of inbreeding and purging that lead to unreliable predictions for the evolution of fitness. The IP estimates of the rate of inbreeding depression become downwardly biased when obtained from long inbreeding processes. However, the effect of this bias is canceled out by a coupled downward bias in the estimate of the purging coefficient so that, unless the population is very small, the joint estimate of these two IP parameters yields good predictions of the evolution of mean fitness in populations of different sizes during periods of different lengths. Therefore, our results support the use of the IP model to detect inbreeding depression and purging, and to estimate reliable parameters for predictive purposes. PMID- 29434338 TI - The validity of three snow leopard subspecies: response to Senn et al. PMID- 29434339 TI - Epidemiology and biomarker profile of pituitary adenohypophysial tumors. AB - Recent studies have reported the prevalence of pituitary tumors to be ~1/1000 population. Many are prolactin-producing tumors that are managed medically, however, the epidemiology of surgically resected pituitary adenohypophysial neuroendocrine tumors has not been reported in a large series with detailed characterization. We reviewed 1055 adenohypophysial tumors from 1169 transsphenoidal resections from the pathology files of University Health Network, Toronto, 2001-2016. Tumors were characterized by immunohistochemical localization of transcription factors (Pit-1, ERalpha, SF-1, Tpit), hormones (adrenocorticotropin, growth hormone, prolactin, beta-thyrotropin, beta folliculotropin, beta-luteotropin, alpha-subunit), and other biomarkers (keratins, Ki67, p27, FGFR4). Electron microscopy was used only for unusual lesions. In this cohort, 51.3% of patients were female; the average age was 51 years. Gonadotroph tumors represented 42.5%. Pit-1-lineage-tumors represented 29.9%; these were subclassified as growth-hormone-predominant (somatotroph/mammosomatotroph/mixed; 53%), prolactin-predominant (lactotroph/acidophil-stem-cell; 28%), thyrotrophs (2%), plurihormonal (14%), and not-otherwise-specified (3%). Corticotroph tumors represented 17.1%. Only 4.5% were null cell tumors and 0.5% were unusual plurihormonal tumors. In 5.5% the tumor was not characterized for technical reasons (sample size, fixation, necrosis or other artifact). All corticotroph and plurihormonal tumors were positive for keratins; others tumors showed variable negativity with highest rates in gonadotroph (37.1%) and null cell tumors (28.2%). Tumors with a Ki67 >= 3% comprised 60% of this cohort. Global loss of p27 was most frequent in corticotroph neoplasms, specifically those associated with elevated glucocorticoid levels. Corticotroph and lactotroph tumors were more common among females; gonadotroph tumors were more common among males. Younger patients had mainly corticotroph and Pit-1-lineage neoplasms, whereas older patients harbored mainly gonadotroph tumors. This represents one of the largest surgical series of morphologically characterized pituitary tumors reported to date and the first to include the routine use of transcription factors for tumor classification. The data provide the basis for clinicopathologic correlations that are helpful for prognostic and predictive patient management. PMID- 29434340 TI - Glucocorticoid receptor expression in resident and hematopoietic cells in IgG4 related disease. AB - Immunoglobulin G4-related disease is a rare immune-mediated disease characterized by the infiltration of IgG4-positive plasma cells and unique storiform fibrosis of multiple organs. The majority of IgG4-related disease patients respond to glucocorticoids, yet the precise mechanism of their action remains unclear. Pathological sections of the submaxillary gland, kidney, and retroperitoneum from 20 patients in total diagnosed with IgG4-related disease were analyzed for glucocorticoid receptor expression and the cell types expressing glucocorticoid receptor. Strong and abundant expression of glucocorticoid receptor was observed in the submaxillary gland, kidney, and retroperitoneum of IgG4-related disease patients, while glucocorticoid receptor was rarely or only faintly observed in the submaxillary gland of patients with Sjogren's syndrome, radicular cysts and sialolithiasis or in the healthy kidney. Glucocorticoid receptor was mainly expressed in fibro/myofibroblasts, CD4-positive T cells and IgG4-positive plasma cells in the submandibular glands and kidneys of IgG4-related disease patients. The abundant expression of glucocorticoid receptor in various types of cells, including resident fibro/myofibroblasts in IgG4-related disease patients might provide clues to the mechanism of steroid responsiveness in IgG4-related disease patients. PMID- 29434341 TI - Hyalinizing clear cell carcinoma of the bronchial glands: presentation of three cases and pathological comparisons with salivary gland counterparts and bronchial mucoepidermoid carcinomas. AB - Hyalinizing clear cell carcinoma of the bronchial glands is a very rare tumor. Since only five reports describing six tumors have been published to date, only a little is known about specific histologic findings and clinical features. Because of its rarity, hyalinizing clear cell carcinoma has not been described in the latest WHO classification of pulmonary tumors yet. Here we present three cases of bronchial hyalinizing clear cell carcinomas, confirmed by both fluorescence in situ hybridization (FISH) and RT-PCR, focusing on histologic and immunohistochemical characteristics in a comparison with three cases of salivary gland origin. In addition, we compared immunohistochemical features with bronchial mucoepidermoid carcinoma, a lesion that needs to be taken into account in differential diagnosis of hyalinizing clear cell carcinoma. All our bronchial hyalinizing clear cell carcinoma cases were surgically resected. Histologically, tumor cells showed clear to eosinophilic cytoplasm with hyalinizing stroma in various proportions, resembling those of salivary gland origin. Immunohistochemically, tumor cells were positive for CK7, CK5/6, p40, p63, and ATF1, while they were negative for TTF1, Napsin A, HMB45, and SOX10. The CK5/6 staining pattern varied in mucoepidermoid carcinomas, while that of hyalinizing clear cell carcinoma was uniformly positive. FISH revealed EWSR1-ATF1 fusion, and RT-PCR with sequencing confirmed specificity of the chimeric gene for hyalinizing clear cell carcinoma. Clinically, bronchial hyalinizing clear cell carcinoma was characterized by occurrence in the fourth to sixth decades, no link with smoking history, and a predilection for the right lung, in line with previous reports. In summary, our study confirmed that the bronchial hyalinizing clear cell carcinoma is a histologically and genetically identical tumor to that of salivary gland origin, and that gene rearrangement analysis can play a critical role in distinction from mucoepidermoid carcinoma. PMID- 29434342 TI - p16 immunostaining in histological grading of anal squamous intraepithelial lesions: a systematic review and meta-analysis. AB - p16 is the most widely studied biomarker in lower anogenital tract squamous intraepithelial lesions and, currently the only recommended biomarker for histological grade assessment. The aim of this systematic review and meta analysis was to evaluate p16-positive rates according to anal squamous intraepithelial lesions/anal intraepithelial neoplasia (AIN) grade. Two investigators independently searched four electronic databases: PubMed, Web of Sciences, Scopus, and Embase from inception until August 2017. Studies that evaluated p16 immunostaining in histological samples of anal and/or perianal squamous intraepithelial lesions and defined a p16-positive result as diffuse block staining with nuclear or nuclear plus cytoplasmic staining were included. A meta-analysis was performed using a random effects model. Fifteen studies consisting of 790 samples were included. The proportion of p16 expression increased with the severity of histological grade. p16 positivity was 2% (95% CI: 0.2-5%) in normal histology, 12% (95% CI: 2-27%) in low-grade squamous intraepithelial lesions (LSILs)/AIN1 (excluding condylomas), 7% (95% CI: 2-13%) in all LSIL (AIN1/LSIL/condyloma), 76% (95% CI: 61-88%) in AIN2, and 90% (95% CI: 82-95%) in AIN3. For anal high-grade squamous intraepithelial lesions (HSILs), in studies using a two-tiered nomenclature, p16 positivity was 84% (95% CI: 66-96%) and for all HSIL (AIN2, AIN3, HSIL combined) it was 82% (95% CI: 72-91%). In summary, p16 positivity in anal squamous intraepithelial lesions appears to be in a similar range to the commonly described cervical squamous intraepithelial lesions, however, for anal low-grade lesions positivity seems to be lower. PMID- 29434343 TI - Differential expression patterns of GATA3 in usual and differentiated types of vulvar intraepithelial neoplasia: potential diagnostic implications. AB - The two main precursors of vulvar squamous cell carcinoma, usual and differentiated vulvar intraepithelial neoplasia (VIN), have distinctive etiology, pathogenesis, and natural history. Usual type VIN is often associated with high risk HPV and differentiated VIN has de novo p53 genetic alterations that are unrelated to HPV infection. GATA-binding protein 3 (GATA3) is a tumor suppressor that shows increased expression in several types of human malignancies including breast and bladder carcinomas. Little is known regarding the expression of GATA3 in vulvar squamous neoplasms. We have systematically examined the expression of GATA3 in 119 vulvar lesions and neoplasms including 20 cases of lichen sclerosus, 12 cases of lichen simplex chronicus, 30 cases of usual type VIN, 34 cases of differentiated VIN, and 23 cases of squamous cell carcinoma. Similar to adjacent non-neoplastic epidermis, moderate to strong GATA3 expression was retained in all cases of lichen sclerosus, lichen simplex chronicus, and usual type VIN. However, in comparison, the GATA3 immunostaining pattern in differentiated VIN was distinct. Partial/complete loss of GATA3 expression in the basal layer with or without loss in the parabasal layer was observed in 30/34 (88%) of differentiated VIN cases. Significant loss of GATA3 expression was also observed in all (7/7) squamous cell carcinomas associated with usual type VIN and in 13/16 (81%) of those associated with differentiated VIN. There was no significant correlation between loss of GATA3 expression and overexpression of p53 in differentiated VIN. Our study shows that loss of GATA3 expression is seen in the vast majority (87%) of vulvar squamous cell carcinomas. Downregulation of GATA3 may be an early event during tumorigenesis in differentiated VIN but not in HPV-related usual type VIN. Our data suggests that application of GATA3 immunohistochemistry along with p53 may be a useful tool in facilitating the accurate diagnosis of VIN. PMID- 29434344 TI - Identification of microRNAs differentially expressed in glioblastoma stem-like cells and their association with patient survival. AB - Glioblastoma stem-like cells (GSCs) are critical for the aggressiveness and progression of glioblastoma (GBM) and contribute to its resistance to adjuvant treatment. MicroRNAs (miRNAs) are small, non-coding RNAs controlling gene expression at the post-transcriptional level, which are known to be important regulators of the stem-like features. Moreover, miRNAs have been previously proved to be promising diagnostic biomarkers in several cancers including GBM. Using global expression analysis of miRNAs in 10 paired in-vitro as well as in vivo characterized primary GSC and non-stem glioblastoma cultures, we identified a miRNA signature associated with the stem-like phenotype in GBM. 51 most deregulated miRNAs classified the cell cultures into GSC and non-stem cell clusters and identified a subgroup of GSC cultures with more pronounced stem-cell characteristics. The importance of the identified miRNA signature was further supported by demonstrating that a Risk Score based on the expression of seven miRNAs overexpressed in GSC predicted overall survival in GBM patients in the TCGA dataset independently of the IDH1 status. In summary, we identified miRNAs differentially expressed in GSCs and described their association with GBM patient survival. We propose that these miRNAs participate on GSC features and could represent helpful prognostic markers and potential therapeutic targets in GBM. PMID- 29434345 TI - Cotranslational protein assembly imposes evolutionary constraints on homomeric proteins. AB - Cotranslational protein folding can facilitate rapid formation of functional structures. However, it can also cause premature assembly of protein complexes, if two interacting nascent chains are in close proximity. By analyzing known protein structures, we show that homomeric protein contacts are enriched toward the C termini of polypeptide chains across diverse proteomes. We hypothesize that this is the result of evolutionary constraints for folding to occur before assembly. Using high-throughput imaging of protein homomers in Escherichia coli and engineered protein constructs with N- and C-terminal oligomerization domains, we show that, indeed, proteins with C-terminal homomeric interface residues consistently assemble more efficiently than those with N-terminal interface residues. Using in vivo, in vitro and in silico experiments, we identify features that govern successful assembly of homomers, which have implications for protein design and expression optimization. PMID- 29434346 TI - Yeast surface display platform for rapid discovery of conformationally selective nanobodies. AB - Camelid single-domain antibody fragments ('nanobodies') provide the remarkable specificity of antibodies within a single 15-kDa immunoglobulin VHH domain. This unique feature has enabled applications ranging from use as biochemical tools to therapeutic agents. Nanobodies have emerged as especially useful tools in protein structural biology, facilitating studies of conformationally dynamic proteins such as G-protein-coupled receptors (GPCRs). Nearly all nanobodies available to date have been obtained by animal immunization, a bottleneck restricting many applications of this technology. To solve this problem, we report a fully in vitro platform for nanobody discovery based on yeast surface display. We provide a blueprint for identifying nanobodies, demonstrate the utility of the library by crystallizing a nanobody with its antigen, and most importantly, we utilize the platform to discover conformationally selective nanobodies to two distinct human GPCRs. To facilitate broad deployment of this platform, the library and associated protocols are freely available for nonprofit research. PMID- 29434347 TI - Unary Non-Structural Fertilizer Response Model for Rice Crops and Its Field Experimental Verification. AB - The quadratic polynomial fertilizer response model (QPFM) is the primary method for implementing quantitative fertilization in crop production, but the success rate of this model's recommended fertilization rates in China is low because the model contains a high setting bias. This paper discusses a new modelling method for expanding the applicability of QPFM. The results of field experiments with 8 levels of N, P, or K fertilization showed that the dynamic trend between rice yield increases and fertilizer application rate exhibited a typical exponential relationship. Therefore, we propose a unary non-structural fertilizer response model (NSFM). The responses of 18 rice field experiments to N, P, or K fertilization indicated that the new models could significantly predict rice yields, while two experimental fitting results using the unary QPFM did not pass statistical significance tests. The residual standard deviations of 13 new models were significantly lower than that of the unary QPFM. The linear correlation coefficient of the recommended application rates between the new model and the unary QPFM reached a significant level. Theoretical analysis showed that the unary QPFM was a simplified version of the new model, and it had a higher fitting precision and better applicability. PMID- 29434348 TI - Rapid evolution of highly variable competitive abilities in a key phytoplankton species. AB - Climate change challenges plankton communities, but evolutionary adaptation could mitigate the potential impacts. Here, we tested with the phytoplankton species Emiliania huxleyi whether adaptation to a stressor under laboratory conditions leads to equivalent fitness gains in a more natural environment. We found that fitness advantages that had evolved under laboratory conditions were masked by pleiotropic effects in natural plankton communities. Moreover, new genotypes with highly variable competitive abilities evolved on timescales significantly shorter than climate change. PMID- 29434349 TI - Genomic tools for behavioural ecologists to understand repeatable individual differences in behaviour. AB - Behaviour is a key interface between an animal's genome and its environment. Repeatable individual differences in behaviour have been extensively documented in animals, but the molecular underpinnings of behavioural variation among individuals within natural populations remain largely unknown. Here, we offer a critical review of when molecular techniques may yield new insights, and we provide specific guidance on how and whether the latest tools available are appropriate given different resources, system and organismal constraints, and experimental designs. Integrating molecular genetic techniques with other strategies to study the proximal causes of behaviour provides opportunities to expand rapidly into new avenues of exploration. Such endeavours will enable us to better understand how repeatable individual differences in behaviour have evolved, how they are expressed and how they can be maintained within natural populations of animals. PMID- 29434350 TI - The factors driving evolved herbicide resistance at a national scale. AB - Repeated use of xenobiotic chemicals has selected for the rapid evolution of resistance, threatening health and food security at a global scale. Strategies for preventing the evolution of resistance include cycling and mixtures of chemicals and diversification of management. We currently lack large-scale studies that evaluate the efficacy of these different strategies for minimizing the evolution of resistance. Here we use a national-scale data set of occurrence of the weed Alopecurus myosuroides (black-grass) in the United Kingdom to address this. Weed densities are correlated with assays of evolved resistance, supporting the hypothesis that resistance is driving weed abundance at a national scale. Resistance was correlated with the frequency of historical herbicide applications, suggesting that evolution of resistance is primarily driven by intensity of exposure to herbicides, but was unrelated directly to other cultural techniques. We find that populations resistant to one herbicide are likely to show resistance to multiple herbicide classes. Finally, we show that the economic costs of evolved resistance are considerable: loss of control through resistance can double the economic costs of weeds. This research highlights the importance of managing threats to food production and healthcare systems using an evolutionarily informed approach in a proactive not reactive manner. PMID- 29434352 TI - Genomic health in an asexual fish. PMID- 29434351 TI - Clonal polymorphism and high heterozygosity in the celibate genome of the Amazon molly. AB - The extreme rarity of asexual vertebrates in nature is generally explained by genomic decay due to absence of meiotic recombination, thus leading to extinction of such lineages. We explore features of a vertebrate asexual genome, the Amazon molly, Poecilia formosa, and find few signs of genetic degeneration but unique genetic variability and ongoing evolution. We uncovered a substantial clonal polymorphism and, as a conserved feature from its interspecific hybrid origin, a 10-fold higher heterozygosity than in the sexual parental species. These characteristics seem to be a principal reason for the unpredicted fitness of this asexual vertebrate. Our data suggest that asexual vertebrate lineages are scarce not because they are at a disadvantage, but because the genomic combinations required to bypass meiosis and to make up a functioning hybrid genome are rarely met in nature. PMID- 29434353 TI - Transcription factor Hoxb5 reprograms B cells into functional T lymphocytes. AB - Deletion of master regulators of the B cell lineage reprograms B cells into T cells. Here we found that the transcription factor Hoxb5, which is expressed in uncommitted hematopoietic progenitor cells but is not present in cells committed to the B cell or T cell lineage, was able to reprogram pro-pre-B cells into functional early T cell lineage progenitors. This reprogramming started in the bone marrow and was completed in the thymus and gave rise to T lymphocytes with transcriptomes, hierarchical differentiation, tissue distribution and immunological functions that closely resembled those of their natural counterparts. Hoxb5 repressed B cell 'master genes', activated regulators of T cells and regulated crucial chromatin modifiers in pro-pre-B cells and ultimately drove the B cell fate-to-T cell fate conversion. Our results provide a de novo paradigm for the generation of functional T cells through reprogramming in vivo. PMID- 29434355 TI - Wheat receptor-kinase-like protein Stb6 controls gene-for-gene resistance to fungal pathogen Zymoseptoria tritici. AB - Deployment of fast-evolving disease-resistance genes is one of the most successful strategies used by plants to fend off pathogens1,2. In gene-for-gene relationships, most cloned disease-resistance genes encode intracellular nucleotide-binding leucine-rich-repeat proteins (NLRs) recognizing pathogen secreted isolate-specific avirulence (Avr) effectors delivered to the host cytoplasm3,4. This process often triggers a localized hypersensitive response, which halts further disease development 5 . Here we report the map-based cloning of the wheat Stb6 gene and demonstrate that it encodes a conserved wall associated receptor kinase (WAK)-like protein, which detects the presence of a matching apoplastic effector6-8 and confers pathogen resistance without a hypersensitive response 9 . This report demonstrates gene-for-gene disease resistance controlled by this class of proteins in plants. Moreover, Stb6 is, to our knowledge, the first cloned gene specifying resistance to Zymoseptoria tritici, an important foliar fungal pathogen affecting wheat and causing economically damaging septoria tritici blotch (STB) disease10-12. PMID- 29434354 TI - Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. AB - CD4+ T regulatory cells (Treg) are central to immune homeostasis, their phenotypic heterogeneity reflecting the diverse environments and target cells that they regulate. To understand this heterogeneity, we combined single-cell RNA seq, activation reporter and T cell receptor (TCR) analysis to profile thousands of Treg or conventional CD4+FoxP3- T cells (Tconv) from mouse lymphoid organs and human blood. Treg and Tconv pools showed areas of overlap, as resting 'furtive' Tregs with overall similarity to Tconvs or as a convergence of activated states. All Tregs expressed a small core of FoxP3-dependent transcripts, onto which additional programs were added less uniformly. Among suppressive functions, Il2ra and Ctla4 were quasiconstant, inhibitory cytokines being more sparsely distributed. TCR signal intensity did not affect resting/activated Treg proportions but molded activated Treg programs. The main lines of Treg heterogeneity in mice were strikingly conserved in human blood. These results reveal unexpected TCR-shaped states of activation, providing a framework to synthesize previous observations of Treg heterogeneity. PMID- 29434356 TI - Stress and sexual reproduction affect the dynamics of the wheat pathogen effector AvrStb6 and strobilurin resistance. AB - Host resistance and fungicide treatments are cornerstones of plant-disease control. Here, we show that these treatments allow sex and modulate parenthood in the fungal wheat pathogen Zymoseptoria tritici. We demonstrate that the Z. tritici-wheat interaction complies with the gene-for-gene model by identifying the effector AvrStb6, which is recognized by the wheat resistance protein Stb6. Recognition triggers host resistance, thus implying removal of avirulent strains from pathogen populations. However, Z. tritici crosses on wheat show that sex occurs even with an avirulent parent, and avirulence alleles are thereby retained in subsequent populations. Crossing fungicide-sensitive and fungicide-resistant isolates under fungicide pressure results in a rapid increase in resistance allele frequency. Isolates under selection always act as male donors, and thus disease control modulates parenthood. Modeling these observations for agricultural and natural environments reveals extended durability of host resistance and rapid emergence of fungicide resistance. Therefore, fungal sex has major implications for disease control. PMID- 29434357 TI - Risk stratification based on components of the complete blood count in patients with acute coronary syndrome: A classification and regression tree analysis. AB - To develop a risk stratification model based on complete blood count (CBC) components in patients with acute coronary syndrome (ACS) using a classification and regression tree (CART) method. CBC variables and the Global Registry of Acute Coronary Events (GRACE) scores were determined in 2,693 patients with ACS. The CART analysis was performed to classify patients into different homogeneous risk groups and to determine predictors for major adverse cardiovascular events (MACEs) at 1-year follow-up. The CART algorithm identified the white blood cell count, hemoglobin, and mean platelet volume levels as the best combination to predict MACE risk. Patients were stratified into three categories with MACE rates ranging from 3.0% to 29.8%. Kaplan-Meier analysis demonstrated MACE risk increased with the ascending order of the CART risk categories. Multivariate Cox regression analysis showed that the CART risk categories independently predicted MACE risk. The predictive accuracy of the CART risk categories was tested by measuring discrimination and graphically assessing the calibration. Furthermore, the combined use of the CART risk categories and GRACE scores yielded a more accurate predictive value for MACEs. Patients with ACS can be readily stratified into distinct prognostic categories using the CART risk stratification tool on the basis of CBC components. PMID- 29434358 TI - Pollen-mediated gene flow from transgenic cotton is constrained by physical isolation measures. AB - The public concern about pollen-mediated gene flow (PGF) from genetically modified (GM) crops to non-GM crops heats up in recent years over China. In the current study, we conducted greenhouse and field experiments to measure PGF with various physical isolation measures, including 90, 80, 60 and 40 holes/cm2 separation nets and Sorghum bicolor, Zea mays and Lycopersicon esculentum separation crops between GM cotton and non-GM line (Shiyuan321) by seed DNA test during 2013 to 2015, and pollen grain dyeing was also conducted to assess the pollen flow in greenhouse during 2013. Our results revealed that (1) PGF varied depending on the physical isolation measures. PGF was the lowest with 90 holes/cm2 separation net and S. bicolor separation crop, and the highest with 40 holes/cm2 separation net and no isolation measure. (2) Similar to PGF results, 90 holes/cm2 separation net and S. bicolor separation crop could minimize the pollen dispersal. (3) PGF declined exponentially with increasing distance between GM cotton and Shiyuan321. Because of the production mode of farm household (limited cultivated area) in China, our study is particularly important, which is not only benefit for constraining PGF, but also has potential application value in practical production and the scientific researches. PMID- 29434359 TI - Surgical device-enabled epicardial LAA closure to achieve safe, complete, and durable LAA occlusion. PMID- 29434360 TI - Mechanical occlusion of the left atrial appendage - lessons from surgical experience. PMID- 29434361 TI - Heart failure: Drug delivery using inhaled nanoparticles. PMID- 29434362 TI - Inflammation: Perivascular inflammation in coronary spasm. PMID- 29434363 TI - Public health: Light smoking and CVD risk. PMID- 29434364 TI - Elevated CO2 delays the early development of scleractinian coral Acropora gemmifera. AB - The effects of elevated CO2 on the early life stages of coral were investigated by culturing the pelagic larvae and new recruits of Acropora gemmifera at three concentrations of CO2 (corresponding to pH = 8.1, 7.8 and 7.5, respectively). Acidified seawater resulted in fewer A. gemmifera larvae settling, and led to the production of smaller new recruits by slowing the development of the skeleton. The delayed development of new recruits due to elevated CO2 was consistent with the downregulation of calcification related genes. Several genes related to HCO3- and Ca2+ transporters were downregulated by elevated CO2, with solute carriers (SLC) (membrane transport proteins) possibly playing an important role. The downregulation of these membrane transport proteins might suppress the transport of calcium, bicarbonate and organic matter, resulting in the delayed development of A. gemmifera. PMID- 29434365 TI - Bladder cancer: BBN mouse model mimics human MIBC. PMID- 29434367 TI - Stones: Individual gut microbiome in nephrolithiasis. PMID- 29434368 TI - Prostate cancer: Genomic drivers of resistance to AR therapies. PMID- 29434366 TI - Potentiating prostate cancer immunotherapy with oncolytic viruses. AB - The clinical effectiveness of immunotherapies for prostate cancer remains subpar compared with that for other cancers. The goal of most immunotherapies is the activation of immune effectors, such as T cells and natural killer cells, as the presence of these activated mediators positively correlates with patient outcomes. Clinical evidence shows that prostate cancer is immunogenic, accessible to the immune system, and can be targeted by antitumour immune responses. However, owing to the detrimental effects of prostate-cancer-associated immunosuppression, even the newest immunotherapeutic approaches fail to initiate the clinically desired antitumour immune reaction. Oncolytic viruses, originally used for their preferential cancer-killing activity, are now being recognized for their ability to overturn cancer-associated immune evasion and promote otherwise absent antitumour immunity. This oncolytic-virus-induced subversion of tumour associated immunosuppression can potentiate the effectiveness of current immunotherapeutics, including immune checkpoint inhibitors (for example, antibodies against programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1), and cytotoxic T lymphocyte antigen 4 (CTLA4)) and chemotherapeutics that induce immunogenic cell death (for example, doxorubicin and oxaliplatin). Importantly, oncolytic-virus-induced antitumour immunity targets existing prostate cancer cells and also establishes long-term protection against future relapse. Hence, the strategic use of oncolytic viruses as monotherapies or in combination with current immunotherapies might result in the next breakthrough in prostate cancer immunotherapy. PMID- 29434371 TI - Kidney cancer: PDL1 as a biomarker in high-risk RCC. PMID- 29434370 TI - Imaging: Predicting 68Ga-PSMA-PET-CT positivity for recurrent disease. PMID- 29434369 TI - Bladder biomechanics and the use of scaffolds for regenerative medicine in the urinary bladder. AB - The urinary bladder is a complex organ with the primary functions of storing urine under low and stable pressure and micturition. Many clinical conditions can cause poor bladder compliance, reduced capacity, and incontinence, requiring bladder augmentation or use of regenerative techniques and scaffolds. To replicate an organ that is under frequent mechanical loading and unloading, special attention towards fulfilling its biomechanical requirements is necessary. Several biological and synthetic scaffolds are available, with various characteristics that qualify them for use in bladder regeneration in vitro and in vivo, including in the treatment of clinical conditions. The biomechanical properties of the native bladder can be investigated using a range of mechanical tests for standardized assessments, as well as mathematical and computational bladder biomechanics. Despite a large body of research into tissue engineering of the bladder wall, some features of the native bladder and the scaffolds used to mimic it need further elucidation. Collection of comparable reference data from different animal models would be a helpful tool for researchers and will enable comparison of different scaffolds in order to optimize characteristics before entering preclinical and clinical trials. PMID- 29434373 TI - Author Correction: Sister chromatid resolution is an intrinsic part of chromosome organization in prophase. AB - In the version of this Letter originally published, the authors omitted a citation of an early study demonstrating topoisomerase-II-dependent sister chromatid resolution. This reference has now been added to the reference list as reference number 28, and the relevant text has been amended as follows to include its citation: 'Resolution must reflect the removal of sister-sister contacts, and we show here that Topo-IIalpha-mediated release of DNA catenation plays a major role (Fig. 4), in agreement with previous findings28, whereas, surprisingly, cohesin dissociation is not strictly required (Fig. 3).' Subsequent references have been renumbered. All online versions of the Letter have been updated to reflect this change. PMID- 29434372 TI - A stage-dependent link between metabolic syndrome components and incident prostate cancer. AB - Metabolic syndrome is associated with increased cancer risk and progression at almost all sites, including the prostate in high-stage prostate cancer. However, several reports have described an inverse relationship between metabolic syndrome and its components and low-stage incident prostate cancer. Such anomalies in cancer research hamper efforts to fight cancer. Evidence suggests that metabolic syndrome and its components have two distinct effects in prostate cancer, concealing prostate cancer in low-stage disease and promoting progression to high stage incident, nonlocalized, and lethal prostate cancer. The concealment of prostate cancer by metabolic syndrome and its components might be related to bias mechanisms that reduce PSA level and lead to a delayed diagnosis of low-stage prostate cancer, meaning that fewer men with metabolic syndrome are diagnosed with low-stage disease. The inverse link between metabolic syndrome and its components and low-stage incident prostate cancer might simply be the result of such bias and the shortcomings of the diagnostic procedure rather than being related to prostate cancer biology itself. The evidence summarized here supports the hypothesis that the link between metabolic syndrome and its components and incident prostate cancer is a two-way and stage-dependent one, a theory that requires further research. PMID- 29434374 TI - Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. AB - Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1 dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal endosomes, active NOX2 is retrogradely transported to the cell body through an importin-beta1-dynein dependent mechanism. Endosomal NOX2 oxidizes PTEN, which leads to its inactivation, thus stimulating PI3K-phosporylated (p-)Akt signalling and regenerative outgrowth. Challenging the view that ROS are exclusively involved in nerve degeneration, we propose a previously unrecognized role of ROS in mammalian axonal regeneration through a NOX2-PI3K-p-Akt signalling pathway. PMID- 29434375 TI - Bidirectional and long-lasting control of alcohol-seeking behavior by corticostriatal LTP and LTD. AB - Addiction is proposed to arise from alterations in synaptic strength via mechanisms of long-term potentiation (LTP) and depression (LTD). However, the causality between these synaptic processes and addictive behaviors is difficult to demonstrate. Here we report that LTP and LTD induction altered operant alcohol self-administration, a motivated drug-seeking behavior. We first induced LTP by pairing presynaptic glutamatergic stimulation with optogenetic postsynaptic depolarization in the dorsomedial striatum, a brain region known to control goal directed behavior. Blockade of this LTP by NMDA-receptor inhibition unmasked an endocannabinoid-dependent LTD. In vivo application of the LTP-inducing protocol caused a long-lasting increase in alcohol-seeking behavior, while the LTD protocol decreased this behavior. We further identified that optogenetic LTP and LTD induction at cortical inputs onto striatal dopamine D1 receptor-expressing neurons controlled these behavioral changes. Our results demonstrate a causal link between synaptic plasticity and alcohol-seeking behavior and suggest that modulation of this plasticity may inspire a therapeutic strategy for addiction. PMID- 29434376 TI - Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. AB - The modification of synaptic strength produced by long-term potentiation (LTP) is widely thought to underlie memory storage. Indeed, given that hippocampal pyramidal neurons have >10,000 independently modifiable synapses, the potential for information storage by synaptic modification is enormous. However, recent work suggests that CREB-mediated global changes in neuronal excitability also play a critical role in memory formation. Because these global changes have a modest capacity for information storage compared with that of synaptic plasticity, their importance for memory function has been unclear. Here we review the newly emerging evidence for CREB-dependent control of excitability and discuss two possible mechanisms. First, the CREB-dependent transient change in neuronal excitability performs a memory-allocation function ensuring that memory is stored in ways that facilitate effective linking of events with temporal proximity (hours). Second, these changes may promote cell-assembly formation during the memory-consolidation phase. It has been unclear whether such global excitability changes and local synaptic mechanisms are complementary. Here we argue that the two mechanisms can work together to promote useful memory function. PMID- 29434378 TI - Synthesis and Characterization of Graphite-Encapsulated Iron Nanoparticles from Ball Milling-Assisted Low-Pressure Chemical Vapor Deposition. AB - Graphite-encapsulated Fe nanoparticles were synthesized using a combined method of high-energy ball milling and low-pressure chemical vapor deposition (LPCVD). Fe2O3 and graphite powders were milled to increase their surface areas and obtain a more homogeneous distribution. LPCVD was performed at a pressure of ~0.57 Torr in a tube furnace under a CH4/H2 atmosphere at 1050 degrees C for 1 and 3 h. As synthesized samples were purified in a 2 M HF solution. Characterization was performed using X-ray diffractometry (XRD), scanning and transmission electron microscopy (SEM and TEM) and alternating gradient magnetometry (AGM). XRD revealed the presence of body centered cubic (BCC) and face centered cubic (FCC) Fe phases without residual iron oxides. SEM confirmed the powders were better mixed and smaller after ball milling compared to mortar and pestle milled powders. High resolution TEM showed all nanoparticles had at least four and on average 16 graphitic layers, around an Fe core ranging from 20-300 nm. Magnetic measurements indicated that nanoparticles exhibit soft ferromagnetic behavior with low saturation magnetization (17-21 emu/g) and coercivity (110 Oe). A chemical stability test performed in a 2 M HCl solution showed that graphitic shells did not degrade, nor was there evidence of core dissolution or shell discontinuity. PMID- 29434377 TI - Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. AB - Analysis of chromatin accessibility can reveal transcriptional regulatory sequences, but heterogeneity of primary tissues poses a significant challenge in mapping the precise chromatin landscape in specific cell types. Here we report single-nucleus ATAC-seq, a combinatorial barcoding-assisted single-cell assay for transposase-accessible chromatin that is optimized for use on flash-frozen primary tissue samples. We apply this technique to the mouse forebrain through eight developmental stages. Through analysis of more than 15,000 nuclei, we identify 20 distinct cell populations corresponding to major neuronal and non neuronal cell types. We further define cell-type-specific transcriptional regulatory sequences, infer potential master transcriptional regulators and delineate developmental changes in forebrain cellular composition. Our results provide insight into the molecular and cellular dynamics that underlie forebrain development in the mouse and establish technical and analytical frameworks that are broadly applicable to other heterogeneous tissues. PMID- 29434379 TI - The Evolving Frontier of Digital Health: Opportunities for Pharmacists on the Horizon. PMID- 29434380 TI - Immediate Attention Required: Another Shortage. PMID- 29434381 TI - ISMP Adverse Drug Reactions: Influenza Vaccine-Induced Stevens-Johnson Syndrome; Vilazodone-Induced Nightmares; Dabigatran-Induced Pustular Eruptions; Neurotoxic and Cardiotoxic Symptoms After Cannabis Concentrate Exposure; Rosuvastatin Induced Skin Eruption. AB - The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID- 29434382 TI - Summaries of Safety Labeling Changes Approved By FDA- Boxed Warnings Highlights July-September 2017. PMID- 29434383 TI - Common Missteps With Medication Safety: Rolling a Single Dice, Ineffective Strategies, and Unexecuted Action Plans. PMID- 29434384 TI - Formulary Drug Review: Betrixaban. AB - Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. PMID- 29434385 TI - Antibiotics in Development for the Treatment of Resistant Bacterial Disease. AB - Many bacterial infections can be treated with the use of antibiotics. These medications continue to reduce morbidity and mortality; unfortunately, their use has brought about drug-resistant pathogens that produce difficult-to-treat infections, which require more extreme treatments. New antibiotics are needed to combat this ever-evolving resistance pathogenesis. PMID- 29434386 TI - Evaluation of the Incidence of Ibuprofen Administration in Alcohol and Opioid Detoxification Patients With Concomitant Thrombocytopenia. AB - Purpose: The purpose of this study was to determine the incidence of ibuprofen administration in patients who are undergoing alcohol and opioid detoxification, and have concomitant alcohol-related thrombocytopenia. Methods: This was a single center, cross-sectional, prospective, observational study. A daily manual review of electronic health records was conducted for patients admitted to the detoxification unit of the hospital. Patients who (1) were of age 18 years or more, (2) were ordered both alcohol and opioid detoxification protocols, and (3) had a platelet count of less than 150 000/uL were included in the study. The incidence of ibuprofen administration was evaluated. Results: Twenty-five patients were included in the analysis. More than 70% of patients had an active ibuprofen order and 50% of patients received ibuprofen. Patients with a platelet count of <100 000/uL were more likely to receive ibuprofen in the presence of an active ibuprofen order and received a higher dose of ibuprofen than patients who had a platelet count of >=100 000/uL. Conclusion: This study highlights a potential medication safety concern in patients with alcohol-related thrombocytopenia who are unintentionally ordered ibuprofen. Future, long-term studies are warranted to further investigate this issue. PMID- 29434387 TI - Antimicrobial Utilization Pattern in Pediatric Patients in Tertiary Care Hospital, Eastern Ethiopia: The Need for Antimicrobial Stewardship. AB - Background: Antimicrobials are among the most frequently prescribed medications for pediatric patients. However, inappropriate use of them can increase morbidity, mortality, healthcare costs, and largely antimicrobial resistance. This study aims to assess the antimicrobial utilization pattern in the pediatric ward of Hiwot Fana Specialized University Hospital. Methods: Retrospective cross sectional study was conducted to assess the antimicrobial utilization. In this study, 403 pediatric medical records selected by systematic random sampling were reviewed. Data were collected using structured data abstraction format. Results: Ceftriaxone (n = 176, 26.5%), gentamicin (n = 125, 18.82%), and ampicillin (n = 119, 17.9%) were the most frequently prescribed antimicrobials, whereas ampicillin and gentamicin combination took the largest percentage share (n = 91, 43.3%). The most common reasons for which antimicrobials prescribed were severe pneumonia (n = 93, 18.82%), severe acute malnutrition (n = 69, 13.97%), and meningitis (n = 67, 13.56%). On average, the highest number of antimicrobials per card was observed in neonates. The percentage of antimicrobials administered by parenteral route was found to be 84.33%. Less than half of antimicrobials (46.98%) were prescribed with dosage form. Besides, strength and duration were recorded in 20.03% and 4.21% of antimicrobial agents, respectively. Conclusion: Generally, there was an overuse of injectables despite the fact that oral formulations are safer alternatives. This result is too far from World Health Organization (WHO) standard (13.4%-21.1%). The degree of polypharmacy of antimicrobials falls within the WHO cutoff point (<2). There are no antibiogram tests conducted in the hospital. By and large, this study provides an impetus towards the establishment of antimicrobial stewardship programs. PMID- 29434388 TI - Acute Hepatocellular Jaundice After Dofetilide Initiation: A Case Report. AB - Dofetilide's hepatotoxicity is not well described. In this case report, we describe acute hepatocellular jaundice related to dofetilide use in a 33-year-old male being treated for atrial fibrillation. Both viral and ischemic causes of hepatocellular damage were ruled out as unlikely in this case. This case report outlines a rare yet probable report of idiosyncratic dofetilide-induced liver injury. PMID- 29434390 TI - The Torch Bearer Microbiologist: Prof. J(Jay) Vakil (1927-2017). PMID- 29434389 TI - Outcomes From a Pharmacist - led Proton Pump Inhibitor Stewardship Program at a Single Institution. AB - Background: Proton pump inhibitors (PPIs) are effective medications for acid related disorders; however, they are also overused and may be associated with several adverse effects. A PPI stewardship program was implemented at one institution to combat the overuse of PPIs. Objective: The purpose of this study is to evaluate the effectiveness of an inpatient PPI stewardship program in reducing PPI use, both during hospitalization and upon discharge. Methods: This was a retrospective cohort study of all patients admitted to an internal medicine service at a single institution from March 14, 2016, to August 14, 2016, with an intervention by the PPI stewardship team. The primary objective was to determine the percentage of patients who tolerated inpatient and outpatient PPI discontinuation, or dose de-escalations upon discharge. Secondary objectives included the identification of risk factors for intolerance of PPI discontinuation, the occurrence of gastrointestinal (GI) complications after PPI discontinuation, and the percentage of patients who required "as needed" acid suppressive therapy (AST) with an antacid or histamine-2 receptor antagonist (H2RA) to control their symptoms while hospitalized. Results: During the study time period, 537 patients with an active outpatient prescription for a PPI were admitted to an internal medicine team with 41.0% (n = 220) not meeting criteria for inpatient continuation. Of these patients, 95.9% (n = 211) tolerated inpatient PPI discontinuation, with 83.4% (n = 176) not requiring any "as needed" AST during hospitalization. Upon discharge, 57.1% patients (n = 24 of 42) tolerated PPI discontinuation at 3 months, while 81.8% patients (n = 18 of 22) tolerated PPI dose de-escalations at 3 months. Risk factors for intolerance of inpatient PPI discontinuation were a higher body mass index (BMI) (33.7 vs 30.3 kg/m2, P = .046) and longer length of stay (7.0 vs 4.0 days, P = .03), while longer duration of PPI use (9.0 vs 5.5 years, P = 0.03) was identified as a risk factor for intolerance of outpatient PPI discontinuation. One patient experienced reflux esophagitis 2 months after PPI discontinuation. Conclusion: A PPI stewardship program at a single institution resulted in the reduction of inappropriate PPI use in both the inpatient and outpatient settings. PMID- 29434391 TI - Gut-Bioreactor and Human Health in Future. AB - Gut-microbiome provides the complementary metabolic potential to the human system. To understand the active participation and the performance of the microbial community in human health, the concept of gut as a plug-flow reactor with the fed-batch mode of operation can provide better insight. The concept suggests the virtual compartmentalized gut with sequential stratification of the microbial community in response to a typical host genotype. It also provides the analysis plan for gut microbiome; and its relevance in developing health management options under the identified clinical conditions. PMID- 29434392 TI - Nanoparticles in Biological Hydrogen Production: An Overview. AB - Biological hydrogen (H2) production enhancement through the use of nanoparticles (NPs) supplement in the media is being recognized as a promising approach. The NPs, including those of metal and metal oxides have shown a significant improvement in the BHP. A number of organisms as pure or mixed cultures can produce H2 in presence of NPs from pure sugars and biowaste as a feed. However, their H2 production efficiencies have been found to vary significantly with the type of NPs and their concentration. In this review article, the potential role of NPs in the enhancement of H2 production has been assessed in dark- and photo fermentative organisms using sugars and biowaste materials as feed. Further, the integrative approaches for commercial applications of NPs in BHP have been discussed. PMID- 29434393 TI - The Mycotoxin Zearalenone Hinders Candida albicans Biofilm Formation and Hyphal Morphogenesis. AB - Yeast-mold mycobiota inhabit several natural ecosystems, in which symbiotic relationships drive strategic pathoadaptation. Mycotoxins are metabolites produced by diverse mycotoxigenic fungi as a defense against yeasts, though at times yeasts secrete enzymes that degrade, detoxify, or bio-transform mycotoxins. The present study is focused on the in vitro inhibitory effects of zearalenone (ZEN), a F2 mycotoxin produced by several Fusarium and Gibberella species, on different microbial strains. ZEN exhibited no effect on the planktonic growth or biofilms of several Gram positive and negative bacteria at the tested concentrations. Remarkably, Candida albicans biofilm formation and hyphal morphogenesis were significantly inhibited when treated with 100 ug/mL of ZEN. Likewise, ZEN proficiently disrupted pre-formed C. albicans biofilms without disturbing planktonic cells. Furthermore, these inhibitions were confirmed by crystal violet staining and XTT reduction assays and by confocal and scanning electron microscopy. In an in vivo model, ZEN significantly suppressed C. albicans infection in the nematode Caenorhabditis elegans. The study reports the in vitro antibiofilm efficacy of ZEN against C. albicans strains, and suggests mycotoxigenic fungi participate in asymmetric competitive interactions, such as, amensalism or antibiosis, rather than commensal interactions with C. albicans, whereby mycotoxins secreted by fungi destroy C. albicans biofilms. PMID- 29434394 TI - Mycobacterium mageritense Parotitis in an Immunocompetent Adult. AB - Mycobacterium mageritense, a rapidly growing mycobacterium, is a rare clinical pathogen. Furthermore, parotitis due to non-tuberculosis mycobacterium is very rare in adults. Herein, we report the first case of M. mageritense parotitis in an immunocompetent adult. A 40-year-old man presented with swelling in a left parotid lesion. He was diagnosed with parotitis. The culture from the parotid abscess grew M. mageritense. He was unsuccessfully treated with levofloxacin monotherapy. Trimethoprim-sulfamethoxazole was added, leading to some clinical response; however, the erythema persisted despite 14 months of antibiotic therapy. Subsequently, the skin lesion was surgically removed. The antibiotic treatment was ceased a week after surgery as the postoperative course was uneventful and the lesion had improved. No recurrence was noted at 7 months after surgery. Although extremely rare, M. mageritense can cause parotitis in immunocompetent adults, and may not be sufficiently treated with antibiotics alone. PMID- 29434395 TI - Co-utilization of Crude Glycerol and Biowastes for Producing Polyhydroxyalkanoates. AB - Polyhydroxyalkanoate (PHA) production by Bacillus thuringiensis EGU45 and defined mixed culture of Bacillus spp. were studied by using crude glycerol (CG) and hydrolyzed biowastes as feed material. Hydrolysates from onion peels (OP), potato peels, pea-shells (PS), apple pomace 2% total solids obtained with defined mixed hydrolytic cultures (MHC2) were inoculated with B. thuringiensis EGU45 and defined mixed bacterial cultures (5MC1), which produced PHA at the rate of 40-350 and 65-450 mg/L, respectively. Addition of CG (1%, v/v) to these hydrolysates resulted in 1.8-fold and 4.5-fold enhancement in PHA production from OP by B. thuringiensis EGU45 and 5MC1, respectively. Co-utilization of OP and PS (in 2:1 ratio) supplemented with CG (1%, v/v) by B. thuringiensis EGU45 resulted in 2 fold increase in PHA production in comparison to OP + CG. This co-metabolism of OP and PS also enabled PHA co-polymer production (1300 mg/L), having an enhanced HV content of 21.2% (w/w). PMID- 29434396 TI - Structural and Functional Properties of Exopolysaccharide Excreted by a Novel Bacillus anthracis (Strain PFAB2) of Hot Spring Origin. AB - Exopolysaccharide produced by a unique avirulent Bacillus anthracis strain PFAB2 of hot spring origin has been characterized and its functional properties are investigated which is a first report. Maximum yield of EPS is 7.66 g/l with 2% glucose and 1% peptone as optimum carbon and nitrogen source respectively. The EPS is found to be a homopolymer consisting of only glucose as principle monosaccharide component. Through 1H NMR study, different dextran-like proton peaks are observed. Molecular weight of the EPS resembles low molecular weight bacterial origin polysaccharides. Melting transition of the EPS has started after 276 degrees C which indicates good thermal stability. The EPS also shows potent antioxidant activity in terms of DPPH and ABTS mediated free radical scavenging property compared to standard ascorbic acid. Emulsifying property of the EPS is also observed and has shown good emulsification of vegetable oils. The polysaccharide forms a thermo resistant gel during the heating phase, with G' higher than G" indicating excellent shear-thinning behaviour and viscoelastic nature of the EPS. PMID- 29434397 TI - Evaluation of Industrial Biocides on a Novel Aspergillus versicolor TANCK-1 and Elucidation of Their Probable Biocidal Mechanism. AB - Abstract: In the present investigation, a novel fungus was isolated from leather watch strap and identified as Aspergillus versicolor TANCK-1 by 18 s rRNA sequencing. The isolated fungus was evaluated against three structurally different fungicides such as 2-(thiocyanomethylthio)benzothiazole (TCMTB), potassium dimethyldithiocarbamate (KDDC) and 2,2-dibromo-3-nitrilopropionamide (DBNP) to control the fungal growth. Among these, TCMTB was found to effectively inhibit the growth at a minimum concentration of 31.2 ug/mL as compared to 1250 and 625 ug/mL for KDDC and DBNP respectively. Increased membrane permeability in the fungicide treated samples was evident from cellular release and decrease in cellular ergosterol content. Nevertheless, SEM analysis revealed a considerable change in fungicide treated mycelium with the collapse of hyphae structure and shrunken spores, which was observed to be very pronounced in KDDC and DBNP. Results indicated that all three biocides bring about inhibition through membrane damage with almost negligible effect on the cell wall. Graphical Abstract: Schematic diagram explaining the fungicidal action on Aspergillus versicolor TANCK-1. PMID- 29434398 TI - A Highly Promiscuous Integron, Plasmids, Extended Spectrum Beta Lactamases and Efflux Pumps as Factors Governing Multidrug Resistance in a Highly Drug Resistant Vibrio fluvialis Isolate BD146 from Kolkata, India. AB - In an earlier study from this laboratory, Vibrio fluvialis BD146, a clinical isolate from Kolkata, India, 2002, was found to be resistant to all the fourteen antibiotics tested. It harboured a high copy number plasmid pBD146 and a low copy number plasmid. In the present study, a more detailed analysis was carried out to unravel different resistance mechanisms in this isolate. Sequencing showed that variable region of class 1 integron located on low copy number plasmid harbored arr3-cmlA-blaOXA10-aadA1 gene cassettes. Analysis for extended spectrum beta lactamases (ESBLs) revealed that BD146 was ESBL positive. Efflux pumps were involved in the drug resistance phenotype for chloramphenicol, kanamycin, streptomycin and tetracycline. Sequence analysis of pBD146 revealed the presence of genes encoding BDint an integrase with a unique sequence having little similarity to other known integrases, toxin-antitoxin (parE/parD), a replicase, trimethoprim resistance (dfrVI) and quinolone resistance (qnrVC5). Presence of cmlA, putative novel integrase and toxin-antitoxin system in V. fluvialis has been documented for the first time in this report. pBD146 showed 99% sequence similarity with pVN84 from V. cholerae O1 of Vietnam, 2004 and a plasmid from V. parahaemolyticus v110 of Hong Kong, 2010. Conjugation experiments proved the ability of pBD146 and the low copy number plasmid, to get transferred to another host imparting their antibiotic resistance traits to the transconjugants. Therefore, present study has indicated that plasmids played an important role for dissemination of drug resistance. PMID- 29434399 TI - Anti-viral Activities of Oroxylum indicum Extracts on Chikungunya Virus Infection. AB - Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus that poses a threat to human worldwide. Driven by the lack of approved medication and vaccination, research on anti-Chikungunya agents has received great attention. In an effort to determine potential inhibitor of CHIKV, this study aimed at investigating the potential anti-viral activity of Oroxylum indicum extracts towards CHIKV-infected Vero cells. The virucidal, pre- and post-treatment effects of O. indicum were evaluated, using the maximum non-toxic dose of O. indicum methanol and aqueous extracts as determined by cytotoxicity assay. The viral inhibitory effect was assessed by the morphological changes of Vero cells and further confirmed by plaque assay. Both methanol and aqueous extracts of O. indicum had similar cytotoxicity in Vero cells. Interestingly, the virucidal effect of O. indicum aqueous extract revealed a significant reduction on the viral titre (p < 0.05). The prophylactic effect of aqueous extract was demonstrated when the pre-treated cells exhibited a significant anti-CHIKV activity (p < 0.05). However, methanol extract of this plant exerted an anti viral activity against CHIKV only to a certain extent. Therefore, the aqueous extract of this plant has a potential to inhibit the virus and acts as prophylactic agent against CHIKV. Further studies however are needed to substantiate the finding and to determine the important compound of this plant as well as the mechanism of action in treating CHIKV infection. PMID- 29434400 TI - Evaluation of Gamma-Radiation Inactivation of a Bioterrorism Agent, Bacillus anthracis Spores, on Different Materials. AB - Decontamination of suspected packages, such as sealed envelopes, liquids and tools that are likely contaminated with biological agents is of great importance. In this study, we aimed to determine the gamma radiation dose required for the decontamination of paper, fabric and liquid materials without causing any damage to the structure of these materials. Each study group included 11 pieces of paper, fabric and sterile saline contaminated with 0.8 * 105 virulent Bacillus anthracis (B. anthracis) spores. These specimens were exposed to doses of 5.49, 11.58, 17.21, 21.75, 27 and 33.1 kilogray (kGy) of gamma radiation from a cobalt 60 source. After irradiation of all the samples, a viability assessment of the B. anthracis spores was performed. It was found that full decontamination was achieved with 11.58 kGy on the paper samples and 17.21 kGy on the fabric and liquid samples. It was concluded that a dose of 20 kGy of gamma radiation may be recommended for the inactivation of B. anthracis for some surfaces when especially sensitive and valuable materials cannot be wet decontaminated were exposed. In addition, serologic and molecular assays of the suspected packets can be performed for forensic purposes without damaging existing evidence in a bioterror incident. PMID- 29434401 TI - Point of Care Tuberculosis Sero-Diagnosis Kit for Wild Animals: Combination of Proteins for Improving the Diagnostic Sensitivity and Specificity. AB - Tuberculosis is a significant problem globally for domestic animals as well as captive and free ranging wild life. Rapid point of care (POC) serology kits are well suited for the diagnosis of TB in wild animals. However, wild animals are invariably exposed to environmental non-pathogenic mycobacterium species with the development of cross reacting antibodies. In the present study, POC TB diagnosis kit was developed using a combination of pathogenic Mycobacteria specific recombinant antigens and purified protein derivatives of pathogenic and non pathogenic Mycobacteria. To benchmark the TB antibody detection kit, particularly in respect to specificity which could not be determined in wildlife due to the lack of samples from confirmed uninfected animals, we first tested well characterized sera from 100 M. bovis infected and 100 uninfected cattle. Then we investigated the kit's performance using sera samples from wildlife, namely Sloth Bears (n = 74), Elephants (n = 9), Cervidae (n = 14), Felidae (n = 21), Cape buffalo (n = 2), Wild bear (n = 1) and Wild dog (n = 1).In cattle, a sensitivity of 81% and a specificity of 90% were obtained. The diagnostic sensitivity of the kit was 94% when the kit was tested using known TB positive sloth bear sera samples. 47.4% of the in-contact sloth bears turned seropositive using the rapid POC TB diagnostic kit. Seropositivity in other wild animals was 25% when the sera samples were tested using the kit. A point of care TB sero-diagnostic kit with the combination of proteins was developed and the kit was validated using the sera samples of wild animals. PMID- 29434402 TI - Synthesis, Antimicrobial and Antioxidant Activity of Pyrazole Based Sulfonamide Derivatives. AB - A series of new sulfonamides have been synthesized from Ampyrone with different benzene sulfonyl chlorides to yield the N-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro 1H-pyrazol-4-yl) benzenesulfonamides (4a-e). All synthesized compounds were characterized on the basis of FTIR, 1H NMR, and 13C NMR, and also by the aid of mass spectral data. Further, all synthesized compounds have studied for their in vitro antimicrobial activities against selected bacterial as well as fungal strains by the agar well diffusion method. Free radical scavenging activity has been investigated by using DPPH method. Among all the synthesized compounds, 4b, 4d, and 4e exhibited significant antimicrobial and antioxidant activities. PMID- 29434403 TI - Synthesis of Protein-Inorganic Nanohybrids with Improved Catalytic Properties Using Co3(PO4)2. AB - In the present study, a method for easy and rapid synthesis of lipase nanohybrids was evaluated using cobalt chloride as an encapsulating agent. The synthesized nanohybrids exhibited higher activity (181%) compared to free lipase and improved catalytic properties at higher temperature and in harsh conditions. The nanohybrids retained 84% of their residual activity at 25 degrees C after 10 days. In addition, these nanohybrids also exhibited high storage stability and reusability. Collectively, the synthesis of carrier-free immobilized biocatalysts was performed rapidly within 24 h at 4 degrees C. Their high reusability and catalytic activities highlight the broad applicability of this method for catalysis in organic and aqueous media. PMID- 29434404 TI - In Vitro Antibacterial Activity of Phlorotannins from Edible Brown Algae, Eisenia bicyclis Against Streptomycin-Resistant Listeria monocytogenes. AB - Listeria monocytogenes (LM) is an important food borne pathogen responsible for listeriosis. Further, LM is an etiological agent associated with life threatening conditions like meningitis and encephalitis. Biofilm forming and drug resistant LM may potentially become difficult to treat infections and hence effective controlling measures are required to prevent LM infections. In view of this, the present study evaluated an anti-listerial potential of edible brown seaweed, Eisenia bicyclis, by disc diffusion and micro-dilution methods. The results of the present study suggested that the anti-listerial activity of various phlorotannins isolated form E. bicyclis were in the range of 16-256 ug/ml. Among the phlorotannins isolated, fucofuroeckol-A (FAA) exhibited the highest anti listerial potential (MIC range 16-32 ug/ml) against LM strains tested. Further, in checker board synergy assays, FFA-streptomycin combination exhibited significant synergy (fractional inhibitory concentration index, ?FIC < 0.5) against aminoglycoside resistant clinical strains of LM. The results of the present study suggested the potential use of edible seaweed E. bicyclis as a source of natural phlorotannins to control food borne pathogenic infections. PMID- 29434405 TI - Inclusion of 2-Mercaptoethanol in Lysis Buffer Could Interfere with Isolation of High Molecular Weight DNA from Freshwater Microalgae. AB - 2-mercaptoethanol (2-ME), alongside polyvinylpyrrolidone is commonly used in plant DNA extractions to deal with polyphenols, which could interfere with extraction and downstream applications. 2-ME is also commonly used to denature proteins and nucleases, especially RNAses. On the contrary, we found that the presence of 2-ME in lysis buffer interfered with DNA extraction from 12 strains of freshwater microalgae, resulting in DNA with poor integrity. We also found that the TNES-urea buffer, commonly used for preservation and DNA extraction from fish, appears as effective as the SDS and CTAB buffer for some microalgae strains. Results from our study suggests that the inclusion of 2-ME in DNA extraction protocols may be detrimental for isolation of good quality DNA from freshwater microalgae, and therefore recommend eliminating it or testing varying concentrations of 2-ME when developing species-specific extraction protocols for microalgae. PMID- 29434406 TI - Phage Application for the Protection from Acute Hepatopancreatic Necrosis Disease (AHPND) in Penaeus vannamei. AB - Acute hepatopancreatic necrosis disease (AHPND) caused by Vibrio parahaemolyticus has been one of the most problematic diseases in marine shrimp aquaculture throughout Southeast Asia and Latin America. To evaluate the effectiveness of a bacteriophage (phage) treatment for AHPND, a series of bioassays were carried out in a marine shrimp (Penaeus vannamei) model using an AHPND-V. parahaemolyticus strain that is highly pathogenic to shrimp. We monitored the mortality and histopathological changes during phage treatment. Shrimps treated with phage prophylaxis and phage therapy displayed significant protection from AHPND and survived a lethal bacterial challenge. PMID- 29434407 TI - Carotenoid Production by a Novel Isolate of Microbacterium paraoxydans. AB - This study reports extraction and characterization of carotenoid pigments from Microbacterium paraoxydans, a non-photosynthetic bacterium, cultivated in Luria Bertani (LB) medium. The isolate was identified to be moderately halo- and osmo tolerant capable of withstanding high (~ 6%) salt and sugar (30% w/v sucrose, 20% w/v glucose) concentrations after a brief period of adaptation. The pigments were characterized using a combination of UV-Vis spectral analysis with the lambdamax at 407, 436 and 466 nm and ESI-MS with an m/z value at 536.44. The absorption profile of the pigments and their nature was influenced by carbon, nitrogen source and presence of salt in the growth medium. Highest level of pigment (~ 16 g kg dry wt cells-1) was produced in NH4Cl supplemented LB medium. The pigment displayed free radical scavenging, anticancer activity, characteristic of the plant carotenoids. Based on the accumulation of pigments under different conditions, a biochemical pathway for synthesis of neurosporene was proposed. PMID- 29434408 TI - Infection and Microbiome: Impact of Tuberculosis on Human Gut Microbiome of Indian Cohort. PMID- 29434409 TI - Is MicroRNA-127 a Novel Biomarker for Acute Pancreatitis with Lung Injury? AB - Background and Aims: The aim of this study was to determine the expression of microRNA-127 (miR-127) in both rat models and patients of acute pancreatitis (AP) with lung injury (LI). Methods: Rats were administrated with retrograde cholangiopancreatography injection of 0.5% or 3.5% sodium taurocholate to induce AP with mild or severe LI and were sacrificed at 6, 12, and 24 h. Rats from the control group received a laparotomy only. Plasma from a prospective cohort of AP patients was collected. The levels of miR-127 in the tissues and plasma were detected using quantitative reverse transcription-polymerase chain reaction (qRT PCR). Results: The upregulation of miR-127 in the lungs of rats was detected in the groups of AP with severe LI at 6 h and 24 h, whereas it was scarcely detectable in plasma. In the pilot study that included 18 AP patients and 5 healthy volunteers, the plasma miR-127 level was significantly downregulated in AP patients with respiratory failure compared with the healthy volunteers (P = 0.014) and those without respiratory failure (P = 0.043). Conclusion: miR-127 might serve as a potential marker for the identification of AP with LI. PMID- 29434410 TI - Circulating Tumor Cells Were Associated with the Number of T Lymphocyte Subsets and NK Cells in Peripheral Blood in Advanced Non-Small-Cell Lung Cancer. AB - In this study, we aim to investigate the correlation between circulating tumor cells (CTCs) and the T lymphocyte subsets and NK cells in peripheral blood in non small-cell lung cancer (NSCLC). The peripheral blood CTCs were determined by SET iFISH. Flow cytometry was used to determine the distribution of T lymphocyte subsets and NK cells. Forty-one (49%) patients showed positivity for CTCs. Logistic regression analysis revealed CTC number was negatively correlated with the ratio of CD3+, CD4+, CD4+/CD8+, and NK % in patients at stage IV, while in a positive correlation was noticed between CTC number and regulatory T cell (Tregs) ratio in these patients. Multivariate analysis was performed in combination with the clinical-pathological materials to identify the risk factors for CTC positivity. Differentiation, NSCLC stage, percentages of CD3+CD4+ cells, Tregs, and NK cells were the independent risk factors for CTCs. CTCs were associated with the decrease of immune surveillance in the peripheral blood in NSCLC patients. The decrease of immune surveillance contributed to the escape of CTCs from the killing effects of the immunocytes, as well as the formation of metastasized lesions in the target organs. PMID- 29434412 TI - The Value of Physiotherapists in Primary Health Care Clinics: Optimizing (Self-) Management Supports for Persons with Complex Health and Social Needs. PMID- 29434413 TI - Influence of Ultrasound Transducer Tilt in the Cranial and Caudal Directions on Measurements of Inter-Rectus Distance in Parous Women. AB - Purpose: An increased inter-rectus distance (IRD) can persist after a pregnancy and may be associated with lumbopelvic dysfunction. Ultrasound imaging (USI) is currently the gold standard for measuring IRD; however, no study has explored the need to standardize the transducer angle during these evaluations. The purpose of this study was to determine whether the angle of the ultrasound transducer relative to the underlying abdominal wall has an effect on measurements of IRD in parous women. Method: Ultrasound images of the linea alba (LA) were captured from 15 women, at rest and during a head lift, beginning with images acquired perpendicular to the LA at the midline, then tilted in 5 degrees increments to 15 degrees in both the cranial and the caudal directions. Repeated-measures analyses of variance were used to test for systematic differences in IRD measurements among the transducer angles in both the rest and the head-lift conditions. An alpha of 0.05 was used for all tests. Results: No significant effect of transducer angle was found in IRD measurements acquired with participants at rest (F2.24,31.3=1.814; p=0.18) or during a head lift (F3.15,44.1=1.315; p=0.28). Conclusion: When using USI, cranial or caudal tilt errors in transducer angle do not appear to pose a problem when measuring IRD. PMID- 29434411 TI - Metabolic Footprints and Molecular Subtypes in Breast Cancer. AB - Cancer treatment options are increasing. However, even among the same tumor histotype, interpatient tumor heterogeneity should be considered for best therapeutic result. Metabolomics represents the last addition to promising "omic" sciences such as genomics, transcriptomics, and proteomics. Biochemical transformation processes underlying energy production and biosynthetic processes have been recognized as a hallmark of the cancer cell and hold a promise to build a bridge between genotype and phenotype. Since breast tumors represent a collection of different diseases, understanding metabolic differences between molecular subtypes offers a way to identify new subtype-specific treatment strategies, especially if metabolite changes are evaluated in the broader context of the network of enzymatic reactions and pathways. Here, after a brief overview of the literature, original metabolomics data in a series of 92 primary breast cancer patients undergoing surgery at the Istituto Nazionale dei Tumori of Milano are reported highlighting a series of metabolic differences across various molecular subtypes. In particular, the difficult-to-treat luminal B subgroup represents a tumor type which preferentially relies on fatty acids for energy, whereas HER2 and basal-like ones show prevalently alterations in glucose/glutamine metabolism. PMID- 29434414 TI - The Unsupported Upper Limb Exercise Test in People Without Disabilities: Assessing the Within-Day Test-Retest Reliability and the Effects of Age and Gender. AB - Purpose: To estimate the within-day test-retest reliability and standard error of measurement (SEM) of the unsupported upper limb exercise test (UULEX) in adults without disabilities and to determine the effects of age and gender on performance of the UULEX. Method: A cross-sectional study was conducted with 100 adults without disabilities (44 men, mean age 44.2 [SD 26] y; 56 women, mean age 38.1 [SD 24.1] y). Participants performed three UULEX tests to establish within day reliability, measured using an intra-class correlation coefficient (ICC) model 2 (two-way random effects) with a single rater (ICC[2,1]) and SEM. The effects of age and gender were examined using two-factor mixed-design analysis of variance (ANOVA) and one-way repeated-measures ANOVA. For analysis purposes, four sub-groups were created: younger adults, older adults, men, and women. Results: Excellent within-day reliability and a small SEM were found in the four sub groups (younger adults: ICC[2,1]=0.88; 95% CI: 0.82, 0.92; SEM~40 s; older adults: ICC[2,1]=0.82; 95% CI: 0.72, 0.90; SEM~50 s; men: ICC[2,1]=0.93; 95% CI: 0.88, 0.96; SEM~30 s; women: ICC[2,1]=0.85; 95% CI: 0.78, 0.91; SEM~45 s). Younger adults took, on average, 308.24 seconds longer than older adults to perform the test; older adults performed significantly better on the third test (p<0.0001; eta2=0.096). Gender effects were not found (p>0.05). Conclusion: The within-day test-retest reliability and SEM values of the UULEX may be used to define the magnitude of the error obtained with repeated measures. One UULEX test seems to be adequate for younger adults to achieve reliable results, whereas three tests seem to be needed for older adults. PMID- 29434415 TI - Advancing Pain Education in Canadian Physiotherapy Programmes: Results of a Consensus-Generating Workshop. AB - Purpose: This article reports on a national stakeholder workshop that focused on advancing pain education in physiotherapy programmes across Canada. Methods: Workshop participants included national leaders from the following stakeholder groups: people living with pain; physiotherapy students and recent graduates; pain educators; physiotherapy programme administrators; and representatives from the Canadian Alliance of Physiotherapy Regulators, Physiotherapy Education Accreditation Canada, Canadian Physiotherapy Association, and Physiotherapy Practice Profile project. During the workshop, barriers to, facilitators of, and strategies for advancing pain education were discussed, and a stakeholder endorsed consensus statement was generated. The workshop was recorded, and data were thematically analyzed. Results: Participants identified important barriers and facilitators associated with the field of pain, standards and regulatory processes, physiotherapy programmes, and physiotherapy students and people living with pain. Strategies for advancing pain education included integrating pain competencies into standards and regulatory policy, encouraging the development of best teaching practices, partnering with people living with pain, building awareness, and setting goals and assessing clear outcomes. The consensus statement highlighted the central importance of pain education for physiotherapists and the need for a reference standard to guide its implementation in the Canadian context. Conclusion: This was the first initiative to specifically explore national stakeholders' perceptions of pain education. The workshop outcomes provide a strong mandate and direction for advancing pain education across Canadian physiotherapy programmes. PMID- 29434416 TI - What Do Patients with Chronic Spinal Pain Expect from Their Physiotherapist? AB - Purpose: Evidence has suggested that patients' expectations influence the clinical course when they present with low back pain (LBP). However, little empirical evidence has outlined the nature of these expectations. The aim of this study was to describe LBP patients' expectations of physiotherapy. Method: Seventy-nine adult patients who had LBP for more than 16 weeks and were referred for physiotherapy at two hospital physiotherapy departments in St. John's, Newfoundland and Labrador, were included. They filled out a questionnaire detailing their expectations of treatment. Results: Before treatment, more than 90% of patients expected a physical examination, tests or investigations, a diagnosis, reassurance and advice, and clear explanations of causation, symptom management, and benefits and risks of treatment. Approximately half hoped for a prescription or referral to a specialist, and about 60% hoped to discuss problems in their life. Conclusions: The findings of this study indicate that patients attend physiotherapy with clear expectations about what information should be provided. Most expected tests or investigations leading to diagnosis and an explanation of causation; this presents a challenge for clinicians, given the current understanding of LBP reflected in international practice guidelines. The fact that more than half of the patients wanted to discuss problems in their life points to the need for physiotherapists to consider LBP from a bio-psychosocial perspective. PMID- 29434417 TI - Relationship between Physical Activity and Fatigue in Adults with Cystic Fibrosis. AB - Purpose: We examined the relationship between the amount of physical activity and level of fatigue in adults with cystic fibrosis (CF). Method: Participants were recruited from the Toronto Adult Cystic Fibrosis Centre at St. Michael's Hospital. Participants completed the Habitual Activity Estimation Scale, the Multidimensional Fatigue Inventory, and the Depression subscale of the Hospital Anxiety and Depression Scale, in that order. Descriptive statistics and linear and multiple regressions were computed. Results: Over a 6-month period, 51 individuals were approached, and 22 (10 men, 12 women) participated in this study. The participants' median age was 33, and forced expiratory volume in 1 second (FEV1) was 64% predicted. When holding both FEV1 and depression constant, a significant negative correlation was found between total active hours per weekday and general fatigue (beta=-0.735, p=0.03); there was a negative trend between total active hours per weekday and physical fatigue (beta=-0.579, p=0.09). Conclusions: This study is the first to demonstrate that among adults with CF, a higher level of physical activity is associated with a lower level of general and physical fatigue when controlling for lung function and level of depression. Physical activity may be used as a means of mitigating the levels of general and physical fatigue in people with CF. PMID- 29434418 TI - Pelvic Floor Morphometric Differences in Elderly Women with or without Urinary Incontinence. AB - Purpose: Urinary incontinence (UI) affects as many as 50% of women aged 60 years and older, but UI pathophysiology, specifically in elderly women, remains unclear. A better understanding of morphometric differences between continent and urinary incontinent elderly women is needed to improve the effectiveness of conservative treatment approaches. We hypothesized that morphometric differences in the pelvic floor muscles (PFM) among elderly women with and without UI could be observed using three- and four-dimensional (3D/4D) transperineal ultrasound (TPU) imaging. Method: A total of 40 elderly women (20 women with and 20 women without UI), with a mean age of 67.10 (SD 4.94) years, participated in the study. This was a case-control study in which TPU images were taken under three conditions: rest, maximal voluntary contraction (MVC), and Valsalva. Independent t-tests were conducted to compare measurements between the groups. Results: The study revealed statistically significant differences between the groups. At rest, the levator hiatal area and transverse diameter were bigger, and the PFM position was lower in the incontinent group. During MVC, all axial plane parameters were bigger in the incontinent group. In the sagittal plane, PFM position was again lower in the incontinent group. During Valsalva, the anorectal angle was wider in the women with incontinence. Conclusion: PFM morphometric differences were present and were observed using 3D/4D TPU imaging in elderly women with and without UI. PMID- 29434419 TI - Physical Activity of ICU Survivors during Acute Admission: Agreement of the activPAL with Observation. AB - Purpose: We estimated the agreement of a thigh-worn accelerometer, the activPAL, used to measure activity and sedentary parameters, with observed mobility assessments of intensive care unit (ICU) survivors. Method: We prospectively compared activPAL measurements with direct observation during assessments at discharge from the ICU or acute hospital in eight participants with a median age of 56 (1st-3rd quartile 48-65) years and an Acute Physiology and Chronic Health Evaluation II score of 23 (1st-3rd quartile 17-24). Frequency of sit-to-stand transitions; time spent standing, stepping, upright (standing and stepping), and sedentary (lying/sitting); and total steps were described; analysis was performed using Bland-Altman plots and calculating the absolute percent error. Results: All sit-to-stand transitions were accurately detected. The mean difference on the Bland-Altman plots suggested an overestimation of standing time with the activPAL of 31 (95% CI: -9, 71) seconds and underestimation of stepping time by 25 (95% CI: -47, -3) seconds. The largest median absolute percent errors were for standing time (21.9%) and stepping time (18.7%); time spent upright (1.7%) or sedentary (0.3%) was more accurately estimated. The activPAL underestimated total steps per session, achieving the largest percent error (70.8%). Conclusion: Because it underestimated step count, the activPAL likely incorrectly recorded stepping time as standing time, so that time spent upright was the measure of activity with the smallest error. Sedentary behaviour, including frequency of transitions, was validly assessed. PMID- 29434420 TI - Smoking-Related Stigma Expressed by Physiotherapists toward Individuals with Lung Disease. AB - Purpose: We determined the extent and nature of stigma exhibited by a sample of Canadian cardiorespiratory physiotherapists toward people with lung disease who had a smoking history. Method: A quantitative online survey was distributed to Canadian cardiorespiratory physiotherapists, and an anti-smoking attitudes questionnaire was used to measure explicit stigma. We used two case studies with questions to measure implicit stigma. The first involved a patient with chronic obstructive pulmonary disease (COPD) and a smoking history, and the second described a patient with COPD with no smoking history. Results: Of the respondents (n=50), 56% demonstrated mild explicit stigma and 44% demonstrated moderate to severe explicit stigma. The extent of explicit stigma was not associated with respondents' age, area of practice, personal smoking history, or family history of lung disease resulting from smoking. The results indicated no evidence of implicit stigma, and no significant differences were found between the participants' prospective treatments and their professional attitudes toward patient cases. Conclusions: Canadian cardiorespiratory physiotherapists demonstrated explicit stigma toward people with lung disease with a significant smoking history, but there was no evidence of implicit stigma. These findings suggest that further research is needed to investigate how stigma held by cardiorespiratory physiotherapists may affect the quality of care provided for patients with a smoking history. PMID- 29434421 TI - Clinical Instructors' Perspectives on the Clinical Education of Internationally Educated Physical Therapists: Diversity's Impact on the Experience. AB - Purpose: The aim of this study was to understand the nature and extent of clinical instructors' (CIs') involvement in the clinical education of internationally educated physical therapists (IEPTs) while exploring CIs' perceptions of the similarities among and differences between IEPTs and Canadian trained students. Method: In this qualitative descriptive study, 13 semi structured interviews were conducted with CIs who were involved in a bridging programme for IEPTs. Data were coded using NVivo version 10, and common themes emerged through qualitative thematic analysis. Results: The majority of CIs perceived IEPTs' backgrounds to be diverse as a result of their varied previous clinical experience, physiotherapy scope of practice, and life stressors. Their diverse backgrounds contributed to the similarities and differences found in their skills, their personal motivation, and the education process, leading to successes and challenges in the clinical environment. Conclusions: Differences between IEPTs and Canadian-trained students stem from IEPTs' diverse backgrounds. Recognizing this diversity while demonstrating cultural competence will promote a successful clinical experience for both IEPT learners and CIs, which will ultimately facilitate the integration of IEPTs into the Canadian health care system. PMID- 29434423 TI - What Does Cochrane Say about ... the Effects of Interventions for ICU Patients? PMID- 29434422 TI - Validity of the Fitbit One for Measuring Activity in Community-Dwelling Stroke Survivors. AB - Purpose: We determined the correlation between the Fitbit One and Actical accelerometer for quantifying the 3-day step count and activity levels in community-dwelling individuals with stroke. Method: Twelve participants with a mean age of 62.6 (SD 9.3) years wore both the Fitbit One and the Actical on the non-paretic ankle for 3 days. Regression analyses were performed to examine concurrent validity between the devices for step counts and sedentary, light, moderate, and vigorous activity. The relative error of the Fitbit One compared with the Actical in measuring step count was calculated. Results: Participants spent about 80% of their days being sedentary. The associations between the Fitbit One and the Actical were r>0.80 for step count and light-intensity activity across the 3 days of free-living activity. The overall relative error in measuring step count was 3.8%, with differences between those with walking speeds of less than 0.58 metres per second and 0.58 metres per second or more (27.4% [SD 34.2] vs. -8.0% [SD 10.7], p<0.001). Conclusions: The Fitbit One was associated with the Actical accelerometer in measuring step count and light-intensity activity during free-living activity after stroke, but had lower error in capturing step count for those with faster walking speeds. The Fitbit One may not be valid for capturing higher intensity activity after stroke. PMID- 29434425 TI - Exit the Cockerel, Enter the Dog. PMID- 29434424 TI - Tuning p-Type Transport in Bottom-Up-Engineered Nanocrystalline Pb Chalcogenides Using Alkali Metal Chalcogenides as Capping Ligands. PMID- 29434426 TI - Reappraisal of Percutaneous Transluminal Laser Angioplasty. AB - Background and aims: We devised a technique to treat peripheral arterial disease (PAD) with laser, i.e. percutaneous transluminal laser angioplasty (PTLA). Considerable good results were obtained with PTLA, but it is apparently considered obsolete as a technique to treat occlusive arterial disease of peripheral arteries, perhaps because of the development and improvement of stents and the ease of their use compared to the somewhat intricate technique required for PTLA. Although the author admits the usefulness of stents, they are foreign to a human body. PTLA does not use a foreign body and contributes to the regeneration of the body's own artery.The aim of this article is to elucidate the beneficial effects of laser procedures in the treatment of PAD and to show the resulting good long-term patency, and to propose PTLA as an option to treat PAD.Some basic experiments and their results useful for PTLA will be introduced. Materials and Methods: Ninety cases with occlusive peripheral arterial diseases were treated with PTLA during the period of March 1985 to March 1991.Our method of PTLA consists of occlusion of the proximal artery by a dilated balloon of a percutaneously introduced balloon catheter, and flushing with normal saline during irradiation by Nd:YAG laser.We used a ceramic tip attached to a laser catheter most of the time and a bare laser fiber under angioscopy or a bare laser fiber itself to treat smaller arteries in the legs. Results: The initial success rate was 90%.The patency rates of PAD at 6 years are 91.4% (iliac artery) and 85.8% (femoropopliteal artery), and the patency rate of leg artery lesions is 100% at 5 years.Some clinical cases with long-term patency (6 and 30 years) will be introduced.Some fundamental experiments useful to the application of laser to atheroma or thrombi will be introduced. Conclusions: PTLA could be a useful option to treat occlusive PAD, because it can produce longterm patency of natural arteries, provided a proper lesion was selected. PMID- 29434427 TI - Picosecond Laser Treatment for Tattoos and Benign Cutaneous Pigmented Lesions (Secondary publication). AB - Background and aims: The selective removal of tattoos and benign cutaneous pigmented lesions with laser energy evolved rapidly with the development of the nanosecond-domain Q-switched laser (ns-laser). Recently, however, a series of picosecond-domain lasers (ps-lasers) with pulsewidths less than 1 ns has become commercially available, enabling more efficient and faster removal of pigmented lesions in the field of dermatologic laser surgery. Rationale behind the ps laser: The efficacy of the ns-laser depended on the theory of selective photothermolysis, whereby an extremely short pulse width was delivered less than the thermal relaxation time (TRT) of a target. At sub-ns pulsewidths, i.e. in the ps-domain, this efficacy is dramatically extended through defeating the stress relaxation time (SRT) of a target allowing for even more effective pigment destruction with even less damage to the surrounding normal tissue. This will be discussed in detail. Clinical applications: The ps-laser has been reported as achieving tattoo removal in fewer sessions than the ns-laser, with less in the way of unwanted side effects. Tattoos recalcitrant to ns-laser treatment have responded well to the ps-laser, and although true 'color blindness' is not yet completely achieved with the ps-domain pulses currently available, multicolored tattoos have also responded very favorably. The ability to limit damage precisely to the pigment target gives greater efficacy in treatment of epidermal lesions with less induction of post-inflammatory hyperpigmentation in the PIH-susceptible Asian skin, and dermal melanocytosis also respond very well to ps-laser treatment. Illustrative clinical examples from the author's experience are given. Conclusions: Current ps-lasers could be a revolutionary advance for laser tattoo removal but may be less effective for some specific aesthetic indications such as melasma and other cosmetic procedures. Manufacturers must make an effort to reduce the current comparatively long ps-domain pulsewidths to deliver a 'true' ps-domain laser, with more basic studies also being required to allow expansion of the safe and effective use of the ps-laser outside of tattoo removal. PMID- 29434428 TI - Evaluation of Endovenous Laser Ablation for Varicose Veins Using a Computer Simulation Model (Secondary publication). AB - Background and aims: Endovenous laser ablation (EVLA) has been well-reported as a minimally invasive method to deal with varices of the lower extremities. The lasers used fall into two categories: pigment, i.e., hemoglobin-specific lasers in the visible and near-infrared (near-IR) wavebands and longer wavelength mid infrared lasers where the chromophore is water. The fiber used to deliver the laser energy is also important, and not enough attention has been paid to this element of EVLA. The present study was therefore designed to compare EVLA delivered through two specific fiber types coupled with a near-IR laser wavelength where water was the major chromophore. Materials and methods: A laser diode system at the wavelength of 1470 nm was used as the laser energy source near a peak in the water absorption spectrum. Laser energy was delivered with two specific types of optical fiber, a RadialTM fiber and a Radial 2ringTM fiber (CeramOptec, Germany), and EVLA was evaluated using a computer simulation model taking light transport into account based on the Monte Carlo method and temperature distribution with the heat conduction equation. Results and conclusions: It was confirmed from both the simulation model and a previously published ex vivo experiment that carbonization and sticking during EVLA caused by excess temperature rise can be minimized by using the Radial 2ring fiber compared with the Radial fiber, coupled with the 1470 nm wavelength. In the future, lasers with different wavelengths or optical fibers with differing irradiation modes may appear as candidate systems for EVLA. It is important to evaluate safety and efficacy carefully using the methods in the present study before moving to in vivo indications in human subjects. PMID- 29434429 TI - Treatment of Carpal Tunnel Syndrome in pregnancy with Polarized Polychromatic Non coherent Light (Bioptron Light): A Preliminary, Prospective, Open Clinical Trial. AB - The aim of this trial was to assess the efficacy of polarized polychromatic noncoherent light (Bioptron light) in the treatment of Carpal Tunnel Syndrome (CTS) in pregnancy. An uncontrolled experimental study was conducted in pregnant patients with CTS who visited our clinic from January 2006 to January 2010. Bioptron light (480-3400 nm; 95% polarization; 40 mW/cm2; and 2.4 J/cm2) was administered perpendicular to the carpal tunnel area. The irradiation time for each session was 6 min at an operating distance of 5-10 cm from the carpal tunnel area, twice each day, five days per week for 2 weeks. Pain and paraesthesia using a visual analogue scale (VAS) and finger pinch strength were evaluated at the end of treatment (week 2) and 1-month (week 6) after the end of treatment. The Student'sttest was used and p values < 0.05 were accepted as statistically significant. 46 patients participated in the study. The mean age of subjects was 27.6 years (range 22-37). The patient population had a mean duration of CTS of 2.3 months (range 1-4). All patients were in the third trimester. Pain and paraesthesia decreased at the end of treatment and at the 1-month follow-up, whereas the finger pinch strength increased at the end of treatment and at the 1 month follow-up. In conclusion, the results of the present study suggest that Bioptron light is a reliable, safe, and effective treatment option in pregnant patients with CTS. Controlled clinical trials are needed to establish the absolute and relative effectiveness of this intervention. PMID- 29434430 TI - Microshear bond strength of self-adhesive composite to ceramic after mechanical, chemical and laser surface treatments. AB - Objectives: This study aimed to assess the microshear bond strength of a repairing self-adhesive flowable composite to ceramic after mechanical, chemical and laser treatment of the ceramic surface. Materials and Methods: Forty zirconia and forty feldspathic ceramic blocks measuring 8 x 8 x 2 mm were fabricated. Feldspathic blocks were divided into four groups of control (1), laser (2780 nm) (2), sandblasting + hydrofluoric (HF) acid + silane (3) and laser (2780 nm) + HF acid + silane (4). Zirconia blocks were also divided into four groups of control (1), laser (2780 nm) (2), sandblasting + Z-Prime Plus (3) and laser (2780 nm) + Z Prime Plus (4). Vertise Flow composite was bonded to treated ceramic surfaces as a repairing material, then the samples were subjected to 1000 thermal cycles. Repair bond strength was measured by Instron machine and data were analyzed using one-way ANOVA and post hoc test (P < 0.05). Results: Maximum and minimum bond strength values were observed in zirconia-control (22.57 +/- 4.76 MPa) and feldspathic-control (8.65 +/- 6.41 MPa) groups, respectively. There was no significant differences between subgroups within the zirconia or feldspathic groups (P > 0.05), however the bond strength of zirconia subgroups was significantly higher than that of feldspathic subgroups. Conclusion: Vertise Flow provides relatively good bond strength to ceramic even with no surface treatment. PMID- 29434431 TI - Venous malformations management by Er,Cr:YSGG laser: An Alternative approach. AB - Background and Aim: Venous malformations (VMs) are slow-flow vascular anomalies composed of ectatic venous channels. Its management with Er,Cr:YSGG laser has been proven effective. In the present case a teenage patient reported with a bluish lesion, soft inconsistency on the dorsal aspect of tongue. The lesion was removed with Er, Cr: YSGG laser (2780 nm) with minimal anaesthetic infiltration. Results: Patient reported no postoperative pain. Clinical follow up after three months showed excellent results and uneventful healing. Conclusion: Er,Cr:YSGG laser showed high clinical safety. Its advantages resulted in excellent healing of lesion and better acceptance by patient. PMID- 29434432 TI - Use of 1070 nm fiber lasers in oral surgery: preliminary ex vivo study with FBG temperature monitoring. AB - Background and Aims: The aim of this ex vivo study was to demonstrate the performances of 1070 nm fiber lasers for the ablation of oral tissues through the evaluation of the histological modifications made by a blind pathologist and the measurement of the thermal elevation during laser irradiation by a sensor based on a fiber Bragg grating. Materials and Methods: The source used was a pulsed fiber laser emitting at 1070 nm, with 20 W maximum average output power and 100 ns fixed pulse duration. Different tests were performed by changing the laser parameters, particularly the peak power of the pulses and the repetition rate. Results: The tissue of the measurements demonstrated that the best properties in term of cutting capability and, at the same time, the lower thermal damages to the tissues can be obtained with a peak power of 3 kW, a repetition rate of 50 kHz and a speed of 5 mm/s. Conclusions: This ex vivo study showed that 1070 nm fiber lasers can be very useful in oral surgery, since they provide a reduced thermal elevation in the irradiated tissues, thus consequently respecting their biological structures. Moreover, this work demonstrates that FBG sensors, based on the optical fiber technology as the laser source considered for the tests, may be good instruments to record thermal elevation when applied to the ex vivo studies on animal models. PMID- 29434434 TI - Retinopathy of prematurity: it is time to take action. PMID- 29434433 TI - Pediatric Multiple Sclerosis and Cognition: A Review of Clinical, Neuropsychologic, and Neuroradiologic Features. AB - Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease. Although cognitive impairment has been well established in adult patients with MS, its occurrence in patients with pediatric-onset MS has recently been reported. In this review, I discuss the main features of cognitive impairment in pediatric MS as determined by long-term follow-up studies, neuropsychiatric test batteries, and the results of neuroradiological imaging studies that investigated the pathogenesis of pediatric MS. The most commonly affected cognitive domains in adults are attention, processing speed, and visuomotor skills; language and intelligence are also affected in pediatric MS. A young age at disease onset is the strongest risk factor for these impairments, which may be due to the effect of inflammatory demyelination and neurodegeneration on the developing central nervous system and neural networks in children. Cognitive impairment has long-term effects on patients' academic life and the quality of their social life. Therefore, all patients with pediatric MS should be screened and monitored for cognitive impairment. This review also highlights the need for neuropsychological test batteries that assess different cognitive domains in children and adolescents with multiple sclerosis and for cognitive rehabilitation programs to improve the quality of their academic and social life. PMID- 29434436 TI - Preventing sight-threatening ROP: a neonatologist's perspective. PMID- 29434435 TI - How does ROP develop? PMID- 29434437 TI - Preventing sight-threatening ROP: the role of nurses in reducing the risk. PMID- 29434438 TI - Classifying retinopathy of prematurity. PMID- 29434439 TI - Screening for ROP. PMID- 29434440 TI - Treating ROP: how and when. PMID- 29434441 TI - Involving the parents of preterm babies. PMID- 29434442 TI - Following up children born preterm. PMID- 29434443 TI - Reaching remote Amazonian communities to eliminate trachoma. PMID- 29434444 TI - MicroRNA-146a Alleviates Experimental Autoimmune Anterior Uveitis in the Eyes of Lewis Rats. AB - Purpose: This study aimed to determine the effect and roles of microRNA (miRNA, miR) treatment in experimental autoimmune anterior uveitis (EAAU). Materials and Methods: Uveitis was induced in Lewis rats by simultaneous injections of bovine melanin-associated antigen into the hind footpad and the intraperitoneal cavity. The animals were injected intravitreally with low-dose (0.5 MUg) or high-dose (1.5 MUg) miR-146a. The clinical scores, leukocyte count in the aqueous humor, and histology were assessed. Cytokine changes were evaluated by relative mRNA expression and enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-kappaB) was assessed by immunofluorescence and Western blotting. Evaluation of the DNA-binding activity of NF-kappaB was performed by electrophoretic mobility shift assay (EMSA). Results: Treatment with miR-146a significantly attenuated clinical scores and leukocyte infiltration in a dose dependent manner, a result that was compatible with histological findings. Following miR-146a injections, downregulation of interleukin- (IL-) 1beta, IL-6, and IL-12 and interferon- (IFN-) gamma and upregulation of IL-10 and IL-17 were noted. The decreased NF-kappaB expression on immunofluorescence and Western blotting and reduced DNA-binding activity on EMSA were demonstrated following miR 146a treatment. Conclusions: miR-146a effectively reduced intraocular inflammation in EAAU through the inhibition of NF-kappaB. miR-146a might be a new treatment choice for uveitis. PMID- 29434446 TI - Hsa-miR-202-3p, up-regulated in type 1 gastric neuroendocrine neoplasms, may target DUSP1. AB - AIM: To detect abnormal microRNA (miRNA) expression in type 1 gastric neuroendocrine neoplasms (g-NENs) and find potential target genes. METHODS: Tumour tissues from patients with type 1 g-NENs were used as experimental samples, and gastric mucosal tissues from the same patients obtained during gastroscopy review after several months were used as control samples. miRNA expression was examined with Agilent human miRNA chips and validated via RT-PCR. Three types of target gene prediction software (TargetScan, PITA, and microRNAorg) were used to predict potential target genes of the differentially expressed miRNAs, and a dual-luciferase reporter assay system was used for verification. RESULTS: Six miRNAs were significantly upregulated or downregulated in the tumours compared to the control samples. Among them, miR-202-3p was extraordinarily upregulated. RT-PCR of seven sample sets confirmed that miR-202 3p was upregulated in tumour tissues. In total, 215 target genes were predicted to be associated with miR-202-3p. Among them, dual-specificity phosphatase 1 (DUSP1) was reported to be closely related to tumour occurrence and development. The dual-luciferase reporter assay showed that miR-202-3p directly regulated DUSP1 in 293T cells. CONCLUSION: miR-202-3p is upregulated in type 1 g-NEN lesions and might play important roles in the pathogenesis of type 1 g-NENs by targeting DUSP1. PMID- 29434447 TI - Enteral nutrition combined with glutamine promotes recovery after ileal pouch anal anastomosis in rats. AB - AIM: To assess the effect of enteral nutrition (EN) supplemented with glutamine on recovery after ileal pouch-anal anastomosis (IPAA) in rats, to provide an experimental basis for nutritional support in patients with ulcerative colitis (UC) after IPAA. METHODS: Male Sprague-Dawley (SD) rats were randomly divided into three groups (n = 8) after IPAA operation using a microsurgical technique. From the third postoperative day, rats in the control group, EN group, and immune nutrition (IN) group were fed standard rat chow, short peptide EN, and short peptide EN combined with glutamine ad libitum, respectively. The rats' general condition was observed throughout the study. Serum levels of total protein (TP), albumin (ALB), prealbumin (PA), and transferrin (TF) were detected on the 30th postoperative day, using an automatic biochemical analyzer. The ileal pouch mucosa was stained with hematoxylin and eosin (HE), and occludin protein levels were detected by immunohistochemistry. RESULTS: The body weight of rats in the EN group (359.20 +/- 10.06 g) was significantly higher than that in the control group (344.00 +/- 9.66 g) (P < 0.05) and lower than that in the IN group (373.60 +/- 9.86 g) (P < 0.05) on the 30th postoperative day. The levels of serum TP, ALB, PA, and TF in the EN group were significantly higher than those in the control group (P < 0.01 for all) and lower than those in the IN group (P < 0.05 for all). Histopathological score (EN: 0.80 +/- 0.37; IN: 0.60 +/- 0.40; control group: 2.29 +/- 0.18) and expression level of occludin protein (EN: 0.182 +/- 0.054; IN: 0.188 +/- 0.048; control group: 0.127 +/- 0.032) were significantly lower in the control group compared with the EN and IN groups (P < 0.05 for all), but there were no significant differences between the latter two groups (P > 0.05 for all). CONCLUSION: EN combined with glutamine may effectively improve nutritional status after IPAA. Our results suggest a benefit of glutamine supplementation in EN for UC patients undergoing IPAA, although human studies are required to confirm this finding. PMID- 29434445 TI - Behind the curtain of non-coding RNAs; long non-coding RNAs regulating hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers worldwide. HCC is the fifth common malignancy in the world and the second leading cause of cancer death in Asia. Long non-coding RNAs (lncRNAs) are RNAs with a length greater than 200 nucleotides that do not encode proteins. lncRNAs can regulate gene expression and protein synthesis in several ways by interacting with DNA, RNA and proteins in a sequence specific manner. They could regulate cellular and developmental processes through either gene inhibition or gene activation. Many studies have shown that dysregulation of lncRNAs is related to many human diseases such as cardiovascular diseases, genetic disorders, neurological diseases, immune mediated disorders and cancers. However, the study of lncRNAs is challenging as they are poorly conserved between species, their expression levels aren't as high as that of mRNAs and have great interpatient variations. The study of lncRNAs expression in cancers have been a breakthrough as it unveils potential biomarkers and drug targets for cancer therapy and helps understand the mechanism of pathogenesis. This review discusses many long non coding RNAs and their contribution in HCC, their role in development, metastasis, and prognosis of HCC and how to regulate and target these lncRNAs as a therapeutic tool in HCC treatment in the future. PMID- 29434448 TI - Promotion of Sema4D expression by tumor-associated macrophages: Significance in gastric carcinoma. AB - AIM: To study the role of semaphorin 4D (Sema4D) expression promoted by tumor associated macrophages (TAMs) in gastric carcinoma cells and its clinical significance in the invasion and metastasis of gastric carcinoma. METHODS: CD68 and Sema4D expression was analyzed in gastric carcinoma and adjacent normal tissues from 290 patients using the immunohistochemical streptavidin-peroxidase method, and their relationships with clinicopathological features were evaluated. Human M2 macrophages were induced in vitro and co-cultured in non-contact with gastric carcinoma SGC-7901 cells. Changes in the secretory Sema4D level in the SGC-7901 cell supernatant were measured using an enzyme-linked immunosorbent assay. The effects of TAMs on SGC-7901 cell invasion and migration were assessed with invasion and migration assays, respectively. RESULTS: CD68 and Sema4D protein expression was significantly higher in gastric carcinoma tissues than in adjacent normal tissues (71.7% vs 33.8% and 74.5% vs 42.8%, respectively; P < 0.01). CD68 and Sema4D protein expression was significantly associated with histological differentiation, TNM stage, and lymph node metastasis (P < 0.05), and their expression levels were positively correlated with one another (r = 0.467, P < 0.01). In the in vitro experiment, secretory Sema4D protein expression was significantly increased in the supernatant of SGC-7901 cells co-cultured with TAMs compared with the blank control (1224.13 +/- 29.43 vs 637.15 +/- 33.84, P < 0.01). Cell invasion and metastasis were enhanced in the Transwell invasion and migration assays (P < 0.01). CONCLUSION: TAMs promote the invasion and metastasis of gastric carcinoma cells possibly through upregulated secretory Sema4D protein expression. Combined detection of TAM markers, CD68 and Sema4D, in gastric carcinoma tissue shows potential to predict the trend of gastric carcinoma progression. PMID- 29434449 TI - Impact of SNP-SNP interactions of DNA repair gene ERCC5 and metabolic gene GSTP1 on gastric cancer/atrophic gastritis risk in a Chinese population. AB - AIM: To investigate the interactions of the DNA repair gene excision repair cross complementing group 5 (ERCC5) and the metabolic gene glutathione S-transferase pi 1 (GSTP1) and their effects on atrophic gastritis (AG) and gastric cancer (GC) risk. METHODS: Seven ERCC5 single nucleotide polymorphisms (SNPs) (rs1047768, rs2094258, rs2228959, rs4150291, rs4150383, rs751402, and rs873601) and GSTP1 SNP rs1695 were detected using the Sequenom MassARRAY platform in 450 GC patients, 634 AG cases, and 621 healthy control subjects in a Chinese population. RESULTS: Two pairwise combinations (ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) influenced AG risk (Pinteraction = 0.008 and 0.043, respectively), and the ERCC5 rs2094258-GSTP1 rs1695 SNP pair demonstrated an antagonistic effect, while ERCC5 rs873601-GSTP1 rs1695 showed a synergistic effect on AG risk OR = 0.51 and 1.79, respectively). No pairwise combinations were observed in relation to GC risk. There were no cumulative effects among the pairwise interactions (ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) on AG susceptibility (Ptrend > 0.05). When the modification effect of Helicobacter pylori (H. pylori) infection was evaluated, the cumulative effect of one of the aforementioned pairwise interactions (ERCC5 rs873601-GSTP1 rs1695) was associated with an increased AG risk in the case of negative H. pylori status (Ptrend = 0.043). CONCLUSION: There is a multifarious interaction between the DNA repair gene ERCC5 SNPs (rs2094258 and rs873601) and the metabolic gene GSTP1 rs1695, which may form the basis for various inter individual susceptibilities to AG. PMID- 29434450 TI - Incidence of hepatocellular carcinoma in patients with chronic liver disease due to hepatitis B or C and coinfected with the human immunodeficiency virus: A retrospective cohort study. AB - AIM: To assess the incidence of hepatocellular carcinoma (HCC) in chronic liver disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfected with human immunodeficiency virus (HIV). METHODS: A retrospective cohort study was performed, including patients with chronic liver disease due to HBV or HCV, with and without HIV coinfection. Patients were selected in the largest tertiary public hospital complex in southern Brazil between January 2007 and June 2014. We assessed demographic and clinical data, including lifestyle habits such as illicit drug use or alcohol abuse, in addition to frequency and reasons for hospital admissions via medical records review. RESULTS: Of 804 patients were included (399 with HIV coinfection and 405 monoinfected with HBV or HCV). Coinfected patients were younger (36.7 +/- 10 vs 46.3 +/- 12.5, P < 0.001). Liver cirrhosis was observed in 31.3% of HIV-negative patients and in 16.5% of coinfected (P < 0.001). HCC was diagnosed in 36 patients (10 HIV coinfected and 26 monoinfected). The incidence density of HCC in coinfected and monoinfected patients was 0.25 and 0.72 cases per 100 patient-years (95%CI: 0.12-0.46 vs 0.47 1.05) (long-rank P = 0.002), respectively. The ratio for the HCC incidence rate was 2.98 for HIV-negative. However, when adjusting for age or when only cirrhotic are analyzed, the absence of HIV lost statistical significance for the development of HCC. CONCLUSION: In this study, the presence of HIV coinfection in chronic liver disease due to HBV or HCV showed no relation to the increase of HCC incidence. PMID- 29434451 TI - Impaired granulocyte-macrophage colony-stimulating factor bioactivity accelerates surgical recurrence in ileal Crohn's disease. AB - AIM: To examine the relationship between elevated granulocyte-macrophage colony stimulating factor (GM-CSF) auto-antibodies (Ab) level and time to surgical recurrence after initial surgery for Crohn's disease (CD). METHODS: We reviewed 412 charts from a clinical database at tertiary academic hospital. Patients included in the study had ileal or ileocolonic CD and surgical resection of small bowel or ileocecal region for management of disease. Serum samples were analyzed for serological assays including GM-CSF cytokine, GM-CSF Ab, ASCA IgG and IgA, and genetic markers including SNPs rs2066843, rs2066844, rs2066845, rs2076756 and rs2066847 in NOD2, rs2241880 in ATG16L1, and rs13361189 in IRGM. Cox proportional hazards models were used to assess the predictors of surgical recurrence. RESULTS: Ninety six percent of patients underwent initial ileocecal resection (ICR) or ileal resection (IR) and subsequently 40% of patients required a second ICR/IR for CD. GM-CSF Ab level was elevated at a median of 3.81 mcg/mL. Factors predicting faster time to a second surgery included elevated GM-CSF Ab [hazard ratio (HR) 3.52, 95%CI: 1.45-8.53, P = 0.005] and elevated GM-CSF cytokine (HR = 2.48, 95%CI: 1.31-4.70, P = 0.005). Factors predicting longer duration between first and second surgery included use of Immunomodulators (HR = 0.49, 95%CI: 0.31 0.77, P = 0.002), the interaction effect of low GM-CSF Ab levels and smoking (HR = 0.60, 95%CI: 0.45-0.81, P = 0.001) and the interaction effect of low GM-CSF cytokine levels and ATG16L1 (HR = 0.65, 95%CI: 0.49-0.88, P = 0.006). CONCLUSION: GM-CSF bioavailability plays a critical role in maintaining intestinal homeostasis. Decreased bioavailability coupled with the genetic risk markers and/or smoking results in aggressive CD behavior. PMID- 29434452 TI - PIK3CA and TP53 mutations predict overall survival of stage II/III colorectal cancer patients. AB - AIM: To investigate the predictive value of PIK3CA and TP53 mutation status in colorectal cancer (CRC) patients treated with 5-fluorouracil-based chemotherapy. METHODS: In this study, a total of 315 patients with histologically proven CRC were enrolled from Yangpu Hospital affiliated to Shanghai Tongji University between 2007 and 2011. Of these patients, 241 with stage II/III CRC received 5 fluorouracil-based adjuvant chemotherapy. Formalin-fixed paraffin-embedded lesion samples of the patients with curatively resected CRC were collected. Next generation sequencing was performed to identify somatic gene mutations. The correlation of PIK3CA and TP53 mutation status with overall survival (OS) was analyzed using a Cox proportional hazard model and the Kaplan-Meier method. RESULTS: Among the 241 patients with stage II/III in this cohort, the PIK3CA and/or TP53 mutation was detected in 177 patients, among which 54 patients had PIK3CA and TP53 double mutations. The PIK3CA or TP53 mutation was not significantly correlated with OS in univariate and multivariate analyses. Compared with patients without PIK3CA and TP53 mutations, those with double PIK3CA-TP53 mutations showed a significantly worse survival (univariate HR = 2.21; 95%CI: 1.15-4.24; multivariate HR = 2.02; 95%CI: 1.04-3.91). The PIK3CA mutation located in the kinase domain showed a trend toward a shorter OS compared with wild-type tumors (multivariate HR = 1.56; 95%CI: 1.00-2.44; P = 0.052). The Kaplan-Meier curve showed that patients harboring the PIK3CA mutation located in the kinase domain had a worse clinical outcome than those with wild-type status (Log-rank P = 0.041). CONCLUSION: Double mutation of PIK3CA and TP53 is correlated with a shorter OS in stage II/III CRC patients treated with 5 fluorouracil-based therapy. PMID- 29434454 TI - Sequential spinal and intracranial dural metastases in gastric adenocarcinoma: A case report. AB - Dural metastasis from primary gastric adenocarcinoma has been rarely reported, and its prognosis is very poor because it frequently leads to acute subdural hematoma. Here, we describe a case with sequential spinal and cranial dural metastases from gastric adenocarcinoma without subdural hematoma. A 43-year-old woman with gastric adenocarcinoma and well-controlled peritoneal carcinomatosis presented with back pain, right radiating leg pain, left facial palsy, and hearing loss. Magnetic resonance imaging of the spine and brain revealed dural masses at the lumbosacral junction with invasion to the L5 and S1 nerve roots and at the skull base with invasion to the internal auditory canal. She was treated with local radiotherapy, and her pain and neurologic symptoms improved after palliative radiotherapy. This is the first reported case of dural metastases of gastric adenocarcinoma of the spine and skull base but with a relatively indolent course and without subdural hematoma. PMID- 29434453 TI - Faecal calprotectin and magnetic resonance imaging in detecting Crohn's disease endoscopic postoperative recurrence. AB - AIM: To assess magnetic resonance imaging (MRI) and faecal calprotectin to detect endoscopic postoperative recurrence in patients with Crohn's disease (CD). METHODS: From two tertiary centers, all patients with CD who underwent ileocolonic resection were consecutively and prospectively included. All the patients underwent MRI and endoscopy within the first year after surgery or after the restoration of intestinal continuity [median = 6 mo (5.0-9.3)]. The stools were collected the day before the colonoscopy to evaluate faecal calprotectin level. Endoscopic postoperative recurrence (POR) was defined as Rutgeerts' index >= i2b. The MRI was analyzed independently by two radiologists blinded from clinical data. RESULTS: Apparent diffusion coefficient (ADC) was lower in patients with endoscopic POR compared to those with no recurrence (2.03 +/- 0.32 vs 2.27 +/- 0.38 * 10-3 mm2/s, P = 0.032). Clermont score (10.4 +/- 5.8 vs 7.4 +/ 4.5, P = 0.038) and relative contrast enhancement (RCE) (129.4% +/- 62.8% vs 76.4% +/- 32.6%, P = 0.007) were significantly associated with endoscopic POR contrary to the magnetic resonance index of activity (MaRIA) (7.3 +/- 4.5 vs 4.8 +/- 3.7; P = 0.15) and MR scoring system (P = 0.056). ADC < 2.35 * 10-3 mm2/s [sensitivity = 0.85, specificity = 0.65, positive predictive value (PPV) = 0.85, negative predictive value (NPV) = 0.65] and RCE > 100% (sensitivity = 0.75, specificity = 0.81, PPV = 0.75, NPV = 0.81) were the best cut-off values to identify endoscopic POR. Clermont score > 6.4 (sensitivity = 0.61, specificity = 0.82, PPV = 0.73, NPV = 0.74), MaRIA > 3.76 (sensitivity = 0.61, specificity = 0.82, PPV = 0.73, NPV = 0.74) and a MR scoring system >= MR1 (sensitivity = 0.54, specificity = 0.82, PPV = 0.70, and NPV = 0.70) demonstrated interesting performances to detect endoscopic POR. Faecal calprotectin values were significantly higher in patients with endoscopic POR (114 +/- 54.5 MUg/g vs 354.8 +/- 432.5 MUg/g; P = 0.0075). Faecal calprotectin > 100 MUg/g demonstrated high performances to detect endoscopic POR (sensitivity = 0.67, specificity = 0.93, PPV = 0.89 and NPV = 0.77). CONCLUSION: Faecal calprotectin and MRI are two reliable tools to detect endoscopic POR in patients with CD. PMID- 29434455 TI - The Relationship Between Volitional Activation and Muscle Properties in Incomplete Spinal Cord Injury. AB - Purpose: Following a motor incomplete spinal cord injury (iSCI), there is decreased volitional activation and changes in composition, architecture, and stiffness of affected muscles. We investigated the relationship between muscle properties and volitional activation. Methods: The relationship between central activation ratio (CAR), maximum volitional torque (MVT), and muscle properties was assessed in the gastrocnemius of 6 participants with iSCI. Results: No significant relationship was found between CAR and muscle properties, while a significant relationship was found between CAR and MVT. Conclusion: Our findings suggest there may be no relationship between volitional activation and muscle; thus, certain patients with iSCI may benefit from therapies targeted at neural control. PMID- 29434456 TI - Does Neuromuscular Electrical Stimulation Therapy Increase Voluntary Muscle Strength After Spinal Cord Injury? A Systematic Review. AB - Background: Physical therapists frequently use neuromuscular electrical stimulation (NMES) therapy in an effort to increase the voluntary strength of partially paralyzed muscles in people with spinal cord injury (SCI), but it is not clear whether this treatment is effective. Objective: To determine the effectiveness of NMES for increasing voluntary strength in the partially paralyzed muscles of people with SCI. Methods: A systematic review of scientific literature was conducted in MEDLINE, CINAHL, PEDro, ScienceDirect, and Embase. Inclusion criteria were randomized controlled trials and controlled trials that compared NMES aimed at increasing strength in partially paralyzed muscles versus placebo/nothing or versus a nonstrengthening intervention or versus any other type of strengthening intervention in adults with SCI. Results: Five studies were included. Two studies found an increase in strength measured by peak force and manual muscle force test after an NMES protocol. One study found a between-group difference in favor of the NMES associated with progressive resistance training, and the other study showed an increase in the number of muscles improved by at least 1 degree of strength after NMES in combination with a cycle ergometer. The other 3 studies made several comparisons and found no differences between groups that received NMES and the controls. Conclusions: There is some suggestion that NMES increases voluntary strength in partially paralyzed muscle following SCI. However, there is no strong evidence to affirm the superiority of NMES over other treatment strategies used to gain strength in partially paralyzed muscles after SCI. These findings need replicating in large high-quality randomized controlled trials. PMID- 29434457 TI - Role and Significance of Trunk and Upper Extremity Muscles in Walker-Assisted Paraplegic Gait: A Case Study. AB - Background and Purpose: Understanding the role and significance of trunk and upper extremity muscles in paraplegic gait can help in designing more effective assistive devices for these patients and also provides valuable information for improving muscle strengthening programs. Methods: In a patient with a spinal cord injury (SCI) who could walk independently (rating scale of ambulatory capacity, 9) with the aid of bilateral ankle-foot orthosis and a walker, the kinematics, kinetics and electromyographic (EMG) activities of 16 muscles from the trunk and upper and lower extremities were recorded during gait. The onset, cessation, and duration of the EMG signal were associated with the 4 phases of each step, distinguished based on the kinematics results. Results: It was found that the reciprocating activation pattern of the quadratus lumborum, latissimus dorsi, pectoralis major, and lower trapezius is responsible for trunk extension during the balance adjustment phase, leg unload and foot clearance creation during the leg raising phase, and propulsion force generation during the leg swing phase. Conclusion: The continuous activation of the rectus abdominis and erector spinae within the gait cycle helps stabilize the thorax and acts in reverse, that is, fixes the proximal joint and moves the distal limb. The shoulder girdle muscles contribute to the leg's unloading and then smooth landing during leg raising and leg swing phases, respectively. PMID- 29434458 TI - Assessing Heart Rate Variability As a Surrogate Measure of Cardiac Autonomic Function in Chronic Traumatic Spinal Cord Injury. AB - Background: Although cardiac autonomic dysfunction is a contributing factor for cardiovascular disease development in individuals with a spinal cord injury (SCI), it remains poorly understood. Heart rate variability (HRV) analysis has the potential to non-invasively assess the cardiac autonomic nervous system. The study objectives are (a) to determine if there are differences in HRV measures across neurological level of impairment (NLI) and American Spinal Cord Injury Association Impairment Scale (AIS) subgroups, and (b) to determine if there is a relationship between HRV frequency measures (low frequency [LF] and high frequency [HF]) at rest. Methods: We conducted a secondary data analysis of a primary data set from a published cross-sectional study of electrocardiogram recordings of 56 subjects (44 men and 12 women, mean age +/- SD = 46.75 +/- 12.44 years) with a chronic traumatic SCI (C1-T12, AIS A-D, >=2 years post injury). HRV was analyzed using time and frequency domain measures. Results: There were no significant HRV differences across NLI and AIS subgroups. The LF and HF indices were positively correlated in the entire sample (r = 0.708, p < .0001) and among impairment subgroups. Conclusion: No differences were observed in the HRV time and frequency measures when compared across NLI and AIS subgroups. The results were considered inconclusive, since possible explanations include inadequate sample size as well as other physiological considerations. A positive correlation was found between LF and HF when assessed at rest. The relationship between LF and HF may not necessarily represent a rebalanced autonomic nervous system, but it does question the utility of solely measuring LF:HF at rest in persons with chronic SCI. PMID- 29434459 TI - Are Comorbid Pain and Depressive Symptoms Associated with Rehabilitation of Individuals with Spinal Cord Injury? AB - Objective: To examine the difference in functional outcomes and therapy intensity among individuals with spinal cord injury (SCI) with comorbid depression and pain symptoms compared to those without these symptoms. Methods: A retrospective chart review was conducted of 100 patients admitted to a specialized SCI inpatient rehabilitation unit. Standard demographic factors were collected. Patients were divided into 2 groups: those with comorbid depression and pain symptoms and those without. Outcomes were compared between the 2 groups using analysis of covariance (ANCOVA). Age, gender, level of injury, severity of injury, and FIM(r) admission were included in the model as covariates. Main outcomes included FIM(r) discharge, length of stay (LOS), intensity of therapy (total physical therapy time [PTt] and total occupational therapy time [OTt]), living arrangement, and vocational status. Results: No significant difference was seen between the 2 groups in FIM(r) discharge or OTt; however, those in the comorbidity group required significantly greater PTt than those without (p = .002). Those in the comorbid group also spent longer in inpatient rehabilitation (p = .005). The groups did not differ in postdischarge living arrangements or vocational status. Conclusion: Inpatient rehabilitation physical therapy and LOS differ substantially among individuals with comorbid depression and pain symptoms. This comorbidity may have a negative impact on functional recovery such that individuals may require more physical therapy time and longer LOS. This may also point to the increased resources required to manage individuals with SCI and comorbid depression and pain symptoms. PMID- 29434460 TI - Relationship Between Comorbidities and Employment Among Veterans with Spinal Cord Injury. AB - Objective: To determine the relationship between medical and mental health comorbidities in a large cohort of veterans with spinal cord injury (SCI). Methods: Data were collected from interviews and electronic medical records of veterans with SCI (N = 1,047) who received care at 7 geographically diverse SCI centers within the Department of Veterans Affairs across the country (https://clinicaltrials.gov/ct2/show/NCT01141647). Employment, medical, functional, and psychosocial data underwent cross-sectional analysis. Results: Lack of any documented mental health diagnosis correlated strongly with being employed at the time of enrollment. No single comorbidity was associated with employment at enrollment, but an increased number of medical and/or mental health comorbidities ("health burden") were associated with a decreased likelihood of employment at the time of enrollment. Conclusion: Further investigation is needed to clarify whether comorbidity severity or combinations of specific comorbidities predict rehabilitation outcome, including employment. PMID- 29434461 TI - Emotional Consequences of Delays in Spinal Rehabilitation Unit Admission or Discharge: A Qualitative Study on the Importance of Communication. AB - Objective: To explore the influence of health communications on the emotional consequences of delays in transfer from acute hospital into a spinal rehabilitation unit (SRU) or delays in discharge from SRU. Methods: Semi structured interviews were conducted in this exploratory, thematic qualitative research design in an SRU, Melbourne, Australia. Results: Six patients experienced delay in admission to (n = 4) or discharge from (n = 3) the SRU, with one person experiencing both an admission and discharge delay. Median admission delay was 41.5 days, primarily related to bed availability and staffing issues. Participants experiencing a delay in transfer from the acute hospital reported feelings of uncertainty, frustration, disappointment, and concern due to a perception that their functional recovery was compromised because of delayed access to specialist rehabilitation. Psychological issues were less common than emotional responses. One participant spent some of the delay period waiting for admission to the SRU in a non-spinal rehabilitation unit and reported no concerns about his recovery. Median discharge delay was 27 days, largely due to a wait in obtaining funding for equipment. Emotional and psychological responses to delayed discharge, particularly frustration, appeared to be influenced by having a sense of control over the discharge process. Conclusion: Patients' experiences during the delay periods partially mitigated the emotional and psychological consequences of a delayed admission or discharge on their psychological well being. Locus of control, where participants reported being able to effect some influence on their situation, appeared to moderate their emotional state. The findings suggest that clinicians can draw on the concept of control to better support patients through periods of delay. PMID- 29434462 TI - Comparison of High-Strength Aluminum Ultralight Wheelchairs Using ANSI/RESNA Testing Standards. AB - Background: The use of ultralight manual wheelchairs has been shown to benefit wheelchair users when compared to other types. New aluminum alloy frame materials coming to the market have not been independently evaluated for durability and cost benefit. Methods: Three 70XX aluminum ultralight wheelchair models were tested and compared based on dimensions, stability, and durability using the ANSI/RESNA standards. The results were also compared to previous manual wheelchair studies. Results: This study found that there were no significant cost benefit or durability differences between the wheelchairs tested and previous aluminum or titanium ultralight rigid models. Additionally, 5 of the 9 wheelchairs tested failed to meet the minimum ANSI/RESNA requirements for durability. Conclusion: These results are similar to results from previous rigid ultralight wheelchair studies and indicate that the quality of wheelchairs of this type has not improved and better requirements are necessary for wheelchairs marketed in the United States. PMID- 29434463 TI - Initial Outcomes from a Multicenter Study Utilizing the Indego Powered Exoskeleton in Spinal Cord Injury. AB - Objective: To assess safety and mobility outcomes utilizing the Indego powered exoskeleton in indoor and outdoor walking conditions with individuals previously diagnosed with a spinal cord injury (SCI). Methods: We conducted a multicenter prospective observational cohort study in outpatient clinics associated with 5 rehabilitation hospitals. A convenience sample of nonambulatory individuals with SCI (N = 32) completed an 8-week training protocol consisting of walking training 3 times per week utilizing the Indego powered exoskeleton in indoor and outdoor conditions. Participants were also trained in donning/doffing the exoskeleton during each session. Safety measures such as adverse events (AEs) were monitored and reported. Time and independence with donning/doffing the exoskeleton as well as walking outcomes to include the 10-meter walk test (10MWT), 6-minute walk test (6MWT), Timed Up & Go test (TUG), and 600-meter walk test were evaluated from midpoint to final evaluations. Results: All 32 participants completed the training protocol with limited device-related AEs, which resulted in no interruption in training. The majority of participants in this trial were able to don and doff the Indego independently. Final walking speed ranged from 0.19 to 0.55 m/s. Final average indoor and outdoor walking speeds among all participants were 0.37 m/s (SD = 0.08, 0.09, respectively), after 8 weeks of training. Significant (p < .05) improvements were noted between midpoint and final gait speeds in both indoor and outdoor conditions. Average walking endurance also improved among participants after training. Conclusion: The Indego was shown to be safe for providing upright mobility to 32 individuals with SCIs who were nonambulatory. Improvements in speed and independence were noted with walking in indoor and outdoor conditions as well as with donning/doffing the exoskeleton. PMID- 29434465 TI - Foreword. PMID- 29434464 TI - Arm Cycling Combined with Passive Leg Cycling Enhances VO2peak in Persons with Spinal Cord Injury Above the Sixth Thoracic Vertebra. AB - Objective: To test whether passive leg cycling (PLC) during arm cycling ergometry (ACE) affects peak oxygen uptake (VO2peak) differently in individuals with spinal cord injury (SCI) at/above the 6th thoracic vertebra (T6) and below T6. Methods: We conducted a cross-sectional study, analyzed by univariate and multivariate regression models. Between- and within-group differences were examined during (a) ACE only, (b) ACE combined with PLC (ACE-PLC), and (c) ACE combined with functional electrical stimulation cycling (FES hybrid). Fifteen SCI subjects were recruited and grouped according to injury level: at/above T6 (SCI-high, n = 8) or below T6 (SCI-low, n = 7). VO2peak tests during ACE only, ACE-PLC, and FES hybrid were performed in random order on separate days. Results: In the SCI-high group, mean (SD) VO2peak was 19% higher during ACE-PLC than during ACE only [21.0 (3.8) vs 17.7 (5.0) mL.kg-1.min-1; p = .002], while VO2peak during FES hybrid cycling was 16% higher than during ACE-PLC [24.4 (4.1) mL.kg-1.min-1; p = .001]. No significant differences among exercise modalities were found for the SCI-low group. Conclusion: Additional training modalities (eg, PLC) during ACE facilitate exercise in SCI-high individuals, but not to the level of the FES hybrid method. Conversely, additional training modalities may not increase training load in SCI low individuals. PMID- 29434467 TI - Genomic Analysis Using Regularized Regression in High-Grade Serous Ovarian Cancer. AB - High-grade serous ovarian cancer (HGSOC) is a complex disease in which initiation and progression have been associated with copy number alterations, epigenetic processes, and, to a lesser extent, germline variation. We hypothesized that, when summarized at the gene level, tumor methylation and germline genetic variation, alone or in combination, influence tumor gene expression in HGSOC. We used Elastic Net (ENET) penalized regression method to evaluate these associations and adjust for somatic copy number in 3 independent data sets comprising tumors from more than 470 patients. Penalized regression models of germline variation, with or without methylation, did not reveal a role in HGSOC gene expression. However, we observed significant association between regional methylation and expression of 5 genes (WDPCP, KRT6C, BRCA2, EFCAB13, and ZNF283). CpGs retained in ENET model for BRCA2 and ZNF283 appeared enriched in several regulatory elements, suggesting that regularized regression may provide a novel utility for integrative genomic analysis. PMID- 29434468 TI - Analysis of Conserved, Computationally Predicted Epitope Regions for VP5 and VP7 Across three Orbiviruses. AB - Orbiviruses are double-stranded RNA viruses that have profound economic and veterinary significance, 3 of the most important being African horse sickness virus (AHSV), bluetongue virus (BTV), and epizootic hemorrhagic disease virus (EHDV). Currently, vaccination and vector control are used as preventative measures; however, there are several problems with the current vaccines. Comparing viral amino acid sequences, we obtained an AHSV-BTV-EHDV consensus sequence for VP5 (viral protein 5) and for VP7 (viral protein 7) and generated homology models for these proteins. The structures and sequences were analyzed for amino acid sequence conservation, entropy, surface accessibility, and epitope propensity, to computationally determine whether consensus sequences still possess potential epitope regions. In total, 5 potential linear epitope regions on VP5 and 11 on VP7, as well as potential discontinuous B-cell epitopes, were identified and mapped onto the homology models created. Regions identified for VP5 and VP7 could be important in vaccine design against orbiviruses. PMID- 29434469 TI - Breast Cancer Survivors, Common Markers of Inflammation, and Exercise: A Narrative Review. AB - Exercise may help positively improve inflammatory marker levels, therefore promoting better outcomes in breast cancer survivors. This narrative review is intended to provide an overview between inflammation and breast cancer, in addition to the effects exercise may have on common inflammatory markers that have been examined in both healthy populations and breast cancer survivors throughout the literature. The inconsistencies and gaps in the literature addressed may be important for future research to further understand the relationship between exercise and inflammation, as well as the underlying biological mechanisms that are responsible for these changes. For the purpose of organization, this review is structured into the following sections: (1) Breast Cancer Facts, Treatment-Related Side Effects, and General Exercise Benefits; (2) Effects of Exercise on Markers of Inflammation in Cancer-Free Populations; (3) Cancer and Markers of Inflammation; (4) Effects of Exercise on Markers of Inflammation in Breast Cancer Survivors; and (5) Conclusions. PMID- 29434471 TI - Prognostic Significance of Low Claudin3 Expression in Luminal Breast Cancers. AB - Aim: To study the prognostic value of immunohistochemically detected low Claudin3 expression in breast cancers. Methods: This retrospective study included patients with breast cancer who were investigated at our unit from 2006 to 2015. Tissue microarrays were constructed, and immunohistochemical staining was done to assess the Claudin3 expression and to classify breast cancers according to the immunohistochemical surrogates for molecular classification. Kaplan-Meier model and log-rank test were used for recurrence-free survival and breast cancer specific survival analysis. Results: Of the 853 patients, overall low expression of Claudin3 was seen in 18.4%. Recurrence-free survival of patients with overall low Claudin3 breast cancers was poor in luminal A (P = .006) and luminal B (Her2 ) (P = .009) subtypes compared with those who had Claudin3 expression in each group. Conclusions: Assessment of Claudin3 expression by immunohistochemistry is suggested for luminal A and luminal B (Her2-) subtypes to identify patients with poor prognosis. PMID- 29434470 TI - Cognitive Behavioral Therapy for Insomnia, Mindfulness, and Yoga in Patients With Breast Cancer with Sleep Disturbance: A Literature Review. AB - The number of patients with breast cancer diagnosed with sleep disturbance has grown substantially within the United States over the past 20 years. Meanwhile, there have been significant improvements in the psychological treatment of sleep disturbance in patients with breast cancer. More specifically, cognitive behavioral therapy for insomnia (CBT-I), mindfulness, and yoga have shown to be 3 promising treatments with varying degrees of benefit, supporting data, and inherent limitations. In this article, we will outline the treatment approach for sleep disturbance in patients with breast cancer and conduct a comprehensive review of CBT-I, mindfulness, and yoga as they pertain to this patient population. PMID- 29434472 TI - Vitamin D and Breast Cancer: Latest Evidence and Future Steps. AB - Vitamin D (the sunshine vitamin) plays a vital role in calcium homeostasis, skeletal metabolism, and immune, cardiovascular, and reproductive systems' functions. The worldwide prevalence of vitamin D deficiency is approximately 1 billion. Vitamin D deficiency is a serious health problem with numerous health consequences; it is associated with diabetes, rheumatic arthritis, Parkinson, Alzheimer diseases, osteomalacia, osteoporosis, and fractures in adults and cancers. Many reports showed an inverse association between serum vitamin D concentration and incidence of several cancers, including breast, colorectal, kidney, lung, and pancreatic. About 20 different cancers have incidence rates inversely related to solar UV-B doses and serum vitamin D concentration. Considering the rising incidence of breast cancer and high prevalence of vitamin D deficiency, this review aimed to reflect an association between serum vitamin D concentration and breast cancer risk, reveal the link between vitamin D receptor genetic polymorphisms and breast cancer risk, and review the relationship between vitamin D level, breast cancer risk, and prognostic factors such as tumor stage, grade, size, lymph node involvement, and hormone receptor status. PMID- 29434473 TI - TRAIL-Induced Apoptosis in TRAIL-Resistant Breast Carcinoma Through Quercetin Cotreatment. AB - Breast cancer is the most commonly diagnosed cancer in women. There is a continued interest for the development of more efficacious treatment regimens for breast carcinoma. Recombinant human tumor necrosis factor-related apoptosis inducing ligand (rhTRAIL) shows potential as a potent anticancer therapeutic for the treatment of breast cancer, whereas displaying minimal toxicity to normal cells. However, the promise of rhTRAIL for the treatment of breast cancer is dismissed by the resistance to rhTRAIL-induced apoptosis exhibited by many breast cancers. Thus, a cotreatment strategy was examined by applying the natural compound quercetin (Q) as a sensitizing agent for rhTRAIL-resistant breast cancer BT-20 and MCF-7 cells. Quercetin was able to sensitize rhTRAIL-resistant breast cancers to rhTRAIL-induced apoptosis as detected by Western blotting through the proteasome-mediated degradation of c-FLIPL and through the upregulation of DR5 expression transcriptionally. Overall, these in vitro findings establish that Q is an effective sensitizing agent for rhTRAIL-resistant breast cancers. PMID- 29434474 TI - Suppression of Breast Cancer Cell Proliferation by Selective Single-Domain Antibody for Intracellular STAT3. AB - Background: The serendipitous discovery of heavy-chain antibodies devoid of light chains in camelids and the subsequent development of VHHs (variable region of camelid heavy chain) have provided a very important tool for research and possibly for therapeutics. In this study, we synthesized single-domain 15-kDa antibody SBT-100 (anti-STAT3 B VHH13) against human STAT3 (signal transducer and activator of transcription) that binds selectively to STAT3 and suppresses the function of phosphorylated STAT3 (p-STAT3). Methods: Single-chain VHH nanobodies were generated by immunizing camelid with humanized STAT3. Commercially available breast cancer cell lines including MDA-MB-231, MDA-MB-468, MDA-MB-453, MCF-7, and BT474 were used. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide assay. The association of anti-STAT3 B VHH13 with STAT3 and p-STAT3 was determined by immunoprecipitation and Western blot analyses. The efficacy of SBT-100 on the growth of MDA-MB-231 xenografts in vivo was determined using athymic mice. Statistical significance for cell proliferation was determined using analysis of variance. If a significant difference (P < .05) was observed, then Tukey-Kramer multiple comparison test was conducted. Results: SBT-100 suppressed cell proliferation of triple-negative breast cancer cells (P < .01) as well as provided significant inhibition of tumor growth (P < .05) in a xenograft model without any toxicity. Results are presented to show that anti-STAT3 B VHH13 selectively binds to STAT3 suggesting that the effects were mediated by inhibiting STAT3. Conclusions: A very large number of human malignancies and benign diseases have constitutive STAT3 activation. Therefore, the results described here suggest that anti-STAT3 B VHH13 can be developed for therapeutic intervention for cancer cells expressing STAT3 or p STAT3. PMID- 29434475 TI - Delays in Breast Cancer Detection and Treatment in Developing Countries. AB - Breast cancer is the most common cancer in women in both developed and developing countries and the second most common cancer in the world. Developing countries are increasingly adopting a Western lifestyle, such as changes in diet and delayed first childbirth, lower parity, and shorter periods of breastfeeding, which are important determinants of a higher incidence of breast cancer among those regions. Low- and middle-income countries (LMICs) represent most of the countries with the highest mortality rates, ranging from 40% to 60%. Furthermore, developing countries account for scarce survival data, and the few data available coincide with the observed incidence and mortality differences. Five-year survival rates for breast cancer are much worse for LMICs countries such as Brazil, India, and Algeria in comparison with the United States and Sweden. Paucity of early detection programs explain these poor survival rates, which results in a high proportion of women presenting with late-stage disease, along with lack of adequate diagnosis and treatment facilities. Emphasis is urgently needed on health education, to promote early diagnosis of breast cancer, highlighting the importance of creating more public facilities that provide treatment, which are key components for the improvement in breast cancer care in developing countries. PMID- 29434476 TI - Interest of Supportive and Barrier Protective Skin Care Products in the Daily Prevention and Treatment of Cutaneous Toxicity During Radiotherapy for Breast Cancer. AB - Purpose: As many as 50% of patients with cancer develop acute skin reactions to some degree with radiotherapy. Proactive skin care is often recommended to minimise these skin reactions and maintain the integrity of the epidermal barrier; nevertheless, no consensual guidelines are systematically used. This multicentre, observational, prospective study evaluated the tolerability and benefit of supportive and barrier protective skin care products in preventing radiotherapy-induced skin reactions in 253 women initiating radiotherapy (exclusive or adjuvant) for breast cancer. Methods: Patients received a kit of 5 commercially available skin care products before the first radiotherapy treatment. The following variables were assessed: cutaneous adverse events, investigator-assessed skin reactions (oedema, erythema, dryness, desquamation) before and after radiotherapy course, investigator, and patient opinion on products benefit. Results were analysed by frequency of product use (heavy versus low). Results: Average age was 60 years (range: 34-85). Over 92% of patients reported good to excellent tolerance on irradiated skin for each product. During the 6-week radiotherapy period, we observed that heavy product users had less skin reactions than the low users, particularly within 10 days of radiotherapy initiation (8% versus 18%; p = .031). Positive physician's opinion on product use was more frequent for high (66.6%) versus low (32%) users. Patient-assessed patient benefit index was generally >1, indicating relevant treatment benefit, with a tendency for better benefit in high versus low users. Conclusions: These results support recommendations to use skin care products to minimise the impact of secondary cutaneous reactions with radiotherapy cancer treatment. PMID- 29434477 TI - High Burden of Human Papillomavirus Infection in Madagascar: Comparison With Other Sexually Transmitted Infections. AB - Background: In Madagascar, human papillomavirus (HPV), human immunodeficiency virus (HIV), and hepatitis B virus (HBV) infection, as well as syphilis share common risk factors but seem to differ in their prevalence. We measured and compared their prevalence in the country. Methods: The data used in this study came from the Saint Damien Health Centre in Ambanja, Madagascar. The tests used for disease detection were the Alere Determine, Virucheck, rapid plasma reagin, and S-DRY self-HPV samples for HIV infection, HBV infection, syphilis, and HPV infection, respectively. Results: In men and women, respectively, the prevalence was 0.6% and 0.4% for HIV infection, 2.2% and 2.0% for HBV infection, and 0.6% and 0.3% for syphilis. The HPV infection prevalence was 39.3%. Conclusions: Despite common risk factors, the prevalence of HPV infection was high, in contrast to a much lower prevalence of other sexually transmitted infections (STIs) in the same geographical area. Further investigations are required to clarify the status of STIs in the Malagasy population. PMID- 29434478 TI - Neisseria gonorrhoeae-Induced Inflammatory Pyroptosis in Human Macrophages is Dependent on Intracellular Gonococci and Lipooligosaccharide. AB - Neisseria gonorrhoeae, the human obligate pathogen responsible for the sexually transmitted disease gonorrhea, has evolved several mechanisms to evade the host immune response. One such mechanism is the modulation of host cell death pathways. In this study, we defined cell death pathways induced by N gonorrhoeae in human monocyte-derived macrophages (MDMs). In a dose-dependent manner, N gonorrhoeae stimulation of MDMs resulted in caspase 1 and 4-dependent cell deaths, indicative of canonical and noncanonical pyroptosis, respectively. Internalization of bacteria or stimulation with lipooligosaccharide (LOS) specifically induced pyroptosis in MDMs and increased secretion of IL-1beta. Collectively, our results demonstrate that N gonorrhoeae induces inflammatory pyroptosis in human macrophages due in part to intracellular LOS. We propose that this in turn may exacerbate inflammatory outcomes observed during mucosal infection. PMID- 29434480 TI - A Rare Presentation of Neuromyelitis Optica Spectrum Disorders. AB - Neuromyelitis optica spectrum disorders (NMOSDs) are a set of demyelinating disorders that primarily target the optic nerves and the spinal cord. Previously thought to be a subset of multiple sclerosis (MS), now is recognized as a distinct entity. We present a 59-year-old female patient who was admitted for acute upper and lower extremity weakness. The patient had woken up from sleep with sudden onset of weakness. Patient was initially diagnosed with a right hemispheric stroke; however, magnetic resonance imaging of the cervical spine later performed showed abnormal enhancement from C2-C4, representing transverse myelitis. Cerebrospinal fluid was negative for organisms and inflammatory biomarkers. An anti-aquaporin-4 receptor antibody titer was found to be elevated with titers >80 units/mL. The patient was treated with high-dose steroids and plasmapheresis. The NMOSD is a rare entity and, here, we present a rare presentation of the disease. Since its description in 1870, it was confused with MS for years. The advent of anti-aquaporin-4 antibody has been instrumental in differentiating the disease process from MS. This distinction is important, in terms of agents used for treatment and prognostication. The NMOSD is a set of debilitating disease, which requires prompt recognition and appropriate treatment, to avoid the disabling sequelae. Future prospects of the disease include development of novel biological treatment modalities which focus on restoring the loss of immune tolerance which is key to the pathogenesis of the disease. PMID- 29434481 TI - Hodgkin Lymphoma: Differences in Treatment Between Europe and the United States/North America: Evolving Trends in Protocol Therapy. AB - With continued progress and success in clinical care, the management of patients with Hodgkin lymphoma (HL) has undergone continuous revision to improve patient care outcomes and limit acute and late treatment effects on normal tissue imposed by therapy. Hodgkin lymphoma is a disease that affects children, adolescents, and adults. Clinical management strategies are influenced by the patient's age at diagnosis, tumor burden, response to induction therapy, and potential expectation of treatment impact on normal tissue. The approach to patient management varies in many parts of the world and is influenced by treatment availability, physician training, and medical culture. Differences in approach are important to understand for accurately comparing and contrasting outcome studies. In this article, we will identify current areas of common ground and points of separation in patient care management for HL. Opportunities for clinical trial strategies will be defined for future clinical trials. PMID- 29434479 TI - Osteoarthritis and the Complement Cascade. AB - Accumulating evidence demonstrates that complement activation is involved in the pathogenesis of osteoarthritis (OA). However, the intimate complement regulation and cross talk with other signaling pathways in joint-associated tissues remain incompletely understood. Recent insights are summarized and discussed here, to put together a more comprehensive picture of complement involvement in OA pathogenesis. Complement is regulated by several catabolic and inflammatory mediators playing a key role in OA. It seems to be involved in many processes observed during OA development and progression, such as extracellular cartilage matrix (ECM) degradation, chondrocyte and synoviocyte inflammatory responses, cell lysis, synovitis, disbalanced bone remodeling, osteophyte formation, and stem cell recruitment, as well as cartilage angiogenesis. In reverse, complement can be activated by various ECM components and their cleavage products, which are released during OA-associated cartilage degradation. There are, however, some other cartilage ECM components that can inhibit complement, underlining the diverse effects of ECM on the complement activation. It is hypothesized that complement might also be directly activated by mechanical stress, thereby contributing to OA. The question arises whether keeping the complement activation in balance could represent a future therapeutic strategy in OA treatment and in the prevention of its progression. PMID- 29434482 TI - Clinical Outcome of Noncardiac Surgery in Patients With History of Coronary Artery Revascularization by Percutaneous Coronary Intervention Versus Coronary Artery Bypass Graft Surgery. AB - Objective: Although safety concerns still remain among patients undergoing unanticipated noncardiac surgery after prior percutaneous coronary intervention (PCI), it has not been directly compared with coronary artery bypass grafting (CABG). The objective of this study was to compare clinical outcomes after noncardiac surgery in patients with prior (>6 months) coronary revascularization by PCI or CABG. Methods: From February 2010 to December 2015, 413 patients with a history of coronary revascularization, scheduled for noncardiac surgery were identified. Patients were divided into PCI group and CABG group and postoperative clinical outcome was compared between 2 groups. The primary outcome was composite of all-cause death, myocardial infarction, and stroke in 1-year follow-up. Results: The 413 patients were divided according to prior coronary revascularization types: 236 (57.1%) into PCI and 177 (42.9%) into CABG group. In multivariate analysis within 1-year follow-up, there was no significant difference in clinical outcome which was composite of all-cause death, myocardial infarction, and stroke (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 0.76-2.93; P = .24). The same result was present in propensity-matched population analysis (HR: 1.43; 95% CI: 0.68-3.0; P = .34). Conclusions: In patients undergoing noncardiac surgery with prior coronary revascularization by PCI or CABG performed on an average of 42 months after PCI and 50 months after CABG, postoperative clinical outcome at 1-year follow-up is comparable. PMID- 29434483 TI - Chemoradiotherapy With Generic Cisplatin Formulations for Head and Neck Cancers. AB - The use of generic drugs has been increasing. However, studies of the safety of generic cisplatin (CDDP) for the treatment of head and neck cancer (HNC) have not been reported. This study investigated the treatment completion rates and incidence of CDDP-related adverse events in patients with advanced HNC treated with concurrent chemoradiotherapy (CRT) using generic CDDP. This study included 72 patients who received concurrent CRT using generic CDDP. The number of courses of CDDP was 3 in 45 patients, 2 in 19 patients, and 1 in 8 patients. During 154 courses of 80 mg/m2 generic CDDP, grade 3/4 leukopenia in 21 (14%), neutropenia in 18 (12%), and hypochromia in 8 (5%) cases were reported. Grade 2 elevated serum creatinine occurred in 4 cases (3%), but no grade 3/4 elevated serum creatinine was reported. These results suggest that CRT using generic CDDP is well tolerated in patients with HNC. PMID- 29434485 TI - First records of the uristid lysianassoids from Korean waters: redescription of Anonyx abei Takekawa & Ishimaru, 2001 and description of Anonyx exilipes sp. n. (Crustacea, Amphipoda, Uristidae). AB - The uristid lysianassoids are reported for the first time from Korean waters with a redescription of Anonyx abei Takekawa & Ishimaru, 2001 and the description of Anonyx exilipessp. n.Anonyx abei is characterized by a distinctively small projection of the posterodistal corner on epimeron 3, different from all species of the Anonyx nugax group which share a constriction at the point of insertion of a distal seta on the inner ramus of uropod 2. Anonyx exilipessp. n. is included in the Anonyx laticoxae group characterized by the unconstricted inner ramus of uropod 2. This new species is distinguished from other A. laticoxae group species by the longer and more slender carpus and propodus of pereopod 6, and the non lobate merus of pereopod 7. PMID- 29434484 TI - Bacterial Pneumonia in Elderly Japanese Populations. AB - Bacterial pneumonia is one of the most important infectious diseases in terms of incidence, effect on quality of life, mortality, and impact on society. Pneumonia was the third leading cause of death in Japan in 2011. In 2016, 119 650 Japanese people died of pneumonia, 96% of whom were aged 65 years and above. The symptoms of pneumonia in elderly people are often atypical. Aspiration pneumonia is seen more frequently than in young people because of swallowing dysfunction in the elderly. The mortality rate is also higher in the elderly than in young people. In Japan, the population is aging at an unprecedented rate, and pneumonia in the elderly will be increasingly important in medicine and medical economics in the future. To manage pneumonia in the elderly, it is important to accurately evaluate its severity, administer appropriate antibiotic treatment, and implement effective preventive measures. PMID- 29434486 TI - An early and mysterious histerid inquiline from Cretaceous Burmese amber (Coleoptera, Histeridae). AB - We describe a new genus and species of Histeridae from Upper Cretaceous Burmese amber, Amplectister tenax Caterino & Maddison, gen. & sp. n. This species represents the third known Cretaceous histerid, which, like the others, is highly distinct and cannot easily be placed to subfamily. It exhibits prosternal characters in common with Saprininae, but other characters appear inconsistent with this possibility. The abdominal venter is strongly concave, and the hind legs are enlarged and modified for grasping. We hypothesize that this represents the earliest example in Histeridae of modifications for phoresy on social insects. PMID- 29434487 TI - New hairworm (Nematomorpha, Gordiida) species described from the Arizona Madrean Sky Islands. AB - Gordiids, or freshwater hairworms, are members of the phylum Nematomorpha that use terrestrial definitive hosts (arthropods) and live as adults in rivers, lakes, or streams. The genus Paragordius consists of 18 species, one of which was described from the Nearctic in 1851. More than 150 years later, we are describing a second Paragordius species from a unique habitat within the Nearctic; the Madrean Sky Island complex. The Madrean Sky Islands are a series of isolated high mountains in northern Mexico and the southwestern United States (Arizona and New Mexico), and are well known for their high diversity and endemicity. The new species is described based on both molecular data (COI barcoding) and morphological characters of the eggs, larvae, cysts, and adults. Adult females have unique small oblong mounds present on the interior of the trifurcating lobes with randomly dispersed long hairs extending from the furrows between the mounds. Marked genetic differences support observed morphological differences. This species represents the second new hairworm to be described from the Madrean Sky Islands, and it may represent the first endemic hairworm from this biodiversity hotspot. PMID- 29434488 TI - Unique extrication structure in a new megaspilid, Dendrocerus scutellaris Trietsch & Miko (Hymenoptera: Megaspilidae). AB - Background: A new species, Dendrocerus scutellaris Trietsch & Miko (Hymenoptera: Megaspilidae), is described here from male and female specimens captured in Costa Rica. This species is the only known ceraphronoid wasp with a straight mandibular surface and raised dorsal projections on the scutellum, called the mesoscutellar comb. It is hypothesised that the function of the mesoscutellar comb is to aid the emergence of the adult from the host, especially since the mandibles lack a pointed surface to tear open the pupal case. The authors also provide phenotypic data in a semantic form to facilitate data integration and accessibility across taxa and provide an updated phenotype bank of morphological characters for megaspilid taxonomic treatments. In updating this phenotype bank, the authors continue to make taxonomic data accessible to future systematic efforts focusing on Ceraphronoidea. New information: A new species, Dendrocerus scutellaris (Hymenoptera: Megaspilidae) Trietsch & Miko, is described from both male and female specimens captured in Costa Rica. PMID- 29434489 TI - The stoneflies (Insecta, Plecoptera) of the Talladega Mountain region, Alabama, USA: distribution, elevation, endemism, and rarity patterns. AB - Background The Talladega Mountain region of eastern Alabama is the southernmost outlier of the ancient Appalachian Mountains, including the highest peaks and ranges in the state. Collections of stoneflies (Plecoptera) previously here have been sporadic yet has led to several new species descriptions in modern times (James 1974, James 1976, Stark and Szczytko 1976, Kondratieff and Kirchner 1996, Szczytko and Kondratieff 2015) and expanded our understanding of southeastern US stoneflies. During the period 2003-2012 we conducted an intensive inventory of the stonefly fauna of the Talladega Mountain region. We collected across all months from 192 unique localities, covering a broad range of stream sizes and elevation gradients present in the region. New information A total of 57 confirmed species across eight of the nine Nearctic families were collected as adults (Table 4), including four species described as new during the study period (Table 2). Leuctra crossi James, 1974 was easily the most common species collected. Median elevations per species ranged from 174 m (Clioperla clio (Newman, 1839)) to 410 m (Leuctra triloba Claassen, 1923 (Fig. 3). Dot distribution maps were included for all 57 species plus one for undetermined nymphs of Pteronarcys Newman, 1838 (Figs. 4-19). As many as seven species may be endemic to the region but sampling efforts northeastward into Georgia, plus additional focused sampling in Alabama and a comprehensive examination of all available material held in museums and personal collections, are needed for confirmation. PMID- 29434490 TI - Prognostic Factors for Post Recurrence Survival in Resected Pathological Stage I Non-small Cell Lung Cancer. AB - Background: Recurrence of lung cancer after surgical resection is a major obstacle in the cure and long-term survival of patients and has become the most common cause of death. However, prognostic factors and efficacy of therapy after recurrence remain controversial. We evaluated the prognostic factors of post recurrence survival (PRS) in patients of resected stage I non-small cell lung cancer (NSCLC). Methods: Of the 551 patients who underwent surgery for stage I NSCLC between 2005 and 2013, we reviewed 89 (16.2%) patients who had recurrence. We examined PRS using the Kaplan-Meier method and multivariate Cox regression analyses. Results: The median follow-up period after recurrence was 21.0 months. The median recurrence free interval (RFI) was 16.8 months. The 1-year PRS and 3 year PRS were 65.6% and 44.7%, respectively. Multivariate analysis revealed that size of primary lesion > 25 mm (P = 0.048), RFI <= 17 months (P = 0.048) and no treatment for recurrence (P < 0.001) were independent poor-prognosis factors of PRS. We further examined PRS in 66 patients who underwent any post recurrence therapy. For the patients who underwent treatment after recurrence, bone metastasis (P = 0.025) and treatment without epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (P = 0.049) were independent poor prognostic factors. Conclusion: PRS may be associated with characteristics of a recurrent lesion, including the biology of the recurrent tumor, RFI, recurrent site, the treatment for recurrence, rather than characteristics of primary lesion. Although further validation is needed, this information is important for the design of clinical trials for post-recurrence therapy. PMID- 29434491 TI - Usefulness of a Novel Ultrasonographic Classification Based on Anechoic Area Patterns for Differentiating Warthin Tumors from Pleomorphic Adenomas of the Parotid Gland. AB - Background: Ultrasonographic homogeneity is an important differential finding between Warthin tumor and pleomorphic adenoma, two types of benign parotid gland tumors, with the former likely to be heterogeneous and the latter homogeneous. However, differences in the performance of ultrasound machines or the homogeneity cut-off level affect the judgment of ultrasonographic homogeneity. Therefore, in this study, we adopted a novel system for classifying the composition of tumors via ultrasonography, using anechoic area as a substitute for differences in homogeneity to differentiate between Warthin tumors and pleomorphic adenomas. Methods: We evaluated 68 tumors that were histopathologically diagnosed as Warthin tumor or pleomorphic adenoma between July 2009 and November 2015. Ultrasonographic images of the tumors were evaluated on the basis of key differentiating features, including features on B-mode imaging and color Doppler imaging. Additionally, the tumors were classified into four groups based on anechoic area, and findings were compared between Warthin tumors and pleomorphic adenomas. Results: While 38 of the tumors were pleomorphic adenomas, 30 were Warthin tumors. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for detection of Warthin tumors using our novel classification system were 73.3%, 76.3%, 71.0%, 78.4% and 75.0%, respectively. Compared to pleomorphic adenomas, Warthin tumors showed large or sponge-like anechoic areas, rich vascularization and an oval shape even at large tumor sizes, and the difference was significant. On defining Warthin tumor as a tumor demonstrating two or more of the findings noted above, the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for its detection were 73.3%, 84.2%, 78.6%, 80.0% and 79.4%, respectively. Conclusion: Our novel classification system based on anechoic area patterns demonstrated by the tumors had high sensitivity, specificity and diagnostic accuracy for differentiating Warthin tumors from pleomorphic adenomas. PMID- 29434492 TI - SR-16234, a Novel Selective Estrogen Receptor Modulator for Pain Symptoms with Endometriosis: An Open-label Clinical Trial. AB - Background: SR-16234 is a selective estrogen receptor modulator (SERM) structurally different from approved SERM and has been reported to have estrogen receptor (ER) alpha antagonistic activity and strong affinity with a weak partial agonistic activity to ERbeta receptor. SR-16234 showed strong inhibitory effects on transplanted endometrial cysts in the endometriosis model of rat and mouse. In this clinical trial, efficacy and safety of SR-16234 have been evaluated in endometriosis patients. Methods: This trial was an open-label single arm clinical trial. Ten patients with dysmenorrhea and pelvic pain associated with endometriosis and adenomyosis were enrolled in this trial, and received 40 mg of SR-16234 once daily for 12 weeks. The primary endpoint was the visual analogue scale (VAS) of pelvic pain. The secondary endpoints included dysmenorrhea score, pelvic pain score, objective observations (stiffness of Douglas' pouch, limitation of uterine movement, size of ovarian chocolate cysts, thickness of endometrium, and serum CA125 concentration) and safety. Results: After oral administration of SR-16234 40 mg for 12 weeks, there were statistically significant decreases in pelvic pain VAS, total pelvic pain score, total dysmenorrhea score, stiffness of Douglas' pouch, limitation of uterine movement compared with the baseline values. Conclusion: The present trial suggested that a selective estrogen receptor modulator could be used for treatment of pain associated with endometriosis for the first time. PMID- 29434493 TI - Comparative Study of Complications in CV Catheter Insertion for Pediatric Patients: Real-time Ultrasound-guided Versus Venography-guided Approach. AB - Background: Tunneled central venous catheters (CVC), called Broviac/Hickman catheter, are widely used in the long-term treatment of pediatric patients. Recently, the percutaneous approach for CVC insertion has become dominant as a less invasive intervention. In this study, we reviewed the mechanical and delayed complications according to different procedures of CVC insertion and assessed the risk factors for complications in CVC insertions for pediatric patients. Methods: A total of 159 pediatric patients (85 males and 74 females) were included in this study. Primary reasons for indication of CVC settlement were hemato-oncologic disorders (66 cases, 42%), malignant solid tumors (30, 19%) and other benign diseases (63, 40%). CVC insertion was performed with surgical venous cut-down (CD) in 51 patients (32%), with real-time ultrasound-guided puncture (RTUS) in 57 (36%), and venography-guided puncture (VG) in 49 (31%). Results: CD was dominantly selected and the frequency of venipuncture increased respective to the increased age of patients. RTUS was dominantly selected for one to four year old patients and VG was dominant in 5 to 15 year old patients. Some types of mechanical complication were observed in 4 of 159 (2.5%) and some delayed types were observed in 66 of 159 cases (42%). No mechanical complications occurred in cases with CD and RTUS; on the other hand, 3 (6%) of 49 insertions with VG were observed. However, we could not show any significant risk factors for the mechanical complications. In the meantime, delayed complications and premature removal were significantly observed in patients under 5 years old. Conclusion: RTUS is superior to our conventional VG considering less frequent mechanical complications. High frequent delayed complication and premature removal should be considered, especially for patients under 5 years old. PMID- 29434494 TI - Schizencephaly and Porencephaly Due to Fetal Intracranial Hemorrhage: A Report of Two Cases. AB - Schizencephaly and porencephaly are extremely rare types of cortical dysplasia. Case 1: Prenatal magnetic resonance imaging (MRI) showed wide clefts in the frontal and parietal lobes bilaterally. On postnatal day 3, MRI T2-weighted images showed multiple hypointensities in the clefts and ventricular walls, suggestive of hemosiderosis secondary to intracranial hemorrhage. Case 2: Prenatal MRI showed bilateral cleft and cyst formation in the fetal cerebrum, as well as calcification and hemosiderosis indicative of past hemorrhage. T2 weighted images showed hypointensities in the same regions as the calcification, corresponding with hemosiderosis due to intracranial hemorrhage on postnatal day 10. Thus, prenatal MRI was useful for diagnosing schizencephaly and porencephaly. Schizencephaly and porencephaly were thought to be due to fetal intracranial hemorrhage, which, in the porencephaly case, may have been related to a mutation of COL4A1. PMID- 29434495 TI - Carcinosarcoma of Stomach Confined to the Mucosa. AB - Carcinosarcoma is a malignant tumor composed of both epithelial and mesenchymal malignant tumor components. A 78-year-old man was transferred to our hospital because of hematemesis and tarry stool. An emergency gastrointestinal endoscopic examination revealed active bleeding from an ulcerative lesion on the posterior wall of the gastric body; endoscopic hemostasis was successfully performed. A gastrointestinal endoscopy performed two months later showed a polypoid lesion at the same place where the ulcer had been. The biopsy specimen was histologically diagnosed as well to moderately differentiated tubular adenocarcinoma. The patient underwent a laparoscopic distal gastrectomy with D2 lymph node dissection under a diagnosis of gastric adenocarcinoma. A 28 * 15 mm polypoid tumor was resected from the gastric body, and was found on microscopic examination to consist of both carcinoma and sarcoma components, showing atypical spindle cells, which were positive for alpha-smooth muscular actin, calponin, and h-caldesmon, but negative for CD34, CD117 (c-kit), desmin, and dog 1. These findings led to a diagnosis of gastric carcinosarcoma. The tumor was confined to the mucous membrane. Lymph node metastasis was found in one node and contained only the carcinoma component. The postoperative course was uneventful. The patient lived without recurrence for 2 years. Carcinosarcoma of the stomach is a rare tumor with high malignant potential and poor prognosis. Careful follow up is required for early detection of any recurrence. PMID- 29434496 TI - Neuroendocrine Tumor Arising From Meckel's Diverticulum Unexpectedly Diagnosed After Diverticulectomy and in Which Multiple Lymph Node Metastases Were Found After Reoperation: A Case Report. AB - A 47-year-old man with progressive anemia possibly due to digestive tract bleeding was referred to our hospital. Contrast-enhanced computed tomography of the abdomen showed a 2-cm tumor lesion arising near the small intestine. Enteroscopy revealed a 3-cm submucosal tumor at the ileum. A gastrointestinal stromal tumor of the small intestine was suspected, and the patient underwent surgery. During the operation, a diverticulum approximately 60 cm orad to the terminal ileum and a tumor at the top of the diverticulum were observed. Considering the location, Meckel's diverticulum was suspected. No lymphadenopathy was present in the mesentery. Laparoscopy-assisted resection of the diverticulum without lymph node dissection was performed. The histological diagnosis of the tumor was a well-differentiated neuroendocrine tumor. Given the possibility of lymph node metastasis, we performed a second operation to remove the small intestine and lymph nodes. Histologically, 7 of the 18 dissected lymph nodes were metastatic. The postoperative course was uneventful, and the patient survived without tumor recurrence for another 2 years 8 months. Neuroendocrine tumors of Meckel's diverticulum are aggressive. Therefore, small intestinal resection along with lymph node dissection might be necessary as part of the surgical strategy. PMID- 29434497 TI - Cerebellar Ganglioglioma in Childhood: Histopathologic Implications for Management During Long-term Survival: A Case Report. AB - We report the case of a 19-year-old female with cerebellar ganglioglioma that was diagnosed at 4 years of age. Despite treatment with partial resection, radiation, and chemotherapy, residual tumor slowly expanded into the brainstem and upper cervical cord, resulting in nocturnal hypopnea, progressive tetraparesis, and feeding difficulty during 8-10 years of age. Initiation of temozolomide and bevacizumab was effective in preventing further expansion of the tumor, and the patient has been treated at home and in school with noninvasive positive pressure ventilation and gastrostomy. Histopathologic examination of the resected tumor tissue revealed phospho-S6-positive tumor cells of either neuronal or astroglial appearance. This suggests that a higher proportion of cells of glial lineage could be linked to the progression of cerebellar ganglioglioma in childhood. Possible treatment options with mammalian target of rapamycin inhibitors are discussed. PMID- 29434498 TI - Qualitative models and experimental investigation of chaotic NOR gates and set/reset flip-flops. AB - It has been observed through experiments and SPICE simulations that logical circuits based upon Chua's circuit exhibit complex dynamical behaviour. This behaviour can be used to design analogues of more complex logic families and some properties can be exploited for electronics applications. Some of these circuits have been modelled as systems of ordinary differential equations. However, as the number of components in newer circuits increases so does the complexity. This renders continuous dynamical systems models impractical and necessitates new modelling techniques. In recent years, some discrete dynamical models have been developed using various simplifying assumptions. To create a robust modelling framework for chaotic logical circuits, we developed both deterministic and stochastic discrete dynamical models, which exploit the natural recurrence behaviour, for two chaotic NOR gates and a chaotic set/reset flip-flop. This work presents a complete applied mathematical investigation of logical circuits. Experiments on our own designs of the above circuits are modelled and the models are rigorously analysed and simulated showing surprisingly close qualitative agreement with the experiments. Furthermore, the models are designed to accommodate dynamics of similarly designed circuits. This will allow researchers to develop ever more complex chaotic logical circuits with a simple modelling framework. PMID- 29434499 TI - Determination of macro-scale soil properties from pore-scale structures: model derivation. AB - In this paper, we use homogenization to derive a set of macro-scale poro-elastic equations for soils composed of rigid solid particles, air-filled pore space and a poro-elastic mixed phase. We consider the derivation in the limit of large deformation and show that by solving representative problems on the micro-scale we can parametrize the macro-scale equations. To validate the homogenization procedure, we compare the predictions of the homogenized equations with those of the full equations for a range of different geometries and material properties. We show that the results differ by [Formula: see text] for all cases considered. The success of the homogenization scheme means that it can be used to determine the macro-scale poro-elastic properties of soils from the underlying structure. Hence, it will prove a valuable tool in both characterization and optimization. PMID- 29434500 TI - Dynamics of flexural gravity waves: from sea ice to Hawking radiation and analogue gravity. AB - The propagation of flexural gravity waves, routinely used to model wave interaction with sea ice, is studied, including the effect of compression and current. A number of significant and surprising properties are shown to exist. The occurrence of blocking above a critical value of compression is illustrated. This is analogous to propagation of surface gravity waves in the presence of opposing current and light wave propagation in the curved space-time near a black hole, therefore providing a novel system for studying analogue gravity. Between the blocking and buckling limit of the compressive force, the dispersion relation possesses three positive real roots, contrary to an earlier observation of having a single positive real root. Negative energy waves, in which the phase and group velocity point in opposite directions, are also shown to exist. In the presence of an opposing current and certain critical ranges of compressive force, the second blocking point shifts from the positive to the negative branch of the dispersion relation. Such a shift is known as the Hawking effect from the analogous behaviour in the theory of relativity which leads to Hawking radiation. The theory we develop is illustrated with simulations of linear waves in the time domain. PMID- 29434501 TI - Matter rogue waves for the three-component Gross-Pitaevskii equations in the spinor Bose-Einstein condensates. AB - To show the existence and properties of matter rogue waves in an F=1 spinor Bose Einstein condensate (BEC), we work on the three-component Gross-Pitaevskii (GP) equations. Via the Darboux-dressing transformation, we obtain a family of rational solutions describing the extreme events, i.e. rogue waves. This family of solutions includes bright-dark-bright and bright-bright-bright rogue waves. The algebraic construction depends on Lax matrices and their Jordan form. The conditions for the existence of rogue wave solutions in an F=1 spinor BEC are discussed. For the three-component GP equations, if there is modulation instability, it is of baseband type only, confirming our analytic conditions. The energy transfers between the waves are discussed. PMID- 29434502 TI - Regular approximate factorization of a class of matrix-function with an unstable set of partial indices. AB - From the classic work of Gohberg & Krein (1958 Uspekhi Mat. Nauk.XIII, 3-72. (Russian).), it is well known that the set of partial indices of a non-singular matrix function may change depending on the properties of the original matrix. More precisely, it was shown that if the difference between the largest and the smallest partial indices is larger than unity then, in any neighbourhood of the original matrix function, there exists another matrix function possessing a different set of partial indices. As a result, the factorization of matrix functions, being an extremely difficult process itself even in the case of the canonical factorization, remains unresolvable or even questionable in the case of a non-stable set of partial indices. Such a situation, in turn, has became an unavoidable obstacle to the application of the factorization technique. This paper sets out to answer a less ambitious question than that of effective factorizing matrix functions with non-stable sets of partial indices, and instead focuses on determining the conditions which, when having known factorization of the limiting matrix function, allow to construct another family of matrix functions with the same origin that preserves the non-stable partial indices and is close to the original set of the matrix functions. PMID- 29434503 TI - Dynamics of non-holonomic systems with stochastic transport. AB - This paper formulates a variational approach for treating observational uncertainty and/or computational model errors as stochastic transport in dynamical systems governed by action principles under non-holonomic constraints. For this purpose, we derive, analyse and numerically study the example of an unbalanced spherical ball rolling under gravity along a stochastic path. Our approach uses the Hamilton-Pontryagin variational principle, constrained by a stochastic rolling condition, which we show is equivalent to the corresponding stochastic Lagrange-d'Alembert principle. In the example of the rolling ball, the stochasticity represents uncertainty in the observation and/or error in the computational simulation of the angular velocity of rolling. The influence of the stochasticity on the deterministically conserved quantities is investigated both analytically and numerically. Our approach applies to a wide variety of stochastic, non-holonomically constrained systems, because it preserves the mathematical properties inherited from the variational principle. PMID- 29434504 TI - Quantum algorithm for multivariate polynomial interpolation. AB - How many quantum queries are required to determine the coefficients of a degree-d polynomial in n variables? We present and analyse quantum algorithms for this multivariate polynomial interpolation problem over the fields [Formula: see text], [Formula: see text] and [Formula: see text]. We show that [Formula: see text] and [Formula: see text] queries suffice to achieve probability 1 for [Formula: see text] and [Formula: see text], respectively, where [Formula: see text] except for d=2 and four other special cases. For [Formula: see text], we show that ?(d/(n+d))(n+dd) ? queries suffice to achieve probability approaching 1 for large field order q. The classical query complexity of this problem is (n+dd) , so our result provides a speed-up by a factor of n+1, (n+1)/2 and (n+d)/d for [Formula: see text], [Formula: see text] and [Formula: see text], respectively. Thus, we find a much larger gap between classical and quantum algorithms than the univariate case, where the speedup is by a factor of 2. For the case of [Formula: see text], we conjecture that [Formula: see text] queries also suffice to achieve probability approaching 1 for large field order q, although we leave this as an open problem. PMID- 29434505 TI - Finite indentation of highly curved elastic shells. AB - Experimentally measuring the elastic properties of thin biological surfaces is non-trivial, particularly when they are curved. One technique that may be used is the indentation of a thin sheet of material by a rigid indenter, while measuring the applied force and displacement. This gives immediate information on the fracture strength of the material (from the force required to puncture), but it is also theoretically possible to determine the elastic properties by comparing the resulting force-displacement curves with a mathematical model. Existing mathematical studies generally assume that the elastic surface is initially flat, which is often not the case for biological membranes. We previously outlined a theory for the indentation of curved isotropic, incompressible, hyperelastic membranes (with no bending stiffness) which breaks down for highly curved surfaces, as the entire membrane becomes wrinkled. Here, we introduce the effect of bending stiffness, ensuring that energy is required to change the shell shape without stretching, and find that commonly neglected terms in the shell equilibrium equation must be included. The theory presented here allows for the estimation of shape- and size-independent elastic properties of highly curved surfaces via indentation experiments, and is particularly relevant for biological surfaces. PMID- 29434506 TI - Parameter-robustness analysis for a biochemical oscillator model describing the social-behaviour transition phase of myxobacteria. AB - We develop a tool based on bifurcation analysis for parameter-robustness analysis for a class of oscillators and, in particular, examine a biochemical oscillator that describes the transition phase between social behaviours of myxobacteria. Myxobacteria are a particular group of soil bacteria that have two dogmatically different types of social behaviour: when food is abundant they live fairly isolated forming swarms, but when food is scarce, they aggregate into a multicellular organism. In the transition between the two types of behaviours, spatial wave patterns are produced, which is generally believed to be regulated by a certain biochemical clock that controls the direction of myxobacteria's motion. We provide a detailed analysis of such a clock and show that, for the proposed model, there exists some interval in parameter space where the behaviour is robust, i.e. the system behaves similarly for all parameter values. In more mathematical terms, we show the existence and convergence of trajectories to a limit cycle, and provide estimates of the parameter under which such a behaviour occurs. In addition, we show that the reported convergence result is robust, in the sense that any small change in the parameters leads to the same qualitative behaviour of the solution. PMID- 29434507 TI - Dynamics and locomotion of flexible foils in a frictional environment. AB - Over the past few decades, oscillating flexible foils have been used to study the physics of organismal propulsion in different fluid environments. Here, we extend this work to a study of flexible foils in a frictional environment. When the foil is oscillated by heaving at one end but is not free to locomote, the dynamics change from periodic to non-periodic and chaotic as the heaving amplitude increases or the bending rigidity decreases. For friction coefficients lying in a certain range, the transition passes through a sequence of N-periodic and asymmetric states before reaching chaotic dynamics. Resonant peaks are damped and shifted by friction and large heaving amplitudes, leading to bistable states. When the foil is free to locomote, the horizontal motion smoothes the resonant behaviours. For moderate frictional coefficients, steady but slow locomotion is obtained. For large transverse friction and small tangential friction corresponding to wheeled snake robots, faster locomotion is obtained. Travelling wave motions arise spontaneously, and move with horizontal speeds that scale as transverse friction coefficient to the power 1/4 and input power that scales as the transverse friction coefficient to the power 5/12. These scalings are consistent with a boundary layer form of the solutions near the foil's leading edge. PMID- 29434508 TI - Quantum machine learning: a classical perspective. AB - Recently, increased computational power and data availability, as well as algorithmic advances, have led machine learning (ML) techniques to impressive results in regression, classification, data generation and reinforcement learning tasks. Despite these successes, the proximity to the physical limits of chip fabrication alongside the increasing size of datasets is motivating a growing number of researchers to explore the possibility of harnessing the power of quantum computation to speed up classical ML algorithms. Here we review the literature in quantum ML and discuss perspectives for a mixed readership of classical ML and quantum computation experts. Particular emphasis will be placed on clarifying the limitations of quantum algorithms, how they compare with their best classical counterparts and why quantum resources are expected to provide advantages for learning problems. Learning in the presence of noise and certain computationally hard problems in ML are identified as promising directions for the field. Practical questions, such as how to upload classical data into quantum form, will also be addressed. PMID- 29434509 TI - A nanoscale perspective on the effects of transverse microprestress on drying creep of nanoporous solids. AB - The Pickett effect describes the excess non-additive strain developed during drying of a nanoporous solid material under creep. One explanation for its origins, developed using micromechanical models, is the progressive relaxation of internally developed microprestress. However, these models have not explicitly considered the effects of this microprestress on nanoscale energy barriers that govern the relative motion and displacement between nanopore walls during deformation. Here, we evaluate the nanoscale effects of transverse microprestresses on the drying creep behaviour of a nanoscale slit pore using coarse-grained molecular dynamics. We find that the underlying energy barrier depends exponentially on the transverse microprestress, which is attributed to changes in the effective viscosity and degree of nanoconfinement of molecules in the water interlayer. Specifically, as the transverse microprestress is relaxed (i.e. its magnitude decreases), the activation energy barrier is reduced, thereby leading to an acceleration of the creep behaviour and a stronger Pickett effect. Based on our simulation results, we introduce a new microprestress-dependent energy term into our existing Arrhenius model, which describes the relative displacement of pore walls as a function of the underlying activation energy barriers. Our findings further verify the existing micromechanical theories for the origin of the Pickett effect and establish a quantitative relationship between the transverse microprestress and the intensity of the Pickett effect. PMID- 29434510 TI - On compressible and piezo-viscous flow in thin porous media. AB - In this paper, we study flow through thin porous media as in, e.g. seals or fractures. It is often useful to know the permeability of such systems. In the context of incompressible and iso-viscous fluids, the permeability is the constant of proportionality relating the total flow through the media to the pressure drop. In this work, we show that it is also relevant to define a constant permeability when compressible and/or piezo-viscous fluids are considered. More precisely, we show that the corresponding nonlinear equation describing the flow of any compressible and piezo-viscous fluid can be transformed into a single linear equation. Indeed, this linear equation is the same as the one describing the flow of an incompressible and iso-viscous fluid. By this transformation, the total flow can be expressed as the product of the permeability and a nonlinear function of pressure, which represents a generalized pressure drop. PMID- 29434511 TI - Discrete-to-continuum modelling of weakly interacting incommensurate two dimensional lattices. AB - In this paper, we derive a continuum variational model for a two-dimensional deformable lattice of atoms interacting with a two-dimensional rigid lattice. The starting point is a discrete atomistic model for the two lattices which are assumed to have slightly different lattice parameters and, possibly, a small relative rotation. This is a prototypical example of a three-dimensional system consisting of a graphene sheet suspended over a substrate. We use a discrete-to continuum procedure to obtain the continuum model which recovers both qualitatively and quantitatively the behaviour observed in the corresponding discrete model. The continuum model predicts that the deformable lattice develops a network of domain walls characterized by large shearing, stretching and bending deformation that accommodates the misalignment and/or mismatch between the deformable and rigid lattices. Two integer-valued parameters, which can be identified with the components of a Burgers vector, describe the mismatch between the lattices and determine the geometry and the details of the deformation associated with the domain walls. PMID- 29434512 TI - Dynamics of lumps and dark-dark solitons in the multi-component long-wave-short wave resonance interaction system. AB - General semi-rational solutions of an integrable multi-component (2+1) dimensional long-wave-short-wave resonance interaction system comprising multiple short waves and a single long wave are obtained by employing the bilinear method. These solutions describe the interactions between various types of solutions, including line rogue waves, lumps, breathers and dark solitons. We only focus on the dynamical behaviours of the interactions between lumps and dark solitons in this paper. Our detailed study reveals two different types of excitation phenomena: fusion and fission. It is shown that the fundamental (simplest) semi rational solutions can exhibit fission of a dark soliton into a lump and a dark soliton or fusion of one lump and one dark soliton into a dark soliton. The non fundamental semi-rational solutions are further classified into three subclasses: higher-order, multi- and mixed-type semi-rational solutions. The higher-order semi-rational solutions show the process of annihilation (production) of two or more lumps into (from) one dark soliton. The multi-semi-rational solutions describe N(N>=2) lumps annihilating into or producing from N-dark solitons. The mixed-type semi-rational solutions are a hybrid of higher-order semi-rational solutions and multi-semi-rational solutions. For the mixed-type semi-rational solutions, we demonstrate an interesting dynamical behaviour that is characterized by partial suppression or creation of lumps from the dark solitons. PMID- 29434513 TI - Hybrid integral transforms for flow development in ducts partially filled with porous media. AB - A hybrid numerical-analytical solution is developed for laminar flow development in a parallel plate duct partially filled with porous media. The integral transform method is employed in combination with a single domain reformulation strategy for representing the heterogeneous media within the channel. A novel eigenfunction expansion basis is proposed, including abrupt spatial variations of physical properties due to the domain transitions. The introduction of the new basis allows for a solution with similar convergence rates as in previous applications with simpler formulations, as demonstrated through a careful convergence analysis of the expansions. The inherent automatic error control characteristic of the integral transforms approach then provides benchmark results for the developing velocity profile. Moreover, a physical analysis further verifies the consistency of both the proposed expansion and the mixed symbolic-numerical code developed. A detailed verification with a finite-element commercial code is also performed. PMID- 29434514 TI - Lightweight steel tidal power barrages with minimal environmental impact: application to the Severn Barrage. AB - For tidal power barrages, a breast-shot water wheel, with a hydraulic transmission, has significant advantages over a conventional Kaplan turbine. It is better suited to combined operations with pumping that maintain the tidal range upstream of the barrage (important in reducing the environmental impact), and is much less harmful to fish. It also does not require tapered entry and exit ducts, making the barrage much smaller and lighter, so that it can conveniently be built in steel. For the case of the Severn Estuary, UK, it is shown that a barrage at Porlock would generate an annual average power of 4 GW (i.e. 35 TWh yr 1), maintain the existing tidal ranges upstream of it and reduce the tidal ranges downstream of it by only about 10%. The weight of steel required, in relation to the annual average power generated, compares very favourably with a recent offshore wind farm. PMID- 29434515 TI - Waves and fluid-solid interaction in stented blood vessels. AB - This paper focuses on the modelling of fluid-structure interaction and wave propagation problems in a stented artery. Reflection of waves in blood vessels is well documented in the literature, but it has always been linked to a strong variation in geometry, such as the branching of vessels. The aim of this work is to detect the possibility of wave reflection in a stented artery due to the repetitive pattern of the stents. The investigation of wave propagation and possible blockages under time-harmonic conditions is complemented with numerical simulations in the transient regime. PMID- 29434516 TI - Does flutter prevent drag reduction by reconfiguration? AB - The static reconfiguration of flexible beams exposed to transverse flows is classically known to reduce the drag these structures have to withstand. But the more a structure bends, the more parallel to the flow it becomes, and flexible beams in axial flows are prone to a flutter instability that is responsible for large inertial forces that drastically increase their drag. It is, therefore, unclear whether flexibility would still alleviate, or on the contrary enhance, the drag when flapping occurs on a reconfiguring structure. In this article, we perform numerical simulations based on reduced-order models to demonstrate that the additional drag induced by the flapping motion is almost never significant enough to offset the drag reduction due to reconfiguration. Isolated and brief snapping events may transiently raise the drag above that of a rigid structure in the particular case of heavy, moderately slender beams. But apart from these short peak events, the drag force remains otherwise always significantly reduced in comparison with a rigid structure. PMID- 29434517 TI - Bifurcation of elastic solids with sliding interfaces. AB - Lubricated sliding contact between soft solids is an interesting topic in biomechanics and for the design of small-scale engineering devices. As a model of this mechanical set-up, two elastic nonlinear solids are considered jointed through a frictionless and bilateral surface, so that continuity of the normal component of the Cauchy traction holds across the surface, but the tangential component is null. Moreover, the displacement can develop only in a way that the bodies in contact do neither detach, nor overlap. Surprisingly, this finite strain problem has not been correctly formulated until now, so this formulation is the objective of the present paper. The incremental equations are shown to be non-trivial and different from previously (and erroneously) employed conditions. In particular, an exclusion condition for bifurcation is derived to show that previous formulations based on frictionless contact or 'spring-type' interfacial conditions are not able to predict bifurcations in tension, while experiments-one of which, ad hoc designed, is reported-show that these bifurcations are a reality and become possible when the correct sliding interface model is used. The presented results introduce a methodology for the determination of bifurcations and instabilities occurring during lubricated sliding between soft bodies in contact. PMID- 29434518 TI - Computational tameness of classical non-causal models. AB - We show that the computational power of the non-causal circuit model, i.e. the circuit model where the assumption of a global causal order is replaced by the assumption of logical consistency, is completely characterized by the complexity class UP?coUP. An example of a problem in that class is factorization. Our result implies that classical deterministic closed timelike curves (CTCs) cannot efficiently solve problems that lie outside of that class. Thus, in stark contrast to other CTC models, these CTCs cannot efficiently solve NP-complete problems, unless NP=UP?coUP=coNP, which lets their existence in nature appear less implausible. This result gives a new characterization of UP?coUP in terms of fixed points. PMID- 29434519 TI - The role of frictional contact of constituent blocks on the stability of masonry domes. AB - The observation of old construction works confirms that masonry domes can withstand tensile hoop stresses, at least up to a certain level. Here, such tensile resistance, rather than a priori assumed as a property of the bulk material, is attributed to the contact forces that are developed at the interfaces between interlocked blocks under normal pressure, specified by Coulomb's friction law. According to this rationale, the aspect ratio of the blocks, as well as the bond pattern, becomes of fundamental importance. To investigate the complex assembly of blocks, supposed rigid, we present a non smooth contact dynamic analysis, implemented in a custom software based on the Project Chrono C++ framework and complemented with parametric-design interfaces for pre- and post-processing complex geometries. Through this advanced tool, we investigate the role of frictional forces resisting hoop stresses in the stability of domes, either circular or oval, under static and dynamic loading, focusing, in particular, on the structural role played by the underlying drum and the surmounting tiburium. PMID- 29434521 TI - Nursing education challenges and solutions in Sub Saharan Africa: an integrative review. AB - Background: The Lancet Commission and the Global Health Workforce Alliance reported that professional education has generally not kept up the pace of health care challenges. Sub Saharan Africa needs an effective and efficient nursing education system to build an adequate, competent and relevant nursing workforce necessary for the achievement of Sustainable Development Goals. The Plan of Action for Scaling up Quality Nursing and Midwifery Education and Practice for the African Region 2012 - 2022 provided a framework for scale up of nurses and midwives. This integrative review examined literature on nursing education challenges and solutions in Sub Saharan Africa to inform development of a model for improving the quality, quantity and relevance of nursing education at local level. Methods: A search of PubMed, Medline on EBCSOhost and Google Scholar was conducted using key words: nursing education, challenges, solutions and/ or Africa. Published works from 2012 to 2016 were reviewed to explore reports about challenges and solution in nursing education in Sub Saharan Africa. Full texts of relevant studies were retrieved after reading the tittles and abstracts. Critical appraisal was undertaken and the findings of the relevant studies were analysed using thematic analysis. Results: Twenty articles and five grey sources were included. Findings of the review generally supports World Health Organisation framework for transformative and scale up of health professions education. Six themes emerged; curriculum reforms, profession regulation, transformative teaching strategies, collaboration and partnership, capacity building and infrastructure and resources. Challenges and solutions in nursing education are common within countries. The review shows that massive investment by development partners is resulting in positive development of nursing education in Sub Saharan Africa. However, strategic leadership, networking and partnership to share expertise and best practices are critical. Conclusion: Sub Saharan Africa needs more reforms to increase capacity of educators and mentors, responsiveness of curricula, strongly regulatory frameworks, and availability of infrastructure and resources. The review adds to the body of knowledge to enhance efforts of stakeholders in the improvement of the quality, quantity and relevance of nursing education in Sub Saharan Africa. PMID- 29434522 TI - MiR-539 inhibits proliferation and migration of triple-negative breast cancer cells by down-regulating LAMA4 expression. AB - Background: Recent studies have shown that laminin subunit alpha 4 (LAMA4) plays an important role in carcinogenesis. However, its molecular biological function in triple-negative breast cancer (TNBC) has not been entirely clarified. This study investigated the expression of LAMA4 in TNBC and its effect on cell proliferation, migration and invasion. Furthermore, we also identified the potential miRNA directly targeting LAMA4. Methods: Western blot, Real-time quantitative PCR (qPCR) and immunohistochemical staining (IHC) were used to detect the expression of LAMA4 in TNBC. The effects of LAMA4 on TNBC cell proliferation, migration and invasion were also explored in vitro. The potential miRNA that targets LAMA4 was determined by dual luciferase reporter assay and verified by qPCR and western blot analysis. Results: Our study showed LAMA4 mRNA (p = 0.001) and protein (p = 0.005) expression in TNBC tissue samples were elevated compared with adjacent normal tissue samples, and LAMA4 was mainly expressed in the cytoplasm of breast carcinoma cells. Knockdown of LAMA4 inhibited TNBC cell proliferation, migration and invasion in vitro. Moreover, further study revealed that LAMA4 was a putative target of miR-539, and miR-539 negatively regulated LAMA4 expression by directly targeting its 3'-UTR. Conclusions: Our study suggested that miR-539 suppressed the expression of LAMA4. LAMA4 plays an important role in tumor progression and may be an important target in treatment of TNBC. PMID- 29434524 TI - The control of allergic rhinitis in real life: a multicenter cross-sectional Italian study. AB - Background: Allergic Rhinitis (AR) is a high-prevalence disease. In Europe about 25% of the general population is affected, and in Italy the prevalence is estimated to be 19.8%. The Allergic Rhinitis and its Impact on Asthma (ARIA) international document underlined that the prevalence of severe or refractory or overlapping rhinitis is increasing and represents a non-negligible socio-economic burden. In general, despite the social healthcare costs, allergic rhinitis remains underestimated, not sufficiently controlled and often undertreated. Aim of the study: In this multi-center Italian observational and prospective study we assessed the control of AR in patients (> 16 years) without previous asthma diagnosis, referred to Allergy Centers. Methods: Patients of both sexes and older than 16 with rhinitis symptoms and without asthma were studied. A Visual Analogue Scale (VAS) and the CARAT (Control of Allergic Rhinitis and Asthma Test) were used as patient reported outcome. The possible causes of poor control of AR, as per protocol, were assessed accordingly. Results: We observed 250 patients in a real-life setting: more than 60% of them had an uncontrolled AR, only about 50% used multiple medications, and only a minority were receiving allergen immunotherapy. Conclusion: This survey, conducted in a real-life setting, confirmed that AR is overall poorly controlled. The VAS assessment well correlates with the structured CARAT questionnaire and with the relevant symptoms of AR. PMID- 29434523 TI - Allergic sensitization to common pets (cats/dogs) according to different possible modalities of exposure: an Italian Multicenter Study. AB - Background: The query "are there animals at home?" is usually administered for collecting information on anamnesis. This modality to consider exposure to pet allergens constitutes a potential bias in epidemiological studies and in clinical practice. The aim of our study was to evaluate/quantify different modalities of exposure to cat/dog in inducing allergic sensitization. Methods: Thirty Italian Allergy units participated in this study. Each centre was required to collect the data of at least 20 consecutive outpatients sensitized to cat/dog allergens. A standardized form reported all demographic data and a particular attention was paid in relieving possible modalities of exposure to cat/dog. Results: A total 723 patients sensitized to cat/dog were recorded, 359 (49.65%) reported direct pet contact, 213 patients (29.46%) were pet owners, and 146 subjects (20.19%) were exposed to pets in other settings. Other patients were sensitized by previous pet ownership (150-20.75%) or indirect contact (103-14.25%), in 111 subjects (15.35%) any contact was reported. Conclusions: Only 213 patients (29.46%) would be classified as "exposed to animals" and 510 (70.54%) as "not exposed" according to usual query. Our classification has shown that many "not exposed" subjects (399-55.19%) were "really exposed". The magnitude of exposure to pet allergens at home is not related exclusively to pet ownership. These considerations should be taken into account during the planning of epidemiological studies and in clinical practice for the management of pet allergic individuals. PMID- 29434525 TI - Detecting clinically relevant rivaroxaban or dabigatran levels by routine coagulation tests or thromboelastography in a cohort of patients with atrial fibrillation. AB - Background: Traditional coagulation tests are included in emergency guidelines for management of patients on direct oral anticoagulants (DOACs) who experience acute bleeding or require surgery. We determined the ability of traditional coagulation tests and fast whole blood thromboelastography (ROTEM(r)) to screen for anticoagulation activity of dabigatran and rivaroxaban as low as 30 ng/mL. Methods: One hundred eighty-four citrated blood samples (75 dabigatran, 109 rivaroxaban) were collected from patients with non-valvular atrial fibrillation (NVAF), to perform screening tests from different manufacturers, (diluted, D) PT, aPTT, TT and ROTEM(r). The activity of DOACs was quantitatively determined by clot detection assays: Hemoclot DTT and DiXaI test (Biophen), on CS2100 (Siemens). The clotting time (CT) of INTEM and EXTEM ROTEM(r) (Werfen) were used as test parameters. Results: Dabigatran, >= 30 ng/mL, was accurately detected by five coagulation tests: APTT Actin FSL (93%), PT Neoplastin (93%), APTT Cephascreen, Thromboclotin, and Thrombin (all 100%), but not by PT Innovin (49%). CT-EXTEM (91%) was sufficiently sensitive, but not CT-INTEM (52%). APTT Cephascreen and Thrombin showed good linearity (R2 = 0.71,R2 = 0.72). For the other tests linearity was moderate to poor. Rivaroxaban was accurately detected by PT Neoplastin (98%) and less so by APTT Cephascreen (85%). In addition, rivaroxaban was also accurately detected by CT-INTEM (96%). PT Neoplastin showed good linearity (R2 = 0.81), all other tests had moderate to poor linearity. Conclusion: In patients with NVAF, the ability of routine coagulation tests to detect the presence of significant levels of DOACs is test and reagent dependent. CT-INTEM and CT-EXTEM may be fast whole blood alternatives. Trial registration: The Institutional Review Board of the MUMC approved this study (December 2011, project number 114069). PMID- 29434526 TI - Improving the first-line treatment of febrile illnesses in Ghana: willingness to pay for malaria rapid diagnostic tests at licensed chemical shops in the Kintampo area. AB - Background: Use of malaria rapid diagnostic test (mRDT) enhances patient management and reduces costs associated with the inappropriate use of antimalarials. Despite its proven clinical effectiveness, mRDT is not readily available at licensed chemical shops in Ghana. Therefore, in order to improve the use of mRDT, there is the need to understand the willingness to pay for and sell mRDT. This study assessed patients' willingness to pay and licensed chemical operators' (LCS) willingness to sell mRDTs. Methods: The study was a cross sectional survey conducted in Kintampo North Municipality and Kintampo South District of Ghana. Contingent valuation method using the dichotomous approach was applied to explore patient's willingness to pay. In-depth interviews (IDIs) were used to obtain information from licensed chemical operators' willingness to sell. Results: Majority 161 (97%) of the customers were willing to pay for mRDT while 100% of licensed chemical operators were also willing to sell mRDT. The average lowest amount respondents were willing to pay was Ghana cedis (GHc) 1.1 (US$ 0.26) and an average highest amount of GHc 2.1 (US$ 0.49). LCS operators were willing to sell the test kit at an average lowest price of GHc1 (US$ 0.23) and average highest price of GHc2 (US$ 0.47). Conclusion: Community members were willing to pay for mRDT and LCS operators are willing to sell mRDTs. However, the high cost of the mRDT is likely to prevent the widespread use of mRDT. There is a clear need to find system-compatible ways to subsidize the use of mRDT via National Health Insurance scheme. PMID- 29434528 TI - Antitumor Efficacy of Human Monocyte-Derived Dendritic Cells: Comparing Effects of two Monocyte Isolation Methods. AB - Background: Dendritic cells (DCs), which can be used as anti-cancer vaccines, are generally obtained in vitro from isolated CD14+ monocytes (MoDCs). This generates high cell numbers and allows instructing DCs to guarantee effective antitumor responses. However, the impact of the monocyte isolation step in the antitumor effectiveness of the generated MoDCs is still unknown. Here, we compared the most used immunomagnetic technologies for monocyte isolation: magnetic activated cell sorting (MACS) from Miltenyi Biotec and EasySep from STEM CELL. Results: MACS technology allowed a higher monocyte yield and purity and, by flow cytometry, monocytes displayed higher size and lower granularity. In the resting state, EasySep_MoDCs showed a higher basal expression of HLA-DR, and no significant response to stimulation by LPS and TNF-alpha. When stimulated with whole tumor cells lysates, both MoDCs expressed similar levels of maturation and co stimulatory markers. However, when cultured with autologous T cells, MACS_MoDCs induced significantly higher IFN-gamma secretion than EasySep_MoDCs, indicating a stronger induction of Th1 cell response profile. Concordantly, T cells induced by MACS_MoDCs also showed a higher release of cytotoxic granules when in contact with tumor cells. Conclusions: Overall, both the MACS and the EasySep isolation immunomagnetic technologies provide monocytes that differentiate into viable and functional MoDCs. In our experimental settings, resting EasySep_MoDCs showed a higher basal level of maturation but show less responsivity to stimuli. On the other hand, MACS_MoDCs, when stimulated with tumor antigens, showed better ability to stimulate Th1 responses and to induce T cell cytotoxicity against tumor cells. Thus, monocyte isolation techniques crucially affect MoDCs' function and, therefore, should be carefully selected to obtain the desired functionality. PMID- 29434527 TI - Visualisation of Multiple Tight Junctional Complexes in Human Airway Epithelial Cells. AB - Background: Apically located tight junctions in airway epithelium perform a fundamental role in controlling macromolecule migration through paracellular spaces. Alterations in their expression may lead to disruptions in barrier integrity, which subsequently facilitates entry of potential bacterial and other pathogens into the host. Furthermore, there is emerging evidence that the barrier integrity of the airway in certain airway inflammatory diseases may be altered. However, there is little consensus on the way this is assessed and measured and the type of cells used to achieve this. Methods: Here, we assessed four fixation methods including; (i) 4% (v/v) paraformaldehyde; (ii) 100% methanol; (iii) acetone or; (iv) 1:1 methanol: acetone. Pre-extraction with Triton X-100 was also performed and assessed on cells prior to fixation with either methanol or paraformaldehyde. Cells were also permeabilized with 0.1% (v/v) Saponin in 1* TBS following fixation and subsequently stained for tight junction proteins. Confocal microscopy was then used to visualise, compare and evaluate staining intensity of the tight junctional complexes in order to determine a standardised workflow of reproducible staining. Results: Positive staining was observed following methanol fixation for claudin-1 and ZO-1 tight junction proteins but no staining was detected for occludin in 16HBE14o- cells. Combinatorial fixation with methanol and acetone also produced consistent positive staining for both occludin and ZO-1 tight junction proteins in these cells. When assessed using primary cells cultured at air-liquid interface, similar positive staining for claudin-1 and ZO 1 was observed following methanol fixation, while similar positive staining for occludin and ZO-1 was observed following the same combinatorial fixation with methanol and acetone. Conclusions: The present study demonstrates the importance of a personalised approach to optimise staining for the visualisation of different tight junction proteins. Of significance, the workflow, once optimised, can readily be translated into primary airway epithelial cell air-liquid interface cultures where it can be used to assess barrier integrity in chronic lung diseases. PMID- 29434529 TI - High protein consumption in trained women: bad to the bone? AB - Background: It has been posited that the consumption of extra protein (> 0.8 g/kg/d) may be deleterious to bone mineral content. However, there is no direct evidence to show that consuming a high-protein diet results in a demineralization of the skeleton. Thus, the primary endpoint of this randomized controlled trial was to determine if a high-protein diet affected various parameters of whole body and lumbar bone mineral content in exercise-trained women. Methods: Twenty-four women volunteered for this 6-month investigation (n = 12 control, n = 12 high protein). The control group was instructed to consume their habitual diet; however, the high-protein group was instructed to consume >=2.2 g of protein per kilogram body weight daily (g/kg/d). Body composition was assessed via dual energy x-ray absorptiometry (DXA). Subjects were instructed to keep a food diary via the mobile app MyFitnessPal(r). Exercise or activity level was not controlled. Subjects were asked to maintain their current levels of exercise. Results: During the 6-month treatment period, there was a significant difference in protein intake between the control and high-protein groups (mean+/-SD; control: 1.5+/-0.3, high-protein: 2.8+/-1.1 g/kg/d); however, there were no differences in the consumption total calories, carbohydrate or fat. Whole body bone mineral density did not change in the control (pre: 1.22+/-0.08, post: 1.22+/-0.09 g/cm2) or high-protein group (pre: 1.25+/-0.11, post: 1.24+/-0.10 g/cm2). Similarly, lumbar bone mineral density did not change in the control (pre: 1.08+/-0.16, post: 1.05+/-0.13 g/cm2) or high-protein group (pre: 1.07+/ 0.11, post: 1.08+/-0.12 g/cm2). In addition, there were no changes in whole body or lumbar T-Scores in either group. Furthermore, there were no changes in fat mass or lean body mass. Conclusion: Despite an 87% higher protein intake (high protein versus control), 6 months of a high-protein diet had no effect on whole body bone mineral density, lumbar bone mineral density, T-scores, lean body mass or fat mass. PMID- 29434530 TI - Active Stiffness Tuning of a Spring-based Continuum Robot for MRI-Guided Neurosurgery. AB - Deep intracranial tumor removal can be achieved if the neurosurgical robot has sufficient flexibility and stability. Towards achieving this goal, we have developed a spring-based continuum robot, namely a Minimally Invasive Neurosurgical Intracranial Robot (MINIR-II) with novel tendon routing and tunable stiffness for use in a magnetic resonance imaging (MRI) environment. The robot consists of a pair of springs in parallel, i.e., an inner inter-connected spring that promotes flexibility with decoupled segment motion and an outer spring that maintains its smooth curved shape during its interaction with the tissue. We propose a shape memory alloy (SMA) spring backbone that provides local stiffness control and a tendon routing configuration that enables independent segment locking. In this work, we also present a detailed local stiffness analysis of the SMA backbone and model the relationship between the resistive force at the robot tip and the tension in the tendon. We also demonstrate through experiments, the validity of our local stiffness model of the SMA backbone and the correlation between the tendon tension and the resistive force. We also performed MRI compatibility studies of the 3-segment MINIR-II robot by attaching it to a robotic platform that consists of SMA spring actuators with integrated water cooling modules. PMID- 29434532 TI - Reflections on the ethics of participatory visual methods to engage communities in global health research. AB - There is a growing body of literature describing conceptual frameworks for working with participatory visual methods (PVM). Through a global health lens, this paper examines some key themes within these frameworks. We reflect on our experiences of working with with an array of PVM to engage community members in Vietnam, Kenya, the Philippines and South Africa in biomedical research and public health. The participants that we have engaged in these processes live in under-resourced areas with high prevalence of communicable and non-communicable diseases. Our paper describes some of the challenges that we have encountered while using PVM to foster knowledge exchange, build relationships and facilitate change among individuals and families, community members, health workers, biomedical scientists and researchers. We consider multiple ethical situations that have arisen through our work and discuss the ways in which we have navigated and negotiated them. We offer our reflections and learning from facilitating these processes and in doing so we add novel contributions to ethical framework concepts. PMID- 29434531 TI - Synthesis and Bioevaluation of Iodine-131 Directly Labeled Cyclic RGD-PEGylated Gold Nanorods for Tumor-Targeted Imaging. AB - Introduction: Radiolabeled gold nanoparticles play an important role in biomedical application. The aim of this study was to prepare iodine-131 (131I) labeled gold nanorods (GNRs) conjugated with cyclic RGD and evaluate its biological characteristics for targeted imaging of integrin alphavbeta3 expressing tumors. Methods: HS-PEG(5000)-COOH molecules were applied to replace CTAB covering the surface of bare GNRs for better biocompatibility, and c(RGDfK) peptides were conjugated onto the carboxyl terminal of GNR-PEG-COOH via EDC/NHS coupling reactions. The nanoconjugate was characterized, and 131I was directly tagged on the surface of GNRs via AuI bonds for SPECT/CT imaging. We preliminarily studied the characteristics of the probe and its feasibility for tumor-targeting SPECT/CT imaging. Results: The [131I]GNR-PEG-cRGD probe was prepared in a simple and rapid manner and was stable in both PBS and fetal bovine serum. It targeted selectively and could be taken up by tumor cells mainly via integrin alphavbeta3-receptor-mediated endocytosis. In vivo imaging, biodistribution, and autoradiography results showed evident tumor uptake in integrin alphavbeta3-expressing tumors. Conclusions: These promising results showed that this smart nanoprobe can be used for angiogenesis-targeted SPECT/CT imaging. Furthermore, the nanoprobe possesses a remarkable capacity for highly efficient photothermal conversion in the near-infrared region, suggesting its potential as a multifunctional theranostic agent. PMID- 29434533 TI - Reference Values and Influencing Factors Analysis for Current Perception Threshold Testing Based on Study of 166 Healthy Chinese. AB - The current perception threshold (CPT) is a device which can evaluate different sensory fibers quantitatively through different frequencies of the electrical stimulus and has been applied in clinical practice. Previous studies have implied that CPT values may be affected by age, gender, and other factors, yet not conclusively. The objective of our study is to clarify the influencing factors of CPT values and establish a reference value range. Twenty healthy volunteers recruited publicly and 146 subjects who took CPT tests in the census of the national project cardiovascular and cerebrovascular diseases in rural areas of China from 2013 to 2015 were analyzed. Past medical history and demographic characteristics such as age, gender, and occupation were collected. Each subject was tested on the left index finger (or back of the left hand) and the right hallux. CPT values of 2000, 250, and 5 Hz on both sites were recorded for statistical analysis. Gender differences were shown at 2000 Hz CPT on the back of the hand and hallux (p < 0.01), and male subjects had a higher CPT. Age had a positive correlation with 250 Hz CPT on the index finger (p < 0.05, r = 1.5), 2000 Hz CPT on the back of the hand (p < 0.001, r = 1.2) and index finger (p < 0.05, r = 2.5). Manual workers had a higher 250 Hz CPT on the hallux than mental workers (p < 0.01). After investigating the impact of different factors on CPT testing, we established the reference value for subjects with different characteristics. PMID- 29434534 TI - Assessment of Cochlear Function during Cochlear Implantation by Extra- and Intracochlear Electrocochleography. AB - Objective: The aims of this study were: (1) To investigate the correlation between electrophysiological changes during cochlear implantation and postoperative hearing loss, and (2) to detect the time points that electrophysiological changes occur during cochlear implantation. Material and Methods: Extra- and intracochlear electrocochleography (ECoG) were used to detect electrophysiological changes during cochlear implantation. Extracochlear ECoG recordings were conducted through a needle electrode placed on the promontory; for intracochlear ECoG recordings, the most apical contact of the cochlear implant (CI) electrode itself was used as the recording electrode. Tone bursts at 250, 500, 750, and 1000 Hz were used as low-frequency acoustic stimuli and clicks as high-frequency acoustic stimuli. Changes of extracochlear ECoG recordings after full insertion of the CI electrode were correlated with pure-tone audiometric findings 4 weeks after surgery. Results: Changes in extracochlear ECoG recordings correlated with postoperative hearing change (r = -0.44, p = 0.055, n = 20). Mean hearing loss in subjects without decrease or loss of extracochlear ECoG signals was 12 dB, compared to a mean hearing loss of 22 dB in subjects with a detectable decrease or a loss of ECoG signals (p = 0.0058, n = 51). In extracochlear ECoG recordings, a mean increase of the ECoG signal of 4.4 dB occurred after opening the cochlea. If a decrease of ECoG signals occurred during insertion of the CI electrode, the decrease was detectable during the second half of the insertion. Conclusion: ECoG recordings allow detection of electrophysiological changes in the cochlea during cochlear implantation. Decrease of extracochlear ECoG recordings during surgery has a significant correlation with hearing loss 4 weeks after surgery. Trauma to cochlear structures seems to occur during the final phase of the CI electrode insertion. Baseline recordings for extracochlear ECoG recordings should be conducted after opening the cochlea. ECoG responses can be recorded from an intracochlear site using the CI electrode as recording electrode. This technique may prove useful for monitoring cochlear trauma intraoperatively in the future. PMID- 29434535 TI - Altered Expression Profile of IgLON Family of Neural Cell Adhesion Molecules in the Dorsolateral Prefrontal Cortex of Schizophrenic Patients. AB - Neural adhesion proteins are crucial in the development and maintenance of functional neural connectivity. Growing evidence suggests that the IgLON family of neural adhesion molecules LSAMP, NTM, NEGR1, and OPCML are important candidates in forming the susceptibility to schizophrenia (SCZ). IgLON proteins have been shown to be involved in neurite outgrowth, synaptic plasticity and neuronal connectivity, all of which have been shown to be altered in the brains of patients with the diagnosis of schizophrenia. Here we optimized custom 5' isoform-specific TaqMan gene-expression analysis for the transcripts of human IgLON genes to study the expression of IgLONs in the dorsolateral prefrontal cortex (DLPFC) of schizophrenic patients (n = 36) and control subjects (n = 36). Uniform 5'-region and a single promoter was confirmed for the human NEGR1 gene by in silico analysis. IgLON5, a recently described family member, was also included in the study. We detected significantly elevated levels of the NEGR1 transcript (1.33-fold increase) and the NTM 1b isoform transcript (1.47-fold increase) in the DLPFC of schizophrenia patients compared to healthy controls. Consequent protein analysis performed in male subjects confirmed the increase in NEGR1 protein content both in patients with the paranoid subtype and in patients with other subtypes. In-group analysis of patients revealed that lower expression of certain IgLON transcripts, mostly LSAMP 1a and 1b, could be related with concurrent depressive endophenotype in schizophrenic patients. Additionally, our study cohort provides further evidence that cannabis use may be a relevant risk factor associated with suicidal behaviors in psychotic patients. In conclusion, we provide clinical evidence of increased expression levels of particular IgLON family members in the DLPFC of schizophrenic patients. We propose that alterations in the expression profile of IgLON neural adhesion molecules are associated with brain circuit disorganization in neuropsychiatric disorders, such as schizophrenia. In the light of previously published data, we suggest that increased level of NEGR1 in the frontal cortex may serve as molecular marker for a wider spectrum of psychiatric conditions. PMID- 29434536 TI - Heparan Sulfate Proteoglycans as Emerging Players in Synaptic Specificity. AB - Neural circuits consist of distinct neuronal cell types connected in specific patterns. The specificity of these connections is achieved in a series of sequential developmental steps that involve the targeting of neurites, the identification of synaptic partners, and the formation of specific types of synapses. Cell-surface proteins play a critical role in each of these steps. The heparan sulfate proteoglycan (HSPG) family of cell-surface proteins is emerging as a key regulator of connectivity. HSPGs are expressed throughout brain development and play important roles in axon guidance, synapse development and synapse function. New insights indicate that neuronal cell types express unique combinations of HSPGs and HS-modifying enzymes. Furthermore, HSPGs interact with cell type-specific binding partners to mediate synapse development. This suggests that cell type-specific repertoires of HSPGs and specific patterns of HS modifications on the cell surface are required for the development of specific synaptic connections. Genome-wide association studies have linked these proteins to neurodevelopmental and neuropsychiatric diseases. Thus, HSPGs play an important role in the development of specific synaptic connectivity patterns important for neural circuit function, and their dysfunction may be involved in the development of brain disorders. PMID- 29434538 TI - Glut9-mediated Urate Uptake Is Responsible for Its Protective Effects on Dopaminergic Neurons in Parkinson's Disease Models. AB - Considerable evidence has shown that elevated plasma or cerebrospinal fluid (CSF) urate levels correlated with a reduced risk of Parkinson's disease (PD). Based on its anti-oxidative properties, urate might serve as one of promising neuroprotective candidates for PD. However, how urate is transported through cell membranes to exert its effects inside the cells in PD is largely unknown. To elucidate this, we showed that increased intracellular urate exerted its neuroprotective effects against 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in MES23.5 cells and elevated urate could antagonize 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic neuronal death in urate oxidase (UOx) knockout (KO) mice. Its transporter, glucose transporter type 9 (Glut9), was observed up-regulated, which was caused by the activation of p53. These protective effects could be abolished by Glut9 blocker and p53 inhibitor. These results suggested that Glut9 was a functional urate transporter, whose up-regulation by activation of p53 resulted in the increased intracellular urate levels in PD models. Our findings suggest that Glut9 could be modified to modulate urate levels in dopaminergic neurons and urate-elevating strategies without increasing systemic levels to avoid side effects might serve as a potential therapeutic target for PD. PMID- 29434537 TI - How Can a Ketogenic Diet Improve Motor Function? AB - A ketogenic diet (KD) is a normocaloric diet composed by high fat (80-90%), low carbohydrate, and low protein consumption that induces fasting-like effects. KD increases ketone body (KBs) production and its concentration in the blood, providing the brain an alternative energy supply that enhances oxidative mitochondrial metabolism. In addition to its profound impact on neuro-metabolism and bioenergetics, the neuroprotective effect of specific polyunsaturated fatty acids and KBs involves pleiotropic mechanisms, such as the modulation of neuronal membrane excitability, inflammation, or reactive oxygen species production. KD is a therapy that has been used for almost a century to treat medically intractable epilepsy and has been increasingly explored in a number of neurological diseases. Motor function has also been shown to be improved by KD and/or medium-chain triglyceride diets in rodent models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and spinal cord injury. These studies have proposed that KD may induce a modification in synaptic morphology and function, involving ionic channels, glutamatergic transmission, or synaptic vesicular cycling machinery. However, little is understood about the molecular mechanisms underlying the impact of KD on motor function and the perspectives of its use to acquire the neuromuscular effects. The aim of this review is to explore the conditions through which KD might improve motor function. First, we will describe the main consequences of KD exposure in tissues involved in motor function. Second, we will report and discuss the relevance of KD in pre-clinical and clinical trials in the major diseases presenting motor dysfunction. PMID- 29434539 TI - Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems. AB - Sedatives target just a handful of receptors and ion channels. But we have no satisfying explanation for how activating these receptors produces sedation. In particular, do sedatives act at restricted brain locations and circuitries or more widely? Two prominent sedative drugs in clinical use are zolpidem, a GABAA receptor positive allosteric modulator, and dexmedetomidine (DEX), a selective alpha2 adrenergic receptor agonist. By targeting hypothalamic neuromodulatory systems both drugs induce a sleep-like state, but in different ways: zolpidem primarily reduces the latency to NREM sleep, and is a controlled substance taken by many people to help them sleep; DEX produces prominent slow wave activity in the electroencephalogram (EEG) resembling stage 2 NREM sleep, but with complications of hypothermia and lowered blood pressure-it is used for long term sedation in hospital intensive care units-under DEX-induced sedation patients are arousable and responsive, and this drug reduces the risk of delirium. DEX, and another alpha2 adrenergic agonist xylazine, are also widely used in veterinary clinics to sedate animals. Here we review how these two different classes of sedatives, zolpidem and dexmedetomideine, can selectively interact with some nodal points of the circuitry that promote wakefulness allowing the transition to NREM sleep. Zolpidem enhances GABAergic transmission onto histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) to hasten the transition to NREM sleep, and DEX interacts with neurons in the preoptic hypothalamic area that induce sleep and body cooling. This knowledge may aid the design of more precise acting sedatives, and at the same time, reveal more about the natural sleep-wake circuitry. PMID- 29434540 TI - Perceptual Color Space Representations in the Oculomotor System Are Modulated by Surround Suppression and Biased Selection. AB - The oculomotor system utilizes color extensively for planning saccades. Therefore, we examined how the oculomotor system actually encodes color and several factors that modulate these representations: attention-based surround suppression and inherent biases in selecting and encoding color categories. We measured saccade trajectories while human participants performed a memory-guided saccade task with color targets and distractors and examined whether oculomotor target selection processing was functionally related to the CIE (x,y) color space distances between color stimuli and whether there were hierarchical differences between color categories in the strength and speed of encoding potential saccade goals. We observed that saccade planning was modulated by the CIE (x,y) distances between stimuli thus demonstrating that color is encoded in perceptual color space by the oculomotor system. Furthermore, these representations were modulated by (1) cueing attention to a particular color thereby eliciting surround suppression in oculomotor color space and (2) inherent selection and encoding biases based on color category independent of cueing and perceptual discriminability. Since surround suppression emerges from recurrent feedback attenuation of sensory projections, observing oculomotor surround suppression suggested that oculomotor encoding of behavioral relevance results from integrating sensory and cognitive signals that are pre-attenuated based on task demands and that the oculomotor system therefore does not functionally contribute to this process. Second, although perceptual discriminability did partially account for oculomotor processing differences between color categories, we also observed preferential processing of the red color category across various behavioral metrics. This is consistent with numerous previous studies and could not be simply explained by perceptual discriminability. Since we utilized a memory-guided saccade task, this indicates that the biased processing of the red color category does not rely on sustained sensory input and must therefore involve cortical areas associated with the highest levels of visual processing involved in visual working memory. PMID- 29434542 TI - Norepinephrine in the Medial Pre-frontal Cortex Supports Accumbens Shell Responses to a Novel Palatable Food in Food-Restricted Mice Only. AB - Previous findings from this laboratory demonstrate: (1) that different classes of addictive drugs require intact norepinephrine (NE) transmission in the medial pre Frontal Cortex (mpFC) to promote conditioned place preference and to increase dopamine (DA) tone in the nucleus accumbens shell (NAc Shell); (2) that only food restricted mice require intact NE transmission in the mpFC to develop conditioned preference for a context associated with milk chocolate; and (3) that food restricted mice show a significantly larger increase of mpFC NE outflow then free fed mice when experiencing the palatable food for the first time. In the present study we tested the hypothesis that only the high levels of frontal cortical NE elicited by the natural reward in food restricted mice stimulate mesoaccumbens DA transmission. To this aim we investigated the ability of a first experience with milk chocolate to increase DA outflow in the accumbens Shell and c-fos expression in striatal and limbic areas of food-restricted and ad-libitum fed mice. Moreover, we tested the effects of a selective depletion of frontal cortical NE on both responses in either feeding group. Only in food-restricted mice milk chocolate induced an increase of DA outflow beyond baseline in the accumbens Shell and a c-fos expression larger than that promoted by a novel inedible object in the nucleus accumbens. Moreover, depletion of frontal cortical NE selectively prevented both the increase of DA outflow and the large expression of c-fos promoted by milk chocolate in the NAc Shell of food-restricted mice. These findings support the conclusion that in food-restricted mice a novel palatable food activates the motivational circuit engaged by addictive drugs and support the development of noradrenergic pharmacology of motivational disturbances. PMID- 29434544 TI - The Contribution of Upper Body Movements to Dynamic Balance Regulation during Challenged Locomotion. AB - Recent studies suggest that in addition to movements between ankle and hip joints, movements of the upper body, in particular of the arms, also significantly contribute to postural control. In line with these suggestions, we analyzed regulatory movements of upper and lower body joints supporting dynamic balance regulation during challenged locomotion. The participants walked over three beams of varying width and under three different verbally conveyed restrictions of arm posture, to control the potential influence of arm movements on the performance: The participants walked (1) with their arms stretched out perpendicularly in the frontal plane, (2) spontaneously, i.e., without restrictions to the arm movements, and (3) with their hands on their thighs. After applying an inverse-dynamics analysis to the measured joint kinematics, we investigated the contribution of upper and lower body joints to balance regulation in terms of torque amplitude and variation. On the condition with the hands on the thighs, the contribution of the upper body remains significantly lower than the contribution of the lower body irrespective of beam widths. For spontaneous arm movements and for outstretched arms we find that the upper body (including the arms) contributes to the balancing to a similar extent as the lower body. Moreover, when the task becomes more difficult, i.e., for narrower beam widths, the contribution of the upper body increases, while the contribution of the lower body remains nearly constant. These findings lend further support to the hypothetical existence of an "upper body strategy" complementing the ankle and hip strategies especially during challenging dynamic balance tasks. PMID- 29434543 TI - Altered Functional Connectivity of Fronto-Cingulo-Striatal Circuits during Error Monitoring in Adolescents with a History of Childhood Abuse. AB - Childhood maltreatment is associated with error hypersensitivity. We examined the effect of childhood abuse and abuse-by-gene (5-HTTLPR, MAOA) interaction on functional brain connectivity during error processing in medication/drug-free adolescents. Functional connectivity was compared, using generalized psychophysiological interaction (gPPI) analysis of functional magnetic resonance imaging (fMRI) data, between 22 age- and gender-matched medication-naive and substance abuse-free adolescents exposed to severe childhood abuse and 27 healthy controls, while they performed an individually adjusted tracking stop-signal task, designed to elicit 50% inhibition failures. During inhibition failures, abused participants relative to healthy controls exhibited reduced connectivity between right and left putamen, bilateral caudate and anterior cingulate cortex (ACC), and between right supplementary motor area (SMA) and right inferior and dorsolateral prefrontal cortex. Abuse-related connectivity abnormalities were associated with longer abuse duration. No group differences in connectivity were observed for successful inhibition. The findings suggest that childhood abuse is associated with decreased functional connectivity in fronto-cingulo-striatal networks during error processing. Furthermore that the severity of connectivity abnormalities increases with abuse duration. Reduced connectivity of error detection networks in maltreated individuals may be linked to constant monitoring of errors in order to avoid mistakes which, in abusive contexts, are often associated with harsh punishment. PMID- 29434541 TI - The Influence of Early Life Experience on Visceral Pain. AB - Pain is the most reported and troublesome symptom of nearly all functional disorders affecting the genitourinary and gastrointestinal organs. Patients with irritable bowel syndrome (IBS), interstitial cystitis/painful bladder syndrome (IC/PBS), vulvodynia, and/or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS; collectively termed chronic pelvic pain syndromes) report pain severe enough to impact quality of life and often suffer from symptoms of or are diagnosed with more than one of these syndromes. This increased comorbidity between chronic pelvic pain syndromes, and with pain disorders of disparate body regions, as well as with mood disorders, can be influenced by disruptions in the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the response to stress and influences the perception of pain. Experiencing trauma, neglect, or abuse in early life can permanently affect the functioning of the HPA axis. As such, a significant proportion of patients suffering from comorbid chronic pelvic pain syndromes report a history of early life stress or trauma. Here we will report on how these early life experiences influence chronic pelvic pain in patients. We will also discuss various rodent models that have been developed to study this phenomenon to understand the mechanisms underlying HPA axis dysfunction, as well as potential underlying mechanisms connecting these syndromes to one another. PMID- 29434545 TI - An Updated Survey on Statistical Thresholding and Sample Size of fMRI Studies. AB - Background: Since the early 2010s, the neuroimaging field has paid more attention to the issue of false positives. Several journals have issued guidelines regarding statistical thresholds. Three papers have reported the statistical analysis of the thresholds used in fMRI literature, but they were published at least 3 years ago and surveyed papers published during 2007-2012. This study revisited this topic to evaluate the changes in this field. Methods: The PubMed database was searched to identify the task-based (not resting-state) fMRI papers published in 2017 and record their sample sizes, inferential methods (e.g., voxelwise or clusterwise), theoretical methods (e.g., parametric or non parametric), significance level, cluster-defining primary threshold (CDT), volume of analysis (whole brain or region of interest) and software used. Results: The majority (95.6%) of the 388 analyzed articles reported statistics corrected for multiple comparisons. A large proportion (69.6%) of the 388 articles reported main results by clusterwise inference. The analyzed articles mostly used software Statistical Parametric Mapping (SPM), Analysis of Functional NeuroImages (AFNI), or FMRIB Software Library (FSL) to conduct statistical analysis. There were 70.9%, 37.6%, and 23.1% of SPM, AFNI, and FSL studies, respectively, that used a CDT of p <= 0.001. The statistical sample size across the articles ranged between 7 and 1,299 with a median of 33. Sample size did not significantly correlate with the level of statistical threshold. Conclusion: There were still around 53% (142/270) studies using clusterwise inference that chose a more liberal CDT than p = 0.001 (n = 121) or did not report their CDT (n = 21), down from around 61% reported by Woo et al. (2014). For FSL studies, it seemed that the CDT practice had no improvement since the survey by Woo et al. (2014). A few studies chose unconventional CDT such as p = 0.0125 or 0.004. Such practice might create an impression that the threshold alterations were attempted to show "desired" clusters. The median sample size used in the analyzed articles was similar to those reported in previous surveys. In conclusion, there seemed to be no change in the statistical practice compared to the early 2010s. PMID- 29434546 TI - Matrine Is Identified as a Novel Macropinocytosis Inducer by a Network Target Approach. AB - Comprehensively understanding pharmacological functions of natural products is a key issue to be addressed for the discovery of new drugs. Unlike some single target drugs, natural products always exert diverse therapeutic effects through acting on a "network" that consists of multiple targets, making it necessary to develop a systematic approach, e.g., network pharmacology, to reveal pharmacological functions of natural products and infer their mechanisms of action. In this work, to identify the "network target" of a natural product, we perform a functional analysis of matrine, a marketed drug in China extracted from a medical herb Ku-Shen (Radix Sophorae Flavescentis). Here, the network target of matrine was firstly predicted by drugCIPHER, a genome-wide target prediction method. Based on the network target of matrine, we performed a functional gene set enrichment analysis to computationally identify the potential pharmacological functions of matrine, most of which are supported by the literature evidence, including neurotoxicity and neuropharmacological activities of matrine. Furthermore, computational results demonstrated that matrine has the potential for the induction of macropinocytosis and the regulation of ATP metabolism. Our experimental data revealed that the large vesicles induced by matrine are consistent with the typical characteristics of macropinosome. Our verification results also suggested that matrine could decrease cellular ATP level. These findings demonstrated the availability and effectiveness of the network target strategy for identifying the comprehensive pharmacological functions of natural products. PMID- 29434547 TI - Effects of Prefrontal Transcranial Direct Current Stimulation and Motivation to Quit in Tobacco Smokers: A Randomized, Sham Controlled, Double-Blind Trial. AB - : Transcranial direct current stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) has been shown to reduce cravings in tobacco addiction; however, results have been somewhat mixed. In this study, we hypothesized that motivation to quit smoking is a critical factor of tDCS effects in smokers. Therefore, we conducted a double-blind, randomized clinical trial to evaluate the effects of both tDCS and motivation to quit on cigarette consumption and the relationship between these two factors. DLPFC tDCS was applied once a day for 5 days. Our primary outcome was the amount of cigarettes smoked per day. We collected this information at baseline (d1), at the end of the treatment period (d5), 2 days later (d7) and at the 4-week follow-up (d35). Visual Analog Scale (VAS) for motivation to quit was collected at the same time-points. 36 subjects (45 +/- 11 years old; 24.2 +/- 11.5 cigarettes daily smoked, 21 women) were randomized to receive either active or sham tDCS. In our multivariate analysis, as to take into account the mediation and moderation effects of motivation to quit, we found a significant main effect of tDCS, showing that tDCS was associated with a significant reduction of cigarettes smoked per day. We also showed a significant interaction effect of motivation to quit and treatment, supporting our hypothesis that tDCS effects were moderated by motivation to quit, indicating that higher levels of motivation were associated with a larger tDCS response. We found that the participants' motivation to quit alone, both at baseline and at follow-up, does not explain the decrease in the average cigarette consumption. Repetitive prefrontal tDCS coupled with high motivation significantly reduced cigarette consumption up to 4-weeks post-intervention. CLINICAL TRIAL REGISTRATION: http://ClinicalTrials.gov, NCT02146014. PMID- 29434548 TI - Transporter-Guided Delivery of Nanoparticles to Improve Drug Permeation across Cellular Barriers and Drug Exposure to Selective Cell Types. AB - Targeted nano-drug delivery systems conjugated with specific ligands to target selective cell-surface receptors or transporters could enhance the efficacy of drug delivery and therapy. Transporters are expressed differentially on the cell surface of different cell types, and also specific transporters are expressed at higher than normal levels in selective cell types under pathological conditions. They also play a key role in intestinal absorption, delivery via non-oral routes (e.g., pulmonary route and nasal route), and transfer across biological barriers (e.g., blood-brain barrier and blood-retinal barrier. As such, the cell-surface transporters represent ideal targets for nano-drug delivery systems to facilitate drug delivery to selective cell types under normal or pathological conditions and also to avoid off-target adverse side effects of the drugs. There is increasing evidence in recent years supporting the utility of cell-surface transporters in the field of nano-drug delivery to increase oral bioavailability, to improve transfer across the blood-brain barrier, and to enhance delivery of therapeutics in a cell-type selective manner in disease states. Here we provide a comprehensive review of recent advancements in this interesting and important area. We also highlight certain key aspects that need to be taken into account for optimal development of transporter-assisted nano-drug delivery systems. PMID- 29434551 TI - Editorial: New Models of Care for Patients with Severe Mental Illness-Bridging In and Outpatients. PMID- 29434550 TI - Select Skeletal Muscle mRNAs Related to Exercise Adaptation Are Minimally Affected by Different Pre-exercise Meals that Differ in Macronutrient Profile. AB - Background: Substantial research has been done on the impact of carbohydrate and fat availability on endurance exercise adaptation, though its role in the acute adaptive response to resistance exercise has yet to be fully characterized. Purpose: We aimed to assess the effects of a pre-resistance exercise isocaloric mixed meal containing different amounts of carbohydrates and fat, on post resistance exercise gene expression associated with muscle adaptation. Methods: Thirteen young (age 21.2 +/- 1.6 year), recreationally trained (VO2max 51.3 +/- 4.8 ml/kg/min) men undertook an aerobic exercise session of 90-min continuous cycling (70% VO2max) in the morning with pre- and post-exercise protein ingestion (10 and 15 g casein in a 500 ml beverage pre- and post-exercise, respectively). Subjects then rested for 2 h and were provided with a meal consisting of either 3207 kJ; 52 g protein; 51 g fat; and 23 g carbohydrate (FAT) or 3124 kJ; 53 g protein; 9 g fat; and 109 g carbohydrate (CHO). Two hours after the meal, subjects completed 5 * 8 repetitions (80% 1-RM) for both bilateral leg press and leg extension directly followed by 25 g of whey protein (500 ml beverage). Muscle biopsies were obtained from the vastus lateralis at baseline (morning) and 1 and 3 h post-resistance exercise (afternoon) to determine intramuscular mRNA response. Results: Muscle glycogen levels were significantly decreased post resistance exercise, without any differences between conditions. Plasma free fatty acids increased significantly after the mixed meal in the FAT condition, while glucose and insulin were higher in the CHO condition. However, PDK4 mRNA quantity was significantly higher in the FAT condition at 3 h post-resistance exercise compared to CHO. HBEGF, INSIG1, MAFbx, MURF1, SIRT1, and myostatin responded solely as a result of exercise without any differences between the CHO and FAT group. FOXO3A, IGF-1, PGC-1alpha, and VCP expression levels remained unchanged over the course of the day. Conclusion: We conclude that mRNA quantity associated with muscle adaptation after resistance exercise is not affected by a difference in pre-exercise nutrient availability. PDK4 was differentially expressed between CHO and FAT groups, suggesting a potential shift toward fat oxidation and reduced glucose oxidation in the FAT group. PMID- 29434549 TI - Protective Mechanism of Hydrogen Sulfide against Chemotherapy-Induced Cardiotoxicity. AB - Over the past few decades, the number of long term survivors of childhood cancers has been increased exponentially. However, among these survivors, treatment related toxicity, especially cardiotoxicity, is becoming the essential cause of morbidity and mortality. Thus, preventing the treatment-related adverse effects is important to increase the event free survival during the treatment of cancer in children and adolescents. Accumulating evidence has demonstrated that hydrogen sulfide (H2S) exerts a protective role on cardiomyocytes through a variety of mechanisms. Here, we mainly reviewed the cardioprotective role of H2S in the chemotherapy, and emphatically discussed the possible mechanisms. PMID- 29434552 TI - Why Cognitive Behavioral Therapy Is the Current Gold Standard of Psychotherapy. PMID- 29434554 TI - Commentary: Physical Functional Capacity and C-Reactive Protein in Schizophrenia. PMID- 29434553 TI - Gambling and Impulsivity Traits: A Recipe for Criminal Behavior? AB - Gambling disorder (GD) is a psychiatric condition that was recently recategorized as a non-substance-related addiction in the Diagnostic and Statistical Manual of Mental Health Disorders. Criminal activity is commonly associated with gambling; however, few empirical studies to date have examined sociodemographic and psychological variables in this population. In this study, we explored criminal behavior history in a sample of consecutively recruited treatment-seeking gamblers (n = 382) and compared subjects with a history of illegal acts (n = 103, 26.9%) to those with no criminal record (n = 279, 73.1%). Impulsivity and personality traits were specifically explored, along with other gambling-related severity factors. We found that gamblers who engaged in illegal activity were more likely to endorse high levels of urgency (i.e., the tendency to act out when experiencing heightened emotional states) and increased lack of premeditation. Gamblers with a history of criminal behavior also had greater GD severity levels and gambling-related debts. Additionally, these gamblers reported lower levels of self-directedness, which is characterized by difficulty in establishing and redirecting behavior toward one's goals. Likewise, gamblers who had conducted criminal acts showed a tendency to engage in greater risk-taking behavior. These results shed new light on this understudied population and provide insights for developing targeted harm-prevention interventions and treatment protocols. PMID- 29434555 TI - An Investigation of First-Year Students' and Lecturers' Expectations of University Education. AB - Transition from school to university can cause concern for many students. One issue is the gap between students' prior expectations and the realities of university life, which can cause significant distress, poor academic performance and increased drop-out rates if not managed effectively. Research has shown several similarities in the expectations of staff and students in regards to which factors determine academic success, but there is also evidence of dissonance. For example, staff consider independent study and critical evaluation as key factors, whereas students view feedback on drafts of work and support from staff as being most important. The aim of the current study was to determine what expectations students hold when starting university education, and what expectations university lecturers have of students entering university. Lecturers (n = 20) and first year students (n = 77) completed a series of questionnaires concerning their expectations of learning in HE (staff and students) and their approach to teaching (staff). Results revealed that students have largely realistic expectations of university. For example, the majority expected to be in charge of their own study. Some unrealistic expectations were also evident, e.g., most expected that teaching would be the same at university as it had been at school. The expectation that lecturers would provide detailed notes varied as a function of student age. Lecturers reported modifying their expectations of students and adapting their teaching approach according to year of study. Information-transmission/teacher-focused style was more common when teaching 1st year students; a more concept-changing/student-focused approach tended to be used when teaching 2nd year students (and above). Lecturer's expectations of student engagement did not differ according to year. Less experienced lecturers reported more negative expectations of student engagement than did experienced lecturers. In line with previous work, we observed overlap in expectations of staff and students, but some clear differences too. PMID- 29434556 TI - Influence of Suboptimally and Optimally Presented Affective Pictures and Words on Consumption-Related Behavior. AB - Affective stimuli can influence immediate reactions as well as spontaneous behaviors. Much evidence for such influence comes from studies of facial expressions. However, it is unclear whether these effects hold for other affective stimuli, and how the amount of stimulus processing changes the nature of the influence. This paper addresses these issues by comparing the influence on consumption behaviors of emotional pictures and valence-matched words presented at suboptimal and supraliminal durations. In Experiment 1, both suboptimal and supraliminal emotional facial expressions influenced consumption in an affect congruent, assimilative way. In Experiment 2, pictures of both high- and low frequency emotional objects congruently influenced consumption. In comparison, words tended to produce incongruent effects. We discuss these findings in light of privileged access theories, which hold that pictures better convey affective meaning than words, and embodiment theories, which hold that pictures better elicit somatosensory and motor responses. PMID- 29434557 TI - A Multi-Functional View of Moral Disengagement: Exploring the Effects of Learning the Consequences. AB - This paper takes us beyond the unethical act and explores the use of moral disengagement as a multi-stage, multi-functional regulatory, and coping mechanism that not only allows individuals to engage in unethical behavior, but also manage the negative emotions (i.e., guilt and shame) from learning the consequences of such behavior. A resource-based lens is applied to the moral disengagement process, suggesting that individuals not only morally disengage prior to committing an unethical act in order to conserve their own resources, but also morally disengage as a coping mechanism to reduce emotional duress upon learning of the consequences of their actions, which we describe as post-moral disengagement. These assertions are tested using a scenario-based laboratory study consisting of 182 respondents. Findings indicate that individuals will morally disengage in order to commit an unethical act, will experience negative emotions from having learned of the consequences, and then will engage in post moral disengagement as a coping mechanism. In addition, the findings suggest that guilt and shame relate differently to moral disengagement. PMID- 29434558 TI - "I Want Her to Make Correct Decisions on Her Own:" Former Soviet Union Mothers' Beliefs about Autonomy Development. AB - This qualitative study examined Former Soviet Union (FSU) mothers' explicit and implicit attitudes and parenting practices around adolescents' autonomy development. Interviews were conducted with 10 mothers who had immigrated from the FSU to the US between 10 and 25 years ago, and who had daughters between the ages of 13 and 17 years. Mothers predominantly defined autonomy in terms of adolescents' ability to carry out instrumental tasks, make correct decisions, and financially provide for themselves, but rarely mentioned psychological or emotional independence. Mothers reflected on the various aspects of autonomy emphasized in their country of origin and America, and balancing the two sets of cultural values in their parenting. Although mothers discussed attempts to adopt a less authoritarian approach to parenting than they themselves experienced as children, some mothers' controlling attitudes were revealed through a close analysis of their language. The findings provide important insights into the parenting experiences of FSU immigrant mothers, and the way in which autonomy related processes may vary cross-culturally. Implications for parenting and clinical practice are also discussed. PMID- 29434559 TI - Perceptual Characterization of the Macronutrient Picture System (MaPS) for Food Image fMRI. AB - Food image fMRI paradigms are used widely for investigating the neural basis of ingestive behavior. However, these paradigms have not been validated in terms of ingestive behavior constructs, engagement of food-relevant neural systems, or test-retest reliability, making the generalizability of study findings unclear. Therefore, we validated the Macronutrient Picture System (MaPS) (McClernon et al., 2013), which includes food images from the six categories represented in the Geiselman Food Preference Questionnaire (FPQ) (Geiselman et al., 1998). Twenty five healthy young adults (n = 21 female, mean age = 20.6 +/- 1.1 years, mean BMI = 22.1 +/- 1.9 kg/m2) rated the MaPS images in terms of visual interest, appetitive quality, nutrition, emotional valence, liking, and frequency of consumption, and completed the FPQ. In a second study, 12 individuals (n=8 female, mean age = 25.0 +/- 6.5 years, mean BMI = 28.2 +/- 8.7 kg/m2) viewed MaPS and control images (vegetables and non-food) during two separate 3T BOLD fMRI scans after fasting overnight. Intuitively, high fat/high sugar (HF/HS) and high fat/high complex carbohydrate (HF/HCCHO) images achieved higher liking and appetitive ratings, and lower nutrition ratings, than low fat/low complex carbohydrate/high protein (LF/LCHO/HP) images on average. Within each food category, FPQ scores correlated strongly with MaPS image liking ratings (p < 0.001). Brain activation differences between viewing images of HF/HS and vegetables, and between HF/HCCHO and vegetables, were seen in several reward related brain regions (e.g., putamen, insula, and medial frontal gyrus). Intra individual, inter-scan agreement in a summary measure of brain activation differences in seven reward network regions of interest was high (ICC = 0.61), and was even higher when two distinct sets of food images with matching visual ratings were shown in the two scans (ICC = 0.74). These results suggest that the MaPS provides valid representation of food categories and reliably activates food reward-relevant neural systems. PMID- 29434560 TI - Gaze Behavior in a Natural Environment with a Task-Relevant Distractor: How the Presence of a Goalkeeper Distracts the Penalty Taker. AB - Gaze behavior in natural scenes has been shown to be influenced not only by top down factors such as task demands and action goals but also by bottom-up factors such as stimulus salience and scene context. Whereas gaze behavior in the context of static pictures emphasizes spatial accuracy, gazing in natural scenes seems to rely more on where to direct the gaze involving both anticipative components and an evaluation of ongoing actions. Not much is known about gaze behavior in far aiming tasks in which multiple task-relevant targets and distractors compete for the allocation of visual attention via gaze. In the present study, we examined gaze behavior in the far-aiming task of taking a soccer penalty. This task contains a proximal target, the ball; a distal target, an empty location within the goal; and a salient distractor, the goalkeeper. Our aim was to investigate where participants direct their gaze in a natural environment with multiple potential fixation targets that differ in task relevance and salience. Results showed that the early phase of the run-up seems to be driven by both the salience of the stimulus setting and the need to perform a spatial calibration of the environment. The late run-up, in contrast, seems to be controlled by attentional demands of the task with penalty takers having habitualized a visual routine that is not disrupted by external influences (e.g., the goalkeeper). In addition, when trying to shoot a ball as accurately as possible, penalty takers directed their gaze toward the ball in order to achieve optimal foot-ball contact. These results indicate that whether gaze is driven by salience of the stimulus setting or by attentional demands depends on the phase of the actual task. PMID- 29434561 TI - Response: Commentary: Seeing the conflict: an attentional account of reasoning errors. PMID- 29434562 TI - Latent Profile Analysis of Schizotypy and Paranormal Belief: Associations with Probabilistic Reasoning Performance. AB - This study assessed the extent to which within-individual variation in schizotypy and paranormal belief influenced performance on probabilistic reasoning tasks. A convenience sample of 725 non-clinical adults completed measures assessing schizotypy (Oxford-Liverpool Inventory of Feelings and Experiences; O-Life brief), belief in the paranormal (Revised Paranormal Belief Scale; RPBS) and probabilistic reasoning (perception of randomness, conjunction fallacy, paranormal perception of randomness, and paranormal conjunction fallacy). Latent profile analysis (LPA) identified four distinct groups: class 1, low schizotypy and low paranormal belief (43.9% of sample); class 2, moderate schizotypy and moderate paranormal belief (18.2%); class 3, moderate schizotypy (high cognitive disorganization) and low paranormal belief (29%); and class 4, moderate schizotypy and high paranormal belief (8.9%). Identification of homogeneous classes provided a nuanced understanding of the relative contribution of schizotypy and paranormal belief to differences in probabilistic reasoning performance. Multivariate analysis of covariance revealed that groups with lower levels of paranormal belief (classes 1 and 3) performed significantly better on perception of randomness, but not conjunction problems. Schizotypy had only a negligible effect on performance. Further analysis indicated that framing perception of randomness and conjunction problems in a paranormal context facilitated performance for all groups but class 4. PMID- 29434563 TI - Determining Factors for Stress Perception Assessed with the Perceived Stress Scale (PSS-4) in Spanish and Other European Samples. AB - Objective: Stress perception depends on cultural and social aspects that vary from one country to another. One of the most widely disseminated methods of assessing psychological stress is the Perceived Stress Scale (PSS-4). Therefore, in order to identify these factors and their impact on mental health, the present study compares the PSS-4 results among three European countries (Great Britain, France and Spain). This study focuses on PSS-4 results within a Spanish sample to determine: (1) normative data, reliability and validity of PSS-4 in a Spanish sample and (2) how stress perception changes depending on cultural and social factors. Methods: The data were obtained from a website representing a service of a smoking cessation program, the study represented a service that was open to all individuals. The number of participants were 37,451. They reported their age, gender, nationality, marital status, education and employment status, and completed two psychological questionnaires (PPS-4 and the anxiety and depression scales of the Symptom Checklist-90-Revised, SCL 90-R). Results: The PSS-4 scores could differentiate between relevant sociodemographic variables (such as sex, age, nationality, marital status, education, parental status, employment status, and income class). The PSS-4 scores showed a positive correlation with the SCL 90 R anxiety and depression scales. The normed values for interpreting the PSS-4 scores are presented. The PSS-4 showed adequate internal consistency and reliability. Conclusions: The PSS-4 is a useful instrument for assessing stress perception levels in the general population in different countries. Its internal consistency is sufficient for a 4-item scale. PMID- 29434564 TI - Cognitive Function and Serum Hormone Levels Are Associated with Gray Matter Volume Decline in Female Patients with Prolactinomas. AB - Background and objective: Cognitive impairments have been reported in patients with hyperprolactinemia; however, there is a lack of knowledge of brain structure alterations relevant to hyperprolactinemia in prolactinomas. Thus, we aimed to identify changes in brain structure in prolactinomas and to determine whether these changes are related to cognitive performance and clinical characteristics. Methods: Participants were 32 female patients with prolactinomas and 26 healthy controls (HC) matched for age, sex, education, and handedness. All participants underwent magnetic resonance imaging brain scans, neuropsychological assessments, and clinical evaluations. Voxel-based morphometry analysis was used to identify changes in gray matter volume (GMV). Partial correlation analysis and multiple linear regression were performed to determine the relationship between GMV, cognition, and clinical characteristics. Results: Compared to HC, patients with prolactinomas demonstrated a decrease in GMV in the left hippocampus, left orbitofrontal cortex, right middle frontal cortex (MFC), and right inferior frontal cortex (IFC). In addition, patients performed worse than controls on tests for verbal memory and executive function, and this was significantly related to the GMV of the left hippocampus and right MFC, respectively. Moreover, in the patients, we found a negative relationship between serum prolactin levels and the GMV of the left hippocampus and right IFC, whereas a positive relationship was found between the GMV of the left hippocampus and serum levels of estradiol and luteinizing hormone. Conclusion: In patients with prolactinomas, specific brain structure abnormalities have been identified and are associated with cognitive impairments and dysfunctional hormones. This study enhances our understanding of brain structure changes that may occur with prolactinomas and provides novel and fundamental evidence for previous behavioral findings relevant to hyperprolactinemia. PMID- 29434565 TI - Semi-Automated Analysis of Diaphragmatic Motion with Dynamic Magnetic Resonance Imaging in Healthy Controls and Non-Ambulant Subjects with Duchenne Muscular Dystrophy. AB - Subjects with Duchenne Muscular Dystrophy (DMD) suffer from progressive muscle damage leading to diaphragmatic weakness that ultimately requires ventilation. Emerging treatments have generated interest in better characterizing the natural history of respiratory impairment in DMD and responses to therapy. Dynamic (cine) Magnetic Resonance Imaging (MRI) may provide a more sensitive measure of diaphragm function in DMD than the commonly used spirometry. This study presents an analysis pipeline for measuring parameters of diaphragmatic motion from dynamic MRI and its application to investigate MRI measures of respiratory function in both healthy controls and non-ambulant DMD boys. We scanned 13 non ambulant DMD boys and 10 age-matched healthy male volunteers at baseline, with a subset (n = 10, 10, 8) of the DMD subjects also assessed 3, 6, and 12 months later. Spirometry-derived metrics including forced vital capacity were recorded. The MRI-derived measures included the lung cross-sectional area (CSA), the anterior, central, and posterior lung lengths in the sagittal imaging plane, and the diaphragm length over the time-course of the dynamic MRI. Regression analyses demonstrated strong linear correlations between lung CSA and the length measures over the respiratory cycle, with a reduction of these correlations in DMD, and diaphragmatic motions that contribute less efficiently to changing lung capacity in DMD. MRI measures of pulmonary function were reduced in DMD, controlling for height differences between the groups: at maximal inhalation, the maximum CSA and the total distance of motion of the diaphragm were 45% and 37% smaller. MRI measures of pulmonary function were correlated with spirometry data and showed relationships with disease progression surrogates of age and months non ambulatory, suggesting that they provide clinically meaningful information. Changes in the MRI measures over 12 months were consistent with weakening of diaphragmatic and inter-costal muscles and progressive diaphragm dysfunction. In contrast, longitudinal changes were not seen in conventional spirometry measures during the same period. Dynamic MRI measures of thoracic muscle and pulmonary function are, therefore, believed to detect meaningful differences between healthy controls and DMD and may be sensitive to changes in function over relatively short periods of follow-up in non-ambulant boys with DMD. PMID- 29434566 TI - Assessment of Platelet Function in Traumatic Brain Injury-A Retrospective Observational Study in the Neuro-Critical Care Setting. AB - Background: Despite seemingly functional coagulation, hemorrhagic lesion progression is a common and devastating condition following traumatic brain injury (TBI), stressing the need for new diagnostic techniques. Multiple electrode aggregometry (MEA) measures platelet function and could aid in coagulopathy assessment following TBI. The aims of this study were to evaluate MEA temporal dynamics, influence of concomitant therapy, and its capabilities to predict lesion progression and clinical outcome in a TBI cohort. Material and methods: Adult TBI patients in a neurointensive care unit that underwent MEA sampling were retrospectively included. MEA was sampled if the patient was treated with antiplatelet therapy, bled heavily during surgery, or had abnormal baseline coagulation values. We assessed platelet activation pathways involving the arachidonic acid receptor (ASPI), P2Y12 receptor, and thrombin receptor (TRAP). ASPI was the primary focus of analysis. If several samples were obtained, they were included. Retrospective data were extracted from hospital charts. Outcome variables were radiologic hemorrhagic progression and Glasgow Outcome Scale assessed prospectively at 12 months posttrauma. MEA levels were compared between patients on antiplatelet therapy. Linear mixed effect models and uni /multivariable regression models were used to study longitudinal dynamics, hemorrhagic progression and outcome, respectively. Results: In total, 178 patients were included (48% unfavorable outcome). ASPI levels increased from initially low values in a time-dependent fashion (p < 0.001). Patients on cyclooxygenase inhibitors demonstrated low ASPI levels (p < 0.001), while platelet transfusion increased them (p < 0.001). The first ASPI (p = 0.039) and TRAP (p = 0.009) were significant predictors of outcome, but not lesion progression, in univariate analyses. In multivariable analysis, MEA values were not independently correlated with outcome. Conclusion: A general longitudinal trend of MEA is identified in this TBI cohort, even in patients without known antiplatelet therapies. Values appear also affected by platelet inhibitory treatment and by platelet transfusions. While significant in univariate models to predict outcome, MEA values did not independently correlate to outcome or lesion progression in multivariable analyses. Further prospective studies to monitor coagulation in TBI patients are warranted, in particular the interpretation of pathological MEA values in patients without antiplatelet therapies. PMID- 29434567 TI - Turn Around Freezing: Community-Living Turning Behavior in People with Parkinson's Disease. AB - Difficulty in turning while walking is common among patients with Parkinson's disease (PD). This difficulty often leads to significant disability, falls, and loss of function; moreover, turning is a common trigger for freezing of gait (FoG). We hypothesized that the quantity and quality of turning mobility while walking during daily life would be different among subjects with PD with and without FoG. Here, we investigated, for the first time, the turning quality during daily life as it relates to FoG in people with PD using a single inertial sensor. Ninety-four subjects with PD (among whom 25 had FoG) wore an inertial sensor attached by a belt on the lower back during normal daily activity consecutively for 3 days. An algorithm identified periods of walking and calculated the number and quality metrics of turning. Quality, but not the quantity, of turning at home was different in freezers compared to the non freezers. The number of turns (19.3 +/- 9.2/30 min in freezers, 22.4 +/- 12.9/30 min non-freezers; p = 0.194) was similar in the two groups. Some aspects of quality of turns, specifically mean jerkiness, mean and variability of medio lateral jerkiness were significantly higher (p < 0.05) in the freezers, compared to non-freezers. Interestingly, subjects with FoG showed specific turning differences in the turns with larger angles compared to those without FoG. These findings suggest that turning during daily activities among patients with PD is impaired in subjects with FoG, compared to subject without freezing. As such, clinical decision-making and rehabilitation assessment may benefit from measuring the quality of turning mobility during daily activities in PD. PMID- 29434568 TI - Restless Legs Syndrome/Willis-Ekbom Disease Is Prevalent in Working Nurses, but Seems Not to Be Associated with Shift Work Schedules. AB - Insomnia and excessive sleepiness are among the most commonly reported sleep problems related to shift work. Sleep-related movement disorders have, however, received far less attention in relation to such work schedules. The objective of this study was to investigate the association between different shift work schedules and the prevalence of Restless legs syndrome/Willis-Ekbom disease (RLS/WED) in a large sample of Norwegian nurses. Our hypothesis was that shift working nurses would report higher prevalence of RLS/WED compared to day workers. A total of 1,788 nurses with different work schedules (day work, two-shift rotation, night work, three shift rotation) participated in a cohort study, started in 2008/2009. Four questions about RLS/WED based on the diagnostic criteria were included in wave 4 (2012). RLS/WED prevalence rates across different shift schedules were explored by the Pearson chi-square test. Logistic regression analysis was used to assess the association between RLS/WED and work schedules and shift work disorder (SWD) with adjustment for sex, age, marital status, smoking, and caffeine use. In total, 90.0% of the nurses were females, mean age 36.5 years (SD = 8.6, range 25-67). The overall prevalence of RLS/WED was 26.8%. We found no significant differences between the prevalence of RLS/WED across the different shift schedules, ranging from 23.3% (day work) to 29.4% (night work). There was a significant difference (p < 0.001) in the prevalence of RLS/WED between nurses having SWD (33.5%) compared to nurses not having SWD (23.8%). SWD remained significantly associated with RLS/WED in the adjusted logistic regression analysis (1.56, CI: 1.24-1.97). This study did not support the hypothesis. RLS/WED was associated with SWD, which might indicate that nurses vulnerable to shift work also are sensitive to other complaints related to a misalignment of the biological clock. PMID- 29434569 TI - Cranio-Caudal Kinematic Turn Signature Assessed with Inertial Systems As a Marker of Mobility Deficits in Parkinson's Disease. AB - Background: Turning is a challenging mobility task requiring proper planning, coordination, and postural stability to be executed efficiently. Turn deficits can impair mobility and lead to falls in patients with neurodegenerative disease, such as Parkinson's disease (PD). It was previously shown that the cranio-caudal sequence involved during a turn (i.e., motion is initiated by the head, followed by the trunk) exhibits a signature that can be captured using an inertial system and analyzed through the Kinematics Theory. The so-called cranio-caudal kinematic turn signature (CCKS) metrics derived from this approach could, therefore, be a promising avenue to develop and track markers to measure early mobility deficits. Objective: The current study aims at exploring the discriminative validity and sensitivity of CCKS metrics extracted during turning tasks performed by patients with PD. Methods: Thirty-one participants (16 asymptomatic older adults (OA): mean age = 69.1 +/- 7.5 years old; 15 OA diagnosed with early PD ON and OFF medication, mean age = 65.8 +/- 8.4 years old) performed repeated timed up-and-go (TUG) tasks while wearing a portable inertial system. CCKS metrics (maximum head to trunk angle reached and commanded amplitudes of the head to trunk neuromuscular system, estimated from a sigma-lognormal model) were extracted from kinematic data recorded during the turn phase of the TUG tasks. For comparison purposes, common metrics used to analyze the quality of a turn using inertial systems were also calculated over the same trials (i.e., the number of steps required to complete the turn and the turn mean and maximum velocities). Results: All CCKS metrics discriminated between OA and patients (p <= 0.041) and were sensitive to change in PD medication state (p <= 0.033). Common metrics were also able to discriminate between OA and patients (p < 0.014), but they were unable to capture the change in medication state this early in the disease (p >= 0.173). Conclusion: The enhanced sensitivity to change of the proposed CCKS metrics suggests a potential use of these metrics for mobility impairments identification and fluctuation assessment, even in the early stages of the disease. PMID- 29434570 TI - Perspectives on How Human Simultaneous Multi-Modal Imaging Adds Directionality to Spread Models of Alzheimer's Disease. AB - Previous animal research suggests that the spread of pathological agents in Alzheimer's disease (AD) follows the direction of signaling pathways. Specifically, tau pathology has been suggested to propagate in an infection-like mode along axons, from transentorhinal cortices to medial temporal lobe cortices and consequently to other cortical regions, while amyloid-beta (Abeta) pathology seems to spread in an activity-dependent manner among and from isocortical regions into limbic and then subcortical regions. These directed connectivity based spread models, however, have not been tested directly in AD patients due to the lack of an in vivo method to identify directed connectivity in humans. Recently, a new method-metabolic connectivity mapping (MCM)-has been developed and validated in healthy participants that uses simultaneous FDG-PET and resting state fMRI data acquisition to identify directed intrinsic effective connectivity (EC). To this end, postsynaptic energy consumption (FDG-PET) is used to identify regions with afferent input from other functionally connected brain regions (resting-state fMRI). Here, we discuss how this multi-modal imaging approach allows quantitative, whole-brain mapping of signaling direction in AD patients, thereby pointing out some of the advantages it offers compared to other EC methods (i.e., Granger causality, dynamic causal modeling, Bayesian networks). Most importantly, MCM provides the basis on which models of pathology spread, derived from animal studies, can be tested in AD patients. In particular, future work should investigate whether tau and Abeta in humans propagate along the trajectories of directed connectivity in order to advance our understanding of the neuropathological mechanisms causing disease progression. PMID- 29434571 TI - Knowledge about Essential Tremor: A Study of Essential Tremor Families. AB - Background: Essential tremor (ET) is among the most common neurological diseases and it often runs in families. How knowledgeable ET patients and their families are about their disease has been the subject of surprisingly little scholarship. Methods: To fill this gap in knowledge, we administered a comprehensive 32-item survey (i.e., questions about etiology, pathophysiology, symptoms and signs, natural history, and treatments) to 427 participants, including 76 ET probands, 74 affected relatives (AFRs), 238 unaffected relatives, and 39 spouses of unaffected relatives, all of whom were participating in two ET family studies. We hypothesized that there would be gaps in knowledge about ET and furthermore, that probands and AFRs would be the most knowledgeable, followed by unaffected relatives and then spouses of unaffected relatives, who would be the least knowledgeable. Results: Overall, ET patients lacked knowledge about their disease. Nearly one-third of probands answered "yes" or "do not know" to the question, "is ET the same or different from the type of tremor that many normal people can get when they become old and frail?" A similar proportion did not know whether children could get ET or they responded "no." Nearly one-fourth of affecteds (i.e., probands and AFRs) did not know whether or to what degree (e.g., very well, moderately well, not well) the symptoms of ET could be medically controlled, and 38.0% either reported that there was no brain surgery for ET or reported that they did not know. Nearly 17% of affecteds did not endorse genes as a cause for ET, which was surprising given the fact that this was a family study of ET. Probands and AFRs were the most knowledgeable, followed by unaffected relatives. Spouses of unaffected relatives were the least knowledgeable. Conclusion: We targeted a large group of ET patients and their families, as this group is perhaps most likely to be informed about the disease. ET patients and their AFRs were more knowledgeable about the features of ET than their family members without ET. Overall, however, knowledge of ET was very limited and this lack of knowledge encompassed all aspects of the disease including its underlying causes, the nature of the symptoms and signs, its natural history and its treatment. Further ET awareness education and programs targeting both families of ET patients and the public would help alleviate this gap in knowledge. PMID- 29434572 TI - Stress and Corticosteroids Aggravate Morphological Changes in the Dentate Gyrus after Early-Life Experimental Febrile Seizures in Mice. AB - Stress is the most frequently self-reported seizure precipitant in patients with epilepsy. Moreover, a relation between ear stress and epilepsy has been suggested. Although ear stress and stress hormones are known to influence seizure threshold in rodents, effects on the development of epilepsy (epileptogenesis) are still unclear. Therefore, we studied the consequences of ear corticosteroid exposure for epileptogenesis, under highly controlled conditions in an animal model. Experimental febrile seizures (eFS) were elicited in 10-day-old mice by warm-air induced hyperthermia, while a control group was exposed to a normothermic condition. In the following 2 weeks, mice received either seven corticosterone or vehicle injections or were left undisturbed. Specific measures indicative for epileptogenesis were examined at 25 days of age and compared with vehicle injected or untreated mice. We examined structural [neurogenesis, dendritic morphology, and mossy fiber sprouting (MFS)] and functional (glutamatergic postsynaptic currents and long-term potentiation) plasticity in the dentate gyrus (DG). We found that differences in DG morphology induced by eFS were aggravated by repetitive (mildly stressful) vehicle injections and corticosterone exposure. In the injected groups, eFS were associated with decreases in neurogenesis, and increases in cell proliferation, dendritic length, and spine density. No group differences were found in MFS. Despite these changes in DG morphology, no effects of eFS were found on functional plasticity. We conclude that corticosterone exposure during early epileptogenesis elicited by eFS aggravates morphological, but not functional, changes in the DG, which partly supports the hypothesis that ear stress stimulates epileptogenesis. PMID- 29434573 TI - Levothyroxine Therapy: Changes of TSH Levels by Switching Patients from Tablet to Liquid Formulation. A Systematic Review and Meta-Analysis. AB - Background: In the last years, levothyroxine (LT4) has been commercialized also in liquid formulation, which is less sensitive to the factors known to reduce the absorption of tablet LT4. To date, there is no robust information that liquid LT4 can improve pharmacologic thyroid homeostasis of patients with reduced efficacy of tablet LT4. This analysis aimed at achieving solid evidence that switching thyroxine treatment from tablet to liquid preparation improves patients' TSH levels. Methods: The search was performed in PubMed/MEDLINE and Scopus database based on the terms "thyroid," "levothyroxine," and "liquid," and updated until September 25, 2017. Studies were included only if they described patients with suboptimal TSH on tablet LT4, subsequently switched to liquid LT4. Results: The literature search retrieved 462 articles and six were finally included. The pooled mean difference of TSH value between tablet and liquid LT4 was 4.23 mIU/L (95% CI from 3.69 to 4.77). Mild heterogeneity was found (I2 60%). Overall mean difference of TSH was significant (p < 0.0001). Conclusion: The present meta analysis showed that patients with suboptimal TSH on tablet LT4 can have a significantly improved TSH by switching to liquid LT4 formulation at unchanged dose. PMID- 29434574 TI - Basal and Dynamic Leptin Secretion: Association with Cardiometabolic Risk and Body Weight Trajectories in African-Americans and European-Americans. AB - Background: Fasting plasma leptin levels reflect fat mass, but dynamic leptin responses to secretagogues, and the influence of race/ethnicity, have not been well studied. Here, we compared basal and stimulated leptin levels in relation to cardiometabolic risk and weight trajectories in black and white subjects. Subjects and methods: We studied 254 (127 black and 127 white) normoglycemic adults enrolled in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. At baseline and annually, POP-ABC participants underwent physical examination, oral glucose tolerance test, and measurements of body fat (dual energy X-ray absorptiometry), fasting plasma leptin, insulin, cortisol, lipids, and leptin secretory response to single-dose (2 mg) dexamethasone (dex). The interactions among basal and stimulated leptin and changes in adiposity/cardiometabolic measures during the ensuing year were then analyzed. Results: The mean (+/-SD) fasting leptin level (50.6 +/- 47.7 vs. 39.5 +/- 37.6 ng/mL, P = 0.004) and body mass index (BMI) (31.9 +/- 7.14 vs. 29.0 +/- 7.66 kg/m2, P = 0.0043) were higher in black women vs. white women, but similar in black men vs. white men (leptin: 12.4 +/- 2.07 vs. 11.1 +/- 1.40 ng/mL; BMI: 29.4 +/- 7.68 vs. 28.1 +/- 4.23 kg/m2). The peak leptin response to dex (~200% baseline) did not differ significantly by gender or race. Total body fat correlated positively with fasting leptin (r = 0.81, P < 0.0001) and inversely stimulated leptin levels (r = -0.26, P < 0.0001). Fasting leptin was unrelated to 1-year change in weight or fat mass, whereas stimulated leptin levels were significantly associated with 1-year trajectories in weight (P = 0.0016) and total fat mass (P = 0.0035). Stimulated leptin levels also had significant interactions with insulin sensitivity (homeostasis model of insulin resistance, P = 0.01), triglycerides (P = 0.0078), fasting glucose (P = 0.027), systolic blood pressure (P = 0.037), and high-sensitivity C-reactive protein (P = 0.027). Conclusion: We found no significant ethnic disparities in basal or dynamic leptin secretion in relation to adiposity. Fasting leptin levels were not associated with 1-year weight change, while stimulated levels showed weak though significant association with 1-year weight change. PMID- 29434575 TI - N-Acetylmuramic Acid (MurNAc) Auxotrophy of the Oral Pathogen Tannerella forsythia: Characterization of a MurNAc Kinase and Analysis of Its Role in Cell Wall Metabolism. AB - Tannerella forsythia is an anaerobic, Gram-negative oral pathogen that thrives in multispecies gingival biofilms associated with periodontitis. The bacterium is auxotrophic for the commonly essential bacterial cell wall sugar N-acetylmuramic acid (MurNAc) and, thus, strictly depends on an exogenous supply of MurNAc for growth and maintenance of cell morphology. A MurNAc transporter (Tf_MurT; Tanf_08375) and an ortholog of the Escherichia coli etherase MurQ (Tf_MurQ; Tanf_08385) converting MurNAc-6-phosphate to GlcNAc-6-phosphate were recently described for T. forsythia. In between the respective genes on the T. forsythia genome, a putative kinase gene is located. In this study, the putative kinase (Tf_MurK; Tanf_08380) was produced as a recombinant protein and biochemically characterized. Kinetic studies revealed Tf_MurK to be a 6-kinase with stringent substrate specificity for MurNAc exhibiting a 6 * 104-fold higher catalytic efficiency (kcat/Km ) for MurNAc than for N-acetylglucosamine (GlcNAc) with kcat values of 10.5 s-1 and 0.1 s-1 and Km values of 200 MUM and 116 mM, respectively. The enzyme kinetic data suggest that Tf_MurK is subject to substrate inhibition (Ki[S] = 4.2 mM). To assess the role of Tf_MurK in the cell wall metabolism of T. forsythia, a kinase deletion mutant (DeltaTf_murK::erm) was constructed. This mutant accumulated MurNAc intracellularly in the exponential phase, indicating the capability to take up MurNAc, but inability to catabolize MurNAc. In the stationary phase, the MurNAc level was reduced in the mutant, while the level of the peptidoglycan precursor UDP-MurNAc-pentapeptide was highly elevated. Further, according to scanning electron microscopy evidence, the DeltaTf_murK::erm mutant was more tolerant toward low MurNAc concentration in the medium (below 0.5 MUg/ml) before transition from healthy, rod-shaped to fusiform cells occurred, while the parent strain required > 1 MUg/ml MurNAc for optimal growth. These data reveal that T. forsythia readily catabolizes exogenous MurNAc but simultaneously channels a proportion of the sugar into peptidoglycan biosynthesis. Deletion of Tf_murK blocks MurNAc catabolism and allows the direction of MurNAc solely to peptidoglycan biosynthesis, resulting in a growth advantage in MurNAc-depleted medium. This work increases our understanding of the T. forsythia cell wall metabolism and may pave new routes for lead finding in the treatment of periodontitis. PMID- 29434577 TI - Adsorption and Desorption Characteristics of Cd2+ and Pb2+ by Micro and Nano sized Biogenic CaCO3. AB - The purpose of this study was to elucidate the characteristics and mechanisms of adsorption and desorption for heavy metals by micro and nano-sized biogenic CaCO3 induced by Bacillus subtilis, and the pH effect on adsorption was investigated. The results showed that the adsorption characteristics of Cd2+ and Pb2+ are well described by the Langmuir adsorption isothermal equation, and the maximum adsorption amounts for Cd2+ and Pb2+ were 94.340 and 416.667 mg/g, respectively. The maximum removal efficiencies were 97% for Cd2+, 100% for Pb2+, and the desorption rate was smaller than 3%. Further experiments revealed that the biogenic CaCO3 could maintain its high adsorption capability for heavy metals within wide pH ranges (3-8). The FTIR and XRD results showed that, after the biogenic CaCO3 adsorbed Cd2+ or Pb2+, it did not produce a new phase, which indicated that biogenic CaCO3 and heavy metal ions were governed by a physical adsorption process, and the high adsorptive capacity of biogenic CaCO3 for Cd2+ and Pb2+ were mainly attributed to its large total specific surface area. The findings could improve the state of knowledge about biogenic CaCO3 formation in the environment and its potential roles in the biogeochemical cycles of heavy metals. PMID- 29434576 TI - Candidatus Nitrosocaldus cavascurensis, an Ammonia Oxidizing, Extremely Thermophilic Archaeon with a Highly Mobile Genome. AB - Ammonia oxidizing archaea (AOA) of the phylum Thaumarchaeota are widespread in moderate environments but their occurrence and activity has also been demonstrated in hot springs. Here we present the first enrichment of a thermophilic representative with a sequenced genome, which facilitates the search for adaptive strategies and for traits that shape the evolution of Thaumarchaeota. Candidatus Nitrosocaldus cavascurensis has been enriched from a hot spring in Ischia, Italy. It grows optimally at 68 degrees C under chemolithoautotrophic conditions on ammonia or urea converting ammonia stoichiometrically into nitrite with a generation time of approximately 23 h. Phylogenetic analyses based on ribosomal proteins place the organism as a sister group to all known mesophilic AOA. The 1.58 Mb genome of Ca. N. cavascurensis harbors an amoAXCB gene cluster encoding ammonia monooxygenase and genes for a 3 hydroxypropionate/4-hydroxybutyrate pathway for autotrophic carbon fixation, but also genes that indicate potential alternative energy metabolisms. Although a bona fide gene for nitrite reductase is missing, the organism is sensitive to NO scavenging, underlining the potential importance of this compound for AOA metabolism. Ca. N. cavascurensis is distinct from all other AOA in its gene repertoire for replication, cell division and repair. Its genome has an impressive array of mobile genetic elements and other recently acquired gene sets, including conjugative systems, a provirus, transposons and cell appendages. Some of these elements indicate recent exchange with the environment, whereas others seem to have been domesticated and might convey crucial metabolic traits. PMID- 29434578 TI - Oligonucleotide Array and VITEK Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry in Species Identification of Blood Yeast Isolates. AB - We evaluated matrix-assisted laser desorption ionization time-of-flight mass spectrometry using VITEK MS (IVD database) and an oligonucleotide array based on the internal transcribed spacer-1 (ITS-1) and ITS-2 sequences of rRNA genes for the identification of Candida spp. from blood cultures. Five-hundred and twelve consecutive bloodstream yeast isolates were collected daily and initially identified by the phenotypic automated method (VITEK YBC or VITEK2 YST card). Inconsistent results were confirmed by D1-D2 region of 28S rRNA genes and ITSs. Excluding two unidentified yeast isolates, the oligonucleotide array and VITEK MS correctly identified 99.6% (508) and 96.9% (494) of 510 yeast isolates, respectively. The oligonucleotide array and VITEK MS demonstrated high correct identification rates for four major Candida species (C. albicans 100%, 98.4%; C. glabrata 100%, 100%; C. parapsilosis 100%, 93.3%; C. tropicalis 100%, 97.3%), but lower correct identification rates for other Candida species (91.7 and 87.5%, respectively). In conclusion, the identification performance of the oligonucleotide array is comparable to that of VITEK MS, and can serve as a supplemental tool for the identification of Candida species. PMID- 29434579 TI - Prevalence and Molecular Characterization of Campylobacter spp. Isolated from Patients with Diarrhea in Shunyi, Beijing. AB - Bacterial pathogens have been confirmed as the major cause of acute diarrhea among outpatients in China. In this study, 370 stool samples from the patients aged from 15 to 87 years old with diarrhea were collected over 12 months (from May 2016 to April 2017) in two hospitals in Shunyi, Beijing. Bacterial isolation was performed for the common enteric pathogens: Campylobacter, Salmonella, Shigella, Diarrheagenic Escherichia coli, and Vibrio parahaemolyticus for 370 samples. The filtration method was used for the Campylobacter isolation in this study. The prevalence and molecular characterization of the Campylobacter were investigated. The isolation ratio for Campylobacter, Salmonella, Shigella, Diarrheagenic E. coli, and V. parahaemolyticus was 7.0% (26/370), 6.2% (23/370), 0.3% (1/370), 7.3% (27/370), and 10.3% (38/370), respectively. Based on the isolation result, Campylobacter positive cases presented in almost every month of the whole year and the isolation ratio was the highest among the tested pathogens during October to March. There was no significant difference between genders of Campylobacter positive cases. More Campylobacter positive cases presented dehydration compared with those who were positive for Salmonella. Twenty-six Campylobacter isolates were obtained in this study and 24 of these were Campylobacter jejuni. The antibiotic susceptibility tests indicated that 83.3% (20/24) of the isolates exhibited resistance to three or more types of antibiotic. Twenty STs were identified for the 26 Campylobacter isolates and four novel STs were identified in this study. No clonal cluster was found among these isolates. This is the first study for Campylobacter isolated using the filtration method in China which indicated the Campylobacter infection might be seriously under-ascertained in the diarrheal patients in China. PMID- 29434580 TI - Genetic and Toxigenic Variability within Aspergillus flavus Population Isolated from Maize in Two Diverse Environments in Kenya. AB - Aspergillus flavus is the main producer of carcinogenic aflatoxins in agricultural commodities such as maize. This fungus occurs naturally on crops, and produces aflatoxins when environmental conditions are favorable. The aim of this study is to analyse the genetic variability among 109 A. flavus isolates previously recovered from maize sampled from a known aflatoxin-hotspot (Eastern region, Kenya) and the major maize-growing area in the Rift Valley (Kenya), and to determine their toxigenic potential. DNA analyses of internal transcribed spacer (ITS) regions of ribosomal DNA, partial beta-tubulin gene (benA) and calmodulin gene (CaM) sequences were used. The strains were further analyzed for the presence of four aflatoxin-biosynthesis genes in relation to their capability to produce aflatoxins and other metabolites, targeting the regulatory gene aflR and the structural genes aflP, aflD, and aflQ. In addition, the metabolic profile of the fungal strains was unraveled using state-of-the-art LC-MS/MS instrumentation. The three gene-sequence data grouped the isolates into two major clades, A. minisclerotigenes and A. flavus. A. minisclerotigenes was most prevalent in Eastern Kenya, while A. flavus was common in both regions. A. parasiticus was represented by a single isolate collected from Rift Valley. Diversity existed within the A. flavus population, which formed several subclades. An inconsistency in identification of some isolates using the three markers was observed. The calmodulin gene sequences showed wider variation of polymorphisms. The aflatoxin production pattern was not consistent with the presence of aflatoxigenic genes, suggesting an inability of the primers to always detect the genes or presence of genetic mutations. Significant variation was observed in toxin profiles of the isolates. This is the first time that a profound metabolic profiling of A. flavus isolates was done in Kenya. Positive associations were evident for some metabolites, while for others no associations were found and for a few metabolite-pairs negative associations were seen. Additionally, the growth medium influenced the mycotoxin metabolite production. These results confirm the wide variation that exists among the group A. flavus and the need for more insight in clustering the group. PMID- 29434581 TI - Site-Specific Recombination at XerC/D Sites Mediates the Formation and Resolution of Plasmid Co-integrates Carrying a blaOXA-58- and TnaphA6-Resistance Module in Acinetobacter baumannii. AB - Members of the genus Acinetobacter possess distinct plasmid types which provide effective platforms for the acquisition, evolution, and dissemination of antimicrobial resistance structures. Many plasmid-borne resistance structures are bordered by short DNA sequences providing potential recognition sites for the host XerC and XerD site-specific tyrosine recombinases (XerC/D-like sites). However, whether these sites are active in recombination and how they assist the mobilization of associated resistance structures is still poorly understood. Here we characterized the plasmids carried by Acinetobacter baumannii Ab242, a multidrug-resistant clinical strain belonging to the ST104 (Oxford scheme) which produces an OXA-58 carbapenem-hydrolyzing class-D beta-lactamase (CHDL). Plasmid sequencing and characterization of replication, stability, and adaptive modules revealed the presence in Ab242 of three novel plasmids lacking self transferability functions which were designated pAb242_9, pAb242_12, and pAb242_25, respectively. Among them, only pAb242_25 was found to carry an adaptive module encompassing an ISAba825-blaOXA-58 arrangement accompanied by a TnaphA6 transposon, the whole structure conferring simultaneous resistance to carbapenems and aminoglycosides. Ab242 plasmids harbor several XerC/D-like sites, with most sites found in pAb242_25 located in the vicinity or within the adaptive module described above. Electrotransformation of susceptible A. nosocomialis cells with Ab242 plasmids followed by imipenem selection indicated that the transforming plasmid form was a co-integrate resulting from the fusion of pAb242_25 and pAb242_12. Further characterization by cloning and sequencing studies indicated that a XerC/D site in pAb242_25 and another in pAb242_12 provided the active sister pair for the inter-molecular site-specific recombination reaction mediating the fusion of these two plasmids. Moreover, the resulting co-integrate was found also to undergo intra-molecular resolution at the new pair of XerC/D sites generated during fusion thus regenerating the original pAb242_25 and pAb242_12 plasmids. These observations provide the first evidence indicating that XerC/D-like sites in A. baumannii plasmids can provide active pairs for site-specific recombination mediating inter-molecular fusions and intra-molecular resolutions. The overall results shed light on the evolutionary dynamics of A. baumannii plasmids and the underlying mechanisms of dissemination of genetic structures responsible for carbapenem and other antibiotics resistance among the Acinetobacter clinical population. PMID- 29434582 TI - Clinical Implications of Digenic Inheritance and Epistasis in Primary Immunodeficiency Disorders. AB - The existence of epistasis in humans was first predicted by Bateson in 1909. Epistasis describes the non-linear, synergistic interaction of two or more genetic loci, which can substantially modify disease severity or result in entirely new phenotypes. The concept has remained controversial in human genetics because of the lack of well-characterized examples. In humans, it is only possible to demonstrate epistasis if two or more genes are mutated. In most cases of epistasis, the mutated gene products are likely to be constituents of the same physiological pathway leading to severe disruption of a cellular function such as antibody production. We have recently described a digenic family, who carry mutations of TNFRSF13B/TACI as well as TCF3 genes. Both genes lie in tandem along the immunoglobulin isotype switching and secretion pathway. We have shown they interact in an epistatic way causing severe immunodeficiency and autoimmunity in the digenic proband. With the advent of next generation sequencing, it is likely other families with digenic inheritance will be identified. Since digenic inheritance does not always cause epistasis, we propose an epistasis index which may help quantify the effects of the two mutations. We also discuss the clinical implications of digenic inheritance and epistasis in humans with primary immunodeficiency disorders. PMID- 29434583 TI - CD70 Deficiency due to a Novel Mutation in a Patient with Severe Chronic EBV Infection Presenting As a Periodic Fever. AB - Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20+ cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node's biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of XIAP, SHA2D1A, ITK, and CD27 genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A>G mutation of the CD70 gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever. PMID- 29434584 TI - TLR3 Ligand Poly(I:C) Exerts Distinct Actions in Synovial Fibroblasts When Delivered by Extracellular Vesicles. AB - Extracellular vesicles (EV) can modulate the responses of cells to toll-like receptor (TLR) ligation; conversely, TLR ligands such as double-stranded RNA (dsRNA) can enhance the release of EV and influence of the composition and functions of EV cargos. Inflamed synovial joints in rheumatoid arthritis (RA) are rich in EV and extracellular RNA; besides, RNA released from necrotic synovial fluid cells can activate the TLR3 signaling in synovial fibroblasts (SFs) from patients with RA. Since EV occur prominently in synovial joints in RA and may contribute to the pathogenesis, we questioned whether EV can interact with dsRNA, a TLR3 ligand, and modify its actions in arthritis. We have used as model the effects on RA SFs, of EV released from monocyte U937 cells and peripheral blood mononuclear cells upon stimulation with Poly(I:C), a synthetic analog of dsRNA. We show that EV released from unstimulated cells and Poly(I:C)-stimulated U937 cells [Poly(I:C) EV] differ in size but bind similar amounts of Annexin V and express comparable levels of MAC-1, the receptor for dsRNA, on the vesicular membranes. Specifically, Poly(I:C) EV contain or associate with Poly(I:C) and at least partially protect Poly(I:C) from RNAse III degradation. Poly(I:C) EV shuttle Poly(I:C) to SFs and reproduce the proinflammatory and antiviral gene responses of SFs to direct stimulation with Poly(I:C). Poly(I:C) EV, however, halt the death receptor-induced apoptosis in SFs, thereby inverting the proapoptotic nature of Poly(I:C). These prosurvival effects sharply contrast with the high toxicity of cationic liposome-delivered Poly(I:C) and may reflect the route of Poly(I:C) delivery via EV or the fine-tuning of Poly(I:C) actions by molecular cargo in EV. The demonstration that EV may safeguard extracellular dsRNA and allow dsRNA to exert antiapoptotic effects on SFs highlights the potential of EV to amplify the pathogenicity of dsRNA in arthritis beyond inflammation (by concurrently enhancing the expansion of the invasive synovial stroma). PMID- 29434585 TI - The Activin A-Peroxisome Proliferator-Activated Receptor Gamma Axis Contributes to the Transcriptome of GM-CSF-Conditioned Human Macrophages. AB - GM-CSF promotes the functional maturation of lung alveolar macrophages (A-MO), whose differentiation is dependent on the peroxisome proliferator-activated receptor gamma (PPARgamma) transcription factor. In fact, blockade of GM-CSF initiated signaling or deletion of the PPARgamma-encoding gene PPARG leads to functionally defective A-MO and the onset of pulmonary alveolar proteinosis. In vitro, macrophages generated in the presence of GM-CSF display potent proinflammatory, immunogenic and tumor growth-limiting activities. Since GM-CSF upregulates PPARgamma expression, we hypothesized that PPARgamma might contribute to the gene signature and functional profile of human GM-CSF-conditioned macrophages. To verify this hypothesis, PPARgamma expression and activity was assessed in human monocyte-derived macrophages generated in the presence of GM CSF [proinflammatory GM-CSF-conditioned human monocyte-derived macrophages (GM MO)] or M-CSF (anti-inflammatory M-MO), as well as in ex vivo isolated human A MO. GM-MO showed higher PPARgamma expression than M-MO, and the expression of PPARgamma in GM-MO was found to largely depend on activin A. Ligand-induced activation of PPARgamma also resulted in distinct transcriptional and functional outcomes in GM-MO and M-MO. Moreover, and in the absence of exogenous activating ligands, PPARgamma knockdown significantly altered the GM-MO transcriptome, causing a global upregulation of proinflammatory genes and significantly modulating the expression of genes involved in cell proliferation and migration. Similar effects were observed in ex vivo isolated human A-MO, where PPARgamma silencing led to enhanced expression of genes coding for growth factors and chemokines and downregulation of cell surface pathogen receptors. Therefore, PPARgamma shapes the transcriptome of GM-CSF-dependent human macrophages (in vitro derived GM-MO and ex vivo isolated A-MO) in the absence of exogenous activating ligands, and its expression is primarily regulated by activin A. These results suggest that activin A, through enhancement of PPARgamma expression, help macrophages to switch from a proinflammatory to an anti-inflammatory polarization state, thus contributing to limit tissue damage and restore homeostasis. PMID- 29434586 TI - Bioactive Lipids and Chronic Inflammation: Managing the Fire Within. AB - Inflammation is an immune response that works as a contained fire that is pre emptively sparked as a defensive process during infections or upon any kind of tissue insult, and that is spontaneously extinguished after elimination or termination of the damage. However, persistent and uncontrolled immune reactions act as a wildfire that promote chronic inflammation, unresolved tissue damage and, eventually, chronic diseases. A wide network of soluble mediators, among which endogenous bioactive lipids, governs all immune processes. They are secreted by basically all cells involved in inflammatory processes and constitute the crucial infrastructure that triggers, coordinates and confines inflammatory mechanisms. However, these molecules are also deeply involved in the detrimental transition from acute to chronic inflammation, be it for persistent or excessive action of pro-inflammatory lipids or for the impairment of the functions carried out by resolving ones. As a matter of fact, bioactive lipids have been linked, to date, to several chronic diseases, including rheumatoid arthritis, atherosclerosis, diabetes, cancer, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis. This review summarizes current knowledge on the involvement of the main classes of endogenous bioactive lipids-namely classical eicosanoids, pro-resolving lipid mediators, lysoglycerophospholipids/sphingolipids, and endocannabinoids-in the cellular and molecular mechanisms that lead to the pathogenesis of chronic disorders. PMID- 29434588 TI - GATA3, HDAC6, and BCL6 Regulate FOXP3+ Treg Plasticity and Determine Treg Conversion into Either Novel Antigen-Presenting Cell-Like Treg or Th1-Treg. AB - We conducted an experimental database analysis to determine the expression of 61 CD4+ Th subset regulators in human and murine tissues, cells, and in T-regulatory cells (Treg) in physiological and pathological conditions. We made the following significant findings: (1) adipose tissues of diabetic patients with insulin resistance upregulated various Th effector subset regulators; (2) in skin biopsy from patients with psoriasis, and in blood cells from patients with lupus, effector Th subset regulators were more upregulated than downregulated; (3) in rosiglitazone induced failing hearts in ApoE-deficient (KO) mice, various Th subset regulators were upregulated rather than downregulated; (4) aortic endothelial cells activated by proatherogenic stimuli secrete several Th subset promoting cytokines; (5) in Treg from follicular Th (Tfh)-transcription factor (TF) Bcl6 KO mice, various Th subset regulators were upregulated; whereas in Treg from Th2-TF GATA3 KO mice and HDAC6 KO mice, various Th subset regulators were downregulated, suggesting that Bcl6 inhibits, GATA3 and HDAC6 promote, Treg plasticity; and (6) GATA3 KO, and Bcl6 KO Treg upregulated MHC II molecules and T cell co-stimulation receptors, suggesting that GATA3 and BCL6 inhibit Treg from becoming novel APC-Treg. Our data implies that while HDAC6 and Bcl6 are important regulators of Treg plasticity, GATA3 determine the fate of plastic Tregby controlling whether it will convert in to either Th1-Treg or APC-T-reg. Our results have provided novel insights on Treg plasticity into APC-Treg and Th1 Treg, and new therapeutic targets in metabolic diseases, autoimmune diseases, and inflammatory disorders. PMID- 29434589 TI - Modeling Human Antitumor Responses In Vivo Using Umbilical Cord Blood-Engrafted Mice. AB - Mice engrafted with human immune cells offer powerful in vivo model systems to investigate molecular and cellular processes of tumorigenesis, as well as to test therapeutic approaches to treat the resulting cancer. The use of umbilical cord blood mononuclear cells as a source of human immune cells for engraftment is technically straightforward, and provides T lymphocytes and autologous antigen presenting cells (including B cells, monocytes, and DCs) that bear cognate antigen presenting molecules. By using a human-specific oncogenic virus, such as Epstein-Barr virus, de novo neoplastic transformation of the human B cells can be induced in vivo in a manner that models progressive stages of tumorigenesis from nascent neoplasia to the establishment of vascularized tumor masses with an immunosuppressive environment. Moreover, since tumorigenesis occurs in the presence of autologous T cells, this type of system can be used to investigate how T cells become suppressed during tumorigenesis, and how immunotherapies counteract immunosuppression. This minireview will provide a brief overview of the use of human umbilical cord blood transplanted into immunodeficient murine hosts to model antitumor responses. PMID- 29434587 TI - Hypoxia Pathway Proteins As Central Mediators of Metabolism in the Tumor Cells and Their Microenvironment. AB - Low oxygen tension or hypoxia is a determining factor in the course of many different processes in animals, including when tissue expansion and cellular metabolism result in high oxygen demands that exceed its supply. This is mainly happening when cells actively proliferate and the proliferating mass becomes distant from the blood vessels, such as in growing tumors. Metabolic alterations in response to hypoxia can be triggered in a direct manner, such as the switch from oxidative phosphorylation to glycolysis or inhibition of fatty acid desaturation. However, as the modulated action of hypoxia-inducible factors or the oxygen sensors (prolyl hydroxylase domain-containing enzymes) can also lead to changes in enzyme expression, these metabolic changes can also be indirect. With this review, we want to summarize our current knowledge of the hypoxia induced changes in metabolism during cancer development, how they are affected in the tumor cells and in the cells of the microenvironment, most prominently in immune cells. PMID- 29434590 TI - Killed Whole-Cell Oral Cholera Vaccine Induces CCL20 Secretion by Human Intestinal Epithelial Cells in the Presence of the Short-Chain Fatty Acid, Butyrate. AB - Short-chain fatty acids (SCFAs), such as acetate, butyrate, and propionate, modulate immune responses in the gut. However, the effect of SCFAs on mucosal vaccine-induced immune cell migration is poorly understood. Here, we investigated whether SCFAs modulate chemokine expression induced by the killed whole-cell oral cholera vaccine, ShancholTM, in human intestinal epithelial cells. ShancholTM induced expression of CCL2, CCL5, CCL20, and CXCL10 at the mRNA level, but not at the protein level. Interestingly, CCL20 secretion was substantially increased by co-stimulation with ShancholTM and butyrate, while neither acetate nor propionate showed such effect. Enhanced CCL20 secretion was associated with GPR109A activation, and histone deacetylase (HDAC) inhibition. In addition, co-treatment with ShancholTM and butyrate synergistically increased the secretion of adenosine triphosphate (ATP). Moreover, CCL20 secretion was decreased by inhibiting the extracellular ATP receptor P2X7. However, neither inflammasomes nor caspases were involved in CCL20 production. The culture supernatant of cells treated with ShancholTM and butyrate augmented human immature dendritic cell migration. Collectively, these results suggest that butyrate enhances ShancholTM-induced CCL20 production in human intestinal epithelial cells via HDAC inhibition and ATP P2X7 signaling by activating GPR109A. These effects potentially enhance the mucosal immune responses in the gut induced by this oral cholera vaccine. PMID- 29434591 TI - Angiotensin-(1-7) Promotes Resolution of Eosinophilic Inflammation in an Experimental Model of Asthma. AB - Defective apoptosis of eosinophils, the main leukocyte in the pathogenesis of asthma, and delay in its removal lead to lung damage and loss of pulmonary function due to failure in the resolution of inflammation. Here, we investigated the ability of angiotensin-(1-7) [Ang-(1-7)], a pivotal peptide of the renin angiotensin system, to promote resolution of an allergic lung inflammatory response. Balb/c mice were sensitized and challenged with ovalbumin and treated with Ang-(1-7) at the peak of the inflammatory process. Bronchoalveolar lavage (BAL) fluid and lungs were collected 24 h after treatment. Different lung lobes were processed for histology to evaluate inflammatory cell infiltration, airway and pulmonary remodeling, total collagen staining, and measurements of (i) collagen I and III mRNA expression by qRT-PCR; (ii) ERK1/2, IkappaB-alpha, and GATA3 protein levels by Western blotting; and (iii) eosinophilic peroxidase activity. Total number of inflammatory cells, proportion of apoptotic eosinophils and immunofluorescence for caspase 3 and NF-kappaB in leukocytes were evaluated in the BAL. Mas receptor immunostaining was evaluated in mouse and human eosinophils. Engulfment of human polimorphonuclear cells by macrophages, efferocytosis, was evaluated in vivo. Ang-(1-7) reduced eosinophils in the lung and in the BAL, increased the number of apoptotic eosinophils, shown by histology criteria and by increase in caspase 3 immunostaining. Furthermore, Ang-(1-7) decreased NF-kB immunostaining in eosinophils, reduced GATA3, ERK1/2, and IkappaB alpha expression in the lung and decreased pulmonary remodeling and collagen deposition. Importantly, Ang-(1-7) increased efferocytosis. Our results demonstrate, for the first time, Ang-(1-7) activates events that are crucial for resolution of the inflammatory process of asthma and promotion of the return of lung homeostasis, indicating Ang-(1-7) as novel endogenous inflammation-resolving mediator. PMID- 29434592 TI - Signaling Lymphocyte Activation Molecule Family 5 Enhances Autophagy and Fine Tunes Cytokine Response in Monocyte-Derived Dendritic Cells via Stabilization of Interferon Regulatory Factor 8. AB - Signaling lymphocyte activation molecule family (SLAMF) receptors are essential regulators of innate and adaptive immune responses. The function of SLAMF5/CD84, a family member with almost ubiquitous expression within the hematopoietic lineage is poorly defined. In this article, we provide evidence that in human monocyte-derived dendritic cells (moDCs) SLAMF5 increases autophagy, a degradative pathway, which is highly active in dendritic cells (DCs) and plays a critical role in orchestration of the immune response. While investigating the underlying mechanism, we found that SLAMF5 inhibited proteolytic degradation of interferon regulatory factor 8 (IRF8) a master regulator of the autophagy process by a mechanism dependent on the E3-ubiquitin ligase tripartite motif-containing protein 21 (TRIM21). Furthermore, we demonstrate that SLAMF5 influences the ratio of CD1a+ cells in differentiating DCs and partakes in the regulation of IL-1beta, IL-23, and IL-12 production in LPS/IFNgamma-activated moDCs in a manner that is consistent with its effect on IRF8 stability. In summary, our experiments identified SLAMF5 as a novel cell surface receptor modulator of autophagy and revealed an unexpected link between the SLAMF and IRF8 signaling pathways, both implicated in multiple human pathologies. PMID- 29434593 TI - Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host. AB - Leishmania donovani, the causative agent of Indian visceral leishmaniasis has to face several barriers of the immune system inside the mammalian host for its survival. The complement system is one of the first barriers and consists of a well-balanced network of proteases including S1A family serine proteases (SPs). Inhibitor of serine peptidases (ISPs) is considered as inhibitor of S1A family serine peptidases and is reported to be present in trypanosomes, including Leishmania. In our previous study, we have deciphered the role of ISPs [LdISP1 and L. donovani inhibitor of serine peptidases 2 (LdISP2)] in the survival of L. donovani inside the sandfly midgut. However, the role of theses ISPs in the survival of L. donovani inside mammalian host still remains elusive. In the present study, we have deciphered the inhibitory effect of LdISPs on the host complement S1A serine peptidases, such as C1r/C1s and MASP1/MASP2. Our study suggested that although both rLdISP1 and rLdISP2 inferred strong interaction with C1complex and MBL-associated serine proteases (MASPs) but rLdISP2 showed the stronger inhibitory effect on MASP2 than rLdISP1. Moreover, we found that rLdISP2 significantly reduces the formation of C3, C5 convertase, and membrane attacking complex (MAC) by lectin pathway (LP) resulting in significant reduction in serum mediated lysis of the parasites. The role of LdISP2 on neutrophil elastase mediated C5aR signaling was also evaluated. Notably, our results showed that infection of macrophages with ISP2-overexpressed Leishmania parasites significantly induces the expression of C5aR both at the transcript and translational level. Simultaneously, infection with ISP2KD parasites results in downregulation of host PI3K/AKT phosphorylation and increased in IL-12 production. Taken together, our findings clearly suggest that LdISP2 promotes parasite survival inside host by inhibiting MAC formation and complement-mediated lysis via LP and by upregulation of C5aR signaling. PMID- 29434594 TI - p38gamma and p38delta Are Involved in T Lymphocyte Development. AB - p38 mitogen-activated protein kinase (MAPK) signal transduction pathways are essential regulators of the immune response. Particularly, p38gamma and p38delta regulate many immune cell functions such as cytokine production, migration, or T cell activation; however, their involvement in immune cell development is largely unknown. Here, we analysed the role of p38 MAPK isoforms p38gamma and p38delta in T cell differentiation in the thymus and in lymph nodes, using mice deficient in p38gamma, p38delta, or in both. We found that the T cell differentiation program in the thymus was affected at different stages in p38gamma-, p38delta-, and p38gamma/delta-deficient mice, and also peripheral T cell homaeostasis was compromised. Particularly, p38delta deletion affects different stages of early CD4-CD8- double-negative thymocyte development, whereas lack of p38gamma favours thymocyte positive selection from CD4+CD8+ double-positive to CD4+ or CD8+ single positive cells. Our results identify unreported functions for p38gamma and p38delta in T cells. PMID- 29434595 TI - Immunometabolism and PI(3)K Signaling As a Link between IL-2, Foxp3 Expression, and Suppressor Function in Regulatory T Cells. AB - CD4+ Foxp3+ regulatory T cells (Tregs) are an essential component of immune homeostasis. Modulation of Treg function has been proposed as a means of treating autoimmune conditions and preventing rejection of organ transplants, although achieving this goal will require a detailed understanding of Treg signaling pathways. Signaling within Tregs is known to differ considerably from that observed in other T cell subsets. Of note, Tregs are the only cell type known to constitutively express CD25, the main ligand-binding subunit of the IL-2 receptor. The PI(3)K/Akt/mTOR cascade constitutes a major signaling pathway downstream of IL-2 and is closely tied to cellular metabolism. Due to increasing recognition of the links between cellular fuel usage and immune cell function, the interplay between IL-2 signaling and Treg metabolism represents an important space for exploration and a potential approach for immunomodulation. Here, we discuss how IL-2 may affect Treg metabolism via PI(3)K signaling, as well as the effects of altered metabolism on Treg lineage stability and suppressor function. PMID- 29434596 TI - Insight into Phosphatidylinositol-Dependent Membrane Localization of the Innate Immune Adaptor Protein Toll/Interleukin 1 Receptor Domain-Containing Adaptor Protein. AB - The toll/interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP) plays an important role in the toll-like receptor (TLR) 2, TLR4, TLR7, and TLR9 signaling pathways. TIRAP anchors to phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) on the plasma membrane and PI (3,4,5)-trisphosphate (PIP3) on the endosomal membrane and assists in recruitment of the myeloid differentiation primary response 88 protein to activated TLRs. To date, the structure and mechanism of TIRAP's membrane association are only partially understood. Here, we modeled an all-residue TIRAP dimer using homology modeling, threading, and protein-protein docking strategies. Molecular dynamics simulations revealed that PIP2 creates a stable microdomain in a dipalmitoylphosphatidylcholine bilayer, providing TIRAP with its physiologically relevant orientation. Computed binding free energy values suggest that the affinity of PI-binding domain (PBD) for PIP2 is stronger than that of TIRAP as a whole for PIP2 and that the short PI-binding motif (PBM) contributes to the affinity between PBD and PIP2. Four PIP2 molecules can be accommodated by distinct lysine-rich surfaces on the dimeric PBM. Along with the known PI-binding residues (K15, K16, K31, and K32), additional positively charged residues (K34, K35, and R36) showed strong affinity toward PIP2. Lysine-to-alanine mutations at the PI-binding residues abolished TIRAP's affinity for PIP2; however, K34, K35, and R36 consistently interacted with PIP2 headgroups through hydrogen bond (H-bond) and electrostatic interactions. TIRAP exhibited a PIP2-analogous intermolecular contact and binding affinity toward PIP3, aided by an H-bond network involving K34, K35, and R36. The present study extends our understanding of TIRAP's membrane association, which could be helpful in designing peptide decoys to block TLR2-, TLR4-, TLR7-, and TLR9-mediated autoimmune diseases. PMID- 29434597 TI - 92R Monoclonal Antibody Inhibits Human CCR9+ Leukemia Cells Growth in NSG Mice Xenografts. AB - CCR9 is as an interesting target for the treatment of human CCR9+-T cell acute lymphoblastic leukemia, since its expression is limited to immature cells in the thymus, infiltrating leukocytes in the small intestine and a small fraction of mature circulating T lymphocytes. 92R, a new mouse mAb (IgG2a isotype), was raised using the A-isoform of hCCR9 as immunogen. Its initial characterization demonstrates that binds with high affinity to the CCR9 N-terminal domain, competing with the previously described 91R mAb for receptor binding. 92R inhibits human CCR9+ tumor growth in T and B-cell deficient Rag2-/- mice. In vitro assays suggested complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity as possible in vivo mechanisms of action. Unexpectedly, 92R strongly inhibited tumor growth also in a model with compromised NK and complement activities, suggesting that other mechanisms, including phagocytosis or apoptosis, might also be playing a role on 92R-mediated tumor elimination. Taken together, these data contribute to strengthen the hypothesis of the immune system's opportunistic nature. PMID- 29434598 TI - Core Fucosylation of the T Cell Receptor Is Required for T Cell Activation. AB - CD4+ T cell activation promotes the pathogenic process of systemic lupus erythematosus (SLE). T cell receptor (TCR) complex are highly core fucosylated glycoproteins, which play important roles in T cell activation. In this study, we found that the core fucosylation of CD4+ T cells was significantly increased in SLE patients. Loss of core fucosyltransferase (Fut8), the sole enzyme for catalyzing the core fucosylation of N-glycan, significantly reduced CD4+ T cell activation and ameliorated the experimental autoimmune encephalomyelitis-induced syndrome in Fut8-/- mice. T cell activation with OVA323-339 loaded major histocompatibility complex II (pMHC-II) on B cell was dramatically attenuated in Fut8-/-OT-II CD4+ T cells compared with Fut8+/+OT-II CD4+ T cells. Moreover, the phosphorylation of ZAP-70 was significantly reduced in Fut8+/+OT-II CD4+ T cells by the treatment of fucosidase. Our results suggest that core fucosylation is required for efficient TCR-pMHC-II contacts in CD4+ T cell activation, and hyper core fucosylation may serve as a potential novel biomarker in the sera from SLE patients. PMID- 29434599 TI - RNA-Seq Analysis of IL-1B and IL-36 Responses in Epidermal Keratinocytes Identifies a Shared MyD88-Dependent Gene Signature. AB - IL-36 cytokines have recently emerged as mediators of inflammation in autoimmune conditions including psoriasis vulgaris (PsV) and generalized pustular psoriasis (GPP). This study used RNA-seq to profile the transcriptome of primary epidermal keratinocytes (KCs) treated with IL-1B, IL-36A, IL-36B, or IL-36G. We identified some early IL-1B-specific responses (8 h posttreatment), but nearly all late IL 1B responses were replicated by IL-36 cytokines (24 h posttreatment). Type I and II interferon genes exhibited time-dependent response patterns, with early induction (8 h) followed by no response or repression (24 h). Altogether, we identified 225 differentially expressed genes (DEGs) with shared responses to all 4 cytokines at both time points (8 and 24 h). These involved upregulation of ligands (IL1A, IL1B, and IL36G) and activating proteases (CTSS) but also upregulation of inhibitors such as IL1RN and IL36RN. Shared IL-1B/IL-36 DEGs overlapped significantly with genes altered in PsV and GPP skin lesions, as well as genes near GWAS loci linked to autoimmune and autoinflammatory diseases (e.g., PsV, psoriatic arthritis, inflammatory bowel disease, and primary biliary cholangitis). Inactivation of MyD88 adapter protein using CRISPR/Cas9 completely abolished expression responses of such DEGs to IL-1B and IL-36G stimulation. These results provide a global view of IL-1B and IL-36 expression responses in epidermal KCs with fine-scale characterization of time-dependent and cytokine specific response patterns. Our findings support an important role for IL-1B and IL-36 in autoimmune or autoinflammatory conditions and show that MyD88 adaptor protein mediates shared IL-1B/IL-36 responses. PMID- 29434600 TI - Negative Effect of Age, but Not of Latent Cytomegalovirus Infection on the Antibody Response to a Novel Influenza Vaccine Strain in Healthy Adults. AB - Older adults are more vulnerable to influenza virus infection and at higher risk for severe complications and influenza-related death compared to younger adults. Unfortunately, influenza vaccine responses tend to be impaired in older adults due to aging of the immune system (immunosenescence). Latent infection with cytomegalovirus (CMV) is assumed to enhance age-associated deleterious changes of the immune system. Although lower responses to influenza vaccination were reported in CMV-seropositive compared to CMV-seronegative adults and elderly, beneficial effects of CMV infection were observed as well. The lack of consensus in literature on the effect of latent CMV infection on influenza vaccination may be due to the presence of pre-existing immunity to influenza in these studies influencing the subsequent influenza vaccine response. We had the unique opportunity to evaluate the effect of age and latent CMV infection on the antibody response to the novel influenza H1N1pdm vaccine strain during the pandemic of 2009, thereby reducing the effect of pre-existing immunity on the vaccine-induced antibody response. This analysis was performed in a large study population (n = 263) in adults (18-52 years old). As a control, memory responses to the seasonal vaccination, including the same H1N1pdm and an H3N2 strain, were investigated in the subsequent season 2010-2011. With higher age, we found decreased antibody responses to the pandemic vaccination even within this age range, indicating signs of immunosenescence to this novel antigen in the study population. Using a generalized estimation equation regression model, adjusted for age, sex, and previous influenza vaccinations, we observed that CMV infection in contrast did not influence the influenza virus-specific antibody titer after H1N1pdm vaccination. Yet, we found higher residual protection rates (antibody level >=40 hemagglutinin units (HAU)) in CMV-seropositive individuals than in CMV seronegative individuals 6 months and 1 year after pandemic vaccination. In the subsequent season, no effect of age or CMV infection on seasonal influenza vaccine response was observed. In conclusion, we observed no evidence for CMV induced impairment of antibody responses to a novel influenza strain vaccine in adults. If anything, our data suggest that there might be a beneficial effect of latent CMV infection on the protection rate after novel influenza vaccination. PMID- 29434601 TI - Inhibition of Osteoblast Function by Brucella abortus is Reversed by Dehydroepiandrosterone and Involves ERK1/2 and Estrogen Receptor. AB - Brucella abortus induces an inflammatory response that stimulates the endocrine system resulting in the secretion of cortisol and dehydroepiandrosterone (DHEA). Osteoarticular brucellosis is the most common presentation of the active disease in humans, and we have previously demonstrated that B. abortus infection inhibits osteoblast function. We aimed to evaluate the role of cortisol and DHEA on osteoblast during B. abortus infection. B. abortus infection induces apoptosis and inhibits osteoblast function. DHEA treatment reversed the effect of B. abortus infection on osteoblast by increasing their proliferation, inhibiting osteoblast apoptosis, and reversing the inhibitory effect of B. abortus on osteoblast differentiation and function. By contrast, cortisol increased the effect of B. abortus infection. Cortisol regulates target genes by binding to the glucocorticoid receptor (GR). B. abortus infection inhibited GRalpha expression. Cell responses to cortisol not only depend on GR expression but also on its intracellular bioavailability, that is, dependent on the activity of the isoenzymes 11beta-hydroxysteroid dehydrogenase (HSD) type-1, 11beta-HSD2 (which convert cortisone to cortisol and vice versa, respectively). Alterations in the expression of these isoenzymes in bone cells are associated with bone loss. B. abortus infection increased 11beta-HSD1 expression but had no effect on 11beta HSD2. DHEA reversed the inhibitory effect induced by B. abortus infection on osteoblast matrix deposition in an estrogen receptor- and ERK1/2-dependent manner. We conclude that DHEA intervention improves osteoblast function during B. abortus infection making it a potential candidate to ameliorate the osteoarticular symptoms of brucellosis. PMID- 29434602 TI - Identification of a Novel CD8 T Cell Epitope Derived from Plasmodium berghei Protective Liver-Stage Antigen. AB - We recently identified novel Plasmodium berghei (Pb) liver stage (LS) genes that as DNA vaccines significantly reduce Pb LS parasite burden (LPB) in C57Bl/6 (B6) mice through a mechanism mediated, in part, by CD8 T cells. In this study, we sought to determine fine antigen (Ag) specificities of CD8 T cells that target LS malaria parasites. Guided by algorithms for predicting MHC class I-restricted epitopes, we ranked sequences of 32 Pb LS Ags and selected ~400 peptides restricted by mouse H-2Kb and H-2Db alleles for analysis in the high-throughput method of caged MHC class I-tetramer technology. We identified a 9-mer H-2Kb restricted CD8 T cell epitope, Kb-17, which specifically recognized and activated CD8 T cell responses in B6 mice immunized with Pb radiation-attenuated sporozoites (RAS) and challenged with infectious sporozoites (spz). The Kb-17 peptide is derived from the recently described novel protective Pb LS Ag, PBANKA_1031000 (MIF4G-like protein). Notably, immunization with the Kb-17 epitope delivered in the form of a minigene in the adenovirus serotype 5 vector reduced LPB in mice infected with spz. On the basis of our results, Kb-17 peptide was available for CD8 T cell activation and recall following immunization with Pb RAS and challenge with infectious spz. The identification of a novel MHC class I restricted epitope from the protective Pb LS Ag, MIF4G-like protein, is crucial for advancing our understanding of immune responses to Plasmodium and by extension, toward vaccine development against malaria. PMID- 29434603 TI - Glycogen Synthase Kinase 3alpha Is the Main Isoform That Regulates the Transcription Factors Nuclear Factor-Kappa B and cAMP Response Element Binding in Bovine Endothelial Cells Infected with Staphylococcus aureus. AB - Glycogen synthase kinase 3 (GSK3) is a constitutive enzyme implicated in the regulation of cytokine expression and the inflammatory response during bacterial infections. Mammals have two GSK3 isoforms named GSK3alpha and GSK3beta that plays different but often overlapping functions. Although the role of GSK3beta in cytokine regulation during the inflammatory response caused by bacteria is well described, GSK3alpha has not been found to participate in this process. Therefore, we tested if GSK3alpha may act as a regulatory isoform in the cytokine expression by bovine endothelial cells infected with Staphylococcus aureus because this bacterium is one of the major pathogens that cause tissue damage associated with inflammatory dysfunction. Interestingly, although both isoforms were phosphorylated-inactivated, we consistently observed a higher phosphorylation of GSK3alpha at Ser21 than that of GSK3beta at Ser9 after bacterial challenge. During a temporal course of infection, we characterized a molecular switch from pro-inflammatory cytokine expression (IL-8), promoted by nuclear factor-kappa B (NF-kappaB), at an early stage (2 h) to an anti inflammatory cytokine expression (IL-10), promoted by cAMP response element binding (CREB), at a later stage (6 h). We observed an indirect effect of GSK3alpha activity on NF-kappaB activation that resulted in a low phosphorylation of CREB at Ser133, a decreased interaction between CREB and the co-activator CREB binding protein (CBP), and a lower expression level of IL-10. Gene silencing of GSK3alpha and GSK3beta with siRNA indicated that GSK3alpha knockout promoted the interaction between CREB and CBP that, in turn, increased the expression of IL 10, reduced the interaction of NF-kappaB with CBP, and reduced the expression of IL-8. These results indicate that GSK3alpha functions as the primary isoform that regulates the expression of IL-10 in endothelial cells infected with S. aureus. PMID- 29434604 TI - Increased Interleukin-23 in Hashimoto's Thyroiditis Disease Induces Autophagy Suppression and Reactive Oxygen Species Accumulation. AB - Hashimoto's thyroiditis (HT) represents the most common organ-specific autoimmune disease. Inflammatory factors and reactive oxygen species (ROS) play detrimental roles during the pathogenesis of HT. In this study, we found that thyroid follicular cells (TFCs) from HT patients expressed an elevated level of interleukin-23 (IL-23), which contributed to autophagy suppression and ROS accumulation. Additionally, IL-23-induced autophagy suppression and ROS accumulation in human TFCs was attributed to AKT/mTOR/NF-kappaB signaling pathway activation. Inhibition of either IL-23 by a specific neutralization antibody, or mTOR by rapamycin, or NF-kappaB by IKK-16, significantly reversed the autophagy suppression and ROS accumulation. These results demonstrate a key role for IL-23 in HT pathogenesis and provide a potential therapeutic strategy against IL-23 or its signaling pathway in HT. PMID- 29434605 TI - MHC Intratumoral Heterogeneity May Predict Cancer Progression and Response to Immunotherapy. AB - An individual tumor can present intratumoral phenotypic heterogeneity, containing tumor cells with different phenotypes that do not present irreversible genetic alterations. We have developed a mouse cancer model, named GR9, derived from a methylcholanthrene-induced fibrosarcoma that was adapted to tissue culture and cloned into different tumor cell lines. The clones showed diverse MHC-I phenotypes, ranging from highly positive to weakly positive MHC-I expression. These MHC-I alterations are due to reversible molecular mechanisms, because surface MHC-I could be recovered by IFN-gamma treatment. Cell clones with high MHC-I expression demonstrated low local oncogenicity and high spontaneous metastatic capacity, whereas MHC-I-low clones showed high local oncogenicity and no spontaneous metastatic capacity. Although MHC-I-low clones did not metastasize, they produced MHC-I-positive dormant micrometastases controlled by the host immune system, i.e., in a state of immunodormancy. The metastatic capacity of each clone was directly correlated with the host T-cell subpopulations; thus, a strong decrease in cytotoxic and helper T lymphocytes was observed in mice with numerous metastases derived from MHC-I positive tumor clones but a strong increase was observed in those with dormant micrometastases. Immunotherapy was administered to the hosts after excision of the primary tumor, producing a recovery in their immune status and leading to the complete eradication of overt spontaneous metastases or their decrease. According to these findings, the combination of MHC-I surface expression in primary tumor and metastases with host T-cell subsets may be a decisive indicator of the clinical outcome and response to immunotherapy in metastatic disease, allowing the identification of responders to this approach. PMID- 29434607 TI - The Role of the Endothelium during Antibody-Mediated Rejection: From Victim to Accomplice. AB - Antibody-mediated rejection (AMR) of solid organ transplants is characterized by the activation and injury of the allograft endothelium. Histological and transcriptomic studies have associated microvascular inflammation and endothelial lesions with the severity of rejection and poor graft outcomes. The allograft endothelium forms the physical barrier between the donor organ and the recipient; this position directly exposes the endothelium to alloimmune responses. However, endothelial cells are not just victims and can actively participate in the pathogenesis of rejection. In healthy tissues, the endothelium plays a major role in vascular and immune homeostasis. Organ transplantation, however, subjects the endothelium to an environment of inflammation, alloreactive lymphocytes, donor specific antibodies, and potentially complement activation. As a result, endothelial cells become activated and have modified interactions with the cellular effectors of allograft damage: lymphocytes, natural killer, and myeloid cells. Activated endothelial cells participate in leukocyte adhesion and recruitment, lymphocyte activation and differentiation, as well as the secretion of cytokines and chemokines. Ultimately, highly activated endothelial cells promote pro-inflammatory alloresponses and become accomplices to AMR. PMID- 29434608 TI - A Case of Type 2 Hypersensitivity to Rasburicase Diagnosed with a Natural Killer Cell Activation Assay. AB - Drug hypersensitivity reactions can lead to different clinical pictures depending on the underlying immunological mechanism. Diagnosis tests are already available to assess the most frequent drugs hypersensitivity reactions, which are mediated by specific IgE or T cells. However, it remains challenging to diagnose type 2 hypersensitivity reactions (T2HR), which can lead to severe cytopenia and liver failure. Here, we describe a case of T2HR to rasburicase, an uricolytic agent used to prevent tumor lysis syndrome. In this patient, sensitization was associated with the production of specific IgG able to bind to leukocytes. We found that patient NK cells were specifically activated in the presence of rasburicase and autologous serum, which led to exocytosis of lytic granules. This antibody-dependent cell cytotoxicity mechanism may lead to cytopenia observed in the patient. Moreover, this NK cell activation assay could be used to improve the diagnosis of a T2HR to rasburicase and, by extent, to other drugs. These data also suggest that NK cells could play an important role in the pathophysiological mechanism of T2HR. PMID- 29434606 TI - Macrophage Recognition of Crystals and Nanoparticles. AB - Inhalation of exogenous crystals such as silica, asbestos, and carbon nanotubes can cause lung fibrosis and cancer. Endogenous crystals such as monosodium urate, cholesterol, and hydroxyapatite are associated with pathogenesis of gout, atherosclerosis, and osteoarthritis, respectively. These crystal-associated inflammatory diseases are triggered by the macrophage NLRP3 inflammasome activation and cell death. Therefore, it is important to understand how macrophages recognize crystals. However, it is unlikely that macrophages have evolutionally acquired receptors specific for crystals or recently emerged nanoparticles. Several recent studies have reported that some crystal particles are negatively charged and are recognized by scavenger receptor family members in a charge-dependent manner. Alternatively, a model for receptor-independent phagocytosis of crystals has also been proposed. This review focuses on the mechanisms by which macrophages recognize crystals and nanoparticles. PMID- 29434609 TI - FRG3, a Target of slmiR482e-3p, Provides Resistance against the Fungal Pathogen Fusarium oxysporum in Tomato. AB - The vast majority of plant disease resistance (R) genes encode nucleotide binding site-leucine-rich repeat (NBS-LRR) proteins, which specifically determine the plant immune response and have been demonstrated to be targets of several microRNA (miRNA) families. The fungus Fusarium oxysporum f. sp. lycopersici (FOL) causes vascular wilt disease in tomato worldwide. Here, we explored a possible role for FGR3 in tomato defense against FOL. FRG3 is a predicted NBS-LRR like gene that is targeted by slmiR482e-3p, a member of slmiR482 miRNA family. Northern blot data demonstrated that all seven members of the slmiR482 family were regulated in diverse ways after infection by FOL. The ability of FRG3 to be regulated by slmiR482e-3p was confirmed at the transcript level by co-expression studies in Nicotiana benthamiana. A virus-induced gene silencing (VIGS) approach revealed that FRG3 confers resistance to the Motelle tomato cultivar. Taken together, our study has identified a novel R gene, FRG3, which is targeted by slmiR482e-3p at the transcript level, and is necessary for resistance to tomato wilt disease in planta. PMID- 29434610 TI - Isolation and Role of PmRGL2 in GA-mediated Floral Bud Dormancy Release in Japanese Apricot (Prunus mume Siebold et Zucc.). AB - Bud dormancy release is regulated by gibberellins (GAs). DELLA proteins are highly conserved and act as negative regulators in GA signaling pathway. The present study established a relationship between PmRGL2 in Japanese apricot and GA4 levels during dormancy release of floral buds. Overexpression of PmRGL2 in poplar delayed the onset of bud dormancy and resulted in dwarf plants, relative to wild-type trees. PmRGL2 exhibited higher expression during ecodormancy and relatively lower expression during endodormancy. The relative level of GA4 exhibited an increasing trend at the transition from endodormancy to ecodormancy and displayed a similar expression pattern of genes related to GA metabolism, PmGA20ox2, PmGA3ox1, PmGID1b, in both Japanese apricot and transgenic poplar. These results suggests that PmRGL2 acts as an integrator and negative regulator of dormancy via a GA-signaling pathway. Moreover, an interaction between RGL2 and SLY1 in a yeast two hybrid (Y2H) system further suggests that SCF E3 ubiquitin ligases, such as SLY1, may be a critical factor in the regulation of RGL2 through an SCF SLY1 -proteasome pathway. Our study demonstrated that PmRGL2 plays a negative role in bud dormancy release by regulating the GA biosynthetic enzymes, GA20ox and GA3ox1 and the GA receptor, GID1b. PMID- 29434611 TI - Sphingolipid Distribution, Content and Gene Expression during Olive-Fruit Development and Ripening. AB - Plant sphingolipids are involved in the building of the matrix of cell membranes and in signaling pathways of physiological processes and environmental responses. However, information regarding their role in fruit development and ripening, a plant-specific process, is unknown. The present study seeks to determine whether and, if so, how sphingolipids are involved in fleshy-fruit development and ripening in an oil-crop species such as olive (Olea europaea L. cv. Picual). Here, in the plasma-membranes of live protoplasts, we used fluorescence to examine various specific lipophilic stains in sphingolipid-enriched regions and investigated the composition of the sphingolipid long-chain bases (LCBs) as well as the expression patterns of sphingolipid-related genes, OeSPT, OeSPHK, OeACER, and OeGlcCerase, during olive-fruit development and ripening. The results demonstrate increased sphingolipid content and vesicle trafficking in olive-fruit protoplasts at the onset of ripening. Moreover, the concentration of LCB [t18:1(8Z), t18:1 (8E), t18:0, d18:2 (4E/8Z), d18:2 (4E/8E), d18:1(4E), and 1,4 anhydro-t18:1(8E)] increases during fruit development to reach a maximum at the onset of ripening, although these molecular species decreased during fruit ripening. On the other hand, OeSPT, OeSPHK, and OeGlcCerase were expressed differentially during fruit development and ripening, whereas OeACER gene expression was detected only at the fully ripe stage. The results provide novel data about sphingolipid distribution, content, and biosynthesis/turnover gene transcripts during fleshy-fruit ripening, indicating that all are highly regulated in a developmental manner. PMID- 29434612 TI - Transcriptomic and Functional Analyses Reveal That PpGLK1 Regulates Chloroplast Development in Peach (Prunus persica). AB - Peach is an ideal species for fruit tree research because of its small, fully sequenced genome. Chloroplast development is dependent on the tight cooperation between the nuclear and plastid genomes, and is regulated by GLK transcription factors. In this work, the pigment content was monitored and the chloroplast-to chromoplast conversion during the fruit ripening was visualized by transmission electron microscopy. Localization and expression analyses showed that PpGLK1 was located in the nucleus and expressed mainly in the leaves and fruit skin. A transcriptome analysis showed that PpGLK1 and its target genes were significantly differentially expressed in ripening peach fruit skin. PpGLK1 silencing affected chlorophyll accumulation in peach leaves and fruits. Overexpression of PpGLK1 rescued the phenotypes of the Arabidopsis Atglk1Atglk2 double mutant and the tomato uniform ripening mutant. The results of a yeast two-hybrid analysis showed that PpGLK1 is autoactivated and that PpGLK1 (301-542 a.a.) interacted with PpARF5. Together, our results indicate that PpGLK1 regulates chloroplast development in green tissues in peach. Therefore, it may be a promising target gene for improving the production and quality of peach by genetic engineering and breeding approaches. PMID- 29434614 TI - Corrigendum: Overexpression of a Grapevine Sucrose Transporter (VvSUC27) in Tobacco Improves Plant Growth Rate in the Presence of Sucrose In vitro. AB - [This corrects the article on p. 1069 in vol. 8, PMID: 28676814.]. PMID- 29434613 TI - Divergent Hd1, Ghd7, and DTH7 Alleles Control Heading Date and Yield Potential of Japonica Rice in Northeast China. AB - The heading date is a vital factor in achieving a full rice yield. Cultivars with particular flowering behaviors have been artificially selected to survive in the long-day and low-temperature conditions of Northeast China. To dissect the genetic mechanism responsible for heading date in rice populations from Northeast China, association mapping was performed to identify major controlling loci. A genome-wide association study (GWAS) identified three genetic loci, Hd1, Ghd7, and DTH7, using general and mixed linear models. The three genes were sequenced to analyze natural variations and identify their functions. Loss-of-function alleles of these genes contributed to early rice heading dates in the northern regions of Northeast China, while functional alleles promoted late rice heading dates in the southern regions of Northeast China. Selecting environmentally appropriate allele combinations in new varieties is recommended during breeding. Introducing the early indica rice's genetic background into Northeast japonica rice is a reasonable strategy for improving genetic diversity. PMID- 29434615 TI - Comparative Transcriptome Profiles of Near-Isogenic Hexaploid Wheat Lines Differing for Effective Alleles at the 2DL FHB Resistance QTL. AB - Fusarium head blight (FHB), caused by the fungus Fusarium graminearum, represents one of the major wheat diseases worldwide, determining severe yield losses and reduction of grain quality due to the accumulation of mycotoxins. The molecular response associated with the wheat 2DL FHB resistance QTL was mined through a comprehensive transcriptomic analysis of the early response to F. graminearum infection, at 3 days post-inoculation, in spikelets and rachis. The analyses were conducted on two near isogenic lines (NILs) differing for the presence of the 2DL QTL (2-2618, resistant 2DL+ and 2-2890, susceptible null). The general response to fungal infection in terms of mRNAs accumulation trend was similar in both NILs, even though involving an higher number of DEGs in the susceptible NIL, and included down-regulation of the primary and energy metabolism, up-regulation of enzymes implicated in lignin and phenylpropanoid biosynthesis, activation of hormons biosynthesis and signal transduction pathways and genes involved in redox homeostasis and transcriptional regulation. The search for candidate genes with expression profiles associated with the 2DL QTL for FHB resistance led to the discovery of processes differentially modulated in the R and S NILs related to cell wall metabolism, sugar and JA signaling, signal reception and transduction, regulation of the redox status and transcription factors. Wheat FHB response related miRNAs differentially regulated were also identified as putatively implicated in the superoxide dismutase activities and affecting genes regulating responses to biotic/abiotic stresses and auxin signaling. Altered gene expression was also observed for fungal non-codingRNAs. The putative targets of two of these were represented by the wheat gene WIR1A, involved in resistance response, and a gene encoding a jacalin-related lectin protein, which participate in biotic and abiotic stress response, supporting the presence of a cross-talk between the plant and the fungus. PMID- 29434617 TI - Tobacco BY-2 Media Component Optimization for a Cost-Efficient Recombinant Protein Production. AB - Plant cells constitute an attractive platform for production of recombinant proteins as more and more animal-free products and processes are desired. One of the challenges in using plant cells as production hosts has been the costs deriving from expensive culture medium components. In this work, the aim was to optimize the levels of most expensive components in the nutrient medium without compromising the accumulation of biomass and recombinant protein yields. Wild type BY-2 culture and transgenic tobacco BY-2 expressing green fluorescent protein-Hydrophobin I (GFP-HFBI) fusion protein were used to determine the most inexpensive medium composition. One particularly high-accumulating BY-2 clone, named 'Hulk,' produced 1.1 +/- 0.2 g/l GFP-HFBI in suspension and kept its high performance during prolonged subculturing. In addition, both cultures were successfully cryopreserved enabling truly industrial application of this plant cell host. With the optimized culture medium, 43-55% cost reduction with regard to biomass and up to 69% reduction with regard to recombinant protein production was achieved. PMID- 29434616 TI - Pollen from the Deep-Sea: A Breakthrough in the Mystery of the Ice Ages. AB - Pollen from deep-sea sedimentary sequences provides an integrated regional reconstruction of vegetation and climate (temperature, precipitation, and seasonality) on the adjacent continent. More importantly, the direct correlation of pollen, marine and ice indicators allows comparison of the atmospheric climatic changes that have affected the continent with the response of the Earth's other reservoirs, i.e., the oceans and cryosphere, without any chronological uncertainty. The study of long continuous pollen records from the European margin has revealed a changing and complex interplay between European climate, North Atlantic sea surface temperatures (SSTs), ice growth and decay, and high- and low-latitude forcing at orbital and millennial timescales. These records have shown that the amplitude of the last five terrestrial interglacials was similar above 40 degrees N, while below 40 degrees N their magnitude differed due to precession-modulated changes in seasonality and, particularly, winter precipitation. These records also showed that vegetation response was in dynamic equilibrium with rapid climate changes such as the Dangaard-Oeschger (D-O) cycles and Heinrich events, similar in magnitude and velocity to the ongoing global warming. However, the magnitude of the millennial-scale warming events of the last glacial period was regionally-specific. Precession seems to have imprinted regions below 40 degrees N while obliquity, which controls average annual temperature, probably mediated the impact of D-O warming events above 40 degrees N. A decoupling between high- and low-latitude climate was also observed within last glacial warm (Greenland interstadials) and cold phases (Greenland stadials). The synchronous response of western European vegetation/climate and eastern North Atlantic SSTs to D-O cycles was not a pervasive feature throughout the Quaternary. During periods of ice growth such as MIS 5a/4, MIS 11c/b and MIS 19c/b, repeated millennial-scale cold-air/warm-sea decoupling events occurred on the European margin superimposed to a long-term air-sea decoupling trend. Strong air-sea thermal contrasts promoted the production of water vapor that was then transported northward by the westerlies and fed ice sheets. This interaction between long-term and shorter time-scale climatic variability may have amplified insolation decreases and thus explain the Ice Ages. This hypothesis should be tested by the integration of stochastic processes in Earth models of intermediate complexity. PMID- 29434618 TI - The Relationship between Insect Resistance and Tree Age of Transgenic Triploid Populus tomentosa Plants. AB - To explore the stability of insect resistance during the development of transgenic insect-resistant trees, this study investigated how insect resistance changes as transgenic trees age. We selected 19 transgenic insect-resistant triploid Populus tomentosa lines as plant material. The presence of exogenous genes and Cry1Ac protein expression were verified using polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) analyses. The toxicity for Clostera anachoreta and Lymantria dispar was evaluated by feeding fresh leaves to first instar larvae after the trees were planted in the field for 2 years and after the sixth year. Results of PCR showed that the exogenous genes had a long term presence in the poplar genome. ELISA analyses showed significant differences existed on the 6-year-old transgenic lines. The insect-feeding experiment demonstrated significant differences in the mortality rates of C. anachoreta and L. dispar among different transgenic lines. The average corrected mortality rates of C. anachoreta and L. dispar ranged from 5.6-98.7% to 35.4-7.2% respectively. The larval mortality rates differed significantly between the lines at different ages. Up to 52.6% of 1-year-old transgenic lines and 42.1% of 2-year-old transgenic lines caused C. anachoreta larval mortality rates to exceed 80%, whereas only 26.3% of the 6-year-old transgenic lines. The mortality rates of L. dispar exhibited the same trend: 89.5% of 1-year-old transgenic lines and 84.2% of 2-year-old transgenic lines caused L. dispar larval mortality rates to exceed 80%; this number decreased to 63.2% for the 6-year-old plants. The proportion of 6-year-old trees with over 80% larval mortality rates was clearly lower than that of the younger trees. The death distribution of C. anachoreta in different developmental stages also showed the larvae that fed on the leaves of 1-year-old trees were killed mostly during L1 and L2 stages, whereas the proportion of larvae that died in L3 and L4 stages was significantly increased when fed on leaves of 6-year-old trees. Results of correlation analysis showed there was a significant correlation between the larvae mortality rates of trees at different ages, as well as between Cry1Ac protein contents and larvae mortality rates of 6 year-old trees. PMID- 29434619 TI - From Bioengineering to CRISPR/Cas9 - A Personal Retrospective of 20 Years of Research in Programmable Genome Targeting. AB - Genome targeting of restriction enzymes and DNA methyltransferases has many important applications including genome and epigenome editing. 15-20 years ago, my group was involved in the development of approaches for programmable genome targeting, aiming to connect enzymes with an oligodeoxynucleotide (ODN), which could form a sequence-specific triple helix at the genomic target site. Importantly, the target site of such enzyme-ODN conjugate could be varied simply by altering the ODN sequence promising great applicative values. However, this approach was facing many problems including the preparation and purification of the enzyme-ODN conjugates, their efficient delivery into cells, slow kinetics of triple helix formation and the requirement of a poly-purine target site sequence. Hence, for several years genome and epigenome editing approaches mainly were based on Zinc fingers and TAL proteins as targeting devices. More recently, CRISPR/Cas systems were discovered, which use a bound RNA for genome targeting that forms an RNA/DNA duplex with one DNA strand of the target site. These systems combine all potential advantages of the once imagined enzyme-ODN conjugates and avoid all main disadvantageous. Consequently, the application of CRISPR/Cas in genome and epigenome editing has exploded in recent years. We can draw two important conclusions from this example of research history. First, evolution still is the better bioengineer than humans and, whenever tested in parallel, natural solutions outcompete engineered ones. Second, CRISPR/Cas system were discovered in pure, curiosity driven, basic research, highlighting that it is basic, bottom-up research paving the way for fundamental innovation. PMID- 29434620 TI - Functional Analyses of a Novel Splice Variant in the CHD7 Gene, Found by Next Generation Sequencing, Confirm Its Pathogenicity in a Spanish Patient and Diagnose Him with CHARGE Syndrome. AB - Mutations in CHD7 have been shown to be a major cause of CHARGE syndrome, which presents many symptoms and features common to other syndromes making its diagnosis difficult. Next generation sequencing (NGS) of a panel of intellectual disability related genes was performed in an adult patient without molecular diagnosis. A splice donor variant in CHD7 (c.5665 + 1G > T) was identified. To study its potential pathogenicity, exons and flanking intronic sequences were amplified from patient DNA and cloned into the pSAD(r) splicing vector. HeLa cells were transfected with this construct and a wild-type minigene and functional analysis were performed. The construct with the c.5665 + 1G > T variant produced an aberrant transcript with an insert of 63 nucleotides of intron 28 creating a premature termination codon (TAG) 25 nucleotides downstream. This would lead to the insertion of 8 new amino acids and therefore a truncated 1896 amino acid protein. As a result of this, the patient was diagnosed with CHARGE syndrome. Functional analyses underline their usefulness for studying the pathogenicity of variants found by NGS and therefore its application to accurately diagnose patients. PMID- 29434621 TI - Extensive Karyotype Reorganization in the Fish Gymnotus arapaima (Gymnotiformes, Gymnotidae) Highlighted by Zoo-FISH Analysis. AB - The genus Gymnotus (Gymnotiformes) contains over 40 species of freshwater electric fishes exhibiting a wide distribution throughout Central and South America, and being particularly prevalent in the Amazon basin. Cytogenetics has been an important tool in the cytotaxonomy and elucidation of evolutionary processes in this genus, including the unraveling the variety of diploid chromosome number (2n = from 34 to 54), the high karyotype diversity among species with a shared diploid number, different sex chromosome systems, and variation in the distribution of several Repetitive DNAs and colocation and association between those sequences. Recently whole chromosome painting (WCP) has been used for tracking the chromosomal evolution of the genus, showing highly reorganized karyotypes and the conserved synteny of the NOR bearing par within the clade G. carapo. In this study, painting probes derived from the chromosomes of G. carapo (GCA, 2n = 42, 30 m/sm + 12 st/a) were hybridized to the mitotic metaphases of G. arapaima (GAR, 2n = 44, 24 m/sm + 20 st/a). Our results uncovered chromosomal rearrangements and a high number of repetitive DNA regions. From the 12 chromosome pairs of G. carapo that can be individually differentiated (GCA1-3, 6, 7, 9, 14, 16, and 18-21), six pairs (GCA 1, 9, 14, 18, 20, 21) show conserved homology with GAR, five pairs (GCA 1, 9, 14, 20, 21) are also shared with cryptic species G. carapo 2n = 40 (34 m/sm + 6 st/a) and only the NOR bearing pair (GCA 20) is shared with G. capanema (GCP 2n = 34, 20 m/sm + 14 st/a). The remaining chromosomes are reorganized in the karyotype of GAR. Despite the close phylogenetic relationships of these species, our chromosome painting studies demonstrate an extensive reorganization of their karyotypes. PMID- 29434622 TI - 2016 Chinese guidelines for the management of dyslipidemia in adults. PMID- 29434623 TI - Chinese expert consensus on the non-invasive imaging examination pathways of stable coronary artery disease. PMID- 29434624 TI - Improvement of increased cQTd is associated with heart function in patients with ischemic heart failure. AB - Background: Chronic heart failure (CHF) is life-threatening without timely or effective intervention. In this study, we investigated the association between QT dispersion corrected for heart rate (cQTd) and heart function in patients with CHF. Methods: From January 2013 to December 2015, we continuously enrolled 240 patients categorized as New York Heart Association functional class (NYHA) III-IV with a left ventricular ejection fraction (LVEF) < 40%. Based on the etiology, the patients were divided into a dilated cardiomyopathy (DCM) group (n = 120) and an ischemic cardiomyopathy (ICM) group (n = 120). Then, based on the cQTd width, the ICM group was divided into two subgroups: a QS group (cQTd <= 60 ms, n = 70) and a QL group (cQTd > 60 ms, n = 50). All patients were examined by echocardiography and 12-lead electrocardiography (ECG) at 1, 3, 6, and 12 months after enrollment. Results: After one year of optimized medical treatment, patients in both groups showed significant improvement in LVEF and NYHA classification from baseline. However, the cQTd in the ICM group, especially the QL, was significantly shorter than that in the DCM group at each time point. In addition, the cQTd was negatively correlated with LVEF and 6-min walking test and positively correlated with NYHA class in the ICM group. Conclusions: The present findings clearly demonstrate that cQTd is a meaningful parameter for assessing heart function in the follow-up of ICM patients. PMID- 29434625 TI - Incidence, pathophysiology, predictive factors and prognostic implications of new onset atrial fibrillation following transcatheter aortic valve implantation. PMID- 29434626 TI - TAVR in 2017-What we know? What to expect? PMID- 29434627 TI - Endocarditis after transcatheter aortic valve implantation: a current assessment. PMID- 29434628 TI - Antithrombotic therapy in TAVI. AB - Transcatheter aortic valve implantation (TAVI) carries a significant thromboembolic and concomitant bleeding risk, not only during the procedure but also during the periprocedural period. Many issues concerning optimal antithrombotic therapy after TAVI are still under debate. In the present review, we aimed to identify all relevant studies evaluating antithrombotic therapeutic strategies in relation to clinical outcomes after the procedure. Four randomized control trials (RCT) were identified analyzing the post-TAVI antithrombotic strategy with all of them utilizing aspirin lifelong plus clopidogrel for 3-6 months. Seventeen registries have been identified, with a wide variance among them regarding baseline characteristics, while concerning antiplatelet therapy, clopidogrel duration was ranging from 3-12 months. Four non-randomized trials were identified, comparing single vs. dual antiplatelet therapy after TAVI, in respect of investigating thromboembolic outcome events over bleeding complications. Finally, limited data from a single RCT and a retrospective study exist with regards to anticoagulant treatment during the procedure and the optimal antithrombotic therapy when concomitant atrial fibrillation. In conclusion, due to the high risk and frailty of the treated population, antithrombotic therapy after TAVI should be carefully evaluated. Diminishing ischaemic and bleeding complications remains the main challenge in these patients with further studies to be needed in this field. PMID- 29434629 TI - Transcatheter versus surgical aortic valve replacement in severe, symptomatic aortic stenosis. AB - Aortic stenosis (AS) is the most common type of valvular heart disease in the elderly. Surgical aortic valve replacement (SAVR) has been the standard practice for treating severe, symptomatic AS, but recently new treatment options have emerged. Transcatheter aortic valve replacement (TAVR) is now an established treatment option in patients at high surgical risk. In this review, we focus on recent developments and compare the two treatment methods in specific populations in terms of efficacy and safety (e.g., in patients with history of prior thoracic surgery, type of anesthesia employed, access site used or need for permanent pacing). The impact of comorbidities (pulmonary hypertension, arterial hypertension and obesity paradox), the cost-effectiveness of TAVR vs. SAVR and advances in transcatheter valve technology as well as issues that merit further investigation are further discussed. Moreover, outcomes and complications of TAVR in patients of different risk category (extremely high, high, intermediate and low risk) are analyzed. We strongly believe that during the following years, TAVR may evolve as the treatment of choice in a broader group of patients with symptomatic AS and beyond those with intermediate and high-risk features. PMID- 29434630 TI - The role of echocardiography and CT angiography in transcatheter aortic valve implantation patients. AB - The transcatheter aortic valve implantation (TAVI) consist an alternative treatment in patients with severe aortic stenosis. Multimodality imaging using transthoracic echocardiography (TTE) or transesophageal echocardiography (TOE) and multislice CT (MSCT) constitute cornerstone techniques for the pre-operative management, peri-procedural guidance, follow up and recognition of possible transcatheter valve related complications. CT angiography is much more accurate regarding the total definition of aortic annulus diameter and circumferential area. Two-dimensional (2D) echocardiography, underestimates the aortic valve annulus diameter compared to 3D imaging techniques (MSCT, MRI and 3D TOE). Three dimensional TOE imaging provides measurements of the aortic valve annulus similar to those delivered by MSCT. The pre-procedural MSCT constitutes the gold standard modality minimizing the presence of paravalvular aortic regurgitation, one of the most frequent complications. TOE/TTE and MSCT performance could predict the possibility of pacemaker implantation post-procedural. The presence of a new transient or persisting MR can be assessed well by TOE. Both TTE and TOE, consist initially the basic examination for post TAVI evaluation. In case of transcatheter heart valve failure, the MSCT could be used as additional imaging technique. PMID- 29434631 TI - Transcatheter aortic valve replacement and stroke: a comprehensive review. AB - Transcatheter aortic valve implantation (TAVR) has emerged as an alternative, rapidly evolving treatment option for patients with severe aortic stenosis and high surgical risk. Stroke is a devastating complication being confined mainly in the periprocedural and 30-day period following TAVR, with a lower and relatively constant frequency thereafter. Early stroke is mainly due to debris embolization during the procedure, whereas later events are associated with patient specific factors. Despite the fact that the rate of clinical stroke has been constantly decreasing compared to initial TAVR experience, modern neuro-imaging with MRI suggests that new ischemic lesions post-TAVR are almost universal. The impact of the latter is largely unknown. However, they seem to correlate with a reduction in neurocognitive function. Because TAVR is set to expand its indication to lower surgical-risk patients, stroke prophylaxis during and after TAVR becomes of paramount importance. Based on clinical and pathophysiological evidence, three lines of research are actively employed towards this direction: improvement in valve and delivery system technology with an aim to reduce manipulations and contact with the calcified aortic arch and native valve, antithrombotic therapy, and embolic protection devices. Careful patient selection, design of the procedure, and tailored antithrombotic strategies respecting the bleeding risks of this fragile population constitute the main defense against stroke following TAVR. PMID- 29434632 TI - Conduction abnormalities after transcatheter aortic valve implantation. AB - In the last few years, transcatheter aortic valve implantation (TAVI) has become an alternative procedure in patients with severe aortic stenosis and high risk for surgical aortic replacement. Due to the anatomic correlation between aortic valve structure and conduction system of the heart, one of the most common complications after TAVI is conduction system disturbances which including bundle branch block, complete heart block and need for permanent pacemaker implantation. Although these disturbances are usually not lethal, they may have a great influence on patients' state and long term-survival. Several risk factors for conduction disturbances have been identified which including age, anatomy of the heart, periprocedural factors, type of implanted valve, preexisting abnormalities and comorbidities. As this technique becomes more familiar to physicians, patients should be carefully screened for risk factors for the development of conduction abnormalities after TAVI in order to provide effective prevention and proper treatment. PMID- 29434633 TI - Restrictive perimembranous ventricular septal defect with left to right Shunt post urgent aortic balloon valvuloplasty and transcatheter aortic valve replacement. PMID- 29434634 TI - Introducing the CONSORT extension to pilot trials: enhancing the design, conduct and reporting of pilot or feasibility trials. PMID- 29434635 TI - Selection of the Optimal Algorithm for Real-Time Estimation of Beta Band Power during DBS Surgeries in Patients with Parkinson's Disease. AB - Deep Brain Stimulation (DBS) is a surgical procedure for the treatment of motor disorders in patients with Parkinson's Disease (PD). DBS involves the application of controlled electrical stimuli to a given brain structure. The implantation of the electrodes for DBS is performed by a minimally invasive stereotactic surgery where neuroimaging and microelectrode recordings (MER) are used to locate the target brain structure. The Subthalamic Nucleus (STN) is often chosen for the implantation of stimulation electrodes in DBS therapy. During the surgery, an intraoperative validation is performed to locate the dorsolateral region of STN. Patients with PD reveal a high power in the beta band (frequencies between 13 Hz and 35 Hz) in MER signal, mainly in the dorsolateral region of STN. In this work, different power spectrum density methods were analyzed with the aim of selecting one that minimizes the calculation time to be used in real time during DBS surgery. In particular, the results of three nonparametric and one parametric methods were compared, each with different sets of parameters. It was concluded that the optimum method to perform the real-time spectral estimation of beta band from MER signal is Welch with Hamming windows of 1.5 seconds and 50% overlap. PMID- 29434636 TI - Discriminant WSRC for Large-Scale Plant Species Recognition. AB - In sparse representation based classification (SRC) and weighted SRC (WSRC), it is time-consuming to solve the global sparse representation problem. A discriminant WSRC (DWSRC) is proposed for large-scale plant species recognition, including two stages. Firstly, several subdictionaries are constructed by dividing the dataset into several similar classes, and a subdictionary is chosen by the maximum similarity between the test sample and the typical sample of each similar class. Secondly, the weighted sparse representation of the test image is calculated with respect to the chosen subdictionary, and then the leaf category is assigned through the minimum reconstruction error. Different from the traditional SRC and its improved approaches, we sparsely represent the test sample on a subdictionary whose base elements are the training samples of the selected similar class, instead of using the generic overcomplete dictionary on the entire training samples. Thus, the complexity to solving the sparse representation problem is reduced. Moreover, DWSRC is adapted to newly added leaf species without rebuilding the dictionary. Experimental results on the ICL plant leaf database show that the method has low computational complexity and high recognition rate and can be clearly interpreted. PMID- 29434637 TI - Multimodality Treatment Including Triplet Regimen as First-Line Chemotherapy May Improve Prognosis of Serum AFP-Elevated Gastric Cancer with Liver Metastasis. AB - Serum alpha-fetoprotein- (AFP-) elevated gastric cancer is a rare tumor that has a poor prognosis due to high incidence of liver metastasis. This study sought to investigate the optimal treatment modality. A total of 319 gastric cancer patients with liver metastasis (GCLM) whose serum AFP levels were tested before treatment were enrolled in this study. They were classified as the serum AFP >= 20 ng/ml group (n = 74) and the AFP < 20 ng/ml group (n = 245). Median OS of the AFP < 20 ng/ml group was significantly longer than that of the AFP >= 20 ng/ml group (15.7 m versus 10.9 m, P = 0.004). ORR of first-line chemotherapy was 43.3% and 56.1% of the two groups, respectively (P = 0.024). Of patients who received doublet regimen, ORR of the AFP >= 20 ng/ml group was significantly lower (38.2 versus 56.9%, P = 0.013), while in those received triplet regimens, ORR between two groups was similar (66.7% versus 66.7%, P = 0.676). Moreover, for patients of the AFP >= 20 ng/ml group, those who reached PR had a longer survival period (15.4 m versus 9.4 m, P = 0.017), and combined with local treatment for liver metastasis also seemed to improve prognosis (19.2 m versus 8.4 m, P = 0.003). In conclusion, serum AFP-elevated GCLM had a poorer prognosis. Multimodality treatment including aggressive first-line chemotherapy with triplet regimen may be needed when treating them. PMID- 29434638 TI - Evaluation of Early Prognostic Factors of Mortality in Patients with Acute Pancreatitis: A Retrospective Study. AB - Early and accurate assessment of severity in acute pancreatitis (AP) is of great importance to provide effective disease management and prevent mortality. In this study, we aim to evaluate early indicators that predict the mortality of AP. We retrospectively analyzed 24-hour clinical characteristics and laboratory data in 166 AP patients recruited between January 2014 and November 2015 in Baotou Central Hospital. In total, 18 patients did not survive the disease. Multivariate logistic regression showed that red cell distribution (RDW) (OR = 2.965, P = 0.001) and creatinine (OR = 1.025, P = 0.005) were early independent risk factors of AP mortality while albumin (OR = 0.920, P = 0.032) levels reduced AP mortality. The corresponding optimal cut-off values were 14.45, 125.5, and 34.95, respectively. The positive predictive values of the AP mortality were 80.1%, 54.5%, and 69.5%. In combined measurement, the area under the curve of RDW, creatinine, and albumin was 0.964 (95% CI: 0.924 to 1.000, P < 0.001). RDW >= 14.45%, creatinine >= 125.5 MUmol/l, and albumin <= 34.95 g/l indicated a good predictive value for mortality in AP patients with a sensitivity of 100% and specificity of 64.2%. RDW, creatinine, and albumin may serve as early indicators for AP mortality which warrants further clinical investigation. PMID- 29434639 TI - Diseases Linked to Polypharmacy in Elderly Patients. AB - Introduction: Polypharmacy in several cases is deemed necessary and elderly patients are prone to this phenomenon. The objective of this study was to identify the prevalence and the predictors of polypharmacy among consecutively unplanned admissions of patients aged >=65 years. Patients and Methods: In 310 patients (51% women), mean age 80.24 years (95% CI 79.35-81.10), demographic characteristics, medical history, medications, and cause of admission were recorded. Parametric tests and multiple logistic regression analysis were applied to identify the factors that have significant association with polypharmacy. Results: 53.5% of patients belonged to polypharmacy group. In multivariate analysis the independent predictors of polypharmacy were arterial hypertension (p = 0.003, OR = 2.708, and 95% CI 1.400-5.238), coronary artery disease (p = 0.001, OR = 8.274, and 95% CI 3.161-21.656), heart failure (p = 0.030, OR = 4.042, and 95% CI 1.145-14.270), atrial fibrillation (p = 0.031, OR = 2.477, and 95% CI 1.086-5.648), diabetes mellitus (p = 0.010, OR = 2.390, and 95% CI 1.232-4.636), dementia (p = 0.001, OR = 4.637, and 95% CI 1.876-11.464), and COPD (p = 0.022, OR = 3.626, and 95% CI 1.208-10.891). Conclusions: Polypharmacy mainly was linked to cardiovascular diseases. If deprescribing is not feasible, physicians must oversee those patients in order to recognise early, possible drug reactions. PMID- 29434640 TI - Natural Composite Reinforced by Lontar (Borassus flabellifer) Fiber: An Experimental Study on Open-Hole Tensile Strength. AB - A research has been conducted in the present study to investigate the effect of hole configuration on tensile strength of lontar fiber-reinforced composites. The lontar fiber-reinforced composites used in this study were produced by hand lay up process. The lontar fiber-reinforced composites consist of short random fiber of 5 cm that contains 32% of nominal fiber volume as the reinforcement and unsaturated polyester as the matrix. The results show that the differences of hole configuration have an effect on tensile strength of lontar fiber-reinforced composites. It is found that the specific area of four-hole specimens experiences smaller strain propagation due to the redistributed stress and no stress passes through the hole. The damage of lontar fiber-reinforced composites with different hole configurations in tension is fairly straight and transverse to the loading axis, where the initial damage occurs in the form of matrix cracking, propagates into interfacial failure in form of delamination, and ultimately failed mainly due to the fiber breakage. PMID- 29434641 TI - Therapeutic Benefit for Late, but Not Early, Passage Mesenchymal Stem Cells on Pain Behaviour in an Animal Model of Osteoarthritis. AB - Background: Mesenchymal stem cells (MSCs) have a therapeutic potential for the treatment of osteoarthritic (OA) joint pathology and pain. The aims of this study were to determine the influence of a passage number on the effects of MSCs on pain behaviour and cartilage and bone features in a rodent model of OA. Methods: Rats underwent either medial meniscal transection (MNX) or sham surgery under anaesthesia. Rats received intra-articular injection of either 1.5 * 106 late passage MSCs labelled with 10 MUg/ml SiMAG, 1.5 * 106 late passage mesenchymal stem cells, the steroid Kenalog (200 MUg/20 MUL), 1.5 * 106 early passage MSCs, or serum-free media (SFM). Sham-operated rats received intra-articular injection of SFM. Pain behaviour was quantified until day 42 postmodel induction. Magnetic resonance imaging (MRI) was used to localise the labelled cells within the knee joint. Results: Late passage MSCs and Kenalog attenuated established pain behaviour in MNX rats, but did not alter MNX-induced joint pathology at the end of the study period. Early passage MSCs exacerbated MNX-induced pain behaviour for up to one week postinjection and did not alter joint pathology. Conclusion: Our data demonstrate for the first time the role of a passage number in influencing the therapeutic effects of MSCs in a model of OA pain. PMID- 29434643 TI - Assessment of Child Immunization Coverage and Associated Factors with Full Vaccination among Children Aged 12-23 Months at Mizan Aman Town, Bench Maji Zone, Southwest Ethiopia. AB - Immunization remains one of the most important and cost-effective public health interventions to reduce child mortality and morbidity. Globally, it is estimated to avert between 2 and 3 million deaths each year. In Ethiopia, immunization coverage rates stagnated and remained very low for many years. Thus, this study was aimed to assess child immunization coverage and factors associated with full vaccination among children aged 12-23 months in Mizan Aman town. The study design was community-based cross-sectional survey. Data was collected by using pretested structured questionnaire. A total of 322 mothers/caretakers were interviewed. Based on vaccination card and mothers/caretakers' recall, 295 (91.6%) of the children took at least a single dose of vaccine. From total children, 27 (8.4%) were not immunized at all, 159 (49.4%) were partially immunized, and 136 (42.2%) were fully immunized. Mothers/caretakers educational level, fathers' educational level, place of delivery, maternal health care utilization, and mothers/caretakers knowledge about vaccine and vaccine-preventable disease showed significant association with full child immunization. The finding from this study revealed that child immunization coverage in the studied area was low. Thus the town health office and concerned stakeholders need to work more to improve performance of the expanded program on immunization in this area. PMID- 29434642 TI - The Impact of CRISPR/Cas9 Technology on Cardiac Research: From Disease Modelling to Therapeutic Approaches. AB - Genome-editing technology has emerged as a powerful method that enables the generation of genetically modified cells and organisms necessary to elucidate gene function and mechanisms of human diseases. The clustered regularly interspaced short palindromic repeats- (CRISPR-) associated 9 (Cas9) system has rapidly become one of the most popular approaches for genome editing in basic biomedical research over recent years because of its simplicity and adaptability. CRISPR/Cas9 genome editing has been used to correct DNA mutations ranging from a single base pair to large deletions in both in vitro and in vivo model systems. CRISPR/Cas9 has been used to increase the understanding of many aspects of cardiovascular disorders, including lipid metabolism, electrophysiology and genetic inheritance. The CRISPR/Cas9 technology has been proven to be effective in creating gene knockout (KO) or knockin in human cells and is particularly useful for editing induced pluripotent stem cells (iPSCs). Despite these progresses, some biological, technical, and ethical issues are limiting the therapeutic potential of genome editing in cardiovascular diseases. This review will focus on various applications of CRISPR/Cas9 genome editing in the cardiovascular field, for both disease research and the prospect of in vivo genome-editing therapies in the future. PMID- 29434644 TI - Self-reported questionnaire survey on the prevalence and symptoms of adverse food reactions in patients with chronic inhalant diseases in Tangshan city, China. AB - Background: The prevalence of adverse food reactions in patients with chronic inhalant diseases has seldom been studied in China. This study is to investigate the prevalence of adverse food reactions and the symptoms caused in respiratory patients. Methods: Respiratory patients in allergy clinics were asked to complete a questionnaire. Patients' information such as age, gender, family history of allergy, and adverse reactions to a list of 48 foods and the symptoms caused, was recorded. Multivariate analyses were performed to determine the prevalence of adverse food reactions and their associated symptoms. Results: 459 subjects, with an average age of 32 years old, completed the questionnaire; 45.3% were male. Among the 459 subjects, 38.1% (175/459) had an adverse reaction to food: 13.6% had an adverse food reaction to crab, 12.4% had an adverse food reaction to shrimp; and 9.9% had an adverse reaction to shellfish. Peach and nectarine were also shown to be common causative foods with 6.8% of the study group showing an adverse reaction to peach and 5.2% to nectarine. Seafood mainly caused skin symptoms and fruits gave rise to more throat, oral, and gastrointestinal problems. Conclusion: The prevalence of adverse food reactions is high for patients with respiratory diseases. This indicates that adverse food reactions should be considered in the treatment and management of patients with chronic inhalant diseases. PMID- 29434645 TI - Atopy and related clinical symptoms among Swiss medical students from 2007 to 2015. AB - Background: Atopic allergy is a widespread disease with increasing prevalence in the second half of the twentieth century and is most often associated with clinical symptoms, like rhinoconjunctivitis, asthma or eczema. This study explored the prevalence of atopy and polysensitization in nine cohorts of Swiss medical students during the period of 2007-2015. Furthermore, the self-reported allergic symptoms, such as rhinoconjunctivitis, asthma and eczema, among students with and without atopy were assessed. Methods: Each cohort was assessed in the third study year. Students underwent an ImmunoCAP rapid test, a qualitative point of-care test, and completed an anonymous questionnaire on age, gender and clinical symptoms including rhinoconjunctivitis, asthma and eczema. Statistical analyses assessed the overall prevalence of atopy in each group and estimated the average annual increase using a linear mixed model. We examined the frequency of occurrence of polysensitization and differences of reported symptoms among students with and without atopy. Results: Data of 1513 students (mean age 22.4 23.3 years across cohorts) in nine cohorts (median cohort size 215 interquartile range IQR 193-222) were available for analysis. Test results consistent with atopy were present in 39.9% of students. Average increase of atopy over the 9 years of observation was 2.25% (95% CI 0.18-4.31%; p = 0.037). Main drivers for this increase were the ubiquitously available allergens, house dust mite, timothy grass and birch pollen. Atopy and polysensitization were more pronounced in male students: Polysensitization also increased in the observation period. The clinical symptoms, rhinoconjunctivitis, asthma and eczema were reported by 463 (76.7%) atopic and by 141 (15.5%) non-atopic students. Conclusions: We observed a slight increase of atopy and polysensitization within 9 years of observation in Swiss medical students. The most frequent sensitization occurred with allergens with the highest chance of exposure. Rhinoconjunctivitis, asthma and eczema are a symptom complex associated with atopy but also found in non-atopic students.Trial registration retrospectively registered by the Cantonal Ethics Committee Zurich on 22.01.2016; Nr: 08-2016. PMID- 29434646 TI - Structural Modulation of Gut Microbiota during Alleviation of Suckling Piglets Diarrhoea with Herbal Formula. AB - To determine whether the traditional Chinese herbal formula of Shen Ling Baizhu (SLB) could modulate the composition of the gut microbiota and alleviate diarrhoea in suckling piglets, twenty-four newly born piglets (Large White * Landrace * Duroc) were selected and allocated to 4 groups (control group and experimental groups I, II, and III) randomly. Faecal microbiome composition was assessed by 16S rRNA gene 454-pyrosequencing. The result indicated that experimental groups I and II exhibited significantly different gut microbiota from the control group. Most notably, the genera Lactobacillus and Bifidobacterium were significantly elevated in experimental group II compared with the control group (P < 0.05). Collinsella and Faecalibacterium were also enhanced in experimental group II compared with the control group (P < 0.05). The results showed that SLB treatment could modulate the gut microbiota composition of suckling piglets, enriching the amount of beneficial bacteria in particular. The observed changes in the gut microbiota could provide the basis for further research on the pharmacological mechanism of the tested Chinese herbal formula. PMID- 29434647 TI - The complex simplicity of the brittle star nervous system. AB - Background: Brittle stars (Ophiuroidea, Echinodermata) have been increasingly used in studies of animal behavior, locomotion, regeneration, physiology, and bioluminescence. The success of these studies directly depends on good working knowledge of the ophiuroid nervous system. Results: Here, we describe the arm nervous system at different levels of organization, including the microanatomy of the radial nerve cord and peripheral nerves, ultrastructure of the neural tissue, and localization of different cell types using specific antibody markers. We standardize the nomenclature of nerves and ganglia, and provide an anatomically accurate digital 3D model of the arm nervous system as a reference for future studies. Our results helped identify several general features characteristic to the adult echinoderm nervous system, including the extensive anatomical interconnections between the ectoneural and hyponeural components, neuroepithelial organization of the central nervous system, and the supporting scaffold of the neuroepithelium formed by radial glial cells. In addition, we provide further support to the notion that the echinoderm radial glia is a complex and diverse cell population. We also tested the suitability of a range of specific cell-type markers for studies of the brittle star nervous system and established that the radial glial cells are reliably labeled with the ERG1 antibodies, whereas the best neuronal markers are acetylated tubulin, ELAV, and synaptotagmin B. The transcription factor Brn1/2/4 - a marker of neuronal progenitors - is expressed not only in neurons, but also in a subpopulation of radial glia. For the first time, we describe putative ophiuroid proprioceptors associated with the hyponeural part of the central nervous system. Conclusions: Together, our data help establish both the general principles of neural architecture common to the phylum Echinodermata and the specific ophiuroid features. PMID- 29434648 TI - Hsp90beta knockdown in DIO mice reverses insulin resistance and improves glucose tolerance. AB - Background: Inhibition of Hsp90 has been shown to improve glucose tolerance and insulin sensitivity in mouse models of diabetes. In the present report, the specific isoform Hsp90ab1, was identified as playing a major role in regulating insulin signaling and glucose metabolism. Methods: In a diet-induced obese (DIO) mouse model of diabetes, expression of various Hsp90 isoforms in skeletal tissue was examined. Subsequent experiments characterized the role of Hsp90ab1 isoform in glucose metabolism and insulin signaling in primary human skeletal muscle myoblasts (HSMM) and a DIO mouse model. Results: In DIO mice Hsp90ab1 mRNA was upregulated in skeletal muscle compared to lean mice and knockdown using anti sense oligonucleotide (ASO) resulted in reduced expression in skeletal muscle that was associated with improved glucose tolerance, reduced fed glucose and fed insulin levels compared to DIO mice that were treated with a negative control oligonucleotide. In addition, knockdown of HSP90ab1 in DIO mice was associated with reduced pyruvate dehydrogenase kinase-4 mRNA and phosphorylation of the muscle pyruvate dehydrogenase complex (at serine 232, 293 and 300), but increased phosphofructokinase 1, glycogen synthase 1 and long-chain specific acyl-CoA dehydrogenase mRNA. In HSMM, siRNA knockdown of Hsp90ab1 induced an increase in substrate metabolism, mitochondrial respiration capacity, and insulin sensitivity, providing further evidence for the role of Hsp90ab1 in metabolism. Conclusions: The data support a novel role for Hsp90ab1 in arbitrating skeletal muscle plasticity via modulation of substrate utilization including glucose and fatty acids in normal and disease conditions. Hsp90ab1 represents a novel target for potential treatment of metabolic disease including diabetes. PMID- 29434649 TI - Occupational exposure to ultrafine particles in police officers: no evidence for adverse respiratory effects. AB - Background: Inhalation exposure to fine and ultrafine particles (UFPs) has been associated with respiratory diseases. However, little is known on the quality, threshold levels and concentration of these particles causing adverse health effects. Methods: The impact of occupational exposure to submicrometer and UFPs was assessed in 30 healthy police shooting instructors by clinical investigation, self-assessment questionnaire, sputum and spirometry and compared to a control group. General laboratory chemistry parameters, circulating cytokines (interleukin [IL]-2, IL-4, IL-5, IL-6, IL-8, interferon-gamma [IFN-gamma]), and granulocyte macrophage colony-stimulating factor (GM-CSF) in serum were measured. UFP exposure was recorded by Scanning Mobility Particle Sizer. Results: Concentrations of submicrometer sized airborne particles (< 700 nm) measured between 3.34 * 105/cm3 and 7.58 * 105/cm3 at shooting sites, with highest concentrations found in the UFP range (< 100 nm). The size of the monodispersed particles ranged from 54.74 +/- 16.25 nm to 98.19 +/- 22.83 nm. Short term exposure (4 h) to high levels of UFPs caused an increase of IFN-gamma in exposed subjects (p = 0.022). 24 h after exposure a significant decrease of IgG, albumin fibrinogen and factor VII was found. Neither directly after 4 h of high levels UFPs exposure nor 24 h after exposure subjective complaints or objective measurements indicating adverse respiratory effects in exposed subjects were found. Conclusions: No consistent indications for adverse respiratory or inflammatory effects directly following exposure and 24 h after exposure to high levels of UFPs in our study group were detected. However we showed the assessment of short-term exposure effects at a genuine occupational setting, which might is relevant when a risk assessment of high level occupational exposures to UFPs is considered. PMID- 29434650 TI - Breastfeeding technique and associated factors among breastfeeding mothers in Harar city, Eastern Ethiopia. AB - Background: Ineffective breastfeeding technique is one of the factors contributing to mothers practicing non-exclusive breastfeeding. Inappropriate breastfeeding technique is the leading cause of nipple pain in Ethiopia, as in other countries. However, no studies have examined breastfeeding technique and associated factors in eastern Ethiopia. Therefore, this study was conducted with the aim of assessing breastfeeding technique and associated factors among breastfeeding mothers. Method: We conducted an institution based cross-sectional study in selected governmental health facilities of Harar city, Eastern, Ethiopia, from January to February 2017. Systematic random sampling technique was used to select 422 study participants. Data were collected using pretested observational checklist and interviewer administered questionnaires containing sociodemographic, maternal and infant characteristics. The variables, positioning, attachment and suckling, were used to assess the outcome variable of breastfeeding technique. Descriptive, bivariate and multivariate logistic regression analysis was done to identify independent predictors of BFT after controlling for confounding variables. Result: The proportion of mothers practicing an effective breastfeeding technique was 43.4% (179/412). Effective breastfeeding technique was 2.3 times more common among mothers with at least secondary school educational status compared to mothers with no formal education (Adjusted Odds Ratio [AOR] 2.3; 95% Confidence Interval [CI] 1.1, 3.9). The practice of effective breastfeeding technique was significantly associated with mothers who had immediate breastfeeding technique counseling after birth (AOR 1.7, 95% CI 1.1, 2.8) and at least two postnatal visits (AOR 5.9; 95% CI 2.1, 15.9) compared to one visit. Absence of breast problems and having previous breastfeeding experience were also associated with the likelihood of effective breastfeeding technique practice (AOR 4.0; 95% CI 1.4, 10.9) and (AOR 3.3; 95% CI 1.1, 10.7) respectively. Conclusion: The practice of effective breastfeeding technique was low. Effective breastfeeding technique practice was associated with higher educational status, previous information about breastfeeding technique, previous breastfeeding experience, absence of breast problems, receiving breastfeeding technique counseling immediately after birth and at least two postnatal visits. Therefore; health services should provide education about effective breastfeeding techniques and ensure postnatal care for all women, particularly primipara. PMID- 29434651 TI - Combining laser-assisted microdissection (LAM) and RNA-seq allows to perform a comprehensive transcriptomic analysis of epidermal cells of Arabidopsis embryo. AB - Background: Genome-wide characterization of tissue- or cell-specific gene expression is a recurrent bottleneck in biology. We have developed a sensitive approach based on ultra-low RNA sequencing coupled to laser assisted microdissection for analyzing different tissues of the small Arabidopsis embryo. Methods and results: We first characterized the number of genes detected according to the quantity of tissue yield and total RNA extracted. Our results revealed that as low as 0.02 mm2 of tissue and 50 pg of total RNA can be used without compromising the number of genes detected. The optimised protocol was used to compare the epidermal versus mesophyll cell transcriptomes of cotyledons at the torpedo-shaped stage of embryo development. The approach was validated by the recovery of well-known epidermal genes such AtML1 or AtPDF2 and genes involved in flavonoid and cuticular waxes pathways. Moreover, the interest and sensitivity of this approach were highlighted by the characterization of several transcription factors preferentially expressed in epidermal cells. Conclusion: This technical advance unlocks some current limitations of transcriptomic analyses and allows to investigate further and efficiently new biological questions for which only a very small amounts of cells need to be isolated. For instance, it paves the way to increasing the spatial accuracy of regulatory networks in developing small embryo of Arabidopsis or other plant tissues. PMID- 29434653 TI - Shuganyin decoction improves the intestinal barrier function in a rat model of irritable bowel syndrome induced by water-avoidance stress. AB - Background: To determine the effect of Shuganyin decoction (SGD) on the intestinal barrier function in an irritable bowel syndrome (IBS) rat model induced by water-avoidance stress. Methods: Forty male Wistar rats were divided into control, water-avoidance stress (WAS) group, WAS plus Shuganyin decoction (SGD) group and WAS plus dicetel (Dicetel) group. IBS was induced in rats by subjecting them to water-avoidance stress for 7 days. On day 4 of the WAS protocol, the rats were treated for 7 consecutive days (days 4-11) with SGD, dicetel or a negative control (saline). The number of feces granules, histopathological changes of the intestine and mast cell (MC) morphometry were determined. Intestinal permeability was approximated by measuring the absorption of FITC-dextran 4400 (FD-4) from the lumen into the bloodstream in vivo and in vitro experiments. Also, the expression of protease active receptor-2 (PAR-2) and tumor necrosis factor-alpha (TNF-alpha) was estimated using immunohistochemical staining and ELISA, respectively. Tight junction (TJ) protein abundance was measured following a quantitative immunofluorescent analysis of intestinal sections and western blotting. Results: In vivo, WAS elicited a significantly increase in the transfer of FD-4 from the intestine to blood about threefold in 30 min compared with control group. After treated with SGD, the intestinal permeability to FD-4 of WAS-induced rats was significantly attenuated (P < 0.05). In vitro, the permeability coefficient (Papp) values were measured for FD-4 absorption across the excised intestine. WAS was shown to increase the intestinal permeability to (4.695 +/- 0.3629) * 10-7 cm/s in 120 min, which was 2.6-fold higher than the control group. Rats treated with SGD showed a significant decrease in Papp values of FD-4 as compared to WAS group (P < 0.05). Furthermore, by immunofluorescent detection we found that WAS elicited the irregular distribution of TJ proteins. Using the quantitative analysis software of the medical image, the average optical density and protein abundance of TJ proteins was shown to be lower in the WAS group as compared to control group, (P < 0.05). SGD could attenuate this response and improve TJ distribution (P < 0.05). Western blot analysis confirmed that TJ protein abundance was significantly decreased in WAS group and that they could be returned to control levels following an SGD treatment. WAS also induced an increase in number of MCs, their area and diameter as compared to controls. These observations were attenuated with an SGD or dicetel treatment. Similarly, the expression of PAR-2 and TNF-alpha exceeded control values in the WAS group and were shown to be successfully attenuated with an SGD treatment. Conclusion: WAS-induced IBS rat model exhibited intestinal barrier dysfunction, which was manifested as tight junction damage and structural rearrangements that increased the intestinal permeability. Under these conditions, MCs were activated and degranulated in the intestinal mucosa leading to the activation of PAR-2. Our data showed that SGD could inhibit the activation of MCs and down-regulate the expression of both PAR-2 and TNF-alpha. In turn, this was shown to improve the expression and structural arrangement of TJ proteins in the intestinal mucosa, thereby regulating the intestinal permeability. It was concluded that Shuganyin could protect the intestinal barrier. PMID- 29434654 TI - Quasispecies variant of pre-S/S gene in HBV-related hepatocellular carcinoma with HBs antigen positive and occult infection. AB - Background: Hepatocellular carcinoma (HCC) can develop in patients who are negative for the hepatitis B surface antigen (HBsAg) in serum but positive for hepatitis B virus (HBV) DNA in the liver, referred to as occult HBV infection (OBI). Previous reports showed that HBV variants in OBI-related HCC are different from those in HBsAg-positive HCC. In the present study, HBV quasispecies based on the pre-S/S gene in OBI-related HCC patients were examined by high throughput sequencing and compared with those in HBsAg-positive HCC. Methods: Nineteen tissue samples (9 OBI-related and 10 HBsAg-positive non-cancerous tissues) were collected at the time of surgery at Kobe University Hospital. The quasispecies with more than 1% variation in the pre-S/S region were isolated and analysed by ultra-deep sequencing. Results: There were no significant differences in the major HBV populations, which exhibit more than 20% variation within the entire pre-S/S region, between OBI-related HCC and HBsAg-positive HCC. However, the prevalences of major populations with pre-S2 region mutations and of minor populations with polymerized human serum albumin-binding domain mutations were significantly higher in OBI-related HCC than in HBsAg-positive HCC. Moreover, the major variant populations associated with the B-cell epitope, located within the pre-S1 region, and the a determinant domain, located in the S region, were detected frequently in HBsAg-positive HCC. The minor populations of variants harbouring the W4R, L30S, Q118R/Stop, N123D and S124F/P mutations in the pre-S region and the L21F/S and L42F/S mutations in the S region were detected more frequently in OBI-related HCC than in HBsAg-positive HCC. Conclusions: Ultra-deep sequencing revealed that the B-cell epitope domain in the pre-S1 region and alpha determinant domain in the S region were variable in HBsAg-positive HCC, although the quasispecies associated with the pre-S2 region were highly prevalent in OBI related HCC. Trial registration: Ref: R000034382/UMIN000030113; Retrospectively registered 25 November 2017. PMID- 29434655 TI - History, aims and present structure of psychosomatic medicine in Germany. AB - Combining its two traditions of integrated psychosomatics in internal medicine and focusing on psychotherapeutic/psychiatric methods in many clinical fields, German psychosomatic medicine has developed well over the last decades. It benefits from its institutional independence and the progressive changes in health care. Clinically, disorder-oriented psychotherapy is a core method integrated with other modes of therapy. As a conceptual base for empirical research, non-reductionist accounts of the interactions of (sick) persons with their environment are most important. Germany has developed a model of Psychosomatic Medicine that has conceptualized and integrated psychotherapeutic methods into clinical practice and realized one way to practice bio-psycho-social medicine in the health care system of the country. PMID- 29434656 TI - Difficulties faced by university students with self-reported symptoms of attention-deficit hyperactivity disorder: a qualitative study. AB - Background: Attention-deficit hyperactivity disorder (ADHD) persists into adolescence and adulthood; however, few studies have analyzed the experiences of university students with ADHD. This study explored the difficulties experienced by university students with ADHD symptoms. Methods: Between December 2015 and February 2016, face-to-face interviews were conducted with 12 university students with self-reported ADHD symptoms. Data were analyzed using thematic analysis. Results: Difficulties in university life were classified into four main themes (lack of daily routine, unsatisfactory academic performance and achievement, reduced interpersonal skills, and continuing worries) and analyzed. University students with ADHD symptoms had difficulties coping with repeated cycles of negative thoughts and worries, irregular lifestyles due to poor time management, dissatisfaction with academic performance and interpersonal relationships, self dissatisfaction, and decreased self-esteem. Conclusion: To improve their university experience, students with ADHD should receive education about ways to stop worrying, to express emotions healthily, and to manage time efficiently. PMID- 29434657 TI - Mental health status, and suicidal thoughts and behaviors of migrant children in eastern coastal China in comparison to urban children: a cross-sectional survey. AB - Purpose: Although adolescents' mental health problems and self-injurious thoughts and behaviors (SITBs) have been a serious public health concern worldwide, descriptions of risk factors for SITBs often fail to take migration into account. There are roughly 35.8 million migrant children in China who, with their parents, moved from original rural residence to urban areas. Little is known about migrant children's mental health status and levels of SITBs. This study aims to explore the mental health status and SITBs of migrant children living in eastern coastal China in comparison to their urban counterparts. Methods: This study was a cross sectional survey conducted in 13 schools. Mental health status and SITBs were measured via self-administered questionnaires. Associations between strengths and difficulties questionnaire outcomes and SITBs were investigated. Results: Data from 4217 students (1858 migrant children and 2359 urban children) were collected. After controlling for gender, age, family economic status, parent's education level and parents' marital status, migrant children scored higher for total difficulties (p < 0.001) and externalizing problems (p < 0.001) than did urban children and reported higher rates of suicidal ideation (p < 0.05) and self injurious behaviors (p < 0.05). Conclusions: Migrant children, compared with urban children, have a higher risk of externalizing problems and SITBs. It is urgent to address these problems by providing both mental health services at migrant-exclusive schools and equitable education and social welfare to migrant children. PMID- 29434652 TI - The open abdomen in trauma and non-trauma patients: WSES guidelines. AB - Damage control resuscitation may lead to postoperative intra-abdominal hypertension or abdominal compartment syndrome. These conditions may result in a vicious, self-perpetuating cycle leading to severe physiologic derangements and multiorgan failure unless interrupted by abdominal (surgical or other) decompression. Further, in some clinical situations, the abdomen cannot be closed due to the visceral edema, the inability to control the compelling source of infection or the necessity to re-explore (as a "planned second-look" laparotomy) or complete previously initiated damage control procedures or in cases of abdominal wall disruption. The open abdomen in trauma and non-trauma patients has been proposed to be effective in preventing or treating deranged physiology in patients with severe injuries or critical illness when no other perceived options exist. Its use, however, remains controversial as it is resource consuming and represents a non-anatomic situation with the potential for severe adverse effects. Its use, therefore, should only be considered in patients who would most benefit from it. Abdominal fascia-to-fascia closure should be done as soon as the patient can physiologically tolerate it. All precautions to minimize complications should be implemented. PMID- 29434658 TI - Healthy living and cancer: evidence from UK Biobank. AB - Context: UK Biobank is a prospective study of half a million subjects, almost all aged 40-69 years, identified in 22 centres across the UK during 2006-2010. Objective: A healthy lifestyle has been described as 'better than any pill, and no side effects [5]. We therefore examined the relationships between healthy behaviours: low alcohol intake, non-smoking, healthy BMI, physical activity and a healthy diet, and the risk of all cancers, colon, breast and prostate cancers in a large dataset. Method: Data on lifestyle behaviours were provided by 343,150 subjects, and height and weight were measured at recruitment. 14,285 subjects were diagnosed with cancer during a median of 5.1 years of follow-up. Results: Compared with subjects who followed none or a single healthy behaviour, a healthy lifestyle based on all five behaviours was associated with a reduction of about one-third in incident cancer (hazard ratio [HR] 0.68; 95% confidence intervals [CI] 0.63-0.74). Colorectal cancer was reduced in subjects following the five behaviours by about one-quarter (HR 0.75; 95% CI 0.58-0.97), and breast cancer by about one-third (HR 0.65; 95% CI 0.52-0.83). The association between a healthy lifestyle and prostate cancer suggested a significant increase in risk, but this can be attributed to bias consequent on inequalities in the uptake of the prostate specific antigen screening test. Conclusions: Taken together with reported reductions in diabetes, vascular disease and dementia, it is clearly important that every effort is taken to promote healthy lifestyles throughout the population, and it is pointed out that cancer and other screening clinics afford 'teachable moments' for the promotion of a healthy lifestyle. PMID- 29434659 TI - Update on intraoperative radiotherapy: new challenges and issues. AB - Intraoperative radiotherapy (IORT) for breast cancer has challenged the standard external beam radiotherapy (EBRT) and has been shown to be non-inferior for treating early breast cancer in the past decade. Several technologies have been tested for IORT and various randomised controlled trials are still ongoing. Different methods of application of IORT have also been evaluated, from early breast cancer to tumour bed boost radiotherapy amongst high risk women. TARGIT-A and ELIOT trials have reported a low incidence of local recurrence and good survival in both arms. Moreover, mortality has been found to be lower amongst women who underwent partial breast radiotherapy compared to those treated with EBRT in a recent meta-analysis. Despite this, IORT has not been introduced in the current clinical practice as yet, and many clinicians do not mention this treatment option to patients awaiting breast cancer surgery. The scientific community does not unanimously support the effectiveness of IORT and still raises concerns about introducing IORT as a standard treatment option for breast cancer. Current evidence demonstrates that IORT is ready for roll-out; it is time to let well-selected and informed patients be offered this treatment option in the current clinical practice. PMID- 29434660 TI - High-intensity focused ultrasound in the treatment of breast tumours. AB - High-intensity focused ultrasound (HIFU) is a minimally invasive technique that has been used for the treatment of both benign and malignant tumours. With HIFU, an ultrasound (US) beam propagates through soft tissue as a high-frequency pressure wave. The US beam is focused at a small target volume, and due to the energy building up at this site, the temperature rises, causing coagulative necrosis and protein denaturation within a few seconds. HIFU is capable of providing a completely non-invasive treatment without causing damage to the directly adjacent tissues. HIFU can be either guided by US or magnetic resonance imaging (MRI). Guided imaging is used to plan the treatment, detect any movement during the treatment and monitor response in real-time. This review describes the history of HIFU, the HIFU technique, available devices and gives an overview of the published literature in the treatment of benign and malignant breast tumours with HIFU. PMID- 29434661 TI - Novel techniques for intraoperative assessment of margin involvement. AB - Breast conserving surgery (BCS) is now the standard of care for the majority of women with early stage breast cancer. There is a finite rate of ipsilateral breast tumour recurrence (IBTR) for breast conserving therapy (BCT) with annual rates of less than 1% for specialist breast practices. There has been recent consensus on the definition of an adequate resection margin for both invasive and noninvasive breast cancer treated with BCS, although some variation in margin policy persists with definitions of 'no tumour at ink', 1 and 2 mm margin mandates. Despite the development of methods for intraoperative assessment of margins, up to 20% of patients require further surgery (cavity re-excision or completion mastectomy) to achieve clear surgical margins. In the past decade, several novel technologies for intraoperative margin assessment have been explored with the aim of reducing rates of re-operation and its attendant patient anxiety, inconvenience and additional cost. Ongoing studies are addressing the safety, feasibility and cost-effectiveness of these novel technologies relative to methods in routine clinical usage. PMID- 29434662 TI - Novel devices for implant-based breast reconstruction: is the use of meshes to support the lower pole justified in terms of benefits? A review of the evidence. AB - The use of novel devices such as acellular dermal matrices (ADMs) to support the lower pole in implant-based breast reconstructions (IBBRs) has been described as one of the most important advances in breast reconstructive surgery following mastectomy. However, the majority of outcomes studies focus primarily on providing evidence for the rates of short-term complications associated with their use, as opposed to their reported benefits. Given the high costs associated with using ADMs, together with an increasing number of alternative, cheaper synthetic products entering the market, it is important to clarify whether their use is actually justified and whether the alternative products offer equivalent or superior outcomes. The purpose of this article is to present a comprehensive and updated review of the evidence for the benefits of using different products for lower pole support (LPS) in IBBR compared to reconstructions without. A secondary aim was to determine if there is any evidence to support the use of one product over another. PMID- 29434663 TI - Natural history of castration-resistant prostate cancer in sub-Saharan African black men: a single-centre study of Nigerian men. AB - Purpose: Native sub-Saharan African black men (SSBM) are disproportionately impacted by higher stage and incurable forms of prostate cancer (PCa). This study evaluates the natural history and survival of a cohort of SSBM with castration resistant prostate cancer (CRPC). Methods: A retrospective study of patients with CRPC as defined by the Prostate Cancer Working Group 2 managed at a centre in sub Saharan Africa between January 2011 and December 2015 was conducted. The principal endpoint was overall survival (OS). Potential prognostic variables were evaluated using Cox proportional hazard regression models. Results: A total of 48 patients were identified. Median (IQR) age and prostate-specific antigen (PSA) at diagnosis were 70 (64-74.5) years and 42 (8.0-123.6) ng/mL, respectively. Only 15 (31.3%) patients received docetaxel and one patient each received the novel drugs enzalutamide and abiraterone. Twenty-eight patients (58.3%) died during follow-up with a median OS of 11 (95% CI: 8-14) months. Docetaxel chemotherapy and ECOG performance status were found to be prognostic (docetaxel use: hazard ratio 0.25, 95% CI 0.10-0.67, p = 0.006; ECOG 0-2: 0.26, 0.11-0.62, p = 0.003). Conclusion: This study of SSBM with CRPC revealed a mainly unmodulated clinical course with poor access to active treatments and poor survival. Improving access to new active therapies would improve survival. PMID- 29434664 TI - Fertility preservation in gynaecologic cancers. AB - Due to substantial improvement in the diagnosis and treatment of gynaecologic cancers, a better understanding of patient care needs to be revised. We reviewed the literature related to fertility preservation strategies in gynaecological cancer and discussed current general management approaches. New technical modalities and patients' own desire for motherhood should be integral and paramount in the clinical evaluation to significantly contribute to preserving fertility in those women diagnosed with gynaecologic cancers during the reproductive years. PMID- 29434665 TI - High activity CAZyme cassette for improving biomass degradation in thermophiles. AB - Background: Thermophilic microorganisms and their enzymes offer several advantages for industrial application over their mesophilic counterparts. For example, a hyperthermophilic anaerobe, Caldicellulosiruptor bescii, was recently isolated from hot springs in Kamchatka, Siberia, and shown to have very high cellulolytic activity. Additionally, it is one of a few microorganisms being considered as viable candidates for consolidated bioprocessing applications. Moreover, C. bescii is capable of deconstructing plant biomass without enzymatic or chemical pretreatment. This ability is accomplished by the production and secretion of free, multi-modular and multi-functional enzymes, one of which, CbCel9A/Cel48A also known as CelA, is able to outperform enzymes found in commercial enzyme preparations. Furthermore, the complete C. bescii exoproteome is extremely thermostable and highly active at elevated temperatures, unlike commercial fungal cellulases. Therefore, understanding the functional diversity of enzymes in the C. bescii exoproteome and how inter-molecular synergy between them confers C. bescii with its high cellulolytic activity is an important endeavor to enable the production of more efficient biomass degrading enzyme formulations and in turn, better cellulolytic industrial microorganisms. Results: To advance the understanding of the C. bescii exoproteome we have expressed, purified, and tested four of the primary enzymes found in the exoproteome and we have found that the combination of three or four of the most highly expressed enzymes exhibit synergistic activity. We also demonstrated that discrete combinations of these enzymes mimic and even improve upon the activity of the whole C. bescii exoproteome, even though some of the enzymes lack significant activity on their own. Conclusions: We have demonstrated that it is possible to replicate the cellulolytic activity of the native C. bescii exoproteome utilizing a minimal gene set, and that these minimal gene sets are more active than the whole exoproteome. In the future, this may lead to more simplified and efficient cellulolytic enzyme preparations or yield improvements when these enzymes are expressed in microorganisms engineered for consolidated bioprocessing. PMID- 29434666 TI - Life-cycle assessment of transportation biofuels from hydrothermal liquefaction of forest residues in British Columbia. AB - Background: Biofuels from hydrothermal liquefaction (HTL) of abundantly available forest residues in British Columbia (BC) can potentially make great contributions to reduce the greenhouse gas (GHG) emissions from the transportation sector. A life-cycle assessment was conducted to quantify the GHG emissions of a hypothetic 100 million liters per year HTL biofuel system in the Coast Region of BC. Three scenarios were defined and investigated, namely, supply of bulky forest residues for conversion in a central integrated refinery (Fr-CIR), HTL of forest residues to bio-oil in distributed biorefineries and subsequent upgrading in a central oil refinery (Bo-DBR), and densification of forest residues in distributed pellet plants and conversion in a central integrated refinery (Wp-CIR). Results: The life-cycle GHG emissions of HTL biofuels is 20.5, 17.0, and 19.5 g CO2-eq/MJ for Fr-CIR, Bo-DBR, and Wp-CIR scenarios, respectively, corresponding to 78-82% reduction compared with petroleum fuels. The conversion stage dominates the total GHG emissions, making up more than 50%. The process emitting most GHGs over the life cycle of HTL biofuels is HTL buffer production. Transportation emission, accounting for 25% of Fr-CIR, can be lowered by 83% if forest residues are converted to bio-oil before transportation. When the credit from biochar applied for soil amendment is considered, a further reduction of 6.8 g CO2-eq/MJ can be achieved. Conclusions: Converting forest residues to bio-oil and wood pellets before transportation can significantly lower the transportation emission and contribute to a considerable reduction of the life-cycle GHG emissions. Process performance parameters (e.g., HTL energy requirement and biofuel yield) and the location specific parameter (e.g., electricity mix) have significant influence on the GHG emissions of HTL biofuels. Besides, the recycling of the HTL buffer needs to be investigated to further improve the environmental performance of HTL biofuels. PMID- 29434667 TI - Transcriptome analysis of the digestive system of a wood-feeding termite (Coptotermes formosanus) revealed a unique mechanism for effective biomass degradation. AB - Background: Wood-feeding termite, Coptotermes formosanus Shiraki, represents a highly efficient system for biomass deconstruction and utilization. However, the detailed mechanisms of lignin modification and carbohydrate degradation in this system are still largely elusive. Results: In order to reveal the inherent mechanisms for efficient biomass degradation, four different organs (salivary glands, foregut, midgut, and hindgut) within a complete digestive system of a lower termite, C. formosanus, were dissected and collected. Comparative transcriptomics was carried out to analyze these organs using high-throughput RNA sequencing. A total of 71,117 unigenes were successfully assembled, and the comparative transcriptome analyses revealed significant differential distributions of GH (glycosyl hydrolase) genes and auxiliary redox enzyme genes in different digestive organs. Among the GH genes in the salivary glands, the most abundant were GH9, GH22, and GH1 genes. The corresponding enzymes may have secreted into the foregut and midgut to initiate the hydrolysis of biomass and to achieve a lignin-carbohydrate co-deconstruction system. As the most diverse GH families, GH7 and GH5 were primarily identified from the symbiotic protists in the hindgut. These enzymes could play a synergistic role with the endogenous enzymes from the host termite for biomass degradation. Moreover, twelve out of fourteen genes coding auxiliary redox enzymes from the host termite origin were induced by the feeding of lignin-rich diets. This indicated that these genes may be involved in lignin component deconstruction with its redox network during biomass pretreatment. Conclusion: These findings demonstrate that the termite digestive system synergized the hydrolysis and redox reactions in a programmatic process, through different parts of its gut system, to achieve a maximized utilization of carbohydrates. The detailed unique mechanisms identified from the termite digestive system may provide new insights for advanced design of future biorefinery. PMID- 29434668 TI - Quantitative trait loci for cell wall composition traits measured using near infrared spectroscopy in the model C4 perennial grass Panicum hallii. AB - Background: Biofuels derived from lignocellulosic plant material are an important component of current renewable energy strategies. Improvement efforts in biofuel feedstock crops have been primarily focused on increasing biomass yield with less consideration for tissue quality or composition. Four primary components found in the plant cell wall contribute to the overall quality of plant tissue and conversion characteristics, cellulose and hemicellulose polysaccharides are the primary targets for fuel conversion, while lignin and ash provide structure and defense. We explore the genetic architecture of tissue characteristics using a quantitative trait loci (QTL) mapping approach in Panicum hallii, a model lignocellulosic grass system. Diversity in the mapping population was generated by crossing xeric and mesic varietals, comparative to northern upland and southern lowland ecotypes in switchgrass. We use near-infrared spectroscopy with a primary analytical method to create a P. hallii specific calibration model to quickly quantify cell wall components. Results: Ash, lignin, glucan, and xylan comprise 68% of total dry biomass in P. hallii: comparable to other feedstocks. We identified 14 QTL and one epistatic interaction across these four cell wall traits and found almost half of the QTL to localize to a single linkage group. Conclusions: Panicum hallii serves as the genomic model for its close relative and emerging biofuel crop, switchgrass (P. virgatum). We used high throughput phenotyping to map genomic regions that impact natural variation in leaf tissue composition. Understanding the genetic architecture of tissue traits in a tractable model grass system will lead to a better understanding of cell wall structure as well as provide genomic resources for bioenergy crop breeding programs. PMID- 29434669 TI - Copy number variation and regions of homozygosity analysis in patients with MULLERIAN aplasia. AB - Background: Little is known about the genetic contribution to Mullerian aplasia, better known to patients as Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Mutations in two genes (WNT4 and HNF1B) account for a small number of patients, but heterozygous copy number variants (CNVs) have been described. However, the significance of these CNVs in the pathogenesis of MRKH is unknown, but suggests possible autosomal dominant inheritance. We are not aware of CNV studies in consanguineous patients, which could pinpoint genes important in autosomal recessive MRKH. We therefore utilized SNP/CGH microarrays to identify CNVs and define regions of homozygosity (ROH) in Anatolian Turkish MRKH patients. Results: Five different CNVs were detected in 4/19 patients (21%), one of which is a previously reported 16p11.2 deletion containing 32 genes, while four involved smaller regions each containing only one gene. Fourteen of 19 (74%) of patients had parents that were third degree relatives or closer. There were 42 regions of homozygosity shared by at least two MRKH patients which was spread throughout most chromosomes. Of interest, eight candidate genes suggested by human or animal studies (RBM8A, CMTM7, CCR4, TRIM71, CNOT10, TP63, EMX2, and CFTR) reside within these ROH. Conclusions: CNVs were found in about 20% of Turkish MRKH patients, and as in other studies, proof of causation is lacking. The 16p11.2 deletion seen in mixed populations is also identified in Turkish MRKH patients. Turkish MRKH patients have a higher likelihood of being consanguineous than the general Anatolian Turkish population. Although identified single gene mutations and heterozygous CNVs suggest autosomal dominant inheritance for MRKH in much of the western world, regions of homozygosity, which could contain shared mutant alleles, make it more likely that autosomal recessively inherited causes will be manifested in Turkish women with MRKH. PMID- 29434670 TI - Advances in spinal muscular atrophy therapeutics. AB - Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families. Greater knowledge of the molecular basis of SMA pathogenesis has fuelled the development of potential therapeutic approaches, which are illustrated here. Nusinersen, a modified antisense oligonucleotide that modulates the splicing of the SMN2 mRNA transcript, is the first approved drug for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN reported positive results in survival and motor milestones achievement. In addition, other strategies are in the pipeline, including modulation of SMN2 transcripts, neuroprotection, and targeting an increasing number of other peripheral targets, including the skeletal muscle. Based on this premise, it is reasonable to expect that therapeutic approaches aimed at treating SMA will soon be changed, and improved, in a meaningful way. We discuss the challenges with regard to the development of novel treatments for patients with SMA, and depict the current and future scenarios as the field enters into a new era of promising effective treatments. PMID- 29434671 TI - Validation of American Joint Committee on Cancer eighth staging system among prostate cancer patients treated with radical prostatectomy. AB - Background: The objective in this paper was to validate the prognostic performance of the American Joint Committee on Cancer (AJCC) 7th and 8th systems among prostate cancer patients treated with radical prostatectomy. Methods: The surveillance, epidemiology and end results (SEER) database (2006-2014) was accessed through the SEER*Stat program and AJCC 7th and 8th editions were calculated utilizing T, N and M stages, histological grade group, as well as baseline prostatic-specific antigen (PSA). Cancer-specific and overall survival analyses according to 7th and 8th editions were conducted. Moreover, multivariate analysis was conducted through a Cox proportional hazard model. Results: A total of 72,999 patients with prostate cancer were identified in the period from 2006 to 2014. Overall survival was assessed according to AJCC 7th and 8th staging systems. The test for trend for overall survival was significant (p < 0.0001) for both staging systems. Concordance index for AJCC 7th system was: 0.791 [standard error of the mean (SE): 0.017; 95% CI: 0.758-0.825]; while concordance index for AJCC 8th system was: 0.840 (SE: 0.015; 95% CI: 0.811-0.869). In a multivariate analysis among patients with M0 disease, lower grade group, N0 stage and pT2 stage were associated with better cancer-specific survival (p < 0.01); while PSA level did not predict cancer-specific survival. Conclusion: There is a clear improvement in the discriminatory ability for AJCC 8th versus AJCC 7th staging system in the postprostatectomy setting. This may be related to better integration of biological factors into the staging system. PMID- 29434672 TI - Pharmacokinetic and pharmacodynamic comparison of subcutaneous versus intramuscular leuprolide acetate formulations in male subjects. AB - Background: The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection. Methods: A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA (n = 16) or IM-LA (n = 16) in this phase I, open-label, parallel-group study. PK was assessed via LA concentrations, and PD via serum luteinizing hormone (LH) and testosterone (T) concentrations. Results: The initial surge of LA was higher for IM-LA than SC-LA (Cmax 27 +/- 4.9 versus 19 +/- 8.0 ng/ml, respectively), with a shorter tmax (1.0 +/- 0.4 versus 2.1 +/- 0.8 h). The duration of quantifiable LA concentration was longer for SC-LA (up to 56 versus 42 days for SC-LA and IM-LA, respectively). Median LH concentrations in both groups rapidly increased, followed by gradual decrease. However, SC-LA demonstrated a longer duration of LH suppression, with median levels remaining below 1.0 IU/l through Day 56 compared with IM-LA where LH started to rise by Day 35. Consequently, serum T began to increase by Day 42 in the IM-LA group, with only four subjects maintaining levels ?50 ng/dl, compared with 14 subjects in the SC-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ?50 ng/dl. Both SC-LA and IM-LA were well tolerated. Conclusions: Both formulations demonstrated consistent delivery of drug over 1 month; however, SC-LA provided a longer duration of action than expected based on the dosing interval. This profile suggests that SC-LA will provide effective suppression of T over a longer period of time, permitting greater injection scheduling flexibility. PMID- 29434673 TI - Practical differences between luteinizing hormone-releasing hormone agonists in prostate cancer: perspectives across the spectrum of care. AB - Background: Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists is well established for the treatment of men with metastatic prostate cancer. As clear differences in efficacy, safety, or tolerability between the available LHRH agonists are lacking, the healthcare management team needs to look to practical differences between the formulations when selecting therapy for their patients. Moreover, as the economic burden of prostate cancer rises alongside earlier diagnosis and improved survival, the possibility for cost savings by using products with specific features is growing in importance. Methods: A review was conducted to summarize the information on the different LHRH agonist formulations currently available and offer insight into their relative benefits and disadvantages from the perspectives of physicians, a pharmacist, and a nurse. Results: The leuprorelin acetate and goserelin acetate solid implants have the advantage of being ready to use with no requirement for refrigeration, whereas powder and microsphere formulations have to be reconstituted and have specific storage or handling constraints. The single step administration of solid implants, therefore, has potential to reduce labor time and associated costs. Dosing frequency is another key consideration, as administering the injection provides an opportunity for face-to-face interaction between the patient and healthcare professionals to ensure therapy is optimized and give reassurance to patients. Prostate cancer patients are reported to prefer 3- or 6-monthly dosing, which aligns with the monitoring frequency recommended in European Association of Urology guidelines and has been shown to result in reduced annual costs compared with 1-month formulations. Conclusions: A number of practical differences exist between the different LHRH agonist preparations available, which may impact on clinical practice. It is important for healthcare providers to be aware and carefully consider these differences when selecting treatments for their prostate cancer patients. PMID- 29434674 TI - Circulating tumor cells in genitourinary tumors. AB - Management of advanced urogenital malignancies has profoundly changed in recent years due to the development of novel targeted drugs that have significantly improved patient's clinical outcomes. This process has been made possible mainly thanks to better knowledge of tumor genetic alterations and molecular altered pathways. Despite these remarkable results, several issues such as early detection of the disease as well as the research into early markers of recurrence or disease progression still remain an open challenge for clinical research. The detection of circulating tumor cells and circulating DNA appears an attractive option since it is a minimally invasive approach potentially able to allow clinicians an accurate diagnosis and maybe lead to more customized treatment strategies. This review focuses on the current techniques adopted for the detection and isolation of circulating tumor cells in genitourinary tumors highlighting their present and possible future application in clinical practice. PMID- 29434675 TI - Best practice in the management of storage symptoms in male lower urinary tract symptoms: a review of the evidence base. AB - Storage lower urinary tract symptoms (LUTS) are characterized by an altered bladder sensation, increased daytime frequency, nocturia, urgency and urgency incontinence. Some evidence underlines the role of metabolic factors, pelvic ischemia, prostatic chronic inflammation and associated comorbidities in the pathophysiology of storage LUTS. A detailed evaluation of the severity of storage LUTS, and the concomitance of these symptoms with voiding and postmicturition symptoms, is mandatory for improving the diagnosis and personalizing treatment. A detailed medical history with comorbidities and associated risk factors, a physical examination, a comprehensive analysis of all the features of LUTS, including their impact on quality of life, and a frequency-volume chart (FVC) or bladder diary, are recommended for men with storage LUTS. Several drugs are available for the treatment of LUTS secondary to benign prostatic obstruction (BPO). Alpha-blockers (alpha-blockers), 5-alpha-reductase inhibitors and phosphodiesterase type 5 inhibitors are commonly used to manage storage LUTS occurring with voiding symptoms associated with BPO. Muscarinic receptor antagonists and Beta 3-agonists (beta3-agonists) alone, or in combination with alpha-blockers, represent the gold standard of treatment in men with predominant storage LUTS. There is no specific recommendation regarding the best treatment options for storage LUTS after prostatic surgery. PMID- 29434676 TI - Plasma levels of lipopolysaccharide correlate with insulin resistance in HIV patients. AB - Background: In HIV patients using HAART insulin resistance is a central pathophysiological condition that can contribute to the development of diabetes and cardiovascular complications. To examine the role of adipocyte hormones and LPS in insulin resistance in HIV patients, we investigated the role of adiponectin, leptin, visfatin and LPS levels in the insulin resistance of HIV infected patients treated with HAART. Methods: This study included 67 HIV positive individuals on HAART and ten healthy controls. All participants performed plasma or serum levels of glucose; insulin; lipids, visfatin, leptin, adiponectin, and LPS. The homeostasis model assessment (HOMA-IR), was used to estimate insulin resistance. Results: The levels of visfatin, leptin and adiponectin were similar between controls and HIV patients. However, circulating levels of LPS were higher in HIV patients on HAART than in controls. There was a positive correlation between LPS and TG (r = 0.49, p = 0.0001), between LPS and TG/HDL (r = 0.50, p = 0.0001), between LPS and insulin (r = 0.52, p = 0.0003), and between LPS and HOMA-IR (r = 0.52, p = 0.0005), in HIV patients. Conclusions: Our results showed a clear correlation between plasma LPS and markers of insulin resistance, suggesting a relationship between LPS levels and metabolic alterations, particularly affecting lipids and insulin resistance in HIV patients. PMID- 29434677 TI - The constitutively active PKG II mutant effectively inhibits gastric cancer development via a blockade of EGF/EGFR-associated signalling cascades. AB - Type II cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG II) is a membrane-anchored enzyme expressed mainly in the intestinal mucosa and the brain, and is associated with various physiological or pathological processes. Upregulation of PKG II is known to induce apoptosis and inhibit proliferation and metastasis of cancer cells. The inhibitory effect of PKG II has been shown to be dependent on the inhibition of the activation of epidermal growth factor receptor (EGFR) and blockade of EGFR downstream signal transduction in vitro. However, it remains unclear whether similar phenomena/mechanisms exist in vivo and whether these effects are independent of cGMP or cGMP analogues. In the present work, nude mice with transplanted orthotopic tumours were infected with adenovirus encoding cDNA of constitutively active PKG II mutant (Ad-a-PKG II) and the effect of constitutively active PKG II (a-PKG II) on tumour development was detected. The results showed that a-PKG II effectively ameliorated gastric tumour development through delaying the growth, inducing the apoptosis, and inhibiting the metastasis and angiogenesis. The effect was related to blockade of EGFR activation and abrogation of the downstream signalling cascades. These findings provide novel insight which will benefit the development of new cancer therapies. PMID- 29434678 TI - Dynamic changes in quality of life after three first-line therapies for EGFR mutation-positive advanced non-small-cell lung cancer. AB - Background: Three different tyrosine kinase inhibitors have been approved as first-line therapies for epidermal growth factor receptor (EGFR) mutation positive advanced non-small-cell lung cancer with similar overall survival. This study determined dynamic changes in quality of life (QoL) for patients using these therapies after controlling for potential confounders. Methods: From 2011 to 2016, we prospectively assessed the utility values and QoL scores of patients using the EuroQol five-dimension and World Health Organization Quality-of-Life - Brief questionnaires. QoL functions after initiation of treatment were estimated using a kernel-smoothing method. Dynamic changes in major determinants were repeatedly assessed for constructing mixed models. Results: A total of 344 patients were enrolled, with 934 repeated assessments. After controlling for performance status, disease progression, EGFR mutation subtype and other confounders, the mixed models showed significantly lower QoL scores for afatinib versus gefitinib in the physical, psychological and social domains, and 10 facets. The differences seemed to appear 10 months after initiation of treatment. In contrast, there was no significant difference between erlotinib and gefitinib in the scores of all domains and facets. Conclusion: QoL in patients receiving afatinib seemed to be lower than in those receiving gefitinib. Since the sample sizes in this study were relatively small, more studies are warranted to corroborate these results. PMID- 29434679 TI - CRISPR-Cas9: a promising genetic engineering approach in cancer research. AB - Bacteria and archaea possess adaptive immunity against foreign genetic materials through clustered regularly interspaced short palindromic repeat (CRISPR) systems. The discovery of this intriguing bacterial system heralded a revolutionary change in the field of medical science. The CRISPR and CRISPR associated protein 9 (Cas9) based molecular mechanism has been applied to genome editing. This CRISPR-Cas9 technique is now able to mediate precise genetic corrections or disruptions in in vitro and in vivo environments. The accuracy and versatility of CRISPR-Cas have been capitalized upon in biological and medical research and bring new hope to cancer research. Cancer involves complex alterations and multiple mutations, translocations and chromosomal losses and gains. The ability to identify and correct such mutations is an important goal in cancer treatment. In the context of this complex cancer genomic landscape, there is a need for a simple and flexible genetic tool that can easily identify functional cancer driver genes within a comparatively short time. The CRISPR-Cas system shows promising potential for modeling, repairing and correcting genetic events in different types of cancer. This article reviews the concept of CRISPR Cas, its application and related advantages in oncology. PMID- 29434680 TI - Predictors of anti-VEGF drug-induced hypertension using different hypertension criteria: a secondary analysis of the COMPARZ study. AB - Background: There is inconsistency in the criteria used to define anti-vascular endothelial growth factor (VEGF) drug-induced hypertension (AVEGF-HT) in published studies. It is unknown whether specific patient characteristics similarly predict AVEGF-HT using different criteria. Methods: We assessed the associations between clinical and demographic factors (n = 22) and AVEGF-HT, using six criteria based on predefined on-treatment blood pressure (BP) thresholds or absolute BP elevations versus baseline, in a post hoc analysis of a phase III trial of 1102 patients with renal cell carcinoma (RCC) randomized to pazopanib or sunitinib (COMPARZ study). Results: The cumulative incidence of AVEGF-HT at any time while on treatment ranged between 14.8% [criterion: grade ?3 toxicity, National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0] and 58.8% (criterion: absolute systolic BP increase ?20 mmHg versus baseline). After adjusting for anti-VEGF treatment and baseline BP, the number of significant (p < 0.05) predictors ranged between one (criterion: absolute systolic BP increase ?20 mmHg, on-treatment systolic BP ?140 mmHg and diastolic BP ?90 mmHg) and nine (criterion: grade ?3 toxicity, NCI CTCAE v3.0). Age, use of antidiabetic drugs and use of antihypertensive drugs each significantly predicted four AVEGF-HT criteria. By contrast, sex, smoking, heart rate, proteinuria, Karnofsky performance status, and use of thiazide diuretics did not predict any criterion. Conclusions: There was a significant variability in the incidence, number and type of predictors of AVEGF-HT, using six different criteria, in a post hoc analysis of the COMPARZ study. The use of specific criteria might affect the assessment of the interaction between anti-VEGF drugs, AVEGF-HT and cancer outcomes. PMID- 29434681 TI - miRNA-145 is associated with spontaneous hypertension by targeting SLC7A1. AB - Previous studies have indicated that microRNAs (miRNAs/miRs) may participate in the pathogenesis of hypertension. miR-145 has been demonstrated to serve important roles in the development of numerous cardiovascular diseases. However, the specific role of miR-145 in hypertension remains unclear. The present study aimed to investigate the role of miR-145 in spontaneously hypertensive rats (SHR) and rat vascular endothelial cells (RVECs). The results of the present study demonstrated that in the SHR group miR-145 expression was significantly upregulated in the thoracic aorta compared with the control group. Furthermore, a significant decrease in nitric oxide (NO) content was observed in the SHR group compared with the control rats. In RVECs, silencing miR-145 induced a significant increase in the expression of solute carrier family 7 member 1 (SLC7A1) and phosphorylated endothelial nitric oxide synthase, and a dual-luciferase reporter assay confirmed that SLC7A1 is a direct target of miR-145. The results of the present study indicate that miR-145 functions as a key mediator in the pathogenesis of hypertension via targeting SLC7A1, which suggests that miR-145 is a potential target for the treatment of hypertension. PMID- 29434682 TI - Drug-induced Rowell syndrome, a rare and difficult to manage disease: A case report. AB - Rowell syndrome is defined as the association between lupus erythematosus, erythema multiforme-like lesions and characteristic immunological changes including positive tests for rheumatoid factor, speckled antinuclear antibody, positive anti-Ro or anti-La antibodies. The present report presents the case of a 45-year-old female patient who was previously diagnosed in January 2010 with terbinafine-induced subacute cutaneous lupus erythematosus and was admitted for a skin eruption consisting of erythematous-papular erythema multiforme-like lesions, primarily on the trunk and limbs. The associated symptoms consisted of fatigability, myalgia and gonalgia. In October 2015, the illness reoccurred ~1 week after the initiation of Helicobacter pylori eradication treatment. Anti-Ro antibodies, rheumatoid factor and antinuclear antibody tests were positive. Given the patient's medical history, clinical manifestations, and laboratory, histopathological and immunofluorescence microscopy findings, a diagnosis of Rowell syndrome was made. Systemic corticosteroids (methylprednisolone; 0.5 mg/kg/day) and immunomodulatory therapy (azathioprine; 50 mg/day) were administered with the associated medication (omeprazole, 20 mg/day; KCl, 1 g/day) and topical dermocorticoids (fluticasone propionate 0.05% cream; 1 application/day), with a favorable outcome. The major diagnostic criteria for Rowell syndrome are the presence of lupus erythematosus (acute, subacute or systemic), erythema multiforme-like lesions and positive testing for antinuclear antibodies. The minor diagnostic criteria for Rowell syndrome are chilblains, the presence of anti-Ro antibodies and positive testing for rheumatoid factor. A diagnosis of Rowell syndrome is made if the patient exhibits all major criteria and at least one minor criterion. The present case met all diagnostic criteria, excluding the presence of chilblains. Notably, in this case there was a co occurrence of subacute lupus erythematosus and Rowell syndrome lesions, which was drug-induced. PMID- 29434683 TI - The inhibitory roles of Ihh downregulation on chondrocyte growth and differentiation. AB - The proliferative rate of chondrocytes affects bone elongation. Chondrocyte hypertrophy is required for endochondral bone formation as chondrocytes secrete factors required for osteoblast differentiation and maturation. Previous studies have demonstrated that the Indian hedgehog (Ihh) signaling pathway is a key regulator of skeletal development and homeostasis. The aim of the present study was to investigate the function of Ihh in chondrocyte proliferation and differentiation, as well as the underlying mechanisms. Ihh was knocked down in mouse chondrocyte cells using short hairpin RNA. Chondrocyte apoptosis and cell cycle arrest were assessed using flow cytometry and the results indicated that knockdown of Ihh significantly inhibited cell growth (P<0.05) and increased apoptosis (P<0.001) compared with negative control cells. Downregulation of Ihh also resulted in cell cycle arrest at G1 to S phase in chondrocytes. It was also observed that knockdown of Ihh decreased alkaline phosphatase activity and mineral deposition of chondrocytes. The inhibitory roles of Ihh downregulation on chondrocyte growth and differentiation may be associated with the transforming growth factor-beta/mothers against decapentaplegic and osteoprotegerin/receptor activator of nuclear factor kappaB ligand signaling pathway. The results of the present study suggest that chondrocyte-derived Ihh is essential for maintaining bone growth plates and that manipulation of Ihh expression or its signaling components may be a novel therapeutic technique for the treatment of skeletal diseases, including achondroplasia. PMID- 29434684 TI - Intraglandular transplantation of adipose-derived stem cells combined with platelet-rich fibrin extract for the treatment of irradiation-induced salivary gland damage. AB - The aim of the present study was to determine the effect of adipose-derived mesenchymal stem cells (ADSCs) combined with heterologous platelet-rich fibrin extract (PRFe) on irradiation-induced salivary gland (SG) damage. ADSCs were isolated from C3H mice, whereas PRFe was obtained from New Zealand rabbits. Twelve weeks post irradiation, the ADSCs or PRFe or their combination were transplanted into the submandibular glands of C3H mice with irradiation-induced damage. The salivary flow rate (SFR) was determined and histopathological analysis was performed at 12 weeks post transplantation. Immunofluorescence, microvessel density measurements and transmission electron microscopy were performed to assess alpha-amylase (AMY) production, apoptosis and microstructural changes in the cells. The administration of ADSCs combined with PRFe increased the SFR at 12 weeks post transplantation, whereas ADSCs alone or PRFe alone failed to do so. The ADSCs+PRFe-treated, irradiated SGs had fewer damaged and atrophied acinar cells, higher AMY levels and an increased microvessel density compared with the untreated irradiated SGs. Moreover, SG tissue from the ADSCs+PRFe group also showed decreased apoptotic and increased proliferative activity compared to that from the irradiated group. In conclusion, ADSCs or PRFe alone did not restore permanent, irradiation-induced damage of SG tissue when used alone, but when used together, they provided effective treatment outcomes. PMID- 29434685 TI - Salidroside attenuates hypoxia/reoxygenation-induced human brain vascular smooth muscle cell injury by activating the SIRT1/FOXO3alpha pathway. AB - It has been reported that salidroside (SAL), a natural dietary isothiocyanate, exhibits neuroprotective roles in cerebral ischemia-reperfusion injury. However, to the best of our knowledge, its underlying protective mechanism remains unknown. Sirtuin 1 (SIRT1) is a class III histone deacetylase involved in a variety of cellular functions. SIRT1 has been identified as a mediator of cerebral ischemia and may induce neuroprotection by activating various intracellular downstream targets, such as forkhead box protein O3alpha (FOXO3alpha). Therefore, the present study aimed to investigate whether SAL protects human brain vascular smooth muscle cells (HBVSMC) against hypoxia/reoxygenation (H/R) injury, which is a cell model of cerebral ischemia reperfusion injury, through regulating the SIRT1-activited signaling pathway. The present study revealed that H/R treatment significantly reduced the expression of SIRT1 protein in HBVSMCs. Additionally, pretreatment with SAL reversed the H/R induced decrease in cellular viability, increased caspase-3 activity, the appearance of apoptotic cells and the apoptosis rate in HBVSMCs. SAL attenuated the H/R-induced decrease in the expression of SIRT1 and phosphorylated FOXO3alpha protein in HBVSMCs, suggesting that the protective role of SAL in H/R injury occurs via the SIRT1/FOXO3alpha pathway. Furthermore, sirtinol, a SIRT1-specific inhibitor, suppressed the inhibitory effects of SAL on H/R-induced cytotoxicity and apoptosis as indicated by the downregulation of cell viability and upregulation of caspase-3 activity and apoptosis rate induced by sirtinol treatment in HBVSMCs. The reversal effects of SAL on H/R-induced alternation of B cell lymphoma (Bcl-2) and Bcl-2 associated X protein expression were also attenuated by sirtinol. These results suggest that SAL exhibits neuroprotective effects against H/R injury by activating the SIRT1/FOXO3alpha pathway, which may become a novel potential therapeutic target for the treatment of cerebral ischemic disease. PMID- 29434686 TI - Pulmonary alveolar microlithiasis: A case report and review of the literature. AB - Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease characterized by the formation of calcium phosphate microliths in the alveoli. Mutations in the gene encoding the solute carrier family 34 member 2 gene are considered to be involved in the pathogenesis of PAM. Although PAM can develop in children, the majority of patients with PAM are diagnosed in adulthood due to the slow progressive nature of the disease within the lungs. In childhood, the majority of patients with PAM are asymptomatic and changes in the lung parenchyma are usually identified incidentally. Symptoms of PAM typically appear in the third or fourth decade of life and there is often a notable dissociation between the advanced radiological findings and the mild clinical presentation. A positive diagnosis of PAM is reached by the combination of a positive chest radiograph and histological examination. Genetic testing may help to identify other latent patients in the family of the patient with PAM. In the present study, the cases of 3 patients diagnosed with PAM have been reported, including their clinical presentation, radio imaging, pathological symptoms, genetic test results and treatment plans, as well as the associated literature. PMID- 29434687 TI - Is fetal-type posterior cerebral artery a risk factor for intracranial aneurysm as analyzed by multislice CT angiography? AB - Fetal-type posterior cerebral artery (FTP) is a common anatomic variation that is closely associated with intracranial aneurysm. In the present study, multislice computed tomography angiography (CTA) was performed to assess whether FTP is a risk factor for intracranial aneurysm. CTA data of 364 consecutive cases of patients who were suspected with cerebrovascular disease or intracranial aneurysm of intracranial artery from 2013 to 2016 were reviewed and the incidence rates of FTP, other variations of the circle of Willis, intracranial aneurysm and FTP with intracranial aneurysm were evaluated. The chi2 test was used to assess the influence of FTP and gender on the incidence rates of other variations of the circle of Willis, intracranial aneurysm and internal carotid artery-posterior communicating artery (ICA-PComA) aneurysm. Binary logistic regression analysis was performed to assess the associations of FTP and gender with intracranial aneurysm and ICA-PComA aneurysm. Compared with non-FTP patients, FTP cases exhibited significantly higher rates of other variations of the circle of Willis (chi2=80.173, P<0.001) and ICA-PComA aneurysm (chi2=4.437, P=0.035). Among patients with FTP and bilateral FTP, more female than male patients with intracranial aneurysm were identified. However, among all patients with intracranial aneurysm, no statistically significant differences in the prevalence of FTP (chi2=2.577, P=0.108) and bilateral FTP (chi2=2.199, P=0.159) between males and females were identified. Binary logistic regression analysis revealed that FTP and gender were risk factors for intracranial aneurysm and ICA-PComA aneurysm. A moderate association between FTP and ICA-PComA aneurysm (OR=2.762) were identified, although there was a weak association between FTP and intracranial aneurysm [odds ratio (OR)=1.365]. Furthermore, a strong association was identified between gender and intracranial aneurysm (OR=0.328), and a moderate association existed between gender and ICA-PComA aneurysm (OR=0.357). In conclusion, female gender is an independent risk factor for intracranial aneurysm, and FTP and female gender are independent risk factors for ICA-PComA aneurysm. PMID- 29434688 TI - Nalbuphine for analgesia after fracture surgery and its effect on circulating inflammatory factors. AB - The present study evaluated the use of nalbuphine for analgesia after fraction reduction surgery. Eighty lower limb fracture patients needing open reduction and internal fixation were selected in the First People's Hospital of Jingzhou from January 2015 to December 2015. Patients were randomly divided into observation and control groups (with 40 cases in each). After surgery, the patients in the observation group were treated with nalbuphine (2 mg/kg) for patient-controlled intravenous analgesia (PCIA), while sufentanil (2.5 ug/kg) was used for patients in the control group. The analgesia treatment lasted for 48 h after surgery. Changes in inflammatory factors and catecholamine hormones during the observation period were determined and compared between the groups. Pain, sedation scores and the number of times the analgesia pump was used were recorded at different time points. Additionally, the life and sleep qualities and any adverse reactions were also recorded. Our results showed that after the operation, the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL 1), high-sensitivity CRP (hs-CRP) cortisol, adrenaline epinephrine (AD) and norepinephrine (NE) were significantly lower in the observation group than in the control group (P<0.05). Pain and sedation scores of patients in the observation group were better than those in the control group at all time-points after operation (P<0.05). Life and sleep qualities of patients in the observation group were also better than those in the control group (P<0.05). Finally, the rates of nausea, vomiting, dizziness, lethargy, urinary retention, skin itch and constipation were significantly lower in the observation group than in control group (P<0.05). Based on our findings, the application of nalbuphine for analgesia in patients with fracture surgeries can reduce the levels of inflammatory cytokines, improve the analgesic effect, bring beneficial sedative effects and reduce the occurrence of adverse reactions. PMID- 29434689 TI - Lower energy radial shock wave therapy improves characteristics of hypertrophic scar in a rabbit ear model. AB - The aim of the present study was to investigate the effects of radial extracorporeal shock wave therapy (rESWT) on scar characteristics and transforming growth factor (TGF)-beta1/Smad signaling in order to explore a potential modality for the treatment of hypertrophic scars (HS). The HS model was generated in rabbit ears, then rabbits were randomly divided into 3 groups: Lower (L)-ESWT [treated with rESWT with lower energy flux density (EFD) of 0.1 mJ/mm2], higher (H)-ESWT (treated with a higher EFD of 0.18 mJ/mm2) and the sham ESWT group (S-ESWT; no ESWT treatment). Scar characteristics (wrinkles, texture, diameter, area, volume of elevation, hemoglobin and melanin) were assessed using the Antera 3D(r) system. The protein and mRNA expression of TGF-beta1, Smad2, Smad3 and Smad7 was assessed by enzyme-linked immunosorbent assay and reverse transcription-quantitative polymerase chain reaction, respectively. The Antera 3D(r) results indicated that wrinkles and hemoglobin of the HS were significantly improved in both of the rESWT groups when compared with the S-ESWT group. However, these changes appeared much earlier in the L-ESWT group than the H-ESWT. Scar texture was also improved in the L-ESWT group. However, rESWT did not influence HS diameter, area, volume of elevation or melanin levels. rESWT had no effect on TGF-beta1 or Smad7 expression in either of rESWT groups. Although no difference was observed in Smad2 mRNA expression in the L-ESWT group, the Smad3 mRNA and protein expression significantly decreased when compared with the H-ESWT and S-ESWT groups. By contrast, Smad2 and Smad3 mRNA expression were upregulated in the H-ESWT group. These results demonstrated that rESWT with 0.1 mJ/mm2 EFD improved some characteristics of the HS tissue. Downregulation of Smad3 expression may underlie this inhibitory effect. Inhibition of the TGF-beta1/Smad signal transduction pathway may be a potential therapeutic target for the management of HS. PMID- 29434690 TI - Changes in inflammatory factors and prognosis of patients complicated with non alcoholic fatty liver disease undergoing coronary artery bypass grafting. AB - This study was designed to assess the relationship between changes in peripheral inflammatory factors of patients complicated with non-alcoholic fatty liver disease (NAFLD) undergoing coronary artery bypass grafting (CABG) before and after operation, and their prognosis. A total of 68 patients with stable angina pectoris treated in Xinjiang Hospital who underwent CABG at some point between August of 2013 and August of 2015 were enrolled in the study, and divided into the NAFLD group (n=31) and the non-NAFLD group (n=37) according to the presence of the condition or its absence. Peripheral blood was drawn from the patients before and at 24 h and 1 month after the operation, and the expression levels of high-sensitivity C-reactive protein (hsCRP), soluble CD40 ligand (sCD40L), intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9) were measured via standard enzyme-linked immunosorbent assay. Our results showed the expression levels of hsCRP and sCD40L of patients in both groups reached a peak 24 h after operation; and there were statistically significant changes compared with the levels before the operation and at 1 month after operation (p<0.01). However, there were no statistically significant differences in the expression levels between the two groups (p>0.05). The expression levels of ICAM 1 at each time-point in both groups were increased after the operation, but the changes were not statistically significant (p>0.05). The expression levels of MMP 9 increased after the operation, and the levels at 1 month after operation were significantly higher than those before operation and at 24 h after the operation (p<0.01). Importantly, the expression levels of MMP-9 of patients in the NAFLD group at 1 month after operation were significantly higher than those of patients in the non-NAFLD group at the same time, and the differences were statistically significant (p<0.01). Finally, logistic regression analysis showed that the expression level of MMP-9 was an important influencing factor for cardiovascular events after CABG (OR=1.182, p<0.05). Based on our findings, the expression levels of inflammatory factors in peripheral blood in patients complicated with NAFLD undergoing CABG differ from those who are not complicated, and the MMP-9 levels may be closely related to the prognosis of patients complicated with NAFLD. PMID- 29434691 TI - 11beta-hydroxysteroid dehydrogenases as targets in the treatment of steroid associated femoral head necrosis using antler extract. AB - The aim of the present study was to investigate the therapeutic effect of deer antler extract on avascular necrosis of the femoral head (ANFH) induced by steroids, and to confirm that 11beta-hydroxysteroid dehydrogenases (11beta-HSD) are one of the targets of treatment with antler extract. A total of 30 rabbits were randomly divided into 5 groups (n=6): A control, ANFH, ANFH + antler (250 mg/kg), ANFH + antler (500 mg/kg) and ANFH + antler (1,000 mg/kg) group. Rabbits in the experimental groups were injected with methylprednisolone and horse serum to establish a steroid-induced ANFH (SANFH) model. Rabbits in the ANFH + antler (250 mg/kg), ANFH + antler (500 mg/kg) and ANFH + antler (1,000 mg/kg) groups were treated with intraperitoneal injection of 250, 500 or 1,000 mg/kg antler extract/day, respectively, for 60 days. Serum samples were then extracted to determine total cholesterol (CT) and triglyceride levels, treat osteoblasts, measure 11beta-HSD (11beta-HSD1) and 11beta-HSD2 and alkaline phosphatase (ALP) levels and cellular apoptosis, and determine the proportion of osteoblasts in each phase of the cell cycle. Serum CT and triglyceride levels in SANFH rabbits significantly decreased as the concentration of antler increased (P<0.05). 11beta HSD1 levels in the femoral heads of SANFH rabbits and osteoblasts following treatment with antler-containing serum decreased as the concentration of antler used increased, whereas levels of 11beta-HSD1 increased significantly (P<0.05). The proliferation of osteoblasts and ALP levels in osteoblasts increased as the antler concentration increased, whereas the number of osteoblasts in the G0/G1 phase decreased significantly (P<0.05). The current study demonstrated that treatment with antler extract has a therapeutic effect on ANFH induced by steroids in rabbits and may regulate the expression of 11beta-HSD in femoral heads and osteoblasts, as well as promoting the proliferation of osteoblasts. PMID- 29434692 TI - Gestational age, not transient hyperthyrotropinemia impacts brain white matter diffusion tensor imaging in premature infants. AB - Transient hypothyroidism is common in premature infants and increases the risk of adverse neurodevelopmental outcomes. Thyroid hormone (TH) is involved in oligodendrocyte development and myelination, however, whether transient hypothyroidism is associated with oligodendrocyte dysplasia and abnormal myelination is unclear. The aim of the present study was to investigate correlations among TH levels, neurodevelopmental outcomes and white matter (WM) microstructure in premature infants. The authors designed a cohort study recruiting 81 premature infants (age, 23-35 weeks). A total of 17 were born with a gestational age (GA) <30 weeks (early preterm group) and 64 of them were born with a GA >=30 weeks (late preterm group). For outcome measurement, thyroid stimulating hormone (TSH) levels at 0, 18, and 24 h of admission were measured. Neurodevelopmental outcomes were assessed using Bayley III test. Diffusion tensor imaging was used to explore the characterization of WM microstructure. The data demonstrated that GA, however not TSH level was associated with neurodevelopmental outcomes in the following 2 years. Fractional anisotrophy (FA) increased with TSH0 levels over anterior limb of internal capsule, while axial diffusivity decreased with TSH0 levels over splenium of corpus callosum (CC). The late preterm group had more intact WM integrity over the internal and external capsule (EC) in FA compared with the early preterm group. Infants with motor dysfunction had significantly increased mean diffusivity (MD) values at regions of interest in the genu and splenium of CC. The results of the present study demonstrated that GA, however not transient hypothyroidism influenced neurodevelopmental outcomes in the premature infants. FA increased with age in a regionally-specific manner over regions of the internal capsule and EC. MD may act as a potential predictor for motor function in premature babies. PMID- 29434693 TI - Overexpression of miR-130a-3p/301a-3p attenuates high glucose-induced MPC5 podocyte dysfunction through suppression of TNF-alpha signaling. AB - Tumor necrosis factor (TNF)-alpha has been reported to be important in glomerulonephritis, which is closely associated with podocyte dysfunction and apoptosis. However, the precise mechanisms by which TNF-alpha expression are regulated remain unclear. The purpose of the present study was to investigate the role of microRNA (miR)-130a-3p/301a-3p in the post-transcriptional control of TNF alpha expression and high glucose (HG)-induced podocyte dysfunction. Mice MPC5 podocytes were incubated with HG and transfected with miR-130a-3p/301a-3p mimics or inhibitors, reactive oxygen species (ROS) levels were measured by flow cytometry assay, and the mRNA and protein levels were assayed by using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The targeted genes were predicted by a bioinformatics algorithm and verified using a dual luciferase reporter assay. It was observed that miR-130a 3p/301a-3p was a novel regulator of TNF-alpha in mouse podocytes. miR-130a 3p/301a-3p mimics inhibited TNF-alpha 3'-untranslated region luciferase reporter activity, in addition to endogenous TNF-alpha protein expression. Furthermore, forced expression of miR-130a-3p or miR-301a-3p resulted in the downregulation of ROS and malondialdehyde (MDA) and the upregulation of superoxide dismutase (SOD) 1 in the presence of HG. Inhibition of TNF-alpha level prevented a remarkable reduction in SOD activity and a marked increase in ROS and MDA levels in HG treated podocytes. Furthermore, TNF-alpha loss-of-function significantly reversed HG-induced podocyte apoptosis. These data demonstrated a novel up-stream role for miR-130a-3p/301a-3p in TNF-alpha-mediated podocyte dysfunction and apoptosis in the presence of HG. PMID- 29434694 TI - Inhibition of miRNA-21 attenuates the proliferation and metastasis of human osteosarcoma by upregulating PTEN. AB - The present study aimed to investigate the expression of micro (mi)RNA-21 in osteosarcoma cells, and its role in inhibiting the invasion and metastasis of osteosarcoma. Human osteosarcoma MG-63 cells and osteoblast hFOB1.19 cells were used to compare the expression of miRNA-21 using reverse transcription quantitative polymerase chain reaction analysis. A miRNA-21 mimic or inhibitor were transfected into the MG-63 cells to upregulate and downregulate the expression of miRNA-21, respectively. The present study investigated the proliferation and invasion of transfected MG-63 cells using MTT and Transwell assays. Western blot analyses were used to investigate the regulation of important proteins in the phosphatase and tensin homolog/phosphoinositide 3 kinase/RAC-alpha serine/threonine-protein kinase (PTEN/PI3K/AKT) signaling pathway. Compared with hFOB1.19 cells, miRNA-21 expression was significantly upregulated in the MG-63 cells (P<0.01), which lead to increased proliferation. Downregulating miRNA-21 expression reduced the proliferation of MG-63 cells compared with hFOB1.19 cells. Invasion assays and western blot analyses revealed that the overexpression of miRNA-21 significantly enhanced the invasion ability of MG-63 cells and the expression of phosphorylated (p-)AKT, while downregulation of miRNA-21 expression reduced the protein level of AKT and p-AKT. In the MG-63 cells, miRNA-21 upregulation significantly inhibited the protein level of PTEN, resulting in significantly increased AKT and PI3K protein levels (P<0.01). In conclusion, the results of the present study indicate that the expression of miRNA-21, PI3K and AKT is increased in the osteosarcoma cell line MG-63, which results in reduced expression of PTEN and increased expression of proteins in the PI3K/AKT signaling pathway, and thus increases the aggressiveness of osteosarcoma cells. PMID- 29434695 TI - TCF4/beta-catenin complex is directly upstream of FGF21 in mouse stomach cancer cells. AB - Fibroblast growth factor 21 (FGF21) as a member of the FGFs serves a key role in glucose homeostasis and protection of the liver, heart, kidney and skin from damage as well as cancer cell development. In addition, transcription of FGF21 is sensitive to diverse damages; however, the role of the transcriptional regulator of FGF21 in cancer cells remains to be elucidated. FGFs were identified to have dominant expression in cancer cells; therefore, mouse forestomach carcinoma (MFC) cells were used in the present study, which is a mouse stomach cancer cell strain for identifying the FGF21 regulators. In promoter analysis of FGF21, the putative transcription factor 4 (TCF4) binding motifs (T/AC/GAAAG) were observed within 1.5 kb of the promoter region. Further chromatin immunoprecipitation and yeast one hybrid assays identified that TCF4 directly bound to one of the two putative binding motifs observed. A co-immunoprecipitation assay identified that beta catenin interacts with TCF4 in MFC cells, and the beta-catenin/TCF4 complex bound to the promoter of FGF21. In order to examine the function of TCF4 and beta catenin in transcriptional regulation of FGF21, TCF4 and beta-catenin was transiently expressed in MFC cells. Reverse transcription-quantitative polymerase chain reaction results revealed that overexpression of TCF4 and beta-catenin activated FGF21 transcription. Besides, suppression of beta-catenin via a specific short interfering RNA resulted in reduction of FGF21 expression. Together these findings suggest that the beta-catenin/TCF complex directly activates FGF21 via promoter binding. The observations of the present study may help elucidate the regulatory mechanism of FGF21, which is a key pharmaceutical protein. PMID- 29434696 TI - TMEM16A regulates portal vein smooth muscle cell proliferation in portal hypertension. AB - The aim of the present study was to elucidate the effect of transmembrane protein 16A (TMEM16A) on portal vein smooth muscle cell (PVSMC) proliferation associated with portal vein remodeling in portal hypertension (PHT). Sprague-Dawley rats were subjected to bile duct ligation to establish a rat model of liver cirrhosis and PHT. Sham-operated animals served as controls. At 8 weeks after bile duct ligation, the extent of liver fibrosis and the portal vein wall thickness were assessed using hematoxylin-eosin staining. The protein expression levels of TMEM16A, extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2) in the portal vein were detected by immunohistochemistry and western blotting. In vitro, the lentivirus vectors were constructed and transfected into PVSMCs to upregulate the expression of TMEM16A. Isolated rat primary PVSMCs were treated with a small molecule inhibitor of TMEM16A, T16A-inhA01. Cell cycle was detected by flow cytometry. The activity of TMEM16A in the portal vein isolated from bile duct ligated rats was decreased, while the expression level of p-ERK1/2 was increased. However, in vitro, upregulation of TMEM16A promoted the proliferation PVSMCs, while inhibition of TMEM16A channels inhibited the proliferation of PVSMCs. The results indicated that TMEM16A contributes to PVSMCs proliferation in vitro, but in vivo, it may be a negative regulator of cell proliferation influenced by numerous factors. PMID- 29434697 TI - Genistein inhibits the S-phase kinase-associated protein 2 expression in breast cancer cells. AB - Breast cancer is one of the most lethal cancers affecting women worldwide and was estimated to account for ~30% of all new cancer diagnoses in women. Although available evidence has proved the tumor suppressor role of genistein in cancer, the underling mechanisms have remained to be fully elucidated. S-phase kinase associated protein 2 (Skp2) has been revealed to critically enhance the pathogenesis of multiple human cancers. The present study determined whether genistein exerts its anti-tumor function by suppressing Skp2 in breast cancer cells. Genistein significantly inhibited the proliferation, invasion and migration of breast cancer cells. Furthermore, genistein treatment also induced marked apoptosis and a typical cell cycle arrest in G2/M phase. Mechanistically, genistein treatment was identified to cause a significant downregulation of Skp2. Two crucial tumor suppressors, p21 and p27, were upregulated in genistein-treated breast cancer cells. The present results revealed that genistein exerted its tumor suppressor effect at least partially via inhibition of Skp2 and promotion of its downstream targets p21 and p27. Therefore, inactivation of Skp2 by genistein may be a promising approach for breast cancer treatment. PMID- 29434699 TI - Neuroprotective effect of (-)-epigallocatechin-3-gallate on autoimmune thyroiditis in a rat model by an anti-inflammation effect, anti-apoptosis and inhibition of TRAIL signaling pathway. AB - (-)-Epigallocatechin-3-gallate (EGCG) is a polyphenol monomer compound extracted and separated from green tea, and is a key catechin in green tea. Recent research has identified that EGCG is equipped with important biological activities, including antitumor, antioxidant, anti-inflammation, blood fat reduction and radiation protection abilities. In the current study, it was investigated whether EGCG exerts a neuroprotective effect on AIT and examined the possible underlying mechanism. The present study sought to establish an experimental autoimmune thyroiditis (AIT) rat model and to investigate the neuroprotective effect of EGCG in this model. EGCG was demonstrated to inhibit urinary iodine values and thyroid pathological features in AIT model rats. Treatment with EGCG significantly reduced interleukin-1beta, interferon-gamma (INF-gamma) and tumor necrosis factor alpha (TNF-alpha) levels in the AIT rats through suppression of nuclear factor kappaB (NF-kappaB) pathway. In addition, pretreatment with EGCG significantly increased B-cell lymphoma-2 protein expression, and suppressed caspase-3 activity and TNF-alpha-related apoptosis-inducing ligand (TRAIL) protein expression levels in the AIT model rats. In conclusion, these results suggested that the neuroprotective effect of EGCG protects against AIT through its anti-inflammatory ability, anti-apoptosis and TRAIL signaling pathway in model rats, and it may be used as a therapeutic agent against AIT caused by inflammation. PMID- 29434698 TI - Effect of Clostridium butyricum supplementation on the development of intestinal flora and the immune system of neonatal mice. AB - The objective of the present study was to examine whether Clostridium butyricum supplementation has a role in the regulation of the intestinal flora and the development of the immune system of neonatal mice. A total of 30 pregnant BALB/c mice, including their offspring, were randomly divided into three groups: In the maternal intervention group (Ba), maternal mice were treated with Clostridium butyricum from birth until weaning at postnatal day 21 (PD21) followed by administration of saline to the offspring at PD21-28; in the offspring intervention group (Ab), breast-feeding maternal mice were supplemented with saline and offspring were directly supplemented with Clostridium butyricum from PD21-28; in the both maternal and offspring intervention group (Bb), both maternal mice and offspring were supplemented with Clostridium butyricum at PD 0 21 and at PD21-28. While mice in the control group were given the same volume of normal saline. Stool samples from the offspring were collected at PD14, -21 and 28 to observe the intestinal flora by colony counts of Enterococcus spp., Enterobacter spp., Bifidobacterium spp. and Lactobacillus spp. Detection of intestinal secreted immunoglobulin A (sIgA) levels and serum cytokine (interferon gamma, and interleukin-12, -4 and -10) levels in offspring was performed to evaluate the effect on their immune system. The results revealed that compared with the control group, offspring in the Ba group displayed significantly decreased stool colony counts of Enterococcus spp. (t=3.123, P<0.01) at PD14 and significantly decreased counts of Enterobacter spp. at PD14 and -21 (t=2.563, P<0.05 and t=2.292, P<0.05, respectively). Compared with the control group, the stool colony counts of Bifidobacterium spp. and Lactobacillus spp. were significantly increased in the Ba group at PD21 (t=3.085, P<0.01 and t=2.8508, P<0.05, respectively). The Ab group had significantly higher stool colony counts of Bifidobacterium spp. and Lactobacillus spp. at PD28, compared with the control group (Q=7.679, P<0.01 and Q=6.149, P<0.01, respectively). There were no significant differences identified in the sIgA levels of the intestinal fluid and serum cytokine levels between the control group and the intervention groups. In conclusion, Clostridium butyricum administered to breast-feeding maternal mice was able to regulate the intestinal flora balance in their offspring. However, due to insignificant effects on sIgA level and the associated cytokines, Clostridium butyricum had a limited influence on the balance of type 1 vs. type 2 T-helper cells. However, using Clostridium butyricum as an invention may be a safe method for improving the balance of intestinal flora and associated processes in offspring. PMID- 29434700 TI - Distinct magnetic resonance imaging features in a patient with novel RARS2 mutations: A case report and review of the literature. AB - Pontocerebellar hypoplasia type 6 (PCH6) is a rare autosomal recessive disease that occurs due to mutations in the mitochondrial arginyl-tRNA synthetase 2 (RARS2) gene. To the best of our knowledge, 23 cases with relatively complete clinical data have been reported thus far. In the present study, a case with PCH6 caused by novel RARS2 mutations is described, in which distinct magnetic resonance imaging (MRI) features were identified. In addition, 23 PCH6 cases found in the literature were reviewed. Early onset hypotonia (43.48%), epileptic seizures (34.78%), encephalopathy (26.08%) and feeding difficulties (17.39%) were common initial symptoms of PCH6. During disease progression, the patients presented refractory epileptic seizures (94.12%), feeding problems (60.87%), severe developmental delay (100%), microcephaly (88.89%) and hyperlactacidemia (76.47%). The clinical features of the present patient were suggestive of PCH6, with early onset epilepsy, feeding difficulties, severe developmental delay, microcephaly, hearing loss and hyperlactacidemia. According to available MRI data from 20 reported cases with PCH6, the characteristic finding in MRI was pontocerebellar dysplasia or progressive cerebral/pontocerebellar atrophy in 16 cases, while 4 cases did not present pontocerebellar hypoplasia, and no basal ganglia involvement was observed in any of the cases. Distinctive MRI features were also identified in the present case, including pontocerebellar preservation after 1 year of age, as well as a high diffusion-weighted imaging signal suggesting intracellular edema in the cerebellar hemispheres, basal ganglia, thalamus and corpus callosum. Progressive loss of cerebral white matter and cortical volume were common features shared by all patients. In conclusion, in the present study, two novel heterozygous mutations were identified in RARS2, namely c.1718C>T(p.Thr573Ile) and c.991A>G (p.Ile331Val). Thus, the present case enriched the phenotypic and genotypic spectrum of the RARS2 mutations. PMID- 29434701 TI - HIPK2 inhibits cell metastasis and improves chemosensitivity in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive and lethal malignancies worldwide. At present, the underlying mechanisms of ESCC development and progression are poorly understood. Previous studies have demonstrated that homeodomain-interacting protein kinase-2 (HIPK2) serves an important role in cancer biology, particularly in proliferation and metastasis. However, the role of HIPK2 in ESCC cells remains unclear. In the current study, the expression of HIPK2 in ESCC specimens, adjacent non-cancerous tissues and cell lines was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The effects of HIPK2 on cell metastasis, epithelial mesenchymal transition (EMT) and proliferation were studied using a Transwell assay, RT-qPCR and a Cell Counting Kit-8 assay, respectively. The results indicated that HIPK2 expression was downregulated in ESCC specimens and cell lines, and HIPK2 expression was associated with tumor invasion and lymph node metastasis. Functional studies demonstrated that HIPK2 overexpression inhibited cell metastasis and EMT. Furthermore, HIPK2 overexpression suppressed cell viability during cisplatin treatment. These results suggest that HIPK2 serves an important role in regulating metastasis and the chemosensitivity of ESCC cells, implicating the potential application of HIPK2 in ESCC therapy. PMID- 29434702 TI - miR-4262 regulates chondrocyte viability, apoptosis, autophagy by targeting SIRT1 and activating PI3K/AKT/mTOR signaling pathway in rats with osteoarthritis. AB - The present study aimed to investigate the effect and underlying mechanism of microRNA (miR)-4262 in the development of osteoarthritis (OA) in rats. Primary chondrocytes were separated from Sprague-Dawley rats and then treated with tumor necrosis factor-alpha (TNF-alpha). The level of miR-4262 was detected in TNF alpha-treated chondrocytes, and then the miR-4262 or its target gene sirtuin type 1 (SIRT1) level was overexpressed, or knocked down. Furthermore, cell viability, cell apoptosis, cell autophagy and matrix synthesis, as well as the expressions of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway were detected. miR 4262 was significantly overexpressed in TNF-alpha-treated chondrocytes compared with untreated cells (P<0.05). TNF-alpha treatment or miR-4262 overexpression significantly decreased cell viability, autophagy-related proteins levels and matrix synthesis-related proteins levels, as well as increased the apoptotic rate in chondrocytes (P<0.05). Overexpression of SIRT1 significantly increased cell viability, autophagy-related proteins levels and matrix synthesis-related proteins levels, as well as decreased the apoptotic rate in TNF-alpha-treated chondrocytes (P<0.05). In addition, the effects of miR-4262 on cell viability, cell apoptosis, cell autophagy and matrix synthesis were inhibited by SIRT1 (P<0.05). Furthermore, upregulated miR-4262 remarkably increased the expressions of phosphorylated (p)-PI3K, p-AKT and p-mTOR (P<0.05) in TNF-alpha treated chondrocytes. The present study revealed that the upregulation of miR-4262 may promote the occurrence and development of OA in rats by regulating cell viability, cell apoptosis, cell autophagy, and matrix synthesis. Furthermore, these roles of miR-4262 may be associated with PI3K/AKT/mTOR signaling pathway. PMID- 29434703 TI - MicroRNA-495 suppresses cell proliferation and invasion of hepatocellular carcinoma by directly targeting insulin-like growth factor receptor-1. AB - Hepatocellular carcinoma (HCC) is the fifth most common malignancy and second most frequent cause of cancer-associated deaths worldwide. Previously, increasing studies report that microRNAs (miRNAs/miRs) are abnormally expressed in various types of human cancers and may participate in the tumourigenesis and tumour development of HCC. miRNA-based targeted therapy is effective against different molecular targets and may increase the sensitisation of cancer cells to therapy by several folds. Therefore, further validation of potentially important miRNAs involved in HCC initiation and progression may provide valuable insights into the treatment of patients with HCC. miR-495 is abnormally expressed in multiple types of human cancers. However, the expression level and roles of miR-495 in HCC have yet to be completely elucidated. In the present study, miR-495 expression was frequently downregulated in HCC tissues and cell lines, and miR-495 expression levels were significantly correlated with tumour size, tumor-node-metastasis (TNM) stage and lymph node metastasis in patients with HCC. Functional assays revealed that miR-495 overexpression inhibited cell proliferation and invasion in HCC. Insulin-like growth factor receptor-1 (IGF1R) was identified as a direct target gene of miR-495 in HCC. IGF1R was upregulated in HCC tissues and negatively correlated with miR-495 expression level. The upregulation of IGF1R rescued the miR-495-induced tumour-suppressive roles in HCC cell proliferation and invasion, and the restored miR-495 expression inactivated the protein kinase B and extracellular regulated protein kinase signalling pathways in HCC. These results provide novel insights into the molecular mechanism underlying HCC progression, and suggest that miR-495 may be investigated as a novel therapeutic target for patients with this disease. PMID- 29434705 TI - Identification of a progression-associated long non-coding RNA signature for predicting the prognosis of lung squamous cell carcinoma. AB - Long non-coding RNAs (lncRNAs) have been indicated to have prognostic roles in various cancer types. However, the association between lncRNAs and lung squamous cell carcinoma (LSCC) progression, and the prognostic value of lncRNAs as a marker for early detection of LSCC have not been systematically investigated. The present study performed a genome-wide comparative analysis in order to determine the expression profiles of 10,207 lncRNAs to investigate the expression patterns between patients with early stages of LSCC (stage I-II) and those with late-stage disease (stage III-IV). It was found that 114 lncRNAs were significantly differentially expressed between late- and early-stage LSCC and therefore associated with the progression of the malignancy. By focusing on progression associated lncRNAs, eight lncRNAs were found to be significantly associated with overall survival of LSCC patients according to univariate Cox proportional hazards regression analysis. These eight prognostic lncRNAs were integrated into a progression-associated eight-lncRNA signature, which stratified patients into two groups with significantly different overall survival (median survival, 2.25 vs. 7.68 years; P=2.06*10-5). In addition, the prognostic value of the progression-associated eight-lncRNA signature was independent of known clinical factors. Functional analysis suggested that eight prognostic lncRNAs may be involved in adipocytokine signaling pathway and glycerophospholipid metabolism. Taken together, the progression-associated eight-lncRNA signature identified by our study not only represents a candidate prognostic biomarker for LSCC patients but also provides insight into the molecular mechanisms in the progression of LSCC. PMID- 29434704 TI - Implications of dietary omega-3 and omega-6 polyunsaturated fatty acids in breast cancer. AB - Breast cancer represents one of the most common forms of cancer in women worldwide, with an increase in the number of newly diagnosed patients in the last decade. The role of fatty acids, particularly of a diet rich in omega-3 and omega 6 polyunsaturated fatty acids (PUFAs), in breast cancer development is not fully understood and remains controversial due to their complex mechanism of action. However, a large number of animal models and cell culture studies have demonstrated that high levels of omega-3 PUFAs have an inhibitory role in the development and progression of breast cancer, compared to omega-6 PUFAs. The present review focused on recent studies regarding the correlation between dietary PUFAs and breast cancer development, and aimed to emphasize the main molecular mechanisms involved in the modification of cell membrane structure and function, modulation of signal transduction pathways, gene expression regulation, and antiangiogenic and antimetastatic effects. Furthermore, the anticancer role of omega-3 PUFAs through the modulation of microRNA expression levels was also reviewed. PMID- 29434706 TI - PTX3 in serum induces renal mesangial cell proliferation but has no effect on apoptosis. AB - The present study aimed to investigate the effect of pentraxin 3 (PTX3) on the regulation of proliferation and apoptosis in human glomerular mesangial cells (HMCs). Small interfering (si)RNA was designed and synthesized to inhibit the expression of endogenous PTX3, and the effects on the proliferation and apoptosis of HMCs were detected by flow cytometry and an MTT assay. Western blot analysis was used to detect the activation of mitogen-activated protein kinase (MAPK) proteins in HMCs with PTX3 knockdown. Three siRNAs targeting PTX3 were individually transfected into HMCs for 48 h, and reverse-transcription quantitative PCR demonstrated that the relative mRNA expression of PTX3 was significantly decreased in all groups by up to 79.62% of that in the control group (P<0.05). Following transfection with PTX3-siRNA, the viability of an HMC line was significantly decreased in comparison with that of a control group transfected with scrambled siRNA. However, PTX3-siRNA did not significantly effect early and late apoptotic cell populations in HMCs compared with those in the control. Endogenous PTX3 interference was found to significantly decrease p38 MAPK, extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase phosphorylation. In conclusion, silencing of PTX3, inhibited the proliferation of HMCs via MAPK pathways, but exerted no effect on the apoptosis of HMCs. PMID- 29434707 TI - Leuconostoc pseudomesenteroides-associated hemophagocytic syndrome: A case report. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome characterized by fever, pancytopenia and splenomegaly. The underlying hemophagocytosis occurs primarily in the bone marrow, liver and lymph nodes. Multiple microbiological agents, including cytomegalovirus, Epstein-Barr virus and Mycobacterium tuberculosis, have been implicated in the pathogenesis of HLH. The present study presents a case of HLH associated with Leuconostoc pseudomesenteroides infection treated successfully with clindamycin. A 33-year old man presented with recurrent episodes of fever and diarrhea. Upon initial treatment at another hospital (the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China), blood chemistry analysis demonstrated moderate anemia (hemoglobin 88 g/l; reference range, 120.0-160.0), elevated ferritin (1,068.47 mg/l; reference range, 21.81-274.66), total bilirubin (392.4 mmol/l; reference range, 5.1-28.0), conjugated bilirubin (335.7 mmol/l; reference range, 0-10.0), and gamma-glutamyl transpeptidase (150 U/l; reference range, 10-60). The patient was treated with antibiotics for suspected pneumonia and cholecystitis, but new symptoms (including diarrhea and inflammatory colitis) started to emerge. The patient was subsequently treated with ganciclovir (5 mg/kg/day for 1 month), but body temperature increased to 41.0 degrees C. Upon transferring to our hospital, the patient had severe anemia (hemoglobin, 39 g/l; red blood cell, 1.61*1012/l; reference range, 4.0-5.5*1012/l). Jaundice was apparent: Total bilirubin, 299.5 mmol/l; conjugated bilirubin, 215.7 mmol/l. The patient was treated with clindamycin (150 mg, taken orally every 12 h for 1 week) and supportive care that included parenteral nutrition. Symptoms rapidly dissipated after the treatment. Blood chemistry analysis 5 days after the first dose of clindamycin revealed substantial improvement in anemia and jaundice. The patient requested discharge for financial reasons, but continued treatment (details not available) at a local hospital (Pengpai Memorial Hospital, Shanwei, China). Upon a visit to our hospital 8 months later, the patient has no notable complaints, with the exception of moderate anemia. The present case suggests that HLH may be associated with L. pseudomesenteroides infection. PMID- 29434708 TI - Research of Mrr1, Cap1 and MDR1 in Candida albicans resistant to azole medications. AB - The aim of the present study was to investigate the association between Mrr1, adenylyl cyclase-associated protein 1 (Cap1) and multi-drug resistance gene 1 (MDR1), and to assess the mutations in Mrr1 and Cap1 in azole-resistant Candida albicans strains. The study isolated 68 C. albicans strains from patients with vulvovaginal candidiasis. Drug susceptibility testing was conducted to characterize the resistance profile of these strains to fluconazole, itraconazole and voriconazole. Polymerase chain reaction (PCR) amplification was performed for Cap1 and Mrr1, and the PCR products were sequenced to identify any mutations. Reverse transcription-quantitative PCR was performed to measure Cap1, Mrr1 and MDR1 mRNA in C. albicans strains. The results of the present study indicated S381N, P311S and A390T missense mutations in Cap1 and T917M, T923I, N937K, E1020Q, F1032L and S1037L missense mutations in Mrr1 in azole-resistant C. albicans strains. Fluconazole-resistant strains had significantly elevated Cap1 and MDR1 mRNA levels compared with fluconazole-sensitive strains (P<0.01). The mRNA levels of Cap1, Mrr1 and MDR1 were significantly increased in the strains resistant to all three of fluconazole, itraconazole and voriconazole compared with strains sensitive to the three agents (P<0.001, P=0.037 and P<0.001, respectively). Cap1 expression was positively correlated with MDR1 expression in fluconazole-resistant strains (P<0.05). No significant correlation was observed between Cap1, Mrr1 and MDR1 in the strains resistant to fluconazole, itraconazole or voriconazole. The results of the present study suggested that fluconazole resistance may involve MDR1 overexpression mediated by Cap1 overexpression. Cross resistance between fluconazole, itraconazole and voriconazole may be associated with mutations in Cap1 and Mrr1, rather than their overexpression. In addition, the present study also revealed two novel mutations in Mrr1; T917M and T923I. These findings may provide a basis for elucidating the molecular mechanisms of and improving therapeutic treatments to tackle azole resistance. PMID- 29434709 TI - Effects of silibinin-loaded thermosensitive liposome-microbubble complex on inhibiting rabbit liver VX2 tumors in sub-hyperthermia fields. AB - In the present study, the effects of silibinin-loaded thermosensitive liposome microbubble complex (STLMC) on rabbit liver VX2 tumors in sub-hyperthermia fields were investigated using two-dimensional ultrasonography (2D US), contrast enhanced US (CEUS), hematoxylin and eosin (H&E) staining, immunohistochemistry and ultrastructure observation. 50 rabbits with VX2 liver tumors were divided into five groups: Sub-hyperthermia microwave ablation group (SHM), STLMC injection group (STLMC), SHM ablation plus STLMC injection group (SHM + STLMC), microbubble injection group and blank control group without any treatment. Rabbits in each group were examined using 2D US and CEUS in order to evaluate the tumor volume and diameter before treatment and at day 7 and 21 after treatment. Morphology, expression of CD163 and CD206, and ultrastructure of the tumors were assessed. The average post-treatment volume of tumors in group SHM + STLMC was 1.17+/-0.88 cm3 at day 7 and 2.15+/-0.96 cm3 at day 21, which was significantly decreased compared with all other groups (P<0.05). H&E staining indicated that the number of disordered macrophages in the SHM + STLMC group significantly increased compared with the other groups (P<0.05). Immunohistochemical results demonstrated that in the SHM + STLMC, the expression of CD163 and CD206 significantly decreased compared with all other groups (P<0.05). These results suggested that STLMC has a potential function in preventing tumor growth, which may be due to its inhibitory effect on tumor-associated macrophages in the tumor microenvironment. PMID- 29434710 TI - Assessment of dermal papillary and microvascular parameters in psoriasis vulgaris using in vivo reflectance confocal microscopy. AB - In vivo reflectance confocal microscopy (RCM) is a modern, non-invasive imaging technique, which allows for real-time examination of the upper layers of the skin at a resolution similar to that of classic microscopy. In addition, it has the advantage of real-time evaluation of blood flow and dynamic monitoring of cutaneous changes while preserving tissue integrity. The present study reported on the in vivo RCM technique as an objective method for the noninvasive assessment of psoriasis vulgaris that is potentially applicable in clinical studies and in monitoring the evolution of lesions under treatment. In psoriasis lesions, RCM virtual horizontal sections at the level of the dermo-epidermal junction featured numerous and prominent dermal papillae that were not surrounded by bright rings of basal cells. Micromorphological examination of the lesions using this technique revealed that mean values of the section area, the perimeter and the Feret's diameter of the dermal papillae were significantly higher in psoriatic lesions than in normal skin. An increased number of capillary vessels per lesional dermal papilla as compared to healthy skin was observed. Furthermore, micromorphological parameters of dermal capillaries were increased in psoriatic skin. These observations point to the utility of in vivo RCM as a promising technique for the non-invasive diagnosis of psoriasis vulgaris, for monitoring the evolution of lesions at a micromorphological level under various treatments and for gaining a better understanding of the pathophysiological processes that occur in the evolution of this disease. PMID- 29434711 TI - Endoscopic management of foreign bodies in the upper gastrointestinal tract: An analysis of 846 cases in China. AB - Foreign body ingestion is a relatively common occurrence, which may lead to morbidity and mortality. The aim of the present study was to report the experience of management of upper gastrointestinal foreign bodies by endoscopy in a large center. All patients who presented at the Department of Gastroenterology at Nanfang Hospital (Guangzhou, China) with complaints regarding upper gastrointestinal (GI) foreign body ingestion from December 1987 to December 2013. Hospital medical charts and endoscopic records were examined to evaluate etiology, treatment, and outcomes for these patients. A total of 846 patients were enrolled in the present study, from which foreign bodies were detected in 737 (87.1%) patients via X-ray or endoscopy. The objects most frequently ingested were bones (n=395, 53.6%). The detected foreign bodies were predominantly located in the cervical esophagus (n=325, 44.1%). Endoscopic foreign body extraction was successful in 92.5% of cases, whereas surgery was required in 6 patients. The most frequently used endoscopic accessory devices were retrieval forceps (n=480, 65.1%). The complication rate was 6.9%, including mucosal laceration (n=10) and others, all of which were managed conservatively. Associated GI diseases were reported in 74 (10.0%) patients, including postesophagectomy (n=34) and others. In conclusion, the endoscopic procedure was safe and effective for the removal of foreign bodies from the upper gastrointestinal tract, with a high success rate and low complication rate. PMID- 29434712 TI - Function and mechanism of microRNA-210 in acute cerebral infarction. AB - Acute cerebral infarction (ACI) is a common cerebrovascular disease. Previous studies have indicated that microRNAs (miRs) are aberrantly expressed in patients with ACI. However, the functions of miRs in the pathogenesis of ACI still require further investigation. The aim of the present study was to investigate the function of miR-210 in ACI and its associated mechanism. The expression of miR 210 in the serum of 40 patients with ACI and 40 normal controls was examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Then, human umbilical vein endothelial cells (HUVECs) were treated with serum from patients with ACI or healthy volunteers, and a CCK-8 assay was performed to examine cell proliferation. Next, cells were stained with PI/Annexin V, and the apoptosis rate was examined using flow cytometry. Furthermore, cells were harvested and lysed, and RT-qPCR and western blotting assays were performed to compare the expression of vascular endothelial growth factor (VEGF), Notch1 and Hes1 in different groups. It was observed that the expression of miR-210 was significantly increased in the serum of patients with ACI compared with normal controls (P<0.01), and receiver operating characteristic curve analysis indicated that the area under the curve for miR-210 was 0.799 (95% confidence interval, 0.700-0.899), the optimum cut-off point was 1.397, and the sensitivity and specificity at the cut-off point were 62.5 and 87.5%, respectively. Furthermore, serum from patients with ACI induced a significant increase in proliferation (P<0.05 at 48 h, P<0.01 at 72 h) and a significant decrease in the apoptosis rate of HUVECs (P<0.01). In addition, serum from patients with ACI significantly increased the expression of VEGF, Notch1 and Hes1 at the mRNA and protein level (all P<0.01 with the exception of Notch1 mRNA expression, P>0.05). In conclusion, these results demonstrate that miR-210 is upregulated in the serum of patients with ACI, and miR-210 may be involved in the pathogenesis of ACI through regulating the proliferation and apoptosis of endothelial cells. PMID- 29434713 TI - Paclitaxel inhibits breast cancer metastasis via suppression of Aurora kinase mediated cofilin-1 activity. AB - The main problem in breast cancer treatment is the recurrence of tumor growth and metastases. Previous studies have suggested that Paclitaxel is widely used to treat various cancers. The present study analyzed the potential signaling pathway of Paclitaxel-inhibited breast cancer metastasis. It was demonstrated that Paclitaxel treatment significantly inhibited growth of breast cancer cell lines including MCF-7 and SKBR3 cells. Results demonstrated that Paclitaxel significantly inhibited breast cancer cell migration and invasion. Results additionally demonstrated that Paclitaxel treatment suppressed Aurora kinase and cofilin-1 activity in breast cancer cells. The potential mechanism indicated that activation of Aurora kinase activity stimulated cofilin-1 activity, which canceled Paclitaxel-inhibited growth and aggressiveness of breast cancer cells. An in vivo assay revealed that Paclitaxel treatment significantly inhibited breast cancer growth. Immunohistochemistry demonstrated that Paclitaxel treatment increased apoptosis of tumor cells in tumor tissue. Notably, Aurora kinase and cofilin-1 activity were downregulated by Paclitaxel in tumor tissues. In conclusion, these results indicated that Paclitaxel inhibited breast cancer cell growth and metastasis via suppression of Aurora kinase-mediated cofilin-1 activity, suggesting Paclitaxel may be an efficient anticancer agent for the treatment of this disease. PMID- 29434714 TI - 20(S)-Protopanaxadiol induces apoptosis in human hepatoblastoma HepG2 cells by downregulating the protein kinase B signaling pathway. AB - Hepatoblastoma is the most common primary liver tumor for children aged <5 years old. 20(S)-Protopanaxadiol (PPD) is a ginsenoside extracted from Pananx quinquefolium L., which inhibits tumor growth in several cancer cell lines. The purpose of the present study was to assess the anticancer activities of 20(S)-PPD in human hepatoblastoma HepG2 cells. The cytotoxicity of 20(S)-PPD on HepG2 cells was evaluated using an MTT assay. Apoptosis was detected using DAPI staining and flow cytometry. The expression of apoptosis-associated proteins was identified by western blotting. The results demonstrated that 20(S)-PPD inhibited the viability of HepG2 cell in a dose and time-dependent manner. The IC50 values were 81.35, 73.5, 48.79 uM at 24, 48 and 72 h, respectively. Topical morphological changes of apoptotic body formation following 20(S)-PPD treatment were detected by DAPI staining. The percentage of Annexin V-fluoroscein isothyiocyanate positive cells were 3.73, 17.61, 23.44 and 65.43% in HepG2 cells treated with 0, 40, 50 and 60 uM of 20(S)-PPD, respectively. Furthermore, 20(S)-PPD upregulated the expression of Bax and downregulated the expression of Bcl-2 and also activated caspases-3 and -9, and Poly [ADP-ribose] polymerase cleavage. In addition, 20(S)-PPD inhibited the phosphorylation of protein kinase B (Akt; Ser473). The results indicate that 20(S)-PPD inhibits the viability of HepG2 cells and induces apoptosis in HepG2 cells by inhibiting the phosphoinositide-3-kinase/Akt pathway. PMID- 29434715 TI - Relationship between osteoporosis and expression of Bcl-2 and CXCL12. AB - The changes of expression of anti-apoptotic factor B-cell lymphoma 2 (Bcl-2) and chemokine C-X-C motif ligand 12 (CXCL12) in the pathological process of osteoporosis (OP) were investigated, to provide new ideas for the diagnosis and treatment of OP. A total of 60 postmenopausal women who needed to undergo hip replacement surgery were enrolled and divided into osteoporosis group (OP, n=32) and control group (CK, n=28) according to the results of dual-energy X-ray bone density measure; after operation, cancellousbone from the femoral head or femoral neck was removed, and osteoblasts and osteoclasts were isolated and cultured in vitro. The proliferation and apoptosis in the two groups of osteoblasts and osteoclasts were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetry and Annexin V/PI double staining method, respectively. The expression levels of Bcl-2 and CXCL12 mRNA and protein in the two groups of osteoblasts and osteoclasts were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The analysis of cell proliferation and apoptosis showed that compared with the CK group, osteoblast proliferation was significantly inhibited and apoptosis rate was distinctly increased in the OP group, compared with the CK group, osteoclast proliferation was distinctly enhanced and apoptosis rate was remarkably reduced in the OP group. The results of RT-qPCR and western blot analysis displayed that Bcl-2 and CXCL12 mRNA and protein levels in osteoblasts of the OP group were significantly lower than those of the CK group, while mRNA and protein levels of Bcl-2 and CXCL12 in osteoclast of the OP group were distinctly increased compared to those in the CK group. The incidence of OP is closely associated with the bone balance maintained by osteoblasts and osteoclasts, and this mechanism may be achieved by inhibiting osteoblast proliferation and osteoclast apoptosis via regulating Bcl-2 and CXCL12 gene expression changes. PMID- 29434716 TI - alpha-thalassaemia combined with hereditary spherocytosis in the same patient. AB - A family of four from the Guangxi Zhuang Autonomous Region of China, including a child with alpha-thalassaemia and hereditary spherocytosis (HS), underwent laboratory identification, and genetic analysis. After harvesting peripheral blood samples from the child patient and his family members, GAP-polymerase chain reaction (PCR) and reverse dot-blot tests were used to identify thalassaemia genotypes. After amplifying exons and the adjacent introns of solute carrier family 4 member 1 (Diego blood group) (SLC4A1), ankyrin 1, spectrin alpha erythrocytic 1, spectrin beta erythrocytic and erythrocyte membrane protein band 4.2 by PCR, DNA sequencing was utilised to detect gene mutations of HS. The thalassaemia gene of the child patient was -alpha3.7/alphaalpha and identical to the genotype of his mother. DNA testing of HS identified two mutation sites on the SLC4A1 gene: Exon 3 c.113A>C (Asp 38 Ala) and intron 7 c.609+86G>A. The father and older sister of the patient also had the same mutations. Due to the mutual interference with disorders of haemoglobin synthesis and erythrocyte membrane defects of laboratory results, it is difficult to diagnose HS when it coexists with thalassaemia. When clinical manifestations and laboratory results cannot be explained by a single haemolytic anaemia, the possibility of combining with another haemolytic anaemia should be considered. Thus, it is necessary to perform pedigree investigation and genetic analyses for a final diagnosis. PMID- 29434717 TI - Efficacy of thermosensitive chitosan/beta-glycerophosphate hydrogel loaded with beta-cyclodextrin-curcumin for the treatment of cutaneous wound infection in rats. AB - Wound infection has been a persistent problem that is common and costly. Thermosensitive hydrogel has been demonstrated to be a suitable dressing candidate due to its high moldability, easy administration and ability to maintain a moist topical environment at the wound bed. In the present study, a novel thermosensitive hydrogel was successfully prepared and characterized to have a porous inner structure and a sustained curcumin-releasing profile. The wound healing ability of the hydrogel was investigated in a wound infection model in rats. On analysis, it was observed that the hydrogel complex-dressed wounds exhibited a faster wound closure rate compared with gauze-covered wounds, which was paralleled with improved histological outcomes that were observed. Additionally, the results of in vitro antimicrobial, anti-oxidant, western blot analysis and reverse transcription-quantitative polymerase chain reaction assays indicated that the hydrogel complex had distinct anti-oxidative, antimicrobial and anti-nuclear factor-kappaB-signaling capacities. These results suggest that this novel hydrogel may be a suitable candidate for facilitating the healing of infected cutaneous wounds in rats. PMID- 29434718 TI - Farnesyltransferase inhibitors prevent HIV protease inhibitor (lopinavir/ritonavir)-induced lipodystrophy and metabolic syndrome in mice. AB - Highly active antiretroviral therapy (HAART) has successfully reduced the mortality rate of patients with human immune deficiency virus (HIV) and HIV protease inhibitors (HIV PIs) are key components of HAART. Complications of HAART, particularly those associated with HIV PIs including lipodystrophy and metabolic disturbance, have emerged as an important public health issue. No specific treatment is available to prevent and/or treat HIV PI-associated lipodystrophy and metabolic syndrome. The present study demonstrated that a relatively low-dose of farnesyltransferase inhibitor (FTI), tipifarnib (3 mg/kg/day, subcutaneous injection) and lonafarnib (5 mg/kg/day, subcutaneous injection), prevented the onset of lipodystrophy and metabolic syndrome induced by the combination of two HIV PIs, lopinavir (50 mg/kg/day, intraperitoneal injection) and ritonavir (12.5 mg/kg/day, intraperitoneal injection), in mice. Consistent with previous studies, treatment with lopinavir/ritonavir for 2 weeks decreased body weight, adipose tissue mass, levels of plasma adiponectin and leptin, and increased plasma levels of triglycerides, total cholesterol and insulin. Tipifarnib and lonafarnb prevented or ameliorated all of these alterations in the HIV PI-treated mice. These data identify FTIs as a novel potential strategy to prevent or treat HIV PI-associated lipodystrophy and metabolic syndrome in HIV-infected patients on HAART. PMID- 29434719 TI - AG490 ameliorates early brain injury via inhibition of JAK2/STAT3-mediated regulation of HMGB1 in subarachnoid hemorrhage. AB - High mobility group box 1 (HMGB1) is a classic damage-associated molecular pattern that has an important role in the pathological inflammatory response. In vitro studies have demonstrated that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is involved in the regulation of HMGB1 expression, mediating the inflammatory response. Therefore, the purpose of the present study was to evaluate JAK2/STAT3 pathway involvement in the subarachnoid hemorrhage (SAH)-dependent regulation of HMGB1, using an in vivo rat model. A SAH model was established by endovascular perforation. Western blotting, immunohistochemistry and immunofluorescence were used to analyze HMGB1 expression after SAH. In addition, the effects of AG490 after SAH on JAK2/STAT3 phosphorylation, HMGB1 expression and brain damage were evaluated. The results of the present study demonstrated that JAK2/STAT3 was significantly phosphorylated (P<0.05) and the total HMGB1 protein level was significantly increased (P<0.05) after SAH. In addition, the cytosolic HMGB1 level after SAH demonstrated an initial increase followed by a decrease to the control level, while the nuclear HMGB1 level after SAH demonstrated the opposite trend, with an initial decrease and subsequent increase. AG490 administration after SAH significantly inhibited JAK2/STAT3 phosphorylation (P<0.05), suppressed the expression and translocation of HMGB1, reduced cortical apoptosis, brain edema and neurological deficits. These results demonstrated the involvement of the JAK2/STAT3 pathway in HMGB1 regulation after SAH. PMID- 29434720 TI - Targeted sequencing reveals genetic variants associated with sensitivity of 79 human cancer xenografts to anticancer drugs. AB - Although there has been progress moving from a 'one-size-fits-all' cytotoxic approach to personalized molecular medicine, the majority of patients with cancer receive chemotherapy using cytotoxic anticancer drugs. The sequencing analysis of 409 genes associated with cancer was conducted in the present study using 59 DNA sequences extracted from human cancer xenografts implanted into nude mice, of which sensitivity to 9 cytotoxic anticancer drugs [5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C (MMC), methotrexate, vincristine (VCR), and vinblastine] was examined. The present study investigated the association between the sensitivities of the xenografts to the 9 anticancer drugs and the frequency of single nucleotide variants (SNV). The correlation between the expression level of the genes and sensitivities to the 9 drugs in the above xenografts was also estimated. In the screening study using 59 xenografts, 3 SNVs (rs1805321, rs62456182 in PMS1 Homolog 2, Mismatch Repair System Component and rs13382825 in LDL Receptor Related Protein 1B), were associated with sensitivity to VCR and MMC, respectively (P<0.001). A replication study of 596 SNVs was subsequently performed, which indicated P<0.05 in the screening study using independent samples of 20 xenografts. A combined result of the screening and replication studies indicated that 35 SNVs were potentially associated with sensitivities to one or more of the nine anticancer drugs (Pcombined=0.0011 0.035). Of the 35 SNVs, rs16903989 and rs201432181 in Leukemia Inhibitory Factor Receptor alpha and Adhesion G Protein-Coupled Receptor A2 were commonly associated with sensitivity to 2 or 4 anticancer drugs, respectively. These findings provide novel insights which may benefit the development of personalized anticancer therapy for patients with cancer in the future. PMID- 29434721 TI - Downregulation of NIMA-related kinase-7 inhibits cell proliferation by inducing cell cycle arrest in human retinoblastoma cells. AB - NIMA-related kinase-7 (Nek7) is a centrosomal kinase involved in various types of cancer, including gallbladder cancer and hepatocellular carcinoma. However, the biological function and the potential underlying mechanism of Nek7 in retinoblastoma remain largely unknown. Therefore, the present study investigated the effects of Nek7 in retinoblastoma cells. The expression of Nek7 was initially determined and observed to be commonly upregulated in retinoblastoma cell lines (Y79, SO-RB50 and WERI-RB1) as compared with that in normal retinal pigment epithelium cells. Next, the endogenous expression of Nek7 was efficiently knocked down in Y79 and SO-RB50 cells using a lentivirus-mediated RNA interference approach, as confirmed by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Loss-of-function assays, including MTT, colony formation and flow cytometry, indicated that knockdown of Nek7 significantly inhibited cell growth, impaired the colony formation ability and induced cell cycle arrest at G0/G1 phase. Furthermore, mechanistic studies demonstrated that silencing of Nek7 resulted in reduced cyclin-dependent kinase 2, cyclin D1 and cyclin E levels in vitro. In conclusion, the present study highlights the crucial role of Nek7 in promoting retinoblastoma cell proliferation, and Nek7-silencing may serve as a novel therapeutic target for retinoblastoma. PMID- 29434722 TI - Analysis of long non-coding RNA expression profiles identifies functional lncRNAs associated with the progression of acute coronary syndromes. AB - It has been demonstrated that long non-coding RNAs (lncRNAs) are important in the gene regulatory network and their dysregulated expression has been implicated in cardiovascular disease. However, little is known regarding lncRNA expression patterns and their function in the progression of acute coronary syndromes (ACSs). In the present study, the expression profiles of lncRNAs from 52 patients with ACS were analyzed by re-annotating existing microarray data. The lncRNA expression profiles in the two distinct clinical entities of ACS, myocardial infarction (MI) and unstable angina (UA), were examined. Out of the 2,332 lncRNAs assessed, it was identified that 18 lncRNAs were upregulated and 35 lncRNAs were downregulated in patients with MI compared to those with UA. Furthermore, the expression profiles of patients with ACS were compared at different time points and significantly altered lncRNA expression was observed during the progression of ACS. A total of 7 candidate lncRNA biomarkers were identified and an lncRNA based classifier was developed to predict MI risk based on the expression data of the 7 lncRNAs using random forest and support vector machine strategies. This achieved a classification accuracy of 90.38% with a sensitivity of 100% and a specificity of 68.75%. Additionally, functional analysis suggested that these 7 lncRNAs may be involved in known MI-associated biological processes and pathways. PMID- 29434723 TI - Screening for key genes and transcription factors in ankylosing spondylitis by RNA-Seq. AB - Ankylosing spondylitis (AS) is a chronic inflammatory arthritis and autoimmune disease, the etiology and pathogenesis of which remain largely unknown. In the present study, blood samples were harvested from patients with AS and from healthy volunteers as a normal control (NC) for RNA-sequencing. Differentially expressed genes (DEGs) in the AS group compared with the NC group were identified, and gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were subsequently performed. Protein protein interaction (PPI) network and AS-specific transcriptional regulatory network construction was performed for the DEGs. A total of 503 DEGs, including 338 upregulated and 165 downregulated DEGs, were identified in patients with AS compared with the NC group. Three upregulated DEGs identified, interferon-induced protein with tetratricopeptide repeats (IFIT)1, IFIT3 and radical S-adenosyl methionine domain containing (RSAD)2, are interferon (IFN)-stimulated genes that serve a role in the IFN signaling pathway. The most significantly enriched GO term was response to other organisms. Osteoclast differentiation was a significantly enriched pathway for eight DEGs [High affinity immunoglobulin gamma Fc receptor (FCGR)1A, FCGR2B, four and a half LIM domains 2, integrin beta3, signal transducer and activator of transcription 2 (STAT2), suppressor of cytokine signaling 3 (SOCS3), leukocyte immunoglobulin like receptor (LILR)A4 and LILRA6]. The six hub genes in the PPI network constructed were interferon stimulated gene 15, heat shock protein beta1, microtubule-associated proteins 1A/1B light chain 3A, IFIT1, IFIT3 and SOCS3. POU domain class 2 transcription factor 1 (1-Oct) and ecotropic virus integration site-1 (Evi-1) were identified as two important transcription factors (TFs) in AS according to the AS-specific transcriptional regulatory network constructed. In addition, IFIT1 and IFIT3 were identified as targets of 1-Oct. The results of the present study indicate that osteoclast differentiation, the IFN signaling pathway and genes associated with these two signaling pathways, particularly FCGR2B, STAT2, SOCS3, IFIT1 and IFIT3, may serve a role in AS. In addition, Evi-1 and 1-Oct may be two important TFs associated with AS. These results may provide a basis for elucidating the underlying mechanisms of and developing novel treatments for AS. PMID- 29434724 TI - Combined usage of Wilms' tumor gene quantitative analysis and multiparameter flow cytometry for minimal residual disease monitoring of acute myeloid leukemia patients after allogeneic hematopoietic stem cells transplantation. AB - High expression of the Wilms' tumor gene (WT1) in acute myeloid leukemia (AML) has been considered as a sensitive marker of minimal residual disease (MRD). The present study investigated the significance of quantitative analysis of WT1 mRNA, combined with multiparameter flow cytometry (MFC) regarding its efficacy and prognostic as well as relapse prediction value for leukemia patients with hematopoietic stem cell transplantation. Reverse-transcription quantitative polymerase chain reaction analysis demonstrated that the expression of WT1 in the initial and relapse group was significant higher than that in the complete remission (CR) group (P<0.01). WT1 and the donor chimerism were negatively correlated (r=-0.73, P<0.05). In all AML patients, WT1 was the highest in the M3 subtype and the lowest in the M1 subtype. Follow-up of 12 AML patients demonstrated that WT1 gene expression levels markedly decreased after CR, but obviously increased after relapse, as did the rate of the leukemia cells detected by MFC. The combined usage of MFC and WT1 monitoring contributed to an improved detection rate of relapse (91.7%), and may be used to monitor MRD, assess the treatment efficacy and prognosis, and predict the risk of recurrence in leukemia patients without specific molecular markers after allogeneic hematopoietic stem cell transplantation. PMID- 29434725 TI - A novel hypothermic machine perfusion system using a LifePort Kidney Transporter for the preservation of rat liver. AB - The protective mechanisms for liver preservation associated with hypothermic machine perfusion (HMP) remain unclear. However, the lack of a common and portable HMP system for rat livers limits the study of HMP. The present study aimed to develop a novel, modified HMP system using a LifePort Kidney Transporter for preserving rat livers. A simple 'Y' shunt combined with a pressoreceptor for flow and pressure regulation was adapted to perfuse rat livers via the portal vein continuously using a LifePort Kidney Transporter under its 'prime mode' setting. An electronic scale was installed under the liver container to calculate the portal inflow according to the association with weight, density and volume of the perfusate. A total of 10 rat livers underwent 6 h of HMP using histidine tryptophan-ketoglutarate solution enriched with acridine orange (AO) and propidium iodide (PI). The perfusion status of HMP was assessed by comparison of AO+PI-positive cell count in core region (CR) and peripheral region (PR) of rat liver under fluorescence microscopy. The dynamics (inflow, pressure and intrahepatic resistance of perfusion) were assessed to identify whether this system met the demands for HMP of rat livers. Biochemical [alanine transaminase (ALT), lactate dehydrogenase (LDH) and endothelin levels] and histological parameters (sinusoidal dilatation, endothelial cell detachment and vacuolization) were measured to determine cellular damage associated with HMP. No significant difference was observed between the CR and PR according to the comparison of the AO+PI-positive cell count, which indicated that complete perfusion was achieved. Intrahepatic resistance significantly decreased during the initial 3 h of HMP (P<0.01), but remained stable during the final 3 h. ALT and LDH levels significantly increased over the 6 h HMP duration: ALT (0 h, 42.67+/-5.81 U/l; 3 h, 90.67+/-6.74 U/l; 6 h, 164.33+/-7.31 U/l; P<0.01) and LDH (0 h, 492.90+/-90.20 U/l; 3 h, 973.53+/-97.4; 6 h, 1,843.40+/-85.78 U/l; P<0.01) However, the levels of endothelin and oxygen consumption were constant throughout HMP. Furthermore, histological analysis indicated sinusoidal dilation was significantly increased in the post-HMP group compared with the pre-HMP group (P<0.01); however, no other significant differences were observed. Combined with the results of ATP test (640.64+/-29.46 nmol/l) and bile production (4.88+/-0.69 ul/h/g of liver) at the end of HMP, the present results demonstrated minimal cellular injury associated with HMP while retaining the dependability and portability of the LifePort Kidney Transporter, which suggests the modified HMP system met the demands required and may be suitable for rat liver preservation. PMID- 29434726 TI - Effects of apolipoprotein E gene polymorphism on the intracellular Ca2+ concentration of astrocytes in the early stages post injury. AB - The present study aimed to investigate the correlation between apolipoprotein E (APOE) polymorphisms and the intracellular concentration of Ca2+ in astrocytes in the early stages after an injury. The chondroitin sulfate region of three APOE alleles (epsilon2, epsilon3 and epsilon4) was obtained by reverse transcription polymerase chain reaction (RT-PCR). A recombinant plasmid, pEGFP-N1-APOE, was constructed and identified by sequencing, while astrocytes were isolated from APOE gene-knockout mice and examined using immunocytochemistry. The recombinant plasmid was transfected into the astrocytes using the liposome-mediated method and cell injury models were constructed by a scratch assay. Laser confocal scanning microscopy (LCSM) was used to detect dynamic alterations in intracellular Ca2+ concentration at 12, 24, 48 and 72 h after injury. Compared with the control group, cells transfected with any of the three alleles demonstrated significant increases in the fluorescence intensity of Ca2+ (P<0.05). The fluorescence intensity of Ca2+ was weak at 12 h after injury, with no statistically significant difference detected between any two groups at this time point (P>0.05). However, the fluorescence intensity increased in a time dependent manner and at 24, 48 and 72 h post injury, the fluorescence intensity of the epsilon4 allele-containing cells was significantly higher when compared with that of cells harboring the other two alleles (P<0.05). These results indicate that intracellular Ca2+ overloading may contribute to the deterioration of brain cells and poor outcome subsequent to traumatic brain injury in APOE epsilon4 carriers. PMID- 29434727 TI - Differentiation of rat adipose-derived mesenchymal stem cells into corneal-like epithelial cells driven by PAX6. AB - Corneal integrity, transparency and vision acuity are maintained by corneal epithelial cells (CECs), which are continuously renewed by corneal limbal stem cells (LSCs). Deficiency of CECs and/or LSCs is associated with numerous ocular diseases. Paired box (PAX)6 is an eye development-associated transcription factor that is necessary for cell fate determination and differentiation of LSCs and CECs. In the present study, the PAX6 gene was introduced into adipose-derived rat mesenchymal stem cells (ADMSCs) to investigate whether PAX6-transfected cells were able to transdifferentiate into corneal-like epithelial cells and to further verify whether the cells were suitable as a cell source for corneal transplantation. The ADMSCs were isolated from the bilateral inguinal region of healthy Sprague Dawley rats. The characteristics of ADMSCs were identified using flow cytometric analysis. After subculture, ADMSCs underwent transfection with recombinant plasmid containing either PAX6-enhanced green fluorescent protein (EGFP) complementary (c)DNA or EGFP cDNA (blank plasmid group), followed by selection with G418 and determination of the transfection efficiency. Subsequently, the morphology of the ADMSCs and the expression profiles of corneal specific markers CK3/12 and epithelial-specific adhesion protein were determined. E-cadherin was detected using immunofluorescence staining and western blot analysis at 21 days following transfection. An MTT cell proliferation and a colony formation assay were performed to assess the proliferative activity and clonogenicity of PAX6-transfected ADMSCs. Finally, the PAX6-expressing ADMSCs were transplanted onto the cornea of a rabbits with limbal stem cell deficiency (LSCD). At 21 days after transfection, the ADMSCs with PAX6 transfection exhibited a characteristic flagstone-like appearance with assembled corneal-like epithelial cells, and concomitant prominent expression of the corneal-specific markers cytokeratin 3/12 and E-cadherin. Furthermore, the proliferation and colony formation ability of PAX6-overexpressing ADMSCs was significantly retarded. The transplantation experiment indicated that PAX6-reprogramed ADMSCs attached to and replenished the damaged cornea via formation of stratified corneal epithelium. Taken together, these results suggested that conversion of ADMSCs into corneal-like epithelium may be driven by PAX6 transfection, which makes ADMSCs a promising cell candidate for the treatment of LSCD. PMID- 29434728 TI - Chitosan temperature-sensitive gel loaded with drug microspheres has excellent effectiveness, biocompatibility and safety as an ophthalmic drug delivery system. AB - In the present study, a temperature-sensitive gel composed of chitosan, carboxymethyl chitosan and glycerophosphate was prepared and loaded with chitosan microspheres encapsulating levofloxacin. The bioavailability of levofloxacin and the safety of this novel opthalmic drug delivery formulation were evaluated. Levofloxacin chitosan microspheres were prepared using the ionic gelation method, and the particle size and entrapment rate were determined. The morphology of the microspheres was observed by scanning electron microscopy. The pH and zeta potential were measured. The in vitro release of levofloxacin by the chitosan temperature-sensitive gel loaded with drug microspheres was determined using spectrophotometry. The eye retention time of the chitosan temperature-sensitive gel was calculated using a fluorescein sodium test. To assess the bioavailability and safety of the chitosan temperature-sensitive gel, a cell compatibility test, a cytotoxicity test and skin irritation test were performed. The entrapment rate of levofloxacin in the chitosan microspheres was determined to be 26.5%. The levofloxacin chitosan microspheres that were formed by chitosan and sodium tripolyphosphate were identified to be suitable for use in an ophthalmic particle dispersion system based on their physical and chemical properties. The pH of the levofloxacin chitosan microsphere suspension was 5.87+/-0.04, the average particle diameter was 2,452+/-342 nm, the polydispersity index was 0.168+/-0.028 and the zeta potential was 28.62+/-1.7 mV. The chitosan temperature-sensitive gel carrying microspheres loaded with drug prevented drug burst release at the initial stage and facilitated the slow release of the drug later on. Furthermore, this delivery system markedly prolonged the contact duration of levofloxacin with the eye. The chitosan temperature-sensitive hydrogel was safe and provided a good bioavailability of the drug. The results revealed that the chitosan temperature sensitive gel had a cytotoxicity of grade 0, and no erythematous response was observed during the entire course of the skin irritation test. The present study provided a basis for the future development of the chitosan-based temperature sensitive hydrogel in ophthalmic drug delivery. PMID- 29434729 TI - A composite mouse model of aplastic anemia complicated with iron overload. AB - Iron overload is commonly encountered during the course of aplastic anemia (AA), but no composite animal model has been developed yet, which hinders drug research. In the present study, the optimal dosage and duration of intraperitoneal iron dextran injection for the development of an iron overload model in mice were explored. A composite model of AA was successfully established on the principle of immune-mediated bone marrow failure. Liver volume, peripheral hemogram, bone marrow pathology, serum iron, serum ferritin, pathological iron deposition in multiple organs (liver, bone marrow, spleen), liver hepcidin, and bone morphogenetic protein 6 (BMP6), SMAD family member 4 (SMAD4) and transferrin receptor 2 (TfR2) mRNA expression levels were compared among the normal control, AA, iron overload and composite model groups to validate the composite model, and explore the pathogenesis and features of iron overload in this model. The results indicated marked increases in iron deposits, with significantly increased liver/body weight ratios as well as serum iron and ferritin in the iron overload and composite model groups as compared with the normal control and AA groups (P<0.05). There were marked abnormalities in iron regulation gene expression between the AA and composite model groups, as seen by the significant decrease of hepcidin expression in the liver (P<0.01) that paralleled the changes in BMP6, SMAD4, and TfR2. In summary, a composite mouse model with iron overload and AA was successfully established, and AA was indicated to possibly have a critical role in abnormal iron metabolism, which promoted the development of iron deposits. PMID- 29434730 TI - Clinical and pathological characteristics of IgG4-related interstitial lung disease. AB - IgG4-related interstitial lung disease (IgG4-RILD), which is characterized by increased IgG4 levels, IgG4+ plasma cell infiltration and irregular whorled fibrosis, is a recently described lung disorder that belongs to the group of systemic fibroinflammatory IgG4-related diseases (IgG4-RD). The aim of the present study was to improve the current knowledge regarding the specific clinical and histopathological characteristics of IgG4-RILD and to investigate its underlying immune mechanism in vivo. A total of 7 patients newly diagnosed with IgG4-RILD were enrolled in the present study (4 men and 3 women; mean age, 57 years; range, 29-71 years). Patients' clinical history was collected and serological indicators, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANAs) and tumor markers were measured. Serum immunoglobulin G (IgG), IgE and IgG4 levels were also evaluated. In addition, computed tomographic (CT) images and pathological examinations were used to determine the characteristics of lung lesions in all patients. The majority of patients presented with symptoms of fever, cough and dyspnea, while allergic symptoms were also encountered. The laboratory examination results revealed different degrees of increased CRP, ESR, tumor markers, ANA, serum IgE and IgG4. The CT images revealed diffuse ground glass opacities, bronchiectasis and thickened bronchovascular bundles. Histologically, the lung lesions were characterized by dense IgG4+ lymphoplasmacytic infiltrates intermixed with extensive fibrous tissue hyperplasia and an irregularly storiform pattern of fibrosis. The mean number of IgG4+ plasma cells was >10 cells/high power field. The ratio of IgG/IgG4+ plasma cells was >50% in inflamed lesions and the number of parenchymal cells was markedly reduced. Obliterative phlebitis or obliterative arteritis was observed in all patients. In conclusion, the clinicopathological similarities between IgG4-RILD and other IgG4-RD suggest that IgG4-related immunopathological processes may be associated with the pathogenesis of pulmonary lesions. Future studies based on the findings herein may elucidate the specific pathological process underlying the development of this fibroinflammatory disorder. PMID- 29434731 TI - Correlation between PPAR-alpha methylation level in peripheral blood and inflammatory factors of NAFLD patients with DM. AB - The correlation between the methylation levels of peroxisome proliferator activated receptor-alpha (PPAR-alpha) in the peripheral blood and the inflammatory factors associated with non-alcoholic fatty liver disease (NAFLD) patients with diabetes mellitus (DM) was investigated. Thirty-two samples of normal liver tissues (group N) and 35 samples of liver tissues from NAFLD patients with DM (group M) were used for the present study. The levels of alanine transaminase (ALT) and aspartate transaminase (AST) were measured using commercially available kits. The accumulation of lipid droplets and glycogen in the two groups was determined through Oil Red O staining and Sudan III staining. mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-lbeta (IL 1beta) and IL-6 in liver tissues of groups N and M were detected using reverse transcription-polymerase chain reaction (RT-PCR). In addition, western blotting was used to detect the protein expression of PPAR-alpha in liver tissues of both groups. The Statistical Product and Service Solutions (SPSS) 17.0 statistical software was used to analyze the expression difference of PPAR-alpha in liver tissues in the groups. The high levels of ALT and AST indicated severe liver injury in group M. Oil Red O staining and Sudan III staining showed a large number of lipid droplets and glycogen accumulation in the liver of group M patients. RT-PCR showed that the expression of inflammatory factors was extremely high and that the inflammatory injury was severe in the liver of group M patients. Western blotting showed that the expression of PPAR-alpha in group N was significantly higher than that in group M. ANOVA results showed that the expression of PPAR-alpha in liver tissues of groups N and M patients were statistically significantly different (P<0.01). Therefore, the abnormal expression of PPAR-alpha is closely associated with the occurrence and development of NAFLD complicated with DM, and that the abnormal expression of PPAR-alpha is closely related to inflammatory factors. Results from the present study suggest PPAR-alpha has important value in the study on NAFLD complicated with DM. The expression of PPAR-alpha can be used as a new basis for the diagnosis and treatment of NAFLD complicated with DM. PMID- 29434732 TI - Sustained multiple organ ischaemia after transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. AB - Transarterial chemoembolization (TACE) with drug-eluting beads (DC beads) may enhance drug delivery to tumours and reduce systemic toxicity. TACE with DC beads leads to significantly fewer serious side-effects compared with conventional TACE. A 66-year-old man with hepatocellular carcinoma (HCC) complained of continuous abdominal pain 1 month after TACE with DC beads. At the time of TACE, angiography revealed severe stenosis of both hepatic arteries. The diagnostic work up on admission suggested severe bile duct injury with regional bile duct dilatation, segmental liver and spleen infarction, necrotizing pancreatitis, as well as gastric and duodenal ulcers. The pathology specimens of the duodenum contained DC beads that had passed through small vessels in the connective tissue. The patient's condition appeared to improve after 2 weeks of antibiotic treatment and supportive care, but new multifocal liver and spleen infarction subsequently developed. After 2 months, he was well enough to be discharged. His HCC partially responded to the TACE with DC beads but eventually progressed and he died after 11 months. The present case report highlights unexpected ongoing multiple organ ischaemia in a 66-year-old man treated for HCC using TACE with DC beads. The use of TACE with DC beads should be carefully considered in patients with vascular strictures or aberrant blood supply. PMID- 29434733 TI - Shikonin causes apoptosis by disrupting intracellular calcium homeostasis and mitochondrial function in human hepatoma cells. AB - Shikonin is known to suppress proliferation and induce apoptosis in a variety of cancer cell lines. In the present study, SMMC-7721 human hepatocellular carcinoma cells were treated with shikonin (1, 2 or 4 uM) for 12-48 h. Cell morphological alterations and DNA damage were determined. Furthermore, changes in cell cycle, mitochondrial transmembrane potential, calcium homeostasis and levels of reactive oxygen species were measured. Shikonin-treated SMMC-7721 cells exhibited morphological changes and DNA damage. Shikonin inhibited cell proliferation causing cell cycle arrest at the G0/G1 phase and induced apoptosis in a dose- and time-dependent manner. Shikonin-induced apoptosis was associated with activation of caspases-3, -8 and -9, elevated levels of intracellular Ca2+ and reactive oxygen species, reduced mitochondrial membrane potential and enhanced efflux of Ca2+ and K+. Gene expression B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), p53 and caspase-3 was up-regulated, whereas Bcl-2 expression was downregulated. Shikonin caused apoptosis by inhibiting cell cycle progression, disrupting Ca2+ homeostasis, inducing oxidative stress and triggering mitochondrial dysfunction. Activation of caspases-3, -8 and -9, K+ efflux, and regulation of Bax, Bcl-2, p53 and caspase-3 expression are involved in the process. These results provide in-depth insight into the mechanisms of action of shikonin in the treatment of cancer. PMID- 29434734 TI - Evaluation of changes in left ventricular structure and function in hypertensive patients with coronary artery disease after PCI using real-time three-dimensional echocardiography. AB - We aimed to evaluate the changes in left ventricular structure and function in hypertensive patients with coronary artery disease before and after percutaneous coronary intervention (PCI) using real-time three-dimensional echocardiography. Two hundred and eighty hypertensive patients with coronary artery disease undergoing PCI and 120 cases who did not receive PCI in our hospital were selected as the subjects of our study. All patients were administered with routine antiplatelet, anticoagulant, lipid-lowering, antihypertensive, dilating coronary artery and other medications. The left ventricular systolic function and systolic synchrony index changes before and after subjects were treated by PCI were analyzed using three-dimensional echocardiography. At 2 days before surgery, there were no significant differences in the left ventricular end-diastolic volume, left ventricular end-systolic volume (LVESV) and ejection fraction (EF) between the two patient groups (P>0.05). At 3 months and 9 months, the two key time points after PCI, the LVESV level in the PCI group was distinctly decreased, while EF was significantly increased (P<0.05). In addition, before treatment, there were no significant differences in the parameters of time from the corresponding segment of the myocardium to the minimal systolic volume in two patient groups, such as Tmsv-16SD, Tmsv-16Dif, Tmsv-12SD, Tmsv-12Dif, Tmsv-6SD and Tmsv-6Dif (P>0.05); however, the parameters of time from the corresponding segment of the myocardium to the minimal systolic volume in patients in the PCI group were significantly reduced at 3 and 9 months after surgery (P<0.05). Three dimensional echocardiography can evaluate the critical parameters in the prognosis of hypertensive patients with coronary artery disease after PCI accurately and in real-time, which may play a significant role. PMID- 29434735 TI - Expression of MMP-9 and IL-6 in patients with subarachnoid hemorrhage and the clinical significance. AB - The purpose of the present study was to investigate the expression of matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6) in patients with subarachnoid hemorrhage (SAH) and the clinical significance thereof. Forty-three patients with SAH and 23 healthy individuals were enrolled in this study. Patients were divided into the cerebral vasospasm (CVS) and non-cerebral vasospasm (non-CVS) groups, or the good and poor prognosis groups. Serum levels of MMP-9 and IL-6 were detected by ELISA. Expression levels of MMP-9 and IL-6 mRNAs were detected by RT-qPCR. Expression levels of MMP-9 and IL-6 were elevated with the increase of grades as determined by the Hunt-Hess grading method. Serum levels of MMP-9 and IL-6 in the CVS and poor prognosis groups were significantly higher than those in the control group. Expression levels of MMP-9 and IL-6 in the CVS group were significantly higher than those in the non-CVS group (P<0.05). Compared with the good prognosis group, the expression levels of MMP-9 and IL-6 were significantly increased in the poor prognosis group at 1, 4, 7 and 10 days after SAH (P<0.05). Additionally, the expression level of MMP-9 was significantly positively correlated with that of IL-6 (P<0.05). Expression levels of MMP-9 and IL-6 were significantly increased in patients with SAH, and the expression level of MMP-9 was positively correlated with that of IL-6. Thus, MMP-9 and IL-6 are involved in the development of SAH. PMID- 29434736 TI - Insulin resistance, blood glucose and inflammatory cytokine levels are risk factors for cardiovascular events in diabetic patients complicated with coronary heart disease. AB - This study was designed to investigate the relation of insulin resistance, blood glucose and inflammatory cytokines with cardiovascular events in diabetic patients complicated with coronary heart disease (CHD). A total of 120 patients with diabetes mellitus type 2 (T2DM) complicated with CHD admitted to Jinan Central Hospital from January 2015 to March 2016 were enrolled in this study. There were 60 cases complicated with cardiovascular events and 60 had no history of cardiovascular events; there were 40 cases with abnormal blood glucose, 40 with insulin resistance and 40 with elevated inflammatory cytokines. Changes in the levels of blood glucose, fasting serum insulin and inflammatory cytokines as well as changes in the homeostasis model assessment of insulin resistance indexes (HOMA-IR) were recorded and compared among groups of patients. Besides, changes in the Global Registry of Acute Coronary Events (GRACE) risk score and the incidence rate of cardiovascular events were also detected and multivariate logistic regression analysis was conducted so as to identify relevant risk factors. Our results showed the fasting blood glucose and the 2 h postprandial blood glucose levels in the non-cardiovascular event group were lower than those in the cardiovascular event group (P<0.05). However, levels of fasting serum insulin and HOMA-IR in the non-cardiovascular event group were significantly higher than those in the cardiovascular event group (P<0.05). Additionally, levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 and C-reactive protein in the non-cardiovascular event group were significantly lower than those in the cardiovascular event group (P<0.05). Moreover, GRACE risk scores in patients with elevated inflammatory cytokines were higher than those in patients with insulin resistance and those in patients with blood glucose abnormalities (P<0.05). The incidence rate of cardiovascular events in patients with blood glucose abnormalities was lower than that in patients with insulin resistance and that in patients with elevated inflammatory cytokines. There was a positive correlation between TNF-alpha and HOMA-IR (P<0.05), and between HOMA-IR and the GRACE risk score (P<0.05). Blood glucose abnormalities, insulin resistance and inflammatory cytokines were all independent risk factors for cardiovascular events. Based on our findings, stronger inflammatory responses in patients with T2DM complicated with CHD lead to higher incidence rates of cardiovascular events. Besides that, elevated blood glucose and insulin resistance levels are also independent risk factors for cardiovascular events. PMID- 29434737 TI - Identification of core pathways based on attractor and crosstalk in ischemic stroke. AB - Ischemic stroke is a leading cause of mortality and disability around the world. It is an important task to identify dysregulated pathways which infer molecular and functional insights existing in high-throughput experimental data. Gene expression profile of E-GEOD-16561 was collected. Pathways were obtained from the database of Kyoto Encyclopedia of Genes and Genomes and Retrieval of Interacting Genes was used to download protein-protein interaction sets. Attractor and crosstalk approaches were applied to screen dysregulated pathways. A total of 20 differentially expressed genes were identified in ischemic stroke. Thirty-nine significant differential pathways were identified according to P<0.01 and 28 pathways were identified with RP<0.01 and 17 pathways were identified with impact factor >250. On the basis of the three criteria, 11 significant dysfunctional pathways were identified. Among them, Epstein-Barr virus infection was the most significant differential pathway. In conclusion, with the method based on attractor and crosstalk, significantly dysfunctional pathways were identified. These pathways are expected to provide molecular mechanism of ischemic stroke and represents a novel potential therapeutic target for ischemic stroke treatment. PMID- 29434738 TI - JNK and NF-kappaB signaling pathways are involved in cytokine changes in patients with congenital heart disease prior to and after transcatheter closure. AB - Congenital heart disease (CHD) is a problem in the structure of the heart that is present at birth. Due to advances in interventional cardiology, CHD may currently be without surgery. The present study aimed to explore the molecular mechanism underlying CHD. A total of 200 cases of CHD treated by transcatheter closure as well as 200 controls were retrospectively assessed. Serum cytokines prior to and after treatment were assessed by reverse-transcription quantitative polymerase chain reaction analysis. Furthermore, the levels of proteins associated with c Jun N-terminal kinase (JNK) and nuclear factor (NF)-kappaB were assessed by western blot analysis and immunohistochemistry. Furthermore, an animal model of CHD in young pigs was successfully constructed and treated with inhibitors of JNK and/or NF-kappaB to investigate the roles of these pathways in CHD. The results revealed that tumor necrosis factor-alpha, interleukin (IL)-6 and IL-8 were significantly elevated in the experimental group following transcatheter closure treatment, compared with those in the healthy control group, and the serum levels of the anti-inflammatory cytokine IL-10 were significantly reduced. Phosphorylated c-Jun and p65 levels in the experimental group were notably higher in the experimental group compared with the control group, but were restored to normal levels following transcatheter closure treatment. Similar results were also obtained in the pig model. The results of the present study suggested that the CHD-associated changes in cytokines, as well as their recovery following transcatheter closure treatment were associated with the JNK and NF-kappaB signaling pathways. The present study may provide further understanding of the underlying molecular mechanisms in CHD and propose a potential novel target for the treatment of CHD. PMID- 29434739 TI - Intravitreal ranibizumab injection combined with photodynamic therapy for polypoidal choroidal vasculopathy. AB - The aim of the present study was to evaluate the efficacy of combination treatment with intravitreal ranibizumab (IVR) injection and photodynamic therapy (PDT) for polypoidal choroidal vasculopathy (PCV). A total of 64 patients with PCV were included in the present study, which were divided into the IVR monotherapy group (Group A) and combination treatment groups (Groups B-D) with different treatment intervals. All subjects were followed-up at 1, 3, 6 and 12 months following treatment, and subjected to the detection of best-corrected visual acuity (BCVA) and central foveal thickness (CFT). Compared with the monotherapy group, more significant BCVA improvement was observed for the combination treatment groups, with the most evident effect exhibited in Group C. At the end of the follow-up period, visual acuity improvement rates were markedly elevated in the combination treatment groups, as compared with the monotherapy group. According to optical coherence tomography, the CFT for the combination treatment groups was thinner than the monotherapy group. Among the combination groups, CFT improvement for Group C was superior to other groups. Fundus angiography demonstrated that, compared with monotherapy, combination treatment may significantly promote the regression and prevent the recurrence of polyps and BVN. The most efficient effectiveness was observed for Group C. In addition, combination treatment may significantly reduce the IVR injection numbers required to treat PCV. Patients receiving combination treatment with IVR injection and PDT have greater vision improvements, reduced macular degeneration and decreased injection numbers. Combination therapy may therefore, represent an effective and safe therapeutic strategy for PCV clinical treatment. PMID- 29434740 TI - A pilot study of a cardiovascular virtual endoscopy system based on multi detector computed tomography in diagnosing tetralogy of Fallot in pediatric patients. AB - The present study aimed to investigate the capabilities of the cardiovascular virtual endoscopy (VE) system in diagnosing tetralogy of Fallot (TOF) and performing measurements. A total of 37 patients underwent two-dimensional echocardiography (2-DE) and multi-detector computed tomography (MDCT) examinations. The obtained MDCT images were applied to a cardiovascular VE system. Diagnostic time by VE was first studied and compared with MDCT. Subsequently, with surgical findings as the ground truth, the capabilities of VE, 2-DE and MDCT in diagnosing TOF and its complications were investigated. Additionally, measurements on aorta overriding ratio and diameters for the left pulmonary artery, right pulmonary artery and right ventricular outflow tract by 2 DE and VE were analyzed. Diagnostic time by VE was significantly shorter than MDCT (188+/-42 vs. 303+/-42 sec, respectively; P<0.0001). VE, MDCT and 2-DE demonstrated comparable diagnostic rates of TOF (35/37 vs. 34/37 vs. 32/37, respectively; P>0.05). Similar findings were demonstrated in diagnosing complications of the muscular ventricular septal defects, patent ductus arteriosus, vagus subclavian artery, right arch, double superior vena cava and pulmonary artery. Furthermore, in diagnosing the atrial septal defect, 2-DE outperformed MDCT and VE (accuracy, 100 vs. 81 vs. 73%, respectively; all P<0.05). In performing relevant measurements, VE outperformed MDCT and 2-DE, particularly in accessing aorta overriding ratios with no intra-operator difference (P=0.3770) and high consistency (r=0.916). In conclusion, cardiovascular VE was demonstrated to have acceptable accuracy in diagnosing TOF, and possess advantages in shortening the diagnostic time and in performing measurements. PMID- 29434741 TI - Inhibition of C-X-C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re-transplant model. AB - The interaction of chemokine (C-X-C motif) ligand 10 (CXCL10) with its receptor (CXCR3) is a critical process in recruiting donor reactive T cells to a graft and alloantigen-specific memory T (Tm) cells exert a principal function in promoting graft dysfunction during accelerated cardiac rejection. However, whether CXCL10 chemokine exerts any effects on acute accelerated rejection mediated by CD8+ Tm cells in a re-transplant model has remained elusive. The present study established a cardiac transplant model by advanced microsurgery technology and improved organ storage. A novel rat model of cardiac re-transplantation was established at 40 days following primary heart transplant. The experiment included two parts, and when models were established, the rats were divided into two groups: Primary cardiac transplant (HTx) and re-transplantation without treatment (HRTx). In part 1, recipients from part 2, including re-transplantation without treatment (HRTx+NS) and re-transplantation treated with anti-CXCL10 antibodies (500 ug every other day by intraperitoneal injection; HRTx+CXCL10 Abs group). The graft survival time was observed and graft infiltration by inflammatory cells was assessed via histology of cardiac graft sections; in addition, the gene expression and the serum concentration of CXCL10 in each group was assessed. Indexes such as rejection-associated cytokines were assayed by reverse-transcription quantitative PCR and ELISA kits, and flow cytometry of splenocytes was used to detect Tm cells in the re-transplantation groups. The results demonstrated that level of CXCL10 was significantly increased and the graft mean survival time was shortened accompanied with aggravated lymphocyte cell infiltration in the HRTx group when compared that in the HTx group; in addition, the serum levels and mRNA expression of interleukin (IL)-2 and interferon (IFN)-gamma were increased, while transforming growth factor (TGF) beta was decreased in the HRTx group. Furthermore, neutralization of CXCL10 prolonged the graft mean survival time and delayed accelerated rejection. Compared with that in the HRTx+NS group, serum levels and graft tissue mRNA expression of IFN-gamma and IL-2 were decreased in the HRTx+CXCL10 Abs group, while TGF-beta mRNA was significantly increased but the serum concentration was not significantly affected. In addition, there was no difference in IL-10 between the two groups, while delayed accelerated rejection paralleled with inflammatory cell infiltration decreased and the proliferation and differentiation of CD8+ Tm cells in secondary lymphoid organs were reduced in the HRTx+CXCL10 Abs group vs. those in the HRTx+NS group. The present study demonstrated that CXCL10 had a crucial role in cardiac transplantation and re-transplantation, and that treatment with CXCL10 antibodies delays accelerated acute rejection mediated by Tm cells in a rat model of cardiac re-transplantation. PMID- 29434742 TI - Resveratrol protects neuronal cells from isoflurane-induced inflammation and oxidative stress-associated death by attenuating apoptosis via Akt/p38 MAPK signaling. AB - The aim of the present study was to determine whether resveratrol protects neuronal cells from inflammation and isoflurane-induced oxidative stress associated death via attenuating apoptosis via Akt/p38 mitogen-activated protein kinase (MAPK) signaling. The PC12 rat pheochromocytoma cell line was treated with 2% isoflurane + 21% O2 + 5% CO2 for 6 h and pre-treated with resveratrol (0-1,000 uM) for 0, 24 or 48 h prior to isoflurane treatment. An MTT assay, flow cytometry and ELISA of tumor necrosis factor-alpha, interleukin-6, malondialdehyde and superoxide dismutase revealed that resveratrol reduced growth inhibition, restrained apoptosis and suppressed inflammation and oxidative stress induced by isoflurane in PC12 cells. Pretreatment with resveratrol effectively reduced caspase-3 activity and inducible nitric oxide synthase protein expression in isoflurane-induced PC12 cells. In addition, western blot analysis demonstrated that resveratrol treatment significantly attenuated isoflurane-induced decreases in the activated phosphorylated (p)-Akt/Akt ratio and increases in the p-p38/p38 MAPK protein ratio in PC12 cells. These findings indicated that resveratrol was able to protect neuronal cells from isoflurane-induced inflammation and oxidative stress-associated death by attenuating apoptosis via Akt/p38 MAPK signaling. PMID- 29434743 TI - Anti-depressant-like effect of atractylenolide I in a mouse model of depression induced by chronic unpredictable mild stress. AB - Atractylenolide I (AT-I), a major component of the rhizoma of Atractylodes macrocephala Koidz., exerts a wide range of activities. The purpose of the present study was to investigate the anti-depressant-like effect of AT-I in a mouse model of chronic unpredictable mild stress (CUMS), and to explore the possible molecular mechanism involved. It was revealed that AT-I significantly ameliorated CUMS-induced depressive-like behaviors, as evidenced by increased sucrose preference as well as shortened immobility time in the forced swimming and the tail suspension test. In addition, AT-I reduced CUMS-induced decreases in the concentrations of serotonin and norepinephrine in the hippocampus. Furthermore, AT-I inhibited the activation of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome as well as the concentration of the pro-inflammatory cytokine interleukin (IL)-1beta in the hippocampi of mice subjected to CUMS. In conclusion, the results of the present study suggested that AT-I exerts anti depressant-like effects in a CUMS-induced model of depression in mice, the molecular mechanism of which is associated with the inhibition of NLRP3 inflammasome activation to decrease IL-1beta production. PMID- 29434744 TI - Interleukin-1 receptor-associated kinase 3 downregulation in peripheral blood mononuclear cells attenuates immunosuppression in sepsis. AB - Sepsis is the leading cause of mortality in intensive care units due to complex inflammatory immune responses and immunosuppression. Recent studies have indicated that the negative regulator of toll like receptors, interleukin-1 receptor-associated kinase 3 (IRAK-3/IRAK-M), serves an important role in immunosuppression during sepsis. In the current study, a cecal ligation puncture model was established in mice using lipopolysaccharide secondary challenge to simulate immunosuppression in sepsis. Peripheral blood mononuclear cells (PBMCs) from this model were then used to evaluate the expression and function of IRAK-M. The results demonstrated that silencing of IRAK-M expression in PBMCs from immunosuppressed mice partially restored the production of pro-inflammatory cytokines. By introducing PBMCs transfected with small-interfering RNA targeting IRAK-M into septic immunosuppressed mice, the survival rate was improved with an increase in splenic CD4+ and CD8+ T cells and a decrease in T cell apoptosis. In conclusion, downregulation of IRAK-M reversed the effects of sepsis on the production of inflammatory cytokines in PBMCs, and improved the survival of septic immunosuppressed mice. These results provide a basis for future studies investigating the immunological mechanisms underlying immune suppression in sepsis. PMID- 29434745 TI - Tubeimoside I attenuates inflammation and oxidative damage in a mice model of PM2.5-induced pulmonary injury. AB - In the present study, the effects of tubeimoside I (TBMS1) on particulate matter <2.5 um in diameter (PM2.5)-induced pulmonary injury and its mechanisms of action were investigated. Male BALB/c mice were randomly assigned into five groups (n=10/group): Control, PM2.5, PM2.5 + TBMS1 45 mg/kg, PM2.5 + TBMS1 90 mg/kg and PM2.5 + TBMS1 180 mg/kg. The dose of the PM2.5 suspension administered to the mice was 40 mg/kg via nasal instillation. The PM2.5 + TBMS1 groups received TBMS1 daily orally for 21 consecutive days, while the mice in the control and PM2.5 groups received equivalent volumes of PBS. Subsequently, lactic dehydrogenase, acid phosphatase, alkaline phosphatase, albumin, tumor necrosis factor-alpha and interleukin-6 protein levels in bronchoalveolar lavage fluid were determined. Oxidative stress was evaluated by detecting the protein levels of malondialdehyde, superoxide dismutase and inducible nitric oxide synthase, and the level of nitric oxide in lung tissue. Lastly, histopathological images of lung sections were obtained to observe changes in the lung tissue with treatment. The results indicated that exposure to PM2.5 induced pathological pulmonary changes, and biofilm and parenchymal cell damage, and promoted inflammation and oxidative stress. Treatment with TBMS1 attenuated the development of PM2.5 induced pulmonary injury. Its mechanisms of action were associated with reducing cytotoxic effects, levels of inflammatory mediators and oxidative damage. In conclusion, the results of the present study indicate that TBMS1 is a potential therapeutic drug for treating PM2.5-induced pulmonary injury. PMID- 29434746 TI - Role of miR-589-3p in human lumbar disc degeneration and its potential mechanism. AB - The present study aimed to investigate the role of miR-589-3p in lumbar disc degeneration (LDD) and to explore the underlying mechanisms. Nucleus pulposus (NP) cells were stimulated with lipopolysaccharide (LPS) to simulate an in vitro model of intervertebral disc degeneration. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression level of microRNA (miR)-589-3p in the NP cells, and the results demonstrated that the increased expression of miR-589-3p in LPS stimulated NP cells compared with the control. To further investigate the role of miR-589-3p in LDD, a human NP cell line with high/low miR-589-3p expression was generated using miR-589-3p mimics/inhibitors. In addition, a human NP cell inflammation model was conducted by LPS (10 uM) treatment. Western blot analysis and RT-qPCR were performed for detection of associated genes and proteins. Protein levels of pro-inflammatory factors, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) 1beta and IL-6 were evaluated by ELISA. Flow cytometry was used for cell apoptosis determination. Furthermore, Targetscan was used to predict potential targets of miR-589-3p, and a dual luciferase reporter assay was used to verify the prediction. The findings verified that miR-589-3p was significantly upregulated in LDD. In vitro, miR-589-3p mimics/inhibitors significantly increased/reduced the production of TNF-alpha, IL-1beta and IL-6 in LPS stimulated NP cells. Furthermore, miR-589-3p mimics/inhibitors significantly promoted/inhibited LPS stimulated NP cell apoptosis. MiR-589-3p mimics/inhibitors significantly repressed/enhanced type II collagen and aggrecan expression in LPS stimulated NP cells. In addition, it was demonstrated that mothers against decapentaplegic homolog (Smad) 4 was a direct target gene of miR-589-3p, and was negatively regulated by miR-589-3p in NP cells. In conclusion, miR-589-3p may function as a promoter in LDD development via the regulation of Smad4. PMID- 29434747 TI - MicroRNA-30a suppresses non-small-cell lung cancer by targeting Myb-related protein B. AB - Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer mortality worldwide. A growing body of evidence indicates that microRNA (miR) have important and diverse roles in the proliferation, apoptosis and metastasis of human cancer cells. In the present study, the molecular regulation mechanism of miR-30a and its potential target, Myb-related protein B (MYBL2) was investigated in NSCLC. Reverse transcription-quantitative polymerase chain reaction results showed that miR-30a was significantly downregulated in NSCLC tissues compared with adjacent normal tissues (P<0.05). MYBL2 has a putative miR 30a target site in its 3'untranslated region according to previous data, prediction databases and TargetScan software. In the present study, a negative correlation was demonstrated between miR-30a and MYBL2 expression in NSCLC. Direct interaction between miR-30a and MYBL2 was also confirmed via a dual luciferase reporter assay. miR-30a overexpression inhibited the growth of A549 and H460 cells via MTT and bromodeoxyuridine incorporation assays, whereas miR 30a downregulation promoted cell proliferation. In addition, miR-30a overexpression not only increased cell apoptosis and induced cell cycle arrest in A549 and H460 cell lines, but also attenuated tumor growth, and mRNA and protein expression levels of MYBL2. The present findings suggest that miR-30a may suppress NSCLC by targeting MYBL2. PMID- 29434748 TI - MAPK pathway mediates the anti-oxidative effect of chicoric acid against cerebral ischemia-reperfusion injury in vivo. AB - The aim of the present study was to investigate the protective effect of chicoric acid on oxidative stress and inflammation in rats with cerebral ischemia reperfusion injury. A cerebral ischemia-reperfusion injury rat model was created via transient middle cerebral artery occlusion (MCAO) and rats were treated with various doses of chicoric acid (0, 1, 10 and 100 mg/kg). Neurological deficits and infarct volume were used to estimate the protective effects of chicoric acid treatment. Levels of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, nitric oxide (NO) and prostaglandin E2 (PGE2) were assessed. Western blot analysis was also used to measure the expression of cyclooxygenase (COX)-2, p38-mitogen activated protein kinase (MAPK), c-Jun, phosphorylated protein kinase B (p-AKT) and AKT. Chicoric acid exposure was observed to reduce neurological deficits and infarct volume in rats with cerebral ischemia-reperfusion injury. In addition, ROS production and inflammation were significantly suppressed following treatment with chicoric acid. Chicoric acid was demonstrated to significantly inhibit the upregulation of NO and PGE2 levels in rats following MCAO. Furthermore, chicoric acid significantly suppressed the MCAO-induced promotion of COX-2, p38-MAPK and c-Jun protein expression and enhanced the inhibition of p-AKT/AKT. These results suggest that chicoric acid has a protective effect, preventing oxidative stress and inflammation in rats with cerebral ischemia-reperfusion injury via the p38 MAPK, c-Jun and AKT signaling pathways. PMID- 29434749 TI - Clipping treatment of posterior communicating artery aneurysms associated with arteriosclerosis and calcification: A single center study of 136 cases. AB - It is widely acknowledged that arteriosclerosis and calcification of the parent artery and aneurysm neck make it difficult to clip posterior communicating artery (PCoA) aneurysms. A total of 136 cases of PCoA aneurysms accompanied by arteriosclerosis and calcification were collected and treated with clipping in the present study. Of the 136 patients, 112 were females (82.4%) and 24 were males (17.6%), with ages ranging from 37 to 76 years (mean age, 60.2 years). Rupture of a PCoA aneurysm was identified in 132 cases (97.1%), and there were 4 cases of unruptured PCoA aneurysms (2.9%). According to the severity of arteriosclerosis and calcification, the aneurysms were divided into type I, II or III. The treatment of type I aneurysms achieved the best curative effect. It is difficult to temporarily occlude type II and III aneurysms during surgery, and temporary occlusion failed in almost 50% of cases. Types II and III were prone to intraoperative aneurysm ruptures. A significantly higher rate of intraoperative aneurysm rupture was seen in type III compared with type II cases. Type II and III cases were more likely to be treated using a fenestrated clip for aneurysm clipping compared with type I cases, and fenestrated clips were used significantly more frequently in type III cases compared with type II cases. Arteriosclerosis and calcification were likely to affect the prognosis of patients, particularly in cases with type III arteriosclerosis and calcification of the parent artery and aneurysm neck. Therefore, the stratification of the arteriosclerosis and calcification of the parent artery and aneurysm neck into types I-III can guide the intraoperative aneurysm clipping strategy, aid in choosing the correct clips, and inform predictions of the occurrence of rupture and hemorrhage, as well as the prognosis for aneurysms. PMID- 29434750 TI - Comparative analysis of 3D time-resolved contrast-enhanced magnetic resonance angiography, color Doppler ultrasound and digital subtraction angiography in symptomatic carotid stenosis. AB - The present study aimed to compare the diagnostic value of contrast-enhanced magnetic resonance angiography (CE MRA) with 3D time-resolved imaging of contrast kinetics, color Doppler ultrasound (CDUS) and digital subtraction angiography (DSA) in extracranial carotid stenosis (CS). A total of 54 patients with symptomatic CS were subjected to CDUS, CE MRA and DSA examination. Results of DSA were defined as the standard, and a total of 216 vessels were examined. In each patient four vessels were examined, namely the bilateral common carotid arteries and the bilateral internal carotid arteries. The sensitivities and specificities of CE MRA and CDUS for various degrees of CS were also determined. It was observed that the sensitivities to mild-level (1-49%), moderate-level (50-69%) and severe-level (70-99%) CS were 85.45, 100 and 100% for CE MRA, and 78.18, 50 and 100% for CDUS, respectively. The corresponding specificities were 95.27, 98.58 and 99.53% for CE MRA, and 79.05, 93.36 and 98.10% for CDUS, respectively. In addition, the carotid sinus plaque detection rate for CDUS was significantly higher than that of DSA and CE MRA (both P<0.001). Detection rates for common carotid artery plaques and internal carotid artery plaques did not significantly differ among the three examination methods (all P>0.05). These data demonstrate that CE MRA has higher sensitivity and specificity than CDUS for the diagnosis of CS, and that CDUS has a higher carotid sinus plaque detection rate than DSA and CE MRA. Therefore, the combination of MRI and CDUS may be a 'gold standard' diagnostic method for the detection of moderate and severe CS. PMID- 29434751 TI - Clinical optimal dose of solifenacin succinate for nursing patients after transurethral resection of the prostate during the perioperative period. AB - Transurethral plasma kinetic resection is an efficient and safe surgery for the treatment of benign prostatic hyperplasia. Solifenacin succinate (SOL) is safe and clinically efficient for patients who endure transurethral resection of the prostate (TURP) during the perioperative period. The objective of this study was to evaluate the clinical optimal dose of SOL for nursing patients after TURP during the perioperative period. Patients were recruited and randomized into three groups: SOL (3 mg), SOL (6 mg), and SOL (10 mg). All patients received medical care for 3 weeks after TURP. Levels of inflammatory cytokines, including IL-6, epithelial neutrophil activation peptide-7 (ENA-7), tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-17 and IL-8, were investigated in the patients of all three groups. The efficacy of SOL was analyzed via the following scores: International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OBSS), short-form voiding (SFV) and storage score (TS) of International Continence Society (ICS). Outcomes showed that IL-2 and ENA-7 plasma concentration levels were upregulated, whereas TNF-alpha, IL-6, IL-17 and IL-8 were downregulated, in all three groups. The findings showed that patients that received SOL (6 mg) exhibited significant improvements compared to the other patient groups from baseline to the end of treatment, as determined by IPSS, OBSS, ICS, SFV, TS (P<0.01). In conclusion, these results indicate that SOL (6 mg) is the optimal dose for patients who undergo TURP during the perioperative period. Notably, treatment with SOL (6 mg) exhibited significant additional benefits in terms of lower urinary tract symptoms during the early recovery period after TURP, suggesting SOL is clinically significant for nursing patients who suffer have undergone TURP during the perioperative period. PMID- 29434752 TI - MicroRNA-152 inhibits ovarian cancer cell proliferation and migration and may infer improved outcomes in ovarian cancer through targeting FOXP1. AB - microRNA (miR) are a class of endogenous small non-coding RNA that are aberrantly expressed and are critical in tumorigenesis. Amongst them, miR-152 was reported to be dysregulated in epithelial ovarian cancer (EOC). However, the function and mechanism of miR-152 is not well understood. In the present study, total RNA was extracted from 58 ovarian epithelial carcinoma tissue samples and adjacent non tumor tissues and measured by reverse transcription-quantitative polymerase chain reaction. The observations of the present study revealed that the expression of miR-152 was significantly downregulated in EOC specimens, as well as three ovarian cancer (OC) cell lines. The higher expression of miR-152 indicated a better overall survival rate in patients with EOC. Following miR-152 mimic transfection into SKOV3 or OVCAR3 cells, MTT assay revealed that cell proliferation was significantly inhibited (P<0.05). Although miR-152 had no effect on SKOV3 cell migration, miR-152 inhibited OVCAR3 cell migration. Bioinformatics analyses and luciferase reporter assays demonstrated that miR-152 targeted the 3'-untranslated region (3'-UTR) of the forkhead box protein 1 (FOXP1). Furthermore, introducing FOXP1 without the 3'-UTR abrogated the effect of miR-152-induced proliferation and migration alteration, respectively. In addition, the expression level of FOXP1 was higher in the EOC tumor tissues and cell lines. Additionally, the level of miR-152 and FOXP1 was inversely correlated in grade 3 and 4 ovarian tumor tissues. Altogether, these observations indicated that miR-152 may be involved in the inhibition of OC through repression of FOXP1. In the future, miR-152 and FOXP1 may act as novel biomarkers for early detection of EOC or therapeutic targets. PMID- 29434753 TI - Smoking increases the risk of diabetic foot amputation: A meta-analysis. AB - Accumulating evidence suggests that smoking is associated with diabetic foot amputation. However, the currently available results are inconsistent and controversial. Therefore, the present study performed a meta-analysis to systematically review the association between smoking and diabetic foot amputation and to investigate the risk factors of diabetic foot amputation. Public databases, including PubMed and Embase, were searched prior to 29th February 2016. The heterogeneity was assessed using the Cochran's Q statistic and the I2 statistic, and odds ratio (OR) and 95% confidence interval (CI) were calculated and pooled appropriately. Sensitivity analysis was performed to evaluate the stability of the results. In addition, Egger's test was applied to assess any potential publication bias. Based on the research, a total of eight studies, including five cohort studies and three case control studies were included. The data indicated that smoking significantly increased the risk of diabetic foot amputation (OR=1.65; 95% CI, 1.09-2.50; P<0.0001) compared with non smoking. Sensitivity analysis demonstrated that the pooled analysis did not vary substantially following the exclusion of any one study. Additionally, there was no evidence of publication bias (Egger's test, t=0.1378; P=0.8958). Furthermore, no significant difference was observed between the minor and major amputation groups in patients who smoked (OR=0.79; 95% CI, 0.24-2.58). The results of the present meta-analysis suggested that smoking is a notable risk factor for diabetic foot amputation. Smoking cessation appears to reduce the risk of diabetic foot amputation. PMID- 29434754 TI - MicroRNA-191-5p exerts a tumor suppressive role in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is a common tumor of the urinary system. Previously, miR-191-5p has been reported to be associated with various types of cancer; however, its specific functions in RCC have not been investigated to date. In the present study, the expression of miR-191-5p in the 786-O and ACHN cell lines was detected in vitro by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results of RT-qPCR revealed that miR-191-5p was significantly downregulated in the two cell lines compared with the 293T cell line. miR-191-5p was also significantly downregulated in RCC tissue compared with paired normal tissue. In addition, the effects of miR-191-5p on cell proliferation, migration, invasion and apoptosis were examined by CCK-8, MTT, wound scratch, Transwell and flow cytometry assays. Downregulation of miR-191-5p was observed to promote cell proliferation, migration and invasion, as well as to repress the cell apoptosis of 786-O and ACHN cells. Therefore, the current study suggests that miR-191-5p functions as a tumor suppressor in RCC. Further studies are required to uncover the underlying signaling pathway of miR-191-5p and its potential role as a biomarker for early detection and prognosis prediction, and as a therapeutic target of RCC. PMID- 29434755 TI - Anti-tumour effects of polysaccharide extracted from Acanthopanax senticosus and cell-mediated immunity. AB - Acanthopanax senticosus, also known as Siberian ginseng, is widely distributed throughout northern Asia and used in traditional Chinese medicine; it has been reported to prevent a number of diseases. However, the association between the antitumour and immunostimulatory activities of polysaccharide extracted from A. senticosus (ASPS) remains to be elucidated. The aim of the present study was to investigate the anti-tumour and immunomodulatory effects of polysaccharide extracted from ASPS on Crocker sarcoma S180, hepatic carcinoma H22 and uterine cervical carcinoma U14 tumour cell lines implanted in mice. High performance liquid chromatography, gas chromatography and infrared spectroscopy were used to analyse the monosaccharide composition of ASPS. The monosaccharide composition of ASPS (Arabic candy: Xylose: Glucose: Mannose) was 7.1:22.3:7.6:1.0. On day 0, female Kunming mice, were injected subcutaneously with 1*108 tumour cells in 0.2 ml. The inoculated mice were subsequently divided into five groups (10 mice/group) as follows: Model group, treated with normal saline; positive control group, treated with 30 mg/kg cyclophosphamide (CTX); and three treatment groups, treated with 200, 100 or 50 mg/kg ASPS. Non-inoculated mice were divided into the normal group, which was treated with normal saline, and the negative control group, which was treated with 200 mg/kg ASPS (n=10/group). CTX and ASPS were administered intragastrically once daily for 10 days. All mice were sacrificed on day 11. ASPS was observed to have an inhibitory effect on the growth of S180, H22 and U14 cells in solid and ascites tumour-bearing mice. Serum interleukin (IL)-2 and IL-12 levels were significantly increased in S180 solid tumour-bearing mice treated with 200 or 100 mg/kg ASPS compared with mice in the normal, control and model groups (P<0.05), whereas serum IL-2 and IL-12 levels were significantly decreased in the cyclophosphamide treatment group compared with the normal, control and model groups (P<0.05). No significant difference in serum levels of tumour necrosis factor-alpha level was observed between any groups. In S180 and U14 solid tumour-bearing mice, no significant differences in serum levels of interferon (INF)-gamma level in were observed between groups; however, in H22 solid tumour-bearing mice, treatment with ASPS significantly increased serum INF gamma compared with the positive control group (P<0.05). The results may provide a basis for the potential application of ASPS in clinical treatment for cancer. PMID- 29434756 TI - Long-term survival after corrective surgeries in two patients with severe deformities due to Roberts syndrome: A Case report and review of the literature. AB - Roberts syndrome (RBS; OMIM 268300) is a rare autosomal recessive disease characterized by retardation before and after birth, cranial and maxillofacial deformities, limb anomalies and intellectual disability. Mutations in the establishment of cohesion 1 homologue 2 (ESCO2) gene on chromosome 8p21.1 have been found to be causative for RBS. We describe two patients with RBS with physical deformities and ll. One is an 8-year-old Yemeni male, and the other is his 13-year-old sister. These patients were diagnosed with RBS and underwent surgeries during their first to third years of life. Here, we present the cases for the two patients, focusing specifically on their surgical management and outcomes. Additionally, by reviewing the literature on RBS, we also summarize the proper surgical interventions for this rare disease. This paper describes the long-term follow-up of two patients with severe deformities who benefitted from corrective surgeries. The findings of this study indicate that patients who survive infancy and reach adulthood, even patients who present with severe disease symptoms, can benefit from corrective surgeries and lead better lives. PMID- 29434757 TI - miR-221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells. AB - Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated mortalities worldwide. MicroRNAs (miRNAs/miRs) serve important roles in tumor development, progression and metastasis. miR-221 has been reported to modulate proliferation, apoptosis, cell cycle distribution and cell migration in a variety of cancers. However, the function of miR-221 in the autophagy of cancer is unclear. In the present study, the role of miR-221 in the autophagy of CRC cells was investigated and its associated target was identified. Survival analysis using The Cancer Genome Atlas data suggested that a higher expression of miR-221 was associated with poor survival in patients with CRC. A Cell Counting kit-8 assay revealed that miR-221 promoted CRC cell proliferation. Autophagy flux analyzed by microtubule-associated protein 1 light chain 3 (LC3) turnover indicated that miR-221 reduced autophagy in CRC cells using different protease inhibitors (E64d and pepstatin A; Bafilomycin A1) in nutrient-rich medium or under starvation conditions. Tumor protein 53-induced nuclear protein 1 (TP53INP1) was identified as a potential novel target of miR-221 by bioinformative prediction. The protein expression of TP53INP1 was inversely regulated by miR-221 in CRC cells. Furthermore, luciferase activity assays were performed and indicated that miR-221 may regulate the luciferase activity of wild type TP53INP1 without interfering with the activity of mutant TP53INP1. These data suggested that miR-221 may promote the cell proliferation of CRC via the inhibition of autophagy and targeted TP53INP1. PMID- 29434758 TI - Protective effects of resveratrol improve cardiovascular function in rats with diabetes. AB - Resveratrol is a flavonoid with a stilbene structure that is able to suppress acute pulmonary thromboembolism-induced pulmonary artery hypertension. Furthermore, it possesses anti-cancer and antioxidant properties, is able to regulate blood lipids and increase life expectancy. In the present study, it was evaluated whether the protective effect of resveratrol was able to improve cardiovascular function in rats with diabetes. The effects of resveratrol on blood glucose, body weight, heart/body weight ratio, plasma triglyceride levels, heart rate, aspartate transaminase (AST)/alanine transaminase (ALT) ratio and total plasma insulin were evaluated. Levels of inflammation and oxidative stress were also evaluated using ELISA kits, and the expressions of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and phosphorylated (p)-p38 protein were evaluated via western blot analysis. The results demonstrated that administration of resveratrol in rats with diabetes related myocardial infarction (DRMI) significantly reduced blood glucose, body weight, plasma triglyceride levels, heart rate and AST/ALT ratio (all P<0.01) and significantly increased total plasma insulin (P<0.01). Furthermore, resveratrol significantly reduced levels of inflammation factors (P<0.01) and malondialdehyde, a marker for oxidative stress, in rats with DRMI (P<0.01). Resveratrol significantly increased the expression of eNOS (P<0.01) and suppressed the expression of VEGF and p-p38 (both P<0.01) in rats with DRMI. These results suggest that treatment with resveratrol is able to improve cardiovascular function via inhibition of eNOS and VEGF, and suppression of p38 phosphorylation in rats with DRMI. PMID- 29434759 TI - miR-613 inhibits gastric cancer progression through repressing brain derived neurotrophic factor. AB - MicroRNA (miR)-613 has been reported to function as a tumor suppressor in several types of cancer. However, the biological function and underlying mechanism in gastric cancer (GC) has remained elusive. Therefore, the aim of the present study was to assess the expression and biological role of miR-613 in GC tissues and cell lines. miR-613 expression was found to be downregulated in 38 GC tissue samples compared to that in their adjacent non-cancerous tissues, and low expression of miR-613 was associated with lymph node metastasis and advanced tumor-nodes-metastasis stage. A gain-of-function assay demonstrated that miR-613 overexpression reduced tumor cell proliferation, migration and invasion of SGC 7901 cells, as determined by MTT and Transwell assays. Furthermore, brain-derived neutrophic factor (BDNF) was identified as a direct target of miR-613 in GC cells by a luciferase reporter assay. BDNF expression was upregulated and inversely correlated with miR-613 levels in GC tissues. In addition, knockdown of BDNF expression mimicked the tumor suppressive effect of miR-613 in GC cells. In conclusion, these findings demonstrated that miR-613 functions as a tumor suppressor in GC by targeting BDNF. Thus, miR-613 is a potential therapeutic target for GC. PMID- 29434760 TI - Gambogic acid exerts cardioprotective effects in a rat model of acute myocardial infarction through inhibition of inflammation, iNOS and NF-kappaB/p38 pathway. AB - Gamboge, the dried resin secreted by Garcinia maingayii (gambogic tree), was previously demonstrated to exert anti-inflammatory effects. The present study examined the effects of gambogic acid, the major active constituent of gamboge, on myocardial infarction (MI) and inflammation in a rat model and explored the possible underlying mechanisms. The results demonstrated that gambogic acid inhibited the ratio of heart weight to body weight and myocardial damage (via lactate dehydrogenase and cardiac troponin T) in rats with MI. Gambogic acid suppressed the activation of interleukin (IL)-6 and tumor necrosis factor-alpha, and increased IL-10 levels in MI rats. Furthermore, gambogic acid reduced inducible nitric oxide synthase (iNOS), matrix metalloproteinase (MMP)-2, MMP-9, intercellular adhesion molecule-1 (ICAM-1), nuclear factor (NF)-kappaB/p65 and phosphorylated p38 protein in ischemic myocardial tissue of MI rats. In conclusion, gambogic acid exerted anti-inflammatory effects in MI rats by targeting the iNOS, MMPs, ICAM-1, NF-kappaB and p38 pathways. Gambogic acid may protect against MI-induced inflammation in rats, which may be associated with the activation of the NF-kappaB/p38 pathway. PMID- 29434761 TI - The value of X-ray digital tomosynthesis in the diagnosis of urinary calculi. AB - Urinary calculus is a common and recurrent condition that affects kidney function. The present study evaluated the use of digital tomosynthesis (DTS) and Kidneys-Ureters-Bladder (KUB) radiography as methods of diagnosing urinary calculi. Unenhanced multidetector computed tomography (UMDCT) was used in the diagnosis of calculi. KUB radiography and DTS procedures were conducted on patients prior to and following bowel preparation to detect kidney, ureteral and bladder calculi. Differences in diagnostic performance of KUB radiography and DTS imaging on prepared and unprepared bowel were evaluated using the chi2 test. The consistency of diagnostic results between two examining physicians was analyzed using the kappa test. A total of 138 calculi from 80 patients were detected via UMDCT. The calculi detection rates of KUB prior to and following bowel preparation were 47.8 and 66.7% respectively, and the calculi detection rate of DTS prior to and following bowel preparation were 94.2 and 96.4%, respectively. The detection rates of calculi >5 mm via KUB prior to and following bowel preparation were 56.6 and 73.5% respectively, and in DTS they were 100% prior to and following bowel preparation. Economically, DTS performed on the unprepared bowel was the most cost effective, followed by DTS on the prepared bowel, KUB on the unprepared bowel and KUB on the prepared bowel. Therefore, the current study concluded that DTS may be an appropriate first-line imaging technique in patients with urinary calculi. PMID- 29434762 TI - Parathyroid hormone promotes osteoblastic differentiation of endothelial cells via the extracellular signal-regulated protein kinase 1/2 and nuclear factor kappaB signaling pathways. AB - Vascular calcification (VC) occurs in patients with chronic kidney disease (CKD) and contributes to cardiovascular dysfunction and mortality. Parathyroid hormone (PTH) is a crucial regulator of VC. High PTH serum levels constitute as a major risk factor for patients with CKD. However, the effect and mechanism of PTH on osteoblastic differentiation in endothelial cells have not been fully elucidated. In the present study, the role of PTH in VC was investigated using an in vitro calcification model. Endothelial cells were stimulated with PTH in the femto- to picomolar range. As determined by western blot analysis and ELISA, osteoblastic differentiation, as indicated by the BMP2 marker, occurred with maximum effect at 1*10-10 mmol/l PTH. The results indicate that PTH promotes osteoblastic differentiation of endothelial cells, as demonstrated by the increased expression of bone morphogenetic protein (BMP) 2 and BMP4. In addition, western blot analysis revealed that PTH activated the extracellular signal-regulated protein kinase (Erk)1/2 and nuclear factor (NF)-kappaB signaling pathways. However, reverse transcription-quantitative polymerase chain reaction demonstrated that inhibitors specific to Erk1/2 and NF-kappaB eradicated the effect of PTH treatment on BMP2, BMP4, ALP and RUNX2 expression. These results demonstrate that PTH promotes the osteoblastic differentiation of endothelial cells via the Erk1/2 and NF-kappaB signaling pathways, which suggests a potential role of PTH in the promotion of VC. These findings provide an insight into the association between PTH and cardiovascular disease. PMID- 29434763 TI - Correlation between upper and lower airway inflammations in patients with combined allergic rhinitis and asthma syndrome: A comparison of patients initially presenting with allergic rhinitis and those initially presenting with asthma. AB - Allergic rhinitis (AR) and asthma often coexist. The terminology combined allergic rhinitis and asthma syndrome (CARAS) was introduced to describe patients with combined AR and asthma. The aim of the present study was to evaluate the correlation between eosinophilic inflammation in the upper and lower airways of patients with CARAS. Stable patients with CARAS initially presenting with AR or asthma were recruited. Healthy subjects and patients with AR alone were recruited as controls. Clinical characteristics, including disease history, lung function, nasal airway inspiratory resistance and upper and lower airway eosinophilic inflammation were evaluated and compared. A total of 73 subjects (22 patients with CARAS initially presenting with AR, 15 patients with CARAS initially presenting with asthma, 25 patients with AR alone and 11 healthy subjects) were studied. The nasal symptoms visual analogue scale scores at the week prior to enrollment and nasal airway inspiratory resistances were comparable among the groups. The percentage of predicted forced expiratory volume in 1 sec and percentage of predicted maximal middle expiratory flow in patients with CARAS initially presenting with asthma were significantly lower compared with the other three groups (P<0.05). No significant different in the percentage of eosinophils in the nasal lavage was observed between patients with CARAS and those with AR only; however, it was significantly increased compared with healthy subjects (P<0.05). The fractional concentration of exhaled nitric oxide and percentage of eosinophils in the sputum were significantly increased in patients with CARAS compared with those in the AR only and healthy subject groups (P<0.05). The difference in the percentage of eosinophils in the nasal lavage and sputum between patients with CARAS initially presenting with AR and initially presenting with asthma was not significant; however, a positive correlation between the percentage of eosinophils in the upper and lower airways was present in patients with CARAS initially presenting with AR only (r=0.526, P=0.030). PMID- 29434764 TI - Pediatric acute respiratory distress syndrome - current views. AB - Acute respiratory distress syndrome (ARDS) mainly involves acute respiratory failure. In addition to this affected patients feel progressive arterial hypoxemia, dyspnea, and a marked increase in the work of breathing. The only clinical solution for the above pathological state is ventilation. Mechanical ventilation is necessary to support life in ARDs but it itself worsen lung injury and the term is known clinically as 'ventilation induced lung injury' (VILI). At the cellular level, respiratory epithelial cells are subjected to cyclic stretch, i.e. repeated cycles of positive and negative strain, during normal tidal ventilation. In aerated areas of diseased lungs, or even normal lungs subjected to injurious positive pressure mechanical ventilation, the cells are at risk of being over distended, and worsening injury by disrupting the alveolar epithelial barrier. Further, hypercapnic acidosis (HCA) in itself confers protection from stretch injury, potentially via a mechanisms involving inhibition of nuclear factor kappaB (NF-kappaB), a transcription factor central to inflammation, injury and repair. Mesenchymal stem cells are the latest in the field and are being investigated as a possible therapy for ARDS. PMID- 29434765 TI - Platelet-rich plasma has beneficial effects in mice with osteonecrosis of the femoral head by promoting angiogenesis. AB - Platelet-rich plasma (PRP) is autologous and multifunctional. Platelet concentrate from blood contains highly concentrated platelets and various types of cells, including growth factors. PRP promotes the recovery of cell proliferation and differentiation. Osteonecrosis of the femoral head is a disease caused by femoral head damage or an insufficient blood supply, which leads to the death of bone cells and abnormal bone marrow composition. The subsequent repair of bone cells may result in changes to the structure of femoral head, femoral head collapse and joint dysfunction. PRP may promote the repair of injured articular cartilage in patients with joint diseases through the removal of harmful inflammatory factors. In the present study, the therapeutic effects and primary mechanism of PRP action were investigated using a glucocorticoid-induced femoral head osteonecrosis mouse model. Dexamethasone (DEX) and phosphate buffered saline were used as controls. The therapeutic efficacy of PRP to treat osteonecrosis in murine femoral heads was evaluated by assessing clinical arthritis scores. The present study indicated that mice with osteonecrosis of the femoral head treated with PRP exhibited downregulated expression of interleukin (IL)-17A, IL-1beta, tumor necrosis factor-alpha, receptor activator of nuclear factor kappa-B ligand, IL-6 and interferon-gamma in the inflammatory tissue. In addition, the levels of hepatocyte growth factor, intercellular adhesion molecule 1, osteopontin, platelet-derived endothelial cell growth factor, vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor-1 and transforming growth factor-beta were increased following treatment with PRP. Joint tissue histological staining demonstrated that PRP alleviated osteonecrosis of the femoral head and reduced humoral and cellular immune responses that promoted beneficial effects on the histological parameters. Furthermore, the concentration of glucocorticoids were significantly decreased in the serum of PRP-treated mice with osteonecrosis compared with the DEX group (P<0.01). Notably, PRP promoted beneficial effects in mice with osteonecrosis of the femoral head by stimulating angiogenesis. Therefore, the present study indicated that treatment with PRP promotes beneficial effects by preventing joint inflammation, cartilage destruction and bone damage, and stimulating the repair of joint tissue in mice with osteonecrosis of the femoral head. These preclinical data suggest that PRP may be developed as a novel method of treating osteonecrosis of the femoral head. PMID- 29434766 TI - MicroRNA-17-5p contributes to osteoarthritis progression by binding p62/SQSTM1. AB - Autophagy has been reported to be widely involved in the pathogenesis of osteoarthritis (OA). Increasing evidence suggested the important role of microRNAs (miRs) in the progression of OA. However, the functional role of miR-17 5p in OA development has remained to be fully elucidated. First, a mouse model of OA was established and the relative level of miR-17-5p was determined using PCR. Safranin O-fast green staining was applied to determine cartilage degeneration. TargetScan software and a dual luciferase reporter assay were applied to determine potential target genes of miR-17-5P. Autophagy measurement was performed using green fluorescent protein-microtubule-associated protein 1 light chain 3 (LC3) dot analysis. The results demonstrated that the relative expression of miR-17-5p was significantly decreased in OA model mice. In addition, the level of miR-17-5p was decreased in SW1353 human chondrosarcoma cells treated with interleukin-1beta. Furthermore, autophagy was found to be suppressed in the knee joints of experimental OA model mice. The dual luciferase reporter assay confirmed that p62/sequestosome 1 was a target gene of miR-17-5p. Of note, miR-17 5p inhibitor-induced reduction of LC3 dots was markedly reversed by knockdown of p62 in SW1353 cells. In conclusion, decreased miR-17-5p expression in chondrocytes induced autophagy mainly through suppressing the expression of p62, thereby contributing to OA progression. PMID- 29434767 TI - Simvastatin inhibits the apoptosis of hippocampal cells in a mouse model of Alzheimer's disease. AB - Alzheimer's disease is associated with cognitive impairments that affect memory and executive functions. Simvastatin is a cholesterol-lowering statin drug that is used to control levels of cholesterol in the blood, particularly in cases of hypercholesterolemia, and may be used in the treatment of aneurysmal subarachnoid hemorrhage. Previous results have indicated that the apoptosis of hippocampal cells may serve a critical role in the progression of Alzheimer's disease. In the present study, it was determined whether Simvastatin inhibited the apoptosis of hippocampal cells in vitro and in vivo. The therapeutic effects of Simvastatin were evaluated in 24-month-old triple-transgenic Alzheimer's disease (3*Tg-AD) mice, and the efficacy of Simvastatin in attenuating memory and cognitive impairment was investigated. Levels of apoptosis-related gene expression in the hippocampus and hippocampal cells of experimental mice were also detected. In addition, neuron excitability was assessed in the functionally relevant brain regions in the hippocampus. The data indicated that Simvastatin significantly suppressed the apoptosis of hippocampal cells in 3*Tg-AD model mice compared with controls (P<0.01). Furthermore, treatment with Simvastatin improved the dementia status of 3*Tg-AD mice, as determined by a learning task in which mice exhibited significantly reduced attention impairment, impulsivity and compulsivity (P<0.01). In addition, results demonstrated that Simvastatin significantly inhibited hippocampal damage and significantly improved neuronal loss in hippocampal structures classically associated with attentional performance when compared with untreated mice (P<0.01). Thus, Simvastatin prevented cognitive impairment by decreasing hippocampal cell apoptosis and improving learning-memory ability. Simvastatin treatment also increased the expression of anti-apoptotic genes and decreased the expression pro-apoptotic genes (P<0.01), which may have been associated with improved motor attention and cognitive competence in 3*Tg-AD mice. Collectively, these preclinical data indicated that Simvastatin was efficient in attenuating memory lapse and hippocampal cell apoptosis in a 3*Tg-AD mouse model. Thus, Simvastatin may be useful in improving the clinical outcome of patients with Alzheimer's disease. PMID- 29434768 TI - MicroRNA-222 regulates the viability of fibroblasts in hypertrophic scars via matrix metalloproteinase 1. AB - The present study aimed to determine the expression of microRNA (miR)-222 in hypertrophic scar (HS) tissues, and investigate the regulatory mechanism of miR 222 in HS. A total of 36 patients diagnosed with HS between August 2013 and May 2016 were included in the present study. HS tissues and HS-adjacent tissues were collected from patients. Primary fibroblasts were obtained from HS tissue. Reverse transcription-quantitative polymerase chain reaction was used to measure mRNA levels of matrix metalloproteinase 1 (MMP1) and miR-222. Western blotting was conducted to determine MMP1 expression and an MTT assay was performed to measure the viability of fibroblasts. A dual luciferase reporter assay was used to identify the binding of miR-222 to MMP1 mRNA. It was demonstrated that MMP1 serves a role in HS at the transcription level and that increased MMP1 expression inhibited the viability of fibroblasts. miR-222 serves a regulatory role in HS by targeting its target gene MMP1 and regulates the expression of MMP1 by binding to its 3'-untranslated region. The decreased expression of miR-222 suppresses the viability of fibroblasts by regulating MMP1 expression. The present study demonstrated that the downregulation of MMP1 in HS tissues is associated with the upregulation of miR-222 expression. miR-222 may therefore regulate the viability of fibroblasts in HS and the expression of related proteins via MMP1. PMID- 29434770 TI - MicroRNA-519a inhibits the proliferation and promotes the apoptosis of ovarian cancer cells through targeting signal transducer and activator of transcription 3. AB - Ovarian cancer is a highly prevalent cancer among women. Recent studies have indicated that microRNAs (miRs) may serve important roles in the pathogenesis of ovarian cancer. miR-519a was observed to be downregulated in tissue samples of patients with ovarian cancer; however, its role in ovarian cancer requires further investigation. The aim of the present study was to examine the role of miR-519a in the pathogenesis of ovarian cancer and determine its direct target. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to examine the expression of miR-519a in 20 patients ovarian cancer and 20 normal ovarian tissue samples. Subsequently, SKOV3 cells were cultured and transfected with miR-519a mimics, while MTT and Annexin V assays were performed to investigate the role of miR-519a in the proliferation and apoptosis of SKOV3 cells. In addition, RT-qPCR and western blotting were used to determine the expression levels of miR-519a, signal transducer and activator of transcription 3 (STAT3), myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-xl) in untransfected and miR-519a mimic-transfected SKOV3 cells. Dual-luciferase reporter assay was also performed to confirm whether STAT3 was a direct target of miR-519a. The results revealed that miR-519a was significantly downregulated in tissue samples of patients with ovarian cancer as compared with the normal ovarian tissues. Furthermore, transient overexpression of miR-519a inhibited the proliferation and promoted the apoptosis of SKOV3 cells, as well as decreased the mRNA and protein expression levels of STAT3, Mcl-1 and Bcl-xl. Finally, dual luciferase reporter assay confirmed that STAT3 was a direct target of miR-519a. In conclusion, the present study proved for the first time that miR-519a functions as a tumor suppressor by targeting STAT3 in ovarian cancer, suggesting that miR-519a may be a potential biomarker for the diagnosis and treatment of ovarian cancer. PMID- 29434769 TI - Protective effect of N-acetylcysteine activated carbon release microcapsule on myocardial ischemia-reperfusion injury in rats. AB - With the development of science and technology, and development of artery bypass, methods such as cardiopulmonary cerebral resuscitation have been practiced in recent years. Despite this, some methods fail to promote or recover the function of tissues and organs, and in some cases, may aggravate dysfunction and structural damage to tissues. The latter is typical of ischemia-reperfusion (IR) injury. Lipid peroxidation mediated by free radicals is an important process of myocardial IR injury. Myocardial IR has been demonstrated to induce the formation of large numbers of free radicals in rats, which promotes the peroxidation of lipids within unsaturated fatty acids in the myocardial cell membrane. Markers of lipid peroxidation include malondialdehyde, superoxide dismutase and lactic dehydrogenase. Recent studies have demonstrated that N-acetylcysteine (NAC) is able to dilate blood vessels, prevent oxidative damage, improve immunity, inhibit apoptosis and the inflammatory response and promote glutathione synthesis in cells. NAC also improves the systolic function of myocardial cells and cardiac function, prevents myocardial apoptosis, protects ventricular remodeling and vascular remodeling, reduces opiomelanocortin levels in the serum and increases the content of nitric oxide in the serum, thus improving vascular endothelial function. Therefore, NAC has potent pharmacological activity; however, the relatively fast metabolism of NAC, along with its large clinical dose and low bioavailability, limit its applications. The present study combined NAC with medicinal activated carbons, and prepared N-acetylcysteine activated carbon sustained-release microcapsules (ACNACs) to overcome the limitations of NAC. It was demonstrated that ACNACs exerted greater effective protective effects than NAC alone on myocardial IR injury in rats. PMID- 29434771 TI - Adeno-associated virus serotype 9 mediated vascular endothelial growth factor gene overexpression in mdx mice. AB - Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by the absence of dystrophin. Vascular endothelial growth factor (VEGF) is a heparin binding dimeric glycoprotein and principal angiogenic factor stimulating the migration, proliferation and expression of various genes in endothelial cells. Recently, VEGF was demonstrated to exhibit an antiapoptotic and direct myogenic effect, as well as to enhance muscle force restoration subsequent to traumatic injury. Therefore, the present study attempted to assess the muscle damage of VEGF overexpression in mdx mice. Adeno-associated virus serotype 9 (AAV9)-VEGF was administered intravenously to mdx mice. At 4 weeks after injection, VEGF was observed to be upregulated in the tibialis anterior muscle. In addition, the serum creatine kinase levels were significantly reduced and fatigue was slowed down, whereas the limb grip strength and weight of mice were markedly increased compared with the saline-treated mdx mice. Furthermore, significantly reduced inflammation and necrosis areas were observed in the muscle tissues of mice in the AAV9-VEGF group. These results suggested that AAV9-mediated VEGF gene overexpression was able to improve the muscle damage in mdx mice. PMID- 29434772 TI - Transcription activated p73-modulated cyclin D1 expression leads to doxorubicin resistance in gastric cancer. AB - Gastric cancer (GC) is one of the leading types of cancer in terms of mortality cases worldwide. Doxorubicin (Dox), a common chemotherapy drug, is frequently used to treat GC; however, acquired resistance to Dox hinders the chemotherapeutic outcome and causes shorter survival in GC patients. Several Dox resistant GC cell lines, including SGC7901, SNU-1 and SNU-5 were generated to investigate the mechanism of Dox resistance in GC. Various methods were used to test the response of Dox-resistant GC cells and parental cells, including flow cytometry, Cell Counting kit-8 assay, reverse transcription polymerase chain reaction and western blot analysis. In the present study, various Dox-resistant cells presented reduced apoptosis and cell cycle arrest in response to Dox treatment. Western blot results revealed that cyclin D1 was upregulated in Dox resistant cells, whereas inhibition or depletion of cyclin D1 re-sensitized the resistant cells to Dox treatment, which indicated that the induction of cyclin D1 expression was a result of the Dox resistance in GC cells. Furthermore, it was observed that a transcription activated form of p73 (TAp73), is the upstream modulator of cyclin D1, manipulating the cyclin D1 transcription with the assistance of activator protein 1 (AP-1). Overall, the present study data provided a rational strategy to overcome the Dox resistance in GC treatment by inhibiting cyclin D1 expression. PMID- 29434773 TI - Human adipose-derived mesenchymal stem cell-conditioned media suppresses inflammatory bone loss in a lipopolysaccharide-induced murine model. AB - Conditioned media (CM) from mesenchymal stem cells (MSCs) contains various cytokines, growth factors and microRNAs, which may serve important roles in modulating the inflammatory process. However, the effect of MSC-CM on inflammatory bone loss remains unknown. The present study investigated the effects of conditioned media from human adipose-derived mesenchymal stem cells (AMSC-CM) on the prevention of lipopolysaccharide (LPS)-mediated bone loss in mice. To investigate the underlying mechanisms of this effect, the effects of AMSC-CM on serum levels of inflammation-associated cytokines [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6 and IL-10] in LPS-treated mice, in addition to their mRNA expression in LPS-treated macrophages, was investigated. Micro-computed tomography and histological analysis revealed that AMSC-CM administration effectively inhibited LPS-induced bone destruction in vivo. ELISA analysis indicated that AMSC-CM significantly reduced the serum levels of proinflammatory cytokines (TNF-alpha, IL-1 and IL-6) in LPS-treated mice. Furthermore, AMSC-CM treatment significantly decreased the mRNA expression levels of TNF-alpha, IL-1 and IL-6 in macrophages treated with LPS. These findings indicate that AMSC-CM inhibits LPS-induced bone loss by decreasing the production of proinflammatory cytokines, suggesting that the use of AMSC-CM may be a potential therapeutic strategy for the treatment of inflammatory bone loss. PMID- 29434774 TI - Tanshinone IIA and Astragaloside IV promote the angiogenesis of mesenchymal stem cell-derived endothelial cell-like cells via upregulation of Cx37, Cx40 and Cx43. AB - Tanshinone IIA (Tan IIA) and Astragaloside IV (AGS-IV) were used as therapeutic treatments for coronary heart diseases (CHDs) in ancient China. However, the underlying mechanisms mediating the effects of Tan IIA and AGS-IV in angiogenesis remain unknown. In the present study, mesenchymal stem cells (MSCs) were induced to differentiate into endothelial cell (EC)-like cells in vitro and the effects of Tan IIA and/or AGS-IV on the functions of these cells, including cell proliferation and tube formation, were assessed. Compared with the single-agent groups (Tan IIA or AGS-IV only), combined-agent (Tan IIA and AGS-IV) treatment significantly enhanced the proliferation and tube formation capacity of EC-like cells. In addition, the expression of connexin 37 (Cx37), Cx40 and Cx43 in the combined-agent group was significantly increased compared with the single-agent groups. Furthermore, enhanced gap junctional intercellular communication (GJIC) was identified in the combined-agent group, as evidenced by increased dye transfer in scrape-loading dye transfer assays. In conclusion, Tan IIA and AGS-IV may promote the angiogenesis of EC-like cells by upregulating the expression of Cx37, Cx40 and Cx43 and enhancing GJIC function. The results of the present study may provide experimental evidence for the clinical application of Tan IIA and AGS IV as a treatment for CHDs. PMID- 29434775 TI - IL-25 promotes Th2 bias by upregulating IL-4 and IL-10 expression of decidual gammadeltaT cells in early pregnancy. AB - Decidual immune cells (DICs), consisting of both innate and adaptive immune cells, have a pivotal role in maintaining immune tolerance for normal pregnancy. Our previous study demonstrated that interleukin (IL)-25 stimulates the proliferation of decidual stromal cells (DSCs) in an autocrine manner. However, the role of IL-25 in functional regulation of DICs is largely unknown. Flow cytometry was used to analyze the expression of IL-25 and its receptor (IL-17RB) in DICs, and the effect of IL-25 on the expression of Ki-67, IL-4, IL-10, interferon (IFN)-gamma and transforming growth factor (TGF)-beta in decidual gammadeltaT cells. In addition, ELISA assays were performed to detect the secretion of IL-10 and TGF-beta in decidual gammadeltaT cells. The present findings indicated that decidual CD56 bright CD16-natural killer (NK) cells, natural killer T (NKT) cells, regulatory T (Treg) cells, CD3+ T cells, macrophages and gammadeltaT cells co-expressed IL-25 and IL-17RB, particularly gammadeltaT cells. Recombinant human (rh) IL-25 protein upregulated the expression of Ki-67, IL-4, and IL-10, but downregulated the expression of IFN gamma in gammadeltaT cells; however, anti-human IL-25 or IL-17RB neutralizing antibody reversed these effects. These data suggest that IL-25 may promote IL-10 production by gammadeltaT cells as well as the proliferation of gammadeltaT cells, and possibly forms a positive feedback loop to maintain a T helper 2 cell bias at the maternal-fetal interface and further contributes to the maintenance of successful pregnancy. PMID- 29434776 TI - Phytochemical screening and biological activity of Lamiaceae family plant extracts. AB - The current study aimed to investigate ethanolic extracts from the following medicinal plant species cultivated in western Romania: Melissa officinalis L., Rosmarinus officinalis L. (RO) and Salvia officinalis L. (SO). Antioxidant activity, total phenolics content and a profile of the main hydroxycinnamic acids (HCAs), including caffeic, ferulic, coumaric and rosmarinic acids, was determined for each plant extract. The in vitro antimicrobial activity against four bacterial strains (Escherichia coli, Listeria-, Pseudomonas aeruginosa and Staphylococcus aureus), and the effect on cell viability in two melanoma cell lines (B164A5 murine melanoma and A375 human melanoma) was also assessed. The results indicated that total phenolics content was 73.76-274.73 mg GAE.g-1 and the antioxidant activity was 2.32-2.87 mM Fe2+.100 g-1. There was found a strong positive correlation (R=0.9691) between total phenolics content and the antioxidant activity in the investigated samples. Regarding the HCA profile obtained by high performance liquid chromatography, the results demonstrated that rosmarinic acid represents the main identified compound. The ethanolic extracts of RO and SO exhibited antibacterial activity against Gram positive and Gram negative bacteria. RO was the most effective in terms of decreasing the cell viability of murine and human melanoma cell lines, while the HCAs did not exhibit any effect on cell viability. These findings suggest that plant extracts from the Lamiaceae family may used in the clinic as natural antibacterial agents. PMID- 29434777 TI - Effects of donepezil on cognitive functions and the expression level of beta amyloid in peripheral blood of patients with Alzheimer's disease. AB - Alzheimer's disease is a degenerative disease affecting the central nervous system for which donepezil is usually prescribed. The aim of the present study was to examine the effects of donepezil on the cognitive functions and expression levels of beta-amyloid (Abeta) in the peripheral blood of patients with Alzheimer's disease. In total, 76 patients with cognitive impairment, who visited the Department of Neurology of Binzhou City Center Hospital from June 2015 to September 2016, had memory decline for more than three consecutive months and underwent mini-mental state examination (MMSE) score screening, were selected for the study. All 76 patients were divided into the experimental (n=38) and control (n=38) groups by random number table. Patients in the control group were treated using conventional drugs combined with Nimotop, and patients in the experimental group received conventional drug therapy combined with donepezil, and the treatment outcomes in the two groups were compared. The MMSE scores and Montreal cognitive assessment (MoCA) scores after treatment in the two groups were significantly increased compared with those before treatment, and the differences were statistically significant (P<0.05). The activities of daily living scale (ADL) was decreased significantly (P<0.05). By comparing with the control group, the MMSE and MoCA scores in the experimental group were higher (P<0.05) while the ADL score was lower (P<0.05), and the adverse reaction rate during the treatment was lower (P<0.05). The Abeta levels in serum after medical treatment were obviously decreased in the two groups, and the difference was statistically significant (P<0.05). The serum Abeta level in the experimental group after treatment was lower than that in the control group (P<0.05). Drug therapy combined with donepezil has a certain degree of influence on the MMSE, ADL and MoCA scores of patients with Alzheimer's disease, which can decrease the Abeta level in peripheral blood and improve the cognitive functions of patients, thus having important clinical significance. PMID- 29434778 TI - Application of GATA-3 gene marker in the detection of hematologic disorders in children. AB - The aim of the present study was to investigate the use of GATA-3 markers in the detection of hematologic disorders in children. In total, 35 pediatric patients diagnosed with blood disease and treated in Henan Red Cross Blood Center from January 2014 to June 2015 were selected for the observation group. Another 32 healthy children were selected for the control group. The differences in the GATA 3 mRNA expression levels between the control and observation groups were detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The differences in the GATA-3 protein expression levels were detected via enzyme linked immunosorbent assay (ELISA) and western blot analysis. Compared with those in the healthy children, the mRNA expression levels of GATA-3 in patients with hematologic malignancies, acute lymphoblastic leukemia, myeloproliferative disorder, acute non-lymphocytic leukemia or thrombocytopenic purpura were significantly higher, and there were statistically significant differences between the groups (P<0.05). The results of ELISA showed that the GATA-3 protein expression levels in patients with hematologic malignancies (241.3+/-42.6 ug/l), acute lymphoblastic leukemia (196.3+/-21.6 ug/l), myeloproliferative disorder (284.2+/-45.1 ug/l), acute non-lymphocytic leukemia (269.3+/-31.4 ug/l) or thrombocytopenic purpura (272.1+/-39.1 ug/l) were significantly higher than those in healthy subjects (69.3+/-15.2 ug/l). The results of western blot analysis were consistent with those of ELISA. Based on our results, the expression levels of GATA-3 in healthy children and pediatric patients with blood diseases exhibit significant differences, and can be used as important markers for the clinical diagnosis of blood diseases in children. PMID- 29434779 TI - Selective activities of STAMPs against Streptococcus mutans. AB - The present study aimed to design, synthesize and screen specifically targeted antimicrobial peptides (STAMPs) that can selectively kill Streptococcus mutans (S. mutans) in the biofilm, and to detect protein metabolism, in order to investigate the mechanism of the antibacterial functions of STAMPs against S. mutans. A series of STAMPs were synthesized, and their effects on the selective antibacterial activity of S. mutans on single species and multi-species biofilms under the condition of the planktonic state were studied. The total protein of S. mutans was extracted before and after C11H, and matrix-assisted laser adsorption ionization-time of flight mass spectrometry identification was performed. The antibacterial activity on planktonic S. mutans was increased 3- to 4-fold via C8H, C11H, C12H, C13H, and C14H compared with hLF1-11 (H) alone, and there was no difference between Streptococcus gordonii (S. gordonii) and Streptococcus sanguis (S. sanguis). C8H, C11H, C12H, C13H, and C14H had significant inhibitory effects on the growth of S. mutans biofilm, but there were no significant effects on S. gordonii and S. sanguis biofilms. The number of S. mutans in biofilm decreased at 4 h after C8H, C11H, C12H, C13H and C14H and C8, C11, C12, C13 and C14 had no effect on the growth of planktonic and biofilm states of S. mutans, S. gordonii and S. sanguis species. C11H and C12H exhibited the most obvious effects, followed by C13H and C14H, and then C8H. A total of 21 protein spots with a mean change ratio of 1.5 were identified, all of which were downregulated after C11H. A total of 19 proteins were successfully identified, including cell cycle relative proteins, nucleic acid metabolism-related enzymes and proteins, virulence factors, protein biosynthesis and regulation, proteins involved in energy metabolism, and proteins with unknown function. In the present study, STAMPs with selective antibacterial activity against S. mutans grown in planktonic or biofilm states but without obvious effects on oral Streptococci and multi-species biofilm were successfully designed and synthesized. Differential protein expression before and after C11H was identified. The mechanism of the antibacterial function was also discussed. Results of the present study laid the foundation for application of STAMPs in the prevention and treatment of dental caries. PMID- 29434780 TI - Berbamine induces SMMC-7721 cell apoptosis via upregulating p53, downregulating survivin expression and activating mitochondria signaling pathway. AB - Hepatocellular carcinoma (HCC) is a primary malignancy in the liver, which is a global health problem. The present study aimed to observe the apoptotic effects of berbamine on SMMC-7721 cell lines and to investigate the effects of berbamine on induction of the intrinsic apoptotic pathway. The human HCC SMMC-7721 cells were cultured and cell morphology observed using a phase contrast microscope. SMMC-7721 cell apoptosis was examined by employing a flow cytometry assay. The nuclei of SMMC-7721 cells were stained with DAPI and observed by utilizing a laser fluorescence microscope. Cytochrome c (Cyto c) levels were evaluated by using immunofluorescence staining. The reverse transcription-semi-quantitative polymerase chain reaction (RT-sqPCR) and western blot analysis were used to examine the mRNA and protein levels of B-cell lymphoma 2, (Bcl-2), Bax, Bcl-2 associated X, apoptosis regulator, p53 and survivin, respectively. Berbamine inhibited SMMC-7721 cell growth at 20 and 0 umol/l, compared with control group (0 umol/l berbamine). DAPI results demonstrated that berbamine affected the nucleus morphology of SMMC-7721 cells. Berbamine at a concentration of 20 umol/l (P<0.05) and 40 umol/l (P<0.01) significantly enhanced apoptosis rate compared with control group. Berbamine triggered Cyto c release from SMMC-7721 cell nuclei to the cytoplasm. Berbamine (10, 20, 40 umol/l) significantly enhanced Bax and p53 levels and decreased Bcl-2 and survivin levels compared with control group, according to RT-sqPCR and western blot assay findings. In conclusion, berbamine induced SMMC-7721 cell apoptosis, through upregulating p53 expression and downregulating survivin expression, which further triggered mitochondria signaling pathway-mediated apoptosis. PMID- 29434781 TI - Metoprolol protects cardiomyocytes in rabbit model of heart failure by regulating Cx43. AB - This study investigated the protective effect of metoprolol on cardiomyocytes in rabbits with heart failure and its possible mechanism. Sixty New Zealand white rabbits were randomly divided into infarction group and non-infarction group, 30 in each group. Myocardial infarction was constructed by ligation of anterior descending branch of coronary artery. Coronary artery threading without ligation after thoracotomy was performed for rabbits in non-infarction group. After model construction, rabbits in each group were further divided into control group (n=15) and metoprolol group (n=15), and fed with normal diet and normal diet + metoprolol. Animals were sacrificed 8 weeks later, and ventricular tissue around infarction area was collected. Expression of connexin 43 (Cx43) in myocardium was detected by immunohistochemistry. Expression of Cx43 protein and mRNA in each group was detected by western blot and reverse transcription PCR. The Cx43 protein was positively expressed in non-infarction group and was evenly distributed in intercellular space. Compared with non-infarction group, expression of Cx43 in infarction group was significantly decreased or even disappeared, while the decrease in expression level of Cx43 and the degree of dispersion were lower in metoprolol group than in control group. There was no significant difference in expression of level of Cx43 protein and mRNA between the subgroups of non-infarction group (P>0.05). In infarction group, expression level of Cx43 protein and mRNA in the metoprolol group were significantly higher than those in control group (P<0.05). The results showed that metoprolol can protect cardiomyocytes after myocardial infarction, and the possible mechanism is related to the regulation of Cx43 expression in cardiomyocytes. PMID- 29434782 TI - Effects of IL-10 on OX62, MHC-II and CD86 in bone marrow DCs in rats with organophosphate poisoning. AB - This study investigated the effect of interleukin (IL)-10 on the expression of OX62, MHC-II and CD86 in bone marrow dendritic cells (DCs) in rats with organophosphorus poisoning. Sixty adult SD rats were randomly divided into normal control group (group A) (20 rats), 20 rats with organophosphorus pesticide poisoning (group B), 20 rats with organophosphorus poisoning, and IL-10 treated (group C). Group A was not treated with special treatment. Group B was treated with 4% omethoate by gavage to establish the model of organophosphate poisoning. Group C was treated with omethoate to establish the model of organophosphate poisoning, then the rats were given intraperitoneal injection of IL-10 for 3 continuous days. Rats were sacrificed after 3 days, bone marrow lymphocytes were extracted, DCs were collected and cultured for 7 days, the expression of DC surface antigen OX62, MHC-II, CD86 and related proteins was detected by flow cytometry and western blotting after cell maturation. The expression of DC surface antigen and corresponding protein increased in group B, and decreased in group C, the difference was statistically significant (P<0.05). The results showed that the expression of OX62, MHC-II and CD86 in bone marrow DCs is enhanced and the cellular immune function is enhanced after organophosphate poisoning. IL-10 can down-regulate the antigen presenting function of DCs, achieve anti-inflammatory effect and assist the treatment of organophosphorus pesticide poisoning. PMID- 29434783 TI - The application of nalbuphine in patient-controlled intravenous analgesia for patients undergoing subtotal gastrectomy. AB - The aim of the present study was to investigate the analgesic effect and safety of the application of different doses of nalbuphine in patient-controlled intravenous analgesia (PCIA) for patients undergoing subtotal gastrectomy. A total of 120 patients, who underwent subtotal gastrectomy at our hospital between May, 2015 and January, 2017 under combined spinal epidural combined anesthesia, were selected. The patients received PCIA after surgery. The patients were randomly divided into four groups, including the morphine (MOP group), nalbuphine 60 mg (N60 group), nalbuphine 80 mg (N80 group) and nalbuphine 100 mg (N100 group). The first dose of PCIA treatment was 2 ml, the background dose was 2 ml/h, PCIA dose was 0.5 ml, and the lockout time was 15 min. Postoperative vital signs and adverse reactions (bleeding, fullness and aching of upper abdomen and vomiting) were recorded. The visual analogue scale (VAS) and Ramsay sedation score of patients were evaluated. The number of PCIA and analgesia-related complications during analgesia were recorded. No significant differences in general data were found among the four groups (P>0.05). The VAS score of the three nalbuphine groups was lower than that of the MOP group, but the differences were not significant. All postoperative Ramsay sedation scores of the four groups showed appropriate sedation, but no significant differences were found between the groups. Compared with the MOP group, the use of postoperative PCIA was significantly delayed and the number of PCIA was significantly smaller in the three nalbuphine groups (P<0.05). The results show that the analgesic effect and safety of the use of PCIA for patients undergoing subtotal gastrectomy were satisfactory. PMID- 29434784 TI - Effects of intratumoral injection of immunoactivator after microwave ablation on antitumor immunity in a mouse model of hepatocellular carcinoma. AB - This study investigated the effects of intratumoral injection of immunoactivator after microwave ablation on antitumor immunity in a mouse model of hepatocellular carcinoma. Hepatocellular carcinoma cell line Hepa1-6 was subcutaneously injected into C57/B6 mice to establish a mouse model of hepatocellular carcinoma. When tumor diameter reached 8 mm, microwave ablation was performed for 3 min with temperature controlled at 55 degrees C. Cytokine sustained-release microspheres (CytoMPS) containing human interleukin-2 (hIL-2) and mouse granulocyte macrophage colony-stimulating factor (mGM-CSF) were injected into the tumor of mice in the experimental group (n=5) at 3, 7 and 14 days after ablation, while sustained release microspheres containing no cytokine were used in the control group (n=5). Mice were sacrificed on the 17th day after ablation, and CD4+ and CD8+ T cells in peripheral blood were counted by flow cytometry. Spleen was collected from the mice to isolate lymphocytes. Lactate dehydrogenase (LDH) release assay was used to determine the cytotoxicity of spleen cells to Hepal-6 cells. Injection of CytoMPS after ablation increased the percentage of CD4+ and CD8+ T cells in peripheral blood. Cytotoxicity of CD8+ CTL to Hepal-6 is significantly higher in experimental group than in control group (P<0.01). The results showed that intratumoral injection of CytoMPS containing hIL-2 and mGM-CSF can significantly increase the proportion of CD4+ and CD8+ T cells in blood and increase the cytotoxicity of CTL cells to tumor cells in mice with hepatocellular carcinoma. PMID- 29434785 TI - Nephroprotective effects of diacylglycerol on diabetic nephropathy in type 2 diabetic rats. AB - Diacylglycerol (DAG) has been reported to reduce the serum lipid and glucose levels more effectively compared with triacylglycerol (TAG). The present study examined the long-term effects of dietary DAG on rats with type 2 diabetic nephropathy (DN). The type 2 DN model was established by administering a high-fat and high-calorie diet along with an intraperitoneal injection of 35 mg/kg body weight streptozocin, and the disease developed over the following 8 weeks. Sprague-Dawley rats were then randomly divided into the control, TAG, low-dose DAG (Low-DAG) and high-dose DAG (High-DAG) groups. Blood glucose (BG), lipid levels and renal function parameters were then measured. The results revealed that the body weight in the High-DAG group was significantly reduced compared with the TAG group, while there was no significant difference in the food intake between TAG and DAG groups. BG, advanced glycation end products (AGEs), TAG, low density lipoprotein cholesterol, urine protein and urine albumin levels were significantly reduced, while high-density lipoprotein cholesterol levels were significantly increased in the two DAG groups. In addition, hematoxylin-eosin stained glomeruli presented decreased glomerular enlargement and mesangial expansion in the DAG groups. Immunohistochemical detection revealed that the levels of transforming growth factor-beta1 and connective tissue growth factor in renal tissues of the DAG groups were also significantly reduced compared with the TAG group. These findings indicate that DAG oils can significantly reduce BG levels and the deposition of AGEs in renal tissue, as well as regulate the levels of transforming growth factor-beta1 and connective tissue growth factor, thus delaying the progression of nephropathy. PMID- 29434786 TI - MicroRNA-429 decreases the invasion ability of gastric cancer cell line BGC-823 by downregulating the expression of heparanase. AB - The present study aimed to measure the expression of microRNA (miRNA/miR) -429 in gastric cancer and investigate the associated mechanism of action. A total of 30 patients with gastric cancer who received radical or palliative resection at Jining No. 1 People's Hospital between January-October 2016 were included in the present study. Resected gastric cancer and tumor-adjacent tissues were resected. Gastric cancer BGC-823 cells were transfected with miR-429 mimics to induce the overexpression of miR-429, or transfected with small interfering (si)RNA of heparanase (HPSE) for the silencing of HPSE. Reverse transcription-quantitative polymerase chain reaction was used to measure the expression of miR-429 or HPSE mRNA. Western blotting was employed to determine the protein expression of HPSE. Cell-Counting Kit-8 assay was carried out to test cell proliferation and a Transwell assay was used to determine cell invasion ability. Expression of HPSE mRNA and protein in gastric cancer tissues was increased compared with tumor adjacent tissues. Reduced expression of miR-429 in gastric cancer tissues may be associated with the targeting of HPSE mRNA by miR-429. Overexpression of miR-429 inhibited the transcription and translation of the HPSE gene. However, overexpression of miR-429 did not affect the proliferation of gastric cancer cells. Notably, overexpression of miR-429 reduced the invasion ability of gastric cancer cells. Transfection with HPSE siRNA decreased the expression of the HPSE protein in BGC-823 cells and inhibited the occurrence and development of gastric cancer by reducing the invasion ability of the cells. The present study demonstrated that expression of miR-429 in gastric cancer tissues was significantly reduced compared with tumor-adjacent tissues. As a tumor-suppressor gene, miR-429 decreases the invasion ability of gastric cancer cells by downregulating the expression of HSPE. PMID- 29434787 TI - Expression and role of microRNA-1271 in the pathogenesis of osteosarcoma. AB - The aim of the current study was to investigate the expression and role of microRNA (miR)-1271 in the pathogenesis of osteosarcoma, and the associated underlying mechanisms. Tissue samples from 45 patients with osteosarcoma were collected, while the 143B, MG-63 and U-2 OS osteosarcoma cell lines were also cultured. The expression levels of miR-1271 in the tissues and cells were detected with reverse transcription-quantitative polymerase chain reaction, and 143B osteosarcoma cells were subjected to miR-1271 manipulation. In addition, the cell proliferation, cell cycle progression, and migration and invasion abilities were assessed by Cell Counting Kit-8 assay, flow cytometry and Transwell chamber assay, respectively. Tissue inhibitor of metalloproteinases 2 (TIMP2) expression level was also detected with western blot analysis. Dual-luciferase reporter assay was performed to investigate the interaction between miR-1271 and TIMP2. The results revealed that miR-1271 expression was significantly elevated in the osteosarcoma tissue and was closely correlated with the clinical TNM staging. The expression levels of miR-1271 were also upregulated in the osteosarcoma cells, with the highest expression observed in 143B cells. Inhibition of miR-1271 significantly inhibited the cell proliferation, G1/S phase transition, and the migration and invasion abilities of 143B cells, while it also resulted in upregulated TIMP2 expression in these cells. Furthermore, overexpression of TIMP2 significantly inhibited the cell proliferation, G1/S phase transition, and migration and invasion abilities of 143B cells. Dual-luciferase reporter assay demonstrated that miR-1271 targeted on the 3'-untranslated region of TIMP2 mRNA. In conclusion, the expression levels of miR-1271 were significantly elevated in osteosarcoma tissues and cells. miR-1271 downregulated the expression of TIMP2 to promote the proliferation and enhance the migration and invasion abilities of 143B osteosarcoma cells, functioning as an oncogene. PMID- 29434788 TI - Combined treatment with simvastatin and rapamycin attenuates cardiac allograft rejection through the regulation of T helper 17 and regulatory T cells. AB - Allograft rejection is an important issue post cardiac transplantation. In order to investigate the effect of combined treatment with simvastatin and rapamycin on allograft rejection, a cardiac transplantation rat model was employed in the present study. The survival time of rats following cardiac transplantation was recorded, while histopathological alterations were assessed by hematoxylin and eosin staining. The levels of transcription factors were measured by reverse transcription-quantitative polymerase chain reaction. In addition, the levels of CD4+ interleukin (IL)-17+ cells and CD4+ forkhead box P3 (FOXP3)+ cells in the allografts and CD4+ T cells and CD8+ T cells in the spleens were detected by flow cytometry. The results of the current study demonstrated that, following treatment with simvastatin and rapamycin, the survival time of model rats was prolonged, and the histopathological damage was attenuated. Treatment with simvastatin and rapamycin also led to decreased retinoic acid receptor-related orphan receptor gammat (RORgammat) level, increased FOXP3 level, reduced levels of CD4+IL-17+, CD4+ T and CD8+ T cells, and increased level of CD4+FOXP3+ cells. In conclusion, the current study observed that simvastatin and rapamycin performed a synergistic effect to reduce cardiac transplantation rejection. Thus, combined therapy of simvastatin and rapamycin may be a promising adjuvant therapy to reduce rejection post cardiac transplantation. PMID- 29434789 TI - Effects of pumpless extracorporeal lung assist on hemodynamics, gas exchange and inflammatory cascade response during experimental lung injury. AB - Pumpless extracorporeal lung assist (pECLA) has been reported to efficiently remove the systemic CO2 production and provide mild to moderate oxygenation, thereby allowing for ventilator settings and modes prioritizing oxygenation and lung protection. However, an adequate bypass flow, the capacity to provide respiratory support and the effect on the inflammatory cascade response and tissue perfusion require further study to be determined. After induction of acute lung injury (ALI) by oleic acid injection, pECLA was implemented in 12 anaesthetized and mechanically ventilated dogs for 48 h. Improved oxygenation [partial oxygen pressure (PaO2) and oxygen saturation (SaO2) was measured by arterial blood gas analysis, and increased by 29 and 18%, respectively] and CO2 elimination (partial CO2 pressure decreased by 43.35%) were obtained after pECLA implementation. A maximum arterio-venous shunt flow of up to 25% of the foundational CO resulted in stable hemodynamics. The pECLA procedure did not elicit any further increase in the concentration of tumor necrosis factor-alpha, interleukin (IL)-6, IL-8 and endothelin-1 compared with that in the group subjected to oleic acid injection only. In addition, the pECLA procedure had no effect on lactate levels and urine production. In conclusion, pECLA is an efficient and promising strategy for providing a mild to moderate oxygenation and adequate decarboxylation, while avoiding excessive inflammatory cascade response and tissue hypoperfusion in an experimental ALI model. PMID- 29434790 TI - Cyanidin ameliorates cisplatin-induced cardiotoxicity via inhibition of ROS mediated apoptosis. AB - Oxidative stress and apoptosis serve an essential role in cisplatin-induced cardiotoxicity, which limits its clinical use, and increases the risk of cardiovascular disease. As a natural drug, the antioxidant and antitumor effects of cyanidin have been recognized, but its protective effect on cisplatin-induced cardiomyocyte cytotoxicity remains unclear. H9c2 cells were treated with cisplatin (1-40 uM) in the presence or absence of cyanidin (40-80 uM), subsequently; oxidative stress, apoptosis and mitochondrial function were assessed using several techniques. The results demonstrated that cyanidin was able to dose-dependently reverse cisplatin-induced cell damage and apoptosis, attenuate the accumulation of reactive oxygen species (ROS), and mitochondrial membrane potential depolarization, downregulate the expression of Bcl-2 homologous antagonist/killer, upregulate the expression of apoptosis regulator Bcl-2, and reduce the activation of caspase 3, caspase 9, but not caspase 8. Furthermore, the results revealed that the translocation of apoptosis regulator Bax (Bax) from the cytoplasm to the mitochondrial membrane serves an essential role in cisplatin-induced apoptosis. Cyanidin was able to block the translocation of Bax and reduce the release of cytochrome c from cytoplasm. These data indicate that cyanidin attenuates cisplatin-induced cardiotoxicity by inhibiting ROS mediated apoptosis, while the mitochondrial and extracellular regulated kinase signaling pathways may also serve important roles. PMID- 29434791 TI - Efficacy and safety of combined immunosuppressive therapy plus umbilical cord blood infusion in severe aplastic anemia patients: A cohort study. AB - The present study aimed to evaluate the efficacy and safety of combined immunosuppressive therapy (IST) plus umbilical cord blood infusion (UCBI) in severe aplastic anemia (SAA) patients. A total of 68 patients with SAA were enrolled in the current prospective cohort study and divided into the IST (n=35; positive control) and IST+UCBI (n=33; experimental) groups according to the treatment conditions. Patients in the IST group were treated with rabbit antithymocyte globulin (r-ATG) at a dose of 2.5 mg/kg through intravenous infusion once a day for five days. This was combined with oral cyclosporine A (CsA) at a dose of 3-5 mg/kg twice a day for 2 years. Patients in the IST+UBCI group were treated with r-ATG and CsA at the same doses and frequencies as the IST group plus one UCBI 1 day after the final treatment with r-ATG. At 6 months post treatment, the complete response and overall response rate (ORR) of the IST+UCBI group were markedly higher compared with those in the IST group. Furthermore, patients in the IST+UCBI group achieved absolute neutrophil count (ANC) and platelet count responses more rapidly as compared with the IST group. However, no difference in the hemoglobin (Hb) response was identified between the two groups. In addition, SAA patients achieved responses in the ANC and platelet count more rapidly in comparison with very severe aplastic anemia (VSAA) patients, while the number of days to Hb responses were similar in the SAA and VSAA patients. Multivariate logistic regression analysis also revealed that IST+UCBI treatment was an independent predicting factor for patients achieving complete response or partial response, whereas VSAA was an independent predictor of a worse ORR. Platelet and reticulocyte were also independent predicting factors. Finally, the survival of patients was similar between the groups, and no difference in the safety of the treatment was observed. In conclusion, combined IST plus UCBI treatment may be applied as an effective and safe therapy for SAA patients. PMID- 29434792 TI - Pine needle oil induces G2/M arrest of HepG2 cells by activating the ATM pathway. AB - Over the last two decades, inducing DNA damage of cancer cells by natural medicines has become a research hotspot in the field of cancer treatment. Although various natural medicines have anticancer effects, very few studies have been conducted to explore the anti-cancer effect of pine needle oil. In the present study, the role of pine needle oil in inducing G2/M arrest in HepG2 cells was investigated. The data revealed that pine needle oil could induce DNA damage in a dose-dependent manner. In the pine needle oil-treated HepG2 cells, the protein levels of phosphorylated (p)-ataxia-telangiectasia mutated (ATM), gamma H2A histone family, member X, p-p53, p-checkpoint kinase 2 and p-cell division cycle 25C were evidently increased, indicating that pine needle oil facilitated G2/M arrest in HepG2 cells through the ATM pathway. In response to the treatment with pine needle oil, ATM was activated in HepG2 cells, which subsequently phosphorylated downstream targets and induced G2/M arrest. In summary, the data of the present study indicated that pine needle oil induces G2/M arrest in HepG2 cells by facilitating ATM activation. PMID- 29434793 TI - Development and identification of Set transgenic mice. AB - As a multifunctional protein involved in numerous biological processes, Set is expressed in several embryonic and adult organs. Furthermore, Set is overexpressed in numerous types of human cancers, including acute myeloid leukemia, breast cancer and pancreatic cancer. The expression of Set in germ cells is involved in gonad development, and the overexpression of Set has been observed in polycystic ovaries. In order to elucidate the physiological and pathological roles of Set, a Set transgenic mouse model was developed, in which the global overexpression of Set in adult tissues could be induced via the Cre/loxP system with the precise deletion of the Stop fragment in double transgenic hybrids. This result was then confirmed by genotypical and protein analysis using polymerase chain reaction and bioluminescence imaging. In conclusion, the conditional Set transgenic mice carrying a reporter system were successfully generated. The transgenic mice open a new window for the further investigation of the function of Set using tissue-specific Cre mice and inducible Cre systems. PMID- 29434794 TI - Biomechanical analysis of brachial plexus injury: Availability of three dimensional finite element model of the brachial plexus. AB - Adult brachial plexus injuries frequently lead to significant and permanent physical disabilities. Investigating the mechanism of the injury using biomechanical approaches may lead to further knowledge with regard to preventing brachial plexus injuries. However, there are no reports of biomechanical studies of brachial plexus injuries till date. Therefore, the present study used a complex three-dimensional finite element model (3D-FEM) of the brachial plexus to analyze the mechanism of brachial plexus injury and to assess the validity of the model. A complex 3D-FEM of the spinal column, dura mater, spinal nerve root, brachial plexus, rib bone and cartilage, clavicle, scapula, and humerus were conducted. Stress was applied to the model based on the mechanisms of clinically reported brachial plexus injuries: Retroflexion of the cervical, lateroflexion of the cervical, rotation of the cervical, and abduction of the upper limb. The present study analyzed the distribution and strength of strain applied to the brachial plexus during each motion. When the cervical was retroflexed or lateroflexed, the strain was focused on the C5 nerve root and the upper trunk of the brachial plexus. When the upper limb was abducted, strain was focused on the C7 and C8 nerve roots and the lower trunk of the brachial plexus. The results of brachial plexus injury mechanism corresponded with clinical findings that demonstrated the validity of this model. The results of the present study hypothesized that the model has a future potential for analyzing pathological conditions of brachial plexus injuries and other injuries or diseases, including that of spine and spinal nerve root. PMID- 29434795 TI - Correlations of MMP-1, MMP-3, and MMP-12 with the degree of atherosclerosis, plaque stability and cardiovascular and cerebrovascular events. AB - We analyzed the effects of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-12 on the degree of carotid atherosclerosis (CAS) and plaque stability, and investigated their correlations with cardiovascular and cerebrovascular events (CCEs). Two hundred CAS patients were enrolled. Carotid intima-media thickness (IMT) was measured using ultrasonic examination. Patients were divided into the no plaque group (NP group), stable plaque group (SP group), and vulnerable plaque group (VP group). The Crouse method was used for the evaluation of plaque scores. Additionally, 60 healthy subjects were enrolled as the control group. Serum triacylglycerol (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were analyzed. The serum protein levels of MMP-1, MMP-3, and MMP-12 were measured by western blotting. The frequency of CCEs within 2 years was recorded, and its correlation with MMP-1, MMP-3, and MMP-12 was analyzed. The CAS plaque scores in the SP and VP groups were significantly increased compared with the NP group, and the difference between the SP and VP groups was significant. The levels of TC, TG, LDL-C, and HDL-C of CAS patients were significantly increased compared with those in the control group, but the differences in these indexes between the patient groups were not significant. Western blotting showed that the levels of MMP-1, MMP-3, and MMP-12 in the patient groups were significantly increased compared with those in the control group, and the protein levels in the VP group were significantly higher than those in the SP and NP groups. Additionally, the levels of MMP-1, MMP-3, and MMP-12 had significantly positive correlations with the occurrence of CCEs in CAS patients. In conclusion, MMP-1, MMP-3, and MMP-12 are positively correlated with CCEs in CAS patients. They can be used as markers for the clinical diagnosis and prognosis of CAS. PMID- 29434796 TI - ADAM proteases involved in inflammation are differentially altered in patients with gastritis or ulcer. AB - ADAM metallopeptidase domain (ADAM)9, 10 and 17 have alpha-secretase activity that regulates ectodomain shedding of factors involved in inflammation, cell proliferation, angiogenesis, and wound healing. The secretase activity of ADAM proteins is known to induce an inflammatory response. However, under certain conditions, a lack of secretase activity may induce inflammation suggesting differential roles of ADAM proteins with secretase activity. To the best of our knowledge, the present study evaluated the changes in alpha-secretase activity and expression of associated ADAM proteases (ADAM9, 10 and 17) in the gastric mucosa of patients with gastritis and ulcers, for the first time. Gastroduedonal mucosal samples from 42 patients were snap-frozen to determine changes in alpha secretase activity. Twenty-four of these patients had gastritis, 9 patients had duedonal ulcers and 9 patients did not have any pathological changes. Paraffin embedded gastric specimens (n=32) were used for immunohistochemical detection of ADAM9, ADAM10 and ADAM17. alpha-secretase activity of the gastric mucosa of healthy subjects was significantly higher compared with the uninvolved mucosa of patients with gastritis or ulcer. These results were associated with the immunohistochemical staining results, which demonstrated that ADAM10 expression markedly decreased in glandular epithelial cells and ADAM9 expression was lost in foveolar epithelial cells of gastric mucosa adjacent to ulcer. However, ADAM17 expression was increased in the normal gastric mucosa of patients with bleeding peptic ulcers and in the gastric mucosa adjacent to the ulcer suggesting a counteracting role of ADAM17. Decreased ADAM9 and 10 expression, and an associated decrease in alpha-secretase activity may predispose to chronic gastritis and ulcer. Further studies are required to determine the possible etiological role of increased ADAM17 expression. PMID- 29434797 TI - Effect of different surface treatments and retainer designs on the retention of posterior Pd-Ag porcelain-fused-to-metal resin-bonded fixed partial dentures. AB - The aim of this study was to investigate the adhesive property of palladium silver alloy (Pd-Ag) and the simulated clinical performance of Pd-Ag porcelain fused-to-metal (PFM), resin-bonded, fixed partial dentures (RBFPDs). A total of 40 Pd-Ag discs (diameter=5 mm) were prepared and divided into the following four groups (n=10): a) No sandblasting, used as a control; and b, 50 um; c, 110 um; and d, 250 um aluminum oxide (Al2O3) particles, respectively. Another 50 discs were pre-sandblasted and divided into five groups (n=10) subjected to different treatments: e) Sandblasting, used as a control; f) silane; g) alloy primer; h) silica coating + silane and i) silica coating + alloy primer. All 90 discs were bonded to enamel with Panavia F 2.0 and then subjected to shear bond strength (SBS) testing. The fracture surfaces were examined by scanning electron microscopy. Next, 40 missing maxillary second premolar models were restored with one of the four following RBFPD designs (n=10): I) A premolar occlusal bar combined with molar double rests (MDR); II) both occlusal bars with a wing (OBB); III) a premolar occlusal bar combined with a molar dental band (MDB); and IV) two single rests adjacent to the edentulous space with a wing (SRB) used as a control. All specimens were aged with thermal cycling and mechanical loading. Subsequently, they were loaded until broken. The data were analyzed by one-way analysis of variance. Al2O3 (250 um) abrasion provided the highest SBS (P<0.05). The alloy primer and silica + silane exhibited increased SBS. Furthermore, fracture analysis revealed that the failure mode varied among the different treatments. Whereas MDB exhibited the highest retention (P<0.05), that of OBB was greater than that of MDR (P<0.05), and the control exhibited the lowest retention. Abrasion with Al2O3 (250 um) effectively increased the adhesive property of Pd-Ag. Additionally, treatment with the alloy primer and silica coating + silane was able to increase the adhesive property of abraded Pd-Ag. Under the present conditions, all three modified retainer types provided improved outcomes for Pd-Ag PFM RBFPDs compared with the control. PMID- 29434798 TI - Morphological and functional changes of microglia cultured under different oxygen concentrations and the analysis of related mechanisms. AB - This study investigated the effects of different concentrations of oxygen exposure on the morphology and function of N9 microglia and analyzed its mechanisms. N9 microglia were cultured under the condition of high (95% O2 and 5% CO2), normal (95% air and 5% CO2) and low oxygen (95% CO2 and 5% O2) concentrations. The cell morphologies were observed under inverted phase contrast microscope after 24 h. Flow cytometry was applied to detect cell survival and apoptotic rate. The mRNA and protein expression levels of interleukin-1beta (IL 1beta) and tumor necrosis factor-alpha (TNF-alpha) were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis, respectively. The results showed that, N9 microglial apoptotic rates in hyperoxia and hypoxia conditions were significantly higher than those in the normal group (P<0.05) and the apoptosis rate in the hypoxia group was higher than that in the hyperoxia group (P<0.05). The mRNA and protein expression levels of IL-1beta and TNF-alpha in the hyperoxia and hypoxia groups were significantly higher than those in the normal group (P<0.05) and the mRNA and protein expression levels in hypoxia group were higher than those in the hyperoxia group (P<0.05). Therefore, N9 microglia cultured under hyperoxia and hypoxia conditions can be activated, enhancing pro-inflammatory response and inducing cell apoptosis. The mechanism may be that the secretion of neurotoxic factors IL-1beta and TNF-alpha is involved in these responses. PMID- 29434799 TI - Inhibition of X-linked inhibitor of apoptosis protein enhances anti-tumor potency of pure total flavonoids on the growth of leukemic cells. AB - Flavonoids, a vast group of polyphenols widely distributed in plants, are known to possess a range of biological activities and potential anti-tumor effects. X linked inhibitor of apoptosis protein (XIAP) promotes the progression of leukemia by preventing tumor cells undergoing apoptosis. The present study investigated the potential effects and underlying mechanisms of pure total flavonoids from Citrus paradisi Macfad (PTFC) on human U937 cells, and explored the effects of short hairpin (sh)RNA-mediated XIAP knockdown on the anti-cancer effects of PTFC. Western blotting was used to determine level of apoptosis-associated effectors following PTFC treatment. A lentiviral vector of RNA interference of XIAP gene was constructed to downregulate XIAP expression. MTT assay and flow cytometry were used to determine the effects of PTFC separately or combined with XIAP-shRNA on inhibition and apoptosis of U937 cells, respectively. Treatment with PTFC effectively inhibited leukemic cell proliferation in a dose- and time-dependent manner. PTFC induced apoptosis of U937 cells in a dose-dependent manner, at a particular concentration range, by decreasing XIAP expression levels and activating caspases-3, -7 and -9. PTFC treatment combined with XIAP-shRNA additionally demonstrated a marked increase in cell apoptosis, compared with PTFC or XIAP-shRNA alone (P<0.05). Therefore, these findings suggest that PTFC inhibits growth and induces apoptosis in U937 cells in vitro. Furthermore, suppression of XIAP expression enhances these effects. PMID- 29434800 TI - Protective effects of scopolamine and penehyclidine hydrochloride on acute cerebral ischemia-reperfusion injury after cardiopulmonary resuscitation and effects on cytokines. AB - The objective of this study was to investigate the protective effects of scopolamine and penehyclidine hydrochloride on acute cerebral ischemia reperfusion injury after cardiopulmonary resuscitation, and the effect on cytokine levels. Eighty patients with cardiac arrest admitted to our hospital from June 2011 to December 2015 were recruited and randomly divided into two groups (n=40 each). Following cardiopulmonary resuscitation, scopolamine was administered in the control group, whereas penehyclidine hydrochloride was administered in the observation group. After intervention, the following medical indicators were compared between the groups: Intracranial pressure, cerebral oxygen partial pressure, cerebral perfusion pressure, assessment of the balance of cerebral oxygen supply and demand, levels of neuron-specific enolase (NSE) and blood lactic acid, levels of oxidative stress markers, and levels of inflammatory related factors. Additionally, the areas of brain tissue edema and National Institutes of Health Stroke Scale (NIHSS) scores before and after intervention were compared. Rescue success rates of the groups were recorded. After intervention, the following indicators were lower in the observation group than in the control group: Intracranial pressure (p<0.05), levels of NSE (p<0.05), levels of blood lactic acid (p<0.05), levels of malondialdehyde (p<0.05), and levels of interleukin 6 (IL-6), tumor necrosis factor-alpha, IL-1, and hs-CRP (p<0.05). However, the following indicators were higher in the observation group than in the control group: Cerebral oxygen partial pressure, cerebral perfusion pressure (p<0.05), levels of CaO2, CjvO2, and CERO2 (p>0.05), and levels of superoxide dismutase and glutathione peroxidase (p<0.05). Additionally, the areas of brain tissue edema after intervention were smaller in the observation group than those before intervention and those after intervention in the control group (p<0.05). Similarly, the NIHSS scores after intervention in the observation group were lower than those before intervention and those after intervention in the control group (p<0.05). Rescue success rate was significantly higher in observation group than in control group (p<0.05). In conclusion, administration of penehyclidine following cardiopulmonary resuscitation can effectively improve cerebral perfusion pressure, lower intracranial pressure, reduce brain tissue edema and inflammation, and improve neurological function. PMID- 29434801 TI - Propofol protects against endotoxin-induced myocardial injury by inhibiting NF kappaB-mediated inflammation. AB - This study investigated whether propofol protects against endotoxin-induced myocardial injury by inhibiting NF-kappaB-mediated inflammation. Thirty clean male SD rats were randomly divided into a control (n=10), a model (n=10) and a propofol group (n=10). The model and propofol groups were injected with lipopolysaccharide (LPS) via the caudal vein to establish animal models of myocardial injury. At the same time, the control group was injected with normal saline via the caudal vein. At 30 min after the injections, the propofol group was treated with a continuous intravenous infusion of propofol, the control and model groups were injected with normal saline, and the three groups were treated continuously for 4 h. The changes in levels of interleukin-1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in serum were detected via enzyme-linked immunosorbent assay (ELISA). The mRNA expression level of nuclear factor-kappaB (NF-kappaB) in myocardial tissues was detected via quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression levels of NF-kappaB, Bax and Bcl-2 in atrial muscles in each group were measured via Western blotting. The damage of myocardial tissues was detected via hematoxylin eosin (H&E) staining of tissues. Our results showed that compared with those in control group, the levels of IL-1, IL-6 and TNF-alpha in serum in the model and propofol groups were significantly higher; however, the levels in the model group, were significantly higher than those in the propofol group (P<0.01). The mRNA and protein expression levels of NF-kappaB in the propofol group were significantly lower than those in the model group (P<0.01). Likewise, the protein expression levels of Bax were significantly lower, while those of Bcl-2 were significantly increased. H&E staining showed that the myocardial tissues in the model group were damaged significantly, but the damage in the propofol group was significantly less severe. Based on our findings, it seems propofol can indeed protect against endotoxin-induced myocardial injury through its inhibition of the NF-kappaB-mediated inflammatory pathway. PMID- 29434802 TI - An investigation of the mechanism of dexmedetomidine in improving postoperative cognitive dysfunction from the perspectives of alleviating neuronal mitochondrial membrane oxidative stress and electrophysiological dysfunction. AB - The aim of this study was to investigate the mechanism of dexmedetomidine in improving postoperative cognitive dysfunction from the perspectives of alleviating neuronal mitochondrial membrane oxidative stress and electrophysiological dysfunction. A total of 120 patients undergoing elective surgery under general anesthesia from June 2013 to May, 2016 were selected as the subjects of the study and randomly divided into the propofol + remifentanil and dexmedetomidine groups. The Rey Auditory Verbal Learning Test (AVLT) and Beck Depression Inventory (BDI) were performed at day 1 before operation and at day 1, 3, 5 and 15 after operation. The mitochondrial membrane potential was detected using a flow cytometer after staining and labeling for mitochondria in leukocytes via JC-1 fluorescence staining using a fluorescence probe at day 1 before operation and at day 1, 3, 5 and 15 after operation. The activities of mitochondrial respiratory chain complexes at day 1 before and after operation were detected via enzyme-linked immunosorbent assay (ELISA). The results showed that there were no statistically significant differences in the comparisons of general conditions (age, body weight, sex ratio, body mass index, anesthesia time, operation time, and length of stay in the ICU and hospital) for the dexmedetomidine and propofol + remifentanil groups (P>0.05). At day 3 and 5 after operation, the National Institutes of Health Stroke Scale (NIHSS) scores and AVLT scores in the two groups were decreased in different degrees, but the decrease range in the dexmedetomidine group was smaller than that in the propofol + remifentanil group, and the differences were statistically significant (P<0.05). At day 3, 5 and 15 after operation, the BDI scores of the two groups were increased in different degrees, but the increase range in the dexmedetomidine group was smaller than that in the propofol + remifentanil group, and the differences were statistically significant (P<0.05). At day 1, 3 and 5 after operation, the mitochondrial membrane potentials of the two groups were decreased in different degrees, but the decrease range in the dexmedetomidine group was smaller than that in the propofol + remifentanil group, and the differences were statistically significant (P<0.05). The mitochondrial membrane potentials of the two groups returned to the preoperative levels at day 15 after operation. The activities of mitochondrial respiratory chain complex I-IV in the propofol + remifentanil group at day 1 after operation were significantly decreased compared with those before operation, and the differences were statistically significant (P<0.05). The decrease in activities of mitochondrial respiratory chain complex I IV in the propofol + remifentanil group at day 1 after operation was more significant than that in the dexmedetomidine group, and the difference was statistically significant (P<0.05). The results suggest that dexmedetomidine can relieve neuronal damage that may be caused by mitochondrial membrane oxidative stress, alleviate the damage to mitochondrial related enzyme system activity, and reduce the damage to the activities of mitochondrial respiratory chain enzyme complex I, II, III and IV, ultimately improving the postoperative cognitive dysfunction of patients. PMID- 29434803 TI - Clinical value of cardiac color ultrasound and cardiac troponin T combined with dynamic electrocardiogram in treatment of acute pulmonary embolism. AB - The clinical value of cardiac color ultrasound and cardiac troponin T (cTnT) combined with dynamic electrocardiogram in evaluating the treatment effect on acute pulmonary embolism (APE) was investigated. Ninety-eight patients with APE treated in Jinan Zhangqiu District Hospital of TCM from March 2016 to February 2017 were selected, and they were examined via the cardiac color ultrasound, cTnT and dynamic electrocardiogram to evaluate the clinical value in the treatment of pulmonary embolism. Electrocardiogram showed that there was no significant difference in the poor prognosis rate between right ventricular strain group and non-right ventricular strain group (P>0.05); the poor prognosis rate in cTnT positive group was significantly higher than that in cTnT negative group (P<0.05). Moreover, the ultrasonic cardiogram revealed that the poor prognosis rate in right ventricular dysfunction group was significantly higher than that in non-right ventricular dysfunction group (P<0.05). It was found in the receiver operating characteristic (ROC) curve analysis that the areas under the curve (AUC) of ROC detected via cardiac color ultrasound and cTnT were >0.9, while that detected via dynamic electrocardiogram was <0.7. Besides, logistic regression analysis showed that cTnT and right ventricular dysfunction were the risk factors affecting the poor prognosis of patients with APE (P<0.05). In conclusion, cardiac color ultrasound can predict the prognosis of patients with APE through monitoring the right ventricular function; cTnT can also evaluate the prognosis of APE; but the electrocardiogram has little significance in evaluating the prognosis of APE. PMID- 29434804 TI - A clinical study on acupuncture in combination with routine rehabilitation therapy for early pain recovery of post-stroke shoulder-hand syndrome. AB - The clinical effect of acupuncture in combination with rehabilitation therapy for post-stroke shoulder-hand syndrome (SHS) was explored. Patients (178) with post stroke SHS who received treatment in the Dalian Second Hospital from March 2012 to March 2016 were included in this study. The patients were divided into experimental group (89 cases) and control group (89 cases). Patients in the control group received rehabilitation therapy, while those in the treatment group received acupuncture treatment in addition to rehabilitation therapy. Visual analogue scale (VAS) was applied to assess the pain degree of patients. Fugl Meyer assessment (FMA), functional comprehensive assessment (FCA) and assessment of quality of life (QoL) were used to evaluate rehabilitation condition of the patients. Early pain relief, rehabilitation of upper extremity motor function and improvement of QoL after treatment were compared between the two groups. The scores of VAS, FMA, FCA and QoL showed obvious differences between the two groups after treatment (P<0.05). The scores of the experimental group were significantly better than those of the control group, and the improvement in upper extremity motor function of the patients in the experimental group was better than that of the patients in the control group. The total effective rate of the patients in the experimental group was higher than that of control group (P<0.05). The effect in improving the upper extremity motor function of the patients in the experimental group was better than that of control group. The scores of QoL of the patients in the experimental group were better than that of the patients in the control group (P<0.05). In conclusion, acupuncture in combination with rehabilitation therapy can improve early pain and rehabilitation significantly and enhance QoL for patients with post-stroke SHS, which is worthy of being widely used in clinical practice. PMID- 29434806 TI - Extracorporeal membrane oxygenation support for a multitrauma patient with ARDS: A case report and literature review. AB - Extracorporeal membrane oxygenation (ECMO) provides rescue treatment for patients with severe acute respiratory distress syndrome (ARDS) when conventional management fails. The present study reported ECMO as a life-saving treatment for ARDS due to bilateral pulmonary contusion in a 24-year-old male multiple trauma patient. ECMO therapy lasted 7 days for the patient and was successively stopped without any complications. ECMO modality should be chosen according to the respiratory and circulatory condition of each individual. Venoarteria-ECMO may be chosen for multiple trauma patients with ARDS, and respiratory and circulatory failure. Morphological changes are observed with ARDS progression. The injured lungs may recover completely with effective ECMO therapy. PMID- 29434805 TI - Overexpression of heart-type fatty acid binding protein enhances fatty acid induced podocyte injury. AB - Deregulated lipid metabolism is a characteristic of metabolic diseases including type 2 diabetes and obesity, and likely contributes to podocyte injury and end stage kidney disease. Heart-type fatty acid binding protein (H-FABP) was reported to be associated with lipid metabolism. The present study investigated whether H FABP contributes to podocyte homeostasis. Podocytes were transfected by lentiviral vector to construct a cell line which stably overexpressed H-FABP. Small interfering RNA capable of effectively silencing H-FABP was introduced into podocytes to construct a cell line with H-FABP knockdown. Certain groups were treated with palmitic acid (PA) and the fat metabolism, as well as inflammatory and oxidative stress markers were measured. PA accelerated lipid metabolism derangement, inflammatory reaction and oxidative stress in podocytes. Overexpression of H-FABP enhanced the PA-induced disequilibrium in podocytes. The mRNA and protein expression levels of acyl-coenzyme A oxidase 3 and monocyte chemotactic protein 1, and the protein expression levels of 8-hydroxy-2' deoxyguanosine and 4-hydroxynonenal were upregulated in the H-FABP overexpression group, while the mRNA and protein expression of peroxisome proliferator activated receptor alpha was downregulated. Knockdown of H-FABP inhibited the PA-induced injury and lipid metabolism derangement, as well as the inflammatory reaction and oxidative stress in podocytes. These results indicated that overexpression of H FABP enhances fatty acid-induced podocyte injury, while H-FABP inhibition may represent a potential therapeutic strategy for the prevention of lipid metabolism associated podocyte injury. PMID- 29434807 TI - Influence of sevoflurane exposure on mitogen-activated protein kinases and Akt/GSK-3beta/CRMP-2 signaling pathways in the developing rat brain. AB - Prolonged exposure to volatile anesthetics causes neurodegeneration in developing animal brains. However, their underlying mechanisms of action remain unclear. The current study investigated the expression of proteins associated with the mitogen activated protein kinases (MAPK) and protein kinase B (Akt)/glycogen synthase kinase-3beta (GSK-3beta)/collapsin response mediator protein 2 (CRMP-2) signaling pathways in the cortices of neonatal mice following exposure to sevoflurane. Seven-day-old (P7) neonatal C57BL/6 mice were randomly divided into 2 groups and either exposed to 2.6% sevoflurane or air for 6 h. Terminal deoxyribonucleotide transferase mediated dUTP nick end labeling (TUNEL) staining, as well as the expression of activated caspase-3 and alpha-fodrin, was used to detect neuronal apoptosis in the cortices of mice. MAPK signaling pathways were investigated by detecting the expression of phosphorylated (p-) extracellular signal-regulated kinase 1/2 (ERK1/2), p-cyclic adenosine monophosphate response element-binding protein (CREB), p-p38, p-nuclear factor (NF-kappaB) and p-c-Jun N-terminal kinase (p-JNK). Akt/GSK-3beta/CRMP-2 signaling pathways were assessed by detecting the expression of p-Akt, p-GSK-3beta and p-CRMP-2 in the cortices of P7 mice 2 h following exposure to sevoflurane. The results demonstrated that sevoflurane significantly increased the apoptosis of cells in the retrosplenial cortex (RS), frontal cortex (FC) and parietal association cortex (PtA), increased the expression of cleaved caspase-3 expression and promoted the formation of 145 kDa and 120 kDa fragments from alpha-fodrin. Sevoflurane inhibited the phosphorylation of ERK1/2 and CREB, stimulated the phosphorylation of p38 and NF kappaB, but did not significantly affect the phosphorylation of JNK. Furthermore, sevoflurane inhibited the phosphorylation of Akt, decreased the phosphorylation of GSK-3beta at ser9 and increased the phosphorylation of CRMP2 at Thr514. These results suggest that multiple signaling pathways, including ERK1/2, P38 and Akt/GSK-3beta/CRMP-2 may be involved in sevoflurane-induced neuroapoptosis in the developing brain. PMID- 29434808 TI - Double-bundle revision anterior cruciate ligament reconstruction is effective in rescuing failed primary reconstruction and re-introducing patients to physical exercise. AB - The anterior cruciate ligament (ACL) is one of a pair of cruciate ligaments in the human knee and is critical for knee stability, as it limits anterior tibial translation on the femur, restrains rotation and resists varus and valgus joint forces. The present study aimed to assess the effect of double-bundle revision anterior cruciate ligament (ACL) reconstruction in improving the subjective and objective functions and re-introducing patients to physical activity after primary ACL reconstruction had failed. A total of 34 patients who underwent double-bundle ACL revision surgeries were included in the present retrospective study. Lysholm, Tegner and IKDC scores as well as KT-2000 arthrometry measures were obtained pre- and post-operatively. The follow-up time was at least 2 years. The results indicated that the IKDC, Lysholm and Tegner scores as well as KT-2000 flexion scores were significantly improved after revision ACL reconstruction. All patients resumed to performing physical exercise activities after revision surgeries, 65% of whom reached pre-injury levels. In conclusion, these results demonstrated that double-bundle revision ACL reconstruction was consistently effective in rescuing failed primary ACL reconstruction and re-introducing patients to physical exercise. PMID- 29434809 TI - MicroRNA-30a-3p overexpression improves sepsis-induced cell apoptosis in vitro and in vivo via the PTEN/PI3K/AKT signaling pathway. AB - The aim of the present study was to explain the mechanism of miR-30a-3p overexpression in sepsis-induced cell apoptosis in vitro and in vivo. For the in vitro cell experiments, H9c2 cells were divided into three groups, including the untreated normal control (NC), lipopolysaccharide (LPS)-treated and miRNA (treated with LPS and transfection with miRNA-30a-3p) groups. The cell proliferation and apoptosis were evaluated by MTT assay and flow cytometry, respectively. The relative protein expression levels were measured by western blot assay. In the in vivo experiment, a sepsis rat model was established by intraperitoneal injection of LPS. Sprague Dawley rats were divided into three groups, including the NC, LPS-injected and miRNA (in which model rats were injected with miR-30a-3p vector at the caudal vein) groups. The myocardial morphology in different groups was observed by hematoxylin and eosin staining. In addition, tissue apoptosis and protein expression levels were evaluated by TUNEL and western blot assay, respectively. The results of cell experiments indicated that the cell proliferation rate was significantly increased and the cell apoptosis rate was significantly downregulated in the miR-30a-3p group compared with the LPS group (both P<0.05). The relative protein expression of phosphatase and tensin homolog (PTEN) was markedly decreased in the miRNA group compared with the LPS group, while the levels of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) were significantly increased in the miRNA group (all P<0.05). In the in vivo experiments, the myocardial morphology of the miRNA group was improved compared with that of the LPS group. Compared with the LPS group, cell apoptosis in the miRNA group was significantly downregulated (P<0.05), while the relative protein levels (PTEN, PI3K and AKT) in the tissues were also significantly altered (P<0.05). In conclusion, miR-30a-3p overexpression may improve the sepsis-induced cell apoptosis in vitro and in vivo via the PTEN/PI3K/AKT signaling pathway. PMID- 29434810 TI - Relationship of renal morphology on 3-dimensional ultrasonography with renal pathologic findings and outcome in biopsy-proven nephropathy. AB - Kidney morphology has been used to estimate renal functions. The present study investigated the usefulness of kidney length and renal parenchymal volume (RPV) measured using three-dimensional ultrasonography (3-D USG) in estimating renal pathological findings, and the outcome in patients with nephropathy who underwent renal biopsy. In this study, 94 adult patients who had native kidney biopsy with 3-D USG results were included. The mean kidney length and RPV were independent factors of, and positively correlated to the estimated glomerular filtration rate (eGFR). The mean kidney length and RPV had inverse associations with the percentage of global glomerulosclerosis. Higher mean RPV, other than longer kidney length, indicated a lower prevalence of tubular atrophy. During 63.3+/ 19.3 months of follow-up, a mean RPV of <125 ml increased the risk of composite outcome by 4.287 fold (95% confidence interval, 1.133-16.227) as compared with a mean RPV of >=125 ml (P=0.032). In conclusion, kidney size was inversely associated with certain nephronal damage and positively associated with eGFR in nephropathy. Furthermore, smaller RPVs predicted worse outcomes of nephropathy. PMID- 29434811 TI - Regulatory effects of four ginsenoside monomers in humoral immunity of systemic lupus erythematosus. AB - Ginsenosides Rb1, Rh1, Rg1 and Rg3 are known as the main active components extracted from the roots of the Panax ginseng C.A. Meyer, and were reported to have immunoregulatory effects. Disruption of B-cell immune regulation during the pathogenesis of systemic lupus erythematosus (SLE) may lead to the production of large amounts of antibodies. The present study investigated the effects of the four ginsenoside monomers on B-cell immune regulation and observed that they inhibited the proliferation and secretion of B cells induced by LPS, caused an upregulation of the expression of apoptosis-associated proteins Fas/Fas ligand and caspase-3, the expression of FcgammaRIIB (CD32) as well as the proportion of inactive B cells (CD19+CD27-). These results indicate that Rb1, Rh1, Rg1 and Rg3 inhibit the humoral immunity of SLE, among which Rh1 exhibited the most obvious inhibitory effect. PMID- 29434812 TI - Combination therapeutic effects of high intensity focused ultrasound and Metformin for the treatment of adenomyosis. AB - Adenomyosis is a pathological gynaecological condition characterized by benign invasion of the endometrium into the myometrium. High intensity focused ultrasound (HIFU) is one of the most common therapeutic strategies for the treatment of adenomyosis. However, the efficacy of single HIFU therapy is insufficient for the treatment of patients with adenomyosis. In the present study, the efficacy of HIFU and metformin for the treatment of adenomyosis was analyzed in 274 patients with adenomyosis who were admitted to Jinan Maternity and Child Care Hospital. The results demonstrated that there was a significant reduction in menstrual flow and pain between patients who received HIFU and metformin, and those who received single HIFU treatment (P<0.01). Furthermore, the outcomes demonstrated that inflammatory cytokines levels were significantly lower compared with the baseline values (P<0.01). In conclusion, the outcomes of the current study indicate that combined HIFU and metformin treatment is more efficacious in patients with enlarged adenomyosis compared with single HIFU treatment. PMID- 29434813 TI - Association between vascular endothelial growth factor promoter polymorphisms and the risk of recurrent implantation failure. AB - The objective of the present study was to investigate the association between recurrent implantation failure (RIF) and vascular endothelial growth factor (VEGF) gene polymorphisms that are associated with various female infertility disorders. A total of 116 women diagnosed with RIF and 218 control subjects were genotyped for the VEGF -2578C>A, -1154G>A, -634C>G and 936C>T polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism assay. The VEGF -2578AA genotype was associated with an increased prevalence (>=4) of RIF [adjusted odds ratio (AOR)=2.77; 95% confidence interval (CI)=1.10-7.02; P=0.031], whereas the VEGF -634CG+GG genotype was associated with an increased incidence of total RIF (AOR=2.03; 95% CI=1.02-4.05; P=0.044) and >=4 RIF (AOR=3.16; 95% CI=1.19-8.37; P=0.021). The results of the haplotype analysis indicated that -2578A/-1154A/-634G/936C (AOR=1.76; 95% CI=1.03-3.00; P=0.040 for total RIF and AOR=2.11; 95% CI=1.12-3.97; P=0.021 for >=4 RIF) was associated with the occurrence of RIF. In addition, it was revealed that there was a significant difference in serum prolactin level associated with the VEGF -634C>G polymorphism (P=0.013). Therefore the findings of the present study indicate that the VEGF -2578AA genotype, -634G allele and -2578A/-1154A/-634G/936C haplotype may be genetic markers for susceptibility to RIF. However, further studies on VEGF promoter polymorphisms that include an independent randomized-controlled population are required to confirm these results. PMID- 29434814 TI - Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway. AB - Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogenism and insulin resistance are the basic characteristics of PCOS. To investigate the combined effect of metformin and pioglitazone on POCS and the potential mechanisms, a rat model of PCOS was established by intramuscular injection of estradiol valerate (EV). The effect of metformin and pioglitazone monotherapy or combination therapy in control rats and PCOS rats was evaluated, involving the testosterone level, follicular development and insulin resistance. The potential mechanism for the therapeutic effect of metformin and pioglitazone on POCS was explored through using three inhibitors of the 5'adenosine monophosphate-activated protein kinase (AMPK)/phosphoinositide-3 kinase (PI3K)/c-Jun N-terminal kinase (JNK) pathway (Compound C, Wortmannin and SP600125). The results showed that EV-induced PCOS rats demonstrated hyperandrogenemia, hyperinsulinemia and follicular dysplasia. Metformin or pioglitazone monotherapy significantly suppressed the high level of testosterone, reduced the raised percentage of cystic follicles and primary follicles, promoted the number of early antral follicles, and markedly decreased the high concentration of fasting insulin and homeostatic model assessment for insulin resistance index in PCOS rats. In addition, metformin and pioglitazone combination therapy demonstrated greater efficacy than its individual components. Furthermore, individual or joint treatment with metformin and pioglitazone affected the phosphorylation level of JNK in PCOS rats. Compound C and Wortmannin eliminated the effect of metformin and pioglitazone combination therapy on improving the follicular growth in PCOS rats, whereas SP600125 treatment enhanced this combination therapy effect. These data suggested that metformin and pioglitazone combination therapy demonstrated great efficacy in ameliorating PCOS through regulating the AMPK/PI3K/JNK pathway. PMID- 29434815 TI - Dopamine receptor D4 promoter hypermethylation increases the risk of drug addiction. AB - Heroin and methylamphetamine (METH) are two addictive drugs that cause serious problems for society. Dopamine receptor D4 (DRD4), a key receptor in the dopaminergic system, may facilitate the development of drug addiction. The aim of the present study was to investigate the association between the promoter methylation level of DRD4 gene and drug addiction. Bisulfite pyrosequencing technology was used to measure the methylation levels of DRD4 promoter in 60 drug addicts and 52 matched controls. Significantly higher levels of DRD4 CpG1 and CpG4 methylation were detected in METH and heroin drug addicts compared with controls (P<0.05). Male METH addicts exhibited significantly higher DRD4 CpG1, CpG2 and CpG4 methylation levels compared with sex-matched controls (P<0.05). In heroin addicts, a positive correlation was observed between depression-dejection and DRD4 CpG5 methylation (r=0.537, P=0.039) whereas there was a negative correlation between drug usage frequency and CpG1 methylation (r=-0.632, P=0.011). In METH addicts, methylation levels were not significantly associated with depression-dejection and drug usage frequency. In addition, luciferase assays demonstrated that the target sequence of the DRD4 promoter upregulates gene expression. The results of the present study suggest that DNA methylation of DRD4 may be responsible for the pathophysiology of drug addiction. PMID- 29434816 TI - Effectiveness of lentivirus-mediated RNA interference targeting mouse tumor necrosis factor alpha in vitro and in vivo. AB - The aim of the present study was to identify the effectiveness of lentivirus mediated RNA interference (RNAi) targeting mouse tumor necrosis factor-alpha (TNF alpha). RNAi lentivirus was used in vitro to transfect RAW264.7 cells, and the expression of TNF-alpha, interleukin (IL)-1beta and IL-6 mRNAs and TNF-alpha protein in RAW264.7 cells was measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay, respectively. In vivo, mice with collagen-induced arthritis (CIA) were injected intravenously with RNAi lentivirus, and CIA arthritis scores and the serum levels of TNF-alpha were detected. Additionally, joint tissues were subjected to pathological examination. In the cells, the expression level of TNF-alpha mRNA in the RNAi lentivirus group was 0.29+/-0.02, which was significantly lower than that of the lentivirus negative control (0.93+/-0.01; t=25.4, P<0.001). In the mice, the serum TNF-alpha level in the RNAi lentivirus group was 249.25+/-11.22 ng/ml, which was significantly lower than that of the negative control group (381.86+/-6.28 ng/ml; P<0.05). However, no difference in IL-1alpha and IL-6 mRNA levels was identified among the groups (t=1.00, P=0.37; t=1.22, P=0.29). The CIA arthritis score in the RNAi lentivirus group was significantly reduced compared with those in the control and negative control groups (P<0.05). Furthermore, the arthritis scores in the RNAi lentivirus and positive control groups continued to decrease for >=2 weeks, and the serum TNF-alpha levels in the RNAi lentivirus and positive control groups were 31.58+/-2.18 and 35.21+/-2.25 pg/ml, which were significantly lower than those in the negative control group (46.62+/-3.02 pg/ml; P<0.05). Thus, targeting of the TNF-alpha gene in mice via lentivirus-mediated RNAi in vitro and in vivo achieved TNF-alpha gene downregulation, which indicates that lentivirus-mediated RNA interference may be an effective form of gene therapy against rheumatoid arthritis. PMID- 29434817 TI - Delta-opioid receptor inhibition prevents remifentanil-induced post-operative hyperalgesia via regulating GluR1 trafficking and AMPA receptor function. AB - The interaction of remifentanil with glutamate systems has an important role in remifentanil-induced thermal and mechanical hyperalgesia. A previous study by our group suggested that the trafficking and function of glutamate receptor 1 (GluR1) subunits contributes to remifentanil-induced hyperalgesia by regulating the phosphorylation of GluR1 in dorsal horn neurons. The present study demonstrated that delta opioid receptor (DOR) inhibition prevented thermal and mechanical hyperalgesia, which was induced by remifentanil infusion via attenuating GluR1 subunit trafficking and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function in dorsal horn neurons. Sprague Dawley rats received a plantar incision and remifentanil infusion to induce a model of postoperative hyperalgesia. Thermal and mechanical pain was tested at 8 different time-points. Expression of AMPAR subunits GluR1 and DOR, as well as the phosphorylation status of GluR1 were evaluated by western blot analysis. Furthermore, the function of AMPAR in the spinal dorsal horn was measured by whole-cell patch-clamp recording. Remifentanil-induced thermal and mechanical hyperalgesia appeared after the 60 min infusions, reaching a peak level on day 2 and persisting for 5 days. Remifentanil infusion led to upregulation of membrane expression of the AMPAR subunit GluR1 and DOR (P=0.003 and 0.001, respectively) no change in total GluR1 and DOR expression levels (P=0.244 and 0.531, respectively). Selective DOR inhibitor naltrindole caused a reduction of remifentanil-induced hyperalgesia, which was accompanied by downregulation of membrane levels of GluR1 in the spinal cord (P=0.0013). In addition, DOR inhibition led to downregulation of GluR1 phosphorylated at Ser845. Furthermore, the AMPAR-mediated miniature excitatory post-synaptic current was increased in frequency and in amplitude in dorsal horn neurons (P=0.002 and 0.0011, respectively), which was decreased by incubation with naltrindole. Combined behavioral, western blot and electrophysiological evidence indicated that remifentanil-induced hyperalgesia was mediated by DOR activation, followed by phosphorylation-dependent GluR1 trafficking and AMPAR function enhancement in the spinal cord. DOR appears to be required for remifentanil and incision-induced hyperalgesia development and to be a potential biochemical target for treating opioid-induced postoperative hyperalgesia. PMID- 29434818 TI - Current characteristics of hemophilia patients co-infected with HIV/HCV in Japan. AB - Over 30 years have passed since co-infection with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) was first documented in hemophilia patients in Japan. In such cases, the leading cause of mortality is reportedly HCV-associated end-stage liver disease. However, the current characteristics of hemophilia patients co-infected with HIV/HCV are unknown. The aim of the present study was to reveal the current characteristics, notably HCV geno-prevalence and liver function, among hemophilia patients co-infected with HIV/HCV in Japan. Current characteristics were evaluated using cross-sectional retrospective data of 44 hemophilia patients positive for anti-HCV and anti-HIV antibodies who underwent screening of liver dysfunction. A total of 56.8% of hemophilia patients co infected with HIV/HCV were positive for HCV RNA. The most common HCV genotypes were 1a, 1b and 3a. Liver cirrhosis was diagnosed in 26.3% patients negative for HCV RNA and 60.0% patients positive for HCV RNA. Decompensated liver cirrhosis was diagnosed in 33.3% HCV RNA-positive patients and none of the HCV RNA-negative patients. The rate of liver cirrhosis was greater for HCV genotype 3a compared with other genotypes. Overall, the current primary HCV RNA genotypes among hemophilia patients co-infected with HIV/HCV are 1a, 1b and 3a. Over 50% of HIV/HCV co-infected hemophilia patients positive for HCV RNA were diagnosed with liver cirrhosis and some were diagnosed with decompensated liver cirrhosis. PMID- 29434819 TI - Tangshen formula improves inflammation in renal tissue of diabetic nephropathy through SIRT1/NF-kappaB pathway. AB - The present study investigated the mechanism underlying the anti-inflammatory effects of Tangshen formula (TS) in Sprague Dawley (SD) rats with diabetic nephropathy (DN). A rat model of DN was established by intraperitoneal injection of 1% (40 mg/kg) streptozotocin and administration of a high fat and glucose diet. Subsequently, SD rats were randomly divided into six groups (n=8): A DN group, a valsartan group, a high-dose TS group, a middle-dose TS group, a low dose TS group and a control group with normal SD rats. Once rats received their allocated treatment for 12 weeks, body weight and kidney weight were recorded, and fasting blood glucose, ratio of urinary protein, beta2-MG and creatinine clearance rate were determined. Furthermore, hemodynamic indices, including plasma viscosity and whole blood reduction viscosity were detected. Immunohistochemistry was used to detect the infiltration of macrophages in the kidneys of rats. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to investigate the activation; mRNA and protein expression levels of monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor (MIF), nuclear factor-kappaB (NF-kappaB) and sirtuin 1 (SIRT1) in each group. In comparison with the DN group, each biochemical indicator of rats in the high-dose TS group was significantly decreased (P<0.05). Blood viscosity in each treatment group was significantly decreased when compared with the DN group (P<0.01). Hematoxylin and eosin staining indicated that the infiltration of macrophages was significantly decreased in the high-dose TS group when compared with the DN group (P<0.01). mRNA and protein expression levels of MCP-1 and MIF in the high-dose TS group were significantly decreased when compared with the DN group (P<0.05). In the treatment groups, SITR1 mRNA expression levels were significantly increased, whereas the mRNA expression levels of NF-kappaB were significantly decreased (P<0.01). Western blotting results indicated a significant decrease in the protein expression levels of acetylated NF-kappaB in the treatment groups when compared with the DN group (P<0.01) and the propensity of protein expression of the other inflammatory factors were consistent with the mRNA findings. The results of the high-dose TS group were similar to those of the valsartan group. The present study indicates that TS was able to activate SITR1, which lead to NF-kappaB deacetylation, thus reducing the release of inflammatory factors and decreasing the severity of diabetic nephropathy. PMID- 29434820 TI - Itraconazole attenuates hepatic gluconeogenesis and promotes glucose uptake by regulating AMPK pathway. AB - The primarily metabolic abnormality in type 2 diabetes mellitus (T2DM) is the defect in gluconeogenesis and glucose uptake. Itraconazole (ITCZ) is a traditional azole drug with anti-fungal and anticancer properties. However, limited attention has been directed towards the contribution of ITCZ to hepatic gluconeogenesis and glucose uptake in T2DM. The present study aimed to investigate the potential effects of ITCZ on hepatic gluconeogenesis and glucose uptake as well as the underlying mechanisms. No obvious change in cell viability was detected by MTT assay in HepG2 cells with ITCZ treatment at gradually increasing concentrations. Western blot analysis demonstrated that the phosphorylation level of 5' adenosine monophosphate-activated protein kinase (AMPK) was significantly elevated by ITCZ treatment at >=5 ug/ml (P<0.05). Moreover, ITCZ repressed the gluconeogenesis of HepG2 cells, as evidenced by the dose-dependently increased glycogen synthase kinase 3beta phosphorylation level and a notably decreased glucose production rate (P<0.05). Simultaneously, the expression of peroxisome proliferator-activated receptor gamma co-activator 1alpha, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in HepG2 cells was reduced by ITCZ in a dose-dependent manner (P<0.001). Furthermore, a 2-deoxyglucose uptake assay revealed that the glucose uptake of HepG2 cells was notably enhanced, accompanied by the ITCZ dose-dependent upregulation of glucose transporter-4 (GLUT-4) (P<0.05). Conversely, silencing of AMPK by small interfering RNA resulted in an increase of ITCZ-reduced gluconeogenesis and inhibition of ITCZ-induced glucose uptake with relative upregulation of PEPCK and G6Pase and downregulation of GLUT4 in the presence of 50 ug/ml ITCZ (P<0.05). Overall, the results indicated that AMPK has an important role in regulating ITCZ-induced glucose uptake by stimulating GLUT4 in HepG2 cells. Therefore, ITCZ may become a promising candidate for T2DM therapy. PMID- 29434821 TI - Preconditioning of physiological cyclic stretch inhibits the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells. AB - The aim of the present study was to investigate the effects of preconditioning of physiological cyclic stretch (CS) on the overexpression of early pro-inflammatory cytokines [including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-8] during the inflammatory response induced by pathologically mechanical stretch in lung epithelial cells, and to determine its molecular mechanism of action. Cells were subjected to 5% CS for various durations (0, 15, 30, 60 and 120 min) prior to 6 h treatment with pathological 20% CS. In a separate experiment, cells were preconditioned with physiological 5% CS or incubated with a nuclear factor (NF)-kappaB inhibitor, pyrroldine dithiocarbamate (PDTC). The expression levels of inflammatory mediators were measured using reverse transcription-quantitative polymerase chain reaction. NF-kappaB was quantified using western blot analysis. Preconditioning with physiological 5% CS for 30, 60 and 120 min was demonstrated to significantly attenuate the release of pathologically mechanical stretch-induced early pro-inflammatory cytokines (TNF alpha, IL-1beta and IL-8) in alveolar epithelial cells (P<0.05) and significantly reduce the expression of NF-kappaB (P<0.05). Peak suppression was observed in cells preconditioned for 60 min. In the second set of experiments, it was demonstrated that mechanical stretch-induced release of TNF-alpha, IL-1beta and IL-8 was significantly inhibited by both PDTC pretreatment and 5% CS pretreatment alone (all P<0.05). Furthermore, significant inhibition was also observed when both 5% CS pretreatment and PDTC pretreatment was used on mechanical stretch induced cells (P<0.05), which was markedly greater than the inhibition induced by either pretreatment alone. The present findings suggest that preconditioning with physiological 5% CS is able to inhibit the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells. These anti inflammatory effects are induced, at least in part, by suppressing the NF-kappaB signaling pathway. PMID- 29434822 TI - The role of Dexamethasone in clinical pharmaceutical treatment for patients with cataract surgery. AB - The aim of the present study is to determine the efficacy of dexamethasone (DEX) vs. indomethacin (IND) and ciprofloxacin (CIP) in modulating immediate inflammation following cataract surgery. A total of 644 patients with cataract were recruited and inflammation was investigated during the perioperative period. The management protocol was similar in both groups. Each drug was given four times a day for 30 days starting 7 days prior to surgery. The primary efficacy criteria for evaluation were the reduction in anterior chamber (AC) flare and AC inflammation score, in addition, a different secondary efficacy and safety evaluation criteria were maintained. The results demonstrated that the average inflammation score was 1.2+/-0.8 in the DEX group, which was significantly lower compared with the IND (1.9+/-0.7) and CIP (1.8+/-0.6) groups. Intra-ocular pressure was decreased following treatment with DEX, while intra-ocular pressure was slightly increased in the IND (1.9+/-0.7) and CIP (1.8+/-0.6) groups. The final visual outcomes for patients postcataract surgery were clinically superior in the DEX group compared with that of the IND and CIP groups (P=0.034 and P=0.042, respectively), but there was no significant difference between the ND and CIP groups (P=0.78). Outcomes indicated that AC inflammation, conjunctival hyperaemia, corneal and lid oedema, ocular infection, pain, photophobia, and tearing were significantly improved in each group. No significant poor local tolerance or adverse reaction was observed in the DEX, IND and CIP groups. In conclusion, the outcomes of the present study suggest that DEX serves an important role in the clinical pharmaceutical treatment of patients with cataract surgery. PMID- 29434823 TI - Long non-coding RNA SOX2OT promotes cell proliferation and motility in human ovarian cancer. AB - Ovarian cancer is one of the most common malignant gynecological cancers. Although conventional chemotherapies have improved the treatment of patients with ovarian cancer, the mortality rate remains high. Hence, it is crucial that the detailed mechanisms that promote ovarian cancer are urgently identified. Therefore, reverse transcription-quantitative polymerase chain reaction was used to reveal the relative transcript levels. Colony formation assay and cell cycle assay were performed in siRNA-treated cells. Transwell assay and western blot assays were also conducted. The results showed that the expression of long non coding RNA SRY-box 2 overlapping transcript (SOX2OT) was upregulated in clinical ovarian cancer tissues and in cultured ovarian cancer cells (HO-8910 and HO 8910PM). High expression of SOX2OT negatively correlated with the prognosis of patients with ovarian cancer. Knockdown of SOX2OT by specific small interfering RNA against SOX2OT suppressed the colony formation capacity of invasive ovarian cancer cells and resulted in cell cycle arrest in G0/G1 phase. Key cell cycle regulators, cyclin B1 and cell division cycle 25C, were consistently downregulated by the knockdown of SOX2OT. Furthermore, knockdown of SOX2O Tinhibited cell migration, cell invasion and decreased the expression of mesenchymal protein N-cadherin, whereas the expression of epithelial protein E cadherin was increased in ovarian cancer cells. Overall, SOX2OT expression levels correlated with the prognosis of patients with ovarian cancer, and SOX2OT promoted cell proliferation and motility in ovarian cancer cells. These findings indicated that SOX2OT may serve as a potential therapeutic target in the treatment of ovarian cancer. PMID- 29434824 TI - Clinical importance of chemokines and inflammatory cytokines for patient care following percutaneous nephrolithotripsy. AB - Chemokines are a class of proteins with low molecular weight that serve important roles in the progression of inflammation. Percutaneous nephrolithotripsy is a surgical technique in which lasers or ultrasound are utilized to break down and/or remove kidney stones. In order to ensure a full recovery following surgery, effective patient care and nursing are required. In the present study, a total of 348 patients with kidney stones were recruited and the clinical importance of chemokines and inflammatory cytokines for the nursing of patients during perioperative period was investigated. Plasma levels of inflammatory cytokines, as well as chemokines in the C, CC and CXC families, were analyzed in patients following percutaneous nephrolithotripsy. Correlations between chemokines and inflammatory cytokines and the urinary concentration of calcium oxalate were also investigated. The results indicated that plasma levels of C and CC chemokines were downregulated in patients following percutaneous nephrolithotripsy, whereas the plasma concentrations of CXC chemokines were upregulated. Plasma concentration levels of inflammatory cytokines interleukin (IL)-8, IL-1, IL-17 and tumor necrosis factor (TNF)-alpha were significantly downregulated in patients following percutaneous nephrolithotripsy; however, no significant differences were observed in plasma levels of IL-6 and IL-10 pre- and post-surgery. Regression analysis revealed that plasma concentration levels of chemokine C motif ligand, which is a C chemokine, chemokine ligand 2, which is a CC chemokine, and TNF-alpha were positively correlated with the urinary concentration of calcium oxalate during the perioperative period. The results of the present study indicate that plasma levels of chemokines and inflammatory cytokines are clinically important for nursing of patients who experienced percutaneous nephrolithotripsy. PMID- 29434825 TI - Changes in inflammatory and oxidative stress factors and the protein synthesis pathway in injured skeletal muscle after contusion. AB - Injury of skeletal muscle, and particularly mechanically-induced damage, including contusion injury, frequently occurs in contact sports as well as in sports with accidental contact. Although the mechanisms of skeletal muscle regeneration are well understood, those involved in muscle contusion are not. A total of 40 male mice were randomly divided into control (n=8) and muscle contusion (n=32) groups. A muscle contusion model was established by weight-drop injury. Subsequently, the gastrocnemius muscles in the two groups were harvested at different times (1, 3, 7 and 14 days) post-injury. The changes in skeletal muscle morphology were assessed by hematoxylin and eosin (H&E) stains. Furthermore, quantitative polymerase chain reaction and western blotting were used to analyze inflammatory cytokines, oxidative stress factors and the Akt/mechanistic target of rapamycin (mTOR) pathway. The results revealed that pro inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma)] increased significantly at day 1 and 3 and still exhibited high levels of expression at days 7 and 14 (except IL-6) post injury. Additionally, the anti-inflammatory cytokine IL-10 increased significantly at 1, 3 and 7 days and reached its peak levels at 7 days post injury. It was revealed that gp91phox mRNA increased significantly at all time points and gp91phox protein increased significantly at day 3 post-injury. Furthermore, it was observed that p-Akt/Akt increased significantly at 1 day post injury. P-mTOR/mTOR increased significantly at day 1 and 7, and p-p70s6k/p70s6k and P-4EBP1/4EBP1 increased significantly at 1, 3, 7 and 14 days post-injury. These results indicate that inflammatory and oxidative stress factors and the Akt/mTOR pathway may serve important roles in the regeneration of muscle contusion. In addition, certain inflammatory factors and oxidative stress factors maintained high levels of expression at 14 days after injury, indicating that the healing process of muscle was still not fully achieved at this time. PMID- 29434826 TI - MicroRNA-584 inhibits cell proliferation and invasion in non-small cell lung cancer by directly targeting MTDH. AB - Lung cancer is the third most frequent human malignant tumour and the leading cause of cancer-associated mortality worldwide. Emerging lines of evidence have demonstrated that microRNAs (miRNAs) are upregulated or downregulated in non small cell lung cancer (NSCLC), and this phenomenon is involved in the regulation of various processes during tumorigenesis and progression, including tumour groWTh, apoptosis, cell invasion, and tumour metastasis. Therefore, understanding the molecular mechanism that associates abnormally expressed miRNAs with NSCLC formation and development may lead to the identification of novel diagnostic, and therapeutic targets for patients with NSCLC. miRNA-584 (miR-584) functions as a tumour suppressor in several types of cancer. However, the expression pattern, detailed biological function and underlying molecular mechanism of miR-584 in NSCLC remain unclear. Therefore, the present study detected the expression of miR 584 in NSCLC, investigated its role in NSCLC cells and determined its underlying molecular mechanism. In the current study, it was demonstrated that miR-584 was downregulated in NSCLC tissues and cell lines. Low miR-584 expression was correlated with tumour size, tumour node metastasis stage and distant metastasis. Overexpression of miR-584 inhibited cell proliferation and invasion in NSCLC. Additionally, metadherin was identified as a direct target gene of miR-584 in NSCLC as confirmed by a series of experiments. Moreover, upregulation of miR-584 was involved in the regulation of the phosphatase and tensin homolog/Akt serine/threonine kinase signalling pathway in NSCLC. Thus, miR-584 may serve as a tumor-suppressor, and the results of the present study provide a reference for future research into the potential mechanisms underlying NSCLC progression. PMID- 29434827 TI - Anti-inflammatory drug resistance selects putative cancer stem cells in a cellular model for genetically predisposed colon cancer. AB - Mutations in the adenomatous polyposis coli (Apc) tumor suppressor gene represent the primary genetic defect in colon carcinogenesis. Apc+/- mouse models exhibit pre-invasive small intestinal adenomas. Cell culture models exhibiting Apc defects in the colon and quantifiable cancer risk provide a novel clinically relevant approach. The tumor-derived Apc-/- colonic epithelial cell line 1638N COL-Pr1 represented the experimental model. The anti-inflammatory drugs sulindac (SUL) and celecoxib (CLX) represented the test compounds. Compared with non tumorigenic Apc+/+ C57COL cells, the Apc+/- 1638N COL cells and Apc-/- 1638N COL Pr1 cells exhibited progressive loss of homeostatic growth control. Compared with Apc+/- cells, Apc-/- cells displayed increased expression of biomarkers specific for hyper-proliferation. Treatment of Apc-/- cells with SUL and CLX resulted in inhibition of anchorage-independent colony formation in vitro, which is indicative of reduced cancer risk in vivo. Mechanistically, SUL and CLX suppressed the expression of the Apc target genes beta-catenin, cyclin D1, c-Myc and cyclooxygenase-2. Long-term treatment with high concentrations of SUL and CLX led to the selection of hyper-proliferative drug-resistant phenotypes. The Apc-/- SUL-resistant phenotype displayed spheroid formation and enhanced the expression of the stem cell-specific molecular markers CD44, CD133 and c-Myc. These data demonstrated the growth-inhibitory efficacy of SUL and CLX and indicated that drug resistance leads to the selection of a putative cancer stem cell phenotype. The study outcome validates a stem cell-targeted mechanistic approach to identify testable alternative leads for chemotherapy-resistant colon cancer. PMID- 29434828 TI - Mitogen-activated protein kinase signaling pathway in oral cancer. AB - The mitogen-activated protein kinase (MAPK) signaling pathway is associated with tumor cell proliferation, differentiation, apoptosis, angiogenesis, invasion and metastasis. The present review assesses the involvement of the MAPK signaling pathway in oral cancer progression and invasion based on analysis of individual sub-pathways and their mechanisms of action. The regulation of this pathway for targeted oral cancer therapy is explored and the challenges confronting this, as well as corresponding potential solutions, are discussed. Exploring this pathway with an emphasis on its components, subfamilies, sub-pathways, interactions with other pathways and clinical practice modes may improve oral cancer treatment. PMID- 29434829 TI - Patellar metastasis from primary tumor. AB - Although bone tumors are frequently located in the knee area, primary tumors of the patella are rare and patellar metastases are even rarer. Knee pain is the most common complaint of patients with patellar metastases. Owing to the low incidence of patellar metastases, misdiagnosis is not unusual. The present review analyzes ~44 cases of patellar metastases originating from distinct primary sites. Reports of malignant tumors of the lung and kidney metastasizing to the patella were more common than those of other patellar metastases. Relative incidence, symptomatology, imaging features, histopathology and treatment options for these patellar metastatic lesions are described respectively along with a review of the literature. Despite numerous experiments demonstrating the reasons for implantation of tumor in patella, the answer to this question has not yet been revealed. In the light of the increasing attention on the diagnosis and the treatment of these lesions, the availability of the integrated information regarding metastases in the patella becomes more relevant. PMID- 29434831 TI - CXCL5 secreted from adipose tissue-derived stem cells promotes cancer cell proliferation. AB - Accumulating data suggest that adipose tissue facilitates breast tumor initiation and progression through paracrine and endocrine pathways, and that adipose tissue derived stem cell (ASC) is likely the major cell type responsible for tumorigenesis and tumor development. However, it remains unknown how ASCs exert their effects. In the present study, in cultured breast cancer cell lines, including estrogen receptor (ER)-positive MCF-7 cells and ER-negative MDA-MB-231 cells, the effects on tumor proliferation of isolated ASCs from human breasts were examined. The expression of 174 cytokines was additionally identified in this medium. With an anti-human C-X-C motif ligand 5 (CXCL5) monoclonal antibody, the effects of neutralization of CXCL5 on the actions of ASCs in a co-culture medium of ASCs and tumor cells were studied The results demonstrated that ASCs significantly increased the number of breast cancer cells compared with controls. Similarly, the co-culture medium of ASCs with breast cancer cells exhibited potent effects on tumor cell proliferation. In the co-culture medium of ASCs with breast cancer cells, CXCL5 levels were significantly increased. In addition, depletion of CXCL5 with its specific antibody in ASC-conditioned medium blocked the stimulatory effect of ASCs on the proliferation of breast cancer cells. To the best of our knowledge, these results indicate for the first time that ASC secreted CXCL5 is a key factor promoting breast tumor cell proliferation. PMID- 29434830 TI - Pediatric sarcomas. AB - Sarcomas arise from primitive mesenchymal cells, which are classified, into two main groups: Bone and soft tissue sarcomas. We have searched all-important electronic databases including Google scholar and PubMed for the collection of latest literature pertaining to pediatric sarcomas. Latest literature confirmed that these tumors are relatively rare and represent only 1% of all malignancies but they have higher incidence in children. Pediatric sarcomas comprise about 13% of all pediatric malignancies and are ranked third in childhood cancers. The highest incidence rates are reported among rhabdomyosarcoma, osteosarcoma and Ewing's sarcomas in children. All of these neoplasms often display highly aggressive behavior with tendency to form metastases. Important globally used management avenues include surgery with systemic chemotherapy and have success rate of 70% at 5-years. Furthermore, in the cases of advanced stages, the prognosis is poor, chances of treatment failure and recurrence are quite high. Utilization of cancer stem cells is the latest approach with great potential in management of above pathological state. The present review article discuss all important aspects of commonly found pediatric sarcomas throughout the world. PMID- 29434832 TI - Effects of liver cirrhosis on portal vein embolization prior to right hepatectomy in patients with primary liver cancer. AB - Preoperative portal vein embolization (PVE) induces compensatory hyperplasia of the future liver remnants (FLR), thus increasing resectability in the non cirrhotic patients with primary liver cancer (PLC). However, it is unclear if it is similar in patients with liver cirrhosis. Therefore, the present study investigated the PVE value prior to liver resection in patients with PLC, and the liver cirrhotic effects on the compensatory hypertrophy of FLRs following PVE. In the present study, 21 patients with PLC who successfully underwent hepatic resection subsequent to PVE, were retrospectively examined. The patients were divided into a non-cirrhosis group and a cirrhosis group according to the absence or presence of cirrhosis, respectively. The FLR volume between the two groups of patients was compared. There was a significant difference in the FLR volume for all patients prior to, and 4-6 weeks following, PVE (P<0.001). PVE induced significant compensatory hypertrophy in the FLRs whether in the non-cirrhosis group (P=0.002) or cirrhosis group (P<0.001). However, no significant difference was identified between the two groups with respect to FLR volume enlargement 4-6 weeks following PVE (P=0.373). In conclusion, PVE prior to hepatectomy may promote FLR compensatory hypertrophy and an increase in the resectability of PLC tumors. No significant effects of liver cirrhosis were identified on liver lobe hyperplasia following PVE. PMID- 29434833 TI - Piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways. AB - Piperlongumine is an alkaloid compound extracted from Piper longum L. It is a chemical substance with various pharmacological effects and medicinal value, including anti-tumor, lipid metabolism regulatory, antiplatelet aggregation and analgesic properties. The present study aimed to understand whether piperlongumine induces the apoptosis and autophagy of leukemic cells, and to identify the mechanism involved. Cell viability and autophagy were detected using MTT, phenazine methyl sulfate and trypan blue exclusion assays. The apoptosis rate was calculated using flow cytometry. The protein expression levels of microtubule-associated protein 1A/1B-light chain 3, Akt and mechanistic target of rapamycin (mTOR) were measured using western blotting. The cell growth of leukemic cells was completely inhibited following treatment with piperlongumine, and marked apoptosis was also induced. Dead cells as a result of autophagy were stained using immunofluorescence and observed under a light microscope. Phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling was suppressed by treatment with piperlongumine, while p38 signaling and caspase-3 activity were induced by treatment with piperlongumine. It was concluded that piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways. PMID- 29434834 TI - Prognostic value of SPARCL1 in patients with colorectal cancer. AB - Secreted protein acidic and rich in cysteine-like 1 (SPARCL1), a member of extracelluar matrix glycoprotein, has been reported to be associated with various tumor types. The present study aimed to evaluate the prognostic value of SPARCL1 in patients with colorectal cancer. Tissue microarray blocks were constructed based on 79 patients who underwent radical surgery at the Kunshan First People's Hospital between 2008 and 2010. Thirty pairs of fresh-frozen tissues were also obtained for total protein extraction. The expression of SPARCL1 protein was analyzed using immunohistochemistry and western blotting analyses, and the association between overexpressed SPARCL1 and clinicopathological factors was evaluated. Survival analysis with Kaplan Meier curves and Cox regression analysis was used to analyze the prognostic value of SPARCL1. According to western blot analyses, SPARCL1 protein expression in colorectal tumors was significantly lower compared with corresponding normal tissues. The expression of SPARCL1 was markedly decreased from differentiation I to III, and the negative rate of SPARCL1 was higher at Duke's stage C compared with B. Though without any difference between 'positive' and 'negative' in overall survival, significantly higher survival in patients with positive SPARCL1 expression at Duke's stage B was detected in the present study. These results indicated that SPARCL1 may be a potential tumor suppressor gene and associated with good prognosis. PMID- 29434835 TI - The ribosome inhibiting protein riproximin shows antineoplastic activity in experimental pancreatic cancer liver metastasis. AB - Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all malignancy types. To improve the survival of patients with PDAC, the development of novel anticancer agents is warranted. Riproximin (Rpx) is a newly identified plant lectin, which was isolated from Ximenia americana. The ribosome inactivating protein of type II exhibits potent anticancer activity as recently demonstrated. The rat PDAC cell line ASML was used for in vitro and in vivo studies. The antiproliferative effect of Rpx was assessed using an MTT assay. The modulation of proteins involved in apoptosis was evaluated using western blotting. Tumor-bearing nude rats were treated with Rpx, gemcitabine (GEM) or dinaline (DIN) as single agents, or a combination of Rpx with GEM, or DIN. Rpx was administered intraperitoneally at doses of 1.7-5.4 ug/kg, three times/week, GEM was administered intravenously (50 mg/kg/week) and DIN perorally (10 mg/kg, 5 times/week). Rpx inhibited ASML cell proliferation at IC50-values of 0.8-172 pM, caused apoptosis and reduced tumor growth significantly by 90% (P<0.05). The survival rate of rats was significantly increased (21.8 days for Rpx treated vs. 17.6 days for control rats; P=0.05). Higher doses of Rpx caused no further reduction in tumor size when compared with the low dose of Rpx or a combination of Rpx with GEM, or DIN. The standard drug GEM alone was less effective compared with Rpx. In addition, DIN was ineffective, and in combination, reduced the activity of Rpx. These results suggest that Rpx has an evident potential for use in pancreatic cancer treatment. Further experiments are required in order to elucidate its affinity for certain cancer cells and to optimize the combination therapy with other antineoplastic agents. PMID- 29434836 TI - Increased expression of mitochondrial transcription factor A and nuclear respiratory factor-1 predicts a poor clinical outcome of breast cancer. AB - Nuclear respiratory factor-1 (Nrf1) and mitochondrial transcription factor A (TFAM) are involved in the regulation of a variety of mitochondrial functional genes, which are associated with decreased sensitivity of tumor cells to chemotherapy. However, the expression status of Nrf1 and TFAM, as well as their clinical significance in breast cancer, is unknown. In the present study, tumor tissues and corresponding adjacent normal tissues were collected from 336 patients with breast cancer, and Nrf1 and TFAM expression was analyzed by immunohistochemistry using a tissue microarray. Expression of Nrf1 and TFAM was significantly increased in breast cancer tissue compared with adjacent normal tissues. In addition, patients positive for Nrf1 or TFAM had a poorer clinical prognosis than patients who were negative, and those positive for Nrf1 and TFAM had the shortest survival time. These results suggest that Nrf1 and TFAM are potential biomarkers for the determination of individualized therapy and the prognosis of breast cancer, and molecular targeting of Nrf1 and TFAM is a promising strategy for the sensitization of breast cancer cells to chemotherapeutics. PMID- 29434837 TI - Altered capicua transcriptional repressor gene expression exhibits distinct prognostic value for isocitrate dehydrogenase-mutant oligodendroglial tumors. AB - To evaluate the prognostic significance of the altered expression of capicua transcriptional repressor (CIC) in isocitrate dehydrogenase (IDH)-mutant oligodendroglial tumors, a cohort of 54 IDH-mutant oligodendroglial tumors (designated as the Xijing cohort) were examined by immunohistochemistry (IHC), and two public expression data sets from The Cancer Genome Atlas (TCGA; n=265) and the Gene Expression Omnibus (GEO; n=45) were analyzed in the present study. The prognostic value was evaluated by survival analysis and Cox hazards models. Overall survival (OS) was investigated with Kaplan-Meier curves and log-rank tests. Gene set enrichment analysis (GSEA) was also performed to characterize the functional profiles of each subgroup. It was revealed that in IDH-mutant, 1p/19q co-deleted oligodendroglial tumors, higher CIC expression (at mRNA and protein levels) was associated with a more favorable OS time (log-rank P-values: TCGA, P=0.034; GEO, P=0.012; Xijing cohort, P=0.029). By contrast, among IDH-mutant, 1p/19q intact tumors, higher CIC expression was associated with poorer OS time (log-rank P-values: TCGA, P=0.007; GEO, P=0.017; Xijing cohort, P=0.012). To the best of our knowledge, this is the first study demonstrating the distinct prognostic value of altered CIC expression with regard to the 1p/19q status among IDH-mutant oligodendroglial tumors. The dual roles of CIC may be influenced by its transcriptional regulatory activity and the consequent functional profiles. Additionally, a simple risk classification scheme based on CIC expression alone is proposed for the optimal prediction of prognosis in patients with oligodendroglial tumors. PMID- 29434838 TI - MicroRNA-150 inhibitors enhance cell apoptosis of melanoma by targeting PDCD4. AB - Malignant melanoma is a tumor with a high mortality rate. Previous studies have demonstrated that the oncogenesis of melanoma is associated with microRNA (miR) 150. However, the role of miR-150 in melanoma and its regulatory mechanisms are still unclear. In the present study, melanoma cancer tissues and adjacent normal tissues were obtained from 20 melanoma patients. The expression level of miR-150 in melanoma tissue and cell lines was detected by reverse transcription quantitative polymerase chain reaction. miR-150 inhibitors/negative control were transfected into melanoma A375 cells in order to investigate the effects of miR 150 on cell proliferation, apoptosis, cell cycle migration and invasion using a Cell Counting Kit-8, colony formation, Hoechst 33528, flow cytometry, and Transwell assays. The association between miR-150 and programmed cell death protein-4 (PDCD4) was detected by a dual luciferase reporter assay. The functional role of PDCD4 in miR-150-affected melanoma cells was confirmed by small interfering (si)RNA knockdown. Results demonstrated that miR-150 was significantly upregulated and mRNA and protein expressions of PDCD4 were decreased in melanoma cancer tissues as compared with adjacent normal tissues. The level of PDCD4 was inversely associated with the level of miR-150. Transfection of miR-150 inhibitors suppressed cell proliferation, migration, and invasion, while the apoptosis of cells was promoted and G2/M cell arrest was induced. MiR-150 inhibitors enhanced the expression of caspase-8 and p21. The PDCD4 was identified as a direct target gene of miR-150. The effects of miR-150 inhibitors on apoptosis and apoptosis-associated proteins, including caspase-8 and p21, of A375 cells, were reversed following transfection of siRNA-PDCD4. Therefore, miR-150 inhibitors enhance cell apoptosis via upregulation of PDCD4 mediated activation of caspase-8 and p21. These findings demonstrate the potential for a promising therapeutic strategy in the management of melanoma. PMID- 29434839 TI - The link between FOXJ1 expression level in bladder carcinoma and tumor recurrence. AB - We studied the expression level of FOXJ1 in bladder epithelial carcinoma and its relation to clinical features and tumor recurrence. From January 2014 to June 2015, 66 patients with bladder epithelial carcinoma were enrolled in this study and their tumor and para-carcinoma tissue samples were collected. FOXJ1 positive expression rate was evaluated using immunohistochemical staining, and FOXJ1 mRNA expression level was measured by RT-PCR. RT-PCR and immunohistochemistry results showed that FOXJ1 expression level in tumor samples was significantly lower than that in para-carcinoma tissue samples. The median survival time in patients with positive expression of FOXJ1 was significantly longer than that of patients with negative expression of FOXJ1. We also showed that FOXJ1 expression level was negatively correlated with neoplasm staging and tumor recurrence rate. We concluded that FOXJ1 was expressed in low quantities in bladder epithelial carcinoma, which was closely correlated with the biological characteristics of the tumor. FOXJ1 expression presents a promising application prospect for further exploration of the specific biological mechanism of FOXJ1 in regulating the occurrence and development of bladder epithelial carcinoma. FOXJ1 may be used as a new marker for early diagnosis and prediction of recurrence. PMID- 29434840 TI - Autophagy activation promotes bevacizumab resistance in glioblastoma by suppressing Akt/mTOR signaling pathway. AB - Glioblastomas are the most common primary and malignant brain tumors. The standard therapy includes surgery and radiotherapy plus chemotherapy, with additional bevacizumab to block the angiogenesis in tumors. However, the ever growing tolerance of glioblastomas to chemotherapeutic drugs impairs the clinical outputs of tumor treatment. The present study investigated the tolerance of glioblastomas to bevacizumab. Although bevacizumab resulted in direct anti proliferation and pro-apoptosis effects on glioblastoma cells via downregulating the anti-apoptotic proteins and upregulating the pro-apoptotic proteins, tolerance was also encountered that was mainly caused by autophagy induction in tumor cells. The suppressed Akt-mTOR signaling pathway led to the upregulated autophagy process. Blockade of the autophagy process significantly increased the tumor-suppressive effect of bevacizumab on glioblastoma cells. To our knowledge, the present study is the first to report the involvement of autophagy in the tolerance of glioblastomas to bevacizumab. Therefore, autophagy inhibition may be considered a novel way to overcome the tolerance of glioblastomas to anti angiogenic agents. PMID- 29434841 TI - Sodium butyrate induces senescence and inhibits the invasiveness of glioblastoma cells. AB - Sodium butyrate (SB), a short chain (C-4) saturated fatty acid, is present in the human bowel at increased concentrations (~2 mM) as a food metabolite. It has been demonstrated that SB exerts an anti-tumor effect as a histone deacetylase inhibitor; however, its precise mechanism of action remains to be elucidated. The present study focused on the mechanisms underlying the effects of SB on glioblastoma (GB) cell proliferation, motility and invasion. In human GB A172 cells, flow cytometry and a Boyden chamber assay demonstrated that physiological concentrations of SB (0.25-4.00 mM) dose-dependently inhibited cell proliferation and invasion. SB also affected cellular morphology, with increases in cell area and the number of focal adhesions observed. However, the phosphorylation (Y397 site) of focal adhesion kinase (FAK) was increased, while that of myosin light chain (S19 site) was unaltered. All of these SB-induced effects were reversible and attenuated following SB withdrawal. In addition, A172 cells treated with SB exhibited positivity for senescence-associated (SA) beta-galactosidase (gal) staining and elevated protein expression of p53 and p21 in a time- and dose dependent manner, whereas the expression of p21 mRNA decreased. Knockdown of p21 expression using small interfering RNA reversed the inhibition of cell growth inhibition and positivity for SA beta-gal staining, but did not reverse the inhibition of cell motility and enhanced phosphorylation of FAK. This suggests that cells require p21 to induce senescence but not for SB-mediated decreased motility. Therefore, the current study demonstrated that SB inhibits GB cell proliferation, induces cells to senesce and inhibits tumor cell invasion, indicating that it may be developed as a novel therapeutic strategy to treat GB. PMID- 29434842 TI - Comprehensive characterization of cancer genes in hepatocellular carcinoma genomes. AB - The present study was performed to detect moderate or low-frequency mutated cancer driver genes in hepatocellular carcinoma (HCC), using OncodriveFM and Dendrix. Following this, integrated analyses were conducted on these novel cancer driver genes. A total of 112,980 somatic mutations were retrieved from TCGA and classified into 11 categories based on their function. Driver genes and pathways were predicted by OncodriveFM and Dendrix, followed by differential expression, DNA-methylation, copy number variations and survival analyses. Overall, non synonymous mutations accounted for >60% (72,149/112, 980) of total variants, 108 and 3 driver genes were determined by OncodriveFM and Dendrix, respectively. Tumor protein p53, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4, smad family member 3, RB transcriptional corepressor 1, catenin beta 1, smad family member 4, mitogen-activated protein kinase 1 and TSC complex subunit 2 are at the core of the driver gene interaction network. Two genes, transportin 1 (TNPO1) and chaperonin containing TCP1 subunit 3 (CCT3), were hypomethylated and overexpressed, and high expression of TNPO1 and CCT3 indicated a poor prognosis in patients with HCC. beta-carotene oxygenase 2 was hypermethylated, under-expressed and associated with favorable prognosis in HCC. The present study has identified a set of novel cancer genes and pathways, offering potential therapeutic targets and prognostic biomarkers for the treatment of HCC. PMID- 29434843 TI - ARK5 promotes invasion and migration in hepatocellular carcinoma cells by regulating epithelial-mesenchymal transition. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. The highly invasive nature of HCC leads to poor prognosis in patients with malignant HCC. AMPK-related protein kinase 5 (ARK5) is a key mediator of migratory activity in human cancer cells. However, the role of ARK5 in invasion and metastasis of HCC cells remains unclear. The present study attempted to determine whether ARK5 is involved in invasion and migration via regulation of epithelial-mesenchymal transition (EMT). Wound healing and Transwell Matrigel invasion assays were utilized to detect the ability of the epithelial Huh7 and mesenchymal SNU387 HCC cells to migrate and invade. Next, the expression of ARK5 and EMT markers, E-cadherin and vimentin, were examined by western blot analysis. Inhibition of ARK5 was able to significantly reduce the ability HCC cells to invade and metastasize. Furthermore, the knockdown of ARK5 was able to reverse the process of EMT in HCC cells. These data suggested that ARK5 may serve an important role in regulating EMT in HCC cells. Taken together, these findings indicate that ARK5 is a potential molecular target for the development of novel HCC therapeutics, which focus on cell invasion and EMT regulation. PMID- 29434844 TI - Oxaliplatin and infliximab synergize to induce regression of colon cancer. AB - There is currently a lack of therapeutic options for patients with advanced colon cancer. Although certain chemotherapies are able to suppress the progression slightly, the response rate is low, and side effects of treatment and tumor recurrence continue to present problems for clinicians. Tumor necrosis factor alpha (TNF-alpha) has been identified to possess tumor-promoting properties. In the present study, the effect of anti-TNF-alpha treatment (infliximab) in combination with chemotherapy on colon cancer was investigated. Tumor tissue samples were collected from patients with colon cancer who received oxaliplatin (OXA) treatment. Their TNF-alpha expression levels were examined with regard to their sensitivity to OXA. OXA-resistant colon cancer cell lines were established to explore the effects of anti-TNF-alpha treatment and OXA treatment. Furthermore, an OXA-resistant colon cancer xenograft mouse model was created and the effects of the combination treatment of anti-TNF-alpha and OXA on the mice were assessed. The results of the present study indicated that TNF-alpha was increased in the tumor tissue of patients with colon cancer who were resistant to OXA and also in OXA-resistant colon cancer cell lines. Anti-TNF-alpha treatment using infliximab inhibited the survival of OXA-resistant colon cancer cell lines by inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity effects. The combination of infliximab and OXA treatment achieved increased efficacy on the OXA-resistant colon cancer xenograft mouse model compared with treatment with OXA alone. On the basis of the results of the present study, it was concluded that infliximab may sensitize colon cancer cells to OXA treatment. PMID- 29434845 TI - All-trans retinoic acid inhibits the proliferation of SGC7901 cells by regulating caveolin-1 localization via the ERK/MAPK signaling pathway. AB - Caveolin-1 is a scaffold protein of caveolae in the mucosa of the gastrointestinal tract and acts as a tumor modulator by interacting with cell adhesion molecules and signaling receptors. Caveolin-1 stabilizes cell-cell and cell-matrix contacts and is a hallmark of a number of different types of human cancer, including gastric cancer. All-trans retinoic acid (ATRA), a derivative of vitamin A, has been demonstrated to exhibit tumor inhibitory effects in acute leukemia and certain types of solid tumor. In the present study, treatment with ATRA was demonstrated to inhibit the proliferation of gastric cancer cell line SGC7901, in a time- and dose-dependent manner. The markedly increased membrane localization of caveolin-1 was observed in the cells that were treated with 10 umol/l ATRA for > 48 h. In addition, it was observed that treatment with ATRA was able to regulate the level of phosphorylation of extracellular signal-regulated kinase (ERK). Therefore, the SGC7901 cells were treated with a specific agonist of ERK/mitogen-activated protein kinase (MAPK) investigate whether ATRA mediated its effects via the ERK/MAPK signaling pathway. The results of the present study demonstrated that ATRA-induced increase in membrane localization of caveolin-1 was reversed by treatment with a specific agonist of ERK/MAPK. Together, these results suggest that ATRA exhibits anti-gastric cancer effects. ATRA may regulate the membrane localization of caveolin-1 in order to inhibit the proliferation of SGC7901 cells. These effects of ATRA may be mediated by inhibiting the activation of ERK/MAPK signaling pathway. These results contribute to the current knowledge on the potential use of ATRA as therapy for solid tumors and provide further insight into the potential molecular mechanisms of ATRA action. PMID- 29434846 TI - Co-existence of benign gynecological tumors with endometriosis in a group of 1,000 women. AB - The purpose of this study was two-fold, first to investigate the association between endometriosis and the risk of benign gynecologic tumors and, secondly, to evaluate the distribution of endometrioma and ovarian cysts in women with endometriosis. The medical and pathological reports of 1,000 women with endometriosis were retrospectively reviewed. The incidence of ovarian cysts, uterine leiomyomas and adenomyosis, as well as the side of ovarian cysts were further compared. A total of 295 cases of endometriomas, 172 cases of adenomyosis, 173 cases of ovarian cysts and 89 cases of uterine leiomyomas were confirmed histologically in patients with endometriosis. Serous cysts represented the most frequent diagnosis (n=81, 8.1%) in women with ovarian cysts, followed by dermoid cysts (n=15, 1.2%). In women with unilateral endometriomas, the observed proportion of left-sided cysts was found in 65.6% (164 of 250), significantly higher compared with right-sided cysts (86 out of 250, 34.4%) (P<0.001). Moreover, patients with other ovarian cysts were recognized as left-sided in 60% (96 out of 160) of cases, significantly higher compared with right-sided cysts (64 out of 160, 40%) (P<0.01). On the whole, the current study indicates that endometriosis may be associated with an increased risk of benign gynecological tumors, such as ovarian cysts, adenomyosis and leiomyomas. The results of this study confirm a left lateral predisposition of endometriomas and ovarian cysts. PMID- 29434847 TI - The relationship between cervical precancerous lesion galectin-3 and p27 protein expression and clinical prognosis. AB - The relationship between galectin-3 and p27kip1 protein expression levels in cervical precancerous lesions and clinical prognosis were studied. A total of 74 patients with cervical intraepithelial neoplasia [(CIN), 20 cases classified as stage I, 24 cases as stage II and 30 cases as stage III] were enrolled in this study. Tissue galectin-3, p27kip1, vascular endothelial growth factor (VEGF)-2 and cyclin D protein levels were detected via immunohistochemical staining and reverse transcription polymerase chain reaction (PCR). Follow-up median duration was 13.5 months and recurrence rate was determined. Galectin-3, VEGF-2, and cyclin D expression was elevated in patients with higher stage CIN, whereas p27kip1 showed the opposite trend (p<0.05). During follow-up, there were 3 cases (15.0%) of recurrence in the CIN-I group, 5 cases (20.8%) in the CIN-II group and 9 cases (30.0%) in CIN-III the group. No significant difference in recurrence rate was noted among the groups (p>0.05). The upregulation of galectin-3 and downregulation of p27kip1 in CIN tissues may be related to tumor progression. This phenomenon will require further verification. PMID- 29434848 TI - BmK CT enhances the sensitivity of temozolomide-induced apoptosis of malignant glioma U251 cells in vitro through blocking the AKT signaling pathway. AB - Temozolomide (TMZ) is a drug that has been demonstrated to improve the survival time of patients with glioblastoma multiforme (GBM) when administered with concomitant radiotherapy. However, chemoresistance is one of the major obstacles in the treatment of GBM. In the present study, an MTT assay and flow cytometry were used to demonstrate that chlorotoxin-like toxin in the venom of the scorpion Buthus martensii Kirsch (BmK CT) markedly inhibited cell proliferation and induced apoptosis in U251 cells when combined with TMZ. In combination with TMZ, BmK CT exhibited a significant and synergistic anti-tumor effect by inhibiting protein kinase B (AKT) independently and triggering the apoptosis signaling cascade in vitro. Furthermore, BmK CT increased the expression of phosphatase and tensin homolog at the transcriptional level, which is a key negative regulator of the AKT signaling pathway. The results of the present study demonstrated that BmK CT enhanced the sensitivity of TMZ-induced U251 cell apoptosis through the downregulation of phosphorylated AKT levels, suggesting that BmK CT and TMZ combination therapy may be a novel approach for glioma therapy. PMID- 29434849 TI - Family with sequence similarity 83, member B is a predictor of poor prognosis and a potential therapeutic target for lung adenocarcinoma expressing wild-type epidermal growth factor receptor. AB - Lung adenocarcinoma (ADC) patients with tumors that harbor no targetable driver gene mutation, such as epidermal growth factor receptor (EGFR) gene mutations, have unfavorable prognosis, and thus, novel therapeutic targets are required. Family with sequence similarity 83, member B (FAM83B) is a biomarker for squamous cell lung cancer. FAM83B has also recently been shown to serve an important role in the EGFR signaling pathway. In the present study, the molecular and clinical impact of FAM83B in lung ADC was investigated. Matched tumor and adjacent normal tissue samples were obtained from 216 patients who underwent complete lung resection for primary lung ADC and were examined for FAM83B expression using cDNA microarray analysis. The associations between FAM83B expression and clinicopathological parameters, including patient survival, were examined. FAM83B was highly expressed in tumors from males, smokers and in tumors with wild-type EGFR. Multivariate analyses further confirmed that wild-type EGFR tumors were significantly positively associated with FAM83B expression. In survival analysis, FAM83B expression was associated with poor outcomes in disease-free survival and overall survival, particularly when stratified against tumors with wild-type EGFR. Furthermore, FAM83B knockdown was performed to investigate its phenotypic effect on lung ADC cell lines. Gene silencing by FAM83B RNA interference induced growth suppression in the HLC-1 and H1975 lung ADC cell lines. FAM83B may be involved in lung ADC tumor proliferation and can be a predictor of poor survival. FAM83B is also a potential novel therapeutic target for ADC with wild-type EGFR. PMID- 29434850 TI - Modulation of G2/M cell cycle arrest and apoptosis by luteolin in human colon cancer cells and xenografts. AB - The aim of the present study was to investigate the underlying molecular mechanisms of the potent cell cycle inhibition and apoptotic effect of luteolin on LoVo human colon cancer cells. In the present study, Cell Counting kit-8 assay revealed that luteolin exerted notable cytotoxicity on LoVo cells in a dose- and time-dependent manner, with a 50% inhibitory concentration value of 66.70 and 30.47 umol/l at the time points of 24 and 72 h, respectively. Flow cytometric analysis confirmed that luteolin promoted cell cycle arrest at the G2/M phase, and subsequently induced cell apoptosis. Western blot analysis further revealed that luteolin exhibited an inhibitory effect on the proliferation of LoVo cells by inhibiting cell cycle arrest at the G2/M phase transition, with an inactivation of cyclin B1/cell division cycle 2 and induction of cell apoptosis, in part via cytochrome c- and deoxyadenosine triphosphate-mediated activation of apoptotic protease activating factor 1. In vivo studies revealed that luteolin effectively decreased the colon tumor body weight of mice. Therefore, the evidence suggests that luteolin may be a potential chemopreventive and chemotherapeutic agent against human colon cancer. PMID- 29434851 TI - Bufadienolides induce p53-mediated apoptosis in esophageal squamous cell carcinoma cells in vitro and in vivo. AB - Bufadienolides are a type of cardiotonic steroids isolated from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor, and exhibit wide spectrum anticancer activities. However, the effects and mechanisms of bufadienolides on esophageal squamous cell carcinoma (ESCC) cells remain unknown. In the present study, the anticancer activities of two bufadienolides, bufotalin and bufalin, were examined in vitro and in vivo. The results demonstrated that bufotalin and bufalin effectively inhibited the viability of ESCC cells, with half-maximal inhibitory concentration (IC50) values of 0.8-3.6 uM. However, bufotalin and bufalin exhibited lower toxicity towards Het-1A human esophageal squamous cells, indicating their high selectivity towards cancer cells. Mechanistic studies revealed that bufotalin effectively induced ESCC cell apoptosis, as characterized by DNA fragmentation and nuclear condensation, which was primarily mediated through activation of caspase family members. In addition, treatment of ESCC cells with bufotalin markedly activated tumor protein p53 (p53) phosphorylation. Transfection of cells with p53 small interfering RNA markedly inhibited bufotalin-induced p53 phosphorylation and significantly inhibited bufotalin-induced cell apoptosis. Furthermore, bufotalin demonstrated in vivo anticancer efficacy in a tumor-bearing nude mice model, where bufotalin effectively inhibited Eca-109 xenograft tumor growth in a time- and dose dependent manner, through activation of the p53 signaling pathway. Collectively, the results from the present study suggested that bufadienolides exert anticancer effects against ESCC by regulating the p53 signaling pathway. PMID- 29434852 TI - Platelet-derived growth factor-D promotes colorectal cancer cell migration, invasion and proliferation by regulating Notch1 and matrix metalloproteinase-9. AB - Colorectal cancer (CRC) has been one of the most common types of cancer for decades worldwide. The pathogenesis of CRC is associated with the processes of activating oncogenes and inactivating anti-oncogenes. Platelet-derived growth factor-D (PDGF-D) was confirmed to regulate migration, invasion, proliferation, apoptosis and metastasis in various cancer cells. Overexpression of PDGF-D exists in a number of human malignancies, including pancreatic, prostate and breast cancer. However, the expression and function of PDGF-D and its associated molecular mechanism in CRC remain unclear. Thus, the expression of PDGF-D was detected in CRC tissues and human colon cancer lines. Subsequently, the effects of PDGF-D on the invasion, migration and proliferation of cancer cells were investigated. The corresponding molecular mechanism had also been explored. The present study revealed that PDGF-D was upregulated not only in CRC tissues but also in CRC cell lines, and simultaneously, facilitated the processes of migration, invasion and proliferation. Silencing PDGF-D in the SW480 cell line inhibited migration, invasion and proliferation distinctly, with reduced expression of Notch1 and matrix metalloproteinase-9. Furthermore, upregulating PDGF-D in HCT116 cells led to the opposite results. These findings indicate that PDGF-D may be developed into a potential therapeutic target for CRC treatment. PMID- 29434853 TI - Intracellular IL-4 and IFN-gamma expression in iNKT cells from patients with chronic lymphocytic leukemia. AB - Malignant B cells in chronic lymphocytic leukemia serve an essential role in the whole immune response, so their interactions with other immune cells are more complex than observed in solid tumors. The latest study results indicate that the immune dysregulation in chronic lymphocytic leukemia (CLL) also affects a small population of invariant natural killer T cells (iNKT). Using peripheral blood iNKT cells obtained from patients with CLL, the objective of the present study was to assess the intracellular expression of typical cytokines involved in the Th1 (IFN-gamma) and Th2 (IL-4) response pathways following stimulation with the iNKT-specific ligand alpha-galactosylceramide. iNKT cells from patients with CLL exhibited upregulated IL-4 and IFN-gamma expression in comparison to those from HVs. No significant association between the ability of iNKT cells to produce IL-4 or IFN-gamma and the expression of CD1d on leukemic B lymphocytes or monocytes was identified. However, the function of iNKT cells was compromised in patients with CLL by a strong Th2 bias (high IL-4 and low IFN-gamma expression). The ratio of iNKT+IFN-gamma+:iNKT+IL-4+ was significantly decreased in the CLL group when compared with HVs, and this decreased further as the disease progressed. This change may result in the promotion of leukemic B lymphocyte survival. Therefore, in the pathogenesis of CLL, Th2 bias may delay the antitumor response that relies on stimulation of the Th1 immune response. PMID- 29434854 TI - Celastrus orbiculatus extracts induce cell cycle arrest and apoptosis in human esophageal squamous carcinoma ECA-109 cells in vitro via the PI3K/AKT/mTOR signaling pathway. AB - Recently, Celastrus orbiculatus ethyl acetate extracts (COE) have been investigated for their anticancer effects on digestive tract tumors. However, the therapeutic effects of COE on esophageal squamous carcinoma cells (ESCC) have not been investigated. In the present study, the effects of COE on the cell cycle and apoptosis of ESCCs were assessed in vitro, and it was revealed that COE treatment triggered G0/G1 cell cycle arrest, and induced DNA damage and apoptosis in a dose dependent manner in ESCC. Activation of the phosphatidylinositol 3-kinase/protein kinase-B/mechanistic target of rapamycin (mTOR) pathway was also suppressed by COE. Additionally, the combined treatment with COE and rapamycin (an mTOR inhibitor) acted synergistically in ECA-109 cells compared with the treatment with COE or rapamycin alone. These findings extend the understanding of the action of COE and suggest that COE has potential as a treatment option for ESCC as a single treatment or in combination. PMID- 29434855 TI - Promoter methylation of RB1, P15, P16, and MGMT and their impact on the clinical course of pilocytic astrocytomas. AB - Promoter methylation of P15, P16, RB transcriptional corepressor 1 (RB1) and O-6 methylguanine-DNA methyltransferase (MGMT) impacts the prognosis of numerous glioma subtypes. However, whether promoter methylation of these genes also has an impact on the clinical course of pilocytic astrocytoma remains unclear. Using methylation-specific polymerase chain reaction, the methylation status of the tumor suppressor genes P15, P16, RB1, and MGMT in pilocytic astrocytomas (n=18) was analyzed. Immunohistochemical staining for the R132H mutation of the isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1) gene was performed. Clinical data including age, gender, localization of tumor, extent of resection, treatment modality, progression-free survival and overall survival were collected. The methylation index for P15, P16, RB1 and MGMT was 0.0, 0.0, 5.6% (1/18) and 44.5% (8/18), respectively. If the MGMT promoter was methylated, the probability of relapse and second subsequent therapy was significantly increased (P=0.019). The one patient with methylation of P15 demonstrated a poor clinical course. The pilocytic astrocytomas of all 18 patients revealed wild-type IDH1. Clinically, there was a significant correlation of subtotal resection with the occurrence of relapse (P=0.005) and of the localization of the tumor with the extent of resection (P=0.031). Gross total resection was achieved significantly more often in pediatric patients than in adult patients (P=0.003). Adult patients demonstrated more relapses following the first tumor resection (P=0.001). The present study indicates that methylation of MGMT is associated with a poor clinical course and represents an age-independent risk factor for an unfavorable outcome. Other influential factors of outcome were the age of the patient and extent of resection. PMID- 29434856 TI - High-fat diet-induced adipokine and cytokine alterations promote the progression of prostate cancer in vivo and in vitro. AB - High-fat diet (HFD) -induced obesity is associated with more aggressive and lethal prostate cancer (PCa) in males, although the exact underlying mechanisms remain unclear. In the present study, transgenic adenocarcinoma of mouse prostate (TRAMP) models fed on an HFD (40% fat) or a control diet (CD; 16% fat) were generated, and cancer differentiation, local invasion and metastasis were compared at 20, 24 and 28 weeks. Mouse sera from each group were collected, and adipokines and cytokines were measured using multiplex immunoassays. HFD-sera and CD-sera were additionally processed into conditioned media (2.5% mixed sera), and in vitro studies were conducted to determine the proliferation, migration and invasion of cancer cells when conditioned media were used for culture. In TRAMP mice, HFD feeding increased body weight and adipose tissue deposition, and promoted the progression of PCa, specifically with regard to poorer differentiation, increased local invasion and metastasis rate. Sera from HFD-fed TRAMP mice contained increased levels of leptin, and a time-dependent increasing trend in the levels of CC chemokine ligand (CCL)3, CCL4, CCL5 and CXC chemokine ligand (CXCL)10 was observed. However, no alterations were detected in the levels of adiponectin, interleukin (IL)-4, IL-5, IL-6, IL-12p70, interferon-gamma, tumor necrosis factor-alpha, CCL2, CCL7, CCL11, CXCL1 and CXCL2. In vitro studies determined that HFD-sera-conditioned medium promoted proliferation, migration and invasion of DU145 cells, as compared with CD-sera-conditioned medium and serum free medium. In conclusion, the results of the present study suggested that the circulating adipokine and cytokine alterations in response to excess adipose tissue deposition induced by HFD feeding contributed to PCa progression. PMID- 29434857 TI - Correlation between TAP detection and common digestive tract precancerous lesions. AB - The aim of the present study was to investigate the clinical significance of abnormal sugar-chain glycoprotein tumor abnormal protein (TAP) in the screening of common digestive tract pre-cancer colon adenocarcinoma lesions. A total of 50 colitis patients, 50 colon polyp patients and 50 colon adenocarcinoma patients admitted to our hospital from March, 2012 to May, 2014 were included. Fresh blood from patient's fingertips was collected and condensation staining was used to detect TAP expression. Positive expressions of TAP in patients in the colitis, colon polyp and colon adenocarcinoma groups prior to treatment were 6,76 and 92%, respectively. The TAP-positive expression rate comparisons between the three groups were statistically significant (P<0.05), and TAP-positive expression showed an increasing trend. TAP-positive expression was not significantly correlated with sex, age or ethnic group (P>0.05). Patient follow-up revealed that the tumor incidence rate in TAP-positive patients was significantly higher than that in TAP-negative in the colitis and colon polyp groups (P<0.05), and the postoperative tumor recurrence rate in TAP-positive patients was significantly higher than that in TAP-negative in the colon adenocarcinoma group (P<0.05). TAP had a higher expression in colon pre-adenocarcinoma lesions. Additionally, TAP participated in the processes from intestinal mucosal inflammation to colon polyp formation to tissue canceration, and was correlated with these. Thus, TAP can be used for the screening of digestive tract precancerous lesions. PMID- 29434858 TI - miR-125b regulates the drug-resistance of breast cancer cells to doxorubicin by targeting HAX-1. AB - MircroRNAs (miRNAs) are considered as essential regulators in the tumorigenesis and chemoresistance of multiple cancer types. In the present study, it was demonstrated that the expression levels of miR-125b were significantly downregulated in the tissues of patients with breast cancer (BC), as well as the BC cell lines in vitro. To study the association between chemoresistance and miR 125b in BC, doxorubicin (DOX)-resistant MCF-7 (MCF-7/R) cells were established, and gain- and loss-of-function experiments were performed. It was demonstrated that the overexpression of miR-125b increased the sensitivity of MCF-7/R cells to DOX. Furthermore, it was revealed that the sensitization of miR-125b mimics to DOX-induced cell death was regulated by the hematopoietic cell-specific protein 1 associated protein X-1 (HAX-1) vector and HAX-1 small interfering RNA. These results emphasized the notable function of miR-125b and its target of HAX-1 in regulating DOX-resistance. In addition, it was demonstrated that the miR-125b mimics promoted the loss of the mitochondrial membrane potential and the generation of reactive oxygen species induced by DOX treatment in MCF-7/R cells. These data suggest that the miR-125b-HAX-1-mitochondria pathway has a notable function in the treatment of DOX-resistant BC cells, which may provide a novel target for the chemotherapy of BC. PMID- 29434859 TI - Silencing of suppressor of cytokine signaling 1 enhances the immunological effect of mucin 1-calreticulin-primed 4T1 cell-treated dendritic cells in breast cancer treatment. AB - In cancer immunotherapy, dendritic cell (DC)-based vaccines represent a promising, yet challenging, treatment method. In addition to overcoming the low expression levels of antigenic epitopes on cancer cells, it is also necessary to overcome the inhibitory effect of suppressor of cytokine signaling 1 (SOCS1) on DC self-antigen presentation. Our group previously demonstrated that calreticulin (CRT) translocated type I transmembrane glycoprotein mucin 1 (MUC1), a breast cancer antigen, to the surface of 4T1 cells, and that treatment with MUC1-CRT primed 4T1 cell-treated DCs induced apoptosis in a breast cancer cell line. In the present study, cell penetrate peptide, hpp10-DRBD was successfully used to deliver siRNAs into bone marrow-derived (BM) DCs to construct SOCS1-silenced DCs, which were incubated with MUC1-CRT-primed 4T1 cells, and antigen-specific antitumor immunity was markedly enhanced in vitro and in vivo. These results demonstrated that SOCS1-silencing, combined with MUC1-CRT-primed 4T1 cell treatment, may induce increased cytokine production and T cell proliferation by DCs. Furthermore, the in vivo experimental data demonstrated that the silencing of SOCS1 combined with MUC1-CRT-primed 4T1 treatment of BMDCs may induce enhanced immunological effects. The results of the present study have implications for the development of more effective DC-based tumor vaccines, suggesting that the combination of high tumor-associated antigen expression levels on cancer cells with the silencing of a critical inhibitor of DC antigen presentation may be beneficial. PMID- 29434860 TI - Effects of HPV16E6 transfection on the biological behavior of Eca109 and Eca9706 cells. AB - The aim of the present study was to investigate the effect of HPV16E6 gene integration on the biological behavior of Eca109 and Eca9706 cells. This was evaluated through positive liposome transfection of HPV16E6 into Eca109 cells and Eca9706 cells. The transfection efficiency was evaluated by calculating the ratio of fluorescent cells to total cells. After stable screening, reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect the target gene and HPV16E6mRNA inside the cells. The distribution of HPV16E6 in esophageal carcinoma cells was observed by immunofluorescence and western blot analysis. A CCK-8 assay was performed to detect cell proliferation. The migration rate was measured by a wound healing assay, and a Transwell Matrigel invasion assay was used to detect invasive ability. The results of RT-PCR, immunofluorescence and western blot analyses indicated that HPV16E6 gene was expressed in the target group. The proliferation rates and clone group numbers were significantly higher in HPV16E6-transfected cell groups compared with nonsense-transfected (negative control) cell groups. The wound healing and Transwell invasion assays indicated that the migration rate and invasive ability were also significantly higher in the HPV16E6-transfected cell groups compared with negative control groups. In conclusion, Eca109 and Eca9706 cell lines with integration of HPV16E6 were successfully established in the present study. It was demonstrated that HPV16E6 expression enhanced the proliferation and migration of esophageal cancer cells. HPV16E6 may serve a key function in the occurrence and development of esophageal cancer. PMID- 29434861 TI - Bioinformatic analysis of gene expression profiles of pituitary gonadotroph adenomas. AB - The aim of the present study was to identify genes, microRNAs (miRNAs/miRs) or pathways associated with the development of pituitary gonadotroph adenomas. The array data of GSE23207, which included 16 samples of multiple endocrine neoplasia associated rat pituitary homozygous mutations and 5 pituitary tissue samples from healthy rats, were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were analyzed prior to functional enrichment analysis and protein-protein interaction (PPI) network construction. miRNAs associated with DEGs were predicted, and an miRNA-target regulatory network was constructed. A total of 187 upregulated and 370 downregulated DEGs were identified in the pituitary gonadotroph adenoma group compared with the healthy (control) group. Cyclin-dependent kinase (Cdk) 1 exhibited the highest degree in the PPI network. The upregulated DEGs were predominately enriched in 'neuroactive ligand-receptor interaction' pathway, and downregulated DEGs were mainly enriched in 'cell cycle'. The DEGs in module were predominately enriched in the 'cell cycle', whereas DEGs in module b and c were enriched in 'neuroactive ligand-receptor interaction'. miR-374, -153, -145 and -33 were identified as important miRNAs in the regulation of the DEGs. Cdk1, cyclin (Ccn) A2, Ccnb1, 'cell cycle' and 'neuroactive ligand-receptor interaction' pathways may serve important roles in the development of pituitary gonadotroph adenomas; Ccna2 and Ccnb1 may contribute to this development via an effect on the 'cell cycle' pathway. Furthermore, miR-374 and -145 may contribute to the development of pituitary gonadotroph adenomas via regulation of the expression of target genes. PMID- 29434862 TI - MiR-370 promotes apoptosis in colon cancer by directly targeting MDM4. AB - MicroRNA (miR)-370 functions as a tumor suppressor or promoter in several cancers. However, the expression and biological role of miR-370 in colon cancer remains undefined. In the present study, miR-370 expression in both normal and malignant colon tissues was quantified by quantitative polymerase chain reaction. An in vitro cell viability and apoptosis assay and an in vitro xenograft tumor model were employed to investigate the role of miR-370 on colon cancer growth. Furthermore, the potential direct target of miR-370 was identified using a luciferase assay. Our results demonstrate that down-regulation of miR-370 expression occurs in malignant tissues and miR-370 expression is inversely correlated with tumor grade. Moreover, we determined that miR-370 functions as a tumor suppressor in colon cancer by inhibiting cell proliferation and promoting cell apoptosis. In addition, overexpression of miR-370 impairs xenograft tumor growth in nude mice. Mechanistically, mouse double minute 4 (MDM4) was demonstrated to be a potential direct target of miR-370, inducing apoptosis in colon cancer. Collectively, these findings suggest that upregulation of miR-370 may impair colon tumor growth by directly targeting MDM4. These findings provide a new direction for the diagnosis and treatment of colon cancer. PMID- 29434863 TI - Identification of common key genes in breast, lung and prostate cancer and exploration of their heterogeneous expression. AB - Cancer is one of the leading causes of mortality worldwide, and in particular, breast cancer in women, prostate cancer in men, and lung cancer in both women and men. The present study aimed to identify a common set of genes which may serve as indicators of important molecular and cellular processes in breast, prostate and lung cancer. Six microarray gene expression profile datasets [GSE45827, GSE48984, GSE19804, GSE10072, GSE55945 and GSE26910 (two datasets for each cancer)] and one RNA-Seq expression dataset (GSE62944 including all three cancer types), were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in each individual cancer type using the LIMMA statistical package in R, and then a comparison of the resulting gene lists was performed to identify common DEGs across cancer types. This analysis was performed for microarray and RNA-Seq datasets individually, revealing a set of 62 and 1,290 differentially expressed genes respectively, which may be associated with the three cancers. Out of these genes, 44 were common to both analyses, and hence termed key genes. Gene Ontology functional annotation, Kyoto Encyclopedia of Genes and Genomes pathway mapping and literature citations were used to confirm the role of the key genes in cancer. Finally, the heterogeneity of expression of the key genes was explored using the I2 statistic (meta package in R). The results demonstrated non-heterogeneous expression of 6 out of the 44 key genes, whereas the remaining genes exhibited significant heterogeneity in expression across microarray samples. In conclusion, the identified DEGs may play important roles in the pathogenesis of breast, prostate and lung cancer and may be used as biomarkers for the development of novel diagnostic and therapeutic strategies. PMID- 29434864 TI - Effect of matrine against breast cancer by downregulating the vascular endothelial growth factor via the Wnt/beta-catenin pathway. AB - The aim of the present study was to investigate the effect of matrine on breast cancer and its underlying mechanism. Matrine is a major component of Sophora flavescens, exhibited antitumor activity in a number of neoplasms, including breast cancer. The present study revealed that matrine inhibited cell viability and induced apoptosis in 4T1 and MCF-7 cells in a dose- and time-dependent manner in vitro. In addition, matrine suppressed the 4T1-tumor growth, induced apoptosis, inhibited the expression of vascular endothelial growth factor and downregulated the Wnt/beta-catenin signaling pathway in vivo. All these findings indicated that matrine may be a novel effective candidate for the treatment of breast cancer. PMID- 29434865 TI - Diagnostic evaluations of ultrasound and magnetic resonance imaging in mammary duct ectasia and breast cancer. AB - The objective of the present study was to evaluate the diagnostic efficiency of ultrasound (US) and magnetic resonance imaging (MRI) in the diagnosis and differential diagnosis of mammary duct ectasia (MDE) and breast cancer. This retrospective study was performed on 35 patients with MDE and 105 patients with breast cancer using US and MRI. Imaging features, semi-quantitative and quantitative parameters were analyzed to determine their diagnostic value for MDE and breast cancer. The average age of patients with breast cancer was increased compared with that of patients with MDE. There were no significant differences in local packages with or without tenderness ratio (P=0.259) and grade of color Doppler flow imaging (P=0.273) between the two groups. However, the morphological changes were significantly increased in breast cancer compared with MDE. In addition, there were significant diagnostic differences in US and MRI between breast cancer and MDE, including resistance index, US elastography, time-signal intensity curve, apparent diffusion coefficient, early-stage enhancement ratio, peak-of-enhancement ratio and Tpeak (P<0.05). However, there were no observable significant diagnostic differences between US, MRI and US with MRI for MDE and breast cancer (P=0.103, P=0.263 and P=0.403 respectively). Diagnosis of MDE and breast cancer requires full evaluation of multiple parameters and morphological changes of US and MRI to increase the diagnostic efficiency. US, MRI and US with MRI were all of diagnostic value for MDE and breast cancer, while US with MRI had the highest efficacy. PMID- 29434866 TI - Logistic regression analysis of risk factors for postoperative recurrence of spinal tumors and analysis of prognostic factors. AB - The aim of the present study was to investigate the risk factors for postoperative recurrence of spinal tumors by logistic regression analysis and analysis of prognostic factors. In total, 77 male and 48 female patients with spinal tumor were selected in our hospital from January, 2010 to December, 2015 and divided into the benign (n=76) and malignant groups (n=49). All the patients underwent microsurgical resection of spinal tumors and were reviewed regularly 3 months after operation. The McCormick grading system was used to evaluate the postoperative spinal cord function. Data were subjected to statistical analysis. Of the 125 cases, 63 cases showed improvement after operation, 50 cases were stable, and deterioration was found in 12 cases. The improvement rate of patients with cervical spine tumor, which reached 56.3%, was the highest. Fifty-two cases of sensory disturbance, 34 cases of pain, 30 cases of inability to exercise, 26 cases of ataxia, and 12 cases of sphincter disorders were found after operation. Seventy-two cases (57.6%) underwent total resection, 18 cases (14.4%) received subtotal resection, 23 cases (18.4%) received partial resection, and 12 cases (9.6%) were only treated with biopsy/decompression. Postoperative recurrence was found in 57 cases (45.6%). The mean recurrence time of patients in the malignant group was 27.49+/-6.09 months, and the mean recurrence time of patients in the benign group was 40.62+/-4.34. The results were significantly different (P<0.001). Recurrence was found in 18 cases of the benign group and 39 cases of the malignant group, and results were significantly different (P<0.001). Tumor recurrence was shorter in patients with a higher McCormick grade (P<0.001). Recurrence was found in 13 patients with resection and all the patients with partial resection or biopsy/decompression. The results were significantly different (P<0.001). Logistic regression analysis of total resection-related factors showed that total resection should be the preferred treatment for patients with benign tumors, thoracic and lumbosacral tumors, and lower McCormick grade, as well as patients without syringomyelia and intramedullary tumors. Logistic regression analysis of recurrence-related factors revealed that the recurrence rate was relatively higher in patients with malignant, cervical, thoracic and lumbosacral, intramedullary tumors, and higher McCormick grade and patient received partial resection or biopsy. Tumor property, tumor location, McCormick grade, tumor resection, and intramedullary tumors are risk factors for the recurrence of spinal tumors. Clinical assessment of these risk factors may be helpful in selecting appropriate treatment strategies. PMID- 29434867 TI - miR-93 enhances cell proliferation by directly targeting CDKN1A in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is an epithelial malignancy of the head and neck with the highest incidence rate in southern China. The aim of the present study was to understand the molecular mechanisms that underlie the progression of NPC. The relative expression of miR-93 and CDKN1A was detected by the reverse transcription quantitative PCR. Western blot analysis was applied to detect the protein levels of genes. Luciferase activity report was applied to verify the target of miRNA. Cell growth was assayed by using 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. miR-93 was upregulated in NPC tissues and cell lines compared with normal samples. Re-expression of miR-93 promoted cell growth in vitro as determined by the MTT assay. CDKN1A was identified by luciferase reporter as a direct target of miR-93. Its expression was downregulated by miR-93. Furthermore, the results showed that the expression of miR-93 was inversely correlated with the expression of CDKN1A protein. miR-93 enhanced cell proliferation in NPC by directly targeting CDKN1A. It is suggested that miR-93/CDKN1A axis may present a new target for the treatment of NPC. PMID- 29434868 TI - Cytotoxic effect of Efavirenz in BxPC-3 pancreatic cancer cells is based on oxidative stress and is synergistic with ionizing radiation. AB - The non-nucleoside reverse transcriptase inhibitor (NNRTI) Efavirenz is frequently used in human immunodeficiency virus treatment, but also efficient against cancer in mouse models. Its radiosensitizing effect makes it a promising drug for combination with radiotherapy. The efficacy of Efavirenz combined with irradiation was assessed with immunostaining of DNA-damage markers and colony formation assays in BxPC-3 pancreatic cancer cells. Gene expression and protein phosphorylation of the Efavirenz-sensitive BxPC-3 cells was compared to the resistant primary fibroblasts SBL-5. Oxidative stress, mitochondrial damage and cell death were studied with live-cell microscopy and flow cytometry. Combined Efavirenz and radiation significantly increased the number of gammaH2AX and phospho-ataxia telangiectasia mutated foci. Efavirenz and ionizing radiation had a synergistic effect using the clonogenic survival assay. Efavirenz selectively induced cell death in the BxPC-3 cells. The differing gene expression of cell cycle and apoptotic regulator genes in both cell cultures after Efavirenz treatment match with this selective effect against cancer cells. In the phosphoprotein array, an early phosphorylation of extracellular signal-related kinase 1/2 and p38 mitogen-activated protein kinase was notably detected in the cancer cells. The phosphorylation of AKT decreased in the cancer cells whereas it increased in the fibroblasts. Oxidative stress and mitochondrial membrane depolarization appeared in the cancer cells immediately after Efavirenz treatment, but not in the fibroblasts. Efavirenz has an anti-cancer effect against pancreatic cancer mainly by the induction of oxidative stress. The antitumor potential of Efavirenz and radiotherapy are additive. PMID- 29434869 TI - A hederagenin saponin isolated from Clematis ganpiniana induces apoptosis in breast cancer cells via the mitochondrial pathway. AB - Natural plants offer a treasure trove of resources for anticancer drug development. Clematis are widely used in Traditional Chinese Medicine. However, studies on the active substances in Clematis are scarce. In the present study, four monomer compounds were successfully extracted from this species and their inhibitory effects on the growth of breast cancer cells were investigated using bioactivity tests. Among them, Clematis hederagenin saponin (CHS) belongs to the class of triterpenoid saponins. CHS showed cytotoxic effects on breast cancer cells in a dose- and time-dependent manner. The compound also induced apoptosis in breast cancer cells in a time-dependent manner. Further investigation into the underlying mechanisms of apoptosis induction in breast cancer cells showed that the compound significantly reduced mitochondrial Apaf-1 and cytochrome c proteins in breast cancer cells. In addition, it upregulated the activities of caspase-3 and -9. In conclusion, CHS induced apoptosis in breast cancer cells through regulation of the mitochondrial apoptosis pathway. The results suggest that the hederagenin saponin extracted from Clematis ganpiniana offers great potential as a novel anti-breast cancer drug. PMID- 29434870 TI - Expression of miR-590 in lung cancer and its correlation with prognosis. AB - The study aim was to evaluate the association of the expression of serum microribonucleic acid-590 (miR-590) with the risk of lung squamous cell carcinoma (LUSC), clinicopathological staging and prognosis. A total of 237 patients with LUSC and 100 healthy volunteers (control group) were included in the study. Total RNA was extracted from the peripheral blood serum of the subjects, and the expression level of miR-590 was detected by reverse transcription real-time quantitative polymerase chain reaction. The baseline clinicopathological information of LUSC patients was evaluated, and the patients were followed up with the median follow-up of 47 months. Compared with that in the control group, the expression level of serum miR-590 in LUSC patients was significantly decreased [0.532 (0.367- 0.821) vs. 1.63 (0.893-1.347), P<0.001]. The receiver operating characteristic (ROC) curve showed that the value of predicting LUSC risk using miR-590 was high, the area under curve (AUC) was 0.883, and 95% confidence interval (CI) was 0.829-0.934. In addition, the expression level of serum miR-590 was correlated with pathological staging (P=0.022), lymph node metastasis (P=0.012), distant metastasis (P<0.001) and tumor, node and metastasis (TNM) staging (P=0.044). The overall survival (OS) of patients in the serum miR 590 low expression group was significantly lower than that of the serum miR-590 high expression group (P=0.012), and the low expression of miR-590 was an independent risk factor for the prognosis of patients [hazard ratio (HR)=2.152, 95% CI=1.285-3.233, P=0.004]. The results suggested that the expression level of miR-590 can be used as a biomarker for the risk of disease, disease staging and prognosis of LUSC patients. PMID- 29434871 TI - Mechanisms for DNA-damaging agent-induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways. AB - Cisplatin (CDDP) and doxorubicin (DOX) are chemotherapeutic drugs that trigger apoptosis by inducing DNA-damage. A previous study using breast cancer cells demonstrated the negative feedback modulation of the epidermal growth factor receptor (EGFR) and receptor tyrosine-protein kinase erbB-2 (ErbB2) via extracellular signal-regulated kinase (ERK)-mediated phosphorylation of conserved Thr-669 and Thr-677 residues, respectively, in the juxtamembrane domain. In addition, CDDP has been identified to cause negative feedback inhibition of activated EGFR in lung cancer cells. In the present study, the role of phosphorylation in the feedback control of the ErbB2/ErbB3 heterodimer in human breast and gastric cancer cells was investigated. Phosphorylation of ErbB2 at Thr 677 was induced by CDDP and DOX, which in turn reduced tyrosine autophosphorylation of ErbB2 and ErbB3. Treatment with trametinib, a mitogen activated protein kinase inhibitor that blocks ERK-mediated Thr-677 phosphorylation, and substitution of Thr-677 to alanine, blocked the feedback inhibition of ErbB2 and ErbB3. In addition, these agents caused the degradation of ErbB proteins through the activation of p38 mitogen-activated protein kinase (p38) and ERK. These results demonstrate that chemotherapeutic agents trigger ERK and p38-mediated post-translational downregulation of ErbB receptors. PMID- 29434872 TI - Regulator of G-protein signaling 5 enhances portal vein invasion in hepatocellular carcinoma. AB - Portal vein invasion (PVI) is a major prognostic factor in hepatocellular carcinoma (HCC). The aim of the present study was to identify molecules that regulate PVI. Sections of cancerous tissue, paired noncancerous tissue and the PVI area were collected from 3 frozen HCC sections, using laser microdissection. The present study focused on 3 upregulated molecules, integrin beta3 (ITGB3), secreted phosphoprotein 1 (SPP1) and regulator of G-protein signaling 5 (RGS5), and 2 molecules that were downregulated in PVI tissue compared with cancer tissue, metallothionein 1G (MT1G) and metallothionein 1H (MT1H), as determined by cDNA microarray analysis. Reverse transcription-quantitative polymerase chain reaction analysis of 32 HCC cases revealed that RGS5 mRNA levels were significantly increased and MT1 G and MT1H mRNA levels were significantly decreased in cancerous tissue compared with noncancerous tissue. However, there was no significant difference in ITGB3 and SPP1 expression. There were no significant differences between the expression of these molecules and any clinicopathologic factors, including PVI. Immunohistochemical staining for RGS5 in 60 HCC cases demonstrated that RGS5 protein levels were higher in cancerous tissue compared with paired noncancerous tissue in 63.3% of HCC cases. Furthermore, high expression of RGS5 in cancerous tissue was significantly associated with PVI and tended to be associated with intrahepatic metastasis. Confluent multinodular type was significantly more frequent in cases with high expression of RGS5 in the cancerous tissue. Therefore, RGS5 may be a useful prognostic biomarker as well as a potential target of molecular therapy to treat HCC. PMID- 29434873 TI - Mechanisms by which CXCR4/CXCL12 cause metastatic behavior in pancreatic cancer. AB - C-X-C motif chemokine receptor (CXCR) 4/CXCL12 is associated with tumor invasion and metastasis in pancreatic cancer. The present study aimed to investigate the possible mechanisms behind this process by studying the association between the expression of CXCR4 and numerous molecular markers. A total of 60 patients with pancreatic cancer who had been treated with radical surgery between July 2012 and February 2016 were included in the present study. The expression of CXCR4/CXCL12 in primary pancreatic cancer lesions, tissues adjacent to cancerous tissue, non cancerous pancreatic tissues and in the surrounding lymph nodes was evaluated by immunohistochemistry. Expression levels of four candidate biomarkers [vascular endothelial growth factor-C (VEGF-C), Ki-67, matrix metalloproteinase 2 (MMP-2) and beta-catenin] were also evaluated. The correlation between CXCR4 and these four biomarkers was assessed. CXCR4 (CXCL12) expression levels were higher in pancreatic cancer 56.7% (86.7%), paracancerous tissue 50.0% (85.0%) and surrounding lymph nodes 53.3% (80.0%), compared with in normal tissues 18.3% (45.0%). CXCR4 expression was significantly associated with the lymph node metastasis of tumors (P=0.001), pathological type (P=0.037) and tumor-node metastasis stage (P=0.031). CXCR4 expression exhibited a positive correlation with VEGF-C (r=0.417; P=0.001), Ki-67 (r=0.316; P=0.014), MMP-2 (r=0.284; P=0.028) and beta-catenin (r=0.368; P=0.04). Furthermore, logistic regression analysis revealed VEGF-C (beta=1.722; P=0.005) and Ki-67 (beta=1.196; P=0.047) to be two biomarkers that cause metastasis via CXCR4. CXCR4/CXCL12 is closely associated with tumor grade and lymphatic metastasis. VEGF-C and Ki-67 are two important biomarkers, through which CXCR4 initiates metastatic behavior in pancreatic cancer. Therefore, angiogenesis inhibitors will continue to be effective agents in treating pancreatic cancer. PMID- 29434874 TI - Antitumor effects of matrine on cancer stem like cells isolated from the human liver cancer SMMC-7721 cell line. AB - The existence of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) is regarded as the cause of tumor formation and recurrence. Matrine has been reported to exhibit antitumor effects in cancer cells. In the present study, a preliminary study was performed on the mechanisms of matrine on hepatocellular carcinoma (HCC) stem-like cells. The HCC SMMC-7721 cell line was cultured in tumor stem cell-specific medium to form spheres, and different concentrations (1, 2 and 5 mg/kg) of cisplatin were then used in order to purify the most drug resistant cells, which were used as CSLCs. An MTT assay was performed to detect the inhibitory effects of matrine against CSLC proliferation. Quantitative polymerase chain reaction (qPCR) and western blot analysis were used to detect changes in cell adhesion regulating gene (CAR), E-cadherin, laminin and fibronectin. As a result, using tryptose sulfite cycloserine medium culture and cisplatin-resistance screening, CSLCs were successfully isolated from the SMMC 7721 cell line. Matrine inhibited the proliferation of CSLCs in vitro. The results of qPCR and western blot analysis demonstrated that matrine upregulated the expression of CAR, E-cadherin, laminin and fibronectin in CSLCs compared with the control treatment. A certain concentration of matrine exhibited antitumor effects on HCC stem like cells. PMID- 29434875 TI - Soluble HER3 predicts survival in bladder cancer patients. AB - The role of soluble human epidermal growth factor receptor (sHER3) in bladder cancer remains unclear. In the present study, an ELISA was developed for the quantification of sHER3 and its role was investigated in patients with bladder cancer (n=82) followed for 10 years. Furthermore, the effects of sHER3 on bladder cancer cell growth and migration were also investigated. The results demonstrated that plasma sHER3 levels were significantly higher in non-invasive tumours (Ta) compared with muscle-invasive tumours (T2-T4). Higher sHER3 levels were associated with a more improved survival rate. However multivariate Cox regression analysis, adjusted for clinical stage, grade, type and size of the tumour, demonstrated that sHER3 was not an independent biomarker of survival. Exogenous sHER3 significantly inhibited bladder cancer cell growth and migration. These results suggest that high sHER3 levels are associated with improved survival rates in patients with bladder cancer, and that sHER3 inhibits bladder cancer cell growth and migration. PMID- 29434876 TI - A retrospective, single-center cohort study on 65 patients with primary retroperitoneal liposarcoma. AB - Primary retroperitoneal liposarcoma (PRPLS) is the most common soft tissue malignancy of the retroperitoneum. To determine the pathological features and the curative effects of surgery in patients with PRPLS, and to elucidate key prognostic factors, the present study retrospectively analyzed the clinical cases of 65 patients with PRPLS. Immunohistochemical analysis demonstrated that vimentin and Ki-67 are better indicators for PRPLS immunohistochemical diagnosis compared with S-100 protein. S-100 protein was predominantly expressed in well differentiated PRPLS. Positive expression of vimentin and Ki-67 were observed in almost all PRPLS samples, and Ki-67 exhibited a higher expression level in high grade PRPLS. The level of Ki-67 expression was negatively correlated with disease specific survival (DSS). Survival analysis revealed that the pathological subtype and histological grade were associated with DSS and local recurrence in the patients, whereas the tumor burden was associated with DSS but not local recurrence. In addition, complete tumor resection and contiguous organ resection were able to improve DSS. Microscopically positive margins did not affect DSS, whereas gross margins did. Multivariate analysis revealed that pathological subtype, histological grade and contiguous organ resection were independent prognostic factors, and that histological grade was an independent factor for local recurrence. Patient sex and age at presentation were not independent factors associated with prognosis or local recurrence. Correlation analysis demonstrated that postoperative local recurrence significantly affected DSS, and local recurrence was the most common cause of mortality among patients. Histological grade was strongly associated with the invasion of adjacent organs but not with tumor burden. Furthermore, the tumor burden was not associated with recurrence or tumor invasion of adjacent organs. Ki-67 expression was associated with prognosis. Pathological subtype, histological grade and contiguous organ resection were independent prognostic factors, while histological grade was an independent factor which affected tumor recurrence. PMID- 29434877 TI - Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer in vitro and in vivo. AB - Previous studies have suggested that metformin may improve the survival rate of patients with pancreatic cancer (PC) by regulating the adenosine monophosphate activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin specifically targets mTOR. In the present study, the efficacy of metformin and rapamycin in isolation and combination were investigated for the treatment of PC. The efficacy of metformin and rapamycin in reducing the proliferation of PC cell line SW1990 in vitro and in vivo was evaluated. It was revealed that metformin (10 mmol/l) + rapamycin (2 ng/ml), metformin (15 mmol/l) + rapamycin (20 ng/ml) and metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly inhibited the viability of PC cells compared with untreated cells. Additionally, metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly suppressed the expression of phosphorylated mTOR compared with metformin or rapamycin alone. Using a xenograft tumor model, it was revealed that combination treatment significantly inhibited the growth of PC cells compared with monotherapy. The present study revealed that a combination of metformin and rapamycin synergistically inhibited the growth of PC in vitro and in vivo and may be a potential treatment option for patients with PC. PMID- 29434878 TI - Progesterone impairs Herceptin effect on breast cancer cells. AB - Breast cancer (BCa) is the most common cancer affecting women worldwide. Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in ~20 25% of invasive ductal breast carcinomas and is associated with the more aggressive phenotype. Herceptin, a humanized antibody against HER2, is a standard therapy in HER2-overexpressing cases. Approximately one-third of patients relapse despite treatment. Therefore numerous studies have investigated the molecular mechanisms associated with Herceptin resistance. An interaction between HER2 signalling and steroid hormone receptor signalling pathways has been previously investigated, but the effect of this relationship on Herceptin resistance has never been studied. The present study analysed an impact of the steroid hormone, progesterone (PG), on Herceptin-dependent cell growth inhibition. Results indicated that Herceptin-inhibited proliferation of breast cancer cell lines overexpressing HER2 (BT474 and MCF/HER2) in 3D culture is abolished by PG. Furthermore, results demonstrated that PG led to the activation of HER2/HER3 mediated signalling. Moreover, PG treatment induced a shift of Herceptin dependent cell cycle arrest in G1 phase towards S and G2 phases with concomitant upregulation of cyclin-dependent kinase 2 (CDK2) and downregulation of CDK inhibitor p27Kip1. These results demonstrate for the first time PG involvement in the failure of Herceptin treatment in vitro. The present observations suggest that cross-talk between PG- and HRG/HER2-initiated signalling pathways may lead to the acquisition of resistance to Herceptin in patients with BCa. PMID- 29434879 TI - A multidisciplinary group for prostate cancer management: A single institution experience. AB - Increased knowledge regarding the heterogeneity of Prostate Cancer (PC) and its variable outcomes has generated controversy over the best clinical approach. Nowadays, it is well-known that patient outcomes and clinical management may be improved by an efficient organization of the national health care system. The Interdisciplinary Group for Oncological Care (GICO) for PC patients was created by our healthcare management company in September 2010. Since then, a multidisciplinary internal report was applied to PC patients. This report highlights our methodology and experience of planning a GICO, and illustrates the results obtained for the management of PC patients before and after the adopted GICO criteria in a single institution, the SS Annunziata Hospital (Chieti, Italy). PMID- 29434880 TI - Clinical significance of BRAFV600E mutation in circulating tumor DNA in Chinese patients with melanoma. AB - The present study aimed to assess the B rapidly accelerated fibrosarcoma (BRAFV600E) status in plasma from Chinese patients with melanoma, and evaluated its prognostic value following treatment with BRAF inhibitors. Mutation-specific 3D digital polymerase chain reaction (dPCR) was used to quantify BRAFV600E in circulating tumor DNA (ctDNA) in 58 patients with melanoma, prior to treatment with BRAF inhibitors. Correlations between baseline ctDNA levels and clinicopathological characteristics and clinical benefits were then statistically analyzed. The concordance and sensitivity of BRAFV600E between ctDNA and tumor tissue were 70.2% and 76%, respectively, in 58 patients with melanoma. BRAFV600E mutation in ctDNA correlated with lactate dehydrogenase concentration (P=0.04) and Eastern Cooperative Oncology Group score (P=0.04). There was no correlation between BRAFV600E of ctDNA with response, progression-free survival (PFS), or overall survival (OS) following targeted therapy. The objective response rate, PFS and OS stratified by BRAFV600E of ctDNA were 30.0% vs. 56.7%, (P=0.3), 8.1 months vs. 6.7 months, (P=0.38) and 65.6 months vs. 42.3 months (P=0.52), respectively, for undetectable and mutant types. In conclusion, 3D dPCR is appropriate for ctDNA detection and BRAFV600E in ctDNA is a non-invasive biomarker in patients with melanoma. PMID- 29434881 TI - 18F-fluorodeoxyglucose positron emission computed tomography for monitoring tumor response in esophageal carcinoma treated with concurrent chemoradiotherapy. AB - The aim of the present study was to explore the value of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in monitoring the early tumor response of esophageal squamous cell carcinoma (ESCC) treated with concurrent chemoradiotherapy (CRT). A total of 48 patients with pathologically proven ESCC were retrospectively analyzed. All patients underwent two serial 18F-FDG PET scans at baseline (pre-CRT) and 40 Gy/4 weeks of starting radiation therapy (inter-CRT). All patients received intensity-modulated radiotherapy (with a total radiation dose of 59.6 Gy) concurrently with cisplatin-based chemotherapy. The maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) were measured using 18F-FDG PET. The percentage changes (Delta) in SUVmax and MTV between two serial scans were calculated and were revealed to be associated with the objective tumor response (oTR), according to the Response Evaluation Criteria in Solid Tumors 1.1. Among the 48 patients, 20.8% achieved a complete response, 68.8% exhibited a partial response and the oTR rate was 89.6%. On the pre-CRT PET scans, the mean SUVmax and MTV were 14.1+/-5.8 and 58.2+/-25.4 cm3, respectively. Following 40 Gy irradiation over 4 weeks, the mean SUVmax and MTV significantly decreased to 4.3+/-3.5 and 19.0+/-12.1 cm3, respectively (P<0.001). A significantly higher DeltaSUVmax and DeltaMTV was observed in the responders compared with that in the non-responders [0.71+/-0.16 vs. 0.51+/-0.26 (P=0.015); and 0.64+/-0.13 vs. 0.42+/-0.09 (P=0.001), respectively]. Univariate analysis revealed that DeltaSUVmax and DeltaMTV were significantly associated with oTR (P=0.010 and P=0.001, respectively). DeltaMTV was used as a predictor and a cut off value of 54% discriminated responders from non-responders with a sensitivity of 69.8% and a specificity of 100% (P=0.001). The area under the receiver operating characteristic curve was 0.837 (95% confidence interval, 0.702-0.928). The results of the present study indicated that interim 18F-FDG PET scans may provide early prognostic value for determining oTR in patients with ESCC undergoing treatment with CRT. PMID- 29434882 TI - Prognostic relevance of FGFR2 expression in stage II/III gastric cancer with curative resection and S-1 chemotherapy. AB - Curative gastrectomy and adjuvant chemotherapy using S-1 is a standard treatment for stage II/III gastric cancer in Japan. The purpose of the present study was to evaluate the prognostic relevance of fibroblast growth factor receptor (FGFR)2 expression in patients with stage II/III gastric cancer that underwent postoperative adjuvant chemotherapy with S-1. Formalin-fixed paraffin-embedded surgical specimens were retrospectively examined in 167 patients with stage II/III gastric cancer that underwent curative gastrectomy followed by adjuvant S1 chemotherapy. FGFR2 expression was measured using immunohistochemistry (IHC) staining. The IHC results for FGFR2 were as follows: Grade 1+, 32; grade 2+, 80; grade 3+, 55 patients. The FGFR2 expression level was not significantly associated with relapse-free or overall survival rates. However, in the diffuse type, the FGFR2 expression level tended to be negatively correlated with relapse free survival. In particular, the proportion of patients who recurred >5 years following surgery was significantly larger in the FGFR2 grade 3+ group than in the grade 1+, 2+ group (4/22 vs. 1/35; P=0.047). The recurrent sites of long-term failure were mostly peritoneum among the diffuse type. To the best of our knowledge, the present study indicated for the first time that FGFR2 could predict long-term failure of adjuvant S-1 chemotherapy in curative advanced gastric cancer. There was no interaction between FGFR2 expression and patient survival outcomes in stage II/III gastric cancer. Patients with FGFR2 3+ in stage II/III gastric cancer should carefully be followed-up for >5 years after surgery. PMID- 29434883 TI - lncRNA FAM83H-AS1 is associated with the prognosis of colorectal carcinoma and promotes cell proliferation by targeting the Notch signaling pathway. AB - The long non-coding RNA, FAM83H antisense RNA 1 (head to head) (FAM83H-AS1), has exhibited a functional role as an oncogene in a number of different types of cancer. The aim of the present study was to reveal the dysregulation of FAM83H AS1 in colorectal carcinoma (CRC) samples and elucidate its underlying associations with the Notch signaling pathway. The expression profiles of FAM83H AS1 and two Notch signaling-associated molecules, Notch1 and Hes family basic helix-loop-helix transcription factor 1 (Hes1), were measured by reverse transcription-polymerase chain reaction and western blot analysis. The Pearson chi2 test was employed to evaluate the associations between FAM83H-AS1 expression and clinical features. A statistically significant positive association between the expression levels of FAM83H-AS1 and those of Notch1 or Hes1 in CRC tissues was analyzed by Spearman's correlation analysis. The Kaplan-Meier method was used to compare the overall survival curves between the highly-expressed and low expressed FAM83H-AS1 groups via a log-rank test. Specific small hairpin RNA was transfected to silence endogenous FAM83H-AS1. MTT and colony formation assays were performed to measure the growth-inhibition effect of silenced FAM83H-AS1. The levels of FAM83H-AS1, Notch1 and Hes1 were significantly increased in CRC samples and cell lines. Cell proliferation was markedly inhibited when FAM83H-AS1 was knocked down and this effect mediated by FAM83H-AS1 could be reversed by Notch1 regulators. Thus, downregulated FAM83H-AS1 exhibited an anti-proliferative role in CRC by repressing the Notch signaling pathway. PMID- 29434884 TI - Endostatin reverses immunosuppression of the tumor microenvironment in lung carcinoma. AB - Endostatin has previously been demonstrated to efficiently inhibit the angiogenesis and growth of endothelial cells. However, the role of endostatin in the tumor microenvironment remains to be elucidated. To investigate the antitumor effect of endostatin in lung cancer, the present study was designed to explore the alterations of microvessel density in Lewis lung cancer models and the expression of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL 17, interferon (IFN)-gamma and hypoxia inducible factor (HIF)-1alpha, following endostatin therapy. It was demonstrated that the growth and angiogenesis of tumors were markedly suppressed by treatment with endostatin, compared with control group. The microvessel density in mice treated with endostatin was significantly inhibited in a dose-dependent manner. The expression levels of VEGF, IL-6 and IL-17 in tumors were decreased, however IFN-gamma and HIF-1alpha expression levels were increased, following treatment with endostatin. In addition, the proportion of myeloid derived suppressor cells and tumor associated macrophages (TAMs; M2 type) were significantly decreased, whereas those of mature dendritic cells and TAMs (M1 type) were increased, and cluster of differentiation (CD)8+ T cells were recruited to infiltrate the tumors following treatment with endostatin. In addition, the expression levels of IL-6, IL-10, tumor growth factor-beta and IL-17 in tumor tissue were potently decreased with endostatin therapy. These results indicated that endostatin efficiently inhibited tumor angiogenesis and reversed the immunosuppressive microenvironment associated with the presence of tumors. PMID- 29434885 TI - Low-dose paclitaxel downregulates MYC proto-oncogene bHLH transcription factor expression in colorectal carcinoma cells. AB - Paclitaxel (PTX) has been commonly used to treat multiple types of tumor. Its anticancer mechanism differs based on different PTX concentrations and types of tumor cell. In the present study, MTT assays of HCT116 and LOVO cells treated with PTX revealed the chemosensitivity of the cell lines for different PTX concentrations. The half-maximal inhibitory concentration values of PTX for these cells were 2.46 and 2.24 nM, respectively. Cell morphology observation revealed that both cell lines exhibited rounded, wrinkled and damaged morphologies with increasing concentrations of PTX. Fluorescence-activated cell sorting analysis indicated that 1 nM PTX increased the proportion of cells in sub-G1 phases and decreased the proportion of cells in G0/G1 phases, whereas the proportions of cells in S and G2/M phases only slightly changed for both cell lines. Western blot analysis indicated that the total/nuclear protein expression of MYC proto oncogene bHLH transcription factor (c-Myc) and phosphorylated (P)-c-Myc decreased in HCT116 cells in a dose-dependent manner, whereas the nuclear protein expression of P-c-Myc increased in LOVO cells in a dose-dependent manner. These results suggest that low-dose PTX downregulates c-Myc and P-c-Myc expression, subsequently inhibiting the cell cycle at G0/G1 in colorectal carcinoma. PMID- 29434886 TI - Association between expression of nuclear receptor co-activator 5 protein and prognosis in postoperative patients with osteosarcoma. AB - The aim of the present study was to investigate the association between the expression of nuclear receptor co-activator 5 protein (NCOA5) and the prognosis of postoperative patients with osteosarcoma. Human osteosarcoma samples were collected from 145 patients and normal bone tissues were collected from 100 individuals as controls. Immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR) were employed to measure the levels of NCOA5 protein in cases of human osteosarcoma. The results from the RT-PCR analysis demonstrated that the positive rate of NCOA5 mRNA expression in human osteosarcoma was 17.24% (25/145). The positive rate in normal bone tissues was 84.00% (84/100), which was significantly higher compared with that of human osteosarcoma tissues (chi2=33.166; P<0.001). IHC staining indicated that the positive rate of NCOA5 protein in the osteosarcoma samples was 26.21% (38/145). The positive rate in normal bone tissues was 82.00% (82/100), which was significantly increased compared with that of human osteosarcoma tissues (chi2=28.166; P<0.001). NCOA5 mRNA and protein expression levels were consistent in human osteosarcoma tissues, and were lower than in control tissues. The expression of NCOA5 was low in human osteosarcoma tissues, while it was high in normal bone tissues. These low NCOA5 expression levels were associated with postoperative survival of human osteosarcoma. PMID- 29434887 TI - PI3K/AKT/Afadin signaling pathway contributes to pathological vascularization in glioblastomas. AB - Glioblastomas are brain tumors with extensive vascularization that are associated with tumor malignancy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is activated in endothelial cell tumors, although its exact function in glioblastoma neovascularization is poorly characterized. The present study identified that endothelial cells derived from human glioblastomas exhibit increased permeability and motility compared with normal brain vascular endothelial cells. Furthermore, the phosphorylation of AKT was significantly induced in glioblastoma-derived endothelial cells and glioblastoma vessels. To the best of our knowledge, the present study demonstrated for the first time that the cell-cell adhesion junction protein Afadin is phosphorylated and re-localized in glioblastoma-derived endothelial cells, and the phosphorylation and re localization of Afadin is PI3K/AKT pathway-dependent. AKT-mediated phosphorylation and re-localization of Afadin may be critically involved in the modulation of brain endothelial permeability and migration. Therapies targeting the PI3K/AKT/Afadin pathway may therefore be beneficial for reducing the angiogenic potential of glioblastoma. PMID- 29434888 TI - AXL is a marker for epithelial-mesenchymal transition in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is a common cancer in China and certain other parts of the world with a dismal prognosis for affected patients. AXL is a member of the TYRO3-AXL-MER family of receptor tyrosine kinases, and has been revealed to be an important mediator of epithelial-mesenchymal transition (EMT) in several types of cancer. However, to the best of our knowledge, its function in EMT in ESCC cells has not yet been examined. The present study employed two independent ESCC mRNA profile datasets and revealed that AXL is associated with several EMT markers. Gene Set Enrichment Analysis indicated that EMT occurs more in ESCC with high AXL expression. Analysis on another dataset demonstrated further that increased expression of AXL in ESCC is associated with increased migratory ability. Collectively, the results of the present study provide evidence that AXL is a marker for EMT in ESCC. PMID- 29434889 TI - Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation. AB - Gemcitabine (GCB) is a pyrimidine antimetabolite widely used in various solid tumors as a single agent or as a component of multidrug regimens. In the majority of patients, GCB is well tolerated, however life-threatening complications occasionally occur. The current report presents four cases of severe acute toxicity, which included two that were fatal, following administration of GCB alone or in combination with cisplatin. Of the four cases, in one, a Naranjo Adverse Drug Reaction Probability Score was definite, in two, probable and in one possible. To determine the potential causes of these toxicities, polymorphic variants of cytidine deaminase, the primary enzyme involved in the hepatic metabolism of GCB, were assessed. The homogeneous c.435TT variant was detected in one patient and a heterozygotic c.435CT variant in two, one of whom additionally harbored a heterozygotic c.79AC variant. PMID- 29434890 TI - MEG3 inhibits proliferation and invasion and promotes apoptosis of human osteosarcoma cells. AB - Osteosarcoma is known as a malignant tumour with a high mortality rate in orthopaedic settings; however, the factors associated with its degree of malignancy and the biological response remains to be elucidated. Although the essential role of the long noncoding RNA (lncRNA) maternally expressed 3 (MEG3) has been recently reported, its biological functions and regulatory mechanism in osteosarcoma cells have not yet been reported. In the present study, reverse transcription-quantitative polymerase chain reaction analysis revealed that the expression of MEG3 in MG63 cells was lower compared with in hFOB1.19 cells. Furthermore, it was observed that overexpressing MEG3 in MG63 cells resulted in a decline in the proliferation and invasion, and a marked increase in apoptosis. Additionally, western blotting was used to detect the changes in expression of p53 and MDM2 proto-oncogene, which may be regulated by MEG3, and proteins that associated with cell proliferation, invasion and apoptosis. It was demonstrated that the upregulation of MEG3 significantly increased the transactivation of p53 and induced downstream changes in protein expression. In conclusion, these experiments have demonstrated that MEG3 serves an essential regulatory role in the biological processes of human osteosarcoma cells, and imply that MEG3 may be a marker for predicting the occurrence and development of osteosarcoma. PMID- 29434891 TI - lncRNA SNHG5 is associated with poor prognosis of bladder cancer and promotes bladder cancer cell proliferation through targeting p27. AB - Long non-coding RNAs (lncRNAs) have been identified as critical regulators in tumorigenesis. In our present study, we measured the level of small nucleolar RNA host gene 5 (SNHG5) in bladder cancer (BC) tissues and cell lines, and the correlation of the level of SNHG5 with clinicopathological features and prognosis of BC patients was analyzed. Reverse transcription-quantitative polymerase chain reaction was performed to determine the level of SNHG5 in the BC tissues and cell lines. The Kaplan-Meier method was used to analyze the long-term survival outcomes. MTT and colony formation assays were applied to assess the influence of SNHG5 on cell proliferation ability. Flow cytometry was used to measure the function of SNHG5 on cell cycle and apoptosis rate. SNGH5 was found upregulated in BC tissues and cell lines and a high level of SNGH5 was correlated with a poor prognosis. Silencing SNHG5 inhibited the proliferation ability of BC cells and such a function was attributed to its influence on cells cycle and apoptosis. Our findings imply that SNHG5 was upregulated in BC tissues and played an important role in BC progression and may be a potential therapeutic target for BC patients. PMID- 29434892 TI - Effects of harmaline on cell growth of human liver cancer through the p53/p21 and Fas/FasL signaling pathways. AB - The effects of harmaline on the viability and apoptosis of human liver carcinoma were investigated in vitro. HepG2 cells were treated with harmaline (0-10 uM), and the proliferation and apoptosis of HepG2 cells were investigated using an MTT assay and flow cytometry, respectively. The protein expression of cellular tumor antigen p53 (p53), cyclin-dependent kinase inhibitor 1 (p21), tumor necrosis factor receptor superfamily member 6 (Fas), Fas ligand (FasL) and caspase-8 was subsequently measured using western blotting. In addition, an ELISA was used to analyze caspase-8/3 activity. Harmaline significantly increased p53, p21, Fas and FasL protein expression in HepG2 cells. Additionally, treatment with harmaline significantly increased the expression of caspase-8 and caspase-8/3 activity. The results from the present study suggest that harmaline suppresses the viability, but induces the apoptosis, of human liver carcinoma cells through upregulation of the p53/p21 and Fas/FasL signaling pathways. PMID- 29434893 TI - Bone marrow stromal cells enhance the survival of chronic lymphocytic leukemia cells by regulating HES-1 gene expression and H3K27me3 demethylation. AB - The majority of patients with chronic lymphocytic leukemia (CLL) are not cured by traditional chemotherapy. One possible explanation for this is that the microenvironment protects CLL cells from both spontaneous- and cytotoxic-mediated apoptosis. The present study was designed to investigate the mechanisms accounting for these effects, since this information is crucial to understanding CLL physiopathology and identifying potential treatment targets. The CLL cell line L1210 and primary CLL cells were cultured under different conditions: With serum, cyclophosphamide (CTX), or with monolayers and conditioned medium (CM) from the stromal cell line HESS-5. Apoptosis, Hes family BHLH transcription factor 1 (HES-1) gene and protein expression, and histone H3K27me3 DNA demethylation were determined. Co-culture of L1210 cells with HESS-5 cells significantly inhibited serum deprivation- and CTX-induced apoptosis of leukemia cells, and resulted in a significant increase in short-term proliferation. Soluble factors in the CM from HESS-5 cells had a negligible effect. The HESS-5 cell-mediated inhibition of apoptosis of CLL cells was associated with increased HES-1 expression and hypomethylation of the H3K27me3 gene in the leukemia cells. These results indicate that stromal cells enhance the survival of CLL cells by regulating the HES-1 gene and protein expression, as well as H3K27me3 DNA demethylation, and suggest that specific interactions between stromal and leukemia cells may enhance the resistance of leukemia cells to chemotherapy. PMID- 29434894 TI - Down-expression of poly(ADP-ribose) polymerase in p53-regulated pancreatic cancer cells. AB - The present study investigated whether poly(ADP-ribose) polymerase (PARP) has an effect on p53-regulated pancreatic cancer. The results of the present study demonstrated that the expression of PARP affects proliferation and apoptosis of pancreatic cancer cells. Olaparib was used to suppress the expression level of PARP-1 in PanC-1 cells. Decreased expression of PARP-1 suppressed cell proliferation and induced apoptosis of PanC-1 cells when compared with controls. Furthermore, decreased expression of PARP-1 resulted in decreased levels of pro caspase-3 expression, increased caspase-3 activity, suppressed B-cell lymphoma 2 (Bcl-2) protein expression and increased p53 protein expression in PanC-1 cells. Subsequently, ataxia telangiectasia mutated (ATM) activity was inhibited alongside down-expression of PARP-1 resulting in significantly decreased cellular viability of PanC-1 cells, increased p53 protein expression, decreased expression of pro-caspase-3, increased caspase-3 activity and suppressed Bcl-2 protein expression, when compared with PARP-1 suppression alone. Overall, the in vitro data confirmed that down-expression of PARP-1 suppressed cell proliferation and induced apoptosis of pancreatic cancer via ATM-deficient p53 signaling pathway. PMID- 29434895 TI - Dihydroartemisinin increases apoptosis of colon cancer cells through targeting Janus kinase 2/signal transducer and activator of transcription 3 signaling. AB - As a derivative of artemisinin, dihydroartemisinin is effective in the treatment of malaria. Dihydroartemisinin has been identified to possess inhibitory effects in numerous types of animal model with tumors, indicating that it has an antineoplastic effect. The aim of the present study was to analyze the potential anticancer effects of dihydroartemisinin, particularly its effect on apoptosis of colon cancer cells. In the present study, it was identified that dihydroartemisinin inhibited cell viability, promoted cell apoptosis, increased B cell lymphoma-2-associated X-protein expression, increased caspase-3/9 activities, decreased poly(ADP-ribose) polymerase levels, decreased phosphorylation of extracellular-signal-regulated kinase, and increased phosphorylation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase in colon cancer cells. Conversely, the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) was suppressed by dihydroartemisinin in colon cancer cells. These results demonstrate that the potential anticancer effects of dihydroartemisinin may increase apoptosis of colon cancer cells through targeting JAK2/STAT3 signaling. PMID- 29434896 TI - Intra-arterial interventional therapy for inoperable local advanced breast cancer: A retrospective study. AB - The aim of the present study was to evaluate the safety and efficacy of intra arterial interventional therapy (IAIT) in the treatment of inoperable local advanced breast cancer (LABC). A total of 7 patients with pathologically proven inoperable LABC were included in the present study. Patients received 1-4 cycles of IAIT prior to mastectomy and postoperative adjuvant therapy. The safety and clinical outcomes of IAIT were retrospectively analyzed. Between February 2009 to September 2016, 7 patients received IAIT. The youngest patient was 34 years old and the eldest was 90 years old. The tumor size ranged between 6 and 20 cm in diameter. A total of 5 patients presented with palpable lymph nodes, while none of the patients exhibited distant metastatic disease. A total of 6 patients received >=1 cycle of neoadjuvant chemotherapy prior to IAIT and no severe side effects were observed. Overall, 6 patients exhibited a partial response and 1 presented with stable disease following treatment. The range of progression-free survival was 6-88 months. In total, 1 patient succumbed as a result of another disease 8 months after IAIT, another succumbed from carcinoma of the right fallopian tube and multiple organ metastases 9 months after IAIT, and another survived for 11 months and died of heart disease after IAIT. The other 4 patients remain alive. IAIT is safe and effective for patients with inoperable LABC, and thus, may be an appropriate alternative for patients who are not responsive to or are unable to tolerate neoadjuvant chemotherapy. PMID- 29434897 TI - Folate deficiency and aberrant DNA methylation and expression of FHIT gene were associated with cervical pathogenesis. AB - Aberrant DNA methylation is a recognized feature in various types of human cancer, and folate has a vital role in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Fragile histidine triad (FHIT) is a tumor suppressor gene that is frequently silenced in cervical cancer (CC) and preneoplastic lesions. Promoter hypermethylation was previously observed in CC, and its epigenetic silencing has been observed at mRNA or protein levels. Changes in folate intake to modulate DNA methylation may be a mechanistic link to cancer, but this remains to be elucidated. The aim of the present study was to evaluate the influences of folate on FHIT gene methylation and expression in the progression of cervical cancerization. In the present study, red blood cell (RBC) folate levels, FHIT gene methylation status, and mRNA and protein expression levels were detected in 254 women, including normal cervix (NC, n=80), cervical intraepithelial neoplasm grade 1 (CIN1, n=55; CIN2/3, n=55) and cervical squamous cell carcinoma (SCC, n=64) samples. The methylation status of FHIT gene and its mRNA and protein expression levels were measured in CaSki (HPV16 positive) and C33A (HPV16 negative) CC cells treated with different concentrations of folate. The results indicated that FHIT gene methylation rate increased with the severity of cervix lesions, however, RBC folate levels, FHIT mRNA and protein expression levels were reduced. The proliferation inhibition rate, apoptosis rate, and FHIT protein and mRNA expression levels increased along with rising concentrations of folate, whereas the degree of FHIT gene methylation gradually weakened in CaSki or C33A cell lines. The present findings indicated that folate deficiency, FHIT gene promoter hypermethylation and reduced expression were significantly associated with cervical carcinogenesis. The results indicated that folate was able to enhance apoptosis and inhibit the cervical cell proliferation while regulating FHIT gene methylation and expression. Adequate intake of folate to maintain normal DNA methylation status is an effective way for cervical lesions prevention, and demethylation treatment may offer a new strategy for therapy of CC. PMID- 29434898 TI - ABT-737 and pictilisib synergistically enhance pitavastatin-induced apoptosis in ovarian cancer cells. AB - There is considerable interest in redeploying drugs for use in combination with other oncology therapeutics. The single-agent activity of statins in ovarian cancer has been widely reported, however the drug concentration required to cause cell death is considerably higher than that achieved in patients receiving statin treatment for hypercholesterolemia. Unfortunately, statins can cause myopathy when administered in high doses. One solution to this is to identify drugs that could be used in combination with statins to reduce the dose required and those that may potentially reduce the incidence of adverse side effects. When the BH3 mimetic ABT-737, or the phosphatidylinositol 3-kinase inhibitor pictilisib, were combined with pitavastatin in cell growth assays using Ovcar-3 and Igrov-1 cells, the drug combinations were more effective than pitavastatin alone. In support of this, ABT-737 or pictilisib markedly increased cell death induced by pitavastatin in several ovarian cancer cell lines. The drugs were also synergistic in apoptosis assays. These observations suggested that either BH3 mimetics or pictilisib in combination with pitavastatin could be used in a subset of ovarian tumours, particularly those sensitive to BH3 mimetics, and phosphatase and tensin homolog inhibition, in the treatment of ovarian cancer. PMID- 29434899 TI - Preclinical study on hypoxic radiosensitizing effects of glycididazole in comparison with those of doranidazole in vitro and in vivo. AB - To overcome the radioresistance of hypoxic cells in solid tumor, numerous types of radiosensitizers specifically against them have been developed. Glycididazole has a chemical structure in which two metronidazole forms are combined, and is widely used as a hypoxic radiosensitizer in China. However, a detailed investigation of its radiosensitizing properties has not been performed. The present study reported a comparative assessment of glycididazole and doranidazole, another hypoxic radiosensitizer. All experiments were performed using the murine squamous cell carcinoma cell line SCCVII. Prior to X irradiation, the cells were treated with the test drugs at concentrations of 10 mM and 200 mg/kg in vitro and in vivo, respectively. Uptake and their intratumor chemical forms were analyzed by high performance liquid chromatography (HPLC). Both drugs enhanced the reproductive cell death induced by X-irradiation under hypoxia. However, the growth delay assay of the transplanted tumor revealed the combination of X-irradiation and glycididazole showed a similar antitumor effect to that of X-irradiation alone, whereas doranidazole significantly sensitized the cells to X-irradiation. HPLC analysis revealed that incorporated glycididazole was decomposed to metronidazole and was therefore present at a lower concentration compared with that of doranidazole. The decomposition of glycididazole to metronidazole reduced its radiosensitizing efficiency in vivo. Elucidation of the kinetics of drugs containing metabolizable chemical forms is necessary for the optimization of clinical treatment. PMID- 29434900 TI - Oridonin increases anticancer effects of lentinan in HepG2 human hepatoblastoma cells. AB - The aim of the present study was to investigate whether oridonin is able to increase the effects of lentinan (LNT) in HepG2 human hepatoblastoma cells by MTT, flow cytometry, reverse transcription-quantitative polymerase chain reaction and western blot analysis. The in vitro results demonstrated that 20 ug/ml of oridonin was a nontoxic concentration for L02 normal liver cells and HepG2 liver cancer cells. Furthermore, treatment with 0-200 ug/ml LNT was only able to decrease the viability of HepG2 liver cancer cells. The growth inhibitory rate of the LNT-L (100 ug/ml) treatment group was 20.7% and the rate of the LNT-H (200 ug/ml) treatment group was 54.8%. Notably, the growth inhibitory rate of the oridonin + LNT-H group was 84.3%. The highest percentage of apoptotic cells was observed in the oridonin + LNT-H group (20 ug/ml oridonin and 200 ug/ml LNT). The percentage of apoptotic cells in the oridonin + LNT-H group was significantly different from the percentage of apoptotic cells in the LNT-H (26.1%) and the LNT L (16.8%) groups. Treatment with LNT produced an increase in caspase-3, caspase 9, Bcl-2-like protein 4, p53, p21, nuclear factor kappaB inhibitor-alpha mRNA and protein expression and a decrease in B-cell lymphoma 2 and nuclear factor-kappaB expression in HepG2 cells compared with untreated control cells. Treatment with a combination of oridonin and LNT-H induced a further increase in expression with the biggest differences in expression observed between the oridonin + LNT-H group and control. It was observed that treatment with oridonin was able to increase the anticancer effects of LNT in HepG2 cells. Therefore, oridonin may be used to sensitize cells to LNT. PMID- 29434901 TI - Reversible growth arrest of 3D tumor spheroids stored in oxygen absorber-induced anoxia. AB - Multicellular tumor spheroids models are of increasing interest in preclinical studies and pharmacological evaluation. However, their storage and transport is often a limitation because it requires adapted and expensive procedures. Here, we propose a very simple method to store 3D spheroids, using a procedure based on oxygen absorber-induced anoxia. We report that oxygen absorbers allow generating an anoxic environment for spheroid storage in culture plates. Oxygen absorber induced anoxia fully and reversibly arrests spheroid growth for 4 days at 37 degrees C and up to 18 days at 4 degrees C. We then show that the response to etoposide is comparable in spheroids preserved in conditions of absorber-induced anoxia at 4 degrees C and spheroids kept in normoxia at 37 degrees C. These results represent a major improvement that should simplify the storage, transport and use of 3D spheroids. PMID- 29434902 TI - Chloroquine exerts antitumor effects on NB4 acute promyelocytic leukemia cells and functions synergistically with arsenic trioxide. AB - Chloroquine (CQ) has been confirmed to exhibit antitumor effects on different types of cancer cell, but whether it exerts the same effect on acute promyelocytic leukemia (APL) cells remains to be confirmed. In the present study, the effects of various concentrations of CQ on the growth, apoptosis and cell cycle distribution of NB4 cells, as well as the potential mechanisms underlying these effects, were examined. The combined effect of CQ and arsenic trioxide (ATO) on the growth of NB4 cells was also determined. The results of the present study demonstrated that CQ treatment inhibited cell proliferation, and induced mitochondrial pathway apoptosis and S phase arrest in a dose-dependent manner by regulating apoptosis- and cell cycle-related proteins. CQ and ATO had a synergistic effect on the growth inhibition of NB4 cells, which may have been induced through the inhibition of autophagy. In conclusion, the results of the present study indicated that CQ exhibits a cytotoxic effect on NB4 cells and has a synergistic effect when combined with ATO, which thereby improves the curative effect of ATO on APL. PMID- 29434903 TI - Surface markers of liver cancer stem cells and innovative targeted-therapy strategies for HCC. AB - Liver cancer stem cells (LCSCs) have important roles in the occurrence, development, recurrence, therapy resistance and metastasis of hepatocellular carcinoma (HCC). Therefore, intensive studies are undergoing to identify the mechanisms by which LCSCs contribute to HCC invasion and metastasis, and to design more efficient treatments for this disease. With continuous efforts in LCSC research over the years, therapies targeting LCSCs are thought to have great potential for the clinical treatment and prognosis of liver cancer. Novel LCSC surface markers are continuously discovered and several have been used in targeted therapies to reduce HCC recurrence, metastasis, and drug resistance following tumor resection. The present review describes the surface markers characterizing LCSCs and the recent progress in therapies targeting these markers, including antibodies and polypeptides. PMID- 29434904 TI - Epigenetic actions of environmental factors and promising drugs for cancer therapy. AB - Carcinogenesis is known to be primarily associated with gene mutations. Recently, increasing evidence has suggested that epigenetic events also serve crucial roles in tumor etiology. Environmental factors, including nutrition, toxicants and ethanol, are involved in carcinogenesis through inducing epigenetic modifications, such as DNA methylation, histone deacetylase and miRNA regulation. Studying epigenetic mechanisms has facilitated the development of early diagnostic strategies and potential therapeutic avenues. Modulation at the epigenetic level, including reversing epigenetic modifications using targeted drugs, has demonstrated promise in cancer therapy. Therefore, identifying novel epigenetic biomarkers and therapeutic targets has potential for the future of cancer therapy. The present review discusses the environmental factors involved in epigenetic modifications and potential drug candidates for cancer therapy. PMID- 29434905 TI - Transcriptome profiling of cancer tissues in Chinese patients with gastric cancer by high-throughput sequencing. AB - Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-associated mortality worldwide. Therefore, there is a requirement to identify sufficiently sensitive biomarkers for GC. Genome-wide screening of transcriptome dysregulation among cancerous and normal tissues may provide insights into the underlying molecular mechanisms of GC initiation and progression. At present, high-throughput sequencing techniques have begun to innovate biomedical studies. The RNA-seq method has become an advanced approach in medical studies; it is capable of the accurate detection of gene expression levels. The present study used RNA-seq to evaluate the transcriptional changes between tumor and matched normal samples, and these changes were confirmed by differentially expressed genes in larger samples using the results of sequencing. In total, the upregulation of 28 mRNAs and downregulation of 22 mRNAs between cancerous and normal tissue samples were identified. Subsequently, five differentially expressed genes were selected to verify in large samples and cadherin-1 (CDH1) was selected to detect protein expression levels. The results revealed that CDH1, cyclooxygenase-2 and matrix metalloproteinase genes had significantly higher expression levels, whereas the expression levels of dermatopontin and transforming growth factor beta receptor 2 were decreased in GC samples. In particular, CDH1 demonstrated a 36-fold higher expression level in cancer tissues. The western blotting results also revealed high CDH1 expression levels in the validation cohorts. Furthermore, these genes are highly enriched in certain gene ontology categories, including the digestive system process, secretion and digestion. The present study provided a preliminary survey of the transcriptome of Chinese patients with GC, which may improve the detection of aberrant gene expression in GC and the understanding of the mechanisms of tumorigenesis. PMID- 29434906 TI - Upregulated solute carrier family 37 member 1 in colorectal cancer is associated with poor patient outcome and metastasis. AB - Solute carrier (SLC) drug transporters exchange various molecules without energy from adenosine triphosphate hydrolysis, indicating an association with anticancer drug resistance. However, the expression and role of SLC transporters in malignant tumors has not yet been fully elucidated. Therefore, in the current study, the expression of SLC37A family genes was evaluated in patients with colorectal cancer (CRC), and it was revealed that SLC family 37 member 1 (SLC37A1) expression was significantly increased in tumorous tissues compared with that in non-tumorous tissues. The cases with upregulated expression of SLC37A1 by immunohistochemical staining were significantly associated with positive venous invasion and liver metastasis. Furthermore, upregulated SLC37A1 expression was associated with poor overall survival time in the present cohort. These results indicated that SLC37A1 is involved in the hematogenous metastasis of CRC. To investigate whether SLC37A1 is associated with hematogenous metastasis and glycolipid metabolism, SLC37A1 was knocked down in colon cancer cells, and the expression of sialyl Lewis A and sialyl Lewis X was observed to be decreased. In summary, upregulation of SLC37A1 was observed in patients with CRC, and was associated with poor patient outcomes and survival. To the best of our knowledge, the present study is the first to propose a key role of SLC37A1 in CRC, and additional studies are warranted to reveal the functional role of SLC37A1 in CRC development. PMID- 29434907 TI - High expression of RACK1 is associated with poor prognosis in patients with pancreatic ductal adenocarcinoma. AB - Receptor for activated C kinase 1 (RACK1) is associated with certain aspects of cancer biology and signaling pathways, but its function in pancreatic ductal adenocarcinoma (PDAC) remains unknown. In the present study, 157 patients with PDAC were enrolled. RACK1 mRNA and protein expression levels were analyzed in PDAC tissues and matched adjacent noncancerous tissues by reverse transcription quantitative polymerase chain reaction and western blotting. RACK1 expression levels in paraffin-embedded PDAC tissues were determined by immunohistochemistry. The associations between RACK1 expression and clinical data were evaluated using chi2 analysis. The relationship between RACK1 expression and the survival data of patients was analyzed using Kaplan-Meier and log rank tests. RACK1 mRNA and protein were revealed to be overexpressed in PDAC tumor tissues compared with adjacent noncancerous tissues. RACK1 expression was associated with clinical stage (P=0.001), lymph node invasion (P=0.003) and liver metastasis (P=0.001). Furthermore, patients with PDAC and high RACK1 expression demonstrated shorter overall survival times compared with patients with low RACK1 expression (P=0.002). Multivariate analysis indicated that RACK1 overexpression was an independent prognostic factor for patients with PDAC. Overexpression of RACK1 may contribute to tumor progression, and may be a potential prognostic biomarker for patients with PDAC. PMID- 29434908 TI - Extranodal presentation of Hodgkin's lymphoma of the sternum: A case report and review of the literature. AB - Hodgkin's lymphoma (HL) is typically a systemic disease with involvement of the cervical, supraclavicular and mediastinal lymph nodes. An extra-nodal presentation of HL is unusual and seldom encountered in the clinic. The most common sites of presentation for extra-nodal extension are the spleen, liver, lungs, bones and marrow. The bones that are frequently involved are the vertebrae, pelvis, ribs and femur. Involvement of the sternum has occasionally been reported. The current study presents an unusual case on the extra-nodal presentation of HL of the sternum arising in a 25-year-old woman, and reviews the relevant literature with particular emphasis on treatment. The extra-nodal infiltration of HL, and the clinical stage and prognosis of the case are also discussed. PMID- 29434909 TI - Fyn knockdown inhibits migration and invasion in cholangiocarcinoma through the activated AMPK/mTOR signaling pathway. AB - Cholangiocarcinoma (CCA) is a rare and fatal tumor. In previous decades, there has been a steady increase in the incidence and mortality rates of this tumor worldwide. Metastasis is regarded as the major factor that contributes to poor prognosis in CCA patients. Studies therefore aim to develop novel therapeutic targets to control CCA metastasis. Fyn is known to enhance expression and promote metastasis in various cancers, including pancreatic cancer, prostate cancer and colorectal cancer. However, the exact function and mechanism of Fyn in CCA metastasis remains unclear. In the present study, mRNA and protein expression levels of Fyn, AMP-activated protein kinase (AMPK), phosphorylated (p-)AMPK, mammalian target of rapamycin (mTOR) and p-mTOR were measured, using the reverse transcription-quantitative polymerase chain reaction and western blot analysis, in CCA tissues and cell lines. In addition, Transwell assays were used to determine the migratory and invasive abilities of human CCA QBC939, following transfection. In the present study, it was found that Fyn was overexpressed in CCA cell lines. Fyn knockdown inhibited CCA cell migration and invasion. Furthermore, it was demonstrated that Fyn knockdown induces phosphorylation of AMPK, inhibits downstream phosphorylation of mTOR, and activate the AMPK/mTOR signaling pathway. Compound C, an AMPK inhibitor, inhibited the AMPK/mTOR signaling pathway, and reversed the effect of Fyn knockdown on migration and invasion of CCA cells. In conclusion, the present study suggests that Fyn knockdown inhibits cell migration and invasion by regulating the AMPK/mTOR signaling pathway in CCA cell lines and that Fyn knockdown is a potential target for anti-CCA therapy. PMID- 29434910 TI - Application values of 3.0T magnetic resonance diffusion weighted imaging for distinguishing liver malignant tumors and benign lesions. AB - The aim of the present study was to investigate the significance and values of 3.0T diffusion weighted imaging (DWI) to differentially diagnose benign and malignant space-occupying liver lesions. A total of 91 patients with liver space occupying lesions (145 lesions) were admitted into Zhongnan Hospital of Wuhan University (Wuhan, China) from November 2015 to May 2016. Routine scanning, DWI and high-resolution T2-weighted imaging using spin-echo echo-planar imaging were performed on all patients, to compare the apparent diffusion coefficient (ADC) values of three regions of interest in lesions with normal liver tissue. The ADC values of malignant liver lesions compared with benign liver cysts demonstrated a statistically significant difference in low b-value (P<0.05) and there was also a significant difference between malignant lesion and hepatic cyst, hepatic hemangioma or hepatic abscess in middle b-value (P<0.05). The measured ADC value may be more conducive to identify the nature of the liver space-occupying lesions; as the ADC values of malignant liver lesion, liver cyst, and liver abscesses demonstrated a statistical significance in high b-value (P<0.05). The mean ADC values between malignant liver tumors compared with benign lesions indicated a statistically significant difference. In the present study, liver space-occupying lesions demonstrated different DWI features and ADC ranges, and 3.0T DWI may be a potential means to accurately determine the nature of lesions, identifying benign and malignant space-occupying lesions. PMID- 29434911 TI - Novel betulin derivative induces anti-proliferative activity by G2/M phase cell cycle arrest and apoptosis in Huh7 cells. AB - Betulin (BT) has been identified to exhibit potential benefits for treating hepatocellular carcinoma (HCC). The results of the present study demonstrated that a new semisynthetic derivative of BT, 3,28-di-(2-nitroxy-acetyl)-oxy-BT, may effectively decrease the viability of Huh7 cells. Mechanistic studies revealed that 3,28-di-(2-nitroxy-acetyl)-oxy-BT inhibited the transition between G2 and M phase of the cell cycle by regulating cell cycle regulatory proteins. Additional study revealed that 3,28-di-(2-nitroxy-acetyl)-oxy-BT may trigger Huh7 cells to undergo caspase-dependent apoptosis as an increased proportion of cells were identified in the sub-G1 phase, which may be a result of poly(ADP-ribose) polymerase cleavage and caspase activation. Furthermore, 3,28-di-(2-nitroxy acetyl)-oxy-BT-induced apoptosis was mitochondrion-mediated. The results of the present study demonstrated that Bcl-2-associated X protein translocated to the mitochondria from the cytosol following 3,28-di-(2-nitroxy-acetyl)-oxy-BT treatment. Notably, the phosphoinositide 3-kinase/protein kinase B signaling pathway was involved in 3,28-di-(2-nitroxy-acetyl)-oxy-BT-treated Huh7 cells. Therefore, the results of the present study demonstrated that 3,28-di-(2-nitroxy acetyl)-oxy-BT may inhibit HCC, which may be a possible application to treat HCC. PMID- 29434912 TI - Notch signaling via regulation of RB and p-AKT but not PIK3CG contributes to MIA PaCa-2 cell growth and migration to affect pancreatic carcinogenesis. AB - Pancreatic cancer is one of the leading causes of cancer-associated mortality. The understanding of the expression pattern of key protein factors and their function in pancreatic cancer cells is therefore vital for the diagnosis and treatment of this malignancy. The results of the present study reveal that the levels of neurogenic locus notch homolog protein 2 (Notch2) and phosphorylated (p)-SMAD family member 2 decreased, whereas the expression of Notch3 and phosphoinositide-3 kinase catalytic subunit-gamma protein increased in human pancreatic cancer tissues compared with tumor-adjacent tissues. Using the human pancreatic cancer MIA PaCa-2 cell line, it was observed that retinoblastoma associated protein (RB) and p-RB expression were inhibited and p-AKT was upregulated when Notch signaling was activated in MIA PaCa-2 cells. Furthermore, inhibition of phosphoinositide-3 kinase catalytic subunit-gamma (PIK3CG) activity by AS-605240 was able to block the growth and migration of MIA PaCa-2 cells. In conclusion, the results of the present study demonstrate that the Notch signal pathway may be involved in pancreatic carcinogenesis by modulating RB and p-AKT. PIK3CG may therefore be a potential target gene for the treatment of pancreatic cancer. PMID- 29434913 TI - p68 prompts the epithelial-mesenchymal transition in cervical cancer cells by transcriptionally activating the TGF-beta1 signaling pathway. AB - Overexpression of p68 has been reported in various types of cancer. However, little study has been conducted on the expression and role of p68 in cervical cancer. Therefore, the present study focuses on the role of p68 in cervical cancer cells, which may elucidate its potential mechanism of cervical cancer progression and shed light on the precision medical treatment of cervical cancer. Firstly, the expression of p68 was analyzed using reverse transcription quantitative polymerase chain reaction and western blot analysis. The changes to cell morphology were observed using an inverted microscope (XDS-500D; Shanghai Caikon Optical Instrument Co., Ltd., Shanghai, China). Cell migration was determined using an in vitro scratch assay. The present study demonstrated that the mRNA and protein levels of p68 were significantly enhanced in cervical cancer CaSki, HeLa [human papillomavirus (HPV)-18-positive], SiHa (HPV-16-positive) and C-33A (HPV-negative) cell lines compared with the human keratinocyte HaCaT cell line. Overexpression of p68 induced an elongated and spindle-shaped morphology in CaSki cells. Upregulation of p68 increased the expression of alpha-smooth muscle actin, vimentin and fibronectin however, epithelial marker E-cadherin was significantly decreased. Furthermore, the in vitro scratch assay demonstrated that overexpression of p68 markedly enhanced CaSki cell migration capacity at 24 and 48 h. Knockdown of p68 partially reversed transforming growth factor-beta1 (TGF-beta1)-induced changes in epithelial-mesenchymal transition (EMT) markers and cell morphological changes. In summary, the present study demonstrated that p68 transcriptionally activated the expression of TGF-beta1, thereby prompting EMT in cervical cancer cells. PMID- 29434914 TI - Long non-coding RNA MALAT-1 contributes to maintenance of stem cell-like phenotypes in breast cancer cells. AB - Due to the accumulating evidence that has demonstrated the vital role of cancer stem cells (CSCs) in tumor initiation, progression and metastasis, the mechanisms that maintain the stemness of CSCs have attracted increasing attention. Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1), a long non coding RNA, which has been revealed to be associated with the malignant behavior of tumors, performs a critical role in maintaining the stemness in several CSCs. In the present study, it was hypothesized that MALAT-1 promotes stem cell-like phenotypes in breast cancer cells. The present data demonstrated that the expression of MALAT-1 was higher in the CSC subpopulation compared with that in the overall MCF7 cell group and that the knockdown of MALAT-1 decreased the proportion of CSCs. The self-renewal assay also demonstrated that knockdown of MALAT-1 decreased the sphere formation rate in vitro. In addition, MALAT-1 is also able to regulate the proliferation, colony formation, migration and invasion of CSCs in vitro. The underlying mechanisms may involve the regulation of self renewal-associated factors, including sex-determining region Y-box 2 (Sox-2). Taken together, the present study demonstrated that MALAT-1 affects the stem cell like phenotypes in breast cancer cells through regulation of Sox-2. PMID- 29434915 TI - Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: A retrospective study of 136 patients. AB - The WHO 2010 classification divides gastrointestinal neuroendocrine neoplasms (GI NENs) into neuroendocrine tumor (NET) G1, NET G2, neuroendocrine carcinoma (NEC) and mixed adenoendocrine carcinoma (MANEC) groups. A total of 136 cases of GI NENs diagnosed at our hospitals as gastrointestinal carcinoids, endocrine cell carcinomas and NENs over the last 11 years, using the WHO 2010 classification were assessed. Among the 136 cases, 88.2% (120/136) were classified into the NET group (NET G1/G2) and 11.8% (16/136) were classified into the NEC group (NEC/MANEC). The incidences of lymphatic and venous invasions were higher in the NEC group compared with in the NET group (P<0.0001 and P=0.0021, respectively). The immunohistochemical staining of cluster of differentiation 73 (CD73) was evaluated in GI-NENs. CD73 is a potentially useful molecule in tumor immunity. In general, CD73 on the tumor cell membrane converts adenosine monophosphate to adenosine, which restrains the production of interferon-gamma and cytocidal activity. Although the association between stem cells of pancreatic NENs and CD73 has been reported, few studies have reported on CD73 expression in GI-NENs. Immunohistochemical CD73 expression on the cytomembrane of neuroendocrine cells was detected in 27.2% (37/136) of the GI-NENs. The positive ratio of CD73 was significantly higher in the NEC group compared with in the NET group (P=0.0015). CD73 is also considered as a potential biomarker of anti-programmed death-1 (PD 1) therapy. The expression of programmed death-ligand 1 (PD-L1) on the cytomembrane of GI-NENs was assessed. The positive ratio of PD-L1 was higher in the NEC group compared with in the NET group (P=0.0011). Furthermore, CD73 expression status was significantly correlated with PD-L1 expression (P<0.0001). These results indicate that CD73 may be an interesting candidate for a biomarker for certain prognostic factors and therapeutics concerning PD-1 therapy. PMID- 29434916 TI - Epidermal growth factor receptor somatic mutation analysis in 354 Chinese patients with non-small cell lung cancer. AB - Lung cancer is one of the most common types of cancer worldwide, with the highest mortality rate of all types of cancer. In the present study, epidermal growth factor receptor (EGFR) mutations of 354 primary patients with non-small cell lung cancer (NSCLC) of Chinese ethnicity were detected following formalin-fixed and paraffin-embedded specimen DNA extraction, polymerase chain reaction amplification, and sanger sequencing. The total rate of occurrence of EGFR somatic mutation in these 354 patients was 48.02%. Of these detected EGFR mutations, 27.40% were located in exon 19 and 25.99% in exon 21. The most frequent mutation in exon 19 was E746-A750del (8.47%), and in exon 21, L858R (10.17%). EGFR mutation rates were significantly associated with sex [female vs. male: 60.13 vs. 38.81%; adjusted odds ratio (OR), 1.93, 95% confidence interval (CI), 1.07-3.51, P=0.029], age (<60 vs. >=60; 58.62 vs. 40.67%; adjusted OR, 1.87; 95% CI, 1.20-2.92; P=0.006) and histology [adenocarcinoma (ADC) vs. non ADC; 52.76 vs. 26.56%; adjusted OR, 2.35; 95% CI, 1.28-4.50; P=0.007]. The frequency of E746_A750del, Q787Q and L858R mutations were significantly different in ADC patients compared with squamous cell carcinoma patients (P<0.001). Furthermore, a novel EGFR mutation, M793K, was detected in 7 NSCLC patients with possible gefitinib resistance. The present study analyzed the EGFR exon 18-21 mutation occurrence profile for Chinese patients with NSCLC and identified significant associations between different EGFR mutations with demographic and histological factors. These results may offer clinical benefits and potential novel treatments. PMID- 29434917 TI - The association between differentially expressed micro RNAs in breast cancer cell lines and the micro RNA-205 gene polymorphism in breast cancer tissue. AB - Micro (mi)RNAs are an endogenous non-coding small RNA comprised of 19-26 nucleotides. miRNAs regulate gene expression through the recognition of its 'seed sequence' and interactions with 3'-untranslated region of target miRNAs. Previous studies identified that miRNAs are associated with the onset and development of breast cancer and that a number of mutations in the coding DNA sequence of miRNAs affect its expression. Therefore, the present study aimed to screen differentially expressed miRNAs using miRNA expression profile chips to analyze the expression of miRNA (miR)-205 in 12 breast cell lines of different metastatic performance and benign proliferative variation as well as breast cancer via in situ hybridization, and screen out single-nucleotide polymorphisms (SNPs) in the miR-205 coding gene region. In addition, the association between SNP and the clinicopathological features of breast lesions was investigated. The results of the present study demonstrated that the expression of miR-205 was decreased in breast cancer cells and tissues compared with benign lesions. SNPs in the miR-205 coding gene region were identified in tumor cell lines and as increasing lengths of the AGC repetitive sequence were lost, miR-205 expression increased. An association was identified between a number of SNPs in the miR-205 coding gene region and breast cancer, as well as between SNPs in miR-205 coding gene region and the clinicopathological features of breast cancer. PMID- 29434918 TI - Knockdown of Arf6 increases drug sensitivity and inhibits proliferation, migration and invasion in gastric cancer SGC-7901 cells. AB - ADP-ribosylation factor 6 (Arf6), a member of the ADP-ribosylation factor family, is overexpressed in different types of cancer cell and promotes invasion, metastasis and drug resistance. However, the potential functions of Arf6 in gastric cancer (GC), and the molecular mechanism underlying these functions, remain to be fully elucidated. In the present study, the results demonstrated that in vitro knockdown of Arf6 decreased proliferation, colony formation, migration and invasion in SGC-7901 cells. Arf6 knockdown also markedly decreased the activity of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Furthermore, knockdown of Arf6 was associated with elevated chemosensitivity of SGC-7901 cells to 5-fluorouracil through inactivation of the ERK1/2 signaling pathway. Taken together, these results suggest that Arf6 is involved in regulating proliferation, migration, invasion and drug resistance in GC, and may be a potential therapeutic target for the treatment of GC. PMID- 29434919 TI - Role of serine/threonine kinase 33 methylation in colorectal cancer and its clinical significance. AB - Serine/threonine kinase 33 (STK33) is a novel protein that has been the focus of an increasing number of studies in recent years; however, the role of STK33 in tumorigenesis remains controversial. Previous studies have demonstrated that STK33 is overexpressed in several human cancers and exerts a pro-tumorigenic effect through the promotion of cell proliferation. However, the role of STK33 in colorectal cancer (CRC), which is one of the most aggressive human malignancies, remains unclear. The aim of the current study was to investigate the methylation status of STK33 in CRC and to determine its clinical significance. The results demonstrated that STK33 was hypermethylated in CRC cell lines and promoted the proliferation of CRC cells. In addition, the methylation status and expression of STK33 in 94 pairs of cancer and noncancerous tissues obtained from patients with CRC was investigated. STK33 methylation was significantly increased in cancer tissues when compared with adjacent noncancerous tissues (P<0.001). STK33 methylation was associated with lymph node metastasis (P<0.05), tumor invasion (P<0.05), distant metastases (P<0.01) and tumor stage (P<0.01). Reduced STK33 mRNA and protein expression in CRC was associated with STK33 hypermethylation (P<0.001). In addition, patients with hypermethylated STK33 exhibited shorter overall survival rates when compared with those with unmethylated STK33 (P<0.01). In conclusion, the results of the current study suggest that STK33 hypermethylation may be a promising novel biomarker for the diagnosis, prognosis and suitable treatment of CRC. PMID- 29434920 TI - Characterization and prognostic significance of mortalin, Bcl-2 and Bax in intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is an aggressive type of cancer, and its incidence and mortality rates are increasing worldwide. Mortalin is a highly conserved chaperone protein involved in multiple pathological and physiological processes, including anti-apoptosis, carcinogenesis and metastasis. The Bcl-2 family of proteins can be divided into pro-survival and pro-apoptotic members, including B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax). The aim of the present study was to investigate the association between mortalin, Bcl-2 and Bax, as well as the prognostic significance of the combined expression of mortalin, Bcl-2 and Bax in ICC. Immunohistochemistry was used to determine the expression of mortalin, Bcl-2 and Bax in 116 ICC samples and to assess the association between expression of 3 markers and clinicopathological features of ICC patients. This revealed that ICC tumor tissues overexpressed mortalin and Bcl 2 and exhibited low expression of Bax in ICC tumor tissues compared with that in corresponding peritumoral samples. According to Pearson's correlation coefficient analysis, high expression of mortalin in ICC was positively correlated with Bcl-2 expression and negatively correlated with Bax expression. Furthermore, multiple linear regression analysis demonstrated that mortalin was positively associated with Bcl-2, but not with Bax, in patients with ICC. Patients with ICC exhibiting high expression of mortalin/Bcl-2 or low expression of Bax were closely associated with a malignant ICC phenotype, a relatively low overall survival rate and a high recurrence rate. Multivariate analysis indicated that mortalin and Bcl 2 were independent prognostic indicators for ICC patients. Meanwhile, the concomitant overexpression of mortalin and Bcl-2 and the low expression of Bax were independent markers for predicting a relatively poor prognosis of ICC. The overexpression of mortalin and Bcl-2 and/or the low expression of Bax are implicated in the anti-apoptotic effect and tumor progression of ICC. Mortalin or Bcl-2, or a combination of mortalin, Bcl-2 and Bax may be used to predict the prognosis of ICC, as well as potential therapeutic targets. PMID- 29434921 TI - Correlation between circulating tumor cells and D-D and platelet in patients with pulmonary malignancies. AB - The aim of the present study was to investigate the correlation between circulating tumor cells (CTC) and D-dimer (D-D) and platelet (PLT) in patients with pulmonary malignancies. A total of 98 patients with lung cancer admitted to West China Hospital, Sichuan University, from June 2016 to February 2017 were enrolled in the present study. D-D and PLT levels were measured in the fasting elbow vein of the patients. The expression of CTC in peripheral blood was detected by negative separation using immunomagnetic beads and immunocytochemical staining. The correlation between CTC and D-D and PLT in patients with lung cancer was analyzed. The mean level of D-D in the peripheral blood of 98 patients was 1.80+/-1.63 ug/l, and the level of D-D was correlated with distant metastasis (P<0.05). The mean level of PLT in peripheral blood was 305.53+/-141.22*109/l in 98 patients, and the level of PLT was correlated with patient age, clinical stage and distant metastasis (P<0.05). The levels of D-D, PLT and distant metastasis were significantly higher in CTC-positive than in CTC-negative patients (P<0.05). Therefore, CTC can predict the distant metastasis of lung cancer, and the incidence of distant metastasis is high in patients with hypercoagulable state. PMID- 29434922 TI - Association of abnormal glucose metabolism and insulin resistance in patients with atypical and typical endometrial cancer. AB - This study aimed to detect glucose metabolism indicators and insulin resistance index in patients with endometrial cancer, and to explore the clinical significance and correlation between them. A total of 65 patients with endometrial cancer (52 of typical endometrial and 13 cases of atypical endometrial cancer patients, 27 with diabetes mellitus, and 38 cases without diabetes mellitus) were selected at the People's Hospital of Rizhao from June, 2010 to June, 2016 to serve as the observation group. During the same period, 62 patients with endometrial benign lesions (24 with diabetes mellitus and 38 cases without diabetes mellitus) were selected as the control group. General information including height, body weight, body mass index (BMI), abdominal, waist and hip circumference, and waist-to-hip ratio (WHR) was compared between the two groups. Fasting blood glucose, glycosylated hemoglobin, fasting insulin level (FINS), insulin resistance index (HOMA-IR), follicle estrogen (FSH), luteinizing hormone and estradiol (estrogen) were detected and compared between the two groups. Multivariate logistic regression was used to analyze the risk factors for endometrial cancer. The results showed that there were no significant differences in the height and hip circumference among the typical, atypical and control groups. By contrast, weight, BMI, waist circumference, abdominal circumference and the WHR of the typical group were significantly higher than those of the atypical and control groups (P<0.05). No significant differences were found between the atypical and control groups (P>0.05). Levels of the FINS and HOMA-IR typical group were significantly higher than those in the atypical and control groups, and the incidence of hyperinsulinemia and insulin resistance was significantly higher in the observation than in the control group (P<0.05). Of the patients with diabetes, the levels of FINS, HOMA-IR and estrogen were significantly higher, but the level of FSH was significantly lower in the observation compared to the control group (P<0.05). For patients without diabetes, significant differences in the levels of FINS and HOMA-IR were found between the observation and control groups (P<0.05). There was no significant difference in the levels of FINS and HOMA-IR among endometrial cancer patients with different pathological features (P>0.05). HOMA-IR (OR=1.240), estrogen (OR=1.192) and FSH (OR=1.002) are risk factors for endometrial cancer. The results suggest that hyperinsulinemia and insulin resistance are risk factors of endometrial cancer. Insulin may therefore be involved in the development of endometrial cancer by affecting the level of sex hormones. PMID- 29434923 TI - Long-term outcomes of patients with soft tissue sarcoma of the chest wall: Analysis of the prognostic significance of microscopic margins. AB - Data on prognostic factors and treatment outcomes for chest wall soft tissue sarcomas (STS) are sparse. Wide resections with negative margins are the mainstay of therapy, but the prognostic impact of surgical margins remains controversial. The purpose of the present study was to determine the significance of microscopic margins through a long-term follow-up. The associations between local recurrence free survival (LRFS), overall survival (OS) and potential prognostic factors were retrospectively assessed in a consecutive series of 110 patients who were suitable for surgical treatment with curative intent. Potential prognostic factors were assessed using univariate and multivariate analyses. The median follow-up time following primary diagnosis was 9.6 years [95% confidence interval (CI), 7.2-10.5]. In the entire cohort, the 5-year estimates of the OS and LRFS rates were 66.0% (95% CI, 55.9-74.3) and 60.6% (95% CI, 50.3-69.4), respectively. A total of 27 patients (24.5%) developed distant metastases with a median survival time of 0.9 years following the diagnosis of metastasis. Surgical margins attained at the initial resection and eventual re-excisions significantly influenced OS in univariate analysis (5-year OS, R0 69.9% vs. R1/R2 38.5%; P=0.046), but this failed to reach statistical significance in the multivariate analysis. In the multivariate analysis, significant adverse prognostic features of LRFS included angiosarcoma subtype, G2 and G3 histology. For OS, the only independent significant predictors were age >50 years, tumor size >5 cm, angiosarcoma subtype and G3 histology. The results of the present study suggest that tumor biology, as reflected by the histological grade, influences the final outcome in patients with chest wall STS. Surgical margins failed to reach statistical significance in multivariate analysis as they demonstrated a dependency towards the independent predictors of OS. Subsequently, a positive margin status may be a result rather than a cause of biological aggressiveness, and it may not influence the outcome directly. PMID- 29434924 TI - Enhanced expression of KIF4A in colorectal cancer is associated with lymph node metastasis. AB - Kinesin family member 4A (KIF4A) is a member of the kinesin 4 subfamily of kinesin-related proteins and serves an important role in cell division. The expression levels of KIF4A have been investigated in numerous types of cancer, including cervical, lung, oral, and breast cancer, and are established to be associated with poor patient prognosis. However, the role of KIF4A, as well as its expression in colorectal cancer (CRC), remains to be elucidated. Therefore, the current study investigated KIF4A expression levels in patients with CRC and demonstrated that its levels were increased in tumor tissues compared with non tumor tissues. To investigate the functional role of KIF4A, KIF4A was knocked down in CRC cells and cell viability was evaluated. CRC cells with KIF4A knockdown exhibited lower cell proliferation compared with control cells. In addition, KIF4A expression levels, as determined by immunohistochemistry, were compared with the expression of Ki-67, but no significant associations were observed in the patients with CRC. Therefore, KIF4A was found to be upregulated in patients with CRC and downregulation of KIF4A reduced cell proliferation in CRC cells. These results suggest that KIF4A may be a potential therapeutic target, which may improve the outcomes of patients with CRC. PMID- 29434925 TI - BRAF V600E mutation is a predictive indicator of upfront chemotherapy for stage IV colorectal cancer. AB - In stage IV colorectal cancer (CRC), initial resection of the primary tumor is considered to be an important strategy for improving disease outcome. However, there is no consensus on the timing as to when the surgical intervention of the primary tumor should occur. The present study hypothesizes that genetic profiles in CRC may indicate the appropriate treatment strategies for patients with stage IV CRC, and a cohort of 113 patients with stage IV CRC resected primary lesions at various periods were analyzed for the presence of mutations in the KRAS, exon 2, and BRAF genes, exon 15, and for the microsatellite instability status of the tumor. These data were additionally correlated with various clinicopathological features. Although BRAF-mutant was revealed to be an independent negative prognostic factor in stage IV CRC (HR, 8.42; 95% confidence interval, 2.72 26.02), BRAF-mutant samples exhibited better prognoses if they were treated with chemotherapy prior to tumor resection. Thus, the presence of BRAF mutations provides a compelling rationale for the establishment of intensive upfront chemotherapy to improve survival in stage IV CRC. PMID- 29434926 TI - PAK5 overexpression is associated with lung metastasis in osteosarcoma. AB - p21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases, which are associated with cytoskeletal organization, cellular morphogenesis, migration and survival. PAKs are overactive in a number of tumor tissues and have attracted attention as a potential target for cancer therapy. In the present study, PAK5 levels were analyzed in primary osteosarcoma (OS) samples (n=65) using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) methods. In the primary OS tissue, increased PAK5 expression (IHC score >2, n=37) was associated with significantly decreased overall survival (P=0.036) compared with decreased PAK5 expression (IHC score <=2, n=28). PAK5 expression was identified to be significantly associated with metastasis (P=0.010). The lung is the most common metastasis site for OS. In addition, the level of PAK5 in lung metastasis tissue (n=13) was detected using RT-qPCR and IHC methods. PAK5 expression was increased in lung metastasis tissue compared with in primary OS samples. PAK5 was silenced using short hairpin RNA in OS cell lines. Wound healing, migration and nude mice model assay results consistently demonstrated that PAK5 knockdown was able to significantly inhibit OS migration. In PAK5-knockdown cells, the alteration in the expression of a number of metastasis-associated factors, including epithelial cadherin, vimentin, fibronectin and matrix metalloproteinase 2 (MMP2), was analyzed. Only MMP2 expression was decreased significantly (P<0.05). The expression level of MMP2 was analyzed in primary OS tissue and lung metastasis tissue using RT-qPCR and IHC methods. Expression of MMP2 was identified to be associated with expression of PAK5. The results of the present study suggest that PAK5 promotes OS cell migration and that PAK5 expression may be used to predict lung metastasis. PMID- 29434927 TI - Upregulation of pyruvate kinase M2 expression by fatty acid synthase contributes to gemcitabine resistance in pancreatic cancer. AB - Pancreatic cancer has one of the highest mortality rates of all cancer types. Fatty acid synthase (FASN) is a multifunctional protein homodimer that can convert acetyl coenzyme A (CoA) and malonyl-CoA into palmitate, thus regulating lipogenesis. FASN overexpression has also been shown to cause resistance to gemcitabine, a chemotherapy treatment for pancreatic cancer; however, the mechanism by which this happens is unclear. Analysis of gene expression of FASN and pyruvate kinase M2 (PKM2) in pancreatic cancer was performed using Oncomine microarray gene expression datasets, which demonstrated that FASN and PKM2 were upregulated in pancreatic cancer compared with normal tissue. Specifically, it was demonstrated that FASN enabled the upregulation of PKM2 expression at the mRNA and protein levels, increasing the glucose consumption rate in pancreatic cancer cells. The present study also revealed that decreased levels of FASN reduced resistance to gemcitabine treatment, which was induced by PKM2 overexpression in pancreatic ductal adenocarcinoma cells. Therefore, FASN may represent a novel therapeutic target in pancreatic cancer. PMID- 29434928 TI - Oxibendazole inhibits prostate cancer cell growth. AB - Prostate cancer (PCa) is one of the most common malignancies among men and is the second leading cause of cancer-associated mortality in the developed world. Androgen deprivation therapy (ADT) is the most common treatment for PCa. However, the majority of androgen-sensitive PCa patients will eventually develop resistance to ADT and the disease will become androgen-independent. There is, therefore, an immediate requirement to develop effective therapeutic techniques towards the treatment of recurrent PCa. Oxibendazole (OBZ) is an anthelmintic drug that has also shown promise in the treatment of malignancies. In the present study, the capability of OBZ to repress the growth of PCa cells was assessed in human androgen-independent PCa 22Rv1 and PC-3 cell lines. The growth of the 22Rv1 and PC-3 cell lines, as assessed with a trypan blue exclusion assay, was markedly inhibited by OBZ treatment in vitro, with half-maximal inhibitory concentration values of 0.25 and 0.64 uM, respectively. The mean size of 22Rv1 tumors in nude mice treated with OBZ (25 mg/kg/day) was 47.96% smaller than that of the control mice. Treatment with OBZ increased the expression of microRNA-204 (miR-204), as determined by reverse transcription-quantitative polymerase chain reaction (RT qPCR), and the level of p53 as determined with western blotting, two well characterized tumor suppressor genes. When miR-204 expression was knocked down by introduction of an miR-204 inhibitor, the inhibitory effect of OBZ was markedly reduced; however, when it was overexpressed, the inhibitory efficiency of OBZ was markedly higher, indicating that upregulation of miR-204 is key for the efficacy of OBZ. Additionally, OBZ was demonstrated with RT-qPCR to repress the expression of the androgen receptor, and by western blotting to reduce prostate-specific androgen in 22Rv1 cells. The results suggest that OBZ has potential for clinical use in the treatment of recurrent PCa. PMID- 29434929 TI - Vernodalol mediates antitumor effects in acute promyelocytic leukemia cells. AB - Acute promyelocytic leukemia (APL) remains a challenge to cure due to the side effects of cytotoxic chemotherapy and drug resistance. The present study demonstrated that vernodalol, an active compound isolated from Centratherum anthelminticum, suppresses APL cell proliferation and induces cell cycle arrest in the G2/M phase through the upregulation of p21 and cell division cycle 25. In addition, vernodalol induced cellular apoptosis via the mitochondrial pathway as observed by the cleavage of caspase-9 as well as the release of cytochrome c and Smac/DIABLO into the cytosol. A mechanistic study revealed that vernodalol may exert its antitumor activity through the suppression of phosphoinositide 3 kinase/protein kinase B/mechanistic target of rapamycin signaling. In conclusion, vernodalol may be developed as a potential therapeutic compound for the treatment of APL. PMID- 29434930 TI - Increased expression of hepcidin and associated upregulation of JAK/STAT3 signaling in human gastric cancer. AB - Gastric cancer is one of the most common malignancies with high cancer-associated mortality rate globally. Hepcidin is the peptide hormone, which is critically important in the regulation of systemic iron homeostasis. Cumulating evidence has reported that the disturbed local expression of hepcidin may serve as a predictive biomarker in assessing the clinical outcomes in a range of cancer types. However, the expression profile of hepcidin in human gastric cancer is remains to be investigated. In the present retrospective study, using archived paraffin-embedded tissue blocks, the local production of hepcidin by immunohistochemical analysis was detected, and then its correlation with clinicopathological characteristics in human gastric cancer was evaluated. In parallel, using western blotting, quantitative reverse transcription polymerase chain reaction and chromatin immunoprecipitation assay, the local status of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling in response to inflammatory stimuli mediated by interleukin (IL)-6, which in turn regulates transcriptional activity of hepcidin gene (HAMP) was also assessed. The results indicated that, the local production of hepcidin was significantly elevated in tumor tissues compared with adjacent non-tumor tissues, and was tightly correlated with increasing tumor stages according to the tumor node metastasis (TNM) classification. In addition, JAK/STAT3 signaling and the STAT3 binding affinity to the HAMP gene promoter were significantly enhanced, in parallel with an increased expression of hepcidin, in tumor tissues compared with adjacent non-tumor tissues. Collectively, the present study indicated that local expression of hepcidin in gastric cancer tumor tissues was positively correlated with increasing tumor stages, which may be closely associated with the upregulation of IL-6-mediated JAK/STAT3 signaling in human gastric cancer. PMID- 29434931 TI - Neuropilin-1 promotes primary liver cancer progression by potentiating the activity of hepatic stellate cells. AB - As a co-receptor for a variety of cytokines, neuropilin-1 (NRP-1) is detectable in primary liver cancer (PLC) cells. Previous studies determined that silencing of NRP-1 expression attenuated the proliferation, migration and invasion of PLC cells. An increasing number of studies have highlighted the crucial role of the tumor microenvironment in the pathogenesis of cancer. Hepatic stellate cells (HSCs) are one of the major interstitial cell types present in the liver tumor microenvironment, and can promote the proliferation, migration and invasion of PLC cells. It remains unknown whether NRP-1 can promote PLC progression by potentiating the activity of HSCs. In the present study, the expression of NRP-1, and its co-expression with platelet-derived growth factor receptor-beta, in HSCs was detected via immunofluorescence. LX2 HSCs were transfected with NRP-1 short hairpin RNA lentiviral vectors and their proliferation was observed. The proliferation, migration and invasion of HepG2 cells co-cultured with LX2 cells were also observed. Finally, LX2 and HepG2 cells were co-injected into nude mice as subcutaneous xenografts, and the tumor growth and alpha-smooth muscle actin expression levels were observed. NRP-1 knockdown attenuated LX2 cell activation, with concomitant downregulation of HepG2 cell proliferation, migration and invasion (P<0.05). Thus, silencing of NRP-1 expression may inhibit the activation of HSCs, as well as the proliferation, migration and invasion of PLC cells. The mechanism underlying the inhibition of PLC cell progression is possibly mediated by the inhibition of HSC activation, reduction of transforming growth factor beta1 levels in the conditioned medium and downregulation of extracellular signal related kinase activity in PLC cells. Thus, NRP-1 could be regarded as a potential gene therapy target for PLC. PMID- 29434932 TI - Quercetin reverses the doxorubicin resistance of prostate cancer cells by downregulating the expression of c-met. AB - Chemotherapy is an irreplaceable treatment for prostate cancer. However, the acquisition of chemoresistance is a common and critical problem that requires urgent solutions for the effective treatment of this disease. The aim of the present study was to determine whether the combination of quercetin with doxorubicin reversed the resistance of prostate cancer cells to doxorubicin-based therapy. A prostate cancer (PC)3 cell line (PC3/R) with acquired doxorubicin resistance was established. A significant drug-resistance to doxorubicin and high activation of the phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) pathway in PC3/R cells, compared with normal PC3 cells, was demonstrated. Notably, combination treatment of doxorubicin with quercetin significantly promoted the doxorubicin-induced apoptosis in PC3/R cells through the mitochondrial/reaction oxygen species pathway. In PC3/R cells, a significant upregulation of tyrosine protein kinase-met (c-met) was observed compared with nromal PC3 cells. However, the response to quercetin treatment in PC3/R cells inhibited c-met expression and the downstream PI3K/AKT pathway. In addition, induced expression of c-met rescued quercetin-promoted apoptosis in PC3/R cells treated with doxorubicin. The results of the present study indicated that quercetin is able to reverse prostate cancer cell doxorubicin resistance by downregulating the expression of c-met. It may represent a potential strategy for reversing the chemoresistance of prostate cancer. PMID- 29434933 TI - PD-L1 expression is associated with p16INK4A expression in non-oropharyngeal head and neck squamous cell carcinoma. AB - PD-L1 expression is critical in helping tumor cells evade the immune system. However, the level of PD-L1 expression in non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC) and its association with patient prognosis remains unclear. A retrospective clinicopathological analysis was performed on 106 patients with non-OPHNSCC diagnosed between 2007 and 2014. In the current study, tissue arrays from paraffin-embedded non-OPHNSCC samples obtained from patients were constructed, and PD-L1 and p16INK4A expression were determined using immunohistochemistry. Systemic inflammatory factors, including C-reactive protein, serum white blood cell, neutrophil, monocyte and lymphocyte counts were also analyzed. The current study demonstrated that PD-L1 was overexpressed in 32.1% (34/106) and p16INK4A in 20.8% (22/106) of patients. The expression of PD L1 was associated with p16INK4A expression (P<0.01) but was not associated with levels of systemic inflammatory factors. Tumor stage was determined to be a significant prognostic value (stage I/II vs. III/IV, P=0.03), however, PD-L1, p16INK4A or other clinicopathological factors were not. The current study identified an association between PD-L1 and p16INK4A expression in non-OPHNSCC. This may facilitate the development of anti-PD1/PDL1 therapies to treat patients with head and neck cancer. PMID- 29434934 TI - Effects of disodium cantharidinate on dendritic cells of patients with bladder carcinoma. AB - The present study explored the effects of disodium cantharidinate (DC) on the peripheral blood-derived dendritic cells of patients with bladder carcinoma. The peripheral blood mononuclear cells from the 15 cases of urinary bladder carcinoma of middle and advanced stage were separated, and dendritic cells were prepared. The morphological changes of dendritic cells were observed. Flow cytometry was used to detect the expression levels of CD1a and CD83 on dendritic cell surface. MTT assay was utilized to measure the proliferation ability of allogeneic lymphocyte stimulated by DC. Annexin V-FITC/propidium iodide (PI) double staining flow cytometry method was carried out to detect cell apoptosis after treatment with DC. The changes in caspase-3 and PARP expression levels were investigated by western blot method. The high-dose DC resulted in a significant increase in the expressions of dendritic cell phenotyptic molecules CDla and CD83 as compared to control group. In addition, the proliferation index of allogenic lymphocyte stimulated by DC was significantly higher than that of control group. Moreover, MTT assay showed significant inhibition of the growth of BIU-87 cells. After 24 h of DC treatment, double staining flow cytometry confirmed the ability of DC to induce cell apoptosis. Further, western blot method showed a significant elevation of caspase-3 and PARP protein expression after DC treatment. In conclusion, DC treatment could induce dendritic cell maturation of patient with carcinoma of urinary bladder and promote its functional changes. Furthermore, DC was able to inhibit the proliferation of cell BIU-87 and also has the ability to induce cell apoptosis. PMID- 29434935 TI - Methylation of the L1 gene and integration of human papillomavirus 16 and 18 in cervical carcinoma and premalignant lesions. AB - High-risk human papillomavirus (HPV) is the primary cause of cervical carcinoma (CC). Viral integration into the host chromosomes is associated with neoplastic progression, and epigenetic changes may occur as a result. The objective of the present study was to analyze HPV L1 gene methylation and to compare the use of quantitative polymerase chain reaction (qPCR), in situ hybridization (ISH) and L1 methylation analysis as methods for detecting HPV integration. Cervical scrapes or biopsy samples positive for HPV 16 or 18, from 187 female patients with CC, squamous intraepithelial lesions (SILs) or no intraepithelial lesion (non-IL) were analyzed. Methylation of the L1 gene was determined using bisulfite modification followed by PCR, and HPV integration was subsequently analyzed. HPV 16 L1 gene methylation was revealed to increase with histological grade, with statistically significant differences observed as follows: Low-grade SIL vs. CC, P<0.0001 and non-IL vs. CC, P<0.0001. HPV 18 L1 gene methylation also increased according to histological grade, however, no statistically significant differences were observed. Methylation at CpG site 5608 of the HPV 16 L1 gene was associated with all grades of cervical lesions, whereas methylation at CpG site 5617 demonstrated the strongest association with CC (odds ratio, 42.5; 95% confidence interval, 4.7-1861; P<0.0001). The concordance rates between the various methods for the detection of the physical status of HPV 16 and HPV 18 were 96.1% for qPCR and ISH, 76.7% for qPCR and L1 gene methylation, and 84.8% for ISH and L1 gene methylation. In conclusion, methylation of the HPV 16 L1 gene increases significantly according to the grade of the cervical lesion, and methylation at CpG sites 5608 and 5617 of this gene may be used as prognostic biomarkers. ISH and L1 gene methylation have good concordance with qPCR with regards to the detection of HPV integration. Therefore, these are useful methods in determining the physical state of HPV. PMID- 29434936 TI - beta-catenin, leucine-rich repeat-containing G protein-coupled receptor 5 and GATA-binding factor 6 are associated with the normal mucosa-adenoma adenocarcinoma sequence of colorectal tumorigenesis. AB - In the present study, the expression of beta-catenin, leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) and GATA6 was investigated during the transition from normal mucosa through to adenoma and adenocarcinoma in colorectal tissue sections obtained from 65 patients with a pathological diagnosis of colorectal adenocarcinoma and a history of adenoma. Immunohistochemical staining of beta-catenin, LGR5 and GATA6 was performed and evaluated. The nuclear expression of beta-catenin and the cytoplasmic expression of LGR5 and GATA6 were increased in samples as they progressed from normal mucosa to adenoma and adenocarcinoma. However, membrane-bound beta-catenin and nuclear GATA6 expression decreased. Positive correlations were observed between the expression of LGR5 and cytoplasmic GATA6 in adenoma (P=0.0005; rs=0.48) and adenocarcinoma samples (P=0.007; rs=0.38): However, no significant association was observed in normal mucosa (P=0.399). The expression of nuclear beta-catenin was significantly increased in the serosal layer compared with the invasive layers of the colorectal wall in samples of adenocarcinoma (P=0.042). The results of the present study suggest that the nuclear expression of beta-catenin and LGR5 and the cytoplasmic expression of GATA6 function together during the development of colorectal carcinoma. PMID- 29434937 TI - Prognostic value and functional role of ROCK2 in pediatric Ewing sarcoma. AB - Ewing's sarcoma (EWS) is a highly aggressive bone cancer that affects children and adolescents. Despite advances in multimodal management, 5-year event-free survival rates for patients presenting with metastases at diagnosis remain at 25%. As key regulators of actin organization, the Rho-associated coiled-coil containing protein kinases, ROCK1 and ROCK2, have been associated with cancer dissemination and poorer prognosis. Recently, in vitro data indicating ROCK2 as a molecular target for the treatment of EWS has been presented. Nonetheless, a deeper exploration of the contribution of this kinase dysregulation in EWS is still necessary. In this regard, the present study aimed to evaluate the expression of ROCK1 and ROCK2 in 23 pediatric tumor samples and to verify the prospect of using their pharmacological inhibition through functional assays. Our results showed positive immunostaining for ROCK1 and ROCK2 in the majority samples (75 and 65%, respectively). A significantly increased risk of incomplete remission in patients with positive immunostaining for ROCK2 was found (P=0.026), though no correlations with other prognostic features (huvos classification, FLI1/EWS status, relapse, metastasis or death) were observed. Associations with survival were merely suggestive. Apparent protein expression of both kinases was also found in EWS cell lines (SK-ES-1 and RD-ES). Treatments with selective ROCK inhibitors did not alter cell viability or migration in vitro. However, a significant increase in invasion was observed after treatment with SR3677 (ROCK2 inhibitor) and hydroxyfasudil (pan-inhibitor). Consequently, even though the majority of EWS samples included in our study showed positivity for ROCK1 and ROCK2, the lack of significant associations with prognosis and absence of appropriate responses to their inhibition in vitro does not support their prospective use as therapeutic targets for the treatment of this metastatic tumor. Larger cohort studies might provide more evidence on whether there is a specific role of ROCK kinases in EWS physiopathology. PMID- 29434938 TI - Genetic characterization and in vitro activity of antimicrobial combinations of multidrug-resistant Acinetobacter baumannii from a general hospital in China. AB - The present study aimed to develop a rational therapy based on the genetic epidemiology, molecular mechanism evaluation and in vitro antibiotic combinations activity in multidrug-resistant Acinetobacter baumannii (MDRAB). MDRAB was screened by the Kirby-Bauer method. The random amplified polymorphic DNA technique was used to establish genetic fingerprinting, and a series of resistance genes were detected by polymerase chain reaction. Antimicrobial agents including amikacin (AK), cefoperazone/sulbactam (SCF I/II), meropenem (MEM), minocycline (MINO) and ciprofloxacin (CIP) were used to determine the minimum inhibitory concentrations (MICs) and interactions between antibiotics by the broth microdilution method and chequerboard assays. In total, 34 MDRAB strains were isolated and classified into 8 phenotypes A-H, according to their general drug susceptibilities. A total of 4 major genotypes (I-IV) were clustered at 60% a genotypic similarity threshold. High positive rates of beta-lactamase TEM-1, topoisomerase IV, oxacillinase (OXA)-23, AdeB family multidrug efflux RND transporter adeB, beta-lactamase AmpC, class 1 integrons (Int-1), 16S rRNA methylase rmtA, phosphotransferase aph(3), 16S rRNA methyltransferase armA were presented to exceed 90%, acetylyltransferase aac(3)-I, aac(6'-I, ant(3")-I, 16S rRNA methylase rmtB, oxacillinase OXA-24 and metallo-beta-lactamase IMP-5 genes demonstrated positive rates of 29.4-85.29%, while adeRS two-component system was not observed in any strain. MEM+SCF I or SCF II primarily exhibited synergistic effects. AK+SCF I, AK+SCF II, MINO+SCF I, MINO+SCF II, MINO+CIP and MINO+MEM primarily presented additive effects. AK+CIP demonstrated 70.59% antagonism. The antibacterial activity of SCF I was superior compared with that of SCF II. The results indicated the polyclonal genetic epidemiological trend of MDRAB in the Second Xiangya Hospital, and verified the complexity of genetic resistance. In addition, combinations suggested to be efficacious were MEM+SCF I and MEM+SCF II, which were more effective compared with other combinations for the management of MDRAB infection. PMID- 29434939 TI - Identification of metabolism-associated genes and pathways involved in different stages of clear cell renal cell carcinoma. AB - The lack of early diagnostic markers and novel therapeutic targets for clear cell renal cell carcinoma (ccRCC) negatively affects patient prognosis. Cancer metabolism is an attractive area for the understanding of the molecular mechanism of carcinogenesis. The present study attempted to identify metabolic changes from the view of the expression of metabolism-associated genes between control samples and those of ccRCC at different disease stages. Data concerning ccRCC gene expression obtained by RNA-sequencing was obtained from The Cancer Genome Atlas and data on metabolism-associated genes were extracted using the Recon2 model. Following analysis of differential gene expression, multiple differentially expressed metabolic genes at each tumor-node-metastasis disease stage were identified, compared with control non-disease samples: Metabolic genes (305) were differentially expressed in stage I disease, 323 in stage II disease, 355 in stage III disease and 363 in stage IV disease. Following enrichment analysis for differential metabolic genes, 22 metabolic pathways were identified to be dysregulated in multiple stages of ccRCC. Abnormalities in hormone, vitamin, glucose and lipid metabolism were present in the early stages of the disease, with dysregulation to reactive oxygen species detoxification and amino acid metabolism pathways occurring with advanced disease stages, particularly to valine, leucine, and isoleucine metabolism, which was substantially dysregulated in stage IV disease. The xenobiotic metabolism pathway, associated with multiple cytochrome P450 family genes, was dysregulated in each stage of the disease. This pathway is worthy of substantial attention since it may aid understanding of drug resistance in ccRCC. The results of the present study offer information to aid further research into early diagnostic biomarkers and therapeutic targets of ccRCC. PMID- 29434940 TI - A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines. AB - The present study investigated the anticancer functions of ursolic acid (UA) and its novel derivatives, with a nitrogen-containing heterocyclic scaffold and the privileged fragment at the C-28 position on apoptosis induction, cell proliferation and cell cycle in human BC lines. UA was chemically modified in the present study to increase its antitumor activity and bioavailability. A novel UA derivative, FZU3010, was synthesized using a nitrogen-containing heterocyclic scaffold and a privileged fragment at the C-28 position. Sulforhodimine B assays were used to measure the effect of UA and different concentrations of FZU3010 on the viability of breast cancer (BC) SUM149PT and HCC1937 cells. FZU3010 significantly repressed the proliferation of the two cancer cell lines in a dose dependent manner, with a half-maximal inhibitory concentration of 4-6 uM, and exhibited decreased cytotoxicity compared with vehicle-treated cell lines. The effect of FZU3010 on cell cycle distribution and cellular apoptosis was also investigated. The results of this investigation indicated that FZU3010 significantly increased the number of SUM149PT and breast cancer HCC1937 cells in the G0/G1 phase in a dose-dependent manner. Additionally, at a concentration of 5 uM, the capability of FZU3010 to induce BC apoptosis was significantly higher than the capability of UA. Thus, the results of the current study indicated that FZU3010 induced apoptosis in BC cells, together with induction of cell cycle arrest at the S and G0/G1 phase. FZU3010 may therefore be considered as a potential therapeutic agent for the treatment of BC. PMID- 29434941 TI - Paclitaxel-induced hypothermia and hypoperfusion increase breast cancer metastasis and angiogenesis in mice. AB - Housing temperature has been shown to influence thermoregulation and behavior of preclinical cancer models; and anti-cancer drugs typically reduce peripheral blood flow and body temperature. In the present study, the effects of paclitaxel (PTX)-induced reduction of body temperature and peripheral blood flow on metastatic 4T1 breast cancer was investigated in a mouse model and the modification of these effects by thermoneutral temperature was also assessed. A single dose of PTX decreased the body temperature and peripheral blood flow in mice housed at a standard temperature (23 degrees C). Furthermore, although lung metastasis and angiogenesis of inoculated 4T1 cells increased in mice pretreated with PTX, mice housed at a thermoneutral temperature (30 degrees C) could compensate their body temperature and peripheral blood flow compared with control mice, and also suppressed 4T1 angiogenesis and metastasis to lung. The present results imply that maintenance of body temperature or efficient energy supply for thermogenesis may prevent tumor relapse or metastasis after chemotherapy. PMID- 29434942 TI - Tumor angiogenesis as an important prognostic factor in advanced non-small cell lung cancer (Stage IIIA). AB - The aim of the present study was to evaluate angiogenesis by determining the micro vascular density (MVD) and the expression of vascular endothelial growth factor (VEGF-A) in advanced non-small cell lung cancer (NSCLC) tumor samples, and to analyze their associations with clinical parameters and survival. Tumor tissue specimens of fifty patients (41 males and 9 females), who underwent radical surgical treatment for NSCLC in stage IIIA (T1-3N2) were collected for immunohistochemical analysis. MVD evaluation was performed using an anti-CD31 monoclonal antibody and VEGF-A expression using a polyclonal anti-VEGF-A antibody. The results were associated with two-year survival. Statistical analysis revealed significant associations in the level of angiogenesis (high MVD) and shorter survival of patients with NSCLC (P=0.0007). VEGF-A expression showed no association with micro vascular density (P=0.51) or survival (P=0.68). There was no significant association between MVD and VEGF-A. The measurable, clinical MVD parameters could be used as a reliable prognostic factor for the survival of patients with advanced NSCLC. PMID- 29434943 TI - Mechanism of anticancer action of novel berenil complex of platinum(II) combined with anti-MUC1 in MCF-7 breast cancer cells. AB - Mucin 1 (MUC1) is a high molecular weight transmembrane glycoprotein, that is overexpressed in >90% of breast cancers. It serves a crucial role in anti apoptosis and tumor progression. MUC1 interacts with proteins in the extracellular matrix, at the cell membrane, in the cytoplasm and in the nucleus. The aim of the present study was to investigate the mechanism of anticancer action induced by novel berenil complex of platinum(II) (Pt12) together with a monoclonal antibody against MUC1 in breast cancer MCF-7 cells. The effect of combined treatment on the concentration of selected markers of apoptosis including proapoptotic B-cell lymphoma 2 associated X protein (Bax), caspase-8, cytochrome c and caspase-9, as well as selected proteins involved in intracellular signal transduction pathways including p53, phosphoinositide 3 kinase and phosphorylated protein kinase B (p-Akt) were analyzed. The results of the present study demonstrated that combined treatment may be a promising strategy in anticancer treatment and represents an alternative to monotherapy. All compounds used alone (Pt12, cisplatin and the anti-MUC1 antibody) increased the concentration of proapoptotic Bax, cytochrome c and caspase-9 in comparison with control, thus suggesting that they activated the mitochondrial apoptotic pathway. Pt12 alone significantly increased the concentration of caspase-8, which is responsible for the initiation of the extrinsic apoptotic pathway. However, the strongest effect was observed following Pt12 (20 uM) treatment combined with the anti-MUC1 antibody (10 ug/ml). These two compounds together strongly induced apoptosis in MCF-7 breast cancer cells via the external and internal apoptotic pathways. It was also demonstrated that combined treatment based on Pt12 and the anti-MUC1 antibody significantly reduced p-Akt concentration. PMID- 29434945 TI - Peroxiredoxin 1 expression in active ulcerative colitis mucosa identified by proteome analysis and involvement of thioredoxin based on immunohistochemistry. AB - Ulcerative colitis (UC) is a chronic, relapsing, inflammatory bowel disease, and patients with long-standing UC are at high risk of developing colorectal cancer as a typical case of the organ-specific chronic inflammation-carcinoma sequence. Interactions between epithelial and stromal cells and alterations in a variety of stromal microenvironments have been demonstrated to have important roles in the carcinogenesis of UC-associated carcinoma. Therefore, the identification of proteins in the inflammatory microenvironment is important not only in the epithelium, however also in the stroma of UC inflammatory foci. To identify proteins associated with UC-associated carcinoma, the present study used proteomic analysis with two-dimensional electrophoresis and mass spectrometry. Differentially expressed proteins were assessed between active and inactive UC biopsy specimens. Results were verified by immunohistochemistry. Peroxiredoxin 1 (PRDX1) was among the proteins identified to have increased expression in active compared with inactive UC. Immunohistochemical analysis indicated that the expression of both PRDX1 and thioredoxin (TRX) increased with increasing inflammation grade in epithelial cells in UC mucosal crypts. PRDX1-positive stromal cells in the lower half of the lamina propria increased along with colitis severity. Furthermore, the expression of both PRDX1 and TRX proteins was increased in UC-associated neoplastic lesions compared with normal mucosa. A stepwise increase in PRDX1 expression was clear with increasing tumor progression in UC-associated tumorigenesis. Since PRDX1 and TRX overexpression was a unique characteristic of UC activity and UC-associated neoplastic lesions, PRDX1 and TRX expression may reflect oxidative stress along with the severity of colitis activity and UC-associated tumorigenesis in patients with UC. PMID- 29434944 TI - MicroRNA-196a-5p is a potential prognostic marker of delayed lymph node metastasis in early-stage tongue squamous cell carcinoma. AB - MicroRNAs (miRs) are expected to serve as prognostic tools for cancer. However, many miRs have been reported as prognostic markers of recurrence or metastasis in oral squamous cell carcinoma patients. We aimed to determine the prognostic markers in early-stage tongue squamous cell carcinoma (TSCC). Based on previous studies, we hypothesized that miR-10a, 10b, 196a-5p, 196a-3p, and 196b were prognostic markers and we retrospectively performed miR expression analyses using formalin-fixed paraffin-embedded sections of surgical specimens. Total RNA was isolated from cancer tissues and adjacent normal tissue as control, and samples were collected by laser-capture microdissection. After cDNA synthesis, reverse transcription-quantitative polymerase chain reaction was performed. Statistical analyses for patient clinicopathological characteristics, recurrence/metastasis, and survival rates were performed to discern their relationships with miR expression levels, and the 2-DeltaDeltaCq method was used. miR-196a-5p levels were significantly upregulated in early-stage TSCC, particularly in the lymph node metastasis (LNM) group. The LNM-free survival rate in the low miR-196a-5p DeltaDeltaCq value regulation group was found to be lower than that in the high DeltaDeltaCq value regulation group (P=0.0079). Receiver operating characteristic analysis of DeltaDeltaCq values revealed that miR-196a-5p had a P-value=0.0025, area under the curve=0.740, and a cut-off value=-0.875 for distinguishing LNM. To our knowledge, this is the first study to examine LNM-related miRs in early-stage TSCC as well as miRs and 'delayed LNM' in head and neck cancer. miR-196a-5p upregulation may predict delayed LNM. Our data serve as a foundation for future studies to evaluate miR levels and facilitate the prediction of delayed LNM during early-stage TSCC, which prevent metastasis when combined with close follow up and aggressive adjuvant therapy or elective neck dissection. Moreover, our data will serve as a foundation for future studies to evaluate whether miR-196a 5p can serve as a therapeutic marker for preventing metastasis. PMID- 29434946 TI - Effects of 16-bit CT imaging scanning conditions for metal implants on radiotherapy dose distribution. AB - Dose distribution was calculated and analyzed on the basis of 16-bit computed tomography (CT) images in order to investigate the effect of scanning conditions on CT for metal implants. Stainless steel and titanium rods were inserted into a phantom, and CT images were obtained by scanning the phantom under various scanning conditions: i) Fixed tube current of 230 mA and tube voltages of 100, 120, and 140 kV; and ii) fixed tube voltage of 120 kV and tube currents of 180, 230, and 280 mA. The CT value of the metal rod was examined and corrected. In a Varian treatment planning system, a treatment plan was designed on the basis of the CT images obtained under the set scanning conditions. The dose distributions in the phantom were then calculated and compared. The CT value of the metal area slightly changed upon tube current alteration. The dose distribution in the phantom was also similar. The maximum CT values of the stainless steel rod were 14,568, 14,127 and 13,295 HU when the tube voltages were modified to 100, 120, and 140 kV, respectively. The corresponding CT values of the titanium rod were 9,420, 8,140 and 7,310 HU. The dose distribution of the radiotherapy plan changed significantly as the tube voltage varied. Compared with the reference dose, the respective maximum dose differences of the stainless steel and titanium rods in the phantom were 5.70, and 6.62% when the tube voltage varied. The changes in tube currents resulted in a maximum dose error of <1% for stainless steel and titanium. In CT imaging, changes in tube voltages can significantly alter the CT values of metal implants. Thus, this can lead to large errors in radiotherapy dose distributions. PMID- 29434947 TI - Association between inflammation and cancer stem cell phenotype in breast cancer. AB - Inflammation and cancer stem cells (CSCs) are becoming increasingly recognized as components of tumorigenesis in breast cancer. In the present study, the association between inflammation and BCSC phenotype was evaluated in human breast cancer tissue. Immunohistochemical staining for cluster of differentiation (CD)24, 44, 4, 8 and 68 was performed using tissue microarray blocks containing 47 consecutive cases of invasive breast carcinoma and 10 normal breast tissue samples. The levels of inflammatory modulators and cytokines, and intratumoral or peritumoral lymphocyte infiltration, were assessed. BCSCs were defined as CD44+/CD24- tumor cells. In total, 21.3% of samples exhibited the CD44+/CD24- phenotype. This phenotype was identified to be significantly inversely associated with lymph node metastasis. In addition, the CD44+/CD24- phenotype was significantly associated with the molecular subtype of breast cancer, and was particularly increased in the basal-like subtype. Furthermore, the CD44+/CD24- phenotype was significantly associated with intratumoral inflammation and tumor infiltrating CD4+ T cell counts. Notably, tumor-infiltrating CD4+ T cells were significantly increased in patients with the basal-like molecular subtype of breast cancer. In conclusion, the present study identified a significant association between inflammation and the CD44+/CD24- phenotype in breast cancer. These results suggest that the interaction between inflammation and CSCs may affect the tumorigenesis and progression of breast cancer. Further studies are required to clarify the role of inflammation and CSCs in breast cancer. PMID- 29434948 TI - Granulocyte-colony stimulating factor producing mucinous cystic neoplasm with an associated invasive carcinoma of the pancreas. AB - The present case study documents an autopsy case of granulocyte-colony stimulating factor (G-CSF)-producing mucinous cystic neoplasm (MCN), with an associated invasive carcinoma of the pancreas. A 65-year-old woman presented to Omuta City Hospital (Omuta Japan) with a primary complaint of abdominal pain. Multiple liver nodules and a pancreatic cyst were detected upon abdominal computed tomography. Initially, liver abscess was suspected as the patient exhibited leukocytosis and elevated C-reactive protein level. However, the serum concentration of G-CSF was 98.8 pg/ml (normal, <39.0 pg/ml). At 6 weeks after admission, the patient succumbed to liver failure. At autopsy, a cystic lesion was identified in the pancreatic tail that contained bloody necrotic fluid. Microscopically, the cystic lesion was composed of columnar and mucin-producing epithelium associated with ovarian-type subepithelial stroma. The stroma exhibited positive immunostaining for vimentin, estrogen receptor and progesterone receptor. Calcification on the cystic wall was observed. The tumor invaded the pancreatic parenchyma and metastasized to the liver and lungs. The lesion was diagnosed as invasive adenocarcinoma arising in MCN. By contrast, liver nodules predominantly consisted of pleomorphic cancer cells with small foci of adenocarcinoma. Pancreatic and hepatic cancer cells were confirmed to be positive for G-CSF staining. The present case report indicates that G-CSF producing MCNs may be associated with an aggressive clinical course, particularly when anaplastic changes are observed. PMID- 29434949 TI - Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of beta-lapachone in melanoma cell lines. AB - NAD(P)H quinone oxidoreductase 1 (NQO1)-dependent antitumor drugs such as beta lapachone (beta-lap) are attractive candidates for cancer chemotherapy because several tumors exhibit higher expression of NQO1 than adjacent tissues. Although the association between NQO1 and beta-lap has been elucidated, the effects of a NQO1-inducer and beta-lap used in combination remain to be clarified. It has previously been reported that melanoma cell lines have detectable levels of NQO1 expression and are sensitive to NQO1-dependent drugs such as 17-allylamino-17 demethoxygeldanamycin. The present study was conducted to investigate the involvement of NQO1 in beta-lap-mediated toxicity and the utility of combination treatment with a NQO1-inducer and beta-lap in malignant melanoma cell lines. Decreased expression or inhibition of NQO1 caused these cell lines to become less sensitive to beta-lap, indicating a requirement of NQO1 activity for beta-lap mediated toxicity. Of note was that carnosic acid (CA), a compound extracted from rosemary, was able to induce further expression of NQO1 through NF-E2 related factor 2 (NRF2) stabilization, thus significantly enhancing the cytotoxicity of beta-lap in all of the melanoma cell lines tested. Taken together, the data presented in the current study indicated that the NRF2-NQO1 axis may have potential value as a therapeutic target in malignant melanoma to improve the rate of clinical response to NQO1-dependent antitumor drugs. PMID- 29434950 TI - Decreased expression of CADM1 and CADM4 are associated with advanced stage breast cancer. AB - Cell adhesion molecule (CADM) genes encode immunoglobulin superfamily molecules, which are involved in cell-cell adhesion in a number of human epithelia. Through the maintenance of epithelia, CADM genes protect against malignant conversion and metastasis. Whilst numerous in vitro studies have investigated the molecular characteristics of CADM1 and CADM4 and in vivo studies have investigated CADM1 and CADM4 expression in a number of tumor types, the roles of CADM1 and CADM4 have yet to be elucidated. Therefore, in the present study, CADM1 and CADM4 expression levels were evaluated using immunohistochemistry staining in 208 patients with breast cancer and compared with clinicopathological factors. CADM1 and CADM4 expression levels were negative in 160 (76.9%) and 166 (79.8%) of the 208 cases, respectively. The lack of expression in these cases was associated with advanced tumor stage, suggesting that inactivation of CADM1 and CADM4 promotes breast cancer development. The prognostic role of CADM1 and CADM4 in breast cancer was also evaluated and the expression of CADM1 and CADM4 were not associated with cancer-specific survival or overall survival rate in the cohort of patients in the present study. Whilst these results suggested that CADM1 and CADM4 possess tumor suppressive roles, further functional experiments are required to address the important mechanisms involving CADM1 and CADM4. PMID- 29434951 TI - A retrospective study of 34 patients with unicentric and multicentric Castleman's disease: Experience from a single institution. AB - The aim of the present study was to share the experience of a single institute in the diagnosis, use of accessory examinations and treatment strategies of Castleman's disease (CD). The present study analyzed 34 patients (13 males and 21 females) with CD who were hospitalized between January 2006 and September 2014. The patients were divided into two groups based on the anatomical distribution of the disease: Unicentric CD (UCD) and multicentric CD (MCD). Histological data was obtained from lymph node biopsies. All clinical data were acquired by reviewing patients' medical records and contacting patients by telephone. A total of 27 patients had UCD and 7 patients had MCD. All 27 patients with UCD with benign symptoms underwent complete diagnostic surgical resection and survived, with the exception of 1 patient who succumbed to pancreatic head carcinoma 13 months after surgery. A total of 7 patients with MCD presented with systemic symptoms and 2 of these patients declined treatment following the definite diagnosis of CD. The remaining 5 patients were treated with various strategies, including surgical resection and further glucocorticoid treatment, intravenous siltuximab, rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy or hematopoietic stem cell transplantation. A total of 3 patients with MCD survived, with a median follow-up period of 69 months. The present study indicates that complete surgical resection is currently the standard treatment for UCD. Perioperative use of multidetector computed tomography and the laparoscopic approach have certain advantages in UCD. Molecular target therapy is effective in patients with stable MCD, and hematopoietic stem cell transplantation may be beneficial in certain patients with MCD and disease progression. PMID- 29434952 TI - Melanocyte-specific gene 1 promotes melanoma progression by enhancing the expression of Bcl-2. AB - Malignant melanoma is a class of highly malignant tumors derived from melanocytes. At present, the dysregulated gene expression involved in the progression of melanoma has attracted much attention. In the present study, the gene expression profile of human melanoma tissue was screened using a cDNA microarray, and it was identified that melanocyte-specific gene 1 (MSG1) was significantly overexpressed in melanoma tissue compared with paired nevus tissues. The overexpression of MSG1 in melanoma was subsequently confirmed using immunohistochemistry in a set of melanoma tissues. It was additionally identified that the overexpression of MSG1 may promote cell viability and inhibit cell apoptosis in human melanoma A375 cells, thus promoting melanoma progression. Mechanistically, following screening of the expression of apoptosis-associated proteins, MSG1 was demonstrated to enhance the expression of the apoptosis inhibitor B-cell lymphoma 2 (Bcl-2) to inhibit melanoma cell apoptosis. Therefore, it was concluded that the overexpression of MSG1 inhibits apoptosis by enhancing Bcl-2 expression in malignant melanoma, thus promoting melanoma progression. PMID- 29434953 TI - Molecular screening and the clinical impacts of BCR-ABL KD mutations in patients with imatinib-resistant chronic myeloid leukemia. AB - The present study aimed to detect the frequency of kinase domain (KD) mutations in order to evaluate their clinical significance and functional importance in 45 patients with chronic myeloid leukemia (CML) who were resistant to imatinib therapy. Sanger sequencing was used (45 patients), along with allele-specific oligonucleotide polymerase chain reaction (ASO-PCR; 3 patients), for the screening of mutations. BCR/ABL KD was amplified by nested PCR and sequencing was performed. Secondly, ASO-PCR was performed to confirm the results of the sequence analysis for E255K mutations. Mutations were detected in 11/45 patients (24.44%) via Sanger sequencing. D241G (4.4%), C369C (4.4%), K285N (2.2%), A380T (2.2%) and A366V (2.2%) mutations were detected. E255K (8.8%) was detected by ASO-PCR and Sanger sequencing. Mutations are a primary reason for suboptimal responses, loss of response and resistance to imatinib. In particular, the E255K mutation, which is characterized by resistance to imatinib and nilotinib, was detected in four patients. Analyzing the mutations and monitoring patients with CML may improve their prognosis and survival rate. ASO-PCR assays will be beneficial for the routine monitoring of mutations. PMID- 29434954 TI - A novel function of NUCB2 in promoting the development and invasion of renal cell carcinoma. AB - Previous studies have assessed nucleobindin 2 (NUCB2) expression in multiple urological cancer cell lines and detected its effect on renal cancer cell apoptosis. Additionally, certain reports have indicated a novel function of NUCB2 in promoting invasion in renal cancer. The levels of NUCB2 expression in different tumor cell lines were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Human NUCB2 and beta-actin (ACTB) cDNA plasmids were inserted into lentivirus plasmids, which were then transfected into 786-O cells. Western blotting and RT-qPCR were then performed to determine the gene expression in NUCB2-knocked down cells. Apoptosis was also examined by flow cytometry subsequent to successful transfection. Finally, a transwell invasion assay was performed to investigate the effects on invasive abilities in renal cancer cells. The RT-qPCR results demonstrated a high expression of NUCB2 in 786 O, ACHN and LNCaP cells, and there was particularly high expression in renal cancer 786-O cells. Following successful transfection, downregulation of NUCB2 facilitated renal carcinoma cell apoptosis, as demonstrated by an increased apoptosis rate in the lenti-NUCB2-KD 786-O cells (13.72+/-0.84 vs. 3.32+/-0.10; lenti-NUCB2-KD group vs. negative control). Notably, a significant decreased invasion rate was observed in the NUCB2 knocked-down cells compared with negative control, suggesting an invasion-promoting effect of NUCB2. These results suggested a novel function of NUCB2 in the process of development and invasion in renal cell carcinoma. NUCB2 may be an important prognostic factor and target in the diagnosis and treatment of human renal cancer. PMID- 29434955 TI - Association between lysyl oxidase and fibrotic focus in relation with inflammation in breast cancer. AB - We hypothesized that lysyl oxidase (LOX) contributes to the formation of fibrotic focus (FF) in association with inflammation and serves a significant role in breast carcinogenesis. In the present study, the association between the expression of LOX family members and FF with regards to with inflammation was analyzed, and the prognostic significance of LOX and FF in breast cancer was investigated. Immunohistochemical staining for LOX, LOX-like protein (LOXL) 1, LOXL2 and LOXL3 was performed in primary breast cancer tissues. The status of FF within the tumor was assessed, including size and grade. Levels of inflammatory markers, intratumoral and peritumoral lymphocyte infiltration were also evaluated. The clinicopathological characteristics were evaluated from the medical records of patients. In the present study, the expression of LOX family members was not associated with the presence of FF. FF was identified to be associated with intratumoral and peritumoral inflammation, tumor stage, larger tumor size, lymph node metastasis, high histologic grade, and p53 expression. LOX and LOXL3 were associated with intratumoral, and peritumoral inflammation. Furthermore, LOXL1 was associated with intratumoral inflammation and interleukin 4. In addition, LOX was associated with cluster of differentiation 8+ T cells. LOXL3 was associated with expression of ER and PR, and molecular subtype. In the survival analysis, overall survival time was statistically significantly longer in the FF-negative compared with that in the FF-positive group. In conclusion, it was demonstrated that FF and the expression of LOX family members were associated with inflammation in breast cancer. FF was associated with poor prognostic markers of breast cancer. Further studies are required to clarify the mechanisms underlying the association between the LOX family, FF and inflammation in breast cancer. PMID- 29434956 TI - Dynamics of CRISPR/Cas9-mediated genomic editing of the AXL locus in hepatocellular carcinoma cells. AB - Genomic editing using the CRISPR/Cas9 technology allows selective interference with gene expression. With this method, a multitude of haploid and diploid cells from different organisms have been employed to successfully generate knockouts of genes coding for proteins or small RNAs. Yet, cancer cells exhibiting an aberrant ploidy are considered to be less accessible to CRISPR/Cas9-mediated genomic editing, as amplifications of the targeted gene locus could hamper its effectiveness. Here we examined the suitability of CRISPR/Cas9 to knockout the receptor tyrosine kinase Axl in the human hepatoma cell lines HLF and SNU449. The genomic editing events were validated in two single cell clones each from putative HLF and SNU449 knockout cells (HLF-Axl--1, HLF-Axl--2, SNU449-Axl--1, SNU449-Axl--2). Sequence analysis of respective AXL loci revealed one to six editing events in each individual Axl- clone. The majority of insertions and deletions in the AXL gene at exon 7/8 resulted in a frameshift and thus a premature stop in the coding region. However, one genomic editing event led to an insertion of two amino acids resulting in an altered protein sequence rather than in a frameshift in the AXL locus of the SNU449-Axl--1 cells. Notably, while no Axl protein expression could be detected by immunoblotting in all four cell clones, both expression of total Axl as well as release of soluble Axl into the supernatant was observed by ELISA in incompletely edited SNU449-Axl--1 cells. Importantly, a comparative genomic hybridization array revealed comparable genomic changes in Axl knockout cells as well as in cells expressing Cas9 nickase without guide RNAs in SNU449 and HLF cells, indicating vast alterations in genomic DNA triggered by nickase. Together, these data show that the dynamics of CRISPR/Cas9 may cause incomplete editing events in cancer cell lines, as gene copy numbers vary based on genomic heterogeneity. PMID- 29434958 TI - Anticancer effects of 10-hydroxycamptothecin induce apoptosis of human osteosarcoma through activating caspase-3, p53 and cytochrome c pathways. AB - In order to evaluate the anticancer effect of 10-hydroxycamptothecin (HCPT) in terms of inducing the apoptosis of human osteosarcoma cells, its apoptosis inducing molecular mechanisms were investigated. In the present study, the anticancer effects of HCPT were revealed to result in suppressed cell viability, increased cytotoxicity, the induction of apoptosis and an augmented apoptotic nucleolus of human osteosarcoma cells. MG-63 cells were cultured with HCPT (0, 20, 40 and 80 nM) for 24 and 48 h. An MTT assay and a lactate dehydrogenase assay were used to analyze the anticancer effect of HCPT on cell viability and cytotoxicity in MG-63 cells. MG-63 cell apoptosis, and caspase-9 and caspase-3 activity levels were evaluated using flow cytometry and an ELISA. Western blot analysis was used to detect the protein expression levels of p53, poly (ADP ribose) polymerase-1 (PARP-1), cytochrome c and B cell lymphoma-2 (Bcl-2) in MG 63 cells. The anticancer effects of HCPT were demonstrated to significantly activate the protein expression of p53, PARP-1 and cytochrome c, and suppress Bcl 2 protein expression and promote the activity of caspase-9 and caspase-3 in human osteosarcoma cells. In conclusion, the anticancer effects of HCPT appear to induce the apoptosis of human osteosarcoma cells through the activation of the caspase-3, p53 and cytochrome c pathways. PMID- 29434957 TI - Experience-based surgical approach to pancreatic mucinous cystic neoplasms with ovarian-type stroma. AB - The present study aimed to elucidate the clinicopathological characteristics of resected mucinous cystic neoplasm (MCN) with ovarian-type stroma and identify a surgical approach for MCN treatment, on the basis of Republic of Korean (Yonsei University College of Medicine, Seoul, South Korea) and Japanese (Nippon Medical School, Tokyo, Japan) bi-institutional collaboration. The present study retrospectively reviewed 55 MCNs with ovarian-type stroma using pathological re examination. Clinicopathological features and preoperative clinical parameters were evaluated to predict malignant alterations in MCNs. The proportion of surgically treated MCNs has recently been increasing. All patients included in the present study were female, with a mean age of 47.9+/-13.3 years. Mural nodules were noted in 8 patients (14.5%) and the mean cyst size was 6.1+/-4.2 cm. A total of 9 patients (16.4%) were identified to exhibit non-invasive mucinous cystadenocarcinoma. The number of patients with small tumors (R2=-0.079, P=0.038) and asymptomatic pancreatic MCNs (P=0.022) was significantly increased (P<0.05), which resulted in the more frequent application of minimally invasive surgery (P<0.001). During the follow-up period (mean, 51.6 months; range, 1.1-242.8 months), no recurrence or tumor-associated mortality was identified. The presence of mural nodules (P=0.002) and a tumor size >=4.5 cm (P=0.027) were identified as potential clinical parameters for predicting malignant transformation. The significance of mural nodules in predicting malignant transformation was increased in large MCNs (>=4.5 cm) of the pancreas compared with small MCNs (<4.5 cm) (P=0.002). Overall, non-invasive pancreatic MCNs are not aggressive, and minimally invasive pancreatectomy may be an effective approach for suitable patients. PMID- 29434959 TI - Retrospective observational cohort study on cosmetic outcome of using Ti-Ni memory alloy wire for intradermal suture following mastectomy in patients with breast cancer. AB - The method of suturing for incisions is crucial for the comprehensive treatment of clinical patients with breast cancer. Suturing is considered a major part of post-surgical recovery and may serve as a marker for evaluation of surgical outcome. The present study aimed to establish an effective means of suturing for patients who received modified radical surgery that helps to improve the cosmetic outcome of the incision. Enrolled patients were divided into an active and a control group. Ti-Ni memory alloy wire for intradermal suture in the active group and silk for interruption suture in the control group were applied to assess the different prognosis-associated factors. The Vancouver Scar Scale (VSS) was used to evaluate the wound size and the recovery time of the scars. The association between diabetes and the number of days of wound healing was also analyzed. The results indicated that the mean VSS score of the active group was decreased compared with that of the control group (P<0.001). The VSS scores of four main features (vascularity, pigmentation, pliability and height) between the two groups also statistically differed (P<0.001). Furthermore, the mean number of days of wound healing was significantly decreased for the active group compared with that for the control group (P=0.0026) in the patients with diabetes. In addition, the usage of Ti-Ni memory alloy wire was able to decrease the mean number of wound healing days between patients with diabetes and their non diabetic counterparts (P=0.7009). The present study indicated that intradermal suture offers improved cosmetic outcome for patients undergoing mastectomy with or without axillary surgery. This technique may be useful for preventing scar overgrowth and for facilitating the recovery process in patients with diabetes. PMID- 29434960 TI - Targeting breast cancer cells with a CuInS2/ZnS quantum dot-labeled Ki-67 bioprobe. AB - The aim of the present study was to develop a water-soluble biomarker for the detection of breast cancer using quantum dots (QDs) conjugated to Ki-67, a nuclear protein associated with the cell cycle. Ki-67 is also a marker of cell proliferation, with expression levels categorizing good and poor prognosis in invasive breast cancer. Ki-67 is a clinically used biomarker for breast cancer diagnosis, treatment and prognosis. Owing to the optical and chemical advantages of QDs, QD-based nanotechnology may aid the construction of a biomedical imaging platform for the study of cancer cell behavior. In the present study, a biomarker was prepared by employing the water-soluble CuInS2/ZnS QDs conjugated to an anti Ki-67 monoclonal antibody to detect Ki-67 expression in breast cancer. The QDs, which were hydrophobic and coated with octadecylamine, were encapsulated with an amphiphilic biocompatible centipede-like polymer, and then conjugated to anti-Ki 67 monoclonal antibodies (QD-Ki-67 probes). The QD-Ki-67 probes retained the original optical properties of the unadorned QDs and did not exhibit distinct toxic side effects in in vitro cytotoxicity experiments. Therefore, this CuInS2/ZnS QD-labeled bioprobe, with a high quantum yield and low cytotoxicity, is a promising candidate for bioimaging and may be used as a cell label. PMID- 29434961 TI - Effect and molecular mechanism of mTOR inhibitor rapamycin on temozolomide induced autophagic death of U251 glioma cells. AB - Glioma is a malignant tumor of the glial tissue that is difficult to excise through surgery, with poor patient prognosis. The use of chemotherapeutic drugs alone to treat glioma following surgery results in a high probability of sequelae, such as tumor recurrence. The present study investigated the effects of a novel treatment combination on glioma cells and determined the molecular mechanisms underlying its action. The effect of temozolomide (TMZ) combined with rapamycin (RAPA) on the TMZ-induced autophagic death of U251 glioma cells was examined. The U251 cell line was treated with TMZ combined with RAPA, and the cell survival rate and half maximal inhibitory concentration (IC50) of TMZ/RAPA was detected using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was used to detect changes in cell cycle distribution. The formation of acidic vesicular organelles (AVOs) in the cytoplasm was identified using fluorescence microscopy and quantitatively analyzed. Western blotting was performed to detect the expression levels of autophagy-associated proteins Beclin-1 and microtubule associated protein 1 light chain 3 alpha (MAP1LC3A)-I and II. RAPA (1.25 nM) combined with 5 uM TMZ markedly inhibited U251 cell growth. RAPA reinforced TMZ induced autophagic death, reducing the IC50 value of treatment when combined (TMZ alone, 22.5+/-3.23 uM vs. TMZ and RAPA, 10.35+/-2.81 uM). Compared with the control group, the proportion of cells in G2/M were markedly increased following treatment with TMZ combined with RAPA. Acridine orange staining demonstrated that TMZ combined with RAPA could markedly enhance the generation of intracellular AVOs compared with TMZ or RAPA alone. In addition, Beclin-1 and LC3-II protein expression was markedly increased compared with the control and single treatment groups (P<0.05). The results of the present study indicate that RAPA reinforces TMZ-induced autophagic death of U251 glioma cells, providing a novel therapeutic combination for the treatment of malignant glioma. PMID- 29434962 TI - Electron microscopic analysis of different cell types in human pancreatic cancer spheres. AB - Cancer stem cells (CSCs), which are pluripotent and self-renewable, contribute to the initiation and metastasis of cancer, and are responsible for resistance to chemotherapy and radiation. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer that is associated with a high incidence of distant metastasis and recurrence. Sphere formation reveals cell proliferation under nonadherent conditions and is commonly used to identify CSCs; measurements of the number, area and volume of the spheres are used to estimate stemness of PDAC cells. However, detailed morphological analysis of such spheres has not been performed. The aim of the present study was to examine the morphology of spheres isolated from PANC-1 human pancreatic cancer cells via scanning electron microscopy (SEM) and transmission electron microscopy (TEM). PANC-1 cells formed round to irregular oblong spheres within 1 week following seeding in ultra-low attachment plates. These spheres exhibited higher levels of expression of CSC markers, including nestin, sex determining region Y-box 2, and CD44 containing variant exon 9, compared with adherent cells. SEM analysis revealed that the spheres exhibited a grape-like appearance, harboring cancer cells with smooth or rough surfaces. Similarly, TEM analysis detected cancer cells with varying surface types within the spheres: Those with smooth surfaces, irregular large protrusions, protrusions and a small number of microvilli, and those with many microvilli throughout the entire cell surface. These morphological differences among cancer cells may be indicative of different stages in the differentiation process, from CSCs to non-CSCs, within the spheres. PMID- 29434963 TI - A rare e14a3 BCR/ABL fusion transcript in acute lymphoblastic leukemia patient treated with CAR-modified T-cell therapy. AB - E14a3 breakpoint cluster region (BCR)/ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL) fusion transcript is rare in Philadelphia chromosome positive disease, particularly in acute lymphoblastic leukemia (ALL). Recently an e14a3 fusion transcript was detected by multiple laboratory examinations, and the patient was suffering from ALL. Except for the BCR/ABL fusion gene, in the present study the patient additionally had an IKAROS family zinc finger 1 deletion which, has been confirmed as a significant adverse prognosis factor. Following 2 rounds of chemotherapy, the patient presented cytological remission; however, the patient then relapsed 2 months later. They then received chimeric antigen receptor modified (CAR-modified) T-cell therapy and achieved complete remission. CAR-modified T-cell therapy is a powerful novel therapy which, exhibited great potential for treating refractory ALL, regardless of the existence and form of the BCR/ABL fusion transcript. PMID- 29434964 TI - Lymph node retrieval after dissolution of surrounding adipose tissue for pathological examination of colorectal cancer. AB - Examination of >12 lymph nodes (LNs) is important for the diagnostic accuracy of nodal status following resection of colorectal cancer. In the present study, the efficacy of a fat dissolution technique for LN retrieval was evaluated using resected colon and rectum mesentery. First, the resected mesentery was searched for LNs by inspection and palpation immediately after surgery. Subsequently, fat dissolution liquid was applied to the remnant fat and the LN search was repeated. The primary endpoint was whether the second assessment would increase the number of evaluated LNs. Recruitment of 20 patients was planned. The study was conducted after institutional review board approval and written informed consent was obtained. Among 20 participants, 1 patient was excluded because LN dissection was not performed. The median number of LNs identified at the first and second assessments was 13 and 6, respectively, producing a significant increase in total LNs evaluated (13 vs. 20, respectively; P<0.01; paired t-test). One positive node was identified among the additionally identified LNs (0.9%, 1/107). The second assessment increased the number of LNs assessed to >12 in 4 patients, and although staging was not changed, the treatment was potentially altered in 2 stage II patients. The maximum diameter of the additionally obtained LNs was significantly smaller compared with those from the first assessment (4 vs. 7.7 mm, respectively; P<0.01; Wilcoxon signed-rank test). After the fat dissolution technique, the tumor cells were satisfactorily stained by carcinoembryonic antigen and cytokeratin-20. In conclusion, applying fat dissolution liquid to the remnant adipose tissue of the mesentery of the colon and rectum identified additional LNs. This method should be considered when insufficient LNs are identified after conventional LN retrieval. PMID- 29434965 TI - Expression of CXC-motif-chemokine 12 and the receptor C-X-C receptor 4 in glioma and theeffect on peritumoral brain edema. AB - The present study aimed to evaluate the association between CXC-motif-chemokine 12 (CXCL12)/C-X-C receptor 4 (CXCR4) expression and peritumoral brain edema (PTBE) in glioma patients. Immunohistochemical techniques were used to detect the expression of CXCR4 and CXCL12 in 58 glioma tissues. Magnetic resonance imaging was used to evaluate the extent and type of brain edema in preoperative glioma patients. The association between edema and CXCL12/CXCR4 expression was examined by chi2 analysis. The prognostic significance of CXCL12 or CXCR4 was determined by log-rank tests and Cox's proportional hazards model. Expression of CXCL12 and CXCR4 was observed in vascular endothelial cells and tumor cells. The degree (P=0.033) and morphology (P=0.033) of PTBE were significantly associated with the level of CXCL12 expression in vascular endothelial cells. The degree (P=0.001) and morphology (P=0.001) of PTBE were associated with the level of CXCR4 expression in tumor cells. CXCR4-positive vascular endothelial cells were significantly associated only with the degree of edema (P=0.030). Therefore, the present study indicated that levels of CXCL12 expression in vascular endothelial cells and CXCR4 expression in tumor cells are associated with PTBE. PMID- 29434966 TI - miR-339-5p inhibits metastasis of non-small cell lung cancer by regulating the epithelial-to-mesenchymal transition. AB - Metastasis is a common event in cancer pathology, and represents the primary cause of cancer-associated mortality. Metastasis, which is the process in which cancer cells at the primary tumor site spread to a different location in the body and form a new tumor, is regulated by multiple factors and includes a number of steps and stages. In our previous study, it was demonstrated miR-339-5p inhibits cell migration and invasion in vitro and is associated with the tumor-node metastasis stage and the lymph node metastasis status of non-small cell lung cancer. In the present study, expression of miR-339-5p was first determined in the tissues and peripheral blood of patients with non-small cell lung cancer (NSCLC) and in NSCLC cell lines. It was then demonstrated that miR-339-5p inhibits A549 and H1299 cell invasion. The underlying molecular events of miR-339 5p action in NSCLC were also explored. By luciferase assay and western blot analysis, B-cell CLL/lymphoma 6 (BCL6) was verified as the direct target gene of miR-339-5p. miR-339-5p may inhibit lung cancer cell invasion and migration by regulating the epithelial-to-mesenchymal transition via BCL6 in vitro. It was also demonstrated that the relative expression of miR-339-5p in the peripheral blood is associated with cancer metastasis in patients with non-small cell lung cancer. PMID- 29434967 TI - Celastrol suppresses the proliferation of lung adenocarcinoma cells by regulating microRNA-24 and microRNA-181b. AB - Cumulative evidence has indicated that celastrol may suppress cancer growth; however, the underlying mechanism requires further investigation. In the present study, A549 cells were treated with various concentrations of celastrol. Lung cancer cell proliferation was evaluated using an MTT assay and observed under a microscope. Cell apoptosis was detected by Annexin V fluorescein isothiocyanate/propidium iodide double-labeled flow cytometry. The results demonstrated that celastrol suppressed proliferation and induced apoptosis in a dose-independent manner. Celastrol may also decrease the phosphorylation levels of signal transducer and activator of transcription 3 (STAT3) and the B cell lymphoma-2 (Bcl-2)/Bcl-2 associated C protein (Bax) ratio. As microRNA (miR-24 and miR-181b) were predicated to target STAT3, STAT3 activation was inhibited in miR-24-or miR-181b-treated A549 cells compared with the control treatment. The ratio of Bcl-2/Bax was further reduced in miR-24 or miR-181b-treated A549 cells. The results were further confirmed by detecting in another lung adenocarcinoma cell line, LTEP-a-2. In summary, the results of the present study demonstrated that celastrol treatment suppressed the proliferation and induced apoptosis by regulating the expression levels of miR-24 and miR-181b. PMID- 29434968 TI - Characterization of circulating tumor cells in newly diagnosed breast cancer. AB - Identification of circulating tumor cells (CTCs) by surface marker expression and ploidy analysis [immunostaining-fluorescence in situ hybridization (iFISH)] has been shown to be a highly sensitive method in the identification of certain solid cancers. In the present study, iFISH analysis was performed to identify CTCs in 184 patients with newly diagnosed non-metastatic breast cancer, and the distribution of CTC subtypes was characterized based on cytokeratin (CK) expression and ploidy status. It was revealed that CTCs of non-metastatic, aneuploid breast cancers, independent of CK expression profile, can be detected with high sensitivity (90.76%) by the iFISH system. Higher CTC counts and sensitivity were observed in patients with increased tumor size burden and unfavorable hormone receptor status. Investigation of CTC subtypes based on ploidy analysis indicated that triploid CTCs constituted the majority of CTCs evaluated. While CK-positive CTCs were detected in a small cohort of patients, an overall low rate of CK expression was observed in the 18 patient samples evaluated. Of note, CK expression was rare in CTCs detected in patients with Herceptin 2 (Her2)-positive or triple-negative [estrogen receptor (ER)-, progesterone receptor (PR)- and Her2-negative], indicating that lack of ER and PR may result in promotion of epithelial-mesenchymal transition and enhancement of tumor aggression. PMID- 29434969 TI - A unique bone marrow lymphoma patient presenting with an isolated mass: A case report. AB - Bone marrow lymphoma with the onset of an isolated mass in the bone marrow is extremely rare. The present case report described a unique case of B cell lymphoblastic lymphoma (LBL) presenting with an isolated mass in the bone marrow cavity, without any organopathy or lymphadenopathy. An isolated mass in bone marrow is a rare primary manifestation of LBL. The patient in the present case report presented with pain in the right elbow, a fever, pancytopenia and splenomegaly. Additionally, no abnormality was determined in the lymph nodes, the bone marrow karyotype or a computed tomography scan of the humerus. Positron emission tomography (PET) examination revealed an increased uptake of 18F fluorodeoxyglucose in right distal humerus. An isolated mass in the bone marrow cavity was removed by surgery. Pathological findings revealed B cell LBL. The patient received an acute lymphocytic leukemia chemotherapy regimen and achieved complete remission. However, 4 months following the initial diagnosis, the patient succumbed due to a relapse. The present case highlighted the importance of PET examination and biopsy, and the requirement to identify appropriate treatments for LBL. Additionally, it is important to broaden the differential diagnosis when an isolated mass is identified in the bone marrow cavity. PMID- 29434970 TI - The expression and underlying angiogenesis effect of DPC4 and VEGF on the progression of cervical carcinoma. AB - The present study aimed to investigate the expression and roles of deleted in pancreatic carcinoma locus 4 (DPC4) and vascular endothelial growth factor (VEGF) in the development of cervical carcinoma. A total of 115 patients aged between 25 and 60 years were involved, including 19 cervical inflammation, 35 cervical intraepithelial neoplasia (CIN), and 61 cervical squamous-cell carcinoma (CSCC). The protein expression rates of DPC4 and VEGF in all samples were detected using immunohistochemistry. The protein levels of DPC4 and VEGF in CSCC samples were measured using ELISA. Microvessel density (MVD) of each CSCC sample was measured according to the Winder method. Association analysis between DPC4, VEGF and thrombospondin-1 (TSP-1) was conducted using Spearman's correlations. The negative expression rate of DPC4 [DPC4 (-)] and positive expression rate of VEGF [VEGF (+)] of the CSCC group were significantly higher compared with that in the cervical inflammation and CIN groups (P<0.05). In the CSCC group, the protein level of DPC4 decreased, while the VEGF level increased significantly compared with the healthy control group (P<0.05). The MVD in the DPC4 (-), VEGF (+) and TSP-1 (-) groups was significantly increased compared with that of the DPC4 (+), VEGF (-), and TSP-1 (+) groups (P<0.05). The expression of DPC4 was negatively associated with VEGF and TSP-1 (P<0.01). These results suggest that DPC4, VEGF and TSP-1 are involved in the carcinogenesis of cervical carcinoma by inducing angiogenesis. In addition, the loss of DPC4 induces angiogenesis through increasing VEGF. Thus, VEGF may be a target gene regulated by DPC4. PMID- 29434971 TI - Development and in vitro evaluation of mucoadhesive patches of methotrexate for targeted delivery in oral cancer. AB - The present study focused on the development of a mucoadhesive patch of methotrexate (MTX) for targeted delivery in oral cancer. Initially, MTX-loaded liposomes were prepared using the thin film hydration method, and had a mean diameter of 105.7-137.4 nm and percentage entrapment efficiency of 54.6+/-3.5. These liposomes were cast in optimized mucoadhesive film. The film was characterized by its release pattern, thickness, weight and percentage swelling index and the sustained release profile of the optimized film was evaluated. The developed liposomes and liposomes cast in the film formulation were evaluated for cytotoxicity in HSC-3 cells using an MTT assay, and a significant decrease in the half maximal inhibitory concentration of MTX was identified with the MTX entrapped liposomal film, M-LP-F7. The results of the mitochondria-dependent intrinsic pathway demonstrated that there was significant mitochondrial membrane potential disruption with M-LP-F7 compared with the plain drug. M-LP-F7 increased the rate of apoptosis in HSC-3 cells by almost 3-fold. Elevated levels of reactive oxygen species provided evidence that M-LP-F7 exerts a pro-oxidant effect in HSC-3 cells. PMID- 29434972 TI - Tanshinone II is a potent candidate for treatment of lipopolysaccharide-induced acute lung injury in rat model. AB - The present study aimed to investigate the effect of tanshinone II, isolated from Salvia miltiorrhiza Bunge, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats. Male Sprague-Dawley rats were divided into three groups: Control, LPS and tanshinone II. Animals in the tanshinone II and LPS groups were administered 10 mg/kg LPS, whereas those in the control group received an equal volume of normal saline. Tanshinone II treatment group were injected with 30 nm/kg tanshinone II at 1 h after LPS administration. The results revealed that LPS administration increased the bronchoalveolar lavage fluid protein concentration significantly compared with the control group. However, tanshinone II treatment significantly inhibited the LPS-induced increase in protein level. Treatment of the LPS-administered rats with tanshinone II prevented the formation of pulmonary edema, which was evidenced by low values for wet to dry lung weight ratio. The activity of myeloperoxidase and expression of malondialdehyde were significantly lower in lung homogenates from the tanshinone II group compared with the LPS group. Furthermore, tanshinone II treatment inhibited the expression of tumor necrosis factor-alpha and interleukin-6 in the blood plasma. Tissue sections of the tanshinone II group exhibited normal morphology and absence of neutrophil accumulation. However, in the LPS group, neutrophils accumulated and penetrated into the pulmonary tissues. These results suggested that tanshinone II protects the rats from LPS-induced ALI. Therefore tanshinone II may have clinical applications in the treatment of ALI. PMID- 29434973 TI - Therapeutic effect of targeted Fas-expressing adenoviruses method combining gammadelta T cells in a mouse model of human ovarian carcinoma. AB - The present study aimed to investigate the therapeutic effect and safety of targeted use of Fas-expressing adenoviruses combined with gammadelta T cell mediated killing to treat human ovarian cancer xenografts in BALB/c mice. Shuttle plasmids containing control elements of human telomerase reverse transcriptase promoter and two-step transcriptional amplification system were constructed and packaged into adenovirus-5 vectors to generate expression of an exogenous Fas gene. A mouse xenograft model of human ovarian carcinoma was constructed. A total of 35 BALB/c mice were randomly divided into five groups, which were injected with PBS, gammadelta T cells, Fas-expressing adenoviruses, taxol, or Fas expressing adenovirus and gammadelta T cells. The weight and volume of tumors in mice in each group was monitored. Tissue sections of the various tissues of mice in the Fas-expressing adenovirus and gammadelta T cells group was compared with those in the PBS group to evaluate the safety of Fas-expressing adenovirus and gammadelta T cells in the treatment of human ovarian cancer xenograft tumors. The results of the present study indicated that mice in all treatment groups were alive at the end of the treatment course. Tumor weight and volume was the highest in the PBS group, followed successively by the adenovirus group, the gammadelta T cell group, the adenovirus and gammadelta T cell group, and the taxol group. The weight and volume inhibition rate in adenovirus and gammadelta T cell group were significantly higher compared with in the PBS group (P<0.05). Pathological observation of tissue samples revealed that none of vital organs in the adenovirus and gammadelta T cell group developed any evident morphological changes during treatment, when compared with healthy controls. In conclusion, the combined therapy with Fas-expressing adenoviruses and gammadelta T cells is efficient and safe for the treatment of mouse human ovarian carcinoma xenografts. PMID- 29434974 TI - Dihydroartemisinin treatment of multiple myeloma cells causes activation of c-Jun leading to cell apoptosis. AB - The aim of the present study was to investigate the effect of dihydroartemisinin (DHA) on a multiple myeloma cell line. An MTT assay, flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR) were used for the analysis of cell viability, cell cycle distribution and c-Jun N-terminal kinase (JNK) expression, respectively. Treatment of U266 cells using DHA caused a significant (P<0.05) decrease in cell viability compared with the control cells. An increase in the concentration of DHA from 1 to 100 umol/l reduced cell viability from 87 to 35% compared with 100% in the control cultures at 48 h. A significant (P<0.05) increase was observed in the sub-G0/G1 phase population of the U266 cells with an increase in DHA concentration from 1 to 100 umol/l. Treatment with 1, 3, 10, 30 and 100 umol/l concentrations of DHA increased the sub-G0/G1 phase cell population to 3.13, 8.25, 24.91, 31.47 and 38.54%, respectively. RT-PCR analysis of DHA-treated or -untreated U266 cells after 48 h demonstrated a significant (P<0.01) increase in caspase-3 expression. Treatment of the cells for 48 h with DHA led to a significant increase in c-Jun expression. DHA treatment at 1, 3, 10, 30 and 100 umol/l concentrations caused an increase in the level of c-Jun by 0.174+/-0.001, 0.254+/-0.002, 0.387+/-0.001, 0.502+/-0.003 and 0.679+/-0.005, respectively, compared with 0.982+/-0.001 in the control cells. The addition of SP600125 to the cells incubated with DHA resulted in a significant decrease in the caspase-3 and c-Jun expression levels compared with those cells incubated with DHA alone. These findings confirm that treatment with DHA increased caspase 3 and c-Jun expression in the U266 cells through activation of the JNK signaling pathway. Thus, DHA inhibited proliferation of multiple myeloma cells by interfering with the JNK signaling pathway. PMID- 29434975 TI - Validation of the novel susceptibility loci for prostate cancer in a Chinese population. AB - The present study evaluated 23 newly identified susceptibility loci for prostate cancer (PCa) in a Chinese population and assessed whether any validated loci were associated with the genetic risk score (GRS) of PCa in a Chinese population. A total of 1,417 patients with PCa and 1,008 controls were recruited in the present study. The association of each single nucleotide polymorphism (SNP) with PCa risk and PCa aggressiveness was analyzed. The predictive ability of two GRSs based on 30 SNPs (GRS30) and the 9 most significant SNPs (GRS9) in the Chinese population were also compared. Among the 19 SNPs evaluated, 1 SNP (rs7153648 at 14q23) was associated with PCa risk [odds ratio (OR)=1.206, P<0.05)] and 1 SNP (rs636291 at 1p23) was associated with PCa aggressiveness (OR=1.123, P<0.05). GRS30 and GRS9 were significantly increased in patients with PCa compared with that among non PCa controls. The areas under receiver operating characteristic curves of GRS9 and GRS 30 were similar (0.792 for GRS9 vs. 0.7994 for GRS30, P=0.138). To conclude, among the 19 SNPs evaluated, only 1 SNP was associated with PCa risk in the Chinese population. SNPs that were weakly associated with PCa were unlikely to improve the predictive ability of existing GRS in the Chinese population. PMID- 29434976 TI - Prediction of long-term survival rates in patients undergoing curative resection for solitary hepatocellular carcinoma. AB - The present study developed a novel laboratory-based algorithm to predict long term survival rates in patients undergoing curative resection for solitary hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The present study included 426 patients with solitary HBV-related HCC who underwent surgery for primary tumors at a single center between 2003 and 2012. Demographic characteristics, laboratory analysis, clinical pathology and immunohistochemistry of topoisomerase II-a and Ki67 were analyzed. A simple prognostic risk calculator was developed using regression coefficients from multivariate models. A prognostic risk calculator incorporating tumor encapsulation, neutrophil-to lymphocyte ratio, vascular invasion, alpha-fetoprotein level, Edmondson-Steiner classification, Topo II-alpha, prognostic nutritional index and Child-Pugh grade was constructed. The prognostic model demonstrated good discrimination with a C index prior to adjustment of 0.81 (95% confidence interval: 0.78-0.84) and a bootstrap-corrected C-index of 0.81. Kaplan-Meier curves demonstrated that the probabilities of overall survival rates in the low-risk group were increased compared with those in the high-risk group. The areas under the receiver operating characteristic curve using the method were greater compared with those under the 7th Tumor-Node-Metastasis system and Cancer of the Liver Italian Program scoring system [0.83 vs. 0.62 and 0.77 (P<0.001), respectively]. The simple prognostic model of the present study accurately predicted survival rates in patients. Such a prognostic risk calculator for staging patients undergoing curative resection for solitary HBV-related HCC facilitates clinical surveillance and therapy. PMID- 29434977 TI - Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin. AB - Inhibiting the protein neddylation pathway using the NEDD8-activating enzyme inhibitor MLN4924 represents an attractive anticancer strategy having been demonstrated to exhibit promising anticancer efficacy and with tolerable levels of toxicity; however, the mechanism by which MLN4924 inhibits cell proliferation in human esophageal squamous cell carcinoma (ESCC) cells requires further investigation. The present study revealed that MLN4924 treatment led to G2 cell cycle arrest and enhanced the protein stability of Wee1-like protein kinase and cyclin dependent protein kinase inhibitor 1A and B and p27. Furthermore, MLN4924 induced DNA damage and sensitized esophageal cancer cells to cisplatin by enhancing apoptosis. These findings extend the understanding of the function and mechanism of MLN4924 in ESCC and provide further evidence for the future development of neddylation inhibitors in clinical trials of esophageal cancer therapy, either alone or in combination. PMID- 29434978 TI - Activin A induces apoptosis of mouse myeloma cells via the mitochondrial pathway. AB - Activin A is a pleiotropic cytokine belonging to the transforming growth factor beta superfamily. Abnormal expression of activin A is associated with tumorigenesis. Multiple myeloma is characterized by the development of osteolytic disease, which ultimately leads to cachexia. However, the involvement of activin A in myeloma cell viability and apoptosis remains to be fully elucidated. For this purpose, mouse myeloma NS-1 cells were treated with activin A, and subsequently subjected to 5-bromo-2'-deoxyuridine analysis, Hoechst 33342 staining, flow cytometry and western blot analysis. The results revealed that activin A significantly suppressed NS-1 cell viability, and induced NS-1 cell apoptosis. In addition, activin A-induced promotion of NS-1 cell apoptosis was accompanied by upregulated expression of BCL2 associated X, apoptosis regulator (Bax), but downregulated expression of B cell lymphoma-2 (Bcl-2), resulting in an increase of the Bax/Bcl-2 ratio. Furthermore, cytochrome c and caspase-3 protein expression also increased following treatment with activin A. These data suggest that activin A induces apoptosis in mouse myeloma NS-1 cells via the mitochondrial pathway, providing a novel insight into multiple myeloma treatment. PMID- 29434979 TI - LATS2 promoter hypermethylation and its effect on gene expression in human breast cancer. AB - Tumor-specific promoter hypermethylation of large tumor suppressor, homolog 2 (LATS2), a tumor suppressor gene, has been investigated using methylation specific polymerase chain reaction (MSP) assays in different types of human cancer producing conflicting results. The aim of the present study was to evaluate the methylation status of the LATS2 promoter region using bisulfite sequencing with a next generation sequencer for breast cancer. In the 11 patients enrolled in the present study, the LATS2 promoter methylation index (MI) was uniformly high in tumor and normal tissues of the breast (median, 84.0 and 87.4%, respectively). The presence of LATS2 promoter hypermethylation was confirmed in isolated tumor cells and normal epithelial cells using the magnetic-activated cell sorting method. In situ hybridization for LATS2 messenger RNA (mRNA) revealed that the mRNA expression of LATS2 was higher in normal epithelial cells, compared with tumor cells, however, it was not significantly associated with LATS2 MI. In 12 breast cancer cell (BCC) lines and two normal breast cell lines, the LATS2 promoter was uniformly hypermethylated with no correlation between the mRNA expression of LATS2 and the LATS2 MI. In addition, treatment of the BCC lines with a demethylating reagent had minimal effect on the mRNA expression of LATS2 in any of these cell lines. These results demonstrated that LATS2 hypermethylation was not involved in silencing the mRNA expression of LATS2 mRNA. The lower mRNA expression level of LATS2 in tumor cells, compared with normal epithelial cells, suggested the possible involvement of downregulation in the mRNA expression of LATS2 in the pathogenesis of breast cancer. Therefore, the conflicting results previously reported for LATS2 promoter methylation in different types of cancer, detected using MSP assays may be attributable to the low fidelity of the MSP assay. PMID- 29434980 TI - Augmentation of antibody-dependent cellular cytotoxicity with defucosylated monoclonal antibodies in patients with GI-tract cancer. AB - Enhancement of antibody-dependent cellular cytotoxicity (ADCC) with some modalities may be a promising approach to enhance the efficacy of therapeutic monoclonal antibodies (mAbs). It has previously been demonstrated that the removal of fucose from antibody oligosaccharides (defucosylation) leads to augmentation of ADCC activity. To establish clinically relevant evidence of this procedure, the present study evaluated trastuzumab- and cetuximab-mediated ADCC by comparing defucosylated mAbs with conventional mAbs using peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 20 patients with gastrointestinal tract cancer and 10 healthy volunteers. ADCCs were measured using PBMCs as effector cells and two gastric cancer cell lines as target cells. ADCCs were significantly enhanced with defucosylated mAbs compared with conventional mAbs using PBMC from the healthy donors and patients with cancer. The results confirmed that the cetuximab- and trastuzumab-mediated ADCCs in advanced disease were impaired in comparison to those in early disease or healthy individuals. However, when the defucosylated mAbs were used instead of the conventional mAbs, the ADCC activities in the advanced cases were almost comparable with those in early disease or healthy individuals. Furthermore, the expression of ADCC associated molecules were modified toward immunosuppressive status with a mitogen-activated protein kinase inhibitor in vitro, the conventional cetuximab- and trastuzumab-mediated ADCC was downregulated, and the defucosylated mAbs overcome the downregulation of ADCC. In conclusion, defucosylated therapeutic mAbs may enhance ADCC activities in patients with cancer, which may lead to more effective anti-cancer treatments. PMID- 29434981 TI - 3-Oxoacid CoA transferase 1 as a therapeutic target gene for cisplatin-resistant ovarian cancer. AB - Ovarian cancer (OC) is the second leading cause of mortality from gynecological malignancies and has the highest mortality rate worldwide. As it is commonly asymptomatic during the early stages of the disease, >70% of patients with OC are diagnosed at advanced stages with metastasis. Despite treatment methods, including optimal debulking surgery and chemotherapy with the platinum-based drug cisplatin, OC recurrence is often inevitable, with an overall 5-year survival rate of 45%, mostly due to the steady development of cisplatin resistance. To identify genes involved in cisplatin resistance, the present study determined the half-maximal inhibitory concentrations of eight different OC cell lines and classified them into two groups (sensitive and resistant). mRNA expression was analyzed with GeneChip Human Gene 1.0 ST Arrays, and DNA methylation profiles were evaluated with the HumanMethylation450 BeadChip. Using an integrated approach of analyzing gene expression levels and DNA methylation profiles simultaneously, 26 genes were selected that were differentially expressed and methylated between the resistant and sensitive groups. Among these 26 genes, 3 oxoacid CoA transferase 1 (OXCT1), which was demonstrated to be downregulated and hypermethylated at promoter CpGs in the cisplatin-resistant group compared with the cisplatin-sensitive group, was selected for further investigation. Treatment with a DNA methyltransferase inhibitor restored hypermethylation-mediated gene silencing of OXCT1 in the cisplatin-resistant group, but not in the cisplatin sensitive group. Furthermore, overexpression of OXCT1 conferred sensitivity to cisplatin in OC cells. The results of the present study suggest that OXCT1 serves an important role in conferring cisplatin sensitivity, and may provide a potential therapeutic target for cisplatin chemotherapy in patients with recurrent OC. PMID- 29434982 TI - Genipin inhibits the growth of human bladder cancer cells via inactivation of PI3K/Akt signaling. AB - Genipin, a natural compound derived from the fruit of Gardenia jasminoides, possesses numerous biological properties. The aim of the present study was to investigate the anticancer effects of genipin in human bladder cancer. T24 and 5637 bladder cancer cells were treated with different concentrations of genipin (0-200 uM) and tested for cell viability, colony formation, cell cycle progression and apoptosis. A xenograft model of bladder cancer was established to determine the anticancer effect of genipin in vivo. The involvement of the phosphoinositide-3 kinase (PI3K)/Akt pathway in the action of genipin was examined. Genipin treatment significantly inhibited the viability and clonogenic growth of bladder cancer cells and inhibited the growth of T24 xenograft tumors, compared with vehicle controls (P<0.05). Genipin-treated cells exhibited a cell cycle arrest at the G0/G1-phase, which was accompanied by a deregulation of numerous cell cycle regulators. Genipin-treated cells demonstrated a significant increase in the percentage of apoptotic cells, loss of mitochondrial membrane potential, Bax translocation to the mitochondria and the release of cytochrome c to the cytosol. Additionally, genipin treatment significantly (P<0.05) reduced the phosphorylation levels of PI3K and Akt in bladder cancer cells. Importantly, genipin-mediated anticancer effects were reversed by the overexpression of constitutively active Akt. In conclusion, to the best of our knowledge, the present study demonstrates for the first time the growth inhibitory effects of genipin in bladder cancer cells, and indicates its potential as a natural anticancer agent for bladder cancer. PMID- 29434983 TI - Analysis of expression profile data identifies key genes and pathways in hepatocellular carcinoma. AB - The aims of the present study were to identify key genes and pathways associated with hepatocellular carcinoma (HCC) progression and predict compounds potentially associated with this type of carcinogenesis. The gene expression profile data of the GSE49515 dataset was obtained from the Gene Expression Omnibus database. The limma software package was used to identify the differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using the Biological Networks Gene Ontology tool and the Database for Annotation, Visualization and Integrated Discovery, respectively. The Michigan Molecular Interactions database plugin within the Cytoscape software platform was used to perform protein-protein interaction (PPI) network analysis. Chemical-gene interaction data for HCC were obtained from the Comparative Toxicogenomics Database to evaluate the associations between drugs and specific genes. A total of 302 DEGs, including 231 downregulated and 71 upregulated, were identified. Cytokine-cytokine receptor interaction and chemokine signaling were the significantly enriched pathways. Additionally, PPI network analysis indicated a total of 13 highest degree hub nodes, including FBJ murine osteosarcoma viral oncogene homolog (FOS) and DNA damage-inducible transcript 3 protein (DDIT3). Chemical-gene interaction analysis revealed that FUN and FOS were targeted by >500 compounds, while >200 genes were targeted by 2,3,7,8-tetrachlorodibenzodioxin and benzo(alpha)pyrene. In conclusion, the present study demonstrated that FOS, DDIT3, the cytokine-cytokine receptor interaction pathway and the chemokine signaling pathway may be key genes and pathways associated with the development of HCC. Furthermore, exposure to 2,3,7,8 tetrachlorodibenzodioxin or benzo(alpha)pyrene may lead to hepatocarcinogenesis. PMID- 29434984 TI - Antitumor effect of membrane-type Tim-3 on hepatocellular carcinoma Hepa1-6 cells of ICR mice. AB - In the present study, the inhibitory effect of transmembrane Tim-3 on hepatocellular carcinoma Hepa1-6 cells and the potential application of Tim-3 on immune system of Institute of Cancer Research (ICR) mice loaded with Hepa1-6 hepatocellular carcinoma was investigated. The animal model was established via inoculation of Hepa1-6 hepatocarcinoma cells at the hind thigh of ICR mice. Recombinant vector plasmids were transfected at the same site for gene therapy by injection to observe the inhibitory effect of Tim-3 on tumor growth. A panel of genes from tumor tissues at various time intervals was analyzed by reverse transcription-polymerase chain reaction. Flow cytometry was used to evaluate the proliferation and cytotoxicity of splenocytes after Tim-3 transfection. Synergistic effects of Tim-3 with tumor abnormal protein-1 (TAP1) was also studied. It was revealed that the growth of tumor was significantly suppressed after the transfection of Tim-3. In the presence of Tim-3, the proliferation of splenocytes and cytolysis in the early phase of tumor development was significantly enhanced, and this antitumor effect was further improved by the synergistic effect of Tim-3 with TAP1. Therefore, the membrane-type Tim-3 may behave as an effective immunoregulator to enhance antitumor immune responses. Furthermore the present findings suggest that antitumor immunity was improved by the combined effect of Tim-3 and TAP1. PMID- 29434985 TI - Capture of mesothelioma cells with 'universal' CTC-chip. AB - Malignant mesothelioma (MM) is a highly aggressive malignant tumor, predominantly associated with job-related exposure to asbestos. Development of effective and non-invasive modalities for diagnosis is an important issue in occupational medicine. Circulating tumor cells (CTCs), which are tumor cells that are shed from primary tumors and circulate in the peripheral blood, may be detected at an earlier stage than malignant tumors, and detection of CTCs may provide a novel insight into the diagnosis of MM. In a previous study evaluating clinical utility of CTCs, detected with a widely used system 'CellSearch', the authors indicated a significant however insufficient capability in the diagnosis of MM, suggesting need for a more sensitive system. Accordingly, the authors developed a novel microfluidic system to capture CTCs (CTC-chip), and demonstrated that the CTC chip effectively captured MM cells (ACC-MESO-4) spiked in the blood by conjugating an anti-podoplanin antibody. The results of the present study demonstrated that the CTC-chip coated with the anti-podoplanin antibody captured another MM cell (ACC-MESO-1). However, the capture efficiencies were lower than those for ACC-MESO-4. In addition, an anti-mesothelin antibody was used to capture CTCs, however the CTC-chip coated with the anti-mesothelin antibody failed to effectively capture MM cells, possibly due to low mesothelin expression. Overall, the CTC-chip may capture specific types of CTCs by conjugating any antibody against an antigen expressed on CTCs, and may be a useful system for the diagnosis of malignant tumors, including MM. PMID- 29434986 TI - Association between clinicopathological factors and postoperative radiotherapy in patients with completely resected pathological N2 non-small cell lung cancer. AB - The function of postoperative radiotherapy (PORT) in patients with completely resected pathologically N2 (pN2) non-small cell lung cancer (NSCLC) remains controversial due to a lack of prospective studies. The present study aimed to evaluate the efficacy of PORT in completely resected pN2 NSCLC when using modern radiation techniques, and to determine the associations between clinicopathological factors and PORT and survival rates. Following patient selection, 246 out of 269 consecutive patients with pN2 NSCLC were enrolled in the present study, with 88 patients having received postoperative chemotherapy (POCT) and PORT, 90 having received adjuvant chemotherapy, 1 having received adjuvant radiotherapy and the remaining 67 having received no adjuvant therapy. Overall survival (OS), local recurrence-free survival (LRFS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. The median age of the patients was 59 years, overall, 175 (71.1%) of the patients were male and the median radiation dose was 50.4 Gy. The median follow-up duration was 38.3 months. The 1-, 3- and 5-year OS rates were 98.9, 71.3 and 54.9%, and 93.0, 58.4 and 36.7% (P=0.011) in the PORT and non-PORT group, respectively. The 1-, 3- and 5 year LRFS rates were 95.5, 84.6 and 78.0%, and 86.6, 70.6 and 52.8% (P<0.001) in the PORT and non-PORT groups, respectively. The 1-, 3- and 5-year DFS rates were 86.5, 55.2 and 37.9%, and 80.9, 40.3 and 26.8% (P=0.132) in the PORT and non-PORT groups, respectively. Univariate analysis revealed that the OS rate was significantly increased in patients with peripheral tumors (P=0.029), pT1-2 (P=0.015), one N2 lymph node (LN) metastasis (P=0.001), single N2 station metastasis (P=0.030), no bronchial involvement (P=0.025), use of PORT (P=0.011) and POCT (P=0.003). Multivariate analysis revealed that PORT (HR, 0.755; 95% CI, 0.498-0.986; P=0.047), POCT (HR, 0.645; 95% CI, 0.420-0.988; P=0.044), bronchial involvement (HR, 1.453; 95% CI, 1.002-2.107; P=0.049) and >=2 N2 metastases (HR, 1.969; 95% CI, 1.228-3.157; P=0.005) were significant independent predictors of OS. Subgroup analysis demonstrated an increased OS rate with PORT only in the patients with positive bronchial involvement and >=2 N2 LN metastases. The results revealed that PORT may improve the LRFS and OS rates in completely resected pN2 NSCLC, and that the patients with positive bronchial involvement and >=2 N2 LN metastases may receive more benefit from PORT. PMID- 29434987 TI - Acridone suppresses the proliferation of human breast cancer cells in vitro via ATP-binding cassette subfamily G member 2. AB - In the past decades, the tricyclic acridone ring system has become a focus of major research by medicinal chemists due to the biological significance of this moiety in drug design and discovery. Acridone has substantial bio-potential since it performs crucial functions, including antibacterial, antimalarial, antiviral and anti-neoplastic activities. However, the anticancer effect and the underlying mechanisms of acridone on breast cancer cells remains unclear. In the present study, the anti-tumor function and the underlying mechanisms of acridone were evaluated in vitro. Firstly, an MTT assay was used to evaluate the inhibitory effect of acridone. Subsequently, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to investigate whether ATP binding cassette subfamily G member 2 (ABCG2) was associated with the function of acridone. Finally, western blotting was used to confirm the results of RT-qPCR. The present study demonstrated that acridone may decrease the proliferation of MDA-MB-231 cells dose-dependently. Further experiments revealed that acridone may downregulate the mRNA and protein expression levels of ABCG2, supporting the potential application of acridone in breast cancer treatment. These findings suggested that acridone is a potential agent in the treatment of human breast cancer. PMID- 29434988 TI - The effects of hemocyanin on T cells cultured in vitro. AB - As a broad-spectrum antibiotic, gentamicin is used extensively in T cell culturing in vitro, but preliminary studies have identified that T cell activity is significantly affected by gentamicin. In the present study, the hemocyanin from Litopenaeus vannamei (L. vannamei) was selected as an additive for T cell cultures in vitro. Compared with those in the control group, the cell quantity exhibited no significant difference, and the formation rate of cell colony increased gradually with increases in the hemocyanin concentration. Additionally, flow cytometry assays identified that cluster of differentiation (CD)3+CD4+ and CD4+CD25+ T cells in the 0.2 ug/ml hemocyanin (Hem 3) group were all significantly increased. Furthermore, cell cycle analysis demonstrated that T cells in the G0/G1 phase were significantly decreased in the Hem 3 group compared with in the control, 0.05 ug/ml (Hem 1) and 0.1 ug/ml (Hem 2) groups, and cells in the S phase were significantly elevated in the Hem 3 group compared with in the control and Hem 1 groups. In addition, MTT analysis indicated that the cytotoxicity of T cells towards HepG2 cells was significantly increased in the Hem 3 group compared with in the control, Hem 1 and Hem 2 groups. Taken together, the present study identified that hemocyanin may improve the proliferation and cytotoxicity of T cells, and the results supported the use of hemocyanin in T cell adoptive immunotherapy. PMID- 29434989 TI - Expression and potential mechanism of metabolism-related genes and CRLS1 in non small cell lung cancer. AB - Cardiolipin (CL) is a phospholipid localized in the mitochondria, which is essential for mitochondrial structure and function. Human cardiolipin synthase 1 (CRLS1) is important in regulating phosphatidylglycerol (PG) remodeling and CL biosynthesis. However, the expression and distinct prognostic value of CRLS1 in neoplasms, including non-small cell lung cancer (NSCLC), is not well established. In the present study, the mRNA expression of CRLS1 was investigated using Oncomine analysis and the prognostic value was assessed using the Kaplan-Meier plotter database for patients with NSCLC. The results of the analyses indicated that the expression of CRLS1 in lung cancer was lower, compared with that in normal lung tissues. Notably, a high expression of CRLS1 was found to be associated with improved overall survival (OS) in all patients with NSCLC and lung adenocarcinoma (Ade). However, this was not observed in patients with squamous cell carcinoma (SCC). The results also demonstrated an association between the mRNA expression of CRLS1 and the clinicopathological parameters of patients with NSCLC, including sex, smoking status, tumor grade, clinical stage, lymph node status and chemotherapy. These results indicated that CRLS1 was associated with improved prognosis in patients with NSCLC, particularly at an early stage (T1N1M0). In addition, it was revealed that CRLS1 was co-expressed with well-known genes associated with metabolism using Gene Ontology term enrichment analysis. Kyoto Encyclopedia of Genes and Genomes pathway analysis also showed that tumor-related metabolism and the mitogen-activated protein kinase (MAPK) signaling pathways were enriched with CRLS1-co-expression genes. The results of the present study suggested that CRLS1 may be a novel tumor suppressor involved in regulating lipid and seleno-amino acid metabolism in the tumor microenvironment, and suppressing the MAPK signaling pathway during tumorigenesis and development. Comprehensive evaluation of the expression, prognosis and potential mechanism of CRLS1 is likely to promote an improved understanding of the complexity of the molecular biology of NSCLC. PMID- 29434990 TI - Abiraterone acetate withdrawal syndrome: Speculations on the underlying mechanisms. AB - A 72-year-old man initially presented with lumbar and right chest pain, but was later found out to also have an elevated prostate-specific antigen (PSA) level at 2,000.0 ng/ml. Further evaluation disclosed metastatic prostate cancer involving the bones and lymph nodes. The patient was initially treated with combined androgen blockade (CAB) with leuprolide acetate and bicalutamide. After 6 months of CAB, the patient's PSA level began to rise from the nadir (85.1 ng/ml) to 113.3 ng/ml. Bicalutamide was withdrawn in anticipation of anti-androgen withdrawal syndrome and the PSA level declined temporally. However, it increased up to 517.0 ng/ml thereafter. Consequently, a year after CAB, abiraterone acetate (AA) was initiated at a standard dose of 1,000 mg daily in combination with 10 mg of prednisolone. PSA rapidly decreased to the nadir of 20.1 ng/ml thereafter. The PSA level remained stable until 2 years after AA administration. However, he decided to reduce the dose of AA to half of the standard dose (500 mg daily). Contrary to our expectations, the serum PSA level promptly decreased to a nadir of 8.1 ng/ml. Thereafter, the PSA level remained stable until 3 years and 9 months after AA administration. Subsequently, the patient stopped taking AA and prednisolone. However, to our surprise, the patient's serum PSA level decreased further to <1.0 ng/ml after AA discontinuation. His PSA remained <1.0 ng/ml without clinical or radiological progression for 1 year after AA withdrawal. Recently, it was reported that cessation of AA is associated with AA withdrawal syndrome in metastatic castration-resistant prostate cancer, defined as a PSA decrease after AA discontinuation, mimicking anti-androgen withdrawal syndrome. In the present study, explanations of the mechanisms underlying this phenomenon were explored, including mutant AR activation by alternative ligands. PMID- 29434991 TI - Mechanism of the anti-angiogenic effect of Avemar on tumor cells. AB - Avemar, a derivative of fermented wheat germ extract, is a non-toxic and natural compound that is used as a dietary supplement by cancer patients undergoing chemotherapy and radiotherapy. Avemar has numerous biological activities, and several recent studies have reported that it may also have metastatic and anti angiogenic effects. In the present study, the mechanism of the anti-angiogenic effect of Avemar on human cancer cells was investigated. The human cell lines NCI N87 (gastric tubular adenocarcinoma), PC3 (prostate carcinoma), HeLa (endocervical adenocarcinoma) and A549 (lung adenocarcinoma) were treated with various doses (400, 800, 1,600 and 3,200 ug/ml) of Avemar, and the changes in mRNA and protein levels of two important markers of angiogenesis, vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (Cox-2), were assessed by reverse transcription-quantitative polymerase chain reaction and ELISA. VEGF and Cox-2 protein and mRNA levels were significantly lower in Avemar-treated cells than in untreated cells. The data suggest that Avemar may exert an anti angiogenic effect on cancer cells. Thus, it is suggested to medical doctors as a potential agent for the anti-angiogenic treatment of cancer. PMID- 29434992 TI - Salvianolic acid B suppresses cell proliferation and induces apoptosis in osteosarcoma through p38-mediated reactive oxygen species generation. AB - The present study aimed to investigate the potential anticancer effect and mechanisms of salvianolic acid B on osteosarcoma. Salvianolic acid B suppressed osteosarcoma cell proliferation and induced apoptosis in the osteosarcoma MG63 cell line, and activated the expressions of cleaved caspase-3, phosphorylated tumor protein (p)38 mitogen-activated protein kinase (p-p38 MAPK) and phosphorylated-p53 (p-p53) proteins in the MG63 cells. Additionally, Salvianolic acid B also increased the level of reactive oxygen species (ROS) generation in the MG63 cells. The silencing of p38 expression inhibited the anticancer effect of salvianolic acid B on the levels of cell proliferation, p-p53 protein expression and ROS generation level in the MG63 cells. All these data supported the hypothesis that the anticancer effect of salvianolic acid B includes the suppression of cell proliferation and induces apoptosis in MG63 cells, and that p38 is important in the anticancer effect of salvianolic acid B on osteosarcoma cells due to the direct regulation of ROS generation. These data suggest that salvianolic acid B is important in the proliferation of osteosarcoma cells due to the direct regulation of p38-mediated ROS signaling. PMID- 29434993 TI - Prediction of decannulation, oral intake recovery, overall survival and lung metastasis following oral malignant tumor resection and reconstruction. AB - The present study investigated whether tongue base and mandibular bone defects were associated with the rate of decannulation and oral intake recovery, and survival time, including overall and lung metastasis-free survival time, in patients that underwent oral malignant tumor (OMT) resection with reconstruction. A total of 105 patients that underwent OMT resection with laryngeal preservation and reconstruction were recruited. The extent of defects was classified according to Urken's classification. The rates of decannulation and oral intake recovery were assessed with the Kaplan-Meier method. It was identified that 4-5 section segmental mandibulectomy (SM) and total glossectomy (TG) were significantly associated with a lower rate of decannulation and oral intake recovery by univariate and multivariate analysis using a Cox's proportional model. Patients in the high risk group (4-5 sections or TG) were significantly less likely to achieve decannulation and unaided oral intake. Patients in the high risk group exhibited a significantly shorter overall and lung metastasis-free survival time. Following multivariate analysis adjusted for the clinical stage (IV/I-III), past history of or postoperative radiotherapy (yes/no) and age (per year), the high risk group was associated with a significantly rate of decannulation and unaided oral intake. In conclusion, TG or wide SM is a prognostic parameter for functional and survival outcomes, including lung metastasis, in OMT. PMID- 29434994 TI - MicroRNA-122-3p inhibits tumor cell proliferation and induces apoptosis by targeting Forkhead box O in A549 cells. AB - The imbalance between cell proliferation and apoptosis was implicated to serve key roles in cancer pathogenesis. The characteristics of microRNAs (miRNAs/miRs) have attracted much attention in research focusing on cancer pathogenesis in recent years. miR-122-3p has been reported to be associated with a number of disease processes and pathogenesis, including lung cancer. The present study aimed to investigate the association of miR-122-3p expression level with cell proliferation and apoptosis in a lung cancer cell line. A549 cells were transfected with miR-122-3p to interrupt the expression of miR-122-3p. Subsequently, MTT and BrdU assay, and western blot were used to analyze the influence of miR-122-3p on lung cancer cell proliferation, cell viability and its underlying mechanism. The present study revealed that, by targeting p27, overexpression of miR-122-3p inhibited cell proliferation in lung cancer. Furthermore, the cell apoptosis analysis suggested that overexpression of miR-122 3p was able to inhibit cell apoptosis by targeting Forkhead box O. These findings suggest that miR-122-3p may be associated with the pathology and progression of lung cancer and be a new therapeutic target for this disease. PMID- 29434995 TI - Overexpression of centrosomal protein 55 regulates the proliferation of glioma cell and mediates proliferation promoted by EGFRvIII in glioblastoma U251 cells. AB - The epidermal growth factor receptor (EGFR) is often amplified in glioma, with the most common extracellular domain mutation being EGFR variant III (EGFRvIII). Abnormal EGFRvIII signaling has been shown to be important in driving tumor progression. Centrosomal protein 55 (CEP55), a member of the centrosomal relative proteins family, participates cytokinesis in the cell cycle. It exists in a few normal tissues and various tumor cells. The expression and function of CEP55 in human glioma cells need to investigate. In this study, the expression of CEP55 was detected in 40 cases of glioma tissues and 10 cases of non-tumor brain tissue. The proliferation of glioblastoma U251 cells was analyzed after transfection with EGFRvIII and CEP55 siRNA. We found that the expression of CEP55 was increased significantly in the glioma tissues than in normal brain tissue. The proliferation of U251 cells increased remarkably after transfection with EGFRvIII. Knockdown of CEP55 inhibited proliferation of U251 cells and was able to eliminate the effect of promoting proliferation induced by EGFRvIII in U251 cells. CEP55 played a key role in the proliferation of glioma cells and mediated EGFRvIII-stimulated proliferation in glioma cells. CEP55 might be a novel molecular therapeutic target in patients with gliomas expressing EGFRvIII. PMID- 29434996 TI - Erratum: A proposed method for the relative quantification of levels of circulating microRNAs in the plasma of gastric cancer patients. AB - [This corrects the article DOI: 10.3892/ol.2017.5816.]. PMID- 29434997 TI - Function of Axl receptor tyrosine kinase in non-small cell lung cancer. AB - Axl receptor tyrosine kinase (hereafter Axl) is a member of the tyrosine-protein kinase receptor Tyro3, Axl and proto-oncogene tyrosine-protein kinase Mer family of receptor tyrosine kinases, possessing multiple different functions in normal cells. Axl is overexpressed and activated in numerous different human cancer types, triggering several signaling pathways and enhancing tumor progression. The present review assesses previous studies on the function of Axl in non-small cell lung cancer (NSCLC). Axl is overexpressed in the tumor tissues of a number of patients with NSCLC and is associated with poorer clinical outcomes; it promotes NSCLC tumor growth, invasion/metastasis, drug resistance and the epithelial mesenchymal transition, thus providing a survival advantage to tumor cells. Therefore, Axl may be a promising target in NSCLC treatment. PMID- 29434998 TI - MicroRNAs and cancer: Key paradigms in molecular therapy. AB - MicroRNAs (miRNAs) are a type of small non-coding RNA molecule that performs an important role in post-transcriptional gene regulation. Since miRNAs were first identified in 1993, a number of studies have demonstrated that they act as tumor suppressors or oncogenes in human cancer, including colorectal, lung, brain, breast and liver cancer, and leukemia. Large high-throughput studies have previously revealed that miRNA profiling is critical for the diagnosis and prognosis of patients with cancer, while certain miRNAs possess the potential to be used as diagnostic and prognostic biomarkers or therapeutic targets in cancer. The present study reviews the studies and examines the roles of miRNAs in cancer diagnosis, prognosis and treatment, and discusses the potential therapeutic modality of exploiting miRNAs. PMID- 29434999 TI - Functions of nuclear actin-binding proteins in human cancer. AB - Nuclear actin-binding proteins (ABPs) perform distinguishable functions compared with their cytoplasmic counterparts in extensive activities of living cells. In addition to the ability to regulate actin cytoskeleton dynamics, nuclear ABPs are associated with multiple nuclear biological processes, including chromatin remodeling, gene transcriptional regulation, DNA damage response, nucleocytoplasmic trafficking and nuclear structure maintenance. The nuclear translocation of ABPs is affected by numerous intracellular or extracellular stimuli, which may lead to developmental malformation, tumor initiation, tumor progression and metastasis. Abnormal expression of certain ABPs have been reported in different types of cancer. This review focuses on the newly identified roles of nuclear ABPs in the pathological processes associated with cancer. PMID- 29435000 TI - Glucagonoma and the glucagonoma syndrome. AB - Glucagonoma is an extremely rare pancreatic alpha-islet cell tumor and is often accompanied by certain clinical symptoms including necrotizing migratory erythema (NME), diabetes, weight loss and anemia. The objectives of the current review were to discern the clinical features, diagnosis, treatment and prognosis of glucagonoma by evaluating 623 reported cases. A 1998 study reviewed 407 cases and 216 cases were reported in studies published after 1998. The current review consisted of 268 males and 339 females, with an average age of 52.4 years. The male-to-female ratio was 0.79. The incidence of typical clinical findings were as follows: NME, 82.4% (350/425); diabetes, 68.5% (291/425); weight loss, 60.2% (256/425); anemia, 49.6% (211/425); and glossitis or stomatitis or cheilitis, 41.2% (175/425). A total of 499 cases reported the location of the tumor as the pancreas and 64.1% (320/499) involved the pancreatic tail. Tumor size was recorded in 58.3% (126/216) cases reported after 1998 and average tumor size was 5.0 cm. Metastasis was detected in 49.2% of patients (293/595 for whom metastasis or no metastasis were recorded) upon diagnosis. These patients were older than those without metastasis (average age, 54.0 years old vs. 50.8 years old). The average time between symptoms and diagnosis of glucagonoma was 31.4 months. Glucagonoma is a very rare disease. It is important for clinicians to learn more about this disease to be able to diagnose and treat it as early as possible, thus improving patient prognosis. PMID- 29435001 TI - Upregulated HOXA9 expression is associated with lymph node metastasis in colorectal cancer. AB - Homeobox A (HOXA) cluster genes, members of the HOX family, perform an important role in normal organ development. It has previously been reported that HOXA gene expression in various types of cancer is associated with poor patient outcomes. However, the role of HOXA genes, as well as their expression, in colorectal cancers (CRC) remains unknown. Therefore, the present study investigated HOXA gene expression in patients with CRC and revealed that HOXA9 expression was significantly increased in tumor tissues compared with non-tumor tissues. Additionally, the functional role of HOXA9 was assessed by knocking down the HOXA9 gene in CRC cells and by evaluating cell growth. Regarding gene expression, cases with positive HOXA9 expression (as detected by immunohistochemical staining) were significantly associated with higher TNM stage and positive lymph node metastasis, although no association was observed between increased HOXA9 levels and the rate of overall survival in the present cohort. Regarding the functional role, HOXA9 expression was demonstrated to be upregulated in patients with CRC and was associated with lymph node metastasis. PMID- 29435002 TI - TERT promoter mutations and their correlation with BRAF and RAS mutations in a consecutive cohort of 145 thyroid cancer cases. AB - Papillary thyroid carcinoma (PTC) is the most common type of endocrine malignancy and accounts for ~80% of thyroid carcinomas in adults and 90% in children. Risk stratification is important for identifying patients at higher risk and, for this reason, recent advances in molecular genetics of thyroid cancer can be applied to provide novel biomarkers useful in understanding tumor behavior. B-Raf proto oncogene, serine/threonine kinase (BRAF) and rat sarcoma (RAS) mutations have been widely studied and appear to have an important role in thyroid tumorigenesis. Somatic telomerase reverse transcriptase (TERT) promoter mutations have been recently identified in several types of malignant tumors, including thyroid neoplasia; however, the actual role of TERT mutations in thyroid tumorigenesis is still under debate. In the present study, the mutational status of BRAF, RAS and TERT was analyzed in order to elucidate the roles of these genes in thyroid tumorigenesis. The TERT mutational analysis was also correlated with an immunohistochemical study of TERT protein expression. According to the literature, our data provide evidence of the BRAF and RAS roles in thyroid tumorigenesis, supporting an association between BRAF (V600E) mutations and the more aggressive clinical and pathological features of thyroid tumors. By contrast, TERT mutations were not significantly associated with any clinical parameters; therefore, its role in initial tumorigenesis should be further investigated. PMID- 29435003 TI - Opposite response to hypoxia by breast cancer cells between cell proliferation and cell migration: A clue from microRNA expression profile. AB - The majority of tumors possess the features of hypoxia. It is generally accepted that hypoxia is a negative prognostic factor for cancer. Low levels of oxygen are able to modify basic cell metabolism status. Elucidating the basic response, including cell proliferation and migration, to hypoxia by cancer cells is important for understanding the role of hypoxia in the development of cancer. In the present study, CoCl2 stimulation was used to simulate hypoxia. A microRNA (miRNA/miR) array was used to systematically detect the changes in miRNA expression profiles. Following treatment with CoCl2 for 12 h, 15 miRNAs were markedly upregulated and 10 miRNAs were markedly decreased compared with the control. After 24 h CoCl2 incubation, 15 miRNAs were increased and 3 miRNAs were decreased compared with the control. Among them, 7 miRNAs were upregulated and 2 miRNAs were downregulated at 12 and 24 h following CoCl2 stimulation. The potential roles of these miRNA were reviewed and it was identified that the majority of them are associated with cell proliferation and migration. Additional experiments demonstrated that CoCl2 incubation inhibited the proliferation of MCF 7 cells but promoted cell migration. miR-491 may be a key miRNA for hypoxia inhibited cell proliferation, as it was identified that hypoxia induced the downregulation of B-cell lymphoma-extra large in a miR-491-dependent manner. As the target of miR-302a, CXCR4 may be a key protein for hypoxia-promoted cell migration. In the present study, it was identified that in the early stage of hypoxia, cell proliferation was inhibited but cell migration was promoted. These results support the hypothesis that hypoxia may be a driving force for tumor cell escape from the primary tumor site to other organs, or other sites of the same organ. PMID- 29435004 TI - Deregulation of microRNA-193b affects the proliferation of liver cancer via myeloid cell leukemia-1. AB - Deregulation of microRNA (miR)-193b has been revealed to be associated with the proliferation of liver cells. However, the interaction between miR-193b and their targets inducing liver cancer remains largely unknown. The aim of the present study was to investigate the hypothesis that miR-193b affects the proliferation of liver cancer cells. In the present study, the overall survival of patients with liver cancer and low fold change of miR-193b was higher compared with that of patients with liver cancer patients and high fold change of miR-193b. The expression level of myeloid cell leukemia-1 (Mcl-1) in patients with liver cancer was lower compared with in the control group. The results of the present study demonstrated that downregulation of miR-193b suppressed the proliferation and induced apoptosis of liver cancer cells, and inhibited the Mcl-1 protein expression level in liver cancer cells. Upregulation of miR-193b increased cell proliferation and decreased apoptosis of liver cancer cells and promoted the expression level of Mcl-1 protein. The results of the present study demonstrated that the expression of miR-193b as a novel tumor suppressor serves an important role in the proliferation of liver cancer cells by mediating Mcl-1 expression. PMID- 29435005 TI - Identification and analysis of key genes in osteosarcoma using bioinformatics. AB - Osteosarcoma (OS) is an invasive malignant neoplasm of the bones. The present study identified and analyzed key genes associated with OS. Expression profiling of the dataset GSE49003, which included 6 metastatic and 6 non-metastatic OS cell lines and was obtained from the Gene Expression Omnibus, was performed. Following data preprocessing, the differentially expressed genes (DEGs) were selected using the limma package in R. Subsequently, bidirectional hierarchical clustering using the pheatmap package in R and an unpaired Students' t-test was performed for the DEGs. Based on the Search Tool for the Retrieval of Interacting Genes database and Cytoscape software, a protein-protein interaction (PPI) network for the DEGs was constructed. Using Database for Annotation, Visualization and Integrated Discovery software and the Kyoto Encyclopedia of Genes and Genomes Orthology Based Annotation System server, functional and pathway enrichment analyses were performed for the DEGs corresponding to the proteins of the network. In addition, the transcription factors (TFs) and CpG islands of the gene promoter were searched for using the TRANSFAC database and CpG Island Searcher software, respectively. A total of 323 DEGs were identified between the metastatic and non metastatic samples. In the PPI network, upregulated epidermal growth factor receptor (EGFR) exhibits a high degree and was therefore highly interconnected with other proteins. Enrichment analysis revealed that EGFR was enriched in cytoskeleton organization, organic substance response and the signaling pathway of focal adhesion. The TFs early growth response 1, nuclear factor-kappaB complex subunits, peroxisome proliferator activated receptor alpha, signal transducer and activator of transcription 3 and MYC proto-oncogene were identified in the EGFR promoter region. Furthermore, multiple CpG islands, starting from the 400 bp of the EGFR promoter sequence, were predicted. Methylated modification of the CpG islands in the EGFR promoter may help to regulate EGFR expression. The TFs identified in the EGFR promoter may function in the progression of OS. PMID- 29435006 TI - PRL-3 promotes breast cancer progression by downregulating p14ARF-mediated p53 expression. AB - Prior studies have demonstrated that phosphatase of regenerating liver-3 (PRL-3) serves avital function in cell proliferation and metastasis in breast cancer. However, the molecular mechanisms underlying the function of PRL-3 in breast cancer remain unknown. PRL-3 expression was analyzed in 24 pairs of breast cancer and normal tissues using the reverse transcription-quantitative polymerase chain reaction assay. The results of the present study identified that the expression of PLR-3 in breast cancer tissues was increased 4.2-fold, compared with normal tissues. Notably, overexpression of PRL-3 significantly promoted the proliferation of cancer cells and inhibited endogenous p53 expression by downregulating the expression level of p14 alternate reading frame (p14ARF). In addition, decreased expression levels of PRL-3 resulted in decreased breast cancer cell proliferation and increased expression level of p14ARF. These results suggested that PRL-3 enhances cell proliferation by downregulating p14ARF expression, which results in decreased levels ofp53. The results of the present study demonstrated that PRL-3 promotes tumor proliferation by affecting the p14ARF-p53 axis, and that it may serve as a prognostic marker for patients with breast cancer. PMID- 29435007 TI - Dexamethasone induced apoptosis of A549 cells via the TGF-beta1/Smad2 pathway. AB - Lung cancers are the most commonly diagnosed malignant tumors, and are one of the leading causes of morbidity and mortality worldwide. Dexamethasone (DEX) serves an important function in the regulation of lung cancer cell proliferation; however, the mechanisms involved still remain unknown. In the present study, the effects of DEX on A549 cell proliferation and apoptosis were examined, in addition to the potential downstream regulatory mechanisms underlying these effects. A549 cells were treated with different concentrations of DEX at 12, 24 and 48 h time points, followed by the addition of SB431542, an inhibitor of the TGF-beta1 receptor, to block the TGF-beta1 signaling pathway. Cell proliferation was analyzed using a 3-(4,5-diethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium, inner salt. The apoptosis rate was measured by Hoechst 33342 and Annexin V/propidium iodide staining and the expression of transforming growth factor (TGF)-beta1, Smad family member 2 (Smad2) and caspase 3 were assessed by western blot. The results from the present study demonstrated that the proliferation of A549 cells decreased and the apoptosis rate significantly increased following DEX treatment (P<0.05). Furthermore, the expression of TGF-beta1, Smad2 and caspase-3 were significantly increased following DEX stimulation (P<0.05), the effects of which were abrogated by the addition of the TGF-beta1 receptor inhibitor, SB431542 (P<0.05). DEX-induced apoptosis in A549 cells, and this effect was abrogated by SB431542, an inhibitor of TGF-beta1 receptor signaling, which indicated that the TGF-beta1/Smad2 pathway may be associated with this process and SB431542 may function as an antitumor drug in the future. PMID- 29435008 TI - Bioinformatical analysis of gene expression signatures of different glioma subtypes. AB - The aim of the present study was to identify the common molecular mechanisms of multiple glioma subtypes, including astrocytoma, glioblastoma and oligodendroglioma, in addition to the specific mechanisms of different types. The gene expression profile set GSE4290 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) from three types of glioma, relative to non-tumor tissue, were calculated by the t-test method with a linear regression model. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs was performed. GeneVenn online analysis software was used for the comparison of the DEGs between subtypes. A total of 795 DEGs, including 619 up and 176 downregulated DEGs were screened from the astrocytoma expression profiles; these were enriched in the KEGG pathways of 'neuroactive ligand-receptor interaction' (upregulated) and 'Wnt signaling pathway' (downregulated). Protein-protein interaction networks for astrocytoma, glioblastoma and oligodendroglioma were constructed with 1,617, 7,027 and 1,172 pairs, respectively. A total of 595 common DEGs were obtained between the three subtypes, which were enriched in pathways associated with neural signaling. Glioblastoma is a subtype of astrocytoma; there were 195 DEGs common between these subtypes that were not also associated with oligodendroglioma. DEGs unique to astrocytoma, glioblastoma and oligodendroglioma were associated with the development of the nervous system, the cell cycle and cell matrix components, respectively. The screened DEG p53 gene is likely to be critical for glioma development, including via the Wnt and p53 signaling pathways. Brain-derived neurotrophic factor and cyclin-dependent kinase 1 genes were also likely to be important in the mechanism of glioma development, and were associated with the cell cycle and p53 signaling pathways. Immune system-associated and cell matrix component pathways may be unique signaling pathways associated with astrocytoma and oligodendroglioma, respectively. PMID- 29435009 TI - Karyopherin subunit-alpha 2 expression accelerates cell cycle progression by upregulating CCNB2 and CDK1 in hepatocellular carcinoma. AB - Different types of cancer exhibit distinct gene expression profiles. The present study aimed to identify a specific gene dysregulated in hepatocellular carcinoma (HCC) that was essential for cancer progression. The whole transcriptomes of primary HCC tissue samples were analyzed with microarrays. The most significantly differentially expressed gene was identified, specifically karyopherin subunit alpha 2 (KPNA2), and an analysis using the Oncomine online tool was performed with data from The Cancer Genome Atlas to predict associated genes in HCC. Reverse transcription-quantitative polymerase chain reaction was performed to confirm the gene expression levels of KPNA2, and the RNA interference knockdown of KPNA2 was performed to identify the effect on putative downstream target genes. A proliferation assay and flow cytometry analysis was used to assess the function of KPNA2 in the regulation of the cell cycle. The results demonstrated that KPNA2 expression was significantly upregulated in HCC tumor tissues compared with liver tissues and was associated with cyclin B2 (CCNB2) and cyclin-dependent kinase 1 (CDK1) expression. KPNA2 expression was identified a novel marker to predict the outcome of patients. In addition, KPNA2 knockdown downregulated CCNB2 and CDK1, inhibited cell proliferation and induced cell cycle arrest in the G2/M phase. In conclusion, it was demonstrated that KPNA2 may promote tumor cell proliferation by increasing the expression of CCNB2/CDK1. KPNA2 could be a target for therapeutic intervention in HCC. PMID- 29435011 TI - Short interfering RNA-mediated silencing of actin-related protein 2/3 complex subunit 4 inhibits the migration of SW620 human colorectal cancer cells. AB - Actin-related protein 2/3 complex subunit 4 (ARPC4) acts as an actin nucleator in actin cytoskeleton branching and contributes to cell migration. ARPC4 has previously been demonstrated to be abnormally expressed in various colorectal carcinoma cell lines, particularly SW620 cells. The present study explored the biological action and the possible mechanisms underlying the function of ARPC4 in the progression of carcinoma. The proliferation and migration of SW620 cells transfected with ARPC4-specific short interfering (si)RNAs were assessed using western blot, cell counting, flow cytometry and transwell assays. SW620 cells exhibited the highest ARPC4 expression of the cell lines investigated, and siRNA538 was the most effective of the siRNAs considered. The results of the present study demonstrated that ARPC4-silencing exhibited a significant effect on the capacity of cells for migration, but did not affect their proliferative ability. ARPC4-silencing inhibited human SW620 cell migration, but not proliferation, in vitro, suggesting that ARPC4 may be a putative therapeutic target for colorectal carcinoma. PMID- 29435010 TI - Chloroquine potentiates the anticancer effect of sunitinib on renal cell carcinoma by inhibiting autophagy and inducing apoptosis. AB - Sunitinib based adjuvant chemotherapy combined with chloroquine (CQ) for the treatment of renal cell carcinoma (RCC) is in clinical trials; however, its anti RCC effect and the mechanism remain unclear. In the present study, the anti-RCC effect of sunitinib with CQ and the underlying mechanism was investigated. An MTT assay demonstrated that CQ enhanced the proliferation inhibitory effect of sunitinib against the OS-RC-2 RCC cell line. CQ inhibited sunitinib-induced autophagy in OS-RC-2, which was evidenced by the inhibition of autophagic vacuoles, acidic vesicular organelle formation, light chain 3 (LC3)-II recruitment to the autophagosomes and the conversion of LC3-I to LC3-II, as induced by sunitinib. The inhibition of autophagy by CQ enhanced sunitinib induced apoptosis, which was characterized by the activation of caspase-3, caspase-9, Bcl-2 and p53. Additionally, the exposure of OS-RC-2 cells to CQ and sunitinib resulted in the inhibition of AKT, tuberous sclerosis complex 2, mechanistic target of rapamycin and p70 ribosomal S6 kinase, which are associated with cell proliferation. In in vivo study, a combination of sunitinib with CQ in mice significantly reduced OS-RC-2 cell xenograft growth compared with the sunitinib alone group. In conclusion, the present study demonstrated that CQ may enhance the anti-RCC effect of sunitinib by inhibiting the autophagy induced by sunitinib, and enhance the rate of apoptosis. Inhibiting cell proliferation may also serve a role in the synergistic antitumor effect of sunitinib and CQ. These data suggest that combination therapy of sunitinib with CQ may be a promising strategy for adjuvant chemotherapy in RCC. PMID- 29435012 TI - MicroRNA-9 functions as a tumor suppressor and enhances radio-sensitivity in radio-resistant A549 cells by targeting neuropilin 1. AB - Radiotherapy is commonly used to treat lung cancer but may not kill all cancer cells, which may be attributed to the radiotherapy resistance that often occurs in non-small cell lung cancer (NSCLC). At present, the molecular mechanism of radio-resistance remains unclear. Neuropilin 1 (NRP1), a co-receptor for vascular endothelial growth factor (VEGF), was demonstrated to be associated with radio resistance of NSCLC cells via the VEGF-phosphoinositide 3-kinase-nuclear factor kappaB pathway in our previous study. It was hypothesized that certain microRNAs (miRs) may serve crucial functions in radio-sensitivity by regulating NRP1. Bioinformatics predicted that NRP1 was a potential target of miR-9, and this was validated by luciferase reporter assays. Functionally, miR-9-transfected A549 cells exhibited a decreased proliferation rate, increased apoptosis rate and attenuated migratory and invasive abilities. Additionally, a high expression of miR-9 also significantly enhanced the radio-sensitivity of A549 cells in vitro and in vivo. These data improve understanding of the mechanisms of cell radio resistance, and suggest that miR-9 may be a molecular target for the prediction of radio-sensitivity in NSCLC. PMID- 29435013 TI - Enhancement of cisplatin cytotoxicity by Retigeric acid B involves blocking DNA repair and activating DR5 in prostate cancer cells. AB - Retigeric acid B (RAB), a natural compound isolated from lichen, has been demonstrated to inhibit cell growth and promote apoptosis in prostate cancer (PCa) cells. The present study evaluated the function of RAB combined with clinical chemotherapeutic drugs in PCa cell lines by MTT assay, reverse transcription quantitative polymerase chain reaction and western blot analysis, and identified that RAB at low doses produced significant synergistic cytotoxicity in combination with cisplatin (CDDP); however, no marked synergism between RAB and the other chemotherapeutics was observed. Additional studies revealed that RAB exerted an inhibitory effect on DNA damage repair pathways, including the nucleotide excision repair and mismatch repair pathways, which are involved in the sensitivity to CDDP-based chemotherapy, as suggested by the significantly downregulated expression of certain associated repair proteins. Notably, Excision repair cross-complementing 1, a critical gene in the nucleotide excision repair pathway, exhibited the most significant decrease. When combined with CDDP, RAB-mediated impairment of DNA repair resulted in prolonged DNA damage, as demonstrated by the long-lasting appearance of phosphorylation of histone H2AX at Ser139, which potentially enhanced the chemosensitivity to CDDP. Concurrently, the proapoptotic protein death receptor 5 (DR5) was activated by RAB, which also enhanced the chemotherapeutic response of CDDP. Knockdown of DR5 partially blocked RAB-CDDP synergism, suggesting the crucial involvement of DR5 in this event. The results of the present study identified that RAB functioned synergistically with CDDP to increase the efficacy of CDDP by inhibiting DNA damage repair and activating DR5, suggesting the mechanistic basis for the antitumor effect of RAB in combination with current chemotherapeutics. PMID- 29435014 TI - Mitochondrial ROS contribute to oridonin-induced HepG2 apoptosis through PARP activation. AB - Oridonin, the main active constituent of Rabdosia rubescens, is known to exert antitumor activity via the induction of apoptosis in numerous types of human cancer cells. However, the underlying regulatory mechanisms of mitochondrial ROS in oridonin-induced HepG2 apoptosis remain largely unknown, due to limitations of subcellular imaging resolution. Previously, it has been suggested that mitochondria serve a potential role in sensing and signaling cellular redox changes in vital biological processes such as cell death and the abiotic stress response, based on studies involving the mitochondrial-targeted redox-sensitive green fluorescent protein (GFP). To address this, a mitochondrial-targeted Grx1 roGFP2 (mtGrx1-roGFP2) biosensor was implemented to monitor real-time mitochondrial redox changes of HepG2 cells in response to either H2O2/DTT or oridonin/SS31 treatment. It was determined that oridonin caused a perturbation in mitochondrial redox status, which in turn contributed to oridonin-induced apoptosis. Furthermore, a novel mechanism underlying the regulation of mitochondrial redox changes in oridonin-induced HepG2 apoptosis, presumably dependent on PARP cleavage, was proposed. In conclusion, the present study provides evidence in support of mitochondrial redox changes as a potential mediator in the apoptotic activities of oridonin in HepG2 cells, which provides insight into the molecular mechanisms by which mitochondrial redox signaling regulates oridonin-induced apoptosis in cancer therapy, and the development of mitochondria-specific oridonin as a promising novel anticancer therapeutic strategy. PMID- 29435015 TI - Phosphoproteomic analysis of the antitumor effects of ginsenoside Rg3 in human breast cancer cells. AB - The incidence of breast cancer has been increasing in China and the age of breast cancer onset is earlier compared with Western countries. Compounds commonly used in Traditional Chinese Medicine (TCM) are an important source of anticancer drugs. Ginseng is one of the most common medicines used in TCM. Ginsenosides, which are saponins found in the ginseng plant, are the major active components responsible for the chemopreventive effects of ginseng in cancer. However, the mechanisms by which ginsenosides exert their anticancer effects remain elusive. The current study combined tandem mass tag (TMT)-based quantification with titanium dioxide-based phosphopeptide enrichment to quantitatively analyze the changes in phosphoproteomes in breast cancer MDA-MB-231 cells that occur following treatment with the ginsenoside Rg3. A total of 5,140 phosphorylation sites on 2,041 phosphoproteins were quantified and it was demonstrated that the phosphorylation status of 13 sites were altered in MDA-MB-231 cells following treatment with Rg3. The perturbed phosphoproteins were: Cleavage and polyadenylation specificity factor subunit 7, elongation factor 2 (EEF2), HIRA interacting protein 3, melanoma-associated antigen D2, myosin phosphatase Rho interacting protein, probable E3 ubiquitin-protein ligase MYCBP2, PRKC apoptosis WT1 regulator protein, protein phosphatase 1 regulatory subunit 12A, E3 SUMO protein ligase RanBP2, Septin-9, thymopoietin, and E3 UFM1-protein ligase 1. Western blotting confirmed that Rg3 increased the phosphorylation of EEF2 on Thr57 but did not alter the protein expression of EEF2 in MDA-MB-231 and HCC1143 cells. These ginsenoside Rg3-regulated proteins are involved in various biological processes, including protein synthesis, cell division and the inhibition of nuclear factor-kappaB signaling. The results of the present study revealed that Rg3 exerts its anticancer effects via a combination of different signaling pathways. PMID- 29435016 TI - Cranial irradiation inhibits hippocampal neurogenesis via DNMT1 and DNMT3A. AB - Impairment of neurogenesis in the hippocampus following whole-brain irradiation is the most important mechanism of radiation-induced cognitive dysfunction. However, the underlying mechanism remains obscure, meaning an ideal therapeutic target has not been identified. Evidence indicates that DNA methylation in neurons regulates synaptic plasticity and neuronal network activity. In the present study, the expression of DNA methyltransferases (DNMTs) in the hippocampus was analyzed to investigate their potential function in radiation induced neurogenesis impairment. Sprague-Dawley rats were used throughout the present study, apportioned to the following groups: Control, radiation only, zebularine (a DNMT inhibitor) only, and radiation and zebularine together. Immunofluorescence staining revealed that radiation inhibited cellular proliferation and dendritic growth within new neurons of the hippocampus. In addition, western blot analysis demonstrated lower expression levels of DNMT1 and DNMT3A protein following radiation treatment compared with that in the non irradiated control. Furthermore, compared with the radiation-only group, the radiation and zebularine group had significantly lower cell proliferative abilities, dendritic growth, and DNMT1 and DNMT3A protein levels. The results of the present study indicated that DNMT1 and DNMT3A may be involved in the pathogenesis of whole-brain radiation-induced neurogenesis impairment. PMID- 29435017 TI - A novel ARMS-based assay for the quantification of EGFR mutations in patients with lung adenocarcinoma. AB - Quantification of epidermal growth factor receptor (EGFR) mutations is important for the prediction of tyrosine kinase inhibitor (TKI) efficacy in patients with non-small cell lung cancer (NSCLC). However, clinicians lack a sensitive and convenient method to quantify EGFR mutant abundance. The present study introduces a novel method, namely amplification refractory mutation system (ARMS)-Plus, for the quantitative analysis of EGFR exon 19 deletion (19Del), L858R and T790M mutations. Formalin-fixed paraffin-embedded tumor samples were collected from 77 patients with lung adenocarcinoma. DNA was extracted and analyzed for EGFR mutations using ARMS-Plus. The performance of ARMS-Plus was then compared with that of conventional ARMS-polymerase chain reaction (ARMS-PCR) and droplet digital PCR (ddPCR). The results demonstrated that the concordance rate of EGFR mutation testing between ARMS-Plus and ddPCR was 98.7% (76/77, Kappa=0.9739). 19Del and L858R mutations were detected in 23 and 12 patients, respectively. There was a significant difference between ARMS-Plus and ddPCR in the evaluation of 19Del mutant abundance (P=0.0002); however, not in that of L858R mutant abundance (P=0.7334). The ARMS-Plus results in L858R mutant abundance were concordant with that of ddPCR (R2=0.8081). These results indicated that the sensitivity and specificity of ARMS-Plus in identifying EGFR mutations were similar to that of ddPCR. For quantitative analysis, the results of ARMS-Plus in evaluating L858R mutant abundance revealed a positive correlation with the ddPCR results. Thus, ARMS-Plus provides an alternative method, which is reliable and cost-effective, to quantify EGFR mutations and thereby, aid treatment decisions in patients with lung adenocarcinoma. PMID- 29435018 TI - Thermographic real-time-monitoring of surgical radiofrequency and microwave ablation in a perfused porcine liver model. AB - Radiofrequency ablation (RFA) and microwave ablation (MWA) are currently the dominant modalities to treat unresectable liver tumors. Monitoring the ablation process with b-mode-sonography is often hampered by artefacts. Furthermore, vessels may cause cooling in the adjacent tumor target (heat-sink-effect) with risk of local recurrence. The present study evaluated infrared-thermography to monitor surgical RFA/MWA and detect heat-sink-effects in real-time. RFA and MWA of perfused porcine livers was conducted at peripheral and central-vessel adjacent locations, and monitored by real-time thermography. Ablation was measured and evaluated by gross pathology. The mean time for ablation was significantly longer in RFA compared with MWA (8 vs. 2 min). Although mean macroscopic ablation diameter was similar (RFA, 3.17 cm; MWA, 3.38 cm), RFA showed a significant heat-sink-effect compared with MWA. The surface temperature during central RFA near vessels was 1/3 lower compared with peripheral RFA (47.11+/-8.35 degrees C vs. 68.72+/-12.70 degrees C; P<0.001). There was no significant difference in MWA (50.52+/-8.35 degrees C vs. 50.18+/-10.35 degrees C; P=0.74). In conclusion, thermography is suitable to monitor the correct ablation with MWA and RFA. The results of the current study demonstrated a significant heat-sink-effect for RFA, but not MWA near vessels. MWA reaches consistent surface temperatures much faster than RFA. With further in vivo validation, thermography may be useful to ensure appropriate ablation particularly near vulnerable or vascular structures. PMID- 29435019 TI - NAC1 promotes the migration of prostate cancer cells and participates in osteoclastogenesis by negatively regulating IFNbeta. AB - Nucleus accumbens-associated protein 1 (NAC1), a transcriptional co-regulator, is overexpressed in advanced prostate cancer. However, the NAC1-regulated transcriptome has not been completely explored. In the present study, the functional silencing of NAC1 blocked the migration of prostate cancer cells and suppress osteoclastogenesis. The present study also determined that NAC1 was overexpressed in the highly aggressive prostate cancer cell lines PC-3, DU-145 and LNCaP. NAC1 small interfering RNA treatment of DU-145 cells decreased cell migration, but interestingly had no significant effects on cell proliferation. Furthermore, microarray analysis showed that a group of genes may be associated with the development of prostate cancer after NAC1 knockdown, including interferon-beta (IFNbeta), which is reported to be involved in osteoclastogenesis, an important factor affecting bone metastasis. The mechanisms of NAC1 function were further explored by co-culture studies using PC-3 and RAW264.7 osteoclast precursor cells, which demonstrated that silencing NAC1 downregulated the genes associated with the activation of osteoclasts. Furthermore, it was revealed that NAC1 had the ability to affect the release of IFNbeta into the extracellular environment. Together, these findings indicated that NAC1 promoted cell migration, and that NAC1 may have a key role in osteoclastogenesis. PMID- 29435020 TI - Analysis of the effect of laparoscopy and hysteroscopy on ovarian function, immune function and quality of sexual life of patients with hysteromyoma at different ages. AB - This study aims to comparatively analyze the impact of laparoscopic myomectomy (LM) and transcervical resection of myoma (TCRM) on ovarian function, immune function and quality of sexual life of patients with hysteromyoma. Two hundred and forty patients with hysteromyoma admitted into the Second Affiliated Hospital of Zhengzhou University from June 2014 to June 2016 were divided into laparoscopic myomectomy group (LM group, n=120) and transcervical resection of myoma group (TCRM group, n=120) according to random figure table. The difference between the two surgical methods were compared among hysteromyoma patients of different age in the following aspects: perioperative indicators, ovarian function, immune function and quality of sexual life before treatment and after operation. 1) there was no significant difference in age structure between LM and TCRM group (P>0.05). 2) There were no significant differences in the amount of bleeding, operative time, analgesics usage rate between the groups (P>0.05), but the anal exhaust time, postoperative ambulation time, hospitalization time and hospitalization costs in TCRM group were significantly less than that in LM group, the difference was statistically significant (P<0.01). 3) Before treatment and in the 3rd, and 6th month after operation, there was no significant difference on follicle stimulating hormone (FSH), luteinizing hormone (LH) or estradiol (E2) level between the two groups (P>0.05); but in the 3rd month after operation, the level of E2 decreased remarkably, with FSH and LH level increased significantly compared with the 6th month after operation and before treatment (P<0.05). 4) Compared with the preoperative status, there was no significant decrease in humoral immunity (IgG, IgA, IgM) and cellular immune function (CD4+, CD8+) in TCRM group at the 3rd and 6th month after operation (P>0.05). While at the 3rd month after operation, the levels of CD4+, CD8+ were decreased significantly in comparison to those at the 6th month after operation (P<0.05), but the levels of IgG, IgA and IgM were not decreased significantly (P>0.05). 5) There was no significant difference in the quality of sexual life between the two groups before operation or at the 3rd and 6th month after operation (P>0.05). In recent years, endoscopic treatment has become the main treatment evolution of hysteromyoma, patients of all ages are paying attention to the preservation of the uterus. This study showed that TCRM is approaching through the natural cavity, which has the features of less damage to body, faster recovery and lower cost of hospitalization than LM. The two surgical methods have no obvious influence on ovarian function, immune function and quality of sexual life. PMID- 29435021 TI - Long-lasting memory of cellular immunity in a chronic myeloid leukemia patient maintains molecular response 5 after cessation of dasatinib. AB - Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib are primarily used in the initial treatment of chronic phase (CP)-chronic myeloid leukemia (CML), as CMLs harbor the BCR-ABL fusion product. An increased number of lymphocytes and large granular lymphocytes (LGLs) have been observed in patients treated with dasatinib, but not other TKIs. The LGLs have been reported to be primarily natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). In the present study, a CP-CML patient who has maintained molecular response 5 for >2.4 years after stopping dasatinib was reported. Memory and effector CTLs and NK cells, were observed after 2.4 years of treatment-free remission, despite the fact that lymphocyte counts are not elevated in the patient. These results suggest that dasatinib may induce cellular immunity, including NK cells and CTLs and this cellular immunity may be maintained for a long period following cessation of dasatinib. The results suggest that this cellular immunity may provide a long-term cure without the need for continued TKI treatment. PMID- 29435023 TI - Primary malignant perivascular epithelioid cell neoplasm (PEComa) of the bone mimicking granular cell tumor in core biopsy: A case report and literature review. AB - The present study investigated the case of a 46-year-old female with primary malignant perivascular epithelioid cell neoplasm (PEComa) of the femur. The patient presented with a 5-month history of right distal thigh pain following trauma. Radiographs of the right distal femur revealed a mixed lytic and sclerotic lesion with subtle areas of cortical destruction and soft tissue extension, consistent with an aggressive tumor. A core biopsy revealed an epithelioid tumor with granular cell features, but a definitive diagnosis could not be made. Due to the aggressive features on radiologic evaluation, the patient underwent a resection of the distal femur and reconstruction with a distal femoral megaprosthesis and hinged knee replacement. The post-resection pathology led to a final diagnosis of primary bone PEComa, with histologic features including epithelioid, granular cell and spindled cell morphologies and biphasic immunoreactivity for melanocytic and smooth muscle markers. The large tumor size (>5 cm), rapid mitotic rate, infiltrative growth pattern, high nuclear grade and cellularity, and the presence of necrosis rendered this a malignant PEComa. The present study discussed the case, including radiographic (radiographs, magnetic resonance imaging and positron emission tomography scans) and histologic appearance and a literature review. PMID- 29435022 TI - Metformin inhibits the migration and invasion of esophageal squamous cell carcinoma cells by downregulating the protein kinase B signaling pathway. AB - Previous studies have suggested that metformin, a biguanide family member widely used as an oral antidiabetic drug, may inhibit proliferation and induce apoptosis in certain types of cancer cell. However, the molecular mechanisms underlying metformin-associated anticancer effects, and in particular antimetastatic effects, remain to be fully understood. The present study assessed the efficacy of metformin in inhibiting the migration and invasion of the esophageal carcinoma cell line EC109, and evaluated the effect of metformin on the protein kinase B (AKT) signaling pathway. EC109 cells were treated with 0, 5, 10 or 20 mM metformin during the logarithmic growth phase. A Transwell assay and western blot analysis revealed that metformin inhibited the migration and invasion of EC109 cells, nuclear factor-kappaB activation, matrix metallopeptidase 9 and N-cadherin expression in a phosphorylated-AKT dependent manner. These results suggested that metformin inhibits the migration and invasion of human esophageal carcinoma cells by suppressing AKT phosphorylation and regulating the expression of migration- and invasion-associated genes. PMID- 29435025 TI - Bromelain has significant clinical benefits after extraction of the third molar during chemotherapy in patients with hematologic tumor. AB - The purpose of this study was to investigate the application of bromelain in the treatment of pain, swelling, and limited mouth opening in patients with hematologic tumor after extraction of the third molar during chemotherapy. We recruited 72 patients with hematologic tumor who were treated by oral and maxillofacial surgery in our hospital, and third molar extraction was performed under local anesthesia. After extraction, patients in the control group were treated with cold - hot compress and patients in the experimental group were treated by oral administration of bromelain. One, three, and seven days after extraction, pain, swelling, and mouth opening in the experimental group improved compared to the control group. Additionally, the levels of IL-25 and TNF-alpha in the experimental group were significantly lower than in the control group, suggesting less inflammatory response. On the other hand, EGFR and beta-FGF were significantly higher in the experimental group, supporting the activation of tissue repair pathways. Quality of life scores were significantly better in the experimental group. Overall, bromelain improves the quality of life, alleviates pain, swelling, and mouth opening, and effectively prevent postoperative complications in patients with hematologic tumors after third molar extraction during chemotherapy. PMID- 29435024 TI - Expression of EZH2 is associated with poor outcome in colorectal cancer. AB - Enhancer of zeste homolog 2 (EZH2), the critical component of polycomb group protein family, has been demonstrated to be overexpressed in various types of human cancer, including hepatocellular carcinoma, breast, bladder and lung cancer. The mechanism of how EZH2 promotes oncogenesis has also been well studied. However, little is known about the role of EZH2 in colorectal cancer (CRC). The main purpose of the present study was to analyze the association between EZH2 expression and the clinicopathological features of CRC. Therefore, the mRNA and protein expression levels were analyzed in tumor tissues and adjacent non-cancerous tissues by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The expression of EZH2 was demonstrated to be significantly increased in tumor tissues compared with adjacent noncancerous tissues, according to the results of western blot analysis and RT-qPCR in the majority of cases. Patients with low EZH2 expression had a longer overall survival rate compared with those with high EZH2 expression. An analysis of the association between clinicopathological features and EZH2 expression indicated that high EZH2 expression was significantly associated with tumor stage, tumor size, histological differentiation and lymph node metastasis. Multivariate analysis demonstrated that high EZH2 expression was an independent predictor of overall survival. In conclusion, to the best of our knowledge, the data presented in the present study is the first to indicate that EZH2 is upregulated in CRC and may serve as a predictor of poor outcome for patients with CRC. PMID- 29435026 TI - DHA induces apoptosis of human malignant breast cancer tissues by the TLR-4/PPAR alpha pathways. AB - Docosahexaenoic acid (DHA) oil is an important polyunsaturated fatty acid for the human body. Evidence has demonstrated that DHA is beneficial for inhibiting mammary carcinogenesis. However, the mechanisms of DHA mediating apoptosis induction have not been fully elucidated. Thus, in the present study, the activity levels of total-superoxide dismutase (t-SOD), catalase (CAT), glutathione-peroxidase (GSH-PX) and the concentration of malondialdehyde (MDA) were determined in DHA oil-treated human malignant breast tissues. The results revealed that compared with control, DHA significantly increased the main antioxidant enzymes levels, including t-SOD, CAT, and GSH-PX, but decreased the MDA concentration in the DHA oil treated breast cancer tissues. Furthermore, DHA significantly increased the ratio of cyclic (c)AMP/cGMP levels and promoted the expression of Toll-like receptor 4 (TLR-4) and peroxisome proliferator activated receptor (PPAR)-alpha, thus DHA induced breast cancer cell apoptosis. We hypothesized that the levels of TLR-4 and PPAR-alpha are involved in the antitumorigenesis properties of DHA in breast cancer. The results of the present study hold significance for the further clinical development of DHA oil in breast cancer treatment. PMID- 29435027 TI - Dynamics of angiogenesis and cellularity in rabbit VX2 tumors using contrast enhanced magnetic resonance imaging and diffusion-weighted imaging. AB - A number of studies have demonstrated that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be used to evaluate microvessel density (MVD), and may quantitatively reflect tumor angiogenesis. To investigate the dynamics, including angiogenesis and tumor cellularity, of rabbit VX2 tumors during the 4 weeks following tumor implantation, the present study used DCE-MRI combined with diffusion-weighted imaging (DWI) to scan the tumors at 3 days, and then at 1, 2, 3 and 4-week intervals, following tumor implantation. The dynamics, volume transfer coefficient (Ktrans) and apparent diffusion coefficient (ADC) of the tumor parenchyma were analyzed. Furthermore, the associations between Ktrans and MVD at 4 weeks after tumor implantation were analyzed. Tumor Ktrans was positively correlated with MVD at 4 weeks (r=0.674, P<0.001). Following tumor implantation, the tumor Ktrans level rose for 2 weeks and then began to decline, reaching its lowest point at 4 weeks (P<0.001). ADC values at 1 week were higher than at 3 days, but declined thereafter (P<0.001). Tumor necrosis appeared by 1 week after tumor implantation. The necrosis degree of tumor was gradually increased from the occurrence of necrosis within the 4-week time span of the present study (1 vs. 2 weeks, P=0.008; 2 vs. 3 weeks, P<0.001; 3 vs. 4 weeks, P<0.001). The present study identified that tumor angiogenesis is a dynamic process that serves a function in tumor growth, and that DCE-MRI may reflect tumor parenchymal MVD and be useful in evaluating angiogenesis. PMID- 29435028 TI - CD133 expression and alpha-fetoprotein levels define novel prognostic subtypes of HBV-associated hepatocellular carcinoma: A long-term follow-up analysis. AB - Hepatocellular carcinoma (HCC) is a highly heterogeneous type of tumor, which may be caused by the stem/progenitor cell features of particular HCC cells. Recent studies have subclassified HCC into different prognostic subtypes according to just one stemness-associated marker. However, one stemness-associated marker is not sufficient to clearly define cancer stem cells, or to decipher the heterogeneous nature of HCC. For a more precise subtype classification for prognostic application, a combination of multiple stemness-associated markers is required. Cluster of differentiation 133 (CD133) and alpha-fetoprotein (AFP) are common stemness-associated markers for HCC that have not yet been employed for HCC subtype classification. In the present study, CD133 expression was assessed by immunohistochemistry in 127 hepatitis B virus-associated HCC tumor specimens. Based on CD133 immunostaining and serum AFP levels, the HCC cases were subclassified into four subtypes, which demonstrated different clinicopathological features and varying prognoses. Among the four subtypes, the number of tumor lesions, histological grade and vascular invasion were significantly different (P=0.002, P=0.018 and P=0.022, respectively). CD133+AFP+ HCC was associated with a relatively poor prognosis, CD133-AFP- HCC was associated with a relatively good prognosis, while CD133+AFP- HCC and CD133-AFP+ HCC were associated with an intermediate prognosis. These prognostic values were confirmed by borderline or statistical significance (between all groups, overall survival, P=0.061; recurrence-free survival, P=0.015). These results define a novel and simple system, based on CD133 and AFP, for classifying HCC into four distinct prognostic subtypes. This classification system may aid the assessment of patients with HCC for personalized therapy. PMID- 29435029 TI - Nucleotide variation in ATG4A and susceptibility to cervical cancer in Southwestern Chinese women. AB - Early detection of human papillomavirus (HPV) is important for the clinical diagnosis of cervical cancer. However, to date, the pathogenesis of cervical cancer is still unclear. Autophagy is a dynamic process that contributes to the maintenance of cellular homeostasis. Here, we investigate whether variants of autophagy genes affect the occurrence of cervical cancer. In this study, our results indicate that single nucleotide polymorphisms (SNPs) of autophagy-related protein 4 (ATG4), including rs4036579, rs5973822, rs807181, rs807182 and rs807183, have a significant relationship with cervical cancer risk. Furthermore, stratified analysis suggests that the homozygous variant genotype could decrease the risk of cervical cancer and should be considered when investigating the role of HPV in cervical cancer. We aim to investigate whether SNPs of ATG4A contribute to HPV infection in the population of Southwestern China. The association of both single SNPs and SNP-SNP interactions with HPV was evaluated in a sample of cancer cases and healthy control subjects. The interaction of rs807181 and rs807183 was associated with HPV infection in case and control subjects (combined P=2.00*10-3 and 3.22*10-2, respectively). This result showed that ATG4A SNP interactions may affect HPV infection in the population of Southwestern China. Notably, the autophagy gene ATG4A may contribute to cervical cancer. PMID- 29435030 TI - Focal adhesion kinase is overexpressed in thymic epithelial tumors and may serve as an independent prognostic biomarker. AB - Focal adhesion kinase (FAK) has long been considered to be a key regulator of growth factor receptor- and integrin-mediated signals, with pivotal roles in tumor cells through its kinase activity and scaffolding function. Increased FAK expression and activity has been observed in tumors of various origins and is often associated with a poor prognosis. However, there have been no studies on the aberrant expression of FAK in thymic epithelial tumors to date. The aim of the present study was to evaluate FAK expression in thymic epithelial tumors and to explore the prognostic significance of FAK. FAK expression was investigated in 100 formalin-fixed, paraffin-embedded human thymic epithelial tumor (TET) specimens using immunohistochemical analysis with FAK-specific monoclonal antibody 4.47, and the associations between FAK expression and clinicopathological parameters (including sex, age, tumor size, myasthenia gravis, World Health Organization classification and Masaoka-Koga stage) were analyzed. FAK was significantly overexpressed in TETs compared with in normal thymus tissues (P<0.001). Additionally, FAK overexpression was significantly associated with advanced tumor stages (stages III or IV; P<0.001) and highly aggressive TET subtypes (type B2 and B3 thymomas and thymic carcinomas; P<0.001). Furthermore, FAK overexpression was significantly associated with a worse 10-year overall survival, as determined by univariate analysis (P<0.001). Multivariate analysis revealed that FAK overexpression was an independent prognostic factor for patients with TETs (P=0.034). The results of the present study suggest that FAK serves an important role in the tumorigenesis and progression of TETs. Therefore, FAK may serve as a prognostic biomarker and is a potential therapeutic target for the treatment of TETs. PMID- 29435031 TI - Analysis of radiation effects in two irradiated tumor spheroid models. AB - Multicellular spheroids have proven suitable as three-dimensional in vivo-like models of non-vascularized micrometastases. Unlike monolayer-based models, spheroids mirror the cellular milieu and the pathophysiological gradients inside tumor nodules. However, there is limited knowledge of the radiation effects at the molecular level in spheroids of human origin. The present study is a presentation of selected cell biological processes that may easily be analyzed with methods available at routine pathology laboratories. Using gamma irradiated pancreatic neuroendocrine BON1 and colonic adenocarcinoma HCT116 spheroids as model systems, the present study assessed the radiobiological response in these models. Spheroid growth after irradiation was followed over time and molecular responses were subsequently assessed with immunohistochemistry (IHC) staining for descriptive analyses and semi-automatic grading of apoptosis, G2-phase and senescence in thin sections of the spheroids. Growth studies demonstrated the BON1 spheroids were slower growing and less sensitive to radiation compared with the HCT116 spheroids. IHC staining for G2-phase was primarily observed in the outer viable P-cell layers of the spheroids, with the 6 Gy irradiated HCT116 spheroids demonstrating a very clear increase in staining intensity compared with unirradiated spheroids. Apoptosis staining results indicated increased apoptosis with increasing radiation doses. No clear association between senescence and radiation exposure in the spheroids were observed. The present results demonstrate the feasibility of the use of multicellular spheroids of human origin in combination with IHC analyses to unravel radiobiological responses at a molecular level. The present findings inspire further investigations, including other relevant IHC-detectable molecular processes in time- and radiation dose dependent settings. PMID- 29435032 TI - Bioinformatics identification of dysregulated microRNAs in triple negative breast cancer based on microRNA expression profiling. AB - Triple negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer cases and is usually more aggressive with a poorer clinical outcome compared with other breast cancer subtypes. Evidence of the involvement of microRNAs (miRNAs) in cancer has provided an opportunity for the development of novel effective therapeutic targets in TNBC. In the present study, the miRNA expression profiles of the human breast cancer cell line, MDA-MB-231, and MCF-7 cells, was evaluated by using miRNA microarray analysis. A total of 107 differentially expressed miRNAs (57 upregulated and 50 downregulated) were identified in MDA-MB-231 cells compared with MCF-7 cells. Five prominently dysregulated miRNAs (miR-200c-3p, miR-221-3p, miR-222-3p, miR-192-5p and miR 146a) were further confirmed by reverse transcription-quantitative polymerase chain reaction. In addition, gene ontology analysis and pathway enrichment analysis revealed that the dysregulated miRNAs and predicted targets were found to be involved in the mitogen-activated protein kinase, Wnt, and transforming growth factor-beta signaling pathways, which were known to contribute to TNBC progression and metastasis. Finally, miRNA gene network analyses suggested that miR-200c may serve as a crucial miRNA in breast cancer. Taken together, these findings may provide a comprehensive view of the function of aberrant miRNAs involved in TNBC, and dysregulated miRNAs hold promise as potential biomarkers and therapeutic targets for patients with TNBC. PMID- 29435033 TI - Prognostic significance of sodium-potassium ATPase regulator, FXYD3, in human hepatocellular carcinoma. AB - The clinical significance of the sodium-potassium ATPase regulator FXYD domain containing ion transport regulator 3 (FXYD3) has been demonstrated in a number of types of cancer. However, the role of this protein in human hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, 217 HCC tissue samples were analyzed to evaluate the expression and prognostic significance of FXYD3 in HCC. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA expression of FXYD3 in 80 primary HCC specimens and paired non-cancerous liver tissue samples, while western blotting was used to analyze the protein expression level of FXYD3 in another 24 pairs. These analyses demonstrated that the expression level of FXYD3 was significantly increasedb at the mRNA and protein levels in HCC tumor tissues compared with adjacent non cancerous tissues. Immunohistochemical analysis of 137 paraffin-embedded HCC tissue samples indicated that the expression of FXYD3 was associated with HCC clinicopathological characteristics. Kaplan-Meier analysis demonstrated that patients with high FXYD3 protein expression (n=60) experienced significantly poorer overall survival time compared with patients with low FXYD3 protein expression (n=77) (P<0.001). Multivariate analysis demonstrated that FYXD3 protein expression level (hazard ratio, 2.137; 95% confidence interval, 1.224 3.732; P=0.008) was an independent prognostic factor in patients with HCC. Overall, the results indicated that FXYD3 expression levels were higher in HCC tumor tissues than in adjacent non-cancerous tissues, and that the FXYD3 protein may serve as a prognostic marker for HCC. PMID- 29435034 TI - Gadd45beta silencing impaired viability and metastatic phenotypes in cholangiocarcinoma cells by modulating the EMT pathway. AB - Growth arrest and DNA damage-inducible-beta (Gadd45beta) is a stress-response protein involved in a number of processes, including cell cycle control, DNA repair, survival and death control, and stress signaling, depending on its interactions. Gadd45beta expression is dysregulated in numerous types of cancer, functioning as either a tumor promoter or a tumor suppressor. However, the functions of Gadd45beta in cholangiocarcinoma (CCA), particularly in metastasis, has not been studied. The immunohistochemical analysis of Gadd45beta expression revealed that 75% of histological specimens from patients with CCA expressed high levels of Gadd45beta, and that high Gadd45beta expression was associated with metastasis. The role of Gadd45beta in CCA was examined using siRNA-mediated gene knockdown in HuCCA-1, a human CCA cell line established from a Thai patient. The effects of Gadd45beta downregulation upon cell viability and death, invasion, migration, matrix metalloproteinase (MMP) activity and epithelial-mesenchymal transition (EMT) marker expression were investigated. Gadd45beta knockdown impaired cell viability, which was associated with the induction of apoptosis. In addition, there was a marked reduction in invasion and migration, although MMP activity was unaffected. Impairment of these metastatic properties was accompanied by the decreased expression of EMT markers, including Slug, vimentin, claudin-1 and zona occludens protein 1, whereas E-cadherin expression was increased. The present study suggests that Gadd45beta is involved in regulating the viability and the metastatic potential of CCA cells, which may be mediated by the modulation of the EMT pathway. PMID- 29435035 TI - Expression of proteins associated with epithelial-mesenchymal transition in esophageal squamous cell carcinoma. AB - Cluster of differentiation 147 (CD147), pituitary tumor transforming gene (PTTG) and CD44v6 are proteins involved in the epithelial-mesenchymal transition (EMT). To investigate the prognostic value of CD147 and PTTG, and CD44v6 expression in esophageal squamous cell carcinoma (ESCC), tissue microarray specimens from 76 patients with ESCC were evaluated by immunohistochemistry staining and scored by intensity and proportion of positive areas. Expression levels of CD147, PTTG and CD44v6 were higher in tumor tissues than in matched adjacent tissues. CD147 expression was positively associated with lymph node metastasis (P=0.025) and American Joint Committee on Cancer (AJCC) system clinical grades (P=0.037). CD147 expression was positively correlated with the expression levels of PTTG (R=0.369; P=0.001) and CD44v6 (R=0.320; P=0.005). In addition, Kaplan-Meier analysis indicated that positive expression of CD147, PTTG and CD44v6 was significantly associated with poor overall survival times (P=0.045, P=0.014 and P=0.027, respectively). Patients exhibiting CD147-PTTG co-expression, CD147-CD44v6 co expression and CD147-PTTG-CD44v6 triple-positive expression had the poorest overall survival rates. In conclusion, the expression of EMT-associated proteins, including CD147, PTTG and CD44v6, was significantly associated with poor survival in ESCC and these novel targets may serve as potential biomarkers for anticancer therapies. PMID- 29435036 TI - Long non-coding RNA cartilage injury-related promotes malignancy in bladder cancer. AB - Recent advances have highlighted the important roles of long non-coding RNAs (lncRNAs) in a number of biological processes, including oncogenesis. However, the function of lncRNA cartilage injury-related (lncRNA-CIR) in bladder cancer progression remains elusive. A novel function for lncRNA-CIR in bladder cancer was identified in the present study. Reverse transcription quantitative polymerase chain reaction, viability, invasion assay and in vivo implantation were used to evaluate the role of lncRNA-CIR. It was identified that the expression of lncRNA-CIR was frequently upregulated in 52 cancerous tissues and selected bladder cancer cell lines. Additionally, upregulating lncRNA-CIR was demonstrated to promote viability and invasion in T24 and SW780 cells, whereas siRNA-mediated lncRNA-CIR-knockdown consistently exhibited the opposite effects. High lncRNA-CIR levels also dictated poor overall survival among patients with bladder cancer. Furthermore, in vivo implantation experiments also supported a tumorigenic function for lncRNA-CIR, as decreasing lncRNA-CIR levels markedly attenuated Ki-67 staining and xenograft tumor growth. Overall, the present study identified a novel function of lncRNA-CIR and indicates that lncRNA-CIR may serve as a potential biomarker for bladder cancer treatment. PMID- 29435037 TI - Analysis of the association of the expression of KiSS-1 in colorectal cancer tissues with the pathology and prognosis. AB - Colorectal cancer is a common malignant tumor of the digestive tract with high morbidity and mortality rates. The aim of the present study was to examine the expression level of KiSS-1 in tumor tissues of patients with colorectal cancer, and to explore the relationship with the clinicopathology and prognosis of patients with colorectal cancer. Frozen tumor tissue and corresponding cancer adjacent normal tissue specimens were selected from 56 patients with colorectal cancer who were treated in the Department of Surgery of our hospital from May 2009 to December 2011. The expression levels of KiSS-1 messenger ribonucleic acid (mRNA) in tumor tissues and cancer-adjacent normal tissues were detected by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). The expression levels of KiSS-1 proteins in colorectal cancer tissues and cancer adjacent normal tissues were further detected by immunohistochemistry. In addition, the association of the expression level of KiSS-1 proteins in tissues of colorectal cancer patients with pathological parameters and the prognosis of patients with colorectal cancer was analyzed combined with clinical data. The RT qPCR results showed that the expression of KiSS-1 mRNA in colorectal cancer tissues was significantly lower than that in cancer-adjacent normal tissues (P<0.05). Immunohistochemistry results indicated that the positive expression rate of KiSS-1 proteins in colorectal cancer tissues (26.79%) was significantly lower than that in cancer-adjacent normal tissues (80.36%). The low expression of KiSS-1 in colorectal cancer tissues was associated with the degree of differentiation, invasion and metastasis, as well as clinical staging. The 5-year overall survival rate of patients with colorectal cancer was 55.36% (31/56). The univariate survival analysis showed that patients with lowly expressed KiSS-1 had worse prognosis. The low expression of KiSS-1 is closely associated with the occurrence and development of colorectal cancer, especially to the degree of differentiation, invasion and metastasis, as well as clinical staging. Thus, the expression of KiSS-1 in colorectal cancer tissues can be used as a reference for the prognosis of colorectal cancer, and KiSS-1 is a potential new target for the treatment of colorectal cancer. PMID- 29435038 TI - High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells is associated with poor clinical response to the immune checkpoint inhibitor nivolumab. AB - The present study aimed to enrich circulating tumor cells (CTCs) from blood samples using a new size-sorting CTC chip. The present study also set out to identify a blood sensitivity marker for the immune checkpoint inhibitor nivolumab in patients with advanced, pre-treatment lung cancer. The CTC sorting efficacy of the chip was investigated and the large cell fraction of blood samples from 15 patients with pre-treatment lung cancer who were later administered nivolumab were purified. The expression levels of carcinoembryonic antigen (CEA), human Telomerase Reverse Transcriptase (hTERT), cytokeratin19 (CK19), and programmed death ligand-1 (PD-L1) were investigated to clarify the association between these CTC markers and the clinical response to nivolumab. The CTC chip effectively enriched cells from lung cancer cell line PC-9. The large cell fraction had a high expression of CEA and hTERT, with the former being significantly associated with the clinical response to nivolumab. The expression of CEA and hTERT in CTCs derived from the blood of a patient with lung cancer were also validated. The evaluation of CEA and possibly hTERT in CTCs collected by the CTC chip may represent a promising predictive blood marker for sensitivity to nivolumab. To the best of our knowledge this is the first report to describe the predictive CTC marker for nivolumab in pre-treatment patients. PMID- 29435039 TI - Characterization of mutations in BRCA1/2 and the relationship with clinic pathological features of breast cancer in a hereditarily high-risk sample of chinese population. AB - The database of BRCA1/2 mutations in Chinese population remains incomplete at present. Therefore, the present study aimed to report specific harmful BRCA1/2 mutations in the Chinese population and discuss the clinicopathological features in mutation carriers. BRCA1/2 germline mutation tests for 71 patients with breast cancer from a hereditarily high-risk Chinese population were performed using next generation sequencing for identification of deleterious mutations. Furthermore, the clinicopathological features between BRCA1/2 mutation carriers and non carriers were compared. A total of 13/71 (18.3%) patients carried a BRCA1 or BRCA2 mutation (7 BRCA1 and 6 BRCA2). The incidence of BRCA1/2 mutation in patients with bilateral breast cancer and patients with family history were 25, and 32.2%, respectively. Eleven pathogenic or likely pathogenic mutations were identified in 13 patients, among the mutation sites 7 were never reported before in Asian populations. The age at diagnosis of BRCA1/2 mutation carriers was older compared with non-mutation carriers (44.73 vs. 35.39 years; P=0.001) in this cohort. BRCA1/2 deleterious mutation carriers had a significantly lower chance of human epidermal growth factor receptor-2 (Her-2) positive status (P=0.010), higher tumor grade at diagnosis (P=0.009), higher probability to have a family history (P=0.016) and older age at diagnosis. Estrogen receptor (ER) and progesterone receptor (PR) status were significantly different between BRCA1, and BRCA2 mutation carriers (P=0.007). The current interpretation of BRCA1/2 status can only explain a small part of hereditary high-risk breast cancer. However, BRCA1/2 gene testing should still be recommended for women with a family history of breast cancer, as well as patients with breast cancer with specific pathologic types, which may be useful to make appropriate clinical decisions for treatment and prevention. PMID- 29435040 TI - Prostate stem cell antigen is expressed in normal and malignant human brain tissues. AB - Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI) anchored cell surface protein and exhibits an organ-dependent expression pattern in cancer. PSCA is upregulated in prostate cancer and downregulated in gastric cancer. PSCA is expressed in a variety of human organs. Although certain studies previously demonstrated its expression in the mammalian and avian brain, its expression in the human brain has not been thoroughly elucidated. Additionally, it was previously reported that PSCA is weakly expressed in the astrocytes of the normal human brain but aberrantly expressed in glioma, suggesting that PSCA is a promising target of glioma therapy and prostate cancer therapy. The current study identified PSCA expression in the neural and choroid plexus cells of the normal human brain by immunohistochemistry. In brain tumors, PSCA was expressed in medulloblastoma and glioma, and its expression was also observed in papilloma and papillary carcinoma of the choroid plexus, ependymoma and meningioma. The results suggest that PSCA may have a tumor-promoting function in brain tumors and is a potential target for their therapy. However, its expression in normal neuronal and choroid plexus cells implies that a PSCA-targeted therapy may lead to certain adverse phenomena. PMID- 29435041 TI - TBX2 expression is associated with platinum-sensitivity of ovarian serous carcinoma. AB - The standard treatment for ovarian serous carcinoma comprises maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate to chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. At present there are no reliable methods to determine or predict platinum resistance. T-box 2 (TBX2) is widely expressed in cancer cells and is involved in embryonic development and cell cycle regulation. TBX2 enables cells to bypass senescence through its ability to repress the cell cycle regulators p21 and p14ARF; silencing TBX2 induces senescence. Ectopic expression of TBX2 is associated with conferred resistance to the DNA-damaging chemotherapeutic drugs cisplatin and doxorubicin. In the present study the association between TBX2 expression and platinum sensitivity was investigated. A total of 54 patients with ovarian serous carcinoma (FIGO stages III and IV) were treated at Osaka City University Hospital (Osaka, Japan) from January 2005 to December 2012. Patients were divided into platinum-sensitive (n=27) and resistant (n=27) groups, according to the platinum free interval calculated from the last platinum administration to the time of recurrence. TBX2 expression in human ovarian serous carcinoma cells was inhibited by a TBX2-specific siRNA and changes in cisplatin and carboplatin sensitivity were determined. The TBX2-weighted score was significantly lower in the platinum sensitive group than the platinum-resistant group (P=0.005) and the low TBX2 expression group was significantly more sensitive to platinum-based chemotherapy (P=0.004). Sensitivity to cisplatin and carboplatin significantly increased when TBX2 expression was inhibited in human ovarian serous carcinoma cells in vitro (P<0.05). TBX2 expression may serve as a predictive marker of the efficacy of platinum-based chemotherapy for patients with ovarian serous carcinoma. PMID- 29435042 TI - Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT-2 pancreatic cancer mouse model. AB - Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer. PMID- 29435043 TI - Wnt3a expression is associated with poor prognosis of esophageal squamous cell carcinoma. AB - The Wnt signaling pathway is widely implicated in various types of cancer. Canonical Wnt signaling, including Wnt3a, may be a key component of cancer progression or chemoresistance. Consequently, it was hypothesized that Wnt3a expression may be a prognostic factor of esophageal squamous cell carcinoma (ESCC) due to its roles in chemoresistance and tumor progression. The aim of the present study was to investigate the association between Wnt3a expression and prognosis in patients with ESCC. Wnt3a expression was evaluated in resected specimens from 139 patients with thoracic ESCC who were subjected to curative surgery without neoadjuvant therapy in Tokai University Hospital between 2007 and 2009. Samples were assessed using immnohistochemistry. Patients with ESCC were divided into two groups according to the expression of Wnt3a in tumor tissue. The influence of Wnt3a expression on clinicopathological findings and prognosis of ESCC were subsequently investigated. Immnohistologically, 68 cases were Wnt3a positive in the cytoplasm of cancer cells, whereas 71 cases were negative. Multivariate analysis by Cox proportional hazard model showed the association between pN (HR=3.539, P=0.001), venous invasion (HR=2.798, P=0.012), Wnt3a expression (HR=1.691, P=0.046) and overall survival (OS). OS rate and disease free survival rate were poorer in Wnt3a-positive group compared with those in the Wnt3a-negative group as indicated by the log-rank test (P=0.012 and P=0.023, respectively). In pathological stages I and II, there was no significant difference in the OS rate between Wnt3a-positive and Wnt3a-negative groups; however, the OS rate of the Wnt3a-positive group was significantly worse than that of Wnt3a-negative group in pathological stage III (log rank test; P=0.017). Wnt3a-positive patients with recurrence had a significantly poorer prognosis compared with Wnt3a-negative patients (log-rank test; P=0.023). The present findings suggested that Wnt3a may be a prognostic factor of ESCC. PMID- 29435045 TI - The protective effects of rutaecarpine on acute pancreatitis. AB - Acute pancreatitis (AP) is the acute inflammation of the pancreas. The morbidity of AP has increased in recent years. Certain patients eventually develop severe AP (SAP), which rapidly progresses to multiple organ dysfunction; the incidence of this occurring in patients with AP is 20-30%. To date, no specific drugs or methods exist to treat this disease. Rutaecarpine relaxes vascular smooth muscle by stimulating calcitonin gene-related peptide (CGRP) release via activation of vanilloid receptor subtype 1 (VR1). It has been demonstrated that rutaecarpine induces a therapeutic effect on SAP. The present study was conducted to characterize the molecular mechanisms underlying the protective effects of rutaecarpine against AP using a rat model of AP. Gross pathological changes of the pancreas, as well as the pancreatic tissue histopathological score, were assessed following treatment with rutaecarpine, capsazepine or a combination of the two. Serum amylase activity was detected using an automatic biochemistry analyzer. Changes in the serum concentrations of interleukin (IL)-6, tumor necrosis factor (TNF-alpha), IL-10 and CGRP were assessed by ELISA and radioimmunoassay. The results demonstrated that pre-treatment with rutaecarpine markedly decreased pancreatic inflammation and necrosis, reduced the volume of ascites, and significantly increased the plasma concentration of CGRP and the serum concentration of IL-10, an anti-inflammatory cytokine. However, serum concentrations of the inflammatory cytokines IL-6 and TNF-alpha were decreased. The effect of rutaecarpine treatment markedly improved with increases in the drug dose. Capsazepine, as a competitive vanilloid receptor antagonist, abolished these protective effects of rutaecarpine against AP. Therefore, the results of the present study indicate that rutaecarpine protects against AP in rats by upregulating endogenous CGRP release via activation VR1 of, to improving the microcirculation of the pancreatic tissue and regulate the expression of inflammatory factors. PMID- 29435044 TI - Soft-shelled turtle peptide modulates microRNA profile in human gastric cancer AGS cells. AB - Cancer prevention using natural micronutrition on epigenetic mechanisms primarily revolves around plant extracts. However, the role of macronutrition, including animal peptides, on epigenetic modification in cancer has been elusive. In traditional Chinese medicine, the soft-shelled turtle has a long-history of being a functional food that strengthens immunity through unknown mechanisms. The present study aimed to investigate the impact of soft-shelled turtle peptide on microRNA (miRNA) expression in gastric cancer (GC) cells and to analyze the potential anticancer mechanisms for GC. Affymetrix GeneChip miRNA 3.0 Array and quantitative polymerase chain reaction were used to detect the miRNA expression profile in human GC AGS cells treated with the soft-shelled turtle peptide. The results demonstrated that 101 miRNAs (49 upregulated miRNAs and 52 downregulated miRNAs) were significantly differentially expressed in the AGS cells following soft-shelled turtle peptide treatment. Several tumor suppressor miRNAs were upregulated markedly, including miRNA-375, let-7d, miRNA-429, miRNA-148a/148b and miRNA-34a. Pathway analysis indicated that soft-shelled turtle peptide may function with anticancer properties through the Hippo signaling pathway and the forkhead box O signaling pathway. Therefore, these results demonstrated that soft shelled turtle peptide has the capacity to influence cancer-related pathways through the regulation of miRNA expression in GC cells. PMID- 29435046 TI - Effect of silencing colon cancer-associated transcript 2 on the proliferation, apoptosis and autophagy of gastric cancer BGC-823 cells. AB - The role of long non-coding RNAs (lncRNAs) in the carcinogenesis and progression of tumors has been receiving increasing attention. Colon cancer-associated transcript 2 (CCAT2), a type of oncogenic lncRNA, is regarded as a novel biomarker of poor prognosis and metastasis in various types of cancer. However, the molecular contributions of CCAT2 to gastric cancer (GC) progression remain largely unclear. The aim of the present study was to demonstrate the effect of silencing CCAT2 on the biological behavior of GC BGC-823 cells and illustrate the potential underlying molecular mechanisms. A short hairpin RNA interference plasmid pRNAT-U6.1-CCAT2 targeting CCAT2 was successfully constructed. At 48 h after transfection with the interference plasmid, the survival rate of BGC-823 cells was significantly decreased, as determined by the MTT assay. In addition, RT-qPCR results revealed that CCAT2 gene expression was effectively suppressed by the transfection, while POU domain class 5 transcription factor 1B (POU5F1B) gene expression was significantly decreased. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay further revealed that the apoptotic index was significantly higher in the interference group. Western blot analysis also demonstrated that the expression of beclin-1 protein was significantly increased, whereas the expression levels of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) proteins were downregulated in the interference group. In conclusion, CCAT2 was able to positively regulate the expression of POU5F1B gene. Furthermore, silencing of CCAT2 gene inhibited the proliferation of BGC-823 cells, as well as induced apoptosis and autophagy in BGC-823 cells, by suppression of the PI3K/mTOR signaling pathways. PMID- 29435047 TI - GTSF1 gene may serve as a novel potential diagnostic biomarker for liver cancer. AB - The gametocyte-specific factor 1 (GTSF1) gene participates in DNA methylation and retrotransposon activation in germ cells, particularly during cell proliferation. The present study aimed to assess the level of GTSF1 gene expression in liver cancer tumor tissues, and its role in human hepatoma cell lines in vitro and in a nude mouse model in vivo. GTSF1 gene expression was detected in liver cancer tumor tissues, compared with in healthy controls, via reverse transcription quantitative polymerase chain reaction. An adeno-associated virus vector was used to study tumor stem cell proliferation in vivo. A plasmid expressing GTSF1 was constructed and transfected into various human hepatoma cell lines, in order to analyze the cellular proliferation and apoptosis of liver cancer cells using small interfering (si)RNAs in vitro. In the present study, GTSF1 gene expression was detected in 18/24 (75.0%) liver cancer tumor tissues from patients with hepatocellular carcinoma (HCC), and elevated GTSF1 expression was identified in the tissue of one of 32 healthy control samples (3.13%; P<0.05). Notably, the GTSF1 gene was expressed at a higher frequency in AFP-positive HCC samples (14/16, 87.50%) compared with in AFP-negative HCC samples (4/8, 50.0%; P=0.129). In addition, there was no statistical significance between GTSF1 expression in non-HBV-infected (71.42%) and HBV-infected HCC specimens (76.47%), as determined by a chi2 test (P=0.921). It was demonstrated that GTSF1 significantly increased the tumorigenicity of Ad-shNC-transfected (GTSF1-positive) HepG2 cells in the nude mouse xenograft model, whereas the sizes and weights of the tumors in the GTSF1-negative group were dercreased in comparison with the GTSF1-positive group (P<0.05). Reduced levels of GTSF1 mRNA, along with fewer and smaller colonies, were identified in two groups of human liver cancer cells treated with with GTSF1 targeting siRNA, when compared with cells without GTSF1 mRNA interference (P<0.05). In summary, the present study elucidated the GTSF1 mRNA expression pattern in liver cancer, and investigated the potential role of GTSF1 in tumorigenesis. The data suggest an important role for the GTSF1 gene in the molecular etiology of hepatocarcinogenesis, and indicate a potential application of GTSF1 mRNA expression in liver cancer diagnosis and therapy. PMID- 29435048 TI - Luteinizing hormone compromises the in vivo anti-tumor effect of cisplatin on human epithelial ovarian cancer cells. AB - Platinum-based chemotherapy is the most common therapeutic regimen used to treat patients with ovarian cancer. However, the emergence of drug resistance to platinum compromises the clinical success of this treatment. Epithelial ovarian cancer is usually accompanied by an increased level of luteinizing hormone (LH). Therefore, the effect of LH on platinum resistance requires further investigation. In the current study, the effect of cisplatin and/or LH on platinum resistance was examined using the SKOV3ip1 and HeyA8 models. Following therapy, tumors were examined for proliferation (ki67) and apoptosis (cleaved caspase-3). Cisplatin alone and in combination with LH significantly inhibited tumor growth in SKOV3ip1- and HeyA8-implanted mice. Treatment with LH alone had minimal effect in the models. However, treatment with cisplatin combined with LH was less effective than treatment with cisplatin alone. Additionally, ki67 counts were significantly increased and cleaved caspase-3 counts were significantly reduced in mice treated with cisplatin combined with LH compared with mice treated with cisplatin alone. Such results indicate that LH weakens the anti tumor effect of cisplatin in vivo and that LH may contribute to the development of drug resistance to cisplatin in ovarian cancer. PMID- 29435049 TI - MED28 increases the colony-forming ability of breast cancer cells by stabilizing the ZNF224 protein upon DNA damage. AB - The regulation of gene expression by transcription factors serves a critical function in cell proliferation. Zinc-finger protein 224 (ZNF224), a Kruppel associated-box-containing zinc finger protein, is known to serve a crucial function in integrating the transcriptional co-factors that activate transcriptional regulation pathways in the cell. A previous study demonstrated that ZNF224 enhances cell proliferation by downregulating the expression of p21 and p53. The present study identified mediator complex subunit 28 (MED28) as a potential binding partner for ZNF224; this was confirmed by co immunoprecipitation and a surface plasmon resonance assay. Additionally, the KRAB domain at the N-terminal of ZNF224 interacts with the MED domain of MED28. Bimolecular fluorescence complementation analysis revealed that ZNF224 associates with MED28 in the nucleus. In addition, ZNF224 was rapidly degraded upon treatment with the DNA-damaging agent camptothecin (CPT). Transient overexpression of MED28 inhibited the CPT-mediated degradation of ZNF224, resulting in increased colony formation by MCF-7 cells. The molecular mechanisms that underlie the biological outcomes of MED28 expression have not yet been fully elucidated. The present study provides molecular evidence for the function of ZNF224 and MED28 in the DNA-damage response. PMID- 29435050 TI - Actein inhibits cell proliferation and migration and promotes cell apoptosis in human non-small cell lung cancer cells. AB - Non-small cell lung cancer (NSCLC) is the leading cause of death in smokers and the most common cause for cancer mortality in both males and females in the United States. Predisposition of this malignancy to distant metastasis leads to poor prognosis; therefore, it is urgent to discover novel therapeutic agents for metastatic NSCLC. The present study aimed to investigate the effects of actein treatment on NSCLC cell growth and migration. Cell viability assays demonstrated that administration of actein markedly inhibited NSCLC cell proliferation in a dose- and time-dependent manner. Transwell assays demonstrated that actein treatment suppressed cell migration and invasion in two NSCLC cell lines, A549 and 95D. Furthermore, treatment with actein remarkably increased the activities of caspase-3 and -9 in NSCLC cells. The protein expression levels of cytoplasmic BCL2 apoptosis regulator (Bcl-2) and BCL2 associated X (Bax) were markedly decreased, while the protein expression levels of mitochondrial Bax, caspase-3, 9 and cytochrome c were upregulated following actein treatment, as evidenced by western blot analysis. The present results demonstrated that actein inhibited cell proliferation and metastasis and promoted cell apoptosis in NSCLC cells, which indicated that actein administration might serve as a potential therapeutic strategy for the treatment of NSCLC in the clinic. PMID- 29435051 TI - Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer. AB - KRAS mutations serve a function in tumorigenesis of colorectal cancer (CRC) and guide the use of targeted drugs. However, the prognostic value of KRAS mutations and their subtypes remain controversial. The present study aimed to investigate the correlations between KRAS mutations and clinicopathological characteristics, and their prognostic significance in Chinese patients with metastatic CRC (mCRC). A total of 135 patients with mCRC were analyzed for KRAS mutations. Mutations in codon 12 and 13 were identified in 45 (33.3%) patients. Only 3 patients harbored a mutation of V600E. Compared with male patients, KRAS codon 12 mutations were more common in female patients (P<0.05). KRAS codon 13 mutations tended to arise in right-sided compared with left-sided colon cancer (P<0.05). Survival analysis was performed in 101 patients receiving primary tumor resection. Compared with KRAS codon 12 wild-type, codon 12 mutations were markedly correlated with a poorer survival (log-rank P=0.002). No prognostic significance was revealed in codon 13 mutations. In univariate analysis, mortality risk was significantly increased by subtypes of G12D and G12V [hazard ratio (HR) =2.313, 95% confidence interval (CI) =1.069-5.004, P=0.03; HR=2.621, 95% CI=1.057-6.497, P=0.04, respectively]. The results of the present study suggested that codon 12 mutations, in particular G12D and G12V, predicted a negative prognosis in Chinese patients with mCRC. These findings require further confirmation via prospective studies with larger samples. PMID- 29435052 TI - Simvastatin in combination with meclofenamic acid inhibits the proliferation and migration of human prostate cancer PC-3 cells via an AKR1C3 mechanism. AB - Statins have become of interest in research due to their anticancer effects. However, the exact mechanism of their anticancer properties remains unclear. The authors previously reported that statins decrease intracellular cholesterol levels in androgen-independent prostate cancer cells. In de novo androgen synthesis, cholesterol is the primary material and certain enzymes have important roles. The present study aimed to determine whether simvastatin alters the expression of androgen synthesis-associated enzymes in androgen-independent prostate cancer cells. A novel combination therapy of statins and other drugs that inhibit the overexpression of enzymes involved in androgen synthesis was explored. The cytotoxicity of simvastatin and meclofenamic acid was assessed in prostate cancer cells using MTS and migration assays. Testosterone and dihydrotestosterone concentrations in the culture medium were measured using liquid chromatography-tandem mass spectrometry. RAC-alpha-serine/threonine protein kinase (Akt) phosphorylation was detected by western blot analysis. Following treatment with simvastatin, aldo-keto reductase family 1 member C3 (AKR1C3) expression increased in PC-3 (>60-fold) and LNCaP-LA cells, however not in 22Rv1 cells. Small interfering (si)RNA was used to clarify the effects of AKR1C3 expression. The reduction in AKR1C3 expression in PC-3 cells following siRNA transfection was not associated with basal cell proliferation and migration; however, treatment with simvastatin decreased cell proliferation and migration. The combination of simvastatin and meclofenamic acid, an AKR1C3 inhibitor, further enhanced the inhibition of cell proliferation and migration compared with treatment with either drug alone. Furthermore, treatment with simvastatin attenuated insulin-like growth factor 1-induced Akt activation; however, the combination of simvastatin and meclofenamic acid further inhibited Akt activation. These results suggest that the combination of simvastatin and meclofenamic acid may be an effective strategy for the treatment of castration resistant prostate cancer. PMID- 29435053 TI - RKIP and peroxiredoxin 2 expression predicts the proliferative potential of gastric cancer stem cells. AB - Gastric cancer is associated with a high mortality rate, with the development of gastric cancer stem cells underlying this. Gastric cancer stem cells are responsible for tumor initiation, progression and recurrence. However, the link between gastric cancer and gastric cancer stem cells remains to be fully understood. Murine models mimic a human microenvironment more accurately than in vitro studies and are useful models for understanding the behavior of different markers. The present study compared the expression of cluster of differentiation 44 (CD44), a stem cell marker, with the expression of other cancer-associated markers, including Raf kinase inhibitor protein (RKIP) and peroxiredoxin 2, in different pathological conditions of gastric cancer development using histological, immunohistological and western blot analyses. Initially, the murine model of gastric cancer was established using N-methyl-N-nitrosourea, a chemical carcinogen. Following initiation of cancer, immunohistochemistry was used to compare the expression of CD44, RKIP and peroxiredoxin 2 at different stages of cancer development. The results suggested CD44 and peroxiredoxin 2 expression was upregulated as the tumor progressed. However, expression of RKIP, a metastasis suppressor, was elevated in the initial stage of gastric cancer and suppressed during the aggressive stages. In agreement with previous data suggesting higher expressions of RKIP in the initial stages of cancer and its downregulation in the advanced stage, the results of the present study revealed that RKIP exhibited a negative effect on initial tumor development, and that the downregulation of RKIP in the advanced stages of cancer facilitated CD44 and peroxiredoxin 2 overexpression. PMID- 29435054 TI - Dihydroartemisinin-induced apoptosis in human acute monocytic leukemia cells. AB - Dihydroartemisinin (DHA) is a derivative of artemisinin. The present study aimed to investigate whether DHA induces apoptosis in the THP-1 human acute monocytic leukemia cell line (AMoL), and to identify the relative molecular mechanisms. The results of the present study demonstrated that the viability of THP-1 cells were inhibited by DHA in a dose- and time-dependent manner, which was accompanied by morphological characteristics associated with apoptosis. After 24 h of 200 uM DHA treatment, the proportion of apoptotic cells was significantly increased compared with the untreated controls (P<0.01). In addition, DHA downregulated the levels of B-cell lymphoma (Bcl)-2, protein kinase B (Akt)1, Akt2 and Akt3 gene expression, and increased the expression of the Bcl-2-associated X protein apoptosis regulator. The protein expression of phospho-Akt and phospho extracellular signal-regulated kinase (ERK) was also decreased, and the protein expression level of cleaved caspase-3 was increased following treatment with DHA. Therefore, DHA may induce apoptosis in the AMoL THP-1 cell line via currently unknown underlying molecular mechanisms, including the downregulation of ERK and Akt, and the activation of caspase-3. PMID- 29435055 TI - Interference of P-REX2a may inhibit proliferation and reverse the resistance of SGC7901 cells to doxorubicin. AB - Drug resistance inhibits the efficacy of doxorubicin in gastric cancer. Phosphatidylinositol 3,4,5-trisphosphate RAC exchanger 2a (P-REX2a) activates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway by binding to and inactivating phosphatase and tensin homolog (PTEN), which functions as a tumor promoter in a number of types of cancer. However, there is no research concerning the association between P-REX2a expression and drug resistance in gastric cancer. In the present study, the expression of P-REX2a in clinical gastric cancer tissues was detected, and the mechanism of doxorubicin resistance in the gastric cancer cell line SGC7901 was investigated. Using reverse transcription-quantitative polymerase chain reaction and western blotting, it was demonstrated that the mRNA and protein expression of P-REX2a was increased in gastric cancer tissues. MTT assays were also used to determine proliferation, and proliferation was revealed to be reduced following transfection of P-REX2a small interfering (si)RNA. When the cells were treated with 0.3 uM doxorubicin for 24 h, the rate of apoptosis in the siRNA-transfected groups significantly increased and no marked changes in of PTEN and Akt expression were observed. By contrast, the activity of PTEN increased, and the expression of p-Akt (S473) decreased in the P-REX2a siRNA-transfected group compared with the control. The detection of PTEN enzymatic activity in the present study was based on phosphatidylinositol-3,4,5-trisphosphate. Therefore, it was concluded that P-REX2a may participate in the generation of resistance to doxorubicin in gastric cancer, and this may be associated with the upregulation of the PI3K/Akt signaling pathway via inactivation of PTEN. PMID- 29435056 TI - Furin inhibitor D6R suppresses epithelial-mesenchymal transition in SW1990 and PaTu8988 cells via the Hippo-YAP signaling pathway. AB - Hexa-D-arginine (D6R), an inhibitor of furin, has potential therapeutic applications in different types of human tumor. However, the function of D6R in targeting pancreatic cancer cells remains to be elucidated. In the present study, the proliferation, invasion and migration abilities of SW1990 and PaTu8988 cells were examined using a Cell Counting Kit-8, and Transwell and wound healing assays. Subsequently, the expression of proteins associated with epithelial mesenchymal transition (EMT) and the Hippo-yes-associated protein (YAP) pathway were detected using western blot analysis. It was revealed that D6R significantly inhibited the proliferation, migration and invasion abilities of SW1990 and PaTu8988 cells. Additionally, D6R led to the upregulation of E-cadherin (an epithelial marker), and the downregulation of N-cadherin and vimentin (mesenchymal markers) in SW1990 and PaTu8988 cells. Furthermore, the results of the present study revealed that D6R significantly affected the YAP phosphorylation level and the total YAP protein level, indicating that D6R was functionally involved in the Hippo-YAP signaling pathway. It has been suggested that D6R-suppressed EMT in SW1990 and PaTu8988 cells may occur via the Hippo-YAP pathway and that it may be a feasible drug to ameliorate the malignant phenotype of SW1990 and PaTu8988 cells. PMID- 29435057 TI - mir-106a regulates cell proliferation and apoptosis of colon cancer cells through targeting the PTEN/PI3K/AKT signaling pathway. AB - Colorectal cancer (CRC) is a common digestive tract tumor. Cancer tissues and healthy tissues were extracted from patients with CRC who were treated at our hospital. Targetscan and PicTar were used to identify microRNAs (miRNAs/miRs) that may interact with phosphatase and tensin homolog deleted on chromosome ten (PTEN). Dual luciferase reporter assay was applied to detect whether the 3' untranslated region (UTR) of PTEN was targeted by miR-106a. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) showed that there was significantly higher miR-106a expression level in cancer tissue compared with in healthy tissue. The expression level of miR-106a in NCM640, SW620 and HT29 cell lines was detected by RT-qPCR, and HT29 cells showed the highest miR-106a level. HT29 cells were used for the present study, separated into control, miR-NC antagomiR and miR-106a antagomiR group. HT29 cell characteristics were tested. The results demonstrated that in the miR-106a antagomiR group, there was a lower cell proliferation and higher cell apoptosis rate compared with the control and miR-NC antagomiR groups. miR-106a was verified to target PTEN 3'-UTR in HT29 cells. In comparison with control and miR-NC antagomiR groups, the protein level of PTEN was increased and phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B was decreased following miR-766 antagomiR administration. The findings propose that miR-106a may serve a therapeutic target for the treatment of CRC. PMID- 29435058 TI - Ursolic acid activates the apoptosis of prostate cancer via ROCK/PTEN mediated mitochondrial translocation of cofilin-1. AB - Ursolic acid has various pharmacological activities, and can reduce blood fat as well as having antihepatic, antitumoral, anti-inflammatory and antiviral properties. However, the pro-apoptotic mechanism by which ursolic acid influences human prostate cancer requires additional study. The aim of the present study was to assess whether ursolic acid activates the apoptosis of prostate cancer and to investigate the mechanism by which the Rho-associated protein kinase 1 (ROCK1)/phosphatase and tensin homolog (PTEN) signaling pathway performs a role in ursolic acid-mediated cofilin-1 to induce apoptosis in human prostate cancer. Firstly, the present study determined the pro-apoptotic mechanism by which ursolic acid influences the cell proliferation and apoptosis of human prostate LNCaP cancer cells. Caspase-3/9 activities and ROCK1, PTEN, Cofilin-1 and cytochrome c protein expression levels were also analyzed. In the present study, it is reported that the pro-apoptotic mechanism of ursolic acid potently suppressed the cell proliferation of human prostate LNCaP cancer cells. The present study revealed that the mediation of ROCK1/PTEN-cofilin-1/cytochrome c protein expression activates caspase-3/9 activities which subsequently induced the apoptosis of human prostate cancer cells. In conclusion, these findings demonstrated that ursolic acid activates the apoptosis of prostate cancer via ROCK/PTEN mediated cofilin-1/cytochrome c which mediated caspase-3/9 activities. PMID- 29435059 TI - MACC1 and HGF are associated with survival in patients with gastric cancer. AB - Metastasis-associsated in colon cancer 1 (MACC1), a newly identified oncogene, promotes tumor cell proliferation and invasion. In the present study, the expression of MACC1, hepatocyte growth factor (HGF) and its receptor, MET proto oncogene (c-Met), was investigated in human gastric cancer tissues and adjacent normal tissues by immunohistochemistry. The association between the expression levels of the proteins and the clinicopathological parameters of the tumors were statistically analyzed. Furthermore, lentiviral particles expressing MACC1 were used to infect the hepatic satellite cell (HSC) line LX2. The expression of alpha smooth muscle actin (SMA), HGF, matrix metallopeptidase (MMP)-2 and MMP-9 in human HSCs was examined by western blotting and reverse transcription quantitative polymerase chain reaction. Transwell assays were used to measure the effect of MACC1-infected or non-infected HSCs on the migration and invasion abilities of MKN45 and MKN74 gastric carcinoma cells in vitro. The results demonstrated that positive protein expression of MACC1, HGF and c-Met was significantly higher in human gastric cancer tissues compared with adjacent normal tissues. Positive expression of MACC1 and c-Met in gastric cancer tissues had no correlation with the sex, age, tumor location and peritoneal metastasis of patients, but was significantly correlated with tumor size, depth of tumor invasion, lymph node metastasis, TNM stage, histological differentiation, and overall (5 years) and disease-free survival (5 years). Positive expression of each MACC1, HGF and c-Met protein was demonstrated to be positively correlated with each other in human gastric cancer tissues. Western blotting results confirmed that MACC1 protein was overexpressed in MACC1-overexpressing lentivirus infected HSCs. Overexpression of MACC1 significantly increased HGF, MMP-2, MMP-9 and alpha-SMA expression levels in HSCs. Results from the Transwell assays indicated an increase in the number of MKN45 or MKN74 cells migrating towards MACC1-overexpressing HSCs, compared with control HSCs. These findings suggested that MACC1 may regulate the expression of HGF, MMP-2 and MMP-9 in HSCs, and may thus promote migration and invasion of gastric carcinoma cells. MACC1, HGF and c Met might cooperatively participate in the malignant progression of gastric cancer. In conclusion, MACC1 might serve as a useful molecular target for the diagnosis, treatment and prognosis of gastric cancer. PMID- 29435060 TI - Screening of FOXD3 targets in lung cancer via bioinformatics analysis. AB - The purpose of the present study was to explore the targets of forkhead box D3 (FOXD3) in lung cancer, and thus contribute to the diagnosis and therapy of the disease. The gene expression profile of GSE64513 was downloaded from the Gene Expression Omnibus database. The dataset contained 3 FOXD3 knockout A549 lung cancer cell samples and 3 normal A549 cell samples. The differentially expressed genes (DEGs) between the FOXD3-knockout and normal A549 cells were identified using the limma package in R. The alternative splicing genes (ASGs) in FOXD3 knockout samples were identified by Replicate Multivariate Analysis of Transcript Splicing software. The Database for Annotation, Visualization and Integrated Discovery was used to identify the enriched functions and pathways of DEGs and ASGs. A protein-protein interaction (PPI) network was constructed based on results from the Search Tool for the Retrieval of Interacting Genes database and visualized using Cytoscape software. A total of 1,853 DEGs and 2,249 ASGs were identified in FOXD3-knockout A549 cells compared with normal A549 cells. The DEGs were enriched in 338 Gene Ontology (GO) terms and 21 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the ASGs were enriched in 470 GO terms and 22 KEGG pathways. A total of 199 overlaps between the DEGs and the ASGs were identified; a PPI network constructed based on the overlapping genes contained 97 nodes and 115 pairs. FOXD3 may serve an important role in regulating the growth, migration and proliferation of tumor cells in lung cancer. The present study indicates that a number of genes, including AURKA and NOS3, may be targets of FOXD3, mediating its effect in lung cancer. PMID- 29435061 TI - Beclin-1 knockdown decreases proliferation, invasion and migration of Ewing sarcoma SK-ES-1 cells via inhibition of MMP-9. AB - Although Beclin-1, a well-known key regulator of autophagy, has been demonstrated to serve a function in a number of disorders, including cancer, aging and degenerative diseases, its biological function in Ewing sarcoma (ES) remains unresolved. The objective of the present study was to determine the in vitro effect of Beclin-1 knockdown on the growth and malignant phenotype of ES SK-ES-1 cells, which have increased endogenous expression of Beclin-1 compared with RD-ES cells, and to investigate the underlying molecular mechanism. Cell proliferation, invasion and migration were investigated using CCK-8, Boyden chamber Transwell, and wound healing assays, respectively. Western blot analysis was used to detect expression levels of matrix metalloproteinase (MMP)-2 and MMP-9, which are associated with the malignant phenotype. Beclin-1 knockdown significantly inhibited proliferation, invasion and migration of SK-ES-1 cells. Western blot analysis revealed that Beclin-1 knockdown caused a significant reduction in the expression of MMP-9; no marked changes in MMP-2 expression were observed in the si-Beclin-1 group compared with the control group. The results of the present study suggest that Beclin-1 serves a function in proliferation, tumor progression and inhibition of autophagy in ES, and demonstrates it's potential as a target to increase the efficacy of anticancer agents. PMID- 29435062 TI - Downregulated cytoplasmic polyadenylation element-binding protein-4 is associated with the carcinogenesis of head and neck squamous cell carcinoma. AB - Cytoplasmic polyadenylation element-binding protein-4 (CPEB4) is involved in several biological processes that are associated with cancer progression. However, it remains unknown whether CPEB4 expression levels are associated with head and neck squamous cell carcinoma (HNSCC). The aim of the present study was to explore the potential function of CPEB4 in HNSCC. The expression of CPEB4 was analyzed in HNSCC from six Gene Expression Omnibus (GEO) datasets. Immunohistochemical staining was conducted to examine CPEB4 protein levels in an HNSCC tissue microarray (TMA). According to the GEO dataset analyses, CPEB4 gene expression was downregulated in HNSCC compared with normal samples (P<0.05). Notably, a statistical difference was observed between different tumor grades (P<0.05). Furthermore, the methylation of the CPEB4 gene in HNSCC was significantly increased compared with that observed in normal samples (P<0.01). The outcome from the TMA demonstrated that CPEB4 protein expression in human HNSCC tumors was significantly decreased compared with normal samples (P<0.05). In addition, the expression of CPEB4 protein was negatively associated with histological grades of HNSCC (P<0.05). The results from the present study suggested that CPEB4 may function as a tumor suppressor gene in HNSCC, which identifies the potential value of CPEB4 in predicting prognosis of HNSCC. Hypermethylation of the CPEB4 gene may be responsible for the downregulation of CPEB4 expression in HNSCC and result in tumorigenesis. PMID- 29435063 TI - Inhibition of enhancer of zeste homolog 2 increases the expression of p16 and suppresses the proliferation and migration of ovarian carcinoma cells in vitro and in vivo. AB - Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase, which targets histone H3 lysine 27. Studies have reported that EZH2 is involved in the development of several types of tumor, including ovarian cancer. p16, a well known cell cycle regulator, has been demonstrated to be a tumor suppressor gene in a variety of malignant cells. However, the regulatory association between EZH2 and p16 in ovarian cancer remains to be fully elucidated. The present study aimed to determine whether EZH2 is involved in the development of ovarian cancer by regulating the expression of p16. An EZH2 short hairpin RNA (shRNA) lentiviral vector was constructed and used for transducing A2780 and SKOV3 ovarian cancer cell lines. The expression levels of EZH2 and p16 in the ovarian cancer cells were detected using a reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. The function of the inhibition of EZH2 in cell proliferation and migration were determined using a CCK-8 assay and Transwell assay. In addition, a nude mouse xenograft model was used to determine the function of EZH2 and p16 in the formation of ovarian cancer in vivo. The results revealed that the inhibition of EZH2 increased the expression of p16, and suppressed the proliferation and migration capabilities of ovarian cancer in vitro. The downregulated expression of EZH2 suppressed ovarian tumor formation in vivo. The results of the study revealed that p16 was negatively regulated by EZH2 in ovarian cancer, and that p16 and EZH2 are important in the tumorigenesis of ovarian cancer. EZH2 and p16 represent potential biomarkers for the diagnosis of ovarian cancer and as targets for ovarian cancer gene therapy. PMID- 29435064 TI - TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate-induced growth inhibition in pancreatic cancer cells. AB - Chemotherapy and radiotherapy are the most common approaches in cancer therapy. They may kill cancer cells through the generation of high levels of reactive oxygen species (ROS), which leads to oxidative DNA damage. However, tumor resistance to ROS is a problem in cancer therapy. MTH1 sanitizes oxidized dNTP pools to prevent the incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, cancer cells require MTH1 activity to avoid the incorporation of oxidized dNTPs, which would result in DNA damage and cell death. By targeting a redox-adaptation mechanism, MTH1 inhibition represents a novel therapeutic strategy against cancer. However, recent reports have indicated that growth inhibition by MTH1 inhibitors may be due to off-target cytotoxic effects. TH588, one of the first-in-class MTH1 inhibitors, kills cancer cells by an off-target effect. However, a low concentration of TH588 may effectively inhibit MTH1 activity without inhibiting cell proliferation. Phenethyl isothiocyanate (PEITC) is a dietary anticarcinogenic compound and an inducer of ROS. In the present study, it has been demonstrated that combined treatment with PEITC and TH588 effectively inhibited the growth of pancreatic cancer MIAPaCa-2 and Panc-1 cells. The antioxidant N-acetylcysteine negated this synergistic growth inhibition. PEITC and TH588 cooperatively induced the formation of 8-oxo-deoxyguanine in nuclei and pH2AX foci, a marker of DNA damage. However, the combined effects are not associated with MTH1 mRNA expression in several cancer cell lines, suggesting that the possibility of an off-target effect of TH588 cannot be eliminated. These results suggest that the combination of PEITC and TH588 has potential as a novel therapeutic strategy against pancreatic cancer. PMID- 29435065 TI - Increased expression of monoamine oxidase A is associated with epithelial to mesenchymal transition and clinicopathological features in non-small cell lung cancer. AB - Monoamine oxidase A (MAOA), a mitochondrial enzyme, is closely associated with neurological disorders. Recently, MAOA has been linked to the progression of prostate cancer, hepatocellular carcinoma, and cholangiocarcinoma. However, MAOA was reported to have different effects on the progression of these types of cancer, and the role of MAOA in non-small cell lung cancer (NSCLC) progression remains unclear. The present study determined the expression of MAOA and epithelial to mesenchymal transition (EMT) markers in 45 pairs of NSCLC and matched non-tumor adjacent lung tissues, and further analyzed the correlation between MAOA expression and the EMT or the development of clinicopathological features. The results demonstrated that protein and mRNA expression levels of MAOA in NSCLC tissues were higher than those observed in the matched non-tumor adjacent lung tissues. Furthermore, the increased MAOA expression in NSCLC tissues was positively correlated with N-cadherin (r=0.525, P=0.002), Slug (r=0.515, P=0.001), and Twist (r=0.448, P=0.008) expressions, but negatively correlated with E-cadherin expression (r=-0.387, P=0.01). Additionally, the elevated MAOA expression in NSCLC tissues was associated with late stage NSCLC (Z=-2.596, P=0.029) and lymph node metastases (Z=-2.378, P=0.020). These findings suggest that MAOA may have a role in promoting NSCLC progression by mediating EMT. PMID- 29435066 TI - Potential anticancer effect of prostratin through SIK3 inhibition. AB - Prostratin, a phorbol ester natural plant compound, has been demonstrated to exert an anti-retroviral effect through activation of latent cluster of differentiation (CD)4+T lymphocytes and inhibition of viral entry into the cell through downregulation of chemokine receptor type 4 (CXCR4) expression. However, the potential effect of prostratin on cancer is yet to be defined. As CXCR4 is well known to induce cancer migration, it was hypothesized that prostratin induces an anti-cancer effect through inhibition of CXCR4 expression. The authors previously demonstrated that high stimulating conditions (sub-minimal IL-17, 0.1 ng/ml, synergized with high salt, Delta0.05 M NaCl) promote breast cancer cell proliferation and CXCR4 expression through upregulation of salt-inducible kinase (SIK)-3. The present study demonstrated that prostratin selectively exerted increased cytotoxicity (IC50 of 7 uM) when breast cancer cells were cultured in high stimulating conditions, compared with regular basal culture conditions (IC50 of 35 uM). Furthermore, the cytotoxic potential of prostratin was increased seven fold in the four breast cancer cell lines (MCF-7, MDA-MB-231, BT-20 and AU-565) compared with the non-malignant MCF10A breast epithelial cell line. This suggested that prostratin specifically targets cancer cells over normal cells. Mechanistic studies revealed that prostratin inhibited CXCR4 expression in breast cancer cells through downregulation of SIK3 expression. Overall, the data suggest that prostratin is a novel drug target for the pro-oncogenic factor SIK3. These studies could form a basis for further research to evaluate the anticancer effect of prostratin in a combinatorial chemotherapeutic regimen. PMID- 29435067 TI - Bergamottin, a natural furanocoumarin abundantly present in grapefruit juice, suppresses the invasiveness of human glioma cells via inactivation of Rac1 signaling. AB - The aim of the present study was to explore the effect of bergamottin, a natural furanocoumarin obtained from grapefruit juice, on the invasiveness of human glioma cells. The results revealed that treatment with bergamottin for 48 h significantly inhibited wound-healing migration and Matrigel invasion of human glioma cells, compared with untreated cells (P<0.05). Bergamottin treatment caused a significant decrease in the expression and secretion of matrix metalloproteinase (MMP)-9 in glioma cells compared with untreated cells (P<0.05). A Rac1-GTP pull-down assay demonstrated that bergamottin-treated glioma cells had a significantly decreased level of active Rac1-GTP compared with untreated cells (P<0.05). However, bergamottin had no significant effect on cell division cycle 42 activity. Expression of constitutively activated Rac1 almost completely restored the migration and invasion of bergamottin-treated glioma cells. In addition, bergamottin-induced downregulation of MMP-9 was prevented by exogenous activated Rac1. The results of the present study demonstrated that bergamottin exhibits anti-invasive activity in human glioma cells through the inactivation of Rac1 and downregulation of MMP-9. PMID- 29435068 TI - Common module analysis reveals prospective targets and mechanisms of pediatric adrenocortical adenoma and carcinoma. AB - Pediatric adrenocortical carcinoma and adrenocortical adenoma are two rare diseases affecting children. Molecular analyses were performed to identify commonalities in gene expression between the diseases. Differentially expressed genes were identified for the pediatric adrenocortical adenoma and carcinoma tissues, as compared with normal tissues, using the expression dataset. Protein protein interaction (PPI) networks were constructed for adenoma and carcinoma disease models, and common modules among the diseases were identified. A total of two common modules with 14 nodes and 20 nodes were revealed among the adenoma and carcinoma networks, respectively. Genes of the common modules were also identified to be the common hub genes of the disease models. Enrichment of the genes of the common modules suggested associations with steroid biosynthesis, the proteasome, cell cycle and metabolic pathways. Modularity, topological and functional analysis of the PPI networks revealed common modules among pediatric adenoma and carcinoma disease models, which provided insight into the underlying disease mechanisms and suggesting prospective targets for future study. PMID- 29435069 TI - Serum microRNA-193b as a promising biomarker for prediction of chemoradiation sensitivity in esophageal squamous cell carcinoma patients. AB - Esophageal squamous cell carcinoma (ESCC) is the most predominantly occurring type of esophageal cancer worldwide. Locally advanced ESCC patients are treated by neoadjuvant chemoradiation for tumor downstaging prior to tumor resection. Patients receiving this treatment have an increased expectation of cure via the following tumor resection and have better survival outcomes. However, not all patients respond well to chemoradiation and poor responders suffer from treatment associated toxicity and complications without benefits. No method is currently available to predict patient chemoradiation response and to exclude poor responders from ineffective treatment. To address this clinical limitation, the present study aimed to identify non-invasive biomarkers for predicting patient chemoradiation response. Due to the features of microRNA (miRNA) in cancer diagnosis, prognosis and treatment response prediction, serum miRNA arrays were performed to identify potential miRNA(s) that may be used for chemoradiation response prediction in ESCC. Using an miRNA array to compare pre-treatment serum sample pools from 10 good responders and 10 poor responders, the present study identified miR-193b, miR-942 and miR-629* as candidate miRNAs for predicting chemoradiation response. Subsequent validation using reverse transcription quantitative polymerase chain reaction confirmed that miR-193b, however not miR 942 and miR-629*, were significantly increased in sera from 24 good responders, compared with 23 poor responders. Further analyses using the receiver operating characteristic curve revealed a strong predictive power of serum miR-193b on discriminating good responders from poor responders to chemoradiation. In addition, a high serum level of miR-193b was significantly associated with better survival outcomes. Therefore, serum miR-193b may be considered a promising biomarker for predicting chemoradiation response and post-therapy survival of ESCC patients. PMID- 29435070 TI - MMP-2 silencing reduces the osteogenic transformation of fibroblasts by inhibiting the activation of the BMP/Smad pathway in ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a common type of rheumatoid disease, which has recently been demonstrated to be associated with the expression of matrix metalloproteinase (MMP)-2. The aim of the present study was to investigate whether MMP-2 interference reduced the osteogenic differentiation of fibroblasts and to explore the mechanism involved in the differentiation. Fibroblasts from patients with AS were divided into control, mock and small interfering (si)RNA MMP-2 groups. Cell viability was assessed using the MTT assay. mRNA and protein expression levels of MMP-2, core-binding factor a1 (Cbfa-1) and bone morphogenetic proteins/Smad-signalling molecules (BMP/Smad) were measured using reverse transcription-quantitative polymerase chain reaction and western blotting. The results indicated that cell viability and fibroblast morphology did not differ significantly between healthy volunteers and patients with AS. However, MMP-2 expression levels in AS fibroblasts were substantially higher. MMP 2 gene silencing markedly downregulated the expression of MMP-2 and Cbfa-1, and inhibitied the activation of the BMP/Smad signalling pathway consequent to the reduction in levels of BMP-2, Smad1, Smad4 and Smad1/5/8. The results showed that MMP-2 gene silencing may reduce the osteogenesis of fibroblasts in AS by inhibiting the activation of the BMP/Smad signalling pathway. PMID- 29435071 TI - Methylation of DACT2 contributes to the progression of breast cancer through activating WNT signaling pathway. AB - The activation of the Wnt/beta-catenin signaling pathway has been demonstrated to play important roles in breast carcinogenesis and to be associated with a poorer prognosis in breast cancer patients. However, genetic mutation is not the major reason for Wnt/beta-catenin activation in breast cancer. Dishevelled-associated antagonist of beta-catenin homolog 2 (DACT2) is a negative regulator of beta catenin and acts as a tumor suppressor in numerous cancer types; however, the expression change and potential role of DACT2 in breast cancer is unknown. The present study detected the expression and function of DACT2 in breast cancer progression. It was identified that the expression of DACT2 significantly decreased in breast cancer tissues compared with paired adjacent normal breast tissues. Additional investigation demonstrated that the hypermethylation of DACT2 gene promoter contributes to the loss of the gene in breast cancer. It was also demonstrated that DACT2 is a tumor suppressor in breast cancer and inhibits the proliferation and invasion of breast cancer cells by repressing the expression of beta-catenin target genes associated with tumor growth and metastasis. The present study indicates that the loss of DACT2 may contribute to breast cancer progression and provides a promising therapeutic target for the treatment of breast cancer. PMID- 29435072 TI - miR-433 accelerates acquired chemoresistance of gallbladder cancer cells by targeting cyclin M. AB - Resistance to chemotherapy is associated with dismal prognosis in patients with gallbladder cancer. Cyclin-dependent kinase 10 (CDK10) influences the chemosensitivity of gallbladder cancer cells, and cyclin M is the activating factor and binding partner of CDK10. To determine the effect of CDK10 or cyclin M overexpression on chemosensitivity, gemcitabine-resistant (GR) subclones were established from CDK10 or cyclin M stable transfectants. Stable overexpression of CDK10 increased the sensitivity to gemcitabine in non-resistant cells and did not further increase the sensitivity to gemcitabine in the GR subclones. GR subclones exhibited a significantly decreased expression of cyclin M while maintaining the expression levels of CDK10, compared with the non-resistant cells. MicroRNA (miR) 433 was identified as a candidate factor involved in the mechanism of the downregulation of M cyclin in GR subclones. Luciferase assays confirmed the interaction between miR-433 and the 3' untranslated region (3'UTR) of cyclin M. Additionally, ectopic expression of miR-433 significantly decreased the expression of cyclin M. Finally, increased expression of circulating miR-433 was associated with poor outcome of chemotherapy. The results of the present study suggest that miR-433 is a potential biomarker for evaluating chemosensitivity in gallbladder cancer. PMID- 29435073 TI - Effects of thalidomide on growth and VEGF-A expression in SW480 colon cancer cells. AB - Lymphatic and hematogenous spread are the most common ways for tumors to metastasize. Angiogenesis is essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) particularly VEGF-A is important in the process of angiogenesis. The current research has indicated that thalidomide (THD) may be able to inhibit angiogenesis, stimulate the activity of the immune system and inhibit the adherence of cancer cells to stromal cells. These changes may lead to suppression of tumor occurrence and development. To date, to the best of our knowledge, the effects of THD on colon cancer SW480 cells have not been reported. In the present study, the effects of THD and a combination of THD and oxaliplatin (L-OHP) on the proliferation of SW480 cells have been investigated. Furthermore, the expression of VEGF-A and hypoxia-inducible factor 1 (HIF-1) was analyzed using MTT assay, quantitative polymerase chain reaction and western blot analysis. The results indicated that THD was able to inhibit SW480 cells in dose and-time dependent manner and inhibit the expression of VEGF-A and HIF-1alpha. Furthermore, treatment with THD and L-OHP had synergistic inhibitory effect, which may provide a novel treatment strategy for advanced colorectal cancer. PMID- 29435074 TI - Over-activated PD-1/PD-L1 axis facilitates the chemoresistance of diffuse large B cell lymphoma cells to the CHOP regimen. AB - Interaction between the programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) contributes to tumor cell resistance to chemotherapeutic agents. PD-L1 is expressed in the cells of diffuse large B-cell lymphoma (DLBCL), one common type of malignant non-Hodgkin lymphomas. However, little is known about how the PD-1/PD-L1 pathway functions in the pathogenesis of DLBCL. Therefore, the present study investigated whether and how the PD-1/PD-L1 axis is involved in regulating the sensitivity of CRL2631, a DLBCL cell line, to the CHOP (Cyclophosphamide, Hydroxydaunorubicin/adriamycin, Oncovin/vincristine and Prednisone) chemotherapeutic regimen. CHOP treatment significantly decreased cell survival rate and increased apoptosis in CRL2631 cells. The application of recombinant human PD-1 (rPD-1) significantly decreased the cytotoxic effects of the CHOP regimen in CRL2631 cells, but not in the CRL2631 cells with PD-L1 deficiency. In the CRL2631 cells, rPD-1 enhanced the activity of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt1) pathway. However, the activity level of the PI3K/Akt1 pathway was decreased in CHOP-treated CRL2631 cells. The selective PI3K inhibitor BKM120 significantly increased CHOP-induced apoptosis, but this effect was abolished by rPD-1 and aggravated by PD-L1 knockdown. In CHOP-treated PD-L1 knockdown cells, the increased apoptosis was markedly inhibited by the overexpression of constitutively active Akt1. Overall, the results demonstrate that the over-activated PD-1/PD-L1 axis is associated with chemotherapeutic resistance of DLBCL cells to the CHOP regimen, potentially through a PI3K-dependent mechanism. PMID- 29435075 TI - BRCA1 homozygous unclassified variant in a patient with non-Fanconi anemia: A case report. AB - The present case report discusses a woman affected by chronic lymphatic leukemia and breast cancer with a familial history of breast cancer; suspected to be hereditary breast and ovarian cancer (HBOC) syndrome. The patient underwent BRCA1 and BRCA2 genetic testing. Sequencing of BRCA1 revealed the presence of the variant of unknown significance (VUS) c.3082C>T (p.Arg1028Cys) at homozygous state, whereas no mutations were detected in BRCA2. Multiplex ligation-dependent probe amplification confirmed the presence of two alleles. Although consanguineity between her parents was reported, which therefore supported the molecular data, her clinical phenotype was not suggestive of typical Fanconi anemia (FA), particularly of a BRCA1-linked FA. In the two cases reported in the literature, carriers of biallelic BRCA1 mutation present a severe and quite typical phenotype. For this reason, the patient was offered a diepoxybutane test, where neither complex rearrangements nor multiradial formation were detected. We were therefore inclined to consider that BRCA1 VUS as of little clinical significance. PMID- 29435076 TI - STAT3 promotes the proliferation and migration of hepatocellular carcinoma cells by regulating AKT2. AB - The aim of the present study was to investigate the correlation of STAT3 and AKT in HCC cells. HCC cells were transfected with si-STAT3 and si-AKT2 in vitro and the mRNA expression of STAT3 and AKT was detected by RT-PCR, and the protein expression was measured by western blot. MTT assays were used to evaluate cell proliferation, and Transwell assays were performed to detect the ability of migration and invasion. The relationship between STAT3 and AKT was analyzed by ChIP and Dual-luciferase reporter (DLR) assays. A nude mice experiment was used to verify the correlation. In the present study, we found that the expression of p-AKT2 and its downstream molecules were reduced in HCC cells transfected with si STAT3, and the expression of p-STAT3 and its downstream molecules was decreased in HCC cells transfected with si-AKT2. Moreover, the ability of HCC cells proliferation, migration and invasion was decreased in si-STAT3 transfection group, but AKT2 reversed the role of si-STAT3 in HCC cells. The ChIP experiment found that STAT3 could bind to the AKT2 promoter in HCC cells. The DLR assay showed that the luciferase activity of AKT2 promoter was enhanced in HCC cells treated by IL-6. The nude mice experiment found that the tumor grew slowly after transfection with the STAT3-siRNA lentiviral vector, while AKT2 reversed the effect. STAT3 and AKT2 had mutual regulatory relationship, and STAT3 promoted the occurrence and development of HCC by regulating AKT2. PMID- 29435077 TI - Clinical value of the preoperative neutrophil-to-lymphocyte ratio and red blood cell distribution width in patients with colorectal carcinoma. AB - The aim of the present study was to investigate the clinical value of the preoperative neutrophil-to-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) in the peripheral blood of colorectal carcinoma (CRC) patients. Clinical data obtained from 240 patients with CRC undergoing radical surgical resection in Shandong Provincial Hospital Affiliated to Shandong University (Jinan, Shandong, China) between January 2011 and April 2015 were retrospectively analyzed. Data were also collected from 110 patients with colon polyps and 48 healthy volunteers to serve as controls for comparative analysis. The clinicopathological characteristics of the patients in the low and high NLR and RDW groups were compared. The NLR and RDW values were compared prior to and following surgery. Kaplan-Meier analyses and Cox regression modeling were performed to predict overall survival (OS) and disease-free survival (DFS). The NLR and RDW levels in the CRC patients were markedly higher than those in the colon polyp patients and the healthy controls. The optimum NLR and RDW cutoff points for CRC were 2.06 and 13.45%, respectively. Significant differences were detected in tumor location, diameter, degree of differentiation, tumor depth, carcinoembryonic antigen and carbohydrate antigen 199 when comparing the high and low NLR groups (P<0.05). A high RDW was significantly associated with distant metastasis and older age in CRC patients. No significant difference was detected in the NLR and RDW levels of CRC patients prior to and following surgery (P>0.05). CRC patients with an increased RDW had significantly worse OS and DFS rates, particularly those with metastatic CRC (P<0.05). Patients with a high NLR exhibited a reduced DFS time in CRC (P=0.053), although this difference was not significant, and a significantly worse DFS time in metastatic CRC (P=0.047). In conclusion, it is convenient to use preoperative NLR and RDW to predict prognosis following surgery for patients with CRC. PMID- 29435078 TI - Gene expression analyses associated with malignant phenotypes of metastatic sub clones derived from a mouse oral squamous cell carcinoma Sq-1979 cell line. AB - To elucidate the genetic events that occur during the development of OSCC, the present study established a model of oral malignancy using a mouse oral squamous cell carcinoma (OSCC) Sq-1979 cell line. Sq-1979 cells were implanted into syngeneic C3H mice. Subsequently, 233 cells and metastatic sub-clones (L cells) from primary OSCC, as well as the metastasized lymph node tissues of Sq-1979 implanted mice were established. Compared with parental Sq-1979 and 233 cells, the majority of L cells exhibited a higher proliferation rate and transplantability, and conferred a lower survival rate on the implanted mice. To investigate the genetic background of L cells, preferentially expressed genes in L cells were identified by cDNA microarray and reverse transcription-polymerase chain reaction analyses. The expression of FYN-binding protein (Fyb), solute carrier family 16 member 13 (Slc16a13), keratin 7, transmembrane portion 173 and Slc44a3 mRNAs was significantly elevated in L cells compared with that in Sq1979 and 233 cells. The mRNA expression was also evaluated in human OSCC and leukoplakia (LP) tissues. Among the 5 aforementioned mRNAs, the expression of FYB and SLC16A13 was significantly higher in OSCC than in LP tissues. Furthermore, the expression of SLC16A13 mRNA was significantly elevated in highly invasive OSCCs, which were classified as grades 3 and 4 by the Yamamoto-Kohama (YK) classification of invasion, compared with those in lower grades (YK-1 and -2). The model proposed in the present study could thus describe essential marker genes for the diagnosis of oral malignancies. PMID- 29435079 TI - MiR-34c induces apoptosis and inhibits the viability of M4e cells by targeting BCL2. AB - The present study aimed to investigate microRNA (miR/miRNA)-34c expression and the association of miR-34c with B cell lymphoma 2 (BCL2) in M4e laryngeal carcinoma cell line. M4e laryngeal carcinoma cells were cultured and transfected with lenti-miR-34c or scramble miRNA for 72 h. Cell viability and the percentage of cells undergoing apoptosis of transfected cells were detected using MTT and Annexin V/allophycocyanin and propidium iodide assays, respectively. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were performed to determine BCL2 mRNA and protein expression in transfected M4e cells. In addition, luciferase reporter assay was performed to identify whether BCL2 is a direct target of miR-34c. Transfection of lenti-miR 34c was able to significantly inhibit cell viability (P<0.01), increase the percentage of cells undergoing apoptosis (P<0.001) and downregulate BCL2 protein expression (P<0.01) in M4e cells. RT-qPCR data revealed that lenti-miR-34c transfection did not affect BCL2 mRNA expression. However, data from the luciferase reporter assay revealed that transfection with miR-34c negative control decreased luciferase activity in M4e cells co-transfected with pGL3-BCL2 MUT plasmid, compared with miR-34c inhibitor (P<0.01). Collectively, the results from the present study provided evidence that miR-34c may be involved in the pathogenesis of laryngeal cancer, and BCL2 may be negatively regulated by miR-34c in M4e cells. PMID- 29435080 TI - A novel approach to glioma therapy using an oncolytic adenovirus with two specific promoters. AB - Gliomas are the most common type of primary brain tumor in adults, where more than half of the cases are malignant, and the prognosis is poor. The early viral 1A (E1A) protein has been widely recognized to be essential for adenoviral replication and production of progeny virions in human cells, a process that is regulated by human telomerase reverse transcriptase. The p53 gene, as a tumor suppressor, regulates diverse cellular processes, including cell cycle arrest, cell autophagy, senescence and apoptosis. Dysfunction of the p53 pathways is common in malignant gliomas. Exogenous expression of p53 during adenovirus replication in human cancer cells may accelerate cell death and improve the release of early virus progeny. In the present study, a conditionally replicative adenovirus (CRAd) Ad-Tp-E1A-Gp-p53, which expressed functional p53 protein when replicating in cancer cells, was constructed. Next, the level of p53 expression in U251 cells was determined by western blot analysis, and the inhibitory effect of Ad-Tp-E1A-Gp-p53 on U251 cells was detected via an MTT assay. The results indicated that p53 expression was upregulated with an increase in the multiplicity of infection (MOI) of Ad-Tp-E1A-Gp-p53. Additionally, the inhibitory effects of Ad-Tp-E1A-Gp-p53 in different groups were significantly different (P<0.05), with the inhibition ratio of the experimental groups being higher, compared with the control group (P<0.05). Furthermore, the inhibition ratio increased with increases in the MOI of Ad-Tp-E1A-Gp-p53. Therefore, the expression of functional p53 and that of E1A may increase the potency of CRAd, and overexpression of p53 through CRAd is a promising approach to more effective treatments in a number of human cancer types. PMID- 29435081 TI - Long non-coding RNA CCAT2 promotes epithelial-mesenchymal transition involving Wnt/beta-catenin pathway in epithelial ovarian carcinoma cells. AB - Long non-coding RNA colon cancer-associated transcript 2 (CCAT2) is dysregulated in a variety of types of human cancer. However, the role of CCAT2 in epithelial ovarian carcinoma (EOC) remains largely unknown. The aim of this study is to investigate the effect of CCAT2 on epithelial-mesenchymal transition (EMT) and related molecular mechanisms in epithelial ovarian cancer cells. In the current paper, we found that CCAT2 was significantly upregulated in EOC SKOV3, A2780 and HO8910 cell lines compared with the normal ovarian epithelial HUM-CELL-0088 cell line. Functional assays demonstrated that the knockdown of CCAT2 inhibited migration and invasion of EOC cells in vitro. Moreover, our results showed that silencing CCAT2 inhibited EMT by the upregulation of epithelial cadherin and downregulation of neural cadherin, zinc finger protein SNAI and Twist-related protein 1 in SKOV3 and A2780 cell lines. But, that was reversed by the treatment with lithium chloride (LiCl), by which the canonical Wnt/beta-catenin pathway could be activated. In addition, we further investigated the role of CCAT2 in the modulation of Wnt/beta-catenin signaling pathway. Our results revealed that knockdown of CCAT2 inhibited the expression of beta-catenin and the activity of T cell factor/lymphoid enhancer factor, acting as a key transcription factor of Wnt signaling pathway. Collectively, these results indicate that CCAT2 may promote EMT, at least partly through Wnt/beta-catenin signaling pathway in EOC cells. Thus, CCAT2 might play a critical role in EOC progression and serve as a valuable target for the treatment of ovarian cancer. PMID- 29435082 TI - Escitalopram oxalate inhibits proliferation and migration and induces apoptosis in non-small cell lung cancer cells. AB - Population-based cohort studies have revealed that neuroleptic medications are associated with a reduced cancer risk. Recent studies have demonstrated that selective serotonin reuptake inhibitors (SSRIs) have an antiproliferative or cytotoxic effect on certain cancer types. Known as a superior SSRI, escitalopram oxalate exhibits favorable tolerability with generally mild and temporary adverse events. The present study aimed to examine the effects of escitalopram oxalate on non-small cell lung cancer (NSCLC) cells. The experimental results revealed that escitalopram oxalate significantly inhibited the proliferation and invasion of A549, and H460 cells compared with BEAS-2B cells. Additionally, escitalopram oxalate significantly increased the sub-G1 population and caspase-3 activity of A549, and H460 cells. Furthermore, escitalopram oxalate significantly induced mitochondria-dependent apoptotic signaling cascades in A549 and H460 cells, which included increases in the protein expression levels of apoptosis regulator Bax, truncated BH3-interacting domain death agonist, cytochrome c, apoptotic protease activating factor 1, and cleaved caspase-9. These findings suggest that escitalopram oxalate could serve a therapeutic agent for the treatment of NSCLC due to its antiproliferative and apoptotic effects. PMID- 29435083 TI - Evaluation of therapeutic effects of 125I particles brachytherapy for recurrent bladder cancer. AB - The aim of the present study was to evaluate the clinical value of 125I particles implantation in the treatment of recurrent bladder cancer. The study is a retrospective analysis of 32 patients with recurrent bladder cancer treated between May 2010 and January 2010. Of these, 16 cases (chemotherapy group) received conventional chemotherapy. A total of 16 patients (125I group) received radiotherapy with 125I particles, followed by conventional chemotherapy. By guidance of B ultrasound, 125I radioactive particles were implanted. All 32 patients were relieved after treatment, and the tumors were significantly reduced after 2 months. However, the tumors in the 125I group were significantly smaller than those in the chemotherapy group (P<0.05). The patients were followed-up for 1 year and no recurrence was found. Additionally, no complications occurred. Compared with the chemotherapy group, the tumor volume of the 125I group was significantly reduced (P<0.05). The disease-free survival and 5-year survival rates of the patients in the follow-up showed that the disease-free survival and 5-year survival rates of the patients in 125I group were significantly improved compared to those in the chemotherapy group. Therefore, the results have shown that 125I radioactive particles in the treatment of bladder cancer improve the symptoms of patients with bladder cancer in the short term, and continuously kill residual tumor and prevent recurrence. PMID- 29435084 TI - Mitigation of stress: new treatment alternatives. AB - Complaints of stress are common in modern life. Psychological stress is a major cause of lifestyle-related issues, contributing to poor quality of life. Chronic stress impedes brain function, causing impairment of many executive functions, including working memory, decision making and attentional control. The current study sought to describe newly developed stress mitigation techniques, and their influence on autonomic and endocrine functions. The literature search revealed that the most frequently studied technique for stress mitigation was biofeedback (BFB). However, evidence suggests that neurofeedback (NFB) and noninvasive brain stimulation (NIBS) could potentially provide appropriate approaches. We found that recent studies of BFB methods have typically used measures of heart rate variability, respiration and skin conductance. In contrast, studies of NFB methods have typically utilized neurocomputation techniques employing electroencephalography, functional magnetic resonance imaging and near infrared spectroscopy. NIBS studies have typically utilized transcranial direct current stimulation methods. Mitigation of stress is a challenging but important research target for improving quality of life. PMID- 29435085 TI - Estimation of effective connectivity using multi-layer perceptron artificial neural network. AB - Studies on interactions between brain regions estimate effective connectivity, (usually) based on the causality inferences made on the basis of temporal precedence. In this study, the causal relationship is modeled by a multi-layer perceptron feed-forward artificial neural network, because of the ANN's ability to generate appropriate input-output mapping and to learn from training examples without the need of detailed knowledge of the underlying system. At any time instant, the past samples of data are placed in the network input, and the subsequent values are predicted at its output. To estimate the strength of interactions, the measure of "Causality coefficient" is defined based on the network structure, the connecting weights and the parameters of hidden layer activation function. Simulation analysis demonstrates that the method, called "CREANN" (Causal Relationship Estimation by Artificial Neural Network), can estimate time-invariant and time-varying effective connectivity in terms of MVAR coefficients. The method shows robustness with respect to noise level of data. Furthermore, the estimations are not significantly influenced by the model order (considered time-lag), and the different initial conditions (initial random weights and parameters of the network). CREANN is also applied to EEG data collected during a memory recognition task. The results implicate that it can show changes in the information flow between brain regions, involving in the episodic memory retrieval process. These convincing results emphasize that CREANN can be used as an appropriate method to estimate the causal relationship among brain signals. PMID- 29435086 TI - Influence of multiple action-outcome associations on the transition dynamics toward an optimal choice in rats. AB - When faced with familiar versus novel options, animals may exploit the acquired action-outcome associations or attempt to form new associations. Little is known about which factors determine the strategy of choice behavior in partially comprehended environments. Here we examine the influence of multiple action outcome associations on choice behavior in the context of rewarding outcomes (food) and aversive outcomes (electric foot-shock). We used a nose-poke paradigm with rats, incorporating a dilemma between a familiar option and a novel, higher value option. In Experiment 1, two groups of rats were trained with different outcome schedules: either a single action-outcome association ("Reward-Only") or dual action-outcome associations ("Reward-Shock"; with the added opportunity to avoid an electric foot-shock). In Experiment 2, we employed the same paradigm with two groups of rats performing the task under dual action-outcome associations, with different levels of threat (a low- or high-amplitude electric foot-shock). The choice behavior was clearly influenced by the action-outcome associations, with more efficient transition dynamics to the optimal choice with dual rather than single action-outcome associations. The level of threat did not affect the transition dynamics. Taken together, the data suggested that the strategy of choice behavior was modulated by the information complexity of the environment. PMID- 29435087 TI - Spontaneous analogising caused by text stimuli in design thinking: differences between higher- and lower-creativity groups. AB - Understanding the cognitive processes used in creative practices is essential to design research. In this study, electroencephalography was applied to investigate the brain activations of visual designers when they responded to various types of word stimuli during design thinking. Thirty visual designers were recruited, with the top third and bottom third of the participants divided into high-creativity (HC) and low-creativity (LC) groups. The word stimuli used in this study were two short poems, adjectives with similar meanings, and adjectives with opposing meanings. The derived results are outlined as follows: (1) the brain activations of the designers increased in the frontal and right temporal regions and decreased in the right prefrontal region; (2) the negative association between the right temporal and middle frontal regions was notable; (3) the differences in activations caused by distinct word stimuli varied between HC and LC designers; (4) the spectral power in the middle frontal region of HC designers was lower than that of LC designers during the short love poem task; (5) the spectral power in the bilateral temporal regions of HC designers was higher than that of LC designers during the short autumn poem task; (6) the spectral power in the frontoparietal region of HC designers was lower than that of LC designers during the similar concept task; and (7) the spectral power in the frontoparietal and left frontotemporal regions of HC designers was higher than that of LC designers during the opposing concept task. PMID- 29435088 TI - Measures of entropy and complexity in altered states of consciousness. AB - Quantification of complexity in neurophysiological signals has been studied using different methods, especially those from information or dynamical system theory. These studies have revealed a dependence on different states of consciousness, and in particular that wakefulness is characterized by a greater complexity of brain signals, perhaps due to the necessity for the brain to handle varied sensorimotor information. Thus, these frameworks are very useful in attempts to quantify cognitive states. We set out to analyze different types of signals obtained from scalp electroencephalography (EEG), intracranial EEG and magnetoencephalography recording in subjects during different states of consciousness: resting wakefulness, different sleep stages and epileptic seizures. The signals were analyzed using a statistical (permutation entropy) and a deterministic (permutation Lempel-Ziv complexity) analytical method. The results are presented in complexity versus entropy graphs, showing that the values of entropy and complexity of the signals tend to be greatest when the subjects are in fully alert states, falling in states with loss of awareness or consciousness. These findings were robust for all three types of recordings. We propose that the investigation of the structure of cognition using the frameworks of complexity will reveal mechanistic aspects of brain dynamics associated not only with altered states of consciousness but also with normal and pathological conditions. PMID- 29435089 TI - Usage of drip drops as stimuli in an auditory P300 BCI paradigm. AB - Recently, many auditory BCIs are using beeps as auditory stimuli, while beeps sound unnatural and unpleasant for some people. It is proved that natural sounds make people feel comfortable, decrease fatigue, and improve the performance of auditory BCI systems. Drip drop is a kind of natural sounds that makes humans feel relaxed and comfortable. In this work, three kinds of drip drops were used as stimuli in an auditory-based BCI system to improve the user-friendness of the system. This study explored whether drip drops could be used as stimuli in the auditory BCI system. The auditory BCI paradigm with drip-drop stimuli, which was called the drip-drop paradigm (DP), was compared with the auditory paradigm with beep stimuli, also known as the beep paradigm (BP), in items of event-related potential amplitudes, online accuracies and scores on the likability and difficulty to demonstrate the advantages of DP. DP obtained significantly higher online accuracy and information transfer rate than the BP (p < 0.05, Wilcoxon signed test; p < 0.05, Wilcoxon signed test). Besides, DP obtained higher scores on the likability with no significant difference on the difficulty (p < 0.05, Wilcoxon signed test). The results showed that the drip drops were reliable acoustic materials as stimuli in an auditory BCI system. PMID- 29435090 TI - Investigating neural efficiency of elite karate athletes during a mental arithmetic task using EEG. AB - Neural efficiency is proposed as one of the neural mechanisms underlying elite athletic performances. Previous sports studies examined neural efficiency using tasks that involve motor functions. In this study we investigate the extent of neural efficiency beyond motor tasks by using a mental subtraction task. A group of elite karate athletes are compared to a matched group of non-athletes. Electroencephalogram is used to measure cognitive dynamics during resting and increased mental workload periods. Mainly posterior alpha band power of the karate players was found to be higher than control subjects under both tasks. Moreover, event related synchronization/desynchronization has been computed to investigate the neural efficiency hypothesis among subjects. Finally, this study is the first study to examine neural efficiency related to a cognitive task, not a motor task, in elite karate players using ERD/ERS analysis. The results suggest that the effect of neural efficiency in the brain is global rather than local and thus might be contributing to the elite athletic performances. Also the results are in line with the neural efficiency hypothesis tested for motor performance studies. PMID- 29435092 TI - Finite-time and fixed-time synchronization analysis of inertial memristive neural networks with time-varying delays. AB - This paper investigates the finite-time synchronization and fixed-time synchronization problems of inertial memristive neural networks with time-varying delays. By utilizing the Filippov discontinuous theory and Lyapunov stability theory, several sufficient conditions are derived to ensure finite-time synchronization of inertial memristive neural networks. Then, for the purpose of making the setting time independent of initial condition, we consider the fixed time synchronization. A novel criterion guaranteeing the fixed-time synchronization of inertial memristive neural networks is derived. Finally, three examples are provided to demonstrate the effectiveness of our main results. PMID- 29435091 TI - Controlling mechanism of absence seizures by deep brain stimulus applied on subthalamic nucleus. AB - Based on a classical model of the basal ganglia thalamocortical network, in this paper, we employed a type of the deep brain stimulus voltage on the subthalamic nucleus to study the control mechanism of absence epilepsy seizures. We found that the seizure can be well controlled by turning the period and the duration of current stimulation into suitable ranges. It is the very interesting bidirectional periodic adjustment phenomenon. These parameters are easily regulated in clinical practice, therefore, the results obtained in this paper may further help us to understand the treatment mechanism of the epilepsy seizure. PMID- 29435093 TI - A roadmap to computational social neuroscience. AB - To complement experimental efforts toward understanding human social interactions at both neural and behavioral levels, two computational approaches are presented: (1) a fully parameterizable mathematical model of a social partner, the Human Dynamic Clamp which, by virtue of experimentally controlled interactions between Virtual Partners and real people, allows for emergent behaviors to be studied; and (2) a multiscale neurocomputational model of social coordination that enables exploration of social self-organization at all levels-from neuronal patterns to people interacting with each other. These complementary frameworks and the cross product of their analysis aim at understanding the fundamental principles governing social behavior. PMID- 29435094 TI - ChemTS: an efficient python library for de novo molecular generation. AB - Automatic design of organic materials requires black-box optimization in a vast chemical space. In conventional molecular design algorithms, a molecule is built as a combination of predetermined fragments. Recently, deep neural network models such as variational autoencoders and recurrent neural networks (RNNs) are shown to be effective in de novo design of molecules without any predetermined fragments. This paper presents a novel Python library ChemTS that explores the chemical space by combining Monte Carlo tree search and an RNN. In a benchmarking problem of optimizing the octanol-water partition coefficient and synthesizability, our algorithm showed superior efficiency in finding high scoring molecules. ChemTS is available at https://github.com/tsudalab/ChemTS. PMID- 29435095 TI - Capsaicin Protects Cardiomyocytes against Anoxia/Reoxygenation Injury via Preventing Mitochondrial Dysfunction Mediated by SIRT1. AB - Capsaicin (Cap) has been reported to have beneficial effects on cardiovascular system, but the mechanisms underlying these effects are still poorly understood. Apoptosis has been shown to be involved in mitochondrial dysfunction, and upregulating expression of SIRT1 can inhibit the apoptosis of cardiomyocytes induced by anoxia/reoxygenation (A/R). Therefore, the aim of this study was to test whether the protective effects of Cap against the injury to the cardiomyocytes are mediated by SIRT1. The effects of Cap with or without coadministration of sirtinol, a SIRT1 inhibitor, on changes induced by A/R in the cell viability, activities of lactate dehydrogenase (LDH), creatine phosphokinase (CPK), levels of intracellular reactive oxygen species (ROS), and mitochondrial membrane potential (MMP), related protein expression, mitochondrial permeability transition pore (mPTP) opening, and apoptosis rate in the primary neonatal rat cardiomyocytes were tested. Cap significantly increased the cell viability, upregulated expression of SIRT1 and Bcl-2, and decreased the LDH and CPK release, generation of ROS, loss of MMP, mPTP openness, activities of caspase-3, release of the cytochrome c, and apoptosis of the cardiomyocytes. Sirtinol significantly blocked the cardioprotective effects of Cap. The results suggest that the protective effects of Cap against A/R-induced injury to the cardiomyocytes are involved with SIRT1. PMID- 29435096 TI - YiQiFuMai Powder Injection Protects against Ischemic Stroke via Inhibiting Neuronal Apoptosis and PKCdelta/Drp1-Mediated Excessive Mitochondrial Fission. AB - YiQiFuMai (YQFM) powder injection has been reported to be used in cardiovascular and nervous system diseases with marked efficacy. However, as a treatment against diseases characterized by hypoxia, lassitude, and asthenia, the effects and underlying mechanisms of YQFM in neuronal mitochondrial function and dynamics have not been fully elucidated. Here, we demonstrated that YQFM inhibited mitochondrial apoptosis and activation of dynamin-related protein 1 (Drp1) in cerebral ischemia-injured rats, producing a significant improvement in cerebral infarction and neurological score. YQFM also attenuated oxidative stress-induced mitochondrial dysfunction and apoptosis through increasing ATP level and mitochondria membrane potential (Deltapsim), inhibiting ROS production, and regulating Bcl-2 family protein levels in primary cultured neurons. Moreover, YQFM inhibited excessive mitochondrial fission, Drp1 phosphorylation, and translocation from cytoplasm to mitochondria induced by oxidative stress. We provided the first evidence that YQFM inhibited the activation, association, and translocation of PKCdelta and Drp1 upon oxidative stress. Taken together, we demonstrate that YQFM ameliorates ischemic stroke-induced neuronal apoptosis through inhibiting mitochondrial dysfunction and PKCdelta/Drp1-mediated excessive mitochondrial fission. These findings not only put new insights into the unique neuroprotective properties of YQFM associated with the regulation of mitochondrial function but also expand our understanding of the underlying mechanisms of ischemic stroke. PMID- 29435097 TI - Omega Class Glutathione S-Transferase: Antioxidant Enzyme in Pathogenesis of Neurodegenerative Diseases. AB - The omega class glutathione S-transferases (GSTOs) are multifunctional enzymes involved in cellular defense and have distinct structural and functional characteristics, which differ from those of other GSTs. Previous studies provided evidence for the neuroprotective effects of GSTOs. However, the molecular mechanisms underpinning the neuroprotective functions of GSTOs have not been fully elucidated. Recently, our genetic and molecular studies using the Drosophila system have suggested that GstO1 has a protective function against H2O2-induced neurotoxicity by regulating the MAPK signaling pathway, and GstO2 is required for the activation of mitochondrial ATP synthase in the Drosophila neurodegenerative disease model. The comprehensive understanding of various neuroprotection mechanisms of Drosophila GstOs from our studies provides valuable insight into the neuroprotective functions of GstOs in vivo. In this review, we briefly introduce recent studies and summarize the novel biological functions and mechanisms underpinning neuroprotective effects of GstOs in Drosophila. PMID- 29435098 TI - RTA-408 Protects Kidney from Ischemia-Reperfusion Injury in Mice via Activating Nrf2 and Downstream GSH Biosynthesis Gene. AB - Acute kidney injury (AKI) induced by ischemia-reperfusion is a critical conundrum in many clinical settings. Here, this study aimed to determine whether and how RTA-408, a novel oleanane triterpenoid, could confer protection against renal ischemia-reperfusion injury (IRI) in male mice. Mice treated with RTA-408 undergoing unilateral ischemia followed by contralateral nephrectomy had improved renal function and histological outcome, as well as decreased apoptosis, ROS production, and oxidative injury marker compared with vehicle-treated mice. Also, we had found that RTA-408 could strengthen the total antioxidant capacity by increasing Nrf2 nuclear translocation and subsequently increased Nrf2 downstream GSH-related antioxidant gene expression and activity. In vitro study demonstrated that GSH biosynthesis enzyme GCLc could be an important target of RTA-408. Furthermore, Nrf2-deficient mice treated with RTA-408 had no significant improvement in renal function, histology, ROS production, and GSH-related gene expression. Thus, by upregulating Nrf2 and its downstream antioxidant genes, RTA 408 presents a novel and potential approach to renal IRI prevention and therapy. PMID- 29435101 TI - What is treatment free remission in chronic myeloid leukemia? PMID- 29435099 TI - Oleic Acid and Hydroxytyrosol Inhibit Cholesterol and Fatty Acid Synthesis in C6 Glioma Cells. AB - Recently, the discovery of natural compounds capable of modulating nervous system function has revealed new perspectives for a healthier brain. Here, we investigated the effects of oleic acid (OA) and hydroxytyrosol (HTyr), two important extra virgin olive oil compounds, on lipid synthesis in C6 glioma cells. OA and HTyr inhibited both de novo fatty acid and cholesterol syntheses without affecting cell viability. The inhibitory effect of the individual compounds was more pronounced if OA and HTyr were administered in combination. A reduction of polar lipid biosynthesis was also detected, while triglyceride synthesis was marginally affected. To clarify the lipid-lowering mechanism of these compounds, their effects on the activity of key enzymes of fatty acid biosynthesis (acetyl-CoA carboxylase-ACC and fatty acid synthase-FAS) and cholesterologenesis (3-hydroxy-3-methylglutaryl-CoA reductase-HMGCR) were investigated in situ by using digitonin-permeabilized C6 cells. ACC and HMGCR activities were especially reduced after 4 h of 25 MUM OA and HTyr treatment. No change in FAS activity was observed. Inhibition of ACC and HMGCR activities is corroborated by the decrease of their mRNA abundance and protein level. Our results indicate a direct and rapid downregulatory effect of the two olive oil compounds on lipid synthesis in C6 cells. PMID- 29435100 TI - Complete genome sequence of Pseudomonas alcaliphila JAB1 (=DSM 26533), a versatile degrader of organic pollutants. AB - In this study, following its isolation from contaminated soil, the genomic sequence of Pseudomonas alcaliphila strain JAB1 (=DSM 26533), a biphenyl degrading bacterium, is reported and analyzed in relation to its extensive degradative capabilities. The P. alcaliphila JAB1 genome (GenBank accession no. CP016162) consists of a single 5.34 Mbp-long chromosome with a GC content of 62.5%. Gene function was assigned to 3816 of the 4908 predicted genes. The genome harbors a bph gene cluster, permitting degradation of biphenyl and many congeners of polychlorinated biphenyls (PCBs), a ben gene cluster, enabling benzoate and its derivatives to be degraded, and phe gene cluster, which permits phenol degradation. In addition, P. alcaliphila JAB1 is capable of cometabolically degrading cis-1,2-dichloroethylene (cDCE) when grown on phenol. The strain carries both catechol and protocatechuate branches of the beta-ketoadipate pathway, which is used to funnel the pollutants to the central metabolism. Furthermore, we propose that clustering of MALDI-TOF MS spectra with closest phylogenetic relatives should be used when taxonomically classifying the isolated bacterium; this, together with 16S rRNA gene sequence and chemotaxonomic data analyses, enables more precise identification of the culture at the species level. PMID- 29435102 TI - Targeting PR1 in myeloid leukemia. PMID- 29435103 TI - Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling. AB - Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic. PMID- 29435104 TI - Niclosamide suppresses acute myeloid leukemia cell proliferation through inhibition of CREB-dependent signaling pathways. AB - CREB (cAMP Response Element Binding protein) is a transcription factor that is overexpressed in primary acute myeloid leukemia (AML) cells and associated with a decreased event-free survival and increased risk of relapse. We recently reported a small molecule inhibitor of CREB, XX-650-23, which inhibits CREB activity in AML cells. Structure-activity relationship analysis for chemical compounds with structures similar to XX-650-23 led to the identification of the anthelminthic drug niclosamide as a potent anti-leukemic agent that suppresses cell viability of AML cell lines and primary AML cells without a significant decrease in colony forming activity of normal bone marrow cells. Niclosamide significantly inhibited CREB function and CREB-mediated gene expression in cells, leading to apoptosis and G1/S cell cycle arrest with reduced phosphorylated CREB levels. CREB knockdown protected cells from niclosamide treatment-mediated cytotoxic effects. Furthermore, treatment with a combination of niclosamide and CREB inhibitor XX 650-23 showed an additive anti-proliferative effect, consistent with the hypothesis that niclosamide and XX-650-23 regulate the same targets or pathways to inhibit proliferation and survival of AML cells. Niclosamide significantly inhibited the progression of disease in AML patient-derived xenograft (PDX) mice, and prolonged survival of PDX mice. Niclosamide also showed synergistic effects with chemotherapy drugs to inhibit AML cell proliferation. While chemotherapy antagonized the cytotoxic potential of niclosamide, pretreatment with niclosamide sensitized cells to chemotherapeutic drugs, cytarabine, daunorubicin, and vincristine. Therefore, our results demonstrate niclosamide as a potential drug to treat AML by inducing apoptosis and cell cycle arrest through inhibition of CREB-dependent pathways in AML cells. PMID- 29435105 TI - Sodium fluoride causes hepatocellular S-phase arrest by activating ATM-p53-p21 and ATR-Chk1-Cdc25A pathways in mice. AB - In this study, experimental pathology, flow cytometry (FCM), quantitative real time polymerase chain reaction (qRT-PCR), and western blot (WB) were used to evaluate the effects of sodium fluoride (NaF) on hepatocellular cell cycle progression in mice. A total of 240 ICR mice were divided equally into four groups; the experimental groups received 12, 24, or 48 mg/kg NaF intragastrically for 42 days, while the control group received distilled water. Doses of NaF above 12 mg/kg increased the percentage of cells in S phase (S-phase arrest), reduced percentages of cells in G0/G1 or G2/M phase, and activated the ATM-p53-p21 and ATR-Chk1-Cdc25A pathways. Activation of these pathways was characterized by up regulation of ATM, p53, p21, ATR, and Chk1 mRNA and protein expression, and down regulation of Cdc25A, cyclin E, cyclin A, CDK2, CDK4, and proliferating cell nuclear antigen (PCNA) mRNA and protein expression. These results indicate that NaF caused S-phase arrest by activating the ATM-p53-p21 and ATR-Chk1-Cdc25A pathways. PMID- 29435106 TI - Overexpression of beta1 integrin contributes to polarity reversal and a poor prognosis of breast invasive micropapillary carcinoma. AB - Invasive micropapillary carcinoma (IMPC) of the breast is a highly aggressive breast cancer. Polarity reversal exemplified by cluster growth is hypothesized to contribute to the invasiveness and metastasis of IMPC. In this study, we demonstrate that levels of beta1 integrin and Rac1 expression were greater in breast IMPC than in invasive breast carcinoma of no specific type and paraneoplastic benign breast tissue. We show that silencing beta1 integrin expression using the beta1 integrin inhibitor AIIB2 partially restored polarity in IMPC primary cell clusters and downregulated Rac1. Thus, overexpression of beta1 integrin upregulates Rac1. Univariate analysis showed that overexpression of beta1 integrin and Rac1 was associated with breast cancer cell polarity reversal, lymph node metastasis, and poor disease-free survival in IMPC patients. Multivariate analysis revealed that polarity reversal was an independent predictor of poor disease-free survival. These findings indicate that overexpression of beta1 integrin and the resultant upregulation of Rac1 contribute to polarity reversal and metastasis of breast IMPC, and that beta1 integrin and Rac1 could be potential prognostic biomarkers and targets for treatment of breast IMPC. PMID- 29435107 TI - Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia. AB - We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b expression. Using Sanger sequencing, we identified a germline thymidine (T) base deletion within the miR 29b-1/miR-29a cluster precursor in 16% of AML patients. Remarkably we found a significant enrichment for the presence of the miR-29 polymorphism in core binding factor (CBF) newly diagnosed AML patients (n = 61/303; 20%) with respect to age, sex and race matched controls (n = 43/402:11%, P < 0.01). Mechanistically, this polymorphism affects the expression ratio of mature miR-29b and miR-29a by dampening the processing of miR-29a. RNA immunoprecipitation assays showed reduced DROSHA binding capacity to the polymorphism with respect to the controls. Finally, we showed that this polymorphism negatively impacts the ability of miR-29b-1/miR-29a cluster to target MCL-1 and CDK6, both known miR-29 targets. PMID- 29435108 TI - Genetic and functional analysis of two missense DUOX2 mutations in congenital hypothyroidism and goiter. AB - Mutations in the dual oxidase 2 gene (DUOX2) impair hydrogen peroxide (H2O2) production and cause dyshormonogenesis. In addition, these mutations have been implicated in autosomal recessive congenital hypothyroidism (CH) with goiter. In this study, we identified DUOX2 mutations that were causative for CH and explored the effects of these mutations on DUOX2 function. Blood samples were collected from 10 infants born with CH and goiter to unrelated parents. We extracted genomic DNA and sequenced all exons by polymerase chain reaction direct sequencing. The effects of DUOX2 mutations were characterized by H2O2 production assays and cycloheximide (CHX) chase experiments. Sequence analysis revealed one novel DUOX2 mutation and one known DUOX2 mutation in unrelated families: c.1060C>T (p.R354W) and c.3616 G>A (p.A1206T). Both mutations impaired H2O2 production. CHX chase experiments demonstrated the DUOX2 mutants had shorter half lives and degraded more rapidly than wild-type DUOX2. Our study identified two novel DUOX2 mutations in Chinese patients with CH and goiter, which were responsible for the deficit in the organification process. PMID- 29435109 TI - Clinical and molecular features of innate and acquired resistance to anti-PD-1/PD L1 therapy in lung cancer. AB - Hypothesis: The majority of non-small cell lung cancer (NSCLC) patients treated with anti-PD-1/PD-L1 therapy develop either innate or acquired resistance. Across tumor types, the "T cell-inflamed" tumor microenvironment correlates with clinical response to immunotherapy. We hypothesize that clinical characteristics may be predictive of resistance and that "T cell-inflamed" NSCLC tumors can be identified by gene expression profiling. Results: Of 93 patients, 36 (38.7%) had innate resistance and 57 (61.3%) had initial benefit to immunotherapy. Innate resistance was associated with non-smokers (p = 0.013), more involved disease sites (p = 0.011), more prior therapy (p = 0.001), and a lower albumin level (p = 0.014). Among patients with initial benefit, factors associated with subsequent progression-free survival included higher Karnofsky Performance Status (KPS) (p = 0.004) and lower depth of response to anti-PD-1 therapy (p = 0.003). A "T cell inflamed" microenvironment was identified in 42% of TCGA adenocarcinoma samples versus 21.0% of squamous cell. Discussion: Specific clinical characteristics appear to be predictive of either innate or acquired resistance to anti-PD-1/PD L1 therapy. A "T cell-inflamed" tumor was more common in adenocarcinoma than squamous histology. Methods: A retrospective review of NSCLC patients treated with anti-PD-1/PD-L1 monotherapy. Patients with innate resistance to anti-PD-1/PD L1 therapy (defined as progression at first CT evaluation) were compared to patients with initial clinical benefit. Among those with initial clinical benefit, we identified prognostic factors for time to progression (acquired resistance) or death. To further corroborate our findings on limited numbers, immune gene expression profiling of all NSCLC samples from the TCGA database was also pursued. PMID- 29435110 TI - Transfusion-associated adverse reactions (TAARs) and cytokine accumulations in the stored blood components: the impact of prestorage versus poststorage leukoreduction. AB - Leukoreduction in blood units could prevent patients undergoing transfusions from transfusion-associated adverse reactions (TAARs) such as febrile nonhemolytic transfusion reactions (FNHTRs). However, the effect of prestorage and poststorage leukoreduction on TAARs and its underlying mechanisms in stored blood components remains to be determined. Therefore, we investigated the impact of prestorage leukocyte-reduced (pre-LR) and poststorage leukocyte-reduced (post-LR) blood products, including red blood cells (RBCs) and apheresis platelets (PHs), on the incidence of FNHTRs and other TAARs in patients who received transfusions from 2009 to 2014 in a tertiary care center. We also investigated the difference of leukocyte-related bioactive mediators between pre- and post-LR blood components. The results indicated that prevalence of TAARs was significantly reduced in the transfusions of pre-LR blood components. Particularly, the prevalence of FNHTRs was significantly reduced in the pre-LR RBC transfusions and the prevalence of allergy reactions was markedly reduced in the pre-LR PH transfusions. Furthermore, in vitro evaluation of cytokines in the pre- and post-LR blood components revealed that IL-1beta, IL-8 and RANTES levels were significantly elevated in the post-LR RBCs during the storage. In contrast, IL-1beta, IL-6 and IL-8 levels were significantly elevated in the post-LR PHs during the storage. These findings suggested that prestorage leukoreduction had a diminishing effect on the development of TAARs, which could be associated with less accumulation of cytokines in the stored blood components. PMID- 29435111 TI - Impact of DLK1-DIO3 imprinted cluster hypomethylation in smoker patients with lung cancer. AB - DNA methylation is important for gene expression and genome stability, and its disruption is thought to play a key role in the initiation and progression of cancer and other diseases. The DLK1-DIO3 cluster has been shown to be imprinted in humans, and some of its components are relevant to diverse pathological processes. The purpose of this study was to assess the methylation patterns of the DLK1-DIO3 cluster in patients with lung cancer to study its relevance in the pathogenesis of this disease. We found a characteristic methylation pattern of this cluster in smoking associated lung cancer, as compared to normal lung tissue. This methylation profile is not patent however in lung cancer of never smokers nor in lung tissue of COPD patients. We found 3 deregulated protein coding genes at this locus: one was hypermethylated (DIO3) and two were hypomethylated (DLK1 and RTL1). Statistically significant differences were also detected in two different families of SNORDs, two miRNA clusters and four lncRNAs (MEG3, MEG8, MEG9 and LINC00524). These findings were validated using data from the cancer genome atlas (TCGA) database. We have then showed an inverse correlation between DNA methylation and expression levels in 5 randomly selected genes. Several targets of miRNAs included in the DLK1-DIO3 cluster have been experimentally verified as tumor suppressors. All of these results suggest that the dysmethylation of the imprinted DLK1-DIO3 cluster could have a relevant role in the pathogenesis of lung cancer in current and former smokers and may be used for diagnostic and/or therapeutic purposes. PMID- 29435112 TI - LncRNA MALAT1 regulates smooth muscle cell phenotype switch via activation of autophagy. AB - Vascular smooth muscle cells (VSMCs), switching from a differentiated to a proliferative phenotype, contribute to various vascular diseases. However, the role of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 MALAT1 in the phenotype switching of VSMCs remains unclear. Here, we report that the knockdown of MALAT1 promotes the transformation of smooth muscle cells from a proliferative phenotype to a differentiated phenotype. MALAT1 knockdown inhibited cellular proliferation and migration, leading to significant cell cycle arrest in the G2 phase. MALAT1 was downregulated in bone morphogenetic protein-7 (BMP-7) induced cellular differentiation, while MALAT1 was upregulated in platelet derived growth factor-BB (PDGF-BB)-induced cellular proliferation. PDGF induced the transformation of smooth muscle cells into a proliferative phenotype accompanied by an increase in autophagy. The downregulation of MALAT1 attenuated PDGF-BB-induced proliferation and migration by inhibiting autophagy. MALAT1 could act as a competing endogenous RNA (ceRNA) to regulate autophagy-related 7 (ATG7) gene expression by sponging miR142-3p. The present study reveals a novel mechanism by which MALAT1 promotes the transformation of smooth muscle cells from contraction to synthetic phenotypes. PMID- 29435113 TI - Comparative gene expression profiling of human metallothionein-3 up-regulation in neuroblastoma cells and its impact on susceptibility to cisplatin. AB - Human metallothionein-3 (hMT-3), also known as growth inhibitory factor, is predominantly expressed in the central nervous system. hMT-3 is presumed to participate in the processes of heavy metal detoxification, regulation of metabolism and protection against oxidative damage of free radicals in the central nervous system; thus, it could play important neuromodulatory and neuroprotective roles. However, the primary functions of hMT-3 and the mechanism underlying its multiple functions in neuroblastoma have not been elucidated so far. First, we confirmed relatively high expression of hMT-3 encoding mRNA in biopsies (n = 23) from high-risk neuroblastoma subjects. Therefore, we focused on investigation of the impact of hMT-3 up-regulation in N-Myc amplifying neuroblastoma cells. The differentially up-regulated genes involved in biological pathways related to cellular senescence and cell cycle were identified using electrochemical microarray with consequent bioinformatic processing. Further, as experimental verification of microarray data, the cytotoxicity of the cisplatin (CDDP) was examined in hMT-3 and mock cells by MTT and clonogenic assays. Overall, our data strongly suggest that up-regulation of hMT-3 positively correlates with the genes involved in oncogene-induced senescence (CDKN2B and ANAPC5) or apoptosis (CASP4). Moreover, we identified a significant increase in chemoresistance to cisplatin (CDDP) due to hMT-3 up-regulation (24IC50: 7.5 vs. 19.8 MUg/ml), indicating its multipurpose biological significance. PMID- 29435114 TI - RAS GTPases are modified by SUMOylation. AB - RAS proteins are GTPases that participate in multiple signal cascades, regulating crucial cellular processes including cell survival, proliferation, differentiation, and autophagy. Mutations or deregulated activities of RAS are frequently the driving force for oncogenic transformation and tumorigenesis. Given the important roles of the small ubiquitin-related modifier (SUMO) pathway in controlling the stability, activity, or subcellular localization of key cellular regulators, we investigated here whether RAS proteins are posttranslationally modified (i.e. SUMOylated) by the SUMO pathway. We observed that all three RAS protein isoforms (HRAS, KRAS, and NRAS) were modified by the SUMO3 protein. SUMOylation of KRAS protein, either endogenous or ectopically expressed, was observed in multiple cell lines. The SUMO3 modification of KRAS proteins could be removed by SUMO1/sentrin-specific peptidase 1 (SENP1) and SENP2, but not by SENP6, indicating that RAS SUMOylation is a reversible process. A conserved residue in RAS, Lys-42, was a site that mediates SUMOylation. Results from biochemical and molecular studies indicated that the SUMO-E3 ligase PIASgamma specifically interacts with RAS and promotes its SUMOylation. Moreover, SUMOylation of RAS appeared to be associated with its activation. In summary, our study reveals a new posttranslational modification for RAS proteins. Since we found that HRAS, KRAS, and NRAS can all be SUMOylated, we propose that SUMOylation might represent a mechanism by which RAS activities are controlled. PMID- 29435115 TI - Fibrosis-related miRNAs as serum biomarkers for pancreatic ductal adenocarcinoma. AB - We investigated whether serum microRNAs (miRNAs) could be diagnostic or prognostic markers in pancreatic ductal adenocarcinoma (PDAC). We first identified miRNAs showing altered expression in human pancreatic stellate cells (hPSCs) co-cultured with PDAC cells (Panc-1 and BxPC-3) as compared to hPSCs cultured alone. Among the miRNAs with altered expression, let-7d exhibited reduced expression in an in silico analysis of The Cancer Genome Atlas data. Inhibition of let-7d resulted in enhanced expression of fibrosis-related genes. We extracted serum miRNA from 45 PDAC patients and 42 healthy controls and quantified expression let-7d using digital PCR. Based on the level of let-7d expression, we were able to distinguish between PDAC patients and controls. Additionally, reduced let-7d expression correlated with poor overall survival. Thus, fibrosis-related miRNAs may be serum biomarkers for PDAC. PMID- 29435116 TI - The inhibition of PLCgamma1 protects chondrocytes against osteoarthritis, implicating its binding to Akt. AB - Previous studies have addressed the involvement of phosphoinositide-specifc phospholipase gamma1 (PLCgamma1) and protein kinase B (PKB/Akt) in osteoarthritis (OA) pathogenesis, but it is not ascertained the possibility of them to be potential targets for OA therapy. Here, through local intra-articular injection of PLCgamma or Akt inhibitor in a rat OA model induced by anterior cruciate ligament transaction plus medial meniscus resection, the architecture of chondrocyte and matrix organization of articular cartilage were observed using histopathological assays and Aggrecan, Col2, PLCgamma1, and Akt levels were detected using immunohistochemistry assays. By treatment of Akt or PLCgamma inhibitor and transfection of different PLCgamma1- or Akt-expressing vectors in rat OA model chondrocytes, Aggrecan, Col2, PLCgamma1, p-PLCgamma1, Akt, and p-Akt levels were detected using western blotting analysis. The binding between PLCgamma1 and Akt was assessed with co-immunoprecipitation assays in human OA chondrocytes. These results showed that PLCgamma inhibition protected chondrocytes against OA, but Akt inhibition did not dramatically aggravate OA progression. There were mutual antagonism and binding between PLCgamma1 and Akt that could be regulated by their phosphorylation levels. Consequently, the data reveal that the inhibition of PLCgamma1 may provide an attractive therapeutic target for OA therapy, implicating its binding to Akt. PMID- 29435117 TI - Replication of hepatitis E virus in the ovary and promotion of oocyte apoptosis in rabbits infected with HEV-4. AB - Hepatitis E virus (HEV) infection can induce infertility and miscarriage in pregnant women and infect neonates through vertical transmission. However, the mechanism of infertility and vertical transmission remains unclear. In the present study, we evaluated the replication of HEV in the ovary and structural and molecular changes induced by HEV after intraperitoneal injection of HEV in rabbits. Positive- and negative-strand HEV RNA was detected in the ovaries at 28 and 49 days post-infection. Positive HEV open reading frames 2 and 3 signals were observed in the ovaries by immunohistochemistry staining. Histopathological changes of ovarian tissues were observed, including scattered cell necrosis and lymphocyte infiltration. The ratio of normal follicles decreased, whereas the ratio of atresia follicles increased in the HEV RNA-positive ovaries compared to the control group by counting the number of follicles at all levels. In addition, TUNEL results showed that apoptosis in follicle cells and oocytes was promoted by HEV infection. These results suggest that the ovary is one of the replication sites of HEV and that the expression of HEV RNA and antigen in ovarian tissue caused structural and molecular changes that promoted germ cell apoptosis. HEV can infect and replicate in the ovum at different stages, which is a novel mechanism for HEV vertical transmission. PMID- 29435118 TI - Assessment of folate receptor alpha and beta expression in selection of lung and pancreatic cancer patients for receptor targeted therapies. AB - A number of folate receptor (FR) targeted small molecular drugs and monoclonal antibodies have been introduced into clinical trials to treat FR positive cancers. Because the therapeutic efficacy of these drugs depends prominently on the level of FR-alpha expression on the cancer cells, patients have been commonly selected for FR-targeted therapies based on the intensity of a folate-targeted radioimaging agent. Unfortunately, uptake of such imaging agents can be mediated by both major isoforms of the folate receptor, FR-alpha and FR-beta. Logically, if the FR positive cell population in a tumor mass is dominated by FR-beta positive macrophages, patients could be selected for therapy that have few FR expressing cancer cells. Although several IHC studies have examined expression of either FR-alpha or FR-beta, no study to date has investigated expression of both FR-alpha and FR-beta in the same tumor mass. Herein, we utilize monoclonal antibodies specific for FR-alpha (mAb343) and FR-beta (m909) to query each isoform's expression in a range of cancers. We show that lung and pancreatic adenocarcinomas express the full spectrum of FR-alpha and FR-beta combinations with ~76% of lung adenocarcinomas expressing both FR-alpha and FR-beta while pancreatic cancers express primarily FR-beta. Thus, while folate-targeted imaging of lung cancer patients might accurately reflect the expression of FR-alpha on lung cancer cells, imaging of pancreatic cancer patients could mislead a physician into treating a nonresponding patient. Overall, these data suggest that an independent analysis of both FR-alpha and FR-beta should be obtained to predict the potential efficacy of a folate-targeted drug. PMID- 29435119 TI - A dual mechanism of activation of the Sonic Hedgehog pathway in anaplastic thyroid cancer: crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma. AB - Sonic Hedgehog (Shh) pathway regulates embryonic development of different organs including the thyroid gland. The aberrant activation of Shh signaling has been found in several types of cancer and according to recent evidences it represents an important regulator of tumor-stroma interaction. In this study, we have analyzed expression, activation and molecular mechanisms regulating the Shh pathway and its involvement in the modulation of tumor stroma interaction in anaplastic thyroid cancer (ATC) cells. Our results suggest that Shh signaling undergoes a dual mechanism of induction in ATC cells: 1) a basal non-canonical Smo-dependent activation of Gli transcription factor that is partly caused by interaction with the RAS/BRAF/MEK oncogenic pathway and is characterized by the absence of Shh ligand expression in thyroid cancer cells and 2) a paracrine response of cancer cells to Shh ligand secreted by tumor stroma (fibroblasts and mesenchymal stromal cells, MSCs) inducing cancer cell migration and in vitro tumorigenesis. Our data therefore suggest Shh as a potential novel therapeutic target in aggressive thyroid cancers. PMID- 29435120 TI - AMPK activation by Tanshinone IIA protects neuronal cells from oxygen-glucose deprivation. AB - The current study tested the potential neuroprotective function of Tanshinone IIA (ThIIA) in neuronal cells with oxygen-glucose deprivation (ODG) and re oxygenation (OGDR). In SH-SY5Y neuronal cells and primary murine cortical neurons, ThIIA pre-treatment attenuated OGDR-induced viability reduction and apoptosis. Further, OGDR-induced mitochondrial depolarization, reactive oxygen species production, lipid peroxidation and DNA damages in neuronal cells were significantly attenuated by ThIIA. ThIIA activated AMP-activated protein kinase (AMPK) signaling, which was essential for neuroprotection against OGDR. AMPKalpha1 knockdown or complete knockout in SH-SY5Y cells abolished ThIIA induced AMPK activation and neuroprotection against OGDR. Further studies found that ThIIA up-regulated microRNA-135b to downregulate the AMPK phosphatase Ppm1e. Notably, knockdown of Ppm1e by targeted shRNA or forced microRNA-135b expression also activated AMPK and protected SH-SY5Y cells from OGDR. Together, AMPK activation by ThIIA protects neuronal cells from OGDR. microRNA-135b-mediated silence of Ppm1e could be the key mechanism of AMPK activation by ThIIA. PMID- 29435121 TI - Lipidomics reveals altered biosynthetic pathways of glycerophospholipids and cell signaling as biomarkers of the polycystic ovary syndrome. AB - Purpose: In this work, a non-targeted approach was used to unravel changes in the plasma lipidome of PCOS patients. The aim is to offer new insights in PCOS patients strictly selected in order to avoid confounding factors such as dyslipemia, obesity, altered glucose/insulin metabolism, cardiovascular disease, or cancer. Results: Multivariate statistics revealed a specific lipidomic signature for PCOS patients without associated pathologies. This signature implies changes, mainly by down-regulation, in glycerolipid, glycerophospholipid and sphingolipid metabolism suggesting an altered biosynthetic pathway of glycerophospholipids and cell signaling as second messengers in women with PCOS. Conclusions: Our study confirms that a lipidomic approach discriminates a specific phenotype from PCOS women without associated pathologies from healthy controls. Methods: In a cross-sectional pilot study, data were obtained from 34 subjects, allocated to one of two groups: a) lean, healthy controls (n = 20), b) PCOS patients (n = 14) with diagnosis based on hyperandrogenaemia, oligo anovulation and abnormal ovaries with small follicular cysts. A detailed biochemical characterization was made and lipidomic profiling was performed via an untargeted approach using LC-ESI-QTOF MS/MS. PMID- 29435122 TI - APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response. AB - APOBEC enzymes are responsible for a mutation signature (TCW>T/G) implicated in a wide variety of tumors. We explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival using sequencing data from The Cancer Genome Atlas (n = 395), Beijing Genomics Institute (n = 99), and Cancer Cell Line Encyclopedia. Tumors were split into "APOBEC-high" and "APOBEC-low" based on APOBEC enrichment. Patients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs. 18.5 months, p = 0.005). APOBEC-high tumors are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2) and chromatin regulatory genes (ARID1A, MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with mutation burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis is associated with increased expression of immune signatures, including interferon signaling, and expression of APOBEC3B is increased after stimulation of APOBEC-high bladder cancer cell lines with IFNgamma. In summary, APOBEC-high tumors are more likely to have mutations in DNA damage response and chromatin regulatory genes, potentially providing more substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response. PMID- 29435123 TI - Signature of survival: a 18F-FDG PET based whole-liver radiomic analysis predicts survival after 90Y-TARE for hepatocellular carcinoma. AB - Purpose: To generate a predictive whole-liver radiomics scoring system for progression-free survival (PFS) and overall survival (OS) in patients undergoing transarterial radioembolization using Yttrium-90 (90Y-TARE) for unresectable hepatocellular carcinoma (uHCC). Results: The generated pPET-RadScores were significantly correlated with survival for PFS (median of 11.4 mo [95% confidence interval CI: 6.3-16.5 mo] in low-risk group [PFS-pPET-RadScore < 0.09] vs. 4.0 mo [95% CI: 2.3-5.7 mo] in high-risk group [PFS-pPET-RadScore > 0.09]; P = 0.0004) and OS (median of 20.3 mo [95% CI: 5.7-35 mo] in low-risk group [OS-pPET-RadScore < 0.11] vs. 7.7 mo [95% CI: 6.0-9.5 mo] in high-risk group [OS-pPET-RadScore > 0.11]; P = 0.007). The multivariate analysis confirmed PFS-pPET-RadScore (P = 0.006) and OS-pPET-RadScore (P = 0.001) as independent negative predictors. Conclusion: Pretreatment 18F-FDG PET whole-liver radiomics signature appears as an independent negative predictor for PFS and OS in patients undergoing 90Y-TARE for uHCC. Methods: Pretreatment 18F-FDG PET of 47 consecutive patients undergoing 90Y-TARE for uHCC (31 resin spheres, 16 glass spheres) were retrospectively analyzed. For each patient, based on PET radiomics signature from whole-liver semi-automatic segmentation, PFS and OS predictive PET-radiomics scores (pPET RadScores) were obtained using LASSO Cox regression. Using X-tile software, the optimal score to predict PFS (PFS-pPET-RadScore) and OS (OS-pPET-RadScore) served as cutoff to separate high and low-risk patients. Survival curves were estimated using the Kaplan-Meier method. The prognostic value of PFS and OS-pPET-RadScore, Barcelona-Clinic Liver Cancer staging system and serum alpha-fetoprotein level was analyzed to predict PFS and OS in multivariate analysis. PMID- 29435124 TI - Adduction to arginine detoxifies aflatoxin B1 by eliminating genotoxicity and altering in vitro toxicokinetic profiles. AB - Aflatoxin B1 (AFB1), a class 1 carcinogen and prominent food contaminant, is highly linked to the development of hepatocellular carcinoma (HCC) and plays a causative role in a large portion of global HCC cases. We have demonstrated that a mixture of common organic acids (citric and phosphoric acid) along with arginine can eliminate >99% of AFB1 in solution as well as on corn kernels and convert it to the AFB2a-Arg adduct, acting as a potential detoxification process for contaminated foods. Evaluation of toxicokinetic changes after AFB2a-Arg formation show that the product is highly stable in biological fluids, is not metabolized by P450 enzymes, is highly plasma protein bound, has low lipid solubility, and has poor intestinal permeability/high intestinal efflux compared to AFB1. Ames' test results show that at mutagenic concentrations of AFB1, AFB2a Arg does not have any measurable mutagenic effect which was confirmed by DNA adduct identification by liquid chromatography-mass spectrometry. Evaluation in HepG2 and HepaRG cells showed that AFB2a-Arg did not cause any significant decreases in cell viability nor did it increase micronuclei formation when administered at toxic concentrations of AFB1. These results show that conversion of AFB1 to AFB2a-Arg is a potential strategy to detoxify contaminated foods. PMID- 29435125 TI - Inhibition of autophagy-attenuated calcium oxalate crystal-induced renal tubular epithelial cell injury in vivo and in vitro. AB - Accumulating evidence suggests that autophagy is involved in the pathophysiological processes of kidney diseases. However, the role of autophagy in the formation of calcium oxalate (CaOx) nephrolithiasis remains unclear. In this study, we investigated the effects of autophagy on renal tubular epithelial cell injury induced by CaOx crystals in vivo and in vitro. We first observed that the expression levels of LC3-II and BECN1 and number of autophagic vacuoles were markedly increased in the renal tissue of CaOx stone patients. We subsequently found that exposure of HK-2 cells to CaOx crystals could increase LC3-II and BECN1 expression as well as the number of GFP-LC3 dots and autophagic vacuoles in a dose- and time-dependent manner. In addition, our results suggest that CaOx crystals induced autophagy, at least in part, via activation of the reactive oxygen species (ROS) pathway in HK-2 cells. Furthermore, inhibition of autophagy using 3-methyladenine or siRNA knockdown of BECN1 attenuated CaOx crystal-induced HK-2 cells injury. However, enhancing autophagic activity with rapamycin exerted an opposite effect. Taken together, our results demonstrate that autophagy is essential for CaOx crystal-induced renal tubular epithelial cell injury and that inhibition of autophagy could be a novel therapeutic strategy for CaOx nephrolithiasis. PMID- 29435126 TI - Quantitative metabolomics for investigating the value of polyamines in the early diagnosis and therapy of colorectal cancer. AB - As an important biomarker for cancer, polyamine levels in body fluid could be employed for monitoring the colorectal cancer (CRC), however the role of polyamines in the development and therapeutics phases of CRC remains uncertain. In this paper, the relationship between polyamines and CRC development and therapeutics had been investigated by the study of changes in plasma polyamine levels during the precancerous, developmental and treatment phases of CRC. After inducing CRC in Wistar rats by intraperitoneal injection of 1, 2 dimethylhydrazine, the animals were given a traditional Chinese medicine, Aidi injections. Firstly, the polyamine levels in the plasma of CRC, healthy and medicated rats were measured by UHPLC-MS/MS assay. In addition, Lasso regression analysis was used for screening and confirming the key markers, which can be employed for distinguishing the healthy and CRC rats as well as the CRC and medication rats. The results obtained showed that polyamine metabolism had been disrupted by CRC but returned to normal levels following Aidi injections and, in particular, putrescine and agmatine were closely correlated with CRC. Our results demonstrate the potential value of plasma polyamine metabolic profiling during the early diagnosis and medical treatment of CRC. Also, the integrated method of polyamine metabolite target analysis and lasso regression analysis can be applied in metabolomics for seeking the differential metabolites. PMID- 29435127 TI - alpha-Tocopherol succinate enhances pterostilbene anti-tumor activity in human breast cancer cells in vivo and in vitro. AB - Vitamin E (Vit. E) is considered an essential dietary nutrient for humans and animals. An enormous body of evidence indicates the biological and protective effects of Vit. E consumption. Tocopherol-associated protein (TAP) is a major tocopherol-binding protein affecting Vit. E stimulation and downstream signaling transduction. However, how Vit. E utilizes TAP as an anti-cancer mechanism remains unclear. Microarray analysis of signature gene profiles in breast cancer cells treated with alpha-tocopheryl succinate (alpha-TOS, a Vit. E isoform) resulted in cell cycle arrest and anti-cancer activity in breast cancer cells. Pterostilbene (PS), a natural dietary antioxidant found in blueberries, in combination with alpha-TOS synergistically maximized breast cancer cell growth inhibition by disrupting signal transduction, transcription factors and cell cycle proteins. In a xenograft mouse model, PS treatment with Vit. E inhibited breast tumor growth and cell invasion, which were evaluated using our recently developed circulating tumor cell (CTC) detection assay. Because dietary Vit. E and PS supplementation contributed to preventative and therapeutic effects in vitro and in vivo, this combination may benefit breast cancer therapy in the clinic. PMID- 29435128 TI - Prognostic factors for olfactory groove meningioma with nasal cavity extension. AB - Objectives: Meningioma recurrence remains a significant issue. No study has described the relationship between the clinical features and prognosis of communicating meningioma that primarily originates from the olfactory groove. The aim of the study was to identify prognostic factors of communicating olfactory groove meningiomas that could be stratified according to their risk of recurrence. Results: A Simpson grade one or two resection was achieved. Complications with cerebrospinal rhinorrhoea occurred in two patients: one required reoperation, and the other was managed successfully with external drainage of lumbar cistern. There were 5 known clinical recurrences within the median follow-up of more than 5 years. The median 5-year recurrence-free survival for patients was 88.4%. Factors such as gender, tumour size, T2 signal and the hyperostotic bone had no significant effect on recurrence-free survival. However, recurrence was activated by oedema range, hyperostosis, dural tail sign and tumor texture (p < 0.05). Interestingly, female patients with the disease were younger than males at diagnosis, and the difference was statistically significant ( p = 0.013). Conclusions: Based on these features of communicating olfactory groove meningiomas, different strategies may be adopted for the follow-up and subsequent treatment. Due to the relatively uncommon incidence, more investigations into the clinical behaviour of this entity are crucial. Patients and Methods: A retrospective study of 43 patients harbouring olfactory groove meningiomas invading the ethmoid or nasal cavity was conducted at three medical centers from 2000 to 2010. The records were reviewed for clinical presentations, imaging studies, surgical observation, histological features and follow-up. PMID- 29435129 TI - Computational methods reveal novel functionalities of PIWI-interacting RNAs in human papillomavirus-induced head and neck squamous cell carcinoma. AB - Human papillomavirus (HPV) infection is the fastest growing cause of head and neck squamous cell carcinoma (HNSCC) today, but its role in malignant transformation remains unclear. This study aimed to conduct a comprehensive investigation of PIWI-interacting RNA (piRNA) alterations and functionalities in HPV-induced HNSCC. Using 77 RNA-sequencing datasets from TCGA, we examined differential expression of piRNAs between HPV16(+) HNSCC and HPV(-) Normal samples, identifying a panel of 30 HPV-dysregulated piRNAs. We then computationally investigated the potential mechanistic significances of these transcripts in HPV-induced HNSCC, identifying our panel of piRNAs to associate with the protein PIWIL4 as well as the RTL family of retrotransposon-like genes, possibly through direct binding interactions. We also recognized several HPV dysregulated transcripts for their correlations with well-documented mutations and copy number variations in HNSCC as well as HNSCC clinical variables, demonstrating the potential ability of our piRNAs to play important roles in large-scale modulation of HNSCC in addition to their direct, smaller-scale interactions in this malignancy. The differential expression of key piRNAs, including NONHSAT077364, NONHSAT102574, and NONHSAT128479, was verified in vitro by evaluating endogenous expression in HPV(+) cancer vs. HPV(-) normal cell lines. Overall, our novel study provides a rigorous investigation of piRNA dysregulation in HPV-related HNSCC, and lends critical insight into the idea that these small regulatory transcripts may play crucial and previously unidentified roles in tumor pathogenesis and progression. PMID- 29435130 TI - O-linked N-acetylglucosamine transferase enhances secretory clusterin expression via liver X receptors and sterol response element binding protein regulation in cervical cancer. AB - O-linked N-acetylglucosamine transferase (OGT) expression is increased in various cancer types, indicating the potential importance of O-GlcNAcylation in tumorigenesis. Secretory clusterin (sCLU) is involved in cancer cell proliferation and drug resistance, and recently, liver X receptors (LXRs) and sterol response element binding protein-1 (SREBP-1) were reported to regulate sCLU transcription. Here, we found that sCLU is significantly increased in cervical cancer cell lines, which have higher expression levels of O-GlcNAc and OGT than keratinocytes. OGT knockdown decreased expression of LXRs, SREBP-1 and sCLU through hypo-O-GlcNAcylation of LXRs. Additionally, treatment with Thiamet G, O-GlcNAcase OGA inhibitor, increased expression of O-GlcNAcylation and sCLU, and high glucose increased levels of LXRs, SREBP-1 and sCLU in HeLa cells. Moreover, OGT knockdown induced G0/G1 phase cell cycle arrest and late apoptosis in cisplatin-treated HeLa cells, and decreased viability compared to OGT intact HeLa cells. Taken together, these findings suggest that OGT, O-GlcNAcylated LXRs, and SREBP-1 increase sCLU expression in cervical cancer cells, which contributes to drug resistance. PMID- 29435131 TI - PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression. AB - Programmed death ligand (PD-L1) expression was associated with tumor immune escape and subsequent poor prognosis in non-small cell lung cancer (NSCLC). This expression was higher in patients with EGFR-mutated NSCLC tumors than in those with EGFR-wild-type (WT) NSCLC tumors. We therefore hypothesized that poor prognosis mediated by higher PD-L1 may be partially through conferring resistance to tyrosine kinase inhibitor (TKI) in NSCLC regardless of EGFR mutation. The change in PD-L1 expression following gene manipulation corresponded with changes in expression of HIF-1alpha and YAP1. The expression of HIF-1alpha and YAP1 was concomitantly decreased by PD-L1 silencing or by ROS scavenger treatment (N acetylcysteine, NAC); however, a ROS inducer treatment (pyocyanin) completely reversed the decreased expression of both genes in EGFR-mutated and -wild-type (WT) NSCLC cells. The MTT assay indicated that the inhibitory concentration of gefitinib yielding 50% cell viability (IC50) depended on PD-L1-mediated YAP1 expression. Mechanistic studies indicated that upregulation of YAP1 by PD-L1 might be responsible for EGFR mutation-independent TKI resistance via the ROS/HIF 1alpha axis. An unfavorable TKI response was more common in patient tumors with high PD-L1 or YAP1 mRNA expression than in patient tumors with low mRNA expression of these genes. In conclusion, PD-L1 might confer EGFR mutation independent TKI resistance in NSCLC cells via upregulation of YAP1 expression. PMID- 29435132 TI - Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma. AB - The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the vast majority of human clear cell renal carcinomas. The pathogenesis of VHL loss is currently best understood to occur through stabilization of the hypoxia-inducible factors, activation of hypoxia-induced signaling pathways, and transcriptional reprogramming towards a pro-angiogenic and pro-growth state. However, hypoxia also drives other pro-tumorigenic processes, including the development of genomic instability via down-regulation of DNA repair gene expression. Here, we find that DNA repair genes involved in double-strand break repair by homologous recombination (HR) and in mismatch repair, which are down-regulated by hypoxic stress, are decreased in VHL-deficient renal cancer cells relative to wild type VHL-complemented cells. Functionally, this gene repression is associated with impaired DNA double-strand break repair in VHL-deficient cells, as determined by the persistence of ionizing radiation-induced DNA double-strand breaks and reduced repair activity in a homology-dependent plasmid reactivation assay. Furthermore, VHL deficiency conferred increased sensitivity to PARP inhibitors, analogous to the synthetic lethality observed between hypoxia and these agents. Finally, we discovered a correlation between VHL inactivation and reduced HR gene expression in a large panel of human renal carcinoma samples. Together, our data elucidate a novel connection between VHL-deficient renal carcinoma and hypoxia induced down-regulation of DNA repair, and identify potential opportunities for targeting DNA repair defects in human renal cell carcinoma. PMID- 29435133 TI - Elucidating mechanisms of sunitinib resistance in renal cancer: an integrated pathological-molecular analysis. AB - Upon sunitinib treatment of metastatic renal cell carcinoma patients eventually acquire resistance. Our aim was to investigate microRNAs behind sunitinib resistance. We developed an in vivo xenograft and an in vitro model and compared morphological, immunhistochemical, transcriptomical and miRNome data changes during sunitinib response and resistance by performing next-generation mRNA and miRNA sequencing. Complex bioinformatics (pathway, BioFunction and network) analysis were performed. Results were validated by in vitro functional assays. Our morphological, immunhistochemical, transcriptomical and miRNome data all pointed out that during sunitinib resistance tumor cells changed to migratory phenotype. We identified the downregulated miR-1 and miR-663a targeting FRAS1 (Fraser Extracellular Matrix Complex Subunit 1) and MDGA1 (MAM Domain Containing Glycosylphosphatidylinositol Anchor 1) in resistant tumors. We proved firstly miR 1-FRAS1 and miR-663a-MDGA1 interactions. We found that MDGA1 knockdown decreased renal cancer cell migration and proliferation similarly to restoration of levels of miR-1 and miR-663. Our results support the central role of cell migration as an adaptive mechanism to secure tumor survival behind sunitinib resistance. MDGA1, FRAS1 or the targeting miRNAs can be potential adjuvant therapeutic targets, through inhibition of cancer cell migration, thus eliminating the development of resistance and metastasis. PMID- 29435134 TI - Silver nanoparticles of different sizes induce a mixed type of programmed cell death in human pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma, with the high resistance to chemotherapeutic agents, remains the fourth leading cause of cancer-death in the world. Due to the wide range of biological activity and unique properties, silver nanoparticles (AgNPs) are indicated as agents with potential to overcome barriers involved in chemotherapy failure. Therefore, in our study we decided to assess the ability of AgNPs to kill pancreatic cancer cells, and then to identify the molecular mechanism underlying this effect. Moreover, we evaluated the cytotoxicity of AgNPs against non-tumor cell of the same tissue (hTERT-HPNE cells) for comparison. Our results indicated that AgNPs with size of 2.6 and 18 nm decreased viability, proliferation and caused death of pancreatic cancer cells in a size- and concentration-dependent manner. Ultrastructural analysis identified that cellular uptake of AgNPs resulted in apoptosis, autophagy, necroptosis and mitotic catastrophe. These alterations were associated with increased pro apoptotic protein Bax and decreased level of anti-apoptotic protein Bcl-2. Moreover, AgNPs significantly elevated the level of tumor suppressor p53 protein as well as necroptosis- and autophagy-related proteins: RIP-1, RIP-3, MLKL and LC3-II, respectively. In addition, we found that PANC-1 cells were more vulnerable to AgNPs-induced cytotoxicity compared to pancreatic non-tumor cells. In conclusion, AgNPs by inducing mixed type of programmed cell death in PANC-1 cells, could provide a new therapeutic strategy to overcome chemoresistance in one of the deadliest human cancer. PMID- 29435135 TI - Association of SNPs in the TIMP-2 gene and large artery atherosclerotic stroke in southern Chinese Han population. AB - Tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) regulates the extracellular matrix degradation, which involved in vascular remodeling and dysfunction, destabilization of atherosclerotic plaque and many other pathological processes. The rupture of atherosclerotic plaque is the trigger of Large artery atherosclerotic (LAA) stroke. We speculate that the Single nucleotide polymorphisms (SNPs) in TIMP-2 may have an association with LAA stroke. To prove this hypothesis, we conducted this case-control study. 250 LAA stroke patients and 250 healthy controls were collected for the analysis of TIMP 2 polymorphisms. Among six SNPs, we detected no deviation from Hardy-Weinberg equilibrium in control group. There was a significant difference in rs4789936 T allele frequency between patient and control groups (OR = 0.68, 95% CI = 0.51 0.91, P = 0.009), which means lower risk of LAA stroke. We observed the rs4789936 had a decreased risk of LAA stroke according to the codominant (OR = 0.64, 95% CI = 0.44-0.92, P = 0.026), dominant (OR = 0.62, 95% CI = 0.43-0.88, P = 0.008), overdominant (OR = 0.68, 95% CI = 0.48-0.98, P = 0.039), log-additive (OR = 0.68, 95% CI = 0.51-0.91, P = 0.009) models analyses. However, these findings could only validate under dominant model (OR = 0.65, 95% CI = 0.42-1.00, P = 0.049) after adjustment of gender and age. The results indicate a potential association between TIMP-2 variants and LAA stroke risk in southern Chinese Han population. PMID- 29435136 TI - Epigenetic silencing of SMOC1 in traditional serrated adenoma and colorectal cancer. AB - Colorectal sessile serrated adenoma/polyps (SSA/Ps) are well-known precursors of colorectal cancer (CRC) characterized by BRAF mutation and microsatellite instability. By contrast, the molecular characteristics of traditional serrated adenoma (TSAs) are not fully understood. We analyzed genome-wide DNA methylation in TSAs having both protruding and flat components. We identified 11 genes, including SMOC1, methylation of which progressively increased during the development of TSAs. SMOC1 was prevalently methylated in TSAs, but was rarely methylated in SSA/Ps (p < 0.001). RT-PCR and immunohistochemistry revealed that SMOC1 was expressed in normal colon and SSA/Ps, but its expression was decreased in TSAs. Ectopic expression of SMOC1 suppressed proliferation, colony formation and in vivo tumor formation by CRC cells. Analysis of colorectal lesions (n = 847) revealed that SMOC1 is frequently methylated in TSAs, high-grade adenomas and CRCs. Among these, SMOC1 methylation was strongly associated with KRAS mutation and CpG island methylator phenotype (CIMP)-low. These results demonstrate that epigenetic silencing of SMOC1 is associated with TSA development but is rarely observed in SSA/Ps. SMOC1 expression could thus be a diagnostic marker of serrated lesions, and SMOC1 methylation could play a role in neoplastic pathways in TSAs and conventional adenomas. PMID- 29435137 TI - Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer. AB - SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials. PMID- 29435138 TI - Personalized adoptive immunotherapy for patients with EBV-associated tumors and complications: Evaluation of novel naturally processed and presented EBV-derived T-cell epitopes. AB - Morbidity and mortality of immunocompromised patients are increased by primary infection with or reactivation of Epstein-Barr virus (EBV), possibly triggering EBV+ post-transplant lymphoproliferative disease (PTLD). Adoptive transfer of EBV specific cytotoxic T cells (EBV-CTLs) promises a non-toxic immunotherapy to effectively prevent or treat these complications. To improve immunotherapy and immunomonitoring this study aimed at identifying and evaluating naturally processed and presented HLA-A*03:01-restricted EBV-CTL epitopes as immunodominant targets. More than 15000 peptides were sequenced from EBV-immortalized B cells transduced with soluble HLA-A*03:01, sorted using different epitope prediction tools and eleven candidates were preselected. T2 and Flex-T peptide-binding and dissociation assays confirmed the stability of peptide-MHC complexes. Their immunogenicity and clinical relevance were evaluated by assessing the frequencies and functionality of EBV-CTLs in healthy donors (n > 10) and EBV+ PTLD-patients (n = 5) by multimer staining, Eli- and FluoroSpot assays. All eleven peptides elicited EBV-CTL responses in the donors. Their clinical applicability was determined by small-scale T-cell enrichment using Cytokine Secretion Assay and immunophenotyping. Mixtures of these peptides when added to the EBV Consensus pool revealed enhanced stimulation and enrichment efficacy. These EBV-specific epitopes broadening the repertoire of known targets will improve manufacturing of clinically applicable EBV-CTLs and monitoring of EBV-specific T-cell responses in patients. PMID- 29435139 TI - Quantitative high-throughput phenotypic screening of pediatric cancer cell lines identifies multiple opportunities for drug repurposing. AB - Drug repurposing approaches have the potential advantage of facilitating rapid and cost-effective development of new therapies. Particularly, the repurposing of drugs with known safety profiles in children could bypass or streamline toxicity studies. We employed a phenotypic screening paradigm on a panel of well characterized cell lines derived from pediatric solid tumors against a collection of ~3,800 compounds spanning approved drugs and investigational agents. Specifically, we employed titration-based screening where compounds were tested at multiple concentrations for their effect on cell viability. Molecular and cellular target enrichment analysis indicated that numerous agents across different therapeutic categories and modes of action had an antiproliferative effect, notably antiparasitic/protozoal drugs with non-classic antineoplastic activity. Focusing on active compounds with dosing and safety information in children according to the Children's Pharmacy Collaborative database, we identified compounds with therapeutic potential through further validation using 3D tumor spheroid models. Moreover, we show that antiparasitic agents induce cell death via apoptosis induction. This study demonstrates that our screening platform enables the identification of chemical agents with cytotoxic activity in pediatric cancer cell lines of which many have known safety/toxicity profiles in children. These agents constitute attractive candidates for efficacy studies in pre-clinical models of pediatric solid tumors. PMID- 29435140 TI - Triplications of human chromosome 21 orthologous regions in mice result in expansion of megakaryocyte-erythroid progenitors and reduction of granulocyte macrophage progenitors. AB - Individuals with Down syndrome (DS) frequently have hematopoietic abnormalities, including transient myeloproliferative disorder and acute megakaryoblastic leukemia which are often accompanied by acquired GATA1 mutations that produce a truncated protein, GATA1s. The mouse has been used for modeling DS based on the syntenic conservation between human chromosome 21 (Hsa21) and three regions in the mouse genome located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. To assess the impact of the dosage increase of Hsa21 gene orthologs on the hematopoietic system, we characterized the related phenotype in the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+ model which carries duplications spanning the entire Hsa21 orthologous regions on Mmu10, Mmu16 and Mmu17, and the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+;Gata1Yeym2 model which carries a Gata1s mutation we engineered. Both models exhibited anemia, macrocytosis, and myeloproliferative disorder. Similar to human DS, the megakaryocyte-erythrocyte progenitors (MEPs) and granulocyte-monocyte progenitors (GMPs) were significantly increased and reduced, respectively, in both models. The subsequent identification of all the aforementioned phenotypes in the Dp(16)1Yey/+ model suggests that the causative dosage sensitive gene(s) are in the Hsa21 orthologous region on Mmu16. Therefore, we reveal here for the first time that the human trisomy 21-associated major segmental chromosomal alterations in mice can lead to expanded MEP and reduced GMP populations, mimicking the dynamics of these myeloid progenitors in DS. These models will provide the critical systems for unraveling the molecular and cellular mechanism of DS-associated myeloproliferative disorder, and particularly for determining how human trisomy 21 leads to expansion of MEPs as well as how such an alteration leads to myeloproliferative disorder. PMID- 29435141 TI - Induction of endoplasmic reticulum stress and mitochondrial dysfunction dependent apoptosis signaling pathway in human renal cancer cells by norcantharidin. AB - Previous studies reported that norcantharidin (NCTD) has anti-tumor effects. We investigated the antitumor effects and underlying mechanism of NCTD on human renal cancer in vitro and in vivo. NCTD significantly decreased renal cancer cell viability by induction of apoptosis, as determined by the MTT assay and annexin V/PI staining. NCTD treatment of 786-O and A-498 cells altered the expression of caspase family proteins and PARP. Moreover, NCTD induced mitochondrial depolarization, which was accompanied by an increased level of Bax and decreased levels of Bcl-2 and Mcl-1. NCTD induced endoplasmic reticulum (ER) stress by increasing the expression of Grp78, p-elF2alpha, ATF4, and CHOP. Pretreatment with an ER stress inhibitor (salubrinal) significantly attenuated the effect of NCTD. NCTD also induced activation of the AKT pathway in 786-O and A-498 cells. Overexpression of AKT partly reversed the effect of NCTD on apoptosis. NCTD treatment led to decreased expression of Bcl-2 and Mcl-1, and increased expression of Bax, cleaved-caspase-9, cleaved-PARP, and p-elF2alpha. Our in vivo studies demonstrated that NCTD significantly inhibited tumor growth in a nude mouse xenograft model. Taken together, our results suggest that NCTD is a potential anti-tumor agent for treatment of renal carcinoma. PMID- 29435142 TI - Co-expression analysis revealed PTCH1-3'UTR promoted cell migration and invasion by activating miR-101-3p/SLC39A6 axis in non-small cell lung cancer: implicating the novel function of PTCH1. AB - Metastasis is the most common cause of mortality for non-small cell lung cancer (NSCLC). PTCH1, a receptor of Hedgehog (Hh) pathway, is reported to suppress cell proliferation. Interestingly, our previous study showed PTCH1 silencing promoted cell proliferation but inhibited cell migration and invasion of NSCLC cells. However, the precise mechanisms of PTCH1 regulating NSCLC metastasis remain unclear. PTCH1 has multiple splicing variants, which all share the same 3'UTR sequence, meanwhile, emerging studies have shown competing endogenous RNAs (ceRNAs) play important roles in regulating cancer progression. Therefore, we hypothesized the functions of PTCH1-3'UTR in NSCLC in present study to reveal its role as a ceRNA. Here, we find overexpression of PTCH1-3'UTR promotes cell migration, invasion and adhesion, but does not affect cell proliferation in NSCLC cells. By combining weighted correlation network analysis (WGCNA) analysis and experimental validation, we reported PTCH1-3'UTR acted as a sponge to absorb miR 101-3p and promoted SLC39A6 expression. Moreover, we observed low expression of miR-101-3p and PTCH1 and high SLC39A6 levels were positively correlated with NSCLC progression. Therefore, our results help to understand the function of PTCH1 in NSCLC tumorigenesis and provide novel insights for the prevention of NSCLC metastasis. PMID- 29435143 TI - A novel classifier based on three preoperative tumor markers predicting the cancer-specific survival of gastric cancer (CEA, CA19-9 and CA72-4). AB - Several studies have highlighted the prognostic value of the individual and the various combinations of the tumor markers for gastric cancer (GC). Our study was designed to assess establish a new novel model incorporating carcino-embryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4). A total of 1,566 GC patients (Primary cohort) between Jan 2000 and July 2013 were analyzed. The Primary cohort was randomly divided into Training set (n=783) and Validation set (n=783). A three-tumor marker classifier was developed in the Training set and validated in the Validation set by multivariate regression and risk-score analysis. We have identified a three-tumor marker classifier (including CEA, CA19-9 and CA72-4) for the cancer specific survival (CSS) of GC (p<0.001). Consistent results were obtained in the both Training set and Validation set. Multivariate analysis showed that the classifier was an independent predictor of GC (All p value <0.001 in the Training set, Validation set and Primary cohort). Furthermore, when the leave-one-out approach was performed, the classifier showed superior predictive value to the individual or two of them (with the highest AUC (Area Under Curve); 0.618 for the Training set, and 0.625 for the Validation set), which ascertained its predictive value. Our three-tumor marker classifier is closely associated with the CSS of GC and may serve as a novel model for future decisions concerning treatments. PMID- 29435144 TI - miRNA regulation of Tip110 expression and self-renewal and differentiation of human CD34+ hematopoietic cells. AB - Tip110 expression regulates hematopoiesis, but the regulatory mechanisms during hematopoiesis are not fully understood. There are a number of putative microRNA (miRNA) binding sites identified within the Tip110 3' untranslated region (3'UTR). In this study, we determined the relationship among Tip110 miRNA, Tip110 expression and self-renewal and differentiation of human CD34+ hematopoietic cells. Using a Tip110 3UTR-based reporter gene assay, 11 miRNA showed the specific activity toward the Tip110 3'UTR and down-regulated constitutive Tip110 mRNA expression. When human cord blood CD34+ cells were differentiated, Tip110 mRNA expression showed significant decreases. Concurrently, five miRNA showed significant increases, five miRNA showed significant decreases, and one miRNA remained unchanged. To further assess the roles of miRNA in Tip110 expression and self-renewal and differentiation of human CD34+ hematopoietic cells, human cord blood CD34+ cells were transduced to express the full-length Tip110 3'UTR RNA. Expression of the Tip110 3'UTR RNA led to significant increases of Tip110 mRNA, and the number of hematopoietic stem cells and progenitor cells. Taken together, these results show important roles of Tip110 miRNA in Tip110 expression control and Tip110 regulation of hematopoiesis and offer a possibility of using Tip110 miRNA or 3'UTR as a strategy to maintain human CD34+ hematopoietic cells. PMID- 29435145 TI - TNF-alpha inhibits SATB2 expression and osteoblast differentiation through NF kappaB and MAPK pathways. AB - Although the mechanisms of Tumor necrosis factor alpha (TNF-alpha) on facilitating osteoclast differentiation and bone resorption is well known, the mechanisms behind the suppression of the osteoblast differentiation from mesenchymal stem cells (MSCs) are still poorly understood. In this study, we observed a negative correlation between TNF-alpha levels and the expression of special AT-rich sequence-binding protein 2 (SATB2), a critical osteoblastogenesis transcription factor, in ovariectomy (OVX)-induced bone loss and IL-1-induced arthritis animal model. We found that TNF-alpha treatment inhibited mesenchymal cell line C2C12 osteoblast differentiation and sharply decreased BMP2-induced SATB2 expression. Upon TNF-alpha treatment, the activity of smad1/5/8 was inhibited, by contrast, extracellular signal-regulated kinase-1/2 (ERK1/2) and P38 was increased in C2C12 cells, the inhibitor of ERK1/2 (U0126) was found to abrogate the TNF-alpha inhibition of SATB2 expression. Furthermore, the NF-kappaB signaling pathway in C2C12 cells was significantly activated by the treatment of TNF-alpha, and TNF-alpha induced NF-kappaB directly binds to SATB2 promoter to suppress its expression. These results suggest that TNF-alpha suppresses SATB2 expression through activating NF-kappaB and MAPK signaling and depressing smad1/5/8 signaling, which contributes to the inhibition of osteoblast differentiation and might be potential therapeutic targets for inflammation induced bone loss. PMID- 29435146 TI - Upregulation of LncRNA BCYRN1 promotes tumor progression and enhances EpCAM expression in gastric carcinoma. AB - Brain cytoplasmic RNA 1 (BCYRN1), along non-coding RNA, plays a critical role in various diseases, including some cancers. However, the expression of BCYRN1 and its roles in gastric carcinoma (GC) still remain unidentified. Thus, this study employed RT-qPCR to detect expression of BCYRN1 in 85 paired GC samples and adjacent normal tissues, and performed in vitro studies to explore effects of BCYRN1 in GC cells on cell proliferation, apoptosis and migration. We found BCYRN1 was significantly upregulated in GC samples, and its expression was positively correlated with advanced TNM stage (p = 0.0012) and tumor size (p = 0.027). Functionally, BCYRN1 knockdown by siRNA could inhibit cell proliferation, induce G1/G0 cell cycle arrest, increase apoptosis and impair migratory ability of AGS cells. Moreover, the results of RT-qPCR and western blotting indicated that knockdown of BCYRN1 notably decreased the expression of epithelial cell adhesion molecules (EpCAM). Otherwise, overexpression of BCYRN1 in GC cells (BGC 823 and SGC-7901) could reverse the effects of BCYRN1 knockdown. Taken together, our data indicate for the first time that BCYRN1 acts as an oncogenic lncRNA in GC progression and may be a potential therapeutic target in GC. PMID- 29435147 TI - Morphologic predictors of pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. AB - Purpose: To evaluate the value of morphological parameters that can be obtained conveniently by MRI for predicting pathologically complete response (pCR) in patients with rectal cancer. Materials and Methods: A cohort of 101 patients was examined using MRI before and after Neoadjuvant chemoradiotherapy (nCRT). Morphological parameters including maximum tumor area (MTA), maximum tumor length (MTL) and maximum tumor thickness (MTT), as well as cylindrical approximated tumor volume (CATV), distance to anal verge (DTA), and the reduction rates were evaluated by two experienced readers independently. Results: Post-nCRT MTA and MTL, reduction rates and pre-nCRT DTA were proved to be significantly different between pCR and non-pCR with the AUCs of 0.672-0.853. The sensitivity and specificity for assessing pCR were 61.1-89.9% and 59.0-80.7% respectively. No significant correlation between pre-nCRT size measurements and pCR was obtained. Conclusion: The convenient morphological measurements may be useful for predicting pCR with moderate sensitivity and specificity. Combining these predictors with the aim of building diagnostic model should be explored. PMID- 29435148 TI - Peptide inhibition of the SETD6 methyltransferase catalytic activity. AB - A large body of evidence accumulating in the past few years indicates the physiological significance of non-histone proteins lysine methylation, catalyzed by protein lysine methyl transferases (PKMTs). Dysregulation of these enzymes was shown to contribute to the development and progression of numerous diseases. SETD6 lysine methylatransferase was recently shown to participate in essential cellular processes, such as the NFkB pathway, oxidative stress and also the Wnt signaling cascade. In order to test the effect of blocking SETD6 catalytic activity, we used the peptide inhibition method, which is considered highly specific and can potentially target almost any protein. We designed a 15 amino acids peptide based on the sequence of the RelA protein (residues 302-316), containing the lysine that is methylated by SETD6. To enable cellular intake, the designed peptide was fused to a cell penetrating peptide (CPP) vp22. The vp22 RelA302-316 peptide showed direct and specific interaction with SETD6 in vitro. This interaction was shown to inhibit SETD6 methyltransferase activity. SETD6 catalytic blockage by the peptide was also observed in cells upon treatment with the vp22-RelA302-316, resulting in induced cellular migration and proliferation. This new insight into the activity of a methylation inhibitory peptide could represent a milestone in the development of therapeutic tools, which can be of use in physiological cases where administration of cell proliferation is required. PMID- 29435149 TI - MiR-361-5p suppresses chemoresistance of gastric cancer cells by targeting FOXM1 via the PI3K/Akt/mTOR pathway. AB - Gastric cancer is a prevalent cancer and chemotherapy is a main treatment for patients. Docetaxel is commonly used as a chemotherapeutic drug for gastric cancer patients. With the increasing emergence of docetaxel resistance, exploring the mechanism of chemoresistance may improve prognosis of patients. In this study, we found that overexpressed miR-361-5p suppressed chemoresistance to docetaxel of gastric cancer cells (SGC-7901, MKN-28) by decreasing IC50 values of docetaxel while increasing cell apoptosis rate, especially in docetaxel resistant SGC-7901 cells. Further researches revealed that overexpressed miR-361-5p inhibited chemoresistance through inhibiting autophagy with a characteristic of declined number of LC3+ puncta, decreased expression of Beclin-1 and the ratio of LC3 II/I and increased expression of p62. Bioinformatics study and Luciferase reporter assay indicated that FOXM1 was a target of miR-361-5p and FOXM1 was negatively regulated by miR-361-5p in gastric cancer. Simultaneously, overexpression of FOXM1 counteracted the inhibitory effects of miR-361-5p on chemoresistance of gastric cancer cells through activating autophagy, further certifying the targeting relationship between the two. Moreover, overexpressed miR-361-5p activated the PI3K/Akt/mTOR pathway. The adding of PI3K inhibitor LY294002 played an opposite role to miR-361-5p mimic by inducing autophagy and chemoresistance to docetaxel of gastric cancer cells compared with docetaxel + miR-361-5p mimic group, indicating that miR-361-5p suppressed autophagy-induced chemoresistance via the PI3K/Akt/mTOR pathway in gastric cancer cells. In conclusion, we found that miR-361-5p suppressed autophagy-induced chemoresistance of gastric cancer cells through targeting FOXM1 via the PI3K/Akt/mTOR pathway, providing a foundation for the mechanism research and treatment of gastric cancer. PMID- 29435150 TI - Blood-brain barrier disruption induced by diagnostic ultrasound combined with microbubbles in mice. AB - Objective: To investigate the effects of the microbubble (MB) dose, mechanism index (MI) and sonication duration on blood-brain barrier (BBB) disruption induced by diagnostic ultrasound combined with MBs as well as to investigate the potential molecular mechanism. Results: The extent of BBB disruption increased with MB dose, MI and sonication duration. A relatively larger extent of BBB disruption associated with minimal tissue damage was achieved by an appropriate MB dose and ultrasound exposure parameters with diagnostic ultrasound. Decreased expression of ZO-1, occludin and claudin-5 were correlated with disruption of the BBB, as confirmed by paracellular passage of the tracer lanthanum nitrate into the brain parenchyma after BBB disruption. Conclusions: These findings indicated that this technique is a promising tool for promoting brain delivery of diagnostic and therapeutic agents in the diagnosis and treatment of brain diseases. Methods: The extent of BBB disruption was qualitatively assessed by Evans blue (EB) staining and quantitatively analyzed by an EB extravasation measurement. A histological examination was performed to evaluate tissue damage. Expression of tight junction (TJ) related proteins ZO-1, occludin and claudin-5 was determined by western blotting analysis and immunohistofluorescence. Transmission electron microscopy was performed to observe ultrastructure changes of TJs after BBB disruption. PMID- 29435152 TI - miR-30a suppresses lung cancer progression by targeting SIRT1. AB - The class III histone deacetylase silent information regulator 1 (SIRT1) is frequently overexpressed in a variety of tumors, including lung cancer; however, its regulatory mechanisms are largely unknown. In this study, we found that an inconsistent trend between SIRT1 protein and mRNA levels in human lung cancer tissues, suggesting that a post-transcriptional mechanism may involved in SIRT1 regulation. Because microRNAs are important post-transcriptional regulators of gene expression, candidate miRNAs that could potentially bind SIRT1 were gained through bioinformatics analyses. We further experimentally validated SIRT1 as the direct target of miR-30a by evaluating SIRT1 expression in lung cancer cells after the overexpression or knockdown of miR-30a and by luciferase assay. Moreover, we showed that miR-30a inhibited proliferation, invasion and promoted apoptosis of lung cancer cells by inhibiting SIRT1 in vitro and in vivo. Taken together, this study identified a new regulatory axis in which miR-30a and SIRT1 regulate the proliferation, invasion and apoptosis of lung cancer cells and lung tumorigenesis. PMID- 29435151 TI - Arsenic exposure assists ccm3 genetic polymorphism in elevating blood pressure. AB - Epidemiologic study has suggested that arsenic exposure is positively related to increased blood pressure. However, the underlying mechanism concerning interaction between genetic polymorphisms and arsenic exposure remains unclear. In present study, within 395 Chinese, the effects of interaction between arsenic exposure and CCM3 gene polymorphisms on elevation of blood pressure were probed by multiple Logistic regression models after adjusting for confounding factors. Firstly, we found that serum arsenic was positively associated with blood pressure, cholesterol, glucose and C-reactive protein. Then, adjusted for confounding factors of age, gender, smoking, alcohol consumption, BMI and degree of education, arsenic exposure incurred the hazard of increased systolic pressure and diastolic pressure, with odds ratios (ORs) being 1.725 and 1.425, respectively. Distinctly, we found that interactions between rs3804610* rs9818496, rs6784267*rs9818496, and rs3804610* rs6784267 variant genotype can increase significantly risks of SBP. Additionally, interactions between rs9818496, rs3804610 and rs6784267 genotypic variantions and arsenic exposure boosted the hazard of increased systolic pressure, with ORs being 1.496, 1.496 and 1.312. In conclusion, our fingdings suggest that As exposure of population can assist CCM3 polymorphism in elevating SBP. PMID- 29435154 TI - Efficacy of granulocyte-macrophage colony-stimulating factor combined with metronomic paclitaxel in the treatment of Lewis lung carcinoma transplanted in mice. AB - Metronomic chemotherapy in combination with immunotherapy is an attractive approach in cancer therapy. The purpose of the present study was to investigate the anti-tumor effect of granulocyte-macrophage colony-stimulating factor (GM CSF) in combination with metronomic paclitaxel (MET PTX) on Lewis lung carcinoma transplanted in mice. In the present study, tumor-bearing mice survival time and tumor growth were monitored. The day after the end of the treatment, white blood cells were counted, and the number and maturation of dendritic cell were determined by flow cytometry. Besides, microvessel density and tumor cell proliferation were determined by immunohistochemistry, while apoptosis was determined by TUNEL (Terminal deoxynucleotidyl transferase-mediated nick end labeling) assay. Micro 18F-FDG PET/CT (18F-Fluorodeoxyglucose positron emission tomography/computed tomography) was used to obtain SUVmax values. White blood cells reduction was not observed in the mice treated with GM-CSF combined with MET PTX. Moreover, GM-CSF combined with MET PTX further reduced proliferation and microvessel density, promoted tumor apoptosis, increased the dendritic cells number and induced their maturation, with concomitant delay in tumor growth and improved survival. Taken together, GM-CSF combined with MET PTX exerted a synergistic anti-tumor effect against lung cancer in a mouse model through an antiangiogenic activity and inducing dendritic cells maturation without exerting pronounced adverse effects. Hence, combined metronomic chemotherapy and immunotherapy could be a potential strategy for the treatment of patients with advanced lung cancer. PMID- 29435153 TI - Heterotypic breast cancer model based on a silk fibroin scaffold to study the tumor microenvironment. AB - An intensive investigation of the development of in vitro models to study tumor biology has led to the generation of various three-dimensional (3D) culture methods that better mimic in vivo conditions. The tumor microenvironment (TME) is shaped by direct interactions among cancer cells, cancer-associated cells and the extracellular matrix (ECM). Recognizing the need to incorporate both tissue dimensionality and the heterogeneity of cells, we have developed a 3D breast cancer model. NIH3T3 fibroblasts and EMT6 breast cancer cell lines were seeded in various ratios onto a silk fibroin scaffold. The porosity of the silk scaffold was optimized to facilitate the growth of cancer cells. EMT6 and NIH3T3 cells were modified to express GFP and turboFP635, respectively, which enabled the direct analysis of the cell morphology and colonization of the scaffold and for the separation of the cells after their co-culture. Use of 3D mono-culture and 3D co-culture methods resulted in the modification of cell morphology and in a significant increase in ECM production. These culture methods also induced cellular changes related to EMT (epithelial-mesenchymal transition) and CAF (cancer-associated fibroblast) markers. The presented model is an easy to manufacture, well-characterized tool that can be used to study processes of the TME. PMID- 29435155 TI - Assessment of a new genomic classification system in acute myeloid leukemia with a normal karyotype. AB - This study was performed to assess if a recently recommended genomic classification is predictive in patients with normal-karyotype (NK) acute myeloid leukemia (AML). A total of 393 patients were included. Analysis of genetic mutations was performed using targeted resequencing with an Illumina Hiseq 2000. We identified driver mutations across 40 genes, with one or more driver mutations identified in 95.7% of patients. The molecular subclassification was as follows: 34.6% patients (n = 136) with AML with the NPM1 mutation, 10.7% (n = 42) with AML with mutated chromatin or RNA-splicing genes or both, 1.5% (n = 6) with AML with TP53 mutations, 13.5% (n = 53) with AML with biallelic CEBPA mutations, 2.0% (n = 8) with AML with IDH2-R172 mutations and no other class-defining lesion, 29.5% (n = 116) with AML with driver mutations but no detected class-defining lesion, 4.3% (n = 17) with AML with no detected driver mutation, and 3.8% (n = 15) patients with AML who met the criteria for >=2 genomic subgroups. The 5-year overall survival and relapse rate of subgroup in AML with mutated chromatin, RNA-splicing genes, or both was 11.6% (95% CI = 1.4-21.8%) and 71.4% (95% CI = 45.7-86.5%), respectively. This study suggests that the recently recommended genomic classification is an appropriate and replicable categorization system in the NK AML population. The subgroup of AML with mutated chromatin, RNA-splicing genes, or both showed extremely poor survival in NK-AML; thus, a novel approach is needed to improve their prognosis. PMID- 29435156 TI - Cis-trimethoxy resveratrol induces intrinsic apoptosis via prometaphase arrest and prolonged CDK1 activation pathway in human Jurkat T cells. AB - Cis-trimethoxy resveratrol (cis-3M-RES) induced dose-dependent cytotoxicity and apoptotic DNA fragmentation in Jurkat T cell clones (JT/Neo); however, it induced only cytostasis in BCL-2-overexpressing cells (JT/BCL-2). Treatment with 0.25 MUM cis-3M-RES induced G2/M arrest, BAK activation, Deltapsim loss, caspase-9 and caspase-3 activation, and poly (ADP-ribose) polymerase (PARP) cleavage in JT/Neo cells time-dependently but did not induce these events, except G2/M arrest, in JT/BCL-2 cells. Moreover, cis-3M-RES induced CDK1 activation, BCL-2 phosphorylation at Ser-70, MCL-1 phosphorylation at Ser-159/Thr-163, and BIM (BIMEL and BIML) phosphorylation irrespective of BCL-2 overexpression. Enforced G1/S arrest by using a G1/S blocker aphidicolin completely inhibited cis-3M-RES induced apoptotic events. Cis-3M-RES-induced phosphorylation of BCL-2 family proteins and mitochondrial apoptotic events were suppressed by a validated CDK1 inhibitor RO3306. Immunofluorescence microscopy showed that cis-3M-RES induced mitotic spindle defects and prometaphase arrest. The rate of intracellular polymeric tubulin to monomeric tubulin decreased markedly by cis-3M-RES (0.1-1.0 MUM). Wild-type Jurkat clone A3, FADD-deficient Jurkat clone I2.1, and caspase-8 deficient Jurkat clone I9.2 exhibited similar susceptibilities to the cytotoxicity of cis-3M-RES, excluding contribution of the extrinsic death receptor-dependent pathway to the apoptosis. IC50 values of cis-3M-RES against Jurkat E6.1, U937, HL-60, and HeLa cells were 0.07-0.17 MUM, whereas those against unstimulated human peripheral T cells and phytohaemagglutinin A stimulated peripheral T cells were >10.0 and 0.23 MUM, respectively. These results indicate that the antitumor activity of cis-3M-RES is mediated by microtubule damage, and subsequent prometaphase arrest and prolonged CDK1 activation that cause BAK-mediated mitochondrial apoptosis, and suggest that cis 3M-RES is a promising agent to treat leukemia. PMID- 29435157 TI - The microtubule-associated protein PRC1 is a potential therapeutic target for lung cancer. AB - In this study, we investigated whether proteins that are involved in cytokinesis are potential targets for therapy of lung cancer. We find that the microtubule associated protein PRC1 (protein required for cytokinesis 1), which plays a key role in organizing anti-parallel microtubule in the central spindle in cytokinesis, is overexpressed in lung cancer cell lines compared to normal cells. Increased expression of PRC1 is correlated with a poor prognosis of human lung adenocarcinoma patients. Lentiviral delivered, inducible RNAi of PRC1 demonstrated that proliferation of lung cancer cell lines strongly depends on PRC1. Significantly, we also show that PRC1 is required for tumorigenesis in vivo using a mouse model for non-small cell lung cancer driven by oncogenic K-RAS and loss of p53. When PRC1 is depleted by in vivo RNA interference, lung tumor formation is significantly reduced. Although PRC1 has been suggested to regulate Wnt/beta-catenin signaling in cancer cells, we find no evidence for a role of PRC1 in this pathway in lung cancer. Instead, we show that the depletion of PRC1 results in a strong increase in bi- and multinuclear cells due to defects in cytokinesis. This ultimately leads to apoptosis and senescence. Together these data establish PRC1 as a potential target for therapy of lung cancer. PMID- 29435158 TI - Osteopontin-integrin engagement induces HIF-1alpha-TCF12-mediated endothelial mesenchymal transition to exacerbate colorectal cancer. AB - Osteopontin (OPN) is a multi-functional phospho-glycoprotein that can stimulate angiogenesis through acting on endothelial cells. As angiogenic sprouting involves endothelial-to-mesenchymal transition (EndoMT), we are intrigued to know whether OPN exerts an effect on EndoMT. Clinically, we indeed detected EndoMT derived cells next to OPN-expressing cells in colorectal cancer tissues. Furthermore, we treated OPN to primary cultures of endothelial cells to investigate the EndoMT-inducing activity and the underlying mechanisms. Integrin alphaVbeta3 rather than CD44 is involved in OPN-induced EndoMT. OPN-integrin alphaVbeta3 engagement induces HIF-1alpha expression through a PI3K/Akt/TSC2 mediated and mTORC1-dependent protein synthesis pathway, which in turn trans activates TCF12 gene expression. TCF12 further interacts with EZH2 and histone deacetylases to transcriptionally repress VE-cadherin gene and thus facilitates EndoMT. Like cancer-associated fibroblasts, EndoMT-derived cells promote tumor growth and metastasis by secreting certain proteins. Secreted HSP90alpha is a candidate suggested by microwestern array assay, and is herein verified to induce stemness properties in colorectal cancer cells. As OPN is overexpressed in human cancers, OPN-induced EndoMT and EndoMT-derived cells can be potentially taken as cancer therapeutic targets. PMID- 29435159 TI - Undermining ribosomal RNA transcription in both the nucleolus and mitochondrion: an offbeat approach to target MYC-driven cancer. AB - The MYC transcription factor coordinates, via different RNA polymerases, the transcription of both ribosomal RNA (rRNA) and protein genes necessary for nucleolar as well as mitochondrial ribogenesis. In this study we tested if MYC coordination of rRNA transcription in the nucleolus and in the mitochondrion drives (cancer) cell proliferation. Here we show that the anti-proliferative effect of CX-5461, a Pol I inhibitor of rRNA transcription, in ovarian (cancer) cell contexts characterized by MYC overexpression is enhanced either by 2'-C Methyl Adenosine (2'-C-MeA), a ribonucleoside that inhibits POLRMT mitochondrial rRNA (mt-rRNA) transcription and doxycycline, a tetracycline known to affect mitochondrial translation. Thus, hindering not only mt-rRNA transcription, but also mitoribosome function in MYC-overexpressing ovarian (cancer) cells, potentiates the antiproliferative effect of CX-5461. Targeting MYC-regulated rRNA transcription and ribogenesis in both the nucleolus and mitochondrion seems to be a novel approach worth of consideration for treating MYC-driven cancer. PMID- 29435160 TI - Comparison of hepatic and serum lipid signatures in hepatocellular carcinoma patients leads to the discovery of diagnostic and prognostic biomarkers. AB - We compared hepatic and serum lipid changes in hepatocellular carcinoma (HCC) patients to have a better understanding of the molecular pathogenesis of this disease and discovery novel lipid biomarkers. Hepatic and serum lipid profiling was conducted in paired liver and serum samples from 50 HCC patients and 24 healthy controls. A total of 20 hepatic and 40 serum lipid signatures were identified, yet there was hardly any significant correlation between them. The results indicated that triglycerides and phosphatidylcholines contributed significantly to altered hepatic lipids, whereas triglycerides and phosphatidylethanolamine-based plasmalogens (PEp) contributed most to altered serum lipids. In serum, PEp (36:4) and (40:6) showed a fair capability to discriminate HCC patients from healthy controls, and were significantly associated with HCC tumor grades (p < 0.05), and thus were identified as potential diagnostic and prognostic biomarkers of HCC. These findings were confirmed by a validation study conducted in an independent cohort consisting of 18 HCC, 20 cirrhosis patients, and 20 healthy controls. This study suggests that hepatic and serum lipid signatures of HCC have to be considered as mostly independent, and the results imply potential roles of PEp species, particularly PEp (36:4) and (40:6), as serum biomarkers for HCC diagnosis and progression. PMID- 29435161 TI - Nonlinear mixed effects dose response modeling in high throughput drug screens: application to melanoma cell line analysis. AB - Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC50). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations. We consider the application of two methods, each rooted in nonlinear mixed effects (NLME) models, that test the relationship relationships between estimated cell line DRCs and factors that might mitigate response. Both methods leverage estimation and testing techniques that consider the simultaneous analysis of different cell lines to draw inferences about any one cell line. One of the methods is designed to provide an omnibus test of the differences between cell line DRCs that is not focused on any one aspect of the DRC (such as the IC50 value). We simulated different settings and compared the different methods on the simulated data. We also compared the proposed methods against traditional IC50-based methods using 40 melanoma cell lines whose transcriptomes, proteomes, and, importantly, BRAF and related mutation profiles were available. Ultimately, we find that the NLME based methods are more robust, powerful and, for the omnibus test, more flexible, than traditional methods. Their application to the melanoma cell lines reveals insights into factors that may be clinically useful. PMID- 29435162 TI - Prognostic value of PD -L1 expression in patients with primary solid tumors. AB - Programmed death-ligand 1 (PD-L1) is thought to play a critical role in immune escape by cancer, but whether PD-L1 expression can influence prognosis of patients with solid tumors is controversial. Therefore, we meta-analyzed available data on whether PD-L1 expression correlates with overall survival (OS) in such patients. PubMed, EMBASE and other databases were systematically searched for cohort or case-control studies examining the possible correlation between PD L1 expression and OS of patients with solid tumors. OS was compared between patients positive or negative for PD-L1 expression using scatter plots, and subgroup analyses were performed based on tumor type and patient characteristics. Data from 59 studies involving 20,004 patients with solid tumors were meta analyzed. The median percentage of tumors positive for PD-L1 was 30.1%. OS was significantly lower in PD-L1-positive patients than in PD-L1-negative patients at 1 year (P = 0.039), 3 years (P < 0.001) and 5 years (P < 0.001). The risk ratios of OS (and associated 95% confidence intervals) were 2.02 (1.56-2.60) at 1 year, 1.57 (1.34-1.83) at 3 years and 1.43 (1.24-1.64) at 5 years. Similar results were obtained in subgroup analyses based on patient ethnicity or tumor type. The available evidence suggests that PD-L1 expression negatively affects the prognosis of patients with solid tumors. PD-L1 might serve as an efficient prognostic indicator in solid tumor and may represent the important new therapeutic target. PMID- 29435163 TI - Aberrant frequency of TNFR2+ Treg and related cytokines in patients with CIN and cervical cancer. AB - Regulatory T (Treg) cells expressing tumor necrosis factor receptor 2 (TNFR2) are highly suppressive and are associated with immune homeostasis in various diseases. However, the role of TNFR2+Treg subset and relevant cytokines in the development of cervical cancer (CC) remained unclear. In this study, 72 patients with CC, 30 patients with cervical intraepithelial neoplasia (CIN) and 30 healthy volunteers were enrolled. The level of circulating TNFR2+Tregs was investigated through flow cytometry. The plasma concentrations of soluble TNFR1 (s-TNFR1) and soluble TNFR2 (s-TNFR2) were determined by enzyme-linked immunosorbent assay. In addition, the mRNA expression levels of TNF-alpha, TNFR1, TNFR2, and Foxp3 were measured using real-time polymerase chain reaction. Results showed that both peripheral and tumor infiltrating TNFR2+Tregs significantly increased in patients with CIN and CC and levels of circulating s-TNFR1 and s-TNFR2 increased in patients with CC. Moreover, the percentage of peripheral TNFR2+Tregs was inversely correlated with the clinical stages of CC. Furthermore, the mRNA expression levels of TNF-alpha, TNFR2, and Foxp3 increased in patients with CIN and CC. Overall, these results indicate that TNFR2+Tregs and relevant cytokines contribute to CC development and are promising targets in future immunotherapeutic approaches. PMID- 29435165 TI - LncRNA gadd7, increased in varicocele patients, suppresses cell proliferation and promotes cell apoptosis. AB - Varicocele-related sperm damages are usually caused by oxidative stresses. Growing evidence indicates that lncRNA growth arrested DNA-damage inducible gene 7 (gadd7) is involved in the regulation of the oxidative stress responses. In this study, we measured the expression level of gadd7 in the sperm and found that the expression of gadd7 was significantly up-regulated in patients with varicocele compared with the healthy control. The relative expression level of gadd7 was negatively correlated with the sperm count. Overexpression of gadd7 suppressed cell proliferation and promoted cell apoptosis in mouse spermatocyte derived cell lines GC-1 and GC-2. Furthermore, the protein level of Bax was raised while Bcl2 expression was reduced after overexpression of gadd7. This work provides a potential novel insight for the varicocele-related sperm impairment and male infertility. PMID- 29435164 TI - Overexpression of Na+/Mg2+ exchanger SLC41A1 attenuates pro-survival signaling. AB - The Na+/Mg2+ exchanger SLC41A1 (A1), a key component of intracellular Mg homeostasis (IMH), is the major cellular Mg2+ efflux system, and its overexpression decreases [Mg2+]intracellular. IMH plays an important role in the regulation of many cellular processes, including cellular signaling. However, whether the overexpression of A1 and the consequent drop of [Mg2+]i impact on intracellular signaling is unknown. To examine the latter, we utilized dynamic mass redistribution (DMR) assay, PathScan(r) RTK signaling antibody (PRSA) array, confirmatory Western blot (WB) analyses of phosphorylation of kinases selected by PRSA, and mag-fura 2-assisted fast filter spectrometry (FFS). We demonstrate here that the overexpression of A1 quantitatively and qualitatively changes the DMR signal evoked by the application of PAR-1-selective activating peptide and/or by changing [Mg2+]extracellular in HEK293 cells. PRSA profiling of the phosphorylation of important signaling nodes followed by confirmatory WB has revealed that, in HEK293 cells, A1 overexpression significantly attenuates the phosphorylation of Akt/PKB on Thr308 and/or Ser473 and of Erk1/2 on Thr202/Tyr204 in the presence of 0 or 1 mM (physiological) Mg2+ in the bath solution. The latter is also true for SH-SY5Y and HeLa cells. Overexpression of A1 in HEK293 cells significantly lowers [Mg2+]i in the presence of [Mg2+]e = 0 or 1 mM. This correlates with the observed attenuation of prosurvival Akt/PKB - Erk1/2 signaling in these cells. Thus, A1 expression status and [Mg2+]e (and consequently also [Mg2+]i) modulate the complex physiological fingerprint of the cell and influence the activity of kinases involved in anti-apoptotic and, hence, pro-survival events in cells. PMID- 29435166 TI - Acquired resistance to tyrosine kinase inhibitors may be linked with the decreased sensitivity to X-ray irradiation. AB - Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian carcinoma SKOV-3 and neuroblastoma NGP 127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks. After 20 weeks of culturing, the half-inhibitory concentrations (IC50) increased by 25 - 186% for the particular combinations of the drugs and cell types. We next subjected cells to 10 Gy irradiation, a dose frequently used in clinical radiation therapy. For the SKOV-3, but not NGP-127 cells, for the TKIs Sorafenib, Pazopanib and Sunitinib, we noticed statistically significant increase in capacity to repair radiation induced DNA double strand breaks compared to naive control cells not previously treated with TKIs. These peculiarities were linked with the increased activation of ATM DNA repair pathway in the TKI-treated SKOV-3, but not NGP-127 cells. Our results provide a new cell culture model for studying anti-cancer therapy efficiency and evidence that there may be a tissue-specific radioresistance emerging as a side effect of treatment with TKIs. PMID- 29435167 TI - Pentraxin-3, procalcitonin and lactate as prognostic markers in patients with sepsis and septic shock. AB - The purpose of this study was to confirm the prognostic value of pentraxin-3 (PTX3), procalcitonin (PCT) and lactate in patients with severe infections requiring ICU management and to develop and validate a model to enhance mortality prediction by combining severity scores with biomarkers. We included 141 patients with the diagnosis of sepsis/septic shock. The levels of PTX3, PCT and lactate were measured on day 0, 3, 7 of hospitalization and Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were also evaluated. The influence of these variables on 28-day mortality was evaluated. The 28-day mortality rate in this study was 28.8%. The baseline levels of PTX3, PCT and lactate in the non-survival group were higher than in the survival group (P < 0.05 for all). Pearson's correlation found that PTX3, PCT and lactate were all positively correlated with SOFA and APACHE II scores (P <0.01 for all). Univariate and multivariate Cox regression revealed that PTX3, PCT and lactate were independently associated with 28-day mortality. The models combining above three biomarkers performed better predictive property than each individual one as determined by receiver operating characteristic (ROC) analysis. In summary, our results suggest that PTX3, PCT and lactate could serve as clinically informative biomarkers of disease severity and patient outcome in sepsis/septic shock. A model combining PTX3, PCT and lactate improves mortality prediction in these patients. PMID- 29435168 TI - Low FAT4 expression is associated with a poor prognosis in gastric cancer patients. AB - In this study, we investigated the role of Fat atypical cadherin 4 (FAT4) in gastric cancer (GC) progression. Immunohistochemical analysis showed lower FAT4 expression in tumor tissues from GC patients than in normal gastric epithelium. Lower FAT4 expression was associated with poor prognosis, tumor size and invasion, and lymph node and distant metastases. Multivariate analysis showed that TNM stage, lymph node and distant metastases, Lauren classification, and FAT4 expression were independent prognostic factors in GC. Methylation-specific PCR analysis showed increased FAT4 promoter methylation in GC tumor tissues and cell lines. Higher FAT4 promoter methylation was associated with low FAT4 expression and a poor prognosis. BGC-823 cells showed increased FAT4 expression upon treatment with 5-azacytidine, demethylating agent. FAT4 knockdown in BGC-823 cells led to increased cell proliferation, migration and invasiveness. Moreover, xenografts of BGC-823 cells with FAT4 knockdown showed enhanced tumor growth and metastasis in nude mice. These findings demonstrate that low FAT4 expression is associated with a poor prognosis in GC patients. PMID- 29435169 TI - MicroRNA-340 inhibits the proliferation and promotes the apoptosis of colon cancer cells by modulating REV3L. AB - DNA Directed Polymerase Zeta Catalytic Subunit (REV3L) has recently emerged as an important oncogene. Although the expressions of REV3L are similar in normal and cancer cells, several mutations in REV3L have been shown to play important roles in cancer. These mutations cause proteins misfolding and mislocalization, which in turn alters their interactions and biological functions. miRNAs play important regulatory roles during the progression and metastasis of several human cancers. This study was undertaken to determine how changes in the location and interactions of REV3L regulate colon cancer progression. REV3L protein mislocalization confirmed from the immunostaining results and the known interactions of REV3L was found to be broken as seen from the PLA assay results. The mislocalized REV3L might interact with new proteins partners in the cytoplasm which in turn may play role in regulating colon cancer progression. hsa-miR-340 (miR-340), a microRNA down-regulated in colon cancer, was used to bind to and downregulate REV3L, and found to control the proliferation and induce the apoptosis of colon cancer cells (HCT-116 and DLD-1) via the MAPK pathway. Furthermore, this down-regulation of REV3L also diminished colon cancer cell migration, and down-regulated MMP-2 and MMP-9. Combined treatment of colon cancer cells with miR-340 and 5-FU enhanced the inhibitory effects of 5-FU. In addition, in vivo experiments conducted on nude mice revealed tumor sizes were smaller in a HCT-116-miR-340 injected group than in a HCT-116-pCMV injected group. Our findings suggest mutations in REV3L causes protein mislocalization to the cytoplasm, breaking its interaction and is believed to form new protein interactions in cytoplasm contributing to colon cancer progression. Accordingly, microRNA-340 appears to be a good candidate for colon cancer therapy. PMID- 29435170 TI - Methyl donor S-adenosylmethionine (SAM) supplementation attenuates breast cancer growth, invasion, and metastasis in vivo; therapeutic and chemopreventive applications. AB - DNA hypomethylation coordinately targets various signaling pathways involved in tumor growth and metastasis. At present, there are no approved therapeutic modalities that target hypomethylation. In this regard, we examined the therapeutic plausibility of using universal methyl group donor S adenosylmethionine (SAM) to block breast cancer development, growth, and metastasis through a series of studies in vitro using two different human breast cancer cell lines (MDA-MB-231 and Hs578T) and in vivo using an MDA-MB-231 xenograft model of breast cancer. We found that SAM treatment caused a significant dose-dependent decrease in cell proliferation, invasion, migration, anchorage-independent growth and increased apoptosis in vitro. These results were recapitulated in vivo where oral administration of SAM reduced tumor volume and metastasis in green fluorescent protein (GFP)-tagged MDA-MB-231 xenograft model. Gene expression analyses validated the ability of SAM to decrease the expression of several key genes implicated in cancer progression and metastasis in both cell lines and breast tumor xenografts. SAM was found to be bioavailable in the serum of experimental animals as determined by enzyme-linked immunosorbent assay and no notable adverse side effects were seen including any change in animal behavior. The results of this study provide compelling evidence to evaluate the therapeutic potential of methylating agents like SAM in patients with breast cancer to reduce cancer-associated morbidity and mortality. PMID- 29435171 TI - Brucella induces unfolded protein response and inflammatory response via GntR in alveolar macrophages. AB - Brucella is an intracellular bacterium that causes the zoonosis brucellosis worldwide. Alveolar macrophages (AM) constitute the main cell target of inhaled Brucella. Brucella thwarts immune surveillance and evokes endoplasmic reticulum (ER) stress to replicate in macrophages via virulence factors. The GntR regulators family was concentrated as an important virulence factor in controlling virulence and intracellular survival of Brucella. However, the detailed underlying mechanism for the host-pathogen interaction is poorly understood. In this study the BSS2_II0438 mutant (DeltaGntR) was constructed. The type IV secretion system (T4SS) virulence factor genes (VirB2, VirB6, and VirB8) were down-expression in DeltaGntR. DeltaGntR could infect and proliferate to high titers in GAMs without a significant difference compared with the parental strain. DeltaGntR infection increased the expression of ER stress marker genes GRP78, ATF6, and PERK in the early stages of its intracellular cycle but decreased the expression of these genes in the late stages. DeltaGntR increased greatly the number of Brucella CFUs in the inactive ER stress state in GAMs. Meanwhile, DeltaGntR infection increased the levels of IFN-gamma, IL-1beta, and TNF-alpha, indicating DeltaGntR could induce the secretion of inflammatory but not anti-inflammatory cytokines IL-10. Taken together, our results clarified the role of the GntR in B. suis. S2 virulence expression and elucidated that GntR is potentially involved in the signaling pathway of the Brucella-induced UPR and inflammatory response in GAMs. PMID- 29435172 TI - Promiximab-duocarmycin, a new CD56 antibody-drug conjugates, is highly efficacious in small cell lung cancer xenograft models. AB - Small cell lung cancer (SCLC) is of a highly invasive and metastatic lung cancer subtype and there had not been effective targeted therapies. CD56, a cell surface marker highly expressed on most SCLC, is a promising therapeutic target for treatment of this aggressive cancer. In this study, we generated a novel anti CD56 antibody named promiximab, characterized by high affinity, internalization and tumor specificity. Then, the promiximab was conjugated with a potent DNA alkylating agent duocarmycin via reduced interchain disulfides to yield the promiximab-Duocarmycin (promiximab-DUBA) conjugates. Mass spectrometry analysis showed promiximab-DUBA had an average DAR (Drug-to-Antibody Ratio) of about 2.04. In vitro, promiximab-DUBA exerted strong inhibitory effects on SCLC cell lines NCI-H526, NCI-H524 and NCI-H69, with IC50 values of 0.07 nmol/L, 0.18 nmol/L and 0.29 nmol/L, respectively. In vivo antitumor activity, promiximab-DUBA at the dose of 5 mg/kg and 10 mg/kg every three days with a total of three times were sufficient to induce sustained regression of NCI-H526 tumors over control treatment with promiximab. Mostly, no recurrence was observed until 65 days post treatment with promiximab-DUBA. In the NCI-H69 subcutaneous xenograft model, significant inhibition of tumor growth was also observed following administration of promiximab-DUBA at the dose of 5 mg/kg or 10 mg/kg. Moreover, body weight and histopathology of major organs (liver, spleen, heart, lung and kidney) showed no significant changes after treatment of promiximab-DUBA. In conclusion, promiximab DUBA is highly efficacious in small cell lung cancer xenograft models, and provides a new immunotherapy approach for SCLC. PMID- 29435173 TI - CRISPR knock out of programmed cell death protein 1 enhances anti-tumor activity of cytotoxic T lymphocytes. AB - Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that functions to attenuate T cell activation. In this study, we knocked out (KO) PD-1 in cytotoxic T lymphocytes (CTLs) using CRISPR-Cas9 system to evaluate its effect on the anti-tumor activity of the CTLs against multiple myeloma (MM). Results show that PD-1 KO CTLs facilitate apoptosis and caspase activation of the co cultured MM cells and enhanced MM cell death by 36% compared with the control. PD 1 KO also increased TNF-alpha and IFN-gamma secretion of the CTLs by 2.4 and 1.9 fold respectively. The effectiveness of PD-1 KO in enhancing anti-tumor activity of the CTLs was verified in vivo using mouse xenograft model. The xenografted mice treated with PD-1 KO CTLs demonstrated repressed MM tumor growth and prolonged survival compared with the control group. We conclude that CRISPR-Cas9 is an efficient system to knock out PD-1 from CTLs and PD-1 KO could significantly enhance the anti-tumor activity of CTLs. PMID- 29435174 TI - Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy. AB - Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 - now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ~3.5-fold and ~65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20 223 has nanomolar potency across multiple CRC cell lines and was on an average >2 fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20 223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy. PMID- 29435175 TI - REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature. AB - Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models. DIPGs are vascularized tumors and interestingly, REST loss in DIPG cells also caused a substantial decline in tumor vasculature as measured by a decrease in CD31 and VEGFR2 staining. These observations were validated in vitro, where a significant decline in tube formation by human umbilical vein endothelial cells (HUVEC) was seen following REST-loss in DIPG cells. Mechanistically, REST controlled the secretion of a pro-angiogenic molecule and ligand for VEGFR2 called Gremlin-1 (GREM-1), and was associated with enhanced AKT activation. Importantly, the decline in tube formation caused by REST loss could be rescued by addition of recombinant GREM-1, which also caused AKT activation in HUVECs and human brain microvascular endothelial cells (HBMECs). In summary, our study is the first to demonstrate autocrine and paracrine functions for REST in DIPG development. It also provides the foundation for future investigations on anti-angiogenic therapies targeting GREM-1 in combination with drugs that target REST-associated chromatin remodeling activities. PMID- 29435176 TI - Carotid artery wall shear stress is independently correlated with renal function in the elderly. AB - Hemodynamic has increasingly been regarded as an important factor of renal function. However, the relationship between carotid artery wall shear stress (WSS) and renal function is not clarified. To investigate the relationship between carotid WSS and renal function, we recruited 761 older subjects aged 60 years and over from community-dwelling in the Shandong area, China. Carotid WSS, endothelial function, and estimated glomerular filtration rate (eGFR) were assessed in all subjects. Subjects were grouped by the interquartile of the carotid artery mean WSS. We found that the eGFRs derived from serum creatinine and/or cystatin C using three CKD-EPI equations were significantly higher and albumin/creatinine ratio was lower in the higher interquartile groups than in the lower interquartile groups (P <0.05). The mean WSS was independently correlated with eGFRs even after adjustment for confounders. Similar findings were found between carotid artery peak WSS and eGFRs and albumin/creatinine ratio. In addition, we found that endothelial function was strongly related to carotid WSS and renal function after adjustment for confounders. In conclusion, there is an independent correlation of carotid WSS with renal function in the elderly. The local rheologic forces may play an important role in renal function changing. The correlation may be mediated by regulation of endothelial function. PMID- 29435177 TI - Prostate-selective alpha antagonists increase fracture risk in prostate cancer patients with and without a history of androgen deprivation therapy: a nationwide population-based study. AB - Introductions: Prostate-selective alpha antagonists are recommended for relief of lower urinary tract symptoms in prostate cancer patients despite uncertainty of fracture risk as an addition to androgen deprivation therapy (ADT). The purpose of this study is to estimate fracture risk associated with these medications in prostate cancer patients who did and did not receive ADT. Methods: The Taiwan National Health Insurance database was used to identify prostate cancer patients. We identified all 90-day person-quarters exposed to and not exposed to prostate selective alpha antagonists. A generalized estimating equation model was used to estimated adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for fracture associated with prostate-selective alpha antagonists with consideration for confounding by indication bias using propensity score. Results: During 1997 2008, 16,601 persons received a diagnosis of prostate cancer, among whom 13,694 received ADT. Among prostate cancer patients receiving ADT, fracture was significantly more common in person-quarters with prostate-selective alpha antagonist use than in quarters without such treatment (OR, 1.08; 95% CI, 1.00 1.18). Prostate-selective alpha antagonist use was most strongly associated with femur fracture (OR, 1.22; 95% CI, 1.09-1.38), followed by skull fracture (OR, 1.29; 95% CIs: 0.93-1.80). Among patients who did not receive ADT, fracture was more common in person-quarters with prostate-selective alpha antagonist use than in those without medication use (OR, 1.19; 95% CI, 0.91-1.55). Conclusions: Prostate-selective alpha antagonist is associated with an increased fracture risk, particular for fractures in skull and femur. Patients should be well informed on this potential risk before taking prostate-selective alpha antagonists. PMID- 29435178 TI - Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer. AB - Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC. The addition of trametinib to chemotherapy regimens showed a trend for an additive effect on tumor growth inhibition in subcutaneous AsPC-1 and Panc-1 PDAC xenografts. In a peritoneal dissemination model, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65% increase), Tra (31 days, a 55% increase), NPT+Tra (37 days, a 85% increase), NPT+Gem (39 days, a 95% increase) and NPT+Gem+Tra (49 days, a 145% increase). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition. Trametinib effects were specifically accompanied by a decrease in phospho-ERK and an increase in cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel-based chemotherapy can be enhanced through specific inhibition of MEK1/2 kinase activity, and supports the clinical application of trametinib in combination with standard nab-paclitaxel-based chemotherapy in PDAC patients. PMID- 29435179 TI - Identifying characteristic miRNAs-genes and risk pathways of multiple sclerosis based on bioinformatics analysis. AB - Multiple sclerosis is a chronic autoimmune disorder of the central nervous system. In MS, the genetic susceptibility is high and currently there is no effective treatment. MicroRNA, a small non-coding RNA, plays a vital role in immune responses. Aberrant or dysfunctional miRNAs may cause several diseases, including MS, thus miRNAs and miRNA related genes may be therapeutic weapons against MS. Here, we identified 21 miRNAs in peripheral blood mono-nuclear cells from over 600 persons, including healthy controls. By using informatics databases, 1637 susceptibility genes were evaluated and Cytoscape was used to integrate and visualize the relation between the miRNA identified and susceptibility genes. By using the cluster Profile package, a total of 10 risk pathways were discovered. Top pathways included: hsa05200 (pathway in cancer), hsa04010 (MAPK signaling pathway), and hsa04060 (cytokine-cytokine receptor interaction). By using the STRING database, a protein-protein interaction network was conducted to identify highly susceptibility genes. Moreover, the GSE21942 dataset was used to indicate the gene expression profiles and to correct prediction results, thereby identifying the most pivotal genes. The MiRSystem database provided information on both pivotal miRNAs and genes. In conclusion, miR-199a and miR-142-3p may be crucial for MS by targeting pivotal susceptibility genes, in particular KRAS and IL7R. PMID- 29435180 TI - New cGMP analogues restrain proliferation and migration of melanoma cells. AB - Melanoma is one of the most aggressive cancers and displays high resistance to conventional chemotherapy underlining the need for new therapeutic strategies. The cGMP/PKG signaling pathway was detected in melanoma cells and shown to reduce migration, proliferation and to increase apoptosis in different cancer types. In this study, we evaluated the effects on cell viability, cell death, proliferation and migration of novel dimeric cGMP analogues in two melanoma cell lines (MNT1 and SkMel28). These new dimeric cGMP analogues, by activating PKG with limited effects on PKA, significantly reduced proliferation, migration and increased cell death. No decrease in cell viability was observed in non-tumor cells suggesting a tumor-specific effect. These effects observed in melanoma are possibly mediated by PKG2 activation based on the decreased toxic effects in tumor cell lines not expressing PKG2. Finally, PKG-associated phosphorylation of vasodilator stimulated-phosphoprotein (VASP), linked to cell death, proliferation and migration was found increased and with a change of subcellular localization. Increased phosphorylation of RhoA induced by activation of PKG may also contribute to reduced migration ability of the SkMel28 melanoma cell line when treated with cGMP analogues. These findings suggest that the cGMP/PKG pathway can be envisaged as a therapeutic target of novel dimeric cGMP analogues for the treatment of melanoma. PMID- 29435181 TI - Hyperglycemia induced testicular damage in type 2 diabetes mellitus rats exhibiting microcirculation impairments associated with vascular endothelial growth factor decreased via PI3K/Akt pathway. AB - As an endocrine disease, type 2 diabetes mellitus (T2DM) can cause testicular damage which induces male infertility. However, the underlying mechanism is still not clear. We prove that T2DM induced testicular microcirculation impairment involves the decrease of VEGF and these actions are regulated by PI3K/Akt pathway. In our study, rats were divided into three groups (n=8): control group, diabetes group and diabetes + VEGF group. Intraperitoneal injection of streptozotocin (STZ, 65mg/Kg, at 9th week) and daily high-fat diet were used to establish T2DM rat model. Serum glucose in diabetes group and diabetes + VEGF group obviously exceeded 13mmol/L after STZ injection. Immunohistochemical studies indicated that VEGF level in diabetes group significantly decreased. In diabetes group, testicular blood velocity and vascular area reduced evaluated by Doppler and FITC. Furthermore, atrophic testicular morphology and increasing apoptosis cells were evaluated by haematoxylin and eosin staining and TUNEL assay. In diabetes + VEGF group, the administration of VEGF (intraperitoneally, 10mg/kg) can significantly alleviated hyperglycemia-induced impairment of testes in above aspects. Finally, we used Western blot to analyze the mechanism of hyperglycemia-induced testicular VEGF decrease. The results indicated that hyperglycemia-induced VEGF decreased is regulated by PI3K/Akt pathway in Rats testicular sertoli cells (RTSCs). Together, we demonstrate that T2DM can reduce testicular VEGF expression, which results in testicular microcirculation impairment, and then induces testicular morphological disarrangement and functional disorder. These actions are triggered by PI3K/Akt pathway. Our findings provide solid evidence for VEGF becoming a therapeutic target in T2DM related male infertility. PMID- 29435182 TI - Dual trigger of triptorelin and HCG optimizes clinical outcome for high ovarian responder in GnRH-antagonist protocols. AB - In this paper, a retrospective cohort study was conducted to the high ovarian responders in GnRH-antagonist protocols of IVF/ICSI cycles. The purpose of the study is to investigate whether dual triggering of final oocyte maturation with a combination of gonadotropin-releasing hormone (GnRH) agonist and human chorionic gonadotropin (HCG) can improve the clinical outcome compared with traditional dose (10000IU) HCG trigger and low-dose (8000IU) HCG trigger for high ovarian responders in GnRH-antagonist in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) cycles. Our study included 226 couples with high ovarian responders in GnRH-antagonist protocols of IVF/ICSI cycles. Standard dosage of HCG trigger (10000 IU of recombinant HCG) versus dual trigger (0.2 mg of triptorelin and 2000 IU of recombinant HCG) and low-dose HCG trigger (8000IU of recombinant HCG) were used for final oocyte maturation. Our main outcome measures were high quality embryo rate, the number of usable embryos, the risk of OHSS, duration of hospitalization and incidence rate of complications. Our evidence demonstrated that dual trigger is capable of preventing severe OHSS while still maintaining excellent high quality embryo rate in in high ovarian responders of GnRH-antagonist protocols. PMID- 29435183 TI - Expression and function of nuclear receptor coactivator 4 isoforms in transformed endometriotic and malignant ovarian cells. AB - Iron is proposed to contribute to the transition from endometriosis to specific subtypes of ovarian cancers (OVCAs). Regulation of intracellular iron occurs via a ferritinophagic process involving NCOA4 (Nuclear Receptor Coactivator 4), represented by two major isoforms (NCOA4alpha and NCOA4beta), whose contribution to ovarian cancer biology remains uninvestigated. We thus generated transformed endometriotic cells (via HRASV12A, c-MYCT58A, and p53 inactivation) whose migratory potential was increased in response to conditioned media from senescent endometriotic cells. We identified elevated NCOA4 mRNA in transformed endometriotic cells (relative to non-transformed). Knockdown of NCOA4 increased ferritin heavy chain (FTH1) and p21 protein which was accompanied by reduced cell survival while NCOA4beta overexpression reduced colony formation. NCOA4alpha and NCOA4beta mRNA were elevated in malignant versus non-malignant gynecological cells; NCOA4alpha protein was increased in the assessed malignant cell lines as well as in a series of OVCA subtypes (relative to normal adjacent tissues). Further, NCOA4 protein expression was regulated in a proteasome- and autophagy independent manner. Collectively, our results implicate NCOA4 in ovarian cancer biology in which it could be involved in the transition from precursors to OVCA. PMID- 29435185 TI - Diagnostic value of WIF1 methylation for colorectal cancer: a meta-analysis. AB - As a common antagonist of Wnt/beta-catenin signaling, Wnt inhibitory factor 1 (WIF1) plays an important role in the tumor progression. The aim of our meta analysis was to summarize the diagnostic value of WIF1 methylation in colorectal cancer (CRC). Eligible studies were retrieved by a systemic search among PubMed, Embase, CNKI, and Wanfang literature databases. The diagnostic value of WIF1 methylation for CRC was assessed by the summary receiver operating characteristics (SROC) test. Our meta-analysis of 12 studies between 1420 CRC samples and 946 control samples showed that WIF1 hypermethylation was significantly associated with CRC (P < 0.001, OR = 30.10, 95% CI = 19.48-46.50). WIF1 hypermethylation, as a diagnostic biomarker for CRC, has a pooled sensitivity of 0.40 (95% CI: 0.37-0.42), a pooled specificity of 0.95 (95% CI: 0.93-0.96), a pooled positive-likelihood ratio (PLR) of 8.65 (95% CI, 4.47 16.73), and a pooled negative-likelihood ratio (NLR) of 0.41 (95% CI, 0.30-0.55), a diagnostic odds ratio (DOR) of 26.86 (95% CI: 15.73-45.89), and an area under the curve (AUC) of 0.9115. In conclusion, our study established that WIF1 hypermethylation might be a promising diagnostic biomarker for CRC. PMID- 29435184 TI - Dipyridamole decreases dialysis risk and improves survival in patients with pre dialysis advanced chronic kidney disease. AB - Introduction: Dipyridamole decreases proteinuria and improves renal function progression in patients with glomerular disease through its inhibition of platelet activation and enhanced nitric oxide expression. Few studies have evaluated the effects of dipyridamole on renal outcome or survival in CKD stage 5 patients who have not yet received dialysis (CKD 5 ND). Materials and Methods: A prospective cohort study was conducted based on the Taiwan National Health Insurance Research Database. From January 1, 2000 to June 30, 2009, we enrolled 28,497 patients who had a serum creatinine > 6 mg/dL and a hematocrit < 28% and who were treated with erythropoiesis-stimulating agents (ESAs). All patients were further divided into two groups with or without dipyridamole use within 90 days after starting ESA therapy. Patient followed-up took place until dialysis, death before initiation of dialysis or December 31, 2009. The primary outcomes were long-term dialysis and death before initiating dialysis. Results: The dipyridamole users and nonusers groups included 7,746 and 20,751 patients, respectively. We found that 20,152 patients (70.7%) required long-term dialysis and 5,697 patients (20.0%) died before a progression to end-stage renal disease required dialysis. After propensity score-matching, dipyridamole users were associated with lower risks for long-term dialysis (adjusted HR, 0.96; 95% CI, 0.93-0.99) and death (adjusted HR, 0.91; 95% CI, 0.85-0.97) compared with nonusers. Conclusions: Dipyridamole exhibited a protective effect in reducing the risk for long-term dialysis and death among CKD 5 ND patients. Randomized studies are needed to validate this association. PMID- 29435187 TI - Diagnostic value of circulating microRNAs for liver cirrhosis: a meta-analysis. AB - Circulating microRNAs are potential biomarkers for various diseases including liver cirrhosis. We designed a meta-analysis to evaluate the diagnostic value of circulating microRNAs for liver cirrhosis patients. Eligible studies were identified by searching PubMed, Embase, and the Cochrane Library up to July 1, 2017. The diagnostic sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic (AUROC) curve were analyzed using a random or fixed effects models based on the between-study heterogeneities. Thirteen studies from 7 articles with 627 patients and 418 healthy controls were included in this meta-analysis. All studies had high quality assessment scores. The pooled sensitivity, specificity, PLR, NLR, DOR and AUROC were 0.83 (95% CI: 0.80-0.86), 0.89 (95% CI: 0.86-0.92), 6.41 (95% CI: 3.93-10.44), 0.22 (95% CI: 0.14-0.33), 35.18 (95% CI: 15.90-77.81) and 0.93 (95% CI: 0.91-0.95), respectively. In conclusion, circulating microRNAs may serve as potential noninvasive biomarkers of liver cirrhosis. PMID- 29435186 TI - Prevalence of celiac disease in patients with Down syndrome: a meta-analysis. AB - Background: The association between Down syndrome and celiac disease has been reported by many studies. However, the prevalence of celiac disease (CD) in Down syndrome (DS) varies considerably across studies (from 0 % to 19 %). The aim of this study was to use meta-analysis to exam the prevalence of CD in patients with DS. Methods: A systematic search of English articles from Pubmed, Web of Science and CNKI without year limitation. Data were extracted by two independent observers and pooled using a random effects model by the Comprehensive Meta Analysis Version 2 software. Results: A pooled analysis, based on 31 studies included 4383 individuals, revealed prevalence of biopsy-confirmed CD of 5.8 % (95 % CI = 4.7-7.2 %) in patients with DS. Sub-group analysis showed a slightly higher prevalence of CD in children with DS (6.6 %; 17 studies), than in age mixed samples with both children and adults (5.1 %; 13 studies). In addition, most of the studies included in this meta-analysis were from Europe and America, with the prevalence of celiac disease of 6 % (21 studies) and 5.7 % (6 studies) in DS patients, respectively. Furthermore, meta-regression analysis suggested that proportion of antibody-positive individuals that underwent small intestine biopsy had moderating effect on the outcome of the meta-analysis. Conclusions: These results demonstrated that patients (children) with Down syndrome had high prevalence of CD (more than one in twenty). The prevalence is high enough to motivate screening CD in DS children. PMID- 29435188 TI - A meta-analysis of the lymphatic microvessel density and survival in gastric cancer with 1809 cases. AB - Lymph node metastasis commonly occurs in gastric cancer. Previous studies have demonstrated that the overexpression of lymphatic microvessel density (LVD) is correlated with various malignancies. To evaluate the potential role of LVD in various malignancies, we conducted a systematic review and meta-analysis to thoroughly investigate the association of LVD expression with tumor progression and survival in gastric cancer. We performed a comprehensive search of common databases and selected studies demonstrating the relationship between LVD expression and gastric cancer prognosis. Hazard ratios (HR) were used to determine the value of LVD for predicting gastric cancer metastasis and prognosis. The data were extracted from the included studies and pooled with the appropriate effects model using STATA 12.0. The results showed that high LVD expression obviously impacted the prognosis of gastric cancer, based on an overall survival (OS) HR of 2.58 (95% CI: 1.91-3.48, P < 0.001) and a disease free survival (DFS) HR of 2.51 (95% CI: 1.35-4.68, P = 0.004) in the univariate analysis. In addition, the results of the multivariate analysis indicated a remarkable relationship between high LVD expression and gastric neoplasm prognosis. The pooled OS HR was 4.12 (95% CI: 3.45-4.91, P < 0.001). The current meta-analysis shows that high LVD is closely related to tumor metastasis and poor prognosis in gastric malignancy. LVD could be a key factor in tumor lymphatic metastasis. Moreover, LVD is likely a potential index and an effective biomarker for the prediction of patient prognosis. PMID- 29435189 TI - Effect of metformin on kidney function in patients with type 2 diabetes mellitus and moderate chronic kidney disease. AB - Background: Impaired renal function can lead to the accumulation of metformin, and elevated concentrations of metformin have been associated with lactic acidosis. The aim of this study was to evaluate the effect of continuous metformin treatment in patients with type 2 diabetes mellitus (DM) and moderate chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) 30-0 ml/min/1.73 m2) on renal function. Methods: A total of the 616 patients were enrolled from the research database of Kaohsiung Medical University Hospital from January 1 to 2009 and December 31, 2013. The patients were divided into two groups: those who continued metformin treatment (continuation group; n = 484), and those who discontinued metformin treatment for at least 100 days (interruption group; n = 132). Results: The slope of eGFR in the metformin interruption group was statistically lower than that in the metformin continuation group (0.75 +/- 0.76 vs. -1.32 +/- 0.24 mL/min/1.73 m2/year, p = 0.0007). After adjusting for baseline covariates in the multivariate linear regression analysis, the continuation of metformin (unstandardized coefficient beta, -2.072; 95% confidence interval, -3.268- -0.876) was a risk factor for the patients with DM and moderate CKD. Conclusions: Metformin may have an adverse effect on renal function in patients with type 2 DM and moderate CKD. PMID- 29435190 TI - Experiment research of focused ultrasound combined with drug and microbubble for treatment of central nervous system leukemia. AB - It has been shown that low frequency ultrasound in the presence of microbubble can effectively open the blood brain barrier (BBB) to allow the drugs to be delivered into the brain with an increased concentration. We aim to apply this method to increase the efficacy of Cytarabine (Ara-c) to treat central nervous system leukemia (CNSL). In the present study, we validated this ultrasound contrast agent Sonovue(r) targeting treatment via in vivo and in vitro experiments. The results showed that Sonovue(r) combined with Cytarabine could significantly inhibit K562 cell (chronic myeloid leukemia cell line) proliferation. In the animal experiments, it has been shown that high dose Ara-c chemotherapy could prevent and cure CNSL effectively and the drug concentration in the brain was much higher compared with low dose Ara-c chemotherapy group. We certified that under ultrasound exposure Sonovue(r) combined with low dose Cytarabine achieved an effective drug concentration in the rat brain, and brain tissue had no significant damage. Further animal experiments will be conducted to confirm these results in a leukemia animal model, considering the blood brain barrier is destroyed at different levels by leukemia cells. We hope this method will reduce the side effects of high-dose Cytarabine and improve the clinically high recurrence and poor prognosis of the central nervous system leukemia. PMID- 29435191 TI - Effect of postoperative systemic therapy on pulmonary adenocarcinoma with unexpected pleural spread detected during thoracotomy or thoracoscopy. AB - Background: Occasionally, malignant pleural disease is only detected unexpectedly during surgery in patients with pulmonary adenocarcinoma. Previous studies mostly focused on the role of main tumor resection on patient's outcome, barely addressing the position of postoperative systemic therapy. Methods: The medical records of 5321 non-small cell lung cancer patients who underwent thoracic surgery between January 1990 and December 2012 were reviewed. Pulmonary adenocarcinoma patients with unexpected pleural spread noted during surgery were included. The clinical and postoperative treatment variables were assessed for correlation with overall survival. Results: In 134 patients identified, main tumor resection was performed in 87 (64.9%) patients, while 89 (66.4%) and 57 (42.5%) patients received postoperative chemotherapy and epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR -TKI) therapy, respectively. Overall, the 5-year survival rate was 30.2% and median survival time was 29.3 months. Multivariate analysis showed main tumor resection and EGFR-TKI therapy were associated with better survival. Mutational status of EGFR was available in 57 patients and 43 (75.4%) had activating mutations. Resection of the main tumor conferred a better outcome in patients without EGFR mutation or with unknown EGFR mutation status and had not been treated with EGFR-TKI therapy (P = 0.003), but not in those with activating EGFR mutation and had been treated with EGFR-TKI (P = 0.857). Conclusions: In pulmonary adenocarcinoma patients with unexpected pleural spread detected during surgery, main tumor resection and EGFR-TKI therapy correlated with better survival. Identifying EGFR mutation status before surgery can provide useful information for clinical decision during surgery. PMID- 29435192 TI - MicroRNA expression and activity in T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid malignancy caused by the oncogenic transformation of immature T-cell progenitors. Many biologically relevant genetic and epigenetic alterations have been identified as driving factors for this transformation. Recently, microRNAs (miRNAs) have been shown to influence various leukemias, including T-ALL. Aberrant expression of miRNAs can function as either oncogenes or tumor suppressors in T-ALL through the regulation of cell migration, invasion, proliferation, apoptosis, and chemoresistance. This occurs by targeting key signaling pathways or transcriptional factors that play a critical role in T-ALL pathology and progression. Different miRNA expression profiles have been linked to specific genetic subtypes of human T-ALL. Furthermore, miRNAs can also act as independent prognostic factors to predict clinical outcomes for T-ALL patients. In the current review, we will focus on the role of miRNAs in the development and progression of T-ALL. PMID- 29435194 TI - miRNA dysregulation and the risk of metastasis and invasion in papillary thyroid cancer: a systematic review and meta-analysis. AB - Thyroid cancer (TC) is the most common endocrine malignancy, with an incidence continuing to grow every year. Although thyroid cancer as a whole is generally indolent and relatively easy to treat, some subtypes carry a higher rate of metastasis and cancer-related mortality. A growing number of studies have focused on the dysregulation of miRNAs in TC. However, differences in methods make comparison of gene profiling data difficult. A meta-analysis of published studies comparing miRNA expression data of invasive thyroid carcinoma with paired non invasive tumors or normal tissues was performed by searching the literature for "invasion", "thyroid cancer", and "miRNA". This revealed 29 dysregulated miRNAs associated with TC in 16 articles; the presence of invasion was confirmed in each respective article by laboratory research or patient follow-up. Among these miRNAs, miRNA-146b, miRNA-221, and miRNA-222 were analyzed further due to their higher frequencies across multiple studies. Of these studies, 6 were included in the meta-analysis, as they compared invasive PTC with paired normal tissues or non-invasive PTC. PMID- 29435193 TI - Targeted drugs for systemic therapy of lung cancer with brain metastases. AB - Brain metastases are very common in lung cancer patients. The condition of these patients is complicated and difficult to treat, and adverse reactions following treatment can affect the nervous system, which severely reduces quality of life. Lung cancers are categorized as small cell lung cancers and non-small cell lung cancers. Patients with brain metastasis of small cell lung cancers are generally treated with brain radiotherapy and systemic chemotherapy, but stage III/IV patients with brain metastasis of non-small cell lung cancers are generally not responsive to radiotherapy or chemotherapy. With the recent development of targeted drugs, tumor molecular profile detection allows the selection of appropriate targeted drugs for adjuvant pharmacological treatment of brain metastasis in lung cancer patients. In recent years, immune checkpoint inhibitors have emerged and have been approved by the Food and Drug Administration (FDA) for the treatment of certain cancers, but their efficacy in lung cancer patients with brain metastases still needs to be confirmed. This paper focuses on highlighting drugs for targeted therapy of brain metastasis in lung cancer patients and their molecular targets and mechanisms of drug resistance. PMID- 29435195 TI - Decorin is a pivotal effector in the extracellular matrix and tumour microenvironment. AB - Decorin (DCN), an extracellular matrix (ECM) protein, belongs to the small leucine-rich proteoglycan family. As a pluripotent molecule, DCN regulates the bioactivities of cell growth factors and participates in ECM assembly. Accumulating evidence has shown that DCN acts as a ligand of various cytokines and growth factors by directly or indirectly interacting with the corresponding signalling molecules involved in cell growth, differentiation, proliferation, adhesion and metastasis and that DCN especially plays vital roles in cancer cell proliferation, spread, pro-inflammatory processes and anti-fibrillogenesis. The multifunctional nature of DCN thus enables it to be a potential therapeutic agent for a variety of diseases and shows good prospects for clinical and research applications. DCN, an extracellular matrix (ECM) protein that belongs to the small leucine-rich proteoglycan family, is widely distributed and plays multifunctional roles in the stroma and epithelial cells. Originally, DCN was known as an effective collagen-binding partner for fibrillogenesis [1] and to modulate key biomechanical parameters of tissue integrity in the tendon, skin and cornea [2]; thus, it was named decorin (DCN). Since being initially cloned in 1986, DCN was discovered to be a structural constituent of the ECM [3]. However, the paradigm has been shifted; it has become increasingly evident that in addition to being a matrix structural protein, DCN affects a wide range of biological processes, including cell growth, differentiation, proliferation, adhesion, spread and migration, and regulates inflammation and fibrillogenesis [4 7]. Two main themes for DCN functions have emerged: maintenance of cellular structure and regulation of signal transduction pathways, culminating in anti tumourigenic effects. Here, we review the interaction network of DCN and emphasize the biological correlations between these interactions, some of which are expected to be therapeutic intervention targets. PMID- 29435197 TI - Successful retreatment with sofosbuvir plus ledipasvir for cirrhotic patients with hepatitis C virus genotype 1b, who discontinued the prior treatment with asunaprevir plus daclatasvir: A case series and review of the literature. AB - Background: Interferon-free treatment results in higher sustained virologic response (SVR) rates, with no serious adverse events in hepatitis C virus (HCV) infected patients. However, in some patients with treatment-failure in HCV NS5A inhibitor-including interferon-free regimens, the treatment-emergent HCV NS5A resistance-associated variants (RAVs), which are resistant to interferon-free retreatment including HCV NS5A inhibitors, are observed. In HCV-infected Japanese patients with daclatasvir and asunaprevir treatment failure, retreatment with sofosbuvir and ledipasvir could lead to only ~70% SVR rates. Case summary: Three HCV genotype (GT)-1b-infected cirrhotic patients who discontinued the combination of daclatasvir and asunaprevir due to adverse drug reactions within 4 weeks; retreatment with sofosbuvir and ledipasvir combination could result in SVR in these patients without RAVs. One HCV GT-1b-infected cirrhotic patient who discontinued the combination of daclatasvir and asunaprevir due to viral breakthrough at week 10; retreatment with sofosbuvir and ledipasvir combination for this patient with the treatment-emergent HCV NS5A RAV-Y93H resulted in viral relapse at week 4 after the end of the treatment. Conclusion: Retreatment with sofosbuvir and ledipasvir is effective for HCV GT-1b patients who discontinue the combination of daclatasvir and asunaprevir within 4 weeks. The treatment response should be related to the existence of treatment-emergent HCV NS5A RAVs, but may not be related to the short duration of treatment. PMID- 29435196 TI - Exon 3 mutations of CTNNB1 drive tumorigenesis: a review. AB - The canonical Wnt/beta-catenin signaling pathway, an important modulator of progenitor cell proliferation and differentiation, is highly regulated for the maintenance of critical biological homeostasis. Decades of studies in cancer genetics and genomics have demonstrated that multiple genes encoding key proteins in this signaling pathway serve as targets for recurrent mutational alterations. Among these proteins, beta-catenin and adenomatosis polyposis coli (APC) are two key nodes. beta-catenin contributes in transporting extracellular signals for nuclear programming. Mutations of the CTNNB1 gene that encodes beta-catenin occur in a wide spectrum of cancers. These mutations alter the spatial characteristics of the beta-catenin protein, leading to drastic reprogramming of the nuclear transcriptional network. Among the outcomes of this reprogramming are increased cell proliferation, enhanced immunosuppression, and disruption of metabolic regulation. Herein we review the current understanding of CTNNB1 mutations, their roles in tumorigenesis and discuss their possible therapeutic implications for cancer. PMID- 29435198 TI - Trauma is a public health issue. AB - Exposure to trauma is pervasive in societies worldwide and is associated with substantial costs to the individual and society, making it a significant global public health concern. We present evidence for trauma as a public health issue by highlighting the role of characteristics operating at multiple levels of influence - individual, relationship, community, and society - as explanatory factors in both the occurrence of trauma and its sequelae. Within the context of this multi-level framework, we highlight targets for prevention of trauma and its downstream consequences and provide examples of where public health approaches to prevention have met with success. Finally, we describe the essential role of public health policies in addressing trauma as a global public health issue, including key challenges for global mental health and next steps for developing and implementing a trauma-informed public health policy agenda. A public health framework is critical for understanding risk and protective factors for trauma and its aftermath operating at multiple levels of influence and generating opportunities for prevention. PMID- 29435199 TI - A new perspective on PTSD symptoms after traumatic vs stressful life events and the role of gender. AB - Background: There is an ongoing debate about the validity of the A1 criterion of PTSD. Whereas the DSM-5 has opted for a more stringent A1 criterion, the ICD-11 will leave it out as a key criterion. Objective: Here we investigated whether formal DSM-IV-TR traumatic (A1) and stressful (non-A1) events differ with regard to PTSD symptom profiles, and whether there is a gender difference in this respect. Method: This was examined in a large, mostly clinical sample from the Netherlands Study of Depression and Anxiety (n = 1433). Participants described their most bothersome (index) event and were assigned to either an A1 or non-A1 event group according to this index event. Results: Remarkably, in men PTSD symptoms were even more severe after non-A1 than A1 events, whereas in women symptoms were equally severe after non-A1 and A1 events. Moreover, while women showed significantly higher PTSD symptoms after A1 events than men (29.9 versus 15.4% met PTSD criteria), there was no gender difference after non-A1 events (women: 28.2%; men: 31.3%). Furthermore, anxiety and perceived impact were higher in women than men, which was associated with PTSD symptom severity. Conclusion: In sum, while women showed similar levels of PTSD symptoms after both event types, men reported even higher levels of PTSD symptoms after non-A1 than A1 events. These findings shed a new light on the role of gender in PTSD symptomatology and the clinical usefulness of the A1 criterion. PMID- 29435200 TI - Exploring optimum cut-off scores to screen for probable posttraumatic stress disorder within a sample of UK treatment-seeking veterans. AB - Background: Previous research exploring the psychometric properties of the scores of measures of posttraumatic stress disorder (PTSD) suggests there is variation in their functioning depending on the target population. To date, there has been little study of these properties within UK veteran populations. Objective: This study aimed to determine optimally efficient cut-off values for the Impact of Event Scale-Revised (IES-R) and the PTSD Checklist for DSM-5 (PCL-5) that can be used to assess for differential diagnosis of presumptive PTSD. Methods: Data from a sample of 242 UK veterans assessed for mental health difficulties were analysed. The criterion-related validity of the PCL-5 and IES-R were evaluated against the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Kappa statistics were used to assess the level of agreement between the DSM-IV and DSM 5 classification systems. Results: The optimal cut-off scores observed within this sample were 34 or above on the PCL-5 and 46 or above on the IES-R. The PCL-5 cut-off is similar to the previously reported values, but the IES-R cut-off identified in this study is higher than has previously been recommended. Overall, a moderate level of agreement was found between participants screened positive using the DSM-IV and DSM-5 classification systems of PTSD. Conclusions: Our findings suggest that the PCL-5 and IES-R can be used as brief measures within veteran populations presenting at secondary care to assess for PTSD. The use of a higher cut-off for the IES-R may be helpful for differentiating between veterans who present with PTSD and those who may have some sy'mptoms of PTSD but are sub threshold for meeting a diagnosis. Further, the use of more accurate optimal cut offs may aid clinicians to better monitor changes in PTSD symptoms during and after treatment. PMID- 29435201 TI - The global collaboration on traumatic stress. AB - Trauma is a global issue. The great majority of the global burden of disease arising from mental health conditions occurs in low- and middle-income countries (LMICs), among populations in political, economic, and/or cultural transition and those struck by forced migration. These mental health problems frequently arise as a result of traumatic events that adversely affect adults, children, and families, including war, mass violence, natural disasters, and accidents. In response to this, the International Society for Traumatic Stress Studies (ISTSS) launched the Global Initiative to have a stronger global impact on trauma-related issues. As part of this initiative, the Global Collaboration was established by representatives of eight professional organizations active in the field of traumatic stress. The group decided to focus on childhood abuse and neglect as its first collaboration. They collected guidelines worldwide, providing the basis for a synthesized core guide for prevention and treatment that can be customized for specific cultural contexts. The resulting 'Internet information on Childhood Abuse and Neglect' (iCAN) is a comprehensive guide for adults who have been affected by childhood abuse and neglect, as well as for the survivors' significant others. It is currently provided in eight languages, and is freely available at the homepage of ISTSS and other websites. A second achievement of the Global Collaboration is the validation of the Computerized Childhood Attachment and Relational Trauma Screen (CARTS), a self-report measure designed to measure occurrences of childhood maltreatment, and its translation into multiple languages, including Croatian, Dutch, French, Georgian, German, Italian, Japanese, Norwegian, Russian, and Spanish. A study is currently planned to collect normative responses to the questionnaire, and to conduct cross-cultural comparisons. The Global Collaboration's success may be seen as an encouraging step towards a truly global structure in the field of traumatic stress. PMID- 29435203 TI - EDITORIAL. Implant Treatment Method's Evolution: Pure Science Guided or Wild Darwin's Evolution? AB - No abstract. PMID- 29435202 TI - Podocyte-derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36. AB - Tubulointerstitial fibrosis is a hallmark of advanced diabetic kidney disease that is linked to a decline in renal function, however the pathogenic mechanisms are poorly understood. Microparticles (MPs) are 100-1000 nm vesicles shed from injured cells that are implicated in intercellular signalling. Our lab recently observed the formation of MPs from podocytes and their release into urine of animal models of type 1 and 2 diabetes and in humans with type 1 diabetes. The purpose of the present study was to examine the role of podocyte MPs in tubular epithelial cell fibrotic responses. MPs were isolated from the media of differentiated, untreated human podocytes (hPODs) and administered to cultured human proximal tubule epithelial cells (PTECs). Treatment with podocyte MPs increased p38 and Smad3 phosphorylation and expression of the extracellular matrix (ECM) proteins fibronectin and collagen type IV. MP-induced responses were attenuated by co-treatment with the p38 inhibitor SB202190. A transforming growth factor beta (TGF-beta) receptor inhibitor (LY2109761) blocked MP-induced Smad3 phosphorylation and ECM protein expression but not p38 phosphorylation suggesting that these responses occurred downstream of p38. Finally, blockade of the class B scavenger receptor CD36 completely abrogated MP-mediated p38 phosphorylation, downstream Smad3 activation and fibronectin/collagen type IV induction. Taken together our results suggest that podocyte MPs interact with proximal tubule cells and induce pro-fibrotic responses. Such interactions may contribute to the development of tubular fibrosis in glomerular disease. PMID- 29435204 TI - Validation of Universal Scale in Oral Surgery (USOS) for Patient's Psycho emotional Status Rating. AB - Objectives: There aren't any objective methods that may help in standard evaluation of oral surgery patient's psycho-emotional status. Without any standardized evaluation, two main problems appear: heterogeneity between studies and ineffective patient's evaluation. Therefore, Universal Scale in Oral Surgery (USOS) for patient's psycho-emotional status rating has previously been proposed by authors. The aim of present study is to assess the clinical effectivity and validate the Universal Scale in Oral Surgery in case of outpatient tooth extraction for adult healthy patients. Material and Methods: Clinical trial to validate the USOS for patient's psycho-emotional status rating was performed. In total 90 patients, that came for outpatient dental extraction to Lithuanian University of Health Sciences Oral and Maxillofacial Surgery Department ambulatory, were enrolled in clinical trial. Patients filled self-reported questionnaires before the procedure. Operating surgeon rated USOS for patient's psycho-emotional status rating doctor's part questionnaire after the procedure. 4 - 6 weeks later all patients were asked to fill USOS for patient's psycho emotional status rating questionnaire retrospectively. Results: According to the statistical analysis, the final composition of USOS for patient's psycho emotional status rating that would fit to reliability coefficient should be composed from 6 patient part questions and 3 general doctor part questions. Conclusions: Universal Scale in Oral Surgery for patient's psycho-emotional status rating is a novel, doctor and patient rated scale which is suitable for clinical and scientific usage. PMID- 29435205 TI - Percutaneous Salivary Gland Ablation using Ethanol in a Rat Model. AB - Objectives: Sialorrhea is a common health and psychosocial problem for children with neuromuscular dysfunction secondary to a variety of disorders such as cerebral palsy. Current accepted treatments include the injection of botulinum toxin into the submandibular glands for temporary symptom relief. The purpose of this study is to demonstrate the feasibility of percutaneous ethanol injection for longer lasting salivary gland ablation in an animal model. Material and Methods: Twenty rats were used in this study. In each rat, 98% ethanol was injected into the right submandibular gland under ultrasound guidance. No intervention was performed on the left gland, which served as the control. Ten rats were sacrificed and glands evaluated at three weeks, with the remaining 10 rats sacrificed and evaluated at three months. Unpaired, 1-tailed T-tests were used to analyse the data. Results: Ethanol injections induced a significant and sustained reduction in salivary gland size. Treated glands were 41% smaller by mass than untreated controls in the 10 rats sacrificed at three weeks (P < 0.001). Treated glands were 43% smaller by mass than untreated controls in the 10 rats sacrificed at three months (P < 0.001). Qualitative histologic analysis demonstrated extensive parenchymal damage, inflammation, and fibrosis at both three week and three month time points. Conclusions: Using a rat model, we demonstrated dramatic and sustained submandibular gland damage after percutaneous injection of ethanol. PMID- 29435206 TI - Bone Healing in Extraction Sockets Covered With Collagen Membrane Alone or Associated With Porcine-Derived Bone Graft: a Comparative Histological and Histomorphometric Analysis. AB - Objectives: The present paper reports data of a randomized study aimed to analyse and compare the histologic and histomorphometric aspects of bone healing in extraction sites covered with collagen membrane alone or associated with porcine derived bone graft. Material and Methods: Thirty patients, with single extraction sockets without severe bone wall defects in the premolar/molar region, were included. Ten extraction sockets were grafted with porcine-derived bone and covered with collagen membrane (group 1), 10 sites were covered with collagen membrane alone (group 2), and 10 sites healed spontaneously (group 3). After 4 months of healing, 26 (8 in group 1, 9 in group 2, and 9 in group 3) bone core specimens were harvested for histologic evaluation, then dental implants were placed. Results: Sites in the group 1 and in the group 2 showed similar histologic and histomorphometric results without significantly differences in the percentage of vital bone (57.43% [SD 4.8] vs. 60.01% [SD 3.2]), and non mineralized connective tissue 22.99% (SD 5.3) vs. 18.53% (SD 6.2). In group 1 a 16.57% (SD 3.8) of residual material was found. Conclusions: Results showed that the use of collagen membrane alone or associated to porcine-derived bone improves the healing bone process compared to that of extraction sites spontaneously healed. Moreover, histomorphometric data related to bone quality, indicated that extraction sites without severe walls defects and with a vestibular bone thickness > 1.5 mm, treated with a low resorbtion rate collagen membrane alone, do not need more than 4 months for dental implant insertion. PMID- 29435207 TI - Supernumerary Molars and Wisdom Tooth Shape Alterations in Patients with Neurofibromatosis Type 1. AB - Objectives: The purpose of the present study was the systematic investigation of numerical and morphological aberrations of teeth in the wisdom teeth region in neurofibromatosis type 1 patients. Material and Methods: The panoramic radiographs of 179 patients were analysed for supernumerary molars and dysplastic wisdom teeth with special reference to facial tumour type. The results were compared to radiographic findings obtained in panoramic radiographs of age- and sex-matched controls. Results: The total number of dysplastic or supernumerary molars was 21 (17 individuals, 4.75%) and predominantly a finding of the maxilla (maxilla: 15, mandible: 1, maxilla and mandible: 1). Differences of dental findings between neurofibromatosis type 1 (NF1) patients (n = 15) and the control group (n = 2) were statistically significant (P < 0.01). All individuals with supernumerary molars were diagnosed as being affected with NF1. This difference achieved statistical significance when it was considered that the event may occur at least once per quadrant, and thus the individual potentially needs to be considered four times (P = 0.0038). Conclusions: This investigation revealed that supernumerary molars and aberrations in wisdom tooth form are more common in patients than in age- and sex-matched controls. There is no association between these findings and a specific feature of the disease, id est facial manifestation of a trigeminal nerve sheath tumour (plexiform neurofibroma). The cause of this phenomenon is unknown. A review of these dental findings on other neurofibromatosis type 1 study groups should be attempted. PMID- 29435208 TI - Reasonable Outcome of Avulsed Permanent Upper Incisor after Seven Years Follow-Up Period: a Case Report. AB - Background: Avulsion of the permanent teeth is one of the most serious oral health problems among active children and adolescents. Traumatized patients require immediate and correct treatment in order to restore damaged structures and function that have major impact on daily patient's life. As a result, proper guidelines and fast treatment methods are necessary. This case report discusses treatment of maxillary right central incisor with an open apex that had been avulsed and replanted. We review applied treatment procedures to manage dental avulsion and restore function and aesthetics. Methods: A 10-year-old male presented with avulsion of his maxillary right central incisor as a result of unintentional playground injury. The tooth had been stored dry before the patient received immediate care. The avulsed tooth was reimplanted and splinted. The applied treatment procedures include endodontic and restorative treatment as well as careful follow-up visits. Results: The patient underwent endodontic therapy of his maxillary right central incisor with calcium hydroxide as an intracanal medicament in apexification technique and the closure of apex was achieved. Canal was obturated and the tooth was restored with composite resin. Clinical and radiographic imaging follow-up showed endodontic success with closed apex. However, severe infra-position of maxillary right central incisor developed due to ankylosis. Conclusions: Ankylosis due to tooth avulsion is a common complication of reimplanted permanent incisors and must be taken into consideration. While addressing ankylosis and its results is supported by little evidence, every case must be diagnosed correctly and treated according to its negative outcomes. PMID- 29435209 TI - The relative contribution of diurnal and nocturnal pollinators to plant female fitness in a specialized nursery pollination system. AB - Plants involved in specialized pollinator interactions, such as nursery pollination, may experience trade-offs in their female fitness, as the larvae of their pollinators may also consume seeds produced by the flowers they pollinate. These interactions could potentially shift between mutualism and parasitism, depending on the presence and abundance of both the nursery pollinator and of other pollinators. We investigated the fitness trade-off in a Mediterranean plant (Silene latifolia), which has a specialist nocturnal nursery pollinator moth (Hadena bicruris) and is also visited by several diurnal pollinators. We estimated the pollination rates and fecundity of S. latifolia in both natural and experimental populations in the Mediterranean. We estimated natural pollination rates in different flowering times and with presence/absence of the H. bicruis moth. Then by exposing plants to each pollinator group either during the day or at night, we quantified the contribution of other diurnal pollinators and the specialized nocturnal nursery pollinator to plant female fitness. We found no difference in plant fruit set mediated by diurnal versus nocturnal pollinators, indicating that non-specialist pollinators contribute to plant female fitness. However, in both natural and experimental populations, H. bicruris was the most efficient pollinator in terms of seeds produced per fruit. These results suggest that the female fitness costs generated by nursery pollination can be overcome through higher fertilization rates relative to predation rates, even in the presence of co-pollinators. Quantifying such interactions is important for our understanding of the selective pressures that promote highly specialized mutualisms, such as nursery pollination, in the Mediterranean region, a centre of diversification of the carnation family. PMID- 29435210 TI - Excitonic splittings in molecular dimers: why static ab initio calculations cannot match them. AB - After decades of research on molecular excitons, only few molecular dimers are available on which exciton and vibronic coupling theories can be rigorously tested. In centrosymmetric H-bonded dimers consisting of identical (hetero)aromatic chromophores, the monomer electronic transition dipole moment vectors subtract or add, yielding S0 -> S1 and S0 -> S2 transitions that are symmetry-forbidden or -allowed, respectively. Symmetry breaking by 12C/13C or H/D isotopic substitution renders the forbidden transition weakly allowed. The excitonic coupling (Davydov splitting) can then be measured between the S0 -> S1 and S0 -> S2 vibrationless bands. We discuss the mass-specific excitonic spectra of five H-bonded dimers that are supersonically cooled to a few K and investigated using two-color resonant two-photon ionization spectroscopy. The excitonic splittings Deltacalc predicted by ab initio methods are 5-25 times larger than the experimental excitonic splittings Deltaexp. The purely electronic ab initio splittings need to be reduced ("quenched"), reflecting the coupling of the electronic transition to the optically active vibrations of the monomers. The so-called quenching factors Gamma < 1 can be determined from experiment (Gammaexp) and/or calculation (Gammacalc). The vibronically quenched splittings Gamma.Deltacalc are found to nicely reproduce the experimental exciton splittings. PMID- 29435211 TI - Fast electrosynthesis of Fe-containing layered double hydroxide arrays toward highly efficient electrocatalytic oxidation reactions. AB - A new electrochemical synthesis route was developed for the fabrication of Fe containing layered double hydroxide (MFe-LDHs, M = Ni, Co and Li) hierarchical nanoarrays, which exhibit highly-efficient electrocatalytic performances for the oxidation reactions of several small molecules (water, hydrazine, methanol and ethanol). Ultrathin MFe-LDH nanoplatelets (200-300 nm in lateral length; 8-12 nm in thickness) perpendicular to the substrate surface are directly prepared within hundreds of seconds (<300 s) under cathodic potential. The as-obtained NiFe-LDH nanoplatelet arrays display promising behavior in the oxygen evolution reaction (OER), giving rise to a rather low overpotential (0.224 V) at 10.0 mA cm-2 with largely enhanced stability, much superior to previously reported electro oxidation catalysts as well as the state-of-the-art Ir/C catalyst. Furthermore, the MFe-LDH nanoplatelet arrays can also efficiently catalyze several other fuel molecules' oxidation (e.g., hydrazine, methanol and ethanol), delivering a satisfactory electrocatalytic activity and a high operation stability. In particular, this preparation method of Fe-containing LDHs is amenable to fast, effective and large-scale production, and shows promising applications in water splitting, fuel cells and other clean energy devices. PMID- 29435212 TI - Photoelectrochemical device based on Mo-doped BiVO4 enables smart analysis of the global antioxidant capacity in food. AB - For a healthy diet, which is an extension of a high quality lifestyle, tremendous attention has been focused on using antioxidant capacity indicators for food inspections and health guides. Although photoelectrochemical transducers have broadened our horizons for global antioxidant activity analysis, a growing body of foods and beverages needs to be quantified in the visible region and the necessary photoelectrochemical instrumentalization is still in its infancy. Generally, BiVO4 is considered as an ideal starting material for antioxidant surveillance under visible light irradiation. However, it is subjected to unsatisfied charge collection and utilization in practical applications. Herein, we studied the effects of successive molybdenum substitution of vanadium on the photocatalytic behavior of BiMo x V(1-x)O4 under visible light illumination. A superior photocurrent density was obtained for BiMo0.015V0.985O4 due to the flower-like architecture and favorable crystalline form. At the same time, this superhybrid BiMo0.015V0.985O4 composite successfully acted as a sensing unit in a photoelectrochemical platform for antioxidant capacity evaluation in foodstuffs. The related mechanism was further unearthed and discussed in-depth. Such a straightforward yet cogent principle was also applied to our integrated device for the "smart" analysis of the global antioxidant capacity, whereby collected data can be treated as a nutritive value index for routine quality control in the food industry. On the basis of this achievement, it is anticipated that mobile app-based quantitative antioxidant capacity detection will soon be realized. PMID- 29435213 TI - A series of tetraazalene radical-bridged M2 (M = CrIII, MnII, FeII, CoII) complexes with strong magnetic exchange coupling. AB - The ability of tetraazalene radical bridging ligands to mediate exceptionally strong magnetic exchange coupling across a range of transition metal complexes is demonstrated. The redox-active bridging ligand N,N',N'',N'''-tetra(2 methylphenyl)-2,5-diamino-1,4-diiminobenzoquinone (NMePhLH2) was metalated to give the series of dinuclear complexes [(TPyA)2M2(NMePhL2-)]2+ (TPyA = tris(2 pyridylmethyl)amine, M = MnII, FeII, CoII). Variable-temperature dc magnetic susceptibility data for these complexes reveal the presence of weak superexchange interactions between metal centers, and fits to the data provide coupling constants of J = -1.64(1) and -2.16(2) cm-1 for M = MnII and FeII, respectively. One-electron reduction of the complexes affords the reduced analogues [(TPyA)2M2(NMePhL3-)]+. Following a slightly different synthetic procedure, the related complex [(TPyA)2CrIII2(NMePhL3-)]3+ was obtained. X-ray diffraction, cyclic voltammetry, and Mossbauer spectroscopy indicate the presence of radical NMePhL3- bridging ligands in these complexes. Variable-temperature dc magnetic susceptibility data of the radical-bridged species reveal the presence of strong magnetic interactions between metal centers and ligand radicals, with simulations to data providing exchange constants of J = -626(7), -157(7), -307(9), and 396(16) cm-1 for M = CrIII, MnII, FeII, and CoII, respectively. Moreover, the strength of magnetic exchange in the radical-bridged complexes increases linearly with decreasing M-L bond distance in the oxidized analogues. Finally, ac magnetic susceptibility measurements reveal that [(TPyA)2Fe2(NMePhL3-)]+ behaves as a single-molecule magnet with a relaxation barrier of Ueff = 52(1) cm-1. These results highlight the ability of redox-active tetraazalene bridging ligands to enable dramatic enhancement of magnetic exchange coupling upon redox chemistry and provide a rare opportunity to examine metal-radical coupling trends across a transmetallic series of complexes. PMID- 29435214 TI - Practical and economic lithiations of functionalized arenes and heteroarenes using Cy2NLi in the presence of Mg, Zn or La halides in a continuous flow. AB - The economic amide base lithium dicyclohexylamide (Cy2NLi) allows fast and convenient (40 s, 0 degrees C) in situ trapping flow metalations of a broad range of functionalized arenes, heteroarenes and acrylate derivatives in the presence of various metal salts (ZnCl2.2LiCl, MgCl2, LaCl3.2LiCl). The resulting Zn-, Mg- or La-organometallic intermediates are trapped with various electrophiles in high yields. These flow metalations are easily scaled-up without further optimization. PMID- 29435215 TI - Hemin-G-quadruplex-crosslinked poly-N-isopropylacrylamide hydrogel: a catalytic matrix for the deposition of conductive polyaniline. AB - A G-rich nucleic acid-tethered acrylamide/N-isopropylacrylamide (NIPAM) copolymer is prepared. The nucleic acid-modified pNIPAM chains assemble, in the presence of K+ ions, into a stimuli-responsive G-quadruplex-crosslinked pNIPAM hydrogel undergoing cyclic and reversible solution/hydrogel/solid transitions. Addition of kryptofix [2.2.2], CP, to the K+-stabilized G-quadruplex-crosslinked hydrogel eliminates the K+ ions from the crosslinking units, resulting in the transition of the hydrogel into a pNIPAM solution. In turn, heating the pNIPAM hydrogel from 25 degrees C to 40 degrees C results in the transition of the hydrogel to the solid state, and cooling the solid to 25 degrees C restores the hydrogel state. Incorporation of hemin into the G-quadruplex-crosslinked hydrogel results in a catalytic hydrogel that catalyzes the oxidation of aniline by H2O2 to form polyaniline. The polyaniline/pNIPAM hydrogel hybrid doped with 2 M HCl forms an emeraldine salt, which exhibits an electrical conductivity of 9 * 10-4 [cm Omega] 1. PMID- 29435216 TI - Cobalt catalyzed sp3 C-H amination utilizing aryl azides. AB - A dinuclear Co(ii) complex supported by a modular, tunable redox-active ligand system is capable of selective C-H amination to form indolines from aryl azides in good yields at low (1 mol%) catalyst loading. The reaction is tolerant of medicinally relevant heterocycles, such as pyridine and indole, and can be used to form 5-, 6-, and 7-membered rings. The synthetic versatility obtained using low loadings of an earth abundant transition metal complex represents a significant advance in catalytic C-H amination technology. PMID- 29435218 TI - Giant colonic diverticulum-a rare cause of acute abdomen. AB - Giant colonic diverticulum (GCD), defined as diverticulum larger than 4 cm, is a rare entity. It is generally a manifestation of colonic diverticular disease and can have dramatic complications such as perforation, abscess, volvulus, infarction and adenocarcinoma. This report documents the case of a 63-year-old man coming to the Emergency Department with acute abdomen due to a perforation of a GCD. In the plain abdominal X-ray the 'Balloon-sign' was revealed, computed tomography scan and Hartmann's procedure were performed. Acute abdomen can occur as a manifestation of a complication of a GCD, and this report highlights the fact that GCD should be considered for patients with a high risk of diverticular disease and abdominal pain. PMID- 29435219 TI - Medullary-like hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most frequent primary hepatic cancer. Pathological features can define the biological behavior and prognosis. Medullary like HCC is a very rare variant that has been described only twice in literature. In the present study, we report the case of a non-cirrhotic 72-year-old man, who presented two HCC lesions on routine screening for hepatitis C virus liver disease. Radiological imaging and biopsy showed two different subtypes: one classic HCC, which was treated with chemoembolization, and a second PET/CT positive carcinoma with a PET/CT-positive metastatic coeliac lymph node, which was resected laparoscopically with a left lateral sectionectomy and extended lymphadenectomy. Histopathology revealed a medullary-like HCC; lymph node analysis confirmed the metastatic nature of the PET/CT-positive coeliac node and showed an incidental B-cell lymphoma in the hepatic pedicle lymph nodes. To the best of our knowledge this is the third case of medullary-like HCC described in the literature, and the first associated to a concomitant typical HCC. PMID- 29435220 TI - After a punch: recurrence of compartment syndrome following minor trauma. AB - Acute compartment syndrome (ACS) is a diagnosis that requires high-clinical suspicion especially in cases when the initial causal event could be considered insignificant. We present a novel case presentation of ACS associated with minor trauma in a patient with a previous history of compartment syndrome in the same extremity from a motor vehicle accident 10 years prior to presentation. To the best of our knowledge, this is the first reported case of recurrent ACS. Due to the possibility of significant morbidity, including loss of limb, it is imperative to recognize the presentation quickly so proper surgical intervention can occur. This case shows compartment syndrome can occur after a low impact mechanism of injury and previous compartment syndrome may be a risk factor, lowering the threshold for a re-occurrence. Serial exams and compartment pressure measurements should be used to aid recognition in ambiguous clinical presentations. PMID- 29435217 TI - Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials. AB - Inhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1-3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of therapeutic interest. We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities versus representatives of other human 2OG oxygenase subfamilies. The 'clinical' PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-alpha oxygen dependent degradation domains (ODDs), and selective against most, but not all, representatives of other human 2OG dependent dioxygenase subfamilies. Crystallographic and NMR studies provide insights into the different active site binding modes of the inhibitors. Cell-based results reveal the inhibitors have similar effects on the upregulation of HIF target genes, but differ in the kinetics of their effects and in extent of inhibition of hydroxylation of the N- and C-terminal ODDs; the latter differences correlate with the biophysical observations. PMID- 29435221 TI - There are only four basic modes of cell death, although there are many ad-hoc variants adapted to different situations. AB - There have been enough cell death modes delineated in the biomedical literature to befuddle all cell death researchers. Mulling over cell death from the viewpoints of the host tissue or organ and of the host animal, we construe that there should be only two physiological cell death modes, i.e. apoptosis and senescent death (SD), as well as two pathological modes, i.e. necrosis and stress induced cell death (SICD). Other death modes described in the literature are ad hoc variants or coalescences of some of these four basic ones in different physiological or pathological situations. SD, SICD and necrosis kill useful cells and will thus trigger regeneration, wound healing and probably also scar formation. SICD and necrosis will likely instigate inflammation as well. Apoptosis occurs as a mechanism to purge no-longer useful cells from a tissue via phagocytosis by cells with phagocytic ability that are collectively tagged by us as scavengers, including macrophages; therefore apoptosis is not followed by regeneration and inflammation. The answer for the question of "who dies" clearly differentiates apoptosis from SD, SICD and necrosis, despite other similarities and disparities among the four demise modes. Apoptosis cannot occur in cell lines in vitro, because cell lines are immortalized by reprogramming the death program of the parental cells, because in culture there lack scavengers and complex communications among different cell types, and because culture condition is a stress to the cells. Several issues of cell death that remain enigmatic to us are also described for peers to deliberate and debate. PMID- 29435222 TI - Comparative impacts of aboveground and belowground enemies on an invasive thistle. AB - Most research examining how herbivores and pathogens affect performance of invasive plants focuses on aboveground interactions. Although important, the role of belowground communities remains poorly understood, and the relative impact of aboveground and belowground interactions is still debated. As well, most studies of belowground interactions have been carried out in controlled environments, so little is known about the role of these interactions under natural conditions or how these relationships may change across a plant's range. Using the invasive plant Cirsium arvense, we performed a reciprocal transplant experiment to test the relative impacts of above- and belowground interactions at three sites across a 509-km latitudinal gradient in its invaded range in Ontario, Canada. At each site, C. arvense seedlings were protected with above- and/or belowground exclosures in a factorial design. Plant performance (biomass, height, stem thickness, number of leaves, length of longest leaf, maximum rhizome length) was greatest when both above- and belowground exclosures were applied and lowest when no exclosures were applied. When only one type of exclosure was applied, biomass generally improved more with belowground exclosures than with aboveground exclosures. Despite site-to-site differences in foliar damage, root damage, and mesofaunal populations, belowground interactions generally had a greater negative impact on performance than aboveground herbivory alone. These results stress the importance of including both aboveground enemy interactions and plant-soil interactions in studies of plant community dynamics and invader performance. PMID- 29435223 TI - Polygyny does not explain the superior competitive ability of dominant ant associates in the African ant-plant, Acacia (Vachellia) drepanolobium. AB - The Acacia drepanolobium (also known as Vachellia drepanolobium) ant-plant symbiosis is considered a classic case of species coexistence, in which four species of tree-defending ants compete for nesting space in a single host tree species. Coexistence in this system has been explained by trade-offs in the ability of the ant associates to compete with each other for occupied trees versus the ability to colonize unoccupied trees. We seek to understand the proximal reasons for how and why the ant species vary in competitive or colonizing abilities, which are largely unknown. In this study, we use RADseq derived SNPs to identify relatedness of workers in colonies to test the hypothesis that competitively dominant ants reach large colony sizes due to polygyny, that is, the presence of multiple egg-laying queens in a single colony. We find that variation in polygyny is not associated with competitive ability; in fact, the most dominant species, unexpectedly, showed little evidence of polygyny. We also use these markers to investigate variation in mating behavior among the ant species and find that different species vary in the number of males fathering the offspring of each colony. Finally, we show that the nature of polygyny varies between the two commonly polygynous species, Crematogaster mimosae and Tetraponera penzigi: in C. mimosae, queens in the same colony are often related, while this is not the case for T. penzigi. These results shed light on factors influencing the evolution of species coexistence in an ant-plant mutualism, as well as demonstrating the effectiveness of RADseq-derived SNPs for parentage analysis. PMID- 29435224 TI - Social structure modulates the evolutionary consequences of social plasticity: A social network perspective on interacting phenotypes. AB - Organisms express phenotypic plasticity during social interactions. Interacting phenotype theory has explored the consequences of social plasticity for evolution, but it is unclear how this theory applies to complex social structures. We adapt interacting phenotype models to general social structures to explore how the number of social connections between individuals and preference for phenotypically similar social partners affect phenotypic variation and evolution. We derive an analytical model that ignores phenotypic feedback and use simulations to test the predictions of this model. We find that adapting previous models to more general social structures does not alter their general conclusions but generates insights into the effect of social plasticity and social structure on the maintenance of phenotypic variation and evolution. Contribution of indirect genetic effects to phenotypic variance is highest when interactions occur at intermediate densities and decrease at higher densities, when individuals approach interacting with all group members, homogenizing the social environment across individuals. However, evolutionary response to selection tends to increase at greater network densities as the effects of an individual's genes are amplified through increasing effects on other group members. Preferential associations among similar individuals (homophily) increase both phenotypic variance within groups and evolutionary response to selection. Our results represent a first step in relating social network structure to the expression of social plasticity and evolutionary responses to selection. PMID- 29435225 TI - Human-mediated introduction of introgressed deer across Wallace's line: Historical biogeography of Rusa unicolor and R. timorensis. AB - In this study we compared the phylogeographic patterns of two Rusa species, Rusa unicolor and Rusa timorensis, in order to understand what drove and maintained differentiation between these two geographically and genetically close species and investigated the route of introduction of individuals to the islands outside of the Sunda Shelf. We analyzed full mitogenomes from 56 archival samples from the distribution areas of the two species and 18 microsatellite loci in a subset of 16 individuals to generate the phylogeographic patterns of both species. Bayesian inference with fossil calibration was used to estimate the age of each species and major divergence events. Our results indicated that the split between the two species took place during the Pleistocene, ~1.8 Mya, possibly driven by adaptations of R. timorensis to the drier climate found on Java compared to the other islands of Sundaland. Although both markers identified two well differentiated clades, there was a largely discrepant pattern between mitochondrial and nuclear markers. While nDNA separated the individuals into the two species, largely in agreement with their museum label, mtDNA revealed that all R. timorensis sampled to the east of the Sunda shelf carried haplotypes from R. unicolor and one Rusa unicolor from South Sumatra carried a R. timorensis haplotype. Our results show that hybridization occurred between these two sister species in Sundaland during the Late Pleistocene and resulted in human-mediated introduction of hybrid descendants in all islands outside Sundaland. PMID- 29435226 TI - Spatial and temporal genetic dynamics of the grasshopper Oedaleus decorus revealed by museum genomics. AB - Analyzing genetic variation through time and space is important to identify key evolutionary and ecological processes in populations. However, using contemporary genetic data to infer the dynamics of genetic diversity may be at risk of a bias, as inferences are performed from a set of extant populations, setting aside unavailable, rare, or now extinct lineages. Here, we took advantage of new developments in next-generation sequencing to analyze the spatial and temporal genetic dynamics of the grasshopper Oedaleus decorus, a steppic Southwestern Palearctic species. We applied a recently developed hybridization capture (hyRAD) protocol that allows retrieving orthologous sequences even from degraded DNA characteristic of museum specimens. We identified single nucleotide polymorphisms in 68 historical and 51 modern samples in order to (i) unravel the spatial genetic structure across part of the species distribution and (ii) assess the loss of genetic diversity over the past century in Swiss populations. Our results revealed (i) the presence of three potential glacial refugia spread across the European continent and converging spatially in the Alpine area. In addition, and despite a limited population sample size, our results indicate (ii) a loss of allelic richness in contemporary Swiss populations compared to historical populations, whereas levels of expected heterozygosities were not significantly different. This observation is compatible with an increase in the bottleneck magnitude experienced by central European populations of O. decorus following human-mediated land-use change impacting steppic habitats. Our results confirm that application of hyRAD to museum samples produces valuable information to study genetic processes across time and space. PMID- 29435227 TI - Tillage and herbicide reduction mitigate the gap between conventional and organic farming effects on foraging activity of insectivorous bats. AB - The increased use of pesticides and tillage intensification is known to negatively affect biodiversity. Changes in these agricultural practices such as herbicide and tillage reduction have variable effects among taxa, especially at the top of the trophic network including insectivorous bats. Very few studies compared the effects of agricultural practices on such taxa, and overall, only as a comparison of conventional versus organic farming without accurately accounting for underlying practices, especially in conventional where many alternatives exist. Divergent results founded in these previous studies could be driven by this lack of clarification about some unconsidered practices inside both conventional and organic systems. We simultaneously compared, over whole nights, bat activity on contiguous wheat fields of one organic and three conventional farming systems located in an intensive agricultural landscape. The studied organic fields (OT) used tillage (i.e., inversion of soil) without chemical inputs. In studied conventional fields, differences consisted of the following: tillage using few herbicides (T), conservation tillage (i.e., no inversion of soil) using few herbicides (CT), and conservation tillage using more herbicide (CTH), to control weeds. Using 64 recording sites (OT = 12; T = 21; CT = 13; CTH = 18), we sampled several sites per system placed inside the fields each night. We showed that bat activity was always higher in OT than in T systems for two (Pipistrellus kuhlii and Pipistrellus pipistrellus) of three species and for one (Pipistrellus spp.) of two genera, as well as greater species richness. The same results were found for the CT versus T system comparison. CTH system showed higher activity than T for only one genus (Pipistrellus spp.). We did not detect any differences between OT and CT systems, and CT showed higher activity than CTH system for only one species (Pipistrellus kuhlii). Activity in OT of Pipistrellus spp. was overall 3.6 and 9.3 times higher than CTH and T systems, respectively, and 6.9 times higher in CT than T systems. Our results highlight an important benefit of organic farming and contrasted effects in conventional farming. That there were no differences detected between the organic and one conventional system is a major result. This demonstrates that even if organic farming is presently difficult to implement and requires a change of economic context for farmers, considerable and easy improvements in conventional farming are attainable, while maintaining yields and approaching the ecological benefits of organic methods. PMID- 29435228 TI - Different responses of ecosystem carbon exchange to warming in three types of alpine grassland on the central Qinghai-Tibetan Plateau. AB - Climate is a driver of terrestrial ecosystem carbon exchange, which is an important product of ecosystem function. The Qinghai-Tibetan Plateau has recently been subjected to a marked increase in temperature as a consequence of global warming. To explore the effects of warming on carbon exchange in grassland ecosystems, we conducted a whole-year warming experiment between 2012 and 2014 using open-top chambers placed in an alpine meadow, an alpine steppe, and a cultivated grassland on the central Qinghai-Tibetan Plateau. We measured the gross primary productivity, net ecosystem CO 2 exchange (NEE), ecosystem respiration, and soil respiration using a chamber-based method during the growing season. The results show that after 3 years of warming, there was significant stimulation of carbon assimilation and emission in the alpine meadow, but both these processes declined in the alpine steppe and the cultivated grassland. Under warming conditions, the soil water content was more important in stimulating ecosystem carbon exchange in the meadow and cultivated grassland than was soil temperature. In the steppe, the soil temperature was negatively correlated with ecosystem carbon exchange. We found that the ambient soil water content was significantly correlated with the magnitude of warming-induced change in NEE. Under high soil moisture condition, warming has a significant positive effect on NEE, while it has a negative effect under low soil moisture condition. Our results highlight that the NEE in steppe and cultivated grassland have negative responses to warming; after reclamation, the natural meadow would subject to loose more C in warmer condition. Therefore, under future warmer condition, the overextension of cultivated grassland should be avoided and scientific planning of cultivated grassland should be achieved. PMID- 29435229 TI - An anthropogenic habitat within a suboptimal colonized ecosystem provides improved conditions for a range-shifting species. AB - Many species are shifting their ranges in response to the changing climate. In cases where such shifts lead to the colonization of a new ecosystem, it is critical to establish how the shifting species itself is impacted by novel environmental and biological interactions. Anthropogenic habitats that are analogous to the historic habitat of a shifting species may play a crucial role in the ability of that species to expand or persist in suboptimal colonized ecosystems. We tested if the anthropogenic habitat of docks, a likely mangrove analog, provides improved conditions for the range-shifting mangrove tree crab Aratus pisonii within the colonized suboptimal salt marsh ecosystem. To test if docks provided an improved habitat, we compared the impact of the salt marsh and dock habitats on ecological and life history traits that influence the ability of this species to persist and expand into the salt marsh and compared these back to baselines in the historic mangrove ecosystem. Specifically, we examined behavior, physiology, foraging, and the thermal conditions of A. pisonii in each habitat. We found that docks provide a more favorable thermal and foraging habitat than the surrounding salt marsh, while their ability to provide conditions which improved behavior and physiology was mixed. Our study shows that anthropogenic habitats can act as analogs to historic ecosystems and enhance the habitat quality for range-shifting species in colonized suboptimal ecosystems. If the patterns that we document are general across systems, then anthropogenic habitats may play an important facilitative role in the range shifts of species with continued climate change. PMID- 29435230 TI - Range expansion of the Asian native giant resin bee Megachile sculpturalis (Hymenoptera, Apoidea, Megachilidae) in France. AB - In 2008, a new species for the French bee fauna was recorded in Allauch near Marseille: the giant resin bee, Megachile sculpturalis (Smith, 1853). This was the first European record of this species that is native to East Asia. To our knowledge, it is the first introduced bee species in Europe. Here, we provide an overview of the current distribution of M. sculpturalis in France and we describe the history of its range expansion. Besides our own observations, information was compiled from literature and Internet websites, and by contacting naturalist networks. We collected a total of 117 records (locality * year combinations) for the 2008-2016 period. The geographical range of M. sculpturalis has extended remarkably, now occupying a third of continental France, with the most northern and western records located 335 and 520 km from Allauch, respectively. Information on its phenology, feeding, and nesting behavior is also provided. We report several events of nest occupation or eviction of Osmia sp. and Xylocopa sp. individuals by M. sculpturalis. Our results show that M. sculpturalis is now well established in France. Given its capacity to adapt and rapidly expand its range, we recommend amplifying the monitoring of this species to better anticipate the changes in its geographical range and its potential impacts on native bees. PMID- 29435231 TI - Mitochondrial DNA variation reveals maternal origins and demographic dynamics of Ethiopian indigenous goats. AB - The Horn of Africa forms one of the two main historical entry points of domestics into the continent and Ethiopia is particularly important in this regard. Through the analysis of mitochondrial DNA (mtDNA) d-loop region in 309 individuals from 13 populations, we reveal the maternal genetic variation and demographic dynamics of Ethiopian indigenous goats. A total of 174 variable sites that generated 231 haplotypes were observed. They defined two haplogroups that were present in all the 13 study populations. Reference haplotypes from the six globally defined goat mtDNA haplogroups show the two haplogroups present in Ethiopia to be A and G, the former being the most predominant. Although both haplogroups are characterized by an increase in effective population sizes (Ne) predating domestication, they also have experienced a decline in Ne at different time periods, suggesting different demographic histories. We observed seven haplotypes, six were directly linked to the central haplotypes of the two haplogroups and one was central to haplogroup G. The seven haplotypes were common between Ethiopia, Kenya, Egypt, and Saudi Arabia populations, suggesting common maternal history and the introduction of goats into East Africa via Egypt and the Arabian Peninsula, respectively. While providing new mtDNA data from a historically important region, our results suggest extensive intermixing of goats mediated by human socio-cultural and economic interactions. These have led to the coexistence of the two haplogroups in different geographic regions in Ethiopia resulting in a large caprine genetic diversity that can be exploited for genetic improvement. PMID- 29435232 TI - What factors shape genetic diversity in cetaceans? AB - Understanding what factors drive patterns of genetic diversity is a central aspect of many biological questions, ranging from the inference of historical demography to assessing the evolutionary potential of a species. However, as a larger number of datasets have become available, it is becoming clear that the relationship between the characteristics of a species and its genetic diversity is more complex than previously assumed. This may be particularly true for cetaceans, due to their relatively long lifespans, long generation times, complex social structures, and extensive ranges. In this study, we used microsatellite and mitochondrial DNA data from a systematic literature review to produce estimates of diversity for both markers across 42 cetacean species. Factors relating to demography, distribution, classification, biology, and behavior were then tested using phylogenetic methods and linear models to assess their relative influence on the genetic diversity of both marker types. The results show that while relative nuclear diversity is correlated with population size, mitochondrial diversity is not. This is particularly relevant given the widespread use of mitochondrial DNA to infer historical demography. Instead, mitochondrial diversity was mostly influenced by the range and social structure of the species. In addition to population size, habitat type (neritic vs. oceanic) had a significant correlation with relative nuclear diversity. Combined, these results show that many often-unconsidered factors are likely influencing patterns of genetic diversity in cetaceans, with implications regarding how to interpret, and what can be inferred from, existing patterns of diversity. PMID- 29435233 TI - Variation in the magnitude of morphological and dietary differences between individuals among populations of small benthic Arctic charr in relation to ecological factors. AB - The early stages of intraspecific diversity are important for the evolution of diversification and speciation. Early stages of diversification can be seen in individual specialization, where individuals consume only a portion of the diet of the population as a whole, and how such specialization is related to phenotypic diversity within populations. Here, we study the strength of the relationship between morphological and dietary distances among individuals in eighteen populations of Icelandic small benthic charr. We furthermore studied if the strength of the relationship could be related to variation in local ecological factors these populations inhabit. In all the populations studied, there was a clear relationship between morphological and dietary distances, indicating that fish that had similar morphology were at the same time-consuming similar food items. Our findings show a systematic variation in the relationship between morphology and diet at early stages of diversification in a highly specialized small benthic charr morph. The results show the importance of fine scale comparisons within populations and furthermore the value that systematic comparisons among populations under parallel evolution can contribute toward our increased understanding of evolutionary and ecological processes. PMID- 29435234 TI - Epizoochorous dispersal by ungulates depends on fur, grooming and social interactions. AB - The transport phase of the animal-mediated plant dispersal process is critical to dispersal effectiveness as it determines the spatial distribution of the diaspores released and their chance for further recruitment. Assessing this specific phase of the dispersal process generally requires combining diaspore retention times with the associated distances covered. Here, we specifically tested the effect of grooming behavior, interindividual contacts and ungulate fur on diaspore retention times and associated dispersal distances for the hooked diaspores of Xanthium strumarium L. experimentally attached to tamed individuals of three ungulate species. We used a comparative approach based on differing fur quality on different body zones of these three ungulates. During 6-hr sessions, we monitored for grooming and social interactions that may induce intended or inadvertent diaspore detachment. Additionally, we proposed innovative approaches to directly assessing diaspore dispersal distances by red deer in situ. Fat tailed functions fitted diaspore retention time, highlighting the potential for long-distance dispersal events. The longer the hair, the higher the retention capacity of diaspores in the animal's fur. As predicted, donkey retained diaspores longer than red deer and dwarf goat; and we also confirmed that diaspores attached to the short hair of the head fell off more quickly than did those on the other body zones. Dwarf goat groomed more often than both red deer and donkey, but also when it carried diaspores. Up to 14% of the diaspores detached from animal fur after specific grooming behavior. We observed, in controlled conditions, for the first time and for each ungulate species, interindividual transfers of diaspores, representing 5% of the diaspores attached to animals' fur. Our results militate for incorporating animal behavior into plant dispersal modeling approaches. PMID- 29435235 TI - Simplifying understory complexity in oil palm plantations is associated with a reduction in the density of a cleptoparasitic spider, Argyrodes miniaceus (Araneae: Theridiidae), in host (Araneae: Nephilinae) webs. AB - Expansion of oil palm agriculture is currently one of the main drivers of habitat modification in Southeast Asia. Habitat modification can have significant effects on biodiversity, ecosystem function, and interactions between species by altering species abundances or the available resources in an ecosystem. Increasing complexity within modified habitats has the potential to maintain biodiversity and preserve species interactions. We investigated trophic interactions between Argyrodes miniaceus, a cleptoparasitic spider, and its Nephila spp. spider hosts in mature oil palm plantations in Sumatra, Indonesia. A. miniaceus co-occupy the webs of Nephila spp. females and survive by stealing prey items caught in the web. We examined the effects of experimentally manipulated understory vegetation complexity on the density and abundance of A. miniaceus in Nephila spp. webs. Experimental understory treatments included enhanced complexity, standard complexity, and reduced complexity understory vegetation, which had been established as part of the ongoing Biodiversity and Ecosystem Function in Tropical Agriculture (BEFTA) Project. A. miniaceus density ranged from 14.4 to 31.4 spiders per square meter of web, with significantly lower densities found in reduced vegetation complexity treatments compared with both enhanced and standard treatment plots. A. miniaceus abundance per plot was also significantly lower in reduced complexity than in standard and enhanced complexity plots. Synthesis and applications: Maintenance of understory vegetation complexity contributes to the preservation of spider host-cleptoparasite relationships in oil palm plantations. Understory structural complexity in these simplified agroecosystems therefore helps to support abundant spider populations, a functionally important taxon in agricultural landscapes. In addition, management for more structurally complex agricultural habitats can support more complex trophic interactions in tropical agroecosystems. PMID- 29435236 TI - Stronger social bonds do not always predict greater longevity in a gregarious primate. AB - In group-living species, individuals often have preferred affiliative social partners, with whom ties or bonds can confer advantages that correspond with greater fitness. For example, in adult female baboons and juvenile horses, individuals with stronger or more social ties experience greater survival. We used detailed behavioral and life history records to explore the relationship between tie quality and survival in a gregarious monkey (Cercopithecus mitis stuhlmanni), while controlling for dominance rank, group size, and life history strategy. We used Cox proportional hazards regressions to model the cumulative (multi-year) and current (single-year) relationships of social ties and the hazard of mortality in 83 wild adult females of known age, observed 2-8 years each (437 subject-years) in eight social groups. The strength of bonds with close partners was associated with increased mortality risk under certain conditions: Females that had strong bonds with close partners that were inconsistent over multiple years had a higher risk of mortality than females adopting any other social strategy. Within a given year, females had a higher risk of death if they were strongly bonded with partners that changed from the previous year versus with partners that remained consistent. Dominance rank, number of adult female groupmates, and age at first reproduction did not predict the risk of death. This study demonstrates that costs and benefits of strong social bonds can be context dependent, relating to the consistency of social partners over time. PMID- 29435237 TI - Save your host, save yourself? Caste-ratio adjustment in a parasite with division of labor and snail host survival following shell damage. AB - Shell damage and parasitic infections are frequent in gastropods, influencing key snail host life-history traits such as survival, growth, and reproduction. However, their interactions and potential effects on hosts and parasites have never been tested. Host-parasite interactions are particularly interesting in the context of the recently discovered division of labor in trematodes infecting marine snails. Some species have colonies consisting of two different castes present at varying ratios; reproductive members and nonreproductive soldiers specialized in defending the colony. We assessed snail host survival, growth, and shell regeneration in interaction with infections by two trematode species, Philophthalmus sp. and Maritrema novaezealandense, following damage to the shell in the New Zealand mud snail Zeacumantus subcarinatus. We concomitantly assessed caste-ratio adjustment between nonreproductive soldiers and reproductive members in colonies of the trematode Philophthalmus sp. in response to interspecific competition and shell damage to its snail host. Shell damage, but not parasitic infection, significantly increased snail mortality, likely due to secondary infections by pathogens. However, trematode infection and shell damage did not negatively affect shell regeneration or growth in Z. subcarinatus; infected snails actually produced more new shell than their uninfected counterparts. Both interspecific competition and shell damage to the snail host induced caste-ratio adjustment in Philophthalmus sp. colonies. The proportion of nonreproductive soldiers increased in response to interspecific competition and host shell damage, likely to defend the parasite colony and potentially the snail host against increasing threats. These results indicate that secondary infections by pathogens following shell damage to snails both significantly increased snail mortality and induced caste-ratio adjustments in parasites. This is the first evidence that parasites with a division of labor may be able to produce nonreproductive soldiers according to environmental factors other than interspecific competition with other parasites. PMID- 29435238 TI - Symbiont-conferred reproduction and fitness benefits can favour their host occurrence. AB - Double infections of Wolbachia and Spiroplasma are frequent in natural populations of Tetranychus truncatus, a polyphagous mite species that has been a dominant species in China since 2009. However, little is known about the causes and ecological importance of such coexistences. In this study, we established T. truncatus strains with different infection types and then inferred the impact of the two endosymbionts on host reproduction and fitness. Double infection induced cytoplasmic incompatibility, which was demonstrated by reduction in egg hatchability of incompatible crosses. However, doubly infected females produced more eggs relative to other strains. Wolbachia and Spiroplasma did not affect host survival, whereas doubly infected females and males developed faster than other strains. Such reproduction and fitness benefits provided by double infections may be associated with the lower densities of each symbiont, and the quantitative results also confirmed competition between Wolbachia and Spiroplasma in doubly infected females. These symbiont-conferred beneficial effects maintain stable prevalence of the symbionts and also help drive T. truncatus outbreaks in combination with other environmental factors. PMID- 29435239 TI - Rule reversal: Ecogeographical patterns of body size variation in the common treeshrew (Mammalia, Scandentia). AB - There are a number of ecogeographical "rules" that describe patterns of geographical variation among organisms. The island rule predicts that populations of larger mammals on islands evolve smaller mean body size than their mainland counterparts, whereas smaller-bodied mammals evolve larger size. Bergmann's rule predicts that populations of a species in colder climates (generally at higher latitudes) have larger mean body sizes than conspecifics in warmer climates (at lower latitudes). These two rules are rarely tested together and neither has been rigorously tested in treeshrews, a clade of small-bodied mammals in their own order (Scandentia) broadly distributed in mainland Southeast Asia and on islands throughout much of the Sunda Shelf. The common treeshrew, Tupaia glis, is an excellent candidate for study and was used to test these two rules simultaneously for the first time in treeshrews. This species is distributed on the Malay Peninsula and several offshore islands east, west, and south of the mainland. Using craniodental dimensions as a proxy for body size, we investigated how island size, distance from the mainland, and maximum sea depth between the mainland and the islands relate to body size of 13 insular T. glis populations while also controlling for latitude and correlation among variables. We found a strong negative effect of latitude on body size in the common treeshrew, indicating the inverse of Bergmann's rule. We did not detect any overall difference in body size between the island and mainland populations. However, there was an effect of island area and maximum sea depth on body size among island populations. Although there is a strong latitudinal effect on body size, neither Bergmann's rule nor the island rule applies to the common treeshrew. The results of our analyses demonstrate the necessity of assessing multiple variables simultaneously in studies of ecogeographical rules. PMID- 29435240 TI - Gut microbiota in the burying beetle, Nicrophorus vespilloides, provide colonization resistance against larval bacterial pathogens. AB - Carrion beetles, Nicrophorus vespilloides, are reared on decomposing carrion where larvae are exposed to high populations of carcass-derived bacteria. Larvae do not become colonized with these bacteria but instead are colonized with the gut microbiome of their parents, suggesting that bacteria in the beetle microbiome outcompete the carcass-derived species for larval colonization. Here, we test this hypothesis and quantify the fitness consequences of colonization with different bacterial symbionts. First, we show that beetles colonized by their endogenous microbiome produce heavier broods than those colonized with carcass-bacteria. Next, we show that bacteria from the endogenous microbiome, including Providencia rettgeri and Morganella morganii, are better colonizers of the beetle gut and can outcompete nonendogenous species, including Serratia marcescens and Escherichia coli, during in vivo competition. Finally, we find that Providencia and Morganella provide beetles with colonization resistance against Serratia and thereby reduce Serratia-induced larval mortality. This effect is eliminated in larvae first colonized by Serratia, suggesting that while competition within the larval gut is determined by priority effects, these effects are less important for Serratia-induced mortality. Our work suggests that an unappreciated benefit of parental care in N. vespilloides is the social transmission of the microbiome from parents to offspring. PMID- 29435241 TI - Interannual variations in needle and sapwood traits of Pinus edulis branches under an experimental drought. AB - In the southwestern USA, recent large-scale die-offs of conifers raise the question of their resilience and mortality under droughts. To date, little is known about the interannual structural response to droughts. We hypothesized that pinon pines (Pinus edulis) respond to drought by reducing the drop of leaf water potential in branches from year to year through needle morphological adjustments. We tested our hypothesis using a 7-year experiment in central New Mexico with three watering treatments (irrigated, normal, and rain exclusion). We analyzed how variation in "evaporative structure" (needle length, stomatal diameter, stomatal density, stomatal conductance) responded to watering treatment and interannual climate variability. We further analyzed annual functional adjustments by comparing yearly addition of needle area (LA) with yearly addition of sapwood area (SA) and distance to tip (d), defining the yearly ratios SA:LA and SA:LA/d. Needle length (l) increased with increasing winter and monsoon water supply, and showed more interannual variability when the soil was drier. Stomatal density increased with dryness, while stomatal diameter was reduced. As a result, anatomical maximal stomatal conductance was relatively invariant across treatments. SA:LA and SA:LA/d showed significant differences across treatments and contrary to our expectation were lower with reduced water input. Within average precipitation ranges, the response of these ratios to soil moisture was similar across treatments. However, when extreme soil drought was combined with high VPD, needle length, SA:LA and SA:LA/d became highly nonlinear, emphasizing the existence of a response threshold of combined high VPD and dry soil conditions. In new branch tissues, the response of annual functional ratios to water stress was immediate (same year) and does not attempt to reduce the drop of water potential. We suggest that unfavorable evaporative structural response to drought is compensated by dynamic stomatal control to maximize photosynthesis rates. PMID- 29435242 TI - Which egg features predict egg rejection responses in American robins? Replicating Rothstein's (1982) study. AB - Rothstein (Behavioral Ecology and Sociobiology, 11, 1982, 229) was one of the first comprehensive studies to examine how different egg features influence egg rejection behaviors of avian brood parasite-hosts. The methods and conclusions of Rothstein (1982) laid the foundation for subsequent experimental brood parasitism studies over the past thirty years, but its results have never been evaluated with replication. Here, we partially replicated Rothstein's (1982) experiments using parallel artificial model egg treatments to simulate cowbird (Molothrus ater) parasitism in American robin (Turdus migratorius) nests. We compared our data with those of Rothstein (1982) and confirmed most of its original findings: (1) robins reject model eggs that differ from the appearance of a natural robin egg toward that of a natural cowbird egg in background color, size, and maculation; (2) rejection responses were best predicted by model egg background color; and (3) model eggs differing by two or more features from natural robin eggs were more likely to be rejected than model eggs differing by one feature alone. In contrast with Rothstein's (1982) conclusion that American robin egg recognition is not specifically tuned toward rejection of brown-headed cowbird eggs, we argue that our results and those of other recent studies of robin egg rejection suggest a discrimination bias toward rejection of cowbird eggs. Future work on egg recognition will benefit from utilizing a range of model eggs varying continuously in background color, maculation patterning, and size in combination with avian visual modeling, rather than using model eggs which vary only discretely. PMID- 29435243 TI - Genotyping strategy matters when analyzing hypervariable major histocompatibility complex-Experience from a passerine bird. AB - Genotyping of classical major histocompatibility complex (MHC) genes is challenging when they are hypervariable and occur in multiple copies. In this study, we used several different approaches to genotype the moderately variable MHC class I exon 3 (MHCIe3) and the highly polymorphic MHC class II exon 2 (MHCIIbetae2) in the bluethroat (Luscinia svecica). Two family groups (eight individuals) were sequenced in replicates at both markers using Ion Torrent technology with both a single- and a dual-indexed primer structure. Additionally, MHCIIbetae2 was sequenced on Illumina MiSeq. Allele calling was conducted by modifications of the pipeline developed by Sommer et al. (BMC Genomics, 14, 2013, 542) and the software AmpliSAS. While the different genotyping strategies gave largely consistent results for MHCIe3, with a maximum of eight alleles per individual, MHCIIbetae2 was remarkably complex with a maximum of 56 MHCIIbetae2 alleles called for one individual. Each genotyping strategy detected on average 50%-82% of all MHCIIbetae2 alleles per individual, but dropouts were largely allele-specific and consistent within families for each strategy. The discrepancies among approaches indicate PCR biases caused by the platform specific primer tails. Further, AmpliSAS called fewer alleles than the modified Sommer pipeline. Our results demonstrate that allelic dropout is a significant problem when genotyping the hypervariable MHCIIbetae2. As these genotyping errors are largely nonrandom and method-specific, we caution against comparing genotypes across different genotyping strategies. Nevertheless, we conclude that high throughput approaches provide a major advance in the challenging task of genotyping hypervariable MHC loci, even though they may not reveal the complete allelic repertoire. PMID- 29435244 TI - Dominant plant species shape soil bacterial community in semiarid sandy land of northern China. AB - Plant species affect soil bacterial diversity and compositions. However, little is known about the role of dominant plant species in shaping the soil bacterial community during the restoration of sandy grasslands in Horqin Sandy Land, northern China. We established a mesocosm pots experiment to investigate short term responses of soil bacterial diversity and composition, and the related soil properties in degraded soils without vegetation (bare sand as the control, CK) to restoration with five plant species that dominate across restoration stages: Agriophyllum squarrosum (AS), Artemisia halodendron (AH), Setaria viridis (SV), Chenopodium acuminatum (CA), and Corispermum macrocarpum (CM). We used redundancy analysis (RDA) to analyze the association between soil bacterial composition and soil properties in different plant species. Our results indicated that soil bacterial diversity was significantly lower in vegetated soils independent of plant species than in the CK. Specifically, soil bacterial species richness and diversity were lower under the shrub AH and the herbaceous plants AS, SV, and CA, and soil bacterial abundance was lower under AH compared with the CK. A field investigation confirmed the same trends where soil bacteria diversity was lower under AS and AH than in bare sand. The high-sequence annotation analysis showed that Proteobacteria, Actinobacteria, and Bacteroidetes were the most common phyla in sandy land irrespective of soil plant cover. The OTUs (operational taxonomic units) indicated that some bacterial species were specific to the host plants. Relative to bare sand (CK), soils with vegetative cover exhibited lower soil water content and temperature, and higher soil carbon and nitrogen contents. The RDA result indicated that, in addition to plant species, soil water and nitrogen contents were the most important factors shaping soil bacterial composition in semiarid sandy land. Our study from the pot and field investigations clearly demonstrated that planting dominant species in bare sand impacts bacterial diversity. In semiarid ecosystems, changes in the dominant plant species during vegetation restoration efforts can affect the soil bacterial diversity and composition through the direct effects of plants and the indirect effects of soil properties that are driven by plant species. PMID- 29435245 TI - Random species loss underestimates dilution effects of host diversity on foliar fungal diseases under fertilization. AB - With increasing attention being paid to the consequences of global biodiversity losses, several recent studies have demonstrated that realistic species losses can have larger impacts than random species losses on community productivity and resilience. However, little is known about the effects of the order in which species are lost on biodiversity-disease relationships. Using a multiyear nitrogen addition and artificial warming experiment in natural assemblages of alpine meadow vegetation on the Qinghai-Tibetan Plateau, we inferred the sequence of plant species losses under fertilization/warming. Then the sequence of species losses under fertilization/warming was used to simulate the species loss orders (both realistic and random) in an adjacently novel removal experiment manipulating plot-level plant diversity. We explicitly compared the effect sizes of random versus realistic species losses simulated from fertilization/warming on plant foliar fungal diseases. We found that realistic species losses simulated from fertilization had greater effects than random losses on fungal diseases, and that species identity drove the diversity-disease relationship. Moreover, the plant species most prone to foliar fungal diseases were also the least vulnerable to extinction under fertilization, demonstrating the importance of protecting low competence species (the ability to maintain and transmit fungal infections was low) to impede the spread of infectious disease. In contrast, there was no difference between random and realistic species loss scenarios simulated from experimental warming (or the combination of warming and fertilization) on the diversity-disease relationship, indicating that the functional consequences of species losses may vary under different drivers. PMID- 29435246 TI - The effect of prescribed burning on plant rarity in a temperate forest. AB - Rare species can play important functional roles, but human-induced changes to disturbance regimes, such as fire, can inadvertently affect these species. We examined the influence of prescribed burns on the recruitment and diversity of plant species within a temperate forest in southeastern Australia, with a focus on species that were rare prior to burning. Floristic composition was compared among plots in landscapes before and after treatment with prescribed burns differing in the extent of area burnt and season of burn (before-after, control impact design). Floristic surveys were conducted before burns, at the end of a decade of drought, and 3 years postburn. We quantified the effect of prescribed burns on species grouped by their frequency within the landscape before burning (common, less common, and rare) and their life-form attributes (woody perennials, perennial herbs or geophytes, and annual herbs). Burn treatment influenced the response of rare species. In spring-burn plots, the recruitment of rare annual herbs was promoted, differentiating this treatment from both autumn-burn and unburnt plots. In autumn-burn plots, richness of rare species increased across all life-form groups, although composition remained statistically similar to control plots. Richness of rare woody perennials increased in control plots. For all other life-form and frequency groups, the floristic composition of landscapes changed between survey years, but there was no effect of burn treatment, suggesting a likely effect of rainfall on species recruitment. A prescribed burn can increase the occurrence of rare species in a landscape, but burn characteristics can affect the promotion of different life-form groups and thus affect functional diversity. Drought-breaking rain likely had an overarching effect on floristic composition during our study, highlighting that weather can play a greater role in influencing recruitment and diversity in plant communities than a prescribed burn. PMID- 29435247 TI - Evolution of a key trait greatly affects underground community assembly process through habitat adaptation in earthworms. AB - Underground community assemblies have not been studied well compared with aboveground communities, despite their importance for our understanding of whole ecosystems. To investigate underground community assembly over evolutionary timescales, we examined terrestrial earthworm communities (Oligochaeta: Haplotaxida) in conserved mountainous primary forests in Japan as a model system. We collected 553 earthworms mostly from two dominant families, the Megascolecidae and the Lumbricidae, from 12 sites. We constructed a molecular taxonomic unit tree based on the analysis of three genes to examine the effects of a biogeographic factor (dispersal ability) and an evolutionary factor (habitat adaptation) on the earthworm community assembly process. The phylogenetic distance of the earthworm communities among sites was positively correlated with geographic distance when intraspecific variation was included, indicating that the divergence within species was affected by biogeographic factors. The community assembly process in the Megascolecidae has also been affected by environmental conditions in relation to an evolutionary relationship between habitat environment and intestinal cecum type, a trait closely related to habitat depth and diet, whereas that in the Lumbricidae has not been affected as such. Intestinal cecum type showed a pattern of niche conservatism in the Megascolecidae lineage. Our results suggest that investigating the evolution of a key trait related to life history can lead to the clear description of community assembly process over a long timescale and that the community assembly process can differ greatly among related lineages even though they live sympatrically. PMID- 29435248 TI - Meta-barcoding insights into the spatial and temporal dietary patterns of the threatened Asian Great Bustard (Otis tarda dybowskii) with potential implications for diverging migratory strategies. AB - Food resources are often not sufficient to satisfy the nutritional and energetic requirements during winter conditions at high latitudes. Dietary analysis is a prerequisite to fully understanding the feeding ecology of a species and the nature of trophic interactions. Previous dietary studies of Asian Great Bustard (Otis tarda dybowskii) relied on behavioral observations, resulting in categorization of diet limited to broad taxonomic groupings. Here, we applied a high-throughput sequencing meta-barcoding approach to quantify the diet of resident and migratory Asian Great Bustard in three wintering sites during early winter and late winter. We detected 57 unique plant taxa in the bustard diet, among which 15 species were confirmed by a local plant database we generated. Both agricultural and natural foods were detected, indicating a relatively broad dietary niche. Spatiotemporal dietary changes were discovered, revealing diet differences among wintering sites and a general shift toward lower plant diversity later in winter. For the nonmigratory population, we detected a significantly more diverse array of plant species in their diet. We hypothesize that dietary variation between resident and migratory populations could be involved in the recent transition to partial migration in this species, although climate change can not be excluded. Collectively, these results support protecting unharvested grain fields and naturally unplowed lands to help conserve and promote population growth of Asian Great Bustard. PMID- 29435249 TI - Genet dynamics of a regenerating dwarf bamboo population across heterogeneous light environments in a temperate forest understorey. AB - Despite the advantage of plant clonality in patchy environments, studies focusing on genet demography in relation to spatially heterogeneous environments remain scarce. Regeneration of bamboos in forest understoreys after synchronous die-off provides an opportunity for assessing how they come to proliferate across heterogeneous light environments. In a Japanese forest, we examined genet demography of a population of Sasa kurilensis over a 7-year period starting 10 years after die-off, shortly after which some genets began spreading horizontally by rhizomes. The aboveground biomass was estimated, and genets were discriminated in 9-m2 plots placed under both canopy gaps and closed canopies. Overall, the results suggest that the survival and spread of more productive genets and the spatial expansion of genets into closed canopies underlie the proliferation of S. kurilensis. Compared to canopy gaps, the recovery rate of biomass was much slower under closed canopies for the first 10 years after the die-off, but became accelerated during the next 7 years. Genet survival was greater for more productive genets (with greater initial number of culms), and the spaces occupied by genets that died were often colonized afterward by clonal growth of surviving genets. The number of genets decreased under canopy gaps due to greater mortality, but increased under closed canopies where greater number of genets colonized clonally from outside the plots than genets died. The colonizing genets were more productive (having larger culms) than those originally germinated within the plots, and the contribution of colonizing genets to the biomass was greater under closed canopies. Our study emphasizes the importance of investigating genet dynamics over relevant spatiotemporal scales to reveal processes underlying the success of clonal plants in heterogeneous habitats. PMID- 29435250 TI - Adaptations of white spruce to climate: strong intraspecific differences in cold hardiness linked to survival. AB - Understanding local adaptation of tree populations to climate allows the development of assisted migration guidelines as a tool for forest managers to address climate change. Here, we study the relationship among climate, a wide range of physiological traits, and field performance of selected white spruce provenances originating from throughout the species range. Tree height, survival, cold hardiness, hydraulic, and wood anatomical traits were measured in a 32-year old common garden trial, located in the center of the species range. Provenance performance included all combinations of high versus low survival and growth, with the most prevalent population differentiation for adaptive traits observed in cold hardiness. Cold hardiness showed a strong association with survival and was associated with cold winter temperatures at the site of seed origin. Tree height was mostly explained by the length of the growing season at the origin of the seed source. Although population differentiation was generally weak in wood anatomical and hydraulic traits, within-population variation was substantial in some traits, and a boundary analysis revealed that efficient water transport was associated with vulnerable xylem and low wood density, indicating that an optimal combination of high water transport efficiency and high cavitation resistance is not possible. Our results suggest that assisted migration prescriptions may be advantageous under warming climate, but pronounced trade-offs between survival and cold hardiness require a careful consideration of the distances of these transfers. PMID- 29435251 TI - Transcriptome response of Atlantic salmon (Salmo salar) to competition with ecologically similar non-native species. AB - Non-native species may be introduced either intentionally or unintentionally, and their impact can range from benign to highly disruptive. Non-native salmonids were introduced into Lake Ontario, Canada, to provide recreational fishing opportunities; however, the establishment of those species has been proposed as a significant barrier to the reintroduction of native Atlantic salmon (Salmo salar) due to intense interspecific competition. In this study, we compared population differences of Atlantic salmon in transcriptome response to interspecific competition. We reared Atlantic salmon from two populations (LaHave River and Sebago Lake) with fish of each of three non-native salmonids (Chinook salmon Oncorhynchus tshawytscha, rainbow trout O. mykiss, and brown trout S. trutta) in artificial streams. We used RNA-seq to assess transcriptome differences between the Atlantic salmon populations and the responses of these populations to the interspecific competition treatments after 10 months of competition in the stream tanks. We found that population differences in gene expression were generally greater than the effects of interspecific competition. Interestingly, we found that the two Atlantic salmon populations exhibited similar responses to interspecific competition based on functional gene ontologies, but the specific genes within those ontologies were different. Our transcriptome analyses suggest that the most stressful competitor (as measured by the highest number of differentially expressed genes) differs between the two study populations. Our transcriptome characterization highlights the importance of source population selection for conservation applications, as organisms with different evolutionary histories can possess different transcriptional responses to the same biotic stressors. The results also indicate that generalized predictions of the response of native species to interactions with introduced species may not be appropriate without incorporating potential population-specific response to introduced species. PMID- 29435252 TI - Experimental estimation of snare detectability for robust threat monitoring. AB - Hunting with wire snares is rife within many tropical forest systems, and constitutes one of the severest threats to a wide range of vertebrate taxa. As for all threats, reliable monitoring of snaring levels is critical for assessing the relative effectiveness of management interventions. However, snares pose a particular challenge in terms of tracking spatial or temporal trends in their prevalence because they are extremely difficult to detect, and are typically spread across large, inaccessible areas. As with cryptic animal targets, any approach used to monitor snaring levels must address the issue of imperfect detection, but no standard method exists to do so. We carried out a field experiment in Keo Seima Wildlife Reserve in eastern Cambodia with the following objectives: (1) To estimate the detection probably of wire snares within a tropical forest context, and to investigate how detectability might be affected by habitat type, snare type, or observer. (2) To trial two sets of sampling protocols feasible to implement in a range of challenging field conditions. (3) To conduct a preliminary assessment of two potential analytical approaches to dealing with the resulting snare encounter data. We found that although different observers had no discernible effect on detection probability, detectability did vary between habitat type and snare type. We contend that simple repeated counts carried out at multiple sites and analyzed using binomial mixture models could represent a practical yet robust solution to the problem of monitoring snaring levels both inside and outside of protected areas. This experiment represents an important first step in developing improved methods of threat monitoring, and such methods are greatly needed in southeast Asia, as well as in as many other regions. PMID- 29435253 TI - Proper experimental design requires randomization/balancing of molecular ecology experiments. AB - Properly designed (randomized and/or balanced) experiments are standard in ecological research. Molecular methods are increasingly used in ecology, but studies generally do not report the detailed design of sample processing in the laboratory. This may strongly influence the interpretability of results if the laboratory procedures do not account for the confounding effects of unexpected laboratory events. We demonstrate this with a simple experiment where unexpected differences in laboratory processing of samples would have biased results if randomization in DNA extraction and PCR steps do not provide safeguards. We emphasize the need for proper experimental design and reporting of the laboratory phase of molecular ecology research to ensure the reliability and interpretability of results. PMID- 29435254 TI - Multiscale landscape genomic models to detect signatures of selection in the alpine plant Biscutella laevigata. AB - Plant species are known to adapt locally to their environment, particularly in mountainous areas where conditions can vary drastically over short distances. The climate of such landscapes being largely influenced by topography, using fine scale models to evaluate environmental heterogeneity may help detecting adaptation to micro-habitats. Here, we applied a multiscale landscape genomic approach to detect evidence of local adaptation in the alpine plant Biscutella laevigata. The two gene pools identified, experiencing limited gene flow along a 1-km ridge, were different in regard to several habitat features derived from a very high resolution (VHR) digital elevation model (DEM). A correlative approach detected signatures of selection along environmental gradients such as altitude, wind exposure, and solar radiation, indicating adaptive pressures likely driven by fine-scale topography. Using a large panel of DEM-derived variables as ecologically relevant proxies, our results highlighted the critical role of spatial resolution. These high-resolution multiscale variables indeed indicate that the robustness of associations between genetic loci and environmental features depends on spatial parameters that are poorly documented. We argue that the scale issue is critical in landscape genomics and that multiscale ecological variables are key to improve our understanding of local adaptation in highly heterogeneous landscapes. PMID- 29435255 TI - Ecological consequences of invasion across the freshwater-marine transition in a warming world. AB - The freshwater-marine transition that characterizes an estuarine system can provide multiple entry options for invading species, yet the relative importance of this gradient in determining the functional contribution of invading species has received little attention. The ecological consequences of species invasion are routinely evaluated within a freshwater versus marine context, even though many invasive species can inhabit a wide range of salinities. We investigate the functional consequences of different sizes of Corbicula fluminea-an invasive species able to adapt to a wide range of temperatures and salinity-across the freshwater-marine transition in the presence versus absence of warming. Specifically, we characterize how C. fluminea affect fluid and particle transport, important processes in mediating nutrient cycling (NH 4-N, NO 3-N, PO 4-P). Results showed that sediment particle reworking (bioturbation) tends to be influenced by size and to a lesser extent, temperature and salinity; nutrient concentrations are influenced by different interactions between all variables (salinity, temperature, and size class). Our findings demonstrate the highly context-dependent nature of the ecosystem consequences of invasion and highlight the potential for species to simultaneously occupy multiple components of an ecosystem. Recognizing of this aspect of invasibility is fundamental to management and conservation efforts, particularly as freshwater and marine systems tend to be compartmentalized rather than be treated as a contiguous unit. We conclude that more comprehensive appreciation of the distribution of invasive species across adjacent habitats and different seasons is urgently needed to allow the true extent of biological introductions, and their ecological consequences, to be fully realized. PMID- 29435256 TI - Specific plasmid patterns and high rates of bacterial co-occurrence within the coral holobiont. AB - Despite the importance of coral microbiomes for holobiont persistence, the interactions among these are not well understood. In particular, knowledge of the co-occurrence and taxonomic importance of specific members of the microbial core, as well as patterns of specific mobile genetic elements (MGEs), is lacking. We used seawater and mucus samples collected from Mussismilia hispida colonies on two reefs located in Bahia, Brazil, to disentangle their associated bacterial communities, intertaxa correlations, and plasmid patterns. Proxies for two broad host-range (BHR) plasmid groups, IncP-1beta and PromA, were screened. Both groups were significantly (up to 252 and 100%, respectively) more abundant in coral mucus than in seawater. Notably, the PromA plasmid group was detected only in coral mucus samples. The core bacteriome of M. hispida mucus was composed primarily of members of the Proteobacteria, followed by those of Firmicutes. Significant host specificity and co-occurrences among different groups of the dominant phyla (e.g., Bacillaceae and Pseudoalteromonadaceae and the genera Pseudomonas, Bacillus, and Vibrio) were detected. These relationships were observed for both the most abundant phyla and the bacteriome core, in which most of the operational taxonomic units showed intertaxa correlations. The observed evidence of host-specific bacteriome and co-occurrence (and potential symbioses or niche space co-dominance) among the most dominant members indicates a taxonomic selection of members of the stable bacterial community. In parallel, host-specific plasmid patterns could also be, independently, related to the assembly of members of the coral microbiome. PMID- 29435257 TI - Bottom-up processes drive reproductive success in an apex predator. AB - One of the central goals of the field of population ecology is to identify the drivers of population dynamics, particularly in the context of predator-prey relationships. Understanding the relative role of top-down versus bottom-up drivers is of particular interest in understanding ecosystem dynamics. Our goal was to explore predator-prey relationships in a boreal ecosystem in interior Alaska through the use of multispecies long-term monitoring data. We used 29 years of field data and a dynamic multistate site occupancy modeling approach to explore the trophic relationships between an apex predator, the golden eagle, and cyclic populations of the two primary prey species available to eagles early in the breeding season, snowshoe hare and willow ptarmigan. We found that golden eagle reproductive success was reliant on prey numbers, but also responded prior to changes in the phase of the snowshoe hare population cycle and failed to respond to variation in hare cycle amplitude. There was no lagged response to ptarmigan populations, and ptarmigan populations recovered quickly from the low phase. Together, these results suggested that eagle reproduction is largely driven by bottom-up processes, with little evidence of top-down control of either ptarmigan or hare populations. Although the relationship between golden eagle reproductive success and prey abundance had been previously established, here we established prey populations are likely driving eagle dynamics through bottom-up processes. The key to this insight was our focus on golden eagle reproductive parameters rather than overall abundance. Although our inference is limited to the golden eagle-hare-ptarmigan relationships we studied, our results suggest caution in interpreting predator-prey abundance patterns among other species as strong evidence for top-down control. PMID- 29435258 TI - No evidence of inbreeding depression in sperm performance traits in wild song sparrows. AB - Inbreeding is widely hypothesized to shape mating systems and population persistence, but such effects will depend on which traits show inbreeding depression. Population and evolutionary consequences could be substantial if inbreeding decreases sperm performance and hence decreases male fertilization success and female fertility. However, the magnitude of inbreeding depression in sperm performance traits has rarely been estimated in wild populations experiencing natural variation in inbreeding. Further, the hypothesis that inbreeding could increase within-ejaculate variation in sperm traits and thereby further affect male fertilization success has not been explicitly tested. We used a wild pedigreed song sparrow (Melospiza melodia) population, where frequent extrapair copulations likely create strong postcopulatory competition for fertilization success, to quantify effects of male coefficient of inbreeding (f) on key sperm performance traits. We found no evidence of inbreeding depression in sperm motility, longevity, or velocity, and the within-ejaculate variance in sperm velocity did not increase with male f. Contrary to inferences from highly inbred captive and experimental populations, our results imply that moderate inbreeding will not necessarily constrain sperm performance in wild populations. Consequently, the widely observed individual-level and population-level inbreeding depression in male and female fitness may not stem from reduced sperm performance in inbred males. PMID- 29435259 TI - Correlated evolution between climate and suites of traits along a fast-slow continuum in the radiation of Protea. AB - Evolutionary radiations are responsible for much of Earth's diversity, yet the causes of these radiations are often elusive. Determining the relative roles of adaptation and geographic isolation in diversification is vital to understanding the causes of any radiation, and whether a radiation may be labeled as "adaptive" or not. Across many groups of plants, trait-climate relationships suggest that traits are an important indicator of how plants adapt to different climates. In particular, analyses of plant functional traits in global databases suggest that there is an "economics spectrum" along which combinations of functional traits covary along a fast-slow continuum. We examine evolutionary associations among traits and between trait and climate variables on a strongly supported phylogeny in the iconic plant genus Protea to identify correlated evolution of functional traits and the climatic-niches that species occupy. Results indicate that trait diversification in Protea has climate associations along two axes of variation: correlated evolution of plant size with temperature and leaf investment with rainfall. Evidence suggests that traits and climatic-niches evolve in similar ways, although some of these associations are inconsistent with global patterns on a broader phylogenetic scale. When combined with previous experimental work suggesting that trait-climate associations are adaptive in Protea, the results presented here suggest that trait diversification in this radiation is adaptive. PMID- 29435261 TI - Facultative pupal mating in Heliconius erato: Implications for mate choice, female preference, and speciation. AB - Mating systems have broad impacts on how sexual selection and mate choice operate within a species, but studies of mating behavior in the laboratory may not reflect how these processes occur in the wild. Here, we examined the mating behavior of the neotropical butterfly Heliconius erato in the field by releasing larvae and virgin females and observing how they mated. H. erato is considered a pupal-mating species (i.e., males mate with females as they emerge from the pupal case). However, we observed only two teneral mating events, and experimentally released virgins were almost all mated upon recapture. Our study confirms the presence of some pupal-mating behavior in H. erato, but suggests that adult mating is likely the prevalent mating strategy in this species. These findings have important implications for the role of color pattern and female mate choice in the generation of reproductive isolation in this diverse genus. PMID- 29435260 TI - Hidden endemism, deep polyphyly, and repeated dispersal across the Isthmus of Tehuantepec: Diversification of the White-collared Seedeater complex (Thraupidae: Sporophila torqueola). AB - Phenotypic and genetic variation are present in all species, but lineages differ in how variation is partitioned among populations. Examining phenotypic clustering and genetic structure within a phylogeographic framework can clarify which biological processes have contributed to extant biodiversity in a given lineage. Here, we investigate genetic and phenotypic variation among populations and subspecies within a Neotropical songbird complex, the White-collared Seedeater (Sporophila torqueola) of Central America and Mexico. We combine measurements of morphology and plumage patterning with thousands of nuclear loci derived from ultraconserved elements (UCEs) and mitochondrial DNA to evaluate population differentiation. We find deep levels of molecular divergence between two S. torqueola lineages that are phenotypically diagnosable: One corresponds to S. t. torqueola along the Pacific coast of Mexico, and the other includes S. t. morelleti and S. t. sharpei from the Gulf Coast of Mexico and Central America. Surprisingly, these two lineages are strongly differentiated in both nuclear and mitochondrial markers, and each is more closely related to other Sporophila species than to one another. We infer low levels of gene flow between these two groups based on demographic models, suggesting multiple independent evolutionary lineages within S. torqueola have been obscured by coarse-scale similarity in plumage patterning. These findings improve our understanding of the biogeographic history of this lineage, which includes multiple dispersal events out of South America and across the Isthmus of Tehuantepec into Mesoamerica. Finally, the phenotypic and genetic distinctiveness of the range-restricted S. t. torqueola highlights the Pacific Coast of Mexico as an important region of endemism and conservation priority. PMID- 29435263 TI - Swift action increases the success of population reinforcement for a declining prairie grouse. AB - Translocations have become an increasingly valuable tool for conservation in recent years, but assessing the successfulness of translocations and identifying factors that contribute to their success continue to challenge biologists. As a unique class of translocation, population reinforcements have received relatively little attention despite representing a substantial portion of translocation programs. Here, we conducted population viability analyses to quantify the effects of 216 reinforcement scenarios on the long-term viability of four populations of Greater Prairie-Chickens (Tympanuchus cupido pinnatus) in Wisconsin, USA, and used multiple linear regression to identify factors that had the greatest relative influence on population viability. We considered reinforcements from outside of the study area in addition to translocations among Wisconsin populations. We observed the largest decreases in site-specific extinction probability and the largest increases in the number of sites persisting for 50 years when more vulnerable populations were targeted for reinforcement. Conversely, reinforcing the most stable sites caused the greatest reduction in regional extinction probability. We found that the number of translocated hens was a comparatively poor predictor of changes in long-term population viability, whereas the earlier onset of reinforcement was consistently associated with the greatest increases in viability. Our results highlight the value of evaluating alternative reinforcement strategies a priori and considering the effects of reinforcement on metrics of long-term population persistence. PMID- 29435262 TI - Ecological drivers of song evolution in birds: Disentangling the effects of habitat and morphology. AB - Environmental differences influence the evolutionary divergence of mating signals through selection acting either directly on signal transmission ("sensory drive") or because morphological adaptation to different foraging niches causes divergence in "magic traits" associated with signal production, thus indirectly driving signal evolution. Sensory drive and magic traits both contribute to variation in signal structure, yet we have limited understanding of the relative role of these direct and indirect processes during signal evolution. Using phylogenetic analyses across 276 species of ovenbirds (Aves: Furnariidae), we compared the extent to which song evolution was related to the direct influence of habitat characteristics and the indirect effect of body size and beak size, two potential magic traits in birds. We find that indirect ecological selection, via diversification in putative magic traits, explains variation in temporal, spectral, and performance features of song. Body size influences song frequency, whereas beak size limits temporal and performance components of song. In comparison, direct ecological selection has weaker and more limited effects on song structure. Our results illustrate the importance of considering multiple deterministic processes in the evolution of mating signals. PMID- 29435264 TI - Climatic forcing and larval dispersal capabilities shape the replenishment of fishes and their habitat-forming biota on a tropical coral reef. AB - Fluctuations in marine populations often relate to the supply of recruits by oceanic currents. Variation in these currents is typically driven by large-scale changes in climate, in particular ENSO (El Nino Southern Oscillation). The dependence on large-scale climatic changes may, however, be modified by early life history traits of marine taxa. Based on eight years of annual surveys, along 150 km of coastline, we examined how ENSO influenced abundance of juvenile fish, coral spat, and canopy-forming macroalgae. We then investigated what traits make populations of some fish families more reliant on the ENSO relationship than others. Abundance of juvenile fish and coral recruits was generally positively correlated with the Southern Oscillation Index (SOI), higher densities recorded during La Nina years, when the ENSO-influenced Leeuwin Current is stronger and sea surface temperature higher. The relationship is typically positive and stronger among fish families with shorter pelagic larval durations and stronger swimming abilities. The relationship is also stronger at sites on the coral back reef, although the strongest of all relationships were among the lethrinids (r = .9), siganids (r = .9), and mullids (r = .8), which recruit to macroalgal meadows in the lagoon. ENSO effects on habitat seem to moderate SOI-juvenile abundance relationship. Macroalgal canopies are higher during La Nina years, providing more favorable habitat for juvenile fish and strengthening the SOI effect on juvenile abundance. Conversely, loss of coral following a La Nina-related heat wave may have compromised postsettlement survival of coral dependent species, weakening the influence of SOI on their abundance. This assessment of ENSO effects on tropical fish and habitat-forming biota and how it is mediated by functional ecology improves our ability to predict and manage changes in the replenishment of marine populations. PMID- 29435265 TI - Prevalence and molecular characterization of oqxAB in clinical Escherichia coli isolates from companion animals and humans in Henan Province, China. AB - Background: The plasmid-encoded multidrug efflux pump oqxAB confers bacterial resistance primarily to olaquindox, quinolones, and chloramphenicol. The aims of this study were to investigate the prevalence of oqxAB among Escherichia coli isolates from dogs, cats, and humans in Henan, China and the susceptibilities of E. coli isolates to common antibiotics. Methods: From 2012 to 2014, a total of 600 samples which included 400 rectal samples and 200 clinical human specimens were tested for the presence of E. coli. All isolates were screened for oqxAB genes by PCR and sequencing. The MICs of 11 antimicrobial agents were determined by the broth microdilution method. A total of 30 representative oqxAB-positive isolates were subjected to ERIC-PCR and MLST. Additionally, conjugation experiments and southern hybridizations were performed. Results: Of 270 isolates, 58.5% (62/106) of the isolates from dogs, 56.25% (36/64) of the isolates from cats, and 42.0% (42/100) of the isolates from humans were positive for the oqxAB. Olaquindox resistance was found for 85.7%-100% of oqxAB-positive isolates. Of oqxAB-positive isolates from dogs, cats, and humans, ciprofloxacin resistance was inspected for 85.8%, 59.1%, and 93.8%, respectively. Several oqxAB-positive isolates were demonstrated by ERIC-PCR and MLST, and have high similarity. Phylogenetic analysis showed that oqxAB-positive isolates could be divided into 7 major clusters. OqxAB-positive conjugants were obtained, southern hybridization verified that the oqxAB gene complex was primarily located on plasmids. Conclusion: In conclusion, oqxAB-positive isolates were widespread in animals and humans in Henan, China. Carriage of oqxAB on plasmids of E. coli isolates may facilitate the emergence of multidrug resistant and its transmission via horizontal transfer, and might pose a potential threat to public health. PMID- 29435266 TI - Atherogenic index of plasma and 10-year risk of cardiovascular disease in adult Africans living with HIV infection: A cross-sectional study from Yaounde, Cameroon. AB - Background: The paucity of data regarding the association between atherogenic index of plasma and risk of cardiovascular disease in HIV-infected populations living in sub-Saharan Africa prompted us to conduct this study which aimed to assess the relationship between atherogenic index of plasma and risk of cardiovascular disease among a Cameroonian HIV-infected population. Methods: This was a cross-sectional study conducted among 452 HIV-infected adults in Yaounde, Cameroon. Risk of cardiovascular disease was calculated using the Framingham risk score; atherogenic index of plasma was derived as log (triglycerides/high-density lipoproteins cholesterol). Results: Participants' mean age (80% females) was 44.4 +/- 9.8 years. Atherogenic index of plasma values ranged from -0.63 to 1.36 with a median of 0.11 (25th-75th percentiles: -0.08-0.31). Most participants (88.5%) were on antiretroviral treatment. There was a significant correlation between atherogenic index of plasma and fasting plasma glucose (r = 0.116; p = 0.014), atherogenic index of plasma and total cholesterol (r = -0.164; p < 0.001). Atherogenic index of plasma was significantly associated with the risk of cardiovascular disease either in univariable (beta = 5.05, 95% CI: 3.31-6.79; p < 0.001, R2 = 0.067) or in multivariable linear regression model after adjusting for socio-demographic, clinical and biological confounders (adjusted beta = 3.79, 95% CI: 1.65 - 4.88; p < 0.001, R2 = 0.187). Conclusion: Atherogenic index of plasma may be an independent factor impacting the risk of cardiovascular disease among Cameroonian HIV-infected people. More studies are needed to better elucidate the association between atherogenic index of plasma and risk of cardiovascular disease in our setting. PMID- 29435267 TI - Women and kidney disease: reflections on World Kidney Day 2018. AB - Chronic kidney disease affects ~10% of the world's adult population: it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women's health, and specifically their kidney health, to the community and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women, so that we may apply those learnings more broadly. Girls and women, who make up ~50% of the world's population, are important contributors to society as a whole and to their families. Gender differences continue to exist around the world in access to education, medical care and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, and also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for child bearing, and for the fetus. Women have different complications on dialysis than men, and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women, kidney health and kidney disease, and what we might learn in the future to improve outcomes worldwide. PMID- 29435268 TI - Common mental disorders and association with telomere length. AB - Telomeres are repeated 5'-TTAGGG-3' sequences at the end of chromosomes, which maintain genomic stability. Their length is related to a number of diseases that affect humans. Apart from cancer, cardiovascular diseases, diabetes and other, telomere length has been associated with chronic diseases. Chronic mental illness includes various types of mental disorders with the most common being depression, schizophrenia and stress-anxiety. The aim of this review is to summarize the current state of knowledge on the role of telomeres in these disorders and to compare telomere length variations in patients receiving medication and patients not taking treatment. Most studies report reduced telomere length in patients suffering from mental disorders, compared to the general population. Since the factors that can affect telomere length are various, more experiments and investigations are required to understand the general impact of different factors on telomere length. PMID- 29435270 TI - Roles of toll-like receptors: From inflammation to lung cancer progression. AB - Lung cancer is among the most common malignant tumors worldwide, and is characterized by a low survival rate compared with other cancers. Toll-like receptors (TLRs) are highly conserved in evolution and widely expressed on immune cells, where they serve an important role in the innate immune system by evoking inflammatory responses. Evasion of immune destruction is an important hallmark in the development of cancer. There is an established association between chronic inflammation and cancer, with TLRs serving important roles in the immune response against tumor cells. Recently, TLRs have been identified on tumor cells, where their activation may orchestrate the downstream signaling pathways that serve crucial functions in tumorigenesis and tumor progression. The present review summarizes the roles of TLRs as sensors on lung cancer cells that regulate lung cancer progression with regard to cell growth and invasion, angiogenesis and cancer stem cell behavior. This aimed to provide theoretical support for the development of therapies that target TLR signaling pathways for the treatment of lung cancer. PMID- 29435271 TI - Gene expression profiling and bioinformatics analysis of hereditary gingival fibromatosis. AB - Hereditary gingival fibromatosis (HGF) is a benign, non-hemorrhagic and fibrous gingival overgrowth that may cover all or part of the teeth. It typically interferes with speech, lip closure and chewing, and can also be a psychological burden that affects the self-esteem of patients. Owing to high genetic heterogeneity, genetic testing to confirm diagnosis is not justified. It is therefore important to identify key signature genes and to understand the molecular mechanisms underlying HGF. The aim of the present study was to determine HGF-related genes and to analyze these genes through bioinformatics methods. A total of 249 differentially expressed genes (DEGs), consisting of 65 upregulated and 184 downregulated genes, were identified in the GSE4250 dataset of Gene Expression Omnibus (GEO) when comparing with the gums of HGF patients with those of healthy controls using the affy and limma packages in R. Subsequently, 28 enriched gene ontology terms were obtained from the Database for Annotation, Visualization and Integrated Discovery, and a protein-protein interaction (PPI) network was constructed and analyzed using STRING and Cytoscape. There were 99 nodes and 118 edges in the PPI network of these DEGs obtained through STRING. Among these nodes, 12 core genes were identified, of which the highest degree node was the gene for POTE ankyrin domain family member I. Collectively the results indicate that bioinformatics methods may provide effective strategies for predicting HGF-related genes and for understanding the molecular mechanisms of HGF. PMID- 29435269 TI - Current understanding of chronic total occlusion of the internal carotid artery. AB - At present, there is limited understanding of chronic total occlusion (CTO) of the internal carotid artery (ICA). Therefore, the present report collected related cases from PubMed and reviewed the literature. Cerebral vessels may form collateral circulation immediately or gradually following CTO of the ICA. The natural history of CTO of the ICA includes a variety of outcomes, all of which are biased toward a non-benign progressive process and are characterized by insufficient cerebral perfusion, embolus detachment and cognitive dysfunction. The majority of cases of CTO of the ICA require treatment. In early studies, the results of external-ICA bypass were unsatisfactory, while recanalization is now considered the only viable option. The current treatment indications mainly depend on the degree of injury to the cerebrovascular reserve and the extent to which the oxygen extraction fraction is increased. The length, height and duration of ICA occlusion are also relevant, though more frequently, the condition depends on multiple factors. Endovascular interventional recanalization, carotid endarterectomy (CEA) and hybrid surgery may be conducted in a select group of patients. As novel materials are developed, the success rate of simple recanalization may gradually increase; however, hybrid surgery may be more representative of the current trend, as advanced CEA can remove carotid atherosclerosis plaques, thus reducing the technological demands of the subsequent interventional recanalization. There are many complications that may result from recanalization following CTO of the ICA, including hyperperfusion and technical errors; therefore, the operation must be conducted carefully. If the recanalization is successful, it typically results in a stable improvement of patient condition in the long term. However, despite these conclusions, more studies are required in the future to further improve current understanding of CTO of the ICA. PMID- 29435272 TI - Optimal antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: A systemic review and meta-analysis. AB - A challenge for antithrombotic treatment is patients who present with atrial fibrillation (AF) and acute coronary syndrome, particularly in patients who have undergone coronary percutaneous intervention with stenting (PCIS). In the present study, a total of nine observational trials published prior to July 2017 that investigated the effects of dual antiplatelet therapy (DAPT; aspirin + clopidogrel) and triple oral antithrombotic therapy (TOAT; DAPT + warfarin) among patients with AF concurrent to PCIS were collected from the Medline, Cochrane and Embase databases and conference proceedings of cardiology, gastroenterology and neurology meetings. A meta-analysis was performed using fixed- or random-effect models according to heterogeneity. The subgroups were also analyzed on the occurrence of major adverse cardiac events (MACE), stroke and bleeding events in the two treatment groups. Analysis of baseline characteristics indicated that there was no significant difference in the history of coexistent disease or conventional therapies between the DAPT and TOAT groups. The primary end point incidence was 2,588 patients in the DAPT group (n=13,773) and 871 patients in the TOAT group (n=5,262) following pooling of all nine trials. There was no statistically significant difference in the incidence of primary end points between the DAPT and TOAT groups. Odds ratio (OR)=0.96, 95% confidence interval (CI)=0.73-1.27, P=0.79, with heterogeneity between trials (I2=82%, P<0.00001). Subsequently, on subgroup analysis, the results indicated no increased risk of major bleeding or ischemic stroke in the DAPT or TOAT group. However, compared with the TOAT group, there was an apparent increased risk of MACE plus ischemic stroke in the DAPT group (OR=1.62, 95% CI=1.43-1.83, P<0.00001) with heterogeneity between trials (I2=70%, P=0.01). In conclusion, the present meta analysis suggests that TOAT (aspirin + clopidogrel + warfarin) therapy for patients with AF concurrent to PCIS significantly reduced the risk of MACE and stroke compared with DAPT (aspirin + clopidogrel) therapy. Further randomized controlled clinical trials are required to confirm the efficacy of the optimal antithrombotic therapy in patients with AF following PCIS. PMID- 29435273 TI - Efficacy of vonoprazan for 24-week maintenance therapy of patients with healed reflux esophagitis refractory to proton pump inhibitors. AB - The aim of the present study was to evaluate the efficacy of a potassium competitive acid blocker (P-CAB), vonoprazan, for the maintenance therapy of healed reflux esophagitis (RE). A total of 60 patients were enrolled in this open label, single-center, prospective study. All patients were diagnosed with RE with a frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) total score >=8 following treatment with standard proton pump inhibitors (PPIs) for a minimum of 8 weeks. Standard PPI treatment was switched to vonoprazan 20 mg once daily for 4 weeks. A total of 52 patients, who had no endoscopic evidence of erosive esophagitis following vonoprazan treatment, received maintenance therapy with vonoprazan 10 mg once daily for 24 weeks. Symptoms were evaluated using the FSSG and Gastrointestinal Symptom Rating Scale (GSRS). Upper gastrointestinal endoscopies were performed following 24 weeks of maintenance therapy. The primary endpoint was to determine the proportion of patients who exhibited maintenance of healed RE refractory to PPIs following 24 weeks of maintenance therapy with vonoprazan 10 mg once daily. Secondary endpoints included evaluation of the proportion of patients with symptomatic non-relapse at 24 weeks. Maintenance therapy with vonoprazan 10 mg once daily prevented relapse of esophageal mucosal breaks in 37/43 (86.0%) patients at 24 weeks. However, the number of patients with symptomatic relapse was 1 (1.9%) and 4 (7.7%) at 4 and 8 weeks, respectively. A total of 4 patients were withdrawn due to loss to follow-up. At the end of the 24-week maintenance period, the symptomatic non-relapse rate for acid reflux-associated and dysmotility symptom FSSG scores were 86.5 and 80.8%, respectively. Furthermore, the symptomatic non-relapse rate for reflux, abdominal pain, indigestion, diarrhea, and constipation GSRS scores at 24 weeks were 86.5, 80.8, 75.0, 71.2 and 76.9%, respectively. No serious adverse events were reported during the study. The mean gastrin level was 1,059 pg/ml. In conclusion, the results of the present study indicate that vonoprazan 10 mg once daily is effective for 24-week maintenance therapy of healed RE refractory to PPIs. PMID- 29435274 TI - Topical 5% potassium permanganate solution accelerates the healing process in chronic diabetic foot ulcers. AB - Potassium permanganate has been reported to be an effective treatment for certain types of wounds. The aim of the present study was to evaluate the use of potassium permanganate in the treatment of diabetic foot ulcers. A single-blind, randomized, controlled clinical trial was conducted on patients with type 2 diabetes mellitus that presented with a foot ulcer persisting for >3 months. The control group (n=10) was treated with the current standard treatment, which comprises of measures for reducing pressure in the ulcerated area, daily cleansing of the ulcer with potable water and antiseptic wash solution, and the application of a disinfectant solution on the entire surface area of the ulcer; while the intervention group (n=15) received the standard treatment plus 5% topical potassium permanganate solution applied once a day for 21 days. In the intervention group, 1 patient did not tolerate the treatment and was eliminated from the study on the first day. The remaining patients tolerated the interventions well. At the end of the treatment period, ulcers in the control group had decreased by 38% whereas those in the intervention group decreased by 73% (P<0.009). The degree of decrease was also investigated; the ulcer size was >=50% decreased in 40% of patients in the control group and in 86% of patients in the intervention group (P=0.02). In conclusion, the results of the present study indicate that topical potassium permanganate is well tolerated and significantly accelerates the healing process of diabetic foot ulcers. PMID- 29435275 TI - Safe use of chemicals by professional users and health care specialists. AB - The awareness of Greek professional users and health care specialists regarding the safe use of chemicals was investigated, to be the best of our knowledge, for the first time after the introduction of Regulations (EC) 1907/2006 (REACH) and 1272/2008 (CLP) on chemicals. A total of 200 professional users and 150 health care specialists from various regions of Greece contributed to the use of a closed-ended, anonymous and validated questionnaire. The findings showed that over 85% of the responders were not aware of classification, labelling and packaging (CLP) and 67.8% of the responders were unaware of any changes made in the labeling of the products they were using. The majority (>75%) of individuals were cognizant that they were using hazardous products; however, the perception of hazard varied significantly between the two groups (P=0.012) and statistically were dependent on the educational (P=0.022) and the profession (P=0.014) level. One third of the professional users read the label as the main source of information for the product, while for health care specialists the number increased to 65% and a strong correlation was detected with the educational level (P=0.017). In both groups, 7% of professional users and health care specialists declared that hazard communication through product labeling is not well understood. The use of personal protective equipment (PPE) is almost universal for health care specialists with women being more sensitive (P=0.041), while 25% of the professional users do not use any PPE. Almost 60% of the health care specialists are required to provide instructions regarding the safe use of chemicals or the action to be undertaken in case of accident. In the latter situation, the National Poisoning Centre is the reference point for information. Limited use of the safety data sheets has been observed both for professional users (18%) and health care specialists (23%). In conclusion, rising awareness campaigns are needed, in collaboration with trade unions and health care professional associations, in order to alert professionals regarding the safe use of chemicals and protect human health and the environment. PMID- 29435276 TI - Serum osteopontin is a predictor of prognosis for HBV-associated acute-on-chronic liver failure. AB - Acute-on-chronic liver failure (ACLF) is a syndrome with a high rate of short term mortality, and clinically it is important to identify patients at high risk of mortality. The present study evaluated the value of osteopontin (OPN) in the prediction of 90-day mortality in patients with ACLF. A total of 54 patients with HBV-associated ACLF were enrolled, and serum OPN levels were determined in a prospective, observational study design. Survival analysis was performed using Kaplan-Meier curves, and multivariate Cox proportional hazards regression was used to analyze independent risk factors of mortality. Serum OPN was significantly higher in HBV-ACLF patients compared with patients with chronic hepatitis B and healthy controls (both P<0.01), and furthermore, was higher in those patients who succumbed to HBV-ACLF compared with surviving patients (P<0.05). OPN level positively correlated with total bilirubin (r=0.554, P<0.001), Model for End-Stage Liver Disease (MELD) score (r=0.234, P=0.038), MELD Na score (r=0.379, P=0.005) and monocyte count (r=0.282, P=0.039), and OPN was an independent risk factor for 90-day mortality in ACLF (P=0.021, odds ratio=1.104, 95% confidence interval: 1.003-1.116). Furthermore, ACLF patients were stratified into three groups according to serum OPN levels (low mortality risk: <6,135 ng/ml; intermediate risk: 6,135-9,043 ng/ml; and high risk: >9,043 ng/ml), for which the 90-day mortality rates were 27.78 (5/18), 52.94 (9/17) and 73.68% (14/19), respectively, and those in the high risk had a poorer prognosis compared with the low risk group (P=0.009). In conclusion, serum OPN may be an independent risk factor associated with HBV-ACLF prognosis. PMID- 29435277 TI - Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms and susceptibility to recurrent pregnancy loss. AB - Several studies have investigated the link between two different polymorphisms (C677T and A1298T) of the gene encoding methylenetetrahydrofolate reductase (MTHFR) and the risk of recurrent pregnancy loss (RPL); however, the results remain controversial. This study aimed to provide greater insight into this debated topic. In the current study, two groups of pregnant women (group A: RPL women; group B: non-RPL women), each of which were subdivided further into two subgroups based on their gestational age, were screened for C677T and A1298T variants of the MTHFR gene. The resulting data were analyzed using receiver operating characteristic (ROC) curve and Z test methods to compare the two groups. These ROC curve and Z test analyses indicated that there were no differences between the groups regarding C677T and A1298T expression. RPL is primarily caused by mutations in prothrombin or factor V Leiden genes. However, a low percentage of RPL cannot be attributed to these mutations. In the last five years, research has focused on the MTHFR gene, the two major variants of which (C677T and A1298T) have been associated with an increased risk of cardiovascular diseases (thrombotic events) in homozygous individuals. In addition, these mutations may be related to an increased rate of neural tube defects in fetuses. While a link between MTHFR mutation and RPL may be expected based on previous findings, the present study indicated the absence of an association between the polymorphisms of the MTHFR gene and RPL risk. PMID- 29435278 TI - Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents. AB - Nefopam, an analgesic drug, effectively elicits antinociception in the majority of noxious and thermal models in rodents. Acetaminophen is among the most commonly used analgesic and antipyretic drugs worldwide, either on prescription or over the counter. The present study aimed to investigate the analgesic activity of nefopam combined with acetaminophen, which was expected to maximize the potency of analgesia and decrease the dose of nefopam required. Three series of experiments, namely acetic acid-induced writhing tests in mice, hot plate tests in mice and tail flick tests in rats, were used to evaluate the analgesic effect. Initially, an optimum proportion of the two drugs, 3.5 mg/kg nefopam (N) + 60 mg/kg acetaminophen (A), was determined by orthogonal array design based on writhing response number. Subsequently, combinations of N and A (1.75 N + 30 A, 3.5 N + 60 A and 7.0 N + 120 A mg/kg) were determined to elicit antinociception in the writhing test (P<0.01 vs. normal saline control) in a dose-dependent manner. In the hot plate test, hot plate latencies up to 60 min after drug treatment were observed. The combination of 7.0 N + 120 A mg/kg exerted a greater cumulative antinociceptive effect throughout the observation period, with an area under the curve value of 1,156.95+/-199.30 area units (AU), compared with that achieved by 7.0 N mg/kg alone (632.12+/-62.38 AU). Furthermore, both monotherapy and compound therapy exhibited antinociception dose-dependently in the tail-flick test. However, a combination of 5.0 N + 84 A mg/kg exerted greater analgesic effect compared with 5.0 N mg/kg alone. The data obtained demonstrate that acetaminophen may enhance the antinociceptive activity of nefopam. Thus, coadministration of nefopam with acetaminophen warrants clinical evaluation. PMID- 29435279 TI - Long non-coding RNA PAX8-AS1 polymorphisms increase the risk of childhood acute lymphoblastic leukemia. AB - The present case-control study was conducted on 110 children with acute lymphoblastic leukemia (ALL) and 120 healthy children to determine the impact of polymorphisms in paired-box gene 8 (PAX8) antisense RNA 1 (PAX8-AS1), namely rs4848320 C>T, rs6726151 T>G and rs1110839 G>T, on ALL risk. Genotyping was performed through the polymerase chain reaction-restriction fragment length polymorphism method. The findings indicated that the rs4848320 variant increased the risk of ALL in codominant [CT vs. CC: odds ratio (OR)=2.13, 95% confidence interval (CI)=1.16-3.90, P=0.014; and TT vs. CC: OR=2.21, 95% CI=1.03-4.74, P=0.041], dominant (CT+TT vs. CC: OR=2.15, 95% CI=1.22-3.81, P=0.009,) and allele (T vs. C: OR=1.55, 95% CI=1.07-2.25, P=0.024) inheritance models. The rs6726151 variant significantly increased the risk of ALL in codominant (GT vs. GG: OR=1.88, 95% CI=1.08-3.27, P=0.036) and overdominant (GT vs. GG+TT: OR=2.08, 95% CI=1.23-3.53, P=0.008) inheritance models. No significant relationship was identified between the rs1110839 G>T variant and disease risk/protection in childhood ALL. In conclusion, the findings of the present study indicated that rs4848320 and rs6726151 polymorphisms of PAX8-AS1 may be a risk factor for the development of childhood ALL. Further studies with larger sample sizes and different ethnicities are now required to confirm these findings. PMID- 29435280 TI - Analysis of the clinical characteristics of hemorrhagic moyamoya disease in the Jilin province of northeastern China: A single-center study of 212 cases. AB - The present study aimed to investigate the clinical characteristics of hemorrhagic moyamoya disease (MMD) in Jilin province in northeast China. A total of 212 cases of hemorrhagic MMD were consecutively enrolled from the First Hospital of Jilin University in Changchun, China between January 2011 and January 2015. The patients' general clinical data, including age and gender characteristics, history of previous illnesses, hemorrhage type and onset symptoms, Hunt-Hess classification at admission, imaging characteristics, association with aneurysms, treatments and prognosis, were recorded and analyzed using SPSS 19.0. The results demonstrated that i) patients with hemorrhagic MMD in Jilin province were 47.7+/-11.5 years of age; ii) hemorrhagic MMD was primarily characterized by subarachnoid hemorrhage; iii) a total of 51.9% of the hemorrhagic MMD cases involved a unilateral artery; iv) a total of 24.1% of the hemorrhagic MMD cases were accompanied by anterior choroid artery and/or posterior communicating artery expansion; and v) following conservative or surgical treatment, patients with a prognostic Glasgow Outcome Scale score of 5 accounted for 65.6% of the study population. Therefore, the present study identified characteristics of MMD in Jilin province in northeast China. These results may improve understanding of the epidemiology of MMD in China, which at present remains not well established. Although the results are representative only of Jilin province in China, the study demonstrated high consistency with other studies, and thus may indirectly contribute to general understanding of hemorrhagic MMD etiology. PMID- 29435281 TI - Effect of anthocyanin-rich bilberry extract on bone metabolism in ovariectomized rats. AB - Menopause is associated with increased oxidative stress, which serves a role, in part, in the pathogenesis of postmenopausal bone loss. Fruits and vegetables are rich in antioxidative nutrients and phytochemicals. Berries are a natural source of anthocyanins, and their intake may improve bone health. The aim of the present study was to determine the effect of an anthocyanin-rich bilberry extract (VME) on bone metabolism in an ovariectomized (Ovx) rat. Female Sprague-Dawley rats (12 weeks old) were randomly divided into the following four groups: Baseline, Sham, Ovx and Ovx+VME (n=8-12 rats per group). Rats in the Baseline group were sacrificed immediately, while those in the other groups were subjected to either sham operation (Sham) or bilateral Ovx (Ovx and Ovx+VME). Rats in the Ovx+VME group were administered VME daily at a dose of 500 mg/kg body weight. At 8 weeks after surgery, bone mass and bone histomorphometry were evaluated. The femur bone mineral density (BMD) in the Ovx group was significantly lower than that in the Sham group (P<0.01). Supplementation of VME in the Ovx rats did not result in an increase in BMD. Histomorphometric analyses revealed that Ovx resulted in decreased measures of bone volume and trabecular number and increased measures of osteoid volume, mineralizing surface and bone formation rates (all P<0.01), whereas VME had no significant effects on these parameters. The present findings indicate that VME did not alter bone metabolism in Ovx rats, suggesting that consumption of VME may not be helpful in preventing postmenopausal bone loss. PMID- 29435283 TI - Targeted immunotherapy of high-grade cervical intra-epithelial neoplasia: Expectations from clinical trials. AB - Targeted immunotherapy of high-grade cervical intra-epithelial neoplasia (CIN) has been developed as an alternative to conization, to preserve future reproductive outcomes and avoid human papillomavirus (HPV) persistence. The objectives of the review are to present drugs according to their process of development and to examine their potential future use. A search for key words associated with CIN and targeted immunotherapy was carried out in the Cochrane library, Pubmed, Embase, and ClinicalTrials.gov from 1990 to 2016. Publications (randomized, prospective and retrospective studies) in any language were eligible for inclusion, as well as ongoing trials registered on the ClinicalTrials.gov website. Targeted immunotherapy includes peptide/protein-based vaccines, nucleic acid-based vaccines (DNA), and live vector-based vaccines (bacterial or viral). A total of 18 vaccines were identified for treatment of CIN at various stages of development, and the majority were well-tolerated. Adverse effects were primarily injection site reactions and flu-like symptoms under grade 2. The efficacy of vaccines defined by regression of CIN2/3 to no CIN or CIN1 ranged from 17 to 59% following a minimum of a 12-week follow-up. In the majority of studies, there was no association demonstrated between histological response and HPV clearance, or between histological or virological response and immune T cell response. Given that the spontaneous regression of CIN2/3 is 20-25% at 6 months, targeted immunotherapy occurs an additional value, which never reaches 50%, with one trial an exception to this. However, research and development on HPV eradication drugs needs to be encouraged, due to HPV-associated disease burden. PMID- 29435282 TI - Circadian clock and oral cancer. AB - The circadian clock is comprised of a master component situated in the hypothalamic suprachiasmatic nucleus and subordinate clock genes in almost every cell of the body. The circadian clock genes and their encoded proteins govern the organism to follow the natural signals of time, and adapt to external changes in the environment. The majority of physiological processes in mammals exhibit variable circadian rhythms, which are generated and coordinated by an oscillation in the expression of the clock genes. A number of studies have reported that alteration in the expression level of clock genes is correlated with several pathological conditions, including cancer. However, little is known about the role of clock genes in homeostasis of the oral epithelium and their disturbances in oral carcinogenesis. The present review summarizes the current state of knowledge of the implications of clock genes in oral cancer. It has been demonstrated that the development of oral squamous cell carcinoma undergoes circadian oscillation in relation to tumor volume and proliferation rate. The circadian clock gene period (PER)1 has been associated with oral cancer pathogenesis and it is suggested that changes in the expression of PER1 may exhibit an important role in the development, invasion, and metastasis of oral squamous cell carcinoma. However, its role remains elusive and there is a need for further research in order to understand the underlying mechanisms of the clock genes in oral cancer pathogenesis. PMID- 29435285 TI - Significance of lung biopsy for the definitive diagnosis of lung nodules in breast cancer patients. AB - The aim of the present study was to evaluate the significance of lung biopsy for the modification of the treatment strategy in breast cancer patients who develop lung nodules during follow-up after breast surgery. Of 53 consecutive patients who underwent lung biopsies in two institutions (Hiroshima University Hospital and Hiroshima Prefectural Hospital, Hiroshima, Japan) between 1997 and 2014, 45 underwent lung surgery and 8 underwent percutaneous or transbronchial tumor biopsy for lung nodules developing after curative surgery for breast cancer. The indications for lung biopsy included lung nodules for which a definitive diagnosis was difficult to achieve, and those for which the treatment strategy depended on the pathological diagnosis. The lung nodules were pathologically diagnosed as primary breast cancer metastases to the lungs in 25 (47%), primary malignant lung tumors in 21 (40%) and benign disease in 7 (13%) patients. Among the 25 metastatic patients confirmed by lung biopsy, phenotype discordance was observed in 6 patients (24%). A total of 3 patients with lung metastasis proven to have estrogen or progesterone receptor upregulation by lung biopsy received endocrine therapy. Univariate analysis revealed that patients with metastatic breast cancer confirmed by lung biopsy were significantly younger and had more locally advanced primary cancers diagnosed via clinical and pathological assessment compared with patients with other diseases. Therefore, mastectomy and axillary lymph node dissection were performed more frequently in the metastasis group compared with the others group. Multivariate analysis revealed that mastectomy (P<0.001) and axillary dissection (P<0.001) were independent factors predicting that the lung nodules would be metastases from breast cancer. Lung biopsy in breast cancer patients who developed lung nodules during the follow-up period after breast cancer surgery was crucial for making a definitive diagnosis and modifying the treatment strategy, which may improve the prognosis of breast cancer patients. PMID- 29435284 TI - 18F-fluoro-2-deoxyglucose positron emission-computed tomography in a rare cutaneous form of Rosai-Dorfman disease: A case report. AB - Rosai-Dorfman disease (RDD), or sinus histiocytosis with massive lymphadenopathy, commonly involves the lymph nodes but may secondarily involve the skin. Purely cutaneous disease without lymphatics or internal organ involvement occurs rarely. The present report detailed a rare case of 18F-fluoro-2-deoxyglucose positron emission-computed tomography (18FDG PET-CT) performed in a 33-year-old male soldier with a purely cutaneous form of RDD. Staging with 18FDG PET-CT was ordered prior to excisional biopsies of the aforedescribed masses and pathology reported RDD. The case demonstrated accurate localization of increased radioglucose metabolism. The present case was also discussed in light of literature data in terms of clinical features, etiologies, histology, medical imaging, therapy planning and prognosis. PMID- 29435286 TI - Prognostic nutritional index as a predictor of survival in patients with recurrent cervical cancer. AB - Systemic inflammatory responses (SIRs) can help predict survival in various cancers. The present study investigated the accuracy of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and prognostic nutritional index (PNI) in predicting survival for patients with recurrent cervical cancer. A retrospective review of prognoses examined the associations among NLR, PLR, and PNI, and clinical characteristics and survival in 79 patients with recurrent cervical cancer after undergoing concurrent chemoradiation therapy (CCRT) or radical hysterectomies with or without CCRT. The Mann-Whitney U-test was used for statistical analyses. In addition, 12-month, 24-month and overall survival were analyzed by the Kaplan-Meier method. Cox's proportional hazard regression was used for univariate and multivariate analyses. Median survival was 15.0 months over follow-up periods of 2-93 months. At the last follow-up point, 54 had succumbed to disease and 25 were alive with disease. In univariate analysis, NLR, PLR and PNI were significantly associated with 12-month, 24 month and overall survival (12 months: P=0.021, P=0.001 and P<0.001; 24 months: P=0.020, P=0.008 and P<0.001; overall; P=0.032, P=0.032 and P<0.001, respectively). In multivariate analyses, PNI was an independent prognostic factor for 12-month, 24 month and overall survival (P=0.001, P=0.001 and P<0.001, respectively). PNI is a useful predictor of survival of recurrent cervical cancer. PMID- 29435288 TI - A post-recurrence survival-predicting indicator for cervical cancer from the analysis of 165 patients who developed recurrence. AB - The aim of the present study was to estimate the post-recurrence survival (PRS) of patients with relapsed uterine cervical cancer (RUCC). In addition, clinicopathological indicators that influenced PRS were investigated. Between 1998 and 2014, of 740 patients with cervical cancer, 165 patients experienced recurrence (recurrence rate, 22.3%), and 83 patients succumbed to the disease within a median follow-up of 34.3 months. A total of 151 stage Ib-IV patients who experienced recurrence after initial treatment for cervical cancer at our institute were analyzed. Uni- and multivariate analyses were performed using the Kaplan Meier method, and Cox regression model. The median age was 55 years (range, 20-88 years). In all, 80 patients succumbed to the disease. The median PRS time of all the patients was 28.4 months. The 1-, 3-, and 5-year PRS rates of patients were 75.1, 41.9, and 32.1%, respectively. In addition, the median survival period in patients who had received surgery as an initial treatment was significantly longer compared with that in patients who had not previously undergone surgery (36.7 vs. 23.3 months, respectively; P=0.0338). Following the univariate analysis, the median PRS in patients with in- and out-field recurrence was 12.6, and 45.9 months, respectively (P<0.0001). Furthermore, in the multivariable analysis, the recurrence site was a significant prognostic indicator of PRS [(In-field vs. Out-field); hazard ratio, 2.848; 95% confidence interval, 1.707-4.738; P<0.0001]. The long-term clinical outcome of patients with RUCC was poor. In particular, the in-field recurrence was identified to be associated with poor post-recurrence oncological outcome in patients with RUCC. PMID- 29435287 TI - Secondary tumours of the ampulla of Vater: Case report and review of the literature. AB - Secondary tumours of the ampulla of Vater are rare. Underlying primary tumours, clinical presentation, macroscopic appearance, treatment strategies and outcome of secondary ampullary lesions have not been systematically analysed. The present case study reported a 57-year old patient with an ampullary metastasis from renal cancer and a literature review was performed in which a further 32 patients were included. The most common responsible primary tumours were malignant melanoma and renal clear cell carcinoma, followed by breast cancer. The time interval between the diagnosis of the primary tumour and the ampullary metastasis was highly variable, and may be as long as 10 years, particularly for renal cancer. Patients may present with unspecific abdominal discomfort, jaundice or upper gastrointestinal bleeding. The gross appearance was largely indistinguishable from that of a primary tumour. Lesions may present as polypoid or irregular, soft and friable tumour mass, in certain cases with superficial ulceration. In ~50% of cases, the ampullary metastasis was the only metastatic lesion, while in the remaining cases, the cancer had spread to one or more organs. The prognosis was generally poor. The management requires a multi-modal approach, including endoscopic, surgical and oncological procedure. PMID- 29435289 TI - Outcomes of abdominal esophageal cancer patients who were treated with esophagectomy. AB - The aim of the present study was to elucidate the characteristics and outcomes of abdominal esophageal cancer patients who were treated with esophagectomy. The records of 210 esophagectomy patients were retrospectively reviewed and the differences in postoperative outcomes and disease-specific survival between squamous cell carcinoma and adenocarcinoma were evaluated. Of the 20 abdominal esophageal cancer patients, 11 had squamous cell carcinoma, 8 had adenocarcinoma and 1 had adenosquamous cell carcinoma. The body mass index and serum albumin levels were significantly lower in the squamous cell carcinoma patients compared with those in the adenocarcinoma patients, and abdominal lymph node metastasis was significantly more frequent in the adenocarcinoma patients. Early recurrence occurred in 5 patients who had postoperative surgical site infection, microscopic residual cancer, and mediastinal lymph node metastasis. A Kaplan-Meier curve indicated a significantly shorter survival time in patients who underwent surgery with a thoraco-abdominal approach, who had postoperative complications, and who had microscopic residual cancer. This study demonstrated the significance of R0 resection and prevention of postoperative complications in improving the prognosis of patients with abdominal esophageal cancer. PMID- 29435290 TI - Palmar fasciitis with polyarthritis-associated ovarian cancer: Case report and literature review. AB - Palmar fasciitis and polyarthritis (PFPA) is an uncommon disorder clinically characterized by rapidly developing bilateral arthritis of the hands and fasciitis of the palms. This cancer-associated syndrome, primarily linked to ovarian cancer, has also been associated with multiple different malignancies. PFPA symptoms usually precede the detection of ovarian cancer. In all patients from case series and single case reports described, ovarian cancer is already present at an advanced stage. Therefore, the authors aimed to present a case and systematically review available evidence on the association between PFPA and ovarian cancer, as gynecological oncologists. Awareness and recognition of PFPA may allow for earlier diagnosis and treatment of an occult ovarian cancer. The commitment of the attending gynecologists to become familiar with and identify rare diseases may lead to the detection at an early and curative stage and potentially life-saving therapeutic interventions. PMID- 29435291 TI - Efficacy and safety of DoceAqualip in a patient with locally advanced cervical cancer: A case report. AB - The standard of care for locally advanced cervical cancer has been the combination of a taxane with platinum based therapy. Conventional docetaxel is known to cause hypersensitivity reactions, fluid retention and other toxicities due to polysorbate-80 and ethanol. Corticosteroid premedication prior to docetaxel administration is required to prevent these toxicities, however, toxicities are still observed, sometimes fatal, despite premedication. DoceAqualip, a nanosomal docetaxel lipid suspension, developed with lipids generally regarded as safe (GRAS) by the US Food and Drug Administration, is devoid of polysorbate-80 and ethanol. DoceAqualip has been demonstrated to be effective and well-tolerated in various cancer types. The authors' report a case of a patient with Stage IIIB cervical cancer who was treated with carboplatin and DoceAqualip (concurrent ChemoRT) and achieved complete response without any serious adverse events. PMID- 29435292 TI - A novel three-way Philadelphia Variant t(9;22;17)(q34;q11.2;q12) in chronic myeloid leukemia: A case report. AB - Chronic myeloid leukemia (CML) is a hematologic malignancy associated with increased circulating myeloid cells and platelets in the peripheral blood, with accompanying bone marrow hyperplasia. The Philadelphia chromosome, t(9;22)(q34;q11), is present in 95% of CML patients, resulting in constitutive tyrosine kinase activity; however, ~5% of CML patients possess a Philadelphia variant. A novel three-way Philadelphia translocation variant, t(9;22;17)(q34;q11.2;q11.2), was identified in a 54-year old man who presented with leukocytosis, anemia and thrombocytosis that was diagnosed with chronic myeloid leukemia, chronic phase. Cytogenetic analysis by G-banding revealed the presence of a three-way translocation involving the long arms of chromosomes 9, 22 and 17. Fluorescence is situ hybridization utilizing a dual-color fusion probe confirmed the presence of the Bcr-Abl fusion gene. PMID- 29435293 TI - A case of peritoneal malignant mesothelioma following radiation therapy for cervical cancer. AB - The present study presents a case of peritoneal malignant mesothelioma (PMM) following radiation therapy for cervical cancer. A 34-year-old Japanese woman, without asbestos exposure, was referred to the Department of Gynecologic Oncology, Saitama Medical University International Medical Center due to a cervical mass, and was diagnosed with cervical squamous cell carcinoma (SCC). The serum levels of tumor markers, including SCC antigen and cancer antigen 125 (CA125) were 229.0 ng/ml and 54.4 U/ml, respectively. The patient underwent concurrent chemoradiotherapy (CCRT), and a complete response was achieved. After 54 months, ascites was found at the rectouterine pouch, but peritoneal cytology suggested reactive mesothelial cell. After 62 months of CCRT, magnetic resonance imaging revealed masses in both the salpinges. The serum levels of SCC and CA125 were 0.9 ng/ml and 506.1 U/ml, respectively. Following this, left salpingectomy and peritoneal biopsy were performed laparoscopically. Histologic examination revealed atypical mesothelial cells with no continuity of background tubal epithelium. Immunohistochemistry showed positive staining for calretinin, thrombomodulin, mesothelin and glucose transporter 1. Based on these findings, the patient was diagnosed with PMM epithelioid type and underwent systemic chemotherapy; stable disease status has been obtained for 3 months. This case demonstrates the possibility of PMM occurrence within 10 years after radiotherapy, and indicates the importance of histological and immunohistochemical examination, particularly in cases of an atypical tumorigenesis pattern from the primary cancer. PMID- 29435294 TI - Therapy-associated myelodysplastic syndrome with monosomy 7 arising in a Muir Torre Syndrome patient carrying SETBP1 mutation. AB - Muir-Torre Syndrome (MTS) is a rare hereditary autosomal dominant cancer syndrome and is linked to hereditary non-polyposis colorectal carcinoma (Lynch Syndrome). Individuals develop various skin neoplasms in addition to colorectal, endometrial and upper gastrointestinal malignancies. Therapy-associated myelodysplastic syndrome (T-MDS) is an aggressive hematologic malignancy and is considered a pre leukemic phase. T-MDS is associated with prior exposure to chemo- and radiotherapy that potentially results in DNA damage. The current case report presents a 74-year-old male MTS patient with prior history of solid tumors and radiation therapy with new onset cytopenia. A subsequent bone marrow biopsy revealed multilineage dysplasia with a high blast count and a diagnosis of high grade T-MDS was rendered. FISH and G-banded karyotype analyses revealed 5q deletion and monosomy 7. This is a unique case of T-MDS arising in the setting of MTS. Secondary malignancies including MDS and acute leukemia may occur in cancer survivors and are often associated with an unfavorable prognosis. This case demonstrates the need to be aware of the risk of secondary hematologic malignancies in cancer patients and a thorough clinical and lab work-up are warranted in patients with persistent or transfusion requiring cytopenia(s). PMID- 29435295 TI - Identification of candidate responders for anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitory therapy in small-cell lung cancer. AB - A useful candidate for small-cell lung cancer (SCLC) therapy is immune checkpoint blockade therapy targeting programmed death-1 (PD-1) and its ligand, PD-L1. Furthermore, rovalpituzumab tesirine (Rova-T), a delta-like protein 3 (DLL3) targeted antibody-drug conjugate, and enhancer of zeste homologue 2 (EZH2) inhibitor are expected to be the first targeted therapy for SCLC. The aim of the present study was to evaluate PD-L1, DLL3 and EZH2 expression in SCLCs to find a candidate responder to those therapies. Immunohistochemical (IHC) staining for PD L1, DLL3 and EZH2 was performed in 20 patients with SCLC and the clinicopathological characteristics and IHC staining intensity were compared. It was demonstrated that 1/20 patients (5.0%) exhibited positive PD-L1 expression in the metastatic lesions, as well as in the primary lung tumor. DLL3 was highly expressed in 14/20 patients (70%) and EZH2 was positive in 17/20 patients (85%). None of these cases exhibited any correlation with age, sex, smoking, stage or treatment, whereas IHC staining was able to identify candidate responders to anti PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitor therapy. PMID- 29435296 TI - Anaphylatoxin C3a: A potential biomarker for esophageal cancer diagnosis. AB - Esophageal carcinoma is a common malignancy worldwide, with a low 5-year survival rate. As the majority of cases are diagnosed at an advanced stage, there is an urgent need for an effective biomarker for early diagnosis of esophageal cancer patients. Surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was applied to detect the serum protein expression in esophageal cancer patients using ProteinChip software, and the results were analyzed and screened using Biomarker Patterns and SPSS16.0 software. The ELISA method was conducted to determine the concentration of anaphylatoxin C3a, which is one of the complement proteins, in the serum of esophageal cancer patients and non-esophageal cancer participants. A total of 144 effective differential expression protein peaks in the window of 1-10 kDa were obtained (P<0.05). M/Z 8,926.478 (P<10-6) protein peak was employed as the diagnostic biomarker for esophageal carcinoma. This established diagnostic biomarker has a sensitivity of 95% (19/20) and an accuracy of 100% (19/19) for positive prediction. The results suggested that anaphylatoxin C3a may be a promising biomarker in the diagnosis of esophageal carcinoma, and may play a key role in promoting esophageal carcinogenesis. PMID- 29435297 TI - A low psoas muscle volume predicts longer hospitalization and cancer recurrence in upper urinary tract urothelial carcinoma. AB - The aging population is becoming a primary global problem. The most important alteration that occurs in the body with age, is the loss of skeletal muscle. Previously, sarcopenia, which is associated with the loss of skeletal muscle, has been reported to be associated with the prognosis of cancer and complications. The present study investigated the importance of sarcopenia with regard to the prognosis or postoperative complications of upper urothelial cancer patients who underwent nephro-ureterectomy. A total of sixty patients (male, n=44; female, n=16) underwent nephro-ureterectomy for upper urothelial carcinoma. The psoas muscle volume was calculated at the level of the umbilicus using axial computed tomography images obtained prior to nephro-ureterectomy. The psoas muscle index (PMI) was calculated by the following formula: (right side psoas muscle area at the level of the umbilicus mm2)/(body height m)2. The median and mean (+/- standard deviation) ages of the 44 patients were 71 and 68.0 years (+/- 12.2 years). The lower PMI group demonstrated a significantly poorer recurrence-free survival compared with the higher PMI group (634 vs. 2,317 days, P=0.005). In terms of the duration of postoperative admission, the long-admission group (>=13 days) demonstrated a significantly lower PMI compared with the short-admission group (<=12 days) (383.0 vs. 433.1, P=0.039). Although the overall survival of the two groups did not differ significantly, the lower PMI group tended to have a shorter survival period compared with the higher PMI group (P=0.080). Of the patients with upper urothelial carcinoma, the lower PMI group exhibited a longer postoperative admission period and poorer recurrence-free survival compared with the higher PMI group. The present findings suggest that sarcopenia is a meaningful factor that should be considered when selecting therapy for upper urothelial carcinoma. PMID- 29435298 TI - Generation of highly differentiated BHY oral squamous cell carcinoma multicellular spheroids. AB - Three-dimensional (3D) multicellular spheroids (MCS) are considered suitable models in cancer research and anticancer drug development. Although studying the complex tumour characteristics from all different degrees of malignancy is vital, MCS generation has only been described in a few moderately- and poorly differentiated oral squamous cell carcinoma (OSCC) cell lines. No previous study has demonstrated the MCS formation in a highly differentiated OSCC cell line. For the first time, the present study aimed to generate MCS from the highly differentiated OSCC cell line BHY. BHY spheroids were grown in three independent experiments in 96-well plates through the use of the liquid overlay technique. Although BHY cells are grow slowly and are difficult to culture, they formed compact MCS within 24 h. After 3 days of incubation, no further increase in spheroid size was observed. MCS were harvested, paraffin-embedded and 2 um tissue sections were prepared for further analysis. The diameter and volume of each spheroid were determined. BHY MCS diameter ranged between 46.76 and 233.26 um, with a volume range from 5.35*104-6.65*106 um3. In conclusion, using the liquid overlay technique, the highly differentiated OSCC cell line BHY forms different sized spheroids, which may be used for further investigations. PMID- 29435299 TI - Multilocular cystic renal cell carcinoma: A case report and review of the literature. AB - Multilocular cystic renal cell carcinoma (MCRCC), which exhibits low-stage and low-grade characteristics, is a special type of RCC. MCRCC is extremely rare and generally develops at ages >50 years. We herein report a case of MCRCC in a 28 year-old man, which, to the best of our knowledge, is the youngest case reported worldwide to date. The patient presented with irritative bladder symptoms for 1 year. Dynamic enhanced computed tomography (CT) imaging revealed a mass with inhomogeneous enhancement in the left kidney, with a rich blood supply. B ultrasonography also revealed a renal protruding mass. As the mass was highly suspicious to be a malignant tumor, laparoscopic radical nephrectomy was performed and MCRCC was definitively diagnosed by pathological examination. The patient has been regularly followed up for 6 months, without complications or disease recurrence. PMID- 29435300 TI - Computed tomography-guided lung biopsy: Association between biopsy needle angle and pneumothorax development. AB - Computed tomography (CT)-guided lung biopsy is a well-established diagnostic method for pulmonary lesions. However, the use of this technique often results in pneumothorax development. The aim of the present study was to evaluate the association between biopsy needle angle and pneumothorax development associated with computed tomography-guided lung biopsy. We retrospectively analyzed the results of CT-guided lung biopsies for 325 cases to investigate physical risk factors for pneumothorax development. Biopsy needle angle and patient positioning were included in the analysis. Pneumothorax occurred in 160 of 325 procedures (49.2%). Discontinuation of the procedure as a result of pneumothorax occurred in 18 of 160 procedures (11.2%). Upper lung lobe pneumothorax occurred in 40.8% (58/142), middle lobe in 17.6% (25/142), and lower lobe pneumothorax occurred in 41.5% (59/142) of these procedures. Discontinuation of the procedure occurred in 2.5% of the upper lobe (4/160), 0.6% of the middle lobe (1/160), and 8.1% of the lower lobe (13/160) biopsies. Mild pneumothorax occurred in 59.4% (95/160), moderate in 25.0% (40/160), and severe in 7.5% (12/160) of the affected cases, and biopsy was discontinued in 11.2% (18/160) of the affected cases. When the needle angle was <90 degrees , 40.3% (131/325) of the patients experienced no pneumothorax development, 40.0% (130/325) developed pneumothorax, and 4.3% (14/325) of the procedures were discontinued. The results showed that use of CT guided lung biopsy can reduce the rate of pneumothorax development that occurs when other procedures are used. The access route is simple and easy to puncture, and proper use of breath holding reduces diaphragmatic movement. PMID- 29435301 TI - Traditional and cumulative meta-analysis: Chemoradiotherapy followed by surgery versus surgery alone for resectable esophageal carcinoma. AB - The role of neoadjuvant chemoradiotherapy followed by surgery (CRTS) compared with surgery alone (SA) for resectable esophageal carcinoma has been established by several randomized controlled trials (RCTs). The present study aimed to investigate the difference in survival between the two treatments by a review of meta-analyses. Related research indicators were extracted from RCTs investigating CRTS or SA for resectable esophageal carcinoma by searching electronic databases for eligible articles. Outcomes were synthesized by adopting a fixed- or random effects model with 95% confidence interval (CI). A total of 22 RCTs including 3,419 patients were selected. The odds ratio (OR) (95% CI, P-value), expressed as CRTS vs. SA, was 1.06 (0.94-1.19, P=0.348) for 1-year overall survival rate (OSR1y), 1.38 (1.20-1.58, P<0.001) for 3-year overall survival rate (OSR3y), and 1.42 (1.22-1.66, P<0.001) for 5-year overall survival rate (OSR5y). The R0 resection rate increased in patients treated by CRTS (OR=2.76, 95% CI: 2.15-3.53, P<0.001). CRTS lowered the locoregional cancer recurrence (OR=0.49, 95% CI: 0.36 6.65, P<0.001) and distant metastasis rate (OR=0.76, 95% CI: 0.60-0.97, P=0.02). However, the incidence of postoperative mortality was similar between the two groups (OR=0.97, 95% CI: 0.72-1.32, P=0.87). The subgroup analysis revealed that OSR3y and OSR5y for Asian, European and American populations were significantly higher in the CRTS group compared with those in the SA group (P<0.05). When comparing the OSR1y between the two groups for patients in all three continents, there was no significant difference (P>0.05). Histological subgroup analysis indicated that patients with esophageal adenocarcinoma may benefit from CRTS in terms of OSR1y (OR=1.55, 95% CI: 1.09-2.20, P=0.01), OSR3y (OR=1.77, 95% CI: 1.34 2.36, P<0.0001) and OSR5y (OR=1.92, 95% CI: 1.34-2.75, P=0.0004). The pooled OR of squamous cell carcinoma in terms of OSR3y and OSR5y between the two groups was 1.57 (95% CI: 1.21-2.04, P=0.0006) and 1.69 (95% CI: 1.32-2.16, P<0.0001), respectively, but there was no statistical difference in terms of OSR1y (OR=1.13, 95% CI: 0.88-1.45, P=0.35). Thus, neoadjuvant CRT followed by surgery may improve long-term survival and surgical parameters, and reduce locoregional cancer recurrence and distant metastasis. PMID- 29435302 TI - Retrospective analysis of surgery for cervical stump carcinoma at early stage. AB - Cervical stump cancer is a rare type of disease as total hysterectomies are performed infrequently. The purpose of this retrospective study was to assess the diagnosis, treatment, follow-up methods and complications of 10 patients with cervical stump carcinoma treated with surgery in Anhui Provincial Hospital affiliated to Anhui Medical University (Hefei, China). From January 2006 to October 2016 a total of 10 patients underwent surgery for carcinoma of the cervical stump. The pathological reports revealed 80% of cases were squamous cell carcinoma and 20% of cases were adenocarcinoma. The FIGO stage distribution was as follows: Carcinoma in situ (10%); IB1 (70%); IIA (20%). The patients received a transvaginal trachelectomy or a radical trachelectomy and pelvic lymphadenectomy (either laparoscopic or laparotomic abdominal); four of the patients were treated with adjuvant chemotherapy, and two with concurrent chemoradiotherapy. The parametrial and resection margin infiltration, lymph node metastasis and lymph vascular space invasion (LVSI) were negative in all patients, and the deep stromal invasion rate was 66.7% (6/9). No incidences of recurrence or mortality were recorded during the follow-up interval of 6-120 months. Compared with the four patients who received laparotomic abdominal surgery, significantly less blood loss was recorded for the five patients who underwent laparoscopic surgery (P<0.01). There was no significant difference observed in the surgery time (P>0.01) or in the hospital stay duration (P>0.01) for the patients treated with laparotomic abdominal surgery and laparoscopic surgery. One patient experienced bladder fistula due to bladder over-dilation, but recovered quickly after the catheter was reinserted. Surgery for cervical stump cancer at an early-stage is a viable and safer procedure, particularly the laparoscopic approach. PMID- 29435303 TI - Non-small-cell lung cancer pathological subtype-related gene selection and bioinformatics analysis based on gene expression profiles. AB - Lung cancer is one of the most common malignant diseases and a major threat to public health on a global scale. Non-small-cell lung cancer (NSCLC) has a higher degree of malignancy and a lower 5-year survival rate compared with that of small cell lung cancer. NSCLC may be mainly divided into two pathological subtypes, adenocarcinoma and squamous cell carcinoma. The aim of the present study was to identify disease genes based on the gene expression profile and the shortest path analysis of weighted functional protein association networks with the existing protein-protein interaction data from the Search Tool for the Retrieval of Interacting Genes. The gene expression profile (GSE10245) was downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database, including 40 lung adenocarcinoma and 18 lung squamous cell carcinoma tissues. A total of 8 disease genes were identified using Naive Bayesian Classifier based on the Maximum Relevance Minimum Redundancy feature selection method following preprocessing. An additional 21 candidate genes were selected using the shortest path analysis with Dijkstra's algorithm. The AURKA and SLC7A2 genes were selected three and two times in the shortest path analysis, respectively. All those genes participate in a number of important pathways, such as oocyte meiosis, cell cycle and cancer pathways with Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The present findings may provide novel insights into the pathogenesis of NSCLC and enable the development of novel therapeutic strategies. However, further investigation is required to confirm these findings. PMID- 29435305 TI - Clinical significance of the C-reactive protein-to-albumin ratio for the prognosis of patients with esophageal squamous cell carcinoma. AB - The aim of the present study was to investigate the prognostic value of the C reactive protein-to-albumin ratio (CAR) and compare it with other inflammation based prognostic scores (Glasgow prognostic score, modified Glasgow prognostic score, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, prognostic nutritional index and prognostic index) in patients with esophageal squamous cell cancer (ESCC). A database of 116 patients with primary ESCC who underwent treatment at the Division of Surgical Oncology at Nagasaki University Hospital between January 2007 and August 2014 was retrospectively reviewed and the correlations between CAR and overall survival (OS) were investigated. Kaplan Meier and Cox regression analyses were used to assess independent prognostic factors. The area under the curve (AUC) was used to compare the prognostic value of different scores. According to the receiver operator characteristics analysis, the recommended cut-off value for CAR was 0.042, with an AUC of 0.678 (sensitivity 31.1%, specificity 66.7%). Thus, patients were dichotomized into low (<0.042) and high (>=0.042) CAR groups. On multivariate analysis, CAR was found to be significantly associated with OS in patients with ESCC [hazard ratio (HR)=2.350; 95% confidence interval (CI): 1.189-4.650; P=0.014], as was tumor node-metastasis stage (HR=3.059; 95% CI: 1.422-6.582; P=0.004). In addition, CAR had a higher AUC value (0.678) compared with several other systemic inflammation based prognostic scores (P<0.001). This study suggested that CAR is a novel and promising inflammation-based prognostic score in patients with ESCC. Due to its simplicity, affordability and availability, CAR may be important for improving clinical decision-making and may contribute to more rational study design and analyses. PMID- 29435304 TI - Knockdown of microRNA-29a regulates the expression of apoptosis-related genes in MCF-7 breast carcinoma cells. AB - MicroRNA (miR), as non-coding small RNA, are key regulators of cancer-related biological cell processes and contribute to tumor growth through regulation of groups of pro- and anti-apoptotic genes. The present study aimed to investigate the effects of miR-29a on the expression of genes involved in apoptosis, including p21, B-cell lymphoma 2 (BCL-2), p53 and survivin. The MCF-7 breast cancer cell line was transfected with anti-miR-29a and treated with Taxol in subdivided treatment groups including: Scramble; anti-miR-29a; anti-miR-29a + Taxol; Taxol; and control. Expression levels of p21, BCL-2, p53 and survivin were evaluated using reverse transcription-quantitative polymerase chain reaction. miR 29a knockdown resulted in p21 and p53 upregulation and a decrease in survivin expression. These results indicated that miR-29a inhibition regulates apoptosis. The present data suggested that miR-29a inhibition may be a promising strategy for the induction of apoptosis of tumor cells. PMID- 29435306 TI - A strategy for the clinical remission of acute lymphoblastic leukemia elicited by treatment of beta-thalassemia major: A case report. AB - Acute lymphoblastic leukemia (ALL) has been suggested as a long-term complication in patients with beta-thalassemia major (beta-TM). A 12-months-old male patient was diagnosed with beta-TM. The patient required a blood transfusion weekly for 2 years. At the age of 4 years, a splenectomy was performed due to massive splenomegaly and frequent transfusion requirements. The histopathological analysis of the spleen revealed extensive hemosiderosis. ALL-L1 with the T immunophenotype and without central nervous system (CNS) involvement was diagnosed when the patient was 5 years old, and treated with anti-leukemic combination chemotherapy and CNS radiotherapy. The patient completed 24 months of treatment and has been in complete remission for 7 years, without long-term adverse events. PMID- 29435308 TI - Complementary and alternative treatment in functional dyspepsia. AB - Introduction and aim: The popularity of complementary and alternative medicine (CAM) in treating functional gastrointestinal disorders (FGIDs) has steadily increased in Western countries. We aimed at analyzing available data on CAM effectiveness in functional dyspepsia (FD) patients. Methods: A bibliographical search was performed in PubMed using the following keywords: "complementary/alternative medicine," "hypnosis," "acupuncture" and/or "functional dyspepsia." Results: In community settings, almost 50% of patients with FGIDs used CAM therapies. Herbal remedies consist of multi-component preparations, whose mechanisms of action have not been systematically clarified. Few studies analyzed the effectiveness of acupuncture in Western countries, yielding conflicting results and possibly reflecting a population bias of this treatment. Hypnosis has been extensively used in irritable bowel syndrome, but few data support its role in treating FD. Conclusions: Although some supporting well-designed studies have been recently performed, additional randomized, controlled trials are needed before stating any recommendation on CAM effectiveness in treating FD. PMID- 29435309 TI - Fecal immunochemical tests in combination with blood tests for colorectal cancer and advanced adenoma detection-systematic review. AB - Background: Colorectal cancer (CRC) is a common but largely preventable cancer. Although fecal immunochemical tests (FITs) detect the majority of CRCs, they miss some of the cancers and most advanced adenomas (AAs). The potential of blood tests in complementing FITs for the detection of CRC or AA has not yet been systematically investigated. Methods: We conducted a systematic review of performance of FIT combined with an additional blood test for CRC and AA detection versus FIT alone. PubMed and Web of Science were searched until June 9, 2017. Results: Some markers substantially increased sensitivity for CRC when combined with FIT, albeit typically at a major loss of specificity. For AA, no relevant increase in sensitivity could be achieved. Conclusion: Combining FIT and blood tests might be a promising approach to enhance sensitivity of CRC screening, but comprehensive evaluation of promising marker combinations in screening populations is needed. PMID- 29435310 TI - Risk of histologic Barrett's esophagus between African Americans and non-Hispanic whites: A meta-analysis. AB - Background: Barrett's esophagus (BE) is rare in African Americans (AA). However, the risk difference magnitude in histologic BE prevalence between AA and non Hispanic whites (nHw) has not been quantified to date. Objective: The objective of this article is to determine the degree of histologic BE risk difference between AA and nHw. Methods: PubMed, Web of Science and EMBASE were searched for studies reporting histologic BE in AA/nHw for inclusion. Pooled odds ratios (ORs) with risk estimates of histologic BE occurrence between AA/nHw were calculated along with 95% confidence intervals (CIs). Forest plots were used to quantify heterogeneity. Funnel plots and the Cochrane Collaboration Risk of Bias tool were used to assess bias risk. Results: Eight studies reported BE histologic confirmation in AA/nHw. Analysis demonstrated a nearly 400% increased histologic BE risk in nHw patients compared to AA (OR 3.949, 95% CI 3.069-5.082). In the model without the case-control study, histologic BE risk remained elevated at approximately 360% in nHw compared to AA (OR 3.618, 95% CI 2.769-4.726). Heterogeneity was not present in either model. Risk of bias was significant. Conclusions: Histologic BE risk is elevated in nHw by 3.6-4 times compared to AA. Investigation into understanding any clinical, molecular or genetic mechanisms underlying this risk disparity is warranted. PMID- 29435311 TI - Rising incidence and prevalence of adult eosinophilic esophagitis in midwestern Spain (2007-2016). AB - Objectives: Epidemiologic studies on eosinophilic esophagitis (EoE) are scarce and patient responders to proton pump inhibitor (PPI) therapy have usually been excluded. We aimed to evaluate population-based incidence rates, prevalence and trends in adult EoE over the past decade, including responders to PPI therapy. Methods: We conducted an analysis of a prospectively established case registry in the health area of Caceres, located in midwestern Spain. From the first EoE case diagnosed in 2007, endoscopy and pathology reports up to December 2016 were manually reviewed. A baseline diagnosis of EoE was confirmed upon symptoms of esophageal dysfunction (dysphagia/food impaction) and esophageal eosinophilia >= 15 eos/HPF. All patients were re-evaluated on PPI therapy during follow-up. Results: A total of 137 patients were diagnosed with EoE during the study period, of whom 63 (46%) achieved clinicohistologic remission on PPI therapy. The prevalence of autoimmune disorders was low. Mean incidence rate was 8.09 new cases/100,000 inhabitants/year, increasing to 9.95 during the last lustrum and peaking in 2016 with 13.7. This trend coincided with late declining of esophageal biopsies rate. Overall prevalence in 2016 was 81.73 patients/100,000 inhabitants, with the highest prevalence in males between age 35 and 44 years (273 cases/100,000). No seasonal variation was observed in the diagnosis of EoE (53% during pollen season vs. 47%, p = 0.4). Conclusions: In midwestern Spain, incidence (13.7 cases/100,000 inhabitants/year) and prevalence (81.73 patients/100,000 inhabitants) in 2016 have grown remarkably in just one decade, coming closer to those figures recently reported for Crohn's disease in Spain. PMID- 29435312 TI - Determinant factors of quality of life in adult patients with eosinophilic esophagitis. AB - Background: Eosinophilic esophagitis (EoE) affects health-related quality of life (HRQoL). Data on determinant factors and the influence of dietary interventions are scarce. Objective: The objective of this article is to evaluate factors influencing HRQoL in adult EoE patients. Methods: We conducted a multicenter observational, cross-sectional study. A validated Spanish version of the self administered Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) questionnaire and specific surveys were used. Multiple linear regression was used to identify and quantify determinant factors of HRQoL. Results: Responses provided by 170 patients were assessed (73.5% male; mean age 33.5 +/- 11.4 years). Overall mean score for the EoE-QoL-A index was 1.4 +/- 0.8, with no differences between patients on dietary or pharmacological therapy (1.82 +/- 0.8 vs. 1.62 +/- 0.8; p = 0.132). Disease anxiety showed the highest mean score (2.13 +/- 0.9 points), followed by choking anxiety (1.97 +/- 1.1); social impact (1.77 +/- 1.1), and diet/eating impact (1.68 +/- 0.9). Emotional impact had the lowest rating (1.15 +/- 0.9), and only with a significantly worse score in patients under dietary restrictions. Recurrent food impaction, a higher educational level, dietary interventions and symptom duration were all independent determinant factors significantly impairing HRQoL. Female gender and empiric elimination diets negatively influenced on diet/eating impact. Conclusion: Recurrent food impaction, dietary interventions and symptom duration are the most important factors influencing the perception of HRQoL in adults with EoE. PMID- 29435313 TI - Comparison of the efficacy of intravenous tranexamic acid with and without topical administration versus placebo in urgent endoscopy rate for acute gastrointestinal bleeding: A double-blind randomized controlled trial. AB - Background: Tranexamic acid (TXA), a synthetic antifibrinolytic drug, is effective as a treatment for serious hemorrhage, including bleeding arising from major trauma and post-operative interventions. Significant acute gastrointestinal bleeding may have a poor outcome despite routine medical and endoscopic treatments. The aim of this study was to assess whether early intravenous and/or intravenous plus topical administration of TXA reduces the need for urgent endoscopy for acute gastrointestinal bleeding. Method: This double-blind randomized clinical trial included 410 patients with proven acute gastrointestinal bleeding. All patients received conventional therapy. The subjects were randomized to three groups: (A) 138 patients received intravenous TXA (1 g q6h); (B) 133 patients received topical TXA (1 g single dose by nasogastric tube) plus systemic TXA; and (C) 139 patients received a placebo (sodium chloride 0.9%) for 24 hours. Subgroup statistical analyses were conducted for urgent endoscopy, mortality, re-bleeding, blood transfusion, endoscopic and/or surgical intervention rates, and health status. Results: The time to endoscopy was significantly shorter in group C (15.58 +/- 7.994, p < 0.001). A need for urgent endoscopy was seen in 14.49%, 10.52%, and 30.21% of patients in groups A, B, and C, respectively (p < 0.001). No significant statistical differences were seen between treatment groups regarding mortality, re-bleeding, blood transfusion, and endoscopic and/or surgical intervention rates. No thromboembolic event was documented during the 1-week follow up. Conclusions: Our results showed that the antifibrinolytic properties of TXA can aid in changing an urgent endoscopy to an elective procedure, with better outcomes for both physicians and patients. PMID- 29435314 TI - Mucosal healing and the risk of serious infections in patients with celiac disease. AB - Background: Patients with celiac disease (CD) are at increased risk of certain infections, but it is unknown if mucosal healing influences this risk. Methods: We collected data on 29,096 individuals with CD (equal to villous atrophy) through Sweden's 28 pathology departments undergoing biopsy 1969-2008. Through the Swedish Patient Register we obtained information on any infection and specifically sepsis, streptococcal infection, influenza, Clostridium difficile, herpes zoster and pneumococcal infection up until December 2009. We used Cox regression to calculate hazard ratios (HRs) for the risk of future diagnosis of infection according to mucosal healing on follow-up biopsy (persistent villous atrophy vs mucosal healing). Results: Of 5598 CD individuals with no record of any infections before follow-up biopsy, 45% had persistent villous atrophy, 619 (24%) of them had a later infection, compared to 579 (19%) in those with mucosal healing (p < 0.01); the yearly incidence was 2.1% in both groups. Adjusting for age, sex, calendar period, time between biopsies and education, persistent villous atrophy was however not associated with later infection overall (HR = 0.99; 95% CI = 0.88-1.11) or with any of the specific infections. Conclusions: In CD, mucosal healing does not influence the risk of serious infection requiring hospital-based medical attention. PMID- 29435315 TI - Fluid resuscitation with lactated Ringer's solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial. AB - Background: Little is known regarding the optimal type of fluid resuscitation in acute pancreatitis (AP). Objective: The objective of this article was to compare the effect of lactated Ringer's solution (LR) vs normal saline (NS) in the inflammatory response in AP. Methods: We conducted a triple-blind, randomized, controlled trial. Patients >= 18 admitted with AP were eligible. Patients were randomized to receive LR or NS. Primary outcome variables were number of systemic inflammatory response syndrome (SIRS) criteria at 24 hours, 48 hours and 72 hours and blood C-reactive protein (CRP) levels at 48 hours and 72 hours. In vitro complementary experiments were performed to further explore the interaction between pH, lactate and inflammation. Results: Nineteen patients receiving LR and 21 receiving NS were analyzed. The median (p25-p75) number of SIRS criteria at 48 hours were 1 (1-2) for NS vs 1 (0-1) for LR, p = 0.060. CRP levels (mg/l) were as follows: at 48 hours NS 166 (78-281) vs LR 28 (3-124), p = 0.037; at 72 hours NS 217 (59-323) vs LR 25 (3-169), p = 0.043. In vitro, LR inhibited the induction of inflammatory phenotype of macrophages and NF-kappaB activation. This effect was not observed when using Ringer's solution without lactate, suggesting a direct anti-inflammatory effect of lactate. Conclusions: Lactated Ringer's is associated with an anti-inflammatory effect in patients with acute pancreatitis. PMID- 29435316 TI - Severe periodontitis and higher cirrhosis mortality. AB - Background: Periodontitis and edentulism are prevalent in patients with cirrhosis, but their clinical significance is largely unknown. Objective: The objective of this article is to determine the association of severe periodontitis and edentulism with mortality in patients with cirrhosis. Methods: A total of 184 cirrhosis patients underwent an oral examination. All-cause and cirrhosis-related mortality was recorded. The associations of periodontitis and edentulism with mortality were explored by Kaplan-Meier survival plots and Cox proportional hazards regression adjusted for age, gender, cirrhosis etiology, Child-Pugh score, Model for End-Stage Liver Disease score, smoker status, present alcohol use, comorbidity, and nutritional risk score. Results: The total follow-up time was 74,197 days (203.14 years). At entry, 44% of the patients had severe periodontitis and 18% were edentulous. Forty-four percent of the patients died during follow-up. Severe periodontitis was associated with higher all-cause mortality in the crude analysis (HR 1.56, 95% CI 1.06-2.54), but not in the adjusted analysis (HR 1.45, 95% CI 0.79-2.45). Severe periodontitis was even more strongly associated with higher cirrhosis-related mortality (crude HR 2.19, 95% CI 1.07-4.50 and adjusted HR 2.29, 95% CI 1.04-4.99). No association was found between edentulism and mortality. Conclusion: The presence of severe periodontitis predicted a more than double one-year cirrhosis mortality. These findings may motivate intervention trials on the effect of periodontitis treatment in patients with cirrhosis. PMID- 29435317 TI - Impact of liver volume on polycystic liver disease-related symptoms and quality of life. AB - Background: Symptoms in polycystic liver disease (PLD) are thought to be caused by compression of organs and structures by the enlarged liver. Aim: The aim of this article is to assess the impact of liver volume on symptoms and quality of life (QoL) in PLD. Methods: We included PLD patients from two prospective studies that used the PLD-questionnaire (PLD-Q) for symptom assessment. QoL was assessed through SF-36, summarized in a physical (PCS) and mental (MCS) component score. Liver volume was correlated with PLD-Q total scores. Patients were classified based on height-corrected liver volume in mild (<1600 ml), moderate (1600-3200 ml), and severe (>3200 ml) disease. PLD-Q and QoL (PCS and MCS) scores were compared across disease stages. Results: We included 82 of 131 patients from the original studies (disease stages; mild n = 26, moderate n = 33, and severe n = 23). Patients with larger liver volume reported higher symptom burden (r = 0.516, p < 0.001). Symptom scores increased with disease progression, except for abdominal pain (p = 0.088). PCS decreased with advancing disease (p < 0.001), in contrast to MCS (p = 0.055). Moderate (p = 0.007) and severe (p < 0.001) PLD patients had lower PCS scores than the general population. Conclusion: PLD with larger liver volume is more likely to be symptomatic and is associated with lower QoL. PMID- 29435319 TI - Serum magnesium concentration is independently associated with non-alcoholic fatty liver and non-alcoholic steatohepatitis. AB - Background: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) has not been well recognized yet. Objective: This study aimed to investigate the association between serum magnesium concentration and NAFLD. Methods: Study participants were healthy individuals who had undergone liver biopsies between January 2012 and August 2015 as a routine pre-transplant check-up before living donor liver transplantation. Liver biopsy specimens were evaluated by an expert pathologist regarding presence of hepatic steatosis and steatohepatitis. Serum magnesium concentration was measured and compared in those with normal liver biopsy and those with steatosis and steatohepatitis. Results: A total of 226 individuals were included. Eighty-two individuals (36.2%) had hepatic steatosis and 22 (9.7%) individuals had steatohepatitis and steatosis in their liver histology. Lower serum magnesium concentration was independently associated with hepatic steatosis (OR: 0.059; 95% CI: 0.011-0.325, p = 0.001). Serum magnesium concentration was independently associated with steatohepatitis compared to those without steatohepatitis (1.80 +/- 0.48 mg/dl and 2.18 +/- 0.31 mg/dl) (OR: 0.11; 95% CI: 0.02-0.41, p = 0.001). Serum magnesium concentration was significantly lower in individuals with steatohepatitis (1.80 +/- 0.48 mg/dl) compared to individuals without steatosis (2.23 +/- 0.31 mg/dl, p < 0.001) and individuals with only steatosis (2.07 +/- 0.29 mg/dl, p = 0.017). Conclusion: Serum magnesium concentration is independently associated with hepatic steatosis and steatohepatitis in our study population. PMID- 29435320 TI - Outcome and natural course of renal dysfunction in liver transplant recipients with severely impaired kidney function prior to transplantation. AB - Background: Since introduction of the MELD score in the liver allograft allocation system, renal insufficiency has emerged as an increasing problem. Here we evaluated the course of kidney function in patients with advanced renal insufficiency prior to liver transplantation (LT). Methods: A total of 254 patients undergoing LT at the University Medical Centre Hamburg-Eppendorf (2011 2015) were screened for renal impairment (GFR < 30 ml/min) prior to LT in this observational study. Results: Eighty (32%) patients (median 60 years; M/F: 48/32) had significant renal impairment prior to LT. Median follow-up post-LT was 619 days. Patient survival at 90 days, one year and two years was 76%, 66% and 64%, respectively. Need for dialysis postoperatively but not preoperatively was associated with increased mortality (p < 0.05). Renal function improved in 75% of survivors, but 78% of patients had chronic kidney disease >= stage 3 at end of follow-up. Of eight (16%) survivors remaining on long-term dialysis, so far only four patients have received a kidney transplant. Conclusion: Postoperative dialysis affected long-term mortality. In 75% of survivors renal function improved, but still the majority of patients had an impaired renal function (CKD stage 3-5) at end of follow-up. Future studies should elucidate the impact of kidney dysfunction and dialysis on recipients' long-term survival. PMID- 29435318 TI - Endoscopic management of bile leaks after liver transplantation: An analysis of two high-volume transplant centers. AB - Background: Bile leak after liver transplantation (LT) is commonly treated with endoscopic retrograde cholangiopancreatography (ERCP); however, there are limited data regarding the optimal treatment strategy. Objective: We aimed to examine the role of ERCP in LT recipients with bile leaks at two large institutions. Methods: We reviewed all ERCPs performed in LT recipients with bile leak and duct-to-duct biliary anastomosis at two high-volume transplant centers. Results: Eighty patients were included. Forty-seven (59%) patients underwent ERCP with plastic stent placement (with or without sphincterotomy) and 33 patients (41%) underwent sphincterotomy alone. Complete resolution was obtained in 94% of the stent group vs. 58% of the sphincterotomy group (p < 0.01). There was no difference in three month survival among both groups. Percutaneous transhepatic therapy and surgery were required in 4% and 6% in the stent group vs. 12% and 42% in the sphincterotomy group, respectively (p = 0.22 and p < 0.001). The only predictive factor of bile leak resolution was stent placement. Conclusion: ERCP with plastic stent placement is highly successful and more effective than sphincterotomy alone for post-LT bile leak treatment. These results indicate that ERCP and plastic stent placement should be considered the standard of care for the treatment of bile leaks in LT. PMID- 29435321 TI - The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease. AB - Background: Patients with primary sclerosing cholangitis associated with inflammatory bowel disease (PSC-IBD) have a very high risk of developing colorectal neoplasia. Alterations in the gut microbiota and/or gut bile acids could account for the increase in this risk. However, no studies have yet investigated the net result of cholestasis and a potentially altered bile acid pool interacting with a dysbiotic gut flora in the inflamed colon of PSC-IBD. Aim: The aim of this study was to compare the gut microbiota and stool bile acid profiles, as well as and their correlation in patients with PSC-IBD and inflammatory bowel disease alone. Methods: Thirty patients with extensive colitis (15 with concomitant primary sclerosing cholangitis) were prospectively recruited and fresh stool samples were collected. The microbiota composition in stool was profiled using bacterial 16S rRNA sequencing. Stool bile acids were assessed by high-performance liquid chromatography tandem mass spectrometry. Results: The total stool bile acid pool was significantly reduced in PSC-IBD. Although no major differences were observed in the individual bile acid species in stool, their overall combination allowed a good separation between PSC-IBD and inflammatory bowel disease. Compared with inflammatory bowel disease alone, PSC IBD patients demonstrated a different gut microbiota composition with enrichment in Ruminococcus and Fusobacterium genus compared with inflammatory bowel disease. At the operational taxonomic unit level major shifts were observed within the Firmicutes (73%) and Bacteroidetes phyla (17%). Specific microbiota-bile acid correlations were observed in PSC-IBD, where 12% of the operational taxonomic units strongly correlated with stool bile acids, compared with only 0.4% in non PSC-IBD. Conclusions: Patients with PSC-IBD had distinct microbiota and microbiota-stool bile acid correlations as compared with inflammatory bowel disease. Whether these changes are associated with, or may predispose to, an increased risk of colorectal neoplasia needs to be further clarified. PMID- 29435322 TI - Effect of aspirin on the diagnostic accuracy of the faecal immunochemical test for colorectal advanced neoplasia. AB - Background: Aspirin (ASA) is a drug that can cause gastrointestinal lesions and symptoms. Colorectal cancer (CRC) is the most prevalent type of cancer in Western countries. We assessed the effect of aspirin on the diagnostic accuracy of the faecal immunochemical test (FIT) for CRC and/or advanced neoplasia (AN) in patients undergoing colonoscopy for gastrointestinal symptoms. Methods: We conducted a prospective multicentre observational study of diagnostic tests that included patients with gastrointestinal symptoms undergoing colonoscopy between March 2012 and 2014 (the COLONPREDICT study). Symptoms were assessed and a FIT and blood tests assessing haemoglobin and carcinoembryonic antigen (CEA) levels were performed. Results: The study included 3052 patients: A total of 2567 did not take aspirin (non-user group) and 485 (16%) took aspirin (user group). Continuous treatment with ASA did not change the AUC (0.88, 0.82; p = 0.06), sensitivity (92%, 88%; p = 0.5) or specificity (71%, 67%; p = 0.2) of the FIT for CRC detection. Similarly, we found no differences in the AUC (0.81, 0.79; p = 0.6), sensitivity (74%, 75.5%; p = 0.3) or specificity (76%, 73.6%; p = 0.3) for AN detection. Patients with an aspirin use of >= 300 mg/day had a lower prevalence of AN and the sensitivity, specificity and AUC for AN for these patients were 54%, 68% and 0.66, significantly lower than for the non-user group (p = 0.03). Conclusions: Aspirin does not modify the diagnostic accuracy of FIT for CRC and/or AN in patients with gastrointestinal symptoms. Aspirin use of >= 300 mg/day decreases the accuracy of the test. PMID- 29435323 TI - Comparison of MRI and colonoscopy in determining tumor height in rectal cancer. AB - Background and aim: Endoscopy and magnetic resonance imaging (MRI) are used routinely in the diagnostic and preoperative work-up of rectal cancer. We aimed to compare colonoscopy and MRI in determining rectal tumor height. Methods: Between 2002 and 2012, all patients with rectal cancer with available MRIs and endoscopy reports were included. All MRIs were reassessed for tumor height by two abdominal radiologists. To obtain insight in techniques used for endoscopic determination of tumor height, a survey among regional endoscopists was conducted. Results: A total of 211 patients with rectal cancer were included. Tumor height was significantly lower when assessed by MRI than by endoscopy with a mean difference of 2.5 cm (95% CI: 2.1-2.8). Although the agreement between tumor height as measured by MRI and endoscopy was good (intraclass correlation coefficient (ICC) 0.7 (95% CI: 0.7-0.8)), the 95% limits of agreement varied from -3.0 cm to 8.0 cm. In 45 patients (21.3%), tumors were regarded as low by MRI and middle-high by endoscopy. MRI inter- and intraobserver agreements were excellent with an ICC of 0.8 (95% CI: 0.7-0.9) and 0.9 (95% CI: 0.9-1.0), respectively. The survey showed no consensus among endoscopists as to how to technically measure tumor height. Conclusion: This study showed large variability in rectal tumor height as measured by colonoscopy and MRI. Since MRI measurements showed excellent inter- and intraobserver agreement, we suggest using tumor height measurement by MRI for diagnostic purposes and treatment allocation. PMID- 29435324 TI - Efficacy and safety of a novel high-dose mesalazine tablet in mild to moderate active ulcerative colitis: a double-blind, multicentre, randomised trial. AB - Background: Adherence to mesalazine treatment is essential for the successful treatment of ulcerative colitis. Objective: The objective of this study was to compare the efficacy, safety and preference of a novel high-dose 1000 mg mesalazine tablet versus conventional treatment for ulcerative colitis remission. Methods: This pivotal phase III trial compared one 1000 mg mesalazine tablet (M1000 group) versus two registered 500 mg mesalazine tablets (M2x500 group), both taken three times daily, in patients with mild to moderately active ulcerative colitis. The primary efficacy variable was clinical remission at week 8. Results: A total of 306 patients were considered for intent-to-treat analysis. Clinical remission was achieved in 45.0% of the patients in the M1000 group versus 41.9% in the M2x500 group (P < 0.001 for non-inferiority). Mucosal healing was achieved by 68.9% of the patients in the M1000 group and 68.4% in the M2x500 group. The majority of patients preferred the intake of one high-dose tablet (47.7%) over two low-dose tablets (10.5%). Oral treatment with high-dose 1000 mg mesalazine tablets was well tolerated without new safety signals. Conclusions: The novel high-dose 1000 mg mesalazine tablet is effective, non-inferior to the registered 500 mg mesalazine tablet, and safe for ulcerative colitis treatment. It was preferred by a majority of patients and may improve ulcerative colitis treatment adherence. PMID- 29435326 TI - European Digestive Health Summit: Combatting the burden of digestive diseases through tighter controls on the alcohol and food industry. PMID- 29435325 TI - Psychological distress, iron deficiency, active disease and female gender are independent risk factors for fatigue in patients with ulcerative colitis. AB - Background: Patients with ulcerative colitis often report fatigue. Objectives: To investigate prevalence of and risk factors for fatigue in patients with ulcerative colitis with active disease and during deep remission. Methods: In this cross-sectional study, disease activity was evaluated with endoscopy and calprotectin, and patients were classified as having active disease (n = 133) or being in deep remission (n = 155). Blood samples were analysed to assess anaemia, iron deficiency and systemic immune activity. Patients completed questionnaires to assess fatigue, psychological distress, gastrointestinal symptoms and quality of life. Results: The prevalence of high fatigue (general fatigue >= 13, Multidimensional Fatigue Inventory) was 40% in the full study population. Among patients with high fatigue, female gender and iron deficiency were more prevalent, and these patients had more severe disease activity and reported higher levels of anxiety, depression and decreased quality of life compared with patients with no/mild fatigue. A logistic regression analysis identified probable psychiatric disorder (odds ratio (OR) (confidence interval) 6.1 (3.1-12.2)), iron deficiency (OR 2.5 (1.2-5.1)), active disease (OR 2.2 (1.2-3.9)) and female gender (OR 2.1 (1.1-3.7)) as independent risk factors for high fatigue. Similar results were found concerning psychological distress, gender and quality of life, but immune markers did not differ in patients in deep remission with high vs. no/mild fatigue. Conclusions: Probable psychiatric disorder, iron deficiency, active disease and female gender are independent risk factors for high fatigue in patients with ulcerative colitis. Low-grade immune activity does not seem to be the cause of fatigue among patients in deep remission. PMID- 29435327 TI - Young gastrointestinal angle: How to prepare and submit a job application. PMID- 29435329 TI - Use of diaphragm thickening fraction combined with rapid shallow breathing index for predicting success of weaning from mechanical ventilator in medical patients. AB - Background: Weaning failure is a crucial hindrance in critically ill patients. Rapid shallow breathing index (RSBI), a well-known weaning index, has some limitations in predicting weaning outcomes. A new weaning index using point-of care ultrasound with diaphragmic thickening fraction (DTF) has potential benefits for improving weaning success. The aim of this study was to evaluate the efficacy of a combination of DTF and RSBI for predicting successful weaning compared to RSBI alone. Methods: This prospective study enrolled patients from the medical intensive care unit or ward who were using mechanical ventilation and readied for weaning. Patients underwent a spontaneous breathing trial (SBT) for 1 h, and then, both hemi-diaphragms were visualized in the zone of apposition using a 10 MHz linear probe. Diaphragm thickness was recorded at the end of inspiration and expiration which supposed the lung volume equal to total lung capacity (TLC) and residual volume (RV), respectively, and the DTF was calculated as a percentage from this formula: thickness at TLC minus thickness at RV divided by thickness at RV. In addition, RSBI was calculated at 1 min after SBT. Weaning failure was defined as the inability to maintain spontaneous breathing within 48 h. Results: Of the 34 patients enrolled, the mean (+/- SD) age was 66.5 (+/- 13.5) years. There were 25 patients with weaning success, 9 patients in the weaning failure group. The receiver operating characteristic curves of right and left DTF and the RSBI for the prediction of successful weaning were 0.951, 0.700, and 0.709, respectively. The most accurate cutoff value for prediction of successful weaning was right DTF >= 26% (sensitivity of 96%, specificity of 68%, positive predictive value of 89%, negative predictive value of 86%). The combination of right DTF >= 26% and RSBI <= 105 increased specificity to 78% but slightly decreased sensitivity to 92%. Intra-observer correlation increased sharply to almost 0.9 in the first ten patients and slightly increased after that. Conclusions: Point-of care ultrasound to assess diaphragm function has an excellent learning curve and helps physicians determine weaning readiness in critically ill patients. The combination of right DTF and RSBI greatly improved the accuracy for prediction of successful weaning compared to RSBI alone. Trial registration: Thai Clinical Trials Registry, TCTR20171025001. Retrospectively registered on October 23, 2017. PMID- 29435331 TI - Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia. AB - Background: 5-Azacitidine administered as a 7-day dosing regimen (7-0-0) is approved in high risk IPSS myelodysplastic syndrome (MDS) patients. Alternative regimens such as a 5-day (5-0-0) or 7-day with a weekend break (5-2-2) are commonly used. No randomized controlled trial has been done directly comparing all three dosing regimens. The objective of this study was to compare the efficacies of the 5-0-0, 5-2-2, and 7-0-0 regimens in MDS and AML. Methods: A systematic review was conducted using MEDLINE, EMBASE and CENTRAL. Eligible studies were randomized controlled trials (RCTs), observational prospective and retrospective studies. The primary clinical outcomes were Objective Response Rate (ORR) defined as the sum of complete response (CR), partial response (PR), and hematological improvement (HI) as defined by the IWG 2006 criteria. A meta analysis of simple proportions was conducted using a random effects model with weights defined according to Laird and Mosteller. Comparisons between groups were not attempted due to the heterogeneity of study designs. Results: The only RCT directly comparing alternative azacitidine regimens showed no difference in ORR between the 5-0-0 and 5-2-2 regimens. All other RCTs compared a dosing regimen to conventional care. The pooled proportion of ORR was 44.8% with 95% CI (42.8%, 45.5%) for 7-0-0, 41.2% with 95% CI (39.2%, 41.9%) for 5-0-0, and 45.8% with 95% CI (42.6%, 46.4%) for 5-2-2. Conclusions: Indirect comparison of alternative azacitidine dosing regimens in MDS and AML shows a benefit for the 7-day regimen in attaining ORR. Additional RCTs are required to definitively address this comparison. PMID- 29435332 TI - More is less, less is more, or does it really matter? The curious case of impact of azacitidine administration schedules on outcomes in patients with myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) encompass a diverse group of hematologic disorders characterized by ineffective and malignant hematopoiesis, peripheral cytopenias and significantly increased risk of progression to acute myeloid leukemia (AML). The hypomethylating agents (HMA) azacitidine and decitabine induce meaningful clinical responses in a significant subset of patients with MDS. Though never compared directly with decitabine, only azacitidine has improved overall survival (OS) compared to conventional care in a randomized trial in patients with higher-risk MDS. The azacitidine regimen used in this pivotal trial AZA-001 included administration at 75 mg/m2/day for 7 consecutive days in 28-day cycles (7-0 regimen). Given the logistical difficulties of weekend administration in the 7-0 regimen, as well as in efforts to improve response rates, alternative dosing schedules have been used. In a typical 28-day cycle, administration schedules of 3, 5, 10, and (with the oral version of azacitidine) 14 and 21 days have been used in clinical trials. Most trials that evaluated alternative administration schedules of azacitidine did so in lower-risk MDS and did not directly compare to the 7-0 schedule. Given the lack of randomized prospective studies comparing the 7-0 schedule to the other regimens of azacitidine in MDS, Shapiro et al. conducted a systematic review in an attempt to answer this question. Here we place the findings of this important work in clinical context and review the current knowledge and unresolved issues regarding the impact of administration schedules of azacitidine on outcomes of patients with both lower-risk and higher-risk MDS. PMID- 29435333 TI - Combining perceptual regulation and exergaming for exercise prescription in low active adults with and without cognitive impairment. AB - Background: Exercise adherence in already low-active older adults with and without mild cognitive impairment (MCI) remains low. Perceptual regulation and exergaming may facilitate future exercise behaviour by improving the affective experience, however evidence that this population can perceptually regulate is lacking. To explore this, we investigated 1) perceptual regulation of exercise intensity during either exergaming or regular ergometer cycling and 2) explored affective responses. Methods: Thirty-two low active older adults (73.9 +/- 7.3 years, n = 16, 8 females) with or without MCI (70.9 +/- 5.5 years, n = 16, 11 females) participated in a sub-maximal fitness assessment to determine ventilatory threshold (VT) and two experimental sessions (counterbalanced: exergaming or regular ergometer cycling). Experimental sessions consisted 21-min of continuous cycling with 7-min at each: RPE 9, 11 and 13. Oxygen consumption (VO2), heart rate (HR), and affect (Feeling Scale) were obtained throughout the exercise. Results: VO2 (p < 0.01) and HR (p < 0.01) increased linearly with RPE, but were not significantly different between exercise modes or cognitive groups. At RPE 13, participants worked above VT in both modes (exergaming: 115.7 +/- 27.3; non-exergaming 114.1 +/- 24.3 VO2 (%VT)). Regardless of cognitive group, affect declined significantly as RPE increased (p < 0.01). However on average, affect remained pleasant throughout and did not differ between exercise modes or cognitive groups. Conclusions: These results suggest low-active older adults can perceptually regulate exercise intensity, regardless of cognition or mode. At RPE 13, participants regulated above VT, at an intensity that improves cardiorespiratory fitness long-term, and affect remained positive in the majority of participants, which may support long-term physical activity adherence. PMID- 29435334 TI - May Thurner syndrome revealed by left calf venous claudication during running, a case report. PMID- 29435335 TI - Health care for all: effective, community supported, healthcare with innovative use of telemedicine technology. AB - Almost half of the world's total population reside in rural and remote areas and a large number of these people remain deprived of most basic facilities like healthcare and education. It is deemed impossible for government with scarce resources in developing countries to open and run a health facility in every remote community using conventional means. One increasingly popular unconventional mean is the use of existing technology to improve exchange of medical information for the purpose of improving health of underprivileged communities. Telemedicine implies the use of information and communication technology to provide health care remotely from a distance. With the induction of telemedicine, patients who live in rural and remote areas can have increased access to medical services. In many developing countries, use of telemedicine however has been limited mainly to teleconferencing between primary and secondary/tertiary care facilities for diagnosis and management of patients. This system still requires patients from remote communities to travel, often long and arduous journeys to the centre where telecom and medical facilities are available. Health Care 4 All International, a not for profit registered charity is providing primary care to patients by taking telemedicine into their homes in remote communities, thus obviating the need and hardships of travel for patient. PMID- 29435336 TI - Marginal socio-economic effects of an employer's efforts to improve the work environment. AB - Background: Workplace health promotion (WHP) strongly requires the employer's efforts to improve the psychosocial, ergonomic, and physical environments of the workplace. There are many studies discussing the socio-economic advantage of WHP intervention programmes and thus the internal and external factors motivating employers to implement and integrate such programmes. However, the socio-economic impacts of the employer's multifactorial efforts to improve the work environment need to be adequately assessed. Methods: Data were collected from Swedish company Sandvik Materials Technology (SMT) through a work environment survey in April 2014. Different regression equations were analysed to assess marginal effects of the employer's efforts on overall labour effectiveness (OLE), informal work impairments (IWI), lost working hours (LWH), and labour productivity loss (LPL) in terms of money. Results: The employer's multifactorial efforts resulted in increasing OLE, decreasing IWI and illness-related LWH, and cost savings in terms of decreasing LPL. Conclusion: Environmental factors at the workplace are the important determinant factor for OLE, and the latter is where socio-economic impacts of the employer's efforts primarily manifest. PMID- 29435337 TI - Sick at work: prevalence and determinants among healthcare workers, western Ethiopia: an institution based cross-sectional study. AB - Background: Going to work despite feeling sick also known as sickness presenteeism is one of the emerging global occupational health challenges. Sickness presenteeism negatively affects both health of work forces and productivity of organizations in general. However, there is insufficient research exploring this situation in majority of the Sub-Saharan African countries, including Ethiopia. Thus this study intended to investigate the prevalence and determinant factors of sickness presenteeism among health care workers, Western Ethiopia. Methods: This study used an institution based cross-sectional quantitative study design. The study period was from February to March, 2017. We employed simple random sampling method to select 360 study samples. Data collection was performed by pre-tested structured and self- administered questionnaire. We used SPSS version 20 to carry out binary logistic regression analysis. Odds ratio with 95% confidence intervals was calculated and significance of associations was determined at p-value < 0.05. Results: A total of 344 respondents fully completed the survey questionnaire. Mean age with standard deviation was 30.28 +/- 6.181. Prevalence of sickness Presenteeism was 52.6% [95%CI: (47.4, 57.8)] in the past 12 months. Educational status [AOR:2.1, 95%CI: (1.17,3.90)], financial problem [AOR:1.9,95%CI:(1.07,3.46)], sickness absenteeism [AOR:2.7,95% CI:(1.50,5.02)], lack of staff replacement [AOR:2.7,95%CI:(1.50,5.02)], absence of occupational health services [AOR:3.0,95%CI:(1.34,6.70)], and pressure from supervisor [AOR:1.8,95% CI:(1.01,3.31)] were significant predictors of the dependent variable. Conclusion: Relatively higher proportions of workers indicated sickness presenteeism as compared to other studies. Risk factors like educational status, personal financial problem, sickness absenteeism, lack of staff replacement, absence of occupational health services, and pressure from supervisors considerably increased the likely occurrence of employees' sick attendance. It is advisable for health care managers to hire adequate health care staffs, to implement basic occupational health services and to design strategies which reduce pressure from supervisors. PMID- 29435338 TI - Probability of causation for occupational cancer after exposure to ionizing radiation. AB - Background: Probability of causation (PC) is a reasonable way to estimate causal relationships in radiation-related cancer. This study reviewed the international trend, usage, and critiques of the PC method. Because it has been used in Korea, it is important to check the present status and estimation of PC in radiation related cancers in Korea. Methods: Research articles and official reports regarding PC of radiation-related cancer and published from the 1980s onwards were reviewed, including studies used for the revision of the Korean PC program. PC has been calculated for compensation-related cases in Korea since 2005. Results: The United States National Institutes of Health first estimated the PC in 1985. Among the 106 occupational diseases listed in the International Labor Organization Recommendation 194 (International Labor Office (ILO), ILO List of Occupational Diseases, 2010), PC is available only for occupational cancer after ionizing radiation exposure. The United States and United Kingdom use PC as specific criteria for decisions on the compensability of workers' radiation related health effects. In Korea, PC was developed firstly as Korean Radiation Risk and Assigned Share (KORRAS) in 1999. In 2015, the Occupational Safety and Health Research Institute and Radiation Health Research Institute jointly developed a more revised PC program, Occupational Safety and Health-PC (OSH-PC). Between 2005 and 2015, PC was applied in 16 claims of workers' compensation for radiation-related cancers. In most of the cases, compensation was given when the PC was more than 50%. However, in one case, lower than 50% PC was accepted considering the possibility of underestimation of the cumulative exposure dose. Conclusions: PC is one of the most advanced tools for estimating the causation of occupational cancer. PC has been adjusted for baseline cancer incidence in Korean workers, and for uncertainties using a statistical method. Because the fundamental reason for under- or over-estimation is probably inaccurate dose reconstruction, a proper guideline is necessary. PMID- 29435339 TI - Perceptions regarding utilization of meteorological information in healthcare in Korea: a qualitative study. AB - Background: Health forecasting has been used in an attempt to provide timely and tailored meteorological information to patients and healthcare providers so that they might take appropriate actions to mitigate health risks and manage healthcare-related needs. This study examined the in-depth perceptions of healthcare providers and the general public regarding the utilization of meteorological information in the healthcare system in Korea. Methods: The COREQ (Consolidated Criteria for Reporting Qualitative Research) checklist was applied to this study. We conducted three focus group discussions in accordance with semi structured guidelines developed to deal with various aspects of the utilization of meteorological information in healthcare settings. The verbatim transcriptions and field notes were analyzed according to content analysis. Results: Six physicians, four nurses, three emergency medical technicians, and seven members of the general public participated in the focus group discussions. There were some individual discrepancies among most participants regarding the health effects of climate change. Although several physician participants felt that meteorological information utilization is not a prime concern during patient care, most of the general public participants believed that it should be used in the patient care process. The provision of meteorological information to patients undergoing care is expected to not only improve the effective management of climate-sensitive diseases, but also boost rapport between healthcare providers and patients. Conclusions: More attempts should be made to provide meteorological information to groups vulnerable to climate change, and the effects of this information should be evaluated in terms of effectiveness and inequality. The findings of this study will be helpful in countries and institutions trying to introduce health forecasting services. PMID- 29435340 TI - Radiation-related occupational cancer and its recognition criteria in South Korea. AB - Ionizing radiation is a well-known carcinogen, and is listed as one carcinogenic agent of occupational cancer. Given the increase in the number of workers exposed to radiation, as well as the increase in concern regarding occupational cancer, the number of radiation-related occupational cancer claims is expected to increase. Unlike exposure assessment of other carcinogenic agents in the workplace, such as asbestos and benzene, radiation exposure is usually assessed on an individual basis with personal dosimeters, which makes it feasible to assess whether a worker's cancer occurrence is associated with their individual exposure. However, given the absence of a threshold dose for cancer initiation, it remains difficult to identify radiation exposure as the root cause of occupational cancer. Moreover, the association between cancer and radiation exposure in the workplace has not been clearly established due to a lack of scientific evidence. Therefore, criteria for the recognition of radiation-related occupational cancer should be carefully reviewed and updated with new scientific evidence and social consensus. The current criteria in Korea are valid in terms of eligible radiogenic cancer sites, adequate latent period, assessment of radiation exposure, and probability of causation. However, reducing uncertainty with respect to the determination of causation between exposure and cancer and developing more specific criteria that considers mixed exposure to radiation and other carcinogenic agents remains an important open question. PMID- 29435341 TI - ARDS following oesophagectomy: a comparison of two trials. AB - Introduction: The Beta Agonist Lung Injury Trial-Prevention (BALTI-P) translational substudy and Vitamin D to Prevent Acute Lung Injury Following Oesophagectomy (VINDALOO) trials recruited patients undergoing oesophagectomy, 4 years apart. The acute respiratory distress syndrome (ARDS) rates were lower in the VINDALOO trial. We sought to identify changes between these two trials and identify risk factors for ARDS in oesophagectomy. Methods: There were data available from 61 patients in the BALTI-P substudy and 68 from VINDALOO. Databases were available for both trials; additional data were collected. Multivariate logistic regression was used to analyse risk factors for ARDS and postoperative complications in the cohorts combined. Results: Logistic regression analysis showed active smoking was associated with an increase in ARDS (OR 3.91; 95% CI 1.33 to 11.5) and dihydropyridine use (OR 5.34;95% CI 1.56 to 18.3). Hospital length of stay was longer for those who took dihydropyridines (median 29 days (IQR 17-42) vs 13 days (IQR 10-18), P=0.0007) or were diabetic (median 25 days (IQR 14-39) vs 13 (IQR 10-19), P=0.023) but not for current smokers (median in never/ex-smokers 13 (IQR 10-23) vs current smokers 15 (IQR 11-20), P=0.73). Conclusions: Smoking cessation trials should be promoted. Dihydropyridine effects perioperatively require further clinical and mechanistic evaluation. Patients undergoing oesophagectomy are a useful model for studying perioperative ARDS. PMID- 29435330 TI - The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016). AB - Background and purpose: The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] 10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc.This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine. Methods: Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members. Results: A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs. Conclusions: Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals. PMID- 29435342 TI - Predictive value of prebronchodilator and postbronchodilator spirometry for COPD features and outcomes. AB - Introduction: We compared the predictive value of prebronchodilator and postbronchodilator spirometry for chronic obstructive pulmonary disease (COPD) features and outcomes. Methods: We analysed COPDGene data of 10 192 subjects with smoking history. We created regressions models with the following dependent variables: clinical, functional and radiographic features, and the following independent variables: prebronchodilator airflow obstruction (PREO) and postbronchodilator airflow obstruction (POSTO), prebronchodilator and postbronchodilator FEV1% predicted. We compared the model performance using the Akaike information criterion (AIC). Results: The COPD prevalence was higher using PREO. About 8.5% had PREO but no airflow obstruction in postbronchodilator spirometry (POSTN) (PREO-POSTN) and 3% of all subjects had no aiflow obstruction in prebronchodilator spirometry (PREN) but POSTO (PREN-POSTO). We found no difference in COPD features and outcomes between PREO-POSTN and PREN-POSTO subjects. Although, both prebronchodilator and postbronchodilator spirometries are both associated with chronic bronchitis, dyspnoea, exercise capacity and COPD radiographic findings, models that included postbronchodilator spirometric measures performed better than models with prebronchodilator measures to predict these COPD features. The predictive value of prebronchodilator and postbronchodilator spirometries for respiratory exacerbations, change in forced expiratory volume in 1 s, dyspnoea and exercise capacity during a 5-year period is relatively similar, but postbronchodilator spirometric measures are better predictors of mortality based on AIC. Conclusions: Postbronchodilator spirometry may be a more accurate predictor of COPD features and outcomes. PMID- 29435343 TI - Effect of a machine learning-based severe sepsis prediction algorithm on patient survival and hospital length of stay: a randomised clinical trial. AB - Introduction: Several methods have been developed to electronically monitor patients for severe sepsis, but few provide predictive capabilities to enable early intervention; furthermore, no severe sepsis prediction systems have been previously validated in a randomised study. We tested the use of a machine learning-based severe sepsis prediction system for reductions in average length of stay and in-hospital mortality rate. Methods: We conducted a randomised controlled clinical trial at two medical-surgical intensive care units at the University of California, San Francisco Medical Center, evaluating the primary outcome of average length of stay, and secondary outcome of in-hospital mortality rate from December 2016 to February 2017. Adult patients (18+) admitted to participating units were eligible for this factorial, open-label study. Enrolled patients were assigned to a trial arm by a random allocation sequence. In the control group, only the current severe sepsis detector was used; in the experimental group, the machine learning algorithm (MLA) was also used. On receiving an alert, the care team evaluated the patient and initiated the severe sepsis bundle, if appropriate. Although participants were randomly assigned to a trial arm, group assignments were automatically revealed for any patients who received MLA alerts. Results: Outcomes from 75 patients in the control and 67 patients in the experimental group were analysed. Average length of stay decreased from 13.0 days in the control to 10.3 days in the experimental group (p=0.042). In-hospital mortality decreased by 12.4 percentage points when using the MLA (p=0.018), a relative reduction of 58.0%. No adverse events were reported during this trial. Conclusion: The MLA was associated with improved patient outcomes. This is the first randomised controlled trial of a sepsis surveillance system to demonstrate statistically significant differences in length of stay and in-hospital mortality. Trial registration: NCT03015454. PMID- 29435344 TI - International perception of lung sounds: a comparison of classification across some European borders. AB - Introduction: Lung auscultation is helpful in the diagnosis of lung and heart diseases; however, the diagnostic value of lung sounds may be questioned due to interobserver variation. This situation may also impair clinical research in this area to generate evidence-based knowledge about the role that chest auscultation has in a modern clinical setting. The recording and visual display of lung sounds is a method that is both repeatable and feasible to use in large samples, and the aim of this study was to evaluate interobserver agreement using this method. Methods: With a microphone in a stethoscope tube, we collected digital recordings of lung sounds from six sites on the chest surface in 20 subjects aged 40 years or older with and without lung and heart diseases. A total of 120 recordings and their spectrograms were independently classified by 28 observers from seven different countries. We employed absolute agreement and kappa coefficients to explore interobserver agreement in classifying crackles and wheezes within and between subgroups of four observers. Results: When evaluating agreement on crackles (inspiratory or expiratory) in each subgroup, observers agreed on between 65% and 87% of the cases. Conger's kappa ranged from 0.20 to 0.58 and four out of seven groups reached a kappa of >=0.49. In the classification of wheezes, we observed a probability of agreement between 69% and 99.6% and kappa values from 0.09 to 0.97. Four out of seven groups reached a kappa >=0.62. Conclusions: The kappa values we observed in our study ranged widely but, when addressing its limitations, we find the method of recording and presenting lung sounds with spectrograms sufficient for both clinic and research. Standardisation of terminology across countries would improve international communication on lung auscultation findings. PMID- 29435346 TI - Effect of anti-podoplanin antibody administration during lipopolysaccharide induced lung injury in mice. AB - Introduction: Acute respiratory distress syndrome (ARDS) is a devastating pulmonary condition in the critically ill patient. A therapeutic intervention is yet to be found that can prevent progression to ARDS. We recently demonstrated that the interaction between podoplanin expressed on inflammatory alveolar macrophages (iAMs) and its endogenous ligand, platelet C-type lectin-like 2 (CLEC 2), protects against exaggerated lung inflammation during a mouse model of ARDS. In this study, we aim to investigate the therapeutic use of a crosslinking/activating anti-podoplanin antibody (alpha-PDPN, clone 8.1.1) during lipopolysaccharide (LPS)-induced lung inflammation in mice. Methods: Intravenous administration of alpha-PDPN was performed 6 hours after intratracheal LPS in wildtype, C57Bl/6 mice. Lung function decline was measured by pulse oximetry as well as markers of local inflammation including bronchoalveolar lavage neutrophilia and cytokine/chemokine expression. In parallel, alveolar macrophages were isolated and cultured in vitro from haematopoietic-specific podoplanin deficient mice (Pdpnfl/flVAV1cre+) and floxed-only controls treated with or without LPS in the presence or absence of alpha-PDPN. Results: Lung function decline as well as alveolar neutrophil recruitment was significantly decreased in mice treated with the crosslinking/activating alpha-PDPN in vivo. Furthermore, we demonstrate that, in vitro, activation of podoplanin on iAMs regulates their secretion of proinflammatory cytokines and chemokines. Conclusions: These data confirm the importance of the CLEC-2-podoplanin pathway during intratracheal (IT) LPS and demonstrate the beneficial effect of targeting podoplanin during IT-LPS in mice possibly via modulation of local cytokine/chemokine expression. Moreover, these data suggest that podoplanin-targeted therapies may have a beneficial effect in patients at risk of developing ARDS. PMID- 29435345 TI - Differentiation of quantitative CT imaging phenotypes in asthma versus COPD. AB - Introduction: Quantitative CT (QCT) imaging-based metrics have quantified disease alterations in asthma and chronic obstructive pulmonary disease (COPD), respectively. We seek to characterise the similarity and disparity between these groups using QCT-derived airway and parenchymal metrics. Methods: Asthma and COPD subjects (former-smoker status) were selected with a criterion of post bronchodilator FEV1 <80%. Healthy non-smokers were included as a control group. Inspiratory and expiratory QCT images of 75 asthmatic, 215 COPD and 94 healthy subjects were evaluated. We compared three segmental variables: airway circularity, normalised wall thickness and normalised hydraulic diameter, indicating heterogeneous airway shape, wall thickening and luminal narrowing, respectively. Using an image registration, we also computed six lobar variables including per cent functional small-airway disease, per cent emphysema, tissue fraction at inspiration, fractional-air-volume change, Jacobian and functional metric characterising anisotropic deformation. Results: Compared with healthy subjects, both asthma and COPD subjects demonstrated a decreased airway circularity especially in large and upper lobar airways, and a decreased normalised hydraulic diameter in segmental airways. Besides, COPD subjects had more severe emphysema and small-airway disease, as well as smaller regional tissue fraction and lung deformation, compared with asthmatic subjects. The difference of emphysema, small-airway disease and tissue fraction between asthma and COPD was more prominent in upper and middle lobes. Conclusions: Patients with asthma and COPD, with a persistent FEV1 <80%, demonstrated similar alterations in airway geometry compared with controls, but different degrees of alterations in parenchymal regions. Density-based metrics measured at upper and middle lobes were found to be discriminant variables between patients with asthma and COPD. PMID- 29435347 TI - Structured lifestyle intervention based on a trans-cultural diabetes-specific nutrition algorithm (tDNA) in individuals with type 2 diabetes: a randomized controlled trial. AB - Objective: Trans-cultural diabetes nutrition algorithm (tDNA) was created by international task force and culturally customized for Malaysian population. This study was designed to evaluate its effectiveness versus usual diabetes care in primary care settings. Research design and methods: We randomized 230 patients with overweight/obesity, type 2 diabetes, and glycated hemoglobin (A1c) 7%-11% to receive usual care (UC) or UC with tDNA for 6 months. The tDNA intervention consisted of structured low-calorie meal plan, diabetes-specific meal replacements, and increased physical activity. Participants were counseled either through motivational interviewing (tDNA-MI) or conventional counseling (tDNA-CC). The UC group received standard dietary and exercise advice through conventional counseling. All patients were followed for another 6 months after intervention. Results: At 6 months, A1c decreased significantly in tDNA-MI (-1.1+/-0.1%, p<0.001) and tDNA-CC (-0.5+/-0.1%, p=0.001) but not in UC (-0.2+/-0.1%, p=NS). Body weight decreased significantly in tDNA-MI (-6.9+/-1.3 kg, p<0.001) and tDNA CC (-5.3+/-1.2 kg, p<0.001) but not in UC (-0.8+/-0.5 kg, p=NS). tDNA-MI patients had significantly lower fasting plasma glucose (tDNA-MI: -1.1+/-0.3 mmol/L, p<0.001; tDNA-CC: -0.6+/-0.3 mmol/L, p=NS; UC: 0.1+/-0.3 mmol/L, p=NS) and systolic blood pressure (tDNA-MI: -9+/-2 mm Hg, p<0.001; tDNA-CC: -9+/-2 mm Hg, p=0.001; UC: -1+/-2 mm Hg, p=NS). At 1 year, tDNA-MI patients maintained significant reduction in A1c (tDNA-MI: -0.5+/-0.2%, p=0.006 vs tDNA-CC: 0.1+/ 0.2%, p=NS and UC: 0.02+/-0.01%, p=NS) and significant weight loss (tDNA-MI: 5.8+/-1.3 kg, p<0.001 vs tDNA-CC: -3.3+/-1.2 kg, p=NS and UC: 0.5+/-0.6 kg, p=NS). Conclusions: Structured lifestyle intervention through culturally adapted nutrition algorithm and motivational interviewing significantly improved diabetes control and body weight in primary care setting. PMID- 29435348 TI - Impact of a primary healthcare quality improvement program on diabetes in Canada: evaluation of the Quality Improvement and Innovation Partnership (QIIP). AB - Objective: Primary healthcare (PHC) quality improvement (QI) initiatives are designed to improve patient care and health outcomes. We evaluated the Quality Improvement and Innovation Partnership (QIIP), an Ontario-wide PHC QI program on access to care, diabetes management and colorectal cancer screening. This manuscript highlights the impact of QIIP on diabetes outcomes and associated vascular risk factors. Research design and methods: A cluster matched-control, retrospective prechart and postchart audit was conducted. One physician per QIIP PHC team (N=34) and control (N=34) were recruited for the audit. Eligible charts were reviewed for prespecified type 2 diabetes mellitus clinical process and outcome data at baseline, during (intervention range: 15-17.5 months) and post. Primary outcome measures were the A1c of patients above study target and proportion of patients with an annual foot exam. Secondary outcome measures included glycemic, hypertension and lipid outcomes and management, screening for diabetes-related complications, healthcare utilization, and diabetes counseling, education and self-management goal setting. Results: More patients in the QIIP group achieved statistically improved lipid testing, eye examinations, peripheral neuropathy exams, and documented body mass index. No statistical differences in A1c, low-density lipoprotein or systolic/diastolic blood pressure values were noted, with no significant differences in medication prescription, specialist referrals, or chart-reported diabetes counseling, education or self-management goals. Patients of QIIP physicians had significantly more PHC visits. Conclusion: The QIIP-learning collaborative program evaluation using stratified random selection of participants and the inclusion of a control group makes this one of the most rigorous and promising efforts to date evaluating the impact of a QI program in PHC. The chart audit component of this evaluation highlighted that while QIIP improved some secondary diabetes measures, no improvements in clinical outcomes were noted. This study highlights the importance of formalized evaluation of QI initiatives to provide an evidence base to inform future program planning and scale-up. PMID- 29435350 TI - Association between cardiorespiratory fitness and metabolic risk factors in a population with mild to severe obesity. AB - Background: Previous literature suggests the beneficial effects of fitness on abdominal obesity may be attenuated in obesity and abolished in severe obesity. It is unclear whether the beneficial association between fitness and health is similarly present in those with mild and severe obesity. Methods: Patients from the Wharton Medical Clinic (n = 853) completed a clinical examination and maximal treadmill test. Patients were categorized into fit and unfit based on age- and sex-categories and body mass index (BMI) class (mild: <= 34.9 kg/m2, moderate: 35 39.9 kg/m2 or severe obesity: >= 40 kg/m2). Results: Within the sample, 41% of participants with mild obesity had high fitness whereas only 25% and 11% of the participants with moderate and severe obesity, respectively, had high fitness. BMI category was independently associated with most of the metabolic risk factors, while fitness was only independently associated with systolic blood pressure and triglycerides (P < 0.05). The prevalent relative risk for pre clinical hypertension, hypertriglyceridemia and hypoalphalipoproteinemia and pre diabetes was only elevated in the unfit moderate and severe obesity groups (P < 0.05), and fitness groups were only significantly different in their relative risk for prevalent pre-clinical hypertension within the severe obesity group (p = 0.03). High fitness was associated with smaller waist circumferences, with differences between high and low fitness being larger in those with severe obesity than mild obesity (Men: P = 0.06, Women: P = 0.0005). Conclusions: Thus, in contrast to previous observations, the favourable associations of having high fitness and health may be similar if not augmented in individuals with severe compared to mild obesity. PMID- 29435349 TI - All-cause mortality in adults with and without type 2 diabetes: findings from the national health monitoring in Germany. AB - Objective: To estimate age-specific and sex-specific all-cause mortality among adults with and without type 2 diabetes (T2D) in Germany. Research design and methods: The German National Health Interview and Examination Survey 1998 (GNHIES98) included a mortality follow-up (median follow-up time 12.0 years) of its nationwide sample representative of the population aged 18-79 years. After exclusion of participants with type 1 diabetes, age- and sex-stratified mortality rates (MR) were calculated for 330 GNHIES98 participants with diagnosed T2D (self reported diagnosis or antidiabetic medication), 245 with undiagnosed T2D (no diagnosed T2D, glycated hemoglobin A1c >=6.5% (>=48 mmol/mol)), and 5975 without T2D. Mortality rate ratios (MRR) comparing MR of persons with and without T2D were estimated. Age-/sex-standardized MR and MRR were calculated including persons aged 45 years or older. MRR were used to estimate the number of years of life lost (YLL) due to diagnosed diabetes in 2010. Results: Over 75 994 person years, 73 persons with undiagnosed T2D, 103 with diagnosed T2D, and 425 persons without T2D died. MRR were significantly higher in younger age groups, except for analyses limited to women or diagnosed T2D. Age- and sex-standardized MRR (95% CI) among persons aged 45 years or older were 1.96 (1.41 to 2.71) for undiagnosed, 1.68 (1.26 to 2.23) for diagnosed, and 1.82 (1.45 to 2.28) for total (undiagnosed or diagnosed) T2D. Sex-stratified analysis revealed similar age standardized MRR for undiagnosed (1.56 (0.79 to 3.06)) and diagnosed T2D (1.56 (1.03 to 2.37)) among women, and a higher age-standardized MRR for undiagnosed (2.06 (1.43 to 2.97)) than diagnosed T2D (1.70 (1.10 to 2.63)) among men. YLL due to diagnosed diabetes in Germany in 2010 were 164 600 (35 000 to 279 300) among women and 169 900 (28 300 to 328 300) among men. Conclusions: In Germany, age- and sex-standardized all-cause mortality is almost twice as high for adults with T2D as for adults without T2D. The T2D-associated excess risk of mortality appears to be most pronounced in younger adults and among men unaware of their T2D. PMID- 29435351 TI - The impact of the 2014 Ebola virus disease outbreak in Liberia on parent preferences for harsh discipline practices: a quasi-experimental, pre-post design. AB - Background: This paper uses data from a cohort of parents and guardians of young children living in Monrovia, Liberia collected before and after the 2014 outbreak of Ebola virus disease (EVD) to estimate the impact of EVD exposure on implicit preferences for harsh discipline. We hypothesized that parents exposed to EVD related sickness or death would exhibit a stronger preference for harsh discipline practices compared with non-exposed parents. Methods: The data for this analysis come from two survey rounds conducted in Liberia as part of an intervention trial of a behavioral parenting skills intervention. Following a baseline assessment of 201 enrolled parents in July 2014, all program and study activities were halted due to the outbreak of EVD. Following the EVD crisis, we conducted a tracking survey with parents who completed the baseline survey 12 months prior. In both rounds, we presented parents with 12 digital comic strips of a child misbehaving and asked them to indicate how they would react if they were the parent in the stories. Results: Parents from households with reported EVD sickness or death became more 'harsh' (Glass's delta = 1.41) in their hypothetical decision-making compared with non-exposed parents, t (167)=-2.3, p < 0.05. Parents from households that experienced EVD-related sickness or death not only reported significantly more household conflict and anxiety, but also reported that their child exhibited fewer difficulties. Conclusions: Results support the need for family-based interventions, including strategies to help parents learn alternatives to harsh punishment. PMID- 29435352 TI - How gender- and violence-related norms affect self-esteem among adolescent refugee girls living in Ethiopia. AB - Background: Evidence suggests adolescent self-esteem is influenced by beliefs of how individuals in their reference group perceive them. However, few studies examine how gender- and violence-related social norms affect self-esteem among refugee populations. This paper explores relationships between gender inequitable and victim-blaming social norms, personal attitudes, and self-esteem among adolescent girls participating in a life skills program in three Ethiopian refugee camps. Methods: Ordinary least squares multivariable regression analysis was used to assess the associations between attitudes and social norms, and self esteem. Key independent variables of interest included a scale measuring personal attitudes toward gender inequitable norms, a measure of perceived injunctive norms capturing how a girl believed her family and community would react if she was raped, and a peer-group measure of collective descriptive norms surrounding gender inequity. The key outcome variable, self-esteem, was measured using the Rosenberg self-esteem scale. Results: Girl's personal attitudes toward gender inequitable norms were not significantly predictive of self-esteem at endline, when adjusting for other covariates. Collective peer norms surrounding the same gender inequitable statements were significantly predictive of self-esteem at endline (beta = -0.130; p = 0.024). Additionally, perceived injunctive norms surrounding family and community-based sanctions for victims of forced sex were associated with a decline in self-esteem at endline (beta = -0.103; p = 0.014). Significant findings for collective descriptive norms and injunctive norms remained when controlling for all three constructs simultaneously. Conclusions: Findings suggest shifting collective norms around gender inequity, particularly at the community and peer levels, may sustainably support the safety and well being of adolescent girls in refugee settings. PMID- 29435353 TI - Exploring links between common mental health problems, alcohol/substance use and perpetration of intimate partner violence: A rapid ethnographic assessment with men in urban Kenya. AB - Introduction: Kenya has some of the highest rates of gender-based violence (GBV) in the world, particularly intimate partner violence. World Vision completed a rapid ethnographic assessment to explore common problems faced by men and local perspectives about the links between men, mental health, alcohol use and GBV. Methods: Data from community free-listing surveys (n = 52), four focus group discussions and two key informant interviews formed the basis for thematic analysis and findings. Results: Lack of jobs, 'idleness' and finances were viewed as top priority concerns facing men; however, alcohol and substance use were equally prioritised. Family problems, crime and general psychosocial issues (e.g., high stress, low self-esteem) were also reported. Men withdrawing socially, changing behaviour and increasing alcohol consumption were described as signs that men were experiencing mental health challenges. The community observed alcohol use as the biggest cause of GBV, believing men resorted to drinking because of having 'too much time', marital conflict, psychosocial issues and access to alcohol. The findings theorise that a circular link between unemployment, alcohol and crime is likely contributing to familial, psychosocial and gender concerns, and that men's mental health support may assist to re-direct a trajectory for individuals at risk of perpetrating GBV. Conclusions: Data confirmed that GBV is a major concern in these Kenya communities and has direct links with alcohol use, which is subsequently linked to mental health and psychosocial problems. Attempting to disrupt progression to the perpetration of violence by men, via mental health care interventions, warrants further research. PMID- 29435354 TI - Evaluating the benefits of a youth mental health curriculum for students in Nicaragua: a parallel-group, controlled pilot investigation. AB - Background: High rates of mental illness and addictions are well documented among youth in Nicaragua. Limited mental health services, poor mental health knowledge and stigma reduce help-seeking. The Mental Health Curriculum (MHC) is a Canadian school-based program that has shown a positive impact on such contributing factors. This pilot project evaluated the impact of the MHC on mental wellness and functioning among youth in Leon, Nicaragua. Methods: High school and university students (aged 14-25 years) were assigned to intervention (12-week MHC; n = 567) and control (wait-list; n = 346) groups in a non-randomized design. Both groups completed measures of mental health knowledge, stigma and function at baseline and 12 weeks. Multivariate analyses and repeated measures analyses were used to compare group outcomes. Results: At baseline, intervention students showed higher substance use (mean difference [MD] = 0.24) and lower perceived stress (MD = -1.36) than controls (p < 0.05); there were no other group differences in function. At 12 weeks, controlling for baseline differences, intervention students reported significantly higher mental health knowledge (MD = 1.75), lower stigma (MD = 1.78), more adaptive coping (MD = 0.82), better lifestyle choices (MD = 0.06) and lower perceived stress (MD = -1.63) (p < 0.05) than controls. The clinical significance as measured by effect sizes was moderate for mental health knowledge, small to moderate for stigma and modest for the other variables. Substance use also decreased among intervention students to similar levels as controls (MD = 0.03) (p > 0.05). Conclusions: This pilot investigation demonstrates the benefits of the MHC in a low-and-middle-income youth population. The findings replicate results found in Canadian student populations and support its cross-cultural applicability. PMID- 29435355 TI - Smartphone use and smartphone addiction in middle school students in Korea: Prevalence, social networking service, and game use. AB - This study aimed to examine smartphone use patterns, smartphone addiction characteristics, and the predictive factors of the smartphone addiction in middle school students in South Korea. According to the Smartphone Addiction Proneness Scale scores, 563 (30.9%) were classified as a risk group for smartphone addiction and 1261 (69.1%) were identified as a normal user group. The adolescents used mobile messengers for the longest, followed by Internet surfing, gaming, and social networking service use. The two groups showed significant differences in smartphone use duration, awareness of game overuse, and purposes of playing games. The predictive factors of smartphone addiction were daily smartphone and social networking service use duration, and the awareness of game overuse. PMID- 29435356 TI - Comparison of serum pools and oral fluid samples for detection of porcine circovirus type 2 by quantitative real-time PCR in finisher pigs. AB - Background: Porcine circovirus type 2 (PCV2) diagnostics in live pigs often involves pooled serum and/or oral fluid samples for group-level determination of viral load by quantitative real-time polymerase chain reaction (qPCR). The purpose of the study was to compare the PCV2 viral load determined by qPCR of paired samples at the pen level of pools of sera (SP) from 4 to 5 pigs and the collective oral fluid (OF) from around 30 pigs corresponding to one rope put in the same pen. Pigs in pens of 2 finishing herds were sampled by cross-sectional (Herd 1) and cross-sectional with follow-up (Herd 2) study designs. In Herd 1, 50 sample pairs consisting of SP from 4 to 5 pigs and OF from around 23 pigs were collected. In Herd 2, 65 sample pairs consisting of 4 (SP) and around 30 (OF) pigs were collected 4 times at 3-week intervals. Results: A higher proportion of PCV2-positive pens (86% vs. 80% and 100% vs. 91%) and higher viral loads (mean difference: 2.10 and 1.83 log(10) PCV2 copies per ml) were found in OF versus SP in both herds. The OF cut-off value corresponding to a positive SP (>3 log(10) PCV2 copies per ml) was estimated to 6.5 and 7.36 log(10) PCV2 copies per ml for Herds 1 and 2, respectively. Significant correlations between SP and OF results were found in Herd 1 (rho = 0.69) and the first sampling in Herd 2 (rho = 0.39), but not for the subsequent consecutive 3 samplings in Herd 2. Conclusions: The proportion and viral loads of PCV2 positive pens were higher in collective OF (including up to 30 pigs) compared to SP (including 4-5 pigs) of the same pens. Also, OF seemed to detect the PCV2 infection earlier with OF values just below 6.5 (Herd 1) and 7.36 (Herd 2) log(10) being associated with a negative SP for the same pen. Nevertheless, a statistically significant correlation between SP and OF could not be found for all sampling time points, probably due to a high within-pen variation in individual pig viral load becoming very evident in SP of only four or five pigs. Consequently, the results imply that OF is well suited for detecting presence of PCV2 but less so for determining the specific viral load of pigs in a pen. PMID- 29435357 TI - Right from the start: protocol for a pilot study for a randomised trial of the New Baby Programme for improving outcomes for children born to socially vulnerable mothers. AB - Background: Children born to mothers who experience social complexity (e.g. substance misuse, intimate partner violence, mental ill health, a history of maltreatment) are at increased risk for a range of adverse outcomes at birth and during development. Home visiting programmes have been advocated as a strategy for improving outcomes for disadvantaged mothers and children, such as the Nurse Family Partnership for young, socially disadvantaged first-time mothers. However, no evidence-based programme is available for multiparous women or older first time mothers. The New Baby Programme was developed in Northern Ireland. It augments the universal health visiting service available in the UK with a content designed to promote maternal health and well-being in pregnancy, maximise secure attachments of children and parents and enhance sensitive parenting and infant cognitive development. Methods/Design: This pilot study is designed to investigate whether it is possible to recruit and retain socially vulnerable mothers in a randomised trial that compares the effects of the New Baby Programme with standard antenatal and postnatal care. Feasibility issues include the referral/recruitment pathway (including inclusion and exclusion criteria), the consent and randomisation, the ability to maintain researcher blinding, the acceptability of the intervention to participants, and the feasibility and acceptability of the outcome measures. The results of the study will inform a definitive phase-3 RCT. Discussion: Trials of complex social interventions often encounter challenges that lead to the trial being abandoned (e.g. because of problems in recruitment) or present considerable analytic challenges relating to dropout, attrition and bias. This pilot study aims to maximise the chances of successful implementation. Trial registration: ISRCTN35456296 retrospectively registered. PMID- 29435358 TI - Association between osteoarthritis and dyslipidaemia: a systematic literature review and meta-analysis. AB - Objectives: We aimed to investigate the prevalence of dyslipidemia in patients with osteoarthritis (OA) and whether OA and dyslipidemia are associated. Methods: We performed a systematic literature review and a meta-analysis, including cross sectional, cohort and case-control studies, to assess the number of patients with OA and/or dyslipidemia. We calculated the mean (+/-SD) prevalence of dyslipidemia in patients with and without OA and the risk of dyslipidemia (OR, 95% CI) among patients with OA. Results: From 605 articles screened, 48 were included in the analysis (describing 29 cross-sectional, 10 cohort and 9 case-control studies). The mean prevalence of dyslipidemia was 30.2%+/-0.6% among 14 843 patients with OA and 8.0%+/-0.1% among 196 168 without OA. The risk of dyslipidemia was greater with than without OA overall (OR 1.98,95% CI 1.43 to 2.75, p<0.0001) and with knee OA (OR 2.27, 1.33 to 3.89, p=0.003) and hand OA (OR 2.12, 1.46 to 3.07), p<0.0001). Conclusion: The risk of dyslipidemia was twofold greater with than without OA, so lipid disturbances could be a risk factor for OA. Such a result supports the individualisation of the metabolic syndrome-associated OA phenotype. PMID- 29435359 TI - Safety and maintenance of response for tofacitinib monotherapy and combination therapy in rheumatoid arthritis: an analysis of pooled data from open-label long term extension studies. AB - Objective: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. This post hoc analysis evaluated patients receiving tofacitinib monotherapy or combination therapy, as well as those who switched from monotherapy to combination therapy (mono->combo) or vice versa (combo->mono) in long-term extension (LTE) studies. Methods: Data were pooled from open-label LTE studies (ORAL Sequel (NCT00413699; ongoing; data collected 14 January 2016) and NCT00661661) involving patients who participated in qualifying index studies. Efficacy outcomes included American College of Rheumatology 20/50/70 rates, change from baseline in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index and DAS28-4(ESR) and CDAI low disease activity and remission. Safety was evaluated over 96 months. Results: Of the 4967 patients treated, 35.4% initiated tofacitinib monotherapy, 64.6% initiated combination therapy, 2.6% were mono->combo switchers and 7.1% were combo->mono switchers. Patients who switched multiple times were excluded. Of those who initiated monotherapy and combination therapy, 87.8% (1543/1757) and 82.0% (2631/3210), respectively, remained on the same regimen throughout the study; efficacy was maintained. Incidence rates (IRs) for serious adverse events with tofacitinib 5 mg and 10 mg twice daily, respectively, were 9.42 and 8.41 with monotherapy and 8.36 and 10.75 with combination therapy; IRs for discontinuations due to AEs were 7.13 and 6.06 with monotherapy and 7.82 and 8.06 with combination therapy (overlapping CIs). For mono->combo and combo->mono switchers, discontinuations due to AEs were experienced by 0.8% and 0.9%, respectively, within 30 days of switching. Conclusion: Tofacitinib efficacy as monotherapy or combination therapy was maintained through month 48 and sustained to month 72, with minimal switching of treatment regimens. Safety was consistent over 96 months. Clinical trial registration: NCT00413699 (Pre-results) and NCT00661661 (Results). PMID- 29435360 TI - Real-world predictors of 12-month intravenous abatacept retention in patients with rheumatoid arthritis in the ACTION observational study. AB - Introduction: An understanding of real-world predictors of abatacept retention is limited. We analysed retention rates and predictors of abatacept retention in biologic-naive and biologic-failure patients in a 12-month interim analysis of the 2-yearAbataCepTIn rOutiNe clinical practice (ACTION) study. Methods: ACTION was an international, observational study of patients with moderate-to-severe rheumatoid arthritis (RA) who initiated intravenous abatacept. In this 12-month interim analysis, crude abatacept retention rates, predictors of retention and European League Against Rheumatism (EULAR) response were evaluated in both biologic-naive and biologic-failure patients. Retention by rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) status was also assessed, in patients with or without baseline radiographic erosions, and by body mass index (BMI). Results: Overall, 2350/2364 enrolled patients were evaluable (674 biologic naive; 1676 biologic failure). Baseline characteristics were largely similar in biologic naive and biologic-failure groups. Crude retention rates (95% CI) at 12 months were significantly higher in biologic-naive (78.1%(74.7% to 81.2%)) versus biologic-failure patients (69.9%(67.6% to 72.1%); P<0.001). RF/anti-CCP double positivity predicted higher retention in both patient groups, and remained associated with higher retention in patients with erosive disease. BMI did not impact abatacept retention in either patient group, irrespective of RF/anti-CCP serostatus. Good/moderate EULAR response rate at 12 months was numerically higher in biologic-naive (83.8%) versus biologic-failure (73.3%) patients. There were no new safety signals. Conclusion: High levels of intravenous abatacept retention in clinical practice were confirmed, particularly in biologic-naive patients, including in those with poor RA prognostic factors. Retention was unaffected by BMI, regardless of RF/anti-CCP serostatus. Trial registration number: NCT02109666; retrospectively registered 8 April 2014. PMID- 29435361 TI - Chronic but not inflammatory changes at the Achilles' tendon differentiate patients with peripheral spondyloarthritis from other diagnoses - Results from a prospective clinical trial. AB - Background: Imaging has an essential role in the new spondyloarthritis (SpA) classification criteria for axial but not for peripheral manifestations. We evaluated the impact of imaging findings for identification and treatment decisions in patients with peripheral spondyloarthritis (pSpA) and controls (non SpA). Methods: Patients with pSpA (Assessment of SpA international Society criteria, n=30) and non-SpA (n=30), aged <45 years, with painful heels or knees, were recruited. Conventional radiography, grey-scale ultrasound including power Doppler (US/PDUS) and MRI of symptomatic areas were performed to assess inflammatory and structural changes. Mann-Whitney U test was used for group comparisons. Results: In total, 105 painful entheses (71 heels, 34 knees) in 60 patients were examined. Differences between diagnoses were found for symptom duration (pSpA: 17.2+/-27.5 vs non-SpA: 4.4+/-4.3 months), human leucocyte antigen B27 prevalence (67% vs 13%) and gender distribution (53.3% vs 20% male, respectively), all P<0.05. Logistic regression analysis for baseline differences showed that chronic changes (erosions and calcification) in the heel were more frequent in pSpA versus non-SpA by US/PDUS (62.5% vs 28.6% patients and 59.5% vs 26.5% entheses, P<0.05). Inflammatory changes in heel or knee by US/PDUS and MRI could not differentiate between non-SpA and pSpA. Conclusions: Differentiation between pSpA and non-SpA was only possible based on structural but not inflammatory changes in the heels and knees of symptomatic patients. US/PDUS was superior to MRI for this purpose. These findings imply that pSpA is associated with erosive changes at enthesitic sites, while inflammation and susceptibility are of minor influence for the development of erosions and calcification to pSpA. PMID- 29435362 TI - Long-term efficacy and safety of antitumour necrosis factor alpha treatment in rhupus: an open-label study of 15 patients. AB - Background: The efficacy of antitumour necrosis factor alpha (anti-TNF-alpha) treatment is well recognised in rheumatoid arthritis (RA) but remains controversial in systemic lupus erythematosus (SLE). Therefore, the role of anti TNF-alpha treatment in 'Rhupus', a disease sharing features of RA and SLE, is still debated. Objective: To evaluate the efficacy and tolerance of anti-TNF alpha in patients with rhupus. Methods: Fifteen patients with rhupus with Disease Activity Score 28 (DAS 28) >3.2 despite conventional disease-modifying anti rheumatic drugs were included in an open-label study. Patients were monitored at months (M) 3, 6, 12, 24 and 60 with SLE Disease Activity Index (SLEDAI) and DAS 28. Statistical analyses were performed using Bayesian methods and Prob >97.5% was considered significant. Results: Twelve patients were treated with etanercept for a median duration of 62.5 (range: 6-112) months and three patients by adalimumab during 36.0 (range: 4-52) months. At baseline, median DAS 28 and SLEDAI were 5.94 (4.83-8.09) and 6 (4-8), respectively. DAS 28 and SLEDAI decreased significantly after 3 months, respectively, to 3.70 (1.80-6.42) and 4 (0-6) (Prob >99.9%, for both). These changes persisted at M6, M12, M24 and M60 (Prob >99.9%, for all). Median prednisone dose decreased significantly from 15 (5 35) mg/day to 5 (0-20) mg/day after 6 months and over the follow-up (Prob >99.9%, for all). Tolerance was acceptable, with a severe infection rate of 3.0 per 100 patient-years. Conclusion: This pilot study suggests that anti-TNF-alpha is effective in patients with rhupus with refractive arthritis and has an acceptable safety profile. PMID- 29435363 TI - Real-world burden of comorbidities in US patients with psoriatic arthritis. AB - Objectives: We assessed comorbidities associated with psoriatic arthritis in a broad cohort of US-insured adult patients using the Truven Health Analytics MarketScan Database. Methods: Prevalence and incidence rates were assessed for 28 comorbid conditions among adult patients in the MarketScan database with a diagnosis of psoriatic arthritis and having two or more health claims for psoriatic arthritis between 1 July 2008 and 31 July 2015. Findings were compared with those of a similar, previously published analysis of patients with psoriasis. Results: Among a total of 186 552 patients with a diagnosis of psoriatic arthritis, 94 302 had two or more health claims for psoriatic arthritis during the study period and were included in the comorbidity analysis. The prevalence and incidence rates of the most common comorbidities were 47.5% and 35.0% for hyperlipidaemia, respectively; 47.3% and 31.3% for hypertension; 21.2% and 15.4% for depression; 20.2% and 13.5% for type 2 diabetes mellitus; and 16.6% and 12.4% for fibromyalgia. Patients with psoriatic arthritis had notably higher incidence rates of uveitis, fibromyalgia, osteoporosis, Crohn's disease and non alcoholic liver disease than patients with psoriasis. Conclusion: This observational retrospective analysis using the MarketScan database provides real world health claims data on the prevalence and incidence of comorbidities in a large US patient population with psoriatic arthritis. The observed high cardiometabolic comorbidity rates align with those reported in the literature and may help healthcare providers in the comprehensive management of patients with psoriatic arthritis. PMID- 29435364 TI - Secukinumab provides sustained improvements in the signs and symptoms of active ankylosing spondylitis with high retention rate: 3-year results from the phase III trial, MEASURE 2. AB - Background: Secukinumab treatment has previously been shown to significantly improve the signs and symptoms of active ankylosing spondylitis (AS), with responses sustained through 2 years. Here, we report the long-term (3 years) efficacy and safety of secukinumab in the MEASURE 2 study. Methods: MEASURE 2 (NCT01649375) is a 5-year phase III, randomised, double-blind, double-dummy, parallel-group, placebo-controlled study to evaluate the efficacy, safety and tolerability of subcutaneous loading and maintenance dosing of secukinumab in adult subjects with active AS. Subjects were randomised to receive subcutaneous secukinumab 150 mg, 75 mg or placebo at baseline, weeks 1, 2 and 3 and every 4 weeks from week 4. At week 16, placebo-treated subjects were rerandomised to receive secukinumab 150/75 mg. Results: Retention rates were high during weeks 16 156 and were 86% and 76% for secukinumab 150 and 75 mg, respectively. Secukinumab 150 mg provided sustained improvements in the Assessment of Spondyloarthritis International Society ASAS 20/40 response rates at week 156 (70.1%/60.9%) compared with week 52 (74.2%/57.0%); however, there was a slight decrease for secukinumab 75 mg (54.3%/37.0% vs 62.5%/43.2%, respectively). Sustained improvements were observed in all other end points, including Bath Ankylosing Spondylitis Disease Activity Index, AS Disease Activity Score with C reactive protein inactive disease, ASAS 5/6, Short Form-36 Physical Component Summary and ASAS partial remission. Clinical benefits were observed regardless of prior exposure to anti-tumour necrosis factor agents. The safety profile remained favourable and was consistent with previous reports. Conclusions: This study showed sustained improvement through 3 years in signs, symptoms and physical function in subjects with AS. Retention rates were high and secukinumab was well tolerated, with a favourable safety profile. PMID- 29435365 TI - Novel active agents in patients with advanced NSCLC without driver mutations who have progressed after first-line chemotherapy. AB - Despite the efficacy of a number of first-line treatments, most patients with advanced-stage non-small cell lung cancer (NSCLC) experience disease progression that warrants further treatment. In this review, we examine the role of novel active agents for patients who progress after first-line therapy and who are not candidates for targeted therapies. More therapeutic options are needed for the management of patients with NSCLC after failure of first-line chemotherapy. A PubMed search was performed for articles from January 2012 to May 2015 using the keywords NSCLC, antiangiogenic, immunotherapy, second-line, novel therapies and English language articles only. Relevant papers were reviewed; papers outside that period were considered on a case-by-case basis. A search of oncology congresses was performed to identify relevant abstracts over this period. In recent years, antiangiogenic agents and immune checkpoint inhibitors have been added to our armamentarium to treat patients with advanced NSCLC who have progressed on first-line chemotherapy. These include nintedanib, a triple angiokinase inhibitor; ramucirumab, a vascular endothelial growth factor receptor 2 antibody; and nivolumab, pembrolizumab and atezolizumab, just three of a growing list of antibodies targeting the programmed death receptor-1 (PD-1)/PD ligand-1 pathway. Predictive and prognostic factors in NSCLC treatment will help to optimise treatment with these novel agents. The approval of new treatments for patients with NSCLC after the failure of first-line chemotherapy has increased options after a decade of few advances, and holds promise for future evolution of the management of NSCLC. PMID- 29435366 TI - Zika, chikungunya and dengue: the causes and threats of new and re-emerging arboviral diseases. AB - The recent emergence and re-emergence of viral infections transmitted by vectors Zika, chikungunya, dengue, Japanese encephalitis, West Nile, yellow fever and others-is a cause for international concern. Using as examples Zika, chikungunya and dengue, we summarise current knowledge on characteristics of the viruses and their transmission, clinical features, laboratory diagnosis, burden, history, possible causes of the spread and the expectation for future epidemics. Arboviruses are transmitted by mosquitoes, are of difficult diagnosis, can have surprising clinical complications and cause severe burden. The current situation is complex, because there is no vaccine for Zika and chikungunya and no specific treatment for the three arboviruses. Vector control is the only comprehensive solution available now and this remains a challenge because up to now this has not been very effective. Until we develop new technologies of control mosquito populations, the globalised and urbanised world we live in will remain vulnerable to the threat of successive arbovirus epidemics. PMID- 29435367 TI - Anti-Myeloperoxidase Antibodies Associate with Future Proliferative Lupus Nephritis. AB - Background: The subclinical pathophysiology of proliferative lupus nephritis (PLN) has not been fully elucidated. Myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) is associated with PLN, but prediagnostic levels have not been reported. Methods: We performed a retrospective case-control Department of Defense Serum Repository (DoDSR) study comparing MPO-ANCA levels in longitudinal prediagnostic serum samples for 23 biopsy confirmed proliferative lupus nephritis (PLN) patients to DoDSR identified age, sex, race, and age of serum matched healthy and SLE without LN disease controls. We also compared the temporal relationship of MPO-ANCA to anti-double stranded DNA antibodies (dsDNAab). Results: A greater proportion of PLN patients had prediagnostic MPO-ANCA levels above >=3 U/mL and >=6 U/mL compared to SLE without LN (91% versus 43%, p < 0.001; 57% versus 5%, p < 0.001, resp.). In subgroup analysis, the MPO-ANCA threshold of >=3 U/mL was significant at <1 year (88% versus 39%, p = 0.007) and 1-4 years (87% versus 38%, p = 0.009) prior to diagnosis. Statistically significant subclinical MPO-ANCA levels (>=3 U/mL) occurred prior to statistically significant dsDNAab >= 3 IU/ml (89% versus 11%, p = 0.003). Conclusions: Subclinical MPO-ANCA levels could distinguish future PLN from SLE without LN. MPO-ANCA manifests prior to clinical disease and subclinical dsDNAab to suggest that it may contribute directly to PLN pathogenicity. PMID- 29435368 TI - Support Needs and Coping Strategies as Predictors of Stress Level among Mothers of Children with Autism Spectrum Disorder. AB - This study examined maternal stress, coping strategies, and support needs among mothers of children with Autism Spectrum Disorder (ASD). A convenience sample of 70 mothers completed the Parent Stress Index Short Form (PSI-SF), Coping Health Inventory for Parents (CHIP), and Modified Family Needs Questionnaire (FNQ). PSI SF scores reflected clinically significant levels of stress for 77% of mothers, and mothers identified 62.4% of important needs as unmet. The five most frequently reported important unmet needs were (1) financial support; (2) break from responsibilities; (3) understanding of other after-school program children; (4) rest/sleep; (5) help remaining hopeful about the future. Most coping strategies (81%) were identified as helpful. Additionally, both coping strategies and support needs served as predictors for maternal stress. Maternal stress scores decreased by .402 points for each percent increase in helpful coping strategy, and stress scores increased by .529 points with each percent increase in unmet needs. Given large variation in questionnaire responses across participants and studies, utilization of user-friendly questionnaires, such as the PSI-SF, CHIP, and FNQ, is advocated to determine the evolving important needs unique to each family over the child's lifetime as well as guide prioritization of care, compilation of resources, and referrals for additional services. PMID- 29435369 TI - In Vitro Evaluation of Cocoa Pod Husk Pectin as a Carrier for Chronodelivery of Hydrocortisone Intended for Adrenal Insufficiency. AB - This study evaluated the in vitro potential of cocoa pod husk (CPH) pectin as a carrier for chronodelivery of hydrocortisone intended for adrenal insufficiency. FTIR studies found no drug-CPH pectin interactions, and chemometric analysis showed that pure hydrocortisone bears closer similarity to hydrocortisone in hot water soluble pectin (HWSP) than hydrocortisone in citric acid soluble pectin (CASP). CPH pectin-based hydrocortisone matrix tablets (~300 mg) were prepared by direct compression and wet granulation techniques, and the tablet cores were film coated with a 15% HPMC formulation for timed release, followed by a 12.5% Eudragit(r) S100 formulation for acid resistance. In vitro drug release studies of the uncoated and coated matrix tablets in simulated gastrointestinal conditions showed that wet granulation tablets exhibit greater retardation of drug release in aqueous medium than directly compressed tablets. CASP showed greater suppression of drug release in aqueous medium than HWSP. Wet granulation HWSP-based matrix tablets coated to a final coat weight gain of ~25% w/w were optimized for chronodelivery of hydrocortisone in the colon. The optimized tablets exhibited a lag phase of ~6 h followed by accelerated drug release in the colonic region and have potential to control night time cortisol levels in patients with adrenal insufficiency. PMID- 29435370 TI - Analysis of Aminoglycoside Modifying Enzyme Genes Responsible for High-Level Aminoglycoside Resistance among Enterococcal Isolates. AB - Enzymatic modification results in high-level resistance to aminoglycoside (HLAR), which eliminates the synergistic bactericidal effect of combined exposure to a cell wall-active agent and an aminoglycoside. So aim of the study was to determine prevalence of HLAR enterococcal isolate and to study distribution of aminoglycoside modifying enzyme genes in them. A total of 100 nonrepeat isolates of enterococci from various clinical samples were analyzed. As per Clinical and Laboratory Standards Institute guidelines enterococci were screened for HLAR by Kirby-Bauer disc diffusion method. Minimum inhibitory concentration of all isolates for gentamicin and streptomycin was determined by E-test. Multiplex polymerase chain reaction (PCR) was carried out for HLAR enterococcal isolates to identify aminoglycoside modifying enzymes genes responsible for resistance. 60% isolates were found to be high-level gentamicin resistant (HLGR) whereas 45% isolates were found to be high-level streptomycin resistant (HLSR). By multiplex PCR 80% HLGR isolates carried bifunctional aminoglycoside modifying enzyme gene aac(6')-Ie-aph(2'')-Ia whereas 18 out of 45 high-level streptomycin resistant, that is, 40%, isolates carried aph(3')-IIIa. However, aph(2'')-Ib, aph(2'')-Ic, aph(2'')-Id, and ant(4')-Ia genes which encode other aminoglycosides modifying enzymes were not detected. Bifunctional aminoglycoside modifying enzyme gene aac(6')-Ie-aph(2'')-Ia is the predominant gene responsible for HLAR. PMID- 29435371 TI - Low-Frequency Repetitive Transcranial Magnetic Stimulation for Stroke-Induced Upper Limb Motor Deficit: A Meta-Analysis. AB - Background and Purpose: This meta-analysis aimed to evaluate the therapeutic potential of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over the contralesional hemisphere on upper limb motor recovery and cortex plasticity after stroke. Methods: Databases of PubMed, Medline, ScienceDirect, Cochrane, and Embase were searched for randomized controlled trials published before Jun 31, 2017. The effect size was evaluated by using the standardized mean difference (SMD) and a 95% confidence interval (CI). Resting motor threshold (rMT) and motor-evoked potential (MEP) were also examined. Results: Twenty-two studies of 1 Hz LF-rTMS over the contralesional hemisphere were included. Significant efficacy was found on finger flexibility (SMD = 0.75), hand strength (SMD = 0.49), and activity dexterity (SMD = 0.32), but not on body function (SMD = 0.29). The positive changes of rMT (SMD = 0.38 for the affected hemisphere and SMD = -0.83 for the unaffected hemisphere) and MEP (SMD = -1.00 for the affected hemisphere and SMD = 0.57 for the unaffected hemisphere) were also significant. Conclusions: LF-rTMS as an add-on therapy significantly improved upper limb functional recovery especially the hand after stroke, probably through rebalanced cortical excitability of both hemispheres. Future studies should determine if LF rTMS alone or in conjunction with practice/training would be more effective. Clinical Trial Registration Information: This trial is registered with unique identifier CRD42016042181. PMID- 29435372 TI - Trans-Synaptic Spread of Amyloid-beta in Alzheimer's Disease: Paths to beta Amyloidosis. AB - Neuronal activity has a strong causal role in the production and release of the neurotoxic beta-amyloid peptide (Abeta). Because of this close link, gradual accumulation of Abeta into amyloid plaques has been reported in brain areas with intense neuronal activity, including cortical regions that display elevated activation at resting state. However, the link between Abeta and activity is not always linear and recent studies report exceptions to the view of "more activity, more plaques." Here, we review the literature about the activity-dependent production of Abeta in both human cases and AD models and focus on the evidences that brain regions with elevated convergence of synaptic connections (herein referred to as brain nodes) are particularly vulnerable to Abeta accumulation. Next, we will examine data supporting the hypothesis that, since Abeta is released from synaptic terminals, beta-amyloidosis can spread in AD brain by advancing through synaptically connected regions, which makes brain nodes vulnerable to Abeta accumulation. Finally, we consider possible mechanisms that account for beta-amyloidosis progression through synaptically linked regions. PMID- 29435374 TI - A Case of Status-Epilepticus-Associated Transient Hyperammonemia in the Emergency Department. AB - This report describes a case of transient hyperammonemia following tonic-clonic status epilepticus with an initial ammonia level of 537 Umol/L. This appears to be the highest transient ammonia level reported in the literature in this clinical scenario. This is an affirmation that an initial elevated ammonia level in the absence of hepatic dysfunction should be interpreted with caution when associated with status epilepticus. Repeat levels should be drawn to identify transient hyperammonemia and determine the need for treatment if levels do not decrease. PMID- 29435373 TI - The Role of Mammalian Glial Cells in Circadian Rhythm Regulation. AB - Circadian rhythms are biological oscillations with a period of about 24 hours. These rhythms are maintained by an innate genetically determined time-keeping system called the circadian clock. A large number of the proteins involved in the regulation of this clock are transcription factors controlling rhythmic transcription of so-called clock-controlled genes, which participate in a plethora of physiological functions in the organism. In the brain, several areas, besides the suprachiasmatic nucleus, harbor functional clocks characterized by a well-defined time pattern of clock gene expression. This expression rhythm is not restricted to neurons but is also present in glia, suggesting that these cells are involved in circadian rhythmicity. However, only certain glial cells fulfill the criteria to be called glial clocks, namely, to display molecular oscillators based on the canonical clock protein PERIOD, which depends on the suprachiasmatic nucleus for their synchronization. In this contribution, we summarize the current information about activity of the clock genes in glial cells, their potential role as oscillators as well as clinical implications. PMID- 29435375 TI - Hydrogen Peroxide Induced Colitis: A Case Report and Literature Review. AB - Constipation is a common condition. Hydrogen peroxide enemas have rarely been reported as a home remedy for constipation in the pediatric age group. We present a case report and literature review of hydrogen peroxide induced colitis in pediatric siblings, aged 2 years and 9 years. The siblings presented with vomiting and bloody diarrhea an hour following the enema. Physical exam, vital signs, blood, and electrolyte counts were normal, but CT scans showed mucosal thickening of the rectum and colon. Their symptoms resolved after oral intake was curtailed and fluids were replaced intravenously. We discuss existing reports of complications from hydrogen peroxide enemas. Patients may present with abdominal pain and bloody diarrhea. Onset of symptoms varied from minutes to a day and bowel ulceration with necrosis and perforation has occurred, although fatality is rare. Diagnostic tests included computed tomography (CT) scan, sigmoidoscopy, or biopsy. Recovery period ranged from 3 days to 8 months. Public education regarding the dangers of hydrogen peroxide enemas is needed. PMID- 29435376 TI - A Rare Encounter with an Expanding Pseudocyst of the Spleen. AB - Background: Splenic Pseudocyst (SP) is a diagnostic rarity, with cystic lesions of spleen themselves being uncommon. Establishing a preoperative diagnosis could help in specific management but this is rather challenging. Here we present a common presentation of an uncommon diagnosis. Case Presentation: A 47-year-old lady, previously well, presented to the outpatient clinic with intermittent left hypochondrial pain radiating towards left shoulder for 2 months not associated with fever, jaundice, or weight loss. Abdominal examination revealed nontender hepatosplenomegaly. The initial abdominal ultrasonogram (USG) was suggestive of a hydatid cyst, for which she received a course of antihelminthics. At follow-up, after finding no clinical improvement and radiological worsening, she underwent an exploratory laparotomy. A cyst replacing entire lower pole and a significant portion of splenic hilum was found. Total splenectomy was performed. The specimen was reported to be a SP. Conclusion: SP is a unique entity, usually misdiagnosed as a parasitic lesion and often treated with antihelminthic medicines. The natural course of disease, however, follows a subsequent failure of symptom resolution and radiological worsening that ultimately demands surgical attention. Based on size, location, and intraoperative findings, either total or partial splenectomy is required. The final histopathological report often presents a diagnostic surprise. PMID- 29435377 TI - A Young, Immunocompetent Woman with Small Bowel and Hepatic Mucormycosis Successfully Treated with Aggressive Surgical Debridements and Antifungal Therapy. AB - A 24-year-old woman with coeliac disease and transient neutropenia developed mucormycosis with extensive involvement of the liver and small intestine. She was successfully treated with aggressive surgical debridements and long-term antifungal therapy with liposomal amphotericin B and posaconazole. PMID- 29435378 TI - Standardized Digital Colposcopy with Dynamic Spectral Imaging for Conservative Patient Management. AB - Background: Colposcopy is subjective and management of young patients with high grade disease is challenging, as treatments may impair subsequent pregnancies and adversely affect obstetric outcomes. Conservative management of selected patients is becoming more popular amongst clinicians; however it requires accurate assessment and documentation. Novel adjunctive technologies for colposcopy could improve patient care and help individualize management decisions by introducing standardization, increasing sensitivity, and improving documentation. Case: A nulliparous 27-year-old woman planning pregnancy underwent colposcopy following high-grade cytology. The colposcopic impression was of low-grade changes, whilst the Dynamic Spectral Imaging (DSI) map of the cervix suggested potential high grade. A DSI-directed biopsy confirmed CIN2. At follow-up, both colposcopy and DSI were suggestive of low-grade disease only, and image comparison confirmed the absence of previously present acetowhite epithelium areas. Histology of the transformation zone following excisional treatment, as per patient's choice, showed no high-grade changes. Conclusion: Digital colposcopy with DSI mapping helps standardize colposcopic examinations, increase diagnostic accuracy, and monitor cervical changes over time, improving patient care. When used for longitudinal tracking of disease and when it confirms a negative colposcopy, it can help towards avoiding overtreatment and hence decrease morbidity related to cervical excision. PMID- 29435379 TI - Mantle Cell Lymphoma in the Thyroid: A Rare Presentation. AB - Background: While 2% of all extranodal Non-Hodgkin Lymphomas present in the thyroid, there exists insufficient data to describe the incidence of mantle cell lymphoma in the thyroid. A case series of 1400 patients revealed that <1% of thyroid lymphomas may be MCL; hence better understanding of the disease course is essential. Patient Findings: A 65-year-old female was referred for a multinodular goiter. Multiple fine needle aspirations from the dominant right nodule were consistent with Hashimoto's thyroiditis and flow cytometry was negative. Due to progressing dysphagia, she underwent total thyroidectomy. Summary: Pathology revealed MCL with mantle zone growth pattern in the right thyroid. Flow cytometry showed monoclonal B cells comprising 9% of total cells. The Ki-67 index was 10%. She was diagnosed as having stage IIE MCL and offered conservative management by medical oncology, given that she had no B symptoms. Conclusion: Though chemotherapy is the treatment of choice in MCL, a subset of patients with low grade disease may be observed. As in our patient, mantle zone growth pattern and a Ki-67 index < 10% suggest a favorable prognosis. A diagnosis of primary MCL in the thyroid remains rare and staging modalities as well as treatment options continue to evolve. PMID- 29435380 TI - Imaging Findings of Jugular Foramen Meningocele in a Neurofibromatosis Type 1 Patient. AB - Neurofibromatosis type I (NF1) is a neurocutaneous disorder that involves autosomal dominant transmission. Skull defects, including sphenoid dysplasia and calvarial defects, are a rare finding in patients with NF1. Spinal meningocele and sphenoid wing dysplasia have been identified in NF1 but the occurrence of meningoceles at the skull base is extremely rare. A rare instance of jugular foramen meningocele being identified in an NF1 patient on imaging is described in this paper. To the best of our knowledge, only two such cases have been reported in the English literature. PMID- 29435381 TI - A Rare Case of Intermittent Claudication Associated with Impaired Arterial Vasodilation. AB - Exercise-related intermittent claudication is marked by reduced blood flow to extremities caused by either stenosis or impaired vascular function. Although intermittent claudication is common in the elderly, it rarely occurs in the young and middle-aged individuals. Here, we report a case of exercise-related claudication in a 41-year-old woman, in the absence of overt vascular pathology. Using a series of imaging and functional tests, we established that her complaints were due to impaired arterial vasodilation, possibly due to a defect in nitrous oxide-mediated dilation. The symptoms were reversible upon administration of a calcium antagonist, showing reversibility of the vascular impairment. Identification of reversible vascular "stiffness" merits consideration in young and otherwise healthy subjects with claudication of unknown origin. PMID- 29435382 TI - High Rates of Tramadol Use among Treatment-Seeking Adolescents in Malmo, Sweden: A Study of Hair Analysis of Nonmedical Prescription Opioid Use. AB - Background: Nonmedical prescription opioid use (NMPOU) is a growing problem and tramadol has been suggested as an emerging problem in young treatment-seeking individuals. The aim of the present study was to investigate, through hair analysis, NMPOU in this group and, specifically, tramadol use. Methods: In a study including 73 treatment-seeking adolescents and young adults at an outpatient facility for young substance users, hair specimens could be obtained from 59 subjects. Data were extracted on sociodemographic background variables and psychiatric diagnoses through MINI interviews. Results: In hair analysis, tramadol was by far the most prevalent opioid detected. Thirty-two percent screened positive for opioids, and of those, all but one were positive for tramadol. Ninety-eight percent reported problematic cannabis use. Significantly more opioid-positive patients also screened positive for other (noncannabis) drugs, compared to nonopioid users. Sixty-four percent fulfilled criteria of DSM IV psychiatric disorders, other than substance use disorders according to MINI. Fifty-three percent met the symptom criteria count of ADHD above cut-off level. Conclusion: In the present setting, tramadol, along with high rates of cannabis use, may represent a novel pattern of substance use among young treatment-seeking subjects with problematic substance use and high rates of concurrent psychiatric problems. PMID- 29435383 TI - Application of QuEChERS for Determining Xenobiotics in Foods of Animal Origin. AB - The use of pesticides and veterinary drugs results in the appearance of residues of xenobiotics in foods. Thus, several methods have been developed for monitoring them; however, most are tedious and expensive. By contrast, the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) methodology involves a microextraction that yields small samples and has been applied for the analysis of various xenobiotics including pesticides, antibiotics, and mycotoxins. QuEChERS has shown advantages over other techniques including fast sample preparation, reduced needs for reagents and labware, and versatility. This approach allows the simultaneous determination of pesticides with various polarities and volatilities and can be easily modified for the analysis of a wide range of xenobiotics in various matrices including animal products rich in fat. Nevertheless, to attain high recoveries, the extraction, cleanup, and concentration steps have to be optimized according to the target compounds and matrix. Hence, QuEChERS is a promising and environmentally friendly methodology for the high-throughput routine analysis of xenobiotics in animal products. This review focuses on the application of QuEChERS to foods of animal origin and describes recent developments for the optimization of the analysis of veterinary drugs, pesticides, polycyclic aromatic hydrocarbons, and other compounds of concern. PMID- 29435384 TI - Optimization of Extract Method for Cynomorium songaricum Rupr. by Response Surface Methodology. AB - The present study aimed to evaluate the quality of Cynomorium songaricum Rupr. from different producing areas, which is an edible, holoparasitic, and desert plant that has been used in traditional medicine for improving immunity and kidney function and treating constipation. We optimized the extract conditions by response surface methodology (RSM) and determined the content of gallic acid, protocatechuic acid, and catechin of C. songaricum simultaneously from different producing areas by high-performance liquid chromatography (HPLC). It is the first study in which the RSM was used to optimize the extract condition of C. songaricum with multiple evaluation factors, ensuring the efficiency and accuracy of the study. The results were analyzed by principal component analysis, and they showed that the quality of C. songaricum from Qinghai Province was the best, while the quality of C. songaricum from Gansu Province was the worst. For the first time, the two ecotypes of C. songaricum, including Outside Great Wall type and Inside Great Wall type, were discovered and identified by the chemical marker protocatechuic acid. This study is the scientific basis for quality evaluation, especially for food safety. PMID- 29435385 TI - The Elevation of LC-ESI-Q-TOF-MS Response in the Analysis of Isoquinoline Alkaloids from Some Papaveraceae and Berberidaceae Representatives. AB - Twenty-five methanol extracts obtained from various representatives of Papaveraceae and Berberidaceae botanical families (genera: Papaver, Argemone, Eschscholzia, Chelidonium, Glaucium, and Berberis) were screened for their alkaloid content in an optimized method suitable for the LC-ESI-Q-TOF-MS analysis. Twelve pharmacologically important isoquinoline alkaloids from four groups, aporphines, benzylisoquinolines, protoberberines, and benzophenanthridines, present in these traditionally used plant species were quantitatively determined in each studied sample, providing their alkaloid profile. A Zorbax Stable Bond RP-18 column and a mobile phase composed of 0.1% formic acid and 0.1% formic acid in acetonitrile (v/v) were used at the flow rate of 0.2 mL/min. A profound study on the optimization of MS response to four groups of isoquinoline alkaloids (validation of capillary voltage, gas flows, nebulizer pressure, skimmer, and fragmentor voltages), repeatability of results, and stability and linearity of measurements were described, showing, among others, 3000 V of capillary voltage, 350 degrees C of gas temperature, 12 L/min of gas flows, nebulizer pressure of 35 psig, 65 V for skimmer voltage, and 30 V for collision energy as the most advantageous operation parameters. PMID- 29435386 TI - Healthcare Reform ? Public Health Reform: On Pathogens, Poverty, and Prevention. PMID- 29435387 TI - Systemic Mastocytosis: The Difficult Patient with a Rare Disease. Case Presentation and Brief Review. AB - Mastocytosis is a rare process involving the activation and accumulation of clonal mast cells categorized by cutaneous or systemic involvement. Although the diagnosis of cutaneous disease can be straightforward and confirmed via skin biopsy, systemic disease mimics more common disease processes making diagnosis a challenge. The widespread physiologic distribution of mast cells causes a variety of symptoms with aberrant expression including fatigue, headache, depression, dyspnea, dyspepsia, nausea, and abdominal pain. We present a patient with a three year history of multiple, non-specific complaints prompting extensive evaluation at significant financial and emotional cost without therapeutic relief. This case presentation illustrates some of the pitfalls of evaluation and management of mastocytosis when symptoms are treated in isolation. Ultimately, our patient was diagnosed with indolent systemic mastocytosis (ISM), which has a good overall prognosis but no curative treatment. Providers must maintain a high index of suspicion for mastocytosis in order to make the diagnosis and facilitate appropriate treatment and screening. PMID- 29435388 TI - Impact of Laboratory Practice Changes on the Diagnosis of Tuberculosis with the Introduction of Xpert MTB/RIF in Kiribati. AB - The Republic of Kiribati, Central Pacific, has the largest tuberculosis epidemic in the region. There is a national tuberculosis control program, which has used smear microscopy for acid-fast bacilli as the main diagnostic tool for many years. In 2015, an Xpert MTB/RIF machine was procured and became functional within the tuberculosis hospital. The aim of this cross-sectional study, using routinely collected data, was to determine the effects of introducing Xpert MTB/RIF on laboratory smear microscopy practices and the pattern of registered tuberculosis cases. Between February 2015 and January 2016, there were 220 Xpert MTB/RIF assays performed with 6.4% errors and 15% detection of Mycobacterium tuberculosis: one patient showed rifampicin-resistance. One year before and after introducing Xpert MTB/RIF, the number of presumptive tuberculosis patients increased by 9% from 2,138 to 2,322. There were no changes in demographic characteristics, smear-positive results, or acid-fast bacilli grade between the two periods. The number of specimens cultured for Mycobacterium tuberculosis significantly declined from 638 to zero, with 76 positive MTB cultures before and none after introducing Xpert MTB/RIF. There was a significant change in the profile of registered tuberculosis cases with more children (34% versus 21%) and fewer bacteriologically-confirmed cases (29% versus 43%) - P < .001. Since the deployment of Xpert MTB/RIF in Kiribati, there have been a small number of assays performed and this has been associated with no adverse effects on smear microscopy, a stoppage in mycobacterial cultures, and a change in the types and categories of diagnosed tuberculosis. PMID- 29435389 TI - Medical School Hotline: School of Medicine Departments - Year in Review 2017, Part 2. PMID- 29435390 TI - Insights in Public Health: In What Ways are Hawaii's HIV Prevention Services Engaging Gay Male Couples and Using Technology? AB - Partner-oriented services and Health Information and Communication technology (HICT) in the forms of mHealth (eg, smartphone applications), eHealth (eg, interactive websites), telemedicine, and social media play an important and growing role in HIV prevention. Accordingly, the present study sought to describe: (1) the primary and secondary HIV prevention services available in Hawai'i, (2) the prevention services that are available for gay male couples and partners, and (3) the prevention services that use HICT. Information about prevention services and use of HICT were obtained from websites and phone calls made to 19 organizations in the state, including the Hawai'i Department of Health. Overall, partner-oriented services were limited and only 1 couples-based service was currently being offered. Technology, namely social media, was used by 14 organizations, primarily to increase HIV awareness and advertise events. These findings may inform how best to adapt and better leverage the use of innovative technological tools to help expand access to HIV testing and counseling, sexual health education, and case management services for gay male couples and other MSM populations in the state. PMID- 29435392 TI - Moving to 3D: relationships between coral planar area, surface area and volume. AB - Coral reefs are a valuable and vulnerable marine ecosystem. The structure of coral reefs influences their health and ability to fulfill ecosystem functions and services. However, monitoring reef corals largely relies on 1D or 2D estimates of coral cover and abundance that overlook change in ecologically significant aspects of the reefs because they do not incorporate vertical or volumetric information. This study explores the relationship between 2D and 3D metrics of coral size. We show that surface area and volume scale consistently with planar area, albeit with morphotype specific conversion parameters. We use a photogrammetric approach using open-source software to estimate the ability of photogrammetry to provide measurement estimates of corals in 3D. Technological developments have made photogrammetry a valid and practical technique for studying coral reefs. We anticipate that these techniques for moving coral research from 2D into 3D will facilitate answering ecological questions by incorporating the 3rd dimension into monitoring. PMID- 29435393 TI - Spontaneous Pneumothoraces and Hemothoraces in Sarcomas. AB - Spontaneous pneumothoraces and hemothoraces are rare manifestations of sarcomas occurring more commonly in specific histologic types, chemotherapy and/or anti angiogenic therapy. Early identification of spontaneous pneumothoraces and hemothoraces improves the clinical outcomes. In this article, we present a case series of three patients with soft tissue and bone sarcomas who developed spontaneous pneumothoraces and/or hemothoraces and discuss the current literature highlighting the evidence behind these complications. PMID- 29435394 TI - Mentor-mentee Relationship: A Win-Win Contract In Graduate Medical Education. AB - Scholarly activities (i.e., the discovery of new knowledge; development of new technologies, methods, materials, or uses; integration of knowledge leading to new understanding) are intended to measure the quality and quantity of dissemination of knowledge. A successful mentorship program is necessary during residency to help residents achieve the six core competencies (patient care, medical knowledge, practice-based learning and improvement, systems-based practice, professionalism, interpersonal and communication skills) required by the Accreditation Council for Graduate Medical Education (ACGME). The role of the mentor in this process is pivotal in the advancement of the residents' knowledge about evidence-based medicine. With this process, while mentees become more self regulated, exhibit confidence in their performance, and demonstrate more insight and aptitude in their jobs, mentors also achieve elevated higher self-esteem, enhanced leadership skills, and personal gratification. As such, we may conclude that mentoring is a two-sided relationship; i.e., a 'win-win' style of commitment between the mentor and mentee. Hence, both parties will eventually advance academically, as well as professionally. PMID- 29435396 TI - Rhodol Derivatives as Selective Fluorescent Probes for the Detection of HgII Ions and the Bioimaging of Hypochlorous Acid. AB - Invited for this month's cover picture is the group of Professor Keith Man-Chung Wong from the Southern University of Science and Technology (P.R. China). The cover picture illustrates a novel rhodol-based fluorescence probe from the structural combination of rhodamine and fluorescein motifs. Read the full text of their Full Paper at 10.1002/open.201700154. PMID- 29435395 TI - Atherothrombosis is a Thrombotic, not Inflammatory Disease. AB - The authors hypothesize that thrombosis causes both the complications of atherosclerosis as well as the underlying lesion, the atherosclerotic plaque, which develops from the organization of mural thrombi. These form in areas of slow blood flow, which develop because of flow separation created by changing vascular geometry and elevated blood viscosity. Many phenomena typically ascribed to inflammation or "chronic oxidative stress", such as the development of fatty streaks, "endothelial dysfunction," "vulnerable plaques," and the association of mild elevations of C-reactive protein and cytokines with atherothrombosis are better explained by hemorheologic and hemodynamic abnormalities, particularly elevated blood viscosity. Elevated blood viscosity decreases the perfusion of skeletal muscle, leading to myocyte expression of the myokine IL-6, decreased glucose uptake, insulin resistance, hyperglycemia, and metabolic syndrome. The hyperfibrinogenemia and hypergammaglobulinemia present in true inflammatory diseases foster atherothrombosis by increasing blood viscosity. PMID- 29435397 TI - Wearable Chemosensors: A Review of Recent Progress. AB - In recent years, there has been growing demand for wearable chemosensors for their important potential applications in mobile and electronic healthcare, patient self-assessment, human motion monitoring, and so on. Innovations in wearable chemosensors are revolutionizing the modern lifestyle, especially the involvement of both doctors and patients in the modern healthcare system. The facile interaction of wearable chemosensors with the human body makes them favorable and convenient tools for the detection and long-term monitoring of the chemical, biological, and physical status of the human body at a low cost with high performance. In this Minireview, we give a brief overview of the recent advances and developments in the field of wearable chemosensors, summarize the basic types of wearable chemosensors, and discuss their main functions and fabrication methods. At the end of this paper, the future development direction of wearable chemosensors is prospected. With continued interest and attention to this field, new exciting progress is expected in the development of innovative wearable chemosensors. PMID- 29435398 TI - Spaced Titania Nanotube Arrays Allow the Construction of an Efficient N-Doped Hierarchical Structure for Visible-Light Harvesting. AB - Regularly spaced TiO2 nanotubes were prepared by anodizing a titanium substrate in triethylene glycol electrolyte at elevated temperature. In comparison to conventional TiO2 nanotubes, spaced nanotubes possess an adjustable spacing between the individual nanotubes; this allows for controlled buildup of a hierarchical nanoparticle-on-nanotube structure. Here, we use this principle for layer-by-layer decoration of the tubes with TiO2 nanoparticles. The hierarchical structure after N doping and NH3 treatment at 450 degrees C shows a significant enhancement of visible-light absorption, although it only carries a low doping concentration of nitrogen. For optimized N-doped and particle-decorated spaced TiO2 nanotubes, a considerable improvement in photocatalytic activity is obtained in comparison with conventional N-doped TiO2 nanotubes or comparable N-doped nanoparticle films. This is attributed to an enhanced visible-light absorption through the N-doped nanoparticle shell and a fast charge separation between the shell and the one-dimensional nanotubular core. PMID- 29435399 TI - Rhodol Derivatives as Selective Fluorescent Probes for the Detection of HgII Ions and the Bioimaging of Hypochlorous Acid. AB - Two sensors, 1 with a spirolactone group and 2 with a spirolactam group containing a phenyl isothiocyanate moiety, based on rhodol, were designed and synthesized in order to obtain materials with excellent optical properties for the detection of environmentally and biologically important Hg2+ and hypochlorous acid (HClO) ions. The crystal structure of 1 revealed two moieties, a rhodamine like portion with a spirolactone and a fluorescein-like portion without a spirolactone. In the absence of analyte, 1 produced an optical output with a maximum absorption and emission at 475 and 570 nm, respectively, which was attributed to the fluorescein-like moiety without a spirolactone. In contrast, the rhodamine-like moiety containing a spirolactone was activated by the addition of H+ or Hg2+ ions, and 1 yielded new absorption and emission peaks at 530 and 612 nm, respectively. Further functionalization with a phenyl isothiocyanate group afforded 2, a fluorescent probe for HClO. High selectivity and sensitivity towards the hypochlorite ion were anticipated, owing to the stoichiometric and irreversible formation of a thiosemicarbazide group, which led to dramatic fluorescence responses. With good functionality at physiological pH, probe 2 was successfully used to image HClO in HeLa cells. PMID- 29435400 TI - Encapsulation of Cadmium Selenide Nanocrystals in Biocompatible Nanotubes: DFT Calculations, X-ray Diffraction Investigations, and Confocal Fluorescence Imaging. AB - The encapsulation of CdSe nanocrystals within single-walled carbon nanotube (SWNT) cavities of varying dimensions at elevated temperatures under strictly air tight conditions is described for the first time. The structures of CdSe nanocrystals under confinement inside SWNTs was established in a comprehensive study, combining both experimental and DFT theoretical investigations. The calculated binding energies show that all considered polymorphs [(3:3), (4:4), and (4:2)] may be obtained experimentally. The most thermodynamically stable structure (3:3) is directly compared to the experimentally observed CdSe structures inside carbon nanotubes. The gas-phase DFT-calculated energy difference between "free" 3:3 and 4:2 structures (whereby 3:3 models a novel tubular structure in which both Cd and Se form three coordination, as observed experimentally for HgTe inside SWNT, and 4:2 is a motif derived from the hexagonal CuI bulk structure in which both Cd and Se form 4 or 2 coordination) is surprisingly small, only 0.06 eV per formula unit. X-ray powder diffraction, Raman spectroscopy, high-resolution transmission electron microscopy, and energy dispersive X-ray analyses led to the full characterization of the SWNTs filled with the CdSe nanocrystals, shedding light on the composition, structure, and electronic interactions of the new nanohybrid materials on an atomic level. A new emerging hybrid nanomaterial, simultaneously filled and beta-d-glucan coated, was obtained by using pristine nanotubes and bulk CdSe powder as starting materials. This displayed fluorescence in water dispersions and unexpected biocompatibility was found to be mediated by beta-d-glucan (a biopolymer extracted from barley) with respect to that of the individual inorganic material components. For the first time, such supramolecular nanostructures are investigated by life-science techniques applied to functional nanomaterial characterization, opening the door for future nano-biotechnological applications. PMID- 29435401 TI - Rapid Synthesis of Sub-10 nm Hexagonal NaYF4-Based Upconverting Nanoparticles using Therminol(r) 66. AB - We report a simple one-pot method for the rapid preparation of sub-10 nm pure hexagonal (beta-phase) NaYF4-based upconverting nanoparticles (UCNPs). Using Therminol(r) 66 as a co-solvent, monodisperse UCNPs could be obtained in unusually short reaction times. By varying the reaction time and reaction temperature, it was possible to control precisely the particle size and crystalline phase of the UCNPs. The upconversion (UC) luminescence properties of the nanocrystals were tuned by varying the concentrations of the dopants (Nd3+ and Yb3+ sensitizer ions and Er3+ activator ions). The size and phase-purity of the as-synthesized core and core-shell nanocrystals were assessed by using complementary transmission electron microscopy, dynamic light scattering, X-ray diffraction, and small-angle X-ray scattering studies. In-depth photophysical evaluation of the UCNPs was pursued by using steady-state and time-resolved luminescence spectroscopy. An enhancement in the UC intensity was observed if the nanocrystals, doped with optimized concentrations of lanthanide sensitizer/activator ions, were further coated with an inert/active shell. This was attributed to the suppression of surface-related luminescence quenching effects. PMID- 29435402 TI - Making and Operating Molecular Machines: A Multidisciplinary Challenge. AB - Movement is one of the central attributes of life, and a key feature in many technological processes. While artificial motion is typically provided by macroscopic engines powered by internal combustion or electrical energy, movement in living organisms is produced by machines and motors of molecular size that typically exploit the energy of chemical fuels at ambient temperature to generate forces and ultimately execute functions. The progress in several areas of chemistry, together with an improved understanding of biomolecular machines, has led to the development of a large variety of wholly synthetic molecular machines. These systems have the potential to bring about radical innovations in several areas of technology and medicine. In this Minireview, we discuss, with the help of a few examples, the multidisciplinary aspects of research on artificial molecular machines and highlight its translational character. PMID- 29435403 TI - Medicinal Attributes of Lignans Extracted from Piper Cubeba: Current Developments. AB - Lignans are a large class of natural products that have been isolated from many plants. They reveal diverse biological activities, especially antiviral and antitumor properties. From Piper cubeba, lignans of several classes can be isolated from the roots, rhizomes, stems, leaves, seeds, and fruits. Among its various chemical constituents, (-)-cubebin and (-)-hinokinin are found in significant quantities. Although they have been known for some time, during the last few decades their biological properties have been studied by several research groups. The cubebins have been identified as a lactol monomer and dimers as a mixture of diastereoisomers. Recently, their structural characterization and the synthesis of the possible structures have led to the correction of some earlier structural proposals. This review describes the more recent developments in the study of the medicinal attributes of cubebin and hinokinin extracted from Piper cubeba and the synthesis and biological testing of some analogues. PMID- 29435404 TI - Magnetic Nature of the CrIII-LnIII Interactions in [CrIII2LnIII3] Clusters with Slow Magnetic Relaxation. AB - Two 3d-4f hetero-metal pentanuclear complexes with the formula {[CrIII2LnIII3L10(OH)6(H2O)2]Et3NH} [Ln=Tb (1), Dy (2); HL=pivalic acid, Et3N=triethylamine] have been produced. The metal core of each cluster is made up of a trigonal bipyramid with three LnIII ions (plane) and two CrIII ions (above and below) held together by six MU3-OH bridges. Also reported with this series is the diamagnetic CrIII-YIII analogue (3). Fortunately, we successfully prepared AlIII-LnIII analogues with the formula {[AlIII2LnIII3L10(OH)6(H2O)2]Et3NH?H2O} [Ln=Tb (4), Dy (5)], containing diamagnetic AlIII ions, which can be used to evaluate the CrIII-LnIII magnetic nature through a diamagnetic substitution method. Subsequently, static (dc) magnetic susceptibility studies reveal dominant ferromagnetic interactions between CrIII and LnIII ions. Dynamic (ac) magnetic susceptibility studies show frequency-dependent out-of-phase (chi'') signals for [CrIII2TbIII3] (1), [CrIII2DyIII3] (2), and [AlIII2DyIII3] (5), which are derived from the single-ion behavior of LnIII ions and/or the CrIII-LnIII ferromagnetic interactions. PMID- 29435405 TI - Does Educational Marginalization Mediate the Path from Childhood Cumulative Risk to Criminal Offending? AB - Purpose: Early exposure to multiple risk factors is known to predict involvement in criminal offending. The purpose of this study was to examine the processes responsible for this association. Specifically, the focus was on the capacity of adolescent educational experience to mediate the effect of childhood cumulative risk (CCR) on criminal offending, net of expected continuity in antisocial propensity and behavior. Methods: Data from the Northern Finland Birth Cohort Study 1986 (n = 5,743) were used to estimate a structural equation model to examine the hypothesized pathways. The educational pathway was captured by a latent variable (educational marginalization) consisting of indicators of low academic performance, weak school attachment, and low educational aspirations. Results: CCR had a strong positive relation with educational marginalization, which, in turn, emerged as a statistically significant predictor of having criminal record by age 19. Although continuity in antisocial behavior accounted for most of the total effect of CCR on criminal offending, one third of it was mediated by educational marginalization. Conclusions: The results highlight the adolescent educational experience as a promising target of intervention in efforts to curb criminal careers among children at risk. PMID- 29435406 TI - The Stl repressor from Staphylococcus aureus is an efficient inhibitor of the eukaryotic fruitfly dUTPase. AB - DNA metabolism and repair is vital for the maintenance of genome integrity. Specific proteinaceous inhibitors of key factors in this process have high potential for deciphering pathways of DNA metabolism and repair. The dUTPase enzyme family is responsible for guarding against erroneous uracil incorporation into DNA. Here, we investigate whether the staphylococcal Stl repressor may interact with not only bacterial but also eukaryotic dUTPase. We provide experimental evidence for the formation of a strong complex between Stl and Drosophila melanogaster dUTPase. We also find that dUTPase activity is strongly diminished in this complex. Our results suggest that the dUTPase protein sequences involved in binding to Stl are at least partially conserved through evolution from bacteria to eukaryotes. PMID- 29435407 TI - BMP3 expression by osteoblast lineage cells is regulated by canonical Wnt signaling. AB - Bone morphogenetic protein (BMP) and canonical Wnt (cWnt) signaling factors are both known to regulate bone mass, fracture risk, fracture repair, and osteoblastogenesis. BMP3 is the most abundant BMP and negatively regulates osteoblastogenesis and bone mass. Thus, identifying the mechanism by which BMP3 acts to depress bone formation may allow for the development of new therapeutics useful in the treatment for osteopenia and osteoporosis. Here, we report that cWnt signaling stimulates BMP3 expression in osteoblast (OB) lineage cells. The expression of BMP3 increases with OB differentiation. Treatment of cells with various cWnt proteins stimulated BMP3 expression. Mice with enhanced cWnt signaling had high expression levels of BMP3. Our data suggest that reduction in BMP3 levels may contribute beneficially to the positive effect of cWnt agonists on bone mass. PMID- 29435408 TI - A putative RNA binding protein from Plasmodium vivax apicoplast. AB - Malaria is caused by Apicomplexa protozoans from the Plasmodium genus entering the bloodstream of humans and animals through the bite of the female mosquitoes. The annotation of the Plasmodium vivax genome revealed a putative RNA binding protein (apiRBP) that was predicted to be trafficked into the apicoplast, a plastid organelle unique to Apicomplexa protozoans. Although a 3D structural model of the apiRBP corresponds to a noncanonical RNA recognition motif with an additional C-terminal alpha-helix (alpha3), preliminary protein production trials were nevertheless unsuccessful. Theoretical solvation analysis of the apiRBP model highlighted an exposed hydrophobic region clustering alpha3. Hence, we used a C-terminal GFP-fused chimera to stabilize the highly insoluble apiRBP and determined its ability to bind U-rich stretches of RNA. The affinity of apiRBP toward such RNAs is highly dependent on ionic strength, suggesting that the apiRBP-RNA complex is driven by electrostatic interactions. Altogether, apiRBP represents an attractive tool for apicoplast transcriptional studies and for antimalarial drug design. PMID- 29435409 TI - miR-204-5p suppresses hepatocellular cancer proliferation by regulating homeoprotein SIX1 expression. AB - Fewer than 30% of patients with hepatocellular carcinoma (HCC) are eligible to receive curative therapies, and so a better understanding of the molecular mechanisms of HCC is needed to identify potential therapeutic targets. The role of microRNA (miRNA) in modulating tumour progression has been demonstrated, and therapies targeting miRNA appear promising. miR-204-5p has been shown to function in numerous types of cancer, but its role in HCC remains unclear. In this study, we found that miR-204-5p expression was downregulated in cancerous HCC tissues compared to nontumour tissues. Kaplan-Meier survival curve analysis also showed that low expression of miR-204-5p predicted worse outcomes of HCC patients. In addition, miR-204-5p expression was significantly lower in HCC cell lines. The function of miR-204-5p was also assessed both in vitro and in vivo. We demonstrated that ectopic expression of miR-204-5p in HCC cell lines inhibited HCC cell proliferation and clonogenicity using CCK8, BrdU and colony-forming assays, while the inhibition of miR-204-5p enhanced proliferation and clonogenicity. Further in vivo studies in mice further confirmed the proliferation capacity of miR-204-5p. We also identified sine oculis homeobox homologue 1 (SIX1) as a direct target of miR-204-5p and showed that it was inversely correlated with miR-204-5p in both human and mouse HCC tissues. Transfection of miR-204-5p mimics in BEL-7404 cells blocked the cell cycle by inhibiting the expression of cyclin-D1 and cyclin-A1, cell cycle-related factors regulated by SIX1. More importantly, overexpression of the 3'UTR mutant SIX1 but not the wild-type SIX1 abolished the suppressive effect of miR-204-5p, and downregulated SIX1 in BEL-7402 cells that transfected with miR-204 inhibitors could partly block the inhibitory effect of miR-204-5p on proliferation. Thus, we have demonstrated that miR-204-5p suppresses HCC proliferation by directly regulating SIX1 and its downstream factors. PMID- 29435410 TI - Comparison of a new nanoform of the photosensitizer chlorin e6, based on plant phospholipids, with its free form. AB - Photodynamic therapy is an advanced method of treating cancer and various benign diseases, including infections. It uses light-activated molecules [photosensitizers (PSs)] to generate reactive oxygen species (ROS) when irradiated with light of a specific wavelength. This study examined the photophysical and photosensitizing activity of the PS chlorin e6 incorporated in a delivery system based on plant phospholipids. This new nanoform of chlorin e6 comprised particles with a diameter of 18.4 +/- 2.5 nm and zeta potential of 34.6 +/- 3.0 mV. Incorporation of chlorin e6 in phospholipid nanoparticles was observed to cause a bathochromic shift of Q-band absorption maximum by 14 nm without an absorption change in the range of the Soret band. Fluorescence intensity of chlorin e6 embedded in the phospholipid nanoparticles increased 1.7 fold. Chlorin e6 in phospholipid nanoparticles, when irradiated, was able to generate ROS as shown by oxidation of polyunsaturated fatty acids of the phospholipid matrix of the delivery system and reduced l-glutathione. In vivo it was demonstrated that the new nanoform of chlorin e6 provides more accumulation of PSs in tumor tissue than its free form. Moreover, its accumulation in the skin was lower and its elimination from the skin almost five times faster than when administered in free form. The observed differences of this new nanoform of chlorin e6 should lead to enhancement of antitumor efficacy and a decrease in phototoxicity. PMID- 29435411 TI - Ellagitannin HeT obtained from strawberry leaves is oxidized by bacterial membranes and inhibits the respiratory chain. AB - Plant secondary metabolism produces a variety of tannins that have a wide range of biological activities, including activation of plant defenses and antimicrobial, anti-inflammatory and antitumoral effects. The ellagitannin HeT (1 O-galloyl-2,3;4,6-bis-hexahydroxydiphenoyl-beta-d-glucopyranose) from strawberry leaves elicits a strong plant defense response, and exhibits antimicrobial activity associated to the inhibition of the oxygen consumption, but its mechanism of action is unknown. In this paper we investigate the influence of HeT on bacterial cell membrane integrity and its effect on respiration. A beta galactosidase unmasking experiment showed that HeT does not disrupt membrane integrity. Raman spectroscopy analysis revealed that HeT strongly interacts with the cell membrane. Spectrochemical analysis indicated that HeT is oxidized in contact with bacterial cell membranes, and functional studies showed that HeT inhibits oxygen consumption, NADH and MTT reduction. These results provide evidence that HeT inhibits the respiratory chain. PMID- 29435412 TI - miRNAexpression profile of retinal pigment epithelial cells under oxidative stress conditions. AB - Deep analysis of regulative mechanisms of transcription and translation in eukaryotes could improve knowledge of many genetic pathologies such as retinitis pigmentosa (RP). New layers of complexity have recently emerged with the discovery that 'junk' DNA is transcribed and, among these, miRNAs have assumed a preponderant role. We compared changes in the expression of miRNAs obtained from whole transcriptome analyses, between two groups of retinal pigment epithelium (RPE) cells, one untreated and the other exposed to the oxidant agent oxidized low-density lipoprotein (oxLDL), examining four time points (1, 2, 4 and 6 h). We found that 23 miRNAs exhibited altered expression in the treated samples, targeting genes involved in several biochemical pathways, many of them associated to RP for the first time, such as those mediated by insulin receptor signaling and son of sevenless. Moreover, five RP causative genes (KLHL7, RDH11,CERKL, AIPL1 and USH1G) emerged as already validated targets of five altered miRNAs (hsa miR-1307, hsa-miR-3064, hsa-miR-4709, hsa-miR-3615 and hsa-miR-637), suggesting a tight connection between induced oxidative stress and RP development and progression. This miRNA expression analysis of oxidative stress-induced RPE cells has discovered new regulative functions of miRNAs in RP that should lead to the discovery of new ways to regulate the etiopathogenesis of RP. PMID- 29435413 TI - The E3 ubiquitin ligase MuRF2 attenuates LPS-induced macrophage activation by inhibiting production of inflammatory cytokines and migration. AB - Muscle RING-finger (MuRF) proteins are E3 ubiquitin ligases that are expressed in striated muscle. MuRF2 is an important member of this family, but whether it is expressed in tissues other than striated muscle has not been thoroughly elucidated to date. In this study, we determined that MuRF2 is also expressed in other vital organs, including liver, lung, brain, spleen and kidney. Moreover, we show that the level of MuRF2 expression is significantly decreased in hepatic mononuclear cells of mice with lipopolysaccharide (LPS)/d-galactosamine-induced hepatitis and negatively correlated with the serum levels of alanine aminotransferase and aspartate aminotransferase in these mice. Furthermore, the expression of MuRF2 was down-regulated in RAW264.7 cells activated with LPS but not in cells treated with polyinosinic-polycytidylic acid (Poly(I:C)) or with lipidosome plus Poly(I:C). We also found that MuRF2 was able to translocate from the cytoplasm to the nucleus in RAW264.7 cells activated with LPS but not in cells treated with Poly(I:C). In addition, we demonstrated that interleukin 6 and tumour necrosis factor alpha production and macrophage migration were inhibited after MuRF2 was overexpressed in RAW264.7 cells. We further verified that nuclear factor-kappaB p65 subunit level was greatly reduced in RAW264.7 macrophage nuclei by gain of function. Taken together, these findings indicate that MuRF2 may rescue LPS-induced macrophage activation by suppressing the production of proinflammatory cytokines and cell migration. We also identify a novel function of MuRF2 in non-muscle tissues and cells. PMID- 29435414 TI - Kinetic analysis of the isoleucyl-tRNA synthetase mechanism: the next reaction cycle can start before the previous one ends. AB - : Aminoacyl-tRNA synthetases join correct amino acids to their cognate tRNA at the start of the protein synthesis. Through the kinetic analysis, it is possible to estimate how their functional details correspond to the known structural features. Kinetic analysis of the isoleucyl-tRNA synthetase (IleRS) from Escherichia coli was accomplished. Sixteen different steady-state two-ligand experiments were statistically analysed simultaneously so that the same rate equations and same rate and dissociation constants applied to all experiments. The so-called rapid equilibrium segments procedure was used to derive the rate equations. The final best-fit mechanism included the normal activation and transfer steps, and reorganization of the steps between them and after the transfer step. In addition, the analysis strongly suggested an additional activation step, formation of a new isoleucyl-AMP before the isoleucyl-tRNA was freed from the enzyme. The removal of Ile-tRNA was possible without the formation of Ile-AMP if both isoleucine and ATP were bound to the E-Ile-tRNA complex, but this route covered only 11% of the total formation of Ile-tRNA. In addition to the Mg2+ in MgATP or MgPPi, only two tRNA-bound Mg2+ were required to explain the magnesium dependence in the best-fit mechanism. The first Mg2+ could be present in all steps before the second activation and was obligatory in the first reorganizing step and transfer step. The second Mg2+ was present only at the transfer step, whereas elsewhere it prevented the reaction, including the activation reactions. Chloride inhibited the IleRS reaction, while 100 mm KCl caused 50% inhibition if the ionic strength was kept constant with K-acetate. The Kmapp (tRNA) value was increased from 0.057 to 1.37 MUm when the KCl concentration was increased from 0 to 200 mm. The total rate equation helps to understand the reaction route and how the simultaneous presence of Ile-tRNA and Ile-AMP can cause new possibilities to proofreading mechanisms of this enzyme. Enzyme: Isoleucyl-tRNA synthetase (EC 6.1.1.5). PMID- 29435415 TI - The postpartum effect of maternal diabetes on the circulating levels of sirtuins and superoxide dismutase. AB - Gestational diabetes mellitus (GDM) is a glucose intolerance disorder which occurs during pregnancy as a result of insulin insensitivity; it usually disappears after delivery. However, some women with GDM can develop type 2 diabetes (T2D) after delivery, and the mechanisms by which this occurs remain unknown. This study compared the levels of sirtuins (NAD-dependent deacetylases) and antioxidative enzymes in postpartum women with previous GDM (pGDM) or T2D and in postpartum women with a previous healthy pregnancy (controls). Women with pGDM showed upregulated levels of sirtuin 1 (SIRT1) mRNA and protein, with reduced expression levels of sirtuin 3 (SIRT3) and superoxide dismutase 2 (SOD2), relative to the controls. Women with T2D similarly showed a lower level of SIRT3 mRNA than the controls. Lipid peroxidation (malondialdehyde) was higher in women with pGDM than in the controls. These data show that in women with pGDM, the reduced level of SIRT3 may play a role in the reduced SOD2 level, possibly leading to oxidative stress, which, in turn, upregulates the level of SIRT1. These results might confer the risk of future diabetes development in women with pGDM, as a similar reduction in SIRT3 was found in women with T2D. PMID- 29435416 TI - Characterisation of an aptamer against the Runt domain of AML1 (RUNX1) by NMR and mutational analyses. AB - Since the invention of systematic evolution of ligands by exponential enrichment, many short oligonucleotides (or aptamers) have been reported that can bind to a wide range of target molecules with high affinity and specificity. Previously, we reported an RNA aptamer that shows high affinity to the Runt domain (RD) of the AML1 protein, a transcription factor with roles in haematopoiesis and immune function. From kinetic and thermodynamic studies, it was suggested that the aptamer recognises a large surface area of the RD, using numerous weak interactions. In this study, we identified the secondary structure by nuclear magnetic resonance spectroscopy and performed a mutational study to reveal the residue critical for binding to the RD. It was suggested that the large contact area was formed by a DNA-mimicking motif and a multibranched loop, which confers the high affinity and specificity of binding. PMID- 29435417 TI - Tip60 is associated with resistance to X-ray irradiation in prostate cancer. AB - Tip60, an oncogene, accelerates cell growth by regulating androgen receptor translocation into the nucleus in prostate cancer. However, the mechanism of Tip60 in the response of prostate cancer to radiotherapy, and radioresistance, has not been studied. Using human prostate cancer samples and two human prostate cancer cell lines (LNCaP and DU145), Tip60 protein expression and the acetylation of ataxia telangiectasia mutant (ATM) were analysed by western blotting and immunoprecipitation. Tip60 was downregulated with small interfering RNA. Cells were irradiated using X-rays at 0.25 Gy.min-1. Cell viability was assessed by the MTT assay. The expression of Tip60 protein was increased in radioresistant prostate cancer tissues in comparison with radiosensitive tissues, which was also confirmed in both irradiated DU145 and LNCaP cells. Furthermore, the acetylation of ATM was also upregulated in a time-dependent manner after irradiation of both DU145 and LNCaP cells. Additionally, depletion of Tip60 decreased the survival of LNCaP and DU145 cells by inducing apoptosis, reduced the acetylation of ATM and decreased the expression of phosphorylated ATM, Chk2 and cdc25A in both DU145 and LNCaP cells after X-ray irradiation. The results of this study demonstrated that the expression of Tip60 may be related to the radioresistance of prostate cancer and could serve as a promising predictive factor for prostate cancer patients receiving radiotherapy. PMID- 29435419 TI - Two nonsense somatic mutations in MEN1 identified in sporadic insulinomas. AB - Insulinomas are functional pancreatic neuroendocrine tumors that cause hypoglycemia and severe morbidity. The aim of our study was to identify gene mutations responsible for tumorigenesis of sporadic insulinoma. Whole exome sequencing analysis was performed on tumors and paired peripheral blood from three patients with insulinomas. After initial analysis, somatic mutations were obtained and a deleterious protein product was further predicted by various bioinformatic programs. Whole exome sequencing identified 55 rare somatic mutations among three insulinoma patients, including MEN1 gene nonsense mutations (c. 681C>G; p.Tyr227* in exon 4 of MEN1 and c. 346G>T; p.Glu116* in exon 2 of MEN1) in two different tumor samples. The mutations resulted in a significant truncation of the protein and a non-functional gene product, which was involved in defective binding of menin to proteins implicated in genetic and epigenetic mechanisms. Our results extend the growing list of pathogenic MEN1 mutations in sporadic cases of insulinoma. PMID- 29435418 TI - Identification of key miRNAs and genes associated with stomach adenocarcinoma from The Cancer Genome Atlas database. AB - Stomach adenocarcinoma (STAD) is the second leading cause of cancer death and a fuller understanding of its molecular basis is needed to develop new therapeutic targets. miRNA and mRNA data were downloaded from The Cancer Genome Atlas database, and the differentially expressed miRNAs and genes were identified. The target genes of differentially expressed miRNAs were screened by prediction tools. Furthermore, the biological function of these target genes was investigated. Several key miRNAs and their target genes were selected for validation using quantitative real-time polymerase chain reaction (qRT-PCR). The Gene Expression Omnibus (GEO) dataset was used to verify the expression of selected miRNAs and target genes. The diagnostic value of identified miRNAs and genes was accessed by receiver operating characteristic analysis. A total of 1248 differentially expressed genes were identified in STAD. Additionally, nine differentially expressed miRNAs were identified and 160 target genes of these nine miRNAs were identified via target gene detection. Interestingly, they were remarkably enriched in the calcium signaling pathway and bile secretion. qRT-PCR confirmed the expression of several key miRNAs and their target genes. The expression levels of hsa-miR-145-3p, hsa-miR-145-5p, ADAM12,ACAN,HOXC11 and MMP11 in the GEO database were compatible with the bioinformatics results. hsa-miR-139 5p, hsa-miR-145-3p and MMP11 have a potential diagnostic value for STAD. Differential expression of the mature form of miRNAs (hsa-miR-139-5p, hsa-miR-145 3p, hsa-miR-145-5p and hsa-miR-490-3p) and genes including ADAM12,ACAN,HOXC11 and MMP11 and calcium and bile secretion signaling pathways may play important roles in the development of STAD. PMID- 29435420 TI - Effect of curcumin on amyloid-like aggregates generated from methionine-oxidized apolipoprotein A-I. AB - Curcumin is a polyphenolic phytonutrient that has antineurodegenerative properties. In this study, we investigated the anti-amyloidogenic properties of curcumin. Following incubation with curcumin, intrinsic tryptophan fluorescence emission of apolipoprotein (apo) A-I was strongly quenched. At the same time, curcumin fluorescence emission was enhanced. The fluorescence emission spectra of curcumin in the presence of amyloid-like aggregates formed by methionine-oxidized (ox) apoA-I varied, depending on whether curcumin was added before, or after, aggregate formation. The impact of curcumin on the structure of the aggregating material was revealed by the lower amount of beta-structure in ox-apoA-I amyloid like aggregates formed in the presence of curcumin, compared to aggregates formed without curcumin. However, the kinetics of ox-apoA-I amyloid-like aggregate formation was not altered by the presence of curcumin. Moreover, electron microscopy analysis detected no discernable differences in amyloid morphology when ox-apoA-I amyloid-like aggregates were formed in the presence or absence of curcumin. In conclusion, curcumin interacts with apoA-I and alters the structure of ox-apoA-I amyloid-like aggregates yet does not diminish the propensity of ox apoA-I to form aggregates. PMID- 29435421 TI - Mother-to-child transmission of HIV and its predictors among HIV-exposed infants at Bamenda Regional Hospital, Cameroon. AB - Background: Mother-to-child transmission (MTCT) of HIV, has been a major global public health burden. Despite the use of antiretroviral prophylaxis by HIV positive pregnant women and their infants, safe obstetric practice and safe infant feeding habits in the prevention of MTCT of HIV, the prevalence of HIV among HIV-exposed infants is still high in Cameroon. Objective: Our objectives were to determine the prevalence, assess the predictors and determine the effect of combination antiretroviral therapy (cART) on MTCT of HIV at the regional hospital in Bamenda, Cameroon. Methods: This was a retrospective study. Secondary data from 877 HIV-exposed infants aged <= 72 weeks were extracted from the records between January 2008 and December 2014. The predictors and effect of cART on MTCT of HIV were analysed using a multivariable logistic regression model and risk analysis, respectively. Results: Out of 877 HIV-exposed infants, 62 were positive for HIV, giving a prevalence of 7.1%. Maternal antiretroviral intervention and infant age group were statistically significant predictors of MTCT of HIV. HIV-positive mothers who were on cART were 2.49 times less likely to transmit HIV than those who were not on cART. Conclusion: In order to reduce the prevalence of HIV among HIV-exposed infants, maternal antiretroviral intervention should be targeted and the use of cART by HIV-positive pregnant women should be encouraged. PMID- 29435422 TI - Use of matrix-assisted laser desorption/ionisation-time of flight mass spectrometry analyser in a diagnostic microbiology laboratory in a developing country. AB - Background: Rapid and accurate identification of pathogens is of utmost importance for management of patients. Current identification relies on conventional phenotypic methods which are time consuming. Matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS) is based on proteomic profiling and allows for rapid identification of pathogens. Objective: We compared MALDI-TOF MS against two commercial systems, MicroScan Walkaway and VITEK 2 MS. Methods: Over a three-month period from July 2013 to September 2013, a total of 227 bacteria and yeasts were collected from an academic microbiology laboratory (N = 121; 87 Gram-negatives, seven Gram-positives, 27 yeasts) and other laboratories (N = 106; 35 Gram-negatives, 34 Gram-positives, 37 yeasts). Sixty-five positive blood cultures were initially processed with Bruker Sepsityper kit for direct identification. Results: From the 65 blood culture bottles, four grew more than one bacterial pathogen and MALDI-TOF MS identified only one isolate. The blood cultures yielded 21 Gram-negatives, 43 Gram-positives and one Candida. There were 21 Escherirchia coli isolates which were reported by the MALDI-TOF MS as E. coli/Shigella. Of the total 292 isolates, discrepant results were found for one bacterial and three yeast isolates. Discrepant results were resolved by testing with the API system with MALDI-TOF MS showing 100% correlation. Conclusion: The MALDI-TOF MS proved to be very useful for rapid and reliable identification of bacteria and yeasts directly from blood cultures and after culture of other specimens. The difference in time to identification was significant for all isolates. However, for positive blood cultures with minimal sample preparation time there was a massive difference in turn-around time with great appreciation by clinicians. PMID- 29435423 TI - Development of a real-time PCR assay and comparison to CHROMagarTM STEC to screen for Shiga toxin-producing Escherichia coli in stool, Cape Town, South Africa. AB - Introduction: Shiga toxin-producing Escherichia coli (STEC) is an emerging infectious pathogen which could lead to haemolytic uremic syndrome. Even though previous studies have compared the performance of CHROMagarTMSTEC to real-time polymerase chain reaction (PCR) in Europe, no study has been done to assess its performance on African isolates. Objectives: This project aimed to validate and test an in-house-developed duplex real-time PCR and use it as a reference standard to determine the performance of CHROMagarTMSTEC on African isolates from diarrhoeic stool samples. Methods: This study evaluated STEC diagnostic technology on African isolates. An in-house-developed duplex real-time PCR assay for detection of stx1 and stx2 was validated and tested on diarrhoeic stool samples and then used as a reference standard to assess the performance of CHROMagarTMSTEC. Real-time PCR was used to screen for stx in tryptic soy broth and the suspected STEC isolates, while conventional PCR was used to detect the other virulence genes possessed by the isolates. Results: The real-time PCR limit of detection was 5.3 target copies/MUL of broth. The mean melting temperature on melt-curve analysis for detection of stx1 was 58.2 degrees C and for stx2 was 65.3 degrees C. Of 226 specimens screened, real-time PCR detected stx in 14 specimens (6.2%, 95% confidence interval = 3.43% - 10.18%). The sensitivity, specificity, negative predictive value and positive predictive value of the CHROMagarTMSTEC were 33.3%, 77.4%, 95.3% and 11.3%. Conclusions: The in-house developed real-time PCR assay is a sensitive and specific option for laboratory detection of STEC as compared to CHROMagarTMSTEC in this setting. PMID- 29435425 TI - Honing in on disease etiology. PMID- 29435424 TI - Point-of-care diagnosis and risk factors of infantile, rotavirus-associated diarrhoea in Calabar, Nigeria. AB - Background: Rotaviruses are the primary cause of acute gastroenteritis in young children worldwide and a significant proportion of these infections occur in Africa. Objectives: In the present study, we determined the prevalence and risk factors of rotavirus infection among children younger than age 5 years with or without diarrhoea in Calabar, Nigeria, using a rapid point-of-care test. Methods: Two hundred infants younger than age 5 years presenting with acute gastroenteritis and a control group of 200 infants without diarrhoea were tested for rotavirus. Each stool sample was homogenised in an extraction buffer and the supernatant added into the sample well of the Rida Quick rotavirus test cassette and allowed to run for 5 minutes at room temperature. When both the control band and test band were visible on the test cassette a positive result was recorded, whereas when only the control band was visible a negative results was recorded. Results: Rotavirus was detected in 25 (12.5%) of children with diarrhoea and in no children without diarrhoea. Our results demonstrated that children who were exclusively breast-fed by their mothers were not infected with rotavirus and that 92% of the infants infected with rotavirus experienced vomiting. Conclusion: These data demonstrate that asymptomatic rotavirus infection is rare and that rotavirus is commonly detected in stool samples of children suffering from diarrhoea with concomitant vomiting. Use of point-of-care rotavirus tests will enhance early diagnosis of rotavirus-associated diarrhoea and reduce irrational use of antibiotics. PMID- 29435426 TI - Detection of the Janus kinase 2 V617F mutation using a locked nucleic-acid, real time polymerase chain reaction assay. AB - The purpose of this study was to develop a real time polymerase chain reaction (PCR) assay for the detection of the JAK2 V617F mutation that could be used in diagnostic laboratories. Sanger sequencing and a newly developed locked nucleic acid, real-time PCR assay were used to detect the JAK2 V617F mutation. There was 100% agreement between the sequencing and PCR analysis. Both assays were able to detect the mutation in all 24 of the 60 test specimens harbouring the mutation. PMID- 29435427 TI - Nanocosmetics: benefits and risks. AB - Various nanomaterials/nanoparticles (NPs) have been used for the development of cosmetic products - a field so-called nanocosmetic formulations. These advanced materials offer some benefits, while their utilization in the cosmetic formulations may be associated with some risks. The main aim of this editorial is to highlight the benefits and risks of the nanomaterials used in the cosmetic products. PMID- 29435428 TI - Study-based registers of randomized controlled trials: Starting a systematic review with data extraction or meta-analysis. AB - Introduction: Despite years of use of study-based registers for storing reports of randomized controlled trials (RCTs), the methodology used in developing such registers/databases has not been documented. Such registers are integral to the process of scientific reviewing. We document and discuss methodological aspects of the development and use of study-based registers. Although the content is focused on the study-based register of randomized/controlled clinical trials, this work applies to developers of databases of all sorts of studies related to the human, animals, cells, genes, and molecules. Methods: We describe necessity, rationale, and steps for the development, utilization and maintenance of study based registers as well as the challenges and gains for the organizations supporting systematic reviews of the published and unpublished literature. Conclusion: The ultimate goal of having a study-based register is to facilitate efficient production of systematic reviews providing rapid, yet accurate, evidence for the decision-makers. We argue that moving towards study-based registers is an inevitable welcome direction and that infrastructures are ready for such movement. PMID- 29435429 TI - Effect of hydroxychloroquine on oxidative/nitrosative status and angiogenesis in endothelial cells under high glucose condition. AB - Introduction: Under the diabetic condition, sustained production of oxidative/nitrosative stress results in irreversible vascular injuries. A great number of diabetic pathologies, such as inefficient or aberrant neo-angiogenesis emerge following chronic hyperglycemic condition. Lack of enough data exists regarding hydroxychloroquine (HCQ) contribution on angiogenesis during diabetes mellitus. Methods: To better address whether HCQ could blunt or exacerbate oxidative status and angiogenesis under high glucose condition (HCG), human umbilical vein endothelial cells (HUVECs) were exposed to 30 uM HCQ in combination with 30 mM glucose over a course of 72 hours. Viability was measured was evaluated by MTT assay. We used Griess method and TBARS assay to monitor changes in the levels of NO and MDA followed by flow cytometric analysis of ROS using DCFDA. To show the impact of HCQ on cell motility and in vitro angiogenic properties, we exploited routine scratch test and in vitro tubulogenesis, respectively. Results: Our data showed that HCQ diminished cell viability under 5 and 30 mM glucose contents. HCQ significantly decreased the total levels of nitric oxide (NO), malondialdehyde (MDA), and reactive oxygen species (ROS) in both sets of environments. Additionally, inhibitory effects were observed on cell migration after exposure to HCQ (P < 0.001). Anti-angiogenic activity of HCQ was confirmed by the reduction of tube areas under a normal or surplus amount of glucose (P < 0.001). Conclusion: In overall, results suggest that HCQ changes the oxidative/nitrosative status of HUVECs both in 5 and 30 mM conditions. HCQ is able to reduce migration and angiogenic activity of HUVECs irrespective of the glucose content. PMID- 29435430 TI - Development and evaluation of exemestane-loaded lyotropic liquid crystalline gel formulations. AB - Introduction: The use of liquid crystalline (LC) gel formulations for drug delivery has considerably improved the current delivery methods in terms of bioavailability and efficacy. The purpose of this study was to develop and evaluate LC gel formulations to deliver the anti-cancer drug exemestane through transdermal route. Methods: Two LC gel formulations were prepared by phase separation coacervation method using glyceryl monooleate (GMO), Tween 80 and Pluronic(r) F127 (F127). The formulations were characterized with regard to encapsulation efficiency (EE), vesicle size, Fourier transform infrared (FTIR) spectroscopy, surface morphology (using light and fluorescence microscopy), in vitro release, ex vivo permeation, in vitro effectiveness test on MDA-MB231 cancer cell lines and histopathological analysis. Results: Results exhibited that the EE was 85%-92%, vesicle size was 119.9-466.2 nm while morphology showed spherical vesicles after hydration. An FTIR result also revealed that there was no significant shift in peaks corresponding to Exemestane and excipients. LC formulations release the drug from cellulose acetate and Strat-MTM membrane from 15%-88.95%, whereas ex vivo permeation ranges from 37.09-63%. The in vitro effectiveness study indicated that even at low exemestane concentrations (12.5 and 25 MUg/mL) the formulations were able to induce cancer cell death, regardless of the surfactant used. Histopathological analysis thinning of the epidermis as the formulations penetrate into the intercellular regions of squamous cells. Conclusion: The results conjectured that exemestane could be incorporated into LC gels for the transdermal delivery system and further preclinical studies such as pharmacokinetic and pharmacodynamic studies will be carried out with suitable animal models. PMID- 29435431 TI - Spectroscopic, thermodynamic and molecular docking studies of bovine serum albumin interaction with ascorbyl palmitate food additive. AB - Introduction: Ascorbyl palmitate (AP) is an example of natural secondary food antioxidant, which has been used for oxidative rancidity prevention in food industry. In this study, the interaction of AP with bovine serum albumin (BSA) was investigated. Methods: The mechanism of BSA interaction with AP was investigated using spectroscopic methods (UV-Vis, fluorescence). The thermodynamic parameters including enthalpy change (DeltaH), entropy change (DeltaS), and Gibb's free energy (DeltaG) were calculated using Van't Hoff equation at different temperatures. Results: The experimental results showed that UV-Vis absorption spectra of BSA decreased upon increasing AP concentration, indicating that the AP can bind to BSA. Formation of the AP-BSA complex was approved by quenching of fluorescence and the quenching mechanism was found to be resultant from dynamic procedure. The positive values of both DeltaH and DeltaS showed that hydrophobic forces were the major binding forces. The negative value of DeltaG demonstrated that AP interacts with BSA spontaneously. Molecular docking results confirmed that AP binds to BSA through hydrophobic forces. Conclusion: The attained results showed that AP can bind to BSA and effectively distributed into the bloodstream. PMID- 29435432 TI - Efficient and stable transformation of Dunaliella pseudosalina by 3 strains of Agrobacterium tumefaciens. AB - Introduction: Several platforms including mammalian, plant and insect cells as well as bacteria, yeasts, and microalgae are available for the production of recombinant proteins. Low efficiency of delivery systems, extracellular and intracellular degradation of foreign genes during transformation, difficulties in targeting and importing into the nucleus, and finally problems in integration into nuclear genome are the most bottlenecks of classical plasmids for producing recombinant proteins. Owing to high growth rate, no common pathogen with humans, being utilized as humans' food, and capability to perform N-glycosylation, microalgae are proposed as an ideal system for such biotechnological approaches. Here, Agrobacterium tumefaciens is introduced as an alternative tool for transformation of the microalga Dunaliella pseudosalina. Methods: The transformation of gfp gene into the D. pseudosalina was evaluated by three strains including EHA101, GV3301 and GV3850 of A. tumefaciens. The integrating and expression of gfp gene were determined by PCR, RT-PCR, Q-PCR and SDS-PAGE analyses. Results: The T-DNA of pCAMBIA1304 plasmid was successfully integrated into the genome of the microalgal cells. Although all of the strains were able to transform the algal cells, GV3301 possessed higher potential to transform the microalgal cells in comparison to EHA101 and GV3850 strains. Moreover, the stability of gfp gene was successfully established during a course of two months period in the microalgal genome. Conclusion : Agrobacterium is introduced as a competent system for stable transformation of Dunaliella strains in order to produce eukaryotic recombinant proteins. PMID- 29435433 TI - Association of glutathione S-transferase polymorphisms with the severity of mustard lung. AB - Introduction: Glutathione S-transferase (GST) is one of the major detoxifiers in alveoli. Polymorphism in GST genes can influence the ability of individuals to suppress oxidative stress and inflammation. The present study was aimed to explore the hypothesis that the genetic polymorphisms of GST T1, M1 and P1 are associated with the severity of the mustard lung in the sulfur mustard-exposed individuals. Methods: Blood samples were taken from 185 sulfur mustard-exposed and 57 unexposed subjects. According to the stage of the mustard lung, sulfur mustard-exposed patients were categorized in the mild/moderate and severe/very severe groups. A multiplex PCR method was conducted to identify GSTM1 and GSTT1 null genotypes. To determine the polymorphisms of GSTP1 in exon 5 (Ile105Val) and exon 6 (Ala114Val), RFLP-PCR method was performed. Results: The frequency of GSTM1 homozygous deletion was significantly higher in the severe/very severe patients compared with the mild/moderate subjects (66.3% vs. 48%, P = 0.013). The GSTM1 null genotype was associated with the severity of mustard lung (adjusted odds ratio [OR], 2.257; 95% CI, 1.219-4.180). There was no significant association between GSTT1 and GSTP1 polymorphisms with the severity of the mustard lung. Conclusion: The different distribution of GSTM1 null genotype in severe/very severe and mild/moderate groups indicated that the severity of the mustard lung might be associated with the genetic polymorphism(s). PMID- 29435434 TI - The study of association between reduced folate carrier 1 (RFC1) polymorphism and non-syndromic cleft lip/palate in Iranian population. AB - Introduction: Cleft lip/palate is one of the most common congenital defects and is supposed to have multifactorial etiology, including a complex interaction between genetics and environment. Reduced folate carrier 1 (RFC1) gene takes part in folate transportation within the cells. In this study, the association of A80G polymorphism in the RFC1 gene with the non-syndromic cleft lip/palate (nsCL/P) was investigated in Iranian infants for the first time. Methods: In this case control survey, 122 Iranian infants with nsCL/P and 164 healthy infants were investigated for RFC1 polymorphism by PCR and RFLP methods. The results were statistically compared with control group, odds ratios with 95% CI were estimated by univariate and multivariate logistic regression model and a P <0.05 was considered statistically significant. Results: The RFC1 G allele was significantly higher (P=0.001; OR=7, 95% CI: 4.7-10.2) in the cases (60.3%) compared with the controls (17.9%). Not only the RFC1 AG genotype was significantly higher (P<0.001; OR=44, 95% CI: 14.6-133) in cases (67.8%) than the controls (27.4%), but also GG genotype (P<0.001; OR=85, 95% CI: 20.5-352) was much higher in cases (26.4%) than the controls (4.3%). Conclusion: Our study indicated that the RFC1 (A80G) polymorphism was associated with the nsCL/P in Iranian population. Moreover, 80GG homozygosity was significant in the cases. The presence of G allele can be considered as a risk factor for the nsCL/P. Infants with the GG and AG genotypes were more prone to cleft lip/palate as compared to the AA ones. This finding emphasizes the role of RFC1 gene and the intracellular levels of folate. PMID- 29435435 TI - Stimuli-responsive chitosan-based nanocarriers for cancer therapy. AB - Introduction: Stimuli-responsive nanocarriers offer unique advantages over the traditional drug delivery systems (DDSs) in terms of targeted drug delivery and on-demand release of cargo drug molecules. Of these, chitosan (CS)-based DDSs offer several advantages such as high compatibility with biological settings. Methods: In this study, we surveyed the literature in terms of the stimuli responsive nanocarriers and discussed the most recent advancements in terms of CS based nanosystems and their applications in cancer therapy and diagnosis. Results: These advanced DDSs are able to release the entrapped drugs in response to a specific endogenous stimulus (e.g., pH, glutathione concentration or certain enzymes) or exogenous stimulus (e.g., temperature, light, ultrasound, and magnetic field) at the desired time and target site. Dual-responsive nanocarriers by the combination of different stimuli have also been developed as efficient and improved DDSs. Among the stimuli-responsive nanocarriers, CS-based DDSs offer several advantages, including biocompatibility and biodegradability, antibacterial activity, ease of modification and functionalization, and non immunogenicity. They are as one of the most ideal smart multifunction DDSs. Conclusion: The CS-based stimuli-responsive multifunctional nanosystems (NSs) offer unique potential for the targeted delivery of anticancer agents and provide great potential for on-demand and controlled-release of anticancer agents in response to diverse external/internal stimuli. PMID- 29435436 TI - Osteosarcoma: Accelerating Progress Makes for a Hopeful Future. AB - Patients who develop osteosarcoma in 2017 receive treatment that remains essentially unchanged since the 1970s. Outcomes likewise remain largely unimproved. Large, collaborative, multinational efforts to improve therapy have evaluated strategies leveraging both cytotoxic intensification and immunomodulatory agents. While these have confirmed our capacity to conduct such trials, results have proved largely disappointing. This has motivated efforts to focus on the basic biology of osteosarcoma, where understanding remains poor but has improved significantly. Recent advances have identified characteristic genetic features of osteosarcoma, including profound chromosomal disruption, marked patient-patient heterogeneity, and a paucity of recurrent mutations. Analyses suggest genesis in early catastrophic genetic events, although the nature of the inciting events remains unclear. While p53 and Rb inactivation occurs in most osteosarcomas, the landscape of associated driver mutations has proved extensive. Few mutations recur with high frequency, though patterns continue to emerge that suggest recurrent alterations within specific pathways. Biological pathways implicated in osteosarcoma biology through genetic and other preclinical studies include PI3K/mTOR, WNT/betacatenin, TGFbeta, RANKL/NF-kappaB, and IGF. Unfortunately, clinical studies evaluating targeted agents have to date yielded disappointing results, as have studies examining modern immunotherapeutics. It remains unclear whether this pattern of clinical failures exposes inadequacies of our preclinical models, unrealistic expectations for single-agent responses in heavily pretreated patients, or biology less relevant than suggested. Nearly all patients who succumb to osteosarcoma develop lung metastases, which exhibit marked chemoresistance. Much scientific effort has recently sought to enhance our mechanistic understanding of metastasis biology. This research has potential to reveal novel targets for preventing and treating metastasis and for uncovering key vulnerabilities of osteosarcoma cells. Efforts to implement drug development strategies that leverage clinical studies in veterinary patients have potential to accelerate the translation of novel experimental regimens toward human studies. These could reduce costs and development timelines, prioritize agents, and refine regimens prior to human clinical trials. The rise of philanthropic groups focused on osteosarcoma has enhanced cross-disciplinary and cross-institutional focus and provided much needed resources. Transformative new therapies will likely arise from collaborative, interdisciplinary efforts that extend our understanding of osteosarcoma's most basic inner workings. PMID- 29435437 TI - Improvement of Antitumor Therapies Based on Vaccines and Immune-Checkpoint Inhibitors by Counteracting Tumor-Immunostimulation. AB - Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth. PMID- 29435438 TI - Feasibility of Physical Activity Assessment with Wearable Devices in Children Aged 4-10 Years-A Pilot Study. AB - Objective: Physical activity (PA) is associated with multiple beneficial health outcomes. Unfortunately, current studies report an alarming decrease of PA throughout all age groups. This study aims to assess general feasibility and PA levels of kindergarten and primary school children with wearable technology specifically manufactured for young children. Patients and methods: From April 2017 to August 2017, a total of 59 children (7.1 +/- 1.7 years, 34 girls) recorded their PA for seven consecutive day wearing a wearable bracelet (Garmin vivofit jr). Afterward, they filled out a short, child-oriented questionnaire to rate the feasibility. Results: The general feasibility of the devices was rated as rather well regarding size, materials, and wearing comfort. Moreover, children achieved a mean of 83 +/- 18 min of moderate-to-vigorous physical activity (MVPA) and 12.202 +/- 2.675 steps per day on a weekly average. Therefore, 52 (88.1%) children, and almost all boys (96%), fulfilled the WHO criteria of 60 min of MVPA per day on a weekly average. Conclusion: Wearables bracelets seem to be feasible devices for PA assessment even in young children. Nevertheless, their potential to increase PA for primary and secondary prevention of cardiovascular disease, as well as the long-term compliance needs to be clarified in further studies. PMID- 29435439 TI - Extracellular Calcium Dictates Onset, Severity, and Recovery of Diarrhea in a Child with Immune-Mediated Enteropathy. AB - Diarrhea causes monovalent and divalent ion losses that can influence clinical outcome. Unlike the losses of monovalent ions, such as Na+, K+, Cl-, and [Formula: see text], which are generally large in quantity (osmoles) and therefore determine the severity of diarrhea, the losses of divalent ions are relatively small in osmoles and are often overlooked during diarrheal treatment. Studies now suggest that despite divalent ions being small in osmoles, their effects are large due to the presence of divalent ion-sensing receptors and their amplifying effects in the gut. As a result, losses of these divalent ions without prompt replacement could also significantly affect the onset, severity, and/or recovery of diarrheal disease. Herein, we report a case of a malnourished child with an immune-mediated enteropathy who developed episodes of "breakthrough" diarrhea with concurrent hypocalcemia while on appropriate immunotherapy. Interestingly, during these periods of diarrhea, stool volume fluctuated with levels of blood Ca2+. When Ca2+ was low, diarrhea occurred; when Ca2+ levels normalized with replacement, diarrhea stopped. Based on this and other observations, a broader question arises as to whether the Ca2+ lost in diarrhea should be replaced promptly in these patients. PMID- 29435441 TI - Emotional Impact of Cardiopulmonary Resuscitation Training on High School Students. AB - Background: The American Heart Association (AHA) has implemented several programs to educate the public about cardiopulmonary resuscitation (CPR). A common issue in bystander CPR is the fear of hurting the victim. As a result, the victim may not receive CPR in time. The purpose of this study was to measure the emotional impact of CPR training on high school students using two approved AHA courses. Methods: A total of 60 students participated in this study. These students had a mean age of 15.4 +/- 1.2 years old and were selected from a high school in Southern California. Subjects were divided into two groups, Basic Life Support (BLS) (n1 = 31) and Hands-OnlyTM CPR (n2 = 29). Emotional impacts were assessed by having each subject answer a questionnaire based on given scenarios before and after their training session. Results: There was a significant difference in both groups when comparing positive-emotion scores before and after the training (BLS: 30.3 +/- 6.0 vs. 34.5 +/- 6.7, p < 0.001; Hands-Only 27.9 +/- 5.0 vs. 32.1 +/- 6.5, p < 0.001). In addition, both groups showed significant reductions in negative-emotion scores (BLS: 29.2 +/- 6.7 vs. 23.7 +/- 6.5, p < 0.001 and Hands Only: 26.8 +/- 6.1vs. 24.8 +/- 7.7, p = 0.05). Conclusion: Our results indicate that the AHA programs have positive effects on students' emotional response. We recommend that future studies include an in-depth study design that probes the complexity of students' emotions after completing an AHA session. PMID- 29435442 TI - The CARPEDIEM Algorithm: A Rule-Based System for Identifying Heart Failure Phenotype with a Precision Public Health Approach. AB - Modern medicine remains dependent on the accurate evaluation of a patient's health state, recognizing that disease is a process that evolves over time and interacts with many factors unique to that patient. The CARPEDIEM project represents a concrete attempt to address these issues by developing reproducible algorithms to support the accuracy in detection of complex diseases. This study aims to establish and validate the CARPEDIEM approach and algorithm for identifying those patients presenting with or at risk of heart failure (HF) by studying 153,393 subjects in Italy, based on patient information flow databases and is not reliant on the electronic health record to accomplish its goals. The resulting algorithm has been validated in a two-stage process, comparing predicted results with (1) HF diagnosis as identified by general practitioners (GPs) among the reference cohort and (2) HF diagnosis as identified by cardiologists within a randomly sampled subpopulation of 389 patients. The sources of data used to detect HF cases are numerous and were standardized for this study. The accuracy and the predictive values of the algorithm with respect to the GPs and the clinical standards are highly consistent with those from previous studies. In particular, the algorithm is more efficient in detecting the more severe cases of HF according to the GPs' validation (specificity increases according to the number of comorbidities) and external validation (NYHA: II-IV; HF severity index: 2, 3). Positive and negative predictive values reveal that the CARPEDIEM algorithm is most consistent with clinical evaluation performed in the specialist setting, while it presents a greater ability to rule out false negative HF cases within the GP practice, probably as a consequence of the different HF prevalence in the two different care settings. Further development includes analyzing the clinical features of false-positive and -negative predictions, to explore the natural clustering of markers of chronic conditions by adding additional methodologies, e.g., Social Network Analysis. CARPEDIEM establishes the potential that an algorithmic approach, based on integrating administrative data with other public data sources, can enable the development of low cost and high value population-based evaluations for improving public health and impacting public health policies. PMID- 29435443 TI - Global Non-Communicable Diseases-The Nutrition Conundrum. PMID- 29435444 TI - Preparation and Evaluation of Adsorbents from Coal and Irvingia gabonensis Seed Shell for the Removal of Cd(II) and Pb(II) Ions from Aqueous Solutions. AB - Cd(II) and Pb(II) ions removal using adsorbents prepared from sub-bituminous coal, lignite, and a blend of coal and Irvingia gabonensis seed shells was investigated. Fourier transform infrared, scanning electron microscope and X-ray fluorescence analyses implicated hydroxyl, carbonyl, Al2O3, and SiO2 as being responsible for attaching the metal ions on the porous adsorbents. The optimum adsorption of carbonized lignite for the uptake of Cd(II) and Pb(II) ions from aqueous media were 80.93 and 87.85%, respectively. Batch adsorption was done by effect of adsorbent dosage, pH, contact time, temperature, particle size, and initial concentration. Equilibrium for the removal of Pb(II) and Cd(II) was established within 100 and 120 min respectively. Blending the lignite-derived adsorbent with I. gabonensis seed shell improved the performance significantly. More improvement was observed on modification of the blend using NaOH and H3PO4. Pb(II) was preferentially adsorbed than Cd(II) in all cases. Adsorption of Cd(II) and Pb(II) ions followed Langmuir isotherm. The adsorption kinetics was best described by pseudo-second order model. The potential for using a blend of coal and agricultural byproduct (I. gabonensis seed shell) was found a viable alternative for removal of toxic heavy metals from aqueous solutions. PMID- 29435440 TI - Basement Membrane Defects in Genetic Kidney Diseases. AB - The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the fusion of two basement membranes during development and its function in the filtration barrier is achieved by key extracellular matrix components including type IV collagen, laminins, nidogens, and heparan sulfate proteoglycans. The characteristics of specific matrix isoforms such as laminin 521 (alpha5beta2gamma1) and the alpha3alpha4alpha5 chain of type IV collagen are essential for the formation of a mature GBM and the restricted tissue distribution of these isoforms makes the GBM a unique structure. Detailed investigation of the GBM has been driven by the identification of inherited abnormalities in matrix proteins and the need to understand pathogenic mechanisms causing severe glomerular disease. A well-described hereditary GBM disease is Alport syndrome, associated with a progressive glomerular disease, hearing loss, and lens defects due to mutations in the genes COL4A3, COL4A4, or COL4A5. Other proteins associated with inherited diseases of the GBM include laminin beta2 in Pierson syndrome and LMX1B in nail patella syndrome. The knowledge of these genetic mutations associated with GBM defects has enhanced our understanding of cell-matrix signaling pathways affected in glomerular disease. This review will address current knowledge of GBM-associated abnormalities and related signaling pathways, as well as discussing the advances toward disease-targeted therapies for patients with glomerular disease. PMID- 29435445 TI - Detection of Collapse and Crystallization of Saccharide, Protein, and Mannitol Formulations by Optical Fibers in Lyophilization. AB - The collapse temperature (Tc) and the glass transition temperature of freeze concentrated solutions (Tg') as well as the crystallization behavior of excipients are important physicochemical characteristics which guide the cycle development in freeze-drying. The most frequently used methods to determine these values are differential scanning calorimetry (DSC) and freeze-drying microscopy (FDM). The objective of this study was to evaluate the optical fiber system (OFS) unit as alternative tool for the analysis of Tc, Tg' and crystallization events. The OFS unit was also tested as a potential online monitoring tool during freeze drying. Freeze/thawing and freeze-drying experiments of sucrose, trehalose, stachyose, mannitol, and highly concentrated IgG1 and lysozyme solutions were carried out and monitored by the OFS. Comparative analyses were performed by DSC and FDM. OFS and FDM results correlated well. The crystallization behavior of mannitol could be monitored by the OFS during freeze/thawing as it can be done by DSC. Online monitoring of freeze-drying runs detected collapse of amorphous saccharide matrices. The OFS unit enabled the analysis of both Tc and crystallization processes, which is usually carried out by FDM and DSC. The OFS can hence be used as novel measuring device. Additionally, detection of these events during lyophilization facilitates online-monitoring. Thus the OFS is a new beneficial tool for the development and monitoring of freeze-drying processes. PMID- 29435446 TI - Effect of Magnesium Incorporation on Solution-Processed Kesterite Solar Cells. AB - The introduction of the alkaline-earth element Magnesium (Mg) into Cu2ZnSn(S,Se)4 (CTZSSe) is explored in view of potential photovoltaic applications. Cu2Zn1 xMgxSn(S,Se)4 absorber layers with variable Mg content x = 0...1 are deposited using the solution approach with dimethyl sulfoxide solvent followed by annealing in selenium atmosphere. For heavy Mg alloying with x = 0.55...1 the phase separation into Cu2SnSe3, MgSe2, MgSe and SnSe2 occurs in agreement with literature predictions. A lower Mg content of x = 0.04 results in the kesterite phase as confirmed by XRD and Raman spectroscopy. A photoluminescence maximum is red-shifted by 0.02 eV as compared to the band-gap and a carrier concentration NCV of 1 * 1016 cm-3 is measured for a Mg-containing kesterite solar cell device. Raman spectroscopy indicates that structural defects can be reduced in Mg containing absorbers as compared to the Mg-free reference samples, however the best device efficiency of 7.2% for a Mg-containing cell measured in this study is lower than those frequently reported for the conventional Na doping. PMID- 29435448 TI - Toward a Tiered Model to Share Clinical Trial Data and Samples in Precision Oncology. AB - The recent revolution in science and technology applied to medical research has left in its wake a trial of biomedical data and human samples; however, its opportunities remain largely unfulfilled due to a number of legal, ethical, financial, strategic, and technical barriers. Precision oncology has been at the vanguard to leverage this potential of "Big data" and samples into meaningful solutions for patients, considering the need for new drug development approaches in this area (due to high costs, late-stage failures, and the molecular diversity of cancer). To harness the potential of the vast quantities of data and samples currently fragmented across databases and biobanks, it is critical to engage all stakeholders and share data and samples across research institutes. Here, we identified two general types of sharing strategies. First, open access models, characterized by the absence of any review panel or decision maker, and second controlled access model where some form of control is exercised by either the donor (i.e., patient), the data provider (i.e., initial organization), or an independent party. Further, we theoretically describe and provide examples of nine different strategies focused on greater sharing of patient data and material. These models provide varying levels of control, access to various data and/or samples, and different types of relationship between the donor, data provider, and data requester. We propose a tiered model to share clinical data and samples that takes into account privacy issues and respects sponsors' legitimate interests. Its implementation would contribute to maximize the value of existing datasets, enabling unraveling the complexity of tumor biology, identify novel biomarkers, and re-direct treatment strategies better, ultimately to help patients with cancer. PMID- 29435449 TI - Video Games and Other Online Activities May Improve Health in Ageing. PMID- 29435447 TI - Novel Insights in Systemic Lupus Erythematosus and Atherosclerosis. AB - Introduction: The systemic inflammatory nature of systemic lupus erythematosus (SLE) is well patent not only in the diverse clinical manifestations of the disease but also in the increased risk of premature atherosclerosis and cardiovascular events (CVE), making SLE one of the most complex diseases to study and manage in clinical practice. Aim: To travel from old aspects to modern insights on the physiopathology, new molecular biomarkers, imaging methods of atherosclerosis assessment, and the potential treatments of atherosclerosis in SLE. Methods: We conducted a literature search using PubMed database and performed a critical review. Conclusion/discussion: Several developments have taken place in the understanding of the relationship between SLE and premature atherosclerosis. Nevertheless, cardiovascular diseases are still the major cause of reduced life expectancy in SLE and the main cause of death. The lack of standardization methods for the imaging assessment of atherosclerosis in SLE and the multifactorial nature of the disease are well patriated in the difficulty of achieving consistent and reproducible results among studies that focus in cardiovascular risk assessment and prediction. A raising number of molecular biomarkers of atherosclerosis have been proposed, but the combination of several biomarkers and risk factors may better estimate cardiovascular disease risk. Moreover, the development of effective therapies to prevent progression of atherosclerosis and CVE shall address systemic inflammation. PMID- 29435450 TI - Commentary: Estimates of Global, Regional, and National Morbidity, Mortality, and Aetiologies of Diarrhoeal Diseases: A Systematic Analysis for the Global Burden of Disease Study 2015. PMID- 29435451 TI - Umbilical Hernia Repair and Pregnancy: Before, during, after.... AB - Umbilical hernias are most common in women than men. Pregnancy may cause herniation or render a preexisting one apparent, because of progressively raised intra-abdominal pressure. The incidence of umbilical hernia among pregnancies is 0.08%. Surgical algorithm for a pregnant woman with a hernia is not thoroughly clear. There is no consensus about the timing of surgery for an umbilical hernia in a woman either who is already pregnant or planning a pregnancy. If the hernia is incarcerated or strangulated at the time of diagnosis, an emergency repair is inevitable. If the hernia is not complicated, but symptomatic an elective repair should be proposed. When the patient has a small and asymptomatic hernia it may be better to postpone the repair until she gives birth. If the hernia is repaired by suture alone, a high risk of recurrence exists during pregnancy. Umbilical hernia repair during pregnancy can be performed with minimal morbidity to the mother and baby. Second trimester is a proper timing for surgery. Asymptomatic hernias can be repaired, following childbirth or at the time of cesarean section (C-section). Elective repair after childbirth is possible as early as postpartum of eighth week. A 1-year interval can give the patient a very smooth convalescence, including hormonal stabilization and return to normal body weight. Moreover, surgery can be postponed for a longer time even after another pregnancy, if the patients would like to have more children. Diastasis recti are very frequent in pregnancy. It may persist in postpartum period. A high recurrence risk is expected in patients with rectus diastasis. This risk is especially high after suture repairs. Mesh repairs should be considered in this situation. PMID- 29435452 TI - Superior Vena Cava (SVC) Endovascular Reconstruction with Implanted Central Venous Catheter Repositioning for Treatment of Malignant SVC Obstruction. AB - Superior vena cava (SVC) syndrome is a group of clinical signs caused by the obstruction or compression of SVC and characterized by edema of the head, neck, and upper extremities, shortness of breath, and headaches. The syndrome may be caused by benign causes but most of the cases are caused by lung or mediastinal malignant tumors. Stenting of SVC has become widely accepted as the palliative treatment for this condition in malignant diseases, as it offers rapid relief of symptoms and improves the quality of life. Preserving previously placed central venous catheters (CVCs) is a major issue in this population. We report the case of a patient with SVC syndrome caused by tumoral obstruction due to central small cell lung cancer who had right subclavian implanted CVC and a preferential head and neck venous drainage through the left internal jugular and brachiocephalic vein (BCV). We describe a complex procedure of SVC reconstruction with two different objectives: left recanalization and stent placement to ensure head and neck venous drainage and right BCV stenting for CVC repositioning and subsequent replacement. We also review published cases of SVC obstructions stenting with catheter repositioning. The patient experienced quick relief of symptoms after treatment. Chemotherapy was rapidly delivered through the preserved implanted CVC access. A 3-month follow-up computed tomography showed stents patency. PMID- 29435453 TI - Reconstitution of Pure Chaperonin Hetero-Oligomer Preparations in Vitro by Temperature Modulation. AB - Chaperonins are large, essential, oligomers that facilitate protein folding in chloroplasts, mitochondria, and eubacteria. Plant chloroplast chaperonins are comprised of multiple homologous subunits that exhibit unique properties. We previously characterized homogeneous, reconstituted, chloroplast-chaperonin oligomers in vitro, each composed of one of three highly homologous beta subunits from A. thaliana. In the current work, we describe alpha-type subunits from the same species and investigate their interaction with beta subtypes. Neither alpha subunit was capable of forming higher-order oligomers on its own. When combined with beta subunits in the presence of Mg-ATP, only the alpha2 subunit was able to form stable functional hetero-oligomers, which were capable of refolding denatured protein with native chloroplast co-chaperonins. Since beta oligomers were able to oligomerize in the absence of alpha, we sought conditions under which alphabeta hetero-oligomers could be produced without contamination of beta homo-oligomers. We found that beta2 subunits are unable to oligomerize at low temperatures and used this property to obtain homogenous preparations of functional alpha2beta2 hetero-oligomers. The results of this study highlight the importance of reaction conditions such as temperature and concentration for the reconstitution of chloroplast chaperonin oligomers in vitro. PMID- 29435454 TI - Garbage Management: An Important Risk Factor for HPAI-Virus Infection in Commercial Poultry Flocks. AB - Garbage management represents a potential pathway of HPAI-virus infection for commercial poultry operations as multiple poultry premises may share a common trash collection service provider, trash collection site (e.g., shared dumpster for multiple premises) or disposal site (e.g., landfill). The types of potentially infectious or contaminated material disposed of in the garbage has not been previously described but is suspected to vary by poultry industry sector. A survey of representatives from the broiler, turkey, and layer sectors in the United States revealed that many potentially contaminated or infectious items are routinely disposed of in the trash on commercial poultry premises. On farm garbage management practices, along with trash hauling and disposal practices are thus key components that must be considered to evaluate the risk of commercial poultry becoming infected with HPAI virus. PMID- 29435455 TI - Estimating Parameters Related to the Lifespan of Passively Transferred and Vaccine-Induced Porcine Reproductive and Respiratory Syndrome Virus Type I Antibodies by Modeling Field Data. AB - The outputs of epidemiological models are strongly related to the structure of the model and input parameters. The latter are defined by fitting theoretical concepts to actual data derived from field or experimental studies. However, some parameters may remain difficult to estimate and are subject to uncertainty or sensitivity analyses to determine their variation range and their global impact on model outcomes. As such, the evaluation of immunity duration is often a puzzling issue requiring long-term follow-up data that are, most of time, not available. The present analysis aims at characterizing the kinetics of antibodies against Porcine Reproductive and Respiratory Syndrome virus (PRRSv) from longitudinal data sets. The first data set consisted in the serological follow-up of 22 vaccinated gilts during 21 weeks post-vaccination (PV). The second one gathered the maternally derived antibodies (MDAs) kinetics in piglets from three different farms up to 14 weeks of age. The peak of the PV serological response against PRRSv was reached 6.9 weeks PV on average with an average duration of antibodies persistence of 26.5 weeks. In the monitored cohort of piglets, the duration of passive immunity was found relatively short, with an average duration of 4.8 weeks. The level of PRRSv-MDAs was found correlated with the dams' antibody titer at birth, and the antibody persistence was strongly related to the initial MDAs titers in piglets. These results evidenced the importance of PRRSv vaccination schedule in sows, to optimize the delivery of antibodies to suckling piglets. These estimates of the duration of active and passive immunity could be further used as input parameters of epidemiological models to analyze their impact on the persistence of PRRSv within farms. PMID- 29435456 TI - Efficient Utilization of Waste Carbon Source for Advanced Nitrogen Removal of Landfill Leachate. AB - A modified single sequencing batch reactor (SBR) was developed to remove the nitrogen of the real landfill leachate in this study. To take the full advantage of the SBR, stir phase was added before and after aeration, respectively. The new mechanism in this experiment could improve the removal of nitrogen efficiently by the utilization of carbon source in the raw leachate. This experiment adopts the SBR process to dispose of the real leachate, in which the COD and ammonia nitrogen concentrations were about 3800 mg/L and 1000 mg/L, respectively. Results showed that the removal rates of COD and total nitrogen were above 85% and 95%, respectively, and the effluent COD and total nitrogen were less than 500 mg/L and 40 mg/L under the condition of not adding any carbon source. Also, the specific nitrogen removal rate was 1.48 mgN/(h.gvss). In this process, polyhydroxyalkanoate (PHA) as a critical factor for the highly efficient nitrogen removal (>95%) was approved to be the primary carbon source in the sludge. Because most of the organic matter in raw water was used for denitrification, in the duration of this 160-day experiment, zero discharge of sludge was realized when the effluent suspended solids were 30-50 mg/L. PMID- 29435457 TI - Tumor Burden and Intraosseous Metabolic Activity as Predictors of Bone Marrow Failure during Radioisotope Therapy in Metastasized Prostate Cancer Patients. AB - Rationale: Radium-223-Dichloride (Ra-223) is an alpha-emitter, used to treat bone metastases. Patients with high metastatic burden and/or with increased trabecular bone uptake could present a higher incidence of hematologic toxicity. We hypothesized that these two factors are predictors of bone marrow failure. Material and Methods: A computer algorithm discriminated between trabecular bone (BVol) and tumor metastases (MVol) within pretherapeutic whole-body skeletal SPECT/CT (N = 47). The program calculated the metastatic invasion percent (INV%) as the MVol/(MVol + BVol) ratio and extracted the BVol mean counts. BVol counts were correlated to % drop of hemoglobin (Hb), leukocytes (WBC), and platelets (PLT) after 3/6 Ra-223 cycles. Patient-specific and computational-derived parameters were tested as predictors of hematologic toxicity with MANOVA. Results: BVol counts correlated with drop of Hb (R = 0,65, p < 0.01) and PLT (R = 0,45, p < 0.01). Appendicular BVol counts showed a better correlation (p < 0.05, p < 0.01, and p < 0.001 for Hb, WBC, and PLT, resp.). INV% directly correlated with BVol counts (R = 0.68, p < 0.001). At MANOVA, grade III/IV toxicity was predicted by INV% (p < 0.01), by long-bone invasion (p < 0.005), and by BVol counts (p < 0.05). Conclusions: In patients with significant bone tumor burden, degree of bone invasion and trabecular bone uptake are predictors of subsequent bone marrow failure. PMID- 29435458 TI - Gastric Residual Volume after Split-Dose Bowel Preparation versus Conventional Single-Dose Regimen before Anesthetic Colonoscopy. AB - The aim of this study was to compare gastric residual volume (GRV) in patients given a split-dose versus a conventional single-dose of polyethylene glycol (PEG) preparation before undergoing anesthetic colonoscopy. Methods. In a prospective observational study, we assessed GRV in outpatients undergoing same-day anesthetic gastroscopy and colonoscopy between October 8 and December 30 of 2016. Outpatients were assigned to the split-dose (1 L PEG in the prior evening and 1 L PEG 2-4 h before endoscopy) or single-dose (ingestion of 2 L PEG >= 6 h before endoscopy) regimen randomly. Bowel cleansing quality was assessed with the Boston Bowel Preparation Scale (BBPS). Results. The median GRV in the split-dose group (17 ml, with a range of 0-50 ml; N = 65) was significantly lower than that in the single-dose group (22 ml, with a range of 0-62 ml; N = 64; p = 0.005), with a better bowel cleansing quality (BBPS score 8.05 +/- 0.82 versus 7.64 +/- 1.21; p = 0.028). GRV was not associated with diabetes or the use of medications. Conclusions. GRV after a split-dose preparation and fasting for 2-4 hours is not larger than that after a conventional single-dose preparation and fasting for 6-8 hours. The data indicates that the split-dose bowel preparation might not increase the risk of aspiration. PMID- 29435459 TI - Physical Activity and Sedentary Behaviors of Urban Chinese Children: Grade Level Prevalence and Academic Burden Associations. AB - The objectives of this study were (a) to report grade level prevalence in physical activity and sedentary behaviors and (b) to examine academic burden associations with these behaviors. School-aged children (n = 48,118) reported their physical activity, perception of physical activity sufficiency, factors for activity insufficiency, homework hours, and screen time in a typical week. Data were analyzed using general linear models and logistic regression models of Complex Samples. Prevalence results showed that children had lower physical activity and lower screen viewing time, but higher homework time during transition grades (6th, 9th, and 12th) and high school years. Academic burden was cited as the primary reason for not having sufficient physical activity (76.6%). Compared to those citing academic burden, students who did not report academic burden were significantly more likely to meet physical activity guidelines (Odds Ratio (OR) = 5.38, 95% CI = 4.74-6.11), but less likely to meet screen time guidelines (OR = 0.78, 95% CI = 0.72-0.84), controlling for body mass index, gender, and grade level. Additionally, children who reported academic burdens had significantly longer average daily homework time than those who did not (p < 0.01). Policy makers should promote physical activity and help children find a balance between homework and physical activity time particularly among the educational transition grades. PMID- 29435460 TI - Prevalence of Urinary Schistosomiasis in Migrants in Apulia, a Region of Southern Italy, in the Years 2006-2016. AB - Schistosomiasis is the most prevalent tropical disease in the world after malaria. According to the World Health Organization, the disease afflicts more than 240 million people in about 80 countries. Recently, an epidemiological surveillance study performed between 1997 and 2010 by the European Network for Tropical Medicine and Health Travel regarding schistosomiasis between immigrants and travelers has been published. No data are available in the literature regarding the situation in South Italy. Herein, we report the prevalence of urinary schistosomiasis in a population of migrants in Apulia referring to our outpatient clinic for immigrant diseases in the period 2006-2016. Since all cases of schistosomiasis were related to the last three years of observation, the demographic and clinical characteristics of the study population were compared before and after 2014. Nearly 51% of all patients visited (1762) were from high/moderate endemic countries for schistosomiasis, and nine cases of urinary schistosomiasis were diagnosed. Prevalence was 1% among migrants from endemic areas and 10% in those from Mali and Senegal. Our findings confirm that schistosomiasis is a widespread infection among immigrants, even if it is often underdiagnosed because of the multifaceted clinical presentation. Changes in migratory dynamics can affect clinical observations very quickly. PMID- 29435462 TI - Surgical Treatment with Locoregional Flap for the Nose. AB - Nonmelanotic skin cancers (NMSCs) are the most frequent of all neoplasms and nasal pyramid represents the most common site for the presentation of such cutaneous malignancies, particularly in sun-exposed areas: ala, dorsum, and tip. Multiple options exist to restore functional and aesthetic integrity after skin loss for oncological reasons; nevertheless, the management of nasal defects can be often challenging and the best "reconstruction" is still to be found. In this study, we retrospectively reviewed a total of 310 patients who presented to our Department of Plastic and Reconstructive Surgery for postoncological nasal reconstruction between January 2011 and January 2016. Nasal region was classified into 3 groups according to the anatomical zones affected by the lesion: proximal, middle, and distal third. We included an additional fourth group for complex defects involving more than one subunit. Reconstruction with loco regional flaps was performed in all cases. Radical tumor control and a satisfactory aesthetic and functional result are the primary goals for the reconstructive surgeon. Despite tremendous technical enhancements in nasal reconstruction techniques, optimal results are usually obtained when "like is used to repair like." Accurate evaluation of the patients clinical condition and local defect should be always considered in order to select the best surgical option. PMID- 29435461 TI - Heterogeneous Periostin Expression in Different Histological Variants of Papillary Thyroid Carcinoma. AB - Background: Periostin (PN) epithelial and stromal overexpression in tumor pathology has been studied according to tumor growth, angiogenesis, invasiveness, and metastasis, but a limited number of studies address PN in thyroid tumors. Aim: Our study aimed to analyze PN expression in different histological variants of PTC and to correlate its expression with the clinicopathological prognostic factors. Material and Methods: PN expression has been immunohistochemically assessed in 50 cases of PTC (conventional, follicular, oncocytic, macrofollicular, and tall cell variants), in tumor epithelial cells and intratumoral stroma. The association between PN expression and clinicopathological characteristics has been evaluated. Results: Our results show that PTC presented different patterns of PN immunoreaction, stromal PN being significantly associated with advanced tumor stage and extrathyroidal extension. No correlations were found between PN overexpression in tumor epithelial cells and clinicopathological features, except for specific histological variants, the highest risk of poor outcome being registered for the conventional subtype in comparison to the oncocytic type. Conclusions: Our study demonstrates differences in PN expression in histological subtypes of PTC. Our results plead in favor of a dominant protumorigenic role of stromal PN, while the action of epithelial PN is less noticeable. PMID- 29435464 TI - Solving a Mystery . . . 8 Years Later. AB - Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis with multisystem involvement and insidious symptoms. In this article, we describe an interesting case of Erdheim-Chester disease that was eventually diagnosed 8 years after symptoms initially started. PMID- 29435463 TI - Gut Microbiome and Inflammation: A Study of Diabetic Inflammasome-Knockout Mice. AB - Aims: Diabetes is a proinflammatory state, evidenced by increased pattern recognition receptors and the inflammasome (NOD-like receptor family pyrin domain (NLRP)) complex. Recent reports have elucidated the role of the gut microbiome in diabetes, but there is limited data on the gut microbiome in NLRP-KO mice and its effect on diabetes-induced inflammation. Methods: Gut microbiome composition and biomarkers of inflammation (IL-18, serum amyloid A) were assessed in streptozotocin- (STZ-) induced diabetic mice on a NLRP3-knockout (KO) background versus wild-type diabetic mice. Results: SAA and IL-18 levels were significantly elevated in diabetic mice (STZ) compared to control (WT) mice, and there was a significant attenuation of inflammation in diabetic NLRP3-KO mice (NLRP3-KO STZ) compared to control mice (p < 0.005). Principal coordinate analysis clearly separated controls, STZ, and NLRP3-KO STZ mice. Among the different phyla, there was a significant increase in the Firmicutes : Bacteroidetes ratio in the diabetic group compared to controls. When compared to the WT STZ group, the NLRP3 KO STZ group showed a significant decrease in the Firmicutes : Bacteroidetes ratio. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a crucial factor that could modify diabetes and complications. PMID- 29435465 TI - Missed Massive Pulmonary Embolism and the Hidden Threat of a Distal Deep Vein Thrombosis. AB - A 47-year-old woman presented to her GP (general practitioner) surgery with a left leg pain of 4 days duration after a recent 4-hour flight. She was taking the oral combined contraceptive pill and had no past medical history. She had a low predictive Wells score for deep vein thrombosis, but her D-dimer was positive, so she had a proximal lower limb vein ultrasound scan as per the National Institute for Clinical Excellence guidelines, which was negative. Two days later, she presented to the emergency department with a collapse and dyspnea. Her blood pressure was unrecordable in the ambulance, and she was severely peripherally cyanosed with a blood pressure of 64/40 mm Hg in the emergency department. She had a computed tomography pulmonary angiogram, which confirmed extensive bilateral pulmonary emboli with right ventricular strain. She had 2 cardiac arrests while in hospital and is now on long-term anticoagulation. PMID- 29435466 TI - Opana ER (Oxymorphone)-Induced Thrombotic Microangiopathy: An Atypical Presentation in a Patient With Hepatitis C. AB - Oxymorphone is a semisynthetic extended release opiate used to treat moderate to severe chronic pain. The Food and Drug Administration approved the oral form of oxymorphone available as Opana and Opana ER (extended release) since 2006. The Food and Drug Administration and the Centers for Disease Control and Prevention issued warning against intravenous use of Opana ER. We are presenting a case report of a 37-year-old female with a history of active intravenous drug abuse who presented to our hospital with acute kidney injury. Urinalysis showed red blood cell sediments, many dysmorphic red blood cell casts along with nephrotic range proteinuria of 12 g/deal per day. Kidney biopsy showed microscopic thrombotic microangiopathy (TMA) involving glomeruli and vessels. Further workup was undertaken for TMA, and apart from mildly elevated lactate dehydrogenase of 380 (normal <243), active hepatitis C, and slightly low ADAMTS-13 (55%), there was no other laboratory evidence of TMA. On literature search, we found that intravenous injection of chronic Opana ER has been reported to cause TMA resulting in chronic kidney disease. Our patient also admitted to use of intravenous Opana ER abuse for the past 5 years. She had a normal platelet count and an absence of schistocytes, which makes it an atypical presentation of TMA resulting in chronic kidney disease in an opiate user. We strongly urge physicians to avoid prescribing opiates for chronic pain, especially Opana ER, which if injected intravenously for recreational purposes can lead to serious side effects like TMA. Treatment is mainly supportive and avoidance of drug in future. PMID- 29435467 TI - A Rare Case of Sphingomonas paucimobilis Meningitis in the Absence of Cerebrospinal Fluid Pleocytosis. AB - Sphingomonas paucimobilis is a nonfermentative gram-negative bacillus of low pathogenicity. The organism has been involved in causing a wide range of infections in community and hospital settings. Only 3 cases of meningitis caused by this organism have been reported so far. We report a rare case of S paucimobilis meningitis who presented with atypical symptoms. A 50-year-old female presented with headache, dizziness, chills, shakiness, and neck pain along with nuchal rigidity. On physical examination, severe neck rigidity along with decreased range of motion was noticed. Her cerebrospinal fluid showed gram negative rods, and she was started on meropenem. The cerebrospinal fluid grew S paucimobilis sensitive to meropenem. She subsequently showed significant improvement and was discharged home on intravenous meropenem for 21 days and showed complete recovering in 5 weeks. PMID- 29435468 TI - The Impact of Workload on the Evolution of Hip Internal and External Rotation in Professional Baseball Players Over the Course of the Season. AB - Background: Although restricted hip range of motion (ROM) is associated with an increased risk for injuries in baseball players, the evolution of hip ROM over the season remains undefined. Hypothesis: Hip ROM profiles would be symmetric between hips and positions (pitchers vs position players) but would decrease from preseason to postseason. Additionally, it was hypothesized that this decrease in motion would correlate with workload. Study Design: Cohort study; Level of evidence, 2. Methods: Bilateral hip ROM was assessed in 96 professional baseball players (54 pitchers, 42 position players) preseason and postseason. ROM comparisons were made between lead and trailing hips, pitchers and position players, and preseason and postseason measures. The change from preseason to postseason was correlated with player demographics and measures of workload for pitchers and position players. Results: Preseason hip ROM was symmetric between hips; however, pitchers demonstrated increased preseason lead hip internal rotation (IR) (P = .018) and bilateral hip total ROM (TROM) (P < .020) compared with position players. From preseason to postseason, position players lost 7 degrees of external rotation (ER) (P <= .005 ). In pitchers, the loss of IR correlated with increased pitches (P = .016) and innings (P = .037), while the loss of ER (P = .005 ) and TROM (P = .014) correlated with increasing mean fastball velocity. Workload for position players did not correlate with motion loss. Conclusion: Symmetric hip ROM profiles should be anticipated in baseball players; however, pitchers may have increased preseason IR and TROM and postseason ER and TROM relative to position players. Although loss of motion correlated with workload in pitchers, this was not the case for position players. Hip motion should be monitored over the course of the season. This is particularly true for pitchers who lose IR as workload increases, which may place them at a greater risk for injuries. PMID- 29435469 TI - Prevalence and Impact of Hip Arthroscopic Surgery on Future Participation in Elite American Football Athletes. AB - Background: Intra-articular injuries to the hip in elite athletes represent a source of significant pain and disability. Hip arthroscopic surgery has become the gold standard for the treatment of disorders involving the hip joint. Purpose: To examine the incidence of and abnormalities treated with hip arthroscopic surgery as well as the impact on future participation in American football athletes invited to the National Football League (NFL) Scouting Combine with a history of hip arthroscopic surgery. Study Design: Cohort study; Level of evidence, 3. Methods: Athletes invited to the NFL Combine from 2012 to 2015 were evaluated for a history of hip arthroscopic surgery. Athlete demographics, imaging findings, and physical examination results were gathered using the NFL Combine database. Information on prospective participation in the NFL with regard to draft status, games played, games started, and current status was gathered using publicly available databases and compared against all other athletes participating in the combine. Results: Fourteen athletes (15 hips) had a history of arthroscopic hip surgery. Acetabular labral tears were treated in 93% (14 hips), with femoroacetabular impingement decompression performed in 33% (5 hips). Compared with athletes who had no history of hip arthroscopic surgery, those undergoing arthroscopic surgery did not possess a lower likelihood of being drafted (66% vs 71%, respectively; P = .78) or of being on an active roster (52% vs 43%, respectively; P = .44) after their first season in the NFL. Moreover, there was no significant difference in the number of regular-season games played (10.9 +/- 4.8 with arthroscopic surgery vs 11.0 +/- 5.1 without; P = .96) or started (7.0 +/- 3.6 with arthroscopic surgery vs 7.1 +/- 5.3 without; P = .98). Conclusion: American football athletes invited to the NFL Combine with a history of hip arthroscopic surgery were not at risk for diminished participation when compared with all other athletes during their first season in the NFL. PMID- 29435470 TI - We Miss You, Allen. PMID- 29435471 TI - HIV-1 Drug Resistance and Third-Line Therapy Outcomes in Patients Failing Second Line Therapy in Zimbabwe. AB - Objectives: To analyze the patterns and risk factors of HIV drug resistance mutations among patients failing second-line treatment and to describe early treatment responses to recommended third-line antiretroviral therapy (ART) in a national referral HIV clinic in Zimbabwe. Methods: Patients on boosted protease inhibitor (PI) regimens for more than 6 months with treatment failure confirmed by 2 viral load (VL) tests >1000 copies/mL were genotyped, and susceptibility to available antiretroviral drugs was estimated by the Stanford HIVdb program. Risk factors for major PI resistance were assessed by logistic regression. Third-line treatment was provided as Darunavir/r, Raltegravir, or Dolutegravir and Zidovudine, Abacavir Lamivudine, or Tenofovir. Results: Genotypes were performed on 86 patients who had good adherence to treatment. The median duration of first- and second-line ART was 3.8 years (interquartile range [IQR], 2.3-5.1) and 2.6 years (IQR, 1.6-4.9), respectively. The median HIV viral load and CD4 cell count were 65 210 copies/mL (IQR, 8728-208 920 copies/mL) and 201 cells/mm3 (IQR, 49 333 cells/mm3). Major PI resistance-associated mutations (RAMs) were demonstrated in 44 (51%) non-nucleoside reverse transcriptase inhibitor RAMs in 72 patients (83%) and nucleoside reverse transcriptase inhibitors RAMs in 62 patients (72%). PI resistance was associated with age >24 years (P = .003) and CD4 cell count <200 cells/mm3 (P = .007). In multivariable analysis, only age >24 years was significantly associated (adjusted odds ratio, 4.75; 95% confidence interval, 1.69-13.38; P = .003) with major PI mutations. Third-line DRV/r- and InSTI-based therapy achieved virologic suppression in 29/36 patients (81%) after 6 months. Conclusions: The prevelance of PI mutations was high. Adolescents and young adults had a lower risk of acquiring major PI resistance mutations, possibly due to poor adherence to ART. Third-line treatment with a regimen of Darunavir/r, Raltegravir/Dolutegravir, and optimized nucleoside reverse transcriptase inhibitors was effective. PMID- 29435472 TI - Cervical spinal cord atrophy: An early marker of progressive MS onset. AB - Objective: To assess whether cervical spinal cord atrophy heralds the onset of progressive MS. Methods: We studied 34 individuals with radiologically isolated syndrome (RIS) and 31 patients with relapsing-remitting MS (RRMS) age matched to 25 patients within a year of onset of secondary progressive MS (SPMS). Two raters independently measured (twice per rater) the cervical spinal cord average segmental area (CASA) (mm2) of axial T2-weighted images between C2 and C7 landmarks. The midsagittal T2-weighted image from the end of C2 to the end of C7 vertebra was used to measure the cervical spine (c-spine) length (mm). Sex, age at cervical MRI, number and location of cervical spinal cord lesions, c-spine length, and diagnoses were analyzed against the outcome measures of CASA and C2 and C7 slice segmental areas. Results: Intrarater and interrater agreement was excellent (intraclass correlation coefficient >0.97). The CASA area (p = 0.03) and C7 area (p = 0.002) were smaller in SPMS compared with RRMS. The C2 area (p = 0.027), CASA (p = 0.004), and C7 area (p = 0.003) were smaller in SPMS compared with RIS. The C2 area did not differ between SPMS and RRMS (p = 0.09). The C2 area (p = 0.349), CASA (p = 0.136), and C7 area (p = 0.228) did not differ between RIS and MS (SPMS and RRMS combined). In the multivariable model, >=2 cervical spinal cord lesions were associated with the C2 area (p = 0.008), CASA (p = 0.009), and C7 area independent of disease course (p = 0.017). Progressive disease course was associated with the C7 area independent of the cervical spinal cord lesion number (p = 0.004). Conclusion: Cervical spinal cord atrophy is evident at the onset of progressive MS and seems partially independent of the number of cervical spinal cord lesions. Classification of evidence: This study provides Class III evidence that MRI cervical spinal cord atrophy distinguishes patients at the onset of progressive MS from those with RIS and RRMS. PMID- 29435473 TI - The new cold war. PMID- 29435474 TI - The IKD current in cold detection and pathological cold pain. PMID- 29435475 TI - Central adenosine and daily torpor in mice. PMID- 29435476 TI - In-play cooling strategies for sport in hot and humid conditions. PMID- 29435477 TI - Pathophysiology of heatstroke in dogs - revisited. AB - Heatstroke results from a failure to dissipate accumulated heat during exposure to hot environments, or during strenuous physical exercise under heat stress. It is characterized by core body temperatures > 41 degrees C, with central nervous system dysfunction. Functional morphology and thermoregulatory effectors differences between dogs and humans may require special heatstroke protective adaptations in dogs, however, the risk factors for developing heatstroke are similar in both. In dogs, these include hot, especially highly humid environments, excessive physical activity, obesity, large (>15 kg) body weight, being of certain breed (e.g., Labrador retrievers and brachycephalic breeds), upper airway obstruction and prolonged seizures. Lack of acclimation to heat and physical fitness decreases the survival of heat stroked dogs. At the systemic level, blood pooling within the large internal organs (e.g., spleen, liver) is a major contributor to the development of shock and consequent intestinal ischemia, hypoxia and endothelial hyperpermeability, commonly occurring in heatstroke patients. Evoked serious complications include rhabdomyolysis, acute kidney injury, acute respiratory distress syndrome and ultimately, sepsis and disseminated intravascular coagulation. The most common clinical signs in dogs include acute collapse, tachypnea, spontaneous bleeding, shock signs and mental abnormalities, including depression, disorientation or delirium, seizures, stupor and coma. In such dogs, presence of peripheral blood nucleated red blood cells uniquely occurs, and is a highly sensitive diagnostic and prognostic biomarker. Despite early, appropriate body cooling, and intensive supportive treatment, with no available specific treatment to ameliorate the severe inflammatory and hemostatic derangements, the mortality rate is around 50%, similar to that of human heatstroke victims. This review discusses the pathophysiology of canine heatstroke from a veterinarian's point of view, integrating new and old studies and knowledge. PMID- 29435479 TI - Intradermal administration of atrial natriuretic peptide has no effect on sweating and cutaneous vasodilator responses in young male adults. AB - Atrial natriuretic peptide (ANP) increases during exercise in the heat wherein heat loss responses of sweating and cutaneous vasodilatation are activated. Hence ANP might be involved in the regulation of sweating and cutaneous vasodilatation. However, whether ANP directly mediates sweating and cutaneous vasodilatation needs to be clarified. Also, muscarinic receptor activation induces sweating and cutaneous vasodilatation, however, it remains to be determined whether ANP modulates these responses. In this study, in 11 young males (25 +/- 5 years), cutaneous vascular conductance and sweat rate were assessed at intradermal microdialysis sites that were continuously perfused with either lactated Ringer (Control) or 3 different concentrations of ANP (0.1, 1, 10 uM). All 4 sites were co-administrated with methacholine, a muscarinic receptor agonist, in a dose dependent fashion (0.0125, 0.25, 5, 100, and 2000 mM, 25 min for each). ANP at all concentrations did not increase sweat rate and cutaneous vascular conductance as compared with pre-ANP infusion values (all P > 0.05). Methacholine increased both sweat rate and cutaneous vascular conductance (all P <= 0.05). However, the responses were unaffected by co-administration of ANP relative to methacholine only, even as assessed in context of the methacholine concentration required to elicit 50% of the maximal response (EC50) (all P > 0.05). We show that exogenous ANP administration intradermally does not directly modulate sweating and cutaneous vasodilatation under room temperature conditions in resting young adults. Further, there is no effect of ANP on muscarinic sweating and cutaneous vasodilatation. PMID- 29435478 TI - Rapid responses of plants to temperature changes. AB - Temperature is one of the main environmental factors that affect plant metabolism. Considering that plants are sessile, their survival depends on the efficient activation of resistance responses to thermal stress. In this comprehensive review, we discuss recent work on rapid biochemical and physiological adjustments, herein referred to as those occurring during the first few hours or a few days after the beginning of the change in the ambient temperature. The short-term metabolic modulation after plant exposure to heat and cold, including chilling and freezing, is discussed. Effects on photosynthesis, cell membranes, antioxidant system, production of heat shock proteins and nitric oxide, as well as an overview of signaling events to heat or cold stress are presented. In addition, we also discuss the acclimation process that occurs when the plant acquires resistance to an increase or decrease in temperature, adjusting its homeostasis and steady-state physiology to the new temperatures. Finally, we present studies with tropical plants that aim at elucidating the effects of temperature and the identification of the resilience levels of these plants to the expected climate changes, and which seek the development of techniques for germplasm conservation of endangered species. PMID- 29435480 TI - Acute physiological and perceptual responses to wearing additional clothing while cycling outdoors in a temperate environment:A practical method to increase the heat load. AB - This investigation assessed the acute physiological and perceptual responses to wearing additional clothing during outdoor cycling to determine if this strategy could increase the heat load while training in temperate environments. Seven male cyclists (age: 32 +/- 13 y, height: 179 +/- 10 cm, body mass: 74 +/- 10 kg, body fat percentage: 10.3 +/- 1.0%) completed 2 randomized outdoor (~17 degrees C and ~82% RH), 80 min cycling sessions at moderate-hard intensities (CR10 RPE = 3-5). They wore spandex shorts and a short sleeve top (CON) or additional clothing including full-length spandex pants and a 'winter' cycling jacket and gloves (AC). Core temperature, heart rate, sweat rate, thermal sensation and thermal comfort were measured across the trials. Moderate increases were observed in AC vs. CON for the change in mean core temperature (0.4 +/- 0.3 degrees C, effect size, ES = 1.16 +/- 0.55), change in maximum core temperature (0.5 +/- 0.3 degrees C, ES = 1.07 +/- 0.48) and sweat rate (0.24 +/- 0.16 L . h-1, ES = 1.04 +/- 0.59). A small increase in mean heart rate (3 +/- 3 bpm, ES = 0.32 +/- 0.28) was observed as well as a 'very likely' (percentage difference = 22.4 +/- 7.1) and 'most likely' (percentage difference = 42.9 +/- 11.9) increase in thermal sensation and thermal comfort, respectively, in AC vs. CON. Dressing in additional clothing while cycling outdoors in a temperate environment increased physiological strain and sensations of warmth and discomfort. Training in additional clothing during outdoor cycling represents a practical alternative to increasing the heat load of a training session. PMID- 29435481 TI - Performance in complex motor tasks deteriorates in hyperthermic humans. AB - Heat stress, leading to elevations in whole-body temperature, has a marked impact on both physical performance and cognition in ecological settings. Lab experiments confirm this for physically demanding activities, whereas observations are inconsistent for tasks involving cognitive processing of information or decision-making prior to responding. We hypothesized that divergences could relate to task complexity and developed a protocol consisting of 1) simple motor task [TARGET_pinch], 2) complex motor task [Visuo-motor tracking], 3) simple math task [MATH_type], 4) combined motor-math task [MATH_pinch]. Furthermore, visuo-motor tracking performance was assessed both in a separate- and a multipart protocol (complex motor tasks alternating with the three other tasks). Following familiarization, each of the 10 male subjects completed separate and multipart protocols in randomized order in the heat (40 degrees C) or control condition (20 degrees C) with testing at baseline (seated rest) and similar seated position, following exercise-induced hyperthermia (core temperature ~ 39.5 degrees C in the heat and 38.2 degrees C in control condition). All task scores were unaffected by control exercise or passive heat exposure, but visuo-motor tracking performance was reduced by 10.7 +/- 6.5% following exercise-induced hyperthermia when integrated in the multipart protocol and 4.4 +/- 5.7% when tested separately (both P < 0.05). TARGET_pinch precision declined by 2.6 +/- 1.3% (P < 0.05), while no significant changes were observed for the math tasks. These results indicate that heat per se has little impact on simple motor or cognitive test performance, but complex motor performance is impaired by hyperthermia and especially so when multiple tasks are combined. PMID- 29435483 TI - About the cover. PMID- 29435482 TI - Thermal imaging reveals sizable shifts in facial temperature surrounding yawning in budgerigars (Melopsittacus undulatus). AB - Accumulating comparative and interdisciplinary research supports a brain cooling function to yawning. In particular, previous research has shown significant decreases in both brain and skull temperature following yawning in mammals. In a recent study using a thermal imaging camera, significant reductions in both the cornea and concha temperature were observed following yawns in the high-yawning subline of Sprague-Dawley rats. Here, we performed a similar experiment to investigate shifts in facial temperature surrounding yawning in an avian species with more typical yawning patterns: budgerigars (Melopsittacus undulatus). In particular, we took maximal surface temperature recordings from the face (cere or eye) from 13 birds over a one-hour period to track changes before and after yawns. Similar to previous findings in high-yawning rats, we identified significant cooling (-0.36 degrees C) of the face 10-20 seconds following yawning in budgerigars. Consistent with the hypothesis that yawns serve a thermoregulatory function, facial temperatures were slightly elevated just prior to yawning and then decreased significantly below baseline levels immediately thereafter. Similarly, birds that yawned during the trials had consistently higher facial temperatures compared to those that did not yawn. Moreover, yawn latency and overall yawn frequency were strongly correlated with the highest facial temperature recorded from each bird across trials. These results provide convergent evidence in support of a brain cooling function to yawning, and further validate the use of thermal imaging to monitor changes in skull temperature surrounding yawning events. PMID- 29435484 TI - Surgical Management of Symptomatic Intraluminal Duodenal Diverticulum in an Adolescent. PMID- 29435485 TI - Evaluating the Effectiveness, Efficiency and Safety of Telemedicine for Urological Care in the Male Prisoner Population. AB - Introduction: We reviewed the safety and effectiveness of our hospital's urologic telemedicine (TM) program that has been utilized for the Iowa prisoner population for over a decade. Methods: A retrospective review of TM visits of male prisoners from 2007 to 2014 was performed. Effectiveness of TM visits was assessed by 1) concordance of TM and in-person diagnoses, 2) compliance with radiologic and medication orders and 3) in-person visits saved with TM. Safety was assessed by analyzing the number of patients in which an ED visit was required after TM visit and missed or delayed cases of malignancy. Estimates were then made of the number of patients that could safely be managed with TM alone. Results: The most common diagnosis was voiding dysfunction (24%) followed by genitourinary pain (23%). Diagnoses were concordant in 90% of patients; compliance was high (radiology 91%, medications 89%); in-person visits were estimated to be saved in 80-94%. No men required peri-TM ED visits and no cases of malignancy were missed in the population that returned for an in-person visit. We estimated that over 50% of urologic complaints in this cohort could have been managed with TM alone. Conclusions: TM was shown to be a safe and effective method to provide general urologic care that obviated the initial in-person visits in nearly 90% of patients. It is likely that TM could safely replace in-person visits for many urologic conditions, especially in younger men and those in which access to specialized care may be limited. PMID- 29435487 TI - Auditory Brainstem Responses to Continuous Natural Speech in Human Listeners. AB - Speech is an ecologically essential signal, whose processing crucially involves the subcortical nuclei of the auditory brainstem, but there are few experimental options for studying these early responses in human listeners under natural conditions. While encoding of continuous natural speech has been successfully probed in the cortex with neurophysiological tools such as electroencephalography (EEG) and magnetoencephalography, the rapidity of subcortical response components combined with unfavorable signal-to-noise ratios signal-to-noise ratio has prevented application of those methods to the brainstem. Instead, experiments have used thousands of repetitions of simple stimuli such as clicks, tone-bursts, or brief spoken syllables, with deviations from those paradigms leading to ambiguity in the neural origins of measured responses. In this study we developed and tested a new way to measure the auditory brainstem response (ABR) to ongoing, naturally uttered speech, using EEG to record from human listeners. We found a high degree of morphological similarity between the speech-derived ABRs and the standard click-evoked ABR, in particular, a preserved Wave V, the most prominent voltage peak in the standard click-evoked ABR. Because this method yields distinct peaks that recapitulate the canonical ABR, at latencies too short to originate from the cortex, the responses measured can be unambiguously determined to be subcortical in origin. The use of naturally uttered speech to measure the ABR allows the design of engaging behavioral tasks, facilitating new investigations of the potential effects of cognitive processes like language and attention on brainstem processing. PMID- 29435486 TI - Transient Receptor Potential Channels TRPM4 and TRPC3 Critically Contribute to Respiratory Motor Pattern Formation but not Rhythmogenesis in Rodent Brainstem Circuits. AB - Transient receptor potential channel, TRPM4, the putative molecular substrate for Ca2+-activated nonselective cation current (ICAN), is hypothesized to generate bursting activity of pre-Botzinger complex (pre-BotC) inspiratory neurons and critically contribute to respiratory rhythmogenesis. Another TRP channel, TRPC3, which mediates Na+/Ca2+ fluxes, may be involved in regulating Ca2+-related signaling, including affecting TRPM4/ICAN in respiratory pre-BotC neurons. However, TRPM4 and TRPC3 expression in pre-BotC inspiratory neurons and functional roles of these channels remain to be determined. By single-cell multiplex RT-PCR, we show mRNA expression for these channels in pre-BotC inspiratory neurons in rhythmically active medullary in vitro slices from neonatal rats and mice. Functional contributions were analyzed with pharmacological inhibitors of TRPM4 or TRPC3 in vitro as well as in mature rodent arterially perfused in situ brainstem-spinal cord preparations. Perturbations of respiratory circuit activity were also compared with those by a blocker of ICAN. Pharmacologically attenuating endogenous activation of TRPM4, TRPC3, or ICANin vitro similarly reduced the amplitude of inspiratory motoneuronal activity without significant perturbations of inspiratory frequency or variability of the rhythm. Amplitude perturbations were correlated with reduced inspiratory glutamatergic pre-BotC neuronal activity, monitored by multicellular dynamic calcium imaging in vitro. In more intact circuits in situ, the reduction of pre BotC and motoneuronal inspiratory activity amplitude was accompanied by reduced post-inspiratory motoneuronal activity, without disruption of rhythm generation. We conclude that endogenously activated TRPM4, which likely mediates ICAN, and TRPC3 channels in pre-BotC inspiratory neurons play fundamental roles in respiratory pattern formation but are not critically involved in respiratory rhythm generation. PMID- 29435488 TI - Evaluating Nonclinical Performance of the Academic Pathologist: A Comprehensive, Scalable, and Flexible System for Leadership Use. AB - Academic pathologists perform clinical duties, as well as valuable nonclinical activities. Nonclinical activities may consist of research, teaching, and administrative management among many other important tasks. While clinical duties have many clear metrics to measure productivity, like the relative value units of Medicare reimbursement, nonclinical performance is often difficult to measure. Despite the difficulty of evaluating nonclinical activities, nonclinical productivity is used to determine promotion, funding, and inform professional evaluations of performance. In order to better evaluate the important nonclinical performance of academic pathologists, we present an evaluation system for leadership use. This system uses a Microsoft Excel workbook to provide academic pathologist respondents and reviewing leadership a transparent, easy-to-complete system that is both flexible and scalable. This system provides real-time feedback to academic pathologist respondents and a clear executive summary that allows for focused guidance of the respondent. This system may be adapted to fit practices of varying size, measure performance differently based on years of experience, and can work with many different institutional values. PMID- 29435489 TI - The Use of Ultrasound as a Potential Adjunct to Cell-Free Fetal DNA Screening for Aneuploidy at Weill Cornell Medical College, New York, USA. AB - Objective To evaluate the utility of ultrasound in identifying fetuses with uncommon chromosomal abnormalities that would be considered not detectable by cell-free fetal deoxyribonucleic acid (cfDNA). Study Design We performed a retrospective study of fetuses with chromosomal abnormalities that would be undetectable by cfDNA, who underwent an 11- to 14-week ultrasound from 2006 to 2016. Results There were 43 pregnancies included. First-trimester ultrasound revealed a fetal abnormality in 19 (44.2%) cases, of which 13 (30.2%) had a thickened nuchal translucency. There were an additional four fetuses with second trimester sonographic abnormalities. Overall, 23 (53.5%) fetuses were found to have a major anomaly diagnosed by ultrasound. The rate of first-trimester sonographic abnormalities varied widely based on category of chromosomal abnormalities with high rates seen with triploidy (87.5%) and autosomal trisomy (80%) and lower rates seen with structurally abnormal chromosomes (33.3%), trisomy mosaicism (27.3%), other forms of mosaicism (11.1%), and deletions or duplications (25.0%), p < 0.001. Conclusion The majority of fetuses with uncommon chromosomal abnormalities in our cohort had major sonographic anomalies. The use of first-trimester ultrasound with nuchal translucency measurement may offer utility in identifying fetuses with risk of aneuploidy that would not be detectable with cfDNA. PMID- 29435490 TI - C-Terminal Farnesylation of UCH-L1 Plays a Role in Transport of Epstein-Barr Virus Primary Oncoprotein LMP1 to Exosomes. AB - Increasing evidence shows that exosomes are key regulators in cancer cell-to-cell communication. Several reports on Epstein-Barr virus (EBV)-related malignancies demonstrate that latent membrane protein 1 (LMP1) secreted by exosomes derived from EBV- or LMP1-positive cells can promote cancer progression and metastasis. However, the mechanism by which LMP1 is loaded into exosomes is still poorly understood. Here, we examined whether the process of LMP1 loading into exosomes is linked to the multifunctional molecule of the ubiquitin system-ubiquitin C terminal hydrolase-L1 (UCH-L1). For the first time, we demonstrate that LMP1 is physically associated with UCH-L1 and that directing of LMP1 to exosomes is mediated by C-terminal farnesylation of UCH-L1. Additionally, we found that the FTI-277 farnesyltransferase inhibitor reduces motility- and anchorage-independent growth of EBV-positive cells in functional assays. On the basis of our results, we conclude that C-terminal farnesylation of UCH-L1 is one of the key mechanisms by which LMP1 is sorted to exosomes. We hypothesize that inhibition of farnesylation with specific small-molecule inhibitors blocks exosome-mediated transfer of prometastatic molecules such as LMP1 during cancer cell-to-cell communications and thereby impedes the process of cancer invasion. IMPORTANCE Exosomes are small vesicles that cells secrete into the extracellular space, and there is increasing evidence that they have pivotal roles in cell-to-cell communication in malignancy. It is reported also that EBV-associated malignant cells, including those derived from nasopharyngeal carcinoma (NPC) and B-cell lymphoma, secrete exosomes. These EBV-related exosomes may contain viral products such as latent membrane protein 1 (LMP1) and may contribute to cancer progression. The aim of this study was to investigate the mechanism by which those viral products are loaded in exosomes. In this study, we show for the first time that ubiquitin C-terminal hydrolase-L1 (UCH-L1) and its C-terminal farnesylation, a posttranslational lipid modification, contribute to this mechanism. Our results also suggest that inhibition of UCH-L1 farnesylation is a potential therapeutic target against cancer metastasis and invasion. PMID- 29435491 TI - Genomewide Identification of Essential Genes and Fitness Determinants of Streptococcus mutans UA159. AB - Transposon mutagenesis coupled with next-generation DNA sequencing (Tn-seq) is a powerful tool for discovering regions of the genome that are required for the survival of bacteria in different environments. We adapted this technique to the dental caries pathogen Streptococcus mutans UA159 and identified 11% of the genome as essential, with many genes encoding products required for replication, translation, lipid metabolism, and cell wall biogenesis. Comparison of the essential genome of S. mutans UA159 with those of selected other streptococci for which such information is available revealed several metabolic pathways and genes that are required in S. mutans, but not in some Streptococcus spp. We further identified genes that are essential for sustained growth in rich or defined medium, as well as for persistence in vivo in a rodent model of oral infection. Collectively, our results provide a novel and comprehensive view of the genes required for essential processes of S. mutans, many of which could represent potential targets for therapeutics. IMPORTANCE Tooth decay (dental caries) is a common cause of pain, impaired quality of life, and tooth loss in children and adults. It begins because of a compositional change in the microorganisms that colonize the tooth surface driven by repeated and sustained carbohydrate intake. Although several bacterial species are associated with tooth decay, Streptococcus mutans is the most common cause. Therefore, it is important to identify biological processes that contribute to the survival of S. mutans in the human mouth, with the aim of disrupting the processes with antimicrobial agents. We successfully applied Tn-seq to S. mutans, discovering genes that are required for survival, growth, and persistence, both in laboratory environments and in a mouse model of tooth decay. This work highlights new avenues for the control of an important human pathogen. PMID- 29435492 TI - Transcriptional Regulation of Carnitine Catabolism in Pseudomonas aeruginosa by CdhR. AB - The common environmental bacterium and opportunistic pathogen Pseudomonas aeruginosa encodes diverse metabolic pathways and associated regulatory networks allowing it to thrive in these different environments. In an effort to understand P. aeruginosa metabolism and detection of host-derived compounds, we previously identified CdhR and GbdR as members of the AraC transcription factor family that regulate catabolism of the quaternary amine compounds carnitine and glycine betaine, respectively. In this study, our goal was to further characterize regulation of carnitine catabolism by the transcription factor CdhR. CdhR binds in a concentration-dependent manner upstream of the carnitine catabolism operon promoter (P caiXcdhCABhocS ). We identified the CdhR binding site and determined that it overlaps with the GbdR binding site in the caiX-cdhR intergenic region. Carnitine catabolism is repressed by glucose and glycine betaine, and here we show this happens at the transcriptional level. Furthermore, we show that CdhR enhances its own expression and that GbdR contributes to cdhR expression by enhancing the level of basal expression. The intertwined regulation of caiX and cdhR transcription by GbdR and CdhR suggests that carnitine catabolism is under tight but tuneable control. IMPORTANCE Pathogens must metabolize host-derived compounds during infection and properly regulate the responsible pathways. Carnitine is a common eukaryotic-associated quaternary amine compound that can be catabolized by Pseudomonas aeruginosa. Here we expand on our understanding of how this metabolic pathway is regulated and provide details on how carnitine catabolism is intertwined with glycine betaine catabolism at the level of transcriptional control. PMID- 29435493 TI - Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion. AB - Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross-protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate that, although rare, antibodies to conserved GII.4 blockade epitopes are generated. The mechanisms by which these epitopes evade immune surveillance are uncertain. Here, we developed a new approach for identifying conserved GII.4 norovirus epitopes. Utilizing a unique set of virus-like particles (VLPs) representing the in vivo-evolved sequence diversity within an immunocompromised person, we identify key residues within epitope F, a conserved GII.4 blockade antibody epitope. The residues critical for antibody binding are proximal to evolving blockade epitope E. Like epitope F, antibody blockade of epitope E was temperature sensitive, indicating that particle conformation regulates antibody access not only to the conserved GII.4 blockade epitope F but also to the evolving epitope E. These data highlight novel GII.4 mechanisms to protect blockade antibody epitopes, map essential residues of a GII.4 conserved epitope, and expand our understanding of how viral particle dynamics may drive antigenicity and antibody-mediated protection by effectively shielding blockade epitopes. Our data support the notion that GII.4 particle breathing may well represent a major mechanism of humoral immune evasion supporting cyclic pandemic virus persistence and spread in human populations. IMPORTANCE In this study, we use norovirus virus-like particles to identify key residues of a conserved GII.4 blockade antibody epitope. Further, we identify an additional GII.4 blockade antibody epitope to be occluded, with antibody access governed by temperature and particle dynamics. These findings provide additional support for particle conformation-based presentation of binding residues mediated by a particle "breathing core." Together, these data suggest that limiting antibody access to blockade antibody epitopes may be a frequent mechanism of immune evasion for GII.4 human noroviruses. Mapping blockade antibody epitopes, the interaction between adjacent epitopes on the particle, and the breathing core that mediates antibody access to epitopes provides greater mechanistic understanding of epitope camouflage strategies utilized by human viral pathogens to evade immunity. PMID- 29435494 TI - Tick-Borne Encephalitis Virus Vaccine-Induced Human Antibodies Mediate Negligible Enhancement of Zika Virus Infection InVitro and in a Mouse Model. AB - Recent reports in the scientific literature have suggested that anti-dengue virus (DENV) and anti-West Nile virus (WNV) immunity exacerbates Zika virus (ZIKV) pathogenesis in vitro and in vivo in mouse models. Large populations of immune individuals exist for a related flavivirus (tick-borne encephalitis virus [TBEV]), due to large-scale vaccination campaigns and endemic circulation throughout most of northern Europe and the southern Russian Federation. As a result, the question of whether anti-TBEV immunity can affect Zika virus pathogenesis is a pertinent one. For this study, we obtained 50 serum samples from individuals vaccinated with the TBEV vaccine FSME-IMMUN (Central European/Neudorfl strain) and evaluated their enhancement capacity in vitro using K562 human myeloid cells expressing CD32 and in vivo using a mouse model of ZIKV pathogenesis. Among the 50 TBEV vaccinee samples evaluated, 29 had detectable reactivity against ZIKV envelope (E) protein by enzyme-linked immunosorbent assay (ELISA), and 36 showed enhancement of ZIKV infection in vitro. A pool of the most highly reacting and enhanced samples resulted in no significant change in the morbidity/mortality of ZIKV disease in immunocompromised Stat2-/- mice. Our results suggest that humoral immunity against TBEV is unlikely to enhance Zika virus pathogenesis in humans. No clinical reports indicating that TBEV vaccinees experiencing enhanced ZIKV disease have been published so far, and though the epidemiological data are sparse, our findings suggest that there is little reason for concern. This study also displays a clear relationship between the phylogenetic distance between two flaviviruses and their capacity for pathogenic enhancement. IMPORTANCE The relationship between serial infections of two different serotypes of dengue virus and more severe disease courses is well documented in the literature, driven by so-called antibody-dependent enhancement (ADE). Recently, studies have shown the possibility of ADE in cells exposed to anti-DENV human plasma and then infected with ZIKV and also in mouse models of ZIKV pathogenesis after passive transfer of anti-DENV human plasma. In this study, we evaluated the extent to which this phenomenon occurs using sera from individuals immunized against tick-borne encephalitis virus (TBEV). This is highly relevant, since large proportions of the European population are vaccinated against TBEV or otherwise seropositive. PMID- 29435495 TI - Correction for Morton et al., "Uncovering the Horseshoe Effect in Microbial Analyses". AB - [This corrects the article DOI: 10.1128/mSystems.00166-16.]. PMID- 29435497 TI - Supplementary Addendum to "Radiation dose of digital radiography (DR) versus micro-dose x-ray (EOS) on patients with adolescent idiopathic scoliosis: 2016 SOSORT- IRSSD "John Sevastic Award" Winner in Imaging Research". AB - Regarding the publication entitle "Radiation dose of digital radiography (DR) versus micro-dose x-ray (EOS) on patients with adolescent idiopathic scoliosis: 2016 SOSORT- IRSSD "John Sevastic Award" Winner in Imaging Research" in Scoliosis and Spinal Disorders, we would like to provide more details to readers about the dose calculated by simulation using PCXMC 2.0. In this study, the data and results are correct based on the given parameters and calculation provided in the manuscript. In the simulation of EOS micro-dose, only a 0.1 mm copper filter was applied. We agree with the suggestion from Dr. Pedersen and colleagues that the inclusion of a 1.5 mm aluminum filter together with the 0.1 mm copper reflects more realistic representation of X-ray filtration which would improve the accuracy of the simulation. We believe that this supplementary addendum would be beneficial to other researchers who are planning to conduct a similar study. PMID- 29435496 TI - Zika Virus Alters DNA Methylation of Neural Genes in an Organoid Model of the Developing Human Brain. AB - Zika virus (ZIKV) infection during early pregnancy can cause microcephaly and associated defects at birth, but whether it can induce neurologic sequelae that appear later in life remains unclear. Using a model of the developing brain based on embryonic stem cell-derived brain organoids, we studied the impact of ZIKV infection on the DNA methylation pattern across the entire genome in selected neural cell types. The virus unexpectedly alters the DNA methylome of neural progenitors, astrocytes, and differentiated neurons at genes that have been implicated in the pathogenesis of a number of brain disorders, most prominently mental retardation and schizophrenia. Our results suggest that ZIKV infection during fetal development could lead to a spectrum of delayed-onset neuropsychiatric complications. IMPORTANCE Scientific research on human neural stem cells and cerebral organoids has confirmed the congenital neurotropic and neurodestructive nature of the Zika virus. However, the extent to which prenatal ZIKV infection is associated with more subtle brain alterations, such as epigenetic changes, remains ill defined. Here, we address the question of whether ZIKV infection induces DNA methylation changes with the potential to cause brain disorders later in life. PMID- 29435498 TI - LETTER TO THE EDITOR CONCERNING: Effectiveness of the Rigo Cheneau versus Boston style orthoses for adolescent idiopathicscoliosis: a retrospective study, by Minsk MK, Venuti KD, Daumit GL, Sponseller PD. Scoliosis Spinal Disord. 2017 Mar 20;12:7. AB - We have read with great interest the article by Minsk et al. in Scoliosis and Spinal Disorders. However, the authors reported a conclusion that is based on possible selection bias in surgical candidates. Physicians are trained in the interpretation of scientific articles; however, not everybody is able to do this. Especially in open access journals, a biased conclusion may have big consequences and may be misleading for patients and family members who can read these articles for free on the internet. PMID- 29435500 TI - Three-dimensional reconstructions of Lenke 1A curves. AB - Background: Scoliosis is a 3D deformity that can be reconstructed through 2D antero-posterior and lateral radiographs, which provide an upper view of the deformed spine as well as regional planes matching all vertebrae of elective plane for each curve. The objective of this study is to explore whether all idiopathic scoliosis classified Lenke 1A have the same 3D representation made with regional planes. Methods: All patients treated for idiopathic thoracic scoliosis during the growth period and classified Lenke 1A were included in this study conducted in the pediatric spinal orthopedic department of Centre des Massues. A photogrammetric technique was used to obtain a 3D reconstruction, from regional planes identified on radiographs made with the EOS system. Three regional planes are usually identified in asymptomatic spines: lumbar, dorsal, and cervical-none of them presenting rotation. In the studied group, the number of planes, the rotation, and the limit vertebrae of each plane were looked for. Results: Sixty-three patients were included (47 girls and 16 boys, mean age 11.3 years). The Cobb angle was meanly 36.5 degrees . The scoliosis was reconstructed with three regional planes (57%) or four ones (43%, with the thoracic plane divided into two planes). Maximal rotation was found in the thoracic plane, especially when scoliosis was represented with four regional planes. The transition between planes 2 and 3 was mainly located between the fourth and sixth dorsal vertebrae. Conclusion: The use of an arbitrary regional plane representation of a 3D shape leads to conclude that there are two types of Lenke 1A scoliosis, which should be taken into account for designing the brace. PMID- 29435501 TI - Prevention of acute kidney injury through accurate fluid balance monitoring. AB - Acute kidney injury (AKI) is associated with increased patient morbidity, mortality and an extended hospital stay. The financial burden to the National Health Service is high and it can affect up to one in five inpatients. Optimal fluid balance management is essential for the prevention of AKI and this can be particularly challenging in the patient with trauma. Our aim was to reduce the rate of AKI in patients with traumatic injuries in the regional trauma centre. We developed new fluid balance charts and documented how well these were completed. The number of AKI alerts per month was calculated on our pathology system. Scenario training was delivered at handover meetings and an e-learning tool was designed at three levels: healthcare assistants; nurses; and medical staff, dietetics and pharmacists. Educational posters were placed in clinical areas and patient information leaflets produced. Junior doctors were regularly informed of AKI rates on the ward. The number of AKI alerts on our trauma ward declined from 50 in January 2016 to 19 in November 2016. The mean monthly rate of AKI fell 33% following the invention (P<0.001). Completion of fluid balance charts improved; 6 hourly urine output documentation increased from 36% to 68% and running 1 hourly output increased from 80% to 96%. Calculation of total daily fluid balance rose from 12% to 72%, before decreasing to 32%. This highlighted the need for continued encouragement. Improved fluid balance monitoring led to a reduction in the prevalence of AKI in patients admitted to this trauma centre. PMID- 29435502 TI - Transition from a dedicated to a non-dedicated, ward-based pharmacist antimicrobial stewardship programme model in a non-academic hospital and its impact on length of stay of patients admitted with pneumonia: a prospective observational study. AB - Pharmacists play an integral role in antimicrobial stewardship (AS). Some AS programmes employ dedicated pharmacists, sometimes with infectious diseases (ID) training, while others employ ward-based pharmacists. The role and impact of both are under investigation. This study compares the length of stay (LOS) of patients admitted to hospital with community-acquired pneumonia (CAP) after the implementation of an AS programme initially led by a dedicated ID-trained pharmacist, and then transitioned to a ward-based pharmacist. Starting 1 April 2013, all adult patients admitted with CAP were prospectively reviewed by the AS programme. The control period (phase 0) lasted 3 months. Thereafter, AS was implemented in each of four medicine wards at 2-month intervals in a staggered fashion. During this period (phase 1), an ID-trained pharmacist and physician performed daily prospective audit and feedback. After 24 months, ward-based pharmacists assumed this AS role (phase 2). Over the 36-month study period, 1125 patients with CAP were entered into the AS database, with 518 and 247 patients receiving an AS audit and feedback in phases 1 and 2, respectively. The acceptance rate for AS recommendations was similar for phases 1 and 2, each exceeding 82%. After accounting for secular trends, the overall reduction in LOS was 19.4% (95% CI 1.4% to 40.5%). There was no difference in LOS between phases 1 and 2. This study demonstrated that an AS audit and feedback intervention reduced the median LOS in patients with CAP by approximately 0.5 days regardless of pharmacist model. However, fewer patients were exposed to the AS intervention in phase 2, suggesting dedicated AS pharmacists may be necessary to realise the full benefits of AS. PMID- 29435503 TI - Adding value to daily chest X-rays in the ICU through education, restricted daily orders and indication-based prompting. AB - Background: Chest X-rays (CXRs) are traditionally obtained daily in all patients on invasive mechanical ventilation (IMV) in the intensive care unit (ICU). We sought to reduce overutilisation of CXRs obtained in the ICU, using a multifaceted intervention to eliminate automated daily studies. Methods: We first educated ICU staff about the low diagnostic yield of automated daily CXRs, then removed the 'daily' option from the electronic health records-based ordering system, and added a query (CXR indicated or not indicated) to the ICU daily rounding checklist to prompt a CXR order when clinically warranted. We built a report from billing codes, focusing on all CXRs obtained on IMV census days in the medical (MICU) and surgical (SICU) ICUs, excluding the day of admission and days that a procedure warranting CXR was performed. This generated the number of CXRs obtained every 1000 'included' ventilator days (IVDs), the latter defined as not having an 'absolute' clinical indication for CXR. Results: The average monthly number of CXRs on an IVD decreased from 919+/-90 (95% CI 877 to 963) to 330+/-87 (95% CI 295 to 354) per 1000 IVDs in the MICU, and from 995+/-69 (95% CI 947 to 1055) to 649+/-133 (95% CI 593 to 697) in the SICU. This yielded an estimated 1830 to 2066 CXRs avoided over 2 years and an estimated annual savings of $191 600 to $224 200. There was no increase in reported adverse events. Conclusion: ICUs can safely transition to a higher value strategy of indication based chest imaging by educating staff, eliminating the 'daily' order option and adding a simplified prompt to avoid missing clinically indicated CXRs. PMID- 29435504 TI - Improving OSA screening and diagnosis in patients with hypertension in an academic safety net primary care clinic: quality improvement project. AB - Obstructive sleep apnoea (OSA) is more prevalent in patients with hypertension (HTN), and associated morbidities include stroke, heart failure and premature death. In the Internal Medicine Clinic (IMC), over 70% of the patients had a diagnosis of HTN and obesity. We identified a lack of OSA screening in patients with HTN. The aim of this quality improvement (QI) was to increase OSA diagnosis to 5% from the baseline rate of less than 1% in patients with HTN between the ages of 18 and 75 years over 6 months at IMC. We used the Plan-Do-Study-Act (PDSA) method. The QI team performed root cause analysis to identify materials/methods, provider and patient-related barriers. PDSA cycle included: (1) integration of customised workflow of loud Snoring, Tiredness, Observed apnea, high blood Pressure (STOP)-Body mass index (BMI), Age, Neck circumference, and Gender (BANG) OSA screening tool in the electronic health record (EHR); (2) physician education of OSA and EHR workflow; and (3) completion of STOP survey by patients, which was facilitated by nursing staff. The outcome measure was the percentage of OSA diagnosis in patients with HTN. The process measures included the percentage of patients with HTN screened for OSA and the increase in sleep study referrals in hypertensive patients with STOP-BANG score of >=3. Increase in patient wait time and cost of sleep study were the balance measures. Data analysis was performed using weekly statistical process control chart. The average increase in OSA screening rate using the STOP-BANG tool was 3.88%. The significant variation seen in relation to PDSA cycles was not sustainable. 32% of patients scored >=3 on the STOP-BANG tool, and 10.4% had a confirmed diagnosis of OSA. STOP-BANG tool integration in the EHR and a team approach did not result in a sustainable increase in OSA screening. OSA diagnosis was increased to 3.3% in IMC patient population within the 6-month period. The team identified multiple barriers to screening and diagnosis of OSA in the IMC. PMID- 29435505 TI - Improving the workflow of nursing assistants at a general hospital in Japan. AB - Transferring non-specialised tasks from registered nurses to nursing assistants may help registered nurses focus on specialised tasks. Optimising the workflow of nursing assistants by making their tasks more efficient may improve problems associated with the shortage of registered nurses. The nursing assistants at our hospital were stressed about referring inpatients to outpatient specialty clinics. Therefore, we initiated a project to optimise the referral process and reduce the time spent by nursing assistants on this task, with the collaboration of physicians, registered nurses and administrative assistants. The Training for Effective & Efficient Action in Medical Service-Better Process (TEAMS-BP) method, which was developed by modifying the Japanese Training Within Industry-Job Method, was used for the optimisation process. TEAMS-BP teaches users how to break each task down into its individual components, to scrutinise the details, and then to develop new processes by eliminating, combining, rearranging and simplifying tasks. At baseline, each referral took 10 min and was performed 39 times over 10 days in six wards. The first TEAMS-BP cycle did not yield satisfactory results for the nursing assistants. In the second TEAMS-BP cycle, participants included inpatient and outpatient physicians, registered nurses and administrative assistants. As a result, we changed the referral process from paper to electronic records and streamlined referrals that were ordered by inpatient physicians to outpatient physicians. The use of this method saved the equivalent of 175 hours of nursing assistants' time per year at no additional cost. If we had been able to define the referral process as an interdisciplinary task and show the merits to each department from the beginning, we may have been able to form the interprofessional team in the first TEAMS-BP. Improving the efficiency of nursing assistants can allow other professionals to focus on their specialised tasks more effectively. PMID- 29435506 TI - Primary care scribes: writing a new story for safety net clinics. AB - The spread of electronic health records systems (EHRs) poses challenges for both patient and provider care experience. Limited research suggests that scribes offer potential benefits to productivity and clinician satisfaction in emergency health and specialty settings. We conducted this evaluation of trained volunteer scribes for primary care clinics serving a diverse, low-income population in a US safety net system, which implemented a new EHR 2011-2014. The scribe programme trained and managed scribes for 51 providers (25% participation) from 5 of 12 San Francisco Health Network primary care clinics. We evaluated the programme using four measures. Providers reported spending less time out of clinic completing notes after sessions with scribes versus sessions without scribes (14.0 min vs 30.2 min, p<0.01). The rate of incomplete EHR notes at 72 hours was not significantly different for clinics using and not using scribes (16.9% vs 16.7%, p=0.4). Mean visit length using EHR-recorded provider cycle time was shorter for sessions with scribes (24.0 min), compared with sessions without scribes (26.4 min, p<0.01). Patients at clinics using scribes were as likely to recommend their provider (74.5%), compared with patients at clinics not using scribes (74.3%). Limitations of our evaluation include selection bias and possible confounding by clinic- and provider-level factors. In a safety net primary care system, trained volunteer scribes were associated with improved clinician efficiency and experience and no difference in patient satisfaction. PMID- 29435507 TI - Improving service user self-management: development and implementation of a strategy for the Richmond Response and Rehabilitation Team. AB - Community rapid response and rehabilitation teams are used to prevent avoidable hospital admissions for adults living with multiple long-term conditions and to support early hospital discharge by providing short-term intensive multidisciplinary support. Supporting self-management is an important service intervention if desired outcomes are to be achieved. A Care Quality Commission inspection of the Richmond Response and Rehabilitation Team in 2014 identified that self-management plans were not routinely developed with service users and reported this as requiring improvement. This quality improvement project aimed to develop and implement a self-management strategy for service users and for 90% of service users to have a personalised self-management plan within 3 months. The quality improvement intervention used the Plan-Do-Study-Act model comprising: (1) the development of a self-management plan, (2) staff education to support service users to self-manage using motivational interviewing techniques, (3) piloting the self-management plan with service users, (4) implementation of the self management plan and (5) monthly audit and feedback. Evaluation involved an audit of the number and quality of self-management plans developed with service users and a survey of staff knowledge and confidence to support service users to self manage. Following implementation of the intervention, the number of self management plans developed in collaboration with service users increased from 0 to 187 over a 4-week period. Monthly audit data confirmed that this improvement has been sustained. Results indicated that staff knowledge and confidence improved after an education intervention. Quality improvement methods facilitated development and operationalisation of a self-management strategy by a community rapid response and rehabilitation team. The next phase of the project is to evaluate the impact of the self-management strategy on key service outcomes including self-efficacy, unplanned and emergency hospital admissions and early discharges. PMID- 29435508 TI - An easy, prompt and reproducible methodology to manage an unexpected increase of incident reports in surgery theatres. AB - Objectives: Surgery is a high-risk hospital area for adverse events (AEs) occurrence. This study aims to develop an effectiveness and reactive methodology to manage an unexpected increase of AEs in the operating rooms (ORs) of a large Academic Hospital providing about 30 000 surgeries per year. Methods: The study included three phases: 1. analysis of the AEs collected through the hospital incident reporting system from 2014 to 2015; 2. development of a programme to improve the surgical patient's safety and 3. application and evaluation of the programme effectiveness. Results: In 2014, all hospital AEs were 825 (10.3% in ORs), while in the first 5 months of 2015, they were 645 (17.7% in ORs) [relative risk (RR) 2015 vs 2014=1.7; 95% CI=1.3 to 2.2; p<0.0001] with two sentinel events. Due to this increase, 177 real-time observations were planned in 12 ORs with external staff (n.25) during 1 week in June, July and November 2015 using a checklist with 14 items related to the patient's pathway (surgical site, time out, medical records and sponges count). After the observations, the AEs decreased from 11.4*1000 surgeries (January-June 2015) to 8.6*1000 (July-December 2015) (RR=0.7, 95% CI=0.6 to 0.9, p<0.05). Compliance to the correct procedures applied by ORs staff has improved during the year for all items. Conclusions: The methodology of this study has been revealed effective to control an unexpected increase in AEs and to improve the healthcare workers' adherence to correct procedures and it could be translated in other patients' safety settings. PMID- 29435509 TI - Assessment of a quality improvement intervention to strengthen pharmaceutical human resources and improve availability and use of HIV medicines in Uganda. AB - Inadequate medication dispensing and management by healthcare providers can contribute to poor outcomes among HIV-positive patients. Gaps in medication availability, often associated with pharmacy workforce shortages, are an important barrier to retention in HIV care in Uganda. An intervention to address pharmacy staffing constraints through strengthening pharmaceutical management, dispensing practices, and general competencies of facility clinical and pharmacy staff was implemented in 14 facilities in three districts in eastern Uganda. Teams of staff were organised in each facility and supported to apply quality improvement (QI) methods to address deficits in availability and rational use of HIV drugs. To evaluate the intervention, baseline and end line data were collected 24 months apart. Dispensing practices, clinical wellness and adherence to antiretrovirals improved by 45%, 28% and 20% from baseline to end line, respectively. All clients at end line received the medications prescribed, and medications were correctly, completely and legibly labelled more often. Clients better understood when, how much and for how long they were supposed to take their prescribed medicines at end line. Pharmaceutical management practices also improved from baseline in most categories by statistically significant margins. Facilities significantly improved on correctly recording stock information about antiretroviral drugs (53%vs100%, P<0.0001). Coinciding with existing staff taking on pharmaceutical roles, facilities improved management of unwanted and expired drugs, notably by optimising use of existing health workers and making pharmaceutical management processes more efficient. Implementation of this improvement intervention in the 14 facilities appeared to have a positive impact on client outcomes, pharmacy department management and providers' self-reported knowledge of QI methods. These results were achieved at a cost of about US$5.50 per client receiving HIV services at participating facilities. PMID- 29435510 TI - Using quality improvement to improve the utilisation of GeneXpert testing at five lab hubs in Northern Uganda. PMID- 29435511 TI - Establishing a new national standard for the documentation of regional anaesthesia in Ireland. PMID- 29435499 TI - 2016 SOSORT guidelines: orthopaedic and rehabilitation treatment of idiopathic scoliosis during growth. AB - Background: The International Scientific Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT) produced its first guidelines in 2005 and renewed them in 2011. Recently published high-quality clinical trials on the effect of conservative treatment approaches (braces and exercises) for idiopathic scoliosis prompted us to update the last guidelines' version. The objective was to align the guidelines with the new scientific evidence to assure faster knowledge transfer into clinical practice of conservative treatment for idiopathic scoliosis (CTIS). Methods: Physicians, researchers and allied health practitioners working in the area of CTIS were involved in the development of the 2016 guidelines. Multiple literature reviews reviewing the evidence on CTIS (assessment, bracing, physiotherapy, physiotherapeutic scoliosis-specific exercises (PSSE) and other CTIS) were conducted. Documents, recommendations and practical approach flow charts were developed using a Delphi procedure. The process was completed with the Consensus Session held during the first combined SOSORT/IRSSD Meeting held in Banff, Canada, in May 2016. Results: The contents of the new 2016 guidelines include the following: background on idiopathic scoliosis, description of CTIS approaches for various populations with flow charts for clinical practice, as well as literature reviews and recommendations on assessment, bracing, PSSE and other CTIS. The present guidelines include a total of 68 recommendations divided into following topics: bracing (n = 25), PSSE to prevent scoliosis progression during growth (n = 12), PSSE during brace treatment and surgical therapy (n = 6), other conservative treatments (n = 2), respiratory function and exercises (n = 3), general sport activities (n = 6); and assessment (n = 14). According to the agreed strength and level of evidence rating scale, there were 2 recommendations on bracing and 1 recommendation on PSSE that reached level of recommendation "I" and level of evidence "II". Three recommendations reached strength of recommendation A based on the level of evidence I (2 for bracing and one for assessment); 39 recommendations reached strength of recommendation B (20 for bracing, 13 for PSSE, and 6 for assessment).The number of paper for each level of evidence for each treatment is shown in Table 8. Conclusion: The 2016 SOSORT guidelines were developed based on the current evidence on CTIS. Over the last 5 years, high-quality evidence has started to emerge, particularly in the areas of efficacy of bracing (one large multicentre trial) and PSSE (three single-centre randomized controlled trials). Several grade A recommendations were presented. Despite the growing high-quality evidence, the heterogeneity of the study protocols limits generalizability of the recommendations. There is a need for standardization of research methods of conservative treatment effectiveness, as recognized by SOSORT and the Scoliosis Research Society (SRS) non-operative management Committee. PMID- 29435512 TI - Importance of an alternative approach to measuring quality in a volume-to-value world: a case study of diabetes care. AB - Background: To develop a statistical tool that allows practitioners and/or their practice managers to easily select the relevant range in which volume and value are maximised. Methods: Data for the study were based on 55 primary care practices that participated in the Colorado Improving Performance in Practice programme in 2014. We used two composite variables including the volume of processes of care variables listed in Diabetes Practice Guidelines and value (quality) as measured by changes in the intermediate outcomes. We assessed volume/value trade-offs using a multilevel model with a time-varying covariate partitioned into a between-practice and within-practice effect. Results: The study revealed a strong linear relationship between volume and value (P<0.0001). Specifically, practices with an above-average volume of care as measured by their process of care scores also had above-average quality outcomes (expected value 57; average volume 49.48) as quantified by their intermediate outcome scores. Additionally, in those months when practices provided a volume of care that exceeded their average process of care score, further improvements occurred in quality as measured by intermediate outcome scores (P<0.0001). Conclusion: Such findings suggest an inherent linkage between volume of care and quality. This statistical approach, if provided as an app containing an easy-to-use statistical calculator, will allow practice managers and clinicians to systematically identify volume/quality trade-offs, thereby reducing undertreatment and/or overtreatment among patients with chronicities. PMID- 29435513 TI - Initiative to improve the cardiogenic safety of antipsychotic medication in community mental health patients. AB - Serious mental illness is reported to reduce a patient's life expectancy by 15-20 years. This disparity is thought to be related to lifestyle factors, access to healthcare, poor health monitoring and the common use of antipsychotics, which can cause serious metabolic and cardiogenic side effects. Therefore, to reduce the risk of cardiac complications, both national and local guidance recommends annual ECG monitoring for patients on antipsychotics. Unfortunately this monitoring is not completed consistently at Manchester Mental Health and Social Care Trust, especially within community mental health teams. A small team of healthcare professionals conducted a quality improvement (QI) project from June 2015 to May 2016 with the aim of addressing this deficiency in care. A multidisciplinary approach was used to implement improvement in four key areas. Awareness of the need for monitoring, patient engagement with this process, identification of patients requiring monitoring and access to ECG equipment were all addressed as separate primary drivers for change over an 8-month period using a 'Plan Do Study Act' model of QI. Outcome, process and balancing measures were gathered monthly to track progress and improvement following the application of change. Compliance with annual ECG monitoring nearly doubled throughout the course of the project from 43% in June 2015 to a peak of 83% in February 2016. Improvement appeared to be sustained as the percentage of patients receiving the required monitoring remained significantly higher than baseline even after no further change interventions were being implemented (76%, 71%, 77%, March, April, May 2016). This QI project has shown that improvements can be made and has documented a recipe for how this change was achieved. PMID- 29435514 TI - Using the plan-do-study-act approach to improve inpatient colonoscopy preparation. AB - Poor inpatient colonoscopy preparations can provide multiple challenges to healthcare providers and patients alike. Poor preparations can make the colonoscopy difficult to perform, and can require the procedure to be repeated. This can in turn lead to greater costs, longer length of stays, less patient satisfaction and worse outcomes. The aim of this quality improvement project was to decrease the rate of poor inpatient colonoscopy preparations using the plan-do study-act approach. Inpatient colonoscopies at our institution from a 3-month span (November 2016 to January 2017) were evaluated, and found to have a 19% rate of poor preparations. A multiphase intervention programme was then conducted to improve the quality of these preparations. This intervention programme was threefold, and involved (1) direct education to physicians and nursing staff on the preparation process and its importance; (2) the implementation of an electronic order set within our electronic medical record (EMR) to standardise and simplify the process of ordering colonoscopy preparations; and (3) patient education in the form of a handout explaining the steps and importance of a good preparation. Through these interventions, we were able to bring down our rate of poor preparations over a 3-month average from 19% to 4%. Specifically, the implementation of an electronic order set within our EMR resulted in the greatest impact. Our interventions can be replicated at other institutions in order to decrease the rate of poor preparations, and thus result in better outcomes for patients, providers and healthcare facilities. PMID- 29435517 TI - A detailed decision tree to create, preserve, transfer, and support the emergence profile in anterior maxillary implants using custom abutments. AB - Rehabilitation with implants in the esthetic zone is one of the most demanding tasks due to the importance of obtaining an optimum esthetic result. The aim of this article was to present a workflow to create, preserve, transfer and support the emergence profile in anterior maxillary implants. Different methods are used surgically as well as prosthetically to construct an ideal restoration. When immediate loading can be applied in cases of increased primary stability, a provisional restoration is placed with occlusal contacts. In cases not permitting the above procedure and requiring extensive augmentation, a resin-bonded partial coverage fixed partial denture can be a predictable and reliable treatment option until the final restoration is delivered. Creating or preserving the emergence profile at immediate post-extraction and delayed implants, respectively, is achieved through customized provisional, healing abutments, a combination of prefabricated healing abutments and partial coverage provisional restoration, or utilization of the patient's own tooth crown. Transferring the individualized soft tissue contour to the final restoration can be achieved by modifying the impression coping intraorally with composite resin, fabricating a cast mimicking the soft tissue contour in the laboratory, or by the use of CAD/CAM technology. A customized abutment is necessary in order to maintain the emergence profile that has been created during the previous stages. The objective of this paper was to present a detailed workflow for the restoration of anterior maxillary implants focused on the creation, preservation, support, and transfer of the emergence profile of the soft tissues through a series of clinical cases. PMID- 29435516 TI - N-of-1 Trial in Person with Pontine Stroke Receiving Repetitive Transcranial Magnetic Stimulation to Improve Hand Function. AB - Stroke characteristics vary widely between individuals making it difficult to assess the value of stroke rehabilitation interventions. To eliminate inter subject variability, this study used an N-of-1 randomized, controlled design to explore the efficacy of repetitive transcranial magnetic stimulation (rTMS) in one unique individual with pontine stroke. We hypothesized that five days of active 6-Hz primed, low-frequency rTMS to the contralesional primary motor area (M1), combined with finger movement tracking training, would accomplish greater gains in hand function than sham rTMS combined with tracking training. We assessed hand function (Box and Block test and finger tracking test), cortical activation (laterality index during functional magnetic resonance imaging), and cortical excitability (interhemispheric inhibition testing (IHI) with transcranial magnetic stimulation (TMS)). Diffusion tensor imaging (DTI) assessed the integrity of his corticospinal tracts at baseline. Results showed no improvement in the Box and Block or finger tracking tests, unreliable IHI findings, and no change in laterality index following active rTMS. DTI suggested truncation of the left corticospinal tract (CST) at the pons. His non-dexterous hand movements combined with no elicitable motor evoked potentials with TMS to ipsilesional M1 and his DTI findings lead us to speculate a reticulospinal mechanism for preserving his rudimentary paretic hand control. We conclude that rTMS combined with tracking training was not effective in the absence of CST pathways and that research is needed to confirm markers of reticulospinal function in humans as an alternative to defective CST function. PMID- 29435515 TI - The Smyd Family of Methyltransferases: Role in Cardiac and Skeletal Muscle Physiology and Pathology. AB - Protein methylation plays a pivotal role in the regulation of various cellular processes including chromatin remodeling and gene expression. SET and MYND domain containing proteins (Smyd) are a special class of lysine methyltransferases whose catalytic SET domain is split by an MYND domain. The hallmark feature of this family was thought to be the methylation of histone H3 (on lysine 4). However, several studies suggest that the role of the Smyd family is dynamic, targeting unique histone residues associated with both transcriptional activation and repression. Smyd proteins also methylate several non-histone proteins to regulate various cellular processes. Although we are only beginning to understand their specific molecular functions and role in chromatin remodeling, recent studies have advanced our understanding of this relatively uncharacterized family, highlighting their involvement in development, cell growth and differentiation and during disease in various animal models. This review summarizes our current knowledge of the structure, function and methylation targets of the Smyd family and provides a compilation of data emphasizing their prominent role in cardiac and skeletal muscle physiology and pathology. PMID- 29435518 TI - Obliteration after recurrent dental trauma in a 7-year-old patient: 4-year follow up. AB - Traumatic dental injuries are reported to have a high prevalence regardless of the region or the age group. Concussion injuries are considered as moderate, but very frequent injuries. They are associated with a wide spectrum of pulpal reactions. Pulp canal obliteration in spite of negative sensitivity proves ongoing pulp vitality. This case report presents multiple traumatic dental injuries in both maxillary central incisors with two different pulpal reactions during a follow-up period of 4 years in a healthy 7-year-old girl. The initial trauma with a concussion required no invasive treatment. Three days later, the child presented again with a new dental trauma. At the follow-up appointments after 3, 4, 6, 12, and 18 months, the traumatized teeth were functional and asymptomatic, but the radiograph after 1 year showed partial obliteration in the coronal part of the maxillary right central incisor. After 4 years, the periapical radiograph showed complete apical closure, and increase in root length and dentin thickness for both maxillary central incisors, with almost complete root canal obliteration in the right central incisor, whereas the left central incisor showed no signs of obliteration. Thus, this case showed different pulpal reactions to traumatic dental injury and that the loss of clinical sensitivity of the obliterated tooth does not automatically mean the loss of vitality and the need for endodontics. Regular follow-ups are essential in concussion cases to observe the pulp vitality and root formation. PMID- 29435519 TI - Analysis of the causes of dental implant fracture: A retrospective clinical study. AB - OBJECTIVE: Fracture of osseointegrated dental implants is the most severe mechanical complication. The aim of the present study was to analyze possible causative factors for implant body fracture. METHOD AND MATERIALS: One hundred and one patients with 218 fitted implants and a follow-up period of 3 to 10 years were studied. Factors associated with biomechanical and physiologic overloading such as parafunctional activity (eg, bruxism), occlusion, and cantilevers, and factors related to the planning of the dental prosthesis, available bone volume, implant area, implant diameter, number of implants, and their inclination were tracked. The impact of their effect was analyzed using the Bonferroni-corrected post-hoc Mann-Whitney test for each group. RESULTS: The incidence of dental implant fracture was 2.3% in the investigated cases. Improper treatment planning, bruxism, and time of the complication setting in were the main factors leading to this complication. Typical size effect was established only for available bruxism, occlusal errors, and their activity duration. These complications were observed most often with single crown prostheses, and in combination with parafunctional activities such as bruxism and lack of implant-protected occlusion. CONCLUSION: Occlusal overload due to bruxism or inappropriate or inadequate occlusion as a single factor or a combination of these factors during the first years after the functional load can cause implant fracture. Fracture of the implant body more frequently occurred with single crowns than with other implant-supported fixed dental prostheses. PMID- 29435520 TI - Chronic non-suppurative mandibular osteomyelitis with proliferative periostitis: A review. AB - Chronic non-suppurative osteomyelitis (CNSO) is a chronic bone disease and may be associated with a reparative periosteum entity called proliferative periostitis (PP). This condition rarely affects the maxillofacial region. Mandibular cases were already described for an infectious dental cause, often with an "onion skin" radiographic aspect, but some rare reported cases showed no obvious etiology. They represent a challenge for diagnosis because of possible misdiagnosis leading to unsuccessful or inappropriate treatment attempts. An uncommon case of mandibular CNSO associated with PP in a 9-year-old boy with no obvious infectious or inflammatory causes is reported. Clinical and radiographic examinations revealed a swelling in the left hemimandible, associated with multiple osteolytic areas inside both medullary and newly formed periosteal bone and cortical bone perforations. Recovery signs were seen after a 22-month follow-up period, and radiographic signs of bone healing were observed. From this new case report, a review of the literature was performed on reported cases of mandibular CNSO with PP, and discussed the etiological, clinical, radiologic, and therapeutic aspects of this pathology. This work highlights the importance of considering CNSO with PP in the differential diagnosis of one-sided painless mandibular swellings, even in the absence of an obvious cause. PMID- 29435521 TI - A theoretical study of the confinement effects on the energetics and vibrational properties of 4,4'-bipyridine adsorption on H-ZSM-5 zeolite. AB - The confinement effects of a zeolite framework on the adsorption of a bidentate 4,4'-bipyridine (44BPY) ligand on the straight channel of H-ZSM-5 have been investigated by density functional theory calculations using B3LYP, B3LYP-D3, M06 2X, M06-2X-D3 functionals, and the MP2 method with two basis sets 6-31+G* and 6 31++G(2d,2p). The straight channel is simulated by a realistic cluster model of 32 tetrahedra (T), having two aluminum atoms located in the straight and intersection regions, respectively. The potential energy surface of the double proton transfer reaction from the Bronsted acid sites of H-ZSM-5 to 44BPY is characterized by three minima corresponding to two monodentate ion pair complexes 44BPYH+/32T- and one bidentate ion pair complex 44BPYH22+/32T2- formed consecutively via two distinct pathways. No energy minimum is found for a neutral hydrogen bonding structure. The relative stabilities of these 44BPY adsorption complexes and the transition states connecting them do not exceed 4.9 and 4.2 kcal mol-1, respectively. Consequently equilibrium between the mono and bidentate complexes could be established. Our results clearly show that the adsorption energy for all complexes is substantially governed by the confinement effects executed through steric constraints and dispersive van der Waals interactions. The calculated vibrational frequencies and frequency shifts of 44BPY adsorbed as mono or diprotonated species are in good agreement with our Raman spectra of 44BPY occluded in H-ZSM-5 of different Si/Al ratios. PMID- 29435522 TI - Magnetic field effects dynamics of ethylammonium nitrate ionic liquid confined between glass plates. AB - Self-diffusion and NMR relaxation of the ethylammonium (EA) cation were studied in the protic ionic liquid, ethylammonium nitrate (EAN), confined between polar glass plates separated by a few MUm distance and exposed to an external magnetic field of 9.4 T. The diffusion coefficient of EA (D) and the transverse NMR relaxation rate (1/T2) of -NH3 protons were increased immediately after placing the sample in the magnetic field by factors of ~2 and ~22, respectively, in comparison with those of bulk EAN. Further exposure of the sample to the magnetic field led to gradual changes in D, T1 and T2 towards their bulk values with a time constant of ~70 min. Complete "recovery" of the sample to the "accelerated" D and "shortened" T2 values occurred at longer than 24 hours after the removal of the EAN sample from the magnet. Because the observed characteristic times of the change far exceed the times of molecular processes in EAN, we suggested that this phenomenon is related to reversible phase transformations occurring in confined EAN. PMID- 29435523 TI - The effect of different organic solvents on sodium ion storage in carbon nanopores. AB - In this study fully atomistic grand canonical Monte Carlo (GCMC) simulations have been employed to study the behaviour of an electrolyte salt (NaPF6) and different non-aqueous (organic) solvents in carbon nanopores, to reveal the structure and storage mechanism. Organic solutions of Na+ and PF6- ions at 1 M concentration were considered, based on the conditions in operational sodium ion batteries and supercapacitors. Three organic solvents with different properties were selected: ethylene carbonate (EC), propylene carbonate (PC), and ethyl methyl carbonate (EMC). The effects of solvents, pore size and surface charge were quantified by calculating the radial distribution functions and ionic density profiles. It is shown that the organic solvent properties and nanopore confinement can affect the structure of the organic electrolyte solution. For the pore size range (1-5 nm) investigated in this paper, the surface charge used in this study can alter the sodium ions but not the solvent structure inside the pore. PMID- 29435524 TI - An ESIPT fluorescent probe and a nanofiber platform for selective and sensitive detection of a nerve gas mimic. AB - An ESIPT based fluorescent probe, containing a hydroxyphenyl-benzothiazole fluorophore and an oxime reaction site, serves as a selective probe for a nerve gas mimic, diethyl cyanophosphonate (DECP), in solutions and the gas phase. The probe exhibits more than a 60-fold fluorescence enhancement in the presence of the target, has a limit of detection of 1.3 nM and displays high selectivity toward DECP over closely related substances, including sulfur mustard stimulants and other nerve agent mimics. Moreover, composite nanofibers with relatively low concentrations of the probe (0.45% w/w) exhibit distinct color and fluorescence changes upon exposure to DECP vapor. PMID- 29435525 TI - Diastereodivergent synthesis of bispirooxindoles via asymmetric Friedel Crafts/aldol cascade reaction: co-catalyst effects on diastereoselective outcomes. AB - A combination of metal- and organo-catalysts sequentially catalyzing the Friedel Crafts/aldol tandem reaction between 3-pyrrolyl-oxindoles and isatin-derived beta,gamma-unsaturated alpha-ketoesters has been reported, which leads to two types of diastereomeric enantio-enriched bispirooxindoles with three quaternary stereocentres and synthetically valuable functional groups in high yields with excellent enantioselectivity and diastereoselectivity. PMID- 29435526 TI - Bicomponent beta-sheet assembly of dipeptide fluorophores of opposite polarity and sensitive detection of nitro-explosives. AB - Fluorescent hydrogels of two dipeptide-pyrene amphiphiles of opposite polarity are developed via bicomponent antiparallel beta-sheet co-assembly. The helical molecular assembly resulted in the formation of fluorescent nanofibers. The sandwich-like interaction of nitroaromatics within the hydrogel matrix enabled selective and sensitive detection of toxic nitro-explosives. PMID- 29435527 TI - A perovskite oxide LaCoO3 cocatalyst for efficient photocatalytic reduction of CO2 with visible light. AB - As a unique class of functional materials, perovskite oxides have shown great opportunities in various energy storage and conversion applications. However, their performance for boosting photocatalytic CO2 reduction is seldom reported. Herein, we report a facile synthesis of coralline-like LaCoO3 perovskite materials and their use as highly efficient and stable cocatalysts for splitting CO2 into CO with visible light. PMID- 29435528 TI - Metal-free stereoselective annulation of quinolines with trifluoroacetylacetylenes and water: an access to fluorinated oxazinoquinolines. AB - Metal-free reaction between quinolines, aryltrifluoroacetylacetylenes and water at -18 degrees C-rt in MeCN resulted in stereoselective assembly of trifluoromethylated oxazinoquinolines with up to 99% yield that was essentially in contrast to a similar reaction with pyridines. The annulation proceeded via the 1,3-dipolar adducts of quinolines with trifluoroacetylacetylenes followed by intramolecular cyclization involving the trifluoroacetyl group and a molecule of water. PMID- 29435529 TI - Strain heterogeneity in sheared colloids revealed by neutron scattering. AB - Recent computational and theoretical studies have shown that the deformation of colloidal suspensions under a steady shear is highly heterogeneous at the particle level and demonstrate a critical influence on the macroscopic deformation behavior. Despite its relevance to a wide variety of industrial applications of colloidal suspensions, scattering studies focusing on addressing the heterogeneity of the non-equilibrium colloidal structure are scarce thus far. Here, we report the first experimental result using small-angle neutron scattering. From the evolution of strain heterogeneity, we conclude that the shear-induced deformation transforms from nearly affine behavior at low shear rates, to plastic rearrangements when the shear rate is high. PMID- 29435530 TI - A high performance catalyst for methane conversion to methanol: graphene supported single atom Co. AB - Employing first principles calculations, we show a two-step reaction mechanism for direct methane oxidation to methanol over a single atom Co-embedded graphene (Gr) catalyst, with N2O as the O-donor molecule. C-H activation is the rate limiting step. The high reaction activity and selectivity under mild conditions were predicted for this catalyst. PMID- 29435531 TI - Substituent control of the ultrafast twisted intramolecular charge transfer rate in dimethylaminochalcone derivatives. AB - The effect of acceptor strength variation on ultrafast twisting relaxation dynamics was investigated by comparing the ultrafast relaxation dynamics in a series of dimethylaminochalcone (DMAC) derivatives. Employing femtosecond resolved transient absorption and fluorescence experiments, the twisted intramolecular charge transfer (TICT) relaxation rate is shown to vary from 2.0 picoseconds in a weak electron accepting system to 420 femtoseconds in a strong electron accepting system. The strength of the acceptor, empirically expressed as Hammett's constant, is shown to exhibit a linear free energy relationship (LFER) with the twisting rate. It is proposed that variation in the charge pulling capacity of the acceptor modifies the torsional barrier along the TICT coordinate in the S1 state, resulting in a tunable TICT relaxation rate, depending on the acceptor strength. PMID- 29435532 TI - Intermolecular chemo- and regioselective aromatic C-H amination of alkoxyarenes promoted by rhodium nitrenoids. AB - Intermolecular aromatic C(sp2)-H amination promoted by neutral rhodium nitrenoids has been developed. The reactions proceeded with various oxygen-substituted arenes (1.5 equiv.) in a chemo- and regioselective manner. The aromatic C(sp2)-H amination took place at the para position of the oxygen substituent in the presence of benzylic C(sp3)-H bonds and/or C(sp3)-H bonds alpha to ethereal oxygen. PMID- 29435533 TI - Highly photoluminescent two-dimensional imine-based covalent organic frameworks for chemical sensing. AB - The strong pi-pi interactions in the stacking layers of two-dimensional covalent organic frameworks (2D-COFs), together with rotationally labile imine linkages, make most of the solid state imine-linked COFs non-fluorescent due to fluorescence quenching processes. Here, we report the successful synthesis of highly photoluminescent imine-based 2D-COFs by integrating a non-planar building unit with a pyrene-based unit and transforming the COF into spherical, sub-micron particles. High photoluminescence quantum yields (PLQY) were achieved with COF sub-micron particles dispersed in organic solvents. The as-prepared COF sub micron particles can be used as a chemical sensor for the detection of explosive chemicals, with high sensitivity and selectivity (up to ppm level). PMID- 29435534 TI - Rolling up graphene oxide sheets through solvent-induced self-assembly in dispersions. AB - Herein we report a new approach to fabricating nanoscrolls through the self assembly of graphene oxide (GO) sheets in a dispersion. The assembly process for GO nanosheets was induced by the dropwise addition of an appropriate organic solvent such as N,N-dimethylformamide (DMF) into the aqueous dispersion. The results show that nanoscrolls were gradually formed from the GO sheets by rolling up in a piece-by-piece manner with the increase of the DMF content. The transmission electron microscopic analysis indicates that for a typical case, the nanoscrolls have an average diameter of 242 +/- 102 nm at the central part and the interlayer spacing between adjacent GO layers is 0.58 nm. The scrolls were estimated to have 207 turns and include on average 42 pieces of GO sheets per scroll. By this method, GO sheets with different sizes and oxidation degrees were proved to be able to form GO nanoscrolls in a similar way. Moreover, it is interesting that the diffraction efficiency of surface-relief-gratings photoinduced on the film of azo molecular glass was significantly enhanced by doping the GO nanoscrolls with a very low content (0.5 wt%); this suggests a possible new application for the GO scrolls in optical devices. This facile approach, which is also feasible by using other organic solvents such as ethanol, can be used to fabricate GO nanoscrolls for large scale applications in supercapacitors, sensors and other devices. PMID- 29435535 TI - Spin splitting and p-/n-type doping of two-dimensional WSe2/BiIrO3(111) heterostructures. AB - The electronic structure of monolayer WSe2/BiIrO3(111) interfaces is investigated by first-principles calculations. The different polar directions of bilayer BiIrO3(111) can induce the p- or n-type doping of WSe2, indicating that the conductivity of monolayer WSe2 can be effectively modulated by switching the polarization of bilayer BiIrO3(111). Meanwhile, in B1 and B4 models, the spin splitting energies of WSe2 are 413.7 and 416.6 meV, which decrease by 52.9 and 50.0 meV compared to that of pristine monolayer WSe2 of 466.6 meV. Additionally, by applying a perpendicular electric field of 0.1 V nm-1, the spin splitting can be increased from 413.7 to 421.5 meV. However, spin splitting shows robustness against large electric fields. The results are useful in the design of novel two dimensional transition metal dichalcogenide devices. PMID- 29435540 TI - Phenothiazine-based small-molecule organic solar cells with power conversion efficiency over 7% and open circuit voltage of about 1.0 V using solvent vapor annealing. AB - We have used two unsymmetrical small molecules, named phenothiazine 1 and 2 with a D-A-D-pi-D configuration, where phenothiazine is used as a central unit, triphenylamine is used as a terminal unit and TCBD and cyclohexa-2,5-diene-1,4 diylidene-expanded TCBD are used as an acceptor between the phenothiazine and triphenylamine units, as a small molecule donor along with PC71BM as an acceptor for solution processed bulk heterojunction solar cells. The variation of acceptors in the phenothiazine derivatives makes an exciting change in the photophysical and electrochemical properties, hole mobility and therefore photovoltaic performance. The optimized device based on phenothiazine 2 exhibited a high power conversion efficiency of 7.35% (Jsc = 11.98 mA cm-2, Voc = 0.99 V and FF = 0.62), while the device based on phenothiazine 1 showed a low PCE of 4.81% (Jsc = 8.73 mA cm-2, Voc = 0.95 V and FF = 0.58) after solvent vapour annealing (SVA) treatment. The higher value of power conversion efficiency of the 2 based devices irrespective of the processing conditions may be related to the broader absorption and lower band gap of 2 as compared to 1. The improvement in the SVA treated active layer may be related to the enhanced crystallinity, molecular ordering and aggregation and shorter pi-pi stacking distance of the small molecule donors. PMID- 29435541 TI - Tuning the phase transition temperature of ferronematics with a magnetic field. AB - The influence of magnetic field on the isotropic-to-nematic phase transition temperature is investigated in neat bent-core and calamitic liquid crystals, in their mixture, and in samples doped with spherical magnetic nanoparticles for two different orientations of the magnetic field. A magnetic-field-induced negative or positive shift of the transition temperature was detected depending on the magnetic field orientation with respect to the initial orientation of the nematic phase, and on the type of liquid crystal matrix. PMID- 29435542 TI - Tunable reactivity of supported single metal atoms by impurity engineering of the MgO(001) support. AB - Development of novel materials may often require a rational use of high price components, like noble metals, in combination with the possibility to tune their properties in a desirable way. Here we present a theoretical DFT study of Au and Pd single atoms supported by doped MgO(001). By introducing B, C and N impurities into the MgO(001) surface, the interaction between the surface and the supported metal adatoms can be adjusted. Impurity atoms act as strong binding sites for Au and Pd adatoms and can help to produce highly dispersed metal particles. The reactivity of metal atoms supported by doped MgO(001), as probed by CO, is altered compared to their counterparts on pristine MgO(001). We find that Pd atoms on doped MgO(001) are less reactive than on perfect MgO(001). In contrast, Au adatoms bind CO much more strongly when placed on doped MgO(001). In the case of Au on N-doped MgO(001) we find that charge redistribution between the metal atom and impurity takes place even when not in direct contact, which enhances the interaction of Au with CO. The presented results suggest possible ways for optimizing the reactivity of oxide supported metal catalysts through impurity engineering. PMID- 29435543 TI - Copper(ii)-mediated, carbon degradation-based amidation of phenylacetic acids toward N-substituted benzamides. AB - The unprecedented synthesis of N-aryl substituted benzamides via the assembly of primary amines and phenylacetic acids has been developed in the presence of copper(ii) acetate. This tandem transformation involving carbon-carbon bond cleavage provides a complementary tool with particular application in the synthesis of secondary benzamides. PMID- 29435544 TI - Intramolecular singlet fission in a face-to-face stacked tetracene trimer. AB - A covalently linked tetracene trimer with a "face-to-face" stacked structure was prepared and its molecular structure is characterized by 1H NMR, MALDI-TOF mass spectroscopy, and elemental analysis. The minimized molecular structure reveals that three tetracene subunits within this trimer adopt a partially "face-to-face" stacked configuration. Its absorption spectrum differs significantly from that of the monomeric and dimeric counterparts in solution due to the strong ground state interactions between the neighboring tetracene subunits. Its fluorescence is almost quenched completely. An ultrafast fluorescence decay component is observed in its fluorescence dynamics, indicating the presence of an ultrafast nonradiative decay channel in the trimer. The nonradiative channel is proved to be intramolecular singlet fission (iSF) by femto-second transient absorption studies. Different from the strongly coupled triplet state observed in the corresponding dimer, weakly coupled triplet states can be formed in this trimer. The triplet quantum yield of trimer 4 can reach up to 126% in solution. PMID- 29435545 TI - Ternary CBe4Au4 cluster: a 16-electron system with quasi-planar tetracoordinate carbon. AB - Planar hypercoordinate carbons as exotic chemical species are dominated by 18 electron counting. We report herein a 16-electron planar tetracoordinate carbon (ptC) cluster, CBe4Au4, which is quasi-planar to be exact, being composed of a C center, a square-planar Be4 ring, and four outer Au bridges. The quasi-ptC cluster is established as a global minimum via computer structural searches, located 14.6 kcal mol-1 below the nearest competitor at the CCSD(T) level. It shows thermodynamic and electronic robustness, with a low electron affinity (1.54 eV at B3LYP) and a large HOMO-LUMO gap (2.21 eV for excitation energy). Bonding analyses reveal 2pi and 6sigma double aromaticity, in addition to four three center two-electron (3c-2e) Be-Au-Be sigma bonds, confirming that 16-electron counting is perfect for the system. We believe that double (pi and sigma) aromaticity is a general concept that governs planar or quasi-planar carbons, which overrides the 18-electron rule. Competition between quasi-ptC and tetrahedral carbon (thC) isomers in the CBe4M4 (M = K, Au, H, Cl) series is also examined, which sheds crucial light on factors that govern the ptC clusters. The present findings offer opportunities for further planar and unconventional molecules. PMID- 29435546 TI - Electrochemical, top-down nanostructured pseudocapacitive electrodes for enhanced specific capacitance and cycling efficiency. AB - Stabilization of the electroactive redox centers on ideally polarisable conductive electrodes is a critical challenge for realizing stable, high performing pseudocapacitive energy storage devices. Here, we report a top-down, electrochemical nanostructuring route based on voltammetric cycling to stabilize beta-MnO2 on a single walled carbon nanotube (CNT) scaffold from a MnMoO4 precursor. Such in situ nanostructuring results in controlled disintegration of an ~8 MUm almond like structure to form ~29 nm beta-MnO2 resulting in a 59% increase in the specific surface area and a 31% increase in the porosity of the pseudocapacitive electrode. Consequently, the specific capacitance and areal capacitance increase by ~75% and ~40%, respectively. Such controlled, top-down nanostructuring is confirmed through binding energy changes to Mo 3d, C 1s, O 1s and Mn 2p respectively in XPS. Furthermore, Raman spectral mapping confirms the sequential nanostructuring initiating from the interface of CNTs with MnMoO4 and proceeding outwards. Thus, the process yields the final CNT/beta-MnO2 electrode that is electrically conductive, facilitates rapid charge transfer, and has increased capacitance and longer stability. Furthermore, the charge-transfer resistance and equivalent resistance are significantly lower compared to conventional activated carbon based electrodes. PMID- 29435547 TI - Theory, experiment, and simulations in laboratory astrochemistry. PMID- 29435548 TI - Coordination numbers for unraveling intrinsic size effects in gold-catalyzed CO oxidation. AB - Geometry-based reactivity descriptors, e.g., regular, generalized, and orbitalwise coordination numbers, were used for unraveling intrinsic size effects of Au nanocatalysts towards CO oxidation. For an ensemble of Au nanoparticles with varying sizes and shapes, s-orbital coordination numbers (CNs) linearly correlate with *CO and *O adsorption energies at the on-top and hollow sites, respectively, outperforming their regular (CN) and generalized (C[combining macron]N[combining macron]) counterparts attributed to an explicit consideration of interatomic interactions. To take into account the geometric strain of surface atoms, the embedded-atom method (EAM) potential trained with ab initio energies of the bulk, nanoclusters, and extended surfaces at the GGA-PBE level was used for optimizing the Wulff-shaped, free-standing Au nanoparticles up to 7.2 nm. Microkinetic analysis of CO oxidation on extended {111}, {100}, {211}, and {532} surfaces, along with a facile and accurate prediction of *CO and *O adsorption energies at nanoparticles using the herein developed structure-reactivity relationships, captures experimentally measured activity trends of supported Au nanoparticles of varying sizes on a wide variety of metal oxides and illustrates the importance of under-coordinated atoms and insensitivity of surface strains in Au-catalyzed CO oxidation. PMID- 29435549 TI - Cost-effective synthesis of hierarchical SAPO-34 zeolites with abundant intracrystalline mesopores and excellent MTO performance. AB - Hierarchical SAPO-34 catalysts with abundant intracrystalline mesopores have been prepared using morpholine as the template combined with a cheap nonsurfactant cationic surfactant. Significantly, the hierarchical SAPO-34 catalysts exhibit more than 5-fold improved lifetime and 12% enhanced selectivity for ethylene and propylene compared to conventional microporous counterparts in methanol-to-olefin (MTO) reactions. PMID- 29435550 TI - Functional amyloid materials at surfaces/interfaces. AB - With the development of nanotechnology, functional amyloid materials are drawing increasing attention, and numerous remarkable applications are emerging. Amyloids, defined as a class of supramolecular assemblies of misfolded proteins or peptides into beta-sheet fibrils, have evolved in many new respects and offer abundant chemical/biological functions. These proteinaceous micro/nano-structures provide excellent biocompatibility, rich phase behaviours, strong mechanical properties, and stability at interfaces not only in nature but also in functional materials, displaying versatile interactions with surfaces/interfaces that have been widely adopted in bioadhesion, synthetic biology, and composites. Overall, functional amyloids at surfaces/interfaces have excellent potential applications in next-generation biotechnology and biomaterials. PMID- 29435551 TI - Impedance-based real-time position sensor for lab-on-a-chip devices. AB - This paper presents the theoretical and experimental development of an integrated position sensor for lab-on-a-chip devices. The interest for single cell analysis is growing. However, this requires monitoring and controlling cell displacements in real time during their journey in the chip. Due to the high number of cells that must be monitored at the same time, classical vision-based sensors are not suitable. This paper aims to present an alternative based on impedance measurement. The position of the cells is obtained from the variation of impedance measured between two electrodes. This technique presents several advantages: the sensor is integrated into the chip, the measurement electrodes are compatible with the fabrication process of actuation electrodes for dielectrophoresis, the sampling time of the sensor is high and the position of the cells can be obtained in real time. This article highlights the concept of position-sensitive impedance sensing. The design of the chip, and in particular of the electrodes, is discussed to improve the sensitivity and repeatability of the measurement. The issue of real-time detection in a noisy environment is solved by using an extended Kalman filter. As a first proof of concept, this article presents experimental validation on a 1D case to determine the longitudinal position of 8.7 MUm diameter beads in a channel. PMID- 29435552 TI - Mild and selective Pd-Ar protonolysis and C-H activation promoted by a ligand aryloxide group. AB - A bidentate nitrogen-donor ligand with an appended phenol group, C5H4NCH[double bond, length as m-dash]N-2-C6H4OH, H(L1) was treated with a palladium cycloneophyl complex [Pd(CH2CMe2C6H4)(COD)], with both Pd-aryl and Pd-alkyl bonds, to give a Pd-alkyl complex, [Pd(CH2CMe2C6H5)(kappa3-N,N',O-OC6H4N[double bond, length as m-dash]CH(2-C5H4N))], 1. The cleavage of the Pd-aryl bond and the deprotonation of the ligand phenol to afford a bound aryloxide, indicates facile Pd-aryl bond protonolysis. Deuterium labelling experiments confirmed that the ligand phenol promotes protonolysis and that the reverse, aryl C-H activation, occurs under very mild reaction conditions (within 10 min at room temperature). An unusual isomerization of the Pd-alkyl complex 1 to a Pd-aryl complex, [Pd(C6H4(2-t-Bu))(kappa3-N,N',O-OC6H4N[double bond, length as m-dash]CH(2 C5H4N))], 2, was observed to give an equilibrium with [2]/[1] = 9 after 5 days in methanol. The isomerization requires that both aryl C-H activation and Pd-alkyl protonolysis steps occur. The very large KIE value (kH/kD = ca. 40) for isomerization of 1 to 2, suggests a concerted SE2-type mechanism for the Pd-alkyl protonolysis step. PMID- 29435553 TI - From supramolecular to conventional polymers: polyethylene glycol. AB - Increasing the polymerization degree of polyethylene glycol (PEG), HO-(CH2CH2O )nH, entails lowering the number of hydroxyl groups per unit volume; therefore, supramolecular polymers are gradually replaced by longer and longer conventional polymers. This paper concerns an estimation of the polymerization degree (n) where PEG changes its nature from a supramolecular polymer to a conventional polymer. It was found that that virtual transformation takes place when n reaches the value of about 9. The conclusion follows from the different thermal behaviors of the dipolar orientational effects in liquid PEG detected for n below and above 9. The result reflects a diametrically different impact of the temperature on the linkages between the monomers in supramolecular and conventional polymers. PMID- 29435554 TI - Understanding Titin Variants in the Age of Next-Generation Sequencing-A Titanic Challenge. PMID- 29435555 TI - Opioid Analgesic Use and Risk for Invasive Pneumococcal Diseases: A Nested Case Control Study. AB - Background: Although certain opioid analgesics have immunosuppressive properties and increase the risk for infections in animals, the clinical effects of prescription opioid use on infection risk among humans are unknown. Objective: To test the hypothesis that prescription opioid use is an independent risk factor for invasive pneumococcal disease (IPD). Design: Nested case-control study. Setting: Tennessee Medicaid database linked to Medicare and Active Bacterial Core surveillance system databases (1995 to 2014). Patients: 1233 case patients with IPD aged 5 years and older matched to 24 399 control participants by diagnosis date, age, and county of residence. Measurements: Opioid use was measured on the basis of pharmacy prescription fills. Invasive pneumococcal disease was defined by the isolation of Streptococcus pneumoniae from a normally sterile site. The odds of current opioid use were compared between the case and control groups, accounting for known IPD risk factors. Secondary analyses categorized opioid use by opioid characteristics, applied an IPD risk score to assure comparability between exposure groups, and analyzed pneumonia and nonpneumonia IPD cases separately. Results: Persons in the case group had greater odds than control participants of being current opioid users (adjusted odds ratio [aOR], 1.62 [95% CI, 1.36 to 1.92]). Associations were strongest for opioids that were long acting (aOR, 1.87 [CI, 1.24 to 2.82]), of high potency (aOR, 1.72 [CI, 1.32 to 2.25]), or were used at high dosages (50 to 90 morphine milligram equivalents [MME]/d: aOR, 1.71 [CI, 1.22 to 2.39]; >=90 MME/d: aOR, 1.75 [CI, 1.33 to 2.29]). Results were consistent when the IPD risk score was taken into account and pneumonia and nonpneumonia IPD were analyzed separately. Limitations: Unmeasured confounding and measurement error, although sensitivity analyses suggested that neither was likely to affect results. Actual opioid use and other nonprescription use (such as illicit opioid use) were not measured. Conclusion: Opioid use is associated with an increased risk for IPD and represents a novel risk factor for these diseases. Primary Funding Source: National Institutes of Health. PMID- 29435557 TI - Admitting What We Do Not Know in Rheumatologic Disease: The First Step Toward Learning More. PMID- 29435556 TI - Breast Biopsy Intensity and Findings Following Breast Cancer Screening in Women With and Without a Personal History of Breast Cancer. AB - Importance: There is little evidence on population-based harms and benefits of screening breast magnetic resonance imaging (MRI) in women with and without a personal history of breast cancer (PHBC). Objective: To evaluate biopsy rates and yield in the 90 days following screening (mammography vs magnetic resonance imaging with or without mammography) among women with and without a PHBC. Design, Setting, and Participants: Observational cohort study of 6 Breast Cancer Surveillance Consortium (BCSC) registries. Population-based sample of 812 164 women undergoing screening, 2003 through 2013. Exposures: A total of 2 048 994 digital mammography and/or breast MRI screening episodes (mammogram alone vs MRI with or without screening mammogram within 30 days). Main Outcomes and Measures: Biopsy intensity (surgical greater than core greater than fine-needle aspiration) and yield (invasive cancer greater than ductal carcinoma in situ greater than high-risk benign greater than benign) within 90 days of a screening episode. We computed age-adjusted rates of biopsy intensity (per 1000 screening episodes) and biopsy yield (per 1000 screening episodes with biopsies). Outcomes were stratified by PHBC and by BCSC 5-year breast cancer risk among women without PHBC. Results: We included 101 103 and 1 939 455 mammogram screening episodes in women with and without PHBC, respectively; MRI screening episodes included 3763 with PHBC and 4673 without PHBC. Age-adjusted core and surgical biopsy rates (per 1000 episodes) doubled (57.1; 95% CI, 50.3-65.1) following MRI compared with mammography (23.6; 95% CI, 22.4-24.8) in women with PHBC. Differences (per 1000 episodes) were even larger in women without PHBC: 84.7 (95% CI, 75.9-94.9) following MRI and 14.9 (95% CI, 14.7-15.0) following mammography episodes. Ductal carcinoma in situ and invasive biopsy yield (per 1000 episodes) was significantly higher following mammography compared with MRI episodes in women with PHBC (mammography, 404.6; 95% CI, 381.2-428.8; MRI, 267.6; 95% CI, 208.0-337.8) and nonsignificantly higher, but in the same direction, in women without PHBC (mammography, 279.3; 95% CI, 274.2-284.4; MRI, 214.6; 95% CI, 158.7-280.8). High risk benign lesions were more commonly identified following MRI regardless of PHBC. Higher biopsy rates and lower cancer yield following MRI were not explained by increasing age or higher 5-year breast cancer risk. Conclusions and Relevance: Women with and without PHBC who undergo screening MRI experience higher biopsy rates coupled with significantly lower cancer yield findings following biopsy compared with screening mammography alone. Further work is needed to identify women who will benefit from screening MRI to ensure an acceptable benefit-to-harm ratio. PMID- 29435559 TI - Future of Neurologic Examination in Clinical Practice. PMID- 29435560 TI - Understanding the Possible Nonmedical Risks of Preexposure Prophylaxis Prescription in Adolescents-Reply. PMID- 29435558 TI - Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease. AB - Importance: It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. Objective: To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation. Design, Setting, and Participants: In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers. Main Outcomes and Measures: We compared carbon 11-labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups. Results: Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. beta-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination (entorhinal cortex: r = -0.60; P = .04; inferior temporal lobe: r = 0.54; P = .06) and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex: r = -0.86; P < .001; inferior temporal lobe: r = -0.70; P = .01). Conclusions and Relevance: The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired. The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression. PMID- 29435561 TI - Future of Neurologic Examination in Clinical Practice. PMID- 29435562 TI - Future of Neurologic Examination in Clinical Practice-Reply. PMID- 29435564 TI - Future of Neurologic Examination in Clinical Practice. PMID- 29435563 TI - Family History and Breast Cancer Risk Among Older Women in the Breast Cancer Surveillance Consortium Cohort. AB - Importance: First-degree family history is a strong risk factor for breast cancer, but controversy exists about the magnitude of the association among older women. Objective: To determine whether first-degree family history is associated with increased risk of breast cancer among older women, and identify whether the association varies by breast density. Design, Setting, and Participants: Prospective cohort study between 1996 and 2012 from 7 Breast Cancer Surveillance Consortium (BCSC) registries located in New Hampshire, North Carolina, San Francisco Bay area, western Washington state, New Mexico, Colorado, and Vermont. During a mean (SD) follow-up of 6.3 (3.2) years, 10 929 invasive breast cancers were diagnosed in a cohort of 403 268 women 65 years and older with data from 472 220 mammography examinations. We estimated the 5-year cumulative incidence of invasive breast cancer by first-degree family history, breast density, and age groups. Cox proportional hazards models were fit to estimate the association of first-degree family history with risk of invasive breast cancer (after adjustment for breast density, BCSC registry, race/ethnicity, body mass index, postmenopausal hormone therapy use, and benign breast disease for age groups 65 to 74 years and 75 years and older, separately). Data analyses were performed between June 2016 and June 2017. Exposure: First-degree family history of breast cancer. Main Outcomes and Measures: Incident breast cancer. Results: In 403 268 women 65 years and older, first-degree family history was associated with an increased risk of breast cancer among women ages 65 to 74 years (hazard ratio [HR], 1.48; 95% CI, 1.35-1.61) and 75 years and older (HR, 1.44; 95% CI, 1.28 1.62). Estimates were similar for women 65 to 74 years with first-degree relative's diagnosis age younger than 50 years (HR, 1.47; 95% CI, 1.25-1.73) vs 50 years and older (HR, 1.33; 95% CI, 1.17-1.51) and for women ages 75 years and older with the relative's diagnosis age younger than 50 years (HR, 1.31; 95% CI, 1.05-1.63) vs 50 years and older (HR, 1.55; 95% CI, 1.33-1.81). Among women ages 65 to 74 years, the risk associated with first-degree family history was highest among those with fatty breasts (HR, 1.67; 95% CI, 1.27-2.21), whereas in women 75 years and older the risk associated with family history was highest among those with dense breasts (HR, 1.55; 95% CI, 1.29-1.87). Conclusions and Relevance: First-degree family history was associated with increased risk of invasive breast cancer in all subgroups of older women irrespective of a relative's age at diagnosis. PMID- 29435565 TI - Pharmaceutical Benefit Managers, Brand-Name Drug Prices, and Patient Cost Sharing. PMID- 29435566 TI - Prenatal Ultrasonography and the Incidence of Autism Spectrum Disorder. PMID- 29435567 TI - Benefits and Harms of Cranial Electrical Stimulation for Chronic Painful Conditions, Depression, Anxiety, and Insomnia: A Systematic Review. AB - Background: Cranial electrical stimulation (CES) is increasingly popular as a treatment, yet its clinical benefit is unclear. Purpose: To review evidence about the benefits and harms of CES for adult patients with chronic painful conditions, depression, anxiety, and insomnia. Data Sources: Several databases from inception to 10 October 2017 without language restrictions and references from experts, prior reviews, and manufacturers. Study Selection: Randomized controlled trials of CES versus usual care or sham CES that reported pain, depression, anxiety, or sleep outcomes in any language. Data Extraction: Single-reviewer extraction checked by another; dual independent quality assessment; strength-of-evidence grading by the first author with subsequent group discussion. Data Synthesis: Twenty-eight articles from 26 randomized trials met eligibility criteria. The 2 trials that compared CES with usual care were small, and neither reported a statistically significant benefit in pain or anxiety outcomes for patients with fibromyalgia or anxiety, respectively. Fourteen trials with sham or placebo controls involving patients with painful conditions, such as headache, neuromuscular pain, or musculoskeletal pain, had conflicting results. Four trials done more than 40 years ago and 1 from 2014 provided low-strength evidence of a possible modest benefit compared with sham treatments in patients with anxiety and depression. Trials in patients with insomnia (n = 2), insomnia and anxiety (n = 1), or depression (n = 3) had inconclusive or conflicting results. Low-strength evidence suggested that CES does not cause serious side effects. Limitation: Most trials had small sample sizes and short durations; all had high risk of bias due to inadequate blinding. Conclusion: Evidence is insufficient that CES has clinically important effects on fibromyalgia, headache, neuromusculoskeletal pain, degenerative joint pain, depression, or insomnia; low-strength evidence suggests modest benefit in patients with anxiety and depression. Primary Funding Source: Veterans Affairs Quality Enhancement Research Initiative. (PROSPERO: CRD42016023951). PMID- 29435568 TI - The April 20 Cannabis Celebration and Fatal Traffic Crashes in the United States. PMID- 29435570 TI - Tau Positron Emission Tomography in Autosomal Dominant Alzheimer Disease: Small Windows, Big Picture. PMID- 29435571 TI - Understanding the Possible Nonmedical Risks of Preexposure Prophylaxis Prescription in Adolescents. PMID- 29435569 TI - Interpreting Genetic Variants in Titin in Patients With Muscle Disorders. AB - Importance: Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Objective: To identify genetic variants in titin in a cohort of patients with muscle disorders. Design, Setting, and Participants: In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Main Outcomes and Measures: The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. Results: Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. Conclusions and Relevance: The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin. PMID- 29435572 TI - Why Internists Might Want Single-Payer Health Care. PMID- 29435574 TI - Cranial Electrical Stimulation: What Is It, and Should We Use It in Practice? PMID- 29435573 TI - Balancing the Benefits and Harms of E-Cigarettes: A National Academies of Science, Engineering, and Medicine Report. PMID- 29435575 TI - Management of Patients With Febrile Neutropenia: A Teachable Moment. PMID- 29435576 TI - Incorrect Term for Variance of the Mean. PMID- 29435577 TI - Association of Early-Life Factors With Life-Course Trajectories of Resting Heart Rate: More Than 6 Decades of Follow-up. AB - Importance: Higher resting heart rate (RHR) is associated with increased risk of cardiovascular and all-cause mortality. Limited attention has been paid to early life determinants of life-course RHR. Objective: To describe trajectories of RHR in the same individuals from age 6 to 69 years. Design, Setting, and Participants: Data were from the Medical Research Council National Survey of Health and Development population-based cohort of individuals who were followed up from birth in 1946 until 2015. Analysis was conducted between September 2016 and June 2017. Multilevel models were used to estimate life-course mean RHR trajectory by sex and to investigate associations with early childhood factors. The maximal sample included participants who had at least 1 measure of RHR since study entry and a measure of birth weight (N = 4779; observations = 26 182). Exposures: Information on early-life factors was ascertained prospectively: childhood socioeconomic position, birth weight, body mass index (calculated as weight in kilograms divided by height in meters squared) change from age 2 to 6 years (conditioned on body mass index at age 2 years), duration of breastfeeding, and markers of neurodevelopment (age at first walking independently and cognitive ability at age 8 years). Main Outcomes and Measures: Resting heart rate measured on 8 occasions between age 6 and 69 years (3 occasions in childhood and 5 in adulthood). Results: Of 4779 participants, 2492 (52.1%) were women, and 2287 (47.9%) were men. Mean estimated RHR decreased with increasing age and plateaued in adulthood. In sex-adjusted analyses, higher birth weight and conditional body mass index change were associated with lower RHR at age 6 years and across the life course (-0.56 bpm [95% CI, -0.95 to -0.17] per 1 kg higher birth weight and 0.30 bpm [95% CI, -0.48 to -0.13] per 1 kg/m2 change in body mass index). Associations between socioeconomic position and breastfeeding on RHR trajectory emerged in adulthood such that by age 69 years, RHR was 1.48 bpm (95% CI, 0.45 to 2.51) higher in participants from a disadvantaged vs advantaged background and 1.34 bpm (95% CI, -2.39 to -0.29) lower for those who were breastfed for 8 months or longer vs never. A later age at first walking was associated with higher RHR at age 6 years (1.49 bpm [95% CI, 0.39 to 2.59] higher for those 18 months or older vs those younger than 12 months) but with lower RHR in adulthood (-1.18 bpm [95% CI, -2.75 to 0.39] at age 69 years). Conclusions and Relevance: Early life is a key period in determining future RHR trajectories with associations with potentially modifiable factors persisting into the seventh decade of life. PMID- 29435579 TI - Prescription Opioids and Infection Risk: Research and Caution Needed. PMID- 29435578 TI - Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy. AB - Importance: More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown. Objective: To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy. Design, Setting, and Participants: The Early Life Epilepsy Study-a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers-enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age. Exposures: Use of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure. Main Outcomes and Measures: The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations. Results: Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n = 117) were older at the time of the first seizure than those treated with phenobarbital (n = 38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P < .001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P = .01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]). Conclusions and Relevance: Levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings. PMID- 29435580 TI - Association of Prenatal Ultrasonography and Autism Spectrum Disorder. AB - Importance: The prevalence of autism spectrum disorder (ASD) has been increasing rapidly, with current estimates of 1 in 68 children affected. Simultaneously, use of prenatal ultrasonography has increased substantially, with limited investigation into its safety and effects on brain development. Animal studies have demonstrated that prenatal ultrasonography can adversely affect neuronal migration. Objective: To quantify prenatal ultrasound exposure by the frequency, timing, duration, and strength of ultrasonographic scans in children with later ASD, developmental delay, and typical development. Design, Setting, and Participants: This case-control study included 107 patients with ASD, 104 control individuals with developmental delay, and 209 controls with typical development. Participants were identified from medical records based on prenatal care and delivery at Boston Medical Center, a diverse, academic, safety-net medical center, from July 1, 2006, through December 31, 2014, with a gestational age at birth of at least 37 weeks. Data were analyzed from May 1, 2015, through November 30, 2017. Exposures: Ultrasonographic exposure was quantified by the number and timing of scans, duration of exposure, mean strength (depth, frame rate, mechanical index, and thermal index), and time of Doppler and 3- and 4 dimensional imaging. Main Outcomes and Measures: Among participants with ASD and controls with developmental delay and typical development, ultrasound exposure was quantified and compared per trimester and for the entire pregnancy, with adjustment for infant sex, gestational age at birth, and maternal age. Results: A total of 420 participants were included in the study (328 boys [78.1%] and 92 girls [21.9%]; mean age as of January 1, 2016, 6.6 years; 95% CI, 6.5-6.8 years). The ASD group received a mean of 5.9 scans (95% CI, 5.2-6.6), which was not significantly different from the 6.1 scans (95% CI, 5.4-6.8) in the developmental delay group or the 6.3 scans (95% CI, 5.8-6.8) in the typical development group. Compared with the typical development group, the ASD group had shorter duration of ultrasound exposure during the first (290.4 seconds [95% CI, 212.8-368.0 seconds] vs 406.4 seconds [95% CI, 349.5-463.3 seconds]) and second (1687.6 seconds [95% CI, 1493.8-1881.4 seconds] vs 2011.0 seconds [95% CI, 1868.9-2153.1 seconds]) trimesters but no difference in the number of scans. The ASD group had greater mean depth of ultrasonographic penetration than the developmental delay group in the first trimester (12.5 cm [95% CI, 12.0-13.0 cm] vs 11.6 cm [95% CI, 11.1-12.1 cm]). The ASD group had greater mean depth than the typical development group during the first (12.5 cm [95% CI, 12.0-13.0 cm] vs 11.6 cm [95% CI, 11.3 12.0 cm]) and the second (12.9 cm [95% CI, 12.6-13.3 cm] vs 12.5 cm [95% CI, 12.2 12.7 cm]) trimesters. Conclusions and Relevance: This study found significantly greater mean depth of ultrasonographic penetration in the ASD group compared with the developmental delay group in the first trimester and compared with the typical development group in the first and second trimesters. Further research is needed to determine whether other variables of ultrasound exposure also have adverse effects on the developing fetus. PMID- 29435581 TI - Error in Data Presentation. PMID- 29435583 TI - Mirror Movements in a Patient With Brain Tumor. PMID- 29435582 TI - The Importance of Contact Precautions for Endemic Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci. PMID- 29435584 TI - A Cautionary Tale of Warning Messages on Food Products: The Case of Sugar Sweetened Beverages. PMID- 29435586 TI - The Care Continuum for Hospitalized Medicare Beneficiaries Near Death. PMID- 29435585 TI - Legal Challenges to State Drug Pricing Laws. PMID- 29435587 TI - A Disease-Associated MicroRNA Cluster Links Inflammatory Pathways and an Altered Composition of Leukocyte Subsets to Noninfectious Uveitis. AB - Purpose: The cause of noninfectious uveitis (NIU) is poorly understood but is considered to be mediated by a complex interplay between genetic, environmental, and-relatively unexplored-epigenetic factors. MicroRNAs (miRNAs) are noncoding small RNAs that are important epigenetic regulators implicated in pathologic signaling. Therefore, we mapped the circulating miRNA-ome of NIU patients and studied miRNA perturbations within the broader context of the immune system. Methods: We designed a strategy to robustly identify changes in the miRNA profiles of two independent cohorts totaling 54 untreated patients with active and eye-restricted disease and 26 age-matched controls. High-resolution miRNA-ome data were obtained by TaqMan OpenArray technology and subsequent RT-qPCR. Flow cytometry data, and proteomic data spanning the cellular immune system, were used to map the uveitis-miRNA signature to changes in the composition of specific leukocyte subsets in blood. Results: Using stringent selection criteria, we identified and independently validated an miRNA cluster that is associated with NIU. Pathway enrichment analysis for genes targeted by this cluster revealed significant enrichment for the PI3K/Akt, MAPK, FOXO, and VEGF signaling pathways, and photoreceptor development. In addition, unsupervised multidomain analyses linked the presence of the uveitis-associated miRNA cluster to a different composition of leukocyte subsets, more specifically, CD16+CD11c+HLA-DR- cells. Conclusions: Together, this study identified a unique miRNA cluster associated with NIU that was related to changes in leukocyte subsets demonstrating systemic changes in epigenetic regulation underlying NIU. PMID- 29435588 TI - EVEREST Report 5: Clinical Outcomes and Treatment Response of Polypoidal Choroidal Vasculopathy Subtypes in a Multicenter, Randomized Controlled Trial. AB - Purpose: The purpose of this study was to describe the characteristics of polypoidal choroidal vasculopathy (PCV) subtypes among patients from a multicenter randomized controlled trial and to determine the impact of PCV subtypes on clinical outcomes. Methods: This was a prospective cohort study of 61 patients with macular PCV from the EVEREST study. Indocyanine green (ICGA) and fluorescein angiography (FA) obtained using standardized imaging protocols were graded to classify PCV into three subtypes. Type A PCV had polyps with interconnecting channels, type B had polyps with branching vascular networks, but no significant leakage on FA, and type C had polyps with branching vascular networks and leakage on FA. The best-corrected visual acuity (BCVA) and proportion of patients with BCVA >= 20/40 were compared among the three PCV subtypes. Results: Of the 61 patients, 54 were gradable for PCV subtype. Among these, 8 had type A PCV (14.8%), 27 had type B (50%), and 19 had type C (35.2%). At baseline, BCVA was 67.1 letters for type A, 58.7 for type B, and 43.5 for type C (P < 0.001). At 6 months, BCVA was highest among patients with type A compared with types B and C (80.1 letters versus 67.2 versus 50.4, respectively; P < 0.001). Type A PCV gained 13 letters compared with 8.5 (type B) and 6.9 (type C). BCVA >= 20/40 was highest for type A compared with types B and C (100% vs. 51.9% vs. 10.5%; P < 0.001). On performing ANCOVA, PCV subtype and baseline BCVA significantly affected final BCVA. Conclusions: The visual outcome following treatment varies with PCV subtype classification. The distinction in clinical outcomes between the PCV subtypes is observed in the initial months following the start of treatment. PMID- 29435589 TI - Three-Dimensional Cataract Crystalline Lens Imaging With Swept-Source Optical Coherence Tomography. AB - Purpose: To image, describe, and characterize different features visible in the crystalline lens of older adults with and without cataract when imaged three dimensionally with a swept-source optical coherence tomography (SS-OCT) system. Methods: We used a new SS-OCT laboratory prototype designed to enhance the visualization of the crystalline lens and imaged the entire anterior segment of both eyes in two groups of participants: patients scheduled to undergo cataract surgery, n = 17, age range 36 to 91 years old, and volunteers without visual complains, n = 14, age range 20 to 81 years old. Pre-cataract surgery patients were also clinically graded according to the Lens Opacification Classification System III. The three-dimensional location and shape of the visible opacities were compared with the clinical grading. Results: Hypo- and hyperreflective features were visible in the lens of all pre-cataract surgery patients and in some of the older adults in the volunteer group. When the clinical examination revealed cortical or subcapsular cataracts, hyperreflective features were visible either in the cortex parallel to the surfaces of the lens or in the posterior pole. Other type of opacities that appeared as hyporeflective localized features were identified in the cortex of the lens. The OCT signal in the nucleus of the crystalline lens correlated with the nuclear cataract clinical grade. Conclusions: A dedicated OCT is a useful tool to study in vivo the subtle opacities in the cataractous crystalline lens, revealing its position and size three-dimensionally. The use of these images allows obtaining more detailed information on the age-related changes leading to cataract. PMID- 29435590 TI - Association of Retinal Vascular Caliber and Age-Related Macular Degeneration in Patients With the Acquired Immunodeficiency Syndrome. AB - Purpose: To evaluate the relationship between retinal vascular caliber and AMD in patients with AIDS. Methods: Participants enrolled in the Longitudinal Study of the Ocular Complications of AIDS had retinal photographs taken at enrollment. Retinal vascular caliber (central retinal artery equivalent [CRAE] and central retinal vein equivalent [CRVE]) and intermediate-stage AMD were determined from these retinal photographs. Photographs were evaluated by graders at a centralized reading center, using the Age-Related Eye Disease Study grading system for AMD and semiautomated techniques for evaluating retinal vascular caliber. Results: Of the 1171 participants evaluated, 110 (9.4%) had AMD and 1061 (90.6%) did not. Compared with participants without AMD, participants with AMD had larger mean CRAEs (151 +/- 16 MUm versus 147 +/- 16 MUm; P = 0.009) and mean CRVEs (228 +/- 24 MUm versus 223 +/- 25 MUm; P = 0.02). The unadjusted differences were: CRAE, 4.3 MUm (95% confidence interval [CI] 1.1-7.5; P = 0.009) and CRVE, 5.5 MUm (95% CI 0.7-10.3; P = 0.02). After adjustment for age, race/ethnicity, sex, human immunodeficiency syndrome (HIV) transmission category, smoking, enrollment and nadir CD4+ T cells, and enrollment and maximum HIV load, the differences between patients with and without AMD were as follows: CRAE, 5.4 MUm (95% CI 2.3-8.5; P = 0.001) and CRVE, 6.0 MUm (95% CI 1.4-10.6; P = 0.01). Conclusions: In patients with AIDS, AMD is associated with greater retinal arteriolar and venular calibers, suggesting a role for shared pathogenic mechanisms, such as persistent systemic inflammation. PMID- 29435591 TI - Effect of Including Alcohol and Cannabis Content in a Sexual Risk-Reduction Intervention on the Incidence of Sexually Transmitted Infections in Adolescents: A Cluster Randomized Clinical Trial. AB - Importance: Adolescents in the juvenile justice system are at high risk for sexually transmitted infections (STIs). Concurrent use of alcohol and cannabis increase this risk. Objective: To determine whether a theory-based sexual risk reduction intervention that included alcohol- and cannabis-focused content resulted in greater reductions in STIs than an intervention that included alcohol related content only and an intervention that did not include substance use content. Design, Setting, and Participants: Cluster randomized clinical trial with 3 conditions. Between July 1, 2010, and December 10, 2014, adolescents living at a juvenile detention facility in the southwestern United States were tested and treated for STI before randomization and again 12 months after the intervention. Data analyses were conducted in July and August 2017. Eligibility criteria included (1) being aged 14 to 18 years, (2) able to speak English, (3) having a remaining detention term of less than 1 month, and (4) signing a release granting access to STI results if tested at intake. Six hundred ninety-three adolescents were assessed for eligibility. Of these, 460 completed baseline assessments and were randomized to 1 of 3 intervention conditions. Data analysis was by intent-to-treat. Interventions: There were 3 intervention conditions: sexual risk reduction intervention (SRRI); SRRI plus alcohol content (SRRI + ETOH); and SRRI + ETOH plus cannabis content (SRRI + ETOH + THC). Interventions were conducted in same-sex groups by trained clinicians and included video presentations with discussion, group activities, and active feedback by participants, consistent with the principles of motivational enhancement therapy. Main Outcomes and Measures: Although not the outcome on which the study was originally powered, the main outcome variable presented herein is STI incidence (Chlamydia trachomatis and/or Neisseria gonorrhoeae) 12 months after the intervention. Results: Of the 460 participants randomized, mean (SD) age was 15.8 (1.1) years, 347 participants (75.4%) were male, and 57.0% were of Hispanic ethnicity. Among the participants, 143 were randomized to SSRI, 155 to SRRI + ETOH, and 162 to SRRI + ETOH + THC. Attrition at 12-month follow-up was 99 (21.5%) for the STI outcome variable. Participants in the SRRI + ETOH + THC intervention had lower incidence of STI at follow-up (3.9%) than those in either the SRRI (12.4%; odds ratio, 0.29; 95% CI, 0.10-0.84) or the SRRI + ETOH (10.2%; odds ratio, 0.36; 95% CI, 0.12-1.05) interventions. Conclusions and Relevance: An intervention delivered in a motivational enhancement therapy format that includes theory-based sexual risk reduction combined with alcohol- and cannabis-focused elements is effective at reducing STI incidence among justice-involved adolescents. This 1-session manualized intervention can be delivered in the context of short-term detention and is easily disseminated to juvenile justice agencies. Trial Registration: clinicaltrials.gov Identifier: NCT01170260. PMID- 29435595 TI - [Blood management in complex reconstructive spine surgery in ASD patients : Do effective measures to reduce bleeding exist?] AB - BACKGROUND: Blood management in reconstructive spine surgery is a challenge and must be managed interdisciplinarily. An experienced team of anesthesiologists and spine surgeons needs to work closely together. THERAPY: After optimal preoperative preparation, the patient is given an initial dose of 1000 mg tranexamic acid. The most adequate medium blood pressure is about 80 mm Hg during surgery. The surgeon must watch for subperiosteal preparation and subtle stypsis. A cell saver is used. If the expected blood loss exceeds 1000 ml, additional tranexamic acid of 1000 mg/6 h will be infused. Epidural bleeding as well as bony hemorrhage are challenges for the spine surgeon. Epidural veins should be coagulated under the microscope before they bleed. Bone wax should be used in bony bleeding. If bleeding is uncontrollable, industrially produced hemostyptics can be used. POST-TREATMENT: Postoperatively the risk of bleeding should be minimized under critical observation of coagulation and blood pressure. Also, a critical assessment of the anticoagulation is to be made. The drainage rate should be well documented. The surgeon must decide whether the drain is to be put on suction or on overflow. He must also decide when to remove the drainage. PMID- 29435594 TI - [Periacetabular osteotomy-what influence does age have on patient-relevant results? : A prospective 5-year investigation]. AB - INTRODUCTION: Periacetabular osteotomy (PAO) is an effective procedure in treatment of symptomatic hip dysplasia. To achieve a good outcome a strict patient selection has to be applied. The aim of this study was to evaluate the influence of patient age at surgery on clinical outcome. METHODS: In a prospective study 86 patients (106 hips) underwent clinical and radiographic follow-up at a mean time of 5 years (2.5-8.5 years) after PAO. Patient-related outcome measurements (PROMs: EQ-5D, WOMAC, OHS, GTO) were applied preoperatively as well as postoperatively and the deformity correction as well as development of osteoarthritis were evaluated. In order to analyze the influence of patient age at surgery on clinical outcome, we subdivided the patient cohort into four different age groups (<20 years, 20-29 years, 30-39 years, >40 years). RESULTS: Of the patients 90% were very satisfied or satisfied with the results 5 years after surgery, and in all age groups PROMs significantly increased. Even though preoperative as well as postoperative algofunction declined in cohorts with increasing age, the overall benefit as measured in WOMAC and EQ-5D scores was equal in all age groups. Increasing age is associated with a progression in osteoarthritis as well as a higher conversion rate to total arthroplasty. DISCUSSION: Age is an important influencing factor on the long-term outcome after PAO. A certain age as cut off for indications could not be identified in this study. Even patients in the age groups 30-39 years and > 40 years showed PROM improvement and satisfaction with outcome at medium-term follow-up. The expected success rate has to be discussed preoperatively with the patient; however, as a higher conversion rate to hip arthroplasty as well as progressive osteoarthritis is associated with higher age, not only patient age alone but also morphological characteristics of the hip joint have to be taken into consideration. PMID- 29435597 TI - [Hedgehog fungi in a dermatological office in Munich : Case reports and review]. AB - Patient 1: After contact to a central European hedgehog (Erinaceus europaeus), a 50-year-old female with atopy developed erythrosquamous tinea manus on the thumb and thenar eminence of the right hand. The patient had previously been scalded by hot steam at the affected site. The zoophilic dermatophyte Trichophyton erinacei could be cultured from the hedgehog as well as from scrapings from the woman's skin. Antifungal treatment of the hedgehog was initiated using 2 weekly cycles of itraconazole solution (0.1 ml/kg body weight, BW). In addition, every other day enilconazole solution was used for topical treatment. The patient was treated with ciclopirox olamine cream and oral terbinafine 250 mg daily for 2 weeks, which led to healing of the Tinea manus .Patient 2: An 18-year-old woman presented for emergency consultation with rimmed, papulous, vesicular and erosive crusted skin lesions of the index finger, and an erythematous dry scaling round lesion on the thigh. The patient worked at an animal care facility, specifically caring for hedgehogs. One of the hedgehogs suffered from a substantial loss of spines. Fungal cultures from skin scrapings of both lesions yielded T. erinacei. Treatment with ciclopirox olamine cream and oral terbinafine 250 mg for 14 days was initiated which led to healing of the lesions. Identification of all three T. erinacei isolates from both patients and from the hedgehog was confirmed by sequencing of the internal transcribed spacer (ITS) region of the ribosomal DNA, and of the translation elongation factor (TEF)-1-alpha gene. Using ITS sequencing discrimination between T. erinacei strains from European and from African hedgehogs is possible. T. erinacei should be considered a so-called emerging pathogen. In Germany the zoophilic dermatophyte T. erinacei should be taken into account as causative agent of dermatomycoses in humans after contact to hedgehogs. PMID- 29435596 TI - RIPK4 activity in keratinocytes is controlled by the SCFbeta-TrCP ubiquitin ligase to maintain cortical actin organization. AB - RIPK4 is a key player in epidermal differentiation and barrier formation. RIPK4 signaling pathways controlling keratinocyte proliferation and differentiation depend on its kinase activity leading to Dvl2, Pkp1 and IRF6 phosphorylation and NF-kappaB activation. However, the mechanism regulating RIPK4 activity levels remains elusive. We show that cultured keratinocytes display constitutive active phosphorylated RIPK4 while PKC signaling can trigger RIPK4 activation in various non-keratinocyte cell lines, in which RIPK4 is present in a non-phosphorylated state. Interestingly, we identified the SCFbeta-TrCP ubiquitin E3 ligase complex responsible for regulating the active RIPK4 protein level. The SCFbeta-TrCP complex binds to a conserved phosphodegron motif in the intermediate domain of RIPK4, subsequently leading to K48-linked ubiquitinylation and degradation. The recruitment of beta-TrCP is dependent on RIPK4 activation and trans autophosphorylation. beta-TrCP knock-down resulted in RIPK4-dependent formation of actin stress fibers, cell scattering and increased cell motility, suggesting that tight control of RIPK4 activity levels is crucial to maintain cell shape and behavior in keratinocytes. PMID- 29435598 TI - Community Structure of Endophytic Actinobacteria in a New Zealand Native Medicinal Plant Pseudowintera colorata (Horopito) and Their Influence on Plant Growth. AB - The role of plant endophytic Actinobacteria remains poorly understood with no reports of these communities in New Zealand native plants. This first investigation of endophytic Actinobacteria in New Zealand targeted the culturally significant medicinal shrub Pseudowintera colorata (horopito) as a model plant. Community analysis in plant tissues collected from ten geographically distinct sites showed that tissue type had the strongest influence on diversity and richness of endophytic Actinobacteria. More denaturing gradient gel electrophoresis (DGGE) bands were obtained from stems (n = 18) compared to roots (n = 13). Sequencing analysis of the major bands (n = 20) identified them as uncultured bacteria, Streptomyces sp. and Angustibacter peucedani. Using two Actinobacteria-specific media, nine isolates were recovered from surface sterilised P. colorata tissues. This was approximately 12% of the total taxa and correlated well with culturable numbers in international studies. In vitro analysis of the functionality of these strains showed that Streptomyces sp. PRY2RB2 inhibited all the tested phytopathogenic fungi (n = 4), Streptomyces sp. UKCW/B and Nocardia sp. TP1BA1B solubilised phosphate and produced siderophores. The functionality of the phosphate solubilising strains (n = 2) in vivo was investigated by inoculation of P. colorata seedlings. After 4 months, the mean shoot height of seedlings treated with Nocardia sp. TP1BA1B was 1.65* longer, had higher shoot dry weight (1.6*) and number of internodes (1.67*) compared to control. This study identified for the first time a key group of endophytic Actinobacteria that are likely to be important in the ecology of New Zealand flora. PMID- 29435599 TI - An overview of lectin-glycan interactions: a key event in initiating fungal infection and pathogenesis. AB - Infections due to microfungi are of serious concern in many parts of the world. Many species of microfungi are known to cause systemic infection in human beings. Pathogenic microorganisms employ various molecular strategies for colonizing a susceptible host. Recent studies have shown the importance of lectins from microfungi that enable the pathogen to interact with the host, resulting in host immune response. These fungal lectins or adhesins show specific affinities to the glycans present on the membrane proteins or lipids. Binding of the pathogen to the receptors, probably toll-like receptors or dectins, present on the host cell surface triggers/initiates a cascade of signalling pathways, leading to the activation of transcription factors such as NF-kappaB resulting in the release of proinflammatory cytokines which in turn recruit cells of the immune system to the site of microbial insult to combat the pathogen or resulting in pathogenesis. In this review, we will focus on the interaction between fungal lectins and the host glycans initiating pathogenesis and how the host immune system tries to suppress the pathogenesis. PMID- 29435600 TI - The role of unfolded protein response and ER-phagy in quantum dots-induced nephrotoxicity: an in vitro and in vivo study. AB - Unfolded protein response (UPR) and endoplasmic reticulum (ER)-phagy are essential for cell homeostasis. Quantum dots (QDs), which have been widely used for biomedical applications, can accumulate in the kidney tissues and may cause renal dysfunction. However, the molecular mechanism of QDs-induced nephrotoxicity is still obscure. The present study was aimed to elucidate the role and mechanism of UPR and ER-phagy in QDs-induced nephrotoxicity. Herein, human embyronic kidney (HEK) cells were exposed to 15, 30, 45, and 60 nM cadmium telluride (CdTe)-QDs for 12 and 24 h. And CdTe-QDs (30-60 nM) inhibited the HEK cell viability. The clathrin-dependent endocytosis was determined as the main pathway of CdTe-QDs cellular uptake. Within cells, CdTe-QDs disrupted ER ultrastructure and induced UPR and FAM134B-dependent ER-phagy. Blocking UPR with inhibitors or siRNA rescued the FAM134B-dependent ER-phagy, which was triggered by CdTe-QDs. Moreover, suppression of UPR or FAM134B-dependent ER-phagy restored the cell vability. In vivo, mice were intravenously injected with 8 and 16 nmol/kg body weight CdTe-QDs for 24 h. Kidney was shown as one of highest distributed organs of CdTe-QDs, resulting in renal dysfunction, as well as UPR and FAM134B-dependent ER-phagy in it. Thus, for the first time, we demonstrated that ER-phagy can be triggered by nanomaterials both in vitro and in vivo. In addition, blocking of UPR and ER phagy showed protective effects against CdTe-QDs-induced toxicity in kideny cells. Notably, a secreted alkaline phosphatase reporter gene system has been developed as a sensitive and rapid method for evaluating the ER quality under the exposure of nanomaterials. PMID- 29435601 TI - Trait Mapping Approaches Through Linkage Mapping in Plants. AB - Quantitative trait loci (QTL) mapping in crop plants has now become a common practice due to the advances made in the area of molecular markers as well as that of statistical genomics. Consequently, large numbers of QTLs have been identified in different crops for a variety of traits. Several computational tools are now available that suit the type of mapping population and the trait(s) to be studied for QTL analyses as well as the objective of the program. These methods are comprised of simpler approaches like single marker analysis and simple interval mapping to relatively exhaustive inclusive composite interval mapping and Bayesian interval mapping. The relative significance of each of these methods varies considerably. The progress made in the area of computational analysis involving the identification of QTLs either through interval mapping or association mapping is unprecedented, and it is expected that it will continue to evolve over the coming years. An overview of the different methods of linkage based QTL analysis is provided in this chapter. Graphical Abstract. PMID- 29435602 TI - Auto-fluorescence of a silk fibroin-based scaffold and its interference with fluorophores in labeled cells. AB - Silk fibroin is increasingly emerging as an important biomaterial for tissue engineering applications. The ability to fluorescently image silk matrices under a microscope would be helpful in differentiating embedded labeled cells from background signal, critical for the study of silk-based engineered tissues. In this study, we fabricated a scaffold using freeze drying and confirmed its structure by X-ray diffraction and Fourier transform infrared spectroscopy. We then examined the fluorescence of the silk fibroin scaffold using confocal microscopy, both before and after cell seeding and fluorescent labeling. We subsequently investigated the fluorescent signature of the silk fibroin scaffold chemically. Fluorophore-labeled cells seeded into the scaffold showed the same fluorescent color as the scaffold itself when excited by the same wavelength of light. UV-Vis and fluorescence spectroscopy of a silk fibroin solution indicated absorption and emission maxima at 277 and 345 nm, respectively, which is a typical protein-derived signal. HPLC and GC-MS were used to detect quercetin and quercetin derivatives, without success. We therefore conclude that unlike silk cocoons, the fluorescent behavior of silk fibroin scaffolds does not derive from quercetin and its derivatives but from the intrinsic fluorescence of fibroin protein. We also find that the fluorescent signals deriving from a scaffold and from labeled cells embedded in it can be distinguished when the different optical channels are merged. PMID- 29435603 TI - Integration of sudden death syndrome resistance loci in the soybean genome. AB - KEY MESSAGE: Complexity and inconsistencies in resistance mapping publications of soybean sudden death syndrome (SDS) result in interpretation difficulty. This review integrates SDS mapping literature and proposes a new nomenclature system for reproducible SDS resistance loci. Soybean resistance to sudden death syndrome (SDS) is composed of foliar resistance to phytotoxins and root resistance to pathogen invasion. There are more than 80 quantitative trait loci (QTL) and dozens of single nucleotide polymorphisms (SNPs) associated with soybean resistance to SDS. The validity of these QTL and SNPs is questionable because of the complexity in phenotyping methodologies, the disease synergism between SDS and soybean cyst nematode (SCN), the variability from the interactions between soybean genotypes and environments, and the inconsistencies in the QTL nomenclature. This review organizes SDS mapping results and proposes the Rfv (resistance to Fusarium virguliforme) nomenclature based on supporting criteria described in the text. Among ten reproducible loci receiving our Rfv nomenclature, Rfv18-01 is mostly supported by field studies and it co-localizes to the SCN resistance locus rhg1. The possibility that Rfv18-01 is a pleiotropic resistance locus and the concern about Rfv18-01 being confounded with Rhg1 is discussed. On the other hand, Rfv06-01, Rfv06-02, Rfv09-01, Rfv13-01, and Rfv16 01 were identified both by screening soybean leaves against phytotoxic culture filtrates and by evaluating SDS severity in fields. Future phenotyping using leaf and root-specific resistance screening methodologies may improve the precision of SDS resistance, and advanced genetic studies may further clarify the interactions among soybean genotypes, F. virguliforme, SCN, and environments. The review provides a summary of the SDS resistance literature and proposes a framework for communicating SDS resistance loci for future research considering molecular interactions and genetic breeding for soybean SDS resistance. PMID- 29435604 TI - Influence of body mass index on short-term subjective improvement and risk of reoperation after mid-urethral sling surgery. AB - INTRODUCTION AND HYPOTHESIS: The objective was to evaluate the impact of body mass index (BMI) on the subjective improvement and risk of reoperation after first-time mid-urethral sling surgery. METHODS: Data were retrieved from the national Danish Urogynaecological Database, including women with first-time surgery with mid-urethral polypropylene slings from 2011 to 2016. The subjective improvement was assessed by the difference in symptoms based on the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) completed pre- and 3 months postoperatively. A reoperation was defined as any new surgical procedure for stress urinary incontinence performed within the study period. RESULTS: During the study period, 6,414 mid-urethral sling procedures were performed; 80.0% of these women filled out both pre- and post-surgical International Consultation on Incontinence Questionnaire (ICI-Q) forms. 42.4% had a BMI < 25, 34.6% had BMI 25-30, 16.9% had BMI 30-35, and 6.0% BMI >35. The subjective improvement after surgery was high in all BMI categories and there were no differences between the categories. The overall cumulative hazard proportion at 2 years of follow-up was 1.9% (CI 95%: 1.6-2.3) and after 5 years 2.4% (CI 95%: 2.0-2.9). Adjusted for age, smoking, and use of alcohol, the cumulative hazard proportion after 2 years of follow-up was 3.2% (CI 95%: 1.6 6.2) for women with BMI >35 and after 5 years 4.0% (CI 95%: 2.0-7.7), which was the highest proportion of reoperation in the study. The crude hazard ratio was 1.84 (CI 95%: 0.89-3.83) women with BMI >35 and the adjusted hazard ratio was 1.94 (CI 95%: 0.92-4.09). CONCLUSIONS: We found high subjective improvement after the first-time surgery unrelated to BMI. Women with a BMI over 35 had the highest proportion of reoperations, although this was not statistically significant. PMID- 29435605 TI - Corticospinal excitability is modulated by distinct movement patterns during action observation. AB - It is well established that excitability of the primary motor cortex increases during action observation. However, the modulation of motor cortex excitability during observation of different actions, with distinct movement patterns, is not fully understood. The aim of the current study was to examine time-dependent changes in corticospinal excitability during observation of two actions with different levels of complexity. We developed videos of two distinct actions (a point and a reach-and-grasp), that were matched in video length, action onset, and onset of kinematics. Single-pulse transcranial magnetic stimulation was used to investigate time-dependent changes in primary motor cortex excitability during observation of the two actions. Motor evoked potentials (MEP) were recorded from two intrinsic hand muscles, namely first dorsal interosseous (FDI) and abductor digiti minimi. Results showed no difference in MEP amplitude during observation of a static hand compared to observation of the actions. When comparing the point to the grasp action, there were two key findings showing time-dependent changes in motor cortex excitability: first, greater MEP amplitude in FDI during observation of the point than the grasp action at an early time-point (index finger extension) and second, greater MEP amplitude in FDI during observation of the grasp than the point action at a later time-point (hand opening to form a grasp). These results show that excitability of the primary motor cortex is differentially modulated during observation of a point and grasp action, suggesting that the action observation network is engaged in a time-dependent manner during action observation. PMID- 29435606 TI - Route previewing results in altered gaze behaviour, increased self-confidence and improved stepping safety in both young and older adults during adaptive locomotion. AB - Older adults with falls risk tend to look away prematurely from targets for safe foot placement to view future hazards; behaviour associated with increased anxiety and stepping inaccuracies. We aimed to determine the effectiveness of route previewing in reducing anxiety and optimizing gaze behaviour and stepping performance of younger and older adults. Nine younger and nine older adults completed six walks with three task complexities over two sessions. Each trial used either an isolated stepping target, or a target followed by either one or two obstacles. Participants with eyes closed, on hearing a signal, opened their eyes and initiated walking (go trials) or stood previewing the route for 10 s before starting (preview trials). Kinematic data were collected using a Vicon motion analysis system. Gaze behaviour was recorded using a Dikablis eye tracker. On average, both older and younger adults fixated the target for significantly longer during walking when they had previewed the route than when they had not. Self-confidence scores were also significantly higher following 'preview trials' than 'go trials'. Stepping performance significantly improved following route previewing (reduced Medial lateral foot placement variability for both groups and reduced anterior/posterior foot placement error in older adults only). These findings implicate route previewing as a potential intervention to increase self confidence and reduce the risk of tripping in older adults. PMID- 29435607 TI - Marked First-Degree Atrioventricular Block and Pseudo-Pacemaker Syndrome in a Pediatric Patient. AB - We describe a 17-year-old female who presented with 3 weeks of abdominal pain, exercise intolerance, and an episode of altered mental status found to have marked first-degree atrioventricular block. Exercise stress test and cardiac catheterization demonstrated pseudo-pacemaker syndrome, and a permanent pacemaker was placed. Following placement, she has resolution of symptoms and markedly improved exercise tolerance. PMID- 29435608 TI - Abnormal alignment of the left lower extremity and irregular gait. 2-year-old male with abnormal alignment of the left lower extremity and irregular gait. PMID- 29435609 TI - Combined endoscopic approach in the management of suprasellar craniopharyngioma. AB - INTRODUCTION: Craniopharyngiomas are dysontogenic tumors with benign histology but aggressive behavior. The surgical challenges posed by the tumor are well recognized. Neuroendoscopy has recently contributed to its surgical management. This study focuses on our experience in managing craniopharyngiomas in recent years, highlighting the role of combined endoscopic trans-ventricular and endonasal approach. CASE SERIES: Ninety-two patients have been treated for craniopharyngioma from 2000 to 2016 by the senior author. A total of 125 procedures, microsurgical (58) and endoscopic (67), were undertaken. Combined endoscopic approach was carried out in 18 of these patients, 16 children and 2 young adults. All of these patients presented with a large cystic suprasellar mass associated with hydrocephalus. In the first instance, they were treated with a transventricular endoscopic procedure to decompress the cystic component. This was followed by an endonasal transsphenoidal procedure for excision within the next 2 to 6 days. All these patients improved after the initial cyst decompression with relief of hydrocephalus while awaiting remaining tumor removal in a more elective setting. Gross total resection could be done in 84% of these patients. Diabetes insipidus was the most common postsurgical complication seen in 61% patients in the immediate period but was persistent in only two patients at 1-year follow-up. None of the children in this group developed morbid obesity. There was one case of CSF leak requiring repair after initial surgery. Peri operative mortality was seen in one patient secondary to ventriculitis. DISCUSSION: The patients who benefit most from the combined approach are those who present with raised intracranial pressure secondary to a large tumor with cyst causing hydrocephalus. Intraventricular endoscopic cyst drainage allows resolution of hydrocephalus with restoration of normal intracranial pressure, gives time for proper preoperative work up, and has reduced incidence of CSF leak after transnasal surgery. CONCLUSION: Combined endoscopic approach thus gives a unique opportunity to remove these lesions more radically with less morbidity. PMID- 29435610 TI - Hydrogen-Bonded Network and Water Dynamics in the D-channel of Cytochrome c Oxidase. AB - Proton transfer in cytochrome c oxidase (CcO) from the cellular inside to the binuclear redox centre as well as proton pumping through the membrane takes place through proton entrance via two distinct pathways, the D- and K-channel. Both channels show a dependence of their hydration level on the protonation states of their key residues, K362 for the K-channel, and E286 or D132 for the D-channel. In the oxidative half of CcO's catalytic cycle the D-channel is the proton conducting path. For this channel, an interplay of protonation state of the D channel residues with the water and hydrogen-bond dynamics has been observed in molecular dynamics simulations of the CcO protein, embedded in a lipid bi-layer, modelled in different protonation states. Protonation of residue E286 at the end of the D-channel results in a hydrogen-bonded network pointing from E286 to N139, that is against proton transport, and favouring N139 conformations which correspond to a closed asparagine gate (formed by residues N121 and N139). Consequently, the hydration level is lower than with unprotonated E286. In those models, the Asn gate is predominantly open, allowing water molecules to pass and thus increase the hydration level. The hydrogen-bonded network in these states exhibits longer life times of the Asn residues with water than other models and shows the D-channel to be traversable from the entrance, D132, to exit, E286. The D-channel can thus be regarded as auto-regulated with respect to proton transport, allowing proton passage only when required, that is the proton is located at the lower part of the D-channel (D132 to Asn gate) and not at the exit (E286). PMID- 29435611 TI - Electrophilic derivatives of omega-3 fatty acids counteract lung cancer cell growth. AB - PURPOSE: 17-oxo-DHA is an electrophilic keto-derivative of the omega-3 fatty acid docosahexaenoic acid (DHA) endogenously generated by cyclooxygenase-2 and a cellular dehydrogenase. 17-oxo-DHA displays anti-inflammatory and cytoprotective actions. DHA, alone or in combination with standard chemotherapy, displays antitumor activity. However, the effects of electrophilic keto-derivatives of DHA on cancer growth have never been evaluated. We investigated whether 17-oxo-DHA, alone or in combination with gemcitabine, displayed antitumor effects. Furthermore, we evaluated whether the enzyme 15-prostaglandin dehydrogenase (15 PGDH) was required for transducing the antitumor effects of DHA. METHODS: A panel of five histologically different human non-small cell lung cancer (NSCLC) cell lines was used. Cells were treated with 17-oxo-DHA and gemcitabine, alone or in combination, and apoptosis, proliferation, Fas and FasL expression (mRNA and protein) and active caspase-3/7 and -8 were assessed. Furthermore, an inhibitor of 15-PGDH was used to test the involvement of this enzyme in mediating the antitumor effects of DHA. RESULTS: 17-oxo-DHA (50 uM, 72 h) significantly reduced proliferation, increased cell apoptosis, Fas and FasL expression as well as active caspase-8 and -3/7. When 17-oxo-DHA was given in combination with gemcitabine, stronger effects were observed compared to gemcitabine alone. The enzyme 15-PGDH was required for DHA to promote its full anti-apoptotic effect suggesting that enzymatically generated keto-derivatives of DHA mediate its antitumor actions. CONCLUSIONS: Data herein provided, demonstrate that 17-oxo-DHA displays antitumor effects in NSCLC cell lines. Of note, the combination of 17 oxo-DHA plus gemcitabine, resulted in stronger anticancer effects compared to gemcitabine alone. PMID- 29435612 TI - Optimization of a Viability PCR Method for the Detection of Listeria monocytogenes in Food Samples. AB - Rapid detection of Listeria and other microbial pathogens in food is an essential part of quality control and it is critical for ensuring the safety of consumers. Culture-based methods for detecting foodborne pathogens are time-consuming, laborious and cannot detect viable but non-culturable microorganism, whereas viability PCR methodology provides quick results; it is able to detect viable but non-culturable cells, and allows for easier handling of large amount of samples. Although the most critical point to use viability PCR technique is achieving the complete exclusion of dead cell amplification signals, many improvements are being introduced to overcome this. In the present work, the yield of dead cell DNA neutralization was enhanced by incorporating two new sample treatment strategies: tube change combined with a double light treatment. This procedure was successfully tested using artificially contaminated food samples, showing improved neutralization of dead cell DNA. PMID- 29435613 TI - Oxidative Stress Parameters, Induction of Lipid Peroxidation, and ATPase Activity in the Liver and Kidney of Oreochromis niloticus Exposed to Lead and Mixtures of Lead and Zinc. AB - The purpose of this investigation was to evaluate the effects of lead (Pb) and lead + zinc (Zn) combination on the oxidative stress, total ATPase and Pb accumulation in the tissues of Oreochromis niloticus (Linnaeus, 1758). The fish were exposed to 0.1 mg/L Pb (T1), 1.0 mg/L Pb (T2) and mixtures of 0.1 mg/L Pb and 0.5 mg/L Zn (M1); 1.0 mg/L Pb and 5.0 mg/L Zn (M2) for 7 and 21 days. Pb accumulation, total ATPase activity, several antioxidant enzyme activities such as catalase, glutathione peroxidase (GPX), glutathione S-transferase, glutathione reductase, and thiobarbituric acid reactive substances concentrations were measured in the liver and kidney tissues. Metal accumulation in the tissues was higher in Pb exposure compare with mixtures of Pb and Zn exposures. Beside the inhibition of liver GPX activity, general increases of antioxidant enzyme activities in the tissues were recorded after metal exposures. This investigation emphasizes the oxidative stress in O. niloticus caused by Pb, and adaptation of the organisms to the changes in enzyme activities. PMID- 29435614 TI - Effect of Boron Toxicity on Oxidative Stress and Genotoxicity in Wheat (Triticum aestivum L.). AB - Boron (B) toxicity, which occurs in semi-arid and arid environments, can adversely affect the growth and yield of many plants. The aim of this study was to determine the effects of different concentrations of boric acid (3, 6, 9 and 12 mM) on growth, oxidative stress and genotoxicity parameters in root and shoot tissues of wheat seedlings. Our results indicate that B stress inhibits root and shoot growth of wheat in a concentration-dependent manner, and leads to increases in TBARS and H2O2 contents in shoot tissue. Moreover, our findings suggest that high concentrations of B may exert a genotoxic effect on wheat. To the best of our knowledge, this is the first report to evaluate the effect of B stress on genotoxicity in both root and shoot tissues of wheat. PMID- 29435615 TI - Leaching of Clothianidin in Two Different Indian Soils: Effect of Organic Amendment. AB - Clothianidin is a widely used insecticide under Indian subtropical condition. The objective of this study was to generate residue data which aims to understand leaching potential of clothianidin [(E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-3 methyl-2- nitroguanidine] through packed soil column. The maximum amount of clothianidin was recovered at 0-5 cm soil depth in both Manipur (67.15%) and Delhi soil (52.0%) under continuous flow condition. Manipur and Delhi soil concentrated maximum residue with or without farm yard manure (FYM) in 0-20 cm soil depth. The effect of varying the amount of water enhanced the distribution of residues in the first 0-5 cm layer. Among the tested soils, residue was detected in the leachate from Delhi soil (0.04 ug/mL). Clothianidin leaching was minimized in soil of Manipur compared to Delhi after incorporation of FYM. As the volume of water increased upto 160 mL, mobility increased and residues moved to lower depth. Clothianidin did not leach out of the 25 cm long soil columns even after percolating water equivalent to 415.42 mm rainfall. Clothianidin is mobile in soil system and mobility can be reduced by organic amendment application. PMID- 29435616 TI - The Response of Lemna minor to Mixtures of Pesticides That Are Commonly Used in Thailand. AB - In the field, aquatic organisms are exposed to multiple contaminants rather than to single compounds. It is therefore important to understand the toxic interactions of co-occurring substances in the environment. The aim of the study was to assess the effects of individual herbicides (atrazine, 2,4-D, alachlor and paraquat) that are commonly used in Thailand and their mixtures on Lemna minor. Plants were exposed to individual and binary mixtures for 7 days and the effects on plant growth rate were assesed based on frond area measurements. Experimental observations of mixture toxicity were compared with predictions based on single herbicide exposure data using concentration addition and independent action models. The single compound studies showed that paraquat and alachlor were most toxic to L. minor, followed by atrazine and then 2,4-D. For the mixtures, atrazine with 2,4-D appeared to act antagonistically, whereas alachlor and paraquat showed synergism. PMID- 29435617 TI - Yeast arming systems: pros and cons of different protein anchors and other elements required for display. AB - Yeast display is a powerful strategy that consists in exposing peptides or proteins of interest on the cell surface of this microorganism. Ever since initial experiments with this methodology were carried out, its scope has extended and many applications have been successfully developed in different science and technology fields. Several yeast display systems have been designed, which all involve introducting into yeast cells the gene fusions that contain the coding regions of a signal peptide, an anchor protein, to properly attach the target to the cell surface, and the protein of interest to be exposed, all of which are controlled by a strong promoter. In this work, we report the description of such elements for the alternative systems introduced by focusing particularly on anchor proteins. The comparisons made between them are included whenever possible, and the main advantages and inconveniences of each one are discussed. Despite the huge number of publications on yeast surface display and the revisions published to date, this topic has not yet been widely considered. Finally, given the growing interest in developing systems for non-Saccharomyces yeasts, the main strategies reported for some are also summarized. PMID- 29435618 TI - Inactivation of an intracellular poly-3-hydroxybutyrate depolymerase of Azotobacter vinelandii allows to obtain a polymer of uniform high molecular mass. AB - A novel poly-3-hydroxybutyrate depolymerase was identified in Azotobacter vinelandii. This enzyme, now designated PhbZ1, is associated to the poly-3 hydroxybutyrate (PHB) granules and when expressed in Escherichia coli, it showed in vitro PHB depolymerizing activity on native or artificial PHB granules, but not on crystalline PHB. Native PHB (nPHB) granules isolated from a PhbZ1 mutant had a diminished endogenous in vitro hydrolysis of the polyester, when compared to the granules of the wild-type strain. This in vitro degradation was also tested in the presence of free coenzyme A. Thiolytic degradation of the polymer was observed in the nPHB granules of the wild type, resulting in the formation of 3-hydroxybutyryl-CoA, but was absent in the granules of the mutant. It was previously reported that cultures of A. vinelandii OP grown in a bioreactor showed a decrease in the weight average molecular weight (Mw) of the PHB after 20 h of culture, with an increase in the fraction of polymers of lower molecular weight. This decrease was correlated with an increase in the PHB depolymerase activity during the culture. Here, we show that in the phbZ1 mutant, neither the decrease in the Mw nor the appearance of a low molecular weight polymers occurred. In addition, a higher PHB accumulation was observed in the cultures of the phbZ1 mutant. These results suggest that PhbZ1 has a role in the degradation of PHB in cultures in bioreactors and its inactivation allows the production of a polymer of a uniform high molecular weight. PMID- 29435619 TI - Acetamidase as a dominant recyclable marker for Komagataella phaffii strain engineering. AB - We have investigated the use of the gene coding for acetamidase (amdS) as a recyclable dominant marker for the methylotrophic yeast Komagataella phaffii in order to broaden its genetic toolbox. First, the endogenous constitutive AMD2 gene (a putative acetamidase) was deleted generating strain LA1. A cassette (amdSloxP) was constructed bearing a codon-optimized version of the Aspergillus nidulans amdS gene flanked by loxP sites for marker excision with Cre recombinase. This cassette was successfully tested as a dominant selection marker for transformation of the LA1 strain after selection on plates containing acetamide as a sole nitrogen source. Finally, amdSloxP was used to sequentially disrupt the K. phaffii ADE2 and URA5 genes. After each disruption event, a Cre mediated marker recycling step was performed by plating cells on medium containing fluoroacetamide. In conclusion, amdS proved to be a suitable tool for K. phaffii transformation and marker recycling thus providing a new antibiotic free system for genetic manipulation of this yeast. PMID- 29435620 TI - Diagnosis of vertebral deformities on chest CT and DXA compared to routine lateral thoracic spine X-ray. AB - : X-ray, CT and DXA enable diagnosis of vertebral deformities. For this study, level of agreement of vertebral deformity diagnosis was analysed. We showed that especially on subject level, these imaging techniques could be used for opportunistic screening of vertebral deformities in COPD patients. INTRODUCTION: X-ray and CT are frequently used for pulmonary evaluation in patients with chronic obstructive pulmonary disease (COPD) and also enable to diagnose vertebral deformities together with dual-energy X-ray absorptiometry (DXA) imaging. The aim of this research was to study the level of agreement of these imaging modalities for diagnosis of vertebral deformities from T4 to L1. METHODS: Eighty-seven subjects (mean age of 65; 50 males; 57 COPD patients) who had X-ray, chest CT (CCT) and DXA were included. Evaluable vertebrae were scored twice using SpineAnalyzerTM software. ICCs and kappas were calculated to examine intra observer variability. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic curve (AUROC) were calculated to compare vertebral deformities diagnosed on the different imaging modalities. RESULTS: ICCs for height measurements were excellent (> 0.94). Kappas were good to excellent (0.64-0.77). At vertebral level, the AUROC was 0.85 for CCT vs. X-ray, 0.74 for DXA vs. X-ray and 0.77 for DXA vs. CCT. Sensitivity (51%-73%) and PPV (57%-70%) were fair to good; specificity and NPV were excellent (>= 96%). At subject level, the AUROC values were comparable. CONCLUSIONS: Reproducibility of height measurements of vertebrae is excellent with all three imaging modalities. On subject level, diagnostic performance of CT (PPV 79-82%; NPV 90-93%), and to a slightly lesser extend of DXA (PPV 73-77%; NPV 80-89%), indicates that these imaging techniques could be used for opportunistic screening of vertebral deformities in COPD patients. PMID- 29435621 TI - Effect of selective serotonin reuptake inhibitors on bone mineral density: a systematic review and meta-analysis. AB - Our work is the first systematic meta-analysis to investigate the effect of selective serotonin reuptake inhibitor (SSRI) medication on bone mineral density. Through meta-analyzed 11 studies, our findings suggested that compared with nonusers, use of SSRIs was significantly associated with lumbar spine BMD reduction, particularly for old people. The use of selective serotonin reuptake inhibitors (SSRIs) has already been associated with bone mass loss. Their effects on bone mineral density (BMD) for the different bone sections have, however, thus been inconsistent. Here, we aim to assess the effects of SSRIs on BMD using a meta-analysis. We searched PubMed, Scopus, ISI Web of Knowledge, the Cochrane Library, and PsycINFO for all English-written studies investigating the effects of SSRIs on BMD and published before November 2017. BMD was compared between non SSRI users and SSRI users using a random-effect model with standardized mean differences (SMD) and 95% confidence intervals (CIs). Furthermore, subgroup analyses were performed based on study design, age, and sex in order to find the origins of high heterogeneity. Eleven studies met the inclusion criteria and were used for the meta-analysis. Our study demonstrated that the use of SSRIs was significantly associated with lower BMD values (SMD - 0.40; 95% CI - 0.79 to 0.00; p = 0.05) and BMD Z-scores (SMD - 0.28; 95% CI - 0.50 to - 0.05; p = 0.02) of the lumbar spine, but not of the total hip and femoral neck. In addition, SSRI use was associated with a greater bone loss in older people. SSRI use is a risk factor of lower BMD of the lumbar spine, especially for older people. Future studies into the relationship between SSRI use and bone metabolism and bone mass need to be conducted with larger sample sizes for both men and women at different bone sites. PMID- 29435622 TI - High bacterial contamination rate of electrocautery tips during total hip and knee arthroplasty. AB - PURPOSE: The aim of the study was to quantify the bacterial contamination rate of electrocautery tips during primary total joint replacement (TJR), as well as during aseptic and septic revision TJR. METHODS: A total of 150 electrocautery tips were collected between April and July 2017. TJR surgeries were divided into three groups: (1) primary, (2) aseptic and (3) septic revisions. In each group, a total of 50 electrocautery tips were collected. A monopolar electrocautery with a reusable stainless-steel blade tip was used in all cases. The rate of bacterial contamination was determined for all groups. Correlation of exposure time and type of surgery was analyzed. RESULTS: The overall bacterial contamination rate was 14.7% (95% CI 9.4 to 21.4%). The highest contamination rate occurred in the septic revision group (30.0%; 95% CI 17.9 to 44.6%), followed by the primary cases group (10.0%; 95% CI 3.3 to 21.8%) and the aseptic revision group (4.0%; 95% CI 0.5 to 13.7%). Exposure time did not affect the bacterial contamination rate. In 12 out of 15 (80%) contaminations identified in the septic group, we found the same causative microorganism of the prosthetic joint infection on the electrocautery tip. CONCLUSIONS: The bacterial contamination of the electrocautery tips is relatively high, especially during septic hip revision arthroplasty. Electrocautery tips should be changed after debridement of infected tissue. PMID- 29435623 TI - The biological basis for concentrated iliac crest aspirate to enhance core decompression in the treatment of osteonecrosis. AB - Core decompression is a surgical procedure that is capable of salvaging the patient's own natural joint, if the operation is performed in the early stages of osteonecrosis, in which the articular surface has not collapsed. The addition of concentrated cells, aspirated from the iliac crest, to the core tract has been shown to enhance the viability of the femoral head, although large, prospective, randomized, blinded multicentre studies are lacking. The rationale for adding these cells to the core decompression tract is to provide osteoprogenitor and vascular progenitor cells to the area of decompressed dead bone, in order to facilitate tissue regeneration and repair. It has become increasingly evident that vast discrepancies exist in different series in regard to the criteria for patient selection, the surgical technique of core decompression, the methods for harvesting, processing, and injecting the cells, and the methodology for determining success or failure in a specific patient cohort. This paper reviews the salient points relevant to the treatment of osteonecrosis by core decompression with addition of concentrated iliac crest aspirates and poses important questions regarding the future successful application of this technique. PMID- 29435625 TI - [Current status and innovations in reconstructive shoulder surgery]. PMID- 29435624 TI - Arthroscopic soft tissue reconstruction in anterior shoulder instability. AB - Anterior glenohumeral instability remains a difficult problem in the athletic and working patient populations. Treatment strategies are variable and range from nonoperative approaches incorporating immobilization and rehabilitation to surgical management. Surgical decision-making can be challenging, especially with a high-level patient who wishes to return to high-demand activities. Operative options range from open soft tissue stabilization to arthroscopic soft tissue stabilization, with both open and arthroscopic options for bony reconstruction in the setting of clinically significant anterior glenoid bone loss. In all cases, understanding appropriate indications and utilizing sound surgical techniques are critical for achieving a successful result. For the majority of patients with anterior shoulder instability, arthroscopic soft tissue reconstruction with suture anchors is a successful, minimally invasive approach that results in a stable shoulder with excellent outcomes and low complication rates. PMID- 29435626 TI - Mini Laparotomy for Sigmoid Volvulus. PMID- 29435627 TI - Wide Surgical Margin Improves the Outcome for Patients with Gastrointestinal Stromal Tumors (GISTs). AB - BACKGROUND: Surgical resection is still the main treatment for gastrointestinal stromal tumor (GIST), and R0 excision, regardless of surgical margins, is considered sufficient. METHODS: A cohort of 79 consecutive GIST cases treated at the Karolinska University Hospital, who were without metastasis at diagnosis and who had not received any pre-or postoperative treatment with tyrosine kinase inhibitors, was included. Surgical margins were evaluated at the time of surgery and classified as wide, marginal or intralesional. Time to local/peritoneal recurrence, distant metastasis, and survival were recorded. Cox regression analysis was used to investigate the association between surgical margin, and recurrence and survival. RESULTS: Local/peritoneal recurrence was diagnosed in 2/39 cases with wide margins, in 7/22 cases with marginal margins, and in 13/18 cases with intralesional surgery. Compared to wide margins this gives a hazard ratio of 6.8 (confidence interval 1.4-32.7) for marginal margins and 13.5 (3-61) for intralesional margins. In multivariate analysis, adjusting for size, site, and mitotic index, surgical margin remained an independent significant predictor of risk for recurrence. When classifying patients according to R0/R1 surgery, patients with R0 surgery showed longer time to peritoneal recurrence and better recurrence-free and disease-specific survival as compared to those with R1 resection. However, when excluding patients operated with wide surgical margin, no significant difference was observed. CONCLUSION: Wide surgical margins are of significant prognostic importance, supporting the strategy of en bloc resection with good margin and careful handling of the tumor to avoid damaging the peritoneal surface in surgical resection of GIST. PMID- 29435628 TI - Hydatid Cyst of the Liver: A Challenge That Can Be Amplified Shifting from Open to Laparoscopic Surgery: Reply. PMID- 29435629 TI - Long-Term Survival and Prognostic Factors of Pulmonary Metastasectomy in Liver Cancer: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Lung is the most common extrahepatic metastatic organ of liver cancer. Surgical resection is a common local treatment for pulmonary metastasis. But the long-term prognosis of pulmonary metastasectomy varies greatly due to the small sample size and different results of previous studies. Therefore, we conducted this meta-analysis to evaluate the combined 5-year overall survival (OS) rate and prognostic factors after pulmonary metastasectomy in liver cancer. METHODS: Key words such as liver cancer pulmonary metastasis and metastasectomy were retrieved firstly in PubMed, Cochrane Library, Embase and Chinese Wanfang databases. Eligible studies were identified by manual searches. Each included study should report 5-year OS rate and/or prognostic factors of pulmonary metastasectomy. Newcastle-Ottawa Scale was used for quality assessment, and heterogeneity was estimated by I2. We calculated the combined 5-year survival rates and determined the prognostic factors for OS by the hazard ratios (HR) and number of events. RESULTS: Seventeen cohort studies with a total of 513 patients were included in this meta-analysis. The combined 5-year survival rates after pulmonary metastasectomy were 33% [95% confidence interval (95% CI) 29-37%]. The poor prognostic factors were disease-free interval (DFI) < 12 months (HR = 2.421 95% CI 1.384 4.236) and existence of cirrhosis (HR = 1.936 95% CI 1.031 3.636). CONCLUSION: The 5-year OS rate of patients with pulmonary metastasectomy after resection of primary liver cancer is 33%. DFI < 12 months and existence of cirrhosis are probably poor prognostic factors. PMID- 29435630 TI - CT assessment of axillary lymphadenopathy in patients with rheumatoid arthritis: association with disease activity and severity. AB - BACKGROUND: Axillary lymph nodes (ALNs) are often seen on chest computed tomography (CT) in rheumatoid arthritis (RA) patients. Early reports described lymphadenopathy as one of the systemic manifestations rather than regional lymphadenopathy secondary to drainage from the affected joints. Subsequently, the importance of the immunological events occurring in draining lymph nodes in the development of arthritis was documented. OBJECTIVE: To identify the relationships of local disease activity and background characteristics, including systemic disease activity, systemic disease activity, with axillary lymphadenopathy (AL) in RA using CT. METHODS: RA patients who had undergone chest CT were retrospectively analyzed. The maximum short axis of the ALNs was measured, and the number of positive ALNs >= 5 mm was counted. Tender and swollen joints in the upper limbs were counted as indicators of local disease activity. Background characteristics and systemic disease activity were assessed based on the selected RA indicators. Correlations between AL and both local disease activity and background characteristics including systemic disease activity were analyzed. RESULTS: Of 135 patients, 58 had positive ALNs (average size 7.97 mm, range up to 15 mm). The presence of positive unilateral ALNs was correlated with the severity of ipsilateral upper limb arthritis. Multivariate analysis showed correlations between AL and both local disease activity and serological findings such as serum C-reactive protein (CRP) and immunoglobulin (Ig) G. CONCLUSION: AL in patients with RA was correlated with local arthritis activity, as well as background characteristics and systemic disease activity. PMID- 29435632 TI - Chemometrics-assisted microfluidic paper-based analytical device for the determination of uric acid by silver nanoparticle plasmon resonance. AB - This manuscript reports on the application of chemometric methods for the development of an optimized microfluidic paper-based analytical device (MUPAD). As an example, we applied chemometric methods for both device optimization and data processing of results of a colorimetric uric acid assay. Box-Behnken designs (BBD) were utilized for the optimization of the device geometry and the amount of thermal inkjet-deposited assay reagents, which affect the assay performance. Measurement outliers were detected in real time by partial least squares discriminant analysis (PLS-DA) of scanned images. The colorimetric assay mechanism is based on the on-device formation of silver nanoparticles (AgNPs) through the interaction of uric acid, ammonia, and poly(vinyl alcohol) with silver ions under mild basic conditions. The yellow color originating from visible light absorption by localized surface plasmon resonance of AgNPs can be detected by the naked eye or, more quantitatively, with a simple flat-bed scanner. Under optimized conditions, the linearity of the calibration curve ranges from 0.1-5 * 10-3 mol L-1 of uric acid with a limit of detection of 33.9 * 10-6 mol L-1 and a relative standard of deviation 4.5% (n = 3 for determination of 5.0 * 10-3 mol L-1 uric acid). Graphical abstract A chemometrics-assisted microfluidic paper-based analytical device was developed as a low-cost and rapid platform for the determination of uric acid (UA). The detection method is based on the chemical interaction of UA, ammonia, and polyvinyl alcohol under mild basic condition with silver ions inducing formation of yellow silver nanoparticles (AgNPs). PMID- 29435633 TI - Multi-layer solid-phase extraction and evaporation-enrichment methods for polar organic chemicals from aqueous matrices. AB - Analysis of polar organic chemicals in the aquatic environment is exacerbated by the lack of suitable and widely applicable enrichment methods. In this work, we assessed the suitability of a novel combination of well-known solid-phase extraction (SPE) materials in one cartridge as well as an evaporation method and for the enrichment of 26 polar model substances (predominantly log D < 0) covering a broad range of physico-chemical properties in three different aqueous matrices. The multi-layer solid-phase extraction (mlSPE) and evaporation method were investigated for the recovery and matrix effects of the model substances and analyzed with hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). In total, 65% of the model substances were amenable (> 10% recovery) to the mlSPE method with a mean recovery of 76% while 73% of the model substances were enriched with the evaporation method achieving a mean recovery of 78%. Target and non-target screening comparison of both methods with a frequently used reversed-phase SPE method utilizing "hydrophilic and lipophilic balanced" (HLB) material was performed. Target analysis showed that the mlSPE and evaporation method have pronounced advantages over the HLB method since the HLB material retained only 30% of the model substances. Non-target screening of a ground water sample with the investigated enrichment methods showed that the median retention time of all detected features on a HILIC system decreased in the order mlSPE (3641 features, median tR 9.7 min), evaporation (1391, 9.3 min), HLB (4414, 7.2 min), indicating a higher potential of the described methods to enrich polar analytes from water compared with HLB-SPE. Graphical abstract Schematic of the method evaluation (recovery and matrix effects) and method comparison (target and non-target analysis) of the two investigated enrichment methods for very polar chemicals in aqueousmatrices. PMID- 29435634 TI - Implementation and evaluation of flipped learning for delivery of analytical chemistry topics. PMID- 29435635 TI - Advances in the analysis of biological samples using ionic liquids. AB - Ionic liquids are a class of solvents and materials that hold great promise in bioanalytical chemistry. Task-specific ionic liquids have recently been designed for the selective extraction, separation, and detection of proteins, peptides, nucleic acids, and other physiologically relevant analytes from complex biological samples. To facilitate rapid bioanalysis, ionic liquids have been integrated in miniaturized and automated procedures. Bioanalytical separations have also benefited from the modification of nonspecific magnetic materials with ionic liquids or the implementation of ionic liquids with inherent magnetic properties. Furthermore, the direct detection of the extracted molecules in the analytical instrument has been demonstrated with structurally tuned ionic liquids and magnetic ionic liquids, providing a significant advantage in the analysis of low-abundance analytes. This article gives an overview of these advances that involve the application of ionic liquids and derivatives in bioanalysis. Graphical abstract Ionic liquids, magnetic ionic liquids, and ionic liquid-based sorbents are increasing the speed, selectivity, and sensitivity in the analysis of biological samples. PMID- 29435636 TI - Standard Reference Material (SRM) 2378 fatty acids in frozen human serum. Certification of a clinical SRM based on endogenous supplementation of polyunsaturated fatty acids. AB - Dietary fatty acids can be both beneficial and detrimental to human health depending on the degree and type of saturation. Healthcare providers and research scientists monitor the fatty acid content of human plasma and serum as an indicator of health status and diet. In addition, both the Centers for Disease Control & Prevention (CDC) and the National Institutes of Health - Office of Dietary Supplements are interested in circulating fatty acids (FAs) because they may be predictive of coronary heart disease. The National Institute of Standards and Technology (NIST) provides a wide variety of reference materials (RMs) and Standard Reference Materials(r) (SRM(r)s) including blood, serum, plasma, and urine with values assigned for analytes of clinical interest. NIST SRM 2378 Fatty Acids in Frozen Human Serum was introduced in 2015 to help validate methods used for the analysis of FAs in serum, and consists of three different pools of serum acquired from (1) healthy donors who had taken fish oil dietary supplements (at least 1000 mg per day) for at least one month (level 1 material), (2) healthy donors who had taken flaxseed oil dietary supplements (at least 1000 mg per day) for at least one month (level 2 material), and (3) healthy donors eating "normal" diets who had not taken dietary supplements containing fish or plant oils (level 3 material). The use of dietary supplements by donors provided SRMs with natural endogenous ranges of FAs at concentrations observed in human populations. Results from analyses using two methods at NIST, including one involving a novel microwave-assisted acid hydrolysis procedure, and one at the CDC are presented here. These results and their respective uncertainties were combined to yield certified values with expanded uncertainties for 12 FAs and reference values with expanded uncertainties for an additional 18 FAs. PMID- 29435637 TI - Ionic liquids as water-compatible GC stationary phases for the analysis of fragrances and essential oils. AB - Fragrances and products deriving from essential oils are often formulated or diluted in aqueous media, usually ethanol/water. Gas chromatography (GC) is the technique of choice to analyze volatiles. However, when using columns coated with conventional stationary phases, its application to aqueous samples often requires time-consuming and/or discriminative sample preparation techniques to extract the target analytes from the aqueous medium, so as to avoid its direct injection. In GC with conventional columns, water produces peak asymmetry, poor sensitivity and efficiency, strong adsorption, stationary phase degradation, and, last but not least, it is not easy to detect reliably when present in high amounts. In 2012, Armstrong's group introduced new fully water-compatible ionic-liquid (IL)-based GC capillary columns based on phosphonium and imidazolium derivative cations combined with trifluoromethanesulphonate. These columns were recently made available commercially by Supelco, under the trade name WatercolTM. These derivatives maintain IL's unique selectivity and chromatographic properties, and enable water to be used as injection solvent, thus avoiding the sample preparation procedures required by conventional columns. This study reports and critically discusses the results of commercially available water-compatible IL columns for direct analysis of aqueous samples in the fragrance and essential oil fields by GC with thermal conductivity (TCD) and/or flame ionization detectors (FID). The results showed that water-compatible IL-based stationary phases can successfully be adopted for qualitative and quantitative analysis of fragrances and essential oils directly diluted in aqueous solvents. On the other hand, the study also shows that their inertness needs to be further increased and (possibly) the range of operative temperature extended when water is the main solvent of the sample. PMID- 29435638 TI - In house validation of a high resolution mass spectrometry Orbitrap-based method for multiple allergen detection in a processed model food. AB - In recent years, mass spectrometry (MS) has been establishing its role in the development of analytical methods for multiple allergen detection, but most analyses are being carried out on low-resolution mass spectrometers such as triple quadrupole or ion traps. In this investigation, performance provided by a high resolution (HR) hybrid quadrupole-OrbitrapTM MS platform for the multiple allergens detection in processed food matrix is presented. In particular, three different acquisition modes were compared: full-MS, targeted-selected ion monitoring with data-dependent fragmentation (t-SIM/dd2), and parallel reaction monitoring. In order to challenge the HR-MS platform, the sample preparation was kept as simple as possible, limited to a 30-min ultrasound-aided protein extraction followed by clean-up with disposable size exclusion cartridges. Selected peptide markers tracing for five allergenic ingredients namely skim milk, whole egg, soy flour, ground hazelnut, and ground peanut were monitored in home-made cookies chosen as model processed matrix. Timed t-SIM/dd2 was found the best choice as a good compromise between sensitivity and accuracy, accomplishing the detection of 17 peptides originating from the five allergens in the same run. The optimized method was validated in-house through the evaluation of matrix and processing effects, recoveries, and precision. The selected quantitative markers for each allergenic ingredient provided quantification of 60-100 MUgingred/g allergenic ingredient/matrix in incurred cookies. PMID- 29435639 TI - Assessment of readability, quality and popularity of online information on ureteral stents. AB - OBJECTIVE: To evaluate the quality and readability of online information on ureteral stents. METHODS: Google.com was queried using the search terms "ureteric stent", "ureteral stent", "double J stent" and, "Kidney stent" derived from Google AdWords. Website popularity was determined using Google Rank and the Alexa tool. Website quality assessment was performed using the following criteria: Journal of the American Medical Association (JAMA) benchmarks, Health on the Net (HON) criteria, and a customized DISCERN questionnaire. The customized DISCERN questionnaire was developed by combining the short validated DISCERN questionnaire with additional stent-specific items including definition, placement, complications, limitations, removal and "when to seek help". Scores related to stent items were considered as the "stent score" (SS). Readability was evaluated using five readability tests. RESULTS: Thirty-two websites were included. The mean customized DISCERN score and "stent score" were 27.1 +/- 7.1 (maximum possible score = 59) and 14.6 +/- 3.8 (maximum possible score = 24), respectively. A minority of websites adequately addressed "stent removal" and "when to seek medical attention". Only two websites (6.3%) had HON certification (drugs.com, radiologyinfo.org) and only one website (3.3%) met all JAMA criteria (bradyurology.blogspot.com). Readability level was higher than the American Medical Association recommendation of sixth-grade level for more than 75% of the websites. There was no correlation between Google rank, Alexa rank, and the quality scores (P > 0.05). DISCUSSION: Among the 32 most popular websites on the topic of ureteral stents, online information was highly variable. The readability of many of the websites was far higher than standard recommendations and the online information was questionable in many cases. These findings suggest a need for improved online resources in order to better educate patients about ureteral stents and also should inform physicians that popular websites may have incomplete information. PMID- 29435640 TI - Feasibility and safety of outpatient cardiac catheterization with intracoronary acetylcholine provocation test. AB - Intracoronary acetylcholine (ACh) provocation test is useful to diagnose vasospastic angina. Although outpatient coronary angiography has been widely performed in current clinical settings, the feasibility and safety of ACh provocation test in outpatient services are unclear. A total of 323 patients, who electively underwent ACh provocation test in hospitalization and outpatient services, were included. Coronary angiography was performed after insertion of a temporary pacing electrode in the right ventricle. The positive diagnosis of intracoronary ACh provocation test was defined as total or subtotal coronary artery narrowing accompanied by chest pain and/or ischemic electrocardiographic changes. Cardiac complications defined as composite of death, ventricular fibrillation or sustained ventricular tachycardia, myocardial infarction, cardiogenic shock, and cardiac tamponade, were evaluated. There were 201 patients (62%) in the hospitalization group and 122 patients (38%) in the outpatient group. The incidence of positive ACh provocation test was similar between the 2 groups (47 vs. 54%, p = 0.21). Coronary angiography in the outpatient group was performed through the radial artery, mostly (98%) with a 4 F sheath. Venous access site was not significantly different between the 2 groups, and the sheath size was 5 F in all cases. There were 2 cases (1.0%) of cardiac complications in the hospitalization group, whereas 1 case (0.8%), which led to unexpected hospitalization, occurred in the outpatient group. In conclusion, intracoronary ACh provocation test for the diagnosis of vasospastic angina in outpatient services was feasible and safe in selected patients. PMID- 29435641 TI - Wave intensity as a useful modality for assessing ventilation-perfusion imbalance in subclinical patients with hypertension. AB - Wave intensity (WI) is a novel noninvasive index of circulatory dynamics that reflects ventriculo-arterial coupling. It is calculated as the product of the first derivative of blood pressure and that of flow velocity measured by carotid echocardiography. This study aimed to clarify the clinical implications of WI and its relation with carbon dioxide production (VE/VCO2 slope). Twenty-one healthy volunteers (control group) and 21 patients with hypertension (HT group) underwent cardiopulmonary exercise testing (CPX) and exercise stress echocardiography. WI was assessed in the right carotid artery using an ultrasound system. The first peak of WI (W1) during the early ejection phase was measured at baseline and mitral annular velocity was assessed by tissue Doppler imaging. Ventilatory kinetics during exercise was assessed using the relation of minute ventilation to VE/VCO2 slope. VE/VCO2 slope, W1, and E/E' were greater in the HT group than in the control group. PeakVO2 and VO2 at the anaerobic threshold were lower in the HT group than in the control group. VE/VCO2 slope was significantly correlated with W1 (r = 0.58, p < 0.01) and E/E' (r = 0.44, p < 0.01). Stepwise multivariate analysis revealed that W1 was an independent determinant of VE/VCO2 slope (beta = 0.43, p < 0.01). In conclusion, W1 might be able to predict the severity of heart failure without the need for CPX. Moreover, WI may be a useful modality in assessing heart failure pathophysiology based on ventriculo-arterial coupling. PMID- 29435642 TI - German version of the Community Balance and Mobility Scale : Translation and evaluation of measurement properties. AB - BACKGROUND: Tools to detect subtle balance deficits in high-functioning community dwelling older adults are lacking. The Community Balance and Mobility Scale (CBM) is a valuable tool to measure balance deficits in this group; however, it is not yet available in the German language. OBJECTIVE: The aim was 1) to translate and cross-culturally adapt the CBM into the German language and 2) to investigate the measurement properties of the German CBM (G-CBM). MATERIAL AND METHODS: The original CBM was translated into the German language according to established guidelines. A total of 51 older adults (mean age 69.9 +/- 7.1 years) were recruited to measure construct validity by comparing the G-CBM against standardized balance and/or mobility assessments including the Fullerton Advanced Balance Scale (FAB), Berg Balance Scale (BBS), 3 m Tandem Walk (3MTW), 8 Level Balance Scale (8LBS), 30 s Chair Stand Test (30CST), Timed Up and Go (TUG) test, gait speed, and the Falls Efficacy Scale International (FES-I). Intrarater and interrater reliability and internal consistency reliability were estimated using intraclass correlations (ICC) and Cronbach's alpha, respectively. Ceiling effects were calculated as the percentage of the sample scoring the maximum score. RESULTS: The G-CBM correlated excellently with FAB and BBS (rho = 0.78-0.85; P < 0.001), good with 3MTW, TUG, and FES-I (rho = -0.55 to -0.61; P < 0.001), and moderately with 8LBS, 30CST, and habitual gait speed (rho = 0.32-0.46; P < 0.001). Intrarater (ICC3,k = 0.998; P < 0.001) and interrater (ICC2,k = 0.996; P < 0.001) reliability, and internal consistency reliability (alpha = 0.998) were also high. The G-CBM did not show ceiling effects. CONCLUSION: The G-CBM is a valid and reliable tool for measuring subtle balance deficits in older high functioning adults. The absence of ceiling effects emphasizes the use of this scale in this cohort. The G-CBM can now be utilized in clinical practice. PMID- 29435643 TI - Effectiveness and baseline factors associated to fingolimod response in a real world study on multiple sclerosis patients. AB - BACKGROUND: Treatment choice in multiple sclerosis (MS) is crucial for optimizing risk-benefit profile. OBJECTIVE: To assess fingolimod (FTY) effectiveness and identify baseline features associated to disease activity in a large Italian cohort of Relapsing-Remitting (RR) MS patients. METHODS: Three-hundred sixty seven RRMS patients starting FTY treatment at San Raffaele Hospital (Milan-Italy) underwent clinical and MRI evaluations for 2 years. Treatment response was assessed considering the proportion of patients with no evidence of disease activity (NEDA) and recording the time to first relapse. Primary analyses were performed stratifying for Natalizumab (NTZ) treatment in the year before (NO_NTZ vs NTZ group), to account for post-NTZ reactivation. RESULTS: Almost half of patients were NEDA after 2 years, 53.4% in the NO_NTZ group and 36.2% in the NTZ group. Despite an opposite trend during the first 6-12 months, at 2-year follow up the two groups were comparable for relapses and number of new/enlarging T2 and Gd-enhancing lesions. Baseline parameters of higher disease activity (ARR, Gd enhancing lesions and age at onset) were associated with increased likelihood of failing NEDA criteria or with shorter time to relapse (p < 0.05). CONCLUSIONS: Our data strengthen FTY effectiveness in everyday clinical practice, even in patients switching from NTZ treatment. Baseline parameters of inflammatory activity are the most important prognostic factors for mid-term disease reactivation also during second-line treatment with FTY, providing hints on how to select therapies towards a more personalized management. PMID- 29435644 TI - Innovative real CSF leak simulation model for rhinology training: human cadaveric design. AB - OBJECTIVE: To study the feasibility of designing a human cadaveric simulation model of real CSF leak for rhinology training. METHOD: The laboratory investigation took place at the surgical academic center of Prince Sultan Military Medical City between 2016 and 2017. Five heads of human cadaveric specimens were cannulated into the intradural space through two frontal bone holes. Fluorescein-dyed fluid was injected intracranialy, then endoscopic endonasal iatrogenic skull base defect was created with observation of fluid leak, followed by skull base reconstruction. The outcome measures included subjective assessment of integrity of the design, the ability of creating real CSF leak in multiple site of skull base and the possibility of watertight closure by various surgical techniques. RESULTS: The fluid filled the intradural space in all specimens without spontaneous leak from skull base or extra sinus areas. Successfully, we demonstrated fluid leak from all areas after iatrogenic defect in the cribriform plate, fovea ethmoidalis, planum sphenoidale sellar and clival regions. Watertight closure was achieved in all defects using different reconstruction techniques (overly, underlay and gasket seal closure). CONCLUSION: The design is simulating the real patient with CSF leak. It has potential in the learning process of acquiring and maintaining the surgical skills of skull base reconstruction before direct involvement of the patient. This model needs further evaluation and competence measurement as training tools in rhinology training. PMID- 29435645 TI - Congruence between PM H+-ATPase and NADPH oxidase during root growth: a necessary probability. AB - Plasma membrane (PM) H+-ATPase and NADPH oxidase (NOX) are two key enzymes responsible for cell wall relaxation during elongation growth through apoplastic acidification and production of OH radical via O2-, respectively. Our experiments revealed a putative feed-forward loop between these enzymes in growing roots of Vigna radiata (L.) Wilczek seedlings. Thus, NOX activity was found to be dependent on proton gradient generated across PM by H+-ATPase as evident from pharmacological experiments using carbonyl cyanide m-chlorophenylhydrazone (CCCP; protonophore) and sodium ortho-vanadate (PM H+-ATPase inhibitor). Conversely, H+ ATPase activity retarded in response to different ROS scavengers [CuCl2, N, N' dimethylthiourea (DMTU) and catalase] and NOX inhibitors [ZnCl2 and diphenyleneiodonium (DPI)], while H2O2 promoted PM H+-ATPase activity at lower concentrations. Repressing effects of Ca+2 antagonists (La+3 and EGTA) on the activity of both the enzymes indicate its possible mediation. Since, unlike animal NOX, the plant versions do not possess proton channel activity, harmonized functioning of PM H+-ATPase and NOX appears to be justified. Plasma membrane NADPH oxidase and H+-ATPase are functionally synchronized and they work cooperatively to maintain the membrane electrical balance while mediating plant cell growth through wall relaxation. PMID- 29435646 TI - Can nitrocobalamin be reduced by ascorbic acid to nitroxylcobalamin? Some surprising mechanistic findings. AB - Despite detailed studies on nitroxylcobalamin (CblNO) formation, the possible intracellular generation of CblNO via reduction of nitrocobalamin (CblNO2) remains questionable. To study this further, spectroscopic studies on the reaction of CblNO2 with the intracellular antioxidant ascorbic acid (HAsc-) were performed in aqueous solution at pH < 5.0. It was found that nitroxylcobalamin is the final product of this interaction, which is not just a simple reaction but a rather complex chemical process. We clearly show that an excess of nitrite suppresses the formation of CblNO, from which it follows that ascorbic acid cannot reduce coordinated nitrite. We propose that under the influence of ascorbic acid, nitrocobalamin is reduced to Cbl(II) and nitric oxide (.NO), which can subsequently react rapidly to form CblNO. It was further shown that this system requires anaerobic conditions as a result of the rapid oxidation of both Cbl(II) and CblNO. PMID- 29435648 TI - Interleukin 6 and complement serum level study in Parkinson's disease. AB - The objective of this study is to assess whether elevation of serum inflammatory markers levels may indicate the progression of clinical impairment in Parkinson's disease (PD) patients. In 47 PD patients, the serum levels of the C3 and C4 part of the complement and Interleukin-6 (IL-6) were measured. The results at baseline and after 2 years were correlated with scales measuring memory, depression, motor symptoms, and quality of life. Patients with higher levels of C3 and C4 at baseline had decreased quality of life, verbal ability, and memory. Patients with higher IL-6 at baseline showed worse depression scores at 2 years. Patients with persistently higher levels of C3 and C4 at 2 years had worse quality of life and memory ability. Uncorrected p values are reported due to the exploratory nature of the study. The results indicate an impact of inflammation on non-motor signs and quality of life in PD. The increase of levels of serum inflammatory biomarkers may indicate the progression of non-motor impairment in PD. PMID- 29435647 TI - The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease. AB - NEET proteins comprise a new class of [2Fe-2S] cluster proteins. In human, three genes encode for NEET proteins: cisd1 encodes mitoNEET (mNT), cisd2 encodes the Nutrient-deprivation autophagy factor-1 (NAF-1) and cisd3 encodes MiNT (Miner2). These recently discovered proteins play key roles in many processes related to normal metabolism and disease. Indeed, NEET proteins are involved in iron, Fe-S, and reactive oxygen homeostasis in cells and play an important role in regulating apoptosis and autophagy. mNT and NAF-1 are homodimeric and reside on the outer mitochondrial membrane. NAF-1 also resides in the membranes of the ER associated mitochondrial membranes (MAM) and the ER. MiNT is a monomer with distinct asymmetry in the molecular surfaces surrounding the clusters. Unlike its paralogs mNT and NAF-1, it resides within the mitochondria. NAF-1 and mNT share similar backbone folds to the plant homodimeric NEET protein (At-NEET), while MiNT's backbone fold resembles a bacterial MiNT protein. Despite the variation of amino acid composition among these proteins, all NEET proteins retained their unique CDGSH domain harboring their unique 3Cys:1His [2Fe-2S] cluster coordination through evolution. The coordinating exposed His was shown to convey the lability to the NEET proteins' [2Fe-2S] clusters. In this minireview, we discuss the NEET fold and its structural elements. Special attention is given to the unique lability of the NEETs' [2Fe-2S] cluster and the implication of the latter to the NEET proteins' cellular and systemic function in health and disease. PMID- 29435649 TI - Genome sequence and description of Haloferax massiliense sp. nov., a new halophilic archaeon isolated from the human gut. AB - By applying the culturomics concept and using culture conditions containing a high salt concentration, we herein isolated the first known halophilic archaeon colonizing the human gut. Here we described its phenotypic and biochemical characterization as well as its genome annotation. Strain Arc-HrT (= CSUR P0974 = CECT 9307) was mesophile and grew optimally at 37 degrees C and pH 7. Strain Arc HrT was also extremely halophilic with an optimal growth observed at 15% NaCl. It showed gram-negative cocci, was strictly aerobic, non-motile and non-spore forming, and exhibited catalase and oxidase activities. The 4,015,175 bp long genome exhibits a G + C% content of 65.36% and contains 3911 protein-coding and 64 predicted RNA genes. PCR-amplified 16S rRNA gene of strain Arc-HrT yielded a 99.2% sequence similarity with Haloferax prahovense, the phylogenetically closest validly published species in the Haloferax genus. The DDH was of 50.70 +/- 5.2% with H. prahovense, 53.70 +/- 2.69% with H. volcanii, 50.90 +/- 2.64% with H. alexandrinus, 52.90 +/- 2.67% with H. gibbonsii and 54.30 +/- 2.70% with H. lucentense. The data herein represented confirm strain Arc-HrT as a unique species and consequently we propose its classification as representative of a novel species belonging to the genus Haloferax, as Haloferax massiliense sp. nov. PMID- 29435650 TI - Targeted knock-in of CreER T2 in zebrafish using CRISPR/Cas9. AB - New genome-editing approaches, such as the CRISPR/Cas system, have opened up great opportunities to insert or delete genes at targeted loci and have revolutionized genetics in model organisms like the zebrafish. The Cre-loxp recombination system is widely used to activate or inactivate genes with high spatial and temporal specificity. Using a CRISPR/Cas9-mediated knock-in strategy, we inserted a zebrafish codon-optimized CreER T2 transgene at the otx2 gene locus to generate a conditional Cre-driver line. We chose otx2 as it is a patterning gene of the anterior neural plate that is expressed during early development. By knocking in CreER T2 upstream of the endogenous ATG of otx2, we utilized this gene's native promoter and enhancer elements to perfectly match CreER T2 and endogenous otx2 expression patterns. Next, by combining this novel driver line with a Cre-dependent reporter line, we show that only in the presence of tamoxifen can efficient Cre-loxp-mediated recombination be achieved in the anterior neural plate-derived tissues like the telencephalon, the eye and the optic tectum. Our results imply that the otx2:CreER T2 transgenic fish will be a valuable tool for lineage tracing and conditional mutant studies in larval and adult zebrafish. PMID- 29435651 TI - The neutrophil: one cell on many missions or many cells with different agendas? AB - The unique role of neutrophils in host defense is not only based on their abilities to kill bacteria but is also due to their abundance in circulation and their ability to quickly migrate and accumulate in great numbers at afflicted sites. The high number of circulating neutrophils is the result of regulated release of new neutrophils from bone marrow as well as from marginated pools to balance their recruitment to tissue. Marginated pools, such as the spleen and lung, have previously been attributed to passively delay neutrophil transit time due to their large capillary network, but recent reports demonstrate that they are comprised of neutrophils with specific functions. The spleen, for instance, holds neutrophil subpopulations at different anatomical locations with distinct functions important for, e.g., bacterial eradication, and the lung was recently shown to re-educate neutrophils that had trafficked from a site of sterile injury to home back to bone marrow for elimination. Further, recent reports demonstrate subpopulations of neutrophils with different actions during homeostasis, infection, tissue restitution and cancer. It is becoming increasingly clear that this cannot be due to different stages of neutrophil activation during their life span but instead points towards distinct subpopulations of neutrophils with different effector functions. Whether these cellular distinctions are due to different education or origin is, however, not yet known. Together, the accumulating information about the heterogeneous neutrophils presents important insights into their role in development of pathologies, as well as revealing novel targets in the form of certain subpopulations to treat disease. PMID- 29435652 TI - Feasibility and outcome of stand-alone trans-articular screw fixation in atlantoaxial instability in children less than 8 years of age. AB - PURPOSE: To study the feasibility and outcome of stand-alone trans-articular screw (TAS) fixation for atlantoaxial instability (AAI) in children less than 8 years of age. METHODS: This prospective study was conducted between 2009 and 2014. Thirteen children suffering from AAI were operated for a TAS fixation. Feasibility of TAS fixation was assessed on CT scan and a screw diameter was chosen based on C2 isthmus diameter. Demographic data collected included the etiology for AAI, age, and sex. Intra-operative data recorded was the duration of surgery, blood loss, vertebral artery injury or any adverse event. Radiological evaluation included pre- and post-operative atlantodens interval (ADI) and space available for cord (SAC) and fusion was evaluated at 3, 6, 12 and 24 months. Statistical analysis was done using SPSS software and statistical significance was set at p < 0.05. RESULTS: The mean age of the final study group was 6.1 +/- 1.5 years, with nine males and four females. Mean isthmus diameter on the left and right side was 3.3 +/- 0.3 and 3.2 +/- 0.2 mm, respectively. Five patients had an isthmus diameter of < 3.2 mm and a 2.7 mm Herbert screw was used in them and in nine patients, a CCS of 3.2 mm was used. Mean pre- and post-op ADI and SAC improved from 5.5 +/- 0.8 to 3.1 +/- 0.1 mm, respectively, and 9.8 +/- 2.8 to 14 +/- 0.6 mm, respectively. Fusion was seen in all patients. CONCLUSIONS: Stand alone TAS with morselized allograft is safe, feasible and successful in managing AAI in children below 8 years of age. These slides can be retrieved under Electronic Supplementary Material. PMID- 29435653 TI - Epidemiological trends in spine surgery over 10 years in a multicenter database. AB - PURPOSE: There are few epidemiological studies of spinal surgery in Asia and none in Japan. The goal of this study was to review spine surgeries performed in our group between 2004 and 2015 in a cross-sectional study, with a focus on the effects of the superaging society on the characteristics and trends of spinal surgeries. METHODS: A retrospective review was performed for all 45,831 spinal surgeries conducted between 2004 and 2015 and recorded in our prospective multicenter database. RESULTS: During the study period, there was a significant increase in annual spine surgeries (p < 0.05). The proportion of elderly patients (aged >= 70) also increased, and the mean age at the time of surgery significantly increased from 54.6 years in 2004 to 63.7 years in 2015 (p < 0.05). Regarding the etiology, there were significant increases in degenerative disease (p < 0.01) and osteoporotic vertebral fracture, and a significant decrease in rheumatic spondylosis from 2004 to 2015 (p < 0.01). Instrumentation surgery increased over time, with the performance of MIS, BKP and LLIF as new procedures in recent years (p < 0.01). The mean reoperation rate was 2.0% and this rate did not change significantly over time, although the rate of reoperation due to surgical site infection significantly increased from 0.9 to 1.5% (p < 0.05). CONCLUSIONS: Our data showed marked increases in the number of spine surgeries, the age of patients, and the number of surgeries for degenerative diseases. This large-scale study provides indicators for planning the future development of spine surgery and for treatment of spinal diseases in daily practice. These slides can be retrieved under Electronic Supplementary Material. PMID- 29435654 TI - Standardised assessment of functioning in ADHD: consensus on the ICF Core Sets for ADHD. AB - Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairments in social, educational, and occupational functioning, as well as specific strengths. Currently, there is no internationally accepted standard to assess the functioning of individuals with ADHD. WHO's International Classification of Functioning, Disability and Health-child and youth version (ICF) can serve as a conceptual basis for such a standard. The objective of this study is to develop a comprehensive, a common brief, and three age-appropriate brief ICF Core Sets for ADHD. Using a standardised methodology, four international preparatory studies generated 132 second-level ICF candidate categories that served as the basis for developing ADHD Core Sets. Using these categories and following an iterative consensus process, 20 ADHD experts from nine professional disciplines and representing all six WHO regions selected the most relevant categories to constitute the ADHD Core Sets. The consensus process resulted in 72 second-level ICF categories forming the comprehensive ICF Core Set these represented 8 body functions, 35 activities and participation, and 29 environmental categories. A Common Brief Core Set that included 38 categories was also defined. Age-specific brief Core Sets included a 47 category preschool version for 0-5 years old, a 55 category school-age version for 6-16 years old, and a 52 category version for older adolescents and adults 17 years old and above. The ICF Core Sets for ADHD mark a milestone toward an internationally standardised functional assessment of ADHD across the lifespan, and across educational, administrative, clinical, and research settings. PMID- 29435655 TI - Intra-abdominal and intra-pelvic complications following operations around the hip: causes and management-a review of the literature. AB - Although successful and well-established procedures, hip operations whether elective or trauma are coupled with a variety of complications. Among the most uncommon complications are injuries to intra-abdominal or intra-pelvic organs which could prove potentially life-threatening. While there are various reports of such injuries in the literature, we aimed to perform a systematic review in order to examine the causes and relationships between intra-abdominal and intra pelvic complications and the mechanism of injury, the pattern of presentation, identification, the course of management and outcomes. We identified 69 reports describing a total of 84 complications in intra-pelvic and intra-abdominal contents in 75 patients. These involved six major categories, including the intestinal tract, the urinary tract, the genital tract, the vascular system, the viscera and peripheral nerves. The most commonly injured system was the urinary (33.33%), followed by the vascular (29.76%) and the intestinal (22.62%). Among these systems, the most prevalent complications involved injury to the urinary bladder (32.14%), the large intestine (68.42%) and the external iliac artery (44%). The majority of recorded complications were postoperative with 71 incidents in 63 cases (84.52%). In intra-operative complications the most prevalent injury was due to hardware penetration (53.85%), while in postoperative it was due to hardware migration (92.06%). The management of injuries varied widely, with the most common approach being open exploration and direct repair (77.33%). The reported management outcomes included death (8%) and Girdlestone resection (2.67%), while the majority of the patients healed uneventfully (82.67%) owing mostly to immediate intervention. Despite being rare, such complications may still occur in a variety of settings and may subsequently lead to potential life-threatening situations. Thus, in order to avoid catastrophic outcomes we emphasize the need for prompt identification, immediate intervention and a multidisciplinary approach when necessary. PMID- 29435656 TI - [Management of inappropriate shocks/T-wave-oversensing in S-ICD(r)-patients]. AB - Inappropriate shocks are a feared complication after implantable cardioverter defibrillator (ICD) implantation and have a tremendous impact on quality of life. Inappropriate shocks in patients with subcutaneous ICD (S-ICD(r), Boston Scientific, Marlborough, MA, USA) have various underlying causes. This review summarizes the current literature on this topic and lists possible treatment options. PMID- 29435657 TI - Increased incidence of preeclampsia in mothers of advanced age conceiving by oocyte donation. AB - PURPOSE: The aim of this study was to evaluate the risk of preeclampsia in women of advanced age who conceived through donated oocytes as compared with natural conceptions. METHODS: A historical prospective study of singleton live births of parturients >= 45 years of age at four university hospitals was conducted. For the purpose of the study, the population was divided by the mode of conception into two groups: oocyte donation and natural conception. The main outcome variable in this study was preeclampsia. Secondary outcomes included pregnancy induced hypertension and Small for Gestational Age. RESULTS: Two hundred and seventy pregnancies were achieved naturally and 135 women conceived by oocyte donation. Mean age at delivery for the natural conception and oocyte donation groups was 45.7 and 47.8, respectively. Preeclampsia complicated 3 out of 270 (1.1%) natural conception pregnancies and 17 out of 135 (12.6%) oocyte donation conceptions. After adjusting for confounders, oocyte donation pregnancies were found to be associated with a 12-fold increased risk for preeclampsia (P = 0.001). Among oocyte donation pregnancies, the risk of preeclampsia was not affected by parity or age. CONCLUSIONS: A substantially increased risk for preeclampsia was found in oocyte donation pregnancies, suggesting that the foreign oocyte may play a specific biologic role in the development of preeclampsia after the age of 45. PMID- 29435658 TI - Correction to: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management. AB - The following information was inadvertently omitted in the original publication. PMID- 29435659 TI - Teenagers and young adults with nephropathic cystinosis display significant bone disease and cortical impairment. AB - BACKGROUND: Bone impairment appears to be a novel complication of nephropathic cystinosis despite cysteamine therapy. Its exact underlying pathophysiology is nevertheless unclear. The objective of this study was to evaluate bone status among patients included in the French Crystobs study. METHODS: In addition to clinical data, bone status was evaluated using biomarkers (ALP, PTH, 25-D, 1-25D, FGF23), DXA (spine and total body), and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the tibia and radius. Results were compared to age- and gender-matched healthy controls (1:2 basis) from the local reference cohorts. RESULTS: At a median age of 22.5 (10.2-34.6) years, 10 patients with nephropathic cystinosis were included (2 receiving conservative therapies, 2 undergoing hemodialysis, 6 with a past of renal transplantation); 7 out of 10 patients complained of a bone symptom (past of fracture, bone deformations, and/or bone pain). Biochemicals and spine DXA did not show any significant abnormalities. Using HR-pQCT, significant decreases in cortical parameters (e.g., cortical thickness 850 (520-1100) versus 1225 (480-1680) MUm; p < 0.05) and total volumetric bone mineral density (290 (233-360) versus 323 (232-406) mg/cm3; p < 0.05) were observed in cystinotic patients in comparison to controls at the tibia. There were no differences for trabecular parameters. Similar results were observed at the radius. CONCLUSIONS: In this pilot study, bone impairment (rather cortical than trabecular) is a significant clinical problem in nephropathic cystinosis; 70% of patients displayed significant bone symptoms, during teenage or young adulthood. This new complication should be known by physicians because of its potential dramatic impact on quality of life. PMID- 29435660 TI - Indications for total esophagogastric dissociation in children with gastroesophageal reflux disease. AB - Total esophagogastric dissociation (TED) is used to treat gastroesophageal reflux (GER) after failed fundoplication in neurologically impaired patients. It is now performed for some otherwise healthy patients with severe GER. In this procedure, the gastrointestinal tract is reconstructed in a non-physiological way with a Roux-en-Y esophagojejunal anastomosis and jejuno-jejunostomy. Although TED eliminates almost all GER, some patients experience late complications. In this review, we investigated the long-term outcomes after TED to determine the best indications. In total, 147 neurologically impaired patients and 28 neurologically normal patients were identified. The total rate of complications requiring re operation was 17.2% in neurologically impaired patients and 32.1% in normal patients, both higher than the rates associated with fundoplication. Although most authors added pyloroplasty when there was a concern of gastric emptying, this sometimes caused bile reflux. Nutritional and metabolic complications, including dumping syndrome and chronic digestive malabsorption, were also reported to occur after TED. TED is an option for the treatment of neurologically impaired patients with recurrent GER after fundoplication or who are at a high risk of recurrence of GER with fundoplication. However, neurologically normal patients who have the ability to obtain nutrition orally should consider options other than TED, as postoperative complications are frequent. PMID- 29435661 TI - Short-Term Effects of Cold Liquids on the Pharyngeal Swallow in Preterm Infants with Dysphagia: A Pilot Study. AB - Cold stimulation reduces airway compromise in adults with dysphagia. However, there is no sufficient evidence to support its use in the pediatric population. The primary goal of this pilot study is to assess the effect of cold liquid on the pharyngeal swallow mechanism in preterm infants with dysphagia. We hypothesized that thermal stimulation from cold liquid will decrease the risk of airway compromise in dysphagic preterm infants. Nine preterm infants with clinical symptoms of dysphagia were included. Video fluoroscopic swallow studies were used to assess the swallowing mechanism of each participant. The occurrence of swallow dysfunctions under room temperature liquid swallows (RTS) vs. short period cold liquid swallows (CS) was compared. Paired t test was used to test significance. The occurrence of deep penetration (p = 0.007) and aspiration (p = 0.002) decreased significantly in the CS condition compared with the RTS condition. There was a trend of less nasopharyngeal reflux with CS but did not reach statistical significance (p = 0.084). No differences were noted for mild penetration (p = 0.824). CS reduced airway compromise in dysphagic preterm infants compared to RTS. These data provide important information regarding the immediate effects of CS on pharyngeal swallowing in preterm infants with dysphagia. However, further investigation regarding its sustained effects is required before introducing to clinical practice. PMID- 29435662 TI - Novel evaluation method of dentin repair by direct pulp capping using high resolution micro-computed tomography. AB - OBJECTIVES: We evaluated a novel micro-computed tomography (micro-CT) assessment for quality and quantity of dentin repair, which is difficult to visualize by histological analysis, after direct pulp capping under standardized cavity preparation. MATERIALS AND METHODS: Standardized cavities were prepared on Wistar rats and direct pulp capping was performed using two commercial bioceramics, ProRoot MTA, and iRoot BP Plus. After 2 or 4 weeks, quality and quantity of tertiary dentin formation were evaluated using high-resolution micro-CT analyses including dentin mineral density, dentin mineral contents, compactness and integrity of tertiary dentin, and dentin volume with/without void space. Reproducibility of micro-CT analyses was confirmed by histological evaluation of the same specimen. RESULTS: The exposed pulp area sizes were similar between iRoot BP Plus and ProRoot MTA. Micro-CT analysis of 2-week samples showing compactness of tertiary dentin was significantly higher in iRoot BP Plus than ProRoot MTA (p < 0.05). Tertiary dentin volume without void space, dentin mineral contents, and density were not significantly different between the groups. In 4 week samples, a significant increase was observed in dentin mineral density, compactness, and dentin volume with/without void space induced by iRoot BP Plus (p < 0.05). Micro-CT analysis of tertiary dentin integrity demonstrated that some ProRoot MTA specimens had small defects and lacked continuity (6/512 images). No defects were observed with iRoot BP Plus. CONCLUSIONS: Micro-CT analysis was confirmed as an accurate, objective, and inclusive approach for evaluating quality and quantity of dentin repair. CLINICAL RELEVANCE: These multifaceted approaches to evaluate pulp capping materials may accelerate review processes, ultimately improving vital pulp therapy. PMID- 29435663 TI - Research interactions between academia and food companies: how to improve transparency and credibility of an inevitable liaison. PMID- 29435664 TI - Deep sequencing of WNT-activated medulloblastomas reveals secondary SHH pathway activation. PMID- 29435665 TI - Coronary Artery Calcium Scoring in Young Adults: Evidence and Challenges. AB - PURPOSE OF REVIEW: This review aims to summarize the evidence and challenges of coronary artery calcium (CAC) scoring as a screening tool for coronary artery disease (CAD) in young adults. RECENT FINDINGS: Several cohort studies have highlighted the value of CAC scoring in CAD risk assessment in young adults. The largest study to date is the Coronary Artery Risk Development in Young Adults (CARDIA) study. The study examined patients at 18-30 years of age and demonstrated that the presence of any degree of CAC was associated with a higher risk of coronary events compared to zero CAC, with an incremental increase in the risk of events with higher scores. However, it is important to note that 70% of patients screened had CAC = 0 at the age of 56. Despite the evidence that higher CAC score cutoff used in guidelines for predicting cardiovascular risk may be "falsely reassuring," however, mass screening of young adults using CAC score may be challenging. The development of prediction tools and scoring systems to identify patients at higher risk of developing CAC based on known CAD risk factors may help reduce the number needed to screen to detect patients with positive CAC. PMID- 29435666 TI - Pregnancy- Associated Changes in Pharmacokinetics and their Clinical Implications. AB - PURPOSE: To critically review pregnancy-induced pharmacokinetic changes and their clinical application. METHODS: Structured review of Pubmed, MBASE and published books. RESULTS: For many drugs, advanced pregnancy is associated with lower maternal serum concentrations. As most drug concentrations are not measured routinely, such changes are not evident to the clinician. Moreover, even for drug concentrations measured clinically, one cannot interpret lower total drug levels as evidence of lower fraction of free drug, which is the pharmacologically- active component, due to lower protein binding of many drugs in late pregnancy. Higher fractions of free drug will lead to higher rate of hepatic metabolism, especially for high extraction medications, leading to lower total drug concentrations.. Pregnancy- induced larger volume of distribution will lead to lower peak of drugs and hence may impact the achievement therapeutic levels. To further complicate matters, the adherence of many women decreases during pregnancy, mostly due to fears of adverse fetal effects. These dynamic and complex processes make changes in recommendations for dose schedule very challenging and in many cases not practical. CONCLUSIONS: Indeed, there are presently no pregnancy- targeted dose schedules, similar to existing dose changes, for example, in renal failure. Similar to the recent increased attention given to pharmacokinetic changes in pregnancy, well designed studies should compare dose-effect relationships in women receiving medications in different stages of pregnancy, to women receiving the same drug before, and/or after pregnancy. Whenever possible, women with chronic conditions can serve as their own controls and decrease the uncertainty created by inter- patient variability. Measuring drug effects in parallel to drug concentrations, will allow pharmacokinetic- pharmacodynamic modelling, leading to evidence-based decisions regarding changes in dose schedules during gestation. PMID- 29435667 TI - Wien effect of Cd/Zn on soil clay fraction and their interaction. AB - BACKGROUND: The coexistence of Cd2+ and Zn2+ ions in nature has a significant influence on their environmental behaviors in soils and bioavailability for plants. While many studies have been done on the mutual toxicity of Cd2+ and Zn2+, few studies can be found in the literature focused on the interaction of Cd2+ and Zn2+ on soil clay fractions especially in terms of energy relationship. RESULTS: The binding energies of Cd2+ on boggy soil (Histosols) particles and Zn2+ on yellow brown soil (Haplic Luvisols) particles were the highest, while those of Cd2+ and Zn2+ on paddy soil (Inceptisols) particles were the lowest. These results indicated that Cd2+ and Zn2+ have a strong capacity to adsorb in the solid phase at the soil-water interface of boggy soil and yellow brown soil, respectively. However, both Cd2+ and Zn2+ adsorbed on paddy soil particles easily release into the solution of the soil suspension. Unlike the binding energy, the higher adsorption energies of ions in boggy and yellow brown soils showed a weak binding force of ions in boggy soil and yellow brown soil. A 1:1 ratio of Cd2+ to Zn2+ promotes the mutual inhibition of their retentions. Cd2+ and Zn2+ have high mobility and bioavailability in paddy soil and yellow drab soil (Ustalfs), whereas they have high potential mobility and bioavailability in boggy soil and yellow brown soil. CONCLUSION: In the combined system, Zn2+ had preferential adsorption than Cd2+ on soil clay fractions. Boggy soil and yellow brown soil have a low environmental risk with lower mobility and bioavailability of Cd2+ and Zn2+ while paddy soil and yellow drab soil present a substantial environmental risk. In the combined system, Cd2+ and Zn2+ restrain each other, resulting in the weaker binding force between ions and soil particles at a 1:1 ratio of Cd2+-Zn2+. PMID- 29435668 TI - Theoretical insights into aggregation-induced helicity modulation of a perylene bisimide derivative. AB - Formation of helical chiroptical self-assemblies via noncovalent interaction is a widely observed phenomenon in nature, the mechanism of which remains insufficiently understood. Employing an amphiphilic perylene-sugar dyad molecule (PBI-HAG) as an example, we report that the modulatable supramolecular helicity may emerge from an aggregating process that is dominated by competition between two types of noncovalent interaction: hydrogen bonding and pi-pi stacking. The interplay between these two driving forces, which is greatly affected by the solvent environment, determines the morphology the supramolecular assembly of PBI HAGs. In particular, a non-layered supramolecular structure was formed in octane owing to stabilization effects of intermolecular hydrogen bonds, whereas a layered supramolecular structure was formed in water because of energetically favorable pi-pi stacking of aromatic rings. The formation of distinct supramolecular architectures in different solvents was reinforced by simulated circular dichroism spectra, which show opposite signals consistent with experimental observations. The results of this study could help us understand aggregation-induced supramolecular chirality of noncovalent self-assemblies. Graphical abstract Left Typical structures of amphiphilic perylene-sugar dyad (PBI-HAG) aggregates in different octane and water. Right Simulated CD and UV-Vis spectra of core PBIs aggregates in octane and water. PMID- 29435669 TI - Assessment of Simple Models for Molecular Simulation of Ethylene Carbonate and Propylene Carbonate as Solvents for Electrolyte Solutions. AB - Progress in understanding liquid ethylene carbonate (EC) and propylene carbonate (PC) on the basis of molecular simulation, emphasizing simple models of interatomic forces, is reviewed. Results on the bulk liquids are examined from the perspective of anticipated applications to materials for electrical energy storage devices. Preliminary results on electrochemical double-layer capacitors based on carbon nanotube forests and on model solid-electrolyte interphase (SEI) layers of lithium ion batteries are considered as examples. The basic results discussed suggest that an empirically parameterized, non-polarizable force field can reproduce experimental structural, thermodynamic, and dielectric properties of EC and PC liquids with acceptable accuracy. More sophisticated force fields might include molecular polarizability and Buckingham-model description of inter atomic overlap repulsions as extensions to Lennard-Jones models of van der Waals interactions. Simple approaches should be similarly successful also for applications to organic molecular ions in EC/PC solutions, but the important case of Li[Formula: see text] deserves special attention because of the particularly strong interactions of that small ion with neighboring solvent molecules. To treat the Li[Formula: see text] ions in liquid EC/PC solutions, we identify interaction models defined by empirically scaled partial charges for ion-solvent interactions. The empirical adjustments use more basic inputs, electronic structure calculations and ab initio molecular dynamics simulations, and also experimental results on Li[Formula: see text] thermodynamics and transport in EC/PC solutions. Application of such models to the mechanism of Li[Formula: see text] transport in glassy SEI models emphasizes the advantage of long time-scale molecular dynamics studies of these non-equilibrium materials. PMID- 29435670 TI - Diagnostic accuracy of a new fluoroenzyme immunoassay for the detection of TSH receptor autoantibodies in Graves' disease. AB - PURPOSE: Thyrotropin receptor (TSHR) autoantibodies (TRAbs) are a hallmark of Graves' disease (GD). The aim of this study was to evaluate the diagnostic accuracy of a new third generation automatic fluorescence enzyme immunoassay for TRAb measurement in GD, in comparison with two current IMAs. METHODS: Sera of 439 subjects (57 patients with untreated GD, 34 with treated GD, 15 with GD and Graves' orbitopathy, 52 with multinodular non-toxic goiter, 86 with Hashimoto's thyroiditis, 20 with toxic adenoma or toxic multinodular goiter, 55 with non thyroid autoimmune diseases and 120 normal controls) were tested for TRAbs with the ELiATM anti-TSH-R assay (ThermoFischer Scientific, Uppsala, Sweden), the TRAKTM RIA, Brahms (Thermo Scientific, Hennigsdorf, Germany) and the ImmuliteTM TSI assay (Siemens Healthcare, Llanberis, UK). RESULTS: Sensitivity and specificity of the ELiATM anti-TSH-R assay, TRAKTM RIA and ImmuliteTM TSI assay were 94.7% and 99.6, 100 and 98.2%, 100 and 98.2%, respectively. Spearman's coefficient and Passing-Bablok regression showed a satisfactory correlation between EliATM and TRAKTM [rho: 0.925; 95% CI: 0.883-0-953. Intercept: - 0.875 (95% CI: - 2.411 to 0.194); slope: 1.086 (95% CI: 0.941 to 1.248)], and between ELiATM and TSITM [rho: 0.947; 95% CI: 0.912 0.969. intercept: 1.085 (95% CI: 0.665 to 2.116); slope 1.315 (95% CI:1.116 to 1.700)]. CONCLUSIONS: The diagnostic performance of ELiATM-TSH-R assay is comparable to that of some current TRAb assays. It may be adopted into clinical practice for the differential diagnosis of hyperthyroidism, to screen for transient hyperthyroidism, and to monitor disease activity and treatment effects. PMID- 29435671 TI - A new SPECT/CT reconstruction algorithm: reliability and accuracy in clinical routine for non-oncologic bone diseases. AB - BACKGROUND: xSPECT Bone(r) (xB) is a new reconstruction algorithm developed by Siemens(r) in bone hybrid imaging (SPECT/CT). A CT-based tissue segmentation is incorporated into SPECT reconstruction to provide SPECT images with bone anatomy appearance. The objectives of this study were to assess xB/CT reconstruction diagnostic reliability and accuracy in comparison with Flash 3D(r) (F3D)/CT in clinical routine. Two hundred thirteen consecutive patients referred to the Brest Nuclear Medicine Department for non-oncological bone diseases were evaluated retrospectively. Two hundred seven SPECT/CT were included. All SPECT/CT were independently interpreted by two nuclear medicine physicians (a junior and a senior expert) with xB/CT then with F3D/CT three months later. Inter-observer agreement (IOA) and diagnostic confidence were determined using McNemar test, and unweighted Kappa coefficient. The study objectives were then re-assessed for validation through > 18 months of clinical and paraclinical follow-up. RESULTS: No statistically significant differences between IOA xB and IOA F3D were found (p = 0.532). Agreement for xB after categorical classification of the diagnoses was high (kappa xB = 0.89 [95% CI 0.84 -0.93]) but without statistically significant difference F3D (kappa F3D = 0.90 [95% CI 0.86 - 0.94]). Thirty-one (14.9%) inter reconstruction diagnostic discrepancies were observed of which 21 (10.1%) were classified as major. The follow-up confirmed the diagnosis of F3D in 10 cases, xB in 6 cases and was non-contributory in 5 cases. CONCLUSIONS: xB reconstruction algorithm was found reliable, providing high interobserver agreement and similar diagnostic confidence to F3D reconstruction in clinical routine. PMID- 29435672 TI - TEM and STEM Studies on the Cross-sectional Morphologies of Dual-/Tri-layer Broadband SiO2 Antireflective Films. AB - Dual-layer and tri-layer broadband antireflective (AR) films with excellent transmittance were successfully fabricated using base-/acid-catalyzed mixed sols and propylene oxide (PO) modified silica sols. The sols and films were characterized by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), transmission electron microscope (TEM), and scanning transmission electron microscope (STEM). FTIR and TEM results suggest that the PO molecules were covalently bonded to the silica particles and the bridge structure existing in PO modified silica sol is responsible for the low density of the top layer. The density ratio between different layers was measured by cross-sectional STEM, and the results are 1.69:1 and 2.1:1.7:1 from bottom-layer to top-layer for dual-layer and tri-layer films, respectively. The dual-layer film demonstrates good stability with 99.8% at the central wavelength of 351 nm and nearly 99.5% at the central wavelength of 1053 nm in laser system, and for the tri-layer AR film, the maximum transmittance reached nearly 100% at both the central wavelengths of 527 and 1053 nm. PMID- 29435673 TI - An eco-efficient and economical optimum evaluation technique for the forest road networks: the case of the mountainous forest of Metsovo, Greece. AB - The sustainable forest management can be achieved only through environmentally sound and economically efficient and feasible forest road networks and transportation systems that can potentially improve the multi-functional use of forest resources. However, road network planning and construction suggest long term finance that require a capital investment (cash outflow), which would be equal to the value of the total revenue flow (cash inflow) over the whole lifecycle project. This paper emphasizes in an eco-efficient and economical optimum evaluation method for the forest road networks in the mountainous forest of Metsovo, Greece. More specifically, with the use of this technique, we evaluated the forest roads' (a) total construction costs, (b) annual maintenance cost, and (c) log skidding cost. In addition, we estimated the total economic value of forest goods and services that are lost from the forest roads' construction. Finally, we assessed the optimum eco-efficient and economical forest roads densities based on linear equations that stem from the internal rate of return method (IRR) and have been presented graphically. Data analysis and its presentation are achieved with the contribution of geographic information systems (GIS). The technique which is described in this study can be for the decision makers an attractive and useful implement in order to select the most eco friendly and economical optimum solution to plan forest road network or to evaluate the existing forest transportation systems. Hence, with the use of this method, we can combine not only the multi-objective utilization of natural resources but also the environmental protection of forest ecosystems. PMID- 29435674 TI - A novel automatic flow method with direct-injection photometric detector for determination of dissolved reactive phosphorus in wastewater and freshwater samples. AB - The novel automatic flow system, direct-injection detector (DID) integrated with multi-pumping flow system (MPFS), dedicated for the photometric determination of orthophosphates in wastewater and freshwater samples is for the first time described. All reagents and the sample were injected simultaneously, in counter current into the reaction-detection chamber by the system of specially selected for this purpose solenoid micro-pumps. The micro-pumps provided good precision and accuracy of the injected volumes. For the determination of orthophosphates, the molybdenum blue method was employed. The developed method can be used to detect orthophosphate in the range 0.1-12 mg L-1, with the repeatability (RSD) about 2.2% at 4 mg L-1 and a very high injection throughput of 120 injections h 1. It was possible to achieve a very small consumption of reagents (10 MUL of ammonium molybdate and 10 MUL of ascorbic acid) and sample (20 MUL). The volume of generated waste was only 440 MUL per analysis. The method has been successfully applied, giving a good accuracy, to determination of orthophosphates in complex matrix samples: treated wastewater, lake water and reference sample of groundwater. The developed system is compact, small in both size and weight, requires 12 V in supply voltage, which are desirable for truly portable equipment used in routine analysis. The simplicity of the system should result in its greater long-time reliability comparing to other flow methods previously described. PMID- 29435676 TI - Vortex dynamics and Lagrangian statistics in a model for active turbulence. AB - Cellular suspensions such as dense bacterial flows exhibit a turbulence-like phase under certain conditions. We study this phenomenon of "active turbulence" statistically by using numerical tools. Following Wensink et al. (Proc. Natl. Acad. Sci. U.S.A. 109, 14308 (2012)), we model active turbulence by means of a generalized Navier-Stokes equation. Two-point velocity statistics of active turbulence, both in the Eulerian and the Lagrangian frame, is explored. We characterize the scale-dependent features of two-point statistics in this system. Furthermore, we extend this statistical study with measurements of vortex dynamics in this system. Our observations suggest that the large-scale statistics of active turbulence is close to Gaussian with sub-Gaussian tails. PMID- 29435675 TI - Transfer of plant protection products from raspberry crops of Laszka and Seedling varieties to beehives. AB - Field studies were conducted to evaluate the transfer of active ingredients (AIs) of plant protection products (PPPs) to beehives. They were applied in two commodity red raspberry plantations of two varieties: Laszka (experiment 1) and Seedling (experiment 2). Samples of flowers, leaves, bees, brood, and honey were examined for the presence of chlorpyrifos, cypermethrin, difenoconazole, cyprodinil, and trifloxystrobin (experiment 1) and chlorpyrifos, boscalid, pyraclostrobin, cypermethrin, difenoconazole, and azoxystrobin (experiment 2). In experiment 1, the highest levels of trifloxystrobin were observed on the surface of flowers, (0.04 MUg/flower) and for difenoconazole on the inside (0.023 MUg/flower). Leaves contained only trace residues of cypermethrin and cyprodinil (0.001 MUg/cm2 of leaves each) and trifloxystrobin (0.01 MUg/cm2 of leaves) on the surface; inside the leaves, the highest levels of trifloxystrobin were observed (0.042 MUg/cm2 of leaves). In experiment 2, boscalid was found on the surface and inside the flowers and leaves (0.063 and 0.018 MUg/flower and 0.057 and 0.033 MUg/cm2 of leaves, respectively). In bees, brood, and honey (experiment 1), chlorpyrifos was present in the highest quantity (7.3, 1.6, and 4.7 MUg/kg, respectively). Additionally, cypermethrin and trifloxystrobin were found in bees, and trifloxystrobin was present in honey. Bees, brood, and honey from plantation 2 contained all studied AIs, with the highest levels of boscalid (28.6 MUg/kg of bees, 37.0 MUg/kg of brood, and 33.9 MUg/kg of honey, respectively). In no case did the PPP residues in honey exceed acceptable maximum residue levels (MRLs) from a formal and legal point of view, in terms of the used plant protection products, the analysed honey was fit for human consumption. PMID- 29435677 TI - Ultrasound assessment of visual loss during severe preeclampsia: a case report. AB - Bilateral retinal detachments and cortical blindness are rare complications of preeclampsia and the association of the two pathologies is exceptional. We report the case of a preeclamptic patient who presented with an acute bilateral vision loss. Besides, her ocular ultrasound revealed bilateral retinal detachments and an elevated optic nerve sheath diameter. The patient underwent an urgent cesarean section. Subsequently, magnetic resonance imaging and ocular fundus examination confirmed the diagnosis. PMID- 29435678 TI - Statistical evaluation of test-retest studies in PET brain imaging. PMID- 29435679 TI - Geospatial distribution of metal(loid)s and human health risk assessment due to intake of contaminated groundwater around an industrial hub of northern India. AB - The study focused on analyzing concentrations of metal(loid)s, their geospatial distribution in groundwater around an industrial hub of northern India. Human health risk posed due to the intake of contaminated groundwater was also evaluated. For this, 240 samples were assayed using inductively coupled plasma emission spectrophotometer. For risk assessment, the methodology proposed by US Environmental Protection Agency was adopted. Geometric mean of Al, As, Mo, Cd, Co, Cr, Fe, Mn, Ni, Pb, Se, and Zn was 193.13, 27.35, 4.22, 2.85, 92.81, 14.97, 271.78, 25.76, 54.75, 19.50, 16.94, and 1830.27 MUg/l, respectively. Levels of Al (84%), As (63%), Ni (63%), Pb (49%), and Se (41%) exceeded the Bureau of Indian Standards (BIS). Principal component analysis is accounted for ~ 88% of the total variance and reflected pollution loads of Al, As, Mo, Cr, Fe, Se, and Pb in the groundwater. Based on it, four sources of metal(loid)s, namely geogenic (34.55%), mixed (industrial and agricultural, 26.76%), waste dumping (15.31%), and industrial (11.25%) were identified. Semi-variogram mapping model demonstrated significant geospatial variations of the metal(loid)s. Hazard index (HI) suggested potential non-carcinogenic risks to the inhabitants due to As, Al, Ni, Se, and Pb, which were the largest contributors. Based on maximum concentrations of metal(loid)s, HI for child and adult was above unity. Arsenic was identified as the most hazardous pollutant that may have chronic carcinogenic health implications. At western side of study area, carcinogenic health risks exceeded critical threshold of 1 * 10-4, indicating that As posed health risks to residents by intake of groundwater. PMID- 29435680 TI - Atherogenic index of plasma: a useful marker for subclinical atherosclerosis in ankylosing spondylitis : AIP associate with cIMT in AS. AB - Ankylosing spondylitis (AS) is associated with an increased risk of atherosclerotic cardiovascular disease (ACD). The atherogenic index of plasma (AIP), which is the logarithmic transformation of the plasma triglyceride (TG) level to the high-density lipoprotein level (HDL) ratio, has been suggested to be a novel marker in the identification of atherosclerosis risk. Therefore, this study aims to determine if the AIP can act as an accurate marker for the detection of subclinical atherosclerosis. Fifty-two male patients with AS and 52 age-, gender-, and body mass index (BMI)-matched healthy control subjects were included in the study. For each patient, AIP and total cholesterol (TC)/HDL values were calculated and carotid artery intima-media thickness (cIMT) was measured. The mean (SD) cIMT and median (range) AIP values for AS patients were higher than that of the healthy control subjects (0.60 +/- 0.18 vs. 0.51 +/- 0.10, p = 0.003 and 0.23 [- 0.32 to 0.85] vs. 0.09 [- 0.53 to 0.49], p = 0.007, respectively). A positive correlation was found between the patients' cIMT and AIP values (r = 0.307, p = 0.002) and TC/HDL values (r = 0.241, p = 0.014). Regression analysis revealed an independent association between the subclinical atherosclerosis and AIP (beta [beta] = 0.309, p = 0.002). There were no independent correlations between subclinical atherosclerosis and TC (beta = 0.245, p = 0.065), TG (beta = 0.185, p = 0.515), HDL (beta = 0.198, p = 0.231), TC/HDL (beta = 0.032, p = 0.862), and low-density lipoprotein (LDL) (beta = 0.151, p = 0.246). A strong and independent correlation exists between AIP and cIMT values. Therefore, the AIP could serve as a better marker than the TC/HDL ratio for the detection of subclinical atherosclerosis in AS patients. PMID- 29435681 TI - Bio-coloration of bacterial cellulose assisted by immobilized laccase. AB - In this work a process for the bio-coloration of bacterial cellulose (BC) membranes was developed. Laccase from Myceliophthora thermophila was immobilized onto BC membranes and retained up to 88% of residual activity after immobilization. Four compounds belonging to the flavonoids family were chosen to test the in situ polymerase activity of immobilized laccase. All the flavonoids were successfully polymerized by laccase giving rise to yellow, orange and dark brown oligomers which conferred color to the BC support. The optimal bio coloration conditions were studied for two of the tested flavonoids, catechol and catechin, by varying the concentration and time of incubation. High color depth and resistance to washing were obtained for both compounds. The highly porous bacterial cellulose material demonstrated great performance as a bio-coloration support, in contrast to other materials cited in literature, like cotton or wool. The process developed is presented as an environmentally friendly alternative for bacterial cellulose bio-coloration and will contribute deeply for the development of new fashionable products within this material. PMID- 29435682 TI - Correction to: Influence of Body Odors and Gender on Perceived Genital Arousal. AB - There were 4 cells in the original Table 2 that reported SEM values instead of SDs. A corrected version of the table is provided below. In the Results section, the corresponding corrections are as follows. PMID- 29435684 TI - Recurrence-Free Survival After Resection of Gastric Gastrointestinal Stromal Tumors Classified According to a Strict Definition of Tumor Rupture: A Population Based Study. AB - BACKGROUND: In gastrointestinal stromal tumors (GISTs), rupture is a high-risk feature and an indication for adjuvant treatment; however, the independent impact of rupture on prognosis is uncertain and the term is inconsistently defined. In the present study, a previously proposed definition of 'tumor rupture' was applied on a population-based cohort of gastric GISTs. METHODS: Patients undergoing surgery for non-metastatic gastric GISTs from 2000 to 2015 were identified in the regional sarcoma database of Oslo University Hospital. Tumor rupture included spillage or fracture, piecemeal resection, incisional biopsy, blood-tinged ascites, gastric perforation, and microscopic adjacent infiltration. Minor defects of tumor integrity were not considered rupture, i.e. core needle biopsy, peritoneal tumor penetration, superficial peritoneal rupture, and R1 resection. Risk was assessed according to the modified National Institutes of Health consensus criteria. RESULTS: Among 242 patients, tumor rupture occurred in 22 patients and minor defects of tumor integrity occurred in 81 patients. Five year recurrence-free survival (RFS) for patients with tumor rupture, minor defects of tumor integrity, and no defect was 37, 91, and 96%, respectively (p < 0.001). In the high-risk group, 5 year RFS for patients with rupture was 37%, versus 77% without rupture (hazard ratio 3.56, 95% confidence interval 1.57-8.08, p = 0.001). On multivariable analysis, tumor rupture and mitotic index were independently associated with recurrence. Of 13 patients who received adjuvant imatinib after tumor rupture, 11 relapsed. CONCLUSIONS: Tumor rupture according to the present definition was independently associated with recurrence. With tumor rupture, patients relapsed despite adjuvant treatment. Without rupture, prognosis was good, even in the high-risk group. PMID- 29435685 TI - Robot-Assisted Technique for Total Gastrectomy and D2 Lymphadenectomy with Anomalous Vasculature. PMID- 29435686 TI - Dynamic changes and molecular analysis of cell death in the spinal cord of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus. AB - Theiler's murine encephalomyelitis (TME) is caused by the TME virus (TMEV) and represents an important animal model for multiple sclerosis (MS). Oligodendroglial apoptosis and reduced apoptotic elimination of encephalitogenic leukocytes seem to participate in autoimmune demyelination in MS. The present study quantified apoptotic cells in BeAn-TMEV-induced spinal cord white matter lesions at 14, 42, 98, and 196 days post infection (dpi) using immunostaining. Apoptotic cells were identified by transmission electron microscopy and double immunofluorescence. The mRNA expression of apoptosis-related genes was investigated using microarray analysis. Oligodendroglial apoptosis was already detected in the predemyelinating phase at 14 dpi. Apoptotic cell numbers peaked at 42 dpi and decreased until 196 dpi partly due to reduced T cell apoptosis. In addition to genes involved in the classical pathways of apoptosis induction, microarray analysis detected the expression of genes related to alternative mechanisms of cell death such as pyroptosis, necroptosis, and endoplasmic reticulum stress. Consequently, oligodendroglial apoptosis is involved in the initiation of the TME demyelination process, whereas the development of apoptosis resistance of T cells potentially favors the maintenance of inflammation and myelin loss. PMID- 29435687 TI - Hypertonicity primes malignant melanoma cells for apoptosis. AB - The tumor environment critically influences responsiveness of cancer cells to chemotherapies, most of which activate the mitochondria-regulated (intrinsic) apoptotic cascade to kill malignant cells. Especially skin tumors encounter an environment with remarkable biophysical properties. Cutaneous accumulation of Na+ locally establishes osmotic pressure gradients in vivo (hypertonicity or hyperosmotic stress), but whether cutaneous hypertonicity is a factor that modulates the responsiveness of skin cancers to therapeutic apoptosis-induction has thus far not been investigated. Here, we show that hyperosmotic stress lowers the threshold for apoptosis induction in malignant melanoma, the deadliest form of skin cancer. Hypertonic conditions enforce addiction to BCL-2-like proteins to prevent initiation of the mitochondria-regulated (intrinsic) apoptotic pathway. Essentially, hyperosmotic stress primes mitochondria for death. Our work identifies osmotic pressure in the tumor microenvironment as a cell extrinsic factor that modulates responsiveness of malignant melanoma cells to therapy. PMID- 29435688 TI - Cloning and expression of ferulic acid esterase gene and its effect on wort filterability. AB - OBJECTIVES: To optimize the expression of type A ferulic acid esterase (FaeA) from Aspergillus niger in Pichia pastoris X-33 using codon optimization. RESULTS: Recombinant FaeA was purified from the fermentation broth, with the maximum specific activity of 48.4 +/- 0.1 U mg-1. Adding it during mashing process for beer brewing raised the filtration rate by 14.5% while the turbidity and viscosity declined by 22 and 6.9%, respectively. Addition of FaeA increased the concentrations of free ferulic acid (FA) and arabinoxylan (AX) in the wort, while the polymeric arabinoxylans content declined significantly. CONCLUSIONS: Recombinant FaeA was capable to prevent the oxidative gelation of PAX formation by breaking the cross-linking of FA among AX chains and improve the filtration performance of wort. PMID- 29435689 TI - Correction to: Pluripotent Stem Cell-Derived Human Tissue: Platforms to Evaluate Drug Metabolism and Safety. AB - The original version of the published article contains errors throughout the text, which were introduced by the typesetter when performing the author's proof corrections. PMID- 29435690 TI - Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism and Cardiometabolic Risk Factors: A Study Among Bhil Tribal Population from Two Environmental Settings. AB - Studies have investigated the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and cardiometabolic risk factors (CMRFs), however with varying results, which could be due to ethnicity differences. Therefore, the present study was conducted among Bhil tribal population (a mendelian population with the common gene pool and same sociocultural attributes), residing in two different environmental settings. The study attempts to understand the distribution and extent of association of ACE I/D gene polymorphism with cardiometabolic risk factors among Bhils from rural and urban settings. All the obesity and blood pressure variables were collected form 432 recruited subjects from both sexes aged 25-65 years and ACE I/D polymorphism was analysed on 299 subjects. Almost all the studied CMRFs were found to be significantly higher among urban Bhils. ACE gene was found to be polymorphic in the studied groups. DD genotype was found to pose more than threefold significant risk for low HDLC only in rural area. Estimate change analysis revealed an increasing D allele dose leads to more than one unit increase in Blood Pressure, and more than three units decrease in HDLC. The study highlights the differential effect of ACE I/D gene polymorphism in different environmental settings. PMID- 29435691 TI - Common data elements collected among universities for sport-related concussion studies. AB - BACKGROUND: Universities are increasingly implementing programs to effectively respond to and manage sport-related concussions (SRCs). One such effort is to develop common data elements (CDEs) and standardize data collection methods. The objectives of this study were to describe CDEs currently collected by Big Ten and Ivy League universities for SRC studies, and to compare the data collected with the core CDEs recommended by the National Institute of Neurological Disorders and Stroke (NINDS). METHODS: We conducted an anonymous cross-sectional online survey among medical staff at the 14 Big Ten and 8 Ivy League universities (one per university) between September and October 2015. The survey instrument, including 9 questions corresponding to the concussion data collected before, during, and after a concussion, was developed and pilot-tested before field use. We analyzed patterns of the concussion CDEs being collected, including when, what, and how the data were collected and stored, and compared them with the NINDS' recommended core CDEs. RESULTS: A total of 19 out of 22 universities were included, with 13 from Big Ten and 6 from Ivy-League universities. All 19 participating universities currently collected concussion data with athletes before, during, and after a concussion. Great similarities in data collection were observed at baseline and acutely post-concussion across participating universities. All 19 universities collected at least one of the ten recommended acute symptoms checklists, and 18 universities collected one of the four recommended core neuropsychological function cognitive measures. However, CDEs in the sub-acute and chronic timeframes were limited, with only 9 (47%) universities collecting post-concussion short to long term outcome data. While over 60% of universities collected and stored concussion data electronically, only 17% to 42% of data collected were readily available for research. CONCLUSIONS: Significant inter institutional similarities in acute concussion CDEs were found. Further efforts should focus on collecting sub-acute and chronic timeframe core CDEs and creating data access protocols to facilitate evidence-based concussion prevention and treatment for all collegiate athletes. PMID- 29435692 TI - Correction to: Ponticoccus alexandrii sp. nov., a novel bacterium isolated from the marine toxigenic dinoflagellate Alexandrium minutum. AB - Subsequent to the publication of this article, it was noted that one of the culture collection numbers given for the type strain was given in error. Consequently, in the abstract "The type strain is AT2-AT (CCTCC AB 2016296T = KCTC 52626T)." should read "The type strain is AT2-AT (CCTCC AB 2016296T = KCTC 62340T)." Likewise, in the protologue section, "The type strain is AT2-AT (= CCTCC AB 201696T = KCTC 52626T), which is a algal-associated bacterium isolated from the culture of a toxigenic marine dinoflagellate, Alexandrium minutum (Amtk 4) collected from southern Taiwan." should read "The type strain is AT2-AT (= CCTCC AB 201696T = KCTC 62340T), which is an algal-associated bacterium isolated from the culture of a toxigenic marine dinoflagellate, Alexandrium minutum (Amtk 4), collected from southern Taiwan." PMID- 29435693 TI - The role of corynomycolic acids in Corynebacterium-host interaction. AB - Within the Actinobacteria, the genera Corynebacterium, Mycobacterium, Nocardia and Rhodococcus form the so-called CMNR group, also designated as mycolic acid containing actinomycetes. Almost all members of this group are characterized by a mycolic acid layer, the mycomembrane, which covers the cell wall and is responsible for a high resistance of these bacteria against chemical and antibiotic stress. Furthermore, components of the mycomembrane are crucial for the interaction of bacteria with host cells. This review summarizes the current knowledge of mycolic acid synthesis and interaction with components of the immune system for the genus Corynebacterium with an emphasis on the pathogenic species Corynebacterium diphtheriae, Corynebacterium pseudotuberculosis and Corynebacterium ulcerans as well as the biotechnology workhorse Corynebacterium glutamicum. PMID- 29435694 TI - We have a long way to go. Invited comment to: A systematic methodological review of reported perioperative variables, postoperative outcomes and hernia recurrence from randomized controlled trials of elective ventral hernia repair: clear definitions and standardized datasets are needed. Samuel G. Parker, C. P. J. Wood, J. W. Butterworth, R. W. Boulton, A. A. O. Plumb, S. Mallett, S. Halligan, A. C. J. Windsor. PMID- 29435695 TI - Assessing Acute Secondary Treatment Outcomes in Early-Onset Obsessive-Compulsive Disorder. AB - Obsessive-compulsive disorder (OCD) in children under 8 years of age, referred to as early-onset OCD, has similar features to OCD in older children, including moderate to severe symptoms, impairment, and significant comorbidity. Family based cognitive behavioral therapy (FB-CBT) has been found efficacious in reducing OCD symptoms and functional impairment in children ages 5-8 years with OCD; however, its effectiveness on reducing comorbid psychiatric symptoms in this same population has yet to be demonstrated. This study examined the acute effects of FB-CBT vs. family-based relaxation treatment over 14 weeks on measures of secondary treatment outcomes (non-OCD) in children with early-onset OCD. Children in the FB-CBT condition showed significant improvements from pre- to post treatment on secondary outcomes, with a decrease in overall behavioral and emotional problems, internalizing symptoms, as well as overall anxiety symptom severity. Neither condition yielded significant change in externalizing symptoms. Clinical implications of these findings are considered. PMID- 29435697 TI - Establishment and characterization of an immortalized human hepatocyte line for the development of bioartificial liver system. AB - For further research and application of Bioartificial liver systems (BAL), active proliferation capacity and full hepatic functionality of the biomaterials is mandatory. However, there are still no suitable cell lines meeting the requirements for an ideal cell source in BAL development that makes it necessary to explore other sources. Here, we constructed a new cell line derived from well differentiated hepatocellular carcinoma tissues designated NHBL2. Immunol staining showed that NHBL2 possessed the capacity of synthesizing albumin and CYP2E1 and quantitative analysis showed that the albumin synthesis ability of NHBL2 was comparable to C3A while urea production was highly abundant of NHBL2 compared with that of C3A. Using gene expression microarray analysis, we found that the expression levels of a set of genes encoding Phase I and Phase II metabolizing enzymes as well as many others related to common bioconversion and metabolic processes were significantly higher in NHBL2 cell line than that in C3A. Moreover, functional optimization assay in Matrigel showed obvious improvements of liver-related function level and a low malignance of this cell line. These findings indicated that NHBL2 possessed relatively attractive and full hepatic functionality that might be a potential cell line for BAL development. PMID- 29435698 TI - Correction to: Testing for medical school selection: What are prospective doctors' experiences and perceptions of the GAMSAT and what are the consequences of testing? AB - The wrong acknowledgement and funding information were provided in the original publication. PMID- 29435696 TI - Early Life Stress and Childhood Aggression: Mediating and Moderating Effects of Child Callousness and Stress Reactivity. AB - Early life stress (ELS) has been implicated in the development of aggression, though the exact mechanisms remain unknown. This study tested associations between ELS, callousness, and stress reactivity in the prediction of school-age and persistent early childhood aggression. A longitudinal sample of 185 mother child dyads completed a lab visit and mothers completed an online follow-up when children were preschool-aged and school-aged, respectively. Physiological and behavioral measures of stress reactivity were collected during the preschool period. Ratings of child aggressive behavior, ELS, and callousness were collected as well. The results suggested that ELS was related to measures of both school age and persistent early childhood aggression, and that callousness had a mediating role in this process. Cortisol reactivity also moderated the association between ELS and persistent childhood aggression, such that the ELS aggression relationship was stronger among children who had higher levels of cortisol reactivity during the preschool period. Clinical implications are discussed. PMID- 29435699 TI - Psychosocial benefits of fertility preservation for young cancer patients. AB - PURPOSE: The risk of ovarian failure after radiotherapy and/or chemotherapy is a concern among oncologic women. There is no doubt regarding the psycho-emotional benefits of fertility preservation (FP) after a cancer diagnosis because concerns about biological conception are a source of anxiety and can even affect the patient's cancer recovery. The aim of this study was to evaluate oncology patients' feelings, concerns, and life quality impacts related to FP. METHODS: This qualitative cross-sectional study was based on a questionnaire administered to a selected group of women diagnosed with cancer who underwent FP. Thirty-four eligible women (23-39 years old) completed this questionnaire. RESULTS: Two of the participants already had a child, and most of them (61.8%) stated a desire to have children at the time of FP. Their feelings primarily involved safety (44.1%) and hope (23.5%). Time and/or financial issues (82.4%) were the main challenge for FP. All of the women noted the importance of FP, with many stating that it is warranted to allow the possibility of a biological pregnancy due to the risk of infertility. Finally, questions about the impact on their lives if they had not undergone FP indicated emotional impairment, low quality of life, relationship problems, and uncertainty about maternity. CONCLUSIONS: FP for oncology patients is a positive strategy. The women in this study felt that FP was a worthwhile process and that the security of having undergone FP brought them peace during oncological treatment and contributed to their quality of life. PMID- 29435700 TI - The Content of Dietary Fibre and Polyphenols in Morphological Parts of Buckwheat (Fagopyrum tataricum). AB - In this report, we presented the profile of polyphenolic substances in flowers, leaves, stalk and roots of Fagopyrum tataricum estimated by using RP-UHPLC-ESI-MS equipment (reversed-phase ultra-high-performance liquid chromatography electrospray ionisation mass spectrometry). The neutral detergent fibre, acid detergent fibre, acid detergent lignin, cellulose and hemicellulose were also determined. Flowers, leaves, stalk and roots showed varying levels of dietary fibre and polyphenols. The highest content of neutral and acid detergent fibre were found in the roots (63.92 and 45.45% d.m., respectively) while the most rich in phenolic compounds were flowers (4.8 mg/1 g d.m.). Root and stalk contained the highest level of cellulose, 38.70 and 25.57% d.m., respectively. Among the investigated polyphenolic substances such as: 2,6-dihydroxybenzoic acid, 3,4 dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, 4-hydrobenzoic acid, caffeic acid, catechin, chlorogenic acid, fagopyrin, ferulic acid, myricetin, gallic acid, isovanilic acid, isovitexin, kaempferol, luteolin, p-coumaric acid, procyanidin B2, quercetin, quercetin 3-D galactoside, rutin, syringic acid and vitexin, we observed that the contents of rutin and chlorogenic acid were the highest. We found some correlation between dietary fibre fractions and individual phenolic substances. The levels of acid detergent fibre (ADF), cellulose and hemicellulose were negatively correlated with isovitexin, kaempferol, vitexin, fagopyrin, caffeic acid and procyanidin B2 content. In this investigation, two solvents (water and methanol) were estimated regarding their extraction efficiency of phenolic compounds. Taking these results into consideration, we recommend using methanol as the extractor to isolate chlorogenic acid, fagopyrin, kaempferol, procyanidin B2, quercetin, quercetin 3-D-galactoside, rutin, vitexin, and water for other investigated polyphenolic substances obtained from Fagopyrum tataricum. PMID- 29435702 TI - Species delimitation and conservation genetics of the Canarian endemic Bethencourtia (Asteraceae). AB - Bethencourtia Choisy ex Link is an endemic genus of the Canary Islands and comprises three species. Bethencourtia hermosae and Bethencourtia rupicola are restricted to La Gomera, while Bethencourtia palmensis is present in Tenerife and La Palma. Despite the morphological differences previously found between the species, there are still taxonomic incongruities in the group, with evident consequences for its monitoring and conservation. The objectives of this study were to define the species differentiation, perform population genetic analysis and propose conservation strategies for Bethencourtia. To achieve these objectives, we characterized 10 polymorphic SSR markers. Eleven natural populations (276 individuals) were analyzed (three for B. hermosae, five for B. rupicola and three for B. palmensis). The results obtained by AMOVA, PCoA and Bayesian analysis on STRUCTURE confirmed the evidence of well-structured groups corresponding to the three species. At the intra-specific level, B. hermosae and B. rupicola did not show a clear population structure, while B. palmensis was aggregated according to island of origin. This is consistent with self incompatibility in the group and high gene flow within species. Overall, the genetic diversity of the three species was low, with expected heterozygosity values of 0.302 (B. hermosae), 0.382 (B. rupicola) and 0.454 (B. palmensis). Recent bottleneck events and a low number of individuals per population are probably the causes of the low genetic diversity. We consider that they are naturally rare species associated with specific habitats. The results given in this article will provide useful information to assist in conservation genetics programs for this endemic genus. PMID- 29435703 TI - Wet depositions of mercury during plum rain season in Taiwan. AB - The plum rain season in Taiwan is in May and June. The severest plum rain season over the last 21 years was in 2017. This study involves the collection of mercury wet depositions in the plum rain season of May-June in 2017. A DMA-80 (Direct Mercury Analyzer) was used to analyze the precipitated mercury concentrations and calculate the wet depositions of mercury in the plum rain season. The results indicate that the highest wet depositions of mercury in the aqueous phase were on 6/16, reaching 209.04 MUg/m2 * day, while the lowest were on 5/15, at 0.18 MUg/m2 * day. The mercury wet depositions in the particulate phase were highest on 6/17, when it exceeded 100 MUg/kg, and lowest on particulate phase were occurred in 6/11, when it was 3.64 MUg/m2 * day. The relationship between the wet depositions of mercury in the aqueous phase and rainfall was insignificant, while that between the wet depositions of mercury in the particulate phase and rainfall was significant. The wet depositions of mercury in this study were second highest (30.73 MUg/m2 day) when compared with those in studies in the years 2007-2017. Although the rainfall in this study was only 564 mm H2O, high mercury concentrations obtained from the plum rain season result in the high wet depositions of mercury in Taichung, Taiwan. PMID- 29435704 TI - Risk factors and indicators of reduced welfare of grazing dairy cows from selected smallholder dairy farms in Midlands Province, Zimbabwe. AB - Zimbabwe's smallholder dairying faces many challenges that affect the welfare of dairy cows; however, the status of this welfare has not yet been determined. A cross-sectional study was conducted in Midlands Province on 41 active smallholder dairy farms with 86 cows in winter and summer to determine the risk factors and indicators to impaired cow welfare. These objectives were achieved using farmer questionnaires and direct observations. Eleven percent of the observed cows were severely lame in summer while only 5% were severely lame in winter. Lameness was significantly associated with season, absence of shade, breed, and low dipping frequency; 58% of the cows had low body condition scores (BC < 3) and this low BC was associated with low frequency of protein (p = 0.002) and vitamin (p = 0.012) supplementation recorded in more than 52% of the farms visited. In winter, only 11% of the observed cows were heavily soiled (score 3), while in summer 64% of the cows were heavily soiled and this was associated with slurry accumulation in more than 80% of the observed cattle pens as well as the study season (p < 0.001). A quarter (26%) of the studied animals had visible teat lesions on the teat skin and this was associated with the type of lubricant used (p = 0.011). Only 34% of the cows allowed an approaching stockman to touch them and this was associated with shouting (p = 0.012) and whipping of cows (p = 0.002). The study concluded that welfare of dairy cows was poor in most of the smallholder dairy farms studied. PMID- 29435705 TI - Vision-based gait impairment analysis for aided diagnosis. AB - Gait is a firsthand reflection of health condition. This belief has inspired recent research efforts to automate the analysis of pathological gait, in order to assist physicians in decision-making. However, most of these efforts rely on gait descriptions which are difficult to understand by humans, or on sensing technologies hardly available in ambulatory services. This paper proposes a number of semantic and normalized gait features computed from a single video acquired by a low-cost sensor. Far from being conventional spatio-temporal descriptors, features are aimed at quantifying gait impairment, such as gait asymmetry from several perspectives or falling risk. They were designed to be invariant to frame rate and image size, allowing cross-platform comparisons. Experiments were formulated in terms of two databases. A well-known general purpose gait dataset is used to establish normal references for features, while a new database, introduced in this work, provides samples under eight different walking styles: one normal and seven impaired patterns. A number of statistical studies were carried out to prove the sensitivity of features at measuring the expected pathologies, providing enough evidence about their accuracy. Graphical Abstract Graphical abstract reflecting main contributions of the manuscript: at the top, a robust, semantic and easy-to-interpret feature set to describe impaired gait patterns; at the bottom, a new dataset consisting of video recordings of a number of volunteers simulating different patterns of pathological gait, where features were statistically assessed. PMID- 29435706 TI - Detail-enhanced multimodality medical image fusion based on gradient minimization smoothing filter and shearing filter. AB - In this paper, a detail-enhanced multimodality medical image fusion algorithm is proposed by using proposed multi-scale joint decomposition framework (MJDF) and shearing filter (SF). The MJDF constructed with gradient minimization smoothing filter (GMSF) and Gaussian low-pass filter (GLF) is used to decompose source images into low-pass layers, edge layers, and detail layers at multiple scales. In order to highlight the detail information in the fused image, the edge layer and the detail layer in each scale are weighted combined into a detail-enhanced layer. As directional filter is effective in capturing salient information, so SF is applied to the detail-enhanced layer to extract geometrical features and obtain directional coefficients. Visual saliency map-based fusion rule is designed for fusing low-pass layers, and the sum of standard deviation is used as activity level measurement for directional coefficients fusion. The final fusion result is obtained by synthesizing the fused low-pass layers and directional coefficients. Experimental results show that the proposed method with shift invariance, directional selectivity, and detail-enhanced property is efficient in preserving and enhancing detail information of multimodality medical images. Graphical abstract The detailed implementation of the proposed medical image fusion algorithm. PMID- 29435707 TI - Antinociceptive effects of novel epibatidine analogs through activation of alpha4beta2 nicotinic receptors. AB - The study of alpha4beta2 nicotinic receptors has provided new indications in the treatment of pain. Efforts have been made to explore new alpha4beta2 nicotinic receptor agonists, including TC-2559, as antinociceptive drugs. In this study, we discovered a set of novel epibatidine analogs with strong binding affinities to the alpha4beta2 nicotinic receptors. Among these compounds, C-159, C-163, and C 9515 attenuated formalin-induced nociceptive responses in mice; C-9515 caused the most potent analgesic effect, which was blocked by mecamylamine, a non-selective nicotinic receptor antagonist. Furthermore, C-9515 potently inhibited chronic constriction injury (CCI)-induced neuropathic pain in rats, which was sensitive to DHbetaE, a selective alpha4beta2 subtype antagonist, indicating that its analgesic effect was mediated by the activation of the alpha4beta2 nicotinic receptors. In conclusion, the epibatidine analog C-9515 was found to be a potent alpha4beta2 nicotinic receptor agonist with potent analgesic function, which demonstrated potential for the further exploration of its druggability. PMID- 29435708 TI - Intrinsic antimicrobial properties of silk spun by genetically modified silkworm strains. AB - The domesticated silkworm, Bombyx mori, is a fundamental insect for silk industry. Silk is obtained from cocoons, protective envelopes produced during pupation and composed of single raw silk filaments secreted by the insect silk glands. Currently, silk is used as a textile fibre and to produce new materials for technical and biomedical applications. To enhance the use of both fabrics and silk-based materials, great efforts to obtain silk with antimicrobial properties have been made. In particular, a convincing approach is represented by the enrichment of the textile fibre with antimicrobial peptides, the main effectors of the innate immunity. To this aim, silkworm-based transgenic techniques appear to be cost-effective strategies to obtain cocoons in which antimicrobial peptides are integrated among the silk proteins. Recently, cocoons transgenic for a recombinant silk protein conjugated to the silkworm Cecropin B antimicrobial peptide were obtained and showed enhanced antibacterial properties (Li et al. in Mol Biol Rep 42:19-25, https://doi.org/10.1007/s11033-014-3735-z , 2015a). In this work we used the piggyBac-mediated germline transformation to generate several transgenic B. mori lines able to overexpress Cecropin B or Moricin antimicrobial peptides at the level of the silk gland. The derived cocoons were characterised by increased antimicrobial properties and the resulting silk fibre was able to inhibit the bacterial growth of the Gram-negative Escherichia coli. Our results suggest that the generation of silkworm overexpressing unconjugated antimicrobial peptides in the silk gland might represent an additional strategy to obtain antimicrobial peptide-enriched silk, for the production of new silk based materials. PMID- 29435709 TI - The prevalence and isolated subtypes of BK polyomavirus reactivation among patients infected with human immunodeficiency virus-1 in southeastern China. AB - BK polyomavirus (BKPyV) is an opportunistic infectious pathogen that is associated with hemorrhagic cystitis and nephropathy, mainly in transplant recipients and human immunodeficiency virus 1 (HIV-1) infected patients. However, molecular characterization studies of BKPyV in China are rare. This study was designed to elucidate the prevalence and to determine the main subtypes of BKPyV among HIV-1-infected patients in southeastern China. In addition, the increased incidences for BKPyV reactivation were analyzed. The isolated BKPyV DNA was amplified by polymerase chain reaction (PCR) and the specimen sequences were aligned with the reference sequences for phylogenetic analysis. In this study, BKPyV viruria was detected in 64.2% (88/137) of HIV-1-infected patients. Patients in the BKPyV-positive group were more diverse with respect to gender (P = 0.039) and age (P = 0.023) than their counterparts in the BKPyV-negative group, and they had a higher rate of co-infection with tuberculosis (TB) (P = 0.026). Viruria was more commonly found in patients with CD4 counts <200 cells/mm (72.7%) than in those with CD4 counts >=200 cells/mm (58.5%) (not significant). All sequenced BKPyV isolates belonged to subtype I (13/32) and IV (19/32). A high prevalence of BKPyV reactivation was discovered in patients with HIV-1 infection. Females and elderly individuals, as well as those with a TB co-infection, appeared more susceptible to BKPyV reactivation in this study. BKPyV viruria was found more often and was associated with lower CD4 counts. PMID- 29435710 TI - Two distinct begomoviruses associated with an alphasatellite coinfecting Emilia sonchifolia in Thailand. AB - Emilia sonchifolia is a traditionally used medicinal plant that is widespread in tropical and subtropical regions of the world. Yellow vein symptoms were observed in E. sonchifolia plants in fields in the county of Koh Samui, Surat Thani Province, Thailand, in August 2015. Two distinct begomoviruses, designated TH4872 6 and TH4872-9, and an associated alphasatellite were obtained from an E. sonchifolia leaf sample (TH4872). Sequence analysis showed that the full-length sequence of TH4872-6 was most closely related to that of ageratum yellow vein China virus (AYVCNV), with 85.7% identity, suggesting that it is a novel begomovirus, while the TH4872-9 sequence closely resembled cotton leaf curl Multan virus (CLCuMuV) with 99.1% identity. The alphasatellite sequence showed the highest nucleotide sequence identity (92.8%) to an isolate of tobacco curly shoot alphasatellite (TbCSA) originating from China. Recombination analysis revealed that the isolate TH4872-6 is a potential recombinant begomovirus, derived from ageratum yellow vein virus (AYVV) and tobacco leaf curl Thailand virus (TbLCTHV). This study represents the first report of begomoviruses identified in E. sonchifolia in Thailand. PMID- 29435711 TI - Development of an antigen-capture ELISA for the quantitation of equine arteritis virus in culture supernatant. AB - Quantitation of virions is one of the important indexes in virological studies. To establish a sensitive and rapid quantitative detection method for equine arteritis virus (EAV), an antigen-capture enzyme-linked immunosorbent assay (AC ELISA) was developed by using two EAV nucleoprotein monoclonal antibodies (mAbs), 2B9 and 2B3, prepared in this study. After condition optimization, mAb 2B9 was used as the capture antibody, and HRP-labeled 2B3 was chosen as the detecting antibody. The AC-ELISA had a good standard curve when viral particles of the Bucyrus EAV strain were used as a reference standard. The detection limit for the Bucyrus EAV strain was 36 PFU, and the method had a good linear relationship between 72-2297 PFU. The AC-ELISA could specifically detect the Bucyrus EAV strain and had no cross-reaction with other equine viruses. The sensitivity of the AC-ELISA was much higher than that of a western blotting assay but lower than that of a real-time PCR method. However, as a quantitative antigen detection method, the sensitivity of the AC-ELISA was approximately 300 times than the western blotting assay. Furthermore, the AC-ELISA assay could be successfully used in quantification of viral content in an in vitro infection assay, such as a one-step growth curve of EAV, as well as in a transfection assay, such as virus rescue from an infectious cDNA clone of EAV. These results show that the AC-ELISA established in this study is a good alternative for antigen detection of EAV, being a simple, convenient and quantitative detection method for EAV antigens. PMID- 29435713 TI - Incidence of infusion hypersensitivity reaction after withholding dexamethasone premedication in early breast cancer patients not experiencing two previous cycles of infusion hypersensitivity reaction for weekly paclitaxel chemotherapy. AB - BACKGROUND: Premedication with dexamethasone is an essential part of the prevention of hypersensitivity reaction (HSR) associated with taxane administration. However, the possibility of stopping dexamethasone premedication has been investigated in previous studies to reduce the steroid's adverse events; however, either the result or the particular protocol was limited. Thus, our study aimed to evaluate the incidence of HSR after dexamethasone premedication discontinuation after lack of HSR in two previous weekly paclitaxel infusions. METHOD: Early breast cancer patients who received adjuvant weekly paclitaxel in a retrospective cohort from January 2012 through February 2016 at the King Chulalongkorn Memorial Hospital were reviewed. All patients received a standard premedication protocol prior to the first and second paclitaxel infusion. Dexamethasone was omitted in later cycles in all patients who did not undergo infusion HSR. Patients who developed HSR during the first or second cycles of paclitaxel infusion were excluded. The incidence of HSR during the later cycle of paclitaxel administration and factors associated with this adverse reaction were collected. RESULTS: Eighty-one of 85 patients who did not undergo infusion HSR after 2 cycles of weekly paclitaxel administration were retrospectively reviewed. The median age was 51 years (range 27-74 years). Only 16% of the patients had a BMI greater than 30 kg/m2, 57.8% were premenopausal, 67.9% had no comorbidity, none had a history of allergy or asthma, 65.4% received weekly paclitaxel as a single agent, and 34.6% received weekly paclitaxel in combination with trastuzumab. Five of 81 patients reported grade I-II HSR (6.25%), which occurred mostly during the first 6 cycles (60%). Temporary discontinuation of paclitaxel infusion was observed in all HSR patients. No differences regarding age, BMI, menopausal status, and underlying disease between the HSR and no HSR groups were identified. Concerning the safety profile, peripheral neuropathy (gr I 60%, gr II 13.5%, and gr III 2.4%), myalgia (43.4%), and edema (10.5%) were commonly reported, whereas dyspepsia (5.3%) and insomnia (14.5%) were rarely described in withholding patients. CONCLUSION: Withholding dexamethasone premedication in non experiencing HSR patients after two previous cycles of weekly paclitaxel administration was safe and did not impact the higher incidence of HSR. A discontinuing dexamethasone protocol should be recommended generally in these patients, especially those with a high risk for steroid-induced side effects. PMID- 29435712 TI - Antimicrobial therapy in palliative care: an overview. AB - In the advanced stages of illness, patients often face challenging decisions regarding their treatment and overall medical care. Terminal ill patients are commonly affected by infections. However, in palliative care, the use of antimicrobials can be an ethical dilemma. Deciding whether to treat, withhold, or withdraw the antimicrobial treatment for an infection can be difficult. Antimicrobial administration can lead to adverse outcomes but the two main benefits, longer survival and symptom relief, are the main reasons why physicians prescribe antimicrobial when treating terminally ill patients. For the patient who has an irreversible advanced heart or lung disease, or an advanced dementia, or a metastatic cancer, it is easier the decision of withholding mechanical ventilation, tube feeding, and dialysis than antibiotherapy. To characterize infections, agents, and their treatments in palliative care, we conducted a review of the literature. We also included some tips to help health professionals to guide their clinical approach. PMID- 29435714 TI - Financial toxicity and symptom burden: what is the big deal? PMID- 29435715 TI - Clinical chameleons: an emergency medicine focused review of carbon monoxide poisoning. AB - Carbon monoxide (CO) is a colorless, odorless gas that is found in the environment, in the home, and in the human body as a normal part of mammalian metabolism. Poisoning from CO, a common exposure, is associated with significant morbidity and mortality if not recognized and treated in a timely manner. This review evaluates the signs and symptoms of CO poisoning, conditions that present similar to CO poisoning, and an approach to the recognition and management for CO poisoning. CO poisoning accounts for thousands of emergency department visits annually. If not promptly recognized and treated, it leads to significant morbidity and mortality. CO poisoning poses a challenge to the emergency physician because it classically presents with non-specific symptoms such as headache, dizziness, nausea, and vomiting. Due to nonspecific presentations, it is easily mistaken for other, more benign diagnoses such as viral infection. The use of specific historical clues such as exposure to non-conventional heat sources or suicide attempts in garages, as well as the use of targeted diagnostic testing with CO-oximetry, can confirm the diagnosis of CO poisoning. Once diagnosed, treatment options range from observation to the use of hyperbaric oxygen. CO poisoning is an elusive diagnosis. This review evaluates the signs and symptoms CO poisoning, common chameleons or mimics, and an approach to management of CO poisoning. PMID- 29435716 TI - Helminth parasites of Mabuya arajara Reboucas-Spieker, 1981 (Lacertilia: Mabuyidae) from Chapada do Araripe, northeastern Brazil. AB - We provide data on the helminth fauna from the digestive tract of the lizard Mabuya arajara Reboucas-Spieker, 1981 from Chapada do Araripe, northeastern Brazil. Seventy one of the 127 lizards examined (56%) were infected with four nematode species: Physalopteroides venancioi and Physaloptera sp. (Physalopteridae), Strongyluris oscari (Heterakidae), and Parapharyngodon alvarengai (Pharyngodonidae), the latter being the component species (prevalence 53.5%; mean intensity of infection 3.37 +/- 2.0; discrepancy index D = 0.69). The helminth P. alvarengai infected M. arajara throughout the year and showed increased infection rates in July, at the beginning of the dry season. In addition to the relationship with seasonality, lizards with greater body length and/or body mass were more infected. Relationships between number of parasites and body mass and with the sexes of lizards, on the other hand, were not found. Mabuya arajara represents a new host for these nematodes. This study contributes to the knowledge of the helminth fauna associated with the digestive tract of lizards from South America and the Caatinga domain. PMID- 29435717 TI - Morphological features and molecular phylogeny of Hoferellus azevedoi n. sp. (Myxozoa: Myxobilatidae) found in Chaetobranchus flavescens Heckel, 1840 (Teleostei: Cichlidae) from Marajo Island, northern Brazil. AB - Hoferellus azevedoi n. sp. was found in the urinary bladder of Chaetobranchus flavescens Heckel, 1840 from the Arari River on Marajo Island in Para, Brazil. This is the first record of a species of the genus Hoferellus in a host from the Brazilian Amazon region. The new species has disporous and polysporous plasmodia, which vary in size and shape, with some being found adhered to the epithelium of the urinary bladder, and others floating in the liquid. The mature spores are sub spherical in the sutural view, with a number of peripheral projections around the whole surface of the spore. In the sutural view, the spores are 5.3 +/- 0.2 (5.2 5.6) MUm in length and 7.0 +/- 0.7 (6.3-7.7) MUm in width, with two piriform polar capsules of equal size, 2.5 +/- 0.2 (2.3-2.8) MUm long and 1.8 +/- 0.2 (1.6 2.0) MUm wide. Based on a partial (1312 bps) sequence of the SSU rDNA gene, Hoferellus azevedoi n. sp. was distinguished from all the other myxozoan species deposited in GenBank. Phylogenetically, based on Bayesian inference and p distances, the new species was allocated to the "Freshwater Urinary-Bladder" clade, together with other myxozoan parasites of the excretory system. Based on the morphological data, supported by the partial sequence of the SSU rDNA gene, we describe a new species of myxozoan, Hoferellus azevedoi n. sp. PMID- 29435718 TI - Varroa destructor parasitism reduces hemocyte concentrations and prophenol oxidase gene expression in bees from two populations. AB - Circulating hemocytes are responsible for defensive and healing mechanisms in the honey bee, Apis mellifera. Parasitism by the mite Varroa destructor and injection of V. destructor homogenate in buffer, but not buffer injection, showed similar reductions in total hemocyte concentrations in both Africanized and European adult honey bees. This indicated that compounds in V. destructor homogenate can have similar effects as V. destructor parasitism and that the response is not solely due to wounding. Samples from honey bees with different hemocyte concentrations were compared for the expression patterns of hemolectin (AmHml), prophenol oxidase (AmPpo), and class C scavenger receptor (AmSRC-C). Of the genes tested, only the expression of AmPpo correlated well with hemocyte counts for all the treatments, indicating that melanization is associated with those responses. Thus, the expression of AmPpo might be a suitable biomarker for hemocyte counts as part of cellular defenses against injection of buffer or mite compounds and V. destructor parasitism and perhaps other conditions involving healing and immunity. PMID- 29435719 TI - Adaptation of the secretome of Echinostoma caproni may contribute to parasite survival in a Th1 milieu. AB - Echinostoma caproni (Trematoda: Echinostomatidae) is an intestinal trematode, broadly employed to study the host-dependent mechanisms that govern the evolution of intestinal helminth infections. Resistance against E. caproni homologous secondary infections has been reported in mice and appears to be related to the generation of a local Th2 response, whereas Th1 responses promote the development of chronic primary infections. Herein, the ability of E. caproni to modulate its secretome according to the host environment is investigated. A two-dimensional differential in gel electrophoresis (2D-DIGE) analysis was performed to elucidate changes in the excretory/secretory products of E. caproni adults after primary and secondary infections in mice. A total of 16 protein spots showed significant differences between groups, and 7 of them were successfully identified by mass spectrometry. Adult worms exposed to a primary infection appear to upregulate proteins involved in detoxification (aldo-keto reductase), stress response (GroEL), and enhancement of parasite survival (acetyl-CoA A-acetyltransferase and UTP-glucose-1-phosphate urydyltransferase). In contrast, any protein was found to be significantly upregulated after secondary infection. Upregulation of such proteins may serve to withstand the hostile Th1 environment generated in primary infections in mice. These results provide new insights into the resistance mechanisms developed by the parasites to ensure their long-term survival. PMID- 29435720 TI - Digeneans of northern fur seals Callorhinus ursinus (Pinnipedia: Otariidae) from five subpopulations on St. Paul Island, Alaska. AB - A parasitological survey of 651 northern fur seals Callorhinus ursinus L. from five subpopulations was conducted on St. Paul Island, Alaska, during July-August 2012-2014. Digenean trematodes were found in 210 of 651 fur seals with a total prevalence of 32.3%. Intensity of infection varied from 1 to 1540 parasites with mean intensity 18.4 +/- 111.1 SD and median intensity of 2 specimens per host. Significant differences in prevalence and intensity of infection in northern fur seals between separate rookeries was not observed (Mann-Whitney test; p > 0.05). Four species of digeneans belonging to the families Heterophyidae (Apophallus zalophi Price, 1932, Phocitrema fusiforme Goto and Ozaki, 1930, and Galactosomum ubelakeri (Dailey, 1969)) and Troglotrematidae (Nanophyetus salmincola (Chapin, 1926)) were found. Nanophyetus salmincola is reported from C. ursinus for the first time. We obtained partial 28S rDNA sequences for all digenean species and conducted molecular phylogenetic analysis to demonstrate their phylogenetic relationships. PMID- 29435721 TI - Selection and identification of novel peptides specifically targeting human cervical cancer. AB - Cervical cancer is the second most commonly diagnosed cancer and the third leading cause of cancer deaths among females in underdeveloped countries. This study aimed to identify several novel cervical cancer-specific targeting peptides (CSPs) to provide new methods for the effective diagnosis and treatment of cervical cancer. Peptide library screening in vivo was performed on human cervical cancer xenografts with Ph.D.TM-12 and C7C phage display peptide libraries. Two specific peptide sequences (GDALFSVPLEVY and KQNLAEG), which were enriched in tumors, were screened, and respectively, named CSP-GD and CSP-KQ through three rounds of biopanning. The in vivo tumor-targeting ability of these peptides was identified by injecting them into mice with cervical cancer xenograft. CSPs were compounded and labeled with fluorescein isothiocyanate (FITC). The specificity and affinity of FITC-CSPs were evaluated in human cervical cancer cell lines and tissue microarrays in vitro by immunofluorescent staining. Results showed that FITC-CSP-GD and FITC-CSP-KQ evidently and specifically bound to the cell membrane and cytoplasm of SiHa, ME-180, and C-33A cells in vitro. In human cervical cancer tissue, FITC-CSP-GD and FITC-CSP-KQ strongly targeted human cervical adenocarcinoma and cervical squamous cell carcinoma tissues, respectively. A bright FITC signal was located mainly on the cell membrane and cytoplasm of tumor cells. In conclusion, the novel 12-residue peptide CSP-GD and 7-residue peptide CSP-KQ could specifically target human cervical cancer and may have the potential to be used in the diagnosis and targeted therapy of cervical cancer. PMID- 29435722 TI - L-Arginine regulates protein turnover in porcine mammary epithelial cells to enhance milk protein synthesis. AB - Milk is an important food for mammalian neonates, but its insufficient production is a nutritional problem for humans and other animals. Recent studies indicate that dietary supplementation with L-arginine (Arg) increases milk production in mammals, including sows, rabbits, and cows. However, the underlying molecular mechanisms remain largely unknown. The present study was conducted with porcine mammary epithelial cells (PMECs) to test the hypothesis that Arg enhances milk protein synthesis via activation of the mechanistic target of rapamycin (mTOR) cell signaling. PMECs were cultured for 4 days in Arg-free basal medium supplemented with 10, 50, 200, or 500 MUmol/L Arg. Rates of protein synthesis and degradation in cells were determined with the use of L-[ring-2,4 3H]phenylalanine. Cell medium was analyzed for beta-casein and alpha-lactalbumin, whereas cells were used for quantifying total and phosphorylated levels of mTOR, ribosomal protein S6 kinase (p70S6K), 4E-binding protein 1 (4EBP1), ubiquitin, and proteasome. Addition of 50-500 MUmol/L Arg to culture medium increased (P < 0.05) the proliferation of PMECs and the synthesis of proteins (including beta casein and alpha-lactalbumin), while reducing the rates of proteolysis, in a dose dependent manner. The phosphorylated levels of mTOR, p70S6K and 4EBP1 were elevated (P < 0.05), but the abundances of ubiquitin and proteasome were lower (P < 0.05), in PMECs supplemented with 200-500 MUmol/L Arg, compared with 10-50 MUmol/L Arg. These results provide a biochemical basis for the use of Arg to enhance milk production by sows and have important implications for improving lactation in other mammals (including humans and cows). PMID- 29435723 TI - Carvedilol protection against endogenous Abeta-induced neurotoxicity in N2a cells. AB - Mutations in amyloid precursor protein (APP) and presenilin1 result in overproduction and accumulation of beta-amyloid (Abeta) peptide, which has been shown to play an important role in Alzheimer's disease (AD) pathogenesis. Carvedilol, a nonselective beta-adrenergic receptor blocker used for treatment for heart failure and hypertension, has displayed its neuroprotective capacity due to its antioxidant property. In this study, we investigated whether Carvedilol has a neuronal protective effect against endogenous Abeta neurotoxicity in mouse Neuro2a (N2a) cells transfected with Swedish amyloid precursor protein (Swe-APP) mutant and Presenilin exon9 deletion mutant (N2a/Swe.D9). Elevated levels of reactive oxygen species (ROS), protein carbonyls, and 4-HNE were found in N2a/Swe.D9 cells, which were ameliorated by administration of Carvedilol in a dose-dependent manner. In addition, the levels of ATP and mitochondrial membrane potential were reduced in N2a/Swe.D9 cells, which were restored by treatment with Carvedilol. N2a/Swe.D9 cells displayed increased vulnerability to H2O2-induced cell death and apoptosis, which could be attenuated by Carvedilol. Mechanistically, we found that Carvedilol prevented apoptosis signals through reducing cytochrome C release and the level of cleaved caspase-3. Taken together, our findings suggest a possible use of Carvedilol in AD treatment. PMID- 29435724 TI - Transcriptome, expression, and activity analyses reveal a vital heat shock protein 70 in the stress response of stony coral Pocillopora damicornis. AB - Coral bleaching occurs worldwide with increasing frequencies and intensities, which is caused by the stress response of stony coral to environmental change, especially increased sea surface temperature. In the present study, transcriptome, expression, and activity analyses were employed to illustrate the underlying molecular mechanisms of heat shock protein 70 (HSP70) in the stress response of coral to environmental changes. The domain analyses of assembled transcripts revealed 30 HSP70 gene contigs in stony coral Pocillopora damicornis. One crucial HSP70 (PdHSP70) was observed, whose expressions were induced by both elevated temperature and ammonium after expression difference analysis. The complete complementary DNA (cDNA) sequence of PdHSP70 was identified, which encoded a polypeptide of 650 amino acids with a molecular weight of 71.93 kDa. The deduced amino acid sequence of PdHSP70 contained a HSP70 domain (from Pro8 to Gly616), and it shared the highest similarity (95%) with HSP70 from Stylophora pistillata. The expression level of PdHSP70 gene increased significantly at 12 h, and returned to the initial level at 24 h after the stress of high temperature (32 degrees C). The cDNA fragment encoding the mature peptide of PdHSP70 was recombined and expressed in the prokaryotic expression system. The ATPase activity of recombinant PdHSP70 protein was determined, and it did not change significantly in a wide range of temperature from 25 to 40 degrees C. These results collectively suggested that PdHSP70 was a vital heat shock protein 70 in the stony coral P. damicornis, whose mRNA expression could be induced by diverse environmental stress and whose activity could remain stable under heat stress. PdHSP70 might be involved in the regulation of the bleaching owing to heat stress in the stony coral P. damicornis. PMID- 29435725 TI - A tribute to Dr. Gordon Hisashi Sato (December 24, 1927-March 31, 2017). AB - Gordon H. Sato, an innovator in mammalian tissue culture and integrated cellular physiology, passed away in 2017. In tribute to Dr. Sato, In Vitro Cellular and Developmental Biology-Animal presents a collection of invited remembrances from six colleagues whose associations with Dr. Sato spanned more than 40 years. Dr. Sato was a past president of the Tissue Culture Association (now the Society for In Vitro Biology), editor-in-chief of In Vitro Cellular and Developmental Biology (1987-1991), and the recipient of the lifetime achievement award from the Society for In Vitro Biology (2002). He was elected to the US National Academy of Sciences in 1984. PMID- 29435726 TI - Thalidomide induces apoptosis during early mesodermal differentiation of human induced pluripotent stem cells. AB - Thalidomide was once administered to pregnant women as a mild sedative; however, it was subsequently shown to be strongly teratogenic. Recently, there has been renewed interest in thalidomide because of its curative effects against intractable diseases. However, the teratogenicity of thalidomide is manifested in various ways and is still not fully understood. In the present study, we evaluated the effects of thalidomide on early mesodermal differentiation by examining the differentiation of human induced pluripotent stem cells (hiPSCs). The most common symptom of thalidomide teratogenicity is limb abnormality, which led us to hypothesize that thalidomide prevents early mesodermal differentiation. Therefore, mesodermal differentiation of hiPSCs was induced over a 6-d period. To induce early mesoderm differentiation, 1 d after seeding, the cells were incubated with the small molecule compound CHIR99021 for 3 d. Thalidomide exposure was initiated at the same time as CHIR99021 treatment. After 5 d of thalidomide exposure, the hiPSCs began expressing a mesodermal marker; however, the number of viable cells decreased significantly as compared to that of control cells. We observed that the proportion of apoptotic and dead cells increased on day 2; however, the proportion of dead cells on day 5 had decreased, suggesting that the cells were damaged by thalidomide during early mesodermal differentiation (days 0-2). Our findings may help elucidate the mechanism underlying thalidomide teratogenicity and bring us closer to the safe use of this drug. PMID- 29435727 TI - Gendered Expectations: Do They Contribute to High Burnout Among Female Physicians? AB - Patients have differing expectations of female versus male physicians. Female patients tend to seek more empathic listening and longer visits, especially with female physicians; however, female doctors are not provided more time for this. Female doctors have more female patients than male doctors, and more patients with psychosocial complexity. We propose that gender differences in patient panels and gendered expectations of female physicians may contribute to the high rate of burnout among female clinicians, as well as to the many female physicians working part-time to reduce stress in their work lives. We propose several mechanisms for addressing this, including brief increments in visit time (20, 30 and 40 min), staff awareness, training in patient expectations during medical school, adjusting for patient gender in compensation plans, and co-locating behavioral medicine specialists in primary care settings. Beneficial outcomes could include fewer malpractice suits, greater patient satisfaction, higher quality care, and lower burnout among female physicians. PMID- 29435728 TI - Professionalism Framings Across Medical Schools. PMID- 29435729 TI - Effect of Kuanxiong Aerosol () on Patients with Angina Pectoris: A Non inferiority Multi-center Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effect and safety of Kuanxiong Aerosol (, KA) on patients with angina pectoris. METHODS: Block randomization was performed to randomly allocate 750 patients into KA (376 cases) and control groups (374 cases). During an angina attack, the KA group received 3 consecutive sublingual sprays of KA (0.6 mL per spray). The control group received 1 sublingual nitroglycerin tablet (NT, 0.5 mg/tablet). Log-rank tests and Kaplan-Meier estimations were used to estimate the angina remission rates at 6 time-points after treatment (1, 2, 3, 4, 5, and >5 min). Logistic regression analysis was performed to observe the factors inflfluencing the rate of effective angina remission, and the remission rates and incidences of adverse reactions were compared for different Canadian Cardiovascular Society (CCS) classes of angina. RESULTS: The 5-min remission rates in the KA and control groups were not signifificantly different (94.41% vs. 90.64%, P>0.05). The angina CCS class signifificantly inflfluenced the rate of remission (95% confidence interval = 0.483-0.740, P<0.01). In the CCS subgroup analysis, the 3-and 5-min remission rates for KA and NT were similar in the CCSII and III subgroups (P>0.05), while they were signifificantly better for KA in the CCSI and II subgroups (P<0.05 or P<0.01). Furthermore, the incidence of adverse reactions was signifificantly lower in the KA group than in the control group for the CCSII and III subgroups (9.29% vs. 26.22%, 10.13% vs. 20.88%, P<0.05 or P<0.01). CONCLUSIONS: KA is not inferior to NT in the remission of angina. Furthermore, in CCSII and III patients, KA is superior to NT, with a lower incidence of adverse reactions. (Registration No. ChiCTRIPR-15007204). PMID- 29435730 TI - Bi-weekly eribulin therapy for metastatic breast cancer: a multicenter phase II prospective study (JUST-STUDY). AB - BACKGROUND: This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule. METHODS: Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and <= 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated. RESULTS: Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events. CONCLUSION: This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491). PMID- 29435731 TI - Using crowd-sourced photos to assess seasonal patterns of visitor use in mountain protected areas. AB - Managing protected areas effectively requires information about patterns of visitor use, but these data are often limited. We explore how geotagged photos on Flickr, a popular photo-sharing social-media site, can generate hotspot maps and distribution models of temporal and spatial patterns of use in two mountain protected areas of high conservation value. In Aconcagua Provincial Park (Argentina), two routes to the summit of Aconcagua were used in summer, but most visitors stayed close to the main road, using formal and informal walking trails and the Visitor Centre, while in winter, there was very limited visitation. In Kosciuszko National Park (Australia), alpine walking trails were popular in summer, but in winter, most visitors stayed in the lower altitude ski resorts and ski trails. Results demonstrate the usefulness of social-media data alone as well as a complement for visitor monitoring, providing spatial and temporal information for site-specific and park-level management of visitors and potential impacts in conservation areas. PMID- 29435732 TI - A discursive review of the textual use of 'trapped' in environmental migration studies: The conceptual birth and troubled teenage years of trapped populations. AB - First mooted in 2011, the concept of Trapped Populations referring to people unable to move from environmentally high-risk areas broadened the study of human responses to environmental change. While a seemingly straightforward concept, the underlying discourses around the reasons for being 'trapped', and the language describing the concept have profound influences on the way in which policy and practice approaches the needs of populations at risk from environmental stresses and shocks. In this article, we apply a Critical Discourse Analysis to the academic literature on the subject to reveal some of the assumptions implicit within discussing 'trapped' populations. The analysis reveals a dominant school of thought that assisted migration, relocation, and resettlement in the face of climate change are potentially effective adaptation strategies along a gradient of migrant agency and governance. PMID- 29435733 TI - Miki (Mitotic Kinetics Regulator) Immunoexpression in Normal Liver, Cirrhotic Areas and Hepatocellular Carcinomas: a Preliminary Study with Clinical Relevance. AB - Hepatocellular carcinoma (HCC) is the most common type of primary malignant tumor in the liver. One of the main features of cancer survival is the generalized loss of growth control exhibited by cancer cells, and Miki is a protein related to the immunoglobulin superfamily that plays an important role in mitosis. We aim to study protein expression levels of Miki in non-tumoral liver and 20 HCCs recruited from a Pathology Department. Clinical information was also obtained. A tissue microarray was performed, and immunohistochemical techniques applied to study protein expression levels of Miki. In normal liver, Miki was weakly expressed, showing nuclear staining in the hepatocytes. Cirrhotic areas and HCCs showed a variety of staining patterns. Most HCC samples showed positive expression, with three different staining patterns being discernible: nuclear, cytoplasmic and mixed. Statistical analysis showed a significant association between grade of differentiation, Ki-67 proliferative index, survival rates and staining patterns. This study has revealed the positive expression of Miki in normal liver, cirrhotic areas and HCCs. Three different staining patterns of Miki expression with clinical relevance were noted in HCCs. PMID- 29435734 TI - Targeting of glutamine transporter ASCT2 and glutamine synthetase suppresses gastric cancer cell growth. AB - PURPOSE: Glutamine (Gln) is essential for the proliferation of most cancer cells, making it an appealing target for cancer therapy. However, the role of Gln in gastric cancer (GC) metabolism is unknown and Gln-targeted therapy against GC remains scarce. The aim of this study was to investigate the relevance of Gln in GC growth and targeting. METHODS: Expression of Gln transporter ASCT2 and glutamine synthetase (GS) in the parental and molecularly engineered GC cells or in human GC specimens was determined by RT-PCR and western blot analysis or immunohistochemistry. Cell proliferation and survival was assessed by CCK-8 assay and colony formation assay. Intracellular Gln content was measured by a HPLC system. Effects of ASCT2 and/or GS inhibitor on tumor growth were investigated in xenograft models. RESULTS: A significant heterogeneity of GC cells was observed with respect to their response to the treatment of ASCT2 inhibitor benzylserine (BenSer). Gln deprivation did not affect the BenSer-resistant cell growth due to endogenous GS expression, whose inhibition remarkably reduced cell proliferation. The differential in vitro sensitivity correlated with overall intracellular Gln content. Combined therapy with both ASCT2 and GS inhibitors produced a greater therapeutic efficacy than the treatment of either inhibitor alone. Furthermore, 77% human GC tissues were found to express moderate and high levels of ASCT2, 12% of which also co-expressed relatively high levels of GS. CONCLUSION: Gln mediates GC growth and the therapeutic efficacy of Gln-targeted treatment relies on distinct ASCT2 and GS expression pattern in specific gastric cancer groups. PMID- 29435736 TI - Cardiovascular Studies in Patients with Chronic Obstructive Pulmonary Disease Due to Biomass Smoke or Tobacco. AB - BACKGROUND AND OBJECTIVE: The cardiovascular effects of biomass smoke exposure in patients with chronic obstructive pulmonary disease are not well characterized, and few studies have assessed the possible differences between patients with disease caused by biomass smoke and tobacco. The aim of this study was to search for differences in cardiovascular variables between both types of the disease. METHODS: Twenty subjects (15 men, 5 women) with chronic obstructive pulmonary disease caused by tobacco were matched one to one for sex, age, and forced expiratory volume in 1 s to 20 patients with biomass-related disease. Echocardiography and carotid ultrasound studies were performed. Flow-mediated endothelium-dependent vasodilatation and endothelium-independent vasodilatation were also measured. RESULTS: There were no significant differences between groups in any of the echocardiographic variables, nor in the intima-media carotid thickness, the number of carotid plaques, or the percentage of endothelium dependent or endothelium-independent vasodilation. A high percentage of patients in both groups showed an abnormal flow-mediated endothelium-dependent vasodilatation pattern. CONCLUSION: The study does not support the hypothesis of a different cardiovascular effect of biomass or tobacco smoke exposure in patients with chronic obstructive pulmonary disease. Cardiovascular comorbidity should be assessed in patients with biomass-associated disease, similarly to subjects with tobacco-related disease. PMID- 29435735 TI - Immunosuppressive tumor microenvironment of usual interstitial pneumonia associated squamous cell carcinoma of the lung. AB - PURPOSE: Patients with usual interstitial pneumonia (UIP) often develop lung cancer. However, the biological features of lung cancer associated with UIP remain unknown. The aim of this study was to elucidate the clinicopathological characteristics of UIP-associated squamous cell carcinoma (SqCC). METHODS: A total of 244 patients with p-stage I lung SqCC who underwent complete surgical resection were enrolled in this study. Clinicopathological differences between UIP-associated SqCC and non-UIP SqCC were examined. Moreover, we performed immunohistochemical studies to clarify the biological differences between these two groups. RESULTS: UIP-associated SqCC was detected in 19 patients (6.0%). Patients with UIP-associated SqCC tended to have shorter recurrence-free survival (RFS) (5-year RFS; UIP-associated SqCC 44% vs non-UIP SqCC 62%, p = 0.05). Immunohistochemical analysis revealed that the expression scores of cancer stem cell- and invasion-related molecules in cancer cells were not significantly different between the two groups. However, PD-L1 expression in cancer cells was significantly higher in UIP-associated SqCC (median score; 5.0 vs 0, p < 0.01). In the stroma of UIP-associated SqCC, the number of Foxp3+ tumor-infiltrating lymphocytes was significantly higher than that in non-UIP SqCC (median number 43/HPF vs 24/HPF, p < 0.01). In addition, CD8+/Foxp3+ T-cell ratio in UIP associated SqCC was significantly lower than that in non-UIP SqCC (median ratio 1.8 vs 3.4, p < 0.01). CONCLUSION: Our current study clearly revealed that the establishment of an immunosuppressive tumor microenvironment is a characteristic feature of UIP-associated SqCC, which can be correlated with poor prognosis in UIP-associated SqCC. PMID- 29435737 TI - Clinical Determinants of Incremental Shuttle Walk Test in Adults with Bronchiectasis. AB - INTRODUCTION: Exercise capacity is impaired in patients with bronchiectasis. Incremental shuttle walk test (ISWT) stresses cardiorespiratory system physiologically to symptom-limited maximal exercise capacity. The purpose of this study was to investigate the clinical determinants of ISWT in adults with non cystic fibrosis (CF) bronchiectasis. METHODS: Forty-one clinically stable bronchiectasis patients aged 18-72 years (27 females, 14 males) participated in the study. Subjects' demographics and physical characteristics were recorded. Bronchiectasis Severity Index was used to identify disease severity. Pulmonary function test was performed. Dyspnea perception was assessed using the modified Medical Research Council Dyspnea Scale. Maximum inspiratory and expiratory pressures were measured. Peripheral muscle strength using a hand held dynamometer was measured. ISWT was performed to determine exercise capacity. Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Leicester Cough Questionnaire were used to determine fatigue, psychosocial status, and quality of life. RESULTS: Patients' mean ISWT distance was 469.5 m. The ISWT distance was significantly related with age (r = - 0.472), height (r = 0.469), gender (r = 0.520), FEV1 (r = 0.651), and FVC (r = 0.545, p < 0.05). Quadriceps muscle strength was higher in males (p = 0.001) as compared to females. Age and gender were identified as independent predictors of the ISWT, explaining 42% of variance in ISWT distance (r = 0.649, r2 = 0.421, F(2,38) = 13.794, p < 0.001). CONCLUSION: The clinical determinants of ISWT in clinically stable patients with non-CF bronchiectasis are age and gender. Pulmonary function, dyspnea perception, muscle strength, disease severity, fatigue, psychosocial factors, and health-related quality of life seems to have an independent effect on ISWT in this group of patients with bronchiectasis. PMID- 29435738 TI - Alveolar Tidal recruitment/derecruitment and Overdistension During Four Levels of End-Expiratory Pressure with Protective Tidal Volume During Anesthesia in a Murine Lung-Healthy Model. AB - PURPOSE: We compared respiratory mechanics between the positive end-expiratory pressure of minimal respiratory system elastance (PEEPminErs) and three levels of PEEP during low-tidal-volume (6 mL/kg) ventilation in rats. METHODS: Twenty-four rats were anesthetized, paralyzed, and mechanically ventilated. Airway pressure (Paw), flow (F), and volume (V) were fitted by a linear single compartment model (LSCM) Paw(t) = Ers * V(t) + Rrs * F(t) + PEEP or a volume- and flow-dependent SCM (VFDSCM) Paw(t) = (E1 + E2 * V(t)) * V(t) + (K1 + K2 * |F(t)|) * F(t) + PEEP, where Ers and Rrs are respiratory system elastance and resistance, respectively; E1 and E2* V are volume-independent and volume-dependent Ers, respectively; and K1 and K2 * F are flow-independent and flow-dependent Rrs, respectively. Animals were ventilated for 1 h at PEEP 0 cmH2O (ZEEP); PEEPminErs; 2 cmH2O above PEEPminErs (PEEPminErs+2); or 4 cmH2O above PEEPminErs (PEEPminErs+4). Alveolar tidal recruitment/derecruitment and overdistension were assessed by the index %E2 = 100 * [(E2 * VT)/(E1 + |E2| * VT)], and alveolar stability by the slope of Ers(t). RESULTS: %E2 varied between 0 and 30% at PEEPminErs in most respiratory cycles. Alveolar Tidal recruitment/derecruitment (%E2 < 0) and overdistension (%E2 > 30) were predominant in the absence of PEEP and in PEEP levels higher than PEEPminErs, respectively. The slope of Ers(t) was different from zero in all groups besides PEEPminErs+4. CONCLUSIONS: PEEPminErs presented the best compromise between alveolar tidal recruitment/derecruitment and overdistension, during 1 h of low-VT mechanical ventilation. PMID- 29435739 TI - Multiparametric Magnetic Resonance Imaging in the Assessment of Pulmonary Hypertension: Initial Experience of a One-Stop Study. AB - INTRODUCTION: Our goal was to assess the diagnostic performance of magnetic resonance imaging (MRI) as a single method to diagnose pulmonary hypertension (PH) compared to right heart catheterization (RHC), computed tomography (CT), and ventilation/perfusion (V/Q) scintigraphy. METHODS: We identified 35 patients diagnosed with PH by RHC in our institution who have also undergone a CT, a scintigraphy, and an MRI within a month. All cases were discussed in multidisciplinary meetings. We performed correlations between the MRI-derived hemodynamic parameters and those from RHC. The sensitivity and specificity of MRI were determined to identify its diagnostic performance to identify chronic thromboembolic pulmonary hypertension (CTEPH) and interstitial lung disease PH. The gold standard reference for the diagnosis of CTEPH and ILD was based on a review of multimodality imaging (V/Q scintigraphy and CT scan) and clinical findings. RESULTS: Our results showed a good correlation between the hemodynamic parameters of cardiac MRI and RHC. Pulmonary vascular resistance had the best correlation between both methods (r = 0.923). The sensitivity and specificity of MRI to diagnose CTEPH was 100 and 96.8%, respectively. For the ILD-related PH, the MRI yielded a sensitivity of 60.0% and a specificity of 100%. Additionally, cardiac MRI was able to confirm all cases of PAH due to congenital heart disease initially detected by echocardiography. CONCLUSIONS: MRI represents a promising imaging modality as an initial, single-shot study, for patients with suspected PH with the advantages of being non-invasive and having no radiation exposure. PMID- 29435740 TI - RV Fractional Area Change and TAPSE as Predictors of Severe Right Ventricular Dysfunction in Pulmonary Hypertension: A CMR Study. AB - BACKGROUND: The right ventricular ejection fraction (RVEF) is a surrogate marker of right ventricular function in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The tricuspid annular plane systolic excursion (TAPSE) measures only the longitudinal component of RV contraction while the right ventricular fractional area change (RVFAC) takes into account both the longitudinal and the transversal components. The aim of our study was to evaluate the relationship between RVEF, RVFAC, and TAPSE according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: Fifty four patients with PAH (n = 15) and CTEPH (n = 39) underwent right heart catheterization and cardiac magnetic resonance (CMR). The ventricular volumes and areas, TAPSE, and eccentricity index were measured. The RVFAC was more strongly correlated with the RVEF (r = 0.81, p < 0.0001) than the TAPSE (r = 0.63, p < 0.0001). RVEF < 35% was better predicted by the RVFAC than the TAPSE (TAPSE: AUC = 0.77 and RVFAC: AUC = 0.91; p = 0.042). In the group with the worse hemodynamic status, the RVFAC correlated much better with the RVEF than the TAPSE. There were no significant differences in the CMR data analyzed between the groups of PAH and CETPH patients. CONCLUSIONS: The RVFAC is a good index to estimate RVEF in PH patients; even better than the TAPSE in patients with more severe hemodynamic profile, possibly for including the transversal component of right ventricular function in its measurement. Furthermore, RVFAC performance was similar in the two PH groups (PAH and CTEPH). PMID- 29435741 TI - The Pivotal Role of Imaging in TAVR Procedures. AB - PURPOSE OF REVIEW: Transcatheter aortic valve replacement (TAVR) is underpinned by an array of imaging techniques designed to not only select an appropriately sized implant but also to identify potential obstacles to procedural success. This review presents currently important aspects of TAVR imaging, describing the salient features of each modality as well as recent developments in the field. RECENT FINDINGS: The latest data on TAVR outcomes reflects the increasing experience of operators and the significant role of pre-procedural imaging. Debate continues as to which modality sizes the aortic annulus most accurately, 3D transoesophageal echocardiography (TEE) or MDCT, as well as to whether the merits of real-time peri-procedural 3D imaging guidance outweigh the possible adverse consequences of general anaesthesia which is requisite for intraprocedural 3D TEE. TAVR is now largely based on pre-acquired roadmaps of the truncal vasculature and intense pre-procedural planning. TEE and Multi-detector computed tomography (MDCT) have been shown to perform similarly in annulus sizing. However, given the complexity of many TAVR patients and the importance of identifying the most suitable pathway to the valve as well as any potentially confounding other structural or functional heart disease, both modalities remain relevant in current TAVR. PMID- 29435742 TI - Information Needs Expressed During Patient-Oriented Oncology Consultations: Quantity, Variation, and Barriers. AB - High-quality oncology consultation includes patient-oriented communication tailored to patients' individualized needs. Common methods used in studies to increase question-asking are prompt lists and coaching pre-consultations. However, our patients were encouraged to ask questions by the physician during their visit. We aimed to estimate the quantity, nature, and variation of their questions when they were invited to ask by their oncologist. During radiotherapy consultations from 2012 to 2016, patient's questions were deliberately elicited and physician-transcribed. We derived mean and median number of questions per patient, variance by patient factors, and a taxonomy of subjects using thematic analysis. Three hundred ninety-six patients asked 2386 questions, median asked per patient = 6 (interquartile range = 4). We found significant variance with age (mean = 6.9 questions for < 60 years, 5.4 for >= 70 years) p = 0.018, insurance type (mean = 4.7 for Medicaid, 7.2 for private insurance) p = 0.0004, and tumor site (mean number of questions: skin = 4.6, lymphoma = 5.2, lung = 5.8, breast = 6.1, prostate = 6.3, rectum = 6.7 head and neck = 6.9, brain = 7.0, bladder = 7.2, anus = 8.8, others = 5.8) p = 0.0440. Of the diverse set of 57 topics, the commonest were 1. logistics, 2. radiotherapy details, 3. side effects, 4. diagnosis, and 5. stage and prognosis. Only 17 topics were asked by more > 10% of patients and 40 topics were asked by < 10% of patients. With median of 6 questions, it is practicable to routinely elicit and address individualized information needs. Potential barriers may be older and underinsured patients. The wide variety of topics, often pertaining to individuals' case, suggests that cancer clinicians should take time-out during consultation to elicit patients' questions to accomplish best-practice communication. PMID- 29435743 TI - Fast Synthesis of Pt Nanocrystals and Pt/Microporous La2O3 Materials Using Acoustic Levitation. AB - Usually, we must use an appropriate support material to keep the metal species stable and finely dispersed as supported metal nanoparticles for industry application. Therefore, the choice of support material is a key factor in determining the dispersion and particle size of the noble metal species. Here, we report the synthesis of a single-atom Pt material in the solution and supported Pt nanoclusters on microporous La2O3 by a one-step acoustic levitation method without any pretreatment/modification of raw oxide. We have strongly contributed to the synthetic methodology of the surface/interfacial heterogeneous catalysts in this study, and this finding could open another door for synthesis of supported metal nanoparticles on porous materials for environmental catalysis. PMID- 29435744 TI - Design and implementation of an electromagnetic ultrasound-based navigation technique for laparoscopic ablation of liver tumors. AB - BACKGROUND: Efficient laparoscopic ablation of liver tumors relies on precise tumor visualization and accurate positioning of ablation probes. This study evaluates positional accuracy and procedural efficiency of a dynamic navigation technique based on electromagnetic-tracked laparoscopic ultrasound (ELUS) for laparoscopic ablation of liver tumors. METHODS: The proposed navigation approach combines intraoperative 2D ELUS-based planning for navigated positioning of ablation probes, with immediate 3D ELUS-based validation of intrahepatic probe position. The environmental influence on electromagnetic-tracking stability was evaluated in the operation room. Accuracy of navigated ablation probe positioning assessed as the target-positioning error (TPE), and procedural efficiency defined as time efforts for target definition/navigated targeting and number of probe repositionings, were evaluated in a laparoscopic model and compared with conventional laparoscopic ultrasound (LUS) guidance. RESULTS: The operation-room environment showed interferences < 1 mm on the EM-tracking system. A total of 60 targeting attempts were conducted by three surgeons, with ten targeting attempts using ELUS and ten using conventional LUS each. Median TPE and time for targeting using ELUS and LUS were 4.2 mm (IQR 2.9-5.3 mm) versus 6 mm (IQR 4.7-7.5 mm), and 39 s (IQR 24-47 s) versus 76 s (IQR 47-121 s), respectively (p < 0.01 each). With ELUS, median time for target definition was 48.5 s, with 0 ablation probe repositionings compared to 17 when using LUS. The navigation technique was rated with a mean score of 85.5 on a Standard Usability Scale. CONCLUSIONS: The proposed ELUS-based navigation approach allows for accurate and efficient targeting of liver tumors in a laparoscopic model. Focusing on a dynamic and tumor-targeted navigation technique relying on intraoperative imaging, this avoids potential inaccuracies due to organ deformation and yields a user-friendly technique for efficient laparoscopic ablation of liver tumors. PMID- 29435745 TI - A step towards stereotactic navigation during pelvic surgery: 3D nerve topography. AB - BACKGROUND: Long-term morbidity after multimodal treatment for rectal cancer is suggested to be mainly made up by nerve-injury-related dysfunctions. Stereotactic navigation for rectal surgery was shown to be feasible and will be facilitated by highlighting structures at risk of iatrogenic damage. The aim of this study was to investigate the ability to make a 3D map of the pelvic nerves with magnetic resonance imaging (MRI). METHODS: A systematic review was performed to identify a main positional reference for each pelvic nerve and plexus. The nerves were manually delineated in 20 volunteers who were scanned with a 3-T MRI. The nerve identifiability rate and the likelihood of nerve identification correctness were determined. RESULTS: The analysis included 61 studies on pelvic nerve anatomy. A main positional reference was defined for each nerve. On MRI, the sacral nerves, the lumbosacral plexus, and the obturator nerve could be identified bilaterally in all volunteers. The sympathetic trunk could be identified in 19 of 20 volunteers bilaterally (95%). The superior hypogastric plexus, the hypogastric nerve, and the inferior hypogastric plexus could be identified bilaterally in 14 (70%), 16 (80%), and 14 (70%) of the 20 volunteers, respectively. The pudendal nerve could be identified in 17 (85%) volunteers on the right side and in 13 (65%) volunteers on the left side. The levator ani nerve could be identified in only a few volunteers. Except for the levator ani nerve, the radiologist and the anatomist agreed that the delineated nerve depicted the correct nerve in 100% of the cases. CONCLUSION: Pelvic nerves at risk of injury are usually visible on high-resolution MRI with dedicated scanning protocols. A specific knowledge of their course and its application in stereotactic navigation is suggested to improve quality of life by decreasing the likelihood of nerve injury. PMID- 29435746 TI - Visual spatial ability for surgical trainees: implications for learning endoscopic, laparoscopic surgery and other image-guided procedures. AB - BACKGROUND: In image-guided procedures, a high level of visual spatial ability may be an advantage for surgical trainees. We assessed the visual spatial ability of surgical trainees. METHODS: Two hundred and thirty-nine surgical trainees and 61 controls were tested on visual spatial ability using 3 standardised tests, the Card Rotation, Cube Comparison and Map-Planning Tests. RESULTS: Two hundred and twenty-one, 236 and 236 surgical trainees and 61 controls completed the Card Rotation test, Cube Comparison test and Map-Planning test, respectively. Two percent of surgical trainees performed statistically significantly worse than their peers on card rotation and map-planning test, > 1% on Cube Comparison test. Surgical trainees performed statistically significantly better than controls on all tests. CONCLUSIONS: Two percent of surgical trainees performed statistically significantly worse than their peers on visual spatial ability. The implication of this finding is unclear, further research is required that can look at the learning and educational portfolios of these trainees who perform poorly on visual spatial ability, and ascertain if they are struggling to learn skills for image-guided procedures. PMID- 29435747 TI - Clinical versus patient-reported measures of depression in bariatric surgery. AB - BACKGROUND: Bariatric surgery patients with mental illness may experience worse surgical outcomes compared to those without. Depression is the most prevalent mental health diagnosis amongst Americans with obesity. Accurate diagnosis and treatment is of paramount importance to mitigate perioperative risk. Unfortunately, there is no standard method to screen patients for depression prior to surgery. Our goal was to understand the relationship between traditional clinical screening tools and a novel patient-reported depression screening survey, Patient Health Questionnaire 8 (PHQ-8), in the setting of the bariatric surgery preoperative assessment. METHODS: The study included all adult bariatric surgery patients from January 2014 through June 2016. Patients who were not assessed using both the PHQ-8 and a traditional clinical depression screening were excluded from the study. There were a total of 4486 patients who met the eligibility criteria and were included in analysis. We used comparative statistics to examine the association between these screening tools and to test for contributing demographic, surgical, and socioeconomic factors. RESULTS: The overall rate of clinically diagnosed depression in the study cohort was 45.6%. In comparison, 14.8% of all patients screened positive for depression using the PHQ 8. Of the patients without a traditional clinical diagnosis of depression, 10.2% screened positive for depression using the PHQ-8. This subset of undiagnosed patients was more likely to be non-white, employed, and had a higher BMI than their clinically diagnosed counterparts. CONCLUSIONS AND RELEVANCE: We found a higher rate of clinically diagnosed depression in our cohort compared to the general population. However, when using the validated PHQ-8 survey, the rate of depression more closely approximated the national incidence. Further, a significant proportion of patients were undiagnosed and/or misdiagnosed by current clinical assessments. Standardizing preoperative depression screening using validated patient-centered tools may prevent the consequences of untreated depression. PMID- 29435748 TI - Surgery for benign esophageal disorders in the US: risk factors for complications and trends of morbidity. AB - BACKGROUND: Gastroesophageal reflux disease (GERD), paraesophageal hernia (PEH), and achalasia are the most frequent benign esophageal disorders that may need surgical treatment. We aimed to identify risk factors for postoperative complications and to characterize trends of morbidity for surgery for benign esophageal disorders in a national cohort. METHODS: A retrospective population based analysis was performed using the National Inpatient Sample for the period 2000-2013. Adult patients (>= 18 years old) diagnosed with GERD, PEH, and achalasia, and who underwent fundoplication, PEH repair, and esophagomyotomy were included. The yearly incidence of complications, stratified by procedure, was calculated using Poisson regression, and multivariable logistic regression was used to determine risk factors for complications. RESULTS: A total of 79,622 patients were included; 38,695 (48.6%) underwent PEH repair, 38,719 (48.6%) fundoplication, and 2208 (2.8%) esophagomyotomy. While the rate of postoperative complications dropped from 26.5 to 10.0% and from 16.1 to 12.2% for PEH repair and esophagomyotomy, respectively, the complication rate after fundoplication increased from 5.7 to 12.7% during the same period (p < 0.0001). Age, black race, diabetes, renal insufficiency, coronary artery disease, peripheral vascular disease, chronic obstructive pulmonary disease, and open surgery were independent risk factors for postoperative complications. The rate of laparoscopic procedures for PEH repair increased from 4.9 to 91.4%, while for fundoplication it increased from 24.2 to 78.3% (p < 0.0001). CONCLUSIONS: Opposite to PEH repair and esophagomyotomy, antireflux surgery has shown an increase in the morbidity rate in the last decade. Patient selection and embracement of laparoscopic techniques are critical to improve the perioperative outcome in surgery for benign esophageal disorders. PMID- 29435749 TI - Skills in minimally invasive and open surgery show limited transferability to robotic surgery: results from a prospective study. AB - BACKGROUND: There is limited evidence on the transferability of conventional laparoscopic and open surgical skills to robotic-assisted surgery. The primary aim of this study was to evaluate the transferability of expertise in conventional laparoscopy and open surgery to robotic-assisted surgery using the da Vinci Skills Simulator (dVSS). Secondary aims included evaluating the influence of individual participants' characteristics. METHODS: Participants performed four tasks on the dVSS: Peg Board 1 (PB), Pick and Place (PP), Thread the Rings (TR), and Suture Sponge 1 (SS). Participants were classified into three groups (Novice, Intermediate, Experts) according to experience in laparoscopic and open surgery. All tasks were performed twice except for SS. Performance was assessed using the built-in scoring system. RESULTS: 37 medical students and 25 surgeons participated. Experts did not perform significantly better than less experienced participants on the dVSS. Specifically, with regard to laparoscopic experience, total simulator scores were: Novices 68.2 +/- 28.8; Intermediates 65.1 +/- 31.2; Experts 65.1 +/- 30.0; p = 0.611. Regarding open surgical experience, scores were: Novices 68.6 +/- 28.7; Intermediates 68.2 +/- 30.8; Experts 63.2 +/- 30.3; p = 0.305. Although there were some significant differences among groups for single parameters in specific tasks, there was no constant superiority of one group. Laparoscopic and open surgical Novices improved significantly in overall score and time for all three tasks (p < 0.05). Laparoscopic intermediates improved only in PP time (4.64 +/- 3.42; p = 0.006), open Intermediates in PB score (11.98 +/- 13.01; p = 0.025), and open Experts in PP score (6.69 +/- 11.48; p = 0.048). Laparoscopic experts showed no improvement. Participants with gaming experience had better overall scores than non-gamers when comparing all second attempts (Gamer 83.62 +/- 7.57; Non-Gamer 76.31 +/- 12.78; p = 0.008) as well as first and second attempts together (Gamer 72.08 +/- 8.86; Non-Gamer 65.45 +/- 11.68; p = 0.039). Musical and sports experience showed no correlation with robotic performance. CONCLUSIONS: Robotic-assisted surgery requires skills distinct from conventional laparoscopy or open surgery. Basic robotic skills training prior to patient contact should be required. PMID- 29435750 TI - Clinical efficacy of endoscopic ultrasonography for decision of treatment strategy of gastric cancer. AB - BACKGROUND: Accurate preoperative tumor staging of gastric cancer is indispensable with expansion of indications for laparoscopic surgery and endoscopic resection. It is important to distinguish mucosal cancer (T1a) in smaller lesion and differentiate early gastric cancer (EGC) in larger lesion considering endoscopic resection indication and laparoscopic surgery indication. We evaluated the clinical outcomes of endoscopic ultrasonography (EUS) for the decision of treatment strategy of gastric cancer compared with pathological staging. METHODS: The patients who underwent EUS and surgical or endoscopic resection for gastric cancer were retrospectively reviewed between September 2005 and February 2016. The depth of tumor invasion (T staging) by EUS was compared with the pathological staging after endoscopic or surgical resection. RESULTS: A total of 6084 patients were finally analyzed. The accuracy rates for T1a and EGC were 75.0 and 89.4%, respectively. The overall accuracy of T staging by EUS was 66.3% when divided by T1a, T1b, and over T2. The accuracy of EUS prior to endoscopic resection was 75.1% in absolute indication and 73.1% in expanded criteria, respectively. The accuracy rates for T1a with lesion <= 2 cm in miniprobe EUS and EGC with lesion > 2 cm in conventional EUS were 84.6 and 83.2%, respectively. In multivariate analysis, presence of ulcer, large tumor size, and radial EUS were associated with overestimation, and small tumor size and miniprobe were associated with underestimation in T staging. CONCLUSIONS: EUS showed the high accuracy of 84.6% for T1a in lesion <= 2 cm in miniprobe EUS and 83.2% for EGC in lesion > 2 cm in conventional EUS, respectively. EUS can be a complementary diagnostic method to determine endoscopic or surgical treatment modality. PMID- 29435751 TI - Impact of anatomical position of the pancreas on postoperative complications and drain amylase concentrations after laparoscopic distal gastrectomy for gastric cancer. AB - BACKGROUND: Laparoscopic surgery for gastric cancer requires traction or compression of the pancreas, with the extent depending on the anatomical position of the pancreas. This study investigated the impact of the position of the pancreas on postoperative complications and drain amylase concentrations after laparoscopic distal gastrectomy (LDG). METHODS: Gastric cancer patients who underwent LDG were assessed retrospectively. The following anatomical parameters were measured retrospectively in preoperative computed tomography sagittal projections: the length of the vertical line between the pancreas and the aorta (P-A length), representing the height of the slope looking down the celiac artery from the top of the pancreas, and the angle between a line drawn from the upper border of the pancreas to the root of the celiac artery and the aorta (UP-CA angle), representing the steepness of the slope. Correlations between each parameter and postoperative complications were analyzed by logistic regression analysis. Pearson's product-moment correlation coefficients were calculated for scatter diagrams for each parameter and drain amylase concentration on postoperative day 1. RESULTS: Analyses were performed in 394 patients. P-A length [odds ratio (OR) 1.905; 95% confidence interval (CI) 1.100-3.300; P = 0.021] was significantly correlated with pancreatic fistula. P-A length (OR 2.771; 95% CI 1.506-5.098; P = 0.001), UP-CA angle (OR 2.323; 95% CI 1.251-4.314; P = 0.008), and low preoperative serum albumin (OR 2.082; 95% CI 1.050-4.128; P = 0.036) were significantly correlated with overall postoperative complications defined as Clavien-Dindo >= grade II. P-A length and UP-CA angle showed significant positive correlations with drain amylase concentration on postoperative day 1. CONCLUSION: The position of the pancreas is an independent predictor of pancreatic fistula and/or postoperative complications and correlates with drain amylase concentration after LDG for gastric cancer. PMID- 29435752 TI - Gastric per-oral endoscopic myotomy for refractory gastroparesis: a detailed description of the procedure, our experience, and review of the literature. AB - BACKGROUND AND AIMS: Gastric per-oral endoscopic myotomy (G-POEM) was introduced four years ago as an investigational procedure for refractory gastroparesis. The safety and efficacy were currently evaluated. With our recent studies on G-POEM, we share our experience and knowledge through the discussion of a detailed description of the procedure and review of the literature. To our knowledge, this is the first systemic review on this new therapeutic endoscopic procedure. METHODS: The indications and contraindications, various aspects of the procedure, and efficacy assessment are discussed based on our experience and current available data. RESULTS: Preoperative preparation, detailed description of the procedure, post-procedural care, and results in the literature are presented. The procedure is safe and effective. 70-80% of patients have significant improvement in overall symptoms and quality of life in short-term (6 months) follow-up, as assessed by Gastric Cardinal Symptom Index and Short Form 36. CONCLUSIONS: G-POEM is a feasible and effective procedure for refractory gastroparesis based on early and limited data. Well-designed prospective studies are expected to advance and evaluate this new procedure in the future. PMID- 29435753 TI - Managing acute cholecystitis among Medicaid insured in New York State: opportunities to optimize care. AB - BACKGROUND: Identifying sources of unnecessary cost within Medicaid will help focus cost containment efforts. This study sought to identify differences in surgical management and associated costs of cholecystitis between Medicaid and privately insured in New York State. METHODS: The New York State all-payer mandatory discharge database from 2003 to 2013, had 297,635 patients with Medicaid (75,512) and privately (222,123) insurance who underwent cholecystectomy for cholecystitis. Patients were stratified by insurance. Four surgical management approaches were delineated based on cholecystectomy timing: primary, interval, emergency, and delayed cholecystectomy. Delayed cholecystectomy was defined as more than one hospital visit from diagnosis to definitive cholecystectomy. Medicaid and privately insured patients were propensity score matched. Surgical management approach and associated costs were compared between matched cohorts. RESULTS: A greater proportion of Medicaid patients underwent delayed cholecystectomy compared to matched privately insured patients, 8.5 versus 4.8%; P < 0.001. Primary initial cholecystectomy was performed in fewer Medicaid compared to privately insured patients, 55.4 versus 66.0%, P < 0.001. Primary initial cholecystectomy was the cheapest surgical management approach, with the median cost of $3707, and delayed cholecystectomy was the most expensive, $12,212, P < 0.001. The median cost per Medicaid patient was $6170 versus $4804 per matched privately insured patient, P < 0.001. The annual predicted cost savings for New York State Medicaid would be $13,097,371, if the distribution of surgical management approaches were proportionally similar to private insurance. CONCLUSIONS: Medicaid patients with cholecystitis were more frequently managed with delayed cholecystectomy than privately insured patients, which had substantial cost implications for the New York Medicaid Program. PMID- 29435755 TI - Surgical management of gastroesophageal reflux disease in patients with systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (scleroderma) is frequently associated with both gastroesophageal reflux disease (GERD) and simultaneous esophageal dysmotility. Anti-reflux procedures in this patient population must account for the existing physiology of each patient and likely disease progression. We aim to compare perioperative and intermediate outcomes of fundoplication versus gastric bypass for the treatment of GERD. METHODS: After IRB approval, patients with systemic sclerosis undergoing fundoplication or gastric bypass for the treatment of GERD from 2004 to 2016 were identified. Demographics, perioperative data, immediate complications, and symptom improvement were retrieved and analyzed. RESULTS: Fourteen patients with systemic sclerosis underwent surgical treatment of GERD during the defined study period. Average body mass index was 26 kg/m2. Seven fundoplications (2 Nissens, 4 Toupets, and 1 Dor) and 7 Roux-en-Y gastric bypasses (RYGB) were performed. No 30-day mortality was observed in either group. Median follow-up was 97 months for the fundoplication group (range 28-204 months), and 19 months for the RYGB group (range 1-164 months). Preoperatively, dysphagia, heartburn, and regurgitation were present in 71% (n = 10), 86% (n = 12), and 64% (n = 9) of patients, respectively. Eleven patients had pH study prior to surgical intervention, and 91% of them had abnormal acid exposure. Esophagitis was evident in 85% (n = 11) of patients during preoperative upper endoscopy, and two patients had Barrett's esophagus. Impaired esophageal motility was present in all RYGB patients and 71% of fundoplication patients. Of the patients who had assessment of their GERD symptoms at follow-up, all five patients in the RYGB group and only 3 (50%) patients in the fundoplication group reported symptom improvement or resolution. CONCLUSIONS: Laparoscopic RYGB as an anti-reflux procedure is safe and may provide an alternative to fundoplication in the treatment of GERD for systemic sclerosis patients with esophageal dysmotility. PMID- 29435754 TI - EAES classification of intraoperative adverse events in laparoscopic surgery. AB - BACKGROUND: Surgical outcomes are traditionally evaluated by post-operative data such as histopathology and morbidity. Although these outcomes are reported using accepted systems, their ability to influence operative performance is limited by their retrospective application. Interest in direct measurement of intraoperative events is growing but no available systems applicable to routine practice exist. We aimed to develop a structured, practical method to report intraoperative adverse events enacted during minimal access surgical procedures. METHODS: A structured mixed methodology approach was adopted. Current intraoperative adverse event reporting practices and desirable system characteristics were sought through a survey of the EAES executive. The observational clinical human reliability analysis method was applied to a series of laparoscopic total mesorectal excision (TME) case videos to identify intraoperative adverse events. In keeping with survey results, observed events were further categorised into non consequential and consequential, which were further subdivided into four levels based upon the principle of therapy required to correct the event. A second survey phase explored usability, acceptability, face and content validity of the novel classification. RESULTS: 217 h of TME surgery were analysed to develop and continually refine the five-point hierarchical structure. 34 EAES expert surgeons (69%) responded. The lack of an accepted system was the main barrier to routine reporting. Simplicity, reproducibility and clinical utility were identified as essential requirements. The observed distribution of intraoperative adverse events was 60.1% grade I (non-consequential), 37.1% grade II (minor corrective action), 2.4% grade III (major correction or change in post-operative care) and 0.1% grade IV (life threatening). 84% agreed with the proposed classification (Likert scale 4.04) and 92% felt it was applicable to their practice and incorporated all desirable characteristics. CONCLUSION: A clinically applicable intraoperative adverse event classification, which is acceptable to expert surgeons, is reported and complements the objective assessment of minimal access surgical performance. PMID- 29435756 TI - Laparoscopic distal pancreatectomy: which factors are related to open conversion? Lessons learned from 68 consecutive procedures in a high-volume pancreatic center. AB - BACKGROUND: Laparoscopic distal pancreatectomy represents a difficult surgical procedure with an high conversion rate to open procedure. The factors related to its difficulty and conversion to open distal pancreatectomy were rarely reported. The aim of the present study was to identify which factors are related to conversion from laparoscopic to open distal pancreatectomy. METHODS: A retrospective study of a prospective database of 68 patients who underwent laparoscopic distal pancreatectomy was conducted at a high-volume center by pancreatic surgeons experienced with laparoscopic surgery. Pre-intra and postoperative data were collected. Patients who completed a laparoscopic distal pancreatectomy were compared with those who needed a conversion to the open approach as regard demographic, clinical, radiological, and surgical data. Univariate and multivariate analyses were carried out. RESULTS: Univariate analysis suggested that the site of the lesion, the extension of pancreatic resection, and the requirement for an extended procedure to adjacent organs were significantly associated with the risk of conversion to the open approach. Multivariate analysis showed that only the extension of the pancreatic resection (subtotal pancreatectomy) was significantly related to the odds of conversion [odds ratio (OR) 19.5; 95% confidence interval (CI) 1.1-32.3; P = 0.038]. Preoperative suspicion of malignancy differed between the two groups; however, this difference did not reach statistical significance (P = 0.078). CONCLUSIONS: Despite the limitations of the study, only the extension of pancreatic resection seemed to be the main factor related to conversion during laparoscopic distal pancreatectomy. PMID- 29435757 TI - Defining minimal clearances for adequate lymphatic resection relevant to right colectomy for cancer: a post-mortem study. AB - BACKGROUND: There has been a lengthy discussion on the extent of lymphatic resection for right-sided colon cancer and the central borders of the mesentery that are not yet defined. The objectives of this study are to define minimal clearances for adequate lymphatic resection in regard to colic artery origins and the superior mesenteric artery (SMA) and vein (SMV) relevant to right colectomy. METHODS: Central mesenteric lymph vessels, nodes, and blood vessels were dissected in 16 cadavers. Cranial-caudal clearances were defined as distances between an individual colic artery origin (ileocolic, right colic, and median colic artery) and the outermost lymphatic vessel within its lymphovascular bundle, cranial and caudal along the SMA. Long lymphatic vessels crossing the SMV between arterial bundles were counted and they constituted the medial clearances. An arbitrary watershed between small bowel and colonic lymph was localized. Immunohistochemistry was performed to histologically verify lymphatic vessels. RESULTS: Cranial-caudal clearances were ileocolic 3.6 +/- 1.9 and 5.7 +/- 1.9; right colic 2.8 +/- 1.6 and 3.3 +/- 1.0; middle colic artery bundle 6.3 +/- 2.7 and 5.9 +/- 2.4 mm, respectively. Long lymphatic vessels crossing the SMV between arterial buntles and approaching the SMA were found in all cadavers (antero/posteriorly in 12, only anteriorly in 4), median 3.5 (1-7) long lymphatic vessels anteriorly, and 1.5 (0-5) posteriorly per cadaver. CONCLUSIONS: Right colonic lymphovascular bundles are volumes of mesenteric tissue that surround the superior mesenteric vessels anteriorly and posteriorly. Long lymphatic vessels traverse the superior mesenteric vein anteriorly/posteriorly approaching the superior mesenteric artery between arterial bundles and placing the medial clearance on the left side of the artery. These do not correlate to arterial crossing patterns. Cranial-caudal clearances determine the tissue to be removed superior/inferior to arterial origins together with long lymphatic vessels transversing independently between the lymphovascular bundles placing the weight of lymphatic resection on the mesenteric tissue and not on the level of vessel division (High tie). PMID- 29435758 TI - LapTrain: multi-modality training curriculum for laparoscopic cholecystectomy results of a randomized controlled trial. AB - BACKGROUND: Multiple training modalities for laparoscopy have different advantages, but little research has been conducted on the benefit of a training program that includes multiple different training methods compared to one method only. This study aimed to evaluate benefits of a combined multi-modality training program for surgical residents. METHODS: Laparoscopic cholecystectomy (LC) was performed on a porcine liver as the pre-test. Randomization was stratified for experience to the multi-modality Training group (12 h of training on Virtual Reality (VR) and box trainer) or Control group (no training). The post-test consisted of a VR LC and porcine LC. Performance was rated with the Global Operative Assessment of Laparoscopic Skills (GOALS) score by blinded experts. RESULTS: Training (n = 33) and Control (n = 31) were similar in the pre-test (GOALS: 13.7 +/- 3.4 vs. 14.7 +/- 2.6; p = 0.198; operation time 57.0 +/- 18.1 vs. 63.4 +/- 17.5 min; p = 0.191). In the post-test porcine LC, Training had improved GOALS scores (+ 2.84 +/- 2.85 points, p < 0.001), while Control did not (+ 0.55 +/- 2.34 points, p = 0.154). Operation time in the post-test was shorter for Training vs. Control (40.0 +/- 17.0 vs. 55.0 +/- 22.2 min; p = 0.012). Junior residents improved GOALS scores to the level of senior residents (pre-test: 13.7 +/- 2.7 vs. 18.3 +/- 2.9; p = 0.010; post-test: 15.5 +/- 3.4 vs. 18.8 +/- 3.8; p = 0.120) but senior residents remained faster (50.1 +/- 20.6 vs. 25.0 +/- 1.9 min; p < 0.001). No differences were found between groups on the post-test VR trainer. CONCLUSIONS: Structured multi-modality training is beneficial for novices to improve basics and overcome the initial learning curve in laparoscopy as well as to decrease operation time for LCs in different stages of experience. Future studies should evaluate multi-modality training in comparison with single modalities. TRIAL REGISTRATION: German Clinical Trials Register DRKS00011040. PMID- 29435759 TI - Prognostic value of preoperative neutrophil-to-lymphocyte ratio in Crohn's disease. AB - BACKGROUND: The Neutrophil-to-lymphocyte-ratio has recently gained increased attention as a prognostic marker for malignant disease and short term outcomes. There is little data available in patients with Crohn's disease, thus the present study was conducted to correlate preoperative Neutrophil-to-lymphocyte-ratio values with disease phenotype and postoperative course. METHODS: We comprised 373 patients, who underwent intestinal resection for symptomatic Crohn's disease at an academic tertiary referral centre between 2000 and 2014. Preoperative Neutrophil-to-lymphocyte-ratio values were calculated and analyzed in regard to disease phenotype and 30-day morbidity rate. All relevant data were obtained from the institutional database and individual chart review. RESULTS: Male patients had significantly higher preoperative Neutrophil-to-lymphocyte-ratio values compared to female patients (5 vs. 4; p = 0.0075). A higher Neutrophil-to lymphocyte-ratio was also found in patients with an acute indication for surgery (6.15 vs. 4.3; p = 0.0374), presenting with abscesses (5.36 vs. 4.28; p = 0.0254), inflammatory masses (5.23 vs. 4.08; p = 0.0294) or malignancy in the resected specimen (9.06 vs. 4.35, p = 0.0231). Surprisingly, patients developing postsurgical complications showed significantly lower Neutrophil-to-lymphocyte ratio values (3.77 vs. 4.67; p = 0.0461). CONCLUSIONS: Elevated preoperative Neutrophil-to-lymphocyte-ratio in symptomatic Crohn's disease is not predictive for complications. However, Neutrophil-to-lymphocyte-ratio showed a significant correlation with specific disease phenotypes. Most strikingly, Neutrophil-to lymphocyte-ratio was highly elevated in patients with a colorectal cancer in the resected specimen, which needs to be addressed in future studies. PMID- 29435760 TI - Prescribing 6-weeks of running training using parameters from a self-paced maximal oxygen uptake protocol. AB - PURPOSE: The self-paced maximal oxygen uptake test (SPV) may offer effective training prescription metrics for athletes. This study aimed to examine whether SPV-derived data could be used for training prescription. METHODS: Twenty-four recreationally active male and female runners were randomly assigned between two training groups: (1) Standardised (STND) and (2) Self-Paced (S-P). Participants completed 4 running sessions a week using a global positioning system-enabled (GPS) watch: 2 * interval sessions; 1 * recovery run; and 1 * tempo run. STND had training prescribed via graded exercise test (GXT) data, whereas S-P had training prescribed via SPV data. In STND, intervals were prescribed as 6 * 60% of the time that velocity at [Formula: see text] ([Formula: see text]) could be maintained (Tmax). In S-P, intervals were prescribed as 7 * 120 s at the mean velocity of rating of perceived exertion 20 (vRPE20). Both groups used 1:2 work:recovery ratio. Maximal oxygen uptake ([Formula: see text]), [Formula: see text], Tmax, vRPE20, critical speed (CS), and lactate threshold (LT) were determined before and after the 6-week training. RESULTS: STND and S-P training significantly improved [Formula: see text] by 4 +/- 8 and 6 +/- 6%, CS by 7 +/- 7 and 3 +/- 3%; LT by 5 +/- 4% and 7 +/- 8%, respectively (all P < .05), with no differences observed between groups. CONCLUSIONS: Novel metrics obtained from the SPV can offer similar training prescription and improvement in [Formula: see text], CS and LT compared to training derived from a traditional GXT. PMID- 29435761 TI - Fibroblasts potentiate melanoma cells in vitro invasiveness induced by UV irradiated keratinocytes. AB - Melanoma represents a malignant disease with steadily increasing incidence. UV irradiation is a recognized key factor in melanoma initiation. Therefore, the efficient prevention of UV tissue damage bears a critical potential for melanoma prevention. In this study, we tested the effect of UV irradiation of normal keratinocytes and their consequent interaction with normal and cancer-associated fibroblasts isolated from melanoma, respectively. Using this model of UV influenced microenvironment, we measured melanoma cell migration in 3-D collagen gels. These interactions were studied using DNA microarray technology, immunofluorescence staining, single cell electrophoresis assay, viability (dead/life) cell detection methods, and migration analysis. We observed that three 10 mJ/cm2 fractions at equal intervals over 72 h applied on keratinocytes lead to a 50% increase (p < 0.05) in in vitro invasion of melanoma cells. The introduction cancer-associated fibroblasts to such model further significantly stimulated melanoma cells in vitro invasiveness to a higher extent than normal fibroblasts. A panel of candidate gene products responsible for facilitation of melanoma cells invasion was defined with emphasis on IL-6, IL-8, and CXCL-1. In conclusion, this study demonstrates a synergistic effect between cancer microenvironment and UV irradiation in melanoma invasiveness under in vitro condition. PMID- 29435762 TI - Establishment of a myelinating co-culture system with a motor neuron-like cell line NSC-34 and an adult rat Schwann cell line IFRS1. AB - Co-culture models of neurons and Schwann cells have been utilized for the study of myelination and demyelination in the peripheral nervous system; in most of the previous studies, however, these cells were obtained by primary culture with embryonic or neonatal animals. A spontaneously immortalized Schwann cell line IFRS1 from long-term cultures of adult Fischer rat peripheral nerves has been shown to retain fundamental ability to myelinate neurites in co-cultures with adult rat dorsal root ganglion neurons and nerve growth factor-primed PC12 cells. Our current investigation focuses on the establishment of stable co-culture system with IFRS1 cells and NSC-34 motor neuron-like cells. NSC-34 cells were seeded at a low density (2 * 103/cm2) and maintained for 5-7 days in serum containing medium supplemented with non-essential amino acids and brain-derived neurotrophic factor (BDNF; 10 ng/mL). Upon observation of neurite outgrowth under a phase-contrast microscope, the NSC-34 cells were exposed to an anti-mitotic agent mitomycin C (1 ug/mL) for 12-16 h, then co-cultured with IFRS1 cells (2 * 104/cm2), and maintained in serum-containing medium supplemented with ascorbic acid (50 ug/mL), BDNF (10 ng/mL), and ciliary neurotrophic factor (10 ng/mL). Double immunofluorescence staining carried out at day 28 of the co-culture showed myelin protein (P0 or PMP22)-immunoreactive IFRS1 cells surrounding the betaIII tubulin-immunoreactive neurites. This co-culture system can be a beneficial tool to study the pathogenesis of motor neuron diseases (e.g., amyotrophic lateral sclerosis, Charcot-Marie-Tooth diseases, and immune-mediated demyelinating neuropathies) and novel therapeutic approaches against them. PMID- 29435763 TI - Functions of vitamin D in bone. AB - Vitamin D, synthesized in the skin or absorbed from the diet, undergoes multi step enzymatic conversion to its active form, 1,25-dihydroxy vitamin D [1,25(OH)2D], followed by interaction with the vitamin D receptor (VDR), to modulate target gene expression. Loss-of function mutations in the genes encoding the enzymes regulating these processes, or in the VDR, result in human diseases, which have demonstrated the paramount role of 1,25(OH)2D in mineral and skeletal homeostasis. Mouse genetics has been used to create disease phenocopies which have produced considerable insight into the mechanisms of 1,25(OH)2D regulation of mineral and skeletal metabolism. Hypophosphatemia resulting from 1,25(OH)2D deficiency or resistance can inhibit apoptosis in hypertrophic chondrocytes leading to abnormal development of the cartilaginous growth plate in rickets. Decreased 1,25(OH)2D may also cause decreased vascular invasion associated with reduced chondroclast and osteoclast activity and thereby contribute to growth plate abnormalities. Reduced 1,25(OH)2D-mediated intestinal and renal calcium transport can reduce calcium availability, increase parathyroid hormone secretion and phosphaturia, and impair mineral availability for normal matrix mineralization, resulting in reduced growth plate mineralization and osteomalacia. 1,25(OH)2D may exert an anabolic effect in bone, apparently via the VDR in mature osteoblasts, by increasing osteoblast activity and reducing osteoclast activity. High ambient levels of exogenous 1,25(OH)2D, or of elevated endogenous 1,25(OH)2D in the presence of reduced calcium balance, can enhance bone resorption, and apparently prevent mineral deposition in bone. These actions demonstrate the critical role of vitamin D in regulating skeletal homeostasis both indirectly and directly via the 1,25(OH)2D/VDR system. PMID- 29435766 TI - Assessment of soil organic carbon fractions and carbon management index under different land use types in Olesharo Catchment, Narok County, Kenya. AB - BACKGROUND: The changes in land use and land cover have a strong effect on the total soil organic carbon, its fractions and its overall soil health. This study carried out in Olesharo Catchment, Kenya, was to quantify the differences in total organic carbon (TOC), particulate organic carbon (POC), mineral organic carbon (MOC) and carbon management index (CMI) among four land use types: grasslands, shrublands, agricultural lands and barelands. It was also purported to evaluate the use of CMI as an indicator for soil degradation or improvement in response to land use and land cover changes. RESULTS: The results of the study show that the mean values of TOC, POC and MOC are significantly different between land use types. Thus, shrublands have significantly higher TOC (22.26 g kg-1) than grasslands (10.29 g kg-1) and bare lands (7.56 g kg-1). They also have significantly higher POC (7.79 g kg-1) and MOC (10.04 g kg-1) than all the other land use types. The agricultural lands have higher CMI than grasslands (53% vs 41% relative to shrublands) suggesting that grasslands face serious degradation through overgrazing. CONCLUSIONS: This study shows that different land use types have an influence on soil organic carbon pools, and consequently on the CMI, the CMI could be used as an indicator for soil degradation or improvement in response to land use and land cover changes. PMID- 29435764 TI - Histochemical examination on the peri-implant bone with early occlusal loading after the immediate placement into extraction sockets. AB - Early and immediate loading of dental implants has become a routine procedure in dental practices throughout the world, but the histological feature of peri implant bone has not been fully understood. Therefore, we aimed to elucidate the histological response of peri-implant bone bearing the early occlusal loading using rat models. Four-week-old male Wistar rats were subjected to extraction of their maxillary left first molars and had titanium implants inserted immediately into the post-extraction sockets. In experimental groups at 1 week after placement, implants were loaded for 1 or 2 weeks by adding adhesive resin on the top of the screws. In control groups, no adhesive resin was added to the implants. After 1 or 2 weeks with loading, rats were fixed with an aldehyde solution for histochemical assessment. Newly-formed bone adhered broadly to the implant surface in both the control and experimental groups. The experimental group loaded for 2 weeks showed thicker trabeculae between the implant threads compared to those in the control group. Osteopontin- and osteocalcin-positive cement lines, which are histological hallmarks of bone remodeling, were narrow and smooth in the experimental groups, while featuring a complex meshwork with thick scalloped lines in the control groups. The index of sclerostin-positive osteocytes located close to implants loaded for 2 weeks was significantly lower than in controls, suggesting that osteoblast activity was preserved. Summarizing, our experimental model suggested that early implant loading increases trabecular thickness in the peri-implant bone tissue in a process that involves the regulation of bone remodeling. PMID- 29435765 TI - Inflammation, mesenchymal stem cells and bone regeneration. AB - Achieving satisfactory reconstruction of bone remains an important goal in orthopedic and dental conditions such as bone trauma, osteoporosis, arthritis, osteonecrosis, and periodontitis. Appropriate temporal and spatial differentiation of mesenchymal stem cells (MSCs) is essential for postnatal bone regeneration. Additionally, an acute inflammatory response is crucial at the onset of bone repair, while an adaptive immune response has important implications during late bone remodeling. Various reports have indicated bidirectional interactions between MSCs and inflammatory cells or molecules. For example, inflammatory cells can recruit MSCs, direct their migration and differentiation, so as to exert anabolic effects on bone repair. Furthermore, both pro-inflammatory and anti-inflammatory cytokines can regulate MSCs properties and subsequent bone regeneration. MSCs have demonstrated highly immunosuppressive functions, such as inhibiting the differentiation of monocytes/hematopoietic precursors and suppressing the secretion of pro inflammatory cytokines. This review emphasizes the important interactions between inflammatory stimuli, MSCs, and bone regeneration as well as the underlying regulatory mechanisms. Better understanding of these principles will provide new opportunities for promoting bone regeneration and the treatment of bone loss associated with immunological diseases. PMID- 29435767 TI - Heat-stable sublingual oxytocin tablets as a potential needle-free approach for preventing postpartum hemorrhage in low-resource settings. AB - Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries. The recommended treatment includes administration of oxytocin; however, oxytocin is a heat-labile protein, and it must be given as an intramuscular injection by skilled health care providers. To address these challenges, we developed a freeze-dried oxytocin fast-dissolving tablet (FDT) for sublingual (SL) needle-free administration. Using methods developed previously, we produced a robust FDT that maintained oxytocin stability at 40 degrees C, 75% relative humidity for 12 months. This formulation contains 9% sucrose, 1.5% (hydroxypropyl)methyl cellulose, 9% mannitol, 4% dextran, 1% carbomer, 1% sodium taurocholate, and 100 IU oxytocin. An in vitro study showed a > 30% reduction in tissue transepithelial electrical resistance after treatment with the oxytocin FDT, implying an increase in the permeability of the mucosal tissue to oxytocin. Anesthetized Yucatan miniature swine were administered a SL FDT, and blood was periodically collected for a pharmacokinetic study. Higher plasma concentrations were seen when larger SL doses were given. The maximum concentrations for SL and intramuscular doses in anesthetized pigs were 207 and 612 pg/mL, respectively. Whether the levels attained will be sufficient to elicit beneficial results in humans is yet to be determined. This study demonstrates the feasibility of our approach for developing a heat-stable oxytocin tablet that can be administered successfully via the SL route. PMID- 29435768 TI - A Multifaceted Mass Spectrometric Method to Probe Feeding Related Neuropeptide Changes in Callinectes sapidus and Carcinus maenas. AB - Food intake is regulated by various neuromodulators, including numerous neuropeptides. However, it remains elusive at the molecular and cellular level as to how these important chemicals regulate internal processes and which regions of the neuronal organs are responsible for regulating the behavior. Here we report a comparative neuropeptidomic analysis of the brain and pericardial organ (PO) in response to feeding in two well-studied crustacean physiology model organisms, Callinectes sapidus and Carcinus maenas, using mass spectrometry (MS) techniques. A multifaceted MS-based approach has been developed to obtain complementary information on the expression changes of a large array of neuropeptides in the brain and PO. The method employs stable isotope labeling of brain and PO extracts for relative MS quantitation, capillary electrophoresis (CE)-MS for fractionation and high-specificity analysis, and mass spectrometric imaging (MSI) for in-situ molecular mapping of peptides. A number of neuropeptides, including RFamides, B type allatostatins (AST-B), RYamides, and orcokinins exhibit significant changes in abundance after feeding in this investigation. Peptides from the AST-B family found in PO tissue were shown to have both altered expression and localization changes after feeding, indicating that they may be a class of vital neuropeptide regulators involved in feeding behavior. Graphical Abstract ?. PMID- 29435769 TI - Mechanisms underlying speech sound discrimination and categorization in humans and zebra finches. AB - Speech sound categorization in birds seems in many ways comparable to that by humans, but it is unclear what mechanisms underlie such categorization. To examine this, we trained zebra finches and humans to discriminate two pairs of edited speech sounds that varied either along one dimension (vowel or speaker sex) or along two dimensions (vowel and speaker sex). Sounds could be memorized individually or categorized based on one dimension or by integrating or combining both dimensions. Once training was completed, we tested generalization to new speech sounds that were either more extreme, more ambiguous (i.e., close to the category boundary), or within-category intermediate between the trained sounds. Both humans and zebra finches learned the one-dimensional stimulus-response mappings faster than the two-dimensional mappings. Humans performed higher on the trained, extreme and within-category intermediate test-sounds than on the ambiguous ones. Some individual birds also did so, but most performed higher on the trained exemplars than on the extreme, within-category intermediate and ambiguous test-sounds. These results suggest that humans rely on rule learning to form categories and show poor performance when they cannot apply a rule. Birds rely mostly on exemplar-based memory with weak evidence for rule learning. PMID- 29435770 TI - Visual artificial grammar learning by rhesus macaques (Macaca mulatta): exploring the role of grammar complexity and sequence length. AB - Humans and nonhuman primates can learn about the organization of stimuli in the environment using implicit sequential pattern learning capabilities. However, most previous artificial grammar learning studies with nonhuman primates have involved relatively simple grammars and short input sequences. The goal in the current experiments was to assess the learning capabilities of monkeys on an artificial grammar-learning task that was more complex than most others previously used with nonhumans. Three experiments were conducted using a joystick based, symmetrical-response serial reaction time task in which two monkeys were exposed to grammar-generated sequences at sequence lengths of four in Experiment 1, six in Experiment 2, and eight in Experiment 3. Over time, the monkeys came to respond faster to the sequences generated from the artificial grammar compared to random versions. In a subsequent generalization phase, subjects generalized their knowledge to novel sequences, responding significantly faster to novel instances of sequences produced using the familiar grammar compared to those constructed using an unfamiliar grammar. These results reveal that rhesus monkeys can learn and generalize the statistical structure inherent in an artificial grammar that is as complex as some used with humans, for sequences up to eight items long. These findings are discussed in relation to whether or not rhesus macaques and other primate species possess implicit sequence learning abilities that are similar to those that humans draw upon to learn natural language grammar. PMID- 29435771 TI - Identification of spider-mite species and their endosymbionts using multiplex PCR. AB - Spider mites of the genus Tetranychidae are severe crop pests. In the Mediterranean a few species coexist, but they are difficult to identify based on morphological characters. Additionally, spider mites often harbour several species of endosymbiotic bacteria, which may affect the biology of their hosts. Here, we propose novel, cost-effective, multiplex diagnostic methods allowing a quick identification of spider-mite species as well as of the endosymbionts they carry. First, we developed, and successfully multiplexed in a single PCR, primers to identify Tetranychus urticae, T. evansi and T. ludeni, some of the most common tetranychids found in southwest Europe. Moreover, we demonstrated that this method allows detecting multiple species in a single pool, even at low frequencies (up to 1/100), and can be used on entire mites without DNA extraction. Second, we developed another set of primers to detect spider-mite endosymbionts, namely Wolbachia, Cardinium and Rickettsia in a multiplex PCR, along with a generalist spider-mite primer to control for potential failure of DNA amplification in each PCR. Overall, our method represents a simple, cost effective and reliable method to identify spider-mite species and their symbionts in natural field populations, as well as to detect contaminations in laboratory rearings. This method may easily be extended to other species. PMID- 29435772 TI - Heart Failure Interventions Targeting Impaired Left Ventricles in Structural Heart Disease. AB - PURPOSE OF REVIEW: Interventional techniques have been developed for a wide spectrum of mechanisms of heart failure (HF), especially in valvular heart disease and cardiomyopathies (ischaemic cardiomyopathy and hypertrophic cardiomyopathy). In this article, we review recent reports on catheter interventions to treat patients with HF. RECENT FINDINGS: Direct modification using the Parachute device and the REVIVENT-TC device for patients with impaired left ventricle with large infarct scars improves geometry and haemodynamic efficiency, resulting in a reduction of HF symptoms. Interatrial shunt therapy improves symptoms and quality of life in HF patients. Uniquely, left ventricular outflow tract obstruction has also been targeted in patients with transcatheter mitral valve implantation. For advanced stage HF patients with prohibitively high surgical risk, emerging transcatheter interventions make it possible to modify life-limiting symptoms. Further results on HF interventions are expected from ongoing clinical trials. PMID- 29435773 TI - Livestock Disease Management for Trading Across Different Regulatory Regimes. AB - The maintenance of livestock health depends on the combined actions of many different actors, both within and across different regulatory frameworks. Prior work recognised that private risk management choices have the ability to reduce the spread of infection to trading partners. We evaluate the efficiency of farmers' alternative biosecurity choices in terms of their own-benefits from unilateral strategies and quantify the impact they may have in filtering the disease externality of trade. We use bovine viral diarrhoea (BVD) in England and Scotland as a case study, since this provides an example of a situation where contrasting strategies for BVD management occur between selling and purchasing farms. We use an agent-based bioeconomic model to assess the payoff dependence of farmers connected by trade but using different BVD management strategies. We compare three disease management actions: test-cull, test-cull with vaccination and vaccination alone. For a two-farm trading situation, all actions carried out by the selling farm provide substantial benefits to the purchasing farm in terms of disease avoided, with the greatest benefit resulting from test-culling with vaccination on the selling farm. Likewise, unilateral disease strategies by purchasers can be effective in reducing disease risks created through trade. We conclude that regulation needs to balance the trade-off between private gains from those bearing the disease management costs and the positive spillover effects on others. PMID- 29435774 TI - PET Molecular Targets and Near-Infrared Fluorescence Imaging of Atherosclerosis. AB - PURPOSE OF REVIEW: With this review, we aim to summarize the role of positron emission tomography (PET) and near-infrared fluorescence imaging (NIRF) in the detection of atherosclerosis. RECENT FINDINGS: 18F-FDG is an established measure of increased macrophage activity. However, due to its low specificity, new radiotracers have emerged for more specific detection of vascular inflammation and other high-risk plaque features such as microcalcification and neovascularization. Novel NIRF probes are engineered to sense endothelial damage as an early sign of plaque erosion as well as oxidized low-density lipoprotein (oxLDL) as a prime target for atherosclerosis. Integrated NIRF/OCT (optical coherence tomography) catheters enable to detect stent-associated microthrombi. Novel radiotracers can improve specificity of PET for imaging atherosclerosis. Advanced NIRF probes show promise for future application in human. Intravascular NIRF might play a prominent role in the detection of stent-induced vascular injury. PMID- 29435775 TI - Quercetin Prevents In Vivo and In Vitro Myocardial Hypertrophy Through the Proteasome-GSK-3 Pathway. AB - PURPOSE: Quercetin, a flavonoid, has been reported to ameliorate cardiovascular diseases, such as cardiac hypertrophy. However, the mechanism is not completely understood. In this study, a mechanism related to proteasome-glycogen synthesis kinase 3 (GSK-3) was elucidated in rats and primary neonatal cardiomyocytes. METHODS: Rats were subjected to sham or constriction of abdominal aorta surgery groups and treated with or without quercetin for 8 weeks. Angiotensin II (Ang II) induced primary cardiomyocytes were cultured with quercetin treatment or not for 48 h. Echocardiography, real-time RT-PCR, histology, immunofluorescence, and Western blotting were conducted. Proteasome activities were also detected using a fluorescent peptide substrate. RESULTS: Echocardiography showed that quercetin prevented constriction of abdominal aorta-induced cardiac hypertrophy and improved the cardiac diastolic function. In addition, quercetin also significantly reduced the Ang II-induced hypertrophic surface area and atrial natriuretic factor (ANF) mRNA level in primary cardiomyocytes. Proteasome activities were obviously inhibited in the quercetin-treated group both in vivo and in vitro. Quercetin also decreased the levels of proteasome subunit beta type (PSMB) 1, PSMB2, and PSMB5 of the 20S proteasome as well as the levels of proteasome regulatory particle (Rpt) 1 and Rpt4 of the 19S proteasome. In particular, the PSMB5 level in the nucleus was reduced after quercetin treatment. Furthermore, phosphorylated GSK-3alpha/beta (inactivation of GSK-3) was decreased, which means that GSK-3 activity was increased. The phosphorylation levels of upstream AKT (PKB (protein kinase B)) and liver kinase B1/AMP activated protein kinase (LKB1/AMPKalpha) and those of downstream extracellular signal regulated kinase (ERK), histone H3, beta-catenin, and GATA binding protein 4 (GATA4) were reduced after quercetin treatment, while hypertrophy was reversed after treatment with the GSK-3 inhibitor. CONCLUSION: In summary, quercetin prevents cardiac hypertrophy, which is related to proteasome inhibition and activation of GSK-3alpha/beta. Upstream (AKT, LKB1/AMPKalpha) and downstream hypertrophic factors, such as ERK, histone H3, beta-catenin, and GATA4, may also be involved. PMID- 29435776 TI - Effect of Anagliptin and Sitagliptin on Low-Density Lipoprotein Cholesterol in Type 2 Diabetic Patients with Dyslipidemia and Cardiovascular Risk: Rationale and Study Design of the REASON Trial. AB - BACKGROUND: Reduction of low-density lipoprotein cholesterol (LDL-C) is important for patients with a high risk for atherosclerotic events, such as patients with diabetes and other risk factors. Anagliptin was reported to reduce LDL-C for 12 weeks in phase III trials regardless of the use of statins, but it is uncertain whether this effect is common to other dipeptidylpeptidase-4 (DPP-4) inhibitors. METHODS: A multicenter, randomized, open-label, parallel-group trial was conducted to confirm the superiority of anagliptin to sitagliptin in terms of the primary endpoint of reduction of LDL-C for 52 weeks in patients with type 2 diabetes and atherosclerotic vascular lesions, as well as the non-inferiority of anagliptin to sitagliptin in terms of change in hemoglobin A1c (HbA1c). Patients are randomly assigned to receive anagliptin or sitagliptin at a ratio of 1:1, with those in the anagliptin group receiving anagliptin 100 mg orally twice per day and those in the sitagliptin group receiving sitagliptin 50 mg orally once per day. During the trial period, hypoglycemic agents and anti-dyslipidemia drugs should not be added and neither should their dosages be changed. A total sample size of 300 was estimated to provide a power of 0.8 with a two-sided alpha of 0.05 for LDL-C, considering a 30% dropout rate. Pre-specified factors for subgroup analyses are HbA1c, use of DPP-4 inhibitors, sex, body mass index, LDL C, age, and the presence of treatment for existing ischemic heart disease. DISCUSSION: If anagliptin were to be shown to reduce LDL-C in patients with type 2 diabetes and atherosclerotic vascular lesions despite pre-existing statin treatment, more intensive cholesterol management would be appropriate. TRIAL REGISTRATION: Clinicaltrials.gov NCT02330406. PMID- 29435777 TI - Clinical Review of the Pharmacogenomics of Direct Oral Anticoagulants. AB - PURPOSE: There is growing interest in the use of pharmacogenomics to optimize the safety and efficacy of anticoagulation therapy. While the pharmacogenomics of warfarin have been well-studied, the pharmacogenomics of direct oral anticoagulants (DOACs) continue to be a fledgling, but growing, field of interest. We present a pertinent clinical review of the present state of research on the pharmacogenomics of DOACs. METHODS AND RESULTS: The present article is a review of pertinent clinical and scientific research on the pharmacogenomics of DOACs between January 2008 and December 2017 using MEDLINE and the United States National Institutes of Health Clinical Trials Registry. Many studies have identified single-nucleotide polymorphisms (SNPs) in genes responsible for DOAC metabolism that impacted serum DOAC concentration but had uncertain clinical significance. CONCLUSIONS: As such, there is currently no strong evidence for the use of pharmacogenomic testing in optimizing the safety and efficacy of DOAC therapy. Nonetheless, genes of interest have been identified for each DOAC that may be of potential clinical utility. Further research is currently underway to elucidate the value of pharmacogenomics in this increasingly prescribed therapy. PMID- 29435779 TI - Therapeutic Options for In-Stent Restenosis. AB - PURPOSE OF REVIEW: In-stent restenosis (ISR) is a complex disease process that became apparent shortly after the introduction of stents into clinical practice. This review seeks to define in-stent restenosis (ISR) as well as to summarize the major treatment options that have been developed and studied over the past two decades. RECENT FINDINGS: Recent developments in drug-coated balloons and bioresorbable vascular scaffolds have added new potential treatments for ISR. Two recent network meta-analyses performed a head-to-head comparison of all the various treatment modalities in order to identify the best approach to management of ISR. Current data suggests that repeat stenting with second-generation drug eluting stents is most likely to lead to the best angiographic and clinical outcomes. In situations where repeat stenting is not preferable, drug-coated balloon therapy seems to be a reasonably effective alternative. PMID- 29435780 TI - Protein-ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes. AB - Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key. PMID- 29435781 TI - Fast and accurate quantitative organic acid analysis with LC-QTOF/MS facilitates screening of patients for inborn errors of metabolism. AB - Since organic acid analysis in urine with gaschromatography-mass spectrometry (GC MS) is a time-consuming technique, we developed a new liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) method to replace the classical analysis for diagnosis of inborn errors of metabolism (IEM). Sample preparation is simple and experimental time short. Targeted mass extraction and automatic calculation of z-scores generated profiles characteristic for the IEMs in our panel consisting of 71 biomarkers for defects in amino acids, neurotransmitters, fatty acids, purine, and pyrimidine metabolism as well as other disorders. In addition, four medication-related metabolites were included in the panel. The method was validated to meet Dutch NEN-EN-ISO 15189 standards. Cross validation of 24 organic acids from 28 urine samples of the ERNDIM scheme showed superiority of the UPLC-QTOF/MS method over the GC-MS method. We applied our method to 99 patient urine samples with 32 different IEMs, and 88 control samples. All IEMs were unambiguously established/diagnosed using this new QTOF method by evaluation of the panel of 71 biomarkers. In conclusion, we present a LC-QTOF/MS method for fast and accurate quantitative organic acid analysis which facilitates screening of patients for IEMs. Extension of the panel of metabolites is easy which makes this application a promising technique in metabolic diagnostics/laboratories. PMID- 29435782 TI - Insulin-resistance in glycogen storage disease type Ia: linking carbohydrates and mitochondria? AB - BACKGROUND: Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). GSDIa patients are at higher risk of developing insulin resistance (IR). Mitochondrial dysfunction has been implicated in the development of IR. Mitochondrial dysfunction can demonstrate abnormalities in plama acylcarnitines (ACs) and urine organic acids (UOA). The aim of the study was to investigate the presence of mitochondrial impairment in GSDI patients and its possible connection with IR. METHODS: Fourteen GSDIa, seven GSDIb patients, 28 and 14 age and sex-matched controls, were enrolled. Plasma ACs, UOA, and surrogate markers of IR (HOMA-IR, QUICKI, ISI, VAI) were measured. RESULTS: GSDIa patients showed higher short-chain ACs and long-chain ACs levels and increased urinary excretion of lactate, pyruvate, 2-ketoglutarate, 3-methylglutaconate, adipate, suberate, aconitate, ethylmalonate, fumarate, malate, sebacate, 4 octenedioate, 3OH-suberate, and 3-methylglutarate than controls (p < 0.05). GSDIb patients showed higher C0 and C4 levels and increased urinary excretion of lactate, 3-methylglutarate and suberate than controls (p < 0.05). In GSDIa patients C18 levels correlated with insulin serum levels, HOMA-IR, QUICKI, and ISI; long-chain ACs levels correlated with cholesterol, triglycerides, ALT serum levels, and VAI. DISCUSSION: Increased plasma ACs and abnormal UOA profile suggest mitochondrial impairment in GSDIa. Correlation data suggest a possible connection between mitochondrial impairment and IR. We hypothesized that mitochondrial overload might generate by-products potentially affecting the insulin signaling pathway, leading to IR. On the basis of the available data, the possible pathomechanism for IR in GSDIa is proposed. PMID- 29435783 TI - Feasibility of Linking Long-Term Cardiovascular Cohort Data to Offspring Birth Records: The Bogalusa Heart Study. AB - Introduction Researchers in perinatal health, as well as other areas, may be interested in linking existing datasets to vital records data when the existence or timing of births is unknown. Methods 5914 women who participated in the Bogalusa Heart Study (1973-2009), a long-running study of cardiovascular health in childhood, adolescence, and adulthood, were linked to vital statistics birth data from Louisiana, Mississippi, and Texas (1982-2010). Deterministic and probabilistic linkages based on social security number, race, maternal date of birth, first name, last name, and Soundex codes for name were conducted. Characteristics of the linked and unlinked women were compared using t-tests, Chi square tests, and multiple regression with adjustment for age and year of examinations. Results The Louisiana linkage linked 4876 births for 2770 women; Mississippi linked 791 births to 487 women; Texas linked 223 births to 153 women; After removal of duplicates and implausible dates, this left a total of 5922 births to 3260 women. This represents a successful linkage of 55% of all women ever seen in the larger study, and an estimated 65% of all women expected to have given birth. Those linked had more study visits, were more likely to be black, and had statistically lower BMIs than unlinked participants. Discussion Linking unrelated study data to vital records data was feasible to a degree. The linked group had a somewhat more favorable health profile and was less mobile than the overall study population. PMID- 29435784 TI - Factors Associated with Quality of Life Among Mothers Rearing 4- and 18-Month Old Infants in Japan. AB - Objective The purpose of the present study was to investigate factors associated with quality of life (QOL) among mothers raising 4 and 18-month-old infants. Methods A cross-sectional study was conducted using self-report questionnaires. Participants included 400 women who took their infants for health checkups at a city in Aichi Prefecture, Japan (4-month-olds: n = 197, 18-month-olds: n = 203). Study variables included the World Health Organization Quality of Life-BREF (WHOQOL-BREF) scale, mother's lifestyle, support from family, and other factors potentially related to QOL. Results For mothers of 4-month-old infants, total QOL was associated with emotional support from families (OR 6.09, 95% CI 2.13-17.43) and having enough sleep (7 h or more; OR 4.18, 95% CI 1.86-9.36). These mothers had shorter sleeping hours than mothers of 18-month-old infants. QOL of mothers of 18-month-old infants was associated with emotional support from families (OR 3.06, 95% CI 1.14-8.22) and using childrearing support facilities (OR 2.02, 95% CI 1.01-4.01). Conclusion Different factors contributed to mothers' QOL as a function of infant age. Emotional support from families was associated with better QOL in both mother groups. Differences were that for mothers of 4-month old infants, enough sleep was relevant to QOL, while in mothers of 18-month-old infants, childcare services helped improving their QOL. PMID- 29435785 TI - Adverse Childhood Experiences and Postpartum Depression in Home Visiting Programs: Prevalence, Association, and Mediating Mechanisms. AB - Objectives In this study, we examined the prevalence of postpartum depression (PPD) and its association with select demographic factors and antenatal conditions. We also investigated whether greater exposure to adverse childhood experiences (ACEs) is associated with PPD, and if antenatal conditions mediate the ACE-PPD relationship. Methods Data were collected from 735 low-income women receiving home visiting services. Descriptive and bivariate analyses provided estimates of PPD and its correlates, and nested path analyses were used to test for mediation. Results We found that rates of PPD were high compared to prevalence estimates in the general population. Sample rates of antenatal depression were even higher than the rates of PPD. Omnibus tests revealed that PPD did not vary significantly by maternal age or race/ethnicity, although Hispanic women consistently reported the lowest rates. American Indian women and non-Hispanic white women reported the highest rates. PPD was significantly associated with increased exposure to ACEs. Nested path models revealed that the effects of ACEs were partially mediated by three antenatal conditions: intimate partner violence (IPV), perceived stress, and antenatal depression. Conclusions for Practice Supporting prior research, rates of PPD appear to be high among low income women. ACEs may increase the risk of antenatal IPV and psychological distress, both of which may contribute to PPD. The findings have implications for screening and assessment as well as the timing and tailoring of interventions through home visiting and other community-based services. PMID- 29435786 TI - Standards of Evidence for Conducting and Reporting Economic Evaluations in Prevention Science. AB - Over a decade ago, the Society for Prevention Research endorsed the first standards of evidence for research in preventive interventions. The growing recognition of the need to use limited resources to make sound investments in prevention led the Board of Directors to charge a new task force to set standards for research in analysis of the economic impact of preventive interventions. This article reports the findings of this group's deliberations, proposes standards for economic analyses, and identifies opportunities for future prevention science. Through examples, policymakers' need and use of economic analysis are described. Standards are proposed for framing economic analysis, estimating costs of prevention programs, estimating benefits of prevention programs, implementing summary metrics, handling uncertainty in estimates, and reporting findings. Topics for research in economic analysis are identified. The SPR Board of Directors endorses the "Standards of Evidence for Conducting and Reporting Economic Evaluations in Prevention Science." PMID- 29435787 TI - A Developmental Perspective on Young Adult Romantic Relationships: Examining Family and Individual Factors in Adolescence. AB - The ability to develop and maintain healthy romantic relationships is a key developmental task in young adulthood. The present study investigated how adolescent interpersonal skills (assertiveness, positive engagement) and family processes (family climate, parenting practices) influence the development of young adult romantic relationship functioning. We evaluated cross-lag structural equation models with a sample of 974 early adolescents living in rural and semi rural communities in Pennsylvania and Iowa, starting in sixth grade (mean age = 12.4, 62.1% female) and followed into young adulthood (mean age = 19.5). Findings revealed that adolescents who had experienced a more positive family climate and more competent parenting reported more effective problem-solving skills and less violent behavior in their young adult romantic relationships. Adolescent assertiveness was consistently positively associated with relationship problem solving skills, and adolescents' positive engagement with their family was associated with feeling more love in young adult romantic relationships. In addition, family functioning and adolescent interpersonal skills exhibited some reciprocal relations over the adolescent years. In summary, family processes and interpersonal skills are mutually influenced by each other across adolescence, and both have unique predictive implications to specific facets of young adult romantic relationship functioning. PMID- 29435788 TI - The Psychosocial Treadmill: the Road to Improving High-risk Behavior in Advanced Therapy Candidates. AB - PURPOSE OF REVIEW: The purpose of this review is to explore the evaluation and identification of psychosocial risk factors during the heart transplant evaluation process with the goal of improving psychosocial candidacy prior to transplant listing. Subsequently, more patients will be able to receive life saving heart transplant and experience success after transplant. RECENT FINDINGS: Evaluating and identifying psychosocial risk factors is an essential component of the transplant evaluation process. Less research exists demonstrating how patients may be able to reduce psychosocial risk factors over time to improve their candidacy for transplant. This review will describe a program developed for patients undergoing heart transplant evaluation at The Ohio State University Wexner Medical Center to improve their psychosocial risk. By implementing a comprehensive, multidisciplinary intervention to address psychosocial risk factors pre-transplant, patients can improve their psychosocial candidacy and go on to be listed for heart transplant. PMID- 29435789 TI - Chronic Right Ventricular Pacing in the Heart Failure Population. AB - PURPOSE OF REVIEW: We review the trials that have demonstrated potentially harmful effects from right ventricular (RV) apical pacing as well as reviewing the evidence of alternative RV pacing sites and cardiac resynchronization therapy (CRT) for patients who have heart failure and atrioventricular (AV) block. RECENT FINDINGS: The role of CRT in patients with AV block and impaired left ventricular function remains an important consideration. The BLOCK HF trial demonstrated better outcomes with CRT pacing over RV pacing in patients with left ventricular systolic dysfunction (LVSD) and AV block who were expected to have a high RV pacing burden, but failed to demonstrate a mortality benefit. CRT seems to have a beneficial effect on left ventricular reverse remodeling, systolic function, and clinical outcomes in patients with New York Heart Association (NYHA) functional class I-III heart failure, moderate to severe LVSD, and AV block compared to RV pacing. However, it is less clear whether there is a similar benefit from CRT in patients with a high percentage of RV pacing who have normal or mild LVSD in the treatment of AV block. PMID- 29435790 TI - Randomized controlled trial of Amigo(r) robotically controlled versus manually controlled ablation of the cavo-tricuspid isthmus using a contact force ablation catheter. AB - BACKGROUND: Radiofrequency catheter ablation (RFCA) of the cavo-tricuspid isthmus (CTI) is a common treatment for atrial flutter (AFL). However, achieving bi directional CTI conduction block may be difficult, partly due to catheter instability. OBJECTIVE: To evaluate the safety and efficacy of the Amigo(r) Remote Catheter System (RCS) compared to manual catheter manipulation, during CTI ablation for AFL. METHODS: Fifty patients (pts) were prospectively randomized to robotically (25 pts) versus manually (25 pts) controlled catheter manipulation during CTI ablation, using a force-contact sensing, irrigated ablation catheter. The primary outcome was recurrence of CTI conduction after a 30-min waiting period. Secondary outcomes included total ablation, procedure, and fluoroscopy times, contact force measurement, and catheter stability. RESULTS: Recurrence of CTI conduction 30 min after ablation was less with robotically (0/25) versus manually (6/25) controlled ablation (p = 0.023). Total ablation and procedure times to achieve persistent CTI block (6.7 +/- 3 vs. 7.4 +/- 2.5 min and 14.9 +/- 7.5 vs. 15.2 +/- 7 min, respectively) were not significantly different (p = 0.35 and p = 0.91, respectively). There was a non-significant trend toward a greater force time integral (FTI in gm/s) with robotically versus manually controlled CTI ablation (571 +/- 278 vs. 471 +/- 179, p = 0.13). Fluoroscopy time was longer with robotically versus manually controlled CTI ablation (6.8 +/- 4.4 min vs. 3.8 +/- 2.3 min, p = 0.0027). There were no complications in either group. CONCLUSION: Robotically controlled CTI ablation resulted in fewer acute recurrences of CTI conduction compared to manually controlled CTI ablation, and a trend toward higher FTI. The longer fluoroscopy time during robotically controlled ablation was likely due to a steep learning curve. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02467179. PMID- 29435791 TI - Morphological and genetic differences between Coptis japonica var. anemonifolia H. Ohba and Coptis japonica var. major Satake in Hokuriku area. AB - Coptis japonica is widely distributed in Japan, and its dried rhizome is a source of the domestic herbal medicine Coptidis Rhizoma ( Oren). There are three varieties of C. japonica, two of which, namely, C. japonica var. anemonifolia and C. japonica var. major, are important as sources of traditional medicines. Coptis japonica var. anemonifolia and C. japonica var. major are distinguishable on the basis of their ternate or biternate compound leaves, respectively. In the Hokuriku area, where both C. japonica var. anemonifolia and C. japonica var. major grow naturally, some individual plants cannot be identified unambiguously on the basis of leaf morphology because changes in leaf morphology may occur due to intra-variety variation or crossbreeding between the two varieties. In addition, genetic differences between the two varieties have remained unclear. In this study, we employed new genetic and morphological classification approaches to discriminate between the two varieties. Based on the single nucleotide polymorphisms of the tetrahydroberberine oxidase gene, we found four conserved SNPs between the two varieties and were able to classify C. japonica into two varieties and crossbreeds. Furthermore, we introduced a new leaf type index based on the overall degree of leaflet dissection calculated by surface area of a leaflet and length of leaflet margin and petiolule. Using our new index we were able to discriminate between the two varieties and their crossbreeds more accurately than is possible with the conventional discrimination method. Our genetic and morphological classification methods may be used as novel benchmarks to discriminate between the two varieties and their crossbreeds. PMID- 29435792 TI - Anti-oral common pathogenic bacterial active acetylenic acids from Thesium chinense Turcz. AB - Discovery of agents for oral infectious diseases is always encouraged in natural products chemistry. A bioassay-guided isolation led to the isolation of two new acetylenic acids (1, 2) along with seven known ones (3-9) from the ethanol extract of Thesium chinense Turcz, a commonly used oral anti-bacterial and anti inflammatory herb. Their structures were elucidated on the basis of spectroscopic and chemical evidence. Exocarpic acid (3) demonstrated the most promising activity against three tested oral pathogenic bacterial strains, Porphyromonas gingivalis, Fusobacterium nucleatum, and Streptococcus mutans, with minimum inhibitory concentration values of 0.86, 3.43, and 13.70 MUg/mL, respectively. Compounds 1, 2, 4, 5 and 7 also showed potential activities against periodontal bacteria (P. gingivalis, F. nucleatum). PMID- 29435793 TI - Reply to the letter to the editor regarding: A prospective randomized trial evaluating the outcomes of transanal hemorrhoidal dearterialization versus tissue selecting technique. PMID- 29435794 TI - Emergency Contraceptive Pills (ECP) Knowledge, Attitudes, and Practices Among Women Working in the Entertainment Industry and Men in the Trucking Industry, Bhutan. AB - Emergency contraceptive pills (ECP) were recently made available over the counter in Bhutan. We evaluated knowledge, attitudes, and practices concerning ECP in 2 populations at risk for HIV and STI (sexually transmitted infections): entertainment women (drayang) and male truck drivers and helpers (truckers). Of 179 drayang and 437 truckers intercepted at venues, 73.7 and 21.1%, respectively, had heard of ECP; 47.0% of drayang had used them. Their concerns about ECP use included harm to the body, impact on future pregnancy, side effects, and HIV/STI risk. Education programs are needed in Bhutan to increase awareness of ECP for unplanned pregnancy and condoms to prevent HIV and STI. PMID- 29435795 TI - Illicit Drug Users in the Tanzanian Hinterland: Population Size Estimation Through Key Informant-Driven Hot Spot Mapping. AB - We mapped hot spots and estimated the numbers of people who use drugs (PWUD) and who inject drugs (PWID) in 12 regions of Tanzania. Primary (ie, current and past PWUD) and secondary (eg, police, service providers) key informants identified potential hot spots, which we visited to verify and count the number of PWUD and PWID present. Adjustments to counts and extrapolation to regional estimates were done by local experts through iterative rounds of discussion. Drug use, specifically cocaine and heroin, occurred in all regions. Tanga had the largest numbers of PWUD and PWID (5190 and 540, respectively), followed by Mwanza (3300 and 300, respectively). Findings highlight the need to strengthen awareness of drug use and develop prevention and harm reduction programs with broader reach in Tanzania. This exercise provides a foundation for understanding the extent and locations of drug use, a baseline for future size estimations, and a sampling frame for future research. PMID- 29435796 TI - Retinal single-layer analysis with optical coherence tomography shows inner retinal layer thinning in Huntington's disease as a potential biomarker. AB - PURPOSE: There have been ongoing clinical trials of therapeutic agents in Huntington's disease (HD) which requires development of reliable biomarkers of disease progression. There have been studies in the literature with conflicting results on the involvement of retina in HD, and up to date there is not a study evaluating the single retinal layers in HD. We aimed to evaluate the specific retinal changes in HD and their usability as potential disease progression markers. METHODS: This cross-sectional study used spectral-domain optical coherence tomography with automatic segmentation to measure peripapillary retinal nerve fiber layer (pRNFL) thickness and the thickness and volume of retinal layers in foveal scans of 15 patients with HD and 15 age- and sex-matched controls. Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scales motor scores were acquired for the patients. RESULTS: Temporal pRNFL, macular RNFL (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer and outer plexiform layer thicknesses and IPL, retinal pigment epithelium and outer macular volume were found lower in HD compared to controls, while outer nuclear layer and outer retinal layer thickness were increased (p < 0.05). We found significant correlations between inner retinal layer thicknesses, most significantly with mRNFL and GCL and disease progression markers. CONCLUSION: The outcomes of this study points out that retinal layers, most significantly mRNFL and GCL, are strongly correlated with the disease progression in HD and could serve as useful biomarkers for disease progression. PMID- 29435797 TI - Phacoemulsification cataract surgery in patients receiving novel oral anticoagulant medications. AB - INTRODUCTION: An increasing number of patients are taking novel oral anticoagulant (NOAC) medication, making perioperative management in phacoemulsification surgery an important issue. This study reports the haemorrhagic complications of NOAC in phacoemulsification surgery. DESIGN: Retrospective case study over a 4-year period. METHODS: Consecutive cases receiving NOAC during the time of phacoemulsification were reviewed. Patients were either advised to continue medications (continued group) or withhold medications before surgery (withheld group). MAIN OUTCOME MEASURES: Details including patient demographics, preoperative assessment, postoperative outcome and intraoperative, postoperative and systemic complications were recorded. RESULTS: A total of 20,100 cases of phacoemulsification were performed. Of which, 66 cases were found to be on NOAC (0.33%). This included 66 eyes of 53 patients, with 42 continued and 24 withheld medications before surgery. There was no statistically significant difference between the two groups in demographics, cataract risk factors, baseline renal function, clotting profile, type of NOAC, incision size, phacoemulsification energy, preoperative and postoperative visual acuity. There was also no significant difference in intraoperative, postoperative and systemic complications (p = 1.00 and 0.53, Fischer's exact test). None of the patients in the continued group had postoperative complications; two cases in the withheld group receiving retrobulbar anaesthesia had bruising and subconjunctival haemorrhage after resumption of NOAC (p = 0.13, Fischer's exact test). CONCLUSION: The present study found no difference in haemorrhagic complications between cases continuing and withholding NOAC during phacoemulsification. Nevertheless, the potential risks and benefits to continue or withhold NOAC perioperatively should be carefully considered via a multidisciplinary approach. PMID- 29435798 TI - Response of soil microbial communities to red mud-based stabilizer remediation of cadmium-contaminated farmland. AB - In this work, a field test was conducted to investigate the effects of heavy metal stabilizer addition on brown rice and microbial variables in a cadmium (Cd) contaminated farmland from April to October in 2016. Compared with the control, red mud-based stabilizer (RMDL) effectively reduced the concentration of Cd in brown rice (with the removal rate of 48.14% in early rice, 20.24 and 47.62% in late rice). The results showed that adding 0.3 kg m-2 RDML in early rice soil or soil for both early and late rice increased the microbial biomass carbon (MBC), the number of culturable heterotrophic bacteria and fungi, and the catalase activity in soil at different stages of paddy rice growth. Furthermore, there was no notable difference in the diversity of the bacterial species, community composition, and relative abundance at phylum (or class) or operational taxonomic unit (OTU) levels between the control and treatment (RMDL addition) groups. In a word, RMDL could be highly recommended as an effective remediation stabilizer for Cd-contaminated farmland, since its continuous application in paddy soil cultivating two seasons rice soil could effectively decrease the Cd content in brown rice and had no negative impact on soil microorganisms. PMID- 29435799 TI - Influence of land use on the health of a detritivorous fish (Ancistrus mullerae) endemic to the Iguassu ecoregion: relationship between agricultural land use and severe histopathological alterations. AB - This study aimed to evaluate the histopathological biomarkers of the gills and liver of endemic catfish to test the hypothesis that, in environments under intense land use by agricultural activities, histopathological alterations occur more severely. Samples were collected by electrofishing in seven streams in the Lower Iguacu basin quarterly from August 2015 to February 2016. The gills and livers were processed according to routine histological methods and examined by light microscopy. The histopathological alterations observed in fish from the streams with a higher percentage of natural vegetation cover were considered modest and indicated normal functioning of the organ (such as edema, hyperplasia, and leukocyte infiltration). As predicted, fish collected in streams with higher agricultural influence presented moderate to severe damage (aneurysm, vacuolization and cytoplasmic degeneration, and pyknotic nucleus). The abundance of chloride cells was significantly increased in the gills of Ancistrus mullerae collected in rural streams. In addition, in most streams, mucous cells were more abundant during the rainy period. Significant differences were observed in the histopathological index (HI) of the gills and livers, where severe histopathological alterations occurred in fish from streams with a higher agricultural influence. The observed alterations were more severe in the liver than in the gills, which are indeed related to the liver's key role in the detoxification of xenobiotics. We conclude that more severe histological alterations occurred in fish from streams with the highest land use by agricultural activities. Thus, our work provides important insight into the conservation and management of natural resources. PMID- 29435800 TI - The 'new normal': relativity of quality of life judgments in individuals with bipolar disorder-a qualitative study. AB - PURPOSE: Quality of life (QoL) is increasingly a target of interventions for bipolar disorders (BD). While the subjective experience of consumers is often elevated as central to the construct of QoL in BD, limited investigation in this area means subjective QoL remains poorly understood. The present qualitative study seeks to address this by investigating how people with BD appraise the quality of their lives in the context of a QoL self-management intervention. METHODS: Semi-structured interviews were conducted with 43 individuals who had participated in a self-management intervention for improving QoL in BD. Individuals were questioned about experiences of the intervention and perceptions of their QoL. Thematic analysis was used to explore participants' appraisal of their QoL. RESULTS: An overarching theme concerned the intrinsic relativity of subjective QoL: individuals located QoL as relative to self, others and possible futures. Incorporating illness-related reference points for QoL ('given my circumstances...') was associated with perceptions of improved QoL. Deliberately modifying reference points for QoL was perceived as self-compassionate. CONCLUSION: The present study generates novel hypotheses about how individuals with BD make sense of their QoL. Data suggest that individuals located their QoL relative to a variety of reference points, use of which was flexible. In accord with gap theories of QoL, individuals experienced acceptance of illness impacts as improving subjective sense of QoL. Rather than 'settling for' a lower standard of QoL, individuals experienced these changes as adaptive and positive. Findings are discussed in relation to the measurement and amelioration of QoL in BD. PMID- 29435801 TI - COSMIN guideline for systematic reviews of patient-reported outcome measures. AB - PURPOSE: Systematic reviews of patient-reported outcome measures (PROMs) differ from reviews of interventions and diagnostic test accuracy studies and are complex. In fact, conducting a review of one or more PROMs comprises of multiple reviews (i.e., one review for each measurement property of each PROM). In the absence of guidance specifically designed for reviews on measurement properties, our aim was to develop a guideline for conducting systematic reviews of PROMs. METHODS: Based on literature reviews and expert opinions, and in concordance with existing guidelines, the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) steering committee developed a guideline for systematic reviews of PROMs. RESULTS: A consecutive ten-step procedure for conducting a systematic review of PROMs is proposed. Steps 1-4 concern preparing and performing the literature search, and selecting relevant studies. Steps 5-8 concern the evaluation of the quality of the eligible studies, the measurement properties, and the interpretability and feasibility aspects. Steps 9 and 10 concern formulating recommendations and reporting the systematic review. CONCLUSIONS: The COSMIN guideline for systematic reviews of PROMs includes methodology to combine the methodological quality of studies on measurement properties with the quality of the PROM itself (i.e., its measurement properties). This enables reviewers to draw transparent conclusions and making evidence-based recommendations on the quality of PROMs, and supports the evidence based selection of PROMs for use in research and in clinical practice. PMID- 29435802 TI - Measuring health related quality of life (HRQoL) in community and facility-based care settings with the interRAI assessment instruments: development of a crosswalk to HUI3. AB - BACKGROUND: Health-related quality of life (HRQoL) measures are of interest because they can be used to describe health of populations and represent a broader health outcome for population health analyses than mortality rates or life expectancy. The most widely used measure of HRQoL for deriving estimates of health-adjusted life expectancy is the Health Utilities Index Mark 3 (HUI3). The HUI3 is available in most national surveys administered by Statistics Canada, and has been used as part of a microsimulation model to examine the impact of neurological conditions over the life course. Persons receiving home care and nursing home services are often not well-represented in these surveys; however, interRAI assessment instruments are now used as part of normal clinical practice in these settings for nine Canadian provinces/territories. Building on previous research that developed a HUI2 crosswalk for the interRAI assessments, the present study examined a new interRAI HRQoL index crosswalked to the HUI3. METHODS: interRAI and survey data were used to examine the distributional properties of global and domain-specific interRAI HRQoL and HUI3 index scores, respectively. Three populations were considered: well-elderly persons not receiving home care, home care clients and nursing home residents. RESULTS: The mean HUI3 and interRAI HRQoL index global scores declined from independent healthy older persons to home care clients, followed by nursing home residents. For the home care and nursing home populations, the interRAI HRQoL global estimates tended to be lower than HUI3 global scores obtained from survey respondents. While there were some statistically significant age, sex and diagnostic group differences in global scores and within attributes, the most notable differences were between populations from different care settings. DISCUSSION: The present study provides strong evidence for the validity of the interRAI HRQoL based on comparisons of distributional properties with those obtained with survey data based on the HUI3. The results demonstrate the importance of admission criteria for home care and nursing home settings, where function plays a more important role than demographic or diagnostic criteria. The interRAI HRQoL has a distinct advantage because it is gathered as part of normal clinical practice in care settings where interRAI instruments are mandatory and are used to assess all eligible persons in those sectors. In particular, those with severe cognitive and functional impairments (who tend to be under represented in survey data) will be evaluated using the interRAI tools. Future research should build on this work by providing direct, person-level comparisons of interRAI HRQoL index and HUI3 scores, as well as longitudinal analyses to examine responsiveness to change. PMID- 29435803 TI - Rifampicin Prevents SH-SY5Y Cells from Rotenone-Induced Apoptosis via the PI3K/Akt/GSK-3beta/CREB Signaling Pathway. AB - In addition to its original application for treating tuberculosis, rifampicin has multiple potential neuroprotective effects in chronic neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease. Inflammatory reactions and the PI3K/Akt pathway are strongly implicated in dopaminergic neuronal death in PD. This study aims to investigate whether rifampicin protects rotenone-lesioned SH-SY5Y cells via regulating PI3K/Akt/GSK-3beta/CREB pathway. Rotenone-treated SH-SY5Y cells were used as the cell model to investigate the neuroprotective effects of rifampicin. Cell viability and apoptosis of SH-SY5Y cells were determined by CCK-8 assay and flow cytometry, respectively. The expression of Akt, p-Akt, GSK-3beta, p-GSK-3beta, CREB and p-CREB were measured by Western blot. Our results showed that the cell viability and level of phospho CREB significantly decreased in SH-SY5Y cells exposed to rotenone when compared to the control group. Both the cell viability and the expression of phospho-CREB in cells pretreated with rifampicin were higher than those of cells exposed to rotenone alone. Moreover, pretreatment of SH-SY5Y cells with rifampicin enhanced phosphorylation of Akt and suppressed activity of GSK-3beta. The addition of LY294002, a PI3K inhibitor, could suppress phosphorylation of Akt and CREB and activate GSK-3beta, resulting in abolishment of neuroprotective effects of rifampicin on cells exposed to rotenone. Rifampicin provides neuroprotection against dopaminergic degeneration, partially via the PI3K/Akt/GSK-3beta/CREB signaling pathway. These findings suggest that rifampicin could be an effective and promising neuroprotective candidate for treating PD. PMID- 29435804 TI - Human Neural Stem Cells with GDNF Site-Specific Integration at AAVS1 by Using AAV Vectors Retained Their Stemness. AB - The neural stem cells (NSCs) have the ability to self-renew, and to migrate to pathologically altered regions of the central nervous system. Glial cell derived neurotrophic factor (GDNF) could protect dopamine neurons and rescue motor neurons in vivo, which has been proposed as a promising candidate for the treatments of degenerative neurological diseases. In order to combine the advantages of neurotrophic factors and stem cells in clinical therapy, we established the modified hNSCs that has site-specific integration of GDNF gene by using recombinant adeno-associated virus (rAAV) vectors. The hNSCs were co infected by rAAV2-EGFP-GDNF and rAAV2-SVAV2 which provide integrase to specifically integrate GDNF gene into AAVS1 site. The GDNF-hNSCs maintained their original stem cell characteristics and the ability to differentiate into neurons in vitro. In the animal model, the GDNF-hNSCs were specifically transplanted into CA1 area of hippocampi and could migrate to the dentate gyrus region and differentiate into neuronal cells while maintaining GDNF expression. hNSCs with GDNF gene site-specific integration at AAVS1 by using AAV vectors retained their stemness and effectively expressed GDNF, which indicates the potential of employing transplanted hNPCs for treatment of brain injuries and degenerative neurological diseases. PMID- 29435806 TI - Critical West Nile Neuroinvasive Disease. AB - BACKGROUND: Data to guide neurointensivists seeing patients with West Nile Neuroinvasive disease (WNND) are lacking. We present a comparatively large series of patients with WNND admitted to the intensive care unit (ICU) and provide data on their early diagnosis, triage to the ICU and predictors of short-term outcomes. METHODS: We retrospectively identified patients aged >= 18 years old with WNND from January 1999 to November 2016. Demographic and clinical data, the modified Rankin Scale at discharge and disposition were collected. Univariate analysis was performed to find predictors of ICU admission and to assess the impact of ICU admission on the short-term outcomes. P values < 0.05 were considered significant. RESULTS: Among 26 patients, 16 were admitted to the ICU. Age < 60 years and the presentation with encephalitis and acute flaccid paralysis predicted ICU admission (P = 0.044 and 0.0007). Among patients requiring ICU admission, four died and no one was discharged home. ICU admission predicted longer hospital stay (P = 0.021), inhospital death (P = 0.034), survival with inability to walk independently (P = 0.0094), and discharge disposition other than home (P = 0.007). In the ICU group, older age was associated with longer hospital stay (P = 0.0001) and inhospital death (P = 0.035). CONCLUSION: WNND requiring ICU care has a high morbidity and mortality, especially among older patients. Survivors are highly disabled at discharge, but many improve over time. Therefore, more data on the long-term prognosis of survivors are needed to guide the goals of care in the acute setting. PMID- 29435805 TI - Kallikrein-related peptidase 6 (KLK6) expression differentiates tumor subtypes and predicts clinical outcome in breast cancer patients. AB - Novel molecular markers that address the heterogeneity of breast cancer (BC) and provide meaningful prognostic information for BC patients are needed. Kallikrein related peptidase 6 (KLK6) is aberrantly expressed and functionally implicated in BC and, like other members of the KLK family, may prove a useful molecular tool for clinical management. Our objective was to assess, for the first time, the clinical relevance of KLK6 mRNA expression in BC. Total RNA was isolated from 165 breast tumors, as well as 100 adjacent non-cancerous tumor specimens. After cDNA synthesis, and following quality control, quantitative real-time PCR for KLK6 expression analysis took place. Receiver operating characteristic curves were constructed in order to assess the ability of KLK6 mRNA expression levels to differentiate between molecular BC subtypes. Survival analyses, using DFS as endpoint, were performed at the univariate and multivariate levels. Publicly available BC databases and online survival analysis tools were used to validate our findings. A significant downregulation of KLK6 mRNA expression was observed in BC tissue sections compared to the non-cancerous component (P < 0.001). The expression of KLK6 is positively associated with tumor grade (P = 0.038) and is overexpressed in TNBC and HER2-positive tumors (P < 0.001). Aberrant KLK6 expression predicts the clinical outcome of BC patients in terms of DFS, independently of currently used prognostic markers (HR = 7.11, 95% CI = 1.19 42.45). The differential expression of KLK6 and its association with unfavorable outcome in BC patients was validated via in silico analyses. Although an independent external cohort is necessary to confirm our findings, we proved for the first time that KLK6 can provide independent prognostic information for BC patients. PMID- 29435807 TI - Treatment outcome of creatine transporter deficiency: international retrospective cohort study. AB - To evaluate the outcome of current treatment for creatine transporter (CRTR) deficiency, we developed a clinical severity score and initiated an international treatment registry. An online questionnaire was completed by physicians following patients with CRTR deficiency on a treatment, including creatine and/or arginine, and/or glycine. Clinical severity score included 1) global developmental delay/intellectual disability; 2) seizures; 3) behavioural disorder. Phenotype scored 1-3 = mild; 4-6 = moderate; and 7-9 = severe. We applied the clinical severity score pre- and on-treatment. Seventeen patients, 14 males and 3 females, from 16 families were included. Four patients had severe, 6 patients had moderate, and 7 patients had a mild phenotype. The phenotype ranged from mild to severe in patients diagnosed at or before 2 years of age or older than 6 years of age. The phenotype ranged from mild to severe in patients with mildly elevated urine creatine to creatinine ratio. Fourteen patients were on the combined creatine, arginine and glycine therapy. On the combined treatment with creatine, arginine and glycine, none of the males showed either deterioration or improvements in their clinical severity score, whereas two females showed improvements in the clinical severity score. Creatine monotherapy resulted in deterioration of the clinical severity score in one male. There seems to be no correlation between phenotype and degree of elevation in urine creatine to creatinine ratio, genotype, or age at diagnosis. Combined creatine, arginine and glycine therapy might have stopped disease progression in males and improved phenotype in females. PMID- 29435808 TI - Moringa oleifera supplemented diet modulates nootropic-related biomolecules in the brain of STZ-induced diabetic rats treated with acarbose. AB - There are strong correlations between diabetes mellitus and cognitive dysfunction. This study sought to investigate the modulatory effects of Moringa oleifera leaf (ML) and seed (MS) inclusive diets on biomolecules [acetylcholinesterase (AChE), butyrylcholinesterase (BChE)] angiotensin-I converting enzyme (ACE), arginase, catalase, glutathione transferase (GST) and glutathione peroxidase (GSH-Px) activities, glutathione (GSH) and nitric oxide (NO) levels] associated with cognitive function in the brain of streptozotocin (STZ)-induced diabetic rats treated with acarbose (ACA). The rats were made diabetic by intraperitoneal administration of 0.1 M sodium-citrate buffer (pH 4.5) containing STZ [60 mg/kg b.w (BW)] and fed with diets containing 2 and 4% ML/MS. Acarbose (25 mg/kg BW) was administered by gavage daily for 14 days. The animals were distributed in eleven groups of eight animals as follows: control, STZ-induced, STZ + ACA, STZ + 2% ML, STZ + ACA + 2% ML, STZ + 4% ML, STZ + ACA + 4% ML, STZ + 2% MS, STZ + ACA + 2% MS, STZ + 4% MS, STZ + ACA + 4% MS. There were marked increase in AChE, BChE, arginase, ACE and concomitant decrease in catalase, GST, GSH-Px, activities and NO levels in STZ-diabetic group compared with the control. However, there was a decrease in AChE, BChE and ACE activities and concomitant increase in the antioxidant molecules in the groups fed with supplemented diets treated with/without ACA compared with the STZ-diabetic group. These findings suggest that ML/MS supplemented diet could prevent cognitive dysfunction-induced by chronic hyperglycemia. PMID- 29435809 TI - Body mass index predicts insulin sensitivity during cardiac surgery: a prospective observational study. AB - PURPOSE: Taking into account the previously described link between body weight and diabetes mellitus (DM) in non-surgical patients, and the understanding that the degree of intraoperative insulin resistance is a predictor of adverse clinical outcomes, we investigated the relationship between body mass index (BMI) and insulin sensitivity during cardiac surgery. METHODS: We prospectively enrolled 400 patients scheduled for elective cardiac surgery and divided them into groups based on the presence or absence of type-2 DM. They were further categorized into four subgroups based on their BMI: group 1- normal weight, BMI 18.5-24.9 kg.m-2; group 2 - overweight, BMI 25-29.9 kg.m-2; group 3 - obese, BMI 30-34.9 kg.m-2; group 4 - morbidly obese, BMI >= 35 kg.m-2. Insulin sensitivity was assessed using the hyperinsulinemic-normoglycemic clamp technique during surgery. We also analyzed the association of BMI, quality of postoperative glycemic control, and postoperative outcomes. RESULTS: A linear negative relationship between BMI and insulin sensitivity (r = 0.42, P < 0.001) was observed, independent of the patients' diabetic state. There was also a positive correlation between BMI and postoperative glycemia (r = 0.30, P < 0.001) though the relationship between BMI and major and infectious complication was not significant (P = 0.56, P = 0.10, respectively). CONCLUSIONS: Patient BMI may be used as a simple predictor of insulin sensitivity during cardiac surgery and as a predictor of the quality of postoperative glycemic control. A larger cohort will be necessary to evaluate the association of BMI, perioperative insulin resistance, and clinical outcomes. PMID- 29435810 TI - Effect of position and positive pressure ventilation on functional residual capacity in morbidly obese patients: a randomized trial. AB - PURPOSE: In morbidly obese patients, the position and ventilation strategy used during pre-oxygenation influence the safe non-hypoxic apnea time and the functional residual capacity (FRC). In awake morbidly obese volunteers, we hypothesized that the FRC would be higher after a five-minute period of positive pressure ventilation compared with spontaneous ventilation at zero inspiratory pressure. METHODS: Using a prospective crossover randomized trial design, obese subjects underwent, in a randomized order, a combination of one of three positions, supine (S), beach chair (BC), and reverse Trendelenburg (RT), and one of two ventilation strategies, spontaneous ventilation at zero inspiratory pressure (ZEEP-SV) or with positive pressure (PP-SV) set to an inspiratory pressure of 8 cmH2O, positive end-expiratory pressure of 10 cmH2O, and fraction of inspired oxygen of 0.21. RESULTS: Seventeen obese volunteers with a mean (standard deviation; SD) body mass index of 50 (8) kg.m-2 were included. Mean (SD) FRC in the three positions (S, BC, RT) was significantly higher using PP-SV compared with ZEEP-SV [2571 (477) vs 2215 (481) mL, respectively; mean difference, 356; 95% confidence interval (CI), 209 to 502; P < 0.001]. Mean (SD) FRC was significantly higher in the RT compared with BC position [2483 (521) vs 2338 (469) mL, respectively; mean difference, 145; 95% CI, 31 to 404; P = 0.01], while there was no difference between S and BC [2359 (519) mL vs 2338 (469) mL, respectively; mean difference, 21; 95% CI, -93 to 135; P = 0.89]. CONCLUSION: In awake morbidly obese volunteers, an increase in the FRC is observed when spontaneous ventilation at zero inspiratory pressure is switched to positive pressure. Compared with S positioning, the BC position had no measurable impact on the FRC. The RT position resulted in an optimal FRC. TRIAL REGISTRATION: clinicaltrials.gov (NCT02121808). Registered 24 April 2014. PMID- 29435811 TI - Comparative Outcomes of Bariatric Surgery in Patients with Impaired Mobility and Ambulatory Population. AB - PURPOSE: This study aims to characterize complications, metabolic improvement, and change in ambulation status for patients with impaired mobility undergoing bariatric surgery. MATERIAL AND METHODS: Individuals undergoing primary sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) from February 2008 to December 2015 were included. Impaired mobility (WC) was defined as using a wheelchair or motorized scooter for at least part of a typical day. The WC group was propensity score matched to ambulatory patients (1:5 ratio). Comparisons were made for 30-day morbidity and mortality and 1-year improvement in weight-related comorbidities. RESULTS: There were 93 patients in the WC group matched to 465 ambulatory controls. The median operative time (180 vs 159 min, p = 0.003) and postoperative length of stay (4 vs 3 days, p <= 0.001) was higher in the WC group. There were no differences in readmission or all-cause morbidity within 30 days. The median percent excess weight loss (%EWL) at 1 year was similar (WC group, 65% available, 53% EWL vs AMB group, 73% available, 54% EWL); however, patients with impaired mobility were less likely to experience improvement in diabetes (76 vs 90%, p = 0.046), hypertension (63 vs 82%, p < 0.005), and obstructive sleep apnea (53 vs 71%, p < 0.001). Within the WC group, 62% had improvement in their mobility status, eliminating dependence on wheelchair or scooter assistance. CONCLUSION: Patients with both obesity and impaired mobility experience similar rates of perioperative morbidity and weight loss at 1 year compared to ambulatory controls. However, improvement in weight-related comorbidities may be less likely with impaired mobility. PMID- 29435812 TI - Predicting remission of diabetes post metabolic surgery: a comparison of ABCD, diarem, and DRS scores. AB - BACKGROUND: Obesity is one of the major causes for development of T2DM. Metabolic surgery has been proved to be a successful and cost-effective treatment modality for managing the patients with obesity and T2DM. Many scoring systems and models have been described in literature to predict the outcome of T2DM after metabolic surgery. The aim of this study is to compare the efficacy of Diarem, DRS, and ABCD score in predicting the T2DM remission. METHODS: A total number of 102 diabetic patients, who underwent LMGB/LOAGB, were selected for this study. A retrospective analysis of the three scoring systems when applied to these patients and their predictive abilities were analyzed. RESULTS: At 1 year after surgery, 72 (70.59%) patients achieved remission of T2DM. Though the pairwise comparisons between AUC on ROC analysis of ABCD, Diarem, and DRS scores does not show statistically significant difference between them, Diarem score has the maximum relative area under ROC curves. By multivariate analysis, it was found that factors significantly associated with T2DM remission were duration of T2DM, C-peptide, and Pre-Op HbA1c. CONCLUSIONS: Among the three scoring systems, though DiaRem score has the best sensitivity and specificity and maximum AUC, no statistically significant difference was found in their diabetes remission predicting abilities. A shorter duration of T2DM, a lower HbA1C, and higher levels of C-peptide were significantly associated with a higher chance of T2DM remission. PMID- 29435813 TI - Expectations Following Rotator Cuff Surgery. AB - PURPOSE OF REVIEW: To outline the radiographic and clinical outcomes after a rotator cuff surgery in order to set the expectations with the patient before the surgery to obtain a better outcome, taking into account the factors that can affect the outcome and the technique used for the repair. RECENT FINDINGS: The majority of surgeons use arthroscopic repair. The double-row repair has better biomechanical strength, footprint coverage, and radiographic healing rates. The principal factors that can affect the outcome of the surgery are the tendon quality, tear size and retraction, fatty infiltration, chronicity of the tear, and concomitant pathologies. Arthroscopic rotator cuff repair can decrease pain and increase function allowing patients to improve their quality of life; 90% of patients are happy 6 months after the surgery and maintain stability during 5 years. Greater preoperative expectations would show better outcomes and patient satisfaction after the surgery. PMID- 29435814 TI - Alterations in Gene and Protein Expression of Cannabinoid CB2 and GPR55 Receptors in the Dorsolateral Prefrontal Cortex of Suicide Victims. AB - Recent studies point to the cannabinoid CB2 receptors (CB2r) and the non cannabinoid receptor GPR55 as potential key targets involved in the response to stress, anxiety, and depression. Considering the close relationship between neuropsychiatric disorders and suicide, the purpose of this study was to evaluate the potential alterations of CB2r and GPR55 in suicide victims. We analyzed gene and protein expression of both receptors by real-time PCR and western blot, respectively, in the dorsolateral prefrontal cortex (DLPFC) of 18 suicide victims with no clinical psychiatric history or treatment with anxiolytics or antidepressants, and 15 corresponding controls. We used in situ proximity ligation assay to evaluate whether the receptors formed heteromeric complexes and to determine the expression level of these heteromers, also assessing the co expression of heteromers in neurons, astroglia, or microglia cells. CB2r and GPR55 gene expressions were significantly lower (by 33 and 41%, respectively) in the DLPFC of suicide cases. CB2r protein expression was higher, as were CB2-GPR55 heteroreceptor complexes. The results also revealed the presence of CB2-GPR55 receptor heteromers in both neurons and astrocytes, whereas microglial cells showed no expression. We did not observe any significant alterations of GPR55 protein expression. Additional studies will be necessary to evaluate if these alterations are reproducible in suicide victims diagnosed with different psychiatric disorders. Taken together, the results suggest that CB2r and GPR55 may play a relevant role in the neurobiology of suicide. PMID- 29435815 TI - Nerve Ultrasound Predicts Treatment Response in Chronic Inflammatory Demyelinating Polyradiculoneuropathy-a Prospective Follow-Up. AB - As reliable biomarkers of disease activity are lacking, monitoring of therapeutic response in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains a challenge. We sought to determine whether nerve ultrasound and electrophysiology scoring could close this gap. In CIDP patients (fulfilling EFNS/PNS criteria), we performed high-resolution nerve ultrasound to determine ultrasound pattern sum scores (UPSS) and predominant echotexture nerve conduction study scores (NCSS) as well as Medical Research Council sum scores (MRCSS) and inflammatory neuropathy cause and treatment disability scores (INCAT) at baseline and after 12 months of standard treatment. We retrospectively correlated ultrasound morphology with nerve histology when available. 72/80 CIDP patients featured multifocal nerve enlargement, and 35/80 were therapy-naive. At baseline, clinical scores correlated with NCSS (r2 = 0.397 and r2 = 0.443, p < 0.01), but not or hardly with UPSS (Medical Research Council sum scores MRCSS r2 = 0.013, p = 0.332; inflammatory neuropathy cause and treatment disability scores INCAT r2 = 0.053, p = 0.048). Longitudinal changes in clinical scores, however, correlated significantly with changes in both UPSS and NCSS (r2 = 0.272-0.414, p < 0.0001). Combining nerve/fascicle size with echointensity and histology at baseline, we noted 3 distinct classes: 1) hypoechoic enlargement, reflecting active inflammation and onion bulbs; 2) nerve enlargement with additional hyperechogenic fascicles/perifascicular tissue in > 50% of measured segments, possibly reflecting axonal degeneration; and 3) almost no enlargement, reflecting "burned out" or "cured" disease without active inflammation. Clinical improvement after 12 months was best in patients with pattern 1 (up to 75% vs up to 43% in pattern 2/3, Fisher's exact test p < 0.05). Nerve ultrasound has additional value not only for diagnosis, but also for classification of disease state and may predict treatment response. PMID- 29435816 TI - Rapid and reliable detection of previous freezing of cerebral tissue by computed tomography and magnetic resonance imaging. AB - Due to slowing or even inhibition of postmortem processes, freezing may make an estimation of the time-since-death very difficult. This is also true in previously frozen and subsequently thawed bodies. Knowledge of prior freezing is important, as it may lead to a different assessment of the time since death. Twelve pig heads were frozen at -20 degrees C, and 6 heads were either kept at room temperature (approximately 20 degrees C) or in a cooling cell (approximately 5 degrees C). The frozen brains and cadavers were thawed at either room temperature or in a cooling cell. All specimens underwent repeated CT and MRI scanning until the brains were sampled for histological examination. Two radiologists assessed the images and two pathologists reviewed the histological slides with regard to thawing artifacts and putrefaction. All raters were blinded regarding whether the samples had been frozen, for how long and how they had been thawed. Imaging revealed distinct, tiny bubble-like artifacts only in previously frozen specimens. Histology also revealed artifacts only seen in such cases, namely very distinct, columnar bubbles in the cerebral cortex. All raters successfully identified previously unfrozen brains (100% specificity) and nearly all previously frozen brains. Our results suggest that initial post-mortem imaging can be of enormous importance in everyday forensic practice by identifying possible cases of previous freezing - cases that would therefore warrant closer scrutiny and thus raise caution regarding the time of death. PMID- 29435817 TI - Analysis of a self-propelling sheet with heat transfer through non-isothermal fluid in an inclined human cervical canal. AB - The present theoretical analysis deals with biomechanics of the self-propulsion of a swimming sheet with heat transfer through non-isothermal fluid filling an inclined human cervical canal. Partial differential equations arising from the mathematical modeling of the proposed model are solved analytically. Flow variables like pressure gradient, propulsive velocity, fluid velocity, time mean flow rate, fluid temperature, and heat-transfer coefficients are analyzed for the pertinent parameters. Striking features of the pumping characteristics are explored. Propulsive velocity of the swimming sheet becomes faster for lower Froude number, higher Reynolds number, and for a vertical channel. Temperature and peak value of the heat-transfer coefficients below the swimming sheet showed an increase by the increment of Brinkmann number, inclination, pressure difference over wavelength, and Reynolds number whereas these quantities decrease with increasing Froude number. Aforesaid parameters have shown opposite effects on the peak value of the heat-transfer coefficients below and above the swimming sheet. Relevance of the current results to the spermatozoa transport with heat transfer through non-isothermal cervical mucus filling an inclined human cervical canal is also explored. PMID- 29435818 TI - Determinants of prolonged survival for breast cancer patient groups with leptomeningeal metastasis (LM). AB - The study aimed to assess factors affecting survival of breast cancer patients suffering leptomeningeal metastasis (LM) and to compare survivals in patients with LM as the first and only site of metastases at presentation to patients with LM and metastases in other organs, along with selecting a patient group which had the best survival outcomes. Subject groups consisted of 187 patients consecutively referred during 1999-2015. A Cox proportional hazards model was used to identify factors associated with prolonged survival from LM. The Cox prognostic index was created to identify the group of patients with the most favorable prognosis. Median survival for all patients and for those with LM as the first site of metastases at presentation was 17 weeks and 1 year-survival was 15 and 16%, respectively. Factors beneficially affecting survival were: KPS >= 70, older age, biological subtype ER/PR+HER2-, systemic treatment, intrathecal treatment and radiation therapy. Based on these factors, 4 prognostic groups were found, with the most favorable group being 24 LM patients with median survival of 9.6 months. In this group, all patients were treated systemically and all were irradiated, 88% had KPS >= 70, about 80% had luminal breast cancer, 75% were treated intrathecally and 58% were more than 53 years old. Out of 4 prognostic groups of patients with LM, the most favorable group was selected. The median survival of breast cancer patients with the leptomeninges as the only site of metastases was comparable to those who had metastases in the leptomeninges and in other organs. PMID- 29435820 TI - Once upon a time ...A special issue for the 10th anniversary of the Journal of Cell Communication and Signaling. PMID- 29435819 TI - Expanding Role of Third Space Endoscopy in the Management of Esophageal Diseases. AB - OPINION STATEMENT: "Third space" endoscopy, also commonly referred as submucosal endoscopy, is founded on the principle that the deeper layers of the gastrointestinal (GI) tract can be accessed by tunneling in the submucosal space without compromising the integrity of the overlying mucosa. Peroral endoscopic myotomy (POEM), endoscopic submucosal dissection (ESD), and submucosal tunneling endoscopic resection (STER) are innovative techniques within the field of third space endoscopy in the management of esophageal disorders. POEM has become an accepted minimally invasive therapy for achalasia and related motility disorders with excellent short-term results, with early studies yielding similar efficacy to surgical myotomy and increased durability when compared to pneumatic balloon dilation (PBD). Data are needed to establish long-term outcomes with POEM, with particular interest on the incidence of gastroesophageal reflux, which appears to be higher than initially anticipated. ESD, a mature endoscopic resection technique in Asia, has recently gained traction in the West as a viable option for the management of early Barrett's esophagus (BE) neoplasia. Compared to standard endoscopic mucosal resection (EMR), ESD allows the en bloc resection of lesions irrespective of size, which may facilitate histological interpretation and reduce recurrence rates. Large prospective randomized controlled trials are needed to validate the efficacy and safety of this technique and to further define its role in the endoscopic armamentarium in early BE neoplasia. STER is an attractive technique that theoretically permits the resection of subepithelial esophageal tumors (SETs) arising from the deeper GI layers. Initial studies from highly experienced endoscopic centers support its technical feasibility and safety, although these results should be interpreted with caution due to variability arising from small numbers and heterogeneity among studies. Overall, third space endoscopy is an expanding field within endoscopic therapeutics for the treatment of esophageal diseases. While initial results have been very promising, large prospective studies, long-term data, and structured training programs with the establishment of competency parameters are needed before third space endoscopy can be advocated outside of highly specialized centers. PMID- 29435821 TI - 7,8-Dihydroxycoumarin exerts antitumor potential on DMBA-induced mammary carcinogenesis by inhibiting ERalpha, PR, EGFR, and IGF1R: involvement of MAPK1/2 JNK1/2-Akt pathway. AB - Breast cancer (BC) is a persistent and impulsive metabolic disorder with the highest prevalence in women, worldwide. 7,12-Dimethylbenz(a)anthracene (DMBA) is a potent polyaromatic hydrocarbon (PAH)-based carcinogen producing mammary carcinomas in rats resembling the human hormone-dependent BC. 7,8 Dihydroxycoumarin (78DC) is a coumarin derivative that possesses diversified and favorable pharmacology profile to be considered in anticancer research against various malignancies. The present study was intended to investigate the antiproliferative and chemotherapeutic potentials of 78DC (20, 40, and 80 mg/kg BW) against DMBA (20 mg in olive oil)-induced mammary carcinoma Sprague-Dawley rats. We established the in silico approach for evaluation of the effect of 78DC on hormonal (estrogen receptor-alpha (ERalpha), progesterone receptor (PR)), growth factor receptors (EGFR and IGFR), 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HD1), and aromatase. Effect of 78DC on estrogen synthesis, tumor growth, proliferation markers (Ki-67 and PCNA), cytokines (IL-10, IL-1beta, IL 12), chemokine (MCP-1), and cellular expressions of ERalpha, PR, EGFR, IGF1R, p MAPK1/2, p-JNK1/2, p-Akt, 17beta-HD1, and aromatase was evaluated in mammary carcinoma bearing SD rats. DMBA induces large tumor burden and histological alterations in mammary gland with a subsequent increase in ERalpha, PR, EGFR, IGF1R, Ki-67, proliferating cell nuclear antigen (PCNA ), cytokines, and chemokine expressions. This was also correlated with the changes in rapid cell differentiation and proliferation. In contrast, 78DC treatment to the cancer bearing animals abbreviated these changes and revealed to possess antitumorigenic and antiproliferative potentials. Further, a significant decrease in expressions of ERalpha, PR, EGFR, IGFR, p-MAPK1/2, p-JNK1/2, p-Akt, 17beta-HD1, and aromatase signifies a reduction in estrogen sensitivity and secondary signaling pathways that may contribute to the prevention of tumor growth. The current findings revealed that 78DC potentially reduce cancer cell proliferation and reverted mammary cancer-induced changes in experimental animals in a dose-dependent manner. PMID- 29435822 TI - Do Simulated Gambling Activities Predict Gambling with Real Money During Adolescence? Empirical Findings from a Longitudinal Study. AB - As technology has developed, the international gambling market has changed markedly in recent years. The supply of internet-based gambling opportunities has become ever more significant. At the same time, the introduction of new gambling opportunities always brings a demand for evidence-based scientific evaluation, with regard to the associated risks of addiction. Simulated internet gambling, which is the focus of this study, represents a relatively new product group located at the interface between gambling and computer gaming. Concerns have been raised in scientific literature, especially with regard to the adolescent age group, as to whether participation in simulated internet gambling directly promotes recruitment to the world of monetary gambling, as defined in the gateway hypothesis. The research design was based on a standardized, representative longitudinal survey (over a 1-year period) with a total of 1178 school pupils from Northern Germany (M = 13.6 years; 47.5% male). It must be borne in mind that 12% of the adolescents belonged to the subgroup of "onset gamblers" and first reported experience with monetary gambling at the second stage of surveying. Logistic regression analysis demonstrates that this migration process is fostered by (1) participation from home in simulated gambling on social networks and (2) significant exposure to advertising (relating to both simulated and monetary gambling). Within the subgroup of simulated internet gamblers, variables such as particular patterns of use (including breadth and depth of involvement with simulated internet gambling, certain motives for participation, and microtransactions) do not serve as significant predictors. Despite this, important needs for action for the purposes of prevention and research can be identified. PMID- 29435823 TI - Testing the Emotional Vulnerability Pathway to Problem Gambling in Culturally Diverse University Students. AB - Loneliness and adapting to an unfamiliar environment can increase emotional vulnerability in culturally and linguistically diverse (CALD) university students. According to Blaszczynski and Nower's pathways model of problem and pathological gambling, this emotional vulnerability could increase the risk of problem gambling. The current study examined whether loneliness was associated with problem gambling risk in CALD students relative to their Australian peers. Additionally, differences in coping strategies were examined to determine their buffering effect on the relationship. A total of 463 female and 165 male university students (aged 18-38) from Australian (38%), mixed Australian and CALD (23%) and CALD (28%) backgrounds responded to an online survey of problem gambling behaviour, loneliness, and coping strategies. The results supported the hypothesis that loneliness would be related to problem gambling in CALD students. There was no evidence of a moderating effect of coping strategies. Future research could test whether the introduction of programs designed to alleviate loneliness in culturally diverse university students reduces their risk of developing problem gambling. PMID- 29435824 TI - Psycholinguistic variables matter in odor naming. AB - People from Western societies generally find it difficult to name odors. In trying to explain this, the olfactory literature has proposed several theories that focus heavily on properties of the odor itself but rarely discuss properties of the label used to describe it. However, recent studies show speakers of languages with dedicated smell lexicons can name odors with relative ease. Has the role of the lexicon been overlooked in the olfactory literature? Word production studies show properties of the label, such as word frequency and semantic context, influence naming; but this field of research focuses heavily on the visual domain. The current study combines methods from both fields to investigate word production for olfaction in two experiments. In the first experiment, participants named odors whose veridical labels were either high frequency or low-frequency words in Dutch, and we found that odors with high frequency labels were named correctly more often. In the second experiment, edibility was used for manipulating semantic context in search of a semantic interference effect, presenting the odors in blocks of edible and inedible odor source objects to half of the participants. While no evidence was found for a semantic interference effect, an effect of word frequency was again present. Our results demonstrate psycholinguistic variables-such as word frequency-are relevant for olfactory naming, and may, in part, explain why it is difficult to name odors in certain languages. Olfactory researchers cannot afford to ignore properties of an odor's label. PMID- 29435825 TI - Word segmentation by alternating colors facilitates eye guidance in Chinese reading. AB - During sentence reading, low spatial frequency information afforded by spaces between words is the primary factor for eye guidance in spaced writing systems, whereas saccade generation for unspaced writing systems is less clear and under debate. In the present study, we investigated whether word-boundary information, provided by alternating colors (consistent or inconsistent with word-boundary information) influences saccade-target selection in Chinese. In Experiment 1, as compared to a baseline (i.e., uniform color) condition, word segmentation with alternating color shifted fixation location towards the center of words. In contrast, incorrect word segmentation shifted fixation location towards the beginning of words. In Experiment 2, we used a gaze-contingent paradigm to restrict the color manipulation only to the upcoming parafoveal words and replicated the results, including fixation location effects, as observed in Experiment 1. These results indicate that Chinese readers are capable of making use of parafoveal word-boundary knowledge for saccade generation, even if such information is unfamiliar to them. The present study provides novel support for the hypothesis that word segmentation is involved in the decision about where to fixate next during Chinese reading. PMID- 29435826 TI - Efficacy of bovine lactoferrin in the post-surgical treatment of patients suffering from bisphosphonate-related osteonecrosis of the jaws: an open-label study. AB - Osteonecrosis of the jaws is an emerging pathological condition characterized by un-exposure or exposure of the necrotic bone, independently from the etiology. This term is usually referred to medication-related osteonecrosis of the jaws due to severe adverse reaction to certain medicines, as bisphosphonates, used for the treatment of cancer and osteoporosis. The management of patients with Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ) remains challenging because surgical and medical interventions may not eradicate this pathology. The goal of treatment of patients at risk of developing BRONJ or of those who have active disease is the preservation of quality of life by controlling pain, managing infection, and preventing the development of new areas of necrosis. The treatment of osteonecrosis consists in the surgical removal of necrotic bone followed by antibiotic therapy and application of sterile greasy gauze until the wound closure. The classical medical treatment has been compared with the innovative one consisting in the application of sterile greasy gauze soaked with bovine lactoferrin (bLf) after surgery. Here, for the first time, bLf efficacy on wound repair in subjects suffering from BRONJ with the progressive destruction of bone in the mandible or maxilla has been demonstrated. The positive results consist in a significant shorter time of wound closure (1 or 2 weeks) compared to that observed with classical surgical treatment (2-3 months). These promising results are an interesting tool for the innovative treatment of this pathology and for increasing the quality of life of these patients. PMID- 29435827 TI - Hydrocephalus in children under the age of five from diagnosis to short-/medium /long-term progression: a retrospective review of 142 children. AB - The aim of this study is to evaluate the clinical history and prognosis of children with early-onset hydrocephalus. The retrospective study's inclusion criteria were hydrocephalus diagnosis before the age of 5 years, independent of aetiology, and birth details, January 1, 2000 to December 31, 2014. Overall, 142 children were entered into the study, divided into 11 aetiological groups: premature-birth post-intraventricular haemorrhage (16%), brain tumours (16%), spina bifida (15%), aqueductal stenosis (8%), post-meningitis (8%), post haemorrhage (8%), Dandy-Walker malformation (6%), unknown origin (6%), arachnoid cyst (5%), miscellaneous obstruction (4%), and various causes (8%). In total, 23 patients died, primarily from the tumour group. Ventriculostomy, performed 42 times, was successful in 20 patients. Overall, 226 internal shunts were placed in 99 children. Infectious complications affected 19% of children after shunt placement and 51% after mechanical complications. Mean follow-up was 4 years 10 months, with 61% of children progressing fairly well, especially those with aqueductal stenosis, cysts, and unknown or diverse obstructive causes. Post meningitis hydrocephalus displayed the poorest outcome. Isolated obstructive hydrocephalus exhibited better prognosis, with most obstructive aetiologies effectively treated via ventriculostomy. Children treated by shunt placement were more at risk of complications. Aetiologies with associated abnormalities and neurological sequelae had poorer outcomes. PMID- 29435828 TI - Relevance of standard intravenous thrombolysis in endovascular stroke therapy of a tertiary stroke center. AB - The majority of patients undergoing endovascular stroke treatment (EST) in randomized controlled trials received additional systemic thrombolysis ("combination or bridging therapy (C/BT)"). Nevertheless, its usefulness in this subtype of acute ischemic stroke (AIS) is discussed controversially. Of all consecutive AIS patients, who received any kind of reperfusion therapy in a tertiary university stroke center between January 2015 and March 2016, those with large vessel occlusions (LVO) and EST with or without additional C/BT, were compared primarily regarding procedural aspects. Data were extracted from an investigator-initiated, single-center, prospective and blinded end-point study. 70 AIS patients with EST alone and 118 with C/BT were identified. Significant baseline differences existed in pre-existing cardiovascular disease (52.9% (EST alone) vs. 35.6% (C/BT), p = 0.023), use of anticoagulation (30.6% vs. 5.9%, p < 0.001), and frequency of unknown time of symptom onset (65.7% vs. 32.2%, p < 0.001), in-hospital stroke (18.6% vs. 1.7%, p < 0.001), pre-treatment ASPECT scores (7.9 vs. 8.9, p = 0.004), and frequency of occlusion in the posterior circulation (18.6% vs. 5.1%, p = 0.003). Pre-interventional procedural time intervals tended to be shorter in the C/BT group, reaching statistical significance in door-to-image time (30.3 (EST alone) vs. 22.2 min (C/BT), p < 0.001). Good clinical outcome (mRS d90) was reached more often in the C/BT group (24.5% vs. 11.8%, p = 0.064). Rates of symptomatic intracranial hemorrhages (sICH) were comparable (4.3% (EST alone) vs. 6.8% (C/BT), p = 0.481). Additional systemic thrombolysis did not delay EST. On the contrary, application of IVRTPA seemed to be a positive indicator for faster EST without increased side effects. PMID- 29435829 TI - An SIV macaque model of SIV and HAND: the need for adjunctive therapies in HIV that target activated monocytes and macrophages. AB - Non-human primate models of AIDS and neuroAIDS are critical to study HIV infection of the CNS, neuropathology, and immune activation and macrophage accumulation that occurs in HAND. SIV, similar to HIV, infects CD4+ T lymphocytes and monocytes/macrophages. Virus enters the CNS early, and macrophage activation correlates with CNS disease, as well as inflammation outside of the CNS. Antiretroviral in HIV+ humans and SIV+ Rhesus macaques results in non-detectable plasma virus, decreased or non-detectable viral RNA or protein in the CNS. But, viral DNA rebounds following therapy interruption, demonstrating the presence of replication competent virus in the CNS within myeloid cells. In this brief review, we discuss our findings using a Rhesus macaque model of SIV-associated CNS infection and pathology, focusing on monocyte/macrophage activation and the link between CNS and cardiac disease. We conclude with recent studies using adjunctive therapy targeting monocytes/macrophages with ART to prevent or diminish CNS pathology that may be associated with HAND. PMID- 29435830 TI - Continuous Production of Isomalto-oligosaccharides by Thermo-inactivated Cells of Aspergillus niger J2 with Coarse Perlite as an Immobilizing Material. AB - The coarse perlite 40-80 mesh was selected as an immobilizing material and put into a packed bed reactor (PBR) to continuously convert maltose to isomalto oligosaccharides (IMOs). The PBR was prepared by mixing the thermo-inactivated cells (TIC) from Aspergillus niger J2 strain with the coarse perlite, then the mixture was put into an overpressure-resistant column. Compared with diatomite 40 80 mesh and thin perlite 80-120 mesh in PBR, coarse perlite was chosen as the best filtration aid, when the ratio of coarse perlite versus TIC was 1:1. The thermal and pH stability of the free and immobilized TIC and the optimum conditions for the transglycosylation reactions were determined. The results show that approximately 75 and 82% and 87 and 91% of alpha-glucosidase activity were reserved for free and immobilized TIC at temperatures from 30 to 60 degrees C and pH from 3.00 to 7.00 for 12 h, respectively. With 30% malt syrup under the conditions of 50 degrees C and pH 4.00, a mini-scale packed bed reactor (Mi-PBR) and medium-scale packed bed reactor (Me-PBR) could continuously produce IMO over 25 and 34 days with the yield of effective IMO (eIMO) >= 35% and total IMO (tIMO) >= 50%, respectively. The strategy of mixing the coarse perlite with TIC in PBR is a novel approach to continuously produce IMO and has great application potential in industry. PMID- 29435831 TI - Preliminary Study of Mechanisms of Fluoride-Induced Suppression of Nitric Oxide Synthesis in Human Umbilical Vein Endothelial Cells. AB - This study was aimed to determine if excessive exposure to fluoride could suppress the synthesis of nitric oxide (NO) and to detail the mechanisms involved. With the exception of the control group, human umbilical vein endothelial cells (HUVECs) were treated with sodium fluoride (NaF) (1.2 MUg/mL) for 24 h, with or without a 2-h pretreatment with 100 nM insulin-like growth factor 1 (IGF-1, a PI3K/AKT agonist), or 10 MUM histamine (HIS, a eNOS agonist). The levels of NO in culture fluids, as well as the expressions of eNOS, p-eNOS, PI3K, AKT, and p-AKT, were compared. The levels of NO significantly decreased in all experimental groups; however, the levels of NO were obviously higher in the NaF + HIS and NaF + IGF-1 groups, compared to the NaF group. The p-eNOS/eNOS ratios dropped clearly in NaF and NaF + HIS groups, while that in the NaF + HIS group was distinctly higher than that in the NaF group. The p-AKT/AKT ratios went down apparently in NaF and NaF + IGF-1 groups, while that in the NaF + IGF-1 group was overtly higher than that of the NaF group. Excessive exposure to fluoride inhibited the synthesis of NO. The PI3K/AKT/eNOS pathway played a crucial role in the reduced expression of NO caused by excessive fluoride exposure. PMID- 29435833 TI - Head and Neck Cancer-The Patient Perspective. AB - The following chapter details diagnosis, treatment, and aftermath from a head and neck cancer patient's point of view. It illustrates the potential daily challenges of undergoing treatment while coping with the diagnosis of cancer. The toxicities of treatment and recovery from them are described to better inform treating physicians, as well as counsel future patients on the preparation needed for a successful outcome. We acknowledge each patient has a unique story to tell. This is one patient's story. PMID- 29435832 TI - Myocardial injury in elderly patients after abdominal surgery. AB - BACKGROUND: The development of sensitive myocardial-specific cardiac biomarkers allows for detection of very small amounts of myocardial injury or necrosis. Myocardial injury (MI) as a prelude of the serious perioperative complication myocardial infarction, should be paid more attention, especially in elderly susceptible patients. Myocardial injury after abdominal surgery in elderly patients has not been described yet. The objectives of this study were to identify the incidence, predictors, characteristics and the impact of MI on outcome in elderly patients underwent abdominal surgery. METHODS: Patients aged >= 65 who underwent abdominal surgery longer than 2 h between January 2016 and March 2017 were reviewed. Patients with peak troponin I level of 0.04 ng/ml or greater (abnormal laboratory threshold) within once-administration-period and without non-ischemia troponin elevation proof (e.g., sepsis) were assessed for characteristics and prognosis. Risk factors of MI were determined by multivariable regression. RESULTS: Among 285 patients with whole information, 36 patients (12.6%) suffered MI, only 2 patients (0.7%) fulfilled definition of myocardial infarction. With most of them occurred within first 7 days after surgery. Multivariable analysis showed that coronary artery disease (CAD) history [odds ratio (OR) 2.817, P = 0.015], non-laparoscopic surgery (OR 5.181, P = 0.030), blood loss >= 800 ml (OR 3.430, P = 0.008), non-venous maintain (OR 2.105, P = 0.047), and infection (OR 4.887, P = 0.008) as risk factors for MI. MI was associated with longer hospital stay (P = 0.006), more cardiac consultation (P = 0.011), higher infection(P = 0.016) and reoperation(P = 0.026) rate. CONCLUSION: MI is common in elderly patients who underwent abdominal surgery, while myocardial infarction is infrequent. They are both associated with risk factors and worse prognosis. MI deserves more attention especially in elderly patients. Troponin I measurement is a useful test after massive surgery, which can help risk-stratifying patients, effective preventing, prompt managing and predicting outcomes. Routine monitoring of cardiac biomarkers especially within 7 days after abdominal surgery in elderly patients is recommended. PMID- 29435834 TI - Physician Assistants and Nurse Practitioners in Head and Neck Surgery. AB - This chapter explores the role of advanced practice clinicians (APCs) and patient care coordinators in the head and neck cancer setting. APCs, which include physician assistants (PAs) and nurse practitioners (NPs), are licensed professional healthcare providers who diagnose and treat illnesses, order and interpret diagnostic tests, and prescribe pharmaceutical and non-pharmaceutical therapies. Although the training, education, and licensure differ between PAs and NPs, their roles are quite similar in head and neck surgery. They collaboratively participate in the medical and surgical management and coordination of head and neck cancer patients in a variety of settings including outpatient clinic, inpatient, and in the surgical suite. APCs can function autonomously in an outpatient clinic with the medical management of postoperative visits and new consults. In an inpatient setting, they perform daily inpatient rounds and manage patient care preoperatively and postoperatively. In head and neck surgery, registered nurses (RNs) usually function in the role of patient care coordinators. They serve as a liaison between the patient and all members of the multidisciplinary team. APCs and patient care coordinators work closely with medical oncologists, radiation oncologists, surgeons, and other allied health professionals to provide high-quality care and achieve optimal patient outcomes in the head and neck cancer setting. PMID- 29435835 TI - Role of the Speech-Language Pathologist (SLP) in the Head and Neck Cancer Team. AB - While treatments for head and neck cancer are aimed at curing patients from disease, they can have significant short- and long-term negative impacts on speech and swallowing functions. Research demonstrates that early and frequent involvement of Speech-Language Pathologists (SLPs) is beneficial to these functions and overall quality of life for head and neck cancer patients. Strategies and tools to optimize communication and safe swallowing are presented in this chapter. PMID- 29435836 TI - Oral and Dental Health in Head and Neck Cancer Patients. AB - A diagnosis of head and neck cancer (HNC) is typically followed by therapy that is associated with immediate and long-lasting toxic consequences. HNC patients' oral health needs may be complex and are best addressed in multidisciplinary collaborative teams including surgical, medical, and radiation oncologists, dental providers, nutrition, speech/swallow specialists, and physical therapists. Oral health maintenance also requires patient compliance and caregiver support. The role of dental providers begins prior to cancer diagnosis and continues through survivorship. This includes oral screening and health maintenance, management of common oral complications such as mucositis, pain, infection, salivary dysfunction, altered taste, and dental decay, as well as complex issues that include soft tissue fibrosis, osteoradionecrosis of the jaw, dysphagia, and recurrent/new primary malignancies. As the number of potential therapeutic interventions for HNC increase, so do the spectrum of side effects affecting the oral cavity, oropharynx, and dentition. Specific approaches to oral care must be tailored to the idiosyncrasies of the patient and his/her therapy and condition. Oral and dental care is impacted by the patient's oral and dental status prior to cancer therapy, as well as the specific cancer type, location, stage, and its treatment and potential comorbid conditions. Communication between the dental professional and the oncology team is required for appropriate therapy and is best accomplished by integrated healthcare teams. PMID- 29435837 TI - Imaging Evaluation of the Head and Neck Oncology Patient. AB - Imaging plays a multifaceted role in the diagnosis and characterization of head and neck oncological patients and is integral to their care. Given the complexity of treatment, a multimodality approach is often necessary. With the advent of new technologies, imaging can also be used to predict tumor behavior and treatment response. In this chapter, with selected case examples, we describe the various imaging modalities available and offer suggestions on their utilization. PMID- 29435838 TI - Challenges in Head and Neck Pathology. AB - The surgical pathologist plays a crucial role in the multidisciplinary team. In nearly all cases, a tissue diagnosis is required to confirm the disease process before treatment begins. Even in settings where the diagnosis appears straightforward, a timely and appropriate report is necessary. The pathologist is also responsible for providing many of the more specific data elements that will guide treatment decisions: examples include evidence of virally driven malignancy, margin status, and the precise depth to which tumor invades. Each of these diagnoses and findings has its own specific set of difficulties and limitations, which require nuanced interpretation by a well-informed pathologist. PMID- 29435839 TI - Surgical Perspectives in Head and Neck Cancer. AB - Head and neck cancer treatment is a complex multidisciplinary undertaking. Cancer cure and survival is a primary goal, yet safe-guarding appearance and function to preserve the quality of life are similarly critical. The head and neck surgeon remains central to multidisciplinary cancer care, with deep knowledge of operative technique and an even deeper understanding of cancer biology. The surgeon models practice based on the highest levels of scientific evidence, but also takes into consideration the approaches that may best suit an individual patient. The surgeon's role moreover spans the life history of a head and neck cancer patient, from diagnosis to surveillance. The intimacy of this role makes the surgeon a trusted and frequent frame of reference for the patient. In this chapter, we provide an overview of the surgeon's role in head and neck cancer management. We discuss surgical perspectives within the multidisciplinary care team and selectively highlight some of the more provocative clinical scenarios in the field. PMID- 29435840 TI - Head and Neck Reconstructive Surgery. AB - Head and neck reconstruction following surgical extirpative management of head and neck cancer requires critical assessment and meticulous correction of both aesthetic and functional deficits to optimize the physical and psychological well being of the patient. Unique to head and neck cancers is the potential alteration of one's senses, breathing, speech, and swallowing functions, as well as overall head and neck aesthetics. When possible, tissue defects are replaced with similar tissues, though donor sites may be anatomically local, regional, or distant. The "reconstructive ladder" provides a heuristic approach to restoring the functional and aesthetic integrity of the head and neck cancer patient. Local tissue rearrangement, grafts, flaps, and prosthetics are all options in the armamentarium of the reconstructive surgeon. The aim of this chapter is to familiarize the reader with the aims of reconstructive surgery, techniques employed to restore form and function as well as challenges and outcomes. PMID- 29435841 TI - Radiation Therapy for the Head and Neck Patient: Advances, Challenges, and Perspectives. AB - Radiation therapy for head and neck malignancies has made remarkable advances in treatment technology, resulting in improved clinical and functional outcomes. It is necessary for the radiation oncologist to have a complex understanding of the patient's tumor and its relationship to the surrounding normal anatomy, in order to safely limit dose to normal tissues. Complications following radiation can be managed with timely intervention, usually on an outpatient basis. This chapter will discuss the technological advances in the field, the impact of human papillomavirus (HPV)-mediated disease on radiation treatment, efforts to limit dose to critical salivary and swallowing structures, and management of certain radiation-related toxicities. PMID- 29435842 TI - Perspectives in Head and Neck Medical Oncology. AB - The modern treatment of locoregionally advanced disease often requires a multimodality combination approach. A number of chemotherapeutic agents can be combined with radiation, but the platinum agent cisplatin, a potent radiation sensitizer, is best studied in head and neck cancer. Newer agents such as cetuximab can be used in combination with radiation therapy for those patients who cannot tolerate cisplatin. For chemotherapy-naive patients with metastatic head and neck cancer who demonstrate a good performance status, platinum doublet regimens are commonly used. Doublet regimens generally improve response rates compared to single-agent chemotherapies, although they have not demonstrated a survival benefit over single agents and they have added toxicity. Immunotherapies, alternative cytotoxic chemotherapies, and targeted therapies are second-line options for patients with disease that has progressed on platinum based therapy. Immunotherapy, in particular, has gained focus by enhancing the ability of the immune system to recognize and destroy malignant cells. When multimodal approaches are used, as in combined chemotherapy and radiation therapy, toxicities are increased. It is imperative that patients are followed closely in order to maximize treatment benefit while minimizing complications. PMID- 29435843 TI - Nutrition Management for the Head and Neck Cancer Patient. AB - Head and neck cancer (HNC) patients often face multiple nutritional challenges before, during, and after treatment due to the close proximity of the cancer to organs that are vital for normal eating function. Common treatment-related side effects, such as dysphagia, odynophagia, dysgeusia, xerostomia, thick saliva, mucositis, nausea, and vomiting, all further impair the patient's ability to maintain adequate oral intake. Malnutrition and unintentional weight loss in HNC patients during and after treatment are associated with poorer treatment outcomes, increased morbidity and mortality, and poor quality of life, even in overweight and obese patients whose Body Mass Index (BMI) is not suggestive of malnutrition. The main nutrition goal for HNC patients is thus to maximize nutrition intake either orally or through nutrition support therapy in order to prevent or limit weight loss, preserve lean body mass, minimize treatment delays and unplanned hospitalizations, and improve treatment outcomes. This chapter will discuss nutrition interventions to manage common symptoms before, during, and after treatment for HNC. Guidelines will be provided for patients that require enteral nutrition or less commonly, parenteral nutrition. PMID- 29435844 TI - Physical Therapy Challenges in Head and Neck Cancer. AB - Treatment sequelae such as trismus, shoulder dysfunction syndrome resulting from spinal accessory nerve palsy, and radiotherapy-induced neck fibrosis are often overlooked when in the management of head and neck cancer patients. This chapter examines these underappreciated issues and their corresponding physical therapy intervention based on current evidence. Head and neck cancer survivors must contend with these disabilities for years after treatment has been concluded. A few quit their jobs which puts a tremendous burden on them and their families with a diminished quality of life. The physical rehabilitative needs of head and neck cancer patients and useful interventions to help meet them are addressed. PMID- 29435845 TI - Occupational Therapy for the Head and Neck Cancer Patient. AB - Occupational therapy is a health profession concerned with promoting health and well-being through occupation. A diagnosis of head and neck cancer (HNC) often invokes fear and anxiety because of the potential negative impact of the diagnosis and/or treatment on lifestyle and well-being. Occupational therapists perform a unique and important role in addressing quality of life concerns for HNC patients through applied expertise in lifestyle management, facilitating the use of positive coping strategies and daily routine management. Occupational therapy concurrently assists HNC patients to effectively manage the debilitating stress and anxiety associated with HNC diagnosis, treatment, and recovery while facilitating a return to prior or adapted daily routines. PMID- 29435846 TI - Psychosocial Needs of Head and Neck Cancer Patients and the Role of the Clinical Social Worker. AB - In this chapter, we examine the demographics and risk factors in the population diagnosed with head and neck cancer (HNC), what challenges these patients face post-treatment and what the role of psychosocial support through clinical social work is in managing these stressors. While many forms of head and neck cancer found in the early stages have a high cure rate, the side effects of treatment for these cancers have major life-altering effects. Previously, the majority of those diagnosed with head and neck cancers were those who used excessive alcohol and tobacco, but the numbers are changing to include the human papillomavirus (HPV) as a major risk factor. Due to the behavioral risk factors that are often causes of head and neck cancers and the effects of treatment that often lend to psychosocial distress, the role of psychosocial intervention at time of diagnosis throughout the disease trajectory is essential for compliance with treatment and healthy coping post-treatment. Clinical social workers play an essential role within the multidisciplinary team of assessment and interventions for managing patient's psychosocial distress. PMID- 29435847 TI - Supportive Care for the Head and Neck Cancer Patient. AB - Patients with head and neck cancers (HNC) face multiple psychosocial and physical challenges that require multidisciplinary attention and care throughout their disease process. The psychoemotional symptoms may be triggered by cosmetic disfigurement and/or functional deficits related to the cancer itself or cancer directed treatments. These physical and emotional symptoms can be demoralizing and require acute and long-term professional assistance throughout a patient's lifespan. HNC remains one of the most challenging cancers to treat due to disfigurement, emotional suffering, social isolation, and loss of self-esteem. The emotional and physical symptoms a supportive care team can address are discussed in this chapter. PMID- 29435848 TI - Survivorship Care Planning and Quality of Life. AB - Roughly 436,000 survivors are living with a history of head and neck cancer (HNC), accounting for approximately 3% of all cancer survivors in the United States [1, 2]. With advances in treatment, long-term survival is increasingly common in HNC populations. Despite increasing awareness of survivorship issues, many challenges remain. These include lack of knowledge on late and long-term effects of treatment, and poor integration of survivorship care guidelines into oncology practice. Survivorship care plans (SCPs) are increasingly important for HNC survivors to improve quality of long-term survival. Quality survivorship care should focus on management of late and long-term effects of treatment, surveillance for cancer recurrence and second primaries, promotion of healthy lifestyle, and care coordination between providers. This chapter will describe common quality of life (QOL) issues in HNC survivorship, and review the current survivorship care guidelines in HNC. PMID- 29435849 TI - Denosumab: A Review in Postmenopausal Osteoporosis. AB - Denosumab (Prolia(r); Pralia(r)) is a human monoclonal antibody targeting the key bone resorption mediator RANKL. The drug is administered via subcutaneous injection once every 6 months and is approved for various indications, including the treatment of postmenopausal (PM) women with osteoporosis at increased/high risk of fracture or failure/intolerance of other osteoporosis therapies (indications featured in this review). Denosumab showed benefit in several phase 3 or 4 studies in PM women with osteoporosis or low bone mineral density (BMD), including the pivotal 3-year double-blind FREEDOM trial and its 7-year open-label extension. Denosumab reduced the risk of vertebral, nonvertebral and hip fractures and increased BMD across skeletal sites versus placebo in FREEDOM, with these benefits maintained over up to 10 years' therapy in the extension. The drug was also more effective in improving BMD than bisphosphonates, including in women switched from a bisphosphonate regimen, in 1-year trials; however, whether these differences translate into differences in anti-fracture efficacy is unclear. Denosumab was generally well tolerated over up to 10 years' treatment, although an increased risk of multiple vertebral fractures was observed after discontinuation of the drug. Thus, denosumab is a key treatment option for PM women with osteoporosis who have an increased/high risk of fracture or failure/intolerance of other osteoporosis therapies, although the potential for multiple vertebral fractures to occur after discontinuation of the drug requires consideration of subsequent management options. PMID- 29435852 TI - Is invasion a necessary step for metastases in breast cancer? Narod SA, Sopik V. PMID- 29435850 TI - Managing Gout in the Patient with Renal Impairment. AB - Hyperuricaemia is an independent risk factor for renal function decline. Evidence is emerging that urate-lowering therapy might be beneficial in subjects with renal impairment. We review the association between renal impairment and gout, some of the related pathogenic processes and the possible impact of gout treatment on the progression of renal impairment. Nevertheless, the management of gout is more complex in the presence of chronic kidney disease. The main aim of gout therapy is to fully dissolve the urate crystals, thus curing the disease. Avoidance of attacks-prophylaxis-and their prompt treatment if they occur, along with accurate information to patients, completes the treatment strategy. This article provides a practical guide to managing gout in older patients and in those with renal impairment. We highlight the shortcomings in our current treatment options and strategies. PMID- 29435853 TI - Do patients whose tumor achieved a pathological response relapse at specific sites? A substudy of the EORTC 10994/BIG-1-00 trial. AB - PURPOSE: To determine the sites of first distant relapse in patients with or without pCR following neoadjuvant chemotherapy in breast cancer patients enrolled in the EORTC 10994/BIG-1-00 trial. METHODS: We included patients enrolled in the EORTC 10994/BIG-1-00 trial who received at least one chemotherapy cycle before surgery and who had been diagnosed with a distant relapse. pCR was defined as no evidence of residual invasive cancer in the primary tumor and axillary lymph nodes with or without residual ductal carcinoma in situ. Site of first distant relapse was categorized as 'soft tissue,' 'visceral,' 'skeletal,' 'central nervous system (CNS),' and 'other.' The association between relapse site and achievement of pCR was assessed using multivariate logistic regression models for molecular subtypes classification and preceding locoregional recurrence. RESULTS: The study included 383 (21%) eligible patients out of the 1856 randomized, of whom 28 (7%) had achieved pCR. Median follow-up was 5.4 years. Achievement of pCR was associated with a trend towards a decreased presentation of skeletal metastases [21% (pCR) vs. 50% (non-pCR), OR 0.32, adjusted p value = 0.071] and an increase in the proportion of patients with CNS metastases as first distant relapse site (21% vs. 9%, OR 2.39, adjusted p value = 0.183). Patients with pCR were more likely to present with only one relapse location category when compared to non-pCR (86% vs. 69%). CONCLUSION: Patients that achieved a pCR appeared less likely to present with skeletal metastases and more frequently presented with CNS metastases as first site of distant relapse, even after adjustment for molecular subtypes. PMID- 29435854 TI - Chest wall recurrence in pT1-2N0-1 breast cancer patients after mastectomy without radiotherapy. AB - PURPOSE: In correlation with the nodal status in the era of modern radiotherapy, the chest wall recurrence (CWR) rate was investigated in pT1-2N0-1 breast cancer patients after a mastectomy without post-mastectomy radiotherapy (PMRT). METHODS: The data from the patients participating in two South Korean multi-institutional studies (KROG 14-22; N = 1842 and KROG 14-23; N = 1382) were analyzed. In total, 3224 pT1-2N0-1 breast cancer patients who underwent mastectomy without PMRT were analyzed. RESULTS: The median follow-up time was 72.2 months (range 0.8-125.2 months). The overall CWRs during the follow-up period were 1.68% in N0 patients and 2.82% in N1 patients. There was no statistically significant difference in 5 year and 10-year CWR-free survival (CWRFS) between the N0 and N1 patients. Of the 70 patients with CWR, 33 (1% of all the patients) had isolated CWR, and the 10 year overall survival rate in this group was 96.9%. After the propensity score matching of the N0 and N1 groups, there was still no difference in CWRFS by nodal status. CONCLUSIONS: The incidence of CWR in pT1-2N0-1 breast cancer patients is very low, especially with isolated recurrence. Also, the obtained data showed that the nodal status had no impact on CWRFS. PMID- 29435855 TI - The clinical impact of molecular breast imaging in women with proven invasive breast cancer scheduled for breast-conserving surgery. AB - PURPOSE: To investigate the clinical utility of molecular breast imaging (MBI) in patients with proven invasive breast cancer scheduled for breast-conserving surgery (BCS). METHODS: Following approval by the institutional review board and written informed consent, records of patients with newly diagnosed breast cancer scheduled for BCS who had undergone MBI for local staging in the period from March 2012 till December 2014 were retrospectively reviewed. RESULTS: A total of 287 women (aged 30-88 years) were evaluated. MBI showed T stage migration in 26 patients (9%), with frequent detection of in situ carcinoma around the tumor. Surgical management was adjusted in 14 of these patients (54%). In 17 of 287 patients (6%), MBI revealed 21 proven additional lesions in the ipsilateral, contralateral breast or both. In 18 of these additional foci (86%), detected in 15 patients, malignancy was found. Thirteen of these 15 patients had ipsilateral cancer and 2 patients bilateral malignancy. In total, MBI revealed a larger tumor extent, additional tumor foci or both in 40 patients (14%), leading to treatment adjustment in 25 patients (9%). CONCLUSION: MBI seems to be a useful imaging modality with a high predictive value in revealing ipsilateral and bilateral disease not visualized by mammography and ultrasound. It may play an important role in delineating the extent of the index lesion during preoperative planning. Incorporation of MBI in the clinical work-up as an adjunct modality to mammography and ultrasound may lead to better selection of patients who could benefit from BCS. PMID- 29435857 TI - A Qualitative Investigation of the Impact of Acne on Health-Related Quality of Life (HRQL): Development of a Conceptual Model. AB - INTRODUCTION: The negative impact of acne on aspects of health-related quality of life (HRQL) has been demonstrated in many quantitative studies; however, there has been relatively little qualitative research exploring the impact of acne and the use of topical treatment. The study aimed to explore the impact of moderate severe acne on HRQL in adolescents and adults with inflammatory and non inflammatory lesions and to develop a conceptual model to illustrate the impact. In addition, the study aimed to identify the attributes of topical acne treatments that are most important for patients. METHODS: Thirty-four adolescents and 16 adults with moderate-severe acne who were currently/recently prescribed topical treatment were recruited in this cross-sectional qualitative study in the UK, Italy, and Germany. In-depth, semi-structured telephone interviews explored patients' experiences of acne and the impact it has on their HRQL, and their experience of topical treatments for acne. Data were analyzed using thematic analysis and a conceptual model was developed. RESULTS: The analysis identified seven main areas of HRQL that are affected by acne: emotional functioning, social functioning, relationships, leisure activities, daily activities, sleep, and school/work. Also common throughout the interviews was the perception and reaction to acne from others, which potentially had an impact on all areas of HRQL. The conceptual model illustrates the impact on HRQL and the links between HRQL domains. For both adolescents and adults, it was most important for acne treatments to be fast-acting, non-irritating, and non-bleaching. CONCLUSION: The results of this qualitative study demonstrate that moderate-severe acne has an extensive impact on adolescents' and adults' HRQL. The conceptual model illustrates the many areas of HRQL that are affected and draws attention to the importance of effective treatments for acne. The study also highlights topical acne treatment attributes that are most important for patients. FUNDING: Meda, a Mylan company. PMID- 29435858 TI - Erratum to: Oxygen Transport to Tissue XXXVI. PMID- 29435856 TI - Modern Theories of Pelvic Floor Support : A Topical Review of Modern Studies on Structural and Functional Pelvic Floor Support from Medical Imaging, Computational Modeling, and Electromyographic Perspectives. AB - PURPOSE OF REVIEW: Weakened pelvic floor support is believed to be the main cause of various pelvic floor disorders. Modern theories of pelvic floor support stress on the structural and functional integrity of multiple structures and their interplay to maintain normal pelvic floor functions. Connective tissues provide passive pelvic floor support while pelvic floor muscles provide active support through voluntary contraction. Advanced modern medical technologies allow us to comprehensively and thoroughly evaluate the interaction of supporting structures and assess both active and passive support functions. The pathophysiology of various pelvic floor disorders associated with pelvic floor weakness is now under scrutiny from the combination of (1) morphological, (2) dynamic (through computational modeling), and (3) neurophysiological perspectives. This topical review aims to update newly emerged studies assessing pelvic floor support function among these three categories. RECENT FINDINGS: A literature search was performed with emphasis on (1) medical imaging studies that assess pelvic floor muscle architecture, (2) subject-specific computational modeling studies that address new topics such as modeling muscle contractions, and (3) pelvic floor neurophysiology studies that report novel devices or findings such as high density surface electromyography techniques. We found that recent computational modeling studies are featured with more realistic soft tissue constitutive models (e.g., active muscle contraction) as well as an increasing interest in simulating surgical interventions (e.g., artificial sphincter). Diffusion tensor imaging provides a useful non-invasive tool to characterize pelvic floor muscles at the microstructural level, which can be potentially used to improve the accuracy of the simulation of muscle contraction. Studies using high-density surface electromyography anal and vaginal probes on large patient cohorts have been recently reported. Influences of vaginal delivery on the distribution of innervation zones of pelvic floor muscles are clarified, providing useful guidance for a better protection of women during delivery. We are now in a period of transition to advanced diagnostic and predictive pelvic floor medicine. Our findings highlight the application of diffusion tensor imaging, computational models with consideration of active pelvic floor muscle contraction, high-density surface electromyography, and their potential integration, as tools to push the boundary of our knowledge in pelvic floor support and better shape current clinical practice. PMID- 29435859 TI - Bridging the Atlantic gap in clinical guidelines for non-ST-elevation acute coronary syndromes. PMID- 29435860 TI - More or less appropriate: The new rule of law for cardiac imaging. PMID- 29435861 TI - The search for water: Is it so easy to diagnose acute myocarditis? PMID- 29435862 TI - Disparities in the Treatment of Substance Use Disorders: Does Where You Live Matter? AB - This study focused on (1) whether disparities in timely receipt of substance use services can be explained in part by the characteristics of the community in which the clients reside and (2) whether the effect of community characteristics on timely receipt of services was similar across racial/ethnic groups. The sample was composed of adults receiving publicly funded outpatient treatment in Washington State. Treatment data were linked to data from the US census. The outcome studied was "Initiation and Engagement" in treatment (IET), a measure noting timely receipt of services at the beginning of treatment. Community characteristics studied included community level economic disadvantage and concentration of American Indian, Latino, and Black residents in the community. Black and American Indian clients were less likely to initiate or engage in treatment compared to non-Latino white clients, and American Indian clients living in economically disadvantaged communities were at even greater risk of not initiating treatment. Community economic disadvantage and racial/ethnic makeup of the community were associated with treatment initiation, but not engagement, although they did not entirely explain the disparities found in IET. PMID- 29435863 TI - Evaluation of a Comprehensive SAMHSA Service Program for Individuals Experiencing Chronic Homelessness. PMID- 29435864 TI - Current knowledge among Japanese experienced general dentists regarding prevention of infective endocarditis. AB - Infective endocarditis (IE), a life-threatening condition predominantly occurring in patients with underlying heart disease, is mainly caused by bacteremia induced by invasive dental treatment. However, the amount of related information shared between cardiologists and dentists appears to be inadequate. In the present study, a survey regarding prevention of IE, composed of 13 major questions, 2 of which also allowed free comments, was sent to approximately 3000 dentists belonging to a prefectural dental association in Japan. Of the 13.6% who returned the forms, more than 80% were general dentists with more than 20 years of experience. Approximately, 55% of the responders reported that they had opportunities to prescribe antibiotics prior to performing treatments with risk of IE, though noted difficulties with designation of which patients with heart disease were at risk. Most of the dentists considered that oral surgery procedures have a high risk for IE, whereas less invasive procedures were considered to be not associated with the disease. Approximately, 35% selected oral amoxicillin, with a dose of 2.0 g (20%) or 500 mg (27%) prescribed for adults, and 50 mg (10%) or 30 mg (12%) per kg of body weight for children. However, the timing of the antibiotics administration varied. The present results reveal current knowledge regarding prevention of IE among general dentists in Japan, and should be valuable for construction of a protocol to establish consensus between dentists and cardiologists. PMID- 29435865 TI - Gene expression profiles in dental follicles from patients with impacted canines. AB - Animal studies suggest that the dental follicle (DF) plays a major role in tooth eruption. However, the role of the DF during tooth impaction and related root resorptions in adjacent teeth is not clear. The hypothesis for the present study is that expression of regulatory factors involved in the bone remodelling process necessary for tooth eruption may differ between dental follicles from teeth with different clinical situations. We have analysed the gene expression profiles in the DF obtained from impacted canines, with (N = 3) or without (N = 5) signs of root resorption, and from control teeth (normal erupting teeth, mesiodens) (N = 3). DF from 11 patients (mean age: 13 years) obtains at the time of surgical exposure of the tooth. Due to the surgical time point, all teeth were in a late developmental stage. Gene expression related to osteoblast activation/bone formation, osteoclast recruitment and activation was analysed by RTqPCR. Genes related to bone formation (RUNX2, OSX, ALP, OCN, CX43) were highly expressed in all the samples, but osteoclast recruitment/activation markers (OPG, RANKL, MCP 1, CSF-1) were negligible. No apparent patterns or significant differences in gene expression were found between impacted canines, with or without signs of root resorption, or when compared to control teeth. Our results suggest the DF regulation of osteoclastic activity is limited in the late pre-emergent stage of tooth development, irrespective if the tooth is normally erupting or impacted. We suggest that the follicle may have an important regulatory function for alveolar bone formation in the final eruption process and CX43-gap junction communication could be an important signalling pathway. PMID- 29435866 TI - Diagnostic accuracy of ICD-9 code 780.2 for the identification of patients with syncope in the emergency department. AB - PURPOSE: Syncope is a common condition that affects individuals of all ages and is responsible for 1-3% of all emergency department (ED) visits. Prospective studies on syncope are often limited by the exiguous number of subjects enrolled. A possible alternative approach would be to use of hospital discharge diagnoses from administrative databases to identify syncope subjects in epidemiological observational studies. We assessed the accuracy of the International Classification of Diseases, Ninth Revision (ICD-9) code 780.2 "syncope and collapse" to identify patients with syncope. METHODS: Patients in two teaching hospitals in Milan, Italy with a triage assessment for ED access that was possibly related to syncope were recruited in this study. We considered the index test to be the attribution of the ICD-9 code 780.2 at ED discharge and the reference standard to be the diagnosis of syncope by the ED physician. RESULTS: The sensitivity, specificity, positive and negative predictive values of the ICD 9 code 780.2 to identify patients with syncope were 0.63 (95% confidence interval [CI] 0.58-0.67), 0.98 (95% CI 0.98-0.99), 0.83 (95% CI 0.79-0.87) and 0.95 (95% CI 0.94-0.95), respectively. CONCLUSIONS: The moderate sensitivity of ICD-9 code 780.2 should be considered when the code is used to identify patients with syncope through administrative databases. PMID- 29435867 TI - Autonomic function testing in spinocerebellar ataxia type 2. AB - PURPOSE: To assess whether autonomic failure belongs to the clinical spectrum of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant genetic disorder showing progressive cerebellar and brainstem dysfunction. METHODS: We evaluated cardiovascular autonomic function in 8 patients with SCA2 and 16 age- and gender matched healthy controls. Other autonomic domains were examined through standardized questionnaires and by testing the skin sympathetic reflex. RESULTS: Patients with SCA2 showed normal responses to cardiovascular autonomic function tests, with the exception of lower baroreflex sensitivity upon standing compared to controls. In questionnaires, 7 out of 8 patients reported bladder disturbances, while 3 out of 6 tested patients had no skin sympathetic reflex. CONCLUSIONS: We did not observe clinically overt cardiovascular autonomic failure in patients with SCA2. Other autonomic domains (i.e., bladder and sudomotor function) may be affected in the disease. PMID- 29435868 TI - Ambulatory blood pressure profiles in familial dysautonomia. AB - OBJECTIVE: Familial dysautonomia (FD) is a rare genetic disease that involves extreme blood pressure fluctuations secondary to afferent baroreflex failure. The diurnal blood pressure profile, including the average, variability, and day-night difference, may have implications for long-term end organ damage. The purpose of this study was to describe the circadian pattern of blood pressure in the FD population and relationships with renal and pulmonary function, use of medications, and overall disability. METHODS: We analyzed 24-h ambulatory blood pressure monitoring recordings in 22 patients with FD. Information about medications, disease severity, renal function (estimated glomerular filtration, eGFR), pulmonary function (forced expiratory volume in 1 s, FEV1) and an index of blood pressure variability (standard deviation of systolic pressure) were analyzed. RESULTS: The mean (+/- SEM) 24-h blood pressure was 115 +/- 5.6/72 +/- 2.0 mmHg. The diurnal blood pressure variability was high (daytime systolic pressure standard deviation 22.4 +/- 1.5 mmHg, nighttime 17.2 +/- 1.6), with a high frequency of a non-dipping pattern (16 patients, 73%). eGFR, use of medications, FEV1, and disability scores were unrelated to the degree of blood pressure variability or to dipping status. INTERPRETATION: This FD cohort had normal average 24-h blood pressure, fluctuating blood pressure, and a high frequency of non-dippers. Although there was evidence of renal dysfunction based on eGFR and proteinuria, the ABPM profile was unrelated to the measures of end organ dysfunction or to reported disability. PMID- 29435869 TI - Ecto-enzymes activities in splenic lymphocytes of mice experimentally infected by Trypanosoma cruzi and treated with specific avian immunoglobulins: an attempt to improve the immune response. AB - The aim of this study was to evaluate the therapeutic efficacy of specific avian polyclonal antibodies (IgY) against Trypanosoma cruzi and their interaction with ecto-enzymes of the purinergic system (NTPDase and adenosine deaminase (ADA) activities) in splenic lymphocytes. For this, mice were divided into six groups: three non-infected (A, B, and C) and three infected (D, E, and F). The groups A and D were composed by negative and positive controls, respectively; while the groups B and E were treated prophylactically with IgY (50 mg/kg), and the groups C and F were treated therapeutically with IgY (50 mg/kg). Treatment with IgY reduced parasitemia on day 6 post-infection (PI) compared to the infected control group, but it was similar on day 8 PI. Moreover, infected and treated animals (the groups E and F) did not show neither amastigotes in the cardiac tissue nor cardiac lesions when compared to the positive control group (the group D). The E NTPDase (ATP and ADP as substrate) and ADA activities in splenic lymphocytes increased significantly in the positive control group (the group D) compared to the negative control group (the group A). The therapeutic treatment of IgY (the group F) was able to prevent the increase of E-NTPDase and E-ADA activities compared to the positive control group (the group D), but this finding was not observed in animals that received the prophylactic treatment (the group E). The therapeutic treatment of IgY may be considered an interesting approach to improve the immune response of mice experimentally infected by T. cruzi. PMID- 29435870 TI - Chemopreventive potential of esculetin in 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis. AB - 7,12-Dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch carcinogenesis is widely preferred to assess the tumor-inhibiting efficacy of the medicinal plants or their constituents. The present study explores the tumor-inhibiting potential of esculetin by utilizing the status of lipid peroxidation by products (thiobarbituric acid reactive substances), antioxidants (vitamin E, reduced glutathione, superoxide dismutase, catalase, and glutathione peroxidase), and phase I and phase II detoxification agents as biochemical end points and by using histopathological studies as well in DMBA-induced hamster buccal pouch carcinogenesis. Oral tumors developed in the buccal pouch were subjected to histopathological studies, and were confirmed as oral squamous cell carcinoma. Hamsters treated with DMBA alone showed an abnormal pattern of lipid peroxidation, antioxidants, and detoxification agents as compared to control hamsters. The status of the above-mentioned biochemical markers and histopathological abnormalities were found to be reversed in DMBA + esculetin treated hamsters. The result of the present study thus indicates the tumor preventive potential of esculetin in DMBA-induced oral carcinogenesis. PMID- 29435871 TI - PI3K-Akt signaling controls PFKFB3 expression during human T-lymphocyte activation. AB - Lymphocyte activation is associated with rapid increase of both the glycolytic activator fructose 2,6-bisphosphate (Fru-2,6-P2) and the enzyme responsible for its synthesis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase 2). PFKFB3 gene, which encodes for the most abundant PFK-2 isoenzyme in proliferating tissues, has been found overexpressed during cell activation in several models, including immune cells. However, there is limited knowledge on the pathways underlying PFKFB3 regulation in human T-lymphocytes, and the role of this gene in human immune response. The aim of this work is to elucidate the molecular mechanisms of PFKFB3 induction during human T-lymphocyte activation by mitotic agents. The results obtained showed PFKFB3 induction during human T lymphocyte activation by mitogens such as phytohemagglutinin (PHA). PFKFB3 increase occurred concomitantly with GLUT-1, HK-II, and PCNA upregulation, showing that mitotic agents induce a metabolic reprograming process that is required for T-cell proliferation. PI3K-Akt pathway inhibitors, Akti-1/2 and LY294002, reduced PFKFB3 gene induction by PHA, as well as Fru-2,6-P2 and lactate production. Moreover, both inhibitors blocked activation and proliferation in response to PHA, showing the importance of PI3K/Akt signaling pathway in the antigen response of T-lymphocytes. These results provide a link between metabolism and T-cell antigen receptor signaling in human lymphocyte biology that can help to better understand the importance of modulating both pathways to target complex diseases involving the activation of the immune system. PMID- 29435874 TI - A tandem approach of tTGA testing: A new approach for celiac disease screening. PMID- 29435873 TI - Oncologic outcomes for open and laparoscopic radical nephroureterectomy in patients with upper tract urothelial carcinoma. AB - BACKGROUND: Oncologic benefits of laparoscopic radical nephroureterectomy (LNU) are unclear. We aimed to evaluate the impact of surgical approach for radical nephroureterectomy on oncologic outcomes in patients with locally advanced upper tract urothelial carcinoma (UTUC). METHODS: Of 426 patients who underwent radical nephroureterectomy at five medical centers between February 1995 and February 2017, we retrospectively investigated oncological outcomes in 229 with locally advanced UTUC (stages cT3-4 and/or cN+). The surgical approach was classified as open nephroureterectomy (ONU) or LNU, and oncologic outcomes, including intravesical recurrence-free survival (RFS), visceral RFS, cancer-specific survival (CSS), and overall survival (OS), were compared between the groups. The inverse probability of treatment weighting (IPTW)-adjusted Cox-regression analyses was performed to evaluate the impact of LNU on the prognosis. RESULTS: Of the 229 patients, 48 (21%) underwent LNU. There were significant differences in patient backgrounds, including preoperative renal function, lymph-node involvement, lymphovascular invasion, and surgical margins, between the groups. Before the background adjustment, intravesical RFS, visceral RFS, CSS, and OS were significantly inferior in the ONU group than in the LNU group. However, in the IPTW-adjusted Cox-regression analysis, no significant differences were observed in intravesical RFS (hazard ratio [HR], 0.65; P = 0.476), visceral RFS (HR, 0.46; P = 0.109), CSS (HR, 0.48; P = 0.233), and OS (HR, 0.40; P = 0.147). CONCLUSION: Surgical approaches were not independently associated with prognosis in patients with locally advanced UTUC. PMID- 29435872 TI - A phase II trial of concurrent chemoradiotherapy with weekly paclitaxel and carboplatin in advanced oesophageal carcinoma. AB - BACKGROUND: This study was performed to assess the efficacy and feasibility of definitive chemoradiotherapy consisting of weekly doses of combined paclitaxel and carboplatin concurrent with radiation therapy, followed by 2 cycles of consolidation chemotherapy for advanced esophageal carcinoma. METHODS: Eligibility criteria included local, advanced, newly diagnosed and postoperative local regional lymph node metastasis; Eastern Cooperative Oncology Group (ECOG) score <= 2; and adequate organ function. Patients received concurrent chemoradiation therapy consisting of radiotherapy (50.4 Gy/28 Fx or 61.2 Gy/34 Fx) and concurrent paclitaxel (50 mg/m2) and carboplatin (area under the curve, AUC = 2) on days 1, 8, 15, 22 and 29. The two-cycle consolidation chemotherapy protocol was paclitaxel (175 mg/m2) plus carboplatin (AUC = 5) administered on days 57 and 85, after concurrent chemoradiotherapy. RESULTS: Between August 2013 and February 2015, 65 patients with oesophageal carcinoma were enrolled in the study; 34 (52.3%) were newly diagnosed and 31 (47.6%) had postoperative local regional lymph node metastasis. The median overall survival time was 21.7 months (95% confidence interval [CI] 16.7-26.6), and the median progression-free survival time was 12.1 months (95% CI 9.0-15.3). A total of 96.9% (63/65) and 67.6% (44/65) patients completed >=5 cycles and all 7 cycles of chemotherapy, respectively. A total of 93.8% (61/65) patients completed radiation therapy. The 1- and 2-year overall survival rates were 73.7 and 42.0%, respectively. The 1- and 2-year progression-free survival rates were 50.6 and 31.1%, respectively. Grade 3-4 toxicity during chemoradiotherapy included neutropenia (24.5%), thrombocytopenia (4.6%), fatigue (1.5%), anaemia (1.5%), radiation dermatitis (1.5%), pneumonitis (1.5%), oesophagitis (4.6%) and vomiting (1.5%). CONCLUSIONS: In patients with locally advanced oesophageal cancer, the combination of weekly doses of paclitaxel and carboplatin was well tolerated and produced comparable results. A three-arm randomised phase III trial (NCT02459457) comparing paclitaxel in combination with cisplatin, carboplatin or 5-fluorouracil with concurrent radiotherapy is on-going at our hospital. PMID- 29435876 TI - Flavonoids from Sonneratia caseolaris. AB - According to the traditional medicinal usage of Sonneratia caseolaris, we tested the extract of S. caseolaris for antioxidant activity using 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging effect on thin-layer chromatography. Following activity-oriented separation, two flavonoids, luteolin (1) and luteolin 7-O-beta-glucoside (2), were isolated. Both of the compounds were found to possess antioxidant activity. PMID- 29435875 TI - A prospective study to evaluate the role of duodenal bulb biopsy in the diagnosis of celiac disease. AB - BACKGROUND: Celiac disease (CeD) requires a biopsy from the small intestine to confirm the diagnosis. Conventionally, duodenal bulb (D1) was avoided as a biopsy site due to histological confounding factors at this site. However, sometimes, the bulb mucosa is the only affected site. The aim of the present study was to assess changes in duodenal bulb histology and compare it to distal duodenal histology and to analyze whether the addition of duodenal bulb biopsy increases the diagnostic yield of the CeD. METHODS: It was a prospective study comprising of 98 patients of CeD who were symptomatic clinically and had positive anti tissue transglutaminase (tTG) antibody. Endoscopically four mucosal biopsies were taken, two each from the bulb and distal duodenum, and morphology was graded as per modified Marsh grade. RESULTS: Iron deficiency anemia (40%) was a most common clinical presentation followed by chronic diarrhea (30%). Sixty patients showed same Marsh grade and 38 showed different Marsh grade at both sites. Patients who were showing the difference in the Marsh grade at the two biopsy sites, in place of; descending duodenum showed higher grade in 24 patients while higher mucosal atrophy was documented in the bulb in 14 patients. No patient of CeD had isolated D1 involvement. In eight patients, the correct diagnosis of CeD could be made only because of bulb biopsy. CONCLUSION: Majority of the patients had no classical symptoms. Different Marsh grade at the two biopsy sites was documented demonstrating the patchy distribution of CeD. Combining biopsy from both bulb and descending duodenum maximizes the diagnostic yield of the CeD. PMID- 29435877 TI - Isolation of ethyl caffeate from the petals of Prunus yedoensis. AB - Ethyl caffeate was isolated from the petals of Prunus yedoensis (Rosaceae). This is the first example of its isolation from Prunus plants. PMID- 29435878 TI - A novel diterpenoid with a rearranged neoclerodane skeleton from Salvia leucantha CAV. AB - A new diterpenoid with a rearranged neoclerodane skeleton, spiroleucantholide (compound "S1"), along with four known diterpenoids-salvifaricin (compound "S2"), isosalvipuberulin (compound "S3"), salvileucantholide (compound "S4"), and salviandulin E (compound "S5")-was isolated from the aerial parts of Salvia leucantha CAV.. The structures were established by spectroscopic methods, including the X-ray analysis of spiroleucantholide (S1). PMID- 29435879 TI - New penicillide derivatives isolated from Penicillium simplicissimum. AB - Two new penicillide derivatives, secopenicillides A (3) and B (4), were isolated along with penicillide (1) and purpactin A (2), and altenusin (5) and dehydroaltenusin (6), the antifungal substances of this fungus, from the extract of Penicillium simplicissimum IFM 53375. The absolute structures of 3 and 4 were determined by spectroscopic investigation and chemical correlation to penicillide (1). The absolute configuration of purpactin A (2) was determined by the chemical method. PMID- 29435880 TI - Composition of the endophytic filamentous fungi isolated from the tea plant Camellia sinensis. AB - It has been found by ribosomal DNA analysis that the endophytic filamentous fungi isolated from the tea plant Camellia sinensis (Theaceae) are composed of six groups; one Fusarium sp., one Penicillium sp., two Schizophyllum sp., and two Diaporthe sp.. PMID- 29435881 TI - Ephedrae herba (Mao) decreased histamine content in RBL-2H3 cells. AB - The effect of Ephedrae herba (Mao) on histamine content was investigated. When rat basophilic leukemia (RBL-2H3) cells were incubated for 48 h with Mao, Mao decreased histamine content in a concentration-dependent manner. However, the ratio of released histamine to total histamine was scarcely affected by Mao treatment when RBL-2H3 cells were stimulated by ionomycin. On the other hand, the content of beta-hexosaminidase, another marker of degranulation, was only slightly decreased by Mao. The expression level of the active form (53 kDa) of L histidine decarboxylase, the enzyme which synthesizes histamine, was partially suppressed by Mao. Furthermore, Mao significantly suppressed proliferation of RBL 2H3 cells in a concentration-dependent manner. The phosphodiesterase inhibitor 3 isobutyl-1-methylxanthine revealed an increasing effect of Mao on cAMP level in RBL-2H3 cells. Since this result suggested that Mao may stimulate adenylate cyclase, we evaluated the effect of adenylate cyclase inhibitor SQ 22536 on Mao induced decrease in histamine content. As a result, we showed that SQ 22536 did not have a reducing effect of Mao. From these results it is understood that Mao decreased histamine content by inhibiting cell proliferation and expression of histidine decarboxylase. However, these effects are not related to the increase in cAMP. PMID- 29435882 TI - Dolichandroside, a new phenolic triglycoside from Dolichandrone serrulata (DC.) Seem. AB - A new phenolic triglycoside, dolichandroside, was isolated from the branches of Dolichandrone serrulata together with decaffeoyl-verbascoside, verbascoside, isoverbascoside, markhamioside A, 2''-O-apiosylverbascoside, luteoside B and ixoside. The structure elucidations were based on analyses of spectroscopic data. PMID- 29435883 TI - Norditerpenoid alkaloids from Aconitum manshuricum. AB - A new norditerpenoid alkaloid, manshuritine (1) has been isolated from Aconitum manshuricum, together with seven known alkaloids; beiwudine (2), beiwutine (3), 16-epi-pyromesaconitine (4), mesaconitine (5), aconitine (6), hypaconitine (7) and 14-benzoylmesaconine (8). The structure of the new compound was elucidated on the basis of spectral data and chemical correlations. PMID- 29435884 TI - Isolation of cytochrome P450 3A (CYP3A) inhibitors from Hyuganatsu, Citrus tamurana Hort. AB - The present study was conducted to identify cytochrome P450 3A (CYP3A) inhibitory components of Hyuganatsu, Citrus tamurana Hort., by investigating the effects on midazolam 1'-hydroxylase activity of human liver microsomes. As a consequence, limonin and nomilin were identified as CYP3A inhibitors from the endocarp of Hyuganatsu. PMID- 29435885 TI - Effects of curcumin on reflux esophagitis in rats. AB - The preventive effect of curcumin, a compound isolated from the rhizome of Curcuma longa, on experimental reflux esophagitis in rats was investigated in order to validate its potential therapeutic use for gastroesophageal reflux disease. Curcumin (20 mg/kg, i.d.), the antioxidative agent dimethyl sulfoxide (DMSO) (1 ml/kg, i.p.) or the proton pump inhibitor lansoprazole (1 mg/kg, i.d.) inhibited the formation of acute acid reflux esophagitis by 52.5, 61.5 and 70.9% respectively. Curcumin alone was not effective in preventing chronic acid reflux esophagitis, but the combination of curcumin and DMSO reduced the mortality rate and the severity of the esophagitis ulcer index to the same extent (56.5%) as did the lansoprazole (53.9%). Intraduodenal administration of curcumin also markedly prevented the formation of acute mixed reflux esophagitis, together with reducing the incidence or the severity of neutrophil infiltration, when compared to a control group. In contrast, lansoprazole tended to increase the severity of all histopathological changes, when compared to either the control or the curcumin treated group. Aminoguanidine, a specific inducible nitric oxide synthase inhibitor, had no preventive effect against both types of acute reflux esophagitis models, and increased the mortality in the chronic acid reflux esophagitis model. From these results, it is indicated that curcumin can effectively prevent acute reflux esophagitis formation. Although curcumin is less potent than lansoprazole in inhibiting acid reflux esophagitis, it is superior to lansoprazole in inhibiting mixed reflux esophagitis. The antiulcerogenic mechanisms are considered to be closely associated with its antioxidant nature and antiinflammatory property. PMID- 29435886 TI - Preventive and curative effects of curcumin on the development of gastric inflammatory diseases in rats. AB - Preventive and curative effects of curcumin on experimental acute and chronic gastric ulcers were investigated to validate its clinical application on a remedy for peptic ulcer. Intraduodenal administration of curcumin, 5-20 mg/kg, inhibited gastric acid secretion in pylorus-ligated rats, and oral administration prevented ethanol-induced acute gastric mucosal lesions. Curcumin (20-80 mg/kg, p.o.) dose dependently prevented both serotonin-induced gastric mucosal lesions and compound 48/80-induced gastric mucosal lesions in rats. Furthermore, oral administration of curcumin, 10-80 mg/kg, twice daily for 10 days, significantly accelerated the healing of acetic acid-induced chronic gastric ulcer and promoted mucosal regeneration in the ulcerated portion in a dose-related manner. Cimetidine prevented the formation of ethanol-induced gastric mucosal lesions, but not of serotonin-induced and compound 48/80-induced gastric mucosal lesions. Consecutive administration of cimetidine showed a marked acceleration in the healing of acetic acid-induced ulcer. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, showed anti-ulcerogenic effects similar to those oberved for curcumin. The present results indicate that curcumin exhibits gastric cytoprotection in the acute lesion models and ulcer healing promotion in the chronic ulcer model. The preventive and curative effects of curcumin might be due to an increase in the mucosal defensive mechanism through its antioxidant property and inhibition of NO or cytokine-mediated inflammation. PMID- 29435887 TI - Distinction of water-soluble constituents between some Paecilomyces (= Isaria) and Cordyceps fungi by capillary electrophoresis. AB - In order to reveal the differences between Cordyceps, Paecilomyces (= Isaria) and Nomuraea, we collected seven entomogenous fungi grown in natural field and analyzed the profiles of water-soluble constituents derived from some different sources of Cordyceps, Paecilomyces and Nomuraea by determination using capillary electrophoresis. C. sinensis and C. kyushuensis showed similar peak clusters of protein migrated at 5-7, 8-9, and 12-20 min. The peak clusters obtained from N. atypicola was similar to those of C. sinensis and C. kyushuensis. The water soluble constituent clusters of C. militaris migrated at 5-9 and 10-15 min were partly different from those of other Cordyceps. It was also revealed that the P. tenuipes and P. cicadae showed lesser peak clusters rather than Cordyceps. These results indicated that the profiles of protein of these entomogenous fungi by capillary electrophoretic analysis could serve as fingerprints for classification and medicinal quality control of Cordyceps. PMID- 29435888 TI - Two fucoidans in the holdfast of cultivated Laminaria japonica. AB - Two fucoidans have been isolated from the holdfast of cultivated Laminaira japonica. One (L-fucoidan) is rich in fucose and sulfate; the other (GA-fucoidan) is rich in uronate. L-fucoidan was found in the fronds of L. japonica (cultivated and wild), L. angustata, and Kjellmaniella crassifolia whereas GA-fucoidan was not detected in these fronds and may be a fucoidan specific to the holdfast. These two fucoidans were proved to have anti-tumor activity against Adenocarcinoma 755-transplanted mice by i.p. and p.o. administration. PMID- 29435889 TI - Immunomodulatory effect and quantitation of a cytotoxic glycosphingolipid from Murdannia loriformis. AB - NMR signal reassignments for a cytotoxic glycosphingolipid compound, 2, beta-O-D glucopyranosyl-2-(2'-hydroxy-Z-6'-enecosamide)sphingosine, isolated from an ethanolic extract of the herb Murdannia loriformis, have been achieved by use of FAB-MS, and 1D and 2D 1H and 13C NMR. The amount of 2 in the herb juice was quantitatively determined by use of a validated HPLC method (RP-18, MeOH-H2O, UV detection at 210 nm). The immunomodulatory effect of the herb juice and of 2 was proved by means of in vitro cellular immunological assays. Compound 2 at a concentration of 13 nmol L-1 stimulated PBMC proliferation and increased the CD 3,4:CD 3,8 ratio in T lymphocytes. PMID- 29435890 TI - Bastadins, cyclic tetramers of brominated-tyrosine derivatives, selectively inhibit the proliferation of endothelial cells. AB - Eight bastadins, tetramers of brominated-tyrosine derivatives, were isolated from the marine sponge Ianthella basta, and their anti-proliferative activities against endothelial cells were examined. A structure-activity relationship study of these compounds revealed that a macrocyclic structure was crucial, and a bastarane-type skeleton was important for the selective activity of these bastadins against endothelial cells. A conformational analysis of the bastadins was also carried out by molecular mechanics calculation. PMID- 29435891 TI - A new lignan from Aphanamixis polystachya. AB - A new lignan, polystachyol (1), two lignan glycosides, lyoniside (2) and nudiposide (3), and a sterol, ergosta-4,6,8(14),22-tetraen-3-one (4), with stigmasterol, and oleic and linoleic acids, have been isolated from an MeOH extract of the dried bark of Aphanamixis polystachya. The structures of the isolated compounds were elucidated by analysis of 1D and 2D NMR and mass spectroscopic data. The compounds did not have growth inhibitory activity against HeLa cells. PMID- 29435892 TI - Chemical constituents of the essential oil from the bark of Cinnamomum illicioides A. Chev. from Vietnam. AB - The chemical constituents of the hydrodistilled essential oil from the bark of Cinnamomum illicioides A. Chev., Lauraceae, from Vietnam, have been studied by GC and GC-MS. Seventeen monoterpenoids, eugenol, and thirty-six sesquiterpenoids, accounting for 25, 41.2, and 27.9% of the oil, respectively, were identified. Terpinen-4-ol (10.4%), eugenol (41.2%), and delta-cadinene (5.6%) are the major components of the oil. PMID- 29435893 TI - Two isoindoline alkaloids from the crude drug, the ant lion (the larvae of Myrmeleontidae species). AB - Two compounds having an isoindoline skeleton were isolated from the ant lion (the larvae of Myrmeleontidae species). They were characterized as 4-hydroxyisoindolin 1-one and 2-(2-hydroxyethyl)-4-hydroxyisoindolin-1-one on the basis of spectroscopic data. PMID- 29435894 TI - Inhibitory effect of Yunnan traditional medicines on hepatitis C viral polymerase. AB - For the purpose of developing novel anti-hepatitis C virus (HCV) agents from natural resources, 93 Yunnan crude drugs were screened for their inhibitory effects on RNA-dependent RNA polymerase (RdRp) of HCV. Although 71 methanol extracts and 50 water extracts inhibited HCV-RdRp by more than 50% at a concentration of 50 MUg/ml, the majority of them contained a high percentage of tannins. However, methanol extracts of Plumbago zeylanica (branch), Maytenus fookerii (leaf) and Huashidancha (Y61, branch and leaf), and water extracts of Potentilla griffithii (whole plant) and Salvia yunnanensis (underground part), having IC50 values of less than 10 MUg/ml, showed less than 10% tannin content. In addition, from a methanol extract of Tripterygium hypoglaucum (root bark), demethylzeylasteral was isolated as a strongly inhibitory substance against HCV RdRp. PMID- 29435895 TI - Prenylated flavonoids and related compounds of the Indonesian Artocarpus (Moraceae). AB - Several species of the genus Artocarpus (Moraceae) have been investigated in our laboratories during the last decade. Over 60 phenolic constituents have been discovered and characterized, including 27 new compounds from 13 Indonesian taxa of Artocarpus, namely A. champeden, A. lanceifolius, A. teysmanii, A. scortechinii, A. rotunda, A. maingayi, A. kemando, A. bracteata, A. altilis, A. fretessi, A. gomezianus, A. reticulatus and A. glaucus. The principal and the most pronounced features of these phenolic constituents are the assembly of an isoprenyl substituent at C-3 of a flavone skeleton by closure of an ether bridge or a carbon-carbon linkage with the B ring of the skeleton, which may further rearrange into xanthone to produce various classes of natural products. The structures of the new and unusual natural products are presented. Many of the metabolites also exhibit cytotoxic effect against murine leukemia P388 cells. PMID- 29435897 TI - Ethnic Harassment, Ethnic Identity Centrality, and Well-Being. AB - In this study, we examined the direct effect of (positive vs. negative) evaluation of potentially harassing experiences due to ethnic background on impaired well-being as well as the moderating effect of ethnic identity centrality on the relationship between (lower vs. higher) frequency of potentially harassing experiences and impaired well-being. Using a gender balanced sample with equal proportions of black and minority ethnic and white undergraduate students (N = 240), we found that, expectedly, ethnic identity centrality intensified the effects of higher frequency of potentially harassing experiences on lower self-esteem and lower positive affect. Unexpectedly, however, gender identity centrality buffered the effects of higher frequency as well as more negative evaluation of potentially harassing experiences on lower self-esteem, indicating that gender identity centrality may be a protective resource, even though it is not specific to ethnic harassment. Exploratory analyses revealed that for black and minority ethnic respondents with high ethnic identity centrality and for white respondents with low ethnic identity centrality, there were associations between more negative evaluation of potentially harassing experiences and lower self-esteem and lower positive affect. This finding might indicate that ethnic identity centrality was a risk factor in black and ethnic minority respondents, but a protective factor in white respondents. PMID- 29435896 TI - Readmission Rates and Diagnoses Following Total Hip Replacement in Relation to Insurance Payer Status, Race and Ethnicity, and Income Status. AB - BACKGROUND: Total hip replacements (THRs) are the sixth most common surgical procedure performed in the USA. Readmission rates are estimated at between 4.0 and 10.9%, and mean costs are between $10,000 and $19,000. Readmissions are influenced by the quality of care received. We sought to examine differences in readmissions by insurance payer, race and ethnicity, and income status. METHODS: We analyzed all THRs from 2007 to 2011 in California, Florida, and New York from the State Inpatient Databases, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. Primary outcomes were readmission at 30 and 90 days after THR. Descriptive statistics were calculated, and multivariate logistic regression analysis was used to estimate adjusted odds ratio (OR) for readmissions. Statistical significance was evaluated at the < 0.05 alpha level. RESULTS: A total of 274,851 patients were included in the analyses. At 30 days (90 days), 5.6% (10.2%) patients had been readmitted. Multivariate logistic regression analysis showed that patients insured by Medicaid (OR 1.23, 95%CI 1.17 1.29) and Medicare (OR 1.58, 95%CI 1.44-1.73) had increased odds of 30-day readmission, as did patients living in areas with lower incomes, Black patients, and patients treated at lower volume hospitals. Ninety-day readmissions showed similar significant results. CONCLUSIONS: The present study has shown that patients on public insurance, Black patients, and patients who live in areas with lower median incomes have higher odds of readmission. Future research should focus on further identifying racial and socioeconomic disparities in readmission after THR with an eye towards implementing strategies to ameliorate these differences. PMID- 29435898 TI - Experiences of Racism and Breastfeeding Initiation and Duration Among First-Time Mothers of the Black Women's Health Study. AB - BACKGROUND: Breastfeeding rates are lower for black women in the USA compared with other groups. Breastfeeding and lactation are sensitive time points in the life course, centering breastfeeding as a health equity issue. In the USA, experiences of racism have been linked to poor health outcomes but racism relative to breastfeeding has not been extensively investigated. AIMS: This study aims to investigate the association between experiences of racism, neighborhood segregation, and nativity with breastfeeding initiation and duration. METHODS: This is a prospective secondary analysis of the Black Women's Health Study, based on data collected from 1995 through 2005. Daily and institutional (job, housing, police) racism, nativity, and neighborhood segregation in relation to breastfeeding were examined. Odds ratios and 95% confidence intervals were calculated using binomial logistic regression for the initiation outcomes (N = 2705) and multinomial logistic regression for the duration outcomes (N = 2172). RESULTS: Racism in the job setting was associated with lower odds of breastfeeding duration at 3-5 months. Racism with the police was associated with higher odds of breastfeeding initiation and duration at 3-5 and 6 months. Being born in the USA or having a parent born in the USA predicted lower odds of breastfeeding initiation and duration. Living in a segregated neighborhood (primarily black residents) as a child was associated with decreased breastfeeding initiation and duration relative to growing up in a predominantly white neighborhood. CONCLUSION: Experiences of institutionalized racism influenced breastfeeding initiation and duration. Structural-level interventions are critical to close the gap of racial inequity in breastfeeding rates in the USA. PMID- 29435899 TI - Do Drains Contribute to Pancreatic Fistulae? Analysis of over 5000 Pancreatectomy Patients. AB - INTRODUCTION: Conflicting evidence exists from randomized controlled trials supporting both increased complications/fistulae and improved outcomes with drain placement after pancreatectomy. The objective was to determine drain practice patterns in the USA, and to identify if drain placement was associated with fistula formation. METHODS: Demographic, perioperative, and patient outcome data were captured from the most recent annual NSQIP pancreatic demonstration project database, including components of the fistula risk score. Significant variables in univariate analysis were entered into adjusted logistic regression models. RESULTS: Of 5013 pancreatectomy patients, 4343 (87%) underwent drain placement and 18% of patients experienced a pancreatic fistula. When controlled for other factors, drain placement was associated with ducts < 3 mm, soft glands, and blood transfusion within 72 h of surgery. Age, obesity, neoadjuvant radiation, preoperative INR level, and malignant histology lost significance in the adjusted model. Drained patients experienced higher readmission rates (17 vs. 14%; p < 0.05) and increased (20 vs. 8%; p < 0.01) pancreatic fistulae. Fistula was associated with obesity, no neoadjuvant chemotherapy, drain placement, < 3 mm duct diameter, soft gland, and longer operative times. Drain placement remained independently associated with fistula after both distal pancreatectomy (OR = 2.84 (1.70, 4.75); p < 0.01) and pancreatoduodenectomy (OR = 2.29 (1.28, 4.11); p < 0.01). CONCLUSIONS: Despite randomized controlled clinical trial data supporting no drain placement, drains are currently placed in the vast majority (87%) of pancreatectomy patients from > 100 institutions in the USA, particularly those with soft glands, small ducts, and perioperative blood transfusions. When these factors are controlled for, drain placement remains independently associated with fistulae after both distal and proximal pancreatectomy. PMID- 29435900 TI - Increased Overall Survival and Decreased Cancer-Specific Mortality in Patients with Hepatocellular Carcinoma Treated by Transarterial Chemoembolization and Human Adenovirus Type-5 Combination Therapy: a Competing Risk Analysis. AB - BACKGROUND: In analyzing cancer patient survival data, the problem of competing risks is often ignored. This study used a competing risk approach to evaluate the efficacy of recombinant human type-5 adenovirus (H101) in patients with hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE). METHODS: In this retrospective study, 476 patients were included. The cumulative probabilities of cancer-specific mortalities were analyzed by the Kaplan-Meier (KM) method and a competing risk model. Competing risk regression was used to assess the predictive factors for cumulative cancer-specific mortalities. RESULTS: Two hundred thirty-eight HCC patients received combination TACE and H101 therapy, and another 238 HCC patients received TACE therapy alone. For patients in the TACE with H101 group, estimated 1-, 2-, and 3-year overall survival (OS) rates were 61.0, 40.0, and 31.5%, respectively, while for patients in the TACE group, the estimated 1-, 2-, and 3-year OS rates were 55.0, 33.4, and 22.3%, respectively. The 1-, 2-, and 3-year cancer-specific mortality rates for patients in the TACE with H101 group vs. the TACE group were 37.3 vs. 42.0%, 55.7 vs. 63.5%, and 61.9 vs. 74.7%, respectively. Multivariate competing risk analysis established that a combination of TACE and H101 therapy was an independent factor in decreasing cancer-specific mortality. CONCLUSIONS: Compared with TACE therapy, patients who were diagnosed with unresectable HCC treated with combined TACE and H101 therapy had increased OS and decreased cancer-specific mortality. The survival benefit was more obvious in patients with elevated AFP, absence of metastasis, single tumor, enlarged tumor, and HBsAg-positivity. PMID- 29435901 TI - Factors Associated with Emergency Department Utilization and Admission in Patients with Colorectal Cancer. AB - PURPOSE: We assessed emergency department (ED) utilization in patients with colorectal cancer to identify factors associated with ED visits and subsequent admission, as well as identify a high-risk subset of patients that could be targeted to reduce ED visits. METHODS: Data from Optum Labs Data Warehouse, a national administrative claims database, was retrospectively analyzed to identify patients with colorectal cancer from 2008 to 2014. Multivariable logistic regression was used to identify factors associated with ED visits and ED "super users" (3+ visits). Repeated measures analysis was used to model ED visits resulting in hospitalization as a logistic regression based on treatments 30 days prior to ED visit. RESULTS: Of 13,466 patients with colorectal cancer, 7440 (55.2%) had at least one ED visit within 12 months of diagnosis. Factors associated with having an ED visit included non-white race, advancing age, increased comorbidities, and receipt of chemotherapy or radiation. 69.2% of patients who visited the ED were admitted to the hospital. A group of 1834 "super users" comprised 13.6% of our population yet accounted for 52.1% of the total number of ED visits and 32.3% of admissions. CONCLUSIONS: Over half of privately insured patients undergoing treatment for colorectal cancer will visit the ED within 12 months of diagnosis. Within this group, we identify common factors for a high-risk subset of patients with three or more ED visits who account for over half of all ED visits and a third of all admissions. These patients could potentially be targeted with alternative management strategies in the outpatient setting. PMID- 29435902 TI - Pediatric Living Donor Liver Transplantation Using a Monosegment Procured by Pure 3D Laparoscopic Left Lateral Sectionectomy and In situ Reduction. AB - BACKGROUND: Improvements in laparoscopic imaging systems and instruments have increased the performance of pure laparoscopic living donor hepatectomy. This operation is no longer limited to left lateral sectionectomy but is used for left hepatectomy and right hepatectomy.1-5 This report describes a donor who underwent pure laparoscopic left lateral sectionectomy and in situ reduction using 3D laparoscopy and indocyanine green (ICG) near-infrared fluorescence cholangiography to obtain a monosegment. METHODS: A 43-year-old woman offered to donate part of her liver to her daughter, who required a transplant for acute liver failure after a Kasai operation for biliary cirrhosis caused by biliary atresia. Donor height was 150.4 cm, body weight was 56.8 kg, and body mass index was 25.1 kg/m2. Liver dynamic CT showed a left lateral liver volume of 223 cm3, and an estimated graft-to-recipient weight ratio (GRWR) of 4.4%. The entire procedure including in situ reduction was performed under 3D laparoscopic view. The optimal bile duct division point was determined by real time ICG fluorescence cholangiography. RESULTS: The total operation time was 320 min, with no transfusion required and no intraoperative complications. Intraoperative real time ICG fluorescence cholangiography revealed the donor's bile duct anatomy and identified the optimal division point. The final graft weighed 167 g, 48 g being reduced in situ, with a GRWR of 3.3%. The donor was discharged on postoperative day 8 with no complications. CONCLUSION: Pure 3D laparoscopic left lateral sectionectomy and in situ reduction are feasible for obtaining a donor monosegment for pediatric living donor liver transplantation. PMID- 29435903 TI - Preparation of Controlled-Release Particles Based on Spherical Porous Silica Used as the Drug Carrier by the Dry Coating Method. AB - A controlled-release formulation is a dosage form that could improve a patient's quality of life by reducing the frequency of administration, while ensuring the continued effect of the medicine and reducing the side effects. To prepare these controlled-release particles, a wet coating method in which a drug is coated with a controlled-release material using water or an organic solvent is used, but with this method, the coating process is very time-consuming and requires large amounts of energy for the drying phase. In addition, contact with water or an organic solvent may cause problems such as alteration of the drug. Therefore, the use of a dry coating method has attracted attention as a means of overcoming these issues. However, since the drug is fixed to the surface of a core particle, it is necessary to further coat it with a water-soluble material. We used spherical porous silica (SPS) particles, considering that the drug fixation via a water-soluble material would not be necessary if the drug were to be placed in the pores of these particles. We used SPS filled with theophylline (TP), a model drug, as the core particles. To prepare controlled-release particles (CRP), a controlled-release layer consisting of hydrogenated castor oil (HCO) was applied to the core particle surface by a dry coating method. The paddle method using 1% w/v polysorbate 80 solution as the test medium was employed to estimate the TP dissolution rate of the resulting CRPs. The 50% dissolution time of TP extended from 14 to 405 min with increasing the amount of the coated HCO. The Korsmeyer Peppas model applied to the TP dissolution behavior yielded an n value of around 1. Moreover, the K value was comparable with the case in which a zero-order model was applied. It is thought that the dissolution of TP from CRPs will conform to the zero-order model. PMID- 29435904 TI - Performance of the Population Bioequivalence (PBE) Statistical Test Using an IPAC RS Database of Delivered Dose from Metered Dose Inhalers. AB - This article reports performance characteristics of the population bioequivalence (PBE) statistical test recommended by the US Food and Drug Administration (FDA) for orally inhaled products. A PBE Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) assembled and considered a database comprising delivered dose measurements from 856 individual batches across 20 metered dose inhaler products submitted by industry. A review of the industry dataset identified variability between batches and a systematic lifestage effect that was not included in the FDA-prescribed model for PBE. A simulation study was designed to understand PBE performance when factors identified in the industry database were present. Neglecting between-batch variability in the PBE model inflated errors in the equivalence conclusion: (i) The probability of incorrectly concluding equivalence (type I error) often exceeded 15% for non-zero between-batch variability, and (ii) the probability of incorrectly rejecting equivalence (type II error) for identical products approached 20% when product and between-batch variabilities were high. Neglecting a systematic through-life increase in the PBE model did not substantially impact PBE performance for the magnitude of lifestage effect considered. Extreme values were present in 80% of the industry products considered, with low-dose extremes having a larger impact on equivalence conclusions. The dataset did not support the need for log-transformation prior to analysis, as requested by FDA. Log transformation resulted in equivalence conclusions that depended on the direction of product mean differences. These results highlight a need for further refinement of in vitro equivalence methodology. PMID- 29435905 TI - Neuroendocrine Carcinoma of Gallbladder: A Step Beyond Palliative Therapy, Experience of 25 Cases. AB - PURPOSE: Published literature on gall bladder neuroendocrine tumors (GB NETs) is limited with none reporting the role of multimodal therapy. METHODS: Patients with histologically confirmed GB NETs treated at Tata Memorial Hospital, Mumbai, from January 2010 to June 2017 were analyzed. Staging was done by contrast enhanced computed tomography (CECT) of abdomen and chest or a positron emission topography (PET) scan. Tumor marker (CA19-9) was measured. WHO-2017 guideline was used to classify GB NETs. GB NETs were categorized as early disease (ED) (T1, T2, N0, i.e., stages I and II); locally advanced disease (LAD) (T3, T4, or N+, i.e., stage III); and metastatic disease (MD). Response to treatment was assessed with RECIST1.1 criteria. RESULTS: Twenty-five patients of GB NETs were identified; 19 with neuroendocrine carcinomas (NECs) and 6 with mixed adenoneuroendocrine carcinomas (MANECs). Two patients (8%) presented with ED, 9 (36%) with LAD, and 14 (56%) had MD. Those with ED underwent open revision radical cholecystectomy. Both received adjuvant chemotherapy (ACT) with six cycles of carboplatin etoposide and were disease-free at 3 months of follow-up. Of the nine patients with LAD, six received three cycles of neoadjuvant chemotherapy (NACT) (carboplatin-etoposide) and three operated upfront. All six patients showed partial response to NACT and five underwent open radical cholecystectomy with R0 resection. All patients operated after NACT received three cycles of ACT. Their median follow-up was 7 months (range 3-22 months). Three patients with LAD developed metastasis after median disease-free survival of 5 months. The median survival in patients with MD was 12 (range 6-23) months. CONCLUSIONS: In carefully selected patients of GB NECs, downsizing with NACT facilitates radical resection with negative margins. PMID- 29435906 TI - Retrospective Assessment of the Diagnostic Accuracy of the Depth of Invasion by Narrow Band Imaging Magnifying Endoscopy in Patients with Superficial Esophageal Squamous Cell Carcinoma. AB - PURPOSE: Treatment strategies for superficial esophageal squamous cell carcinoma (S-ESCC) are determined mainly on the basis of the depth of invasion. We retrospectively studied the accuracy of the depth of tumor invasion, comprehensively assessed using the Japan Esophageal Society (JES) classification. METHODS: The study group comprised 256 patients who underwent narrow band imaging (NBI) magnifying endoscopy, and endoscopic submucosal dissection for S-ESCC. The depth of invasion of S-ESCC was classified into three groups: EP/LPM, MM/SM1, and SM2. The following variables were studied retrospectively: (1) the diagnostic accuracy of non-magnifying white-light endoscopy, (2) the diagnostic accuracy of type B vessels, (3) the diagnostic accuracy of avascular area (AVA), (4) the diagnostic accuracy of the JES classification, and (5) the diagnostic accuracy of comprehensive diagnosis. The depth of invasion was assessed by white-light non magnifying endoscopy, followed by NBI magnifying endoscopy. RESULTS: The positive predictive value (PPV) of white-light non-magnifying endoscopy was 86% for EP/LPM, 53% MM/SM1, and 74% for SM2. The PPV of the diagnosis of type B vessels was 93% for EP/LPM, 62% for MM/SM1, and 74% for SM2. The PPV of the AVA diagnosis was 73% for EP/LPM, 89% for MM/SM1, and 100% for SM2. The PPV of diagnosis according to the JES classification was 93% for EP/LPM, 65% for MM/SM1, and 77% for SM2. The PPV of the comprehensive diagnosis was 94% for EP/LPM, 63%, for MM/SM1, and 75% for SM2. CONCLUSIONS: The additional use of NBI magnifying endoscopy can enhance the diagnostic accuracy of the depth of invasion in patients with S-ESCC. PMID- 29435907 TI - Sustained Virological Response in Special Populations with Chronic Hepatitis C Using Interferon-Free Treatments: A Systematic Review and Meta-analysis of Observational Cohort Studies. AB - BACKGROUND AND OBJECTIVES: Hepatitis C treatment has changed considerably in recent years, and many interferon (IFN)-free therapies are now available. Considering the high rates of sustained virological response (SVR) presented by clinical trials for these treatments, high rates of effectiveness are also expected in real-world clinical practice. Hence, this study aimed to conduct a systematic review and meta-analysis of observational cohort studies to evaluate the clinical effectiveness and safety of IFN-free therapies for hepatitis C. METHODS: The search was performed in four electronic databases and included cohort studies that evaluated IFN-free schemes and provided data on SVR at 12 weeks after the end of treatment (SVR12) as the primary outcome. Overall and subgroup meta-analyses of patients' clinical conditions (e.g. co-infection with human immunodeficiency virus (HIV), cirrhosis, liver transplant, specific genotypes, and other conditions) were performed. RESULTS: Sixty-eight studies encompassing a total of 24,151 patients were included for quantitative and qualitative analyses, evaluating six treatments: sofosbuvir with ledipasvir, daclatasvir, or simeprevir; daclatasvir with asunaprevir; paritaprevir/ritonavir in combination with ombitasvir and dasabuvir; and sofosbuvir with ribavirin. The overall analysis showed SVR rates of 88-96% for all treatments except sofosbuvir combined with ribavirin, which had SVR rates of approximately 80%. The results of subgroup analyses showed that the genotype 3 virus appears to be the most difficult to treat. CONCLUSION: In order to choose the best treatment option, it is necessary to consider the patients' conditions and characteristics. In conclusion, the use of IFN-free therapies meets the high expectations created by clinical trials, including patients in special clinical conditions. PMID- 29435908 TI - Differences in Metabolic Factors Between Antipsychotic-Induced Weight Gain and Non-pharmacological Obesity in Youths. AB - BACKGROUND: Youth exposed to antipsychotics may experience several metabolic consequences that often limit the effectiveness of this class of drugs. OBJECTIVES: The aim of this study was to compare several metabolic markers between subjects who experienced antipsychotic-induced weight gain and untreated obese patients. METHODS: Nineteen non-diabetic youth (mean age 159 months, mean body mass index z-score 1.81) experiencing antipsychotic-induced weight gain and an age-, sex-, and body mass index-matched group of non-diabetic obese patients with no record of treatment (n = 19, mean age 147 months, mean body mass index z score 2) were compared for a wide range of metabolic factors using a Bioplex Multiplex system. RESULTS: C-peptide, glucose-dependent insulinotropic polypeptide, and adipsin were significantly higher in the antipsychotic-induced weight gain group, whereas visfatin was significantly higher in the untreated obese patients. When age, sex, pubertal status, and body mass index were controlled, C-peptide, glucose-dependent insulinotropic polypeptide, and visfatin remained significant, whereas adipsin fell slightly below the threshold of statistical significance. No other statistically significant difference emerged. CONCLUSIONS: Antipsychotic-induced weight gain and untreated obesity showed some similarities, confirming that levels of some hormones, such as leptin and ghrelin, are related to body mass index rather than to antipsychotic exposure. Some differences were also noted; for example, the antipsychotic-induced weight gain group displayed higher C-peptide, glucose-dependent insulinotropic polypeptide, and adipsin, which may reflect beta-cell stress and may suggest susceptibility to insulin resistance and lower visfatin, possibly indicating a lower inflammatory status. PMID- 29435909 TI - Efficacy and Safety of Teneligliptin 40 mg in Type 2 Diabetes: A Pooled Analysis of Two Phase III Clinical Studies. AB - INTRODUCTION: Teneligliptin, an antihyperglycemic agent belonging to the dipeptidyl peptidase-4 inhibitor class, is usually prescribed at a dose of 20 mg/day. In Japan, the dose can be increased to 40 mg/day if needed. We examined the treatment response when the teneligliptin dose was increased from 20 to 40 mg in a post hoc pooled analysis of data from two 52-week, open-label, phase III clinical trials of teneligliptin 20-40 mg/day as monotherapy or combination treatment in Japanese patients with type 2 diabetes. METHODS: In both studies, patients received teneligliptin 20 mg for at least 28 weeks; thereafter the dose was increased if glycemic control was inadequate. The data set for this post hoc analysis comprised those patients whose teneligliptin dose was increased to 40 mg at week 28 (N = 204). We assessed (i) the proportion of patients achieving HbA1c reduction after teneligliptin dose increase [<= - 0.1% change in HbA1c during weeks 28-52 (24 weeks); responders] and (ii) the response to teneligliptin 40 mg according to whether or not patients experienced HbA1c re-elevation (>= 0.1% increase) during 28 weeks of teneligliptin 20 mg. RESULTS: Of 204 patients, 108 (52.9%) showed a response to teneligliptin 40 mg (HbA1c change <= - 0.1% during weeks 28-52) and had mean (+/- SD) HbA1c reduction of 0.50 +/- 0.44%. Of patients showing re-elevation of HbA1c during treatment with teneligliptin 20 mg, 89/143 (62.2%) achieved HbA1c reduction after dose increase to 40 mg. Logistic regression analyses suggested that change in body weight is one of the parameters linked to HbA1c reduction after dose increase to teneligliptin 40 mg. The incidence of adverse events was not changed after teneligliptin dose increase. CONCLUSION: Increasing the dosage of teneligliptin from 20 to 40 mg/day has potential as a well-tolerated and effective option for treating type 2 diabetes. FUNDING: Mitsubishi Tanabe Pharma Corporation. PMID- 29435910 TI - The impact of cardiovascular medication use on patients' daily lives: a cross sectional study. AB - Background The management of multiple long-term medicines of patients with chronic diseases creates a burden for patients. However, limited research is performed on its impact on patients' daily lives. Objective The aim of this study was to explore the impact of cardiovascular medication on different daily life aspects and to examine differences of these aspects between adherent and non adherent patients. Setting Two community pharmacies in the Netherlands. Method In this cross-sectional study patients (>= 45 years) using cardiovascular medication participated. Two equally group sized samples of patients non-adherent as assessed with pharmacy refill data, and patients adherent were selected. Main outcome measure Data were collected by means of the Living with Medicines Questionnaire measuring the impact of medicines use on patients' daily lives. Results In total, 196 patients participated, including 96 non-adherent patients. Substantial proportions of patients experienced medication-related burden on different daily life aspects. This burden was mainly related to the acceptance of long-term medicine use, medication-related concerns or dissatisfaction, the interference of medicines with social and daily lives, and the interaction and communication with health care providers. No statistically significant results were found when comparing the impact on patients' daily lives between adherent and nonadherent patients. Conclusion Health care providers should acknowledge the impact of multiple long-term medicines on patient's daily lives and should make an effort to diminish patients' medication-related burden by improving patient provider relationships and by providing adequate treatment information incorporating patients' individual circumstances. This may facilitate the integration of long-term medicine use in patients' daily lives. PMID- 29435912 TI - Concreteness norms for 1,659 French words: Relationships with other psycholinguistic variables and word recognition times. AB - Words that correspond to a potential sensory experience-concrete words-have long been found to possess a processing advantage over abstract words in various lexical tasks. We collected norms of concreteness for a set of 1,659 French words, together with other psycholinguistic norms that were not available for these words-context availability, emotional valence, and arousal-but which are important if we are to achieve a better understanding of the meaning of concreteness effects. We then investigated the relationships of concreteness with these newly collected variables, together with other psycholinguistic variables that were already available for this set of words (e.g., imageability, age of acquisition, and sensory experience ratings). Finally, thanks to the variety of psychological norms available for this set of words, we decided to test further the embodied account of concreteness effects in visual-word recognition, championed by Kousta, Vigliocco, Vinson, Andrews, and Del Campo (Journal of Experimental Psychology: General, 140, 14-34, 2011). Similarly, we investigated the influences of concreteness in three word recognition tasks-lexical decision, progressive demasking, and word naming-using a multiple regression approach, based on the reaction times available in Chronolex (Ferrand, Brysbaert, Keuleers, New, Bonin, Meot, Pallier, Frontiers in Psychology, 2; 306, 2011). The norms can be downloaded as supplementary material provided with this article. PMID- 29435911 TI - Efficacy of a telephone-based intervention among patients with type-2 diabetes; a randomized controlled trial in pharmacy practice. AB - Background Pharmacists' interventions to improve outcomes of diabetes management have been promising. However, evidence on using telephone-based interventions in pharmacy practice are limited, particularly in developing countries. Objective To evaluate the efficacy of a telephone-based intervention to improve care and clinical outcomes in type-2 diabetes. Setting A referral community pharmacy and drug information center. Method We conducted a two-armed randomized controlled trial on 100 patients with type-2 diabetes. The intervention consisted of 16 telephone calls in 3 month by a trained pharmacist working in an academic drug information center, while the control group received usual care. Before random allocation, patients attended a live education session delivered by pharmacists to learn the basics of diabetes care and to confirm the eligibility criteria. Assessments were performed at baseline, month-3 (after intervention), and month-9 (follow-up). Main outcome measure Hemoglobin A1c (HbA1c). Results Eighty four patient completed the trial. Baseline variables were comparable between the two groups and the baseline value of hemoglobin A1c was 8.00 +/- 1.44 in the study population. HbA1c was significantly improved in both groups at month-3 (6.97 +/- 1.41 vs. 7.09 +/- 1.78) and remained steady at month-9 (6.96 +/- 1.44 vs. 7.26 +/ 1.85). Lipid profile showed small improvements in the intervention group but was not significant. The adherence score and self-care score improvement was significantly higher in the intervention group at month-3 and were maintained at month-9. Conclusion Medication adherence and self-care significantly improved in the telephone-based intervention group. However, the improvement of clinical outcomes might have been diluted due to the live diabetes education session. PMID- 29435913 TI - Validating a visual version of the metronome response task. AB - The metronome response task (MRT)-a sustained-attention task that requires participants to produce a response in synchrony with an audible metronome-was recently developed to index response variability in the context of studies on mind wandering. In the present studies, we report on the development and validation of a visual version of the MRT (the visual metronome response task; vMRT), which uses the rhythmic presentation of visual, rather than auditory, stimuli. Participants completed the vMRT (Studies 1 and 2) and the original (auditory-based) MRT (Study 2) while also responding to intermittent thought probes asking them to report the depth of their mind wandering. The results showed that (1) individual differences in response variability during the vMRT are highly reliable; (2) prior to thought probes, response variability increases with increasing depth of mind wandering; (3) response variability is highly consistent between the vMRT and the original MRT; and (4) both response variability and depth of mind wandering increase with increasing time on task. Our results indicate that the original MRT findings are consistent across the visual and auditory modalities, and that the response variability measured in both tasks indexes a non-modality-specific tendency toward behavioral variability. The vMRT will be useful in the place of the MRT in experimental contexts in which researchers' designs require a visual-based primary task. PMID- 29435914 TI - Retrieving relevant factors with exploratory SEM and principal-covariate regression: A comparison. AB - Behavioral researchers often linearly regress a criterion on multiple predictors, aiming to gain insight into the relations between the criterion and predictors. Obtaining this insight from the ordinary least squares (OLS) regression solution may be troublesome, because OLS regression weights show only the effect of a predictor on top of the effects of other predictors. Moreover, when the number of predictors grows larger, it becomes likely that the predictors will be highly collinear, which makes the regression weights' estimates unstable (i.e., the "bouncing beta" problem). Among other procedures, dimension-reduction-based methods have been proposed for dealing with these problems. These methods yield insight into the data by reducing the predictors to a smaller number of summarizing variables and regressing the criterion on these summarizing variables. Two promising methods are principal-covariate regression (PCovR) and exploratory structural equation modeling (ESEM). Both simultaneously optimize reduction and prediction, but they are based on different frameworks. The resulting solutions have not yet been compared; it is thus unclear what the strengths and weaknesses are of both methods. In this article, we focus on the extents to which PCovR and ESEM are able to extract the factors that truly underlie the predictor scores and can predict a single criterion. The results of two simulation studies showed that for a typical behavioral dataset, ESEM (using the BIC for model selection) in this regard is successful more often than PCovR. Yet, in 93% of the datasets PCovR performed equally well, and in the case of 48 predictors, 100 observations, and large differences in the strengths of the factors, PCovR even outperformed ESEM. PMID- 29435915 TI - Eculizumab: A Review in Generalized Myasthenia Gravis. AB - The humanized monoclonal antibody eculizumab (Soliris(r)) is a complement inhibitor indicated for use in anti-acetylcholine receptor (AChR) antibody positive adults with generalized myasthenia gravis (gMG) in the USA, refractory gMG in the EU, or gMG with symptoms that are difficult to control with high-dose IVIg therapy or PLEX in Japan. It is the first complement inhibitor to be approved for use in these patients. In the well-designed, 26-week REGAIN study in patients with anti-AChR-positive refractory gMG, although a statistically significant benefit of eculizumab over placebo in the prespecified primary endpoint analysis (change from baseline in MG-activities of daily living (ADL) score assessed by worst-rank ANCOVA) was not formally demonstrated, preplanned and post hoc sensitivity analyses of this outcome, as well as other secondary outcomes supported the efficacy of eculizumab. Overall, patients receiving eculizumab experienced significant improvements in the ADL, muscle strength and health-related quality of life (HR-QOL) parameters relative to patients receiving placebo. Moreover, an ongoing extension of REGAIN showed that treatment benefits with eculizumab were sustained during continued therapy for at least 52 weeks. Eculizumab was generally well tolerated in these studies, with a tolerability profile similar to that reported previously in other indications. Although several questions remain, such as duration of treatment, cost effectiveness and long-term efficacy and tolerability, current evidence indicates that eculizumab is a valuable emerging therapy for patients with refractory gMG. PMID- 29435916 TI - The Metabolic Disturbances of Motoneurons Exposed to Glutamate. AB - Glutamate-induced excitotoxicity is considered as one of the major pathophysiological factors of motoneuron death in amyotrophic lateral sclerosis and other motoneuron diseases. In order to expand our knowledge on mechanisms of glutamate-induced excitotoxicity, the present study proposes to determine the metabolic consequences of glutamate and astrocytes in primary enriched motoneuron culture. Using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS), we showed that the presence of astrocytes and glutamate profoundly modified the metabolic profile of motoneurons. Our study highlights for the first time that crosstalk between astrocytes and enriched motoneuron culture induced alterations in phenylalanine, tryptophan, purine, arginine, proline, aspartate, and glutamate metabolism in motoneurons. We observed that astrocytes modulate the sensitivity of motoneurons to glutamate, since metabolites altered by glutamate in motoneurons cultured alone were different (except 5-hydroxylysine) from those altered in co-cultured motoneurons. Our findings provide new insight into the metabolic alterations associated to astrocytes and glutamate in motoneurons and provide opportunities to identify novel therapeutic targets. PMID- 29435919 TI - The MicroRNA. AB - MicroRNAs (miRNAs), widely distributed, small regulatory RNA genes, target both messenger RNA (mRNA) degradation and suppression of protein translation based on sequence complementarity between the miRNA and its targeted mRNA. Different names have been used to describe various types of miRNA. During evolution, RNA retroviruses or transgenes invaded the eukaryotic genome and were inserted itself in the noncoding regions of DNA, conceivably acting as transposon-like jumping genes, providing defense from viral invasion and fine-tuning of gene expression as a secondary level of gene modulation in eukaryotes. When a transposon is inserted in the intron, it becomes an intronic miRNA, taking advantage of the protein synthesis machinery, i.e., mRNA transcription and splicing, as a means for processing and maturation. MiRNAs have been found to play an important, but not life-threatening, role in embryonic development. They might play a pivotal role in diverse biological systems in various organisms, facilitating a quick response and accurate plotting of body physiology and structures. Based on these unique properties, manufactured intronic miRNAs have been developed for in vitro evaluation of gene function, in vivo gene therapy, and generation of transgenic animal models. The biogenesis of miRNAs, circulating miRNAs, miRNAs and cancer, iPSCs, and heart disease are presented in this chapter, highlighting some recent studies on these topics. PMID- 29435917 TI - Acupuncture Prevents the Impairment of Hippocampal LTP Through beta1-AR in Vascular Dementia Rats. AB - It is widely accepted that the synaptic dysfunction and synapse loss contribute to the cognitive deficits of vascular dementia (VD) patients. We have previously reported that acupuncture improved cognitive function in rats with VD. However, the mechanisms involved in acupuncture improving cognitive ability remain to be elucidated. The present study aims to investigate the pathways and molecules involved in the neuroprotective effect of acupuncture. We assessed the effects of acupuncture on hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation. Acupuncture enhanced LTP and norepinephrine (NE) levels in the hippocampus. Inhibition of the beta-adrenergic receptor (AR), but not the alpha-AR, was able to block the effects of acupuncture on hippocampal LTP. Furthermore, inhibition of beta1-AR, not beta2-AR, abolished the enhanced LTP induced by acupuncture. The expression analysis revealed a significant upregulation of beta1-AR and unchanged beta2-AR with acupuncture, which supported the above findings. Specifically, increased beta1-ARs in the dentate gyrus were expressed on neurons exclusively. Taken together, the present data supports a beneficial role of acupuncture in synaptic plasticity challenged with VD. A likely mechanism is the increase of NE and activation of beta1-AR in the hippocampus. PMID- 29435920 TI - Target mRNA-Driven Biogenesis of Cognate MicroRNAs In Vitro. AB - miRNAs are 20-22 nucleotide long noncoding RNAs that act as post-transcriptional regulators of gene expression controlling more than half of protein coding genes in humans. Being the critical modulators of the mRNA translation process, biogenesis, function, and turnover of these small RNAs are tightly regulated in cells. We have reported that target mRNAs induce increased biogenesis of cognate miRNAs from pre-miRNAs by increased activity of Ago-associated Dicer endonuclease that processes precursor miRNAs to their mature form. In the current chapter, we discuss how target mRNA-driven RISC loading can be monitored in vitro using affinity-purified miRISC or recombinant AGO2 and DICER1 proteins and scoring the processivity of AGO2-associated DICER1 in vitro. PMID- 29435918 TI - PLP1 Gene Variation Modulates Leftward and Rightward Functional Hemispheric Asymmetries. AB - Molecular neurobiological factors determining corpus callosum physiology and anatomy have been suggested to be one of the major factors determining functional hemispheric asymmetries. Recently, it was shown that allelic variations in two myelin-related genes, the proteolipid protein 1 gene PLP1 and the contactin 1 gene CNTN1, are associated with differences in interhemispheric integration. Here, we investigated whether three single nucleotide polymorphisms that were associated with interhemispheric integration via the corpus callosum in a previous study also are relevant for functional hemispheric asymmetries. To this end, we tested more than 900 healthy adults with the forced attention dichotic listening task, a paradigm to assess language lateralization and its modulation by cognitive control processes. Moreover, we used the line bisection task, a paradigm to assess functional hemispheric asymmetries in spatial attention. We found that a polymorphism in PLP1, but not CNTN1, was associated with performance differences in both tasks. Both functional hemispheric asymmetries and their modulation by cognitive control processes were affected. These findings suggest that both left and right hemisphere dominant cognitive functions can be modulated by allelic variation in genes affecting corpus callosum structure. Moreover, higher order cognitive processes may be relevant parameters when investigating the molecular basis of hemispheric asymmetries. PMID- 29435921 TI - Isolation of Viral-Infected Brain Regions for miRNA Profiling from Formalin-Fixed Paraffin-Embedded Tissues by Laser Capture Microdissection. AB - Brain is a highly heterogeneous organ with numerous layers of specialized cells. Viral infection further adds complexity to downstream analysis because only a subpopulation of the brain is infected. In these instances, molecular changes that occur within infected cells are not truly reflected when whole tissue is used for downstream analysis. Laser capture microdissection (LCM) is a tool that allows for the selection and isolation of cells or regions of interest as determined by microscopic observation. It provides a platform for visually selecting the tissue that truly represents the material one wishes to study, such as viral infected cells. Formalin-fixed paraffin-embedded viral-infected tissue allows for safe handling and processing by LCM. Here, we describe a method whereby viral-infected regions of the brain were specifically isolated by LCM from the rest of the FFPE tissue. The isolated regions were then used to extract RNA for microRNA profiling. This approach can be applied to study microRNA changes from any viral infection in any given tissue. PMID- 29435922 TI - Isolation and Analysis of Exosomal MicroRNAs from Ovarian Follicular Fluid. AB - Mammalian ovarian follicular growth is characterized by development of a large fluid filled antrum that separates mural granulosa cells and cumulus cells. Extensive communication between the different cell types is necessary for maturation of a developmentally competent oocyte. Here, we describe an approach for the isolation of cell-secreted exosomes from ovarian follicular fluid, identification of small RNAs (i.e., microRNAs) in exosomes, labeling of exosomes, and examining cell uptake of exosomes by follicular cells. PMID- 29435923 TI - Profiling of MicroRNAs in the Biofluids of Livestock Species. AB - The value of circulating microRNAs (miRNAs) as noninvasive biomarkers of human disease has been extensively demonstrated. Significant potential also exists in other species, particularly in relation to control of veterinary diseases and selection/monitoring of production traits in livestock. Although robust protocols have been developed for miRNA profiling of human biofluids, significant optimization may be required before these can be applied to other species. In this chapter, we describe protocols for small-RNA sequencing and RT-qPCR analyses of plasma samples from livestock species. In addition, we provide brief data analysis protocols for small-RNA sequencing and RT-qPCR data. Finally, we highlight important considerations for these protocols such as low RNA yield, platform-specific biases, and optimal normalization approaches. PMID- 29435924 TI - Exosomal MicroRNAs as Potential Biomarkers in Neuropsychiatric Disorders. AB - This chapter will discuss the potential use of microRNAs, particularly those located in peripherally-isolated exosomes, as biomarkers in neuropsychiatric disorders. These extracellular vesicles are released as a form of cell-to-cell communication and may mediate the soma-to-germline transmission of brain-relevant information, thereby potentially contributing to the inter- or transgenerational transmission of behavioral traits. Recent novel methods allow for the enrichment of peripheral exosomes specifically released by neurons and astrocytes and may provide valuable brain-relevant biosignatures of disease. PMID- 29435925 TI - Identification and Validation of Potential Differential miRNA Regulation via Alternative Polyadenylation. AB - MiRNAs control gene expression via recognition of specific sequences in the 3' untranslated region of target genes, leading to mRNA degradation and consequently translational repression. The regulatory impact of miRNAs does not only depend on their expression levels, but also on their targets' mRNA configuration. Via alternative polyadenylation mRNA isoforms are created that may or may not contain the respective miRNA target sequence, turning the regulatory between these two on or off. In the following article, we describe our protocol on how to combine a bioinformatics evaluation of a potential miRNA-target gene interaction using the public web framework miRIAD with 5' rapid amplification of cDNA ends (5'-RACE) in order to explore differential gene regulation by miRNAs through alternative polyadenylation. PMID- 29435926 TI - How to Explore the Function and Importance of MicroRNAs: MicroRNAs Expression Profile and Their Target/Pathway Prediction in Bovine Ovarian Cells. AB - Micro RNAs (miRNA) are integral components of genetic regulatory networks and act by binding to the transcripts of their corresponding target genes, leading to a decrease in protein production levels either by mRNA degradation or by translational repression. While the role of miRNAs is ubiquitous, they have a particular importance with regard to cell differentiation. The miRNA-target mRNA interaction has a significant impact on many signaling pathways and the cross talk between them; playing a regulatory role in a variety of different physiological processes within the cells. Ovarian follicle development is a physiological process that is not fully understood with regard to miRNA regulation; there are many questions that remain with respect to the molecular regulation of this important process. Bovine follicular cells are a good experimental model for the investigation of these mechanisms, having direct implications on reproductive health in humans. This chapter describes how differentially expressed miRNAs are identified in the granulosa and theca cells of dominant and subordinate bovine ovarian follicles and the identification of their associated targets and pathways. This chapter systematically describes how the granulosa and theca cells are dissected from the ovarian follicles. Afterward, we present a detailed protocol for miRNA extraction, based on a combined TRI reagent/column clean-up method, and also miRNA expression profiling using both microarray and RT-qPCR. In addition, an outline is provided of the bioinformatic analysis which enables the prediction of miRNAs targets. Pathways associated with the differentially expressed miRNAs are also elucidated using DIANA-miRPath software. PMID- 29435927 TI - Gene Silencing In Vitro and In Vivo Using Intronic MicroRNAs. AB - MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Numerous miRNAs have been reported to induce RNA interference (RNAi), a post-transcriptional gene-silencing mechanism. Recent evidence also indicates that they are involved in the transcriptional regulation of genome activities. They were first discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development, and are now recognized as small gene silencers transcribed from the noncoding regions of a genome. In humans, nearly 97% of the genome is noncoding DNA, which varies from one individual to another, and changes in these sequences are frequently noted to manifest in clinical and circumstantial malfunction; for example, type 2 myotonic dystrophy and fragile X syndrome were found to be associated with miRNAs derived from introns. Intronic miRNA is a new class of miRNAs derived from the processing of non-protein-coding regions of gene transcripts. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of RNA polymerase (Pol)-II and spliceosomal components for its biogenesis. Several kinds of intronic miRNAs have been identified in C. elegans, mouse, and human cells; however, their functions and applications have not been reported. Here, we show for the first time that intron-derived miRNA is not only able to induce RNAi in mammalian cells but also in fish, chicken embryos, and adult mice cells, demonstrating the evolutionary preservation of this gene regulation system in vivo. These miRNA-mediated animal models provide artificial means to reproduce the mechanisms of miRNA-induced disease in vivo and will shed further light on miRNA-related therapies. PMID- 29435928 TI - Mining Exosomal MicroRNAs from Human-Induced Pluripotent Stem Cells-Derived Cardiomyocytes for Cardiac Regeneration. AB - Myocardial infarction is the leading cause of morbidity and mortality worldwide. Recent advances in cardiac regenerative therapy have allowed for novel modalities in replenishing the damaged myocardium. However, poor long-term engraftment and survival of transplanted cells have largely precluded effective cell replacement. As an alternative to direct cell replacement, the release of paracrine protective factors may be a more plausible effector for cardioprotection which may partially be mediated through secretion of microvesicles, or exosomes, that contribute to cell-cell communication. In this chapter, we describe the isolation of exosomes from induced pluripotent stem cells-derived cardiomyocytes for subsequent microRNA profiling for a better understanding of the biological cargo contained within exosomes. PMID- 29435929 TI - Quantitative Analysis of Precursors MicroRNAs and Their Respective Mature MicroRNAs in Cancer Exosomes Overtime. AB - Exosomes are a cell-to-cell communication system that transports information to neighbor and/or distant cells. Their content is composed of lipids, proteins, RNAs, and DNA. The role of exosomes released by cancer cells in disease progression has been widely studied. Here, we report a detailed protocol to quantify precursor microRNAs and mature microRNAs overtime in exosomes of cancer cells. Those precursor microRNAs that are packaged together with RISC proteins will get further processed in the exosomes overtime and an accumulation of the mature form of the microRNAs will occur. PMID- 29435930 TI - Quantum Language of MicroRNA: Application for New Cancer Therapeutic Targets. AB - MicroRNA (miRNA) is the noncoding gene: therefore, the miRNA gene inheritably controls protein gene expression through transcriptional and post-transcriptional levels. Aberrant expression of miRNA genes causes various human diseases, especially cancers. Although cancer is a complex disease, cancer/miRNA implication has yet been grasped from the perspective of miRNA profile in bed side. Since miRNA is the mobile genetic element, the clinical verification of miRNA in microvesicle of blood is too much straggle to predict potential cancer/miRNA associations without bioinformatical computing. Further, experimental investigation of miRNA/cancer pathways is expensive and time consuming. While the accumulated data (big data) of miRNA profiles has been on line as the databases in cancers, using the database algorithms for miRNA target prediction have reduced required time for conventional experiments and have cut the cost. Computational prediction of miRNA/target mRNA has shown numerous significant outcomes that are unobtainable only by experimental approaches. However, ID of miRNA in the annotation is an arbitrary number and the ID is not related with miRNA its functions. Therefore, it has not been physicochemically shown why multiple miRNAs in blood or tissues are useful for diagnosis and porgnosis of human diseases or why function of single miRNA in cancer is rendered to oncomir or tumopr suppressor. In addition, it is less cleared why environmental factors, such as temperature, radiation, therapeutic anti-cancer immune or chemical agents can alter the expression of miRNAs in the cell. The ceRNA theory would not be enough for the investigation of such subjects. Given miRNA/target prediction tools, to elucidate such issues with computer simulation we have previously introduced the quantum miRNA/miRNA interaction as a new scoring using big database. The quantum score was implicated in miRNA synergisms in cancer and participated in the miRNA/target interaction on human diseases. On the other hand, ribosomal RNA (rRNA) is the dominant RNA species of the cells. It is well known that ribosomopathies, such as Diamond-Blackfan anemia, dyskeratiosis congenital, Shwachman-Diamond syndrome, 5q-myelodysplastic syndrome, Treacher Collins syndrome, cartilage-hair hypoplasia, North American Indian childhood cirrhosis, isolated congenital asplenia, Bowen-Conradi syndrome and cancer are caused by altered expression of ribosomal proteins or rRNA genes. We have proposed the hypothesis that the interaction among miRNAs from rRNA and/or other cellular miRNAs would be involved into cancer as the ribosomopathy. Subsequently, we found rRNA-derived miRNAs (rmiRNAs) by using the sequence homology search (miPS) with miRNA database (miRBase). Further, the pathway related with cancer between rmiRNA/target protein gene was predicted by miRNA entangling target sorting (METS) algorithm. In this chapter, we describe about the usage of in silico miRNA identification program, miRNA/target prediction search through the database and quantum language of miRNA by the METS, and the ontology analysis. In particular, the METS algorithm according to the quantum value would be useful simulator to discover a new therapeutic target aganist cancer. It may also partly contribute to the elucidation of complex mechanisms and development of agents of anti-cancer. PMID- 29435931 TI - In Vitro Methods for Analyzing miRNA Roles in Cancer Cell Proliferation, Invasion, and Metastasis. AB - MicroRNAs (miRNAs) are small noncoding, single-stranded RNAs consisting of 20-24 nucleotides (Bartel, Cell 116:281-297, 2004), which regulate target genes expression by interacting with 3'-untranslated regions (3'-UTRs) of target mRNAs, leading to translation repression or mRNA degradation (Filipowicz et al., Nat Rev Genet 9:102-114, 2008; Nilsen, Trends Genet 23:243-249, 2007). Accumulating evidence has elucidated them as oncogenes or tumor suppressors in cancers such as hepatocellular carcinoma, breast cancer, and lung cancer (Liu et al., Gastroenterology 136:683-693, 2009; Yu et al., Cell 131:1109-1123, 2007; Zhou et al., Sci Rep 7:42680, 2017; Iorio and Croce, Carcinogenesis 33:1126-1133, 2012). MiRNAs are involved in various biological processes, including cell proliferation (Liu et al., Mol Cancer Res 11:1314-1325, 2013), differentiation (Liu et al., Mol Cancer Res 11:1314-1325, 2013), apoptosis (Pan et al., Oncol Res 24:429-435, 2016), invasion and metastasis (Liu et al., Nat Commun 8:14270, 2017). Understanding the role of miRNAs in tumor gives new perspective on cancer diagnosis and therapy (Rupaimoole and Slack, Nat Rev Drug Discov 16:203-222, 2017; Berindan-Neagoe et al., CA Cancer J Clin 64:311-336, 2014). This chapter will focus on the in vitro methods for identifying miRNAs roles in cell proliferation, invasion, and metastasis in tumor development, which includes CCK 8 assay, Wound Healing assay, and Transwell assay. PMID- 29435932 TI - Isolation and Identification of Gene-Specific MicroRNAs. AB - Computer programming has identified hundreds of genomic hairpin sequences, many with functions yet to be determined. Because transfection of hairpin-like microRNA precursors (pre-miRNAs) into mammalian cells is not always sufficient to trigger RNA-induced gene silencing complex (RISC) assembly, a key step for inducing RNA interference (RNAi)-related gene silencing, we have developed an intronic miRNA expression system to overcome this problem by inserting a hairpin like pre-miRNA structure into the intron region of a gene, and hence successfully increase the efficiency and effectiveness of miRNA-associated RNAi induction in vitro and in vivo. This intronic miRNA biogenesis mechanism has been found to depend on a coupled interaction of nascent messenger RNA transcription and intron excision within a specific nuclear region proximal to genomic perichromatin fibrils. The intronic miRNA so obtained is transcribed by type-II RNA polymerases, coexpressed within a primary gene transcript, and then excised out of the gene transcript by intracellular RNA splicing and processing machineries. After that, ribonuclease III (RNaseIII) endonucleases further process the spliced introns into mature miRNAs. Using this intronic miRNA expression system, we have shown for the first time that the intron-derived miRNAs are able to elicit strong RNAi effects in not only human and mouse cells in vitro but also in zebrafishes, chicken embryos, and adult mice in vivo. We have also developed a miRNA isolation protocol, based on the complementarity between the designed miRNA and its targeted gene sequence, to purify and identify the mature miRNAs generated. As a result, several intronic miRNA identities and structures have been confirmed. According to this proof-of-principle methodology, we now have full knowledge to design various intronic pre-miRNA inserts that are more efficient and effective for inducing specific gene silencing effects in vitro and in vivo. PMID- 29435933 TI - Comprehensive Measurement of Gene Silencing Involving Endogenous MicroRNAs in Mammalian Cells. AB - MicroRNAs (miRNAs) are functional small noncoding RNAs that work as mediators in gene silencing and that play important roles in gene regulation. A number of miRNAs have been found and their expression profiles have been examined by means of various microarray systems and real-time polymerase chain reaction (PCR) systems. Conventional microarrays as well as real-time PCR are able to detect existing miRNAs, in which inactive miRNAs that hardly contribute to gene silencing may be also contained. Here, we describe a comprehensive miRNA bioassay system with reporter genes for the detection of active miRNAs that are present in the RNA-induced silencing complexes, and actually working as mediators in gene silencing. PMID- 29435934 TI - Screening miRNA for Functional Significance by 3D Cell Culture System. AB - Cell-based assays play important roles in cell biology and drug discovery. 3D cell culture, which allows cells to grow or interact with their surrounding in all three dimensions, provides more physiological information for the in vivo tests. Here, we describe a tunable collagen-based 3D cell culture system based on collagen material crosslinked with transgluminase, to study the function of miR. Methods including gel handling, proliferation assays, gene, and protein expressions in a 3D setting are described. PMID- 29435935 TI - Neonatal Rat Cardiomyocytes Isolation, Culture, and Determination of MicroRNAs' Effects in Proliferation. AB - Cardiomyocytes loss is a major contributor for many cardiovascular diseases including heart failure and myocardial infarction. Although extremely limited, adult cardiomyocytes are able to proliferate. Understanding the molecular mechanisms controlling cardiomyocytes proliferation is extremely important for enhancing cardiomyocyte proliferation to promote cardiac regeneration and repair. MicroRNAs (miRNAs, miRs) are powerful controllers of many essential biological processes including cell proliferation. Here, we described in detail a protocol for isolation and culture of neonatal rat cardiomyocytes and the determination of miRNAs' effects in proliferation based on two well-established methods including EdU and Ki67 immunofluorescent stainings. PMID- 29435936 TI - Gene Manipulation with Micro RNAs at Single-Human Cancer Cell. AB - Micro RNAs (miRNAs) are small RNAs processed from longer precursor RNA transcripts that can fold back on themselves to form Watson-Crick paired hairpin structures. Once processed from the longer molecule, the small RNA is much too short to code for proteins but can play other very important roles, like gene regulation. The phenomenon of RNA interference was initially observed by Napoli and Jorgensen in transgenic petunia flowers, where gene suppression was observed after introducing a transgene of chalcone synthase (CHS) belonging to the flavonoid biosynthesis pathway. miRNAs were first discovered for their roles in development but it has quickly become evident that they have causal roles in cancer as well. miRNA can also be used to manipulate genes for the investigation of carcinogenesis. Single-cell transcriptome profiling studies in our laboratory suggest that carcinogenesis often is the result of the malfunction of multiple members of a molecular pathway. Here, we describe a protocol to manipulate multiple cancer-related genes in a single human cell to investigate how multiple genes interact during carcinogenesis. PMID- 29435938 TI - Transgene-Like Animal Models Using Intronic MicroRNAs. AB - Transgenic animal models are valuable tools for testing gene functions and drug mechanisms in vivo. They are also the best similitude for a human body for etiological and pathological research of diseases. All pharmaceutically developed medicines must be proven to be safe and effective in animals before approval by the Food and Drug Administration (FDA) to be used in clinical trials. To this end, the transgenic animal models of diseases serve as the front line of drug evaluation. However, there is currently no transgenic animal model for microRNA (miRNA)-related research. MiRNAs, small single-stranded regulatory RNAs capable of silencing intracellular gene transcripts (mRNAs) that contain either complete or partial complementarity to the miRNA, are useful for the design of new therapies against cancer polymorphism and viral mutation. Recently, varieties of natural miRNAs have been found to be derived from hairpin-like RNA precursors in almost all eukaryotes, including yeast (Schizosaccharomyces pombe), plant (Arabidopsis spp.), nematode (Caenorhabditis elegans), fly (Drosophila melanogaster), fish, mouse and human, involving intracellular defense against viral infections and regulation of certain gene expressions during development. To facilitate the miRNA research in vivo, we have developed a state-of-the-art transgenic strategy for silencing specific genes in zebrafish, chicken, and mouse, using intronic miRNAs. By the insertion of a hairpin-like pre-miRNA structure into the intron region of a gene, we have found that mature miRNAs were successfully transcribed by RNA polymerases type II (Pol-II), coexpressed with the encoding gene transcripts, and excised out of the encoding gene transcripts by intracellular RNA splicing and processing mechanisms. In conjunction with retroviral transfection, the designed hairpin-like pre-miRNA construct has also been placed in the intron regions of a cellular gene for tissue-specific expression, specifically regulated by the gene promoter of interest. Because the retroviral vectors are integrated into the genome of its host cells, we can select and propagate the most effective transgenic animals to form a stable model line for further research. Here, we have shown for the first time that transgene like animal models were generated using the intronic miRNA expression system reported previously, which has been proven to be useful for studying miRNA function as well as the related gene regulation in vivo. PMID- 29435937 TI - Laser Capture Microdissection of Epithelium from a Wound Healing Model for MicroRNA Analysis. AB - MicroRNAs are ~22 nucleotide-long noncoding RNAs influencing many cellular processes (including wound healing) by their regulatory functions on gene expression. The ability to analyze microRNA in different cells at the wound site is essential for understanding the critical role(s) of microRNA during various phases of wound healing. Laser capture micro-dissection (LCM) is an effective method to distinguish between relevant and non-relevant cells or tissues and enables the researcher to obtain homogeneous, ultra-pure samples from heterogeneous starting material. We present here our protocol for procuring epithelial cells from a mouse wound healing model using a Leica LMD7000 Laser Microdissection system, as well as the RNA isolation and downstream microRNA analysis. Using this method, researchers can selectively and routinely analyze regions of interest down to single cells to obtain results that are relevant, reproducible, and specific. PMID- 29435939 TI - Application of TALE-Based Approach for Dissecting Functional MicroRNA-302/367 in Cellular Reprogramming. AB - MicroRNAs are small 18-24 nt single-stranded noncoding RNA molecules involved in many biological processes, including stemness maintenance and cellular reprogramming. Current methods used in loss-of-function studies of microRNAs have several limitations. Here, we describe a new approach for dissecting miR-302/367 functions by transcription activator-like effectors (TALEs), which are natural effector proteins secreted by Xanthomonas and Ralstonia bacteria. Knockdown of the miR-302/367 cluster uses the Kruppel-associated box repressor domain fused with specific TALEs designed to bind the miR-302/367 cluster promoter. Knockout of the miR-302/367 cluster uses two pairs of TALE nucleases (TALENs) to delete the miR-302/367 cluster in human primary cells. Together, both TALE-based transcriptional repressor and TALENs are two promising approaches for loss-of function studies of microRNA cluster in human primary cells. PMID- 29435940 TI - Mechanism and Method for Generating Tumor-Free iPS Cells Using Intronic MicroRNA miR-302 Induction. AB - Today's researchers generating induced pluripotent stem cells (iPS cells or iPSCs) usually consider their pluripotency rather than potential tumorigenicity. Oncogenic factors such as c-Myc and Klf4 are frequently used to boost the survival and proliferative rates of iPSCs, creating an inevitable problem of tumorigenicity that hinders the therapeutic usefulness of these iPSCs. To prevent stem cell tumorigenicity, we have examined mechanisms by which the cell cycle genes are regulated in embryonic stem cells (ESCs). Naturally, ESCs possess two unique stemness properties: pluripotent differentiation into almost all cell types and unlimited self-renewal without the risk of tumor formation. These two features are also important for the use of ESCs or iPSCs in therapy. Currently, despite overwhelming reports describing iPSC pluripotency, there is no report of any tumor prevention mechanism in either ESCs or iPSCs. To this, our studies have revealed for the first time that an ESC-specific microRNA (miRNA), miR-302, regulates human iPSC tumorigenicity through cosuppression of both cyclin E-CDK2 and cyclin D-CDK4/6 cell cycle pathways during G1-S phase transition. Moreover, miR-302 also silences BMI-1, a cancer stem cell gene marker, to promote the expression of two senescence-associated tumor suppressor genes, p16Ink4a and p14/p19Arf. Together, the combinatory effects of inhibiting G1-S cell cycle transition and increasing p16/p14(p19) expression result in an attenuated cell cycle rate similar to that of 2-to-8-cell-stage embryonic cells in early zygotes (20-24 h/cycle), which is however slower than the fast proliferation rate of iPSCs induced by the four defined factors Oct4-Sox2-Klf4-c-Myc (12-16 h/cycle). These findings provide a means to control iPSC tumorigenicity and improve the safety of iPSCs for the therapeutic use. In this chapter, we review the mechanism underlying miR-302-mediated tumor suppression and then demonstrate how to apply this mechanism to generate tumor-free iPSCs. The same strategy may also be used to prevent ESC tumorigenicity. PMID- 29435941 TI - The miR-302-Mediated Induction of Pluripotent Stem Cells (iPSC): Multiple Synergistic Reprogramming Mechanisms. AB - Pluripotency represents a unique feature of embryonic stem cells (ESCs). To generate ESC-like-induced pluripotent stem cells (iPSCs) derived from somatic cells, the cell genome needs to be reset and reprogrammed to express the ESC specific transcriptome. Numerous studies have shown that genomic DNA demethylation is required for epigenetic reprogramming of somatic cell nuclei to form iPSCs; yet, the mechanism remains largely unclear. In ESCs, the reprogramming process goes through two critical stages: germline and zygotic demethylation, both of which erase genomic DNA methylation sites and hence allow for different gene expression patterns to be reset into a pluripotent state. Recently, miR-302, an ESC-specific microRNA (miRNA), was found to play an essential role in four aspects of this reprogramming mechanism-(1) initiating global genomic DNA demethylation, (2) activating ESC-specific gene expression, (3) inhibiting developmental signaling, and (4) preventing stem cell tumorigenicity. In this review, we will summarize miR-302 functions in all four reprogramming aspects and further discuss how these findings may improve the efficiency and safety of the current iPSC technology. PMID- 29435942 TI - Identification and Isolation of Novel Sugar-Like RNA Protecting Materials: Glycylglycerins from Pluripotent Stem Cells. AB - Pluripotent stem cells are a resourceful treasure box for regenerative medicine. They contain a large variety of novel materials useful for designing and developing new medicines and therapies directed against many aging-associated degenerative disorders, including Alzheimer's disease, Parkinson's disease, stroke, diabetes, osteoporosis, and cancers. Currently, identification of these novel stem cell-specific materials is one of major breakthroughs in the field of stem cell research. Particularly, since the discovery of induced pluripotent stem cells (iPSC) in year 2006, the methods of iPSC derivation further provide an unlimited resource for screening, isolating, and even producing theses novel stem cell-specific materials in vitro. Using iPSCs, we can now prepare high quality and quantity of pure stem cell-specific agents for testing their therapeutic functions in treating various illnesses. These newly found stem cell-specific agents are divided into four major categories, including proteins, saccharides, nucleic acids, and small molecules (chemicals). In this article, we herein disclose one of the methodologies for isolating and purifying glycylglycerins-a group of glycylated sugar alcohols that protect hairpin-like microRNA precursors (pre-miRNA) and some of tRNAs in pluripotent stem cells. In view of such a unique RNA-protecting feature, glycylglycerins may be used to preserve and deliver functional small RNAs, such as pre-miRNAs and small interfering RNAs (siRNA), into human cells for eliciting their specific RNA interference (RNAi) effects, which may greatly advance the use of RNAi technology for treating human diseases. PMID- 29435943 TI - Abstracts from the 16th National Congress of the Italian Society of Cardiovascular Prevention (SIPREC), Naples, 8-10 March 2018. PMID- 29435944 TI - Cancer and aging in Ibero-America. AB - Population aging represents a worldwide challenge. In Ibero-America (Spain, Portugal, and the American countries in which the Spanish or Portuguese language are spoken), the number of older adults is growing, leading to an increase in aging-related diseases such as cancer. Older adults already account for half of all cancer cases in Ibero-America, and this proportion will continue to increase. Furthermore, Ibero-American healthcare systems are not adequately prepared to provide care for older adults with cancer, mainly due to a lack of resources and generalized paucity of geriatric training for healthcare providers. Across the region, several clinical initiatives, educational activities and research collaborations have been established to set the foundations of Ibero-American geriatric oncology and to increase the geriatric knowledge among healthcare providers. This article provides an overview of the current landscape of geriatric oncology in Ibero-America, highlighting its critical challenges, opportunities for improvement and collaboration, and future directions. PMID- 29435945 TI - Collaborating with Families: Exploring Family Member and Health Care Provider Perspectives on Engaging Families Within Medical Education. AB - OBJECTIVE: With 40 to 65% of mental health patients being cared for by family members, nearly 500,000 Canadians are serving as caregivers. Yet family members are often excluded from daily clinical interactions and the development of mental health continuing medical education (CME). This qualitative study aimed to understand how best to involve families in mental health CME and how to advance their meaningful and equitable engagement in such initiatives. METHODS: Semi structured interviews were conducted with two samples: mental health care providers (n = 8) and family members of individuals diagnosed with a co-occurring addiction and mental health problems (n = 12) to explore barriers, facilitators, and strategies for family engagement. RESULTS: Several themes related to the perception of expertise emerged from the interviews, including the tension between the validity of knowledge based on education/credentials and knowledge based on lived experience, as well as expressions of "voice." Participants also identified barriers to, and ethical considerations related to, family engagement, including stigma and confidentiality, and recommended strategies and supports to meaningfully include the family perspective within mental health CME. CONCLUSIONS: Aligning with the movement to improve collaboration between mental health professionals and service users requires developing relationships with family members. Identifying strategies to involve families in the development of CME is crucial to initiating and maintaining family engagement. PMID- 29435947 TI - Characteristics of Physical Aggression in Children of Immigrant Mothers and Non immigrant Mothers: A Cross-Sectional Analysis of the Survey of Young Canadians. AB - Physical aggression (PA) is important to regulate as early as the preschool years in order to ensure healthy development of children. This study aims to determine the prevalence and characteristics of PA in children of immigrant and non immigrant mothers. Secondary data analysis was conducted using the nationwide 2010 Survey for Young Canadians, limited to children 4-9 years of age. Bivariate and multivariable logistic regression was performed, with the outcome, PA, and covariates including maternal, child, household and neighbourhood characteristics. Twenty percent of children of non-immigrant mothers and 16% of children of immigrant mothers reported PA. The only common characteristic of PA between children of non-immigrant (Adj OR 1.44, 95% CI 1.09-1.89) and immigrant mothers (Adj OR 2.08, 95% CI 1.07-4.03) was viewing violent movies/shows. The characteristics of PA differ between children of immigrant versus non-immigrant mothers therefore healthcare providers, policy makers, and researchers should be mindful to address PA in these two groups separately, and find ways to tailor current recommended coping strategies and teach children alternative ways to solve problems based on their needs. PMID- 29435946 TI - Ethnic Variations in Adiponectin Levels and Its Association with Age, Gender, Body Composition and Diet: Differences Between Iranians, Indians and Europeans Living in Australia. AB - Adiponectin is an adipocyte-derived protein with anti-diabetic, anti-atherogenic and anti-inflammatory action, but there are few studies on its association with cardiovascular and metabolic risk factors in different ethnic groups in Australia. This cross-sectional study evaluated ethnic differences in adiponectin levels and its association with age, gender, body composition and diet in 89 adult Australians of European (n = 28), Indian (n = 28) and Iranian (n = 33) ancestries. Different measures of adiposity were assessed using the method of whole body dual energy X-ray absorptiometry (DEXA). Total adiponectin levels determined in Indians and Iranians were significantly lower than those in Europeans (p values < 0.001). There was no significant difference between the adiponectin levels in Indians and Iranians (p value > 0.05). There was no substantial change in the results after adjustment for potential confounders. Circulating levels of adiponectin was associated with age, truncal fat percentage, dietary glycemic index, glycemic load and carbohydrate intake, by correlation analysis (p values < 0.05). Using multiple linear regression analysis, a model including truncal fat percentage (p < 0.001), ethnicity (p = 0.001), age (p = 0.001) and dietary glycemic index (p = 0.04) could predict 50% of the variance in adiponectin levels (R2 = 0.504). Among different variables assessed, truncal fat percentage (in Indian and Iranian groups) and glycemic index (in European group) were the strongest predictors of serum adiponectin when data were analysed for three ethnic groups, separately. In conclusion, individuals with Iranian or Indian ancestries may have lower adiponectin levels compared to Europeans. Ethnicity was found as an independent factor affecting adiponectin levels. Our results also highlighted age, truncal adiposity and dietary glycemic index as other determinants of serum adiponectin, however the extent to which these factors influence adiponectin concentrations may vary across ethnicities. PMID- 29435948 TI - Racial/Ethnic Discrimination and Diabetes-Related Outcomes Among Latinos with Type 2 Diabetes. AB - Discrimination is associated with adverse health outcomes, but few studies have examined the association of discrimination with diabetes-related outcomes including mental health and glycemic control, particularly for immigrant and US born Latinos. We analyzed survey data (n = 222) collected at baseline of a diabetes intervention. Using multiple linear regression, we examined the association of racial/ethnic discrimination with depressive symptoms, diabetes related distress, and HbA1c, and variation in these associations by nativity and, for immigrants, length of US residence. Racial/ethnic discrimination was positively associated with depressive symptoms (b = 2.57, SE = 0.45, p < 0.01) and diabetes-related distress (b = 0.30, SE = 0.09, p < 0.01). We could not reject the null hypothesis of no cross-sectional association of racial/ethnic discrimination with HbA1c (b = - 0.27, SE = 0.18, p = 0.14). Although racial/ethnic discrimination did not directly affect HbA1c, racial/ethnic discrimination had a significant mediating effect on HbA1c through diabetes related distress (p = 0.02). Results suggest that racial/ethnic discrimination is detrimental for health for Latinos with diabetes. PMID- 29435950 TI - Evaluation of performance of distributed delay model for chemotherapy-induced myelosuppression. AB - The distributed delay model has been introduced that replaces the transit compartments in the classic model of chemotherapy-induced myelosuppression with a convolution integral. The maturation of granulocyte precursors in the bone marrow is described by the gamma probability density function with the shape parameter (nu). If nu is a positive integer, the distributed delay model coincides with the classic model with nu transit compartments. The purpose of this work was to evaluate performance of the distributed delay model with particular focus on model deterministic identifiability in the presence of the shape parameter. The classic model served as a reference for comparison. Previously published white blood cell (WBC) count data in rats receiving bolus doses of 5-fluorouracil were fitted by both models. The negative two log-likelihood objective function (-2LL) and running times were used as major markers of performance. Local sensitivity analysis was done to evaluate the impact of nu on the pharmacodynamics response WBC. The nu estimate was 1.46 with 16.1% CV% compared to nu = 3 for the classic model. The difference of 6.78 in - 2LL between classic model and the distributed delay model implied that the latter performed significantly better than former according to the log-likelihood ratio test (P = 0.009), although the overall performance was modestly better. The running times were 1 s and 66.2 min, respectively. The long running time of the distributed delay model was attributed to computationally intensive evaluation of the convolution integral. The sensitivity analysis revealed that nu strongly influences the WBC response by controlling cell proliferation and elimination of WBCs from the circulation. In conclusion, the distributed delay model was deterministically identifiable from typical cytotoxic data. Its performance was modestly better than the classic model with significantly longer running time. PMID- 29435949 TI - A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data. AB - Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants < 2 years old, so our analysis was restricted to this group. The final combined dataset consisted of 266 plasma drug concentrations in 45 subjects with a median (interquartile range) postnatal age of 40.1 (11.0-120.4) days and weight of 3.9 (3.1-5.1) kg. Since the median sampling time after the first dose was short (study: 95 h; literature: 72 h) relative to the terminal half-life estimated in adult PopPK studies, values of the deep compartment volume and flow were fixed to literature values. A 3-compartment model best described the data and was validated by visual predictive checks and non-parametric bootstrap analysis. The final model included body weight as a covariate on all volumes and on both inter-compartmental and elimination clearances. The empiric Bayesian estimates for clearance (CL), volume of distribution at steady state, and terminal half-life were 0.25 (90% CL 0.14-0.36) L/kg/h, 93 (68-174) L/kg, and 266 (197-477) h, respectively. These studies will provide useful information for future PopPK studies of amiodarone in infants and children that could improve dosage regimens. PMID- 29435951 TI - Correction of Huntington's Disease Phenotype by Genistein-Induced Autophagy in the Cellular Model. AB - Huntington's disease (HD) is a monogenic disorder, caused by mutations in the HTT gene which result in expansion of CAG triplets. The product of the mutated gene is misfolded huntingtin protein that forms aggregates leading to impairment of neuronal function, neurodegeneration, motor abnormalities and cognitive deficits. No effective cure is currently available for HD. Here we studied effects of genistein (trihydroxyisoflavone) on a HD cellular model consisting of HEK-293 cells transfected with a plasmid bearing mutated HTT gene. Both level of mutated huntingtin and number of aggregates were significantly decreased in genistein treated HD cell model. This led to increased viability of the cells. Autophagy was up-regulated while inhibition of lysosomal functions by chloroquine impaired the genistein-mediated degradation of the mutated huntingtin aggregates. Hence, we conclude that through stimulating autophagy, genistein removes the major pathogenic factor of HD. Prolonged induction of autophagy was suspected previously to be risky for patients due to putative adverse effects; however, genistein has been demonstrated recently to be safe and suitable for long-term therapies even at doses as high as 150 mg/kg/day. Therefore, results presented in this report provide a basis for the use of genistein in further studies on development of the potential treatment of HD. PMID- 29435952 TI - Erratum to: Fluorescence Quenching Studies of gamma-Butyrolactone-Binding Protein (CprB) from Streptomyces coelicolor A3(2). PMID- 29435953 TI - Role of Noncommunicable Diseases (NCDs) in Resource-Limited Settings (RLS). AB - PURPOSE OF REVIEW: As access to effective antiretroviral therapy (ART) expands globally, a decline in AIDS-related morbidity and mortality has been complicated by rising rates of noncommunicable diseases (NCDs). This review provides a brief description of NCDs and existing gaps on knowledge about NCDs among HIV-infected adults mostly in Africa. RECENT FINDINGS: Recent reports show that one in every five persons living with HIV has a chronic illness, predominantly diabetes and/or hypertension, depression, and most of these conditions are either not diagnosed or not being managed. Human papilloma virus-associated anal dysplasia occurs among 70% of HIV-infected women in RLS. Recognizing risk factors for NCDs and providing effective screening and optimal care remains challenging. Research is urgently needed to carefully characterize HIV-associated NCDs in RLS. Such studies should provide a framework for high-priority NCDs that the limited resources can be focused on in these settings. PMID- 29435954 TI - Large-scale Exploration of Neuronal Morphologies Using Deep Learning and Augmented Reality. AB - Recently released large-scale neuron morphological data has greatly facilitated the research in neuroinformatics. However, the sheer volume and complexity of these data pose significant challenges for efficient and accurate neuron exploration. In this paper, we propose an effective retrieval framework to address these problems, based on frontier techniques of deep learning and binary coding. For the first time, we develop a deep learning based feature representation method for the neuron morphological data, where the 3D neurons are first projected into binary images and then learned features using an unsupervised deep neural network, i.e., stacked convolutional autoencoders (SCAEs). The deep features are subsequently fused with the hand-crafted features for more accurate representation. Considering the exhaustive search is usually very time-consuming in large-scale databases, we employ a novel binary coding method to compress feature vectors into short binary codes. Our framework is validated on a public data set including 58,000 neurons, showing promising retrieval precision and efficiency compared with state-of-the-art methods. In addition, we develop a novel neuron visualization program based on the techniques of augmented reality (AR), which can help users take a deep exploration of neuron morphologies in an interactive and immersive manner. PMID- 29435955 TI - Effects of Manual Somatic Stimulation on the Autonomic Nervous System and Posture. AB - Low back pain frequently involves a multifactorial etiology and requires medical attention. The aim of the study was to assess the associations among pain, posture, and autonomic nervous system function in patients with low back pain, using neuromuscular manual therapy versus a generic peripheral manual stimulation (back massage therapy). Twenty young patients with low back pain were enrolled into the study. The patients were randomly divided into two groups: treated with neuromuscular manual therapy performed after a specific structural evaluation and treated with back massage therapy. Both groups performed eight sessions of 30 min each, once a week for two months. There were three main time points of the assessment: during the first, the fourth, and the last eighth session. In each of these three sessions, data were collected before onset of session (baseline), 5 min from onset, at end of session, and 5 min after the end. All patients were subjected to stabilometric evaluation and were assessed on a visual analogue scale to quantify postural and pain changes. Tabletop capnography and pulse oximetry were used to monitor autonomic changes. The findings were that the improvement in posture and pain reduction were appreciably better in patients subjected to neuromuscular manual therapy than in those subjected to back massage therapy, with a comparable autonomic response in both groups. In conclusion, the study demonstrates that posture modification was significantly more advantageous in patient treated with neuromuscular manual therapy. PMID- 29435956 TI - Robot-Assisted Body-Weight-Supported Treadmill Training in Gait Impairment in Multiple Sclerosis Patients: A Pilot Study. AB - This study deals with the use of a robot-assisted body-weight-supported treadmill training in multiple sclerosis (MS) patients with gait dysfunction. Twenty MS patients (10 men and 10 women) of the mean of 46.3 +/- 8.5 years were assigned to a six-week-long training period with the use of robot-assisted treadmill training of increasing intensity of the Lokomat type. The outcome measure consisted of the difference in motion-dependent torque of lower extremity joint muscles after training compared with baseline before training. We found that the training uniformly and significantly augmented the torque of both extensors and flexors of the hip and knee joints. The muscle power in the lower limbs of SM patients was improved, leading to corrective changes of disordered walking movements, which enabled the patients to walk with less effort and less assistance of care givers. The torque augmentation could have its role in affecting the function of the lower extremity muscle groups during walking. The results of this pilot study suggest that the robot-assisted body-weight-supported treadmill training may be a potential adjunct measure in the rehabilitation paradigm of 'gait reeducation' in peripheral neuropathies. PMID- 29435957 TI - Oscillations of Subarachnoid Space Width as a Potential Marker of Cerebrospinal Fluid Pulsatility. AB - In the cerebrospinal fluid (CSF) circulation, two components can be distinguished: bulk flow (circulation) and pulsatile flow (back and forth motion). CSF pulsatile flow is generated by both cardiac and respiratory cycles. Recent years have seen increased interest in cardiac- and respiratory-driven CSF pulsatility as an important component of cerebral homeostasis. CSF pulsatility is affected by cerebral arterial inflow and jugular outflow and potentially linked to white matter abnormalities in various diseases, such as multiple sclerosis or hypertension. In this review, we discuss the physiological mechanisms associated with CSF pulsation and its clinical significance. Finally, we explain the concept of using the oscillations of subarachnoid space width as a surrogate for CSF pulsatility. PMID- 29435958 TI - Understanding the Relationship Between Food Variety, Food Intake, and Energy Balance. AB - PURPOSE OF REVIEW: In accordance with US dietary guidance, incorporating variety into the diet can align with energy balance, though greater food variety in some categories may make energy balance more challenging. Thus, experimental and epidemiologic evidence is summarized on the relationship between food variety, food and energy intake, and energy balance. RECENT FINDINGS: Lab-based, experimental research consistently demonstrates that greater variety within foods or sensory characteristics of food increases food and energy intake within an eating occasion. Epidemiologic evidence is less consistent, potentially driven by differing methodologies, particularly in defining and measuring food variety. Moreover, the effect of variety on energy balance appears to be moderated by food energy density. Integrating insights from experimental and epidemiologic research are essential for strengthening food variety guidance including developing evidence-based definitions of food variety, understanding moderators of the relationship, and developing practical guidance interpretable to consumers. PMID- 29435960 TI - Alkaloids, Plants and Butterflies: a Farewell to Jose Roberto Trigo (1956-2017). PMID- 29435959 TI - Hyperpalatability and the Generation of Obesity: Roles of Environment, Stress Exposure and Individual Difference. AB - PURPOSE OF REVIEW: This review investigates how exposure to palatable food and its associated cues alters appetite regulation and feeding behaviour to drive overeating and weight gain. RECENT FINDINGS: Both supraphysiological and physiological feeding systems are affected by exposure to palatable foods and its associated cues. Preclinical research, largely using rodents, has demonstrated that palatable food modulates feeding-related neural systems and food-seeking behaviour by recruiting the mesolimbic reward pathway. This is supported by studies in adolescents which have shown that mesolimbic activity in response to palatable food cues and consumption predicts future weight gain. Additionally, stress exposure, environmental factors and individual susceptibility have been shown to modulate the effects of highly palatable foods on behaviour. Further preclinical research using free-choice diets modelling the modern obesogenic environment is needed to identify how palatable foods drive overeating. Moreover, future clinical research would benefit from more appropriate quantification of palatability, making use of rating systems and surveys. PMID- 29435962 TI - Context cue focality influences strategic prospective memory monitoring. AB - Monitoring the environment for the occurrence of prospective memory (PM) targets is a resource-demanding process that produces cost (e.g., slower responding) to ongoing activities. However, research suggests that individuals are able to monitor strategically by using contextual cues to reduce monitoring in contexts in which PM targets are not expected to occur. In the current study, we investigated the processes supporting context identification (i.e., determining whether or not the context is appropriate for monitoring) by testing the context cue focality hypothesis. This hypothesis predicts that the ability to monitor strategically depends on whether the ongoing task orients attention to the contextual cues that are available to guide monitoring. In Experiment 1, participants performed an ongoing lexical decision task and were told that PM targets (TOR syllable) would only occur in word trials (focal context cue condition) or in items starting with consonants (nonfocal context cue condition). In Experiment 2, participants performed an ongoing first letter judgment (consonant/vowel) task and were told that PM targets would only occur in items starting with consonants (focal context cue condition) or in word trials (nonfocal context cue condition). Consistent with the context cue focality hypothesis, strategic monitoring was only observed during focal context cue conditions in which the type of ongoing task processing automatically oriented attention to the relevant features of the contextual cue. These findings suggest that strategic monitoring is dependent on limited-capacity processing resources and may be relatively limited when the attentional demands of context identification are sufficiently high. PMID- 29435964 TI - Uncertainty processing in bees exposed to free choices: Lessons from vertebrates. AB - Bees tend to avoid or to show indifference to uncertain ("risky") relative to certain ("safe") food rewards, whether in nectar volume or in nectar concentration. The unattractiveness of uncertain food rewards is also sometimes independent of the energy budget of bees. This pattern of responses seems to differ from that observed in mammals and birds, which may exhibit a strong preference for the uncertainty over the certainty of food delivery on a given trial in dual-choice tasks. Upon analysis of the conditions that determine preference and aversion for uncertain food rewards in "higher" vertebrates, I attempt to demonstrate that bees react to uncertainty in a similar way. It is argued that, because of their social organization and of the type of resources they seek, bees are essentially exposed to situations in which "higher" vertebrates find reward uncertainty unattractive as well. The nature of their representation of food distribution is discussed, and it is suggested that scout bees may differ from recruits with respect to uncertainty processing. PMID- 29435965 TI - [Remodelling of the Scientific Committee and a new series of neuroepidemiology reviews]. PMID- 29435963 TI - Pupil dilation as an index of effort in cognitive control tasks: A review. AB - Pupillometry research has experienced an enormous revival in the last two decades. Here we briefly review the surge of recent studies on task-evoked pupil dilation in the context of cognitive control tasks with the primary aim being to evaluate the feasibility of using pupil dilation as an index of effort exertion, rather than task demand or difficulty. Our review shows that across the three cognitive control domains of updating, switching, and inhibition, increases in task demands typically leads to increases in pupil dilation. Studies show a diverging pattern with respect to the relationship between pupil dilation and performance and we show how an effort account of pupil dilation can provide an explanation of these findings. We also discuss future directions to further corroborate this account in the context of recent theories on cognitive control and effort and their potential neurobiological substrates. PMID- 29435966 TI - [School assistance for attention deficit hyperactivity disorder in the Spanish autonomous regions]. AB - INTRODUCTION: In recent years different Spanish autonomous regions have presented policies on school assistance for attention deficit hyperactivity disorder (ADHD) or coordination between the educational and healthcare services, which result in protocols, instructions or guidelines of action. AIM: To determine and compare the proposals put forward by the different Spanish regions with respect to school assistance for ADHD. SUBJECTS AND METHODS: After searching for the documents that contain these policies, the information therein was analysed with the aim of being able to compare them in several different areas: document, scope of application, detection of ADHD, diagnosis, school measures, follow-up of the proposals of the Guidelines on clinical practice in attention deficit hyperactivity disorder, grounds and resources offered. RESULTS: The Valencian Region is the only one for which no documents were found. The document for the Balearic Islands was not analysed because it is not public, and in the other regions differences were found in the degree of compliance with the criteria assessed in each area. The policies in Extremadura, Galicia, Catalonia and Navarra are the ones that meet the largest number of criteria. All the regions with policies on ADHD propose some kind of school measures and resources such as bibliographical references, contacts or models of documents or screening tools. All of them, except Madrid, offer information about the detection and diagnosis of ADHD. CONCLUSION: There are differences among the proposals for school assistance for ADHD in Spain, and those of Extremadura, Galicia, Catalonia and Navarra are found to be the most complete. PMID- 29435967 TI - [The effect of age on the prognosis of patients with traumatic brain injury who undergo a craniotomy: analysis of a surgical series]. AB - INTRODUCTION: In our setting, the ageing of the population has led to management of traumatic brain injury (TBI) in the later stages of life becoming an increasingly frequent problem. AIM: To evaluate the association between age and the functional and survival prognosis of patients who have undergone surgery due to TBI. PATIENTS AND METHODS: We performed a retrospective analysis of a series of 404 patients submitted to surgery between the years 2000 and 2015: 144 youngsters (12-44 years), 77 adults (45-64 years), 148 geriatric patients (65-79 years) and 26 'super geriatric' patients (> 80 years). We reviewed the demographic and nosological characteristics of the population, the survival and functional prognosis (Glasgow Outcome Scale, GOS) on discharge and at six months. RESULTS: Age presents a positive linear association with both intra-hospital mortality and the proportion of patients with an unfavourable prognosis (GOS 1-3) on hospital discharge and at six months (p < 0.001). Taking the population of youngsters as a reference, the relative risk for an unfavourable prognosis at six months was 1.5 (95% CI: 1.04-2.19) for adults; 2.37 (95% CI: 1.77-3.17) for the geriatric patients; and 3.5 (95% CI: 2.63-4.7) for the 'super geriatric' patients. These latter present a mortality rate while in hospital of 77.78% and a percentage of poor functional prognosis at six months of 94.44%. CONCLUSION: Increased age is a major negative determining factor in the prognosis of patients who undergo a craniotomy due to TBI. More precise knowledge of these outcomes and an adequate pre-operative discussion with the family will be an invaluable aid in the decision-making process. PMID- 29435968 TI - [A new phenotype of infantile-onset Pompe disease]. AB - INTRODUCTION: Infantile-onset Pompe disease is a kind of glycogenosis resulting from a deficit of the enzyme acid alpha-glucosidase. Before specific enzyme replacement therapy (ERT) became available, the classic form was fatal during the first two years of life. ERT increases survival and improves cardiac, respiratory and motor functioning. CASE REPORTS: Case 1: 2-month-old infant with predominantly axial hypotonia who required the use of a nasogastric tube as a result of difficulties in sucking and swallowing. Myopathy and hypertrophic cardiomyopathy were observed. The patient was diagnosed with Pompe disease, ERT was established and improved heart and motor functioning were noted. Nevertheless, she presented recurring respiratory infections that finally made it necessary to perform a tracheostomy. She is currently still undergoing ERT, walks with a walker and presents a mild ventricular dysfunction. Case 2: 3-week-old infant who was taken to see his paediatrician for a routine check-up. The examination revealed a systolic bruit and axial and proximal hypotonia. Cardiology tests revealed hypertrophic cardiomyopathy. The patient was sent to a referral centre, where he was diagnosed with Pompe disease and a cross-reactive immunological material-negative status. The patient received immunomodulator treatment and ERT. Progress was favourable, although he presented frequent respiratory infections. The patient is currently capable of walking by himself, although the gait is unsteady. CONCLUSIONS: Both cases illustrate the new phenotype of infantile-onset Pompe disease treated with ERT. Despite the motor limitations and respiratory involvement presented by the patients, both survival and autonomy have increased. PMID- 29435969 TI - [Epidemiology of Parkinson's disease in Spain and its contextualisation in the world]. AB - INTRODUCTION: The study of the epidemiology of Parkinson's disease (PD) is essential because it is a public health problem and because the differences in its prevalence and incidence offer clues as to the existence of aetiologically important environmental or biological factors. AIMS: To report the most relevant data about the descriptive epidemiology (prevalence, incidence and mortality) of PD from studies conducted in different countries, with special emphasis on those carried out in Spain and Latin America. Likewise, the study also includes a discussion of some of the main risk factors or protectors of this disease (analytical epidemiology) that have emerged thanks to the data obtained from large cohorts in the literature. DEVELOPMENT: We conduct an analysis of the most significant population-based studies, focusing especially on those conducted using the 'door-to-door' methodology. CONCLUSIONS: Its prevalence and incidence vary greatly around the world. In general, prevalence is higher in Europe and the United States than in other countries and is relatively uniform, fluctuating over a range that is not very noteworthy. In Asian, Latin American and African countries it is lower, especially in this last continent. These differences could be partly due to the specific factors of the population studied (that is to say, higher mortality rate due to lower economic resources). The most firmly established risk factors are ageing and being male. PMID- 29435970 TI - [Easing access to all information should be mandatory to medical journals]. PMID- 29435971 TI - [Treatment of encephalopathy by means of valproic acid with carglumic acid]. PMID- 29435972 TI - [Treatment of encephalopathy by means of valproic acid with carglumic acid. Reply]. PMID- 29435973 TI - Inhibition of experimental small-cell and non-small-cell lung cancers by novel antagonists of growth hormone-releasing hormone. AB - We investigated the effects of novel antagonists of growth hormone releasing hormone (GHRH)-MIA602 and MIA690-on three human small cell lung cancer (SCLC) lines (H446, DMS53 and H69) and two non-SCLC (NSCLC) lines (HCC827 and H460). In vitro exposure of cancer cells to these GHRH antagonists significantly inhibited cell viability, increased cell apoptosis, decrease cellular levels of cAMP and reduced cell migration. In vivo, the antagonists strongly inhibited tumor growth in xenografted nude mice models. Subcutaneous administration of MIA602 at the dose of 5 MUg/day for 4-8 weeks reduced the growth of HCC827, H460 and H446 tumors by 69.9%, 68.3% and 53.4%, respectively, while MIA690 caused a reduction of 76.8%, 58.3% and 54.9%, respectively. Western blot and qRT-PCR analyses demonstrated a downregulation of expression of the pituitary-type GHRH-R and its splice-variant, cyclinD1/2, cyclin-dependent kinase4/6, p21-activated kinase-1, phosphorylation of activator of transcription 3 and cAMP response element binding protein; and an upregulation of expression of E-cadherin, beta-catenin and P27kip1 in cancer cells and in xenografted tumor tissues. The study demonstrates the involvement of GHRH antagonists in multiple signaling pathways in lung cancers. Our findings suggest the merit of further investigation with these GHRH antagonists on the management of both SCLC and NSCLC. PMID- 29435974 TI - Association between metformin use after surgery for colorectal cancer and oncological outcomes: A nationwide register-based study. AB - Colorectal cancer is one of the most common malignancies in the Western world, and even after surgical removal, there is a high recurrence rate. Metformin treatment has been associated with a reduced risk of developing cancer, but whether metformin influences the risk of recurrence is unknown. The aim of our study was to examine the association between treatment with metformin and recurrence-free, disease-free survival and all-cause mortality after surgery for colorectal cancer. The study was an observational register-based study and included 25,785 patients, of which 1,116 had medically treated diabetes and 966 started metformin treatment at some point postoperatively. Diabetes was not associated with neither disease-free (HRadjusted = 1.09, 95% CI 0.97-1.21, p = 0.15) nor recurrence-free survival (HRadjusted = 1.13, 95% CI 0.95-1.35, p = 0.17). The study found no difference in regards to disease-free or recurrence free survival between the metformin treated group (HRRFS = 1.06, 95% CI 0.87 1.15, p = 0.57, HRDFS = 1.01, 95% CI 0.89-1.15, p = 0.85) and non-diabetic patients. Patients with diabetes had increased all-cause mortality (HRadjusted = 1.29, 95% CI 1.16-1.45, p < 0.0001). Metformin treatment did not affect all-cause mortality (HR = 1.07, 95% CI 0.94-1.22, p = 0.33) compared to non-diabetic patients. In conclusion, our study did not find an association between diabetes or metformin treatment and recurrence-free or disease-free survival after surgery for colorectal cancer. However, diagnosis of diabetes is associated with increased all-cause mortality. PMID- 29435975 TI - Quantifying Magnitude of Group-Level Differences in Patient Experiences with Health Care. AB - OBJECTIVE: Review approaches assessing magnitude of differences in patient experience scores between different providers. DATA SOURCES: 1990-2016 literature. STUDY DESIGN: Systematic literature review. DATA EXTRACTION METHODS: Of 812 articles mentioning "CAHPS," "patient experience," "patient satisfaction," "important(ce)," "difference," or "significance," we identified 79 possible articles, yielding 35 for data abstraction. We included 22 articles measuring magnitude of differences in patient experiences. PRINCIPAL FINDINGS: We identified three main ways of estimating magnitude of differences in patient experience scores: (1) by distribution/range of patient experience variable, (2) against external anchor, and (3) comparing a difference in patient experience on one covariate to differences in patient experience on other covariates. CONCLUSIONS: We suggest routine estimation of magnitude in patient experience research. More work is needed documenting magnitude of differences between providers to make patient experience data more interpretable and usable. PMID- 29435976 TI - Post-diagnosis alcohol intake and prostate cancer survival: A population-based cohort study. AB - Alcohol consumption has been declared a Group 1 carcinogen by the International Agency for Research on Cancer (IARC) and is a potential risk factor for several types of cancer mortality. However, evidence for an association with prostate cancer survival remains inconsistent. We examined how alcohol consumption post diagnosis was associated with survival after prostate cancer diagnosis. Men diagnosed with prostate cancer (n = 829) in Alberta, Canada between the years 1997 and 2000 were recruited into a population-based case-control study and then followed for up to 19 years for survival outcomes. Pre- and post-diagnosis alcohol consumption, clinical characteristics and lifestyle factors were collected through in-person interviews shortly after diagnosis and again 2-3 years post-diagnosis. Cox proportional hazards were used to examine how post diagnosis alcohol consumption was associated with all-cause and prostate cancer specific mortality (competing risk analysis too), in addition to first recurrence/progression or new primary cancer. Most participants reported drinking alcohol (>=once a month for 6 months) post-diagnosis (n = 589, 71.0%). Exceeding Canadian Cancer Society (CCS) alcohol consumption recommendations (>=2 drinks/day) post-diagnosis was associated with prostate cancer-specific mortality relative to non-drinkers (aHR: 1.82, 95% CI: 1.07-3.10) with borderline evidence of a linear trend. Interestingly, those in the highest quartile of drinks/week pre- and post-diagnosis also had a twofold increase for prostate-specific mortality (aHR: 2.67, 95% CI: 1.28-5.56) while controlling for competing risks. Our results support post-diagnosis alcohol consumption was associated with increased mortality after prostate cancer diagnosis, specifically for prostate cancer-related death. Future studies focused on confirming this burden of disease are warranted. PMID- 29435977 TI - Characterization of mesenchymal stem/stromal cells with lymphoid tissue organizer cell potential in tonsils from children. AB - Lymphoid tissue organizer (LTo) cells, identified in mouse and human embryos, are thought to be precursors of stromal cells in secondary lymphoid organs. Whether LTo cells are present in human adults, however remains unknown. We obtained 15 stromal cell lines from tonsils from children who underwent tonsillectomy, and studied the antigen phenotype of these tonsil stromal cell (TSC) lines by flow cytometry and RT-PCR. Cell lines met the minimal criteria proposed by the International Society for Cellular Therapy to define human mesenchymal stem/stromal cells (MSCs): plastic-adherent capacity; expression of CD73, CD90 and CD105, lack of CD45, CD19 and HLA-DR; and capacity to differentiate into adipocytes, osteoblasts and chondrocytes. Furthermore, our TSC lines exhibited an antigen phenotype and functional characteristics very similar to those seen in murine embryo LTo cells: they expressed chemokines CCL19, CCL21 and CXCL13, cytokines TRANCE and IL-7, and adhesion molecules ICAM-1, mucosal addressin cell adhesion molecule (MadCAM)-1 and VCAM-1. The expression of LTo cell-associated markers and functions were upregulated by lymphotoxin (LT)alpha1beta2 and TNF, two cytokines involved in the development and maturation of secondary lymphoid tissues. Our results show that TSCs are tonsil MSCs that differentiate into LTo like cells in response to the effects of these cytokines. PMID- 29435978 TI - How Geriatrics Saved This Family Caregiver. PMID- 29435979 TI - Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results. AB - Novel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib +/- low-dose dexamethasone in patients who received >=2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib +/- weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2-stage design. The primary objective was clinical benefit rate (CBR; >=minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9.2 months (range, 3.0-14.7). Progression-free survival was 4.6 months (range, 0.4 17.3). Grade 3-4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3-4 non-haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment. PMID- 29435981 TI - Forty-nine gastric cancer cell lines with integrative genomic profiling for development of c-MET inhibitor. AB - Receptor tyrosine kinase MET (c-MET) has received considerable attention as a potential target for gastric cancer (GC) therapy and a number of c-MET inhibitors have been developed. For successful drug development, proper preclinical studies especially using patient derived cancer cell lines are very important. We profiled MET and MET-related characteristics in 49 GC cell lines to utilize them as models in preclinical studies of GC. Forty-nine cell lines were analyzed for genetic, biological, and molecular status to characterize MET and MET-related molecules. Four c-MET inhibitors were tested to elucidate the dependency on MET pathway in the 49 GC cell lines. Six of 49 cell lines were MET amplified with overexpression of c-MET and p-MET. The variants of MET were not associated with c MET expression or amplification. Hs746T showed an exon 14 deletion in conjunction with MET amplification. The cell lines were divided into 6 MET amplified, 2 c-MET overexpressed, 2 hepatocyte growth factor (HGF) overexpressed, and 39 MET negative subgroups. Except tivantinib, the c-MET inhibitors showed higher inhibition (%) in MET amplified than in MET nonamplified cell lines that MET amplified cell lines showed MET pathway dependency. However, the c-MET overexpressed and HGF overexpressed cell lines showed moderate dependency on MET pathway. Well-characterized cell lines are very important in studying drug development. Our 49 GC cell lines had various characteristics of MET and MET related molecules and MET pathway dependency. These provide a promising platform for development of various RTK inhibitors including c-MET inhibitors. PMID- 29435982 TI - Nitrate in drinking water and colorectal cancer risk: A nationwide population based cohort study. AB - Nitrate in drinking water may increase risk of colorectal cancer due to endogenous transformation into carcinogenic N-nitroso compounds. Epidemiological studies are few and often challenged by their limited ability of estimating long term exposure on a detailed individual level. We exploited population-based health register data, linked in time and space with longitudinal drinking water quality data, on an individual level to study the association between long-term drinking water nitrate exposure and colorectal cancer (CRC) risk. Individual nitrate exposure was calculated for 2.7 million adults based on drinking water quality analyses at public waterworks and private wells between 1978 and 2011. For the main analyses, 1.7 million individuals with highest exposure assessment quality were included. Follow-up started at age 35. We identified 5,944 incident CRC cases during 23 million person-years at risk. We used Cox proportional hazards models to estimate hazard ratios (HRs) of nitrate exposure on the risk of CRC, colon and rectal cancer. Persons exposed to the highest level of drinking water nitrate had an HR of 1.16 (95% CI: 1.08-1.25) for CRC compared with persons exposed to the lowest level. We found statistically significant increased risks at drinking water levels above 3.87 mg/L, well below the current drinking water standard of 50 mg/L. Our results add to the existing evidence suggesting increased CRC risk at drinking water nitrate concentrations below the current drinking water standard. A discussion on the adequacy of the drinking water standard in regards to chronic effects is warranted. PMID- 29435983 TI - Epigenetic dysregulation of key developmental genes in radiation-induced rat mammary carcinomas. AB - With the increase in the number of long-term cancer survivors worldwide, there is a growing concern about the risk of secondary cancers induced by radiotherapy. Epigenetic modifications of genes associated with carcinogenesis are attractive targets for the prevention of cancer owing to their reversible nature. To identify genes with possible changes in functionally relevant DNA methylation patterns in mammary carcinomas induced by radiation exposure, we performed microarray-based global DNA methylation and expression profiling in gamma-ray induced rat mammary carcinomas and normal mammary glands. The gene expression profiling identified dysregulation of developmentally related genes, including the downstream targets of polycomb repressive complex 2 (PRC2) and overexpression of enhancer of zeste homolog 2, a component of PRC2, in the carcinomas. By integrating expression and DNA methylation profiles, we identified ten hypermethylated and three hypomethylated genes that possibly act as tumor suppressor genes and oncogenes dysregulated by aberrant DNA methylation; half of these genes encode developmental transcription factors. Bisulfite sequencing and quantitative PCR confirmed the dysregulation of the polycomb-regulated developmentally related transcription-factor genes Dmrt2, Hoxa7, Foxb1, Sox17, Lhx8, Gata3 and Runx1. Silencing of Hoxa7 was further verified by immunohistochemistry. These results suggest that, in radiation-induced mammary gland carcinomas, PRC2-mediated aberrant DNA methylation leads to dysregulation of developmentally related transcription-factor genes. Our findings provide clues to molecular mechanisms linking epigenetic regulation and radiation-induced breast carcinogenesis and underscore the potential of such epigenetic mechanisms as targets for cancer prevention. PMID- 29435980 TI - The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD-linked amyloid-beta oligomers (AbetaOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AbetaOs into the lateral cerebral ventricle of non-human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD-related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP-1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29435984 TI - Economics of Pharmacogenetic-Guided Treatments: Underwhelming or Overstated? AB - Economic evaluations have dispelled a perception that precision medicine, achieved through pharmacogenetic testing, reduces healthcare costs. For many tests aimed at preventing adverse drug reactions, cost-effectiveness analyses predict modest improvements in health benefits and increases in total costs. While there are many uncertainties in estimating the value of testing, factors that influence cost-effectiveness include the rarity of the outcome, the effectiveness of alternative treatments, and the scope and perspective of analysis. PMID- 29435985 TI - Farewell to Our Good Friend, Outstanding Mentor, and Colleague Darrell R. Abernethy (1949-2017). PMID- 29435986 TI - Role of recoverin in rod photoreceptor light adaptation. AB - KEY POINTS: Recoverin is a small molecular-weight, calcium-binding protein in rod outer segments that can modulate the rate of rhodopsin phosphorylation. We describe two additional and perhaps more important functions during photoreceptor light adaptation. Recoverin influences the rate of change of adaptation. In wild type rods, sensitivity and response integration time adapt with similar time constants of 150-200 ms. In Rv-/- rods lacking recoverin, sensitivity declines faster and integration time is already shorter and not significantly altered. During steady light exposure, rod circulating current slowly increases during a time course of tens of seconds, gradually extending the operating range of the rod. In Rv-/- rods, this mechanism is deleted, steady-state currents are already larger and rods saturate at brighter intensities. We propose that recoverin modulates spontaneous and light-activated phophodiesterase-6, the phototransduction effector enzyme, to increase sensitivity in dim light but improve responsiveness to change in brighter illumination. ABSTRACT: Recoverin is a small molecular-weight, calcium-binding protein in rod outer segments that binds to G-protein receptor kinase 1 and can alter the rate of rhodopsin phosphorylation. A change in phosphorylation should change the lifetime of light activated rhodopsin and the gain of phototransduction, but deletion of recoverin has little effect on the sensitivity of rods either in the dark or in dim-to moderate background light. We describe two additional functions perhaps of greater physiological significance. (i) When the ambient intensity increases, sensitivity and integration time decrease in wild-type (WT) rods with similar time constants of 150-200 ms. Recoverin is part of the mechanism controlling this process because, in Rv-/- rods lacking recoverin, sensitivity declines more rapidly and integration time is already shorter and not further altered. (ii) During steady light exposure, WT rod circulating current slowly increases during a time course of tens of seconds, gradually extending the operating range of the rod. In Rv-/- rods, this mechanism is also deleted, steady-state currents are already larger and rods saturate at brighter intensities. We argue that neither (i) nor (ii) can be caused by modulation of rhodopsin phosphorylation but may instead be produced by direct modulation of phophodiesterase-6 (PDE6), the phototransduction effector enzyme. We propose that recoverin in dark-adapted rods keeps the integration time long and the spontaneous PDE6 rate relatively high to improve sensitivity. In background light, the integration time is decreased to facilitate detection of change and motion and the spontaneous PDE6 rate decreases to augment the rod working range. PMID- 29435988 TI - A novel, simple, economic and effective method for retarding maize tortilla staling. AB - BACKGROUND: Staling of maize tortillas is a major drawback affecting their manufacture, commercialization and consumption. The development of methods that may help retard staling of maize tortillas is an ongoing research topic. In this work, a novel, simple, economic and effective method is proposed, based on adding completely gelatinized nixtamalized maize flour (GMF) dispersion to the basic masa formulation recipe (water, 600 g kg-1 ; nixtamalized maize flour, 400 g kg-1 ) in substitution of 50, 100 and 150 g kg-1 of water. RESULTS: Masa added with GMF showed increased water retention capacity, reduced freezable water content and improved flow and dynamic rheological properties and produced tortillas with decreased firmness. The infrared 1047/1022 cm-1 spectral ratio indicated that a more disordered starch granule arrangement was formed, while enthalpy peaks associated with starch retrogradation decreased. All the above indicators were more pronounced the higher was the GMF content. CONCLUSION: This work showed that GMF can play the role of a self-hydrocolloid anti-staling agent by retarding the retrogradation of maize starch and deterring the loss of water and rheological properties of masa and the increase in undesirable sensory characteristics of tortilla such as increased firmness. (c) 2018 Society of Chemical Industry. PMID- 29435989 TI - Improved potassium nutrition retrieves phosphorus-induced decrease in zinc uptake and grain zinc concentration of wheat. AB - BACKGROUND: The negative effect of soil-applied phosphorus (P) on zinc (Zn) uptake by plants and its concentration in food grains could be a possible reason for low dietary intake of Zn. Likewise, owing to its critical role in plant tolerance to other abiotic stresses, potassium (K) was thought to retrieve P induced decrease in grain Zn concentration of wheat. To test the above hypothesis, the effect of K application (50 mg kg-1 soil) on Zn concentration in shoot/grains and its shoot-to-grain translocation was studied in wheat (Triticum aestivum L. cv. Galaxy-2013) under low and optimal supply of both P (10 and 50 mg kg-1 ) and Zn (0 and 5 mg kg-1 ). RESULTS: The response of growth parameters and grain yield to optimal Zn, P and K applications indicated that all nutrients were limiting plant growth at low levels. Irrespective of P level, Zn application at optimal rate increased Zn concentration and uptake by straw and grains of wheat. Contrarily, optimal P application decreased Zn concentration but increased Zn uptake by wheat straw. More specifically, combined application of Zn and P at optimal levels decreased Zn concentration in grains from 43 to 32 mg kg-1 compared with optimal Zn application alone. Potassium application to optimal P- and Zn-supplied plants increased remobilization of pre-anthesis straw Zn store to grains by 50% and decreased Zn concentration in straw. Consequently, K application along with optimal Zn and P supply to plants completely retrieved P induced loss in grain Zn concentration and also increased grain Zn uptake from 891 to 1249 ug per pot without significantly affecting grain yield. CONCLUSION: The K-induced increase in grain Zn concentration is attributed to K-driven higher post-anthesis Zn uptake and remobilization of pre-anthesis straw Zn store to grains. (c) 2018 Society of Chemical Industry. PMID- 29435987 TI - The PHD1 oxygen sensor in health and disease. AB - The hypoxia-inducible factor (HIF) co-ordinates the adaptive transcriptional response to hypoxia in metazoan cells. The hypoxic sensitivity of HIF is conferred by a family of oxygen-sensing enzymes termed HIF hydroxylases. This family consists of three prolyl hydroxylases (PHD1-3) and a single asparagine hydroxylase termed factor inhibiting HIF (FIH). It has recently become clear that HIF hydroxylases are functionally non-redundant and have discrete but overlapping physiological roles. Furthermore, altered abundance or activity of these enzymes is associated with a number of pathologies. Pharmacological HIF-hydroxylase inhibitors have recently proven to be both tolerated and therapeutically effective in patients. In this review, we focus on the physiology, pathophysiology and therapeutic potential of the PHD1 isoform, which has recently been implicated in diseases including inflammatory bowel disease, ischaemia and cancer. PMID- 29435990 TI - Solid state fermentation and crude cellulase based bioconversion of potential bamboo biomass to reducing sugar for bioenergy production. AB - BACKGROUND: Lignocellulosic biomass from bamboo is an attractive feedstock for the bioethanol industry owing to its high cellulosic content and fast growth rate. In this study, powdery biomass was first enzymatically delignified and then saccharified using crude enzymes. RESULTS: The biological pretreatment decreased the lignin content of the biomass from an initial value of 295 to 137.7 g kg-1 , with a simultaneous increase in exposed cellulose content from 379.3 to 615.9 g kg-1 . For optimization of the saccharification, response surface methodology was adopted using a three-factor/three-level Box-Behnken design with crude fungal cellulase loading (FPU g-1 substrate), substrate concentration (% w/v) and saccharification temperature ( degrees C) as the main process parameters. A maximum saccharification yield of 47.19% was achieved under the optimized conditions (cellulase enzyme 18.4 FPU g-1 substrate, substrate concentration 1.0% w/v, temperature 39.49 degrees C). Biological delignification and saccharification of the biomass were further confirmed through scanning electron microscopy analysis. CONCLUSION: It is evident from the study that bamboo, as a renewable energy bioresource, can be hydrolysed to reducing sugars by using crude laccase/cellulase enzymes of fungal origin with good saccharification yield. Thus crude enzyme preparations could be utilized efficiently for eco-friendly and cost effective bioethanol production. (c) 2018 Society of Chemical Industry. PMID- 29435991 TI - Vagus nerve injury symptoms after catheter ablation for atrial fibrillation. AB - BACKGROUND: Vagus nerve injury during catheter ablation for atrial fibrillation can significantly impact quality of life and result in lingering gastrointestinal symptoms. This study was designed to define risk factors of vagus nerve injury, symptoms, prevalence, and temporal resolution. METHODS: A total of 100 patients undergoing radiofrequency catheter ablation (RFCA) were enrolled and consented to participate in the study. Patients completed a 22-item questionnaire that included questions specific to vagus nerve injury symptomatology during their baseline visit and at 1 and 3 months post-RFCA. RESULTS: The average age of the population was 63 +/- 10.6 years and 68% were male. A total of 100 patients completed their baseline questionnaire (90 patients completed the 1-month questionnaires and 85 patients completed the 3-month questionnaires). Symptoms rated as moderate were prevalent at baseline (trouble swallowing 13%, bloating 26%, feeling full 20%), and increased in all categories analyzed at 1 month and with the exception of trouble swallowing returned to the preablation percentages at 3 months (heartburn 22.4%, trouble swallowing 18.8%, bloating 16.5%, nausea 8.2%, vomiting 3.5%, constipation 18.8%, diarrhea 16.4%, feeling full 15.3%). Severe rated symptoms of trouble swallowing (2-5.5%), bloating (5-7.6%), and early satiety (5-9.8%) increased at 1 month and bloating and early satiety percentages remained approximately two times higher at 3 months (trouble swallowing 2.4%, bloating 8.2%, early satiety 7.1%). CONCLUSION: The majority of symptoms were resolved by 3 months, although those patients who rate bloating and early satiety at a severe rating may have persistent symptoms. PMID- 29435992 TI - Feasibility and Safety of a Cemented PEEK-on-PE Knee Replacement in a Goat Model: A Preliminary Study. AB - Polyether-ether-ketone (PEEK) is a potential alternative to metal alloys for use in the orthopedic implants; however, an in vivo study in an appropriate animal model is essential and has not yet been initiated. The aim of the present study was to gather some preliminary evidence regarding the performance and safety of a cemented PEEK-based knee replacement device in a goat model. Fifteen adult goats were randomly divided into two groups; the control group (n = 5), which received a sham operation, and the experimental group (n = 10), which received a total knee arthroplasty with a PEEK-based knee replacement device. The animals were sacrificed at 12 (control n = 5; experimental n = 5) or 24 weeks (experimental n = 5). Blood parameter measurements and radiographs of the knee joints were obtained. The synovium and main organs were removed and histologically assessed. The knee joints with the prosthesis were analyzed via micro-computed tomography and laser confocal microscopy. There was no occurrence of implant fracture or prosthesis sinking during the 24 weeks of radiological observations, except for one case of prosthesis dislocation at 4 weeks. There was a 6% decrease in femoral bone density (BD) at 12 weeks, but no further decrease by 24 weeks. No changes in BD were observed in the tibial ends. The bulk implant was biocompatible in terms of histological analysis of the local synovium and organs. There were no optical scratches on the surface of the retrieved components; the femoral component surface was rougher, while the tibial insert was smoother after 24 weeks. The novel PEEK-based knee replacement device in a goat model was feasible and safe; however, prior to use in humans, further studies concerning PEEK high load bearing implant designs should be carried out to expand on our results. PMID- 29435994 TI - Evaluation of the Novel Centrifugal Pump, CAPIOX SL, in Chronic Large Animal Experiments. AB - In the development of a new device for extracorporeal circulation, long-term durability and biocompatibility are required. The CAPIOX SL Pump (SL pump, Terumo Corporation, Tokyo, Japan), which is a centrifugal pump using a two-pivot bearing, was developed with the hope of suppressing pump thrombus formation around the bearings. This study aimed to evaluate the in vivo performance of the SL pump in the condition assumed severe clinical situation for long-term extracorporeal membrane oxygenation (ECMO) support. Extracorporeal circulation using the SL pump was installed in three goats, with drainage from the inferior vena cava and infusion into the right jugular artery. The animals were maintained with target pump flow of 2.0-3.0 L/min for 3 or 7 days. Anticoagulation was performed by continuous infusion of heparin with a target activated coagulation time (ACT) of 200 +/- 50 s. Blood tests were performed regularly. After 3 or 7 days, autopsies were performed on all animals. The pumps were disassembled and observed for thrombus formation. The results were compared with those of our previous study of the current model of the centrifugal pump (SP pump). All animals were successfully managed within target pump flows and ACT values during the scheduled period, with no adverse events. No thrombus formation was found around the bearing of the SL pump. The blood tests showed normal major organ functions, and platelet consumption and hemolysis were significantly lower in this study compared to the previous study of the SP pump. The CAPIOX SL Pump showed excellent durability and biocompatibility in a large animal experiment. PMID- 29435993 TI - Different role of TTX-sensitive voltage-gated sodium channel (NaV 1) subtypes in action potential initiation and conduction in vagal airway nociceptors. AB - KEY POINTS: The action potential initiation in the nerve terminals and its subsequent conduction along the axons of afferent nerves are not necessarily dependent on the same voltage-gated sodium channel (NaV 1) subunits. The action potential initiation in jugular C-fibres within airway tissues is not blocked by TTX; nonetheless, conduction of action potentials along the vagal axons of these nerves is often dependent on TTX-sensitive channels. This is not the case for nodose airway Adelta-fibres and C-fibres, where both action potential initiation and conduction is abolished by TTX or selective NaV 1.7 blockers. The difference between the initiation of action potentials within the airways vs. conduction along the axons should be considered when developing NaV 1 blocking drugs for topical application to the respiratory tract. ABSTRACT: The action potential (AP) initiation in the nerve terminals and its subsequent AP conduction along the axons do not necessarily depend on the same subtypes of voltage-gated sodium channels (NaV 1s). We evaluated the role of TTX-sensitive and TTX-resistant NaV 1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT-PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Almost all of the jugular neurons expressed the TTX-sensitive channel NaV 1.7 along with TTX resistant NaV 1.8 and NaV 1.9. Tracheal nodose neurons also expressed NaV 1.7 but, less frequently, NaV 1.8 and NaV 1.9. NaV 1.6 were expressed in ~40% of the jugular and 25% of nodose tracheal neurons. Other NaV 1 alpha subunits were only rarely expressed. Single fibre recordings were made from the vagal nodose and jugular nerve fibres innervating the trachea or lung in the isolated perfused vagally-innervated preparations that allowed for selective drug delivery to the nerve terminal compartment (AP initiation) or to the desheathed vagus nerve (AP conduction). AP initiation in jugular C-fibres was unaffected by TTX, although it was inhibited by NaV 1.8 blocker (PF-01247324) and abolished by combination of TTX and PF-01247324. However, AP conduction in the majority of jugular C-fibres was abolished by TTX. By contrast, both AP initiation and conduction in nodose nociceptors was abolished by TTX or selective NaV 1.7 blockers. Distinction between the effect of a drug with respect to inhibiting AP in the nerve terminals within the airways vs. at conduction sites along the vagus nerve is relevant to therapeutic strategies involving inhaled NaV 1 blocking drugs. PMID- 29435995 TI - Atmosphere in an urban nightlife setting: A case study of the relationship between the socio-physical context and aggressive behavior. AB - Aggression is strongly influenced by the surrounding socio-physical context, and the development of aggressive behavior is best understood through a continuous cycle of ongoing person-environment interactions. Empirical studies, nevertheless, have been predominantly conducted in the laboratory, studying aggression as a short-lived phenomenon, emerging from and within an individual, and - with situational factors studied in isolation - devoid of its context. The present field study, conducted in an urban nightlife area, complements this research. A qualitative, multi-method approach was followed by thematic analysis to investigate ongoing behavioral patterns of the crowd vis-a-vis the changes in the context that co-occurred with the development of unwanted behaviors, including aggression. In our study, we identified atmosphere as a dynamic and mood-like, but extra-individual state of the socio-physical setting related to the development of aggression. Our results suggest that atmosphere affects the behavior of groups and individuals by emerging from and feeding into ongoing interactions between people and the environment. At the individual level, it appears to play its part as proximate determinant of behavior; at the crowd level it reflects the synergetic product of all those persons' states, behaviors and interactions. Implications for aggression theory and for applications aimed at curbing aggression are discussed. PMID- 29435996 TI - Type II Minimal-Invasive Extracorporeal Circuit for Aortic Valve Replacement: A Randomized Controlled Trial. AB - Extracorporeal circulation triggers systemic inflammatory response and coagulation disorders which may lead to unfavorable clinical outcome. A type II minimally-invasive extracorporeal circuit (MiECC) is a closed system with markedly reduced artificial surface as compared to conventional extracorporeal circuits (CECC). The aim of this study was to investigate and compare inflammatory responses, complement activation and selected clinical end-points in isolated surgical aortic valve replacement (SAVR) performed with a type II MiECC circuit or a CECC. Fifty patients were prospectively randomized to MiECC or CECC perfusion regimen. Complement activation (sC5b-9), inflammation (IL-6, TNF-alpha, sCD40-ligand) and activation of the coagulation system (D-dimer, TAT-complex) were determined before operation, at 2 hours and 24 hours after surgery. Clinical end-points included perfusion time, transfusion of allogeneic blood products, postoperative bleeding, sepsis, new onset of atrial fibrillation, stroke and in hospital mortality. Patient characteristics and baseline plasma markers were similar in both groups. Levels for sC5b-9, TNF-alpha, sCD40 ligand, TAT-complex and D-dimers were not significantly different between MiECC and CECC at 2 hours and 24 hours after surgery. The IL-6 plasma concentration was lower in the CECC group at 24 hours (P = 0.026, vs. MiECC). Comparisons of the baseline level to values at 2 hours and 24 hours, adjusted for the type of oxygenator and hemoglobin, showed a significantly lower sC5b-9 in MiECC at 2 hours (P = 0.013), but no difference at 24 hours (P=0.990). Compared with CECC, MiECC patients had a shorter perfusion time (P = 0.037) and less transfusion requirements (P = 0.04). In this selected cohort of SAVR patients, the type II MiECC was not inferior to CECC in terms of inflammatory response and complement activation. Thus, MiECC might be an alternative perfusion strategy to conventional. PMID- 29435997 TI - Coronary venous angioplasty to facilitate transvenous left ventricular lead placement: A single-center 13-year experience. AB - BACKGROUND: Barriers to successful left ventricular lead placement within the coronary venous anatomy may include focal stenoses, thromboses, phrenic nerve stimulation, vessel tortuosity, small vessel caliber, nonexcitable tissue, and valve presence. A large series describing the utilization of coronary venous angioplasty (CVAP) for relief of these issues is absent in the literature. OBJECTIVE: We report our experience on all patients treated with CVAP in a single center 13-year experience. METHODS: Forty-seven patients with CVAP (64% male, mean age 67 +/- 12 years) were treated by five different implanting physicians for approved cardiac resynchronization therapy indications. The reason for CVAP was categorized by obstacle (focal occlusion, valve presence, small caliber vessel) and location. The number, type, and size of balloon used, inflation characteristics, complications, and success of lead deployment crossing the point of intervention were all tabulated. RESULTS: Seventy-seven percent of patients (36/47) had successful CVAP. The most common reason for intervention was a focal occlusion (24/47; 51%), followed by valve presence (13/47; 28%), and small vessel caliber (10/47; 21%). Focal occlusions were most successfully managed with CVAP (23/24; 96%), followed by small vessel caliber (7/10; 70%) and valve presence (6/13; 46%). The reason for failure was most commonly due to failure to relieve the obstruction (5/11; 45%), thrombosis (3/11; 27.3%), dissection (2/11; 18.2%), and inability to pass the balloon through the occlusion (1/11; 9.0%). There were no significant complications developed from CVAP utilization. CONCLUSION: In a large analysis, CVAP can be safely and successfully performed in the majority of instances required. PMID- 29435998 TI - Environmental mixture with estrogenic activity increases Hsd3b1 expression through estrogen receptors in immature rat granulosa cells. AB - Humans are exposed not only to single endocrine disruptors, but also to chemical mixtures that can adversely affect their reproductive health. Steroidogenesis in reproductive tissues is emerging as the key target of endocrine disruptor action. Here, we analyzed the effect of environmental chemical mixtures with estrogenic activity on steroidogenic processes in immature rat granulosa cells and whether the observed steroidogenic effects were mediated through estrogen receptors. Extracts from untreated wastewater were prepared by solid-phase extraction and silica gel fractionation. ER-CALUX assay showed that the polar fractions of wastewater exerted different levels of estrogenic activity. Exposure of immature granulosa cells to the polar fraction exerting 9 ng of 17beta-estradiol equivalents per liter of water of estrogenic activity increased mRNA expression of the key enzymes of progesterone biosynthetic pathway Star and Hsd3b1, but did not alter the level of Cyp19a1 and Lhr. Addition of estrogen receptor inhibitor ICI 182 780 prevented the estrogenic mixture-induced increase in Hsd3b1, but not Star mRNA level in immature granulosa cells. These results indicate that the environmental chemical mixtures with estrogenic activity exert endocrine disrupting effects by augmenting the progesterone biosynthetic pathway in immature rat granulosa cells, which is an effect achieved in part through activation of the estrogen receptors. PMID- 29435999 TI - The effect of greenhouse covering materials on phytochemical composition and antioxidant capacity of tomato cultivars. AB - BACKGROUND: The effect of light transmission (direct and diffuse) on the phenolic compounds of five tomato cultivars was investigated under controlled conditions in greenhouses covered with different covering materials. RESULTS: The type of covering material and type of diffusion of light simultaneously affected the reducing power of cultivars. Two-way analysis of variance showed statistically significant differences in total phenolic content for the different cultivars (P < 0.05) but not for the covering materials. Analysis by ultrahigh-performance liquid chromatography with diode array detection and liquid chromatography/tandem mass spectrometry showed the presence of major phenolic acid compounds such as chlorogenic acid, hydroxycinnamic acid/rutin, caffeic acid, ferulic acid and coumaric acid as well as flavonoid compounds such as myricetin, quercetin and naringenin. Most of the identified compounds showed a significant difference in different treatments due to both cultivar and covering material (P < 0.05). Statistical analysis showed that the type of covering material used influenced the total carotenoid and lycopene content (P < 0.05); however, the amount of lutein was not influenced by the type of covering material (P > 0.05). CONCLUSION: This study showed that the use of solar energy transmission could positively affect the reducing power of cultivars and alter the biosynthesis of certain phytochemicals that are health-beneficial. Further study could lead to applications for producing greenhouse vegetables with greater health attributes. (c) 2018 Society of Chemical Industry. PMID- 29436000 TI - Bascule syndrome associated with syncopal episodes. AB - Bascule syndrome is a recently described benign vasomotor dermatosis characterized by Bier anemic spots, cyanosis, and urticaria-like eruption. We report a case of a 13-year-old girl with cutaneous lesions consistent with Bascule syndrome who had had three exercise-related syncopal episodes. It would be recommended to exclude orthostatic intolerance or postural orthostatic tachycardia syndrome when evaluating patients with Bascule syndrome. PMID- 29436001 TI - Effects of Pulsatile Blood Flow on Oxygenator Performance. AB - Extracorporeal membrane oxygenation (ECMO) is mainly used for the therapy of acute respiratory distress syndrome and chronic obstructive lung disease. In the last years, the development of these systems underwent huge steps in optimization, but there are still problems with thrombus formation, clogging, and thus insufficient gas exchange. One idea of ECMO optimization is a pulsatile blood flow through the oxygenator, but this is still a controversy discussion. Analyzing available publications, it was not possible to identify a general statement about the effect of pulsatile blood flow on the gas exchange performance. The variety of parameters and circuit components have such a high influence on the outcome that a direct comparison of the studies is difficult. For this reason, we performed a structured study to evaluate the effects of pulsatile blood flow on the gas exchange performance of oxygenator. In in vitro tests according to DIN EN ISO 7199, we tested a small oxygenator (0.25 m2 exchange surface, polymethylpentene fibers, 33 mL priming volume) with constant and pulsatile blood flow in comparison. Therefore, we varied the mean blood flow from 250 to 1200 mL/min, the amplitude of 0, 20, and 50%, and the frequency of 30, 60, and 90 bpm. The results demonstrate that the gas transfer for pulsatile and constant blood flow was similar (oxygen: 36-64 mLO2 /LBlood ; carbon dioxide 35-80 mLCO2 /LBlood ) for the same mean blood flow ranges. Over all, the results and analyses showed a statistically nonsignificant difference between pulsatile and nonpulsatile flow. Consequently, we conclude that the implementation of pulsatile blood flow has only a small to no effect on the gas exchange performance in an oxygenator. As the results were obtained using an oxygenator with a coiled fiber bundle, the test must be verified for a stacked fiber oxygenator. PMID- 29436003 TI - Is hospitalisation necessary? A survey of frail older persons with cognitive impairment transferred from nursing homes to the emergency department. AB - BACKGROUND: Providing care for frail older persons is complex and demanding, and the transfer of older persons with cognitive impairment to the emergency department is associated with a high risk of them developing complications. AIM: To survey the most ill and frail older persons with cognitive impairment who were transferred from nursing homes to the emergency department, considering reasons for referral, symptoms and actions taken at the hospital. METHOD: A retrospective descriptive survey, conducting a review of 588 referral notes and medical records, analysed and presented with descriptive statistics and visualised with typical case narratives. FINDINGS: The persons who were transferred to the emergency department were frail with complex symptomology. When reviewing the medical records in the light of criteria for avoidable hospitalisation, 75% of the patients could have been examined and treated at the nursing homes or in primary care. CONCLUSION: Frail older persons with cognitive impairment, who are in need of end-of-life care, should be prevented from unnecessary hospitalisation. The majority of these transfers to the emergency department can be avoided if there is better planning beforehand, more specially trained nurses in elderly care in the municipalities, and more physicians making house calls. PMID- 29436002 TI - Peripheral Artery Disease and Continuous Flow Left Ventricle Assist Device: An Engaging Complement Analysis May Help to Guide Treatment. AB - Use of continuous flow left ventricle assist device (CF-LVAD) in advanced heart failure (HF) patients results in clinically relevant improvements in survival, functional capacity, and quality of life. Peripheral artery disease (PAD) can occur in patients with CF-LVAD due to the high rate of concomitance between risk factors for atherosclerosis and HF. Diagnosis of PAD can be difficult in the specific setting of a patient supported by this kind of device because of the marked alteration in waveform morphology and velocity created by the artificial physiology of an LVAD. We report the case of a 53-year-old man with HF secondary to ischemic cardiomyopathy supported by the HeartWare HVAD as bridge to transplant, who after the implant developed symptoms suggestive of PAD. We describe additional computational flow analysis for the study of PAD-related hemodynamic disturbances induced by a CF-LVAD. Flow simulations enhance the information of clinical image data, and may have an application in clinical investigations of the risk of hemodynamic disturbances induced by LVAD implantation. PMID- 29436004 TI - Homeobox transcriptional factor engrailed homeobox 1 is expressed specifically in normal and neoplastic sweat gland cells. AB - AIMS: A number of homeobox transcriptional factors are utilised as organ-specific markers in the histopathological diagnosis of neoplasms. We have screened a homeobox gene that is expressed specifically in normal sweat gland cells and is useful for the histopathological diagnosis of sweat gland neoplasms. METHODS AND RESULTS: By screening an open database resource of The Human Protein Atlas, 37 genes among the 235 homeobox transcriptional factors were found to be expressed specifically in the skin. Among those 37 genes, the engrailed homeobox 1 (En1) was expressed in normal eccrine glands but not in the epidermal keratinocytes. Expression of En1 was found throughout the eccrine glands, but not in the apocrine secretory coils, sebaceous glands or hair follicles. Expression of En1 was examined immunohistochemically in 111 cases of cutaneous epithelial neoplasms. All nine cases of poroma, seven cases of spiradenoma and six cases of syringoma, which are considered to differentiate towards eccrine glands, showed positive nuclear staining in most of the tumour cells. Sebaceous gland and hair follicle tumours were immunonegative. En1 was expressed focally in the epidermal neoplasms of seborrheic keratosis and squamous cell carcinoma. CONCLUSION: Engrailed homeobox 1 was expressed specifically in normal eccrine glands and was expressed in most of the tumour cells of sweat gland neoplasms with eccrine gland differentiation. En1 was expressed focally in epidermal neoplasms; however, it was absent in sebaceous or hair follicle neoplasms. These findings will help in the histopathological diagnosis as well as understanding of the histogenesis of sweat gland neoplasms. PMID- 29436005 TI - How to achieve a collaborative approach in health promotion: preferences and ideas of users of mental health services. AB - BACKGROUND: Collaborative approaches to consensus building or decision-making are beneficial in health-promoting activities targeting users of mental health services (users). However, little is known about how to achieve a collaborative approach in practice. AIM: The purpose of this study was to explore: (1) users' preferences and ideas related to achieving a collaborative approach in health related communication and (2) perspectives of healthcare and social work professionals and family members on users' ideas and preferences. METHODS: Data were collected through interactive workshops with users (n = 15), professionals (n = 21) and users' family members (n = 12). Data were analysed using systematic text condensation. RESULTS: Users provided three recommendations for establishing a collaborative approach in communication about health: (1) involving users in deciding the agenda and setting for health-promoting activities; (2) exchanging knowledge between users and professionals about health and values; and (3) exploring users' motivation for change. Users and professionals had diverging perceptions of the value of establishing a collaborative approach. Professionals regarded relationship building and health promotion as separate phenomena, whereas users perceived relationship building as inherently health promoting. Family members of users requested specific guidance and support with regard to clarifying and fulfilling the best possible support role as a family member. CONCLUSIONS: The findings suggest that a collaborative approach in health promotion may be difficult to achieve without a focus on professional development for healthcare and social work professionals. PMID- 29436006 TI - Endogenous purines modulate K+ -evoked ACh secretion at the mouse neuromuscular junction. AB - At the mouse neuromuscular junction, adenosine triphosphate (ATP) is co-released with the neurotransmitter acetylcholine (ACh), and once in the synaptic cleft, it is hydrolyzed to adenosine. Both ATP/adenosine diphosphate (ADP) and adenosine modulate ACh secretion by activating presynaptic P2Y13 and A1 , A2A , and A3 receptors, respectively. To elucidate the action of endogenous purines on K+ dependent ACh release, we studied the effect of purinergic receptor antagonists on miniature end-plate potential (MEPP) frequency in phrenic diaphragm preparations. At 10 mM K+ , the P2Y13 antagonist N-[2-(methylthio)ethyl]-2-[3,3,3 trifluoropropyl]thio-5'-adenylic acid, monoanhydride with (dichloromethylene)bis[phosphonic acid], tetrasodium salt (AR-C69931MX) increased asynchronous ACh secretion while the A1 , A3 , and A2A antagonists 8-cyclopentyl 1,3-dipropylxanthine (DPCPX), (3-Ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl 1, 4-(+/-)-dihydropyridine-3,5-, dicarboxylate (MRS-1191), and 2-(2-Furanyl)-7-(2 phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH 58261) did not modify neurosecretion. The inhibition of equilibrative adenosine transporters by S-(p-nitrobenzyl)-6-thioinosine provoked a reduction of 10 mM K+ evoked ACh release, suggesting that the adenosine generated from ATP is being removed from the synaptic space by the transporters. At 15 and 20 mM K+ , endogenous ATP/ADP and adenosine bind to inhibitory P2Y13 and A1 and A3 receptors since AR-C69931MX, DPCPX, and MRS-1191 increased MEPP frequency. Similar results were obtained when the generation of adenosine was prevented by using the ecto-5' nucleotidase inhibitor alpha,beta-methyleneadenosine 5'-diphosphate sodium salt. SCH-58261 only reduced neurosecretion at 20 mM K+ , suggesting that more adenosine is needed to activate excitatory A2A receptors. At high K+ concentration, the equilibrative transporters appear to be saturated allowing the accumulation of adenosine in the synaptic cleft. In conclusion, when motor nerve terminals are depolarized by increasing K+ concentrations, the ATP/ADP and adenosine endogenously generated are able to modulate ACh secretion by sequential activation of different purinergic receptors. PMID- 29436007 TI - Survivors' experiences of consequences and recovery five years after a major bus crash. AB - RATIONALE: There is a lack of long-term follow-up studies focused on injured and uninjured survivors' experiences of the recovery process after major traffic crashes. AIM: To explore all survivors' experiences of long-term physical and psychological consequences and recovery 5 years after a major bus crash. METHODOLOGICAL DESIGN AND JUSTIFICATION: A qualitative design was used to explore experiences in a 5-year follow-up study. RESEARCH METHODS: Participants were 54 survivors of a bus crash with 56 survivors and six fatalities. Telephone interviews were analysed with qualitative content analysis. RESULTS: The first category, 'Being resilient or suffering in daily life', has four subcategories covering quick recovery, suffering in daily life, distress in traffic situations and long-term pain. Reasons for quick recovery among survivors were previous crisis experiences, travelling alone, being uninjured and not being exposed to traumatic impressions. For the other survivors, being reminded of the crash caused disturbing reactions, such as sweating, anxiety and flashbacks. Survivors avoided going by bus if they could. A group of the injured survivors was still suffering from limiting and painful injuries. The second category, 'Reassessing oneself and social connections', has three subcategories covering self-awareness, impact on relationships and connectedness. Survivors either developed a stronger bond to their significant other or separated from their partner within the first couple of years. Friendships and a sense of connectedness among survivors were sources of long-lasting comfort and support. The theme overarching the categories is 'Visible and existential marks in everyday life', representing the various ways in which the crash influence the survivors' lives. CONCLUSION: There is a need for more information about disruptive long-lasting consequences, such as travel anxiety, and available treatments. Initially, health-promoting connectedness can be facilitated by treating survivors as a group of people who belong together, from the day of the crash and throughout the recovery process. PMID- 29436008 TI - Treatment outcomes of vitiligo in Asian children. AB - This retrospective study aimed to identify factors that predict treatment response in a cohort of Asian children with vitiligo. Shorter duration of vitiligo was associated with better repigmentation. Patients with focal vitiligo of short duration have a good chance of achieving repigmentation with topical agents alone. PMID- 29436009 TI - Geographic tonguelike presentation in a child with pityriasis rosea: Case report and review of oral manifestations of pityriasis rosea. AB - Oral lesions are rarely reported in patients with pityriasis rosea. We report a case of a 3-year-old boy with clinical evidence of generalized pityriasis rosea who developed asymptomatic oral lesions similar in appearance to geographic tongue. The generalized eruption and tongue lesions resolved simultaneously within 4 weeks. We also review the literature on the oral manifestations of Pityriasis rosea. PMID- 29436010 TI - Changes in Total Cardiac Output and Oxygen Extraction During Exercise in Patients Supported With an HVAD Left Ventricular Assist Device. AB - Following implantation of a left ventricular assist device (LVAD), acceptable functional performance is now being achieved; however, peak VO2 and peak work load (watts) remain considerably limited. Maximum physical capacity is essentially dependent on generated cardiac output (CO) and arteriovenous oxygen difference (avDO2 ). We investigated the changes in CO and avDO2 during exercise in LVAD patients with an HVAD pump (HeartWare Inc., Framingham, MA, USA). Approximately 6 weeks after implantation, 20 patients (100% male, 60.8 +/- 7.3 years old, BMI 25.7 +/- 3.3) underwent a six-minute walk test (6MWT), a cardiopulmonary exercise test (CPET), and noninvasive hemodynamic measurement. The mean six-minute walking distance (6MWD) was 403 m (68% of predicted), and mean peak VO2 was 10.9 mL/kg/min (39% of predicted). Mean total CO improved from 3.8 L at rest to 7.0 L at maximum exercise. The mean avDO2 increased from 7.4 mL/dL (44% of oxygen content) at rest to 13.2 mL/dL (75% of oxygen content) at maximum exercise. There was a significant increase in both total CO (P < 0.01) and avDO2 (P < 0.05) between rest and sub-maximum exercise. As exercise levels increased, however, no further significant changes were achieved. Long-term studies, especially in combination with exercise programs, would be desirable in order to observe the development of these parameters. PMID- 29436011 TI - Improving disease knowledge in 6- to 10-year-olds with sickle cell disease: A quasi-experimental study. AB - BACKGROUND: Increasing knowledge and understanding of disease is known to improve outcomes in persons living with a chronic illness. In this paper, we aim to compare the disease knowledge of children with sickle cell disease (SCD), age 6 10 years, who received an intervention (an educational colouring book on SCD) geared towards improving disease knowledge, to those who did not received the colouring book. METHODS: A quasi-experimental study was conducted where disease knowledge was determined in 56 children who had received the colouring book and compared to 60 children who did not receive this intervention. RESULTS: The mean knowledge score was significantly higher in the intervention group (mean difference = 2.65; 95% CI [1.43, 3.86]), as well as in older children and in those in higher grades but there was no difference between sexes. In a multiple regression model (adjusted R2 : 0.39; p value < .001), knowledge score was significantly higher in those who received the intervention (beta: 2.62; 95% CI [1.48, 3.76]) while adjusting for age, gender, persons living at home, and the father's employment status. CONCLUSION: The study highlights that a simple, inexpensive (cost: US$1/book) child-friendly intervention can significantly improve knowledge about SCD even in young children. It also underlines various social factors that are associated with children's understanding of their disease. PMID- 29436012 TI - Skin lesions serve as clues to relapse of pediatric blastic plasmacytoid dendritic cell neoplasm. AB - A 10-year-old girl with a history of blastic plasmacytoid dendritic cell neoplasm, a rare malignancy in children, presented with recurrent skin eruptions beginning while on maintenance chemotherapy, including mildly pruritic skin colored plaques, tender indurated nodules, and violaceous bound-down plaques. This case highlights an unusual presentation of relapsed blastic plasmacytoid dendritic cell neoplasm on chemotherapy, with skin lesions providing important clues to the progression of systemic disease. PMID- 29436013 TI - Time-resolved fluorescence spectroscopy for the diagnosis of oral lichen planus. AB - BACKGROUND: Lichen planus (LP) is a T-cell mediated autoimmune disorder of unknown aetiology that affects the skin, nails, oral and genital mucous membranes. Conventionally, oral LP (OLP) is diagnosed through clinical assessment and histopathological confirmation by oral biopsy. AIM: To explore the use of time-resolved fluorescence spectroscopy (TRFS) to detect fluorescence lifetime changes between lesional OLP and perilesional normal mucosa. METHODS: In this pilot study, measurements of lesional and perilesional buccal and mouth floor mucosa were conducted in vivo with a TRFS system. Histopathological findings were consistent with OLP in 8 out of 10 patients biopsied. Two patients with histopathological diagnoses of frictional hyperkeratosis and oral candidiasis, respectively, were excluded from the study. RESULTS: Our preliminary data show that lifetime values in the 360-560 nm spectral range indicate a significant differentiation between normal and diseased tissue. In contrast to the standard oral biopsy procedure, this technique is noninvasive, painless, time-efficient and safe. CONCLUSIONS: Future studies are needed to better elucidate the diagnostic capability of TRFS and to further explore the sources of fluorescence contrast. This pilot study suggests that, based on fluorescence lifetime parameters, TRFS is a very promising technology for the development of a novel OLP diagnostic technique. PMID- 29436014 TI - Comparison of dysplastic fundic gland polyps in patients with and without familial adenomatous polyposis. AB - AIMS: Dysplastic fundic gland polyps (d-FGPs) typically arise in patients with familial adenomatous polyposis (FAP) but may occur in non-syndromic patients. They rarely become malignant, but their significance is unclear, especially in non-syndromic patients. We aimed to compare d-FGPs in patients with and without FAP, using clinicopathologic findings and beta-catenin immunohistochemistry (IHC). METHODS AND RESULTS: We identified 124 fundic gland polyps with low-grade dysplasia (LGD) or high-grade dysplasia (HGD) or indefinite for dysplasia (IFD) from 66 patients (27 with FAP; 39 non-syndromic). We recorded patient sex, age at first d-FGP, time until subsequent d-FGP (if any), history of non-gastric cancer (no patients had gastric cancer), proton-pump inhibitor use, and the presence of Helicobacter pylori. beta-Catenin IHC was performed on cases with available blocks. The mean age at d-FGP diagnosis was 31 years for FAP patients and 61 years for non-syndromic patients (P < 0.0001). Sixteen FAP patients (59%) developed at least one subsequent d-FGP, as compared with 10 (27%) non-syndromic patients (P = 0.0099). The median time between d-FGP detection was 11.5 months in FAP patients and 7 months in non-syndromic patients (P = 0.82). Six FAP patients (22%) and 17 non-syndromic patients (44%) had non-gastric malignancies (P = 0.11). beta-Catenin IHC showed nuclear positivity in 14 of 112 (13%) d-FGPs: 12 of 94 with LGD, two of three with HGD, and none of 15 with IFD polyps. CONCLUSIONS: Familial adenomatous polyposis patients develop d-FGPs earlier and more often develop additional ones than non-syndromic patients. d-FGPs in FAP and non-syndromic patients have similar low rates of beta-catenin nuclear IHC positivity. FAP and non-syndromic patients developed non-gastric cancers at similar rates, suggesting that d-FGPs may portend a general increased risk of carcinogenesis in non-syndromic patients. PMID- 29436016 TI - Identification of caries risk in 2-year-olds. AB - OBJECTIVE: The first aim was to describe presence of plaque, caries and oral health behaviours in 2-year-old children. The second aim was to measure increments in caries experience from 2 to 5 years of age and to study whether national background, visible plaque, caries and oral health behaviour at 2 years of age were associated with increments in caries experience. METHODS: The study population consisted of 392 children, of whom 211 were monitored from 2 to 5 years of age. At age 2 years, parents completed a questionnaire about family background and oral health behaviour. The presence of plaque and caries at tooth level was obtained from dental records. Data were tested with chi-square statistics and Mann-Whitney U test. Negative binomial regression analysis was conducted to explore the association between caries increment between 2 and 5 years of age and national background, visible plaque, caries and oral health behaviour at 2 years of age. RESULTS: Caries was found in 4.6% of 2-year-olds, and 4.6% had visible plaque. More than half of these children (57.9%) brushed twice daily, toothbrushing was introduced when the child was 7 months or older in 61.0% of the children, and 15.6% consumed sugary snacks daily. Non-Western children more often had caries, visible plaque and unfavourable oral health behaviour than Western children (P < .05). At age 5 years, 28.9% of the children had caries experience. Non-Western background, toothbrushing less than twice daily, not using fluoridated toothpaste, not using fluoride lozenges, consuming sugary drinks at night, consuming sugary snacks daily, presence of plaque and caries at 2 years of age were associated with caries increment between 2 and 5 years of age in bivariable analyses. The results from multivariable analysis showed that children who started toothbrushing late, children who brushed less than twice daily at 2 years of age and children of non-Western background had a higher probability of having caries increment from 2 to 5 years of age than other children. CONCLUSIONS: A small proportion of 2-year-olds had caries, but these children had several decayed teeth. Substantial differences in oral health and oral health behaviour were found between Western and non-Western children. The preventive care delivered to the studied children failed to prevent caries increment from 2 to 5 years of age. PMID- 29436015 TI - Medical prescriptions falsified by the patients: a 12-year national monitoring to assess prescription drug diversion. AB - Diversion of prescription drugs is difficult to assess in quality and quantity. This study aimed to characterize diversion of prescription drugs in France through a comparative analysis of falsified prescriptions collected during three periods from 2001 to 2012. The data recorded in a national program which records all falsified prescriptions presented to community pharmacies were studied. Included data regarded: subjects, prescription forms, and drugs. Description of the dataset in three periods (2001-2004, 2005-2008, and 2009-2012) was completed with clustering analyses to characterize profiles of prescriptions and subjects associated with the most reported drugs. The 4469 falsified prescriptions concerned most often females (51.6%). Average age was 46.5 years. Zolpidem, bromazepam, and buprenorphine were the most frequent drugs. Alone, 13 drugs (1.7%, 13/772) represented more than 40% of the total reports (3055/7272). They were associated with three diversion profiles: (i) buprenorphine, flunitrazepam, and morphine were mentioned on overlapping secure prescription forms presented by young men; (ii) alprazolam, bromazepam, zolpidem, codeine/acetaminophen were mentioned on simple prescription forms presented by experienced women; and (iii) acetaminophen and lorazepam were mentioned on modified prescription forms presented by elderly subjects. Clonazepam, clorazepate, dextropropoxyphene, zopiclone moved between those profiles. The patterns of falsified prescriptions provided in this study contribute to enhance the scientific knowledge on the most diverted prescription drugs. The latter follow distinct trajectories across time depending on their pharmacology (including their abuse/addiction potential) and on their regulation's history. The close and continuous analysis of falsified prescriptions is an excellent way to monitor prescription drug diversion. PMID- 29436017 TI - Nanomaterials Safer-by-Design: An Environmental Safety Perspective. AB - Designing safer nanomaterials and nanostructures has gained increasing attention in the field of nanoscience and technology in recent years. Based on the body of experimental evidence contributed by environmental health and safety studies, materials scientists now have a better grasp on the relationships between the nanomaterials' physicochemical characteristics and their hazard/safety profiles. Therefore, it is expected that an integration of design synthesis and safety assessment will foster nanomaterials safer-by-design by considering both applications and implications. From the environmental safety perspective, the most recent advances that demonstrate effective nanomaterials safer-by-design are highlighted. PMID- 29436018 TI - Subacute cutaneous lupus erythematosus presenting in twins. AB - Subacute cutaneous lupus erythematosus is a clinically distinct form of cutaneous lupus erythematosus, with age of onset typically in the second to fifth decades. Eleven cases have been reported in childhood, and we present the first known case of subacute cutaneous lupus erythematosus in identical twins. Although flares are typically photo-induced, we present an annular eruption typical of subacute cutaneous lupus erythematosus with concurrent pinworm infestation, with recurrence of disease with cutaneous larva migrans. The patient's identical twin had a similar eruption with pinworm infection. This case highlights the possibility of parasitic infestation as a trigger for subacute cutaneous lupus erythematosus in genetically susceptible individuals. PMID- 29436020 TI - Young Investigator Award 2017. PMID- 29436019 TI - Melatonin attenuates homocysteine-induced injury in human umbilical vein endothelial cells. AB - Homocysteine (Hcy) is a major risk factor for vascular disease and is closely associated with endothelial dysfunction. Melatonin is a neurohormone that is mostly produced by the pineal gland. Studies have reported that melatonin exhibits neuroprotective effects in several neurodegenerative disorders. The aim of the current study was to investigate the possible protective effect of melatonin against Hcy-induced endothelial cell apoptosis in human umbilical vein endothelial cells (HUVECs) and to explore the underlying mechanisms. HUVECs were exposed to Hcy in the presence or absence of melatonin. The effect of melatonin on viability was examined by MTT assay. Intracellular reactive oxygen species (ROS) levels were determined by 2',7'-dichlorofluorescein diacetate (DCF-DA). Further, expression of Bax, Bcl-2, and caspase-3 was analyzed by Western blot analysis. Lipid peroxidation (LPO) levels, total antioxidant power (TAP), and total thiol molecules were also evaluated. The results of this study revealed that melatonin significantly prevented Hcy-induced loss in cell viability in HUVECs. It was found that ROS significantly increased in the presence of Hcy, whereas melatonin reduced ROS production. Melatonin also downregulated Bax, upregulated Bcl-2, and decreased the expression and activity of caspase-3. Hcy increased the levels of LPO, and this effect was significantly attenuated by melatonin. Melatonin also increased the levels of TAP and total thiol molecules. It was concluded that melatonin played a protective role against Hcy-induced endothelium cell apoptosis through inhibition of ROS accumulation and the mitochondrial-dependent apoptotic pathway. PMID- 29436021 TI - Apnea Test on Extracorporeal Life Support System: Feasible and Needed. PMID- 29436022 TI - In-Line CRRT via Centrifugal Flow RVAD for Management of AKI During Mechanical Circulatory Support of End-Stage Heart Disease. PMID- 29436023 TI - Treatment of an Intercostal Left Ventricular Assist Device Prolapse by Upgrading From HeartMate II to HeartMate 3. PMID- 29436024 TI - Lee West Henderson (1930-2017). PMID- 29436025 TI - Parathyroidectomy Before or After Transplantation: A Dilemma Still Open! PMID- 29436026 TI - Titanium Surface Chemical Composition Interferes in the Pseudomonas aeruginosa Biofilm Formation. AB - Bacterial adhesion on three different surfaces: untreated Ti, plasma nitriding, and plasma carbonitriding Ti substrates were investigated. The samples were placed in bacterial cultures of Pseudomonas aeruginosa to assess biofilm formation. The correlation between the amount of bacteria attached to the surface after a lapse of time with nanotopography and physicochemical properties was performed. TiN showed the highest capacity to avoid bacterial adhesion, while presenting intermediate roughness and wettability. Although the surface of TiCN had the highest surface roughness and low contact angle (high wettability), bacterial adhesion was intermediate on this sample. Untreated Ti, even though presenting a smooth surface and low wettability, had the highest tendency to form biofilms. PMID- 29436027 TI - Reflections on My Lifetime Teacher: Dr. Willem J. Kolff. PMID- 29436028 TI - Biomedical Applications of Recombinant Silk-Based Materials. AB - Silk is mostly known as a luxurious textile, which originates from silkworms first cultivated in China. A deeper look into the variety of silk reveals that it can be used for much more, in nature and by humanity. For medical purposes, natural silks were recognized early as a potential biomaterial for surgical threads or wound dressings; however, as biomedical engineering advances, the demand for high-performance, naturally derived biomaterials becomes more pressing and stringent. A common problem of natural materials is their large batch-to batch variation, the quantity available, their potentially high immunogenicity, and their fast biodegradation. Some of these common problems also apply to silk; therefore, recombinant approaches for producing silk proteins have been developed. There are several research groups which study and utilize various recombinantly produced silk proteins, and many of these have also investigated their products for biomedical applications. This review gives a critical overview over of the results for applications of recombinant silk proteins in biomedical engineering. PMID- 29436029 TI - In Situ Grown Epitaxial Heterojunction Exhibits High-Performance Electrocatalytic Water Splitting. AB - Electrocatalytic performance can be enhanced by engineering a purposely designed nanoheterojunction and fine-tuning the interface electronic structure. Herein a new approach of developing atomic epitaxial in-growth in Co-Ni3 N nanowires array is devised, where a nanoconfinement effect is reinforced at the interface. The Co Ni3 N heterostructure array is formed by thermal annealing NiCo2 O4 precursor nanowires under an optimized condition, during which the nanowire morphology is retained. The epitaxial in-growth structure of Co-Ni3 N at nanometer scale facilitates the electron transfer between the two different domains at the epitaxial interface, leading to a significant enhancement in catalytic activities for both hydrogen and oxygen evolution reactions (10 and 16 times higher in the respective turn-over frequency compared to Ni3 N-alone nanorods). The interface transfer effect is verified by electronic binding energy shift and density functional theory (DFT) calculations. This nanoconfinement effect occurring during in situ atomic epitaxial in-growth of the two compatible materials shows an effective pathway toward high-performance electrocatalysis and energy storages. PMID- 29436031 TI - A Magnetofluorescent Carbon Dot Assembly as an Acidic H2 O2 -Driven Oxygenerator to Regulate Tumor Hypoxia for Simultaneous Bimodal Imaging and Enhanced Photodynamic Therapy. AB - Recent studies indicate that carbon dots (CDs) can efficiently generate singlet oxygen (1 O2 ) for photodynamic therapy (PDT) of cancer. However, the hypoxic tumor microenvironment and rapid consumption of oxygen in the PDT process will severely limit therapeutic effects of CDs due to the oxygen-dependent PDT. Thus, it is becoming particularly important to develop a novel CD as an in situ tumor oxygenerator for overcoming hypoxia and substantially enhancing the PDT efficacy. Herein, for the first time, magnetofluorescent Mn-CDs are successfully prepared using manganese(II) phthalocyanine as a precursor. After cooperative self assembly with DSPE-PEG, the obtained Mn-CD assembly can be applied as a smart contrast agent for both near-infrared fluorescence (FL) (maximum peak at 745 nm) and T1 -weighted magnetic resonance (MR) (relaxivity value of 6.97 mM-1 s-1 ) imaging. More interestingly, the Mn-CD assembly can not only effectively produce 1 O2 (quantum yield of 0.40) but also highly catalyze H2 O2 to generate oxygen. These collective properties of the Mn-CD assembly enable it to be utilized as an acidic H2 O2 -driven oxygenerator to increase the oxygen concentration in hypoxic solid tumors for simultaneous bimodal FL/MR imaging and enhanced PDT. This work explores a new biomedical use of CDs and provides a versatile carbon nanomaterial candidate for multifunctional nanotheranostic applications. PMID- 29436030 TI - Activating transcription factor 6alpha deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases. AB - Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune-mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN gamma, a key pro-inflammatory cytokine in MS and EAE, in the CNS. Several studies also demonstrate that PERK activation preserves oligodendrocyte viability and function, protecting mice against EAE. While evidence suggests activation of the ATF6alpha branch of the UPR in oligodendrocytes under normal and disease conditions, the effects of ATF6alpha activation on oligodendrocytes in immune mediated demyelinating diseases remain unknown. Herein, we showed that ATF6alpha deficiency had no effect on oligodendrocytes under normal conditions. Interestingly, we showed that ATF6alpha deficiency exacerbated ER stressed induced myelinating oligodendrocyte death and subsequent myelin loss in the developing CNS of IFN-gamma-expressing mice. Moreover, we found that ATF6alpha deficiency increased EAE severity and aggravated EAE-induced oligodendrocyte loss and demyelination, without affecting inflammation. Thus, these data suggest the protective effects of ATF6alpha activation on oligodendrocytes in immune-mediated demyelinating diseases. PMID- 29436032 TI - Graphene-Graphene Interactions: Friction, Superlubricity, and Exfoliation. AB - Graphite's lubricating properties due to the "weak" interactions between individual layers have long been known. However, these interactions are not weak enough to allow graphite to readily exfoliate into graphene on a large scale. Separating graphite layers down to a single sheet is an intense area of research as scientists attempt to utilize graphene's superlative properties. The exfoliation and processing of layered materials is governed by the friction between layers. Friction on the macroscale can be intuitively understood, but there is little understanding of the mechanisms involved in nanolayered materials. Using molecular dynamics and a new forcefield, graphene's unusual behavior in a superlubric state is examined, and the energy dissipated between two such surfaces sliding past each other is shown. The dependence of friction on temperature and surface roughness is described, and agreement with experiment is reported. The accuracy of the simulated behavior enables the processes that drive exfoliation of graphite into individual graphene sheets to be described. Taking into account the friction between layers, a peeling mechanism of exfoliation is predicted to be of lower energy cost than shearing. PMID- 29436033 TI - RhII -Catalyzed Intermolecular C-H Arylation of Aromatics with Diazo Quinones. AB - We developed an efficient synthesis of biaryls by a dirhodium(II)-catalyzed aromatic C-H arylation with diazo quinones. The new biaryl synthesis can be performed under mild and neutral conditions and without directing group chelation assistance. The reaction tolerates various functionalities and is applicable to a broad range of aromatics. The regioselectivity of the C-H arylation was often high and predictable. The synthetic utility of the method was demonstrated by the late-stage modifications of a series of pharmaceuticals and functional materials as well as a short synthesis of a transthyretin amyloid inhibitor. PMID- 29436034 TI - Low-Density Self-Assembled Poly(N-Isopropyl Acrylamide) Sponges with Ultrahigh and Extremely Fast Water Uptake and Release. AB - Poly(N-isopropyl acrylamide) (PNIPAM) hydrogels are well known for their temperature-dependent water uptake and release. Hence, they are ideal candidates for water management applications. However, efficiency and rate of water uptake and release, respectively, have to be optimized. Here, highly stable 3D PNIPAM sponges that show a sufficiently low density and high specific pore volume, required for maximizing the amount and rate of water absorption-desorption, are presented. They are prepared by a top-down approach based on freeze-drying a dispersion of short crosslinked PNIPAM fibers coated with crosslinked PNIPAM. The sponges have low densities (4.10-21.04 mg cm-3 ), high porosities >98%, and high specific pore volumes in the range of 47-243 cm3 g-1 depending on the concentration of the dispersions. The sponges absorb high amounts of water (~7000%) at temperatures below the lower critical solution temperature (LCST) of PNIPAM and can release more than 80% of the absorbed water above the LCST in less than 2 min. Moreover, the water-swollen sponges are reversibly foldable, can be confined to different shapes, and have compressive elastic modulus below 10 Pa. Hence, these spongy materials are of interest not only for water management but also for biomedical applications, smart textiles, and catalysis. PMID- 29436036 TI - Dobutamine stress echocardiography, myocardial perfusion scintigraphy, invasive coronary angiography, and post-liver transplantation events: Systematic review and meta-analysis. AB - The impact of coronary artery disease on the clinical course of patients enrolled for liver transplantation (LT) has changed over the years as these patients become older and sicker. The purpose of this systematic review and meta-analysis was to investigate the value of dobutamine stress echocardiography (DSE), myocardial perfusion scintigraphy (MPS), and invasive coronary angiography (ICA) in predicting cardiac events post-LT in cirrhotic patients. A literature search was conducted using Scopus, Web of Science, EMBASE, MEDLINE (via PubMed), BIREME (regional medical library of the Pan American Health Organization), LILACS (Latin American and Caribbean Health Sciences Literature), Cochrane Library for Systematic Reviews, and OpenGrey Repository (www.opengrey.eu) electronic databases. A total of 322 records were retrieved for DSE, 90 for MPS, and 149 for ICA. In the final analysis, 11 records for DSE, 7 for MPS, and 8 for ICA were included. The relative risk and confidence interval for major adverse cardiac events were 30.2 (2.8-325.4) for DSE, 2.6 (1.09-6.1) for MPS, and 2.1 (1.0-2.3) for ICA, while the relative risk and confidence interval for all-cause mortality was 4.7 for DSE (1.8-12.0), 2.7 (1.25-5.9) for MPS, and 1.5 (0.89-3.2) for ICA. In conclusion, this meta-analysis found that DSE, MPS, and ICA do not satisfactorily predict increased risk of perioperative MACE or all-cause mortality among cirrhotic patients listed for LT, among small and heterogenous studies. PMID- 29436035 TI - Palladium-Catalyzed Asymmetric Allylic Alkylation of 4-Substituted Isoxazolidin-5 ones: Straightforward Access to beta2,2 -Amino Acids. AB - We report here an unprecedented and highly enantioselective palladium-catalyzed allylic alkylation applied to 4-substituted isoxazolidin-5-ones. Ultimately, the process provides a straightforward access to beta2,2 -amino acids bearing an all carbon quaternary stereogenic center in great yields and a high degree of enantioselectivity. PMID- 29436037 TI - Parental use of sun protection for their children-does skin color matter? AB - BACKGROUND/OBJECTIVES: Excessive sun exposure during childhood is a risk factor for skin cancer. This study aimed to compare the frequency of ideal sun protection use between parents with lighter- and darker-skinned children and explore their attitudes and beliefs on sun safety and their choice of sun protection. METHODS: Parents of children aged 6 months to 6 years completed self administered questionnaires about sun protection practices for their children. Parents assessed their child's Fitzpatrick phototype and were divided into lighter- (Fitzpatrick phototype I-III) and darker-skinned (Fitzpatrick phototype IV-VI) groups. Sun safety guidelines from the Canadian Dermatology Association were used to qualify ideal sun protection. RESULTS: A total of 183 parents were included. Overall, 31 parents (17%) used ideal sun protection for their children. As their children grew older, parents were less likely to use ideal sun protection (odds ratio = 0.69, 95% confidence interval = 0.53-0.90). Parents in the lighter-skinned group were more likely to use ideal sun protection for their children (odds ratio = 7.4, 95% confidence interval = 2.7-20.1), believe that sun exposure was harmful (odds ratio = 17.2, 95% confidence interval = 4.0-74.9), and perceive value in sun protection (odds ratio = 11.4, 95% confidence interval = 3.3-39.0); the darker-skinned group believed that darker skin tones provided more sun protection (odds ratio = 12.4, 95% confidence interval = 6.1-25.4). CONCLUSION: Ideal parental sun protection efforts are overall low, particularly in parents of darker-skinned children. The identified attitudes toward and beliefs about sun safety may aid in delivery of future sun protection interventions, especially in multiracial populations. PMID- 29436038 TI - Comparison of reproducibility of single voxel spectroscopy and whole-brain magnetic resonance spectroscopy imaging at 3T. AB - To date, single voxel spectroscopy (SVS) is the most commonly used MRS technique. SVS is relatively easy to use and provides automated and immediate access to the resulting spectra. However, it is also limited in spatial coverage. A new and very promising MRS technique allows for whole-brain MR spectroscopic imaging (WB MRSI) with much improved spatial resolution. Establishing the reproducibility of data obtained using SVS and WB-MRSI is an important first step for using these techniques to evaluate longitudinal changes in metabolite concentration. The purpose of this study was to assess and directly compare the reproducibility of metabolite quantification at 3T using SVS and WB-MRSI in 'hand-knob' areas of motor cortices and hippocampi in healthy volunteers. Ten healthy adults were scanned using both SVS and WB-MRSI on three occasions one week apart. N-acetyl aspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) were quantified using SVS and WB-MRSI with reference to both Cr and H2 O. The reproducibility of each technique was evaluated using the coefficient of variation (CV), and the correspondence between the two techniques was assessed using Pearson correlation analysis. The measured mean (range) intra-subject CVs for SVS were 5.90 (2.65-10.66)% for metabolites (i.e. NAA, Cho, mI) relative to Cr, and 8.46 (4.21-21.07)% for metabolites (NAA, Cr, Cho, mI) relative to H2 O. The mean (range) CVs for WB-MRSI were 7.56 (2.78-11.41)% for metabolites relative to Cr, and 7.79 (4.57-14.11)% for metabolites relative to H2 O. Significant positive correlations were observed between metabolites quantified using SVS and WB-MRSI techniques when the Cr but not H2 O reference was used. The results demonstrate that reproducibilities of SVS and WB-MRSI are similar for quantifying the four major metabolites (NAA, Cr, Cho, mI); both SVS and WB-MRSI exhibited good reproducibility. Our findings add reference information for choosing the appropriate 1 H-MRS technique in future studies. PMID- 29436039 TI - Cortical structural involvement and cognitive dysfunction in early Parkinson's disease. AB - Magnetic resonance imaging (MRI) studies in early Parkinson's disease (PD) have shown promise in the detection of disease-related brain changes in the white and deep grey matter. We set out to establish whether intrinsic cortical involvement in early PD can be detected with quantitative MRI. We collected a rich, multi modal dataset, including diffusion MRI, T1 relaxometry and cortical morphometry, in 20 patients with early PD (disease duration, 1.9 +/- 0.97 years, Hoehn & Yahr 1-2) and in 19 matched controls. The cortex was reconstructed using FreeSurfer. Data analysis employed linked independent component analysis (ICA), a novel data driven technique that allows for data fusion and extraction of multi-modal components before further analysis. For comparison, we performed standard uni modal analysis with a general linear model (GLM). Linked ICA detected multi-modal cortical changes in early PD (p = 0.015). These comprised fractional anisotropy reduction in dorsolateral prefrontal, cingulate and premotor cortex and the superior parietal lobule, mean diffusivity increase in the mesolimbic, somatosensory and superior parietal cortex, sparse diffusivity decrease in lateral parietal and right prefrontal cortex, and sparse changes to the cortex area. In PD, the amount of cortical dysintegrity correlated with diminished cognitive performance. Importantly, uni-modal analysis detected no significant group difference on any imaging modality. We detected microstructural cortical pathology in early PD using a data-driven, multi-modal approach. This pathology is correlated with diminished cognitive performance. Our results indicate that early degenerative processes leave an MRI signature in the cortex of patients with early PD. The cortical imaging findings are behaviourally meaningful and provide a link between cognitive status and microstructural cortical pathology in patients with early PD. PMID- 29436040 TI - Emerging themes in cognitive control: Commentary on the special issue of Psychophysiology entitled "Dynamics of Cognitive Control: A View Across Methodologies". PMID- 29436041 TI - Dynamics of cognitive control: A view across methodologies. PMID- 29436042 TI - Fulfilling the promise of choice architecture interventions for addictive behaviors. PMID- 29436043 TI - Fusing Benzo[c][1,2,5]oxadiazole Unit with Thiophene for Constructing Wide bandgap High-performance IDT-based Polymer Solar Cell Donor Material. AB - Benzo[c][1,2,5]oxadiazole (BO) moiety is a strong electron-withdrawing unit compared to benzo[c][1,2,5]thiadiazole (BT). It is usually introduced as an acceptor to construct narrow band-gap donor-acceptor (D-A) materials. Herein, the pi-extended conjugated moiety dithieno[3',2':3,4";2,3":5,6]benzo[1,2 c][1,2,5]oxadiazole (BOT) was adopted as the acceptor moiety to design D-A polymers. Considering the more extended pi-conjugated molecular system of BOT compared to the BO unit, a narrower optical band-gap is expected for BOT-based IDT polymer (PIDT-BOT). Unexpectedly, the UV-vis absorption spectra of PIDT-BOT films display a great hypochromatic shift of about 60 nm compared to a BO-based analog (PIDT-BO). The optical band-gaps of the materials are broadened from 1.63 eV (PIDT-BO) to 2.00 eV (PIDT-BOT) accordingly. Although the range of external quantum efficiency (EQE) of PIDT-BOT-based polymer solar cell (PSC) devices is not as wide as for PIDT-BO-based devices, the EQE response intensities of the PIDT-BOT based device are evidently high. As a result, PSC devices based on PIDT BOT reveal the best power conversion efficiency at 6.08%. PMID- 29436044 TI - An Efficient Amphiphilic-Type Triphenylamine-Based Organic Hole Transport Material for High-Performance and Ambient-Stable Dopant-Free Perovskite and Organic Solar Cells. AB - A new set of simply structured triphenylamine-based small molecules are synthesized and evaluated as dopant-free hole transporting materials (HTMs) for high-performance perovskite solar cells (PSCs) and bulk heterojunction inverted organic solar cells (BHJ IOSCs). Surprisingly, the new amphiphilic-type HTM-1 (with internal hydrophilic groups and peripheral hydrophobic alkyl tails) showed better compatibility and performance than the actual target molecule, that is, HTM-2 in PSCs and BHJ IOSCs. Importantly, the HTM-1-based dopant-free PSCs and BHJ IOSCs exhibited high power conversion efficiencies (PCEs) of 11.45 % and 8.34 %, respectively. These performances are superior and comparable to those of standard HTMs Spiro-OMeTAD (2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9' spirobifluorene) and PEDOT:PSS (poly(3,4-ethylenedioxythiophene)/polystyrene sulfonate) in PSCs and BHJ IOSCs, respectively. The enhanced device performance of the HTM-1-based PSCs is ascribed to its strong affinity towards the perovskite, properly aligned energy levels with respect to the perovskite valence band, and excellent hole transporting behavior. In addition, the well-organized energy levels of the HTMs showed excellent compatibility in BHJ IOSCs. The new amphiphilic-type HTM-based photovoltaic devices also showed long-term air stability over 700 h. These promising results offer new and unexpected prospects for engineering the interface between the photoactive material and HTMs in PSCs and BHJ IOSCs. PMID- 29436045 TI - Spontaneous resolution of labial adhesions in pre-pubertal girls. AB - AIMS: This study sought to observe the rate and timing of spontaneous resolution of labial adhesions that had been diagnosed in pre-pubertal girls. The secondary aim was to evaluate the conservative approach to management of labial adhesions that has been advocated by the Gynaecology Department, by assessing the rates of concurrent uro-gynaecological symptoms in this population, as well as parent satisfaction with their child's management. METHODS: A retrospective chart review was performed of all patients diagnosed with labial adhesions in the Department of Paediatric and Adolescent Gynaecology between 2000 and 2017. Patients and their parents (depending on the age of the patient at the time of this study) were then invited to participate in follow-up surveys and questionnaires and clinical examination. RESULTS: Of 148 girls identified, the median age of the follow-up participants (n = 45) was 6.1 years (2.6-27.2 years), compared with that of the entire cohort of 7.4 years (1-27 years). After a median follow-up period of 2.6 years (0.4-20.7 years), 40% (18/45) of girls reported and/or had findings that supported resolution of labial adhesions without treatment. Two parents (4%) sought treatment elsewhere after their appointment. A history of UTI was reported in 30% (14/45) of patients, and 16% (7/45) had a known history of vulvovaginitis. CONCLUSIONS: Our findings support the natural history of spontaneous resolution of labial adhesions. Concurrent uro-gynaecological conditions that developed were successfully treated according to standard treatments. A conservative approach to the management of labial adhesions is associated with very low rates of parental concern and intervention. PMID- 29436046 TI - Improving Photovoltaic Performance of a Fused-Ring Azepinedione Copolymer via a D A-A Design. AB - Two conjugated copolymer donors, PTTABDT and PBTTABDT, based on a fused-ring azepinedione acceptor unit, 5-(2-octyldodecyl)-4H-thieno[2',3':4,5]thieno[3,2 c]thieno[2',3':4,5]thieno[2,3-e]azepine-4,6(5H)-dione (TTA), are prepared. PTTABDT possesses a conventional donor-acceptor (D-A) structure with one TTA in the repeat unit, while PBTTABDT has a D-A-A structure with two TTAs in the repeat unit. Compared with PTTABDT, PBTTABDT shows a deeper highest occupied molecular orbital (HOMO) level, a narrower bandgap, and a higher hole mobility, and exhibits better performance in bulk heterojunction solar cells. Power conversion efficiencies of 6.18% and 7.81% are achieved from PTTABDT:PC71 BM and PBTTABDT:PC71 BM solar cells, respectively. The higher performance of PBTTABDT:PC71 BM solar cells results from the enhanced open-circuit voltage (V oc ) and short-circuit current density ( J sc ). PMID- 29436047 TI - Congenital Langerhans cell histiocytosis presenting in a 27-week-gestation neonate. AB - Langerhans cell histiocytosis is exceedingly rare in premature infants, and the few cases reported suggest a poor prognosis with systemic involvement. We present a case of Langerhans cell histiocytosis limited to a single cutaneous lesion, presenting in a 27-week-gestation infant, which is the youngest gestational age of reported Langerhans cell histiocytosis cases. The lesion showed spontaneous resolution by 41 weeks corrected gestational age, and systemic involvement was absent, demonstrating a mild course of skin-only Langerhans cell histiocytosis in a premature infant. PMID- 29436048 TI - Home birth integration into the health care systems of eleven international jurisdictions. AB - BACKGROUND: The purpose of this study was to develop assessment criteria that could be used to examine the level of integration of home birth within larger health care systems in developed countries across 11 international jurisdictions. METHODS: An expert panel developed criteria and a definition to assess home birth integration within health care systems. We selected jurisdictions based on the publications that were eligible for inclusion in our systematic review and meta analysis on planned place of birth. We sent the authors of the included publications a questionnaire about home birth practitioners and practices in their respective health care system at the time of their studies. We searched published peer-reviewed, non-peer-reviewed, and gray literature, and the websites of professional bodies to document information about home birth integration in each jurisdiction based on our criteria. Where information was lacking, we contacted experts in the field from the relevant jurisdiction. RESULTS: Home birth is well integrated into the health care system in British Columbia (Canada), England, Iceland, the Netherlands, New Zealand, Ontario (Canada), and Washington State (USA). Home birth is less well integrated into the health care system in Australia, Japan, Norway, and Sweden. CONCLUSIONS: This paper is the first to propose criteria for the evaluation of home birth integration within larger maternity care systems. Application of these criteria across 11 international jurisdictions indicates differences in the recognition and training of home birth practitioners, in access to hospital facilities, and in the supplies and equipment available at home births, which give rise to variation in the level of integration across different settings. Standardized criteria for the evaluation of systems integration are essential for interpreting planned home birth outcomes that emerge from contextual differences. PMID- 29436049 TI - Care associated with stillbirth for the most disadvantaged women: A multi-method study of care in England. AB - BACKGROUND: Most research on women experiencing stillbirth relies on online user group surveys or qualitative interviews. The objective of this study was to investigate the experience of women who are at a higher risk of stillbirth, living in areas of greatest deprivation, and are commonly not well represented. METHODS: This study used birth and death registrations in 2012-2013 to identify a sample of mothers whose babies had died as a result of stillbirth. These women were sent a survey 6-9 months after the stillbirth. We undertook descriptive analysis of quantitative data and used binary logistic regression with the Index of Multiple Deprivation as a measure of disadvantage. We used thematic analysis to describe free text responses. RESULTS: The survey response rate was 30% (N = 473). Ethnic minority, younger age, and single parenthood were associated with disadvantage. Women residents in the most deprived areas perceived care more negatively: during labor they were significantly less likely to be spoken to by medical staff so they could understand (73% compared with 90%, adjusted odds ratio [aOR] 0.33 [95% confidence interval {CI} 0.18-0.65]), or treated with respect by midwives (79% compared with 90%, aOR 0.41 [95% CI 0.22-0.77]). The qualitative themes identified were: "Difficulty in accessing care," "More could have been done," "Ineffective communication," and "Cared for and not cared for" which support the quantitative findings. CONCLUSION: Women living in the most deprived areas reported poorer experiences of care compared with more advantaged women. All women need compassionate and sensitive care around the time of a stillbirth. PMID- 29436050 TI - OsNAC2 positively affects salt-induced cell death and binds to the OsAP37 and OsCOX11 promoters. AB - Plant development and adaptation to environmental stresses are intimately associated with programmed cell death (PCD). Although some of the mechanisms regulating PCD [e.g., accumulation of reactive oxygen species (ROS)] are common among responses to different abiotic stresses, the pathways mediating salt induced PCD remain largely uncharacterized. Here we report that overexpression of OsNAC2, which encodes a plant-specific transcription factor, promotes salt induced cell death accompanied by the loss of plasma membrane integrity, nuclear DNA fragmentation, and changes to caspase-like activity. In OsNAC2-knockdown lines, cell death was markedly decreased in response to severe salt stress. Additionally, OsNAC2 expression was enhanced in rice seedlings exposed to a high NaCl concentration. Moreover, the results of quantitative real-time PCR, chromatin immunoprecipitation, dual-luciferase, and yeast one-hybrid assays indicated that OsNAC2 targeted genes that encoded an ROS scavenger (OsCOX11) and a caspase-like protease (OsAP37). Furthermore, K+ -efflux channels (OsGORK and OsSKOR) were clearly activated by OsNAC2. Overall, our results suggested that OsNAC2 accelerates NaCl-induced PCD and provide new insights into the mechanisms that affect ROS accumulation, plant caspase-like activity, and K+ efflux. PMID- 29436051 TI - Alum-adjuvanted allergoids induce functional IgE-blocking antibodies. PMID- 29436052 TI - A RAndomized Trial to compare the acute reconnection after pulmonary vein ISolation with Laser-BalloON versus radiofrequency Ablation: RATISBONA trial. AB - INTRODUCTION: Dormant conduction and acute reconnection in the pulmonary veins (PV) during a PV isolation can be detected by performing an adenosine provocation test (APT). Visually guided laser balloon ablation (VGLB) creates deep transmural lesions, thus causing less acute reconnection. This study compared the acute PV reconnection rate after isolation with VGLB or with RF using an APT. METHODS AND RESULTS: Patients with paroxysmal AF were randomized to PVI with the VGLB or RF ablation. Each PV underwent an APT at least 20 minutes after successful isolation with injection of 18 mg adenosine. Primary endpoint was the difference between the two ablation methods regarding acute PV reconnection rate detected with APT. A total of 50 patients were randomized into the study (25 VGLB). The basic characteristics and mean procedure time were not different between the two groups. Note that 96% of the 97 targeted PVs in the VGLB group and 98% of the 96 targeted PVs in the RF group could be isolated (P = 0.41). APT was performed at similar times (after 28 minutes in VGLB-arm vs. after 31.5 minutes in RF-arm; P = 0.12). Significantly less PVs were reconnected during APT in the VGLB group than in the RF group (10 PV [10.8%] vs. 29 PV [30.9%]; P = 0.001). CONCLUSION: The acute PV reconnection rate is significantly less after PVI with VGBL than with RF. The clinical significance of this apparently better procedural efficiency of the VGBL ablation should be assessed with new randomized studies looking at AF recurrence. PMID- 29436053 TI - Human immunodeficiency virus status disclosure and education for children and adolescents in Papua New Guinea. AB - AIM: How to provide human immunodeficiency virus (HIV) disclosure and awareness for children and young people has not been studied in Papua New Guinea or Pacific Island countries. We aimed to determine the current practices of HIV disclosure and evaluate whether an incremental disclosure education model, as recommended by World Health Organization (WHO), would increase children's knowledge about their condition and improve adherence to antiretroviral therapy (ART). METHODS: We enrolled HIV-infected children on ART whose parents consented, and we identified whether they were aware that they were HIV positive or not. An incremental education model was used to teach the children about their illness and to disclose their HIV status if that was the parents' wishes. Knowledge of HIV and adherence to ART before and following education sessions was assessed. RESULTS: A total of 138 children HIV-positive children were recruited. Only 7% had previously been made aware of their HIV test results; the mean disclosure age was 12.7 years. By 10 years of age, 25 of 34 participants (74%) had not been told they had HIV. The common reasons caregivers gave for not disclosing were that the child was too young and the potential psychosocial impacts on the child and the family. Using an education model of HIV disclosure, children's knowledge of HIV increased significantly, and ART adherence, which was good at 95%, increased to 99% an average of 9 months after education. CONCLUSION: There is a low rate of disclosure for HIV-infected children in Papua New Guinea. This study underlines the importance and value of incorporating age-appropriate HIV education within HIV services. PMID- 29436054 TI - Sensorimotor network alterations in children and youth with prenatal alcohol exposure. AB - Children with prenatal alcohol exposure (PAE) often have impaired sensorimotor function. While altered brain structure has been noted in sensorimotor areas, the functional brain alterations remain unclear. This study aims to investigate sensorimotor brain networks in children and youth with PAE using resting-state functional magnetic resonance imaging (rs-fMRI). A parcellation-based network analysis was performed to identify brain networks related to hand/lower limb and face/upper limb function in 59 children and youth with PAE and 50 typically developing controls. Participants with PAE and controls had similar organization of the hand and face areas within the primary sensorimotor cortex, but participants with PAE had altered functional connectivity (FC) between the sensorimotor regions and the rest of the brain. The sensorimotor regions in the PAE group showed less connectivity to certain hubs of the default mode network and more connectivity to areas of the salience network. Overall, our results show that despite similar patterns of organization in the sensorimotor network, subjects with PAE have increased FC between this network and other brain areas, perhaps suggesting overcompensation. These alterations in the sensorimotor network lay the foundation for future studies to evaluate interventions and treatments to improve motor function in children with PAE. PMID- 29436055 TI - Deep recurrent neural network reveals a hierarchy of process memory during dynamic natural vision. AB - The human visual cortex extracts both spatial and temporal visual features to support perception and guide behavior. Deep convolutional neural networks (CNNs) provide a computational framework to model cortical representation and organization for spatial visual processing, but unable to explain how the brain processes temporal information. To overcome this limitation, we extended a CNN by adding recurrent connections to different layers of the CNN to allow spatial representations to be remembered and accumulated over time. The extended model, or the recurrent neural network (RNN), embodied a hierarchical and distributed model of process memory as an integral part of visual processing. Unlike the CNN, the RNN learned spatiotemporal features from videos to enable action recognition. The RNN better predicted cortical responses to natural movie stimuli than the CNN, at all visual areas, especially those along the dorsal stream. As a fully observable model of visual processing, the RNN also revealed a cortical hierarchy of temporal receptive window, dynamics of process memory, and spatiotemporal representations. These results support the hypothesis of process memory, and demonstrate the potential of using the RNN for in-depth computational understanding of dynamic natural vision. PMID- 29436056 TI - Assessing neuropathic pain in patients with low back-related leg pain: Comparing the painDETECT Questionnaire with the 2016 NeuPSIG grading system. AB - BACKGROUND: Low back-related leg pain with nerve root involvement is conceptually regarded as a neuropathic condition. However, it is uncertain to what extent patients with this condition can be formally classified with neuropathic pain. METHOD: First, we used the 2016 revision of the IASP Special Interest Group on Neuropathic Pain (NeuPSIG) grading system for neuropathic pain to grade patients suffering from low back-related leg pain and a corresponding disc herniation with either unlikely, possible, probable or definite neuropathic pain. Examination included bedside quantitative sensory testing. Next, we used the clinical classification based on the 2016 NeuPSIG grading system as a reference standard to assess the ability of the painDETECT Questionnaire to identify patients with neuropathic pain. RESULTS: Of the 50 included patients, six (12%) fulfilled the clinical classification criteria for probable and 44 (88%) for definite neuropathic pain, while none were graded unlikely or possible. According to painDETECT, 23 patients (46%) were classified with unlikely neuropathic pain, 18 patients (36%) had an uncertain condition and in nine patients (18%) neuropathic pain was likely. Among the 44 patients graded as having definite neuropathic pain by the clinical classification, eight were classified as likely neuropathic pain by painDETECT, resulting in an agreement of 18%. Of these 44 patients graded with definite neuropathic pain, painDETECT classified 21 patients (48%) as unlikely and 15 (34%) as uncertain. CONCLUSION: Our results do not support the use of painDETECT as a screening tool to classify or grade neuropathic components in patients with low back-related leg pain. SIGNIFICANCE: The painDETECT Questionnaire performed poorly at detecting neuropathic pain among patients with low back-related leg pain, compared to clinical examination based on the 2016 NeuPSIG grading system as a reference standard. Our results do not support the use of painDETECT as a screening tool to classify or grade neuropathic components in this population. PMID- 29436057 TI - Cleaning capacity of octenidine as root canal irrigant: A scanning electron microscopy study. AB - The aim of this study was to assess the cleaning capacity of the octenidine hydrochloride (OCT) used as root canal irrigant by scanning electron microscopy (SEM) analysis. Sixty human unirradicular extracted teeth were randomly distributed in 6 groups (n = 10) according to irrigant solutions which were used during root canal preparation: G1, 0.1% OCT; G2, 2% chlorhexidine (CHX); G3, 2.5% sodium hypochlorite (NaOCl); G4, OCT + 17% ethylenediaminetetraacetic acid (EDTA); G5, 2.5% NaOCl + 17% EDTA and G6, distilled water. All specimens were instrumented with ProTaper system up to F4. Teeth were sectioned and prepared for SEM. The smear layer was evaluated using a 5-score system and the data were analyzed by Kruskal-Wallis and Dunn (alpha = 0.05). In all root canal thirds there was no significant difference between OCT, CHX, NaOCl, and water groups (p > .05), and these groups showed higher smear layer values than NaOCl + EDTA and OCT + EDTA groups (p < .05). There was no significant difference between NaOCl + EDTA and OCT + EDTA groups (p > .05). It was concluded that OCT used as a single root canal irrigant presented poor cleaning capacity and could be used in association with a final irrigation with EDTA to obtain smear layer removal. PMID- 29436058 TI - Effects of a Standard American Diet and an anti-inflammatory diet in male and female mice. AB - BACKGROUND: Obesity and chronic pain are prevalent concerns. Pain is frequently experienced in weight-bearing joints, but is common in other areas of the body as well, suggesting other factors. Poor diet often contributes to obesity and can directly influence the immune system. We have shown that poor diet prolongs recovery from inflammatory injury. Therefore, our goal was to determine whether poor-quality diet-induced consequences could be prevented or reversed by an anti inflammatory diet (AID). METHODS: A Standard American Diet (SAD) was developed to investigate the effects of poor diet on pain. The SAD includes amounts of refined sugar, carbohydrates and fats that better model the typical American diet, as compared to high-fat diets. We developed an AID to explore whether the effects of the SAD could reverse or whether the AID would enhance recovery prophylactically. The AID was developed using ingredients (epigallocatechin gallate, sulforaphane, resveratrol, curcumin and ginseng) with known anti-inflammatory properties. Following 15 weeks of diet [SAD, AID or regular (REG)] exposure, male and female mice underwent inflammatory injury, at which point some animals had their diets switched for the remainder of the study. RESULTS: Animals who consumed the SAD showed longer recovery compared to the AID- and REG-fed animals. Animals switched off the SAD had faster recovery times, with AID-fed animals recovering as fast as REG-fed animals. CONCLUSIONS: Poor diet prolonged recovery from inflammatory injury. Substitution of SAD with AID or REG promoted faster recovery. These findings suggest diet can be used as a non-pharmacological intervention following injury. SIGNIFICANCE: Obesity may increase susceptibility to chronic pain often due to poor diet. Diet has potential to be used as treatment for pain. This study investigates the use of a novel translatable diet to act as a preventative (i.e. prior to surgery) or an intervention (i.e. following an injury). PMID- 29436059 TI - Outcomes of Penetrating Keratoplasty Following Autologous Cultivated Limbal Epithelial Stem Cell Transplantation. AB - The purpose of this study is to investigate the outcomes of penetrating keratoplasty (PKP) following autologous cultivated limbal epithelial stem cell transplantation (CLET). A prospective, single center, interventional cohort study investigating patients with unilateral total limbal stem cell deficiency (LSCD) treated with CLET who underwent PKP. Patients with confirmed corneal re epithelialization > 6 months post-CLET, and with best-corrected visual acuity (BCVA) <0.3 logMAR were offered PKP. CLET survival assessed by slit lamp, corneal impression cytology (CIC), and in vivo confocal microscopy. Confirmation of corneal re-epithelialization by histological and immunocytochemical (ICC) examination of trephined corneal buttons. Mean change in best-corrected visual acuity (logMAR) following PKP and PKP survival at 12 months were calculated. Twenty patients underwent PKP. Mean time of PKP was 19 months (range 11-41 months, SD 7.26) post-CLET. Median follow-up time post-PKP was 15 months (range 1 32, SD 10.2). CIC and ICC of all corneas confirmed corneal re-epithelialization before PKP. Mean pre-PKP BCVA was 1.46 (range 0.3-2.7, SD 0.94) improving to a mean post-PKP BCVA of 0.74 (range 0-2.7, SD 0.87); mean improvement in BCVA post PKP of 36 letters (95% CI 15.0-57.1, p = .002). Kaplan-Meier mean graft survival was 90.9% (95% CI 50.8-98.7) at 12 months. We recommend a two-stage approach with CLET followed by PKP >12 months later. Patients experienced a significant improvement in BCVA following PKP. PKP did not have a detrimental effect on CLET survival. PKP survival post-CLET is better than that reported for high risk PKP. Stem Cells 2018;36:925-931. PMID- 29436060 TI - Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy. PMID- 29436061 TI - Anterior insular volume decrease is associated with dysfunction of the reward system in patients with chronic pain. AB - BACKGROUND: Chronification of pain is associated with both anatomical and functional alterations of the brain. Alteration in regional grey matter volume might potentially be associated with modified activity of specific brain networks. In this cross-sectional, observational study, we sought to identify brain regions with grey matter volume changes in patients with chronic pain and to reveal its significance by analysing alteration in functional connectivity from those regions. We further explored relevance of such alterations with psychometrics of chronic pain. METHODS: We recruited 23 patients with chronic pain and 17 age-, gender-matched healthy control subjects. After completing multiple psychophysical questionnaires, each subject underwent resting-state functional magnetic resonance imaging and three-dimensional anatomical imaging on a 3 Tesla magnetic resonance imaging scanner. RESULTS: Patients with chronic pain showed significant volume decrease at the right anterior insular cortex (p < 0.001) and the left middle cingulate cortex (p < 0.001) compared with healthy controls. They also showed decreased connectivity between the right anterior insular cortex and the left nucleus accumbens in negative association with the Pain Catastrophizing Scale (R2 = 0.20, p = 0.046) and the Beck's Depression Inventory scores (R2 = 0.24, p = 0.017). CONCLUSIONS: Decreased grey matter volumes of those core regions for affective processing of pain might be a common cerebral feature shared by, at least some of, different aetiologies of chronic pain. Dysfunctional network between the anterior insular cortex and the nucleus accumbens might reflect affective and motivational disability involved in chronic pain. Such anatomical and functional profiles could potentially be part of a cerebral signature for chronification of pain. SIGNIFICANCE: This article illustrates decreased network activity of the reward system in association with insular cortical volume decrease in patients with chronic pain, and its close relationships with affective and cognitive morbidity of pain. Attenuation of brain's reward system involving cortical plastic changes might have a key role in chronification of pain. PMID- 29436062 TI - Simultaneous independent double tachycardias: What is the mechanism? PMID- 29436064 TI - Randomized double-blind controlled study of bedtime low-dose amitriptyline in chronic neck pain. AB - BACKGROUND: Amitriptyline has well-established efficacy in several chronic pain conditions. While optimal treatment for chronic neck pain (CNP) remains controversial, amitriptyline was not tested for CNP. We evaluated the effect of bedtime amitriptyline in the management of CNP. METHODS: A total of 220 patients suffering from idiopathic CNP were randomized to receive either placebo pill (n = 108) or 5 mg of amitriptyline (n = 112) at bedtime for 2 months. Primary outcome measure was visual analog scale (VAS) for pain. Secondary outcome measures were neck pain disability index (NPDI), Bergen Insomnia Score (BIS) and Hospital Anxiety and Depression Scale (HAD), measured before and at the end of 2 months of treatment, with the percentage of patient satisfaction measured at the end of follow-up only. RESULTS: Eight of 112 patients (7.14%) in the amitriptyline group withdrew from the study because of intolerance. Amitriptyline group showed significantly lower VAS scores than placebo group (3.34 +/- 1.45 vs. 6.12 +/- 0.92; p < 0.0001), which corresponds to a 53.06 +/- 20.29% of improvement from baseline pain as compared to 14.41 +/- 11.05%, respectively (p < 0.0001). Similar significant improvements were observed with lesser extents for secondary outcome measures: NPDI, BIS, HAD-A, HAD-D and percentage of patient satisfaction. CONCLUSION: Low-dose amitriptyline is effective for the management of idiopathic CNP with few side effects and high patients' satisfaction. SIGNIFICANCE: This randomized controlled trial is the first to show the effectiveness and tolerance of a medication, low-dose amitriptyline, in managing idiopathic chronic neck pain and its related comorbidities. The optimal treatment of this condition was still controversial in the literature. It extends the indication of low-dose amitriptyline to another chronic pain condition. PMID- 29436063 TI - Sequence variants in GDF5 and TRPS1 underlie brachydactyly and tricho-rhino phalangeal syndrome type III. PMID- 29436066 TI - Corrigendum. PMID- 29436065 TI - Breaking the Current-Retention Dilemma in Cation-Based Resistive Switching Devices Utilizing Graphene with Controlled Defects. AB - Cation-based resistive switching (RS) devices, dominated by conductive filaments (CF) formation/dissolution, are widely considered for the ultrahigh density nonvolatile memory application. However, the current-retention dilemma that the CF stability deteriorates greatly with decreasing compliance current makes it hard to decrease operating current for memory application and increase driving current for selector application. By centralizing/decentralizing the CF distribution, this current-retention dilemma of cation-based RS devices is broken for the first time. Utilizing the graphene impermeability, the cation injecting path to the RS layer can be well modulated by structure-defective graphene, leading to control of the CF quantity and size. By graphene defect engineering, a low operating current (~1 uA) memory and a high driving current (~1 mA) selector are successfully realized in the same material system. Based on systematically materials analysis, the diameter of CF, modulated by graphene defect size, is the major factor for CF stability. Breakthrough in addressing the current-retention dilemma will instruct the future implementation of high-density 3D integration of RS memory immune to crosstalk issues. PMID- 29436067 TI - Identification and functional analyses of differentially expressed metabolites in early stage endometrial carcinoma. AB - Diagnosis of endometrial cancer is primarily based on symptoms and imaging, with early-stage disease being difficult to diagnose. Therefore, development of potential diagnostic biomarkers is required. Metabolomics, a quantitative measurement of the dynamic metabolism in living systems, can be applied to determine metabolite profiles in different disease states. Here, serum metabolomics was performed in 46 early stage endometrial cancer patients and 46 healthy volunteers. In addition, the effect of identified metabolites on tumor cell behavior (invasion, migration, proliferation, apoptosis and autophagy) was examined in endometrial cancer cell lines. Compared with controls, phenylalanine, indoleacrylic acid (IAA), phosphocholine and lyso-platelet-activating factor-16 (lyso-PAF) were differentially detected in patients. Functional analyses demonstrated that IAA, PAF and phenylalanine all dose-dependently inhibited tumor cell invasion and migration, and suppressed cell proliferation. PAF also induced tumor cell apoptosis and autophagy, while phenylalanine had no effect on apoptosis or autophagy. IAA triggered apoptosis and had a biphasic effect on autophagy: inhibiting autophagy with doses <1 mmol/L but inducing at 1 mmol/L. Interestingly, the alterations in proliferation, apoptosis and autophagy caused by 1 mmol/L IAA, were all reversed by the concomitant treatment of tryptophan (100 MUmol/L). Phosphocholine inhibited tumor cell invasion and migration, and promoted cell proliferation and autophagy, all in a dose-dependent manner. Phosphocholine also protected cells from TNF-alpha-induced apoptosis. In conclusion, 4 serum metabolites were identified by serum metabolomics in endometrial cancer patients and functional analyses suggested that they may play roles in modulation of tumor cell behavior, although their exact mode of action still needs to be determined. PMID- 29436069 TI - Tunable Tribotronic Dual-Gate Logic Devices Based on 2D MoS2 and Black Phosphorus. AB - With the Moore's law hitting the bottleneck of scaling-down in size (below 10 nm), personalized and multifunctional electronics with an integration of 2D materials and self-powering technology emerge as a new direction of scientific research. Here, a tunable tribotronic dual-gate logic device based on a MoS2 field-effect transistor (FET), a black phosphorus FET and a sliding mode triboelectric nanogenerator (TENG) is reported. The triboelectric potential produced from the TENG can efficiently drive the transistors and logic devices without applying gate voltages. High performance tribotronic transistors are achieved with on/off ratio exceeding 106 and cutoff current below 1 pA MUm-1 . Tunable electrical behaviors of the logic device are also realized, including tunable gains (improved to ~13.8) and power consumptions (~1 nW). This work offers an active, low-power-consuming, and universal approach to modulate semiconductor devices and logic circuits based on 2D materials with TENG, which can be used in microelectromechanical systems, human-machine interfacing, data processing and transmission. PMID- 29436068 TI - Transient SHG Imaging on Ultrafast Carrier Dynamics of MoS2 Nanosheets. AB - Understanding the collaborative behaviors of the excitons and phonons that result from light-matter interactions is important for interpreting and optimizing the underlying fundamental physics at work in devices made from atomically thin materials. In this study, the generation of exciton-coupled phonon vibration from molybdenum disulfide (MoS2 ) nanosheets in a pre-excitonic resonance condition is reported. A strong rise-to-decay profile for the transient second-harmonic generation (TSHG) of the probe pulse is achieved by applying substantial (20%) beam polarization normal to the nanosheet plane, and tuning the wavelength of the pump beam to the absorption of the A-exciton. The time-dependent TSHG signals clearly exhibit acoustic phonon generation at vibration modes below 10 cm-1 (close to the Gamma point) after the photoinduced energy is transferred from exciton to phonon in a nonradiative fashion. Interestingly, by observing the TSHG signal oscillation period from MoS2 samples of varying thicknesses, the speed of the supersonic waves generated in the out-of-plane direction (Mach 8.6) is generated. Additionally, TSHG microscopy reveals critical information about the phase and amplitude of the acoustic phonons from different edge chiralities (armchair and zigzag) of the MoS2 monolayers. This suggests that the technique could be used more broadly to study ultrafast physics and chemistry in low dimensional materials and their hybrids with ultrahigh fidelity. PMID- 29436070 TI - Microsatellite instability-high endocervical serous carcinoma manifesting as pulmonary thromboembolism: A case report and review of the literature. AB - A 53-year-old obese woman was referred because of sudden onset of dyspnea and chronic vaginal bleeding. In addition to severe anemia, multiple pulmonary emboli were identified. Pelvic imaging showed an irregular-shaped mass in the region of the endocervix extending to the lower uterine segment. After successful anticoagulant therapy, followed by placement of an inferior vena cava filter, transabdominal hysterectomy and bilateral salpingo-oophorectomy were performed. An immunopathological study resulted in the diagnosis of endocervical serous carcinoma. After the identification of a high level of microsatellite instability (MSI), an immunohistochemical analysis of mismatch repair (MMR) proteins showed the isolated loss of PMS2. Germline testing of MMR genes showed no mutations, indicating that the high MSI had occurred as a result of sporadic isolated loss of the PMS2 gene expression. PMID- 29436071 TI - The impact of a short educational movie on promoting chronic pain health literacy in school: A feasibility study. AB - BACKGROUND: School-based health education programs on chronic pain providing information about the proper management of recurrent and chronic pain may increase health literacy in terms of pain knowledge, may thereby prevent dysfunctional coping and may decrease the risk of pain chronification. The aim of the present feasibility study was to evaluate the effectiveness of an educational movie on recurrent and chronic pain in increasing pain knowledge among students. METHODS: N = 95 adolescent students provided demographic and pain-related information and completed a pain knowledge questionnaire before and after viewing an educational movie on recurrent and chronic pain. Participants were classified as experiencing frequent pain if they reported pain at least once a week in the last 3 months. RESULTS: One-third of the participants experienced frequent pain. There was a significant increase in pain knowledge for all participants (etap2 = 0.544). Students with frequent pain had a stronger knowledge increase regarding the management of chronic and recurrent pain than those without frequent pain (etap2 = 0.087). Sex did not moderate the gain in pain knowledge. CONCLUSIONS: This feasibility study provides first evidence that a short educational movie on recurrent and chronic pain may increase chronic pain health literacy in students. Future studies should investigate the long-term retention of pain knowledge and any associated effects on behaviour change. Due to barriers to the implementation of interventional studies in the school setting, these studies should use a waitlist control group design and online data collection. SIGNIFICANCE: This feasibility study provides first evidence for the effectiveness of an 11-min educational movie on chronic pain in increasing chronic pain knowledge in students. Students with frequent pain benefitted more from the education than students without frequent pain. PMID- 29436072 TI - Bronchial perforation with aortic pseudo-aneurysm due to aspirated foreign body. PMID- 29436073 TI - No sweat, no genes: A diagnostic dilemma. PMID- 29436074 TI - Hepatitis C infection in a Greek population with inherited bleeding disorders. PMID- 29436075 TI - Ligneous cervicitis and endometritis: A gynaecological presentation of congenital plasminogen deficiency. AB - BACKGROUND: Congenital plasminogen deficiency is a rare autosomal recessive condition. Plasminogen deficiency is thought to result in an inability of fibrin breakdown and therefore accumulation of fibrin and formation of ligneous changes. Ligneous lesions can form on a number of mucosal membranes including the cervix and endometrium. METHODS: We report the case of a 25-year-old woman with type 1 plasminogen deficiency with ligneous cervicitis and endometritis and her treatment and clinical course over the last few years. We then review the current literature of ligneous cases of the female genital tract and discuss available treatment options. KEY RESULTS: We found 30 reported cases of ligneous lesions affecting the female genital tract, with the cervix being the most affected part. A number of treatment options have been tried by our patient and other cases in the literature. These include use of the combined oral contraceptive pill, fresh frozen plasma infusion, topical plasmin and plasminogen and trial use of plasminogen concentrate. CONCLUSIONS: This is a chronic condition requiring a multidisciplinary approach. There is currently no definitive treatment for the condition, current trials with plasminogen concentrate replacement therapy may provide a promising option for these patients in the future. PMID- 29436076 TI - mRNA expression of drug metabolism enzymes and transporter genes at birth using human umbilical cord blood. AB - Growth and maturation changes are mainly responsible for differences in drug pharmacokinetics and pharmacodynamics observed between adults and children, especially neonates. Ontogeny of drug-metabolizing enzymes and transporters plays an important role in drugs interindividual pharmacokinetic variability but data are limited in both term and preterm neonates. This study aimed to characterize mRNA expression of the main drug-metabolizing enzymes and transport proteins involved in drug disposition, using umbilical cord blood (UCB), according to gender, gestational age, and genetic background. A large panel of genes was quantified as follows: cytochrome P450 system (n = 12), UGT family (n = 6), TPMT and transporters (n = 3), in 56 samples of UCB of twin neonates. Gene expression was measured using real-time reverse transcription polymerase chain reaction with 18S rRNA as the endogenous control for normalization of data. Relative expression of the samples was expressed using the 2-DeltaDeltaCt method for comparison of gene expression levels. Twenty genes were expressed in UCB at birth with variable levels of expression and tissue-specific gene expression when compared to data on the fetal liver. Gestational age, gender, and genetic background influenced the expression of the genes tested. Easily accessible UCB samples will enable further studies to evaluate the influence of covariates. This suggests that these covariates need to be considered when assessing substrate drugs disposition mediated by these metabolizing enzymes and transporters in the neonatal population. PMID- 29436077 TI - Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis. AB - INTRODUCTION: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. AIM: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. METHODS: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. RESULTS: Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (<=0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. CONCLUSIONS: Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI. PMID- 29436078 TI - Multisensory exercise programme improves cognition and functionality in institutionalized older adults: A randomized control trial. AB - AIM: The aim of this study was to verify the effects of a multisensory exercise programme on the cognition and functionality of institutionalized older adults. METHODS: Forty-five volunteers were randomly allocated to 2 groups, the multisensory exercise programme (n = 24) and the control group that received no treatment (n = 21). The programme consisted of 3 50-min sessions of progressive exercises per week for 16 weeks that challenged their strength, balance, coordination, multisensory stimulation, and flexibility in different tasks. Cognition (Montreal Cognitive Assessment), balance (Berg Scale), mobility (Timed Up and Go), and functional performance (Physical Performance Test) were measured preintervention and postintervention. Statistical analyses were performed using Student's t test and 2-way ANOVA. RESULTS: The multisensory exercise programme showed statistically significant improvements (p < .05) on cognition (effect size [ES]: 0.92), balance (ES: 0.77), mobility (ES: 0.51), and functional performance (ES: 0.86) as compared with the control group, which showed no statistical significant differences at the postintervention time point. CONCLUSIONS: The multisensory exercise programme improved the cognition and functionality of institutionalized older adults. The introduction of a motor and multisensory based approach in care routines may improve residents' health and engagement to the environment. PMID- 29436079 TI - Pocket handheld ultrasound for evaluation of the bleeding haemophilic joint: A novel and reliable way to recognize joint effusions. PMID- 29436081 TI - "We anatomists are like porters in Paris...". PMID- 29436080 TI - Fetoscopic laser photocoagulation for twin-twin transfusion syndrome. AB - The aim of this study was to review fetoscopic laser photocoagulation (FLP), which ablates placental vascular anastomoses to treat twin-twin transfusion syndrome (TTTS). A review of studies reporting on the procedures, outcomes, complications and nonconventional applications of FLP for TTTS was conducted. FLP has been established as the primary treatment for monochorionic twin pregnancy associated with TTTS at 16-26 weeks. FLP is the only therapy that directly addresses the underlying pathophysiology. The recent technique modification of FLP, referred to as the 'Solomon technique', induces selective coagulation to connect the anastomoses ablation sites and has been introduced to reduce residual anastomoses. The perinatal survival following FLP improved significantly with advances in the technique after its introduction. The recent survival rates of both twins and at least one twin are 70% and more than 90%, respectively. However, there is still an 11-14% risk of long-term neurodevelopment impairment. The premature rupture of membranes that leads to preterm labor is a common complication after FLP. FLP is a valuable treatment option for feto-fetal transfusion syndrome in triplets and for TTTS after 26 weeks. FLP for selective intrauterine growth restriction may be potentially beneficial when accompanied by abnormal Doppler findings and oligohydramnios. FLP is the optimal treatment option for TTTS at 16-26 weeks of gestation. FLP appears to be applicable in triplets, TTTS after 26 weeks and cases of selective intrauterine growth restriction with abnormal Doppler findings and oligohydramnios. FLP is the most common and successful fetal intervention. Improvement in the neurodevelopmental outcomes after FLP is a future focus. PMID- 29436082 TI - Asymmetric Alkyl Side-Chain Engineering of Naphthalene Diimide-Based n-Type Polymers for Efficient All-Polymer Solar Cells. AB - The design and synthesis of three n-type conjugated polymers based on a naphthalene diimide-thiophene skeleton are presented. The control polymer, PNDI 2HD, has two identical 2-hexyldecyl side chains, and the other polymers have different alkyl side chains; PNDI-EHDT has a 2-ethylhexyl and a 2-decyltetradecyl side chain, and PNDI-BOOD has a 2-butyloctyl and a 2-octyldodecyl side chain. These copolymers with different alkyl side chains exhibit higher melting and crystallization temperatures, and stronger aggregation in solution, than the control copolymer PNDI-2HD that has the same side chain. Polymer solar cells based on the electron-donating copolymer PTB7-Th and these novel copolymers exhibit nearly the same open-circuit voltage of 0.77 V. Devices based on the copolymer PNDI-BOOD with different side chains have a power-conversion efficiency of up to 6.89%, which is much higher than the 4.30% obtained with the symmetric PNDI-2HD. This improvement can be attributed to the improved charge-carrier mobility and the formation of favorable film morphology. These observations suggest that the molecular design strategy of incorporating different side chains can provide a new and promising approach to developing n-type conjugated polymers. PMID- 29436083 TI - Direct Cyclization of Tertiary Aryl Amines with Iodonium Ylides. AB - Described herein is a direct cyclization of simple tertiary aryl amines with iodonium ylides leading to a broad range of N-heterocycles. Completely different from the known reactivity of iodonium ylides, the finding reported herein is that an iodonium ylide is capable of cleaving a C(sp3 )-H bond and accepting two hydrogen atoms of a tertiary aryl amine, thus inducing a novel cyclization process. This transformation can proceed without the assistance of a transition metal catalyst and eliminates the need for the premodification of the amine or the use of an additional initiator/oxidant. PMID- 29436084 TI - Clinical trials and registries in haemophilia: Opponents or collaborators? Comparison of PUP data derived from different data sources. AB - INTRODUCTION: The "Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products" (ClinGL) provides the requirements for the performing of clinical trials (CTs) for marketing authorization in Europe. The number of eligible previously untreated patients (PUPs) for CTs might be difficult to meet because of the concurrent development of FVIII concentrates, and additional data sources must be explored. AIM: The extent to which CTs and the PedNet registry met relevant parameters, identified in the ClinGL, as well as inhibitor incidences were investigated in patients from both sources. METHODS: Anonymized data of eight CTs in 369 PUPs performed from 1987 to 2009 were compared with each other and with 632 PUPs (born 2000-2009) from PedNet. RESULTS: Clinical trials in PUPs performed for marketing authorization were too heterogeneous in their investigated parameters; therefore, a comparison of single factor concentrates was not possible. Data collection in PedNet met relevant parameters required for PUPs in accordance with the ClinGL. The overall inhibitor incidences were comparable (CT = 30.9% vs PedNet = 30.6%) when only severe haemophilia A (HA) patients from both data sources were considered. CONCLUSIONS: Previously performed CTs in PUPs were divergent, which prevented a direct comparison of outcomes. However, this study demonstrated that data from CTs and carefully designed registries may complement each other in the establishing of sufficient safety information for single products to improve clinical insights and support regulatory decisions. PMID- 29436085 TI - Catalyst-Enabled Site-Divergent Stereoselective Michael Reactions: Overriding Intrinsic Reactivity of Enynyl Carbonyl Acceptors. AB - A site-divergent stereoselective Michael reaction system is developed based on the identification of two distinct catalysts. Cinchonidine-derived thiourea catalyzes the 1,4-addition of prochiral azlactone enolates to enynyl N-acyl pyrazoles in a highly diastereo- and enantioselective manner to give stereochemically defined alkynes, while P-spiro chiral triaminoiminophosphorane catalytically controls the stereoselective 1,6-addition and the consecutive gamma protonation of the vinylogous enolate intermediate to afford Z,E-configured conjugated dienes. This 1,6-adduct serves as a valuable precursor for the synthesis of a 2-amino-2-deoxy sugar. PMID- 29436086 TI - Global spread of helminth parasites at the human-domestic animal-wildlife interface. AB - Changes in species distributions open novel parasite transmission routes at the human-wildlife interface, yet the strength of biotic and biogeographical factors that prevent or facilitate parasite host shifting are not well understood. We investigated global patterns of helminth parasite (Nematoda, Cestoda, Trematoda) sharing between mammalian wildlife species and domestic mammal hosts (including humans) using >24,000 unique country-level records of host-parasite associations. We used hierarchical modelling and species trait data to determine possible drivers of the level of parasite sharing between wildlife species and either humans or domestic animal hosts. We found the diet of wildlife species to be a strong predictor of levels of helminth parasite sharing with humans and domestic animals, followed by a moderate effect of zoogeographical region and minor effects of species' habitat and climatic niches. Combining model predictions with the distribution and ecological profile data of wildlife species, we projected global risk maps that uncovered strikingly similar patterns of wildlife parasite sharing across geographical areas for the different domestic host species (including humans). These similarities are largely explained by the fact that widespread parasites are commonly recorded infecting several domestic species. If the dietary profile and position in the trophic chain of a wildlife species largely drives its level of helminth parasite sharing with humans/domestic animals, future range shifts of host species that result in novel trophic interactions may likely increase parasite host shifting and have important ramifications for human and animal health. PMID- 29436087 TI - Training using a new multidirectional reach tool improves balance in individuals with stroke. AB - BACKGROUND AND PURPOSE: Previous studies suggested that limits of stability (LOS) training with visual feedback using commercial equipment could be used to improve balance ability in individuals with stroke. However, this system is expensive. In this study, we created a new tool from inexpensive elements based on LOS training using visual feedback. The aim of this study was to investigate the effect of training using a new multidirectional reach tool on balance in individuals with stroke. METHODS: A single-blind randomized control trial was conducted. Individuals with stroke (n = 16; age range 38-72 years) were recruited. Participants in the experimental group were trained with the multidirectional reach training for 30 min and conventional physical therapy for 30 min per day, 3 days a week for 4 weeks. Participants in the control group received conventional physical therapy for 30 min per day, 3 days a week for 4 weeks. The outcomes were LOS, weight-bearing squat, and Fullerton Advanced Balance scale. All of the outcome measures were measured at pretraining, post-training, and 1 month follow up. RESULTS: At post-training and 1-month follow-up, the participants in the experimental group had an improvement of dynamic balance than the control group. Furthermore, the activity assessment by Fullerton Advanced Balance scale was more improved at 1 month follow-up in the experimental group than control group. CONCLUSION: The results of this study provide evidence that training using a new multidirectional reach tool is effective for improving balance in individuals with stroke. PMID- 29436088 TI - Which ventricle should be mapped first in catheter ablation of ventricular arrhythmias originating from the ventricular outflow tract? PMID- 29436089 TI - Pleural effusion associated with peripherally inserted central catheter in the inferior vena cava. PMID- 29436090 TI - Neuroscience-based Nomenclature: What is it, why is it needed, and what comes next? PMID- 29436091 TI - Artwork Description. PMID- 29436093 TI - The Editor recommends this issue's article to the reader: Survival of extensive restorations in primary molars: 15-year practice-based study. PMID- 29436094 TI - Editorial: We have to learn how to listen. PMID- 29436092 TI - Development and evaluation of the children's experiences of dental anxiety measure. AB - BACKGROUND: Existing measures of children's dental anxiety have not been developed with children or based on a theoretical framework of dental anxiety. AIM: To develop the children's experiences of dental anxiety measure (CEDAM) and evaluate the measure's properties. DESIGN: The measure was developed from interviews with dentally anxious children. Children recruited from a dental hospital and secondary school completed the CEDAM and Modified Child Dental Anxiety Scale (MCDAS). A subgroup of children completed the CEDAM before and after receiving an intervention to reduce dental anxiety to examine the measure's responsiveness. Rasch and Classical test analyses were undertaken. RESULTS: Children were aged between 9 and 16 years (N = 88 recruited from a dental hospital and N = 159 recruited from a school). Rasch analysis confirmed the measure's unidimensionality. The CEDAM correlated well with the MCDAS (rho = 0.67, P < 0.01) and had excellent internal consistency (Cronbach's alpha = 0.88) and test-retest reliability (ICC = 0.98). The CEDAM was also able to detect changes in dental anxiety following the intervention (baseline mean = 22.36, SD = 2.57 and follow-up mean = 18.88, SD = 2.42, t(df = 37) = 9.54, P < 0.01, Cohen's d = 1.39). CONCLUSIONS: The results support the reliability, validity and responsiveness of the CEDAM. Initial findings indicate it has potential for use in future intervention trials or in clinical practice to monitor children's dental anxiety. PMID- 29436095 TI - Solid-Solution Alloy Nanoparticles of the Immiscible Iridium-Copper System with a Wide Composition Range for Enhanced Electrocatalytic Applications. AB - For the first time, we synthesize solid-solution alloy nanoparticles of Ir and Cu with a size of ca. 2 nm, despite Ir and Cu being immiscible in the bulk up to their melting over the whole composition range. We performed a systematic characterization on the nature of the Irx Cu1-x solid-solution alloys using powder X-ray diffraction, scanning transmission electron microscopy coupled with energy-dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy. The results showed that the Irx Cu1-x alloys had a face-centered-cubic structure; charge transfer from Cu to Ir occurred in the alloy nanoparticles, as the core level Ir 4f peaks shifted to lower energy region with the increase in Cu content. Furthermore, we observed that the alloying of Ir with Cu enhanced both the electrocatalytic oxygen evolution and oxygen reduction reactions. The enhanced activities could be attributed to the electronic interaction between Ir and Cu arising from the alloying effect at atomic-level. PMID- 29436096 TI - Nephrotic syndrome complicated with femoral vein catheter-related phlegmasia cerulea dolens: A case report. AB - Nephrotic syndrome is a well-known risk factor of deep vein thrombosis (DVT). Catheter-related DVT under the setting of nephrotic syndrome may be presented as a more fulminant form, phlegmasia cerulea dolens. Phlegmasia cerulea dolens may lead to severe obstruction of venous drainage of the extremities and presents with compartment syndrome that impairs arterial perfusion. Aggressive management with thrombolysis and/or thrombectomy are considered with simultaneous anticoagulant treatment. PMID- 29436097 TI - Amyloids of multiple species: are they helpful in survival? AB - Amyloids are primarily known for their roles in neurodegenerative disorders, as well as in systemic diseases like diabetes. Evolutionary forces tend to maintain a healthy set of heritable characteristics, while eliminating toxic or unfavourable elements; but amyloids seem to represent an exception to this fundamental concept. In addition to their presence in mammals, amyloids also persist in the proteome of many lower organisms that may be linked with possible roles in survival, which are still unexplored. Herein, we address some unanswered questions regarding amyloids: are these well-structured proteinaceous aggregates a by-product of inefficient folding events, or have they been retained in our protein repertoire for as yet unknown functional roles; and how do protein misfolding and associated disorders originate, despite the presence of protein quality-control systems inside the cells? This review aims to extend our current understanding about the multifaceted useful properties of amyloids and their functional interactions with other molecular pathways in various species; this may provide new insights to identify novel therapeutic strategies for ageing and neurodegenerative diseases. PMID- 29436098 TI - Mitigation of Inflammatory Immune Responses with Hydrophilic Nanoparticles. AB - While hydrophobic nanoparticles (NPs) have been long recognized to boost the immune activation, whether hydrophilic NPs modulate an immune system challenged by immune stimulators and how their hydrophilic properties may affect the immune response is still unclear. To answer this question, three polymers, poly(ethylene glycol) (PEG), poly(sulfobetaine) (PSB) and poly(carboxybetaine) (PCB), which are commonly considered hydrophilic, are studied in this work. For comparison, nanogels with uniform size and homogeneous surface functionalities were made from these polymers. Peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide (LPS) and an LPS-induced lung inflammation murine model were used to investigate the influence of nanogels on the immune system. Results show that the treatment of hydrophilic nanogels attenuated the immune responses elicited by LPS both in vitro and in vivo. Moreover, we found that PCB nanogels, which have the strongest hydration and the lowest non-specific protein binding, manifested the best performance in alleviating the immune activation, followed by PSB and PEG nanogels. This reveals that the immunomodulatory effect of hydrophilic materials is closely related to their hydration characteristics and their ability to resist non-specific binding in complex media. PMID- 29436100 TI - Lupeol alters ER stress-signaling pathway by downregulating ABCG2 expression to induce Oxaliplatin-resistant LoVo colorectal cancer cell apoptosis. AB - Colorectal cancer (CRC) is one of the most common cancers and causes of cancer related death. There are several first-line chemotherapeutic drugs used to treat CRC. Oxaliplatin (OXA) is an alkylating cytotoxic agent that is usually combined with other chemotherapeutic drugs to treat stage II and stage III CRC. However, cancer cells commonly acquire multidrug resistance (MDR), which is a major obstruction to cancer treatment. Recent studies have shown that natural components from traditional Chinese medicine or foods that have many biological functions may be new adjuvant therapies in clinical trials. We challenged LoVo CRC cell lines with OXA in a dose-dependent manner to create an OXA-resistant model. The expression of ABCG2 was significantly higher, and levels of endoplasmic reticulum (ER) stress markers were lower than those Parental cells. However, Lupeol, which is found in fruits and vegetables, has been shown to have bioactive properties, including anti-tumor properties that are relevant to many diseases. In our study, Lupeol downregulated cell viability and activated cell apoptosis. Moreover, Lupeol decreased the expression of ABCG2 and activated ER stress to induce OXA-resistant cell death. Importantly, the anti-tumor effect of Lupeol in OXA-resistant cells was higher than that of LoVo Parental cells. In addition, we also confirmed our results with a xenograft animal model, and the tumor size significantly decreased after Lupeol injections. Our findings show that Lupeol served as a strong chemoresistant sensitizer and could be a new adjuvant therapy method for chemoresistant patients. PMID- 29436101 TI - Chemoembolization related to good survival for selected patients with hepatocellular carcinoma invading segmental portal vein. AB - BACKGROUND & AIMS: We evaluated survival outcomes and prognostic factors associated with survival after TACE in a large cohort of 331 patients with HCC with segmental PVTT. METHODS: From 1997 to 2015, a total of 331 patients were included in this study from among 507 patients who underwent TACE as a first-line treatment for HCC with segmental PVTT. RESULTS: After TACE, the median survival of the whole cohort was 10.7 months, and the 1-year, 3-year and 5-year survival rates were 44.9%, 16% and 12% respectively. Objective tumour response after TACE was achieved in 53.8% of patients. Multivariable Cox regression analyses confirmed that up-to-11 criteria, extrahepatic metastasis, Child-Pugh class, and tumour response to TACE were independent prognostic factors for patient survival. The expected median survival times among patients with 0, 1 and 2-4 risk factors were 29.1, 15.1 and 5.3 months respectively. The 30-day mortality and major complications rates after TACE were 0.9% and 5.4% respectively. CONCLUSIONS: TACE was well-tolerated and effective in selected patients with HCC with segmental PVTT. We found that four risk factors were associated with decreased length of patient survival after TACE: a major tumour burden (up-to-11 criteria out), extrahepatic spread, Child-Pugh class B liver function and nonregression to TACE. TACE may not be recommended for HCC patients with segmental PVTT with 2-4 risk factors because of poor survival outcome. PMID- 29436103 TI - Genomic hotspots but few recurrent fusion genes in breast cancer. AB - The advent of next generation sequencing technologies has boosted the interest in exploring the role of fusion genes in the development and progression of solid tumors. In breast cancer, most of the detected gene fusions seem to be "passenger" events while the presence of recurrent and driver fusions is still under study. We performed RNA sequencing in 55 well-characterized breast cancer samples and 10 adjacent normal breast tissues, complemented by an analysis of SNP array data. We explored the presence of fusion genes and defined their association with breast cancer subtypes, clinical-pathologic characteristics and copy number aberrations. Overall, 370 fusions were detected across the majority of the samples. HER2+ samples had significantly more fusions than triple negative and luminal subtypes. The number of fusions was correlated with histological grade, Ki67 and tumor size. Clusters of fusion genes were observed across the genome and a significant correlation of fusions with copy number aberrations and more specifically amplifications was also revealed. Despite the large number of fusion events, only a few were recurrent, while recurrent individual genes forming fusions with different partners were also detected including the estrogen receptor 1 gene in the previously detected ESR1-CCDC170 fusion. Overall we detected novel gene fusion events while we confirmed previously reported fusions. Genomic hotspots of fusion genes, differences between subtypes and small number of recurrent fusions are the most relevant characteristics of these events in breast cancer. Further investigation is necessary to comprehend the biological significance of these fusions. PMID- 29436104 TI - Gathering Perspectives - Finding Solutions for Chronic and End Stage Kidney Disease. PMID- 29436102 TI - Clinical nursing and midwifery research in Latin American and Caribbean countries: A scoping review. AB - AIM: To identify and describe published, nursing-led and midwifery-led, clinical research that has been conducted in Latin America and the Caribbean. BACKGROUND: Peer-reviewed published research may correspond to and elucidate country's realities, priorities, and needs. DESIGN: A 6-stage scoping review methodology was used to search scientific databases using an applied search strategy. DATA SOURCES: Five databases were searched for articles published in English, Spanish, or Portuguese conducted in a Latin American or Caribbean country between January 1, 2006 and June 14, 2016. REVIEW METHODS: Articles were independently considered for inclusion by 2 researchers, data extracted, and study characteristics described. RESULTS: Of 6922 articles identified, 404 were included. The majority were conducted in Brazil (90.6%) followed by Chile (2.5%). Most were nurse-led (95.8%) and were implemented in hospitals (48.6%). Studies frequently explored patient knowledge or characterized patient populations (61.3%) and commonly assessed chronic disease (19.3%) or maternity/child health outcomes (15.9%). CONCLUSION: Findings revealed a large number of publications but an uneven geographical distribution of nurse-led clinical research and an evident gap of midwifery-related research in Latin America and the Caribbean. Results may be used to build research agendas to promote nursing and midwifery research capacity and further establish evidence-based practice. PMID- 29436105 TI - The association of nocturnal hypertension and nondipping blood pressure with treatment-resistant hypertension: The Jackson Heart Study. AB - Apparent treatment-resistant hypertension (aTRH), nocturnal hypertension, and nondipping blood pressure (BP) have shared risk factors. The authors studied the association between aTRH and nocturnal hypertension and aTRH and nondipping BP among 524 black Jackson Heart Study participants treated for hypertension. Nocturnal hypertension was defined by mean nighttime systolic BP >=120 mm Hg or diastolic BP >=70 mm Hg. Nondipping BP was defined by mean nighttime to daytime systolic BP ratio >0.90. aTRH was defined by mean clinic systolic BP >=140 mm Hg and/or diastolic BP >=90 mm Hg with three medication classes or treatment with four or more classes. The risk for developing aTRH associated with nondipping BP and nocturnal hypertension was estimated. After multivariable adjustment, participants with aTRH were more likely to have nocturnal hypertension (prevalence ratio, 1.20; 95% confidence interval, 1.03-1.39) and nondipping (prevalence ratio, 1.25; 95% confidence interval, 1.09-1.43). Over a median 7.3 years of follow-up, nocturnal hypertension and nondipping BP at baseline were not associated with developing aTRH after adjustment. PMID- 29436106 TI - Corticosteroid and Cortisol Serum Levels Following Intra-articular Triamcinolone Acetonide Lumbar Facet Joint Injections. AB - BACKGROUND: Facet joint steroid injections are used to treat chronic low back pain. However, little is known about the systemic absorption and serum levels of steroids following intra-articular facet joint injections. The primary objective of this preliminary study was to investigate the pharmacokinetics of triamcinolone acetonide following fluoroscopically guided intra-articular lumbar facet joint injections in a cohort of patients with chronic low back pain. A secondary aim was to investigate the effects of triamcinolone on serum cortisol levels following lumbar facet joint injections. METHODS: The study cohort included 5 patients undergoing fluoroscopically guided intra-articular lumbar facet joint injections at a pain medicine specialty clinic. Blood was collected prior to the injections and on days 1, 2, 4, 6, 8, 14, 21, 28, 35, and 42 following the injections. RESULTS: The terminal elimination half-life of triamcinolone in a noncompartmental analysis was 213 hours. The peak median triamcinolone concentration of 3.6 ng/mL was detected within 24 hours after the injections. Serum cortisol levels were < 30 ng/mL for an average of 4.4 days. The maximum effect of triamcinolone on cortisol suppression was observed with triamcinolone serum levels of > 1.9 ng/mL. CONCLUSIONS: The peak serum concentration of triamcinolone following intra-articular facet joint injections occurred within 24 hours. The median terminal elimination half-life was 213 hours, but baseline cortisol levels were suppressed for an average of 4.4 days. Clinically, the prolonged half-life and endocrine effects of triamcinolone could increase the risk for serious drug-drug interactions in patients taking medications that inhibit corticosteroid metabolism. PMID- 29436107 TI - Rationale and developmental methodology for the SIMPLE approach: A Systematised, Interdisciplinary Malnutrition Pathway for impLementation and Evaluation in hospitals. AB - AIM: Changing population demographics, service demands, and healthcare provider expectations suggest that a shift is required regarding how malnutrition care is managed in hospitals. The present study aims to build the reason for required change, and to describe the process used to develop a model for managing malnutrition for implementation across six Queensland hospitals. METHODS: A cross sectional survey of approaches to managing malnutrition in Queensland public hospitals, and development of a new model of care (guided by Knowledge-to-Action Framework and qualitative interviews) for testing within a broader implementation program. RESULTS: Twenty-three surveys were distributed with 21 completed by metropolitan (n = 11), regional (n = 8), and rural/remote (n = 2) settings. Substantial within and across site variance was observed, with care processes focused towards highly individualised, dietitian delivered care. Some early adopter sites demonstrated systematic, interdisciplinary or delegated malnutrition care processes; however, the latter was rarely or never undertaken in eight sites. A model for the Systematised, Interdisciplinary Malnutrition Pathway for impLementation and Evaluation (SIMPLE) in hospitals was drafted based on identified contemporary models and supporting literature. A mixed-methods approach combined survey data with structured interviews conducted in six sites, purposively sampled for maximal variation to iteratively refine the model. Consensus for implementation of the final model was achieved across site clinicians, leaders, and governance structures. CONCLUSIONS: Systematised, delegated, and interdisciplinary nutrition care activities are realistic in at least some settings. A model is now available to provide interdisciplinary care. Next steps including testing implementation will determine if this interdisciplinary model improves malnutrition care delivered in hospitals. PMID- 29436108 TI - A fetus coexisting with a complete hydatidiform mole with trisomy 9 of maternal origin. AB - A complete hydatidiform mole (CHM) coexisting with a viable fetus is a rare finding in pregnancies. Accurate diagnosis often relies on ultrasonographic, histopathological and molecular techniques in the definite diagnosis. To the best of our knowledge, a liveborn fetus coexisting with CHM with trisomy 9 has not been described. The use of molecular genotyping and immunohistochemical laboratory investigations enabled the CHM to be fully characterized. Postzygotic diploidization of a triploid conception arising from dispermy is the proposed mechanism of its formation. PMID- 29436109 TI - Engineering Gold Nanorod-Copper Sulfide Heterostructures with Enhanced Photothermal Conversion Efficiency and Photostability. AB - Plasmonic gold nanorods (Au NRs)-copper sulfide heterostructures have recently attracted much attention owing to the synergistically enhanced photothermal properties. However, the facile synthesis and interface tailoring of Au NRs copper sulfide heterostructures remain a formidable challenge. In this study, the rational design and synthesis of Au NRs-Cu7 S4 heterostructures via a one-pot hydrothermal process is reported. Specifically, core-shell and dumbbell-like Au NRs-Cu7 S4 heterostructures are obtained with well-controlled interfaces by employing the Au NRs with different aspect ratios. Both core-shell and dumbbell like Au NRs-Cu7 S4 have proven effective as photothermal therapy agents, which offer both high photothermal stability and significant photothermal conversion efficiency up to 62%. The finite-difference time domain simulation results confirm the coupling effect that leads to the enhanced local field as well as the optical absorption at the heterostructure interface. Importantly, these Au NRs Cu7 S4 heterostructures can be compatibly used as an 808 nm laser-driven photothermal therapy agents for the efficient photothermal therapy of cancer cells in vitro. This study will provide new insight into the design of other noble metal-semiconductor heterostructures for a broad range of applications utilizing surface plasmon resonance enhancement phenomena. PMID- 29436110 TI - Catastrophizing, pain and traumatic stress symptoms following burns: A prospective study. AB - BACKGROUND: Pain and posttraumatic stress disorder (PTSD) symptoms are significant problems in the aftermath of a burn injury and they often co-occur. Catastrophizing has been linked to both phenomena. The aim of this study was to investigate the underlying role of catastrophizing in PTSD symptoms and pain following burns. METHODS: This prospective study included 216 patients with burns. PTSD symptoms and pain were measured during hospitalization (T1) and 6 (T2) and 12 months (T3) postburn. The Impact of Event Scale-Revised (IES-R) indexed PTSD symptoms. Acute pain (T1) was the mean pain during the first two weeks of hospitalization measured using an 11-point graphic numeric rating scale. Chronic pain was indexed using the single item 'average' pain from the Brief Pain Inventory (BPI). Catastrophizing was measured at T1 and T2 using the Cognitive Emotion Regulation Questionnaire (CERQ). Data were analysed using structural equation modelling (SEM). RESULTS: The results showed that T2 catastrophizing mediated between acute and chronic PTSD symptoms, and T3 pain. Furthermore, the study revealed significant associations between catastrophizing, PTSD symptoms and pain at the respective measurements, and significant longitudinal associations between the constructs. CONCLUSION: A negative cognitive-affective response to a burn event, such as catastrophizing, mediated the relationship between acute and chronic PTSD symptoms and later chronic pain. Screening for catastrophizing and acute PTSD symptoms is recommended to identify persons at risk for chronic PTSD symptoms and pain. SIGNIFICANCE: The identification of individuals who have the tendency to catastrophize may assist in finding those at risk for development of both chronic PTSD symptoms and chronic pain. Individuals may benefit from early psychological therapy focussing on catastrophizing and acute PTSD symptoms that may ameliorate both chronic PTSD symptoms and pain. PMID- 29436112 TI - Cost effectiveness of focal impulse and rotor modulation guided ablation added to pulmonary vein isolation for atrial fibrillation. AB - BACKGROUND: Although ablation with focal impulse and rotor modulation (FIRM), as an adjunct to pulmonary vein isolation (PVI), has been shown to decrease atrial fibrillation (AF) recurrence, cost-effectiveness has not been assessed. OBJECTIVE: We aimed to evaluate the cost effectiveness of FIRM-guided ablation when added to PVI in a mixed AF population. METHODS AND RESULTS: We used a Markov model to estimate the costs, quality-adjusted survival, and cost effectiveness of adding FIRM ablation to PVI. AF recurrence rates were based on 3-year data from the CONFIRM trial. Model inputs for event probabilities and utilities were obtained from literature review. Costs were based on Medicare reimbursement, wholesale acquisition costs, and literature review. Three-year total costs FIRM+PVI versus PVI alone were $27,686 versus $26,924. QALYs were 2.338 versus 2.316, respectively, resulting in an incremental cost-effectiveness ratio (ICER) of $34,452 per QALY gained. Most of the cost (65-81%) was related to the index ablation procedure. Lower AF recurrence generated cost offsets of $4,266, primarily due to a reduced need for medications and repeat ablation. Probabilistic sensitivity analysis demonstrated ICER below $100,000/QALY in 74% of simulations. CONCLUSION: Based on data from the CONFIRM study, the addition of FIRM to PVI does have the potential to be cost-effective due to higher quality adjusted life years and lower follow-up costs. Value is sensitive to the incremental reduction in AF recurrence, and FIRM may have the greatest economic value in patients with greater AF symptom severity. Results from ongoing randomized trials will provide further clarity. PMID- 29436113 TI - Journal clubs in health professional practice. PMID- 29436111 TI - A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis. AB - Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes. PMID- 29436114 TI - Interprofessional learning in ambulatory care. AB - BACKGROUND: Interprofessional practice amongst health care professionals can facilitate effective collaboration and can improve health outcomes for patients. Interprofessional clinical placements have mainly been established within inpatient settings; however, ambulatory care settings can also provide interprofessional education. This study evaluates an interprofessional placement in ambulatory care for medical and nursing students. METHODS: Medical and nursing students undertook a 2-week interprofessional placement in respiratory, diabetes and chronic pain clinics, as well as within the patient's home. An electronic post-placement survey including 14 fixed-response and five open-ended questions was conducted to evaluate the students' experiences. RESULTS: Ninety-two students undertook the interprofessional placement: 74% were medical students and 26% were nursing students. The overall response rate was 81%. Students strongly supported the model of clinical supervision with the nurse educator and teaching registrar working collaboratively to facilitate the placement. Both medical and nursing students felt that the placement facilitated the development of interprofessional principles, with 78.7% agreeing or strongly agreeing with the statement 'the clinical placement allowed me to reflect on interprofessional learning and practice'. In terms of future practice, 67% of medical students and 81% of nursing students agreed that 'this placement has altered how [they] will practice as a professional in the future'. Interprofessional practice can facilitate effective collaboration and can improve health outcomes for patients DISCUSSION: Medical and nursing students found that the ambulatory care setting facilitated a mix of learning opportunities that complemented learning from the inpatient setting, and the interactions with other health professionals provided a valuable learning experience that contributed to their understanding of interprofessional practice. PMID- 29436115 TI - Efficacy and safety of trans-bronchial cryo in comparison with forceps biopsy in lung allograft recipients: Analysis of 402 procedures. AB - BACKGROUND: Trans-bronchial forceps biopsy (TBFB) is the gold standard to establish the presence of allograft rejection or infection after lung transplantation. We aimed to analyze the diagnostic yield and safety of trans bronchial cryobiopsy (TBCB) in lung allografts. METHODS: Retrospective analysis of 402 TBB procedures in 362 lung recipients was performed between 2011 and 2016. Half of the cases (201) were performed by TBCB and the other half by TBFB. One hundred random slides of TBB specimens from lung allografts were reviewed for artifacts, bleeding, and histological evidence. RESULTS: Both TBB groups were comparable in age, gender distribution, and time following transplantation. Acute rejection was diagnosed in 21.9% of the TBCB group vs 14.9% in the TBFB group (P = .09) and only 2 cases (1%) of nondiagnostic tissue in TBCB group and 4 cases (2%) in TBFB group (P = .685). Complications of pneumothorax and bleeding occurred in 9 (4.5%) vs 8 (4%) and 5 (2.5%) vs 4 (2%) in TBCB vs TBFB groups, respectively. The TBCB specimens were larger than TBFB (average 16.6 vs 6.6 mm2 ; P < .001). Crush and bleeding artifacts were seen in 11 (22%) and 23 (46%) of TBFB, respectively, yet none in TBCB group (P < .001). CONCLUSION: Trans bronchial cryobiopsy is safe and effective for diagnosis of lung allograft rejection. PMID- 29436116 TI - Minimization of Ion-Solvent Clusters in Gel Electrolytes Containing Graphene Oxide Quantum Dots for Lithium-Ion Batteries. AB - This study uses graphene oxide quantum dots (GOQDs) to enhance the Li+ -ion mobility of a gel polymer electrolyte (GPE) for lithium-ion batteries (LIBs). The GPE comprises a framework of poly(acrylonitrile-co-vinylacetate) blended with poly(methyl methacrylate) and a salt LiPF6 solvated in carbonate solvents. The GOQDs, which function as acceptors, are small (3-11 nm) and well dispersed in the polymer framework. The GOQDs suppress the formation of ion-solvent clusters and immobilize PF6- anions, affording the GPE a high ionic conductivity and a high Li+ -ion transference number (0.77). When assembled into Li|electrolyte|LiFePO4 batteries, the GPEs containing GOQDs preserve the battery capacity at high rates (up to 20 C) and exhibit 100% capacity retention after 500 charge-discharge cycles. Smaller GOQDs are more effective in GPE performance enhancement because of the higher dispersion of QDs. The minimization of both the ion-solvent clusters and degree of Li+ -ion solvation in the GPEs with GOQDs results in even plating and stripping of the Li-metal anode; therefore, Li dendrite formation is suppressed during battery operation. This study demonstrates a strategy of using small GOQDs with tunable properties to effectively modulate ion-solvent coordination in GPEs and thus improve the performance and lifespan of LIBs. PMID- 29436117 TI - Play games and score points with students. PMID- 29436118 TI - Cortistatin inhibits arterial calcification in rats via GSK3beta/beta-catenin and protein kinase C signalling but not c-Jun N-terminal kinase signalling. AB - AIM: Cortistatin (CST) is a newly discovered endogenous active peptide that exerts protective effects on the cardiovascular system. However, the relationship between CST and aortic calcification and the underlying mechanism remain obscure. Therefore, we investigated effects of CST on aortic calcification and its signalling pathways. METHODS: Calcium content and alkaline phosphatase (ALP) activity were measured using the o-cresolphthalein colorimetric method and ALP assay kit respectively. Protein expression of smooth muscle (SM)-alpha-actin, osteocalcin (OCN), beta-catenin, glycogen synthase kinase 3beta (GSK3beta), p GSK3beta, protein kinase C (PKC), p-PKC, c-Jun N-terminal kinase (JNK) and p-JNK was determined using Western blotting. RESULTS: In aorta from a rat vitamin D3 calcification model, CST abrogated calcium deposition and pathological damage, decreased the protein expression of OCN and beta-catenin and increased SM-alpha actin expression. In a rat cultured vascular smooth muscular cell (VSMC) calcification model induced by beta-glycerophosphate (beta-GP), CST inhibited the increase in ALP activity, calcium content and OCN protein and the decrease in SM alpha-actin expression. CST also inhibited the beta-GP-induced increase in p GSK3beta and beta-catenin protein (both P < .05). The inhibitory effects of CST on ALP activity, calcium deposition and beta-catenin protein were abolished by pretreatment with lithium chloride, a GSK3beta inhibitor. CST promoted the protein expression of p-PKC by 68.5% (P < .01), but not p-JNK. The ability of CST to attenuate beta-GP-induced increase in ALP activity, calcium content and OCN expression in the VSMC model was abolished by pretreatment with the PKC inhibitor Go6976. CONCLUSION: These results indicate that CST inhibits aortic calcification and osteogenic differentiation of VSMCs likely via the GSK3beta/beta-catenin and PKC signalling pathways, but not JNK signalling pathway. PMID- 29436120 TI - Intermittent exercise and insulin sensitivity in older individuals-It's a HIIT. PMID- 29436119 TI - Laparoscopic diagnosis and treatment of an isolated epithelioid trophoblastic tumor in recto-uterine pouch. AB - A 30-year-old Chinese woman with irregular vaginal bleeding was admitted to our department. Serum beta-human chorionic gonadotropin (beta-hCG) was moderately elevated, and ultrasound and magnetic resonance imaging revealed an irregular, retro-uterine lesion without intrauterine pregnancy. Ectopic pregnancy was the primary consideration, with trophoblastic tumor being another possibility. Laparoscopy revealed a 2 * 3 * 3 cm3 irregular, infiltrating, yellow-white lesion in the left recto-uterine pouch, which was completely resected without rectal damage. Final pathological/immunohistochemical analyses revealed an epithelial trophoblastic tumor (ETT) (Ki-67 reactive index~45%). Postoperative recovery was smooth, and the patient received three chemotherapy courses (etoposide, methotrexate and actinomycin, alternating weekly with cyclophosphamide and vincristine) beginning 6 days postsurgery (beta-hCG = 46.4 mIU/mL). beta-hCG returned to an undetectable level after one chemotherapy course. Herein, we describe a rare case of isolated ETT that was difficult to differentiate from other pregnancy-related diseases. Laparoscopy could be an effective, safe diagnostic method in select patients. PMID- 29436121 TI - Antiplatelet therapy combined with acenocoumarol in relation to major bleeding, ischaemic stroke and mortality. AB - BACKGROUND: Vascular disease is a frequent comorbidity in atrial fibrillation (AF) patients, resulting in concomitant use of antiplatelet therapy. In the present study, we investigated the incidence and risk of major bleeding, ischaemic stroke, and mortality in a cohort of AF patients taking acenocoumarol plus antiplatelet therapy, in comparison with AF patients taking only acenocoumarol monotherapy. METHODS: We consecutively included 1361 "real-world" AF patients stable for at least the previous 6 months on acenocoumarol (INR 2.0 3.0). The primary endpoint was major bleeding defined using the 2005 International Society on Thrombosis and Haemostasis (ISTH) criteria. As secondary endpoints, we analysed ischaemic strokes and all-cause mortality. During follow up, all adverse events were recorded and compared within patients taking acenocoumarol plus antiplatelet therapy and patients taking only acenocoumarol. RESULTS: During 6.5 years (IQR 4.3-7.9) of follow-up, there were 250 (2.83%/year) bleeds, 130 (1.47%/year) ischaemic strokes and 511 (6.23%/year) deaths. After multivariate Cox regression analyses, combined antithrombotic therapy was associated with major bleeding (HR 1.40, 95% CI 1.01-1.94; P = .048), but not lower mortality (HR 0.95, 95% CI 0.75-1.21; P = .674) or ischaemic stroke (HR 1.45, 95% CI 0.97-2.17; P = .072). CONCLUSIONS: In AF patients, the risk of bleeding is higher when antiplatelet therapy is combined with acenocoumarol, but the risk of mortality and stroke was not significantly different from that of patients taking only acenocoumarol. PMID- 29436122 TI - The zebrafish: A fintastic model for hematopoietic development and disease. AB - Hematopoiesis is a complex process with a variety of different signaling pathways influencing every step of blood cell formation from the earliest precursors to final differentiated blood cell types. Formation of blood cells is crucial for survival. Blood cells carry oxygen, promote organ development and protect organs in different pathological conditions. Hematopoietic stem and progenitor cells (HSPCs) are responsible for generating all adult differentiated blood cells. Defects in HSPCs or their downstream lineages can lead to anemia and other hematological disorders including leukemia. The zebrafish has recently emerged as a powerful vertebrate model system to study hematopoiesis. The developmental processes and molecular mechanisms involved in zebrafish hematopoiesis are conserved with higher vertebrates, and the genetic and experimental accessibility of the fish and the optical transparency of its embryos and larvae make it ideal for in vivo analysis of hematopoietic development. Defects in zebrafish hematopoiesis reliably phenocopy human blood disorders, making it a highly attractive model system to screen small molecules to design therapeutic strategies. In this review, we summarize the key developmental processes and molecular mechanisms of zebrafish hematopoiesis. We also discuss recent findings highlighting the strengths of zebrafish as a model system for drug discovery against hematopoietic disorders. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Vertebrate Organogenesis > Musculoskeletal and Vascular Nervous System Development > Vertebrates: Regional Development Comparative Development and Evolution > Organ System Comparisons Between Species. PMID- 29436124 TI - Academie des Sciences Prizes: M. Taillefer, G. Masson, L. Peng, D. Matt / Horst Dietrich Hardt Prize: L. H. Gade / Yamada-Koga Prize: J.-E. Backvall. PMID- 29436125 TI - Refractory hypertension focus on nighttime blood pressure and nondipping. PMID- 29436123 TI - A novel sorbent based on carbon nanotube/amino-functionalized sol-gel for the headspace solid-phase microextraction of alpha-bisabolol from medicinal plant samples using experimental design. AB - A novel sol-gel coating on a stainless-steel fiber was developed for the first time for the headspace solid-phase microextraction and determination of alpha bisabolol with gas chromatography and flame ionization detection. The parameters influencing the efficiency of solid-phase microextraction process, such as extraction time and temperature, pH, and ionic strength, were optimized by the experimental design method. Under optimized conditions, the linear range was between 0.0027 and 100 MUg/mL. The relative standard deviations determined at 0.01 and 1.0 MUg/mL concentration levels (n = 3), respectively, were as follows: intraday relative standard deviations 3.4 and 3.3%; interday relative standard deviations 5.0 and 4.3%; and fiber-to-fiber relative standard deviations 6.0 and 3.5%. The relative recovery values were 90.3 and 101.4% at 0.01 and 1.0 MUg/mL spiking levels, respectively. The proposed method was successfully applied to various real samples containing alpha-bisabolol. PMID- 29436126 TI - Aerobic exercise prior to task-specific training to improve poststroke motor function: A case series. AB - BACKGROUND: Aerobic exercise can improve upper limb motor function in both healthy and stroke populations. Research in animals after stroke has shown that aerobic exercise combined with forelimb motor training improved forelimb motor function more than aerobic exercise or motor training alone. There is a lack of knowledge about this combined intervention in humans after stroke. PURPOSE: These 2 case reports describe the exploratory implementation of a combined aerobic exercise and task-specific training intervention to improve upper limb motor function in one person in subacute stroke recovery and one person in chronic stroke recovery. METHODS: Case descriptions Subacute participant: 45-year-old female, 3 months after ischemic stroke resulting in left-sided hemiparesis affecting her non-dominant upper limb, with a baseline Action Research Arm Test (ARAT) score of 10/57 and Wolf Motor Function Test (WMFT) score of 39/75. Chronic participant: 69-year-old female, 14 years after ischemic stroke resulting in right-sided hemiparesis affecting her non-dominant upper limb, with a baseline ARAT score of 13/57 and WMFT score of 34/75. Intervention Participants performed 30 min of lower limb cycling immediately prior to 30 min of upper limb task specific training. Sessions were undertaken 3 times a week for 8 weeks in a university rehabilitation laboratory. Results The combined intervention was feasible and perceived as acceptable and beneficial. Participants improved their upper limb motor function on the ARAT (subacute participant = 4 points; chronic participant = 2 points) and WMFT (subacute participant = 5 points; chronic participant = 3 points). Participants improved their aerobic fitness (subacute participant = +4.66 ml O2 /kg/min; chronic participant = +7.34 ml O2 /kg/min) and 6-minute walking distance (subacute participant = +50 m; chronic participant = +37 m). Discussion Combining aerobic exercise with task-specific training may be a worthwhile therapeutic approach to improve upper limb motor function suitable for persons in the subacute or chronic phase after stroke. PMID- 29436127 TI - Reply to Anju Bhalotra regarding the comment "Breathing circuit compliance and displayed tidal volume during pressure-controlled ventilation of infants". PMID- 29436128 TI - Breathing circuit compliance and displayed tidal volume during pressure controlled ventilation of infants. PMID- 29436129 TI - Ultrasound-guided blind nasal intubation in a patient with massive oral tumor. PMID- 29436130 TI - Reply to comments on 'The association between caudal anesthesia and increased risk of postoperative surgical complications in boys undergoing hypospadias repair'. PMID- 29436131 TI - Understanding primary outcomes, sample size calculation, and the perils of online calculators. PMID- 29436132 TI - The use of dipyrone (metamizol) as an analgesic in children: what is the evidence? A review. PMID- 29436133 TI - Reply to Clark, Natasha; Morris, Stephen; Sargant, Nicholas, regarding their comment "Comment on Case Report 'Anaphylactic reaction to tranexamic acid in an adolescent undergoing posterior spinal fusion' by Chiem J, Ivanova I, Jimenez N et al. Paediatric Anaesthesia 2017;27: 774-775." PMID- 29436134 TI - Using cuffed tracheal tubes below recommended body weight: Compromising safety or exploring limits safely? PMID- 29436135 TI - News from the pediatric anesthesia societies: SARNePI-SICP Guidelines for Pediatric Day Surgery. PMID- 29436136 TI - The use of flow-volume loops and an electronic continuous cuff pressure controller to ensure cuff inflation with the minimum occluding pressure for Microcuff endotracheal tubes. PMID- 29436137 TI - Caudal and intravenous dexamethasone as an adjuvant to pediatric caudal block: A systematic review and meta-analysis. AB - BACKGROUND: Dexamethasone has become a popular additive for regional anesthesia. The aim of this meta-analysis was to assess the effectiveness of this additive on the duration of postoperative analgesia, postoperative vomiting, and possible adverse events in pediatrics. METHODS: We searched databases, conference records, and registered trials for randomized controlled trials. The databases included the Cochrane Library, JBI Database of Systematic Reviews, PubMed, ISI Web of Knowledge, Science-Direct, and Embase. Odds ratio, weighted mean difference, and the corresponding 95% confidence intervals were calculated using the REVMAN software, version 5.3, for data synthesis and statistical analysis, which following the PRISMA statement. The main outcomes were duration of postoperative analgesia (time from the end of surgery to first administration of analgesics as evidenced by a pain score) and postoperative vomiting. RESULTS: Seven studies were selected for this meta-analysis, involving 647 pediatric patients. All the patients were randomized to receive caudal or intravenous dexamethasone with caudal block (experimental group) or plain caudal block (control group). There was significantly longer duration of postoperative analgesia in the experimental group compared with control group (weighted mean difference: 238.40 minutes; 95% CI: 193.41-283.40; P < .00001). The experimental group had fewer patients who needed analgesics after surgery (odds ratio: 0.18 minutes; 95% CI: 0.05-0.66; P = .009). Additionally, the number of subjects who remained pain-free to 2, 6, 24, and 48 hours after operation was significantly greater in the experimental group than control group. Side effects in these 2 groups were comparable (odds ratio: 0.94; 95% CI: 0.34-2.56; P = .90). The incidence of postoperative vomiting was significantly decreased in the experimental group compared with control group (odds ratio: 0.29; 95% CI: 0.13-0.63; P = .002). CONCLUSION: Caudal and intravenous dexamethasone could provide longer duration of postoperative analgesia and reduced the incidence of postoperative vomiting with comparable adverse effects than plain caudal block. However, any additive to the caudal space carries with it the potential for neurotoxicity and that caution should always be exercised when weighting the risks and benefits of any additive. The result was influenced by small numbers of participants and significant heterogeneity. PMID- 29436138 TI - The incidence of postoperative respiratory complications: A retrospective analysis of cuffed vs uncuffed tracheal tubes in children 0-7 years of age. AB - BACKGROUND: The use of cuffed vs uncuffed endotracheal tubes in pediatric anesthesia is widely debated. This study aimed to investigate whether the use of cuffed vs uncuffed tubes is associated with an increased incidence of acute postoperative respiratory complications. METHODS: We retrospectively studied all children aged 0-7 years in which the trachea was intubated between September 28, 2006 and August 26, 2016 in a pediatric university hospital. Logistic regression analysis was performed to estimate the association between tube design (cuffed vs uncuffed) and the incidence of acute postoperative respiratory complications (stridor, wheezing, or dyspnea; desaturations <=90%) in need of intervention (epinephrine, dexamethasone, nebulizers, supplementary oxygen, or reintubation), adjusting for potential confounders. RESULTS: In 5247 of 6796 cases (77%), a cuffed tube was used. Acute postoperative respiratory complications in need of intervention occurred in 334 cases (4.9%) and were less common after cuffed than after uncuffed tubes (N = 236, 4.5% vs N = 98, 6.3%, respectively, odds ratio 0.70; 95%CI 0.55-0.89). Desaturation occurred less often after cuffed tubes (cuffed: N = 1365, 26.0%; uncuffed: N = 512, 33.1%; OR: 0.71 (0.61-0.84)). After adjusting for confounders, there was no difference in acute postoperative respiratory complications between cuffed tubes and uncuffed tubes (OR 0.74; 95%CI 0.55-1.01). Subgroup analyses in various age groups did not show significant differences between the use of cuffed or uncuffed tubes. CONCLUSION: After adjustment for multiple confounders, the use of cuffed tubes was not associated with an increased incidence of acute respiratory complications in postanesthesia care unit. PMID- 29436140 TI - In this issue: March 2018. PMID- 29436139 TI - Incidence and factors contributing to postdischarge nausea and vomiting in pediatric ambulatory surgical cases. AB - BACKGROUND: Little is known regarding the incidence and contributing factors of postdischarge nausea and vomiting in children. AIMS: The aim of this study was to determine the incidence of postdischarge nausea and vomiting in day surgery patients and to identify demographic, intraoperative, and postoperative variables that influence the risk. METHODS: In this prospective observational study, a postdischarge questionnaire was administered to parents of ambulatory patients who received anesthesia and the electronic records were reviewed. RESULTS: Of 1041 ambulatory patients who received general anesthesia, 143 (14%) experienced postdischarge nausea and vomiting. Patients who did not receive intraoperative opioids had a lower incidence (8%) than those who received short-acting opioids (14%) (difference of 6%, 95% CI 1.9%-10.2%, P < .001) or long-acting opioids (24%) (difference of 16%, 95% CI 8.1%-24.3%, P < .001). Patients who received short-acting opioids also had a lower incidence than those who received long acting opioids (difference of 10%, 95% CI 2.2%-18.1%, P < .001). The incidence also differed between those patients who received postdischarge opioids at home (29%) and those who did not (13%) (difference of 16%, 95% CI 7.5%-27.6%, P < .001). There was no association with age, gender, airway management, nitrous oxide use, amount of intravenous fluids, duration of anesthesia, intraoperative antiemetic administration or dosage, length of time from recovery room discharge to first oral intake, or length of ride home from the hospital. Multivariate generalized linear regression analysis confirmed intraoperative (short-acting opioids odds ratio 1.686, 95% CI 1.020-2.787; long-acting opioids odds ratio 3.093, 95% CI 1.634-5.874) and postdischarge (odds ratio 2.037 95% CI 1.142 3.632) opioids to be independent risk factors for postdischarge nausea and vomiting. CONCLUSION: We found an incidence of postdischarge nausea and vomiting of 14%. Intraoperative and postdischarge opioids increase the risk, with long acting intraoperative opioids further accentuating the risk. PMID- 29436141 TI - Reply to Ziesenitz, Victoria; Erb Thomas; Trachsel, Daniel; van den Anker Johannes, regarding their comment "Safety of dipryone (metamizole) in children what's the risk of agranulocytosis?" PMID- 29436142 TI - The effect of arabinoxylooligosaccharides on upper gastroduodenal motility and hunger ratings in humans. AB - BACKGROUND AND AIMS: Prebiotics such as Arabinoxylooligosaccharides (AXOS) are non-digestible, fermentable food ingredients stimulating growth/activity of colonic bacteria with enhanced carbohydrates fermentation (CF) in humans. The migrating motor complex (MMC) of the gastrointestinal tract has been recently identified as an important hunger signal, but no data are available yet on the role of acute CF on MMC activity and related hunger ratings. Thus, we aimed to study the effect of acute AXOS CF on MMC and hunger in humans. METHODS: A total of 13 healthy volunteers were randomized in a single-blind crossover placebo controlled study where 9.4 g of AXOS or 10 g of maltodextrin and 1 g of unlabelled lactose ureide (LU) were given 12 hours prior to the study and, in the next morning, together with a pancake containing 500 mg of 13 C-LU. In 10 hours after the meal, 13 CO2 and hydrogen excretion were determined every 15 minutes while hunger/appetite ratings every 2 minutes through a VAS questionnaire. Five hours after the meal, antroduodenal motility was measured using HRM. KEY RESULTS: AXOS significantly increased CF (158 +/- 81 vs 840 +/- 464 H2 ppm*minute, placebo vs AXOS, P < .05) without affecting the orocecal transit time (OCTT). AXOS had no significant effect on the occurrence, origin, and duration of phase III and on the total number, origin, and duration of phases I and II. Hunger and appetite scores prior and after phase III were not affected by AXOS. CONCLUSIONS: AXOS acutely increases colonic fermentation, but this neither affects OCTT, activity of the MMC, nor interdigestive hunger scores in man. PMID- 29436143 TI - Infertility treatment strategy involving combined freeze-all embryos and single vitrified-warmed embryo transfer during hormonal replacement cycle for in vitro fertilization of women with hypogonadotropic hypogonadism. AB - AIM: Hypogonadotropic hypogonadism (HH) is a condition caused by the deficient secretion of pituitary gonadotropins, leading to diminished ovarian function. Several studies of in vitro fertilization (IVF) in women with HH revealed acceptable clinical pregnancy outcomes but high multiple pregnancy rates after multiple fresh embryo transfer (ET). The purpose of this study was to analyze the outcomes of combined freeze-all embryos and single vitrified-warmed ET in women with HH. METHODS: Of 91 infertile women with HH (basal luteinizing hormone and follicle-stimulating hormone levels <2.0 mIU/mL), we excluded patients aged >=40 years (n = 2) and women who preferred fresh ET (n = 10). Seventy-nine women underwent 117 oocyte retrieval cycles and 135 vitrified-warmed ET during hormone replacement (HR) cycles from 2008 to 2014 at the Kato Ladies Clinic and Juntendo University Hospital. RESULTS: In 26 single cleavage ET cycles, the rates of clinical pregnancy and live birth were 34.6% (9/26 ET) and 26.9% (7/26 ET), respectively. Regarding the outcomes after single vitrified-warmed blastocyst transfer, clinical pregnancy and live birth rates were 65.1% (71/109 ET) and 50.5% (55/109 ET), respectively. Multiple conceptions and ovarian hyperstimulation syndrome did not occur in any of the women with HH. CONCLUSION: Our results demonstrated that IVF followed by single vitrified-warmed ET in adjusted endocrine milieu during the HR cycle is an effective fertility treatment for women with HH and decreases the incidence of complications, including multiple conceptions. PMID- 29436144 TI - Phase 1-3 of the cross-cultural development of an EORTC questionnaire for the assessment of sexual health in cancer patients: the EORTC SHQ-22. AB - To develop and pretest an European Organization for the Research and Treatment of Cancer Sexual Health Questionnaire (EORTC SHQ-22) for the assessment of physical, psychological, and social aspects of sexual health (SH) in male and female cancer patients and survivors. Questionnaire construction started with creating a list of relevant SH issues based on a comprehensive literature review. Issues were subsequently evaluated for relevance and prioritization by 78 healthcare professionals (HCP) and 107 patients from 12 countries during in-depth interviews (phase 1). Extracted issues were operationalized into items (phase 2). Phase 3 focused on pretesting the preliminary questionnaire in a cross-cultural patient sample (n = 171) using debriefing interviews. Psychometric properties were preliminary determined using a principal component analysis and Cronbach's alpha. We derived 53 relevant SH issues from the literature. Based on HCP and patient interviews, 22 of these 53 issues were selected and operationalized into items. Testing the preliminary 22-item short questionnaire resulted in a change of wording in five items and two communication-related items; no items were removed. Preliminary psychometric analysis revealed a two-factor solution and 11 single items; both scales showed good reliability indicated by a Cronbach's alpha of 0.87 (sexual satisfaction) and 0.82 (sexual pain). Cross-cultural pretesting of the preliminary EORTC SH questionnaire has indicated excellent applicability, patient acceptance, and comprehensiveness as well as good psychometric properties. The final development phase, that is psychometric validation (phase four) including large-scale, cross-cultural field testing of the EORTC SHQ-22, has commenced. PMID- 29436145 TI - Accumulated Spinal Axial Biomechanical Loading Induces Degeneration in Intervertebral Disc of Mice Lumbar Spine. AB - OBJECTIVE: To investigate the effect of accumulated spinal axial biomechanical loading on mice lumbar disc and the feasibility of applying this method to establish a mice intervertebral disc degeneration model using a custom-made hot plate cage. In previous studies, we observed that the motion pattern of mice was greatly similar to that of humans when they were standing and jumping on their lower limbs. There is little data to demonstrate whether or not accumulated spinal axial biomechanical loading could induce intervertebral disc degeneration in vivo. METHODS: Twenty-four 0-week-old mice were randomly divided into model 1 month and 3-month groups, and control 1-month and 3-month groups (n = 6 per group). The model groups was transferred into the custom-made hot plate cage three times per day for modeling. The control group was kept in a regular cage. The intervertebral disc samples of the L3 -L5 were harvested for histologic, molecular, and immunohistochemical studies after modeling for 1 and 3 months. RESULTS: Accumulated spinal axial biomechanical loading affects the histologic, molecular, and immunohistochemical changes of mice L3- L5 intervertebral discs. Decreased height of disc and endplate, fissures of annulus fibrosus, and ossification of cartilage endplate were found in morphological studies. Immunohistochemical studies of the protein level showed a similar expression of type II collagen at 1 month, but a slightly decreased expression at 3 months, and an increased expression level of type X collagen and matrix metalloproteinase 13 (MMP13). Molecular studies showed that ColIIa1 and aggrecan mRNA expression levels were slightly increased at 1 month (P > 0.05), but then decreased slightly (P > 0.05). ColXa1, ADAMTS-5, and MMP-13 expression levels werer increased both at 1 and 3 months (P < 0.05). In addition, increased expression of Runx2 was observed. CONCLUSION: Accumulated spinal axial loading provided by a custom-made hot plate accelerated mice lumbar disc and especially endplate degeneration. However, this method requires further development to establish a lumbar disc degeneration model. PMID- 29436147 TI - Accuracy of alcohol and breast cancer risk information on Drinkaware's website. AB - A recent paper in Drug and Alcohol Review analysed the information on cancer disseminated by 27 alcohol industry funded organisations. The independent UK alcohol education charity Drinkaware was among the organisations whose information was studied, and based on the analysis claims were made of misrepresentation of evidence about the alcohol-related risk of cancer and alcohol industry influence. This commentary challenges the validity of these findings in respect to the evidence relating to the Drinkaware information, as the analysis is found to be misrepresenting the information by both disregarding the wider information content provided and the order and prominence with which alcohol-related cancer risk is presented. Furthermore, it is argued that the public has a right to be provided with relevant evidence-based information about cancer risk. It is critical that Drinkaware's important public health function is not compromised by unjustified allegations of inaccuracy and by unwarranted attacks on its independence and integrity. PMID- 29436148 TI - High-Efficiency and UV-Stable Planar Perovskite Solar Cells Using a Low Temperature, Solution-Processed Electron-Transport Layer. AB - Efficient metal-halide perovskite solar cells (PSCs) with a regular structure typically use high-temperature-processed TiO2 electron-transport layers (ETLs), which suffer from high electron recombination and inherent UV instability. Herein, we present low-temperature solution-processed lithium bis(trifluoromethanesulfonyl)imide (Li-TFSI)-doped C60 (Li-C60 ) ETLs for high efficiency and UV-stable planar PSCs with an n-i-p architecture. We found that simple Li-TFSI doping ensured a better energy match between the active layer and the cathode, considerably enhanced the electron mobility of the ETL, and even improved CH3 NH3 PbI3 crystallization finally to increase the power conversion efficiency (PCE) from 15.3 to 17.8 % with a minor hysteresis effect. Moreover, it was demonstrated that replacing TiO2 with Li-C60 resulted in PSCs that were much more stable under UV light under an air atmosphere with almost no degradation after 3000 h under a nitrogen atmosphere. PMID- 29436146 TI - Natural history and genotype-phenotype correlations in 72 individuals with SATB2 associated syndrome. AB - SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance. PMID- 29436149 TI - Arctic moistening provides negative feedbacks to riparian plants. AB - Arctic moistening will affect the circumpolar forested riparian ecosystems. Upward trends observed for precipitation in high latitudes illustrate that the moistening may be underway to influence the woody biomass production near the inland waters, lakes and streams with effects on carbon pools and fluxes. Although the flooding and waterlogging tolerance of seedlings has been investigated, our understanding of responses in mature trees is still limited. Here we employ tree-ring delta13 C and width data from a subarctic riparian setting in Lapland, where artificially high lake level (HLL) has already altered the ecophysiological and growth responses of riparian Pinus sylvestris trees to external drivers under conditions simulating moister environment. Prior to the HLL event, the carbon assimilation rate was primarily limited by irradiance as reflected in the delta13 C data and the radial growth of south-facing riparian trees remained increased in comparison to shaded upland trees. By contrast, the riparian trees were not similarly benefited during the HLL period when reduced assimilation depleted the riparian in comparison to upland delta13 C despite of increased irradiance. As a result, the radial growth of riparian trees was markedly reduced over the HLL event while the upland trees benefited from increased irradiance and summer time warming. Although the production of biomass at high latitudes is commonly considered temperature-limited, our results highlight the increasing role of Arctic moistening to limit the growth when increased precipitation (cloudiness) reduces the incoming solar radiation in general and when the riparian habitat becomes increasingly waterlogged in particular. The effects of high-latitude warming to induce higher biomass productivity may be restricted by negative feedbacks. PMID- 29436151 TI - Antihypertensive medication withholding practices in hemodialysis: A survey study of patients and providers. PMID- 29436150 TI - Broad-Spectrum Neutralization of Pore-Forming Toxins with Human Erythrocyte Membrane-Coated Nanosponges. AB - Neutralization of bacterial toxins has become a compelling approach to treating bacterial infections as it may pose less selective pressure for the development of bacterial resistance. Currently, the majority of toxin neutralization platforms act by targeting the molecular structure of the toxin, which requires toxin identification and customized design for different diseases. Therefore, their development has been challenged by the enormous number and complexity of bacterial toxins. Herein, biomimetic toxin nanosponges are formulated by coating membranes of human red blood cells (hRBCs) onto polymeric nanoparticles, which act as a toxin decoy to absorb and neutralize a broad-spectrum of hemolytic toxins regardless of their molecular structure. When tested with model pore forming toxins, including melittin, alpha-hemolysin of methicillin-resistant Staphylococcus aureus, listeriolysin O of Listeria monocytogenes, and streptolysin O of Group A Streptococcus, the hRBC nanosponges are able to completely inhibit toxin-induced hemolysis in a concentration-dependent manner. In addition, the nanosponge-detained toxins show no cytotoxicity when tested on human umbilical vein endothelial cells and no lethality when injected into mice, which together indicate effective toxin neutralization. Overall, these results demonstrate the broad applicability and high effectiveness of the hRBC nanosponges as a novel antivirulence platform against hemolytic toxins from various strains of bacteria. PMID- 29436152 TI - Immersion-enhanced fluid redistribution can prevent intradialytic hypotension: A prospective, randomized, crossover clinical trial. AB - INTRODUCTION: Intradialytic hypotension (IDH) is an important cause of morbidity and mortality among hemodialysis patients. We used an immersion model to evaluate the role of reduced effective circulating volume, and to examine whether facilitated refilling can prevent IDH. METHODS: Ten male hemodialysis patients who had frequent episodes of IDH were randomized to a mid-week "wet" or "dry" hemodialysis session, and subsequently underwent the other session in a crossover manner. The wet sessions were performed while immersed up to the neck in a 34 to 35 degrees C bath, and the dry session was standard hemodialysis. Ultrafiltration goals were determined as the mean ultrafiltration during the 10 sessions preceding the first study session +/- 10%. FINDINGS: Mean ultrafiltration was similar for the wet and dry sessions (2.99 +/- 0.64 kg vs. 2.96 +/- 0.74 kg). Symptomatic hypotension did not develop in any of the patients during the wet session, compared to 4 (40%) during the dry session. Systolic blood pressure adjusted to ultrafiltration was stable during the wet session, 0.22 mmHg/15 min (95% CI -0.27 to 0.70), P = 0.38, and significantly decreased during the dry session, -0.68 mmHg/15 min (95%CI -1.24 to -0.11), P = 0.02. Diastolic blood pressure did not change during the sessions. Mean atrial natriuretic peptide significantly increased in the wet session, by 31.36 pgr/mL (95%CI 8.73-53.99), P = 0.007, and slightly and insignificantly decreased in the dry session, by 21.66 pgr/mL (95% CI -52.59 to 9.25), P = 0.167. Aldosterone blood levels did not change. DISCUSSION: Reduced effective circulating volume is a major cause for IDH, which can be prevented using head-out water immersion facilitated redistribution. PMID- 29436153 TI - Advanced imaging technology applications in cytology. AB - Novel techniques have been developed to image cells at cellular and subcellular levels. They allow images to be analyzed with ultra-high resolution, in 2D and/or 3D. Several of these tools have been tested on cytology specimens demonstrating emerging applications that are likely to change the field of cytopathology. This review covers several of these advanced imaging methods. The use of optical coherence tomography to perform optical biopsies during endoscopic ultrasound procedures or visualize cells within effusion samples is discussed. The potential for quantitative phase microscopy to accurately screen Pap test slides or resolve indeterminate diagnoses in urine cytology is reviewed. The article also examines the application of 3D cytology using LuCED for lung cancer detection in sputum samples and the feasibility of imaging flow and mass cytometry to measure multiple biomarkers at the single cell level. Although these novel technologies have great potential, further research is necessary to validate their routine use in cytopathology practice. PMID- 29436154 TI - New methodology for automated SPOT synthesis of peptides on cellulose using 1,3,5 triazine derivatives as linkers and as coupling reagents. AB - Two new rigid bi-aromatic linkers for synthesis of peptide arrays by SPOT methodology were obtained from cellulose treated with 2,4-dichloro-6-methoxy 1,3,5-triazine. Reaction with m-phenylenediamine gave non-cleavable TYPE I linker which enabled attachment of the peptides via resistant to harsh reaction conditions amide, ether, and amine bonds. Reaction with 3-Fmoc-aminobenzoic acid followed by thermal isomerization of the intermediate "superactive" ester producing an amide-like bond gave TYPE II linker that was very stable during peptide synthesis. However, the peptide was cleavable, with fragment of the linker, in the presence of 1 M LiOH solution. The uniform loading of the cellulose and efficient synthesis of the peptide array was achieved by using N (4,6-dimethoxy-1,3,5-triazin-1-yl)-N-methylmorpholinium 4-toluenesulfonate as the coupling reagent. PMID- 29436155 TI - Design of cyclic and d-amino acids containing peptidomimetics for inhibition of protein-protein interactions of HER2-HER3. AB - HER2 receptors are surface proteins belonging to the epidermal growth factor family of receptors. Their numbers are elevated in breast, lung, and ovarian cancers. HER2-positive cancers are aggressive, have higher mortality rate, and have a poor prognosis. We have designed peptidomimetics that bind to HER2 and block the HER2-mediated dimerization of epidermal growth factor family of receptors. Among these, a symmetrical cyclic peptidomimetic (compound 18) exhibited antiproliferative activity in HER2-overexpressing lung cancer cell lines with IC50 values in the nanomolar concentration range. To improve the stability of the peptidomimetic, d-amino acids were introduced into the peptidomimetic, and several analogs of compound 18 were designed. Among the analogs of compound 18, compound 32, a cyclic, d-amino acid-containing peptidomimetic, was found to have an IC50 value in the nanomolar range in HER2 overexpressing cancer cell lines. The antiproliferative activity of compound 32 was also measured by using a 3D cell culture model that mimics the in vivo conditions. The binding of compound 32 to the HER2 protein was studied by surface plasmon resonance. In vitro stability studies indicated that compound 32 was stable in serum for 48 hours and intact peptide was detectable in vivo for 12 hours. Results from our studies indicated that 1 of the d-amino acid analogs of 18, compound 32, binds to the HER2 extracellular domain, inhibiting the phosphorylation of kinase of HER2. PMID- 29436156 TI - Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People. AB - Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites. Only the CYP2D6 variation was significantly associated with concentrations of endoxifen (P = 0.0008) and 4 hydroxytamoxifen (P = 0.0074), tamoxifen's principal active metabolites, as well as key metabolic ratios. The CYP2D6 was also the most significant predictor of active metabolites and metabolic ratios in a multivariate regression model, including all four genes as predictors, with minor roles for other CYP genes. In AIAN populations, CYP2D6 is the largest contributor to tamoxifen bioactivation, illustrating the importance of validating pharmacogenetic testing for therapy optimization in an understudied population. PMID- 29436158 TI - Spinal Cord Stimulator Electrode Dislodging into the Ligamentum Flavum: A Case Report. AB - To date, no case studies specifically reporting an electrode dislodging from its lead wire have been reported. Here we describe a case involving an electrode shearing from the spinal cord stimulator lead, and lodging into the ligamentum flavum during implantation. In this case, an experienced board certified interventional pain management specialist was performing the implantation procedure of a magnetic resonance imaging (MRI) compatible spinal cord stimulator with MR conditional leads. After successful placement of the first lead, the epidural space was accessed via a T11/12 interlaminar approach using loss of resistance technique. When the lead would not advance past the tip of the needle, it was removed in order to reposition the needle slightly. Upon removal of the lead, it was discovered that the first electrode was no longer attached to the wire. Subsequent fluoroscopic imaging revealed that the electrode had lodged within the ligamentum flavum. Upon discussion with the medical director of the device company, it was agreed upon that the electrode should be left in place. The decision was made to proceed with only one lead in place and the remainder of the procedure was completed uneventfully. The patient followed up two weeks later in clinic, and no adverse effect related to the dislodged electrode was reported. The indications and common complications associated with spinal cord stimulation are discussed, followed by factors to consider to help guide decision making in the event of a retained foreign body during a procedure. PMID- 29436159 TI - Thermally Rearranged Polymer Membranes Containing Troger's Base Units Have Exceptional Performance for Air Separations. AB - The influence of segmental chain motion on the gas separation performance of thermally rearranged (TR) polymer membranes is established for TR polybenzoxazoles featuring Troger's base (TB) monomer subunits as exceptionally rigid sites of contortion along the polymer backbone. These polymers are accessed from solution-processable ortho-acetate functionalized polyimides, which are readily synthesized as high-molecular-weight polymers for membrane casting. We find that thermal rearrangement leads to a small increase in d-spacing between polymer chains and a dramatic pore-network reconfiguration that increases both membrane permeability and O2 /N2 selectivity, putting its performance above the 2015 upper bound. PMID- 29436160 TI - Patterns and predictors of exhaustion episodes in patients with stable COPD: A longitudinal study. AB - BACKGROUND AND OBJECTIVE: Exhaustion is the perception of low energy. Little is known about how exhaustion persists, remits or reappears over time in patients with chronic obstructive pulmonary disease (COPD) or how to predict these events. We determined the likelihood of transitions between states of exhaustion and no exhaustion among patients with stable COPD followed up for 2 years. We investigated combinations of potential factors for their abilities to predict new onset exhaustion episodes. METHODS: We prospectively included 137 patients with stable COPD (mean age, 66.9 years +/- 8.3). Exhaustion states were measured at baseline and 1 and 2 years later. Exhaustion was defined as an answer of "most of the time" or "a moderate amount of time" to 1 of 2 questions: "How often have you found it hard to get going?" and "How often does everything seem to require effort?" We evaluated demographic, non-respiratory and respiratory variables as potential predictors. The likelihoods of new episodes and recovery were calculated. Predictors were evaluated with generalised estimating equations. RESULTS: At baseline, 27 patients (19.7%) displayed exhaustion. Of the 110 patients without exhaustion at baseline, 17 (15.5%) displayed exhaustion at least once during the follow-up period. During the study period, a total of 204 annual transitions displaying no exhaustion at the beginning were identified. Of them, 10.3% transitioned to exhaustion in the next year. The likelihood of recovery after exhaustion was 50%. Independent predictors of new-onset exhaustion episodes within the following year were: the COPD assessment test score (odds ratio [OR] = 1.10; 95% confidence interval [CI] 1.01-1.21), depression (OR = 6.89; 95% CI: 1.00-47.41) and female gender (OR = 6.88; 95% CI: 1.83-25.73). CONCLUSIONS: Patients in stable COPD with high CAT scores and depression were most likely to experience new-onset exhaustion episodes Thus, exhaustion might be predicted by a combination of psychological factors and respiratory health status. Nevertheless, exhaustion is dynamic in COPD; half of patients recover from exhaustion. PMID- 29436157 TI - Precision engineering of targeted nanocarriers. AB - Since their introduction in 1980, the number of advanced targeted nanocarrier systems has grown considerably. Nanocarriers capable of targeting single receptors, multiple receptors, or multiple epitopes have all been used to enhance delivery efficiency and selectivity. Despite tremendous progress, preclinical studies and clinically translatable nanotechnology remain disconnected. The disconnect in targeting efficacy may stem from poorly-understood factors such as receptor clustering, spatial control of targeting ligands, ligand mobility, and ligand architecture. Further, the relationship between receptor distribution and ligand architecture remains elusive. Traditionally, targeted nanocarriers were engineered assuming a "static" target. However, it is becoming increasingly clear that receptor expression patterns change in response to external stimuli and disease progression. Here, we discuss how cutting-edge technologies will enable a better characterization of the spatiotemporal distribution of membrane receptors and their clustering. We further describe how this will enable the design of new nanocarriers that selectively target the site of disease. Ultimately, we explore how the precision engineering of targeted nanocarriers that adapt to receptor dynamics will have the potential to drive nanotechnology to the forefront of therapy and make targeted nanomedicine a clinical reality. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Biology-Inspired Nanomaterials > Lipid-Based Structures Biology-Inspired Nanomaterials > Protein and Virus-Based Structures. PMID- 29436161 TI - Cumulative effects of multiple pain sites in youth with chronic pain. AB - BACKGROUND: The experience of persistent pain in multiple locations is common in youth. Based on current literature, youth with multiple pain sites (MPS) are at risk of experiencing poorer emotional outcomes and a spread of symptoms into late adolescence and adulthood. Little is known regarding the association between MPS with physical and school functioning domains, particularly after initiation of multidisciplinary pain treatment. Therefore, the objective of this study was to examine the association of MPS with disability and school functioning among youth with chronic pain. METHODS: A total of 195 patients with chronic pain, aged 8-17, and their parents completed measures assessing patient distress and functioning at a multidisciplinary pain clinic evaluation and at 4-month follow-up. RESULTS: At evaluation, 63% of patients presented with MPS; 25% reporting MPS endorsed pain in five or more locations. When controlling for relevant demographic and emotional distress factors, MPS were associated with lower school functioning at evaluation with a persistent trend at follow-up. Although MPS were not a significant predictor of pain-related disability at evaluation, it emerged as significant at follow-up. CONCLUSIONS: Potentially due to the MPS load and the inverse effects that such a pain state has on function, such patients may be at risk for poorer health and school-related outcomes. The mechanisms influencing these relationships appear to extend beyond psychological/emotional factors and warrant further investigation in order to aid in our understanding of youth with MPS. SIGNIFICANCE: Youth with MPS may be at risk for experiencing poorer physical and school functioning in comparison with single-site peers, despite treatment initiation. Further research is warranted to inform assessment and treatment approaches for this subgroup of patients. PMID- 29436162 TI - Therapeutic alliance in dietetic practice for weight loss: Insights from health coaching. AB - AIM: The psychological construct of 'therapeutic alliance' can be used to better understand the effectiveness of consultations, particularly goal setting for weight management. We analysed audio-recorded health coaching sessions during a weight loss trial to explore relationships between therapeutic alliance and various contextual factors. METHODS: Audio recordings of 50 health coaching sessions were analysed. After assessing fidelity to the protocol, therapeutic alliance was measured using an adapted Working Alliance Inventory Observer-rated Short Version (WAI-O-S), and examined by (i) identifying relationships between contextual factors and WAI-O-S scores (Spearman's coefficients); (ii) testing the impact of preparatory exercises and body mass index on WAI-O-S scores (one-way analysis of variance and least-squared differences tests) and (iii) comparing differences in WAI-O-S scores based on relationship status, gender and follow-up session completion (independent samples t-tests). RESULTS: Fidelity was high (mean 88%). WAI-O-S total scores ranged from 55 to 70 (out of 84). Session duration was significantly correlated with WAI-O-S component of 'Bond' (r = 0.42, P = 0.002). Those who completed preparatory exercises had significantly higher total WAI-O-S scores, 'Goal' and 'Task' scores. Participants who completed the follow-up session scored significantly higher for 'Goal' compared to no follow up. CONCLUSIONS: Spending more time in a session appears related to increased bonding, a key component of therapeutic alliance. Preparatory work may help build therapeutic alliance and agreement on goals appears to influence follow-up completion. These exploratory findings provide directions for research addressing the professional relationship in dietetic consultations for weight loss. PMID- 29436163 TI - Using gEUD based plan analysis method to evaluate proton vs. photon plans for lung cancer radiation therapy. AB - The goal of this study was to exam the efficacy of current DVH based clinical guidelines draw from photon experience for lung cancer radiation therapy on proton therapy. Comparison proton plans and IMRT plans were generated for 10 lung patients treated in our proton facility. A gEUD based plan evaluation method was developed for plan evaluation. This evaluation method used normal lung gEUD(a) curve in which the model parameter "a" was sampled from the literature reported value. For all patients, the proton plans delivered lower normal lung V5 Gy with similar V20 Gy and similar target coverage. Based on current clinical guidelines, proton plans were ranked superior to IMRT plans for all 10 patients. However, the proton and IMRT normal lung gEUD(a) curves crossed for 8 patients within the tested range of "a", which means there was a possibility that proton plan would be worse than IMRT plan for lung sparing. A concept of deficiency index (DI) was introduced to quantify the probability of proton plans doing worse than IMRT plans. By applying threshold on DI, four patients' proton plan was ranked inferior to the IMRT plan. Meanwhile if a threshold to the location of curve crossing was applied, 6 patients' proton plan was ranked inferior to the IMRT plan. The contradictory ranking results between the current clinical guidelines and the gEUD(a) curve analysis demonstrated there is potential pitfalls by applying photon experience directly to the proton world. A comprehensive plan evaluation based on radio-biological models should be carried out to decide if a lung patient would really be benefit from proton therapy. PMID- 29436164 TI - Investigation of estimated glomerular filtration rate and its perioperative change in patients with upper urinary tract urothelial carcinoma: A multi institutional retrospective study. AB - AIM: To investigate the association of perioperative estimated glomerular filtration rate (eGFR) with prognosis in patients with upper urinary tract urothoelial caicinoma (UTUC). METHODS: A total of 433 patients underwent radical nephroureterectomy with excision of the bladder cuff (RNU) at six hospitals affiliated with Kitasato University in Japan. Patients were divided into three groups each in terms of preoperative eGFR: normal eGFR (>60 mL/min/1.73 m2 ; n = 172), moderately reduced eGFR (45-60 mL/min/1.73 m2 ; n = 147) and severely reduced eGFR (<45 mL/min/1.73 m2 ; n = 114), and with regard to changes between pre- and postoperative eGFR: normal change (increased or <10% decreased; n = 132), moderate change (10%-30% decreased; n = 172) and severe change (>30% decreased; n = 129). Statistical analyses were performed to investigate the association between perioperative eGFR and prognosis. RESULTS: Patients in the preoperative normal and moderately reduced eGFR group had significantly better progression-free survival (PFS) and cancer-specific survival (CSS) than those in the severely reduced eGFR group (both; P < 0.001). With regard to changes in postoperative eGFR, PFS and CSS were significantly better in patients in the severe and moderate change group than in those in the normal change group (both; P < 0.001). When adjusted for the effects of clinicopathological features, pathologic factors were associated with both PFS and CSS, but perioperative eGFR were not independent prognostic factors. CONCLUSIONS: Patients with preoperative normal and moderately reduced eGFR and those with severe and moderate change in postoperative eGFR appeared to have a significantly better prognosis. PMID- 29436165 TI - Digital rectal examination in Indian graduates. AB - BACKGROUND: Digital rectal examination (DRE) is an important component of physical examination and an essential skill for medical graduates. DRE is often underutilised in clinical practice. The lack of confidence and expertise and also underutilization of DRE have been associated with inadequate training of medical students during their undergraduate studies. The training of Indian undergraduates in DRE has not been studied. METHODS: A questionnaire on undergraduate training in DRE was administered to students from various medical colleges joining specialty postgraduate courses in Jawaharlal Institute of Postgraduate Medical Education and Research. RESULTS: A total of 101 out of 131 students participated in the survey. Ninety-one percent of students were taught DRE as undergraduates but only three-quarters had performed DRE on patients. Among the respondents who had performed DRE, two-thirds had performed fewer than five DREs before the completion of their medical education. Respondents who had performed fewer DREs were less confident about performing DRE (p < 0.05). Only 8% had performed DRE with manikins. Patients declining DRE and the need to minimise DRE influenced the decisions to perform DRE during training. DRE was never taught in paediatrics. DREs were most often performed only in the final year of the Bachelor of Medicine and Bachelor of Surgery (MBBS) degree, and mostly without supervision (49.3%); 61.4% were unsatisfied with their training in DRE and would like to be trained better. A lack of confidence, expertise and use of DRE are associated with inadequate training of medical students CONCLUSION: The survey indicates a lack of importance given to DRE training of undergraduate students and huge gaps in imparting this clinical skill. Training may be improved by introducing manikins, changing attitudes to DRE by incorporating it in clinical problem solving, and with more frequent opportunities to practise under supervision. PMID- 29436166 TI - NeuroSpine Surgery Research Group (NSURG) Classification System for Grading Lumbar Synovial Cysts. AB - To classify facet joint cysts (FJC) which will assist in identification of patient groups to best fit with a particular intervention. Sagittal T2 -weighted magnetic resonance images (MRI) of these patients are used to measure cyst size, while axial T2 -weighted MRI are used to determine the percentage of the vertebral canal occupied by the cyst. The degree of spondylolisthesis is also measured through standing X-rays or sagittal MRI. The proposed grading system is as follows. Grade I includes cysts that occupy less than 25% of the canal diameter that usually present with unilateral radiculopathy. Grade II includes cysts that occupy less than 50% of the canal diameter and may present with radiculopathy, with or without claudicant symptoms. Grade III cysts may present with radiculopathy and claudication with bilateral leg symptoms, along with facetogenic pain symptoms. Grades IV and V include potential instability as defined by greater than 15% spondylolisthesis in addition to either less than or greater than 50% canal stenosis. With higher grade cysts, presentation may include: facetogenic back pain, radiculopathy and claudicant pain in variable degrees of severity. The optimal classification system grades FJC from I to V on the basis of canal compression and degree of spondylolisthesis. Prospective studies are required to confirm the validity of this grading scale for long-term use. PMID- 29436167 TI - Sestrin2 facilitates glutamine-dependent transcription of PGC-1alpha and survival of liver cancer cells under glucose limitation. AB - Differential utilization of metabolites and metabolic plasticity can confer adaptation to cancer cells under metabolic stress. Glutamine is one of the vital and versatile nutrients that cancer cells consume avidly for their proliferation, and therefore mechanisms related to glutamine metabolism have been identified as targets. Recently, sestrin2 (SESN2), a stress-inducible protein, has been reported to regulate survival in glutamine-depleted cancer cells; based on this, we explored if SESN2 could regulate glutamine metabolism during glucose starvation. This report highlights the role of SESN2 in the regulation of glutamine-dependent activation of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) under glucose scarcity in liver cancer cells (HepG2). We demonstrate that down regulation of SESN2 induces a decrease in the levels of intracellular glutamine and PGC-1alpha under glucose deprivation, concomitant with a decline in cell survival, but no effect was observed on the invasive or migration potential of the cells. Under similar metabolic conditions, SESN2 forms a complex with c-Jun N terminal kinase (JNK) and forkhead box protein O1 (FOXO1). Absence of SESN2 or inhibition of JNK reduces nuclear translocation of FOXO1, consequently causing transcriptional inhibition of PGC-1alpha. Notably, our observations demonstrate a reduction in cell viability under high glutamine and low glucose conditions during SESN2 down-regulation that could be rescued on JNK inhibition. To recover from acetaminophen-induced mitochondrial damage, SESN2 was crucial for glutamine mediated activation of PGC-1alpha in HepG2 cells. Collectively, we demonstrate a novel role of SESN2 in mediating activation of PGC-1alpha by modulating glutamine metabolism that facilitates cancer cell survival under glucose-limited metabolic conditions. PMID- 29436168 TI - Feasibility study of individualized optimal positioning selection for left-sided whole breast radiotherapy: DIBH or prone. AB - The deep inspiration breath hold (DIBH) and prone (P) position are two common heart-sparing techniques for external-beam radiation treatment of left-sided breast cancer patients. Clinicians select the position that is deemed to be better for tissue sparing based on their experience. This approach, however, is not always optimum and consistent. In response to this, we develop a quantitative tool that predicts the optimal positioning for the sake of organs at risk (OAR) sparing. Sixteen left-sided breast cancer patients were considered in the study, each received CT scans in the supine free breathing, supine DIBH, and prone positions. Treatment plans were generated for all positions. A patient was classified as DIBH or P using two different criteria: if that position yielded (1) lower heart dose, or (2) lower weighted OAR dose. Ten anatomical features were extracted from each patient's data, followed by the principal component analysis. Sequential forward feature selection was implemented to identify features that give the best classification performance. Nine statistical models were then applied to predict the optimal positioning and were evaluated using stratified k-fold cross-validation, predictive accuracy and receiver operating characteristic (AUROC). For heart toxicity-based classification, the support vector machine with radial basis function kernel yielded the highest accuracy (0.88) and AUROC (0.80). For OAR overall toxicities-based classification, the quadratic discriminant analysis achieved the highest accuracy (0.90) and AUROC (0.84). For heart toxicity-based classification, Breast volume and the distance between Heart and Breast were the most frequently selected features. For OAR overall toxicities-based classification, Heart volume, Breast volume and the distance between ipsilateral lung and breast were frequently selected. Given the patient data considered in this study, the proposed statistical model is feasible to provide predictions for DIBH and prone position selection as well as indicate important clinical features that affect the position selection. PMID- 29436169 TI - Rethinking developmental toxicity testing: Evolution or revolution? AB - BACKGROUND: Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo-fetal development testing, are we ready to consider a different approach to human developmental toxicity testing? METHODS: A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We first consider what changes to the current protocols might be recommended to make them more predictive for human risk (evolution). RESULTS: The evolutionary approach includes modifications of existing protocols and can include humanized models, disease models, more accurate assessment and testing of metabolites, and informed approaches to dose selection. The revolution could start with hypothesis driven testing where we take what we know about a compound or close analog and answer specific questions using targeted experimental techniques rather than a one-protocol-fits-all approach. Central to the idea of hypothesis-driven testing is the concept that testing can be done at the level of mode of action. It might be feasible to identify a small number of key events at a molecular or cellular level that predict an adverse outcome and for which testing could be performed in vitro or in silico or, rarely, using limited in vivo models. Techniques for evaluating these key events exist today or are in development. DISCUSSION: Opportunities exist for refining and then replacing current developmental toxicity testing protocols using techniques that have already been developed or are within reach. PMID- 29436170 TI - Simultaneous determination and pharmacokinetics study of four quinones in rat plasma by ultra high performance liquid chromatography with electrospray ionization tandem mass spectrometry after the oral administration of Qianzhi capsules. AB - A sensitive, specific, and accurate ultra high-performance liquid chromatography with electrospray ionization tandem mass spectrometry method was developed and validated for the simultaneous quantification of purpurin, munjistin, mollugin, and alizarin from Qianzhi capsules in rat plasma. Chromatographic separation was performed on an Agilent Eclipse Plus C18 RRHD column with a mobile phase consisting of methanol and 5 mM ammonium acetate/water with gradient elution. The analytes were quantified on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring mode and switching the electrospray ion source polarity with positive electrospray ionization in a single run. Samples were pretreated by liquid-liquid extraction with cyclohexane. The intra- and interday precision and accuracy of the assay were within acceptable ranges. Matrix effects for all of the analytes were between 90.16 and 100.21%. The average recovery ranged from 75.38 to 88.96%. This method was successfully applied to study the pharmacokinetic parameters of the four compounds in rat plasma after oral administration of Qianzhi capsules. Four quinones could be rapidly absorbed into blood (tmax , 0.80-1.93 h) and eliminated relatively slowly (t1/2 , 8.07-11.97 h). The results might be helpful for guiding the clinical application of Qianzhi capsules in the future. PMID- 29436171 TI - Ischaemic heart disease following conventional and hypofractionated radiation treatment in a contemporary breast cancer series. AB - INTRODUCTION: We report the incidence of ischaemic cardiac toxicity in a contemporary cohort of patients receiving conventional (CFRT) or hypofractionated (HFRT) radiation after surgery for early breast cancer and investigate the interplay of cardiac risk factors and fractionation. METHODS: Included were patients receiving external beam radiation treatment from 2002 to 2006 at the Christchurch public hospital. Hospital coding databases, oncology databases and medical records were reviewed for baseline characteristics, treatment details and outcomes. The primary outcome was cardiac toxicity (including myocardial infarction, admission for cardiac chest pain, coronary angiogram positivity and ischaemic cardiac death). Kaplan-Meier methods were used to derive ischaemic cardiac event free and overall survival. Predefined univariate and multivariate analysis was performed to investigate interaction with radiation fraction size, cardiac risk factors, age and side of cancer. Standardised mortality ratios were constructed. RESULTS: Five hundred and one patients were identified, 220 treated with CFRT and 281 with HFRT. The median age was 56 and median follow-up 10.33 years. The 10-year breast cancer specific survival was 81.8% (95% CI %.78.1 85.0). The 10-year freedom from cardiac death was 98.6% (95% CI 96.9-99.4). There were 27 post radiation cardiac events including 5 cardiac deaths and 19 cases of acute myocardial infarction. 265 (53%) had at least one cardiac risk factor. Twenty five of the 27 patients with a cardiac event had cardiac risk factors. On univariate and multivariate analysis, fractionation schedule was not significantly associated with a post radiation ischaemic event, however, there was a significant relationship with age and the presence of a cardiac risk factor. The standardised mortality ratio was 0.89 (95% CI: 0-3.13). CONCLUSIONS: Our study has shown a low rate of ischaemic cardiac disease for both CFRT and HFRT in women treated for breast cancer with no evidence of an effect with fractionation schedule. Coexisting cardiac risk factors are common in the population. PMID- 29436172 TI - Population Pharmacokinetic/Pharmacodynamic Modeling of Depot Testosterone Cypionate in Healthy Male Subjects. AB - A randomized, double-blind clinical trial was conducted to investigate long-term abuse effects of testosterone cypionate (TC). Thirty-one healthy men were randomized into a dose group of 100, 250, or 500 mg/wk and received 14 weekly injections of TC. A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize testosterone concentrations and link exposure to change in luteinizing hormone and spermatogenesis following long-term TC administration. A linear one-compartment model best described the concentration-time profile of total testosterone. The population mean estimates for testosterone were 2.6 kL/day for clearance and 14.4 kL for volume of distribution. Weight, albumin, and their changes from baseline were identified as significant covariates for testosterone. The estimated potency of total testosterone (tT) with respect to suppression of luteinizing hormone (LH) synthesis was 9.33 ng/mL. Simulation based on the indirect response model suggests the suppression of endogenous testosterone secretion, LH synthesis, and spermatogenesis was more severe and of greater duration in the 250 mg and the 500 mg dose groups. PMID- 29436173 TI - Development and validation of a reproducible model for studying post-inflammatory hyperpigmentation. PMID- 29436174 TI - Copper-Catalyzed Asymmetric Synthesis of Borylated cis-Disubstituted Indolines. AB - A copper-catalyzed, intramolecular borylative cyclization of vinyl arenes with imines is reported, which affords enantio-enriched indolines as a single diastereomer under mild conditions. A benzylcopper species is generated by Cu Bpin addition to the alkene, which then acts as a nucleophile for intramolecular imine addition. The reaction is applicable to various vinyl arenes with an imine moiety at the ortho-position, including heterocycles, for formation of borylated indolines in good yields and ee values up to 90 %. PMID- 29436175 TI - Mindset theory in medical education. PMID- 29436176 TI - Exploring the impact of Aboriginal health placement experiences on the preparation of dietetic graduates for practice with Aboriginal communities. AB - AIM: A health workforce with the ability to practice with Aboriginal communities is crucial to bridge the health gap between Aboriginal and non-Aboriginal Australians. This study aimed to explore the impact of university Aboriginal health placements on preparing dietetic graduates for practice with Aboriginal communities. METHODS: A mixed methods sequential explanatory design was used. A sample of 594 dietetic graduates was invited to complete a survey that identified Aboriginal health experiences and measured attitudes and self-confidence towards working in Aboriginal health using a five-point Likert scale. Participants were divided into placement versus no-placement groups and compared using chi-squared tests. Sixteen of 33 participants who had completed an Aboriginal health placement were invited to participate in a semi-structured interview to explore how placement influenced practice with Aboriginal communities. Interviews were analysed using content analysis. RESULTS: A final sample of 120 participants showed that placement participants reported significantly higher self-confidence towards working in Aboriginal health compared with no-placement participants (No placement = 35% agree, 36% neutral, 29% disagree; Placement = 74% agree, 11% neutral, 16% disagree; chi2 (2, 88) = 9.4; P = 0.01). Fifteen participants were interviewed. Interview data indicated that situated learning experiences, breaking down stereotypes, empathy through learning from Aboriginal people, and Aboriginal health role-models were key components of Aboriginal health placements in preparing dietetic graduates for practice with Aboriginal communities. CONCLUSIONS: The results suggest that Aboriginal health placements may be an effective strategy for preparing dietetic graduates for practice with Aboriginal communities. The feasibility of placement or alternative curriculum content needs to be explored. PMID- 29436177 TI - Graphene-doped electrochemical copolymer coating of 2,2-bithiophene and 3 methylthiophene for the highly effective solid-phase microextraction of volatile benzene homologues. AB - We report the electrochemical fabrication of a poly(2,2-bithiophene-co-3 methylthiophene)-graphene composite coating and its application in the headspace solid-phase microextraction and gas chromatography determination of benzenes (i.e., bromobenzene, 4-bromotoluene, 2-nitrotoluene, 3-nitrotoluene and 1,2,4 trichlorobenzene). The coating was uniform and showed cauliflower-like microstructure. It had high thermal stability (up to 375 degrees C) and could be used for at least 180 times of solid-phase microextraction without a decrease in extraction performance. Furthermore, it presented high extraction capacity for the benzenes due to the hydrophobic effect and pi-pi interaction between the analytes and the coating. Under optimized extraction conditions, good linearity (correlation coefficients higher than 0.9946), wide linear range (0.01-50 MUg/L), and low limits of detection (5.25-12.5 ng/L) were achieved for these analytes. The relative standard deviation was lower than 5.7% for five successive measurements with one fiber, and the relative standard deviation for fiber-to fiber was 4.9-6.8% (n = 5). The solid-phase microextraction and gas chromatography method was successfully applied for the determination of three real samples, and the recoveries for standards added were 89.6-106% for nail polish, 85.8-110% for hair dye, and 90-106.2% for correction fluid, respectively. PMID- 29436179 TI - Frequent Pitfalls in the Characterization of Electrodes Designed for Electrochemical Energy Conversion and Storage. AB - Focus on the importance of energy conversion and storage boosted research interest in various electrocatalytic materials. Characterization of solid-liquid interfaces during faradaic and non-faradaic processes is routinely conducted in many laboratories worldwide on a daily basis. This can be deemed as a very positive tendency. However, careful insight into modern literature suggests frequent misuse of electroanalytical tools. This can have very negative implications and postpone overall development of electrocatalytic materials with the desired properties. This work points out some of the frequent pitfalls in electrochemical characterization, suggests potential solutions, and above all encourages comprehensive analysis and in-depth thinking about electrochemical phenomena. PMID- 29436178 TI - Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. AB - Microsatellite instability (MSI) testing identifies patients who may benefit from immune checkpoint inhibitors. We developed an MSI assay that uses data from a commercially available next-generation sequencing (NGS) panel to determine MSI status. The assay is applicable across cancer types and does not require matched samples from normal tissue. Here, we describe the MSI-NGS method and explore the relationship of MSI with tumor mutational burden (TMB) and PD-L1. MSI examined by PCR fragment analysis and NGS was compared for 2189 matched cases. Mismatch repair status by immunohistochemistry was compared to MSI-NGS for 1986 matched cases. TMB was examined by NGS, and PD-L1 was determined by immunohistochemistry. Among 2189 matched cases that spanned 26 cancer types, MSI-NGS, as compared to MSI by PCR fragment analysis, had sensitivity of 95.8% (95% confidence interval [CI] 92.24, 98.08), specificity of 99.4% (95% CI 98.94, 99.69), positive predictive value of 94.5% (95% CI 90.62, 97.14), and negative predictive value of 99.2% (95% CI, 98.75, 99.57). High MSI (MSI-H) status was identified in 23 of 26 cancer types. Among 11,348 cases examined (including the 2189 matched cases), the overall rates of MSI-H, TMB-high, and PD-L1 positivity were 3.0%, 7.7%, and 25.4%, respectively. Thirty percent of MSI-H cases were TMB-low, and only 26% of MSI-H cases were PD-L1 positive. The overlap between TMB, MSI, and PD-L1 differed among cancer types. Only 0.6% of the cases were positive for all three markers. MSI-H status can be determined by NGS across cancer types. MSI-H offers distinct data for treatment decisions regarding immune checkpoint inhibitors, in addition to the data available from TMB and PD-L1. PMID- 29436181 TI - Happy Times for the Macromolecular Journals. PMID- 29436180 TI - Sweet Vector for Gene Delivery: the Sugar Decoration of Polyplexes Reduces Cytotoxicity with a Balanced Effect on Gene Expression. AB - The use of sugar-functionalized polyplexes as a nonviral gene delivery vector with lower cytotoxicity than the well-known polymeric carrier branched polyethyleneimine (BPEI) is investigated. The substitution of primary amine groups in the BPEI chains with lactose residues leads to larger polyplexes, presumably due to the higher amount of polymer required to complete DNA condensation. Nevertheless, the sugar functionalization substantially reduces the cytotoxicity of the assemblies. The nanocomplexes are taken up by the cells to a greater extent, whereas the levels of gene expression are maintained compared to those obtained using BPEI, which is known for its excellent transfection efficiency. Accordingly, the preparation of lower-cytotoxicity polyplexes while maintaining gene expression, which is highly relevant to the field, is demonstrated. PMID- 29436182 TI - Dr. Myung-Sun Kim (1897-1982): An Eternal Teacher of Yonsei University. PMID- 29436183 TI - Dr. Charles Inglis McLaren (1882-1957): A Psychiatrist who Treated the Korean Soul. PMID- 29436184 TI - Systems Biology-Based Platforms to Accelerate Research of Emerging Infectious Diseases. AB - Emerging infectious diseases (EIDs) pose a major threat to public health and security. Given the dynamic nature and significant impact of EIDs, the most effective way to prevent and protect against them is to develop vaccines in advance. Systems biology approaches provide an integrative way to understand the complex immune response to pathogens. They can lead to a greater understanding of EID pathogenesis and facilitate the evaluation of newly developed vaccine-induced immunity in a timely manner. In recent years, advances in high throughput technologies have enabled researchers to successfully apply systems biology methods to analyze immune responses to a variety of pathogens and vaccines. Despite recent advances, computational and biological challenges impede wider application of systems biology approaches. This review highlights recent advances in the fields of systems immunology and vaccinology, and presents ways that systems biology-based platforms can be applied to accelerate a deeper understanding of the molecular mechanisms of immunity against EIDs. PMID- 29436185 TI - Emotional Labor and Burnout: A Review of the Literature. AB - This literature review was conducted to investigate the association between emotional labor and burnout and to explore the role of personality in this relationship. The results of this review indicate that emotional labor is a job stressor that leads to burnout. Further examination of personality traits, such as self-efficacy and type A behavior pattern, is needed to understand the relationships between emotional labor and health outcomes, such as burnout, psychological distress, and depression. The results also emphasized the importance of stress management programs to reduce the adverse outcomes of emotional labor, as well as coping repertories to strengthen the personal potential suitable to organizational goals. Moreover, enhancing employees' capacities and competence and encouraging a positive personality through behavior modification are also necessary. PMID- 29436186 TI - Hypofractionated Re-irradiation after Maximal Surgical Resection for Recurrent Glioblastoma: Therapeutic Adequacy and Its Prognosticators of Survival. AB - PURPOSE: To evaluate the adequacy of retreatment, including hypofractionated re irradiation (HFReRT), after surgery for recurrent glioblastoma (GBM) and related prognosticators of outcomes. MATERIALS AND METHODS: From 2011 to 2014, 25 consecutive patients with recurrent (n=17) or secondary (n=7) disease underwent maximal surgery and subsequent HFReRT after meeting the following conditions: 1) confirmation of recurrent or secondary GBM after salvage surgery; 2) Karnofsky performance score (KPS) >=60; and 3) interval of >=12 months between initial radiotherapy and HFReRT. HFReRT was delivered using a simultaneous integrated boost technique, with total dose of 45 Gy in 15 fractions to the gross tumor volume (GTV) and 37.5 Gy in 15 fractions to the clinical target volume. RESULTS: During a median follow-up of 13 months, the median progression-free and overall survival (OS) were 13 and 16 months, respectively. A better KPS (p=0.026), no involvement of the eloquent area at recurrence (p=0.030), and a smaller GTV (p=0.005) were associated with better OS. Additionally, OS differed significantly between risk groups stratified by the National Institutes of Health Recurrent GBM Scale (low-risk vs. high-risk, p=0.025). Radiologically suspected radiation necrosis (RN) was observed in 16 patients (64%) at a median of 9 months after HFReRT, and 8 patients developed grade 3 RN requiring hospitalization. CONCLUSION: HFReRT after maximal surgery prolonged survival in selected patients with recurrent GBM, especially those with small-sized recurrences in non-eloquent areas and good performance. PMID- 29436187 TI - Efficacy of Pemetrexed-based Chemotherapy in Comparison to Non-Pemetrexed-based Chemotherapy in Advanced, ALK+ Non-Small Cell Lung Cancer. AB - PURPOSE: Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC. MATERIALS AND METHODS: We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors. RESULTS: Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p<0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p<0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (>=70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03-1.42; p=0.106). CONCLUSION: Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC. PMID- 29436188 TI - Peptide Nucleic Acid Clamping and Direct Sequencing in the Detection of Oncogenic Alterations in Lung Cancer: Systematic Review and Meta-Analysis. AB - PURPOSE: Molecular testing in non-small cell lung cancer (NSCLC) aids in identifying oncogenic alterations. The aim of this study was to compare the rates of detection of oncogenic alterations and responsiveness to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) according to EGFR mutation status as determined by peptide nucleic acid (PNA) clamping or direct sequencing (DS). MATERIALS AND METHODS: We performed a systematic literature search using MEDLINE, EMBASE, and the Cochrane Central Register. Data from included studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and receiver operating characteristic curves. A meta-regression analysis was conducted to identify potential sources of heterogeneity between selected studies. RESULTS: We identified 10 studies comprising 924 patients. Oncogenic alterations were detected in 340 of 924 cases (36.8%) with PNA clamping and in 250 of 924 (27.1%) with DS. The pooled sensitivities of PNA clamping and DS were 0.93 [95% confidence interval (CI): 0.90-0.95] and 0.69 (95% CI: 0.64-0.73), respectively. According to meta regression analysis, none of the covariates were found to be significant sources of heterogeneity. With respect to treatment responses to EGFR-TKIs, there was no significant difference therein between EGFR mutations detected by PNA clamping and DS (53.4% vs. 50.8%; risk ratio, 0.99; 95% CI 0.83-1.19; p=0.874). CONCLUSION: We demonstrated that PNA clamping has a higher sensitivity than DS for detecting oncogenic alterations in NSCLC. Our findings suggest that PNA clamping is a more useful method for clinical practice. PMID- 29436189 TI - Prostate-Specific Antigen Kinetics Following 5alpha-Reductase Inhibitor Treatment May Be a Useful Indicator for Repeat Prostate Biopsy. AB - PURPOSE: To evaluate parameters for determining repeat prostate biopsy in patients with 5alpha-reductase inhibitor (5ARI) treatment after initial negative biopsy. MATERIALS AND METHODS: From January 2007 to December 2015, patients who underwent a repeat prostate biopsy after an initial negative biopsy were enrolled from multiple institutions. Serial prostate-specific antigen (PSA) levels after the initial biopsy were analyzed for PSA kinetics. Clinicopathologic variables were evaluated according to the use of 5ARIs after the initial negative biopsy. RESULTS: Of 419 patients with initial negative biopsies (median age=67.0 years, median PSA=6.31 ng/mL), 101 patients (24.1%) were diagnosed with prostate cancer at the repeat biopsy. An increase in PSA level at 18 months, compared to that at 6 months, was a predictor of a positive repeat biopsy. However, the use of 5ARIs was not identified as a predictor. Of 126 patients receiving 5ARI treatment after the initial biopsy, 30 (23.8%) were diagnosed with prostate cancer at the repeat biopsy. Increase in PSA level at more than two time points after 6 months of 5ARI treatment (odds ratio=4.84, p=0.005) was associated with cancer detection at the repeat biopsy. There were no significant 5ARI group-related differences in the detection rates of prostate and high-grade cancers (Gleason score >=7). CONCLUSION: The effects of 5ARIs on prostate cancer detection and chemoprevention remain uncertain. However, more than two increases in PSA level after 6 months of 5ARI treatment may indicate the presence of prostate cancer. PMID- 29436190 TI - Long Non-Coding RNA TUG1 Promotes Proliferation and Inhibits Apoptosis of Osteosarcoma Cells by Sponging miR-132-3p and Upregulating SOX4 Expression. AB - PURPOSE: Long non-coding RNA taurine upregulated gene 1 (TUG1) is reported to be a vital regulator of the progression of various cancers. This study aimed to explore the exact roles and molecular mechanisms of TUG1 in osteosarcoma (OS) development. MATERIALS AND METHODS: Real-time quantitative PCR was applied to detect the expressions of TUG1 and microRNA-132-3p (miR-132-3p) in OS tissues and cells. Western blot was performed to measure protein levels of sex determining region Y-box 4 (SOX4). Cell viability was assessed using XTT assay. Cell apoptosis was evaluated using flow cytometry and caspase-3 activity detection assays. Bioinformatics analysis and luciferase reporter experiments were employed to confirm relationships among TUG1, miR-132-3p, and SOX4. RESULTS: TUG1 was highly expressed in human OS tissues, OS cell lines, and primary OS cells. TUG1 knockdown hindered proliferation and induced apoptosis in human OS cell lines and primary OS cells. Moreover, TUG1 inhibited miR-132-3p expression by direct interaction, and introduction of miR-132-3p inhibitor partly abrogated the effect of TUG1 knockdown on the proliferation and apoptosis of OS cells. Furthermore, SOX4 was validated as a target of miR-132-3p. Further functional analyses revealed that miR-132-3p inhibited proliferation and induced apoptosis of OS cells, while this effect was greatly abated following SOX4 overexpression. Moreover, TUG1 knockdown suppressed proliferation and promoted apoptosis by upregulating miR-132-3p and downregulating SOX4 in primary OS cells. CONCLUSION: TUG1 facilitated proliferation and suppressed apoptosis by regulating the miR-132 3p/SOX4 axis in human OS cell lines and primary OS cells. This finding provides a potential target for OS therapy. PMID- 29436191 TI - CHA2DS2-VASc Score in the Prediction of Ischemic Stroke in Patients after Radiofrequency Catheter Ablation of Typical Atrial Flutter. AB - PURPOSE: Despite undergoing successful catheter ablation of typical atrial flutter (AFL), patients remain at increased risk for ischemic stroke. However, data on risk prediction tools for the development of stroke after AFL ablation are lacking. This study investigates whether CHA2DS2-VASc score is useful for predicting ischemic stroke after successful ablation of typical AFL. MATERIALS AND METHODS: A total of 293 patients (236 men, mean age 56.1+/-13.5 years) who underwent successful radiofrequency catheter ablation for typical AFL were included in this study. The clinical end point was occurrence of ischemic stroke during follow-up after AFL ablation. RESULTS: During the follow-up period (60.8+/ 45.9 months), ischemic stroke occurred in 18 (6%) patients at a median of 34 months (interquartile range, 13-65 months). CHA2DS2-VASc score [hazard ratio 2.104; 95% confidence interval (CI), 1.624-2.726; p<0.001] was an independent predictor for the occurrence of stroke after AFL ablation. The area under the receiver operating characteristic curve for CHA2DS2-VASc score was 0.798 (95% CI, 0.691-0.904). The CHA2DS2-VASc score could be used to stratify patients into two groups with different incidences of ischemic stroke (1.6% vs. 14.4%, p<0.001) at a cutoff value of 2. CONCLUSION: CHA2DS2-VASc score is useful in a prediction model for the risk of stroke after catheter ablation of typical AFL. PMID- 29436192 TI - Effects of Physician Volume on Readmission and Mortality in Elderly Patients with Heart Failure: Nationwide Cohort Study. AB - PURPOSE: Readmission and mortality rates of patients with heart failure are good indicators of care quality. To determine whether hospital resources are associated with care quality for cardiac patients, we analyzed the effect of number of physicians and the combined effects of number of physicians and beds on 30-day readmission and 1-year mortality. MATERIALS AND METHODS: We used national cohort sample data of the National Health Insurance Service (NHIS) claims in 2002 2013. Subjects comprised 2345 inpatients (age: >65 years) admitted to acute-care hospitals for heart failure. A multivariate Cox regression was used. RESULTS: Of the 2345 patients hospitalized with heart failure, 812 inpatients (34.6%) were readmitted within 30 days and 190 (8.1%) had died within a year. Heart-failure patients treated at hospitals with low physician volumes had higher readmission and mortality rates than high physician volumes [30-day readmission: hazard ratio (HR)=1.291, 95% confidence interval (CI)=1.020-1.633; 1-year mortality: HR=2.168, 95% CI=1.415-3.321]. Patients admitted to hospitals with low or middle bed and physician volume had higher 30-day readmission and 1-year mortality rates than those admitted to hospitals with high volume (30-day readmission: HR=2.812, 95% CI=1.561-5.066 for middle-volume beds & low-volume physicians, 1-year mortality: HR=8.638, 95% CI=2.072-36.02 for middle-volume beds & low-volume physicians). CONCLUSION: Physician volume is related to lower readmission and mortality for heart failure. Of interest, 30-day readmission and 1-year mortality were significantly associated with the combined effects of physician and institution bed volume. PMID- 29436193 TI - Coronary Flow Reserve in Non-Infarcted Myocardium Predicts Long-Term Clinical Outcomes in Patients Undergoing Percutaneous Coronary Intervention. AB - PURPOSE: Coronary flow reserve (CFR) is recognized as an indicator of myocardial perfusion. The aim of this study was to assess the relationship between CFR in the non-infarcted myocardium and the incidence of major adverse cardiac events (MACEs). MATERIALS AND METHODS: 100 consecutive patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) were enrolled in the present study, and divided into MACE and non-MACE groups according to the incidence of 12-month MACEs. Left ventricular function and CFR were analyzed using two-dimensional echocardiography and myocardial contrast echocardiography at one week after PCI. Cardiac troponin I levels were assayed to estimate peak concentrations thereof. RESULTS: The MACE group was associated with lower CFR, compared to the non-MACE group (2.41 vs. 2.77, p<0.001). In the multivariable model, CFR in the non-infarcted myocardium was an independent predictor of 12-month MACE (hazard ratio: 0.093, 95% confidence interval: 0.020 0.426, p=0.002) after adjustment for baseline demographic and clinical characteristics. CONCLUSION: CFR in the non-infarcted myocardium is a useful marker for predicting 12-month MACEs in patients with AMI undergoing primary PCI. PMID- 29436194 TI - Comparison of Rhythm and Rate Control Strategies for Stroke Occurrence in a Prospective Cohort of Atrial Fibrillation Patients. AB - PURPOSE: Comparisons of rhythm and rate control strategies for stroke prevention in patients with atrial fibrillation (AF) are still inconclusive. We compared differences in clinical outcomes between the rhythm and rate control strategies. MATERIALS AND METHODS: The COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation (CODE-AF) registry prospectively enrolled 6000 patients who were treated for AF using real-world guideline adherence at multiple referral centers. In total, 2508 (41.8%) patients were clinically followed up for over six months. Of these, 1134 (45.2 %) patients treated by rhythm control and 1374 (54.8 %) patients treated by rate control were analyzed for clinical outcomes, including stroke and cardiovascular outcomes. RESULTS: Among all patients (age, 68+/-10 years; male, 62.4%), those treated with the rhythm control strategy were significantly younger, had more symptomatic paroxysmal AF, and a shorter AF duration, and were less likely to have diabetes, renal dysfunction, and heart failure, compared to those treated with the rate control strategy (CHA2DS2-VASc score 2.4+/-1.5 vs. 3.1+/-1.7, p<0.001). Even though oral anticoagulation was similarly prescribed in both groups, occurrence of stroke was less likely to occur in the rhythm control strategy group (0.0% vs. 0.7%, p=0.015). Multivariate Cox hazard regression showed that only age, especially more than 75 years old, were significantly correlated with the occurrence of stroke, regardless of the strategy used for treatment. CONCLUSION: In this prospective AF cohort, compared with the rate control strategy, the rhythm control strategy was associated with fewer cardiovascular events and strokes in a short-term period. PMID- 29436195 TI - Impact of Ambulatory Blood Pressure on Early Cardiac and Renal Dysfunction in Hypertensive Patients without Clinically Apparent Target Organ Damage. AB - PURPOSE: Impaired left ventricular (LV) global longitudinal strain (GLS) and the presence of microalbuminuria indicate early cardiac and renal dysfunction. We aimed to determine the relationships among 24-h ambulatory blood pressure (BP) variables, LV GLS, and urine albumin creatinine ratio (UACR) in hypertensive patients. MATERIALS AND METHODS: A total of 130 hypertensive patients (mean age 53 years; 59 men) underwent 24-h ambulatory BP monitoring, measurements of peripheral and central BPs, and transthoracic echocardiography. Patients with apparent LV systolic dysfunction (LV ejection fraction <50%) or chronic kidney disease were not included. LV GLS was calculated using two-dimensional speckle tracking, and UACR was analyzed from spot urine samples. RESULTS: In simple correlation analysis, LV GLS showed the most significant correlation with mean daytime diastolic BP (DBP) (r=0.427, p<0.001) among the various BP variables analyzed. UACR revealed a significant correlation only with night-time mean systolic BP (SBP) (r=0.253, p=0.019). In multiple regression analysis, daytime mean DBP and night-time mean SBP were independent determinants for LV GLS (beta=0.35, p=0.028) and log UACR (beta=0.49, p=0.007), respectively, after controlling for confounding factors. Daytime mean DBP showed better diagnostic performance for impaired LV GLS than did peripheral or central DBPs, which were not diagnostic. Night-time mean SBP showed satisfactory diagnostic performance for microalbuminuria. CONCLUSION: There are different associations for daytime and night-time BP with early cardiac and renal dysfunction. Ambulatory BP monitoring provides more relevant BP parameters than do peripheral or central BPs regarding early cardiac and renal dysfunction in hypertensive patients. PMID- 29436196 TI - Predictors of Long-Term Outcomes of Percutaneous Mitral Valvuloplasty in Patients with Rheumatic Mitral Stenosis. AB - PURPOSE: We determined factors associated with long-term outcomes of patients who underwent successful percutaneous mitral balloon valvuloplasty (PMV). MATERIALS AND METHODS: Between August 1980 and May 2013, 1187 patients underwent PMV at Severance Hospital, Seoul, Korea. A total of 742 patients who underwent regular clinic visits for more than 10 years were retrospectively analyzed. The endpoints consisted of repeated PMV, mitral valve (MV) surgery, and cardiovascular-related death. RESULTS: The optimal result, defined as a post-PMV mitral valve area (MVA) >1.5 cm2 and mitral regurgitation <=Grade II, was obtained in 631 (85%) patients. Over a mean follow up duration of 214+/-50 months, 54 (7.3%) patients underwent repeat PMV, 4 (0.5%) underwent trido-PMV, and 248 (33.4%) underwent MV surgery. A total of 33 patients (4.4%) had stroke, and 35 (4.7%) patients died from cardiovascular-related reasons. In a multivariate analysis, echocardiographic score [p=0.003, hazard ratio=1.56, 95% confidence interval (CI): 1.01-2.41] and post-MVA cut-off (p<0.001, relative risk=0.39, 95% CI: 0.37-0.69) were the only significant predictors of long-term clinical outcomes after adjusting for confounding variables. A post-MVA cut-off value of 1.76 cm2 showed satisfactory predictive power for poor long-term clinical outcomes. CONCLUSION: In this long term follow up study (up to 20 years), an echocardiographic score >8 and post-MVA <=1.76 cm2 were independent predictors of poor long-term clinical outcomes after PMV, including MV reintervention, stroke, and cardiovascular-related death. PMID- 29436197 TI - The Role of Serotonin in Ventricular Repolarization in Pregnant Mice. AB - PURPOSE: The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. MATERIALS AND METHODS: We measured current amplitudes and the expression levels of voltage gated K+ (Kv) channels in freshly-isolated left ventricular myocytes from wild type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(-/-)-NP). RESULTS: During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(-/-)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. CONCLUSION: Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents. PMID- 29436198 TI - Serum Fibroblast Growth Factor 21 and New-Onset Metabolic Syndrome: KoGES-ARIRANG Study. AB - PURPOSE: Fibroblast growth factor 21 (FGF21) is a crucial metabolic regulator, with multiple favorable effects on glucose homeostasis and lipid metabolism. Since serum FGF21 level has been implicated as a potential marker for the early identification of metabolic syndrome (MetS), we investigated the association between serum FGF21 level and the development of MetS in a population-based prospective study. MATERIALS AND METHODS: We conducted a prospective study of 221 randomly sampled adults without MetS from a general population-based cohort study who were examined from 2005-2008 (baseline) and from 2008-2011 (follow-up). Baseline serum FGF21 levels were analyzed using enzyme-linked immunosorbent assay. RESULTS: During the average 2.8-year follow-up period, 82 participants (36.6%) developed new-onset MetS. Serum FGF21 levels were significantly higher in patients with new-onset MetS than in those without MetS (209.56+/-226.80 vs. 110.09+/-81.10, p<0.01). In multivariate adjusted models, the odds for MetS development were greater in patients with serum FGF21 levels in the highest quartile, compared to those in the lowest quartile (3.84, 95% confidence interval: 1.59-9.28). CONCLUSION: Serum FGF21 level was an independent predictor for new-onset MetS in a population-based prospective study. PMID- 29436199 TI - Red Blood Cell Distribution Width Can Predict Vasculitis Activity and Poor Prognosis in Granulomatosis with Polyangiitis. AB - PURPOSE: We investigated whether red blood cell distribution width (RDW) predicts vasculitis activity based on Birmingham vasculitis activity score (BVAS) or BVAS for granulomatosis with polyangiitis (GPA) at diagnosis and poor prognosis during follow-up in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). MATERIALS AND METHODS: We reviewed the medical records of 150 patients with AAV. We defined severe GPA as BVAS for GPA >=7 (the highest quartile). Correlation and standardised correlation coefficients were analysed by linear regression tests. The differences between groups were evaluated by Mann Whitney test. Relative risk (RR) was assessed by chi square test and Cox hazards model. RESULTS: RDW was correlated only with the vasculitis activity of GPA among patients with AAV. An increase in RDW was associated with the absence of ear nose throat (ENT) manifestation, but not proteinase 3-ANCA. Significant differences were noted in cumulative refractory free survival according to RDW >=15.4% (p=0.007) and the absence of ENT manifestation (p=0.036). Multivariate Cox hazards analysis identified RDW >=15.4% as the only significant predictor of refractory disease in GPA (RR 17.573). CONCLUSION: RDW predicts vasculitis activity in GPA, and RDW >=15.4% at diagnosis may increase the risk of severe GPA at diagnosis and predict refractory diseases during follow-up. PMID- 29436200 TI - Digital Videoscopic Retrograde Intrarenal Surgeries for Renal Stones: Time-to Maximal Stone Length Ratio Analysis. AB - PURPOSE: To investigate 100 consecutive cases of videoscopic retrograde intrarenal surgery (RIRS) by a single surgeon and to evaluate factors associated with stone-free status and the learning curve thereof. MATERIALS AND METHODS: We analyzed the results of videoscopic RIRS in 100 patients who underwent primary treatment for renal stones from January 2015 to August 2016. Videoscopic RIRS were performed with URF-V and URF-V2 flexible video uteroscopes (Olympus) or a Flex-Xc flexible ureterorenoscope (KARL STORZ). Non-contrast computed tomography was taken at 3 months postoperatively to confirm the absence of stones. The stone characteristics included the location, maximal stone length (MSL), stone heterogeneity index (SHI), and mean stone density (MSD). Fragmentation efficacy was calculated as operative time (min) divided by removed MSL (mm), and was evaluated in the sequential order of operations. RESULTS: The mean age of the total patient was 60.0+/-14.0 years. The mean MSL was 13.1+/-6.2 mm. The average MSD was 734.2+/-327.6 Hounsfield unit (HU) and the SHI was 241.0+/-120.0 HU. The mean operation time was 65.1+/-45.7 min considering each renal unit. The stone free rate at 3 months post-surgery was 87%. The estimated cut-off of the time-to MSL ratio below 5 min/mm was 50. Multivariate analyses indicated a lower MSD [odds ratio (OR): 0.998; 95% confidence interval (CI): 0.996-0.999; p=0.047) and the last 50 cases (OR: 5.408, 95% CI: 1.337-30.426; p=0.030) as independent predictors of stone-free status after videoscopic RIRS. CONCLUSION: Low MSDs and the last 50 cases were significant predictors of stone-free rate in videoscopic RIRS. PMID- 29436201 TI - Infarct Core Expansion on Computed Tomography before and after Intravenous Thrombolysis. AB - PURPOSE: Infarct core can expand rapidly in acute stroke patients receiving intravenous tissue plasminogen activator (IV t-PA). We investigated changes in the extent of infarct core during IV t-PA treatment, and explored the associative factors of this infarct core expansion in patients with proximal artery occlusion. MATERIALS AND METHODS: We included patients who were considered for sequential intra-arterial therapy (IAT) due to occlusion of intracranial proximal artery after IV t-PA. Patients who had a baseline Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS) >=6 and who underwent two consecutive CT scans before and shortly after IV t-PA infusion were enrolled. Patients were classified into no, moderate, and marked expansion groups based on decreases in ASPECTS (0-1, 2-3, and >=4, respectively) on follow-up CT. Collateral status was graded using CT angiography. RESULTS: Of the 104 patients, 16 (15.4%) patients showed moderate and 13 (12.5%) patients showed marked infarct core expansion on follow-up CT scans obtained at 71.1+/-19.1 min after baseline CT scan. Sixteen (15.4%) patients had an ASPECTS value <6 on the follow-up CT. None of the patients with marked expansion were independent at 3 months. Univariate analysis and ordinal logistic regression analysis demonstrated that the infarct core expansion was significantly associated with collateral status (p<0.001). CONCLUSION: Among patients who were considered for IAT after IV t-PA treatment, one out of every seven patients exhibited marked expansion of infarct core on follow-up CT before IAT. These patients tend to have poor collaterals and poor outcomes despite rescue IAT. PMID- 29436202 TI - Prevalence of Frailty in Patients with Osteoporotic Vertebral Compression Fracture and Its Association with Numbers of Fractures. AB - PURPOSE: To assess the association between frailty and osteoporotic vertebral compression fracture (OVCF) and to evaluate the relationship between numbers of OVCFs and frailty. MATERIALS AND METHODS: We enrolled 760 subjects, including 59 patients (with OVCF) and 701 controls (without OVCF). Successful matching provided 56 patient-control pairs. We analyzed principal clinical and demographic information, which included sex, age, height, weight, body mass index (BMI), variable frailty phenotypes, and Oswestry Disability Index (ODI) and EuroQol 5 dimension questionnaire (EQ-5D) scores. The association between frailty and OVCF was ascertained. In addition, the degrees of disability and quality of life attributable to frailty were determined. RESULTS: The prevalence of frailty was significantly higher in the OVCF group than in the control group (p<0.001). Most of the frailty phenotypes, such as exhaustion, physical inactivity, slowness, and handgrip strength, were also significantly observed in the OVCF group. Within the OVCF group, the participants with frailty had significantly higher disability and lower quality of life than those in a robust state (p<0.001 for ODI and EQ-5D). In addition, the multivariate logistic regression analysis demonstrated that the patients with low BMI [odds ratio (OR)=0.704; 95% confidence interval (CI), 0.543 0.913] and >=3 fractures (OR=9.213; 95% CI, 1.529-55.501) within the OVCF group were associated with higher odds of frailty. CONCLUSION: The present study showed significant relationships between frailty and OVCF, severity of symptoms, and disability induced by OVCF. Furthermore, frailty could be a causal and/or resulting factor of OVCFs. PMID- 29436203 TI - Development of a Gustatory Function Test for Clinical Application in Korean Subjects. AB - PURPOSE: To obtain validated clinical values suitable for developing a gustatory function test, including umami taste, in a Korean population. MATERIALS AND METHODS: The investigation involved 297 participants with self-reported normal sense of taste and smell. Liquid solutions were used for the assessment of gustatory function. The test consisted of 30 taste solutions [six concentrations of five tastants (sweet, bitter, salty, sour, and umami)]. For evaluation of overall gustatory function, the number of detected or correctly recognized taste thresholds was combined to form a "taste score." RESULTS: Mean values of each detection and recognition threshold for the five tastes in men were consistently lower than those of women. The 10th percentile of taste score for recognition was used as the cut-off value for distinguishing normogeusia from hypogeusia. In subgroup analysis, total taste score from recognition thresholds revealed a significant negative correlation with age, indicating lower scores for increasing age. Taste score for non-smokers was significantly higher than that of smokers, in terms of detection and recognition of taste sensitivities. CONCLUSION: This gustatory function test was easy to perform, affordable, and time-saving, with the capacity to self-produce and obtain reliable data. Gustatory function was more sensitive in young people, women, and non-smokers. PMID- 29436204 TI - Improvement in Ovarian Tissue Quality with Supplementation of Antifreeze Protein during Warming of Vitrified Mouse Ovarian Tissue. AB - Ice easily recrystallizes during warming after vitrification, and antifreeze protein (AFP) can inhibit the re-crystallization. However, no study has evaluated the effect of AFP treatment only thereon during warming. This study sought to compare AFP treatment protocols: a conventional protocol with AFP treatment during vitrification and first-step warming and a new protocol with AFP treatment during the first-step warming only. According to the protocols, 10 mg/mL of LeIBP (a type of AFP) was used. Five-week-old B6D2F1 mouse ovaries were randomly divided into a vitrified-warmed control and two experimental groups, one treated with the conventional AFP treatment protocol (LeIBP-all) and the other with the new AFP treatment protocol (LeIBP-w). For evaluation, ratios of ovarian follicle integrity, apoptosis, and DNA double-strand (DDS) damage/repairing were analyzed. The LeIBP-treated groups showed significantly higher intact follicle ratios than the control, and the results were similar between the LeIBP-treated groups. Apoptotic follicle ratios were significantly lower in both LeIBP-treated groups than the control, and the results were not significantly different between the LeIBP-treated groups. With regard to DDS damage/repairing follicle ratio, significantly lower ratios were recorded in both LeIBP-treated groups, compared to the control, and the results were similar between the LeIBP-treated groups. This study demonstrated that both protocols with LeIBP had a beneficial effect on maintaining follicle integrity and preventing follicle apoptosis and DDS damage. Moreover, the new protocol showed similar results to the conventional protocol. This new protocol could optimize the mouse ovary vitrification-warming procedure using AFP, while minimizing the treatment steps. PMID- 29436205 TI - FAT1 Gene Alteration in Facioscapulohumeral Muscular Dystrophy Type 1. AB - Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array. Recent studies revealed that the FAT1 expression is associated with disease activity of FSHD, and the FAT1 alterations result in myopathy with a FSHD-like phenotype. We describe a 59-year-old woman with both contracted D4Z4 repeat units and a FAT1 mutation. Shoulder girdle muscle weakness developed at the age of 56 years, and was followed by proximal leg weakness. When we examined her at 59 years of age, she displayed asymmetric and predominant weakness of facial and proximal muscles. Muscle biopsy showed increased variation in fiber size and multifocal degenerating fibers with lymphocytic infiltration. Southern blot analysis revealed 8 D4Z4 repeat units, and targeted sequencing of modifier genes demonstrated the c.10331 A>G variant in the FAT1 gene. This FAT1 variant has previously been reported as pathogenic variant in a patient with FSHD like phenotype. Our study is the first report of a FAT1 mutation in a FSHD1 patient, and suggests that FAT1 alterations might work as a genetic modifier. PMID- 29436206 TI - Olmsted Syndrome Caused by a Heterozygous p.Gly568Val Missense Mutation in TRPV3 Gene. AB - Olmsted syndrome (OS) is a rare congenital skin disorder characterized by severe palmoplantar and periorificial keratoderma, alopecia, onychodystrophy, and severe pruritus. Recently, pathogenic 'gain-of-function' mutations of the transient receptor potential vanilloid 3 gene (TRPV3), which encodes a cation channel involved in keratinocyte differentiation and proliferation, hair growth, inflammation, pain and pruritus, have been identified to cause OS. Due to the rarity, the pattern of inheritance of OS is still unclear. We report a case of OS in a 3-year-old Korean girl and its underlying gene mutation. The patient presented with a disabling, bilateral palmoplantar keratoderma with onychodystrophy. She also exhibited pruritic eczematous skin lesions around her eyes, ears and gluteal fold. Genetic analysis identified a heterozygous p.Gly568Val missense mutation in the exon 13 of TRPV3. To our knowledge, this is the first case of OS in the Korean population showing a missense mutation p.Gly573Ser. PMID- 29436207 TI - Alternative Surgical Methods in Patients with Recurrent Palmar Hyperhidrosis and Compensatory Hyperhidrosis. AB - Recurrent hyperhidrosis after thoracic sympathectomy is an uncomfortable condition, and compensatory hyperhidrosis (CH) is one of the most troublesome side effects. Here, we describe two patients with recurrent palmar hyperhidrosis (PH) and CH over the whole body simultaneously. They were treated with bilateral T4 sympathetic clipping and reconstruction of the sympathetic nerve from a T5 to T8 sympathetic nerve graft, which was transferred to the resected T3 sympathetic bed site. They reported improvements in sweating and were fully satisfied with the results. Our method can be considered as an alternative approach for patients with recurrent PH and CH. PMID- 29436208 TI - Use of OCTA, FA, and Ultra-Widefield Imaging in Quantifying Retinal Ischemia: A Review. AB - As ischemia remains a key prognostic factor in the management of various diseases including diabetic retinopathy, an increasing amount of research has been dedicated to its quantification as a potential biomarker. Advancements in the quantification of retinal ischemia have been made with the imaging modalities of fluorescein angiography (FA), ultra-widefield imaging (UWF), and optical coherence tomography angiography (OCTA), with each imaging modality offering certain benefits over the others. FA remains the gold standard in assessing the extent of ischemia. UWF imaging has allowed for the assessment of peripheral ischemia via FA. It is, however, OCTA that offers the best visualization of retinal vasculature with its noninvasive depth-resolved imaging and therefore has the potential to become a mainstay in the assessment of retinal ischemia. The primary purpose of this article is to review the use of FA, UWF, and OCTA to quantify retinal ischemia and the various methods described in the literature by which this is achieved. PMID- 29436209 TI - Focus on gastroesophageal reflux (GER) and laryngopharyngeal reflux (LPR): new pragmatic insights in clinical practice. AB - Introduction: Gastroesophageal reflux (GER) is a common disease usually limited to the oesophagus. Laryngopharyngeal reflux (LPR) is an inflammatory reaction of the mucosa of pharynx, larynx, and other associated upper respiratory organs, caused by a reflux of stomach contents outside the oesophagus. LPR is considered to be a relatively new clinical entity with a vast number of clinical manifestations which are treated sometimes empirically and without a correct diagnosis. However, there is disagreement between specialists about its definition and management: gastroenterologists consider LPR to be a substantially rare manifestation of gastroesophageal reflux disease (GERD), whereas otolaryngologists believe that LPR is an independent, but common in their practice, disorder. Patients suffering from LPR firstly consult their general practitioners, but a multidisciplinary approach may be fruitful to define a unified strategy based on specific medications and behavioural changes. The present Supplement would review the topic, considering LPR and GER characteristics, pathophysiology, diagnostic work-up, and new therapeutic strategies also comparing different specialist points of view and patient populations. In particular, new insights derive from an interesting gel compound, containing magnesium alginate and E-Gastryal(r) (hyaluronic acid, hydrolysed keratin, Tara gum, and Xantana gum). In particular, two very large Italian surveys were conducted in real-world setting, such as outpatient clinics. The most relevant outcomes are presented and discussed in the current Issue. Actually, laryngopharyngeal reflux (LPR) is considered an extraesophageal manifestation of the gastroesophageal reflux disease (GERD). Both GERD and its extraesophageal manifestation are very common in clinical practice. Both disorders have a relevant burden for the society: about this topic most of pharmaco-economic studies were conducted in the United States. In population based studies, 19.8% of North Americans complain of typical symptoms of GERD (heartburn and regurgitation) at least weekly (1). Also in the late 1990s, GERD accounted for $9.3 to $12.1 billion in direct annual healthcare costs in the United States, higher than any other digestive disease. As a result, acid suppressive agents were the leading pharmaceutical expenditure in the United States. The prevalence of GERD in the primary care setting becomes even more evident when one considers that, in the United States, 4.6 million office encounters annually are primarily for GERD, whereas 9.1 million encounters include GERD in the top 3 diagnoses for the encounter. GERD is also the most frequently first-listed gastrointestinal diagnosis in ambulatory care visits (2, 3) Extraesophageal manifestations of reflux, including LPR, asthma, and chronic cough, have been estimated to cost $5438 per patient in direct medical expenses in the first year after presentation and $13,700 for 5 years. PMID- 29436210 TI - Relieving laryngopharingeral reflux (RELIEF) survey in otolaryngology - the viewpoint of the otorhinolaryngologist. AB - Laryngopharyngeal Reflux (LPR) should be considered as part of extraesophageal reflux (EER). Thisreflux involves respiratory structures other than, or in addition to, the oesophagus. A new medical devicefor the treatment of gastric reflux, including LPR, has been launched in Italy: Marial(r). Therefore, theaim of the present survey was to analyse the prescriptive behaviour both considering the past or currenttreatments and clinical features during a specialist routine visit. The current survey was conducted in86 Otorhinolaryngological centers, distributed in all of Italy. Globally, 4.418 subjects [47% males and53% females, 50.1 (14.5) years-of-age] were visited. The visits included laryngoscopy, Reflux Finding Score(RFS) and Reflux Symptom Index (RSI) questionnaires. The total RSI median score was 15 (12-19) andthe total median RFS value was 10 (8-12). Interestingly, a significant change in the new drug prescriptionwas observed (p<0.0001): over two-third of patients (67%) received Marial(r) as monotherapy, whereas PPIplus add-on were prescribed to almost one-third of the patients. PPI alone was prescribed in less than 1%.In conclusion, LPR is a common disorder characterized by typical signs and symptoms; LPR patients maybe correctly identified and scored by evidence-based criteria. In addition, the present survey reported thatLPR treatment has been considerably changed by the introduction of a new medical device. PMID- 29436211 TI - Relieving laryngopharingeral reflux (RELIEF) survey in otolaryngology - II the viewpoint of the patient. AB - As LPR diagnostic work-up is complex in the absence of a definitive gold standard diagnostic test,patient symptoms have become a primary method to identify those with LPR. In this regard, RefluxSymptom Index (RSI) is a reliable self administered questionnaire useful also to monitor changes aftertreatment. An Italian survey on patients with LPR evaluated the effect of treatments for LPR that wereprescribed in a real-world setting, such as Otolaryngological clinics. In this part of the survey, 1,680subjects [45.2% males, 54.8% females, 50.4 (14.7) years] were visited in the 86 Italian ORL centers. About70% of patients were treated with Marial(r) alone, 27% with PPI plus add-on. RSI change assessment wasthe primary outcome. Both therapeutic options significantly (p<0.0001) reduced RSI score interestinglysince the second week. The inter-group comparison demonstrated the Marial(r) monotherapy induced agreater reduction of RSI than PPI plus add-on since the second week. In conclusion, the present surveyreported that a new medical device (Marial(r)) may be considered a valid option for the treatment of LPR. PMID- 29436212 TI - Correlation between the reflux finding score and the reflux symptom index in patients with laryngopharyngeal reflux. AB - LaryngoPharyngeal Reflux (LPR) is characterized by symptoms, signs, and/or tissue damageresulting from the aggression of the gastrointestinal contents in the upper airways. The Reflux FindingScore (RFS) assesses the laryngeal signs through laryngoscopy. The Reflux Symptom Index (RSI) scoresthe LPR symptoms. The objective of this real-world study was to compare RFS with RSI in a cohort ofItalian LPR patients. Globally, 3932 patients with LPR were evaluated and RFS and RSI were assessed inall subjects. A moderate correlation was found between RSI and RFS (r=0.484, p<0.0001). In conclusion,the RSI and RFS can easily be included in the LPR work-up as objective and consistent parameters,with low cost and high practicality. Based on these clinical outcomes, the specialist can easily use thesetests in clinical practice. PMID- 29436213 TI - Gastric reflux: comparison between the gastroenterologist and the otorhinolaryngologist's approach. Pragmatic conclusive remarks. AB - Conclusions: Gastroesophageal reflux (GER) is a normal physiological process that usually happens after eating in healthy infants, children, young people and adults. In contrast, gastroesophageal reflux disease (GERD) occurs when the effect of GER leads to symptoms severe enough to merit medical treatment. In clinical practice, it is difficult to differentiate between GER and GERD, and health professionals and families use the terms interchangeably alike. There is no simple, reliable and accurate diagnostic test to confirm whether the condition is GER or GERD, and this in turn affects research and clinical decisions (1-6). Furthermore, the term GERD covers a number of specific conditions that have different effects and present in different ways. This makes it difficult to identify the person who genuinely has GERD, and to estimate the real prevalence and burden of the problem. PMID- 29436214 TI - Three-Dimensional Graphene Structure for Healable Flexible Electronics Based on Diels-Alder Chemistry. AB - Wearable electronics with excellent stretchability and sensitivity have emerged as a very promising field with wide applications such as e-skin and human motion detection. Although three-dimensional (3D) graphene structures (GS) have been reported for high-performance strain sensors, challenges still remain such as the high cost of GS preparation, low stretchability, and the lack of ability to heal itself. In this paper, we reported a novel self-healing flexible electronics with 3D GS based on Diels-Alder (DA) chemistry. Furfurylamine (FA) was employed as a reducing as well as a modifying agent, forming GS by FA (FAGS)/DA bonds contained polyurethane with the "infiltrate-gel-dry" process. The as-prepared composite exhibited excellent stretchability (200%) and intrinsic conductivity with low incorporation of graphene (about 2 wt %), which could be directly employed for flexible electronics to detect human motions. Besides, the FAGS/DAPU composite exhibited lower temperature retro-DA response for the continuous graphene networks. Highly effective healing of the composites by heat and microwave has been demonstrated successfully. PMID- 29436215 TI - Organelle-Targeting Gold Nanorods for Macromolecular Profiling of Subcellular Organelles and Enhanced Cancer Cell Killing. AB - Subcellular organelles, for example, nucleus, mitochondria, and lysosome, are the vital organelles with responsibilities that maintain cell operation and metabolism. Owing to their roles in energy production and programmed cell death, these organelles have become prime therapeutic targets in different diseases and states. In this study, biocompatible, organelle-targeting nanoprobes were developed by modifying gold nanorods (AuNRs) with specific targeting peptides. These nanoprobes were employed to directly profile subcellular biomolecules and vital organelles by surface-enhanced Raman scattering (SERS) spectroscopy. Macromolecular spectral profiles of subcellular organelles were achieved and compared. Further, these organelle-targeting AuNRs were used for the photothermal treatment of cancer cells (HepG2, HeLa, and MCF-7 cell lines). The cell viability assays show that the nucleus- and mitochondria-targeting AuNRs provide higher photothermal efficiencies under an 808 nm laser relative to the lysosome targeting ones. This study makes critical insights into the spectral profiles of subcellular organelles and also inspires people in the development of high efficacy cancer therapeutic strategies by subcellular organelle-targeting drugs. PMID- 29436216 TI - Cervical Cancer HeLa Cell Autocrine Apoptosis Induced by Coimmobilized IFN-gamma plus TNF-alpha Biomaterials. AB - Using external methods to induce the death of cancer cells is recognized as one of the main strategies for cancer treatment. Research indicated that TNF-alpha is frequently used in tumor biotherapy while IFN-gamma can directly inhibit tumor cell proliferation. In our study, TNF-alpha and IFN-gamma were coimmobilized on polystyrene material (PSt) or Fe3O4-oleic acid nanoparticles (NPs). Then the structural change of these two proteins can be observed. Meanwhile, the expressions of both TNF-alpha and IFN-alpha increased significantly, as determined by gene microarray analysis; however, in the presence of TNF-alpha plus IFN-alpha inhibitors, TNF-alpha and IFN-alpha did not increase in HeLa cells induced by coimmobilized IFN-gamma plus TNF-alpha. Our results indicate that such change can stimilate HeLa cells to secrete more TNF-alpha and IFN-alpha, by which the apoptosis of HeLa cells could be further induced. This study is the first report of autocrine-induced apoptosis of HeLa cells. In addition, we performed ELISA, RT-PCR, flow cytometry, and Western blot analyses, as well as a series of analytical tests at the animal level. our data also indicate that the PSt coimmobilized IFN-gamma plus TNF-alpha has apparent effects for cancer treatment in vivo, which is of great significance for translation into clinical medicine. PMID- 29436217 TI - "Stealth and Fully-Laden" Drug Carriers: Self-Assembled Nanogels Encapsulated with Epigallocatechin Gallate and siRNA for Drug-Resistant Breast Cancer Therapy. AB - For codelivery of therapeutic genes and chemical agents in combined therapy, the ideal drug delivery system entails high-capacity and low-body toxicity carriers, allowing adequate drug dose for tumor regions while yielding low residues in normal tissues. To augment the gene/drug load capacity and circumvent the potential toxicity brought by traditional inorganic and polymeric nanocarriers, a "stealth" carrier was herein designed in a simple self-assembly of (-) epigallocatechin-3- O-gallate (EGCG) and small interfering RNA (siRNA) by recruiting protamine as a biodegradable medium for the treatment of drug resistant triple-negative breast cancer. In the self-assembled nanogel, entrapped siRNA played a central role in sensitizing the tumor response to EGCG-involved chemotherapy, and the positively charged protamine served as the assembly skeleton to fully accommodate gene and drug molecules and minimize the factors causing side effects. As compared to stand-alone chemotherapy with EGCG, the multicomponent nanogel revealed a 15-fold increase in the cytotoxicity to drug resistant MDA-MB-231 cell line. Moreover, equipped with hyaluronic acid and tumor homing cell-penetrating peptide as the outmost targeting ligands, the siRNA- and EGCG-loaded nanogel demonstrates superior selectivity and tumor growth inhibition to free EGCG in xenograft MDA-MB-231 tumor-bearing mice. Meanwhile, thanks to the acknowledged biosafety of protamine, little toxicity was found to normal tissues and organs in the animal model. This gene/drug self-assembly caged in a biodegradable carrier opens up an effective and secure route for drug-resistant cancer therapy and provides a versatile approach for codelivery of other genes and drugs for different medical purposes. PMID- 29436218 TI - Application of in Vitro T Cell Assay Using Human Leukocyte Antigen-Typed Healthy Donors for the Assessment of Drug Immunogenicity. AB - It is unclear whether priming of naive T cells to drugs is detectable in healthy human donors expressing different human leukocyte antigen (HLA) alleles. Thus, we examined T cell priming with drugs associated with HLA risk alleles and control compounds in 14 HLA-typed donors. Nitroso sulfamethoxazole and piperacillin activated T cells from all donors, whereas responses to carbamazepine and oxypurinol were only seen in donors expressing HLA-B*15:02 and HLA-B*58:01, respectively. Weak flucloxacillin-specific T cell responses were detected in donors expressing HLA-B*57:01 and HLA-B*58:01. These data show that the priming of T cells with certain drugs is skewed toward donors expressing specific HLA alleles. PMID- 29436219 TI - Wavelength-Selective Three-Dimensional Thermal Emitters via Imprint Lithography and Conformal Metallization. AB - Metallic photonic crystals (MPCs) exhibit wavelength-selective thermal emission enhancements and are promising thermal optical devices for various applications. Here, we report a scalable fabrication strategy for MPCs suitable for high temperature applications. Well-defined double-layer titanium dioxide (TiO2) woodpile structures are fabricated using a layer-by-layer soft-imprint method with TiO2 nanoparticle ink dispersions, and the structures are subsequently coated with high purity, conformal gold films via reactive deposition from supercritical carbon dioxide. The resulting gold-coated woodpile structures are effective MPCs and exhibit emissivity enhancements at a selective wavelength. Gold coatings deposited using a cold-wall reactor are found to be smoother and result in a greater thermal emission enhancement compared to those deposited using a hot-wall reactor. PMID- 29436220 TI - Chiral Nanoparticles with Full-Color and White CPL Properties Based on Optically Stable Helical Aromatic Imide Enantiomers. AB - Chiral self-assembled organic nanoparticles with circularly polarized luminescence (CPL) properties can be utilized as a new kind of chiral luminescent materials for practical applications. However, no such chiral organic nanoparticles with full-color and white CPL properties have been reported so far. Herein, five pairs of self-assembled chiral nanoparticles based on optically stable helical aromatic amide enantiomers were conveniently obtained. The chiral nanoparticles showed about 200 nm uniform sphere, high fluorescence quantum yields, and large Stokes shifts. Especially, the chiral nanoparticles exhibited both obvious mirror-image circular dichroism signals and full-color CPL properties with luminescence dissymmetry factors of about 10-3, which were comparable to those of CPL-active quantum dots. Moreover, the chiral organic nanoparticles with white CPL could also be easily achieved using the three primary-color enantiomers via intermolecular energy resonance transfer. PMID- 29436221 TI - Cross-Linked Peptide Nanoclusters for Delivery of Oncofetal Antigen as a Cancer Vaccine. AB - Peptide subunit vaccines are desirable because they increase control over the immune response and safety of the vaccine by reducing the risk of off-target responses to molecules other than the target antigen. The immunogenicity of most peptides, however, is low. Peptide nanoclusters (PNC) are proposed as a subunit peptide vaccine delivery system made completely of cross-linked peptide antigen that could improve the immunogenicity of a peptide vaccine. Proof of concept is demonstrated with oncofetal antigen (OFA), an immature laminin receptor protein expressed by many hematologic cancer cells but not by healthy cells. Peptide epitopes from this protein, called OFA 1, 2, and 3, were synthesized into PNC as a potential cancer peptide vaccine delivery system. PNC were formed by desolvation and stabilized with disulfide bonds using a trithiol cross-linker. Cysteines were added to the C-terminus of each peptide to assist in this cross linking step, denoted OFA 1C, 2C, and 3C PNC. OFA 2C was found to form the smallest PNC, 148 +/- 15 nm in diameter and stable in solution. This size is in the range where particles are readily internalized by dendritic cells (DCs) and may also passively diffuse to regional lymph nodes. OFA 2C PNC and soluble OFA 2C were internalized similarly by DCs in vitro, but only PNC resulted in significant peptide presentation by DCs. This indicates the potential for PNC to improve immune activation against this antigen. Additionally, PNC displayed higher retention at the intradermal injection site in vivo than soluble peptide, allowing more time to interact with DCs in an area of increased DC activity. While offering traditional nanoparticle benefits such as increased DC recognition, slower diffusion, and potential for multivalent cellular interactions, PNC also maximize antigen delivered per particle while minimizing off-target material delivery because the antigens are the main building blocks of the particle. With these properties, PNC are a delivery system with potential to increase peptide subunit vaccine immunogenicity for OFA and other peptide antigens. PMID- 29436222 TI - Characterization of Gas-Phase Organics Using Proton Transfer Reaction Time-of Flight Mass Spectrometry: Residential Coal Combustion. AB - Residential coal combustion is a significant contributor to particulate urban air pollution in Chinese mega cities and some regions in Europe. While the particulate emission factors and the chemical characteristics of the organic and inorganic aerosol from coal combustion have been extensively studied, the chemical composition and nonmethane organic gas (NMOG) emission factors from residential coal combustion are mostly unknown. We conducted 23 individual burns in a traditional Chinese stove used for heating and cooking using five different coals with Chinese origins, characterizing the NMOG emissions using a proton transfer reaction time-of-flight mass spectrometer. The measured emission factors range from 1.5 to 14.1 g/kgcoal for bituminous coals and are below 0.1 g/kgcoal for anthracite coals. The emission factors from the bituminous coals are mostly influenced by the time until the coal is fully ignited. The emissions from the bituminous coals are dominated by aromatic and oxygenated aromatic compounds with a significant contribution of hydrocarbons. The results of this study can help to improve urban air pollution modeling in China and Eastern Europe and can be used to constrain a coal burning factor in ambient gas phase positive matrix factorization studies. PMID- 29436223 TI - Piezotronic Effect Enhanced Flexible Humidity Sensing of Monolayer MoS2. AB - We report the piezotronic effect on the performance of humidity detection based on a back-to-back Schottky contacted monolayer MoS2 device. By introducing an upswept mechanical strain, the in-plane electrical polarization can be induced at the MoS2/metal junction region. The polarization charges can modify the Schottky barrier height at the interface of MoS2/metal junction, subsequently improving the sensitivity of the humidity sensing. An energy band diagram is proposed to explain the experiment phenomenon of the humidity sensor. This work provides a simple way to enhance the sensitivity of ultrathin two-dimensional-materials based sensors by the piezotronic effect, which has great potential applications in electronic skin, human-computer interfacing, gas sensing, and environment monitoring. PMID- 29436224 TI - Dynamic Stocks and Flows Analysis of Bisphenol A (BPA) in China: 2000-2014. AB - Bisphenol A (BPA), a synthetic organic chemical, is creating a new category of ecological and human health challenges due to unintended leakage. Effectively managing the use and leakage of BPA can benefit from an understanding of the anthropogenic BPA cycles (i.e., the size of BPA flows and stocks). In this work, we provide a dynamic analysis of the anthropogenic BPA cycles in China for 2000 2014. We find that China's BPA consumption has increased 10-fold since 2000, to ~3 million tonnes/year. With the increasing consumption, China's in-use BPA stock has increased 500-fold to 14.0 million tonnes (i.e., 10.2 kg BPA/capita). It is unclear whether a saturation point has been reached, but in 2004-2014, China's in use BPA stock has been increasing by 0.8 kg BPA/capita annually. Electronic products are the biggest contributor, responsible for roughly one-third of China's in-use BPA stock. Optical media (DVD/VCD/CDs) is the largest contributor to China's current End-of-Life (EoL) BPA flow, totaling 0.9 million tonnes/year. However, the EoL BPA flow due to e-waste will increase quickly, and will soon become the largest EoL BPA flow. The changing quantities and sources of EoL BPA flows may require a shift in the macroscopic BPA management strategies. PMID- 29436225 TI - Ultrahigh Storage and Fast Diffusion of Na and K in Blue Phosphorene Anodes. AB - In the wake of blue phosphorene's (BP) computational discovery and experimental realization, it has emerged as a versatile material with interesting optical, electrical, and mechanical properties. In this study, using first principles density functional theory calculations, we have investigated the adsorption and diffusion of Na and K over monolayer BP to assess its suitability as Na-ion and K ion battery anodes. The optimized adsorption energies were found to be -0.96 eV for Na and -1.54 eV for K, which are sufficiently large to ensure stability and safety during operation. In addition, BP could adsorb Na and K atoms up to a stoichiometric ratio of 1:1 which yields a high storage capacity of 865 mA h/g for both adatom species. Through examination of the electronic structure and projected density of states of BP as a function of Na/K concentration, we predict that the band gap of the system increasingly shrinks, and in the case of maximum K adsorption, the band gap diminishes completely. Additionally, the diffusion of Na and K over BP is observed to be ultrafast, especially for K, and anisotropic with modest energy barriers of 0.11 and 0.093 eV for Na and K, respectively. Building upon these findings, we employed vibrational analysis techniques with transition state theory to incorporate kinetic effects and predicted a diffusivity of 7.2 * 10-5 cm2/s for Na and 8.58 * 10-5 cm2/s for K on BP. Given these advantages, that is, ultrahigh capacity, electrical conductivity, and high Na/K diffusivity, we conclude that BP can be considered as an excellent candidate for anodes in Na- and K-ion batteries. PMID- 29436226 TI - Total Synthesis of Nucleoside Antibiotics Plicacetin and Streptcytosine A. AB - Disaccharide nucleoside antibiotics plicacetin and streptcytosine A (also named rocheicoside A) were effectively synthesized through the common precursor cytosamine. The amosamine and amicetose moieties were efficiently assembled through an alpha-selective O-glycosylation, and the cytosine nucleus was subsequently introduced through a beta-selective gold(I)-catalyzed N glycosylation. Further microwave-assisted amidation reactions completed the modular syntheses. PMID- 29436227 TI - Uranyl Peroxide Nanocluster (U60) Persistence and Sorption in the Presence of Hematite. AB - The presence of uranium-based nanomaterials in environmental systems may significantly impact our current understanding of the fate and transport of U(VI). Sorption of the uranyl peroxide nanocluster [(UO2)(O2)(OH)]6060- (U60) to hematite (alpha-Fe2O3) was studied using batch sorption experiments with varying U60, hematite, and alkali electrolyte (i.e., NaCl, KCl, and CsCl) concentrations. Data from electrospray ionization mass spectrometry and centrifugal microfiltration revealed that U60 persisted in the presence of hematite and the background electrolyte for at least 120 days. K+ ions were removed from solution with uranium whereas Li+ ions remained in solution, indicating that the U60 cluster behaved like an anion and that the Li+ ions did not play a significant role in the sorption mechanism. Analysis of the reacted mineral surface using X ray photoelectron and Raman spectroscopies confirmed the presence of U(VI) and uranyl species with bridged peroxo groups associated with the mineral surface. These results indicate that uranyl peroxide nanoclusters may persist in the aqueous phase under environmentally relevant conditions for reasonably long periods of time, as compared to that of the uranyl cation. PMID- 29436228 TI - Generation of 2-Furfurylthiol by Carbon-Sulfur Lyase from the Baijiu Yeast Saccharomyces cerevisiae G20. AB - 2-Furfurylthiol is the representative aroma compound of Chinese sesame-flavored baijiu. Previous studies demonstrated that baijiu yeasts could generate 2 furfurylthiol using furfural and l-cysteine as precursors and that the Saccharomyces cerevisiae genes STR3 and CYS3 are closely related to 2 furfurylthiol biosynthesis. To confirm the mechanism of the STR3- and CYS3-gene products on 2-furfurylthiol biosynthesis, their encoded proteins were purified, and we confirmed their activities as carbon-sulfur lyases. Str3p and Cys3p were able to cleave the cysteine-furfural conjugate to release 2-furfurylthiol. Moreover, the characterization of the enzymatic properties of the purified proteins shows good thermal stabilities and wide pH tolerances, which enable their strong potential for various applications. These data provide direct evidence that yeast Str3p and Cys3p release 2-furfurylthiol in vitro, which can be applied to improve baijiu flavor. PMID- 29436229 TI - Transpeptidation-Mediated Assembly of Tripartite Split Green Fluorescent Protein for Label-Free Assay of Sortase Activity. AB - Transpeptidation of surface proteins catalyzed by the transpeptidase sortase plays a critical role in the infection process of Gram-positive pathogen, and probing sortase activity and screening its inhibitors are of great significance to fundamental biological research and pharmaceutical development, especially novel antivirulence drug design. Herein, we developed a novel fluorescent biosensor to detect sortase activity based on a transpeptidation-triggered assembly of tripartite split green fluorescent protein (split GFP). Peptide P1, composed the 10th beta-sheet of GFP (GFP10) and the sortase A (SrtA) recognition sequence (LPETX), and peptide P2, the 11th beta-sheet of GFP (GFP11) with oligoglycine at N-terminal, were designed and synthesized, respectively. Existence of SrtA enables P1 and P2 to ligate into one peptide, which could spontaneously bind to GFP1-9 (the 1st to 9th beta-sheets of GFP) and assemble into functional GFP. Thus, the sortase-catalyzed transpeptidation can switch on the fluorescence signal of GFP. The method was successfully applied to detect SrtA activity with a low detection limit of 0.16 nM and for its inhibition measurement. Moreover, the feasibility of the proposed assay was further expanded to detect SrtA in human blood and further Gram-positive pathogens analysis in frozen food. Our method, using tripartite split GFP as a readout, is facile, label-free, and sensitive and exhibits great potential as a promising platform for sortase detection and inhibitor screening. PMID- 29436230 TI - Metagenomic Taxonomy-Guided Database-Searching Strategy for Improving Metaproteomic Analysis. AB - Metaproteomics provides a direct measure of the functional information by investigating all proteins expressed by a microbiota. However, due to the complexity and heterogeneity of microbial communities, it is very hard to construct a sequence database suitable for a metaproteomic study. Using a public database, researchers might not be able to identify proteins from poorly characterized microbial species, while a sequencing-based metagenomic database may not provide adequate coverage for all potentially expressed protein sequences. To address this challenge, we propose a metagenomic taxonomy-guided database-search strategy (MT), in which a merged database is employed, consisting of both taxonomy-guided reference protein sequences from public databases and proteins from metagenome assembly. By applying our MT strategy to a mock microbial mixture, about two times as many peptides were detected as with the metagenomic database only. According to the evaluation of the reliability of taxonomic attribution, the rate of misassignments was comparable to that obtained using an a priori matched database. We also evaluated the MT strategy with a human gut microbial sample, and we found 1.7 times as many peptides as using a standard metagenomic database. In conclusion, our MT strategy allows the construction of databases able to provide high sensitivity and precision in peptide identification in metaproteomic studies, enabling the detection of proteins from poorly characterized species within the microbiota. PMID- 29436231 TI - Wavelength-Dependent Optical Force Imaging of Bimetallic Al-Au Heterodimers. AB - Many important applications of nanometer-scale metallic complexes arise from the light-induced, near-field interactions between their component structures. Here we examine the near-field interactions in bimetallic Al-Au plasmonic nanodisk heterodimers, where the coupling between the primitive plasmons of nanostructures composed of two different metals is studied. Understanding the correlations between nanoparticle morphology and near-field optical properties, particularly for nanostructures composed of two different metals, requires spectrally resolved near-field spatial information. An ideal tool for such investigations is the recently developed photoinduced force microscopy, where the electromagnetic forces between an optically excited plasmonic nanostructure and an adjacent scanning nanoscale tip are measured. Using this approach, we visualize the wavelength-dependent near-field interactions in these bimetallic heterodimers. This system provides a prime example of the diabatic, antenna-reactor picture of plasmon coupling where for a given wavelength the more resonant primitive "driving" plasmon induces a response, the "forced" plasmon, in the off-resonant component. We critically examine spectrally resolved tip-nanostructure forces, comparing experiment with theory, for tips and nanoscale structures of realistic dimensions relative to frequently used approximations for tip geometries. The contrasting effects of dielectric versus metallic tips on acquired spectral force profiles are also examined. PMID- 29436232 TI - Drug Clearance from Cerebrospinal Fluid Mediated by Organic Anion Transporters 1 (Slc22a6) and 3 (Slc22a8) at Arachnoid Membrane of Rats. AB - Although arachnoid mater epithelial cells form the blood-arachnoid barrier (BAB), acting as a blood-CSF interface, it has been generally considered that the BAB is impermeable to water-soluble substances and plays a largely passive role. Here, we aimed to clarify the function of transporters at the BAB in regulating CSF clearance of water-soluble organic anion drugs based on quantitative targeted absolute proteomics (QTAP) and in vivo analyses. Protein expression levels of 61 molecules, including 19 ATP-binding-cassette (ABC) transporters and 32 solute carrier (SLC) transporters, were measured in plasma membrane fraction of rat leptomeninges using QTAP. Thirty-three proteins were detected; others were under the quantification limits. Expression levels of multidrug resistance protein 1 (Mdr1a/P-gp/Abcb1a) and breast cancer resistance protein (Bcrp/Abcg2) were 16.6 and 3.27 fmol/MUg protein (51.9- and 9.82-fold greater than in choroid plexus, respectively). Among those organic anion transporters detected only at leptomeninges, not choroid plexus, organic anion transporter 1 (oat1/Slc22a6) showed the greatest expression (2.73 fmol/MUg protein). On the other hand, the protein expression level of oat3 at leptomeninges was 6.65 fmol/MUg protein, and the difference from choroid plexus was within two-fold. To investigate oat1's role, we injected para-aminohippuric acid (PAH) with or without oat1 inhibitors into cisterna magna (to minimize the contribution of choroid plexus function) of rats. A bulk flow marker, FITC-inulin, was not taken up from CSF up to 15 min, whereas uptake clearance of PAH was 26.5 MUL/min. PAH uptake was completely blocked by 3 mM cephalothin (inhibits both oat1 and oat3), while 17% of PAH uptake was inhibited by 0.2 mM cephalothin (selectively inhibits oat3). These results indicate that oat1 and oat3 at the BAB provide a distinct clearance pathway of organic anion drugs from CSF independently of choroid plexus. PMID- 29436233 TI - Intratissue Percutaneous Electrolysis vs Corticosteroid Infiltration for the Treatment of Plantar Fasciosis. AB - BACKGROUND: Corticosteroid infiltration (CI) is commonly used for treatment of plantar fasciosis. In recent years, however, interest has grown in the use of intratissue percutaneous electrolysis (EPI) for the treatment of tendinopathies. The aim of our study was to compare the effectiveness of the above techniques in the treatment of plantar fasciosis. METHODS: The results achieved over a period of 1 year following the use of these techniques to treat plantar fasciosis were examined. There were 64 patients; 32 of whom were treated with ultrasound-guided EPI and 32 with ultrasound-guided CI. A clinical examination was performed and ultrasound taken before treatment and at 3, 6, and 12 months. Clinical assessments were made using a visual analog scale (VAS) to record pain and the Foot and Ankle Disability Index (FADI) to evaluate function. Ultrasound was used to determine the thickness of the plantar fascia. RESULTS: Both the ultrasound guided EPI and CI techniques were associated with significant clinical and echographic improvements at 12 months post-treatment ( P < .001). CONCLUSION: Both techniques were effective in the treatment of PF, providing excellent VAS pain and FADI results at 12 months. However, CI required fewer patient visits and appeared to provide somewhat better VAS and FADI results. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29436234 TI - Influence of HOTAIR rs920778 and rs12826786 genetic variants on prostate cancer risk and progression-free survival. AB - AIM: Evaluate the impact of the single nucleotide polymorphisms rs920778 and rs12826786 in the long noncoding RNA HOTAIR in the susceptibility and prognosis of prostate cancer (PCa) patients. PATIENTS & METHODS: HOTAIR single nucleotide polymorphisms were genotyped by restriction fragment length polymorphism in 151 PCa cases and 180 cancer-free controls. Odds ratio, 95% CIs and prognostic significance were calculated. RESULTS: Our data showed no statistically significant associations between HOTAIR polymorphic variants in rs920778 and rs12826786 and PCa susceptibility. However, the CC genotype in rs12826786 was significantly associated with shorter biochemical recurrence-free survival in pT3 stage PCa patients. CONCLUSION: Our results indicate that HOTAIR rs12826786 CC genotype may be an independent prognostic biomarker in a particular subset of PCa tumors. PMID- 29436235 TI - Long-term effects of vaginal erbium laser in the treatment of genitourinary syndrome of menopause. AB - OBJECTIVES: To evaluate the long-term efficacy of a second generation of vaginal laser treatment, the vaginal erbium laser, as a non-ablative photothermal therapy for the management of genitourinary syndrome of menopause. METHODS: The study was performed using an erbium laser crystal yttrium-aluminum-garnet (XS Fotona SmoothTM, Fotona, Ljubljana, Slovenia) with a wavelength of 2940 nm. Postmenopausal women (n = 205) were treated with three laser applications at 30 day intervals. Symptoms were assessed before and after treatment throughout 24 months, using the subjective visual analog scale (VAS) and the objective vaginal health index score (VHIS). In addition, postmenopausal women suffering from stress urinary incontinence were evaluated with the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF). RESULTS: Vaginal erbium laser treatment induced a significant (p < 0.01) decrease in VAS for both vaginal dryness and dyspareunia, as well an increase in VHIS (p < 0.01) up to the 12th month after the last laser treatment. The values returned to levels similar to the baseline after 18 and 24 months. In addition, vaginal erbium laser treatment improved mild-moderate stress urinary incontinence in 114 postmenopausal women. Less than 3% of patients discontinued treatment due to adverse events. CONCLUSIONS: These results suggest that vaginal erbium laser may be effective and safe for the treatment of genitourinary syndrome of menopause. PMID- 29436236 TI - Thiol/disulphide homeostasis in thoracic aortic aneurysm and acute aortic syndrome. AB - AIM: The aim of this study was to evaluate whether ranging values of thiol and disulphide herald a dilatation or impending acute aortic syndrome at thoracic aorta. Results/methodology: Study population consisted of patients with aortic aneurysm (n = 58), with acute aortic syndrome (n = 32) and without aortic aneurysm (control group; n = 61). A spectrophotometric method was used to determine thiol and disulphide. Native and total thiol levels were moderately correlated with maximal aortic diameter. At the end of 6 months, there was statistically significant increase in native, total thiol levels and decrease in disulfide and disulphide/native thiol ratio in operated group. DISCUSSION/CONCLUSION: Lower thiol levels may be associated with the higher risk of aortic aneurysm development and may increase after surgical therapy. PMID- 29436237 TI - Solid Variant of Aneurysmal Bone Cyst of the Temporal Bone. AB - OBJECTIVES: Aneurysmal bone cysts (ABC) are benign, rapidly growing osteolytic lesions. Solid variant of ABC (SVABC) is a rare subtype of ABC that has not been reported in the temporal bone. METHODS: We report the case of a 6-year-old boy presenting with a slowly enlarging bony protuberance over the right zygomatic/malar eminence region. Computed tomography and magnetic resonance imaging demonstrated a 2.6 * 5.8 * 5.1 cm temporal bone mass involving the right mastoid, petrous, and temporal squamosal calvarium, with extradural intracranial extension to the middle cranial fossa. RESULTS: The patient underwent preoperative embolization of feeder arteries followed by combined neurosurgical and neurotologic resection. Histopathology revealed characteristic ABC features with interspersed areas of intralesional osteoid formation. CONCLUSION: Solid variant of ABCs are rare lesions of the skull base that present a diagnostic challenge given their unique radiographic and histologic features. Thorough cytogenetic evaluation is warranted to rule out potential malignant secondary causes. Early surgical resection is essential due to the risk of intracranial extension. This is the first report of ABC of any type with concurrent involvement of the squamous, mastoid, and petrous portions of the temporal bone and the first report of SVABC of the temporal bone. PMID- 29436238 TI - The incremental role of trait emotional intelligence on perceived cervical screening barriers. AB - Researchers have become increasingly interested in investigating the role of the psychological aspects related to the perception of cervical screening barriers. This study investigates the influence of trait EI on perceived cervical screening barriers. Furthermore, this study investigates the incremental validity of trait EI beyond the Big Five, as well as emotion regulation in the perceived barrier towards the Pap test as revealed in a sample of 206 Italian women that were undergoing cervical screening. Results have shown that trait EI is negatively related to cervical screening barriers. Furthermore, trait EI can be considered as a strong incremental predictor of a woman's perception of screening over and above the Big Five, emotion regulation, age, sexual intercourse experience and past Pap test. Detailed information on the study findings and future research directions are discussed. PMID- 29436239 TI - The mRNA export factor Sac3 maintains nuclear homeostasis and regulates cytoskeleton organization in Candida albicans. AB - AIM: In eukaryotes, the nuclear export of mRNAs is essential for gene expression and regulations of numerous cellular processes. This study aimed to identify the mRNA export factor Sac3 in Candida albicans. MATERIALS & METHODS: A sac3Delta/Delta mutant was obtained using PCR-mediated homologous recombination. RESULTS: Disruption of SAC3 caused abnormal accumulation of mRNA in the nuclei. Further investigations revealed that sac3Delta/Delta mutant exhibited a severely growth defect, which was related to abnormal aggregation of microtubules. Moreover, loss of Sac3 caused a defect in hyphal polarized growth, which was associated with depolarization of actin cytoskeleton. In addition, the virulence of sac3Delta/Delta mutant was seriously attenuated. CONCLUSION: Our findings provide new insights into the mRNA export factor Sac3 in C. albicans. PMID- 29436240 TI - Oxidative stress as a biomarker for Alzheimer's disease. PMID- 29436241 TI - Bladder regeneration through stem cell therapy. AB - INTRODUCTION: Impaired bladder function in children and adults often causes lifelong morbidity, as functional therapeutic approaches in this field are nonexistent. If reconstructive procedures are required, intestinal tissue is used as a gold standard for bladder repair. As this procedure is associated with significant long-term complications there is a strong clinical need for alternative sources of stable and reliable bladder tissue, of which stem cells are considered most promising. Areas covered: This review focusses on the recent development in stem cell use for bladder bioengineering. Further, we discuss the importance of the microenvironment in stem cell differentiation, function and tissue regeneration and its effect on the development of functional bladder tissue. Expert opinion: Functional bladder bioengineering requires a complex approach that involves the development of a multi-layered scaffold, with each layer offering a specific microenvironment for the generation and support of the respective cell type used in its redevelopment. The formation of cellular cross talk within and between the layers is the key in this process. While autologous stem cells may provide a viable source of tissue for bladder reconstruction, their in situ activation combined with repair of the diseased microenvironment may offer better, more lasting solutions for functional bladder regeneration. PMID- 29436242 TI - Prediction in obstructive sleep apnoea: diagnosis, comorbidity risk, and treatment outcomes. AB - INTRODUCTION: Obstructive sleep apnoea (OSA) is common disorder, under-diagnosed, and can be difficult to treat adequately across the lifespan. OSA is a heterogeneous disorder with different risk factors, clinical presentations, pathophysiology and morbidity. Prediction has an important role in OSA recognition and management, embodied in screening methods to circumvent the need for diagnosis by overnight sleep studies and prediction of treatment efficacy and adherence. Other opportunities exist in predicting susceptibility to comorbidity and health outcomes. Areas covered: This review summarizes current prediction strategies as applied to OSA, covering diagnosis, consequences and treatment outcomes, as well as potential emergent areas of focus. Expert commentary: Prediction of disease risk, susceptibility to comorbidity, and treatment outcomes are important aspects of precision medicine. The key to accurate prediction in OSA relies on comprehensive understanding of disease phenotypes. PMID- 29436243 TI - The impact of using three-dimensional printed liver models for patient education. AB - Objective To investigate the impact of using a three-dimensional (3D) printed liver model for patient education. Methods Children with hepatic tumours who were scheduled for hepatectomy were enrolled, and patient-specific 3D liver models were printed with photosensitive resin, based on computed tomography (CT) images. Before surgery, their parents received information regarding liver anatomy, physiology, tumour characteristics, planned surgery, and surgical risks using these CT images. Then, parents completed questionnaires regarding this information. Thereafter, 3D printed models of each patient were presented along with an explanation of the general printing process, and the same questionnaire was completed. The median number of correct responses in each category before and after the 3D printed model presentation was compared. Results Seven children and their 14 parents were enrolled in the study. After the presentation of 3D printed models, parental understanding of basic liver anatomy and physiology, tumour characteristics, the planned surgical procedure, and surgical risks significantly improved. Parents demonstrated improvements in their understanding of basic liver anatomy by 26.4%, basic liver physiology by 23.6%, tumour characteristics by 21.4%, the planned surgical procedure by 31.4%, and surgical risks by 27.9%. Conclusions Using 3D printed liver models improved parental education regarding the understanding of liver anatomy and physiology, tumour characteristics, surgical procedure, and associated surgical risks. PMID- 29436244 TI - Improving multiple sclerosis management and collecting safety information in the real world: the MSDS3D software approach. AB - INTRODUCTION: For safety evaluation, randomized controlled trials (RCTs) are not fully able to identify rare adverse events. The richest source of safety data lies in the post-marketing phase. Real-world evidence (RWE) and observational studies are becoming increasingly popular because they reflect usefulness of drugs in real life and have the ability to discover uncommon or rare adverse drug reactions. Areas covered: Adding the documentation of psychological symptoms and other medical disciplines, the necessity for a complex documentation becomes apparent. The collection of high-quality data sets in clinical practice requires the use of special documentation software as the quality of data in RWE studies can be an issue in contrast to the data obtained from RCTs. The MSDS3D software combines documentation of patient data with patient management of patients with multiple sclerosis. Following a continuous development over several treatment specific modules, we improved and expanded the realization of safety management in MSDS3D with regard to the characteristics of different treatments and populations. Expert opinion: eHealth-enhanced post-authorisation safety study may complete the fundamental quest of RWE for individually improved treatment decisions and balanced therapeutic risk assessment. MSDS3D is carefully designed to contribute to every single objective in this process. PMID- 29436246 TI - Oscillating-gradient diffusion magnetic resonance imaging detects acute subcellular structural changes in the mouse forebrain after neonatal hypoxia ischemia. AB - The recently developed oscillating-gradient diffusion MRI (OG-dMRI) technique extends our ability to examine brain structures at different spatial scales. In this study, we investigated the sensitivity of OG-dMRI in detecting cellular and subcellular structural changes in a mouse model of neonatal hypoxia ischemia (HI). Neonatal mice received unilateral HI injury or sham injury at postnatal day 10, followed by in vivo T2-weighted and diffusion MRI of the brains at 3-6 h and 24 h after HI. Apparent diffusion coefficient (ADC) maps were acquired using conventional pulsed-gradient dMRI (PG-dMRI) and OG-dMRI with oscillating frequencies from 50 to 200 Hz. Pathology at cellular and subcellular levels was evaluated using neuronal, glial, and mitochondrial markers. We found significantly higher rates of ADC increase with oscillating frequencies (Delta fADC) in the ipsilateral edema region, compared to the contralateral side, starting as early as 3 h after HI. Even in injured regions that showed no apparent change in PG-ADC or pseudo-normalized PG-ADC measurements, Delta fADC remained significantly elevated. Histopathology showed swelling of sub-cellular structures in these regions with no apparent whole-cell level change. These results suggest that OG-dMRI is sensitive to subcellular structural changes in the brain after HI and is less susceptible to pseudo-normalization than PG-dMRI. PMID- 29436245 TI - Vitamin A intake of Brazilian mothers and retinol concentrations in maternal blood, human milk, and the umbilical cord. AB - Objectives To analyse intake of vitamin A (VA) and retinol concentrations in maternal blood, breast milk (BM), and the umbilical cord (UC) of newborns, and to determine the associations among these variables. Methods We performed a cross sectional, epidemiological study of 180 mother-newborn dyads. Maternal and UC blood samples and BM were collected. VA intake by the mother over 30 days was assessed using a questionnaire. Results Mean retinol concentrations in maternal serum, the UC, and BM were 0.65 +/- 0.27, 0.36 +/- 0.18, and 2.95 +/- 2.70 umol/L, respectively. Retinol concentrations <0.70 umol/L were found in 57.2% of maternal blood samples and in 94.9% of UC samples. A total of 27.9% of BM samples showed retinol concentrations <1.05 umol/L. Mean VA intake by the mothers was 1041.33 +/- 1187.86 ug retinol activity equivalents/day and was inadequate (<550 ug retinol activity equivalents/day) in 44.7%. Conclusions High proportions of insufficient retinol concentrations were observed in the UC, maternal blood, and BM. A high percentage of pregnant women had inadequate VA intake. Mothers with insufficient serum retinol concentrations had newborns with lower retinol concentrations in the UC. Higher retinol concentrations were observed in maternal blood and the UC with a higher VA intake. PMID- 29436247 TI - Comparing the Value of Nonprofit Hospitals' Tax Exemption to Their Community Benefits. AB - The tax-exempt status of nonprofit hospitals has received increased attention from policymakers interested in examining the value they provide instead of paying taxes. We use 2012 data from the Internal Revenue Service (IRS) Form 990, Centers for Medicare and Medicaid Services (CMS) Hospital Cost Reports, and American Hospital Association's (AHA) Annual Survey to compare the value of community benefits with the tax exemption. We contrast nonprofit's total community benefits to what for-profits provide and distinguish between charity and other community benefits. We find that the value of the tax exemption averages 5.9% of total expenses, while total community benefits average 7.6% of expenses, incremental nonprofit community benefits beyond those provided by for profits average 5.7% of expenses, and incremental charity alone average 1.7% of expenses. The incremental community benefit exceeds the tax exemption for only 62% of nonprofits. Policymakers should be aware that the tax exemption is a rather blunt instrument, with many nonprofits benefiting greatly from it while providing relatively few community benefits. PMID- 29436248 TI - Factors Influencing the Total Inpatient Pharmacy Cost at a Tertiary Hospital in Malaysia: A Retrospective Study. AB - The steady growth of pharmaceutical expenditures is a major concern for health policy makers and health care managers in Malaysia. Our study examined the factors affecting the total inpatient pharmacy cost (TINPC) at the Universiti Kebangsaan Malaysia Medical Centre (UKMMC). In this retrospective study, we used 2011 administration electronic prescriptions records and casemix databases at UKMMC to examine the impact of sociodemographic, diagnostic, and drug variables on the TINPC. Bivariate and multivariate analyses of the factors associated with TINPC were conducted. The mean inpatient pharmacy cost per patient was USD 102.07 (SD = 24.76). In the multivariate analysis, length of stay (LOS; B = 0.349, P < .0005) and severity level III ( B = 0.253, P < .0005) were the primary factors affecting the TINPC. For each day increase in the LOS and each increase of a case of severity level III, there was an increase of approximately USD 11.97 and USD 171.53 in the TINPC per year, respectively. Moreover, the number of prescribed items of drugs and supplies was positively associated with the TINPC ( B = 0.081, P < .0005). Gender appears to have affected the TINPC; male patients seem to be associated with a higher TINPC than females (mean = 139.55, 95% confidence interval [CI]: 112.97-166.13, P < .001). Surgical procedures were associated with higher cost than medical cases (mean = 87.93, 95% CI: 61.00-114.85, P < .001). Malay (MYR 242.02, SD = 65.37) and Chinese (MYR 214.66, SD = 27.99) ethnicities contributed to a lower TINPC compared with Indian (MYR 613.93, SD = 98.41) and other ethnicities (MYR 578.47, SD = 144.51). A longer hospitalization period accompanied by major complications and comorbidities had the greatest influence on the TINPC. PMID- 29436249 TI - Rare symptomatic bladder leiomyoma: case report and literature review. AB - Bladder leiomyoma is a rare, benign tumour of the bladder. We present a clinical case of a 47-year-old asymptomatic woman with symptomatic bladder leiomyoma. Computed tomography showed well-defined bladder leiomyoma in the right posterior bladder wall. After partial cystectomy, pathology findings confirmed leiomyoma of bladder, and the patient achieved clinical recovery in 8 months. We discuss the relevant recent literature of bladder leiomyoma. PMID- 29436250 TI - Effects of preconditioned plasma collected during the late phase of remote ischaemic preconditioning on ventricular arrhythmias caused by myocardial ischaemia reperfusion in rats. AB - Objective The administration of preconditioned plasma collected during the late phase of preconditioning has been shown to reduce myocardial infarct size. This study aimed to investigate if preconditioned plasma could attenuate ventricular arrhythmias in a rat model in vivo. Methods Eighty rats were randomized to eight groups (10 rats/group). Two groups provided preconditioned or non-preconditioned plasma 48 h after transient limb ischaemia or the control protocol. Six groups of ischaemia-reperfusion (IR) rats received normal saline, non-preconditioned plasma, or preconditioned plasma, respectively, 1 h (groups A1, A2, A3) or 24 h (groups B1, B2, B3) before undergoing myocardial IR. Electrocardiograms were monitored using a BIOPAC system, and the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) were analysed. Results No significant differences existed in the incidence and duration of VT or VF among groups A1-A3 or in the incidence and duration of VT among groups B1-B3. However, there was a significantly lower incidence and shorter duration of VF in group B3 rats than in group B1 rats. Conclusion Preconditioned plasma collected during the late phase of preconditioning can reduce the incidence and duration of VF compared with normal saline, suggesting its anti-arrhythmic potential. PMID- 29436251 TI - Improvement of Metabolic Control and Diabetes Management in Insulin-Treated Patients Results in Substantial Cost Savings for the German Health System. AB - BACKGROUND: Self-monitoring of blood glucose (SMBG) using the ColourSureTM Technology to visualize target range showed improvement of metabolic control and overall diabetes self-management in insulin-treated patients. This economic analysis aimed to identify cost savings for the German health system resulting from an HbA1c reduction due to the utilization of user-friendly glucose meters. METHODS: Patient data from a recently published observational study on SMBG were used for risk evaluations using the UKPDS risk engine. These values were integrated in an economic analysis regarding costs of myocardial infarctions (MIs) related to diabetes for the German health system. Based on an earlier assessment these calculations were combined with a 10% reduction of severe hypoglycemic episodes. In the current study, 0% severe hypoglycemic episodes were observed. RESULTS: An HbA1c reduction of 0.69% over 6 months was associated with a 3% decreased risk of MI in 10 years. In this model the decrease led to cost savings of ?4.90 per patient-year. Considering 2.3 million insulin-treated patients in Germany, this 3% reduction of MI could result in annual savings of ?11.27 million. Combining this with a 10% reduction in severe hypoglycemic events, the cost savings would increase to ?30.61 per patient-year or ?70.4 million for 2.3 million insulin-treated patients in Germany. CONCLUSION: The improvement of metabolic control and diabetes self-management that was achieved with the ColourSureTM Technology has the potential to generate substantial cost savings for the German health system underlining the importance of user-friendly methods for SMBG. PMID- 29436253 TI - Promoting activity, independence and stability in early dementia and mild cognitive impairment (PrAISED): development of an intervention for people with mild cognitive impairment and dementia. AB - : This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless, they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is an understanding of how to develop an intervention for people with mild cognitive impairment and dementia to promote their independence, stability, and physical activity. INTRODUCTION: Older adults with dementia are at a high risk of falls. Standard interventions have not been shown to be effective in this patient population potentially due to poor consideration of dementia-specific risk factors. An intervention is required that addresses the particular needs of older people with dementia in a community setting. METHODS: We followed guidelines for the development of an intervention, which recommend a structured approach considering theory, evidence and practical issues. The process used 15 information sources. Data from literature reviews, clinician workshops, expert opinion meetings, patient-relative interviews, focus groups with people with dementia and clinicians, a cross-sectional survey of risk factors, a pre-post intervention study and case studies were included. Data were synthesized using triangulation to produce an intervention suitable for feasibility testing. Practical consideration of how an intervention could be delivered and implemented were considered from the outset. RESULTS: Elements of the intervention included individually tailored, dementia-appropriate, balance, strength and dual-task exercises, functional training, and activities aimed at improving environmental access, delivered using a motivational approach to support adherence and long-term continuation of activity. We focussed on promoting safe activity rather than risk or prevention of falls. CONCLUSION: We used a systematic process to develop a dementia-specific intervention to promote activity and independence while reducing falls risk in older adults with mild dementia. PMID- 29436256 TI - Serum potassium and acute coronary syndrome: In medio stat virtus. PMID- 29436255 TI - Coronary tortuosity is associated with an elevated high-sensitivity C-reactive protein concentration and increased risk of ischemic stroke in hypertensive patients. AB - Objective The clinical implication of coronary tortuosity is unclear. The present study was conducted to determine the relationships between coronary tortuosity and the high-sensitivity C-reactive protein (hs-CRP) concentration and between coronary tortuosity and cerebrovascular accident in hypertensive patients without coronary artery disease. Methods In total, 236 patients with normal coronary angiography findings were categorized into 3 different groups: control participants (n = 58), who had neither hypertension nor coronary tortuosity; patients with hypertension but no coronary tortuosity (H-NCT group, n = 93); and patients with both hypertension and coronary tortuosity (H-CT group, n = 85). The hs-CRP concentration was measured in every patient, and 168 hypertensive patients were followed up for at least 2 years to check for the development of cerebrovascular accident. Results The hs-CRP concentration was significantly higher in the H-CT group than in the control and H-NCT groups (4.33 +/- 3.15 vs. 1.52 +/- 1.31 and 2.31 +/- 2.09 mg/L, respectively). The incidence of lacunar infarction was higher in the H-CT than H-NCT group during the follow-up. Conclusions Hypertensive patients with coronary tortuosity have a higher serum hs CRP level concentration and have a higher incidence of lacunar infarction than hypertensive patients without coronary tortuosity. PMID- 29436254 TI - Therapeutic targets for altering mitochondrial dysfunction associated with diabetic retinopathy. AB - INTRODUCTION: Retinopathy remains as one of the most feared blinding complications of diabetes, and with the prevalence of this life-long disease escalating at an alarming rate, the incidence of retinopathy is also climbing. Although the cutting edge research has identified many molecular mechanisms associated with its development, the exact mechanism how diabetes damages the retina remains obscure, limiting therapeutic options for this devastating disease. Areas covered: This review focuses on the central role of mitochondrial dysfunction/damage in the pathogenesis of diabetic retinopathy, and how damaged mitochondria initiates a self-perpetuating vicious cycles of free radicals. We have also reviewed how mitochondria could serve as a therapeutic target, and the challenges associated with the complex double mitochondrial membranes and a well defined blood-retinal barrier for optimal pharmacologic/molecular approach to improve mitochondrial function. Expert opinion: Mitochondrial dysfunction provides many therapeutic targets for ameliorating the development of diabetic retinopathy including their biogenesis, DNA damage and epigenetic modifications. New technology to enhance pharmaceuticals uptake inside the mitochondria, nanotechnology to deliver drugs to the retina, and maintenance of mitochondrial homeostasis via lifestyle changes and novel therapeutics to prevent epigenetic modifications, could serve as some of the welcoming avenues for a diabetic patient to target this sight-threatening disease. PMID- 29436257 TI - Accelerated collagen turnover in women with angina pectoris without obstructive coronary artery disease: An iPOWER substudy. AB - Aim Collagens are major cardiac extracellular matrix components, known to be actively remodelled and accumulated during diffuse myocardial fibrosis. We evaluated whether accelerated collagen turnover described by neo-epitope biomarkers reflecting collagen formation and degradation separates patients with diffuse myocardial fibrosis from asymptomatic controls. Methods and results Seventy-one women with angina pectoris without significant coronary artery disease assessed by invasive coronary angiogram were included. Competitive enzyme linked immunosorbent assays (ELISAs) measuring circulating protein fragments in serum assessed the formation and degradation of collagen type III (Pro-C3, C3M and C3C), IV (P4NP7S and C4M), V (Pro-C5 and C5M) and VI (Pro-C6 and C6M), and degradation of collagen type I (C1M). Serum samples from 32 age-matched asymptomatic women were included as controls. Symptomatic women presented significantly elevated levels of Pro-C6, C3C, C3M, C4M and C8-C ( p < 0.0001 0.0058) and significantly decreased levels of Pro-C3, C5M and C6M ( p < 0.0001 0.041), reflecting accelerated collagen turnover and an imbalanced collagen formation and degradation compared to controls. Cardiac magnetic resonance T1 mapping was performed to determine extracellular volume fraction and thus diffuse myocardial fibrosis. A significant association was identified between C5M and extracellular volume fraction by cardiac magnetic resonance ( p = 0.01). Conclusion Women with angina pectoris, but without significant obstructive coronary artery disease, showed an imbalanced collagen turnover compared to asymptomatic controls. The examined biomarkers are tools to monitor active collagen remodelling in patients with angina pectoris, in risk of developing myocardial fibrosis. PMID- 29436258 TI - Amnesic patients have residual prospective memory capacities. AB - OBJECTIVE: To investigate, in two separate studies, whether amnesic patients with a severe memory impairment can learn to perform a habitual prospective memory task when they receive immediate feedback on prospective memory failures (Study 1) and whether amnesic patients are able to benefit from previous habitual prospective memory performance after a 24-h retention interval. METHOD: A prospective memory task was embedded in a lexical decision task (Study 1) and in a perceptual discrimination task (Study 2). Performance was compared across test halves. Participants received immediate performance feedback on prospective memory failures that served as a reminder for the prospective memory task. A retest was performed after 24 h in Study 2, but without immediate feedback in the first test half. RESULTS: In Study 1, amnesic patients performed at a lower level than the control group, but they improved significantly across the experiment. In Study 2, the results of the first session replicated this pattern. The results of the second session showed a performance breakdown in amnesic patients. However, one single reminder was enough to boost performance again on the level of the second part of day one. CONCLUSIONS: This indicates that amnesic patients have residual prospective memory capacities and that providing immediate feedback is a promising strategy to draw on these capacities. PMID- 29436259 TI - Two Novel Approaches to Improve Otolaryngology Resident Wellness: The ACGME Back to Bedside Initiative. AB - Rates of burnout, mental illness, and suicide are disproportionately elevated among physicians, and surgical specialists, including otolaryngologists, are at even higher risk for professional burnout. These trends have been identified at both the trainee and attending level. To combat resident burnout, the Accreditation Council for Graduate Medical Education (ACGME) Council of Review Committee Residents (CRCR) designed the Back to Bedside Initiative, the goals of which are to foster meaning in the learning environment and to help trainees to engage more deeply with patients. Two funded Back to Bedside proposals involve otolaryngology training programs. Herein, we discuss these 2 approaches in an effort to foster additional novel resident wellness initiatives and awareness thereof across our subspecialty. PMID- 29436260 TI - Treatment Patterns and Associated Health Care Costs Before and After Treatment Initiation Among Pulmonary Arterial Hypertension Patients in the United States. AB - BACKGROUND: Despite multiple treatment options, the prognosis of pulmonary arterial hypertension (PAH) remains poor. PAH patients experience a high economic burden due to comorbidities, hospitalizations, and medication costs. Although combination therapy has been shown to reduce hospitalizations, the relationship between treatment, health care utilization, and costs remains unclear. OBJECTIVE: To provide a characterization of health care utilization and costs in real-world settings by comparing periods before and after initiating PAH-specific treatment. METHODS: This retrospective study identified PAH patients in the Truven Health MarketScan Commercial and Medicare Supplemental Databases between 2010 and 2014 who initiated treatment with endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE-5Is), or soluble guanylate cyclase (sGC) stimulators. The index date was the date of the first PAH pharmacy claim. We included patients with >= 2 medical claims with diagnoses for PAH (ICD-9-CM: 416.0, 416.8) or PAH-related conditions and continuous enrollment in medical and pharmacy benefits for the 6 months before and after the index date. Treatment patterns were assessed at the drug class level (ERAs, PDE-5Is, sGC stimulators, and prostacyclins) from outpatient pharmacy claims during the 6-month post-index period. All-cause and PAH-related utilization and costs were measured. McNemar's and paired t-tests were used to compare patients' health care resource utilization and costs in the 6-month pre- and posttreatment periods. RESULTS: A total of 3,908 patients met the selection criteria. The study sample was 63% female with a mean age of 63 +/- 15 years. Only 5% of patients began initial combination therapy for PAH, defined as claims for >= 2 medication classes within the first 30 days of treatment. Treatment interruption (>= 30-day gap in days supply) of any PAH-specific medication was observed in 38% of patients. Compared with the 6-month pre-index period, the proportion of patients in the 6-month post index period with any inpatient admission decreased, 42% versus 30% (P < 0.001). In addition, PAH-related inpatient admissions decreased in the 6-month post-index period from 7% to 3% (P < 0.001). After treatment initiation, patients' nonpharmacy medical costs decreased from $48,200 (SD = $117,686) to $33,962 (SD = $90,294; P < 0.001), mainly attributable to reduced inpatient costs. However, total average medical costs including pharmacy costs remained comparable after treatment initiation (pre-index period = $51,455 vs. post-index period = $53,923; P = 0.213). CONCLUSIONS: This study found that while patients' PAH-related pharmacy costs increased after treatment initiation, the increase was offset by reduced inpatient utilization; therefore, total health care costs remained constant. While the majority of patients in this study were treated with monotherapy, the recently completed AMBITION study indicated that initial combination therapy with ambrisentan plus tadalafil reduced PAH-related hospitalizations compared with initial monotherapy with either of these agents. Future cost analyses of patients treated with combination therapy will be required to determine the economic effect of initial combination therapy. DISCLOSURES: This study was sponsored and funded by Gilead Sciences. Ozbay is an employee of Gilead Sciences. At the time that this project and manuscript were developed, Lazarus was an employee of Gilead Sciences and may own stock/stock options. Riehle, Montejano, and Lenhart are employees of Truven Health Analytics, an IBM company, which received funding from Gilead Sciences to conduct this study. Burger and White do research with, and are paid consultants for, Gilead Sciences; they do not own equity and received no personal compensation for the work here. Burger also reports consultancy and advisory board work for Actelion Pharmaceuticals and grants from Gilead Sciences, Actelion Pharmaceuticals, Bayer, and United Therapeutics. PMID- 29436262 TI - Commentary: One Small Step. PMID- 29436263 TI - Use Strategic Marketing to Maintain a Healthy Practice. AB - Market research is key to optimizing your marketing efforts and budget. Although it is often the most time-consuming step, having a plan will pay off in the long run, so conduct research on consumers in your market area, referring physicians, and your competition. PMID- 29436261 TI - An epigenomic approach to identifying differential overlapping and cis-acting lncRNAs in cisplatin-resistant cancer cells. AB - Long noncoding RNAs (lncRNAs) are critical regulators of cell biology whose alteration can lead to the development of diseases such as cancer. The potential role of lncRNAs and their epigenetic regulation in response to platinum treatment are largely unknown. We analyzed four paired cisplatin-sensitive/resistant non small cell lung cancer and ovarian cancer cell lines. The epigenetic landscape of overlapping and cis-acting lncRNAs was determined by combining human microarray data on 30,586 lncRNAs and 20,109 protein coding mRNAs with whole-genome bisulfite sequencing. Selected candidate lncRNAs were further characterized by PCR, gene-ontology analysis, and targeted bisulfite sequencing. Differential expression in response to therapy was observed more frequently in cis-acting than in overlapping lncRNAs (78% vs. 22%, fold change >=1.5), while significantly altered methylation profiles were more commonly associated with overlapping lncRNAs (29% vs. 8%; P value <0.001). Moreover, overlapping lncRNAs contain more CpG islands (CGIs) (25% vs. 17%) and the majority of CGI-containing overlapping lncRNAs share these CGIs with their associated coding genes (84%). The differences in expression between sensitive and resistant cell lines were replicated in 87% of the selected candidates (P<0.05), while our bioinformatics approach identifying differential methylation was confirmed in all of the selected lncRNAs (100%). Five lncRNAs under epigenetic regulation appear to be involved in cisplatin resistance (AC091814.2, AC141928.1, RP11-65J3.1-002, BX641110, and AF198444). These novel findings provide new insights into epigenetic mechanisms and acquired resistance to cisplatin that highlight specific lncRNAs, some with unknown function, that may signal strategies in epigenetic therapies. PMID- 29436264 TI - The Sisters Network: A National African American Breast Cancer Survivor Advocacy Organization. AB - Founded in 1994 by an African American woman who was diagnosed with breast cancer only a few months earlier, the Sisters Network advocacy organization today has nearly 3,000 members in 35 chapters throughout the country. PMID- 29436265 TI - ASCO Announces New Program Designed to Increase Workforce Diversity and Reduce Cancer Care Disparities. AB - ASCO's Diversity in Oncology Initiative, funded by Susan G. Komen for the Cure, is the first program of its kind designed to increase the number of oncologists practicing in medically underserved areas. PMID- 29436266 TI - Sick Sigmas. PMID- 29436267 TI - News and Notes From the 2009 Carrier Advisory Committee Meeting: Medical Necessity, Off-Label Chemotherapy, and More. AB - A discussion of two compelling topics at this summer's Hematology-Oncology Carrier Advisory Committee Network Meeting: coverage for off-label uses of anticancer drugs and medical necessity for oral versus intravenous antiemetics. PMID- 29436268 TI - Patient Decision Making in Vestibular Schwannoma: A Survey of the Acoustic Neuroma Association. AB - Objective To assess the decision-making process of patients with vestibular schwannoma (VS). Study Design Patients with VS completed a voluntary survey over a 3-month period. Setting Surveys were distributed online through email, Facebook, and member website. Subjects and Methods All patients had a diagnosis of VS and were members of the Acoustic Neuroma Association (ANA). A total of 789 patients completed the online survey. Results Of the 789 participants, 474 (60%) cited physician recommendation as a significant influential factor in deciding treatment. In our sample, 629 (80%) saw multiple VS specialists and 410 (52%) sought second opinions within the same specialty. Of those who received multiple consults, 242 (59%) of patients reported receiving different opinions regarding treatment. Those undergoing observation spent significantly less time with the physician (41 minutes) compared to surgery (68 minutes) and radiation (60 minutes) patients ( P < .001). A total of 32 (4%) patients stated the physician alone made the decision for treatment, and 29 (4%) felt they did not understand all possible treatment options before final decision was made. Of the 414 patients who underwent surgery, 66 (16%) felt they were pressured by the surgeon to choose surgical treatment. Conclusion Deciding on a proper VS treatment for patients can be complicated and dependent on numerous clinical and individual factors. It is clear that many patients find it important to seek second opinions from other specialties. Moreover, second opinions within the same specialty are common, and the number of neurotologists consulted correlated with higher decision satisfaction. PMID- 29436269 TI - Unrepaired Complete Tracheal Rings: Natural History and Management Considerations. AB - Objectives To document the natural growth pattern of unrepaired complete tracheal rings (UCTRs) and describe the patient population managed conservatively. Study Design Case series with chart review. Setting Tertiary pediatric academic center. Subjects/Methods Medical records of patients with confirmed complete tracheal rings on bronchoscopy from 1993 to 2017 were reviewed. Patients aged 0 to 18 who had documented tracheal sizing over time and did not require surgical intervention were included. Exclusion criteria included tracheal stenosis not caused by complete tracheal rings. Comorbidities and airway characteristics were documented in addition to endoscopic findings. These were compared with children requiring surgical repair. Results In total, 149 patients with complete tracheal rings were identified. Twenty-five had UCTRs for an overall 16.8% rate of conservative management. Nineteen patients met inclusion criteria and underwent a total of 90 microlaryngoscopy and bronchoscopies (MLBs) with sizing. The growth of the UCTRs over time, based on MLB sizing, was chronicled. The median airway growth noted was 0.38 mm/y. A moderately strong positive correlation was seen between age and airway size ( rs = 0.72, P < .0001). Children with UCTRs were less likely to have long-segment involvement than those who required repair (92%, P = .024). Conclusions A select group of children with complete tracheal rings can be managed expectantly without surgical intervention. Conservative management may be less successful in children with long-segment complete tracheal rings. Airway growth does occur in this population and can be monitored over time. Having a standardized method for sizing UCTRs allows for more effective communication between providers and assurance of continued growth of the airway while following these patients. PMID- 29436271 TI - CPC: Let It Be. PMID- 29436270 TI - Where Does Telemedicine Fit into Otolaryngology? An Assessment of Telemedicine Eligibility among Otolaryngology Diagnoses. AB - Telemedicine applications are expanding to improve access to specialty care in rural areas. Telemedicine is not routinely used to evaluate new patients in otolaryngology, and it remains unclear which patients could benefit from this technology. This study estimates the rate of telemedicine eligibility among specific otolaryngology diagnoses. We conducted a retrospective cohort study of all ear, nose, and throat consults between August 1, 2013, and July 31, 2015. We paired diagnoses ( International Classification of Disease, Ninth Revision) with office-based procedures ( Current Procedural Terminology) and applied prespecified telemedicine eligibility criteria to encounters retroactively. If a specialized procedure was necessary to reach a diagnosis, the diagnosis was considered ineligible for telemedicine. We found that 62% of otolaryngology encounters would likely be eligible for telemedicine. Patients with inner and middle ear problems were more likely eligible for telemedicine, while patients with problems affecting the larynx and external ear were least likely eligible. Nearly 90% of veterans drove >1 hour round-trip for services. Understanding which otolaryngology problem types are more frequently eligible for telemedicine may assist those who are planning to implement a telemedicine program. PMID- 29436272 TI - Anatomy of a Cancer Center Transaction: Part II. AB - The second of a two-part series comparing two models for structuring a community based cancer center on a collaborative basis between oncologists and a hospital. PMID- 29436273 TI - Appropriate Billing for Infusion Pumps Used in Prolonged Chemotherapy Provided in the Office Setting. PMID- 29436275 TI - Predictors of Readmission and Reoperation in Patients Undergoing Parathyroidectomy for Primary Hyperparathyroidism. AB - Objective Identify risk factors for 30-day reoperation and readmission after parathyroidectomy for primary hyperparathyroidism. Study Design Retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database from 2012 through 2014. Subjects and Methods Patients undergoing parathyroidectomy and parathyroid reexploration for primary hyperparathyroidism. Univariate and multivariate analyses were conducted to determine risk factors for reoperation and readmission. Results Of the 9439 patients who underwent parathyroidectomy, 72 patients underwent 1 reoperation in the first 30 days after surgery, and 8 patients underwent 2 reoperations. The most common reasons were hematoma (25%) and persistent hyperparathyroidism (15.9%). Risk factors included smoking (odds ratio [OR], 1.86; 95% confidence interval [CI], 0.97-3.31), insulin-dependent diabetes (OR, 2.38; 95% CI, 1.02 4.86), and history of bleeding disorder (OR, 3.95; 95% CI, 1.48-8.79). In total, 182 (1.9%) patients were readmitted within 30 days of surgery; the most common cause was hypocalcemia (17.0%). Risk factors included operative time (hours) (OR, 1.3; 95% CI, 1.1-1.5), insulin-dependent diabetes mellitus (OR, 2.01; 95% CI, 1.2 3.3), dyspnea with moderate exertion (OR, 5.77; 95% CI, 0.86-14.67), and age (decade) (OR, 1.16; 95% CI, 1.02-1.32). Patients undergoing outpatient surgery were less likely to be readmitted (OR, 0.49; 95% CI, 0.35-0.69) or undergo reoperation (OR, 0.44; 95% CI, 0.27-0.73). Conclusions Thirty-day reoperation rate after parathyroidectomy was low and most commonly occurred due to hematoma. Risk factors for readmission were multifactorial and associated with perioperative factors, patient factors, and medical comorbidities. Preoperative counseling for patients at increased risk of readmission and reoperation may decrease these rates. PMID- 29436276 TI - Utility of the Modified Surgical Apgar Score in a Head and Neck Cancer Population. AB - Objective The Surgical Apgar Score (SAS) is a validated postoperative complication prediction model. The purpose of this study was to investigate the utility of the SAS in a diverse head and neck cancer population and to compare it with a recently developed modified SAS (mSAS) that accounts for intraoperative transfusion. Study Design Case series with chart review. Setting Academic tertiary care medical center. Subjects and Methods This study comprised 713 patients undergoing surgery for head and neck cancer from April 2012 to March 2015. SAS values were calculated according to intraoperative data obtained from anesthesia records. The mSAS was computed by assigning an estimated blood loss score of zero for patients receiving intraoperative transfusions. Primary outcome was 30-day postoperative morbidity. Results Mean SAS and mSAS were 6.3 +/- 1.5 and 6.2 +/- 1.7, respectively. SAS and mSAS were significantly associated with 30 day postoperative morbidity, length of stay, operative time, American Society of Anesthesiologists status, race, and body mass index ( P < .05); however, no significant association was detected for age, sex, and smoking status. Multivariable analysis identified SAS and mSAS as independent predictors of postoperative morbidity, with the mSAS ( P = .03) being a more robust predictor than the SAS ( P = .15). Strong inverse relationships were demonstrated for the SAS and mSAS with length of stay and operative time ( P < .0001). Conclusion The SAS serves as a useful metric for risk stratification of patients with head and neck cancer. With the inclusion of intraoperative transfusion, the mSAS demonstrates superior utility in predicting those at risk for postoperative complications. PMID- 29436277 TI - Initial Load Stability of Different Trachea Suture Techniques: Tests on an Ex Vivo Model. AB - Objective Tracheal anastomosis can be performed with different suture techniques. In this experimental work, the resilience of anastomotic techniques to pressure and tensile stress was studied. Study Design Ex vivo pig model. Setting Experimental. Subjects and Methods The trachea with the 2 main bronchi in freshly slaughtered pigs was isolated and intubated (CH 8.0). Both main bronchi were closed distally by a stapler. After resection of the trachea, an anastomosis (n = 15 per group) was created: group 1, single interrupted sutures; group 2, continuous running suture; group 3, mixed technique. A continuous tensile stress of 0, 500, 1000, or 1500 g was applied to the preparations. Mechanical ventilation with a maximum pressure of 70 mbar was initiated. The airtightness of the anastomosis was verified by submerging the entire preparation under water. Results At tensile loads of 0.5 and 1.0 kg, all anastomoses created in the single stitch technique were airtight; at 1.5 kg, 93.3% were without leaks. In the continuous suture technique, the airtightness of anastomoses decreased with increasing tensile load: from 93.3% at 500 g to 73.3% at 1 kg and 66.6% at 1.5 kg ( P = .02 at 1.5 kg). Anastomoses in the mixed technique were airtight in 80% at 500 g, 66.6% at 1 kg, and 46.6% at 1.5 kg ( P = .01 in comparison with single stitches). Conclusion Anastomoses created with single interrupted sutures showed the highest resilience against combined pressure and tensile stress. PMID- 29436278 TI - Assessing the Impact of Targeting CEACAM1 in Head and Neck Squamous Cell Carcinoma. AB - Objective In conjunction with advances made in cytotoxic chemotherapy, radiation, and surgery, immunotherapy has emerged as a fourth modality of treatment for head and neck squamous cell carcinoma (HNSCC). Understanding the mechanisms by which HNSCC evades immune-mediated control will aid in the development of new therapies to augment an antitumor immune response. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a cell surface receptor that is expressed on malignant cells and lymphocytes such as natural killer (NK) cells. We sought to determine whether tumor-derived CEACAM1 inhibits NK cell cytotoxicity and whether blockade of CEACAM1 restores antitumor immunity. Study Design In vitro HNSCC cell line study. Setting Research laboratory. Subject and Methods We utilized a real time cell analyzer to assess NK cell cytotoxicity against an oral squamous cell carcinoma cell line after modulating CEACAM1 expression by cytokines and shRNA knockdown of CEACAM1 expression. Results NK cells and HNSCC cells both demonstrated cytokine-inducible expression of CEACAM1. Coincubation of NK cells and HNSCC cells resulted in the upregulation of CEACAM1 on the tumor cells. When compared with CEACAM1- cells, CEACAM1+ tumor cells exhibited increased cell growth and increased size and number of organoids in 3-dimensional culture. Notably, CEACAM1+ HNSCC cells were more resistant to NK cell-mediated killing, but the inhibited expression of CEACAM1 by an shRNA construct restored NK cell cytotoxicity. Conclusion Together, these data indicate that CEACAM1 acts as an inducible checkpoint molecule, and they support the idea that targeting CEACAM1 could serve as a novel immunotherapy approach in HNSCC. PMID- 29436279 TI - Integrated palliative care is about professional networking rather than standardisation of care: A qualitative study with healthcare professionals in 19 integrated palliative care initiatives in five European countries. AB - BACKGROUND: Integrated palliative care aims at improving coordination of palliative care services around patients' anticipated needs. However, international comparisons of how integrated palliative care is implemented across four key domains of integrated care (content of care, patient flow, information logistics and availability of (human) resources and material) are lacking. AIM: To examine how integrated palliative care takes shape in practice across abovementioned key domains within several integrated palliative care initiatives in Europe. DESIGN: Qualitative group interview design. SETTING/PARTICIPANTS: A total of 19 group interviews were conducted (2 in Belgium, 4 in the Netherlands, 4 in the United Kingdom, 4 in Germany and 5 in Hungary) with 142 healthcare professionals from several integrated palliative care initiatives in five European countries. The majority were nurses ( n = 66; 46%) and physicians ( n = 50; 35%). RESULTS: The dominant strategy for fostering integrated palliative care is building core teams of palliative care specialists and extended professional networks based on personal relationships, shared norms, values and mutual trust, rather than developing standardised information exchange and referral pathways. Providing integrated palliative care with healthcare professionals in the wider professional community appears difficult, as a shared proactive multidisciplinary palliative care approach is lacking, and healthcare professionals often do not know palliative care professionals or services. CONCLUSION: Achieving better palliative care integration into regular healthcare and convincing the wider professional community is a difficult task that will take time and effort. Enhancing standardisation of palliative care into education, referral pathways and guidelines and standardised information exchange may be necessary. External authority (policy makers, insurance companies and professional bodies) may be needed to support integrated palliative care practices across settings. PMID- 29436280 TI - Clinicopathologic Characteristics and Survival Outcomes in Floor of Mouth Squamous Cell Carcinoma: A Population-Based Study. AB - Objective To describe the determinants of survival for patients with floor of mouth (FOM) squamous cell carcinoma (SCC) from 1973 to 2013 with the SEER database (Surveillance, Epidemiology, and End Results). Study Design and Setting Retrospective cohort study with a national database. Subjects and Methods The SEER registry was utilized to calculate survival trends for patients with FOM SCC between 1973 and 2013. Patient data were analyzed with respect to age, sex, race, primary site, stage at presentation, tumor size, grade, and treatment modalities (surgery and radiotherapy). Overall survival (OS) and disease-specific survival (DSS) were calculated. Results A total of 14,010 FOM SCC cases were identified. The cohort was 69.5% male, and the median age at diagnosis was 62 years. Forty six percent of cases were treated with surgery, while 14% received radiotherapy. Kaplan-Meier analysis demonstrated OS and DSS of 39% and 59% at 5 years, respectively. Multivariate analysis showed that age, grade, stage, size, and surgery were determinants for OS and DSS (all P < .05). For early- and advanced stage cancers, age, grade, size, and surgery predicted OS and DSS, while radiotherapy was a predictor of OS and DSS in advanced-stage tumors only (all P < .05). Conclusion To our knowledge, this study is the largest to date investigating prognostic factors for survival of patients diagnosed with FOM SCC. Determinants of survival include age, grade, stage, size, and surgery. Surgery appears to play a critical role in the management of these tumors. PMID- 29436281 TI - Professional Disappointment as a Cause of Burnout. AB - Burnout is common among physicians. Chronic sources of burnout have been previously examined, but little is known about the impact of acute stressors on physician burnout. Otolaryngology residents applying for competitive fellowships provide a good example for how professional disappointment may cause burnout. As otolaryngology comprises highly successful, highly competitive individuals, a long history of success may leave otolaryngologists ill-equipped to cope with such failures. Otolaryngologists should be aware of such pitfalls, preparing appropriate coping mechanisms in cases of professional disappointment. PMID- 29436282 TI - Patient Choice of Nonsurgical Treatment Contributes to Disparities in Head and Neck Squamous Cell Carcinoma. AB - Objectives There are well-established outcome disparities among different demographic groups with head and neck squamous cell carcinoma (HNSCC). We aimed to investigate the potential contribution of patient choice of nonsurgical treatment to these disparities by estimating the rate of this phenomenon, identifying its predictors, and estimating the effect on cancer-specific survival. Study Design Retrospective nationwide analysis. Settings Surveillance, Epidemiology, and End Results Database (2004-2014). Subjects and Methods Patients with HNSCC, who were recommended for primary surgery, were included. Multivariable logistic regression was used to identify demographic and clinical factors associated with patient choice of nonsurgical treatment, and Kaplan Meier/Cox regression was used to analyze survival. Results Of 114,506 patients with HNSCC, 58,816 (51.4%) were recommended for primary surgery, and of those, 1550 (2.7%) chose nonsurgical treatment. Those who chose nonsurgical treatment were more likely to be older (67.1 +/- 12.6 vs 63.6 +/- 13.1, P < .01), were of Black (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.28-1.74) or Asian (OR = 1.79; 95% CI, 1.46-2.20) ethnicity, were unmarried (OR married, 0.50; 95% CI, 0.44-0.58), had an advanced tumor, and had a hypopharyngeal or laryngeal primary. Choice of nonsurgical treatment imparted a 2.16-fold (95% CI, 2.02-2.30) increased risk of cancer-specific death. Conclusion Of the patients, 2.7% chose nonsurgical treatment despite a provider recommendation that impairs survival. Choice of nonsurgical treatment is associated with older age, having Black or Asian ethnicity, being unmarried, having an advanced stage tumor, and having a primary site in the hypopharynx or larynx. Knowledge of these disparities may help providers counsel patients and help patients make informed decisions. PMID- 29436283 TI - Universal Sellar Anatomical Reconstruction Using the Sellar Floor Flap after Endoscopic Pituitary Adenoma Surgery. AB - Postoperative cerebrospinal fluid (CSF) leaks still occur in patients without intraoperative CSF leaks after endoscopic endonasal pituitary adenoma surgery. We propose a reconstructive technique, the sellar floor flap (SFF), for universal sellar anatomical reconstruction. A total of 113 patients without intraoperative CSF leaks after endoscopic endonasal pituitary adenoma surgery from July 2013 to June 2016 were reviewed: 43 underwent sellar reconstruction with the SFF (the SFF group) and 70 underwent sellar packing only (the nonreconstruction group). No case of postoperative CSF leak was reported in the SFF group, whereas 7 cases were reported in the nonreconstruction group ( P < .05). The SFF is suitable for universal reconstruction after endoscopic endonasal pituitary adenoma surgery and may decrease postoperative CSF leak. PMID- 29436284 TI - Compassion fatigue and compassion satisfaction among family physicians in the Republic of Srpska, Bosnia and Herzegovina. AB - AIMS: The aim of this study was to examine self-perceived compassion fatigue and compassion satisfaction among family physicians in Bosnia and Herzegovina and describe potential contributing factors. METHODS: The cross-sectional study enrolled 120 family physicians. Professional quality of life compassion satisfaction and fatigue version 5 (ProQOL5) was used to assess compassion satisfaction and two components of compassion fatigue, secondary traumatic stress and burnout. The symptoms of chronic fatigue were evaluated using the Chalder fatigue scale. RESULTS: The majority of family physicians had moderate levels of compassion satisfaction (70%), burnout (75%) and secondary traumatic stress (55.8%). Family physicians with higher levels of secondary traumatic stress reported chronic fatigue (p = 0.001), longer length of service (p = 0.024) and residency training (p = 0.041). Chronic fatigue (p = 0.001), living in a rural environment (p = 0.033), larger size of practice (p = 0.006) and high number of patients with chronic disease (p = 0.001) were associated with a higher risk of burnout. CONCLUSION: Family physicians with large practices, long years of experience, a high number of chronically ill patients and experiencing chronic fatigue are at risk of developing compassion fatigue. A systematic exploration of compassion fatigue in relation to working conditions might provide an appropriate starting point for the development of preventive interventions. PMID- 29436285 TI - Meniere's Disease Pathophysiology: Endolymphatic Sac Immunohistochemical Study of Aquaporin-2, V2R Vasopressin Receptor, NKCC2, and TRPV4. AB - Objectives Endolymphatic sac (ELS) pathophysiology in Meniere's disease (MD) remains poorly understood. We identified from the literature a group of proteins expressed on the ELS and involved in endolymph volume regulation: aquaporin-2 (AQP2), vasopressin receptor V2R, sodium potassium chloride cotransporter 2 (NKCC2), and transient receptor potential cation channel V4 (TRPV4). Our objective was to determine whether their ELS expression was altered in MD, to better understand the pathophysiology of endolymphatic hydrops. Study Design Prospective case-control study. Setting Tertiary care center. Subjects Twenty four patients with definite MD undergoing endolymphatic duct blockage surgery were recruited, as well as 23 controls with no history of MD undergoing surgery for vestibular schwannoma (VS). Methods ELS biopsies and blood samples for plasma arginine vasopressin (AVP) were obtained. Immunohistochemistry for AQP2, V2R, NKCC2, and TRPV4 was performed. Slides were scanned digitally for highly sensitive pixel density analysis by specialized software (VIS; Visiopharm). Results Global scores generated by the software represent total and relative protein expression density of 3 staining intensity levels, exclusively on ELS epithelium. AQP2 expression density was significantly elevated in MD compared to VS ( P = .003). There was no significant difference in plasma AVP, V2R, NKCC2, and TRPV4 expression. Conclusion This original study evaluates simultaneous in situ expression of AQP2, V2R, NKCC2, and TRPV4 on the human ELS in MD, with a control group. Our results show only AQP2 upregulation on the ELS of patients with MD. We suggest a constitutively increased expression of AQP2 in MD, independent of its regulatory axis (AVP-V2R). Acquired regulator sequence mutations could support this model. PMID- 29436286 TI - Hematologic and biochemical characteristics of stranded green sea turtles. AB - To improve understanding of pathophysiologic processes occurring in green sea turtles ( Chelonia mydas) stranded along the east coast of Australia, we retrospectively examined the hematologic and biochemical blood parameters of 127 green turtles admitted to 2 rehabilitation facilities, Dolphin Marine Magic (DMM) and Taronga Zoo (TZ), between 2002 and 2016. The predominant size class presented was small immature animals (SIM), comprising 88% and 69% of admissions to DMM and TZ, respectively. Significant differences in blood profiles were noted between facility, size, and outcome. Elevated levels of aspartate aminotransferase (AST) and heterophils were poor prognostic indicators in animals from TZ, but not DMM. SIM animals at both institutions had lower protein levels than large older (LO) animals. SIM animals at DMM also had lower hematocrit and monocyte concentration; SIM animals at TZ had lower heterophil counts. Urea was measured for 27 SIM animals from TZ, but the urea-to-uric acid ratio was not prognostically useful. Strong correlations were seen between AST and glutamate dehydrogenase (GDH; r = 0.68) and uric acid and bile acids ( r = 0.72) in the 45 SIM animals from DMM in which additional analytes were measured. chi2 contingency tests showed that the most recently published reference intervals were not prognostically useful. A paired t-test showed that protein levels rose and heterophil numbers fell in the 15 SIM animals from TZ during the rehabilitation process. Our results indicate that further work is required to identify reliable prognostic biomarkers for green turtles. PMID- 29436287 TI - Which Assessment Method of Malnutrition in Head and Neck Cancer? AB - Objective To assess the value of several diagnostic methods of nutritional status during the initial management of a head and neck cancer. Study Design Single center prospective study. Setting Tertiary referral center. Subjects and Methods Ninety patients with head and neck cancer participated in the study. Assessment of their nutritional status was made with anthropometric, biological, body, and muscle measurements (the last by computed tomography: L3 muscle mass index [L3MMI]). Assessment of muscle performance (functional reflection of nutritional status) was made via the Short Physical Performance Battery test. The malnutrition thresholds were set according to the literature. Results Mean body mass index (BMI) was 24.6 +/- 5.4 kg/m2. Mean weight loss and albumin levels were -4.5 +/- 10.5 kg and 37.1 +/- 5.2 g/L, respectively. Fourteen percent of patients were diagnosed as malnourished on the basis of BMI, 54% according to the Nutritional Risk Index (NRI), and 58% by L3MMI. There was 64% agreement between NRI and L3MMI ( P < .001). All patients identified as malnourished by BMI were considered as such by the other assessment methods; however, many malnourished patients had normal or high BMI. The Short Physical Performance Battery score was low particularly among patients considered to be the most undernourished by the other methods. Conclusion NRI and L3MMI are the best methods to identify patients as being malnourished. Functional muscle assessment can determine the severity of malnutrition. PMID- 29436288 TI - Psychological interventions for treating neuropsychiatric consequences of acquired brain injury: A systematic review. AB - Anxiety, aggression/agitation, apathy and disinhibition are common neuropsychiatric consequences of acquired brain injury (ABI); these consequences can cause functional impairment and lead to reduced social integration. This systematic review aims to provide an examination of the current evidence on psychological interventions for treating these consequences. Two reviewers selected potential relevant articles, retrieved from five literature databases; methodological quality was assessed and appraised. A total of 5207 studies were found, of which 43 were included: 21 studies for anxiety, 18 for aggression, two studies for apathy, and six for disinhibition. Three studies addressed multiple consequences. Four high-quality (i.e., Class I and II) studies showed significant decreases in anxiety after cognitive behavioural therapy (CBT). In total, 14 studies consistently showed significant decreases in aggression/agitation after behavioural management techniques or anger management sessions. Substantial variability existed in the examined interventions and in their effects on apathy and disinhibition. Unfortunately, firm conclusions and recommendations for clinical practice are considered premature, due to concerns about the methodology used. However, this review yielded new evidence on the effectiveness of CBT for anxiety symptoms post-ABI and there has been some response to the ongoing call for studies with high methodological quality. PMID- 29436289 TI - A comparative analysis of lumbar spine mechanics during barbell- and crate lifting: implications for occupational lifting task assessments. AB - PURPOSE: To compare the effects of object handled and handgrip used on lumbar spine motion and loading during occupational lifting task simulations. METHODS: Eight male and eight female volunteers performed barbell and crate lifts with a pronated (barbell) and a neutral (crate) handgrip. The mass of barbells/crates lifted was identical across the objects and fixed at 11.6 and 9.3 kg for men and women, respectively. The initial heights of barbells/crates were individualized to mid-shank level. Body segment kinematics and foot-ground reaction kinetics were collected, and then input into an electromyography-assisted dynamic biomechanical model to quantify lumbar spine motion and loading. RESULTS: Lumbar compression and net lumbosacral moment magnitudes were 416 N and 17 Nm lower when lifting a barbell than when lifting a crate (p < 0.001), respectively. There were no between-condition differences in lumbar flexion displacements (p > 0.392) or flexion/extension velocities (p > 0.085). CONCLUSIONS: Crate- and barbell-lifting tasks can be used interchangeably if assessing lifting mechanics based on peak spine motion variables. If assessments are based on the spine loading responses to task demands, however, then crate- and barbell-lifting tasks cannot be used interchangeably. PMID- 29436290 TI - Psychological Risk Factors for Posttraumatic Stress Disorder in Workers After Toxic Chemical Spill in Gumi, South Korea. AB - The extent and severity of the psychological effects following chemical release disasters have not been widely reported. The aim of this study was to examine the prevalence of hydrogen fluoride (HF)-related posttraumatic stress disorder (PTSD) and to identify associated psychological risk factors. On September 2012, an estimated 8 to 12 tons of HF gas, which dissolves in air moisture to form droplets of corrosive hydrofluoric acid, escaped from an industrial complex in Gumi, South Korea. Ten months later, structured questionnaires that included items from the Impacts of Event Scale (revised Korean version) as well as questions about demographic and psychological risk factors related to PTSD were distributed to workers in the affected area. The prevalence rate of PTSD was 5.7%. The odds of PTSD in non-alcohol-dependent workers (odds ratio [OR] = 3.10, 95% confidence interval [CI] = [1.27, 7.60]) was significantly higher than in alcohol-independent workers. The OR for PTSD in workers with anxiety (OR = 7.63, 95% CI = [2.10, 27.71) was significantly higher than the OR workers without anxiety. The odds of PTSD in workers with high perceived stress scale (PSS) scores (OR = 8.72, 95 % CI = [2.29, 33.16]) was significantly higher than for workers with low PSS. Alcohol dependence, psychiatric symptoms at the time of the event, anxiety, and high PSS were associated with HF-related PTSD. Long-term employee assistance programs are needed to assist occupational health nurses and clinicians to reduce PTSD after industrial disasters. PMID- 29436291 TI - Helicopter pilots' views of air traffic controller responsibilities: a mismatch. AB - Controllers and pilots must work together to ensure safe and efficient helicopter flight within the London control zone. Subjective ratings of pilot perception of controller responsibility for five key flight tasks were obtained from thirty helicopter pilots. Three types of airspace were investigated. Results indicate that there is variation in pilot understanding of controller responsibility compared to the formal regulations that define controller responsibility. Significant differences in the perception of controller responsibility were found for the task of aircraft separation in class D airspace and along helicopter routes. Analysis of the patterns of response suggests that task type rather than the airspace type may be the key factor. Results are framed using the concept of a shared mental model. This research demonstrates that pilots flying in complex London airspace have an expectation of controller responsibility for certain flight tasks, in certain airspace types that is not supported by aviation regulation. Practitioner Summary: The responsibility for tasks during flight varies according to the flight rules used and airspace type. Helicopter pilots may attribute responsibility to controllers for tasks when controllers have no responsibility as defined by regulation. This variation between pilot perceptions of controller responsibility could affect safety within the London control zone. PMID- 29436293 TI - Parental and Self-Weight Perceptions in U.S. Children and Adolescents, NHANES 2005-2014. AB - This study aimed to describe the parental and child self-weight perceptions and their associated sociodemographic factors. The 2005-2014 National Health and Nutrition Examination Survey (NHANES) sample of 16,869 children aged 2 to 17 years was used. For overweight/obese children aged 2 to 15 years, 61.2% of parents underestimated their child's weight. For overweight/obese children aged 8 to 17 years, 55.2% underestimated their own weight. For children aged 8 to 15 years, 77.8% parents and children agreed on the weight classification. Parents of boys and those with low income were more likely to underestimate their child's weight. Girls, older children, and those living in larger or high-income families were less likely to underestimate their own weight. Hispanic and Black children tended to underestimate their weight. With increasing child age, parents and children were more likely to disagree on the child's weight. Future efforts should focus on low-income families with larger number of children and Hispanic and Black young children who were more likely to underestimate their weight. PMID- 29436292 TI - Is it a match? a novel method of evaluating medical school success. AB - BACKGROUND: Medical education program evaluation allows for curricular improvements to both Undergraduate (UME) and Graduate Medical Education (GME). UME programs are left with little more than match rates and self-report to evaluate success of graduates in The Match. OBJECTIVE: This manuscript shares a novel method of program evaluation through a systematic assessment of Match outcomes. DESIGN: Surveys were developed and distributed to Program Training Directors (PTDs) at our institution to classify residency programs into which our UME graduates matched using an ordinal response scale and open-ended responses. Outcomes-based measures for UME graduates were collected and analyzed. The relationship between PTD survey data and UME graduates' outcomes were explored. Open-ended response data were qualitatively analyzed using iterative cycles of coding and identifying themes. RESULTS: The PTD survey response rate was 100%. 71% of our graduates matched to programs ranked as 'elite' (36%) or 'top' (35%) tier. The mean total number of 'Honors' grades achieved by UME graduates was 2.6. Data showed that graduates entering elite and top GME programs did not consistently earn Honors in their associated clerkships. A positive correlation was identified between USMLE Step 1 score, number of honors, and residency program rankings for a majority of the programs. Qualitative analysis identified research, faculty, and clinical exposure as necessary characteristics of 'elite' programs:. Factors considered by PTDs in the rating of programs included reputation, faculty, research, national presence and quality of graduates. CONCLUSIONS: This study describes a novel outcomes-based method of evaluating the success of UME programs. Results provided useful feedback about the quality of our UME program and its ability to produce graduates who match in highly-regarded GME programs. The findings from this study can benefit Clerkship Directors, Student Affairs and Curriculam Deans, and residency PTDs as they help students determine their competitiveness forspecialties and specific residency programs. PMID- 29436301 TI - Geriatric Assessment: Precision Medicine for Older Adults With Cancer. PMID- 29436302 TI - Care Provider or Service Provider: What Should the Role of Radiation Oncologists Be in the Future? PMID- 29436294 TI - Health dynamics in camps and on campuses: stressors and coping strategies for wellbeing among labourers and students in Cameroon. AB - PURPOSE: For many people living in low-income countries, poverty implies an increased exposure to conditions that threaten health and wellbeing as well as reduced capacity to maintain health. Despite the challenging conditions caused by poverty, people may consider themselves healthy because they have learned to cope with their situation probably as a result of life experiences which expose people to both challenges and potential solutions. In this paper we present results from studying health and wellbeing challenges and mechanisms to cope with challenges among two different groups of people who are living under conditions of poverty: workers of the Cameroon Development Corporation (CDC) and students of the university of Buea and the university of Yaounde. METHODS: We performed a cross sectional study, interviewing 21 CDC workers and 21 students. Results Our study reveals context-specific stressors emerging from poor work conditions and study pressure as well as non-context-specific stressors perceived by respondents as living conditions, poor healthcare and financial uncertainty. Respondents devised coping mechanisms to overcome exactly those stressors such as searching for additional money sources, preventive action towards hazardous living conditions and alternative medical support. CONCLUSION: We conclude that supporting and promoting such avenues is essential for enhanced and continuous coping with stressors. PMID- 29436303 TI - Trends in Insurance Status Among Patients Diagnosed With Cancer Before and After Implementation of the Affordable Care Act. AB - PURPOSE: The Affordable Care Act (ACA) aimed to increase insurance coverage through key provisions such as expansion of Medicaid eligibility and enforcement of an individual mandate. The objective of this study is to examine the impact of the ACA on insurance rates among patients newly diagnosed with colon, lung, or breast cancer. METHODS: Using the SEER database, patients younger than age 65 years diagnosed with colon, lung, or breast cancer between 2008 and 2014 were identified. Insurance rates were examined before versus after passage of the ACA (2011) and before (2011 to 2013) versus after (2014) Medicaid expansion in nine expansion states and five nonexpansion states. Difference-in-differences models were used to estimate the differential impact of ACA in expansion compared with nonexpansion states. RESULTS: A total of 414,085 patients with known insurance status were diagnosed with colon, lung, or breast cancer between 2008 and 2014. For all cancer types, there was a significant increase in patients enrolled in Medicaid after 2011 in expansion states. Between 2011 to 2013 and 2014, in patients living in states with Medicaid expansion, the uninsured rates decreased by >= 50% among patients with a new diagnosis of lung and colon cancer (6.5% in 2011 to 2013 to 3.1% in 2014 and 6.8% in 2011 to 2013 to 3.4% in 2014, respectively; P < .001); the uninsured rate decreased to a lesser degree for patients with breast cancer (2.7% in 2011 to 2013 to 1.6% in 2014; P < .001). This decrease in the rate of uninsured patients was absent in patients living in nonexpansion states. CONCLUSION: The ACA resulted in expanded insurance coverage for patients diagnosed with colon, lung, and breast cancer. However, the impact was only observed in states that increased their Medicaid eligibility. PMID- 29436304 TI - Challenges and Opportunities for Developing New Therapeutics for Salivary Gland Cancers. PMID- 29436305 TI - Evolution of Geriatric Assessment in Oncology. PMID- 29436307 TI - Cancers of the Major Salivary Gland. AB - Salivary gland malignancies are rare tumors that comprise multiple histologic entities with diverse clinical behavior. Mucoepidermoid carcinoma is the most frequent primary salivary malignancy, followed by adenoid cystic and acinic cell carcinoma. Although most salivary malignancies are asymptomatic, presentation with a rapidly enlarging mass may be accompanied by pain, functional neurologic deficits, soft-tissue invasion, or nodal enlargement. Assessment of clinical behavior and physical exam greatly contributes to diagnostic workup. Preoperative imaging, to include ultrasound, computed tomography, or magnetic resonance imaging, may assist with surgical planning. Limitations of preoperative fine needle aspiration cytology mean that, in some cases, definitive histologic diagnosis may not be established until therapeutic surgery is undertaken. Treatment strategies rely on oncologic resection of the primary site with negative margins as well as adjuvant radiotherapy in patients with high-risk features, such as high-grade histology, advanced T class, or perineural invasion. Regional lymphadenectomy is recommended for involved nodal basins. Patients with clinically node-negative disease at high risk for occult nodal metastases may be considered for elective lymphadenectomy or radiotherapy. Use of chemotherapy in the adjuvant setting, in combination with radiotherapy, remains controversial. The rate of objective response to palliative chemotherapy in recurrent or metastatic salivary gland malignancy remains low. In studies that include a significant proportion of adenoid cystic carcinomas, whether disease stability represents an indolent disease process or the true effect of a therapeutic drug may be difficult to discern. Recognition of genetic alterations and protein expression unique to salivary malignancies presents exciting new opportunities for molecularly targeted therapy, although the response to molecularly targeted therapy in studies has been modest thus far. PMID- 29436308 TI - Development and Validation of the Consumer Health Activation Index. AB - BACKGROUND: Although there has been increasing interest in patient engagement, few measures are publicly available and suitable for patients with limited health literacy. OBJECTIVE: We sought to develop a Consumer Health Activation Index (CHAI) for use among diverse patients. METHODS: Expert opinion, a systematic literature review, focus groups, and cognitive interviews with patients were used to create and revise a potential set of items. Psychometric testing guided by item response theory was then conducted among 301 English-speaking, community dwelling adults. This included differential item functioning analyses to evaluate item performance across participant health literacy levels. To determine construct validity, CHAI scores were compared to scales measuring similar personality constructs. Associations between the CHAI and physical and mental health established predictive validity. A second study among 9,478 adults was used to confirm CHAI associations with health outcomes. RESULTS: Exploratory factor analyses revealed a single-factor solution with a 10-item scale. The CHAI showed good internal consistency (alpha = 0.81) and moderate test-retest reliability (ICC = 0.53). Reading grade level was found to be at the 6th grade. Moderate to strong correlations were found with similar constructs (Multidimensional Health Locus of Control, r = 0.38, P < 0.001; Conscientiousness, r = 0.41, P < 0.001). Predictive validity was demonstrated through associations with functional health status measures (depression, r = 0.28, P < 0.001; anxiety, r = -0.22, P < 0.001; and physical functioning, r = 0.22, P < 0.001). In the validation sample, the CHAI was significantly associated with self-reported physical and mental health ( r = 0.31 and 0.32 respectively; both P < 0.001). CONCLUSIONS: The CHAI appears to be a valid, reliable, and easily administered tool that can be used to assess health activation among adults, including those with limited health literacy. Future studies should test the tool in actual use and explore further applications. PMID- 29436309 TI - Are Perceived Prevalences of Infection also Biased and How? Lessons from Large Epidemics of Mosquito-Borne Diseases in Tropical Regions. AB - BACKGROUND: Although people are likely to underestimate the frequencies of risks to health from common diseases and overestimate those from rare diseases, we still do not know much about reasons for this systematic bias, which is also referred to as "primary bias" in the literature. In this study, we take advantage of a series of large epidemics of mosquito-borne diseases to examine the accuracy of judgments of risk frequencies. In this aim, we assessed the perceived v. observed prevalence of infection by Zika, chikungunya or dengue fever during these outbreaks, as well as their variations among different subpopulations and epidemiological settings. METHODS: We used data drawn from 4 telephone surveys, conducted between 2006 and 2016, among representative samples of the adult population in tropical regions (Reunion, Martinique, and French Guiana). The participants were asked to estimate the prevalence of these infections by using a natural frequency scale. RESULTS: The surveys showed that 1) most people greatly overestimated the prevalence of infection by arbovirus, 2) these risk overestimations fell considerably as the actual prevalence of these diseases increased, 3) the better-educated and male participants consistently yielded less inaccurate risk estimates across epidemics, and 4) these biases in the perception of prevalence of these infectious diseases are relatively well predicted by the probability weighting function developed in the field of behavioral decision making. CONCLUSIONS: These findings suggest that the primary bias, which has been found in laboratory experiments to characterize a variety of probabilistic judgments, equally affects perception of prevalence of acute infectious diseases in epidemic settings. They also indicate that numeracy may play a considerable role in people's ability to transform epidemiological observations from their social environment to more accurate risk estimates. PMID- 29436306 TI - What Every Oncologist Should Know About Geriatric Assessment for Older Patients With Cancer: Young International Society of Geriatric Oncology Position Paper. AB - Aging is a heterogeneous process. Most newly diagnosed cancers occur in older adults, and it is important to understand a patient's underlying health status when making treatment decisions. A geriatric assessment provides a detailed evaluation of medical, psychosocial, and functional problems in older patients with cancer. Specifically, it can identify areas of vulnerability, predict survival and toxicity, assist in clinical treatment decisions, and guide interventions in routine oncology practice; however, the uptake is hampered by limitations in both time and resources, as well as by a lack of expert interpretation. In this review, we describe the utility of geriatric assessment by using an illustrative case and provide a practical approach to geriatric assessment in oncology. PMID- 29436310 TI - Ultrasound-Assisted Catheter-Directed Thrombolysis for Submassive Pulmonary Embolism. AB - PURPOSE: Catheter-directed thrombolysis (CDT) is a relatively new therapy for pulmonary embolism that achieves the superior clot resolution compared to systemic thrombolysis while avoiding the high bleeding risk intrinsically associated with that therapy. In order to examine the efficacy and safety of CDT, we conducted a retrospective cohort study of patients undergoing ultrasound assisted CDT at our institution. METHODS: The charts of 30 consecutive patients who underwent CDT as a treatment of pulmonary embolism at our institution were reviewed. Risk factors for bleeding during thrombolysis were noted. Indicators of the right heart strain on computed tomography and echocardiogram, as well as the degree of pulmonary vascular obstruction, were recorded before and after CDT. Thirty-day mortality and occurrence of bleeding events were recorded. RESULTS: Nine (30%) patients had 3 or more minor contraindications to thrombolysis and 14 (47%) had major surgery in the month prior to CDT. Right ventricular systolic pressure and vascular obstruction decreased significantly after CDT. There was a significant decrease in the proportion of patients with right ventricular dilation or hypokinesis. Decrease in pulmonary vascular obstruction was associated with nadir of fibrinogen level. No patients experienced major or moderate bleeding attributed to CDT. CONCLUSION: Catheter-directed thrombolysis is an effective therapy in rapidly alleviating the right heart strain that is associated with increased mortality and long-term morbidity in patients with pulmonary embolism with minimal bleeding risk. Catheter-directed thrombolysis is a safe alternative to systemic thrombolysis in patients with risk factors for bleeding such as prior surgery. Future studies should examine the safety of CDT in patients with contraindications to systemic thrombolysis. PMID- 29436312 TI - Self-Stigma in Relatives of people with Mental Illness scale: development and validation. AB - BACKGROUND: Serious mental illness (SMI) is profoundly stigmatised, such that there is even an impact on relatives of people with SMI. Aims To develop and validate a scale to comprehensively measure self-stigma among first-degree relatives of individuals with SMI. METHOD: We conducted group interviews focusing on self-stigma with first-degree relatives (n = 20) of people with SMI, from which 74 representative quotations were reframed as Likert-type items. Cognitive interviews with relatives (n = 11) identified 30 items for the Self-Stigma in Relatives of people with Mental Illness (SSRMI) scale. Relatives (n = 195) completed the scale twice, a month apart, together with four external correlate scales. RESULTS: The 30-item SSRMI was reliable, with scores stable over time. Its single-factor structure allowed generation of a 10-item version. Construct validity of 30- and 10-item versions was supported by expected relationships with external correlates. CONCLUSIONS: Both versions of the SSRMI scale are valid and reliable instruments appropriate for use in clinical and research contexts. Declaration of interest None. PMID- 29436313 TI - Pre-eclampsia and the risk of autism-spectrum disorder in offspring: meta analysis. AB - BACKGROUND: Evidence about the effect of intrauterine exposure to pre-eclampsia on offspring autism-spectrum disorder (ASD) is not well established. Aims To examine the association between pre-eclampsia and ASD. METHOD: PubMed, Embase and PsycINFO databases were searched. Pooled relative risks (RR) with 95% confidence intervals were calculated. Subgroup and sensitivity analyses were performed. Heterogeneity was assessed using Cochran's Q- and the I 2-test. The presence of publication bias was evaluated by Egger's test and visual inspection of the symmetry in funnel plots. RESULTS: Ten studies meet the inclusion criteria. The risk of ASD was 32% higher in offspring who had intrauterine exposure to pre eclampsia compared with those not exposed (RR = 1.32, 95% CI 1.20-1.45). Sensitivity analysis revealed consistent pooled estimates ranging from RR = 1.30 (95% CI 1.17-1.44) to RR = 1.37 (95% CI 1.26-1.48). We found no significant heterogeneity and evidence of publication bias. CONCLUSION: Pre-eclampsia increased the risk of ASD in offspring. The finding suggests a need for early screening for ASD in offspring of women with pre-eclampsia. Declaration of interest None. PMID- 29436314 TI - Clinical outcomes of staff training in positive behaviour support to reduce challenging behaviour in adults with intellectual disability: cluster randomised controlled trial. AB - BACKGROUND: Staff training in positive behaviour support (PBS) is a widespread treatment approach for challenging behaviour in adults with intellectual disability. Aims To evaluate whether such training is clinically effective in reducing challenging behaviour during routine care (trial registration: NCT01680276). METHOD: We carried out a multicentre, cluster randomised controlled trial involving 23 community intellectual disability services in England, randomly allocated to manual-assisted staff training in PBS (n = 11) or treatment as usual (TAU, n = 12). Data were collected from 246 adult participants. RESULTS: No treatment effects were found for the primary outcome (challenging behaviour over 12 months, adjusted mean difference = -2.14, 95% CI: -8.79, 4.51) or secondary outcomes. CONCLUSIONS: Staff training in PBS, as applied in this study, did not reduce challenging behaviour. Further research should tackle implementation issues and endeavour to identify other interventions that can reduce challenging behaviour. Declaration of interest None. PMID- 29436315 TI - Antibiotic Prophylaxis for Breast Oncosurgery in a Setting With a High Prevalence of Multidrug-Resistant Bacteria: Common Sense Infection Control Measures Are More Important Than Prolonged Antibiotics. PMID- 29436316 TI - Temporal patterns in principal Salmonella serotypes in the USA; 1996-2014. AB - Analysing temporal patterns in foodborne illness is important to designing and implementing effective food safety measures. The reported incidence of illness due to Salmonella in the USA. Foodborne Diseases Active Surveillance Network (FoodNet) sites has exhibited no declining trend since 1996; however, there have been significant annual trends among principal Salmonella serotypes, which may exhibit complex seasonal patterns. Data from the original FoodNet sites and penalised cubic B-spline regression are used to estimate temporal patterns in the reported incidence of illness for the top three Salmonella serotypes during 1996 2014. Our results include 95% confidence bands around the estimated annual and monthly curves for each serotype. The results show that Salmonella serotype Typhimurium exhibits a statistically significant declining annual trend and seasonality (P < 0.001) marked by peaks in late summer and early winter. Serotype Enteritidis exhibits a significant annual trend with a higher incidence in later years and seasonality (P < 0.001) marked by a peak in late summer. Serotype Newport exhibits no significant annual trend with significant seasonality (P < 0.001) marked by a peak in late summer. PMID- 29436317 TI - The Role of an Antimicrobial Stewardship Team in the Use of Rapid Diagnostic Testing in Acute Care: An Official Position Statement of the Society of Infectious Diseases Pharmacists. AB - Rapid diagnostic technologies can assist Antimicrobial Stewardship Programs (ASPs) in achieving the goals of reducing unnecessary antimicrobial exposure and optimizing patient care. The Society of Infectious Diseases Pharmacists supports all members of the ASP team as essential components of optimal use of these technologies for management of antibiotic prescribing and cost-reduction strategies. Infect Control Hosp Epidemiol 2018;39:473-475. PMID- 29436318 TI - Chickenpox outbreak in a tribal and industrial zone from the Union Territory of Dadra and Nagar Haveli, India. AB - During 9th December 2016 and 12th February 2017, 149-chickenpox cases were reported in a tribal and industrial zone of Rakholi (n = 80) and Surangi (n = 69) villages from Union Territory of India. An epidemiological investigation was performed to assess the characteristics and determinants of the chickenpox outbreak. Overall, the attack rate per 100 population in Rakholi village (n = 1757) was 4.5% and 19.1% in Surangi village (n = 360). Ages of the cases were ranged from 6 months to 55 years and there were 53 females and 96 males. For the laboratory investigations, 25 serum samples, three urine specimens, three throat swabs and six blister/skin swabs were collected from 37-suspected chickenpox cases. Altogether, 30-suspected cases were laboratory confirmed by either IgM EIA or varicella zoster virus (VZV) DNA PCR. Both VZV-specific IgM and IgG antibodies were detected in 19-suspected cases. Two suspected cases showed the presence of VZV-specific IgG antibodies but not IgM antibodies. On the contrary, three suspected cases showed VZV-specific IgM but not IgG antibodies. Overall, 31 of 37 suspected cases (including one equivocal case) were laboratory confirmed. The partial sequencing of ORF-28 gene of VZV revealed circulation of clade-1 viruses. In conclusion, this investigation provides detail information about the chickenpox outbreak in the tribal and industrial setting from India. Furthermore, the study emphasises the need to investigate more chickenpox outbreaks in different parts of India. PMID- 29436319 TI - From Dusk to Dawn: Understanding the Impact of Ertapenem Resistance Mechanisms on the In Vitro Potency of Other Drugs Among Enterobacter cloacae Complex Isolates. PMID- 29436320 TI - Long-term outcomes of trauma-focused treatment in psychosis. AB - We present 12-month follow-up results for a randomised controlled trial of prolonged exposure and eye movement desensitisation and reprocessing (EMDR) therapy in 85 (78.8%) participants with psychotic disorder and comorbid post traumatic stress disorder (PTSD). Positive effects on clinician-rated PTSD, self rated PTSD, depression, paranoid-referential thinking and remission from schizophrenia were maintained up to 12-month follow-up. Negative post-traumatic cognitions declined in prolonged exposure and were stable in EMDR. A significant decline in social functioning was found, whereas reductions in interference of PTSD symptoms with social functioning were maintained. These results support that current PTSD guidelines apply to individuals with psychosis. Declaration of interest M.v.d.G. and D.v.d.B. receive income for published books on psychotic disorders and for the training of postdoctoral professionals in the treatment of psychotic disorders. A.d.J. receives income for published books on EMDR therapy and for the training of postdoctoral professionals in this method. A.v.M. receives income for published book chapters on PTSD and for the training of postdoctoral professionals in prolonged exposure. C.d.R. receives income for the training of postdoctoral professionals in EMDR therapy. PMID- 29436321 TI - Effects of selective serotonin reuptake inhibitors on rating-scale-assessed suicidality in adults with depression. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have been claimed to elicit or aggravate suicidal ideation. Aims To explore the effect of SSRIs on the suicidality item of the Hamilton Rating Scale for Depression (HRSD). METHOD: We undertook a patient-level mega-analysis of adults with depression participating in industry-sponsored studies of sertraline, paroxetine or citalopram, comparing patients on an SSRI (n = 5681) with those on placebo (n = 2581) with respect to HRSD-rated suicidality. Separate analyses were conducted for young adults (age 18 24; n = 537) and adults (age >=25; n = 7725). RESULTS: Among adults, the reduction in mean rating of suicidality was larger and the risk for aggravation of suicidality lower in patients receiving an SSRI from week 1 and onwards. In young adults, SSRI treatment neither reduced nor increased suicidality ratings relative to placebo at the end-point. CONCLUSIONS: The net effect of SSRIs on suicidality appears beneficial in people above the age of 24 and neutral in those aged 18-24. Declaration of interest F.H. has received speaker's fees from Servier. E.E. has previously been on the advisory boards and/or received speaker's honoraria and/or research grants from Eli Lilly, GlaxoSmithKline, Servier and Lundbeck. PMID- 29436322 TI - Does the community-based combined Meeting Center Support Programme (MCSP) make the pathway to day-care activities easier for people living with dementia? A comparison before and after implementation of MCSP in three European countries. AB - : ABSTRACTBackground:The "pathway to care" concept offers a helpful framework for preparing national dementia plans and strategies and provides a structure to explore the availability and accessibility of timely and effective care for people with dementia and support for their informal carers. Within the framework of the JPND-MEETINGDEM implementation project the pathways to regular day-care activities and the Meeting Centers Support Programme (MCSP), an innovative combined support form for people with dementia and carers, was explored. METHODS: An exploratory, descriptive, qualitative, cross-country design was applied to investigate the pathways to day care in several regions in four European countries (Italy, Poland, United Kingdom, and the Netherlands). RESULTS: Before implementation of MCSP, of the four countries the United Kingdom had the most structured pathway to post-diagnostic support for people with dementia. MCSP introduction had a positive impact on the pathways to day-care activities in all countries. MCSP filled an important gap in post-diagnostic care, increasing the accessibility to support for both people with dementia and carers. Key elements such as program of activities, target group, and collaboration between healthcare and social services were recognized as success factors. CONCLUSIONS: This study shows that MCSP fills (part of) the gap between diagnosis and residential care and can therefore be seen as a pillar of post-diagnostic care and support. Further dissemination of Meeting Centers in Europe may have a multiple impact on the structure of dementia services in European countries and the pathways to day care for people with dementia and their carer(s). PMID- 29436323 TI - The elder abuse and neglect phenomenon in the ultra-Orthodox Jewish society: social workers' perspectives. AB - : ABSTRACTBackground:In the last 30 years, elder abuse and neglect has been recognized as a social and health-related problem. The aim of this paper is to describe the phenomenon of elder abuse and neglect in a separatist faith-based society (ultra-Orthodox Jewish society-UOJS). METHODS: A qualitative phenomenological study with 28 social workers who underwent in-depth semi structured interviews based on an interview guide consisting of the following items: visibility of the elder abuse and neglect phenomenon in the ultra-Orthodox society, and dilemmas and sensitive issues that arise when working with this population. RESULTS: Three main themes emerged: (1) Between the commandment to honor one's parents and concealment patterns: Cultural barriers to exposing the abuse and neglect phenomenon; (2) "Life is demanding:" The unique expression of abusive and neglectful behavior in the UOJS; (3) Culturally related dilemmas when intervening with cases of elder abuse and neglect. CONCLUSIONS: Ultra-Orthodox Jewish cultural belief is a differentiating component in the context of elder abuse and neglect. Social workers need to develop a deep understanding of the unique characteristics of the phenomenon and cultural sensitivity to cope with it to address the well-being of older ultra-Orthodox Jews. PMID- 29436324 TI - Community-based group guided self-help intervention for low mood and stress: randomised controlled trial. AB - BACKGROUND: To date no studies have explored the effectiveness of written cognitive-behavioural therapy (CBT) resources for low mood and stress delivered via a course of self-help classes in a community setting. Aims To assess the effectiveness of an 8-week community-based CBT self-help group classes on symptoms of depression, anxiety and social function at 6 months (trial registration: ISRCTN86292664). METHOD: In total, 142 participants were randomly allocated to immediate (n = 71) or delayed access to a low-intensity CBT intervention (n = 71). Measures of depression, anxiety and social function were collected at baseline and 6 months. RESULTS: There was a significant improvement for the primary outcome of Patient Health Questionnaire-9 (PHQ-9) score (mean between-group difference: -3.64, 95% CI -6.06 to -1.23; P = 0.004). The percentage of participants reducing their PHQ-9 score between baseline and 6 months by 50% or more was 17.9% for the delayed access group and 43.8% for the immediate access group. Secondary outcomes also improved including anxiety and social function. The intervention was cost neutral. The probabilities of a net benefit at willingness to pay thresholds of L20 000, L25 000 or L30 000 were 0.928, 0.944 and 0.955, respectively. CONCLUSIONS: Low-intensity class-based CBT delivered within a community setting is effective for reducing depression, anxiety and impaired social function at little additional cost. Declaration of interest C.W. is president of British Association for Behavioural & Cognitive Psychotherapies (BABCP) - the lead body for CBT in the UK. He is also author of a range of CBT-based resources available commercially. He is developer of the LLTTF classes evaluated in this study. He receives royalty, and is shareholder and director of a company that commercialises these resources. PMID- 29436325 TI - Return of the asylum. AB - Rates of involuntary admission are increasing in England. Personality disorder should be excluded as a criterion for involuntary admission; stronger restraint reduction programmes should be instigated; and involuntary care should be based on treating illness (something we can do) and not on predicting violence (something we cannot). Declaration of interest None. PMID- 29436326 TI - Addressing alcohol-related dementia should involve better detection, not watchful waiting. AB - Alcohol-related dementia represents an underrecognised mental disorder with both clinical and public mental health aspects. There is considerable scope for improving its assessment within both mainstream and specialist mental health services, but ongoing challenges remain in ensuring its timely detection so that appropriate preventative and rehabilitative interventions can be applied. Declaration of interest None. PMID- 29436327 TI - Guided self-help in a brave new world. AB - Cognitive-behavioural therapy self-help offers an accessible and efficient way to treat common mental disorders. The evidence-based self-help movement has an important foothold in the healthcare arena. This article surveys the emergence of self-help at a particular social and historical junction, and summarises key lessons from experimental and practice-based studies. Declaration of interest None. PMID- 29436328 TI - In-patient treatment in functional and sectorised care: patient satisfaction and length of stay. AB - BACKGROUND: Debate exists as to whether functional care, in which different psychiatrists are responsible for in- and out-patient care, leads to better in patient treatment as compared with sectorised care, in which the same psychiatrist is responsible for care across settings. Aims To compare patient satisfaction with in-patient treatment and length of stay in functional and sectorised care. METHOD: Patients with an ICD-10 diagnosis of psychotic, affective or anxiety/somatoform disorders consecutively admitted to an adult acute psychiatric ward in 23 hospitals across 11 National Health Service trusts in England were recruited. Patient satisfaction with in-patient care and length of stay (LoS) were compared (trial registration ISRCTN40256812). RESULTS: In total, 2709 patients were included, of which 1612 received functional and 1097 sectorised care. Patient satisfaction was significantly higher in sectorised care (beta = 0.54, 95% CI 0.35-0.73, P<0.001). This difference remained significant when adjusting for locality and patient characteristics. LoS was 6.9 days shorter for patients in sectorised care (beta = -6.89, 95% CI -11.76 to -2.02, P<0.001), but this difference did not remain significant when adjusting for clustering by hospital (beta = -4.89, 95% CI -13.34 to 3.56, P = 0.26). CONCLUSIONS: This is the first robust evidence that patient satisfaction with in-patient treatment is higher in sectorised care, whereas findings for LoS are less conclusive. If patient satisfaction is seen as a key criterion, sectorised care seems preferable. Declarations of interest None. PMID- 29436329 TI - Efficacy of web-based cognitive-behavioural therapy for chronic fatigue syndrome: randomised controlled trial. AB - BACKGROUND: Face-to-face cognitive-behavioural therapy (CBT) leads to a reduction of fatigue in chronic fatigue syndrome (CFS). Aims To test the efficacy of internet-based CBT (iCBT) for adults with CFS. METHOD: A total of 240 patients with CFS were randomised to either iCBT with protocol-driven therapist feedback or with therapist feedback on demand, or a waiting list. Primary outcome was fatigue severity assessed with the Checklist Individual Strength (Netherlands Trial Register: NTR4013). RESULTS: Compared with a waiting list, intention-to treat (ITT) analysis showed a significant reduction of fatigue for both iCBT conditions (protocol-driven feedback: B = -8.3, 97.5% CI -12.7 to -3.9, P < 0.0001; feedback on demand: B = -7.2, 97.5% CI -11.3 to -3.1, P < 0.0001). No significant differences were found between both iCBT conditions on all outcome measures (P = 0.3-0.9). An exploratory analysis revealed that feedback-on-demand iCBT required less therapist time (mean 4 h 37 min) than iCBT with protocol driven feedback (mean 6 h 9 min, P < 0.001) and also less than face-to-face CBT as reported in the literature. CONCLUSIONS: Both iCBT conditions are efficacious and time efficient. Declaration of interest None. PMID- 29436330 TI - Prediction of electroconvulsive therapy response and remission in major depression: meta-analysis. AB - BACKGROUND: Electroconvulsive therapy (ECT) is considered to be the most effective treatment in severe major depression. The identification of reliable predictors of ECT response could contribute to a more targeted patient selection and consequently increased ECT response rates. Aims To investigate the predictive value of age, depression severity, psychotic and melancholic features for ECT response and remission in major depression. METHOD: A meta-analysis was conducted according to the PRISMA statement. A literature search identified recent studies that reported on at least one of the potential predictors. RESULTS: Of the 2193 articles screened, 34 have been included for meta-analysis. Presence of psychotic features is a predictor of ECT remission (odds ratio (OR) = 1.47, P = 0.001) and response (OR = 1.69, P < 0.001), as is older age (standardised mean difference (SMD) = 0.26 for remission and 0.35 for response (P < 0.001)). The severity of depression predicts response (SMD = 0.19, P = 0.001), but not remission. Data on melancholic symptoms were inconclusive. CONCLUSIONS: ECT is particularly effective in patients with depression with psychotic features and in elderly people with depression. More research on both biological and clinical predictors is needed to further evaluate the position of ECT in treatment protocols for major depression. Declaration of interest None. PMID- 29436331 TI - Impact of adherence to antidepressants on long-term prescription opioid use cessation. AB - BACKGROUND: Depression contributes to persistent opioid analgesic use (OAU). Treating depression may increase opioid cessation. Aims To determine if adherence to antidepressant medications (ADMs) v. non-adherence was associated with opioid cessation in patients with a new depression episode after >90 days of OAU. METHOD: Patients with non-cancer, non-HIV pain (n = 2821), with a new episode of depression following >90 days of OAU, were eligible if they received >=1 ADM prescription from 2002 to 2012. ADM adherence was defined as >80% of days covered. Opioid cessation was defined as >=182 days without a prescription refill. Confounding was controlled by inverse probability of treatment weighting. RESULTS: In weighted data, the incidence rate of opioid cessation was significantly (P = 0.007) greater in patients who adhered v. did not adhered to taking antidepressants (57.2/1000 v. 45.0/1000 person-years). ADM adherence was significantly associated with opioid cessation (odds ratio (OR) = 1.24, 95% CI 1.05-1.46). CONCLUSIONS: ADM adherence, compared with non-adherence, is associated with opioid cessation in non-cancer pain. Opioid taper and cessation may be more successful when depression is treated to remission. Declaration of interest None. PMID- 29436332 TI - Cardiometabolic dysregulation and cognitive decline: potential role of depressive symptoms. AB - BACKGROUND: Previous studies have examined associations of cardiometabolic factors with depression and cognition separately. Aims To determine if depressive symptoms mediate the association between cardiometabolic factors and cognitive decline in two community studies. METHOD: Data for the analyses were drawn from the Rotterdam Study, the Netherlands (n = 2940) and the Whitehall II study, UK (n = 4469). RESULTS: Mediation analyses suggested a direct association between cardiometabolic factors and cognitive decline and an indirect association through depression: poorer cardiometabolic status at time 1 was associated with a higher level of depressive symptoms at time 2 (standardised regression coefficient 0.07 and 0.06, respectively), which, in turn, was associated with greater cognitive decline between time 2 and time 3 (standardised regression coefficient of -0.15 and -0.41, respectively). CONCLUSIONS: Evidence from two independent cohort studies suggest an association between cardiometabolic dysregulation and cognitive decline and that depressive symptoms tend to precede this decline. Declaration of interest None. PMID- 29436333 TI - Effect of singing interventions on symptoms of postnatal depression: three-arm randomised controlled trial. AB - This study assessed whether a novel psychosocial intervention could reduce symptoms of postnatal depression (PND) in the first 40 weeks post-birth. Analyses were carried out of 134 mothers with symptoms of PND randomised into 10 weeks of group singing workshops or group play workshops for them and their babies, or usual care (trial registration: NCT02526407). Overall, among all mothers with symptoms of PND, there was a non-significant faster improvement in symptoms in the singing group (F 4,262 = 1.66, P = 0.16, eta 2 = 0.012). When isolating mothers with moderate-severe symptoms of PND, this result became significant, with a faster improvement in symptoms in the singing group (F 3.9,139.8 = 2.74, P = 0.033, eta 2 = 0.028). Declaration of interest None. PMID- 29436334 TI - Effect of Groundwater Iron on Residual Chlorine in Water Treated with Sodium Dichloroisocyanurate Tablets in Rural Bangladesh. AB - We assessed the ability of sodium dichloroisocyanurate (NaDCC) to provide adequate chlorine residual when used to treat groundwater with variable iron concentration. We randomly selected 654 tube wells from nine subdistricts in central Bangladesh to measure groundwater iron concentration and corresponding residual-free chlorine after treating 10 L of groundwater with a 33-mg-NaDCC tablet. We assessed geographical variations of iron concentration using the Kruskal-Wallis test and examined the relationships between the iron concentrations and chlorine residual by quantile regression. We also assessed whether user-reported iron taste in water and staining of storage vessels can capture the presence of iron greater than 3 mg/L (the World Health Organization threshold). The median iron concentration among measured wells was 0.91 (interquartile range [IQR]: 0.36-2.01) mg/L and free residual chlorine was 1.3 (IQR: 0.6-1.7) mg/L. The groundwater iron content varied even within small geographical regions. The median free residual chlorine decreased by 0.29 mg/L (95% confidence interval: 0.27, 0.33, P < 0.001) for every 1 mg/L increase in iron concentration. Owner-reported iron staining of the storage vessel had a sensitivity of 92%, specificity of 75%, positive predictive value of 41%, and negative predictive value of 98% for detecting > 3 mg/L iron in water. Similar findings were observed for user-reported iron taste in water. Our findings reconfirm that chlorination of groundwater that contains iron may result in low level or no residual. User reports of no iron taste or no staining of storage containers can be used to identify low-iron tube wells suitable for chlorination. Furthermore, research is needed to develop a color-graded visual scale for iron staining that corresponds to different iron concentrations in water. PMID- 29436335 TI - Identification and Preliminary Evaluation of a Novel Recombinant Protein for Serodiagnosis of Strongyloidiasis. AB - Strongyloides stercoralis is a human parasite that can cause a long-term infection. In immunosuppressed patients, strongyloidiasis may be fatal when there is overwhelming autoinfection resulting in the migration of large numbers of larvae through many organs. Definitive diagnosis is still a challenge, and a combination of symptoms, microscopic identification, and serology test results are often used to arrive at a clinical decision. However, intermittent larval excretion, low parasite burden, and occult infections are challenges with parasitological diagnosis of infection with S. stercoralis. Meanwhile, serologic tests using immunoglobulin G and parasite antigen extract have problems of cross reactivity with other helminthic infections. Recombinant antigen-based serodiagnosis is a good alternative to overcome the laboratory diagnostic issues. Herein, we report on the isolation of cDNA clone encoding an antigen of potential diagnostic value identified from immunoscreening of a S. stercoralis cDNA library. The translated protein had highest similarity to Strongyloides ratti immunoglobulin-binding protein 1. The recombinant antigen produced, rSs1a, was assessed using western blot and enzyme-linked immunosorbent assay. The latter showed 96% diagnostic sensitivity and 93% specificity; thus, rSs1a has good potential for use in serodiagnosis of human strongyloidiasis. PMID- 29436336 TI - Indirect Rotavirus Vaccine Effectiveness for the Prevention of Rotavirus Hospitalization: A Systematic Review and Meta-Analysis. AB - Two rotavirus vaccines, RotaTeq and Rotarix, are licensed for global use; however, the protection they confer to unvaccinated individuals through indirect effects remains unknown. We systematically reviewed the literature and quantified indirect rotavirus vaccine effectiveness (VE) for preventing rotavirus hospitalization in children aged less than 5 years. From 148 identified abstracts, 14 studies met our eligibility criteria. In our main analysis using a random-effects model, indirect rotavirus VE was 48% (95% confidence interval [CI]: 39-55%). In a subgroup analysis by country income level, indirect VE was greater in high-income countries (52%; 95% CI: 43-60%) than in low- and middle income countries (LMICs) (25%; 95% CI: 5-41%). In a sensitivity analysis using a quality-effects model, the indirect VE in LMICs was not statistically significant (25%; 95% CI: 0-44%). Our findings highlight the importance of increasing rotavirus vaccine coverage, particularly in LMICs where evidence for indirect VE is limited and rotavirus burden is high. PMID- 29436337 TI - Rifaximin Reduces Markers of Inflammation and Bacterial 16S rRNA in Zambian Adults with Hepatosplenic Schistosomiasis: A Randomized Control Trial. AB - Cirrhosis is the dominant cause of portal hypertension globally but may be overshadowed by hepatosplenic schistosomiasis (HSS) in the tropics. In Zambia, schistosomiasis seroprevalence can reach 88% in endemic areas. Bacterial translocation (BT) drives portal hypertension in cirrhosis contributing to mortality but remains unexplored in HSS. Rifaximin, a non-absorbable antibiotic may reduce BT. We aimed to explore the influence of rifaximin on BT, inflammation, and fibrosis in HSS. In this phase II open-label trial (ISRCTN67590499), 186 patients with HSS in Zambia were evaluated and 85 were randomized to standard care with or without rifaximin for 42 days. Changes in markers of inflammation, BT, and fibrosis were the primary outcomes. BT was measured using plasma 16S rRNA, lipopolysaccharide-binding protein, and lipopolysaccharide, whereas hyaluronan was used to measure fibrosis. Tumor necrosis factor receptor 1 (TNFR1) and soluble cluster of differentiation 14 (sCD14) assessed inflammation. 16S rRNA reduced from baseline (median 146 copies/uL, interquartile range [IQR] 9, 537) to day 42 in the rifaximin group (median 63 copies/uL, IQR 12, 196), P < 0.01. The rise in sCD14 was lower (P < 0.01) in the rifaximin group (median rise 122 ng/mL, IQR-184, 783) than in the non-rifaximin group (median rise 832 ng/mL, IQR 530, 967). TNFR1 decreased (P < 0.01) in the rifaximin group (median -39 ng/mL IQR-306, 563) but increased in the non-rifaximin group (median 166 ng/mL, IQR 3, 337). Other markers remained unaffected. Rifaximin led to a reduction of inflammatory markers and bacterial 16S rRNA which may implicate BT in the inflammation in HSS. PMID- 29436338 TI - Multiple Phenotypic and Genotypic Artemisinin Sensitivity Evaluation of Malian Plasmodium falciparum Isolates. AB - We assessed the ex vivo/in vitro sensitivity of 54 Malian Plasmodium falciparum isolates to artemisinin for the monitoring of drug resistance in this area. The artemisinin sensitivity of parasites was evaluated using 1) the ex vivo and in vitro parasite recrudescence detection after treatment of the ring stage with 1 200 nM artemisinin for 48 hours and 2) the in vitro parasite recrudescence kinetics assay over 7 days after 6-hour treatment of the ring stage with 700 nM dihydroartemisinin (DHA). In addition, as recommended by the World Health Organization for artemisinin resistance characterization, the ring-stage survival assay (RSA0-3 h) was performed and the parasite isolates were sequenced at the kelch 13 propeller locus. No clinical and molecular evidence of artemisinin resistance was observed. However, these isolates present different phenotypic profiles in response to artemisinin treatments. Despite all RSA0-3 h values less than 1.5%, six out of 46 (13.0%) isolates tested ex vivo and four out of six (66.7%) isolates tested in vitro were able to multiply after 48-hour treatments with 100 nM artemisinin. Moreover, five out of eight isolates tested showed faster parasite recovery after DHA treatment in kinetic assays. The presence of such phenotypes needs to be taken into account in the assessment of the efficacy of artemisinins in Mali. The assays presented here appear as valuable tools for the monitoring of artemisinin sensitivity in the field and thus could help to evaluate the risk of emergence of artemisinin resistance in Africa. PMID- 29436339 TI - Surveillance of Antimalarial Resistance Molecular Markers in Imported Plasmodium falciparum Malaria Cases in Anhui, China, 2012-2016. AB - Between 2012 and 2016, over 80% of registered malaria cases in Anhui province were Plasmodium falciparum returned from Africa. However, drug-resistance marker polymorphisms in imported P. falciparum cases have not been assessed. This study looked at the distribution of antimalarial-drug resistance by evaluating K13 propeller, pfmdr1, and pfcrt gene mutations. Fourteen synonymous and 15 nonsynonymous mutations in the K13-propeller gene were detected in samples from nine African countries, yet no candidate and validated K13 resistance mutations were found. The prevalence of pfcrt K76T and pfmdr1 N86Y mutants was 27.7% and 19.9%, respectively. Six different pfcrt genotypes were found, with C72V73M74N75T76 being the most common (89.2%). The pfcrt 76-pfmdr1 86 haplotype combination was evaluated in 173 isolates, and the N86T76 genotype was the most prevalent (50.3%). Notably, the prevalence of the N86Y mutation in Africa marked a decline from 31.0% in 2012 to 8.2% in 2016. Our findings suggest that there is no immediate threat to artemisinin efficacy in imported P. falciparum infections returned from Africa to Anhui province. Nevertheless, pfcrt K76T and pfmdr1 N86Y mutations were modestly prevalent, suggesting the presence of chloroquine resistance in these cases. Accordingly, dihydroartemisinin + piperaquine may be a better choice than artesunate + amodiaquine for the treatment of uncomplicated P. falciparum infections in Anhui province. In addition to, artemether-lumefantrine can be introduced as an alternative measure. PMID- 29436340 TI - Characterization of the Gamboa Virus Serogroup (Orthobunyavirus Genus, Peribunyaviridae Family). AB - Comprehensive comparative phylogenetic analyses were performed on 17 Gamboa serogroup viruses (GAMSVs) from distinct geographic regions in the Americas and other representative members of the genus Orthobunyavirus (Peribunyaviridae), based on small (S), medium (M), and large (L) open reading frame full-length and partial sequences. Genome characterization showed that the GAMSVs divide into four clades or genotypes. The GAMSVs have a genetic organization similar to other orthobunyaviruses, except that they have a larger NSm protein than other orthobunyaviruses. A serosurvey for Gamboa virus antibodies was performed in plasma from birds, other wild animals, and humans living around the Tucurui hydroelectric dam in Para state, northern Brazil, a known focus of GAMSV activity. Newborn chicks (Gallus gallus domesticus) were experimentally infected with a GAMSV, and the pathogenesis is described. Histopathological changes were primarily in the lungs and liver. Also, a review of the ecology of the GAMSVs in the Americas is included. In sum, this study presents the genomic and evolutionary characterization of the Gamboa group and the potential model of pathogenesis, which would be helpful for diagnostic purposes, epidemiology, and immunopathogenesis studies. PMID- 29436341 TI - Retrospective Analysis of Fever and Sepsis Patients from Cambodia Reveals Serological Evidence of Melioidosis. AB - Burkholderia pseudomallei, the etiologic agent of melioidosis, is predicted to be ubiquitous in tropical regions of the world with areas of highest endemicity throughout Southeast Asia (SEA). Nevertheless, the distribution of B. pseudomallei and the burden of melioidosis in many SEA countries remain unclear. In Cambodia, only two human endemic cases of melioidosis were reported through 2008 and since then only a few hundred cases have been described in the literature. This is in sharp contrast to the annual burden of thousands of cases in surrounding areas. To further investigate the prevalence of melioidosis in Cambodia, we used a recently developed O-polysaccharide-based rapid enzyme-linked immunosorbent assay to detect B. pseudomallei-specific antibodies in serum samples obtained from 1,316 febrile illness or sepsis patients from 10 different provinces. Based on a cutoff value derived through culture-confirmed melioidosis cases, the proportion of positive samples in our cohort was approximately 12%. Regression analysis indicated that the odds of obtaining a positive result were 2.2 times higher for males than females controlling for age and province (95% confidence interval: 1.6-3.2, P < 0.001). Consistent with this, 9.2% of females were positive versus 18.2% of males (P < 0.001). Notably, 22.5% of grain or rice farmers were positive versus 10.1% of subjects with occupations not involving regular contact with soil. Positive results varied significantly by province. Collectively, the results of this study suggest that the true burden of melioidosis in Cambodia is greater than has previously been reported. PMID- 29436343 TI - Case Report: Conjunctival Infestation with Thelazia gulosa: A Novel Agent of Human Thelaziasis in the United States. AB - We report a case of thelaziasis in a 26-year-old female, acquired in Oregon. A total of 14 worms were removed from the patient's left eye and were morphologically identified as being Thelazia gulosa. Until now, only two species of Thelazia have been implicated in causing human disease, Thelazia callipaeda in Asia and Europe and occasional reports of Thelazia californiensis from the United States of America. Here, we describe a third, previously unreported parasite of humans, T. gulosa (the cattle eyeworm) as an agent of human thelaziasis and the first reported case of human thelaziasis in North America in over two decades. PMID- 29436342 TI - Competence of Phortica variegata from the United States as an Intermediate Host of the Thelazia callipaeda Eyeworm. AB - Over the past 20 years, Thelazia callipaeda (the oriental eyeworm) has become endemic in Europe, infecting domestic and wild carnivores and humans. The vector of this nematode, the fruit fly Phortica variegata, has recently been discovered in the United States, and its vector competence is demonstrated for T. callipaeda in this article, therefore representing a potential new threat for infection of carnivores and humans in the United States. PMID- 29436344 TI - Challenges in Assessing Combined Interventions to Promote Linear Growth. AB - Despite the recognition of stunting as a public health priority, nutritional and nonnutritional interventions to reduce or prevent linear growth failure have demonstrated minimal impact. Investigators and policymakers face several challenges that limit their ability to assess the potential benefits of combining available interventions into a linear growth promotion package. We use two common but very different interventions, deworming and multiple micronutrient supplements, to illustrate barriers to recommending an optimal linear growth promotion package based on the currently available literature. These challenges suggest that combining individual- and population-based as well as model-based approaches would complement existing research using systematic review, meta analysis, and factorial randomized trials, and help integrate existing fields of research to inform the development of optimal linear growth promotion packages for children living in resource-limited settings. PMID- 29436345 TI - A Cross Sectional Study of the Association between Sanitation Type and Fecal Contamination of the Household Environment in Rural Bangladesh. AB - We conducted a cross sectional study to assess 1) the association between access to basic sanitation and fecal contamination of sentinel toy balls and 2) if other sanitation factors such as shared use and cleanliness are associated with fecal contamination of sentinel toy balls. We assessed sanitation facilities in 454 households with a child aged 6-24 months in rural Bangladesh. We defined "basic" sanitation as access to improved sanitation facilities (pit latrine with a slab or better) not shared with other households. In each household, an identical toy ball was given to the target child. After 24 hours, the balls were rinsed to enumerate fecal coliforms as an indicator of household fecal contamination. Households with basic sanitation had lower fecal coliform contamination than households with no access to basic sanitation (adjusted difference in means: 0.31 log10 colony forming units [CFU]/toy ball; 95% confidence interval [CI]: 0.61, -0.01). Shared sanitation facilities of otherwise improved type were more likely to have visible feces on the latrine slab compared with private facilities. Among households with access to improved sanitation, households with no visible feces on the latrine slab had less toy ball contamination than households with visible feces on the latrine slab (adjusted difference in means: 0.38 log10 CFU/toy ball; 95% CI: -0.77, 0.02). Access to basic sanitation may prevent fecal contamination of the household environment. An Improved sanitation facility used by an individual household may be better in preventing household fecal contamination compared with improved facilities shared with other households. PMID- 29436346 TI - Molecular Detection of Anaplasma, Bartonella, and Borrelia theileri in Raccoon Dogs (Nyctereutes procyonoides) in Korea. AB - Anaplasmosis, cat-scratch disease, and Lyme disease are emerging vector-borne infectious diseases in Korea. Although the prevalence of vector-borne pathogens (VBPs) in domestic animals and vector arthropods has been documented, there is limited information on the presence of VBPs in wild animals. The raccoon dog (Nyctereutes procyonoides), a wild canid found in East Asia and Europe, represents a potential wildlife reservoir for zoonotic diseases. To investigate the prevalence of VBPs in raccoon dogs, 142 carcasses and 51 blood samples from captured raccoon dogs were collected from 2003 to 2010 and from 2008 to 2009, respectively, in Korea. In addition, 105 Haemaphysalis flava (14 larvae, 43 nymphs, 32 males, and 16 females) and nine Haemaphysalis longicornis (all female) were collected from three raccoon dogs. Samples of the spleen and blood were tested for the presence of VBPs by using nested polymerase chain reaction. Among the samples collected from 193 raccoon dogs and 114 ticks, two samples were positive for Anaplasma phagocytophilum, four for Anaplasma bovis, two for Borrelia theileri, and two for Bartonella henselae. To the best of our knowledge, this study is the largest survey of raccoon dogs aimed at the analysis of VBPs in this species. Moreover, the present study represents the first identification of A. phagocytophilum, B. henselae, and B. theileri in raccoon dogs in their native habitat (East Asia). PMID- 29436347 TI - The Spatial-Temporal Trend Analysis of Schistosomiasis from 1997 to 2010 in Anhui Province, Eastern China. AB - Schistosomiasis is still prevalent in some parts of China. A shift in strategy from morbidity control to elimination has led to great strides in the past several decades. The objective of this study was to explore the spatial and temporal characteristics of schistosomiasis in Anhui, an eastern province of China. In this study, township-based parasitological data were collected from annual cross-sectional surveys during 1997-2010. The kernel k-means method was used to identify spatial clusters of schistosomiasis, and an empirical mode decomposition technique was used to analyze the temporal trend for Schistosoma japonicum in each clustered region. Overall, the prevalence of schistosomiasis remained at a low level except for the resurgence in 2005. According to the Calinski-Harabas index, all the townships were classified into three different clusters (median prevalence: 3.6 per 10,100, 1.8 per 10,000 and 1.7 per 10,000), respectively representing high-, median-, and low-risk clusters. There was an increasing tendency observed for the disease over time. The prevalence increased rapidly from 2003 to 2005, peaked in 2006, and then decreased afterward in the high-risk cluster. A moderate increase was observed in the median-risk cluster from 1998 to 2006, but there was an obvious decreasing tendency in the low-risk cluster after the year 2000. The spatial and temporal patterns of schistosomiasis were nonsynchronous across the three clusters. Disease interventions may be adjusted according to the risk levels of the clusters. PMID- 29436348 TI - Prevalence and Association of Escherichia coli and Diarrheagenic Escherichia coli in Stored Foods for Young Children and Flies Caught in the Same Households in Rural Bangladesh. AB - Consumption of contaminated stored food can cause childhood diarrhea. Flies carry enteropathogens, although their contribution to food contamination remains unclear. We investigated the role of flies in contaminating stored food by collecting food and flies from the same households in rural Bangladesh. We selected 182 households with children <= 24 months old that had stored foods for later feeding at room temperature for >= 3 hours. We collected food samples and captured flies with fly tapes hung by the kitchen. We used the IDEXX Quanti-Tray System (Colilert-18 media; IDEXX Laboratories, Inc., Westbrook, ME) to enumerate Escherichia coli with the most probable number (MPN) method. Escherichia coli positive IDEXX wells were analyzed by polymerase chain reaction for pathogenic E. coli genes (eae, ial, bfp, ipaH, st, lt, aat, aaiC, stx1, and stx2). Escherichia coli was detected in 61% (111/182) of food samples, with a mean of 1.1 log10 MPN/dry g. Fifteen samples (8%) contained pathogenic E. coli; seven (4%) had enteropathogenic E. coli (EPEC) genes (eae and/or bfp); and 10 (5%) had enteroaggregative E. coli genes (aat and/or aaiC). Of flies captured in 68 (37%) households, E. coli was detected in 41 (60%, mean 2.9 log10 MPN/fly), and one fly (1%) had an EPEC gene (eae). For paired fly-food samples, each log10 MPN E. coli increase in flies was associated with a 0.31 log10 MPN E. coli increase in stored food (95% confidence interval: 0.07, 0.55). In rural Bangladesh, flies possibly a likely route for fecal contamination of stored food. Controlling fly populations may reduce contamination of food stored for young children. PMID- 29436351 TI - What Is Your Career Legacy? PMID- 29436349 TI - The Dynamics of Liver Function Test Abnormalities after Malaria Infection: A Retrospective Observational Study. AB - Liver dysfunction has long been recognized as a clinical feature of malaria. We have observed delayed elevation in the transaminase portion of liver function tests (LFTs) after treatment in some participants undergoing induced blood stage malaria infection. We sought to determine whether similar LFT elevations occur after naturally acquired infection. We performed a retrospective audit of confirmed cases of Plasmodium falciparum and Plasmodium vivax in Queensland, Australia, from 2006 to 2016. All LFT results from malaria diagnosis until 28 days after diagnosis were collected with demographic and clinical information to describe longitudinal changes. The timing of peak LFT elevations was classified as early (0-3 days), delayed (4-11 days), or late (12-28 days) with respect to the day of diagnosis. Among 861 cases with LFT evaluated, an elevated bilirubin level was identified in 12.4% (N = 107/861), whereas elevated alanine transaminase (ALT) and aspartate transaminase levels were observed in 15.1% (N = 130/861) and 14.8% (N = 127/861) of cases, respectively. All peak bilirubin results occurred in the early period, whereas ALT elevations were biphasic, with elevations in the early and delayed periods, with 35.4% (N = 46/130) of cases delayed. Univariate and paired stepwise logistic regression analyses were performed to investigate factors associated with the incidence and timing of transaminase elevation. A raised ALT level at diagnosis was strongly associated with the timing of transaminase elevation. No other demographic, parasitic, or treatment factors were associated. Liver function test abnormalities are likely an inherent although variable aspect of human malaria, and individual-specific factors may confer susceptibility to hepatocyte injury. PMID- 29436350 TI - A Longitudinal Study of Household Water, Sanitation, and Hygiene Characteristics and Environmental Enteropathy Markers in Children Less than 24 Months in Iquitos, Peru. AB - Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has been proposed as a biological mechanism underlying child stunting and oral vaccine failure. Characteristics related to household sanitation, water use, and hygiene were measured among a birth cohort of 270 children from peri-urban Iquitos Peru. These children had monthly stool samples and urine samples at four time points and serum samples at (2-4) time points analyzed for biomarkers related to intestinal inflammation and permeability. We found that less storage of fecal matter near the household along with a reliable water connection were associated with reduced inflammation, most prominently the fecal biomarker myeloperoxidase (MPO) (no sanitation facility compared with those with an onsite toilet had -0.43 log MPO, 95% confidence interval [CI]: -0.74, 0.13; and households with an intermittent connection versus those with a continuous supply had +0.36 log MPO, 95% CI: 0.08, 0.63). These results provide preliminary evidence for the hypothesis that children less than 24 months of age living in unsanitary conditions will have elevated gut inflammation. PMID- 29436352 TI - Does Changing Newborn Bath Procedure Alter Newborn Temperatures and Exclusive Breastfeeding? AB - PURPOSE: This evidence-based practice project evaluated effects of changing timing/character of initial newborn baths on infant temperatures and breastfeeding status. BACKGROUND: The hospital protocol for initial bathing procedures was updated: immersion baths; 12 hours postpartum; family included. METHODS: Staff nurse champions provided staff training. The evaluation included three seven-week periods (2016-2017) and three measures: adherence, temperature stabilization, and exclusive breastfeeding. RESULTS: Of 1,205 38-week healthy newborns, 322 were born preimplementation (Pre), 486 after (Post), and 397 during maintenance (M). Adherence to bath timing increased and was maintained: 28 percent Pre; 83 percent Post; 85 percent M. Almost 100 percent of newborns had stable temperatures. Breastfeeding exclusivity rates did not change (ps greater than or equal to .05): baths less than 12 hours: 79 percent Pre, 74 percent Post, and 68 percent M; baths 12 hours: 68 percent Pre, 71 percent Post, and 73 percent M. IMPLICATIONS: Changing bath time/character for healthy newborns maintained thermoregulation and exclusive breastfeeding rates. Nurses changed practice quickly, maintaining adherence over time. PMID- 29436353 TI - Feeding Infants with Neonatal Abstinence Syndrome: Finding the Sweet Spot. AB - PURPOSE: The purpose of this study is to learn how caregivers who are expert in feeding infants with neonatal abstinence syndrome (NAS) successfully feed these infants during withdrawal. DESIGN/SAMPLE: Focus group methodology was used to gather information from self-identified experts from three large regional NICUs. Twelve NICU nurses and speech therapists participated in open-ended, recorded discussions. Detailed flip chart notes were taken, reviewed, and verified by the participants before the group ended. RESULTS: Four major themes emerged verified by the participants: (1) optimal medication management, (2) follow the baby's cues, (3) calm and comfortable, and (4) nurture the relationship. Participants reported using both common and creative techniques. Keeping the infant calm was crucial to being successful, as well as maintaining good control of withdrawal signs. Feeding the infant facing away from them to avoid eye contact was used, as well as vertical rocking, continuous butt patting, bundling, "shhing" sound, and a novel feeding position. PMID- 29436354 TI - Surrogacy: Pathway to Parenthood. AB - Assistive reproductive technology has progressed significantly over the past few decades. In spite of the advances, people may still resort to a surrogate for bearing and birthing a baby. Surrogacy, though an altruistic act, has been commercialized in the past few years, leading to emergence of several ethico legal concerns. Nurses care for the surrogates, the infants, and the intended parents through their journey with sensitivity, advocacy, compassion, and confidentiality. This article intends to explore the implications of surrogacy to individuals, families, nations, and health care. PMID- 29436355 TI - Care of the Neonate on Nasal Continuous Positive Airway Pressure: A Bedside Guide. AB - Respiratory distress continues to be a major cause of neonatal morbidity. Current neonatal practice recommends the use of nasal continuous positive airway pressure (nCPAP) in the immediate resuscitation and continued support of neonates of all gestations with clinical manifestations of respiratory distress. Despite the many short- and long-term benefits of nCPAP, many neonatal care units have met resistance in its routine use. Although there have been numerous recent publications investigating the use and outcomes of various modes of nCPAP delivery, surfactant administration, mechanical ventilation, and other forms of noninvasive respiratory support (high-flow nasal cannula, nasal intermittent positive pressure ventilation), there has been a relative lack of publications addressing the practical bedside care of infants managed on nCPAP. Effective use of nCPAP requires a coordinated interprofessional team approach, ongoing assessment of the neonate, troubleshooting the nCPAP circuit, and parent education. PMID- 29436357 TI - Acid Suppression for Gastroesophageal Reflux Disease in Infants. AB - Gastroesophageal reflux is a normal physiologic occurrence that is common throughout infancy and usually resolves on its own. Infrequently, reflux causes complications and turns into gastroesophageal reflux disease (GERD), which may warrant intervention. Available interventions vary in invasiveness and supporting data may be lacking for efficacy and safety. Nonpharmacologic interventions are first-line therapy for GERD in infants, whereas pharmacologic and surgical approaches are controversial. Efficacy data are limited for pharmacologic strategies for infantile GERD and safety data have demonstrated serious risks, especially in younger infants. Utilization of these medications should be approached cautiously in this population, if appropriate diagnostic techniques determine acid suppression could be beneficial. A robust monitoring plan with frequent reassessment of need for therapy may optimize benefit and minimize risk. PMID- 29436358 TI - Ethical Implications of Rapid Whole-Genome Sequencing in Neonates. AB - Using rapid whole-genome sequencing (WGS), an infant's genome can now be sequenced in as little as 26 hours allowing for rapid diagnosis and precise, individualized management of monogenetic causes of disease. The potential for decreasing cost and valuable time to diagnosis along with pain and suffering is becoming a reality in the NICU. Coupled with rapidly developing technology is a need to explore the associated ethical implication. PMID- 29436359 TI - Providing Equal Family-Centered Care in Every NICU. AB - Family-centered care is a constant buzzword in a NICU. However, there are consistent gaps in units across the country and beyond. Addressing this goes beyond a simple certification. That is where Sara Mosher, former NICU nurse, NICU manager, and NICU support specialist, steps in with an online course and community to support parents and ease the family-centered care strain on NICUs. PMID- 29436360 TI - Continuing Education Course. PMID- 29436361 TI - News of the Academy of Neonatal Nursing. PMID- 29436362 TI - Screening Tool for Psychological Intimate Partner Violence: Portuguese Validation of the Psychological Maltreatment of Women Inventory. AB - BACKGROUND/OBJECTIVE: The Psychological Maltreatment of Women Inventory-Short Form (PMWI-SF) is a well-established and brief instrument for assessing psychological intimate partner violence (IPV). In the absence of a specific tool to assess psychological IPV in Portuguese women, this study sought to confirm the factor structure of the Portuguese PMWI-SF and analyze its psychometric properties. METHOD: Five hundred and six women filled out the e-survey including the assessment of IPV (Revised Conflict Tactics Scales, Psychological Abuse Survey, and PMWI-SF) and psychopathology through the Brief Symptom Inventory. Sociodemographic characteristics, construct validity, and internal consistency were analyzed, and a cutoff for the PMWI-SF was established. RESULTS: Confirmatory factor analysis for the 2-factor structure (emotional/verbal abuse and domination/isolation) showed an excellent fit for the last 6 months and across the life span. Factors possessed good internal consistency (alpha >= .70) and test-retest reliability (r >= .90). Pearson's correlation analysis revealed the PMWI factors were positively correlated with proximal variables. PMWI-SF scores demonstrated excellent differentiation between women with and without psychological IPV (area under the curve [AUC] = .948; confidence interval or CI [.93, .97]). The PMWI-SF cutoff score that provided the optimal balance was 32 (sensitivity = 83.8%; specificity = 91.7%). CONCLUSIONS: The PMWI-SF is a valid and reliable instrument for assessing the experience of psychological IPV in Portuguese women. PMID- 29436363 TI - Unacknowledged Rape in the Community: Rape Characteristics and Adjustment. AB - Unacknowledged rape, labeling a rape as a nonvictimizing event, remains largely unstudied among non-college women. This study therefore sought to examine differences in assault characteristics, adjustment, and disclosure by rape acknowledgment status among a sample of lower income rape victims (n = 104) recruited from a reproductive health clinic (mean age = 28.8 years). Although unacknowledged rape was infrequent (17.1% of victims), unacknowledged victims reported that the perpetrator used less force and were less likely to have assertively resisted, as compared to acknowledged victims. There were no significant differences in disclosure, depression, and somatic complaints between unacknowledged and acknowledged rape victims. Implications of the findings for understanding rape acknowledgment and postrape adjustment among community women are discussed. PMID- 29436364 TI - The West Midlands ActiVe lifestyle and healthy Eating in School children (WAVES) study: a cluster randomised controlled trial testing the clinical effectiveness and cost-effectiveness of a multifaceted obesity prevention intervention programme targeted at children aged 6-7 years. AB - BACKGROUND: Systematic reviews suggest that school-based interventions can be effective in preventing childhood obesity, but better-designed trials are needed that consider costs, process, equity, potential harms and longer-term outcomes. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of the WAVES (West Midlands ActiVe lifestyle and healthy Eating in School children) study intervention, compared with usual practice, in preventing obesity among primary school children. DESIGN: A cluster randomised controlled trial, split across two groups, which were randomised using a blocked balancing algorithm. Schools/participants could not be blinded to trial arm. Measurement staff were blind to allocation arm as far as possible. SETTING: Primary schools, West Midlands, UK. PARTICIPANTS: Schools within a 35-mile radius of the study centre and all year 1 pupils (aged 5-6 years) were eligible. Schools with a higher proportion of pupils from minority ethnic populations were oversampled to enable subgroup analyses. INTERVENTIONS: The 12-month intervention encouraged healthy eating/physical activity (PA) by (1) helping teachers to provide 30 minutes of additional daily PA, (2) promoting 'Villa Vitality' (interactive healthy lifestyles learning, in an inspirational setting), (3) running school-based healthy cooking skills/education workshops for parents and children and (4) highlighting information to families with regard to local PA opportunities. MAIN OUTCOME MEASURES: The primary outcomes were the difference in body mass index z scores (BMI-zs) between arms (adjusted for baseline body mass index) at 3 and 18 months post intervention (clinical outcome), and cost per quality-adjusted life year (QALY) (cost-effectiveness outcome). The secondary outcomes were further anthropometric, dietary, PA and psychological measurements, and the difference in BMI-z between arms at 27 months post intervention in a subset of schools. RESULTS: Two groups of schools were randomised: 27 in 2011 (n = 650 pupils) [group 1 (G1)] and another 27 in 2012 (n = 817 pupils) [group 2 (G2)]. Primary outcome data were available at first follow-up (n = 1249 pupils) and second follow-up (n = 1145 pupils) from 53 schools. The mean difference (MD) in BMI-z between the control and intervention arms was -0.075 [95% confidence interval (CI) -0.183 to 0.033] and -0.027 (95% CI -0.137 to 0.083) at 3 and 18 months post intervention, respectively. The main analyses showed no evidence of between-arm differences for any secondary outcomes. Third follow-up included data on 467 pupils from 27 G1 schools, and showed a statistically significant difference in BMI-z (MD -0.20, 95% CI -0.40 to -0.01). The mean cost of the intervention was L266.35 per consented child (L155.53 per child receiving the intervention). The incremental cost-effectiveness ratio associated with the base case was L46,083 per QALY (best case L26,804 per QALY), suggesting that the intervention was not cost-effective. LIMITATIONS: The presence of baseline primary outcome imbalance between the arms, and interschool variation in fidelity of intervention delivery. CONCLUSIONS: The primary analyses show no evidence of clinical effectiveness or cost-effectiveness of the WAVES study intervention. A post hoc analysis, driven by findings at third follow-up, suggests a possible intervention effect, which could have been attenuated by baseline imbalances. There was no evidence of an intervention effect on measures of diet or PA and no evidence of harm. FUTURE WORK: A realist evidence synthesis could provide insights into contextual factors and strategies for future interventions. School-based interventions need to be integrated within a wider societal framework and supported by upstream interventions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97000586. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 8. See the NIHR Journals Library website for further project information. PMID- 29436365 TI - Teaching Case 2-2018: Sclerosing myxopapillary ependymoma mimicking whorling sclerosing meningioma. PMID- 29436366 TI - Spermiogenesis and spermatozoon ultrastructure in basal polyopisthocotylean monogeneans, Hexabothriidae and Chimaericolidae, and their significance for the phylogeny of the Monogenea. AB - Sperm ultrastructure provides morphological characters useful for understanding phylogeny; no study was available for two basal branches of the Polyopisthocotylea, the Chimaericolidea and Diclybothriidea. We describe here spermiogenesis and sperm in Chimaericola leptogaster (Chimaericolidae) and Rajonchocotyle emarginata (Hexabothriidae), and sperm in Callorhynchocotyle callorhynchi (Hexabothriidae). Spermiogenesis in C. leptogaster and R. emarginata shows the usual pattern of most Polyopisthocotylea with typical zones of differentiation and proximo-distal fusion of the flagella. In all three species, the structure of the spermatozoon is biflagellate, with two incorporated trepaxonematan 9 + "1" axonemes and a posterior nucleus. However, unexpected structures were also seen. An alleged synapomorphy of the Polyopisthocotylea is the presence of a continuous row of longitudinal microtubules in the nuclear region. The sperm of C. leptogaster has a posterior part with a single axoneme, and the part with the nucleus is devoid of the continuous row of microtubules. The spermatozoon of R. emarginata has an anterior region with membrane ornamentation, and posterior lateral microtubules are absent. The spermatozoon of C. callorhynchi has transverse sections with only dorsal and ventral microtubules, and its posterior part shows flat sections containing a single axoneme and the nucleus. These findings have important implications for phylogeny and for the definition of synapomorphies in the Neodermata. We point out a series of discrepancies between actual data and interpretation of character states in the matrix of a phylogeny of the Monogenea. Our main conclusion is that the synapomorphy "lateral microtubules in the principal region of the spermatozoon" does not define the Polyopisthocotylea but is restricted to the Mazocraeidea. PMID- 29436367 TI - Transgenerational dynamics of rDNA copy number in Drosophila male germline stem cells. AB - rDNA loci, composed of hundreds of tandemly duplicated arrays of rRNA genes, are known to be among the most unstable genetic elements due to their repetitive nature. rDNA instability underlies aging (replicative senescence) in yeast cells, however, its contribution to the aging of multicellular organisms is poorly understood. In this study, we investigate the dynamics of rDNA loci during aging in the Drosophila male germline stem cell (GSC) lineage, and show that rDNA copy number decreases during aging. Our study further reveals that this age-dependent decrease in rDNA copy number is heritable from generation to generation, yet GSCs in young animals that inherited reduced rDNA copy number are capable of recovering normal rDNA copy number. Based on these findings, we propose that rDNA loci are dynamic genetic elements, where rDNA copy number changes dynamically yet is maintained through a recovery mechanism in the germline. PMID- 29436369 TI - Cupping Therapy: An Overview from a Modern Medicine Perspective. AB - Cupping therapy is an ancient traditional and complementary medicine practice. Recently, there is growing evidence of its potential benefits in the treatment of pain-related diseases. This article gives an overview of cupping therapy practice. Furthermore, this article suggests a new classification of cupping therapy sets, a new classification of cupping therapy adverse events, and an updated classification of cupping therapy types. PMID- 29436368 TI - Mild myelin disruption elicits early alteration in behavior and proliferation in the subventricular zone. AB - Myelin, the insulating sheath around axons, supports axon function. An important question is the impact of mild myelin disruption. In the absence of the myelin protein proteolipid protein (PLP1), myelin is generated but with age, axonal function/maintenance is disrupted. Axon disruption occurs in Plp1-null mice as early as 2 months in cortical projection neurons. High-volume cellular quantification techniques revealed a region-specific increase in oligodendrocyte density in the olfactory bulb and rostral corpus callosum that increased during adulthood. A distinct proliferative response of progenitor cells was observed in the subventricular zone (SVZ), while the number and proliferation of parenchymal oligodendrocyte progenitor cells was unchanged. This SVZ proliferative response occurred prior to evidence of axonal disruption. Thus, a novel SVZ response contributes to the region-specific increase in oligodendrocytes in Plp1-null mice. Young adult Plp1-null mice exhibited subtle but substantial behavioral alterations, indicative of an early impact of mild myelin disruption. PMID- 29436370 TI - Isoflurane and the Analgesic Effect of Acupuncture and Electroacupuncture in an Animal Model of Neuropathic Pain. AB - The present study aimed to determine whether isoflurane interferes with the analgesic effects of acupuncture (Ac) and electroacupuncture (EA), using a neuropathic pain (NP) rat model. In total, 140 male Wistar rats were used; isoflurane-induced nociceptive response was evaluated using the von Frey test, serum calcium-binding protein beta (S100beta) levels and nerve growth factor (NGF) levels in the left sciatic nerve. The NP model was induced by chronic constriction injury of the sciatic nerve at 14 days after surgery. Treatment was initiated after NP induction with or without isoflurane anesthesia (20 min/day/8 days). The von Frey test was performed at baseline, 14 days postoperatively, and immediately, 24 h, and 48 h after the last treatment. Results of the nociceptive test and three-way analysis of variance were analyzed by generalized estimating equations, the Bonferroni test, followed by Student-Newman-Keuls or Fisher's least significant difference tests for comparing biochemical parameters (significance defined as p <= 0.05). At baseline, no difference was noted in the nociceptive response threshold among all groups. Fourteen days after surgery, compared with other groups, NP groups showed a decreased pain threshold, confirming establishment of NP. Ac and EA enhanced the mechanical pain threshold immediately after the last session in the NP groups, without anesthesia. Isoflurane administration caused increased nociceptive threshold in all groups, and this effect persisted for 48 h after the last treatment. There was an interaction between the independent variables: pain, treatments, and anesthesia in serum S100beta levels and NGF levels in the left sciatic nerve. Isoflurane enhanced the analgesic effects of Ac and EA and altered serum S100beta and left sciatic nerve NGF levels in rats with NP. PMID- 29436371 TI - Comparison of the Cost-utility Analysis of Electroacupuncture and Nonsteroidal Antiinflammatory Drugs in the Treatment of Chronic Low Back Pain. AB - INTRODUCTION AND OBJECTIVE: Chronic low back pain (CLBP) is among the most common and important reasons for visiting a spine surgeon by patients; it is the second cause of visiting a doctor. Low back pain can cause considerable suffering and is a major financial burden in the society. There are many different methods available for the treatment of CLBP. This study aimed to compare the cost-utility of electroacupuncture (EA) and nonsteroidal antiinflammatory drugs (NSAIDs), as two common treatment methods for patients with CLBP. METHODS: This study was conducted on 100 patients suffering from CLBP. Cases were randomly selected from patients referring to two hospitals and four acupuncture clinics in Tehran. Forty one patients received EA, and 59 patients were prescribed NSAIDs. The EuroQol five dimensions questionnaire was used to calculate quality-adjusted life-year. For calculating the total cost of the two treatment methods, face to face interview with patients was conducted by the researchers (using specific basic literature questionnaire), neurologists, and spine surgeons. The study perspective was social (direct and indirect costs calculated). RESULTS: The mean age for EA group was 41 +/- 2.3 years, and for NSAIDs group, it was 38.0 +/- 4.4 years. The average of the utility of patients under treatment by EA and NSAIDs was estimated as 0.70 and 0.627, respectively. The difference in utility between the two groups was significant (p <= 0.05). The total cost of EA and NSAIDs was estimated as 461.48 +/- 57.8$ and 497.77 +/- 85.2$ for one year (2016), respectively, which was also significant (p <= 0.05). CONCLUSION: The results indicate a significant difference between EA and NSAIDs in cases of both utility and total cost. The findings demonstrate that EA is more cost-effective than NSAIDs, as therefore can be considered as an alternative treatment for CLBP, with reasonable cost-utility. PMID- 29436372 TI - The Acupuncture Therapeutic Approach in Temporal Arteritis Vasculitis: A Case Report. AB - Temporal arteritis is a form of vasculitis that involves the large- and medium diameter arteries and leads to progressive headache. Symptoms may be accompanied by vision disorder, subfebrile temperature, fatigue, lack of appetite, weight loss, sweating, and joint pains. While cortisone therapy reduces the symptoms, its effects in terms of improving quality of life are limited. We opted to benefit from the effects of acupuncture to reduce symptoms and increase quality of life in a case of temporal arteritis, a chronic disease. A 75-year-old woman presented with pain on both sides of the head. The pain occurred in the form of agonizing attacks 2-3 times a week. Accompanying neck pain was present, together with continuous lethargy and fatigue. Physical examination revealed decreased cutaneous elasticity and muscle mass, and a depressive mood state was present. The patient was first administered six sessions of acupuncture therapy directed toward the migraine etiology. When no response was achieved, we investigated temporal and parietal region points associated with headache in the literature. Points GB1,8,18, ST8, SI19, and BL8 were added to the treatment. The pain attacks and their frequency decreased following acupuncture therapy. In conclusion, while cortisone is the first preference in the treatment of temporal arteritis, we think that acupuncture aimed at the cause of accompanying symptoms can also be useful. PMID- 29436373 TI - Electroacupuncture for the Treatment of Calcific Tendonitis. A Pilot Study. AB - Current treatment for calcific tendonitis consists of arm rest, antiinflammatory medications, and corticosteroid injections. If unsuccessful, a lot of clinicians suggest several physiotherapy modalities, such as shockwave therapy and electrotherapy. The purpose of our study was to assess the efficacy of electroacupuncture, as a substitute for failed medical treatment in calcific tendonitis. In a pilot study, we prospectively followed 10 patients treated with electroacupuncture for calcific tendonitis who failed to respond to medical treatment. Its efficacy was assessed by evaluating the level of pain, the Beck Depression Inventory, the range of active elbow mobility, and by repeated radiological evaluation of the course of calcific deposits. All clinical and radiological observations were recorded before and within 6 months after the onset of treatment. After electroacupuncture treatment (2 Hz, 180 mA for 30-60 seconds at GB21, GB34, LI4, LI 14, LI15, TW5, TW14, Chien Chien SI9, SI12, S37, S38), the visual analog score decreased notably, and the range of motion returned to normal. Radiological evaluation demonstrated almost complete absorption of calcific deposits within 6 months, after treatment. We conclude that electroacupuncture relieved skeletal pain, improved the quality of patient's life, and contributed to total regression of the calcific depositions in followed patients. So, electroacupuncture may be a valuable treatment option for calcific tendonitis, when medical treatment fails to relieve symptoms. PMID- 29436374 TI - Kinesio Taping Associated with Acupuncture in the Treatment of the Paretic Upper Limb After Stroke. AB - The leading cause of disability in adults, leads to different consequences, such as hemiparesis and loss of function in the upper limb which can impair the performance of activities of daily living. Different techniques, such as like acupuncture and Kinesio Taping (KT), have been used to ameliorate this condition. However, there is no consensus on their concomitant effect on neurological patients. This study aimed to analyze the effects of acupuncture associated with KT on the upper limb of patients with chronic hemiparesis after stroke. In this clinical study, 16 subjects were divided into two intervention groups: acupuncture (ACP)-12 sessions of acupuncture-and acupuncture + Kinesio Taping (ACP-KT)-12 sessions of acupuncture plus KT. The Modified Ashworth Scale (spasticity), active goniometry [range of motion (ROM)], and the Wolf Motor Function Test (speed of movement) were used to assess the function of the affected upper limb. As a main result, both groups reduced spasticity in some studied musculature and increased ROM (p < 0.05), without intergroup difference. Moreover, there was no significant improvement concerning speed of movement in either group. Acupuncture was effective in reducing spasticity and increasing ROM of paretic upper limb after stroke, but did not contribute significantly to speed and quality of movement. KT did not show significant benefits concerning the analyzed variables. PMID- 29436375 TI - Scalp Acupuncture for the Treatment of Motor Function in Acute Spinal Cord Injury: A Case Report. AB - An acute spinal cord injury is the result of a traumatic injury to the spinal cord caused by a contusion, compression, or severing of the spinal cord. There are approximately 17,000 new cases each year, of which, males account for 80%. Approximately 65% of these injuries cause incomplete or partial damage to the spinal cord. Comprehensive treatment is essential to restore maximum function. Surgical procedures, stem cell therapy, pharmaceutical agents, and physical therapy are employed to minimize and repair damage done to the nervous system. The majority of motor and sensory recovery occurs during the first 12 to 15 weeks after the injury. Acupuncture has shown promising results in mediating neural plasticity and could be a useful treatment modality in hospital and rehabilitation settings. This case presents the treatment of an acute spinal cord injury, level T5, incomplete, with scalp acupuncture both within and beyond the optimal recovery window. The treatments given within the optimal window seemed to facilitate better restoration of nervous system communication when performing specific action. PMID- 29436376 TI - Breast carcinoma in sclerosing adenosis: a clinicopathological and immunophenotypical analysis on 206 lesions. AB - AIMS: To fully elucidate the clinicopathological features of breast carcinoma in sclerosing adenosis (SA-BC). METHODS: Clinical and histological characteristics of 206 SA-BCs from 180 patients were retrospectively evaluated. Immunohistochemical phenotype was examined. The clinicopathological relevance of the topographical pattern of SA-BCs was analysed. RESULTS: Overall, up to 46 patients (25.6%) had contralateral cancer, either SA associated or not. Of 99 cases who underwent core needle biopsy (CNB), 36 were underestimated as adenosis or atypical ductal hyperplasia at CNB, 5 invasive cases were misinterpreted as in situ carcinomas, whereas 4 ductal carcinoma in situ (DCIS) cases were overdiagnosed as invasive carcinoma. Microscopically, 163 tumours were in situ, including 136 DCIS, 19 lobular carcinomas in situ (LCIS) and 8 mixed DCIS/LCIS; of these carcinomas in situ (CIS), 37 had microinvasion. The DCIS group exhibited low, intermediate and high grades in 53.7%, 34.6% and 11.8% of cases, respectively, mostly with solid (43.4%) or cribriform (41.9%) pattern. Forty out of 43 invasive cases were invasive ductal carcinoma (IDC), mostly DCIS predominant. Immunophenotypically, luminal A phenotype was identified in 55.1%, 63.2% and 45.0% of DCIS, LCIS and IDC cases, respectively. Topographical type A group (carcinoma being entirely confined to SA, n=176) was characterised by smaller size, less invasiveness, lower grade and more frequency of luminal A immunophenotype compared with type B group (>= 50% but not all of the carcinomatous lesion being located in SA, n=30) (all P<0.05). CONCLUSIONS: CIS, especially non-high-grade DCIS, represents the most common variant of SA-BC, and luminal A is the most predominant immunophenotype. CNB assessment might be challenging in some SA-BCs. The topographical pattern has great clinicopathological relevance. Careful evaluation of the contralateral breast and long-term follow-up for patients with SA-BC is necessary given its high prevalence of bilaterality. PMID- 29436378 TI - Establishment of Community-Based Reference Intervals for Fructosamine, Glycated Albumin, and 1,5-Anhydroglucitol. AB - BACKGROUND: There is growing interest in fructosamine, glycated albumin, and 1,5 anhydroglucitol (1,5-AG) as alternative measures of hyperglycemia, particularly for use in settings where traditional measures (glucose and HbA1c) are problematic or where intermediate (2-4 weeks) glycemic control is of interest. However, reference intervals for these alternative biomarkers are not established. METHODS: We measured fructosamine, glycated albumin, and 1,5-AG in a community-based sample of US black and white adults who participated in the Atherosclerosis Risk in Communities (ARIC) Study. We calculated reference intervals, evaluated demographic differences, and derived cutoffs aligned with current diagnostic cutpoints for HbA1c and fasting glucose. RESULTS: In a healthy reference population of 1799 individuals (mean age, 55 years; 51% women; 15% black), the 2.5 and 97.5 percentiles, respectively, were 194.8 and 258.0 MUmol/L for fructosamine, 10.7% and 15.1% for glycated albumin, and 8.4 and 28.7 MUg/mL for 1,5-AG. Distributions differed by race, sex, and body mass index. Equivalent concentrations of fructosamine and glycated albumin corresponding to an HbA1c of 6.5% (96.5 percentile) were 270.2 MUmol/L and 15.6%, respectively. Equivalent concentrations of fructosamine and glycated albumin corresponding to a fasting glucose of 126 mg/dL (93.9 percentile) were 261.7 MUmol/L and 15.0%, respectively. CONCLUSIONS: The reference intervals for these biomarkers should inform their clinical use. Diagnostic cutpoint equivalents for fructosamine and glycated albumin could be useful to identify persons with hyperglycemia in settings where fasting glucose or HbA1c are not available or where the interpretation of these traditional measures is problematic. PMID- 29436377 TI - Elevated Medium-Chain Acylcarnitines Are Associated With Gestational Diabetes Mellitus and Early Progression to Type 2 Diabetes and Induce Pancreatic beta-Cell Dysfunction. AB - Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type 2 diabetes (T2D) and linked to peripheral insulin resistance. However, the effect of acylCs on pancreatic beta-cell function is not well understood. Here, we profiled circulating acylCs in two diabetes cohorts: 1) women with gestational diabetes mellitus (GDM) and 2) women with recent GDM who later developed impaired glucose tolerance (IGT), new-onset T2D, or returned to normoglycemia within a 2-year follow-up period. We observed a specific elevation in serum medium-chain (M)-acylCs, particularly hexanoyl- and octanoylcarnitine, among women with GDM and individuals with T2D without alteration in long-chain acylCs. Mice treated with M-acylCs exhibited glucose intolerance, attributed to impaired insulin secretion. Murine and human islets exposed to elevated levels of M-acylCs developed defects in glucose-stimulated insulin secretion and this was directly linked to reduced mitochondrial respiratory capacity and subsequent ability to couple glucose metabolism to insulin secretion. In conclusion, our study reveals that an elevation in circulating M-acylCs is associated with GDM and early stages of T2D onset and that this elevation directly impairs beta-cell function. PMID- 29436379 TI - Advances in the Diagnosis and Management of Cystic Fibrosis in the Genomic Era. AB - BACKGROUND: Cystic fibrosis (CF) is a complex autosomal recessive disease that continues to present unique diagnostic challenges. Because CF was first described in 1938, there has been a substantial growth of genetic and phenotypic information about the disorder. During the past few years, as more evidence has become available, a consortium of international experts determined that the 2008 guidelines from the CF Foundation needed to be reviewed and updated. CONTENT: The goal of this review is to highlight the latest advances in CF multidisciplinary care, together with the recent updates to the 2017 CF Foundation diagnostic guidelines. SUMMARY: Data from newborn screening programs, patient registries, clinical databases, and functional research have led to a better understanding of the CF transmembrane conductance regulator (CFTR) gene. Recent consensus guidelines have provided recommendations for clinicians and laboratorians to better assist with interpretation of disease status and related CF mutations. The highly recommended Clinical and Functional Translation of CFTR project should be the first resource in the evaluation of disease severity for CF mutations. Screen positive newborns and patients with high clinical suspicion for CF are always recommended to undergo confirmatory sweat chloride testing with interpretations based on updated reference intervals. Every patient diagnosed with CF should receive genotyping, as novel molecular therapies are becoming standard of practice. The future of CF management must consider healthcare system disparities as CF transitions from a historically childhood disease to a predominantly adult epidemic. PMID- 29436381 TI - Subcutaneous treprostinil in congenital heart disease-related pulmonary arterial hypertension. AB - OBJECTIVE: To assess the efficacy and safety of subcutaneous treprostinil in adult patients with congenital heart disease (CHD)-associated pulmonary arterial hypertension (PAH) after 12 months of treatment. METHODS: Consecutive adult patients with CHD-PAH received subcutaneous treprostinil to maximum tolerated doses in an observational study. RESULTS: Advanced CHD-PAH patients with WHO class III or IV disease (n=32, age 40+/-10 years, 20 females) received treprostinil for suboptimal response to bosentan (n=12), WHO functional class IV disease (FC, n=7) or prior to bosentan approval (n=13). In the multivariate mixed model, mean increase in 6 min walk distance (6-MWD) from baseline to 12 months was 114 m (76; 152) (P<0.001). WHO FC improved significantly (P=0.001) and B-type brain natriuretic peptide decreased from 1259 (375; 2368) pg/mL to 380 (144; 1468) pg/mL (P=0.02). In those 14 patients who had haemodynamic data before and after initiation of treprostinil, pulmonary vascular resistance decreased significantly (from 18.4+/-11.1 to 12.6+/-7.9 Wood units, P=0.003). The most common adverse events were infusion-site erythema and pain. One patient stopped treatment because of intolerable infusion-site pain after 8 months of treatment. No other major treatment-related complications were observed. Five patients died during early follow-up, having experienced a decrease in their 6-MWD prior. CONCLUSIONS: Subcutaneous treprostinil therapy is generally safe and effective for at least 12 months and may be used in CHD-related PAH class III and IV. PMID- 29436380 TI - Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. AB - OBJECTIVES: To compare the efficacy and safety of topical non-steroidal anti inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA). METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched from 1966 to January 2017. Randomised controlled trials (RCTs) comparing topical NSAIDs with placebo or each other in patients with OA and observational studies comparing topical NSAIDs with no treatment or each other irrespective of disease were included. Two investigators identified studies and independently extracted data. Bayesian network and conventional meta-analyses were conducted. The primary outcomes were pain relief for RCTs and risk of adverse effects (AEs) for observational studies. RESULTS: 43 studies, comprising 36 RCTs (7 900 patients with OA) and seven observational studies (218 074 participants), were included. Overall, topical NSAIDs were superior to placebo for relieving pain (standardised mean difference (SMD)=-0.30, 95% CI -0.40 to 0.20) and improving function (SMD=-0.35, 95% CI -0.45 to -0.24) in OA. Of all topical NSAIDs, diclofenac patches were most effective for OA pain (SMD=-0.81, 95% CI -1.12 to -0.52) and piroxicam was most effective for functional improvement (SMD=-1.04, 95% CI -1.60 to -0.48) compared with placebo. Although salicylate gel was associated with higher withdrawal rates due to AEs, the remaining topical NSAIDs were not associated with any increased local or systemic AEs. CONCLUSIONS: Topical NSAIDs were effective and safe for OA. Diclofenac patches may be the most effective topical NSAID for pain relief. No serious gastrointestinal and renal AEs were observed in trials or the general population. However, confirmation of the cardiovascular safety of topical NSAIDs still warrants further observational study. PMID- 29436382 TI - Acupuncture relieves motion sickness via the IRbeta-ERK1/2-dependent insulin receptor signalling pathway. AB - OBJECTIVE: Acupuncture has been widely used for the treatment of motion sickness (MS), but the underlying mechanisms are unclear. The aim of this research was to study the mechanism of acupuncture in the treatment of MS. METHODS: To observe the effects of acupuncture in the treatment of MS, 80 rats were randomised into five groups that were subjected to acceleration and either remained untreated (CTRL), or received restraint (REST), scopolamine (SCOP) or acupuncture at SP4 (sham) or PC6+ST36 (verum) acupuncture points. To study the mechanism underlying the effects of acupuncture in the treatment of MS, 48 rats were randomised into three groups: acupuncture+extracellular regulated protein kinases (ERK) 1/2 inhibitor (ERKinh), acupuncture+insulin receptor (IR) antagonist (IRant), and acupuncture+vehicle (VEH). After acceleration, the MS index (MSI) and spontaneous activity (SA) of the rats were recorded. Serum stress hormones, Fos-positive cells, c-fos mRNA in the vestibular nucleus, and IRbeta-, p-IRbeta-, ERK1/2- and p-ERK1/2-positive cells in the dorsal motor nucleus of the vagus nerve (DMV) were detected. RESULTS: After acceleration, MS symptoms in the PC6+ST36 and SCOP groups were reduced compared with the CTRL, REST, and SP4 groups. The number of p IRbeta- and p-ERK1/2-positive cells and insulin levels were higher in the PC6+ST36 group than in the CTRL, REST, and SP4 groups. After ERK1/2 inhibitor and IR antagonist treatment, MS symptoms in the VEH group were lower than in the ERKinh and IRant groups. CONCLUSIONS: Our study demonstrates that acupuncture significantly alleviates MS through the IRbeta-ERK1/2-dependent insulin receptor signalling pathway in the DMV. PMID- 29436383 TI - Effect of long-term electroacupuncture stimulation on recovery of sensorimotor function after peripheral nerve anastomosis. AB - BACKGROUND: Recently, application of electroacupuncture (EA) to stimulate nerve regeneration has become a mainstream treatment in clinical rehabilitation and related basic research, but the efficacy of long-term stimulation has not been confirmed. OBJECTIVE: To evaluate the influence of long term EA on peripheral nerve injury (PNI) from multiple angles. METHOD: Twenty-four rats were divided into three groups: control, PNI and PNI+EA. In the latter two groups, PNI was modelled by transection followed by re-anastomosis of thesciatic nerve. In the PNI+EA group only,EA was delivered using a discontinuous wave with frequency 5 Hz, pulse width 2 ms, and intensity approximately 2 mA, until the affected limb was observed to twitch slightly. The treatment was given for 15 min each time, six times a week (continuously for 6 days followed by a 1-day break) for a total of 8 weeks. The effects of EA on anastomotic sciatic nerve regeneration were evaluated using the sciatic function index (SFI), mechanical withdrawal thresholds, thermo-nociceptive thresholds, conduction velocity of the sciatic nerve and bilateral gastrocnemius wet weight. RESULTS: From weeks 2 to 4 after modelling, the SFI recovery rate in the PNI+EA group was faster than that in the PNI group. In week 4, the SFI of the PNI+EA group was significantly higher than that of the PNI group (p<0.05). However, a significant effect of EA was no longer evident from weeks 5 to 8. There was no effect of acupuncture on anti-amyotrophy and conduction velocity of the sciatic nerve at 8 weeks after modelling. EA did not shorten the paw withdrawal threshold time, but appeared to alleviate thermo nociceptive sensitivity. CONCLUSION: Long term repeated stimulation of the same site with EA does not appear to be conducive to the functional recovery of an injured sciatic nerve in rats. PMID- 29436384 TI - Increasing Mortality in Adults With Diabetes and Low Estimated Glomerular Filtration Rate in the Absence of Albuminuria. AB - OBJECTIVE: Improved blood pressure control and use of renin-angiotensin aldosterone system blockers have altered the clinical presentation or phenotype of chronic kidney disease (CKD) in U.S. adults with diabetes. These changes may influence mortality. RESEARCH DESIGN AND METHODS: Data from the National Health and Nutrition Examination Surveys (NHANES) 1988-2006 were used to examine mortality trends in adults with diabetes, defined as physician diagnosis, fasting glucose >=126 mg/dL, HbA1c >6.5% (48 mmol/mol), or use of glucose-lowering medications. Mortality trends by CKD phenotype (estimated glomerular filtration rate [eGFR] and urine albumin-to-creatinine ratio [ACR] level) were obtained via linkage with the National Death Index through 31 December 2011 while accounting for the complex survey design. RESULTS: From 1988 to 2006, adults with an eGFR <60 mL/min/1.73 m2 and an ACR <30 mg/g increased from ~0.9 million (95% CI 0.7, 1.1) or 6.6% of the total population with diabetes during years 1988-1994 to 2.4 million (95% CI 1.9, 2.9) or 10.1% of the total population with diabetes during years 2007-2010. Mortality rates generally trended downward for adults with diabetes and an ACR >=30 mg/g but increased in those with eGFR <60 mL/min/1.73 m2 and an ACR <30 mg/g from 35 deaths per 1,000 person-years (95% CI 22, 55) during years 1988-1994 to 51 deaths per 1,000 person-years (95% CI 33, 83) during years 2003-2006. CONCLUSIONS: ACR values are decreasing in U.S. adults with diabetes, but optimal management strategies are needed to reduce mortality in those with a low eGFR and an ACR <30 mg/g. PMID- 29436385 TI - Cholesterol efflux capacity does not associate with coronary calcium, plaque vulnerability, and telomere length in healthy octogenarians. AB - Several studies have revealed that traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Here, we evaluated the association between serum cholesterol efflux capacity (CEC), an atheroprotective property of HDL recently identified as a novel marker of CVD risk, and atherosclerotic burden in a cohort of very old, healthy individuals. Serum CEC values were not significantly correlated either with calcium score or with markers of vulnerable plaque, such as positive remodeling, hypodensity, spotty calcification, or napking-ring sign. In addition, no association was detected between CEC and telomere length, a marker of biological aging that has been linked to atherosclerosis extent. Interestingly, elderly subjects presented a remarkably higher CEC (+30.2%; P < 0.0001) compared with values obtained from a cohort of sex-matched, cardiovascular event-free, middle-aged individuals. In conclusion, serum CEC is not related to traditional risk factors in very old, cardiovascular event-free subjects, but has significantly higher values compared with a healthy, younger population. Whether this improved HDL functionality may represent a protective factor in CVD onset must be established in future studies. PMID- 29436387 TI - Response to: 'Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma'. PMID- 29436388 TI - Do DPP-4 Inhibitors Cause Heart Failure Events by Promoting Adrenergically Mediated Cardiotoxicity? Clues From Laboratory Models and Clinical Trials. AB - RATIONALE: DPP-4 (dipeptidyl peptidase-4) inhibitors have increased the risk of heart failure events in both randomized clinical trials and observational studies, but the mechanisms that underlie their deleterious effect remain to be elucidated. Previous work has implicated a role of these drugs to promote cardiac fibrosis. OBJECTIVE: This article postulates that DPP-4 inhibitors increase the risk of heart failure events by activating the sympathetic nervous system to stimulate cardiomyocyte cell death, and it crystallizes the findings from both experimental studies and clinical trials that support the hypothesis. METHODS AND RESULTS: Inhibition of DPP-4 not only potentiates the actions of GLP-1 (glucagon like peptide-1; which can increase myocardial cAMP) but also potentiates the actions of SDF-1 (stromal cell-derived factor 1), NPY (neuropeptide Y), and substance P to activate the sympathetic nervous system and stimulate beta adrenergic receptors to cause cardiomyocyte apoptosis, presumably through a CaMKII (Ca++/calmodulin-dependent protein kinase II) pathway. An action of SDF-1 to interfere with cAMP and protein kinase A signaling may account for the absence of a clinically overt positive chronotropic effect. This conceptual framework is supported by the apparent ability of beta-blocking drugs to attenuate the increased risk of DPP-4 inhibitors in a large-scale clinical trial. CONCLUSIONS: Sympathetic activation may explain the increased risk of heart failure produced by DPP-4 inhibitors. The proposed mechanism has major implications for clinical care because in the treatment of patients with type 2 diabetes mellitus, DPP-4 inhibitors are widely prescribed, but beta-blockers are underutilized because of fears that they might mask hypoglycemia. PMID- 29436386 TI - Limitations of insulin resistance assessment in polycystic ovary syndrome. AB - BACKGROUND: Though insulin resistance (IR) is common in polycystic ovary syndrome (PCOS), there is no agreement as to what surrogate method of assessment of IR is most reliable. SUBJECTS AND METHODS: In 478 women with PCOS, we compared methods based on fasting insulin and either fasting glucose (HOMA-IR and QUICKI) or triglycerides (McAuley Index) with IR indices derived from glucose and insulin during OGTT (Belfiore, Matsuda and Stumvoll indices). RESULTS: There was a strong correlation between IR indices derived from fasting values HOMA-IR/QUICKI, r = 0.999, HOMA-IR/McAuley index, r = -0.849 and between all OGTT-derived IR indices (e.g. r = -0.876, for IRI/Matsuda, r = -0.808, for IRI/Stumvoll, and r = 0.947, for Matsuda/Stumvoll index, P < 0.001 for all), contrasting with a significant (P < 0.001), but highly variable correlation between IR indices derived from fasting vs OGTT-derived variables, ranging from r = -0.881 (HOMA-IR/Matsuda), through r = 0.58, or r = -0.58 (IRI/HOMA-IR, IRI/QUICKI, respectively) to r = 0.41 (QUICKI/Stumvoll), and r = 0.386 for QUICKI/Matsuda indices. Detailed comparison between HOMA-IR and IRI revealed that concordance between HOMA and IRI was poor for HOMA-IR/IRI values above 75th and 90th percentile. For instance, only 53% (70/132) women with HOMA-IR >75th percentile had IRI value also above 75th percentile. There was a significant, but weak correlation of all IR indices with testosterone concentrations. CONCLUSIONS: Significant number of women with PCOS can be classified as being either insulin sensitive or insulin resistant depending on the method applied, as correlation between various IR indices is highly variable. Clinical application of surrogate indices for assessment of IR in PCOS must be therefore viewed with an extreme caution. PMID- 29436389 TI - Deletion of IRF8 (Interferon Regulatory Factor 8)-Dependent Dendritic Cells Abrogates Proatherogenic Adaptive Immunity. AB - RATIONALE: Despite an established role for adaptive immune responses in atherosclerosis, the contribution of dendritic cells (DCs) and their various subsets is still poorly understood. OBJECTIVE: Here, we address the role of IRF8 (interferon regulatory factor 8)-dependent DCs (lymphoid CD8alpha+ and their developmentally related nonlymphoid CD103+ DCs) in the induction of proatherogenic immune responses during high fat feeding. METHODS AND RESULTS: Using a fate-mapping technique to track DCs originating from a DNGR1+ (dendritic cell natural killer lectin group receptor 1) precursor (Clec9a+/creRosa+/EYFP mice), we first show that YFPhiCD11chiMHCIIhi (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor-deficient (Ldlr-/-) mice and are CD11b-CD103+IRF8hi. Restricted deletion of IRF8 in DCs (Irf8flox/floxCd11cCre ) reduces the accumulation of CD11chiMHCIIhi DCs in the aorta without affecting CD11b+CD103- DCs or macrophages but completely abolishes the accumulation of aortic CD11b-CD103+ DCs. Lymphoid CD8alpha+ DCs are also deleted. This is associated with a significant reduction of aortic T-cell accumulation and a marked reduction of high-fat diet-induced systemic T-cell priming, activation, and differentiation toward T helper type 1 cells, T follicular helper cells, and regulatory T cells. As a consequence, B cell activation and germinal center responses to high-fat diet are also markedly reduced. IRF8 deletion in DCs significantly reduces the development of atherosclerosis, predominantly in the aortic sinus, despite a modest increase in total plasma cholesterol levels. CONCLUSIONS: IRF8 expression in DCs plays a nonredundant role in the development of proatherogenic adaptive immunity. PMID- 29436390 TI - Identification of Galeterone and Abiraterone as Inhibitors of Dehydroepiandrosterone Sulfonation Catalyzed by Human Hepatic Cytosol, SULT2A1, SULT2B1b, and SULT1E1. AB - Galeterone and abiraterone acetate are antiandrogens developed for the treatment of metastatic castration-resistant prostate cancer. In the present study, we investigated the effect of these drugs on dehydroepiandrosterone (DHEA) sulfonation catalyzed by human liver and intestinal cytosols and human recombinant sulfotransferase enzymes (SULT2A1, SULT2B1b, and SULT2E1) and compared their effects to those of other antiandrogens (cyproterone acetate, spironolactone, and danazol). Each of these chemicals (10 MUM) inhibited DHEA sulfonation catalyzed by human liver and intestinal cytosols. Enzyme kinetic analysis showed that galeterone and abiraterone acetate inhibited human liver cytosolic DHEA sulfonation with apparent Ki values at submicromolar concentrations, whereas cyproterone acetate, spironolactone, and danazol inhibited it with apparent Ki values at low micromolar concentrations. The temporal pattern of abiraterone formation and abiraterone acetate depletion suggested that the metabolite abiraterone, not the parent drug abiraterone acetate, was responsible for the inhibition of DHEA sulfonation in incubations containing human liver cytosol and abiraterone acetate. Consistent with this proposal, similar apparent Ki values were obtained, regardless of whether abiraterone or abiraterone acetate was added to the enzymatic incubation. Abiraterone was more effective than abiraterone acetate in inhibiting DHEA sulfonation when catalyzed by human recombinant SULT2A1 or SULT2B1b. In conclusion, galeterone and abiraterone are novel inhibitors of DHEA sulfonation, as determined in enzymatic incubations containing human tissue cytosol (liver or intestinal) or human recombinant SULT enzyme (SULT2A1, SULT2B1b, or SULT1E1). Our findings on galeterone and abiraterone may have implications in drug-drug interactions and biosynthesis of steroid hormones. PMID- 29436391 TI - Associations Between Pediatric Palliative Care Consultation and End-of-Life Preparation at an Academic Medical Center: A Retrospective EHR Analysis. AB - OBJECTIVES: Our aim in this study was to understand usage patterns of pediatric palliative care (PPC) consultation and associations with end-of-life preparation among pediatric patients who are deceased. METHODS: We reviewed 233 pediatric mortalities. Data extraction from the electronic health record included determination of PPC consultation by using Current Procedural Terminology codes. Diagnoses were identified by International Classification of Disease codes and were classified into categories of life-threatening complex chronic conditions (LT-CCCs). Data analysis included Student's t test, Wilcoxon rank test, Fisher's exact test, chi2 test, and multivariable logistic regression. RESULTS: The overall PPC consultation rate for pediatric patients who subsequently died was 24%. A PPC consultation for patients admitted to the pediatric ward and PICU was more likely than for patients cared for in the NICU (31% vs 12%, P < .01) and was more likely for those with an LT-CCC (40% vs 10%, P < .01), particularly malignancy (65% vs 35%, P < .01). Also noted were increased completion of Physician Orders for Life-Sustaining Treatment forms (8 vs 0, P < .01) and increased documentation of mental health disorders (60% vs 40%, P = .02). CONCLUSIONS: Our findings suggest that PPC consultation for patients in the pediatric ward and PICU is more likely among patients with a greater number of LT CCCs, and is associated with increased Physician Orders for Life-Sustaining Treatment preparation and documentation of mental health disorders. Patients at risk to not receive PPC consultation are those with acute illness and patients in the NICU. PMID- 29436392 TI - Significance of Coronary Artery Spasm Diagnosis in Patients With Early Repolarization Syndrome. AB - BACKGROUND: Previously described patients with early repolarization syndrome (ERS) may have experienced silent coronary artery spasm (CAS) because the diagnosis of CAS was mainly based on symptoms or coronary angiography findings, without performing a spasm provocation test. This study investigated the significance of CAS diagnosis and evaluated the incidence of silent CAS in patients with possible ERS (ie, idiopathic ventricular fibrillation [VF] and inferolateral J wave). METHODS AND RESULTS: The study included 34 patients with idiopathic VF and inferolateral J wave. Thirteen patients (38%) were diagnosed as having CAS on the basis of coronary angiography with spasm provocation test (n=8) and documentation of spontaneous ST elevation (n=5). Of the 13 patients with CAS, 5 (38%) did not experience chest symptoms before and during VF, and were diagnosed as having silent CAS. The remaining 21 patients (62%), with a negative provocation test result and absence of chest symptoms, were considered to have ERS. During the 92 months of follow-up, patients with CAS receiving appropriate medical treatment with antianginal drugs showed a favorable outcome. In contrast, 4 of 21 patients with ERS (19%) had VF recurrences. The use of monotherapy or combination therapy, consisting of quinidine, cilostazol, and bepridil, in the 4 patients with ERS, was effective in suppressing VF. CONCLUSIONS: Approximately 40% of patients with CAS with documented VF and inferolateral J wave did not experience chest symptoms at the first VF, and could have been misdiagnosed as having ERS. The use of the spasm provocation test is considered essential to differentiate patients for optimal medical treatment. PMID- 29436394 TI - Optimized RNP transfection for highly efficient CRISPR/Cas9-mediated gene knockout in primary T cells. AB - CRISPR (clustered, regularly interspaced, short palindromic repeats)/Cas9 (CRISPR associated protein 9) has become the tool of choice for generating gene knockouts across a variety of species. The ability for efficient gene editing in primary T cells not only represents a valuable research tool to study gene function but also holds great promise for T cell-based immunotherapies, such as next generation chimeric antigen receptor (CAR) T cells. Previous attempts to apply CRIPSR/Cas9 for gene editing in primary T cells have resulted in highly variable knockout efficiency and required T cell receptor (TCR) stimulation, thus largely precluding the study of genes involved in T cell activation or differentiation. Here, we describe an optimized approach for Cas9/RNP transfection of primary mouse and human T cells without TCR stimulation that results in near complete loss of target gene expression at the population level, mitigating the need for selection. We believe that this method will greatly extend the feasibly of target gene discovery and validation in primary T cells and simplify the gene editing process for next-generation immunotherapies. PMID- 29436393 TI - Therapeutically targeting tumor microenvironment-mediated drug resistance in estrogen receptor-positive breast cancer. AB - Drug resistance to approved systemic therapies in estrogen receptor-positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down regulation of Bim as mediators of drug resistance. FGF2-driven drug resistance in anti-estrogen-sensitive and -resistant models, including patient-derived xenografts, was reverted by neutralizing FGF2 or FGFRs. A transcriptomic signature of FGF2 signaling in primary tumors predicted shorter recurrence-free survival independently of age, grade, stage, and FGFR amplification status. These findings delineate FGF2 signaling as a ligand-based drug resistance mechanism and highlights an underdeveloped aspect of precision oncology: characterizing and treating patients according to their TME constitution. PMID- 29436395 TI - Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity. AB - Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state. Combination therapy reduced the frequency of these subsets, while simultaneously inducing a separate polyfunctional inflammatory TAM subset cosecreting TNF-alpha, IL-6, and IL-12. Tumor suppression by this combined therapy was partially dependent on T cells, and on TNF-alpha and IFN-gamma. Together, this study demonstrates the potential for targeting TAMs to convert a "cold" into an "inflamed" tumor microenvironment capable of eliciting protective T cell responses. PMID- 29436397 TI - Impacts of an opioid overdose prevention intervention delivered subsequent to acute care. AB - BACKGROUND: Opioid overdose is a major and increasing cause of injury and death. There is an urgent need for interventions to reduce overdose events among high risk persons. METHODS: Adults at elevated risk for opioid overdose involving heroin or pharmaceutical opioids who had been cared for in an emergency department (ED) were randomised to overdose education combined with a brief behavioural intervention and take-home naloxone or usual care. Outcomes included: (1) time to first opioid overdose-related event resulting in medical attention or death using competing risks survival analysis; and (2) ED visit and hospitalisation rates, using negative binomial regression and adjusting for time at risk. RESULTS: During the follow-up period, 24% of the 241 participants had at least one overdose event, 85% had one or more ED visits and 55% had at least one hospitalisation, with no significant differences between intervention and comparison groups. The instantaneous risk of an overdose event was not significantly lower for the intervention group (sub-HR: 0.83; 95% CI 0.49 to 1.40). DISCUSSION: These null findings may be due in part to the severity of the population in terms of housing insecurity (70% impermanently housed), drug use, unemployment and acute healthcare issues. Given the high overdose and healthcare utilisation rates, more intensive interventions, such as direct referral and provision of housing and opioid agonist treatment medications, may be necessary to have a substantial impact on opioid overdoses for this high-acuity population in acute care settings. TRIAL REGISTRATION NUMBER: NCT0178830; Results. PMID- 29436396 TI - Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity. AB - Depletion of immunosuppressive tumor-associated macrophages (TAMs) or reprogramming toward a proinflammatory activation state represent different strategies to therapeutically target this abundant myeloid population. In this study, we report that inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling sensitizes TAMs to profound and rapid reprogramming in the presence of a CD40 agonist before their depletion. Despite the short-lived nature of macrophage hyperactivation, combined CSF-1R+CD40 stimulation of macrophages is sufficient to create a proinflammatory tumor milieu that reinvigorates an effective T cell response in transplanted tumors that are either responsive or insensitive to immune checkpoint blockade. The central role of macrophages in regulating preexisting immunity is substantiated by depletion experiments, transcriptome analysis of ex vivo sorted TAMs, and gene expression profiling of whole tumor lysates at an early treatment time point. This approach enabled the identification of specific combination-induced changes among the pleiotropic activation spectrum of the CD40 agonist. In patients, CD40 expression on human TAMs was detected in mesothelioma and colorectal adenocarcinoma. PMID- 29436398 TI - Gun retailers as storage partners for suicide prevention: what barriers need to be overcome? AB - INTRODUCTION: Safe storage of guns outside the household while someone is at risk for suicide is important for suicide prevention. Some gun retailers offer temporary firearm storage as a community resource. Others may be willing if perceived barriers can be addressed. METHODS: We invited all gun retailers in eight Mountain West states to respond to a questionnaire about the barriers they perceive in offering temporary, voluntary gun storage for community members. RESULTS: Ninety-five retailers responded (25% response rate). Fifty-eight percent believed federal laws make it harder to store guns and 25% perceived state laws to be obstacles. Over 60% cited legal liability in storing and returning guns as barriers. Other important barriers included cost, space and logistical issues of drop off and pick up. CONCLUSIONS: Strategies to reduce legal and other barriers will need to be addressed to better engage gun retailers as a community resource for safe gun storage. PMID- 29436399 TI - Type 2 choroidal neovascularisation in polypoidal choroidal vasculopathy: a retrospective case series. AB - BACKGROUND AND OBJECTIVE: To demonstrate the coexistence of polypoidal choroidal vasculopathy (PCV) with type 2 neovascularisation (NV), we used multimodal imaging, including spectral-domain optical coherence tomography angiography (SD OCTA), to identify both types of lesions in the same eye. STUDY DESIGN: This retrospective case series reviewed patients with PCV diagnosed with indocyanine green angiography (ICGA), fluorescein angiography (FA), SD-OCT and SD-OCTA. RESULTS: 15 eyes of 14 patients were imaged and diagnosed with PCV by ICGA. ICGA identified polyps in all these eyes, while SD-OCTA imaging identified polypoidal lesions in only 11 (73%) of these eyes with PCV. Branching vascular networks (BVNs) were detected in 12 eyes (80%) by ICGA and SD-OCTA. Type 2 NV was detected in four eyes (27%) by FA and SD-OCTA. In these eyes, a combination of polyps, BVNs and type 2 NV were detected using FA, ICGA and SD-OCTA. CONCLUSION: BVN and type 2 NV can coexist in the same PCV eye and communicate with each other. This suggests that polyps may represent a structural variant of neovascular tissue rather than a distinct pathogenic process in NV. PMID- 29436400 TI - Association of the PAX6 gene with extreme myopia rather than lower grade myopias. AB - AIMS: To investigate the association of the paired box gene 6 (PAX6) with different severities of myopia. METHODS: A total of four haplotype-tagging single nucleotide polymorphisms (SNPs; rs2071754, rs3026354, rs3026390 and rs628224) and two previously reported SNPs (rs644242 and rs662702) in the PAX6 gene were analysed in a Hong Kong Chinese cohort of 1288 myopia subjects (including 252 extreme myopia, 277 high myopia, 393 moderate myopia and 366 mild myopia) and 791 no myopia controls. Allelic association analyses were performed for individual SNPs in different subgroups of myopia and in combined myopia, followed by a meta analysis of our current data with reported data on PAX6 in myopia. RESULTS: The association of tagging SNPs rs2071754 and rs644242 with extreme myopia could not withstand multiple correction (rs2071754: OR=1.25, P value=0.031; rs644242: OR=1.33, P value=0.032). In the meta-analysis, rs644242 showed an enhanced, significant association with extreme myopia (OR=1.27, 95% CI 1.10 to 1.46, P value=0.001; I2=0%). In contrast, there was no significant association between the PAX6SNPs and high, moderate or mild myopia. No linear correlation was found between the PAX6SNPs and axial length. CONCLUSION: This study provides additional evidence suggesting that the PAX6 SNP rs644242 is associated with extreme myopia but not lower grade myopia. Thus, PAX6 may be implicated in the development or progression into severe myopia. Further longitudinal studies are warranted. PMID- 29436401 TI - Evaluation of a hub-and-spoke model for the delivery of femtosecond laser assisted cataract surgery within the context of a large randomised controlled trial. AB - AIMS: To test a hypothesis that cataract operating room (OR) productivity can be improved with a femtosecond laser (FL) using a hub-and-spoke model and whether any increase in productivity can offset additional costs relating to the FL. METHODS: 400 eyes of 400 patients were enrolled in a randomised-controlled trial comparing FL-assisted cataract surgery (FLACS) with conventional phacoemulsification surgery (CPS). 299 of 400 operations were performed on designated high-volume theatre lists (FLACS=134, CPS=165), where a hub-and-spoke FLACS model (1*FL, 2*ORs=2:1) was compared with independent CPS theatre lists. Details of operative timings and OR utilisation were recorded. Differences in productivity between hub-and-spoke FLACS and CPS sessions were compared using an economic model including testing hypothetical 3:1 and 4:1 models. RESULTS: The duration of the operation itself was 12.04+/-4.89 min for FLACS compared with CPS of 14.54+/-6.1 min (P<0.001). Total patient time in the OR was reduced from 23.39+/-6.89 min with CPS to 20.34+/-5.82 min with FLACS (P<0.001)(reduction of 3.05 min per case). There was no difference in OR turnaround time between the models. Average number of patients treated per theatre list was 9 for FLACS and 8 for CPS. OR utilisation was 92.08% for FLACS and 95.83% for CPS (P<0.001). Using a previously established economic model, the FLACS service cost L144.60 more than CPS per case. This difference would be L131 and L125 for 3:1 and 4:1 models, respectively. CONCLUSION: The FLACS hub-and-spoke model was significantly faster than CPS, with patients spending less time in the OR. This enabled an improvement in productivity, but insufficient to meaningfully offset the additional costs relating to FLACS. PMID- 29436402 TI - Best supportive care for idiopathic pulmonary fibrosis: current gaps and future directions. AB - Best supportive care (BSC) is generally defined as all the interventions and the multiprofessional approach aimed to improve and optimise quality of life (QoL) in patients affected by progressive diseases. In this sense, it excludes and might be complementary to other interventions directly targeting the disease. BSC improves survival in patients with different types of cancer. Patients with idiopathic pulmonary fibrosis (IPF) experience a vast range of symptoms during the natural history of the disease and might have a beneficial effect of BSC interventions. This review highlights the current evidence on interventions targeting QoL and gaps for the clinical assessment of BSC in the treatment of IPF patients. Very few interventions to improve QoL or improve symptom control are currently supported by well-designed studies. Sound methodology is paramount in evaluating BSC in IPF, as well as the use of validated tools to measure QoL and symptom control in this specific group of patients. PMID- 29436403 TI - Chronic interstitial lung disease in children. AB - Children's interstitial lung diseases (chILD) are increasingly recognised and contain many lung developmental and genetic disorders not yet identified in adult pneumology. Worldwide, several registers have been established. The Australasian Registry Network for Orphan Lung Disease (ARNOLD) has identified problems in estimating rare disease prevalence; focusing on chILD in immunocompetent patients, a period prevalence of 1.5 cases per million children and a mortality rate of 7% were determined. The chILD-EU register highlighted the workload to be covered per patient included and provided protocols for diagnosis and initial treatment, similar to the United States chILD network. Whereas case reports may be useful for young physicians to practise writing articles, cohorts of patients can catapult progress, as demonstrated by recent studies on persistent tachypnoea of infancy, hypersensitivity pneumonitis in children and interstitial lung disease related to interferonopathies from mutations in transmembrane protein 173. Translational research has linked heterozygous mutations in the ABCA3 transporter to an increased risk of interstitial lung diseases, not only in neonates, but also in older children and adults. For surfactant dysfunction disorders in infancy and early childhood, lung transplantation was reported to be as successful as in adult patients. Mutual potentiation of paediatric and adult pneumologists is mandatory in this rapidly extending field for successful future development.This brief review highlights publications in the field of paediatric interstitial lung disease as reviewed during the Clinical Year in Review session presented at the 2017 European Respiratory Society (ERS) Annual Congress in Milan, Italy. It was commissioned by the ERS and critically presents progress made as well as drawbacks. PMID- 29436404 TI - From systems biology to P4 medicine: applications in respiratory medicine. AB - Human health and disease are emergent properties of a complex, nonlinear, dynamic multilevel biological system: the human body. Systems biology is a comprehensive research strategy that has the potential to understand these emergent properties holistically. It stems from advancements in medical diagnostics, "omics" data and bioinformatic computing power. It paves the way forward towards "P4 medicine" (predictive, preventive, personalised and participatory), which seeks to better intervene preventively to preserve health or therapeutically to cure diseases. In this review, we: 1) discuss the principles of systems biology; 2) elaborate on how P4 medicine has the potential to shift healthcare from reactive medicine (treatment of illness) to predict and prevent illness, in a revolution that will be personalised in nature, probabilistic in essence and participatory driven; 3) review the current state of the art of network (systems) medicine in three prevalent respiratory diseases (chronic obstructive pulmonary disease, asthma and lung cancer); and 4) outline current challenges and future goals in the field. PMID- 29436405 TI - Neutrophil to lymphocyte ratio and clinical outcomes in COPD: recent evidence and future perspectives. AB - Chronic obstructive pulmonary disease (COPD) is a disabling condition that is characterised by poorly reversible airflow limitation and inflammation. Acute exacerbations of COPD are a common cause of hospitalisation and death among COPD patients. Several biochemical markers have been studied as outcome predictors in COPD; however, their measurement often requires significant time and resources. Relatively simple biomarkers of inflammation calculated from routine complete blood count tests, such as the neutrophil to lymphocyte ratio (NLR), might also predict COPD progression and outcomes. This review discusses the available evidence from studies investigating the associations between the NLR, COPD exacerbations and death in this patient group. PMID- 29436406 TI - Management of suspected paediatric meningitis: a multicentre prospective cohort study. AB - OBJECTIVE: To quantify delays during management of children with suspected meningitis. DESIGN: Multicentre prospective cohort study. SETTING: Three UK tertiary paediatric centres; June 2011-June 2012 PATIENTS: 388 children aged <16 years hospitalised with suspected meningitis or undergoing lumbar puncture (LP) during sepsis evaluation. MAIN OUTCOME MEASURES: Time of prehospital and in hospital assessments, LP, antibiotic treatment and discharge; types of prehospital medical assessment and microbiological results. Data collected from hospital records and parental interview. RESULTS: 220/388 (57%) children were seen by a medical professional prehospitalisation (143 by a general practitioner). Median times from initial hospital assessment to LP and antibiotic administration were 4.8 hours and 3.1 hours, respectively; 62% of children had their LP after antibiotic treatment. Median time to LP was shorter for children aged <3 months (3.0 hours) than those aged 3-23 months (6.2 hours, P<0.001) or age >=2 years (20.3 hours, P<0.001). In meningitis of unknown cause, cerebrospinal fluid (CSF) PCR was performed for meningococcus in 7%, pneumococcus in 10% and enterovirus in 76%. When no pathogen was identified, hospital stay was longer if LP was performed after antibiotics (median 12.5 days vs 5.0 days, P=0.037). CONCLUSIONS: Most children had LP after antibiotics were administered, reducing yield from CSF culture, and PCRs were underused despite national recommendations. These deficiencies reduce the ability to exclude bacterial meningitis, increasing unnecessary hospital stay and antibiotic treatment. PMID- 29436407 TI - Infant deaths from congenital anomalies: novel use of Child Death Overview Panel data. AB - OBJECTIVE: We aimed to assess Child Death Overview Panel (CDOP) data validity, and cause of death classification, by comparison with information from a local birth cohort study (Born in Bradford, BiB), and another cause of death coding system (causes of death and associated conditions-CODAC). We then aimed to use CDOP data to calculate ethnic-specific infant mortality rates (IMRs), and compare characteristics of infants who died of congenital anomalies (CA) with those who died from other causes (non-CA). DESIGN: Retrospective cohort study. SETTING: Bradford Metropolitan District. PATIENTS: All infant deaths, 2008 to 2013. MAIN OUTCOME MEASURES: Infant mortality rates from CA and non-CA causes. RESULTS: 315 infant deaths were included, 56 of whom were BiB recruits. Agreement between CDOP and BiB was moderate to perfect for all characteristics except ethnicity, which showed weak agreement (kappa=0.58). The same deaths (27/56) were classified as CA by CDOP and CODAC. IMRs (per 1000 live births, 2009-2013) were highest in Pakistani infants (all causes 9.8, CA cause 5.5) compared with white British (all causes 4.3, CA cause 1.3) and other infants (all causes 5.1, CA cause 1.4). In multivariate analysis, infants who died of CA cause were more likely to have been born at term (OR 3.18) and to consanguineous parents (OR 3.28) than infants who died of non-CA cause. CONCLUSIONS: Excess Pakistani mortality appears to be partly explained by an excess of deaths from CA, which in this population appears associated with a greater prevalence of consanguinity. PMID- 29436408 TI - Enhanced detection services for developmental dysplasia of the hip in Scottish children, 1997-2013. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) remains common. If detected early, DDH can usually be corrected with conservative management. Late presentations often require surgery and have worse outcomes. OBJECTIVE: We estimated the risk of undergoing surgery for DDH by age 3 years before and after the introduction of enhanced DDH detection services. DESIGN: Retrospective cohort study. SETTING: Scotland, 1997/98-2010/11. PATIENTS: All children. METHODS: Using routinely collected national hospital discharge records, we examined rates of first surgery for DDH by age 3 by March 2014. Using a difference in difference analysis, we compared rates in two areas of Scotland before (to April 2002) and after (from April 2005) implementation of enhanced DDH detection services to those seen in the rest of Scotland. RESULTS: For children born in the study period, the risk of first surgery for DDH by age 3 was 1.18 (95% CI 1.11 to 1.26) per 1000 live births (918/777 375).Prior to April 2002, the risk of surgery was 1.13 (95% CI 0.88 to 1.42) and 1.31 (95% CI 1.16 to 1.46) per 1000 live births in the intervention and non-intervention areas, respectively. In the intervention areas, from April 2005, this risk halved (RR 0.47; 95% CI 0.32 to 0.68). The risk remained unchanged in other areas (RR 1.01; 95% CI 0.86 to 1.18). The ratio for the difference in change of risk was 0.46 (95% CI 0.31 to 0.70). CONCLUSIONS: The implementation of enhanced DDH detection services can produce substantial reductions in the number of children having surgical correction for DDH. PMID- 29436409 TI - Congenital perineal groove. PMID- 29436410 TI - Gastric outlet obstruction due to pyloric mass in a 12-year-old girl. PMID- 29436411 TI - T Cell Expression of C5a Receptor 2 Augments Murine Regulatory T Cell (TREG) Generation and TREG-Dependent Cardiac Allograft Survival. AB - C5aR2 (C5L2/gp77) is a seven-transmembrane spanning receptor that binds to C5a but lacks motifs essential for G protein coupling and associated signal transduction. C5aR2 is expressed on immune cells, modulates various inflammatory diseases in mice, and has been shown to facilitate murine and human regulatory T cell (TREG) generation in vitro. Whether and how C5aR2 impacts in vivo TREG generation and pathogenic T cell-dependent disease models have not been established. In this article, we show that murine T cells express and upregulate C5aR2 during induced TREG (iTREG) generation and that the absence of T cell expressed C5aR2 limits in vivo iTREG generation following adoptive transfer of naive CD4+ T cells into Rag1-/- recipients. Using newly generated C5aR2 transgenic mice, we show that overexpression of C5aR2 in naive CD4+ T cells augments in vivo iTREG generation. In a model of TREG-dependent cardiac allograft survival, recipient C5aR2 deficiency accelerates graft rejection associated with lower TREG/effector T cell ratios, whereas overexpression of C5aR2 in immune cells prolongs graft survival associated with an increase in TREG/effector T cell ratios. T cell-expressed C5aR2 modulates TREG induction without altering effector T cell proliferation or cytokine production. Distinct from reported findings in neutrophils and macrophages, TREG-expressed C5aR2 does not interact with beta arrestin or inhibit ERK1/2 signaling. Rather, cumulative evidence supports the conclusion that C5aR2 limits C5aR1-initiated signals known to inhibit TREG induction. Together, the data expand the role of C5aR2 in adaptive immunity by providing in vivo evidence that T cell-expressed C5aR2 physiologically modulates iTREG generation and iTREG-dependent allograft survival. PMID- 29436412 TI - Cell-Specific Requirements for STAT Proteins and Type I IFN Receptor Signaling Discretely Regulate IL-24 and IL-10 Expression in NK Cells and Macrophages. AB - Il10 forms a cytokine cluster with Il19, Il20, and Il24 in a conserved region of chromosome 1. The latter genes are in the IL-20 subfamily of IL-10-related cytokines and, although they are not as well studied their biologic actions and expression patterns, seem to have little in common with IL-10. IL-24, like IL-10, however, is uniquely expressed in T cells and is a signature gene of the Th2 lineage, which suggests they could be coregulated in certain cell types. Little is known about other cellular sources of IL-24. We investigated IL-24 and IL-10 expression in murine macrophages and NK cells, and found that although they are coexpressed under most stimulation conditions, IL-24 and IL-10 are controlled by distinct, cell type-specific pathways. In bone marrow-derived macrophages, optimal IL-24 expression required LPS+IL-4 costimulation and STAT6 but was independent of type I IFN receptor signaling and STAT4. Conversely, LPS-induced IL-10 was independent of IL-4/STAT6 and STAT4 but, consistent with other reports, required type I IFN receptor signaling for optimal expression. Remarkably, NK specific IL-24 (but not IL-10) expression was dependent on both type I IFN receptor signaling and STAT4. Induction of IL-24 expression was accompanied by cell-specific recruitment of STAT6 and STAT4 to multiple sites that we identified within Il24, which mediated STAT-dependent histone modifications across the gene. Collectively, our results indicate that despite being coexpressed, IL-10 and IL 24 are independently regulated by different type I IFN receptor signaling pathways in innate immune cells and provide insight into the mechanisms that fine tune cell type-specific gene expression within the Il10 cluster. PMID- 29436413 TI - Many Th Cell Subsets Have Fas Ligand-Dependent Cytotoxic Potential. AB - CD4+ Th cells can have cytotoxic activity against cells displaying relevant peptide-MHC class II (p:MHCII) ligands. Cytotoxicity may be a property of Th1 cells and depends on perforin and the Eomes transcription factor. We assessed these assertions for polyclonal p:MHCII-specific CD4+ T cells activated in vivo in different contexts. Mice immunized with an immunogenic peptide in adjuvant or infected with lymphocytic choriomeningitis virus or Listeria monocytogenes bacteria induced cytotoxic Th cells that killed B cells displaying relevant p:MHCII complexes. Cytotoxicity was dependent on Fas expression by target cells but was independent of Eomes or perforin expression by T cells. Although the priming regimens induced different proportions of Th1, Th17, regulatory T cells, and T follicular helper cells, the T cells expressed Fas ligand in all cases. Reciprocally, Fas was upregulated on target cells in a p:MHCII-specific manner. These results indicate that many Th subsets have cytotoxic potential that is enhanced by cognate induction of Fas on target cells. PMID- 29436414 TI - Differential Expression of PU.1 and Key T Lineage Transcription Factors Distinguishes Fetal and Adult T Cell Development. AB - The PU.1 transcription factor plays a critical role in the regulation of T cell development, so a report that it is dispensable for fetal thymopoiesis is puzzling. To understand this paradox, we examined the requirement for PU.1, encoded by Spi1, during fetal, neonatal, and adult thymopoiesis in a PU.1 hypomorphic mouse generated by deletion of the Spi1 14-kb upstream regulatory element and by analysis of patterns of gene expression in fetal and adult T cell progenitors. Our data demonstrate that the initiation of thymopoiesis during early gestation is less dependent on PU.1 compared with T cell differentiation in adults and that fetal T cell progenitors express lower levels of Spi1 compared with their adult counterparts. We also show that expression of the core network of T lineage transcription factors regulated by PU.1 differs in fetal and adult T cell progenitors. In particular, PU.1-regulated genes that promote T cell differentiation are differentially expressed in fetal versus adult early T lineage progenitors. These results indicate that the transcriptional differences between the fetal and adult T cell developmental programs are driven in part by differential levels of PU.1 expression and that this likely underlies the differences in the properties of fetal and adult T cell progenitors. PMID- 29436415 TI - Impact of 21st Century Cures Act on Breakpoints and Commercial Antimicrobial Susceptibility Test Systems: Progress and Pitfalls. AB - Antimicrobial resistance is the most pressing medical challenge of the past decade. At the front line are clinical laboratories, which are responsible for accurately reporting antimicrobial susceptibility test (AST) results to clinicians and public health authorities. The ability of the laboratory to detect resistance has been hampered by several factors. In 2016, the 21st Century Cures Act was signed into law, marking an important step toward resolving many regulatory dilemmas that hampered development and updates to commercial AST systems (cASTs). We describe the pathway and history of U.S. regulation of cASTs and outline both the rewards and unmet needs possible from the 21st Century Cures Act. PMID- 29436416 TI - Persistent Pandemic Lineages of Uropathogenic Escherichia coli in a College Community from 1999 to 2017. AB - The incidence of drug-resistant community-acquired urinary tract infections (CA UTI) continues to increase worldwide. In 1999 to 2000, a single lineage of uropathogenic Escherichia coli (UPEC) sequence type 69 (ST69) caused 51% of trimethoprim-sulfamethoxazole-resistant UTI in a Northern California university community. We compared the clonal distributions of UPEC and its impact on antimicrobial resistance prevalence in the same community during two periods separated by 17 years. We analyzed E. coli isolates from urine samples from patients with symptoms of UTI who visited a health service between September 2016 and May 2017 and compared them to UPEC isolates collected similarly between October 1999 and March 2000. Isolates were tested for antimicrobial drug susceptibility and genotyped by multilocus sequence typing. In 1999 to 2000, strains belonging to ST95, ST127, ST73, ST69, ST131, and ST10 caused 125 (56%) of 225 UTI cases, while the same STs caused 148 (64%) of 233 UTI cases in 2016 to 2017. The frequencies of ampicillin resistance and ciprofloxacin resistance rose from 24.4% to 41.6% (P < 0.001) and from 0.9% to 5.1% (P < 0.003), respectively. The six STs accounted for 78.6% and 72.7% of these increases, respectively. Prevalence of drug-resistant UTI in this community appears to be largely influenced by a small set of dominant UPEC STs circulating in the same community 17 years apart. Further research to determine the origin and reasons for persistence of these dominant genotypes is necessary to combat antimicrobial resistant CA-UTI. PMID- 29436417 TI - The Slow March toward Rapid Phenotypic Antimicrobial Susceptibility Testing: Are We There Yet? AB - Antimicrobial susceptibility testing (AST) provides critical information for the management of patients with infections. The gold standard methods for assessing organism susceptibility are still based on growth and require incubation over relatively long periods of time. Until now, little progress has been made in developing rapid, growth-based, phenotypic AST systems. This commentary puts the recently FDA-cleared Accelerate PhenoTest (P. Pancholi et al., J Clin Microbiol 56:e01329-17, 2018, https://doi.org/10.1128/JCM.01329-17) in context by providing a historical perspective on attempts to accelerate phenotypic susceptibility results. In addition, some promising new innovations that promise to shorten the turnaround time for phenotypic AST will be briefly reviewed. PMID- 29436419 TI - Fungemia Surveillance in Denmark Demonstrates Emergence of Non-albicans Candida Species and Higher Antifungal Usage and Resistance Rates than in Other Nations. AB - Recent changes in the occurrence of fungal species and the difficulties in performing reference antifungal susceptibility testing highlight the importance of surveillance of fungal organisms and antifungal resistance rates. K. M. T. Astvad et al. report results from recent (2012 to 2015) fungemia surveillance in Denmark and compare the results to previous data (2004 to 2011), showing a decrease in Candida albicans infections accompanied by an increase in C. glabrata and C. dubliniensis infections (J Clin Microbiol 56:e01564-17, 2018, https://doi.org/10.1128/JCM.01564-17). Azole resistance among C. tropicalis and C. parapsilosis isolates and echinocandin resistance in C. krusei isolates were higher in Denmark than in other regions. Interestingly, the usage of antifungals is higher in Denmark than in other Nordic countries. PMID- 29436420 TI - CHTyper, a Web Tool for Subtyping of Extraintestinal Pathogenic Escherichia coli Based on the fumC and fimH Alleles. PMID- 29436418 TI - Validation of the Pockit Dengue Virus Reagent Set for Rapid Detection of Dengue Virus in Human Serum on a Field-Deployable PCR System. AB - Dengue virus (DENV) infection, a mosquito-borne disease, is a major public health problem in tropical countries. Point-of-care DENV detection with good sensitivity and specificity enables timely early diagnosis of DENV infection, facilitating effective disease management and control, particularly in regions of low resources. The Pockit dengue virus reagent set (GeneReach Biotech), a reverse transcription insulated isothermal PCR (RT-iiPCR), is available to detect all four serotypes of DENV on the field-deployable Pockit system, which is ready for on-site applications. In this study, analytical and clinical performances of the assay were evaluated. The index assay did not react with 14 non-DENV human viruses, indicating good specificity. Compared to the U.S. CDC DENV-1-4 real-time quantitative RT-PCR (qRT-PCR) assay, testing with serial dilutions of virus spiked human sera demonstrated that the index assay had detection endpoints that were separately comparable with the 4 serotypes. Excellent reproducibility was observed among repeat tests done by six operators at three sites. In clinical performance, 195 clinical sera collected around Kaohsiung city in 2012 and 21 DENV-4-spiked sera were tested with the RT-iiPCR and qRT-PCR assays in parallel. The 121 (11 DENV-1, 78 DENV-2, 11 DENV-3, and 21 DENV-4) qRT-PCR-positive and 95 qRT-PCR-negative samples were all positive and negative by the RT-iiPCR reagent results, respectively, demonstrating high (100%) interrater agreement (95% confidence interval [CI95%], ~98.81% to 100%; kappa = 1). With analytical and clinical performance equivalent to those of the reference qRT-PCR assay, the index PCR assay on the field-deployable system can serve as a highly sensitive and specific on-site tool for DENV detection. PMID- 29436421 TI - Evaluation of a Commercial Multiplex Molecular Panel for Diagnosis of Infectious Meningitis and Encephalitis. AB - Rapid and accurate laboratory tests are important for the timely diagnosis and treatment of central nervous system infections. The FilmArray meningitis/encephalitis (ME) panel (BioFire Diagnostics, Salt Lake City, UT) is an FDA-cleared, multiplex molecular panel that allows the detection of 14 pathogens (bacterial [n = 6], viral [n = 7], and fungal [n = 1] pathogens) from cerebrospinal fluid (CSF). In this study, we evaluated the performance characteristics of the FilmArray ME panel using clinical, residual CSF samples (n = 291) that tested positive by a routine method(s) (e.g., bacterial culture, individual real-time PCR assay) for a pathogen represented on the ME panel. Of note, a subset (n = 76) of the CSF specimens was collected during the prevaccine era and had been characterized as positive for a bacterial pathogen. The FilmArray ME panel demonstrated an overall percent positive agreement (PPA) of 97.5% (78/80) for bacterial pathogens, 90.1% (145/161) for viruses, and 52% (26/50) for Cryptococcusneoformans/C. gattii Despite the low overall agreement (52%) between the ME panel and antigen testing for detection of C. neoformans/C. gattii, the percent positive agreement of the FilmArray assay for C. neoformans/C. gattii was 92.3% (12/13) when the results were compared directly to the results of routine fungal smear or culture. The FilmArray ME panel offers a rapid (~60-min), syndrome-based approach for the detection of select meningitis and encephalitis pathogens. PMID- 29436422 TI - Species Identification and Delineation of Pathogenic Mucorales by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry. AB - This study aimed to validate the effectiveness of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS)-based identification of filamentous fungi of the order Mucorales. A total of 111 isolates covering six genera preserved at the Research Center for Medical Mycology of Peking University were selected for MALDI-TOF MS analysis. We emphasized the study of 23 strains of Mucor irregularis predominantly isolated from patients in China. We first used the Bruker Filamentous Fungi library (v1.0) to identify all 111 isolates. To increase the identification rate, we created a compensatory in-house database, the Beijing Medical University (BMU) database, using 13 reference strains covering 6 species, including M. irregularis, Mucor hiemalis, Mucor racemosus, Cunninghamella bertholletiae, Cunninghamella phaeospora, and Cunninghamella echinulata All 111 isolates were then identified by MALDI-TOF MS using a combination of the Bruker library and BMU database. MALDI TOF MS identified 55 (49.5%) and 74 (66.7%) isolates at the species and genus levels, respectively, using the Bruker Filamentous Fungi library v1.0 alone. A combination of the Bruker library and BMU database allowed MALDI-TOF MS to identify 90 (81.1%) and 111 (100%) isolates at the species and genus levels, respectively, with a significantly increased accuracy rate. MALDI-TOF MS poorly identified Mucorales when the Bruker library was used alone due to its lack of some fungal species. In contrast, this technique perfectly identified M. irregularis after main spectrum profiles (MSPs) of relevant reference strains were added to the Bruker library. With an expanded Bruker library, MALDI-TOF MS is an effective tool for the identification of pathogenic Mucorales. PMID- 29436423 TI - Evaluation of the Diagnostic Accuracy of Two Immunochromatographic Tests Detecting Campylobacter in Stools and Their Role in Campylobacter Infection Diagnosis. AB - The detection of campylobacters in stools is performed essentially by culture, but this technique has a low sensitivity. New detection methods are now available. Among them, immunochromatography tests (ICTs) are very attractive in that they offer a result within 15 min. However, previous studies suggest that these tests have a relatively low specificity. The objective of this study was to evaluate the performance of these tests. During the study period, all patients who consulted the emergency units and had a stool culture were included. Their stool samples were tested with two ICTs, Ridaquick Campylobacter and ImmunoCard STAT! Campy. Stools were also tested by a home-made PCR and two commercially available enzyme-linked immunosorbent assays (ELISAs) when one of the ICTs was positive. The composite reference standard (CRS) was defined as positive if the culture was positive or, in case of a negative culture, if the PCR and one of the ELISAs were positive simultaneously. Three hundred and five patients were included. Among the 50 positive specimens with Ridaquick Campylobacter, 47 were considered true positives by the CRS, corresponding to a positive predictive value (PPV) of 94.0%. Among the 52 positive specimens with ImmunoCard STAT! Campy, 44 were considered true positives by the CRS, corresponding to a PPV of 84.6%. The negative predictive values were estimated at 94.9 and 92.4% for the Ridaquick Campylobacter and ImmunoCard STAT! Campy tests, respectively. ICTs appear to be very efficient and allow a very rapid detection of campylobacters, which is important for treating early campylobacter infections with an adapted antibiotherapy. PMID- 29436424 TI - Analysis of Potential beta-Lactam Surrogates To Predict In Vitro Susceptibility and Resistance to Ceftaroline for Clinical Isolates of Enterobacteriaceae. AB - Ceftaroline fosamil was approved by the United States Food and Drug Administration in 2010 and by the European Medicines Agency in 2012. As of April 2017, only one commercial antimicrobial susceptibility testing device offered a Gram-negative panel that included ceftaroline. This circumstance is unfortunate, as many clinical microbiology laboratories rely solely on commercial devices to generate in vitro antimicrobial susceptibility testing results for common bacterial pathogens. In lieu of device-based testing of clinical isolates of Enterobacteriaceae, laboratories wishing to test ceftaroline must either opt for disk diffusion testing or use a gradient strip; however, both alternatives interrupt laboratory workflow and require additional labor and expense. Identification of a reliable surrogate beta-lactam to predict in vitro susceptibility to ceftaroline may offer another interim solution as laboratories await availability of ceftaroline for testing on their commercial devices. We tested six beta-lactams (aztreonam, ceftazidime, ceftriaxone, cefotaxime, cefoxitin, and cefpodoxime) as potential surrogates for ceftaroline against a collection of 543 clinical isolates of Enterobacteriaceae selected to approximate the distribution of ceftaroline MICs observed in AWARE global surveillance studies conducted in 2013. All six potential surrogates generated very major error rates of 16.3% to 56.6%, far exceeding the accepted limit of 1.5% set by the Clinical and Laboratory Standards Institute (CLSI) and the United States Food and Drug Administration (FDA) Center for Devices and Radiological Health. Failure to identify a reliable surrogate to predict in vitro susceptibility and resistance to ceftaroline for clinical isolates of Enterobacteriaceae underscores the need for expedited addition of newer antimicrobial agents to commercial antimicrobial susceptibility testing devices. PMID- 29436426 TI - Detection and Serogrouping of Dichelobacter nodosus Infection by Use of Direct PCR from Lesion Swabs To Support Outbreak-Specific Vaccination for Virulent Footrot in Sheep. AB - Virulent footrot is an economically significant disease in most sheep-rearing countries. The disease can be controlled with vaccine targeting the fimbriae of virulent strains of the essential causative agent, Dichelobacter nodosus However, the bacterium is immunologically heterogeneous, and 10 distinct fimbrial serogroups have been identified. Ideally, in each outbreak the infecting strains would be cultured and serogrouped so that the appropriate serogroup-specific mono or bivalent vaccine could be administered, because multivalent vaccines lack efficacy due to antigenic competition. If clinical disease expression is suspected to be incomplete, culture-based virulence tests are required to confirm the diagnosis, because control of benign footrot is economically unjustifiable. Both diagnosis and vaccination are conducted at the flock level. The aims of this study were to develop a PCR-based procedure for detecting and serogrouping D. nodosus directly from foot swabs and to determine whether this could be done accurately from the same cultured swab. A total of 269 swabs from the active margins of foot lesions of 261 sheep in 12 Merino sheep flocks in southeastern Australia were evaluated. DNA extracts taken from putative pure cultures of D. nodosus and directly from the swabs were evaluated in PCR assays for the 16S rRNA and fimA genes of D. nodosus Pure cultures were tested also by the slide agglutination test. Direct PCR using extracts from swabs was more sensitive than culture for detecting and serogrouping D. nodosus strains. Using the most sensitive sample collection method of the use of swabs in lysis buffer, D. nodosus was more likely to be detected by PCR in active than in inactive lesions, and in lesions with low levels of fecal contamination, but lesion score was not a significant factor. PCR conducted on extracts from swabs in modified Stuart's transport medium that had already been used to inoculate culture plates had lower sensitivity. Therefore, if culture is required to enable virulence tests to be conducted, it is recommended that duplicate swabs be collected from each foot lesion, one in transport medium for culture and the other in lysis buffer for PCR. PMID- 29436427 TI - Pyruvate Dehydrogenase PDH-E1beta Controls Tumor Progression by Altering the Metabolic Status of Cancer Cells. AB - Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable as it relies on PDH kinases that are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, we found that the PDH-E1beta subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia. After restoration of normoxic conditions, reduced expression of PDH-E1beta was sustained such that glycolysis remained highly activated. Notably, PDH-E1beta silencing in cancer cells produced a metabolic state strongly resembling the Warburg effect, but inhibited tumor growth. Conversely, enforced exogenous expression of PDH-E1beta durably increased PDH activity and promoted the malignant growth of breast cancer cells in vivo Taken together, our results establish the specific mechanism through which PDH acts as an oncogenic factor by tuning glycolytic metabolism in cancer cells.Significance: This seminal study offers a mechanistic explanation for why glycolysis is aberrantly activated in normoxic cancer cells, offering insights into this long-standing hallmark of cancer termed the Warburg effect. Cancer Res; 78(7); 1592-603. (c)2018 AACR. PMID- 29436425 TI - Optimization of Brucella abortus Protocols for Downstream Molecular Applications. AB - We compared the performances of various DNA extraction kits for their ability to recover Brucella abortus strain 19 inoculated into Brucella-free bovine tissues. Tissues were homogenized in a FastPrep bead homogenizer and extracted in triplicate by using one of five kits (Qiagen DNeasy, GE Illustra, Omega Bio-tek E.Z.N.A., Quanta Extracta, and IBI Science DNA Tissue kit). Whole blood was also taken from animals prior to chemical euthanasia, aliquoted, and then fractioned into buffy coat, red blood cells, and plasma. DNA was extracted from whole blood, buffy coat, and plasma by using four kits (Qiagen DNeasy, Omega Bio-tek E.Z.N.A., IBI Science DNA Blood kit, and 5PRIME PerfectPure). Previously reported primers targeting strain 19 were used to amplify extracted DNA and identify the optimal extraction kit. Real-time PCR was performed, and kits were compared for statistical differences by using quantification cycles as an outcome measure. Omega Bio-tek E.Z.N.A. was superior (P < 0.0068) in its lower quantification cycle values across all tissue kits. The IBI Science DNA Blood kit was superior to Qiagen DNeasy, 5PRIME PerfectPure, and Quanta Extracta (P < 0.0001, P = 0.0004, and P = 0.0013, respectively) but was not different from Omega Bio-tek E.Z.N.A. (P = 1.0). In summary, the optimal extraction kit for B. abortus strain 19 for tissues is Omega Bio-tek E.Z.N.A., and that for blood and its fractions is the IBI Science Mini Genomic DNA kit. Eluted DNA was also concentrated by using the Zymo Research DNA Clean & Concentrator-25 kit. Concentrated eluted DNA with the target was superior (P = <0.0001) to unconcentrated eluted DNA. PMID- 29436428 TI - Delivering a dignified death in a challenged national health system. PMID- 29436429 TI - How are we serving those patients that are reaching the end of their life? PMID- 29436430 TI - End-of-life care: Updates for busy clinicians. PMID- 29436431 TI - Compassionate communities and end-of-life care. AB - Compassionate communities as part of the public health approach to end-of-life care (EoLC) offers the possibility of solving the inequity of the difference in provision of care for those people with incurable cancer and those with non cancer terminal illnesses. The naturally occurring supportive network surrounding the patient is the starting point for EoLC. The network can provide both hands-on care and support to those providing hands-on care. Healthcare professionals can build much stronger partnerships with these supportive networks and transform EoLC at home. Further possibilities of support can be developed through communities, with implementation of the Compassionate City Charter. PMID- 29436432 TI - Passing the baton of trust. AB - Proactive, shared decision making between key professionals and sensitive communication with patients, and those important to them, can never be overestimated. Projected annual deaths in England and Wales are set to rise, highlighting the increasing need for high quality palliative and end-of-life care. The Royal College of General Practitioners and Marie Curie have worked in partnership to develop the Daffodil Standards, an evidenced-based, structured approach for practices using quality improvement methodology to help improve care for patients at an advanced stage of serious illness or approaching end of life. PMID- 29436433 TI - Updates in palliative care - recent advancements in the pharmacological management of symptoms. AB - Symptom management is an important part of both palliative care and end-of-life care. This article will examine the recent research evidence about drugs commonly used for symptom management in adult patients receiving palliative care. In particular, the management of symptoms where recent palliative care-based evidence has changed recommended practice will be reviewed. This includes: breathlessness, delirium, nausea and vomiting in bowel obstruction, opioid induced constipation and upper respiratory tract secretions. For each symptom, a review of recent pharmacological evidence has been undertaken, with emphasis on potential important changes to physicians' practice. PMID- 29436434 TI - Updates in palliative care - overview and recent advancements in the pharmacological management of cancer pain. AB - Pain is a common symptom in many types of cancer. Interdisciplinary team management, including pain assessment, explanation to the patient/family, treating the reversible, non-pharmacological treatments and reassessment are essential. This article focuses on the pharmacological management of cancer pain, and overviews and updates on the recent advances in this field. Both non-opioid and opioid analgesia as well as coanalgesics (adjuvants) are reviewed. Within non opioid analgesia the risks of non-steroidal anti-inflammatory drugs (NSAIDs) are considered and recommendations for NSAIDs in patients at risk of gastrointestinal and cardiovascular toxicity are made. For opioid analgesics, side effects of opioids are discussed alongside practical guidance on opioid prescribing and converting between opioids. Newer drugs such as tapentadol are considered in this update. Amitriptyline, duloxetine, gabapentin and pregabalin, and the guidance for their use are reviewed in the coanalgesics (adjuvants) section. PMID- 29436435 TI - An overview of the spiritual importances of end-of-life care among the five major faiths of the United Kingdom. AB - For many who pertain to particular theological paradigms, their faith cannot be compartmentalised, but is mobilised to inform all aspects of their being, most notably their ethical and moral persuasions. As clinicians, the concept that there are good and bad deaths is already known; understanding the origin and depth of non-physical suffering, and aiming to alleviate it is not possible without learning the individual experiences and beliefs that go with it. Spiritual care forms a fundamental consideration in the endeavor to address the holistic experience of those patients receiving palliative care. Good palliative care seeks to promote the wellbeing and priorities of those with faltering health in a way that continues to support individualised notions of self-determination. The last few decades have resulted in a multicultural and multi-ethnic patient population. Addressing the spiritual and physical needs of patients allows healthcare professionals to deliver truly holistic care. Exploring and understanding the specific nuances of the five major religions of the UK provides healthcare professionals the opportunity to comfort the religiously observant patient at the end of life. PMID- 29436436 TI - Legal and practical issues at the end of life. PMID- 29436437 TI - Treatment of tobacco dependence in UK hospitals: an observational study. AB - Over a million smokers are admitted to hospitals in the UK each year. The extent to which tobacco dependence is identified and addressed in this population is unclear. Data on 14,750 patients from 146 hospitals collected for the British Thoracic Society smoking cessation audit were analysed to determine smoking prevalence, attempts to ask smokers about quitting, and referrals to smoking cessation services. Associations with hospital organisational factors were assessed by logistic regression. Overall hospital smoking prevalence was 25%. Only 28% of smokers were asked whether they would like to quit, and only one in 13 smokers was referred for treatment of tobacco dependence. There was a higher chance of smokers being asked about quitting in organisations with smoke-free sites, dedicated smoking cessation practitioners, regular staff training, and availability of advanced pharmacotherapy. Treatment of tobacco dependence in smokers attending UK hospitals is poor and could be associated with organisational factors. PMID- 29436438 TI - Healthcare reconsultation in working-age adults following hospitalisation for community-acquired pneumonia. AB - Community-acquired pneumonia (CAP) is associated with prolonged symptom persistence during recovery. However, the effect of the residual symptom load on healthcare utilisation is unknown. The aim of this study was to quantify healthcare reconsultation within 28 days of hospital discharge for an index episode of CAP, and explore reasons for these reconsultations. Adults of working age admitted to any of four hospitals in the UK, with a primary diagnosis of CAP, were prospectively studied. Of 108 patients, 71 (65.7%) reconsulted healthcare services within 28 days of discharge; of these, 90.1% consulted their GP. Men were less likely to reconsult than women (adjusted odds ratio [aOR] 0.34, 95% confidence interval 0.13-0.91, p=0.032). Persistence of respiratory symptoms accounted for the majority of these reconsultations. Healthcare utilisation is high in working-age adults after an episode of hospitalised CAP and, in most cases, is due to failure to resolve index symptoms. PMID- 29436439 TI - The National Early Warning Score and its subcomponents recorded within +/-24 h of emergency medical admission are poor predictors of hospital-acquired acute kidney injury. AB - Hospital-acquired acute kidney injury (H-AKI) is a common cause of avoidable morbidity and mortality. Therefore, in the current study, we investigated whether vital signs data from patients, as defined by a National Early Warning Score (NEWS), can predict H-AKI following emergency admission to hospital. We analysed all emergency admissions (n=33,608) to York Hospital with NEWS data over a 24 month period. Here, we report the area under the curve (AUC) for logistic regression models that used the index NEWS (model A0), plus age and sex (A1), plus subcomponents of NEWS (A2) and two-way interactions (A3), and similarly for maximum NEWS (models B0,B1,B2,B3). Of the total emergency admissions, 4.05% (1,361/33,608) had H-AKI. Models using the index NEWS had lower AUCs (0.59-0.68) than models using the maximum NEWS AUCs (0.75-0.77). The maximum NEWS model (B3) was more sensitive than the index NEWS model (A0) (67.60% vs 19.84%) but identified twice as many cases as being at risk of H-AKI (9581 vs 4099) at a NEWS of 5. Based on these results, we suggest that the index NEWS is a poor predictor of H-AKI. The maximum NEWS is a better predictor but appears to be unfeasible because it is only knowable in retrospect and is associated with a substantial increase in workload, albeit with improved sensitivity. PMID- 29436440 TI - Systematic review of the efficacy of statins for the treatment of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common type of dementia. Recent studies have assessed the possibility of using statins as treatment for AD. However, their efficacy is not clear. In this study, we collected the most relevant information about the efficacy of statins for the treatment of AD. We conducted a systematic literature search using MEDLINE, EMBASE and The Cochrane Library. We included clinical trials, meta-analyses and systematic reviews that analysed the efficacy of statins in AD. We also extracted the characteristics and efficacy results of the studies selected. Of the 304 articles identified, 13 complied with the inclusion criteria. The scientific quality of studies was high and their results indicated that there were no significant differences in the main efficacy variables between statins and placebo treatment for AD. Therefore, according to the available scientific evidence, statins have not shown an improvement in cognition and do not appear to offer significant benefits to patients with AD. PMID- 29436441 TI - Sepsis - thoughtful management for the non-expert. AB - Sepsis is a common and often devastating medical emergency with a high mortality rate and, in many survivors, long-term morbidity. It is defined as the dysregulated host response to infection resulting in organ dysfunction, and its incidence is increasing as the population ages. However, it is a treatable and potentially reversible condition, especially if identified and treated promptly. A sound understanding of sepsis is crucial for optimal care. Although general guidelines are available for management, here we provide a foundation of understanding to encourage thoughtful, personalised management of sepsis during the acute phase. We provide an overview of the epidemiology, the new Sepsis-3 definitions, pathophysiology, clinical presentations, and investigation and management of sepsis for the non-expert. PMID- 29436442 TI - Ambulatory emergency care - improvement by design. AB - Ambulatory emergency care (AEC) has been developed by clinicians as a means of providing emergency care without the traditional bed base of a hospital. Given that AEC is provided in a clinic-style setting, it can continue to operate during periods of high bed occupancy, alleviating bed pressures and continuing to provide timely care for selected patients. Although different models of AEC have developed according to local context, there are common principles that apply to AEC services, including early access to senior decision-makers, opening hours matching demand, access to diagnostics, close collaboration with other clinical services, a mixed workforce and patient selection processes. Some of the key AEC developments have been related to technology, including high-sensitivity troponin, low-molecular-weight heparins and computer tomography (CT) pulmonary angiography. Risk stratification tools are useful for assessing the appropriateness of using AEC as a care model for patients. PMID- 29436443 TI - Diagnosis and management of cerebral venous thrombosis. AB - Cerebral venous thrombosis (CVT) is rare and accounts for 0.5% of all strokes. Its clinical presentation is variable and diagnosis requires a high index of clinical suspicion in conjunction with neuroradiological diagnostic support. Treatment options are limited and are mostly based on consensus. Therefore, familiarity with international guidelines is important. Outcome is often good and most patients make a full recovery, although a small proportion suffers death or disability. Here, we describe the clinical features, risk factors, acute imaging features, management and complications of CVT. PMID- 29436444 TI - When psychiatric symptoms reflect medical conditions. AB - The brain dysfunction associated with certain medical and neurological conditions can produce essentially any psychiatric symptom. This means there is always a chance that presentations thought to be 'psychiatric' are actually explained by unidentified medical pathology. This paper aims to outline an approach to minimise these missed diagnoses. PMID- 29436445 TI - A systematic approach to the unconscious patient. AB - Unconscious patients are commonly seen by physicians. They are challenging to manage and in a time sensitive condition, a systematic, team approach is required. Early physiological stability and diagnosis are necessary to optimise outcome. This article focuses on unconscious patients where the initial cause appears to be non-traumatic and provides a practical guide for their immediate care. PMID- 29436446 TI - CME Acute medicine (113043) self-assessment questionnaire. PMID- 29436447 TI - An acute transfusion reaction. AB - We present the case of a 67-year-old man who suffered an acute anaphylactic reaction during red cell transfusion due to the presence of anti-IgA antibodies. The incidence and clinical relevance of anti-IgA antibodies in IgA deficiency is reviewed, and the wider investigation and management of acute transfusion reactions is also discussed. This case highlights the need to consider the potential risks of blood component transfusion against the purported benefit. PMID- 29436448 TI - Acute myocarditis secondary to acute Campylobacter jejuni infection. AB - We report a case of myocarditis complicating gastroenteritis caused by Campylobacter jejuni The patient had an uncomplicated course and made a full recovery. Cardiac MRI was useful in securing an early diagnosis and establishing baseline heart function. Myocarditis should be considered in younger patients presenting with chest pain and elevations in serum troponin. The occurrence of myocarditis complicating Campylobacter jejuni gastroenteritis is reviewed. PMID- 29436449 TI - Lesson of the month 1: Lemierre's syndrome: a reminder of the 'forgotten disease'. AB - Lemierre's syndrome is a condition characterised by suppurative thrombophlebitis of the internal jugular (IJ) vein following a recent oropharyngeal infection, with resulting septicaemia and metastatic lesions. It is strongly associated with Fusobacterium necrophorum, a Gram-negative bacilli. Key to early diagnosis is awareness of the classical history and course of this illness, and therefore to ask about a history of recent oropharyngeal infections when a young patient presents with fever and rigors. Diagnosis can be confirmed by showing thrombophlebitis of the IJ vein, culturing F necrophorum from normally sterile sites or demonstrating metastatic lesions in this clinical setting. The cornerstone of management is draining of purulent collection where possible and prolonged courses of appropriate antibiotics. In this article, we review a case study of a young man with Lemierre's syndrome and discuss the condition in more detail. PMID- 29436450 TI - Lesson of the month 2: Pulmonary embolism in a patient on rivaroxaban and concurrent carbamazepine. AB - A 71-year-old female with a history of pulmonary embolism treated with rivaroxaban presented with acute onset shortness of breath, chest pain and palpitations. Computed tomographic pulmonary angiography (CTPA) revealed multiple bilateral pulmonary emboli. The patient was concurrently prescribed carbamazepine and was later diagnosed with recurrence of breast cancer during the admission. We discuss common drug interactions pertinent to direct oral anticoagulants (DOACs) that can increase the risk of further venous thromboembolism. This case report highlights the importance of reviewing patient medications when considering anticoagulants and the need to raise awareness of these drug interactions among clinicians when making their choice of anticoagulation. It also reinforces the current lack of evidence for use of DOACs in patients with solid organ malignancies. PMID- 29436451 TI - A novel CT finding in cardiac amyloid. PMID- 29436452 TI - Medical problems in pregnancy. PMID- 29436453 TI - Screening for obstructive sleep apnoea using the STOPBANG questionnaire. PMID- 29436454 TI - Thoracic ultrasound experiences among respiratory specialty trainees in the UK. PMID- 29436455 TI - Sleep in adolescents and young adults. PMID- 29436456 TI - Endocrine abnormalities in lithium toxicity. PMID- 29436457 TI - Regular and frequent feedback of specific clinical criteria delivers a sustained improvement in the management of diabetic ketoacidosis. PMID- 29436458 TI - Response. PMID- 29436459 TI - Corrigendum: Image of the month: Dysphagia due to injury of the corticobulbar tract following traumatic brain injury. PMID- 29436460 TI - CMS expands Medicare's chronic care management services. PMID- 29436461 TI - Medicare poised to cover diabetes prevention services. PMID- 29436462 TI - Integration of physical assessment into pharmacy practice. PMID- 29436463 TI - Dealing with the unexpected during and after Hurricane Irma. PMID- 29436464 TI - Treatment of pulmonary hypertension with inhaled agents in the pediatric intensive care unit. PMID- 29436465 TI - Impact of a pharmacy team-led intervention program on the readmission rate of elderly patients with heart failure. AB - PURPOSE: The results of a study to determine whether pharmacy team-led postdischarge intervention can reduce the rate of 30-day hospital readmissions in older patients with heart failure (HF) are reported. METHODS: A retrospective chart review was performed to identify patients 60 years of age or older who were admitted to an academic medical center with a primary diagnosis of HF during the period March 2013-June 2014 and received standard postdischarge follow-up care provided by physicians, nurses, and case managers. The rate of 30-day readmissions in that historical control group was compared with the readmission rate in a group of older patients with HF who were admitted to the hospital during a 15-month intervention period (July 2014-October 2015); in addition to usual postdischarge care, these patients received medication reconciliation and counseling from a team of pharmacists, pharmacy residents, and pharmacy students. RESULTS: Twelve of 97 patients in the intervention group (12%) and 20 of 80 patients in the control group (25%) were readmitted to the hospital within 30 days of discharge (p = 0.03); 11 patients in the control group (55%) and 7 patients in the intervention group (58%) had HF-related readmissions (p = 0.85). CONCLUSION: In a population of older patients with HF, the rate of 30-day all cause readmissions in a group of patients targeted for a pharmacy team-led postdischarge intervention was significantly lower than the all-cause readmission rate in a historical control group. PMID- 29436466 TI - Evaluation of prescriber responses to pharmacogenomics clinical decision support for thiopurine S-methyltransferase testing. AB - PURPOSE: Results of a study of prescribers' responses to a pharmacogenomics-based clinical decision support (CDS) alert designed to prompt thiopurine S methyltransferase (TPMT) status testing are reported. METHODS: A single-center, retrospective, chart review-based study was conducted to evaluate prescriber compliance with a pretest CDS alert that warned of potential thiopurine drug toxicity resulting from deficient TPMT activity due to TPMT gene polymorphism. The CDS alert was triggered when prescribers ordered thiopurine drugs for patients whose records did not indicate TPMT status or when historical thiopurine use was documented in the electronic health record. The alert pop-up also provided a link to online educational resources to guide thiopurine dosing calculations. RESULTS: During the 9-month study period, 500 CDS alerts were generated: in 101 cases (20%), TPMT phenotyping or TPMT genotyping was ordered; in 399 cases (80%), testing was not ordered. Multivariable regression analysis indicated that documentation of historical thiopurine use was the only independent predictor of test ordering. Among the 99 patients tested subsequent to CDS alerts, 70 (71%) had normal TPMT activity, 29 (29%) had intermediate activity, and none had deficient activity. The online resources provided thiopurine dosing recommendations applicable to 24 patients, but only 3 were prescribed guideline-supported doses after CDS alerts. CONCLUSION: The pretest CDS rule resulted in a large proportion of neglected alerts due to poor alerting accuracy and consequent alert fatigue. Prescriber usage of online thiopurine dosing resources was low. PMID- 29436467 TI - Effect of provider-selected order indications on appropriateness of antimicrobial orders in a pediatric hospital. AB - PURPOSE: The effect of mandatory provider-selected order indications (PSOIs) on appropriateness of antimicrobial ordering in a tertiary pediatric hospital was evaluated. METHODS: Mandatory PSOIs for 14 antimicrobials were implemented in September 2013. Data on initial and final orders in the first 24 hours after ordering were collected from the electronic medical record. Orders from pre-PSOI and post-PSOI implementation were randomly selected and compared with documentation at the time of order to elicit the documentation-determined clinical indication (DDCI). Appropriateness of the order for the DDCI was evaluated and compared between groups using 2-sample t tests, chi-square tests, and logistic regression. RESULTS: Among the total 1,304 orders included in the review, 275 (21.1%) were inappropriate based on DDCI. The indications associated with the greatest number of inappropriate orders in both groups were suspected sepsis/bacteremia, meningitis/central nervous system infection, and pneumonia. A total of 128 (18.3%) of 700 initial orders were inappropriate compared with the DDCI in the pre-PSOI period, and 82 (17.8%) of 461 initial orders were inappropriate in the post-PSOI period (p = 0.83). A total of 78 (11.1%) of 700 final orders were inappropriate in the pre-PSOI period, and 29 (6.3%) of 461 final orders were inappropriate in the post-intervention period (p = 0.01). Overall, 84 (12%) of 700 inappropriate orders reached the patient in the pre-PSOI period versus 43 (9.3%) of 461 inappropriate orders in the post-PSOI period (p = 0.15). CONCLUSION: PSOIs were effective in reducing inappropriate antimicrobial orders in the first 24 hours after ordering if the correct indication was selected. PMID- 29436468 TI - Shared responsibility for the education of pharmacy students. PMID- 29436469 TI - Understanding inpatient antimicrobial stewardship metrics. PMID- 29436470 TI - Improving medication-related clinical decision support. AB - PURPOSE: Current uses of medication-related clinical decision support (CDS) and recommendations for improving these systems are reviewed. SUMMARY: Using a systematic approach, articles published from 2007 through 2014 were identified in MEDLINE and EMBASE using MeSH terms and keywords relating to the 5 basic medication-related CDS functionalities. A total of 156 full-text articles and 28 conference abstracts were reviewed across each of the 5 areas: drug-drug interaction (DDI) checks (n = 78), drug allergy checks (n = 20), drug dose support (n = 55), drug duplication checks (n = 11), and drug formulary support (n = 20). The success of medication-related CDS depends on users finding the alerts valuable and acting on the information received. Improving alert specificity and sensitivity is important for all domains. Tiering is important for improving the acceptance of DDI alerts. The ability to perform appropriate cross-sensitivity checks is key to producing appropriate drug allergy checks. Drug dosage alerts should be individualized and deliver practical recommendations. How the system is configured to identify certain drug duplications is important to prevent possible patient toxicity. Accurate knowledge databases are needed to produce relevant drug formulary alerts and encourage formulary adherence. Medication-related CDS is still relatively immature in some organizations and has substantial room for improvement. For example, decision support should consider more patient-specific factors, human factors principles should always be considered, and alert specificity must be improved in order to reduce alert fatigue. CONCLUSION: Standardization, integration of patient-specific parameters, and consideration of human factors design principles are central to realizing the potential benefits of medication-related CDS. PMID- 29436471 TI - Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair. AB - OBJECTIVE: Human adult articular cartilage (AC) has little capacity for repair, and joint surface injuries often result in osteoarthritis (OA), characterised by loss of matrix, hypertrophy and chondrocyte apoptosis. Inflammation mediated by interleukin (IL)-6 family cytokines has been identified as a critical driver of proarthritic changes in mouse and human joints, resulting in a feed-forward process driving expression of matrix degrading enzymes and IL-6 itself. Here we show that signalling through glycoprotein 130 (gp130), the common receptor for IL 6 family cytokines, can have both context-specific and cytokine-specific effects on articular chondrocytes and that a small molecule gp130 modulator can bias signalling towards anti-inflammatory and antidegenerative outputs. METHODS: High throughput screening of 170 000 compounds identified a small molecule gp130 modulator termed regulator of cartilage growth and differentiation (RCGD 423) that promotes atypical homodimeric signalling in the absence of cytokine ligands, driving transient increases in MYC and pSTAT3 while suppressing oncostatin M- and IL-6-mediated activation of ERK and NF-kappaB via direct competition for gp130 occupancy. RESULTS: This small molecule increased proliferation while reducing apoptosis and hypertrophic responses in adult chondrocytes in vitro. In a rat partial meniscectomy model, RCGD 423 greatly reduced chondrocyte hypertrophy, loss and degeneration while increasing chondrocyte proliferation beyond that observed in response to injury. Moreover, RCGD 423 improved cartilage healing in a rat full-thickness osteochondral defect model, increasing proliferation of mesenchymal cells in the defect and also inhibiting breakdown of cartilage matrix in de novo generated cartilage. CONCLUSION: These results identify a novel strategy for AC remediation via small molecule-mediated modulation of gp130 signalling. PMID- 29436472 TI - A novel variant in GLIS3 is associated with osteoarthritis. AB - OBJECTIVES: Osteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date. METHODS: We carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR. RESULTS: We detect a genome-wide significant association at rs10116772 with TJR (P=3.7*10-8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes. CONCLUSIONS: We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits. PMID- 29436474 TI - CORRECTION. PMID- 29436473 TI - High erythrocyte levels of the n-6 polyunsaturated fatty acid linoleic acid are associated with lower risk of subsequent rheumatoid arthritis in a southern European nested case-control study. AB - OBJECTIVES: Findings relating to dietary intake of n-3 polyunsaturated fatty acids (PUFA) and risk of rheumatoid arthritis (RA) are mixed. Erythrocyte membrane PUFA is an accurate objective biomarker of PUFA status; however, there are little data on erythrocyte membrane PUFA and risk of RA. The objective was therefore to compare erythrocyte membrane PUFA between pre-RA individuals and matched controls from a population-based sample, and specifically to test the hypothesis that higher levels of longer chain n-3 PUFA are associated with lower risk of RA. METHODS: The European Prospective Investigation into Cancer and Nutrition (EPIC) is a large European prospective cohort study of apparently healthy populations. We undertook a nested case-control study by identifying RA cases with onset after enrolment (pre-RA) in four EPIC cohorts in Italy and Spain. Confirmed pre-RA cases were matched with controls by age, sex, centre, and date, time and fasting status at blood collection. Conditional logistic regression analysis was used to estimate associations of PUFA with the development of RA, adjusting for potential confounders including body mass index, waist circumference, education level, physical activity, smoking status and alcohol intake. RESULTS: The study analysed samples from 96 pre-RA subjects and 258 matched controls. In this analysis, the median time to diagnosis (defined as time between date of blood sample and date of diagnosis) was 6.71 years (range 0.8-15). A significant inverse association was observed with n-6 PUFA linoleic acid (LA) levels and pre-RA in the fully adjusted model (highest tertile: OR 0.29; 95% CI 0.12 to 0.75; P for trend 0.01). No association was observed with any individual n-3 PUFA, total n-3 PUFA or total n-3:n-6 ratio. CONCLUSIONS: Erythrocyte levels of the n-6 PUFA LA were inversely associated with risk of RA, whereas no associations were observed for other n-6 or n-3 PUFA. Further work is warranted to replicate these findings and to investigate if lower LA levels are a bystander or contributor to the process of RA development. PMID- 29436475 TI - Goldilocks Principle: MtNFH1 Ensures Optimal Nod Factor Activity. PMID- 29436476 TI - OPAQUE11 Is a Central Hub of the Regulatory Network for Maize Endosperm Development and Nutrient Metabolism. AB - Maize (Zea mays) endosperm is a primary tissue for nutrient storage and is highly differentiated during development. However, the regulatory networks of endosperm development and nutrient metabolism remain largely unknown. Maize opaque11 (o11) is a classic seed mutant with a small and opaque endosperm showing decreased starch and protein accumulation. We cloned O11 and found that it encodes an endosperm-specific bHLH transcription factor (TF). Loss of function of O11 significantly affected transcription of carbohydrate/amino acid metabolism and stress response genes. Genome-wide binding site analysis revealed 9885 O11 binding sites distributed over 6033 genes. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq) assays, we identified 259 O11-modulated target genes. O11 was found to directly regulate key TFs in endosperm development (NKD2 and ZmDOF3) and nutrient metabolism (O2 and PBF). Moreover, O11 directly regulates cyPPDKs and multiple carbohydrate metabolic enzymes. O11 is an activator of ZmYoda, suggesting its regulatory function through the MAPK pathway in endosperm development. Many stress-response genes are also direct targets of O11. In addition, 11 O11-interacting proteins were identified, including ZmIce1, which coregulates stress response targets and ZmYoda with O11. Therefore, this study reveals an endosperm regulatory network centered around O11, which coordinates endosperm development, metabolism and stress responses. PMID- 29436477 TI - Combat-related foot injuries: impact on gait and functional outcome. AB - INTRODUCTION: Prior to deployment of the Netherlands Army Task Force Urozgan in Afghanistan, the Dutch Military and civilian healthcare systems had limited experience in treating blast injuries and their long-term consequences. This meant that guidelines for treatment and rehabilitation were lacking. The aim of this cohort study was to quantify kinematic and kinetic abnormalities in service members with foot injuries in relation to functional outcome using gait analysis. METHOD: In nine service members with combat-related talus, calcaneus and/or navicular bone (TCN) fractures and nine controls, gait parameters were measured using Gait Real-Time Analysis Interactive Lab system. High-level mobility was evaluated by the Comprehensive High-Level Activity Mobility Predictor (CHAMP), and functional ability was assessed by Lower Extremity Functional Scale (LEFS) questionnaire. RESULTS: Significant differences were found for LEFS and CHAMP scores (P<0.01), comfortable walking speed and ankle joint range of motion (ROM) (P<0.05), all lower in the group with TCN fractures. For this group, a trend (0.1>P>0.05) for higher step width and lower stride duration and peak power was found. A strong correlation (0.6>r>0.79) is shown between LEFS and comfortable walking speed and CHAMP and ankle joint ROM. The correlations between LEFS and stride duration, step width, ankle joint ROM and peak power, and between CHAMP and comfortable walking speed and stride duration, were moderate (0.4>r>0.59). CONCLUSIONS: This study demonstrated that service members with TCN fractures, compared with healthy controls, have altered gait characteristics, specifically lower walking speed and ankle joint ROM, both related to lower physical functioning. Patients with bilateral depressed Bohler's angle had the worse functional performance, and further research is recommended to evaluate the relationship between Bohler's angle and physical performance. CLINICAL TRIAL: The Dutch Ministry of Defence (MOD) and the Institutional Review Board and Medical Ethics Review Committee Brabant, The Netherlands, approved this study (P1550). PMID- 29436480 TI - At the intersection of self and not-self: finding the locus of 'self' in autoimmunity. AB - Individuals with chronic autoimmune disease experience a sense of vulnerability. In part, this relates to the struggle for finding the meaning of the illness. The consequent existential distress may manifest in an unseated sense of personhood. Insight into the mechanism of this state of powerlessness and of perceived loss of agency is central to establishing a supportive clinician-patient relationship. This present exposition underscores the concept of autoimmunity as one that represents a demarcation in the psyche: one that is not just a threat to our sense of self-hood but also to our humanity. Autoimmunity exposes the challenge imposed on the relating of the self to one's own self and hence is an ontological challenge. The breach of the boundary between self and not-self that is caused by the autoimmune process culminates in feelings of alienation. PMID- 29436481 TI - Long-term diet-induced hypertension in rats is associated with reduced expression and function of small artery SKCa, IKCa, and Kir2.1 channels. AB - Abdominal obesity and/or a high intake of fructose may cause hypertension. K+ channels, Na/K-ATPase, and voltage-gated Ca2+ channels are crucial determinants of resistance artery tone and thus the control of blood pressure. Limited information is available on the role of K+ transporters in long-term diet-induced hypertension in rats. We hypothesized that a 28-week diet rich in fat, fructose, or both, will lead to changes in K+ transporter expression and function, which is associated with increased blood pressure and decreased arterial function. Male Sprague-Dawley (SD) rats received a diet containing normal chow (Control), high fat chow (High Fat), high-fructose in drinking water (High Fructose), or a combination of high-fat and high-fructose diet (High Fat/Fruc) for 28 weeks from the age of 4 weeks. Measurements included body weight (BW), systolic blood pressure (SBP), mRNA expression of vascular K+ transporters, and vessel myography in small mesenteric arteries (SMAs). BW was increased in the High Fat and High Fat/Fruc groups, and SBP was increased in the High Fat/Fruc group. mRNA expression of small conductance calcium-activated K+ channel (SKCa), intermediate conductance calcium-activated K+ (IKCa), and Kir2.1 inward rectifier K+ channels were reduced in the High Fat/Fruc group. Reduced endothelium-derived hyperpolarization (EDH)-type relaxation to acetylcholine (ACh) was seen in the High Fat and High Fat/Fruc groups. Ba2+-sensitive dilatation to extracellular K+ was impaired in all the experimental diet groups. In conclusion, reduced expression and function of SKCa, IKCa, and Kir2.1 channels are associated with elevated blood pressure in rats fed a long-term High Fat/Fruc. Rats fed a 28-week High Fat/Fruc provide a relevant model of diet-induced hypertension. PMID- 29436482 TI - The angiotensin type 2 receptor in the human adrenocortical zona glomerulosa and in aldosterone-producing adenoma: low expression and no functional role. AB - The angiotensin II (Ang II) type 2 receptor (AT2R) and the angiotensin-(1-7) (Ang (1-7)) receptor (MasR) play a cardiovascular protective role by counter regulating Ang II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R, and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of Compound 21 (C21), an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, was also assessed using the AT1R antagonist irbesartan to ascertain the specificity of C21 effect. We found that the AT1R, AT2R, and MasR were expressed in APA and APA-adjacent tissue, albeit heterogeneously. The gene expression of AT1R and AT2R was lower, and that of the MasR higher in APAs than in APA-adjacent tissue. In steroid-producing NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, C21 was ineffective at nanomolar concentrations, but increased CYP11B1 and CYP11B2 gene expression at micromolar concentrations through AT1R, as this effect was blunted by irbesartan. The scant expression of the AT2R, along with the lack of any effect of C21 at low concentrations on CYP11B2, do not support the contention that the protective arm of renin-angiotensin system (RAS) blunts aldosterone synthase in the normal adrenal cortex and primary aldosteronism. PMID- 29436479 TI - The Ontogeny of a Neutrophil: Mechanisms of Granulopoiesis and Homeostasis. AB - Comprising the majority of leukocytes in humans, neutrophils are the first immune cells to respond to inflammatory or infectious etiologies and are crucial participants in the proper functioning of both innate and adaptive immune responses. From their initial appearance in the liver, thymus, and spleen at around the eighth week of human gestation to their generation in large numbers in the bone marrow at the end of term gestation, the differentiation of the pluripotent hematopoietic stem cell into a mature, segmented neutrophil is a highly controlled process where the transcriptional regulators C/EBP-alpha and C/EBP-epsilon play a vital role. Recent advances in neutrophil biology have clarified the life cycle of these cells and revealed striking differences between neonatal and adult neutrophils based on fetal maturation and environmental factors. Here we detail neutrophil ontogeny, granulopoiesis, and neutrophil homeostasis and highlight important differences between neonatal and adult neutrophil populations. PMID- 29436478 TI - Regulation of Sensing, Transportation, and Catabolism of Nitrogen Sources in Saccharomyces cerevisiae. AB - Nitrogen is one of the most important essential nutrient sources for biogenic activities. Regulation of nitrogen metabolism in microorganisms is complicated and elaborate. For this review, the yeast Saccharomyces cerevisiae was chosen to demonstrate the regulatory mechanism of nitrogen metabolism because of its relative clear genetic background. Current opinions on the regulation processes of nitrogen metabolism in S. cerevisiae, including nitrogen sensing, transport, and catabolism, are systematically reviewed. Two major upstream signaling pathways, the Ssy1-Ptr3-Ssy5 sensor system and the target of rapamycin pathway, which are responsible for sensing extracellular and intracellular nitrogen, respectively, are discussed. The ubiquitination of nitrogen transporters, which is the most general and efficient means for controlling nitrogen transport, is also summarized. The following metabolic step, nitrogen catabolism, is demonstrated at two levels: the transcriptional regulation process related to GATA transcriptional factors and the translational regulation process related to the general amino acid control pathway. The interplay between nitrogen regulation and carbon regulation is also discussed. As a model system, understanding the meticulous process by which nitrogen metabolism is regulated in S. cerevisiae not only could facilitate research on global regulation mechanisms and yeast metabolic engineering but also could provide important insights and inspiration for future studies of other common microorganisms and higher eukaryotic cells. PMID- 29436483 TI - Leptin-induced inflammation by activating IL-6 expression contributes to the fibrosis and hypertrophy of ligamentum flavum in lumbar spinal canal stenosis. AB - The ongoing chronic inflammation and subsequent fibrosis play an important role in ligamentum flavum (LF) fibrosis and hypertrophy in patients with lumbar spinal canal stenosis (LSCS). Leptin is a chronic inflammatory mediator and involved in the fibrotic process in multiple organ systems. The present study aimed to investigate the role of leptin in LF fibrosis and its related regulatory mechanisms. The LF specimens were obtained during the surgery from 12 patients with LSCS (LSCS group) and 12 control patients with lumbar disc herniation (LDH) group. The morphologic changes and fibrosis score of LF were assessed by Hematoxylin and eosin (H&E) and Masson's trichrome staining respectively. The location and expression of leptin in LF tissues were determined. Then, the LF cells were cultured and exposed to recombinant human leptin (rhleptin). Collagen I and III were used as fibrosis markers and IL-6 was used as the inflammatory factor. As a result, the LF thickness and fibrosis score in the LSCS group were significantly higher than those in the LDH group (P<0.05). Leptin was detected in the hypertrophied LF and its expression was substantially increased in the LSCS group and positively correlated with LF thickness and fibrosis score (P<0.05). Moreover, our in vitro experiments revealed that rhleptin treated LF cells elevated the expression of collagen I and III. Finally, leptin administration induced IL-6 expression via nuclear factor-kappaB (NF-kappaB) pathway in LF cell (P<0.05). Our study demonstrated novel molecular events for leptin-induced inflammation in LF tissue by promoting IL-6 expression and thus might have potential implications for clarifying the mechanism underlying LF fibrosis and hypertrophy. PMID- 29436484 TI - Recombinant production of eukaryotic cytochrome P450s in microbial cell factories. AB - Cytochrome P450s (P450s) comprise one of the largest known protein families. They occur in every kingdom of life and catalyze essential reactions, such as carbon source assimilation, synthesis of hormones and secondary metabolites, or degradation of xenobiotics. Due to their outstanding ability of specifically hydroxylating complex hydrocarbons, there is a great demand to use these enzymes for biocatalysis, including applications at an industrial scale. Thus, the recombinant production of these enzymes is intensively investigated. However, especially eukaryotic P450s are difficult to produce. Challenges are faced due to complex cofactor requirements and the availability of a redox-partner (cytochrome P450 reductase, CPR) can be a key element to get active P450s. Additionally, most eukaryotic P450s are membrane bound which complicates the recombinant production. This review describes current strategies for expression of P450s in the microbial cell factories Escherichia coli, Saccharomyces cerevisiae, and Pichia pastoris. PMID- 29436485 TI - Comparative analysis of plant isochorismate synthases reveals structural mechanisms underlying their distinct biochemical properties. AB - Isochorismate synthase (ICS) converts chorismate into isochorismate, a precursor of primary and secondary metabolites including salicylic acid (SA). SA plays important roles in responses to stress conditions in plants. Many studies have suggested that the function of plant ICSs is regulated at the transcriptional level. In Arabidopsis thaliana, the expression of AtICS1 is induced by stress conditions in parallel with SA synthesis, and AtICS1 is required for SA synthesis. In contrast, the expression of NtICS is not induced when SA synthesis is activated in tobacco, and it is unlikely to be involved in SA synthesis. Studies on the biochemical properties of plant ICSs are limited, compared with those on transcriptional regulation. We analyzed the biochemical properties of four plant ICSs: AtICS1, NtICS, NbICS from Nicotiana benthamiana, and OsICS from rice. Multiple sequence alignment analysis revealed that their primary structures were well conserved, and predicted key residues for ICS activity were almost completely conserved. However, AtICS1 showed much higher activity than the other ICSs when expressed in Escherichia coli and N. benthamiana leaves. Moreover, the levels of AtICS1 protein expression in N. benthamiana leaves were higher than the other ICSs. Construction and analysis of chimeras between AtICS1 and OsICS revealed that the putative chloroplast transit peptides (TPs) significantly affected the levels of protein accumulation in N. benthamiana leaves. Chimeric and point-mutation analyses revealed that Thr531, Ser537, and Ile550 of AtICS1 are essential for its high activity. These distinct biochemical properties of plant ICSs may suggest different roles in their respective plant species. PMID- 29436486 TI - Randomised, double-blind, placebo-controlled crossover study of single-dose guanfacine in unilateral neglect following stroke. AB - OBJECTIVE: Unilateral neglect is a poststroke disorder that impacts negatively on functional outcome and lacks established, effective treatment. This multicomponent syndrome is characterised by a directional bias of attention away from contralesional space, together with impairments in several cognitive domains, including sustained attention and spatial working memory. This study aimed to test the effects of guanfacine, a noradrenergic alpha-2A agonist, on ameliorating aspects of neglect. METHODS: Thirteen right hemisphere stroke patients with leftward neglect were included in a randomised, double-blind, placebo-controlled proof-of-concept crossover study that examined the effects of a single dose of guanfacine. Patients were tested on a computerised, time-limited cancellation paradigm, as well as tasks that independently assessed sustained attention and spatial working memory. RESULTS: On guanfacine, there was a statistically significant improvement in the total number of targets found on the cancellation task when compared with placebo (mean improvement of 5, out of a possible 64). However, there was no evidence of a change in neglect patients' directional attention bias. Furthermore, Bayesian statistical analysis revealed reliable evidence against any effects of guanfacine on search organisation and performance on our sustained attention and spatial working memory tasks. CONCLUSIONS: Guanfacine improves search in neglect by boosting the number of targets found but had no effects on directional bias or search organisation, nor did it improve sustained attention or working memory on independent tasks. Further work is necessary to determine whether longer term treatment with guanfacine may be effective for some neglect patients and whether it affects functional outcome measures. TRIAL REGISTRATION NUMBER: NCT00955253. PMID- 29436487 TI - Intraoperative identification of the corticospinal tract and dorsal column of the spinal cord by electrical stimulation. AB - OBJECTIVES: Anatomical identification of the corticospinal tract (CT) and the dorsal column (DC) of the exposed spinal cord is difficult when anatomical landmarks are distorted by tumour growth. Neurophysiological identification is complicated by the fact that direct stimulation of the DC may result in muscle motor responses due to the centrally activated H-reflex. This study aims to provide a technique for intraoperative neurophysiological differentiation between CT and DC in the exposed spinal cord. METHODS: Recordings were obtained from 32 consecutive patients undergoing spinal cord tumour surgery from July 2015 to March 2017. A double train stimulation paradigm with an intertrain interval of 60 ms was devised with recording of responses from limb muscles. RESULTS: In non spastic patients (55% of cohort) an identical second response was noted following the first CT response, but the second response was absent after DC stimulation. In patients with pre-existing spasticity (45%), CT stimulation again resulted in two identical responses, whereas DC stimulation generated a second response that differed substantially from the first one. The recovery times of interneurons in the spinal cord grey matter were much shorter for the CT than those for the DC. Therefore, when a second stimulus train was applied 60 ms after the first, the CT fibre interneurons had already recovered ready to generate a second response, whereas the DC interneurons were still in the refractory period. CONCLUSIONS: Mapping of the spinal cord using double train stimulation allows neurophysiological distinction of CT from DC pathways during spinal cord surgery in patients with and without pre-existing spasticity. PMID- 29436488 TI - Worldwide prevalence of neuromyelitis optica spectrum disorders. PMID- 29436489 TI - 'Cryptogenic Drop Attacks' revisited: evidence of overlap with functional neurological disorder. AB - OBJECTIVE: In their 1973 BMJ paper 'Cryptogenic Drop Attacks', Stevens and Matthews described 40, mostly middle-aged, female patients with drop attacks of unknown cause. Although clinically common, there has been little on this topic since. We aimed to determine clinical features, comorbidity and outcome of patients with drop attacks. METHODS: We carried out a retrospective review of patients with cryptogenic drop attacks seen consecutively by one clinician (JS) between 2006 and 2016. Demographics, phenomenology, duration and frequency of attacks, attack description and comorbid diagnoses were recorded. Patients were followed up with a notes review. RESULTS: 83 patients with cryptogenic drop attacks were predominantly female (89%, n=79), mean age 44 years. The majority (93%, n=77) could not remember the fall itself and almost half (43%, n=36) experienced prodromal dissociative symptoms. Mechanical trips or syncope preceded drop attacks, historically, in 24% (n=20) of cases. Persistent fatigue (73%, n=61), chronic pain (40%, n=33), functional limb weakness (31%,n=26) and dissociative (non-epileptic) attacks 28% (n=23) were common, with the latter usually preceding or emerging from drop attacks. At follow-up (88%, mean 38 months), 28% (n=23) had resolution of their drop attacks. Predisposing (but non causative) disease comorbidity was found at baseline (n=12) and follow-up (n=5). CONCLUSIONS: Cryptogenic drop attacks are associated with high frequency of comorbid functional somatic and functional neurological disorders. Patients commonly have prodromal dissociative symptoms and in some there was a clear relationship with prior or subsequent dissociative (non-epileptic) attacks. Some cryptogenic drop attacks may be best understood as phenomena on the spectrum of dissociative attacks. PMID- 29436490 TI - Subthalamic stimulation and neuropsychiatric symptoms in Parkinson's disease: results from a long-term follow-up cohort study. AB - BACKGROUND: Reports on behavioural outcomes after subthalamic nucleus deep brain stimulation in Parkinson's disease are controversial and limited to short-term data. Long-term observation in a large cohort allows a better counselling and management. METHODS: To determine whether a long-term treatment with subthalamic stimulation induces or reduces impulse control behaviours, neuropsychiatric fluctuations and apathy, 69 patients treated with subthalamic stimulation are prospectively and retrospectively assessed using Ardouin Scale of Behavior in Parkinson's Disease before and after 3-10 years of stimulation. RESULTS: At a mean follow-up of 6 years, all impulse control disorders and dopaminergic addiction were significantly decreased, apart from eating behaviour and hypersexuality. Neuropsychiatric fluctuations also significantly improved (ON euphoria: 38% of the patients before surgery and 1% after surgery, P<0.01; OFF dysphoria: 39% of the patients before surgery and 10% after surgery, P<0.01). However, apathy increased (25% of the patients after surgery and 3% before, P<0.01). With the retrospective analysis, several transient episodes of depression, apathy, anxiety and impulse control disorders occurred. CONCLUSIONS: Bilateral subthalamic nucleus stimulation was overall very effective in improving impulse control disorders and neuropsychiatric fluctuations in parkinsonian patients in the long term despite a counteracting frequent apathy. Transient episodes of impulse control disorders still occurred within the follow-up. These findings recommend a close follow-up in parkinsonian patients presenting with neuropsychiatric symptoms before deep brain stimulation surgery. CLINICAL TRIAL REGISTRATION: NCT01705418;Post-results. PMID- 29436491 TI - Long Noncoding RNA LINC00657 Acting as a miR-590-3p Sponge to Facilitate Low Concentration Oxidized Low-Density Lipoprotein-Induced Angiogenesis. AB - Angiogenesis in atherosclerotic plaque promotes plaque growth, causes plaque hemorrhage, and violates plaque stability. LINC00657 is a long noncoding RNA highly conserved and abundantly expressed in vascular endothelial cells. The present study was designed to investigate the effects and mechanisms of LINC00675 on low concentrations of oxidized low-density lipoprotein (oxLDL)-induced angiogenesis. Cell proliferation, transwell, wound healing, and tube formation assays were conducted to detect the effects of low concentrations of oxLDL on angiogenesis; the results discovered that oxLDL promoted cell proliferation, migration, and tube formation. oxLDL also upregulated LINC00657 expression. Inhibition of LINC00657 by siRNA significantly suppressed oxLDL-induced endothelial cell proliferation, migration, and tube formation. Bioinformatic assay indicated six binding sites in the LINC00657 sequence to miR-590-3p. The upregulation of LINC00657 was related to the downregulation of miR-590-3p in oxLDL-treated endothelial cells; while downregulation of LINC00657 resulted in upregulation of miR-590-3p. The antiangiogenesis effects of si-LINC00657 were partly abrogated by miR-590-3p inhibitor. Further dual-luciferase assay found miR 590-3p inhibited the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) by binding to the position of 689-696 in HIF-1alpha 3'-untranslated region directly. MiR-590-3p also inhibited the oxLDL-induced upregulation of HIF-1alpha, vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9). These results suggested that in oxLDL treated endothelial cells, LINC00657 acted as a miR-590-3p sponge to attenuate the suppression of miR-590-3p on HIF-1alpha, and to promote angiogenesis through VEGF, MMP-2, and MMP-9. The present study provided new insight into the roles of LINC00657 and miR-590-3p in preventing oxLDL-induced angiogenesis and may provide a novel strategy for atherosclerosis treatment. PMID- 29436492 TI - Allosterism within delta Opioid-kappa Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of kappa Opioid Agonist Efficacy. AB - There is abundant evidence for formation of G protein-coupled receptor heteromers in heterologous expression systems, but little is known of the function of heteromers in native systems. Heteromers of delta and kappa opioid receptors (DOR KOR heteromers) have been identified in native systems. We previously reported that activation of DOR-KOR heteromers expressed by rat pain-sensing neurons (nociceptors) produces robust, peripherally mediated antinociception. Moreover, DOR agonist potency and efficacy is regulated by KOR antagonists via allosteric interactions within the DOR-KOR heteromer in a ligand-dependent manner. Here we assessed the reciprocal regulation of KOR agonist function by DOR antagonists in adult rat nociceptors in culture and in a behavioral assay of nociception. Naltrindole enhanced the potency of the KOR agonist 2-(3,4-dichlorophenyl)-N methyl-N-[(1S)-1-phenyl-2-pyrrolidin-1-ylethyl]acetamide (ICI-199441) 10- to 20 fold, but did not alter responses to 2-(3,4-dichlorophenyl)-N-methyl-N-[(1R,2R)-2 pyrrolidin-1-ylcyclohexyl]acetamide (U50488). By contrast, the potency of U50488 was enhanced 20-fold by 7-benzylidenenaltrexone. The efficacy of 6' guanidinonaltrindole (6'-GNTI) to inhibit nociceptors was blocked by small interfering RNA knockdown of DOR or KOR. Replacing 6'-GNTI occupancy of DOR with either naltrindole or 7-benzylidenenaltrexone abolished 6'-GNTI efficacy. Further, peptides derived from DOR transmembrane segment 1 fused to the cell membrane-penetrating HIV transactivator of transcription peptide also blocked 6' GNTI-mediated responses ex vivo and in vivo, suggesting that 6'-GNTI efficacy in nociceptors is due to its positive allosteric regulation of KOR via occupancy of DOR in a DOR-KOR heteromer. Together, these results provide evidence for the existence of functional DOR-KOR heteromers in rat peripheral sensory neurons and that reciprocal, ligand-dependent allosteric interactions occur between the DOR and KOR protomers. PMID- 29436493 TI - G Protein Preassembly Rescues Efficacy of W6.48 Toggle Mutations in Neuropeptide Y2 Receptor. AB - Ligand binding and pathway-specific activation of G protein-coupled receptors is currently being studied with great effort. Individual answers may depend on the nature of the ligands and the effector pathway. Recently, we have presented a detailed model of neuropeptide Y bound to the Y2R. Accordingly, the C-terminal part of the peptide binds deeply in the transmembrane bundle and brings the side chain of the most essential Y36 in close proximity to W6.48 Here, we investigate the role of this interaction for ligand binding and activation of this receptor. BRET sensors were used for detailed investigation of effector coupling and led to the identification of preassembly of the Y2R-Gi complex. It further confirmed ligand-dependent recruitment of arrestin3. Using equally sensitive readouts for Gi activation and arrestin recruitment as well as quantification with operational models of agonism allowed us to identify a strong inherent bias for Gi activation over arrestin3 recruitment for the wild-type receptor. By systematic mutagenesis, we found that W6.48 does not contribute to the binding affinity, but acts as an allosteric connector to couple ligand binding to Gi activation and arrestin3 recruitment. However, even mutagenesis to a small threonine did not lead to a complete loss of signaling. Interestingly, signaling was restored to wild-type levels by ligands that contain a naphthylalanine as the C-terminal residue instead of Y36 Steric and polar contributions of W6.48 for the activation of the receptor are discussed in the context of different mechanisms of G protein coupling and arrestin recruitment. PMID- 29436494 TI - Evolutionary time drives global tetrapod diversity. AB - Global variation in species richness is widely recognized, but the explanation for what drives it continues to be debated. Previous efforts have focused on a subset of potential drivers, including evolutionary rate, evolutionary time (maximum clade age of species restricted to a region), dispersal (migration from one region to another), ecological factors and climatic stability. However, no study has evaluated these competing hypotheses simultaneously at a broad spatial scale. Here, we examine their relative contribution in determining the richness of the most comprehensive dataset of tetrapods to our knowledge (84% of the described species), distinguishing between the direct influences of evolutionary rate, evolutionary time and dispersal, and the indirect influences of ecological factors and climatic stability through their effect on direct factors. We found that evolutionary time exerted a primary influence on species richness, with evolutionary rate being of secondary importance. By contrast, dispersal did not significantly affect richness patterns. Ecological and climatic stability factors influenced species richness indirectly by modifying evolutionary time (i.e. persistence time) and rate. Overall, our findings suggest that global heterogeneity in tetrapod richness is explained primarily by the length of time species have had to diversify. PMID- 29436495 TI - Evidence for parent-of-origin effects and interparental conflict in seeds of an ancient flowering plant lineage. AB - Theoretical and empirical studies have long connected the evolutionary innovation of endosperm, a genetically biparental product of a double fertilization process unique to flowering plants (angiosperms), to conflicting parental interests over offspring provisioning. Yet, none of these studies examined interparental conflict in representatives of any of the most ancient angiosperm lineages. We performed reciprocal interploidy crosses in the water lily Nymphaea thermarum, a member of one of the most ancient angiosperm lineages, Nymphaeales. We find that an excess of paternal genomes is associated with an increase in endosperm growth. By contrast, maternal ploidy negatively influences development or growth of all seed components, regardless of paternal genome dosage. Most relevant to the conflict over distribution of maternal resources, however, is that growth of the perisperm (seed storage tissue derived from the maternal sporophyte, found in all Nymphaeales) is unaffected by paternal genome dosage-ensuring maternal control of maternal resources. We conclude that the evolutionary transfer of embryo nourishing function from a genetically biparental endosperm to a genetically maternal perisperm can be viewed as an effective maternal strategy to recapture control of resource distribution among progeny, and thus that interparental conflict has influenced the evolution of seed development in this ancient angiosperm lineage. PMID- 29436496 TI - Repeatable group differences in the collective behaviour of stickleback shoals across ecological contexts. AB - Establishing how collective behaviour emerges is central to our understanding of animal societies. Previous research has highlighted how universal interaction rules shape collective behaviour, and that individual differences can drive group functioning. Groups themselves may also differ considerably in their collective behaviour, but little is known about the consistency of such group variation, especially across different ecological contexts that may alter individuals' behavioural responses. Here, we test if randomly composed groups of sticklebacks differ consistently from one another in both their structure and movement dynamics across an open environment, an environment with food, and an environment with food and shelter. Based on high-resolution tracking data of the free swimming shoals, we found large context-associated changes in the average behaviour of the groups. But despite these changes and limited social familiarity among group members, substantial and predictable behavioural differences between the groups persisted both within and across the different contexts (group-level repeatability): some groups moved consistently faster, more cohesively, showed stronger alignment and/or clearer leadership than other groups. These results suggest that among-group heterogeneity could be a widespread feature in animal societies. Future work that considers group-level variation in collective behaviour may help understand the selective pressures that shape how animal collectives form and function. PMID- 29436497 TI - Genomics of end-Pleistocene population replacement in a small mammal. AB - Current species distributions at high latitudes are the product of expansion from glacial refugia into previously uninhabitable areas at the end of the last glaciation. The traditional view of postglacial colonization is that southern populations expanded their ranges into unoccupied northern territories. Recent findings on mitochondrial DNA (mtDNA) of British small mammals have challenged this simple colonization scenario by demonstrating a more complex genetic turnover in Britain during the Pleistocene-Holocene transition where one mtDNA clade of each species was replaced by another mtDNA clade of the same species. Here, we provide evidence from one of those small mammals, the bank vole (Clethrionomys glareolus), that the replacement was genome-wide. Using more than 10 000 autosomal SNPs we found that similar to mtDNA, bank vole genomes in Britain form two (north and south) clusters which admix. Therefore, the genome of the original postglacial colonists (the northern cluster) was probably replaced by another wave of migration from a different continental European population (the southern cluster), and we gained support for this by modelling with approximate Bayesian computation. This finding emphasizes the importance of analysis of genome-wide diversity within species under changing climate in creating opportunities for sophisticated testing of population history scenarios. PMID- 29436498 TI - Rapid juvenile hormone downregulation in subordinate wasp queens facilitates stable cooperation. AB - In many cooperatively breeding animals, subordinate group members have lower reproductive capacity than dominant group members. Theory suggests subordinates may downregulate their reproductive capacity because dominants punish subordinates who maintain high fertility. However, there is little direct experimental evidence that dominants cause physiological suppression in subordinates. Here, we experimentally test how social interactions influence subordinate reproductive hormones in Polistes dominula paper wasps. Polistes dominula queens commonly found nests in cooperative groups where the dominant queen is more fertile than the subordinate queen. In this study, we randomly assigned wasps to cooperative groups, assessed dominance behaviour during group formation, then measured levels of juvenile hormone (JH), a hormone that mediates Polistes fertility. Within three hours, lowest ranking subordinates had less JH than dominants or solitary controls, indicating that group formation caused rapid JH reduction in low-ranking subordinates. In a second experiment, we measured the behavioural consequences of experimentally increasing subordinate JH. Subordinates with high JH-titres received significantly more aggression than control subordinates or subordinates from groups where the dominant's JH was increased. These results suggest that dominants aggressively punished subordinates who attempted to maintain high fertility. Low-ranked subordinates may rapidly downregulate reproductive capacity to reduce costly social interactions with dominants. Rapid modulation of subordinate reproductive physiology may be an important adaptation to facilitate the formation of stable, cooperative groups. PMID- 29436500 TI - Seed ingestion and germination in rattlesnakes: overlooked agents of rescue and secondary dispersal. AB - Seed dispersal is a key evolutionary process and a central theme in the population ecology of terrestrial plants. The primary producers of most land based ecosystems are propagated by and maintained through various mechanisms of seed dispersal that involve both abiotic and biotic modes of transportation. By far the most common biotic seed transport mechanism is zoochory, whereby seeds, or fruits containing them, are dispersed through the activities of animals. Rodents are one group of mammals that commonly prey on seeds (granivores) and play a critical, often destructive, role in primary dispersal and the dynamics of plant communities. In North America, geomyid, heteromyid and some sciurid rodents have specialized cheek pouches for transporting seeds from plant source to larder, where they are often eliminated from the pool of plant propagules by consumption. These seed-laden rodents are commonly consumed by snakes as they forage, but unlike raptors, coyotes, bobcats, and other endothermic predators which eat rodents and are known or implicated to be secondary seed dispersers, the role of snakes in seed dispersal remains unexplored. Here, using museum preserved specimens, we show that in nature three desert-dwelling rattlesnake species consumed heteromyids with seeds in their cheek pouches. By examining the entire gut we discovered, furthermore, that secondarily ingested seeds can germinate in rattlesnake colons. In terms of secondary dispersal, rattlesnakes are best described as diplochorous. Because seed rescue and secondary dispersal in snakes has yet to be investigated, and because numerous other snake species consume granivorous and frugivorous birds and mammals, our observations offer direction for further empirical studies of this unusual but potentially important channel for seed dispersal. PMID- 29436499 TI - Profound genetic divergence and asymmetric parental genome contributions as hallmarks of hybrid speciation in polyploid toads. AB - The evolutionary causes and consequences of allopolyploidization, an exceptional pathway to instant hybrid speciation, are poorly investigated in animals. In particular, when and why hybrid polyploids versus diploids are produced, and constraints on sources of paternal and maternal ancestors, remain underexplored. Using the Palearctic green toad radiation (including bisexually reproducing species of three ploidy levels) as model, we generate a range-wide multi-locus phylogeny of 15 taxa and present four new insights: (i) at least five (up to seven) distinct allotriploid and allotetraploid taxa have evolved in the Pleistocene; (ii) all maternal and paternal ancestors of hybrid polyploids stem from two deeply diverged nuclear clades (6 Mya, 3.1-9.6 Mya), with distinctly greater divergence than the parental species of diploid hybrids found at secondary contact zones; (iii) allotriploid taxa possess two conspecific genomes and a deeply diverged allospecific one, suggesting that genomic imbalance and divergence are causal for their partly clonal reproductive mode; (iv) maternal versus paternal genome contributions exhibit asymmetry, with the maternal nuclear (and mitochondrial) genome of polyploids always coming from the same clade, and the paternal genome from the other. We compare our findings with similar patterns in diploid/polyploid vertebrates, and suggest deep ancestral divergence as a precondition for successful allopolyploidization. PMID- 29436501 TI - Foraging and fasting can influence contaminant concentrations in animals: an example with mercury contamination in a free-ranging marine mammal. AB - Large fluctuations in animal body mass in relation to life-history events can influence contaminant concentrations and toxicological risk. We quantified mercury concentrations in adult northern elephant seals (Mirounga angustirostris) before and after lengthy at sea foraging trips (n = 89) or fasting periods on land (n = 27), and showed that mercury concentrations in blood and muscle changed in response to these events. The highest blood mercury concentrations were observed after the breeding fast, whereas the highest muscle mercury concentrations were observed when seals returned to land to moult. Mean female blood mercury concentrations decreased by 30% across each of the two annual foraging trips, demonstrating a foraging-associated dilution of mercury concentrations as seals gained mass. Blood mercury concentrations increased by 103% and 24% across the breeding and moulting fasts, respectively, demonstrating a fasting-associated concentration of mercury as seals lost mass. In contrast to blood, mercury concentrations in female's muscle increased by 19% during the post breeding foraging trip and did not change during the post-moulting foraging trip. While fasting, female muscle mercury concentrations increased 26% during breeding, but decreased 14% during moulting. Consequently, regardless of exposure, an animal's contaminant concentration can be markedly influenced by their annual life-history events. PMID- 29436503 TI - Diversity change during the rise of tetrapods and the impact of the 'Carboniferous rainforest collapse'. AB - The Carboniferous and early Permian were critical intervals in the diversification of early four-limbed vertebrates (tetrapods), yet the major patterns of diversity and biogeography during this time remain unresolved. Previous estimates suggest that global tetrapod diversity rose continuously across this interval and that habitat fragmentation following the 'Carboniferous rainforest collapse' (CRC) drove increased endemism among communities. However, previous work failed to adequately account for spatial and temporal biases in sampling. Here, we reassess early tetrapod diversity and biogeography with a new global species-level dataset using sampling standardization and network biogeography methods. Our results support a tight relationship between observed richness and sampling, particularly during the Carboniferous. We found that subsampled species richness initially increased into the late Carboniferous, then decreased substantially across the Carboniferous/Permian boundary before slowly recovering in the early Permian. Our analysis of biogeography does not support the hypothesis that the CRC drove endemism; instead, we found evidence for increased cosmopolitanism in the early Permian. While a changing environment may have played a role in reducing diversity in the earliest Permian, our results suggest that the CRC was followed by increased global connectivity between communities, possibly reflecting both reduced barriers to dispersal and the diversification of amniotes. PMID- 29436502 TI - How oxygen gave rise to eukaryotic sex. AB - How did full meiotic eukaryotic sex evolve and what was the immediate advantage allowing it to develop? We propose that the crucial determinant can be found in internal reactive oxygen species (ROS) formation at the start of eukaryotic evolution approximately 2 * 109 years ago. The large amount of ROS coming from a bacterial endosymbiont gave rise to DNA damage and vast increases in host genome mutation rates. Eukaryogenesis and chromosome evolution represent adaptations to oxidative stress. The host, an archaeon, most probably already had repair mechanisms based on DNA pairing and recombination, and possibly some kind of primitive cell fusion mechanism. The detrimental effects of internal ROS formation on host genome integrity set the stage allowing evolution of meiotic sex from these humble beginnings. Basic meiotic mechanisms thus probably evolved in response to endogenous ROS production by the 'pre-mitochondrion'. This alternative to mitosis is crucial under novel, ROS-producing stress situations, like extensive motility or phagotrophy in heterotrophs and endosymbiontic photosynthesis in autotrophs. In multicellular eukaryotes with a germline-soma differentiation, meiotic sex with diploid-haploid cycles improved efficient purging of deleterious mutations. Constant pressure of endogenous ROS explains the ubiquitous maintenance of meiotic sex in practically all eukaryotic kingdoms. Here, we discuss the relevant observations underpinning this model. PMID- 29436504 TI - Deep-sea starfish from the Arctic have well-developed eyes in the dark. AB - Asteroids, starfish, are important members of the macro-benthos in almost all marine environments including the deep sea. Starfish are in general assumed to be largely olfactory guided, but recent studies have shown that two tropical shallow water species rely on vision alone to find their habitat at short distances. Their compound eyes are found at the tip of each arm and they vary little between examined species. Still, nothing is known about vision in the species found in the aphotic zone of the deep sea or whether they even have eyes. Here, 13 species of starfish from Greenland waters, covering a depth range from shallow waters to the deep sea below 1000 m, were examined for the presence of eyes and optical and morphological examinations were used to estimate the quality of vision. Further, species found in the aphotic zone below 320 m were checked for bioluminescence. All species, except the infaunal Ctenodiscus crispatus, had eyes, and two were found to be bioluminescent. Interestingly, one of the species found in the aphotic zone, Novodinia americana, had close to the highest spatial resolution known for starfish eyes along with being bioluminescent. Accordingly, we hypothesize that this species communicates visually using bioluminescent flashes putatively for reproductive purposes. Other species have greatly enhanced sensitivity with few large ommatidia but at the sacrifice of spatial resolution. The discovery of eyes in deep-sea starfish with a huge variation in optical quality and sensitivity indicates that their visual ecology also differs greatly. PMID- 29436505 TI - 'Drip-and-drive': shipping the neurointerventionalist to provide mechanical thrombectomy in primary stroke centers. AB - BACKGROUND: To satisfy the increasing demand of mechanical thrombectomy (MT) for acute ischemic stroke treatment, new organizational concepts for patient care are required. This study evaluates time intervals of acute stroke management in two stroke care models, including one based on transportation of the interventionalist from a comprehensive stroke center (CSC) to treat patients in two primary stroke centers (PSC). We hypothesized that time intervals were not inferior for the 'drip-and-drive' concept compared with the traditional 'drip-and ship' concept. METHODS: Patients treated with MT at the PSC ('drip-and-drive', 'D+D group') were compared with patients transferred from PSC to CSC for MT ('drip-and-ship', 'D+S group') with regard to time delays. Time intervals assessed were: symptom onset to initial CT, to angiography, and to recanalization; time from initial CT to telephone call activation, to arrival, and to angiography; and time from telephone call activation to arrival and from arrival to angiography. RESULTS: 42 patients were treated at the PSC after transfer of the interventionalist, and 32 patients were transferred to the CSC for MT. The groups did not differ with regard to median Onset-CT and CT-Phone times. Significant differences between the groups were found for the primary outcome measure CT-Arrival time ('D+D group': median 121 (IQR 108-134) min vs 181 (157-219) min for the 'D+S group'; P<0.001). Time difference between the groups increased to more than 2 hours for median CT-Angio times (median 123 (IQR 93-147) min vs 252 (228-275) min; P<0.001). CONCLUSION: Time intervals for the 'D+D group' were not inferior to those of the 'D+S group'. Moreover, under certain conditions, the 'drip-and-drive' concept might even be superior. PMID- 29436506 TI - Non-enhanced MR imaging for preinterventional assessment of the angioarchitecture in vein of Galen malformations. AB - BACKGROUND AND PURPOSE: Endovascular treatment of vein of Galen malformations (VGMs) requires sufficient preceding MR imaging. Standardized, preinterventional, non-invasive imaging has not been established. Our study is the first to examine the role of a dedicated, standardized, non-invasive imaging protocol in the evaluation of VGM angioarchitecture by non-contrast MRI/MR angiography. MATERIALS AND METHODS: We retrospectively evaluated a consecutive series of VGM patients who underwent a 1.5 T MRI protocol, including standard T2 weighted images (T2WI), arterial time of flight (TOF), and thin T2WI without flow compensation (T2OffPh). The primary outcome was the proportion of patients in whom VGM subtypes and all arterial feeders (anterior (AChA) and posterior (PChA) choroidal arteries, pericallosal arteries, basilar tip, and leptomeningeal supply) could be accurately identified compared with a DSA gold standard. RESULTS: A total of 26 VGM patients who underwent 108 studies were used in the statistical analysis. VGM subtype was best seen in axial T2OffPh (92.1%) and TOF (89.8%). AChA feeders were best seen in TOF (86.5%) and axial T2OffPh (72.2%). PChA feeders were best seen in TOF (95.1%) and axial T2OffPh (88.1%). Pericallosal feeders were best seen in axial T2OffPh (95.4%) and TOF (95.1%). Basilar tip feeders were best seen in TOF (90.6%) and axial T2OffPh (88.4%). CONCLUSION: VGM angioarchitecture is best seen in TOF and axial T2OffPh. It can be used as an alternative to global angiographic series. PMID- 29436507 TI - A multiscale active structural model of the arterial wall accounting for smooth muscle dynamics. AB - Arterial wall dynamics arise from the synergy of passive mechano-elastic properties of the vascular tissue and the active contractile behaviour of smooth muscle cells (SMCs) that form the media layer of vessels. We have developed a computational framework that incorporates both these components to account for vascular responses to mechanical and pharmacological stimuli. To validate the proposed framework and demonstrate its potential for testing hypotheses on the pathogenesis of vascular disease, we have employed a number of pharmacological probes that modulate the arterial wall contractile machinery by selectively inhibiting a range of intracellular signalling pathways. Experimental probes used on ring segments from the rabbit central ear artery are: phenylephrine, a selective alpha1-adrenergic receptor agonist that induces vasoconstriction; cyclopiazonic acid (CPA), a specific inhibitor of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; and ryanodine, a diterpenoid that modulates Ca2+ release from the sarcoplasmic reticulum. These interventions were able to delineate the role of membrane versus intracellular signalling, previously identified as main factors in smooth muscle contraction and the generation of vessel tone. Each SMC was modelled by a system of nonlinear differential equations that account for intracellular ionic signalling, and in particular Ca2+ dynamics. Cytosolic Ca2+ concentrations formed the catalytic input to a cross-bridge kinetics model. Contractile output from these cellular components forms the input to the finite element model of the arterial rings under isometric conditions that reproduces the experimental conditions. The model does not account for the role of the endothelium, as the nitric oxide production was suppressed by the action of L NAME, and also due to the absence of shear stress on the arterial ring, as the experimental set-up did not involve flow. Simulations generated by the integrated model closely matched experimental observations qualitatively, as well as quantitatively within a range of physiological parametric values. The model also illustrated how increased intercellular coupling led to smooth muscle coordination and the genesis of vascular tone. PMID- 29436508 TI - How humans transmit language: horizontal transmission matches word frequencies among peers on Twitter. AB - Language transmission, the passing on of language features such as words between people, is the process of inheritance that underlies linguistic evolution. To understand how language transmission works, we need a mechanistic understanding based on empirical evidence of lasting change of language usage. Here, we analysed 200 million online conversations to investigate transmission between individuals. We find that the frequency of word usage is inherited over conversations, rather than only the binary presence or absence of a word in a person's lexicon. We propose a mechanism for transmission whereby for each word someone encounters there is a chance they will use it more often. Using this mechanism, we measure that, for one word in around every hundred a person encounters, they will use that word more frequently. As more commonly used words are encountered more often, this means that it is the frequencies of words which are copied. Beyond this, our measurements indicate that this per-encounter mechanism is neutral and applies without any further distinction as to whether a word encountered in a conversation is commonly used or not. An important consequence of this is that frequencies of many words can be used in concert to observe and measure language transmission, and our results confirm this. These results indicate that our mechanism for transmission can be used to study language patterns and evolution within populations. PMID- 29436509 TI - Tracking random walks. AB - In empirical studies, trajectories of animals or individuals are sampled in space and time. Yet, it is unclear how sampling procedures bias the recorded data. Here, we consider the important case of movements that consist of alternating rests and moves of random durations and study how the estimate of their statistical properties is affected by the way we measure them. We first discuss the ideal case of a constant sampling interval and short-tailed distributions of rest and move durations, and provide an exact analytical calculation of the fraction of correctly sampled trajectories. Further insights are obtained with simulations using more realistic long-tailed rest duration distributions showing that this fraction is dramatically reduced for real cases. We test our results for real human mobility with high-resolution GPS trajectories, where a constant sampling interval allows one to recover at best 18% of the movements, while over evaluating the average trip length by a factor of 2. Using a sampling interval extracted from real communication data, we recover only 11% of the moves, a value that cannot be increased above 16% even with ideal algorithms. These figures call for a more cautious use of data in quantitative studies of individuals' movements. PMID- 29436510 TI - Hidden Markov models for monitoring circadian rhythmicity in telemetric activity data. AB - Wearable computing devices allow collection of densely sampled real-time information on movement enabling researchers and medical experts to obtain objective and non-obtrusive records of actual activity of a subject in the real world over many days. Our interest here is motivated by the use of activity data for evaluating and monitoring the circadian rhythmicity of subjects for research in chronobiology and chronotherapeutic healthcare. In order to translate the information from such high-volume data arising we propose the use of a Markov modelling approach which (i) naturally captures the notable square wave form observed in activity data along with heterogeneous ultradian variances over the circadian cycle of human activity, (ii) thresholds activity into different states in a probabilistic way while respecting time dependence and (iii) gives rise to circadian rhythm parameter estimates, based on probabilities of transitions between rest and activity, that are interpretable and of interest to circadian research. PMID- 29436511 TI - Analysing the structure and glass transition behaviour of silks for archaeology and conservation. AB - Silk is an iconic material in many cultures. Silk archaeology and conservation is affected by silk production technology as well as subsequent environmental effects such as humidity, temperature, UV radiation and ageing. The complex interactions and various effects on silk materials affect the practical use of silk, for example, in the conservation of ancient manuscripts. This study examines the various influences of silk provenance and processing, adhesive coatings and chemical treatments as well as natural and artificial ageing of the silk material. We use infrared spectroscopy (FTIR) and dynamic mechanical thermal analysis to investigate the glass transition behaviours in a range of archaeological and control silk samples. This allows us to establish structural differences in century-old museum silks and predict the effects of silk ageing and degradation. PMID- 29436512 TI - Shark skin-inspired designs that improve aerodynamic performance. AB - There have been significant efforts recently aimed at improving the aerodynamic performance of aerofoils through the modification of their surfaces. Inspired by the drag-reducing properties of the tooth-like denticles that cover the skin of sharks, we describe here experimental and simulation-based investigations into the aerodynamic effects of novel denticle-inspired designs placed along the suction side of an aerofoil. Through parametric modelling to query a wide range of different designs, we discovered a set of denticle-inspired surface structures that achieve simultaneous drag reduction and lift generation on an aerofoil, resulting in lift-to-drag ratio improvements comparable to the best-reported for traditional low-profile vortex generators and even outperforming these existing designs at low angles of attack with improvements of up to 323%. Such behaviour is enabled by two concurrent mechanisms: (i) a separation bubble in the denticle's wake altering the flow pressure distribution of the aerofoil to enhance suction and (ii) streamwise vortices that replenish momentum loss in the boundary layer due to skin friction. Our findings not only open new avenues for improved aerodynamic design, but also provide new perspective on the role of the complex and potentially multifunctional morphology of shark denticles for increased swimming efficiency. PMID- 29436513 TI - Overcoming clofazimine intrinsic toxicity: statistical modelling and characterization of solid lipid nanoparticles. AB - The aim of this work was to develop solid lipid nanoparticles (SLNs) loaded with clofazimine (CLZ) (SLNs-CLZ) to overcome its intrinsic toxicity and low water solubility, for oral drug delivery. A Box-Behnken design was constructed to unravel the relations between the independent variables in the selected responses. The optimized SLNs-CLZ exhibited the following properties: particle size ca 230 nm, zeta potential of -34.28 mV, association efficiency of 72% and drug loading of 2.4%, which are suitable for oral delivery. Further characterization included Fourier transformed infrared spectroscopy that confirmed the presence of the drug and the absence of chemical interactions. By differential scanning calorimetry was verified the amorphous state of CLZ. The storage stability studies ensured the stability of the systems over a period of 12 weeks at 4 degrees C. In vitro cytotoxicity studies evidenced no effect of both drug-loaded and unloaded SLNs on MKN-28 gastric cells and on intestinal cells, namely Caco-2 and HT29-MTX cells up to 25 ug ml-1 in CLZ. Free CLZ solutions exhibited IC50 values of 16 and 20 ug ml-1 for Caco-2 and HT29-MTX cells, respectively. It can be concluded that the optimized system, designed considering important variables for the formulation of poorly soluble drugs, represents a promising platform for oral CLZ delivery. PMID- 29436514 TI - Small cities face greater impact from automation. AB - The city has proved to be the most successful form of human agglomeration and provides wide employment opportunities for its dwellers. As advances in robotics and artificial intelligence revive concerns about the impact of automation on jobs, a question looms: how will automation affect employment in cities? Here, we provide a comparative picture of the impact of automation across US urban areas. Small cities will undertake greater adjustments, such as worker displacement and job content substitutions. We demonstrate that large cities exhibit increased occupational and skill specialization due to increased abundance of managerial and technical professions. These occupations are not easily automatable, and, thus, reduce the potential impact of automation in large cities. Our results pass several robustness checks including potential errors in the estimation of occupational automation and subsampling of occupations. Our study provides the first empirical law connecting two societal forces: urban agglomeration and automation's impact on employment. PMID- 29436515 TI - Realizing 'integral control' in living cells: how to overcome leaky integration due to dilution? AB - A major problem in the design of synthetic genetic circuits is robustness to perturbations and uncertainty. Because of this, there have been significant efforts in recent years in finding approaches to implement integral control in genetic circuits. Integral controllers have the unique ability to make the output of a process adapt perfectly to disturbances. However, implementing an integral controller is challenging in living cells. This is because a key aspect of any integral controller is a 'memory' element that stores the accumulation (integral) of the error between the output and its desired set-point. The ability to realize such a memory element in living cells is fundamentally challenged by the fact that all biomolecules dilute as cells grow, resulting in a 'leaky' memory that gradually fades away. As a consequence, the adaptation property is lost. Here, we propose a general principle for designing integral controllers such that the performance is practically unaffected by dilution. In particular, we mathematically prove that if the reactions implementing the integral controller are all much faster than dilution, then the adaptation error due to integration leakiness becomes negligible. We exemplify this design principle with two synthetic genetic circuits aimed at reaching adaptation of gene expression to fluctuations in cellular resources. Our results provide concrete guidance on the biomolecular processes that are most appropriate for implementing integral controllers in living cells. PMID- 29436518 TI - Synthesis of KMnO4-treated magnetic graphene oxide nanocomposite (Fe3O4@GO/MnO x ) and its application for removing of Cu2+ ions from aqueous solution. AB - A magnetic KMnO4-treated graphene-oxide-based nanocomposite, Fe3O4@GO/MnO x , was synthesized through a facile hydrothermal technique. The properties of the Fe3O4@GO/MnO x nanocomposite were characterized by SEM, XRD and FTIR. Batch experiments showed that the maximum adsorption capacity calculated by the Langmuir model for Cu2+ was 62.65 mg g-1 at T = 303.15 K. Kinetics and XPS analysis also revealed that the mechanism of Cu2+ removal was mainly a chemical adsorption process involving both the MnO x particles and oxygen functional groups. The prepared Fe3O4@GO/MnO x was found to be an ideal adsorbent for the removal of Cu2+ ions due to the MnO x particle coating, and was easily separated using a magnetic field after utilization. Reusability studies imply that Fe3O4@GO/MnO x is a suitable material for heavy metal ion removal from aqueous solutions in real applications. PMID- 29436516 TI - Protein Kinase 2beta Is Expressed in Neural Crest-Derived Urinary Pacemaker Cells and Required for Pyeloureteric Contraction. AB - Nonobstructive hydronephrosis, defined as dilatation of the renal pelvis with or without dilatation of the ureter, is the most common antenatal abnormality detected by fetal ultrasound. Yet, the etiology of nonobstructive hydronephrosis is poorly defined. We previously demonstrated that defective development of urinary tract pacemaker cells (utPMCs) expressing hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) and the stem cell marker cKIT causes abnormal ureteric peristalsis and nonobstructive hydronephrosis. However, further investigation of utPMC development and function is limited by lack of knowledge regarding the embryonic derivation, development, and molecular apparatus of these cells. Here, we used lineage tracing in mice to identify cells that give rise to utPMCs. Neural crest cells (NCCs) indelibly labeled with tdTomato expressed HCN3 and cKIT. Furthermore, purified HCN3+ and cKIT+ utPMCs were enriched in Sox10 and Tfap-2alpha, markers of NCCs. Sequencing of purified RNA from HCN3+ cells revealed enrichment of a small subset of RNAs, including RNA encoding protein kinase 2beta (PTK2beta), a Ca2+-dependent tyrosine kinase that regulates ion channel activity in neurons. Immunofluorescence analysis in situ revealed PTK2beta expression in NCCs as early as embryonic day 12.5 and in HCN3+ and cKIT+ utPMCs as early as embryonic day 15.5, with sustained expression in HCN3+ utPMCs until postnatal week 8. Pharmacologic inhibition of PTK2beta in murine pyeloureteral tissue explants inhibited contraction frequency. Together, these results demonstrate that utPMCs are derived from NCCs, identify new markers of utPMCs, and demonstrate a functional contribution of PTK2beta to utPMC function. PMID- 29436517 TI - Endogenous IL-33 Contributes to Kidney Ischemia-Reperfusion Injury as an Alarmin. AB - Inflammation is a prominent feature of ischemia-reperfusion injury (IRI), which is characterized by leukocyte infiltration and renal tubular injury. However, signals that initiate these events remain poorly understood. We examined the role of the nuclear alarmin IL-33 in tissue injury and innate immune response triggered by experimental kidney ischemia-reperfusion. In wild-type mice, we found that IL-33 was constitutively expressed throughout the kidney in peritubular and periglomerular spaces, mainly by microvascular endothelial cells, from which it was released immediately during IRI. Compared with wild-type mice, mice lacking IL-33 (IL-33Gt/Gt) exhibited reductions in early tubular cell injury and subsequent renal infiltration of IFN-gamma/IL-17A-producing neutrophils, with preservation of renal functions. This protection associated with decreased renal recruitment of myeloid dendritic cells, natural killer (NK) cells, and invariant natural killer T (iNKT) cells, the latter of which were reported as deleterious in IRI. Increases in the level of circulating IL-12, a key IL-33 cofactor, and the expression of ST2, an IL-33-specific receptor, on the surface of iNKT cells preceded the IL-33- and iNKT cell-dependent phase of neutrophil infiltration. Furthermore, IL-33 directly targeted iNKT cells in vitro, inducing IFN-gamma and IL-17A production. We propose that endogenous IL-33 is released as an alarmin and contributes to kidney IRI by promoting iNKT cell recruitment and cytokine production, resulting in neutrophil infiltration and activation at the injury site. Our findings show a novel molecular mediator contributing to innate immune cell recruitment induced by renal ischemia-reperfusion and may provide therapeutic insights into AKI associated with renal transplantation. PMID- 29436519 TI - Low-intensity focused ultrasound alters the latency and spatial patterns of sensory-evoked cortical responses in vivo. AB - OBJECTIVE: The use of transcranial, low intensity focused ultrasound (FUS) is an emerging neuromodulation technology that shows promise for both therapeutic and research applications. Among many, one of the most exciting applications is the use of FUS to rehabilitate or augment human sensory capabilities. While there is compelling empirical evidence demonstrating this capability, basic questions regarding the spatiotemporal extent of the modulatory effects remain. Our objective was to assess the basic, yet often overlooked hypothesis that FUS in fact alters sensory-evoked neural activity within the region of the cerebral cortex at the beam's focus. APPROACH: To address this knowledge gap, we developed an approach to optically interrogate patterns of neural activity in the cortex directly at the acoustic focus, in vivo. Implementing simultaneous wide-field optical imaging and FUS stimulation in mice, our experiments probed somatosensory evoked electrical activity through the use of voltage sensitive dyes (VSDs) and, in transgenic mice expressing GCaMP6f, monitored associated Ca2+ responses. MAIN RESULTS: Our results demonstrate that low-intensity FUS alters both the kinetics and spatial patterns of neural activity in primary somatosensory cortex at the acoustic focus. When preceded by 1 s of pulsed ultrasound at intensities below 1 W cm-2 (I sppa), the onset of sensory-evoked cortical responses occurred 3.0 +/- 0.7 ms earlier and altered the surface spatial morphology of Ca2+ responses. SIGNIFICANCE: These findings support the heretofore unconfirmed assumption that FUS-induced sensory modulation reflects, at least in part, altered reactivity in primary sensory cortex at the site of sonication. The findings are significant given the interest in using FUS to target and alter spatial aspects of sensory receptive fields on the cerebral cortex. PMID- 29436521 TI - How did they do that? PMID- 29436520 TI - Insulin Resistance Is Associated with Interleukin 1beta (IL-1beta) in Non Diabetic Hemodialysis Patients. AB - BACKGROUND Insulin resistance (IR) and inflammation are associated with increased risk of complications in chronic kidney disease (CKD) patients. However, the relationship between IR and the important proinflammatory interleukin-1beta (IL 1beta) is unclear in CKD patients. MATERIAL AND METHODS We conducted a cross sectional study including 79 non-diabetic patients who received hemodialysis after the exclusion process. Homeostasis model assessment (HOMA-IR) and leptin adiponectin ratio (LAR) were used to evaluate IR. Inflammation was assessed through C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-1beta evaluation. We tested associations of IR with IL 1beta using logistic analysis and linear regression. RESULTS Patients were divided into a HOMA-IR-positive group and a HOMA-IR-negative group. Although there were no differences between the 2 groups in terms of etiological causes, age, sex, BMI, triglyceride, cholesterol, ferritin, uric acid, and inflammatory indicators such as CRP, we found that IL-6, TNF-alpha, and IL-1beta were significantly increased in the HOMA-IR-positive group compared with the HOMA-IR negative group. Moreover, IL-1beta contributed to HOMA-IR positivity and was positively correlated with LAR after adjusting for possible confounding factors. CONCLUSIONS Insulin resistance correlates positively with IL-1beta among non diabetic hemodialysis patients, which suggests that IL-1beta may be involved in the pathogenesis of IR in this setting. PMID- 29436522 TI - Correction: All-cause mortality in adults with and without type 2 diabetes: findings from the national health monitoring in Germany. AB - [This corrects the article DOI: 10.1136/bmjdrc-2017-000451.][This corrects the article DOI: 10.1136/bmjdrc-2017-000451.]. PMID- 29436523 TI - Correction to: The Strengths and Difficulties Questionnaire (SDQ) in Africa: a scoping review of its application and validation. AB - [This corrects the article DOI: 10.1186/s13034-017-0212-1.]. PMID- 29436524 TI - Clinician's Commentary on Oliveira et al.1. PMID- 29436525 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/0018578717720507.]. PMID- 29436526 TI - Correction to: Effect of long non-coding RNA Gas5 on proliferation, migration, invasion and apoptosis of colorectal cancer HT-29 cell line. AB - [This corrects the article DOI: 10.1186/s12935-017-0478-7.]. PMID- 29436527 TI - Corrigendum: Pathogenicity of Human ST23 Streptococcus agalactiae to Fish and Genomic Comparison of Pathogenic and Non-pathogenic Isolates. AB - [This corrects the article on p. 1933 in vol. 8, PMID: 29056932.]. PMID- 29436528 TI - Clinician's Commentary on Baldwin et al.1. PMID- 29436529 TI - Clinician's Commentary on Wideman et al.1. PMID- 29436530 TI - Clinician's Commentary on Hui et al.1. PMID- 29436531 TI - The new "cold war" is a reality. PMID- 29436532 TI - Correction: Diagnostic performance enhancement of pancreatic cancer using proteomic multimarker panel. AB - [This corrects the article DOI: 10.18632/oncotarget.21861.]. PMID- 29436533 TI - Corrigendum to "Metabolic Syndrome, Inflammation, and Cancer". AB - [This corrects the article DOI: 10.1155/2017/8259356.]. PMID- 29436534 TI - Corrigendum: Characterization of Metagenomes in Urban Aquatic Compartments Reveals High Prevalence of Clinically Relevant Antibiotic Resistance Genes in Wastewaters. AB - [This corrects the article on p. 2200 in vol. 8, PMID: 29201017.]. PMID- 29436535 TI - Small stoichiometric (MoS2)n clusters with the 1T phase. AB - Stoichiometric (MoS2)n clusters (n = 1-6) were systematically studied by density functional theory calculations with hybrid B3LYP and pure GGA PW91 functionals. The most stable structures of these clusters were obtained by global optimizations with a genetic algorithm. A triangle of Mo3 capped with a S atom was found to be a favourite building block, which can construct the most stable structures (or at least candidates) for n = 3-6 clusters. These types of structures can be viewed as fragments of MoS2 monolayer with the 1T phase, which is an important phase that has unique reactivity and conductivity properties. Electronic structures were analyzed by means of density of states and frontier molecular orbitals (FMOs), which suggest that both Mo and S contribute to the FMOs below the Fermi energy while Mo atoms contribute more toward the unoccupied FMOs. PMID- 29436536 TI - Quantum dots for a high-throughput Pfu polymerase based multi-round polymerase chain reaction (PCR). AB - Multi-round PCR is an important technique for obtaining enough target DNA from rare DNA resources, and is commonly used in many fields including forensic science, ancient DNA analysis and cancer research. However, multi-round PCR is often aborted, largely due to the accumulation of non-specific amplification during repeated amplifications. Here, we developed a Pfu polymerase based multi round PCR technique assisted by quantum dots (QDs). Different PCR assays, DNA polymerases (Pfu and Taq), DNA sizes and GC amounts were compared in this study. In the presence of QDs, PCR specificity could be retained even in the ninth-round amplification. Moreover, the longer and more complex the targets were, the earlier the abortion happened in multi-round PCR. However, no obvious enhancement of specificity was found in multi-round PCR using Taq DNA polymerase. Significantly, the fidelity of Pfu polymerase based multi-round PCR was not sacrificed in the presence of QDs. Besides, pre-incubation at 50 degrees C for an hour had no impact on multi-round PCR performance, which further authenticated the hot start effect of QDs modulated in multi-round PCR. The findings of this study demonstrated that a cost-effective and promising multi-round PCR technique for large-scale and high-throughput sample analysis could be established with high specificity, sensibility and accuracy. PMID- 29436537 TI - Photosensitizer-induced self-assembly of antigens as nanovaccines for cancer immunotherapy. AB - Herein, the photosensitizer indocyanine green (ICG) is used to induce the self assembly of antigens to form nanovaccines. Under near-infrared (NIR) laser irradiation, reactive oxygen species can be generated by nanovaccines to disrupt the membranes of endo/lysosomes, which helps to release antigens into the cytosol efficiently, thereby enhancing antigen cross-presentation and anti-cancer immunity. To the best of our knowledge, this study represents the first example of ICG as a biocompatible adjuvant to improve cancer vaccine efficacy. PMID- 29436538 TI - Sulfur nanocomposite as a positive electrode material for rechargeable potassium sulfur batteries. AB - A pyrolyzed polyacrylonitrile/sulfur nanocomposite (SPAN) was used as a positive electrode material for a room temperature K-S battery operated in carbonate electrolyte. SPAN presented a high reversible capacity of 270 mA h g-1 (710 mA h gsulfur-1) and excellent rate performance, which demonstrate that it is a promising positive electrode material for K-ion and K-batteries. PMID- 29436539 TI - Insights into the enhanced photoelectrochemical performance of hydrothermally controlled hematite nanostructures for proficient solar water oxidation. AB - In this paper, we focus on the controlled growth mechanism of alpha-Fe2O3 nanostructures via the hydrothermal method. The field emission scanning electron microscopy (FESEM) results reveal that at a lower hydrothermal time, the initial nucleation involves the formation of short and thin beta-FeOOH nanorods. The subsequent increase in the hydrothermal time leads beta-FeOOH to form thicker and longer nanorods. However, high-temperature quenching (HTQ) at 800 degrees C for 10 min causes the conversion of akaganeite to the hematite phase and activation of hematite by Sn4+ diffusion from a FTO substrate. Sn4+ diffusion from the FTO substrate to the hematite nanostructure was elaborated by X-ray photoelectron spectroscopy (XPS). An alpha-Fe2O3 nanorod photoanode prepared by a hydrothermal reaction for 3 h and HTQ exhibits the highest photocurrent density of 1.04 mA cm 2. The excellent photoelectrochemical performance could be ascribed to the synergistic effect of the optimum growth of alpha-Fe2O3 nanorod arrays and Sn4+ diffusion. Intensity modulated photovoltage spectroscopy (IMVS) studies revealed that the alpha-Fe2O3 photoanodes prepared at 3 h and HTQ exhibited a long electron lifetime (132.69 ms), and contribute to the enhanced PEC performance. The results confirmed that the controlled growth of the beta-FeOOH nanorods, as well as Sn4+ diffusion, played a key role in charge transfer during the photoelectrochemical application. The charge transfer mechanisms in alpha-Fe2O3 nanostructure photoanodes prepared at different hydrothermal times and high temperature quenching are also investigated. PMID- 29436540 TI - Water driven formation of channels: unusual solid-state structural transformation of a heterometallic polymer. AB - The backbone hetero-organometallic polymer trans-{[RuCp(PTA)2-MU-CN-RuCp(PTA)2-MU CoCl3]}n.(DMSO)n (1.DMSO) has been synthesized and transformed into cis {[{RuCp(PTA)2-MU-CN-1kappaC:2kappa2N-RuCp(PTA)2}-MU-CoCl3]}n.{[RuCp(PTA)2-MU-CN 1kappaC:2kappa2N-RuCp(PTA)2]Cl}0.5n.(15H2O)n (2.15H2O) by addition of water to crystallization media (PTA = 1,3,5-triaza-7-phosphaadamantane). The new polymer 2.15H2O presents a nano-channeled molecular packing with pores filled by water molecules. The crystal structures of 1.DMSO and 2.15H2O and the transformation process are herein presented and discussed. PMID- 29436543 TI - Stepwise synthesis, characterization, DNA binding properties and cytotoxicity of diruthenium oligopyridine compounds conjugated with peptides. AB - Although the interactions of oligopyridine ruthenium complexes with DNA have been widely studied, the biological activity of similar diruthenium oligopyridine complexes conjugated with peptides has not been investigated. Herein, we report the stepwise synthesis and characterization of diruthenium complexes with the general formula [(La)Ru(tppz)Ru(Lb)]n+ (tppz = 2,3,5,6-tetra(2-pyridyl)pyrazine, La = 2,2':6',2''-terpyridine or 4-phenyl-2,2':6',2''-terpyridine and Lb = 2,2':6',2''-terpyridine-4'-CO(Gly1-Gly2-Gly3-LysCONH2) (5), (6), n = 5; 2,2':6',2''-terpyridine-4'-CO(Gly1-Gly2-Lys1-Lys2CONH2) (7), (8), n = 6; 2,2':6',2''-terpyridine-4'-CO(Ahx-Lys1Lys2CONH2) (9), (10), n = 5, Ahx = 6 aminohexanoic acid). The compounds [(trpy)Ru(tppz)Ru(trpy-CO2H)](PF6)4, (2)(PF6)4, [(ptrpy)Ru(tppz)Ru(trpy-CO2H)](PF6)4, (3)(PF6)4 and [(ptrpy)Ru(tppz)Ru(trpy)](PF6)4, (4)(PF6)4 were also characterized by single crystal X-ray methods. Moreover, the interactions of the chloride salts (5), (6) and (4) with the self-complementary dodecanucleotide duplex d(5'-CGCGAATTCGCG 3')2 were studied by NMR spectroscopic techniques. The results show that complex (4) binds in the central part of the oligonucleotide, from the minor groove through the ligand ptrpy, while the ligand trpy, which was located on the other side of the diruthenium core, does not contribute to the binding. Complex (5) binds similarly, through the ligand ptrpy. However, the induced upfield shifts of the ptrpy proton signals are significantly lower than the corresponding ones in the case of (4), indicating much lower binding affinity. This is clear evidence that the tethered peptide Gly1-Gly2-Gly3-Lys1CONH2 hinders the complex binding, even though it contains groups that are able to assist it (e.g., the positively charged amino group of lysine, the peptidic backbone, the terminal amide). Complex (6) shows a non-specific binding, interacting through electrostatic forces. The chloride salts of (4), (5) and (6) had insignificant effects on the cell cycle distribution and marginal cytotoxicity (IC50 > 750 MUM) against human lung cancer cell lines H1299 and H1437, indicating that their binding to the oligonucleotide is not a sufficient condition for their cytotoxicity. PMID- 29436544 TI - Control of nuclearity in heterometallic CuII-MnII complexes derived from asymmetric Schiff bases: structures and magnetic properties. AB - Two new N2O3 donor ligands N-(3-methoxysalicylidene)-N'-(salicylidene)-1,3 propanediamine (H2L2) and N-(3-methoxysalicylidene)-N'-(alpha-methylsalicylidene) 1,3-propanediamine (H2L3) and their Cu(ii) complexes have been synthesized. Using these complexes and another Cu-complex with one asymmetric N2O2 donor ligand N (alpha-methylsalicylidene)-N'-(salicylidene)-1,3-propanediamine (H2L1) as metalloligands, four new heterometallic Cu(ii)-Mn(ii) complexes [(CuL1)2Mn2Cl4].3CH3OH (1), [(CuL1)2MnCl2].2CH3CN (2), [CuL2MnCl2].H2O (3) and [CuL3MnCl2] (4) have been synthesized with MnCl2.4H2O. The tetranuclear (1) and trinuclear (2) complexes were prepared by varying the ratio of the metalloligand [CuL1] and MnCl2 whereas dinuclear complexes 3 and 4 are the sole products irrespective of the metalloligand : MnCl2 ratio. All the complexes 1-4 were structurally characterized by single crystal X-ray diffraction. The tetranuclear (CuMn) structure of 1 is formed by the dimerization of phenoxido bridged CuIIMnII units whereas the bent CuMnII trinuclear species 2 is formed by the coordination of two metalloligands (CuL1) to Mn(ii) via a diphenoxido bridge. Complexes 3 and 4 possess a similar dinuclear CuIIMnII structure in which two phenoxido groups form a bridge between the two metal centres. The variable temperature dc magnetic susceptibility measurements reveal that the Cu(ii) and Mn(ii) ions are antiferromagnetically coupled in all the complexes, 1-4. The values of exchange coupling constants (JMn-Cu) are -45.54, -39.66, -71.54 and -48.40 cm-1 for complexes 1-4, respectively. A DFT study of all the complexes has also been performed to rationalize the experimental results of magnetic measurements. PMID- 29436545 TI - Compartmentalized supramolecular hydrogels based on viral nanocages towards sophisticated cargo administration. AB - Introduction of compartments with defined spaces inside a hydrogel network brings unique features, such as cargo quantification, stabilization and diminishment of burst release, which are all desired for biomedical applications. As a proof of concept, guest-modified cowpea chlorotic mottle virus (CCMV) particles and complementary guest-modified hydroxylpropyl cellulose (HPC) were non-covalently cross-linked through the formation of ternary host-guest complexes with cucurbit[8]uril (CB[8]). Furthermore, CCMV based virus-like particles (VLPs) loaded with tetrasulfonated zinc phthalocyanine (ZnPc) were prepared, with a loading efficiency up to 99%, which are subsequently successfully integrated inside the supramolecular hydrogel network. It was shown that compartments provided by protein cages not only help to quantify the loaded ZnPc cargo, but also improve the water solubility of ZnPc to avoid undesired aggregation. Moreover, the VLPs together with ZnPc cargo can be released in a controlled way without an initial burst release. The photodynamic effect of ZnPc molecules was retained after encapsulation of capsid protein and release from the hydrogel. This line of research suggests a new approach for sophisticated drug administration in supramolecular hydrogels. PMID- 29436546 TI - Detailed correlations between SERS enhancement and plasmon resonances in subwavelength closely spaced Au nanorod arrays. AB - Depending on the experimental conditions and plasmonic systems, the correlations between near-field surface enhanced Raman scattering (SERS) behaviors and far field localized surface plasmon resonance (LSPR) responses have sometimes been accepted directly or argued or explored. In this work, we focus on the attractive subwavelength closely spaced metallic nanorod arrays and investigate in detail the complex relationship between their SERS behaviors and plasmon resonances. This is achieved utilizing a combination of array fabrication, conventional LSPR spectra, SERS measurements, electron microscopy and numerical modeling. Three key factors that may impact the correlations have been comprehensively analyzed: the intrinsic near-field to far-field red-shift is found to be rather small in the lattice; the surface roughness has actually little impact on the spectral alignment of the near- and far-field responses; the continuous dependence of individual SERS peak heights on the Stokes Raman shift has been visualized and further clarified. By 3D finite element method (FEM) plasmon mapping, the physical origin of the collective resonances in the lattice is verified directly to be the Fabry-Perot-like cavity mode. The strong near-field enhancement results from the coupling of surface plasmon polaritons (SPPs) propagating at the two sidewalls of neighbouring nanorods forming the resonant cavity. The physical principles demonstrated here benefit significantly the optimization of nano-optic devices based on closely spaced metallic nanorod arrays, as well as the fundamental understanding of the near- and far-field relationship. PMID- 29436547 TI - Largely enhanced photocatalytic activity of Au/XS2/Au (X = Re, Mo) antenna reactor hybrids: charge and energy transfer. AB - An antenna-reactor hybrid coupling plasmonic antenna with catalytic nanoparticles is a new strategy to optimize photocatalytic activity. Herein, we have rationally proposed a Au/XS2/Au (X = Re, Mo) antenna reactor, which has a large Au core as the antenna and small satellite Au nanoparticles as the reactor separated by an ultrathin two-dimensional transition-metal dichalcogenide XS2 shell (~2.6 nm). Due to efficient charge transfer across the XS2 shell as well as energy transfer via coupling of the Au antenna and Au reactor, the photocatalytic activity has been largely enhanced: Au/ReS2/Au exhibits a 3.59-fold enhancement, whereas Au/MoS2/Au exhibits a 2.66-fold enhancement as compared to that of the sum of the three individual components. The different enhancement in the Au/ReS2/Au and Au/MoS2/Au antenna-reactor hybrid is related to the competition and cooperation of charge and energy transfer. These results indicate the great potential of the Au/XS2/Au antenna-reactor hybrid for the development of highly efficient plasmonic photocatalysts. PMID- 29436548 TI - Analysis of nanoparticle biomolecule complexes. AB - Nanoparticles exposed to biological fluids adsorb biomolecules on their surface forming a biomolecular corona. This corona determines, on a molecular level, the interactions and impact the newly formed complex has on cells and organisms. The corona formation as well as the physiological and toxicological relevance are commonly investigated. However, an acknowledged but rarely addressed problem in many fields of nanobiotechnology is aggregation and broadened size distribution of nanoparticles following their interactions with the molecules of biological fluids. In blood serum, TiO2 nanoparticles form complexes with a size distribution from 30 nm to more than 500 nm. In this study we have separated these complexes, with good resolution, using preparative centrifugation in a sucrose gradient. Two main apparent size populations were obtained, a fast sedimenting population of complexes that formed a pellet in the preparative centrifugation tube, and a slow sedimenting complex population still suspended in the gradient after centrifugation. Concentration and surface area dependent differences are found in the biomolecular corona between the slow and fast sedimenting fractions. There are more immunoglobulins, lipid binding proteins, and lipid-rich complexes at higher serum concentrations. Sedimentation rate and the biomolecular corona are important factors for evaluating any experiment including nanoparticle exposure. Our results show that traditional description of nanoparticles in biological fluids is an oversimplification and that more thorough characterisations are needed. PMID- 29436549 TI - Enhanced delivery of siRNA to triple negative breast cancer cells in vitro and in vivo through functionalizing lipid-coated calcium phosphate nanoparticles with dual target ligands. AB - The conjugation of ligands to nanoparticle platforms for the target delivery of therapeutic agents to the tumor tissue is one of the promising anti-cancer strategies. However, conventional nanoparticle platforms are not so effective in terms of the selectivity and transfection efficiency. In this study, we designed and developed a dual-target drug/gene delivery system based on lipid-coated calcium phosphate (LCP) nanoparticles (NPs) for significantly enhanced siRNA cellular uptake and transfection efficiency. LCP NPs loaded with therapeutic siRNA were conjugated with a controlled number of folic acid and/or EGFR-specific single chain fragment antibody (ABX-EGF scFv). The uptake of ABX-EGF scFv modified (LCP-scFv) and folic acid-modified LCP NPs (LCP-FA) by human breast tumor cells (MDA-MB-468) was significantly higher with an optimal ligand density on each NP surface (LCP-125scFv and LCP-100FA). Co-conjugation with sub-optimal dual ligands (50 FA and 75 ABX-EGF scFv) per LCP NP (LCP-50FA-75scFv) further enhanced the cellular uptake. More significantly, much more NPs were delivered to the MDA-MB-468 tumor tissue in the nude mouse model when LCP-50FA-75scFv NPs were used. Therefore, the new dual-ligand LCP NPs may be a valuable targeting system for human breast cancer diagnosis and therapy. PMID- 29436552 TI - Real-time multiplexed PCR using surface enhanced Raman spectroscopy in a thermoplastic chip. AB - Surface enhanced Raman spectroscopy (SERS) has the potential to enable point-of care sensing across the spectrum of chemical and biological analytes. In diagnostic assays, SERS has been demonstrated to increase the multiplexing density while reducing the burden of fluorescence hardware. One particular application of interest is the use of SERS to provide a multiplexed optical read out following polymerase chain reaction (PCR). To date, however, the reported PCR SERS assays require endpoint mixing with a plasmonic nanoparticle solution for detection, thus adding manual steps and preventing real-time, quantitative PCR. In this work, we detail a real-time PCR-SERS thermoplastic microsystem that allows simultaneous nucleic acid amplification and product separation into a SERS active silver colloid for real-time detection. Specifically, a laser cut thermoplastic fluidic chip has been devised to utilize a dialysis membrane capable of isolating a PCR reaction from the silver colloid. As the reaction progresses, a Raman-reporter-labeled DNA probe is degraded, liberating the reporter from probe DNA, allowing passage across the size-restricting dialysis membrane into the SERS-active colloid, where the accumulating reporter can be measured in real time. Here, we demonstrate that this system is capable of real time and single-well multiplexed readout of a PCR reaction to simultaneously detect two biomarker genes for methicillin-resistant S. aureus (MRSA). PMID- 29436553 TI - Carbon dot-Au(i)Ag(0) assembly for the construction of an artificial light harvesting system. AB - Artificial light harvesting systems (LHS) with inorganic counterparts are considered to be robust as well as mechanistically simple, where the system follows the donor-acceptor principle with an unchanged structural pattern. Plasmonic gold or silver nanoparticles are mostly chosen as inorganic counterparts to design artificial LHS. To capitalize on its electron accepting capability, Au(i) has been considered in this work for the synergistic stabilization of a system with intriguingly fluorescing silver(0) clusters produced in situ. Thus a stable fluorescent Au(i)Ag(0) assembly is generated with electron accepting capabilities. On the other hand, carbon dots have evolved as new fluorescent probes due to their unique physicochemical properties. Utilizing the simple electronic behavior of carbon dots, an electronic interaction between the fluorescent Au(i)Ag(0) and a carbon dot has been investigated for the construction of a new artificial light harvesting system. This coinage metal assembly allows surface energy transfer where it acts as an acceptor, while the carbon dot behaves as a good donor. The energy transfer efficiency has been calculated experimentally to be significant (81.3%) and the Au(i)Ag(0)-carbon dot assembly paves the way for efficient artificial LHS. PMID- 29436554 TI - Surface ligand modification of cesium lead bromide nanocrystals for improved light-emitting performance. AB - Cesium lead halide perovskite nanocrystals (NCs) possess excellent optical properties at visible wavelengths with great promise for applications in luminous display fields. We demonstrate a method to modify the surface ligand passivation of perovskite NCs for enhanced colloidal stability and emitting properties by incorporating didodecyl dimethyl ammonium bromide (DDAB). The photoluminescence quantum yield of the NC solution was improved to 96% from 70% and the perovskite film showed fewer trapped sites and enhanced carrier transport ability. The thus fabricated electroluminescent perovskite NC-LEDs exhibited a bright luminance of 11 990 cd m-2, corresponding to 4-times improved external quantum efficiency (EQE), compared to the control device using regular NCs without DDAB. PMID- 29436555 TI - Ultra-broadband nonlinear optical response of two-dimensional h-BN nanosheets and their hybrid gel glasses. AB - Hydrophilic hydroxylated hexagonal boron nitride nanosheets (BNNSs), also called 'white graphene', exhibit high water solubility, compatibility, dispersity with physical and/or chemical effects on the gel matrix, and unexpected but outstanding near-infrared adsorption and nonlinear optical limiting properties. These properties mean that hydroxylated BNNSs are suitable for practical applications in solidification and devices. Hydroxylated BNNSs are doped into an organically modified silicate matrix through a facile sol-gel process. The resulting BNNS-organically modified silicate glass hybrids demonstrate various solid structures (glass, coating, and film), good uniformity, thermostability, toughness, and high linear transmittance in the visible and near-infrared regions. Hybrid glasses showed large optical limiting effects and high doping concentrations without the addition of a compatibiliser, and their limiting thresholds and concentration exceed those of the corresponding suspensions by factors of 1.3-2 and 20-130, respectively. The optical limiting performance of BNNSs is almost equal to or may exceed those of graphene oxide and graphene in solutions and doped glasses. The combined mechanisms of nonlinear absorption, refraction, and scattering are deduced. A solid organically modified silicate hybrid transparent system doped with BNNSs is a promising candidate material for optical limiters and nonlinear optical devices. This system could be an efficient solid-state optical limiter in the visible and long-wavelength near-infrared regions (532-2000 nm). PMID- 29436556 TI - An unusual alkylidyne homologation. AB - The reaction of [W([triple bond, length as m-dash]CH)Br(CO)2(dcpe)] (dcpe = 1,2 bis(dicyclohexylphosphino)ethane) with tBuLi and SiCl4 affords the trichlorosilyl ligated neopentylidyne complex [W([triple bond, length as m dash]CtBu)(SiCl3)(CO)2(dcpe)]. This slowly reacts with H2O to afford [W([triple bond, length as m-dash]CCH2tBu)Cl3(dcpe)] and ultimately H2C[double bond, length as m-dash]CHtBu via an unprecedented alkylidyne homologation in which coordinated CO is the source of the additional carbon atom with potential relevance to the Fischer-Tropsch process. PMID- 29436557 TI - Tunable quantum dot arrays as efficient sensitizers for enhanced near-infrared electroluminescence of erbium ions. AB - Under electrical pumping conditions, high-efficiency Si-based near-infrared light generation and amplification on a chip have long been pursued for future optical interconnection technology. However, the overall performance of Si-based near infrared electroluminescence (EL) devices, including the overall efficiency, turn on voltage and stability under operational conditions, can rarely meet the requirements of monolithic optoelectronic integration. In this work, we designed a confined crystallization growth strategy for fabricating metal oxide quantum dot (QD) arrays embedded in Si-based films as sensitizers of Er3+ ions. Through the precise control of particle size and number density of QD sensitizers, the near-infrared photoluminescence (PL) emission of Er3+ ions can be enhanced by more than three orders of magnitude. More significantly, such hierarchical control over the regular arrangement of QD arrays not only considerably enhances the resonance energy transfer efficiency, but also offers an effective conduction path for carrier transport. Therefore, the corresponding near-infrared EL device exhibits a decreased turn-on voltage of 4.5 V, a high external quantum efficiency of 0.7%, and a long operational lifetime of more than 1000 hours, making this device superior to most Si-based on-chip near-infrared EL devices. This well controlled metal oxide QD array represents an ideal sensitizer to effectively promote the EL emission of rare earth ions and reduce the turn-on voltage. Meanwhile, the analysis of the carrier transport mechanism paves the way for future research into resonance energy transfer under electrical pumping conditions. PMID- 29436558 TI - The Royal College of Physicians of London 500th Anniversary. AB - [No Abstract Available ]. PMID- 29436559 TI - Natural products in endodontics. AB - Herbal remedies are used throughout the world, either in earlier or in recent times. The number of studies on this alternative therapeutic system increased in the last decades. In this paper, the relevant literature on the use of natural products in root canal therapy is revised from a MEDLINE database search. The uses of medicinal plants in endodontics include cleaning and disinfection of root canals, intracanal medicaments between appointments, sealer cements, and for removal of obturation material. Other studies showed the effect of natural products in pulpal and dentin repair. Their use is anecdotal, and their effectiveness showed to be variable and is always compared to the chemical standards currently being used. Alkaloids, coumarins, saponins, and flavonoids are aromatic substances that are produced by plants and evaluated for their therapeutic potential. Further investigation into benefits of natural products is warranted. PMID- 29436560 TI - The role of non-invasive ventilation used immediately after planned extubation for adults with chronic respiratory disorders. AB - OBJECTIVE: To estimate the benefits of non-invasive ventilation (NIV) used immediately after planned postextubation in patients with chronic respiratory disorders. METHODS: Cochrane Library, PubMed, the Chinese BioMedical Literature Database of clinical trials (CBD) and Embase were searched for pertinent studies by 2 trained investigators. Pooled odds ratios and 95% confidence intervals (CIs) were calculated by employing both fixed-effects and random-effects models. RESULTS: Eight studies enrolling 736 patients were included in the meta analysis. Compared with general oxygen therapy, NIV used immediately after planned extubation in patients with chronic respiratory disease reduced the reintubation rate (p=0.02), ventilator-associated pneumonia (VAP) incidence rate (p=0.000), and ICU mortality (p=0.002) and increased the level of PO2 (p=0.03). CONCLUSION: Non-invasive ventilation used immediately after planned extubation seems to be advantageous for decreasing the reintubation rate, VAP incidence, and ICU death rate in patients with chronic respiratory disease. PMID- 29436561 TI - Legionella confirmation in cooling tower water. Comparison of culture, real-time PCR and next generation sequencing. AB - OBJECTIVES: To investigate the presence of Legionella spp in cooling tower water. Legionella proliferation in cooling tower water has serious public health implications as it can be transmitted to humans via aerosols and cause Legionnaires' disease. METHODS: Samples of cooling tower water were collected from King Fahd Hospital of the University (KFHU) (Imam Abdulrahman Bin Faisal University, 2015/2016). The water samples were analyzed by a standard Legionella culture method, real-time polymerase chain reaction (RT-PCR), and 16S rRNA next generation sequencing. In addition, the bacterial community composition was evaluated. RESULTS: All samples were negative by conventional Legionella culture. In contrast, all water samples yielded positive results by real-time PCR (105 to 106 GU/L). The results of 16S rRNA next generation sequencing showed high similarity and reproducibility among the water samples. The majority of sequences were Alpha-, Beta-, and Gamma-proteobacteria, and Legionella was the predominant genus. The hydrogen-oxidizing gram-negative bacterium Hydrogenophaga was present at high abundance, indicating high metabolic activity. Sphingopyxis, which is known for its resistance to antimicrobials and as a pioneer in biofilm formation, was also detected. CONCLUSION: Our findings indicate that monitoring of Legionella in cooling tower water would be enhanced by use of both conventional culturing and molecular methods. PMID- 29436562 TI - Comparison of 3-dimensional and 2-dimensional endoscopic thyroid lobectomy via the trans-thoracoareolar approach. AB - OBJECTIVES: To evaluate retrospectively the safety, efficacy, and feasibility of 3-dimensional (3D) endoscopic thyroid lobectomy via a trans-thoracoareolar approach in comparison with the 2-dimensional (2D) approach. METHODS: We performed a retrospective and cross-sectional analysis of the data of 100 patients who underwent endoscopic thyroid lobectomy via the trans-thoracoareolar approach between January 2014 and November 2016. The patients were classified into 2 equal groups depending on whether the 3D or 2D endoscopic approach was employed. The 2 groups were compared for various intraoperative and postoperative parameters. RESULTS: The values of total operative time, lobectomy time, suture time, and intraoperative blood loss in the 3D endoscopy group were significantly less than those in the 2D endoscopy group. Additionally, the incidence rates of complications in the 3D endoscopy group were significantly less than those in the 2D endoscopy group. However, the groups were similar with regard to the incidence of transient hypocalcemia, subcutaneous congestion, subcutaneous effusion, and cough; postoperative drainage volume; extubation time; postoperative hospitalization time; and total hospitalization expenses. CONCLUSIONS: Three dimensional endoscopic thyroid lobectomy required less operative time and entailed a low risk of injury to adjacent structures, without causing any increase in the rate of postoperative complications, indicating that the 3D endoscopic technique was superior to 2D endoscopy. PMID- 29436563 TI - The rising trend in papillary thyroid carcinoma. True increase or over diagnosis? AB - OBJECTIVES: To assess the changes in parameters of thyroid carcinoma, particularly papillary type, in the era of widespread use of sensitive diagnostic methods. We aim to investigate whether the increased frequency of thyroid cancer is true or resulted from over diagnosis. Methods: We conducted a retrospective study of 313 cases of thyroid carcinoma diagnosed at Jordan University Hospital and King Hussein Cancer Center from 2007-2015. Papillary carcinoma accounted for 290 (92.7%) of all cases. Cases were sub classified according to demographic features, histological type, size, stage, and other variables. For comparison of data, cases were subdivided into 2 study periods: Group I included patients diagnosed in the period 2007-2010, and Group II in the period 2011-2015. Results: The frequency of thyroid carcinoma has increased across the study period. Papillary carcinoma was the major type accounting for this increase. Papillary micro carcinomas <=1cm accounted for 34.8% of cases of PTC. Most cases (52.4%) of papillary thyroid carcinoma (PTC) were localized stage tumors. Group II of the study witnessed a more than doubled number of cases of PTC compared to group I, with increased frequency of tumors of all sizes as well as tumors of both localized and regional stages. Conclusions: Our observed trend cannot be totally explained by over diagnosis and increased diagnostic scrutiny. This increase could be of true nature and cannot be explained by single cause. PMID- 29436564 TI - The effects of celery leaf (apium graveolens L.) treatment on blood glucose and insulin levels in elderly pre-diabetics. AB - OBJECTIVES: To analyze the effect of celery leaf extract on blood glucose and plasma insulin levels in elderly pre-diabetics. Methods: This study was conducted between March and November 2014 at the Faculty of Medicine, Syiah Kuala University, Banda Aceh, Indonesia. A quasi-experimental pretest-posttest with a control group was conducted with elderly pre-diabetic volunteers. The subjects included 16 elderly pre-diabetics older than 60 (6 males and 10 females). The subjects were randomly divided into 2 groups: a control group (placebo-treated) and a treatment group (celery-treated). The treatment consisted of celery leaf extract capsules at the dose of 250 mg, 3 times per day (morning, afternoon and evening), 30 minutes before a meal, for 12 days. Data analysis was performed using the t-test (p less than 0.05). Results: There was a significant decrease in pre-prandial plasma glucose levels (p=0.01) and post-prandial plasma glucose levels (p=0.00), but no significant increase in plasma insulin levels (p=0.15) after celery leaf treatment in elderly pre-diabetics. Conclusion: Celery was effective at reducing blood glucose levels, but there was a lack of association between blood glucose levels and plasma insulin levels in elderly pre-diabetics. PMID- 29436565 TI - Level of diabetes knowledge among adult patients with diabetes using diabetes knowledge test. AB - OBJECTIVES: To determine the level of diabetes knowledge and to identify the main knowledge gaps among patients with diabetes (both types 1 and 2) as there is a high prevalence of diabetes in Saudi Arabia. METHODS: A cross-sectional study was conducted in Makkah city, Kingdom of Saudi Arabia and included governmental primary healthcare centers and hospitals from November 2016 until February 2017. A self-administrated Diabetes Knowledge Test 2 (DKT2) was used to determine the level of diabetes knowledge. It consisted of two parts: general knowledge and insulin use with a global score out of 23. RESULTS: A total of 942 patients with diabetes were enrolled in this study. Male to female ratio was 55.1:44.9, with mean global DKT2 score of 13.3+/-3.2 (57.8%+/-13.3%). The majority of patients (66.1%) had average diabetes knowledge while 29.2% had low knowledge, and 4.7% had high knowledge. Better knowledge and significant associations were found with younger ages, high educational levels, longer duration of diabetes, and positive family history of diabetes. CONCLUSION: Patients' knowledge regarding diabetes was found poor in this study. Hence healthcare providers should pay more attention to diabetes education, especially with respect to dietary concepts. We are strongly advising researchers and physicians in Saudi Arabia to do similar research to determine the level of diabetes knowledge in their fields to get a more comprehensive picture of their patients' knowledge of diabetes. PMID- 29436566 TI - Effectiveness of presurgical nasoalveolar molding therapy on unilateral cleft lip nasal deformity. AB - OBJECTIVES: To evaluate the effectiveness of pre-surgical nasoalveolar molding (PNAM) in patients with unilateral cleft lip nasal deformities. Methods: This was a retrospective study involving 29 patients with unilateral cleft lip and palate defects, of whom 13 were treated with palatal devices with nasal stents (PNAM group) and 16 were treated with palatal devices without nasal stents or surgical tapes (control group). Submental oblique photographs and orthodontic models were longitudinally obtained at the initial visit (T1) and immediately before (T2) and after cheiloplasty (T3). Asymmetry of the external nose, degree of columellar shifting, nasal tip/ala nose ratio, nasal base angle, interalveolar gap, and the sagittal difference in the alveolar gap were measured. The study was conducted in the Orthodontic Clinic at Tokushima University Hospital, Tokushima, Japan between 1997 and 2012. Results: At T1, there were no significant intergroup differences in the first 4 asymmetry parameters. At T2, the PNAM group showed a significant improvement in all values compared to the control group. At T3, the PNAM group showed significant improvement in nasal asymmetry and columellar shifting. Model analysis showed significantly greater changes in the inter-alveolar gap and the sagittal difference of the alveolar cleft gap from T1 to T2 in the PNAM group. Conclusion: The use of PNAM is indispensable for pre-surgical orthodontic treatment at the early postnatal age. PMID- 29436567 TI - Asthma prevalence among adults in Saudi Arabia. AB - OBJECTIVES: To investigate asthma prevalence and to measure asthma symptoms among Saudi adults in Riyadh, Kingdom of Saudi Arabia. METHODS: A cross-sectional survey using the European Community Respiratory Health Survey (ECRHS)questionnaire carried out between April and June 2016, among male and female Saudi nationals aged 20-44 years living in Riyadh. Disproportionate cluster sampling method was used. Asthma was defined based on answering "yes" to any of the following: Have you had wheezing when you did not have a cold in the last 12 months? Have you been told by a physician to have asthma? Are you taking medicine for asthma? RESULTS: A total of 2,405 participants completed the survey. The prevalence of wheezing in the last 12 months when not having a cold was 18.2% with no significant difference between males and females (p=0.107). The prevalence of physician-diagnosed asthma was 11.3% with no significant difference between males and females (p=0.239). The prevalence of taking medicine for asthma was 10.6%. There were no significant differences between asthmatic vs. non asthmatic in terms of residency area (p=0.07), education level (p=0.11) and smoking tobacco (p=0.06). However, significant differences found between asthmatic and non-asthmatic in relation to nasal allergies (p less than 0.001). CONCLUSION: Asthma prevalence is high and much higher than the prevalence reported in most countries using the ECRHS questionnaire. PMID- 29436568 TI - Depression among the elderly population in Sohag governorate. AB - OBJECTIVES: To determine the proportion of geriatric depression and factors associated with its occurrence among a sample of the elderly population in Sohag Governorate. Methods: A cross-sectional, community-based study was conducted from May 2016 to March 2017 with 1,027 elderly individuals (aged >=60 years) living in Sohag Governorate, Egypt. A questionnaire was designed and included inquiries on socio-demographic variables (age, gender, and residence) and the 15-item Geriatric Depression Scale (GDS-15) to determine the outcome variable, the presence of depression, among the studied elderly population. Results: About two thirds (62.7%) of participants suffered from depression. Regarding depression levels, 450 (43.8%) participants had mild depression with GDS-15 scores between 5 and 8, and 18.9% of participants had moderate depression, represented by GDS-15 scores between 9 and 11. No participants had severe depression. Applying logistic regression analysis, increased age, female gender, and living in rural areas were significantly linked to the occurrence of geriatric depression among participants. Conclusion: These findings highlight the need to introduce geriatric clinics into healthcare services and to provide counseling and psychiatric services, and to support high-risk groups and evaluate them regularly for early detection in order to positively impact their life quality. PMID- 29436569 TI - Knowledge, attitudes, practices and perceptions of clinicians towards conducting clinical trials in an Academic Tertiary Care Center. AB - OBJECTIVES: To investigate the knowledge, attitudes practices and perceptions of clinicians concerning the conducting of clinical trials (CTs). Methods: A cross sectional study was conducted on clinicians at King Fahad Medical City, Riyadh, Saudi Arabia. Data were collected using a self-administered questionnaire which divided into 5 sections: Section 1 covered respondents' demographics. The other 4 sections explored respondents' knowledge, attitudes, perceptions and practice towards conducting CTs. Results: A total of 316 clinicians completed the questionnaire. The majority were assistant consultants and consultants 125 (39.5%) and 108 (34.2%), respectively. One hundred sixty-nine (56%) respondents were not aware of the Declaration of Helsinki at all. Two hundred seventy-five (88.4%) respondents expressed interest in conducting CTs and 61.7% and participants showed their willingness to facilitate and assist in CTs conducted by other clinicians. Moreover, 112 (35.9%) respondents participated in CTs previously. Regarding the disadvantages in conducting CTs, participants indicated that the paperwork was complicated and they believed that they might lose patients from their clinical practice once they are recruited in CTs. Lack of research protected time for clinicians 295 (97.7%), and a shortage of clinical research coordinators 293 (97%) were the main problems reported by respondents. Conclusions: Although the majority of participants had an unsatisfactory level of knowledge and misperceptions about CTs, they showed an interest in and positive attitudes about conducting CTs. PMID- 29436570 TI - The effects of irradiance and exposure time on the surface roughness of bulk-fill composite resin restorative materials. AB - OBJECTIVES: To evaluate the surface roughness of 4 different bulk-fill resin based composites cured using different irradiance levels. Methods: This in vitro study was performed in February 2017 to August 2017 at the College of Dentistry, King Saud University. Twenty-four specimens were prepared from each of the bulk fill materials [Tetric N-Ceram (TNC), SonicFill (SF), Smart Dentin Replacement (SDR), and Filtek Bulk-Fill (FB)] using a brass metal mold, resulting in a total of 96 specimens, cured using a Bluephase N light curing unit. Half of the total number of specimens (N=48) were cured using high-power irradiance (1200 mW/cm2) for 20 seconds, while the remaining half (N=48) were cured using low power irradiance (650 mW/cm2) for 40 seconds. After 24 hours, baseline surface roughness of each specimen was analyzed using a profilometer, then polished using Sof-lex abrasive disks, and the surface roughness of all groups was assessed. Results: Post-polished SonicFill cured at high irradiance had the highest mean surface roughness (0.23+/-0.03), whereas pre-polished Smart Dentin Replacement (0.11+/-0.01) and SonicFill (0.11+/-0.02) cured at low irradiance had the lowest mean surface roughness. Conclusion: High curing irradiance (1,200 mW/cm2) had no positive influence on the surface roughness of Filtek Bulk Fill and Tetric N Ceram bulk-fill RBCs compared with lower curing irradiance (650 mW/cm2). However, the difference of curing irradiance significantly affected the surface roughness in SDR and sonic fill RBCs. PMID- 29436571 TI - A novel method to accelerate orthodontic tooth movement. AB - This clinical case report presents fixed orthodontic treatment of a patient with moderately crowded teeth. It was performed with a new technique called 'discision'. Discision method that was described for the first time by the present authors yielded predictable outcomes, and orthodontic treatment was completed in a short period of time. The total duration of orthodontic treatment was 4 months. Class I molar and canine relationships were established at the end of the treatment. Moreover, crowding in the mandible and maxilla was corrected, and optimal overjet and overbite were established. No scar tissue was observed in any gingival region on which discision was performed. The discision technique was developed as a minimally invasive alternative method to piezocision technique, and the authors suggest that this new method yields good outcomes in achieving rapid tooth movement. PMID- 29436572 TI - Recurrent venous thrombosis in a patient with Ebstein's anomaly. AB - Herein, we report a case of a 27-year-old man with Ebstein's anomaly and a history of unexplained recurrent venous thrombosis despite adequate anticoagulation. After surgical correction of the Ebstein's anomaly, the venous thromboembolic events did not recur. This case demonstrates the possible etiopathogenesis of Ebstein's anomaly in causing recurrent venous thromboembolism, which is likely caused through impedance of venous blood flow.Our objective in presenting this particular case is to highlight the possible association between Ebstein's anomaly and venous thrombosis. PMID- 29436573 TI - Malignant tumor of outer root sheath epithelium, trichilemmal carcinoma. Clinical presentations, treatments and outcomes. AB - OBJECTIVES: To emphasize different clinical features of tumor that can be misdiagnosed clinically. METHODS: A total of 8 cases operated between September 2009 and 2016 at the Celal Bayar University, Faculty of Medicine were included in the study. Patients' clinicopathological features, type of surgery and follow up information were evaluated. Results: Six patients were male. The average age was 75.50. The lesions were located on the head and neck, and chest wall. Six patients had a history of the rapid growth of lesion. There was no metastasis at the time of diagnosis. None of the patients needed adjuvant therapy. Mean follow up time was 19.37 months. None of the patients developed recurrence or metastasis. Conclusion: This tumor resembles basal or squamous cell carcinoma. The histopathological evaluation may lead to misdiagnosis. Regional or distant metastasis is very rare. There is no consensus about adjuvant therapy. Screening for metastasis and close follow up are mandatory. PMID- 29436574 TI - The association between body mass index and academic performance. AB - [No Abstract Available]. PMID- 29436575 TI - Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study. AB - DNA methylation is an important epigenetic modification that has been implicated in the pathogenesis of atherosclerosis. Although previous studies have identified various CpG sites and genes whose methylation is associated with atherosclerosis in populations with European or Mexican ancestry, the genome-wide pattern of DNA methylation in the atherosclerotic human aorta is yet to be elucidated in Japanese individuals. In the present study, a genome-wide analysis of DNA methylation at ~853,000 CpG sites was performed using 128 postmortem aortic intima specimens obtained from 64 Japanese patients. To avoid the effects of interindividual variation, intraindividual paired comparisons were performed between atheromatous plaque lesions and corresponding plaque-free tissue for each patient. Bisulfite-modified genomic DNA was analyzed using a specific microarray for DNA methylation. DNA methylation at each CpG site was calculated as the beta value, where beta = (intensity of the methylated allele)/(intensity of the methylated allele + intensity of the unmethylated allele + 100). Bonferroni's correction for statistical significance of association was applied to compensate for multiple comparisons. The methylation of 2,679 CpG sites differed significantly (P<5.86x10-8) between atheromatous plaque lesions and the corresponding plaque-free intima, with 2,272 and 407 CpG sites in atheromatous plaques being hyper- or hypomethylated, respectively. A total of 5 hypermethylated CpG sites in atheromatous plaques were demonstrated to have a difference in beta value of >0.15 (plaque lesion-plaque-free intima) and 11 had a beta ratio of >1.50 (plaque/plaque-free intima). A further 15 and 17 hypomethylated CpG sites in atheromatous plaques were observed to have a difference in beta value of <-0.15 or a beta ratio of <0.67, respectively. According to these limits, a total of 16 novel genes that were significantly hyper- or hypomethylated in atheromatous plaque lesions compared with the plaque free intima were identified in the present study. The results of the present study suggest that the methylation of these genes may contribute to the pathogenesis of atherosclerosis in the Japanese population. PMID- 29436576 TI - The effects of TRAF6 on proliferation, apoptosis and invasion in osteosarcoma are regulated by miR-124. AB - The present study aimed to verify tumor necrosis factor receptor-associated factor 6 (TRAF6) as the target gene of microRNA-124 (miR-124). In addition, the expression of miR-124 was investigated in osteosarcoma tissues and cells, and its effects on the biological characteristics of osteosarcoma cells were determined, in order to provide an experimental and theoretical basis for the application of TRAF6 in the treatment of osteosarcoma. A fluorescence reporter enzyme system was used to verify TRAF6 as a target gene of miR-124, and western blotting was used to detect the effects of miR-124 on the protein expression levels of TRAF6 in cells. The expression levels of miR-124 were detected in osteosarcoma tissues and an osteosarcoma cell line (MG-63) by quantitative polymerase chain reaction (qPCR). In addition, a total of 48 h post-transfection of MG-63 cells with a miR 124 mimic, qPCR was used to detect the expression levels of miR-124, and the effects of miR-124 on the viability of MG-63 human osteosarcoma cells was determined using the MTT method. The effects of miR-124 on the cell cycle progression and apoptosis of MG-63 cells were analyzed by flow cytometry, whereas the effects of miR-124 on the migration of MG-63 cells was detected using the Transwell invasion chamber analysis method. A TRAF6 recombinant expression plasmid (pcDNA3.1-TRAF6) was also constructed, and MG-63 cells were transfected with the recombinant plasmid and a miR-124 mimic, in order to further validate the biological role of miR-124 via the regulation of TRAF6. The results of the present study indicated that, compared with in the normal control group, the expression levels of miR-124 were significantly increased in MG-63 cells transfected with a miR-124 mimic (P<0.01). In addition, the luciferase reporter gene system demonstrated that, compared with in the control group, relative luciferase activity was significantly reduced in the miR-124 mimic group (P<0.01). The results of MTT analysis indicated that cell viability was also significantly reduced in response to the overexpression of miR-124 in MG-63 cells (P<0.01). Flow cytometric analysis demonstrated that the proportion of cells in S phase and G2/M phase was significantly decreased (P<0.01) in cells overexpressing miR-124, and the number of apoptotic cells was significantly increased (P<0.01). Furthermore, the results of the Transwell invasion assay suggested that the number of invasive cells was significantly decreased following enhanced expression of miR-124 (P<0.01). In MG-63 cells overexpressing miR-124 and TRAF6, the results of MTT, flow cytometric and Transwell assay analyses demonstrated that the overexpression of TRAF6 had the opposite biological effects compared to miR-124 overexpression. In conclusion, the present study indicated that the expression levels of miR-124 were downregulated in human osteosarcoma tissues and cells, and that miR-124 is associated with negative regulation of TRAF6 expression; therefore, the role of TRAF6 in primary osteosarcoma may be regulated by miR-124. Therapeutic strategies that enhance miR-124 expression or inhibit TRAF6 expression may be beneficial for the treatment of patients with osteosarcoma. PMID- 29436577 TI - RP105 protects PC12 cells from oxygen-glucose deprivation/reoxygenation injury via activation of the PI3K/AKT signaling pathway. AB - Radioprotective 105 kDa protein (RP105) has been reported to produce favorable outcomes in various cardiovascular disorders via a toll-like receptor 4-dependent or -independent manner. However, whether RP105 exerts neuroprotective effects against oxygen-glucose deprivation (OGD)/reoxygenation (OGD/R) injury remains to be elucidated. In the present study, the PC12 neuronal cell line was exposed to 4 h of OGD followed by 24 h of reoxygenation. Adenoviral vectors encoding RP105 were utilized to upregulate the level of RP105 in PC12 cells prior to OGD/R induction. The results demonstrated that OGD/R reduced the expression of RP105 at the mRNA and protein levels. The overexpression of RP105 significantly reversed OGD/R-induced neuronal injuries, as demonstrated by the reduced release of lactate dehydrogenate and enhanced cellular viability, in addition to decreased inflammation, apoptosis and reactive oxygen species. The mechanistic evaluations indicated that the neuroprotective functions of RP105 were, in part, a result of activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. In addition, elimination of the PI3K/AKT axis via the use of a pharmacological inhibitor inhibited the OGD/R-inhibitory effects induced by the overexpression of RP105. Taken together, RP105 protected PC12 cells from OGD/R injury through promotion of the PI3K/AKT pathway; therefore, the RP105-PI3K-AKT axis may provide a novel therapeutic target for the prevention of cerebral ischemia/reperfusion injury. PMID- 29436578 TI - Protective effect of adenovirus-mediated erythropoietin expression on the spiral ganglion neurons in the rat inner ear. AB - The aim of the present study was to evaluate the expression of erythropoietin (Epo) and the Epo receptor (Epo-R) in the spiral ganglion neurons (SGNs) of the rat inner ear, and to assess the effect of Epo adenovirus vector (Ad-Epo) on the spontaneous apoptosis of SGNs. A total of 60 ears from 30 healthy neonatal (2-3 days postnatal) Sprague-Dawley rats were used to examine the expression of Epo in the SGNs. The rats were divided into three groups: The negative control group, the vector control group [infected with a green fluorescent protein expression vector (Ad-GFP)] and the Ad-Epo group (infected with Ad-Epo). The expression of Epo and Epo-R was detected by immunohistochemistry and dual immunofluorescence staining using polyclonal antibodies directed against Epo and Epo-R, followed by confocal laser-scanning microscopy. An adenovirus vector was constructed and used to transfect the cultured SGNs. Following adenovirus infection, apoptosis of the SGNs was evaluated and Epo protein expression was assessed. Epo and Epo-R were widely expressed in the plasma membrane and the cytoplasm of the SGNs, as well as in the organ of Corti and the stria vascularis within the inner ear. Epo protein expression was upregulated in the Ad-Epo group compared with that in the other two groups (P<0.05). Apoptotic cells were seldom observed at day 4 of SGN culture in the negative control group. At day 7, marked apoptotic cells were detected in the negative control group and the vector control group. The apoptosis level in the Ad-Epo group was significantly decreased compared with that in the negative control group or the vector control group at day 7 (P<0.05). In conclusion, Epo and Epo-R are expressed in the SGNs of the inner ear of the rat, and Ad-Epo can decrease the spontaneous apoptosis of SGNs, which may provide a basis for the prevention or alleviation of sensorineural hearing loss. PMID- 29436579 TI - Long noncoding RNA ENSRNOG00000037522 is involved in the podocyte epithelial mesenchymal transition in diabetic rats. AB - Diabetic nephropathy (DN) is one of the most common complications associated with type I and II diabetes mellitus. Long noncoding RNAs (lncRNAs) have been implicated in various physiological and pathological processes, and recent evidence has demonstrated that they are involved in the process of the epithelial mesenchymal transition (EMT). In the present study, the potential functions of lncRNA ENSRNOG00000037522 during the EMT process in DN were investigated. The results identified that the level of the lncRNA ENSRNOG00000037522 was significantly increased in kidney tissues collected from rats with streptozocin (STZ)-induced DN accompanied by impairment of the glomerular podocytes. It was further demonstrated that the silencing of lncRNA ENSRNOG00000037522 by small interfering RNA transfection partially restored the podocyte function. In addition, knockdown of lncRNA ENSRNOG00000037522 repaired the damage to the podocytes via regulating vimentin, podocalyxin-like 1 and nephrin expression. In conclusion, the current results demonstrated that lncRNA ENSRNOG00000037522 serves a pivotal role in the podocyte EMT in DN. PMID- 29436580 TI - Iron limitation promotes the atrophy of skeletal myocytes, whereas iron supplementation prevents this process in the hypoxic conditions. AB - There is clinical evidence that patients with heart failure and concomitant iron deficiency have increased skeletal muscle fatigability and impaired exercise tolerance. It was expected that a skeletal muscle cell line subjected to different degrees of iron availability and/or concomitant hypoxia would demonstrate changes in cell morphology and in the expression of atrophy markers. L6G8C5 rat skeletal myocytes were cultured in normoxia or hypoxia at optimal, reduced or increased iron concentrations. Experiments were performed to evaluate the iron content in cells, cell morphology, and the expression of muscle specific atrophy markers [Atrogin1 and muscle-specific RING-finger 1 (MuRF1)], a gene associated with the atrophy/hypertrophy balance [mothers against decapentaplegic homolog 4 (SMAD4)] and a muscle class-III intermediate filament protein (Desmin) at the mRNA and protein level. Hypoxic treatment caused, as compared to normoxic conditions, an increase in the expression of Atrogin-1 (P<0.001). Iron-deficient cells exhibited morphological abnormalities and demonstrated a significant increase in the expression of Atrogin-1 (P<0.05) and MuRF1 (P<0.05) both in normoxia and hypoxia, which indicated activation of the ubiquitin proteasome pathway associated with protein degradation during muscle atrophy. Depleted iron in cell culture combined with hypoxia also induced a decrease in SMAD4 expression (P<0.001) suggesting modifications leading to atrophy. In contrast, cells cultured in a medium enriched with iron during hypoxia exhibited inverse changes in the expression of atrophy markers (both P<0.05). Desmin was upregulated in cells subjected to both iron depletion and iron excess in normoxia and hypoxia (all P<0.05), but the greatest augmentation of mRNA expression occurred when iron depletion was combined with hypoxia. Notably, in hypoxia, an increased expression of Atrogin-1 and MuRF1 was associated with an increased expression of transferrin receptor 1, reflecting intracellular iron demand (R=0.76, P<0.01; R=0.86, P<0.01). Hypoxia and iron deficiency when combined exhibited the most detrimental impact on skeletal myocytes, especially in the context of muscle atrophy markers. Conversely, iron supplementation in in vitro conditions acted in a protective manner on these cells. PMID- 29436581 TI - The PI3K/Akt/FOXO3a pathway regulates regeneration following spinal cord injury in adult rats through TNF-alpha and p27kip1 expression. AB - The aim of the present study was to elucidate the expression and role of the phosphatidylinositol 3-kinase (PI3K)/Akt/forkhead box O3 (FOXO3a) pathway in the regeneration of the spinal cord following spinal cord injury (SCI), and its regulatory effect on tumor necrosis factor (TNF)-alpha and cyclin-dependent kinase inhibitor 1B (p27kip1) expression. Firstly, in a Sprague-Dawley rat model of SCI, western blot analysis revealed that the protein levels of PI3K, phosphorylated Akt and FOXO3a were markedly inhibited compared with those in the sham control group. In vitro experiments were also conducted, in which primary dissociated cultures of rat dorsal spinal cord cells were induced with lipopolysaccharide (LPS; 4 ug/ml). The downregulation of PI3K using LY294002 markedly suppressed cell viability, reduced the protein levels of FOXO3a and p27kip1, and increased TNF-alpha protein production in the LPS-induced spinal cord cells. In addition, when the LPS-induced spinal cord cells were infected with FOXO3a adenoviral vectors, the overexpression of FOXO3 markedly promoted cell proliferation, activated p27kip1 protein levels and inhibited TNF-alpha protein production in the spinal cord cells. These results suggest that the PI3K/Akt/FOXO3a pathway regulates regeneration following SCI in adult rats via its modulatory effects on TNF-alpha and p27kip1 expression. PMID- 29436582 TI - Transplantation of allogenic nucleus pulposus cells attenuates intervertebral disc degeneration by inhibiting apoptosis and increasing migration. AB - Transplantation of nucleus pulposus cells (NPCs) into the intervertebral disc (IVD) has been demonstrated to be an effective treatment of degenerative disc disease (DDD). However, the underlying mechanisms have remained to be sufficiently elucidated. The aim of the present study was to explore the potential cell migration and anti-apoptosis efficacy of NPCs in the treatment of DDD. NPCs cultured from rats expressing green fluorescent protein (GFP-NPCs) were transplanted into the degenerated IVD, and the migration of GFP-NPCs, as well as the degeneration and apoptosis of the IVD were detected to evaluate the therapeutic effect in vivo. In vitro, disc chondrocytes (DCs) and annulus fibrosus cells (AFCs) were co-cultured to explore the underlying mechanism. The results demonstrated that injection of NPCs suppressed DDD by inhibiting apoptosis and increasing extracellular matrix in vivo and in vitro. NPCs migrated into the inner AF in vivo, and NPC migration was observed to be promoted by AFCs and DCs in vitro, particularly by damaged AFCs. These results demonstrated the anti-apoptotic effects and migratory capacity of allogenic NPCs transplanted into the IVD, which evidences the contribution of NPCs to disc regeneration and provide a novel strategy for treating DDD. PMID- 29436583 TI - Antiproliferative effects of the CDK6 inhibitor PD0332991 and its effect on signaling networks in gastric cancer cells. AB - PD0332991 (palbociclib/Ibrance(r)) is a cyclin-dependent kinase (CDK)4/6 inhibitor that has recently been approved for the treatment of estrogen receptor positive advanced breast cancer. The present study investigated the antiproliferative effects of PD0332991 on gastric cancer (GC) cells and the underlying molecular mechanisms. The activity of PD0332991 was tested in several GC cell lines, including AGS, KATO-III, NCI-N87 and HS746T. Growth inhibitory activity of PD0332991, alone or in combination with fluorouracil (5-FU), was measured by MTT assay. The effects of PD0332991 on cell cycle progression were analyzed by flow cytometry and western blotting. Protein pathway array and Ingenuity Pathway Analysis were used to identify signaling pathways that may mediate the antiproliferative effects of PD0332991. PD0332991 inhibited proliferation in a dose-dependent manner and enhanced the activity of 5-FU in all GC cell lines tested. Cells treated with PD0332991 exhibited cell cycle arrest in G1 phase of the cell cycle, whereas the number of cells in G2/M phase was decreased. PD0332991 also inhibited CDK6-specific phosphorylation of retinoblastoma on Ser780, reduced the expression of cyclin D1, and induced expression of p53 and p27. Furthermore, 31 proteins were identified, the expression of which was significantly altered following treatment with PD0332991 in at least three cell lines. Pathway analysis indicated that the altered proteins were frequently associated with cell death, cell cycle and the molecular mechanism of cancer. The results of the present study indicated that PD0332991 may inhibit cell proliferation via modulation of the cell cycle, and may affect numerous oncogenic signaling pathways. Therefore, PD0332991 may be considered effective for the treatment of GC. PMID- 29436584 TI - Mitochondrial protective mechanism of simvastatin protects against amyloid beta peptide-induced injury in SH-SY5Y cells. AB - Mitochondrial dysfunction is implicated in the pathology of neuronal damage during Alzheimer's disease (AD). Previous studies suggest that simvastatin (SV) ameliorates amyloid beta (Abeta)-mediated cognitive impairment in AD patients and transgenic mice; however, the mechanisms remain unknown. To investigate the potential mechanisms by which SV protects against AD neurotoxicity, the present study used a series of cellular and molecular assays to analyze the effects of SV in an in vitro model of Abeta1-42-induced injury. The results demonstrated that SV protected against Abeta1-42-induced SH-SY5Y cell injury by inhibiting the release of cytochrome c from the mitochondria to the cytoplasm, and reducing the production of intracellular reactive oxygen species. In addition, SV downregulated cleaved-caspase-3 protein levels, increased the ratio of B cell lymphoma 2 (Bcl-2) to Bcl-2-associated X protein, and increased the protein levels of peroxisome proliferator-activated receptor gamma coactivator-1alpha in the Abeta1-42-treated cells. Furthermore, SV increased the mitochondrial membrane potential and adenosine triphosphate levels, and enhanced the cell respiratory function and mitochondrial mass of the cells. In conclusion, the present study revealed that SV protected SH-SY5Y cells against Abeta1-42-induced injury through regulating the mitochondrial apoptosis pathway and mitochondrial function. PMID- 29436585 TI - Methylation-induced downregulation and tumor-suppressive role of microRNA-98 in glioma through targeting Sal-like protein 4. AB - MicroRNAs (miRs) have been found to play key roles in various human cancers, but the detailed regulatory mechanism of miR-98 in glioma remains largely unknown. The findings of the present study demonstrated that miR-98 was frequently downregulated in glioma tissues and cell lines (U87, U251, U373 and SHG44), and the decreased miR-98 levels were associated with DNA methylation. Treatment with 5-Aza-20-deoxycytidine, a DNA methyltransferase inhibitor, significantly increased the expression of miR-98 in glioma cells. Moreover, both miR-98 downregulation and methylation were significantly associated with a more aggressive tumor phenotype in glioma, as well as shorter survival time of glioma patients. Restoration of miR-98 expression caused a marked decrease in the migration and invasion of U87 cells, but did not affect cell proliferation. Sal like protein 4 (SALL4) was further identified as a novel target gene of miR-98, and its protein expression was negatively regulated by miR-98 in U87 cells. Restoration of SALL4 expression reversed the suppressive effects of miR-98 on the migration and invasion of U87 cells. Furthermore, SALL4 was significantly upregulated in glioma tissues and cell lines, and an inverse correlation between miR-98 and SALL4 expression in glioma tissues was identified. In addition, the increased expression of SALL4 was significantly associated with glioma progression. Taken together, these data demonstrated that downregulation of miR 98, induced by methylation, promotes glioma cell migration and invasion via targeting SALL4. Therefore, miR-98 may become a potential therapeutic candidate for glioma. PMID- 29436586 TI - Amelioration of inflammatory responses by Socheongryong-Tang, a traditional herbal medicine, in RAW 264.7 cells and rats. AB - Socheongryong-Tang (SCRT) is a natural medicine prescription that has been mainly used in East Asia for the treatment of inflammatory disorders, including asthma and allergic rhinitis. The present study evaluated the anti-inflammatory effects of SCRT on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and in a rat model of carrageenan (CA)-induced paw edema. Levels of tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-1beta, IL-6 and prostaglandin E2 (PGE2) in the culture supernatant were quantified and nitric oxide (NO) production was monitored. In addition, the effect of SCRT on the protein expression of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinases (MAPKs), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) was assessed by western blot analysis. Furthermore, the effects of SCRT on acute inflammation in vivo and changes in the histomorphometry and histopathology of paw skin were observed using CA-treated rats. SCRT (1 mg/ml) inhibited the LPS-induced changes in the protein expression of NF-kappaB, JNK, ERK1/2, iNOS and COX-2, as well as the production of NO, PGE2 and cytokines. In the rat paw edema assay, administration of 1 g/kg of lyophilized powder obtained from the aqueous extracts of SCRT for 3 consecutive days inhibited the CA-induced increases in skin thickness, mast cell degranulation, and infiltration of inflammatory cells in the ventral and dorsal pedis skin within 4 h. These results demonstrated that SCRT exerts its anti inflammatory activities in LPS-stimulated RAW 264.7 cells through decreasing the production of inflammatory mediators, including PGE2, NO and cytokines, via suppression of the NF-kappaB and JNK and ERK1/2 signaling pathways. In addition, the data of the CA-induced paw edema indicated an anti-edema effect of SCRT. SCRT (1 g/kg) reduced acute edematous inflammation through inhibition of mast cell degranulation and infiltration of inflammatory cells. Therefore, the present study provided scientific evidence for the anti-inflammatory activities of SCRT as well as the underlying mechanisms. PMID- 29436587 TI - Hypoxia induces pulmonary arterial fibroblast proliferation, migration, differentiation and vascular remodeling via the PI3K/Akt/p70S6K signaling pathway. AB - The present study was designed to examine whether hypoxia induces the proliferation, migration and differentiation of pulmonary arterial fibroblasts (PAFs) via the PI3K/Akt/p70S6K signaling pathway. PAFs were subjected to normoxia (21% O2) or hypoxia (1% O2). The proliferation, migration, differentiation and cellular p110alpha, p-Akt, and p-p70S6K expression levels of the PAFs were examined in vitro. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and right ventricular weight/body weight ratio (RV/BW) were examined. The expression levels of p110alpha, p-Akt, p70S6K, fibronectin and alpha-SMA in the rat pulmonary vessels were also examined. Hypoxia significantly elevated the proliferation, migration and differentiation of rat PAFs. It also strongly elevated the expression of p110alpha, p-Akt and p-p70S6K in PAFs in vitro. NVP-BEZ235 was revealed to significantly reduce the hypoxia-induced proliferation, migration and differentiation. In vivo experiments demonstrated that hypoxia significantly induced the elevation of RVSP, RVHI, RV/BW, medial thickening, adventitious thickening, and fibronectin and collagen deposition around pulmonary artery walls. The expression of p110alpha, p-Akt and p70S6K was evident in the pulmonary arteries of the hypoxic rats. NVP-BEZ235 significantly reduced the hypoxia-induced hypoxic pulmonary vascular remodeling, as well as fibronectin and collagen deposition in the pulmonary arteries. Therefore, hypoxia was demonstrated to induce the proliferation, migration and differentiation of PAFs and the hypoxic pulmonary vascular remodeling of rats via the PI3K/Akt/p70S6K signaling pathway. PMID- 29436588 TI - Resveratrol protects against sodium nitroprusside induced nucleus pulposus cell apoptosis by scavenging ROS. AB - Oxidative stress induced disc cell apoptosis plays an important role in intervertebral disc (IVD) degeneration. The present study aims to investigate effects of resveratrol (RV), a natural polyphenol compound, on sodium nitroprusside (SNP) induced nucleus pulposus (NP) cell apoptosis and related mechanism. Rat NP cells were pretreated with RV, N-acetyl cysteine (NAC) and carboxy-PTIO (PTIO) before SNP treatment. Cell Counting Kit-8 assay was carried out for cell viability evaluation. Annexin V/propidium iodide (PI), Hoechst 33258 and Actin-Tracker Green and Tubulin-Tracker Red staining were conducted to detect NP cell apoptosis and apoptotic structural changes. Mitochondrial membrane potential (DeltaPsim) was analyzed with tetramethylrhodamine methyl ester staining. DCFH-DA and DAF-FM DA staining was used to determine intracellular reactive oxygen species (ROS) and nitric oxide (NO) levels. An ex vivo experiment was also carried out followed by TUNEL assay of sections of discs. SNP induced NP cell apoptosis, excessive production of intracellular ROS and NO, reduction of DeltaPsim as well as disruption of cytoskeletal and morphological structure. Meanwhile, organ culture results showed that SNP induced NP cell apoptosis ex vivo. RV and NAC siginificantly inhibited SNP induced NP cell apoptosis, production of intracellular ROS, deline of DeltaPsim as well as disruption of cytoskeletal and morphological structure, while RV did not suppress NO production. RV and NAC could also suppress SNP induced NP cell apoptosis ex vivo. However, PTIO did not prevent SNP induced NP cell apoptosis, though it scavenged NO significantly. In conclusion, RV protects against SNP induced NP cell apoptosis by scavenging ROS but not NO, suggesting a promising prospect of RV in IVD degeneration retardation. PMID- 29436589 TI - Ferroptosis is associated with oxygen-glucose deprivation/reoxygenation-induced Sertoli cell death. AB - Sertoli cell death contributes to spermatogenesis impairment, which is associated with male infertility. Testicular ischemia-reperfusion (I/R) injury induces the cell death of germ cells and Sertoli cells, whereas inhibition of cell death ameliorates acute testicular I/R damage. The aim of the present study was to investigate the mechanism of I/R stress-induced cell death in TM4 cells. Oxygen glucose deprivation and reoxygenation (OGD/R) was demonstrated to induce I/R injury and cell death in TM4 cells. Cell death was blocked by the reactive oxygen species (ROS) inhibitor N-acetylcysteine, as well as lipid peroxidation inhibitors Liproxstatin-1 and iron chelator deferoxamine; however, inhibitors of apoptosis, necrosis or autophagy had no effect. It was also demonstrated that iron and lipid ROS levels were elevated in I/R injury and that mitochondria decreased in size and increased in membrane density, which is indicative of ferroptosis. Furthermore, the generation of lipid ROS suggests iron accumulation and glutathione (GSH) depletion. The expression of ferroportin (Fpn) protein and mRNA was decreased in TM4 cells. Notably, overexpression of Fpn inhibited ferroptosis, lipid ROS generation and iron accumulation. In addition, GSH dependent peroxidase 4 (GPX4) was inactivated via GSH depletion following I/R injury, whereas GPX4 activation blocked I/R-induced ferroptosis by reducing lipid ROS levels. The mitogen-activated protein kinase (MAPK) pathway was also investigated in the present study; it was observed that I/R-induced ferroptosis was blocked by inhibiting p38 MAPK activation. The results of the present study demonstrate that ferroptosis is a pervasive and dynamic type of cell death induced by OGD/R injury in Sertoli cells. This may provide a novel insight into the application of cytoprotection in testicular I/R damage-induced cell loss. PMID- 29436590 TI - 17beta-estradiol protects INS-1 insulinoma cells from mitophagy via G protein coupled estrogen receptors and the PI3K/Akt signaling pathway. AB - 17beta-estradiol (17beta-E2) is a steroid hormone that is known to exert effects on blood glucose homeostasis. The G protein-coupled estrogen receptor (GPER) has been identified as a non-genomic estrogenic receptor, and is involved in numerous physiological processes, including cell survival, energy provision and metabolism. 17beta-E2 may decrease apoptosis by binding to the GPER. The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is involved in physiological and pathological functions such as autophagy. The purpose of the present study was to investigate the role of the PI3K/Akt signaling pathway in the mediation of the effects of GPERs, and the effects of 17beta-E2 on mitophagy in INS-1 cells, a rat insulin-secreting beta-cell line. In vitro, INS-1 cells were treated with different concentrations of 17beta-E2 with and without pretreatment with a GPER antagonist (G15) or PI3K antagonist (LY294002) and compared with a negative control. An immunofluorescence assay demonstrated that GPERs are expressed in INS-1 cells. Western blot assays demonstrated that 17beta E2 increased GPER levels and the phosphorylation of Akt. Transmission electronic microscopy revealed that 17beta-E2 reduced the formation of mitophagosomes and autophagosomes in INS-1 cells. An immunofluorescence staining assay indicated that the co-localization of translocase of mitochondrial outer membrane complex 20 (TOM20) with lysosomal-associated membrane protein 2 (LAMP2) was decreased in INS-1 cells treated with 17beta-E2 alone. Western blotting demonstrated that 17beta-E2 reduced the protein levels of activated microtubule-associated protein 1 light chain 3, and increased those of TOM20 and mitochondrial heat-shock protein 60. Notably, the protective effects of 17beta-E2 were significantly diminished by G15 or LY294002. In conclusion, the present study suggests that 17beta-E2 activates the PI3K/Akt pathway via the GPER in INS-1 cells. Furthermore, 17beta-E2 may be involved in mitophagy by the regulating the GPER/PI3K/Akt pathway. PMID- 29436591 TI - Downregulation of secreted clusterin potentiates the lethality of sorafenib in hepatocellular carcinoma in association with the inhibition of ERK1/2 signals. AB - Secretory clusterin (sCLU) is overexpressed in cancer and is associated with resistance to chemotherapy in several types of cancer, including hepatocellular carcinoma (HCC). Sorafenib (SOR), a multikinase inhibitor of Raf/mitogen activated protein kinase kinase/extracellular signal-regulated kinase (ERK) signaling and the receptor tyrosine kinase, is recognized as the standard therapeutic strategy for patients with advanced HCC. However, the role of sCLU in the resistance of HCC to SOR remains to be fully elucidated. In the present study, sCLU was silenced by CLU short hairpin (sh)RNA in Bel-7402 and SMMC-7721 cell lines, following which the cells were treated with SOR. Cell proliferation was determined using a CCK-8 assay. Apoptosis was quantified using flow cytometry. The production of sCLU, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X sprotein and phosphorylated (p)ERK1/2 was analyzed using western blot analysis. The results showed that sCLU was overexpressed in three HCC cell lines. The downregulation of sCLU by CLU shRNA synergistically increased SOR sensitivity in the Bel-7402 and SMMC-7721 cells, and potentiated SOR-induced cell apoptosis. In addition, silencing sCLU or combination with PD98059 decreased the SOR-induced activation of pERK1/2. These findings indicate a novel treatment strategy for HCC. PMID- 29436592 TI - Concomitant modulation of PTEN and Livin in gastric cancer treatment. AB - Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Livin are important in the development of gastric cancer (GC). PTEN and Livin are involved in the regulation of tumor cell proliferation, migration and apoptosis. The modulation of PTEN or Livin has been investigated extensively in various cancer models. However, no studies have been performed to evaluate the combined effect of concurrently modulating these two genes on the development of GC. In the present study, the BGC823 human gastric carcinoma cell line was transfected with a dual gene modified vector (pCL-neo-PTEN-siLivin) in parallel with single gene modified vectors (pCL-neo-PTEN or pRNAT-U6.1-siLivin), and an empty control vector. Dual gene modulation (pCL-neo-PTEN-siLivin) had a more marked effect on the inhibition of cell proliferation, induction of apoptosis, and reduction of cell penetration in Matrigel, compared with either single gene alone or empty vector transfection. In a xenograft nude mouse model, the inoculation of pCL-neo PTEN-siLivin-transfected BGC823 cells led to a markedly reduced tumor burden, compared with that in all other inoculation groups. In conclusion, the overexpression of PTEN concomitant with Livin gene silencing was confirmed as a feasible and effective in vitro and in vivo gene modulation method, which may represent a potential therapeutic strategy for the treatment of GC. PMID- 29436593 TI - L-histidine augments the oxidative damage against Gram-negative bacteria by hydrogen peroxide. AB - Excessive damage to DNA and lipid membranes by reactive oxygen species reduces the viability of bacteria. In the present study, the proliferation of recA deficient Escherichia coli strains was revealed to be inhibited by 1% L-histidine under aerobic conditions. This inhibition of proliferation was not observed under anaerobic conditions, indicating that L-histidine enhances oxidative DNA damage to E. coli cells. Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that the expression of recA in E. coli MG1655 increased ~7 fold following treatment with 10 mM hydrogen peroxide (H2O2) plus 1% L-histidine, compared with that following exposure to H2O2 alone. L-histidine increased the genomic fragmentation of E. coli MG1655 following exposure to H2O2. In addition, L-histidine increased the generation of intracellular hydroxyl radicals in the presence of H2O2 in E. coli cells. Next, our group investigated the disinfection properties of the H2O2 and L-histidine combination. The combination of 100 mM H2O2 and 1.0% L-histidine significantly reduced the number of viable cells of extended-spectrum-beta-lactamase-producing E. coli and multidrug-resistant Pseudomonas aeruginosa, and this treatment was more effective than 100 mM H2O2 alone, but this effect was not observed in methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium. The combination of L histidine and H2O2 may be a useful strategy to selectively increase the microbicidal activity of oxidative agents against Gram-negative bacteria. PMID- 29436594 TI - UVB induces apoptosis via downregulation of CALML3-dependent JNK1/2 and ERK1/2 pathways in cataract. AB - The aim of the current study was to understand the mechanisms of apoptosis occurring in cultured human lens epithelial cells (HLECs) following ultraviolet B (UVB) irradiation. The investigations intended to confirm the presence of apoptosis and to reveal the roles of oxidative stress, calcium (Ca2+), c-Jun NH2 terminal kinase (JNK)1/2, and extracellular signal-regulated kinase (ERK)1/2 signaling pathway in these progresses. Cell apoptosis, ROS generation and intracellular Ca2+ concentration was measured by flow cytometry. The expression of CALML3, caspase-3, Bax, Bcl-2, p-JNK1/2, JNK1/2, p-ERK1/2 and ERK1/2 was measured by RT-qPCR and western blot analysis. Annexin V-fluorescein isothiocyanate/propidium iodide staining demonstrated that UVB irradiation increased the apoptotic rate, reactive oxygen species (ROS) production and intracellular Ca2+ concentration of HLECs in dose- and time-dependent manners. Overexpression of calmodulin like 3 (CALML3) reversed the effects of UVB irradiation on apoptosis, ROS production and Ca2+ concentration of HLECs, and decreased expressions of caspase-3 and Bax, with increased expressions of Bcl-2. Notably, silencing of CALML3 had similar effects to UVB irradiation and inhibited the activation JNK1/2 and ERK1/2 pathways. Nimodipine, a Ca2+-channel antagonist, significantly attenuated the damages induced by CALML3 downregulation. In conclusion, UVB irradiation induced increase in apoptosis, ROS production and Ca2+ concentration of HLECs, in part, by downregulating the expression of CALML3 and involved oxidative stress, Ca2+, JNK1/2 and ERK1/2 signaling pathways, suggesting that investigating CALML3 may useful for developing cataract treatment. PMID- 29436595 TI - Anti-apoptotic effects of glycosaminoglycans via inhibition of ERK/AP-1 signaling in TNF-alpha-stimulated human dermal fibroblasts. AB - It has been established that glycosaminoglycans (GAGs) serve an important role in protecting the skin against the effects of aging. A previous clinical trial by our group identified that a cream containing GAGs reduced wrinkles and increased skin elasticity, dermal density and skin tightening. However, the exact molecular mechanism underlying the anti-aging effect of GAGs has not yet been fully elucidated. The present study assessed the influence of GAGs on cell viability, collagen synthesis and collagen synthesis-associated signaling pathways in tumor necrosis factor-alpha (TNF-alpha)-stimulated human dermal fibroblasts (HDFs); an in vitro model of aging. The results demonstrated that GAGs restored type I collagen synthesis and secretion by inhibiting extracellular signal-regulated kinase (ERK) signaling in TNF-alpha-stimulated HDFs. However, GAGs did not activate c-jun N-terminal kinase or p38. It was determined that GAGs suppressed the phosphorylation of downstream transcription factors of ERK activation, activator protein-1 (AP-1; c-fos and c-jun), leading to a decrease in matrix metalloproteinase-1 (MMP-1) levels and the upregulation of tissue inhibitor of metalloproteinase-1 in TNF-alpha-stimulated HDFs. In addition, GAGs attenuated the apoptosis of HDFs induced by TNF-alpha. The current study revealed a novel mechanism: GAGs serve a crucial role in ameliorating TNF-alpha-induced MMP-1 expression, which causes type I collagen degeneration via the inactivation of ERK/AP-1 signaling in HDFs. The results of the present study indicate the potential application of GAGs as effective anti-aging agents that induce wrinkle reduction. PMID- 29436596 TI - Homeobox protein MSX1 inhibits the growth and metastasis of breast cancer cells and is frequently silenced by promoter methylation. AB - Deregulation of msh homeobox 1 (MSX1) has been identified to be associated with multiple human malignant neoplasms. However, the association of the expression and biological function of MSX1 with breast tumorigenesis, and the underlying mechanism remain largely unknown. Therefore, the present study examined the expression and promoter methylation of MSX1 in breast tumor cell lines, primary breast tumors and normal breast tissues using semi-quantitative, quantitative and methylation-specific reverse transcription-polymerase chain reaction. Colony formation assays, flow cytometric analysis, and wound healing and Transwell assays were used to assess various functions of MSX1. Western blot analyses were also conducted to explore the mechanism of MSX1. The results revealed that MSX1 was broadly expressed in normal human tissues, including breast tissues, but was frequently downregulated or silenced in breast cancer cell lines and primary tumors by promoter methylation. Methylation of the MSX1 promoter was observed in 7/9 (77.8%) breast cancer cell lines and 47/99 (47.5%) primary tumors, but not in normal breast tissues or surgical margin tissues, suggesting that tumor-specific methylation of MSX1 occurs in breast cancer. Pharmacological demethylation reduced MSX1 promoter methylation levels and restored the expression of MSX1. The ectopic expression of MSX1, induced by transfection with a lentiviral vector, significantly inhibited the clonogenicity, proliferation, migration and invasion of breast tumor cells by inducing G1/S cell cycle arrest and apoptosis. Ectopic MSX1 expression also inhibited the expression of active beta-catenin and its downstream targets c-Myc and cyclin D1, and also increased the cleavage of caspase-3 and poly (ADP-ribose) polymerase. In conclusion, MSX1 exerts tumor suppressive functions by inducing G1/S cell cycle arrest and apoptosis in breast tumorigenesis. Its methylation may be used as an epigenetic biomarker for the early detection and diagnosis of breast cancer. PMID- 29436597 TI - The interplay of BMP4 and IL-7 regulates the apoptosis of intestinal intraepithelial lymphocytes under conditions of ischemiareperfusion. AB - The number and function of intestinal intraepithelial lymphocytes (IELs) have been found to be significantly reduced following induction of acute intestinal mucosal damage via intestinal ischemiareperfusion (IR). However, the mechanism underlying this reduction remains unclear. Therefore, it was hypothesized that the interplay of bone morphogenetic protein (BMP)4 and interleukin (IL)-7 regulates IEL function and number. Recent studies have demonstrated that the different components of the BMP24 signaling pathway are expressed in intestinal epithelial cells (IECs) via the activation of nuclear factor (NF)-kappaB. In the present study, reverse transcription-polymerase chain reaction analysis and flow cytometry demonstrated that IELs express BMP receptors (BMPRIA, BMPRIB, ActRIA and BMPRII) and non-canonical signal transduction molecules (NF-kappaB). an in vivo mouse intestinal IR model was used, and IR was shown to increase the expression of BMP4 in IECs and upregulate the expression levels of BMPRIA, BMPRIB and phosphorylated NF-kappaB in IELs. Following isolation and culture of IELs, it was observed that exogenous BMP4 also upregulated the expression of BMPRIA and BMPRIB and activated NF-kappaB signaling in IELs, inducing IEL apoptosis. In addition, the rate of apoptosis of IELs decreased following treatment with the BMP-specific antagonist Noggin or with the NF-kappaB inhibitor pyrrolidine dithiocarbamate. Furthermore, it was observed that exogenous IL-7 can decrease BMP4 protein expression in IECs and the expression of phosphorylated NF-kappaB protein in IELs. The findings of the present study suggest that, under conditions of IR, IEC-derived BMP4 activates NF-kappaB signaling in IELs, inducing IEL apoptosis, further aggravating the dysfunction of the intestinal mucosal barrier. However, these effects may be alleviated by IL-7 treatment. Therefore, BMP4 and IL-7 appear to be involved in the interaction between IECs and IELs and in the mechanism underlying intestinal mucosal barrier dysfunction. PMID- 29436598 TI - Madecassoside activates anti-neuroinflammatory mechanisms by inhibiting lipopolysaccharide-induced microglial inflammation. AB - Neurodegeneration is typically preceded by neuroinflammation generated by the nervous system to protect itself from tissue damage, however, excess neuroinflammation may inadvertently cause more harm to the surrounding tissues. Attenuating neuroinflammation with non-steroidal anti-inflammatory drugs can inhibit neurodegeneration. However, such treatments induce chronic side effects, including stomach ulcers. Madecassoside, a triterpene derived from Centella asiatica, is considered to be an alternative treatment of inflammation. In the present study, the anti-neuroinflammatory properties of madecassoside were assessed in BV2 microglia cells, which were pre-treated with madecassoside at a maximum non-toxic dose (MNTD) of 9.50 ug/ml and a 1/2 MNTD of 4.75 ug/ml for 3 h and stimulated with 0.1 ug/ml lipopolysaccharide (LPS). The effect of madecassoside was assessed by determining reactive oxygen species (ROS) levels in all groups. Furthermore, the expression of pro- and anti-neuroinflammatory genes and proteins were analyzed using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that ROS levels in cells treated with the MNTD of madecassoside were significantly reduced compared with cells treated with LPS alone (P<0.05). The expression of pro-neuroinflammatory genes, including inducible nitric oxide synthase, cyclooxygenase-2, signal transducer and activator of transcription 1 and nuclear factor-kappaB, were significantly downregulated in a dose-independent manner following treatment with madecassoside. Conversely, the anti-neuroinflammatory component heme oxygenase 1 was significantly upregulated by 175.22% in the MNTD treated group, compared with cells treated with LPS alone (P<0.05). The gene expression profiles of pro- and anti-inflammatory genes were also consistent with the results of western blotting. The results of the present study suggest that madecassoside may be a potent anti-neuroinflammatory agent. The antioxidative properties of madecassoside, which serve a major role in anti-neuroinflammation, indicate that this compound may be a functional natural anti-neuroinflammatory agent, therefore, further in vivo or molecular studies are required. PMID- 29436599 TI - Experimental study on the neurotoxic effect of beta-amyloid on the cytoskeleton of PC12 cells. AB - The aim of the present study was to establish a cell model of Alzheimer's disease (AD) and investigate the neurotoxic effects of beta-amyloid (Abeta) on the cytoskeleton. PC12 cells were cultured and treated with Abeta25-35, and cell survival was analyzed with the MTT assay. Cell apoptosis was visualized using 4',6-diamidino-2-phenylindole staining and the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Immunocytochemistry and phalloidin staining were used to label the cytoskeleton of PC12 cells. Abeta25-35 was found to induce PC12 cell apoptosis in a dose-dependent manner (P<0.05). Moreover, Abeta25-35 also caused dose-dependent disintegration of the cytoskeleton (P<0.05). Therefore, the PC12 cell cytoskeleton was found to be sensitive to Abeta25-35 neurotoxicity. The disintegration of the cytoskeleton is likely an important pathological alteration in AD, and Abeta is a key molecule involved in AD pathogenesis. PMID- 29436600 TI - Adenovirus-mediated P311 ameliorates renal fibrosis through inhibition of epithelial-mesenchymal transition via TGF-beta1-Smad-ILK pathway in unilateral ureteral obstruction rats. AB - Epithelial-mesenchymal transition (EMT) is a critical step and key factor during renal fibrosis. Preventing renal tubular EMT is important for delaying the progression of chronic kidney disease (CKD). P311, a highly conserved 8-kDa intracellular protein, has been indicated as an important factor in myofibroblast transformation and in the progression of fibrosis. However, the related studies on P311 on renal fibrosis are limited and the mechanisms of P311 in the progression of renal tubulointerstitial fibrosis remain largely unknown. In the present study, we examined the effect of P311 on transforming growth factor-beta1 (TGF-beta1)-mediated EMT in a rat model of unilateral ureteral occlusion (UUO) renal fibrosis. The recombinant adenovirus p311 (also called Ad-P311) was constructed and transferred it into UUO rats, the preventive effect and possible mechanism of P311 on TGF-beta1-mediated EMT were explored. The UUO model was established successfully and Ad-P311 was administered into UUO rats each week for 4 weeks, then the serum levels of Cr, blood urea nitrogen (BUN) and albumin (ALB) were evaluated. H&E staining and Masson staining were performed to observe the pathological changes of kidneys. Immunohistochemical staining and western blot analysis were used to examine the EMT markers [E-cadherin and alpha-smooth muscle actin (alpha-SMA)], and signal transducers (p-Smad2/3 and Smad7). Integrin linked kinase (ILK) as a keyintracellular mediator that controls TGF-beta1-mediated-EMT was also assayed by western blot analysis. The results showed that P311 could alleviate renal tubular damage and interstitial fibrosis improving Cr, BUN and ALB serum levels in UUO kidneys. Furthermore, P311 attenuated TGF-beta1-mediated EMT through Smad-ILK signaling pathway with an increase in alpha-SMA, pSmad2/3 and ILK expression, and a decrease in E-cadherin and Smad7 expression in UUO kidneys. In conclusion, P311 may be involved in the pathogenesis of renal fibrosis by blocking TGF-beta1-mediated EMT via TGF-beta1-Smad-ILK pathway in UUO kidneys. P311 may be a novel target for the control of renal fibrosis and the progression of CKD. PMID- 29436601 TI - Changed immune and miRNA response in RAW264.7 cells infected with cell wall deficient mycobacterium tuberculosis. AB - Cell wall deficient (CWD) forms of Mycobacterium tuberculosis (Mtb) confers a marked resistance to immune system of the host. However, there is limit data on the effect of intracellular CWD-Mtb infection on macrophages. In the study, effects of CWD-Mtb on cell viability, cytokine response and miRNA expression of macrophages were analyzed. Cell viability was reduced, levels of interleukin 1alpha (IL-1alpha), IL-1beta, IL-6, IL-10 and interferon-gamma (IFN-gamma) were also significantly changed after infection of RAW264.7 cells with CWD-Mtb. A total of 105 miRNAs were deregulated between CWD-Mtb and wild Mtb group, and among them, miR-29b was upregulated in CWD-Mtb group. Downregulation of miR-29b resulted in significant elevation level of IFN-gamma mRNA. Involved signaling pathways of potential target genes of differentially expressed miRNAs mainly focused on T cell receptor signaling pathway, MAPK signaling pathway, neurotrophin signaling pathway, and regulation of actin cytoskeleton. Taken together, the results showed that cytokine production of CWD-Mtb infected macrophages was altered and many miRNAs were involved in regulation of macrophage response to CWD-Mtb infection, which probably determined the differential outcome following different phenotype Mtb infection. These findings open up a new and interesting avenue for an improved understanding of pathogenesis of CWD-Mtb. PMID- 29436602 TI - The expression and activation of sex steroid receptors in the preeclamptic placenta. AB - Estrogen and progesterone are the main pregnancy hormones produced by the placenta. It is well understood that estrogen stimulates angiogenesis in the uterus during the reproductive cycle. Although the estrogen and progesterone signaling pathways are assumed to be associated with placental vascularization and preeclampsia, expression of estrogen receptors (ESRs) and progesterone receptor (PGR) in the placenta have not been well studied. The present study examined the expression patterns of steroid hormone receptors in placentas. Human placenta samples were collected and divided into normal and preeclampsia groups. Results revealed that expression levels of ESR1 were reduced, whereas ESR2 and PGR were elevated in preeclamptic placentas. To generate an in vitro preeclampsia environment, human placenta-derived BeWo cells were incubated under hypoxic conditions, or treated with catechol-O-methyl transferase inhibitor (COMT-in) or L-NG-nitroarginine methyl ester (L-NAME). Expression levels of ESR1, ESR2 and PGR in hypoxic cells demonstrated similar regulation as those in placentas from women with preeclampsia. Although COMT-in and L-NAME did not significantly regulate the expression levels of the receptors, COMT-in translocated ESR2 and PGR from the nucleus to the cytoplasm, indicating that these receptors were inactivated. These results suggested that ESRs and PGR are associated with symptoms of preeclampsia in the placenta. The expression of ESR1 was reduced in preeclamptic placenta and hypoxic BeWo cells. In addition, the activation of ESR2 and PGR was blocked in placenta cells subjected to COMT-in treatment. The reduced ESR1 expression and inactivation of ESR2 and PGR proteins may affect the physiological complications of preeclampsia in the placenta. PMID- 29436603 TI - alpha-lipoic acid can greatly alleviate the toxic effect of AGES on SH-SY5Y cells. AB - The aim of the study was to explore the influence of alpha-lipoic acid (alpha-LA) on the cytotoxicity of advanced glycation end-products (AGEs) against SH-SY5Y cells. AGE-bovine serum albumin (BSA) was incubated in vitro using SH-SY5Y cells as a target model, and the control group was set. Cells were exposed to AGE-BSA, and alpha-LA was selectively added to the cells. Cell growth and death was determined by the MTT assay, which measures cellular metabolic rate, lactate dehydrogenase (LDH) leakage rate and cellular axonal length. Immunocytochemistry was employed to detect the expression of beta-amyloid (Abeta) protein in cells, and mRNA expression of amyloid precursor protein (APP) and the receptor for AGE (RAGE) were assayed by PT-PCR. The metabolism of MTT was clearly increased, the rate of LDH leakage was significantly decreased, and axonal length was significantly increased in cells treated with alpha-LA (0.1 g/l) as compared to untreated cells. Furthermore, the expression levels of Abeta protein were also decreased. In addition, alpha-LA (0.1 g/l) markedly inhibited the expression of RAGE mRNA, and did not influence APP mRNA expression as compared the control group. alpha-LA (0.1 g/l) was effective at dampening the cytotoxicity of AGE-BSA, a preliminary observation that confirms the ability of alpha-LA to significantly alleviate the cytotoxicity of AGEs against SH-SY5Y cells. PMID- 29436604 TI - Cav 1.2 and Cav 2.2 expression is regulated by different endogenous ghrelin levels in pancreatic acinar cells during acute pancreatitis. AB - Ghrelin influences pancreatic endocrine and exocrine functions, regulates intracellular calcium [Ca2+]i levels, and has an anti-inflammatory role in acute pancreatitis. This study investigated the role of endogenous ghrelin in the expression of Cav 1.2 (L-type of Ca2+ channel) and Cav 2.2 (N-type of Ca2+ channel) in acute pancreatitis. For this purpose, acute edematous pancreatitis (AEP) and acute necrotizing pancreatitis (ANP) rat models were established. Cav 1.2 and Cav 2.2 expression was assessed by immunohistochemistry in the pancreatic tissues of rats; ghrelin, interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) serum levels were detected using ELISA. Next, in AR42J cells with either knock-out or overexpression of ghrelin, Cav 1.2 and Cav 2.2 expression was examined using western blot analysis, and intracellular calcium [Ca2+]i was detected with confocal microscopy. In this study, the ghrelin serum level was highest in the ANP group and was higher in the AEP group than the normal group. Expression of Cav 1.2 and Cav 2.2 in the ANP and AEP groups was higher than in the respective control groups. The serum IL-1beta and TNF-alpha levels were significantly higher in the ANP group compared to the other groups. Cav 1.2 and Cav 2.2 expression and [Ca2+]i decreased in ghrelin knockdown AR42J cells but increased in ghrelin overexpressing cells. In conclusion, Cav 1.2 and Cav 2.2 expression increased in ANP. The [Ca2+]i level, which is mediated by Cav 1.2 and Cav 2.2 expression, is directly regulated by ghrelin in pancreatic acinar cells, and serum ghrelin levels may be involved in the severity of acute pancreatitis. PMID- 29436605 TI - Novel iridium (III)-derived organometallic compound for the inhibition of human platelet activation. AB - Since cisplatin achieved clinical success, transition metal platinum (Pt) drugs have been effectively used for the treatment of cancer. Iridium (Ir) compounds are considered to be potential alternatives to Pt compounds, as they possess promising anticancer effects with minor side effects. Platelet activation is associated with the metastasis and progression of cancer, and also with arterial thrombosis. Therefore, it is necessary to develop novel, effective antithrombotic agents. An Ir (III)-derived complex, [Ir (Cp*) 1-(2-pyridyl)-3-(3 methoxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-3), was developed as a novel antiplatelet drug. Ir-3 exerted more potent inhibitory activity on platelet aggregation stimulated by collagen compared with other agonists, including thrombin. In collagen-activated platelets, Ir-3 also inhibited adenosine trisphosphate release, intracellular Ca+2 mobilization and surface P-selectin expression, as well as the phosphorylation of phospholipase Cgamma2 (PLCgamma2), protein kinase C (PKC), protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) 1, but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinases. Ir-3 did not markedly affect phorbol 12, 13-dibutyrate-stimulated platelet aggregation. Neither the adenylate cyclase inhibitor SQ22536 nor the guanylate cyclase inhibitor 1H-[1, 2, 4] oxadiazolo [4,3-a]quinoxalin-1-one significantly reversed the Ir-3-mediated inhibition of platelet aggregation. Furthermore, Ir-3 had no considerable diminishing effects on OH radical signals in collagen-stimulated platelets or Fenton reaction solution. In conclusion, Ir-3 serves a novel function in the inhibition of platelet aggregation through inhibiting the PLCgamma2-PKC cascade, and the subsequent suppression of Akt and JNK1 activation. Therefore, Ir-3 may be a potential novel therapeutic agent for the treatment of thromboembolic disorders, or the interplay between platelets and tumor cells which contributes to tumor cell proliferation and progression. PMID- 29436606 TI - LMO3 promotes gastric cancer cell invasion and proliferation through Akt-mTOR and Akt-GSK3beta signaling. AB - The present study assessed the biological functions of LIM domain only 3 (LMO3) in gastric cancer (GC) investigated and the underlying molecular mechanisms. It was revealed that the expression of LMO3 was significantly upregulated in GC tissues. A GC tissue microarray (n=164) indicated that LMO3 expression was closely associated with clinicopathological factors, as well as overall survival and disease-free survival of patients. After knockdown of LMO3 in MGC-803 and SGC 7901 cells, the invasion and proliferation were obviously suppressed. Furthermore, LMO3 knockdown suppressed the phosphorylation of Akt, mammalian target of rapamycin (mTOR) and glycogen synthase kinase (GSK)3beta signaling. An inhibitor of mTOR, dactolisib, abrogated recombinant LMO3 protein-induced GC cell invasion and proliferation, while an inhibitor of GSK3beta, CHIR-98014, only abrogated rLMO3 protein-induced proliferation. These results suggested that LMO3 promotes GC cell invasion and proliferation mainly through Akt/mTOR and Akt/GSK3beta signaling. LMO3 may serve as a potential therapeutic target for GC in the future. PMID- 29436607 TI - Decreased hyperpolarization-activated cyclic nucleotide-gated channels are involved in bladder dysfunction associated with spinal cord injury. AB - Spinal cord injury (SCI) leads to bereft voluntary control of bladder, but the possible role of spontaneous excited system in bladder of SCI patients is poorly understood. Hyper-polarization-activated cyclic nucleotide-gated (HCN) channels are deemed to regulate the spontaneous contraction of bladder, our study explored the functional role of HCN channels in SCI induced neurogenic bladder. Sixty female Sprague-Dawley rats were randomized into control, sham and SCI groups. Rat models subjected to SCI at S2 levels were successfully established and were assessed using hematoxylin and eosin staining and cystometry. In SCI rats, the mRNA and protein expression levels of HCN channels and the Ih density were significantly reduced, and expression levels of several bladder HCN1 channel regulatory proteins were also significantly changed. The effects of 50 uM forskolin and 50 uM 8-bromoadenosine 3',5'-cyclic monophosphate on [Ca2+]i of isolated bladder interstitial cells of Cajal-like cells were significantly decreased in SCI rats. The spontaneous contractions in detrusor strips from SCI rats were significantly weakened. Furthermore, detrusor strips from SCI rats exhibited decreased tolerance to two doses of ZD7288 (10 and 50 uM). Taken together, our results indicate that the decreased bladder HCN channel expression and function induced by altered regulatory proteins are involved in the pathological process of SCI induced neurogenic bladder, which present HCN channels as valid therapeutic targets for treating this disease. PMID- 29436608 TI - microRNA expression profiles of scar and normal tissue from patients with posterior urethral stricture caused by pelvic fracture urethral distraction defects. AB - Pelvic fracture urethral distraction defect (PFUDD) seriously affects the quality of life of patients. At present, there are few effective drug treatments available for PFUDD-induced urethral stricture, which is associated with fibrosis and scar formation in urethra lumen. Emerging evidence suggests that microRNAs (miRNAs/miRs) may be involved in the regulation of fibrosis, and analysis of miRNA expression profiles in urethral scar and normal urethra tissues may therefore benefit the discovery of novel treatments for urethral stricture with micro invasive procedures. In the present study, miRNA sequencing and quantitative polymerase chain reaction (qPCR) validation using paired scar and normal tissues from patients with PFUDD, and functional analysis of the miRNAs involved in the fibrosis associated signaling pathway was performed. A total of 94 differentially expressed miRNAs were identified in the scar tissue of patients with PFUDD. Among them, 26 miRNAs had significantly altered expression in the scar tissue compared with the normal tissue from the same patient. qPCR validation confirmed that miR-129-5p was overexpressed in scar tissue. The TGF beta pathway-associated functions of a total of 5 miRNAs (hsa-miR-129-5p, hsa-miR 135a-5p, hsa-miR-363-3p, hsa-miR-6720-3p and hsa-miR-9-5p) were further analyzed, as well as their key molecular targets and functional mechanisms in signaling regulation. To conclude the miRNA sequencing indicated a significantly altered expression of hsa-miR-129-5p, hsa-miR-135a-5p, hsa-miR-363-3p, hsa-miR-6720-3p and hsa-miR-9-5p in patients with PFUDD. These miRNAs and their potential target genes were associated with fibrosis in several diseases, and the data from the present study may help explore potential miRNA targets for future precision treatments for urethral stricture. PMID- 29436609 TI - Enhancement of malignant properties of human glioma cells by ganglioside GD3/GD2. AB - Sialic acid-containing glycosphingolipids, gangliosides, are considered as cancer associated antigens in neuro-ectoderm-derived tumors such as melanomas and neuroblastomas. In particular, gangliosides GD3 and GD2 are expressed in human gliomas. It has been reported that their expression levels increase along with increased malignant properties. However, the implication of GD3/GD2 in human glioma cells has never been clarified, at least to the best of our knowledge. In this study, we introduced the cDNA of GD3 synthase (GD3S)(ST8SIA1) into a glioma cell line, U-251MG, that expresses neither GD3 nor GD2, thereby establishing transfectant cells U-251MG-GD3S(+) expressing high levels of GD3 and GD2 on the cell surface. In these U-251MG-GD3S(+) cell lines, signaling molecules such as Erk1/2, Akt, p130Cas, paxillin and focal adhesion kinase were activated, leading to the enhancement of invasion activity and motility. It was then demonstrated that the U-251MG-GD3S(+) cells could proliferate under culture conditions with low or no serum concentrations without undergoing cell cycle arrest by escaping the accumulation of p16 and p21. All these results suggested that GD3 and GD2 highly expressed in gliomas confer increased invasion and mobility, cell growth abilities under low serum conditions, and increased ratios of the S-G2/M phase in the cell cycle. PMID- 29436610 TI - Decreased expression of TERT correlated with postnatal cochlear development and proliferation reduction of cochlear progenitor cells. AB - Cochlear progenitor cells are considered as one of the best candidates for hair cell regeneration, thus, the regulation of cochlear progenitor cell proliferation has become a focus in this field. Several genes expressed in the inner ear during postnatal development have been demonstrated to be involved in maintaining the proliferative potential of progenitor cells, but the mechanism for regulating the proliferation and differentiation of cochlear progenitor cells remains poorly understood. Telomerase reverse transcriptase (TERT) has rate limiting telomerase activity and the overexpression of TERT has been shown to promote cell proliferation in series of cell lines. The aim of the present study was to evaluate the expression of TERT in the postnatal development of the cochlea and progenitor cells. The results demonstrated that TERT was expressed in the basilar membranes during the first postnatal week. In vitro, TERT expression in progenitor cells reached a maximum at day 4 after culture and decreased as the culture time prolonged or the cell passage number increased. These results led us to hypothesize that TERT may be involved in the development of the cochlea and in maintaining the proliferation ability of progenitor cells. PMID- 29436611 TI - Androgen receptor reverts dexamethasone-induced inhibition of prostate cancer cell proliferation and migration. AB - The aim of the present study was to determine the role of androgen receptor in the effect of dexamethasone on cell proliferation and migration of multiple prostate cancer cells. The prostate cancer cell lines LNCaP, 22Rv1, C4-2 and PC3 were cultured in vitro. For glucocorticoid-induced experiments, the cells were transferred and cultured in RPMI-1640 medium with 10% charcoal-stripped serum from RPMI-1640 medium with 10% fetal bovine serum for at least 24 h. The effects of dexamethasone on the proliferation and migration of various cell lines were analyzed by MTT and migration assays. Dexamethasone exhibited no effect on LNCaP, C4-2 and 22Rv1 cell lines, but suppressed proliferation of glucocorticoid receptor (GR)+ androgen receptor (AR)- PC3 cell line. Dexamethasone suppressed PC3 cell migration, and did not affect migration of PC3-AR9 cells. Dexamethasone positively or negatively regulated proliferation of various prostate cancer cells based on AR and GR expression profiles. The data presented in the present study indicates that androgen receptor reverts the dexamethasone-induced inhibition of prostate cancer cell proliferation and migration. PMID- 29436612 TI - Seawater inhalation induces acute lung injury via ROS generation and the endoplasmic reticulum stress pathway. AB - Seawater (SW) inhalation can induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In the present study, SW induced apoptosis of rat alveolar epithelial cells and histopathological alterations to lung tissue. Furthermore, SW administration increased generation of reactive oxygen species (ROS), whereas pretreatment with the ROS scavenger, N-acetyl-L-cysteine (NAC), significantly decreased ROS generation, apoptosis and histopathological alterations. In addition, SW exposure upregulated the expression levels of glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP), which are critical proteins in the endoplasmic reticulum (ER) stress response, thus indicating that SW may activate ER stress. Conversely, blocking ER stress with 4-phenylbutyric acid (4-PBA) significantly improved SW-induced apoptosis and histopathological alterations, whereas an ER stress inducer, thapsigargin, had the opposite effect. Furthermore, blocking ROS with NAC inhibited SW-induced ER stress, as evidenced by the downregulation of GRP78, phosphorylated (p)-protein kinase R-like ER kinase (PERK), p-inositol requiring kinase 1alpha (IRE1alpha), p-50 activating transcription factor 6alpha and CHOP. In addition, blocking ER stress with 4-PBA decreased ROS generation. In conclusion, the present study indicated that ROS and ER stress pathways, which are involved in alveolar epithelial cell apoptosis, are important in the pathogenesis of SW-induced ALI. PMID- 29436613 TI - Rhein protects against cerebral ischemic-/reperfusion-induced oxidative stress and apoptosis in rats. AB - The present study aimed to investigate the protective effects of rhein on cerebral ischemic/reperfusion (I/R) injury in rats. The present study focused on the effect of rhein on oxidative stress and apoptotic factors, which are considered to serve an important role in the onset of I/R injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion. Neurological functional scores (NFSs) were evaluated according to the Zea Longa's score criteria and the area of brain infarct was determined by triphenyltetrazolium chloride staining. The morphology of the nerve cells in the cortex was observed following hematoxylin and eosin staining. In addition, levels of oxidative stress were assessed by measuring the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA). Levels of B-cell lymphoma-2 (Bcl-2), apoptosis regulator Bax (BAX), caspase-9, caspase-3 and cleaved caspase-3 expression were analyzed using western blot analysis. Levels of caspase-9 and caspase-3 mRNA expression were obtained using reverse transcription quantitative polymerase chain reaction. The results revealed that treatment with 50 or 100 mg/kg rhein significantly improved the NFS and markedly attenuated the area of infarction. Rhein also significantly reduced the content of MDA and significantly increased SOD, GSH-Px and CAT activity. Western blot analysis indicated that rhein significantly decreased the expression of BAX and enhanced the expression of Bcl-2. Compared with the I/R group, levels of caspase-9, caspase-3 and cleaved caspase-3 protein expression were significantly decreased in the rhein treatment groups. Additionally, rhein treatment significantly reduced levels of caspase-9 and caspase-3 mRNA expression. These results suggest that rhein exhibits protective effects during cerebral I/R injury and its underlying mechanism of action may involve the inhibition of oxidative stress and apoptosis. PMID- 29436614 TI - Arctigenin inhibits the activation of the mTOR pathway, resulting in autophagic cell death and decreased ER expression in ER-positive human breast cancer cells. AB - Arctigenin, a member of the Asteraceae family, is a biologically active lignan that is consumed worldwide due to its several health benefits. However, its use may pose a problem for patients with estrogen receptor (ER)alpha-positive breast cancer, since studies have shown that arctigenin is a phytoestrogen that exerts a proliferative effect by binding to the ER. Thus, in this study, we examined the effect of arctigenin on ERalpha-positive MCF-7 human breast cancer cells to determine whether the consumption of arctigenin is safe for patients with breast cancer. First, we found that arctigenin inhibited the viability of the MCF-7 cells, and colony formation assay confirmed that this effect was cytotoxic rather than cytostatic. The cytotoxic effects were not mediated by cell cycle arrest, apoptosis, or necroptosis, despite DNA damage, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and phosphorylated H2A.X. An increase in lipidated LC3, a marker of autophagosome formation, was observed, indicating that autophagy was induced by arctigenin, which was found to be triggered by the inhibition of the mechanistic target of rapamycin (mTOR) pathway. We then examined the effects of arctigenin on ERalpha expression and determined whether it affects the sensitivity of the cells to tamoxifen, as tamoxifen is commonly used against hormone-responsive cancers and is known to act via the ERalpha. We found that treatment with arctigenin effectively downregulated ERalpha expression, which was found to be a consequence of the inhibition of the mTOR pathway. However, treatment with arctigenin in combination with tamoxifen did not affect the sensitivity of the cells to tamoxifen, but instead, exerted a synergistic effect. On the whole, our data indicate that the phytoestrogen, arctigenin, mainly targeted the mTOR pathway in ERalpha-positive MCF-7 human breast cancer cells, leading to autophagy-induced cell death and the downregulation of ERalpha expression. Furthermore, the synergistic effects between arctigenin and tamoxifen suggest that the consumption of arctigenin is not only safe for patients with hormone-sensitive cancers, but may also be an effective co-treatment. PMID- 29436615 TI - Identification and validation of the role of matrix metalloproteinase-1 in cervical cancer. AB - Lymph node (LN) metastasis at an early stage of cervical cancer is often an indicator of poor prognosis and is critical for subsequent adjuvant therapy. The current study aimed to identify aberrant gene signatures and biomarkers of metastasis for patients with cervical cancer. RNA-sequencing data of 132 LN negative (N0) and 60 LN positive (N1) cervical cancer samples obtained from The Cancer Genome Atlas database were analyzed. Differentially expressed genes were identified using R packages 'edgeR' and 'limma'. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and Gene Set Enrichment Analysis (GSEA) were conducted. The GSE9750 dataset obtained from Gene Expression Omnibus was analyzed to identify genes that are persistently aberrantly expressed during the development of cervical cancer. The peroxisome proliferator-activated receptor (PPAR) signaling pathway was screened out to be significant during LN metastasis. In the two analyzed datasets, 11 genes were aberrantly expressed, while matrix metalloproteinase 1 (MMP1) was the only gene that was persistently overexpressed. Cell viability, wound healing and Transwell assays were performed to evaluate the effects of MMP1 knockdown in cervical cancer cell lines, and the expression of epithelial mesenchymal transition (EMT) markers was detected. Finally, the clinical significance of MMP1 was investigated. The current study identified that MMP1 was overexpressed and the PPAR signaling pathway was associated LN metastasis in patients with cervical cancer. Following knockdown of MMP1, the proliferation, migration and invasion of cervical cancer cell lines were weakened, the expression of epithelial marker E-cadherin was increased, and the expression of metastasis-associated gene vimentin was decreased. MMP1 was an independent prognostic factor for cervical cancer. The current study indicated that MMP1 has a key role in the regulation of cervical tumor growth and LN metastasis via EMT to a certain extent. The results suggest that MMP1 may be a biomarker for LN metastasis of cervical cancer, and further validation should be performed. PMID- 29436616 TI - Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells. AB - Pentoxifylline (PTX), a xanthine family molecule and simvastatin (SIM), an anti hypercholesterolemic agent, have recently been considered as sensitizers to chemotherapy and radiotherapy. The present in vitro study evaluated their antitumor synergistic effects on MDA-MB-231 breast cancer cells characterized by the triple-negative phenotype (TNP). The anti-proliferative effects of these two agents were evaluated by MTT and clonogenic assays. Cell cycle progression was examined using propidium iodide staining. Apoptosis was investigated by Annexin V labeling, and by examining caspase 3 activity and DNA fragmentation. Autophagic vesicles and reactive oxygen species (ROS) levels were monitored by flow cytometry. Western blot analysis was performed to evaluate molecular targets. Our results revealed that when used alone, PTX and SIM exerted antitumor effects. Nevertheless, used in combination, the inhibition of cell proliferation was synergistically superior (80% vs 42%) than that observed following treatment with each agent alone after 48 h. PTX alone (0.5 mM) induced both apoptosis (25%) and autophagy (25%); however, when used in combination with SIM (0.5 uM), the balance between these processes was disrupted and the cells underwent apoptosis (>65%) as opposed to autophagy (<13%). This imbalance was associated with an increase in ERK1/2 and AKT activation, but not with an increase in mTOR phosphorylation, and with the suppression of the NF-kappaB pathway. In addition, in the cells treated with both agents, almost 78% of the cells were arrested at the G0/G1 phase and lost their colony-forming ability (38+/-5%) compared to the cells treated with PTX alone (115+/-5%). On the whole, these results suggest that the induction of autophagy may be a protective mechanism preventing MDA-MB-231 cancer cell death. The combined use of PTX and SIM may drive dormant autophagic cancer cells to undergo apoptosis and thus this may be a novel treatment strategy for breast cancer characterized by the TNP. PMID- 29436617 TI - RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling. AB - Pancreatic cancer is a lethal disease with a high metastatic potential. In our previous study, we identified a specific subgroup of patients with pancreatic cancer with a serum signature of carcinoembryonic antigen (CEA)+/cancer antigen (CA)125+/CA19-9 >=1,000 U/ml. In this study, by using high-throughput screening analysis, we found that receptor-interacting protein kinases 4 (RIPK4) may be a key molecule involved in the high metastatic potential of this subgroup of patients with pancreatic cancer. A high RIPK4 expression predicted a poor prognosis and promoted pancreatic cancer cell migration and invasion via the RAF1/MEK/ERK pathway. Moreover, RIPK4 activated the RAF1/MEK/ERK pathway by regulating proteasome-mediated phosphatidylethanolamine binding protein 1 (PEBP1) degradation. The suppression of PEBP1 degradation eliminated the RIPK4-induced activation of RAF1/MEK/ERK signaling and pancreatic cancer cell migration or invasion. Thus, on the whole, the findings of this study indicated that RIPK4 was upregulated in the subgroup of pancreatic cancer with a high metastatic potential. RIPK4 overexpression promoted pancreatic cancer cell migration and invasion via the PEBP1 degradation-induced activation of the RAF1/MEK/ERK pathway. PMID- 29436618 TI - Role of autophagy in breast cancer and breast cancer stem cells (Review). AB - Autophagy is a key catabolic process, in which cytosolic cargo is engulfed by the formation of a double membrane and then degraded through the fusing of autophagosomes with lysosomes. Autophagy is a constitutively active, evolutionarily conserved, catabolic process important for the maintenance of homeostasis in cellular stress responses and cell survival. Although the mechanisms of autophagy have not yet been fully elucidated, emerging evidence suggests that it plays a dual role in breast cancer and in maintaining the activity of breast cancer stem cells (CSCs). However, it may play a complex role in breast CSC therapy. Breast CSCs, a population of cells with the ability to self-renew, differentiate, and initiate and sustain tumor growth, play an essential role in cancer recurrence, anticancer resistance and metastasis. In addition, the elucidation of the association between autophagy and apoptosis in the tumor context is crucial in order to better address appropriate therapy strategies. In the present review, a summary of the mechanisms and roles of autophagy in breast cancer and CSCs is presented. The potential value of such autophagy modulators in the development of novel breast cancer therapies is discussed. PMID- 29436619 TI - A six-long non-coding RNA signature predicts prognosis in melanoma patients. AB - The aim of this study was to identify long non-coding RNAs (lncRNAs) which may prove useful for risk-classifying patients with melanoma. For this purpose, based on a dataset from The Cancer Genome Atlas (TCGA), we selected and analyzed samples from melanoma stages I, II, III and IV, from which differentially expressed lncRNAs were identified. The lncRNAs were classified using two-way hierarchical clustering analysis and analysis of support vector machine (SVM), followed by Kaplan-Meier survival analysis. The prognostic capacity of the signature was verified on an independent dataset. lncRNA-mRNA networks were built using signature lncRNAs and corresponding target genes. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was conducted on the target genes. A total of 48 differentially expressed lncRNAs were identified, from which 6 signature lncRNAs (AL050303 and LINC00707, LINC01324, RP11-85G21, RP4-794I6.4 and RP5-855F16) were identified. Two-way hierarchical clustering analysis revealed that the accuracy of the six-lncRNA signature in risk-stratifying samples was 84.84%, and the accuracy of the SVM classifier was 85.9%. This predictive signature performed well on the validation dataset [accuracy, 86.76; area under the ROC curve (AUROC), 0.816]. A total of 720 target genes of the 6 lncRNAs were selected for the lncRNA-mRNA networks. These genes were significantly related to mitogen-activated protein kinase (MAPK), the neurotrophin signaling pathway, focal adhesion pathways, and several immune and inflammation-related pathways. On the whole, we identified a six-lncRNA prognostic signature for risk-stratifying patients with melanoma. These lncRNAs may affect prognosis by regulating the MAPK pathway, immune and inflammation-related pathways, the neurotrophin signaling pathway and focal adhesion pathways. PMID- 29436621 TI - Expression and functional analysis of TCF4 isoforms in human glioma cells. AB - Transcription factor 4 (TCF4) is a member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family in the Wnt/beta-catenin signaling pathway. The alternative splicing of TCF4 has been reported to exhibit potential carcinogenic properties in various cancer types. In the present study, TCF4 isoforms were cloned and identified in three human glioma cell lines, with the majority of splicing regions being exons 4, 5, 14, 15, and 16. Using MTT assays, it was demonstrated that the overexpression of TCF4 isoforms inhibits the proliferation of U251 cells. Flow cytometry and wound healing analyses revealed that the overexpression of TCF4 isoforms induced cell apoptosis and migration. Taken together, the beta-catenin binding domain of the TCF4 isoforms inhibited cell proliferation, and induced cell apoptosis and migration in glioma. Furthermore, all the isoforms identified contained the N-terminal part of TCF4 including the beta-catenin binding domain. This implied that a high expression of TCF4 isoforms may lead to Wnt/beta-catenin signal activation and potentially promote malignant glioma development. PMID- 29436620 TI - High glucose induces podocyte epithelial-to-mesenchymal transition by demethylation-mediated enhancement of MMP9 expression. AB - Abnormal expression of matrix metalloproteinase 9 (MMP9) is correlated with podocyte epithelial-to---mesenchymal transition (EMT) in diabetic nephropathy (DN). However, the mechanisms underlying this process are not well defined. Site specific demethylation may sustain high expression levels of target genes. In the present study, in order to investigate the association between DNA demethylation of MMP9 promoter and podocyte EMT in DN, human podocytes were cultured in high glucose (HG) medium and a rat model of DN was established by intraperitoneal injection of streptozotocin (STZ) to determine whether site-specific demethylation of the MMP9 promoter was involved in regulating podocyte EMT in DN. The MTT assay was used to assess the effects of HG culture on the growth of podocytes, and the demethylation status of the MMP9 promoter was assessed by bisulfite sequencing polymerase chain reaction. mRNA and protein expression levels of MMP9, alpha-smooth muscle actin (alpha-SMA), podocalyxin and fibronectin-1 in podocytes were assessed by reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses. The results demonstrated that HG treatment up regulated the expression of MMP9, alpha-SMA and fibronectin-1, but down regulated the expression of podocalyxin in podocytes. The MMP9 promoter region was revealed to contain a variety of demethylated CpG sites, and HG treatment reduced the rate of MMP9 promotermethylation, which, in turn, enhanced its promoter activity. In summary, these data suggested that demethylation of the MMP9 promoter may serve an important role in podocyte EMT in DN. The demethylation status of the MMP9 promoter maybe used as an important prognostic marker of DN in clinic. PMID- 29436622 TI - Hepatocyte growth factor improves bone regeneration via the bone morphogenetic protein-2-mediated NF-kappaB signaling pathway. AB - Bone regeneration is an important process associated with the treatment of osteonecrosis, which is caused by various factors. Hepatocyte growth factor (HGF) is an active biological factor that has multifunctional roles in cell biology, life sciences and clinical medicine. It has previously been suggested that bone morphogenetic protein (BMP)-2 exerts beneficial roles in bone formation, repair and angiogenesis in the femoral head. The present study aimed to investigate the benefits and molecular mechanisms of HGF in bone regeneration. The viability of osteoblasts and osteoclasts were studied in vitro. In addition, the expression levels of tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP) 1, interleukin (IL)-1 and IL-6 were detected in a mouse fracture model following treatment with HGF. The expression and activity of nuclear factor (NF)-kappaB were also analyzed in osteocytes post-treatment with HGF. Histological analysis was used to determine the therapeutic effects of HGF on mice with fractures. The migration and differentiation of osteoblasts and osteoclasts were investigated in HGF-incubated cells. Furthermore, angiogenesis and BMP-2 expression were analyzed in the mouse fracture model post-treatment with HGF. The results indicated that HGF regulates the cell viability of osteoblasts and osteoclasts, and also balanced the ratio between osteoblasts and osteoclasts. In addition, HGF decreased the serum expression levels of TNF-alpha, MCP-1, IL-1 and IL-6 in experimental mice. The results of a mechanistic analysis demonstrated that HGF upregulated p65, IkappaB kinase-beta and IkappaBalpha expression in osteoblasts from experimental mice. In addition, the expression levels of vascular endothelial growth factor, BMP-2 receptor, receptor activator of NF-kappaB ligand and macrophage colony-stimulating factor were upregulated by HGF, which may effectively promote blood vessel regeneration, and contribute to the formation and revascularization of tissue-engineered bone. Furthermore, HGF promoted BMP-2 expression and enhanced angiogenesis at the fracture location. These results suggested that HGF treatment may significantly promote bone regeneration in a mouse fracture model. In conclusion, these results indicated that HGF is involved in bone regeneration, angiogenesis and the balance between osteoblasts and osteoclasts, thus suggesting that HGF may be considered a potential agent for the treatment of fractures via the promotion of bone regeneration through regulation of the BMP-2-mediated NF-kappaB signaling pathway. PMID- 29436623 TI - Development of uracil-DNA-glycosylase-supplemented loop-mediated isothermal amplification coupled with nanogold probe (UDG-LAMP-AuNP) for specific detection of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa (P. aeruginosa) is an important opportunistic pathogen that causes serious infections in humans, including keratitis in contact lens wearers. Therefore, establishing a rapid, specific and sensitive method for the identification of P. aeruginosa is imperative. In the present study, the uracil DNA-glycosylase-supplemented loop-mediated isothermal amplification combined with nanogold labeled hybridization probe (UDG-LAMP-AuNP) was developed for the detection of P. aeruginosa. UDG-LAMP was performed to prevent carry over contamination and the LAMP reactions can be readily observed using the nanogold probe. A set of 4 primers and a hybridization probe were designed based on the ecfX gene. The UDG-LAMP reactions were performed at 65C for 60 min using the ratio of 40% deoxyuridine triphosphate to 60% deoxythymidine triphosphate. The detection of UDG-LAMP products using the nanogold labeled hybridization probe, which appeared as a red-purple color, was examined at 65C for 5 min with 40 mM MgSO4. The UDG-LAMP-AuNP demonstrated specificity to all tested isolates of P. aeruginosa without cross reaction to other bacteria. The sensitivity for the detection of pure culture was 1.6x103 colony-forming units (CFU) ml-1 or equivalent to 3 CFU per reaction while that of polymerase chain reaction was 30 CFU per reaction. The detection limit of spiked contact lenses was 1.1x103 CFU ml 1 or equivalent to 2 CFU per reaction. In conclusion, the UDG-LAMP-AuNP assay was rapid, simple, specific and was effective for the identification of P. aeruginosa in contaminated samples. PMID- 29436624 TI - Clinical verification of Lou type warfarin pharmacokinetic dosing algorithms equation. AB - Warfarin is the most commonly used oral anti-coagulant in clinic practice. However, it is difficult to recommend the correct dosage due to its narrow therapeutic window. The aim of the present study was to verify the clinical value of the Lou type equation, using pharmacogenetics-based warfarin dosing algorithms to appropriately predict the actual maintenance dose. A total of 87 Chinese Han patients who required treatment with warfarin were enrolled and randomly divided into the experimental and control groups. In the experimental group, the first 3 doses of warfarin were calculated according to the Lou type equation. While in the control group, these 3 treatments were performed following the doctors' recommendations. Then the dose of warfarin was gradually adjusted to the stable dose according to the changes in the international standardized ratio. At the end of the 50 day experimental period, there were a greater number of patients in the experimental group who exhibited a stable blood concentration of warfarin than those in the control group (83.35 and 64.4%, respectively). In addition, the mean and median times for patients to obtain a stable dose in the experimental group were significantly shorter than those in the control group (mean, 18.2+/-1.7 and 27.3+/-2.0 days; and median, 11.7+/-1.1 and 20.5+/-1.8 days, respectively). The adverse reaction rate of the experimental group (9.5%) was markedly lower than that of the control group (26.7%). The occurrence of adverse reactions in the experimental group was also significantly later when compared with the control group (43.9+/-1.6 and 38.6+/-1.5 days, respectively). Furthermore, there was no significant difference between the average predicted dose (3.4+/-1.1 mg/day) and the average actual dose (3.5+/-1.4 mg/day; P=0.313). In conclusion, using the Lou type warfarin pharmacokinetic dosing algorithm equation to administer warfarin markedly shortened the adjustment time of warfarin to reach a stable dose and reduced the adverse reactions rate, thus supporting clinical feasibility. PMID- 29436625 TI - Allicin induces apoptosis through activation of both intrinsic and extrinsic pathways in glioma cells. AB - Allicin is an extract purified from Allium sativum (garlic), and previous research has indicated that Allicin has an inhibitory effect on many kinds of tumor cells. The aim of the present study was to explore the anticancer activity of Allicin on human glioma cells and investigate the underlying mechanism. MTT and colony-formation assays were performed to detect glioma cell proliferation, and explore the effect of Allicin at various doses and time-points. The apoptosis of glioma cells was measured by fluorescence microscopy with Hoechst 33258 staining, and then flow cytometry was used to analyzed changes in glioma cell apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the effect of Allicin on the expression levels of Fas/Fas ligand (FasL), caspase-3, B-cell lymphoma 2 and Bcl-2 associated X protein. Allicin suppressed the proliferation and colony formation ability of U251 cells in a dose- and time-dependent manner. A cytotoxic effect of Allicin was observed in glioma cells in a dose-dependent manner. Changes in nuclear morphology were observed in U251 cells with Hoechst 33258 staining. The activity of caspases were significantly elevated and Fas/FasL expression levels were increased following treatment with Allicin, at both the mRNA and protein level. These results demonstrated that Allicin suppresses proliferation and induces glioma cell apoptosis in vitro. Both intrinsic mitochondrial and extrinsic Fas/FasL-mediated pathways react in glioma cell after treating with Allicin, which then activate major apoptotic cascades. These results implicate Allicin as a novel antitumor agent in treating glioma. PMID- 29436626 TI - Effects of recombinant human parathyroid hormone (1-34)on cell proliferation, chemokine expression and the Hedgehog pathway in keratinocytes. AB - Psoriasis is an autoimmune disease involving the excessive proliferation of keratinocytes mediated by T-cells. Parathyroid hormone (PTH) has been identified as an essential factor in the treatment of psoriasis. In the present study, the mechanism underlying the effect of recombinant human parathyroid hormone (rhPTH) (1-34) in keratinocytes was investigated. The effects of rhPTH (1-34) on cell proliferation, cell cycle, and the secretion and expression of C-X-C motif chemokine 11 (CXCL11) and components of the Hedgehog signaling pathway were examined in HaCaT cells by MTT assay, flow cytometric analysis, ELISA and gene chip analysis. The data showed that rhPTH (1-34) significantly inhibited keratinocyte proliferation at concentrations >8x10-7 mol/l. rhPTH (1-34) induced G1 phase arrest of the cell cycle in the keratinocytes. The secretion of CXCL11 in tumor necrosis factor (TNF)-alpha-induced keratinocytes was downregulated by rhPTH (1-34) in a dose-dependent manner, compared with that in keratinocytes treated with TNF-alpha alone. It was also found that rhPTH (1-34) inhibited the expression of CXCL11 in the HaCaT cells. rhPTH (1-34) also affected the Hedgehog signaling pathway specifically by regulating the expression of associated genes. In conclusion, these data suggested that rhPTH (1-34) inhibited cell proliferation, and the secretion and expression of CXCL11 in HaCaTs. rhPTH (1-34) also altered the expression of associated genes in the Hedgehog pathway. Therefore, rhPTH (1-34) can be considered as a novel therapeutic agent for the treatment of psoriasis. PMID- 29436627 TI - Combination of Runx2 and Cbfbeta upregulates Amelotin gene expression in ameloblasts by directly interacting with cis-enhancers during amelogenesis. AB - Amelotin (Amtn) is a recently identified enamel protein secreted by ameloblasts at late stage of enamel development. Runt-related transcription factor 2 (Runx2) in combination with the coactivator core-binding factor beta (Cbfbeta) regulates the early stages of tooth development. The aim of the present study was to investigate the role of Runx2 in the regulation of Amtn gene expression in ameloblasts. Immunohistochemistry was performed and the results revealed that Runx2 protein was predominantly expressed in the nuclei of ameloblasts during the transition stage and the maturation stage of enamel development, whereas Cbfbeta was expressed in ameloblasts from the secretory stage to the maturation stage. Reverse transcription-quantitative polymerase chain reaction results demonstrated that Runx2 knockdown decreased Amtn expression in ameloblast-lineage cells and co expression of Runx2 and Cbfbeta in ameloblast lineage cells induced an upregulation in Amtn gene expression. Two putative Runx2-binding sites within the Amtn promoter were identified using bioinformatics analysis. Results of an electrophoretic mobility shift assay and chromatin immunoprecipitation indicated that Runx2/Cbfbeta bound to specific DNA sequences. Site-directed mutagenesis of the Runx2 binding sites within the Amtn promoter resulted in decreased basal promoter activity and did not affect the overexpressed Runx2/Cbfbeta. The results of the present study suggest that Runx2 upregulates Amtn gene expression via binding directly to Runx2 sites within the Amtn promoter during amelogenesis. PMID- 29436628 TI - Gene expression profile analysis of the progression of carotid atherosclerotic plaques. AB - The present study aimed to examine the universal gene expression signature and the underlying molecular mechanisms involved in the progression of carotid atherosclerotic plaques. The gene expression dataset, GSE28829, containing 13 early and 16 advanced carotid atherosclerotic plaques was selected for analysis. The differentially expressed genes (DEGs) were identified and analyzed using bioinformatics analyses, including cluster analysis, Gene Ontology (GO) and pathway enrichment analyses. Finally, a protein-protein interaction (PPI) was constructed and analyzed. A total of 515 downregulated and 243 downregulated DEGs were identified. The cluster analysis revealed two separate two groups. In addition, the GO terms enriched by the upregulated DEGs were associated with immune response, and the downregulated DEGs were associated with cell adhesion. The upregulated DEGs were enriched in pathways associated with signaling in the immune system, and the downregulated DEGs were enriched in pathways associated with muscle contraction. In the PPI network analysis, ITGAM and ACTN2 had the highest decrees of connectivity in the upregulated and downregulated DEGs, respectively. These findings suggested that deregulation of the immune system and smooth muscle cell cytoskeleton accelerates the progression of carotid atherosclerotic plaques. The DEGs identified may offer potential in the prevention and treatment of atherosclerosis in the carotid artery. PMID- 29436629 TI - Cognitive improvement following ischemia/reperfusion injury induced by voluntary running-wheel exercise is associated with LncMALAT1-mediated apoptosis inhibition. AB - Previous human and animal studies demonstrated that voluntary exercise may improve cognitive function and facilitate neuronal plasticity in ischemia/reperfusion (I/R) models. However, the possible underlying mechanisms remain to be elucidated. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA (lncRNA), may be associated with the functions and dysfunctions of endothelial cells. The present study investigated whether spontaneous running-wheel (RW) exercise-induced MALAT1 expression changes may be associated with the cognitive improvement of mice following I/R injury. The expression of MALAT1 was evaluated using reverse transcription-quantitative polymerase chain reaction. Artificial MALAT1 and MALAT1 lentiviral mall interfering (siRNA) were used to alter MALAT1 expression levels in vivo. The Morris Water Maze test was performed to evaluate spatial learning and memory retention in the mice. Changes in the apoptotic rates of hippocampal neurons and levels of apoptosis-associated proteins were also detected. The data revealed that MALAT1 increased in the hippocampus of mice in the RW-treated I/R group and that this was associated with neurological, learning and memory improvement, reduced infarction volumes, decreased apoptosis and alterations to expression levels of apoptosis-associated proteins. Following RW training in I/R-injured mice, lentiviral MALAT1 siRNA conduction partially attenuated the protections induced by voluntary RW. However, exogenous MALAT1 treatment increased the protection. The current findings suggested that voluntary RW protected hippocampal neurons from I/R injury and promoted cognitive restoration, which was associated with lncRNA MALAT1-mediated apoptosis inhibition. PMID- 29436630 TI - Silencing of B7-H4 suppresses the tumorigenicity of the MGC-803 human gastric cancer cell line and promotes cell apoptosis via the mitochondrial signaling pathway. AB - B7-H4 is a transmembrane protein which is a member of the B7 superfamily. It is overexpressed in various types of cancer, including gastric cancer. However, the effects of B7-H4 on the tumorigenicity of gastric cancer and the underlying mechanisms have not yet been fully explored. Thus, the aim of this study was to examine the effects of B7-H4 on the tumorigenicity of gastric cancer cells and to elucidate the underlying mechanisms. For this purpose, B7-H4 expression in gastric cancer tissues was detected by immunohistochemical staining. The effects of B7-H4 on the biological behavior of the MGC-803 human gastric cancer cell line were examined by Cell Counting kit-8 (CCK-8) assay, cell cycle analysis, wound healing assay, Annexin V/propidium iodide staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Moreover, the expression levels of apoptotic markers, such as cleaved caspase-3, cleaved caspase-9, Bcl-2 and Bax were examined by western blot analysis. Immunohistochemical staining revealed that a high expression of B7-H4 was found in about 41.8% of tissues obtained from patients with gastric cancer. Comparative analysis revealed that B7-H4 expression significantly correlated with lymph node metastasis and the TNM stage. The results of CCK-8 assay, cell cycle analysis, wound healing assay, Annexin V/propidium iodide staining assay and TUNEL assay all demonstrated that the silencing of B7-H4 by small interfering RNA decreased cell proliferation, suppressed cell motility, and induced cell cycle arrest and the apoptosis of MGC 803 human gastric cancer cells. Furthermore, the results of western blot analysis indicated that the downregulation of B7-H4 induced the apoptosis of the MGC-803 cells via the mitochondrial signaling pathway through the activation of caspase-3 and caspase-9, and by altering the Bax/Bcl-2 ratio in a manner that favored apoptosis. Based on the findings on human gastric cancer cell line MGC-803, the findings of this study suggested that B7-H4 may have the potential to be a valuable prognostic marker and a target for individualized therapies for gastric cancer. However, further investigations are required in order to confirm our findings on a larger scale. PMID- 29436631 TI - TRP-2 mediates coat color pigmentation in sheep skin. AB - Tyrosinase-related protein 2 (TRP-2) is one of the most important members of the tyrosinase family, and is a key enzyme involved in melanin biosynthesis. In the present study, a skin transcriptome profile, immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction were used to investigate TRP-2 expression in sheep with different coat colors, namely, black, white and black-white. TRP-2 was overexpressed in melanocytes in order to study the effect of TRP-2 on melanin production. Results revealed differing TRP-2 levels in sheep of different coat colors and in various parts of the coat with different colors in the same sheep. TRP-2 expression levels in dark-colored areas were significantly increased compared with light-colored areas in piebald sheep. TRP-2 overexpression may regulate melanogenesis and significantly increase melanogenesis associated transcription factor expression in vitro. Therefore, TRP 2 may affect melanin production in sheep, and different expression levels determine coat color. The results may provide novel approaches for developing therapeutic strategies for skin diseases associated with pigmentation disorders. PMID- 29436632 TI - Sparstolonin B attenuates spinal cord injury-induced inflammation in rats by modulating TLR4-trafficking. AB - The present study used a spinal cord injury (SCI) model to evaluate whether sparstolonin B was able to prevent SCI, and to investigate the underlying signaling mechanism. Sparstolonin B attenuated the SCI-induced Batto, Beattie and Bresnahan score and water content in rats. Sparstolonin B attenuated the mRNA expression of proinflammatory cytokines interleukin (IL)-18, IL-6, IL-1beta, and IL-23, decreased the levels of tumor necrosis factor-alpha and interferon-gamma, and decreased caspase-3 activity and apoptosis regulator Bax protein expression in SCI rats. Similarly, sparstolonin B inhibited monocyte chemoattractant protein 1 mRNA levels, and Toll-like receptor (TLR) 4, myeloid differentiation primary response protein MyD88 (MyD88) and nuclear factor (NF)-kappaB protein levels in SCI rats. The present results suggested that sparstolonin B may attenuate SCI induced inflammation and apoptosis in rats by modulating the TLR4/MyD88/NF-kappaB signaling pathway. PMID- 29436633 TI - Microarray analysis for the identification of specific proteins and functional modules involved in the process of hepatocellular carcinoma originating from cirrhotic liver. AB - In order to identify the potential pathogenesis of hepatocellular carcinoma (HCC) developing from cirrhosis, a microarray-based transcriptome profile was analyzed. The GSE63898 expression profile was downloaded from the Gene Expression Omnibus database, which included data from 228 HCC tissue samples and 168 cirrhotic tissue samples. The Robust Multi-array Average in the Affy package of R was used for raw data processing and Student's t-test was used to screen differentially expressed genes (DEGs). An enrichment analysis was then conducted using the Database for Annotation, Visualization and Integrated Discovery online tool, and the protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. Furthermore, the MCODE plug-in of Cytoscape was used to conduct a sub-module analysis. A total of 634 DEGs were identified between HCC and cirrhosis, of which 165 were upregulated and 469 were downregulated. According to the cut-off criteria, the PPI network was constructed and Jun proto-oncogene, AP-1 transcription factor subunit (degree, 39), Fos proto-oncogene, AP-1 transcription factor subunit (degree, 34) and v-myc avian myelocytomatosis viral oncogene homolog (degree, 32) were identified as the hub nodes of the PPI network. Based on the sub-module analysis, four specific modules were identified. In particular, module 1 was significantly enriched in the chemokine signaling pathway, and C-X-C motif chemokine ligand 12, C-C motif chemokine receptor 7 (CCR7) and C-C motif chemokine ligand 5 (CCL5) were three important proteins in this module. Module 4 was significantly enriched in chemical carcinogenesis, and cytochrome P450 family 2 subfamily E member 1, cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily A member 6 (CYP2A6) were three important proteins in this module. In conclusion, the present study revealed that CCR7, CCL5, CYP2C9 and CYP2A6 are novel genes identified in the development of HCC; however, the actual functions of these genes require verification. PMID- 29436634 TI - Capsaicin inhibits glycolysis in esophageal squamous cell carcinoma by regulating hexokinase-2 expression. AB - Capsaicin is a principal component of hot red peppers and chili peppers. Previous studies have reported that capsaicin exhibits antitumor functions in a variety of tumor models. Although various mechanisms underlying the capsaicin-mediated inhibition of tumor growth have been demonstrated, the impact of capsaicin on tumor metabolism has rarely been reported. The present study demonstrated that capsaicin exhibited an inhibitory effect on tumor glycolysis in esophageal squamous cell carcinoma (ESCC) cells. Following treatment with capsaicin, glucose consumption and lactate production in ESCC cells was decreased. Capsaicin resulted in a decrease of hexokinase-2 (HK-2) expression, which is known for its important role in tumor glycolysis. Further investigations demonstrated that phosphatase and tensin homolog (PTEN) expression was increased in ESCC cells treated with capsaicin, and that the RAC-alpha serine threonine-protein kinase signaling pathway was downregulated. In PTEN-knockdown KYSE150 cells, the decrease in HK-2 and inhibition of glycolysis caused by capsaicin was attenuated, which suggested that the impact of capsaicin on tumor metabolism was associated with its effect on PTEN. PMID- 29436635 TI - Differential expression profiles of long noncoding RNA and mRNA in colorectal cancer tissues from patients with lung metastasis. AB - Lungs are the most common extra-abdominal site of metastasis of colorectal cancer (CRC), in which long noncoding RNA (lncRNA) may serve a role. In the present study, a high-throughput microarray assay was performed to detect lncRNA expression and identify novel targets for further study of lung metastasis in CRC. In the CRC tissues from patients with lung metastasis, 7,632 lncRNA (3,574 upregulated and 4,058 downregulated) and 6,185 mRNA (3,394 upregulated and 2,791 downregulated) were detected to be differentially expressed with a fold change >=2 and P<0.05 compared with the CRC tissues without metastasis. A total of six differentially regulated lncRNA were confirmed by reverse transcription quantitative polymerase chain reaction in 20 pairs of CRC samples. Furthermore, gene ontology and pathway analysis were conducted to predict the possible roles of the identified mRNA. The upregulated mRNA were associated with cell division (biological processes), protein kinase B binding (molecular functions) and cellular components. The downregulated mRNA were associated with cell adhesion, platelet-derived growth factor binding and membrane components. Pathway analysis determined that the upregulated mRNA were associated with the Wnt signaling pathway in the CRC tissues from patients with lung metastasis, while the downregulated mRNA were associated with the phosphoinositide 3-kinase/Akt signaling pathway. The results of the present study suggested that differentially expressed lncRNA may be associated with lung metastasis and may provide insights into the biology and prevention of lung metastasis. PMID- 29436637 TI - Nicotinamide phosphoribosyltransferase and the hypothalamic-pituitary-adrenal axis of the rat. AB - Nicotinamide phosphoribosyltransferase (Nampt), also termed visfatin, catalyses the rate-limiting step in the nicotinamide adenine dinucleotide (NAD) salvage pathway. In addition to its intracellular function (iNampt), extracellular Nampt (eNampt) also affects numerous intracellular signalling pathways. The current study investigated the role of Nampt in the regulation of the hypothalamic pituitary-adrenal (HPA) axis in rats. At 1 h after intraperitoneal administration of eNampt (4 ug/100 g) in adult male rats, serum adrenocorticotropic hormone(ACTH) and aldosterone levels remained unchanged, while corticosterone levels were notably elevated compared with the control group, as determined by ELISA. The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) demonstrated that, in the hypothalami of eNampt-treated rats, the mRNA expression levels of Fos proto-oncogene, which is also termed c-Fos, were not significantly different compared with the control group; however, the mRNA expression levels of proopiomelanocortin (POMC) were markedly increased in the pituitary gland of eNampt-treated rats compared with the control group. Furthermore, in hypothalamic explants, ELISA results demonstrated that the addition of the eNampt protein exhibited no effect on corticotropin-releasing hormone (CRH) release into the incubation medium and prevented potassium ion induced CRH release. Additionally, the eNampt-induced increase in ACTH output by pituitary gland explants was not statistically significant, compared with the control group. However, RT-qPCR indicated that exposure of pituitary gland explants to eNampt and CRH increased the levels of POMC mRNA expression; the effect of eNampt, but not CRH, was inhibited by FK866, which is a specific Nampt inhibitor. In primary rat adrenocortical cell cultures, eNampt exhibited no effect on basal aldosterone or corticosterone secretion, while increases in aldosterone and corticosterone levels in response to ACTH were retained. To assess the potential role of iNampt in the regulation of adrenal steroidogenesis, experiments involving a specific Nampt inhibitor, FK866, were performed. Exposure of cultured cells to FK866 notably lowered basal aldosterone and corticosterone output compared with the control group, and completely eliminated the response of cultured cells to ACTH. The results of the present study indicated that the injected eNampt may have increased the corticosterone serum levels by acting at the pituitary level. In addition, iNampt may exert a tonic stimulating effect on the secretion of aldosterone and corticosterone from rat adrenocortical cells, as normal iNampt levels were required to retain the response of cultured rat adrenocortical cells to ACTH. Thus, these data suggest an important physiological role of both iNampt and eNampt in the regulation of the HPA axis activity in the rat. PMID- 29436636 TI - Effects of bradykinin on TGF-beta1-induced epithelial-mesenchymal transition in ARPE-19 cells. AB - The aim of the present study was to investigate the effects of bradykinin (BK) on an epithelial-mesenchymal transition (EMT) model in retinal pigment epithelium (RPE) cells through exposure to transforming growth factor-beta1 (TGF-beta1). The aim was to improve the effect of BK on proliferative vitreoretinopathy (PVR) progression, and to find a novel method of clinical prevention and treatment for PVR. The morphology of ARPE-19 cells was observed using an inverted phase contrast microscope. A Cell Counting Kit-8 was used to assess the effects of TGF beta1 on the proliferation of ARPE-19 cells. Western blotting and immunofluorescence were used to detect the expression levels of the epithelial marker E-cadherin, mesenchymal markers alpha-smooth muscle actin (SMA) and vimentin, and phosphorylated (p) mothers against decapentaplegic homolog (Smad)3 and Smad7 of the TGF/Smad signaling pathway. Wound healing tests and Transwell assays were performed to detect cell migration ability. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis was performed to detect the expression levels of pSmad3 and Smad7 in the TGF/Smad signaling pathway. The results revealed that the addition of 10 ng/ml TGF-beta1 resulted in the expression of factors associated with EMT in ARPE-19 cells. BK decreased the expression levels of the mesenchymal markers alpha-SMA and vimentin, and increased the expression of the epithelial marker E-cadherin. BK decreased cell migration in TGF-beta1-induced EMT. These effects were reversed by HOE-140, a specific BK 2 receptor antagonist. BK significantly downregulated the expression of pSmad3 and upregulated the expression of Smad7 in TGF-beta1-treated ARPE-19 cells, and the protective alterations produced by BK were inhibited by HOE-140. In conclusion, 10 ng/ml TGF-beta1 resulted in EMT in ARPE-19 cells and BK served a negative role in TGF-beta1-induced EMT. BK had effects in TGF-beta1-induced EMT by upregulating the expression of Smad7 and downregulating the expression of pSmad3 in TGF-beta/Smad signaling pathway, indicating that BK may be a novel and effective therapy for PVR. PMID- 29436638 TI - Anticancer activity of caffeic acid n-butyl ester against A431 skin carcinoma cell line occurs via induction of apoptosis and inhibition of the mTOR/PI3K/AKT signaling pathway. AB - Skin cancer is one of the primary causes of mortality worldwide. With an increasing frequency of skin cancers, there is an urgent requirement for the development of numerous treatment options. The present study investigated the anticancer activity of caffeic acid n-butyl ester (CAE) against the A431 skin cancer cell line. Antiproliferative effects were investigated using an MMT assay. Apoptosis was examined by DAPI and Annexin V/fluorescein isothiocyanate and propidium iodide staining. Reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and cell cycle analyses were performed via flow cytometry. Protein expression was determined by western blotting. The findings of the present study demonstrated that among a variety of cancer cell lines, CAE exhibited significant anticancer activity against the A431 skin cancer cell line with a half-maximal inhibitory concentration of 20 uM. CAE was associated with apoptosis and cell cycle arrest of A431 cells, and induced ROS-mediated alterations in MMP. In addition, CAE considerably suppressed the expression of some of the important proteins of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) cascade. The results of the present study indicated that CAE exerted anticancer effects on the A431 skin carcinoma cell line via the induction of apoptosis and suppression of the PI3K/AKT/mTOR signaling pathway. Therefore, CAE may be beneficial for the development of chemotherapy for skin cancers. PMID- 29436639 TI - Glycyrrhizin affects monocyte migration and apoptosis by blocking HMGB1 signaling. AB - Monocytes serve an important role in systemic inflammation. High mobility group box-1 protein (HMGB1) promotes recruitment and suppresses apoptosis in monocytes through the receptor for advanced glycation end products/ nuclear factor (NF) kappaB and toll-like receptor 4/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways. Glycyrrhizin (GL), an effective component of licorice, weakens the proinflammatory effect of HMGB1. The present study investigated the effect of GL on the migration and apoptosis of monocytes associated with HMGB1 signaling. THP 1 cells were used to evaluate the behavior of monocytes in response to GL treatment, and the downstream pathways were investigated. GL suppressed HMGB1 induced monocyte migration and increased HMGB1-inhibited monocyte apoptosis. GL inhibited the activation of the NF-kappaB and MAPK/ERK signaling pathways induced by HMGB1 and decreased the expression of monocyte chemoattractant protein-1 (MCP 1) and myeloid cell leukemia 1 (Mcl-1). Taken together, the results indicated that GL may suppress the migration of monocytes and induce apoptosis to reduce systemic inflammation by blocking downstream NF-kappaB/MCP-1 and MAPK/ERK/Mcl-1 signaling pathways. PMID- 29436640 TI - [Corrigendum] Roles and mechanisms of TRPC3 and the PLCgamma/PKC/CPI-17 signaling pathway in regulating parturition. AB - Subsequent to the publication of the above paper, the authors have realized that there were errors in Fig. 1 on page 902; essentially, the experimental data described as being 'Preterm' and 'Infected preterm' should have been labelled as 'Full-term without labor' and 'Preterm', respectively. Note that these errors in Fig. 1 were not reflected in the published figure legend. The corrected version of Fig. 1 is shown here. The authors sincerely apologize for this mistake, and regret any inconvenience this mistake has caused. [the original article was published in the Molecular Medicine Reports 17: 898-910, 2018; DOI: 10.3892/mmr.2017.7998]. PMID- 29436641 TI - miR-203 contributes to pre-eclampsia via inhibition of VEGFA expression. AB - Pre-eclampsia (PE) is a common but complex condition that can occur in pregnancy. It is estimated to affect 3-8% of pregnancies worldwide. PE development is thought to be multifactorial and to involve the dysregulation of microRNA (miR) expression. However, the precise mechanisms of PE development remain unclear. The present study aimed to illustrate the association between miR-203 expression and PE development in samples of human placenta collected from mothers with (n=18) and without (n=20) PE. It was demonstrated that miR-203 expression was significantly increased in the PE placenta compared with the normal placenta samples, while the expression of vascular endothelial growth factor A (VEGFA) was decreased. In vitro experiments revealed that miR-203 overexpression significantly downregulated VEGFA expression and inhibited the proliferation, migration and invasion ability of HTR-8/SVneo cells. Suppression of miR-203 expression alleviated these effects. A luciferase reporter assay confirmed the interaction of the 3'-untranslated region of VEGFA with miR-203. Thus, miR-203 may have significant contribution to the development of PE by targeting VEGFA in the human placenta and may have potential as a biomarker or therapeutic target in the treatment of PE. PMID- 29436642 TI - Synergistic anticancer effects of ruxolitinib and calcitriol in estrogen receptor positive, human epidermal growth factor receptor 2-positive breast cancer cells. AB - The Janus kinase (JAK)1 and JAK2 inhibitor, ruxolitinib, and the active form of vitamin D (calcitriol) were previously reported to possess anticancer effects in breast cancer. The present study investigated the combined effects of ruxolitinib and calcitriol on an estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive, breast cancer cell line. The ER and HER2 positive MCF7-HER18 breast cancer cell line was used to investigate the combination effect of ruxolitinib and calcitriol. A bromodeoxyuridine (BrdU) assay was used to investigate cell growth inhibition. The synergism of this combination therapy was examined using the Chou-Talalay method. Cell cycle analysis was performed by flow cytometry, and apoptosis was evaluated by flow cytometry following Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) staining. Alterations in protein expression levels were analyzed by western blotting. The BrdU assay indicated that combination treatment using ruxolitinib and calcitriol produced a synergistic anti-proliferative effect in MCF7-HER18 breast cancer cells. Annexin V-FITC/PI staining and cell cycle analysis identified a synergistic increase in apoptosis and sub-G1 arrest in the presence of ruxolitinib and calcitriol. Western blot analysis revealed that these synergistic effects of ruxolitinib and calcitriol were associated with reduced protein levels of JAK2, phosphorylated JAK2, c-Myc proto oncogene protein, cyclin D1, apoptosis regulator Bcl-2 and Bcl-2-like protein 1, and with increased levels of caspase-3 and Bcl-2-associated agonist of cell death proteins. The results of the present study demonstrated the synergistic anticancer effects of ruxolitinib and calcitriol in ER and HER2-positive MCF7-HER18 breast cancer cells. Based on these findings, ruxolitinib and calcitriol may have potential as a combination therapy for patients with ER and HER2-positive breast cancer. PMID- 29436643 TI - Neuroprotective effect of lurasidone via antagonist activities on histamine in a rat model of cranial nerve involvement. AB - Cranial nerve involvement frequently involves neuron damage and often leads to psychiatric disorder caused by multiple inducements. Lurasidone is a novel antipsychotic agent approved for the treatment of cranial nerve involvement and a number of mental health conditions in several countries. In the present study, the neuroprotective effect of lurasidone by antagonist activities on histamine was investigated in a rat model of cranial nerve involvement. The antagonist activities of lurasidone on serotonin 5-HT7, serotonin 5-HT2A, serotonin 5-HT1A and serotonin 5-HT6 were analyzed, and the preclinical therapeutic effects of lurasidone were examined in a rat model of cranial nerve involvement. The safety, maximum tolerated dose (MTD) and preliminary antitumor activity of lurasidone were also assessed in the cranial nerve involvement model. The therapeutic dose of lurasidone was 0.32 mg once daily, administered continuously in 14-day cycles. The results of the present study found that the preclinical prescriptions induced positive behavioral responses following treatment with lurasidone. The MTD was identified as a once daily administration of 0.32 mg lurasidone. Long-term treatment with lurasidone for cranial nerve involvement was shown to improve the therapeutic effects and reduce anxiety in the experimental rats. In addition, treatment with lurasidone did not affect body weight. The expression of the language competence protein, Forkhead-BOX P2, was increased, and the levels of neuroprotective SxIP motif and microtubule end-binding protein were increased in the hippocampal cells of rats with cranial nerve involvement treated with lurasidone. Lurasidone therapy reinforced memory capability and decreased anxiety. Taken together, lurasidone treatment appeared to protect against language disturbances associated with negative and cognitive impairment in the rat model of cranial nerve involvement, providing a basis for its use in the clinical treatment of patients with cranial nerve involvement. PMID- 29436644 TI - Phenformin inhibits cell proliferation and induces cell apoptosis and autophagy in cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is an aggressive malignant tumor and the prognosis of patients with advanced stage disease remains poor. Therefore, the identification of novel treatment agents for CCA is required. In the present study, the biological effects of the diabetes therapeutic agent, phenformin, in CCA cell lines was investigated. Cell Counting Kit-8 cell viability, cellular clone formation and subcutaneous tumor formation assays were performed, which revealed that phenformin inhibited CCA cell proliferation and growth both in vitro and in vivo. In addition, phenformin induced CCA cell apoptosis and autophagy. Phenformin partly activated the liver kinase B1 (LKB1)/5' AMP-activated protein kinase signaling pathway to exert its biological effects on CCA cell lines, as demonstrated by knockdown of LKB1, which reversed these effects. In conclusion, the present study demonstrated the biological effects of phenformin in CCA and suggested that phenformin may be a potential novel agent for CCA treatment. PMID- 29436645 TI - Ouabain suppresses the growth and migration abilities of glioma U-87MG cells through inhibiting the Akt/mTOR signaling pathway and downregulating the expression of HIF-1alpha. AB - Glioma is one of the most malignant forms of brain tumor, and has been of persistent concern due to its high recurrence and mortality rates, and limited therapeutic options. As a cardiac glycoside, ouabain has widespread applications in congestive heart diseases due to its positive cardiac inotropic effect by inhibiting Na+/K+-ATPase. Previous studies have demonstrated that ouabain has antitumor activity in several types of human tumor, including glioma. However, the exact underlying mechanism remains to be elucidated. The purpose of present study was to elucidate the effect of ouabain on human glioma cell apoptosis and investigate the exact mechanism. U-87MG cells were treated with various concentrations of ouabain for 24 h, following which cell viability and survival rate were assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The dynamic changes and cell motility were observed using digital holographic microscopy. Additionally, western blot analysis and high-content screening assays were used to detect the protein expression levels of phosphorylated (p-)Akt, mammalian target of rapamycin (mTOR), p-mTOR and hypoxia inducible factor (HIF)-1alpha, respectively. Compared with the control group, ouabain suppressed U-87MG cell survival, and attenuated cell motility in a dose dependent manner (P<0.01). The downregulation of p-Akt, mTOR, p-mTOR and HIF 1alpha were observed following treatment with 2.5 and 25 umol/l of ouabain. These results suggested that ouabain exerted suppressive effects on tumor cell growth and motility, leading to cell death via regulating the intracellular Akt/mTOR signaling pathway and inhibiting the expression of HIF-1alpha in glioma cells. The present study examined the mechanism underlying the antitumor property of ouabain, providing a novel potential therapeutic agent for glioma treatment. PMID- 29436646 TI - In vitro evaluation of a bone morphogenetic protein-2 nanometer hydroxyapatite collagen scaffold for bone regeneration. AB - Scaffold fabrication and biocompatibility are crucial for successful bone tissue engineering. Nanometer hydroxyapatite (nHAP) combined with collagen (COL) is frequently utilized as a suitable osseous scaffold material. Furthermore, growth factors, including bone morphogenetic protein-2 (BMP-2), are used to enhance the scaffold properties. The present study used blending and freeze-drying methods to develop a BMP-2-nHAP-COL scaffold. An ELISA was performed to determine the BMP-2 release rate from the scaffold. Flow cytometry was used to identify rat bone marrow-derived mesenchymal stem cells (BMSCs) prior to their combination with the scaffold. Scanning electron microscopy was used to observe the scaffold structure and BMSC morphology following seeding onto the scaffold. BMSCs were also used to assess the biological compatibility of the scaffold in vitro. BMP-2-nHAP-COL and nHAP-COL scaffolds were assessed alongside the appropriate control groups. Cells were counted to determine early cell adhesion. Cell Counting kit-8 and alkaline phosphatase assays were used to detect cell proliferation and differentiation, respectively. Gross morphology confirmed that the BMP-2-nHAP-COL scaffold microstructure conformed to the optimal characteristics of a bone tissue engineering scaffold. Furthermore, the BMP-2-nHAP-COL scaffold exhibited no biological toxicity and was demonstrated to promote BMSC adhesion, proliferation and differentiation. The BMP-2-nHAP-COL scaffold had good biocompatibility in vitro, and may therefore be modified further to construct an optimized scaffold for future bone tissue engineering. PMID- 29436647 TI - miR-21-5p regulates type II alveolar epithelial cell apoptosis in hyperoxic acute lung injury. AB - Hyperoxia-induced acute lung injury (HALI) as one of the most common complications in patents on mechanical ventilation, and there are no efficient methods to overcome this at present. It was hypothesized that microRNA 21-5p(miR 21-5p) can promote the survival of type II alveolar epithelial cells (AECII), alleviating HALI. The present study aimed to combine gene chip analysis with the overexpression miR-21-5p to develop a novel therapeutic option for HALI. It was found that AECII apoptosis was an important pathogenic event in the development of HALI, and the overexpression of miR-21-5p prevented HALI, associated with reducing AECII apoptosis. These results were obtained using adenoviral/lentiviral vectors, which overexpressed miR-21-5p, to transfect AECII cells in vitro and in vivo. It was found that the overexpression of miR-21-5p reduced the apoptotic rate of the AECII cells. In addition, miR-21-5p decreased the ratio of B-cell lymphoma 2 (Bcl-2)-associated X protein/Bcl-2 and the expression of caspase-3. It was also revealed that the overexpression of miR-21-5p alleviated acute lung injury in adult rats exposed to a hyperoxic environment. These results suggest that miR-21-5p may become a novel therapeutic option for patients with HALI, by protecting AECII cells from apoptosis. PMID- 29436648 TI - miR-539 suppresses proliferation and induces apoptosis in renal cell carcinoma by targeting high mobility group A2. AB - Renal cell carcinoma (RCC) is one of the most common urinary malignancies with a high rate of morbidity. MicroRNAs (miRNAs) have been shown to be critical post transcriptional regulators in tumorigenesis. The present study aimed to investigate the effect of miRNA (miR)-539 on the proliferation and apoptosis of RCC. The expression of miR-539 and high mobility group AT-hook 2(HMGA2) were examined in clinical RCC specimens. The 786-O RCC cell line was also used and was transfected with miR-539 mimics or inhibitors. The correlation between miR-539 and HMGA2 was confirmed using a luciferase reporter assay. Cell viability and apoptosis were detected using MTT and flow cytometry assays. The protein levels of HMGA2, AKT, phosphorylated (p)-AKT, mammalian target of rapamycin (mTOR) and p mTOR were analyzed using western blot analysis. The results revealed that miR-539 was negatively correlated with the expression of HMGA2 in clinical RCC specimens. Further experiments identified HMGA2 as a direct target of miR-539. The overexpression of miR-539 downregulated the expression of HMGA2, reduced cell proliferation and promoted cell apoptosis, whereas the knockdown of miR-539 led to the opposite results. miR-539 also suppressed the phosphorylation of AKT and mTOR, without altering the levels of total AKT and mTOR. Taken together, the results of the present study indicated that miR-539 negatively regulated the expression of HMGA2 in clinical specimens and in vitro. miR539 inhibited cell proliferation and induced apoptosis in RCC cells. This regulatory effect of miR 539 may be associated with the AKT signaling pathway. Therefore, miR-539 may be used as a biomarker for predicting the progression of RCC. PMID- 29436649 TI - Interleukin-10 promotes primary rat hepatic stellate cell senescence by upregulating the expression levels of p53 and p21. AB - Liver fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) components, and activated hepatic stellate cells (HSCs) are a primary source of ECM. Several studies have revealed that the induction of HSC senescence may reduce liver fibrosis. The effect of interleukin-10 (IL-10) on the senescence of activated HSCs is not fully understood. Therefore, the present study examined its effects and potential mechanisms in activated primary rat HSCs. Collagenase perfusion and density gradient centrifugation methods were used to isolate rat HSCs. HSCs were identified by autofluorescence, Oil Red O staining and immunocytochemical analysis. Activated HSCs were treated with 0, 10, 20 or 40 ng/ml IL-10 for 24 h. Senescence-associated beta-galactosidase (SA-beta-Gal) staining, flow cytometry analysis and a cell counting kit-8 assay were performed to detect the senescence, apoptosis and viability of rat HSCs, respectively. Reverse transcription-quantitative polymerase chain reaction, western blot analysis and enzyme linked immunosorbent assays were used to detect the expression of senescence-associated proteins and cytokines. Freshly isolated rat HSCs exhibited a striking blue-green autofluorescence and HSC retinoid droplets were stained bright red by Oil Red O. Immunocytochemical analysis demonstrated the cytoplasmic expression of HSC markers desmin and alpha-smooth muscle actin. The number of SA-beta-Gal positive HSCs, the apoptotic rate and the expression levels of p53, p21 and tumor necrosis factor-alpha were significantly increased following IL-10 treatment. HSC viability and IL-6 and IL-8 expression levels were significantly decreased compared with the control group. In summary, primary rat HSCs were successfully isolated and IL-10 was demonstrated to promote the senescence of activated primary rat HSCs through the upregulation of p53 and p21 expression. PMID- 29436650 TI - Toll-like receptor 2 mediates deposition of collagen I in adipose tissue of high fat diet-induced obese mice. AB - Obesity is marked by deposition of collagen I in adipose tissue. Toll like receptor (TLR)2 is involved in lipid metabolism, however the association between TLR2 and collagen I remains unclear. The present study was designed to investigate the effect of TLR2 knockout on collagen I in adipose tissue in obese mice. TLR2 knockout and C57BL/6J mice (aged 4 weeks) were fed normal chow or a high-fat-diet for 16 weeks. Compared with adipose tissue from lean controls, that from C57BL/6J mice fed a high-fat diet had increased levels of collagen I, TIMP1 and TGFbeta1 and lower levels of MMP1. However, adipose tissue from TLR2 knockout mice fed a high-fat diet revealed decreased levels of collagen I, TIMP metallopeptidase inhibitor (TIMP)1, and transforming growth factor (TGF)beta1, in addition to increased levels of matrix metallopeptidase (MMP)1. These findings suggest that, in the adipose tissue of obese mice, TLR2 is involved in the metabolism of collagen I and may exhibit a role in the metabolism of MMP1, TIMP1 and TGFbeta1. PMID- 29436651 TI - Identification of bioactive heterocyclic compounds from mulberry and their protective effect against streptozotocin-induced apoptosis in INS-1 cells. AB - A phytochemical investigation of the MeOH extracts from mulberries (the fruit of Morus alba L.) led to the identification of six heterocyclic compounds (1-6). These compounds were screened to detect whether they protected pancreatic INS-1 cells from streptozotocin (STZ)-induced cytotoxicity. Compound 3 was the most effective at preventing STZ-induced cytotoxicity and the production of reactive oxygen species (ROS) in INS-1 cells. In addition, compound 3 effectively prevented apoptosis induced by STZ in INS-1 cells. Compound 3 also prevented STZ mediated cleavage of caspase-8, caspase-3 and poly (ADP-ribose) polymerase and increased the expression of B-cell lymphoma-2 (Bcl-2), an anti-apoptotic Bcl-2 family protein. In conclusion, the results of the present study indicate that compound 3 extracted from the fruit of M. alba was highly effective in preventing type 1 diabetes mellitus and may be a novel treatment option. PMID- 29436652 TI - Neuronalinjury and roles of apoptosis and autophagy in a neonatal rat model of hypoxia-ischemia-induced periventricular leukomalacia. AB - As research into periventricular leukomalacia (PVL) gradually increases, concerns are emerging about long-term neuron injury. The present study aimed to investigate neuronal injury and the relevant alterations in apoptosis and autophagy in a PVL model established previously. A rat model of hypoxia-ischemia induced PVL was established. In the model group, Sprague-Dawley (SD) rats [postnatal day 3 (P3)] were subjected to right common carotid artery ligation followed by suturing and exposed to 6-8% oxygen for 2 h; in the control group, SD rats (P3) were subjected to right common carotid artery dissection followed by suturing, without ligation and hypoxic exposure. At 1, 3, 7 and 14 days following modeling, brain tissue samples were collected and stained with hematoxylin and eosin. Cellular apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and the protein and mRNA expression alterations of neuronal nuclei (NeuN), caspase-3 and Beclin 1 in the model group were detected by western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses. Compared with the control group, the protein and mRNA expression levels of NeuN (a marker of mature neurons) were markedly reduced, the number of positive cells was increased as detected by TUNEL, and the protein and mRNA expression levels of caspase-3 and Beclin 1 were elevated in the model group. In the rat model of hypoxia-ischemia-induced PVL, oligodendrocyte injury and myelinization disorders were observed, in addition to neuron injury, a decrease in mature neurons and the co-presence of apoptosis and autophagy. However, apoptosis and autophagy exist in different phases: Apoptosis is involved in neuron injury, while autophagy is likely to have a protective role. PMID- 29436653 TI - Upregulation of phosphatase and tensin homolog is essential for the effect of 4 aminopyridine on A549/CDDP cells. AB - 4-aminopyridine (4-AP), a voltage-gated potassium channel blocker, was revealed to possess pro-apoptotic properties in various types of cancer cells. The present study aimed to explore the effect of 4-AP on a cisplatin (DDP) resistant lung cancer cell line A549/CDDP and the underlying mechanism by which it had an effect. In the present study, an MTT assay and cell cycle analysis were used to determine that 4-AP inhibited cell growth in vitro and a tumorigenesis assay in nude mice determined that 4-AP also inhibited cell growth in vivo. 4-AP induced cell apoptosis of A549/CDDP cells observed by electron microscopy and Annexin V APC/7-ADD analysis. In addition, 4-AP enhanced the sensitivity of A549/CDDP cells to DDP as revealed by an MTT assay. Mechanistically, 4-AP upregulated the phosphatase and tensin homolog (PTEN) and modulated the phosphoinositide 3 kinase/protein kinase B signaling pathway and its downstream cell cycle factors, including cyclin D1, cyclin-dependent kinase 4 and p21, as well as apoptosis associated proteins B-cell lymphoma 2, pro-caspase 9, pro-caspase 3, cleaved caspase 9 and cleaved caspase 3. The effects of 4-AP on cell growth and apoptosis were reversed by PTEN silencing. In conclusion, the results indicated that 4-AP inhibited cell growth, induced apoptosis and sensitized A549/CDDP cells to DDP via the upregulation of PTEN. 4-AP may be a potential therapeutic agent for patients with DDP resistance. PMID- 29436654 TI - Tetrahydrocurcumin-induced autophagy via suppression of PI3K/Akt/mTOR in non small cell lung carcinoma cells. AB - Lung carcinoma is the leading cause of mortality due to cancer worldwide. Autophagy has a significant role in the development and progression of non-small cell lung carcinoma (NSCLC). A previous study has revealed that tetrahydrocurcumin (THC), a traditional Chinese medicine isolated from Curcuma wenyujin (Chen & Ling, 1981), induces autophagy in human A549 NSCLC cells. The present study evaluated THC-induced autophagy in A549 cells using various assays, including the Cell Counting Kit-8, acridine orange staining, flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blot analysis of the markers of autophagy. THC inhibited the growth and proliferation of A549 cells (P<0.05). Acridine orange staining and flow cytometry revealed that THC treatment significantly enhanced autophagic cell proliferation inhibition (P<0.05). The RT-qPCR analysis revealed that THC treatment increased Beclin-1 expression level and compared with the control group (P<0.05). The light chain 3 (LC3)-II/LC3-I ratio was reduced in THC-treated cells when compared with the control group (P<0.05). Protein expression of various markers of autophagy, including p62, phosphorylated (p)-mechanistic target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K), p-PI3K, protein kinase B (Akt), and p-Akt was significantly reduced in THC-treated cells (P<0.05). In conclusion, the present study revealed the underlying mechanisms associated with THC-induced autophagy. A promising method of enhancing the therapeutic efficacy of THC against NSCLC cells may include inducing autophagy via inhibition of the PI3K/Akt/mTOR signaling pathway. PMID- 29436655 TI - Effects of dexmedetomidine post-treatment on BDNF and VEGF expression following cerebral ischemia/reperfusion injury in rats. AB - Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) serves a significant role in neural protection by activating the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which also was associated with the neuroprotective the treatment with dexmedetomidine (DEX). The present study aimed to further explore whether treatment with DEX post-IR increased the expression level of BDNF and VEGF in the rat brain. A total of 30 healthy, clean male Wistar rats were randomly divided into 3 experimental groups: Control group, ischemia/reperfusion (I/R) group and DEX treatment group. Subsequently, BDNF and VEGF mRNA and protein expression levels were analyzed. The results indicated that the mRNA expression levels of BDNF and VEGF were higher in the I/R and DEX groups compared with expression levels in the Control group at 6 h and 1 day post-treatment; the levels of BNDF mRNA expression were higher in the DEX group compared with the I/R group. The levels of BDNF and VEGF protein expression in the I/R and DEX groups were also significantly higher compared with those in the Control group. I/R surgery significantly increased the expression of BDNF and VEGF protein DEX group at 6 h, day 1 and day 3 compared with expression levels in the I/R group. Results from the present study indicated that post surgical treatment with DEX may increase the expression of BDNF and VEGF following I/R, which may serve a role in nerve protection. PMID- 29436656 TI - Early quantitative profiling of differential retinal protein expression in lens induced myopia in guinea pig using fluorescence difference two-dimensional gel electrophoresis. AB - The current study aimed to investigate the differential protein expression in guinea pig retinas in response to lens-induced myopia (LIM) before fully compensated eye growth. Four days old guinea pigs (n=5) were subjected to -4D LIM for 8 days. Refractive errors were measured before and at the end of the lens wear period. Ocular dimensions were also recorded using high-frequency A-scan ultrasonography. After the LIM treatment, retinas of both eyes were harvested and soluble proteins were extracted. Paired retinal protein expressions in each animal were profiled and compared using a sensitive fluorescence difference two dimensional gel electrophoresis. The quantitative retinal proteomes of myopic and control eye were analysed using computerised DeCyder software. Those proteins that were consistently changed with at least 1.2-fold difference (P<0.05) in the same direction in all five animals were extracted, trypsin digested and identified by tandem mass spectrometry. Significant myopia was induced in guinea pigs after 8 days of lens wear. The vitreous chamber depth in lens-treated eyes was found to be significantly elongated. Typically, more than 1,000 protein spots could be detected from each retina. Thirty-two of them showed differential expression between myopic and untreated retina. Among these proteins, 21 spots were upregulated and 11 were downregulated. Eight protein spots could be successfully identified which included beta-actin, enolase 1, cytosolic malate dehydrogenase, Ras-related protein Rab-11B, protein-L-isoaspartate (D-aspartate) O-methyltransferase, PKM2 protein, X-linked eukaryotic translation initiation factor 1A and ACP1 protein. The present study serves as the first report to uncover the retinal 2D proteome expressions in mammalian guinea pig myopia model using a top-down fluorescent dyes labelling gel approach. The results showed a downregulation in glycolytic enzymes that may suggest a significant alteration of glycolysis during myopia development. Other protein candidates also suggested multiple pathways which could provide new insights for further study of the myopic eye growth. PMID- 29436657 TI - Effect of Notoginsenoside R1 on autologous adipose graft in rats. AB - Autologous fat particle transplantation has been widely used by surgeons. The present study evaluated the effect of Notoginsenoside R1 (NR1) treatment on rat autologous fat graft, along with the quality and retention rates. Male Sprague Dawley rats (n=60) received fat particle auto-transplantation from the left abdominal cavity into lateral dorsum. A total of 14 days after surgery, NR1 in different doses (50, 100 and 200 mg/kg/day) was injected into rats, following which blood and fat graft samples were harvested at days 7, 14 and 28. Assessments were carried out by hematoxylin and eosin staining, western blotting, ELISA and immunohistochemistry (IHC). The survival rate of fat grafts was increased in three experimental groups, as detected by weight measurement. Histological scoring demonstrated that there were significant differences in tissue integrity between the 100 mg/kg/day group and the other 3 groups. hepatocyte growth factor, vascular endothelial growth factor, fibroblast growth factor, angiotensin and S100 levels in the 100 mg/kg/day NR1 group was increased compared with the other 2 treatment groups; however, all 3 treatment groups demonstrated increased expression of these proteins compared with the control group. Additionally, cluster of differentiation (CD)68 exhibited negative expression and CD31 showed weakly positive expression in all three experiments, as assessed by IHC. In conclusion, 100 mg/kg/day NR1 may potentially promote the retention rate and enhance the quality of autologous fat grafts via increasing vascularity in the recipient site. These results implicate NR1 as a therapeutic strategy for the improvement of outcome following fat graft surgery. PMID- 29436658 TI - Effect of garlic on rats with chronic intermittent hypoxia combined with diabetes mellitus. AB - The present study investigated the effect of garlic (G) on serum, liver, renal and cerebral parameters of rats with chronic intermittent hypoxia (CIH) combined with diabetes mellitus (DM). A total of 32 rats were divided into eight groups, with 4 rats/group. A total of three models were established, including CIH, DM and CIH-DM, and an additional healthy control (C) group. Rats in C-G, CIH-G, DM-G and CIH-DM-G groups were injected with a G extract daily. Serum, liver, renal and cerebral parameters were detected. The results demonstrated that the rats' weight increased gradually, but at a slower rate in the CIH, DM and CIH-DM groups compared with the healthy rats. Blood glucose increased in the DM and CIH-DM groups compared with the healthy control group, while insulin level increased in the CIH group, but decreased in the DM and CIH-DM groups, resulting in increased homeostatic model assessment of insulin resistance (HOMA-IR) value in the CIH group, compared with healthy controls. Serum thiobarbituric acid reactive substances (TBARS), glutathione S-transferase (GST), uric acid (UA), urine protein (UP), total cholesterol (TC), triglycerides (TG), total lipids (TL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP) and acid phosphatase (ACP) increased in the CIH, DM and CIH-DM groups, while albumin and superoxide dismutase (SOD) decreased in all model groups compared with healthy controls. Nitric oxide (NO) increased in the DM and CIH-DM groups but decreased in the CIH group, compared with the control group. Glutathione peroxidase (GSH-Px) increased in the CIH group but decreased in the DM and CIH-DM groups, compared with the control group. Glutathione reductase (GR) increased in the DM group but decreased in the CIH and CIH-DM groups, compared with the control group. Liver TBARS and GST increased, while AST, ALT, LDH, ALP, ACP, catalase activity (CAT) and SOD decreased in the CIH, DM and CIH-DM groups, compared with the control group. Liver GSH-Px decreased in the DM and CIH-DM groups, compared with the control group. Renal TBARS in the DM and CIH-DM groups increased compared with the control group. Renal GST increased while CAT and SOD decreased in the CIH, DM and CIH-DM groups, compared with the control group. Cerebral TBARS increased in the CIH, DM and CIH-DM groups and LDH increased in the DM and CIH-DM groups, compared with the control group. Cerebral LDH in CIH decreased compared with the control group. G treatment improved weight gain, blood insulin and HOMA-IR in the DM and CIH-DM groups, reduced blood glucose in the DM and CIH-DM groups, and insulin and HOMA-IR in the CIH group, compared with the respective G-untreated groups. G treatment increased serum SOD in CIH-G, DM-G and CIH-DM-G groups, GSH-Px and albumin in the DM-G and CIH-DM-G groups, and GR in the DM-G group, compared with the respective G-untreated groups. G treatment decreased serum TBARS, UA, UP, TC, TG, TL, AST, ALT, LDH and ACP in the CIH-G, DM-G and CIH-DM-G groups; NO in the DM-G group; GST and GR in the CIH-G and CIH-DM-G groups; and ALP in the DM-G and CIH-DM-G groups, compared with the respective G-untreated groups. Liver AST, ALT, LDH, ALP, CAT, SOD in the CIH-G, DM-G and CIH-DM-G groups increased as a result of G treatment. GSH-Px increased in the DM-G and CIH-DM-G groups, ACP in the CIH G and DM-G groups, renal CAT in the CIH-DM-G group, and renal SOD in the CIH-G and CIH-DM-G groups, compared with the respective G-untreated groups. Liver and cerebral TBARS decreased in all G-treated experimental groups, and liver and renal GST, and cerebral LDH decreased in the DM-G and CIH-DM-G groups, compared with the respective G-untreated groups. The present study concluded that G aided in the recovery of homeostasis and metabolism in rats with CIH combined with DM, and protected rats' organs from damage induced by CIH combined with DM. PMID- 29436659 TI - Cholangiocarcinoma-associated genes identified by integrative analysis of gene expression data. AB - Cholangiocarcinoma (CCA) is characterized by delayed diagnosis and poor survival rate. Research efforts have focused on novel diagnostic technologies for this type of cancer. Transcriptomic microarray technology is a useful research strategy for investigating the molecular properties of CCA. The objective of the present study was to identify candidate biomarkers with high potential for clinical application in CCA using a meta-analysis-based approach. Gene expression profiles of CCA were downloaded from the Gene Expression Omnibus database for integrated analysis. All differentially expressed genes (DEGs) were analyzed by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Protein-protein interaction (PPI) networks were further constructed, hub proteins were identified and functional modules were extracted. Following integrated analysis of the seven eligible datasets (428 cases and 46 controls), a set of 1,080 DEGs was identified, including 710 upregulated and 370 downregulated genes. Functional enrichment analysis demonstrated that 'chromosome organization' was a significantly enriched GO term in the biological process category. 'DNA replication', 'influenza A', and 'lysosome' were the top three significantly enriched KEGG pathways. Furthermore, PPI network analysis indicated that the significant hub proteins were histone deacetylase 1, cullin-associated NEDD8-dissociated protein 1, ubiquitin D, early growth response protein 1 and glycogen synthase kinase 3beta. The majority of these proteins are involved in CCA. These results provided a set of targets that may help researchers to clarify further the underlying mechanisms of CCA tumorigenesis. PMID- 29436660 TI - Cartilage intermediate layer protein is regulated by mechanical stress and affects extracellular matrix synthesis. AB - Lumbar disc disease (LDD) is common in aged populations, and it is primarily caused by intervertebral disc degeneration (IDD). Cartilage intermediate layer protein (CILP), which is specifically expressed in intervertebral discs (IVDs), is suspected to be associated with IDD. However, it remains unclear whether CILP contributes to IDD in humans. Furthermore, the regulation of CILP in human IVDs is poorly understood, especially by mechanical stimuli, which are regarded as primary factors promoting IDD. To address these issues, the present study collected nucleus pulposus (NP) cells from patients undergoing lumbar spinal surgery for degenerative disc disease (DDD). Subsequently, CILP expression was measured in human NP cells in response to mechanical stimuli, including cyclic compressive stress and cyclic tensile strain (CTS), by reverse transcription quantitative polymerase chain reaction and western blotting. Aggrecan and collagen II, which are the main components of the extracellular matrix (ECM) and traditional degenerative markers for IDD, were detected following the treatment with CILP small interfering (si)RNA or recombinant human CILP (rhCILP) at various concentrations to determine whether CILP contributes to IDD by negatively regulating expression of the ECM. The results revealed that CILP expression in loaded NP cells was significantly increased compared with that in non-loaded cells under compressive loading, and that it was markedly decreased in cells under tensile loading, in contrast with the expression of aggrecan and collagen II in response to the same stimuli. Furthermore, CILP siRNA effectively inhibited CILP expression and significantly increased the expression of aggrecan and collagen II. In addition, treatment of NP cells with a high concentration of rhCILP resulted in significantly decreased expression of aggrecan and collagen II. In conclusion, these results demonstrated for the first time, to the best of our knowledge, that in human NP cells, CILP is regulated by mechanical stress and that its expression affects ECM synthesis. Therefore, CILP represents a promising therapeutic target for preventing loss of the matrix during IDD as a novel treatment strategy. PMID- 29436661 TI - Transdifferentiation of type II alveolar epithelial cells induces reactivation of dormant tumor cells by enhancing TGF-beta1/SNAI2 signaling. AB - Dormant tumor cells (DTCs) serve a crucial role in the pathogenesis of metastasis and may compromise the efficacy of existing therapeutic modalities aimed at fully eradicating cancer. However, the mechanisms underlying the dormant-to proliferating switch of DTCs remain largely unknown. The lung is one of the most common sites of metastatic recurrence. The transdifferentiation of alveolar epithelial cells II (AEC IIs) to AEC Is is a hallmark of alveolar epithelial stimulation. However, the role of AEC II transdifferentiation during the reactivation of DTCs has not been fully elucidated. In the present study, we found that tumor cells promoted the transdifferentiation of AEC IIs. Furthermore, the supernatant of the transdifferentiation of AEC IIs to AEC Is (Super-TDA) promoted the dormant-to-proliferating switch of DTCs via the autocrine effect of TGF-beta1 on the 3D BME culture system in vitro. Monensin and LY2109761 blocked the dormant-to-proliferating switch of DTCs induced by Super-TDA. Although lipopolysaccharide did not directly stimulate the reactivation of DTCs, it promoted DTC reactivation by increasing the secretion of TGF-beta1 in the Super TDA. We further demonstrated that the upregulation of SNAI2 expression was required for Super-TDA facilitating the DTC dormant-to-proliferating switch. Taken together, our findings demonstrated that tumor cells may promote AEC II transdifferentiation. Furthermore, the transdifferentiation of AEC IIs may, in turn, induce the reactivation of 3D-established DTCs by promoting TGF-beta1/SNAI2 signaling. Targeting this process may provide novel therapeutic strategies for the inhibition of the dormant-to-proliferating switch. PMID- 29436662 TI - Comparison of the properties of neural stem cells of the hippocampus in the tree shrew and rat in vitro. AB - Neural stem cells (NSCs) are characterized by the ability of self-renewal and capacity to proliferate and produce new nervous tissue. NSCs are capable of differentiating to three lineages of neural cells, including neurons, oligodendrocytes and astrocytes. Furthermore, hippocampal NSCs transplantation can improve the neurological deficits associated with expression of cytokines. Therefore, to compare the properties of NSCs of tree shrews and rats in vitro, NSCs from tree shrews (tsNSCs) and rats f(rNSCs) were isolated. Nestin was used as a marker to identify the cultured NSCs. Neuronal nuclei protein and glial fibrillary acidic protein (GFAP) were utilized to demonstrate the differentiation of NSCs towards neurons and astrocytes, respectively, in vitro. Furthermore, the expression of neurotrophin 3 (NT3), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and transforming growth factor (TGF)beta1 was also investigated in tsNSCs and rNSCs. The expression of all of the aforementioned proteins was detected using immunofluorescence methods. The results demonstrated that, after 5 days of culture, the average number of neurospheres in the cultured tsNSCs was significantly lower compared with rNSCs (P=0.0031). Additionally, compared with the rNSCs, tsNSCs exhibited an enhanced differentiation ability towards neurons. Furthermore, the expression of NT3 in the tsNSCs was higher compared with rNSCs (P<0.01), while the expression of BDNF was lower (P=0.045). However, no significant differences were observed in the expression level of GDNF and TGFbeta1 between rNSCs and tsNSCs. Therefore, these results indicate that tsNSCs exhibit specific characteristics that are different from rNSCs, which provides novel information for the understanding of NSCs obtained from tree shrews. Overall, the results of the current study provide evidence to support the increased application of tree shrews as models for diseases of the central nervous system. PMID- 29436664 TI - Knockout of microRNA-26a promotes lung development and pulmonary surfactant synthesis. AB - Normal formation and function of the lungs are essential for the transition of the fetus to an air-breathing environment at birth. The synthesis of pulmonary surfactant (PS), which is produced by type II alveolar epithelial cells (AECIIs), is required for proper lung development. Previous in vitro studies have suggested that PS synthesis is regulated by microRNA (miR)-26a in fetal rat AECIIs. The present study explored the potential role of miR-26a in lung development and PS synthesis by using a miR-26a-1/miR-26a-2 double knockout mouse model. Hematoxylin and eosin staining and transmission electron microscopy were used to observe the morphology of fetal lungs. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to examine the mRNA and protein levels of surfactant-associated proteins. The results demonstrated that the lung formation in the knockout mice was more mature, and that there were more mature lamellar bodies inside AECIIs in miR-26a knockout mice at late stages of lung development. The findings further demonstrated that knockout of miR-26a increased surfactant-associated mRNA and protein expression levels. The results indicated that knockout of miR-26a promotes lung development and PS synthesis. PMID- 29436663 TI - The effect of foxp3-overexpressing Treg cells on non-small cell lung cancer cells. AB - The aim of the present study was to investigate the novel mechanisms of forkhead box protein P3 (foxp3) in T regulatory (Treg) cells in lung cancer behavior. Treg cells were isolated from the peripheral blood of healthy volunteers and then co cultured with 95D cells. A plasmid overexpressing foxp3 was constructed and transfected into Treg cells and an MTS assay was performed to assess cell viability. Flow cytometry was performed to evaluate cell apoptosis and reverse transcription-quantitative polymerase chain reaction was used to measure mRNA expression. A Transwell assay was used to assess cell invasion. Treg cells were successfully isolated from peripheral blood with purity of 94.26%. Foxp3 expression in Treg cells was significantly increased following co-culture with 95D cells, while matrix metalloproteinase-9 expression was upregulated in 95D cells co-cultured with Treg cells. The apoptosis, invasion and migration abilities of 95D cells were suppressed by co-culture with Treg cells, whereas the adhesive ability was enhanced. Foxp3 overexpression in Treg cells enhanced the viability and invasiveness of 95D cells, whereas cell adhesion and migration were decreased. The results of the present study demonstrate that the viability and invasiveness of 95D cells are enhanced by foxp3 overexpression in Treg cells, indicating that increased levels of foxp3 in the tumor microenvironment may promote tumor cell growth. PMID- 29436665 TI - MicroRNA-375 inhibits glioma cell proliferation and migration by downregulating RWDD3 in vitro. AB - Derived from brain glial cells, gliomas are currently the most common primary tumours in the central nervous system and are characterised by a high recurrence rate and poor prognosis. RWDD3 (RWD domain-containing sumoylation enhancer, also termed RSUME), which can be induced by cellular stress, such as CoCl2, heat shock and hypoxia, may play a crucial role in tumour angiogenesis, growth and metastasis. MicroRNAs (miRNAs) have been demonstrated to act as negative regulators of post-transcriptional gene expression and are involved in tumour growth and metastasis. In the present study, we explored the role of RWDD3 in glioma cell proliferation and invasion by the knockdown of RWDD3 with lentiviral shRNA and demonstrated that miRNA hsa-miR-375, regulates RWDD3 and has an important role in glioma progression. We found that expression of RWDD3 in high grade gliomas was significantly higher than that noted in normal brain tissues and lower-grade gliomas in vivo. Knockdown of RWDD3 effectively led to cell cycle arrest, decreased proliferation and invasion, and increased apoptosis in human glioma cell lines. Furthermore, miR-375 was downregulated in human gliomas and overexpression of miR-375 caused downregulation of RWDD3 in glioma cells as well as inhibited their motility. Thus, these findings suggest that RWDD3 and miR-375 may function as therapeutic biomarkers for glioma patients. PMID- 29436666 TI - Daidzein induces choriocarcinoma cell apoptosis in a dose-dependent manner via the mitochondrial apoptotic pathway. AB - Choriocarcinoma is a malignant gestational trophoblastic disease and relapse or drug resistance occurs in ~25% of gestational trophoblastic tumors. Cell apoptosis serves a role in the progression from hydatidiform mole to persistent gestational trophoblastic disease. It has been demonstrated that daidzein [7 hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one] may induce apoptosis in a number of cancer types via the mitochondrial apoptotic pathway by altering the B-cell lymphoma (Bcl)-2/Bcl-2 associated X, apoptosis regulator (Bax) ratio, and activating the caspase cascade. Daidzein also serves a role in regulation of production of human chorionic gonadotropin in trophoblast cells and inhibition of cell proliferation. However, few reports have been published regarding the effect of daidzein on apoptosis in choriocarcinoma. Therefore, in the present study, JAR and JEG-3 human gestational choriocarcinoma cells were used to investigate the effect of daidzein on apoptosis of choriocarcinoma cells. Treatment with daidzein for 48 h reduced cell viability in a dose-dependent manner. The percentages of early and late apoptotic cells also increased following treatment with daidzein in a dose-dependent manner, with the number of late apoptotic cells increasing more prominently. Furthermore, treatment with daidzein led to apoptosis associated alterations in nuclear morphology of JAR and JEG-3 cells. Expression levels of cleaved poly(ADP-ribose) polymerase, cleaved caspase-3 and cleaved caspase-9 increased following treatment with daidzein, whereas the Bcl-2/Bax ratio decreased in a dose-dependent manner. In conclusion, the results of the present study demonstrate that daidzein may induce apoptosis of choriocarcinoma cells in a dose-dependent manner via the mitochondrial apoptotic pathway. PMID- 29436667 TI - Secretory leukocyte peptidase inhibitor expression and apoptosis effect in oral leukoplakia and oral squamous cell carcinoma. AB - Oral leukoplakia (OL) is one of the most common oral precancerous lesions with the possibility of malignant transformation, ranging from 17 to 24% of patients with a median follow-up of >7 years. Previous research has revealed that compared with normal oral epithelial tissues, the expression of secretory leukocyte peptidase inhibitor (SLPI) protein is significantly reduced in oral squamous cell carcinoma (OSCC). Based on the above-mentioned research, it is known that SLPI is a potential predictive and diagnostic tool for the progression of oral carcinogenesis. Therefore, we investigated the correlation between the abundance of SLPI protein and the different histological grades of OL by immunohistochemistry. The results indicated that the level of SLPI was negatively correlated with the histological grades of the oral premalignant lesions, indicating that it may be a potential predictive tool for the malignant transformation presented in oral precancerous patients. Subsequently, we investigated the biological effects of SLPI using Cell Counting Kit (CCK)-8, Annexin V/PI apoptosis assay and Caspase-Glo(r) 3/7 assay. The findings revealed that SLPI promoted apoptosis in the Leuk1 and WSU-HN4 cell lines. Mechanistic studies indicated that SLPI, at least in part, regulated cell apoptosis by inhibiting the expression of TNF receptor-associated factor 1 (TRAF1), which has a close relationship with the nuclear factor-kappaB (NF-kappaB) pathway. PMID- 29436668 TI - Kynurenine promotes the goblet cell differentiation of HT-29 colon carcinoma cells by modulating Wnt, Notch and AhR signals. AB - Various amino acids regulate cell growth and differentiation. In the present study, we examined the ability of HT-29 cells to differentiate into goblet cells in RPMI and DMEM which are largely different in the amounts of numerous amino acids. Most of the HT-29 cells differentiated into goblet cells downregulating the stem cell marker Lgr5 when cultured in DMEM, but remained undifferentiated in RPMI. The goblet cell differentiation in DMEM was inhibited by 1-methyl tryptophan (1-MT), an inhibitor of indoleamine 2,3 dioxygenase-1 which is the initial enzyme in tryptophan metabolism along the kynurenine (KN) pathway, whereas tryptophan and KN induced goblet cell differentiation in RPMI. The levels of Notch1 and its activation product Notch intracytoplasmic domain in HT-29 cells were lower in DMEM than those in RPMI and were increased by 1-MT in both media. HT-29 cells grown in both media expressed beta-catenin at the same level on day 2 when goblet cell differentiation was not observed. beta-catenin expression, which was increased by 1-MT in both media, was decreased by KN. DMEM reduced Hes1 expression while enhancing Hath1 expression. Finally, aryl hydrocarbon receptor (AhR) activation moderately induced goblet cell differentiation. Our results suggest that KN promotes goblet cell differentiation by regulating Wnt, Notch, and AhR signals and expression of Hes1 and Hath1. PMID- 29436669 TI - Effect of recombinant vascular endothelial growth factor and translationally controlled tumor protein on 2-hydroxyethyl methacrylate-treated pulp cells. AB - Vascular endothelial growth factor (VEGF)-A is a potential signaling protein that may promote angiogenesis. VEGF also helps cells survive in stressfull or hazardous conditions. The present study aimed to compare the effect of VEGF with translationally controlled tumor protein (TCTP), an anti-apoptotic protein in human dental pulp cells (HDPCs), following exposure to 2-hydroxyethyl methacrylate (HEMA), which is a major residual monomer from resin restorative dental materials. Cell viability, alkaline phosphatase (ALP) activity, mineralization and gene expressions for odontogenic and osteogenic differentiation markers of HDPCs were investigated, following exposure to HEMA and in combination with TCTP and VEGF. The results revealed that TCTP at 1 ng/ml and VEGF at 10 ng/ml significantly promoted the proliferation of HDPCs (P<0.05). TCTP (1 ng/ml) and VEGF (10 ng/ml) maintained the cell viability of 4 mM HEMA treated cells at the same percentage as the control. However, cells treated with HEMA+TCTP+VEGF had a lower cell viability than the groups treated with HEMA and TCTP or VEGF alone. TCTP and VEGF promoted cell proliferation, ALP activity and mineralization, and upregulated of DSPP, DMP-1, BMP-2, and ALP mRNA expression compared with the control. Furthermore, the HEMA+TCTP and HEMA+VEGF groups had significantly higher percentages of calcium deposition than HEMA-treated cells (P<0.001). HEMA was cytotoxic to HDPCs, reduced ALP activity and caused the significant downregulation of odontogenic and osteogenic gene expressions (P<0.05). It was concluded that VEGF and TCTP promoted pulp cell growth and the survival of HEMA-treated cells without synergistic effects. TCTP was required in lower concentrations for these effects. VEGF and TCTP enhanced cell differentiation and mineralization. PMID- 29436670 TI - Hypothyroidism increases cyclooxygenase-2 levels and pro-inflammatory response and decreases cell proliferation and neuroblast differentiation in the hippocampus. AB - The present study investigated the effects of hypothyroidism on cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines in the dentate gyrus to elucidate the roles of COX-2 in the hypothyroid hippocampus. Hypothyroidism was induced in rats by treating with 0.03% 2-mercapto-1-methyl-imidazole dissolved in drinking water for 5 weeks. The animals were sacrificed at 12 weeks of age. Hypothyroidism rats exhibited decreased triiodothyronine and thyroxine levels in the serum, while the levels of thyroid-stimulating hormone and the weight of thyroid glands were significantly higher in the hypothyroid rats compared with those in the vehicle treated group. COX-2 immunoreactivity was significantly increased in the hippocampal CA2/3 region and the dentate gyrus compared with the vehicle-treated group. Levels of pro-inflammatory cytokines including interleukin (IL)-1beta, IL 6 and tumor necrosis factor-alpha were significantly higher in the hippocampal homogenates of hypothyroid rats. Cell proliferation and neuroblast differentiation based on Ki67 and doublecortin immunohistochemistry were decreased in the dentate gyrus of hypothyroid rats compared with those in the vehicle-treated group. These results suggested that hypothyroidism-mediated COX-2 expression affected hippocampal plasticity by upregulating the levels of pro inflammatory cytokines in the hippocampus. Therefore, COX-2 may be suggested as a candidate molecule for preventing hypothyroidism-induced neurological side effects. PMID- 29436671 TI - Protective effect of curcumin against cyclosporine A-induced rat nephrotoxicity. AB - This study explored the potential value of curcumin, a natural product, in the protection of CsA-induced nephrotoxicity. The aim of the present study was to investigate the effects of curcumin on Cyclosporine A (CsA)-induced renal oxidative stress and determine the potential underlying molecular mechanisms of the renal protective effects of Cur. HK-2 human renal cells were co-treated with CsA and various doses of Cur. Cell survival rate was determined by an MTT assay, total cellular protein was collected and oxidative stress in cell homogenates was evaluated by determining the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and total antioxidant capacity. Furthermore, Bcl-2 and Bcl-2-associated X (Bax) protein expression was measured by western blot analysis. In addition, a CsA-induced nephrotoxicity (CAN) rat model was also established. Renal function was analyzed by measuring creatinine (Crea) and blood urea nitrogen (BUN) in the serum of rats, and histopathological examination was performed on renal tissues using hematoxylin and eosin staining, periodic acid Schiff staining and nuclear factor-kappaB (NF-kappaB) immunostaining. The results demonstrated that treatment of HK-2 cells with CsA significantly increased ROS and MDA levels, and decreased the activities of SOD, GSH-Px and CAT, compared with the control group. However, these effects of CsA were dose-dependently improved by treatment with Cur. In addition, Cur treatment increased Bcl-2 and decreased Bax protein in HK-2 cells, compared with cells treated with CsA alone. In the CAN rat model CsA (30 mg/kg) treatment significantly elevated serum Crea levels and BUN, but lowered endogenous Crea clearance rate, compared with the control group. Co-administration of Cur with CsA significantly reversed the effects of CsA on serum Crea levels, BUN and Crea clearance rate (Ccr). Additionally, Cur alleviated CsA-induced renal cell injury, as less vacuolar degeneration of glomerular cells was observed compared with the CsA alone group. In conclusion, Cur may increase renal antioxidant capacity and reduce the Bax/Bcl 2 ratio, subsequently improving CsA-induced renal failure and renal tubular deformation and cell vacuolization. PMID- 29436672 TI - Mechanism of ECM-induced dormancy and chemoresistance in A549 human lung carcinoma cells. AB - It is now widely accepted that the tumor microenvironment influences the fate of cancer cells and plays crucial roles in regulating tumor dormancy and chemoresistance. The standard cell culture system on plastic surfaces does not account for cell interactions with the extracellular matrix (ECM), and is thus a less reliable approach to analyze cellular activity ex vivo. In the present study, A549 lung cancer cells were cultured in a semi-solid growth substrate (Matrigel) to mimic the tumor microenvironment and to investigate the role played by ECM proteins, as well as to evaluate the mechanism of cell-ECM communication. A549 cells embedded in semi-solid Matrigel exhibited dormant cell characteristics, including decreased cell proliferation, migration and invasion rates, compared with the corresponding cells cultured on plastic plates. Exposure of A549 cells to Matrigel leads to resistance against conventional chemotherapeutic drugs (etoposide, paclitaxel, vinblastine, doxorubicin and 2 deoxy-D-glucose). Cell cycle distribution analysis indicated that a larger percentage of the cells embedded within semi-solid Matrigel was arrested in the G0/G1 phase. RT-qPCR analysis revealed that A549 cells cultured in semi-solid Matrigel exhibited a marked decrease in the expression levels of genes that are related to tumor progression and invasion (uPA, uPAR, MMP2, MMP7, MMP9 and CXCR4). The effects of altering various signaling pathways, such as p-ERK, p-Akt and p-STAT3, were evaluated, in order to assess whether these pathways could account for the observed responses of the cells. The inhibition of ERK1/2 and Akt activation using specific inhibitors induced G0/G1 arrest and drug resistance. These results demonstrated that Matrigel drove A549 cells into a drug-resistant dormancy state, most likely through inhibition of the ERK1/2 and PI3K/Akt pathways. Cell culture within semi-solid Matrigel offered a simple in vitro model for studying the mechanisms responsible for tumor dormancy and drug resistance. These studies may lead to therapeutic approaches that can eliminate dormant tumor cells and prevent disease recurrence. PMID- 29436673 TI - Differentially expressed circRNAs in melanocytes and melanoma cells and their effect on cell proliferation and invasion. AB - Circular RNAs (circRNAs) play critical roles in the occurrence of human diseases, including cancer. However, the detailed functions of circRNAs in melanoma have not been fully elucidated. In the present study, a circRNA microarray was performed to analyze the variability of circRNAs in the low-metastatic melanoma WM35 cell line and in the high-metastatic melanoma WM451 cell line in comparison to control human melanocytes. The results revealed that five circRNAs were upregulated and four circRNAs were downregulated in both the WM35 and WM451 cells. qRT-PCR revealed an upregulated expression of circ0000082 and circ0016418 and a downregulation of circ0023988, circ0008157 and circ0030388 in the cells which was consistent with the results of the microarray assay. Functional tests revealed that knockdown of circ0023988, circ0008157 or circ0030388 significantly promoted the proliferation and invasion of the WM35 cells. Following the silencing of circ0000082 or circ0016418 in WM451 cells, the proliferation and invasion of the WM451 cells were inhibited. Bioinformatic analysis predicted that the circ0000082-, circ0023988- and circ0008157-circRNA-miRNA-mRNA network may participate in the occurrence, development, invasion and metastasis of malignant tumors. The present study revealed several differentially expressed circRNAs, indicating that the newly identified circRNAs may provide new therapeutic targets for melanoma. PMID- 29436674 TI - The targeted inhibition of Hsp90 by a synthetic small molecule, DPide offers an effective treatment strategy against TNBCs. AB - Triple-negative breast cancers (TNBCs) are the most aggressive and metastatic subtype of breast cancers and exhibit poor clinical outcome due to the lack of drug target receptors such as estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (Her2). The limited effectiveness of therapeutic options and the poor prognosis of TNBC patients emphasize the urgent need for identifying new therapeutic agents. In this regard, heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of TNBCs. Hsp90 is a molecular chaperone that regulates the folding, stability, and function of many oncogenic proteins. Hence, the inhibition of Hsp90 chaperone function leads to a simultaneous blockage of multiple signaling pathways in the proliferation and survival of cancers. In the present study, we performed the design, synthesis, and biological evaluation of Hsp90 inhibitors and found that a synthetic small molecule, DPide exerted a potent anticancer activity against TNBC cell line, MDA-MB-231 and non-small cell lung cancer (NSCLC) cell line, H1975 with GI50 values of 0.478 and 1.67 uM, respectively. Soft-agar colony formation assay also revealed that DPide suppressed the anchorage-independent growth of MDA-MB-231 cells. Western blot analysis indicated that the treatment of MDA-MB-231 cells with DPide induced the proteasomal degradation of EGFR, Her2, Met, Akt, c-Raf, and Cdk4 and the consequent cleavage of PARP, leading to apoptotic cell death. DPide also inhibited the migration and MMP9 activity of MDA-MB-231 cells, suggesting that the metastatic potential of TNBCs could be suppressed by DPide. Collectively, DPide offers an effective therapeutic option for the treatment TNBCs. PMID- 29436675 TI - Combination of salinomycin and radiation effectively eliminates head and neck squamous cell carcinoma cells in vitro. AB - The antibiotic drug salinomycin has been reported to mediate cancer cell-specific cytotoxicity, especially regarding cancer stem cells. Since salinomycin has also been reported to arrest cancer cells in the G2 phase, it may have possible radiosensitizing effects. Radiotherapy is a common therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). The aim of the present study was to evaluate a possible influence of salinomycin on the radiosensitivity of the HNSCC cell line HLaC-78 in vitro. HLaC-78 cells were incubated with 5 uM salinomycin or control medium for 24 h and then received 5-Gy irradiation. Subsequently, analysis of cell viability, apoptosis, necrosis and motility through an MTT and a colony formation assay, as well as an Annexin V/propidium-iodide test, a consecutive cell count for four days and a scratch assay were conducted. Additionally, interleukin-8 secretion was assessed using ELISA, due to its role in tumor progression and angiogenesis. Combined treatment with salinomycin and radiation revealed a significantly higher reduction of tumor cell viability, proliferation, motility and secretory capacity compared to cells receiving only one of the treatments alone. Therefore, it is postulated that radiation and salinomycin are an effective combination therapy against HNSCC, a hypothesis which warrants further investigation in cell lines, as well as in an animal model. PMID- 29436676 TI - Vandetanib inhibits cisplatin-resistant neuroblastoma tumor growth and invasion. AB - Resistance is the major cause of cisplatin treatment failure in neuroblastoma (NB). Vandetanib is widely used in the treatment of several cancers. In the present study, we aimed to determine the potential of vandetanib in cisplatin resistant NB therapy. Immunohistochemistry (IHC) staining was employed to detect p-RET and CXCR4 expression in cisplatin-resistant or -sensitive NB tissues from patients. Vandetanib was added to treat selected cisplatin-resistant SH-SY5Y cells (SH-SY5Y-R); this was followed by CCK8 assay, colony formation assay, and invasion assay. Furthermore, the effect of vandetanib on subcutaneous tumor growth was investigated in mice. Our results demonstrated greater expression of p RET and CXCR4 in cisplatin-resistant neuroblastomas (NBs). Vandetanib significantly inhibited SH-SY5Y-R cell proliferation, colony formation, and invasion, while downregulating p-RET and CXCR4 expression. Furthermore, vandetanib was as effective as high-dose cisplatin in impairing cisplatin resistant NB subcutaneous tumor growth. Notably, vandetanib caused less severe liver toxicity in mice compared with high-dose cisplatin. In summary, this study identified Vandetanib as a potential drug for cisplatin-resistant NB treatment. PMID- 29436677 TI - [Retracted] Apogossypolone inhibits the proliferation of LNCaP cells in vitro and in vivo. AB - An interested reader drew to the attention of the Editorial Board of Molecular Medicine Reports that certain data in the above paper had already been published in a previous study featuring several of the same authors [Zhang XQ, Huang XF, Hu XB, Zhan YH, An QX, Yang SM, Xia AJ, Yi J, Chen R, Mu SJ and Wu DC: "Apogossypolone, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces autophagy of PC-3 and LNCaP prostate cancer cells in vitro". Asian J Androl 12: 697-708, 2010]. Specifically, Figs. 2A and 5C were originally featured, either in their entirety or in part, as Figs 6C and 2G, respectively, in the Asian J Androl paper. Following an internal investigation, the Editorial Board was able to confirm that these data were published previously in the Asian J Androl paper, and therefore it has been decided that the above-mentioned paper should be retracted on account of the incidences of data sharing. The authors have agreed to this decision, and we apologize to the readership of the Journal for any inconvenience caused. [the original article was published in Molecular Medicine Reports 10: 1184-1194, 2014; DOI: 10.3892/mmr.2014.2379]. PMID- 29436678 TI - TRIB2 knockdown as a regulator of chemotherapy resistance and proliferation via the ERK/STAT3 signaling pathway in human chronic myelogenous leukemia K562/ADM cells. AB - Acquired resistance to chemotherapy plays a critical role in human drug treatment failure in many tumor types. Multidrug resistance (MDR) to Adriamycin (ADM) also limits the efficacy of therapy in human chronic myelogenous leukemia (CML). The overexpression of drug efflux transporters is one mechanism uderlying MDR. In particular, the consistent activation of MDR1 and MDR-associated protein 1 (MRP1) is involved in drug resistance. In the present study, ADM-resistant human CML K562/ADM cells were stably transfected with a Tribbles homolog 2 (TRIB2)-targeted vector. A CCK-8 assay showed that the half maximal inhibitory concentration (IC50) of ADM and the cell proliferation were lower in the transfected cells compared with that in the parental K562/ADM cells. The mRNA and protein expression levels of MDR1 and MRP1 were determined by reverse transcription polymerase chain reaction (RT-PCR), RT-quantitative PCR and western blot analysis. The results showed that the expression of MDR1 and MRP1 was significantly reduced in K562/ADM cells transfected with pGPU6/GFP/Neo-TRIB2. Due to the downregulation of MDR1 and MRP1, the intracellular accumulation of ADM was increased in the transfected cells compared with that in the parental K562/ADM cells. Therefore, the sensitivity of the K562/ADM cells to ADM was enhanced and proliferation was inhibited. Our research revealed that protein expression of the ERK signaling pathway was inhibited by downregulating TRIB2, indicating that the ERK pathway was involved in cell drug resistance and proliferation. Furthermore, we used the ERK-specific blocker U0126 to demonstrate this phenomenon. In summary, our research suggested that knockdown of TRIB2 could slow cell growth and reverse resistance, implying that TRIB2 is a potential therapy target for resistant human CML. PMID- 29436680 TI - Curcumin increases cholesterol efflux via heme oxygenase-1-mediated ABCA1 and SR BI expression in macrophages. AB - Curcumin, which is an extract from a traditional Chinese medicine, has previously been demonstrated to exhibit an anti-atherosclerotic effect, which is closely associated with an increase in cholesterol efflux. However, it is unclear as to whether the increased effect is mediated by heme oxygenase (HO)-1. Macrophages were treated with different concentrations of curcumin, HO-1 inhibitor and small interfering (si)RNA in different experiments. Analysis of protein expression was conducted via western blotting. mRNA expression levels were measured using reverse transcription-polymerase chain reaction. Antioxidant response element (ARE)-driven promoter activity was measured by a dual-luciferase reporter assay. The cholesterol efflux analysis was performed by fluorescence-labelled cholesterol (NBD) using a multi-label counter. In the present study, the results indicated that curcumin increased the cholesterol efflux from macrophages. Additionally, curcumin significantly upregulated HO-1 expression. The HO-1 inhibitor (zinc protoporphyrin) partly blocked this effect. Curcumin also promoted scavenger receptor class B type I (SR-BI) and ATP-binding cassette transporter A1 (ABCA1) expression. HO-1 small interfering (si)RNA partly abolished the increased SR-BI and ABCA1 expression induced by curcumin. Furthermore, the nuclear factor, erythroid 2 like 2 (Nrf2) expression in the nucleus was dose-dependently increased by curcumin. Nrf2 siRNA successfully inhibited the curcumin-induced HO-1 expression. Curcumin significantly increased Nrf2-driven luciferase activity. Overall, these data indicated that curcumin activates the Nrf2-ARE signaling pathway and upregulates HO-1 expression, which mediates SR-BI and ABCA1 expression and thereby increases cholesterol efflux. PMID- 29436679 TI - Long non-coding RNA BC168687 small interfering RNA reduces high glucose and high free fatty acid-induced expression of P2X7 receptors in satellite glial cells. AB - Purinergic signaling contributes to inflammatory and immune responses. The activation of the P2X purinoceptor 7 (P2X7) in satellite glial cells (SGCs) may be an essential component in the promotion of inflammation and neuropathic pain. Long non-coding RNAs (lncRNAs) are involved in multiple physiological and pathological processes. The aim of the present study was to investigate the effects of a small interfering RNA for the lncRNA BC168687 on SGC P2X7 expression in a high glucose and high free fatty acids (HGHF) environment. It was demonstrated that BC168687 small interfering (si)RNA downregulated the co expression of the P2X7 and glial fibrillary acidic protein and P2X7 mRNA expression. Additionally, HGHF may activate the mitogen-activated protein kinase signaling pathway by increasing the release of nitric oxide and reactive oxygen species in SGCs. Taken together, these results indicate that silencing BC168687 expression may downregulate the increased expression of P2X7 receptors in SGCs induced by a HGHF environment. PMID- 29436681 TI - miR-199a-3p enhances cisplatin sensitivity of ovarian cancer cells by targeting ITGB8. AB - Drug resistance remains a large obstacle for the treatment of ovarian cancer. miRNAs have been reported to be involved in cisplatin (CDDP) resistance in ovarian cancer. The aim of the present study was to investigate the function and mechanism of miR-199a-3p in the CDDP resistance in ovarian cancer. We found that miR-199a-3p was significantly downregulated in chemoresistant ovarian cancer tissues, as well as CDDP-resistant SKOV3/CDDP cells, compared to chemosensitive carcinomas and SKOV3 cells. Restoration of miR-199a-3p in SKOV3/CDDP cells reduced cell proliferation, G1 phase cell cycle arrest, cell invasion, and increased cell apoptosis, resulting in enhanced CDDP sensitivity, while miR-199a 3p inhibition resulted in the opposite effects. Luciferase reporter assay showed that integrin beta8 (ITGB8), one of the integrins that is involved in the regulation of cell cycle and motility, was a direct target of miR-199a-3p. Overexpression of miR-199a-3p downregulated ITGB8 expression via binding to its 3'-UTR. In addition, overexpression of ITGB8 restored CDDP resistance inhibited by miR-199a-3p. Moreover, orthotopic ovarian cancer mouse model showed that miR 199a-3p enhanced CDDP sensitivity of ovarian cancer in vivo. Therefore, our results indicate that miR-199a-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ITGB8 expression, and miR-199a-3p may serve as a therapeutic target for the treatment of ovarian cancer patients with CDDP resistance. PMID- 29436682 TI - Fatostatin suppresses growth and enhances apoptosis by blocking SREBP-regulated metabolic pathways in endometrial carcinoma. AB - Fatostatin, a chemical inhibitor of the sterol regulatory element-binding protein (SREBP) pathway, has been reported to possess high antitumor activity against prostate and pancreatic cancer. The main aim of the present study was to investigate the effects and mechanism of fatostatin in endometrial carcinoma (EC). In the present study, we determined that fatostatin inhibited EC cell viability and colony formation capacity, decreased the invasive and migratory capacities of EC cells, induced EC cell cycle arrest at the G2/M phase and stimulated caspase-mediated apoptosis of EC cells. In addition, fatostatin significantly decreased the protein expression levels of nuclear SREBPs and their downstream genes and increased the protein expression levels of cleaved caspase 9, caspase-3 and PARP in EC cells. In addition, the mRNA expression levels of SREBP-controlled downstream genes were also significantly downregulated. The quantification assays of fatty acids and total cholesterol revealed that the levels of free fatty acids and total cholesterol in EC cells were decreased. The present study indicated that fatostatin exhibited antitumor effects by blocking SREBP-regulated metabolic pathways and inducing caspase-mediated apoptosis in EC and may be a potent therapeutic strategy for the treatment of EC. PMID- 29436683 TI - Knockdown of angiopoietin-like 4 inhibits the development of human gastric cancer. AB - Human gastric cancer (GC) is the second most common cause of cancer-related deaths worldwide and is one of the most common metastatic cancers. Tumor proliferation, apoptosis, metastasis and invasion are important predictors of the invasiveness of GC and are key factors in cancer-induced death. Angiopoietin-like 4 (ANGPTL4) is a secreted protein that belongs to the angiopoietin (ANGPTL) family and is involved in the regulation of cancer metastasis. However, whether ANGPTL4 plays a role in the progression of GC remain unclear. In the present study, immunoreactivity of ANGPTL4 demonstrated that ANGPTL4 expression was upregulated in GC tissues with the development of GC. The siRNA targeting ANGPTL4 effectively knocked down ANGPTL4 in the SNU-1 and BGC823 cell lines at the mRNA and protein levels. Following ANGPTL4 downregulation, the proliferation and invasion abilities of GC cell lines were suppressed as determined by MTT and Transwell assays, and cell apoptosis level and sensitivity to cisplatin were increased as determined by flow cytometry and MTT assay. In conclusion, these findings suggest that ANGPTL4 may be a new potential therapeutic target for GC. PMID- 29436684 TI - Lactoferrin promotes murine C2C12 myoblast proliferation and differentiation and myotube hypertrophy. AB - Lactoferrin (Lf) is a multifunctional glycoprotein, which promotes the proliferation of murine C2C12 myoblasts. In the present study, it was investigated how Lf promotes myoblast proliferation and whether Lf promotes myoblast differentiation or induces myotube hypertrophy. Lf promoted the proliferation of myoblasts in a dose-dependent manner. Myoblast proliferation increased on day 3 when myoblasts were cultured in the presence of Lf for three days and also when myoblasts were cultured in the presence of Lf for the first day and in the absence of Lf for the subsequent two days. In addition, Lf induced the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in myoblasts. The mitogen-activated protein kinase kinase 1/2 inhibitor U0126 inhibited Lf-induced ERK1/2 phosphorylation and repressed Lf-promoted myoblast proliferation. C2C12 myoblasts, myotubes and skeletal muscle expressed low density lipoprotein receptor-related protein (LRP)1 mRNA and Lf-promoted myoblast proliferation was attenuated by an LRP1 antagonist or LRP1 gene silencing. The knockdown of LRP1 repressed Lf-induced phosphorylation of ERK1/2. Furthermore, when myoblasts were induced to differentiate, Lf increased the expression of the myotube-specific structural protein, myosin heavy chain (MyHC) and promoted myotube formation. Knockdown of LRP1 repressed Lf-induced MyHC expression. Lf also increased myotube size following differentiation. These results indicate that Lf promotes myoblast proliferation and differentiation, at least partially through LRP1 and also stimulates myotube hypertrophy. PMID- 29436685 TI - Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models. AB - A small molecule that was developed for blocking vascular endothelial growth factor receptor 2 (VEGFR2) has been tested and confirmed for its anti-angiogenic activity. Subsequently, it was modified into a water soluble salt form (JFD-WS) to increase bioavailability and distribution during in vivo pre-clinical testing. The present study was designed to further evaluate the anti-angiogenic and pro apoptotic effects of JFD-WS in monotherapy as well as in combination with paclitaxel (Taxol) using a mouse xenograft model. The in vitro anti-angiogenic effects of JFD-WS were investigated using cell proliferation, migration, Matrigel tube formation and VEGFR2 phosphorylation assays. The anti-angiogenic effect of JFD-WS was further established using chorioallantoic membrane (CAM) assay followed by in vivo efficacy testing on GI-101A breast adenocarcinoma cells. Pharmacokinetic and toxicity studies were performed using BALB/c mice. Finally, the apoptotic signals were assessed in the control and experimental tumor samples, and the plasma mucin 1 (MUC1) levels were analyzed. In the in vitro tests, JFD-WS effectively inhibited HUVEC proliferation, migration, tube formation and VEGFR2 phosphorylation. Additionally, JFD-WS inhibited the formation of blood vessels in chick chorioallantoic membrane. While inhibiting the xenograft tumor growth in experimental mice, JFD-WS decreased the plasma MUC1 levels. The western blot analysis of apoptotic markers and fragmentation analysis of DNA confirmed the pro-apoptotic effects of JFD-WS. These results indicated that JFD-WS alone or in combination with paclitaxel exerted antitumor and pro apoptotic effects in the breast cancer xenograft model due to an anti-angiogenic effect. These results strongly support the clinical translation of its use. PMID- 29436686 TI - Downregulation of the long non-coding RNA XLOC_010588 inhibits the invasion and migration of colorectal cancer. AB - Long non-coding RNAs (lncRNAs) have emer-ged as major players in many biological and pathological processes; however, investigation into the function of lncRNAs in the development and progression of cancer is in its infancy. Therefore, clarification of the mechanism by which cancer-related lncRNAs function is of critical importance in research on tumorigenesis. It has been demonstrated that the lncRNA XLOC_010588 is expressed at a low level in cervical cancer, and that this has significant impact on the proliferation of cervical cancer cells. However, the expression pattern and functional roles of XLOC_010588 in colorectal cancer (CRC) remain unclear. In the present study, it was demonstrated that the expression of XLOC_010588 was significantly higher in CRC tissues when compared with that in adjacent normal tissues, and that XLOC_010588 was closely associated with metastasis and poor prognosis, thus indicating that XLOC_010588 may function as an oncogene. Additionally, downregulation of XLOC_010588 expression markedly inhibited the invasion and migration of CRC cells. Furthermore, it was demonstrated that XLOC_010588 may regulate the progression of CRC via the epithelial-mesenchymal transition (EMT) pathway. Notably, downregulation of XLOC_010588 inhibited the invasion and migration of CRC cells by regulating genes associated with EMT. Our findings revealed that XLOC_010588 may be considered as a novel potential diagnostic biomarker in CRC. PMID- 29436688 TI - Necrostatin-1 protects C2C12 myotubes from CoCl2-induced hypoxia. AB - Necrostatin-1 (Nec-1) is a selective and potent allosteric inhibitor of necroptosis by specifically inhibiting the activity of receptor-interacting protein (RIP) 1 kinase. The aim of the present study was to determine the effect of Nec-1 on an anoxia model comprising mouse skeletal C2C12 myotubes. In the present study, a hypoxic mimetic reagent, cobalt chloride (CoCl2), was used to induce hypoxia in C2C12 myotubes. The cytotoxic effects of CoCl2-induced hypoxia were determined by a Cell Counting kit-8 assay and flow cytometry. Transmission electron microscopy (TEM) was used to characterize the morphological characteristics of dead cells at the ultrastructural level. To clarify the signaling pathways in CoCl2-mediated cell death, the expression levels of RIP1, RIP3, extracellular signal-regulated kinase (ERK)1/2, hypoxia-inducible factor (HIF)-1alpha and B cell lymphoma-2 adenovirus E1B 19-kDa interacting protein 3 (BNIP3) were investigated by western blotting. Oxidative stress was determined using 2',7'-dichlorofluorescin diacetate to measure intracellular reactive oxygen species (ROS) and the fluorescent dye JC-1 was used to measure mitochondrial membrane potential (Deltapsim). The results showed that the ratios of apoptotic and necrotic C2C12 cells were increased following CoCl2 treatment, typical necroptotic morphological characteristics were able to observe by TEM, whereas Nec-1 exhibited a protective effect against CoCl2-induced oxidative stress. Treatment with Nec-1 significantly decreased the levels of RIP1, p-ERK1/2, HIF 1alpha, BNIP3 and ROS induced by CoCl2, and promoted C2C12 differentiation. Nec-1 reversed the CoCl2-induced decrease in mitochondrial membrane potential. Together, these findings suggested that Nec-1 protected C2C12 myotubes under conditions of CoCl2-induced hypoxia. PMID- 29436687 TI - Laminins in an in vitro anterior lens capsule model established using HLE B-3 cells. AB - Cataracts are the most common eye disease to cause blindness in patients. The abnormal deposition of laminins (LMs) in the lens capsule and the disruption of capsular epithelium contribute to cataract development, although the mechanism by which this occurs is currently unclear. The present study aimed to reproduce HLE B-3 basement membranes (BMs) using HLE B-3 cells and to analyze the similarities of LM expression between HLE B-3 BMs and human anterior lens capsule (ALC). Immunohistochemistry (IHC), ELISA, western blot analysis and immunoprecipitation (IP)-western blot analysis were used to detect total LMs, LM trimers and 11 LM subunits in HLE B-3 cells, HLE B-3 BMs and human ALCs. In IHC staining, HLE B-3 cells and human ALCs were positive for LMs. In LM ELISA, all samples analyzed were positive for LMs. Western blot analysis detected all LM subunits except for LMgamma3 in HLE B-3 cell lysate, 4 subunits (LMalpha4, LMalpha2, LMalpha1 and LMgamma1) in HLE B-3 cell culture supernatant, 5 subunits (LMalpha4, LMalpha2, LMalpha1, LMbeta3 and LMgamma1) in HLE B-3 BMs, and 3 subunits (LMalpha4, LMgamma2 and LMgamma1) in human ALCs. The results of IP-western blot analysis revealed that the LM411 trimer was detected in HLE B-3 cell culture supernatant. These results indicated that HLE B-3 BMs were similar to human ALCs in terms of LM expression. Therefore, HLE B-3 BMs could be used as an in vitro ALC model to determine the role of LMs in ALC in the pathogenesis of cataracts and to select potential anti-cataract drugs. PMID- 29436689 TI - MicroRNA-655 attenuates the malignant biological behaviours of retinoblastoma cells by directly targeting PAX6 and suppressing the ERK and p38 MAPK signalling pathways. AB - Numerous studies have indicated that microRNAs (miRNAs) regulate signalling molecules by acting as oncogenes or tumour-suppressor genes in retinoblastoma (RB). Therefore, investigation of the expression pattern, biological roles and associated mechanisms of cancer-related miRNAs in RB may provide novel therapeutic targets for patients with this disease. miRNA-655 (miR-655) has been reported to be aberrantly expressed in many types of cancers. However, the expression pattern, detailed biological function and underlying molecular mechanisms of miR-655 in RB remain to be clarified. Therefore, the aims of the present study were to detect miR-655 in RB, investigate its biological roles in RB and determine the underlying molecular mechanisms. The results of the present study showed that miR-655 was significantly downregulated in RB tissues and cell lines. Overexpression of miR-655 inhibited the proliferation and invasion ability while it increased the apoptosis of RB cells. Additionally, paired box 6 (PAX6) was identified as a direct target of miR-655 in RB. Furthermore, PAX6 was highly expressed in RB tissues and was negatively correlated with miR-655 expression. PAX6 knockdown recapitulated effects similar to those observed following miR-655 overexpression regarding the proliferation, invasion and apoptosis of RB cells. Rescue experiments demonstrated that restoration of PAX6 expression reversed the tumour-suppressing roles of miR-655 in RB cells. Moreover, upregulation of miR 655 reduced activation of the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase signalling pathways in RB cells through PAX6 regulation. Therefore, restoration of miR-655 expression may be a promising therapeutic strategy for treating patients with RB in the future. PMID- 29436690 TI - Effects of low-intensity ultrasound combined with low-dose carboplatin in an orthotopic hamster model of tongue cancer: A preclinical study. AB - Low-intensity ultrasound (LIUS) combined with chemotherapy is an innovative modality for cancer treatment, but its effect on orthotopic carcinoma remains unknown. Our previous study revealed that LIUS enhanced the growth inhibitory effects of several chemotherapeutic drugs in nude mice with transplanted tumors. In the present study, we used 7,12-dimethylbenz(alpha)anthracene to induce orthotopic tongue carcinogenesis in hamsters. We used the first-line chemotherapy drug for tongue cancer, carboplatin (CBP) in combination with LIUS to investigate the synergistic effect. The results revealed that LIUS combined with low-dose CBP enhanced the inhibitory effects of CBP on tumor growth, prolonged survival, and did not increase the incidence of side-effects. It also enhanced the inherent DNA damage caused by CBP, suppressed the expression of the DNA repair proteins O6 methylguanine DNA methyltransferase (MGMT) and Chk1, and increased the expression of DNA damage-inducible protein GADD45alpha. Furthermore, compared with CBP alone, LIUS combined with CBP reduced the expression of cyclin D1 and cyclin B1, induced the expression of caspase-3, cleaved caspase-3, caspase-8, Bax, and Bak, and inhibited the expression of Bcl-2. Examination of clinical samples revealed that MGMT, Chk1, and Gadd45alpha were higher in OTSCC than in adjacent normal tissue. Hence, our results indicated that LIUS enhanced the ability of low-dose CBP to damage DNA in an orthotopic hamster model of tongue cancer, induced apoptosis, inhibited tumor growth and progression, while it did not increase the toxic side-effects of the drug, suggesting additional clinical benefits for patients treated with the combination of CBP with LIUS. PMID- 29436691 TI - Novel structural approaches concerning HPV proteins: Insight into targeted therapies for cervical cancer (Review). AB - Cervical cancer incidence is tightly linked to HPV infection, and particularly virus types 16 and 18 cause the majority of cases presenting with pre-cancerous stages of cervical intraepithelial neoplasia (CIN). Structural and functional information concerning HPV proteins can offer novel insight into the mechanism(s) of cancer progression in the cervical epithelium. Recently, novel structural determinants of the interactions of viral proteins with their targets in keratinocytes have been elucidated. These exciting findings open the way for the development of targeted anti-oncogenic therapies, and may eventually allow the introduction of novel approaches for a rational cervical cancer treatment. PMID- 29436692 TI - Synergistic antitumor effects of histone deacetylase inhibitor scriptaid and bortezomib against ovarian cancer cells. AB - Despite debulking surgery and good initial response to chemotherapy, the majority of patients with advanced ovarian cancer relapse and succumb to their disease. Thus, there is a pressing need to improve treatment outcome. In the present study, the antitumor activity of histone deacetylase (HDAC) inhibitor scriptaid in combination with bortezomib or conventional chemotherapeutics was tested in vitro against representative ovarian cancer cell lines: SKOV-3, MDAH 2774, and OVP-10. Incubation of ovarian cancer cells with scriptaid and bortezomib (or doxorubicin) led to synergistic antitumor effects. As shown in the Annexin V FITC/PI assay and western blot analysis of caspase-3/-9 and p21 protein expression, these synergistic antitumor effects were due to both induction of apoptosis and inhibition of proliferation. Since synergistic antitumor activity of scriptaid and bortezomib appeared in suboptimal concentrations, one can assume that the administration of the combination of these agents to ovarian cancer patients can exert the therapeutic effect in parallel with limited general toxicity of the treatment. PMID- 29436693 TI - Yap regulates gastric cancer survival and migration via SIRT1/Mfn2/mitophagy. AB - Gastric cancer is the fifth most common cancer worldwide and Hippo-Yap is the novel signaling pathway which plays an important role in gastric cancer tumor development and progression. However, little insight is available to date regarding the specific role of Yes-associated protein (Yap) in gastric cancer. In the present study, we identified the mechanism through which Yap sustains gastric cancer viability and migration. Yap was greatly upregulated in gastric cancer cells and its expression promoted cellular migration and survival. Functional studies found that knockdown of Yap reduced the mitophagy activity, which subsequently caused mitochondrial apoptosis and cellular oxidative stress. The latter impaired adhesive protein expression, alleviated F-actin expression, blunted lamellipodium formation, leading to inhibition of cancer cell motility. Mechanistically, Yap preserved Sirtuin 1 (SIRT1) activity which manipulated mitofusin 2 (Mfn2) expression and subsequent mitophagy. Loss of Yap reduced SIRT1 expression and inhibited Mfn2-mediated mitophagy. Collectively, our results identified Hippo-Yap as a tumor promoter in gastric cancer that was mediated via activation of the SIRT1/Mfn2/mitophagy axis, with potential applications to gastric cancer therapy involving cancer survival and migration. PMID- 29436694 TI - LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer. AB - Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are characterized by genomic rearrangements and point mutations in the proto-oncogene RET. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a suppressor of various receptor tyrosine kinases, including RET. LRIG1 expression levels are associated with patient survival in many cancer types. In the present study, we investigated whether the oncogenic RET mutants RET2A (C634R) and RET2B (M918T) were regulated by LRIG1, and the possible effects of LRIG1 expression in thyroid cancer were investigated in three different clinical cohorts and in a RET2B-driven mouse model of MTC. LRIG1 was shown to physically interact with both RET2A and RET2B and to restrict their ligand-independent activation. LRIG1 mRNA levels were downregulated in PTC and MTC compared to normal thyroid gland tissue. There was no apparent association between LRIG1 RNA or protein expression levels and patient survival in the studied cohorts. The transgenic RET2B mice developed pre-cancerous medullary thyroid lesions at a high frequency (36%); however, no overt cancers were observed. There was no significant difference in the incidence of pre-cancerous lesions between Lrig1 wild-type and Lrig1-deficient RET2B mice. In conclusion, the findings that LRIG1 is a negative regulator of RET2A and RET2B and is also downregulated in PTC and MTC may suggest that LRIG1 functions as a thyroid tumor suppressor. PMID- 29436697 TI - [Ketamine: breakthrough as 'anti-antidepressivum'?] PMID- 29436696 TI - CXCR4 receptor blockage reduces the contribution of tumor and stromal cells to the metastatic growth in the liver. AB - The liver is a common site for the metastatic spread of primary malignancies including colorectal cancer, and liver metastasis is a main cause of death in cancer patients. This is due to the complexity of the interactions taking place in the liver between tumor and stromal cells. In fact, cancer-associated fibroblasts (CAFs) have been shown to support tumor growth through the CXCL12/CXCR4 axis. However, along with cancer cells, myeloid-derived suppressor cells (MDSCs), immature dendritic cells with immunosuppressive potential, also express CXCR4. It has recently been demonstrated that reducing CXCL12 availability in the tumor microenvironment decreases liver metastasis. Therefore, blocking CXCL12 chemokine receptor CXCR4 may be a successful approach to diminish the metastatic spread of colorectal cancer to the liver. However, the subjacent mechanisms by which this chemokine influences the tumor are not fully understood. Thus, in order to uncover the role of CXCR4 during tumor cell/liver fibroblast crosstalk driving liver metastasis, the CXCR4 antagonist AMD3100 was used for in vitro studies and in an in vivo approach using an orthotopic model of liver metastasis in immune competent mice through intrasplenic injection of grafted C26 cells. In vitro blockage of CXCR4 led to an impaired migratory potential of tumor and hepatic stellate cells (HSCs) and a reduced tumor response to CXCL12. In vivo administration of AMD3100 to tumor-bearing mice resulted in attenuated metastatic development in the liver, which was accompanied by an impaired infiltration of alphaSMA-expressing cells within the tumors. In addition, a reduced CD11+Ly6G+ cell count in the liver was directly correlated with a reduction in MDSC numbers in the blood of AMD3100-treated mice compared to the vehicle-treated mice. Therefore, disruption of the CXCR4/CXCL12 axis by CXCR4 antagonist AMD3100 blocked the contribution of both cancer and stromal cells to the metastatic cascade in the liver. PMID- 29436695 TI - Inhibition of mammalian target of rapamycin complex 1 signaling by n-3 polyunsaturated fatty acids promotes locomotor recovery after spinal cord injury. AB - The present study aimed to explore the effects of n-3 polyunsaturated fatty acids (PUFAs) on autophagy and their potential for promoting locomotor recovery after spinal cord injury (SCI). Primary neurons were isolated and cultured. Sprague Dawley rats were randomly divided into three groups and fed diets with different amounts of n-3 PUFAs. A model of spinal cord contusion was created at the T10 spinal segment and the composition of PUFAs was analyzed using gas chromatography. Spinal repair and motor function were evaluated postoperatively. Assessment of the effects of n-3 PUFAs on autophagy and mammalian target of rapamycin complex 1 (mTORC1) was performed using immunofluorescence staining and western blotting. In vitro, n-3 PUFAs inhibited mTORC1 and enhanced autophagy. The n-3 PUFA levels and the ratio of n-3 PUFA to n-6 PUFA in the spinal cord and serum of rats fed a high-n-3 PUFA diet were higher before and after operation (P<0.05). Additionally, rats in the high-n-3 PUFA group showed improved motor function recovery, spinal cord repair-related protein expression level (MBP, Galc and GFAP). Expression levels if these protiens in the high-n-3 PUFA diet group expressed the highest levels, followed by the low-n-3 PUFA diet group and finally the control group (P<0.05). high-n-3 PUFA diet promoted autophagy ability and inhibited activity of the mTORC1 signaling pathway compared with the low-n-3 PUFA diet group or the control group (P<0.05). These results suggest that exogenous dietary n-3 PUFAs can inhibit mTORC1 signaling and enhance autophagy, promoting functional recovery of rats with SCI. PMID- 29436698 TI - [How reliable are the predictors of sexual recidivism? Moral considerations can colour the judgement of pro Justitia reporters]. AB - BACKGROUND: When estimating the risk of sexual recidivism, the specialised behavioural pro Justitia reporter in the Netherlands generally uses risk assessment tools, although it is the reporter who pronounces the final judgement.
AIM: To examine which risk factors reporters take into account when assessing the risk of sexual recidivism, to test to what degree this assessment is based on the scientific accuracy of the risk factors and to what extent the assessment is influenced by moral considerations.
METHOD: 151 reporters indicated how important they considered risk factors to be in the assessment of sexual recidivism risk in adult sex offenders. This assessment was compared to the predictive value of the risk factors based on current scientific knowledge and to the moral 'unacceptability' of these factors.
RESULTS: The reporters' judgement was moderately correlated to current scientific knowledge, but was also strongly correlated to moral 'unacceptability'. Morally unacceptable behaviour (e.g. a lack of empathy with victim) was given too much emphasis. On the other hand, behaviour that was morally more acceptable (e.g. behavioural problems in childhood) was given insufficient weight in the risk assessment of recidivism.
CONCLUSION: There seems to be a considerable discrepancy between the reporters' judgement and the actual predictors of sexual recidivism. It is undesirable that pro Justitia reporters allow themselves to be swayed by moral consideration. The risk of bias and subjectivity points to the need for substantial restructuring of risk assessment in the cases of sexual recidivism. PMID- 29436699 TI - [Bipolar disorder and alcohol use disorder: practical recommendations for treatment, based on a literature review]. AB - BACKGROUND: A fairly large proportion (25-50%) of patients with bipolar disorder (bd) also suffer from comorbid alcohol use disorder (aud). However, little is known how this type of morbidity should be treated. It is also unclear whether the current guidelines on bd have been influenced by aud.
AIM: To provide an overview of recent literature concerning the diagnosis and treatment of comorbid bd and aud.
METHOD: We systematically reviewed studies that have addressed three treatment options for this group of patients: pharmaco-therapy, psychological interventions and self-management techniques.
RESULTS: If health professionals decide to treat bd using a pharmaco-therapeutic intervention, they must proceed with caution because the patient may also be suffering from aud. From the very limited number of published articles on this subject, we conclude that the best solution to the problem is to add valproate to the lithium-based treatment. There is also limited evidence that other effective treatments may include the use of integrated psychological interventions, cognitive behavioural therapy and self-management techniques, but these possibilities need further investigation.
CONCLUSION: Treatment of patients suffering from both bd and aud should always focus on both disorders, either simultaneously or separately. If this approach is successful it is vitally important that care is better organised and that there is cooperation between institutions involved in treating addiction disorders and departments that specialise in the care of bd. These improvements are likely to lead to further developments and to more research into new forms of integrated treatment. PMID- 29436700 TI - [A valid quality system for mental health care: from accountability and control in institutionalised settings to co-creation in small areas and a focus on community vital signs]. AB - BACKGROUND: In a given year, around 25% of the Dutch population may experience significant mental health problems, much more than the mental health service can attend to, given a maximum capacity of 6% of the population per year. Due to the lack of a public mental health system, there is fierce competition over who gets to receive care from mental health services and little control over how the level of needs can be matched with the appropriate intensity of care. As a result, resources are being wasted and both overtreatment and undertreatment are prevalent.
AIM: To propose a valid quality system that benefits the mental health of the entire population and does not simply attend to the symptoms of a strategically selected group.
METHOD: Literature review from an epidemiological and public mental health perspective.
RESULTS: In our view, a valid quality system for mental health care needs to focus on two distinct areas. The first area involves the analysis of about 20 quantitative population parameters or 'Community Vital Signs' (care consumption, pharmaco-epidemiological indicators, mortality, somatic morbidity, social care, housing, work, benefits, involuntary admissions). This analysis will reveal regional variation in the mental health of the entire population rather than in the relatively small, selected group receiving mental health care. The second area to which attention needs to be directed comprises a system of simple qualitative visits to mental health care institutions based on 10 quality parameters that currently remain invisible; these parameters will measure the impact at local community level. The focus of these will be on a transition from accountability and control in large institutions to provision of care in small areas that was co-designed with users and other stakeholders.
CONCLUSION: A valid quality system for mental health care is within reach, provided it is combined with a novel system of public mental health and transition of care to a system of co-design with users in small areas. PMID- 29436701 TI - [The dysregulated brain - Consequences of spatial and temporal brain complexity for bipolar disorder pathophysiology and diagnosis]. AB - BACKGROUND: Despite the existence of several pathophysiological theories about bipolar disorder, it has so far been difficult to find diagnostic biomarkers and to develop new pharmacologic treatments based on the more novel theories. AIM: To reflect on the causes and consequences of problems that beset pathophysiological research into psychiatric disorders in general and bipolar disorder in particular. METHOD: In this essay we address the problems facing professionals engaged in research into bipolar disorder and we interpret these problem in the light of brain complexity. RESULTS: The complexity of the brain can be divided into two types: spatial complexity, which reflects the various physiological levels of the central nervous system (genetic, molecular, cellular, neuronal circuits and phenomenological levels), and temporal complexity, i.e. neurodevelopment. We discuss the consequences of these two types of complexity and make suggestions relating to clinical practice and pathophysiological psychiatric research. CONCLUSION: To achieve further progress in the field of brain research, we need to acquire a deeper understanding of the spatial and temporal complexity of the brain and consider the possible consequences of such knowledge for the pathophysiology and treatment of psychiatric illnesses such as bipolar disorder. PMID- 29436702 TI - [Staging and profiling of patients with dual disorders]. AB - BACKGROUND: Although there is a great need for staging and profiling in psychiatry, no-one has so far devised a staging and profiling model to aid diagnosis and treatment. AIM: To devise a basic staging and profiling strategy that can be used to treat patients suffering from both substance abuse disorder and a psychiatric disorder. METHOD: On the basis of existing staging model for addiction, we explore how staging could also be useful for the treatment of comorbidity in psychiatry. RESULTS: Since there is hardly any evidence of the use of staging for this kind of comorbidity, we present a staging model that might help to provide a solution. To the described stages we add a recommended treatment setting or treatment intensity. CONCLUSION: Further research is needed to ascertain whether the staging model that we have presented will lead to improvements in the prognosis and treatment of patients with dual disorders referred to Dutch psychiatrists. PMID- 29436703 TI - [Hashimoto encephalopathy as explanation of psychotic symptoms in an adolescent]. AB - Hashimoto encephalopathy (he) is a rare disorder with a great diversity in clinical presentation of neurological and/or psychiatric symptoms. We describe a case of Hashimoto thyroiditis with hypothyroidism and Hashimoto encephalopathy in a fifteen-year-old boy who was referred to a child and adolescent psychiatrist due to a suspicion of a psychotic episode. Patient recovered after treatment with levothyroxine and corticosteroids. PMID- 29436704 TI - [Reaction on 'Mental health as a front-line service for bewildered persons']. PMID- 29436705 TI - [Reaction on 'The care cluster model as basis for the further development of the Dutch mental health payment system']. PMID- 29436706 TI - Low-intensity pulsed ultrasound increases blood vessel size during fracture healing in patients with a delayed-union of the osteotomized fibula. AB - Disturbed vascularity leads to impaired fracture healing. Since low-intensity pulsed ultrasound (LIPUS) increases new bone formation in delayed-unions, we investigated whether LIPUS increases blood supply in delayed-unions of the osteotomized fibula, and if LIPUS-increased bone formation is correlated to increased blood supply. Blood vessel parameters were analysed using histology, immunohistochemistry, and histomorphometric analysis as well as their correlation with bone formation and resorption parameters. Fibular biopsies of thirteen patients with a delayed-union of the osteotomized fibula treated for 2-4 months with or without LIPUS originating from a randomized prospective double-blind placebo-controlled clinical trial were studied. In histological sections of the fibular biopsies parameters of blood vessel formation were measured and were related to histomorphometric bone characteristics of newly formed bone of the same samples analysed in our previously published study on the effects of LIPUS on bone healing at the tissue level in delayed-unions. LIPUS-treated delayed unions and sham-treated delayed-unions as well as healed delayed-unions and failed-to-heal delayed-unions were compared. The volume density of blood vessels was increased in LIPUS-treated delayed-unions compared to sham-treated controls. LIPUS did not change blood vessel number, but significantly increased blood vessel size. Healed delayed-unions as well as LIPUS-treated and sham-treated delayed-unions showed significant correlations between blood vessel size and osteoid volume. LIPUS increases blood vessel size, essential for fracture healing, in bone from patients with a delayed-union of the osteotomized fibula. The increased osteoid volume in delayed-unions can largely be explained by increased blood supply and perfusion. PMID- 29436707 TI - The molecular pathology of cancer: from pan-genomics to post-genomics. AB - As the cancer genomics of most major cancer types have been comprehensively catalogued over the past decade through a variety of national and international efforts, the delineation of cancer subtypes has been refined, and our understanding of critical cancer drivers and of the potentially targetable vulnerabilities that they create has grown tremendously. The 2018 Annual Review Issue of the Journal of Pathology provides in-depth assessments of how these pan genomic approaches have enabled advances in cancer classification, targeted therapy selection, and assessment of cancer progression, all of which are now genomically informed, using several cancer types as examples. Beyond these areas of by now conventional pan-genomic tumour analysis, there are also reviews of diverse 'post-genomic' areas, such as the analysis of circulating free tumour DNA in plasma, concurrent germline cancer predisposition profiling in the setting of apparently sporadic cancer, genetic alterations in epigenetic control and DNA repair, proteomics of tumour heterogeneity, computational pathology, and the roles of the cellular stress response and the microbiome in human cancers. As we are able to derive more and more biologically useful information from diverse human biospecimens, these many advances are informing and transforming the practice of cancer pathology. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29436708 TI - Nursing wound care practices in Haiti: facilitators and barriers to quality care. AB - AIM: To describe the facilitators and barriers for nurses to perform quality wound care in three surgical wards of a hospital in Port-au-Prince, Haiti. BACKGROUND: Up to a quarter of patients in low- and middle-income countries may acquire at least one infection while hospitalized. There is a paucity of research investigating nursing wound care practices in low- and middle-income countries regarding the prevention of hospital-acquired infections. METHODS: The design was qualitative descriptive. We observed nursing staff on the general surgery, orthopaedics and maternity units while they performed routine dressing changes (n = 15). We interviewed nursing (n = 13) and medical residents (n = 3) and inquired about their perceptions of facilitators and barriers for nurses to perform quality wound care. FINDINGS: A number of wound care practices appeared well integrated including using gloves to remove dressings, applying sterile dressings, properly disposing of soiled materials, inspecting wounds for signs of infection and employing comfort and privacy measures. Areas that may need improvement included aseptic technique, hand hygiene, pain assessments, patient education and documentation. We identified four themes related to barriers and facilitators to perform quality wound care: (i) materials and resources; (ii) nurse-to-patient ratios, workload and support; (iii) roles and responsibilities of nurses; and (iv) knowledge and training of nurses. CONCLUSION: Nursing wound care practices may be optimized by improving nurses' professional status and working conditions. IMPLICATIONS FOR NURSING PRACTICE AND HEALTH POLICY: Greater financial investment in health care and (continuing) education, self-regulation and development of the nursing role, including more autonomy, are needed to elevate the professional status of nurses in Haiti. Institutional policies should promote best practices, clarify nursing roles and responsibilities and foster interdisciplinary collaboration in patient care. PMID- 29436709 TI - Fast and efficient genetic engineering of hematopoietic precursor cells for the study of dendritic cell migration. AB - Estrogen inducible Hoxb8 leads to conditional immortalization of hematopoietic precursors. These cells can be cultured and infected with the CRISPR/Cas9 system for genome editing, circumventing resource consuming generation of mouse models. The resultant cells retain their ability to differentiate into migratory dendritic cells. PMID- 29436710 TI - Mesophyll conductance does not contribute to greater photosynthetic rate per unit nitrogen in temperate compared with tropical evergreen wet-forest tree leaves. AB - Globally, trees originating from high-rainfall tropical regions typically exhibit lower rates of light-saturated net CO2 assimilation (A) compared with those from high-rainfall temperate environments, when measured at a common temperature. One factor that has been suggested to contribute towards lower rates of A is lower mesophyll conductance. Using a combination of leaf gas exchange and carbon isotope discrimination measurements, we estimated mesophyll conductance (gm ) of several Australian tropical and temperate wet-forest trees, grown in a common environment. Maximum Rubisco carboxylation capacity, Vcmax , was obtained from CO2 response curves. gm and the drawdown of CO2 across the mesophyll were both relatively constant. Vcmax estimated on the basis of intercellular CO2 partial pressure, Ci , was equivalent to that estimated using chloroplastic CO2 partial pressure, Cc , using 'apparent' and 'true' Rubisco Michaelis-Menten constants, respectively Having ruled out gm as a possible factor in distorting variations in A between these tropical and temperate trees, attention now needs to be focused on obtaining more detailed information about Rubisco in these species. PMID- 29436711 TI - Evidence for dispensability of protein kinase R in host control of tuberculosis. AB - Genetic deficiency of protein kinase R (PKR) in mice was reported to enhance macrophage activation in vitro in response to interferon-gamma (IFNgamma) and to reduce the burden of Mycobacterium tuberculosis (Mtb) in vivo (Wu et al. PloS One. 2012 7:e30512). Consistent with this, treatment of wild-type (WT) macrophages in vitro with a novel PKR inhibitor (Bryk et al., Bioorg. Med. Chem. Lett. 2011 21:4108-4114) also enhanced IFN-gamma-dependent macrophage activation (Wu et al. PloS One. 2012 7:e30512). Here we show that co-treatment with IFN gamma and a new PKR inhibitor identified herein to be highly but not completely selective likewise induced macrophages to produce more reactive nitrogen intermediates (RNI) and tumor necrosis factor alpha (TNF-alpha) and less interleukin 10 (IL-10) than seen with IFN-gamma alone. Unexpectedly, however, this new PKR inhibitor had a comparable effect on PKR-deficient macrophages. Retrospective investigation revealed that the PKR-deficient mice in (Wu et al. PloS One. 2012 7:e30512) had not been backcrossed. On comparing genetically matched PKR-deficient and WT mice, we saw no impact of PKR deficiency on macrophage activation in vitro or during the course of Mtb infection in vivo. In addition, although 129S1/SvImJ macrophage responses to IFN-gamma were greater than those of C57BL/6J macrophages, PKR was not required to mediate the IFN-gamma dependent production of IL-10, RNI or TNF-alpha in either strain. Together the data cast doubt on PKR as a potential therapeutic target for tuberculosis. PMID- 29436712 TI - Impact Factors, Reads and Real Values. PMID- 29436713 TI - When ultrasound anomalies are present: An estimation of the frequency of chromosome abnormalities not detected by cell-free DNA aneuploidy screens. AB - OBJECTIVES: This study characterizes cytogenetic abnormalities with ultrasound findings to refine counseling following negative cell-free DNA (cfDNA). METHODS: A retrospective cohort of pregnancies with chromosome abnormalities and ultrasound findings was examined to determine the residual risk following negative cfDNA. Cytogenetic data was categorized as cfDNA detectable for aneuploidies of chromosomes 13, 18, 21, X, or Y or non-cfDNA detectable for other chromosome abnormalities. Ultrasound reports were categorized as structural anomaly, nuchal translucency (NT) >=3.0 mm, or other "soft markers". Results were compared using chi squared and Fishers exact tests. RESULTS: Of the 498 fetuses with cytogenetic abnormalities and ultrasound findings, 16.3% (81/498) had non cfDNA detectable results. In the first, second, and third trimesters, 12.4% (32/259), 19.5% (42/215), and 29.2% (7/24) had non-cfDNA detectable results respectively. The first trimester non-cfDNA detectable results reduced to 7.7% (19/246) if triploidy was detectable by cfDNA testing. For isolated first trimester NT of 3.0-3.49 mm, 15.8% (6/38) had non-cfDNA detectable results, while for NT >=3.5 mm, it was 12.3% (20/162). For cystic hygroma, 4.3% (4/94) had non cfDNA detectable results. CONCLUSIONS: Counseling for residual risk following cfDNA in the presence of an ultrasound finding is impacted by gestational age, ultrasound finding, and cfDNA detection of triploidy. PMID- 29436714 TI - GCH1 attenuates cardiac autonomic nervous remodeling in canines with atrial tachypacing via tetrahydrobiopterin pathway regulated by microRNA-206. AB - BACKGROUND/AIMS: Cardiac autonomic nerve remodeling (ANR) is an important mechanism of atrial fibrillation (AF). GTP cyclohydrolase I, encoded by GCH1, is the rate-limiting enzyme in de novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthesis. Previous studies reported that increased BH4 and NO content negatively regulated nerve regeneration. This study investigated the effects of GCH1 on ANR via BH4 pathway, regulated by microRNA-206 (miR-206). METHODS AND RESULTS: In canines, atrial tachypacing (A TP), together with miR-206 overexpression, increased PGP9.5 level and inhibited GCH1 expression by quantitative real-time polymerase chain reaction and western blot analysis. GCH1 was validated to be a direct target of miR-206 by luciferase assays. Meanwhile, miR-206 overexpression by lentiviruses infection into right superior pulmonary vein fat pad decreased GCH1 expression to ~40% and further reduced BH4 and NO content compared with the control canines. After infection of GCH1 overexpression lentiviruses for two weeks, atrial effective refractory period was increased compared with the control group (105.8 +/- 1.537 ms vs 99.17 +/- 2.007 ms, P < 0.05). Moreover, GCH1 overexpression attenuated canines' atrial PGP9.5 level to ~56% of the controls. In myocardial cells, transfection of GCH1 overexpression lentiviruses also decreased PGP9.5 expression to 26% of the control group. In patients, plasma was collected and miR-206 expression was upregulated in AF patients (n = 18) than the controls (n = 12). CONCLUSIONS: Our findings suggested that GCH1 downregulation exacerbated ANR by decreasing atrial BH4 and NO content modulated by miR-206 in A-TP canines. This indicates that GCH1 may prevent the initiation of AF through inhibiting ANR. PMID- 29436715 TI - TNF-alpha level affects etanercept clearance: TNF-alpha concentration as a new correction factor of allometric scaling to predict individual etanercept clearances in patients with ankylosing spondylitis. AB - Etanercept (ETN) is a widely used anti-tumour necrosis factor-alpha (TNF-alpha) agent, which relieves the symptoms of ankylosing spondylitis (AS) by binding to TNF-alpha to inhibit its inflammation effects. In this study, the effect of TNF alpha level on ETN clearance (CL) was investigated, and the TNF-alpha concentration was initially set as a correction factor for allometric scaling to improve the predictions of individual ETN CLs. Individual ETN CLs and TNF-alpha concentrations in healthy volunteers and patients with AS were determined by performing ETN pharmacokinetic studies in the two cohorts. Accordingly, individual ETN CLs in both healthy volunteers and patients with AS were predicted from data of two animal species using different methods, including simple allometric scaling, scaling with a correction factor of maximum life span potential or brain weight, and scaling with a correction factor of the TNF-alpha concentration. The accuracies of such predictions were evaluated by the percentage errors. Consequently, increased TNF-alpha concentration was shown to improve ETN CL, by comparing both ETN CLs and TNF-alpha concentrations between healthy volunteers and patients with AS. More importantly, better predictions of individual ETN CLs were achieved in patients with AS using allometric scaling with TNF-alpha concentration as the correction factor. In conclusion, in vivo levels of TNF-alpha can affect ETN CL, and allometric scaling corrected with the TNF-alpha concentration can be used to estimate the individual CLs of anti-TNF alpha monoclonal antibodies based on preclinical data. PMID- 29436716 TI - Chemocoding as an identification tool where morphological- and DNA-based methods fall short: Inga as a case study. AB - The need for species identification and taxonomic discovery has led to the development of innovative technologies for large-scale plant identification. DNA barcoding has been useful, but fails to distinguish among many species in species rich plant genera, particularly in tropical regions. Here, we show that chemical fingerprinting, or 'chemocoding', has great potential for plant identification in challenging tropical biomes. Using untargeted metabolomics in combination with multivariate analysis, we constructed species-level fingerprints, which we define as chemocoding. We evaluated the utility of chemocoding with species that were defined morphologically and subject to next-generation DNA sequencing in the diverse and recently radiated neotropical genus Inga (Leguminosae), both at single study sites and across broad geographic scales. Our results show that chemocoding is a robust method for distinguishing morphologically similar species at a single site and for identifying widespread species across continental-scale ranges. Given that species are the fundamental unit of analysis for conservation and biodiversity research, the development of accurate identification methods is essential. We suggest that chemocoding will be a valuable additional source of data for a quick identification of plants, especially for groups where other methods fall short. PMID- 29436717 TI - Early hemodynamic changes after fetal aortic stenosis valvuloplasty predict biventricular circulation at birth. AB - OBJECTIVE: To describe the early hemodynamic changes after fetal aortic valvuloplasty (FAV) for evolving hypoplastic left heart syndrome due to mid gestational aortic stenosis and to assess whether these early changes predict biventricular (BiV) circulation at neonatal discharge. METHOD: We retrospectively reviewed all technically successful FAV cases resulting in live birth between 2000 and 2015 (n = 93, 45% BiV circulation at neonatal discharge). Paired testing methods were used to compare pre-intervention and post-intervention measures of left ventricular hemodynamics. Logistic regression was used to determine whether these changes were predictive of post-natal outcome. RESULTS: Measures of left heart physiology were markedly abnormal pre-FAV and improved significantly post FAV. No subjects had systolic antegrade transverse aortic arch flow pre-FAV and 65% of subjects had antegrade flow post-FAV. The number of subjects with abnormal left-to-right patent foramen ovale flow decreased, and the number with biphasic mitral valve inflow increased. The median left ventricular ejection fraction improved after intervention. Amongst the pre-post changes, gaining partially or exclusively antegrade systolic arch flow was the most significant independent predictor of BiV circulation (OR 9.80 and 19.83, respectively, both P < 0.001). CONCLUSION: Technically successful FAV is associated with immediate improvements in left heart physiology that are predictive of BiV circulation at neonatal discharge. PMID- 29436718 TI - Fetal Doppler changes 1 week after endoscopic equatorial laser for twin-to-twin transfusion syndrome: A longitudinal study. AB - OBJECTIVE: To investigate sequential Doppler changes in donors and recipients before and 1 week after endoscopic laser for twin-to-twin transfusion syndrome (TTTS) and to examine factors that may be associated with such changes. METHODS: In TTTS pregnancies undergoing laser treatment, we examined fetal Doppler changes before and 1 week postintervention. Intrauterine death rates and preoperative factors were analyzed in relation to Doppler changes. RESULTS: Among 129 (85.4%) donors surviving at 1 week after laser, there was normalization of umbilical artery flow in 26 (72.2%) of 36 cases with preoperative abnormal Dopplers. In the remaining 10 (27.8%) fetuses, abnormal findings persisted. The rate of later intrauterine death was significantly higher in the latter group (6 of 10, 60.0%) compared with fetuses in which Doppler findings normalized (4 of 26, 15.4%; P < .05), with no difference in the rate of severe donor growth restriction between the 2 groups (80.0% vs 65.4%, respectively; P = .688). CONCLUSIONS: In about 70% of TTTS donors with preoperative abnormal umbilical artery Doppler, there was normalization 1 week after endoscopic laser. The incidence of fetal growth restriction was not significantly different in donors with persistence of Doppler abnormalities compared with those with normalized findings. PMID- 29436719 TI - Artificial selection sheds light on developmental mechanisms of limb elongation. AB - Species diversity in limb lengths and proportions is thought to have evolved adaptively in the context of locomotor and habitat specialization, but the heritable cellular processes that drove this evolution within species are poorly understood. In this study, we take a novel "micro-evo-devo" approach, using artificial selection on relative limb length to amplify phenotypic variation in a population of mice, known as Longshanks, to examine the cellular mechanisms of postnatal limb development that contribute to intraspecific limb length variation. Cross-sectional growth data indicate that differences in bone length between Longshanks and random-bred controls are not due to prolonged growth, but to accelerated growth rates. Histomorphometric and cell proliferation assays on proximal tibial growth plates show that Longshanks' increased limb bone length is associated with an increased number of proliferative chondrocytes. In contrast, we find no differences in other growth plate cellular features known to underlie interspecific differences in limb bone size and shape, such as the rates of chondrocyte proliferation or the size and number of hypertrophic cells in the growth plate. These data suggest that small differences among individuals in the number of proliferating chondrocytes are a potentially important determinant of selectable intraspecific variation in individual limb bone lengths, independent of body size. PMID- 29436720 TI - An expanded study of long-pulsed 1064 nm Nd:YAG laser treatment of basal cell carcinoma. AB - BACKGROUND AND OBJECTIVE: Basal cell carcinoma (BCC) is an indolent form of skin cancer that is rarely life threatening, but can cause significant cosmetic and functional morbidity. Surgical treatments often result in disfiguring scars, while topical therapies frequently result in recurrence. The need for a more effective nonsurgical alternative has led to the investigation of laser treatment of BCC. We have previously conducted a pilot study which showed 100% histologic clearance at high fluences. Treatments were well tolerated with no significant adverse events. The objective of this larger study was to confirm preliminary results that the 1064 nm Nd:YAG laser is a safe and effective method for treating non-facial BCC. DESIGN: This is an IRB-approved, prospective, multi-center study evaluating the safety and efficacy of the 1064 nm Nd:YAG laser for the treatment of BCC on the trunk and extremities. Thirty-three subjects seeking treatment for biopsy-proven BCC that did not meet the criteria for Mohs surgery were recruited. Subjects on current anticoagulation therapy, or with a history of immunosuppression were excluded. Subjects received one treatment with the 1064 nm Nd:YAG laser as follows: 5-6 mm spot, fluence of 125-140 J/cm2 and a pulse duration of 7-10 ms. Standard excision with 5 mm clinical margins was performed at 30 days after laser treatment to evaluate clinical and histologic clearance of BCC. Standardized photographs and adverse assessments were taken at the baseline visit, immediately after laser treatment and on the day of excision. RESULTS: Thirty-one subjects completed the study. BCC tumors had a 90% (28 of 31 BCC tumors) histologic clearance rate after one treatment with the long-pulsed 1064 nm Nd:YAG laser. Treatments were generally well tolerated without any anesthesia. Immediate side effects included edema and erythema. At 1-month follow-up, some patients had residual crusting. No significant adverse events occurred. CONCLUSION: The 1064 nm long-pulsed Nd:YAG laser is an alternative for treating non-facial BCC for those that are poor surgical candidates. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 29436721 TI - Cytosolic N-Glycans: Triggers for Ubiquitination Directing Proteasomal and Autophagic Degradation: Molecular Systems for Monitoring Cytosolic N-Glycans as Signals for Unwanted Proteins and Organelles. AB - Proteins on the cell surface and secreted proteins are modified with sugar chains that generate and modulate biological complexity and diversity. Sugar chains not only contribute physically to the conformation and solubility of proteins, but also exert various functions via sugar-binding proteins (lectins) that reside on the cell surface or in organelles of the secretory pathway. However, some glycosidases and lectins are found in the cytosol or nucleus. Recent studies of cytosolic sugar-related molecules have revealed that sugar chains on proteins in the cytosol act as signals of adverse cellular conditions. In this review, we summarize recent reports that cytosolic sugar chains can trigger ubiquitination, followed by proteasomal and autophagic degradation to maintain cellular homeostasis. In addition, we discuss the functions of sugar-binding proteins revealed to date, along with possibilities not yet explored. PMID- 29436722 TI - The prognosis of different distant metastases pattern in prostate cancer: A population based retrospective study. AB - BACKGROUND: The present of metastases is a poor prognostic factor in prostate cancer, but the prognostic impact of different distant metastases pattern is unclear. The aim of this study is to investigate the impact of different distant metastases pattern on the survival of patients with stage IV prostate cancer. METHODS: Data queried for this study include prostate cancer (2010-2014) from the Surveillance, Epidemiology, and End Results (SEER) program. Metastatic distribution information was provided for bone, brain, liver and lung. The overall survival was calculated by the Kaplan-Meier method. Multivariable Cox regression models were used to analyze survival outcome and risk factors. RESULTS: A total of 265 900 eligible patients were identified from SEER database. Among these patients, stage of IV prostate cancer accounted for 7.53% (20 034/265 900) at diagnosis. Patients who suffered metastasis to either one of the four organs occupied 61.24% (12 268/20 034) in stage of IV patients. Comparing with other three single metastases, the patients with liver metastasis exhibited worst OS whose mean survival was 17.529 months (P < 0.001). The mean survival of metastases with bong and lung was 25.238 months, which was the best survival of the six forms with two metastatic sites (P < 0.001). The results of univariate survival analysis showed that metastatic forms, race, N-classification and differentiated grade did not have impact on the overall survival of patients with three metastatic sites (all, P > 0.05). CONCLUSIONS: In analysis of both one and two metastatic sites, patients with liver metastasis seemed to have worse survival outcome. On the other hand, bone metastasis had better outcome than other three visceral metastases. Knowledge of these differences in metastatic patterns may help to better guide pre-treatment evaluation of prostate cancer and make determination regarding curative-intent interventions. PMID- 29436723 TI - Variable prenatal presentation of Pfeiffer syndrome: Suggested aids to prenatal sonographic diagnosis. AB - BACKGROUND: Our purpose was to describe and compare the cranial and extracranial abnormalities of Pfeiffer syndrome on prenatal imaging with postnatal or postmortem findings, which may help in prenatal diagnosis of Pfeiffer syndrome (PS). METHODS: Cases of fetuses with a confirmed diagnosis of PS over a 4-year period (2012-2016) were retrospectively reviewed. Prenatal imaging findings, postnatal, or postmortem investigations and genetic test results were analyzed. RESULTS: Four fetuses were ascertained, 3 with prenatal sonographic findings compatible with PS and one only diagnosed at postmortem. Cases were referred between 22 and 24 weeks' gestation. Three of the 4 cases were terminated, and details of postmortem/postnatal examination were available in all. There was variable presentation of features. Craniosynostosis was present in 3 cases, but only detected prenatally in 2. Extracranial signs included abnormalities of thumbs and/or big toes, detected prenatally in 3 of the 4 cases. A sacral appendage and vertebral or coronal clefts were present at postmortem in 3 cases but only detected prenatally in one. A cartilaginous tracheal sleeve was detected at postmortem in all 3 cases but not detected by prenatal ultrasound. Other findings included ventriculomegaly, posterior fossa, and facial anomalies. Molecular testing revealed mutations of the fibroblast growth factor receptor 2 (FGFR2) gene in all cases. CONCLUSION: Pfeiffer syndrome has a highly variable phenotype, and the absence of craniosynostosis on prenatal US does not exclude the diagnosis. Presence of abnormal thumbs and big toes, a sacral appendage, vertebral fusions, and coronal clefts should lead to prenatal molecular testing for PS. PMID- 29436724 TI - In situ mycorrhizal function - knowledge gaps and future directions. AB - We know a lot about the potential functions of mycorrhizas, but whether or not these are realized in the field where plants simultaneously experience a range of biotic interactions and fluctuating abiotic conditions is more or less unknown. In this Viewpoint, we present findings from a literature survey of papers on mycorrhizal function published in New Phytologist during the past 30 years. This survey showed that most functional studies are still conducted under controlled conditions, target mostly arbuscular and ectomycorrhizas, and focus on nutrient and carbon dynamics of the symbiosis. We also share discussions from a workshop, 'In situ mycorrhizal function: how do we get relevant data from a messy world?', held at the 9th International Conference on Mycorrhiza (ICOM9) in August 2017. In this workshop, we examined possibilities and limitations of old and new techniques for field research, and participants expressed the need to learn more about fungal traits and how they may relate to function. We argue that moving mycorrhizal experiments into the field will allow us not only to quantify realized functions, but also to revisit old paradigms and possibly discover new functions. PMID- 29436725 TI - Differences in muscle performance during fatigue may explain the differences in motoneurone excitability between acute and chronic hypoxia. PMID- 29436727 TI - Erratum. PMID- 29436726 TI - Molecular testing practices and perceptions among dermatopathologists. AB - BACKGROUND: We evaluated how dermatopathologists are employing molecular testing in the setting of neoplastic skin diseases, and assessed their opinions of the broader role and utility of molecular technologies in clinical practice. METHODS: A 15-question online survey was sent to Fellows of the American Society of Dermatopathology in April 2017. RESULTS: One hundred and thirty-six dermatopathologists completed the survey (response rate = 16%). A majority (94%) of respondents reported experience with one or more molecular testing strategies. Sixty-two percent of dermatopathologists order 12 or more molecular tests per year, while 5% of respondents order 2 or fewer assays per year. More frequent utilization of molecular testing is associated with relevant instruction during residency training (P = .009), primary board certification in pathology (P = .008), academic medical center affiliation (P = <.0001), higher volume clinical practice (P = .0004), presence of on-site clinical molecular pathology/cytogenetics laboratory (P = .007), and greater physician confidence incorporating test results into histopathological assessments (P = <.0001). CONCLUSIONS: Wider adoption of molecular testing in dermatopathology may be limited by factors such as physician training, test costs/insurance coverage, logistical issues and lack of evidence-based clinical practice guidelines. Dermatopathologists have concerns regarding clinical validity/utility and inappropriate/overuse of some molecular tests. The importance of longitudinal education in molecular technologies and their applications for trainee and practicing physicians is highlighted. PMID- 29436728 TI - Performance of the Movement Disorders Society criteria for prodromal Parkinson's disease: A population-based 10-year study. AB - OBJECTIVE: We aimed to identify prodromal Parkinson's disease (PD) and its predictive accuracy for incident PD in an unselected elderly population and to estimate the relevance of this approach for future neuroprotection trials. METHODS: We applied the recently published Movement Disorders Society (MDS) research criteria for prodromal PD to participants of the prospective population based Bruneck Study of the 2005 assessment (n = 574, ages 55-94 years). Cases of incident PD were identified at 3-year, 5-year, and 10-year follow-up visits. We calculated predictive accuracies of baseline prodromal PD status for incident cases, and, based on them, estimated sample sizes for neuroprotection trials with conversion to PD as the primary outcome. RESULTS: Baseline status of probable prodromal PD (n = 12) had a specificity in predicting incident PD of 98.8% (95% confidence interval, 97.3%-99.5%), a sensitivity of 66.7% (29.6%-90.8%), and a positive predictive value of 40.0% (16.7%-68.8%) over 3 years. Specificity remained stable with increasing follow-up time, sensitivity decreased to 54.6% (28.0%-78.8%) over 5 years and to 35.0% (18.0%-56.8%) over 10 years, whereas positive predictive value rose to 60.0% (31.2%-83.3%) and 77.8% (44.3%-94.7%), respectively. Sample size estimates at 80% power in an intention-to-treat approach ranged from 108 to 540 patients with probable prodromal PD depending on trial duration (3-5 years) and effect size of the agent (30%-50%). CONCLUSIONS: Our findings show that the MDS criteria for prodromal PD yield moderate to high predictive power for incident PD in a community-based setting and may thus be helpful to define target populations of future neuroprotection trials. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29436730 TI - Ultrastructural description of the spermatogenesis and spermatozoa in Phaenocora unipunctata (Platyhelminthes, Neotyphloplanida). AB - Ultrastructural studies of spermiogenesis and sperm morphology have found many characters that are likely to provide clues to the phylogeny of the Platyhelminthes. However, the lack of information on many free-living groups has been a limiting factor. There is a single description of the spermatogenesis and spermatozoa in a Phaenocora species, namely P. anomalocoela, therefore a similar analysis was made in Phaenocora unipunctata to compare the intrageneric variation of sperm ultrastructure and spermatogenesis in the Neotyphloplanida. The comparison of the two Phaenocora species shows that several characters have the potential to be relevant to hypothesize phylogenetic relationships at different taxonomic levels. The presence of superficially incorporated axonemes outside the ring of cortical microtubules in the mature sperm cell, resulting from the fusion of the axonemes with the median cytoplasmic process during spermiogenesis, as well as the presence of a constant number of microtubules in the different regions of the spermatozoon, seem to constitute apomorphies of the genus Phaenocora. Furthermore, the presence of an axonemal spur, the compression of cortical microtubules by the rotation of the basal bodies during spermiogenesis, and the presence of a connection between the nucleus and the plasma membrane in the mature spermatozoon, support previous proposals that these characters are apomorphies of Dalytyphloplanida. The comparison of spermatogenesis and spermatozoa of P. unipunctata and P. anomalocoela demonstrates that studying intrageneric variation can give valuable insights into the significance of many characters proposed for phylogenetic studies of the Rhabdocoela. PMID- 29436729 TI - Adverse events linked with the use of chimeric and humanized anti-CD20 antibodies in children with idiopathic nephrotic syndrome. AB - AIMS: Anti-CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti-CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions. METHODS: We investigated the side effects associated with the use of rituximab (a chimeric antibody; 130 patients) and ofatumumab (a humanized antibody; 37 patients) in children with INS (steroid dependent and steroid/calcineurin inhibitor-dependent disease) treated at a national referral centre over a 9-year period (400 treatments; follow-up 1-9 years). RESULTS: Infusion reactions were mainly absent in children with steroid dependent disease. Rash, dyspnoea, fever, cough and itchy throat (5% and 18% following rituximab and ofatumumab infusion, respectively) were resolved by using premedication with salbutamol. Other short-term reactions (up to 3 months), including arthritis (2%) and lung injury (1%), were more common with rituximab. Infections were observed 3-9 months following infusion, were similarly common in the two groups and resolved with targeted therapies [antibiotic, fluconazole, immunoglobulins (Igs), etc.]. The number of circulating CD19/20 cells fell to 0 at month 1 and were reconstituted at month 3; circulating IgG antibodies remained within the normal range for 1 year. Tetanus and hepatitis B virus immunization was not modified by either treatment; Epstein-Barr virus and John Cunningham virus activation markers were occasionally observed. CONCLUSION: Overall, the toxicity of anti-CD20 monoclonal antibodies was limited to post-infusion side effects in children with more complex disease. The relatively safe profile of anti-CD20 antibodies supports their use as steroid-sparing agents in children with INS. PMID- 29436731 TI - A controversy on the role of short-chain fatty acids in the pathogenesis of Parkinson's disease. PMID- 29436732 TI - A Neutral RuII Hydride Complex for the Regio- and Chemoselective Reduction of N Silylpyridinium Ions. AB - A detailed experimental analysis of the 1,4-selective reduction of pyridine with hydrosilanes catalyzed by a coordinatively unsaturated RuII thiolate complex is reported. The previously suggested intermediates, N-silylpyridinium ions and a neutral RuII hydride, have been independently synthesized and do indeed participate in the catalytic cycle. The resting state is not the cationic RuII complex initially used as the catalyst but its pyridine-coordinated congener. All RuII complexes, including the one resulting from hydrosilane activation, are in equilibrium with each other. The N-silylated 1,4-dihydropyridine together with the cationic RuII complex convert back into the corresponding N-silylpyridinium ion and the neutral RuII hydride (retro-hydrosilylation), followed by further backward reaction into the hydrosilane and the pyridine adduct of the cationic complex. These steps prove the overall reversibility of the transformation. PMID- 29436734 TI - Risk of Malnutrition Evaluated by Mini Nutritional Assessment and Sarcopenia in Noninstitutionalized Elderly People. AB - BACKGROUND: Malnutrition indices and muscle mass and strength in the elderly are poorly investigated. Moreover, malnutrition seems to be 1 of the more important factors in the cause of sarcopenia. The presence of sarcopenia and its relationship with malnutrition indices were studied in noninstitutionalized elderly people who underwent Comprehensive Geriatric Assessment (CGA). METHODS: A total of 473 elderly subjects (mean age, 80.9 +/- 6.6 years) admitted to CGA were studied. Malnutrition risk was evaluated with Mini Nutritional Assessment (MNA) score, whereas muscle mass and muscle strength were evaluated by bioimpedentiometry and hand grip, respectively. Sarcopenia was assessed as indicated in the European Working Group on Sarcopenia in Older People (EWGSOP) consensus. RESULTS: Overall prevalence of sarcopenia was 13.1%, and it increased from 6.1% to 31.4% as MNA decreased (P < .001). MNA score was lower in elderly subjects with sarcopenia (15.4 +/- 4.2) than without sarcopenia (22.0 +/- 4.0) (P = .024). Linear regression analysis showed that MNA score is linearly related both with muscle mass (r = 0.72; P < .001) and strength (r = 0.42; P < .001). Multivariate analysis, adjusted for several confounding variables including comorbidity and disability, confirmed these results. CONCLUSIONS: MNA score is low in noninstitutionalized elderly subjects with sarcopenia, and it is linearly related to muscle mass and muscle strength. These data indicate that MNA score, when evaluated with muscle mass and strength, may recognize elderly subjects with sarcopenia. PMID- 29436733 TI - Placental perfusion imaging using velocity-selective arterial spin labeling. AB - PURPOSE: The placenta remains the least understood human organ, in large part because of the lack of noninvasive tools currently available to examine placental function in vivo. This study investigates the feasibility of using velocity selective arterial spin labeling (VSASL) to assess placental perfusion. METHODS: In placental perfusion imaging, VSASL was compared with pseudocontinuous ASL (PCASL), which is currently the standard technique in brain arterial spin labeling (ASL). Reproducibility of placental VSASL was evaluated using two repeated scans within the same imaging session. Inflow dependence of placental VSASL was investigated by modulating VSASL signal using maternal inhalation of 100% oxygen and variation of cut-off velocity. All experiments were performed in healthy pregnant volunteers at 1.5 Tesla. RESULTS: Apparent placental perfusion measured using PCASL with two different labeling locations was only 16% and 9% of that of VSASL (n = 7; P < 0.01 for both). Placental VSASL was highly reproducible based on within-subject coefficient of variation of 3.5%, repeatability of 19.7 mL/100 g/min, and intraclass correlation coefficient of 0.97 (n = 14). Placental VSASL was also found to be dependent on blood inflow given that the absolute change in apparent placental perfusion with maternal hyperoxia was significantly larger than that of two repeated scans under normoxia (n = 7; P < 0.01), and there was a significant difference in apparent placental perfusion between different cut-off velocities (n = 6; P < 0.01). CONCLUSION: This study demonstrates the feasibility of noninvasive placental perfusion imaging using VSASL and lays the groundwork for acquiring placental perfusion images in pregnancies at high risk where placental function is impaired. PMID- 29436735 TI - Relationship between cerebrospinal fluid biomarkers and structural brain network properties in Parkinson's disease. AB - BACKGROUND: Pathological accumulation of alpha-synuclein, amyloid-beta42 , and tau proteins in the brain is considered critical for development of various neurodegenerative diseases. OBJECTIVES: We investigated the association between CSF levels of these biomarkers, brain structural connectivity, and the UPDRS in PD. METHODS: Diffusion tensor images and CSF biomarkers (alpha-synuclein, amyloid beta42 , total tau, and phosphorylated tau181) from 132 drug-naive, nondemented PD patients and 61 healthy controls were obtained from the Parkinson's Progression Markers Initiative database. After network reconstruction of structural connectivity patterns, global interconnectivity measures (including global efficiency, clustering coefficient, and characteristic path length) and local efficiency were calculated. Network properties and CSF biomarkers were compared between PD patients and healthy controls. The association of CSF biomarkers with network properties and UPDRS-III score was investigated. RESULTS: Global measures (but not local efficiency) and CSF alpha-synuclein were significantly lower in PD patients. Global efficiency and clustering coefficient correlated positively with alpha-synuclein, Abeta42 , and total tau CSF levels. Furthermore, these CSF biomarkers showed no significant association with the UPDRS-III score. CONCLUSIONS: This study examined the association of CSF biomarkers that reflect the brain pathology, with structural brain connectivity and UPDRS-III in PD. Our results revealed an association between the abnormal aggregation of alpha-synuclein, Abeta42 , and tau proteins and structural connectivity disruption in PD patients. In summary, a combination of structural imaging and measurement of CSF biomarkers provide a better understanding of the pathogenesis of PD. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29436737 TI - Autonomic dysfunction in Parkinson's disease and other synucleinopathies: Introduction to the series. PMID- 29436736 TI - Psychological stress-induced cerebrovascular dysfunction: the role of metabolic syndrome and exercise. AB - NEW FINDINGS: What is the central question of this study? How does chronic stress impact cerebrovascular function and does metabolic syndrome accelerate the cerebrovascular adaptations to stress? What role does exercise training have in preventing cerebrovascular changes to stress and metabolic syndrome? What is the main finding and its importance? Stressful conditions lead to pathological adaptations of the cerebrovasculature via an oxidative nitric oxide pathway, and the presence of metabolic syndrome produces a greater susceptibility to stress induced cerebrovascular dysfunction. The results also provide insight into the mechanisms that may contribute to the influence of stress and the role of exercise in preventing the negative actions of stress on cerebrovascular function and structure. ABSTRACT: Chronic unresolvable stress leads to the development of depression and cardiovascular disease. There is a high prevalence of depression with the metabolic syndrome (MetS), but to what extent the MetS concurrent with psychological stress affects cerebrovascular function is unknown. We investigated the differential effect of MetS on cerebrovascular structure/function in rats (16 17 weeks old) following 8 weeks of unpredictable chronic mild stress (UCMS) and whether exercise training could limit any cerebrovascular dysfunction. In healthy lean Zucker rats (LZR), UCMS decreased (28%, P < 0.05) ex vivo middle cerebral artery (MCA) endothelium-dependent dilatation (EDD), but changes in MCA remodelling and stiffness were not evident, though cerebral microvessel density (MVD) decreased (30%, P < 0.05). The presence of UCMS and MetS (obese Zucker rats; OZR) decreased MCA EDD (35%, P < 0.05) and dilatation to sodium nitroprusside (20%, P < 0.05), while MCA stiffness increased and cerebral MVD decreased (31%, P < 0.05), which were linked to reduced nitric oxide and increased oxidative levels. Aerobic exercise prevented UCMS impairments in MCA function and MVD in LZR, and partly restored MCA function, stiffness and MVD in OZR. Our data suggest that the benefits of exercise with UCMS were due to a reduction in oxidative stress and increased production of nitric oxide in the cerebral vessels. In conclusion, UCMS significantly impaired MCA structure and function, but the effects of UCMS were more substantial in OZR vs. LZR. Importantly, aerobic exercise when combined with UCMS prevented the MCA dysfunction through subtle shifts in nitric oxide and oxidative stress in the cerebral microvasculature. PMID- 29436738 TI - Ataxia-telangiectasia: A review of movement disorders, clinical features, and genotype correlations. AB - Ataxia-telangiectasia is an autosomal recessive neurodegenerative disorder that was initially thought to present exclusively in childhood. With the discovery of the ATM gene, the phenotypic spectrum of the condition has expanded. This review elaborates the expanded phenomenology, including oculomotor apraxia and immunodeficiency, and estimates the presence of each movement disorder feature from previously reported literature. Initial manifestations of Ataxia telangiectasia include cerebellar symptoms (67%), dystonia (18%), choreoathetosis (10%), and tremor (4%), with parkinsonism and myoclonus not reported as initial features. The prevalence of movement disorders during the course of the disease includes cerebellar symptoms (96%), dystonia (89%), parkinsonism (41%), choreoathetosis (89%), myoclonus (92%), and tremor (74%). Phenomenology and age of onset is modulated by presence of residual ATM kinase activity, with genotypes heavily truncating the ATM protein associated with the most severe phenotypes. Ataxia-telangiectasia commonly results in a spectrum of movement disorders beyond ataxia and telangiectasias. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29436739 TI - Magnetic Slow Relaxation in a Metal-Organic Framework Made of Chains of Ferromagnetically Coupled Single-Molecule Magnets. AB - We report the study of a Dy-based metal-organic framework (MOF) with unprecedented magnetic properties. The compound is made of nine-coordinated DyIII magnetic building blocks (MBBs) with poor intrinsic single-molecule magnet behavior. However, the MOF architecture constrains the MBBs in a one-dimensional structure that induces a ferromagnetic coupling between them. Overall, the material shows a magnetic slow relaxation in absence of external static field and a hysteretic behavior at 0.5 K. Low-temperature magnetic studies, diamagnetic doping, and ab initio calculations highlight the crucial role played by the Dy-Dy ferromagnetic interaction. Overall, we report an original magnetic object at the frontier between single-chain magnets and single-molecule magnets that host intrachain couplings that cancel quantum tunneling between the MBBs. This compound is evidence that a bottom-up approach through MOF design can induce spontaneous organization of MBBs able to produce remarkable molecular magnetic materials. PMID- 29436741 TI - Targeting epithelial to mesenchymal transition in prostate cancer by a novel compound, plectranthoic acid, isolated from Ficus microcarpa. AB - Epithelial-to-mesenchymal transition (EMT) plays a crucial role in prostate cancer (PCa) metastasis. This has led to a surge in the efforts for identification of safer and more effective compounds which can modulate EMT and consequently inhibiting migration and invasion of PCa cells. We reported previously that Plectranthoic acid (PA), a natural compound isolated from the extracts of Ficus microcarpa, has the capability to induce cell cycle arrest and apoptosis in PCa cells. Here, we determined the effects of PA on EMT, migration, and invasion of PCa cells. Inhibition of EMT induced by different mitogens was effectively inhibited by PA treatment with subsequent decrease in migration of PCa cells. Employing a PCa cell culture model of TGF-beta-induced EMT, we showed that PA has the ability to reverse EMT. PA treatment was associated with induction of epithelial markers and decrease in the expression of mesenchymal markers in PCa cells. Proteomic analysis identified Rac1 as the major cadherin signaling protein modulated with PA treatment. In silico studies indicated that PA docked to the CH domain of NEDD9 protein with an estimated free binding energy of -7.34 Kcal/moL. Our studies revealed significant inhibition of Rac1/NEDD9 pathway in PA treated cells thereby providing a molecular basis of the inhibitory effect of PA on PCa cell migration and invasion. In conclusion, our data suggest that PA should be investigated further as an adjuvant treatment in human PCa cells, given its potential as an anti-invasive agent. PMID- 29436740 TI - Multitarget transcranial direct current stimulation for freezing of gait in Parkinson's disease. AB - BACKGROUND: Recent findings suggest that transcranial direct current stimulation of the primary motor cortex may ameliorate freezing of gait. However, the effects of multitarget simultaneous stimulation of motor and cognitive networks are mostly unknown. The objective of this study was to evaluate the effects of multitarget transcranial direct current stimulation of the primary motor cortex and left dorsolateral prefrontal cortex on freezing of gait and related outcomes. METHODS: Twenty patients with Parkinson's disease and freezing of gait received 20 minutes of transcranial direct current stimulation on 3 separate visits. Transcranial direct current stimulation targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously, primary motor cortex only, or sham stimulation (order randomized and double-blinded assessments). Participants completed a freezing of gait-provoking test, the Timed Up and Go, and the Stroop test before and after each transcranial direct current stimulation session. RESULTS: Performance on the freezing of gait-provoking test (P = 0.010), Timed Up and Go (P = 0.006), and the Stroop test (P = 0.016) improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after primary motor cortex only or sham stimulation. CONCLUSIONS: Transcranial direct current stimulation designed to simultaneously target motor and cognitive regions apparently induces immediate aftereffects in the brain that translate into reduced freezing of gait and improvements in executive function and mobility. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29436742 TI - Biomechanical influence of deficient posterolateral corner structures on knee joint kinematics: A computational study. AB - The posterolateral corner (PLC) structures including the popliteofibular ligament (PFL), popliteus tendon (PT) and lateral collateral ligament (LCL) are important soft tissues for posterior translational, external rotational, and varus angulation knee joint instabilities. The purpose of this study was to determine the effects of deficient PLC structures on the kinematics of the knee joint under gait and squat loading conditions. We developed subject-specific computational models with full 12-degree-of-freedom tibiofemoral and patellofemoral joints for four male subjects and one female subject. The subject-specific knee joint models were validated with computationally predicted muscle activation, electromyography data, and experimental data from previous study. According to our results, deficiency of the PFL did not significantly influence knee joint kinematics compared to an intact model under gait loading conditions. Compared with an intact model under gait and squat loading conditions, deficiency of the PT led to significant increases in external rotation and posterior translation, while LCL deficiency increased varus angulation. Deficiency of all PLC structures led to the greatest increases in external rotation, varus angulation, and posterior translation. These results suggest that the PT is an important structure for external rotation and posterior translation, while the LCL is important for varus angulation under dynamic loading conditions. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-8, 2018. PMID- 29436743 TI - Plasma N-acylethanolamine and endocannabinoid levels in burning mouth syndrome: Potential role in disease pathogenesis. AB - OBJECTIVE: The objective was to measure endocannabinoid (eCB) ligands and non cannabinoid N-acylethanolamine (NAE) molecules in plasma from individuals with burning mouth syndrome (BMS) and to determine whether plasma eCB/NAE levels correlated with pain, inflammation and depressive symptomatology in this cohort. STUDY DESIGN: Plasma content of the eCBs, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), and the NAE molecules, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were assessed in healthy subjects (n = 8) and in a cohort of newly diagnosed BMS patients (n = 9) using liquid chromatography-tandem mass spectrometry. Plasma eCBs and NAE profiles were correlated with self-rated oral cavity pain intensities, depressive symptomatology and plasma IL-8 levels. RESULTS: Plasma levels of PEA, but not OEA, AEA or 2-AG, were significantly elevated in patients with BMS, when compared to plasma from healthy individuals. Plasma PEA, OEA and AEA levels correlated with depressive symptomatology. CONCLUSIONS: This is the first evidence to indicate that circulating eCB/NAE levels are altered in BMS. PMID- 29436744 TI - Long-Term Use of Mixed-Oil Lipid Emulsion in Adult Home Parenteral Nutrition Patients: A Case Series. AB - BACKGROUND: Despite providing significant benefits, home parenteral nutrition (HPN) can be associated with complications such as infections, intestinal failure associated liver disease, and metabolic abnormalities. Soybean oil (SO)-based intravenous lipid emulsion (ILE) has been noted to contribute to some of these complications, leading to the development of alternative sources of ILE. Mixed oil (MO) ILE has recently been approved for use in adults with short-term studies revealing a benefit over SO ILE. Currently there is a paucity of data regarding long-term use in the HPN population. METHODS: The current study reports our experience with MO ILE in 9 HPN patients. RESULTS: A total of 9 patients (3 women and 6 men) with average age of 48.1 +/- 15.1 years and a median HPN use of 9.9 years (9.0 months-30.7 years) were transitioned from SO ILE to MO ILE as a result of intolerance. The 9 patients tolerated MO ILE well for 140.7 +/- 29.7 days. The percentage of calories provided through ILE increased from 7.6 +/- 6.5% to 18.4 +/- 8.2% (P = .003), whereas the dextrose decreased from 66.9 +/- 8.4% to 56.9 +/ 5.5% (P = .0007). Although statistical significance was not reached, there was a trend toward improvement in alkaline phosphatase from 138.0 (52-884) to 106 (47 512; P = .09). CONCLUSION: MO ILE was well tolerated in this small cohort and led to improvement in the macronutrient composition of HPN while providing a trend toward improvement in liver studies. These results are promising; however, additional randomized control trials are needed to delineate the true benefit. PMID- 29436745 TI - Rationale for dopa-responsive CTNNB1/beta-catenin deficient dystonia. PMID- 29436746 TI - Learning Nature: Recyclable Monomers and Polymers. AB - Recycling processes (such as carbon, oxygen, nitrogen cycles etc.) occur each day as an essential character for nature. Managed ecosystems have maintained the natural environment in a state of great harmony for millions of years. In recent decades, various polymers with long-term durability have been developed to be the most predominantly used materials, and have drastically changed the lifestyle of human beings. However, the tremendous growth of plastic debris, with no or very low degradability, over the past decades significantly affects the natural environment. The use of alternative recycling materials is the best option from the environmental point of view. This critical review highlights the most significant progress in chemically recyclable materials, especially several typical systems, which embody perfect recycling between polymers and the starting monomers. PMID- 29436747 TI - Why Palliative Care Applies to Parkinson's Disease. PMID- 29436748 TI - The Good, the Bad, and the Ugly of Medical Information on the Internet. PMID- 29436749 TI - HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5-FU resistance by a p53-dependent pathway. AB - 5-FU-based chemotherapy is recently most recommended as the first-line treatment for gastric cancer (GC). However, 5-FU resistance is common for many postoperative GC patients. Homeobox A13 (HOXA13) is a member of homeobox genes highly expressed in many human tumors. Its potential roles and mechanisms of resistance to 5-FU in GC are poorly understood. In this study, we discovered that HOXA13 played an oncogenic role in vivo and in vitro. The patients with HOXA13 overexpression were closely related with poor prognosis and more prone to be resistant to 5-FU. Moreover, dehydrogenase/reductase 2 (DHRS2) was identified as a downstream gene of HOXA13. HOXA13 played a role of carcinogenesis through directly down-regulating DHRS2 to increase MDM2. Furthermore, HOXA13 conferred 5 FU resistance through MRP1 by a p53-dependent pathway. Therefore, HOXA13 might serve as a potential signature that recognized patients who were insensitive to 5 FU, and timely recommended them to other chemotherapy regimens. PMID- 29436750 TI - A Moisture-Stable 3D Microporous CoII -Metal-Organic Framework with Potential for Highly Selective CO2 Separation under Ambient Conditions. AB - Selective adsorption and separation of CO2 from flue gas and landfill gas mixtures have drawn great attention in industry. Porous MOF materials are promising alternatives to achieve such separations; however, the stability in the presence of moisture must be taken into consideration. Herein, we have constructed a microporous metal-organic framework (MOF) {[Co(OBA)(L)0.5 ]?S}n (IITKGP-8), by employing a V-shaped organic linker with an azo-functionalized N,N' spacer forming a 3D network with mab topology and 1D rhombus-shaped channels along the crystallographic 'b' axis with a void volume of 34.2 %. The activated MOF reveals a moderate CO2 uptake capacity of 55.4 and 26.5 cm3 g-1 at 273 and 295 K/1 bar, respectively, whereas it takes up a significantly lower amount of CH4 and N2 under similar conditions and thus exhibits its potential for highly selective sorption of CO2 with excellent IAST selectivity of CO2 /N2 (106 at 273 K and 43.7 at 295 K) and CO2 /CH4 (17.7 at 273 K and 17.1 at 295 K) under 1 bar. More importantly, this MOF exhibits excellent moisture stability as assessed through PXRD experiments coupled with surface area analysis. PMID- 29436751 TI - Nigrostriatal dopamine transporter availability in early Parkinson's disease. AB - BACKGROUND: The imaging of biomarkers for characterization of dopaminergic impairment in Parkinson's disease (PD) is useful for diagnosis, patient stratification, and assessment of treatment outcomes. [18 F]FE-PE2I is an improved imaging tool allowing for detailed mapping of the dopamine transporter protein in the nigro-striatal system at the level of cell bodies (substantia nigra), axons, and presynaptic terminals (striatum). OBJECTIVES: The objective of this study was to compare the dopamine transporter protein loss in the presynaptic terminals to that in the cell bodies and axons in early PD patients using [18 F](E)-N-(3-iodoprop-2-enyl)-2b-carbofluoroethoxy-3b-(4'-methyl-phenyl) nortropane ([18 F]FE-PE2I) and high-resolution PET. METHODS: A total of 20 early PD patients (15 men/5 women, 62 +/- 8 years) and 20 controls (15 men/5 women, 62 +/- 7 years) underwent high-resolution [18 F]FE-PE2I PET. Dopamine transporter protein availability was estimated for the different nigro-striatal regions and expressed as nondisplaceable binding potential values. RESULTS: When compared with controls, the binding potential values in PD patients were reduced by 36% to 70% in presynaptic terminals and by 30% in cell bodies. Dopamine transporter availability along the tracts was not different between the 2 groups (controls 0.5 +/- 0.1 vs PD 0.4 +/- 0.1). CONCLUSIONS: This is the first study that examines dopamine transporter protein availability in vivo within the entire nigro-striatal pathway. The results suggest that at early stages of symptomatic PD a greater loss is observed at the level of the axonal terminals when compared with cell bodies and axons of dopaminergic neurons. The findings suggest a relative preservation of cell bodies in early PD, which might be relevant for novel disease-modifying strategies. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29436753 TI - Catalytic Enantioselective Aza-Benzoin Reactions of Aldehydes with 2H-Azirines. AB - The unprecedented enantioselective aza-benzoin reaction of aldehydes with 2H azirines was developed by utilizing a chiral N-heterocyclic carbene as the catalyst. A wide range of corresponding aziridines can be obtained in good yields with high enantioselectivities. The obtained optically active aziridines should be useful in the synthesis of other valuable molecules. PMID- 29436754 TI - Reversible Hydrogen Activation by a Pyridonate Borane Complex: Combining Frustrated Lewis Pair Reactivity with Boron-Ligand Cooperation. AB - A pyridone borane complex that liberates dihydrogen under mild conditions is described. The reverse reaction, dihydrogen activation by the formed pyridonate borane complex, is achieved under moderate H2 pressure (2 bar) at room temperature. DFT and DLPNO-CCSD(T) computations reveal that the active form of the pyridonate borane complex is a boroxypyridine that can be described as a single component frustrated Lewis pair (FLP). Significantly, the boroxypyridine undergoes a chemical transformation to a neutral pyridone donor ligand in the course of the hydrogen activation. This unprecedented mode of action may thus, in analogy to metal-ligand cooperation, be regarded as an example of boron-ligand cooperation. PMID- 29436755 TI - Feather content of porphyrins in Eurasian eagle owl (Bubo bubo) fledglings depends on body condition and breeding site quality. AB - Porphyrins are pigments produced in most animal cells during the synthesis of heme, but their importance for external coloration is unclear. Owls (Order Strigiformes) are among the few animals that accumulate porphyrins in the integument, where it could serve as a means of signaling. Here we hypothesized that the porphyrin content of feathers may depend on body condition and breeding site quality in Eurasian eagle owl (Bubo bubo) fledglings and, thus, constitute amplifiers of the quality of the area where they are born. Using high-performance liquid chromatography, we found 2 porphyrins (protoporphyrin IX and coproporphyrin III) in the body feathers of 19 eagle owl fledglings from 7 breeding territories. Coproporphyrin III, but not protoporphyrin IX feather concentration, was positively associated with the body mass of fledglings and with the quality of the breeding sites where they were reared with respect to food quality and availability. As coproporphyrin III is produced under oxidative stress, we suggest that good breeding sites may lead to fledglings in good condition. This, in turn, may make fledglings induce a certain level of free radical and coproporphyrin III production to signal to conspecifics their site mediated capacity to cope with oxidative stress. This is the first time that porphyrin content in the integument has been found to be related to individual quality, opening a new scenario for studying evolution of animal coloration. PMID- 29436757 TI - Microstructured Photo-Crosslinked Poly(Trimethylene Carbonate) for Use in Soft Lithography Applications: A Biodegradable Alternative for Poly(Dimethylsiloxane). AB - Photo-crosslinkable poly(trimethylene carbonate) (PTMC) macromers were used to fabricate microstructured surfaces. Microstructured PTMC surfaces were obtained by hot embossing the macromer against structured silicon masters and subsequent photo-crosslinking, resulting in network formation. The microstructures of the master could be precisely replicated, limiting the shrinkage. Microstructured PTMC was investigated for use in two different applications: as stamping material to transfer a model protein to another surface and as structured substrate for cell culture. Using the flexible and elastic materials as stamps, bovine serum albumin labelled with fluorescein isothiocyanate was patterned on glass surfaces. In cell culture experiments, the behavior of human mesenchymal stem cells on nonstructured and microstructured PTMC surfaces was investigated. The cells strongly adhered to the PTMC surfaces and proliferated well. Compared to poly(dimethylsiloxane) (PDMS), which is commonly used in soft lithography, the PTMC networks offer significant advantages. They show better compatibility with cells, are biodegradable, and have much better mechanical properties. Both materials are transparent, flexible, and elastic at room temperature, but the tear resistance of PTMC networks is much higher than that of PDMS. Thus, PTMC might be an alternative material to PDMS in the fields of biology, medicine, and tissue engineering, in which microfabricated devices are increasingly being applied. PMID- 29436756 TI - Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY DM DYSLIPIDEMIA randomized trial. AB - AIM: To compare alirocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, with usual care (UC) in individuals with type 2 diabetes (T2DM) and mixed dyslipidaemia not optimally managed by maximally tolerated statins in the ODYSSEY DM-DYSLIPIDEMIA trial (NCT02642159). MATERIALS AND METHODS: The UC options (no additional lipid-lowering therapy; fenofibrate; ezetimibe; omega-3 fatty acid; nicotinic acid) were selected prior to stratified randomization to open-label alirocumab 75 mg every 2 weeks (with increase to 150 mg every 2 weeks at week 12 if week 8 non-HDL cholesterol concentration was >=2.59 mmol/L [100 mg/dL]) or UC for 24 weeks. The primary efficacy endpoint was percentage change in non-HDL cholesterol from baseline to week 24. RESULTS: The randomized population comprised 413 individuals (intention-to-treat population, n = 409; safety population, n = 412). At week 24, the mean non-HDL cholesterol reductions were superior with alirocumab (-32.5% difference vs UC, 97.5% confidence interval -38.1 to -27.0; P < .0001). Overall, 63.6% of alirocumab-treated individuals were maintained on 75 mg every 2 weeks. Alirocumab also reduced LDL cholesterol ( 43.0%), apolipoprotein B (-32.3%), total cholesterol (-24.6%) and LDL particle number (-37.8%) at week 24 vs UC (all P < .0001). Consistent with the overall trial comparison, alirocumab reduced non-HDL cholesterol to a greater degree within each UC stratum at week 24. The incidence of treatment-emergent adverse events was 68.4% (alirocumab) and 66.4% (UC). No clinically meaningful effect on glycated haemoglobin, or change in number of glucose-lowering agents, was seen. CONCLUSIONS: In individuals with T2DM and mixed dyslipidaemia on maximally tolerated statin, alirocumab showed superiority to UC in non-HDL cholesterol reduction and was generally well tolerated. PMID- 29436758 TI - Perception of dental students on risk factors of musculoskeletal disorders. AB - OBJECTIVE: To evaluate the validity and reliability of the Job Factors Questionnaire, and the influence of gender, academic level and pain/discomfort on dental students' perception regarding risk factors of musculoskeletal disorders. METHODS: One hundred forty-five dental students from Stony Brook School of Dental Medicine participated voluntarily in this study. The survey was organised in two sections: (i) Job Factors Questionnaire with 15 items that evaluated students' perceptions about job/study environmental risk factors and their potential contribution to musculoskeletal disorders. The tri-factorial structure (repetitiveness, work posture and external factors) was used; (ii) Part of the Nordic Questionnaire with questions referring to 9 body areas: Neck, shoulders, upper back, elbows, lower back, wrists/hands, hips, knees and ankles/feet. Students answered if they have had a job-related pain/discomfort in any of these body areas in the previous 12 months. The data were evaluated statistically by confirmatory factor analysis, convergent and discriminant validities, internal consistency and Z-test (alpha = .05). RESULTS: The tri-factorial structure was considered valid and reliable for the sample after excluding item 8 and inserting correlations between items 11 and 12, and between 14 and 15. The academic level presented a significant effect on the factors "Work Posture" (P = .02) and "External Factors" (P = .01). Most of the students reported pain in their neck (73.79%), lower back (62.06%) and shoulders (53.10%) in the previous 12 months. CONCLUSION: The Work Posture and External Factors were influenced only by academic level. The lower the students' academic level, the higher their perception for both factors of musculoskeletal disorders. PMID- 29436759 TI - Summer egg diapause in a matchstick grasshopper synchronises the life cycle and buffers thermal extremes. AB - The phenological response is among the most important traits affecting a species' sensitivity to climate. In insects, strongly seasonal environments often select for a univoltine life-cycle such that one seasonal extreme is avoided as an inactive stage. Through understanding the underlying mechanisms for univoltinism, and the consequences of its failure, we can better predict insect responses to climate change. Here we combine empirical data and simulation studies to investigate the consequences of an unusual diapause mechanism in a parthenogenetic matchstick grasshopper, Warramaba virgo, from arid southern Australia. Our field body temperature measurements indicate that this species is a thermoconformer and our laboratory studies of the thermal response of feeding rate imply strong constraints on winter activity. However, the species exhibits no obligate winter diapause, and eggs can develop in one month under constant temperatures approximating the mean soil temperature at the time of oviposition (summer). We show that diurnal temperature cycles exceeding a peak of 36 degrees C inhibit egg development in summer, and that this is sufficient to prevent autumnal hatching of eggs. Development is also strongly retarded below 24 degrees C. Microclimate-driven simulation studies of egg development show that these thermal responses provide robust maintenance of a univoltine life cycle, thereby resulting in survival of heat stress as an egg (due to limited developmental state) and avoidance of cold stress as a nymph and adult (due to overwintering in the soil as an egg). This article is protected by copyright. All rights reserved. PMID- 29436760 TI - SILAC Expands its Territory to the Pathogenic Yeast, Candida albicans. AB - Quantitative proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC), as metabolic labeling with MS, has been used as an excellent technique to measure relative abundance change in proteins and post transitional modifications. Since its development in 2002, SILAC has proven to have unique and specific advantage compared to other labeling methods such as Isobaric tags for relative and absolute quantitation (iTRAQ) and Tandem Mass Tag (TMT). However, SILAC has limitations in its application to human tissue/organ samples and some types of unicellular organisms that convert supplemented heavy amino acids to others. In this issue, Kaneva et al. (Proteomics 2018, 18, 1700278) introduces a new application of SILAC to a pathogen, which allows quantitative proteomics analysis to be performed without the need of arginine auxotrophs for SILAC experiment. In fungal pathogens, such as Candida albicans and other yeast family, arginine metabolism is one of the factors that helps pathogen escape host's defenses. This prevents arginine auxotrophs from being used in C. albicans research and limits SILAC-based MS method as a choice of quantitation. However, possibilities for quantitative proteomic analysis of a pathogenic yeast C. albicans using SILAC has now opened by Kaneva et al. PMID- 29436761 TI - A 52-week extension study of switching from gemigliptin vs sitagliptin to gemigliptin only as add-on therapy for patients with type 2 diabetes who are inadequately controlled with metformin alone. AB - We investigated the long-term efficacy and safety of gemigliptin and the efficacy and safety of gemigliptin treatment after once-daily treatment with sitagliptin 100 mg, in patients with type 2 diabetes. This was a 28-week extension of a 24 week, randomized, double-blind, parallel study of gemigliptin or sitagliptin added to ongoing metformin therapy. After randomization to sitagliptin 100 mg qd (S), gemigliptin 25 mg bid (G1) or gemigliptin 50 mg qd (G2) and after completing 24 weeks of treatment, 118 patients switched from gemigliptin 25 mg bid to 50 mg qd (G1/G2), 111 patients continued gemigliptin 50 mg qd (G2/G2) and 106 patients switched from sitagliptin 100 mg qd to gemigliptin 50 mg qd (S/G2). All 3 treatments reduced glycated haemoglobin (HbA1c) (S/G2,-0.99% [95% CI -1.25%, 0.73%]; G1/G2, -1.11% [95% CI -1.33%, -0.89%]; G2/G2, -1.06% [95% CI -1.28%, 0.85%]). The percentage of patients achieving HbA1c < 6.5% was 27.6% in the G1/G2 group at both Week 24 and Week 52, and ranged from 27.3% to 32.7% in the G2/G2 group (difference in proportions, 5% [95% CI -6%, 17%]), while it increased from 6.8% to 27.3% from Week 24 to Week 52 in the S/G2 group (difference in proportions, 20% [95% CI 7%, 34%]). Addition of gemigliptin 50 mg qd to metformin was shown to be efficacious for 52 weeks. Switching from sitagliptin 100 mg to gemigliptin 50 mg showed consistent glyacemic control over the previous treatment. PMID- 29436762 TI - Social learning in nest-building birds watching live-streaming video demonstrators. AB - Determining the role that social learning plays in construction behaviours, such as nest building or tool manufacture, could be improved if more experimental control could be gained over the exact public information that is provided by the demonstrator, to the observing individual. Using video playback allows the experimenter to choose what information is provided, but will only be useful in determining the role of social learning if observers attend to, and learn from, videos in a manner that is similar to live demonstration. The goal of the current experiment was to test whether live-streamed video presentations of nest building by zebra finches Taeniopygia guttata would lead observers to copy the material choice demonstrated to them. Here, males that had not previously built a nest were given an initial preference test between materials of two colours. Those observers then watched live-stream footage of a familiar demonstrator building a nest with material of the colour that the observer did not prefer. After this experience, observers were given the chance to build a nest with materials of the two colours. Although two-thirds of the observer males preferred material of the demonstrated colour after viewing the demonstrator build a nest with material of that colour more than they had previously, their preference for the demonstrated material was not as strong as that of observers that had viewed live demonstrator builders in a previous experiment. Our results suggest researchers should proceed with caution before using video demonstration in tests of social learning. This article is protected by copyright. All rights reserved. PMID- 29436763 TI - Increasing clinical relevance in oral radiology: Benefits and challenges when implementing digital assessment. AB - AIMS: The aims of the study were to investigate benefits and challenges in implementing a digital examination and study the clinical relevance of the digital examination in relation to clinical training and practice. MATERIAL AND METHOD: The study was based on semi-structured focus-group interviews from two distinct student populations (2016 and 2017) in a bachelor programme in dental hygiene. In addition, conversational data from a plenary discussion from the whole second student population (2017) were collected and analysed. The data were approached on basis of content analysis. RESULTS: A benefit experienced in the digital examination was the ease in typing and editing answers on the computer. This suggests an increased effectiveness in computer-based compared to analogue examinations. An additional advantage was the experienced relevance of the examination related to the clinic. This finding refers not only to the digital presentations of images, but also to the entire setting in the clinic and dental practice. The limitations reported by the students were non-optimal viewing conditions for presenting radiographic images and difficulties in obtaining an overview of the assignments compared to paper-based examinations due to the linear digital examination format. The last finding on lacking overview revealed an influence on student performances which should be taken seriously in designing digital examinations. CONCLUSION: In conclusion, the digital layout increases efficiency and clinical relevance of examinations to a certain extent. Obstacles were found in limitations related to image presentation and lack of overview of the examination. The latter challenge raises questions related to developing suitable assessment software. PMID- 29436764 TI - Environmental variation shifts the relationship between trees and scatterhoarders along the continuum from mutualism to antagonism. AB - The conditional mutualism between scatterhoarders and trees varies on a continuum from mutualism to antagonism and can change across time and space, and among species. We examined 4 tree species (red oak [Quercus rubra], white oak [Quercus alba], American chestnut [Castanea dentata] and hybrid chestnut [C. dentata * Castanea mollissima) across 5 sites and 3 years to quantify the variability in this conditional mutualism. We used a published model to compare the rates of seed emergence with and without burial to the probability that seeds will be cached and left uneaten by scatterhoarders to quantify variation in the conditional mutualism that can be explained by environmental variation among sites, years, species, and seed provenance within species. All species tested had increased emergence when buried. However, comparing benefits of burial to the probability of caching by scatterhoarders indicated a mutualism in red oak, while white oak was nearly always antagonistic. Chestnut was variable around the boundary between mutualism and antagonism, indicating a high degree of context dependence in the relationship with scatterhoarders. We found that different seed provenances did not vary in their potential for mutualism. Temperature did not explain microsite differences in seed emergence in any of the species tested. In hybrid chestnut only, emergence on the surface declined with soil moisture in the fall. By quantifying the variation in the conditional mutualism that was not caused by changes in scatterhoarder behavior, we show that environmental conditions and seed traits are an important and underappreciated component of the variation in the relationship between trees and scatterhoarders. PMID- 29436765 TI - Cognition and the Brain of Brood Parasitic Cowbirds. AB - Cowbirds are brood parasites. Females lay their eggs in the nests of other species which then incubate the cowbird eggs and raise the young cowbirds. Finding and returning to heterospecific nests presents cowbirds with a number of cognitive challenges. In some species, such as brown-headed cowbirds (Molothrus ater), females but not males, search for and remember the locations of potential host nests. We describe recent research on sex differences in cognition and the hippocampus associated with this sex difference in search for host nests. Female brown-headed cowbirds perform better than males on some, but not all, tests of spatial memory and females show a pattern of adult hippocampal neurogenesis not found in males or in closely related non-parasitic birds. Because of the apparent specialization of the hippocampus, brown-headed cowbirds may be a good model in which to examine spatial information processing in the avian hippocampus and we also describe recent research on the spatial response properties of brown-headed cowbird hippocampal neurons. This article is protected by copyright. All rights reserved. PMID- 29436766 TI - Burnout among female emergency medicine physicians: A nationwide study. AB - OBJECTIVE: The challenging and stressful nature of emergency medicine place the practitioners of this young branch of medicine at risk of burnout. In Iran, the number of women choosing the specialty of emergency medicine has been increasing in recent years. No studies have focused on burnout among female emergency medicine physicians. We conducted this study to evaluate the level of burnout in female emergency medicine physicians in Iran. METHODS: In this cross-sectional study, all Iranian female emergency medicine physicians with more than 2 years of work experience as specialists, received a questionnaire containing 22-item Maslach Burnout Inventory scales and 7-item Cassidy social support scale, as well as questions about workload and career satisfaction. RESULTS: In total, 77 questionnaires were analysed (response rate: 75%; median age: 36 years, median for work experience = 3 years). A total of 34% of participants were academic faculties. The level of burnout in three subscales of emotional exhaustion, depersonalisation and perceived low personal accomplishment was moderate to high in 84.5, 48.1 and 80.5% of participants respectively. A total of 94.8% of female emergency medicine physicians perceived their workload to be moderate to high and only 1.3% of them had high job satisfaction. CONCLUSIONS: Alarming high rate of burnout and job dissatisfaction among female emergency medicine physicians in our study requires careful attention. Further investigations are suggested to identify the contributory factors to burnout and the probability of some gender disparities in this field. PMID- 29436767 TI - Evaluation of solid-phase extraction procedures for the quantitation of venlafaxine in human saliva by high-performance liquid chromatography. AB - In recent years, the use of human saliva for diagnostic purposes has evoked great interest. Thus, the aim of this study was to choose the optimal solid-phase extraction cartridges and extraction solvents for the quantitation of venlafaxine in saliva. Blank saliva samples spiked with venlafaxine concentrations between 25 and 750 ng/mL were analyzed using five solid-phase extraction columns (C18, C8, Strata-X, Strata-X-C, and Strata-X-AW), washing solvents (deionized water, phosphate buffer at pH 5.5, and their mixtures with methanol), and elution solvents (methanol, acetonitrile, and their mixtures with 25% ammonia). A high performance liquid chromatography system was used to quantify venlafaxine in saliva. The results of this study revealed that nine of 25 procedures enabled quantitation of venlafaxine in the tested concentration range. The procedure that used a C18 cartridge, a mixture of methanol and deionized water as the washing solvent, and methanol as the elution solvent was the most effective and allowed quantitation of all venlafaxine concentrations with an acceptable recovery. In contrast, the Strata-X-C cartridge could not detect venlafaxine at the lowest concentration (25 ng/mL). The data acquired from the high-performance liquid chromatography system were confirmed by a multivariate data analysis. PMID- 29436768 TI - Climate change, thermal niches, extinction risk and maternal-effect rescue of Toad-headed lizards, Phrynocephalus, in thermal extremes of the Arabian Peninsula to the Tibetan Plateau. AB - Determining the susceptibility of species to changing thermal niches is a major goal for biologists. In this paper we develop an eco-physiological model of extinction risk under climate change premised on behavioral thermoregulation. Our method downscales operative environmental temperatures, which restrict hours of activity of lizards, hr , for present-day climate (1975) and future climate scenarios (2070). We apply our model using occurrence records of 20 Phrynocephalus lizards (or taxa in species complexes) drawn from literature and museum records. Our analysis is phylogenetically informed, because some clades may be more sensitive to rising temperatures. Computed hr limits predict local extirpations among Phrynocephalus lizards at continental scales and delineate upper boundaries of thermal niches as defined by Extreme Value Distributions. Under the 8.5 Representative Concentration Pathway scenario, we predict extirpation of 64% of local populations by 2070 across 20 Phrynocephalus species, and 12 are at high risk of total extinction due to thermal limits being exceeded. In tandem with global strategies of lower CO2 emissions, we propose regional strategies for establishing new National Parks to protect extinction-prone taxa by preserving high-elevation climate refugia within existing sites of species occurrence. We propose that evolved acclimatization - maternal plasticity - may ameliorate risk, but is poorly studied. Previous studies revealed that adaptive maternal plasticity by thermoregulating gravid females alter progeny thermal preferences by +/-1 degrees C. We describe plasticity studies for extinction prone species that could assess whether they might be buffered from climate warming - a self-rescue. We discuss an epigenetic framework for studying such maternal-effect evolution. This article is protected by copyright. All rights reserved. PMID- 29436769 TI - What the patient wants: Addressing patients' treatment targets in an integrative group psychotherapy programme. AB - OBJECTIVES: Limited empirical attention has been devoted to individualized treatment objectives in intensive group therapy for personality dysfunction. This study investigated patients' ratings of distress associated with individual therapy goals - referred to as target object severity - in an intensive Evening Treatment Programme for patients with personality dysfunction. DESIGN: Change in target objective severity was examined in a sample of 81 patients who completed treatment in an intensive, integrative group therapy programme. METHODS: Correlation and regression analyses were used to examine associations between change in target object severity and patients' pre-treatment diagnosis, symptom distress, and treatment outcome expectancy, and between change in target objective severity and patients' ratings of group therapy process (group climate, therapeutic alliance, group cohesion). The relationship between change in target objective severity and longer-range life satisfaction was also examined in a subsample of patients who rated life satisfaction at follow-up. RESULTS: While change in target objective severity was not significantly related to pre treatment variables, significant associations were found with several aspects of group therapy process. Patients' experience of a highly engaged group climate was uniquely associated with improvement in target object severity. Such improvement was significantly related to longer-term life satisfaction after controlling for general symptom change. CONCLUSION: The working atmosphere in group therapy contributes to patients' progress regarding individual treatment targets, and such progress is an important factor in later satisfaction. Attention to individualized treatment targets deserves further clinical and research attention in the context of integrative group therapy for personality dysfunction. PRACTITIONER POINTS: This study found that patients attending an integrative group treatment programme for personality dysfunction experienced significant improvement in severity of distress related to individual treatment objectives. Improvement in severity of distress related to individual treatment objectives was uniquely associated with patients' experience of an engaged, collaborative working atmosphere. Improvement in individual target objective severity was associated with patients' ratings of overall life satisfaction, rated an average of 9 months following termination, after controlling for change in general symptom severity. PMID- 29436770 TI - A review of the role of estrogen in dermal aging and facial attractiveness in women. AB - Estrogens are known to have protective and favorable influences on skin health; conversely, androgens oppose the actions of estrogens. Estrogen's chemical messages are transmitted via the classical nuclear hormone estrogen receptors (ER) alpha and beta and the rapid-acting G-coupled membrane estrogen receptor. Androgens [both testosterone and 5alpha-dihydrotestosterone (5alpha-DHT)] bind the same androgen receptor. Estrogen levels peak in the mid- to late 20s in women and then decline by 50% by 50 years of age and dramatically decrease further after menopause. The loss of estrogens with aging contributes to diminished dermal health, whereas estrogen hormone therapy [eg, oral conjugated equine estrogens (CEE)] restores skin health. Several reports suggest positive correlations between the levels of circulating estrogens and: (1) perceived age, (2) attractiveness, (3) enhanced skin health, and (4) facial coloration in women. Based upon a psychological dermato-endocrine perspective, the positive correspondence of high estrogens levels with perceived age and facial attractiveness in women especially with aging demonstrates the importance of hormonal influences on observed dermal health and youthful appearance. PMID- 29436771 TI - A Manganese Nanosheet: New Cluster Topology and Catalysis. AB - While the coordination chemistry of monometallic complexes and the surface characteristics of larger metal particles are well understood, preparations of molecular metallic nanoclusters remain a great challenge. Discrete planar metal clusters constitute nanoscale snapshots of cluster growth but are especially rare owing to the strong preference for three-dimensional structures and rapid aggregation or decomposition. A simple ligand-exchange procedure has led to the formation of a novel heteroleptic Mn6 nanocluster that crystallized in an unprecedented flat-chair topology and exhibited unique magnetic and catalytic properties. Magnetic susceptibility studies documented strong electronic communication between the manganese ions. Reductive activation of the molecular Mn6 cluster enabled catalytic hydrogenations of alkenes, alkynes, and imines. PMID- 29436772 TI - Asthma and its related socioeconomic factors: The Shiraz Adult Respiratory Disease Study 2015. AB - OBJECTIVE: This study aimed to explore the association between the prevalence of asthma and the socioeconomic factors using data from the Shiraz Adult Respiratory Disease Study, 2015(SARDS). METHODS: The SARDS was conducted from June to October 2015 among adult subjects of the general population of Shiraz, Iran. Current asthma was defined as the presence of at least 1 of the following factors in the preceding 12 months: (1) being awakened by an attack of shortness of breath, coughing, or chest tightness without any identifiable cause; (2) having an asthma attack; (3) currently using medication for asthma; or (4) having wheezing or whistling in the chest not associated with a cold or the flu. Information on individual socioeconomic status was derived from self-reported education level, occupation, income, and residence location. A value of P < .05 was considered statistically significant. RESULTS: A total of 4582 respondents aged 20-60 years were included in the analysis. The overall prevalence of adult asthma was 7.8%. The prevalence of asthma was higher significantly among female and subjects with higher body mass index, allergic rhinitis, smokers, jobless, and individuals who live in suburban areas. In the adjusted logistic regression model, being jobless (odds ratio [OR], 2.256; 95% confidence interval [CI], 1.123-4.535) and living in a suburban area (OR, 1.735; 95% CI, 1.058-2.845) were the most significant socioeconomic predictive factors for adult current asthma. CONCLUSIONS: It can be concluded that lower socioeconomic status is associated with higher adult current asthma prevalence. Target interventions are necessary to reduce disparities in healthcare systems. PMID- 29436773 TI - From Synthesis of Amino Acids and Peptides to Enzymatic Catalysis: A Bottom-Up Approach in Mechanochemistry. AB - Recently, chemical reactions induced or facilitated by mechanical energy have gained recognition in diverse areas of chemical synthesis. In particular, mechanosyntheses of amino acids and short peptides, along with their applications in catalysis, have revealed the high degree of stability of peptide bonds in environments of harsh mechanical stress. These observations quickly led to the recent interest in developing mechanochemical enzymatic reactions. Experimentally, manual grinding, ball-milling techniques, and twin-screw extrusion technology have proven valuable to convey mechanical forces into a chemical synthesis. These practices have enabled the establishment of more sustainable alternatives for chemical synthesis by reducing the use of organic solvents and waste production, thereby having a direct impact on the E-factor of the chemical process. In this Minireview, the series of events that allowed the development of mechanochemical enzymatic reactions are described from a bottom-up perspective. PMID- 29436775 TI - Effects of rodent abundance and richness on cache pilfering. AB - Scatterhoarding is a common behavioral strategy to conserve food during periods of scarcity, but this type of food storage is vulnerable to theft or pilferage. A variety of environmental factors and cache characteristics influence the rate of pilferage. Here we investigate 2 environmental factors, which heretofore have not received much attention: the abundance and species richness of scatterhoarding animals in the vicinity of scatterhoarded seeds. We measured the rate of cache pilferage at 7 sites that differed in the number and species composition of granivorous rodents in western Nevada using local native seeds and sunflower seeds. We found that there was no difference between the pilferage rate of native seeds and sunflower seeds, but that sites with different rodent abundances had different pilferage rates. Pilferage rates were proportional to the abundance of scatterhoarding rodents. Scatterhoarding rodents removed seeds at the rate of 1.3%/day/rodent individual. Species richness of scatterhoarding rodents was not correlated with rates of pilferage. These results suggest that density-dependent competition for scatterhoarded seeds is a strong determinant of pilferage rates. PMID- 29436774 TI - Oxytocin structure and function in New World monkeys: from pharmacology to behavior. AB - Oxytocin (OT) is a hypothalamic nonapeptide that mediates a host of physiological and behavioral processes including reproductive physiology and social attachments. While the OT sequence structure is highly conserved among mammals, New World monkeys (NWMs) represent an unusual "hot spot" in OT structure variability among mammals. At least 6 distinct OT ligand variants among NWMs exist, yet it is currently unclear whether these evolved structural changes result in meaningful functional consequences. NWMs offer a new area to explore how these modifications to OT and its canonical G-protein coupled OT receptor (OTR) may mediate specific cellular, physiological and behavioral outcomes. In this review, we highlight relationships between OT ligand and OTR structural variability, specifically examining coevolution between OT ligands, OTRs, and physiological and behavioral phenotypes across NWMs. We consider whether these evolved modifications to the OT structure alter pharmacological profiles at human and marmoset OTRs, including changes to receptor binding, intracellular signaling and receptor internalization. Finally, we evaluate whether exogenous manipulation using OT variants in marmoset monkeys differentially enhance or impair behavioral processes involved in social relationships between pairmates, opposite-sex strangers, and parents and their offspring. Overall, it appears that changes to OT ligands in NWMs result in important changes ranging from cellular signaling to broad measures of social behavior. PMID- 29436776 TI - Providing antiretroviral therapy to all who are HIV positive: the clinical, public health and programmatic benefits of Treat All. PMID- 29436778 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 8/2018. PMID- 29436777 TI - Optimisation of antithrombin resistance assay as a practical clinical laboratory test: Development of prothrombin activator using factors Xa/Va and automation of assay. AB - INTRODUCTION: Antithrombin resistance (ATR) is a novel thrombotic risk in abnormal prothrombins. A manual ATR assay using Oxyuranus scutellatus (Ox) venom as a prothrombin activator was established for detecting antithrombin-resistant prothrombin. However, this assay was limited because of Ox snake venom availability and its throughput capacity. Here, we have improved the ATR assay using bovine factors Xa and Va (FXa/Va) as prothrombin activators and have optimised assay conditions for an automated instrument (ACL TOP 500). METHODS: Diluted plasma was incubated with a prothrombin activator mix (phospholipids, CaCl2 , and bovine FXa/Va), followed by inactivation with antithrombin for 10, 20 and 30 minutes. We added a chromogenic substrate S-2238, and assessed changes in absorbance/min at 405 nm. We also adapted assay conditions for ACL TOP 500. RESULTS: Optimum conditions for FXa/Va treatment were 6.25% phospholipids, 5 mM CaCL2 , 0.01 MUg/mL FXa and 0.1 MUg/mL FVa. ATR assay kinetics with the FXa/Va activator was comparable with that with the Ox activator in heterozygous reconstituted plasma with the recombinant wild-type or antithrombin-resistant prothrombin. Using ACL TOP 500, optimum conditions for the FXa/Va treatment were 10.0% phospholipids, 5 mM CaCl2 , 0.02 MUg/mL FXa and 0.2 MUg/mL FVa. The automated ATR assay with the FXa/Va activator demonstrated good detectability for antithrombin-resistant prothrombin in plasma from a heterozygous carrier with prothrombin Yukuhashi or Belgrade. CONCLUSION: We optimised the ATR assay with the FXa/Va activator and adapted the assay for ACL TOP 500; the assay showed the ability to clearly detect antithrombin-resistant prothrombin in manual and automated procedures. PMID- 29436779 TI - Prioritization of antiretroviral therapy in patients with high CD4 counts, and retention in care: lessons from the START and Temprano trials. AB - Initiation of antiretroviral therapy is not a once in a lifetime opportunity. In some resource constrained settings financial limitations make it necessary to prioritize treatment initiation for some groups of patients. In developed countries, there are patients who are reluctant to initiate treatment. Subgroup analysis of the START trial can inform recommendations for which patients with CD4 counts >500 cells mm3 temporary postponement of treatment initiation is safer. These include individuals aged <30 years and/or with CD4/CD8 ratio of >0.8 and/or viral load of <5000. This is because these individuals are at very low risk of disease progression in the subsequent 2 to 3 years, the risk is minimally diminished by antiretroviral therapy and is virtually identical in the first 18 months of therapy regardless of treatment initiation. In addition, asymptomatic young individuals are at higher risk of loss-to-follow and of low adherence to treatment, and those with low viral loads are less likely to transmit the virus. In addition, lessons from START and Temprano can help design trials to investigate strategies to decrease losses-to-follow-up, while minimizing risks to patients. PMID- 29436780 TI - Autosomal Tubulointerstitial Kidney Disease-MUC1 Type: Differential Proteomics Suggests that Mutated MUC1 (insC) Affects Vesicular Transport in Renal Epithelial Cells. AB - Autosomal dominant tubulointerstitial kidney disease associated to the MUC1 gene (ADTKD-MUC1; formerly MCKD1) belongs to a heterogeneous group of rare hereditary kidney diseases that is prototypically caused by frameshift mutations in the MUC1 repeat domain. The mutant MUC1 (insC) lacks the transmembrane domaine, exhibits aberant cellular topology, and hence might gain a function during the pathological process. To get insight into potential pathomechanisms we perform differential proteomics of extracellular vesicles shed by renal epithelia into the urine of patients. The study is based on three ADTKD patients and individual controls applying iTRAQ/LC-MS/MS. A total of 796 proteins were identified across all biological and technical replicates, and 298 proteins were quantified. A proportion of 47 proteins were fold-changed species. GO Term Enrichment analysis revealed proteins with significantly changed expression in ADTKD-associated extracellular vesicles as vesicular transport-associated proteins. Among these VTA1 is involved in the endosomal multivesicular body pathway associated with transport to lysosomes or export via exosomes. VTA1 is also claimed to play roles as a cofactor of the AAA ATPases VPS4A and VPS4B in the disassembly of ESCRT III. Protein interaction databases list VPS4B, CHMP2A, and IST1 as VTA1 binding partners. (Data are available via ProteomeXchange with identifier PXD008389.). PMID- 29436781 TI - RSV prophylaxis guideline changes and outcomes in children with congenital heart disease. AB - OBJECTIVE: The aim of this study was to compare inpatient outcomes and costs for children with respiratory syncytial virus and congenital heart disease before and after the change in management guidelines for respiratory syncytial virus prophylaxis. DESIGN: Hospital discharge data from the Vizient (formerly University HealthSystem Consortium) were queried from October 2012 to June 2014 (Era 1) and July 2014 to April 2016 (Era 2) for patients aged <24 months with an any International Classification of Disease (ICD)-9 or ICD-10 code for congenital heart disease (745-747.49, Q20.0-Q26.4) and a primary or secondary admitting diagnosis of respiratory syncytial virus infection (079.6, J20.5), acute bronchiolitis due to respiratory syncytial virus (466.11, J21.0) or respiratory syncytial virus pneumonia (480.1, J12.1). SETTING: This study is a review of a national administrative discharge database. PATIENTS: Respiratory syncytial virus admissions were identified in 1269 patients aged <24 months with congenital heart disease, with 644 patients in Era 1 and 625 in Era 2. Patients 0-12 months old represented 83% of admissions. INTERVENTIONS: Prior to 2014, children aged 0-24 months with congenital heart disease were eligible to receive respiratory syncytial virus prophylaxis. Updated guidelines, published in 2014, restricted the recommendation to administer palivizumab respiratory syncytial virus prophylaxis to children with congenital heart disease only if they are <=12 months old. OUTCOME MEASURES: The outcome measures are hospital length of stay, ICU admission rate, mortality, and direct costs. RESULTS: There was no change in length of stay, ICU admission rate, in-hospital mortality, or direct costs for children 13-24 months old with congenital heart disease after the change in guidelines. There were no deaths in 13-24 month olds, regardless of era. CONCLUSIONS: Our findings provide additional support for the new guideline recommendations to provide respiratory syncytial virus prophylaxis only for children <=12 months old with congenital heart disease. PMID- 29436782 TI - Determination of the Selection Capacity of Antibiotics for Gene Selection. AB - Choosing a potent selection antibiotic (SA), is a crucial success factor when creating stably transfected cell lines using an antibiotic selection marker. The selection capacity of this antibiotic is defined as its ability to kill sensitive, untransfected parental cells, while leaving resistant, transfected cells unharmed. Currently, no procedure has been described to determine this selection capacity. Therefore, a protocol to obtain a numerical value, called the "selectivity factor" (SF), that defines the selection capacity of SAs is developed. The SF is determined by using a modified MTT (3-(4,5-dimethylthiazol-2 yl)-diphenyltetrazolium bromide) assay for both sensitive and resistant cells, and applies to commonly used cell lines. To prove the concept, the SF of the SA G418 and hygromycin B (HmB) on several cell lines is determined. The SF of G418 on BHK-21 cells is very high, indicating that G418 is an ideal SA for transfected BHK-21 cells. For HeLa cells, the SF of G418 is very low suggesting G418 is not an optimal SA for selecting transfected HeLa cells. For these cells, HmB would be a better choice. These conclusions are confirmed by an independent cell death assay. The SF identifies the most optimal SA for a certain cell line, reduces the risk of selecting spontaneously resistant cell clones, and streamlines the process of generating stable cell lines. Most importantly, the method is especially time saving when obtaining stable cell lines expressing toxic genes, and reduces culture times for generating large numbers of cell lines from the same parental cell line. PMID- 29436784 TI - Standardizing Interoperability is a Team Effort. AHIMA and other key stakeholders continue to drive national and global progress to achieve information systems interoperability in healthcare. PMID- 29436783 TI - Advancing Metabolic Engineering of Saccharomyces cerevisiae Using the CRISPR/Cas System. AB - Thanks to its ease of use, modularity, and scalability, the clustered regularly interspaced short palindromic repeats (CRISPR) system has been increasingly used in the design and engineering of Saccharomyces cerevisiae, one of the most popular hosts for industrial biotechnology. This review summarizes the recent development of this disruptive technology for metabolic engineering applications, including CRISPR-mediated gene knock-out and knock-in as well as transcriptional activation and interference. More importantly, multi-functional CRISPR systems that combine both gain- and loss-of-function modulations for combinatorial metabolic engineering are highlighted. PMID- 29436785 TI - Open Source, Open Standards, Open Minds: How the Shifting Standardization Landscape May Impact Health IT. PMID- 29436786 TI - New ONC Chief Touts Importance of Standards Development Work. PMID- 29436787 TI - Using Aliases to Protect Privacy in Healthcare. PMID- 29436788 TI - Universal Scientific Education and Research Network (USERN): Twinkling Stars Unite to Make the World Glow. PMID- 29436789 TI - Evaluation of Chronic Losartan Treatment Effect on Cardiac Chronotropic Dysfunction in Biliary Cirrhotic Rats. AB - Cirrhosis is associated with cardiac chronotropic and inotropic dysfunction which is known as cirrhotic cardiomyopathy. Cardiac responsiveness to adrenergic stimulation is impaired in cirrhosis. Moreover, there is vagal nerve dysfunction which is related to neuromodulatory dysfunction of the angiotensin II in the cirrhosis. This study was aimed to explore the hypothesis that administration of Losartan-angiotensin II receptor antagonist increases cardiac chronotropic response to isoproterenol in cirrhotic rats; and if so, whether this is associated with altered cardiac TGF-beta receptor expression. Cirrhosis was induced by surgical ligation of the bile duct (BDL) in male Wister rats. Half of the BDL-group and control group were treated with losartan for four weeks. Four weeks after bile duct ligation or sham surgery the atria were isolated and spontaneously beating rate and chronotropic responsiveness to beta-adrenergic stimulation was assessed using standard organ bath. The pathological assessment was done on the atria. Moreover, the expression of TGF-beta has assessed the atria using quantitative RT-PCR. Bile duct ligation could induce a significant hypo-responsiveness to adrenergic stimulation. In cirrhotic rats, the chronotropic responses increased after chronic treatment with losartan, but it was not significant. The pathological study showed that losartan could not decrease fibrosis in atria in losartan treated cirrhotic group. TGF-beta expression is markedly increased in cirrhotic rats which are significantly decreased in atria following administration of losartan. These results might be considered as angiotensin II role in cirrhotic cardiomyopathy, but further studies are required to elaborate the mechanism as well as the possible advantage of losartan. We conclude that cirrhosis in rats is associated with altered expression of TGF-beta in the atrium which losartan can ameliorate it. PMID- 29436790 TI - Cromakalim, a Potassium Channel Opener, Ameliorates the Organophosphate and Carbamate-Induced Seizure in Mice. AB - Organophosphates (OPs) and carbamates are acetylcholine esterase inhibitors (AChEIs), which can cause seizure and lethality. Anticonvulsant properties of potassium channel openers including cromakalim have been determined in previous studies. In the present experiment, the possible effect of cromakalim on the convulsion and death induced by OPs and carbamates was studied in mice. Dichlorvos (an OP, 50 mg/kg) and physostigmine (a carbamate, 2 mg/kg) were used to induce seizure in animals. Cromakalim at doses of 0.1, 10, and 30 ug/kg was injected 30 min before dichlorvos and physostigmine, and 5 min before glibenclamide (a potassium channel blocker, 1 mg/kg) administration. All injections were performed intraperitoneally. After drugs administration, the onset of convulsion, death, the severity of seizure, and rate of mortality were investigated. Results revealed that both dichlorvos and physostigmine induced seizure activity and lethality in 100% of the animals. Cromakalim at doses of 0.1, 10, and 30 ug/kg significantly increased the latency of both seizure and death (P<0.05). Also, cromakalim decreased the mortality rate induced by dichlorvos and physostigmine (P<0.05). On the other hand, glibenclamide blocked all aspects of the anticonvulsant effect of cromakalim (P<0.05). This study revealed for the first time that cromakalim (a KATP channel opener) diminishes the seizure and death induced by dichlorvos and physostigmine in mice, and introduces a new aspect to manage the patients who suffer from OPs/carbamates induced seizure. PMID- 29436791 TI - Promoter Hypermethylation of the Eyes Absent 4 Gene is a Tumor-Specific Epigenetic Biomarker in Iranian Colorectal Cancer Patients. AB - The aim of this study was to investigate whether hypermethylation of Eyes Absent 4 (EYA4) is also implicated in Iranian Colorectal Cancer (CRC) patients or not. From fresh frozen tissues, samples from 38 paired (cancer and normal) CRC tissue specimens were used in this study, the DNA was isolated, sodium bisulfite treated and analyzed by methylation-specific polymerase (MSP) chain reaction using primers specific for unmethylated or methylated promoter sequences of the EYA4 gene. We also analyzed EYA4 mRNA expression using real time RT-PCR. Demographic characteristics of these patients including age, sex, tumor grade, location, stage, and TNM classification were evaluated and the relationship between methylation status of the gene and clinicopathological features was analyzed. Current study indicated that EYA4 promoter hypermethylation has a sensitivity of 81.57% and specificity of 78.94%. Findings showed lower expression of EYA-4 in methylated samples in comparison with its normal adjacent tissue, although it was not significant (P>0.05). No significant associations were observed between EYA4 hypermethylation and the clinicopathological characteristics. Although the clinical patient outcome of our 38 CRC patients was not associated with EYA4 promoter hypermethylation, the high frequency of this methylation and its high sensitivity and specificity to neoplastic cells may qualify EYA4 promoter methylation as a potential candidate screening marker in Iranian population and may help to improve early detection of CRC. PMID- 29436792 TI - Wharton's Jelly Derived-Mesenchymal Stem Cells: Isolation and Characterization. AB - Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs), have a high proliferation valency and they do not produce teratogen or carcinogen after subsequent transplantation. They are known as regenerative medicine. Thus more research is needed on the isolation and characterization of mesenchymal stem cells. In this experimental study, we obtained Wharton's jelly tissues from mothers during normal vaginal delivery, after obtaining their informed consent. Mesenchymal stem cells were isolated from cultured Wharton's jelly, cultured, and were then examined for their proliferation, immunophenotypes, and differentiation capacities. The immunophenotypes of WJ-MSCs were analyzed by flow cytometry. Differentiation was performed resulting in osteogenic, chondrogenic and adipogenic cells. WJ-MSCs formed a homogenous monolayer of adherent spindle shaped cells. Our results showed the high capacity of the proliferation of WJ MSCs. Immunophenotyping further confirmed the purity of the isolated cells; their surface antigen expression showed the phenotypical properties like those of WJ MSCs. The expanded cells were positive for CD 90, CD105, and CD44; they were negative for CD34 and HLA-DR surface markers. The cells had the adipocytic, osteocytic and chondrogenic differentiation capacity. The isolation and characterization of WJ-MSCs with high purity had been conducted, and the results were obtained in a short span. The present study has revealed the feasibility of the culture medium with high glucose and 15% FBS in isolation and proliferation of WJ-MSCs. When Wharton's jelly pieces were put in the dry bottom of the flask, very effective separation of the MSCs was achieved. PMID- 29436793 TI - Gonadotropin Regulation of Retinoic Acid Activity in the Testis. AB - Initiation of spermatogenesis in primates is triggered at puberty by an increase in gonadotropins; i.e., follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prior to puberty, testis of the monkey contains only undifferentiated germ cells. However, sermatogonial differentiation and spermatogenesis may be initiated prior to puberty after stimulation with exogenous LH and FSH. Retinoic acid (RA) signaling is considered to be a major component that drives spermatogonial differentiation. We were interested in evaluating the relative role of LH and FSH, either alone or in combination, in regulating the retinoic acid signaling in monkey testis. Sixteen juvenile male rhesus monkeys (Macaca mulatta) were infused with intermittent recombinant single chain human LH (schLH) or recombinant human FSH (rhFSH) or a combination of both for 11 days. We then analyzed the expression of the several putative RA signaling pathway related genes; i.e. RDH10, RDH11, ALDH1A1, ALDH1A2, CYP26B1, CRABP1, CRABP2, STRA6, STRA8 in the testis after 11 days of stimulation with vehicle, LH, FSH and combination LH/FSH using quantitative real-time PCR (qPCR). The qPCR results analysis showed that administration of gonadotropins affected a significant change in expression of some RA signaling related genes in the monkey testis. The gonadotropins, either alone or in combination dramatically increased expression of CRABP2 (p<=0.001), whereas there was a decrease in ALDH1A2 expression (p<=0.001). Moreover, combined gonadotropin treatment led to the significant decrease in CRABP1 expression (p<=0.05). These findings are the first evidence that the activity of retinoic acid signaling in the monkey testis is regulated through gonadotropins (LH/FSH) levels. PMID- 29436794 TI - The Follow-Up Role of the Vestibular Evoked Myogenic Potential Test in Meniere's Disease. AB - Despite some proposed roles for the diagnostic impact of the cervical vestibular evoked myogenic potential test in the patients with Meniere's disease, the role of this test as an objective instrument in following up the patients with Meniere's disease who underwent. Intratympanic steroid injection is not cleared. In a prospective study, thirty-one adult patients with definite one-sided Meniere's disease with vertigo as main complaint refractory to medical treatments for three months, were selected. Patients underwent three times of intratympanic dexamethasone injection with one-week intervals. We performed cervical vestibular evoked myogenic potential test at first and four weeks after the last injection for all participants. We followed the patients for one year. The study results were analyzed with the chi-square test. Cervical vestibular evoked myogenic potential test could not be recorded in 26 patients (83.9%), and the test results were abnormal in the remaining 5 patients. The results were abnormal in the healthy ear of 32.3% of the patients. Despite the clinical improvement of the symptoms after intratympanic injection, the test results were not changed. Cervical vestibular evoked myogenic potential test could not be recorded in the majority of the patients with Meniere's disease; while it is usually recorded in normal ears. On the other hand, results of the cervical vestibular evoked myogenic potential test do not change during the early phase after treatment and could not be a good option for follow up and evaluating the response in this situation. PMID- 29436795 TI - Assessing the Phenylketonuria Screening Program in Newborns, Iran 2015-2016. AB - Phenylketonuria is one of the most important congenital disorders and an autosomal recessive metabolic disease that can cause irreversible brain damages, mental retardation, and cognitive disorders if left untreated. In order to reduce the genetic abnormalities caused by this metabolic disease, screening programs are implemented. The quality of the program must be properly assessed to achieve the objectives of this program if promoting children's health is of concern. The descriptive-analytic method is adopted here to assess the phenylketonuria screening program in practice in Chaharmahal and Bakhtiari province since 2012 and analyze the incidence and program coverage. The quality of the screening program is assessed through analyzing the time of diagnosis, beginning of the treatment and the healthcare centers' facilities with checklists. The parental and the staff awareness is assessed through knowledge measuring questionnaires. Cumulative incidence of phenylketonuria in Chaharmahal and Bakhtiari province from 2012 to 2015, is 1 in every 6662 live births. The program coverage across the region is 100%. The recorded on-time sampling index before 5 days of age, indicate 84.6 % in 2015 from 80% in 2012. The treatment begun before the newborn 4 weeks was over in all cases. Program sensitivity was 100 %, and its specificity was 99.9%. Staff awareness is fair with no impact on parental awareness. General quality of the screening program is appropriate, and as to sensitivity and on time curing specificity, higher staff and parental awareness supervision are recommended as well. PMID- 29436796 TI - Predictive Value of Braden Risk Factors in Pressure Ulcers of Outpatients With Spinal Cord Injury. AB - Pressure Ulcers (PUs) remain among the most common complications after traumatic spinal cord Injuries (SCIs). The main goal of risk factor assessment with different tools has been to provisionally estimate the chance of developing pressure ulcers in patients with Spinal Cord Injury (SCI). Braden tool has been of good predictive value and most commonly employed in hospital communities for risk assessment of pressure sore development. The objective of this study was to determine the Braden risk factors as well as the prevalence of pressure injuries in SCI patients. This cross-sectional study was performed from June 2013 to December 2015 on 163 consecutive referred outpatients with chronic traumatic SCI in our tertiary SCI rehabilitation clinic. We assessed pressure induced skin injuries as well as their Braden risk factors and analyzed their association with stage and location of Pressure Ulcer (PU) and calculated prevalence of PU. One hundred and sixty-three patients out of 580 were found to have active pressure sores, with a prevalence of 28.1%. In the multiple models, only the Braden scale had significant association with the presence of active pressure sore. Patients with severe and moderate Braden scores were 2.36 and 1.82 times, more at risk of pressure sore development, as compared with those having mild scores (P<=0.01). It may be deduced that in various stages of SCI rehabilitation, the Braden scale may be calculated, and patients with moderate and severe risks (according to Braden sale) may need more attention and/or inpatient care for PU prevention. PMID- 29436797 TI - A Case of Kleine-Levin Syndrome: Diagnostic and Therapeutic Challenge. AB - Kleine-Levin syndrome (KLS) is a rare sleep disorder mainly affecting teenage boys in which the main features are intermittent hypersomnolence, behavioral and cognitive disturbances, hyperphagia, and in some cases hyper sexuality. Etiology is unknown, and there is no specific clinical or imaging test for this syndrome even though the illness has well-defined clinical features. Also, there is no effective treatment for KLS. KLS is self-limited, so the prognosis for these patients is not so bad. This study presents our case report and comprehensive workout that led to diagnosis which is primarily clinical. Our patient is a 20 year-old man referred to our clinic because of sleeping problems. At the age of 14, he presented with complaints of the excessive duration of sleep, increased appetite, excessive daytime sleepiness, loss of interest in social activities during attendance of high school and hallucinations. The excessive diagnostic procedure does not find pathological. Kleine-Levin syndrome (KLS) is a rare sleep disorder of unknown etiology which diagnosis is clinical and diagnostic workup is mainly to exclude other similar conditions. There is no specific therapy, but the disease is self-limited and with good prognosis. PMID- 29436798 TI - A Road to the Heart From Uterine Closet: A Case Report. AB - Angiosarcomas of the uterine is a malignant and poor prognostic tumor and can either be a primary sarcoma or arising secondary to radiotherapy of a more complex tumor. Primary uterine angiosarcomas are exceptional and probably arise from embryonic vascular remnants, teratoma or from the rich uterine vasculature. We reported a rare case of primary angiosarcoma of uterine that at the time of diagnosis presented with sign and symptom of local and distant metastasis. The patient presented with dyspnea, chest pain, and history of vaginal bleeding and pelvic pain. The physical exam revealed pallor, prominent jugular pulse pressure, a palpable fixed mass in the pelvic however vaginal exam was unremarkable. Transthoracic echocardiography (TTE) revealed massive pericardial effusion and also a large mass in the right atrium. The abdominal ultrasound showed echogenic and poor echogenic segments in uterine mass combined with central necrosis. The patient underwent total hysterectomy and Bilateral salpingo-oophorectomy followed by radiotherapy and adjuvant chemotherapy. The patient underwent open heart surgery with resection of cardiac mass and further received a four cycle of radiotherapy (50 MG) to the mediastinum. The further follow-up (6 month) revealed no recurrence of tumor in a mediastinum. However, patient died from metastasis to the liver and its hepatic failure sequels. PMID- 29436800 TI - [Understanding people with Steinert's disease to better care for them.] AB - INTRODUCTION: the lifestyles of people with myotonic dystrophy type 1 (DM1) are poorly understood and yet their consideration is essential for effective long term care. The nursing care provided in the reference centers integrates the diversity clinic of this disease in interdisciplinary care, but it is more complicated from a relational point of view. The objective of this qualitative study was to understand the ways of living for a person with DM1, his body and the coping strategies developed. METHOD: this research in social sciences and nursing is based on a problem of care and is based on an ethnosociological problematization. RESULTS: the aim is to make visible the evolution of the body affected by Steinert's disease, participating in the construction of the body pattern and the social identity of the person, which allows him to maintain himself in a "normal" daily life as long as possible but can reach limits imposing him radical reorientations in his life. These results are discussed in the light of a framework of analysis based on the four levels of reading of the body proposed by Nicolas Vonarx: the "material body" ; the "capable body", the "body feeling" and the "knowing/judging body" ; "socializing body" will be proposed to discuss the place the body takes for people living with a DM1 when it comes to living within a normative society. PMID- 29436799 TI - "Eye of the Tiger" in a Non-Responsive Neuropsychiatric Patient: A Case Report. AB - Hallervorden-Spatz syndrome is a rare neurodegenerative disorder with hereditary properties. It usually occurs in young adolescents with extrapyramidal symptoms besides disturbed mental function. In this study, we present a 23-year-old neuropsychiatric patient who primarily misdiagnosed to have conversion disorder. She had 5-year history of progressive dysarthria and generalized abnormal movements. After detecting the pathognomonic sign of "eye of the tiger" diagnosis was confirmed. The patient was discharged. She had satisfactory condition in her follow-up. Such a rare syndrome should be considered in patients with similar presentation, and upon the diagnosis, PKAN2 gene study should be done to detect possible new mutations. PMID- 29436801 TI - [How can employers support home care nurses' continuing education and nursing professional development at workplace? Results of a Canadian qualitative survey.] AB - INTRODUCTION: this article provides a new knowledge on employer's support for home care nurses' continuing education. CONTEXT: so far, literature has sustained that providing support to nurses in continuing education is mainly a matter of money. However, only few researchers have been interested in home care, especially in continuing education. OBJECTIVE: one of the objectives of the survey was to identify factors that could influence nurses' commitment, participation and choice in the matter of continuing education activities. METHODS: a qualitative survey was conducted with eight nurses, coming from one clinical home care setting (Quebec, Canada), who participated in a semi structured individual interview. Thematic analysis was used. Results were validated by intra- and inter-rater controls. Furthermore, participants were involved in the process of validation. Results have shown that support given by the employer in the matter of continuing education can be seen into five different aspects : financial, training, affective, instrumental and normative. Despite a lack of financial and training support, most of home care nurses have a positive perception of their employer's support. DISCUSSION: nevertheless, employers should pay more attention to nurses' needs. To do so, nurses should be involved into the process of continuing education at their workplace. PMID- 29436802 TI - [Generation Y healthcare students' expectations: hard skills but also soft skills.] AB - Generation Y's (born between 1981 and 1999) educational approach in healthcare studies raises questions about their expectations and which teaching methods to use with this generation. The study involved third year students of occupational therapy. One hundred and twelve students were consulted in September 2012 and September 2013 about their expectations regarding the courses and the teaching methods which were offered. Results allowed to highlight firstly the importance of the usefulness of the course and secondly expectations regarding the teachers' soft skills. If the link between soft skills and success was pointed out in many studies, only a few studies focus on the teachers' own soft skills development in order to respond to students' expectations in higher education. This is the topic of this article, which main interest could be the means to develop teaching methods adapted to this students' generation. PMID- 29436803 TI - ? PMID- 29436804 TI - [Nurses working at patients' home: mastering the space and time of a professional exercise (a french japanese survey in four regions: Picardie, Paca, Nagano and Fukushima).] AB - INTRODUCTION: this article presents the main results of a survey comparing works and opinions of nurses working at their patients homes in France and in Japan. CONTEXT: previous studies on hospital nurses had shown some differences mainly linked to the way the tensionbetween cure and care is managed in the two countries. OBJECTIVE: the hypothesis is made according to which this tension involves nurses beyond their professional practices. At stake, are the characteristics of the two professional spaces and the mobility they made possible. METHOD: an original questionnaire has been conducted gathering 200 nurses working at patient's home. Four Regions have been chosen (two in France, two in Japan) in order to take into account environmental differences. RESULTS: it appears that representations as well as the relations to the labor itself are heavily shaped by each nurse passed experience, the hospital setting being the main reference. However, the way this experience is included in the professional trajectory is mainly built by private choices. DISCUSSION: grounded on a qualitative study, these results have to be confirmed using a larger survey. PMID- 29436805 TI - [The vision of nursing provided by Leonie Chaptal: a strategic mistake in the development of nursing science in France ?] AB - The issue of the development of the discipline displayed by nursing sciences in France is crucial, especially since the Law of Modernization of the Health System has established a legal framework for advanced practice since 2016. This article presents a discussion on the important role that Leonie Chaptal has played in the development of nursing care in France, based on a purely professional vision, guaranteeing the subordination of the nurses to the medical physicians the in the spirit of the law of November 30, 1892 which had established a stranglehold of medical profession on health. We have drawn from this discussion some lessons that we consider essential for the future development of a true discipline of nursing in France, in the context of the deep organizational transformation initiated by the health system. PMID- 29436806 TI - [Development of a care performance management system in a Swiss university hospital.] AB - Studies show high variability in the quality of care and a significant incidence of adverse events. The care management direction of a university hospital center (CHU) has developed a care performance measuring system. The aim of the article is to present the different development stages of this system. The authors used May's Normalization Process Theory, which focuses on factors influencing the engagement of individuals, groups, and organizations in sustaining change.The CHU's approach led to the following results : 1) reaching a consensus on performance concept and identifying five areas of performance, 2) selection of 12 priority indicators to assess performance, 3) measures development, 4) setting up the method of collecting information 5) creation of a mechanism for analyzing the results by care teams and 6) dissemination of results via dashboards.The approach focuses on strategies for mobilizing managers and health care teams. Specific recommendations relate to the need to provide expert resources, review clinical guidance and ensure accountability of health care providers. PMID- 29436807 TI - [An interprofessional simulation: an exploration of the experiences of nursing students.] AB - BACKGROUND: the literature suggests that simulation is an effective strategy to meet the learning needs of nursing students. Traditionally, simulation learning for nursing students takes place at nursing schools ; at a distance from the clinical setting, patients, and the interprofessional team. AIM: the objective of this pilot project is to explore the experiences of Francophone nursing students following their participation in an interprofessional simulation in a hospital setting during their third year clinical placements. METHOD: a case study using Yin's (2003) approach was used to explore this phenomenon through focus groups and individual interviews. RESULTS: thirteen people participated in three simulation sessions that each included two scenarios. Content analysis of the focus groups revealed four themes : 1) the need for a realistic, but safe environment ; 2) simulation helps to build self-confidence ; 3) simulation improves knowledge of the role of the nurse ; and 4) simulation improves knowledge of teamwork. Two themes emerged from individual interviews : 1) the knowledge and skills acquired during the simulation were retained over time ; and 2) perceptions of the effects on the quality and safety of patient care. CONCLUSION: the use of simulation could be effective for the development of knowledge of nursing role, teamwork, and self-confidence. PMID- 29436808 TI - [Anna Hamilton (1864-1935), the excellence of nursing.] AB - A Frenchwoman, Anna Hamilton (1864-1935), daughter of a Franco-English couple, reads with passion the works of Florence Nightingale and takes an interest in nursing. In order to practice it, she first passes the equivalent of a bachelor's degree in self-education and registers at the Marseille medical school. She wants to prepare a medical thesis on the nursing staff in the hospitals in Europe and is conducting an investigation throughout Europe. She passed her thesis on June 15, 1900 entitled "Considerations on hospital nurses". This work is immediately published. That same year, she took up a post at the "Maison de sante protestante" in Bordeaux (MSP), founded in 1863. Without managerial staff, she is forced to recruit them abroad. She publishes a professional journal : "La Garde Malade hospitaliere" (1906-1914). Then the war turned the MSP into a military hospital, but the institution continued to receive local paying patients. She was given permission to call the school of nurses : Florence Nightingale School. Anna Hamilton is working with American women to create a medical and social service in Aisne. A graduate, Antoinette Hervey, then opened a medical-social service in Rouen, which would employ up to 30 visiting nurses. In 1916, the MSP received a donation from the domain of Bagatelle. The board of directors wants to sell it, but Anna Hamilton manages to finance a hospital-school thanks to families bereaved by the war and a subscription announced in the "Journal of Nursing". Other establishments created by former students of the MSP opened : the School hospital Ambroise Pare in Lille, a nursing home for nurses in Chambon-sur-Lignon in 1927 (the Edith-Seltzer foundation) and a sanatorium in Briancon. After a busy life, Anna Hamilton died of cancer in 1935 and is buried in Bordeaux. PMID- 29436809 TI - HIM Connections in the Kaleidoscope of Informatics. PMID- 29436810 TI - Connecting Functional and Semantic Interoperability--The HIM Professional's Role in HIT Standardization. PMID- 29436811 TI - The Information Governance Road Map: Mile Marker 4-Demonstrating the Value of Clinical, Financial, and Administrative Information to IG. PMID- 29436812 TI - Extremely Low Roll-Off and High Efficiency Achieved by Strategic Exciton Management in Organic Light-Emitting Diodes with Simple Ultrathin Emitting Layer Structure. AB - Phosphorescent organic light-emitting diodes (OLEDs) possess the property of high efficiency but have serious efficiency roll-off at high luminance. Herein, we manufactured high-efficiency phosphorescent OLEDs with extremely low roll-off by effectively locating the ultrathin emitting layer (UEML) away from the high concentration exciton formation region. The strategic exciton management in this simple UEML architecture greatly suppressed the exciton annihilation due to the expansion of the exciton diffusion region; thus, this efficiency roll-off at high luminance was significantly improved. The resulting green phosphorescent OLEDs exhibited the maximum external quantum efficiency of 25.5%, current efficiency of 98.0 cd A-1, and power efficiency of 85.4 lm W-1 and still had 25.1%, 94.9 cd A 1, and 55.5 lm W-1 at 5000 cd m-2 luminance, and retained 24.3%, 92.7 cd A-1, and 49.3 lm W-1 at 10 000 cd m-2 luminance, respectively. Compared with the usual structures, the improvement demonstrated in this work displays potential value in applications. PMID- 29436813 TI - Asymmetrically Curved Hyperbolic Metamaterial Structure with Gradient Thicknesses for Enhanced Directional Spontaneous Emission. AB - We demonstrate hyperbolic metamaterials (HMMs) on a curved surface for an efficient outcoupling of nonradiative modes, which lead to an enhanced spontaneous emission. Those high-wavevector plasmonic modes can propagate along the curved structure and emit into the far field, realizing a directional light emission with maximal fluorescent intensity. Detailed simulations disclose a high Purcell factor and a spatial power distribution in the curved HMM, which agrees with the experimental result. Our work presents remarkable enhancing capability in both the Purcell factor and emission intensity, which could suggest a unique structure design in metamaterials for potential application in, e.g., high-speed optical sensing and communications. PMID- 29436814 TI - Electrophoretic Desalting To Improve Performance in Electrospray Ionization Mass Spectrometry. AB - Mass spectrometers are sensitive tools used to identify and quantify both small and large analytes using the mass-to-charge ratios ( m/ z) of ions generated by electrospray ionization (ESI) or other methods. Ionization typically generates protonated or deprotonated forms of the analytes or adducts with adventitious metal ions derived from the spray solvent. The formation of a variety of ionized forms of the analyte as well as the presence of cluster ions complicates the data and can have deleterious effects on the performance of the mass spectrometer, especially under high salt or buffer conditions. To address this, a method involving a dual-electrode nano-electrospray source has been implemented to rapidly and temporarily desalt the spray solution of interfering cationic and anionic species using electrophoretic transport from the spray tip. Peptides, proteins, and pharmaceutical drugs all showed improved results after the desalting process as measured by the quality of the mass spectra and the limits of detection achieved. Importantly ordinary phosphate buffers could be used to record protein mass spectra by nano-ESI. PMID- 29436815 TI - Si Nanostrip Optical Waveguide for On-Chip Broadband Molecular Overtone Spectroscopy in Near-Infrared. AB - The ability to probe the molecular fundamental or overtone (high harmonics) vibrations is fundamental to modern healthcare monitoring techniques and sensing technologies since it provides information about the molecular structure. However, since the absorption cross section of molecular vibration overtones is much smaller compared to the absorption cross section of fundamental vibrations, their detection is challenging. Here, a silicon nanostrip rib waveguide structure is proposed for label-free on-chip overtone spectroscopy in near-infrared (NIR). Utilizing the large refractive index contrast (Delta n > 2) between the silicon core of the waveguide and the silica substrate, a broadband NIR lightwave can be efficiently guided. We show that the sensitivity for chemical detection is increased by more than 3 orders of magnitude when compared to the evanescent-wave sensing predicted by the numerical model. This spectrometer distinguished several common organic liquids such as N-methylaniline and aniline precisely without any surface modification to the waveguide through the waveguide scanning over the absorption dips in the NIR transmission spectra. Planar NIR Si nanostrip waveguide is a compact sensor that can provide a platform for accurate chemical detection. Our NIR Si nanostrip rib waveguide device can enable the development of sensors for remote, on-site monitoring of chemicals. PMID- 29436816 TI - Laser-Induced Graphene by Multiple Lasing: Toward Electronics on Cloth, Paper, and Food. AB - A simple and facile method for obtaining patterned graphene under ambient conditions on the surface of diverse materials ranging from renewable precursors such as food, cloth, paper, and cardboard to high-performance polymers like Kevlar or even on natural coal would be highly desirable. Here, we report a method of using multiple pulsed-laser scribing to convert a wide range of substrates into laser-induced graphene (LIG). With the increased versatility of the multiple lase process, highly conductive patterns can be achieved on the surface of a diverse number of substrates in ambient atmosphere. The use of a defocus method results in multiple lases in a single pass of the laser, further simplifying the procedure. This method can be implemented without increasing processing times when compared with laser induction of graphene on polyimide (Kapton) substrates as previously reported. In fact, any carbon precursor that can be converted into amorphous carbon can be converted into graphene using this multiple lase method. This may be a generally applicable technique for forming graphene on diverse substrates in applications such as flexible or even biodegradable and edible electronics. PMID- 29436817 TI - Protective Layer Development for Enhancing Stability and Drug-Delivery Capabilities of DES Surface-Crystallized Coatings. AB - Carrier-free drug-eluting stents (DES)-based crystalline coatings are gaining prominence because of their function, skipping many limitations and clinical complications of the currently marketed DES. However, their usage has been humbled by inflexibility of the crystalline coating and limited mechanical and physical properties. This study reports for the first time the development of a protective top coating for enhancing the merits and delivery capabilities of the crystalline coating. Flexible and water-soluble polysaccharide top coating was developed and applied onto rapamycin (RM) crystalline carpet. The top coating prevented crystalline coating delamination during stent crimping and expansion without affecting its release profile. Crystalline coating strata and its interfaces with the metallic substrate and top coating were fully studied and characterized. The crystalline top-coated stents showed significant physical, mechanical, and chemical stability enhancement with ~2% RM degradation after 1 year under different storage conditions. Biocompatibility study of the top-coated stents implanted subcutaneously for 1 month into SD rats did not provoke any safety concerns. Incorporating RM into the top coating to develop a bioactive protective coating for multilayer release purposes was also investigated. The developed protective coating had wide applicability and may be further implemented for various drugs and implantable medical devices. PMID- 29436818 TI - Large-Area Heterostructures from Graphene and Encapsulated Colloidal Quantum Dots via the Langmuir-Blodgett Method. AB - This work explores the assembly of large-area heterostructures comprised of a film of silica-encapsulated, semiconducting colloidal quantum dots, deposited via the Langmuir-Blodgett method, sandwiched between two graphene sheets. The luminescent, electrically insulating film served as a dielectric, with the top graphene sheet patterned into an electrode and successfully used as a top gate for an underlying graphene field-effect transistor. This heterostructure paves the way for developing novel hybrid optoelectronic devices through the integration of 2D and 0D materials. PMID- 29436820 TI - Strategy for Generating Sequence-Defined Aptamer Reagent Sets for Detecting Protein Contaminants in Biotherapeutics. AB - Biologic drugs are typically manufactured in mammalian host cells, and it is critical from a drug safety and efficacy perspective to detect and remove host cell proteins (HCPs) during production. This is currently achieved with sets of polyclonal antibodies (pAbs), but these suffer from critical shortcomings because their composition is inherently undefined, and they cannot detect nonimmunogenic HCPs. In this work, we report a high-throughput screening and array-based binding characterization strategy that we employed to generate a set of aptamers that overcomes these limitations to achieve sensitive, broad-spectrum detection of HCPs from the widely used Chinese hamster ovary (CHO) cell line. We identified a set of 32 DNA aptamers that achieve better sensitivity than a commercial pAb reagent set and can detect a comparable number of HCPs over a broad range of isoelectric points and sizes. Importantly, these aptamers detect multiple contaminants that are known to be responsible for therapeutic antibody degradation and toxicity in patients. Because HCP aptamer reagents are sequence defined and chemically synthesized, we believe they may enable safer production of biologic drugs, and this strategy should be broadly applicable for the generation of HCP detection reagents for other cell lines. PMID- 29436819 TI - Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry. AB - Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain. PMID- 29436821 TI - pH-Sensitive Compounds for Selective Inhibition of Acid-Producing Bacteria. AB - Stimuli-responsive compounds that provide on-site, controlled antimicrobial activity promise an effective approach to prevent infections, reducing the need for systemic antibiotics. We present a novel pH-sensitive quaternary pyridinium salt (QPS), whose antibacterial activity is boosted by low pH and controlled by adjusting the pH between 4 and 8. Particularly, this compound selectively inhibits growth of acid-producing bacteria within a multispecies community. The successful antibacterial action of this QPS maintains the environmental pH above 5.5, a threshold pH, below which demineralization/erosion takes place. The design, synthesis, and characterization of this QPS and its short-chain analogue are discussed. In addition, their pH-sensitive physicochemical properties in aqueous and organic solutions are evaluated by UV-vis spectroscopy, dynamic light scattering, and NMR spectroscopy. Furthermore, the mechanism of action reveals a switchable assembly that is triggered by acid-base interaction and formed by tightly stacked pi-conjugated systems and base moieties. Finally, a model is proposed to recognize the correlated but different mechanisms of pH sensitivity and acid-induced, pH-controlled antibacterial efficacy. We anticipate that successful application of these QPSs and their derivatives will provide protections against infection and erosion through targeted treatments to acid producing bacteria and modulation of environmental pH. PMID- 29436822 TI - Detection of Sudan Dyes Based on Inner-Filter Effect with Reusable Conjugated Polymer Fibrous Membranes. AB - Developing effective methods for detecting illegal additives in food or seasoning is of great significance. In this study, a sensing strategy for selective detection of Sudan dyes was designed based on the fluorescence inner-filter effect (IFE) by using poly(phenylenevinylene) (PPV) solid materials in combination with an optimized experimental protocol. Two types of fluorescent solid materials, electrospun fibrous membranes and drop-cast films, were fabricated with PPV as the fluorophore and poly(vinyl alcohol) as the matrix, respectively. Sudan dyes greatly quenched the fluorescence of the membrane and film, whereas other food colorings or possible food ingredients displayed a much smaller or negligible quenching effect. The sensing mechanism was studied, and the selectivity was ascribed to IFE, which requires the overlap between the absorption of the analyte and absorption/emission of the sensing material. The form of materials (membrane or film), the content of PPV, and the cross-linking process did not have much influence on the selectivity and sensitivity, which is consistent with the IFE mechanism and demonstrates the advantage of not requiring strict control of the preparative process. All the cross-linked materials were found to be stable against water/humidity and displayed good reversibility in sensing and can be reused at least for 10 cycles with negligible influence on the sensing performance. A cross-linked membrane was selected for detecting Sudan dyes in chili powder because folding did not affect the mechanical stability of the membrane. Two different protocols were used to pretreat the chili samples, which allowed the detection of Sudan dyes in chili powder as well as the discrimination of Sudan dyes from synthetic food coloring such as allura red. This study provides a facile and cost-effective method for preparing reusable sensing materials for detecting some dyes in commercial foods or food seasonings. PMID- 29436823 TI - How to Bend the Uranyl Cation via Crystal Engineering. AB - Bending the linear uranyl (UO22+) cation represents both a significant challenge and opportunity within the field of actinide hybrid materials. As part of related efforts to engage the nominally terminal oxo atoms of uranyl cation in noncovalent interactions, we synthesized a new uranyl complex, [UO2(C12H8N2)2(C7H2Cl3O2)2].2H2O (complex 2), that featured both deviations from equatorial planarity and uranyl linearity from simple hydrothermal conditions. Based on this complex, we developed an approach to probe the nature and origin of uranyl bending within a family of hybrid materials, which was done via the synthesis of complexes 1-3 that display significant deviations from equatorial planarity and uranyl linearity (O-U-O bond angles between 162 degrees and 164 degrees ) featuring 2,4,6-trihalobenzoic acid ligands (where Hal = F, Cl, and Br) and 1,10-phenanthroline, along with nine additional "nonbent" hybrid materials that either coformed with the "bent" complexes (4-6) or were prepared as part of complementary efforts to understand the mechanism(s) of uranyl bending (7-12). Complexes were characterized via single crystal X-ray diffraction and Raman, infrared (IR), and luminescence spectroscopy, as well as via quantum chemical calculations and density-based quantum theory of atoms in molecules (QTAIM) analysis. Looking comprehensively, these results are compared with the small library of bent uranyl complexes in the literature, and herein we computationally demonstrate the origin of uranyl bending and delineate the energetics behind this process. PMID- 29436824 TI - Accessing Heterobiaryls through Transition-Metal-Free C-H Functionalization. AB - Herein we report a transition-metal-free synthetic protocol for heterobiaryls, one of the most important pharmacophores in the modern drug industry, employing a new multidonor phenalenyl (PLY)-based ligand. The current procedure offers a wide substrate scope (24 examples) with a low catalyst loading resulting in an excellent product yield (up to 95%). The reaction mechanism involves a single electron transfer (SET) from a phenalenyl-based radical to generate a reactive heteroaryl radical. To establish the mechanism, we have isolated the catalytically active SET initiator, characterizing by a magnetic study. PMID- 29436825 TI - Extreme Sensitivity of a Topochemical Reaction to Cation Substitution: SrVO2H versus SrV1- xTi xO1.5H1.5. AB - The anion-ordered oxide-hydride SrVO2H is an antiferromagnetic insulator due to strong correlations between vanadium d electrons. In an attempt to hole-dope SrVO2H into a metallic state, a strategy of first preparing SrV1- xTi xO3 phases and then converting them to the corresponding SrV1- xTi xO2H phases via reaction with CaH2 was followed. This revealed that the solid solution between SrVO3 and SrTiO3 is only stable at high temperature. In addition, reactions between SrV0.95Ti0.05O3 and CaH2 were observed to yield SrV0.95Ti0.05O1.5H1.5 not SrV0.95Ti0.05O2H. This dramatic change in reactivity for a very modest change in initial chemical composition is attributed to an electronic destabilization of SrVO2H on titanium substitution. Density functional theory calculations indicate that the presence of an anion-ordered, tetragonal SrMO2H phase is uniquely associated with a d2 electron count and that titanium substitution leads to an electronic destabilization of SrV1- xTi xO2H phases, which, ultimately, drives further reaction of SrV1- xTi xO2H to SrV1- xTi xO1.5H1.5. The observed sensitivity of the reaction products to the chemical composition of initial phases highlights some of the difficulties associated with electronically doping metastable materials prepared by topochemical reactions. PMID- 29436826 TI - Fluorescent Cyanine Dye J-Aggregates in the Fluorous Phase. AB - We present a perfluorocarbon-hydrocarbon amphiphilic cyanine dye that J aggregates in fluorous solvent. J-Aggregation is a special type of fluorophore aggregation, affording enhanced photophysical properties. Cyanine dyes are excellent J-aggregators in water but, until now, cyanine J-aggregates have not been translated to nonaqueous media. The fluorous phase J-aggregate displays enhanced photostability and processability compared to analogous aqueous aggregates. PMID- 29436827 TI - Novel alpha-Oxoamide Advanced-Glycation Endproducts within the N6-Carboxymethyl Lysine and N6-Carboxyethyl Lysine Reaction Cascades. AB - The highly reactive alpha-dicarbonyl compounds glyoxal and methylglyoxal are major precursors of posttranslational protein modifications in vivo. Model incubations of N2-t-Boc-lysine and either glyoxal or methylglyoxal were used to further elucidate the underlying mechanisms of the N6-carboxymethyl lysine and N6 carboxyethyl lysine reaction cascades. After independent synthesis of the authentic reference standards, we were able to detect N6-glyoxylyl lysine and N6 pyruvoyl lysine for the first time by HPLC-MS2 analyses. These two novel amide advanced-glycation endproducts were exclusively formed under aerated conditions, suggesting that they were potent markers for oxidative stress. Analogous to the well-known Strecker degradation pathway, leading from amino acids to Strecker acids, the oxidation of an enaminol intermediate is suggested to be the key mechanistic step. A highly sensitive workup for the determination of AGEs in tissues was developed. In support of our hypothesis, the levels of N6-glyoxylyl lysine and N6-pyruvoyl lysine in rat livers indeed correlated with liver cirrhosis and aging. PMID- 29436828 TI - A Cancer Cell-Selective and Low-Toxic Bifunctional Heterodinuclear Pt(IV)-Ru(II) Anticancer Prodrug. AB - Although different types of metal-based anticancer complexes have been synthesized, novel complexes to reduce the serious side effect of cisplatin and conquer cancer metastasis are still highly desired. Here, we report the synthesis, characterization, and biological activity of a novel heterodinuclear Pt(IV)-Ru(II) anticancer prodrug. The Pt(IV)-Ru(II) complex exhibits good stability in both water and PBS solution. Biological evaluation revealed that this bifunctional Pt(IV)-Ru(II) complex utilizes the advantages of two metal centers to have both cytotoxicity and antimetastatic property as designed. Although the complex has comparable cytotoxicities to cisplatin in tested cancer cell lines, this prodrug selectively kills cancer but not normal cells, and the IC50 values of the Pt(IV)-Ru(II) complex are 7-10 times higher than those of cisplatin toward normal cells. The cancer cell selectivity is further demonstrated by a cancer-normal cell coculture system. In addition, the antimetastatic properties of the heterodinuclear complex are assessed by using highly metastatic human breast cancer cells, and the results show that the migration and invasion of cancer cells are effectively restrained after the treatment. Moreover, the Pt(IV)-Ru(II) complex displays lower toxicity than cisplatin in developing zebrafish embryos. We, therefore, report an example of heterodinuclear Pt(IV)-Ru(II) complex not only to defeat both drug resistance and cancer metastasis but also having significantly improved cancer cell selectivity and reduced in vivo toxicity than cisplatin. PMID- 29436830 TI - Equivalence between the Classical and Quantum IR Spectral Density Approaches of Weak H-Bonds in the Absence of Damping. AB - The aim of this paper is to overhaul the quantum elucidation of the spectral density (SD) of weak H-bonds treated without taking into account any of the damping mechanisms. The reconsideration of the SD is performed within the framework the linear response theory. Working in the setting of the strong anharmonic coupling theory and the adiabatic approximation, the simplified expression of the classical SD, in the absence of dampings, is equated to be ICl(omega) = Re[?0infinityGCl(t)e-iOmegat dt] in which the classical-like autocorrelation function (ACF), GCl(t), is given by GCl(t) = tr{rho(beta){MU(0)}{MU(t)}?}. With this consideration, we have shown that the classical SD is equivalent to the line shape obtained by F(omega) = OmegaICl(omega), which in turn is equivalent to the quantum SD given by IQu(omega) = Re[?0infinityGQu(t)e-iOmegat dt], where GQu(t) is the corresponding quantum ACF having for expression GQu(t) = (1/beta) tr{rho?0beta[MU(0)}{MU(t + ilambdah)}? dlambda}. Thus, we have shown that for weak H-bonds dealt without dampings, the SDs obtained by the quantum approaches are equivalent to the SDs geted by the classical approach in which the incepation ACF is, however, of quantum nature and where the line shape is the Fourier transform of the ACF times the angular frequency. It is further shown that the classical approach dealing with the SD of weak H-bonds leads identically to the result found by Marechal and Witkowski in their pioneering quantum treatment where they ignored the linear response theory and dampings. PMID- 29436829 TI - Deamidation of Protonated Asparagine-Valine Investigated by a Combined Spectroscopic, Guided Ion Beam, and Theoretical Study. AB - Peptide deamidation of asparaginyl residues is a spontaneous post-translational modification that is believed to play a role in aging and several diseases. It is also a well-known small-molecule loss channel in the MS/MS spectra of protonated peptides. Here we investigate the deamidation reaction, as well as other decomposition pathways, of the protonated dipeptide asparagine-valine ([AsnVal + H]+) upon low-energy activation in a mass spectrometer. Using a combination of infrared ion spectroscopy, guided ion beam tandem mass spectrometry, and theoretical calculations, we have been able to identify product ion structures and determine the energetics and mechanisms for decomposition. Deamidation proceeds via ammonia loss from the asparagine side chain, initiated by a nucleophilic attack of the peptide bond oxygen on the gamma-carbon of the Asn side chain. This leads to the formation of a furanone ring containing product ion characterized by a threshold energy of 129 +/- 5 kJ/mol (15 kJ/mol higher in energy than dehydration of [AsnVal + H]+, the lowest energy dissociation channel available to the system). Competing formation of a succinimide ring containing product, as has been observed for protonated asparagine-glycine ([AsnGly + H]+) and asparagine-alanine ([AsnAla + H]+), was not observed here. Quantum-chemical modeling of the reaction pathways confirms these subtle differences in dissociation behavior. Measured reaction thresholds are in agreement with predicted theoretical reaction energies computed at several levels of theory. PMID- 29436831 TI - Formation of C2v-C72(11188)Cl4: A Particularly Stable Non-IPR Fullerene. AB - Halogenation has been one of the most used strategies to explore the reactivity of empty carbon cages. In particular, the higher reactivity of non-IPR fullerenes, i.e., those fullerenes that do not satisfy the isolated pentagon rule (IPR), has been used to functionalize and capture these less stable fullerenes. Here, we have explored the stability of the non-IPR isomer C72(11188) with C2v symmetry, which is topologically linked to the only IPR isomer of C70, as well as its reactivity to chlorination. DFT calculations and Car-Parrinello molecular dynamics simulations suggest that chlorination takes places initially in nonspecific sites, once carbon cages are formed. When the temperature in the arc reactor decreases sufficiently, Cl atoms are trapped on the fullerene surface, migrating from not-so-favored positions to reach the most favored sites in the pentalene. We have also discussed why cage C2v-C72(11188) is found to take four chlorines, whereas cage C1-C74(14049) is observed to capture 10 of them, even though these two fullerenes are closely related by a simple C2 insertion. PMID- 29436832 TI - Droplet Impact on Anisotropic Superhydrophobic Surfaces. AB - A droplet impacting on a superhydrophobic surface exhibits complete bouncing. The impacting process usually consists of spreading and retracting stages, during which the droplet contacts the underlying substrate. Recent research has been devoted to reducing the contact time using textured surfaces with different morphologies or flexibilities. Here, we design submillimeter superhydrophobic ridges and show that impacting droplets bounce off the surface immediately after capillary emptying in a petal-like shape at a certain Weber number range. The absence of a horizontal retraction process in two directions leads to ~70% reduction in contact time. We demonstrate that the petal bouncing is attributed to the synergistic cooperation of the hierarchical structures and anisotropic property, which endows effective energy storage and release. When touching the bottom of the grooves, obvious flying wings appear along the ridges with a velocity component in the vertical direction, which help the energy releasing process in achieving fast droplet detachment. At higher Weber numbers, the anisotropic surface distorts the mass distribution and promotes uniform fragmentation of the droplet, and therefore the overall contact time is dramatically reduced. Simple analyses are proposed to explain these phenomena, showing a good agreement with the experimental results. The contact time reduction on anisotropic superhydrophobic surfaces is expected to have a great influence on the design and fabrication of anti-icing and self-cleaning surfaces. PMID- 29436833 TI - Photochemically Powered AgCl Janus Micromotors as a Model System to Understand Ionic Self-Diffusiophoresis. AB - Micromotors are an emerging class of micromachines that could find potential applications in biomedicine, environmental remediation, and microscale self assembly. Understanding their propulsion mechanisms holds the key to their future development. This is especially true for a popular category of micromotors that are driven by asymmetric surface photochemical reactions. Many of these micromotors release ionic species and are propelled via a mechanism termed "ionic self-diffusiophoresis". However, exactly how it operates remains vague. To address this fundamental yet important issue, we have developed a dielectric-AgCl Janus micromotor that clearly moves away from the AgCl side when exposed to UV or strong visible light. Taking advantage of numerical simulations and acoustic levitation techniques, we have provided tentative explanations for its speed decay over time as well as its directionality. In addition, photoactive AgCl micromotors demonstrate interesting gravitactic behaviors that hint at three dimensional transport or sensing applications. The current work presents a well controlled and easily fabricated model system to understand chemically powered micromotors, highlighting the usefulness of acoustic levitation for studying active matter free from the effect of boundaries. PMID- 29436834 TI - Dehydrative Mannich-Type Reaction for the Synthesis of Azepinobisindole Alkaloid Iheyamine A. AB - A concise synthesis of the azepinobisindole alkaloid iheyamine A from an indole 2,3-epoxide equivalent has been achieved. This method features a formal C3 electrophilic reaction of an indole-2,3-epoxide equivalent with tryptamine to form a 3-aminoindoline and a novel In-catalyzed dehydrative Mannich-type reaction of the hemiaminal to give the azepinobisindole core. PMID- 29436836 TI - Thermochromic Uranyl Isothiocyanates: Influencing Charge Transfer Bands with Supramolecular Structure. AB - The synthesis and structural characterization of seven new [UO2(NCS)5]3-- and [UO2(NCS)4Cl]3--containing materials charge balanced by 4-phenylpyridinium or 4,4'-bipyridinium cations are reported. Assembly of these materials occurs via a diverse set of noncovalent interactions, with the most prevalent involving the terminal sulfur atoms, which can both accept hydrogen bonds and/or form S...S and S...Oyl interactions. The electrostatic potential of the [UO2(NCS)5]3- and [UO2(NCS)4Cl]3- anions was calculated and mapped on the 0.001 au isodensity surface to rationalize the observed assembly modes and to provide an electrostatic basis to elucidate the role of the S atoms as both donors and acceptors of noncovalent interactions. Compounds 1-7 display a range of colors (red to yellow) as well as pronounced thermochromism. A computational treatment (time-dependent density functional theory, TDDFT) of the absorbance properties supports the temperature dependence on the ratio of inter- to intramolecular ligand to metal charge transfer (LMCT) bands as obtained from UV-vis diffuse reflectance analysis. Finally, the luminescence profiles of these materials feature additional peaks atypical for most uranyl-containing materials, and a combined spectroscopic (Raman, IR, and fluorescence) and computational (harmonic frequency calculations) effort assigns these as originating from vibronic coupling between the nu1 U?O symmetric stretch and bending modes of the isothiocyanate ligands. PMID- 29436837 TI - Nickel-Catalyzed Remote Arylation of Alkenyl Aldehydes Initiated by Radical Alkylation with Tertiary alpha-Carbonyl Alkyl Bromides. AB - A novel nickel-catalyzed remote arylation of alkenyl aldehydes triggered by radical alkylation with tertiary alpha-carbonyl alkyl bromides is described, thus producing a quaternary carbon center containing ketones in promising yields with broad functional group compatibility. Preliminary mechanistic studies suggest that the combination of a 1,n-HAT (n = 5 or 6) from alkyl radicals to aldehyde C H bonds with nickel catalysis may account for the realization of this reaction. PMID- 29436835 TI - Pharmacokinetic and Chemical Synthesis Optimization of a Potent d-Peptide HIV Entry Inhibitor Suitable for Extended-Release Delivery. AB - Peptides often suffer from short in vivo half-lives due to proteolysis and renal clearance that limit their therapeutic potential in many indications, necessitating pharmacokinetic (PK) enhancement. d-Peptides, composed of mirror image d-amino acids, overcome proteolytic degradation but are still vulnerable to renal filtration due to their small size. If renal filtration could be slowed, d peptides would be promising therapeutic agents for infrequent dosing, such as in extended-release depots. Here, we tether a diverse set of PK-enhancing cargoes to our potent, protease-resistant d-peptide HIV entry inhibitor, PIE12-trimer. This inhibitor panel provides an opportunity to evaluate the PK impact of the cargoes independently of proteolysis. While all the PK-enhancing strategies (PEGylation, acylation, alkylation, and cholesterol conjugation) improved in vivo half-life, cholesterol conjugation of PIE12-trimer dramatically improves both antiviral potency and half-life in rats, making it our lead anti-HIV drug candidate. We designed its chemical synthesis for large-scale production (CPT31) and demonstrated that the PK profile in cynomolgous monkeys supports future development of monthly or less frequent depot dosing in humans. CPT31 could address an urgent need in both HIV prevention and treatment. PMID- 29436838 TI - Rhodium-Catalyzed Asymmetric Cyclization/Addition Reactions of 1,6-Enynes and Oxa/Azabenzonorbornadienes. AB - A mild, efficient, and novel rhodium catalyzed asymmetric cyclization-addition domino reaction of oxa/azabenzonorbornadienes and 1,6-enynes is documented. Through the use of a [Rh(COD)2]BF4-(R)-An-SDP catalytic system, highly enantioenriched cyclization-addition products were obtained in good yields and with excellent enantioselectivities. PMID- 29436839 TI - Enhancing the Spreading Behavior on Pulmonary Mucus Mimicking Subphase via Catanionic Surfactant Solutions: Toward Effective Drug Delivery through the Lungs. AB - Effective and efficient spreading of drug formulations on the pulmonary mucosal layer is key to successful delivery of therapeutics through the lungs. The pulmonary mucus layer, which covers the airway surface, acts as a barrier against therapeutic agents, especially in the case of chronic lung diseases due to increased thickness and viscosity of the mucus. Therefore, spreading of the drug formulations on the airways gets harder. Although spreading experiments have been conducted with different types of formulations on mucus-mimicking subphases, a highly effective formulation is yet to be discovered. Adding surfactant to such formulations decreases the surface tension and triggers the Marangoni forces to enhance the spreading behavior. In this study, catanionic (cationic + anionic) surfactant mixtures composed of dodecyltrimethylammonium bromide (DTAB) and dioctyl sulfosuccinate sodium salt (AOT) mixed at various mole ratios are prepared and their spreading behavior on both mucin and cystic fibrosis (CF) mucus models is investigated for the first time in the literature. Synergistic interaction is obtained between the components of the DTAB/AOT mixtures, and this interaction has enhanced the spreading of the formulation drop on both the mucin and CF mucus models when compared with the spreading performances of selected conventional surfactants. It is proposed that the catanionic surfactant mixtures, especially when mixed at the molar ratios of 8/2 and 7/3 (DTAB/AOT), improve the spreading even on the cystic fibrosis sputum model. As it is vital to transport a sufficient amount of drug to the targeted region for the treatment of diseases, this study presents an important application of the fundamentals of colloidal science to pharmaceutical nanotechnology. PMID- 29436840 TI - In Gratitude: Personal Memories of the Late Dr. Mathilde Krim (July 9, 1926 January 15, 2018). PMID- 29436841 TI - Fat suppression in magnetic resonance imaging of the head and neck region: is the two-point DIXON technique superior to spectral fat suppression? AB - OBJECTIVE: The aim of our study was to systematically compare two-point Dixon fat suppression (FS) and spectral FS techniques in contrast enhanced imaging of the head and neck region. METHODS: Three independent readers analysed coronal T1 weighted images recorded after contrast medium injection with Dixon and spectral FS techniques with regard to FS homogeneity, motion artefacts, lesion contrast, image sharpness and overall image quality. RESULTS: 85 patients were prospectively enrolled in the study. Images generated with Dixon-FS technique were of higher overall image quality and had a more homogenous FS over the whole field of view compared with the standard spectral fat-suppressed images (p < 0.001). Concerning motion artefacts, flow artefacts, lesion contrast and image sharpness no statistically significant difference was observed. CONCLUSION: The Dixon-FS technique is superior to the spectral technique due to improved homogeneity of FS and overall image quality while maintaining lesion contrast. Advances in knowledge: T1 with Dixon FS technique offers, compared to spectral FS, significantly improved FS homogeneity and over all image quality in imaging of the head and neck region. PMID- 29436842 TI - Histogram analysis derived from apparent diffusion coefficient (ADC) is more sensitive to reflect serological parameters in myositis than conventional ADC analysis. AB - OBJECTIVE: Diffusion-weighted imaging (DWI) has the potential of being able to reflect histopathology architecture. A novel imaging approach, namely histogram analysis, is used to further characterize tissues on MRI. The aim of this study was to correlate histogram parameters derived from apparent diffusion coefficient (ADC) maps with serological parameters in myositis. METHODS: 16 patients with autoimmune myositis were included in this retrospective study. DWI was obtained on a 1.5 T scanner by using the b-values of 0 and 1000 s mm-2. Histogram analysis was performed as a whole muscle measurement by using a custom-made Matlab-based application. The following ADC histogram parameters were estimated: ADCmean, ADCmax, ADCmin, ADCmedian, ADCmode, and the following percentiles ADCp10, ADCp25, ADCp75, ADCp90, as well histogram parameters kurtosis, skewness, and entropy. In all patients, the blood sample was acquired within 3 days to the MRI. The following serological parameters were estimated: alanine aminotransferase, aspartate aminotransferase, creatine kinase, lactate dehydrogenase, C-reactive protein (CRP) and myoglobin. All patients were screened for Jo1-autobodies. RESULTS: Kurtosis correlated inversely with CRP (p = -0.55 and 0.03). Furthermore, ADCp10 and ADCp90 values tended to correlate with creatine kinase (p = -0.43, 0.11, and p = -0.42, = 0.12 respectively). In addition, ADCmean, p10, p25, median, mode, and entropy were different between Jo1-positive and Jo1 negative patients. CONCLUSION: ADC histogram parameters are sensitive for detection of muscle alterations in myositis patients. Advances in knowledge: This study identified that kurtosis derived from ADC maps is associated with CRP in myositis patients. Furthermore, several ADC histogram parameters are statistically different between Jo1-positive and Jo1-negative patients. PMID- 29436843 TI - Synthesis and substrate properties towards HIV-1 reverse transcriptase of new diphosphate analogues of 9-[(2-phosphonomethoxy)ethyl]adenine. AB - Background The replacement of beta,gamma-pyrophosphate by beta,gamma-phosphonate moieties within the triphosphate chain of 5'-triphosphate nucleoside analogues was previously studied for various antiviral nucleoside analogues such as AZT and 2',3'-dideoxynucleosides. Thus, it has been shown that these chemical modifications could preserve, in some cases, the terminating substrate properties of the triphosphate analogue for HIV-RT. Herein, we aimed to study such 5' triphosphate mimics based on the scaffold of the well-known antiviral agent 9-[(2 phosphonomethoxy)ethyl]adenine (PMEA, Adefovir). Methods Synthesis involved coupling of a morpholidate derivative of PMEA with appropriate pyrophosphoryl analogues. The relative efficiencies of incorporation of the studied diphosphate phosphonates were measured using subtype B WT HIV-1 RT in an in vitro susceptibility assay, in comparison to the parent nucleotide analogue (PMEApp). Results Searching for nucleoside 5'-triphosphate mimics, we have synthesized and studied a series of diphosphate analogues of PMEA bearing non hydrolysable bonds between the and phosphorus atoms. We also examined their relative inhibitory capacity towards HIV-1 reverse transcriptase in comparison to the parent nucleotide analogue (PMEApp). Only one of them appeared as a weak inhibitor (IC50 = 403.0 +/- 75.5 uM) and proved to be less effective than PMEApp (IC50 = 6.4 +/- 0.8 uM). Conclusion PMEA diphosphoryl derivatives were designed as potential substrates and/or inhibitors of various viral polymerases. These modifications dramatically affect their ability to inhibit HIV-RT. PMID- 29436844 TI - The prevalence and patterns of substance use by birth cohort among HIV-positive adults in Florida. AB - OBJECTIVES: Antiretroviral therapy is affording longer lifespans for people living with HIV (PLWH), yet factors such as substance use play an increasing role in morbidity and mortality in this population. Though previous studies have examined substance use differences between age cohorts of PLWH, no study has examined the influence of birth cohort on current substance use patterns. Thus, this study investigated the prevalence of past 12-month self-reported substance use between four birth cohorts, <1970 (M age = 54.1), 1970s (M age = 41.5), 1980s (M age = 31.3 years old), and 1990s (M age = 23.2 years old) of PLWH in Florida. METHODS: PLWH (N = 934) recruited from community health clinics in Florida completed a questionnaire assessing sociodemographics, health status, and substance use. Multivariate logistic regressions utilizing the <1970 cohort as the referent group examined the relationship between birth cohort and substance use. RESULTS: The 1980s cohort had significantly greater odds of marijuana use compared to the oldest cohort (<1970s), while the three younger cohorts (1970s, 1980s, and 1990s) evidenced a significantly greater odds of ecstasy use compared to the oldest group. Contrastingly, the three younger birth cohorts reported significantly less crack use than the oldest cohort, while the youngest group (1990s) also demonstrated an 80% reduction in injection drug use compared to the oldest group. CONCLUSION: The older cohort evidenced significantly greater crack and injection drug use, while the younger cohorts evidenced greater marijuana and ecstasy use. Therefore, it is important to develop age-specific substance use interventions among PLWH. PMID- 29436845 TI - Sum-Frequency Generation Vibrational Spectroscopy Investigations of Phosphonic Acids on Anodic Aluminum Oxide Films. AB - Self-assembled monolayers of alkyl phosphonic acids on anodic aluminum oxide (AlOx) surfaces are important as dielectric layers in thin film electronic devices. Assessing the properties and quality of these monolayers on amorphous AlOx is limited to a few surface-sensitive methods. In this work, we study using nonlinear optical measurements the molecular ordering in n-alkyl phosphonic acids with various alkyl chain lengths (6 to 18 carbons) deposited on AlOx and show the influence of temperature on stability and conformational order. The results demonstrate that the octadecylphosphonic acid has fewest defects in the chain orientation. A detailed comparison of the longest and the shortest alkyl chain revealed different behavior in conformational ordering upon annealing. PMID- 29436847 TI - Targeting tumour hypoxia: shifting focus from oxygen supply to demand. AB - Tumour hypoxia is a well-recognised barrier to anti-cancer therapy and represents one of the best validated targets in oncology. Previous attempts to tackle hypoxia have focussed primarily on increasing tumour oxygen supply; however, clinical studies using this approach have yielded only modest clinical benefit, with often significant toxicity and practical limitations. Therefore, there are currently no anti-hypoxia treatments in widespread clinical use. As an emerging alternative strategy, we discuss the relevance of inhibiting tumour oxygen metabolism to alleviate hypoxia and highlight recently initiated clinical trials using this approach. PMID- 29436846 TI - Effect of dimethyl fumarate on renal disease progression in a genetic ortholog of nephronophthisis. AB - Dimethyl fumarate is an FDA-approved oral immunomodulatory drug with anti inflammatory properties that induces the upregulation of the anti-oxidant transcription factor, nuclear factor erythroid-derived factor 2. The aim of this study was to determine the efficacy of dimethyl fumarate on interstitial inflammation and renal cyst growth in a preclinical model of nephronophthisis. Four-week-old female Lewis polycystic kidney disease (a genetic ortholog of human nephronophthisis-9) rats received vehicle (V), 10 mg/kg (D10) or 30 mg/kg (D30) ( n = 8-9 each) dimethyl fumarate in drinking water for eight weeks. Age-matched Lewis control rats were also studied ( n = 4 each). Nuclear factor erythroid derived factor 2 was quantified by whole-slide image analysis of kidney sections. Renal nuclear factor erythroid-derived factor 2 activation was partially reduced in vehicle-treated Lewis polycystic kidney disease rats compared to Lewis control (21.4 +/- 1.7 vs. 27.0 +/- 1.6%, mean +/- SD; P < 0.01). Dimethyl fumarate upregulated nuclear factor erythroid-derived factor 2 in both Lewis Polycystic Kidney Disease (D10: 35.9 +/- 3.8; D30: 33.6 +/- 3.4%) and Lewis rats (D30: 34.4 +/- 1.3%) compared to vehicle-treated rats ( P < 0.05). Dimethyl fumarate significantly reduced CD68+ cell accumulation in Lewis polycystic kidney disease rats (V: 31.7 +/- 2.4; D10: 23.0 +/- 1.1; D30: 21.5 +/- 1.9; P < 0.05). In Lewis polycystic kidney disease rats, dimethyl fumarate did not alter the progression of kidney enlargement (V: 6.4 +/- 1.6; D10: 6.9 +/- 1.2; D30: 7.3 +/- 1.3%) and the percentage cystic index (V: 59.1 +/- 2.7; D10: 55.7 +/- 3.5; D30: 58.4 +/- 2.9%). Renal dysfunction, as determined by the serum creatinine (Lewis + V: 26 +/ 4 vs. LPK + V: 60 +/- 25 P < 0.01; LPK + D10: 47 +/- 7; LPK + D30: 47 +/- 9 umol/L), and proteinuria were also unaffected by dimethyl fumarate treatment. In conclusion, the upregulation of nuclear factor erythroid-derived factor 2 by dimethyl fumarate reduced renal macrophage infiltration in nephronophthisis without adverse effects, suggesting that it could potentially be used in combination with other therapies that reduce the rate of renal cyst growth. Impact statement This is the first study to investigate the effects of dimethyl fumarate in a model of cystic kidney disease. The study assessed the therapeutic efficacy of dimethyl fumarate in upregulating renal nuclear factor erythroid derived factor 2 expression, reducing macrophage accumulation and cyst progression in a Lewis polycystic kidney disease rat model. This study demonstrates that dimethyl fumarate significantly upregulated renal nuclear factor erythroid-derived factor 2 expression and attenuates renal macrophage infiltration, but had no effect on renal cyst progression, cardiac enlargement, and improving renal function. PMID- 29436849 TI - Testing of diagnosis criteria of tension-type headache: A multicenter clinical study. AB - Objective Tension-type headache is *These authors contributed equally to this work. usually manifested as head pain without associated symptoms, and the validation of diagnostic criteria presented are lacking and highly required in the International Classification of Headache Disorders. The aim of the present study was to explore the diagnosis criteria of tension-type headache in a multicenter-based sample from Chongqing, China. Methods Clinical characteristics and demographics were systematically and prospectively collected between March 2014 and December 2015 from 15 participating hospitals in Chongqing, using a semi structured face-to-face interview. All patients were asked to complete a headache diary for at least 4 weeks. Results Out of 1832 patients with headache, 150 patients (97 female/53 male, 44.56 +/- 11.9 years old) were diagnosed with tension-type headache based on the standard International Classification of Headache Disorders, 3rd edition beta version, and interestingly, 114 (76%) patients were diagnosed with tension-type headache based on the alternative criteria. One patient was excluded because only two of the four characteristics were fulfilled. Thirty-five (23.3%) patients did not meet the alternative criteria because of associated symptoms, including mild nausea (n = 6), photophobia (n = 1), and phonophobia (n = 28). All patients with TTH had mild or moderate headaches, 98.0% of patients suffered from non-pulsating headaches, 99.3% of patients said their headaches were not aggravated by routine physical activity, and 77.3% of patients had bilateral headache. Conclusions Non-pulsating headaches and headaches that are not aggravated by routine physical activity may represent core criteria for screening patients with tension-type headache. Nausea might not be an exclusion feature for diagnosis of TTH, but an important criterion for screening. Further studies are needed. PMID- 29436848 TI - Image-guided biopsy of small (<=4 cm) renal masses: the effect of size and anatomical location on biopsy success rate and complications. AB - OBJECTIVE: To study the influence of tumour diameter and anatomy on the success and complication rates of small renal mass (SRM, <=4 cm) core biopsy. METHODS: Retrospective analysis of SRMs that underwent ultrasound or CT-guided biopsy. Diagnostic and complication rates were compared according to tumour size (subcategorised as axial diameter <=2 cm, >2 to- <=3 cm, >3-<=4 cm) and anatomical disposition (exophytic/endophytic, centrality, polar location and anterior/posterior). RESULTS: 94 patients (54 male; age range 21.8-84.3 years) with 95 SRMs underwent biopsy. The first biopsy was diagnostic in 81/95 (85.3%). Seven patients underwent repeat biopsy (6/7 diagnostic), to give an overall diagnostic rate of 91.5%. The primary diagnostic rates in the <=2, >2-<=3 , >3 <=4 cm groups were 21/25 (84%); 38/44 (86.4%) and 22/26 (84.6%) respectively and were similar (p = 1.00). Anterior and upper pole SRMs were more likely to fail initial biopsy (odds ratio 13.8, p < 0.01; and odds ratio 4.35, p = 0.04) respectively, but other anatomical factors were not relevant. Complications occurred in 14% (all conservatively managed perinephric haematomas; Clavien-Dindo Grade 1) and size or location were not relevant. CONCLUSION: Image-guided biopsy of SRMs has a high diagnostic rate irrespective of tumour size. Anterior and upper pole location had lower diagnostic rates. Biopsy should be considered for all patients with SRMs, if the result will impact on management and we list specific scenarios where an SRM biopsy may be helpful. Advances in knowledge: SRM size does not affect the likelihood of a diagnostic biopsy. PMID- 29436851 TI - Potential of food to inspire. PMID- 29436850 TI - Mammography cancer detection: comparison of single 8MP and pair of 5MP reporting monitors. AB - OBJECTIVE:: To compare breast cancer detection using a single 8MP display with using a standard pair of 5MP monitors. METHODS:: An observer study was carried out in which mammograms were read using full field views only, and again with the additional use of magnified quadrant views. Seven observers read 300 cases, one view per breast, using each display type. Cases comprised 100 normal cases and 200 cases with cancers of subtle or very subtle appearance: 100 with malignant calcification clusters and 100 with non-calcified lesions. JAFROC software was used to analyse the results. RESULTS:: When mammograms were viewed full field only, observers performed better (p = 0.050) in detecting malignant calcification clusters when using the pair of 5MP monitors compared with a single 8MP monitor. This result became non-significant when results were generalised to a population of readers. Performance in detecting calcification clusters was improved by using quadrant view in addition to full field view when using either the pair of 5MP monitors or the 8MP monitor. There was no significant difference in detection of all types of cancer between the pair of 5MP monitors and the 8MP monitor when quadrant zoom was used. CONCLUSION:: Providing quadrant view is used in addition to full field view, there is no significant difference in cancer detection between the 8MP monitor and the pair of 5MP monitors. ADVANCES IN KNOWLEDGE:: Effect of magnification on the detectability of subtle malignant calcification clusters in breast screening. PMID- 29436852 TI - Comparing photon and proton-based hypofractioned SBRT for prostate cancer accounting for robustness and realistic treatment deliverability. AB - OBJECTIVE: To investigate whether photon or proton-based stereotactic body radiation therapy (SBRT is the preferred modality for high dose hypofractionation prostate cancer treatment. Achievable dose distributions were compared when uncertainties in target positioning and range uncertainties were appropriately accounted for. METHODS: 10 patients with prostate cancer previously treated at our institution (Montefiore Medical Center) with photon SBRT using volumetric modulated arc therapy (VMAT) were identified. MRI images fused to the treatment planning CT allowed for accurate target and organ at risk (OAR) delineation. The clinical target volume was defined as the prostate gland plus the proximal seminal vesicles. Critical OARs include the bladder wall, bowel, femoral heads, neurovascular bundle, penile bulb, rectal wall, urethra and urogenital diaphragm. Photon plan robustness was evaluated by simulating 2 mm isotropic setup variations. Comparative proton SBRT plans employing intensity modulated proton therapy (IMPT) were generated using robust optimization. Plan robustness was evaluated by simulating 2 mm setup variations and 3% or 1% Hounsfield unit (HU) calibration uncertainties. RESULTS: Comparable maximum OAR doses are achievable between photon and proton SBRT, however, robust optimization results in higher maximum doses for proton SBRT. Rectal maximum doses are significantly higher for Robust proton SBRT with 1% HU uncertainty compared to photon SBRT (p = 0.03), whereas maximum doses were comparable for bladder wall (p = 0.43), urethra (p = 0.82) and urogenital diaphragm (p = 0.50). Mean doses to bladder and rectal wall are lower for proton SBRT, but higher for neurovascular bundle, urethra and urogenital diaphragm due to increased lateral scatter. Similar target conformality is achieved, albeit with slightly larger treated volume ratios for proton SBRT, >1.4 compared to 1.2 for photon SBRT. CONCLUSION: Similar treatment plans can be generated with IMPT compared to VMAT in terms of target coverage, target conformality, and OAR sparing when range and HU uncertainties are neglected. However, when accounting for these uncertainties during robust optimization, VMAT outperforms IMPT in terms of achievable target conformity and OAR sparing. Advances in knowledge: Comparison between achievable dose distributions using modern, robust optimization of IMPT for high dose per fraction SBRT regimens for the prostate has not been previously investigated. PMID- 29436855 TI - Anthropogenic changes of nitrogen loads in a small river: external nutrient sources vs. internal turnover processes. AB - Anthropogenic nutrient inputs increase the N-load in many aquatic systems, leading to eutrophication and potential changes of biological N-retention capacity. In this study, nitrate inputs in a small river were investigated along a gradient of anthropogenic influence. We aimed to determine changes in nitrate load and isotope signatures in the water column and to identify the anthropogenic influence on biological nitrogen assimilation and nitrification or denitrification in sediments. In seasonal sampling campaigns, we analysed dissolved inorganic nitrogen concentrations, and stable isotopes of nitrate. To differentiate rates of nitrate production and consumption in the pristine vs. agricultural river section, intact sediment cores were incubated with 15N labelled nitrate. delta15N values of nitrate in the pristine river section were low, reflecting natural sources, but, as expected, increased with nitrate concentration in all seasons along the gradient. In general, nitrate retention and consumption were higher in the anthropogenically impacted than in the pristine river section, and nitrate consumption exceeded production. In addition to our measurements, modelled results also show that even in a small river, the anthropogenically enhanced consumption capacity is overwhelmed by surplus N inputs, and nitrate consumption cannot increase in turn with external loads. PMID- 29436853 TI - Electrophysiological response during auditory gap detection: Biomarker for sensory and communication alterations in autism spectrum disorder? AB - Sensory symptoms, including auditory processing deficits, are common in autism spectrum disorder (ASD). Processing of temporal aspects of auditory input is understudied; yet, deficits in this domain could contribute to language-related impairments. In children with ASD and well-matched controls, this study examined electrophysiological response to silent gaps in auditory stimuli. Results revealed attenuated amplitude of the P2 event-related potential (ERP) component in ASD. The P2 amplitude reduction was also associated with sensory, language, and diagnostic features. These results suggest that neural response during auditory gap detection is a promising ASD biomarker that could be useful for stratifying subgroups and evaluating treatment response. PMID- 29436854 TI - Feasibility of event-related potential (ERP) biomarker use to study effects of mother's voice exposure on speech sound differentiation of preterm infants. AB - Atypical maturation of auditory neural processing contributes to preterm-born infants' language delays. Event-related potential (ERP) measurement of speech sound differentiation might fill a gap in treatment-response biomarkers to auditory interventions. We evaluated whether these markers could measure treatment effects in a quasi-randomized prospective study. Hospitalized preterm infants in passive or active, suck-contingent mother's voice exposure groups were not different at baseline. Post-intervention, the active group had greater increases in/du/-/gu/differentiation in left frontal and temporal regions. Infants with brain injury had lower baseline/ba/-/ga/and/du/-/gu/differentiation than those without. ERP provides valid discriminative, responsive, and predictive biomarkers of infant speech-sound differentiation. PMID- 29436856 TI - Chondroitinase ABC for neurological recovery after acute brain injury: systematic review and meta-analyses of preclinical studies. AB - OBJECTIVES: Damage to critical brain regions causes deficits in important neurological functions. Chondroitinase ABC (ChABC) has been shown to promote neuroplasticity and may ameliorate neurological deficits caused by disease or trauma. This systematic review identifies and evaluates preclinical studies of ChABC as a treatment for acute brain injury. METHODS: Four databases were searched for studies relating to ChABC and brain or brain injuries. Controlled studies in mammals with acute brain injuries treated with ChABC were included in meta-analyses of neurobehavioural outcomes. Means and standard deviations from the fifth day of treatment were extracted, and normalised mean differences were calculated. RESULTS: Of 775 identified records, 16 studies administered ChABC after acute brain injury, of which 9 reported neurobehavioural outcomes. The estimated treatment effect on neurological recovery over the duration of included studies was 49.4% (CI: 30.3-68.4% with Hartung-Knapp-Sidik-Jonkman adjustment, p = 0.0002). The mechanisms of action may involve decreasing astroglial scar formation, promoting neuronal sprouting, and selective synaptic strengthening of sprouting neurites and activated neural pathways. CONCLUSIONS: The summary of published evidence suggests that ChABC treatment is effective in improving neurological outcomes in preclinical models of acute brain injury. However, more studies are needed for better assessment of the specific translational potential of ChABC. ABBREVIATIONS: AVM - Arteriovenous Malformation; ChABC - Chondroitinase ABC; CI - Confidence Interval; CSPG - Chondroitin Sulphate Proteoglycans; HKSJ - Hartung-Knapp-Sidik-Jonkman; MCA - Middle Cerebral Artery; NMD - Normalised Mean Difference; NSPC - Neural Stem/Progenitor Cells; PI - Prediction Interval; SD - Standard Deviation; SMD - Standardised Mean Difference; TBI - Traumatic Brain Injury. PMID- 29436858 TI - Kaurene as the major constituent of the essential oils of the narcotic plant, Khat (Catha edulis Forsk). AB - Khat (Catha edulis Forsk) is a narcotic plant which contains significant amounts of amphetamines, like alkaloids. Herein, analysis of the essential oil composition showed that Khat has useful volatile chemicals in addition to its alkaloids. Results indicated that among 35 identified constituents including mono and sesquiterpenes, the diterpene kaurene, comprises the major part of the essential oil, around 50 percent of total. Kaurene is known as a potent biological agent for the treatment of cancer patients. The presence of kaurene at high levels indicates that the essential oil of Catha edulis can potentially be more effectively exploited rather than its narcotic stimulant amphetamine-like alkaloids. PMID- 29436857 TI - Effect of thyme and oregano essential oils on the shelf life of salmon and seaweed burgers. AB - The effect of different essential oils on the quality and shelf life of fish and seaweed burgers during storage was evaluated. For this purpose, thyme and oregano essential oils were selected at a concentration of 0.05% (v/w). Three types of salmon and seaweed burgers were prepared: without essential oil, burgers with red thyme essential oil (0.05% (v/w)) and burgers with oregano essential oil (0.05% (v/w)), which were vacuum packaged and stored at 4 C for 17 days. Physicochemical and microbiological analyses were carried out periodically throughout storage. The addition of both essential oils did not have any effect on the evolution of the pH, the moisture content or texture parameters. Only the thyme essential oil managed to slightly slow down the increase of total volatile basic nitrogen and trimethylamine nitrogen. The samples with oregano essential oil and especially those with thyme essential oil showed minor oxidation. The salmon and seaweed burgers without essential oils and those which contained oregano essential oil showed a faster increase of mesophilic counts than those which had thyme essential oil, but no noticeable improvement was observed in the shelf life of the burgers with thyme essential oil. To improve the shelf life of the fish and seaweed burgers, it would be necessary to increase the concentration of both essential oils. PMID- 29436859 TI - Concomitant administration of resveratrol and insulin protects against diabetes mellitus type-1-induced renal damage and impaired function via an antioxidant mediated mechanism and up-regulation of Na+/K+-ATPase. AB - This study investigated if a combination of resveratrol (RES) and insulin could reverse type 1 diabetic mellitus-induced (T1DM) nephropathy and illustrates mechanism of action. Rats were divided into six groups (n = 10/group) as follows: control, control + RES (20 mg/kg), T1DM, T1DM + RES, T1DM + insulin (1 U/g), and T1DM + RES + insulin and treated for eight weeks. While individual administrations of both drugs significantly but partially restored renal function and cortex architectures, combination therapy of both RES and insulin produced the maximum improvements. Mechanism of actions revealed a synergist effect of both drugs due to hypoglycaemic effect of insulin and the ability of both drugs to increase renal cortex antioxidant enzymes activities, inhibit lipid peroxidation, and up-regulate Na+/K+-ATPase, independent of each others. In conclusion, these data suggest the combined therapy with insulin and RES could provide an excellent combined drug therapy against T1DM-induced nephropathy. PMID- 29436860 TI - Associations of methylenetetrahydrofolate reductase C677T genotype with blood pressure levels in Chinese population with essential hypertension. AB - OBJECTIVE: To confirm the association between baseline blood pressure (BP) levels and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in patients with essential hypertension. METHODS: A total of 347 patients were enrolled from the Dongzhi community in Anhui Province, China. The C677T polymorphism of the MTHFR gene was detected using high-throughput TaqMan allelic discrimination assay. Baseline BP was measured using a standardized mercury gravity monometer. RESULTS: In the whole sample, the frequency of the MTHFR C677T genotypes CC, CT, and TT were 38.6%, 48.1%, and 13.3%, respectively. In a recessive model (CC+CT versus TT genotypes), baseline diastolic blood pressure (DBP) was significantly higher in patients with the TT genotype compared to those with the CT or CC genotypes (P= 0.013). We also divided all patients into three groups based on the tertiles of the baseline BP distribution. Compared to subjects in the lowest tertile of DBP, the adjusted odds of having the TT genotype among subjects in the highest tertile was 2.6 (95% CI: 1.1 to 6.2). However, no significant associations were observed between baseline systolic blood pressure (SBP) and the MTHFR C677T polymorphism. CONCLUSIONS: The MTHFR gene polymorphism could be an important genetic determinant of baseline DBP levels in Chinese essential hypertensive patients. PMID- 29436861 TI - Individual Correlates of Sleep Among Childbearing Age Women in Canada. AB - OBJECTIVE/BACKGROUND: Women of childbearing age (WOCBA) may be at high risk for short or poor sleep. Yet few studies have focused on this population. The study objective was to identify individual correlates of sleep duration and quality among WOCBA. PARTICIPANTS: The sample consisted of 9,749 WOCBA aged 18-44 years from the Canadian Community Health Survey 2011-2014. METHODS: All variables were self-reported. Sleep duration was dichotomized as insufficient (< 7 hr/night) or adequate (>= 7 hr/night). A composite score of sleep quality was dichotomized as having sleeping problems none/little or some/most/all the time. Age, ethnicity, level of education, household income, mood disorders, parity, geographical location, fruit and vegetable (FV) intake, physical activity, smoking and alcohol consumption were tested as correlates of sleep duration or quality using hierarchical logistic regression. RESULTS: Ethnicity, parity, geographical location and smoking were correlates of sleep duration; this model discriminated 56.9% of WOCBA. Ethnic minorities, WOCBA with many children, living in urban areas and smoking were associated with lower odds of having adequate sleep duration. Ethnicity, level of education, mood disorders, geographical location, FV intake, and alcohol consumption were correlates of sleep quality; this model discriminated 59.0% of WOCBA. Ethnic minorities, lower level of education, mood disorders, living in urban areas, low FV intake, and alcohol consumption were associated with lower odds of having quality sleep. CONCLUSIONS: Some WOCBA may be more at risk for short or poor sleep based on their demographics and health behaviors. This can be used to identify which WOCBA are most in need of sleep interventions. PMID- 29436862 TI - Differentiation of isomeric haloanilines by tosylation in combination with electrospray ionization mass spectrometry. AB - Differentiation of the isomeric haloanilines still remains a challenging and necessary analytic task due to their identical retention time in chromatography and similar mass spectra. In this work, p-tosylation of haloanilines by reaction of haloanilines with p-toluenesulfonyl chloride resulted in the corresponding N tosyl haloanilines. Fragmentation of protonated N-tosyl haloanilines in electrospray ionization tandem mass spectrometry (ESI-MS/MS) mainly resulted in tosyl cation, haloaniline radical cation, and halohydroxyaniline radical cation. The MS/MS of the three group isomeric derivatives showed significant difference in abundance distribution of these product ions, respectively. Theoretical calculations showed that the stability of the ion-neutral complex (INC) is a key factor influencing the relative intensity of the product ions. The three group isomeric derivatives were also separated by high performance liquid chromatograph (HPLC) at conventional conditions. p-Tosylation combined tandem MS (or HPLC) technique were carried out to realize the differentiation of isomeric haloanilines. PMID- 29436863 TI - Proinsulin-expressing dendritic cells in type 2 neuropathic diabetic patients with and without foot lesions. AB - Diabetic neuropathy is the most common complication of diabetes and is frequently associated with foot ischemia and infection, but its pathogenesis is controversial. We hypothesized that proinsulin expression in peripheral blood mononuclear cells is a process relevant to this condition and could represent a link among hyperglycemia, nerve susceptibility, and diabetic foot lesions. We assessed proinsulin expression by using flow cytometry in dendritic cells from control participants and patients with type 2 diabetes with or without peripheral neuropathy or accompanied by diabetic foot. Among 32 non-neuropathic and 120 neuropathic patients with type 2 diabetes, we performed leg electromyography and found average sensory sural nerve conduction velocities of 48 +/- 4 and 30 +/- 4 m/s, respectively ( P < 0.03). Of those with neuropathy, 42 were without lesions, 39 had foot lesions, and 39 had neuroischemic foot lesions (allux oximetry <30 mmHg). In this well-defined diabetic population, but not in nondiabetic participants, a progressively increasing level of peripheral blood dendritic cell proinsulin expression was detected, which directly correlated with circulating TNF-alpha levels ( P < 0.002) and multiple conduction velocities of leg nerves ( P < 0.05). These results are consistent with the hypothesis that, in type 2 diabetes, proinsulin-expressing blood cells, possibly via their involvement in innate immunity, may play a role in diabetic peripheral neuropathy and foot lesions.-Sambataro, M., Sambado, L., Trevisiol, E., Cacciatore, M., Furlan, A., Stefani, P. M., Seganfreddo, E., Durante, E., Conte, S., Della Bella, S., Paccagnella, A., dei Tos, A. P. Proinsulin-expressing dendritic cells in type 2 neuropathic diabetic patients with and without foot lesions. PMID- 29436864 TI - Mental health literacy as theory: current challenges and future directions. AB - BACKGROUND: Mental health literacy (MHL) is one increasingly researched factor thought to influence mental health behaviors. Researchers have argued for expanding the definition of MHL to include additional constructs, but no consensus has yet been reached on what constructs should be included as part of MHL. AIMS: The purpose of this paper is to (i) elucidate how the expansion of the MHL construct has impeded the growth of MHL research and (ii) through the lens of construct and theory development, highlight how these challenges might be remedied. METHODS: An inclusive search of the literature was undertaken to identify MHL studies. The principles of construct and theory development guided a critical analysis of MHL. RESULTS: The review of the literature found that MHL violates many principles of what constitutes an acceptable construct definition. To address these concerns, we proposed conceptualizing MHL as a theory and recommended principles of theory development that should be taken into consideration. CONCLUSION: A theory of MHL can guide future researchers to clearly delineate important constructs and their interrelationships. For practitioners, a theory of MHL can help inform how to improve MHL at both the individual and community level. PMID- 29436865 TI - Sexual function and quality of life of women adopting the levonorgestrel releasing intrauterine system (LNG-IUS 13.5 mg) after abortion for unintended pregnancy. AB - PURPOSE: The aim of the study was to investigate the impact of the long-acting reversible contraception (LARC) levonorgestrel-releasing intrauterine system (LNG IUS 13.5 mg) on sexual function and quality of life (QoL) in women after having undergone abortion for unintended pregnancy. METHODS: In a prospective controlled study, 128 women aged 16-35 years received counseling to adopt LNG-IUS contraception after termination of pregnancy. The Visual Analog Scale (VAS), the Short Form-36 questionnaire (SF-36), the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) were used to investigate, respectively, pelvic pain levels, QoL, sexual function and sexual distress of these women at baseline (T0) and at 6 (T1) and 12 (T2) months after LNG-IUS placement. RESULTS: Sixty-six (51.6%) women adopted a SARC method, mainly because of the cost of the LNG-IUS. They constituted the control group. The study group consisted of 62 (48.4%) women. Improvement of QoL was observed at T1 (p < .05) and T2 (p < .01). Moreover, sexual function improved and dyspareunia decreased over the study period compared to baseline (p < .001). Dysmenorrhea measured by VAS improved at T1 and at T2 (p < .001). The women of the control group did not experience statistically significant changes at T1 and T2 compared to T0 (p = NS). CONCLUSIONS: Women who underwent termination of pregnancy experienced positive changes in QoL and sexual function during LNG-IUS use. These results have to be confirmed in larger studies. However, not all women could adopt the LNG-IUS because of the cost of the contraceptive. PMID- 29436868 TI - Effect of oxygen therapy on chest pain in patients with ST elevation myocardial infarction: results from the randomized SOCCER trial. AB - OBJECTIVE: Oxygen (O2) have been a cornerstone in the treatment of acute myocardial infarction. Studies have been inconclusive regarding the cardiovascular and analgesic effects of oxygen in these patients. In the SOCCER trial, we compared the effects of oxygen treatment versus room air in patients with ST-elevation myocardial infarction (STEMI). There was no difference in myocardial salvage index or infarct size assessed with cardiac magnetic resonance imaging. In the present subanalysis, we wanted to evaluate the effect of O2 on chest pain in patients with STEMI. DESIGN: Normoxic patients with first time STEMI were randomized in the ambulance to standard care with 10 l/min O2 or room air until the end of the percutaneous coronary intervention (PCI). The ambulance personnel noted the patients' chest pain on a visual analog scale (VAS; 1-10) before randomization and after the transport but before the start of the PCI, and also registered the amount of morphine given. RESULTS: 160 patients were randomized to O2 (n = 85) or room air (n = 75). The O2 group had a higher median VAS at randomization than the air group (7.0 +/- 2.3 vs 6.0 +/- 2.9; p = .02) and also received a higher median total dose of morphine (5.0 mg +/- 4.4 vs 4.0 mg +/ 3.7; p = .02). There was no difference between the O2 and air groups in VAS at the start of the PCI (4.0 +/- 2.4 vs 3.0 +/- 2.5; p = .05) or in the median VAS decrease from randomization to the start of the PCI (-2.0 +/- 2.2 vs -1.0 +/- 2.9; p = .18). CONCLUSION: Taken together with previously published data, these results do not support a significant analgesic effect of oxygen in patients with STEMI. European Clinical Trials Database (EudraCT): 2011-001452-11. ClinicalTrials.gov Identifier: NCT01423929. PMID- 29436869 TI - Quality of web-based family-building information for LGBTQ individuals. AB - OBJECTIVE: The number of patients who seek health information on the internet is increasing. Rates are particularly high among lesbian, gay, bisexual, transgender and queer (LGBTQ) individuals, due to health care barriers. The aim of this study was to evaluate the quality and inclusivity of web-based information pertaining to LGBTQ family building. METHODS: The first 100 US-based websites pertaining to LGBTQ family building were identified through a terminology-based internet search. After eliminating 45 websites, 55 websites were found to be eligible. The 2016 Website Information Reliability Evaluation Instrument (of the Office of Disease Prevention and Health Promotion, US Department of Health and Human Services) was used to analyse the quality of information on each website. Websites were analysed for inclusivity of important topics surrounding LGBTQ family building. RESULTS: A total of 46 websites (83.6%) belonged or were related to reproductive services and served as advertisements for their respective owners; nine websites (16.4%) belonged to third parties. No website met more than four of the six major reliability criteria, and 42 websites (76.4%) met only one or two of the six major reliability criteria. When inclusivity was considered, 29 websites (52.7%) mentioned options for transgender individuals and nine websites (16.4%) mentioned adoption. CONCLUSIONS: There is a lack of reliable web-based information for LGBTQ family building and a need for improvement in quality and scope. Improvements could lead to a shift in reproductive health care towards better inclusion of and catering to LGBTQ individuals. PMID- 29436870 TI - Libre chercheur: Hormones, DHEA, RU486, Alzheimer ... Les reponses d'un grand savant Francais by Etienne-Emile Baulieu with Caroline Fourest (2013) Flammarion, Paris. PMID- 29436871 TI - Erratum. PMID- 29436872 TI - Renal transplantation in anti-neutrophil cytoplasmic antibody vasculitis. AB - INTRODUCTION: Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has the propensity to acquire a devastating disease course. Despite the advances in therapeutics, a significant proportion of patients progress to end-stage renal disease (ESRD). Renal transplantation is being increasingly employed in this population, with gradual improvement in outcomes over the years, however, recurrence of disease requires constant surveillance and is associated with graft failure. Areas covered: A structured literature search in PubMed and Medline and abstracts of international conferences was performed to identify cases and cohorts of AAV patients who had undergone renal transplantation for ESRD. The primary objective was to describe the long-term allograft and patient survival and to reflect on current trends in transplantation in AAV and provide recommendations for the phases of pre- and post-transplantation. Expert commentary: Renal transplantation is the treatment of choice for AAV patients with ESRD. The risk of relapse is low with modern immunosuppressive regimes employing mycophenolate mofetil and tacrolimus. It is recommended that the vasculitis be in clinical remission for 12 months prior to transplantation. Although ANCA positivity is not a contraindication for renal transplantation, these patients should be monitored closely for vasculitis relapse post transplant. PMID- 29436874 TI - The influence of fiber dispersion on the mechanical response of aortic tissues in health and disease: a computational study. AB - Changes in the structural components of aortic tissues have been shown to play a significant role in the pathogenesis of aortic degeneration. Therefore, reliable stress analyses require a suitable and meaningful constitutive model that captures micro-structural changes. As recent data show, in-plane and out-of-plane collagen fiber dispersions vary significantly between healthy and aneurysmatic aortic walls. The aim of this study is to computationally investigate the influence of fiber dispersion on the mechanical response of aortic tissues in health and disease. In particular, the influence of three different fiber dispersions is studied: (i) non-rotationally symmetric dispersion, the most realistic assumption for aortic tissues; (ii) transversely isotropic dispersion, a special case; (iii) perfectly aligned fibers (no dispersion in either plane), another special case. Explicit expressions for the stress and elasticity tensors as needed for the implementation in a finite element code are provided. Three representative numerical examples are studied: planar biaxial extension, inflation of residually stressed and pre-stretched aortic segments and inflation of an idealized abdominal aortic aneurysm (AAA) geometry. For the AAA geometry the case of isotropic dispersion is additionally analyzed. Documented structural and mechanical parameters are taken from human aortas (healthy media/adventitia and AAA). The influence of fiber dispersions upon magnitudes and distributions of stresses and deformations are presented and analyzed. Stresses vary significantly, especially in the AAA case, where material stiffening is significantly influenced by fiber dispersion. The results highlight the need to incorporate the structural differences into finite element simulations to obtain more accurate stress predictions. Additionally, results show the capability of one constitutive model to represent different scenarios of aortic micro structures allowing future studies of collagen reorientation during disease progression. PMID- 29436875 TI - Synthesis, in vitro characterization, and anti-tumor effects of novel polystyrene poly(amide-ether-ester-imide) co-polymeric micelles for delivery of docetaxel in breast cancer in Balb/C mice. AB - OBJECTIVE: The goal of the present work was to make novel co-polymeric micellar carriers for the delivery of docetaxel (DTX). SIGNIFICANCE: Co-polymeric micelles can not only solubilize DTX and eliminate the need for toxic surfactants to dissolve it, but also cause passive targeting of the drug to the tumor and reduce its toxic side effects. METHODS: Poly(styrene-maleic acid) (SMA) was conjugated to poly (amide-ether-ester-imide)-poly ethylene glycol (PAEEI-PEG). Copolymer synthesis was proven by Fourier transform infrared (FTIR) and 1H-nuclear magnetic resonance (1H-NMR). The SMA-PAEEI-PEG micelles loaded with DTX were prepared and their critical micelle concentration (CMC), zeta potential, particle size, entrapment efficiency, and their release efficiency were studied. MCF-7 and MDA MB231 breast cancer cells were used to evaluate the cellular uptake and cytotoxicity of the micelles. The antitumor activity of the DTX-loaded nanomicelles was measured in Balb/c mice. RESULTS: The FTIR and HNMR spectroscopy confirmed successful conjugation of SMA and PAEEI-PEG. The drug loading efficiency was in the range of 34.01-72.75% and drug release lasted for 120 h. The CMC value of the micelles was affected by the SMA/PAEEI-PEG ratio and was in the range of 29.85-14.28 ug/ml. The DTX-loaded micelles showed five times more cytotoxicity than the free drug. The DTX loaded micelles were more effective in tumor growth suppression in vivo and the animals showed an enhanced rate of survival. CONCLUSION: The results show that the SMA-PAEEI-PEG micelles of DTX could potentially provide a suitable parenteral formulation with more stability, higher cytotoxicity, and improved antitumor activity. PMID- 29436876 TI - The Relationship between Anxiety, External Structure, Behavioral History and Becoming Locked into Restricted and Repetitive Behaviors in Autism Spectrum Disorder. AB - Restricted and repetitive behaviors (RRBs) are central to the diagnosis of autism spectrum disorder (ASD), yet there remains a paucity of research in this domain. What is clear is that people with ASD are vulnerable to getting locked into rigid patterns of thought and behavior that contribute to a lack of adaptation. This study utilized an online survey to explore the relationship between anxiety, external structure, the measurement of RRBs and behavioral history of being locked into RRBs. A significant relationship was identified between level of anxiety and a history of becoming locked into RRBs. The likelihood of becoming locked into RRBs increased at times of decreased external structure in the routine of people with ASD. PMID- 29436877 TI - What is the Psychosocial Impact of Disasters? A Meta-Analysis. AB - The psychosocial impact concept improves the understanding of the effects of disasters on people and communities. However, its definition is not clear. This work explores consistencies between studies (k = 21) that refer to the psychosocial impact of disasters by way of a meta-analytic synthesis. This synthesis indicates that people are more prone to illness when they are exposed to a disaster, and less when they are protected (OR = 2.737). Please check the change conveys the intended meaning or amend Nevertheless, there are no differences in healthy responses, regardless of how protected or exposed they are (OR = 1.053). Finally, a model is proposed to explain four types of psychosocial impact: resilient, traumatic, sensitive, witness. PMID- 29436878 TI - Development of a University Campus Healthy Sleep Promotion Program. AB - This article provides a preliminary evaluation of a campus sleep health program for undergraduate university students. In this study, 5 focus groups with 38 undergraduates assessed perceptions about sleep in relationship to college experiences. Additionally, 35 undergraduate students participated in campus sleep improvement workshops, and completed a brief self-report survey before and after the workshop. Results showed five themes emerged from focus groups: (a) Sleep and its impact on academics, (b) Understanding of the importance of sleep, (c) Procrastination and its impact on sleep, (d) Stress, and (e) Sleep and extracurricular/social activities. Based on self-report surveys, there was no improvement in perceived sleep importance, but perceived sleep confidence of undergraduate student-participants increased significantly after the workshop. The sleep health program for undergraduates showed promising results, and should be evaluated using a larger, more rigorous design in future studies. PMID- 29436879 TI - An Exploration of the Perspectives of Associate Nurse Unit Managers Regarding the Implementation of Smoke-free Policies in Adult Mental Health Inpatient Units. AB - CONTEXT: In Adult Mental Health Inpatient Units, it is not unexpected that leadership of Associate Nurse Unit Managers contributes to successful implementation of smoke-free policies. AIM: In light of challenges facing mental health nursing, and limited research describing their leadership and the role it plays in addressing smoke-free policy implementation, the aim of this study is to explore Associate Nurse Unit Managers perspectives' regarding the implementation of smoke-free policies, which were introduced on 1 July, 2015. DESIGN, SETTING, PARTICIPANTS: Individual in-depth semi-structured interviews were undertaken six months post the implementation of smoke-free policies. In this qualitative descriptive study, six Associate Nurse Unit Managers working in a Victorian public Adult Mental Health Inpatient Unit, were asked eight questions which targeted leadership and the implementation and enforcement of smoke-free policies. Associate Nurse Unit Managers provide leadership and role modeling for staff and they are responsible for setting the standards that govern the behavior of nurses within their team. All participants interviewed believed that they were leaders in the workplace. MAIN OUTCOMES: Education and consistency were identified as crucial for smoke-free policies to be successful. Participants acknowledged that the availability of therapeutic interventions, staff resources and the accessibility of nicotine replacement therapy were crucial to assist consumers to remain smoke-free while on the unit. CONCLUSION: The findings from this research may help to improve the understanding of the practical challenges that Associate Nurse Unit Manager's face in the implementation of smoke-free policies with implications for policies, nursing practice, education and research. PMID- 29436880 TI - Cotard's Syndrome Triggered by Fear in a Patient with Intellectual Disability: Causal or Casual Link? AB - Cotard's syndrome is a neuropsychiatric disease characterized by a variety of nihilistic delusions, commonly associated with several psychotic and major affective disorders, and neurological diseases, including stroke, dementia, and mental retardation. A 39-year-old male with mental retardation developed Cotard's syndrome, following an important episode of fear. During admission to our neurological unit, the patient underwent an accurate assessment, including neuroradiological, clinical, and neuropsychological examinations. At the psychiatric evaluation, he presented nihilistic delusions, in which he negated the existence of his body parts and the existence of his family members. The neuropsychological assessment ruled out other possible causes of misidentification, including the post-traumatic stress disorder. Thus, since also organic causes of Cotard's syndrome were excluded, the correlation between fear and the syndrome has been postulated and the patient opportunely treated, using a multidisciplinary approach. Our case suggests that in predisposed individuals negative emotions, including fear, may lead to delusional syndromes. PMID- 29436881 TI - Psychiatric Nurses' Attitudes Towards Violent Behaviour: A Brazilian Study. AB - This study examines nurses' attitudes towards violent behaviour and the management of aggressiveness. A convenience sample of 185 nurses working in psychiatric urgent care and emergency services in Brazil responded to the MAVAS BR. The results show that nurses' attitudes are more reflective of the external and situational models of violent behaviour and the use of control methods to manage aggressiveness. The mapping of this phenomenon using the same tools in a different context from those traditionally studied while observing similar results suggests a pattern of attitudes towards violent behaviour and the management of aggressiveness among nurses around the world. PMID- 29436882 TI - Type-D Personality and Elevated Psychological Symptoms In Early Adjustment of Severe Burn Injury Patients. AB - Severe burn injuries are highly traumatic requiring lengthy recovery. High levels of distress in the early stages of treatment have been associated with poor physical and psychosocial recovery outcomes. Identifying traits relating to distress and personal coping styles may aid screening. Type-D, or 'distressed', personality may be such a trait. Type-D personality refers to an ongoing personality organization defined by a tendency to experience greater negative emotions and thoughts while simultaneously socially inhibiting their expression (Denollet et al., 1996 . Type-D has been linked to poor health outcomes in those with cardiovascular disease as well as other populations and has been found to be associated with elevated psychological symptoms. Currently, there are no investigations in the literature looking at Type-D in the severe burns injury population. This study aimed to investigate Type-D in severe burn injury patients, specifically regarding the presence of psychological symptoms in early treatment, using data gathered during a pilot study conducted at a severe burn injury unit. The DS-16, Davidson Trauma scale and Depression Anxiety and Stress Scale scores were analysed along with demographic and clinical data in 54 participants (40 males, 14 females). Participants who were found to have Type-D displayed significantly higher levels of psychopathology. Additionally, Type-D was found to be a significant predictor of psychological symptoms. PMID- 29436883 TI - Academic and non-academic predictors of student psychological distress: the role of social identity and loneliness. AB - BACKGROUND: University students experience high rates of stress and mental illness; however, few studies have comprehensively examined the impact of academic and non-academic stressors on student mental health. Similarly, there has been little focus on the role of social groups in protecting against mental distress in this young adult group. AIM: To identify the key social determinants of mental health symptoms in a student population. METHODS: Using an online survey, we administered measures of social connectedness and mental health symptoms alongside academic and non-academic stressors to a large sample of UK university students. RESULTS: Loneliness was the strongest overall predictor of mental distress, while assessment stress was the most important academic predictor. Strong identification with university friendship groups was most protective against distress relative to other social identities, and the beneficial impact of identification on symptoms was mediated by reduced loneliness. CONCLUSIONS: The study highlights the benefits of establishing strong social connections at university and the importance of minimising stress associated with assessment tasks. PMID- 29436884 TI - Standardizing Data and HIM Practices for Interoperability. PMID- 29436885 TI - Cerebral perfusion and compensatory blood supply in patients with recent small subcortical infarcts. AB - Hypoperfusion is the typical perfusion pattern associated with recent small subcortical infarcts of the brain, but other perfusion patterns may be present in patients with these infarcts. Using CT perfusion, we studied 67 consecutive patients who had a small subcortical infarct at a follow-up MRI study to investigate the correlation between the perfusion pattern and the clinical and radiological course. On CT perfusion map analysis, 51 patients (76%) had focal hypoperfusion, 4 patients (6%) had hyperperfusion and the remaining 12 patients (18%) showed no abnormalities. On dynamic sequential imaging analysis obtained from the source perfusion images, 32 patients (48%) had a sustained hypoperfusion pattern, 11 patients (16%) had a reperfusion pattern, and 18 patients (27%) had a delayed compensation pattern. Systolic blood pressure was higher in patients with sustained hypoperfusion although the perfusion pattern was independent of the final volume of infarction. These results reinforce the notion that mechanisms other than hypoperfusion are at play in patients with small subcortical infarcts including the intervention of compensatory sources of blood flow. The ultimate clinical significance of these perfusion patterns remains to be determined in larger series of patients assessed longitudinally. PMID- 29436886 TI - Anti-Xa based dose changes during low molecular weight heparin anticoagulation for mechanical prosthetic heart valves during pregnancy. PMID- 29436887 TI - Machine learning in autistic spectrum disorder behavioral research: A review and ways forward. AB - Autistic Spectrum Disorder (ASD) is a mental disorder that retards acquisition of linguistic, communication, cognitive, and social skills and abilities. Despite being diagnosed with ASD, some individuals exhibit outstanding scholastic, non academic, and artistic capabilities, in such cases posing a challenging task for scientists to provide answers. In the last few years, ASD has been investigated by social and computational intelligence scientists utilizing advanced technologies such as machine learning to improve diagnostic timing, precision, and quality. Machine learning is a multidisciplinary research topic that employs intelligent techniques to discover useful concealed patterns, which are utilized in prediction to improve decision making. Machine learning techniques such as support vector machines, decision trees, logistic regressions, and others, have been applied to datasets related to autism in order to construct predictive models. These models claim to enhance the ability of clinicians to provide robust diagnoses and prognoses of ASD. However, studies concerning the use of machine learning in ASD diagnosis and treatment suffer from conceptual, implementation, and data issues such as the way diagnostic codes are used, the type of feature selection employed, the evaluation measures chosen, and class imbalances in data among others. A more serious claim in recent studies is the development of a new method for ASD diagnoses based on machine learning. This article critically analyses these recent investigative studies on autism, not only articulating the aforementioned issues in these studies but also recommending paths forward that enhance machine learning use in ASD with respect to conceptualization, implementation, and data. Future studies concerning machine learning in autism research are greatly benefitted by such proposals. PMID- 29436888 TI - Treatment of amblyopia: Part 2. PMID- 29436889 TI - Improving the Knowledge, Attitudes, and Practices of Mental Health Professionals Regarding Dual Diagnosis Treatment - a Mixed Methods Study of an Intervention. AB - This study examined an intervention, which aimed at improving the dual diagnosis treatment at eight Danish mental health centres. The intervention included training in dual diagnosis treatment to program champions who were intended to implement at their workplace the knowledge gained from training. The study used mixed methods (questionnaires, interviews, and field observations) to examine whether there was a change in the knowledge, attitudes, and practices of the colleagues of the program champions following the intervention. Results showed that the intervention overall yielded improvement in knowledge and attitudes, while the impact on assessment and treatment practices was limited. Possible factors that might have affected the implementation of the intervention as well as the weaknesses of the intervention and the study are discussed. PMID- 29436891 TI - Identification of UGTs and BCRP as potential pharmacokinetic determinants of the natural flavonoid alpinetin. AB - Alpinetin is a natural flavonoid showing a variety of pharmacological effects such as anti-inflammatory, anti-tumor and hypolipidemic activities. Here, we aim to determine the roles of UDP-glucuronosyltransferases (UGTs) and breast cancer resistance protein (BCRP) in disposition of alpinetin. Glucuronidation potential of alpinetin was evaluated using pooled human liver microsomes (pHLM), pooled human intestine microsomes (pHIM) and expressed UGT enzymes supplemented with the cofactor UDPGA. Activity correlation analyses with a bank of individual HLMs were performed to identify the main contributing UGT isozymes in hepatic glucuronidation of alpinetin. The effect of BCRP on alpinetin disposition was assessed using HeLa cells overexpressing UGT1A1 (HeLa1A1) cells. Alpinetin underwent extensive glucuronidation in pHLM and pHIM, generating one glucuronide metabolite. Of 12 test UGT enzymes, UGT1A3 was the most active one toward alpinetin with an intrinsic clearance (CLint = Vmax/Km) value of 66.5 MUl/min/nmol, followed by UGT1A1 (CLint = 48.6 MUl/min/nmol), UGT1A9 (CLint = 21.0 MUl/min/nmol), UGT2B15 (CLint = 16.7 MUl/min/nmol) and UGT1A10 (CLint = 1.60 MUl/min/nmol). Glucuronidation of alpinetin was significantly correlated with glucuronidation of estradiol (an activity marker of UGT1A1), chenodeoxycholic acid (an activity marker of UGT1A3), propofol (an activity marker of UGT1A9) and 5-hydroxyrofecoxib (an activity marker of UGT2B15), confirming the important roles of UGT1A1, UGT1A3, UGT1A9 and UGT2B15 in alpinetin glucuronidation. Inhibition of BCRP by its specific inhibitor Ko143 significantly reduced excretion of alpinetin glucuronide, leading to a significant decrease in cellular glucuronidation of alpinetin. Our data suggest UGTs and BCRP as two important determinants of alpinetin pharmacokinetics. PMID- 29436892 TI - Expression and activities of sulfotransferase in rat brain. AB - Sulfotransferase (SULT) has been found in the brain; however, the details of its function remain unclear. The present study aimed to elucidate the regional differences in the expression of SULT1 and SULT2 mRNA and SULT activities in the eight functional regions of the rat brain (cerebellum, cortex, hippocampus, medulla oblongata, midbrain, olfactory bulb, striatum, and thalamus). All SULT1 isoforms were detected in the medulla oblongata and thalamus. SULT2A1 mRNA was not observed in any of the eight regions, whereas SULT2B1a and SULT2B1b were found in all regions. The SULT2B1b mRNA expression level in the medulla oblongata was 1.7-fold higher than that in the liver. The sulfonation of p-nitrophenol and pregnenolone was detected in all regions. The kinetics of p-nitrophenol sulfonation in the cerebellum fitted to the substrate inhibition model (Km = 37.6 nM, Vmax = 2.72 pmol/min/mg, Vinh = 1.60 pmol/min/mg, and Ki = 0.87 MUM). The pregnenolone sulfonation also exhibited substrate inhibition kinetics (Km = 0.99 MUM, Vmax = 1.53 pmol/min/mg, and Ki = 54.67 MUM). We clarified that SULT1 and SULT2 were expressed and had metabolizing capacities in the rat brain, suggesting that brain SULTs may be involved in metabolism of endogenous compounds and drugs. PMID- 29436893 TI - A Literature Review on the Experience of Long-Term Mental Illness. AB - PURPOSE: To illuminate long-term experiences of mental illness from both research and autobiographical accounts. DESIGN: A literature review of English-language papers, 1950-2014, relating to the experience of long-term mental illness indexed in AgeInfo, AMED, ASSIA, British Nursing Index (BNI), CINAHL, MEDLINE, PsycEXTRA, and PsychINFO. FINDINGS: Twenty-five research papers and nine autobiographic accounts met the review criteria. Thematic analysis revealed nine themes: fear, explanation seeking, stigma, disability, coping strategies, control, support, change and learning, and life history. Specific gaps of note relate to age differences, acknowledgement of longevity of mental illnesses, and different cultural perspectives. Research Implications: There is an absence of longitudinal studies focused on experiences of long-term mental illness. The considerable length-of-time implicated in the experiences suggests that more individual life experience rather than illness focused studies are needed, enabling a holistic understanding. This includes studies from cultures other than the Western world. Greater transparency is needed in justifying age inclusions or passive exclusion of older peoples' perspectives. PRACTICAL IMPLICATIONS: Knowledge of long-term mental illness experiences is of great importance to mental health practitioners. Evidence-based services cannot be provided if we do not have an holistic understanding of long-term mental illness. Social Implications: This review questions our ability to provide effective support for those experiencing long term mental illness, in particular older people and different cultural perspectives. ORIGINALITY/VALUE: There appear to be no literature reviews that focus on the individual experience of long-term mental illness. It highlights the surprisingly small number of research studies available to inform mental health practitioners. PMID- 29436894 TI - Encountering Ambivalence - A Qualitative Study of Mental Health Nurses' Experiences with Dual Relationships. AB - Nurses are obliged to set professional boundaries in nurse-patient relationships. Relationships with patients that are pursued outside of working hours (dual relationships) are commonly prohibited by legislation and professional codes of ethics, but some nurses still engage in them. A thematic analysis of qualitative interviews revealed that the nurses experienced ambivalence regarding how they see the patients, their assessment of the dual relationships and how people around the nurses react to the relationships. Ambivalence was characterized by contradictory and indeterminate thoughts and attitudes toward patients and dual relationships. Results indicated that dual relationship decisions were complex and highly contextually dependent. PMID- 29436896 TI - The Impact of Combined Music and Tai Chi on Depressive Symptoms Among Community Dwelling Older Persons: A Cluster Randomized Controlled Trial. AB - BACKGROUND: The effectiveness of pharmacological treatment may be limited in older persons. Several studies using Tai Chi or music therapy separately confirmed positive effects in the reduction of depressive symptoms. We conducted a cluster randomized controlled trial to evaluate the possible synergistic effect of combined music and Tai Chi on depressive symptoms. METHODS: One hundred and seven older adults with mild to moderate depressive symptoms were recruited from Ya'an city. Fifty-five participants were cluster randomized to combined music and Tai Chi group for three months, while the other fifty-two individuals were randomized to the control group that entailed routine health education delivered monthly by community nurses. The primary outcome of depressive symptoms was measured with the Geriatric Depression Scale (GDS) at baseline and monthly for three months. RESULTS: At three-month follow-up, a statistically significant improvement in depressive symptoms was found in the intervention group compared with control group (F(3,315) = 69.661, P < 0.001). Following adjustments for socio-demographic data, the true effect of intervention on depressive symptoms was significant (F = 41.725, P < 0.01, etap2 = 0.574). CONCLUSIONS: Combined music and Tai Chi reduced depressive symptoms among community-dwelling older persons. This represents an economically viable solution to the management of depression in highly populous developing nations. PMID- 29436895 TI - A model to study complement involvement in experimental retinal degeneration. AB - BACKGROUND: The complement system (CS) plays a role in the pathogenesis of a number of ocular diseases, including diabetic retinopathy (DR), glaucoma, uveitis, and age-related macular degeneration (AMD). Given that many of the complex eye-related degenerative diseases have limited treatment opportunities, we aimed to mimic the in vivo retinal degenerative process by developing a relevant co-culture system. METHOD AND MATERIALS: The adult porcine retina was co cultured with the spontaneously arising human retinal pigment epithelial cells-19 (ARPE-19). RESULTS: Inflammatory activity was found after culture and included migrating microglial cells, gliosis, cell death, and CS activation (demonstrated by a minor increase in the secreted anaphylotoxin C3a in co-culture). CS components, including C1q, C3, C4, soluble C5b-9, and the C5a receptor, were expressed in the retina and/or ARPE cells after culture. C1q, C3, and CS regulators such as C4 binding protein (C4BP), factor H (CFH), and factor I (CFI) were secreted after culture. DISCUSSION: Thus, our research indicates that this co-culturing system may be useful for investigations of the CS and its involvement in experimental neurodegenerative diseases. PMID- 29436897 TI - Influence of disulfide bond isoforms on drug conjugation sites in cysteine-linked IgG2 antibody-drug conjugates. AB - Cysteine-linked antibody-drug conjugates (ADCs) produced from IgG2 monoclonal antibodies (mAbs) are more heterogeneous than ADCs generated from IgG1 mAbs, as IgG2 ADCs are composed of a wider distribution of molecules, typically containing 0 - 12 drug-linkers per antibody. The three disulfide isoforms (A, A/B, and B) of IgG2 antibodies confer differences in solvent accessibilities of the interchain disulfides and contribute to the structural heterogeneity of cysteine-linked ADCs. ADCs derived from either IgG2-A or IgG2-B mAbs were compared to better understand the role of disulfide isoforms on attachment sites and distribution of conjugated species. Our characterization of these ADCs demonstrated that the disulfide configuration affects the kinetics of disulfide bond reduction, but has minimal effect on the primary sites of reduction. The IgG2-A mAbs yielded ADCs with higher drug-to-antibody ratios (DARs) due to the easier reduction of its interchain disulfides. However, hinge-region cysteines were the primary conjugation sites for both IgG2-A and IgG2-B mAbs. PMID- 29436898 TI - Attitudes toward Tobacco, Alcohol, and Non-Alcoholic Beverage Advertisement Themes among Adolescent Boys. AB - BACKGROUND: Previous studies have examined what adolescents find appealing in tobacco and alcohol advertisements and how different themes in advertisements are used to manipulate consumer behaviors. Yet, we know little about the relationship between the themes portrayed in advertisements and youth attitudes towards those themes. OBJECTIVES: This study compared attitudes towards advertisements for different consumer products in a sample of urban and rural adolescent boys in order to examine how key marketing themes impact adolescent attitudes towards those advertisements. METHODS: Participants were 11- to 16-year-old boys (N = 1220) residing in either urban or rural Ohio Appalachian counties. Each participant viewed five print advertisements (one each for cigarettes, electronic cigarettes (e-cigarettes), smokeless tobacco (SLT), non-alcoholic beverages, and alcohol), presented in a random order, for eight seconds each. All advertisements had appeared in magazines that adolescent males commonly read. Attitudes towards each of the five advertisements were assessed. The advertisements were then coded for the presence of various themes, including social acceptance and masculinity. Analyses were conducted to determine associations between advertisement type and the attitude measure, and between the presence of a theme and the attitude measure. RESULTS: Overall, participants preferred non-tobacco advertisements to tobacco advertisements, rural participants had less positive attitudes and participants who had peers who used tobacco had more positive attitudes. Social acceptance and entertainment themes increased the appeal of SLT advertisements, and sex appeal increased the appeal of e-cigarette advertisements. Conclusions/Importance: Findings suggest that advertisements that promote the social nature of use in SLT advertisements may be of particular concern for their influence on adolescent boys. PMID- 29436899 TI - The capsule of Cryptococcus neoformans. AB - The capsule of Cryptococcus neoformans is its dominant virulence factor and plays a key role in the biology of this fungus. In this essay, we focus on the capsule as a cellular structure and note the limitations inherent in the current methodologies available for its study. Given that no single method can provide the structure of the capsule, our notions of what is the cryptococcal capsule must be arrived at by synthesizing information gathered from very different methodological approaches including microscopy, polysaccharide chemistry and physical chemistry of macromolecules. The emerging picture is one of a carefully regulated dynamic structure that is constantly rearranged as a response to environmental stimulation and cellular replication. In the environment, the capsule protects the fungus against desiccation and phagocytic predators. In animal hosts the capsule functions in both offensive and defensive modes, such that it interferes with immune responses while providing the fungal cell with a defensive shield that is both antiphagocytic and capable of absorbing microbicidal oxidative bursts from phagocytic cells. Finally, we delineate a set of unsolved problems in the cryptococcal capsule field that could provide fertile ground for future investigations. PMID- 29436900 TI - A fungus among us: The emerging opportunistic pathogen Candida tropicalis and PKA signaling. PMID- 29436904 TI - PDAs for Oncologists. PMID- 29436902 TI - Both live and dead Enterococci activate Caenorhabditis elegans host defense via immune and stress pathways. AB - The innate immune response of the nematode Caenorhabditis elegans has been extensively studied and a variety of Toll-independent immune response pathways have been identified. Surprisingly little, however, is known about how pathogens activate the C. elegans immune response. Enterococcus faecalis and Enterococcus faecium are closely related enterococcal species that exhibit significantly different levels of virulence in C. elegans infection models. Previous work has shown that activation of the C. elegans immune response by Pseudomonas aeruginosa involves P. aeruginosa-mediated host damage. Through ultrastructural imaging, we report that infection with either E. faecalis or E. faecium causes the worm intestine to become distended with proliferating bacteria in the absence of extensive morphological changes and apparent physical damage. Genetic analysis, whole-genome transcriptional profiling, and multiplexed gene expression analysis demonstrate that both enterococcal species, whether live or dead, induce a rapid and similar transcriptional defense response dependent upon previously described immune signaling pathways. The host response to E. faecium shows a stricter dependence upon stress response signaling pathways than the response to E. faecalis. Unexpectedly, we find that E. faecium is a C. elegans pathogen and that an active wild-type host defense response is required to keep an E. faecium infection at bay. These results provide new insights into the mechanisms underlying the C. elegans immune response to pathogen infection. PMID- 29436901 TI - An anti-TL1A antibody for the treatment of asthma and inflammatory bowel disease. AB - TL1A is an attractive therapeutic target for the treatment of mucosal inflammation associated with inflammatory bowel disease (IBD) and asthma. Blockade of the TL1A pathway has been shown to reduce inflammatory responses while leaving baseline immunity intact, and to be beneficial in animal models of colitis and asthma. Given the therapeutic potential of blocking this pathway in IBD and asthma, we developed C03V, a human antibody that binds with high affinity to soluble and membrane-bound TL1A. In an assay measuring apoptosis induced by exogenous TL1A, C03V was 43-fold more potent than the next most potent anti-TL1A antibody analyzed. C03V also potently inhibited endogenous TL1A activity in a primary cell-based assay. This potency was linked to the C03V-binding epitope on TL1A, encompassing the residue R32. This residue is critical for the binding of TL1A to its signaling receptor DR3 but not to its decoy receptor DcR3, and explains why C03V inhibited TL1A-DR3 binding to a much greater extent than TL1A DcR3 binding. This characteristic may be advantageous to preserve some of the homeostatic functions of DcR3, such as TL1A antagonism. In colitis models, C03V significantly ameliorated microscopic, macroscopic and clinical aspects of disease pathology, and in an asthma model it significantly reduced airways inflammation. Notable in both types of disease model was the reduction in fibrosis observed after C03V treatment. C03V has the potential to address unmet medical needs in asthma and IBD. PMID- 29436905 TI - Podcasts: A New Way for Patients to Receive PLWC Information. PMID- 29436906 TI - Y-ME Empowers Those Living With Breast Cancer. PMID- 29436903 TI - Understanding Mucor circinelloides pathogenesis by comparative genomics and phenotypical studies. AB - The increasing number of infections by species of Mucorales and their high mortality constitute an important concern for public health. This study aims to decipher the genetic basis of Mucor circinelloides pathogenicity, which displays virulence in a strain dependent manner. Assuming that genetic differences between strains may be linked to different pathotypes, we have conducted a study to explore genes responsible for virulence in M. circinelloides by whole genome sequencing of the avirulent strain NRRL3631 and comparison with the virulent strain CBS277.49. This genome analysis revealed 773 truncated, discontiguous and absent genes in the NRRL3631 strain. We also examined phenotypic traits resulting in reduced heat stress tolerance, chitosan content and lower susceptibility to toxic compounds (calcofluor white and sodium dodecyl sulphate) in the virulent strain, suggesting the influence of cell wall on pathogenesis. Based on these results, we focused on studying extracellular protein-coding genes by gene deletion and further pathotype characterization of mutants in murine models of pulmonary and systemic infection. Deletion of gene ID112092, which codes for a hypothetical extracellular protein of unknown function, resulted in significant reduction of virulence. Although pathogenesis is a multifactorial process, these findings highlight the crucial role of surface and secreted proteins in M. circinelloides virulence and should promote further studies of other differential genes. PMID- 29436907 TI - Coding for Smoking and Tobacco-Use Cessation Counseling. PMID- 29436908 TI - American College of Physicians: Sharing Common Goals. PMID- 29436909 TI - Matters of Antitrust: Professional Society Communication With Private Payers. PMID- 29436910 TI - Benchmarking Practice Operations: Results From a Survey of Office-Based Oncology Practices. PMID- 29436911 TI - An Introduction to Advocacy. PMID- 29436912 TI - Physician Payment Policy: An American Pie. PMID- 29436913 TI - Best Practices for State Societies: Working With Community and Academic Oncologists. PMID- 29436914 TI - Guideline Summary: American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor HER2 Testing in Breast Cancer. PMID- 29436915 TI - Joining a Practice As a Shareholder. PMID- 29436916 TI - Middle cerebral artery pressure changes following Pipeline flow diversion. AB - Objective Pipeline embolization devices (PED) are commonly used for endovascular treatment of cerebral aneurysms but changes in intracranial hemodynamics after PED deployment are poorly understood. Here, we assess middle cerebral artery (MCA) and systemic blood pressure before and after PED treatment. Methods Records of patients with cerebral aneurysms proximal to the internal carotid artery terminus treated with PED at our institution between 2015 and 2017 were retrospectively reviewed. Patients were included if ipsilateral MCA pressure measurements were available. Ipsilateral MCA pressure was transduced via the microcatheter before and after PED deployment. Systemic arterial blood pressure was also simultaneously recorded. MCA, systemic blood pressure, and ratios of MCA to systemic blood pressure values were compared before and after treatment among the study cohort using the two-sample paired Student t test. Results Fourteen patients were included. Mean age was 54 years. Among the entire cohort, the ratio of MCA to systemic systolic and mean blood pressure were significantly higher after treatment (respectively 0.76 vs. 0.69, p = 0.01, and 0.94 vs. 0.89, p = 0.03), and the ratio of MCA to systemic diastolic pressures showed an increasing trend (1.08 vs. 1.03, p = 0.09). The percentage of ratio increase was independent of aneurysm size ( r = -0.24, p = 0.42 for systolic ratio; r = -0.09, p = 0.74 for diastolic ratio; r = -0.09; p = 0.76 for mean ratio, respectively). Conclusions Following PED deployment, the ratio of ipsilateral MCA to systemic systolic and mean blood pressure increased. These pressure changes should be further evaluated in a larger sample size. PMID- 29436917 TI - Improved procedural safety following protocol changes for selective ophthalmic arterial infusion of chemotherapy for treatment of ocular retinoblastoma. AB - Purpose The aim was to evaluate the impact of protocol changes in selective ophthalmic arterial infusion (SOAI) for treatment of retinoblastoma (Rb). Methods A retrospective review was completed of 35 patients with Rb who were treated with SOAI between March 2010 and January 2017. Treatment details were tabulated for each SOAI session. SOAI protocol was changed in June 2015, and differences before and after this change were evaluated using two-tail chi-square tests and independent sample t-tests to note any differences in technical complications, need for enucleation, and other outcome variables Results 125 SOAI sessions occurred. No technical complications occurred during the study. Two complications (1.6%) occurred in the postoperative setting. Both complications occurred prior to the change in protocol. Comparing the complication rates between the two protocols showed no significant difference (2.2% versus 0.0%; p = 0.505); 29 of 43 (67.4%) eyes had their vision preserved overall. Conclusions SOAI is an effective treatment for Rb. The refined protocol described herein was associated with fewer complications. PMID- 29436918 TI - The impact of posttraumatic stress symptoms, posttraumatic stress cognitions and interpersonal dependency on psychological co-morbidities following relationship dissolution among college students. AB - BACKGROUND: Relationship dissolution is a distressing experience which can result in the emergence of posttraumatic stress (i.e. post-dissolution PTSS) and other psychological symptoms among college students. Little is known, however, whether posttraumatic stress cognitions and interpersonal dependency may influence the severity of these distress outcomes. AIMS: This study examined the interrelationship between posttraumatic stress symptoms (PTSS), posttraumatic stress cognitions, interpersonal dependency and psychological co-morbidities following relationship dissolution. METHODS: One hundred and eighty college students (M = 69, F = 111) who had experienced relationship dissolution completed the Posttraumatic Stress Diagnostic Scale, Posttraumatic Stress Cognition Inventory, Interpersonal Dependency Inventory and General Health Questionnaire 28. RESULTS: Posttraumatic stress symptoms following relationship dissolution (post-dissolution PTSS) were associated with increased psychological co morbidities. Negative view of oneself and self-blame mediated between PTSS and psychological co-morbidities. Assertion of autonomy moderated the mediational effects of negative cognitions on psychological co-morbidities. CONCLUSIONS: People can develop PTSSs and other psychological symptoms following the dissolution of a romantic relationship. Their concept of self and tendency to seek independence and control played a key role in determining the severity of distress symptoms. PMID- 29436920 TI - Author Correction. PMID- 29436919 TI - Journal Correction. PMID- 29436921 TI - Volumetric and linear measurements of lung tumor burden from non-gated micro-CT imaging correlate with histological analysis in a genetically engineered mouse model of non-small cell lung cancer. AB - In vivo micro-computed tomography (CT) imaging allows longitudinal studies of pulmonary neoplasms in genetically engineered mouse models. Respiratory gating increases the accuracy of lung tumor measurements but lengthens anesthesia time in animals that may be at increased risk for complications. We hypothesized that semiautomated, volumetric, and linear tumor measurements performed in micro-CT images from non-gated scans would have correlation with histological findings. Primary lung tumors were induced in eight FVB mice with two transgenes (FVB/N Tg(tetO-Kras2)12Hev/J; FVB.Cg-Tg(Scgb1a1-rtTA)1Jaw/J). Non-gated micro-CT scans were performed and the lungs were subsequently harvested. In the acquired micro CT scans, measurements of all identified tumors were determined using the following methods: semiautomated three-dimensional (3D) volume, ellipsoid volume, Response Evaluation Criteria in Solid Tumors (RECIST; sum of largest axial (i.e., transverse) diameter from five tumors), sum of largest axial diameters from all tumors (modified RECIST), and average axial diameter. For histological analysis, all five lung lobes were analyzed and the tumor area was summed from measurements made on five histological sections that were 300 um apart from each other (covering a total depth of 1200 um). All micro-CT measurement methods had very strong correlation with histological tumor burden (Pearson's correlation coefficient, 0.87 ( p = 0.0053) -0.98 ( p < 0.0001)). The only methods found to have different correlations were the semiautomated 3D method and the RECIST method (Williams' test for dependent overlapping correlations, p = 0.013). Our results suggest quantification of lung tumor burden from non-gated micro-CT imaging will reflect histological differences between mice and can therefore be used for between-group comparisons or when concerns about systemic health of research animals may limit lengthy anesthetic procedures. PMID- 29436923 TI - Thriving on Pressure: A Factor Mixture Analysis of Sport Performers' Responses to Competitive Encounters. AB - Although considerable research exists on performers' responses to sporting encounters, little is known about thriving in sport contexts. The current study examined if distinct response patterns existed between sport performers who thrived in competitive encounters compared with those who did not. Participants were 535 sport performers (134 women; Mage = 23.60 years, SDage = 8.08; Mcompeting = 11.84 years, SDcompeting = 7.11). Results of factor mixture analysis supported a four-profile solution comprising a thriving group (n = 146), a low functioning group (n = 38), and two groups characterized by scores marginally above (n = 131) and below (n = 209) the sample mean. Profile membership was found to be predicted by personal enablers (viz., personal resilient qualities, psychological skills use) and process variables (viz., basic psychological need satisfaction and frustration, challenge appraisal). This examination of thriving in sport performers offers significant implications for research and practice. PMID- 29436924 TI - Effects of emotional content on working memory capacity. AB - Emotional events tend to be remembered better than neutral events, but emotional states and stimuli may also interfere with cognitive processes that underlie memory performance. The current study investigated the effects of emotional content on working memory capacity (WMC), which involves both short term storage and executive attention control. We tested competing hypotheses in a preregistered experiment (N = 297). The emotional enhancement hypothesis predicts that emotional stimuli attract attention and additional processing resources relative to neutral stimuli, thereby making it easier to encode and store emotional information in WMC. The emotional impairment hypothesis, by contrast, predicts that emotional stimuli interfere with attention control and the active maintenance of information in working memory. Participants completed a common measure of WMC (the operation span task; Turner, M. L., & Engle, R. W. [1989]. Is working memory capacity task dependent? Journal of Memory and Language, 28, 127 154) that included either emotional or neutral words. Results revealed that WMC was reduced for emotional words relative to neutral words, consistent with the emotional impairment hypothesis. PMID- 29436926 TI - Winter Olympic Games: A Lens on the Good and Bad in Top Sport. PMID- 29436922 TI - Breast cancer family history and allele-specific DNA methylation in the legacy girls study. AB - Family history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6-13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (Delta4.9%, P = 0.003) and SEC16B (Delta3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences. PMID- 29436925 TI - Validation of RT-qPCR Approaches to Monitor Pseudomonas syringae Gene Expression During Infection and Exposure to Pattern-Triggered Immunity. AB - Pseudomonas syringae pv. tomato DC3000 is an important model plant pathogen, with a fully annotated genome and multiple compatible plant hosts. Very few studies have examined the regulation of DC3000 gene expression in vivo. We developed a quantitative reverse transcription-polymerase chain reaction assay to monitor transcriptional changes in DC3000 inoculated into Arabidopsis thaliana leaves during disease and exposure to pattern-triggered immunity (PTI). In our approach, bacterial RNA concentrations in total tissue RNA are standardized using P. syringae-specific 16S ribosomal RNA primers. We validated multiple stable reference genes for normalization in calculating the relative expression of genes of interest. We used empirically derived rates of amplification efficiency to calculate relative expression of key marker genes for virulence-associated regulation. We demonstrated that exposure to PTI alters DC3000 expression of type III secretion system, coronatine synthesis genes, and flagellar marker genes. PMID- 29436927 TI - Quantitative analysis of glycation and its impact on antigen binding. AB - Glycation has been observed in antibody therapeutics manufactured by the fed batch fermentation process. It not only increases the heterogeneity of antibodies, but also potentially affects product safety and efficacy. In this study, non-glycated and glycated fractions enriched from a monoclonal antibody (mAb1) as well as glucose-stressed mAb1 were characterized using a variety of biochemical, biophysical and biological assays to determine the effects of glycation on the structure and function of mAb1. Glycation was detected at multiple lysine residues and reduced the antigen binding activity of mAb1. Heavy chain Lys100, which is located in the complementary-determining region of mAb1, had the highest levels of glycation in both stressed and unstressed samples, and glycation of this residue was likely responsible for the loss of antigen binding based on hydrogen/deuterium exchange mass spectrometry analysis. Peptide mapping and intact liquid chromatography-mass spectrometry (LC-MS) can both be used to monitor the glycation levels. Peptide mapping provides site specific glycation results, while intact LC-MS is a quicker and simpler method to quantitate the total glycation levels and is more useful for routine testing. Capillary isoelectric focusing (cIEF) can also be used to monitor glycation because glycation induces an acidic shift in the cIEF profile. As expected, total glycation measured by intact LC-MS correlated very well with the percentage of total acidic peaks or main peak measured by cIEF. In summary, we demonstrated that glycation can affect the function of a representative IgG1 mAb. The analytical characterization, as described here, should be generally applicable for other therapeutic mAbs. PMID- 29436932 TI - John Guyett Scadding's scepticism and pragmatism in addressing treatment uncertainties in clinical practice. PMID- 29436928 TI - Response to articles on mortality in England and Wales. PMID- 29436933 TI - Patient safety after death. PMID- 29436934 TI - Review - Evidence-Informed assessment and practice in child welfare. PMID- 29436936 TI - Erratum. PMID- 29436935 TI - Cell phone-induced ostracism threatens fundamental needs. AB - Cell phones are useful tools with both practical and social benefits. However, using them in the context of face-to-face conversations may be problematic. We consider this behavior a form of ostracism and test its effects on the satisfaction of basic psychological needs for belonging, self-esteem, control, and meaningful existence. In Study 1 participants who recalled a time in which a friend was checking a cell phone during a serious conversation reported feeling more ostracized (ignored and excluded), greater pain, and threat to basic needs than participants recalling a conversation without a cell phone interruption or a control event. Study 2 replicated and extended this effect: Cell phone-induced ostracism's effects were partially mediated by decreased feelings of relational evaluation, and threatened basic needs both in serious and casual conversation contexts. Findings from both studies also indicated that cell phone-induced ostracism hurts women more so than men. PMID- 29436937 TI - Who Are We and Where Are We Headed? PMID- 29436938 TI - Consultation Code Confusion. PMID- 29436939 TI - Feasibility of using low-cost, byproduct materials as sorbents to remove heavy metals from aqueous solutions. AB - This work investigates the sorption of heavy metals by low-cost, byproducts such as charcoal fines (CF), waste green sand, and rice husk ash, in order to examine the feasibility of their use as alternative filter materials for metal contaminated waters. The sorption of Cd, Cu, Pb, and Zn was investigated in batch experiments and sorption isotherms were constructed. The three byproducts showed high metal removal efficiencies (>95%, regardless of the metal concentration tested). The highest metal sorption distribution coefficients were obtained for CF, with maximum values within the 105-106 L kg-1 range for all the target metals. The sorption isotherms were satisfactorily fitted using the Freundlich equation and a linear model, the latter only being valid for initial metal concentrations lower than 0.4 mmol L-1. Sorption reversibility was very low, with desorption yields lower than 2% and desorption distribution coefficients often higher than 106 L kg-1. The values of the sorption and desorption parameters indicated that the use of these materials, especially CF, could constitute a low cost alternative for the remediation of contaminated waters. PMID- 29436940 TI - Biomarker threshold adaptive designs for survival endpoints. AB - Due to the importance of precision medicine, it is essential to identify the right patients for the right treatment. Biomarkers, which have been commonly used in clinical research as well as in clinical practice, can facilitate selection of patients with a good response to the treatment. In this paper, we describe a biomarker threshold adaptive design with survival endpoints. In the first stage, we determine subgroups for one or more biomarkers such that patients in these subgroups benefit the most from the new treatment. The analysis in this stage can be based on historical or pilot studies. In the second stage, we sample subjects from the subgroups determined in the first stage and randomly allocate them to the treatment or control group. Extensive simulation studies are conducted to examine the performance of the proposed design. Application to a real data example is provided for implementation of the first-stage algorithms. PMID- 29436941 TI - Relationship maintenance across platonic and non-platonic cross-sex friendships in emerging adults. AB - Prior research examining maintenance in cross-sex friendships focuses heavily on platonic (i.e., nonsexually active) friendships with limited research examining sexually involved cross-sex friendships (i.e., "friends with benefits relationships"). In this study, we investigated differences in relational maintenance behaviors between sexually and nonsexually active cross-sex friendships types. In an online survey, 531 emerging adult participants from large southwestern and southeastern universities identified either a friends with benefits or platonic opposite sex friendship and then completed items asking them to report the frequency with which they enacted each of 36 relationship maintenance behaviors. Overall, participants involved in casual sex friendships engaged in the least, and those who transitioned from a friends-with-benefits relationship to a romantic relationship engaged in the most frequent relationship maintenance. Platonic friendships employed more frequent maintenance than casual sex friendships but less than either true friends with benefits or participants who transitioned to a romantic relationship. PMID- 29436942 TI - Short Versus Longer Implants in Mandibular Alveolar Ridge Augmented Using Osteogenic Distraction: One-Year Follow-up of a Randomized Split-Mouth Trial. AB - The aim of this study was to evaluate the reliability of 6-mm-long implants compared with normal-length implants placed in a vertical augmented atrophic posterior mandible, supporting cemented single crowns. Thirty-six patients with bilateral posterior edentulous mandible and presenting a bone availability height less than 9 mm from the mandibular canal were enrolled in this study. Patient hemiarches were randomized to receive both 6-mm-long and normal-length implants (10 mm). The technique used for the vertical bone augmentation was the "sandwich" technique, using a bone substitute block as graft. The data outcomes at 1 year postloading follow-up were the loss of implants and complications. Eighty-six 6 mm-long implants and 84 normal implants were inserted. Five short implants and 13 normal implants were lost. In 28 patients, complications occurred, and in 21 cases, the complication was present on the side of the ridge vertical augmentation. From the statistical analysis, the association between the side of the ridge augmentation and the side of occurrence of the complication was statistically significant ( P < .05). The results from this trial suggest short implants can be preferred over vertical bone augmentation for the placement of longer implants in the rehabilitation of edentulous posterior mandibles. These initial results must be confirmed by larger and longer follow-ups of 5 years or more. PMID- 29436943 TI - Heterozygous genotype at codon 129 correlates with prolonged disease course in Heidenhain variant sporadic CJD: case report. AB - Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapid and fatal neurodegenerative disease defined by misfolded prion proteins accumulating in the brain. A minority of cases initially present with posterior cortical atrophy (PCA) phenotype, also known as Heidenhain variant or visual variant CJD. This case provides further evidence of sCJD presenting as PCA. The case also provides evidence for early DWI changes and cortical atrophy over 30 months before neurologic decline and subsequent death. The prolonged disease course correlates with prion protein codon 129 heterozygosity and coexistence of multiple prion strains. PMID- 29436945 TI - Acknowledgment of Authors. PMID- 29436947 TI - Need Coding or Reimbursement Assistance? PMID- 29436948 TI - APPRISE Oncology Program for Erythropoiesis-Stimulating Agents. AB - The FDA recently announced an oncology-specific Risk Evaluation and Mitigation Strategy for erythropoiesis-stimulating agents prescribed under approved indications: The APPRISE program. PMID- 29436946 TI - What Patients Want to Know about Imaging Examinations: A Multiinstitutional U.S. Survey in Adult and Pediatric Teaching Hospitals on Patient Preferences for Receiving Information before Radiologic Examinations. AB - Purpose To identify what information patients and parents or caregivers found useful before an imaging examination, from whom they preferred to receive information, and how those preferences related to patient-specific variables including demographics and prior radiologic examinations. Materials and Methods A 24-item survey was distributed at three pediatric and three adult hospitals between January and May 2015. The chi2 or Fisher exact test (categorical variables) and one-way analysis of variance or two-sample t test (continuous variables) were used for comparisons. Multivariate logistic regression was used to determine associations between responses and demographics. Results Of 1742 surveys, 1542 (89%) were returned (381 partial, 1161 completed). Mean respondent age was 46.2 years +/- 16.8 (standard deviation), with respondents more frequently female (1025 of 1506, 68%) and Caucasian (1132 of 1504, 75%). Overall, 78% (1117 of 1438) reported receiving information about their examination most commonly from the ordering provider (824 of 1292, 64%), who was also the most preferred source (1005 of 1388, 72%). Scheduled magnetic resonance (MR) imaging or nuclear medicine examinations (P < .001 vs other examination types) and increasing education (P = .008) were associated with higher rates of receiving information. Half of respondents (757 of 1452, 52%) sought information themselves. The highest importance scores for pre-examination information (Likert scale >=4) was most frequently assigned to information on examination preparation and least frequently assigned to whether an alternative radiation-free examination could be used (74% vs 54%; P < .001). Conclusion Delivery of pre examination information for radiologic examinations is suboptimal, with half of all patients and caregivers seeking information on their own. Ordering providers are the predominant and preferred source of examination-related information, with respondents placing highest importance on information related to examination preparation. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29436949 TI - Anatomy of a Cancer Center Transaction. AB - The first of a two-part series, this article presents one of two models for structuring a community-based cancer center through collaborative arrangements between oncologists and a hospital. PMID- 29436951 TI - Responding to the Impending Realignment of Medicare Administrative Contractors. PMID- 29436950 TI - Thanks From the Other Side (or I Know Dead People). PMID- 29436953 TI - Developing Effective Communication Skills. PMID- 29436952 TI - Reporting National Drug Code Numbers on Medicaid Claims. PMID- 29436954 TI - American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. PMID- 29436955 TI - Selecting an Electronic Health Record for Your Practice. PMID- 29436956 TI - American Society of Clinical Oncology 2007 Clinical Practice Guideline Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer. PMID- 29436957 TI - Screening New Hires? Identifying Potentially Disruptive Players. PMID- 29436958 TI - The Internet Immigrant. PMID- 29436959 TI - Cancer Care Ontario and American Society of Clinical Oncology Adjuvant Chemotherapy and Adjuvant Radiation Therapy for Stages I-IIIA Resectable Non Small-Cell Lung Cancer Guideline. PMID- 29436960 TI - Cancer and the Holidays: ASCO's Resources for Patients and Caregivers. PMID- 29436961 TI - The Physicians' Electronic Health Record Coalition. PMID- 29436963 TI - The 2011 Medicare Electronic Health Records Incentive Program. PMID- 29436964 TI - The Magic Pill: The Branding of Impotence and the Positioning of Viagra as Its Solution through Edutainment. AB - Product placement can be presented through edutainment. A drug such as Viagra is introduced or impotence is branded in movies and TV series in different ways to raise awareness of impotence disorder and Viagra as a solution. This study aims to analyze strategies of framing and branding Viagra and impotence disorder, based on a qualitative method analysis of 40 movies and TV series. Findings show that Viagra is shown as not only for older men but also for young and healthy men. Out of 40 movies and TV series in the study sample, in 14 (32.5%), the age of the target audience ranged from 20 to 40 years, in 12 (31.6%) movies and series, the age of the target audience was over 40, and in 12 (31.6%) movies and series, the target audience was very old (over 70). Viagra is shown as not only treating impotence but is presented as a wonder drug that provides a solution for psychological and social needs. The movies show usage instructions, side effects, and risks, and how to store the drug. We recommend that the viewing audience be educated for critical viewing of movies/series in order to empower viewers and give them tools for their decision-making processes concerning their health. PMID- 29436965 TI - Gene-to-Gene Network Analysis of the Mediation of Plant Innate Immunity by the Eliciting Plant Response-Like 1 (Epl1) Elicitor of Trichoderma formosa. AB - A new clade, Trichoderma formosa, secretes eliciting plant response-like 1 (Epl1), a small peptide elicitor that stimulates plant immunity. Nicotiana benthamiana pretreated with Epl1 for 3 days developed immunity against Tomato mosaic virus (ToMV) infection. The transcriptome profiles of T. formosa and N. benthamiana were obtained by deep sequencing; the transcript of Epl1 is 736 nt in length and encodes a 12-kDa peptide. Identifying critical genes in Epl1-mediated immunity was challenging due to high similarity between the transcriptome expression profiles of Epl1-treated and ToMV-infected N. benthamiana samples. Therefore, an efficient bioinformatics data mining approach was used for high throughput transcriptomic assays in this study. We integrated gene-to-gene network analysis into the ContigViews transcriptome database, and genes related to jasmonic acid and ethylene signaling, salicylic acid signaling, leucine-rich repeats, transcription factors, and histone variants were hubs in the gene-to gene networks. In this study, the Epl1 of T. formosa triggers plant immunity against various pathogen infections. Moreover, we demonstrated that high throughput data mining and gene-to-gene network analysis can be used to identify critical candidate genes for further studies on the mechanisms of plant immunity. PMID- 29436966 TI - Trust Ecologies and Channel Complementarity for Information Seeking in Cancer Prevention. AB - Our paper extends channel complementarity theory, which has focused on evidence of complementarity and patterns of channel use, by elucidating the notion of trust complementarity. We examined trust, an information-carrier characteristic and a core construct in health-focused decision-making to understand cancer information seeking, based on data from two nationally representative surveys in Singapore. Trust is found to be differential, relational, and ecological, with implications for individuals' access to and reliance on doctors, family/friends, newspapers/magazines, radio, TV, and the Internet for cancer prevention information. In an ideal trust complementarity environment, an individual should be able to traverse a range of communication channels seamlessly. Our findings however suggest that although individuals trust different channels complementarily, their trust patterns are limited and fettered. We identified two types of trust ecologies shaped by dual-channel and polymorphic complementarity patterns that suggest that health information seekers are trapped within specific trust ecologies that prevent them from navigating a broader range of communication channels for cancer prevention. PMID- 29436967 TI - Photocatalytic degradation of H2S in the gas-phase using a continuous flow reactor coated with TiO2-based acrylic paint. AB - For the photocatalytic degradation of the hydrogen sulphide (H2S) in the gas phase it was developed a rectangular reactor, coated with acrylic paint supported on fiber cement material. The surface formed by the paint coverage was characterized structural and morphologically by scanning electron microscopy with energy dispersive X-ray and X-ray diffraction analysis. The flow rate and the inlet concentration of H2S were evaluated as operational performance parameters of the reactor. Removal efficiencies of up to 94% were obtained at a flow rate of 2 L min-1 (residence time of 115 s) and inlet concentration of 31 ppm of H2S. In addition, the H2S degradation kinetics was modelled according to the Langmuir Hinshelwood (L-H) model for the inlet concentrations of 8-23 ppm of H2S. The results suggest that flow rate has a more important influence on photocatalytic degradation than the inlet concentration. It is assumed that H2S has been oxidized to [Formula: see text], a condition that led to a deactivation of the photocatalyst after 193 min of semi-continuous use. PMID- 29436968 TI - Diversity of gamma- glutamyl peptides and oligosaccharides, the "kokumi" taste enhancers, in seeds from soybean mini core collections. AB - Soybeans (Glycine max (L,) Merr,) contain gamma-glutamyl peptides and oligosaccharides, and these components play an important role in imparting the "kokumi" taste to foods. To gain insight into the genetic diversities and molecular mechanisms of accumulation of gamma-glutamyl peptides and oligosaccharides in soybean, we measured the contents of these components using the Japan and World mini core collections. Similar to other previously reported traits, wide variations were detected among the accessions in the core collections with respect to the content of gamma-glutamyl peptides and oligosaccharides. We found a positive relationship between the content of gamma glutamyl tyrosine and gamma-glutamyl phenylalanine and between the content of raffinose and stachyose. Furthermore, there were unique accessions that included high levels of gamma-glutamyl peptides and oligosaccharides. These accessions may be helpful in understanding the accumulation mechanism of gamma-glutamyl peptides and oligosaccharides and to increase the "kokumi" taste components in soybean by performing a genetic analysis. PMID- 29436969 TI - Evaluation of Effectiveness of Cement Removal From Implant-Retained Crowns Using a Proposed "Circular Crisscross" Flossing Technique. AB - Extruded cement during dental implant crown cementation may cause peri-implant diseases if not removed adequately. The purpose of this study was to evaluate the efficiency of removal of cement after cementation of implant crowns using an experimental circular crisscross flossing technique (CCFT) flossing technique, compared to the conventional "C"-shape flossing technique (CSFT). Twenty-four patients rendered 29 experimental and 29 control crowns. Prefabricated abutments were secured to the implant such that the margins were at least 1 mm subgingivally. The abutments were scanned using computer-aided design/computer aided manufacturing technology and Emax crowns were fabricated in duplicates. Each crown was cemented individually and excess cement was removed using the CSFT and the CCFT techniques. After completion of cementation was completed, the screw access holes were accessed and the crown was unscrewed along with the abutment. The samples were disinfected using 70% ethanol for 10 minutes. Crowns were divided into 4 parts using a marker to facilitate measurement data collection. Vertical and horizontal measurements were made for extruded cement for each control and experimental groups by means of a digital microscope. One-hundred and seventeen measurements were made for each group. Mann-Whitney test was applied to verify statistical significance between the groups. The CCFT showed a highly statistically significant result (104.8 +/- 13.66, P < .0001) for cement removal compared with the CSFT (291.8 +/- 21.96, P < .0001). The vertical measurements of the extruded cement showed a median of 231.1 MUm (IQR = 112.79-398.39) and 43.62 MUm (IQR = 0-180.21) for the control and the experimental flossing techniques, respectively. The horizontal measurements of the extruded cement showed a median of 987.1 MUm (IQR = 476.7-1,933.58) and 139.2 MUm (IQR = 0-858.28) for the control and the experimental flossing techniques, respectively. The CCFT showed highly statistically significant less cement after implant crowns cementation when compared with the CSFT. PMID- 29436972 TI - Claim MoreTM: Empowering African American Women to Make Healthy Choices. PMID- 29436970 TI - Why did I get cancer? Perceptions of childhood cancer survivors in Korea. AB - This study explored whether and how childhood cancer survivors in Korea ask and resolve the question of what may have caused their cancer. Thirty-one childhood cancer survivors participated in in-depth interviews about their self-questioning process in this regard. The findings indicate that Korean childhood cancer survivors pondered this question alone due to the stigma attached to cancer in the family and society. Their answers included internal factors (doing "bad things," having unhealthy eating habits, engaging in magical thinking, having a stress-prone personality, or having a biological susceptibility) or external factors (stressors, random events, the environment, or medical conditions). How they perceived the cause of cancer had an impact on aspects of their current lives. Psychosocial care standards or guidelines are needed in regard to the provision of a safe environment in which Korean cancer survivors and their parents can share their perceptions and process their thoughts. PMID- 29436973 TI - Nurses' Perceptions of Competence in Providing Spiritual Care. AB - PURPOSE: The study examined nurses' perception of competence in providing spiritual care. DESIGN OF STUDY: A descriptive correlational research design with a convenience sample was used. METHOD: Participates completed a demographic questionnaire and the Spiritual Care Competence Scale, which has six domains: assessment and implementation of spiritual care, professionalization and improving the quality of spiritual care, personal support and patient counseling, referral to professionals, attitude toward the patient's spirituality, and communication. FINDINGS: The domain of communication had the most favorable perception among participants and the domain of professionalization and improving the quality of spiritual care had the least favorable perception. CONCLUSIONS: It is important for nurses to have the opportunity to gain knowledge regarding this significant component of holistic care. PMID- 29436974 TI - A Dyadic Approach to Infertility Stress, Marital Adjustment, and Depression on Quality of Life in Infertile Couples. AB - PURPOSE: This study was conducted to examine the level of infertility stress, marital adjustment, depression, and quality of life in infertile couples and assess the actor and partner effects in these areas using the actor-partner interdependence model. DESIGN: Cross-sectional study. METHOD: Participants were 121 infertile couples. After pilot study, data were collected from November 2012 to March 2013 using the following questionnaires: the Fertility Quality of Life, Fertility Problem Inventory, Revised Dyadic Adjustment Scale, and Beck Depression Inventory. FINDINGS: There was a gender difference in infertility stress, depression, and quality of life. Infertility stress had actor and partner effects on the quality of life. Marital adjustment had an actor effect on the quality of life for the wives. Depression had actor and partner effects on quality of life for the wives, but only an actor effect for the husbands. CONCLUSION: This study found that there were actor and partner effects of infertility stress, marital adjustment, and depression on the quality of life in infertile couples. These findings may help nurses be aware of such effects and can be used as a baseline data in the development of nursing interventions for infertile couples. PMID- 29436976 TI - Where Is Holistic Nursing? PMID- 29436975 TI - The Effect of Listening to Music on Postoperative Pain in Adult Orthopedic Patients. AB - PURPOSE: Pain is a common occurrence after orthopedic surgery. Patients need additional resources to manage their pain. The purpose of this study was to determine if listening to music has a positive effect on pain scores and satisfaction in the postoperative adult orthopedic patient. There are limited studies demonstrating statistically significant decreases in postoperative pain in this group. A secondary purpose was to expose nurses on a standard medical surgical unit to an intervention, supported by the holistic nursing model that they could use in their care. DESIGN AND METHOD: This study was a descriptive, comparative, quasi-experimental design. Patients listened to prerecorded music on individual CD players and recorded pre-post pain scores with the intervention. A satisfactory survey was completed at discharge. FINDINGS: Results demonstrated a statistically significant reduction in patients' pain scores after listening to music. Length of listening time had no effect. Patients expressed overall satisfaction, and 100% of participants would recommend this intervention to others. CONCLUSIONS: Listening to music is beneficial as an adjunct to pain medication and contributes to increased patient satisfaction. It is hoped that the information gained from this study will lead to an enhancement in the standard of care for postoperative patients. PMID- 29436977 TI - Injection-related hepatitis C serosorting behaviors among people who inject drugs: An urban/rural comparison. AB - Although previous research has focused on injection drug use behaviors in both urban and rural settings, few have drawn direct comparisons between adjacent rural and urban areas. Using data from the National HIV Behavioral Surveillance study as well as original data collected in a similar fashion, we compare the risk behaviors of people who inject drugs (PWID) in San Juan, Puerto Rico, with those of PWID in nearby rural areas. Specifically, we examine whether one's own hepatitis C (HCV) infection status can be used to predict whether one asked their most recent co-injection partner about their HCV status. Acquiring such information allows injectors to seek out co-injection partners of concordant status as a way to minimize the risk of viral transmission. Results indicate that urban PWID with a known HCV+ status were more likely to know their last co injector partner's HCV status than were their peers with a negative or unknown HCV status. However, this relationship was not present in the rural data. These findings suggest that there are different risk norms in rural and urban PWID communities and that interventions successful in one type of community may not be so in others. PMID- 29436978 TI - Aged women, witchcraft, and social relations among the Igbo in South-Eastern Nigeria. AB - Belief in the existence of witchcraft has remained a social phenomenon in Igbo society, especially with aged women who are often labeled witches. This study is exploratory and explains the implication of labeling an aged woman a witch and social relations in Igbo society in South-Eastern Nigeria. Twenty interviews were conducted with aged women who are victims of the witchcraft label and their relatives using qualitative methods of data collection, key informant interviews, and in-depth interviews. Data collected were analyzed using ethnographic content analysis. Findings reveal different social views attached to witchcraft and how it relates to aged women. PMID- 29436979 TI - Thoracoscopic total esophagogastrectomy with supercharged colon interposition for the treatment of esophageal adenocarcinoma in situs inversus. AB - BACKGROUND: Esophagectomy in situs inversus is challenging. With long-segment supercharged reconstruction, it becomes more perplexing and multidisciplinary surgical skills are needed. Challenges met and the surgical technique used is presented in this case report. METHODS: The case of a 49-year old patient with situs inversus abdominus and a locally advanced distal esophageal adenocarcinoma extending to the stomach is presented. RESULTS: Following neoadjuvant chemotherapy and due to inability to use the stomach as a conduit, a thoracoscopic total esophagogastrectomy with long-segment reconstruction was performed. The conduit used was the left colon and was supercharged with venous and arterial anastomoses in the neck. Conduit perfusion, as assessed by the Spy system revealed marked improvement post supercharging. No anastomotic leak was noted and oral diet was started on day 4. On day 26 the patient developed pneumonia necessitating intubation that was declined. Organ support was withheld with patient death at day 29. CONCLUSION: In long-segment esophageal reconstruction with supercharged colon, although thoracoscopy is feasible, laparoscopy is found unsafe. Careful preoperative planning and colon assessment via computed tomography(CT) colonography/angiography and a multidisciplinary team approach is recommended. Adjuncts to assess conduit perfusion like the Spy system are helpful. Supercharging the long colonic conduit is a way of minimizing ischemia-related complications. PMID- 29436980 TI - Virtual screening of natural inhibitors targeting ornithine decarboxylase with pharmacophore scaffolding of DFMO and validation by molecular dynamics simulation studies. AB - Ornithine decarboxylase (ODC) is an enzyme that initiates polyamine synthesis in human. Polyamines play key roles in cell-cell adhesion, cell motility and cell cycle regulation. Higher synthesis of polyamines also occurs in rapidly proliferating cancer cells are mediated by ODC. As per earlier studies, di-flouro methyl-orninthine (DFMO) is a proven efficient inhibitor ODC targeting the catalytic activity, however, its usage is limited due to side effects. Targeting ODC is considered as a potential therapeutic modality in the treatment of cancer. In this study, it is attempted to use DFMO scaffold to build a ligand-based pharmocophore query using MOE to screen similar active compounds from Universal Natural Products Database with better ADMET properties. The identified compounds were virtually screened against the active cavity of ODC using Glide. Further, potential natural hits targeting ODC were shortlisted based on Molecular Mechanics/Generalized-Born/Surface Area (MM-GBSA) score. Finally, molecular dynamics simulations were performed for the natural molecule hit and DFMO in complex with ODC using Desmond. Among the hits shortlisted, 2-amino-5, 9, 13, 17 tetramethyloctadeca-8, 16-diene-1, 3, 14-triol (UNPD208110) was found to be highly potential, as it showed a higher binding affinity in terms of interactions with key active cavity residues, and also showed better ADMET property, HUMO-LUMO gap energy and more stable complex formation with ODC compared to DFMO. Hence, the proposed molecule (UNPD208110) shall be favourably considered as a potential natural inhibitor targeting ODC-mediated disease conditions. PMID- 29436981 TI - Self-Reported Perceptions of Sleep Quality and Resilience Among Dance Students. AB - This study examined relationships between self-perceived sleep quality and resilience among 116 dance students (Mean age = 21.6 years; SD = 4.348). who self reported sleep quality with the Pittsburgh Sleep Quality Index (PSQI) and personal resilience with the Resilience Scale (RS). Most participants (59.5%) reported poor sleep quality on the PSQI, with 62.9% of the women and 42.1% of the men ( p = .092) scoring higher than five points on this instrument. On the RS, a large majority of the participants (75%) obtained scores less than 147, indicating low resilience, with no significant gender differences observed. Those reporting poor sleep quality (PSQI scores > 5) obtained lower resilience scores (RS < 147) than those reporting good sleep quality (PSQI scores <= 5; p = .025), and participants with poorer sleep quality were at higher risk of low resilience (Odds Ratio = 3.273) relative to those with good sleep quality ( p = .006). Those with shorter duration sleep (claiming they slept <7 hours/night) were also at higher risk for low resilience (Odds Ratio = 3.266), relative to those with longer duration sleep (>7 hours/night). These findings can help students and dance professionals improve their performance and face pressures inherent in dance practice. Follow-up research should verify these findings in varied populations with objective sleep measures and observational data from multiple respondents. PMID- 29436982 TI - Examining the Association Between Executive Functions and Developmental Domains of Low-Income Children in the United States and Turkey. AB - : This study examined the relations between executive functions and developmental domains of preschool children from low-income families through an intercultural perspective in the U.S. and Turkey. A total of 471 children and their primary caregivers participated in the Turkey part of the study, while 286 children and their parents engaged in U.S. SAMPLE: Regression analyses revealed that fine motor, problem solving, and executive functions of children between two contexts were significantly different from each other. In the U.S., executive functions predicted communication, problem solving, and fine motor development, whereas in the Turkish sample, executive functions did not predict domain scores. Child gender predicted four of five developmental outcomes in the U.S., whereas maternal education predicted two of five outcomes in Turkey. In addition, invariance testing demonstrated that predictors to outcomes were not significantly different between the two countries. Country differences from the first set of outcomes were explained in the context of the research sites, children's socialization, and cultural expectations surrounding child development. This study raises questions about relations between executive functions and developmental domains for future research. PMID- 29436983 TI - The Structure of Subjective Well-Being and Its Relation to Objective Well-Being Indicators: Evidence from EU-SILC for Serbia. AB - In this article, we examine the structure of the subjective well-being and its relation to objective well-being indicators using the data from the European Union's Survey on Income and Living Conditions (EU-SILC) from Serbia. This is one of the first papers to analyze a new module on subjective well-being from EU-SILC micro-dataset (with over 20,000 respondents). We investigate the factor structure of the items and the differences in the association of subjective well-being dimensions with objective indicators of well-being within the Organisation for Economic Co-operation and Development Better Life Initiative framework. Three factors emerge from the principal components analysis: general life satisfaction, affective well-being, and satisfaction with the local environment. The analysis further reveals that life satisfaction is more related to the material living conditions, such as income, unemployment, and housing conditions, while affective well-being is more related to non-material indicators of well-being such as perceived health, personal security, and social connections. On the other hand, positive and negative affect within the affective well-being are not clearly separable, nor is the eudaimonic indicator from either life satisfaction or affective well-being. PMID- 29436984 TI - Effectiveness of pharmacological or psychological interventions for smoking cessation in smokers with major depression or depressive symptoms: A systematic review of the literature. AB - BACKGROUND: Smokers with major depressive disorder (MDD) or depressive symptoms (DS) represent a subgroup in need of attention, since they have specific clinical features and prognosis. METHODS: A systematic review of the literature (Cochrane, MEDLINE, ScienceDirect, Web of Science databases from inception to June 2017) of randomized clinical trials assessing the effectiveness of pharmacological, psychological, or combined interventions for smoking cessation in subjects with current or past MDD/DS without medical or comorbid psychiatric disorder(s) was run following the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. RESULTS: Twenty-seven studies met the inclusion criteria. Nicotine, varenicline, and staged-care intervention were more effective in smokers with current MDD; nicotine and fluoxetine plus nicotine were more effective in smokers with DS; naltrexone and nicotine plus fluoxetine were more effective in smokers with severe current DS. Cognitive-behavioral therapy and cognitive and behavioral cessation and relapse prevention skills training were superior to placebo in smokers with past MDD. CONCLUSIONS: More research is needed into effectively addressing smoking in people with concurrent mental disorder. Data currently available need to be confirmed in randomized trials aimed at replicating the results and disentangling the effects of each therapeutic ingredient when a combination therapy is proposed. Studies on tolerability of treatments are warranted, as well as those aimed at identifying factors of vulnerability to adverse effects. PMID- 29436985 TI - Phylogenetic Diversity and Host Specialization of Corynespora cassiicola Responsible for Emerging Target Spot Disease of Cotton and Other Crops in the Southeastern United States. AB - Corynespora cassiicola is a ubiquitous fungus causing emerging plant diseases worldwide, including target spot of cotton, soybean, and tomato, which have rapidly increased in incidence and severity throughout the southeastern United States. The objectives of this study were to understand the causes for the emerging target spot epidemics in the United States by comparing phylogenetic relationships of isolates from cotton, tomato, soybean, and other crop plants and ornamental hosts, and through the determination of the host range of isolates from emerging populations. Fifty-three isolates were sampled from plants in the southeastern United States and 1,380 nucleotides from four nuclear loci were sequenced. Additionally, sequences of the same loci from 23 isolates representing each of the distinct lineages of C. cassiicola described from previous studies were included. Isolates clustered based on host of origin, regardless of the geographic location of sampling. There was no genetic diversity detected among isolates from cotton, which were genetically distinct from isolates from other host species. Furthermore, pathogenicity and virulence assays of 40 isolates from various hosts onto cotton, soybean, tomato, and cucumber showed that isolates from cotton were more aggressive to cotton than those from other hosts. Soybean and tomato were most susceptible to isolates that originated from the same host, providing evidence of host specialization. These results suggest that emerging target spot epidemics in the United States are caused by either the introduction of host-specific isolates or the evolution of more aggressive strains on each host. PMID- 29436986 TI - Causative Role of Grapevine Red Blotch Virus in Red Blotch Disease. AB - Grapevine red blotch virus (GRBV) has a monopartite single-stranded DNA genome and is the type species of the genus Grablovirus in the family Geminiviridae. To address the etiological role of GRBV in the recently recognized red blotch disease of grapevine, infectious GRBV clones were engineered from the genome of each of the two previously identified phylogenetic clades for Agrobacterium tumefaciens-mediated inoculations of tissue culture-grown Vitis spp. plants. Following agroinoculation and one or two dormancy cycles, systemic GRBV infection was detected by multiplex polymerase chain reaction (PCR) in Vitis vinifera exhibiting foliar disease symptoms but not in asymptomatic vines. Infected rootstock genotype SO4 (V. berlandieri * V. riparia) exhibited leaf chlorosis and cupping, while infection was asymptomatic in agroinoculated 110R (V. berlandieri * V. rupestris), 3309C (V. riparia * V. rupestris), and V. rupestris. Spliced GRBV transcripts of the replicase-associated protein coding region accumulated in leaves of agroinfected vines, as shown by reverse-transcription PCR; this was consistent with systemic infection resulting from virus replication. Additionally, a virus progeny identical in nucleotide sequence to the infectious GRBV clones was recovered from agroinfected vines by rolling circle amplification, cloning, and sequencing. Concomitantly, subjecting naturally infected grapevines to microshoot tip culture resulted in an asymptomatic plant progeny that tested negative for GRBV in multiplex PCR. Altogether, our agroinoculation and therapeutic experiments fulfilled Koch's postulates and revealed the causative role of GRBV in red blotch disease. PMID- 29436987 TI - Direct Observation of Intermediate State(s) in the Mechanistic Investigation of Domain Specific Protein-Surfactant Interaction. AB - INTRODUCTION: Interaction of surfactants with proteins can decipher important information regarding the stability and behavior of proteins. For multi-domain proteins, these interactions vary domain wise and these details are crucial in understanding the contribution of different domains of the protein in its overall activity. OBJECTIVE: The objective of the present work is to study the interaction of surfactants with domain III of Human Serum Albumin (HSA) and to compare the same with the global interaction. METHODS: Interaction of the anionic Sodium Dodecyl Sulphate (SDS) and the Cationic Cetyltrimethylammonium Bromide (CTAB) surfactants with domain III of Human Serum Albumin (HSA) has been studied using 8-Anilino-1-Naphthalene-Sulphonate (ANS) as a fluorescent marker. Circular Dichroism (CD) spectroscopy has been used to study the protein-surfactant interaction for the overall protein. RESULTS: SDS is found to interact sequentially with domain III of HSA having two detectable intermediate states in the binding process. In case of CTAB, we have observed only one intermediate state for its interaction with domain III. Although Quantum yield measurement can reflect the presence of such intermediate state, the overall conformational change of the HSA on addition of surfactants, studied by Circular Dichroism (CD) spectroscopy, and the ANS-Trp distance measurement by FRET could not resolve the presence of such intermediate states. The esterase activity of HSA in presence of different amount of surfactants is also in accordance with our above observation. CONCLUSION: The interaction of both the surfactants with HSA is found to be sequential in nature. The most important conclusion revealed from our study is that the nature of protein-surfactant interaction is not same throughout the entire protein. Our study reveals that different parts of the multi-domain HSA have different affinity to the surfactant molecules. PMID- 29436988 TI - Binding Studies of Andrographolide with Human Serum Albumin: Molecular Docking, Chromatographic and Spectroscopic Studies. AB - BACKGROUND: Human serum albumin acts as a carrier protein to a variety of drugs and aids their transport. Andrographis paniculata, a herbal plant has been used as a source of traditional medicine in the Asian countries. Among the various constituents of this plant, andrographolide is the most active and is being used from centuries in the treatment of many chronic and infectious diseases. OBJECTIVE: The present study was designed to evaluate the interaction and binding affinity of andrographolide with HSA, by molecular docking, chromatographic and spectral studies. METHODS: Andrographolide was docked with crystal structure of human serum albumin (1AO6) using Auto Dock Vina software and the interactions were analyzed by a visualizing software py- MOL. For further characterization and confirmation, andrographolide (3x10-5 M) and HSA (0.001, 0.005, 0.01, 0.02, 0.04 M) sample mixtures were incubated at 37 degrees C for 3h in a metabolic shaker, followed by centrifugation. The supernatant and the filtrate were analyzed by UV spectroscopy, HPLC, CD and FTIR spectral analysis. RESULTS: The docking studies revealed that andrographolide interacted with HSA and formed hydrogen bonds with Trp 214, Arg 218 and Lys 444 amino acid residues. The UV spectral analysis revealed a decrease in the absorption peak of HSA due to its interaction with andrographolide. A new peak was observed at retention time 7.45 min by HPLC analysis and the Bmax was found to be 7.5 +/- 0.4 mg protein with a Kd value of 1.89 mM, indicating interaction of andrographolide with HSA. The CD spectra results suggested, a marginal decrease in the negative ellipticity without any significant shift in peak, indicating the stabilization of the HSA andrographolide complex. The FTIR analysis of the andrographolide-HSA mixture showed a peak at wave number 1637 cm-1 (a shift of amide I groups from 1646 cm-1) and 1016 cm-1 which corresponded to the ligand, confirming the complex formation. CONCLUSION: The molecular docking studies demonstrated the interactions of andrographolide to the crystal structure of HSA. The chromatographic and spectroscopic analysis confirmed the binding of andrographolide with HSA and their complex formation. Overall the present studies conclude the binding of andrographolide to HSA protein, favoring its pharmacokinetics. PMID- 29436989 TI - Analytical Approaches to the Characterization of Solid Drug Delivery Systems with Porous Adsorbent Carriers. AB - A large variety of analytical techniques are available to meet the needs of characterization of solid samples. But, when solid drug delivery systems are concerned we are faced with demanding methodologies which have to compile capabilities of analytical techniques in regard to large diversity of structures and surface functionality of analyzed adsorbent carriers. In this review, the most commonly used analytical techniques are presented with their basic principles, advantages and disadvantages in applications of interest. Adsorbent carriers are widely used today as ingredients in the formulation of pharmaceutical forms, for increasing the dissolution rate of the drug and hence the bioavailability. They are also used in the formulation of substances with modified or target drug release into a specific tissue. Methods of thermal analysis (Thermogravimetry - TGA, Differential Scanning Calorimetry - DSC and Thermal microscopy - TM), spectroscopic methods (Infrared Spectroscopy - IR, especially Fourier Transform Infrared Spectroscopy - FTIR and Raman spectroscopy), crystallographic methods (Powder X-Ray Diffraction - PXRD) and finally Scanning Electron Microscopy (SEM) are the most powerful in the characterization of modern therapeutic systems with porous adsorbents. The problem-solving power of each particular analytical method is often enhanced by using simultaneous methods rather than a single technique. PMID- 29436990 TI - The role of hydrogen sulfide and H2S-donors in myocardial protection against ischemia/reperfusion injury. AB - Hydrogen sulfide (H2S), previously known only as a toxic agent, in the last decades has been recognized as an important endogenous gasotransmitter, playing a key role in the homeostasis of the cardiovascular system. In the last years, the growing evidence about a protective role exhibited by H2S against myocardial ischemia/reperfusion (I/R), led to an increasing interest for the possible mechanism of action accounting for the H2S cardioprotective effect, and to the discovery of the involvement of several targets. Currently, many mechanisms of action have been proposed and verified through in vitro and in vivo models of I/R injury, such as the anti-inflammatory or the anti-oxidant ones, or mechanisms of S-sufhydration able to modify proteins such as ion channels. Particular attention was focused on the mitochondrial preservation and on anti-apoptotic mechanisms, and finally even a pro-angiogenesis effect has been described. At the same time, the design, the development and the pharmacological characterization of moieties able to release H2S, employed alone as H2S-donor, or conjugated with another drug in hybrid molecules, led to the production of novel chemical entities in the panorama of cardioprotective drugs. PMID- 29436991 TI - Antibacterial Strategies for Wound Dressing: Preventing Infection and Stimulating Healing. AB - Wound management is an important and increasing global issue. Infection of a wound can cause a delay in wound healing and pain, but also more serious complications like tissue necrosis or even sepsis, which can lead to loss of tissue, limbs or life. Antibacterial agents have been introduced into wound infection care. In this review, we provide an insight into the current antibacterial strategies of wound dressings, including wound infection process, antibacterial agents, and controlled drug release systems. We also emphasize the development of intelligent wound dressing and introduce a promising research direction. PMID- 29436992 TI - Antimicrobial Synthetic Polymers: An Update on Structure-Activity Relationships. AB - The rising incidence of antibiotic-resistant infections, combined with a declining number of new antibiotic drug approvals, has generated an alarming therapeutic gap that critically undermines public health. Host Defense Peptides (HDPs), sometimes referred to as "Nature's Antibiotics", are short chain, amphiphilic and cationic peptide sequences found in all multicellular organisms as part of their innate immunity. While there is a vast diversity in terms of HDP sequence and secondary structure, they all seem to share physiochemical characteristics that can be appropriated for macromolecular design by the synthetic polymer chemist. Over the past decade, remarkable progress has been made in the design and synthesis of polymer-based materials that effectively mimic HDP action - broad-spectrum antibacterial potency, rapid bactericidal kinetics, and minimal toxicity to human cells - while offering the additional benefits of low cost, high scalability, and lower propensity to induce resistance, relative to their peptide-based counterparts. A broad range of different macromolecular structures and architectures have been explored in this design space, including polynorbornenes, poly(meth)acrylates, poly(meth)acrylamides, nylon-2 polymers, and polycarbonates, to name a just few. Across all of these diverse chemical categories, the key determinants of antibacterial and hemolytic activity are the same as in HDPs: net cationic charge at neutral pH, well-balanced facial amphiphilicity, and the molecular weight of the compounds. In this review, we focus in particular on recent progress in the polymethacrylate category first pioneered by Kuroda and DeGrado and later modified, expanded upon and rigorously optimized by Kuroda's and many other groups. Key findings and future challenges will be highlighted. PMID- 29436993 TI - The Modification and Design of Antimicrobial Peptide. AB - The antimicrobial peptides (AMPs) are a group of unique naturally occurring anti microbial compounds with around 50 amino acids. It represents promising therapeutic agents to the infectious disease without concerning about drug resistance. However, commercial development of these peptides for even the simplest application has been hindered by the limitations of sources, instability, toxicity and bioavailability. To improve the properties of the artificial synthesized AMPs, the modification and design are the hotspots of the AMPs research. In fact, more than half of the known AMPs are naturally modified. In this review, two types of modification strategies, biochemical modification and chemical modification were summarized. Although, the chemical modification is versatile and direct, the manufacturing cost is greatly increased compared to the antibiotics. With the recent progress of the protein modification enzyme, the biochemical modification of the antimicrobial peptide followed by heterologous expression has great application prospects. PMID- 29436994 TI - Hydrogels as Antibacterial Biomaterials. AB - Hydrogels, as a class of materials for tissue engineering and drug delivery, have high water content and solid-like mechanical properties. Currently, hydrogels with an antibacterial function are a research hotspot in biomedical field. Many advanced antibacterial hydrogels have been developed, each possessing unique qualities, namely high water swellability, high oxygen permeability, improved biocompatibility, ease of loading and releasing drugs and structural diversity. In this article, an overview is provided on the preparation and applications of various antibacterial hydrogels. Furthermore, the prospects in biomedical researches and clinical applications are predicted. PMID- 29436995 TI - Bacterial Luciferase Gene Cassette as a Real-time Bioreporter for Infection Model and Drug Evaluation. AB - The bacterial luciferase gene cassette (lux) is an ideal bioreporter for real time monitoring of the dynamics of bacteria because it is a fully autonomous, substrate-free bioluminescent reporter system available in a prokaryotic or eukaryotic host background. The lux operon is emerging as a powerful bioreporter for the study of a wide range of biological processes such as gene function, drug discovery and development, cellular trafficking, protein-protein interactions, and especially tumorigenesis and cancer treatment. Furthermore, the use of a high signal to noise bioluminescent bioreporter is quickly replacing traditional fluorescent bioreporter because of the lack of endogenous bioluminescent reactions in living animals. This review briefly describes how the lux operon is used for bioluminescence imaging. Current advances in bioluminescence bacteria development are summarized, focusing on their construction strategy and applications in bacterial infection and antibiotic treatment. Different construction methods of lux-expressing cell lines are also discussed. Taken together, this review provides valuable guidelines toward the development of an ideal bioluminescent bacteria or cell lines to evaluate the efficacy of a drug. PMID- 29436996 TI - Herbal Products for Common Auto-Inflammatory Disorders - Novel Approaches. AB - BACKGROUND: Common auto-inflammatory disorders (CAIDs) constitute a wide array of ailments ranging from acute allergies to chronic conditions. Globally, CAIDs remain one of the leading causes of disability and morbidity. Despite playing a leading therapeutic role, the vast profusion of anti-inflammatory synthetic agents have not been able to fully resolve a panoply of CAIDs. Additionally, contemporary synthetic therapy approaches remain bounded by a wide array of limitations essentially being adverse effects and unaffordable costs. In this advent, the use of herbal products provides an interesting avenue to explore in view of developing such treatment regimens. OBJECTIVE: This review article endeavors to highlight potential herbal products and isolated phytochemicals which can be of benefit in the prophylaxis, management, and treatment alongside avoiding the relapse of CAIDs. CONCLUSION: This review article has highlighted that herbals, herbal products, and isolated metabolites hold a huge potential in the prophylaxis, management, and treatment of CAIDs. Herbals can act on various targets involved in the pathogenesis of inflammatory disorders. In addition, novel approaches for the management of CAIDs are numerous. Indeed, nanoparticles loaded with phytochemicals have been developed to specifically target the colon for IBD treatment. In silico approaches using herbals also offer unlimited avenues to decipher new pharmacophores. Investigating the potential of polyherbal formulations is another unique approach which can be investigated. Given the inefficacy of conventional medicines, the concomitant use of conventional and herbal medicines can also be explored. PMID- 29436997 TI - Pyrazole Schiff Base Hybrids as Anti-Malarial Agents: Synthesis, In Vitro Screening and Computational Study. AB - BACKGROUND: Malaria is one of the most vital infectious diseases caused by protozoan parasites of the Plasmodium genus. As P. falciparum, the cause of most of the severe cases of malaria, is increasingly resistant to available drugs such as amodioquine, chloroquine, artemisinin, and antifolates, there is an urgent need to identify new targets for chemotherapy. OBJECTIVE: This study screened novel pyrazole derivatives carrying iminium & benzothiazole group for antimalarial potential against P. falciparum chloroquine sensitive (3D7) strain. MATERIALS & METHODS: Several pyrazole schiff base hybrids with a wide range of substitution have been synthesized via condensation of substituted aniline with substituted 4-formylpyrazole and evaluated for their in vitro antimalarial activity against asexual blood stages of human malaria parasite, Plasmodium falciparum. The interaction of these conjugate hybrids was also investigated by molecular docking studies in the binding site of P. falciparum cystein protease falcipain-2. The pharmacokinetic properties were also studied using ADME prediction. RESULTS: Among all compounds, 6bf and 6bd were found to be potential molecules with EC50 1.95ug/ml and 1.98ug/ml respectively. Docking study results reveal that the pyrazole schiff base derivatives occupy the PfFP binding sites and they show good interactions with significant values of binding energies. CONCLUSION: We provide evidence which implicates pyrazole Schiff base hybrids as potential prototypes for the development of antimalarial agents. PMID- 29436998 TI - QSAR Analysis for Antioxidant Activity of Dipicolinic Acid Derivatives. AB - AIMS AND OBJECTIVES: The aim of this study was to derive robust and reliable QSAR models for clarification and prediction of antioxidant activity of 43 heterocyclic and Schiff bases dipicolinic acid derivatives. According to the best obtained QSAR model, structures of new compounds with possible great activities should be proposed. METHODS: Molecular descriptors were calculated by DRAGON and ADMEWORKS from optimized molecular structure and two algorithms were used for creating the training and test sets in both set of descriptors. Regression analysis and validation of models were performed using QSARINS. RESULTS: The model with best internal validation result was obtained by DRAGON descriptors (MATS4m, EEig03d, BELm4, Mor10p), split by ranking method (R2 = 0.805; R2 ext = 0.833; F = 30.914). The model with best external validation result was obtained by ADMEWORKS descriptors (NDB, MATS5p, MDEN33, TPSA), split by random method (R2 = 0.692; R2 ext = 0.848; F = 16.818). CONCLUSION: Important structural requirements for great antioxidant activity are: low number of double bonds in molecules; absence of tertial nitrogen atoms; higher number of hydrogen bond donors; enhanced molecular polarity; and symmetrical moiety. Two new compounds with potentially great antioxidant activities were proposed. PMID- 29436999 TI - Pharmacoinformatics and Molecular Docking Studies Reveal Potential Novel Compounds Against Schizophrenia by Target SYN II. AB - BACKGROUND: Synapsin II regulates neurotransmitter release from mature nerve terminals and plays important role in the formation of new nerve terminals. The associations of SYN II are identified in various studies that are linked to the onset of Schizophrenia. Schizophrenia is characterized by abnormal behavior like obsession, dampening of emotions and auditory hallucination. METHODS: The bioinformatics approaches were utilized for structural modeling and docking analyses of SYN II followed by pharmacophore generation to identify potent inhibitors. RESULTS: The comparative modeling approach was employed to generate the 3D model having 82.404% quality factor calculated by Errat. Pharmacophore was constructed by utilizing merge molecular and chemical features of selected five FDA approved Schizophrenia drugs by LigandScout 4.1.5. Comparative docking analyses were performed by utilizing the selected drugs and top screened hits by GOLD and AutoDock Vina. CONCLUSION: It was proposed that Aripiprazole drug and scrutinized compounds have strong binding affinities among the other selected drugs. The reported compounds may be used for further analyses in the drug discovery processes, as they have shown good human intestinal absorption and are noncarcinogenic. The present study provides the structural insights which may be used for further understating of the Schizophrenia therapeutic purposes by targeting SYN II and other inhibitors haunting. PMID- 29437000 TI - Extraction, Identification and Biological Activities of Saponins in Sea Cucumber Pearsonothuria graeffei. AB - AIMS AND OBJECTIVES: Secondary metabolism in marine organisms produces a diversity of biologically important natural compounds that are not present in terrestrial species. Sea cucumbers belong to the invertebrate Echinodermata and are famous for their nutraceutical, medical and food values. They are known for possession triterpenoid glycosides (saponins) with various ecological roles. The current work aimed to separate, identify and test various biological activities (antibacterial, antifungal, antileishmanial and anticancer properties) of saponins produced by the holothurian Pearsonothuria graeffei from the Red Sea, Egypt. MATERIALS AND METHODS: The structures were identified by 1D and 2D NMR (1H, 13C, TOCSY, COSY, HSQC, HMBC, and ROESY) experiments and acid hydrolysis. The crude and purified fractions was analyzed using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)/MS to identify saponins and characterize their molecular structures. Partially purified fraction, mainly containing compounds 1 and 2, was screened for its antifungal activity against three clinical isolates of Candida albicans (Candida 580 (1), Candida 581(2) and Candida MEO47228. Antileishmanial activity against Leishmania major and toxicity on colon cell-line were also evaluated. RESULTS: Two lanostane type sulfated triterpene monoglycosides were isolated from the Holothurian Pearsonothuria graeffei from the Red Sea, Egypt. Holothurin A (1) and echinoside A (2) triterpene saponins were separated by reversed phase semi-preparative HPLC. LC50 values (ug/mL); calculated for the fraction containing saponins 1 and 2 as major constituents; against Candida albicans, Leishmania major and colon cell-line were 10, 20 and 0.50, respectively. CONCLUSION: Consequently, this study demonstrated the potential use of sea cucumber Pearsonothuria graeffei not only as appreciated functional food or nutraceuticals but also as the source of functional ingredients for pharmaceutical products with antifungal, antileishmanial and anticancer properties. PMID- 29437001 TI - Predictive and Descriptive CoMFA Models: The Effect of Variable Selection. AB - : Aims & Scope: In this research, 8 variable selection approaches were used to investigate the effect of variable selection on the predictive power and stability of CoMFA models. MATERIALS & METHODS: Three data sets including 36 EPAC antagonists, 79 CD38 inhibitors and 57 ATAD2 bromodomain inhibitors were modelled by CoMFA. First of all, for all three data sets, CoMFA models with all CoMFA descriptors were created then by applying each variable selection method a new CoMFA model was developed so for each data set, 9 CoMFA models were built. Obtained results show noisy and uninformative variables affect CoMFA results. Based on created models, applying 5 variable selection approaches including FFD, SRD-FFD, IVE-PLS, SRD-UVEPLS and SPA-jackknife increases the predictive power and stability of CoMFA models significantly. RESULT & CONCLUSION: Among them, SPA jackknife removes most of the variables while FFD retains most of them. FFD and IVE-PLS are time consuming process while SRD-FFD and SRD-UVE-PLS run need to few seconds. Also applying FFD, SRD-FFD, IVE-PLS, SRD-UVE-PLS protect CoMFA countor maps information for both fields. PMID- 29437002 TI - Real-time Monitoring of Nanoparticle-based Therapeutics: A Review. AB - BACKGROUND: With the development of nanomaterials, nanoparticle-based therapeutics have found increasing application in various fields, including clinical and basic medicine. Real-time monitoring of nanoparticle-based therapeutics is considered critical to both pharmacology and pharmacokinetics. METHODS: In this review, we discuss the different methods of real-time monitoring of nanoparticle-based therapeutics comprising different types of nanoparticle carriers, such as metal nanoparticles, inorganic nonmetallic nanoparticles, biodegradable polymer nanoparticles, and biological nanoparticles. RESULTS: In the light of examples and analyses, we conclude that the methods of analysis of the four types of nanoparticle carriers are commonly used methods and mostly not necessary. Under most circumstances, real-time monitoring differs according to nanoparticle type, drugs, diseases, and surroundings. CONCLUSION: With technology development and advanced researches, there have been increasing measures to track the real-time changes in nanoparticles, and this has led to great progress in pharmacology and therapeutics. However, future studies are warranted to determine the accuracy, applicability, and practicability of different technologies. PMID- 29437003 TI - Rutin and Its Cyclodextrin Inclusion Complexes: Physico-chemical Evaluation and in vitro Activity on B164A5 Murine Melanoma Cell Line. AB - BACKGROUND: Recent studies have shown that rutin presents a heightened interest due to the plethora of biological activities. The major drawback for this phytocompound is the poor water solubility, a parameter that limits its bioavailability. The study aimed to prepare and assess the inclusion complexes of rutin with beta-cyclodextrin (BCD) and hydroxypropyl-beta-cyclodextrin (HPBCD), followed by the evaluation of the antioxidant, antiproliferative and pro apoptotic activity against B164A5 murine melanoma cell line. METHODS: Inclusion complexes were prepared by kneading method. Scanning electron microscopy, differential scanning calorimetry and X-ray powder diffraction were used in order to assess their formation. Antioxidant activity was determined by DPPH assay. Antiproliferative and pro-apoptotic effects where tested by MTT, respectively Annexin V-PI assays. Physico-chemical methods proved that incorporation took place. RESULTS: Results show that rutin presents antioxidant activity, and complexation increases this property. After 72 h of incubation at the concentration of 100 uM rutin proved to be an active antiproliferative and pro apoptotic compound against B164A5 cells. CONCLUSION: Incorporation in BCD and HBCD maintained the activity, thus representing an important finding and open path for in vivo experiments. PMID- 29437004 TI - Therapeutic Drug Monitoring of Phenytoin by Simple, Rapid, Accurate, Highly Sensitive and Novel Method and Its Clinical Applications. AB - BACKGROUND: Phenytoin has very challenging pharmacokinetic properties. To prevent its toxicity and ensure efficacy, continuous therapeutic monitoring is required. It is hard to get a simple, accurate, rapid, easily available, economical and highly sensitive assay in one method for therapeutic monitoring of phenytoin. OBJECTIVE: The present study is directed towards establishing and validating a simpler, rapid, an accurate, highly sensitive, novel and environment friendly liquid chromatography/mass spectrometry (LC/MS) method for offering rapid and reliable TDM results of phenytoin in epileptic patients to physicians and clinicians for making immediate and rational decision. METHODS: 27 epileptics patients with uncontrolled seizures or suspected of non-compliance or toxicity of phenytoin were selected and advised for TDM of phenytoin by neurologists of Qilu Hospital Jinan, China. The LC/MS assay was used for performing of therapeutic monitoring of phenytoin. The Agilent 1100 LC/MS system was used for TDM. The mixture of Ammonium acetate 5mM: Methanol at (35: 65 v/v) was used for the composition of mobile phase. The Diamonsil C18 (150mm*4.6mm, 5MUm) column was used for the extraction of analytes in plasma. The samples were prepared with one step simple protein precipitation method. The technique was validated with the guidelines of International Conference on Harmonisation (ICH). RESULTS: The calibration curve demonstrated decent linearity within (0.2-20 ug/mL) concentration range with linearity equation, y= 0.0667855 x +0.00241785 and correlation coefficient (R2) of 0.99928. The specificity, recovery, linearity, accuracy, precision and stability results were within the accepted limits. The concentration of 0.2 ug/mL was observed as lower limit of quantitation (LLOQ), which is 12.5 times lower than the currently available enzyme-multiplied immunoassay technique (EMIT) for measurement of phenytoin in epilepsy patients. CONCLUSION: A rapid, simple, economical, precise, highly sensitive and novel LC/MS assay has been established, validated and applied successfully in TDM of 27 epileptics patients. It was alarmingly found that TDM results of all these patients were out of safe range except two patients. However, it needs further evaluation. Besides TDM, the stated method can also be applied in bioequivalence, pharmacokinetics, toxicokinetics and pharmacovigilance studies. PMID- 29437005 TI - S-Nitrosylation in Regulation of Inflammation and Cell Damage. AB - BACKGROUND: Cell signaling through nitric oxide (NO) is a multifaceted mechanism, which regulates metabolic activities and fate in different tissues. The peroxynitrite (ONOO-) formed as reaction product of nitric oxide radical and superoxide interacts with cell membrane phospholipids and proteins causing damage. OBJECTIVE: The reaction kinetics to form nitrotyrosine (ONOO-tyrosine) and/or nitrosylated cysteine (ONOO-cysteine) in protein molecules during posttranslational modification and nitration of lipids are therefore critical in determining cells' signaling mechanism for survival or apoptosis. RESULTS: The nitrosylation was found to modulate GPCRs and activation of guanylate cyclase as well as regulate NF-kappaB activation. The recent findings have shown the neuroprotective effects of S- nitrosylation, though mechanism is unclear. CONCLUSION: While keeping the background in mind, we address here the biological function of NO derivatives in medicine. We target four known compounds: SNAP, SIN 1 chloride, SNP and GSNO to understand the effect of NO in different tissues. Here we analyze the existing findings to assess therapeutic relevance of NO signaling during inflammation, vasodilation and tolerance. PMID- 29437006 TI - Enteral Administration of TKIs: Report of a Response to Ceritinib in an ALK positive NSCLC Patient and Literature Review. AB - INTRODUCTION: Several reports attest the feasibility and the favorable outcomes of kinase inhibitors administration through feeding tubes or Percutaneous Endoscopic Gastrostomies (PEG), mainly in Non-Small Cell Lung Cancer (NSCLC) patients exposed to first-generation compounds. Here we present the case of an ALK-positive NSCLC patient who achieved cerebral and extra-cranial disease response with ceritinib (a novel ALK inhibitor) administered through a Nasogastric Tube (NGT). We moreover provide a review gathering clinical successes obtained with targeted agents intake through NGT or PEG. CASE PRESENTATION: A 53 year-old never-smoker woman was diagnosed with ALK-rearranged stage IV lung adenocarcinoma. After a brilliant response to crizotinib and several lines of systemic therapy, NGT positioning intended for ceritinib administration was required, given the development of a pleuro-esophageal fistula. Enteral drug administration allowed a significant reduction of hepatic and cerebral disease localizations. Literature review and discussion: The majority of kinase inhibitors administration through NGT or PEG accounts for EGFR-mutated (seven) or ALK-positive (seven, including our report) NSCLC patients. Five additional cases concerning different malignancies were described. Enteral drug administration was mostly required by disease-related respiratory impairment, requiring mechanical ventilation in the emergency setting. In our case, the cerebral and extra-cranial response obtained with enteral ceritinib intake suggests the proposition of novel inhibitors in these circumstances may take place after first-generation compounds failure or even upfront. Indeed, their grater potency and activity against brain metastases point out the role of their enteral administration in the first-line setting too, when a rapid systemic and intra-cerebral disease response is required. PMID- 29437007 TI - Blood Eosinophils as Biomarkers to Drive Treatment Choices in Asthma and COPD. AB - BACKGROUND: Asthma and COPD are complex, heterogeneous conditions comprising a wide range of phenotypes, some of which are refractory to currently available treatments. Elucidation of these phenotypes and identification of biomarkers with which to recognize them and guide appropriate treatment remain a priority. OBJECTIVE: This review describes the utility of blood eosinophils as a surrogate biomarker of eosinophilic airway inflammation, a common feature of specific asthma and COPD phenotypes. The role of blood eosinophils in airway disease is described, as is their relevance in reflecting airway eosinophilia. Each disease is discussed separately as the manner in which blood eosinophils might be used as biomarkers differs. Focusing on patients with severe disease (persistent eosinophilic asthma and exacerbating COPD), we evaluate evidence examining eosinophils as biomarkers. RESULTS: In asthma, the rationale for using blood eosinophils to guide treatment is clearly defined, backed by prospective, well controlled studies. Higher eosinophil counts identify patients with more severe disease and poorer outcomes, patients for whom biologic therapies targeting allergic and/or eosinophilic pathways are recommended. In COPD, the evidence is less robust. High blood eosinophil counts are a modest predictor of future exacerbations, and may predict a favourable response to ICS on top of LABA/LAMA, especially in patients with a history of frequent exacerbations. CONCLUSION: Before extensive application in clinical practice, further evaluation of these findings in prospective clinical studies, and standardization of the appropriate thresholds of clinically relevant eosinophilia are needed, together with establishing whether single or multiple measurements are required in different clinical settings. PMID- 29437008 TI - Identification of a Good-Prognosis IDH-Mutant-Like Population of Patients with Diffuse Gliomas. AB - BACKGROUND: Isocitrate dehydrogenase (IDH) mutation is the initiating event that defines major clinical and prognostic classes of gliomas, but the potential mechanisms have not been well interpreted yet. The main objective of the current study was to better understand the underlying biology of IDH mutant gliomas as captured by gene expression profiles. METHODS: RNA sequencing data of WHO grade II-IV gliomas from the Chinese Glioma Genome Atlas (CGGA, N=325) were used to assess differentially expressed genes between IDH mutant and wild type gliomas and to construct a gene expression-based classifier to detect IDH mutant samples with high sensitivity and specificity. The classifier was validated in independent RNA sequencing data from the Cancer Genome Atlas (TCGA, N=699), and the prognostic value of the classifier was also assessed in the two datasets. RESULTS: A 58-gene-pair IDH mutation signature was developed by using the top scoring pairs algorithm. In CGGA dataset, 98.5% and 100% IDH mutant samples were also predicted to be mutant by gene expression based IDH status in grade II-III and grade IV gliomas, respectively. In TCGA dataset, the proportions were 99.8% and 100%, respectively. The signature remained to be a prognostic marker in multivariate cox analysis both in CGGA and TCGA datasets. CONCLUSION: A characteristic gene expression signature is associated with and accurately predicts IDH mutation status. This suggests a common biology between these tumors and adds prognostic and biologic information that is not captured by the mutation status alone. These results may help in population stratification for clinical trials. As RNA-seq is more and more prevalent and cost-effective in glioma molecular diagnosis, this gene signature would provide a precise method to predict IDH mutation status with RNA-seq data. PMID- 29437010 TI - Neuronal Expression of Junctional Adhesion Molecule-C is Essential for Retinal Thickness and Photoreceptor Survival. AB - BACKGROUND: Photoreceptor cell death is a key pathology of retinal degeneration diseases. To date, the molecular mechanisms for this pathological process remain largely unclear. Junctional adhesion molecule-c (Jam-c) has been shown to play important roles in different biological events. However, its effect on retinal neuronal cells is unknown. OBJECTIVE: To determine the effect of Jam-c on adult mouse eyes, particularly, on retinal structure, vasculature and photoreceptor cells, in order to explore potential important target molecules for ocular diseases. METHODS: Jam-c global knockout mice, endothelial-specific and neuronal specific Jam-c conditional knockout mice using Tie2-Cre and Nestin-Cre mice respectively were used in this study. Mouse eyes were harvested from the different groups and eye size examined. Cryosections of the eyes were made and stained with Hematoxylin and Eosin (H&E) and the thicknesses of retinal layers measured. Retinal blood vessels and cone and rod photoreceptors were analyzed using isolectin B4, peanut agglutinin and rhodopsin as markers respectively. In vivo Jam-c knockdown in mouse eyes was performed by intravitreal injection of Jam c shRNA. Jam-c expression in the retinae was quantified by real-time PCR. RESULTS: Global Jam-c gene deletion in mice resulted in smaller eyes and decreased the diameters of lens and iris. Jam-c-/- mice display marked thinning of the outer nuclear layer (ONL), less numbers of photoreceptor cells, and abnormal retinal vasculature. Importantly, neuronal-specific Jam-c deletion led to similar phenotype, whereas no obvious defect was observed in endothelial specific Jam-c knockout mice. Moreover, Jam-c knockdown by shRNA also decreased ONL thickness and photoreceptor numbers. CONCLUSION: We found that Jam-c is critically required for the normal size and retinal structure. Particularly, Jam c plays important roles in maintaining the normal retinal thickness, vasculature and photoreceptor numbers. Jam-c thus may therefore have important roles in various ocular diseases. PMID- 29437009 TI - The bHLH Protein Nulp1 is Essential for Femur Development Via Acting as a Cofactor in Wnt Signaling in Drosophila. AB - BACKGROUND: The basic helix-loop-helix (bHLH) protein families are a large class of transcription factors, which are associated with cell proliferation, tissue differentiation, and other important development processes. We reported that the Nuclear localized protein-1 (Nulp1) might act as a novel bHLH transcriptional factor to mediate cellular functions. However, its role in development in vivo remains unknown. METHODS: Nulp1 (dNulp1) mutants are generated by CRISPR/Cas9 targeting the Domain of Unknown Function (DUF654) in its C terminal. Expression of Wg target genes are analyzed by qRT-PCR. We use the Top-Flash luciferase reporter assay to response to Wg signaling. RESULTS: Here we show that Drosophila Nulp1 (dNulp1) mutants, generated by CRISPR/Cas9 targeting the Domain of Unknown Function (DUF654) in its C terminal, are partially homozygous lethal and the rare escapers have bent femurs, which are similar to the major manifestation of congenital bent-bone dysplasia in human Stuve- Weidemann syndrome. The fly phenotype can be rescued by dNulp1 over-expression, indicating that dNulp1 is essential for fly femur development and survival. Moreover, dNulp1 overexpression suppresses the notch wing phenotype caused by the overexpression of sgg/GSK3beta, an inhibitor of the canonical Wnt cascade. Furthermore, qRT-PCR analyses show that seven target genes positively regulated by Wg signaling pathway are down regulated in response to dNulp1 knockout, while two negatively regulated Wg targets are up-regulated in dNulp1 mutants. Finally, dNulp1 overexpression significantly activates the Top-Flash Wnt signaling reporter. CONCLUSION: We conclude that bHLH protein dNulp1 is essential for femur development and survival in Drosophila by acting as a positive cofactor in Wnt/Wingless signaling. PMID- 29437011 TI - Involvement of PI3K, Akt, and RhoA in oestradiol regulation of cardiac iNOS expression. AB - BACKGROUND: Oestradiol is an important regulatory factor with several positive effects on the cardiovascular (CV) system. We evaluated the molecular mechanism of the in vivo effects of oestradiol on the regulation of cardiac inducible nitric oxide (NO) synthase (iNOS) expression and activity. METHODS: Male Wistar rats were treated with oestradiol (40 mg/kg, intraperitoneally) and after 24 h the animals were sacrificed. The concentrations of NO and L-Arginine (L-Arg) were determined spectrophotometrically. For protein expressions of iNOS, p65 subunit of nuclear factor-kappaB (NFkappaB-p65), Ras homolog gene family-member A (RhoA), angiotensin II receptor type 1 (AT1R), insulin receptor substrate 1 (IRS-1), p85, p110 and protein kinase B (Akt), Western blot method was used. Co immunoprecipitation was used for measuring the association of IRS-1 with the p85 subunit of phosphatidylinositol-3-kinase (PI3K). The expression of iNOS messenger ribonucleic acid (mRNA) was measured with the quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of the tissue was used to detect localization and expression of iNOS in heart tissue. RESULTS: Oestradiol treatment reduced L-Arg concentration (p<0.01), iNOS mRNA (p<0.01) and protein (p<0.001) expression, level of RhoA (p<0.05) and AT1R (p<0.001) protein. In contrast, plasma NO (p<0.05), Akt phosphorylation at Thr308 (p<0.05) and protein level of p85 (p<0.001) increased after oestradiol treatment. CONCLUSION: Our results suggest that oestradiol in vivo regulates cardiac iNOS expression via the PI3K/Akt signaling pathway, through attenuation of RhoA and AT1R. PMID- 29437012 TI - Marinobufagenin in Urine: A Potential Marker of Predisposition to Ethanol and a Target for Spironolactone. AB - BACKGROUND AND OBJECTIVE: Previously it was demonstrated that digitalis-like cardiotonic steroid, marinobufagenin (MBG), is implicated in the development of ethanol addiction in rats. We hypothesized that (i) levels of sodium pump ligand, MBG, would be negatively correlated with the amount of ethanol consumed by rats, and (ii) that spironolactone would oppose the MBG induced ethanol-seeking behavior and blood pressure in rats. METHODS: Voluntary consumption of 9% alcohol (vs. water) during 10 days period by 11 adult male Wistar rats was studied. Eight weeks after the beginning of the experiment, the animals were divided into two treatment subgroups: high alcohol drinkers (HAD, n=6, daily consumption of ethanol > 4 g/kg) and low alcohol drinkers (LAD, n=5, daily consumption of ethanol < 4 g/kg) rats. Spironolactone treatment (7 days) was started following 3 day habituation to intragastric vehicle administration. Consumption of ethanol and blood pressure were recorded daily. RESULTS: Urinary MBG excretion at baseline was 11.2+/-0.6 pmoles in HAD rats and 19.1+/-2.9 pmoles (p<0.05) in LAD rats, respectively. Seven days of spironolactone treatment was associated with reduction in ethanol intake (2.9 g/kg/24 hr), reduction in systolic blood pressure (5 mm Hg), and increase in sodium excretion (1 mmol/24 hr). CONCLUSION: Levels of MBG may be a predisposing factor to voluntary ethanol intake. Spironolactone, along with antihypertensive effect, decreases ethanol intake. PMID- 29437013 TI - A Probable Topiramate-Induced Limbs Paraesthesia and Rigid Fingers Flexion. AB - INTRODUCTION: Topiramate is a well-known anticonvulsant drug with a broad spectrum of actions. It has been proposed in the treatment of several types of epileptic seizures both in monotherapy and in add-on. Its usage has been extended to other disorders including migraine, essential tremor, obesity, alcohol and drug addiction. The most frequent side-effects of topiramate include dizziness, somnolence, insomnia, and ataxia. Paraesthesia, metabolic acidosis, kidney stones, hypohidrosis, cognitive impairment and eye symptoms have also been reported. CASE REPORT: We report on a girl affected by epileptic seizures treated with levetiracetam for five years. Due to worsening of the seizures, the dosage of this drug was increased and afterwards lowdosage topiramate was initiated. After 12 days from the introduction of topiramate, the girl began to present neurologic signs including limbs rigidity, pain, incoordination and flexed fingers. Gradual withdrawn of the topiramate resulted in progressive resolution of the symptomatology. This clinical episode could represent a probable topiramate-related side effect (Naranjo score 5), never reported before in this form. PMID- 29437014 TI - Drug-Induced Epistaxis: An Often-Neglected Adverse Effect. AB - BACKGROUND: Epistaxis is an active nose bleeding with a population occurrence of approximately 60%. Although epistaxis is a common clinical complaint, the majority of the cases are benign and caused by local induced factors (e.g., trauma and local inflammation). Nevertheless, it is also recognised that epistaxis can be induced after some drugs intake. AIMS: Due to the increasing use of drugs or drug combinations that potentially may induce epistaxis, this review aims to alert healthcare professionals for this often neglected adverse drug effect and its possible complications. METHODS: A comprehensive literature search was performed on PubMed and Google Scholar databases, considering the literature published from January 1985 to December 2015, using medical terms related to drug induced epistaxis, nosebleeds and nasal blood supply. RESULTS AND DISCUSSION: As expected, anticoagulant and antiplatelet drugs are the main pharmacotherapeutic agents associated with epistaxis, particularly warfarin, dabigatran, rivaroxaban and aspirin. However, it was reported that some selective serotonin reuptake inhibitors, intranasal corticosteroids, certain antibiotics and other drugs or drug associations can also be responsible for nosebleeds. Although most of these epistaxis episodes are mild to moderate, being spontaneously reversed or requiring only minor medical approaches to control it, there are several case reports, as well as retrospective and prospective studies, documenting severe epistaxis episodes after specific medicines intake. In these cases, some invasive medical interventions are demanded to manage the bleeding and avoid life threatening consequences. CONCLUSION: This work provides an integrated and comprehensive review on drug-induced epistaxis bridging the gap in the current scientific literature addressing this topic. Therefore, the scientific information gathered and discussed will be valuable to raise awareness among doctors and pharmacists for this drug-related problem, as well as to promote their active pharmacovigilance and reinforce patient education. PMID- 29437015 TI - The Yin and Yang of BK Channels in Epilepsy. AB - BACKGROUND & OBJECTIVE: The large conductance calcium-activated potassium (BK) channel, extensively distributed in the central nervous system (CNS), is considered as a vital player in the pathogenesis of epilepsy, with evidence implicating derangement of K+ as well as regulating action potential shape and duration. However, unlike other channels implicated in epilepsy whose function in neurons could clearly be labeled "excitatory" or "inhibitory", the unique physiological behavior of the BK channel allows it to both augment and decrease the excitability of neurons. Thus, the role of BK in epilepsy is controversial so far, and a growing area of intense investigation. CONCLUSION: Here, this review aims to highlight recent discoveries on the dichotomous role of BK channels in epilepsy, focusing on relevant BK-dependent pro- as well as antiepileptic pathways, and discuss the potential of BK specific modulators for the treatment of epilepsy. PMID- 29437016 TI - Commentary: Endophenotypes as Disease Modifiers: Decoding the Biology of Alzheimer's by Genome-wide Association Studies. PMID- 29437017 TI - Commentary: Recalling Memory by Brain Stimulation. PMID- 29437018 TI - Immunomodulatory and Anti-inflammatory Effects of Thymoquinone. AB - BACKGROUND: The immunomodulatory properties of Nigella sativa seed, as a basis of its clinical applications by many cultures have been reviewed. Thymoquinone (TQ) is one of the major bioactive components of the volatile oil of N. sativa seeds. METHODS: The review on immunomodulatory and anti- inflammatory effects of TQ was focused on published literature in the English language. The literature search was conducted in the following databases: PubMed (2004-2017), Scopus (2004-2017) and Google Scholar (2004-2017). The keywords used were the following terms: thymoquinone, immunomodulation, inflammation, autoimmune and asthma. RESULTS: The present investigations provide a comprehensive review of the ability of TQ to modulate inflammation and immune-related disorders in the various important disease states. This finding showed that TQ has anti-inflammatory properties that prevent the biosynthesis of important mediators in inflammatory processes and asthma such as 5-LO, COX, PGD2 and LTs. TQ also reduced LPS-induced proinflammatory cytokines such as interleukins (ILs) and TNF-alpha. In addition, TQ showed immunomodulatory role in the cellular and humoral immunity. This study also found that TQ improves imidacloprid toxicity through reducing oxidative stress and increasing chemokinesis, chemotaxis, phagocytic activity, antibody levels and the hemagglutination of immunoglobulins as well as by reducing serum MDA levels and hepatic enzymes. CONCLUSION: The study indicated the beneficial effects of TQ in immune-related diseases, however, well designed clinical trials in humans are required to confirm these effects. PMID- 29437019 TI - What Genetics Tells us about Cardiovascular Disease in Diabetic Patients? AB - BACKGROUND: Long-term diabetes causes other disease development such as cardiovascular diseases (CVD). OBJECTIVE: Genetics can help us to predict cardiovascular diseases in diabetic patients. Method and Search Strategy: We searched PubMed and Google scholar for the terms: Cardiovascular disease, Diabetes, Polymorphism, Genetics from 2000 to 2017, and then included the relevant studies in our study. DISCUSSION: Essential role of inheritance in multifactorial disease is obviously clear, however, varies by disease and by other factors such as age of disease onset and subtype of disease. CVD is a multifactorial disease which can develop in diabetes patients as a result of increase in oxidative stress. It may also increase expression of pro-inflammatory factors and induce apoptosis in cardiomyocytes. CONCLUSION: Predictive polymorphisms are risk estimators for CVD incidence in diabetes patients. SNPs such as 894G>T in NOS3 gene, V16 in MnSOD gene, Rs3918188 in NOS3 gene and Rs11614913 in MiR-196a2 increase the risk of CVD in diabetic patients are precious polymorphisms for CVD prediction in diabetic population. CDKN2B, MTHFR and ACE genes have polymorphisms which increase the risk of diabetes and other polymorphisms on these genes increase the risk of CVD, we suggest these genes are valuable to study and find out if there are any polymorphisms that predict CVD susceptibility in diabetic patients. PMID- 29437020 TI - Anorexia Nervosa and Comorbid Psychopathology. AB - BACKGROUND AND OBJECTIVE: There is great interest, supported by clinical experience, in the relationship between Eating Disorders (EDs) and psychiatric symptoms and diseases. The psychopathology of EDs is also referred to many risk and protective factors, and there is some evidence in the literature, also about genetic and neurobiological factors involved. The aim of this review is to examine and synthesize the recent scientific literature on this topic, in particular the complex relationship between Anorexia Nervosa and Neuropsychiatric Disorders. METHODS: We analyzed the best of published literature on the topic, identifying keywords and MeSH terms in Pubmed and then searching them. The last search was performed on November 2017. RESULTS: Psychiatric comorbidities are very common in anorexia nervosa. Mood disorders, major depressive disorders, anxiety disorders, obsessive-compulsive disorders, developmental disorders among autistic spectrum and attention-deficit hyperactivity disorder and even some personality disorders, substance abuse and borderline traits have been reported, and some observations suggest a positive genetic correlation between anorexia nervosa and schizophrenia. CONCLUSION: The great amount of scientific articles dealing with the relationship between EDs and psychopathology confirms the complexity of these problems and the difficulties in diagnosis and treatment. An accurate diagnosis and assessment of clinical risk about psychological, psychiatric, nutritional and somatic aspects are therefore essential for an appropriate therapeutic management of patients affected by anorexia nervosa. PMID- 29437021 TI - Homocysteine Levels in Autism Spectrum Disorder: A Clinical Update. AB - BACKGROUND AND OBJECTIVE: Homocysteine (Hcy) is a non-protein alpha-amino acid, which plays several important roles in human physiology and in the central nervous system. Although Hcy has several known biological properties in one carbon metabolism, its overproduction might be harmful, and could add to the pathophysiology associated with ASD. We reviewed the current evidence about changes in Hcy concentration in ASD and tried to correlate its changes with the clinical profile Discussion: The concentration of the amino acid in biological fluids (blood and urine) in children/ youngs with ASD is increased in the majority of studies when comparing to typically developing control subjects. Some report demonstrated a significant association between the severity of the disorder and the abnormalities in Hcy levels. CONCLUSION: Further research is needed to correlate the increase in Hcy with specific symptoms/ deficits in ASD and to evaluate the clinical impact of strategies that can reduce Hcy concentration in ASD. PMID- 29437022 TI - Lower Urinary Tract Symptoms in Metabolic Syndrome in Young Adults. AB - BACKGROUND AND OBJECTIVE: Metabolic syndrome (MS) is widespread among middle age people and presents an acute issue in preventive cardiology. A list of conditions associated with MS is quite long and it is constantly growing. Despite the data, described in scientific literature, on general pathogenetic mechanisms, the conditions associated with androgynous status, are not included into the register of MS associated nosologies. Such association is identified in men older than 60 years old and is explained by age related hypoandrogenaemia. However, the issue of occurrence rate of lower urinary tract syndromes (LUTS) in young men with MS and their association of androgen levels remains open. METHODS: 62 European men aged from 25 to 40 (30 patients with MS and 32 conditionally healthy persons) were examined. Apart from generally accepted methods of physical and instrumental examination, evaluation of hormonal status (insulin, testosterone, dehydrotestosteron), IPSS-QOI testing and transrectal USI of prostate and bladder were performed. RESULTS: Revealed a high frequency of increasing the size and volume of the prostate gland, the number of points on the IPSS questionnaire, corresponding to the initial manifestation of hyperplastic prostate diseases on the background of insulin resistance and normal androgen levels raises questions about the search for new pathogenetic links of the metabolic syndrome with the processes of induction of prostate growth. CONCLUSION: Modern standards of examination of patients with MS do not include routine methods for the detection of prostate diseases. The above data raise questions about the need for further study in young patients with verified MS, including IPSS-QOI questionnaire surveying and TRUS. PMID- 29437023 TI - Serum DHEA-S, Testosterone and Cortisol Levels in Female Patients with Schizophrenia. AB - OBJECTIVE: To compare the relation symptom severity and testosterone levels, and DHEA-S and cortisol in premenopausal women with schizophrenia and an age- and sex matched control group. METHODS: Thirty-two women with schizophrenia and 32 age- and sex-matched healthy controls were included in the study. All participants were aged between 20 and 45 years, and their previous treatments were olanzapine (n=14) and quetiapine (n=18). Symptom severity was assessed using the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS). A chemiluminescence immunoassay was used to investigate hormone profiles of the two groups, which were then compared and analyzed. The relation between the hormone levels and SANS and SAPS scores of the study group and controls was examined. RESULTS: There were statistically significantly higher levels of serum DHEA-S (p=0.002) in the study group than in the control group. No statistically significant difference was determined between the groups regarding serum testosterone and cortisol levels. A positive correlation was determined between the study groups' SANS scores and DHEA-S levels (p=0.012, r=0.440). CONCLUSION: DHEA-S might be a potential biologic marker for schizophrenia because there is evidence of an association between DHEA-S and the pathophysiology of schizophrenia. However, further research with greater patient numbers is required to verify these findings. PMID- 29437024 TI - Uric Acid, Metabolic Syndrome and Atherosclerosis: The Chicken or the Egg, Which Comes First? AB - BACKGROUND: A great debate in literature exists nowadays on the role of uric acid as a marker of cardiovascular and metabolic organ damage or a risk factor for cardiovascular and metabolic disease. METHODS: The study aimed to determine the relationship among serum uric acid and metabolic syndrome and atherosclerosis, by means of carotid intima media-thickness, in a cohort of 811 otherwise healthy overweight/obese subjects, without overt atherosclerosis not using any kind of drug. RESULTS: Uric acid levels were positively related to male gender, waist circumference, BMI, systolic and diastolic pressure levels, fasting insulin, fasting glucose, HOMA-IR, triglycerides, total cholesterol, LDL cholesterol, the presence of metabolic syndrome and the number of the components of metabolic syndrome and negatively related to HDL cholesterol levels. No correlation was found between uric acid and carotid intima media thickness. At the multiple regression analysis, only waist circumference and triglycerides (positively) and HDL-cholesterol (negatively) maintained an independent association with uric acid as dependent variable, while age, female gender and uric acid showed a significant independent association with metabolic syndrome as dependent variable. Moreover, the analysis of the odd ratios showed that the risk of developing metabolic syndrome was consistent with uric acid levels ranging from 3 mg/dl to 8 mg/dl. CONCLUSION: The presence of metabolic syndrome does not seem to provide hyperuricemia. By contrast, higher serum uric acid level may predict the risk of metabolic syndrome. Moreover, our results suggest that uric acid cannot be considered a risk factor for early atherosclerosis, at least when assessed using carotid ultrasound. PMID- 29437025 TI - Association between Vitamin K Epoxide Reductase (VKORC1) -1639G>A Polymorphism and Osteoporosis in Postmenopausal Women. AB - : Introduction: Osteoporosis is a common disease, and several factors contribute to its development. Recently, there has been increasing evidence that vitamin K (VK) plays a critical role in maintaining bone strength. Vitamin K serves as a co factor for the gamma-carboxylation of particular proteins to convert specific glutamic acid residues to gamma-carboxyglutamic acid residues. This process involves two enzymes, gamma-glutamyl carboxylase and vitamin K epoxide reductase (VKORC1). The number of studies investigating the effects of VKORC1 gene mutations on bone mineral density in postmenopausal osteoporosis patients is limited. The aim of this study was to investigate the relationship between the VKORC1 -1639G>A polymorphism and osteoporosis in postmenopausal Turkish women. METHODS: The study group consisted of 176 postmenopausal women with osteoporosis and 140 healthy postmenopausal women. The selection criteria for the healthy controls included non-osteoporotic bone mineral density (BMD) and similar demographic characteristics to the osteoporosis group. The genotyping of the VKORC1 -1639G>A polymorphism was conducted using the restriction fragment-length polymorphism method. RESULTS: We found that the genotype frequencies of the GG, GA and AA genotypes were 25.6, 64.2 and 10.2% in the patients and 33.6, 55.8 and 10.7% in the controls, respectively. In the patient and control groups, the genotype distribution of the studied locus was found to be non-compatible with Hardy-Weinberg equilibrium. We found a nonsignificant association between the 1639G>A polymorphism in the VKORC1 gene and osteoporosis in postmenopausal Turkish women. CONCLUSION: We have shown that the VKORC1 -1639G>A polymorphism is not a risk factor for postmenopausal osteoporosis. PMID- 29437026 TI - Vasopressin in Heart Failure. AB - BACKGROUND AND OBJECTIVE: The nonapeptide hypothalamic hormone vasopressin (VP), exerts important effects on cardiovascular system via its receptors V1, V2 and V3. Patients with congestive heart failure (CHF) present elevated plasma VP levels. Aim of this paper is to review the role of vasopressin in CHF. METHODS: We analyzed the best of published literature dealing with the role of VP in patients affected by CHF, identifying keywords and MeSH terms in Pubmed and then searching them. The last search was performed on August 2017. RESULTS: Scientific articles dealing with the relationship between VP and CHF show that circulating high VP levels found in CHF despite an exaggerated increase in circulatory blood volume can contribute to CHF exacerbation. In particular, the stimulation of V1R induces vascular constriction responsible for increased systemic vascular resistance and afterload, and, in addition, coronary vasoconstriction with consequent reduced coronary circulation and cardiac contractility, whereas the stimulation of V2R induces free water reabsorption and this is responsible of preload increase and congestion of pulmonary vascular bed with edema and hyponatremia, markers of advanced CHF. CONCLUSION: VP can play an important role among the derangements of the endocrine system in CHF even being a possible target in the treatment of this condition. Vaptans, antagonists of VP receptors, in fact, are able to increase urine output and plasma sodium levels without the increased risk of arrhythmic death induced by diuretics, even though, further studies are needed to establish a possible role of these drugs in the treatment of CHF. PMID- 29437028 TI - Changes in the Peripheral Endocannabinoid System as a Risk Factor for the Development of Eating Disorders. AB - BACKGROUND AND OBJECTIVE: Eating Disorder (ED) is characterized by persistently and severely disturbed eating behaviours. They arise from a combination of long standing behavioural, emotional, psychological, interpersonal, and social factors and result in insufficient nutrient ingestion and/or adsorption. The three main EDs are: anorexia nervosa, bulimia nervosa, and binge eating disorder. We review the role of peripheral endocannabinoids in eating behaviour. DISCUSSION: The neuronal pathways involved in feeding behaviours are closely related to catecholaminergic, serotoninergic and peptidergic systems. Accordingly, feeding is promoted by serotonin, dopamine, and prostaglandin and inhibited by neuropeptide Y, norepinephrine, GABA, and opioid peptides. The endocannabinoid system plays a role in EDs, and multiple lines of evidence indicate that the cannabinoid signalling system is a key modulatory factor of the activity in the brain areas involved in EDs as well as in reward processes. CONCLUSION: Besides their central role in controlling food behaviours, peripheral cannabinoids are also involved in regulating adipose tissue and insulin signalling as well as cell metabolism in peripheral tissues such as liver, pancreas, fatty tissue, and skeletal muscle. Altogether, these data indicate that peripheral cannabinoids can provide new therapeutic targets not only for EDs but also for metabolic disease. PMID- 29437029 TI - Formulation, In-Vitro and Ex-Vivo Evaluation of Tretinoin Loaded Cubosomal Gel for the Treatment of Acne. AB - OBJECTIVE: The current work was attempted to formulate and evaluate the topical sustained release delivery systems called cubosomes containing Tretinoin for the acne treatment. The recent patents on various formulations of tretinoin (EP0408370A2) helped in selecting a new formulation and evaluation. METHODS: Tretinoin loaded cubosomes were prepared by bottom-up technique, using varying the concentration of lipid and surfactant and keeping the drug concentration constant, a total of nine formulations of tretinoin was developed. These preparations were evaluated for surface charge, particle size, particle morphology, encapsulation efficiency, in-vivo and in-vitro release studies of gel enriched with cubosome dispersion. Finally, the stability studies of cubosomal gel were performed on optimized formulations. RESULTS: Significant result were obtained with tretinoin formulation as the drug is lipophilic, so it gives more depot effect on the epidermis and good retention property. The data obtained from the formulations showed that formulation TCF-5 was the optimized formulation which exhibited better drug release and entrapment efficiency. CONCLUSION: It can be concluded that cubosomes offer benefits of quick onset as well as the maximal release of drug with fewer side effects. Thus, cubosomes represent a capable transporter having the property to sustain the release of drug, potential to localize the drug in the skin with a possible clinical application for acne vulgaris treatment due to cubosome depot effect on the epidermis. PMID- 29437027 TI - Benefits of Olive Oil Phenolic Compounds in Disease Prevention. AB - BACKGROUND AND OBJECTIVE: The preventive effects of olive oil against different diseases have been attributed to its high phenolic compound content. The objective of this study was to examine available scientific evidence on the beneficial effects against chronic diseases of olive oil phenolic compounds. METHOD: This article examines recently published data on olive oil phenolic compounds and their potential benefits in the prevention of cardiovascular disease, cancer, neurodegenerative disease, and osteoporosis. RESULTS: The antioxidant, anti-proliferative, pro-apoptotic, and anti-inflammatory activities of olive oil phenolic compounds have preventive effects against heart disease and cancer. These compounds also exert neuroprotective and neuromodulator effects against neurodegenerative disease, inhibiting the development of amyloid plaques. Finally, they are known to protect against osteoporosis, favoring bone regeneration. CONCLUSION: Dietary intake of olive oil can be recommended by healthcare professionals as an important source of phenolic compounds that play a role in the prevention of chronic disease and the consequent improvement in quality of life. PMID- 29437030 TI - Preliminary Human Radiation Dose Estimates of PET Renal Agents, Para-18F Fluorohippuric Acid and Ortho-124I-Iodohippuric Acid from Rat Biodistribution Data. AB - BACKGROUND: Para-18F-fluorohippuric acid (18F-PFH) and ortho-124I-iodohippuric acid (124IOIH) were recently identified as potential radiotracers suitable for conducting renography using positron emission tomography (PET). The aim of this work was to estimate preliminary human-equivalent internal radiation dose of 18F PFH and 124I-OIH using the biodistribution data reported in healthy rats. The results were compared with the absorbed dose data of technetium-99m mercaptoacetyltriglycine (99mTc- MAG3) as documented in the International Commission on Radiological Protection (ICRP) publication 80. METHODS: The medical internal radiation dose (MIRD) formula was applied to extrapolate data from rats to human and to project the absorbed radiation dose for various organs in humans. S factor was calculated by Monte-Carlo N-particle (MCNP) simulation. RESULTS: Our dose prediction shows that an injection of 18F-PFH or 124I-OIH in humans would result in an estimated effective absorbed dose of 0.09 or 0.17 uSv/MBq respectively for whole body, which is about 135 or 73 times respectively lower than that obtained with an injection of 99mTc-MAG3. All organs except kidneys would receive an estimated effective absorbed dose of <0.1 uSv/MBq for 18F-PFH or 124I-OIH. Kidneys would receive a dose of 0.83 or 0.77 uSv/MBq respectively for 18F-PFH or 124I-OIH. CONCLUSIONS: Our results indicate that 18F-PFH and 124I-OIH would deliver much safer levels and lower radiation doses to the patients compared to 99mTc-MAG3 and warrants a clinical trial to estimate the radiation doses more accurately. PMID- 29437031 TI - Underexpression of miR-486-5p but not Overexpression of miR-155 is Associated with Lung Cancer Stages. AB - BACKGROUND: Evidence is increasing that microRNAs (miR) are particularly important in lung homeostasis and development and have been shown to be involved in many pulmonary diseases such as asthma, chronic obstructive pulmonary disease, sarcoidosis, Lung Cancer (LC) and other smoking-related diseases. OBJECTIVE: The objective of this study was to investigate the expression of miR-155 and miR-486 5p in tissues from LC patients and healthy endobronchial mucosa as prognostic biomarkers for diagnosing LC. METHODS: Bronchoscopic and thoracoscopic tissue biopsies were taken from 50 LC patients and other 50 control subjects without lung mass, who were planned for a clinical bronchoscopy. The expressions of miR 155 and miR-486-5p in both tumor tissue and healthy mucosa were detected by quantitative real-time polymerase chain reaction. RESULTS: Histopathology showed that 72% of LC patients were in advanced stages III and IV, with non-small cell lung carcinoma and adenocarcinoma being the most common diagnosis. miR-155 was significantly overexpressed while, miR-486-5p was underexpressed, in LC patients as compared to controls. Area under receiver operating characteristic curves of miR-155 (<-0.9) and miR-486 (>-0.62) had sensitivity of 92 and 96% and specificity of 80 and 84%, respectively, in discriminating LC patients from controls with benign solitary pulmonary nodules. CONCLUSION: miR-155 was highly overexpressed, yet it did not correlate with stages, while miR-486- 5p was extremely underexpressed and significantly correlated with stages of LC. Thus, their detection represents an excellent diagnostic/prognostic tool to support more established techniques linked to LC spread locally and systemically. PMID- 29437032 TI - Computerised interpretation of the fetal heart rate during labour: a randomised controlled trial (INFANT). AB - BACKGROUND: Continuous electronic fetal monitoring (EFM) in labour is widely used and computerised interpretation has the potential to increase its utility. OBJECTIVES: This trial aimed to find out whether or not the addition of decision support software to assist in the interpretation of the cardiotocograph (CTG) reduced the number of poor neonatal outcomes, and whether or not it was cost effective. DESIGN: Two-arm individually randomised controlled trial. The allocations were computer generated using stratified block randomisation employing variable block sizes. The trial was not masked. SETTING: Labour wards in England, Scotland and the Republic of Ireland. PARTICIPANTS: Women in labour having EFM, with a singleton or twin pregnancy, at >= 35 weeks' gestation. INTERVENTIONS: Decision support or no decision support. MAIN OUTCOME MEASURES: The primary outcomes were (1) a composite of poor neonatal outcome {intrapartum stillbirth or early neonatal death (excluding lethal congenital anomalies), or neonatal morbidity [defined as neonatal encephalopathy (NNE)], or admission to a neonatal unit within 48 hours for >= 48 hours (with evidence of feeding difficulties, respiratory illness or NNE when there was evidence of compromise at birth)}; and (2) developmental assessment at the age of 2 years in a subset of surviving children. RESULTS: Between 6 January 2010 and 31 August 2013, 47,062 women were randomised and 46,042 were included in the primary analysis (22,987 in the decision support group and 23,055 in the no decision support group). The short-term primary outcome event rate was higher than anticipated. There was no evidence of a difference in the incidence of poor neonatal outcome between the groups: 0.7% (n = 172) of babies in the decision support group compared with 0.7% (n = 171) of babies in the no decision support group [adjusted risk ratio 1.01, 95% confidence interval (CI) 0.82 to 1.25]. There was no evidence of a difference in the long-term primary outcome of the Parent Report of Children's Abilities Revised with a mean score of 98.0 points [standard deviation (SD) 33.8 points] in the decision support group and 97.2 points (SD 33.4 points) in the no decision support group (mean difference 0.63 points, 95% CI -0.98 to 2.25 points). No evidence of a difference was found for health resource use and total costs. There was evidence that decision support did change practice (with increased fetal blood sampling and a lower rate of repeated alerts). LIMITATIONS: Staff in the control group may learn from exposure to the decision support arm of the trial, resulting in improved outcomes in the control arm. This was identified in the planning stage and felt to be unlikely to have a significant effect on the results. As this was a pragmatic trial, the response to CTG alerts was left to the attending clinicians. CONCLUSIONS: This trial does not support the hypothesis that the use of computerised interpretation of the CTG in women who have EFM in labour improves the clinical outcomes for mothers or babies. FUTURE WORK: There continues to be an urgent need to improve knowledge and training about the appropriate response to CTG abnormalities, including timely intervention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98680152. FUNDING: This project was funded by the National Institute for Health Research (NIHR) HTA programme and will be published in full in Health Technology Assessment; Vol. 22, No. 9. See the NIHR Journals Library website for further project information. Sara Kenyon was part funded by the NIHR Collaboration for Leadership in Applied Health Research and Care West Midlands. PMID- 29437033 TI - The impact of Objective Mathematical Analysis during Fractional Flow Reserve measurement: results from the OMA-FFR study. AB - AIMS: Fractional flow reserve (FFR), the reference standard for guiding coronary revascularisation, is most commonly acquired during intravenous adenosine infusion. Results may be sensitive to system- and operator-dependent variability in how pressure data are analysed and interpreted. To quantify FFR objectively, we developed a computational protocol to process the recorded pressure signals in a consistent manner. We studied the impact on lesion (re)classification and compared this with the operator-selected FFR obtained during cardiac catheterisation. METHODS AND RESULTS: The algorithm used a moving average and Fourier transformation to identify the Pd/Pa ratio at its nadir (FFRmin) and during the stable hyperaemic period (FFRstable) in <2 s with 100% repeatability, in 163 coronary stenoses (93 patients). The mean operator-selected FFR (FFRCL) was higher than FFRmin and lower than FFRstable (0.779 vs. 0.762 vs. 0.806, p=<0.01). Compared with FFRmin, FFRstable resulted in 16.5% of all lesions being reclassified, all from significant to non-significant (p<0.01). FFRCL classified lesion significance differently from both FFRstable and FFRmin (11.7% and 6.1% lesions reclassified, respectively, p<0.01). CONCLUSIONS: Subtle differences in how pressure data are analysed and interpreted by the operator during adenosine infusion result in significant differences in the classification of physiological lesion significance. An algorithmic analysis may be helpful in standardising FFR analysis, providing an objective and repeatable result. PMID- 29437034 TI - Haemodynamic impact of a new pulsatile mechanical circulatory support in high risk coronary stenting. PMID- 29437035 TI - Interventional cardiology: review of the year 2017. PMID- 29437036 TI - Five-year outcome of a randomised trial comparing second-generation drug-eluting stents using either biodegradable polymer or durable polymer: the NOBORI biolimus eluting versus XIENCE/PROMUS everolimus-eluting stent trial (NEXT). PMID- 29437037 TI - Comparative analysis of cerebrovascular events in transcatheter and surgical aortic valve replacement: a systematic review and meta-analysis of randomised trials. AB - AIMS: Transcatheter aortic valve replacement (TAVR) has become the procedure of choice for inoperable patients and a safe alternative to surgical aortic valve replacement (SAVR) among moderate-risk patients. We used meta-analysis to compare the incidence of cerebrovascular events amongst patients undergoing TAVR and SAVR in randomised controlled trials (RCT). METHODS AND RESULTS: Our search revealed five RCT published between 2011 and 2017 with a total of 5,414 patients. Data were summarised as Mantel-Haenszel relative risk (RR) and 95% confidence intervals (CI). The risk of major stroke (RR 0.89, 95% CI: 0.53-1.51), all strokes (RR 0.85, 95% CI: 0.59-1.22) and all cerebrovascular events (RR 0.94, 95% CI: 0.75-1.17) was comparable between patients undergoing TAVR and SAVR at 30 days of follow-up. The risk of all strokes (RR 0.92, 95% CI: 0.69-1.22), major stroke (RR 0.92, 95% CI: 0.62-1.37) and all cerebrovascular events (RR 1.03, 95% CI: 0.79-1.33) was comparable between TAVR and SAVR at one year of follow-up. The incidence of major stroke (RR 1.02, 95% CI: 0.64-1.61), all strokes (RR 1.12, 95% CI: 0.78-1.62) and all cerebrovascular events (RR 1.23, 95% CI: 0.91-1.66) was comparable between TAVR and SAVR between 30 days and one year of follow-up. CONCLUSIONS: In our meta-analysis of RCT comparing TAVR and SAVR, we showed comparable risk of major stroke, all stroke and all cerebrovascular events. PMID- 29437038 TI - Double wire rotational atherectomy technique in a heavily calcified coronary bifurcation. PMID- 29437039 TI - microRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer. AB - Because of high heterogeneity, molecular characterization of prostate cancer based on biopsy sampling is often challenging. Hence, a minimally invasive method to determine the molecular imprints of a patient's tumor for risk stratification would be advantageous. In this study, we employ a novel, digital amplification free quantification method using the nCounter technology (NanoString Technologies) to profile exosomal serum miRNAs (ex-miRNA) from aggressive prostate cancer cases, benign prostatic hyperplasia, and disease-free controls. We identified several dysregulated miRNAs, one of which was the tumor suppressor miR-1246. miR-1246 was downregulated in prostate cancer clinical tissues and cell lines and was selectively released into exosomes. Overexpression of miR-1246 in a prostate cancer cell line significantly inhibited xenograft tumor growth in vivo and increased apoptosis and decreased proliferation, invasiveness, and migration in vitro miR-1246 inhibited N-cadherin and vimentin activities, thereby inhibiting epithelial-mesenchymal transition. Ex-miR-1246 expression correlated with increasing pathologic grade, positive metastasis, and poor prognosis. Our analyses suggest ex-miR-1246 as a promising prostate cancer biomarker with diagnostic potential that can predict disease aggressiveness.Significance: Dysregulation of exosomal miRNAs in aggressive prostate cancer leads to alteration of key signaling pathways associated with metastatic prostate cancer. Cancer Res; 78(7); 1833-44. (c)2018 AACR. PMID- 29437040 TI - Durable Clinical Benefit in Metastatic Renal Cell Carcinoma Patients Who Discontinue PD-1/PD-L1 Therapy for Immune-Related Adverse Events. AB - The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti-PD-1/PD-L1 therapy as second line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7-46.5) and median TTP was 18.4 months (95% CI, 4.7-54.3) per Kaplan-Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients (n = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% (n = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti-PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti-PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. Cancer Immunol Res; 6(4); 402-8. (c)2018 AACR. PMID- 29437041 TI - Preoperative exercise halves the postoperative complication rate in patients with lung cancer: a systematic review of the effect of exercise on complications, length of stay and quality of life in patients with cancer. AB - OBJECTIVE: To investigate the effectiveness of preoperative exercises interventions in patients undergoing oncological surgery, on postoperative complications, length of hospital stay and quality of life. DESIGN: Intervention systematic review with meta-analysis. DATA SOURCES: MEDLINE, Embase and PEDro. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Trials investigating the effectiveness of preoperative exercise for any oncological patient undergoing surgery were included. The outcomes of interest were postoperative complications, length of hospital stay and quality of life. Relative risks (RRs), mean differences (MDs) and 95% CI were calculated using random-effects models. RESULTS: Seventeen articles (reporting on 13 different trials) involving 806 individual participants and 6 tumour types were included. There was moderate quality evidence that preoperative exercise significantly reduced postoperative complication rates (RR 0.52, 95% CI 0.36 to 0.74) and length of hospital stay (MD -2.86 days, 95% CI -5.40 to -0.33) in patients undergoing lung resection, compared with control. For patients with oesophageal cancer, preoperative exercise was not effective in reducing length of hospital stay (MD 2.00 days, 95% CI -2.35 to 6.35). Although only assessed in individual studies, preoperative exercise improved postoperative quality of life in patients with oral or prostate cancer. No effect was found in patients with colon and colorectal liver metastases. CONCLUSIONS: Preoperative exercise was effective in reducing postoperative complications and length of hospital stay in patients with lung cancer. Whether preoperative exercise reduces complications, length of hospital stay and improves quality of life in other groups of patients undergoing oncological surgery is uncertain as the quality of evidence is low. PROSPEROREGISTRATION NUMBER. PMID- 29437042 TI - Site-1 protease regulates skeletal stem cell population and osteogenic differentiation in mice. AB - Site-1 protease (S1P) is a proprotein convertase with essential functions in the conversion of precursor proteins to their active form. In earlier studies, we demonstrated that S1P ablation in the chondrocyte lineage results in a drastic reduction in endochondral bone formation. To investigate the mechanistic contribution of S1P to bone development we ablated S1P in the osterix lineage in mice. S1P ablation in this lineage results in osteochondrodysplasia and variable degrees of early postnatal scoliosis. Embryonically, even though Runx2 and osterix expression are normal, S1P ablation results in a delay in vascular invasion and endochondral bone development. Mice appear normal when born, but by day 7 display pronounced dwarfism with fragile bones that exhibit significantly reduced mineral density, mineral apposition rate, bone formation rate and reduced osteoblasts indicating severe osteopenia. Mice suffer from a drastic reduction in bone marrow mesenchymal progenitors as analyzed by colony-forming unit-fibroblast assay. Fluorescence-activated cell sorting analysis of the skeletal mesenchyme harvested from bone marrow and collagenase-digested bone show a drastic reduction in hematopoietic lineage-negative, endothelial-negative, CD105 + skeletal stem cells. Bone marrow mesenchymal progenitors are unable to differentiate into osteoblasts in vitro, with no effect on adipogenic differentiation. Postnatal mice have smaller growth plates with reduced hypertrophic zone. Thus, S1P controls bone development directly by regulating the skeletal progenitor population and their differentiation into osteoblasts.This article has an associated First Person interview with the first author of the paper. PMID- 29437043 TI - The histone deacetylase HDAC1 positively regulates Notch signaling during Drosophila wing development. AB - The Notch signaling pathway is highly conserved across different animal species and plays crucial roles in development and physiology. Regulation of Notch signaling occurs at multiple levels in different tissues and cell types. Here, we show that the histone deacetylase HDAC1 acts as a positive regulator of Notch signaling during Drosophila wing development. Depletion of HDAC1 causes wing notches on the margin of adult wing. Consistently, the expression of Notch target genes is reduced in the absence of HDAC1 during wing margin formation. We further provide evidence that HDAC1 acts upstream of Notch activation. Mechanistically, we show that HDAC1 regulates Notch protein levels by promoting Notch transcription. Consistent with this, the HDAC1-associated transcriptional co repressor Atrophin (Atro) is also required for transcriptional activation of Notch in the wing disc. In summary, our results demonstrate that HDAC1 positively regulates Notch signaling and reveal a previously unidentified function of HDAC1 in Notch signaling. PMID- 29437044 TI - Mechanical properties of silk of the Australian golden orb weavers Nephila pilipes and Nephilaplumipes. AB - Silks from orb-weaving spiders are exceptionally tough, producing a model polymer for biomimetic fibre development. The mechanical properties of naturally spun silk threads from two species of Australian orb-weavers, Nephila pilipes and Nephilaplumipes, were examined here in relation to overall thread diameter, the size and number of fibres within threads, and spider size. N. pilipes, the larger of the two species, had significantly tougher silk with higher strain capacity than its smaller congener, producing threads with average toughness of 150 MJ m 3, despite thread diameter, mean fibre diameter and number of fibres per thread not differing significantly between the two species. Within N. pilipes, smaller silk fibres were produced by larger spiders, yielding tougher threads. In contrast, while spider size was correlated with thread diameter in N. plumipes, there were no clear patterns relating to silk toughness, which suggests that the differences in properties between the silk of the two species arise through differing molecular structure. Our results support previous studies that found that the mechanical properties of silk differ between distantly related spider species, and extends on that work to show that the mechanical and physical properties of silk from more closely related species can also differ remarkably. PMID- 29437046 TI - Zika and Public Health: Understanding the Epidemiology and Information Environment. AB - Because Zika is a newly emerging infectious disease with little previous information known about it, there are many epidemiologic and clinical questions. The complexity of providing care to those who are at risk for infection or are already infected with Zika in this evidence-scarce environment cannot be understated. In this article, we provide an overview of the Zika virus (ZIKV) in the context of public health and pediatric health care. A broad public health focus is used to provide relevant information for addressing important questions about the epidemic and to facilitate communication with patients, parents, and caregivers within the current information environment. We explore issues regarding the epidemiology of the virus (including why ZIKV outbreaks are occurring), what has changed since the sporadic case reports before the outbreaks, why the true incidence is difficult to estimate, why attack rates vary by population and geography, and why the association between Zika and congenital Zika syndrome and Guillain-Barre syndrome have only come to light recently. Additionally, challenges related to the current information environment, traditional and informal information sources about the ZIKV, and examples of Zika public health communication campaigns are discussed. Importantly, we review the existing findings regarding the US population's Zika-related knowledge, attitudes, beliefs, and behavior by highlighting variations and gaps. We conclude by identifying related research questions that remain critical. PMID- 29437048 TI - Development of Infants With Congenital Zika Syndrome: What Do We Know and What Can We Expect? AB - The association between Zika virus infection during pregnancy and severe birth defects in infants has led to worldwide attention focused on the mechanisms of the disease and the prevention of future exposure. Surveillance efforts around the world continue with the goal of identifying and monitoring all potentially exposed women and their newborns. For infants who were born with congenital Zika syndrome (CZS) and their families, an uncertain future awaits. As infants who were born with CZS during the most recent outbreak enter their second year of life, new developments in the outcomes of the condition continue to unfold, providing some insight into the likely long-term sequalae. In this article, I review the literature on emerging findings regarding the impact of CZS on the developing infant and provide some predictions regarding the long-term outcomes and lifetime needs of these children and their families. PMID- 29437047 TI - Public Health Approach to Addressing the Needs of Children Affected by Congenital Zika Syndrome. AB - We have learned much about the short-term sequelae of congenital Zika virus (ZIKV) infection since the Centers for Disease Control and Prevention activated its ZIKV emergency response in January 2016. Nevertheless, gaps remain in our understanding of the full spectrum of adverse health outcomes related to congenital ZIKV infection and how to optimize health in those who are affected. To address the remaining knowledge gaps, support affected children so they can reach their full potential, and make the best use of available resources, a carefully planned public health approach in partnership with pediatric health care providers is needed. An essential step is to use population-based data captured through surveillance systems to describe congenital Zika syndrome. Another key step is using collected data to investigate why some children exhibit certain sequelae during infancy and beyond, whereas others do not, and to describe the clustering of anomalies and the timing of when these anomalies occur, among other research questions. The final critical step in the public health framework for congenital Zika syndrome is an intervention strategy with evidence-based best practices for longer-term monitoring and care. Adherence to recommended evaluation and management procedures for infants with possible congenital ZIKV infection, including for those with less obvious developmental and medical needs at birth, is essential. It will take many years to fully understand the effects of ZIKV on those who are congenitally infected; however, the lifetime medical and educational costs as well as the emotional impact on affected children and families are likely to be substantial. PMID- 29437049 TI - Ophthalmologic Manifestations Associated With Zika Virus Infection. AB - Vision plays an important role in the development of communication, social interaction, spatial awareness, and the motor skills needed to explore the environment. In the past 2 years, researchers have described the broad spectrum of clinical features that comprise congenital Zika syndrome (CZS). The ocular manifestations are considered 1 important pillar of this new entity. The most characteristic ophthalmic findings include chorioretinal scars and focal pigmentary changes seen in the macular region. Since these findings were first reported, other researchers have validated and extended them, leading to a more complete picture of the spectrum of ocular manifestations related to CZS. In this article, we summarize the current knowledge on the ocular implications of CZS and emphasize the importance of early rehabilitation to enhance visual performance in affected children. PMID- 29437050 TI - Motor Abnormalities and Epilepsy in Infants and Children With Evidence of Congenital Zika Virus Infection. AB - Initial reports of congenital Zika virus (ZIKV) infection focused on microcephaly at birth with severe brain anomalies; the phenotype has broadened to include microcephaly that develops after birth and neurodevelopmental sequelae. In this narrative review, we summarize medical literature describing motor abnormalities and epilepsy in infants with evidence of congenital ZIKV infection and provide information on the impact of these conditions. Specific scenarios are used to illustrate the complex clinical course in infants with abnormalities that are consistent with congenital Zika syndrome. A search of the English-language medical literature was done to identify motor abnormalities and epilepsy in infants with evidence of congenital ZIKV infection by using Medline and PubMed, Embase, Scientific Electronic Library Online, Scopus, the OpenGrey Repository, and the Grey Literature Report in Public Health. Search terms included "Zika" only and "Zika" in combination with any of the following terms: "epilepsy," "seizure," "motor," and "cerebral palsy." Clinical features of motor abnormalities and epilepsy in these children were reviewed. Thirty-six publications were identified; 8 were selected for further review. Among infants with clinical findings that are consistent with congenital Zika syndrome, 54% had epilepsy and 100% had motor abnormalities. In these infants, impairments that are consistent with diagnoses of cerebral palsy and epilepsy occur frequently. Pyramidal and extrapyramidal motor abnormalities were notable for their early development and co-occurrence. Prompt identification of potential disabilities enables early intervention to improve the quality of life for affected children. Long-term studies of developmental outcomes and interventions in children with congenital ZIKV infection are needed. PMID- 29437051 TI - The Likely Impact of Congenital Zika Syndrome on Families: Considerations for Family Supports and Services. AB - Congenital Zika virus infection has obvious implications for infants, and considerable research has addressed the nature and consequences of congenital Zika syndrome (CZS). Children with classic CZS meet the criteria for "children with medical complexity," and ongoing research is required to understand the range of needs and optimal treatment options. Far less attention has been given to the consequences of CZS for families, which are both immediate and lifelong. Although families of children with CZS have much in common with families of other children with disabilities, at least 4 features of CZS have special family implications: (1) the severity of the impact on children with obvious abnormalities at birth, coupled with the anticipation of a lifetime of caregiving and economic burdens; (2) uncertainty about the unfolding consequences, both for obviously affected children and for exposed children with no symptoms at birth; (3) a lack of specialized professional knowledge about the course of the disease or treatment options; and (4) social isolation, a lack of social or community supports, and potential stigma. Supporting families will require a family centered approach to services, extensive care coordination, access to evolving new information, ongoing surveillance, formal and informal supports, and individualized child and family services. PMID- 29437052 TI - Next generation sequencing: is this the moment? PMID- 29437053 TI - Can next generation sequencing play a role in detecting pathogens in synovial fluid? AB - AIMS: The diagnosis of periprosthetic joint infection can be difficult due to the high rate of culture-negative infections. The aim of this study was to assess the use of next-generation sequencing for detecting organisms in synovial fluid. MATERIALS AND METHODS: In this prospective, single-blinded study, 86 anonymized samples of synovial fluid were obtained from patients undergoing aspiration of the hip or knee as part of the investigation of a periprosthetic infection. A panel of synovial fluid tests, including levels of C-reactive protein, human neutrophil elastase, total neutrophil count, alpha-defensin, and culture were performed prior to next-generation sequencing. RESULTS: Of these 86 samples, 30 were alpha-defensin-positive and culture-positive (Group I), 24 were alpha defensin-positive and culture-negative (Group II) and 32 were alpha-defensin negative and culture-negative (Group III). Next-generation sequencing was concordant with 25 results for Group I. In four of these, it detected antibiotic resistant bacteria whereas culture did not. In another four samples with relatively low levels of inflammatory biomarkers, culture was positive but next generation sequencing was negative. A total of ten samples had a positive next generation sequencing result and a negative culture. In five of these, alpha defensin was positive and the levels of inflammatory markers were high. In the other five, alpha-defensin was negative and the levels of inflammatory markers were low. While next-generation sequencing detected several organisms in each sample, in most samples with a higher probability of infection, there was a predominant organism present, while in those presumed not to be infected, many organisms were identified with no predominant organism. CONCLUSION: Pathogens causing periprosthetic infection in both culture-positive and culture-negative samples of synovial fluid could be identified by next-generation sequencing. Cite this article: Bone Joint J 2018;100-B:127-33. PMID- 29437054 TI - The effect of bearing surface on risk of periprosthetic joint infection in total hip arthroplasty: a systematic review and meta-analysis. AB - AIMS: Periprosthetic joint infection (PJI) is a serious complication of total hip arthroplasty (THA). Different bearing surface materials have different surface properties and it has been suggested that the choice of bearing surface may influence the risk of PJI after THA. The objective of this meta-analysis was to compare the rate of PJI between metal-on-polyethylene (MoP), ceramic-on polyethylene (CoP), and ceramic-on-ceramic (CoC) bearings. PATIENTS AND METHODS: Electronic databases (Medline, Embase, Cochrane library, Web of Science, and Cumulative Index of Nursing and Allied Health Literature) were searched for comparative randomized and observational studies that reported the incidence of PJI for different bearing surfaces. Two investigators independently reviewed studies for eligibility, evaluated risk of bias, and performed data extraction. Meta-analysis was performed using the Mantel-Haenzel method and random-effects model in accordance with methods of the Cochrane group. RESULTS: Our search strategy revealed 2272 studies, of which 17 met the inclusion criteria and were analyzed. These comprised 11 randomized controlled trials and six observational studies. The overall quality of included studies was high but the observational studies were at high risk of bias due to inadequate adjustment for confounding factors. The overall cumulative incidence of PJI across all studies was 0.78% (1514/193 378). For each bearing combination, the overall incidence was as follows: MoP 0.85% (1353/158 430); CoP 0.38% (67/17 489); and CoC 0.53% (94/17 459). The meta-analysis showed no significant difference between the three bearing combinations in terms of risk of PJI. CONCLUSION: On the basis of the clinical studies available, there is no evidence that bearing choice influences the risk of PJI. Future research, including basic science studies and large, adequately controlled registry studies, may be helpful in determining whether implant materials play a role in determining the risk of PJI following arthroplasty surgery. Cite this article: Bone Joint J 2018;100-B:134-42. PMID- 29437055 TI - Aseptic revision total hip arthroplasty in the elderly : quantifying the risks for patients over 80 years old. AB - AIMS: The aim of this study was to compare the rate of perioperative complications following aseptic revision total hip arthroplasty (THA) in patients aged >= 80 years with that in those aged < 80 years, and to identify risk factors for the incidence of serious adverse events in those aged >= 80 years using a large validated national database. PATIENTS AND METHODS: Patients who underwent aseptic revision THA were identified in the 2005 to 2015 National Surgical Quality Improvement Program (NSQIP) database and stratified into two age groups: those aged < 80 years and those aged >= 80 years. Preoperative and procedural characteristics were compared. Multivariate regression analysis was used to compare the risk of postoperative complications and readmission. Risk factors for the development of a serious adverse event in those aged >= 80 years were characterized. RESULTS: The study included 7569 patients aged < 80 years and 1419 were aged >= 80 years. Multivariate analysis showed a higher risk of perioperative mortality, pneumonia, urinary tract infection and the requirement for a blood transfusion and an extended length of stay in those aged >= 80 years compared with those aged < 80 years. Independent risk factors for the development of a serious adverse event in those aged >= 80 years include an American Society of Anesthesiologists score of >= 3 and procedures performed under general anaesthesia. CONCLUSION: Even after controlling for patient and procedural characteristics, aseptic revision THA is associated with greater risks in patients aged >= 80 years compared with younger patients. This is important for counselling and highlights the need for medical optimization in these vulnerable patients. Cite this article: Bone Joint J 2018;100-B:143-51. PMID- 29437056 TI - Efficacy and safety of intra-articular versus intravenous tranexamic acid in reducing perioperative blood loss in total knee arthroplasty: a prospective randomized double-blind equivalence trial. AB - AIMS: The aims of this study were to compare the efficacy and safety of intra articular and intravenous (IV) tranexamic acid (TXA) in controlling perioperative blood loss in total knee arthroplasty (TKA) using a randomized, double-blinded equivalence trial. PATIENTS AND METHODS: A total of 182 patients aged between 45 and 75 years undergoing unilateral TKA at a tertiary centre were randomized to receive TXA, either 1.5 g intra-articularly after closure of the wound (n = 91) or two doses of 10 mg/kg IV (n = 91). The primary outcome measure was the reduction in the level of haemoglobin (Hb) in the blood on the fifth postoperative day. Secondary outcome measures were the total, visible, and hidden blood losses (TBL, VBL, HBL). We assumed equivalence of the primary outcome in both routes with a margin of +/- 0.35gm/dl. Block randomization using computer generated random numbers was used. The patients and the assessor of outcome were blinded. RESULTS: All patients completed the study. The mean difference in the reduction of the level of Hb between the two groups was -0.0055 gm/dl, with two sided 95% confidence interval (CI) being -0.29 to 0.27, well within the predefined equivalence margin of +/- 0.35gm/dl. The groups were comparable with regard to TBL, VBL, HBL, and complications. No patient needed a blood transfusion. CONCLUSION: A single intra-articular dose and two IV doses of TXA give equivalent efficacy and safety in the management of blood loss at TKA. Cite this article: Bone Joint J 2018;100-B:152-60. PMID- 29437057 TI - Three groups of dissatisfied patients exist after total knee arthroplasty: early, persistent, and late. AB - AIMS: The primary aim of this study was to assess whether patient satisfaction one year after total knee arthroplasty (TKA) changed with longer follow-up. The secondary aims were to identify predictors of satisfaction at one year, persistence of patient dissatisfaction, and late onset dissatisfaction in patients that were originally satisfied at one year. PATIENTS AND METHODS: A retrospective cohort consisting of 1369 patients undergoing a primary TKA for osteoarthritis that had not undergone revision were identified from an established arthroplasty database. Patient demographics, comorbidities, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and Short Form 12 (SF-12) questionnaire scores were collected preoperatively, and one and five years postoperatively. In addition, patient satisfaction was assessed at one and five years postoperatively. Logistic regression analysis was used to identify independent predictors of satisfaction at one and five years. RESULTS: The overall rate of satisfaction did not change from one (91.7%, n = 1255) to five (90.1%, n = 1234) years (p = 0.16). Approximately half (n = 53/114) of the patients who were dissatisfied at one year became satisfied with their TKA at five years, whereas 6% (n = 74/1255) of those who were satisfied at one year became dissatisfied at five years. At one year, patients with lung disease (p = 0.04), with depression (p = 0.001), with back pain (p < 0.001), undergoing unilateral TKA (p = 0.001), or with a worse preoperative WOMAC pain score (p = 0.04) were more likely to be dissatisfied. Patients with gastric ulceration (p = 0.04) and a worse WOMAC stiffness score (p = 0.047) were at increased risk of persistent dissatisfaction at five years. In contrast, a worse WOMAC pain score (p = 0.01) at one year was a predictor of dissatisfaction in previously satisfied patients at five years. CONCLUSION: Three groups of dissatisfied patients exist after TKA: 'early' dissatisfaction at one year, 'persistent' dissatisfaction with longer follow-up, and 'late' dissatisfaction developing in previously satisfied patients at one year. All three groups have different independent predictors of satisfaction, and potentially addressing risk factors specific to these groups may improve patient outcome and their satisfaction. Cite this article: Bone Joint J 2018;100-B:161-9. PMID- 29437058 TI - Inducible displacement of cemented tibial components ten years after total knee arthroplasty. AB - AIMS: The aim of this study was to evaluate the long-term inducible displacement of cemented tibial components ten years after total knee arthroplasty (TKA). PATIENTS AND METHODS: A total of 15 patients from a previously reported prospective trial of fixation using radiostereometric analysis (RSA) were examined at a mean of 11 years (10 to 11) postoperatively. Longitudinal supine RSA examinations were acquired at one week, one year, and two years postoperatively and at final follow-up. Weight-bearing RSA examinations were also undertaken with the operated lower limb in neutral and in maximum internal rotation positions. Maximum total point motion (MTPM) was calculated for the longitudinal and inducible displacement examinations (supine versus standing, standing versus internal rotation, and supine versus standing with internal rotation). RESULTS: All patients showed some inducible displacement. Two patients with radiolucent lines had greater mean standing-supine MTPM displacement (1.35; sd 0.38) compared with the remaining patients (0.68; sd 0.36). These two patients also had a greater mean longitudinal MTPM at ten years (0.64; sd 0.50) compared with the remaining patients (0.39; sd 0.13 mm). CONCLUSION: Small inducible displacements in well-fixed cemented tibial components were seen ten years postoperatively, of a similar magnitude to that which has been reported for well fixed components one to two years postoperatively. Greater displacements were found in components with radiolucent lines. Cite this article: Bone Joint J 2018;100-B:170-5. PMID- 29437060 TI - Degenerative subtalar joints complicated by medial plantar intraneural cysts : cutting the cystic articular branch prevents recurrence. AB - AIMS: The pathogenesis of intraneural ganglion cysts is controversial. Recent reports in the literature described medial plantar intraneural ganglion cysts (mIGC) with articular branches to subtalar joints. The aim of the current study was to provide further support for the principles underlying the articular theory, and to explain the successes and failures of treatment of mICGs. PATIENTS AND METHODS: Between 2006 and 2017, five patients with five mICGs were retrospectively reviewed. There were five men with a mean age of 50.2 years (33 to 68) and a mean follow-up of 3.8 years (0.8 to 6). Case history, physical examination, imaging, and intraoperative findings were reviewed. The outcomes of interest were ultrasound and/or MRI features of mICG, as well as the clinical outcomes. RESULTS: The five intraneural cysts followed the principles of the unifying articular theory. Connection to the posterior subtalar joint (pSTJ) was identified or suspected in four patients. Re-evaluation of preoperative MRI demonstrated a degenerative pSTJ and denervation changes in the abductor hallucis in all patients. Cyst excision with resection of the articular branch (four), cyst incision and drainage (one), and percutaneous aspiration/steroid injection (two) were performed. Removing the connection to the pSTJ prevented recurrence of mIGC, whereas medial plantar nerves remained cystic and symptomatic when resection of the communicating articular branch was not performed. CONCLUSION: Our findings support a standardized treatment algorithm for mIGC in the presence of degenerative disease at the pSTJ. By understanding the pathoanatomic mechanism for every cyst, we can improve treatment that must address the articular branch to avoid the recurrence of intraneural ganglion cysts, as well as the degenerative pSTJ to avoid extraneural cyst formation or recurrence. Cite this article: Bone Joint J 2018;100-B:183-9. PMID- 29437059 TI - A new and reliable classification system for fractures of the navicular and associated injuries to the midfoot. AB - AIMS: Fractures of the navicular can occur in isolation but, owing to the intimate anatomical and biomechanical relationships, are often associated with other injuries to the neighbouring bones and joints in the foot. As a result, they can lead to long-term morbidity and poor function. Our aim in this study was to identify patterns of injury in a new classification system of traumatic fractures of the navicular, with consideration being given to the commonly associated injuries to the midfoot. PATIENTS AND METHODS: We undertook a retrospective review of 285 consecutive patients presenting over an eight- year period with a fracture of the navicular. Five common patterns of injury were identified and classified according to the radiological features. Type 1 fractures are dorsal avulsion injuries related to the capsule of the talonavicular joint. Type 2 fractures are isolated avulsion injuries to the tuberosity of the navicular. Type 3 fractures are a variant of tarsometatarsal fracture/dislocations creating instability of the medial ray. Type 4 fractures involve the body of the navicular with no associated injury to the lateral column and type 5 fractures occur in conjunction with disruption of the midtarsal joint with crushing of the medial or lateral, or both, columns of the foot. RESULTS: In order to test the reliability and reproducibility of this new classification, a cohort of 30 patients with a fracture of the navicular were classified by six independent assessors at two separate times, six months apart. Interobserver reliability and intraobserver reproducibility both had substantial agreement, with kappa values of 0.80 and 0.72, respectively. CONCLUSION: We propose a logical, all-inclusive, and mutually exclusive classification system for fractures of the navicular that gives associated injuries involving the lateral column due consideration. We have shown that this system is reliable and reproducible and have described the rationale for the subsequent treatment of each type. Cite this article: Bone Joint J 2018;100-B:176-82. PMID- 29437061 TI - Mid-term follow-up of patients with hindfoot arthrodesis with retrograde compression intramedullary nail in Charcot neuroarthropathy of the hindfoot. AB - AIMS: Hindfoot arthrodesis with retrograde intramedullary nailing has been described as a surgical strategy to reconstruct deformities of the ankle and hindfoot in patients with Charcot arthropathy. This study presents case series of Charcot arthropathy patients treated with two different retrograde intramedullary straight compression nails in order to reconstruct the hindfoot and assess the results over a mid-term follow-up. PATIENTS AND METHODS: We performed a retrospective analysis of 18 consecutive patients and 19 operated feet with Charcot arthropathy who underwent a hindfoot arthrodesis using a retrograde intramedullary compression nail. Patients were ten men and eight women with a mean age of 63.43 years (38.5 to 79.8). We report the rate of limb salvage, complications requiring additional surgery, and fusion rate in both groups. The mean duration of follow-up was 46.36 months (37 to 70). RESULTS: The limb salvage rate was 16 of 19 limbs. Three patients had to undergo below-knee amputation due to persistent infection followed by osteomyelitis resistant to parenteral antibiotic therapy and repeated debridement. Complications including infection, hardware removal, nonunion, and persistent ulcers requiring further intervention were also observed. Postoperative functional scores revealed significant improvement compared with preoperative scores on American Orthopaedic Foot and Ankle Society (AOFAS) - Hindfoot scale, Foot Function Index (FFI), visual analogue scale (VAS), and Foot and Ankle Outcome Score (FAOS). CONCLUSION: The use of retrograde intramedullary compression nail results in good rates of limb salvage when used for hindfoot reconstruction in patients with Charcot arthropathy. Cite this article: Bone Joint J 2018;100-B:190-6. PMID- 29437063 TI - Cost minimization analysis of the treatment of distal radial fractures in the elderly. AB - AIMS: The aim of this study was to test the null hypothesis that there is no difference, from the payer perspective, in the cost of treatment of a distal radial fracture in an elderly patient, aged > 65 years, between open reduction and internal fixation (ORIF) and closed reduction (CR). MATERIALS AND METHODS: Data relating to the treatment of these injuries in the elderly between January 2007 and December 2015 were extracted using the Humana and Medicare Advantage Databases. The primary outcome of interest was the cost associated with treatment. Secondary analysis included the cost of common complications. Statistical analysis was performed using a non-parametric t-test and chi-squared test. RESULTS: Our search yielded 8924 patients treated with ORIF and 5629 patients treated with CR. The mean cost of an uncomplicated ORIF was more than a CR ($7749 versus $2161). The mean additional cost of a complication in the ORIF group was greater than in the CR group ($1853 versus $1362). CONCLUSION: These findings show that there are greater payer fees associated with ORIF than CR in patients aged > 65 years with a distal radial fracture. CR may be a higher-value intervention in these patients. Cite this article: Bone Joint J 2018;100-B:205 11. PMID- 29437062 TI - Mid-term outcomes of routine proximal row carpectomy compared with proximal row carpectomy with dorsal capsular interposition arthroplasty for the treatment of late-stage arthropathy of the wrist. AB - AIMS: The aims of this study were to compare the mid-term outcomes of patients with late-stage arthritis of the wrist treated with proximal row carpectomy (PRC) and dorsal capsular interposition (DCI) arthroplasty with a matched cohort treated with routine PRC alone. PATIENTS AND METHODS: A total of 25 arthritic wrists (24 patients) with pre-existing degenerative changes of the proximal capitate and/or the lunate fossa of the radius were treated with PRC + DCI over a ten-year period. This group of patients were matched 1:2 with a group of 50 wrists (48 patients) without degenerative changes in the capitate or lunate fossa that were treated with a routine PRC alone during the same period. The mean age of the patients at the time of surgery was 56.8 years (25 to 81), and the demographics and baseline range of movement of the wrist, grip strength, Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, and Patient-Rated Wrist Evaluation (PRWE) score were similar in both groups. RESULTS: At a mean follow-up of 5.9 years (1.8 to 11.8), significant improvements in mean grip strength, the flexion-extension arc of movement of the wrist, QuickDASH, and PRWE scores were seen in both groups. There was no diifference between the groups for any of the outcomes. One patient in the PRC + DCI group required additional surgery for a deep infection, while two in the PRC group had complications (one wound dehiscence requiring revision closure, one transient radial sensory neuritis). One patient in each group required total arthrodesis of the wrist for progressive degenerative radiocarpal changes. A total of 70 patients (93%) were satisfied with the outcomes. CONCLUSION: PRC with DCI is an effective form of treatment for late-stage arthritis of the wrist involving the capitolunate joint, with mid-term outcomes that are similar to those in patients without degenerative changes affecting the capitate or lunate fossa who are treated with a routine PRC alone. Cite this article: Bone Joint J 2018;100-B:197-204. PMID- 29437064 TI - The challenge of Monteggia-like lesions of the elbow: mid-term results of 46 cases. AB - AIMS: The aim of this retrospective multicentre study was to evaluate mid-term results of the operative treatment of Monteggia-like lesions and to determine the prognostic factors that influence the clinical and radiological outcome. PATIENTS AND METHODS: A total of 46 patients (27 women and 19 men), with a mean age of 57.7 years (18 to 84) who had sustained a Monteggia-like lesion were followed up clinically and radiologically after surgical treatment. The Mayo Modified Wrist Score (MMWS), Mayo Elbow Performance Score (MEPS), Broberg and Morrey Score, and Disabilities of the Arm, Shoulder and Hand (DASH) score were used for evaluation at a mean of 65 months (27 to 111) postoperatively. All ulnar fractures were stabilized using a proximally contoured or precontoured locking compression plate. Mason type I fractures of the radial head were treated conservatively, type II fractures were treated with reconstruction, and type III fractures with arthroplasty. All Morrey type II and III fractures of the coronoid process was stabilized using lag screws. RESULTS: Good results were found for the MMWS, with a mean of 88.4 (40 to 100). There were 29 excellent results (63%), nine good (20%), seven satisfactory (15%), and one poor (2%). Excellent results were obtained for the MEPS, with a mean of 90.7 (70 to 100): 31 excellent results (68%), 13 good (28%), and two fair (4%). Good results were also found for the functional rating index of Broberg and Morrey, with a mean score of 86.6 (57 to 100). There were 16 excellent results (35%), 22 good (48%), six fair (13%), and two poor (4%). The mean DASH score was 15.1 (0 to 55.8). Two patients had delayed wound healing; four patients had nonunion requiring bone grafting. One patient had asymptomatic loosening of the radial head prosthesis. CONCLUSION: Monteggia like lesions are rare. With correct identification, classification, and understanding using CT scans followed by appropriate surgical treatment that addresses all components of the injury, good to excellent mid-term results can be achieved. Cite this article: Bone Joint J 2018;100-B:212-18. PMID- 29437065 TI - The presence of Waddell signs depends on age and gender, not diagnosis. AB - AIMS: The aim of this study was to determine if positive Waddell signs were related to patients' demographics or to perception of their quality of life. PATIENTS AND METHODS: This prospective cross-sectional study included 479 adult patients with back pain from a university spine centre. Each completed SF-12 and Oswestry Disability Index (ODI) questionnaires and underwent standard spinal examinations to elicit Waddell signs. The relationship between Waddell signs and age, gender, ODI, Mental Component Score (MCS), and Physical Component Score (PCS) scores was determined. RESULTS: Of the 479 patients, 128 (27%) had at least one positive Waddell sign. There were significantly more women with two or more Waddell signs than men. The proportion of patients with at least one positive Waddell sign increased with age until 55 years, and then declined rapidly; none had a positive sign over the age of 75 years. Functional outcome scores were significantly worse in those with a single Waddell sign (p < 0.01). With one or more Waddell signs, patients' PCS and ODI scores indicated a perception of severe disability; with three or more Waddell signs, patients' MCS scores indicated severe disability. With five Waddell signs, ODI scores indicated that patients perceived themselves as crippled. CONCLUSION: Positive Waddell signs, a potential indicator of central sensitization, indicated a likelihood of having functional limitations and an impaired quality of life, particularly in young women. Cite this article: Bone Joint J 2018;100-B:219-25. PMID- 29437066 TI - Missing data may lead to changes in hip fracture database studies: a study of the American College of Surgeons National Surgical Quality Improvement Program. AB - AIMS: The aims of this study were to characterize the frequency of missing data in the National Surgical Quality Improvement Program (NSQIP) database and to determine how missing data can influence the results of studies dealing with elderly patients with a fracture of the hip. PATIENTS AND METHODS: Patients who underwent surgery for a fracture of the hip between 2005 and 2013 were identified from the NSQIP database and the percentage of missing data was noted for demographics, comorbidities and laboratory values. These variables were tested for association with 'any adverse event' using multivariate regressions based on common ways of handling missing data. RESULTS: A total of 26 066 patients were identified. The rate of missing data was up to 77.9% for many variables. Multivariate regressions comparing three methods of handling missing data found different risk factors for postoperative adverse events. Only seven of 35 identified risk factors (20%) were common to all three analyses. CONCLUSION: Missing data is an important issue in national database studies that researchers must consider when evaluating such investigations. Cite this article: Bone Joint J 2018;100-B:226-32. PMID- 29437067 TI - The impact of external fixation on mortality in patients with an unstable pelvic ring fracture: a propensity-matched cohort study. AB - AIM: There is not adequate evidence to establish whether external fixation (EF) of pelvic fractures leads to a reduced mortality. We used the Japan Trauma Data Bank database to identify isolated unstable pelvic ring fractures to exclude the possibility of blood loss from other injuries, and analyzed the effectiveness of EF on mortality in this group of patients. PATIENTS AND METHODS: This was a registry-based comparison of 1163 patients who had been treated for an isolated unstable pelvic ring fracture with (386 patients) or without (777 patients) EF. An isolated pelvic ring fracture was defined by an Abbreviated Injury Score (AIS) for other injuries of < 3. An unstable pelvic ring fracture was defined as having an AIS >= 4. The primary outcome of this study was mortality. A subgroup analysis was carried out for patients who required blood transfusion within 24 hours of arrival in the Emergency Department and those who had massive blood loss (AIS code: 852610.5). Propensity-score matching was used to identify a cohort like the EF and non-EF groups. RESULTS: With the use of propensity-score matching using the completed data, 346 patients were matched. When the propensity-score matching was adjusted, EF was associated with a significantly lower risk of death (p = 0.047). In the subgroup analysis of patients who needed blood transfusion within 24 hours and those who had massive blood loss, EF was associated with a significantly lower risk of death in patients who needed blood transfusion within 24 hours (p = 0.014) and in those with massive blood loss (p = 0.016). CONCLUSION: The use of EF to treat unstable pelvic ring fractures was associated with a significantly lower risk of death, especially in patients with severe fractures. Cite this article: Bone Joint J 2018;100-B:233-41. PMID- 29437068 TI - An interobserver reliability comparison between the Orthopaedic Trauma Association's open fracture classification and the Gustilo and Anderson classification. AB - AIMS: To evaluate interobserver reliability of the Orthopaedic Trauma Association's open fracture classification system (OTA-OFC). PATIENTS AND METHODS: Patients of any age with a first presentation of an open long bone fracture were included. Standard radiographs, wound photographs, and a short clinical description were given to eight orthopaedic surgeons, who independently evaluated the injury using both the Gustilo and Anderson (GA) and OTA-OFC classifications. The responses were compared for variability using Cohen's kappa. RESULTS: The overall interobserver agreement was K = 0.44 for the GA classification and K = 0.49 for OTA-OFC, which reflects moderate agreement (0.41 to 0.60) for both classifications. The agreement in the five categories of OTA OFC was: for skin, K = 0.55 (moderate); for muscle, K = 0.44 (moderate); for arterial injury, K = 0.74 (substantial); for contamination, K = 0.35 (fair); and for bone loss, K = 0.41 (moderate). CONCLUSION: Although the OTA-OFC, with similar interobserver agreement to GA, offers a more detailed description of open fractures, further development may be needed to make it a reliable and robust tool. Cite this article: Bone Joint J 2018;100-B:242-6. PMID- 29437069 TI - Risk analysis factors for local recurrence in Ewing's sarcoma: when should adjuvant radiotherapy be administered? AB - AIMS: The aim of this study was to analyse a group of patients with non metastatic Ewing's sarcoma at presentation and identify prognostic factors affecting the development of local recurrence, in order to assess the role of radiotherapy. PATIENTS AND METHODS: A retrospective review of all patients with a Ewing's sarcoma treated between 1980 and 2012 was carried out. Only those treated with chemotherapy followed by surgery and/or radiotherapy were included. Patients were grouped according to site (central or limb) for further analysis of the prognostic factors. RESULTS: A total of 388 patients were included in the study. Of these, 60 (15%) developed local recurrence at a mean median of 27 months (sd 24, range 7 to 150) and the five-year local recurrence-free survival (5yrLRFS) was 83%. For central tumours, the size of the tumour and histological response to chemotherapy were found to be significant factors for local recurrence. For limb tumours, local recurrence was affected by intralesional and marginal resections, but not by the histological response to chemotherapy. Radiotherapy in those with a marginal resection reduced the risk of local recurrence (5yrLRFS: 96% versus 81%, p = 0.044). CONCLUSION: Local recurrence significantly affects the overall survival in patients with a Ewing's sarcoma. For those with a tumour in a limb, radiotherapy reduced the risk of local recurrence, especially in those with a marginal margin of excision, but the effect in central tumours was less clear. Radiotherapy for those who have had a wide margin of resection does not reduce the risk of local recurrence, regardless of the histological response to chemotherapy. Cite this article: Bone Joint J 2018;100-B: 247-55. PMID- 29437070 TI - Outcomes after extensive manual curettage and limited burring for atypical cartilaginous tumour of long bone. AB - AIMS: Adjuvant treatment after intralesional curettage for atypical cartilaginous tumours (ACTs) of long bones is widely accepted for extending surgical margins. However, evaluating the isolated effect of adjuvant treatment is difficult, and it is unclear whether not using such adjuvants provides poor oncological outcomes. Hence, we analyzed whether intralesional curettage without cryosurgery or chemical adjuvants provides poor oncological outcomes in patients with an ACT. PATIENTS AND METHODS: A total of 24 patients (nine men, 15 women) (mean age 45 years; 18 to 62) were treated for ACTs of long bones and followed up for a median of 66 months (interquartile range 50 to 84). All patients were treated with extensive manual curettage and limited burring. Bone cement and grafts were used to fill bone defects in 16 and eight patients, respectively. No chemical adjuvants or cryosurgery were used. RESULTS: No local recurrence was detectable on plain radiographs and MRI or CT images. At the last follow-up, there were no distant metastases or disease-specific deaths. No procedure-related complications or postoperative fractures developed. CONCLUSION: Intralesional curettage without cryosurgery or chemical adjuvants may provide excellent oncological outcomes for patients with ACTs of long bones, without the risk of complications related to adjuvant use. Our investigation suggests thorough curettage alone is a reasonable treatment option for ACT. However, we acknowledge the limited size of our investigation warrants a multicentre collaborative study to confirm our findings. Cite this article: Bone Joint J 2018;100-B:256-61. PMID- 29437071 TI - Does a less intensive surveillance protocol affect the survival of patients after treatment of a sarcoma of the limb? updated results of the randomized TOSS study. AB - AIMS: A single-centre prospective randomized trial was conducted to investigate whether a less intensive follow-up protocol would not be inferior to a conventional follow-up protocol, in terms of overall survival, in patients who have undergone surgery for sarcoma of the limb. Initial short-term results were published in 2014. PATIENTS AND METHODS: The primary objective was to show non inferiority of a chest radiograph (CXR) group compared with a CT scan group, and of a less frequent (six-monthly) group than a more frequent (three-monthly) group, in two-by-two comparison. The primary outcome was overall survival and the secondary outcome was a recurrence-free survival. Five-year survival was compared between the CXR and CT scan groups and between the three-monthly and six-monthly groups. Of 500 patients who were enrolled, 476 were available for follow-up. Survival analyses were performed on a per-protocol basis (n = 412). RESULTS: The updated results recorded 12 (2.4%) local recurrences, 182 (36.8%) metastases, and 56 (11.3%) combined (local + metastases) recurrence at a median follow-up of 81 months (60 to 118). Of 68 local recurrences, 60 (88%) were identified by the patients themselves. The six-monthly regime (overall survival (OS) 54%, recurrence-free survival (RFS) 46%) did not lead to a worse survival and was not inferior to the three-monthly regime (OS 55%, RFS 47%) in terms of detecting recurrence. Although CT scans (OS 53%, RFS 54%) detected pulmonary metastasis earlier, it did not lead to a better survival compared with CXR (OS 56%, RFS 59%). CONCLUSION: The overall survival of patients who are treated for a sarcoma of the limb is not inferior to those followed up with a less intensive regimen than a more intensive protocol, in terms of frequency of visits and mode of imaging. CXR at six-monthly intervals and patient education about examination of the site of the surgery will detect most recurrences without deleterious effects on the eventual outcome. Cite this article: Bone Joint J 2018;100-B:262-8. PMID- 29437073 TI - Overlooking an Integral Lynchpin of Patient Care: The Caregiver at Home. PMID- 29437074 TI - Letting the Patient Decide: A Case Report of Self-Administered Sedation During Mechanical Ventilation. AB - It is common for critical care nurses to administer sedative medications to patients receiving mechanical ventilation. Although patient-controlled analgesia is frequently used in practice to promote effective self-management of pain by patients, it is not known if patient-controlled sedation can be used to promote effective self-management of distressing symptoms associated with mechanical ventilation. A randomized pilot trial was conducted to evaluate whether patient self-administered sedation with dexmedetomidine is safe and acceptable for self management of anxiety during ventilator support. This case report details the experiences of one patient enrolled in the pilot trial who was randomly assigned to the experimental dexmedetomidine intervention, completed the study protocol, and provided feedback. In a poststudy survey, the patient responded positively to the use of self-administered sedation with dexmedetomidine during ventilator support. PMID- 29437075 TI - Changing the Time of Blood Collection to Determine Vancomycin Concentrations in Intensive Care Unit Patients. AB - BACKGROUND: Clinical practice guidelines for initiation and therapeutic drug monitoring, but not timing, of vancomycin dosing exist at many institutions. Scheduling vancomycin trough measurements and doses around the morning blood sample collection could yield more interpretable troughs and increase patient safety. OBJECTIVE: To evaluate the appropriateness of blood sample collection times for vancomycin trough measurements before and after an initiative to change the timing of blood sampling to determine vancomycin doses and trough levels in a medical intensive care unit. METHODS: A retrospective cohort study was conducted of patients in a medical intensive care unit who received intravenous vancomycin at a scheduled interval. Differences in continuous and categorical data were compared between pre- and postintervention groups. The primary outcome was proportion of blood samples collected for vancomycin trough measurements within 30 minutes of the next scheduled vancomycin dose. RESULTS: Baseline characteristics were similar between the preintervention (n = 68) and postintervention (n = 176) groups except for the percentage of blood samples drawn for trough measurements and morning laboratory tests (6% vs 81%; P < .001). Frequency of loading doses was similar between patients in the pre- and postintervention groups, as was weight-based maintenance dosing. There was no significant difference in the percentage of blood samples collected to measure vancomycin trough levels appropriately at 30, 60, or 75 minutes from the next scheduled dose. CONCLUSION: Measuring vancomycin trough levels in morning blood samples did not affect the percentage of inappropriately collected blood samples used to measure vancomycin trough levels. PMID- 29437076 TI - Transcatheter Pulmonary Valve Replacement in Patients With Congenital Heart Disease. AB - Transcatheter pulmonary valve replacement is now a feasible alternative to surgical pulmonary valve replacement in children and adults with dysfunctional right ventricular outflow conduits. Currently, 2 types of valves can be used for this application. This article provides an overview of the procedure and how it is performed, indications and contraindications for transcatheter pulmonary valve replacement, and short- and long-term outcomes. Nursing considerations mainly focus on educating patients, preventing bleeding and infection, monitoring renal function, and preventing injury to the catheter insertion site. This article enhances the knowledge of nurses working in cardiac catheterization laboratories and post-procedure recovery and cardiac units so that the nurses can anticipate interventions and understand the management of patients who have transcatheter pulmonary valve replacement. PMID- 29437077 TI - Delirium Assessment Tools for Use in Critically Ill Adults: A Psychometric Analysis and Systematic Review. AB - BACKGROUND: Delirium is highly prevalent in critically ill patients. Its detection with valid tools is crucial. OBJECTIVE: To analyze the development and psychometric properties of delirium assessment tools for critically ill adults. METHODS: Databases were searched to identify relevant studies. Inclusion criteria were English language, publication before January 2015, 30 or more patients, and patient population of critically ill adults (>18 years old). Search terms were delirium, scales, critically ill patients, adult, validity, and reliability. Thirty-six manuscripts were identified, encompassing 5 delirium assessment tools (Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), Cognitive Test for Delirium, Delirium Detection Score, Intensive Care Delirium Screening Checklist (ICDSC), and Nursing Delirium Screening Scale). Two independent reviewers analyzed the psychometric properties of these tools by using a standardized scoring system (range, 0-20) to assess the tool development process, reliability, validity, feasibility, and implementation of each tool. RESULTS: Psychometric properties were very good for the CAM-ICU (19.6) and the ICDSC (19.2), moderate for the Nursing Delirium Screening Scale (13.6), low for the Delirium Detection Score (11.2), and very low for the Cognitive Test for Delirium (8.2). CONCLUSIONS: The results indicate that the CAM-ICU and the ICDSC are the most valid and reliable delirium assessment tools for critically ill adults. Additional studies are needed to further validate these tools in critically ill patients with neurological disorders and those at various levels of sedation or consciousness. PMID- 29437078 TI - MI: Not a Heart Attack but a Gut Attack. AB - Mesenteric ischemia and infarction are infrequent but often deadly conditions in acute and critically ill patients. Mesenteric ischemia may be a primary admission diagnosis or may develop secondary to another diagnosis. Having a high index of suspicion for patients at risk of mesenteric ischemia and mesenteric infarction can alter a poor outcome. This article reviews the pathophysiology, risk factors, assessment, medical and nursing diagnoses, as well as collaborative management for mesenteric ischemia. Early identification of patients at risk and the appropriate diagnostic testing are stressed. Nurses armed with the knowledge of this condition are better able to provide safe care to their patients. PMID- 29437079 TI - Launching a New Strategy for Multidisciplinary Management of Single-Ventricle Heart Defects. AB - Children born with single-ventricle heart defects, particularly hypoplastic left heart syndrome, have a lifetime high risk of mortality and comorbidities. They have complex medical challenges in addition to their cardiac needs, including growth and feeding complications and neurodevelopmental issues. These concerns require a coordinated effort among specialties to help patients maximize their potential. Additionally, because many complex heart defects are diagnosed prenatally, coordination of care between the pre- and postnatal care teams is imperative. Nursing leadership improves program coordination and efficiency. The purpose of this article is to describe the development and implementation of our hospital's synchronized, multidisciplinary team to support children with single ventricle heart defects and their families. (Critical Care Nurse. 2018;38[1]:60 71). PMID- 29437080 TI - Going for Gold ... Daily. PMID- 29437081 TI - Building Moral Resilience. PMID- 29437082 TI - Prevention of Catheter-Associated Urinary Tract Infections in Adults. PMID- 29437083 TI - The Fontan Procedure for Single-Ventricle Physiology. AB - The Fontan procedure is the final procedure in staged palliation for patients with functional single-ventricle physiology. The goal of the procedure is to separate systemic and pulmonary blood flow by directing systemic venous return through the Fontan connection to the pulmonary arteries and the lungs without ventricular contribution. Following the procedure, pulmonary blood flow is completely passive and dependent on pressure gradients, resulting in complex postoperative cardiopulmonary interactions. Understanding the physiology is essential to effectively manage these patients. Critical care nurses caring for patients after a Fontan procedure must understand preoperative data, risk factors, and unique postoperative physiology so they can anticipate specific postoperative problems, recognize trends in clinical status, and develop an appropriate plan of care. This paper reviews the first 2 stages of single ventricle palliation, relevant modifications to the Fontan procedure, important preoperative cardiac catheterization data, common postoperative problems, and outcomes after the Fontan procedure. PMID- 29437084 TI - Increasing Adherence to Brain Trauma Foundation Guidelines for Hospital Care of Patients With Traumatic Brain Injury. AB - BACKGROUND: The Brain Trauma Foundation has developed treatment guidelines for the care of patients with acute traumatic brain injury. The Adam Williams Initiative is a program established to provide education and resources to encourage hospitals across the United States to incorporate the guidelines into practice. OBJECTIVE: To explore the relationship in hospitals between participation in the Adam Williams Initiative and adherence to the Brain Trauma Foundation guidelines for patients with acute traumatic brain injury. METHOD: Hospitals that participated in the Adam Williams Initiative entered data into an online tracking system of patients with traumatic brain injury for at least 2 years after the initial site training. Data included baseline hospital records and daily records on hospital care of patients with traumatic brain injury, including blood pressure, intracranial pressure, cerebral perfusion pressure, oxygenation, and other data relevant to the 15 key metrics in the Brain Trauma Foundation guidelines. RESULTS: The 16 hospitals funded by the Adam Williams Initiative had good overall adherence to the 15 key metrics of the recommendations detailed in the Brain Trauma Foundation guidelines. Variability in results was primarily due to data collection methods and analysis. CONCLUSIONS: The Adam Williams Initiative helps promote adherence to the Brain Trauma Foundation guidelines for hospital care of patients with traumatic brain injury by providing a platform for developing and standardizing best practices. Participation in the initiative is associated with high adherence to clinical guidelines, a situation that may subsequently improve care and outcomes for patients with traumatic brain injury. PMID- 29437085 TI - Draft Genome Sequences of Novel Pseudomonas, Flavobacterium, and Sediminibacterium Species Strains from a Freshwater Ecosystem. AB - Freshwater ecosystems represent 0.01% of the water on Earth, but they support 6% of global biodiversity that is still mostly uncharacterized. Here, we describe the genome sequences of three strains belonging to novel species in the Pseudomonas, Flavobacterium, and Sediminibacterium genera recovered from a water sample of Lake Garda, Italy. PMID- 29437086 TI - Draft Genome Sequence of the Endophyte Bacillus mycoides Strain GM6LP Isolated from Lolium perenne. AB - Bacillus mycoides GM6LP is an endophyte isolated from plant tissues of Lolium perenne L. Here, we report its draft genome sequence (6.2 Mb), which contains 96 contigs and 6,129 protein-coding genes. Knowledge about its genome will enable us to evaluate the potential use of GM6LP as a plant growth-promoting bacterium. PMID- 29437087 TI - Draft Genome Sequences of 11 Salmonella enterica Serovar Typhimurium Strains Isolated from Human Systemic and Nonsystemic Sites in Brazil. AB - Salmonella enterica serovar Typhimurium strains isolated from systemic sites outside sub-Saharan Africa have been rarely sequenced. Here, we report the draft genome sequences of S Typhimurium sequence type 19 (ST19) (n = 9), ST1649 (n = 1), and ST313 (n = 1) strains isolated from human systemic (e.g., blood) and nonsystemic (e.g., stool and wounds) sites in Brazil. PMID- 29437088 TI - Draft Genome Sequence of Monaibacterium marinum C7T, Isolated from Seawater from the Menai Straits, Wales, United Kingdom. AB - Here, we report the draft genome sequence of Monaibacterium marinum C7T, a strain that represents a new member of the Roseobacter clade of the family Rhodobacteraceae (Alphaproteobacteria). The genome size of Monaibacterium marinum C7T is 3.7 Mb (3,734,267 bp), with a G+C content of 58.86%. PMID- 29437089 TI - Draft Genome Sequences of Three Strains of a Novel Rhizobiales Species Isolated from Forest Soil. AB - Three strains of a novel Rhizobiales species were isolated from temperate deciduous forest soil in central Massachusetts. Their genomes consist of 9.09 to 10.29 Mb over 3 to 4 scaffolds each and indicate that diverse nitrogenous compounds are used by these organisms. PMID- 29437090 TI - Complete Genome Sequences of 44 Arthrobacter Phages. AB - We report here the complete genome sequences of 44 phages infecting Arthrobacter sp. strain ATCC 21022. These phages have double-stranded DNA genomes with sizes ranging from 15,680 to 70,707 bp and G+C contents from 45.1% to 68.5%. All three tail types (belonging to the families Siphoviridae, Myoviridae, and Podoviridae) are represented. PMID- 29437091 TI - Whole-Genome Sequences and Annotation of the Opportunistic Pathogen Candida albicans Strain SC5314 Grown under Two Different Environmental Conditions. AB - The genetic variability of the opportunistic pathogen Candida albicans is an important adaptive mechanism. Here, we present the whole-genome sequences of the C. albicans SC5314 strain under two different growth conditions, providing useful information for comparative genomic studies and further intraspecific analysis. PMID- 29437092 TI - De Novo Genome Assembly of a Plasmodium falciparum NF54 Clone Using Single Molecule Real-Time Sequencing. AB - Plasmodium falciparum is the species of human malaria parasite that causes the most severe form of the disease. Here, we used single-molecule real-time (SMRT) sequencing technology from Pacific Biosciences (PacBio) to sequence, assemble de novo, and annotate the genome of a P. falciparum NF54 clone. PMID- 29437093 TI - Draft Genome Sequences of 42 Helicobacter pylori Isolates from Rural Regions of South India. AB - Helicobacter pylori is a successful human gastric pathogen that is associated with the development of gastric cancer. The draft genome sequences of 42 H. pylori clinical strains isolated from South Indian rural populations will provide further insights into the evolution and genetic makeup of Indian H. pylori strains. PMID- 29437094 TI - Draft Genome Sequences of Anaplasma phagocytophilum, A. marginale, and A. ovis Isolates from Different Hosts. AB - Here, we report the draft genome sequences of isolates of Anaplasma phagocytophilum, Anaplasma marginale, and Anaplasma ovis The genomes of A. phagocytophilum (human), A. marginale (cattle), and A. ovis (goat) isolates from the United States were sequenced and characterized. This is the first report of an A. ovis genome sequence. PMID- 29437095 TI - Draft Genome Sequence of the Wine Yeast Strain Saccharomyces cerevisiae I-328. AB - Saccharomyces cerevisiae I-328 is a yeast strain used for production of sherry like wine in Russia. Here we report the draft genome sequence of this strain, which will facilitate comparative genomic studies of yeast strains used for winemaking. PMID- 29437096 TI - Draft Genome Sequence of Escherichia coli Strain M15-4, a Typical Enteropathogenic E. coli Strain Isolated in Mexico. AB - We present here the first draft genome sequence of a typical enteropathogenic Escherichia coli serotype O55:H51 strain, M15-4, isolated from a 2-month-old infant girl with acute diarrhea. The study of this Mexican isolate will provide insights to the virulence and drug resistance traits involved in its pathogenic potential. PMID- 29437097 TI - Draft Genome Sequence of Aeromonas hydrophila Strain Ae25, Isolated from a Septicemic Moribund Koi Carp (Cyprinus carpio) in Sri Lanka. AB - Motile aeromonad septicemia caused by mesophilic strains of Aeromonas hydrophila is a widespread problem in cultured freshwater fish. We announce here the draft genome sequence of the multidrug-resistant A. hydrophila strain Ae25, isolated from a koi carp (Cyprinus carpio) with motile aeromonad septicemia that was collected from an ornamental fish-breeding farm in Sri Lanka. PMID- 29437098 TI - Complete Genome Sequence of a New Halophilic Archaeon, Haloarcula taiwanensis, Isolated from a Solar Saltern in Southern Taiwan. AB - We report here the completion of the genome sequence of a new species of haloarchaea, Haloarcula taiwanensis, isolated in southern Taiwan. The 3,721,706 bp genome consisted of chromosome I (2,966,258 bp, 63.6% GC content), chromosome II (525,233 bp, 59.6% GC content), plasmid pNYT1 (129,893 bp, 55.3% GC content), and plasmid pNYT2 (100,322 bp, 55.7% GC content). PMID- 29437099 TI - Complete Genome Sequence of a Type Strain of Mycobacterium abscessus subsp. bolletii, a Member of the Mycobacterium abscessus Complex. AB - Mycobacterium abscessus subsp. bolletii is a rapidly growing mycobacterial organism for which the taxonomy is unclear. Here, we report the complete genome sequence of a Mycobacterium abscessus subsp. bolletii type strain. This sequence will provide essential information for future taxonomic and comparative genome studies of these mycobacteria. PMID- 29437100 TI - Draft Genome Sequence of Zhihengliuella sp. Strain ISTPL4, a Psychrotolerant and Halotolerant Bacterium Isolated from Pangong Lake, India. AB - Zhihengliuella sp. strain ISTPL4, a psychrotolerant bacterium, was isolated from brackish water of the high-altitude Pangong Lake in India. In this study, we report its draft genome sequence, which contains 3,529,629 bp with a G+C content of 69.84%. The genome is enriched in genes associated with cold adaptation and plant growth promotion. PMID- 29437102 TI - Complete Nucleotide Sequence of an Escherichia coli Sequence Type 410 Strain Carrying blaNDM-5 on an IncF Multidrug Resistance Plasmid and blaOXA-181 on an IncX3 Plasmid. AB - Using Nanopore sequencing, we describe here the circular genome of an Escherichia coli sequence type 410 (ST410) strain with five closed plasmids. A large 111-kb incompatibility group F (IncF) plasmid harbored blaNDM-5 and 16 other resistance genes. A 51-kb IncX3 plasmid carried QnrS1 and blaOXA-181E. coli isolates with both blaNDM-5 and blaOXA-181 carbapenemases are rare. PMID- 29437103 TI - Draft Genome Sequences of Two Thermotolerant Cyanobacterial Strains Isolated from Hot Springs. AB - We report here two draft cyanobacterial genome sequences, those of Cyanobacterium aponinum IPPAS B-1201, isolated from a hot spring in the Turgen Gorge (Kazakhstan), and the uncharacterized cyanobacterium IPPAS B-1203, isolated from a hot spring in Karlovy Vary (Czech Republic). These two strains were deposited at the Collection of Microalgae (IPPAS) of the Timiryazev Institute of Plant Physiology. PMID- 29437101 TI - Complete Genome Sequence of Cluster J Mycobacteriophage Superphikiman. AB - Mycobacteriophage Superphikiman is a cluster J bacteriophage which was isolated from soil collected in Philadelphia, PA. Superphikiman has a 109,799-bp genome with 239 predicted genes, including 2 tRNA genes. PMID- 29437104 TI - Improved Draft Genome Sequence of Microcystis aeruginosa NIES-298, a Microcystin Producing Cyanobacterium from Lake Kasumigaura, Japan. AB - Microcystis aeruginosa is a globally well-known bloom-forming cyanobacterium. An improved draft whole-genome sequence of M. aeruginosa NIES-298, which is a microcystin-producing strain isolated from Lake Kasumigaura, Japan, is published here. The genome comprises approximately 5.0 Mbp, with an average G+C content of 42.6% and 4,537 predicted protein-coding genes. PMID- 29437105 TI - Draft Genome Sequences of Eight Staphylococcus aureus Strains Isolated during Foodborne Outbreaks. AB - We report here the draft genome sequences of eight Staphylococcus aureus strains isolated during three large food poisoning outbreaks in the Russian Federation. The strains were collected from clinical specimens and various foodstuff samples. PMID- 29437106 TI - Draft Genome Sequence of a Trimethylamine-Producing Staphylococcus Isolate from Blood of a Coronary Atherosclerotic Heart Disease Patient. AB - Trimethylamine (TMA), which is produced by various bacteria, is associated with heart disease, but little information about the production of TMA in blood is available. We present here the genome sequence of a multidrug-resistant strain, Staphylococcus epidermidis bTMA-013, with a TMA synthesis pathway, which was isolated from the blood of a coronary atherosclerotic heart disease patient. PMID- 29437107 TI - Complete Closed Genome Sequence of Nontoxigenic Invasive Corynebacterium diphtheriae bv. mitis Strain ISS 3319. AB - The genome sequence of the human pathogen Corynebacterium diphtheriae bv. mitis strain ISS 3319 was determined and closed in this study. The genome is estimated to have 2,404,936 bp encoding 2,257 proteins. This strain also possesses a plasmid of 1,960 bp. PMID- 29437108 TI - Complete Genome Sequences of Sweet potato feathery mottle virus and Sweet potato virus G from Brazil. AB - In Brazil, Potyvirus species in sweet potatoes have been detected mostly by serology. Here, we report the complete genome sequences of two Potyvirus species, Sweet potato feathery mottle virus strain (SPFMV-UNB-01) and Sweet potato virus G strain (SPVG-UNB-01). PMID- 29437109 TI - Draft Genome Sequence of Lysinibacillus fusiformis Strain Juneja, a Laboratory Derived Pathogen of Drosophila melanogaster. AB - Drosophila melanogaster is a model for the study of innate immunity, yet we have limited knowledge of its natural pathogens. In this study, we sequenced the genome of Lysinibacillus fusiformis strain Juneja, isolated from laboratory fly stocks. As a Gram-positive bacterium with unique peptidoglycans, this strain may provide a new model for pathogen recognition. PMID- 29437110 TI - Draft Genome Sequence of Bacillus altitudinis Strain KU-skv2(2), Isolated from a Microbial Mat on an Anthropogenic Pipe from Caldera Uzon (Kamchatka, Russia). AB - Bacillus altitudinis strain KU-skv2(2) was isolated from a microbial mat on an anthropogenic pipe from Caldera Uzon (Kamchatka, Russia, 54 degrees 30'0.23"N, 160 degrees 0'15.18"E). The sequenced and annotated genome is 3,739,340 bp in size and encodes 3,929 genes. PMID- 29437111 TI - Complete Genome Sequence of Xanthomonas citri pv. anacardii Strain IBSBF2579 from Brazil. AB - The bacterium Xanthomonas citri pv. anacardii is the agent of angular leaf spot of the cashew tree (Anacardium occidentale L.). The complete genome sequencing of the strain IBSBF2579 was done on an Illumina HiSeq 2500 platform. The de novo assembly of the X. citri pv. anacardii strain IBSBF2579 genome yielded 133 contigs, with a size of 5,329,247 bp and a G+C content of 64.03%. The prediction was performed by GeneMarkS and the automatic annotation by Rapid Annotations using Subsystems Technology (RAST), with 4,406 identified genes. PMID- 29437112 TI - Whole-Genome Sequence of Human Rhinovirus C47, Isolated from an Adult Respiratory Illness Outbreak in Butte County, California, 2017. AB - Here, we report the full coding sequence of rhinovirus C47 (RV-C47), obtained from a patient respiratory sample collected during an acute respiratory illness investigation in Butte County, California, in January 2017. This is the first whole-genome sequence of RV-C47 to be reported. PMID- 29437113 TI - Genome Sequence of Hydrogenovibrio sp. Strain SC-1, a Chemolithoautotrophic Sulfur and Iron Oxidizer. AB - Hydrogenovibrio sp. strain SC-1 was isolated from pyrrhotite incubated in situ in the marine surface sediment of Catalina Island, CA. Strain SC-1 has demonstrated autotrophic growth through the oxidation of thiosulfate and iron. Here, we present the 2.45-Mb genome sequence of SC-1, which contains 2,262 protein-coding genes. PMID- 29437114 TI - Complete Genome Sequence of Dietzia sp. Strain WMMA184, a Marine Coral-Associated Bacterium. AB - Dietzia sp. strain WMMA184 was isolated from the marine coral Montastraea faveolata as part of ongoing drug discovery efforts. Analysis of the 4.16-Mb genome provides information regarding interspecies interactions as it pertains to the regulation of secondary metabolism and natural product biosynthesis potential. PMID- 29437115 TI - Complete Genome Sequence of Legionella sainthelensi Isolated from a Patient with Legionnaires' Disease. AB - Legionella sainthelensi is an aquatic environmental bacterium that in humans can cause Legionnaires' disease (LD), an often severe form of pneumonia. Here, we report the first complete genome of a L. sainthelensi clinical isolate obtained in 2001 from a patient with LD in Canterbury, New Zealand. PMID- 29437116 TI - Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association. AB - Cardiovascular disease (CVD) remains the leading cause of mortality in women, yet many people perceive breast cancer to be the number one threat to women's health. CVD and breast cancer have several overlapping risk factors, such as obesity and smoking. Additionally, current breast cancer treatments can have a negative impact on cardiovascular health (eg, left ventricular dysfunction, accelerated CVD), and for women with pre-existing CVD, this might influence cancer treatment decisions by both the patient and the provider. Improvements in early detection and treatment of breast cancer have led to an increasing number of breast cancer survivors who are at risk of long-term cardiac complications from cancer treatments. For older women, CVD poses a greater mortality threat than breast cancer itself. This is the first scientific statement from the American Heart Association on CVD and breast cancer. This document will provide a comprehensive overview of the prevalence of these diseases, shared risk factors, the cardiotoxic effects of therapy, and the prevention and treatment of CVD in breast cancer patients. PMID- 29437117 TI - Cardioprotective Role of Myeloid-Derived Suppressor Cells in Heart Failure. AB - BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand in cancer, inflammation, and infection and negatively regulate inflammation and the immune response. Heart failure (HF) is a complex clinical syndrome wherein inflammation induction and incomplete resolution can potentially contribute to HF development and progression. However, the role of MDSCs in HF remains unclear. METHODS: The percentage of MDSCs in patients with HF and in mice with pressure overload-induced HF using isoproterenol infusion or transverse aortic constriction (TAC) was detected by flow cytometry. The effects of MDSCs on isoproterenol- or TAC-induced HF were observed on depleting MDSCs with 5-fluorouracil (50 mg/kg) or gemcitabine (120 mg/kg), transferring purified MDSCs, or enhancing endogenous MDSCs with rapamycin (2 mg.kg-1.d-1). Hypertrophic markers and inflammatory factors were detected by ELISA, real-time polymerase chain reaction, or Western blot. Cardiac functions were determined by echocardiography and hemodynamic analysis. RESULTS: The percentage of human leukocyte antigen-D-related (HLA-DR)-CD33+CD11b+ MDSCs in the blood of patients with HF was significantly increased and positively correlated with disease severity and increased plasma levels of cytokines, including interleukin-6, interleukin-10, and transforming growth factor-beta. Furthermore, MDSCs derived from patients with HF inhibited T-cell proliferation and interferon gamma secretion. Similar results were observed in TAC- and isoproterenol-induced HF in mice. Pharmaceutical depletion of MDSCs significantly exacerbated isoproterenol- and TAC-induced pathological cardiac remodeling and inflammation, whereas adoptive transfer of MDSCs prominently rescued isoproterenol- and TAC induced HF. Consistently, administration of rapamycin significantly increased endogenous MDSCs by suppressing their differentiation and improved isoproterenol- and TAC-induced HF, but MDSC depletion mostly blocked beneficial rapamycin mediated effects. Mechanistically, MDSC-secreted molecules suppressed isoproterenol-induced hypertrophy and proinflammatory gene expression in cardiomyocytes in a coculture system. Neutralization of interleukin-10 blunted both monocytic MDSC- and granulocytic MDSC-mediated anti-inflammatory and antihypertrophic effects, but treatment with a nitric oxide inhibitor only partially blocked the antihypertrophic effect of monocytic MDSCs. CONCLUSIONS: Our findings revealed a cardioprotective role of MDSCs in HF by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin-10 and nitric oxide. Pharmacological targeting of MDSCs by rapamycin constitutes a promising therapeutic strategy for HF. PMID- 29437118 TI - Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study. AB - BACKGROUND: Studies examining the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes have reported conflicting results. Our objective was to test the hypothesis that early postresuscitation hyperoxia is associated with poor neurological outcome. METHODS: This was a multicenter prospective cohort study. We included adult patients with cardiac arrest who were mechanically ventilated and received targeted temperature management after return of spontaneous circulation. We excluded patients with cardiac arrest caused by trauma or sepsis. Per protocol, partial pressure of arterial oxygen (Pao2) was measured at 1 and 6 hours after return of spontaneous circulation. Hyperoxia was defined as a Pao2 >300 mm Hg during the initial 6 hours after return of spontaneous circulation. The primary outcome was poor neurological function at hospital discharge, defined as a modified Rankin Scale score >3. Multivariable generalized linear regression with a log link was used to test the association between Pao2 and poor neurological outcome. To assess whether there was an association between other supranormal Pao2 levels and poor neurological outcome, we used other Pao2 cut points to define hyperoxia (ie, 100, 150, 200, 250, 350, 400 mm Hg). RESULTS: Of the 280 patients included, 105 (38%) had exposure to hyperoxia. Poor neurological function at hospital discharge occurred in 70% of patients in the entire cohort and in 77% versus 65% among patients with versus without exposure to hyperoxia respectively (absolute risk difference, 12%; 95% confidence interval, 1-23). Hyperoxia was independently associated with poor neurological function (relative risk, 1.23; 95% confidence interval, 1.11-1.35). On multivariable analysis, a 1-hour-longer duration of hyperoxia exposure was associated with a 3% increase in risk of poor neurological outcome (relative risk, 1.03; 95% confidence interval, 1.02-1.05). We found that the association with poor neurological outcome began at >=300 mm Hg. CONCLUSIONS: Early hyperoxia exposure after resuscitation from cardiac arrest was independently associated with poor neurological function at hospital discharge. PMID- 29437122 TI - Correction: Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases. PMID- 29437119 TI - Transplant-Free Survival and Interventions at 6 Years in the SVR Trial. AB - BACKGROUND: In the SVR trial (Single Ventricle Reconstruction), 1-year transplant free survival was better for the Norwood procedure with right ventricle-to pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt in patients with hypoplastic left heart and related syndromes. At 6 years, we compared transplant-free survival and other outcomes between the groups. METHODS: Medical history was collected annually using medical record review, telephone interviews, and the death index. The cohort included 549 patients randomized and treated in the SVR trial. RESULTS: Transplant-free survival for the RVPAS versus modified Blalock-Taussig shunt groups did not differ at 6 years (64% versus 59%, P=0.25) or with all available follow-up of 7.1+/-1.6 years (log-rank P=0.13). The RVPAS versus modified Blalock-Taussig shunt treatment effect had nonproportional hazards (P=0.009); the hazard ratio (HR) for death or transplant favored the RVPAS before stage II surgery (HR, 0.66; 95% confidence interval, 0.48-0.92). The effect of shunt type on death or transplant was not statistically significant between stage II to Fontan surgery (HR, 1.36; 95% confidence interval, 0.86-2.17; P=0.17) or after the Fontan procedure (HR, 0.76; 95% confidence interval, 0.33 1.74; P=0.52). By 6 years, patients with RVPAS had a higher incidence of catheter interventions (0.38 versus 0.23/patient-year, P<0.001), primarily because of more interventions between the stage II and Fontan procedures (HR, 1.72; 95% confidence interval, 1.00-3.03). Complications did not differ by shunt type; by 6 years, 1 in 5 patients had had a thrombotic event, and 1 in 6 had had seizures. CONCLUSIONS: By 6 years, the hazards of death or transplant and catheter interventions were not different between the RVPAS versus modified Blalock Taussig shunt groups. Children assigned to the RVPAS group had 5% higher transplant-free survival, but the difference did not reach statistical significance, and they required more catheter interventions. Both treatment groups have accrued important complications. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00115934. PMID- 29437123 TI - Correction: Morphoproteomic Characterization of Lung Squamous Cell Carcinoma Fragmentation, a Histological Marker of Increased Tumor Invasiveness. PMID- 29437124 TI - The Many Faces of Guillain-Barre Syndrome. PMID- 29437120 TI - Cytosolic DNA Sensing Promotes Macrophage Transformation and Governs Myocardial Ischemic Injury. AB - BACKGROUND: Myocardium irreversibly injured by ischemic stress must be efficiently repaired to maintain tissue integrity and contractile performance. Macrophages play critical roles in this process. These cells transform across a spectrum of phenotypes to accomplish diverse functions ranging from mediating the initial inflammatory responses that clear damaged tissue to subsequent reparative functions that help rebuild replacement tissue. Although macrophage transformation is crucial to myocardial repair, events governing this transformation are poorly understood. METHODS: Here, we set out to determine whether innate immune responses triggered by cytoplasmic DNA play a role. RESULTS: We report that ischemic myocardial injury, along with the resulting release of nucleic acids, activates the recently described cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Animals lacking cyclic GMP-AMP synthase display significantly improved early survival after myocardial infarction and diminished pathological remodeling, including ventricular rupture, enhanced angiogenesis, and preserved ventricular contractile function. Furthermore, cyclic GMP-AMP synthase loss of function abolishes the induction of key inflammatory programs such as inducible nitric oxide synthase and promotes the transformation of macrophages to a reparative phenotype, which results in enhanced repair and improved hemodynamic performance. CONCLUSIONS: These results reveal, for the first time, that the cytosolic DNA receptor cyclic GMP-AMP synthase functions during cardiac ischemia as a pattern recognition receptor in the sterile immune response. Furthermore, we report that this pathway governs macrophage transformation, thereby regulating postinjury cardiac repair. Because modulators of this pathway are currently in clinical use, our findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure. PMID- 29437125 TI - Pediatric Solid Tumors of Infancy: An Overview. PMID- 29437126 TI - Recognizing and Referring Children with Posttraumatic Stress Disorder: Guidelines for Pediatric Providers. PMID- 29437127 TI - Kawasaki Disease. PMID- 29437128 TI - Case 1: Vomiting and Ventricular Arrhythmia in a 2-year-old Girl. PMID- 29437129 TI - Case 2: Headache and Behavior Changes in an 11-year-old Boy. PMID- 29437130 TI - Case 3: Progressive Leg Pain and Weakness in a 16-year-old Boy. PMID- 29437131 TI - Case 4: Poor Feeding and Lethargy in a 32-day-old Infant. PMID- 29437132 TI - Case 5: Prolonged Fever in a 5-year-old Girl of Myanmese Descent. PMID- 29437133 TI - Case 6: An Infant Presenting with Hematuria and Pallor. PMID- 29437134 TI - Cyclic Vomiting Syndrome. PMID- 29437135 TI - Human Trafficking. PMID- 29437136 TI - Trisomies. PMID- 29437137 TI - Visual Diagnosis: A Rapidly Progressive Soft Tissue Shoulder Mass in a 3-month old Infant. PMID- 29437138 TI - Left Axis Deviation in Children Without Previously Known Heart Disease. AB - BACKGROUND: Left axis deviation (LAD) discovered in children via electrocardiogram (ECG) is uncommon but can be associated with heart disease (HD). The optimal diagnostic approach in a seemingly healthy child with LAD is unclear. We sought to better stratify which patients with LAD but without previously known HD may warrant additional workup. METHODS: A retrospective chart review was performed to identify patients >=1 to <18 years of age with LAD (QRS frontal plane axis 0 to -90) on an ECG between January 2002 and December 2014. Patients with known HD before their initial ECG were excluded. RESULTS: Overall, 296 patients were identified (n = 181 [61%] male; mean age: 10.8 +/- 4.6 years; mean QRS axis: -24 +/- 22 degrees ). An echocardiogram was performed in 158 (53%) patients, with 24 (15%) having HD. Compared with those with an echocardiogram but without HD (n = 134), patients with HD had a more negative mean QRS axis (-42 vs 27 degrees ; P = .002) and were more likely to have a QRS axis <=-42 degrees (58% vs 26%; P = .003), ECG chamber enlargement or hypertrophy (38% vs 5%; P < .0001), and abnormal cardiac physical examination findings (75% vs 8%; P < .0001). CONCLUSIONS: LAD discovered in isolation in the asymptomatic pediatric patient may not necessitate further cardiovascular investigation. Clinicians should consider obtaining an echocardiogram in patients with LAD and ECG cardiac chamber enlargement or hypertrophy, a QRS axis <=-42 degrees , and/or the presence of abnormal cardiac physical examination findings. PMID- 29437139 TI - Seeking Professional Resilience. PMID- 29437140 TI - Survival Analysis and Associated Factors in Thai Patients on Peritoneal Dialysis Under the PD-First Policy. AB - BACKGROUND: The peritoneal dialysis First (PD-First) policy means that PD is the first modality of dialysis chosen for patients with end-stage renal disease (ESRD), as put forth by the Universal Health Coverage (UHC) scheme. It was initiated in Thailand in 2008. Our aim is to analyze patient survival, technique survival, and associated factors. METHODS: Data of PD patients from January 2008 to November 2016 were studied. We calculated patient and technique survival rates (censored for death and kidney transplantation). Factors associated with survival were analyzed by the Cox proportional hazard model. Patient and technique survival rates between 2008 - 2012 and 2013 - 2016 were compared. RESULTS: Our study included 11,477 patients. The mean (standard deviation [SD]) age at initiation of PD was 54.0 (14.4) years. The level of education in 85.2% of cases was illiterate or primary school. A total of 60.9% of patients developed ESRD secondary to diabetes. The 1- to 5-year patient survival rates were 82.6, 71.8, 64.0, 58.5, and 54.0%, respectively. The first-year technique survival rate was 94.8%. The patient and technique survival rates during 2013 - 2016 were better than those seen during 2008 - 2012. Factors associated with lower patient survival rates were: female gender, increased age at start of PD, coverage with civil servant medical benefit scheme, low educational levels, and a history of diabetes. CONCLUSION: Most patients had diabetes and low educational levels as seen in the outcomes in the previous literature. These factors impacted the survival of patients under the PD-First policy. PMID- 29437141 TI - Laparoscopic Omentopexy, Rectus Sheath Tunneling and Implantation of the Peritoneal Dialysis Catheter Using a Peritoneal Dialysis Port. AB - BACKGROUND: Prophylactic laparoscopic omentopexy is a safe technique to prevent peritoneal dialysis (PD) catheter obstruction. For the first time, we would like to describe a surgical technique in which the omentopexy is done using a single PD port which is used for the omentopexy, PD catheter insertion, and the rectus sheath tunneling of the catheter. METHODS: The surgical method of the omentopexy using the PD port (US Patent 20170119430) will be thoroughly described. To evaluate the surgical method, we performed the procedure in 15 consecutive patients with chronic renal failure and followed up the patients. RESULTS: No intraoperative complication was observed. During the follow-up period, catheter flow failure due to omental wrapping was found in none of the patients. No other complication including exit-site infection, peritonitis, or catheter leakage was detected. CONCLUSION: Using this technique the catheter can not only be implanted through a proper and long rectus sheath, but the omentopexy can also be done without an additional port. This can reduce port-site complications and dialysis fluid leakage. PMID- 29437142 TI - Prevalence-Based Targets Underestimate Home Dialysis Program Activity and Requirements for Growth. AB - BACKGROUND: Many renal programs have targets to increase home dialysis prevalence. Data from a large Canadian home dialysis program were analyzed to determine if home dialysis prevalence accurately reflects program activity and whether prevalence-based assessments adequately reflect the work required for program growth. METHODS: Data from home dialysis programs in British Columbia, Canada, were analyzed from 2005 to 2015. Prevalence data were compared to dialysis activity data including intakes and exits to describe program turnover. Using current attrition rates, recruitment rates needed to increase home dialysis prevalence proportions were identified. RESULTS: We analyzed 7,746 patient-years of peritoneal dialysis (PD) and 1,362 patient-years of home hemodialysis (HHD). The proportion of patients on home dialysis increased by 3.34% over the ten years examined, while the number of prevalent home dialysis patients increased 2.65% per year and the number of patients receiving home dialysis at any time in the year increased 4.04% per year. For every 1 patient net home dialysis growth, 13.6 new patients were recruited. Patient turnover included higher rates of transplantation in home dialysis than facility-based HD. Overall, the proportion dialyzing at home increased from 29.3 to 32.6%. CONCLUSIONS: There is high patient turnover in home dialysis such that program prevalence is an incomplete marker of total program activity. This turnover includes high rates of transplantation, which is a desirable interaction that affects home dialysis prevalence. The shortcomings of this commonly used metric are important for renal programs to consider, and better understanding of the activities that support home dialysis and the complex trajectories that home dialysis patients follow is needed. PMID- 29437144 TI - What We're Reading: Article Recommendations from Our Deputy and Senior Editors. PMID- 29437143 TI - Outcomes of Acinetobacter Peritonitis in Peritoneal Dialysis Patients: A Multicenter Registry Analysis. AB - BACKGROUND: Acinetobacter is a rare but important cause of peritonitis in peritoneal dialysis (PD) patients. As the complication has not been comprehensively evaluated previously, the present study examined the outcomes of Acinetobacter peritonitis in a large, national cohort of PD patients. METHODS: The study included all episodes of peritonitis in Australia from January 2004 to December 2014 using Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data. The primary outcome was peritonitis cure and secondary outcomes were catheter removal, hemodialysis transfer, recurrent/relapsing peritonitis, peritonitis-related hospitalization, and death. Outcomes were compared using multivariable logistic regression. RESULTS: Overall, 5,367 patients experienced 11,122 episodes of peritonitis across 51 centers in Australia. Of these, 228 (4.2%) patients experienced 253 (2.3%) episodes of Acinetobacter peritonitis (176 episodes were due to Acinetobacter alone and 77 involved co-infection with other organisms). Of the 176 solitary Acinetobacter episodes, 131(74%) achieved cure with antibiotics alone. Compared with Acinetobacter, significantly lower odds of peritonitis cure were observed for Pseudomonas (adjusted odds ratio [AOR] 0.24, 95% confidence interval [CI]: 0.16 - 0.36), other gram-negative organisms (AOR 0.54, 95% CI 0.37 - 0.77), fungi (AOR 0.02, 95% CI 0.01 - 0.03), and polymicrobial organisms (AOR 0.36, 95% CI 0.25 - 0.51), whilst similar odds of cure were observed for Staphylococcus (AOR 0.73, 95% CI 0.50 - 1.06), other gram positive organisms (AOR 1.32,95% CI 0.93 - 1.89), culture-negative (AOR 1.19, 95% CI 0.82 -1.71), and other organisms (AOR 0.72, 95% CI 0.49 - 1.07). The odds of catheter removal and hemodialysis transfer were higher with Pseudomonas, other gram-negative, fungal, and polymicrobial peritonitis than with Acinetobacter peritonitis. The odds of death were also higher with Pseudomonas and fungal peritonitis than with Acinetobacter peritonitis. Treatment of Acinetobacter peritonitis with gentamicin, ciprofloxacin, or ceftazidime achieved comparable outcomes. CONCLUSIONS: Outcomes of Acinetobacter peritonitis were favorable compared with most other forms of organism-specific peritonitis. Commonly used antibiotics covering gram-negative bacteria achieved comparable outcomes in Acinetobacter peritonitis. PMID- 29437145 TI - Report on the NCI Microbial-Based Cancer Therapy Conference. AB - The National Cancer Institute Inaugural Microbial-Based Cancer Therapy Conference was held in Bethesda, Maryland, on July 11-12, 2017. This interdisciplinary forum included industry leaders, academic investigators, and regulatory officers involved in the development of microbial-based therapies for the treatment of cancer. The aim of the meeting was to discuss the potential of virus- and bacteria-based therapies to halt tumorigenesis and induce immune responses in cancers where conventional therapy is inadequate. This summary highlights topics and viewpoints raised by the presenters and discussants and should not be viewed as the conclusions or recommendations of the workshop as a whole. Cancer Immunol Res; 6(2); 122-6. (c)2017 AACR. PMID- 29437146 TI - Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. AB - There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor-mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans. PMID- 29437147 TI - Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis. AB - We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA. PMID- 29437149 TI - Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance. AB - There is a clinical need for new bronchodilator drugs in asthma, because more than half of asthmatic patients do not receive adequate control with current available treatments. We report that inhibition of metallothionein-2 protein expression in lung tissues causes the increase of pulmonary resistance. Conversely, metallothionein-2 protein is more effective than beta2-agonists in reducing pulmonary resistance in rodent asthma models, alleviating tension in tracheal spirals, and relaxing airway smooth muscle cells (ASMCs). Metallothionein-2 relaxes ASMCs via transgelin-2 (TG2) and induces dephosphorylation of myosin phosphatase target subunit 1 (MYPT1). We identify TSG12 as a nontoxic, specific TG2-agonist that relaxes ASMCs and reduces asthmatic pulmonary resistance. In vivo, TSG12 reduces pulmonary resistance in both ovalbumin- and house dust mite-induced asthma in mice. TSG12 induces RhoA phosphorylation, thereby inactivating the RhoA-ROCK-MYPT1-MLC pathway and causing ASMCs relaxation. TSG12 is more effective than beta2-agonists in relaxing human ASMCs and pulmonary resistance with potential clinical advantages. These results suggest that TSG12 could be a promising therapeutic approach for treating asthma. PMID- 29437148 TI - Targeting p53-dependent stem cell loss for intestinal chemoprotection. AB - The gastrointestinal (GI) epithelium is the fastest renewing adult tissue and is maintained by tissue-specific stem cells. Treatment-induced GI side effects are a major dose-limiting factor for chemotherapy and abdominal radiotherapy and can decrease the quality of life in cancer patients and survivors. p53 is a key regulator of the DNA damage response, and its activation results in stimulus- and cell type-specific outcomes via distinct effectors. We demonstrate that p53 dependent PUMA induction mediates chemotherapy-induced intestinal injury in mice. Genetic ablation of Puma, but not of p53, protects against chemotherapy-induced lethal GI injury. Blocking chemotherapy-induced loss of LGR5+ stem cells by Puma KO or a small-molecule PUMA inhibitor (PUMAi) prevents perturbation of the stem cell niche, rapid activation of WNT and NOTCH signaling, and stem cell exhaustion during repeated exposures. PUMAi also protects human and mouse colonic organoids against chemotherapy-induced apoptosis and damage but does not protect cancer cells in vitro or in vivo. Therefore, targeting PUMA is a promising strategy for normal intestinal chemoprotection because it selectively blocks p53-dependent stem cell loss but leaves p53-dependent protective effects intact. PMID- 29437151 TI - Study of crystal-field excitations and infrared active phonons in TbMnO3. AB - The Tb3+ (4f 8) crystal-field (CF) excitations and the infrared phonons in TbMnO3 are studied as a function of temperature and under an applied magnetic field. The phonon energy shifts reflect local displacement of the oxygen ions that contribute to the CF energy level shifts below 120 K and under magnetic field. The CF polarized transmission spectra provide interesting information about the debated nature of the excitations at 41, 65, 130 cm-1. We also evaluate the contribution of the charge transfer mechanism to the magnetoelectric process in TbMnO3 under magnetic field. PMID- 29437150 TI - PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+ human leukemia. AB - Overcoming drug resistance and targeting leukemic stem cells (LSCs) remain major challenges in curing BCR-ABL+ human leukemia. Using an advanced drug/proliferation screen, we have uncovered a prosurvival role for protein phosphatase 2A (PP2A) in tyrosine kinase inhibitor (TKI)-insensitive leukemic cells, regulated by an Abelson helper integration site-1-mediated PP2A-beta catenin-BCR-ABL-JAK2 protein complex. Genetic and pharmacological inhibition of PP2A impairs survival of TKI nonresponder cells and sensitizes them to TKIs in vitro, inducing a dramatic loss of several key proteins, including beta-catenin. We also demonstrate that the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, selectively eliminate treatment-naive TKI insensitive stem and progenitor cells, while sparing healthy counterparts. In addition, PP2A inhibitors and TKIs act synergistically to inhibit the growth of TKI-insensitive cells, as assessed by combination index analysis. The combination eliminates infiltrated BCR-ABL+ blast cells and drug-insensitive LSCs and confers a survival advantage in preclinical xenotransplant models. Thus, dual PP2A and BCR-ABL inhibition may be a valuable therapeutic strategy to synergistically target drug-insensitive LSCs that maintain minimal residual disease in patients. PMID- 29437152 TI - Focused ultrasound transducer spatial peak intensity estimation: a comparison of methods. AB - Characterisation of the spatial peak intensity at the focus of high intensity focused ultrasound transducers is difficult because of the risk of damage to hydrophone sensors at the high focal pressures generated. Hill et al (1994 Ultrasound Med. Biol. 20 259-69) provided a simple equation for estimating spatial-peak intensity for solid spherical bowl transducers using measured acoustic power and focal beamwidth. This paper demonstrates theoretically and experimentally that this expression is only strictly valid for spherical bowl transducers without a central (imaging) aperture. A hole in the centre of the transducer results in over-estimation of the peak intensity. Improved strategies for determining focal peak intensity from a measurement of total acoustic power are proposed. Four methods are compared: (i) a solid spherical bowl approximation (after Hill et al 1994 Ultrasound Med. Biol. 20 259-69), (ii) a numerical method derived from theory, (iii) a method using measured sidelobe to focal peak pressure ratio, and (iv) a method for measuring the focal power fraction (FPF) experimentally. Spatial-peak intensities were estimated for 8 transducers at three drive powers levels: low (approximately 1 W), moderate (~10 W) and high (20 70 W). The calculated intensities were compared with those derived from focal peak pressure measurements made using a calibrated hydrophone. The FPF measurement method was found to provide focal peak intensity estimates that agreed most closely (within 15%) with the hydrophone measurements, followed by the pressure ratio method (within 20%). The numerical method was found to consistently over-estimate focal peak intensity (+40% on average), however, for transducers with a central hole it was more accurate than using the solid bowl assumption (+70% over-estimation). In conclusion, the ability to make use of an automated beam plotting system, and a hydrophone with good spatial resolution, greatly facilitates characterisation of the FPF, and consequently gives improved confidence in estimating spatial peak intensity from measurement of acoustic power. PMID- 29437153 TI - Micro-structure and motion of two-dimensional dense short spherocylinder liquids. AB - We numerically investigate the micro-structure and motion of 2D liquids composed of dense short spherocylinders, by reducing the shape aspect ratio from 3. It is found that reducing shape aspect ratio from 3 causes a smooth transition from heterogeneous structures composed of crystalline ordered domains with good tetratic alignment order to those with good hexagonal bond-orientational order at an aspect ratio equaling 1.35. In the intermediate regime, both structural orders are strongly deteriorated, and the translational hopping rate reaches a maximum due to the poor particle interlocking of the disordered structure. Shortening rod length allows easier rotation, induces monotonic increase of rotational hopping rates, and resumes the separation of rotational and translational hopping time scales at the small aspect ratio end, after the crossover of their rates in the intermediate regime. At the large shape aspect ratio end, the poor local tetratic order has the same positive effects on facilitating local rotational and translational hopping. In contrast, at the small shape aspect ratio end, the poor local bond orientational order has the opposite effects on facilitating local rotational and translational hopping. PMID- 29437154 TI - Impact of intense x-ray pulses on a NaI(Tl)-based gamma camera. AB - In SPECT/CT systems x-ray and gamma-ray imaging is performed sequentially. Simultaneous acquisition may have advantages, for instance in interventional settings. However, this may expose a gamma camera to relatively high x-ray doses and deteriorate its functioning. We studied the NaI(Tl) response to x-ray pulses with a photodiode, PMT and gamma camera, respectively. First, we exposed a NaI(Tl)-photodiode assembly to x-ray pulses to investigate potential crystal afterglow. Next, we exposed a NaI(Tl)-PMT assembly to 10 ms LED pulses (mimicking x-ray pulses) and measured the response to flashing LED probe-pulses (mimicking gamma-pulses). We then exposed the assembly to x-ray pulses, with detector entrance doses of up to 9 nGy/pulse, and analysed the response for gamma-pulse variations. Finally, we studied the response of a Siemens Diacam gamma camera to gamma-rays while exposed to x-ray pulses. X-ray exposure of the crystal, read out with a photodiode, revealed 15% afterglow fraction after 3 ms. The NaI(Tl)-PMT assembly showed disturbances up to 10 ms after 10 ms LED exposure. After x-ray exposure however, responses showed elevated baselines, with 60 ms decay-time. Both for x-ray and LED exposure and after baseline subtraction, probe-pulse analysis revealed disturbed pulse height measurements shortly after exposure. X ray exposure of the Diacam corroborated the elementary experiments. Up to 50 ms after an x-ray pulse, no events are registered, followed by apparent energy elevations up to 100 ms after exposure. Limiting the dose to 0.02 nGy/pulse prevents detrimental effects. Conventional gamma cameras exhibit substantial dead time and mis-registration of photon energies up to 100 ms after intense x-ray pulses. This is due PMT limitations and due to afterglow in the crystal. Using PMTs with modified circuitry, we show that deteriorative afterglow effects can be reduced without noticeable effects on the PMT performance, up to x-ray pulse doses of 1 nGy. PMID- 29437155 TI - Relaxation dynamics of magnetization transitions in synthetic antiferromagnet with perpendicular anisotropy. AB - Two synthetic antiferromagnet bilayer systems with strong perpendicular anisotropy CoFeB/Ta/CoFeB and Pt/Co/Ir/Co/Pt have been grown using sputtering techniques. For both systems two types of magnetization transitions have been studied. The first one concerns transitions from a state where magnetizations of the two magnetic layers are parallel (P state) to a state where magnetizations of the two layers are aligned antiparallel (AP state). The second one concerns transitions between the two possible antiparallel alignments (AP+ to AP-). For both systems and both transitions after-effect measurements can be understood in the frame of nucleation-propagation model. Time derivative analysis of magnetic relaxation curves and mapping of the first order reversal curves at different temperature allowed us to demonstrate the presence of different pinning centers, which number can be controlled by magnetic field and temperature. PMID- 29437156 TI - Exotic superconducting states in the extended attractive Hubbard model. AB - We show that the extended attractive Hubbard model on a square lattice allows for a variety of superconducting phases, including exotic mixed-symmetry phases with [Formula: see text] and [Formula: see text] symmetries, and a novel [Formula: see text] state. The calculations are performed within the Hartree-Fock Bardeen Cooper-Schrieffer framework. The ground states of the mean-field Hamiltonian are obtained via a minimization scheme that relaxes the symmetry constraints on the superconducting solutions, hence allowing for a mixing of s-, p- and d-wave order parameters. The results are obtained within the assumption of uniform-density states. Our results show that extended attractive Hubbard model can serve as an effective model for investigating properties of exotic superconductors. PMID- 29437157 TI - Tuning the electrical and optical anisotropy of a monolayer black phosphorus magnetic superlattice. AB - We investigate theoretically the effects of modulated periodic perpendicular magnetic fields on the electronic states and optical absorption spectrum in monolayer black phosphorus (phosphorene). We demonstrate that different phosphorene magnetic superlattice (PMS) orientations can give rise to distinct energy spectra, i.e. tuning the intrinsic electronic anisotropy. Rashba spin orbit coupling (RSOC) develops a spin-splitting energy dispersion in this phosphorene magnetic superlattice. Anisotropic momentum-dependent carrier distributions along/perpendicular to the magnetic strips are demonstrated. The manipulations of these exotic electronic properties by tuning superlattice geometry, magnetic field and the RSOC term are addressed systematically. Accordingly, we find bright-to-dark transitions in the ground-state electron-hole pair transition rate spectrum and the PMS orientation-dependent anisotropic optical absorption spectrum. This feature offers us a practical way of modulating the electronic anisotropy in phosphorene by magnetic superlattice configurations and detecting this modulation capability by using an optical technique. PMID- 29437158 TI - Dataset of human medial temporal lobe single neuron activity during declarative memory encoding and recognition. AB - We present a dataset of 1,576 single neurons recorded from the human amygdala and hippocampus in 65 sessions from 42 patients undergoing intracranial monitoring for localization of epileptic seizures. Subjects performed a recognition memory task with pictures as stimuli. Subjects were asked to identify whether they had seen a particular image the first time ('new') or second time ('old') on a 1-6 confidence scale. This comprehensive dataset includes the spike times of all neurons and their extracellular waveforms, behavior, electrode locations determined from post-operative MRI scans, demographics, and the stimuli shown. As technical validation, we provide spike sorting quality metrics and assessment of tuning of cells to verify the presence of visually-and memory selective cells. We also provide analysis code that reproduces key scientific findings published previously on a smaller version of this dataset. Together, this large dataset will facilitate the investigation of the neural mechanism of declarative memory by providing a substantial number of hard to obtain human single-neuron recordings during a well characterized behavioral task. PMID- 29437159 TI - Single cell RNA sequencing of stem cell-derived retinal ganglion cells. AB - We used single cell sequencing technology to characterize the transcriptomes of 1,174 human embryonic stem cell-derived retinal ganglion cells (RGCs) at the single cell level. The human embryonic stem cell line BRN3B-mCherry (A81-H7), was differentiated to RGCs using a guided differentiation approach. Cells were harvested at day 36 and prepared for single cell RNA sequencing. Our data indicates the presence of three distinct subpopulations of cells, with various degrees of maturity. One cluster of 288 cells showed increased expression of genes involved in axon guidance together with semaphorin interactions, cell extracellular matrix interactions and ECM proteoglycans, suggestive of a more mature RGC phenotype. PMID- 29437160 TI - Protective effect of black relative to white race against non-alcoholic fatty liver disease in patients with severe obesity, independent of type 2 diabetes. AB - Severe obesity (body mass index ?35 kg m-2) and type 2 diabetes (T2D) are potent and additive risk factors for non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH). Scant available evidence indicates that black relative to white patients with severe obesity are less susceptible to NAFLD, but it is unclear if T2D abolishes this apparent racial disparity. Therefore, we compared biopsy-proven NAFLD and its progression between black (n=71) and white (n=155) patients with severe obesity stratified by presence or absence of T2D. Although prevalence of T2D was similar between races (37%, P>0.9), whites were significantly more likely than blacks to have NAFLD, NASH and advanced fibrosis (defined as bridging fibrosis and/or cirrhosis). Importantly, T2D was associated with increased odds of NAFLD, NASH and advanced fibrosis (defined as bridging fibrosis or cirrhosis) in whites only (P<0.05). In turn, a higher proportion of blacks than whites with T2D were free of NAFLD (58 versus 22%, P<0.01). These preliminary findings question translation of the powerful interconnection between T2D and NAFLD in whites with severe obesity to blacks and point to an important role of race in the pathophysiology and treatment of these diseases. PMID- 29437161 TI - Associations of adult genetic risk scores for adiposity with childhood abdominal, liver and pericardial fat assessed by magnetic resonance imaging. AB - BACKGROUND: Genome-wide association studies (GWASs) identified single-nucleotide polymorphisms (SNPs) involved in adult fat distribution. Whether these SNPs also affect abdominal and organ-specific fat accumulation in children is unknown. METHODS: In a population-based prospective cohort study among 1995 children (median age: 9.8 years, 95% range 9.4-10.8), we tested the associations of six genetic risk scores based on previously identified SNPs for childhood body mass index (BMI), adult BMI, liver fat, waist-hip ratio, pericardial fat mass, visceral and subcutaneous adipose tissue ratio (VAT/SAT ratio) and four individual SAT- and VAT-associated SNPs for association with SAT (N=1746), VAT (N=1742), VAT/SAT ratio (N=1738), liver fat fraction (N=1950) and pericardial fat mass (N=1803) measured by magnetic resonance imaging. RESULTS: Per additional risk allele in the childhood BMI genetic risk score, SAT increased 0.020 s.d. scores (SDS) (95% confidence interval (CI): 0.009 to 0.031, P-value: 3.28 * 10-4) and VAT increased 0.021 SDS (95% CI: 0.009 to 0.032, P-value: 4.68 * 10-4). The adult BMI risk score was positively associated with SAT (0.022 SDS increase, CI: 0.015 to 0.029, P-value: 1.33 * 10-9) and VAT (0.017 SDS increase, CI: 0.010 to 0.025, P-value: 7.00 * 10-6) and negatively with VAT/SAT ratio (-0.012 SDS decrease, CI: -0.019 to -0.006, P-value: 2.88 * 10-4). The liver fat risk score was associated with liver fat fraction (0.121 SDS, CI: 0.086 to 0.157, P-value: 2.65 * 10-11). Rs7185735 (SAT) was associated with SAT (0.151 SDS, CI: 0.087 to 0.214, P-value: 3.00 * 10-6) and VAT/SAT ratio (-0.126 SDS, CI: -0.186 to -0.065, P-value: 4.70 * 10-5). After stratification by sex the associations of the adult BMI risk score with SAT and VAT and of the liver fat risk score with liver fat fraction remained in both sexes. Associations of the childhood BMI risk score with SAT, and the adult BMI risk score with VAT/SAT ratio, were present among boys only, whereas the association of the pericardial fat risk score with pericardial fat was present among girls only. CONCLUSION: Genetic variants associated with BMI, body fat distribution, liver and pericardial fat already affect body fat distribution in childhood. PMID- 29437162 TI - Compilation of climate data from heterogeneous networks across the Hawaiian Islands. AB - Long-term, accurate observations of atmospheric phenomena are essential for a myriad of applications, including historic and future climate assessments, resource management, and infrastructure planning. In Hawai'i, climate data are available from individual researchers, local, State, and Federal agencies, and from large electronic repositories such as the National Centers for Environmental Information (NCEI). Researchers attempting to make use of available data are faced with a series of challenges that include: (1) identifying potential data sources; (2) acquiring data; (3) establishing data quality assurance and quality control (QA/QC) protocols; and (4) implementing robust gap filling techniques. This paper addresses these challenges by providing: (1) a summary of the available climate data in Hawai'i including a detailed description of the various meteorological observation networks and data accessibility, and (2) a quality controlled meteorological dataset across the Hawaiian Islands for the 25-year period 1990-2014. The dataset draws on observations from 471 climate stations and includes rainfall, maximum and minimum surface air temperature, relative humidity, wind speed, downward shortwave and longwave radiation data. PMID- 29437163 TI - Starter formula enriched in prebiotics and probiotics ensures normal growth of infants and promotes gut health: a randomized clinical trial. AB - This corrects the article DOI: 10.1038/pr.2016.270. PMID- 29437164 TI - Primary distal renal tubular acidosis: novel findings in patients studied by next generation sequencing. AB - This corrects the article DOI: 10.1038/pr.2015.243. PMID- 29437166 TI - Simultaneous acquisition of EEG and NIRS during cognitive tasks for an open access dataset. AB - We provide an open access multimodal brain-imaging dataset of simultaneous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) recordings. Twenty-six healthy participants performed three cognitive tasks: 1) n-back (0-, 2 and 3-back), 2) discrimination/selection response task (DSR) and 3) word generation (WG) tasks. The data provided includes: 1) measured data, 2) demographic data, and 3) basic analysis results. For n-back (dataset A) and DSR tasks (dataset B), event-related potential (ERP) analysis was performed, and spatiotemporal characteristics and classification results for 'target' versus 'non-target' (dataset A) and symbol 'O' versus symbol 'X' (dataset B) are provided. Time-frequency analysis was performed to show the EEG spectral power to differentiate the task-relevant activations. Spatiotemporal characteristics of hemodynamic responses are also shown. For the WG task (dataset C), the EEG spectral power and spatiotemporal characteristics of hemodynamic responses are analyzed, and the potential merit of hybrid EEG-NIRS BCIs was validated with respect to classification accuracy. We expect that the dataset provided will facilitate performance evaluation and comparison of many neuroimaging analysis techniques. PMID- 29437168 TI - The Brain/MINDS 3D digital marmoset brain atlas. AB - We present a new 3D digital brain atlas of the non-human primate, common marmoset monkey (Callithrix jacchus), with MRI and coregistered Nissl histology data. To the best of our knowledge this is the first comprehensive digital 3D brain atlas of the common marmoset having normalized multi-modal data, cortical and sub cortical segmentation, and in a common file format (NIfTI). The atlas can be registered to new data, is useful for connectomics, functional studies, simulation and as a reference. The atlas was based on previously published work but we provide several critical improvements to make this release valuable for researchers. Nissl histology images were processed to remove illumination and shape artifacts and then normalized to the MRI data. Brain region segmentation is provided for both hemispheres. The data is in the NIfTI format making it easy to integrate into neuroscience pipelines, whereas the previous atlas was in an inaccessible file format. We also provide cortical, mid-cortical and white matter boundary segmentations useful for visualization and analysis. PMID- 29437167 TI - Dynamic contrast-enhanced magnetic resonance imaging for head and neck cancers. AB - Dynamic myraidpro contrast-enhanced magnetic resonance imaging (DCE-MRI) has been correlated with prognosis in head and neck squamous cell carcinoma as well as with changes in normal tissues. These studies implement different software, either commercial or in-house, and different scan protocols. Thus, the generalizability of the results is not confirmed. To assist in the standardization of quantitative metrics to confirm the generalizability of these previous studies, this data descriptor delineates in detail the DCE-MRI digital imaging and communications in medicine (DICOM) files with DICOM radiation therapy (RT) structure sets and digital reference objects (DROs), as well as, relevant clinical data that encompass a data set that can be used by all software for comparing quantitative metrics. Variable flip angle (VFA) with six flip angles and DCE-MRI scans with a temporal resolution of 5.5 s were acquired in the axial direction on a 3T MR scanner with a field of view of 25.6 cm, slice thickness of 4 mm, and 256*256 matrix size. PMID- 29437169 TI - Pectin oligosaccharides from sugar beet pulp: molecular characterization and potential prebiotic activity. AB - Pectin oligosaccharides (POS) have been indicated as a new class of potential prebiotic compounds, which can be produced from pectin-rich food byproducts. In the present study, different technological means of POS production were explored to produce tailor-made POS mixtures starting from sugar beet pulp. The overall POS production process consisted of two steps: the extraction of pectin and the hydrolysis of pectin to tailored POS by combined hydrolysis/fractionation approaches. Different extraction as well as hydrolysis and fractionation methodologies were applied. The obtained POS were characterized for their total galacturonic acid content and, at a deeper level, using a HILIC-ESI/MS methodology, for the POS structure and composition. The composition of POS fractions was studied as a function of the technology used to obtain them. Finally, the potential prebiotic properties of the POS mixtures obtained were thoroughly explored by several in vitro experiments aimed at detecting lactic acid bacteria (LAB) stimulation by POS fractions. Several fractions were very efficient in stimulation, in a species-dependent manner. The overall best fractions were in general those rich in arabinans having a low degree of polymerization, obtained from the enzymatic extraction of biomass and subsequent fractionation with low-medium molecular weight cut-off. Quite interestingly, no POS fraction was able to stimulate pathogenic E. coli strains. The data reported here clearly indicate the possibility to obtain diverse fractions with different prebiotic properties starting from the same biomass, and outline clear potential for POS obtained from sugar beet pulp with the appropriate technology to act as prebiotic compounds. PMID- 29437170 TI - Carbohydrate metabolism and gene expression of sirtuin 1 in healthy subjects after Sacha inchi oil supplementation: a randomized trial. AB - BACKGROUND: The postprandial stage is related to cardiovascular risk and it depends on the type of meal consumed. We study the effects of Sacha inchi oil on the postprandial glycemic state caused by meals rich in saturated fat. METHODS AND RESULTS: A double blind randomized trial in which 42 adult men ingested two breakfasts rich in saturated fat, one of them containing additionally 15 mL of Sacha inchi oil. Blood samples were obtained before or after 1 and 4 hours post ingestion to quantify glucose, insulin and lipid profile in serum. The insulinogenic and sensitivity indices were calculated and the expression of sirtuin-1 in circulating mononuclear cells by qPCR was determined. RESULTS: Oil addition attenuated the increase of glucose in 16 (38.1%) participants. This group showed a higher concentration of fasting triacylglycerides and sirtuin-1 expression at 4 hours post-Sacha inchi oil correlated with glucose at the same time (r = -0.724; p = 0.012), and with postprandial insulin sensitivity (r = 0.636; p = 0.035). CONCLUSIONS: The addition of Sacha inchi oil to a highly fatty meal improves insulin sensitivity in people with higher basal triglyceridemia and higher glycemic responses after a fat load. Under these conditions, sirtuin-1 expression correlates with postprandial insulin sensitivity. PMID- 29437171 TI - Impact of dietary supplementation with olive and thyme phenols on alpha tocopherol concentration in the muscle and liver of adult Wistar rats. AB - A preliminary study to evaluate the effect of dietary supplementation with olive phenols (oleuropein, hydroxytyrosol and secoiridoids), thyme phenols and a combination of these (5 mg per kg rat weight per day) on the alpha-tocopherol concentrations in the muscle and liver of healthy adult Wistar rats over 21 days was conducted. In addition, the excretion of alpha-tocopherol through the faeces was examined. The results demonstrated that the diet supplemented with some phenolic compounds of olive and thyme increased alpha-tocopherol (P < 0.05) in the liver of female rats, although the alpha-tocopherol content in the diet of all groups was identical. In addition, a synergic effect between the olive phenols and thyme was observed. Therefore, our study indicates a protective effect of olive and thyme phenols supplemented in the diet on alpha-tocopherol, resulting in a higher concentration of endogenous alpha-tocopherol in the rat liver. PMID- 29437172 TI - Closed-loop feedback control for microfluidic systems through automated capacitive fluid height sensing. AB - Precise fluid height sensing in open-channel microfluidics has long been a desirable feature for a wide range of applications. However, performing accurate measurements of the fluid level in small-scale reservoirs (<1 mL) has proven to be an elusive goal, especially if direct fluid-sensor contact needs to be avoided. In particular, gravity-driven systems used in several microfluidic applications to establish pressure gradients and impose flow remain open-loop and largely unmonitored due to these sensing limitations. Here we present an optimized self-shielded coplanar capacitive sensor design and automated control system to provide submillimeter fluid-height resolution (~250 MUm) and control of small-scale open reservoirs without the need for direct fluid contact. Results from testing and validation of our optimized sensor and system also suggest that accurate fluid height information can be used to robustly characterize, calibrate and dynamically control a range of microfluidic systems with complex pumping mechanisms, even in cell culture conditions. Capacitive sensing technology provides a scalable and cost-effective way to enable continuous monitoring and closed-loop feedback control of fluid volumes in small-scale gravity-dominated wells in a variety of microfluidic applications. PMID- 29437173 TI - Human brain organoid-on-a-chip to model prenatal nicotine exposure. AB - Nicotine has been recognized to trigger various neuronal disabilities in the fetal brain and long-lasting behavioral deficits in offspring. However, further understanding of fetal brain development under nicotine exposure is challenging due to the limitations of existing animal models. Here, we create a new brain organoid-on-a-chip system derived from human induced pluripotent stem cells (hiPSCs) that allows us to model neurodevelopmental disorders under prenatal nicotine exposure (PNE) at early stages. The brain organoid-on-a-chip system facilitates 3D culture, in situ neural differentiation, and self-organization of brain organoids under continuous perfused cultures in a controlled manner. The generated brain organoids displayed well-defined neural differentiation, regionalization, and cortical organization, which recapitulates the key features of the early stages of human brain development. The brain organoids exposed to nicotine exhibited premature neuronal differentiation with enhanced expression of the neuron marker TUJ1. Brain regionalization and cortical development were disrupted in the nicotine-treated organoids identified by the expressions of forebrain (PAX6 and FOXG1), hindbrain (PAX2 and KROX20) and cortical neural layer (preplate TBR1 and deep-layer CTIP2) markers. Moreover, the neurite outgrowth showed abnormal neuronal differentiation and migration in nicotine-treated brain organoids. These results suggest that nicotine exposure elicits impaired neurogenesis in early fetal brain development during gestation. The established brain organoid-on-a-chip system provides a promising platform to model neurodevelopmental disorders under environmental exposure, which can be extended for applications in brain disease studies and drug testing. PMID- 29437174 TI - Synthesis of the 10-oxabicyclo[5.2.1]decane framework present in bioactive natural products. AB - The present work deals with the synthesis of the 10-oxabicyclo[5.2.1]decane framework present in bioactive natural products like physalins, with potential as antitumor agents. This synthetic methodology involves several key reactions: (a) synthesis of polyfunctionalized cycloheptenones by [4 + 3] cycloaddition reactions of furan precursors with oxyallyl cations; (b) Nicholas reaction with propargyl cations stabilized as dicobalt hexacarbonyl complexes; (c) demetallation and hydration of the resulting acetylenes; (d) stereoconvergent aldol cyclization to generate a key oxatricyclic intermediate and (e) a beta fragmentation process that affords, under hypoiodite photolysis, the desired product with moderate to good yield. The final compounds are the result of a radicalary beta-fragmentation at the level of C2-C6 with respect to the tertiary hydroxyl group on C6, with an unexpected contraction from a ten- to a nine membered ring system, via a radical addition to the carbonyl group on C4. The synthetic methodology has been scaled up to multigram level with good overall yield. Further biological, biochemical and biophysical studies are being carried out in our laboratory on these 1,7-epoxycyclononane derivatives to determine the potential of this kind of oxabicyclic compound as future hits and/or leads for the development of new anticancer drugs. The preliminary evaluation of the anticancer activity of the representative synthesized compounds, against the leukaemia cancer cell lines K-562 and SR, shows a promising activity with a GI50 = 0.01 MUM and a LC50 = 7.4 MUM for a conveniently functionalized 10 oxabicyclo[5.2.1]decane. PMID- 29437180 TI - Semi-quantitative evaluation of molecular meshing via surface analysis with varying probe radii. AB - A novel method for the semi-quantitative evaluation of molecular meshing in molecular complexes and assemblies (SAVPR: surface analysis with varying probe radii) is proposed. SAVPR revealed that the extremely high stability of hexameric assemblies (nanocubes) is due to tight molecular meshing between the components in the assemblies, indicating the importance of van der Waals interactions in hydrophobic molecular assemblies. PMID- 29437181 TI - Quality of motivational interviewing matters: the effect on participation in health-promotion activities in a cluster randomized controlled trial. AB - Objectives This study aims to evaluate the effectiveness of a "blended" workplace health-promotion intervention, alongside identification of key components beneficial for future implementation strategies. Methods Within a cluster randomized controlled trial, 491 employees at increased risk of cardiovascular disease were allocated to the limited (N=217; 9 clusters) or extensive (N=274; 8 clusters) intervention. The extensive intervention consisted of motivational interviewing (MI) within the framework of a web-based health risk assessment (HRA), a blended care approach. The limited intervention received solely the web based HRA. Occupational health physicians (N=21) within three organizations delivered the intervention. Implementation components investigated included: HRA (reach and participation), newsletters (percentage read), and MI sessions (number and quality). MI quality was determined by scoring audiotaped MI sessions, using the MI treatment integrity code. After 6 and 12 months, effects on participation in health-promotion activities and its associations with components of implementation were determined by mixed-effects models. Results Over 80% of employees participated in health-promotion activities, with an additional 8% in the extensive compared to the limited group. In the extensive intervention, those with more or better quality MI sessions were more likely to participate in health promotion activities. Increased MI quality was associated with sustained participation. Conclusions This study suggests that participation in health promotion activities can be increased by adding MI to a web-based approach and improving the quality of the MI delivered. Interventions with MI should include optimized delivery and quality of MI sessions. PMID- 29437182 TI - Videoconferencing for Management of Heart Failure: An Integrative Review. AB - Heart failure (HF) is a chronic disease associated with poor prognosis, poor quality of life (QOL), and high medical costs among older adults. Monitoring symptoms, interpreting symptoms, and decision making are self-care skills required for effective HF management. Telemonitoring (TM) is increasingly used to reduce incidence of symptom exacerbation leading to rehospitalization. An integrative review was performed to describe the efficacy of TM interventions that include videoconferencing (VC) on the HF outcomes of hospital service s use, self-care, and QOL. A review of 11 studies using VC combined with remote physiological monitoring demonstrated promising results in all areas except self care. Additional research is needed to better specify the goals of VC interventions, the mechanisms by which VC interventions improve health outcomes, and the effect of VC interventions with adults of diverse race and ethnicity. [Journal of Gerontological Nursing, 44(4), 45-52.]. PMID- 29437183 TI - Ask the Right Questions: What Do Non-Caregiving Adult Children Need From Health Care Providers? AB - Extended healthy life spans are a relatively recent phenomenon that increase the amount of time families spend with older adults in non-caregiving roles. As the emphasis of health care moves to population health and health prevention, nurses caring for older adults must be knowledgeable about this family life stage. To learn more about the lived experience of non-caregiving adult children, 16 non caregiving adult children were interviewed. The purpose of the current article is to share what needs non-caregiving adult children have from the health care system as they obtain care for themselves and accompany their parent for health care visits. Content analysis of transcribed interviews revealed three main themes: Lack of Holistic Care, Lack of Effective Communication, and Fragmented Care and Need for Better Care Management. Participants suggested interventions that are patient- and family-centered and culturally safe. Nurses can use findings from the current study to research interventions using family-centered care strategies to improve health outcomes for older adults. [Journal of Gerontological Nursing, 44(5), 26-31.]. PMID- 29437184 TI - Real-Time Observation of Apathy in Long-Term Care Residents With Dementia: Reliability of the Person-Environment Apathy Rating Scale. AB - Apathy is prevalent in individuals with dementia. Lack of responsiveness to environmental stimulation is a key characteristic of apathy. The Person Environment Apathy Rating (PEAR) scale consists of environment and apathy subscales, which allow for examination of environmental impact on apathy. The interrater reliability of the PEAR scale was examined via real-time observation. The current study included 45 observations of 15 long-term care residents with dementia. Each participant was observed at three time points for 10 minutes each. Two raters observed the participant and surrounding environment and independently rated the participant's apathy and environmental stimulation using the PEAR scale. Weighted Kappa was 0.5 to 0.82 for the PEAR-Environment subscale and 0.5 to 0.8 for the PEAR-Apathy subscale. Overall, with the exception of three items with relatively weak reliability (0.50 to 0.56), the PEAR scale showed moderate to strong interrater reliability (0.63 to 0.82). The results support the use of the PEAR scale to measure environmental stimulation and apathy via real-time observation in long-term care residents with dementia. [Journal of Gerontological Nursing, 44(4), 23-28.]. PMID- 29437185 TI - Certified Nursing Assistants' Understanding of Nursing Home Residents' Pain. AB - Pain is a significant problem for nursing home residents, yet its assessment is complex. Certified nursing assistants (CNAs) spend significant time with residents, but their role in understanding residents' pain is largely unexplored. The current qualitative grounded theory study analyzed interviews with 16 CNAs who described their experiences caring for residents in pain. Findings revealed how CNAs understood, recognized, interpreted, and responded to residents' pain. CNAs were found to differentiate between pain that they considered normal (everyday pain) and new pain judged significant enough to report to licensed nurses. CNAs exhibited a holistic understanding of pain, knowledge of strategies to identify and interpret pain, and actions to independently mitigate and report pain. Although additional confirmatory data are needed, the differentiation made between everyday and reportable pain may have important clinical implications suggesting that CNAs should always report to a licensed nurse when they perceive or suspect that residents have pain. [Journal of Gerontological Nursing, 44(4), 29-36.]. PMID- 29437186 TI - Evaluation of IgG4+ Plasma Cell Infiltration in Patients with Systemic Plasmacytosis and Other Plasma Cell-infiltrating Skin Diseases. AB - Systemic plasmacytosis is a rare skin disorder characterized by marked infiltration of plasma cells in the dermis. IgG4-related disease is pathologically characterized by lymphoplasmacytic infiltration rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, accompanied by elevated levels of serum IgG4. Reports of cases of systemic plasmacytosis with abundant infiltration of IgG4+ plasma cells has led to discussion about the relationship between systemic plasmacytosis and IgG4-related disease. This study examined IgG4+/IgG+ plasma cell ratios in 4 patients with systemic plasmacytosis and 12 patients with other skin diseases that show marked infiltration of plasma cells. Furthermore, we examined whether these cases met one of the pathological diagnostic criteria for IgG4-related disease (i.e. IgG4+/IgG plasma cells ratio of over 40%). Only one out of 4 patients with systemic plasmacytosis met the criterion. These results suggest that systemic plasmacytosis and IgG4-related disease are distinct diseases. PMID- 29437187 TI - Generalized Chronic Itch as a First Sign of Malignancy Resembling Paraneoplastic Sensomotoric Neuropathy. PMID- 29437188 TI - Folate Supplementation During Methotrexate Therapy: A Population-based Retrospective Cohort Study. PMID- 29437189 TI - Aquagenic Pruritus in Polycythemia Vera: Clinical Characteristics. AB - Aquagenic pruritus is one of the main clinical features of polycythemia vera. The aim of this study was to analyse the clinical characteristics of aquagenic pruritus. The study group comprised 102 patients with molecularly confirmed polycythemia vera. Demographic data, data on disease history, polycythemia vera status and treatment modalities were collected. Moreover, various clinical features of aquagenic pruritus (including intensity, localization, quality, descriptors) and the most common factors responsible for its aggravation or alleviation were examined. Aquagenic pruritus was observed in 41.2% of individuals, mean duration 6.6 +/- 8.6 years, and its onset was noticed in the majority of patients (52.4%) before the diagnosis of polycythemia vera. The mean intensity of aquagenic pruritus was 4.8 +/- 1.9 points (visual analogue scale). One-third of patients with aquagenic pruritus avoided any contact with water. Antipruritic treatment was received only by 3 patients. Aquagenic pruritus seems to be an important, but frequently neglected, symptom in patients with polycythemia vera. PMID- 29437191 TI - Yellow-brown Papules on the Cheeks and Limbs of a Male Infant: A Quiz. PMID- 29437192 TI - ? PMID- 29437193 TI - ? PMID- 29437194 TI - ? PMID- 29437195 TI - ? PMID- 29437196 TI - ? PMID- 29437197 TI - ? PMID- 29437199 TI - ? PMID- 29437198 TI - ? PMID- 29437200 TI - ? AB - Substantial differences in valuation of lifestyle-related knowledge at Swedish medical schools Lifestyle factors are crucial for prevention and management of many non-communicable diseases such as hypertension, stroke, diabetes, coronary heart disease and chronic obstructive pulmonary disease. Lifestyle medicine is included in national learning outcomes for undergraduate medical education in Sweden. Since assessment drives learning, we reviewed questions from 124 written examinations from all 7 medical schools in Sweden, conducted between 2012 and 2015. There is up to a 5-fold difference between different universities in the weight attached to lifestyle-related knowledge compared to knowledge related to pharmacological treatments. PMID- 29437201 TI - Variations during ageing in the three-dimensional anatomical arrangement of fascicles within the equine superficial digital flexor tendon. AB - BiTendons are constructed from collagenous fascicles separated by endotenon/interfascicular matrix (IFM). Tendons may be specialised for precision movement or to store energy during locomotion and for the latter the elasticity of the endotenon/IFM is particularly important. The equine superficial digital flexor tendon (SDFT) is a dedicated energy-storing tendon with a similar function to the human Achilles tendon. Classical anatomical descriptions portray fascicles as longitudinally arranged distinct anatomical structures. In the present study, using three-dimensional reconstruction from whole tissue slices and histological sections, the fascicles of the equine SDFT were found to adopt a complex interweaved arrangement. Fascicles were found to fully and partially converge and diverge within the tendon and fascicle bundles were observed. Fascicle morphology was not homogenous with narrowing, broadening and twisted fascicles observed in addition to relatively straight fascicles. The number of fascicle bundles observed in cross-section increased from the proximal to the distal end of the tendon, whilst the number of fascicles decreased with age in the proximal region. Fascicular patterns were not similar between the left and right limbs, across different regions or at different ages. A decrease in thickness of the endotenon/IFM between fascicles with age was found in the distal tendon region. The results provide a rationale for considering fascicular organisation when diagnosing and treating tendon injuries, for bioengineering tendon and when modelling tendon function. PMID- 29437203 TI - Reply to Cross-cultural communication in pediatric oncology: Catch them when they're young. PMID- 29437202 TI - Lymphedema in ovarian cancer survivors: Assessing diagnostic methods and the effects of physical activity. AB - BACKGROUND: Lymphedema is a poorly understood side effect of gynecologic cancer treatment. This study was designed to determine the prevalence of lower limb lymphedema (LLL) in a sample of ovarian cancer survivors via 3 different diagnostic methods and to assess the effect of a randomized exercise intervention. METHODS: Physically inactive ovarian cancer survivors (n = 95) were enrolled in a 6-month randomized trial of exercise (primarily brisk walking) versus attention control. LLL was measured at baseline and 6-month visits via a self-report questionnaire, optoelectronic perometry, and an evaluation by a certified lymphedema specialist. RESULTS: LLL prevalence ranged from 21% to 38% according to the diagnostic method, and there was substantial agreement between the self-report questionnaire and the lymphedema specialist evaluation (kappa = 0.61). There was no agreement between the evaluation with optoelectronic perometry and the specialist evaluation. With LLL defined by any method, the baseline prevalence was 38% in both groups. At 6 months, both groups experienced a decreased LLL prevalence: 28% in the exercise group and 35% in the control group. There was no difference in the change in lymphedema prevalence between the 2 groups (P = .64). Body mass index was a significant predictor of LLL. CONCLUSIONS: With a potential prevalence of LLL as high as 40%, further evaluation of diagnostic methods is required to better characterize this side effect of ovarian cancer treatment. No adverse effect of exercise on LLL was found. Further research is strongly needed to evaluate predictors of LLL and the effects of exercise on LLL in order to develop effective physical activity recommendations for women with ovarian cancer. Cancer 2018;124:1929-37. (c) 2018 American Cancer Society. PMID- 29437205 TI - Effect of Chikungunya Virus Infection on Individuals and the Healthcare System. PMID- 29437204 TI - Early-stage breast cancer and employment participation after 2 years of follow up: A comparison with age-matched controls. AB - BACKGROUND: Although cancer survivors are more likely to be unemployed than individuals without a cancer history, employment participation after treatment of early-stage breast cancer has not been widely studied to date. The objectives of the current study were to evaluate employment trajectories in a cohort of patients with early-stage breast cancer and age-matched controls from the time of diagnosis to the 2-year follow-up, and identify factors associated with diminished and emerging employment participation. METHODS: As part of a larger cohort study of 1096 patients with early-stage breast cancer and same-aged women without breast cancer, data from 723 working-age (aged 40-64 years) women (347 patients and 376 controls) were analyzed to evaluate 4 employment trajectories (sustained unemployment, diminished employment, emerging employment, and sustained employment). Multivariable logistic regression models were used to identify factors associated with diminished employment versus sustained employment, and emerging employment versus sustained unemployment. RESULTS: Lower percentages of patients (71%) compared with controls (79%) reported full-time or part-time employment at enrollment (P<.01). Fatigue was a significant predictor of diminished employment for both patients (odds ratio [OR], 5.71; 95% confidence interval [95% CI], 2.48-13.15) and controls (OR, 2.38; 95% CI, 1.21-4.68). Among patients, African American race (OR, 4.02; 95% CI, 1.57-10.28) and public/uninsured insurance status (OR, 4.76; 95% CI, 1.34-12.38) were found to be associated with diminished employment. Among controls, high social support was associated with emerging employment (OR, 3.12; 95% CI, 1.25-7.79). CONCLUSIONS: Fatigued patients, African American patients, and publicly insured/uninsured patients with cancer were more likely to experience diminished employment after 2 years of follow-up. Further investigation with longer follow-up is warranted to identify factors associated with these disparities in employment participation after treatment of early-stage breast cancer. Cancer 2018;124:2026-35. (c) 2018 American Cancer Society. PMID- 29437206 TI - The Burden of Chikungunya Virus Infection: The Need for Systematic and Geriatric Specific Epidemiological Monitoring. PMID- 29437208 TI - Checking expertise in anticipated difficult airway situations. PMID- 29437207 TI - Kinetic Control in the Regioselective Alkylation of Pterin Sensitizers: A Synthetic, Photochemical, and Theoretical Study. AB - Alkylation patterns and excited-state properties of pterins were examined both experimentally and theoretically. 2D NMR spectroscopy was used to characterize the pterin derivatives, revealing undoubtedly that the decyl chains were coupled to either the O4 or N3 sites on the pterin. At a temperature of 70 degrees C, the pterin alkylation regioselectively favored the O4 over the N3. The O4 was also favored when using solvents, in which the reactants had increased solubility, namely N,N-dimethylformamide and N,N-dimethylacetamide, rather than solvents in which the reactants had very low solubility (tetrahydrofuran and dichloromethane). Density functional theory (DFT) computed enthalpies correlate to regioselectivity being kinetically driven because the less stable O-isomer forms in higher yield than the more stable N-isomer. Once formed these compounds did not interconvert thermally or undergo a unimolecular "walk" rearrangement. Mechanistic rationale for the factors underlying the regioselective alkylation of pterins is suggested, where kinetic rather than thermodynamic factors are key in the higher yield of the O-isomer. Computations also predicted greater solubility and reduced triplet state energetics thereby improving the properties of the alkylated pterins as 1 O2 sensitizers. Insight on thermal and photostability of the alkylated pterins is also provided. PMID- 29437209 TI - Advances in thromboelastograph technology. PMID- 29437210 TI - Documenting facemask ventilation before administering neuromuscular blocking drugs. PMID- 29437211 TI - An observational feasibility study of a new anaesthesia drug storage tray. AB - Drug errors in the anaesthetic domain remain a serious cause of iatrogenic harm. To help reduce this issue, we explored the potential safety impact of using a simple colour-coded tray for anaesthetic drug preparation and storage. Over a six month period, three different trained researchers observed 30 cases at three NHS Trusts. Ten observations involved standard drug trays in 'normal' practice, and 20 observations, involved 'Rainbow trays' before and after their introduction. We conducted 20 semi-structured interviews immediately after completing the Rainbow tray observation with the anaesthetists involved. All discussions and detailed notes taken were transcribed, qualitatively analysed using line-by-line coding and then synthesised into narrative themes. We found that using standard, single compartment trays enabled quick, cheap, and portable drug preparation and storage, but was linked to potential or actual harmful errors, such as syringe swaps. Rainbow trays were perceived to be easy to use and effective at all three sites, aiding drug identification and separation, and hence likely to reduce drug error and increase patient safety. We have demonstrated that it is feasible to introduce a new colour-coded compartmentalised Rainbow drugs tray into clinical practice at three NHS hospitals in England. Further research is needed into their effect on the prevalence of drug error. PMID- 29437213 TI - Comparing bougie-guided and conventional nasotracheal intubations using videolaryngoscopy - a reply. PMID- 29437212 TI - Pre-operative variables and complications after oesophagectomy. PMID- 29437214 TI - Comparing bougie-guided and conventional nasotracheal intubations using videolaryngoscopy - a reply. PMID- 29437215 TI - Postoperative pulmonary complications and thoracic patients - a reply. PMID- 29437216 TI - Pre-operative variables and complications after oesophagectomy - a reply. PMID- 29437217 TI - Postoperative pulmonary complications and thoracic patients. PMID- 29437218 TI - Frozen ultrasound image as a prompt for stop before you block. PMID- 29437219 TI - Comparing bougie-guided and conventional nasotracheal intubations using videolaryngoscopy. PMID- 29437220 TI - Removing air bubbles from a 1-ml syringe. PMID- 29437221 TI - The Complexity of Determining Whether a Nursing Home Transfer Is Avoidable at Time of Transfer. AB - OBJECTIVES: To describe the relationship between nursing facility resident risk conditions and signs and symptoms at time of acute transfer and diagnosis of conditions associated with potentially avoidable acute transfers (pneumonia, urinary tract infection, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) or asthma, dehydration, pressure sores). DESIGN: As part of a demonstration project to reduce potentially avoidable hospital transfers, Optimizing Patient Transfers, Impacting Medical Quality, Improving Symptoms: Transforming Institutional Care (OPTIMISTIC) project clinical staff collected data on residents who transferred to the emergency department (ED) or hospital. Cross-tabulations were used to identify associations between risk conditions or symptoms and hospital diagnoses or death. Mixed-effects logistic regression models were used to describe the significance of risk conditions, signs, or symptoms as predictors of potentially avoidable hospital diagnoses or death. SETTING: Indiana nursing facilities (N=19). PARTICIPANTS: Long-stay nursing facility residents (N=1,174), who experienced 1,931 acute transfers from November 2014 to July 2016. MEASUREMENTS: Participant symptoms, transfers, risk factors, and hospital diagnoses. RESULTS: We found that 44% of acute transfers were associated with 1 of 6 potentially avoidable diagnoses. Symptoms before transfer did not discriminate well among hospital diagnoses. Symptoms mapped into multiple diagnoses and most hospital diagnoses had multiple associated symptoms. For example, more than two-thirds of acute transfers of residents with a history of CHF and COPD were for reasons other than exacerbations of those two conditions. CONCLUSION: Although it is widely recognized that many transfers of nursing facility residents are potentially avoidable, determining "avoidability" at time of transfer is complex. Symptoms and risk conditions were only weakly predictive of hospital diagnoses. PMID- 29437222 TI - Cross-cultural communication in pediatric oncology: Catch them when they're young. PMID- 29437223 TI - "Things Ain't Changed Much Since Momma Marched". PMID- 29437224 TI - Perception and measurement of food texture: Solid foods. AB - : There is still a gap between instrumental measurement and sensory evaluation because of the complexity of food texture in spite of many efforts. In sensory evaluation, the terms describing the texture should be well understood by panelists, which poses a problem of establishing lexicons and training panelists. In the instrumental measurement, more efforts are required to understand the large deformation and fracture behavior of foods. The texture profile analysis (TPA) proposed by Alina Szczesniak, Malcolm Bourne, and Sherman has been applied to many foods, and was useful to develop the understanding of textures. But sometimes confusion of the interpretation of TPA parameters appeared. Many new techniques have been introduced to quantify TPA parameters. Recent efforts to fill the gap between sensory evaluation and instrumental measurements, human measurements, or physiological measurements have been introduced. This endeavor is an effort of synthesizing the dentistry and biomedical approach, sensory and psychological approach, and material science approach, and therefore, the collaboration among these disciplines is necessary. This manuscript mainly discusses texture studies for solid foods. PRACTICAL APPLICATIONS: To fill the gap between the sensory evaluation and the instrumental measurement of texture, it is necessary to examine the physical change of foods during the oral processing. This will give us the designing principle of palatable and safe foods. PMID- 29437225 TI - Landscapes of facilitation: how self-organized patchiness of aquatic macrophytes promotes diversity in streams. AB - Spatial heterogeneity plays a crucial role in the coexistence of species. Despite recognition of the importance of self-organization in creating environmental heterogeneity in otherwise uniform landscapes, the effects of such self-organized pattern formation in promoting coexistence through facilitation are still unknown. In this study, we investigated the effects of pattern formation on species interactions and community spatial structure in ecosystems with limited underlying environmental heterogeneity, using self-organized patchiness of the aquatic macrophyte Callitriche platycarpa in streams as a model system. Our theoretical model predicted that pattern formation in aquatic vegetation - due to feedback interactions between plant growth, water flow and sedimentation processes - could promote species coexistence, by creating heterogeneous flow conditions inside and around the plant patches. The spatial plant patterns predicted by our model agreed with field observations at the reach scale in naturally vegetated rivers, where we found a significant spatial aggregation of two macrophyte species around C. platycarpa. Field transplantation experiments showed that C. platycarpa had a positive effect on the growth of both beneficiary species, and the intensity of this facilitative effect was correlated with the heterogeneous hydrodynamic conditions created within and around C. platycarpa patches. Our results emphasize the importance of self-organized patchiness in promoting species coexistence by creating a landscape of facilitation, where new niches and facilitative effects arise in different locations. Understanding the interplay between competition and facilitation is therefore essential for successful management of biodiversity in many ecosystems. PMID- 29437226 TI - Antifungal, Mechanical, and Physical Properties of Edible Film Containing Williopsis saturnus var. saturnus Antagonistic Yeast. AB - The molding of food products causing health risks is a main problem in the food industry. In this study, as an alternative solution for preventing mold growth, an antifungal edible film was developed by incorporating Williopsis saturnus var. saturnus (0; 3; 7; and 9 logs CFU/cm2 ) into whey protein concentrate (WPC) based films. Antifungal properties of the films against Penicilium expansum and Aspergillus niger were analyzed using the disc diffusion method. Physical (barrier, solubility, color), mechanical (tensile strength and percent elongation) properties of the films as well as the survival of W. saturnus in the film were assessed during 28 days of storage at 23 degrees C. According to the results, the viability of W. saturnus (7 and 9 logs CFU/cm2 ) in WPC films stored for 28 days under vacuum or non-vacuum decreased to 36% and 60%, respectively. In addition, films containing W. saturnus decreased the viability of P. expansum and A. niger by 29% and 19%, respectively. Adding yeast did not change the tensile strength (P > 0.05), but significantly decreased % elongation and increased water vapor and oxygen permeability and water solubility (P < 0.05). In conclusion, this study showed that the developed films may be useful for inhibiting mold growth on foods. PMID- 29437227 TI - Molecular Analysis, Biochemical Characterization, Antimicrobial Activity, and Immunological Analysis of Proteus mirabilis Isolated from Broilers. AB - Proteus mirabilis, a Gram-negative bacterium, is ubiquitous in the environment and is considered as the normal microflora in the human gastrointestinal tract. However, this bacterium is an opportunistic pathogen in humans, often causing urinary tract infections. Moreover, Proteus has been frequently isolated from food animals, including poultry. Whether this bacterium contributes to the foodborne illness in humans is unclear. In this report, P. mirabilis isolates recovered from broilers during housing in the units were characterized, their antimicrobial activity was assayed, and broiler immune response to the soluble proteins was determined. Cecal contents and fecal droppings were treated according to the standard protocol for isolation. Speciation based on biochemical reactions and the antimicrobial activity of the isolates were carried out using commercial kits. Immunoblot was assayed to determine immune status of broilers against P. mirabilis. A total of 10 isolates of P. mirabilis were selected for further characterization. These isolates could grow in pH 6.0 and 1% NaCl conditions. They were resistant to sodium lactate, troleandomycin, rifamycin SV, vancomycin, but sensitive to nalidixic acid, cefotaxime and novobiocin. Moreover, the CTX, ACC, CMY-1, BIC, NDM, VEB, qnrB and qnrD genes were detected by PCR amplification in all isolates. Sera from broilers harboring this bacterium reacted to the P. mirabilis soluble proteins, but not from litter- and age matched P. mirabilis negative and SPF chickens, indicating that this bacterium infected chickens that could have humoral immune response against P. mirabilis. This study provides a rationale for further monitoring P. mirabilis during poultry production to determine whether this bacterium poses potential threats to public health. PMID- 29437228 TI - Mechanism of UV-driven Photoelectrocatalytic Degradation of Berberine Chloride Form Using the ESR Spin-trapping Method. AB - Photoelectrocatalytic (PEC) system greatly improves the migration of photoexcited charges, retards the fast recombination of electron-hole and increases the lifetime of photogenerated holes. In this article, we constructed a novel PEC system to degrade berberine chloride form (BCF). XRD patterns indicated aging time was an important condition for the crystal type of TiO2, and the best proportion of anatase/rutile was 80/20. The band gap energy of the TiO2 was 3.01 eV. We demonstrated that a synergistic effect existed between photocatalysis (PC) and electrocatalysis (EC). Besides, we discussed the influence of pH, current density, the amount of catalyst and initial BCF concentration on the degradation of BCF. Electron spin resonance (ESR) through spin trap 5, 5-dimethyl-1-pyrroline N-oxide (DMPO) and the scavenging experiments suggested that the reactive oxygen species (ROS) were superoxide radicals (O2.-), hydroxyl radicals (.OH) and sulfate radical (SO4.-) in PEC system. Furthermore, we compared the two pathway of formation DMPO-SO4 adducts and found that SO4.- was the most major oxidized species in degrading BCF. We proposed a plausible reaction mechanism. Intriguingly, even under lower current and weaker light conditions, the PEC process maintained its effectiveness, demonstrating the feasibility of the PEC approach. PMID- 29437230 TI - Lectin Isolated from Japanese Red Sword Beans (Canavalia gladiata) as a Potential Cancer Chemopreventive Agent. AB - : In this study, we investigated the chemical and biological profile of lectin isolated from Japanese red sword beans (Canavalia gladiata; RSBs). RSB lectin was purified using maltamyl-Sepharose 4B and subjected to amino acid composition and partial amino acid sequencing analyses, and evaluated for blood and carbohydrate specificity, mitogenic activity, splenic natural killer (NK) cell activity, and its effect on B16 melanoma cell proliferation, compared with Concanavalin A (Con A). The amino acid composition and sequences of RSB lectin were similar to those of Con A. RSB lectin showed specificity to mannose, glucose, maltose, methyl-D mannoside, and thyroglobulin, but not rhamnose, using mouse, sheep, and rabbit erythrocytes. Compared with Con A, RSB lectin showed low resistance to proteases and to temperatures greater than 70 degrees C, but high mitogenic activity for mouse splenic cells. Notably, while treatment with RSB lectin and Con A (0.01 and 0.1 MUg/mL) promoted similar levels of splenic NK cell activity, which were higher than that observed in the control (0 MUg/mL) and interleukin 2 (IL-2) (25 U)-treated populations, RBS lectin exerted a significantly stronger anti proliferative effect than Con A at a concentration of 125.0 MUg per well. Overall, our results show that RSB lectin might exert immunological effects on mouse splenic cells and could thus be used as a potential cancer chemopreventive agent. PRACTICAL APPLICATION: Japanese red sword bean (RSB) is a tropical perennial legume consumed in many Asian countries. RSB lectin shows specificity to mannose, glucose, maltose, methyl-d-mannoside, and thyroglobulin, but not to rhamnose, using mouse, sheep, and rabbit erythrocytes. RSB lectin exhibits similarities to Concanavalin A in amino acid composition and sequence, shows mitogenic activity for mouse splenic cells and strong anti-proliferative activity for B16 melanoma cells, and also enhances the activity of splenic natural killer (NK) cells against YAC-1 cells. Thus, RSB lectin has the potential to be used as a bioactive protein in medical research. PMID- 29437229 TI - IL-27: a double agent in the IL-6 family. AB - The cytokine interleukin (IL)-6 is a major therapeutic target for the treatment of various inflammatory and autoimmune diseases. While IL-6 receives considerable attention in studies of innate and adaptive immunity, the IL-6-related family member IL-27 is recognized increasingly for its effects on cellular proliferation, differentiation and leucocyte effector functions. Both cytokines activate responses in myeloid and stromal tissue cells, where they direct the transition from innate to adaptive immunity. However, they are identified frequently as lymphokines that control responses in T cells and B cells. In this regard, IL-27 often opposes the action of IL-6. Here, we will review the role of IL-6 and IL-27 in inflammation, with a particular focus on inflammatory arthritis, and discuss their importance in the diagnosis, stratification and treatment of autoimmune disease. PMID- 29437231 TI - Ultrasound-Assisted Extraction of Cannabinoids from Cannabis Sativa L. Optimized by Response Surface Methodology. AB - : Ultrasonication was used to extract bioactive compounds from Cannabis sativa L. such as polyphenols, flavonoids, and cannabinoids. The influence of 3 independent factors (time, input power, and methanol concentration) was evaluated on the extraction of total phenols (TPC), flavonoids (TF), ferric reducing ability of plasma (FRAP) and the overall yield. A face-centered central composite design was used for statistical modelling of the response data, followed by regression and analysis of variance in order to determine the significance of the model and factors. Both the solvent composition and the time significantly affected the extraction while the sonication power had no significant impact on the responses. The response predictions obtained at optimum extraction conditions of 15 min time, 130 W power, and 80% methanol were 314.822 mg GAE/g DW of TPC, 28.173 mg QE/g DW of TF, 18.79 mM AAE/g DW of FRAP, and 10.86% of yield. A good correlation was observed between the predicted and experimental values of the responses, which validated the mathematical model. On comparing the ultrasonic process with the control extraction, noticeably higher values were obtained for each of the responses. Additionally, ultrasound considerably improved the extraction of cannabinoids present in Cannabis. PRACTICAL APPLICATION: Low frequency ultrasound was employed to extract bioactive compounds from the inflorescence part of Cannabis. The responses evaluated were-total phenols, flavonoids, ferric reducing assay and yield. The solvent composition and time significantly influenced the extraction process. Appreciably higher extraction of cannabinoids was achieved on sonication against control. PMID- 29437232 TI - Fermented Nut-Based Vegan Food: Characterization of a Home made Product and Scale Up to an Industrial Pilot-Scale Production. AB - : Because of the impossibility to consume food of animal origin, vegan consumers are looking for substitutes that could enrich their diet. Among many substitutes, fermented nut products are made from different nut types and obtained after soaking, grinding, and fermentation. Although other fermented vegetable products have been deeply investigated, there are few data about the fermentative processes of nut-based products and the microbial consortia able to colonize these products are not yet studied. This study characterized a hand-made vegan product obtained from cashew nut. Lactic acid bacteria responsible for fermentation were identified, revealing a succession of hetero- and homo fermentative species during process. Successively, some lactic acid bacteria isolates from the home-made vegan product were used for a pilot-scale fermentation. The products obtained were characterized and showed features similar to the home-made one, although the microbiological hazards have been prevented through proper and rapid acidification, enhancing their safety features. PRACTICAL APPLICATION: Spontaneous fermented products are valuable sources of microorganisms that can be used in many food processes as starter cultures. The lactic acid bacteria isolated in this research can be exploited by industries to develop new foods and therefore to enter new markets. The use of selected starter cultures guarantees good organoleptic characteristics and food safety (no growth of pathogens). PMID- 29437233 TI - Prediction of Firmness and pH for "Golden Delicious" Apple Based on Elasticity Index from Modal Analysis. AB - : An experimental modal test system was established to extract the natural frequencies of "Golden Delicious" apple, after which the elasticity index was calculated to predict the apple quality parameters based on the orthogonal polynomials method. The elasticity index in every vibration mode changed dramatically (P = 0.01) along time revolution. The multivariate regression methods were used to model the predictive relationship between the elasticity index and the apple quality parameters. The models of the apple juice pH based on support vector regression presented adequate determination coefficients of calibration set (Q2 = 0.68) and prediction set (R2 = 0.55), respectively. The models based on partial least squares regression could be used for predicting the apple firmness parameter offset gradient (Q2 = 0.76 and R2 = 0.72). It helped understanding the fruit dynamic properties of the fruit and spontaneously obtaining the fruit chemical parameters. A nondestructive and portable device was viable for fruit quality estimation by the modal test system during storage, transport, and even growth on the tree. PRACTICAL APPLICATION: A nondestructive and portable device was provided for fruit quality detection during storage, transport and even growth based on experimental modal analysis. A systematic statistical analysis method about outlier detection, data set partitioning, parameter optimization, and multiple regression models were provided. PMID- 29437234 TI - Simultaneous measurement of quantum yield ratio and absorption ratio between acceptor and donor by linearly unmixing excitation-emission spectra. AB - Quantum yield ratio (QA /QD ) and absorption ratio (KA /KD ) in all excitation wavelengths used between acceptor and donor are indispensable to quantitative fluorescence resonance energy transfer (FRET) measurement based on linearly unmixing excitation-emission spectra (ExEm-spFRET). We here describe an approach to simultaneously measure QA /QD and KA /KD values by linearly unmixing the excitation-emission spectra of at least two different donor-acceptor tandem constructs with unknown FRET efficiency. To measure the QA /QD and KA /KD values of Venus (V) to Cerulean (C), we used a wide-field fluorescence microscope to image living HepG2 cells separately expressing each of four different C-V tandem constructs at different emission wavelengths with 435 nm and 470 nm excitation respectively to obtain the corresponding excitation-emission spectrum (SDA ). Every SDA was linearly unmixed into the contributions (weights) of three excitation-emission spectra of donor (WD ) and acceptor (WA ) as well as donor acceptor sensitisation (WS ). Plot of WS /WD versus WA /WD for the four C-V plasmids from at least 40 cells indicated a linear relationship with 1.865 of absolute intercept (QA /QD ) and 0.273 of the reciprocal of slope (KA /KD ), which was validated by quantitative FRET measurements adopting 1.865 of QA /QD and 0.273 of KA /KD for C32V, C5V, CVC and VCV constructs respectively in living HepG2 cells. PMID- 29437235 TI - Exome sequencing reveals three homozygous missense variants in SNRPA in two sisters with syndromic intellectual disability. AB - Splicing-related gene mutations might affect the expression of a single gene or multiple genes and cause clinically heterogeneous diseases. With the advent of next-generation sequencing, several splicing gene mutations have been exposed, yet most major spliceosome genes have no reports of germline mutations and therefore, their effects are largely unknown. We describe the previously unreported concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in 2 female siblings with 3 homozygous missense variants in SNRPA (a component of the U1 small nuclear ribonucleoprotein complex) characterized by homozygosity mapping and whole exome sequencing. Combined, c.97A>G, c.98T>C, and c.100T>A, in exon 2 of SNRPA lead to p.Ile33Ala and p.Phe34Ile exchanges, which were predicted in silico to be deleterious. Although both patients exhibited some clinical features seen in other spliceosomal disorders, their complete clinical phenotype appears to be rather uncommon, a finding that may further support the notion that mutations in components of the major spliceosome do not strictly lead to the same syndromes/phenotypes. PMID- 29437236 TI - A Novel Modified Lipid: Enzymatic Esterification of 2-Monoacylglycerol with N acetyl-l-leucine. AB - : The objective of this research was to synthesize and characterize a novel modified lipid which is composed of mainly oleic acid at sn-2 position and a hydrophobic essential amino acid derivative (N-acetyl-l-leucine) at sn-1(3) or sn 1, 3 positions. LC-MS-MS analysis indicated that the target modified lipid structure was obtained at the end of the developed reaction. Response surface methodology was applied to enhance a reliable empirical model for prediction and to optimize reaction conditions: reaction time (8 to 24 hr), reaction temperature (40 to 55 degrees C), and enzyme load (15 to 30 wt%). The percentage of total reaction products was found to be 28.5 at the optimum conditions of 54 degrees C, 8 hr and 15% (by mass) enzyme load. This result is closely correlated to the predicted highest total reaction product (29.3%) obtained by response surface methodology. The physical and thermal characteristics of the modified lipid and refined olive pomace oil were compared and found to be similar. Caloric value of modified lipid was decreased by 18.65% compared to that of refined olive pomace oil. A novel modified lipid which may have potential uses in healthy food industries was successfully produced with the incorporation of N-acetyl-l-leucine to 2-monoacylglycerol. PRACTICAL APPLICATION: A novel modified lipid was synthesized by enzymatic incorporation of a "hydrophobic and essential amino acid derivative" into 2-monoacylglycerol. This modified lipid contains mainly oleic acid at sn-2 position and N-acetyl-l-leucine at sn-1,3 positions. The product behaved as an oil above 10 degrees C. Caloric value of the novel oil-like product was reduced by 18.65%. The modified lipid may have the potential for replacement with the oil in food products such as margarine, shortenings, salad dressing, and mayonnaise. PMID- 29437237 TI - Intraoperative transesophageal echocardiographic predictors of recurrent left ventricular outflow tract obstruction in children undergoing subaortic stenosis resection. AB - BACKGROUND: Intraoperative transesophageal echocardiography (iTEE) is used to assess for residual left ventricular outflow tract obstruction (LVOTO) after surgical resection of subaortic membrane causing subaortic stenosis (sub-AS). We aimed to identify the iTEE features associated with recurrence of LVOTO. METHODS: We conducted a retrospective study of children undergoing sub-AS resection from June 2006 to June 2014. Doppler assessment of the flow velocity and the anatomical features of the left ventricular outflow tract were analyzed from stored echocardiograms. Recurrent LVOTO was defined as an increase in the mean pressure gradient across the left ventricular outflow tract of > 15 mm Hg on the most recent follow-up echocardiogram from the mean pressure gradient on the predischarge echocardiogram or as doubling of the mean pressure gradient to a value >=20 mm Hg. RESULTS: Thirty-five patients were included, with median age at surgery was 8.1 years (range: 0.7-29 years) and median follow-up was 47 months (2 91 months). Ten patients (29%) had recurrent LVOTO, which was associated with a shorter distance between the narrowest diameter of the outflow tract and the aortic valve on iTEE [median 0.59 cm (range 0.39-0.74) vs 0.98 cm (0.75-1.5), P = .03]. No patients with more than mild residual LVOTO on iTEE regressed to mild or no LVOTO on follow-up echocardiograms. CONCLUSIONS: LVOTO recurrence after sub-AS resection is common, and residual LVOTO remains the same or increases over time. Proximity of the LVOTO to the aortic valve is a risk factor for recurrent LVOTO. These findings may be useful in counseling patients and to guide the frequency of postoperative follow-up. PMID- 29437238 TI - A unified model of melatonin, 6-sulfatoxymelatonin, and sleep dynamics. AB - A biophysical model of the key aspects of melatonin synthesis and excretion has been developed, which is able to predict experimental dynamics of melatonin in plasma and saliva, and of its urinary metabolite 6-sulfatoxymelatonin (aMT6s). This new model is coupled to an established model of arousal dynamics, which predicts sleep and circadian dynamics based on light exposure and times of wakefulness. The combined model thus predicts melatonin levels over the sleep wake/dark-light cycle and enables prediction of melatonin-based circadian phase markers, such as dim light melatonin onset (DLMO) and aMT6s acrophase under conditions of normal sleep and circadian misalignment. The model is calibrated and tested against group average data from 10 published experimental studies and is found to reproduce quantitatively the key dynamics of melatonin and aMT6s, including the timing of release and amplitude, as well as response to controlled lighting and shift work. PMID- 29437239 TI - Depressional wetlands affect watershed hydrological, biogeochemical, and ecological functions. AB - Depressional wetlands of the extensive U.S. and Canadian Prairie Pothole Region afford numerous ecosystem processes that maintain healthy watershed functioning. However, these wetlands have been lost at a prodigious rate over past decades due to drainage for development, climate effects, and other causes. Options for management entities to protect the existing wetlands, and their functions, may focus on conserving wetlands based on spatial location vis-a-vis a floodplain or on size limitations (e.g., permitting smaller wetlands to be destroyed but not larger wetlands). Yet the effects of such management practices and the concomitant loss of depressional wetlands on watershed-scale hydrological, biogeochemical, and ecological functions are largely unknown. Using a hydrological model, we analyzed how different loss scenarios by wetland size and proximal location to the stream network affected watershed storage (i.e., inundation patterns and residence times), connectivity (i.e., streamflow contributing areas), and export (i.e., streamflow) in a large watershed in the Prairie Pothole Region of North Dakota, USA. Depressional wetlands store consequential amounts of precipitation and snowmelt. The loss of smaller depressional wetlands (<3.0 ha) substantially decreased landscape-scale inundation heterogeneity, total inundated area, and hydrological residence times. Larger wetlands act as hydrologic "gatekeepers," preventing surface runoff from reaching the stream network, and their modeled loss had a greater effect on streamflow due to changes in watershed connectivity and storage characteristics of larger wetlands. The wetland management scenario based on stream proximity (i.e., protecting wetlands 30 m and ~450 m from the stream) alone resulted in considerable landscape heterogeneity loss and decreased inundated area and residence times. With more snowmelt and precipitation available for runoff with wetland losses, contributing area increased across all loss scenarios. We additionally found that depressional wetlands attenuated peak flows; the probability of increased downstream flooding from wetland loss was also consistent across all loss scenarios. It is evident from this study that optimizing wetland management for one end goal (e.g., protection of large depressional wetlands for flood attenuation) over another (e.g., protecting of small depressional wetlands for biodiversity) may come at a cost for overall watershed hydrological, biogeochemical, and ecological resilience, functioning, and integrity. PMID- 29437240 TI - Comparison of Characteristics of Female Drivers with Single and Multiple DUI Convictions. AB - BACKGROUND: Women are increasingly involved in drunk driving and fatal crashes, yet except for the screening performed in criminal justice settings, little is known about their life context, psychiatric histories, and family backgrounds. This study describes a sample of women with histories of arrest for driving under the influence of alcohol (DUI) who were interviewed outside a criminal justice setting and contrasts women with single versus multiple DUI convictions. METHODS: Women with recent documented histories of DUI participated in a study of women's health behaviors. Thirty-six women with 1 DUI and 62 with 2 or more DUIs participated in a diagnostic telephone interview which assessed demographics, alcohol use and problems, psychiatric problems, treatment, and partner violence. RESULTS: The sample overall had high rates of co-occurring psychiatric problems, parental alcohol problems, early sexual and physical abuse, and head injuries. Alcohol use severity and the prevalence of head injuries and partner alcohol problems were significantly higher among women with multiple DUIs than women with a single DUI. Measures reflecting life context, such as marital status, number of children, and childhood trauma, were not associated with number of DUIs. CONCLUSIONS: Findings suggest that DUI recidivism in women is accounted for primarily by AUD severity and is not influenced by previous life events such as partner violence, psychiatric problems, and family context such as divorce/separation or number of children. Multiple DUIs in women may mark an alcohol severity threshold beyond which few factors account for additional risk. PMID- 29437241 TI - Tenotomy of the semitendinosus muscle under standing sedation versus general anesthesia: Outcomes in 20 horses with fibrotic myopathy. AB - OBJECTIVE: To compare outcomes after semitendinosus tenotomy performed under standing sedation versus general anesthesia. STUDY DESIGN: Retrospective case series. SAMPLE POPULATION: 20 horses with fibrotic myopathy of the semitendinosus muscle. METHODS: Medical records (2002-2015) of horses undergoing tenotomy of the semitendinosus muscle for the treatment of fibrotic myopathy were reviewed. Signalment, history, affected muscles, restrain method, surgical procedures, and short-term outcome as well as complications were retrieved from records. Long term outcome (gait and athletic function) was assessed at least 6 months postoperatively by conversation with the owners. Pearson's chi2 statistical analysis was used to compare restrain method and affected muscles with overall outcome. Significance was set at P < .05. RESULTS: Tenotomy of the semitendinosus muscle was performed under standing sedation in 8 horses and under general anesthesia in 12 horses. Follow-up period ranged from 9 months to 10 years. Gait was improved to variable degrees in 8 of 14 horses when the semitendinosus muscle alone was affected and in 4 of 6 horses when both the semitendinosus and semimembranosus muscles were involved (P = .11). Six of 8 horses treated under standing sedation and 6 of 12 horses treated under general anesthesia exhibited some improvement in the characteristic fibrotic gait (P = .4473). Five of 6 athletic horses treated under standing sedation and 6 of 9 athletic horses treated under general anesthesia returned to their preinjury level of athleticism. Horses treated under standing sedation had no incisional complications; 2 of 12 horses treated under general anesthesia exhibited incisional drainage. CONCLUSION: Tenotomy of the semitendinosus muscle in horses with fibrotic myopathy leads to similar improvement in gait, whether performed under standing sedation or general anesthesia. PMID- 29437242 TI - Impact of procedure-related conduction disturbances after transcatheter aortic valve implantation on myocardial performance and survival evaluated by conventional and speckle tracking echocardiography. AB - OBJECTIVES: Although procedure-related new cardiac conduction disturbances (CCDs) remain an important issue in transcatheter aortic valve implantation (TAVI), their effect on myocardial function and overall patient outcome remains unclear. The goal of this study was to analyze the influence of procedure-related CCDs on systolic and diastolic LV performance and on patient survival after TAVI. METHODS AND RESULTS: Ninety-five patients who underwent TAVI for severe symptomatic aortic stenosis (AS) and had a complete follow-up were evaluated with respect to procedure-related CCDs. Left ventricular (LV) performance was measured using standard echocardiographic parameters and speckle tracking analysis. Survival was assessed during longer-term follow-up (mean: 29.1 +/- 16.9 months). After TAVI, the improvement of global LV function expressed as ejection fraction (LVEF; from 45.5 +/- 10.0 to 47.8 +/- 13.9%, P = .13) was not significant. New CCDs were found in 35.7% of TAVI recipients. A comparison between patients with and without new CCDs showed that LV systolic function improved in those without CCDs, while it tended to deteriorate in patients with CCDs (change in LVEF: 5.5 +/- 12.3% vs 4.9% +/- 11.5%, P = .001; change in global longitudinal strain (GLS): -1.1 +/- 4.6% vs 1.2 +/- 4.5%, P = .01). Changes in diastolic function did not differ significantly between the groups (changes in transmitral E/A-ratio: -0.3 +/- 0.6 vs -0.5 +/- 0.5, P = .1). Kaplan-Meier survival analysis revealed no significant differences between the two cohorts (P = .795). CONCLUSION: Procedure-related conduction abnormalities after TAVI lead to an LBBB-related dyssynchrony with impairment of LV performance but not of overall survival. PMID- 29437244 TI - Epothilone D - correct drug, wrong disease. PMID- 29437243 TI - Melatonin attenuates smoking-induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats. AB - Epidemiology survey indicated that cigarette smoking is a risk factor of diabetes. However, the precise mechanisms remain to be clarified. In this study, we found that smoking caused metabolic malfunctions on pancreas and liver in experimental animal model. These were indicated by hyperglycemia, increased serum hemoglobin A1c level and decreased insulin secretion, inhibition of liver glycogen synthase (LGS), and hepatic glycogen synthesis. Mechanistic studies revealed that all these alterations were caused by the inflammatory reaction and reactive oxygen species (ROS) induced by the smoking. Melatonin treatment significantly preserved the functions of both pancreas and liver by reducing beta cell apoptosis, CD68-cell infiltration, ROS production, and caspase-3 expression. The siRNA-knockdown model identified that the protective effects of melatonin were mediated by melatonin receptor-2 (MT2). This study uncovered potentially underlying mechanisms related to the association between smoking and diabetes. In addition, it is, for first time, to report that melatonin effectively protects against smoking-induced glucose metabolic alterations and the signal transduction pathway of melatonin is mainly mediated by its MT2 receptor. These observations provide solid evidence for the clinically use of melatonin to reduce smoking related diabetes, and the therapeutic regimens are absent currently. PMID- 29437245 TI - Phospholipase D isoforms differentially regulate leukocyte responses to acute lung injury. AB - Phospholipase D (PLD) plays important roles in cellular responses to tissue injury that are critical to acute inflammatory diseases, such as the acute respiratory distress syndrome (ARDS). We investigated the expression of PLD isoforms and related phospholipid phosphatases in patients with ARDS, and their roles in a murine model of self-limited acute lung injury (ALI). Gene expression microarray analysis on whole blood obtained from patients that met clinical criteria for ARDS and clinically matched controls (non-ARDS) demonstrated that PLD1 gene expression was increased in patients with ARDS relative to non-ARDS and correlated with survival. In contrast, PLD2 expression was associated with mortality. In a murine model of self-resolving ALI, lung Pld1 expression increased and Pld2 expression decreased 24 h after intrabronchial acid. Total lung PLD activity was increased 24 h after injury. Pld1-/- mice demonstrated impaired alveolar barrier function and increased tissue injury relative to WT and Pld2-/- , whereas Pld2-/- mice demonstrated increased recruitment of neutrophils and macrophages, and decreased tissue injury. Isoform-specific PLD inhibitors mirrored the results with isoform-specific Pld-KO mice. PLD1 gene expression knockdown in human leukocytes was associated with decreased phagocytosis by neutrophils, whereas reactive oxygen species production and phagocytosis decreased in M2-macrophages. PLD2 gene expression knockdown increased neutrophil and M2-macrophage transmigration, and increased M2-macrophage phagocytosis. These results uncovered selective regulation of PLD isoforms after ALI, and opposing effects of selective isoform knockdown on host responses and tissue injury. These findings support therapeutic strategies targeting specific PLD isoforms for the treatment of ARDS. PMID- 29437246 TI - Early movement restriction leads to enduring disorders in muscle and locomotion. AB - Motor control and body representation in the central nervous system (CNS) as well as musculoskeletal architecture and physiology are shaped during development by sensorimotor experience and feedback, but the emergence of locomotor disorders during maturation and their persistence over time remain a matter of debate in the absence of brain damage. By using transient immobilization of the hind limbs, we investigated the enduring impact of postnatal sensorimotor restriction (SMR) on gait and posture on treadmill, age-related changes in locomotion, musculoskeletal histopathology and Hoffmann reflex in adult rats without brain damage. SMR degrades most gait parameters and induces overextended knees and ankles, leading to digitigrade locomotion that resembles equinus. Based on variations in gait parameters, SMR appears to alter age-dependent plasticity of treadmill locomotion. SMR also leads to small but significantly decreased tibial bone length, chondromalacia, degenerative changes in the knee joint, gastrocnemius myofiber atrophy and muscle hyperreflexia, suggestive of spasticity. We showed that reduced and atypical patterns of motor outputs, and somatosensory inputs and feedback to the immature CNS, even in the absence of perinatal brain damage, play a pivotal role in the emergence of movement disorders and musculoskeletal pathologies, and in their persistence over time. Understanding how atypical sensorimotor development likely contributes to these degradations may guide effective rehabilitation treatments in children with either acquired (ie, with brain damage) or developmental (ie, without brain injury) motor disabilities. PMID- 29437247 TI - Developmental endothelial locus-1 (Del-1) antagonizes Interleukin-17-mediated allergic asthma. AB - Interleukin (IL)-17 is a major contributor to the pathogenesis of allergic asthma. Developmental endothelial locus-1 (Del-1) is an endothelial cell-secreted protein known to inhibit IL-17 expression. However, little is known about the association between Del-1 and IL-17 in the pathogenesis of allergic asthma. Using bronchoalveolar lavage fluid (BALF) and peripheral blood samples collected from allergic asthmatic patients and controls, we explored the role of Del-1 in relation to IL-17 in allergic asthma. We found that the negative correlation between Del-1 and IL-17 was significant in BALF of allergic asthmatics. Del-1 treatment inhibited the expression of IL-17, the differentiation of IL-17 secreting leukocytes and associated cytokines. Contrarily, IL-17 levels were increased after treatment with anti-Del-1 mAb. Consistent with this, Del-1 treatment led to downregulation of IL-5, CCL5 and IL-4, thus reducing secretion of eosinophil cationic protein. Furthermore, Del-1 significantly downregulated the expression of ICAM-1 and may have the potential to reduce leukocyte transendothelial migration. Our data demonstrate that Del-1 can negatively regulate IL-17 and its proinflammatory function, thereby limiting airway inflammation in allergic asthmatics, and suggest Del-1 as a potential candidate for prevention and treatment of allergic asthma. PMID- 29437249 TI - A Multifunctional Pincer Ligand for Cobalt-Promoted Oxidation by N2 O. AB - The divalent cobalt complex of the diprotic pincer ligand bis-pyrazolylpyridine, (H2 L)CoCl2 , is dehydrohalogenated twice by LiN(SiMe3 )2 in the presence of PEt3 to give monomeric S=1/2 LCo(PEt3 )2 (1), fully characterized in the solid-state and solution as a square pyramidal monomer with a long axial Co-P bond. This 17 electron species reacts in time of mixing with N2 O to form L2 Co2 (MU-OPEt3 ) (2)+3 OPEt3 , the former the first example of phosphine oxide bridging two transition metals. The same products are formed from O2 , and divalent cobalt persists even in the presence of excess oxidant. Species (2) catalyzes oxygen atom transfer (OAT) for generation of O=PEt3 from PEt3 from either N2 O or O2 . Bridging and terminal cobalt oxo intermediates are suggested, and the electron donor power, and potential redox activity of the dianionic pincer ligand is emphasized. PMID- 29437248 TI - Mechanism of agonism and antagonism of the Pseudomonas aeruginosa quorum sensing regulator QscR with non-native ligands. AB - Pseudomonas aeruginosa is an opportunistic pathogen that uses the process of quorum sensing (QS) to coordinate the expression of many virulence genes. During quorum sensing, N-acyl-homoserine lactone (AHL) signaling molecules regulate the activity of three LuxR-type transcription factors, LasR, RhlR and QscR. To better understand P. aeruginosa QS signal reception, we examined the mechanism underlying the response of QscR to synthetic agonists and antagonists using biophysical and structural approaches. The structure of QscR bound to a synthetic agonist reveals a novel mode of ligand binding supporting a general mechanism for agonist activity. In turn, antagonists of QscR with partial agonist activity were found to destabilize and greatly impair QscR dimerization and DNA binding. These results highlight the diversity of LuxR-type receptor responses to small molecule agonists and antagonists and demonstrate the potential for chemical strategies for the selective targeting of individual QS systems. PMID- 29437250 TI - Melatonin-mediated inhibition of Cav3.2 T-type Ca2+ channels induces sensory neuronal hypoexcitability through the novel protein kinase C-eta isoform. AB - Recent studies implicate melatonin in the antinociceptive activity of sensory neurons. However, the underlying mechanisms are still largely unknown. Here, we identify a critical role of melatonin in functionally regulating Cav3.2 T-type Ca2+ channels (T-type channel) in trigeminal ganglion (TG) neurons. Melatonin inhibited T-type channels in small TG neurons via the melatonin receptor 2 (MT2 receptor) and a pertussis toxin-sensitive G-protein pathway. Immunoprecipitation analyses revealed that the intracellular subunit of the MT2 receptor coprecipitated with Galphao . Both shRNA-mediated knockdown of Galphao and intracellular application of QEHA peptide abolished the inhibitory effects of melatonin. Protein kinase C (PKC) antagonists abolished the melatonin-induced T type channel response, whereas inhibition of conventional PKC isoforms elicited no effect. Furthermore, application of melatonin increased membrane abundance of PKC-eta (PKCeta ) while antagonism of PKCeta or shRNA targeting PKCeta prevented the melatonin-mediated effects. In a heterologous expression system, activation of MT2 receptor strongly inhibited Cav3.2 T-type channel currents but had no effect on Cav3.1 and Cav3.3 current amplitudes. The selective Cav3.2 response was PKCeta dependent and was accompanied by a negative shift in the steady-state inactivation curve. Furthermore, melatonin decreased the action potential firing rate of small TG neurons and attenuated the mechanical hypersensitivity in a mouse model of complete Freund's adjuvant-induced inflammatory pain. These actions were inhibited by T-type channel blockade. Together, our results demonstrated that melatonin inhibits Cav3.2 T-type channel activity through the MT2 receptor coupled to novel Gbetagamma -mediated PKCeta signaling, subsequently decreasing the membrane excitability of TG neurons and pain hypersensitivity in mice. PMID- 29437251 TI - Chiral molecules adsorbed on a solid surface: Tartaric acid diastereomers and their surface explosion on Cu(111). AB - The adsorption of diastereoisomers of tartaric acid, namely, meso (R,S)-tartaric acid, (R,R)-tartaric acid, and the racemic mixture of (R,R) and (S,S) tartaric acid on the (111) surface of a copper single crystal has been studied by means of reflection-absorption IR Spectroscopy, X-ray photoelectron spectroscopy, low energy electron diffraction, and thermal desorption spectroscopy. Two distinct adsorption modes are identified for all three adsorbate systems. All molecules undergo an identical thermally induced autocatalytic decomposition reaction above 510 K. The pure enantiomers show 2D chiral long-range ordered structures of opposite handedness. PMID- 29437252 TI - High temporal resolution motion estimation using a self-navigated simultaneous multi-slice echo planar imaging acquisition. AB - BACKGROUND: Subject motion is known to produce spurious covariance among time series in functional connectivity that has been reported to induce distance dependent spurious correlations. PURPOSE: To present a feasibility study for applying the extended Kalman filter (EKF) framework for high temporal resolution motion correction of resting state functional MRI (rs-fMRI) series using each simultaneous multi-slice (SMS) echo planar imaging (EPI) shot as its own navigator. STUDY TYPE: Prospective feasibility study. POPULATION/SUBJECTS: Three human volunteers. FIELD STRENGTH/SEQUENCE: 3T GE DISCOVERY MR750 scanner using a 32-channel head coil. Simultaneous multi-slice rs-fMRI sequence with repetition time (TR)/echo time (TE) = 800/30 ms, and SMS factor 6. ASSESSMENT: Motion estimates were computed using two techniques: a conventional rigid-body volume wise registration; and a high-temporal resolution motion estimation rigid-body approach. The reference image was resampled using the estimates obtained from both approaches and the difference between these predicted volumes and the original moving series was summarized using the normalized mean squared error (NMSE). STATISTICAL TESTS: Direct comparison of NMSE values. RESULTS: High temporal motion estimation was always superior to volume-wise motion estimation for the sample presented. For staged continuous rotations, the NMSE using high temporal resolution motion estimates ranged between [0.130, 0.150] for the first volunteer (in-plane rotations), between [0.060, 0.068] for the second volunteer (in-plane rotations), and between [0.063, 0.080] for the third volunteer (through plane rotations). These values went up to [0.384, 0.464]; [0.136, 0.179]; and [0.080, 0.096], respectively, when using volume-wise motion estimates. DATA CONCLUSION: Accurate high-temporal rigid-body motion estimates can be obtained for rs-fMRI taking advantage of simultaneous multi-slice EPI sub-TR shots. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. PMID- 29437253 TI - LytM factor Alr3353 affects filament morphology and cell-cell communication in the multicellular cyanobacterium Anabaena sp. PCC 7120. AB - Heterocyst-forming cyanobacteria are organized as multicellular filaments of tightly interacting, functionally specialized cells. N2 -fixing heterocysts differentiate from vegetative cells under nitrogen limitation in a semi-regular pattern along the filament. Diazotrophic growth requires metabolite exchange between neighboring cells within the filament. This exchange occurs via cell-cell junction complexes that span the gap between the plasma membranes and thereby cross the septal peptidoglycan through an array of uniform nanopores formed by AmiC-type cell wall hydrolases. We investigated how the lytic hydrolase AmiC1 (Alr0092) from Anabaena sp. PCC 7120, whose activity needs to be tightly controlled to avoid cell lysis, is regulated by the LytM factor Alr3353. Inactivation of alr3353 resulted in significantly fewer nanopores and as a consequence, a lower rate of fluorescent tracer exchange between cells. The mutant was not able to grow with N2 as sole nitrogen source, although heterocysts were formed. Alr3353 localized mainly to fully developed intercellular septa of vegetative cells. The purified protein bound to peptidoglycan and enhanced the hydrolytic activity of AmiC1 in vitro. Our data show that the LytM factor Alr3353 regulates nanopore formation and cell-cell communication by directly interacting with AmiC1. PMID- 29437254 TI - CRISPR/Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV-1 infection in macrophages. AB - The IFN-stimulated gene ubiquitin-specific proteinase 18 (USP18) encodes a protein that negatively regulates T1 IFN signaling via stearic inhibition of JAK1 recruitment to the IFN-alpha receptor 2 subunit (IFNAR2). Here, we demonstrate that USP18 expression is induced by HIV-1 in a T1 IFN-dependent manner. Experimental depletion of USP18 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing results in a significant restriction of HIV-1 replication in an induced pluripotent stem cell (iPSC)-derived macrophage model. In the absence of USP18, macrophages have increased responsiveness to stimulation with T1 IFNs with prolonged phosphorylation of STAT1 and STAT2 and increased expression of IFN stimulated genes that are key for antiviral responses. Interestingly, HIV-1 requires some signaling through the T1 IFN receptor to replicate efficiently because a neutralizing antibody that inhibits T1 IFN activity reduces HIV-1 replication rate in monocyte-derived macrophages. USP18 induction by HIV-1 tunes the IFN response to optimal levels allowing for efficient transcription from the HIV-1 LTR promoter while minimizing the T1 IFN-induced antiviral response that would otherwise restrict viral replication and spread. Finally, iPSC and CRISPR/Cas9 gene targeting offer a powerful tool to study host factors that regulate innate immune responses. PMID- 29437255 TI - Diabetic Medicine and Diabetes UK. PMID- 29437257 TI - Corrigendum. PMID- 29437258 TI - Highly Efficient Photocatalytic System Constructed from CoP/Carbon Nanotubes or Graphene for Visible-Light-Driven CO2 Reduction. AB - Visible-light-driven conversion of CO2 to CO and high-value-added carbon products is a promising strategy for mitigating CO2 emissions and reserving solar energy in chemical form. We report an efficient system for CO2 transformation to CO catalyzed by bare CoP, hybrid CoP/carbon nanotubes (CNTs), and CoP/reduced graphene oxide (rGO) in mixed aqueous solutions containing a Ru-based photosensitizer, under visible-light irradiation. The in situ prepared hybrid catalysts CoP/CNT and CoP/rGO show excellent catalytic activities in CO2 reduction to CO, with a catalytic rates of up to 39 510 and 47 330 MUmol h-1 g-1 in the first 2 h of reaction, respectively; a high CO selectivity of 73.1 % for the former was achieved in parallel competing reactions in the photoreduction of CO2 and H2 O. A combination of experimental and computational studies clearly shows that strong interactions between CoP and carbon-supported materials and partially adsorbed H2 O molecules on the catalyst surface significantly improve CO-generating rates. PMID- 29437259 TI - Early fetal sexing in the rhinoceros by detection of male-specific genes in maternal serum. AB - Genetic sexing of animals with long gestation time benefits the management of captive populations. Here, X and Y chromosome-specific primers, based on equine gene sequencing data, were developed and tested on captive rhinoceroses (10 males, 20 females) representing four species (Diceros bicornis, Certaotherium simum simum, Rhinoceros unicornis, and Dicerorhinus sumatrensis). The Y chromosome-specific primer set targeted SRY (Sex-determining region Y), and amplified a 177-bp product following PCR of DNA extracted from males, but not females, of all species. A primer set based on the equine AMEL (Amelogenin) gene resulted in a 232-bp product following PCR of all rhinoceros species. These gene specific primer sets were then evaluated for their ability to determine gender in cell-free DNA from rhinoceros serum. Modifications to the original extraction and PCR protocols were required to obtain sufficient DNA quantities from serum, and both DNA yield and PCR amplification were substantially reduced or absent following multiple freeze-thaw cycles of serum. When fresh serum from 14 pregnant rhinoceroses (ultimately bearing seven male and seven female calves), representing four species at different stages of gestation (Days 61-490), were probed in a PCR-based assay, an accuracy of 71% was achieved for male-specific gene detection of SRY, which improved to 100% by including a reamplification step into the protocol. Such early sex determination should be a valuable tool for current management practices as well as future assisted reproduction of rhinoceroses. PMID- 29437260 TI - Tetrylones: An Intriguing Class of Monoatomic Zero-valent Group 14 Compounds. AB - Tetrylones (ylidones) represent a class of zero-valent group 14 compounds with the general formula EL2 (E=C, Si, Ge, Sn, or Pb; L=neutral sigma-donating ligand), wherein the tetrel atom, E(0), possess its four valence electrons in the form of two electron lone pairs, and is moreover coordinated by two ligands (L) via donor-acceptor interactions (L->E<-L). This review focuses on the synthesis, structure, reactivity, and computational examination of the isolable heavier tetrylones (Si, Ge, Sn) that have been discovered recently. A comprehensive review on carbone chemistry is beyond the scope of this review. It should also be noted that tetrylones contain two different types of lone pairs, that is, one that exhibits p-type and one that exhibits s-type characteristics. Different behavior should thus be expected when these lone pairs react with Lewis acids. PMID- 29437261 TI - Different effects of phospholipase Dzeta2 and non-specific phospholipase C4 on lipid remodeling and root hair growth in Arabidopsis response to phosphate deficiency. AB - Phosphate (Pi) deficiency in soils is a major limiting factor for plant growth. In response to Pi deprivation, one prominent metabolic adaptation in plants is the decrease in membrane phospholipids that consume approximately one-third cellular Pi. The level of two phospholipid-hydrolyzing enzymes, phospholipase Dzeta2 (PLDzeta2) and non-specific phospholipase C4 (NPC4), is highly induced in Pi-deprived Arabidopsis. To determine the role of PLDzeta2 and NPC4 in plant growth under Pi limitation, Arabidopsis plants deficient in both PLDzeta2 and NPC4 (npc4pldzeta2) were generated and characterized. Lipid remodeling in leaves and roots was analyzed at three different durations of Pi deficiency. NPC4 affected lipid changes mainly in roots at an early stage of Pi deprivation, whereas PLDzeta2 exhibited a more overt effect on lipid remodeling in leaves at a later stage of Pi deprivation. Pi deficiency-induced galactolipid increase and phospholipid decrease were impeded in pldzeta2 and npc4pldzeta2 plants. In addition, seedlings of npc4pldzeta2 had the same root hair density as pldzeta2 but shorter root hair length than pldzeta2 in response to Pi deficiency. The loss of NPC4 decreased root hair length but had no effect on root hair density. These data suggest that PLDzeta2 and NPC4 mediate the Pi deprivation-induced lipid remodeling in a tissue- and time-specific manner. PLDzeta2 and NPC4 have distinctively different roles in root hair growth and development in response to Pi deprivation; PLDzeta2 negatively modulates root hair density and length, whereas NPC4 promotes root hair elongation. PMID- 29437262 TI - Assessing intracardiac thrombus prior to cardioversion: A story yet to be told. PMID- 29437263 TI - Human blood MAIT cell subsets defined using MR1 tetramers. AB - Mucosal-associated invariant T (MAIT) cells represent up to 10% of circulating human T cells. They are usually defined using combinations of non-lineage specific (surrogate) markers such as anti-TRAV1-2, CD161, IL-18Ralpha and CD26. The development of MR1-Ag tetramers now permits the specific identification of MAIT cells based on T-cell receptor specificity. Here, we compare these approaches for identifying MAIT cells and show that surrogate markers are not always accurate in identifying these cells, particularly the CD4+ fraction. Moreover, while all MAIT cell subsets produced comparable levels of IFNgamma, TNF and IL-17A, the CD4+ population produced more IL-2 than the other subsets. In a human ontogeny study, we show that the frequencies of most MR1 tetramer+ MAIT cells, with the exception of CD4+ MAIT cells, increased from birth to about 25 years of age and declined thereafter. We also demonstrate a positive association between the frequency of MAIT cells and other unconventional T cells including Natural Killer T (NKT) cells and Vdelta2+ gammadelta T cells. Accordingly, this study demonstrates that MAIT cells are phenotypically and functionally diverse, that surrogate markers may not reliably identify all of these cells, and that their numbers are regulated in an age-dependent manner and correlate with NKT and Vdelta2+ gammadelta T cells. PMID- 29437264 TI - Insight on specificity of uracil permeases of the NAT/NCS2 family from analysis of the transporter encoded in the pyrimidine utilization operon of Escherichia coli. AB - The uracil permease UraA of Escherichia coli is a structurally known prototype for the ubiquitous Nucleobase-Ascorbate Transporter (NAT) or Nucleobase-Cation Symporter-2 (NCS2) family and represents a well-defined subgroup of bacterial homologs that remain functionally unstudied. Here, we analyze four of these homologs, including RutG of E. coli which shares 35% identity with UraA and is encoded in the catabolic rut (pyrimidine utilization) operon. Using amplified expression in E. coli K-12, we show that RutG is a high-affinity permease for uracil, thymine and, at low efficiency, xanthine and recognizes also 5 fluorouracil and oxypurinol. In contrast, UraA and the homologs from Acinetobacter calcoaceticus and Aeromonas veronii are permeases specific for uracil and 5-fluorouracil. Molecular docking indicates that thymine is hindered from binding to UraA by a highly conserved Phe residue which is absent in RutG. Site-directed replacement of this Phe with Ala in the three uracil-specific homologs allows high-affinity recognition and/or transport of thymine, emulating the RutG profile. Furthermore, all RutG orthologs from enterobacteria retain an Ala at this position, implying that they can use both uracil and thymine and, possibly, xanthine as substrates and provide the bacterial cell with a range of catabolizable nucleobases. PMID- 29437265 TI - Diagnostic accuracy of 3.0T diffusion-weighted MRI for patients with uterine carcinosarcoma: Assessment of tumor extent and lymphatic metastasis. AB - BACKGROUND: Assessment of tumor extent and lymphatic metastasis of uterine carcinosarcomas is important for treatment planning. PURPOSE/HYPOTHESIS: To evaluate the diagnostic accuracy of 3.0T diffusion-weighted (DW) MRI for patients with uterine carcinosarcoma, in assessment of tumor extent and lymphatic metastasis. STUDY TYPE: Retrospective diagnostic accuracy study. POPULATION: A consecutive cohort of 68 patients with pathologically proved carcinosarcoma between January 2006 and July 2014. FIELD STRENGTH/SEQUENCE: 3T DW MRI. ASSESSMENT: Maximal tumor and uterus size, presence of deep myometrial invasion, cervical invasion, adnexal invasion, lymphadenopathy, and the apparent diffusion coefficient (ADC) values of each tumor were used. Histopathology was the gold standard. STATISTICAL TESTS: Diagnostic accuracy. Logistic regression. RESULTS: In all, 38 patients entered the final analysis, with median age of 58 years (range, 35-79 years). The sensitivity and specificity in detecting deep myometrial invasion, cervical stromal invasion, adnexal invasion, as well as pelvic and para-aortic lymph node metastases were 65% and 72%, 91% and 85%, 50% and 100%, 33% and 89%, and 33% and 100%, respectively. The largest tumor diameters predicted deep myometrium invasion (anteroposterior direction, P = 0.004) and cervical stroma invasion (craniocaudal direction, P = 0.008). Tumor ADCmin significantly predicted the lymphovascular permeation (P = 0.025; odds ratio = 0.96). DATA CONCLUSION: Preoperative DW MRI is useful to assess deep myometrial or cervical stromal invasion in uterine carcinosarcoma, yet the diagnostic performance for detecting adnexal invasion and lymphatic metastasis requires further improvement. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29437266 TI - Noninvasive assessment of intracranial elastance and pressure in spontaneous intracranial hypotension by MRI. AB - BACKGROUND: Spontaneous intracranial hypotension (SIH) is often misdiagnosed, and can lead to severe complications. Conventional MR sequences show a limited ability to aid in this diagnosis. MR-based intracranial pressure (MR-ICP) may be able to detect changes of intracranial elastance and pressure. PURPOSE: To determine whether MR-ICP is able to differentiate SIH patients from normal subjects, improve diagnostic sensitivity, and provide an insight into the pathophysiology. STUDY TYPE: Prospective. SUBJECTS: Twenty-eight SIH cases with orthostatic headache and 20 healthy volunteers. FIELD STRENGTH/SEQUENCE: Cine phase-contrast MRI on a 1.5T scanner. ASSESSMENT: Intracranial elastance (IE) was derived from the ratio of the peak-to-peak cerebrospinal fluid (CSF) pressure gradient (PGcsf-pp ) and intracranial volume change, obtained by summing all flows before each sequential cardiac frame. STATISTICAL TESTS: Student's t-test was used to compare the MR-ICP indexes and flow parameters between SIH patients and healthy volunteers (P < 0.01). RESULTS: The SIH patients with cervical epidural venous dilatation (EVD) had an IE of 0.121 +/- 0.027 mmHg/cm/ml, significantly higher than that of the normal volunteers (0.085 +/- 0.027 mmHg/cm/ml; P = 0.002). In contradistinction, the EVD-negative SIH patients, including four with no sign of CSF leaks, had significantly lower IE (0.055 +/- 0.012 mmHg/cm/ml) compared with the normal volunteers and the EVD-positive group (P = 0.001, P < 0.001). The EVD-negative patients had significantly lower PGcsf pp (0.024 +/- 0.007 mmHg/cm) compared with the normal volunteers and the EVD positive group (0.035 +/- 0.011 mmHg/cm, 0.040 +/- 0.010 mmHg/cm; P = 0.003, P < 0.001). Additionally, the MRI flow study showed a significant decrease in transcranial inflow and outflow of SIH patients (P < 0.01). DATA CONCLUSION: We found that the MR-ICP method is potentially more sensitive than morphological MRI in the early diagnosis of SIH. Also, contrary to common belief, our results suggest that an abnormal craniospinal elastance might be the cause of SIH, instead of CSF leak. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1255-1263. PMID- 29437267 TI - Pharmacoproteomics Profile in Response to Acamprosate Treatment of an Alcoholism Animal Model. AB - Acamprosate is an FDA-approved medication for the treatment of alcoholism that is unfortunately only effective in certain patients. Although acamprosate is known to stabilize the hyper-glutamatergic state in alcoholism, pharmacological mechanisms of action in brain tissue remains unknown. To investigate the mechanism of acamprosate efficacy, the authors employ a pharmacoproteomics approach using an animal model of alcoholism, type 1 equilibrative nucleoside transporter (ENT1) null mice. The results demonstrate that acamprosate treatment significantly decreased both ethanol drinking and preference in ENT1 null mice compared to that of wild-type mice. Then, to elucidate acamprosate efficacy mechanism in ENT1 null mice, the authors utilize label-free quantification proteomics comparing both genotype and acamprosate treatment effects in the nucleus accumbens (NAc). A total of 1040 protein expression changes are identified in the NAc among 3634 total proteins detected. The proteomics and Western blot result demonstrate that acamprosate treatment decreased EAAT expression implicating stabilization of the hyper-glutamatergic condition in ENT1 null mice. Pathway analysis suggests that acamprosate treatment in ENT1 null mice seems to rescue glutamate toxicity through restoring of RTN4 and NF-kappaB medicated neuroimmune signaling compared to wild-type mice. Overall, pharmacoproteomics approaches suggest that neuroimmune restoration is a potential efficacy mechanism in the acamprosate treatment of certain sub-populations of alcohol dependent subjects. PMID- 29437268 TI - Using support vector machine analysis to assess PartinMR: A new prediction model for organ-confined prostate cancer. AB - BACKGROUND: Partin tables represent the most widely used predictive tool for prostate cancer stage at prostatectomy but with potential limitations. PURPOSE: To develop a new PartinMR model for organ-confined prostate cancer (OCPCA) by incorporating Partin table and mp-MRI with a support vector machine (SVM) analysis. STUDY TYPE: Retrospective. POPULATION: In all, 541 patients with biopsy confirmed prostate cancer underwent mp-MRI. FIELD STRENGTH: T2 -weighted, diffusion-weighted imaging with a 3.0T MR scanner. ASSESSMENT: Candidate predictors included age, prostate-specific antigen, clinical stage, biopsy Gleason score (GS), and mp-MRI findings, ie, tumor location, Prostate Imaging and Reporting and Data System (PI-RADS) score, diameter (D-max), and 6-point MR stage. The PartinMR model with combination of a Partin table and mp-MRI findings was developed using SVM and 5-fold crossvalidation analysis. STATISTICAL TESTS: The predicted ability of the PartinMR model was compared with a standard Partin and a modified Partin table (mPartin) which used for mp-MRI staging. Statistical tests were made by area under receiver operating characteristic curve (AUC), adjusted proportional hazard ratio (HR), and a cost-effective benefit analysis. RESULTS: The rate of OCPCA at prostatectomy was 46.4% (251/541). Using MR staging, mPartin table (AUC, 0.814, 95% confidence interval [CI]: 0.779-0.846, P = 0.001) is appreciably better than the Partin table (AUC, 0.730, 95% CI: 0.690 0.767). Contrarily, adding all MR variables, the PartinMR model (AUC, 0.891, 95% CI: 0.884-0.899, P < 0.001) outperformed any other scheme, with 79.3% sensitivity, 75.7% specificity, 79% positive predictive value, and 76.0% negative predictive value for OCPCA. MR stage represented the most influential predictor of extracapsular extension (HR, 2.77, 95% CI: 1.54-3.33), followed by D-max (2.01, 95% CI: 1.31-2.68), biopsy GS (1.64, 95% CI: 1.35-2.12), and PI-RADS score (1.21, 95% CI: 1.01-1.98). DATA CONCLUSION: The new PartinMR model is superior to the conventional Partin table for OCPCA. Clinical implications of mp-MRI for prostate cancer stage must be confirmed in further trials. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2018;48:499-506. PMID- 29437269 TI - Deep learning enables reduced gadolinium dose for contrast-enhanced brain MRI. AB - BACKGROUND: There are concerns over gadolinium deposition from gadolinium-based contrast agents (GBCA) administration. PURPOSE: To reduce gadolinium dose in contrast-enhanced brain MRI using a deep learning method. STUDY TYPE: Retrospective, crossover. POPULATION: Sixty patients receiving clinically indicated contrast-enhanced brain MRI. SEQUENCE: 3D T1 -weighted inversion recovery prepped fast-spoiled-gradient-echo (IR-FSPGR) imaging was acquired at both 1.5T and 3T. In 60 brain MRI exams, the IR-FSPGR sequence was obtained under three conditions: precontrast, postcontrast images with 10% low-dose (0.01mmol/kg) and 100% full-dose (0.1 mmol/kg) of gadobenate dimeglumine. We trained a deep learning model using the first 10 cases (with mixed indications) to approximate full-dose images from the precontrast and low-dose images. Synthesized full-dose images were created using the trained model in two test sets: 20 patients with mixed indications and 30 patients with glioma. ASSESSMENT: For both test sets, low-dose, true full-dose, and the synthesized full-dose postcontrast image sets were compared quantitatively using peak-signal-to-noise ratios (PSNR) and structural-similarity-index (SSIM). For the test set comprised of 20 patients with mixed indications, two neuroradiologists scored blindly and independently for the three postcontrast image sets, evaluating image quality, motion-artifact suppression, and contrast enhancement compared with precontrast images. STATISTICAL ANALYSIS: Results were assessed using paired t-tests and noninferiority tests. RESULTS: The proposed deep learning method yielded significant (n = 50, P < 0.001) improvements over the low-dose images (>5 dB PSNR gains and >11.0% SSIM). Ratings on image quality (n = 20, P = 0.003) and contrast enhancement (n = 20, P < 0.001) were significantly increased. Compared to true full-dose images, the synthesized full-dose images have a slight but not significant reduction in image quality (n = 20, P = 0.083) and contrast enhancement (n = 20, P = 0.068). Slightly better (n = 20, P = 0.039) motion artifact suppression was noted in the synthesized images. The noninferiority test rejects the inferiority of the synthesized to true full-dose images for image quality (95% CI: -14-9%), artifacts suppression (95% CI: -5-20%), and contrast enhancement (95% CI: -13-6%). DATA CONCLUSION: With the proposed deep learning method, gadolinium dose can be reduced 10-fold while preserving contrast information and avoiding significant image quality degradation. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. MAGN. RESON. IMAGING 2018;48:330-340. PMID- 29437270 TI - Clinicians' attitudes and approaches to evaluating the potential living kidney donor-recipient relationship: an interview study. AB - AIM: Careful assessment of the potential donor-recipient relationship is recommended by guidelines to prevent undue coercion, and ensure realistic expectations and genuine motivations. However, relationships are complex, nuanced and value-laden, and can be challenging to evaluate in living kidney donation. We aimed to describe the attitudes and approaches of transplant clinicians towards assessing the relationship between potential living kidney donors and their recipients. METHODS: Semi-structured interviews were conducted with 54 transplant clinicians (nephrologists, surgeons, coordinators, social workers, psychiatrists and psychologists) from 32 transplant centres across nine countries including Australia, United States, Canada and New Zealand. Transcripts were analyzed thematically. RESULTS: Four themes were identified: protecting against vulnerability and premature decisions (ensuring genuine motivation, uncovering precarious dynamics and pre-empting conflict, shared accountability, relying on specialty psychosocial expertise, trusting intimate bonds, tempering emotional impulsivity); safeguarding against coercion (discerning power imbalance, justified inquiry, awareness of impression management); minimizing potential threat to relationships (preserving the bond, giving equitable attention to donors and recipients, ensuring realistic expectations); and ambiguities in making judgments (adjudicating appropriateness and authenticity of relationships, questioning professional intervening, uncertainties in subjective and emotional assessments). CONCLUSIONS: Clinicians felt ethically compelled to minimise the risk of undue coercion and to protect donors and recipients when evaluating the donor-recipient relationship. However, disentangling voluntariness and altruism from potential undisclosed pressures to enact societal and family duty, making decisions within this complex, multi-stakeholder context, and avoiding the imposition of undue paternalism and donor autonomy, were challenging. Multidisciplinary expertise and practical strategies for managing uncertainties are required. PMID- 29437271 TI - Novel radiomic signature as a prognostic biomarker for locally advanced rectal cancer. AB - BACKGROUND: Locally advanced rectal cancer (LARC) patient stratification by clinicoradiologic factors may yield variable results. Therefore, more efficient prognostic biomarkers are needed for improved risk stratification of LARC patients, personalized treatment, and prognostication. PURPOSE/HYPOTHESIS: To compare the ability of a radiomic signature to predict disease-free survival (DFS) with that of a clinicoradiologic risk model in individual patients with LARC. STUDY TYPE: Retrospective study. POPULATION: In all, 108 consecutive patients (allocated to a training and validation set with a 1:1 ratio) with LARC treated with neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). FIELD STRENGTH/SEQUENCE: Axial 3D LAVA multienhanced MR sequence at 3T. ASSESSMENT: ITK-SNAP software was used for manual segmentation of 3D pre nCRT MR images. All manual tumor segmentations were performed by a gastrointestinal tract radiologist, and validated by a senior radiologist. The clinicoradiologic risk factors with potential prognostic outcomes were identified in univariate analysis based on the Cox regression model for the whole set. The results showed that ypT, ypN, EMVI, and MRF were potential clinicoradiologic risk factors. Interestingly, only ypN and MRF were identified as independent predictors in multivariate analysis based on the Cox regression model. STATISTICAL TESTS: A radiomic signature based on 485 3D features was generated using the least absolute shrinkage and selection operator (LASSO) Cox regression model. The association of the radiomic signature with DFS was investigated by Kaplan-Meier survival curves. Survival curves were compared by the log-rank test. Three models were built and assessed for their predictive values, using the Harrell concordance index and integrated time-dependent area under the curve. RESULTS: The novel radiomic signature stratified patients into low- and high-risk groups for DFS in the training set (hazard ratio [HR] = 6.83; P < 0.001), and was successfully validated in the validation set (HR = 2.92; P < 0.001). The model combining the radiomic signature and clinicoradiologic findings had the best performance (C index = 0.788, 95% confidence interval [CI] 0.72-0.86; integrated time-dependent area under the curve of 0.837 at 3 years). DATA CONCLUSION: The novel radiomic signature could be used to predict DFS in patients with LARC. Furthermore, combining this radiomic signature with clinicoradiologic features significantly improved the ability to estimate DFS (P = 0.001, 0.005 in training set and in validation set, respectively), and may help guide individualized treatment in such patients. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018. PMID- 29437272 TI - Bioactivity and composition of a preserved connective tissue matrix derived from human placental tissue. AB - There are a wide variety of extracellular matrices that can be used for regenerative purposes. Placental tissue-based matrices are quickly becoming an attractive option given the availability of the tissue source and the wide variety of bioactive molecules knows to exist in unprocessed placental tissues. As fresh placental tissues are seldom an option at the point of care, we examined both the composition and bioactivity of a commercially packaged flowable placental connective tissue matrix (FPTM) (BioECM(r) , Skye Biologics, Inc.) that was preserved by the proprietary HydraTek(r) process. The FPTM contained significant amounts of collagen and various growth factors such as bFGF, EGF, PDGF, KGF, and PIGF. In addition, it contained high levels of tissue inhibitors of metalloproteinases (TIMP-1 and 2) and molecules known to modulate the immune response including TGF-beta and IL-4. In terms of its bioactivity, the FPTM displayed the ability (1) to suppress INF-gamma secretion in activated T-cells nearly fourfold over control media, (2) to inhibit methicillin resistant Staphylococcus aureus (MRSA) and Staphylococcus saprophyticus proliferation, (3) to increase the migration of adipose-derived stem cells (ASCs) nearly threefold over control media and (4) to adhere to ASCs in culture. When ASCs were exposed to FPTM in culture, the cells maintained healthy morphology and showed no significant changes in the expression of five genes involved in tissue growth and repair as compared to culture in standard growth media. (c) 2018 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2731 2740, 2018. PMID- 29437273 TI - Isolation and characterization of pectolytic bacterial pathogens infecting potatoes in Nakuru County, Kenya. AB - AIMS: Isolation and characterization of pectolytic bacteria associated with soft rot disease of potatoes in Nakuru, Kenya, to provide the basis for the development of disease control measures. METHODS AND RESULTS: Potato tubers showing symptoms of soft rot were collected from different farms in Molo and Mau Narok regions within Nakuru county. Isolation was done using crystal violet pectate medium (CVPM). Out of the 71 isolates that showed growth on CVPM, pathogenicity tests revealed that 36 of them had the ability to macerate tissues of potato tubers. All the isolates yielded a fragment of approximately 1500 bp after 16S rDNA amplification. Using the BIOLOG microbial identification system, 20 bacterial isolates were identified as Pectobacterium carotovorum subsp. carotovorum, 7 were Pseudomonas fluorescens B while 9 were Ps. fluorescens A. Y1/Y2 primers successfully amplified pectate lyase-encoding (pel) gene, approximately 434 bp, in all the 20 P. carotovorum species. The virulence of the isolated strains to cause disease, according to pectinolytic tests, varied with change in incubation temperature of the test samples. Pectobacterium carotovorum strains were the most virulent at 30 degrees C while disease severity due to infection by Ps. fluorescens A strains was high at 20 degrees C compared to the other isolates. CONCLUSION: This study reveals the identity of pectolytic bacterial species from two genera, Pectobacterium and Pseudomonas, as causative agents of potato soft rot in Nakuru, Kenya. SIGNIFICANCE AND IMPACT OF THE STUDY: Research findings from this study will aid in developing suitable risk mitigation methods for adoption by farmers to prevent losses due to soft rot. PMID- 29437274 TI - Hybrid Indicators for Fast and Sensitive Voltage Imaging. AB - Membrane voltage is an important biophysical signal that underlies intercellular electrical communications. A fluorescent voltage indicator is presented that enables the investigation of electrical signaling at high spatial resolution. The method is built upon the site-specific modification of microbial rhodopsin proteins with organic fluorophores, resulting in a hybrid indicator scaffold that is one of the most sensitive and fastest orange-colored voltage indicators developed to date. We applied this technique to optically map electrical connectivity in cultured cells, which revealed gap junction-mediated long-range coupling that spanned over hundreds of micrometers. PMID- 29437275 TI - Intersection of endocytic and exocytic systems in Toxoplasma gondii. AB - Host cytosolic proteins are endocytosed by Toxoplasma gondii and degraded in its lysosome-like compartment, the vacuolar compartment (VAC), but the dynamics and route of endocytic trafficking remain undefined. Conserved endocytic components and plant-like features suggest T. gondii endocytic trafficking involves transit through early and late endosome-like compartments (ELCs) and potentially the trans-Golgi network (TGN) as in plants. However, exocytic trafficking to regulated secretory organelles, micronemes and rhoptries, also proceeds through ELCs and requires classical endocytic components, including a dynamin-related protein, DrpB. Here, we show that host cytosolic proteins are endocytosed within 7 minutes post-invasion, trafficked through ELCs en route to the VAC, and degraded within 30 minutes. We could not definitively interpret if ingested protein is trafficked through the TGN. We also found that parasites ingest material from the host cytosol throughout the parasite cell cycle. Ingested host proteins colocalize with immature microneme proteins, proM2AP and proMIC5, in transit to the micronemes, but not with the immature rhoptry protein proRON4, indicating that endocytic trafficking of ingested protein intersects with exocytic trafficking of microneme proteins. Finally, we show that conditional expression of a DrpB dominant negative mutant increases T. gondii ingestion of host-derived proteins, suggesting that DrpB is not required for parasite endocytosis. PMID- 29437276 TI - Editorial Comment on Validation of the digital PCR system for use in tyrosine kinase inhibitor-resistant EGFR-mutant non-small-cell lung cancer. PMID- 29437277 TI - Identification of Native and Posttranslationally Modified HLA-B*57:01-Restricted HIV Envelope Derived Epitopes Using Immunoproteomics. AB - The recognition of pathogen-derived peptides by T lymphocytes is the cornerstone of adaptive immunity, whereby intracellular antigens are degraded in the cytosol and short peptides assemble with class I human leukocyte antigen (HLA) molecules in the ER. These peptide-HLA complexes egress to the cell surface and are scrutinized by cytotoxic CD8+ T-cells leading to the eradication of the infected cell. Here, naturally presented HLA-B*57:01 bound peptides derived from the envelope protein of the human immunodeficiency virus (HIVenv) are identified. HIVenv peptides are present at a very small percentage of the overall HLA-B*57:01 peptidome (<0.1%) and both native and posttranslationally modified forms of two distinct HIV peptides are identified. Notably, a peptide bearing a natively encoded C-terminal tryptophan residue is also present in a modified form containing a kynurenine residue. Kynurenine is a major product of tryptophan catabolism and is abundant during inflammation and infection. Binding of these peptides at a molecular level and their immunogenicity in preliminary functional studies are examined. Modest immune responses are observed to the modified HIVenv peptide, highlighting a potential role for kynurenine-modified peptides in the immune response to HIV and other viral infections. PMID- 29437278 TI - Heteroleptic Copper(I)-Based Complexes for Photocatalysis: Combinatorial Assembly, Discovery, and Optimization. AB - A library of 50 copper-based complexes derived from bisphosphines and diamines was prepared and evaluated in three mechanistically distinct photocatalytic reactions. In all cases, a copper-based catalyst was identified to afford high yields, where new heteroleptic complexes derived from the bisphosphine BINAP displayed high efficiency across all reaction types. Importantly, the evaluation of the library of copper complexes revealed that even when photophysical data is available, it is not always possible to predict which catalyst structure will be efficient or inefficient in a given process, emphasizing the advantages for catalyst structures with high modularity and structural variability. PMID- 29437279 TI - Radiomic features of pretreatment MRI could identify T stage in patients with rectal cancer: Preliminary findings. AB - BACKGROUND: Recent studies have shown that magnetic resonance (MR) radiomic analysis is feasible and has some value in identifying tumor characteristics, but there are few data regarding the role of MR-based radiomic features in rectal cancer. PURPOSE: The aim of this study was to determine whether radiomic features extracted from T2 -weighted imaging (T2 WI) can identify pathological features in rectal cancer. STUDY TYPE: Retrospective study. POPULATION/SUBJECTS: A cohort comprising 119 rectal cancer patients who underwent surgery between January 2015 and November 2016. FIELD STRENGTH/SEQUENCE: 3.0T, axial high-resolution T2 weighted turbo spin echo (TSE) sequence. ASSESSMENT: Patients were classified according to pathological features such as T stage, N stage, perineural invasion, histological grade, lymph-vascular invasion, tumor deposits, and circumferential resection margin (CRM). The whole tumor volume (WTV) was distinguished, and segments were quantified on axial high-resolution T2 WI by a radiologist. A total of 256 radiomic features were extracted. STATISTICAL TESTS: To achieve reliable results, cluster analysis and least absolute shrinkage and selection operator (LASSO) were implemented. In the cluster analysis, the patients were divided into two groups, and chi-square tests were performed to investigate the relationship between the pathological features and the radiomic-based clusters. The area under the curve (AUC) was calculated to evaluate the predictability of the model in the LASSO analysis. RESULTS: The cluster results revealed that patients could be stratified into two groups, and the chi-square test results indicated that the pT stage was correlated with the radiomic feature cluster results (P = 0.002). The prediction model AUC for the diagnostic T stage was 0.852 (95% confidence interval: 0.677-1; sensitivity: 79.0%, specificity: 82.0%). DATA CONCLUSION: The use of MRI-derived radiomic features to identify the T stage is feasible in rectal cancer. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29437280 TI - Nucleophilic Activation of Sulfur Hexafluoride: Metal-Free, Selective Degradation by Phosphines. AB - The development of new methods for the chemical activation of the extremely inert greenhouse gas sulfur hexafluoride (SF6 ) not only is of current environmental interest, but also offers new opportunities for applications of SF6 as a reagent in organic synthesis. We herein report the first nucleophilic activation of SF6 by Lewis bases, namely by phosphines, which results either in its complete degradation to phosphine sulfides and difluorophosphoranes or in the selective conversion of SF6 into a bench-stable, crystalline salt containing the SF5- anion. Quantum chemical calculations reveal a nucleophilic substitution mechanism (SN 2) for the initial fluorine abstraction from SF6 by the phosphine. Furthermore, a scalable one-pot procedure for the complete decomposition of SF6 into solid, nonvolatile products is presented based on cheap and commercially available starting materials. PMID- 29437281 TI - Free-breathing dynamic contrast-enhanced MRI for assessment of pulmonary lesions using golden-angle radial sparse parallel imaging. AB - BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been shown to be a promising technique for assessing lung lesions. However, DCE MRI often suffers from motion artifacts and insufficient imaging speed. Therefore, highly accelerated free-breathing DCE-MRI is of clinical interest for lung exams. PURPOSE: To test the performance of rapid free-breathing DCE-MRI for simultaneous qualitative and quantitative assessment of pulmonary lesions using Golden-angle RAdial Sparse Parallel (GRASP) imaging. STUDY TYPE: Prospective. POPULATION: Twenty-six patients (17 males, mean age = 55.1 +/- 14.4) with known pulmonary lesions. FIELD STRENGTH/SEQUENCE: 3T MR scanner; a prototype fat saturated, T1 -weighted stack-of-stars golden-angle radial sequence for data acquisition and a Cartesian breath-hold volumetric-interpolated examination (BH VIBE) sequence for comparison. ASSESSMENT: After a dual-mode GRASP reconstruction, one with 3-second temporal resolution (3s-GRASP) and the other with 15-second temporal resolution (15s-GRASP), all GRASP and BH-VIBE images were pooled together for blind assessment by two experienced radiologists, who independently scored the overall image quality, lesion delineation, overall artifact level, and diagnostic confidence of each case. Perfusion analysis was performed for the 3s-GRASP images using a Tofts model to generate the volume transfer coefficient (Ktrans ) and interstitial volume (Ve ). STATISTICAL TESTS: Nonparametric paired two-tailed Wilcoxon signed-rank test; Cohen's kappa; unpaired Student's t-test. RESULTS: 15s-GRASP achieved comparable image quality with conventional BH-VIBE (P > 0.05), except for the higher overall artifact level in the precontrast phase (P = 0.018). The Ktrans and Ve in inflammation were higher than those in malignant lesions (Ktrans : 0.78 +/- 0.52 min-1 vs. 0.37 +/- 0.22 min-1 , P = 0.020; Ve : 0.36 +/- 0.16 vs. 0.26 +/- 0.1, P = 0.177). Also, the Ktrans and Ve in malignant lesions were also higher than those in benign lesions (Ktrans : 0.37 +/- 0.22 min-1 vs. 0.04 +/- 0.04 min-1 , P = 0.001; Ve : 0.26 +/- 0.12 vs. 0.10 +/- 0.00, P = 0.063). DATA CONCLUSION: This feasibility study demonstrated the performance of high spatiotemporal resolution free-breathing DCE-MRI of the lung using GRASP for qualitative and quantitative assessment of pulmonary lesions. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:459-468. PMID- 29437282 TI - Phagocytosis of antibody-opsonized tumor cells leads to the formation of a discrete vacuolar compartment in macrophages. AB - Despite the rapidly expanding use of antibody-based therapeutics to treat cancer, knowledge of the cellular processes following phagocytosis of antibody-opsonized tumor cells is limited. Here we report the formation of a phagosome-associated vacuole that is observed in macrophages as these degradative compartments mature following phagocytosis of HER2-positive cancer cells in the presence of the HER2 specific antibody, trastuzumab. We demonstrate that this vacuole is a distinct organelle that is closely apposed to the phagosome. Furthermore, the size of the phagosome-associated vacuole is increased by inhibition of the mTOR pathway. Collectively, the identification of this vacuolar compartment has implications for understanding the subcellular trafficking processes leading to the destruction of phagocytosed, antibody-opsonized cancer cells by macrophages. PMID- 29437283 TI - Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc-Catalyzed Asymmetric Hydrosilylation. AB - A diastereo- and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile heterobiaryl ketones is described. The DKR proceeds by zinc-catalyzed hydrosilylation of the carbonyl group, thus leading to secondary alcohols bearing axial and central chirality. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a Lewis acid-base interaction between a nitrogen atom in the heterocycle and the ketone carbonyl group. The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N-ligands or appealing axially chiral, bifunctional thiourea organocatalysts. PMID- 29437284 TI - Formation of osteon-like structures in unidirectional porous hydroxyapatite substitute. AB - Unidirectional porous hydroxyapatite (UDPHAp) bone substitute comprises a microstructure of cross-sectionally oval pores with diameters ranging from 30 to 300 um. Bone remodeling within the UDPHAp is expected upon implantation into bone; however, the mechanism and factors influencing this bone growth remain unclear. The objectives of the present study were to assess the vasculature and microstructure of newly formed bone and to determine how bone formation is affected by load transfer and UDPHAp pore size. Formation of osteon-like structures, defined by the presence of lacunae, canaliculi and a central lumen containing capillaries, was observed within the implanted UDPHAp material in all animals after six weeks. The number of osteocytes and osteon-like structures in areas adjacent to the cortex of recipient bone was significantly higher than in areas next to the medullary cavity throughout the recovery period. Notably, osteon-like structures tended to form in smaller diameter pores. Continuous bone remodeling might be promoted by the rapid formation of unidirectional capillaries and the osteocyte lacunae-canalicular system. Load transfer and smaller pore size could positively affect cortical bone regeneration. (c) 2018 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2665-2672, 2018. PMID- 29437285 TI - Three siblings with Prader-Willi syndrome caused by imprinting center microdeletions and review. AB - Prader-Willi syndrome (PWS) is a complex genetic imprinting disorder characterized by childhood obesity, short stature, hypogonadism/hypogenitalism, hypotonia, cognitive impairment, and behavioral problems. Usually PWS occurs sporadically due to the loss of paternally expressed genes on chromosome 15 with the majority of individuals having the 15q11-q13 region deleted. Examples of familial PWS have been reported but rarely. To date 13 families have been reported with more than one child with PWS and without a 15q11-q13 deletion secondary to a chromosome 15 translocation, inversion, or uniparental maternal disomy 15. Ten of those 13 families were shown to carry microdeletions in the PWS imprinting center. The microdeletions were found to be of paternal origin in nine of the ten cases in which family studies were carried out. Using a variety of techniques, the microdeletions were identified in regions within the complex SNRPN gene locus encompassing the PWS imprinting center. Here, we report the clinical and genetic findings in three adult siblings with PWS caused by a microdeletion in the chromosome 15 imprinting center inherited from an unaffected father that controls the activity of genes in the 15q11-q13 region and summarize the 13 reported cases in the literature. PMID- 29437286 TI - Kidney exchange match rates in a large multicenter clearinghouse. AB - Kidney paired donation (KPD) can facilitate living donor transplantation for candidates with an incompatible donor, but requires waiting for a match while experiencing the morbidity of dialysis. The balance between waiting for KPD vs desensitization or deceased donor transplantation relies on the ability to estimate KPD wait times. We studied donor/candidate pairs in the National Kidney Registry (NKR), a large multicenter KPD clearinghouse, between October 2011 and September 2015 using a competing-risk framework. Among 1894 candidates, 52% were male, median age was 50 years, 66% were white, 59% had blood type O, 42% had panel reactive antibody (PRA)>80, and 50% obtained KPD through NKR. Median times to KPD ranged from 2 months for candidates with ABO-A and PRA 0, to over a year for candidates with ABO-O or PRA 98+. Candidates with PRA 80-97 and 98+ were 23% (95% confidence interval , 6%-37%) and 83% (78%-87%) less likely to be matched than PRA 0 candidates. ABO-O candidates were 67% (61%-73%) less likely to be matched than ABO-A candidates. Candidates with ABO-B or ABO-O donors were 31% (10%-56%) and 118% (82%-162%) more likely to match than those with ABO-A donors. Providers should counsel candidates about realistic, individualized expectations for KPD, especially in the context of their alternative treatment options. PMID- 29437287 TI - Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families. AB - BACKGROUND AND PURPOSE: The aim was to determine the genetic background of unknown muscular dystrophy in five French families. METHODS: Twelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro. RESULTS: Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation. CONCLUSIONS: The mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families. PMID- 29437288 TI - Staphylococcus aureus-induced complement activation promotes tissue factor mediated coagulation. AB - : Essentials Complement, Toll-like receptors and coagulation cross-talk in the process of thromboinflammation. This is explored in a unique human whole-blood model of S. aureus bacteremia. Coagulation is here shown as a downstream event of C5a-induced tissue factor (TF) production. Combined inhibition of C5 and CD14 efficiently attenuated TF and coagulation. SUMMARY: Background There is extensive cross-talk between the complement system, the Toll-like receptors (TLRs), and hemostasis. Consumptive coagulopathy is a hallmark of sepsis, and is often mediated through increased tissue factor (TF) expression. Objectives To study the relative roles of complement, TLRs and TF in Staphylococcus aureus-induced coagulation. Methods Lepirudin-anticoagulated human whole blood was incubated with the three S. aureus strains Cowan, Wood, and Newman. C3 was inhibited with compstatin, C5 with eculizumab, C5a receptor 1 (C5aR1) and activated factor XII with peptide inhibitors, CD14, TLR2 and TF with neutralizing antibodies, and TLR4 with eritoran. Complement activation was measured by ELISA. Coagulation was measured according to prothrombin fragment 1 + 2 (PTF1 + 2 ) determined with ELISA, and TF mRNA, monocyte surface expression and functional activity were measured with quantitative PCR, flow cytometry, and ELISA, respectively. Results All three strains generated substantial and statistically significant amounts of C5a, terminal complement complex, PTF1 + 2 , and TF mRNA, and showed substantial TF surface expression on monocytes and TF functional activity. Inhibition of C5 cleavage most efficiently and significantly inhibited all six markers in strains Cowan and Wood, and five markers in Newman. The effect of complement inhibition was shown to be completely dependent on C5aR1. The C5 blocking effect was equally potentiated when combined with blocking of CD14 or TLR2, but not TLR4. TF blocking significantly reduced PTF1 + 2 levels to baseline levels. Conclusions S. aureus-induced coagulation in human whole blood was mainly attributable to C5a induced mRNA upregulation, monocyte TF expression, and plasma TF activity, thus underscoring complement as a key player in S. aureus-induced coagulation. PMID- 29437289 TI - Ion-Pair SN 2 Reaction of OH- and CH3 Cl: Activation Strain Analyses of Counterion and Solvent Effects. AB - We have theoretically studied the non-identity SN 2 reactions of Mn OH(n-1) +CH3 Cl (M+ =Li+ , Na+ , K+ , and MgCl+ ; n=0, 1) in the gas phase and in THF solution at the OLYP/6-31++G(d,p) level using polarizable continuum model (PCM) implicit solvation. We want to explore and understand the effect of the metal counterion M+ and solvation on the reaction profile and the stereoselectivity of these processes. To this end, we have explored the potential energy surfaces of the backside (SN 2-b) and frontside (SN 2-f) pathways. To explain the computed trends, we have carried out analyses with an extended activation strain model (ASM) of chemical reactivity that includes the treatment of solvation effects. PMID- 29437290 TI - Recurrent rearrangements of the PLAG1 and HMGA2 genes in lacrimal gland pleomorphic adenoma and carcinoma ex pleomorphic adenoma. AB - PURPOSE: Lacrimal gland tumours constitute a wide spectrum of neoplastic lesions that are histologically similar to tumours of the salivary gland. In the salivary gland, pleomorphic adenoma (PA) is frequently characterized by recurrent chromosomal rearrangements of the PLAG1 and HMGA2 genes, a genetic feature retained in carcinoma ex pleomorphic adenoma (ca-ex-PA) that makes it possible to distinguish ca-ex-PA from de novo carcinomas. However, whether PLAG1 and HMGA2 gene rearrangements are found in lacrimal gland PA and ca-ex-PA is not known. METHODS: Twenty-one lacrimal gland PAs and four ca-ex-PAs were retrospectively reviewed and subjected to break-apart fluorescence in situ hybridization (FISH) for rearrangements of the PLAG1 gene. Cases without PLAG1 abnormalities were subjected to HMGA2 break-apart FISH. Immunohistochemical staining for PLAG1 and HMGA2 protein was performed and correlated with gene status. RESULTS: Sixteen of 21 PAs showed rearrangement of PLAG1 and were all positive for PLAG1 protein. Two of the remaining five PAs showed rearrangement of HMGA2 and were the only cases positive for HMGA2 with immunohistochemistry. The three FISH-negative PAs expressed PLAG1 protein. All four ca-ex-PAs showed rearrangement of PLAG1 and expressed PLAG1 protein. None of the de novo carcinomas showed rearrangement of either of the two genes or expression of the two proteins. CONCLUSION: Rearrangement of PLAG1 and HMGA2 and expression of the corresponding proteins are frequent and specific findings in lacrimal gland PA and ca-ex-PA. The mechanism for PLAG1 overexpression in FISH-negative PAs is yet to be clarified. PMID- 29437291 TI - Much ado about flu: A mixed methods study of parental perceptions, trust and information seeking in a pandemic. AB - BACKGROUND: Effective public health messaging is essential in both the planning phase and duration of a pandemic. OBJECTIVES: This study aimed to gain an understanding of parental information seeking, trusted sources and needs in relation to pandemic influenza A 2009 (pH1N1) to inform future policy planning and resource development. PATIENTS/METHODS: We conducted a mixed methods study; parents from 16 childcare centres in Sydney, Australia, were surveyed between 16 November and 9 December 2009, and interviews were conducted with participants from six childcare centres between June 2009 and May 2011. RESULTS: From 972 surveys distributed, 431 were completed; a response rate of 44%. Most parents (90%) reported that doctors were "trusted a lot" as a source of influenza information, followed by nurses (59%), government (56%) and childcare centres (52%). Less trusted sources included media (7% selected "trusted a lot"), antivaccination groups (6%) and celebrities (1%). Parents identified a range of key search terms for influenza infection and vaccine. From 42 in-depth interviews, key themes were as follows: "Action trigger," "In an emergency, think Emergency," "Fright to hype" and "Dr Google and beyond." Parents relied heavily on media messages, but cynicism emerged when the pandemic was milder than expected. Parents viewed a range of information sources as trustworthy, including doctors, authoritative hospital or government websites, and childcare centres and schools. CONCLUSIONS: A user-centred orientation is vital for pandemic communications including tailored information provision, via trusted sources based on what parents want to know and how they can find it. PMID- 29437292 TI - Non-high-density lipoprotein cholesterol: High-density lipoprotein cholesterol ratio is an independent risk factor for diabetes mellitus: Results from a population-based cohort study. AB - BACKGROUND: Dyslipidemia predicts the development and progression of diabetes. A higher non-high-density lipoprotein cholesterol (HDL-C): HDL-C ratio is reportedly associated with metabolic syndrome and insulin resistance, but its relationship with glycemic levels and diabetes remains unclear. METHODS: In all, 4882 subjects aged >=40 years without diabetes and not using lipid-lowering drugs were enrolled in the study. The non-HDL-C: HDL-C ratio was log10 transformed to achieve normal distribution. Multivariate logistic regression was used to investigate the association between the log10 -transformed non-HDL-C: HDL-C ratio and diabetes. Stratified analyses of the association by age, gender, and body mass index (BMI) were also performed. RESULTS: After 3 years of follow-up, 704 participants developed diabetes. After adjustment for age, gender, current smoking, current drinking, physical activity, BMI, systolic blood pressure, and family history of diabetes, each 1-SD increase in the log(non-HDL-C: HDL-C ratio) was associated with higher fasting blood glucose (FPG) levels (beta = 0.1; 95% confidence interval [CI] 0.1-0.1), 2-h postload plasma glucose levels (2-h glucose; beta = 0.2; 95% CI 0.1-0.2), and risk of diabetes (odds ratio [OR] 1.1; 95% CI 1.0-1.2). In a multivariate model, subjects in the top quartile of non-HDL C: HDL-C ratio had higher FPG (beta = 0.2; 95% CI 0.2-0.3), 2-h glucose (beta = 0.5; 95% CI 0.3-0.7) and HbA1c (beta = 0.1; 95% CI 0.1-0.2) levels, and a 40% increased risk of diabetes (OR 1.4; 95% CI 1.1-1.8) than participants in the bottom quartile. CONCLUSIONS: The non-HDL-C: HDL-C ratio was found to be an independent risk factor for diabetes. PMID- 29437293 TI - Exploiting a readily available but hard to digest resource: A review of exudativorous mammals identified thus far and how they cope in captivity. AB - Gum is a widely available carbohydrate, composed mainly of non-digestible structural carbohydrates. No mammalian enzymes can digest gum; therefore, a mammal ingesting gum must rely on microbial fermentation to access the energy it possesses. Gums are relatively nutrient poor. Despite this, some mammals have evolved to exploit this food resource. We aim to review the literature for all mammal species which have been recorded to ingest gum, whether quantified or not, and discuss this in the context of their evolutionary adaptations. We also investigated the recommended captive diets for these species to look at whether gum is recommended. We conducted a literature search on ISI Web of Knowledge to tabulate all mammal species observed ingesting gum and classified them as obligate, facultative or opportunistic feeders. We encountered 94 mammal species that eat gum in the wild (27 obligate feeders, 34 facultative feeders and 33 opportunistic feeders). Obligate feeders have entirely evolved to exploit this resource but were found to not be given gum in captivity, which may explain why they are failing to thrive, as opposed to facultative feeders, which have fewer issues. Gum may be necessary for the health of obligate feeders in captivity. Future research should focus on the physiological effects that gum ingestion poses on different digestive systems. PMID- 29437294 TI - Dynamin's helical geometry does not destabilize membranes during fission. AB - It is now widely accepted that dynamin-mediated fission is a fundamentally mechanical process: dynamin undergoes a GTP-dependent conformational change, constricting the neck between two compartments, somehow inducing their fission. However, the exact connection between dynamin's conformational change and the scission of the neck is still unclear. In this paper, we re-evaluate the suggestion that a change in the pitch or radius of dynamin's helical geometry drives the lipid bilayer through a mechanical instability, similar to a well known phenomenon occurring in soap films. We find that, contrary to previous claims, there is no such instability. This lends credence to an alternative model, in which dynamin drives the membrane up an energy barrier, allowing thermal fluctuations to take it into the hemifission state. PMID- 29437295 TI - The Global Influenza Surveillance and Response System-65 years of building trust and sharing and a role model for global health security. PMID- 29437296 TI - Patient-specific goals significantly improve after endobronchial coil treatment in patients with severe emphysema. PMID- 29437297 TI - SNOT-22-based clusters in chronic rhinosinusitis without nasal polyposis exhibit distinct endotypic and prognostic differences. AB - BACKGROUND: Endotypic and prognosticating features of chronic rhinosinusitis without nasal polyposis (CRSsNP) are poorly understood. Our objectives were to use an unbiased symptom-based approach to: (1) study symptoms, clinical and endotypic features; and (2) identify features predicating outcomes from endoscopic sinus surgery (ESS). METHODS: Clinical, computed tomography (CT), histopathology, and 22-item Sino-Nasal Outcome Test (SNOT-22) data was collected on 146 adult CRSsNP patients who underwent ESS. Unsupervised network modeling of presurgical SNOT-22 scores was performed to classify symptom-based clusters. Subject characteristics and post-ESS SNOT-22 scores were compared between clusters. RESULTS: Baseline characteristics of the subject population were as follows: females, 56.2%; revision ESS status in 35%; asthma prevalence, 32.6%; median Lund-Mackay CT score, 8; and median SNOT-22 total score, 43. Network mapping and unsupervised clustering of preoperative SNOT-22 scores revealed 4 clusters: (A) severely burdened with high scores in all 4 subdomains; (B) moderately burdened with high scores in the rhinologic subdomain; (C) moderately burdened with high scores in psychological-sleep subdomains; and (D) mildly burdened. The number of previous ESS and asthma prevalence differed significantly between clusters; CT scores were similar. Asthma burden and tissue eosinophilia were greatest in cluster A (p = 0.03). All groups showed significant improvement at 3 months post-ESS (p < 0.0001). At 6 months, patients in cluster C tended to worsen. CONCLUSION: SNOT-22-based network modeling of CRSsNP patients yielded 4 clusters with distinct features. Asthma prevalence and tissue eosinophilia were highest in the cluster with highest SNOT-22 scores. All patients showed significant improvement from ESS at 3 months; those with high sleep-psychosocial symptoms tended to show worsening at 6 months. PMID- 29437298 TI - Moving beyond HbA1c and plasma glucose levels to understand glycemic status in type 2 diabetes mellitus. PMID- 29437299 TI - Proneness to guilt, shame, and pride in children with Autism Spectrum Disorders and neurotypical children. AB - : Self-conscious emotions (e.g., guilt, shame, and pride) are complex emotions that require self-reflection and self-evaluation, and are thought to facilitate the maintenance of societal norms and personal standards. Despite the importance of self-conscious emotions, most research has focused on basic emotion processing in children with Autism Spectrum Disorders (ASD). Therefore, in the present study, we used the Test of Self-Conscious Affect for Children (TOSCA-C) to assess proneness to, or propensity to experience, the self-conscious emotions guilt, shame, and pride in children with ASD and neurotypical children. The TOSCA-C is designed to capture a child's natural tendency to experience a given emotion across a range of everyday situations [Tangney, Stuewig, & Mashek, 2007]. We also assessed how individual characteristics contribute to the development of proneness to self-conscious emotions, including theory of mind (ToM) and ASD symptomatology. In comparison to neurotypical children, children with ASD showed less proneness to guilt, although all children showed relatively high levels of proneness to guilt. Greater ToM ability was related to more proneness to guilt and authentic pride in children with ASD. Additionally, we found that children with ASD with more severe symptomatology were more prone to hubristic pride. Our results provide evidence of differences in proneness to self-conscious emotions in children with ASD, as well as highlight important mechanisms contributing to how children with ASD may experience self-conscious emotions. Autism Res 2018,11:883-892. (c)2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This research examined proneness to guilt, shame, and pride in children with Autism Spectrum Disorders (ASD) and neurotypical children. We found that children with ASD showed less proneness to guilt than neurotypical children. Better understanding of theory of mind was related to greater proneness to guilt and pride, but only for children with ASD. These findings are important because these complex emotions are linked with both positive and negative social behaviors towards others and oneself. PMID- 29437301 TI - Change: a driver of growth for EMERGENCIAS. PMID- 29437302 TI - We're still young: Let's Educate the Next Generation. PMID- 29437300 TI - Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants. AB - Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S) hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2 yl)carbamate). Using structure-based design, we incorporated an unprecedented 6-5 5-ring-fused crown-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand, and a 3,5-difluorophenylmethyl group as the P1-ligand. The resulting inhibitor 5 exhibited exceptional HIV-1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC50 values in the picomolar range against a wide panel of highly multidrug-resistant HIV-1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug-resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. We determined a high-resolution X-ray crystal structure of the complex between inhibitor 5 and HIV-1 protease, which provides molecular insight into the unprecedented activity profiles observed. PMID- 29437303 TI - Flu transmission in emergency departments. PMID- 29437304 TI - Risk of influenza transmission in a hospital emergency department during the week of highest incidence. AB - OBJECTIVES: To estimate the risk of influenza transmission in patients coming to a hospital emergency department during the week of highest incidence and to analyze factors associated with transmission. MATERIAL AND METHODS: Retrospective observational analysis of a cohort of patients treated in the emergency room during the 2014-2015 flu season. The following variables were collected from records: recorded influenza diagnosis, results of a rapid influenza confirmation test, point of exposure (emergency department, outpatient clinic, or the community), age, sex, flu vaccination or not, number of emergency visits, time spent in the waiting room, and total time in the hospital. We compiled descriptive statistics and performed bivariate and multivariate analyses by means of a Poisson regression to estimate relative risk (RR) and 95% CIs. RESULTS: The emergency department patients had a RR of contracting influenza 3.29 times that of the communityexposed population (95% CI, 1.53-7.08, P=.002); their risk was 2.05 times greater than that of outpatient clinic visitors (95% CI, 1.04-4.02, P=.036). Emergency patients under the age of 15 years had a 5.27 greater risk than older patients (95% CI, 1.59-17.51; P=.007). The RR of patients visiting more than once was 11.43 times greater (95% CI, 3.58-36.44; P<.001). The risk attributable to visiting the emergency department risk was 70.5%, whereas risk attributable to community exposure was 2%. CONCLUSION: The risk of contracting influenza is greater for emergency department patients than for the general population or for patients coming to the hospital for outpatient clinic visits. Patients under the age of 15 years incur greater risk. PMID- 29437305 TI - Adjustment of antidiabetic treatment regimens on discharge from the emergency department: effect on 90-day outcomes in patients admitted to a short-stay unit. AB - OBJECTIVES: To determine whether the adjustment of antidiabetic treatment of patients discharged from a short-stayunit (SSU) after a hyperglycemic crisis reduces the rate of adverse events in the next 90 days. MATERIAL AND METHODS: Retrospective study of patients admitted to an emergency SSU in June 2011. We gathered information onpatient demographics, concurrent diseases, reason for admission, and appropriateness of antidiabetic treatment on discharge. Patients were classified as diabetic, nondiabetic, or newly hyperglycemic. Patients with altered carbohydrate metabolism were subclassified according to the appropriateness of the antidiabetic treatment prescribed on discharge. The main outcome variable was the occurrence of an adverse event within 90 days of discharge. RESULTS: We included 750 patients with a mean (SD) age of 68.1 (19.5) years; 357 (47.6%) were men. A new adverseevent occurred in 262 (36%) patients within 90 days; 15.6 (31.5%) of these patients were not diabetic, 77 (41.8%)were diabetic, and 29 (59.2%) were newly hyperglycemic (P<.001). Failure to provide an appropriate antidiabeticregimen when discharging patients with altered carbohydrate metabolism was an independent risk factor for an adverse event within 90 days (adjusted odds ratio, 7.2; 95% CI, 3.9-13.3). CONCLUSION: Lack of appropriate antidiabetic treatment after discharge from an emergency SSU is a risk factor for adverseevents within 90 days. PMID- 29437306 TI - Clinical predictors of ceftriaxone resistance in microorganisms causing febrile urinary tract infections in men. AB - OBJECTIVES: Because of high rates of resistance to fluoroquinolones, ceftriaxone has become one of the main options for treating febrile urinary tract infection (FUTI). This study aimed to identify predictors of ceftriaxone resistance in community-acquired FUTIs in men. MATERIAL AND METHODS: Cross-sectional ambispective study enrolling men with FUTIs treated in the emergency department of a local area hospital in Spain. RESULTS: A total of 552 FUTI episodes were studied; 103 (18.6%) were caused by a ceftriaxone-resistant microorganism. Variables associated with a ceftriaxone-resistant FUTI were older age, health care-associated FUTI, dementia, diabetes mellitus, neoplasms, a history of UTIs, urologic disease, and complicated FUTI. Patients with ceftriaxone-resistant FUTIs also had higher rates of recent antibiotic treatment. Independent variables associated with FUTI due to a ceftriaxoneresistant microorganism were cirrhosis of the liver (odds ratio [OR], 6,00 95% CI, 1.25-28; P = .025), health careassociated FUTI (OR, 2.3 95% CI, 1.23-4.27; P = .009), and prior treatment with antibiotics (OR, 2.15; 95% CI, 1.23-3.76 P = .007). Components of health care-associated FUTI were a history of admission to a long-term residence (OR, 2.90 95% CI, 1.21-7.16; P = .017) and use of penicillins with or without beta lactamase inhibitors (OR, 2.16; 95% CI, 1.05-4.42; P = .035). CONCLUSION: Cirrhosis of the liver; history of health care-associated FUTI, especially in patients residing in a long-term care facility; and recent use of antibiotics, mainly penicillins with or without beta-lactamase inhibitors, are risk factors for ceftriaxone-resistant FUTI in men. PMID- 29437307 TI - Learning cardiopulmonary resuscitation theory with face-to-face versus audiovisual instruction for secondary school students: a randomized controlled trial. AB - OBJECTIVES: To compare secondary students' learning of basic life support (BLS) theory and the use of an automatic external defibrillator (AED) through face-to face classroom instruction versus educational video instruction. MATERIAL AND METHODS: A total of 2225 secondary students from 15 schools were randomly assigned to one of the following 5 instructional groups: 1) face-to-face instruction with no audiovisual support, 2) face-to-face instruction with audiovisual support, 3) audiovisual instruction without face-to-face instruction, 4) audiovisual instruction with face-to-face instruction, and 5) a control group that received no instruction. The students took a test of BLS and AED theory before instruction, immediately after instruction, and 2 months later. RESULTS: The median (interquartile range) scores overall were 2.33 (2.17) at baseline, 5.33 (4.66) immediately after instruction (P<.001) and 6.00 (3.33) (P<.001). All groups except the control group improved their scores. Scores immediately after instruction and 2 months later were statistically similar after all types of instruction. CONCLUSION: No significant differences between face-to-face instruction and audiovisual instruction for learning BLS and AED theory were found in secondary school students either immediately after instruction or 2 months later. PMID- 29437308 TI - Presenteeism among emergency health care staff. AB - OBJECTIVES: To estimate the prevalence of presenteeism among different categories of hospital and pre-hospital emergency health care professionals in the Principality of Asturias, Spain, and to define the sociodemographic characteristics and workplace factors associated with presenteeism in all categories. MATERIAL AND METHODS: Cross-sectional descriptive study carried out during the last half of 2014 and first half of 2015. A self-administered questionnaire was used to collecta data on sociodemographic and work-related variables and perception of work as stressful. The respondents, who answered voluntarily and anonymously, assessed themselves on the Stanford Presenteeism Scale-6 adapted for use in Spain. RESULTS: The prevalence of presenteeism was 52.9% among the 323 respondents. Presenteeism was associated with stress (P<.01), place of work (P=.004), and bearing responsibility for dependent persons (P=.034) in the group overall. The association between stress and presenteeism was clearly present in emergency physicians (P=.049) and in nurses with dependents under their care (P=.016). CONCLUSION: The prevalence of presenteeism is high among emergency staff in the Principality of Asturias. Presenteeism is associated with diverse factors. PMID- 29437309 TI - Classification of the severe trauma patient with the Abbreviated Injury Scale: degree of correlation between versions 98 and 2005 (2008 update). AB - OBJECTIVES: To explore differences in severity classifications according to 2 versions of the Abbreviated Injury Scale (AIS): version 2005 (the 2008 update) and the earlier version 98. To determine whether possible differences might have an impact on identifying severe trauma patients. MATERIAL AND METHODS: Descriptive study and cross-sectional analysis of a case series of patients admitted to two spanish hospitals with out-of-hospital injuries between February 2012 and February 2013. For each patient we calculated the Injury Severity Score (ISS), the New Injury Severity Score (NISS), and the AIS scores according to versions 98 and 2005. RESULTS: The sample included 699 cases. The mean Severity (SD) age of patients was 52.7 (29.2) years, and 388 (55.5%) were males. Version 98 of the AIS correlated more strongly with both the ISS (2.6%) and the NISS (2.9%). CONCLUSION: The 2008 update of the AIS (version 2005) classified fewer trauma patients than version 98 at the severity levels indicated by the ISS and NISS. PMID- 29437310 TI - SUHCAT study, part 5: Comparison of staff and chiefs' perceptions of emergency department quality in Catalonia. AB - OBJECTIVES: To study the perceptions of Catalan Society of Emergency Medicine (SoCMUE) members who staff hospital emergency departments regarding measures taken to cope with overcrowding, staff rest areas, and staff size. MATERIAL AND METHODS: Descriptive cross-sectional analysis of a survey sent to SoCMUE members. We compared opinions expressed by physicians and nurses in this survey and also compared them to opinions expressed by heads of departments in prior SUHCAT studies. RESULTS: Responses were received from 363 members who worked in hospital departments. More nurses than physicians expressed the opinion that ambulance unloading was habitually blocked (P=.045), patients were being redirected (P<.001), and staffing was inadequate (P=.007). When the results of our SoCMUE survey were compared to those of the earlier SUHCAT surveys of department chiefs, we found that more SoCMUE members believed that measures to cope with overcrowding are frequently applied, quality in rest areas is poorer, and staffing is inadequate. CONCLUSION: Physicians and nurses who are members of SoCMUE and work in hospital emergency departments have different views on measures taken to cope with overcrowding, quality of rest areas, and staff size. In addition, the SoCMUE members' opinions differed from those of respondents in prior SUHCAT studies. PMID- 29437311 TI - Sudden headache, lumbar puncture, and the diagnosis of subarachnoid hemorrhage in patients with a normal computed tomography scans. AB - OBJECTIVES: To assess the usefulness of computed tomography (CT) to identify subarachnoid bleeding in patients with neurologic deficits seeking emergency care for sudden headache within 6 hours of onset of symptoms. MATERIAL AND METHODS: Retrospective observational study of patients presenting with sudden nontraumatic headache peaking during the previous hour in the absence of neurologic deficits. We ordered CT scans for all patients, and if the scan was normal we performed a lumbar puncture. All patients were then followed for 6 months. RESULTS: Eighty five patients were included. Subarachnoid bleeding was identified in 10 (10.2%) patients by CT. Seventy- four lumbar punctures were performed in patients with negative CTs; the lumbar puncture was positive in 1 patient and inconclusive in 2 patients. In all 3 patients, bleeding was ruled out with later images; thus, no cases of subarachnoid hemorrhage were confirmed in the 74 patients who underwent lumbar puncture. Nor were any cases found in any of these patients during follow up. CONCLUSION: A CT scan taken within 6 hours of onset of sudden headache is sufficient for confirming or ruling out subarachnoid bleeding in patients with sudden headache who have no neurologic deficits. PMID- 29437312 TI - Stroke care in Galicia: telemedicine in the early, multidisciplinary treatment of all acute stroke cases. AB - EN: Stroke is the main cause of morbidity and mortality in Spain and in Galicia in particular. Tissue viability after stroke depends on the time taken to restore circulation. The widely dispersed and aging population of this region challenges efforts to provide equal care for patients with time-sensitive emergencies such as stroke. Two regional hospitals (Hospital do Salnes and Hospital do Barbanza) and the reference Hospital Clinico de Santiago launched a telestroke pilot program in 2011 in which patients whose treatment was guided at a distance were discharged with lower levels of stroke severity and mortality. That outcome was probably attributable to more rapid diagnosis. Given those preliminary results and the characteristics of the population, the centrally coordinated Galician Stroke Care Plan was launched in 2016 to provide a telemedicine service that connects all hospitals in the health system of Galicia. This paper summarizes the experience of developing and implementing the program. PMID- 29437313 TI - Serotonin syndrome during a heat wave. PMID- 29437314 TI - Report of a case of leptospirosis: the importance of asking the patient about workplace factors. PMID- 29437315 TI - Double false result in a drug screen after accidental pediatric poisoning. PMID- 29437316 TI - Obligations of emergency responders and staff in cases of refractory asystole. PMID- 29437317 TI - Prehospital evaluation and treatment of pain due to trauma. PMID- 29437318 TI - Acute infectious purpura fulminans secondary to a dog bite. PMID- 29437320 TI - FY 2017 Updates to ICD-10-CM. PMID- 29437319 TI - FY 2017 Updates to ICD-10-PCS. PMID- 29437321 TI - Millennials Most Enthusiastic About Telemedicine. PMID- 29437373 TI - Porous Heat-Treated Polyacrylonitrile Scaffolds for Bone Tissue Engineering. AB - Heat-treated polyacrylonitrile (HT-PAN), also referred to as black orlon (BO), is a promising carbon-based material used for applications in tissue engineering and regenerative medicine. To the best of our knowledge, no such complex bone morphology-mimicking three-dimensional (3D) BO structure has been reported to date. We report that BO can be easily made into 3D cryogel scaffolds with porous structures, using succinonitrile as a porogen. The cryogels possess a porous morphology, similar to bone tissue. The prepared scaffolds showed strong osteoconductive activity, providing excellent support for the adhesion, proliferation, and mitochondrial activity of human bone-derived cells. This effect was more apparent in scaffolds prepared from a matrix with a higher content of PAN (i.e., 10% rather than 5%). The scaffolds with 10% of PAN also showed enhanced mechanical properties, as revealed by higher compressive modulus and higher compressive strength. Therefore, these scaffolds have a robust potential for use in bone tissue engineering. PMID- 29437374 TI - Stereospecificity of Enoylreductase Domains from Modular Polyketide Synthases. AB - An enoylreductase (ER) domain of a polyketide synthase module recruiting a methylmalonate extender unit sets the C2 methyl branch to either the S or R configuration during processing of a polyketide intermediate carried by an acyl carrier protein (ACP) domain. In the present study, pantetheine- and ACP-bound trans-2-methylcrotonyl substrate surrogates were used to scrutinize the stereospecificity of the ER domains. The pantetheine-bound thioester was reduced to mixtures of both 2 R and 2 S products, whereas the expected 2 S epimer was almost exclusively generated when the cognate ACP-bound substrate surrogate was utilized. The analogous incubation of an ER with the substrate surrogate carried by a noncognate ACP significantly increased the generation of the unexpected 2 R epimer, highlighting the dependence of stereospecificity on proper protein protein interactions between ER and ACP domains. The ER mutant assays revealed the involvement of the conserved tyrosine and lysine in stereocontrol. Taken together, these results expand the current understanding of the ER stereochemistry and help in the engineering of modular PKSs. PMID- 29437375 TI - Tailoring Polyelectrolyte Architecture To Promote Cell Growth and Inhibit Bacterial Adhesion. AB - An important challenge facing the application of implanted biomaterials for tissue engineering is the need to facilitate desirable tissue interactions with the implant while simultaneously inhibiting bacterial colonization, which can lead to implant-associated infection. In this study, we explore the relevance of the physical parameters of polyelectrolyte multilayers, such as surface charge, wettability, and stiffness, in tissue cell/surface and bacteria/surface interactions, and investigate the tuning of the multilayer architecture to differentially control such interactions. Polyions with different side-chain chemical structures were paired with polyethylenimine to assemble multilayers with parallel control over surface charge and wettability under controlled conditions. The multilayers can be successfully cross-linked to yield stiffer (the apparent Young's modulus was increased more than three times its original value) and more stable films while maintaining parallel control over surface charge and wettability. The initial adhesion and proliferation of 3T3 fibroblast cells were found to be strongly affected by surface charge and wettability on the non-cross-linked multilayers. On the other hand, these cells adhered and proliferated in a manner similar to those on the cross-linked multilayers (apparent Young's modulus ~2 MPa), regardless of surface charge and wettability. In contrast, Staphylococcus aureus ( S. aureus) and Escherichia coli ( E. coli) adhesion was primarily controlled by surface charge and wettability on both cross linked and non-cross-linked multilayers. In both cases, negative charge and hydrophilicity inhibited their adhesion. Thus, a surface coating with a relatively high degree of stiffness from covalent cross-linking coupled with negative surface charge and high wettability can serve as an efficient strategy to enhance host cell growth while resisting bacterial colonization. PMID- 29437376 TI - "Brick-and-Mortar" Nanostructured Interphase for Glass-Fiber-Reinforced Polymer Composites. AB - The fiber-matrix interface plays a critical role in determining composite mechanical properties. While a strong interface tends to provide high strength, a weak interface enables extensive debonding, leading to a high degree of energy absorption. Balancing these conflicting requirements by engineering composite interfaces to improve strength and toughness simultaneously still remains a great challenge. Here, a nanostructured fiber coating was realized to manifest the critical characteristics of natural nacre, at a reduced length scale, consistent with the surface curvature of fibers. The new interphase contains a high proportion (~90 wt %) of well-aligned inorganic platelets embedded in a polymer; the window of suitable platelet dimensions is very narrow, with an optimized platelet width and thickness of about 130 and 13 nm, respectively. An anisotropic, nanostructured coating was uniformly and conformally deposited onto a large number of 9 MUm diameter glass fibers, simultaneously, using self limiting layer-by-layer assembly (LbL); this parallel approach demonstrates a promising strategy to exploit LbL methods at scale. The resulting nanocomposite interphase, primarily loaded in shear, provides new mechanisms for stress dissipation and plastic deformation. The energy released by fiber breakage in tension appear to spread and dissipate within the nanostructured interphase, accompanied by stable fiber slippage, while the interfacial strength was improved up to 30%. PMID- 29437377 TI - Investigating the Role of Copper Oxide in Electrochemical CO2 Reduction in Real Time. AB - Copper oxides have been of considerable interest as electrocatalysts for CO2 reduction (CO2R) in aqueous electrolytes. However, their role as an active catalyst in reducing the required overpotential and improving the selectivity of reaction compared with that of polycrystalline copper remains controversial. Here, we introduce the use of selected-ion flow tube mass spectrometry, in concert with chronopotentiometry, in situ Raman spectroscopy, and computational modeling, to investigate CO2R on Cu2O nanoneedles, Cu2O nanocrystals, and Cu2O nanoparticles. We show experimentally that the selective formation of gaseous C2 products (i.e., ethylene) in CO2R is preceded by the reduction of the copper oxide (Cu2OR) surface to metallic copper. On the basis of density functional theory modeling, CO2R products are not formed as long as Cu2O is present at the surface because Cu2OR is kinetically and energetically more favorable than CO2R. PMID- 29437378 TI - DOPO-Modified Two-Dimensional Co-Based Metal-Organic Framework: Preparation and Application for Enhancing Fire Safety of Poly(lactic acid). AB - Co-based metal-organic framework (Co-MOF) nanosheets were successfully synthesized by the organic ligands with Schiff base structure. The laminated structure gives Co-MOF nanosheets a great advantage in the application in the flame retardant field. Meanwhile, -C?N- from Schiff base potentially provides active sites for further modification. In this work, 9,10-dihydro-9-oxa-10 phosphaphenanthrene-10-oxide (DOPO) was used to modify Co-MOF (DOPO@Co-MOF) to further enhance its flame retardant efficiency. It is attractive that DOPO has a synergistic effect with Co-MOF on improving fire safety of poly(lactic acid) (PLA). The obvious decrease in the values of peak heat release (27%), peak smoke production (56%), and total CO yield (20%) confirmed the enhanced fire safety of PLA composites. The possible flame retardant mechanism was proposed based on characterization results. Moreover, the addition of DOPO@Co-MOF had a positive influence on the mechanical performance, including tensile properties and impact resistance. This work designed and synthesized two-dimensional MOFs with active groups. As-prepared Co-MOF with expected structure shows a novel direction of preparing MOFs for flame retardant application. PMID- 29437379 TI - Separations at the Speed of Sensors. AB - The virtue of chemical sensors is speed and analyte specificity. The response time to generate an analytical signal typically varies from ~1 to 20 s, and they are generally limited to a single analyte. Chemical sensors are significantly affected by multiple interferents, matrix effects, temperature, and can vary widely in sensitivity depending on the sensor format. Separation-based analyses remove matrix effects and interferents and are compatible with multiple analytes. However, the speed of such analyses has not been commensurate with traditional sensors until now. Beds of very small size with optimal geometry, containing core shell particles of judicious immobilized selectors, can be used in an ultrahigh flow regime, thereby providing subsecond separations of up to 10 analytes. Short polyether ether ketone lined stainless steel columns of various geometries were evaluated to determine the optimal bed geometry for subsecond analysis. Coupling these approaches provides subsecond-based detection and quantitation of multiple chiral and achiral species, including nucleotides, plant hormones, acids, amino acid derivatives, and sedatives among a variety of other compounds. The subsecond separations were reproducible with 0.9% RSD on retention times and showed consistent performance with 0.9% RSD on reduced plate height in van Deemter curves. A new powerful signal processing algorithm is proposed that can further enhance separation outputs and optical spectra without altering band areas on more complex separations such as 10 peaks under a second. PMID- 29437380 TI - Ligand-Directed Chemistry of AMPA Receptors Confers Live-Cell Fluorescent Biosensors. AB - AMPA-type glutamate receptors (AMPARs) mediate fast excitatory synaptic transmission in the central nervous system. Dysregulation of AMPAR function is associated with many kinds of neurological, neurodegenerative, and psychiatric disorders. As a result, molecules capable of controlling AMPAR functions are potential therapeutic agents. Fluorescent semisynthetic biosensors have attracted considerable interest for the discovery of ligands selectively acting on target proteins. Given the large protein complex formation of AMPARs in live cells, biosensors using full-length AMPARs retaining original functionality are ideal for drug screening. Here, we demonstrate that fluorophore-labeled AMPARs prepared by ligand-directed acyl imidazole chemistry can act as turn-on fluorescent biosensors for AMPAR ligands in living cells. These biosensors selectively detect orthosteric ligands of AMPARs among the glutamate receptor family. Notably, the dissociation constants of agonists and antagonists for AMPARs were determined in live cells, which revealed that the ligand-binding properties of AMPARs to agonists are largely different in living cells, compared with noncellular conditions. We also show that these sensors can be applied to detecting allosteric modulators or subunit-selective ligands of AMPARs. Thus, our protein based biosensors can be useful for discovering pharmaceutical agents to treat AMPAR-related neurological disorders. PMID- 29437381 TI - Optimizing Nanoelectrode Arrays for Scalable Intracellular Electrophysiology. AB - Electrode technology for electrophysiology has a long history of innovation, with some decisive steps including the development of the voltage-clamp measurement technique by Hodgkin and Huxley in the 1940s and the invention of the patch clamp electrode by Neher and Sakmann in the 1970s. The high-precision intracellular recording enabled by the patch clamp electrode has since been a gold standard in studying the fundamental cellular processes underlying the electrical activities of neurons and other excitable cells. One logical next step would then be to parallelize these intracellular electrodes, since simultaneous intracellular recording from a large number of cells will benefit the study of complex neuronal networks and will increase the throughput of electrophysiological screening from basic neurobiology laboratories to the pharmaceutical industry. Patch clamp electrodes, however, are not built for parallelization; as for now, only ~10 patch measurements in parallel are possible. It has long been envisioned that nanoscale electrodes may help meet this challenge. First, nanoscale electrodes were shown to enable intracellular access. Second, because their size scale is within the normal reach of the standard top-down fabrication, the nanoelectrodes can be scaled into a large array for parallelization. Third, such a nanoelectrode array can be monolithically integrated with complementary metal-oxide semiconductor (CMOS) electronics to facilitate the large array operation and the recording of the signals from a massive number of cells. These are some of the central ideas that have motivated the research activity into nanoelectrode electrophysiology, and these past years have seen fruitful developments. This Account aims to synthesize these findings so as to provide a useful reference. Summing up from the recent studies, we will first elucidate the morphology and associated electrical properties of the interface between a nanoelectrode and a cellular membrane, clarifying how the nanoelectrode attains intracellular access. This understanding will be translated into a circuit model for the nanobio interface, which we will then use to lay out the strategies for improving the interface. The intracellular interface of the nanoelectrode is currently inferior to that of the patch clamp electrode; reaching this benchmark will be an exciting challenge that involves optimization of electrode geometries, materials, chemical modifications, electroporation protocols, and recording/stimulation electronics, as we describe in the Account. Another important theme of this Account, beyond the optimization of the individual nanoelectrode-cell interface, is the scalability of the nanoscale electrodes. We will discuss this theme using a recent development from our groups as an example, where an array of ca. 1000 nanoelectrode pixels fabricated on a CMOS integrated circuit chip performs parallel intracellular recording from a few hundreds of cardiomyocytes, which marks a new milestone in electrophysiology. PMID- 29437382 TI - Glycoconjugate Oxime Formation Catalyzed at Neutral pH: Mechanistic Insights and Applications of 1,4-Diaminobenzene as a Superior Catalyst for Complex Carbohydrates. AB - The reaction of unprotected carbohydrates with aminooxy reagents to provide oximes is a key method for the construction of glycoconjugates. Aniline and derivatives serve as organocatalysts for the formation of oximes from simple aldehydes, and we have previously reported that aniline also catalyzes the formation of oximes from the more complex aldehydes, carbohydrates. Here, we present a comprehensive study of the effect of aniline analogues on the formation of carbohydrate oximes and related glycoconjugates depending on organocatalyst structure, pH, nucleophile, and carbohydrate, covering more than 150 different reaction conditions. The observed superiority of the 1,4-diaminobenzene (PDA) catalyst at neutral pH is rationalized by NMR analyses and DFT studies of reaction intermediates. Carbohydrate oxime formation at pH 7 is demonstrated by the formation of a bioactive glycoconjugate from a labile, decorated octasaccharide originating from exopolysaccharides of the soil bacterium Mesorhizobium loti. This study of glycoconjugate formation includes the first direct comparison of aniline-catalyzed reaction rates and equilibrium constants for different classes of nucleophiles, including primary oxyamines, secondary N alkyl oxyamines, as well as aryl and arylsulfonyl hydrazides. We identified 1,4 diaminobenzene as a superior catalyst for the construction of oxime-linked glycoconjugates under mild conditions. PMID- 29437383 TI - Encoding Stem-Cell-Secreted Extracellular Matrix Protein Capture in Two and Three Dimensions Using Protein Binding Peptides. AB - Capturing cell-secreted extracellular matrix (ECM) proteins through cooperative binding with high specificity and affinity is an important function of native tissue matrices during both tissue homeostasis and repair. However, while synthetic hydrogels, such as those based on poly(ethylene glycol) (PEG), are often proposed as ideal materials to deliver human mesenchymal stem cells (hMSCs) to sites of injury to enable tissue repair, they do not have this capability-a capability that would enable cells to actively remodel their local extracellular microenvironment and potentially provide the required feedback control for more effective tissue genesis. In this work, we detail a methodology that engenders poly(ethylene glycol) (PEG)-based two-dimensional substrates and three dimensional porous hydrogels with the ability to capture desired extracellular matrix (ECM) proteins with high specificity. This "encoded" ECM protein capture is achieved by decorating the PEG-based materials with protein binding peptides (PBPs) synthesized to be specific in their binding of fibronectin, laminin, and collagen I, which are not only the most omnipresent ECM proteins in human tissues but, as we confirmed, are also secreted to differing extents by hMSCs under in vitro maintenance conditions. By encapsulating hMSCs into these PBP functionalized hydrogels, and culturing them in protein-free maintenance media, we demonstrate that these PBPs not only actively recruit targeted ECM proteins as they are secreted from hMSCs but also retain them to much higher levels compared to nonfunctionalized gels. This novel approach thus enables the fabrication of encoded surfaces and hydrogels that capture cell-secreted proteins, with high specificity and affinity, in a programmable manner, ready for applications in many bioengineering applications, including bioactive surface coatings, bioassays, stem cell culture, tissue engineering, and regenerative medicine. PMID- 29437384 TI - Zirconium Metal-Organic Frameworks Assembled from Pd and Pt PNNNP Pincer Complexes: Synthesis, Postsynthetic Modification, and Lewis Acid Catalysis. AB - Carboxylic acid-functionalized Pd and Pt PNNNP pincer complexes were used for the assembly of two porous Zr metal-organic frameworks (MOFs), 2-PdX and 2-PtX. Powder X-ray diffraction analysis shows that the new MOFs adopt cubic framework structures similar to the previously reported Zr6O4(OH)4[(POCOP)PdX]3, [POCOP = 2,6-(OPAr2)2C6H3); Ar = p-C6H4CO2-, X = Cl-, I-] (1-PdX). Elemental analysis and spectroscopic characterization indicate the presence of missing linker defects, and 2-PdX and 2-PtX were formulated as Zr6O4(OH)4(OAc)2.4[M(PNNNP)X]2.4 [M = Pd, Pt; PNNNP = 2,6-(HNPAr2)2C5H3N; Ar = p-C6H4CO2-; X = Cl-, I-]. Postsynthetic halide ligand exchange reactions were carried out by treating 2-PdX with Ag(O3SCF3) or NaI followed by PhI(O2CCF3)2. The latter strategy proved to be more effective at activating the MOF for the catalytic intramolecular hydroamination of an o-substituted alkynyl aniline, underscoring the advantage of using halide exchange reagents that produce soluble byproducts. PMID- 29437385 TI - Spatial Analysis of Nanofluidic-Embedded Biosensors for Wash-Free Single Nucleotide Difference Discrimination. AB - In this work, we demonstrate that the analysis of spatially resolved nanofluidic embedded biosensors permits the fast and direct discrimination of single nucleotide difference (SND) within oligonucleotide sequences in a single step interaction. We design a sensor with a linear dimension much larger than the channel depth in order to ensure that the reaction over the whole sensor is limited by the convection rate. Thus, the targets are fully collected, inducing a nonuniform spatial hybridization profile. We also use the nanoscale height of the channel, which enables us to minimize the amount of labeled molecules flowing over the sensor and hence to reduce the fluorescence background, to carry out real-time hybridization detection by fluorescence microscopy. Taken together, these design rules allow us to show that the spatial hybridization profile depends on the duplex affinity, and we speculate that the on and off-rate constants can be inferred during target injection, which is not possible in local analysis where the dissociation step through rinsing must be conducted. We finally manage to discriminate a GT mismatch on a microRNA sequence by optimizing the interaction temperature and the probe design after a few minutes of interaction in a single step protocol. This work may be applied to any biosensing transduction scheme with spatial resolution, e.g., surface plasmon resonance imaging, integrated into nanofluidic channels for applications where high oligonucleotide sequence selectivity and short analysis times are required. PMID- 29437386 TI - Tozasertib Analogues as Inhibitors of Necroptotic Cell Death. AB - Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Because tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors. In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model. PMID- 29437387 TI - Household Dust as a Repository of Chemical Accumulation: New Insights from a Comprehensive High-Resolution Mass Spectrometric Study. AB - Chemical exposure in household dust poses potential risks to human health but has been studied incompletely thus far. Most analytical studies have focused on one or several compound classes, with analysis performed by either liquid or gas chromatography coupled with mass spectrometry (LC-MS or GC-MS). However, a comprehensive investigation of individual dust samples is missing. The present study comprehensively characterizes chemicals in dust by applying a combination of target, suspect, and nontarget screening approaches using both LC and GC with quadrupole time-of-flight (Q/TOF) MS. First, the extraction method was optimized to streamline detection of LC-Q/TOF and GC-Q/TOF amenable compounds and was successfully validated with over 100 target compounds. Nontarget screening with GC-Q/TOF was done by spectral deconvolution followed by a library search. Suspect screening by LC-Q/TOF was carried out with an accurate mass spectral library. Finally, LC-Q/TOF nontarget screening was carried out by extracting molecular features, acquiring tandem mass spectrometric (MS/MS) spectra, and performing compound identification by use of in silico fragmentation software tools. In total, 271 chemicals could be detected in 38 dust samples, 163 of which could be unambiguously confirmed by a reference standard. Many of them, such as the plastic leachable 7,9-di- tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione (CAS 82304-66-3) and three organofluorine compounds, are of emerging concern and their presence in dust has been underestimated. Advantages and drawbacks of the different approaches and analytical instruments are critically discussed. PMID- 29437388 TI - C-QDs@UiO-66-(COOH)2 Composite Film via Electrophoretic Deposition for Temperature Sensing. AB - Temperature plays a crucial role in both scientific research and industry. However, traditional temperature sensors, such as liquid-filled thermometers, thermocouples, and transistors, require contact to obtain heat equilibrium between the probe and the samples during the measurement. In addition, traditional temperature sensors have limitations when being used to detect the temperature change of fast-moving samples at smaller scales. Herein, the carbon quantum dots (C-QDs) functionalized metal-organic framework (MOF) composite film, a novel contactless solid optical thermometer, has been prepared via electrophoretic deposition (EPD). Instead of terephthalic acid (H2BDC), 1',2',4',5'-benzenetetracarboxylic (H4BTEC) acid was employed to construct a UiO 66 framework to present two uncoordinated carboxylic groups decorated on the pore surface. The uncoordinated carboxylic groups can generate negative charges, which facilitates the deposition of film on the positive electrode during the EPD process. Moreover, UiO-66-(COOH)2 MOFs can absorb C-QDs from the solution and prevent C-QDs from aggregating, and the well-dispersed C-QDs impart fluorescence characteristics to composites. As-synthesized composite film was successfully used to detect temperature change in the range of 97-297 K with a relative sensitivity up to 1.3% K-1 at 297 K. PMID- 29437389 TI - Mechanism and Origins of Regio- and Enantioselectivities of Iridium-Catalyzed Hydroarylation of Alkenyl Ethers. AB - The iridium-catalyzed hydroarylation of alkenyl ethers developed by Nishimura and co-workers (Ebe, Y.; Onoda, M.; Nishimura, T.; Yorimitsu, H. Angew. Chem. Int. Ed. 2017, 56, 5607-5611) represents a rare example of regio- and enantioselective hydroarylation of challenging internal alkenes. In the present study, density functional theory calculations were performed in order to investigate the detailed reaction mechanism and the origins of the experimentally observed regio- and enantioselectivities. The computations show that the initial C-H oxidative addition and the isomerization between the allylic ethers and the 1-alkenyl ethers via the migratory insertion into the Ir-H bond/beta-hydride elimination are both feasible. The reaction was found to proceed through the modified Chalk Harrod-type mechanism via the migratory insertion into the Ir-C bond/C-H reductive elimination. The migratory insertion into the Ir-C bond constitutes the rate- and selectivity-determining step of the overall reaction. The calculations reproduced quite well the experimentally observed regio- and enantioselectivities. The enantioselectivity of the reaction was found to arise from the reactions of the (E)- and (Z)-1-alkenyl ethers, which afford the opposite enantiomers of product with the aryl group installed at the alpha position to the alkoxy group. It turns out that the strong electron-donating character of the alkoxy group plays an important role in determining the regioselectivity, since it can stabilize the developed positive charge of the alpha-insertion transition state, leading to the aryl group being selectively installed at the alpha-position. PMID- 29437390 TI - Development and Application of a Novel Bioassay System for Dioxin Determination and Aryl Hydrocarbon Receptor Activation Evaluation in Ambient-Air Samples. AB - Airborne persistent toxic substances are associated with health impacts resulting from air pollution, for example, dioxins, dioxin-like polychlorinated biphenyls, and certain polycyclic aromatic hydrocarbons (PAHs), which activate aryl hydrocarbon receptors (AhR) and thereby produce adverse outcomes. Thus, a bioassay for evaluating AhR activation is required for risk assessment of ambient air samples, and for this purpose, we developed a new and sensitive recombinant mouse hepatoma cell line, CBG2.8D, in which a novel luciferase-reporter plasmid containing two copies of a newly designed dioxin-responsive domain and a minimal promoter derived from a native gene were integrated. The minimal detection limit for 2,3,7,8-tetrachlorodibenzo- p-dioxin with this assay system was 0.1 pM. We used CBG2.8D to determine dioxin levels in 45 ambient-air samples collected in Beijing. The measured bioanalytical equivalent (BEQ) values were closely correlated with the toxic equivalent values obtained from chemical analysis. In haze ambient-air samples, the total activation of aryl hydrocarbon receptors (TAA) was considerably higher than the BEQ of dioxin-rich fractions, according to the results of the cell-based bioassay. Notably, the haze samples contained abundant amounts of PAHs, whose relative toxicity equivalent was correlated with the TAA; this finding suggests that PAHs critically contribute to the AhR-related biological impacts of haze ambient-air samples. PMID- 29437391 TI - Impact of Simulated California Rice-Growing Conditions on Chlorantraniliprole Partitioning. AB - Chlorantraniliprole (3-bromo-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]-1-(3 chloro-2-pyridine-2-yl)-1H-pyrazole-5-carboxamide, CAP; water solubility 1.023 mg.L-1) was recently registered for application on California rice fields. Air- and soil-water partitioning of CAP were investigated under simulated California rice field conditions through calculation of KH and DeltaawH and a batch equilibrium method following OECD 106 guidelines, respectively. KH and DeltaawH were determined to be 1.69 * 10-16 - 2.81 * 10-15 atm.m3.mol-1 (15-35 degrees C) and 103.68 kJ.mol-1, respectively. Log(Koc) ranged from 2.59 to 2.96 across all soil and temperature treatments. Log(KF) ranged from 0.61 to 1.14 across all soil, temperature, and salinity treatments. Temperature and salinity increased sorption significantly at 35 degrees C (P < 0.05) and 0.2 M (P < 0.0001), respectively, while soil properties impacted sorption across all treatments. Overall results, corroborated using the Pesticides in Flooded Applications Model, indicate that volatilization of CAP is not a major route of dissipation and sorption of CAP to California rice field soils is moderately weak and reversible. PMID- 29437392 TI - Thermostability of the PYL-PP2C Heterodimer Is Dependent on Magnesium: In Silico Insights into the Link between Heat Stress Response and Magnesium Deficiency in Plants. AB - Magnesium deficiency increases the susceptibility of plants toward heat stress. The correlation between magnesium levels and stress response has been studied at the physiological level; albeit, the molecular explanation to this relationship remains elusive. Among diverse pathways implicated in the heat stress, the abscisic acid (ABA) signal modulates the heat stress response by magnesium dependent phosphatases (PP2Cs). Exclusively, sequestration of PP2Cs by ABA receptors (PYLs) in the heterodimer form activates the stress response through ABA responsive transcription factors. In this study, the molecular interplay between magnesium levels and ABA related heat stress response was investigated. Molecular dynamics simulations have been applied to two different PYL-PP2C heterodimer systems representing normal and magnesium deficient conditions. The heterodimer conformation and stability were delineated at high temperatures mimicking heat stress. Results showed that the thermostability of the heat stress response heterodimer was significantly dependent on the magnesium. Furthermore, a conserved aromatic cluster at the dimer interface acted synergistically with the metal to confer thermostability to the heterodimer structure. These structural insights into one of the possible links between magnesium levels and stress highlight the importance of metal micronutrients for tuning the stability of the stress-related proteins and optimizing tolerance. PMID- 29437393 TI - Rhodium Catalyzed Asymmetric Hydroamination of Internal Alkynes with Indoline: Mechanism, Origin of Enantioselectivity, and Role of Additives. AB - A comprehensive mechanistic study on the title reaction by using DFT(B3LYP-D3) computational method is reported. Explicit consideration of mono- (m-xylylic) and dicarboxylic acid (phthalic) in the key transition states reveals active participation of the carboxylic acid, beginning with the generation of a monomeric Rh(I) active catalyst and in the ensuing catalytic steps. In the early catalytic event, uptake of alkyne is predicted to take place only after the oxidative addition of the Rh(I) active catalyst to the carboxylic acid. The hydrometalation of the alkyne bound to the Rh(III)-H intermediate then generates a Rh(III)-vinyl intermediate, which in turn converts to a Rh(III)-allyl species. The inclusion of m-xylylic acid results in a two-step pathway to Rh(III)-allyl species via Rh-allene intermediate. A number of weak noncovalent interactions (hydrogen bonding and C-H...pi) between the catalyst and the substrates and that involving m-xylylic acid are found to have a direct impact on the regiochemical preference toward the branched product and the enantiocontrolling hydroamination step involving C-N bond formation leading to the major enantiomer (S-allylic amine). The chiral induction is enabled by cumulative effect of noncovalent interactions, which is an insight that could aid future developments of chiral ligands for asymmetric hydroamination. PMID- 29437394 TI - Physical Removal of Anions from Aqueous Media by Means of a Macrocycle-Containing Polymeric Network. AB - Reported here is a hydrogel-forming polymer network that contains a water-soluble tetracationic macrocycle. Upon immersion of this polymer network in aqueous solutions containing various inorganic and organic salts, changes in the physical properties are observed that are consistent with absorption of the constituent anions into the polymer network. This absorption is ascribed to host-guest interactions involving the tetracationic macrocyclic receptor. Removal of the anions may then be achieved by lifting the resulting hydrogels out of the aqueous phase. Treating the anion-containing hydrogels with dilute HCl leads to the protonation-induced release of the bound anions. This allows the hydrogels to be recycled for reuse. The present polymer network thus provides a potentially attractive approach to removing undesired anions from aqueous environments. PMID- 29437395 TI - Visible-Light-Mediated Nitration of Protected Anilines. AB - The photocatalytic nitration of protected anilines proceeds with riboflavin tetraacetate as an organic photoredox catalyst. Sodium nitrite serves as the NO2 source in this visible-light-driven room temperature reaction. Various nitroanilines are obtained in moderate to good yields without the addition of acid or stoichiometric oxidation agents. The catalytic cycle is closed by aerial oxygen as the terminal oxidant. PMID- 29437396 TI - Supramolecular Photochirogenesis Driven by Higher-Order Complexation: Enantiodifferentiating Photocyclodimerization of 2-Anthracenecarboxylate to Slipped Cyclodimers via a 2:2 Complex with beta-Cyclodextrin. AB - Chiral slipped 5,8:9',10'-cyclodimers were preferentially produced over classical 9,10:9',10'-cyclodimers upon supramolecular photocyclodimerization of 2 anthracenecarboxylate (AC) mediated by beta-cyclodextrin (beta-CD). This photochirogenic route to the slipped cyclodimers, exclusively head-to-tail (HT) and highly enantioselective, has long been overlooked in foregoing studies but is dominant in reality and is absolutely supramolecularly activated by 2:2 complexation of AC with beta-CD. The intricate structural and photophysical aspects of this higher-order complexation-triggered process have been comprehensively elucidated, while the absolute configurations of the slipped cyclodimers have been unambiguously assigned by comparing the experimental and theoretical circular dichroism spectra. In the 2:2 complex, two ACs packed in a dual beta-CD capsule are not fully overlapped with each other but are only partially stacked in a slipped anti- or syn-HT manner. Hence, they do not spontaneously cyclodimerize upon photoexcitation but instead emit long-lived excimer fluorescence at wavelengths slightly longer than the monomer fluorescence, indicating that the slipped excimer is neither extremely reactive nor completely relaxed in conformation and energy. Because of the slipped conformation of the AC pair in the soft capsule, the subsequent photocyclodimerization becomes manipulable by various internal or external factors, such as temperature, pressure, added salt, and host modification, enabling us to exclusively obtain the slipped cyclodimers with high regio- and enantioselectivities. In this supramolecularly driven photochirogenesis, the dual beta-CD capsule functions as a chiral organophotocatalyst to trigger and accelerate the nonclassical photochirogenic route to slipped cyclodimers by preorganizing the conformation of the encapsulated AC pair, formally mimicking a catalytic antibody. PMID- 29437397 TI - Catalytic Reduction of Nitrous Oxide by the Low-Symmetry Pt8 Cluster. AB - The search for a catalyst for the reduction of nitrous oxide (N2O) is now imperative, as this molecule is a very dangerous pollutant. We found that the low symmetry Pt8 cluster presents multiple reaction pathways for N2O rupture, which are regioselective. This result was revealed by means of density functional theory calculations within the zero-order-regular approximation, ZORA, explicitly including relativistic effects. It is further proved that Pt8 is a competitive N2O catalyst compared to sub-nanometric rhodium clusters, obtaining similar reaction barriers. The hot adsorption site, a tip atom of Pt8, and the rotation of the N2O molecule over the metallic cluster promote the formation of a frustrated bridge activated transition state, Pt8-N2O. This transition structure yields to spontaneous dissociation of N2O without bridge formation. Along this catalytic process, rearrangements within the metal cluster take place, preserving its stability. Moreover, in addition to being important attributes of the Pt8 particle in the N2O reduction, fluxionality and multiple reaction pathways may also prevent poisoning effects. Overall, this differs from reported results for more symmetric metal particles also used as catalysts. PMID- 29437398 TI - Structural Rearrangement of Energetic Materials under an External Electric Field: A Case Study of Nitromethane. AB - As a significant stimulus, the external electric field (EEF) can change the decomposition mechanism and energy release of energetic materials (EMs). Hence, understanding the response of EMs to an EEF is greatly meaningful for their safe usage. Herein, the structural arrangement, a crucial factor in the impact sensitivity and detonation performance of EMs, under the EEF ranging from 0.0 to 0.5 V/A was investigated via molecular dynamics simulation. Nitromethane (NM) was taken as a case study due to the simple structure. The simulation results show that there exists a critical EEF strength between 0.2 and 0.3 V/A, which can induce the transition of NM molecules from relatively disordered distribution to solidlike ordered and compacted arrangement with a large density. In this ordered structure, NM dipoles are aligned in a head-to-tail pattern parallel to the EEF direction because of the favored dipole-dipole interactions and weak C-H...O hydrogen bonds. As the EEF strength is enhanced, the potential energy and cohesive energy density of the NM system gradually decrease and increase, respectively, indicative of high thermodynamics stability of ordered arrangement. The results reported here also shed light on the potential of the EEF to induce the nucleation and crystallization to explore new polymorphs of EMs. PMID- 29437399 TI - Bobbing of Oxysterols: Molecular Mechanism for Translocation of Tail-Oxidized Sterols through Biological Membranes. AB - Translocation of sterols between cellular membrane leaflets is of key importance in membrane organization, dynamics, and signaling. We present a novel translocation mechanism that differs in a unique manner from the established ones. The bobbing mechanism identified here is demonstrated for tail-oxidized sterols, but is expected to be viable for any molecule containing two polar centers at the opposite sides of the molecule. The mechanism renders translocation across a lipid membrane possible without a change in molecular orientation. For tail-oxidized sterols, the bobbing mechanism provides an exceptionally facile means to translocate these signaling molecules across membrane structures and may thus represent an important pathway in the course of their biological action. PMID- 29437400 TI - More than a Solvent: Donor-Acceptor Complexes of Ionic Liquids and Electron Acceptors. AB - The applicability of room-temperature ionic liquids (RTILs) as inert solvents is generally based on their electrochemical window. We herein show that this concept has its limitations if RTILs are exposed to an oxidizing environment in the presence of light. Acetonitrile solutions of RTILs with 1-methyl-3 ethylimidazolium as cation and five different anions, including thiocyanate (SCN ) and dicyanamide (DCA-), were investigated. Upon addition of organic electron acceptors to solutions of RTILs with SCN- or DCA-, charge-transfer (CT) absorption bands due to the formation of donor-acceptor complexes between the anion and the electron acceptor were observed. Time-resolved measurements from the femtosecond to the microsecond regimes were used to investigate the nature and the excited-state dynamics of these complexes upon excitation in the CT band. We show that even though the RTILs are seemingly inert according to their electrochemical properties, the dicyanamide and thiocyanate based RTILs can actively participate in photochemical reactions in oxidizing environments and therefore differ from the behavior expected for an inert solvent. This has not only important implications for the long-term stability of RTIL-based systems but can also lead to misinterpretation of photochemical studies in these solvents. PMID- 29437401 TI - High-Contrast Infrared Absorption Spectroscopy via Mass-Produced Coaxial Zero Mode Resonators with Sub-10 nm Gaps. AB - We present a wafer-scale array of resonant coaxial nanoapertures as a practical platform for surface-enhanced infrared absorption spectroscopy (SEIRA). Coaxial nanoapertures with sub-10 nm gaps are fabricated via photolithography, atomic layer deposition of a sacrificial Al2O3 layer to define the nanogaps, and planarization via glancing-angle ion milling. At the zeroth-order Fabry-Perot resonance condition, our coaxial apertures act as a "zero-mode resonator (ZMR)", efficiently funneling as much as 34% of incident infrared (IR) light along 10 nm annular gaps. After removing Al2O3 in the gaps and inserting silk protein, we can couple the intense optical fields of the annular nanogap into the vibrational modes of protein molecules. From 7 nm gap ZMR devices coated with a 5 nm thick silk protein film, we observe high-contrast IR absorbance signals drastically suppressing 58% of the transmitted light and infer a strong IR absorption enhancement factor of 104~105. These single nanometer gap ZMR devices can be mass produced via batch processing and offer promising routes for broad applications of SEIRA. PMID- 29437402 TI - Diastereoselective Palladium-Catalyzed (3 + 2)-Cycloadditions from Cyclic Imines and Vinyl Aziridines. AB - The synthesis of cyclic imidazolidines via two N-C bond-forming sequences has been developed. The transformation goes through a (3 + 2)-cycloaddition reaction in the presence of catalytic amounts of palladium by combining several vinyl aziridines and cyclic N-sulfonyl imines. Interestingly, the use of LiCl as additive allowed the improvement of diastereoselectivities when less encumbered substrates were used. The imidazolidine derivatives that bear aminal cores are isolated in high yields (15 examples, up to 96% yield) and diastereoselectivities (up to >20:1). PMID- 29437403 TI - Rapid Access to Ortho-Alkylated Vinylarenes from Aromatic Acids by Dearomatization and Tandem Decarboxylative C-H Olefination/Rearomatization. AB - A two-step straightforward method for the preparation of ortho-alkylated vinylarenes from readily available benzoic acids is described. The synthetic route involves the dearomatization of benzoic acids by Birch reduction providing alkylated cyclohexa-2,5-dienyl-1-carboxylic acids. The diene subsequently undergoes a decarboxylative C-H olefination followed by rearomatization to deliver ortho-alkylated vinylarene. Mechanistic studies suggest that a Pd/Ag bimetallic catalytic system is important in the tandem decarboxylative C-H olefination/rearomatization step. PMID- 29437404 TI - Many-Body Spectral Functions from Steady State Density Functional Theory. AB - We propose a scheme to extract the many-body spectral function of an interacting many-electron system from an equilibrium density functional theory (DFT) calculation. To this end we devise an ideal scanning tunneling microscope (STM) setup and employ the recently proposed steady-state DFT formalism (i-DFT) which allows one to calculate the steady current through a nanoscopic region coupled to two biased electrodes. In our setup, one of the electrodes serves as a probe ("STM tip"), which is weakly coupled to the system we want to measure. In the ideal STM limit of vanishing coupling to the tip, the system is restored to quasi equilibrium and the normalized differential conductance yields the exact equilibrium many-body spectral function. Calculating this quantity from i-DFT, we derive an exact relation expressing the interacting spectral function in terms of the Kohn-Sham one. As illustrative examples, we apply our scheme to calculate the spectral functions of two nontrivial model systems, namely the single Anderson impurity model and the Constant Interaction Model. PMID- 29437405 TI - Continuous-Variable Triple-Photon States Quantum Entanglement. AB - We investigate the quantum entanglement of the three modes associated with the three-photon states obtained by triple-photon generation in a phase-matched third order nonlinear optical interaction. Although the second-order processes have been extensively dealt with, there is no direct analogy between the second and third-order mechanisms. We show, for example, the absence of quantum entanglement between the quadratures of the three modes in the case of spontaneous parametric triple-photon generation. However, we show robust, seeding-dependent, genuine triple-photon entanglement in the fully seeded case. PMID- 29437407 TI - Viscous Dissipation and Heat Conduction in Binary Neutron-Star Mergers. AB - Inferring the properties of dense matter is one of the most exciting prospects from the measurement of gravitational waves from neutron star mergers. However, it requires reliable numerical simulations that incorporate viscous dissipation and energy transport as these can play a significant role in the survival time of the post-merger object. We calculate time scales for typical forms of dissipation and find that thermal transport and shear viscosity will not be important unless neutrino trapping occurs, which requires temperatures above 10 MeV and gradients over length scales of 0.1 km or less. On the other hand, if direct-Urca processes remain suppressed, leaving modified-Urca processes to establish flavor equilibrium, then bulk viscous dissipation could provide significant damping to density oscillations right after merger. When comparing with data from state-of the-art merger simulations, we find that the bulk viscosity takes values close to its resonant maximum in a typical merger, motivating a more careful assessment of the role of bulk viscous dissipation in the gravitational-wave signal from merging neutron stars. PMID- 29437408 TI - Energy- and Momentum-Resolved Photoelectron Spin Polarization in Multiphoton Ionization of Xe by Circularly Polarized Fields. AB - We perform a joint experimental and theoretical study on momentum- and energy resolved photoelectron spin polarization in multiphoton ionization of Xe atoms by circularly polarized fields. We experimentally measure the photoelectron momentum distributions of Xe atoms in circularly polarized near-infrared (800 nm) and ultraviolet (400 nm) light, respectively. We analyze the momentum- and energy resolved photoelectron spin polarization by comparing the experimental photoelectron momentum distributions with the simulations, although we cannot derive the spin polarization solely from the experiment. We show that the use of circularly polarized ultraviolet light at 400 nm can create better than 90% spin polarization with focal volume effect considered, which enables the separation of the spin states by momentum gating. This paves the way to produce high-degree spin-polarized electron sources from strong-field multiphoton ionization. PMID- 29437409 TI - First Detected Arrival of a Quantum Walker on an Infinite Line. AB - The first detection of a quantum particle on a graph is shown to depend sensitively on the distance xi between the detector and initial location of the particle, and on the sampling time tau. Here, we use the recently introduced quantum renewal equation to investigate the statistics of first detection on an infinite line, using a tight-binding lattice Hamiltonian with nearest-neighbor hops. Universal features of the first detection probability are uncovered and simple limiting cases are analyzed. These include the large xi limit, the small tau limit, and the power law decay with the attempt number of the detection probability over which quantum oscillations are superimposed. For large xi the first detection probability assumes a scaling form and when the sampling time is equal to the inverse of the energy band width nonanalytical behaviors arise, accompanied by a transition in the statistics. The maximum total detection probability is found to occur for tau close to this transition point. When the initial location of the particle is far from the detection node we find that the total detection probability attains a finite value that is distance independent. PMID- 29437410 TI - Controlling Heat Transport and Flow Structures in Thermal Turbulence Using Ratchet Surfaces. AB - In this combined experimental and numerical study on thermally driven turbulence in a rectangular cell, the global heat transport and the coherent flow structures are controlled with an asymmetric ratchetlike roughness on the top and bottom plates. We show that, by means of symmetry breaking due to the presence of the ratchet structures on the conducting plates, the orientation of the large scale circulation roll (LSCR) can be locked to a preferred direction even when the cell is perfectly leveled out. By introducing a small tilt to the system, we show that the LSCR orientation can be tuned and controlled. The two different orientations of LSCR give two quite different heat transport efficiencies, indicating that heat transport is sensitive to the LSCR direction over the asymmetric roughness structure. Through a quantitative analysis of the dynamics of thermal plume emissions and the orientation of the LSCR over the asymmetric structure, we provide a physical explanation for these findings. The current work has important implications for passive and active flow control in engineering, biofluid dynamics, and geophysical flows. PMID- 29437411 TI - Curvature-Induced Instabilities of Shells. AB - Induced by proteins within the cell membrane or by differential growth, heating, or swelling, spontaneous curvatures can drastically affect the morphology of thin bodies and induce mechanical instabilities. Yet, the interaction of spontaneous curvature and geometric frustration in curved shells remains poorly understood. Via a combination of precision experiments on elastomeric spherical shells, simulations, and theory, we show how a spontaneous curvature induces a rotational symmetry-breaking buckling as well as a snapping instability reminiscent of the Venus fly trap closure mechanism. The instabilities, and their dependence on geometry, are rationalized by reducing the spontaneous curvature to an effective mechanical load. This formulation reveals a combined pressurelike term in the bulk and a torquelike term in the boundary, allowing scaling predictions for the instabilities that are in excellent agreement with experiments and simulations. Moreover, the effective pressure analogy suggests a curvature-induced subcritical buckling in closed shells. We determine the critical buckling curvature via a linear stability analysis that accounts for the combination of residual membrane and bending stresses. The prominent role of geometry in our findings suggests the applicability of the results over a wide range of scales. PMID- 29437412 TI - Adiabatic Expansion of Electron Gas in a Magnetic Nozzle. AB - A specially constructed experiment shows the near perfect adiabatic expansion of an ideal electron gas resulting in a polytropic index greater than 1.4, approaching the adiabatic value of 5/3, when removing electric fields from the system, while the polytropic index close to unity is observed when the electrons are trapped by the electric fields. The measurements were made on collisionless electrons in an argon plasma expanding in a magnetic nozzle. The collision lengths of all electron collision processes are greater than the scale length of the expansion, meaning the system cannot be in thermodynamic equilibrium, yet thermodynamic concepts can be used, with caution, in explaining the results. In particular, a Lorentz force, created by inhomogeneities in the radial plasma density, does work on the expanding magnetic field, reducing the internal energy of the electron gas that behaves as an adiabatically expanding ideal gas. PMID- 29437413 TI - Erratum: Emergence of Correlated Optics in One-Dimensional Waveguides for Classical and Quantum Atomic Gases [Phys. Rev. Lett. 117, 143602 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.117.143602. PMID- 29437414 TI - Quantification of Turbulent Driving Forces for the Geodesic Acoustic Mode in the JFT-2M Tokamak. AB - We investigate spatial structures of turbulence and turbulent transport modulated by the geodesic acoustic mode (GAM), from which the excitation mechanism of the GAM is discussed. The GAM is found to be predominantly excited through a localized Reynolds stress force, rather than the dynamic shearing force. The evaluated growth rate is larger than the linear damping coefficients and is on the same order of magnitude as the effective growth rate evaluated from time evolution in the GAM kinetic energy. PMID- 29437415 TI - Correlated Dynamics in a Synthetic Lattice of Momentum States. AB - We study the influence of atomic interactions on quantum simulations in momentum space lattices (MSLs), where driven transitions between discrete momentum states mimic transport between sites of a synthetic lattice. Low-energy atomic collisions, which are short ranged in real space, relate to nearly infinite ranged interactions in momentum space. However, the added exchange energy between atoms in distinguishable momentum states leads to an effectively attractive, finite-ranged interaction between atoms in momentum space. In this Letter, we observe the onset of self-trapping driven by such interactions in a momentum space double well, paving the way for more complex many-body studies in tailored MSLs. We consider the types of phenomena that may result from these interactions, including the formation of chiral solitons in zigzag flux lattices. PMID- 29437416 TI - Superior Valley Polarization and Coherence of 2s Excitons in Monolayer WSe_{2}. AB - We report the experimental observation of 2s exciton radiative emission from monolayer tungsten diselenide, enabled by hexagonal boron nitride protected high quality samples. The 2s luminescence is highly robust and persists up to 150 K, offering a new quantum entity for manipulating the valley degree of freedom. Remarkably, the 2s exciton displays superior valley polarization and coherence than 1s under similar experimental conditions. This observation provides evidence that the Coulomb-exchange-interaction-driven valley-depolarization process, the Maialle-Silva-Sham mechanism, plays an important role in valley excitons of monolayer transition metal dichalcogenides. PMID- 29437417 TI - Ultimate Confinement of Phonon Propagation in Silicon Nanocrystalline Structure. AB - Temperature-dependent thermal conductivity of epitaxial silicon nanocrystalline (SiNC) structures composed of nanometer-sized grains separated by ultrathin silicon-oxide (SiO_{2}) films (~0.3 nm) is measured by the time domain thermoreflectance technique in the range from 50 to 300 K. The thermal conductivity of SiNC structures with a grain size of 3 and 5 nm is anomalously low at the entire temperature range, significantly below the values of bulk amorphous Si and SiO_{2}. The phonon gas kinetic model, with intrinsic transport properties obtained by first-principles-based anharmonic lattice dynamics and phonon transmittance across ultrathin SiO_{2} films obtained by atomistic Green's function, reproduces the measured thermal conductivity without any fitting parameters. The analysis reveals that mean free paths of acoustic phonons in the SiNC structures are equivalent or even below half the phonon wavelength, i.e., the minimum thermal conductivity scenario. The result demonstrates that the nanostructures with extremely small length scales and a controlled interface can give rise to ultimate classical confinement of thermal phonon propagation. PMID- 29437418 TI - Violation of Bell's Inequality Using Continuous Variable Measurements. AB - A Bell inequality is a fundamental test to rule out local hidden variable model descriptions of correlations between two physically separated systems. There have been a number of experiments in which a Bell inequality has been violated using discrete-variable systems. We demonstrate a violation of Bell's inequality using continuous variable quadrature measurements. By creating a four-mode entangled state with homodyne detection, we recorded a clear violation with a Bell value of B=2.31+/-0.02. This opens new possibilities for using continuous variable states for device independent quantum protocols. PMID- 29437419 TI - Nonreciprocal Localization of Photons. AB - We demonstrate that it is possible to localize photons nonreciprocally in a moving photonic lattice made by spatiotemporally modulating the atomic response, where the dispersion acquires a spectral Doppler shift with respect to the probe direction. A static defect placed in such a moving lattice produces a spatial localization of light in the band gap with a shifting frequency that depends on the direction of incident field with respect to the moving lattice. This phenomenon has an impact not only in photonics but also in broader areas such as condensed matter and acoustics, opening the doors for designing new devices such as compact isolators, circulators, nonreciprocal traps, sensors, unidirectional tunable filters, and possibly even a unidirectional laser. PMID- 29437420 TI - Discrete Time-Crystalline Order in Cavity and Circuit QED Systems. AB - Discrete time crystals are a recently proposed and experimentally observed out-of equilibrium dynamical phase of Floquet systems, where the stroboscopic dynamics of a local observable repeats itself at an integer multiple of the driving period. We address this issue in a driven-dissipative setup, focusing on the modulated open Dicke model, which can be implemented by cavity or circuit QED systems. In the thermodynamic limit, we employ semiclassical approaches and find rich dynamical phases on top of the discrete time-crystalline order. In a deep quantum regime with few qubits, we find clear signatures of a transient discrete time-crystalline behavior, which is absent in the isolated counterpart. We establish a phenomenology of dissipative discrete time crystals by generalizing the Landau theory of phase transitions to Floquet open systems. PMID- 29437421 TI - Circular-Polarization-Dependent Study of Microwave-Induced Conductivity Oscillations in a Two-Dimensional Electron Gas on Liquid Helium. AB - The polarization dependence of the photoconductivity response at cyclotron resonance harmonics in a nondegenerate two-dimensional (2D) electron system formed on the surface of liquid helium is studied using a setup in which a circular polarization of opposite directions can be produced. Contrary to the results of similar investigations reported for semiconductor 2D electron systems, for electrons on liquid helium, a strong dependence of the amplitude of magnetoconductivity oscillations on the direction of circular polarization is observed. This observation is in accordance with theoretical models based on photon-assisted scattering, and, therefore, it presents a principal argument in the dispute over the origin of microwave-induced conductivity oscillations. PMID- 29437422 TI - Entropy Stabilizes Floppy Crystals of Mobile DNA-Coated Colloids. AB - Grafting linkers with open ends of complementary single-stranded DNA makes a flexible tool to tune interactions between colloids, which facilitates the design of complex self-assembly structures. Recently, it has been proposed to coat colloids with mobile DNA linkers, which alleviates kinetic barriers without high density grafting, and also allows the design of valency without patches. However, the self-assembly mechanism of this novel system is poorly understood. Using a combination of theory and simulation, we obtain phase diagrams for the system in both two and three dimensional spaces, and find stable floppy square and CsCl crystals when the binding strength is strong, even in the infinite binding strength limit. We demonstrate that these floppy phases are stabilized by vibrational entropy, and "floppy" modes play an important role in stabilizing the floppy phases for the infinite binding strength limit. This special entropic effect in the self-assembly of mobile DNA-coated colloids is very different from conventional molecular self-assembly, and it offers a new axis to help design novel functional materials using mobile DNA-coated colloids. PMID- 29437423 TI - Acoustic Virtual Vortices with Tunable Orbital Angular Momentum for Trapping of Mie Particles. AB - Acoustic vortices can transfer angular momentum and trap particles. Here, we show that particles trapped in airborne acoustic vortices orbit at high speeds, leading to dynamic instability and ejection. We demonstrate stable trapping inside acoustic vortices by generating sequences of short-pulsed vortices of equal helicity but opposite chirality. This produces a "virtual vortex" with an orbital angular momentum that can be tuned independently of the trapping force. We use this method to adjust the rotational speed of particles inside a vortex beam and, for the first time, create three-dimensional acoustics traps for particles of wavelength order (i.e., Mie particles). PMID- 29437424 TI - Decondensation in Nonequilibrium Photonic Condensates: When Less Is More. AB - We investigate the steady state of a system of photons in a pumped dye-filled microcavity. By varying pump and thermalization the system can be tuned between Bose-Einstein condensation, multimode condensation, and lasing. We present a rich nonequilibrium phase diagram which exhibits transitions between these phases, including decondensation of individual modes under conditions that would typically favor condensation. PMID- 29437425 TI - Relating Out-of-Time-Order Correlations to Entanglement via Multiple-Quantum Coherences. AB - Out-of-time-order correlations (OTOCs) characterize the scrambling, or delocalization, of quantum information over all the degrees of freedom of a system and thus have been proposed as a proxy for chaos in quantum systems. Recent experimental progress in measuring OTOCs calls for a more thorough understanding of how these quantities characterize complex quantum systems, most importantly in terms of the buildup of entanglement. Although a connection between OTOCs and entanglement entropy has been derived, the latter only quantifies entanglement in pure systems and is hard to access experimentally. In this work, we formally demonstrate that the multiple-quantum coherence spectra, a specific family of OTOCs well known in NMR, can be used as an entanglement witness and as a direct probe of multiparticle entanglement. Our results open a path to experimentally testing the fascinating idea that entanglement is the underlying glue that links thermodynamics, statistical mechanics, and quantum gravity. PMID- 29437426 TI - Mutual Unbiasedness in Coarse-Grained Continuous Variables. AB - The notion of mutual unbiasedness for coarse-grained measurements of quantum continuous variable systems is considered. It is shown that while the procedure of "standard" coarse graining breaks the mutual unbiasedness between conjugate variables, this desired feature can be theoretically established and experimentally observed in periodic coarse graining. We illustrate our results in an optics experiment implementing Fraunhofer diffraction through a periodic diffraction grating, finding excellent agreement with the derived theory. Our results are an important step in developing a formal connection between discrete and continuous variable quantum mechanics. PMID- 29437427 TI - Network Dynamics of Innovation Processes. AB - We introduce a model for the emergence of innovations, in which cognitive processes are described as random walks on the network of links among ideas or concepts, and an innovation corresponds to the first visit of a node. The transition matrix of the random walk depends on the network weights, while in turn the weight of an edge is reinforced by the passage of a walker. The presence of the network naturally accounts for the mechanism of the "adjacent possible," and the model reproduces both the rate at which novelties emerge and the correlations among them observed empirically. We show this by using synthetic networks and by studying real data sets on the growth of knowledge in different scientific disciplines. Edge-reinforced random walks on complex topologies offer a new modeling framework for the dynamics of correlated novelties and are another example of coevolution of processes and networks. PMID- 29437428 TI - Identification of Majorana Modes in Interacting Systems by Local Integrals of Motion. AB - Recently, there has been substantial progress in methods of identifying local integrals of motion in interacting integrable models or in systems with many-body localization. We show that one of these approaches can be utilized for constructing local, conserved, Majorana fermions in systems with an arbitrary many-body interaction. As a test case, we first investigate a noninteracting Kitaev model and demonstrate that this approach perfectly reproduces the standard results. Then, we discuss how the many-body interactions influence the spatial structure and the lifetime of the Majorana modes. Finally, we determine the regime for which the information stored in the Majorana correlators is also retained for arbitrarily long times at high temperatures. We show that it is included in the regime with topologically protected soft Majorana modes, but in some cases is significantly smaller. PMID- 29437429 TI - Signal Tracking Beyond the Time Resolution of an Atomic Sensor by Kalman Filtering. AB - We study causal waveform estimation (tracking) of time-varying signals in a paradigmatic atomic sensor, an alkali vapor monitored by Faraday rotation probing. We use Kalman filtering, which optimally tracks known linear Gaussian stochastic processes, to estimate stochastic input signals that we generate by optical pumping. Comparing the known input to the estimates, we confirm the accuracy of the atomic statistical model and the reliability of the Kalman filter, allowing recovery of waveform details far briefer than the sensor's intrinsic time resolution. With proper filter choice, we obtain similar benefits when tracking partially known and non-Gaussian signal processes, as are found in most practical sensing applications. The method evades the trade-off between sensitivity and time resolution in coherent sensing. PMID- 29437430 TI - h/e Superconducting Quantum Interference through Trivial Edge States in InAs. AB - Josephson junctions defined in strong spin orbit semiconductors are highly interesting for the search for topological systems. However, next to topological edge states that emerge in a sufficient magnetic field, trivial edge states can also occur. We study the trivial edge states with superconducting quantum interference measurements on nontopological InAs Josephson junctions. We observe a SQUID pattern, an indication of superconducting edge transport. Also, a remarkable h/e SQUID signal is observed that, as we find, stems from crossed Andreev states. PMID- 29437431 TI - Effective Landau Level Diagram of Bilayer Graphene. AB - The E=0 octet of bilayer graphene in the filling factor range of -4v_{2}{4}~v_{2}{6}~v_{2}{8} of two, four, six, and eight particle correlations. While such patterns are often interpreted as signatures of collectivity arising from hydrodynamic flow, our results provide an alternative description of the multiparticle correlations seen in p+A collisions. PMID- 29437438 TI - Cosmic-Ray Lithium Production at the Nova Eruptions Followed by a Type Ia Supernova. AB - Recent measurements of cosmic-ray (CR) light nuclei by AMS-02 have shown that there is an unexpected component of CR lithium whose spectral index is harder than that expected from the secondary production scenario. We propose the nearby type Ia supernova following a nova eruption as the origin of lithium nuclei in the CRs. By fitting the data of CR protons, helium, and lithium fluxes provided by AMS-02 with our theoretical model we show that this scenario is consistent with the observations. The observational tests that can check our hypothesis are briefly discussed. PMID- 29437439 TI - Anion Order and Spontaneous Polarization in LaTiO_{2}N Oxynitride Thin Films. AB - The perovskite oxynitride LaTiO_{2}N is a promising material for photocatalytic water splitting under visible light. One of the obstacles towards higher efficiencies of this and similar materials stems from charge-carrier recombination, which could be suppressed by the surface charges resulting from the dipolar field in polar materials. In this study, we investigate the spontaneous polarization in epitaxially strained LaTiO_{2}N thin films via density functional theory calculations. The effect of epitaxial strain on the anion order, resulting out-of-plane polarization, energy barriers for polarization reversal, and corresponding coercive fields are studied. We find that for compressive strains larger than 4% the thermodynamically stable anion order is polar along the out-of-plane direction and has a coercive field comparable to other switchable ferroelectrics. Our results show that strained LaTiO_{2}N could indeed suppress carrier recombination and lead to enhanced photocatalytic activities. PMID- 29437440 TI - Metasurface for Water-to-Air Sound Transmission. AB - Effective transmission of sound from water to air is crucial for the enhancement of the detection sensitivity of underwater sound. However, only 0.1% of the acoustic energy is naturally transmitted at such a boundary. At audio frequencies, quarter-wave plates or multilayered antireflection coatings are too bulky for practical use for such enhancement. Here we present an acoustic metasurface of a thickness of only ~lambda/100, where lambda is the wavelength in air, consisting of an array of meta-atoms that each contain a set of membranes and an air-filled cavity. We experimentally demonstrate that such a meta-atom increases the transmission of sound at ~700 Hz by 2 orders of magnitude, allowing about 30% of the incident acoustic power from water to be transmitted into air. Applications include underwater sonic sensing and communication. PMID- 29437441 TI - Operational Markov Condition for Quantum Processes. AB - We derive a necessary and sufficient condition for a quantum process to be Markovian which coincides with the classical one in the relevant limit. Our condition unifies all previously known definitions for quantum Markov processes by accounting for all potentially detectable memory effects. We then derive a family of measures of non-Markovianity with clear operational interpretations, such as the size of the memory required to simulate a process or the experimental falsifiability of a Markovian hypothesis. PMID- 29437442 TI - Chiral Response of Twisted Bilayer Graphene. AB - We present an effective (minimal) theory for chiral two-dimensional materials. These materials possess an electromagnetic coupling without exhibiting a topological gap. As an example, we study the response of doped twisted bilayers, unveiling unusual phenomena in the zero frequency limit. An in-plane magnetic field induces a huge paramagnetic response at the neutrality point and, upon doping, also gives rise to a substantial longitudinal Hall response. The system also accommodates nontrivial longitudinal plasmonic modes that are associated with a longitudinal magnetic moment, thus endowing them with a chiral character. Finally, we note that the optical activity can be considerably enhanced upon doping and our general approach would enable systematic exploration of 2D material heterostructures with optical activity. PMID- 29437443 TI - Proposal for a Quantum Test of the Weak Equivalence Principle with Entangled Atomic Species. AB - We propose an experiment to test the weak equivalence principle (WEP) with a test mass consisting of two entangled atoms of different species. In the proposed experiment, a coherent measurement of the differential gravity acceleration between the two atomic species is considered, by entangling two atom interferometers operating on the two species. The entanglement between the two atoms is heralded at the initial beam splitter of the interferometers through the detection of a single photon emitted by either of the atoms, together with the impossibility of distinguishing which atom emitted the photon. In contrast to current and proposed tests of the WEP, our proposal explores the validity of the WEP in a regime where the two particles involved in the differential gravity acceleration measurement are not classically independent, but entangled. We propose an experimental implementation using ^{85}Rb and ^{87}Rb atoms entangled by a vacuum stimulated rapid adiabatic passage protocol implemented in a high finesse optical cavity. We show that an accuracy below 10^{-7} on the Eotvos parameter can be achieved. PMID- 29437444 TI - Erratum: Fluctuation-Dissipation Relations of a Tunnel Junction Driven by a Quantum Circuit [Phys. Rev. Lett. 114, 126801 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.114.126801. PMID- 29437446 TI - Generalized Arcsine Laws for Fractional Brownian Motion. AB - The three arcsine laws for Brownian motion are a cornerstone of extreme-value statistics. For a Brownian B_{t} starting from the origin, and evolving during time T, one considers the following three observables: (i) the duration t_{+} the process is positive, (ii) the time t_{last} the process last visits the origin, and (iii) the time t_{max} when it achieves its maximum (or minimum). All three observables have the same cumulative probability distribution expressed as an arcsine function, thus the name arcsine laws. We show how these laws change for fractional Brownian motion X_{t}, a non-Markovian Gaussian process indexed by the Hurst exponent H. It generalizes standard Brownian motion (i.e., H=1/2). We obtain the three probabilities using a perturbative expansion in epsilon=H-1/2. While all three probabilities are different, this distinction can only be made at second order in epsilon. Our results are confirmed to high precision by extensive numerical simulations. PMID- 29437445 TI - Erratum: Spin-Dependent Weakly-Interacting-Massive-Particle-Nucleon Cross Section Limits from First Data of PandaX-II Experiment [Phys. Rev. Lett. 118, 071301 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.071301. PMID- 29437406 TI - Combined Forward-Backward Asymmetry Measurements in Top-Antitop Quark Production at the Tevatron. AB - The CDF and D0 experiments at the Fermilab Tevatron have measured the asymmetry between yields of forward- and backward-produced top and antitop quarks based on their rapidity difference and the asymmetry between their decay leptons. These measurements use the full data sets collected in proton-antiproton collisions at a center-of-mass energy of sqrt[s]=1.96 TeV. We report the results of combinations of the inclusive asymmetries and their differential dependencies on relevant kinematic quantities. The combined inclusive asymmetry is A_{FB}^{tt[over -]}=0.128+/-0.025. The combined inclusive and differential asymmetries are consistent with recent standard model predictions. PMID- 29437447 TI - Coulomb-Driven Relativistic Electron Beam Compression. AB - Coulomb interaction between charged particles is a well-known phenomenon in many areas of research. In general, the Coulomb repulsion force broadens the pulse width of an electron bunch and limits the temporal resolution of many scientific facilities such as ultrafast electron diffraction and x-ray free-electron lasers. Here we demonstrate a scheme that actually makes use of the Coulomb force to compress a relativistic electron beam. Furthermore, we show that the Coulomb driven bunch compression process does not introduce additional timing jitter, which is in sharp contrast to the conventional radio-frequency buncher technique. Our work not only leads to enhanced temporal resolution in electron-beam-based ultrafast instruments that may provide new opportunities in probing material systems far from equilibrium, but also opens a promising direction for advanced beam manipulation through self-field interactions. PMID- 29437448 TI - Two-Loop Binding Corrections to the Electron Gyromagnetic Factor. AB - We compute corrections to the gyromagnetic factor of an electron bound in a hydrogenlike ion at order alpha^{2}(Zalpha)^{5}. This result removes a major uncertainty in predictions for silicon and carbon ions, used to determine the atomic mass of the electron. PMID- 29437449 TI - Determination of the Spin-Rotation Fine Structure of He_{2}^{+}. AB - Measuring spin-rotation intervals in molecular cations is challenging, particularly so when the ions do not have electric-dipole-allowed rovibrational transitions. We present a method, based on an angular-momentum basis transformation, to determine the spin-rotational fine structure of molecular ions from the fine structure of high Rydberg states. The method is illustrated by the determination of the so far unknown spin-rotation fine structure of the fundamentally important He_{2}^{+} ion in the X ^{2}Sigma_{u}^{+} state. The fine structure splittings of the v^{+}=0, N^{+}=1, 3, and 5 levels of He_{2}^{+} are 7.96(14), 17.91(32), and 28.0(6) MHz, respectively. The experiment relies on the use of single-mode cw radiation to record spectra of high Rydberg states of He_{2} from the a ^{3}Sigma_{u}^{+} metastable state. PMID- 29437451 TI - Yielding and Flow of Soft-Jammed Systems in Elongation. AB - So far, yielding and flow properties of soft-jammed systems have only been studied from simple shear and then extrapolated to other flow situations. In particular, simple flows such as elongations have barely been investigated experimentally or only in a nonconstant, partial volume of material. We show that using smooth tool surfaces makes it possible to obtain a prolonged elongational flow over a large range of aspect ratios in the whole volume of material. The normal force measured for various soft-jammed systems with different microstructures shows that the ratio of the elongation yield stress to the shear yield stress is larger (by a factor of around 1.5) than expected from the standard theory which assumes that the stress tensor is a function of the second invariant of the strain rate tensor. This suggests that the constitutive tensor of the materials cannot be determined solely from macroscopic shear measurements. PMID- 29437450 TI - Stroboscopic Qubit Measurement with Squeezed Illumination. AB - Microwave squeezing represents the ultimate sensitivity frontier for superconducting qubit measurement. However, measurement enhancement has remained elusive, in part because integration with standard dispersive readout pollutes the signal channel with antisqueezed noise. Here we induce a stroboscopic light matter coupling with superior squeezing compatibility, and observe an increase in the final signal-to-noise ratio of 24%. Squeezing the orthogonal phase slows measurement-induced dephasing by a factor of 1.8. This scheme provides a means to the practical application of squeezing for qubit measurement. PMID- 29437452 TI - Unidirectional Spin-Wave-Propagation-Induced Seebeck Voltage in a PEDOT:PSS/YIG Bilayer. AB - We clarify the physical origin of the dc voltage generation in a bilayer of a conducting polymer film and a micrometer-thick magnetic insulator Y_{3}Fe_{5}O_{12} (YIG) film under ferromagnetic resonance and/or spin wave excitation conditions. The previous attributed mechanism, the inverse spin Hall effect in the polymer [Nat. Mater. 12, 622 (2013)NMAACR1476 112210.1038/nmat3634], is excluded by two control experiments. We find an in plane temperature gradient in YIG which has the same angular dependence with the generated voltage. Both vanish when the YIG thickness is reduced to a few nanometers. Thus, we argue that the dc voltage is governed by the Seebeck effect in the polymer, where the temperature gradient is created by the nonreciprocal magnetostatic surface spin wave propagation in YIG. PMID- 29437453 TI - Evidence of an Improper Displacive Phase Transition in Cd_{2}Re_{2}O_{7} via Time Resolved Coherent Phonon Spectroscopy. AB - We have used a combination of ultrafast coherent phonon spectroscopy, ultrafast thermometry, and time-dependent Landau theory to study the inversion symmetry breaking phase transition at T_{c}=200 K in the strongly spin-orbit coupled correlated metal Cd_{2}Re_{2}O_{7}. We establish that the structural distortion at T_{c} is a secondary effect through the absence of any softening of its associated phonon mode, which supports a purely electronically driven mechanism. However, the phonon lifetime exhibits an anomalously strong temperature dependence that decreases linearly to zero near T_{c}. We show that this behavior naturally explains the spurious appearance of phonon softening in previous Raman spectroscopy experiments and should be a prevalent feature of correlated electron systems with linearly coupled order parameters. PMID- 29437455 TI - Realizing Fulde-Ferrell Superfluids via a Dark-State Control of Feshbach Resonances. AB - We propose that the long-sought Fulde-Ferrell superfluidity with nonzero momentum pairing can be realized in ultracold two-component Fermi gases of ^{40}K or ^{6}Li atoms by optically tuning their magnetic Feshbach resonances via the creation of a closed-channel dark state with a Doppler-shifted Stark effect. In this scheme, two counterpropagating optical fields are applied to couple two molecular states in the closed channel to an excited molecular state, leading to a significant violation of Galilean invariance in the dark-state regime and hence to the possibility of Fulde-Ferrell superfluidity. We develop a field theoretical formulation for both two-body and many-body problems and predict that the Fulde Ferrell state has remarkable properties, such as anisotropic single-particle dispersion relation, suppressed superfluid density at zero temperature, anisotropic sound velocity, and rotonic collective mode. The latter two features can be experimentally probed using Bragg spectroscopy, providing a smoking-gun proof of Fulde-Ferrell superfluidity. PMID- 29437454 TI - Post hoc Verification of Quantum Computation. AB - We propose a set of protocols for verifying quantum computing at any time after the computation itself has been performed. We provide two constructions: one requires five entangled provers and a completely classical verifier; the other requires a single prover, a verifier, who is restricted to measuring qubits in the X or Z basis, and one-way quantum communication from the prover to the verifier. These results demonstrate that the verification can be achieved independently from the blindness. We also show that a constant round protocol with a single prover and a completely classical verifier is not possible, unless bounded error quantum polynomial time (BQP) is contained in the third level of the polynomial hierarchy. PMID- 29437456 TI - Exactly Solvable BCS-Hubbard Model in Arbitrary Dimensions. AB - We introduce in this Letter an exact solvable BCS-Hubbard model in arbitrary dimensions. The model describes a p-wave BCS superconductor with equal spin pairing moving on a bipartite (cubic, square, etc.) lattice with on-site Hubbard interaction U. We show that the model becomes exactly solvable for arbitrary U when the BCS pairing amplitude Delta equals the hopping amplitude t. The nature of the solution is described in detail in this Letter. The construction of the exact solution is parallel to the exactly solvable Kitaev honeycomb model for S=1/2 quantum spins and can be viewed as a generalization of Kitaev's construction to S=1/2 interacting lattice fermions. The BCS-Hubbard model discussed in this Letter is just an example of a large class of exactly solvable lattice fermion models that can be constructed similarly. PMID- 29437457 TI - Empirical Determination of Dark Matter Velocities Using Metal-Poor Stars. AB - The Milky Way dark matter halo is formed from the accretion of smaller subhalos. These sub-units also harbor stars-typically old and metal-poor-that are deposited in the Galactic inner regions by disruption events. In this Letter, we show that the dark matter and metal-poor stars in the Solar neighborhood share similar kinematics due to their common origin. Using the high-resolution eris simulation, which traces the evolution of both the dark matter and baryons in a realistic Milky Way analog galaxy, we demonstrate that metal-poor stars are indeed effective tracers for the local, virialized dark matter velocity distribution. The local dark matter velocities can therefore be inferred from observations of the stellar halo made by the Sloan Digital Sky Survey within 4 kpc of the Sun. This empirical distribution differs from the standard halo model in important ways and suggests that the bounds on the spin-independent scattering cross section may be weakened for dark matter masses below ~10 GeV. Data from Gaia will allow us to further refine the expected distribution for the smooth dark matter component, and to test for the presence of local substructure. PMID- 29437458 TI - Quantum Fluctuation Theorems, Contextuality, and Work Quasiprobabilities. AB - We discuss the role of contextuality within quantum fluctuation theorems, in the light of a recent no-go result by Perarnau-Llobet et al. We show that any fluctuation theorem reproducing the two-point-measurement scheme for classical states either admits a notion of work quasiprobability or fails to describe protocols exhibiting contextuality. Conversely, we describe a protocol that smoothly interpolates between the two-point-measurement work distribution for projective measurements and Allahverdyan's work quasiprobability for weak measurements, and show that the negativity of the latter is a direct signature of contextuality. PMID- 29437459 TI - Spin and Angular Momentum in Strong-Field Ionization. AB - The spin polarization of electrons from multiphoton ionization of Xe by 395 nm circularly polarized laser pulses at 6*10^{13} W/cm^{2} has been measured. At this photon energy of 3.14 eV the above-threshold ionization peaks connected to Xe^{+} ions in the ground state (J=3/2, ionization potential I_{p}=12.1 eV) and the first excited state (J=1/2, I_{p}=13.4 eV) are clearly separated in the electron energy distribution. These two combs of above-threshold ionization peaks show opposite spin polarizations. The magnitude of the spin polarization is a factor of 2 higher for the J=1/2 than for the J=3/2 final ionic state. In turn, the data show that the ionization probability is strongly dependent on the sign of the magnetic quantum number. PMID- 29437460 TI - Accelerating Science with Generative Adversarial Networks: An Application to 3D Particle Showers in Multilayer Calorimeters. AB - Physicists at the Large Hadron Collider (LHC) rely on detailed simulations of particle collisions to build expectations of what experimental data may look like under different theoretical modeling assumptions. Petabytes of simulated data are needed to develop analysis techniques, though they are expensive to generate using existing algorithms and computing resources. The modeling of detectors and the precise description of particle cascades as they interact with the material in the calorimeter are the most computationally demanding steps in the simulation pipeline. We therefore introduce a deep neural network-based generative model to enable high-fidelity, fast, electromagnetic calorimeter simulation. There are still challenges for achieving precision across the entire phase space, but our current solution can reproduce a variety of particle shower properties while achieving speedup factors of up to 100 000*. This opens the door to a new era of fast simulation that could save significant computing time and disk space, while extending the reach of physics searches and precision measurements at the LHC and beyond. PMID- 29437461 TI - Simultaneous Conduction and Valence Band Quantization in Ultrashallow High Density Doping Profiles in Semiconductors. AB - We demonstrate simultaneous quantization of conduction band (CB) and valence band (VB) states in silicon using ultrashallow, high-density, phosphorus doping profiles (so-called Si:P delta layers). We show that, in addition to the well known quantization of CB states within the dopant plane, the confinement of VB derived states between the subsurface P dopant layer and the Si surface gives rise to a simultaneous quantization of VB states in this narrow region. We also show that the VB quantization can be explained using a simple particle-in-a-box model, and that the number and energy separation of the quantized VB states depend on the depth of the P dopant layer beneath the Si surface. Since the quantized CB states do not show a strong dependence on the dopant depth (but rather on the dopant density), it is straightforward to exhibit control over the properties of the quantized CB and VB states independently of each other by choosing the dopant density and depth accordingly, thus offering new possibilities for engineering quantum matter. PMID- 29437462 TI - Higher-Dimensional Caustics in Nonlinear Compton Scattering. AB - A description of the spectral and angular distributions of Compton scattered light in collisions of intense laser pulses with high-energy electrons is unwieldy and usually requires numerical simulations. However, due to the large number of parameters affecting the spectra such numerical investigations can become computationally expensive. Using methods of catastrophe theory we predict higher-dimensional caustics in the spectra of the Compton scattered light, which are associated with bright narrow-band spectral lines, and in the simplest case can be controlled by the value of the linear chirp of the pulse. These findings require no full-scale calculations and have direct consequences for the photon yield enhancement of future nonlinear Compton scattering x-ray or gamma-ray sources. PMID- 29437463 TI - Soliton Gases and Generalized Hydrodynamics. AB - We show that the equations of generalized hydrodynamics (GHD), a hydrodynamic theory for integrable quantum systems at the Euler scale, emerge in full generality in a family of classical gases, which generalize the gas of hard rods. In this family, the particles, upon colliding, jump forward or backward by a distance that depends on their velocities, reminiscent of classical soliton scattering. This provides a "molecular dynamics" for GHD: a numerical solver which is efficient, flexible, and which applies to the presence of external force fields. GHD also describes the hydrodynamics of classical soliton gases. We identify the GHD of any quantum model with that of the gas of its solitonlike wave packets, thus providing a remarkable quantum-classical equivalence. The theory is directly applicable, for instance, to integrable quantum chains and to the Lieb-Liniger model realized in cold-atom experiments. PMID- 29437464 TI - Deep-Ultraviolet Frequency Metrology of H_{2} for Tests of Molecular Quantum Theory. AB - Molecular hydrogen and its isotopic and ionic species are benchmark systems for testing quantum chemical theory. Advances in molecular energy structure calculations enable the experimental verification of quantum electrodynamics and potentially a determination of the proton charge radius from H_{2} spectroscopy. We measure the ground state energy in ortho-H_{2} relative to the first electronically excited state by Ramsey-comb laser spectroscopy on the EF^{1}Sigma_{g}^{+}-X^{1}Sigma_{g}^{+}(0,0) Q1 transition. The resulting transition frequency of 2 971 234 992 965(73) kHz is 2 orders of magnitude more accurate than previous measurements. This paves the way for a considerably improved determination of the dissociation energy (D_{0}) for fundamental tests with molecular hydrogen. PMID- 29437465 TI - Treatment Modality-Dependent Risk of Diabetic Ketoacidosis in Patients with Type 1 Diabetes: Danish Adult Diabetes Database Study. AB - BACKGROUND AND AIMS: The aim of this study was to evaluate the incidence rates of diabetic ketoacidosis (DKA) according to treatment modality in patients with type 1 diabetes (T1D) in Denmark, either multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). MATERIALS AND METHODS: A total of 20,902 T1D registered in the Danish Adult Diabetes Database were followed for an average of 5.4 years. Poisson regression analyses with risk time as offset were used to compare differences in rates of DKA between CSII and MDI. Model was adjusted for age, sex, diabetes duration, previous DKA events, and hemoglobin A1c (HbA1c). A modifying effect of number of CSII patients on the DKA rates was tested. RESULTS: During 113,731 person-years, 3100 DKA events were registered (53 among CSII). CSII patients were younger (42.3 vs. 47.9 years), a larger proportion was female (59% vs. 43%), had a shorter diabetes duration (19 vs. 21 years), and a lower HbA1c (61.9 vs. 66.6 mmol/mol). There was no significant difference in the incidence rate of DKA between CSII and MDI (rate ratio: 1.30, 95% confidence interval: 0.97-1.76). However, in clinics with at least 250 CSII patients, rates of DKA events were lower among CSII users, while the opposite was true for the smaller clinics (P = 0.016). CONCLUSIONS: Delivery of CSII in large diabetes clinics with sufficient support and patient education may ensure that CSII treatment does not lead to an increased risk of DKA. PMID- 29437467 TI - The Analytical Challenge in the Determination of Cathinones, Key-Players in the Worldwide Phenomenon of Novel Psychoactive Substances. AB - Since the turn of the century, the synthesis, availability, and use of new psychoactive substances (NPS) have been increasingly reported worldwide, being considered a complex global phenomenon. As most NPS are not detected in routine drug screening, extra efforts have been made to develop new analytical methods for the detection of these compounds, with several approaches being successfully applied and reported in the literature. The increased traffic of NPS is often related to the limited capacity for detecting and monitoring these compounds, which makes it essential to explore in detail both conventional and more recent approaches to prospect novel sensing strategies and develop in-the-field sensors that are able to detect NPS in a time-efficient manner, within a wide range of concentrations, and in a variety of sample matrices, such as biological samples, wastewater, powders, crystals, and post-mortem specimens. In this context, this review aims to provide an overview of the state of the art in the identification and analytical detection of cathinones, a considerable group within NPS, as well as a critical discussion of the most frequently described sample preparation techniques. PMID- 29437466 TI - Gene Promoter Hypermethylation Detected in Sputum Predicts FEV1 Decline and All Cause Mortality in Smokers. AB - RATIONALE: Gene promoter hypermethylation detected in sputum assesses the extent of field cancerization and predicts lung cancer (LC) risk in ever-smokers. A rapid decline of FEV1 is a major driver for development of airway obstruction. OBJECTIVES: To assess the effects of methylation of 12 genes on FEV1 decline and of FEV1 decline on subsequent LC incidence using two independent, longitudinal cohorts (i.e., LSC [Lovelace Smokers Cohort] and PLuSS [Pittsburgh Lung Screening Study]). METHODS: Gene methylation was measured in sputum using two-stage nested methylation-specific PCR. The linear mixed effects model was used to assess the effects of studied variables on FEV1 decline. MEASUREMENTS AND MAIN RESULTS: A dose-dependent relationship between number of genes methylated and FEV1 decline was identified, with smokers with three or more methylated genes having 27.8% and 10.3% faster FEV1 decline than smokers with zero to two methylated genes in the LSC and PLuSS cohort, respectively (all P < 0.01). High methylation in sputum was associated with a shorter latency for LC incidence (log-rank P = 0.0048) and worse all-cause mortality (log-rank P < 0.0001). Smokers with subsequent LC incidence had a more rapid annual decline of FEV1 (by 5.2 ml, P = 0.038) than smoker control subjects. CONCLUSIONS: Gene methylation detected in sputum predicted FEV1 decline, LC incidence, and all-cause mortality in smokers. Rapid FEV1 decline may be a risk factor for LC incidence in smokers, which may explain a greater prevalence of airway obstruction seen in patients with LC. PMID- 29437468 TI - Dual FLT3/TOPK inhibitor with activity against FLT3-ITD secondary mutations potently inhibits acute myeloid leukemia cell lines. AB - AIM: Approximately 30% of acute myeloid leukemia (AML) patients carry FLT3 tyrosine kinase domain (TKD) mutations or internal tandem duplication (FLT3-ITD). Currently there is a paucity of compounds that are active against drug-resistant FLT3-ITD, which contains secondary mutations in the TKD, mainly at residues D835/F691. RESULTS: HSD1169, a novel compound, is active against FLT3-ITD (D835 or F691). HSD1169 is also active against T-LAK cell-originated protein kinase (TOPK), a collaborating kinase that is highly expressed in AML cell lines. HSD1169 was active against MV4-11 and Molm-14 (FLT3-ITD cell lines) but not NOMO 1 or HL60 (FLT3-WT cell lines). HSD1169 was also active against sorafenib resistant Molm13-res cell line (containing FLT3-ITD/D835Y). CONCLUSION: HSD1169 or an analog could become a therapeutic agent for AML containing drug-resistant FLT3-ITD. PMID- 29437469 TI - DTT: 20 Years and Counting .... PMID- 29437470 TI - Diabetes Technology and Therapy in the Pediatric Age Group. PMID- 29437471 TI - Self-Monitoring of Blood Glucose. PMID- 29437472 TI - New Medications for the Treatment of Diabetes. PMID- 29437473 TI - Technologies in Diabetes-the Ninth ATTD Yearbook. PMID- 29437474 TI - Diabetes Technology and the Human Factor. PMID- 29437475 TI - Insulin Pumps. PMID- 29437476 TI - Continuous Glucose Monitoring in 2017. PMID- 29437477 TI - New Insulins, Biosimilars, and Insulin Therapy. PMID- 29437478 TI - Closing the Loop. PMID- 29437480 TI - Immune Intervention for Type 1 Diabetes. PMID- 29437481 TI - Using Digital Health Technology to Prevent and Treat Diabetes. PMID- 29437482 TI - Advances in Exercise, Physical Activity, and Diabetes Mellitus. PMID- 29437483 TI - Technology and Pregnancy. PMID- 29437484 TI - The Effects of Thai Yoga on Physical Fitness: A Meta-Analysis of Randomized Control Trials. AB - OBJECTIVES: Thai yoga is a traditional Thai exercise used for improving health related physical fitness. Many studies have evaluated these effects, but their results remain inconclusive. This meta-analysis aimed to examine the effectiveness of Thai yoga on physical fitness. DESIGN/METHODS: PubMed, EMBASE, CINAHL, Cochrane library, Thai Library Integrated System (ThaiLis), Physiotherapy Evidence Database (PEDro), National Rehabilitation Information Center (Rehabdata), Scopus, Web of Science, Thai University library databases/journals, and Thai Physical Therapy database up to March 2016 were searched for randomized controlled trials (RCTs) examining the effect of Thai yoga exercise compared with normal daily activities as controls, in any language. The weighted mean difference (WMD) and 95% confidence intervals (95% CI) were performed using the random-effects model. RESULTS: Seven RCTs met the inclusion criteria. Thai yoga training significantly improved body flexibility by 3.9 cm after 4 weeks [95% CI = 3.9-4.0; p < 0.001: no heterogeneity chi2 = 0.66, d.f.2, p = 0.7; I2 0.00%] and 8.9 cm after 8 weeks [95% CI = 7.4-10.5; p < 0.001: no heterogeneity chi2 = 0.16, d.f.2, p = 0.9; I2 0.00%] compared to controls. It also significantly increased range of motion (ROM) of right shoulder extension by 1.5 degrees at week 8, compared to controls [95% CI = 0.12-2.81; p = 0.03; low heterogeneity chi2 = 1.61, d.f.1, p = 0.2; I2 37.9%]. Greater ROM for right shoulder abduction was observed after 12 weeks compared to controls [22.2 degrees (95% CI = 20-24; p < 0.001): no heterogeneity chi2 = 0.29, d.f.1, p = 0.6; I2 0.00%]. CONCLUSIONS: Thai yoga exercises appeared useful, in particular, on body and right shoulder joint flexibility. Regular stretching exercise of Thai yoga and/or in combination with exercises could promote health-related physical fitness. PMID- 29437487 TI - Swim exercise inhibits hemostatic abnormalities in a rat model of obesity and insulin resistance. AB - BACKGROUND: We sought to determine whether swim exercise can inhibit high carbohydrate and fat diet (HCFD)-induced biomarkers of coagulation and thrombosis. MATERIAL AND METHODS: Rats were either fed with HCFD (model group) or a standard laboratory chow (control group) for 15 weeks. Swim exercise-'treated' rats started swim exercise training from the 11th week until being sacrificed, on Week 15. RESULTS: HCFD caused a significant increase in blood glucose, insulin resistance (HOMA-IR), lipidemia, and inflammatory biomarkers. In addition, HCFD significantly modulated coagulation and thrombosis biomarkers; fibrinogen, plasminogen activator inhibitor-1, von Willebrand factor, prothrombin time, activated partial thromboplastin time, blood clotting and bleeding time, and ADP induced platelet aggregation that was effectively inhibited by swimming exercises. CONCLUSIONS: We demonstrate that in an animal model of obesity and insulin resistance, there is a significant change in hemostasis, which is ameliorated by swim exercise. PMID- 29437488 TI - A Stepwise Procedure to Define a Data Collection Framework for a Clinical Biobank. AB - INTRODUCTION: Current guidelines for clinical biobanking have a strong focus on obtaining, handling, and storage of biospecimens. However, to allow for research tying biomarker analysis to clinical decision making, there should be more focus on collection of data on donor characteristics. Therefore, our aim was to develop a stepwise procedure to define a framework as a tool to help start the data collection process in clinical biobanking. MATERIALS AND METHODS: The Radboud Biobank (RB) is a central clinical biobanking facility designed in accordance with the standards set by the Parelsnoer Institute, a Dutch national biobank originally initiated with eight different disease cohorts. To organize the information of these cohorts, we used our experience and knowledge in the field of biobanking and translational research to identify research domains and information categories to classify data. We extended this classification system to a stepwise procedure for defining a data collection framework and examined its utility for existing RB biobanks. RESULTS: Our approach resulted in the definition of a three-step procedure: (1) Identification of research domains and relevant questions within the field that may benefit from biobank samples. (2) Identification of information categories and accompanying subcategories that are relevant for answering questions in identified research domains. (3) Reduction to an efficient framework based on essentiality and quality criteria. We showed the utility of the procedure for three existing RB biobanks. DISCUSSION: We developed guidelines for the definition of a framework that supports the standardization of the biobank data collection process. Connecting the biobank database to pertinent information collected from the electronic health record will improve data quality and efficiency for both care and research. This is crucial when using the corresponding biospecimens for scientific research. Further, it also facilitates the combination of different clinical biobanks for a specific disease. PMID- 29437489 TI - Controller adherence following hospital discharge in high risk children: A pilot randomized trial of text message reminders. AB - OBJECTIVE: To assess the feasibility of a mobile health, inhaled corticosteroid (ICS) adherence reminder intervention and to characterize adherence trajectories immediately following severe asthma exacerbation in high-risk urban children with persistent asthma. METHODS: Children aged 2-13 with persistent asthma were enrolled in this pilot randomized controlled trial during an asthma emergency department (ED) visit or hospitalization. Intervention arm participants received daily text message reminders for 30 days, and both arms received electronic sensors to measure ICS use. Primary outcomes were feasibility of sensor use and text message acceptability. Secondary outcomes included adherence to prescribed ICS regimen and 30-day adherence trajectories. Group-based trajectory modeling was used to examine adherence trajectories. RESULTS: Forty-one participants (mean age 5.9) were randomized to intervention (n = 21) or control (n = 20). Overall, 85% were Black, 88% had public insurance, and 51% of the caregivers had a high school education or less. Thirty-two participant families (78%) transmitted medication adherence data; of caregivers who completed the acceptability survey, 25 (96%) chose to receive daily reminders beyond that study interval. Secondary outcome analyses demonstrated similar average daily adherence between groups (intervention = 36%; control = 32%, P = 0.73). Three adherence trajectories were identified with none ever exceeding 80% adherence. CONCLUSIONS: Within a high risk pediatric cohort, electronic monitoring of ICS use and adherence reminders delivered via text message were feasible for most participants, but there was no signal of effect. Adherence trajectories following severe exacerbation were suboptimal, demonstrating an important opportunity for asthma care improvement. PMID- 29437491 TI - Human Donor Milk or Formula: A Qualitative Study of Maternal Perspectives on Supplementation. AB - BACKGROUND: Breastfeeding is fundamental to maternal and child health and is the most cost-effective intervention to reduce child mortality. Pasteurized human donor milk (HDM) is increasingly provided for term newborns requiring temporary supplementation. Few studies examine maternal perspectives on supplementation of term newborns. MATERIALS AND METHODS: We conducted semistructured in-person interviews with mothers of term newborns (n = 24) during postpartum hospitalization. Mothers were asked whether they had chosen or would choose to supplement with HDM versus infant formula, if medically indicated, and why. Data were gathered to saturation and analyzed inductively by consensus. Emerging semantic themes were compared between mothers who chose or would choose HDM and those who chose or would choose infant formula. RESULTS: Most mothers had concerns about HDM, including uncertainty regarding screening and substances passed through HDM. Experiences with prior children influenced decision-making. Mothers who chose or would choose HDM (56%, n = 14) praised it as "natural," and some felt suspicious of infant formula as "synthetic." Mothers who chose or would choose infant formula (44%, n = 10) did not know enough about HDM to choose it, and many viewed infant formula as a short-term solution to supply concerns. Mothers unanimously mistrusted online milk purchasing sources, although the majority felt positively about using a friend or family member's milk. CONCLUSIONS: Counseling regarding term newborn supplementation should focus on HDM education, specifically on areas of greatest concern and uncertainty such as donor selection, screening, transmission of substances, and mother's milk supply. Research is needed to assess the long-term impact of attitudes and choices on breastfeeding. PMID- 29437490 TI - H2 Receptor Antagonist Use and Mortality in Pulmonary Hypertension: Insight from the VA-CART Program. PMID- 29437492 TI - The Experience of Adolescents and Young Adults Treated for Cancer in an Adult Setting: A Review of the Literature. AB - The purpose of this review is to explore the literature on the experience of adolescents and young adults (AYAs) having cancer treatment in an adult setting, rather than on a specialist adolescent cancer unit. The integrative review method was used to explore the current literature. Primary research on the topic was located systematically and then synthesized into a thematic narrative. The experience of AYAs undergoing treatment in an adult setting was generally negative. This can be attributed to three themes: feeling isolated in the adult setting; the lack of empathy from staff working in the adult setting; and the inappropriateness of the adult environment for this age group. As many AYAs with cancer will continue to have treatment in adult settings, staff working in this environment should be aware of the negative experience of this cohort and the impact this can have on a vulnerable group of patients. Staff could consider simple ways of improving the AYA experience, such as connecting AYA patients with their peers to reduce isolation; adapting their approach to take account of the unique emotional needs of this age group; and considering ways of making the environment more welcoming and age-appropriate. PMID- 29437493 TI - Identification of Five Novel Variants in Chinese Oculocutaneous Albinism by Targeted Next-Generation Sequencing. AB - BACKGROUND: The diagnosis of oculocutaneous albinism (OCA) is established using clinical signs and symptoms. OCA is, however, a highly genetically heterogeneous disease with mutations identified in at least nineteen unique genes, many of which produce overlapping phenotypic traits. Thus, differentiating genetic OCA subtypes for diagnoses and genetic counseling is challenging, based on clinical presentation alone, and would benefit from a comprehensive molecular diagnostic. AIM: To develop and validate a more comprehensive, targeted, next-generation sequencing-based diagnostic for the identification of OCA-causing variants. MATERIALS AND METHODS: The genomic DNA samples from 28 OCA probands were analyzed by targeted next-generation sequencing (NGS), and the candidate variants were confirmed through Sanger sequencing. RESULTS: We observed mutations in the TYR, OCA2, and SLC45A2 genes in 25/28 (89%) patients with OCA. We identified 38 pathogenic variants among these three genes, including 5 novel variants: c.1970G>T (p.Gly657Val), c.1669A>C (p.Thr557Pro), c.2339-2A>C, and c.1349C>G (p.Thr450Arg) in OCA2; c.459_470delTTTTGCTGCCGA (p.Ala155_Phe158del) in SLC45A2. CONCLUSION: Our findings expand the mutational spectrum of OCA in the Chinese population, and the assay we developed should be broadly useful as a molecular diagnostic, and as an aid for genetic counseling for OCA patients. PMID- 29437494 TI - Targeted Next-Generation Sequencing Reveals a Novel Frameshift Mutation in the MERTK Gene in a Chinese Family with Retinitis Pigmentosa. AB - BACKGROUND: Retinitis pigmentosa (RP) is a group of inherited retinal diseases that result in severe progressive visual impairment. AIMS: The purpose of this article was to apply targeted next-generation sequencing (NGS) to identify the causative mutation in a Chinese RP family. METHODS: Blood samples were collected from a Chinese proband diagnosed with RP and her family members. A total of 163 genes that have been previously found to be involved in inherited retinal diseases were selected for NGS. Rigorous NGS data analysis; Sanger sequencing validation; and segregation analysis were applied to evaluate a novel frameshift mutation. RESULTS: Sequence analysis revealed that the proband and her affected sister both carried a novel homozygous frameshift mutation in MERTK (p.I103Nfs*4). Other family members carrying a heterozygous mutation were unaffected. This mutation was found to cosegregate with the disease phenotype in this family. This mutation was not found in 1,000 control individuals. CONCLUSIONS: The targeted NGS strategy employed provides an efficient tool for RP pathogenic gene detection. This study identified a new autosomal recessive mutation in the RP-related gene MERTK, which expands the spectrum of RP disease causing mutations. PMID- 29437495 TI - Incidence of Endophthalmitis after Intravitreal Injections: Risk Factors, Microbiology Profile, and Clinical Outcomes. AB - PURPOSE: To report the incidence and characteristics of endophthalmitis after intravitreal injections (IVI) of antivascular endothelial growth factor agents and triamcinolone acetonide. METHODS: Patients' medical records were retrospectively reviewed from January 2009 to June 2016, and the incidence, risk factors, clinical and microbiological characteristics of post-IVI endophthalmitis were evaluated. RESULTS: The total number of intravitreal injections given, which included ranibizumab, bevacizumab, and triamcinolone acetonide, was 20,566, of which 27 cases developed endophthalmitis, giving an overall incidence of 0.131%. Significant reduction (p < 0.003) in incidence of endophthalmitis was observed in patients who received prefilled compounded bevacizumab injections (0.050%) compared to multiple bevacizumab injections from a single vial (0.235%). In the triamcinolone acetonide group, the incidence was 0.26%. Staphylococcus species were isolated from 18 cases (67%), and all strains were sensitive to vancomycin. CONCLUSIONS: Adherence to strict aseptic protocols and use of prefilled compounded bevacizumab injections reduces the rate of post-IVI endophthalmitis. PMID- 29437496 TI - Essential oil of Croton Zehntneri attenuates lung injury in the OVA-induced asthma model. AB - OBJECTIVE: Croton zehntneri Pax et Hoffm. is a Euphorbiaceae species, popularly known as "canela de cunha," a native plant of northeastern Brazil, whose essential oil (EOCZ) shows relatively specific myorelaxant action for the smooth muscle of the airways and in the respiratory tract. Based on this information, EOCZ figures as a candidate for testing in the treatment of asthma, and the present study investigated the benefits of using EOCZ in an ovalbumin-induced asthma model. METHODS: 48 male BALB/c mice were divided into six groups (n = 8). In the ST, SO100, and SO300 groups, mice were sensitized and challenged with saline, and then treated with 200 uL of 0.1% Tween 80, 100 mg/kg EOCZ and 300 mg/kg EOCZ, respectively. In the OT, OO100, and OO300 groups, mice were sensitized and challenged with OVA, and then treated with 200 uL of 0.1% Tween 80, 100 mg/kg EOCZ and 300 mg/kg EOCZ, respectively. RESULTS: Our results demonstrated significant changes in all respiratory mechanics variables analyzed between the OO300 and OT groups demonstrating the effectiveness of EOCZ to attenuate the OVA-induced lung injury. In addition, the use of EOCZ at a dose of 300 mg/kg showed an antioxidant effect and decreased inflammatory cells in the pulmonary parenchyma. In conclusion, our results demonstrated that EOCZ was able to improve the lesion in the respiratory system of mice subjected to OVA-induced asthma. CONCLUSIONS: The antioxidant action of EOCZ was likely the main mechanism of action in the reversal of this lesion, so more tests should be performed for its confirmation. PMID- 29437497 TI - Competency-Based Training and Simulation: Making a "Valid" Argument. AB - The use of simulation as an assessment tool is much more controversial than is its utility as an educational tool. However, without valid simulation-based assessment tools, the ability to objectively assess technical skill competencies in a competency-based medical education framework will remain challenging. The current literature in urologic simulation-based training and assessment uses a definition and framework of validity that is now outdated. This is probably due to the absence of awareness rather than an absence of comprehension. The following review article provides the urologic community an updated taxonomy on validity theory as it relates to simulation-based training and assessments and translates our simulation literature to date into this framework. While the old taxonomy considered validity as distinct subcategories and focused on the simulator itself, the modern taxonomy, for which we translate the literature evidence, considers validity as a unitary construct with a focus on interpretation of simulator data/scores. PMID- 29437498 TI - Association of WNT Pathway Genes With Nonsyndromic Cleft Lip With or Without Cleft Palate. AB - OBJECTIVE: Nonsyndromic cleft lip with or without cleft palate (NSCL+/-P) is a common craniofacial anomaly with multifactorial etiology. Evidence suggests that variations in WNT pathway genes contribute to an increased susceptibility to NSCL+/-P. The aim of this study was to investigate the association of AXIN1, APC, CTNNB1, DVL2, and GSK3beta gene variants with NSCL+/-P in a case-control data set from Brazil. PATIENTS: 471 individuals with NSCL+/-P and 504 unrelated control individuals of Caucasian ethnicity. DESIGN: Twenty single-nucleotide polymorphisms (SNPs) in/nearby AXIN1, APC, CTNNB1, DVL2, and GSK3B genes were genotyped using Taqman chemistry in a Viia7 sequence detection instrument. Genotype, allele, and haplotype frequencies were compared among NSCL+/-P patients and controls using Fisher exact test, implemented in PLINK software. The level of significance was established at P <=.002 under Bonferroni correction. In silico analysis of SNP function was assessed using MirSNP database. RESULTS: Significant association was found between GSK3B rs13314595 genotypes and NSCL+/-P ( P = .0006). Additionally, nominal associations were found between DVL2 (rs35594616) and APC (rs448475) with NSCL+/-P ( P = .02 and P = .03, respectively). SNP haplotypes for GSK3B and APC genes showed nominal associations with NSCL+/-P ( P < .05). In silico analysis predicted that APC rs448475 harbors a binding site for the microRNA miR-617 and that the switch from a G allele to C allele enhances binding, whereas DVL2 rs35594616 did not appear to harbor microRNA-binding sites. CONCLUSION: This study shows for the first time the association between GSK3B and NSCL+/-P and confirms the role of additional WNT pathway genes as candidates for NSCL+/-P. PMID- 29437499 TI - Primer on State Statutory Mandates of Third-Party Orthodontic Coverage for Cleft Palate and Craniofacial Care in the United States. AB - Provision and timing of orthodontic treatment is a crucial part of comprehensive cleft palate and craniofacial care. Some states statutorily mandate orthodontic coverage for the medically necessary care of cleft palate and craniofacial anomalies. However, application of the medically necessary standard varies broadly. Disputes over medical necessity lead to orthodontic coverage denials and surgical intervention delays. Provider-friendly statutory definitions of medical necessity enable patients and providers to avoid such hurdles. The objective of this study is to evaluate state mandates and highlight language favorable to patients and providers. PMID- 29437500 TI - Use of the Sphenoid Flap in Repair of the Wide Cleft Palate. AB - OBJECTIVE: In wide palatal defects, closure of the nasal layer can prove a considerable challenge. Mobilizing nasal flaps posteriorly usually facilitates soft palate closure. However, the defect is often too wide within the hard palate; hence, bilateral vomerine flaps are frequently required. Despite this, there is often a small defect in the nasal layer at the posterior septum (typically equating to the hard-soft palate junction), which has to be left to heal by secondary intention with the resulting increased risk of fistula formation and the potential deleterious long-term effect on speech due to cicatricial migration of the reconstructed levator sling anteriorly. We describe our experience in the use of the sphenoid flap to obtain tension-free primary closure of the nasal layer. METHODS: A retrospective multi-center study assessing all sphenoid flap procedures undertaken at both Birmingham Children's Hospital and Great Ormond Street Hospital. Key demographic and medical data was collected pre-, peri-, and postoperatively across the 2 sites. RESULTS: A total of 66 patients underwent the use of a sphenoid flap to aid closure of the nasal layer. The average age at time of repair was 9.7 months. More than half (55%, n = 36) were isolated cleft palates, and 35% (n = 23) were BCLPs. Forty-two percent of all patients had Robin sequence. The average cleft width was 14.4 mm. The overall fistula rate was 25.8% (n = 17). CONCLUSIONS: We describe the operative technique, indications, and our experience in the use of the sphenoid flap in wide cleft palate repair. PMID- 29437501 TI - The Significance of Uvula After Palatoplasty: A New Technique to Improve the Aesthetic Outcome. AB - OBJECTIVE: This study aims to examine the importance of the uvula as a part of palatoplasty outcome and to assess the aesthetic results of the conventional versus a new technique for uvuloplasty. DESIGN/PARTICIPANTS: The study included 2 groups of patients undergoing palatoplasty. Group I consisted of 20 cleft palate patients repaired with the conventional uvula repair, combining the 2 hemi uvulae. Group II consisted of 20 patients repaired with our new technique, sacrificing one hemi-uvula and centralizing the remaining one. The aesthetic outcome was assessed in both groups. A questionnaire was distributed to the families of both groups to assess their concern about the uvula after palate repair. SETTING: Cleft unit at a tertiary care center. RESULTS: Sixty-five percent of parents considered the uvula as important functionally and aesthetically after palate repair whereas 35% either did not care or were not sure about its importance. Results of the aesthetic outcome of the 2 techniques for uvula reconstruction showed that uvula was absent in 4 cases in group I versus 1 in group II ( P > .05), small in 8 cases of group I versus 4 in group II ( P > .05), bifid in 5 cases of group I versus none in group II ( P < .05), became deviated in no case of group I versus 4 in group II ( P > .05), and was satisfactory in 3 cases of group I versus 11 in group II ( P < .05). CONCLUSIONS: Among the respondents, the uvula was a significant concern to the parents of cleft patients and should be given more attention during repair. The described technique had better aesthetic outcome over the conventional one of combining the 2 hemi-uvulae. PMID- 29437502 TI - Should Children With Cleft Palate Receive Early Long-Term Tympanostomy Tubes: One Institution's Experience. AB - OBJECTIVES: To determine whether children with cleft palate might benefit from early long-term tympanostomy tubes with the hypothesis that receiving multiple tubes is associated with shorter duration of first tubes. DESIGN: Retrospective cohort study. SETTING: Tertiary care children's hospital. PARTICIPANTS: Records from 401 consecutive children with cleft palate +/- cleft lip, born April 2005 to April 2010, were reviewed. After exclusion of children with cleft repair at an outside hospital, no follow-up after 5 years of age, intact secondary palate, no tubes, or tube replacement at palatoplasty, 105 children remained. MAIN OUTCOME MEASURE: Number of tubes. RESULTS: Armstrong grommet tubes were placed at a median age of 6.7 months (range 2.3-19.6 months). Tubes were replaced in 55.3% of patients, with 34.0% receiving >=3 sets. Duration of first tubes was significantly longer for children with 1 set of tubes compared with those with multiple sets (median 26 vs 19 months, P = .004). Otorrhea, but not perforation, was associated with longer duration of first tubes (median 27 vs 20.5 months, P = .028). Cleft type did not impact the proportion of patients with multiple tubes. Median age at last tube placement for children with multiple tubes was 5.0 years (range 1.9-8.7 years). CONCLUSION: Short duration of first tubes is associated with receiving multiple tubes. Because most patients require repeat tubes and many require tubes until school age, there is a significant need for controlled, prospective trials of early long-term tube placement in this population. PMID- 29437503 TI - A Novel Treatment of Nasal Stenosis Using Steel Gauging Earrings. AB - Nasal stenosis is an uncommon and challenging deformity. Most common etiologies for nasal stenosis include congenital, iatrogenic, trauma, and infection. Repair techniques typically include tissue replacement with grafts or flaps with subsequent stent placement. These procedures often require general anesthesia and carry high rates of restenosis. We describe a case of a 10-year-old girl with Teebi syndrome and iatrogenic nasal stenosis who underwent successful nasal dilation with inexpensive, minimally invasive steel gauge earrings. PMID- 29437504 TI - Surgery for Velopharyngeal Dysfunction: A Systematic Review of Interventions and Outcomes. AB - OBJECTIVE: This systematic review sought to evaluate the consensus in the literature regarding the surgical management of VPD and to determine whether a particular procedure results in superior speech outcome or less morbidity Design: A systematic review was carried out according to PRISMA-P guidelines. Systematic review software was used to facilitate 3-stage screening and data extraction by 2 reviewers. SETTING: University teaching hospital. PATIENTS, PARTICIPANTS: Studies that reported perceptual speech assessment or obstructive sleep apnea (OSA) in patients who had undergone surgery for VPD were included in the review. INTERVENTIONS: Four categories of surgery for VPD were examined-pharyngeal flap, sphincter pharyngoplasty, palatoplasty, and posterior pharyngeal wall augmentation. MAIN OUTCOME MEASURES: Perceptual speech assessment, need for further surgery, and occurrence of OSA were the outcomes of interest. RESULTS: Eighty-three relevant studies were identified, comprising data on 4011 patients. Pharyngeal flap was the most common procedure (64% of patients). Overall, 70.7% of patients attained normal resonance and 65.3% attained normal nasal emission. There was no notable difference in speech outcomes, need for further surgery, or occurrence of OSA across the 4 categories of surgery examined. Heterogeneous groups of patients were reported upon and a variety of perceptual speech assessment scales were used. CONCLUSIONS: There is a lack of consensus in the literature to guide procedure selection for patients with VPD. The development of a standardized minimum data set to record postoperative speech, OSA, and patient reported outcomes is required. PMID- 29437505 TI - Cleft Skeletal Asymmetry: Asymmetry Index, Classification and Application. AB - OBJECTIVE: To quantitatively measure the extent of 3D asymmetry of the facial skeleton in patients with unilateral cleft lip and palate (UCLP) using an asymmetry index (AI) approach, and to illustrate the applicability of the index in guiding and measuring treatment outcome. METHOD: Two groups of subjects between the ages of 15 and 20 who had archived CBCT scan were included in this study. Twenty-five patients with complete UCLP were compared with 50 age-matched noncleft subjects. The CBCT scans were segmented and landmarked for 3D anthropometric analysis. An AI was calculated as a quantitative measure of the extent of facial skeletal asymmetry. RESULTS: For the control group, the AI ranged from 0.72 +/- 0.47 at A point to 4.77 +/- 1.59 at Gonion. The degree of asymmetry increased with the increasing laterality of the landmark from the midsagittal plane. In the UCLP group, the values of AI significantly increased compared to the control group at nearly all measured landmarks. The extent of the asymmetry to involve the upper, middle, and lower facial skeleton varied widely with the individual patient with UCLP. CONCLUSION: The asymmetry index is capable of capturing the 3D facial asymmetry of subjects with UCLP and as a basis for classification of the extent of the asymmetry. We found the index to be applicable in surgical planning and in measuring the outcome in improving the symmetry in patients who have undergone orthognathic surgery. PMID- 29437506 TI - Speech and Surgical Outcomes in Children With Veau Types III and IV Cleft Palate: A Comparison of Internationally Adopted and Nonadopted Children. AB - OBJECTIVE: This study compares speech and surgical outcomes in internationally adopted and nonadopted patients undergoing cleft palate repair, and examines the influence of age at initial palatoplasty. DESIGN: Retrospective cohort study setting: Tertiary Care Children's Hospital. PATIENTS: 70 international adoptees and 211 nonadoptees with Veau type III and IV clefts (without associated syndrome) repaired at our institution. OUTCOME MEASURES: Outcomes included VPI, compensatory misarticulations, intelligibility, nasal air emission, oronasal fistula, and secondary speech surgery. Speech evaluations completed near 5 years of age were gathered from a prospectively collected database. RESULTS: Adoptees underwent palatoplasty 5.2 months after arrival, a mean of 10.4 months later than nonadoptees. Adoptees were significantly more likely to develop moderate/severe VPI and trended toward more frequent need for secondary speech surgery. Oronasal fistula occurred at similar rates. Increased age at initial palatoplasty was a significant predictor of moderate to severe VPI, and need for secondary speech surgery. CONCLUSIONS: International adoptees undergo palatoplasty 10.4 months later than nonadoptees and are significantly more likely to develop moderate/severe VPI, with a trend toward increased secondary speech surgery. An association between treatment delay and moderate/severe VPI and secondary speech surgery has been demonstrated. While a causal relationship between delayed repair and inferior outcomes in international adoptees has not been proven, this data suggests that surgical intervention upon unrepaired cleft palates soon after adoption may be beneficial. The opportunity for a change in practice exists, as half of the 10.4-month relative delay in palate repair occurs postadoption. PMID- 29437507 TI - An Innovative Collaborative Treatment Model: The Community-Based Speech-Language Pathologist and Cleft Palate Team. PMID- 29437508 TI - What Matters to Patients With Cleft Lip and/or Palate: An International Qualitative Study Informing the Development of the CLEFT-Q. AB - OBJECTIVE: The goal of treatment for individuals with cleft lip and/or palate (CL/P) is to improve physical, psychological, and social health. Outcomes of treatment are rarely measured from the patient's perspective. The aim of the study was to develop a conceptual framework for a patient-reported outcome (PRO) instrument for individuals with clefts (CLEFT-Q) by developing an in-depth understanding of issues that individuals consider to be important. DESIGN: The qualitative methodology of interpretive description was used. Setting, Participants, and Intervention: We performed 136 individual in-depth interviews with participants with clefts of any age, presenting for cleft care, across 6 countries. Parents were involved if the child was more comfortable. Interviews were audio-recorded, transcribed verbatim, and coded using constant comparison. The data were used to develop a refined conceptual framework. RESULTS: Participants described concepts of interest in 3 top-level domains, each of which included subdomains: appearance (face, nose, nostrils, teeth, lips, jaw, cleft lip scar), health-related quality of life (psychological, social, school, speech related distress), and facial function (speech, eating/drinking). Participants were able to describe changes over time with regard to the 3 domains. CONCLUSIONS: A conceptual framework of concepts of interest to individuals with CL/P formed the basis of the scales in the CLEFT-Q. Each subdomain represents an independently functioning scale. Understanding what matters to patients is essential in guiding PRO measurement. PMID- 29437509 TI - 3D-Printed Models of Cleft Lip and Palate for Surgical Training and Patient Education. AB - BACKGROUND: Sculpted physical models and castings of the anatomy of cleft lip and palate are used for parent, patient, and trainee education of cleft lip and palate conditions. In this study, we designed a suite of digital 3-dimensional (3D) models of cleft lip and palate anatomy with additive manufacturing techniques for patient education. METHODS: CT scans of subjects with isolated cleft palate, unilateral and bilateral cleft lip and palate, and a control were obtained. Soft tissue and bony structures were segmented and reconstructed into digital 3D models. The oral soft tissues overlying the cleft palate were manually molded with silicone putty and scanned using CT to create digital 3D models. These were then combined with the original model to integrate with segmentable soft tissues. Bone and soft tissues were 3D printed in different materials to mimic the rigidity/softness of the relevant anatomy. These models were presented to the parents/patients at our craniofacial clinic. Visual analog scale (VAS) surveys were obtained pertaining to the particular use of the models, to ascertain their value in parental education. RESULTS: A total of 30 parents of children with cleft conditions completed VAS evaluations. The models provided the parents with a better understanding of their child's condition with an overall evaluation score of 9.35 +/- 0.5. CONCLUSIONS: We introduce a suite of 3D-printed models of cleft conditions that has a useful role in patient, parental, and allied health education with highly positive feedback. PMID- 29437510 TI - Factors Predicting Hospital Length of Stay Following Pharyngeal Flap for Velopharyngeal Insufficiency. AB - OBJECTIVE: Routine hospital admission following pharyngeal flap (PF) to correct velopharyngeal insufficiency (VPI) is the standard at most hospitals. Nevertheless, there is increasing resistance from third-party providers to approve stays longer than a "short stay" (23-hour) observation period. The purpose of the current study was to evaluate length of stay (LOS) and document potential influencing factors following PF. DESIGN: Retrospective chart review. Demographic and perioperative data were collected, and statistical analyses were performed to determine associations with hospital length of stay (LOS). Readiness for discharge was determined by oral intake, analgesic requirement, and respiratory status. SETTING: Tertiary care children's hospital Participants: All patients undergoing PF for VPI between 1990 and 2014. OUTCOME MEASURES: (1) LOS, (2) % satisfying all discharge criteria within a 23-hour observational time frame. RESULTS: Seventy-five patients were studied, with an average age of 6.8 years. Mean LOS was 65.4 hours. Only 11 patients (14.9%) met all discharge criteria by 23 hours. Multivariate predictors of shorter LOS were increasing patient age, male gender, lack of syndromic association, administration of an intraoperative antiemetic and steroids, and shorter anesthetic duration. Time to first oral intake correlated positively with LOS. Administration of intraoperative antiemetics increased the odds of meeting all discharge criteria within 23 hours by a factor of 12. CONCLUSIONS: Identification of factors associated with LOS after PF may allow providers to predict and potentially mitigate hospital stays. Nevertheless, most patients undergoing PF are not clinically ready for discharge within a short-stay (23-hour) observation period. PMID- 29437511 TI - Computer Simulation and Optimization of Cranial Vault Distraction. AB - OBJECTIVE: The objective of this study was to validate the proof of concept of a computer-simulated cranial distraction, demonstrating accurate shape and end volume. DESIGN: Detailed modeling was performed on pre- and postoperative computed tomographic (CT) scans to generate accurate measurements of intracranial volume. Additionally, digital distraction simulations were performed on the preoperative scan and the resultant intracranial volume and shape were evaluated. SETTING: Tertiary Children's Hospital. PATIENTS, PARTICIPANTS: Preoperative and postoperative CT images were used from 10 patients having undergone cranial distraction for cephalocranial disproportion. INTERVENTIONS: None; computer simulation. MAIN OUTCOME MEASURE: Computer simulation feasibility of cranial vault distraction was demonstrated through creation of digital osteotomies, simulating distraction through translating skull segments, followed by simulated consolidation. Accuracy of the model was evaluated through comparing the intracranial volumes of actual and simulated distracted skulls. RESULTS: The developed digital distraction simulation was performed on the CT images of 10 patients. Plotting the relationship between the actual and simulated postdistraction volumes for the 10 patients yielded a slope of 1.0 and a correlation coefficient of 0.99. The average actual resultant volume change from distraction was 77.0 mL, compared to a simulated volume change of 76.9 mL. CONCLUSIONS: Digital simulation of cranial distraction was demonstrated through manipulation of the CT images and confirmed by comparing the actual to simulated volume change. This process may provide objective data in designing an individual distraction plan to optimize volume expansion and resultant cranial shape as well as patient education. PMID- 29437512 TI - Observation of Cleft Palate in an Individual with SOX11 Mutation: Indication of a Role for SOX11 in Human Palatogenesis. AB - OBJECTIVE: Point mutations and deletions within the SOX11 gene have recently been described in individuals with a rare variant of Coffin-Siris syndrome, OMIM 615866, an intellectual disability syndrome with associated features of nail hypoplasia, microcephaly, and characteristic facial features including a wide mouth and prominent lips. PARTICIPANT: We describe a further patient with a mutation in SOX11 and phenotype resembling mild Coffin-Siris syndrome. RESULTS: This boy had a cleft palate, a feature not previously seen in other patients with SOX11 mutations. CONCLUSION: We discuss This adds to the current evidence that SOX11 is a gene involved in palatogenesis. PMID- 29437513 TI - Cleft Lip and Palate in CHARGE Syndrome: Phenotypic Features That Influence Management. AB - OBJECTIVE: Infants with syndromic cleft lip and/or cleft palate (CL/P) often require more complex care than their nonsyndromic counterparts. Our purpose was to (1) determine the prevalence of CL/P in patients with CHARGE syndrome and (2) highlight factors that affect management in this subset of children. DESIGN: This is a retrospective review from 1998 to 2016. PATIENTS: Patients with CHARGE syndrome were diagnosed clinically and genetically. MAIN OUTCOMES MEASURES: Prevalence of CL/P was determined and clinical details tabulated: phenotypic anomalies, cleft types, operative treatment, and results of repair. RESULTS: CHARGE syndrome was confirmed in 44 patients: 11 (25%) had cleft lip and palate and 1 had cleft palate only. Surgical treatment followed our usual protocols. Two patients with cardiac anomalies had prolonged recovery following surgical correction, necessitating palatal closure prior to nasolabial repair. One of these patients was too old for dentofacial orthopedics and underwent combined premaxillary setback and palatoplasty, prior to labial closure. Velopharyngeal insufficiency was frequent (n = 3/7). All patients had feeding difficulty and required a gastrostomy tube. All patients had neurosensory hearing loss; anomalies of the semicircular canals were frequent (n = 3/4). External auricular anomalies, colobomas, and cardiovascular anomalies were also common (n = 8/11). Other associated anomalies were choanal atresia (n = 4/11) and tracheoesophageal fistula (n = 2/11). CONCLUSIONS: CHARGE syndrome is an under-recognized genetic cause of cleft lip and palate. Hearing loss and speech and feeding difficulties often occur in these infants. Diagnosis can be delayed if the child presents with covert phenotypic features, such as chorioretinal colobomas, semicircular canal hypoplasia, and unilateral choanal atresia. PMID- 29437514 TI - Reliability of Oronasal Fistula Classification: Methodological Issue. PMID- 29437515 TI - Association Between CRISPLD2 Polymorphisms and the Risk of Nonsyndromic Clefts of the Lip and/or Palate: A Meta-analysis. AB - OBJECTIVE: Nonsyndromic clefts of the lip and/or palate (NSCL/P) are one of the most common polygenic diseases. Recently, many studies focused on the association between CRISPLD2 polymorphisms and NSCL/P risk. However, some studies have shown opposite results. In this study, meta-analysis was used to confirm whether CRISPLD2 polymorphism was associated with NSCL/P, and the possible mechanism between CRISPLD2 and NSCL/P was explored. METHODS: Relevant studies were conducted on PubMed, Ovid, EBSCO, CINAHL, FMRS, Web of Science, CNKI, and Wanfang databases from their inception up to June 31, 2016. Review Manager 5.0.24 was used to analyze whether CRISPLD2 polymorphism was involved in NSCL/P by pooling odds ratios (ORs) and 95% confidence intervals (CIs). Potential publication bias was evaluated by visual inspection of the funnel plot. RESULTS: CRISPLD2 rs4783099 was associated with cleft lip and/or palate (CL/P) statistically (OR = 3.18, P < .01). Compared to genotype TT, genotypes CC and CT were correlated significantly (OR = 2.04, P = .04) with CL/P. No evidence showed an association between genetic variation at the CRISPLD2 locus and cleft palate only (CP). CONCLUSION: The polymorphism of CRISPLD2 rs4783099 is correlated with an increased risk of CL/P. PMID- 29437516 TI - Ideal Versus Late Secondary Alveolar Bone Graft Surgery: A Bone-Thickness Cone Beam Computed Tomographic Assessment. AB - OBJECTIVE: To compare the bone morphology after secondary alveolar bone graft surgery (SABG) performed before and after permanent canine eruption. DESIGN: Cross-sectional study. SETTING: Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo, Bauru, SP, Brazil. PATIENTS: 25 cone-beam computed tomography (CBCT) scans of complete unilateral cleft lip and palate (CLP) individuals who underwent SABG before or after eruption of the permanent canine taken 2 and 6 months (T1 and T2) after SAGB, resulting in 50 CBCT scans. Two groups were assessed, Ideal Group (IG; n = 10) and Late Group (LG; n = 15), according to the time of the SABG. INTERVENTIONS: SABG buccal-palatal thicknesses were measured in 3 different root levels: cement-enamel junction (cervical slice), middle point of the root (intermediate slice), and apex of the central incisor (apical slice). Thickness measurements were assessed in the mesial, distal, and intermediate aspects of the alveolar bone graft. Clinical long-term follow-up was also done. RESULTS: The IG showed significantly greater bone thickness, especially in the intermediate and apical slices, when compared to LG, in T1 and T2. Bone thickness was maintained over time. Clinically, all the IG individuals completed orthodontics, and no major complications were observed. In contrast, 27% of the LG individuals had failures, and rehabilitation was achieved through prosthesis. CONCLUSION: Ideal SABG presents with better results compared with late ABG. When it is not possible to perform SABG at the ideal time, acceptable outcomes still can be expected for late bone grafting. PMID- 29437517 TI - The Temporal Region in Unilateral Coronal Craniosynostosis: Fronto-orbital Advancement Versus Endoscopy-Assisted Strip Craniectomy. AB - OBJECTIVE: To compare postoperative temporal expansion in patients treated with fronto-orbital advancement or endoscopy-assisted craniectomy with cranial orthotic therapy. DESIGN: This is a retrospective, multicenter cohort study of patients with unilateral coronal craniosynostosis (UCS). SETTING: Computed tomographic (CT) scans were drawn from UCS patients treated at Boston Children's Hospital or St Louis Children's Hospital. PATIENTS: The study included 56 patients with UCS after fronto-orbital advancement (n = 32) or endoscopic repair (n = 24) and 10 age-matched controls. INTERVENTION: Fronto-orbital advancement entails a craniotomy of the frontal bone and superior orbital rim followed by reshaping and forward advancement. Endoscopic repair is the release of the synostotic suture and guidance of further growth of the cranium using a molding orthotic. MAIN OUTCOME MEASURES: Measures included posterior temporal width, anterior temporal width, orbital width, and anterior cranial fossa area taken preoperatively and 1 year postoperatively. Linear regression was performed to assess 1 year postoperative improvement in symmetry; covariates included preoperative symmetry and type of surgery. RESULTS: Both treatments showed improvement in orbital width and anterior cranial fossa area symmetry 1 year postoperatively ( P < .001), but no significant improvement in posterior or anterior temporal width symmetry. Linear regression revealed no difference between the 2 procedures in any of the 4 measurements (.096 <= P <= .898). CONCLUSIONS: Fronto-orbital advancement and endoscopic repair show equivalent outcomes 1 year postoperatively in all 3 width measurements and anterior cranial fossa area. Neither procedure produced significant improvement in temporal width. PMID- 29437518 TI - Safety and Efficacy Concerns of Autologous Fat Grafting for Velopharyngeal Insufficiency. AB - OBJECTIVE: Autologous fat grafting of the velopharynx has been well described for the treatment of velopharyngeal insufficiency (VPI), with most studies purporting it as a technique with low morbidity useful in the treatment of mild VPI. Prompted by 3 cases of obstructive sleep apnea (OSA) following fat grafting of the velopharynx, we undertook a review of the outcomes of this procedure at our unit. DESIGN: Retrospective case series. PARTICIPANTS: All patients who underwent autologous fat grafting for VPI at the Royal Children's Hospital Melbourne. MAIN OUTCOME MEASURES: Preoperative nasendoscopy findings, perceptual speech assessment results, and rates of revisional surgery and complications. RESULTS: Twenty-eight patients were included in the study. Three patients (11%) developed severe OSA requiring removal of the grafted fat. In a subanalysis of cleft patients, there was a reported improvement in hypernasality in 63% though only 25% had complete resolution of their hypernasality. Patients who had an improvement in speech were more likely to have a velopharyngeal gap of less than 0.5 cm2 on preoperative nasendoscopy. All 3 patients who developed OSA had syndromes associated with hypotonia. CONCLUSIONS: This study raises serious concerns over the safety and efficacy of fat grafting for VPI. Overall, there was a relatively high complication rate with generally poor speech results in our series of patients. Stringent criteria should be used to select candidates for fat grafting, namely, a velopharyngeal gap less than 0.5 cm2 and the absence of a syndrome associated with hypotonia. PMID- 29437519 TI - Molecular Analysis of Gli3, Ihh, Rab23, and Jag1 in a Rabbit Model of Craniosynostosis: Likely Exclusion as the Loci of Origin. AB - OBJECTIVE: Craniosynostosis (CS) involves the premature fusion of one or more cranial sutures. The etiology of CS is complex and mutations in more than 50 distinct genes have been causally linked to the disorder. Many of the genes that have been associated with CS in humans play an essential role in tissue patterning and early craniofacial development. Among these genes are members of the Hedgehog (HH) and Notch signal transduction pathways, including the GLI family member Gli3, Indian Hedgehog ( Ihh), the RAS oncogene family member Rab23, and the Notch ligand JAGGED1 ( Jag1). We have previously described a colony of rabbits with a heritable pattern of coronal suture synostosis, although the genetic basis for synostosis within this model remains unknown. The present study was performed to determine if coding errors in Gli3, Ihh, Rab23, or Jag1 could be causally linked to craniosynostosis in this unique animal model. DESIGN: Sequencing of cDNA templates was performed using samples obtained from wild-type and craniosynostotic rabbits. RESULTS: Several nucleotide polymorphisms were identified in Gli3, Ihh, and Rab23, although these variants failed to segregate by phenotype. No nucleotide polymorphisms were identified in Jag1. CONCLUSIONS: These data indicate that the causal locus for heritable craniosynostosis in this rabbit model is not located within the protein coding regions of Gli3, Ihh, Rab23, or Jag1. PMID- 29437521 TI - Randomness in DNA Encoded Library Selection Data Can Be Modeled for More Reliable Enrichment Calculation. AB - DNA Encoded Libraries (DELs) use unique DNA sequences to tag each chemical warhead within a library mixture to enable deconvolution following affinity selection against a target protein. With next-generation sequencing, millions to billions of sequences can be read and counted to report binding events. This unprecedented capability has enabled researchers to synthesize and analyze numerically large chemical libraries. Despite the common perception that each library member undergoes a miniaturized affinity assay, selections with higher complexity libraries often produce results that are difficult to rank order. In this study, we aimed to understand the robustness of DEL selection by examining the sequencing readouts of warheads and chemotype families among a large number of experimentally repeated selections. The results revealed that (1) the output of DEL selection is intrinsically noisy but can be reliably modeled by the Poisson distribution, and (2) Poisson noise is the dominating noise at low copy counts and can be estimated even from a single experiment. We also discuss the shortcomings of data analyses based on directly using copy counts and their linear transformations, and propose a framework that incorporates proper normalization and confidence interval calculation to help researchers better understand DEL data. PMID- 29437520 TI - Timing of Furlow Palatoplasty for Patients With Submucous Cleft Palate. AB - BACKGROUND: Submucous cleft palate (SMCP) is the most common form of cleft involving the posterior palate, resulting in variable degrees of velar dysfunction and speech disturbance. Although early surgical intervention is indicated for patients with true cleft palate, the indications for palatoplasty and timing of surgical intervention for patients with SMCP remain controversial. METHODS: Twenty-nine patients with SMCP were retrospectively reviewed. Patients treated with Furlow palatoplasty were dichotomized based on patient age at the time of surgical correction into early speech development and late speech development. Primary outcome measures included standardized assessments of hypernasal resonance and quantitative pre- and postoperative nasometry scores. Patients managed nonoperatively were included for comparison of early and late speech outcomes. RESULTS: Both early and late groups demonstrated improvement in qualitative assessment of hypernasal resonance following Furlow palatoplasty. Early and late groups also had significant improvement in pre- to postoperative nasometry scores from 7.4 to 2.3 SD from norm ( P = .01) and 6.0 to 3.6 SD from norm ( P = .02), respectively. There was no difference in postoperative nasometry scores between early and late groups, 2.3 and 3.6 SD ( P = .12). CONCLUSION: Furlow palatoplasty significantly improves the degree of hypernasality in patients with SMCP based on pre- and postoperative nasometry scores and on qualitative assessment of hypernasality. There were no differences in speech outcomes based on early compared with late operative intervention. Therefore, early palatal repair is not obligatory for optimal speech outcomes in children with SMCP and palatoplasty should be deferred until the emergence of overt velopharyngeal insufficiency. PMID- 29437522 TI - Inhibition of Human Papillomavirus Type 16 Infection Using an RNA Aptamer. AB - Human papillomavirus type 16 (HPV16) DNA has been found in ~50% of cervical tumors worldwide. HPV infection starts with the binding of the virus capsid to heparan sulfate (HS) receptors exposed on the surface of epithelial basal layer keratinocytes. Previously, our group isolated a high-affinity RNA aptamer (Sc5c3) specific for HPV16 L1 virus-like particles (VLPs). In this study, we report the inhibition of HPV16 infection by Sc5c3 in a pseudovirus (PsVs) model. 293TT cells were infected by HPV16 PsVs containing the yellow fluorescent protein (YFP) as reporter gene. Incubation of HPV16 PsVs with Sc5c3 before infection resulted in a dose-dependent decrease in YFP fluorescence, suggesting infection inhibition. Aptamer degradation by RNase A restored PsVs infectivity, supporting the previous observation that Sc5c3 aptamer can inhibit infection. VLP mutants with removed HS binding sites were used in binding assays to elucidate the Sc5c3 blocking mechanism; however, no binding difference was observed between wild-type and mutant VLPs, suggesting that pseudoinfection inhibition relies on mechanisms additional to electrostatic HS binding site interaction. A DNA/RNA Sc5c3 version also inhibited HPV PsVs infection, suggesting that a modified, nuclease-resistant Sc5c3 may be used to inhibit HPV16 infection in vivo. PMID- 29437523 TI - Risk and Age of Cardiovascular Event in Women with Metabolic Syndrome: Menopause Age in Focus. AB - BACKGROUND: There is still a controversy about the causal relationship between menopause status and cardiovascular disease (CVD). The present study aimed to evaluate whether premature menopause would predict higher risk and lower the age of CVD occurrence and how this differs in women with metabolic syndrome (MetS). METHODS: Using a population-based Isfahan Cohort Study (ICS), 1154 postmenopause women were followed up from 2001 to 2013 for any CVD occurrence. Cox proportional hazards regression analyses were used to estimate the association between menopause age of (<=45, 46-50, 51-55, >=56 years) and CVD incidence. The menopause age group of 46-50 years was considered as reference group. RESULTS: During 12 years follow-up, 235 CV events were recorded. The mean age of menopause (+/-standard deviation) was 48.06 +/- 5.48 years. The age at menopause was not predictive of total CV events, in women with and without MetS. In women without MetS, a trend with increasing incidence of stroke was observed at menopause age of <=45 years (age adjusted hazard ratio: 4.84, 95% confidence interval: 0.99 23.5, P = 0.05). Women with menopause age of <=45 years suffered from CV events, 5.7 years earlier than women with menopause age of >=56 years (P = 0.11); this difference was 5.3 years in women with MetS (P = 0.4). CONCLUSION: This study showed that younger age at menopause is not predictive of the occurrence of CV events. It also revealed that age at menopause is not associated with earlier CV events in postmenopause women, with and without MetS. PMID- 29437524 TI - Assessment of Nonresearch Industry Payments to Otolaryngologists in 2014 and 2015. AB - Objective To characterize, describe, and compare nonresearch industry payments made to otolaryngologists in 2014 and 2015. Additionally, to describe industry payment variation within otolaryngology and among other surgical specialties. Study Design Retrospective cross-sectional database analysis. Setting Open Payments Database. Subjects and Methods Nonresearch payments made to US otolaryngologists were characterized and compared by payment amount, nature of payment, sponsor, and census region between 2014 and 2015. Payments in otolaryngology were compared with those in other surgical specialties. Results From 2014 to 2015, there was an increase in the number of compensated otolaryngologists (7903 vs 7946) and in the mean payment per compensated otolaryngologist ($1096 vs $1242), as well as a decrease in the median payment per compensated otolaryngologist ($169 vs $165, P = .274). Approximately 90% of total payments made in both years were attributed to food and beverage. Northeast census region otolaryngologists received the highest median payment in 2014 and 2015. Compared with other surgical specialists, otolaryngologists received the lowest mean payment in 2014 and 2015 and the second-lowest and lowest median payment in 2014 and 2015, respectively. Conclusion The increase in the mean payment and number of compensated otolaryngologists can be explained by normal annual variation, stronger industry-otolaryngologist relationships, or improved reporting; additional years of data and improved public awareness of the Sunshine Act will facilitate determining long-term trends. The large change in disparity between the mean and median from 2014 to 2015 suggests greater payment variation. Otolaryngologists continue to demonstrate limited industry ties when compared with other surgical specialists. PMID- 29437525 TI - 3,5-Disubstituted Thiazolidine-2,4-Diones: Design, Microwave-Assisted Synthesis, Antifungal Activity, and ADMET Screening. AB - A series of 12 new thiazolidine-2,4-dione derivatives were obtained by microwave assisted synthesis. All compounds were physicochemically characterized by quantitative elemental C, H, N, S analysis and spectral data (mass spectrometry [MS], infrared [IR], and nuclear magnetic resonance [NMR]), with the results being in agreement with the expected data. An in vitro screening performed on Candida albicans ATCC 10231 showed their moderate antifungal activity, which was further investigated by determining the minimum inhibitory concentration and minimum fungicidal concentration values for the most active compounds on four strains of Candida. The molecular docking studies, performed against a fungal lanosterol 14alpha-demethylase, emphasized the importance of different molecular fragments in the compounds' structures for their antifungal activity. The synthesized compounds were subjected to in silico screening for the prediction of their absorption, distribution, metabolism, excretion, and toxicity (ADMET) and molecular properties. The results of the antifungal activity assays, docking study, and ADMET predictions revealed that the synthesized compounds are potential anti- Candida agents that might act by interacting with the fungal lanosterol 14alpha-demethylase and could be further optimized and developed as antifungal agents. PMID- 29437526 TI - Tracheotomy for Difficult Airway Foreign Bodies in Children. PMID- 29437527 TI - First victim, later aggressor: How the intestinal microbiota drives the pro inflammatory effects of dietary emulsifiers? AB - The intestinal tract is inhabited by a large and diverse community of bacteria, collectively referred to as the gut microbiota. Composed of 500-1000 distinct species, the intestinal microbiota plays an important role in immunity and metabolism. However, alterations in its composition are associated with a variety of inflammatory diseases including obesity, diabetes, and inflammatory bowel disease (IBD). Among many other factors, our diet impacts microbiota composition and function, in either beneficial or detrimental ways. In this addendum, we will discuss our recent findings on how dietary emulsifying agents can directly and detrimentally impact the microbiota, leading to inflammatory diseases and cancer. PMID- 29437528 TI - Impact of Surgical Site Infections on Elective Incisional Hernia Surgery: A Prospective Study. AB - BACKGROUND: Although incisional hernia repair is classified as a clean surgery, it still has a high incidence of surgical site infection (SSI) (0.7%-26.6%). The presence of an SSI could increase early recurrence rates after incisional hernia repair. PATIENTS AND METHODS: Patients undergoing elective incisional hernia repair with no bowel contamination between January and December 2015 were assessed prospectively. Demographic and surgical data, local post-operative complications, and one-year recurrence rates in patients with and without SSI were compared. The management of SSI was determined. RESULTS: Patients with SSI (16/101) showed more prolonged surgical procedures (91 +/- 39 vs. 63 +/- 30 min, p = 0.012), more post-operative sero-hematomas (38% vs. 8%, p = 0.001), and a higher one-year recurrence rate (19% vs. 4%, p = 0.047). Multivariable analysis revealed the only identified risk factor for SSI to be post-operative sero hematomas (p = 0.042; odds ratio [OR] = 4.17 [1.05-16.54]). Patients who developed an SSI required antibiotic agents and daily treatment from one to five months. One of these required the removal of the mesh. CONCLUSIONS: Surgical site infection rates are high for incisional hernia surgery (16%), and associated with local complications. Surgical site infection requires long-term treatments and leads to a higher one-year recurrence rate. PMID- 29437529 TI - Underutilization of Supplemental Magnetic Resonance Imaging Screening Among Patients at High Breast Cancer Risk. PMID- 29437530 TI - Endosomal Escape of Antisense Oligonucleotides Internalized by Stabilin Receptors Is Regulated by Rab5C and EEA1 During Endosomal Maturation. AB - Second-generation (Gen 2) Antisense oligonucleotides (ASOs) show increased nuclease stability and affinity for their RNA targets, which has translated to improved potency and therapeutic index in the clinic. Gen 2 ASOs are typically modified using the phosphorothioate (PS) backbone modification, which enhances ASO interactions with plasma, cell surface, and intracellular proteins. This facilitates ASO distribution to peripheral tissues and also promotes cellular uptake after injection into animals. Previous work identified that Stabilin receptors specifically internalize PS-ASOs in the sinusoidal endothelial cells of the liver and the spleen. By modulating expression of specific proteins involved in the trafficking and maturation of the endolysosomal compartments, we show that Rab5C and EEA1 in the early endosomal pathway, and Rab7A and lysobisphosphatidic acid in the late endosomal pathway, are important for trafficking of PS-ASOs and facilitate their escape from endolysosomal compartments after Stabilin-mediated internalization. In conclusion, this work identifies key rate-limiting proteins in the pathway for PS-ASO translocation and escape from the endosome. PMID- 29437531 TI - Improving Population Health Among Uninsured Patients with Diabetes. AB - Diabetes is a leading cause of morbidity and mortality; prevalence of diabetes is especially high in the southeastern United States among minority populations and those from lower socioeconomic sectors without access to health care services. The purpose of this project was to evaluate the clinical and financial outcomes of a nurse-led, interprofessional collaborative practice model that provides care coordination and transitional care for uninsured patients with diabetes. Data for this study were collected and evaluated from medical records of patients seen at the Providing Access to Health Care (PATH) Clinic between August 1, 2015, through May 30, 2017. Clinical outcomes were evaluated by comparing hemoglobin A1c (HbA1c) values before and after referral to the PATH Clinic. Cost savings to the academic medical center were evaluated by comparing costs associated with inpatient or emergency department encounters before and after referral to the PATH Clinic. A significant decrease in HbA1c (P < .0005) was noted for patients attending the PATH Clinic. In addition, financial analyses revealed a 55% decrease in pre to post PATH Clinic patients' direct costs. Similarly, a 42% decrease in the pre to post PATH Clinic patients' direct cost per encounter was noted. Average length of stay also was reduced when these patients were readmitted to the academic medical center. Results from this study support the effectiveness of the PATH Clinic model in caring for uninsured patients with clinically complex medical and social needs, often with behavioral health problems, who incur high health care spending and are often readmitted. PMID- 29437532 TI - Using a Dihydrofolate Reductase-Based Strategy for Producing the Biosimilar Version of Pertuzumab in CHO-S Cells. AB - Targeted therapy using monoclonal antibodies (mAbs) against epidermal growth factor receptor-2 (ErbB2) has been utilized for the treatment of breast cancer, recently. Pertuzumab, one of the anti-ErbB2 mAbs, was approved by FDA in 2012 for the treatment of metastatic breast cancer. The aim of this study was to produce biosimilar version of pertuzumab in Chinese hamster ovary (CHO)-S cell line, and compare its ErbB2-binding and biological activities, with commercial drug, Perjeta. To this end, a dihydrofolate reductase (DHFR)-based strategy was used to produce a CHO-S stable cell pool capable of producing high levels of pertuzumab. A two-phase selection strategy based on increasing concentrations of puromycin and MTX was used for selection of stably transfected cell pools. Finally, three stable CHO-S cell pools were achieved and analyzed for productivity in a simple fed-batch culture system. Results showed that, the pool with Puromycin to the final concentration of 50 MUg/mL and MTX to 1000 nM in the selection phase 2 produced and secreted the highest amount of mAb (442.578 mg/L at 8 days) to the culture medium. Assessment of in vitro ErbB2-binding and biological activities of produced pertuzumab revealed its high similarity with Perjeta. PMID- 29437533 TI - Effects of Continuous Gamma-Ray Exposure In Utero in B6C3F1 Mice on Gestation Day 18 and at 10 Weeks of Age. AB - Pregnant C57BL/6JJcl mice were exposed to gamma rays at low dose rate (20 mGy/day, LDR) or medium dose rate (200 and 400 mGy/day, MDR) from gestation day (GD) 0-18 to total accumulated doses of 360, 3,600 and 7,200 mGy, respectively. An additional group of pregnant mice were acutely exposed to 2 Gy at high dose rate (HDR) of 0.77 Gy/min on GD 11. In experiment 1, fetuses collected via cesarean section on GD 18 were examined for external and skeletal abnormalities. While the results of LDR exposure (20 mGy/day) did not significantly differ from the nonirradiated controls in all parameters examined, MDR (200 and 400 mGy/day) and acute HDR (2 Gy) exposure caused growth retardation and significantly increased incidence of unossified bones. Increased incidence of external abnormalities was observed only in the acute HDR group. In experiment 2, the dams were allowed to give birth and the pups were clinically monitored and weighed periodically until 10 weeks of age when they were sacrificed and subjected to pathological examination. Pups exposed at MDRs of 200 and 400 mGy/dayand at acute HDR of 0.77 Gy/min had lower bodyweights from weaning (3 weeks) to 10 weeks of age except for females exposed to 400 mGy/day MDR. None of the pups exposed to an acute 2 Gy dose on GD 11 survived to 10 weeks of age. Histopathological changes were not significantly different between the nonirradiated control and the 20 mGy/day LDR groups. However, at both MDR exposures of 200 and 400 mGy/day. gonadal (testes and ovary) hypoplasia/atrophy was observed in all the 10-week-old pups. Our results show that in utero LDR exposure to 20 mGy/day for the entire gestation period did not cause any significant effect in pups when compared to the nonirradiated controls up to 10 weeks of age. However, pups exposed in utero to MDRs showed dose-related growth retardation with delayed ossifications (400 mGy/day) and gonadal hypoplasia/atrophy. These findings suggest that increased post-implantation loss in dams exposed at MDR is due to early embryonic deaths resulting in early resorption. PMID- 29437534 TI - Oncolytic Virotherapy for Malignant Gliomas. PMID- 29437536 TI - Opioid Stewardship in Otolaryngology: State of the Art Review. AB - Objective The United States is facing an epidemic of opioid addiction. Deaths from opioid overdose have quadrupled in the past 15 years and now surpass annual deaths during the height of the human immunodeficiency virus epidemic. There is a link between opioid prescriptions after surgery, opioid misuse, opioid diversion, and use of other drugs of abuse. As surgeons, otolaryngologists contribute to this crisis. Our objective is to outline the risk of abuse from opioids in the management of acute postoperative pain in otolaryngology-head and neck surgery (OHNS) and strategies to avoid misuse. Data Sources PubMed/MEDLINE. Review Methods We conducted a review of the literature on the rate of opioid abuse after surgery, methods of safe opioid use, and strategies to minimize the dangers of opioids. Conclusions Otolaryngologists have a responsibility to treat pain. This begins preoperatively by discussing perioperative pain control and developing a personalized pain control plan. Patients should be aware that opioids carry significant risks of adverse events and abuse. Perioperative use of multimodal nonopioid agents enables pain control and avoidance of opioids in many otolaryngologic cases. When this approach is inadequate, opioids should be used in short duration under close surveillance. Institutional standards for opioid prescribing after common procedures can minimize misuse. Implications for Practice Otolaryngologists need to acknowledge the potential harm that opioids cause. It is essential that we evaluate our practices to ensure that opioids are used responsibly. Furthermore, opioid stewardship should become a priority in otolaryngology. PMID- 29437535 TI - Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors. AB - Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1-treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-gamma induced gene expression. Results A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced dose-limiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-gamma-associated genes from post SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response. Conclusion Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1-directed immunotherapy are warranted. PMID- 29437537 TI - Impact of Comprehensive Medication Management on Hospital Readmission Rates. AB - In 2012, the Fairview Health System implemented a formal care transitions process that included referrals to outpatient services provided by medication therapy management (MTM) pharmacists, among other clinical services. This analysis evaluates the impact of the MTM-provided comprehensive medication management (CMM) service on readmission rates. Retrospective electronic medical record (EMR) data were used to identify hospital admissions between December 1, 2012, and July 31, 2015. Thirty- and 60-day readmission rates were calculated in both a CMM and comparator cohort. Readmission rates also were stratified by readmission risk category. A total of 43,711 patients, contributing 57,673 hospitalizations, were included in the analysis. Of those, 1291 hospitalizations had a CMM visit within 30 days of discharge (median 6 days) and were considered the CMM cohort. Patients who received a CMM visit had a significantly lower rate of 30-day readmissions (8.6% vs. 12.8%, P < 0.001). The 60-day readmission rate remained lower among CMM patients but did not reach statistical significance (15.6% vs. 17.6%; P = 0.0528). When patients in each cohort were stratified by readmission risk category, the CMM cohort had a statistically significant lower rate of 30-day readmission in the highest risk groups (Average: 7.1% vs. 9.5%, P = 0.025; Elevated: 9.9% vs. 21.4%, P < 0.001; High: 18.3% vs. 35.9%, P < 0.001; Extreme: 36.4% vs. 77.7%, P = 0.006). CMM performed by an MTM pharmacist reduces the rate of readmission at 30 days post discharge and may have the largest impact among patients at highest risk of readmission. PMID- 29437538 TI - Leveraging Rational Protein Engineering to Improve mRNA Therapeutics. AB - Messenger RNA (mRNA) is a promising new class of therapeutics that has potential for treatment of diseases in fields such as immunology, oncology, vaccines, and inborn errors of metabolism. mRNA therapy has several advantages over DNA-based gene therapy, including the lack of the need for nuclear import and transcription, as well as limited possibility of genomic integration. One drawback of mRNA therapy, especially in cases such as metabolic disorders where repeated dosing will be necessary, is the relatively short in vivo half-life of mRNA (~6-12 h). We hypothesize that protein engineering designed to improve translation, yielding longer-lasting protein, or modifications that would increase enzymatic activity would be helpful in alleviating this issue. In this study, we present two examples where sequence engineering improved the expression and duration, as well as enzymatic activity of target proteins in vitro. We then confirmed these findings in wild-type mice. This work shows that rational engineering of proteins can lead to improved therapies in vivo. PMID- 29437539 TI - Genotoxicity of Turnera subulata and Spondias mombin * Spondias tuberosa Extracts from Brazilian Caatinga Biome. AB - Medicinal plants have been used in primary healthcare since the earliest days of humankind. Turnera subulata and Spondias mombin * Spondias tuberosa are widely used in the Brazilian Northeast to treat several diseases. The aim of this study was to evaluate the genotoxic effects of the leaf extracts of these species by the somatic mutation and recombination test in the somatic cells of Drosophila melanogaster wings. The experiments were performed using standard and high bioactivation cross and three concentrations of the test substance [aqueous extract (AET and AES) at 5.0, 10.0, and 20.0 mg/mL and ethanolic extract (EET and EES) and ethyl acetate fraction (EAFT and EAFS) at 0.625, 1.25, and 2.5 mg/mL]. Results indicated that the extracts and fractions induced spontaneous frequencies of mutant spots in both D. melanogaster crosses. Nevertheless, the highest concentrations of the tested plant chemical agents were responsible for the statistically significant genotypic effect. T. subulata and S. mombin * S. tuberosa displayed genotoxic effect under the experimental conditions. The results from this study are crucial as they indicated the deleterious and side effects, considering the indiscriminate use of the extracts of these plants for disease treatment. PMID- 29437540 TI - A Comparison of Genotypic and Phenotypic Methods for Analyzing the Susceptibility to Sulfamethoxazole and Trimethoprim in Edwardsiella piscicida. AB - In a study of 39 isolates of Edwardsiella piscicida made from Korean aquaculture sites, sul genes were detected in 16 isolates and dfr genes in 19. Ten isolates were shown to contain both sul and dfr genes. MIC and disc diffusion zones assays were performed to measure the phenotypic susceptibilities of the 39 isolates. Normalized resistance interpretation was applied to these data to categorize isolates as either fully susceptible or as manifesting reduced susceptibility. The standard CLSI protocols specify the use of a mixture of sulfamethoxazole/trimethoprim (20:1) in both MIC and disc diffusion tests. Using the CLSI MIC protocol, 100% of the isolates containing dfr genes, but only 75% of the isolates containing sul genes, were categorized as manifesting reduced susceptibility. Using the CLSI disc diffusion protocol, only 58% of the isolates containing dfr genes and 69% of those containing sul genes were categorized as manifesting reduced susceptibility. When the single agent trimethoprim was substituted for the combined mixture in both the MIC and disc diffusion protocols, 100% of the dfr-positive isolates were categorized as NWT. When the single-agent sulfamethoxazole was substituted, the analysis of the MIC characterized 100% and the disc zone data 94% of the sul-positive isolates as manifesting reduced susceptibility. It is argued that the use of trimethoprim and sulfamethoxazole as single agents in phenotypic susceptibility tests would provide more meaningful data than the currently recommended use of these two agents combined. PMID- 29437541 TI - Molecular Characterization of Extended-Spectrum Beta Lactamase- and Carbapenemase Producing Pseudomonas aeruginosa Strains from a Malaysian Tertiary Hospital. AB - Pseudomonas aeruginosa infections account for high morbidity and mortality rates worldwide. Increasing resistance toward beta-lactams, especially carbapenems, poses a serious therapeutic challenge. However, the multilocus sequence typing (MLST) of extended-spectrum beta lactamase (ESBL)- and carbapenemase-producing clinical P. aeruginosa has not been reported in Malaysia. This study aimed to determine the antibiotic susceptibility profiles, resistance genes, pulsotypes, and sequence types (STs) of clinical P. aeruginosa from a Malaysian tertiary hospital. These characteristics were analyzed by disk diffusion, minimum inhibitory concentration, polymerase chain reaction, pulsed-field gel electrophoresis (PFGE), and MLST for 199 nonreplicate clinical strains. The susceptibility of the strains toward the carbapenems and piperacillin-tazobactam was the lowest (<=90%), while >=90% of the strains remained susceptible to all other classes of antimicrobial agents tested. The multidrug-resistant strains displayed high level resistance to cephalosporins (48 to >=256 mg/L) and carbapenems (4-32 mg/L). Eleven strains harbored class 1 integrons containing blaGES-13, blaVIM-2, blaVIM-6, blaOXA-10, aacA(6')-Ib, aacA(6')-II, aadA6, and gcuD gene cassettes. Extra-integron genes, blaGES-20, blaIMP-4, blaVIM-2, and blaVIM-11, were also found. Overall, the maximum likelihood tree showed concordance in the clustering of strains having the same STs and PFGE clusters. ST708 was the predominant antibiotic-susceptible clone detected from the neonatal intensive care unit. The STs 235, 809, and 1076 clonal clusters consisted of multidrug resistant strains. ST235 is a recognized international high-risk clone. This is the first report of blaGES-13 and blaGES-20 ESBL-encoding gene variants and novel STs (STs 2329, 2335, 2337, 2338, 2340, and 2341) of P. aeruginosa in Malaysia. PMID- 29437542 TI - Quality of Life Questionnaires in Breast Cancer-Related Lymphedema Patients: Review of the Literature. AB - PURPOSE: Lymphedema of the arm is one of the most common and underestimated side effects of breast cancer treatment. It is known to negatively affect the quality of life (QoL) in breast cancer survivors. However, there are multiple questionnaires used to measure QoL in lymphedema patients. The current study aimed to determine the most complete and accurate questionnaire. METHODS: A systematic literature search in Cochrane Library database CENTRAL, MEDLINE, and EMBASE was conducted in August 2016 by two independent researchers. The strategy used for the search was: (("Lymphedema"[Mesh]) AND ("Quality of life"[Mesh])). All QoL questionnaires for patients with breast cancer-related lymphedema (BCRL) were included. An overview of the assessed QoL domains and arm symptom-specific questions was made, to assess the most complete and accurate questionnaire. RESULTS: A total of 142 studies were identified, of which 49 met the inclusion criteria and 15 different questionnaires were extracted. The Lymphedema Quality of Life Inventory (LyQLI), assesses all QoL domains, except for the possibility of wearing the clothes of choice, and assess all specific arm symptoms. The Lymphedema Functioning, Disability, and Health (Lymph-ICF) Questionnaire assesses all QoL domains, except for sexual functioning, and does assess all specific arm symptoms. CONCLUSION: According to the results obtained, the LyQLI and Lymph-ICF questionnaires were the two most complete and accurate questionnaires to assess QoL in patients with BCRL, because these questionnaires assess the largest number of QoL domains and specific arm symptoms. PMID- 29437543 TI - Acute copper overload induces vascular dysfunction in aortic rings due to endothelial oxidative stress and increased nitric oxide production. AB - The mechanisms involved in vascular reactivity alterations promoted by copper (Cu) overload were investigated. Thoracic aorta obtained from male Wistar rats were cut into rings and exposed for 1 h to 10 ug/ml Cu. Exposure to Cu decreased the contractile responses of aortic rings to phenylephrine (PHE). Removal of endothelium and subsequent administration of N-nitro-L arginine methyl ester (L NAME), tetrahydrobiopterin, aminoguanidine, diethyldithiocarbamic acid, catalase, or tetraethylammonium increased contractile responses. Incubation with apocinyn and tiron enhanced the sensitivity to PHE. Data demonstrated that high concentrations of Cu reduced PHE-mediated vascular reactivity which was associated with elevated production of nitric oxide (NO), which was attributed to activation of inducible NO synthase, and elevated levels of hydrogen peroxide probably related to a rise in superoxide dismutase activity and reactive oxygen species generation. PMID- 29437544 TI - Applicability of an in vitro gastrointestinal digestion method to evaluation of toxic elements bioaccessibility from algae for human consumption. AB - This study aimed to investigate the bioaccessibility of toxic elements, including aluminum (Al), arsenic (As), nickel (Ni), cadmium (Cd), and lead (Pb) in five commercial algae consumed by humans in Italy. The degree of bioaccessibility of these elements may have important implications for human health. Simulation of gastrointestinal tract (GIT) digestion was divided into three stages through use of synthetic saliva, gastric, and bile-pancreas solutions. After pre-treatment with a saliva solution, seaweed samples underwent one of the following treatments: (1) simulated gastric digestion only or (2) simulated complete GIT digestion (gastric digestion followed by bile-pancreas digestion). The bioaccessibility of these toxic elements ranged from approximately 5% to 73% and from 4% to 77% in gastric and GIT digestion, respectively. The bioaccessibility of Al and Pb is poor (5-15%), As and Ni were fairly (40-55%), while Cd displayed a high bioaccessibility. No significant differences in toxic elements mobility was found between samples that only underwent gastric digestion compared to those that underwent a complete GIT digestion. PMID- 29437545 TI - Are Repeated Self-Reports of Psychological Variables Feasible for Patients Near the End of Life at a Palliative Care Unit? AB - BACKGROUND: Patient-reported outcome (PRO) measurement is crucial to assess the benefit of psychotherapeutic interventions. Is repeated assessment of psychometric self-report data possible, as inpatient palliative care patients suffer from physical and psychological symptoms? What is the self-perceived strain caused by the assessment? Objective The main objective of this study was to investigate the feasibility of a repeated comprehensive psychometric self assessment of inpatient palliative care patients. Secondary objectives were the PROs of the psychometric assessment. DESIGN: We conducted a prospective cohort study. Patients admitted to our palliative care unit (PCU) were reviewed for eligibility within 72 hours. They were asked for weekly self-reports regarding hope (HHI-D), well-being (FACIT-Sp), anxiety and depression (STADI), and quality of life (QoL; EORTC-QLQ-C-30 single item). The strain caused by the assessment was assessed by a numeric rating scale (0-10) and free comments. RESULTS: Within 11 months, 219 patients were admitted to the PCU. In total, 92 patients were eligible. The most frequent exclusion criterion was "life expectancy <1 week." A total of 60 patients participated at the first point of measurement. The mean of self-perceived strain (Likert scale 0-10) due to the assessment was 1.44 (SD 1.99) at T1. Twenty-four patients participated twice. Here we found increased scores for physical well-being and QoL. CONCLUSION: Repeated assessment of psychological conditions is feasible for 27.4% of inpatients at a German PCU. The most limiting factor is life expectancy of only days at admission to the PCU. However, the self-perceived strain is low. PMID- 29437546 TI - Theories Applied to m-Health Interventions for Behavior Change in Low- and Middle Income Countries: A Systematic Review. AB - BACKGROUND: Recently there has been dramatic increase in the use of mobile technologies for health (m-Health) in both high and low- and middle-income countries (LMICs). However, little is known whether m-Health interventions in LMICs are based on relevant theories critical for effective implementation of such interventions. This review aimed to systematically identify m-Health studies on health behavioral changes in LMICs and to examine how each study applied behavior change theories. MATERIALS AND METHODS: A systematic review was conducted using the standard method from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. By searching electronic databases (MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials [CENTRAL]), we identified eligible studies published in English from inception to June 30, 2017. For the identified m-Health studies in LMICs, we examined their theoretical bases, use of behavior change techniques (BCTs), and modes of delivery. RESULTS: A total of 14 m-Health studies on behavioral changes were identified and, among them, only 5 studies adopted behavior change theory. The most frequently cited theory was the health belief model, which was adopted in three studies. Likewise, studies have applied only a limited number of BCTs. Among the seven BCTs identified, the most frequently used one was the social support (practical) technique for medication reminder and medical appointment. m Health studies in LMICs most commonly used short messaging services and phone calls as modes of delivery for behavior change interventions. CONCLUSIONS: m Health studies in LMICs are suboptimally based on behavior change theory yet. To maximize effectiveness of m-Health, rigorous delivery methods as well as theory based intervention designs will be needed. PMID- 29437547 TI - Imidacloprid affects rat liver mitochondrial bioenergetics by inhibiting FoF1-ATP synthase activity. AB - Imidacloprid (IMD) is a neonicotinoid insecticide widely used in crops, pets, and on farm animals for pest control. Several studies were conducted examining the adverse effects of IMD on animals often exhibiting hepatic damage. The aim of this study was to determine the effects of IMD on bioenergetics of mitochondria isolated from rat liver. Imidacloprid (50-200 uM) produced a concentration dependent decrease in oxygen consumption and ATP production without markedly affecting mitochondrial membrane potential (MMP). Oxygen consumption experiments showed that IMD did not significantly affect the respiratory chain, and this was similar to findings with oligomycin and carboxyatractyloside, suggesting a direct action on FoF1-ATP synthase and/or the adenine nucleotide translocator (ANT). Imidacloprid inhibited FoF1-ATP synthase activity only in disrupted mitochondria and induced a partial inhibition of ADP-stimulated depolarization of the MMP. Our results indicate that IMD interacts specifically with FoF1-ATP synthase resulting in functional inhibition of the enzyme with consequent impairment of mitochondrial bioenergetics. These effects of IMD on mitochondrial bioenergetics may be related to adverse effects of this insecticide on the liver. PMID- 29437548 TI - A Serosurvey of Flavivirus Infection in Horses and Birds in Slovakia. AB - In central Europe, at least three flaviviruses circulate among vectors and vertebrate hosts. West Nile virus (WNV) and Usutu virus (USUV) are mosquito-borne viruses maintained in the nature by enzootic cycle between mosquitoes and birds. Tick-borne encephalitis virus (TBEV) is a flavivirus causing annual human cases in Slovakia. The aim of this study is the prevalence assessment of flavivirus infections in horses (n = 145) and birds (n = 109) by enzyme-linked immunosorbent assay (ELISA) and confirmation by neutralization test (VNT). WNV antibodies have been detected in 11.7% of tested horses and 11.9% of tested birds and confirmed in 6.9% of horse and 9.2% of bird samples. None of the WNV seropositive or dubious horses had WNV IgM (ELISA), and none of the tested horses had USUV neutralizing antibodies. Autochthonous WNV infections have been confirmed in 16.7% of horses without international travelling history. Most of them were from western Slovakia with known endemic WNV transmission. An autochthonous WNV infection in a horse from highland area of Kremnicke vrchy (central Slovakia) with unknown data of WNV circulation and without travelling history was detected. TBEV antibody was detected in 6.2% of horses and in 3.4% has been confirmed. In two horses, WNV and TBEV infection could not be distinguished. Confirmed WNV seropositive were eight raptors showing nonspecific signs or suffering from trauma, one white stork, and one house sparrow. The sparrow was caught in a locality in eastern Slovakia, where WNV RNA had been previously detected in sparrows. USUV neutralizing antibodies were present in pooled sample from four Eurasian great tits. Because of insufficient volume, TBEV VNT was not carried out in birds. Results further prove the endemicity of WNV and other vector-borne flaviviruses in natural and accidental hosts in Slovakia, giving better insight in flavivirus epidemiology in European countries in general. PMID- 29437549 TI - Hepatic and renal histology and mercury concentrations of North West and North East Greenland narwhals (Monodon monoceros). AB - Narwhals (Monodon monoceros) are at the top of the Arctic food web and therefore might biomagnify high total mercury (Hg) concentrations in organs and tissues. The aim of this study was to determine histopathology and Hg concentrations in liver and kidneys from 15 North East Greenland narwhals (3 subadult females, 8 adult females, 3 subadult males, and 1 adult male) and compare data with previous observations of 12 North West Greenland specimens (1 subadult female, 4 adult females, 1 subadult male, and 6 adult males). The zoological length was significantly larger and hepatic and renal concentrations significantly higher in adults compared to subadults. When comparing tissues, the Hg levels were significantly the highest in liver, while a correlation between metal levels in liver and kidneys was positive and significant. Histological examination of renal tissues presented four types of glomerular lesions (capillary dilatation [0 100%], membrane thickening [0-100%], dilatation of space [0-80%], and sclerosis [0-70%]) and two tubular lesions (atrophy/hyalinization [0-40%] and casts [0 60%]). Hepatic tissues exhibited three portal lesions (fibrosis [0-33%], cell infiltrates [0-40%], and bile duct proliferation [0-40%]) and two parenchymal lesions (steatosis [83-100%] and lipid-filled Ito cells [0-33%]). All 12 lesions were found in adult whales from North West Greenland while eight were present in adult whales from North East Greenland. Six lesions were detected in subadults from North East Greenland and four in subadults from North West Greenland. A significantly higher frequency of dilatation and hyalinization of Bowman's space and capsule and glomerular capillary dilatation was found in adult narwhals from West Greenland. There was no marked difference in Hg concentrations in whales with and without histological lesions. In conclusion, the prevalence of histological changes and Hg levels were the highest in adults and therefore both age and metal are important factors to include when evaluating liver and kidney lesions in narwhals. PMID- 29437550 TI - A Simple Method of Cataract Induction in Adult Zebrafish. AB - We have developed a simple method for the induction of cataracts in adult zebrafish using hydrogen peroxide. Our method uses a corneal puncture followed by intraocular injection of hydrogen peroxide into the anterior chamber. The procedure can be done rapidly, forming a highly opaque cataract almost immediately, and fish recover quickly. The optical clarity of the lens is gradually regained over time, showing the innate ability of zebrafish to regenerate healthy lens tissue. This technique provides a simple in vivo system with which to assess mutant strains or targeted disruptions to genes expressed in the lens. PMID- 29437551 TI - Parallel Survey of Two Widespread Renal Syndrome-Causing Zoonoses: Leptospira spp. and Hantavirus in Urban Environment, Hungary. AB - Rodents are important reservoir hosts for several zoonotic pathogens that cause significant morbidity and mortality in humans. Among others, leptospirosis is one of the most widespread zoonotic diseases worldwide and has the similar clinical manifestation with hantavirus infection in humans. Despite the fact that both pathogens have great epidemiological significance in Europe, no epizootiological data exist for urbanized areas so far. Therefore, this study was conducted to investigate the occurrence and prevalence of Leptospira spp. and hantaviruses in small wild rodents living in close proximity to humans. Altogether, 338 small rodents representing five different species (Apodemus agrarius, A. flavicollis, A. sylvaticus, Microtus arvalis, and Myodes glareolus) were captured in the city of Pecs (Hungary) and screened for pathogens by different types of PCR methods (TaqMan-based real-time PCR/PCR, RT-PCR/PCR). A total of 18.3% of the rodents were positive for Leptospira kirschneri, L. interrogans, and L. borgpetersenii. Nucleic acid of Tula hantavirus and human pathogen Dobrava-Belgrade orthohantavirus were detected in 8% of tested specimens. Furthermore, dual infections with both Leptospira spp. and hantaviruses were shown in 2.6% of animals, suggesting that the same rodent host can be infected with several pathogens at the same time, therefore, representing a serious threat to public health. Overall, this study provides important surveillance data on the prevalence of Leptospira spp. and hantaviruses from rodents in urbanized environment for the first time in Hungary and emphasizes the importance of further ecoepidemiological investigations. PMID- 29437553 TI - A novel reporter allele for monitoring Dll4 expression within the embryonic and adult mouse. AB - Canonical Notch signaling requires the presence of a membrane bound ligand and a corresponding transmembrane Notch receptor. Receptor engagement induces multiple proteolytic cleavage events culminating in the nuclear accumulation of the Notch intracellular domain and its binding to a transcriptional co-factor to mediate gene expression. Notch signaling networks are essential regulators of vascular patterning and angiogenesis, as well as myriad other biological processes. Delta like 4 (Dll4) encodes the earliest Notch ligand detected in arterial cells, and is enriched in sprouting endothelial tip cells. Dll4 expression has often been inferred by proxy using a lacZ knockin reporter allele. This is problematic, as a single copy of Dll4 is haploinsufficient. Additionally, Notch activity regulates Dll4 transcription, making it unclear whether these reporter lines accurately reflect Dll4 expression. Accordingly, precisely defining Dll4 expression is essential for determining its role in development and disease. To address these limitations, we generated a novel BAC transgenic allele with a nuclear-localized beta-galactosidase reporter (Dll4-BAC-nlacZ). Through a comparative analysis, we show the BAC line overcomes previous issues of haploinsufficiency, it recapitulates Dll4 expression in vivo, and allows superior visualization and imaging. As such, this novel Dll4 reporter is an important addition to the growing Notch toolkit. PMID- 29437555 TI - Transformation of chronic lymphocytic leukemia into B-cell acute lymphoblastic leukemia. PMID- 29437556 TI - A primary role for human central memory cells in tissue immunosurveillance. AB - Central memory T cells (TCM) patrol lymph nodes, providing central immunosurveillance against known pathogens, but have not been described as conducting primary tissue immunosurveillance. We analyzed the expression of tissue-homing addressins in human TCM vs effector memory T cells (TEM) from the same donors. In humans, the majority of human TCM were tropic for either skin or gut, and the overall tissue tropism of TCM was comparable to that of TEM TCM were present in healthy, noninflamed human skin, lung, colon, and cervix, suggesting a role for TCM in the primary immunosurveillance of peripheral tissues. TCM also had potent effector functions; 80% of CD8+ TCM produced TC1/TC2/TC17/TC22 cytokines. TCM injected into human skin-grafted mice migrated into skin and induced inflammatory eruptions comparable to TEM-injected mice. In summary, human TCM express peripheral tissue-homing receptors at levels similar to their effector memory counterparts, are found in healthy human tissues, have impressive effector functions, and can act alone to induce skin inflammation in human engrafted mice. Our studies support a novel role for human TCM in primary immunosurveillance of peripheral tissues and highlight the important role of this long-lived cell type in tissue-based immune responses. PMID- 29437554 TI - hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival. AB - Chronic myeloid leukemia (CML) stem/progenitor cells (SPCs) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPCs maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase-dependent pathway mediated by the upregulation of hsa-mir183, the downregulation of its direct target early growth response 1 (EGR1), and, as a consequence, upregulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPCs. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPCs, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication. PMID- 29437558 TI - IgG4-related disease of the mitral valve demonstrated by immunohistochemistry. PMID- 29437557 TI - A transgenic zebrafish model for the in vivo study of the blood and choroid plexus brain barriers using claudin 5. AB - The central nervous system (CNS) has specific barriers that protect the brain from potential threats and tightly regulate molecular transport. Despite the critical functions of the CNS barriers, the mechanisms underlying their development and function are not well understood, and there are very limited experimental models for their study. Claudin 5 is a tight junction protein required for blood brain barrier (BBB) and, probably, choroid plexus (CP) structure and function in vertebrates. Here, we show that the gene claudin 5a is the zebrafish orthologue with high fidelity expression, in the BBB and CP barriers, that demonstrates the conservation of the BBB and CP between humans and zebrafish. Expression of claudin 5a correlates with developmental tightening of the BBB and is restricted to a subset of the brain vasculature clearly delineating the BBB. We show that claudin 5a-expressing cells of the CP are ciliated ependymal cells that drive fluid flow in the brain ventricles. Finally, we find that CP development precedes BBB development and that claudin 5a expression occurs simultaneously with angiogenesis. Thus, our novel transgenic zebrafish represents an ideal model to study CNS barrier development and function, critical in understanding the mechanisms underlying CNS barrier function in health and disease. PMID- 29437561 TI - India's antibiotic combinations thwart efforts to curb drug resistance, say researchers. PMID- 29437562 TI - Big data and medical research in China. PMID- 29437563 TI - Clinical errors: I've asked the GMC to investigate me. PMID- 29437559 TI - DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. METHODS: DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses. RESULTS: We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus. CONCLUSIONS: Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes. PMID- 29437564 TI - Clinical practice guidelines in China. PMID- 29437566 TI - Maintaining public confidence in doctors-at what cost? PMID- 29437565 TI - Research in health policy making in China: out-of-pocket payments in Healthy China 2030. PMID- 29437567 TI - Cutting contraceptive services will have dire consequences. PMID- 29437568 TI - BMA took legal action to keep doctors' bonus scheme. PMID- 29437569 TI - Myopia: its historical contexts. AB - Worldwide, and especially in Asia, myopia is a major vision-threatening disorder. From AD 1600 on, to prevent myopia, authors warned against near work without sufficient pauses. There was an abundance of theories about the causes of myopia, the most common one being the necessity of extra convergence on nearby work with thickened extraocular muscles and elevated intraocular pressure. Ocular tenotomies against myopia were in vogue for a while. Axial lengthening of the eye in myopia was mentioned around 1700, but it took 150 years to become accepted as the most prevalent sign of high myopia. In 1864, a lucid concept of myopia and other ametropias arose through a clear separation between accommodation and refraction. Posterior staphyloma was known around 1800 and its association with myopia became evident some 30 years later. There still seems to be no generally accepted classification of myopia and particularly not of degenerative or pathologic myopia. This review focuses on myopia from 350 BC until the 21st century and on the earliest writings on the histology of eyes with posterior staphyloma. A proposal for myopia classification is given. PMID- 29437570 TI - Immunosuppression by a subconjunctival implant releasing dexamethasone in a rabbit model of penetrating keratoplasty. AB - AIMS: To evaluate the efficacy of a subconjunctival dexamethasone-releasing implant in preventing rejection of penetrating keratoplasty (PK) in an animal model. METHODS: Twenty-two rabbits underwent allogenic PK. After randomisation, they received either a 700 ug dexamethasone implant under the conjunctiva at the end of surgery (n=10), one dexamethasone 1 mg/mL eye-drop thrice daily (n=6) or a placebo thrice daily (n=6). The suture was left in place. Animals were observed weekly by slit-lamp and optical coherence tomography with quantification of transparency, neovascularisation and central corneal thickness (CCT). At 5-6 weeks, they were euthanised for histology. The residual dexamethasone concentration in ocular tissues was measured with an ultra-performance liquid chromatography-tandem mass spectrometer. RESULTS: Placebo group: early neovascularisation was systematic, penetrating the graft by 270-360 degrees at 5 6 weeks. Rejection occurred in 50% of cases. Eye-drop and implant groups: similar course without rejection at 6 weeks and normal CCT. Neovascularisation was observed in 5/6 rabbits in the eye-drop group and in 6/8 in the implant group, with two cases of new vessels penetrating the graft from week 3. Neovascularisation scores did not differ significantly between the two treatments and were significantly lower than for the placebo. Histology was in agreement in all cases. Implants disappeared after 3-5 weeks. No local side effect was observed. Tissue concentrations were all higher at day 8 (n=2) in the implant group than in the eye drop group and lower at 6 weeks (n=8). CONCLUSIONS: In this PK model characterised by a high rejection rate, a subconjunctival dexamethasone implant was for 6 weeks as effective as the topical form in preventing allograft rejection. PMID- 29437571 TI - Impact of varying the definition of myopia on estimates of prevalence and associations with risk factors: time for an approach that serves research, practice and policy. AB - BACKGROUND: Refractive error is an increasing global public health concern that requires robust and reliable research to identify modifiable risk factors and provide accurate estimates of population burden. We investigated the impact of reclassification of individuals when using different threshold values of spherical equivalent (SE) to define myopia, on estimates of frequency, distribution and associations with risk factors, to inform current international initiatives to standardise definitions. METHODS: A random sample of 1985 individuals from the 1958 British birth cohort, at age 44, had autorefraction and self-reported on educational attainment and social class.Refraction status assigned in three different models using SE: (A) moderate to high myopia -3 diopters (D) or more extreme (<=-3.00D), (B) hypermetropia +1.00D or more extreme (>=+1.00D) and (C) mild myopia using three different thresholds: -1.00D, -0.75D or -0.50D, hence reciprocal changes in definition of emmetropia. RESULTS: Frequency estimates and associations with risk factors altered significantly as the threshold value for myopia moved towards SE 0.0D: prevalence of mild myopia increased from 28% to 47%, the association with highest educational attainment attenuated and with higher social class strengthened, with changes in risk ratios of approximately 20%. CONCLUSION: Even small changes in the threshold definition of myopia (+/-0.25D) can significantly affect the conclusions of epidemiological studies, creating both false-positive and false-negative associations for specific risk factors. An international classification for refractive error, empirically evidenced and cognisant of the question(s) being addressed and the population(s) being studied, is needed to serve better translational research, practice and policy. PMID- 29437572 TI - Cilostazol Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysms but Not Atherosclerosis in Apolipoprotein E-Deficient Mice. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta associated with rupture, which frequently results in fatal consequences. AAA tissue is commonly characterized by localized structural deterioration accompanied with inflammation and profound accumulation of leukocytes, although the specific function of these cells is unknown. Cilostazol, a phosphodiesterase III inhibitor, is commonly used for patients with peripheral vascular disease or stroke because of its anti-platelet aggregation effect and anti-inflammatory effect, which is vasoprotective effect. In this study, we evaluated the effects of cilostazol on angiotensin II-induced AAA formation. APPROACH AND RESULTS: Male apolipoprotein E-deficient mice were fed either normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, mice were infused with angiotensin II (1000 ng/kg per minute) for 4 weeks. Angiotensin II infusion increased maximal diameters of abdominal aortas, whereas cilostazol administration significantly attenuated dilatation of abdominal aortas, thereby, reducing AAA incidence. Cilostazol also reduced macrophage accumulation, matrix metalloproteinases activation, and inflammatory gene expression in the aortic media. In cultured vascular endothelial cells, cilostazol reduced expression of inflammatory cytokines and adhesive molecules through activation of the cAMP-PKA (protein kinase A) pathway. CONCLUSIONS: Cilostazol attenuated angiotensin II-induced AAA formation by its anti inflammatory effect through phosphodiesterase III inhibition in the aortic wall. Cilostazol may be a promising new therapeutic option for AAAs. PMID- 29437574 TI - CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients. AB - OBJECTIVE: CSL112 (apolipoprotein A-I [apoA-I; human]) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease. Here, we determined whether infused apoA-I improves CEC when administered to patients with stable atherosclerotic disease versus healthy volunteers. APPROACH AND RESULTS: Measurements of apoA-I, HDL unesterified cholesterol, HDL esterified cholesterol, pre-beta1-HDL, and CEC were determined in samples from patients with stable atherosclerotic disease before and after intravenous administration of CSL112. These measures were compared with 2 prior studies in healthy volunteers for differences in CEC at baseline and after CSL112 infusion. Patients with stable atherosclerotic disease exhibited significantly lower ATP-binding cassette transporter 1-mediated CEC at baseline (P<0.0001) despite slightly higher apoA-I levels when compared with healthy individuals (2 phase 1 studies pooled; P<=0.05), suggesting impaired HDL function. However, no differences were observed in apoA-I pharmacokinetics or in pre-beta1-HDL (P=0.5) or CEC (P=0.1) after infusion of CSL112. Similar elevation in CEC was observed in patients with low or high baseline HDL function (based on tertiles of apoA-I normalized CEC; P=0.1242). These observations were extended and confirmed using cholesterol esterification as an additional measure. CONCLUSIONS: CSL112 shows comparable, strong, and immediate effects on CEC despite underlying cardiovascular disease. CSL112 is, therefore, a promising novel therapy for lowering the burden of atherosclerosis and reducing the risk of recurrent cardiovascular events. PMID- 29437575 TI - Saturated Fatty Acids Undergo Intracellular Crystallization and Activate the NLRP3 Inflammasome in Macrophages. AB - OBJECTIVE: Inflammation provoked by the imbalance of fatty acid composition, such as excess saturated fatty acids (SFAs), is implicated in the development of metabolic diseases. Recent investigations suggest the possible role of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3) inflammasome, which regulates IL-1beta (interleukin 1beta) release and leads to inflammation, in this process. Therefore, we investigated the underlying mechanism by which SFAs trigger NLRP3 inflammasome activation. APPROACH AND RESULTS: The treatment with SFAs, such as palmitic acid and stearic acid, promoted IL-1beta release in murine primary macrophages while treatment with oleic acid inhibited SFA-induced IL-1beta release in a dose-dependent manner. Analyses using polarized light microscopy revealed that intracellular crystallization was provoked in SFA-treated macrophages. As well as IL-1beta release, the intracellular crystallization and lysosomal dysfunction were inhibited in the presence of oleic acid. These results suggest that SFAs activate NLRP3 inflammasome through intracellular crystallization. Indeed, SFA-derived crystals activated NLRP3 inflammasome and subsequent IL-1beta release via lysosomal dysfunction. Excess SFAs also induced crystallization and IL-1beta release in vivo. Furthermore, SFA-derived crystals provoked acute inflammation, which was impaired in IL-1beta-deficient mice. CONCLUSIONS: These findings demonstrate that excess SFAs cause intracellular crystallization and subsequent lysosomal dysfunction, leading to the activation of the NLRP3 inflammasome, and provide novel insights into the pathogenesis of metabolic diseases. PMID- 29437573 TI - Effects of Increasing Exercise Intensity and Dose on Multiple Measures of HDL (High-Density Lipoprotein) Function. AB - OBJECTIVE: Measures of HDL (high-density lipoprotein) function are associated with cardiovascular disease. However, the effects of regular exercise on these measures is largely unknown. Thus, we examined the effects of different doses of exercise on 3 measures of HDL function in 2 randomized clinical exercise trials. APPROACH AND RESULTS: Radiolabeled and boron dipyrromethene difluoride-labeled cholesterol efflux capacity and HDL-apoA-I (apolipoprotein A-I) exchange were assessed before and after 6 months of exercise training in 2 cohorts: STRRIDE-PD (Studies of Targeted Risk Reduction Interventions through Defined Exercise, in individuals with Pre-Diabetes; n=106) and E-MECHANIC (Examination of Mechanisms of exercise-induced weight compensation; n=90). STRRIDE-PD participants completed 1 of 4 exercise interventions differing in amount and intensity. E-MECHANIC participants were randomized into 1 of 2 exercise groups (8 or 20 kcal/kg per week) or a control group. HDL-C significantly increased in the high amount/vigorous-intensity group (3+/-5 mg/dL; P=0.02) of STRRIDE-PD, whereas no changes in HDL-C were observed in E-MECHANIC. In STRRIDE-PD, global radiolabeled efflux capacity significantly increased 6.2% (SEM, 0.06) in the high amount/vigorous-intensity group compared with all other STRRIDE-PD groups (range, -2.4 to -8.4%; SEM, 0.06). In E-MECHANIC, non-ABCA1 (ATP-binding cassette transporter A1) radiolabeled efflux significantly increased 5.7% (95% CI, 1.2 10.2%) in the 20 kcal/kg per week group compared with the control group, with no change in the 8 kcal/kg per week group (2.6%; 95% CI, -1.4 to 6.7%). This association was attenuated when adjusting for change in HDL-C. Exercise training did not affect BODIPY-labeled cholesterol efflux capacity or HDL-apoA-I exchange in either study. CONCLUSIONS: Regular prolonged vigorous exercise improves some but not all measures of HDL function. Future studies are warranted to investigate whether the effects of exercise on cardiovascular disease are mediated in part by improving HDL function. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00962962 and NCT01264406. PMID- 29437577 TI - MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation. AB - OBJECTIVE: Atrial fibrillation (AF) patients experience adverse cardiovascular events (ACEs) despite anticoagulant therapy. We reported that rs2431697 of miR 146a, a negative regulator of inflammation, predicts ACEs in patients with AF. The relationship between neutrophil extracellular traps and thrombogenesis is known. Thus, our aim was to evaluate the role of neutrophil extracellular trap compounds as prognostic markers of ACEs in AF and to study whether miR-146a affects NETosis. APPROACH AND RESULTS: We included 336 steadily anticoagulated AF patients with a median follow-up of 7.9 years (interquartile range, 7.3-8.1) and 127 healthy subjects. The reviewed ACEs included stroke (ischemic/embolic), acute coronary syndrome, acute heart failure, and global or vascular death. We quantified cell-free DNA and NE (neutrophil elastase) at diagnosis. Rs2431697 was genotyped. Neutrophils from human and mice were seeded to analyze shed cell-free DNA and H3cit (citrullinated histone 3) after activation. In human plasmas, higher NE levels (>55.29 ng/mL), but not cell-free DNA, were independently associated with higher risk of all-cause mortality (hazard ratio, 2.24; 95% CI, 1.36-3.68), cardiovascular mortality (hazard ratio, 4.77; 95% CI, 1.11-20.47), and composite cardiovascular events (hazard ratio, 1.84; 95% CI, 1.01-3.76). In patients, NE levels were associated with rs2431697 (TT: 51.82+/-2.73 versus CC: 40.01+/-3.05 ng/mL; P=0.040). In vitro, both human (TT for rs2431697) and miR 146a-/- mice neutrophils yielded higher levels of cell-free DNA and H3cit than CC or wild-type cells, respectively. CONCLUSIONS: NE activity can provide new ACE prognostic information in AF patients. These findings provide evidence of a potential role of miR-146a in neutrophil extracellular trap generation and cardiovascular risk in AF. PMID- 29437576 TI - Deletion of BMAL1 in Smooth Muscle Cells Protects Mice From Abdominal Aortic Aneurysms. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) has high mortality rate when ruptured, but currently, there is no proven pharmacological therapy for AAA because of our poor understanding of its pathogenesis. The current study explored a novel role of smooth muscle cell (SMC) BMAL1 (brain and muscle Arnt-like protein-1)-a transcription factor known to regulate circadian rhythm-in AAA development. APPROACH AND RESULTS: SMC-selective deletion of BMAL1 potently protected mice from AAA induced by (1) MR (mineralocorticoid receptor) agonist deoxycorticosterone acetate or aldosterone plus high salt intake and (2) angiotensin II infusion in hypercholesterolemia mice. Aortic BMAL1 was upregulated by deoxycorticosterone acetate-salt, and deletion of BMAL1 in SMCs selectively upregulated TIMP4 (tissue inhibitor of metalloproteinase 4) and suppressed deoxycorticosterone acetate-salt-induced MMP (matrix metalloproteinase) activation and elastin breakages. Moreover, BMAL1 bound to the Timp4 promoter and suppressed Timp4 transcription. CONCLUSIONS: These results reveal an important, but previously unexplored, role of SMC BMAL1 in AAA. Moreover, these results identify TIMP4 as a novel target of BMAL1, which may mediate the AAA protective effect of SMC BMAL1 deletion. PMID- 29437578 TI - Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis. AB - Tissue factor (TF) is the high-affinity receptor and cofactor for factor (F)VII/VIIa. The TF-FVIIa complex is the primary initiator of blood coagulation and plays an essential role in hemostasis. TF is expressed on perivascular cells and epithelial cells at organ and body surfaces where it forms a hemostatic barrier. TF also provides additional hemostatic protection to vital organs, such as the brain, lung, and heart. Under pathological conditions, TF can trigger both arterial and venous thrombosis. For instance, atherosclerotic plaques contain high levels of TF on macrophage foam cells and microvesicles that drives thrombus formation after plaque rupture. In sepsis, inducible TF expression on monocytes leads to disseminated intravascular coagulation. In cancer patients, tumors release TF-positive microvesicles into the circulation that may contribute to venous thrombosis. TF also has nonhemostatic roles. For instance, TF-dependent activation of the coagulation cascade generates coagulation proteases, such as FVIIa, FXa, and thrombin, which induce signaling in a variety of cells by cleavage of protease-activated receptors. This review will focus on the roles of TF in protective hemostasis and pathological thrombosis. PMID- 29437579 TI - Mouse Platelet Ral GTPases Control P-Selectin Surface Expression, Regulating Platelet-Leukocyte Interaction. AB - OBJECTIVE: RalA and RalB GTPases are important regulators of cell growth, cancer metastasis, and granule secretion. The purpose of this study was to determine the role of Ral GTPases in platelets with the use of platelet-specific gene-knockout mouse models. APPROACH AND RESULTS: This study shows that platelets from double knockout mice, in which both GTPases have been deleted, show markedly diminished (~85% reduction) P-selectin translocation to the surface membrane, suggesting a critical role in alpha-granule secretion. Surprisingly, however, there were only minor effects on stimulated release of soluble alpha- and delta-granule content, with no alteration in granule count, morphology, or content. In addition, their expression was not essential for platelet aggregation or thrombus formation. However, absence of surface P-selectin caused a marked reduction (~70%) in platelet-leukocyte interactions in blood from RalAB double knockout mice, suggesting a role for platelet Rals in platelet-mediated inflammation. CONCLUSIONS: Platelet Ral GTPases primarily control P-selectin surface expression, in turn regulating platelet-leukocyte interaction. Ral GTPases could therefore be important novel targets for the selective control of platelet mediated immune cell recruitment and inflammatory disease. PMID- 29437580 TI - The epidemiology of childhood blindness and severe visual impairment in Indonesia. AB - BACKGROUND: The magnitude of blindness among children in Indonesia is unknown. In this study, we aimed to define the magnitude and aetiology of childhood blindness in two parts of Indonesia. METHOD: Children aged 0-15 years, identified through key informant method and from special schools and community-based rehabilitation programme in Sumba and Yogyakarta, were assessed following WHO protocol and definitions for ophthalmological assessment and classification of visual impairment and blindness among children. RESULTS: Out of 195 children assessed, 113 had blindness/severe visual impairment (BL/SVI), 48 had visual impairment (VI) and 34 had no VI. 43.4% children with BL/SVI were female.The main anatomical site of BL/SVI was lens (n=35, 31.0%), followed by retina (n=13, 11.5%) and cornea (n=9, 8.0%). Among the known aetiologies, childhood factors predominated (n=14, 12.4%), followed by hereditary diseases (n=12, 10.6%) where parental consanguinity was found among 33.3% (n=4) of them. Overall, 77.8% (n=88) had avoidable causes of BL/SVI: 69.0% (n=78) treatable and 8.8% (n=10) preventable causes.The estimated prevalence of BL/SVI was 0.25 (95% CI 0.19 to 0.32) and 0.23 (95% CI 0.18 to 0.29) per 1000 children in Sumba and Yogyakarta, respectively. The estimated prevalence of cataract was 0.07 per 1000 children (95% CI 0.04 to 0.12) in Sumba and 0.05 per 1000 children (95% CI 0.03 to 0.09) in Yogyakarta. Based on our conservative estimates, there are 17 241 children with BL/SVI in Indonesia; 4270 are blind due to cataract. CONCLUSION: The magnitude of childhood BL/SVI in Sumba and Yogyakarta is high. Our study suggests that a large proportion of childhood BL/SVI in Indonesia is avoidable. PMID- 29437581 TI - Decreased severity of age-related macular degeneration in amblyopic eyes. AB - AIM: To evaluate whether people with age-related macular degeneration (AMD) and a history of amblyopia have equal severity of AMD in both eyes. METHODS: Billing records were used to locate all people with a history of amblyopia and AMD evaluated between 1 January 2003 and 1 June 2015 at a single ophthalmology institute. Two ophthalmic graders blinded to amblyopia status determined the severity of AMD in each eye using fundus photos and a validated grading scale. RESULTS: A total of 14 people were found to have AMD and a documented history of amblyopia. Average patient age was 77.0 years and average best corrected visual acuity was 20/160 in eyes with a history of amblyopia and 20/40 in fellow eyes without amblyopia. Eyes with a history of amblyopia were found to have a lower AMD severity score (mean lower score: -1.38; paired t-test P=0.019). Of the 11 people with asymmetric disease severity, 10 individuals had worse AMD in the non amblyopic eye while one person had worse AMD in the amblyopic eye (P=0.0067). CONCLUSIONS: Our pilot study suggests that eyes with a history of amblyopia may manifest decreased severity of AMD compared with non-ambylopic eyes in the same patient. Further research is warranted to investigate this clinical observation. PMID- 29437582 TI - Number of incident cases of the main eye diseases of ageing in the UK Biobank cohort, projected over a 25-year period from time of recruitment. AB - OBJECTIVES: To estimate the number of new cases of age-related macular degeneration, cataract and glaucoma accruing in the UK Biobank cohort, over a period of 25 years from time of recruitment. Our secondary objective was to assess the statistical power of nested case-control studies of these eye diseases. We aimed to provide quantitative information relevant to UK Biobank's eye disease case ascertainment efforts and to the potential for UK Biobank-based research into the causes of eye disease. METHODS: We constructed a Markov discrete-time state transition model to simulate the population dynamics of the eye disorders within the UK Biobank cohort, using prevalence data from population based epidemiological studies to derive incidence, and Office for National Statistics data on mortality and migration overseas. RESULTS: By 2023, >900 new cases of each of 'wet' (neovascular) and 'dry' age-related macular degeneration, >1200 cases of primary open angle glaucoma and almost 15 000 cases of cataracts are expected to have accrued in the subcohort of 68 500 participants who had ocular assessment at baseline, with around seven times as many cases of each disease in the whole cohort of 500 000 participants. These predicted incident case numbers generate good or substantial statistical power for a range of nested case-control studies of potential genetic, lifestyle and environmental determinants of disease. CONCLUSIONS: Over the next few years, UK Biobank is expected to generate sufficient numbers of new cases for statistically well powered studies of the determinants of the major causes of sight loss: age related macular degeneration, vision-impairing cataract and glaucoma. PMID- 29437583 TI - Response to: 'Can we prescribe TMP/SMX prophylaxis without any concerns equally for all patients with rheumatic disease?' by Suyama and Okada. PMID- 29437584 TI - Can we prescribe TMP/SMX prophylaxis without any concerns equally for all patients with rheumatic disease? PMID- 29437586 TI - Baseline ultrasound examination as possible predictor of relapse in patients affected by juvenile idiopathic arthritis (JIA). AB - OBJECTIVES: To define the correlation between joint ultrasonography and clinical examination in patients with juvenile idiopathic arthritis (JIA) and to assess whether synovitis detected by ultrasonography in clinically inactive patients predicts arthritis flares. METHODS: 88 consecutive patients with JIA-46 (52%) with persistent oligoarthritis, 15 (17%) with extended oligoarthritis, 15 (17%) with rheumatoid factor-negative polyarthritis and 12 (14%) with other forms of JIA, all clinically inactive for a minimum of 3 months-underwent ultrasound (US) assessment of 44 joints. Joints were scanned at study entry for synovial hyperplasia, joint effusion and power Doppler (PD) signal. Patients were followed clinically for 4 years. RESULTS: US was abnormal in 20/88 (22.7%) patients and in 38/3872 (0.98%) joints. Extended oligoarthritis and rheumatoid factor-negative polyarthritis were more frequent in US-positive than in US-negative patients (35.0% vs 11.8% and 30.0% vs 13.2%, respectively; P=0.005). During 4 years of follow-up, 41/88 (46.6%) patients displayed a flare; 26/68 (38.2%) were US negative and 15/20 (75%) were US-positive at baseline. Abnormality on US examination, after correction for therapy modification, significantly increased the risk of flare (OR=3.8, 95% CI 1.2 to 11.5). The combination of grey scale and PD abnormalities displayed a much higher predictive value of relapse (65%, 13/20) than grey scale alone (33%, 6/18). CONCLUSIONS: US abnormalities are a strong predictor of relapse at individual patient level. Irrespective of treatment, the risk of flare in US-positive versus US-negative patients was almost four times higher. In case of US abnormalities, patients should be carefully followed regardless of both the International League of Associations for Rheumatology and Wallace categories. PMID- 29437585 TI - MR-PheWAS: exploring the causal effect of SUA level on multiple disease outcomes by using genetic instruments in UK Biobank. AB - OBJECTIVES: We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank. METHODS: We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelianrandomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS. We next applied MR Egger analysis to detect and account for potential pleiotropy, which conventional MR analysis might mistake for causality, and used the HEIDI (heterogeneity in dependent instruments) test to remove cross-phenotype associations that were likely due to genetic linkage. RESULTS: Our PheWAS identified 25 disease groups/outcomes associated with SUA genetic risk loci after multiple testing correction (P<8.57e-05). Our conventional MR analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. Our analysis highlighted a locus (ATXN2/S2HB3) that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy. CONCLUSIONS: Elevated SUA level is convincing to cause gout and inflammatory polyarthropathies, and might act as a marker for the wider range of diseases with which it associates. Our findings support further investigation on the clinical relevance of SUA level with cardiovascular, metabolic, autoimmune and respiratory diseases. PMID- 29437587 TI - New insights into the biomechanics of Legg-Calve-Perthes' disease: The Role of Epiphyseal Skeletal Immaturity in Vascular Obstruction. AB - OBJECTIVES: Legg-Calve-Perthes' disease (LCP) is an idiopathic osteonecrosis of the femoral head that is most common in children between four and eight years old. The factors that lead to the onset of LCP are still unclear; however, it is believed that interruption of the blood supply to the developing epiphysis is an important factor in the development of the condition. METHODS: Finite element analysis modelling of the blood supply to the juvenile epiphysis was investigated to understand under which circumstances the blood vessels supplying the femoral epiphysis could become obstructed. The identification of these conditions is likely to be important in understanding the biomechanics of LCP. RESULTS: The results support the hypothesis that vascular obstruction to the epiphysis may arise when there is delayed ossification and when articular cartilage has reduced stiffness under compression. CONCLUSION: The findings support the theory of vascular occlusion as being important in the pathophysiology of Perthes disease.Cite this article: M. Pinheiro, C. A. Dobson, D. Perry, M. J. Fagan. New insights into the biomechanics of Legg-Calve-Perthes' disease: The Role of Epiphyseal Skeletal Immaturity in Vascular Obstruction. Bone Joint Res 2018;7:148 156. DOI: 10.1302/2046-3758.72.BJR-2017-0191.R1. PMID- 29437588 TI - Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. AB - Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present. PMID- 29437590 TI - Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial. AB - We tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS (P < .0001) and OS (P = .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (>147 cm3) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (<=147 cm3). In multivariable analysis including iPET2, TMTV was the only baseline prognosticator compared with the current staging systems proposed by the European Organization for Research and Treatment of Cancer/Groupe d'Etude des Lymphomes de l'Adulte, German Hodgkin Study Group, or National Comprehensive Cancer Network. TMTV and iPET2 were independently prognostic and, combined, identified 4 risk groups: low (TMTV<=147+DS1-3; 5-year PFS, 95%), low-intermediate (TMTV>147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV<=147+DS4-5; 5-year PFS, 50%), and high (TMTV>147+DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well. PMID- 29437589 TI - Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin. AB - B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of their propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B-cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms. Here, we identify prolyl 4-hydroxylase 2 (P4HA2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/extracellular signal-regulated kinase pathway and increasing B cell lymphoma proliferation. P4HA2 is undetectable in normal B cells but upregulated in the diffuse large B-cell lymphoma (DLBCL), driving Carabin inactivation and lymphoma proliferation. Our results indicate that P4HA2 is a potential prognosis marker for DLBCL and a promising pharmacological target for developing treatment of molecularly stratified B-cell lymphomas. PMID- 29437591 TI - B-cell targeting in chronic graft-versus-host disease. AB - Over the last decade, our understanding of the pathophysiology of chronic graft versus-host disease (cGVHD) has improved considerably. In this spotlight, we discuss emerging insights into the pathophysiology of cGVHD with a focus on B cells. First, we summarize supporting evidence derived from mouse and human studies. Next, novel cGVHD therapy approaches that target B cells will be covered to provide treating physicians with an overview of the rationale behind the emerging armamentarium against cGVHD. PMID- 29437592 TI - Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. AB - We previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naive (TN) older patients (>=65 years of age) and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N = 31) and R/R (N = 101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN patients and 10% in R/R patients. The median progression-free survival (PFS) was not reached in TN patients. The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups. Survival outcomes were less robust for R/R patients with del(17p) and those who received more prior therapies. The onset of grade >=3 cytopenias, such as neutropenia and thrombocytopenia, decreased over time. Treatment--limiting adverse events were more frequent during the first year compared with subsequent periods. These results demonstrate sustained efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL. These trials were registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01109069. PMID- 29437593 TI - alpha1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus host disease. AB - Corticosteroid resistance after acute graft-versus-host disease (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation. Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness because of poor response or excessive toxicity, primarily from infection. alpha1-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (Treg) to effector T cells (Teffs). In this prospective multicenter clinical study, we sought to determine the safety and response rate of AAT administration in SR-aGVHD. Forty patients with a median age of 59 years received intravenous AAT twice weekly for 4 weeks as first-line treatment of SR-aGVHD. The primary end point was overall response rate (ORR), the proportion of patients with SR-aGVHD in complete (CR) or partial response by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug-related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rates by day 28 were 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with preclinical data, correlative samples showed an increase in ratio of activated Tregs to Teffs after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01700036. PMID- 29437594 TI - HO-1hi patrolling monocytes protect against vaso-occlusion in sickle cell disease. AB - Patients with sickle cell disease (SCD) suffer from intravascular hemolysis associated with vascular injury and dysfunction in mouse models, and painful vaso occlusive crisis (VOC) involving increased attachment of sickle erythrocytes and activated leukocytes to damaged vascular endothelium. Patrolling monocytes, which normally scavenge damaged cells and debris from the vasculature, express higher levels of anti-inflammatory heme oxygenase 1 (HO-1), a heme degrading enzyme. Here, we show that HO-1-expressing patrolling monocytes protect SCD vasculature from ongoing hemolytic insult and vaso-occlusion. We found that a mean 37% of patrolling monocytes from SCD patients express very high levels of HO-1 (HO-1hi) vs 6% in healthy controls and demonstrated that HO-1hi expression was dependent on uptake of heme-exposed endothelium. SCD patients with a recent VOC episode had lower numbers of HO-1hi patrolling monocytes. Heme-mediated vaso-occlusion by mouse SCD red blood cells was exacerbated in mice lacking patrolling monocytes, and reversed following transfer of patrolling monocytes. Altogether, these data indicate that SCD patrolling monocytes remove hemolysis-damaged endothelial cells, resulting in HO-1 upregulation and dampening of VOC, and that perturbation in patrolling monocyte numbers resulting in lower numbers of HO-1hi patrolling monocyte may predispose SCD patients to VOC. These data suggest that HO-1hi patrolling monocytes are key players in VOC pathophysiology and have potential as therapeutic targets for VOC. PMID- 29437595 TI - Integrated molecular profiling of juvenile myelomonocytic leukemia. AB - Juvenile myelomonocytic leukemia (JMML), a rare and aggressive myelodysplastic/myeloproliferative neoplasm that occurs in infants and during early childhood, is characterized by excessive myelomonocytic cell proliferation. More than 80% of patients harbor germ line and somatic mutations in RAS pathway genes (eg, PTPN11, NF1, NRAS, KRAS, and CBL), and previous studies have identified several biomarkers associated with poor prognosis. However, the molecular pathogenesis of 10% to 20% of patients and the relationships among these biomarkers have not been well defined. To address these issues, we performed an integrated molecular analysis of samples from 150 JMML patients. RNA sequencing identified ALK/ROS1 tyrosine kinase fusions (DCTN1-ALK, RANBP2-ALK, and TBL1XR1-ROS1) in 3 of 16 patients (18%) who lacked canonical RAS pathway mutations. Crizotinib, an ALK/ROS1 inhibitor, markedly suppressed ALK/ROS1 fusion positive JMML cell proliferation in vitro. Therefore, we administered crizotinib to a chemotherapy-resistant patient with the RANBP2-ALK fusion who subsequently achieved complete molecular remission. In addition, crizotinib also suppressed proliferation of JMML cells with canonical RAS pathway mutations. Genome-wide methylation analysis identified a hypermethylation profile resembling that of acute myeloid leukemia (AML), which correlated significantly with genetic markers with poor outcomes such as PTPN11/NF1 gene mutations, 2 or more genetic mutations, an AML-type expression profile, and LIN28B expression. In summary, we identified recurrent activated ALK/ROS1 fusions in JMML patients without canonical RAS pathway gene mutations and revealed the relationships among biomarkers for JMML. Crizotinib is a promising candidate drug for the treatment of JMML, particularly in patients with ALK/ROS1 fusions. PMID- 29437596 TI - Antiplatelet Therapy Changes for Patients With Myocardial Infarction With Recurrent Ischemic Events: Insights Into Contemporary Practice From the TRANSLATE ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) Study. AB - BACKGROUND: Guidelines recommend P2Y12 inhibitor therapy for 1 year after myocardial infarction (MI), yet little guidance is provided on antiplatelet management for patients with recurrent ischemic events during that year. We describe changes in P2Y12 inhibitor type among patients with recurrent ischemic events in the first year after MI. METHODS AND RESULTS: The TRANSLATE-ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study enrolled 12 365 patients with MI treated with percutaneous coronary intervention. We examined whether P2Y12 inhibitor choice changed among patients with recurrent MI, stent thrombosis, and/or unplanned revascularization during the first year after MI, and modeled factors associated with P2Y12 inhibitor intensification (changing clopidogrel to prasugrel or ticagrelor). In the first year after MI, 1414 patients (11%) had a total of 1740 recurrent ischemic events (771 recurrent MIs, 969 unplanned revascularizations, and 165 stent thromboses). Median time to the first recurrent ischemic event was 154 days (25th-75th percentiles, 55-287 days). Of those with recurrent ischemic events, 101 of 1092 (9.3%) occurring in clopidogrel-treated patients led to P2Y12 inhibitor intensification. Recurrent events involving stent thrombosis or MI were the strongest factors associated with P2Y12 inhibitor intensification, yet only 40% of patients with stent thrombosis and 14% of patients with recurrent MI had P2Y12 inhibitor intensification. Increasing age and longer time from the index MI were associated with lower likelihood for intensification. CONCLUSIONS: Few patients after MI with a recurrent ischemic event who were taking clopidogrel switched to a more potent P2Y12 inhibitor, even after stent thrombosis events. Specific guidance is needed for patients who have recurrent ischemic events, particularly when closely spaced. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01088503. PMID- 29437597 TI - Conventional and Ambulatory Blood Pressure as Predictors of Diastolic Left Ventricular Function in a Flemish Population. AB - BACKGROUND: No longitudinal study compared associations of echocardiographic indexes of diastolic left ventricular function studies with conventional (CBP) and daytime ambulatory (ABP) blood pressure in the general population. METHODS AND RESULTS: In 780 Flemish (mean age, 50.2 years; 51.7% women), we measured left atrial volume index (LAVI), peak velocities of the transmitral blood flow (E) and mitral annular movement (e') in early diastole and E/e' 9.6 years (median) after CBP and ABP. In adjusted models including CBP and ABP, we expressed associations per 10/5-mm Hg systolic/diastolic blood pressure increments. LAVI and E/e' were 0.65/0.40 mL/m2 and 0.17/0.09 greater with higher systolic/diastolic ABP (P<=0.028), but not with higher baseline CBP (P>=0.086). e' was lower (P<=0.032) with higher diastolic CBP (-0.09 cm/s) and ABP (-0.19 cm/s). When we substituted baseline CBP by CBP recorded concurrently with echocardiography, LAVI and E/e' remained 0.45/0.38 mL/m2 and 0.15/0.08 greater with baseline ABP (P<=0.036), while LAVI (+0.53 mL/m2) and E/e' (+0.19) were also greater (P<0.001) in relation to concurrent systolic CBP. In categorized analyses of baseline data, sustained hypertension or masked hypertension compared with normotension or white-coat hypertension was associated with greater LAVI (24.0 versus 22.6 mL/m2) and E/e' (7.35 versus 6.91) and lower e' (10.7 versus 11.6 cm/s; P<=0.006 for all) with no differences (P>=0.092) between normotension and white-coat hypertension or between masked hypertension and sustained hypertension. CONCLUSIONS: ABP is a long-term predictor of diastolic left ventricular function, statistically outperforming distant but not concurrent CBP. Masked hypertension and sustained hypertension carry equal risk for deterioration of diastolic left ventricular function. PMID- 29437598 TI - Bilateral Transcutaneous Electrical Nerve Stimulation Improves Lower-Limb Motor Function in Subjects With Chronic Stroke: A Randomized Controlled Trial. AB - BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) has been used to augment the efficacy of task-oriented training (TOT) after stroke. Bilateral intervention approaches have also been shown to be effective in augmenting motor function after stroke. The purpose of this study was to compare the efficacy of bilateral TENS combined with TOT versus unilateral TENS combined with TOT in improving lower-limb motor function in subjects with chronic stroke. METHODS AND RESULTS: Eighty subjects were randomly assigned to bilateral TENS+TOT or to unilateral TENS+TOT and underwent 20 sessions of training over a 10-week period. The outcome measures included the maximal strength of the lower-limb muscles and the results of the Lower Extremity Motor Coordination Test, Berg Balance Scale, Step Test, and Timed Up and Go test. Each participant was assessed at baseline, after 10 and 20 sessions of training and 3 months after the cessation of training. The subjects in the bilateral TENS+TOT group showed greater improvement in paretic ankle dorsiflexion strength (beta=1.32; P=0.032) and in the completion time for the Timed Up and Go test (beta=-1.54; P=0.004) than those in the unilateral TENS+TOT group. However, there were no significant between-group differences for other outcome measures. CONCLUSIONS: The application of bilateral TENS over the common peroneal nerve combined with TOT was superior to the application of unilateral TENS combined with TOT in improving paretic ankle dorsiflexion strength after 10 sessions of training and in improving the completion time for the Timed Up and Go test after 20 sessions of training. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02152813. PMID- 29437599 TI - "Malignant" Left Ventricular Hypertrophy Identifies Subjects at High Risk for Progression to Asymptomatic Left Ventricular Dysfunction, Heart Failure, and Death: MESA (Multi-Ethnic Study of Atherosclerosis). AB - BACKGROUND: As heart failure (HF)-associated morbidity and mortality continue to escalate, enhanced focus on prevention is increasingly important. "Malignant" left ventricular (LV) hypertrophy (LVH): LVH combined with an elevated cardiac biomarker reflecting either injury (high-sensitivity cardiac troponin T), or strain (amino-terminal pro-B-type natriuretic peptide) has predicted accelerated progression to HF. We sought to determine whether malignant LVH identified community-dwelling adults initially free of cardiovascular disease at high risk of asymptomatic decline in LV ejection fraction or a clinical cardiovascular event. METHODS AND RESULTS: A total of 4985 of 6814 individuals without prevalent cardiovascular disease underwent baseline cardiac magnetic resonance for LVH in combination with measurement of plasma high-sensitivity cardiac troponin T and amino-terminal pro-B-type natriuretic peptide as part of MESA (Multi-Ethnic Study of Atherosclerosis) and were subsequently divided into 4 groups: (1) No LVH, no elevated biomarkers (n=2206; 44.3%); (2) No LVH, >=1 elevated biomarkers (n=2275; 45.7%); (3) LVH, no elevated biomarkers (n=153; 3.0%); and (4) LVH, >=1 elevated biomarkers (malignant LVH; n=351; 7.0%). Cardiac magnetic resonance was repeated 10 years later (n=2831) for assessment of LV ejection fraction <50%. Median follow-up was 12.2 years. Malignant LVH was associated with 7.0-, 3.5-, and 2.6 fold adjusted increases in incidence of HF, cardiovascular death, and asymptomatic LV dysfunction, respectively, versus group 1. New-onset HF was predominately HF with reduced ejection fraction (9.5-fold increase). CONCLUSIONS: Malignant LVH is predictive of progression to asymptomatic LV dysfunction, HF (particularly HF with reduced ejection fraction), and cardiovascular death. Consequently, malignant LVH represents a high-risk phenotype among individuals without known cardiovascular disease, which should be targeted for increased surveillance and more-aggressive therapies. PMID- 29437601 TI - Relationship Between the Ambulatory Arterial Stiffness Index and the Lower Limit of Cerebral Autoregulation During Cardiac Surgery. AB - BACKGROUND: Pulse pressure, the ambulatory arterial stiffness index (AASI), and the symmetric AASI are established predictors of adverse cardiovascular outcomes. However, little is known about their relationship to cerebral autoregulation. This study evaluated whether these markers of vascular properties relate to the lower limit of cerebral autoregulation (LLA). METHODS AND RESULTS: The LLA was determined during cardiac surgery with transcranial Doppler ultrasonography in 181 patients. All other variables were calculated from continuous intraoperative readings obtained before cardiopulmonary bypass. The LLA varied directly with the AASI (beta=3.12 per 0.1 change in AASI, P<0.001) and to a lesser extent the symmetric AASI (beta=2.02 per 0.1 change in symmetric AASI, P<=0.022), while peripheral pulse pressure was not significantly related (beta=0.0, P>0.99). Logistic regression revealed that the likelihood of LLA being >65 mm Hg increased by 50% (95% confidence interval, 11%-102%, P=0.008) for every 0.1 increase in the AASI. The AASI was able to predict a LLA above certain thresholds (area under the curve receiver operating characteristic for AASI predicting an LLA >65 mm Hg: 0.60; 95% confidence interval, 0.51%-0.68%, P=0.043). Incorporating additional variables improved the model's predictive ability (area under the curve for AASI predicting a LLA >65 mm Hg: 0.75; 95% confidence interval, 0.68-0.82, P=0.036). CONCLUSIONS: These data indicate that the LLA is related to the mechanical properties of the vasculature as represented by the AASI. The AASI can be used to predict LLA threshold levels during cardiac surgery. It is now possible to link elevations in the LLA with an increased AASI as determined from readily accessible intraoperative variables. PMID- 29437600 TI - Physical Activity in the Prevention and Treatment of Coronary Artery Disease. PMID- 29437602 TI - Adult Congenital Heart Disease in a Nationwide Population 2000-2014: Epidemiological Trends, Arrhythmia, and Standardized Mortality Ratio. AB - BACKGROUND: The adult congenital heart disease (ACHD) population will grow with medical advances, but data are limited. We investigated the epidemiological profile of ACHD in Taiwan, a country with a congenital heart disease program since 1955, population of 23 million, and easily accessible high-standard medical care. METHODS AND RESULTS: ACHD patients, born after 1954, were identified from the nationwide database 2000-2014. The ACHD prevalence in the population aged 18 to 59 was 140.53, 157.08, 182.45, and 217.00 per 100 000 in 2000, 2005, 2010, and 2014, respectively (increasing time trend, P<0.0001). Percentage of severe ACHD also increased over time (P<0.0001) and was 11.70% in 2014. The 5 leading ACHD diagnoses were ventricular septal defect, secundum atrial septal defect, patent ductus arteriosus, pulmonary stenosis, and tetralogy of Fallot. Freedom from tachyarrhythmia at age 50 years was 0.574 and 0.710 for severe and simple ACHD, respectively. Cardiac causes accounted for the majority of deaths, followed by malignancy in simple ACHD and external causes/sudden death/out-of-hospital death in severe ACHD patients. The proportion of unexpected death was 10%. Compared with the general population, the standardized mortality ratio was higher not only in severe ACHD (3.164; 95% confidence interval, 2.664-3.664), but also in women with simple ACHD (1.704; 95% confidence interval, 1.499-1.909), with a higher proportion of cardiac, labor, and sudden death as causes of death. CONCLUSIONS: We demonstrated an increasing trend in ACHD prevalence and medical complexity. They are at risk of tachyarrhythmia, higher mortality, and unexpected deaths, suggesting a gap in their medical care. PMID- 29437604 TI - Derivation and Validation of an In-Hospital Mortality Prediction Model Suitable for Profiling Hospital Performance in Heart Failure. AB - BACKGROUND: Comparing heart failure (HF) outcomes across hospitals requires adequate risk adjustment. We aimed to develop and validate a model that can be used to compare quality of HF care across hospitals. METHODS AND RESULTS: We included patients with HF aged >=18 years admitted to one of 433 hospitals that participated in the Premier Inc Data Warehouse. This model (Premier) contained patient demographics, comorbidities, and acute conditions present on admission, derived from administrative and billing records. In a separate data set derived from electronic health records, we validated the Premier model by comparing hospital risk-standardized mortality rates calculated with the Premier model to those calculated with a validated clinical model containing laboratory data (LAPS [Laboratory-Based Acute Physiology Score]). Among the 200 832 admissions in the Premier Inc Data Warehouse, inpatient mortality was 4.0%. The model showed acceptable discrimination in the warehouse data (C statistic 0.75; 95% confidence interval, 0.74-0.76). In the validation data set, both the Premier model and the LAPS models showed acceptable discrimination (C statistic: Premier: 0.76 [95% confidence interval, 0.74-0.77]; LAPS: 0.78 [95% confidence interval, 0.76 0.80]). Risk-standardized mortality rates for both models ranged from 2% to 7%. A linear regression equation describing the association between Premier- and LAPS specific mortality rates revealed a regression line with a slope of 0.71 (SE: 0.07). The correlation coefficient of the standardized mortality rates from the 2 models was 0.82. CONCLUSIONS: Compared with a validated model derived from clinical data, an HF mortality model derived from administrative data showed highly correlated risk-standardized mortality rate estimates, suggesting it could be used to identify high- and low-performing hospitals for HF care. PMID- 29437606 TI - Opening a can of worms in AL progression. PMID- 29437603 TI - Atherosclerotic Calcification: Wnt Is the Hint. PMID- 29437607 TI - Removal of destructive brain-borne microdust. PMID- 29437605 TI - Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis. AB - BACKGROUND: To investigate whether neutrophil elastase (NE) plays a causal role in atherosclerosis, and the molecular mechanisms involved. METHODS AND RESULTS: NE genetic-deficient mice (Apolipoprotein E-/-/NE-/- mice), bone marrow transplantation, and a specific NE inhibitor (GW311616A) were employed in this study to establish the causal role of NE in atherosclerosis. Aortic expression of NE mRNA and plasma NE activity was significantly increased in high-fat diet (HFD) fed wild-type (WT) (Apolipoprotein E-/-) mice but, as expected, not in NE deficient mice. Selective NE knockout markedly reduced HFD-induced atherosclerosis and significantly increased indicators of atherosclerotic plaque stability. While plasma lipid profiles were not affected by NE deficiency, decreased levels of circulating proinflammatory cytokines and inflammatory monocytes (Ly6Chi/CD11b+) were observed in NE-deficient mice fed with an HFD for 12 weeks as compared with WT. Bone marrow reconstitution of WT mice with NE-/- bone marrow cells significantly reduced HFD-induced atherosclerosis, while bone marrow reconstitution of NE-/- mice with WT bone marrow cells restored the pathological features of atherosclerotic plaques induced by HFD in NE-deficient mice. In line with these findings, pharmacological inhibition of NE in WT mice through oral administration of NE inhibitor GW311616A also significantly reduced atherosclerosis. Mechanistically, we demonstrated that NE promotes foam cell formation by increasing ATP-binding cassette transporter ABCA1 protein degradation and inhibiting macrophage cholesterol efflux. CONCLUSIONS: We outlined a pathogenic role for NE in foam cell formation and atherosclerosis development. Consequently, inhibition of NE may represent a potential therapeutic approach to treating cardiovascular disease. PMID- 29437608 TI - A "foamy" mastocytosis case. PMID- 29437609 TI - Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808. PMID- 29437611 TI - Understanding the Proline-Centric Design of a Peptide-Mediated Macrolide Resistance Mechanism. PMID- 29437610 TI - Optimization of a Meropenem-Tobramycin Combination Dosage Regimen against Hypermutable and Nonhypermutable Pseudomonas aeruginosa via Mechanism-Based Modeling and the Hollow-Fiber Infection Model. AB - Hypermutable Pseudomonas aeruginosa strains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild type strain and its isogenic hypermutable PAODeltamutS strain (MICmeropenem of 1.0 mg/liter and MICtobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ~108.4 CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAODeltamutS strain in the HFIM, all monotherapies resulted in rapid regrowth to >108.7 CFU/ml with near complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log10 bacterial killing followed by regrowth to >6 log10 CFU/ml by day 5 and high-level resistance (MICmeropenem, 32 mg/liter; MICtobramycin, 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log10 over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem. PMID- 29437612 TI - Azole Resistance of Environmental and Clinical Aspergillus fumigatus Isolates from Switzerland. AB - Aspergillus fumigatus is a ubiquitous opportunistic pathogen. This fungus can acquire resistance to azole antifungals due to mutations in the azole target (cyp51A). Recently, cyp51A mutations typical for environmental azole resistance acquisition (for example, TR34/L98H) have been reported. These mutations can also be found in isolates recovered from patients. Environmental azole resistance acquisition has been reported on several continents. Here we describe, for the first time, the occurrence of azole-resistant A. fumigatus isolates of environmental origin in Switzerland with cyp51A mutations, and we show that these isolates can also be recovered from a few patients. While the TR34/L98H mutation was dominant, a single azole-resistant isolate exhibited a cyp51A mutation (G54R) that was reported only for clinical isolates. In conclusion, our study demonstrates that azole resistance with an environmental signature is present in environments and patients of Swiss origin and that mutations believed to be unique to clinical settings are now also observed in the environment. PMID- 29437613 TI - Evolution of the Pseudomonas aeruginosa Aminoglycoside Mutational Resistome In Vitro and in the Cystic Fibrosis Setting. AB - Inhaled administration of high doses of aminoglycosides is a key maintenance treatment of Pseudomonas aeruginosa chronic respiratory infections in cystic fibrosis (CF). We analyzed the dynamics and mechanisms of stepwise high-level tobramycin resistance development in vitro and compared the results with those of isogenic pairs of susceptible and resistant clinical isolates. Resistance development correlated with fusA1 mutations in vitro and in vivo. pmrB mutations, conferring polymyxin resistance, were also frequently selected in vitro In contrast, mutational overexpression of MexXY, a hallmark of aminoglycoside resistance in CF, was not observed in in vitro evolution experiments. PMID- 29437614 TI - Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects. AB - Meropenem-vaborbactam is a fixed combination of the novel beta-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.). PMID- 29437615 TI - The Novel Fungal Cyp51 Inhibitor VT-1598 Is Efficacious in Experimental Models of Central Nervous System Coccidioidomycosis Caused by Coccidioides posadasii and Coccidioides immitis. AB - Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungus-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of central nervous system coccidioidomycosis caused by C. posadasii and C. immitis Infection was introduced via intracranial inoculation, and therapy began 48 h postinoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in the C. immitis study and VT-1161 in the C. posadasii study. Treatment continued for 7 and 14 days in the fungal-burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 h posttreatment in the fungal-burden studies, on the days the mice succumbed to infection, or at prespecified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in the C. posadasii study. VT-1598 resulted in significant improvements in survival in mice infected with either species. In addition, the fungal burden was significantly reduced in the fungal-burden studies. Plasma concentrations 48 h after dosing stopped remained above the VT-1598 MIC against the C. posadasii isolate, although levels were undetectable in the survival study after a 4-week washout. Whereas fungal burden remained suppressed after a 2-week washout in the C. immitis model, a higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis. PMID- 29437616 TI - A Novel Rabbit Spirometry Model of Type E Botulism and Its Use for the Evaluation of Postsymptom Antitoxin Efficacy. AB - Botulinum neurotoxins (BoNTs), the most poisonous substances known in nature, pose significant concern to health authorities. The only approved therapeutic for botulism is antitoxin. While administered to patients only after symptom onset, antitoxin efficacy is evaluated in animals mostly in relation to time postintoxication regardless of symptoms. This is most likely due to the difficulty in measuring early symptoms of botulism in animals. In this study, a rabbit spirometry model was developed to quantify early respiratory symptoms of type E botulism that were further used as a trigger for treatment. Impaired respiration, in the form of a reduced minute volume, was detected as early as 18.1 +/- 2.9 h after intramuscular exposure to 2 rabbit 50% lethal doses (LD50) of BoNT serotype E (BoNT/E), preceding any visible symptoms. All rabbits treated with antitoxin immediately following symptom onset survived. Postsymptom antitoxin efficacy was further evaluated in relation to toxin and antitoxin dosages as well as delayed antitoxin administration. Our system enabled us to demonstrate, for the first time, full antitoxin protection of animals treated with antitoxin after the onset of objective and quantitative type E botulism symptoms. This model may be utilized to evaluate the efficacy of antitoxins for additional serotypes of BoNT as well as that of next-generation anti-BoNT drugs that enter affected cells and act when antitoxin is no longer effective. PMID- 29437617 TI - Systematic Review and Meta-analysis of the Safety of Antistaphylococcal Penicillins Compared to Cefazolin. AB - Recent studies and experience suggest that cefazolin might be equally as effective as antistaphylococcal penicillins for methicillin-susceptible Staphylococcus aureus (MSSA), with a better safety profile and lower cost. The objective of these meta-analyses was to compare the safeties of antistaphylococcal penicillins and cefazolin. The PubMed, Embase, and International Pharmaceutical Abstracts databases and websites for clinical trial registries through 23 June 2017 were searched. In addition, recent abstracts from infectious disease and pharmacy conferences were reviewed. We estimated Peto odds ratios (ORs) with 95% confidence intervals (CIs) using random-effects models. One analysis focused on hospitalized patients, and the other focused on outpatients. Eleven retrospective studies of hospitalized patients and three retrospective studies of outpatients were included. In hospitalized patients, lower rates of nephrotoxicity (Peto OR, 0.225; 95% CI, 0.127 to 0.513), acute interstitial nephritis (Peto OR, 0.189; 95% CI, 0.053 to 0.675), hepatotoxicity (Peto OR, 0.160; 95% CI, 0.066 to 0.387), and drug discontinuation due to adverse reactions (Peto OR, 0.192; 95% CI, 0.089 to 0.414) were found with cefazolin. In outpatients, lower rates of nephrotoxicity (Peto OR, 0.372; 95% CI, 0.192 to 0.722), hepatotoxicity (Peto OR, 0.313; 95% CI, 0.156 to 0.627), and hypersensitivity reactions (Peto OR, 0.372; 95% CI, 0.201 to 0.687) were observed with cefazolin. Compared to antistaphylococcal penicillins, cefazolin was associated with significant reductions in nephrotoxicity and hepatotoxicity in hospitalized patients and outpatients. Additionally, cefazolin was associated with lower likelihoods of discontinuation due to side effects in hospitalized patients and hypersensitivity reactions in outpatients. Cefazolin should be considered a first-line option for patients with MSSA infections for which efficacy is presumed to be similar to that of antistaphylococcal penicillin therapy. PMID- 29437618 TI - In Vitro and In Vivo Activities of DS86760016, a Novel Leucyl-tRNA Synthetase Inhibitor for Gram-Negative Pathogens. AB - The emergence of multidrug-resistant (MDR) Gram-negative bacilli is a major concern in the treatment of nosocomial infections. Antibacterial agents with novel modes of action can be useful, as these pathogens have become resistant to almost all existing standard-of-care agents. GSK2251052, a leucyl-tRNA synthetase inhibitor, has a novel mode of action against Gram-negative bacteria. However, the phase 2 studies with this drug were terminated due to microbiological failures based on the rapid emergence of drug resistance during the treatment of complicated urinary tract infections. DS86760016 is a novel leucyl-tRNA synthetase inhibitor active against MDR Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, with an improved pharmacokinetic profile. DS86760016 showed lower plasma clearance, longer plasma half-life, and higher renal excretion than GSK2251052 did in mice, rats, monkeys and dogs. DS86760016 also showed lower mutant prevention concentrations against P. aeruginosa than did GSK2251052. No resistant bacteria were observed in murine urinary tract infection models at a dose that maintained urinary concentrations above the mutant prevention concentration. DS86760016 also showed a lower risk of resistance development than did GSK2251052 in comparative in vivo studies with murine urinary tract infection models. These results suggest that DS86760016 has potential as a new drug for the treatment of MDR Gram negative bacterial infections, with a lower risk of drug resistance development than that of GSK2251052. PMID- 29437619 TI - Synergy between Pyrvinium Pamoate and Azoles against Exophiala dermatitidis. PMID- 29437621 TI - Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses. AB - Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified. PMID- 29437620 TI - Antifungal Susceptibility of the Aspergillus viridinutans Complex: Comparison of Two In Vitro Methods. AB - Cryptic species of Aspergillus fumigatus, including the Aspergillus viridinutans species complex, are increasingly reported to be causes of invasive aspergillosis. Their identification is clinically relevant, as these species frequently have intrinsic resistance to common antifungals. We evaluated the susceptibilities of 90 environmental and clinical isolates from the A. viridinutans species complex, identified by DNA sequencing of the calmodulin gene, to seven antifungals (voriconazole, posaconazole, itraconazole, amphotericin B, anidulafungin, micafungin, and caspofungin) using the reference European Committee on Antimicrobial Susceptibility Testing (EUCAST) method. The majority of species demonstrated elevated MICs of voriconazole (geometric mean [GM] MIC, 4.46 mg/liter) and itraconazole (GM MIC, 9.85 mg/liter) and had variable susceptibility to amphotericin B (GM MIC, 2.5 mg/liter). Overall, the MICs of posaconazole and the minimum effective concentrations of echinocandins were low. The results obtained by the EUCAST method were compared with the results obtained with Sensititre YeastOne (YO) panels. Overall, there was 67% agreement (95% confidence interval [CI], 62 to 72%) between the results obtained by the EUCAST method and those obtained with YO panels when the results were read at 48 h and 82% agreement (95% CI, 78 to 86%) when the results were read at 72 h. There was a significant difference in agreement between antifungals; agreement was high for amphotericin B, voriconazole, and posaconazole (70 to 86% at 48 h and 88 to 93% at 72 h) but was very low for itraconazole (37% at 48 h and 57% at 72 h). The agreement was also variable between species, with the maximum agreement being observed for A. felis isolates (85 and 93% at 48 and 72 h, respectively). Elevated MICs of voriconazole and itraconazole were cross correlated, but there was no correlation between the other azoles tested. PMID- 29437623 TI - Development of Echinocandin Resistance in Candida tropicalis following Short-Term Exposure to Caspofungin for Empiric Therapy. AB - Isolation of two echinocandin-resistant Candida tropicalis strains from endotracheal secretions of a patient following short-term exposure to caspofungin is described. Both strains exhibited resistance to echinocandins by Etest and reference broth microdilution, showing a homozygous S645P mutation within the hot spot 1 (HS-1) region of FKS1 and belonging to a unique multilocus sequence type. Other C. tropicalis isolates collected from patients in the same intensive care unit within a 60-day period were susceptible to echinocandins and contained wild type FKS1 sequences. PMID- 29437622 TI - In Vivo Transfer and Microevolution of Avian Native IncA/C2blaNDM-1-Carrying Plasmid pRH-1238 during a Broiler Chicken Infection Study. AB - The emergence and spread of carbapenemase-producing Enterobacteriaceae (CPE) in wildlife and livestock animals pose an important safety concern for public health. With our in vivo broiler chicken infection study, we investigated the transfer and experimental microevolution of the blaNDM-1-carrying IncA/C2 plasmid (pRH-1238) introduced by avian native Salmonella enterica subsp. enterica serovar Corvallis without inducing antibiotic selection pressure. We evaluated the dependency of the time point of inoculation on donor (S Corvallis [12-SA01738]) and plasmid-free Salmonella recipient [d-tartrate-fermenting (d-Ta+) S Paratyphi B (13-SA01617), referred to here as S Paratyphi B (d-Ta+)] excretion by quantifying their excretion dynamics. Using plasmid profiling by S1 nuclease restricted pulsed-field gel electrophoresis, we gained insight into the variability of the native plasmid content among S Corvallis reisolates as well as plasmid acquisition in S Paratyphi B (d-Ta+) and the enterobacterial gut microflora. Whole-genome sequencing enabled us to gain an in-depth insight into the microevolution of plasmid pRH-1238 in S Corvallis and enterobacterial recipient isolates. Our study revealed that the fecal excretion of avian native carbapenemase-producing S Corvallis is significantly higher than that of S Paratyphi (d-Ta+) and is not hampered by S Paratyphi (d-Ta+). Acquisition of pRH 1238 in other Enterobacteriaceae and several events of plasmid pRH-1238 transfer to different Escherichia coli sequence types and Klebsiella pneumoniae demonstrated an interspecies broad host range. Regardless of the microevolutionary structural deletions in pRH-1238, the single carbapenem resistance marker blaNDM-1 was maintained on pRH-1238 throughout the trial. Furthermore, we showed the importance of the gut E. coli population as a vector of pRH-1238. In a potential scenario of the introduction of NDM-1-producing S Corvallis into a broiler flock, the pRH-1238 plasmid could persist and spread to a broad host range even in the absence of antibiotic pressure. PMID- 29437624 TI - Posaconazole MIC Distributions for Aspergillus fumigatus Species Complex by Four Methods: Impact of cyp51A Mutations on Estimation of Epidemiological Cutoff Values. AB - Estimating epidemiological cutoff endpoints (ECVs/ECOFFS) may be hindered by the overlap of MICs for mutant and nonmutant strains (strains harboring or not harboring mutations, respectively). Posaconazole MIC distributions for the Aspergillus fumigatus species complex were collected from 26 laboratories (in Australia, Canada, Europe, India, South and North America, and Taiwan) and published studies. Distributions that fulfilled CLSI criteria were pooled and ECVs were estimated. The sensitivity of three ECV analytical techniques (the ECOFFinder, normalized resistance interpretation [NRI], derivatization methods) to the inclusion of MICs for mutants was examined for three susceptibility testing methods (the CLSI, EUCAST, and Etest methods). The totals of posaconazole MICs for nonmutant isolates (isolates with no known cyp51A mutations) and mutant A. fumigatus isolates were as follows: by the CLSI method, 2,223 and 274, respectively; by the EUCAST method, 556 and 52, respectively; and by Etest, 1,365 and 29, respectively. MICs for 381 isolates with unknown mutational status were also evaluated with the Sensititre YeastOne system (SYO). We observed an overlap in posaconazole MICs among nonmutants and cyp51A mutants. At the commonly chosen percentage of the modeled wild-type population (97.5%), almost all ECVs remained the same when the MICs for nonmutant and mutant distributions were merged: ECOFFinder ECVs, 0.5 MUg/ml for the CLSI method and 0.25 MUg/ml for the EUCAST method and Etest; NRI ECVs, 0.5 MUg/ml for all three methods. However, the ECOFFinder ECV for 95% of the nonmutant population by the CLSI method was 0.25 MUg/ml. The tentative ECOFFinder ECV with SYO was 0.06 MUg/ml (data from 3/8 laboratories). Derivatization ECVs with or without mutant inclusion were either 0.25 MUg/ml (CLSI, EUCAST, Etest) or 0.06 MUg/ml (SYO). It appears that ECV analytical techniques may not be vulnerable to overlap between presumptive wild type isolates and cyp51A mutants when up to 11.6% of the estimated wild-type population includes mutants. PMID- 29437625 TI - Penetration of Cefotaxime into Cerebrospinal Fluid in Neonates and Young Infants. AB - Cefotaxime is the first-line treatment for meningitis in neonates and young infants. However, limited data on cefotaxime cerebrospinal fluid (CSF) concentrations in neonates and young infants were available. The aim of the present study was to evaluate the penetration of cefotaxime into CSF in neonates and young infants. Blood and CSF samples were collected from neonates and young infants treated with cefotaxime using an opportunistic pharmacokinetic sampling strategy, and concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry. The analysis was performed using NONMEM and R software. Thirty neonates and young infants (postmenstrual age range, 25.4 to 47.4 weeks) were included. A total of 67 plasma samples and 30 CSF samples were available for analysis. Cefotaxime plasma and CSF concentrations ranged from 2.30 to 175.42 mg/liter and from 0.39 to 25.38 mg/liter, respectively. The median ratio of the CSF concentration to the plasma concentration was 0.28 (range, 0.06 to 0.76). Monte Carlo simulation demonstrated that 88.4% and 63.9% of hypothetical neonates treated with 50 mg/kg of body weight three times a day (TID) would reach the pharmacodynamic target (the percentage of the dosing interval that the free antimicrobial drug concentration remains above the MIC, 70%) using the standard EUCAST MIC susceptibility breakpoints of 2 mg/liter and 4 mg/liter, respectively. The penetration of cefotaxime into the CSF of neonates and young infants was evaluated using an opportunistic sampling approach. A dosage regimen of 50 mg/kg TID could cover the most causative pathogens with MICs of <2 mg/liter. Individual dosage adaptation was required for more resistant bacterial strains, such as Staphylococcus aureus. PMID- 29437626 TI - Compounds with Potential Activity against Mycobacterium tuberculosis. AB - The high acquisition rate of drug resistance by Mycobacterium tuberculosis necessitates the ongoing search for new drugs to be incorporated in the tuberculosis (TB) regimen. Compounds used for the treatment of other diseases have the potential to be repurposed for the treatment of TB. In this study, a high-throughput screening of compounds against thiol-deficient Mycobacterium smegmatis strains and subsequent validation with thiol-deficient M. tuberculosis strains revealed that DeltaegtA and DeltamshA mutants had increased susceptibility to azaguanine (Aza) and sulfaguanidine (Su); DeltaegtB and DeltaegtE mutants had increased susceptibility to bacitracin (Ba); and DeltaegtA, DeltamshA, and DeltaegtB mutants had increased susceptibility to fusaric acid (Fu). Further analyses revealed that some of these compounds were able to modulate the levels of thiols and oxidative stress in M. tuberculosis This study reports the activities of Aza, Su, Fu, and Ba against M. tuberculosis and provides a rationale for further investigations. PMID- 29437627 TI - Drug Susceptibility Profiling and Genetic Determinants of Drug Resistance in Mycobacterium kansasii. AB - Very few studies have examined drug susceptibility of Mycobacterium kansasii, and they involve a limited number of strains. The purpose of this study was to determine drug susceptibility profiles of M. kansasii isolates representing a spectrum of species genotypes (subtypes) with two different methodologies, i.e., broth microdilution and Etest assays. To confirm drug resistance, drug target genes were sequenced. A collection of 85 M. kansasii isolates, including representatives of eight different subtypes (I to VI, I/II, and IIB) from eight countries, was used. Drug susceptibility against 13 and 8 antimycobacterial agents was tested by using broth microdilution and Etest, respectively. For drug resistant or high-MIC isolates, eight structural genes (rrl, katG, inhA, embB, rrs, rpsL, gyrA, and gyrB) and one regulatory region (embCA) were PCR amplified and sequenced in the search for resistance-associated mutations. All isolates tested were susceptible to rifampin (RIF), amikacin (AMK), co-trimoxazole (SXT), rifabutin (RFB), moxifloxacin (MXF), and linezolid (LZD) according to the microdilution method. Resistance to ethambutol (EMB), ciprofloxacin (CIP), and clarithromycin (CLR) was found in 83 (97.7%), 17 (20%), and 1 (1.2%) isolate, respectively. The calculated concordance between the Etest and dilution method was 22.6% for AMK, 4.8% for streptomycin (STR), 3.2% for CLR, and 1.6% for RIF. For EMB, INH, and SXT, not even a single MIC value determined by one method equaled that by the second method. The only mutations disclosed were A2266C transversion at the rrl gene (CLR-resistant strain) and A128G transition at the rpsL gene (strain with STR MIC of >64 mg/liter). In conclusion, eight drugs, including RIF, CLR, AMK, SXT, RFB, MXF, LZD, and ethionamide (ETO), showed high in vitro activity against M. kansasii isolates. Discrepancies of the results between the reference microdilution method and Etest preclude the use of the latter for drug susceptibility determination in M. kansasii Drug resistance in M. kansasii may have different genetic determinants than resistance to the same drugs in M. tuberculosis. PMID- 29437628 TI - Prophylactic Antiheparanase Activity by PG545 Is Antiviral In Vitro and Protects against Ross River Virus Disease in Mice. AB - Recently we reported on the efficacy of pentosan polysulfate (PPS), a heparan sulfate mimetic, to reduce the recruitment of inflammatory infiltrates and protect the cartilage matrix from degradation in Ross River virus (RRV)-infected PPS-treated mice. Here, we describe both prophylactic and therapeutic treatment with PG545, a low-molecular-weight heparan sulfate mimetic, for arthritogenic alphaviral infection. We first assessed antiviral activity in vitro through a 50% plaque reduction assay. Increasing concentrations of PG545 inhibited plaque formation prior to viral adsorption in viral strains RRV T48, Barmah Forest virus 2193, East/Central/South African chikungunya virus (CHIKV), and Asian CHIKV, suggesting a strong antiviral mode of action. The viral particle-compound dissociation constant was then evaluated through isothermal titration calorimetry. Furthermore, prophylactic RRV-infected PG545-treated mice had reduced viral titers in target organs corresponding to lower clinical scores of limb weakness and immune infiltrate recruitment. At peak disease, PG545-treated RRV-infected mice had lower concentrations of the matrix-degrading enzyme heparanase in conjunction with a protective effect on tissue morphology, as seen in the histopathology of skeletal muscle. Enzyme-linked immunosorbent assay quantification of cartilage oligomeric matrix protein and cross-linked C telopeptides of type II collagen as well as knee histopathology showed increased matrix protein degradation and cartilage erosion in RRV-infected phosphate buffered saline-treated mice compared to their PG545-treated RRV-infected counterparts. Taken together, these findings suggest that PG545 has a direct antiviral effect on arthritogenic alphaviral infection and curtails RRV-induced inflammatory disease when administered as a prophylaxis. PMID- 29437629 TI - Identification of Anti-Trypanosoma cruzi Lead Compounds with Putative Immunomodulatory Activity. AB - In seeking substitutions for the current Chagas disease treatment, which has several relevant side effects, new therapeutic candidates have been extensively investigated. In this context, a balanced interaction between mediators of the host immune response seems to be a key element for therapeutic success, as a proinflammatory microenvironment modulated by interleukin-10 (IL-10) is shown to be relevant to potentiate anti-Trypanosoma cruzi drug activity. This study aimed to identify the potential immunomodulatory activities of the anti-T. cruzi K777, pyronaridine (PYR), and furazolidone (FUR) compounds in peripheral blood mononuclear cells (PBMC) from noninfected (NI) subjects and chronic Chagas disease (CD) patients. Our results showed low cytotoxicity to PBMC populations, with 50% cytotoxic concentrations (CC50) of 71.0 MUM (K777), 9.0 MUM (PYR), and greater than 20 MUM (FUR). In addition, K777 showed no impact on the exposure index (EI) of phytohemagglutinin-stimulated leukocytes (PHA), while PYR and FUR treatments induced increased EI of monocytes and T lymphocytes at late stages of apoptosis in NI subjects. Moreover, K777 induced a more prominent proinflammatory response (tumor necrosis factor alpha-positive [TNF-alpha+] CD8+/CD4+, gamma interferon-positive [IFN-gamma+] CD4+/CD8+ modulated by interleukin-10-positive [IL-10+] CD4+ T/CD8+ T) than did PYR (TNF-alpha+ CD8+, IL-10+ CD8+) and FUR (TNF alpha+ CD8+, IL-10+ CD8+). Signature analysis of intracytoplasmic cytokines corroborated the proinflammatory/modulated (K777) and proinflammatory (PYR and FUR) profiles previously found. In conclusion, the lead compound K777 may induce beneficial changes in the immunological profile of patients presenting the chronic phase of Chagas disease and may contribute to a more effective therapy against the disease. PMID- 29437630 TI - Establishment and Validation of Galleria mellonella as a Novel Model Organism To Study Mycobacterium abscessus Infection, Pathogenesis, and Treatment. AB - Treatment of Mycobacterium abscessus infections is extremely challenging due to its intrinsic resistance to most antibiotics, and research of pathogenesis is limited due to a lack of a practical in vivo model of infection. The objective of this study was to establish a simple in vivo model for M. abscessus infection, virulence, and drug testing in Galleria mellonella larvae. We inoculated larvae with M. abscessus bacteria and assessed histopathology, CFU count, and mortality with and without antibiotic treatment. We also constructed a luminescent, recombinant M. abscessus mutant, mDB158, and imaged infected larvae using the IVIS in vivo imaging system. M. abscessus proliferated and induced granuloma-like responses in infected larvae, leading to larval mortality. The G. mellonella model was further validated successfully by demonstration of the expected favorable antimicrobial effect of treatment with meropenem and the superiority of combination treatment (meropenem and tigecycline) over that with single agents. We then used IVIS imaging of larvae infected with luminescent M. abscessus, allowing live real-time assessment of bacterial load. We used this method to compare the antimicrobial effects of various antibiotics (meropenem, amikacin, linezolid, levofloxacin, etc.) on bacterial proliferation and larval survival. Meropenem and amikacin had the most favorable effects, correlating well with common clinical practice guidelines. These findings suggest G. mellonella to be an excellent in vivo model for research of M. abscessus infection, pathogenesis, and treatment. Luminescent M. abscessus and IVIS imaging further facilitates this model. Results obtained in this model clearly substantiated common clinical practice, thus validating the model as a predictor of treatment efficacy and outcome. PMID- 29437631 TI - Short Proline-Rich Lipopeptide Potentiates Minocycline and Rifampin against Multidrug- and Extensively Drug-Resistant Pseudomonas aeruginosa. AB - A series of 16 short proline-rich lipopeptides (SPRLPs) were constructed to mimic longer naturally existing proline-rich antimicrobial peptides. Antibacterial assessment revealed that lipopeptides containing hexadecanoic acid (C16) possess optimal antibacterial activity relative to others with shorter lipid components. SPRLPs were further evaluated for their potential to serve as adjuvants in combination with existing antibiotics to enhance antibacterial activity against drug-resistant Pseudomonas aeruginosa Out of 16 prepared SPRLPs, C12-PRP was found to significantly potentiate the antibiotics minocycline and rifampin against multidrug- and extensively drug-resistant (MDR/XDR) P. aeruginosa clinical isolates. This nonhemolytic C12-PRP is comprised of the heptapeptide sequence PRPRPRP-NH2 acylated to dodecanoic acid (C12) at the N terminus. The adjuvant potency of C12-PRP was apparent by its ability to reduce the MIC of minocycline and rifampin below their interpretative susceptibility breakpoints against MDR/XDR P. aeruginosa An attempt to optimize C12-PRP through peptidomimetic modification was performed by replacing all l- to d-amino acids. C12-PRP demonstrated that it was amenable to optimization, since synergism with minocycline and rifampin were retained. Moreover, C12-PRP displayed no cytotoxicity against human liver carcinoma HepG2 and human embryonic kidney HEK 293 cell lines. Thus, the SPRLP C12-PRP is a lead adjuvant candidate that warrants further optimization. The discovery of agents that are able to resuscitate the activity of existing antibiotics against drug-resistant Gram negative pathogens, especially P. aeruginosa, is of great clinical interest. PMID- 29437632 TI - Time to Multidrug-Resistant Tuberculosis Treatment Initiation in Association with Treatment Outcomes in Shanghai, China. AB - In high tuberculosis (TB)-burden countries such as China, the diagnosis of multidrug-resistant tuberculosis (MDR-TB) using conventional drug susceptibility testing (DST) takes months, making treatment delay inevitable. Poor outcomes of MDR-TB might be associated with delayed, even inappropriate, treatment. The purposes of this study were to investigate the time to MDR-TB treatment initiation and to assess the association between early treatment and treatment outcomes. Between April 2011 and December 2014, this population-based retrospective cohort study collected the demographic and clinical characteristics and the drug susceptibility profiles of all registered MDR-TB patients in Shanghai, China. The dates of TB and MDR-TB diagnoses, DST performance, and treatment initiation were extracted to calculate the times to treatment. In total, 284 of 346 MDR-TB patients were eligible for analysis, and 68.3% (194/284) had favored outcomes. The median time to treatment initiation from TB diagnosis was 172 days among those with favored outcomes and 190 days among those with poor outcomes. Treatments initiated within 60 days after performing DST (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.22 to 5.36) and empirical treatments (OR, 2.09; 95% CI, 1.01 to 4.32) were positively associated with favored outcomes. Substantial delays to MDR-TB treatment were observed when conventional DST was used. Early treatment predicted favored outcomes. Rapid diagnostic methods should be scaled up and improvements should be made in patient management and information linkage to reduce treatment delay. PMID- 29437633 TI - High Genetic Plasticity in Multidrug-Resistant Sequence Type 3-IncHI2 Plasmids Revealed by Sequence Comparison and Phylogenetic Analysis. AB - We report a novel fusion plasmid, pP2-3T, cointegrating sequence type 3 (ST3) IncHI2 with an IncFII plasmid backbone mediating multidrug resistance (MDR) and virulence. Phylogenetic analysis and comparative genomics revealed that pP2-3T and other MDR ST3-IncHI2 plasmids clustered together, representing a unique IncHI2 lineage that exhibited high conservation in backbones of plasmids but possessed highly genetic plasticity in various regions by acquiring numerous antibiotic resistance genes and fusing with other plasmids. Surveillance studies should be performed to monitor multiresistance IncHI2 plasmids among Enterobacteriaceae. PMID- 29437634 TI - NHS in Scotland must face up to "difficult decisions" to remain sustainable. PMID- 29437635 TI - Pulsed electromagnetic field stimulation may improve fusion rates in cervical arthrodesis in high-risk populations. AB - OBJECTIVES: Pulsed electromagnetic field (PEMF) stimulation was evaluated after anterior cervical discectomy and fusion (ACDF) procedures in a randomized, controlled clinical study performed for United States Food and Drug Administration (FDA) approval. PEMF significantly increased fusion rates at six months, but 12-month fusion outcomes for subjects at elevated risk for pseudoarthrosis were not thoroughly reported. The objective of the current study was to evaluate the effect of PEMF treatment on subjects at increased risk for pseudoarthrosis after ACDF procedures. METHODS: Two evaluations were performed that compared fusion rates between PEMF stimulation and a historical control (160 subjects) from the FDA investigational device exemption (IDE) study: a post hoc (PH) analysis of high-risk subjects from the FDA study (PH PEMF); and a multicentre, open-label (OL) study consisting of 274 subjects treated with PEMF (OL PEMF). Fisher's exact test and multivariate logistic regression was used to compare fusion rates between PEMF-treated subjects and historical controls. RESULTS: In separate comparisons of PH PEMF and OL PEMF groups to the historical control group, PEMF treatment significantly (p < 0.05, Fisher's exact test) increased the fusion rate at six and 12 months for certain high-risk subjects who had at least one clinical risk factor of being elderly, a nicotine user, osteoporotic, or diabetic; and for those with at least one clinical risk factor and who received at least a two- or three-level arthrodesis. CONCLUSION: Adjunctive PEMF treatment can be recommended for patients who are at high risk for pseudoarthrosis.Cite this article: D. Coric, D. E. Bullard, V. V. Patel, J. T. Ryaby, B. L. Atkinson, D. He, R. D. Guyer. Pulsed electromagnetic field stimulation may improve fusion rates in cervical arthrodesis in high-risk populations. Bone Joint Res 2018;7:124-130. DOI: 10.1302/2046-3758.72.BJR-2017 0221.R1. PMID- 29437636 TI - Outcomes following limb salvage after combat hindfoot injury are inferior to delayed amputation at five years. AB - OBJECTIVES: The surgical challenge with severe hindfoot injuries is one of technical feasibility, and whether the limb can be salvaged. There is an additional question of whether these injuries should be managed with limb salvage, or whether patients would achieve a greater quality of life with a transtibial amputation. This study aims to measure functional outcomes in military patients sustaining hindfoot fractures, and identify injury features associated with poor function. METHODS: Follow-up was attempted in all United Kingdom military casualties sustaining hindfoot fractures. All respondents underwent short-form (SF)-12 scoring; those retaining their limb also completed the American Academy of Orthopaedic Surgeons Foot and Ankle (AAOS F&A) outcomes questionnaire. A multivariate regression analysis identified injury features associated with poor functional recovery. RESULTS: In 12 years of conflict, 114 patients sustained 134 fractures. Follow-up consisted of 90 fractures (90/134, 67%), at a median of five years (interquartile range (IQR) 52 to 80 months).The median Short-Form 12 physical component score (PCS) of 62 individuals retaining their limb was 45 (IQR 36 to 53), significantly lower than the median of 51 (IQR 46 to 54) in patients who underwent delayed amputation after attempted reconstruction (p = 0.0351).Regression analysis identified three variables associated with a poor F&A score: negative Bohler's angle on initial radiograph; coexisting talus and calcaneus fracture; and tibial plafond fracture in addition to a hindfoot fracture. The presence of two out of three variables was associated with a significantly lower PCS compared with amputees (medians 29, IQR 27 to 43 vs 51, IQR 46 to 54; p < 0.0001). CONCLUSIONS: At five years, patients with reconstructed hindfoot fractures have inferior outcomes to those who have delayed amputation. It is possible to identify injuries which will go on to have particularly poor outcomes.Cite this article: P. M. Bennett, T. Stevenson, I. D. Sargeant, A. Mountain, J. G. Penn-Barwell. Outcomes following limb salvage after combat hindfoot injury are inferior to delayed amputation at five years. Bone Joint Res 2018;7:131-138. DOI: 10.1302/2046-3758.72.BJR-2017-0217.R2. PMID- 29437637 TI - Altered expression of microRNA during fracture healing in diabetic rats. AB - OBJECTIVES: Diabetes mellitus (DM) is known to impair fracture healing. Increasing evidence suggests that some microRNA (miRNA) is involved in the pathophysiology of diabetes and its complications. We hypothesized that the functions of miRNA and changes to their patterns of expression may be implicated in the pathogenesis of impaired fracture healing in DM. METHODS: Closed transverse fractures were created in the femurs of 116 rats, with half assigned to the DM group and half assigned to the control group. Rats with DM were induced by a single intraperitoneal injection of streptozotocin. At post-fracture days five, seven, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was performed with miRNA samples from each group on post-fracture days five and 11. For further analysis, real time polymerase chain reaction (PCR) analysis was performed at each timepoint. RESULTS: Microarray analysis showed that there were 14 miRNAs at day five and 17 miRNAs at day 11, with a greater than twofold change in the DM group compared with the control group. Among these types of miRNA, five were selected based on a comparative and extended literature review. Real-time PCR analysis revealed that five types of miRNA (miR-140-3p, miR-140-5p, miR-181a-1-3p, miR-210-3p, and miR 222-3p) were differentially expressed with changing patterns of expression during fracture healing in diabetic rats compared with controls. CONCLUSIONS: Our findings provide information to further understand the pathology of impaired fracture healing in a diabetic rat model. These results may allow the potential development of molecular therapy using miRNA for the treatment of impaired fracture healing in patients with DM.Cite this article: S. Takahara, S. Y. Lee, T. Iwakura, K. Oe, T. Fukui, E. Okumachi, T. Waki, M. Arakura, Y. Sakai, K. Nishida, R. Kuroda, T. Niikura. Altered expression of microRNA during fracture healing in diabetic rats. Bone Joint Res 2018;7:139-147. DOI: 10.1302/2046 3758.72.BJR-2017-0082.R1. PMID- 29437638 TI - g(HbF): a genetic model of fetal hemoglobin in sickle cell disease. AB - Fetal hemoglobin (HbF) is a strong modifier of sickle cell disease (SCD) severity and is associated with 3 common genetic loci. Quantifying the genetic effects of the 3 loci would specifically address the benefits of HbF increases in patients. Here, we have applied statistical methods using the most representative variants: rs1427407 and rs6545816 in BCL11A, rs66650371 (3-bp deletion) and rs9376090 in HMIP-2A, rs9494142 and rs9494145 in HMIP-2B, and rs7482144 (Xmn1-HBG2 in the beta globin locus) to create g(HbF), a genetic quantitative variable for HbF in SCD. Only patients aged >=5 years with complete genotype and HbF data were studied. Five hundred eighty-one patients with hemoglobin SS (HbSS) or HbSbeta0 thalassemia formed the "discovery" cohort. Multiple linear regression modeling rationalized the 7 variants down to 4 markers (rs6545816, rs1427407, rs66650371, and rs7482144) each independently contributing HbF-boosting alleles, together accounting for 21.8% of HbF variability (r2) in the HbSS or HbSbeta0 patients. The model was replicated with consistent r2 in 2 different cohorts: 27.5% in HbSC patients (N = 186) and 23% in 994 Tanzanian HbSS patients. g(HbF), our 4-variant model, provides a robust approach to account for the genetic component of HbF in SCD and is of potential utility in sickle genetic and clinical studies. PMID- 29437640 TI - The immunoglobulin heavy chain 3' regulatory region superenhancer controls mouse B1 B-cell fate and late VDJ repertoire diversity. AB - The immunoglobulin heavy chain (IgH) 3' regulatory region (3'RR) superenhancer controls B2 B-cell IgH transcription and cell fate at the mature stage but not early repertoire diversity. B1 B cells represent a small percentage of total B cells differing from B2 B cells by several points such as precursors, development, functions, and regulation. B1 B cells act at the steady state to maintain homeostasis in the organism and during the earliest phases of an immune response, setting them at the interface between innate and acquired immunity. We investigated the role of the 3'RR superenhancer on B1 B-cell fate. Similar to B2 B cells, the 3'RR controls MU transcription and cell fate in B1 B cells. In contrast to B2 B cells, 3'RR deletion affects B1 B-cell late repertoire diversity. Thus, differences exist for B1 and B2 B-cell 3'RR control during B cell maturation. For the first time, these results highlight the contribution of the 3'RR superenhancer at this interface between innate and acquired immunity. PMID- 29437639 TI - Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI. AB - Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU) for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28- and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 5'-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients. PMID- 29437641 TI - Pride comes before denial of a fall? PMID- 29437642 TI - Thunderstorm asthma: controlling (deadly) grass pollen allergy. PMID- 29437643 TI - Commentary: Palliative care and assisted dying are not mutually exclusive. PMID- 29437644 TI - Real world evidence: experience and lessons from China. PMID- 29437645 TI - Nine in 10 CCGs don't know how long patients wait for talking therapies. PMID- 29437646 TI - Chinese translations on bmj.com. PMID- 29437647 TI - European drug agency wins victory over drug companies that wanted to withhold data. PMID- 29437649 TI - Margaret McCartney: Mandatory flu vaccination won't fix the NHS. PMID- 29437648 TI - Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study. AB - OBJECTIVE: To evaluate the cardiovascular safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, in direct comparisons with DPP-4 inhibitors (DPP-4i), GLP-1 receptor agonists (GLP-1RA), or sulfonylureas, as used in routine practice. DESIGN: Population based retrospective cohort study. SETTING: Nationwide sample of patients with type 2 diabetes from a large de-identified US commercial healthcare database (Optum Clinformatics Datamart). PARTICIPANTS: Three pairwise 1:1 propensity score matched cohorts of patients with type 2 diabetes 18 years and older who initiated canagliflozin or a comparator non-gliflozin antidiabetic agent (ie, a DPP-4i, a GLP-1RA, or a sulfonylurea) between April 2013 and September 2015. MAIN OUTCOME MEASURES: The primary outcomes were heart failure admission to hospital and a composite cardiovascular endpoint (comprised of being admitted to hospital for acute myocardial infarction, ischemic stroke, or hemorrhagic stroke). Hazard ratios and 95% confidence intervals were estimated in each propensity score matched cohort controlling for more than 100 baseline characteristics. RESULTS: During a 30 month period, the hazard ratio for heart failure admission to hospital associated with canagliflozin was 0.70 (95% confidence interval 0.54 to 0.92) versus a DPP-4i (n=17 667 pairs), 0.61 (0.47 to 0.78) versus a GLP-1RA (20 539), and 0.51 (0.38 to 0.67) versus a sulfonylurea (17 354 ). The hazard ratio for the composite cardiovascular endpoint associated with canagliflozin was 0.89 (0.68 to 1.17) versus a DPP-4i, 1.03 (0.79 to 1.35) versus a GLP-1RA, and 0.86 (0.65 to 1.13) versus a sulfonylurea. Results were similar in sensitivity analyses further adjusting for baseline hemoglobin A1c levels and in subgroups of patients with and without prior cardiovascular disease or heart failure. CONCLUSIONS: In this large cohort study, canagliflozin was associated with a lower risk of heart failure admission to hospital and with a similar risk of myocardial infarction or stroke in direct comparisons with three different classes of non-gliflozin diabetes treatment alternatives as used in routine care. PMID- 29437650 TI - Man flu is related to health communication rather than symptoms and suffering. PMID- 29437652 TI - Most UK doctors support assisted dying, a new poll shows: the BMA's opposition does not represent members. PMID- 29437651 TI - Antibiotics after incision and drainage for uncomplicated skin abscesses: a clinical practice guideline. PMID- 29437653 TI - Staff in the NHS are, first and foremost, people. PMID- 29437654 TI - Failing health of the United States. PMID- 29437655 TI - Should doctor assisted dying be legal? PMID- 29437656 TI - Evolutionary benefit of "man flu"? Try rephrasing the question. PMID- 29437657 TI - Peppa Pig: a helpful portrayal of visiting the doctor. PMID- 29437658 TI - "Curious George Goes to the Hospital": teaching toddlers how good healthcare works. PMID- 29437659 TI - Vaginal mesh procedures need compulsory register, says royal college. PMID- 29437661 TI - Muscle bound: five minutes with Greg James. PMID- 29437660 TI - China's medical research revolution. PMID- 29437662 TI - Health secretary orders review into use of medical manslaughter. PMID- 29437663 TI - Doctors should state clearly that vaping is much lower risk than smoking, says report. PMID- 29437665 TI - US public health agency to cut global surveillance by 80. PMID- 29437664 TI - North American public health schools decline funding from tobacco funded foundation. PMID- 29437666 TI - Assisted dying in US and Canada: controversy subsides after legalisation. PMID- 29437668 TI - Surgeon who faked keyhole experience is jailed for six years. PMID- 29437670 TI - Number of older people with four or more diseases will double by 2035, study warns. PMID- 29437667 TI - Effectiveness of a childhood obesity prevention programme delivered through schools, targeting 6 and 7 year olds: cluster randomised controlled trial (WAVES study). AB - OBJECTIVE: To assess the effectiveness of a school and family based healthy lifestyle programme (WAVES intervention) compared with usual practice, in preventing childhood obesity. DESIGN: Cluster randomised controlled trial. SETTING: UK primary schools from the West Midlands. PARTICIPANTS: 200 schools were randomly selected from all state run primary schools within 35 miles of the study centre (n=980), oversampling those with high minority ethnic populations. These schools were randomly ordered and sequentially invited to participate. 144 eligible schools were approached to achieve the target recruitment of 54 schools. After baseline measurements 1467 year 1 pupils aged 5 and 6 years (control: 28 schools, 778 pupils) were randomised, using a blocked balancing algorithm. 53 schools remained in the trial and data on 1287 (87.7%) and 1169 (79.7%) pupils were available at first follow-up (15 month) and second follow-up (30 month), respectively. INTERVENTIONS: The 12 month intervention encouraged healthy eating and physical activity, including a daily additional 30 minute school time physical activity opportunity, a six week interactive skill based programme in conjunction with Aston Villa football club, signposting of local family physical activity opportunities through mail-outs every six months, and termly school led family workshops on healthy cooking skills. MAIN OUTCOME MEASURES: The protocol defined primary outcomes, assessed blind to allocation, were between arm difference in body mass index (BMI) z score at 15 and 30 months. Secondary outcomes were further anthropometric, dietary, physical activity, and psychological measurements, and difference in BMI z score at 39 months in a subset. RESULTS: Data for primary outcome analyses were: baseline, 54 schools: 1392 pupils (732 controls); first follow-up (15 months post-baseline), 53 schools: 1249 pupils (675 controls); second follow-up (30 months post-baseline), 53 schools: 1145 pupils (621 controls). The mean BMI z score was non significantly lower in the intervention arm compared with the control arm at 15 months (mean difference -0.075 (95% confidence interval -0.183 to 0.033, P=0.18) in the baseline adjusted models. At 30 months the mean difference was -0.027 ( 0.137 to 0.083, P=0.63). There was no statistically significant difference between groups for other anthropometric, dietary, physical activity, or psychological measurements (including assessment of harm). CONCLUSIONS: The primary analyses suggest that this experiential focused intervention had no statistically significant effect on BMI z score or on preventing childhood obesity. Schools are unlikely to impact on the childhood obesity epidemic by incorporating such interventions without wider support across multiple sectors and environments. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97000586. PMID- 29437669 TI - The failure of anti-obesity programmes in schools. PMID- 29437672 TI - GPs are told to amend flu vaccine orders for next season. PMID- 29437671 TI - Pharmacological TLR4 Antagonism Using Topical Resatorvid Blocks Solar UV-Induced Skin Tumorigenesis in SKH-1 Mice. AB - An urgent need exists for the development of more efficacious molecular strategies targeting nonmelanoma skin cancer (NMSC), the most common malignancy worldwide. Inflammatory signaling downstream of Toll-like receptor 4 (TLR4) has been implicated in several forms of tumorigenesis, yet its role in solar UV induced skin carcinogenesis remains undefined. We have previously shown in keratinocyte cell culture and SKH-1 mouse epidermis that topical application of the specific TLR4 antagonist resatorvid (TAK-242) blocks acute UV-induced AP-1 and NF-kappaB signaling, associated with downregulation of inflammatory mediators and MAP kinase phosphorylation. We therefore explored TLR4 as a novel target for chemoprevention of UV-induced NMSC. We selected the clinical TLR4 antagonist resatorvid based upon target specificity, potency, and physicochemical properties. Here, we confirm using ex vivo permeability assays that topical resatorvid can be effectively delivered to skin, and using in vivo studies that topical resatorvid can block UV-induced AP-1 activation in mouse epidermis. We also report that in a UV-induced skin tumorigenesis model, topical resatorvid displays potent photochemopreventive activity, significantly suppressing tumor area and multiplicity. Tumors harvested from resatorvid-treated mice display reduced activity of UV-associated signaling pathways and a corresponding increase in apoptosis compared with tumors from control animals. Further mechanistic insight on resatorvid-based photochemoprevention was obtained from unsupervised hierarchical clustering analysis of protein readouts via reverse-phase protein microarray revealing a significant attenuation of key UV-induced proteomic changes by resatorvid in chronically treated high-risk SKH-1 skin prior to tumorigenesis. Taken together, our data identify TLR4 as a novel molecular target for topical photochemoprevention of NMSC. Cancer Prev Res; 11(5); 265-78. (c)2018 AACRSee related editorial by Sfanos, p. 251. PMID- 29437673 TI - How should doctors use e-portfolios in the wake of the Bawa-Garba case? PMID- 29437674 TI - Sixty seconds on . . . Heineken. PMID- 29437675 TI - GP who squeezed and stroked girl's breasts unnecessarily is struck off. PMID- 29437676 TI - Proportionate response to "man flu". PMID- 29437677 TI - Management of patients after laparoscopic procedures. PMID- 29437678 TI - Multidisciplinary surgical team approach for excision of squamous cell carcinoma overlying pacemaker site. AB - We report an unusual case of an elderly man presenting with a fast-growing large malignant tumour involving the skin overlying his permanent pacemaker site. The fast-growing cutaneous squamous cell carcinoma appeared 2 years after pacemaker implantation. Joint specialist input was required to tackle this complex problem as a wide surgical excision would expose the pacemaker generator risking device infection particularly if the skin graft reconstruction failed. Having established that the patient had minimal pacing needs, it was determined through expedited multidisciplinary discussion that the best option was excision of the lesion with skin grafting of the defect by maxillofacial surgical team and pacemaker generator removal by a cardiologist in a joint surgical procedure. The procedure was successful and uneventful. This case highlights how effective multidisciplinary planning can help achieve a favourable clinical outcome in a patient with a rare case of a squamous cell carcinoma overlying a pacemaker site. PMID- 29437679 TI - Tuberculous osteomyelitis of the wrist presenting as a monoarthritis syndrome. AB - Osteoarticular tuberculosis is the third most frequent location of tuberculosis after the lung and lymph nodes, accounting for approximately 10%-20% of all cases of extrapulmonary disease. Tuberculosis of the hand and wrist is the rarest osteoarticular location after the shoulder. The authors report the case of a 50 year-old woman without medical history who was diagnosed with isolated tuberculosis of the wrist presenting as monarthritis. The diagnosis was confirmed by histopathological and microbiological examination. Late stages of osteomyelitis are even rarer without any predisposing factors such as immunosuppression. This case underlines the importance of including tuberculosis in the differential diagnosis of monoarthritic syndromes to prevent delayed initiation of therapy and consequent complications and bone damage. PMID- 29437681 TI - Michael Lavelle-Jones: Training driver. PMID- 29437680 TI - Pulmonary arteriovenous fistula complicated by venous thromboembolism and paradoxical cerebral infarction during early pregnancy. AB - A 39-year-old Japanese woman was diagnosed with a pulmonary arteriovenous fistula (PAVF) complicated by paradoxical cerebral infarction during pregnancy. She received an inferior vena cava filter (IVCF), but it was difficult to indwell because of the risk of repeat thromboembolism via PAVF. Therefore, we temporarily occluded the pulmonary artery with a balloon to prevent free thrombi from reaching the IVCF. Detection and treatment of PAVF are recommended in fertile young women. Obstruction of the pulmonary artery trunk with a balloon catheter may be useful during IVCF removal in patients with untreated PAVF. PMID- 29437682 TI - David Oliver: Do bed and chair sensors really stop falls in hospital? PMID- 29437684 TI - Article on "man flu" encourages negative views of male health. PMID- 29437683 TI - Skin changes after a magnetic resonance imaging scan. PMID- 29437685 TI - "Son" at risk of inheriting of cancer can test DNA of dead man who might be his father. PMID- 29437687 TI - How it feels to help a terminally ill patient to die a dignified death. PMID- 29437688 TI - Man flu: less inflammation but more consequences in men than women. PMID- 29437690 TI - Trust must pay L4.4m for failure to warn about risks of spinal surgery. PMID- 29437689 TI - Antibiotics for uncomplicated skin abscesses: systematic review and network meta analysis. AB - OBJECTIVE: To assess the impact of adjunctive antibiotic therapy on uncomplicated skin abscesses. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. STUDY SELECTION: A BMJ Rapid Recommendation panel provided input on design, important outcomes and the interpretation of the results. Eligible randomised controlled trials (RCTs) included a comparison of antibiotics against no antibiotics or a comparison of different antibiotics in patients with uncomplicated skin abscesses, and reported outcomes prespecified by the linked guideline panel. REVIEW METHODS: Reviewers independently screened abstracts and full texts for eligibility, assessed risk of bias and extracted data. We performed random-effects meta-analyses that compared antibiotics with no antibiotics, along with a limited number of prespecified subgroup hypotheses. We also performed network meta-analysis with a Bayesian framework to compare effects of different antibiotics. Quality of evidence was assessed with The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Fourteen RCTs including 4198 patients proved eligible. Compared with no antibiotics, antibiotics probably lower the risk of treatment failure (OR 0.58, 95% CI 0.37 to 0.90; low quality), recurrence within 1 month (OR 0.48, 95% CI 0.30 to 0.77; moderate quality), hospitalisation (OR 0.55, 95% CI 0.32 to 0.94; moderate quality) and late recurrence (OR 0.64, 95% CI 0.48 to 0.85; moderate quality). However, relative to no use, antibiotics probably increase the risk of gastrointestinal side effects (trimethoprim and sulfamethoxazole (TMP-SMX): OR 1.28, 95% CI 1.04 to 1.58; moderate quality; clindamycin: OR 2.29, 95% CI 1.35 to 3.88; high quality) and diarrhoea (clindamycin: OR 2.71, 95% CI 1.50 to 4.89; high quality). Cephalosporins did not reduce the risk of treatment failure compared with placebo (moderate quality). CONCLUSIONS: In patients with uncomplicated skin abscesses, moderate-to-high quality evidence suggests TMP-SMX or clindamycin confer a modest benefit for several important outcomes, but this is offset by a similar risk of adverse effects. Clindamycin has a substantially higher risk of diarrhoea than TMP-SMX. Cephalosporins are probably not effective. PMID- 29437692 TI - Patient Commentary: "I don't want to go to Switzerland, and I don't want to attempt suicide". PMID- 29437693 TI - Web-based educational intervention improves enrolled nurses' knowledge and performance with deteriorating patients. PMID- 29437691 TI - Five and 10 minute Apgar scores and risks of cerebral palsy and epilepsy: population based cohort study in Sweden. AB - OBJECTIVE: To investigate associations between Apgar score at five and 10 minutes across the entire range of score values (from 0 to 10) and risks of childhood cerebral palsy or epilepsy, and to analyse the effect of changes in Apgar scores from five to 10 minutes after birth in infants born >=37 completed weeks. DESIGN, SETTING, AND PARTICIPANTS: Population based cohort study in Sweden, including 1 213 470 non-malformed live singleton infants, born at term between 1999 and 2012. Data on maternal and pregnancy characteristics and diagnoses of cerebral palsy and epilepsy were obtained by individual record linkages of nationwide Swedish registries. EXPOSURES: Apgar scores at five and 10 minutes. MAIN OUTCOME MEASURE: Cerebral palsy and epilepsy diagnosed up to 16 years of age. Adjusted hazard ratios were calculated, along with 95% confidence intervals. RESULTS: 1221 (0.1%) children were diagnosed as having cerebral palsy and 3975 (0.3%) as having epilepsy. Compared with children with an Apgar score of 10 at five minutes, the adjusted hazard ratio for cerebral palsy increased steadily with decreasing Apgar score: from 1.9 (95% confidence interval 1.6 to 2.2) for an Apgar score of 9 to 277.7 (154.4 to 499.5) for an Apgar score of 0. Similar and even stronger associations were obtained between Apgar scores at 10 minutes and cerebral palsy. Associations between Apgar scores and epilepsy were less pronounced, but increased hazard ratios were noted in infants with a five minute Apgar score of 7 or less and a 10 minute Apgar score of 8 or less. Compared with infants with an Apgar of 9-10 at both five and 10 minutes, hazard ratios of cerebral palsy and epilepsy were higher among infants with a five minute Apgar score of 7-8 and a 10 minute Apgar score of 9-10. CONCLUSION: Risks of cerebral palsy and epilepsy are inversely associated with five minute and 10 minute Apgar scores across the entire range of Apgar scores. PMID- 29437694 TI - Mouse GTSF1 is an essential factor for secondary piRNA biogenesis. AB - The piRNA pathway is a piRNA-guided retrotransposon silencing system which includes processing of retrotransposon transcripts by PIWI-piRNAs in secondary piRNA biogenesis. Although several proteins participate in the piRNA pathway, the ones crucial for the cleavage of target RNAs by PIWI-piRNAs have not been identified. Here, we show that GTSF1, an essential factor for retrotransposon silencing in male germ cells in mice, associates with both MILI and MIWI2, mouse PIWI proteins that function in prospermatogonia. GTSF1 deficiency leads to a severe defect in the production of secondary piRNAs, which are generated from target RNAs of PIWI-piRNAs. Furthermore, in Gtsf1 mutants, a known target RNA of PIWI-piRNAs is left unsliced at the cleavage site, and the generation of secondary piRNAs from this transcript is defective. Our findings indicate that GTSF1 is a crucial factor for the slicing of target RNAs by PIWI-piRNAs and thus affects secondary piRNA biogenesis in prospermatogonia. PMID- 29437695 TI - SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting Dynamin 2. AB - Trafficking of mammalian ATG9A between the Golgi apparatus, endosomes and peripheral ATG9A compartments is important for autophagosome biogenesis. Here, we show that the membrane remodelling protein SNX18, previously identified as a positive regulator of autophagy, regulates ATG9A trafficking from recycling endosomes. ATG9A is recruited to SNX18-induced tubules generated from recycling endosomes and accumulates in juxtanuclear recycling endosomes in cells lacking SNX18. Binding of SNX18 to Dynamin-2 is important for ATG9A trafficking from recycling endosomes and for formation of ATG16L1- and WIPI2-positive autophagosome precursor membranes. We propose a model where upon autophagy induction, SNX18 recruits Dynamin-2 to induce budding of ATG9A and ATG16L1 containing membranes from recycling endosomes that traffic to sites of autophagosome formation. PMID- 29437696 TI - Clinical Outcomes after Conservative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in Women Ages 21-39 Years. AB - Cervical intraepithelial neoplasia grade 2 (CIN2) frequently regresses, is typically slow-growing, and rarely progresses to cancer. Some women forgo immediate treatment, opting for conservative management (heightened surveillance with cytology and colposcopy), to minimize overtreatment and increased risk of obstetric complications; however, there are limited data examining clinical outcomes in these women. We performed a retrospective cohort analysis of younger women diagnosed with initially untreated CIN1/2, CIN2 and CIN2/3 lesions at Kaiser Permanente Northern California between 2003 and 2015. Clinical outcomes were categorized into five mutually exclusive hierarchical groups: cancer, treated, returned to routine screening, persistent high-grade lesion, or persistent low-grade lesion. Median follow-up for the 2,417 women was 48 months. Six women were diagnosed with cancer (0.2%), all with history of high-grade cytology, and none after a negative cotest. Thirty percent of women were treated, and only 20% returned to routine screening; 50% remained in continued intensive follow-up, of which 86% had either low-grade cytology/histology or high-risk human papillomavirus (HPV) positivity, but not necessarily persistence of a single HPV type. No cancers were detected after a single negative cotest in follow-up. Almost half of initially untreated women did not undergo treatment, but remained by protocol in colposcopy clinic for 2 or more years in the absence of persisting CIN2+ Their incomplete return to total negativity was possibly due to sequential new and unrelated low-grade abnormalities. The prolonged colposcopic surveillance currently required to return to routine screening in the absence of persisting CIN2+ might not be necessary after a negative cotest.Significance: Many younger women under conservative management following an initial CIN2 result remain in a clinical protocol of prolonged intensified surveillance without a subsequent diagnosis of CIN2 or more severe diagnoses. More research is needed to determine whether such prolonged management might be unnecessary following a negative cotest for those women with an initial CIN2 but otherwise only low-grade findings. Cancer Prev Res; 11(3); 165-70. (c)2018 AACR. PMID- 29437697 TI - Insulin Detemir Use Is Associated With Higher Occurrence of Hypoglycemia in Hospitalized Patients With Hypoalbuminemia. PMID- 29437699 TI - Metformin and Helicobacter pylori Infection in Patients With Type 2 Diabetes. PMID- 29437698 TI - Islet Interleukin-1beta Immunoreactivity Is an Early Feature of Cystic Fibrosis That May Contribute to beta-Cell Failure. AB - OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), increasing patient morbidity and mortality. Poor understanding of CFRD pathogenesis limits the development of targeted therapies to treat and/or prevent the disease. The aim of this study was to evaluate islet pathology, specifically, inflammation, amyloid deposition, and endocrine cell composition in subjects with CF with diabetes and with CF without diabetes. RESEARCH DESIGN AND METHODS: A retrospective analysis of archived pancreas tissue collected at autopsy was conducted using pancreas tissue from subjects with CF and diabetes (CFRD) (n = 18) and CF without diabetes (CF-no DM) (n = 17). Two cohorts of control non-CF subjects were identified, each matched to CFRD and CF no DM subjects for age, sex, and BMI (non-CF older, n = 20, and non-CF younger, n = 20), respectively. Immunohistochemistry was performed to assess interleukin 1beta (IL-1beta) and islet hormone (insulin, glucagon, somatostatin, and pancreatic polypeptide) immunoreactivity; histochemistry was performed to quantify amyloid deposition. RESULTS: Islet IL-1beta immunoreactivity was substantially increased in both CFRD and CF-no DM subjects compared with non-CF subjects and was common in young subjects with CF (<=10 years of age). In contrast, islet amyloid deposition was increased only in CFRD subjects. We also observe abnormal islet hormone immunoreactivity, characterized by increased glucagon immunoreactivity, in CF-no DM and CFRD subjects compared with non-CF subjects. CONCLUSIONS: These findings reveal novel molecular pathways and therapeutic targets underlying islet pathology in CF subjects and may be important in developing new approaches to treat CFRD. PMID- 29437700 TI - "Please. Don't. Die.": A Grounded Theory Study of Bystander Cardiopulmonary Resuscitation. AB - BACKGROUND: Bystander cardiopulmonary resuscitation (CPR) is an important determinant of survival from out-of-hospital cardiac arrest (OHCA), yet rates of bystander CPR are highly variable. In an effort to promote bystander CPR, the procedure has been streamlined, and ultrashort teaching modalities have been introduced. CPR has been increasingly reconceptualized as simple, safe, and easy to perform; however, current methods of CPR instruction may not adequately prepare lay rescuers for the various logistical, conceptual, and emotional challenges of resuscitating a victim of cardiac arrest. METHODS AND RESULTS: We adopted a constructivist grounded theory methodology to qualitatively explore bystander CPR and invited lay rescuers who had recently (ie, within 1 week) intervened in an OHCA to participate in semistructured interviews and focus groups. We used constant comparative analysis until theoretical saturation to derive a midrange explanatory theory of bystander CPR. We constructed a 3-stage theoretical model describing a common experiential process for lay rescuer intervention in OHCA: Being called to act is disturbing, causing panic, shock, and disbelief that must ultimately be overcome. Taking action to save the victim is complicated by several misconceptions about cardiac arrest, where victims are mistakenly believed to be choking, and agonal respirations are misinterpreted to mean the victim is alive. Making sense of the experience is challenging, at least in the short term, where lay rescuers have to contend with self-doubt, unanswered questions, and uncomfortable emotional reactions to a traumatic event. CONCLUSIONS: Our study suggests that current CPR training programs may not adequately prepare lay rescuers for the reality of an OHCA and identifies several key knowledge gaps that should be addressed. The long-term psychological consequences of bystander intervention in OHCA remain poorly understood and warrant further study. PMID- 29437701 TI - Are Lay Rescuers Adequately Prepared for Cardiopulmonary Resuscitation and Its Aftermath? PMID- 29437702 TI - Diagnosis and Treatment of Intradialytic Hypotension in Maintenance Hemodialysis Patients. PMID- 29437704 TI - Coronary intervention door-to-balloon time and outcomes in ST-elevation myocardial infarction: a meta-analysis. AB - OBJECTIVE: This study aims to determine the relationship between door-to-balloon delay in primary percutaneous coronary intervention and ST-elevation myocardial infarction (MI) outcomes and examine for potential effect modifiers. METHODS: We conducted a systematic review and meta-analysis of prospective observational studies that have investigated the relationship of door-to-balloon delay and clinical outcomes. The main outcomes include mortality and heart failure. RESULTS: 32 studies involving 299 320 patients contained adequate data for quantitative reporting. Patients with ST-elevation MI who experienced longer (>90 min) door-to-balloon delay had a higher risk of short-term mortality (pooled OR 1.52, 95% CI 1.40 to 1.65) and medium-term to long-term mortality (pooled OR 1.53, 95% CI 1.13 to 2.06). A non-linear time-risk relation was observed (P=0.004 for non-linearity). The association between longer door-to-balloon delay and short-term mortality differed between those presented early and late after symptom onset (Cochran's Q 3.88, P value 0.049) with a stronger relationship among those with shorter prehospital delays. CONCLUSION: Longer door-to-balloon delay in primary percutaneous coronary intervention for ST-elevation MI is related to higher risk of adverse outcomes. Prehospital delays modified this effect. The non-linearity of the time-risk relation might explain the lack of population effect despite an improved door-to-balloon time in the USA. CLINICAL TRIAL REGISTRATION: PROSPERO (CRD42015026069). PMID- 29437703 TI - The Functional Specialization of Exomer as a Cargo Adaptor During the Evolution of Fungi. AB - Yeast exomer is a heterotetrameric complex that is assembled at the trans-Golgi network, which is required for the delivery of a distinct set of proteins to the plasma membrane using ChAPs (Chs5-Arf1 binding proteins) Chs6 and Bch2 as dedicated cargo adaptors. However, our results show a significant functional divergence between them, suggesting an evolutionary specialization among the ChAPs. Moreover, the characterization of exomer mutants in several fungi indicates that exomer's function as a cargo adaptor is a late evolutionary acquisition associated with several gene duplications of the fungal ChAPs ancestor. Initial gene duplication led to the formation of the two ChAPs families, Chs6 and Bch1, in the Saccaromycotina group, which have remained functionally redundant based on the characterization of Kluyveromyces lactis mutants. The whole-genome duplication that occurred within the Saccharomyces genus facilitated a further divergence, which allowed Chs6/Bch2 and Bch1/Bud7 pairs to become specialized for specific cellular functions. We also show that the behavior of S. cerevisiae Chs3 as an exomer cargo is associated with the presence of specific cytosolic domains in this protein, which favor its interaction with exomer and AP-1 complexes. However, these domains are not conserved in the Chs3 proteins of other fungi, suggesting that they arose late in the evolution of fungi associated with the specialization of ChAPs as cargo adaptors. PMID- 29437705 TI - NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3Kalpha. AB - Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here, we report that coinhibition of NRAS or MEK plus PI3Kalpha triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kalpha-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivoNRAS- or HRAS mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo We identified BCL 2-modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased. BMF silencing ablated MEK162/BYL719-induced apoptosis. Mechanistic investigations implicated a proapoptotic rebalancing of BCL-2 family members and suppression of cap-dependent translation in apoptotic sensitivity upon MEK162/BYL719 cotreatment. Our results offer a rationale for combining MEK- and PI3Kalpha-specific inhibitors in clinical treatment of RAS-mutated RMS.Significance: These findings offer a mechanistic rationale for combining MEK- and PI3Kalpha-specific inhibitors in the clinical treatment of RAS-mutated forms of often untreatable rhabdomyosarcomas. Cancer Res; 78(8); 2000-13. (c)2018 AACR. PMID- 29437706 TI - Targeting Cyclin D-CDK4/6 Sensitizes Immune-Refractory Cancer by Blocking the SCP3-NANOG Axis. AB - Immunoediting caused by antitumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen-specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOGhigh cancer stem cell-like cells. In this study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immunoedited cells and upregulates NANOG by hyperactivating the cyclin D1-CDK4/6 axis. The SCP3-cyclin D1-CDK4/6 axis was preserved across various types of human cancer and correlated negatively with progression-free survival of cervical cancer patients. Targeting CDK4/6 with the inhibitor palbociclib reversed multiaggressive phenotypes of SCP3high immunoedited tumor cells and led to long term control of the disease. Collectively, our findings establish a firm molecular link of multiaggressiveness among SCP3, NANOG, cyclin D1, and CDK4/6 and identify CDK4/6 inhibitors as actionable drugs for controlling SCP3high immune-refractory cancer.Significance: These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3high immune-refractroy cancer. Cancer Res; 78(10); 2638-53. (c)2018 AACR. PMID- 29437707 TI - Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis. AB - Resistance to anoikis allows cancer cells to survive during systemic circulation; however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75NTR) and subsequent generation of the p75NTR intracellular domain (ICD) endow cancer cells with resistance to anoikis. p75NTR ICD promoted expression of TNF receptor-associated factor 6 (TRAF6), a critical intermediary in p75NTR ICD-mediated signal transduction, at the translational level. Cell detachment-induced activation of EGFR triggered autoubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NFkappaB, and eventually led to anoikis resistance. ADAM10 and p75NTR ICD also promoted tumor metastasis formation in vivo Together, our findings uncover a previously unknown function for the ADAM10-p75NTR ICD-TRAF6-NFkappaB axis in preventing anoikis and suggest ADAM10 and p75NTR ICD as potential cancer therapeutic targets.Significance: These findings identify the ADAM10-p75NTR ICD-TRAF6 NFkappaB signaling axis as a potential candidate for cancer therapy. Cancer Res; 78(9); 2262-76. (c)2018 AACR. PMID- 29437709 TI - Prader-Willi syndrome: a nest for premature coronary artery disease? AB - Individuals affected by Prader-Willi syndrome (PWS) may show increased risk for coronary artery disease (CAD), which probably relates, at least, with high burden of cardiovascular risk factors.A 27-year-old man with PWS, obesity, hypertension, diabetes mellitus and dyslipidaemia attended the emergency department with complaints of flu-like condition and chest pain. The ECG revealed a mild ST segment elevation in inferior leads, followed by positive myocardial necrosis biomarkers. Attending to the high cardiovascular risk profile, ST-segment elevation in inferior territory and wall motion abnormalities, a coronary angiogram was performed. The latter showed a three-vessel CAD, 60% stenosis in midanterior descending artery, total occlusion (100%) of the obtuse marginal artery and 99% stenosis with high thrombi burden in the proximal right coronary artery.The present case report emphasises the plausibility of premature CAD in patients with PWS, a possible underdiagnosed feature of this condition. PMID- 29437708 TI - Expression of Adipocyte/Macrophage Fatty Acid-Binding Protein in Tumor-Associated Macrophages Promotes Breast Cancer Progression. AB - Tumor-associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically relevant markers for protumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid-binding protein (A-FABP) in TAM promotes breast cancer progression. Although upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis. Furthermore, the protumor effect of A-FABP was mediated by TAM, in particular, in a subset of TAM with a CD11b+F4/80+MHCII-Ly6C- phenotype. A-FABP expression in TAM facilitated protumor IL6/STAT3 signaling through regulation of the NFkappaB/miR-29b pathway. Collectively, our results suggest A-FABP as a new functional marker for protumor TAM.Significance: These findings identify A-FABP as a functional marker for protumor macrophages, thus offering a new target for tumor immunotherapy. Cancer Res; 78(9); 2343-55. (c)2018 AACR. PMID- 29437710 TI - Total patellectomy with extensor mechanism reconstruction following pathological fracture due to patellar Ewing's sarcoma. AB - A young patient presented with a progressive right knee pain and swelling that was worse on ambulation. Following appropriate investigations, he was confirmed having Ewing's sarcoma of the right patella. Two cycles of chemotherapy were initiated before he sustained a fall and a resultant pathological patellar fracture. He finally underwent a total right patellectomy and extensor mechanism reconstruction using Achilles tendon allograft in an attempt to eradicate the disease and salvage his knee extensor mechanism. At 1-year follow-up, no disease recurrence was observed, and the patient had a full range of motion but with slight weakness of the extensor mechanism. PMID- 29437711 TI - Bilateral testicular torsion in a 36-week neonate. AB - A male neonate born after uncomplicated vaginal delivery at 36 weeks' gestation was noted to have large and firm testicles bilaterally on routine examination. A testicular ultrasound scan was subsequently organised that showed detailed appearances consistent with bilateral testicular torsion. This was thought to have taken place antenatally and as such was unfortunately not suitable for intervention. The patient was therefore managed conservatively with the testicles left to involute naturally. He was started on testosterone replacement therapy after follow-up when gonadotrophin levels were found to be raised and testosterone low (suggesting absent testicular function) and will be closely followed up regarding his future development which is normal to this point. PMID- 29437712 TI - Fast-growing cervical mass: anaplastic thyroid carcinoma. PMID- 29437713 TI - Temporal bone neoplasia: a rare entity. PMID- 29437714 TI - Symmetrical peripheral gangrene of bilateral feet and unilateral hand after administration of vasopressors during septic shock. AB - We report a case of a 75-year-old Hispanic man treated for septic shock after undergoing surgery for impacted renal stones. He was given vasopressors and later developed symmetrical peripheral gangrene (SPG) on both his feet and left hand. SPG is a serious and rare condition presenting clinically as an acute onset of ischaemia with no vessel occlusion. Vasopressors are identified as a contributing factor in SPG development. The patient ultimately underwent transmetatarsal amputations of both feet and amputation of three digits on his left hand. Early monitoring and swift management of peripheral ischaemia are essential when using vasopressors for the treatment of septic shock. PMID- 29437715 TI - Recurrent central catheter complications in a newborn: can we blame neonatal lupus? PMID- 29437716 TI - Transfemoral thrombectomy in the cavernous sinus and superior ophthalmic vein. AB - Cavernous sinus thrombosis (CST) is a rare condition that can cause death, neurologic disability, and visual loss. A pre-teen with septic CST leading to ocular hypertension and acute visual loss was treated at our institution with thrombectomy and thrombolysis of the cavernous sinuses and superior ophthalmic veins. Successful recanalization of the bilateral cavernous sinuses and superior ophthalmic veins was achieved in two separate procedures without complication. The patient showed immediate symptomatic relief. He was neurologically intact without visual deficits at the 2 month follow-up. This is the first report in the literature showing the feasibility of cavernous sinus thrombectomy using current devices and techniques. Early endovascular therapy may help preserve vision in patients with acute CST. PMID- 29437717 TI - Isolated intraventricular hemorrhage secondary to dural arteriovenous fistula. AB - Isolated intraventricular hemorrhage due to dural arteriovenous fistula (dAVF) is extremely rare and has been reported only a few times in the literature. The pathophysiological cause of isolated intraventricular hemorrhage in these cases was hypothetically attributed to retrograde venous flow into subependymal vessels, although none of these cases demonstrated radiographic evidence of such reflux. We present the first case of a dAVF with radiographic evidence of severe cortical venous reflux into the subependymal venous network causing isolated intraventricular hemorrhage, thus lending proof for the underlying pathophysiology. Furthermore, ours is the first case of dAVF with isolated intraventricular hemorrhage that was successfully treated using multimodality transvenous and transarterial embolization techniques. In cases of high-grade dAVF, multimodality treatment may offer the greatest chance for success, and should be strongly considered for management. PMID- 29437718 TI - Spinal cord compression secondary to epidural abscess: the importance of prompt diagnosis and management. AB - A 66-year-old woman presented with a 4-day history of fever, lethargy, neck and lower back pain. Neurological examination revealed mild quadraparesis. In view of this, MRI whole spine with contrast was performed and showed extensive spinal epidural abscess extending from the cervical to lumbar region causing compression of the thecal sac, spinal cord and nerves. The patient received multiple laminectomies to decompress the spinal cord and required a prolonged course of intravenous flucloxacillin as Staphylococcus aureus was cultured from three sets of blood cultures. Although spinal epidural abscess is rare, it is important for clinicians to have a high index of suspicion; so appropriate imaging is performed to determine the diagnosis. Patient age, degree of thecal sac compression and duration of symptoms are all independently associated with poor outcome. 1. PMID- 29437719 TI - Dieulafoy's Lesion In The Oesophagus: A Rare Cause Of Upper Gastrointestinal Bleeding. AB - A Dieulafoy's lesion is defined as a dilated, aberrant, submucosal artery that erodes overlying mucosa in the absence of an underlying ulcer, aneurysm or intrinsic mural abnormality. It is a rare cause of upper gastrointestinal (GI) bleed with a very high mortality rate if it goes unidentified. It is most commonly located in the lesser curvature of the stomach but is extremely rare in the oesophagus. We are reporting a 55-year-old man who had massive haematemesis. Emergent endoscopy showed Dieulafoy's lesion in the distal oesophagus. It was sclerosed using endoscopic therapy. Patient's symptoms of GI bleeding resolved, and he was discharged home in a stable manner. Although a Dieulafoy's lesion is exceedingly rare in the oesophagus, it is associated with a high mortality if undiscovered. Its amenability to life-saving endoscopic therapy prompts us to keep this as a possible differential diagnosis of an upper GI bleed. PMID- 29437720 TI - Uterine fibroid or ovarian fibroma: importance of comprehensive preoperative consent-taking to include unexpected findings with management implications. AB - A 35-year-old woman presented with an abdominal mass found incidentally on an ultrasound scan. On examination, the uterus was mobile and 14 weeks in size. Further imaging showed a large subserosal pedunculated fibroid, and she was counselled for laparoscopic myomectomy, morcellation in a bag, kept in open view. Intraoperatively, the mass was noted to be arising from the right ovarian ligament instead of the uterus, and decision was made to convert to open surgery. This case highlights important issues of consent-taking preoperatively and critical points to note regarding change in operative consent intraoperatively. This also highlights the importance of multidisciplinary cooperation as the decision had to be made with inputs made from gynae-oncology and pathology. PMID- 29437721 TI - An intertidal mollusk found in a boy's skin abscess. AB - Skin abscesses are commonly seen by primary care physicians in the outpatient setting. The majority of these soft tissue infections arise from penetration wounds by inanimate objects, but rarely, a living organism may present as a contributing factor. We present a case of an 11-year-old boy with an unusual skin abscess containing a chequered periwinkle marine snail (Littorina scutulata). The unique characteristics of this intertidal mollusk appear to have enabled it to survive in the subcutaneous tissue for a week, despite the hostile environment of a skin abscess. This case emphasises adherence to current professional guidelines that recommend incision and drainage of suspected skin abscesses and encourages clinicians to take a careful history of present illness which may aid in identification of subsequent cases of marine snails, or other living organisms, residing in skin abscesses. PMID- 29437722 TI - Transudative chylothorax: an uncommon illness due to a common cause. AB - Chylothorax is defined as presence of chyle in the pleural space. It is commonly associated with cardiothoracic surgery, trauma, malignancy or some benign disorders. Transudative chylothorax is uncommon. A 52-year-old man presented with bilateral chylothorax with preceding history of blunt trauma to the chest. On further evaluation, he was diagnosed to have a transudative chylothorax due to cirrhosis of liver with coexisting chylous ascites and evidence of peritoneopleural communication. The patient was managed with diuretics followed by chemical pleurodesis with iodopovidone. PMID- 29437723 TI - Isolated unilateral ptosis as a presenting feature of midbrain infarction. PMID- 29437724 TI - Nailing septo-optic dysplasia. PMID- 29437725 TI - Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer. AB - Histone acetylation is associated with active transcription in eukaryotic cells. It helps to open up the chromatin by neutralizing the positive charge of histone lysine residues and providing binding platforms for "reader" proteins. The bromodomain (BRD) has long been thought to be the sole protein module that recognizes acetylated histones. Recently, we identified the YEATS domain of AF9 (ALL1 fused gene from chromosome 9) as a novel acetyl-lysine-binding module and showed that the ENL (eleven-nineteen leukemia) YEATS domain is an essential acetyl-histone reader in acute myeloid leukemias. The human genome encodes four YEATS domain proteins, including GAS41, a component of chromatin remodelers responsible for H2A.Z deposition onto chromatin; however, the importance of the GAS41 YEATS domain in human cancer remains largely unknown. Here we report that GAS41 is frequently amplified in human non-small cell lung cancer (NSCLC) and is required for cancer cell proliferation, survival, and transformation. Biochemical and crystal structural studies demonstrate that GAS41 binds to histone H3 acetylated on H3K27 and H3K14, a specificity that is distinct from that of AF9 or ENL. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) analyses in lung cancer cells reveal that GAS41 colocalizes with H3K27ac and H3K14ac on the promoters of actively transcribed genes. Depletion of GAS41 or disruption of the interaction between its YEATS domain and acetylated histones impairs the association of histone variant H2A.Z with chromatin and consequently suppresses cancer cell growth and survival both in vitro and in vivo. Overall, our study identifies GAS41 as a histone acetylation reader that promotes histone H2A.Z deposition in NSCLC. PMID- 29437727 TI - Unique case of gyrate atrophy with a well-preserved electroretinogram (ERG). AB - Gyrate atrophy is a rare autosomal recessive disorder caused by a mutation in the ornithine-delta-amino transferase gene. We present an interesting case of a 33 year-old woman who presented with increasing myopia, nyctalopia and failing vision. Examination revealed posterior subscapsular cataracts, narrowed peripheral visual fields and scalloped atrophic peripheral chorioretinal lesions. Blood investigations showed a raised plasma ornithine level at 917 MUmol/L (normal range: 32-88 MUmol/L) confirming the diagnosis of gyrate atrophy. The patient, despite not tolerating dietary treatment, had retained central vision over a follow-up period of 18 years. The electroretinogram, which normally diminishes with disease progression, was still nearly normal when last tested at 16 years follow-up. Genetic testing did not reveal any novel mutation that could account for this variation. PMID- 29437726 TI - Protein synthesis controls phosphate homeostasis. AB - Phosphorus is an essential element assimilated largely as orthophosphate (Pi). Cells respond to Pi starvation by importing Pi from their surroundings. We now report that impaired protein synthesis alone triggers a Pi starvation response even when Pi is plentiful in the extracellular milieu. In the bacterium Salmonella enterica serovar Typhimurium, this response entails phosphorylation of the regulatory protein PhoB and transcription of PhoB-dependent Pi transporter genes and is eliminated upon stimulation of adenosine triphosphate (ATP) hydrolysis. When protein synthesis is impaired due to low cytoplasmic magnesium (Mg2+), Salmonella triggers the Pi starvation response because ribosomes are destabilized, which reduces ATP consumption and thus free cytoplasmic Pi. This response is transient because low cytoplasmic Mg2+ promotes an uptake in Mg2+ and a decrease in ATP levels, which stabilizes ribosomes, resulting in ATP consumption and Pi increase, thus ending the response. Notably, pharmacological inhibition of protein synthesis also elicited a Pi starvation response in the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae Our findings identify a regulatory connection between protein synthesis and Pi homeostasis that is widespread in nature. PMID- 29437729 TI - Correction: Cold agglutinins in a patient undergoing normothermic cardiac operation with warm cardioplegia. PMID- 29437728 TI - Large vessel stroke as initial presentation of thrombotic thrombocytopenic purpura. AB - A 67-year-old right-handed woman presented with dysarthria, left upper extremity weakness and right-sided neglect of 3 hours duration. Imaging of the brain revealed acute right middle cerebral artery stroke; however, tissue plasminogen activator could not be administered due to severe thrombocytopenia. A peripheral smear revealed schistocytes and the patient was treated empirically for thrombotic thrombocytopenic purpura (TTP) with therapeutic plasma exchange. An extensive workup revealed no embolic source or other cause for stroke, and a diagnosis of large vessel infarct secondary to TTP was made. After a prolonged hospital course, the patient had partial neurological recovery and was discharged to a rehabilitation facility. Although transient neurologic deficits due to small vessel occlusions are well described in TTP, large vessel infarct can occur as well. This diagnosis should be considered in patients presenting with concomitant stroke and thrombocytopenia, as untreated TTP is nearly always fatal. PMID- 29437730 TI - Tuberculosis and pauci-immune crescentic glomerulonephritis. AB - We report here a case that highlights tuberculosis (TB) as a possible cause for pauci-immune crescentic glomerulonephritis (c-GN), an important and often treatable cause of kidney injury. A 47-year-old HIV-negative man of mixed ethnicity presented with a 2-week history of cough, haemoptysis and unintentional weight loss. Chest examination revealed crepitations over the right upper zone and urinalysis demonstrated an active urinary sediment with red cell casts. Chest radiograph confirmed right upper lobe cavitation. Serum laboratory investigations revealed a serum creatinine of 632 umol/L and were negative for antineutrophil cytoplasmic antibodies. A diagnosis of pauci-immune c-GN was made on renal biopsy. In addition, sputum PCR confirmed infection with drug-sensitive Mycobacterium tuberculosis Standard TB treatment and immunosuppression with prednisone and cyclophosphamide was commenced, and over the course of 6 months, renal function improved to an estimated glomerular filtration rate >60 mL/min. PMID- 29437731 TI - Massive thoracic ganglioneuroma with significant mass effect on left hemithorax. AB - A 42-year-old, otherwise healthy, woman presented with persistent left-sided chest pain. A chest X-ray revealed a large opacity in the left hemithorax which prompted further investigation with an MRI. MRI revealed a large left apical mass occupying approximately two-thirds of the left hemithorax. The mass was investigated further with a CT with contrast which did not reveal any vascular involvement or invasion into adjacent structures. The patient successfully underwent tumour resection via left thoracotomy. The tumour was removed in its entirety. Grossly, the tumour was a 23*10*10 cm, well encapsulated, ovoid, fibrous nodule. Histopathology revealed ganglion cells, nerve fibres and Schwann cells in a mucous matrix consistent with ganglioneuroma. Postoperative course was unremarkable. PMID- 29437732 TI - Fatal air embolism following local anaesthetisation: does needle size matter? AB - A 76--year--old male cigarette smoker presented with a 2-week history of cough and haemoptysis. Chest CT on admission revealed multiple new lung nodules concerning for malignancy. CT--guided biopsy of the nodule in left lower lobe was attempted in prone oblique position for tissue diagnosis. Local anaesthetic (lidocaine) was administered using a 25--gauge (1.5-inch) needle to anaesthetise the skin and subcutaneous tissue. This was followed by insertion of a 25-gauge (3.5-inch) Whitacre needle to anaesthetise deeper tissues and parietal pleura. Due to patient's coughing and proximity of the nodule to the diaphragm, the circumstances were judged to be too risky for a needle biopsy. Therefore, it was decided to biopsy another nodule in the left lung that was visible on the same CT section. During this portion of the procedure, the patient became hypoxic and developed pulseless electrical activity arrest. Cardiopulmonary resuscitation was unsuccessful and the efforts ceased after 45 min. Subsequent review of CT scan revealed air in the left ventricle. PMID- 29437733 TI - Cough as the sole manifestation of pericardial effusion. AB - A 59-year-old woman with paroxysmal atrial fibrillation (AF) presented with severe non-productive cough, malaise, low-grade fever and AF flare-up 3 weeks following pulmonary vein isolation with radiofrequency catheter ablation. She denied chest pain or dyspnoea. Patient was haemodynamically stable. There was no pulsus paradoxus. Laboratories showed leucocytosis and elevated C-reactive protein. ECG showed sinus tachycardia. CT abdomen and pelvis showed a large pericardial effusion (PE). Shortly after admission, she developed AF with rapid ventricular response, responsive to intravenous amiodarone. Transthoracic echocardiogram revealed 2.4 cm posterior PE without tamponade physiology, non amenable to pericardiocentesis via sub-xiphoid approach. Patient underwent left thoracoscopic pericardial window with removal of 250 cc bloody fibrinous fluid. Cough improved significantly and she was discharged on oral amiodarone and apixaban. Repeat CT chest after 2 weeks for recurrent cough showed a small PE, treated with oral prednisone for suspected postablation pericarditis, with complete resolution of cough. Amiodarone was stopped without recurrence of AF. PMID- 29437734 TI - Consecutive siblings, each with two separate small bowel atresias. AB - The familial occurrence of multiple-level intestinal atresia in newborn is extremely uncommon, with very sporadic similar cases reported in the literature. We present a case of multiple intestinal atresia in two consecutive siblings who successfully underwent surgical repair. PMID- 29437735 TI - Successful treatment of extensive splanchnic vein thrombosis in a patient with mycosis fungoides. AB - A 33-year-old man of a Middle Eastern origin presented to us with abdominal pain and distension secondary to refractory ascites of 1-month duration. The patient had a history of taking oral retinoic acid 25 mg for 4 months for mycosis fungoides. Investigations revealed thrombosis of hepatic veins with extensive thrombosis of the porto-mesenteric axis. A combination of transjugular intrahepatic portosystemic shunt, balloon angioplasty and thrombolysis with recombinant tissue plasminogen activator was successfully used to treat his condition. PMID- 29437736 TI - Vertebro-vertebral fistula presenting as a pulsatile tinnitus. AB - Tinnitus is the perception of sound in the absence of a corresponding external acoustic stimulus, resulting in an estimated prevalence of 10% to 15% in adults. Tinnitus may be classified as pulsatile (PT) or continuous (non-PT), and may be subjective (heard only by the patient) or objective (also audible to the examiner). PT is usually related to vascular causes and is pulse synchronous (coinciding with the patient's heartbeat). PT is much less common affecting approximately 4% of patients with tinnitus, but unlike non-PT, usually has a specific identifiable cause. We present a case of a man without previous otological disease or head trauma, with a left-ear subjective PT. MR angiography detected a left vertebro-vertebral arteriovenous fistula, which was treated by endovascular embolisation with important symptomatic relief. PMID- 29437737 TI - Acute pericarditis following endoscopy. AB - The differential diagnoses for patients presenting with chest discomfort after endoscopy remain broad. In addition to infectious, traumatic and bleeding complications, intrinsic cardiac pathology should be considered. Though rare, pericarditis and pericardial tamponade are additional entities that the clinician should consider when evaluating these patients. We present a 74-year-old man who arrived to the emergency department with substernal chest discomfort that began shortly after upper and lower endoscopy the previous day. Biopsies were obtained during the procedure (ileal and colonic mucosa) without complication. The patient reported worsening chest discomfort with deep inspiration or lying flat. ECG was significant for diffuse ST-segment elevation and PR depression. Cardiac workup was otherwise negative; the patient improved with conservative measures. In this case report, we describe a little known complication after upper endoscopy. By highlighting the clinical features of pericarditis in this setting, the provider can be alert to recognise and promptly treat this clinical entity. PMID- 29437738 TI - An unusual presentation of pulmonary embolism leading to infarction, cavitation, abscess formation and bronchopleural fistulation. AB - We report an unusual presentation of pulmonary embolism (PE) where a 58-year-old man first developed symptoms of community-acquired pneumonia. Despite antibiotic therapy, he remained unwell with rising inflammatory markers, general malaise and persistent cough. He developed stony dull percussion and absent breath sounds to his left mid to lower zones. Serial chest x-rays showed progression from lobar consolidation to a large loculated left-sided pleural collection. CT chest showed left-sided lung abscess, empyema and bronchopleural fistulation. Incidentally, the scan revealed acute left-sided PE and its distribution corresponded with the location of the left lung abscess and empyema. The sequence of events likely started with PE leading to infarction, cavitation, abscess formation and bronchopleural fistulation. This patient was managed with a 6-month course of rivaroxaban. After completing 2 weeks of intravenous meropenem, he was converted to 4-week course of oral co-amoxiclav and metronidazole and attained full recovery. PMID- 29437739 TI - A foreign older diabetic woman with an acute myocardial infarction: when cognitive biases in clinical decision-making become especially important. AB - We present a case of an 80-year-old Turkish female patient with diabetes who suffered an acute myocardial infarction (AMI) and underwent percutaneous coronary balloon angioplasty (PTCA)/stenting. Due to new ischaemic episodes, a second PTCA/stenting had to be preformed 6 days later, which revealed a partial restent thrombosis. This case report raises several important issues. First, language problems are an important barrier for safety and quality in healthcare. Second, gender, ethnicity and age differences in patients with AMI need to be considered in order to eliminate inequities in clinical practice. Third, strategies to raise the awareness of cognitive biases as well as professional training about critical thinking and decision-making skills are needed. PMID- 29437740 TI - Improvements in exercise capacity following cardiac transplantation in a patient born with double inlet left ventricle. AB - A 32-year-old man born with double inlet left ventricle (DILV) and other significant cardiac abnormalities underwent surgical palliation at 1 day, 2 years and 20 years, before receiving a donor heart at 29 years. To our knowledge, there are no case reports or cohort studies of the effect of exercise training on exercise capacity and peak oxygen uptake (VO2peak) following heart transplantation (HTx) for individuals born with DILV. The patient accessed our clinical exercise physiology service for assessment, advice and support for exercise training over a 7-year period spanning pre-HTx and post-HTx. An individualised exercise plan, together with careful assessment and monitoring, and the patient's own motivation have contributed to him achieving an outstanding post-HTx doubling of VO2peak and exercise capacity. PMID- 29437742 TI - Implantable cardioverter defibrillators in the context of hypertrophic cardiomyopathy: a lesson in patient autonomy. AB - Hypertrophiccardiomyopathy (HCM) is common, whereas the decision not to have an implantable cardioverterdefibrillator (ICD) when probably falling into a 'high risk' category is not. A solicitor aged 45 years attended the inherited cardiac conditions clinic for review of her HCM and discussion about ICD implantation for primary prevention of sudden cardiac death (SCD). Despite a predicted 7% risk of SCD within the next 5 years, according to the European Society of Cardiology endorsed HCM Risk-SCD risk stratification tool, the patient opted against implantation of an ICD and comprehensively justifies her decision. This report discusses ethical aspects of a consultation offering ICD protection against SCD in the context of HCM and emphasises the clinicians' role in respecting patient autonomy. PMID- 29437741 TI - Pontine haemorrhage disguised as Bell's palsy. AB - Isolated facial nerve palsy is a common presentation of Bell's palsy, but rarely seen in pontine lesions. The patient being reported is a middle-aged man who developed isolated facial nerve palsy and was initially treated as Bell's palsy. However, on MRI of the brain, he was found to have pontine haemorrhage. He was managed conservatively and improved. Pontine haemorrhage as an aetiology for isolated facial nerve palsy is a rare scenario, which often goes misdiagnosed and treated as Bell's palsy. PMID- 29437743 TI - Minimal change disease with maximum immunosuppression: successful treatment of steroid-dependent minimal change disease with rituximab. AB - Minimal change disease (MCD) is usually steroid sensitive, although in case of steroid dependent and multiple relapses we can struggle with different immunosuppressive agents, sometimes with no response. Rituximab has been emerging as an alternative therapeutic option.We describe a case of a young patient with MCD that had frequent relapses and steroid dependency, with no response to several immunosuppressive agents during 15 years of disease. He was kept under high-dose steroids and ciclosporin. He started treatment with rituximab (two administrations of 1 g 2 weeks apart, repeating after 6 months). The steroids dose was gradually reduced and the ciclosporin was stopped. During the entire 2 years follow-up period, he remained in remission and had no adverse events.This remarkable outcome reinforces the option of using rituximab in difficult cases, allowing the reduction of steroid burden and its adverse effects, which is of extreme importance, especially in young patients. PMID- 29437744 TI - Can aldosterone break your heart? Takotsubo cardiomyopathy in a patient with newly diagnosed primary aldosteronism. AB - We report a case of a 47-year-old Caucasian woman with medical history of hypertension and hypokalemia, who presented to Emergency Room with symptoms resembling acute coronary syndrome ST-segment elevation myocardial infarction. Coronary angiogram revealed clear coronary arteries and left ventriculogram confirmed the diagnosis of Takotsubo cardiomyopathy. She was treated conservatively with good clinical outcome. Subsequent testing revealed underlying primary aldosteronism. PMID- 29437746 TI - From renal salt wasting to SIADH. AB - Hyponatraemia is common following major head injury and is associated with significant morbidity and mortality. A 20-year-old man presented with reduced consciousness after head trauma and was found to have a fractured skull base with bilateral frontal contusions. On day 3 of his admission, he developed hyponatraemia with raised urine sodium and osmolality, despite receiving dexamethasone and intravenous fluid therapy. His hyponatraemia worsened after the treatment with fluid restriction and oral salt. He was in negative fluid balance suggesting possible renal salt wasting. A trial of isotonic normal saline resulted in a further fall in serum sodium level. He was subsequently treated for suspected syndrome of inappropriate ADH with a hypertonic (3%) saline infusion. His sodium level and neurological status improved. This case report illustrates the confounding factors that commonly affect clinical decision-making when treating patients with hyponatraemia following head injury. The guidelines for diagnosis and management are discussed. PMID- 29437745 TI - Chronic and severe prosthetic joint infection complicated by amyloid A amyloidosis with renal and bladder impairment. PMID- 29437747 TI - Sister Mary Joseph nodule: a diagnostic challenge. AB - We present the case of a 72-year-old woman who presented with, to our knowledge, the largest reported Sister Mary Joseph lesion in the literature. Often associated with a poor prognosis, the patient went on to have a wide local excision of the lesion and has made a full recovery 2 years after the nodule initially developed. Histological examination confirmed the presence of underlying endometrial cancer and the patient subsequently underwent a total hysterectomy and bilateral salpingo-oopherectomy. PMID- 29437748 TI - Subretinal cysticercosis with a mobile scolex. PMID- 29437749 TI - Clinical guidelines - more PDAs please. PMID- 29437750 TI - Incidence and determinants of tuberculosis infection among adult patients with HIV attending HIV care in north-east Ethiopia: a retrospective cohort study. AB - OBJECTIVE: This study assessed the incidence of tuberculosis (TB) and its predictors among adults living with HIV/AIDS in government health facilities in north-east Ethiopia. SETTING: A 5-year retrospective cohort study was conducted from May to June 2015 on 451 adult HIV/AIDS-infected individuals who enrolled in the HIV care clinics of government health facilities in north-east Ethiopia. PARTICIPANTS: A total of 451 HIV-infected adults who newly enrolled in the adult HIV care clinic from 1 July 2010 with complete information were followed until May 2015. PRIMARY OUTCOME MEASURE: The primary outcome was the proportion of patients diagnosed with TB or the TB incidence rate. SECONDARY OUTCOME MEASURE: The incidence of TB was investigated in relation to years of follow-up. RESULTS: A total of 451 charts with complete information were followed for 1377.41 person years (PY) of observation. The overall incidence density of TB was 8.6 per 100 PYof observation. Previous TB disease (adjusted HR (AHR) 3.65, 95% CI 1.97 to 6.73), being bedridden (AHR 5.45, 95% CI 1.16 to 25.49), being underweight (body mass index (BMI) <18.5 kg/m2) (AHR 2.53, 95 % CI 1.27 to 5.05), taking isoniazid preventive therapy (IPT) (AHR 0.14, 95% CI 0.05 to 0.39), haemoglobin below 11 g/dL (AHR 2.31, 95% CI 1.35 to 3.93), and being in WHO clinical stages III and IV (AHR 2.84, 95% CI 1.11 to 7.27; AHR 3.07, 95% CI 1.08 to 8.75, respectively) were significant for the incidence of TB. CONCLUSION: The incidence of TB among adults living with HIV/AIDS in the first 3 years of follow-up was higher compared with that of subsequent years. Previous TB disease, no IPT, low BMI and haemoglobin level, advanced WHO clinical stage, and bedridden condition were the determinants of the incidence of TB. Therefore, addressing the significant predictors and improving TB/HIV collaborative activities should be strengthened in the study setting. PMID- 29437751 TI - What are the costs associated with child and maternal healthcare within Australia? A study protocol for the use of data linkage to identify health service use, and health system and patient costs. AB - INTRODUCTION: The current literature in Australia demonstrates that there are variations in access and outcomes in perinatal care based on socioeconomic factors. However, little has been done looking at the level of out-of-pocket healthcare costs associated with perinatal care. The primary aim of this project will be to quantify health service use and out-of-pocket healthcare expenditure associated with childbearing and early childhood in Queensland, Australia. METHODS AND ANALYSIS: This project will build Australia's first model (called Maternal & Child Cost MOD) of out-of-pocket healthcare expenditure by using administrative data from the Queensland Perinatal Data Collection, of all childbearing women and their resultant children, who gave birth in Queensland between 1 July 2012 and 30 June 2016.The current costs to the health system and out-of-pocket health care expenditure of patients associated with maternity and early childhood health care will be identified. The differences in costs based on indigenous identification, socioeconomic status and geographic location will be assessed using linear regression modelling and counterfactual modelling techniques. ETHICS AND DISSEMINATION: Human Research Ethics approval has been obtained from Townsville Hospital and Health Service Human Research Ethics Committee (HREC) (HREC Reference number: HREC/16/QTHS/223). Consent will not be sought from participants whose de-identified data will be used in this study. Permission to waive consent has been gained from Queensland Health under the Public Health Act 2005.The results of this study will be disseminated through publications in peer-reviewed journals and through presentations at conferences, regionally and nationally. Our target audience is clinicians, health professionals and health policy-makers. PMID- 29437753 TI - Dynamic changes of circulating tumour DNA in surgical lung cancer patients: protocol for a prospective observational study. AB - INTRODUCTION: Circulating tumour DNA (ctDNA) has potential applications in cancer management. Most previous studies about ctDNA focused on advanced stage cancer patients. We have completed a clinical prospective study (NCT02645318) and showed the feasibility and clinical application of ctDNA detection in early stage non small cell lung cancer (NSCLC) patients. The aim of this study is to investigate the elimination rate of ctDNA level after surgery. This is the first prospective study to evaluate the perioperative dynamic changes of ctDNA in surgical lung cancer patients. METHODS AND ANALYSIS: This is a prospective observational study to determine the elimination rate of circulating tumour DNA after surgery. Consecutive patients with suspected lung cancer who undergo curative-intent lung resection will be enrolled. 10 mL blood samples are taken by intravenous puncture. Plasma samples are obtained before surgery (time A) and at a series of scheduled time-points (2 min to 72 hours, time B to F) after tumour resection. DNA is prepared from 4 mL of purified plasma. A multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART) is used to simultaneously detect and quantitate hot spot EGFR, KRAS, BRAF, ERBB2, PIK3CA, TP53, ALK, RET and MET plasma DNA variants. Positive plasma mutations are validated in tumour tissue and normal lung tissue by targeted sequencing. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Peking University People's Hospital Medical Ethics Committee (2016PHB156-01). Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02965391; Pre-results. PMID- 29437752 TI - Towards high-quality, useful practice guidelines for child and youth mental health disorders: protocol for a systematic review and consensus exercise. AB - INTRODUCTION: The quality of clinical practice guidelines (PGs) has not been evaluated in child and youth mental health (CYMH). To address this gap, we will: (1) conduct a systematic review (SR) to answer the question 'among eligible PGs relevant to the prevention or treatment of CYMH conditions, which PGs meet criteria for minimum and high quality?'; (2) apply nominal group methods to create recommendations for how CYMH PG quality, completeness and usefulness can be strengthened. METHODS AND ANALYSIS: SR: Potentially eligible PGs will be identified in 12 databases using a reproducible search strategy developed by a research librarian. Trained raters will: (1) apply prespecified criteria to identify eligible PGs relevant to depression, anxiety, suicidality, bipolar disorder, behaviour disorder (attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder) and substance use disorder; (2) extract descriptive data and (3) assess PG quality using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Scores on three AGREE II domains (rigour of development, stakeholder involvement, editorial independence) will designate PGs as minimum (>=50%) or high quality (>=70%). Nominal group: Four CYMH PG knowledge user groups (clinicians, mental health service planners, youth and adult family members) will participate in structured exercises derived using nominal group methods to generate recommendations to improve PG quality, completeness and usefulness. ETHICS AND DISSEMINATION: Ethics approval is not required. Study products will be disseminated as follows. A cross-platform website will house eligible CYMH PGs and their quality ratings. Twitter and Facebook tools will promote it to a wide variety of PG users. Data from Google Analytics, Twitonomy and Altmetrics will inform usage evaluation. Complementary educational workshops will be conducted for CYMH professionals. Print materials and journal articles will be produced. PROSPERO REGISTRATION NUMBER: CRD42017060738. PMID- 29437754 TI - Epidemiological and clinical features of human metapneumovirus in hospitalised paediatric patients with acute respiratory illness: a cross-sectional study in Southern China, from 2013 to 2016. AB - OBJECTIVES: Human metapneumovirus (HMPV) is one of the most important respiratory viral pathogens affecting infants and children worldwide. Our study describes the epidemiological and clinical characteristics of HMPV present in patients hospitalised with acute respiratory illness (ARI) in Guangzhou, Southern China. STUDY DESIGN: A cross-sectional study. SETTING: Two tertiary hospitals in Guangzhou. PARTICIPANTS AND METHODS: Throat swabs were collected over a 3-year period from 5133 paediatric patients (<=14 years) hospitalised with ARI. Patients who are HMPV positive with clinical presentations (101/103) were recorded for further analysis. RESULTS: Of the 5133 patients included in the study, 103 (2.0%) were positive for HMPV. HMPV was more prevalent in children <=5 years (2.2%, 98/4399) compared with older children (>5-14 years) (0.7%, 5/734) (P=0.004). Two seasonal HMPV peaks were observed each year and mainly occurred in spring and early summer. Overall, 18.4% (19/103) of patients who are HMPV positive were codetected with other pathogens, most frequently respiratory syncytial virus (36.8%, 7/19). Patients who are HMPV positive presented with a wide spectrum of clinical features, including cough (100.0%, 101/101), abnormal pulmonary breath sound (91.1%, 92/101), fever (88.1%, 89/101), expectoration (77.2%, 78/101), coryza (50.5%, 51/101) and wheezing (46.5%, 47/101). The main diagnosis of patients who are HMPV positive was bronchopneumonia (66.7%, 56/84). Fever (>=38C) (91.6%, 76/83) was detected more often in patients with only HMPV detected than in patients with HMPV plus other pathogen(s) detected (72.2%, 13/18) (P=0.037), whereas diarrhoea was more common in patients with HMPV plus other pathogen(s) detected (22.2%, 4/18), compared with patients with HMPV only (3.6%, 3/83) (P=0.018). CONCLUSIONS: HMPV is an important respiratory pathogen in children with ARI in Guangzhou, particularly in children <=5 years old. HMPV has a seasonal variation. Bronchopneumonia is a major diagnosis in patients who are HMPV positive. PMID- 29437755 TI - A diagnostic cohort study on the accuracy of 18-fluorodeoxyglucose (18FDG) positron emission tomography (PET)-CT for evaluation of malignancy in anterior mediastinal lesions: the DECiMaL study. AB - OBJECTIVES: The aim of this study is to collate multi-institutional data to determine the value by defining the diagnostic performance of fluorodeoxyglucose positron emission tomography (FDG PET)/CT for malignancy in patients undergoing surgery with an anterior mediastinal mass in order to ascertain the clinical utility of PET/CT to differentiate malignant from benign aetiologies in patients presenting with an anterior mediastinal mass SETTING: DECiMaL Study is a multicentre, retrospective, collaborative cohort study in seven UK surgical sites. PARTICIPANTS: Between January 2002 and June 2015, a total of 134 patients were submitted with a mean age (SD) of 55 years (16) of which 69 (51%) were men. We included all patients undergoing surgery who presented with an anterior mediastinal mass and underwent PET/CT. PET/CT was considered positive for any reported avidity as stated in the official report and the reference was the resected specimen reported by histopathology using WHO criteria. PRIMARY AND SECONDARY OUTCOME MEASURES: Sensitivity, specificity, positive and negative predicted values of [18F]-FDG PET in determining malignant aetiology for an anterior mediastinal mass. RESULTS: The sensitivity and specificity of PET/CT to correctly classify malignant disease were 83% (95% CI 74 to 89) and 58% (95% CI 37 to 78). The positive and negative predictive values were 90% (95% CI 83% to 95%) and 42% (95% CI 26% to 61%). CONCLUSIONS: The results of our study suggest reasonable sensitivity but no specificity implying that a negative PET/CT is useful to rule out the diagnosis of malignant disease whereas a positive result has no value in the discrimination between malignant and benign diseases of the anterior mediastinum. PMID- 29437756 TI - Pre-post, mixed-methods feasibility study of the WorkingWell mobile support tool for individuals with serious mental illness in the USA: a pilot study protocol. AB - INTRODUCTION: Successful competitive employment has been found to be related to enhanced self-esteem, higher quality of life and reduced mental health service use for individuals living with serious mental illnesses (SMIs) including schizophrenia, bipolar disorder and major depression. The effectiveness of the individual placement and support model has been demonstrated in multiple randomised controlled trials in many countries. The management of stress, depression and anxiety in the workplace may be effectively enhanced through digital mental health interventions. The WorkingWell mobile support tool ('app') is specifically designed to meet the need for illness management support for individuals with SMI in the workplace, as an adjunct to professional treatment. METHODS AND ANALYSIS: The WorkingWell app, grounded in evidence-based supported employment, is informed by user experience design. It will be tested in a pre post design, mixed-methods pilot study to explore issues of feasibility, acceptability and usefulness, and to provide preliminary data on the impact of use. Putative mediators of improved job tenure and psychological well-being, including postintervention changes in social support, self-efficacy and work related motivation, will be investigated. Forty individuals at least 18 years of age, meeting the eligibility requirements for supported employment services (ie, diagnosed with a mental illness meeting the criteria for severity, duration and treatment), working a minimum of 10 hours per week at study enrolment, and speaking, reading and writing in English will be recruited for the pilot study. Research staff will recruit individuals at community-based mental health agencies; provide orientation to the study, the study smartphones and the WorkingWell app; conduct research interviews including standardised measures as well as semistructured items; and provide technical assistance in telephone calls and inperson meetings. A sample of 10 agency staff will be recruited to obtain further information on the feasibility, acceptability and usefulness of WorkingWell. ETHICS AND DISSEMINATION: The study design and procedures are approved by the Dartmouth-Hitchcock Medical Center Committee for the Protection of Human Subjects, the Massachusetts Department of Mental Health Central Office Research Review Committee and the Vermont Agency of Human Services Institutional Review Board. Study findings will be disseminated to agency partners, state agencies and funders, and to the research and technology development communities. Findings from the study will inform the design, data collection procedures and protocol for future full-scale randomised controlled trial testing of the effectiveness of the WorkingWell app, as well as investigations of work-related variables as mediators of psychological well-being and quality of life for individuals with SMI. PMID- 29437757 TI - Sexual inequality in incident tuberculosis: a cohort study in Taiwan. AB - OBJECTIVE: Animal studies showed that male subjects had lower activity of immune response to infections than female subjects, which may increase the risk of the development of tuberculosis in male population. This study intended to investigate the risk of incident tuberculosis in male and female adults in Taiwan. DESIGN: This is a retrospective cohort study. SETTING: The present analyses used data of Taiwan National Health Interview Survey 2001, 2005 and 2009, National Register of Deaths Dataset, and National Health Insurance Research Database from 2000 to 2013. PARTICIPANTS: A total of 43 424 subjects with a mean age of 43.04 years were analysed. PRIMARY OUTCOME MEASURES: Incidence of tuberculosis. RESULTS: During 381 561 person-years of follow-up period, incident tuberculosis was recognised in 268 individuals. The incidence rates of tuberculosis were 97.56 and 43.24 per 100 000 person-years among male and female participants, respectively. Kaplan-Meier curves comparing male and female subjects showed statistical significance (log-rank test, P value<0.01). After adjusting for subjects' demographics and comorbidities, men showed increased risks of incident tuberculosis (adjusted HR, 1.68; 95% CI 1.21 to 2.34; P value<0.01) compared with women. On subgroup analysis, after stratifying by age, smoking and alcohol use, men had a higher risk of incident tuberculosis than women in all patient subgroups, except those who were current smokers. CONCLUSIONS: This study suggests that men had a higher risk of incident tuberculosis than women. Future tuberculosis control programmes should particularly target the male population. PMID- 29437759 TI - A critically ill child with dark urine. PMID- 29437758 TI - Lack of efficacy in a randomised trial of a brief intervention to reduce drug use and increase drug treatment services utilisation among adult emergency department patients over a 12-month period. AB - OBJECTIVES: Assess the 12-month efficacy of a brief intervention (BI) on reducing drug use and increasing drug treatment services utilisation among adult emergency department (ED) patients. METHODS: This randomised, controlled trial enrolled 18 64-year-old ED patients needing a drug use intervention. Treatment arm participants received a tailored BI while control arm participants only completed the study questionnaires. Self-reported past 3-month drug use and engagement in drug treatment services were compared by study arm at 3-month intervals over 1 year. Multiple imputations were performed to overcome loss-to-follow-up. RESULTS: Of the 1030 participants, follow-up completion ranged 55%-64% over the four follow-ups. At 12 months, the two study arms were similar in regards to mean: (1) proportion reporting any drug use (treatment: 67.1% (61.6 to 72.6), control: 74.4% (69.4 to 79.4)); (2) drug use frequency on a five-point scale (treatment: 3.7 (3.3 to 4.2), control: 4.6 (4.0 to 5.2)); (3) total days of drug use (treatment: 28.3 (23.2 to 33.4), control: 33.4 (28.5 to 38.2)); (4) most number of times drugs used/day (treatment: 4.6 (3.6 to 5.5), control: 6.1 (4.8 to 7.3)) and (5) typical number of times drugs used/day (treatment: 3.3 (2.5 to 4.1), control: 5.1 (3.9 to 6.2)). Utilisation of drug treatment services also was similar by study arm. In multivariable regression analyses, patients who were homeless or had higher drug use at baseline continued to have greater drug use in follow-up. CONCLUSIONS: Among adult ED patients requiring a drug use intervention, this BI did not decrease drug use or increase drug treatment services utilisation over a 12-month period more than the control condition. TRIAL REGISTRATION NUMBER: NCT01124591; Pre-trial. PMID- 29437760 TI - Transvenous Lead Extraction in Adults With Congenital Heart Disease: Insights From a 20-Year Single-Center Experience. AB - BACKGROUND: Safety and feasibility data on transvenous lead extraction (TLE) in the challenging population of adults with congenital heart disease (A-CHD) are limited. Herein, we report the results of TLE in A-CHD during a 20-year period. METHODS AND RESULTS: All consecutive TLE procedures in A-CHD were included in a monocentric prospective registry from 1996. A total of 121 leads were extracted in 49 A-CHD (median age, 38 years; 51% men) during 71 TLE procedures. Twenty-four (49%) patients had transposition of the great arteries. Main indications for extraction were infection in 34 (48%) and lead failure in 22 (31%). A laser sheath was required for 56 (46%) leads and a femoral approach for 10 (8%). Complete TLE was achieved for 111 leads (92%). In multivariable analysis, lead duration (odds ratio, 1.02; 95% confidence interval, 1.00-1.04; P<0.01) and number of previous cardiac surgeries (odds ratio, 2.65; 95% confidence interval, 1.52-4.67; P<0.01) were predictive of TLE failure. No perioperative death or pericardial effusion was observed. Subpulmonary atrioventricular valve regurgitation increased in 8 patients (5 with transposition of the great arteries) and was independently associated with an implantable cardioverter defibrillator lead (odds ratio, 9.69; 95% confidence interval, 1.31-71.64; P=0.03) and valvular vegetation (odds ratio, 7.29; 95% confidence interval, 1.32 40.51; P=0.02). After a median of 54 (19-134) months of follow-up after the first TLE, 3 deaths occurred independently from lead management. CONCLUSIONS: Despite complex anatomic issues, TLE can be achieved successfully in most A-CHD using advanced extraction techniques. Subpulmonary atrioventricular valve regurgitation is a prevalent complication, particularly in patients with transposition of the great arteries. PMID- 29437762 TI - Right Ventricular Outflow Tract Electroanatomical Abnormalities Predict Ventricular Fibrillation Inducibility in Brugada Syndrome. PMID- 29437763 TI - Letter by Houston et al Regarding Article, "Localized Optogenetic Targeting of Rotors in Atrial Cardiomyocyte Monolayers". PMID- 29437761 TI - Altered Repolarization Reserve in Failing Rabbit Ventricular Myocytes: Calcium and beta-Adrenergic Effects on Delayed- and Inward-Rectifier Potassium Currents. AB - BACKGROUND: Electrophysiological remodeling and increased susceptibility for cardiac arrhythmias are hallmarks of heart failure (HF). Ventricular action potential duration (APD) is typically prolonged in HF, with reduced repolarization reserve. However, underlying K+ current changes are often measured in nonphysiological conditions (voltage clamp, low pacing rates, cytosolic Ca2+ buffers). METHODS AND RESULTS: We measured the major K+ currents (IKr, IKs, and IK1) and their Ca2+- and beta-adrenergic dependence in rabbit ventricular myocytes in chronic pressure/volume overload-induced HF (versus age-matched controls). APD was significantly prolonged only at lower pacing rates (0.2-1 Hz) in HF under physiological ionic conditions and temperature. However, when cytosolic Ca2+ was buffered, APD prolongation in HF was also significant at higher pacing rates. Beat-to-beat variability of APD was also significantly increased in HF. Both IKr and IKs were significantly upregulated in HF under action potential clamp, but only when cytosolic Ca2+ was not buffered. CaMKII (Ca2+/calmodulin-dependent protein kinase II) inhibition abolished IKs upregulation in HF, but it did not affect IKr. IKs response to beta-adrenergic stimulation was also significantly diminished in HF. IK1 was also decreased in HF regardless of Ca2+ buffering, CaMKII inhibition, or beta-adrenergic stimulation. CONCLUSIONS: At baseline Ca2+-dependent upregulation of IKr and IKs in HF counterbalances the reduced IK1, maintaining repolarization reserve (especially at higher heart rates) in physiological conditions, unlike conditions of strong cytosolic Ca2+ buffering. However, under beta-adrenergic stimulation, reduced IKs responsiveness severely limits integrated repolarizing K+ current and repolarization reserve in HF. This would increase arrhythmia propensity in HF, especially during adrenergic stress. PMID- 29437764 TI - Response by Feola et al to Letter Regarding Article, "Localized Optogenetic Targeting of Rotors in Atrial Cardiomyocyte Monolayers". PMID- 29437765 TI - Repolarization Reserve and Action Potential Dynamics in Failing Myocytes. PMID- 29437766 TI - Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize. AB - Circulating tumor cell (CTC) clusters may represent one of the key mechanisms initiating the metastasis process. However, the series of pathophysiologic events by which CTC clusters originate, enter the circulation, and reach the distant sites remain to be identified. The cellular and molecular mechanisms that provide survival advantage for CTC clusters during the transit in the blood stream are also still largely unknown. Understanding the biology of CTC clusters is critical to assess this unified scheme employed by cancer and to device strategies to overcome key pathways responsible for their improved metastatic potential. CTC clusters remain an underdeveloped area of research begging the attention of multidisciplinary cancer research teams. Here, we provide insight on existing preclinical evidence on the potential mechanisms leading to CTC cluster formation and dissemination and on processes that may offer survival advantage. We also offer our perspective on future directions to delineate the role of CTC clusters in metastatic cascade and discuss their clinical significance. Cancer Res; 78(4); 845-52. (c)2018 AACR. PMID- 29437768 TI - FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. AB - On March 13, 2017, the FDA approved ribociclib (KISQALI; Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer. The approval was based on a randomized, double-blind, placebo controlled, international clinical trial (MONALEESA-2). A total of 668 patients were randomized to receive either ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). An improvement in progression-free survival (PFS) was observed in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole [HR = 0.556; 95% confidence interval (CI), 0.429 0.720]. Overall response rate (ORR) in patients with measurable disease was 52.7% (95% CI, 46.6-58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI, 31.1 43.2) in the placebo plus letrozole arm. Overall survival data were immature. The most common adverse reactions observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. This article summarizes FDA decision-making and data supporting the approval of ribociclib. Clin Cancer Res; 24(13); 2999-3004. (c)2018 AACRSee related commentary by Spring and Bardia, p. 2981. PMID- 29437767 TI - T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma. AB - Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM.Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNgamma, TNFalpha, and IL2 were assessed by flow cytometry. T-cell receptor Vbeta chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers.Results: Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations.Conclusions: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM. Clin Cancer Res; 24(17); 4175-86. (c)2018 AACRSee related commentary by Jackson and Lim, p. 4059. PMID- 29437769 TI - Intracaval misplacement of a double-J ureteral stent. AB - Double-J ureteral stent (DJUS) is an important therapeutic tool in endourology. There are well-known frequent complications associated with DJUS placement such as distal and proximal migration within the urinary tract. However, perforation and stent misplacement are uncommon but serious complications of this technique. We present a case of a 63-year-old man who had a misplacement of a DJUS into the inferior vena cava during an elective procedure of ureteral catheterisation. The stent placement was performed under fluoroscopic control and it seemed well positioned. Actually, the DJUS was misplaced in the inferior vena cava after drilling at the level of the crossing of the ureter with the ipsilateral iliac vessels. Diagnosis was incidentally made 3 months after the placement of the stent in a renal CT scan. The patient was always asymptomatic. We performed an endoscopic removal of the ureteral stent, which took place without complications. PMID- 29437770 TI - Double invasive fungal infection due to dematiaceous moulds in a renal transplant patient. AB - Alternaria and Verruconis are two dematiaceous moulds that occasionally cause disease in immunocompromised hosts. We present the case of a 58-year-old man with history of deceased donor renal transplantation 14 months prior, who presented with fevers and cough. He was found to have right upper lobe pneumonia and a non healing eschar of his right knee. Dematiaceous fungi grew from bronchoalveolar lavage (BAL) and was sent to reference lab for identification. Meanwhile, the eschar on his right knee was biopsied and grew Alternaria spp. Pathology was consistent with invasive mould infection and he was treated as having disseminated Alternaria infection with voriconazole and amphotericin B lipid complex. Later on, the dematiaceous mould from a BAL specimen was identified as Verruconis gallopava The patient was discharged on voriconazole awaiting minimal inhibitory concentrations for V. gallopava but was readmitted 2 days later with high fevers and died from acute respiratory failure. PMID- 29437771 TI - Hepatotoxicity Associated With Vismodegib. AB - An 82-year-old Caucasian woman with a history of basal cell carcinoma on vismodegib presented with nausea, vomiting and intermittent abdominal pain. Laboratory results were remarkable for the elevation of liver enzymes. Endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiogram (PTC) did not show evidence of intrahepatic or extrahepatic obstruction of the biliary tract. During PTC external biliary catheter was placed; however, bilirubin continued to rise. Further, laboratory work-up and imaging studies ruled out other possible aetiologies for hepatotoxicity such as infections, autoimmune hepatitis and other drugs known to be hepatotoxic thus leaving vismodegib the most likely cause of hepatotoxicity. PMID- 29437772 TI - Pathological fracture of femoral neck in a middle-aged woman: a rare presentation of primary hydatid cyst disease in humans. AB - Hydatid disease in humans is caused by Echinococcus granulosus. It most commonly involves the liver and, to a lesser extent, the lungs and spleen; however, it is known to involve other areas, too. Involvement of bone by hydatid cyst is rare. Here, we describe the case of a 37-year-old woman who presented with pain in the left groin and swelling in the left thigh. The radiological imaging showed a fracture of the femoral neck and cysts in the shaft of the femur. Diagnosis of hydatid cyst was confirmed on the basis of histopathology of biopsy specimens. The patient recovered after surgical excision of the cyst. This case illustrates the various sites and presentations of hydatid cyst disease, and the need to investigate for it if cystic bony lesions are encountered especially in endemic regions, as a delay in diagnosis can lead to long-term morbidity and even death. PMID- 29437773 TI - Autoimmune fasciitis triggered by the anti-programmed cell death-1 monoclonal antibody nivolumab. AB - A 43-year-old woman with a history of recently diagnosed metastatic melanoma was commenced on systemic therapy with nivolumab, an anti-programmed cell death-1 monoclonal antibody and one of an increasing group of the so-called 'immune checkpoint inhibitors'. She experienced a dramatic complete response within 6 months of initiation. However, in addition to developing incident autoimmune hypothyroidism, she also developed progressive fatigue, proximal weakness, myalgia and dysphagia. Initial investigations with blood tests, electrophysiology and a muscle biopsy were non-specific or normal. Subsequent examination revealed 'woody' thickening of the subcutaneous tissues of the forearms, thighs and calves consistent with fasciitis. MRI and a full-thickness skin-muscle biopsy were ultimately diagnostic of a likely iatrogenic autoimmune myofasciitis. The clinical manifestations only responded partly to prednisolone 30 mg orally and treatment was escalated to include intravenous immunoglobulin. At 3 months, this has only resulted in a modest incremental improvement. PMID- 29437774 TI - Uncharted waters: Next-generation sequencing and machine learning software allow forensic science to expand into phenotype prediction from DNA samples. PMID- 29437775 TI - ZBTB2 reads unmethylated CpG island promoters and regulates embryonic stem cell differentiation. AB - Proteins that bind to DNA depending on its methylation status play an important role in methylation-mediated regulation of gene expression. Using a variety of genomics and proteomics approaches, we identify zinc finger and BTB domain containing protein 2 (ZBTB2) as a reader of unmethylated DNA in mouse embryonic stem cells. ZBTB2 preferentially binds to CpG island promoters, where it acts as a transcriptional activator. The binding of ZBTB2 to its targets is direct and independent of two other zinc finger proteins, ZBTB25 and ZNF639, which we show to interact with ZBTB2. Our data suggest an anticorrelation between ZBTB2 DNA binding and DNA methylation, indicating that ZBTB2-binding dynamics in vivo are sensitive to differential DNA methylation. ZBTB2 is intricately interwoven with DNA methylation, as we find not only that its binding to DNA is methylation sensitive, but also that ZBTB2 regulates the turnover of methylated DNA In ZBTB2 knockout cells, several pluripotency factors are upregulated, inducing a delay in differentiation. We propose that ZBTB2 is a novel DNA methylation-sensitive transcription factor that regulates cellular differentiation. PMID- 29437776 TI - Rapid whole-genome sequencing identifies a novel AIRE variant associated with autoimmune polyendocrine syndrome type 1. AB - Autoimmune polyendocrine syndrome type 1 (APS-1; OMIM #240300), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. APS-1 is classically characterized by a triad of chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and autoimmune adrenocortical insufficiency. We report a 5-yr-old female who presented with symptoms of tetany due to hypocalcemia and was subsequently found to be secondary to hypoparathyroidism. Rapid trio whole-genome sequencing revealed compound heterozygous variants in AIRE in the proband, with a paternally inherited, pathogenic, frameshift variant (c.1265delC; p.Pro422LeufsTer58) and a novel, likely pathogenic, maternally inherited missense variant (c.268T>C; p.Tyr90His). PMID- 29437777 TI - Trehalose 6-Phosphate Regulates Photosynthesis and Assimilate Partitioning in Reproductive Tissue. AB - Transgenic maize (Zea mays) that expresses rice (Oryza sativa) TREHALOSE PHOSPHATE PHOSPHATASE1 (TPP1) from the rice MADS6 promoter, which is active over the flowering period, produces higher yields than wild type. This yield increase occurs with or without drought conditions during flowering. To understand the mechanistic basis of the increased yield, we characterized gene expression and metabolite profiles in leaves and developing female reproductive tissue, comprising florets, node, pith, and shank, over the flowering period with and without drought. The MADS6 promoter was most active in the vasculature, particularly phloem companion cells in florets and pith, consistent with the largest decreases in trehalose 6-phosphate (T6P) levels (2- to 3-fold) being found in pith and florets. Low T6P led to decreased gene expression for primary metabolism and increased gene expression for secondary metabolism, particularly lipid-related pathways. Despite similar changes in gene expression, the pith and floret displayed opposing assimilate profiles: sugars, sugar phosphates, amino acids, and lipids increased in florets, but decreased in pith. Possibly explaining this assimilate distribution, seven SWEET genes were found to be up regulated in the transgenic plants. SnRK1 activity and the expression of the gene for the SnRK1 beta subunit, expression of SnRK1 marker genes, and endogenous trehalose pathway genes were also altered. Furthermore, leaves of the transgenic maize maintained a higher photosynthetic rate for a longer period compared to wild type. In conclusion, we found that decreasing T6P in reproductive tissues down-regulates primary metabolism and up-regulates secondary metabolism, resulting in different metabolite profiles in component tissues. Our data implicate T6P/ SnRK1 as a major regulator of whole-plant resource allocation for crop yield improvement. PMID- 29437779 TI - The elmo-mbc complex and rhogap19d couple Rho family GTPases during mesenchymal to-epithelial-like transitions. AB - Many metazoan developmental processes require cells to transition between migratory mesenchymal- and adherent epithelial-like states. These transitions require Rho GTPase-mediated actin rearrangements downstream of integrin and cadherin pathways. A regulatory toolbox of GEF and GAP proteins precisely coordinates Rho protein activities, yet defining the involvement of specific regulators within a cellular context remains a challenge due to overlapping and coupled activities. Here we demonstrate that Drosophila dorsal closure is a powerful model for Rho GTPase regulation during transitions from leading edges to cadherin contacts. During these transitions a Rac GEF elmo-mbc complex regulates both lamellipodia and Rho1-dependent, actomyosin-mediated tension at initial cadherin contacts. Moreover, the Rho GAP Rhogap19d controls Rac and Rho GTPases during the same processes and genetically regulates the elmo-mbc complex. This study presents a fresh framework to understand the inter-relationship between GEF and GAP proteins that tether Rac and Rho cycles during developmental processes. PMID- 29437778 TI - Identification of potential therapeutic targets in prostate cancer through a cross-species approach. AB - Genetically engineered mouse models of cancer can be used to filter genome-wide expression datasets generated from human tumours and to identify gene expression alterations that are functionally important to cancer development and progression. In this study, we have generated RNAseq data from tumours arising in two established mouse models of prostate cancer, PB-Cre/PtenloxP/loxP and p53loxP/loxPRbloxP/loxP, and integrated this with published human prostate cancer expression data to pinpoint cancer-associated gene expression changes that are conserved between the two species. To identify potential therapeutic targets, we then filtered this information for genes that are either known or predicted to be druggable. Using this approach, we revealed a functional role for the kinase MELK as a driver and potential therapeutic target in prostate cancer. We found that MELK expression was required for cell survival, affected the expression of genes associated with prostate cancer progression and was associated with biochemical recurrence. PMID- 29437782 TI - Getting to the root of xylem plasticity. PMID- 29437780 TI - Mesenchymal Wnt/beta-catenin signaling limits tooth number. AB - Tooth agenesis is one of the predominant developmental anomalies in humans, usually affecting the permanent dentition generated by sequential tooth formation and, in most cases, caused by mutations perturbing epithelial Wnt/beta-catenin signaling. In addition, loss-of-function mutations in the Wnt feedback inhibitor AXIN2 lead to human tooth agenesis. We have investigated the functions of Wnt/beta-catenin signaling during sequential formation of molar teeth using mouse models. Continuous initiation of new teeth, which is observed after genetic activation of Wnt/beta-catenin signaling in the oral epithelium, was accompanied by enhanced expression of Wnt antagonists and a downregulation of Wnt/beta catenin signaling in the dental mesenchyme. Genetic and pharmacological activation of mesenchymal Wnt/beta-catenin signaling negatively regulated sequential tooth formation, an effect partly mediated by Bmp4. Runx2, a gene whose loss-of-function mutations result in sequential formation of supernumerary teeth in the human cleidocranial dysplasia syndrome, suppressed the expression of Wnt inhibitors Axin2 and Drapc1 in dental mesenchyme. Our data indicate that increased mesenchymal Wnt signaling inhibits the sequential formation of teeth, and suggest that Axin2/Runx2 antagonistic interactions modulate the level of mesenchymal Wnt/beta-catenin signaling, underlying the contrasting dental phenotypes caused by human AXIN2 and RUNX2 mutations. PMID- 29437781 TI - A genetically encoded fluorescent probe for imaging of oxygenation gradients in living Drosophila. AB - Oxygen concentrations vary between tissues of multicellular organisms and change under certain physiological or pathological conditions. Multiple methods have been developed for measuring oxygenation of biological samples in vitro and in vivo However, most require complex equipment, are laborious and have significant limitations. Here we report that oxygen concentration determines the choice between two maturation pathways of DsRed FT (Timer). At high oxygen levels, this DsRed derivate matures predominantly into a red fluorescent isoform. By contrast, a green fluorescent isoform is favored by low oxygen levels. Ratiometric analysis of green and red fluorescence after a pulse of Timer expression in Drosophila larvae provides a record of the history of tissue oxygenation during a subsequent chase period, for the whole animal with single-cell precision. Tissue spreads revealed fine differences in oxygen exposure among different cells of the same organ. We expect that the simplicity and robustness of our approach will greatly impact hypoxia research, especially in small animal models. PMID- 29437783 TI - Estimating the international burden of sport-related death: a review of data sources. AB - INTRODUCTION: Despite detailed recommendations for sports injury data capture provided since the mid-1990s, international data collection efforts for sport related death remains limited in scope. The purpose of this paper was to review the data sources available for studying sport-related death and describe their key features, coverage, accessibility and strengths and limitations. METHODS: The outcomes of interest for this review was death occurring as a result of participation in organised sport-related activity. Data sources used to enumerate death in sport were identified, drawing from the authors' knowledge/experience and review of key references from international organisations. The general purpose, case identification, structure, strengths and limitations of each source in relation to collection of data for sport-related death were summarised, drawing on examples from the international published literature to illustrate this application. RESULTS: Seven types of resources were identified for capturing deaths in sport. Data sources varied considerably in their ability to identify: participant status, sport relatedness of the death, types of sport-related deaths they capture, level of detail provided about the circumstances and medical care received. The most detailed sources were those that were dedicated to sports surveillance. Sport relatedness and type of sport may not be reliably captured by systems not dedicated to sports injury surveillance. Only one source permitted international comparisons and was limited to one sport (soccer). CONCLUSION: Data on sport-related death are currently collected across a wide variety of data sources. This review highlights the need for robust, comprehensive approaches with standardised methodologies enabling linkage between sources and international comparisons. PMID- 29437784 TI - Role of iodide metabolism in physiology and cancer. AB - Iodide (I-) metabolism is crucial for the synthesis of thyroid hormones (THs) in the thyroid and the subsequent action of these hormones in the organism. I- is principally transported by the sodium iodide symporter (NIS) and by the anion exchanger PENDRIN, and recent studies have demonstrated the direct participation of new transporters including anoctamin 1 (ANO1), cystic fibrosis transmembrane conductance regulator (CFTR) and sodium multivitamin transporter (SMVT). Several of these transporters have been found expressed in various tissues, implicating them in I- recycling. New research supports the exciting idea that I- participates as a protective antioxidant and can be oxidized to hypoiodite, a potent oxidant involved in the host defense against microorganisms. This was possibly the original role of I- in biological systems, before the appearance of TH in evolution. I- per se participates in its own regulation, and new evidence indicates that it may be antineoplastic, anti-proliferative and cytotoxic in human cancer. Alterations in the expression of I- transporters are associated with tumor development in a cancer-type-dependent manner and, accordingly, NIS, CFTR and ANO1 have been proposed as tumor markers. Radioactive iodide has been the mainstay adjuvant treatment for thyroid cancer for the last seven decades by virtue of its active transport by NIS. The rapid advancement of techniques that detect radioisotopes, in particular I-, has made NIS a preferred target-specific theranostic agent. PMID- 29437786 TI - Identification of Novel Pathways of Osimertinib Disposition and Potential Implications for the Outcome of Lung Cancer Therapy. AB - Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non-small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy.Experimental Design: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolism in vitro A panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathways in vivoResults: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved. The murine Cyp2d gene cluster played a predominant role in mouse, whereas CYP3A4 was the major human enzyme responsible for osimertinib metabolism. Induction of this enzyme in CYP3A4 humanized mice substantially decreased circulating osimertinib exposure. Importantly, we discovered a further novel pathway of osimertinib disposition involving CPY1A1. Modulation of CYP1A1/CYP1A2 levels markedly reduced parent drug concentrations, significantly altering metabolite pharmacokinetics (PK) in humanized mice in vivoConclusions: We demonstrate that a P450 enzyme expressed in smokers' lungs and lung tumors has the capacity to metabolise osimertinib. This could be a significant factor in defining the outcome of osimertinib treatment. This work also illustrates how P450-humanized mice can be used to identify and mitigate species differences in drug metabolism and thereby model the in vivo effect of critical metabolic pathways on anti-tumor response. Clin Cancer Res; 24(9); 2138-47. (c)2018 AACR. PMID- 29437787 TI - REGgamma Controls Hippo Signaling and Reciprocal NF-kappaB-YAP Regulation to Promote Colon Cancer. AB - Purpose: Colorectal cancer is one of the most commonly diagnosed cancers closely associated with inflammation and hyperactive growth. We previously demonstrated a regulatory circuit between the proteasome activator REGgamma and NF-kappaB (NF kappaB) during colon inflammation, known to be important in the development of colitis-associated cancer as well as sporadic colorectal cancer. How the inflammatory microenvironment affects the Hippo pathway during colorectal cancer development is largely unknown.Experimental Design: Here, we used REGgamma deficient colon cancer cell lines, REGgamma knockout mice, and human colorectal cancer samples to identify the novel molecular mechanism by which REGgamma functions as an oncoprotein in the development of colorectal cancer.Results: REGgamma can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REGgamma deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REGgamma depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of the YAP and NF-kappaB pathways was observed in human colon cancer cells. REGgamma overexpression was found in over 60% of 172 colorectal cancer specimens, highly correlating with the elevation of YAP and p65. Postoperative follow-up revealed a significantly lower survival rate in patients with concomitantly high expression of REGgamma, YAP, and p-p65.Conclusions: REGgamma could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross talks between inflammation and growth pathways, and REGgamma might be a new marker for prognosis of colorectal cancer patients. Clin Cancer Res; 24(8); 2015 25. (c)2018 AACR. PMID- 29437788 TI - Harnessing the Power of Patient-Reported Outcomes in Oncology. AB - Patient-reported outcomes (PRO) represent an increasingly important mechanism for incorporating patients' experiences and perspectives into their care to enhance cancer care delivery and outcomes. In this article, we discuss the importance of integrating PROs into both the clinical and research settings in oncology and highlight potential challenges. Clin Cancer Res; 24(8); 1777-9. (c)2018 AACRSee related article by Kim et al., p. 1780. PMID- 29437785 TI - Dia1-dependent adhesions are required by epithelial tissues to initiate invasion. AB - Developing tissues change shape and tumors initiate spreading through collective cell motility. Conserved mechanisms by which tissues initiate motility into their surroundings are not known. We investigated cytoskeletal regulators during collective invasion by mouse tumor organoids and epithelial Madin-Darby canine kidney (MDCK) acini undergoing branching morphogenesis in collagen. Use of the broad-spectrum formin inhibitor SMIFH2 prevented the formation of migrating cell fronts in both cell types. Focusing on the role of the formin Dia1 in branching morphogenesis, we found that its depletion in MDCK cells does not alter planar cell motility either within the acinus or in two-dimensional scattering assays. However, Dia1 was required to stabilize protrusions extending into the collagen matrix. Live imaging of actin, myosin, and collagen in control acini revealed adhesions that deformed individual collagen fibrils and generated large traction forces, whereas Dia1-depleted acini exhibited unstable adhesions with minimal collagen deformation and lower force generation. This work identifies Dia1 as an essential regulator of tissue shape changes through its role in stabilizing focal adhesions. PMID- 29437789 TI - Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors. AB - Purpose: Immunotherapy with bispecific T-cell engagers has achieved striking success against hematologic malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T-cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination.Experimental Design: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens. Replicative and oncolytic potential were assessed by infection and cell viability assays, respectively. Functionality of virus-derived BiTEs was tested in vitro by complementary binding and cytotoxicity assays. In vivo efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers.Results: We verified secretion of functional BiTE antibodies by MV-BiTE infected cells. Further, we demonstrated therapeutic efficacy of MV-BiTE against established tumors in fully immunocompetent mice. MV-BiTE efficacy was associated with increased intratumoral T-cell infiltration and induction of protective antitumor immunity. In addition, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of peripheral blood mononuclear cells.Conclusions: MV-BiTE treatment was effective in two distinct models of solid tumors without signs of toxicity. This provides strong evidence for therapeutic benefits of tumor-targeted BiTE expression by oncolytic MV. Thus, this study represents proof of concept for an effective strategy to treat solid tumors with BiTEs. Clin Cancer Res; 24(9); 2128 37. (c)2018 AACR. PMID- 29437790 TI - HER3-Mediated Resistance to Hsp90 Inhibition Detected in Breast Cancer Xenografts by Affibody-Based PET Imaging. AB - Purpose: Recent studies have highlighted a role of HER3 in HER2-driven cancers (e.g., breast cancer), implicating the upregulation of the receptor in resistance to HER-targeted therapies and Hsp90 inhibitors (e.g., AUY922). Therefore, we have developed an affibody-based PET radioconjugate that quantitatively assesses HER3 changes induced by Hsp90 inhibition in vivoExperimental Design: ZHER3:8698 affibody molecules were conjugated via the C-terminus cysteine to DFO-maleimide for 89Zr radiolabeling. The probe was characterized in vitro and in vivo in a panel of human breast cell lines and xenograft models with varying HER3 receptor levels. In addition, the radioconjugate was investigated as a tool to monitor the outcome of AUY922, an Hsp90 inhibitor, in an MCF-7 xenograft model.Results: We demonstrated that 89Zr-DFO-ZHER3:8698 can track changes in receptor expression in HER3-positive xenograft models and monitor the outcome of AUY922 treatment. Our in vitro findings showed that MCF-7 cells, which are phenotypically different from BT474, develop resistance to treatment with AUY922 through HER3/IGF-1Rbeta mediated signaling. Of note, the lack of response in vitro due to HER3 recovery was confirmed in vivo using 89Zr-DFO-ZHER3:8698-based imaging. Upon AUY922 treatment, higher radioconjugate uptake was detected in treated MCF-7 xenografts, correlating with an AUY922-induced HER3 upregulation concomitant with an increase in IGF-1Rbeta expression.Conclusions: These data underline the potential of HER3 based PET imaging to noninvasively provide information about HER3 expression and to identify patients not responding to targeted therapies due to HER3 recovery. Clin Cancer Res; 24(8); 1853-65. (c)2018 AACR. PMID- 29437792 TI - Mechanistic Exploration of Cancer Stem Cell Marker Voltage-Dependent Calcium Channel alpha2delta1 Subunit-mediated Chemotherapy Resistance in Small-Cell Lung Cancer. AB - Purpose: Chemoresistance in small-cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSC). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. This study explored the role of the voltage-dependent calcium channel alpha2delta1 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of alpha2delta1-mediated chemoresistance and strategies of overcoming the resistance.Experimental Design: alpha2delta1-positive cells were identified and isolated from SCLC cell lines and patient-derived xenograft (PDX) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western blotting were carried out to identify pathways involved in alpha2delta1-mediated chemoresistance in SCLC. In addition, possible interventions to overcome alpha2delta1-mediated chemoresistance were examined.Results: Different proportions of alpha2delta1+ cells were identified in SCLC cell lines and PDX models. alpha2delta1+ cells exhibited CSC-like properties (self-renewal, tumorigenic, differentiation potential, and high expression of genes related to CSCs and drug resistance). Chemotherapy induced the enrichment of alpha2delta1+ cells instead of CD133+ cells in PDXs, and an increased proportion of alpha2delta1+ cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the alpha2delta1-positive H1048 cell line was identified at the protein level. mAb 1B50-1 was observed to improve the efficacy of chemotherapy and delay relapse as maintenance therapy in PDX models.Conclusions: SCLC cells expressing alpha2delta1 demonstrated CSC-like properties, and may contribute to chemoresistance. ERK may play a key role in alpha2delta1-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti SCLC drug. Clin Cancer Res; 24(9); 2148-58. (c)2018 AACR. PMID- 29437791 TI - A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia. AB - Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and alpha-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060-73. (c)2018 AACR. PMID- 29437793 TI - Prediction of Chemotherapeutic Efficacy in Non-Small Cell Lung Cancer by Serum Metabolomic Profiling. AB - Purpose: No validated biomarkers that could identify the subset of patients with lung adenocarcinoma who might benefit from chemotherapy have yet been well established. This study aimed to explore potential biomarker model predictive of efficacy and survival outcomes after first-line pemetrexed plus platinum doublet based on metabolomics profiling.Experimental Design: In total, 354 consecutive eligible patients were assigned to receive first-line chemotherapy of pemetrexed in combination with either cisplatin or carboplatin. Prospectively collected serum samples before initial treatment were utilized to perform metabolomics profiling analyses under the application of LC/MS-MS. Binary logistic regression analysis was carried out to establish discrimination models.Results: There were 251 cases randomly sorted into discovery set, the rest of 103 cases into validation set. Seven metabolites including hypotaurine, uridine, dodecanoylcarnitine, choline, dimethylglycine, niacinamide, and l palmitoylcarnitine were identified associated with chemo response. On the basis of the seven-metabolite panel, a discriminant model according to logistic regression values g(z) was established with the receiver operating characteristic curve (AUC) of 0.912 (Discovery set) and 0.909 (Validation set) in differentiating progressive disease (PD) groups from disease control (DC) groups. The median progression-free survival (PFS) after chemotherapy in patients with g(z) <=0.155 was significantly longer than that in those with g(z) > 0.155 (10.3 vs.4.5 months, P < 0.001).Conclusions: This study developed an effective and convenient discriminant model that can accurately predict the efficacy and survival outcomes of pemetrexed plus platinum doublet chemotherapy prior to treatment delivery. Clin Cancer Res; 24(9); 2100-9. (c)2018 AACR. PMID- 29437794 TI - Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain? AB - The brain is the most common site of first metastasis for patients with HER2 positive breast cancer treated with HER2-targeting drugs. However, the development of effective therapies for breast cancer brain metastases (BCBM) is limited by an incomplete understanding of the mechanisms governing drug sensitivity in the central nervous system. Pharmacodynamic data from patients and in vivo models suggest that inadequate drug penetration across the "blood-tumor" barrier is not the whole story. Using HER2-positive BCBMs as a case study, we highlight recent data from orthotopic brain metastasis models that implicate brain-specific drug resistance mechanisms in BCBMs and suggest a translational research paradigm to guide drug development for treatment of BCBMs. Clin Cancer Res; 24(8); 1795-804. (c)2018 AACR. PMID- 29437796 TI - Erratum for Hou et al., "The Novel Transcriptional Regulator LmbU Promotes Lincomycin Biosynthesis through Regulating Expression of Its Target Genes in Streptomyces lincolnensis". PMID- 29437795 TI - Statins Synergize with Hedgehog Pathway Inhibitors for Treatment of Medulloblastoma. AB - Purpose: The role of cholesterol biosynthesis in hedgehog pathway activity and progression of hedgehog pathway medulloblastoma (Hh-MB) were examined in vivo Statins, commonly used cholesterol-lowering agents, were utilized to validate cholesterol biosynthesis as a therapeutic target for Hh-MB.Experimental Design: Bioinformatic analysis was performed to evaluate the association between cholesterol biosynthesis with hedgehog group medulloblastoma in human biospecimens. Alterations in hedgehog signaling were evaluated in medulloblastoma cells after inhibition of cholesterol biosynthesis. The progression of endogenous medulloblastoma in mice was examined after genetic blockage of cholesterol biosynthesis in tumor cells. Statins alone, or in combination with vismodegib (an FDA-approved Smoothened antagonist), were utilized to inhibit medulloblastoma growth in vivoResults: Cholesterol biosynthesis was markedly enhanced in Hh-MB from both humans and mice. Inhibition of cholesterol biosynthesis dramatically decreased Hh pathway activity and reduced proliferation of medulloblastoma cells. Statins effectively inhibited medulloblastoma growth in vivo and functioned synergistically in combination with vismodegib.Conclusions: Cholesterol biosynthesis is required for Smoothened activity in the hedgehog pathway, and it is indispensable for the growth of Hh-MB. Targeting cholesterol biosynthesis represents a promising strategy for treatment of Hh-MB. Clin Cancer Res; 24(6); 1375-88. (c)2018 AACR. PMID- 29437797 TI - A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance. AB - Aquaporin-4, encoded by AQP4, is the major water channel in the central nervous system and plays an important role in the brain's water balance, including edema formation and clearance. Using genomic copy-number analysis and trio-exome sequencing, we investigated a male patient with intellectual disability, hearing loss, and progressive gait dysfunction and found a de novo missense change Ser111Thr in AQP4 as the only suspicious finding. Perinatally, signs of brain ischemia were detected in relation to acute collapse 2 h after birth that resolved a few days later. At the age of 3 mo, cardiac hypertrophy was detected that persisted through childhood but was completely resolved by age 16. In theory, this neurodevelopmental disorder with transient cardiomyopathy could be caused by a disturbance of cellular water balance. Ser111 is an extremely conserved residue in the short cytoplasmic loop between AQP4 transmembrane helix 2 and 3, present across all AQP isoforms from plants to mammals, and it does not appear to be a phosphorylation site. We found that the Ser111Thr change does not affect water permeability or protein stability, suggesting another and possibly regulatory role. Although causality remains unproven, this case study draws attention to AQP4 as a candidate gene for a unique developmental disorder and to a specific serine as a residue of possibly great functional importance in many AQPs. PMID- 29437798 TI - Points to consider for sharing variant-level information from clinical genetic testing with ClinVar. AB - Data sharing between laboratories, clinicians, researchers, and patients is essential for improvements and standardization in genomic medicine; encouraging genomic data sharing (GDS) is a key activity of the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen). The ClinGen initiative is dedicated to evaluating the clinical relevance of genes and variants for use in precision medicine and research. Currently, data originating from each of the aforementioned stakeholder groups is represented in ClinVar, a publicly available repository of genomic variation, and its relationship to human health hosted by the National Center for Biotechnology Information at the NIH. Although policies such as the 2014 NIH GDS policy are clear regarding the mandate for informed consent for broad data sharing from research participants, no clear guidance exists on the level of consent appropriate for the sharing of information obtained through clinical testing to advance knowledge. ClinGen has collaborated with ClinVar and the National Human Genome Research Institute to develop points to consider for clinical laboratories on sharing de-identified variant-level data in light of both the NIH GDS policy and the recent updates to the Common Rule. We propose specific data elements from interpreted genomic variants that are appropriate for submission to ClinVar when direct patient consent was not sought and describe situations in which obtaining informed consent is recommended. PMID- 29437799 TI - High versus standard dose caffeine for apnoea: a systematic review. AB - BACKGROUND: Placebo-controlled trials have shown that caffeine is highly effective in treating apnoea of prematurity and reduces the risk of bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI). OBJECTIVE: To identify, appraise and summarise studies investigating the modulating effect of different caffeine dosages. METHODS: A systematic review identified all randomised controlled trials (RCTs) comparing a high versus a standard caffeine treatment regimen in infants with a gestational age <32 weeks, by searching the main electronic databases and abstracts of the Pediatric Academic Societies. Studies comparing caffeine to placebo or theophylline only were excluded. Primary outcomes were BPD and mortality at 36 weeks postmenstrual age. Secondary key-outcome was neurodevelopmental outcome at 12 and 24 months corrected age. Meta-analysis was performed using RevMan 5.3. RESULTS: Six RCTs including 620 infants were identified. Meta-analysis showed a significant decrease in BPD, the combined outcome BPD or mortality, and failure to extubate in infants allocated to a higher caffeine dose. No differences were found in mortality alone and NDI. The quality of the outcome measures were deemed low to very low according to the Grading of Recommendations Assessment, Development and Evaluation guidelines. CONCLUSIONS: Although this review suggests that administering a higher dose of caffeine might enhance its beneficial effect on death or BPD, firm recommendations on the optimal caffeine dose cannot be given due to the low level of evidence. A large RCT is urgently needed to confirm or refute these findings and determine the optimal dose of caffeine. PMID- 29437800 TI - Ventricular tachyarrhythmia in a 78-year-old woman with essential thrombocythaemia. AB - Anagrelide is a phosphodiesterase-3 inhibitor used in the treatment of essential thrombocythaemia. Cardiovascular side effects such as ventricular tachycardia and cardiomyopathy are rare but potentially fatal and should be made known to patients before starting the medication. It usually arises within the first 6 months after initiation of therapy and may be dose related. The elderly population are particularly susceptible. These cardiotoxicities result from an increase in cyclic AMP that induces positive inotropic and chronotropic effects and are often reversible with cessation of use. We report a case of a 78-year-old woman with essential thrombocythaemia and recently started on anagrelide who presented with syncope and multiple bruises and facial trauma and found to have developed ventricular tachyarrhythmia. PMID- 29437801 TI - Successful treatment of non-tuberculous mycobacterial pleurisy with acute fever by antimycobacterial therapy. AB - We report two cases of pleurisy caused by non-tuberculous mycobacteria followed by pneumothorax. The onset of pleurisy was accompanied by acute fever. Cultured samples of the pleural effusions from the two patients, an 80-year-old man and an 87-year-old woman, were ultimately found to contain Mycobacterium intracellulare and Mycobacterium kansasii, respectively. Both patients were initially administered antibiotics, but their fevers persisted. Therefore, different combinations of antimycobacterial drugs were used, which reduced the fever in a few days. In these patients, pleurisy caused by non-tuberculous mycobacteria followed by pneumothorax was characterised by acute fever and improvement in the fever after administration of antimycobacterial drugs; however, the aetiology remains to be clarified. PMID- 29437802 TI - Acute haemorrhage from a retroperitoneal liposarcoma: a rare presentation. AB - A previously healthy 61-year-old Caucasian woman presented to the emergency department after collapsing at home with associated abdominal pain radiating to her back. An urgent CT angiogram was requested to rule out a ruptured aortic aneurysm. This showed a large 21 cm fat-containing lesion arising from the mid pole of the left kidney, with an adjacent 4 cm perirenal haematoma. An initial diagnosis of a ruptured angiomyolipoma was made. Her haemoglobin was 105 g/L, with a creatinine of 104 mmol/L and an eGFR of 47 mL/min. Her clotting profile was normal. Following resuscitation, she was taken to the operating room and underwent an emergency open left radical nephrectomy via a left flank incision. Her recovery was uneventful and she was discharged home after 6 days. The histopathology confirmed a well-differentiated liposarcoma. PMID- 29437803 TI - Nasopharyngeal angiofibroma in a 32-year-old man. AB - Nasopharyngeal angiofibroma (NA) is a benign, highly vascularised tumour of the nasopharynx, which typically occurs in young males aged 14-25 years. We report an interesting case of an NA arising de novo in a 32-year-old male. He was referred to our facility for severe nasal haemorrhage after biopsy of a left nasopharyngeal mass. In the operating room, extensive bleeding was noted, and an endoscopic medial maxillectomy was performed, and the left internal maxillary artery was ligated allowing for near total resection of the lesion. The pathological specimen confirmed the diagnosis of NA. To our knowledge, this is one of the oldest patients presenting with a de novo NA, in his fourth decade of life, confirming that this diagnosis must be considered in all those with large nasopharyngeal masses. PMID- 29437804 TI - Bleeding or clotting: an intracranial dilemma. PMID- 29437805 TI - Food protein-induced enterocolitis syndrome: a challenging diagnosis. AB - Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity triggered by food proteins. It may present acutely, with repetitive vomiting, diarrhoea and lethargy leading to dehydration and eventually shock or insidiously with intermittent emesis, chronic diarrhoea or failure to thrive. We describe a paediatric male patient with recurrent sepsis like episodes of fever, lethargy, ashen-grey skin colouration and vomiting followed by diarrhoea. These episodes were triggered by cow's milk formula and grains. Laboratory tests revealed leucocytosis, thrombocytosis, metabolic acidosis and elevated C reactive protein. After exclusion of other differential diagnoses, the diagnosis of FPIES was established on clinical improvement with withdrawal of the offending food and positive oral food challenge. FPIES diagnosis requires a high index of suspicion and is frequently delayed, which contributes to an increased morbidity. This is due to the wide spectrum of clinical presentations and due to the absence of specific diagnostic tests. PMID- 29437806 TI - Rhabdomyolysis in Stuve-Wiedemann syndrome. AB - A 6-month-old male infant with Stuve-Wiedemann syndrome (SWS) presented with an acute respiratory arrest secondary to a rhinovirus respiratory infection from which he was rapidly resuscitated. He developed an acute kidney injury requiring supportive treatment and on day 3 of his illness was noted to have developed severe rhabdomyolysis (creatine kinase level 132 040 U/L (normal <320 U/L)). He was born from consanguineous parents with homozygous mutations in the leukaemia inhibitory factor receptor. He had skeletal dysplasia with metabolic bone disease and episodes of hyperthermia with lactic acidosis. He also had paroxysmal ventricular tachycardia treated with prophylactic propranolol. This is a case report of a child with SWS who had a febrile illness and epileptic seizures which led to severe rhabdomyolysis outside the context of anaesthesia, and we would like to draw the attention of clinicians to this potential complication. PMID- 29437807 TI - Lymphangitis carcinomatosa of a cutaneous squamous cell carcinoma. PMID- 29437808 TI - Reversible bioprosthetic valve thrombosis from eosinophilia. AB - A 31-year-old man with a mitral bioprosthetic valve presented with recent worsening of exertional dyspnoea 7 years after the mitral valve replacement. Evaluation revealed an increased gradient across the thickened mitral bioprosthetic valve leaflets. Marked eosinophilia was present and was considered as a putative cause for bioprosthetic valve thrombosis. The treatment with systemic corticosteroids and oral anticoagulation led to complete resolution of symptoms with significant decrease in mitral bioprosthetic valve gradient and leaflet thinning. The case is reported to highlight the fact that eosinophilia may cause reversible bioprosthetic valve thrombosis. PMID- 29437809 TI - 21st century obstetrics: a 50-year-old nullip-walk in the park? AB - We discuss the case of a 50-year-old nulliparous woman who conceived after in vitro fertilisation. She had multiple medical comorbidities and presented an obstetric and medical challenge. She was carefully managed through pregnancy and had a successful outcome. In this report, we explore the medical complexity, as well as ethical and logistic issues involved. PMID- 29437810 TI - Down syndrome with posterior cortical atrophy. AB - Down syndrome (DS) is caused by trisomy of chromosome 21. The average age of onset of Alzheimer's disease (AD) ranged from 50 to 55 years in DS, with early symptoms usually characterised by changes in behaviour and executive dysfunction. On the other hand, posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterised by progressive impairment of visual functions in the absence of visual deficits and a pattern of atrophy involving posterior cortex. This syndrome is mostly caused by AD pathology. We report the case of patient with DS who developed PCA. While atypical variants of AD are commonly associated with an early age at onset, all focal forms of AD may potentially appear in DS. Specifying the phenotype has an impact on the care of DS patients and could help us to know the evolution. It could also provide a better understanding of the underlying mechanisms of focal forms. PMID- 29437811 TI - Giant granadilla's seeds phytobezoar rectal impactation: a very unusual case of intestinal obstruction. AB - A 78-year-old Caucasian man presented to the emergency department with bloody diarrhoea, diffuse abdominal pain and fever with 1-week duration. He had just returned from Angola where he had been treated for a presumed Clostridium difficile infection without improvement. He had no relevant medical or familiar history except for hypertension and prostate benign hyperplasia. He was drowsy, feverish and eupnoeic. His oxygen saturation on pulse oximetry was 92%, blood pressure was 173/99 mm Hg and pulse rate 100 beats per minute. Except for a distended, silent and painful abdomen, particularly on lower quadrants, the rest of the examination was unremarkable. A CT showed a mesh-like mass inside the rectum conditioning colonic obstruction and distention. This turned to be a giant granadilla's seeds phytobezoar and was removed endoscopically. Five days later, the patient had a colonic perforation requiring total colectomy. He made a full recovery after rehabilitation for 3 months. PMID- 29437812 TI - Melioidosis: the great mimicker presenting as spondylodiscitis. AB - Melioidosis, a syndrome with protean clinical manifestations, is caused by Gram negative soil saprophyte Burkholderiapseudomallei Among its diverse clinical presentations, the involvement of spine is a rare phenomenon and can mimic tuberculosis on presentation. A 65-year-old female with a known case of diabetes presented with fever with lower back pain. Blood culture grew Staphylococcus aureus, and as per sensitivity report, clindamycin and cefazolin were started. X ray and MRI lumbosacral spine showed spondylodiscitis (likely Koch's). Decompression and biopsy were done, and a sample was sent for microbiological investigations that showed no growth of any significant pathogen; furthermore, all tests for tuberculosis diagnosis also remained negative. Active Melioidosis Detect Lateral Flow Assay was used on the tissue sample, which was positive for B. pseudomallei Capsular Polysaccharide (CPS) antigen; the case was confirmed by typethree secretion system 1 PCR for melioidosis. Antibiotics were changed to parenteral ceftazidime for 2 weeks followed by oral cotrimoxazole. A dedicated team of microbiologists and physicians is required to identify and treat the disease. PMID- 29437813 TI - Follicular dendritic cell sarcoma of the porta hepatis. AB - Follicular dendritic cell (FDC) sarcoma is a very rare neoplasm which commonly involves the lymph nodes and less commonly involves extranodal organs such as the liver. Most cases of FDC sarcoma are idiopathic, however some cases are associated with other disease states. Management of FDC sarcoma is primarily focused on surgical resection of the mass, and secondarily focused on radiotherapy, chemotherapy and/or biologic pharmacotherapy. We report the case of a patient who was found to have FDC sarcoma presenting as an obstructing mass of the porta hepatis, a manifestation which does not appear to be reported in the literature. PMID- 29437814 TI - Isolated splenic mucormycosis in a case of aplastic anaemia. AB - Mucormycosis, a rare opportunistic infection seen in immunocompromised hosts, is caused by fungi of Mucorales family. It may be confined to the organs, such as rhinocerebral and pulmonary mucormycosis, or may cause disseminated infection. A 14-year-old boy presented to our clinic with fever and left upper quadrant abdominal pain, and on evaluation was found to have pancytopaenia, and imaging revealed ill-defined splenic collection with thrombus in the splenic vein. He was started on empirical intravenous antibiotics, followed by antifungals empirically as he did not show any improvement clinically. Eventually, splenectomy was done, which on histopathological examination revealed mucormycosis. The patient finally succumbed to his illness as he developed peritonitis and refractory shock. To date, only two cases of isolated splenic mucormycosis have been reported. Aggressive treatment is needed, which includes the use of antifungals (amphotericin B) and surgical debridement or resection of the involved tissues or organs. PMID- 29437815 TI - Successful management of benign paroxysmal positional vertigo (BPPV) in a patient who was ventilated with a C3 complete spinal injury on a regional spinal unit intensive care. AB - Benign paroxysmal positional vertigo (BPPV) occurs in 14.5% of patients with spinal cord injury (SCI) and may require intervention on intensive care unit (ICU). A 61-year-old man was admitted to a spinal injury ICU with a traumatic C3 complete SCI following a mountain bike accident. Ventilated but stable he complained of severe dizziness on rolling, during personal cares, which lasted for 40 s. Clinical examination was limited due to the injury and ventilation. Subjective questioning, visio-ocular control and a modified Dix-Hallpike and roll tests confirmed a right posterior canalithiasis BPPV. A modified right Epley was performed with assistance of four people, medical supervision, monitoring of tracheal ventilation and vital signs. No adverse reaction was observed. Resolution of dizziness on rolling was achieved with no recurrence at 1 year. BPPV can be successfully and safely managed on ICU. PMID- 29437816 TI - Teenage boy with high fever and rash: what could we be missing? AB - A 15-year-old boy was admitted to a local hospital with high fever, generalised rash and a mild sore throat. He was started on intravenous flucloxacillin and 12 hours later develops a sustained low diastolic blood pressure (DBP), unresponsive to fluid volume expansion and cardiovascular support with dopamine. Intravenous clindamycin was added and transportation to paediatric intensive care unit arranged. Dopamine dosing was increased and norepinephrine infusion was added subsequently with immediate stabilisation of DBP. A sacrococcygeal pilonidal abscess was identified, requiring prompt surgical drainage. The microbiological culture of abscess material was positive for an enterotoxin-producing Staphylococcus aureus and Peptostreptococcus magnus He was free of symptoms after 4 days. This case report summarises a potential severe complication of the pilonidal disease. PMID- 29437817 TI - Atherothrombotic out-of hospital cardiac arrest: watch out for a second train. AB - A 63-year-old man presented with an out-of-hospital cardiac arrest. The coronary angiogram with intravascular imaging was performed and showed a mid-left anterior descending artery atherosclerotic cap rupture with thrombus burden treated with drug-eluting stent (DES) implantation. During the hospitalisation in the intensive care unit, the patient experienced recurrent ventricular fibrillations and asystole with transient ST-segment elevation in the inferior leads with normal coronary angiography. A methylergonovine provocative test was therefore performed and showed an occlusive right coronary artery (RCA) spasm. Due to recurrent RCA spasm, the patient was treated with DES implantation with favourable results at 3-month follow-up. PMID- 29437818 TI - Tinea of vellus hair: a diagnostic and therapeutic challenge. AB - Tinea infection is a common superficial fungal infection of the skin, hair and nails. Tinea of vellus hair is a rare form of dermatophytosis that is difficult to diagnose and treat. Herein, the authors report the case of a patient who had an itchy rash on the cheek. Microscopic and mycological studies confirmed the diagnosis of tinea of vellus hair. The patient was treated with systemic antifungal therapy with clinical improvement. This report aims to describe an infrequent subtype of common disease and review clinical clues, tools for diagnosis as well as treatment plans. PMID- 29437819 TI - Echocardiographic evaluation of 'sandwich plug' closure of mechanical aortic valve at left ventricular assist device implantation. PMID- 29437820 TI - Emphysematous gastritis secondary to Sarcina ventriculi. PMID- 29437821 TI - Adiposity Impacts Intrarenal Hemodynamic Function in Adults With Long-standing Type 1 Diabetes With and Without Diabetic Nephropathy: Results From the Canadian Study of Longevity in Type 1 Diabetes. AB - OBJECTIVE: Central adiposity is considered to be an important cardiorenal risk factor in the general population and in type 1 diabetes. We sought to determine the relationship between central adiposity and intrarenal hemodynamic function in adults with long-standing type 1 diabetes with and without diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes (n = 66, duration >=50 years) and age-/sex-matched control subjects (n = 73) were studied. The cohort was stratified into 44 DN Resistors (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2 and <30 mg/day urine albumin) and 22 patients with DN (eGFR <=60 mL/min/1.73 m2 or >=30 mg/day urine albumin). Intrarenal hemodynamic function (glomerular filtration rate for inulin [GFRINULIN], effective renal plasma flow for p-aminohippuric acid [ERPFPAH]) was measured. Afferent arteriolar resistance, efferent arteriolar resistance, renal blood flow, renal vascular resistance [RVR], filtration fraction, and glomerular pressure were derived from the Gomez equations. Fat and lean mass were quantified by DXA. RESULTS: Whereas measures of adiposity did not associate with GFRINULIN or ERPFPAH in healthy control subjects, trunk fat mass inversely correlated with GFRINULIN (r = -0.46, P < 0.0001) and ERPFPAH (r = -0.31, P = 0.01) and positively correlated with RVR (r = 0.53, P = 0.0003) in type 1 diabetes. In analyses stratified by DN status, greater central adiposity related to lower GFRINULIN values in DN and DN Resistors, but the relationships between central adiposity and ERPFPAH and RVR were attenuated and/or reversed in patients with DN compared with DN Resistors. CONCLUSIONS: The adiposity-intrarenal hemodynamic function relationship may be modified by the presence of type 1 diabetes and DN, requiring further study of the mechanisms by which adiposity influences renal hemodynamic function. PMID- 29437822 TI - Elevated Serum Xanthine Oxidase Activity Is Associated With the Development of Type 2 Diabetes: A Prospective Cohort Study. AB - OBJECTIVE: We aimed to evaluate whether xanthine oxidase (XO), a key enzyme in uric acid (UA) metabolism and a major source of reactive oxygen species, plays a causal and important role in the development of type 2 diabetes mellitus (T2DM) in a large prospective cohort study. RESEARCH DESIGN AND METHODS: A total of 4,412 diabetes-free adults (2,071 women and 2,341 men) aged 30-65 years at baseline in 2008 were involved. Participants were followed for incident change of glucose metabolism during an average of 4.7 years. At baseline, serum XO and UA, serum lipids, and glucose homeostasis indexes including fasting blood glucose (FBG), 2-h blood glucose (PBG), glycosylated hemoglobin A1c (HbA1c), and fasting insulin were tested for analysis. RESULTS: During an average follow-up period of 4.7 years, 249 women and 360 men developed new-onset T2DM. Serum XO activity was positively associated with UA concentration (all P values <0.001). When XO activity and UA concentration were considered in the same model of the sex specific analysis, only XO activity was significantly associated with the incidence of T2DM, with the hazard ratios from the bottom to the top quartile of XO activity being 1.00, 1.67 (95% CI 1.00-2.79), 1.86 (1.11-3.13), and 2.36 (1.43 3.90) in women and 1.00, 1.01 (0.68-1.52), 1.41 (0.98-2.03), and 1.90 (1.30-2.78) in men. CONCLUSIONS: Elevated serum XO activity, but not UA concentration, was associated with an increased risk of developing T2DM in women and men with mutual adjustment for XO and UA. Further studies are needed to examine the underlying mechanisms. PMID- 29437823 TI - Comparative Safety of Sulfonylureas and the Risk of Sudden Cardiac Arrest and Ventricular Arrhythmia. AB - OBJECTIVE: To examine the association between individual antidiabetic sulfonylureas and outpatient-originating sudden cardiac arrest and ventricular arrhythmia (SCA/VA). RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using 1999-2010 U.S. Medicaid claims from five large states. Exposures were determined by incident use of glyburide, glimepiride, or glipizide. Glipizide served as the reference exposure, as its effects are believed to be highly pancreas specific. Outcomes were ascertained by a validated ICD-9-based algorithm indicative of SCA/VA (positive predictive value ~85%). Potential confounding was addressed by adjustment for multinomial high dimensional propensity scores included as continuous variables in a Cox proportional hazards model. RESULTS: Of sulfonylurea users under study (N = 519,272), 60.3% were female and 34.9% non-Hispanic Caucasian, and the median age was 58.0 years. In 176,889 person-years of sulfonylurea exposure, we identified 632 SCA/VA events (50.5% were immediately fatal) for a crude incidence rate of 3.6 per 1,000 person-years. Compared with glipizide, propensity score-adjusted hazard ratios for SCA/VA were 0.82 (95% CI 0.69-0.98) for glyburide and 1.10 (0.89-1.36) for glimepiride. Numerous secondary analyses showed a very similar effect estimate for glyburide; yet, not all CIs excluded the null. CONCLUSIONS: Glyburide may be associated with a lower risk of SCA/VA than glipizide, consistent with a very small clinical trial suggesting that glyburide may reduce ventricular tachycardia and isolated ventricular premature complexes. This potential benefit must be contextualized by considering putative effects of different sulfonylureas on other cardiovascular end points, cerebrovascular end points, all-cause death, and hypoglycemia. PMID- 29437824 TI - Neurogenic differentiation by hippocampal neural stem and progenitor cells is biased by NFIX expression. AB - Our understanding of the transcriptional programme underpinning adult hippocampal neurogenesis is incomplete. In mice, under basal conditions, adult hippocampal neural stem cells (AH-NSCs) generate neurons and astrocytes, but not oligodendrocytes. The factors limiting oligodendrocyte production, however, remain unclear. Here, we reveal that the transcription factor NFIX plays a key role in this process. NFIX is expressed by AH-NSCs, and its expression is sharply upregulated in adult hippocampal neuroblasts. Conditional ablation of Nfix from AH-NSCs, coupled with lineage tracing, transcriptomic sequencing and behavioural studies collectively reveal that NFIX is cell-autonomously required for neuroblast maturation and survival. Moreover, a small number of AH-NSCs also develop into oligodendrocytes following Nfix deletion. Remarkably, when Nfix is deleted specifically from intermediate progenitor cells and neuroblasts using a Dcx-creERT2 driver, these cells also display elevated signatures of oligodendrocyte gene expression. Together, these results demonstrate the central role played by NFIX in neuroblasts within the adult hippocampal stem cell neurogenic niche in promoting the maturation and survival of these cells, while concomitantly repressing oligodendrocyte gene expression signatures. PMID- 29437825 TI - Mutational Pleiotropy and the Strength of Stabilizing Selection Within and Between Functional Modules of Gene Expression. AB - Variational modules, sets of pleiotropically covarying traits, affect phenotypic evolution, and therefore are predicted to reflect functional modules, such that traits within a variational module also share a common function. Such an alignment of function and pleiotropy is expected to facilitate adaptation by reducing the deleterious effects of mutations, and by allowing coordinated evolution of functionally related sets of traits. Here, we adopt a high dimensional quantitative genetic approach using a large number of gene expression traits in Drosophila serrata to test whether functional grouping, defined by gene ontology (GO terms), predicts variational modules. Mutational or standing genetic covariance was significantly greater than among randomly grouped sets of genes for 38% of our functional groups, indicating that GO terms can predict variational modularity to some extent. We estimated stabilizing selection acting on mutational covariance to test the prediction that functional pleiotropy would result in reduced deleterious effects of mutations within functional modules. Stabilizing selection within functional modules was weaker than that acting on randomly grouped sets of genes in only 23% of functional groups, indicating that functional alignment can reduce deleterious effects of pleiotropic mutation but typically does not. Our analyses also revealed the presence of variational modules that spanned multiple functions. PMID- 29437827 TI - Normocalcaemic primary hyperparathyroidism: a pragmatic approach. AB - It is well recognised that over the past three to four decades the incidence of asymptomatic primary hyperparathyroidism has increased significantly. However, more recently this pattern has further evolved into a presentation with normocalcaemia and raised parathyroid hormone (PTH) level without the presence of a recognised stimulus for its rise, in the form of vitamin D deficiency or renal impairment. A diagnostic label of normocalcaemic hyperparathyroidism (NPHPT) has been given to this phenotype and in most such individuals, the initial PTH measurement is driven by the presence of metabolic bone disease. The reported prevalence, degree of end-organ involvement and the rate of progression vary considerably and are related to patients studied and the biochemical cut-offs used in its definition. A majority of patients are diagnosed during assessment of metabolic bone disease of varying degrees. Once the diagnosis is confirmed by excluding confounding factors, the patient should undergo full assessment of end organ involvement, which is the main determinant of further therapeutic decisions. Surgery, with prior localisation, is considered in patients with significant end-organ involvement in keeping with the guidance for hypercalcaemic patients. If a patient does not meet these criteria, annual clinical and biochemical surveillance is recommended to identify progression to hypercalcaemia or worsening end-organ involvement. It is less clear if patients identified during 'routine' requests for evaluation of unrelated symptoms require similar close monitoring. In conclusion, in this review on NPHPT we focus on its definition, planning of further investigations, selection of patients for intervention and devising an appropriate follow-up strategy. PMID- 29437828 TI - Population exposure to smoking and tobacco branding in the UK reality show 'Love Island'. AB - BACKGROUND: Reality television shows are popular with children and young adults; inclusion of tobacco imagery in these programmes is likely to cause smoking in these groups. Series 3 of the UK reality show Love Island, broadcast in 2017, attracted widespread media criticism for high levels of smoking depicted. We have quantified this tobacco content and estimated the UK population exposure to generic and branded tobacco imagery generated by the show. METHODS: We used 1-min interval coding to quantify actual or implied tobacco use, tobacco paraphernalia or branding, in alternate episodes of series 3 of Love Island, and Census data and viewing figures from Kantar Media to estimate gross and per capita tobacco impressions. RESULTS: We coded 21 episodes comprising 1001 min of content. Tobacco imagery occurred in 204 (20%) intervals; the frequency of appearances fell significantly after media criticism. An identifiable cigarette brand, Lucky Strike Double Click, appeared in 16 intervals. The 21 episodes delivered an estimated 559 million gross tobacco impressions to the UK population, predominantly to women, including 47 million to children aged <16 and 44 million gross impressions of Lucky Strike branding, including 4 million to children <16. CONCLUSION: Despite advertising legislation and broadcasting regulations intended to protect children from smoking imagery in UK television, series 3 of Love Island delivered millions of general and branded tobacco impressions both to children and adults in the UK. More stringent controls on tobacco content in television programmes are urgently needed. PMID- 29437826 TI - RNA-Interference Pathways Display High Rates of Adaptive Protein Evolution in Multiple Invertebrates. AB - Conflict between organisms can lead to a reciprocal adaptation that manifests as an increased evolutionary rate in genes mediating the conflict. This adaptive signature has been observed in RNA-interference (RNAi) pathway genes involved in the suppression of viruses and transposable elements in Drosophila melanogaster, suggesting that a subset of Drosophila RNAi genes may be locked in an arms race with these parasites. However, it is not known whether rapid evolution of RNAi genes is a general phenomenon across invertebrates, or which RNAi genes generally evolve adaptively. Here we use population genomic data from eight invertebrate species to infer rates of adaptive sequence evolution, and to test for past and ongoing selective sweeps in RNAi genes. We assess rates of adaptive protein evolution across species using a formal meta-analytic framework to combine data across species and by implementing a multispecies generalized linear mixed model of mutation counts. Across species, we find that RNAi genes display a greater rate of adaptive protein substitution than other genes, and that this is primarily mediated by positive selection acting on the genes most likely to defend against viruses and transposable elements. In contrast, evidence for recent selective sweeps is broadly spread across functional classes of RNAi genes and differs substantially among species. Finally, we identify genes that exhibit elevated adaptive evolution across the analyzed insect species, perhaps due to concurrent parasite-mediated arms races. PMID- 29437829 TI - Multivariate Analysis of the Cotton Seed Ionome Reveals a Shared Genetic Architecture. AB - To mitigate the effects of heat and drought stress, a better understanding of the genetic control of physiological responses to these environmental conditions is needed. To this end, we evaluated an upland cotton (Gossypium hirsutum L.) mapping population under water-limited and well-watered conditions in a hot, arid environment. The elemental concentrations (ionome) of seed samples from the population were profiled in addition to those of soil samples taken from throughout the field site to better model environmental variation. The elements profiled in seeds exhibited moderate to high heritabilities, as well as strong phenotypic and genotypic correlations between elements that were not altered by the imposed irrigation regimes. Quantitative trait loci (QTL) mapping results from a Bayesian classification method identified multiple genomic regions where QTL for individual elements colocalized, suggesting that genetic control of the ionome is highly interrelated. To more fully explore this genetic architecture, multivariate QTL mapping was implemented among groups of biochemically related elements. This analysis revealed both additional and pleiotropic QTL responsible for coordinated control of phenotypic variation for elemental accumulation. Machine learning algorithms that utilized only ionomic data predicted the irrigation regime under which genotypes were evaluated with very high accuracy. Taken together, these results demonstrate the extent to which the seed ionome is genetically interrelated and predictive of plant physiological responses to adverse environmental conditions. PMID- 29437831 TI - Lsd1 interacts with cMyb to demethylate repressive histone marks and maintain inner ear progenitor identity. AB - During development, multipotent progenitor cells must maintain their identity while retaining the competence to respond to new signalling cues that drive cell fate decisions. This depends on both DNA-bound transcription factors and surrounding histone modifications. Here, we identify the histone demethylase Lsd1 as a crucial component of the molecular machinery that preserves progenitor identity in the developing ear prior to lineage commitment. Although Lsd1 is mainly associated with repressive complexes, we show that, in ear precursors, it is required to maintain active transcription of otic genes. We reveal a novel interaction between Lsd1 and the transcription factor cMyb, which in turn recruits Lsd1 to the promoters of key ear transcription factors. Here, Lsd1 prevents the accumulation of repressive H3K9me2, while allowing H3K9 acetylation. Loss of Lsd1 function causes rapid silencing of active promoters and loss of ear progenitor genes, and shuts down the entire ear developmental programme. Our data suggest that Lsd1-cMyb acts as a co-activator complex that maintains a regulatory module at the top of the inner ear gene network. PMID- 29437830 TI - Face morphogenesis is promoted by Pbx-dependent EMT via regulation of Snail1 during frontonasal prominence fusion. AB - Human cleft lip with or without cleft palate (CL/P) is a common craniofacial abnormality caused by impaired fusion of the facial prominences. We have previously reported that, in the mouse embryo, epithelial apoptosis mediates fusion at the seam where the prominences coalesce. Here, we show that apoptosis alone is not sufficient to remove the epithelial layers. We observed morphological changes in the seam epithelia, intermingling of cells of epithelial descent into the mesenchyme and molecular signatures of epithelial-mesenchymal transition (EMT). Utilizing mouse lines with cephalic epithelium-specific Pbx loss exhibiting CL/P, we demonstrate that these cellular behaviors are Pbx dependent, as is the transcriptional regulation of the EMT driver Snail1. Furthermore, in the embryo, the majority of epithelial cells expressing high levels of Snail1 do not undergo apoptosis. Pbx1 loss- and gain-of-function in a tractable epithelial culture system revealed that Pbx1 is both necessary and sufficient for EMT induction. This study establishes that Pbx-dependent EMT programs mediate murine upper lip/primary palate morphogenesis and fusion via regulation of Snail1. Of note, the EMT signatures observed in the embryo are mirrored in the epithelial culture system. PMID- 29437833 TI - Deficiency of Complement C3a and C5a Receptors Prevents Angiotensin II-Induced Hypertension via Regulatory T Cells. AB - RATIONALE: Inflammation and immunity play crucial roles in the development of hypertension. Complement activation-mediated innate immune response is involved in the regulation of hypertension and target-organ damage. However, whether complement-mediated T-cell functions could regulate blood pressure elevation in hypertension is still unclear. OBJECTIVE: We aim to determine whether C3aR (complement component 3a receptor) and C5aR (complement component 5a receptor) could regulate blood pressure via modulating regulatory T cells (Tregs). METHODS AND RESULTS: We showed that angiotensin II (Ang II)-induced hypertension resulted in an elevated expression of C3aR and C5aR in Foxp3 (forkhead box P3)+ Tregs. By using C3aR and C5aR DKO (double knockout) mice, we showed that C3aR and C5aR deficiency together strikingly decreased both systolic and diastolic blood pressure in response to Ang II compared with WT (wild type), single C3aR deficient (C3aR-/-), or C5aR-deficient (C5aR-/-) mice. Flow cytometric analysis showed that Ang II-induced Treg reduction in the kidney and blood was also blocked in DKO mice. Histological analysis indicated that renal and vascular structure remodeling and damage after Ang II treatment were attenuated in DKO mice compared with WT mice. In vitro, Ang II was able to stimulate C3aR and C5aR expression in cultured CD4+CD25+ natural Tregs. CD3 and CD28 antibody stimuli downregulated Foxp3 expression in WT but not DKO Tregs. More important, depletion of Tregs with CD25 antibody abolished the protective effects against Ang II induced hypertension and target-organ damage in DKO mice. Adoptive transfer of DKO Tregs showed much more profound protective effects against Ang II-induced hypertension than WT Treg transfer. Furthermore, we demonstrated that C5aR expression in Foxp3+ Tregs was higher in hypertensive patients compared with normotensive individuals. CONCLUSIONS: C3aR and C5aR DKO-mediated Treg function prevents Ang II-induced hypertension and target-organ damage. Targeting C3aR and C5aR in Tregs specifically may be an alternative novel approach for hypertension treatment. PMID- 29437832 TI - ES cell-derived presomitic mesoderm-like tissues for analysis of synchronized oscillations in the segmentation clock. AB - Somites are periodically formed by segmentation of the anterior parts of the presomitic mesoderm (PSM). In the mouse embryo, this periodicity is controlled by the segmentation clock gene Hes7, which exhibits wave-like oscillatory expression in the PSM. Despite intensive studies, the exact mechanism of such synchronous oscillatory dynamics of Hes7 expression still remains to be analyzed. Detailed analysis of the segmentation clock has been hampered because it requires the use of live embryos, and establishment of an in vitro culture system would facilitate such analyses. Here, we established a simple and efficient method to generate mouse ES cell-derived PSM-like tissues, in which Hes7 expression oscillates like traveling waves. In these tissues, Hes7 oscillation is synchronized between neighboring cells, and the posterior-anterior axis is self-organized as the central-peripheral axis. This method is applicable to chemical-library screening and will facilitate the analysis of the molecular nature of the segmentation clock. PMID- 29437836 TI - Prospective Observational Study on High-Value Care Topics Discussed on Multidisciplinary Rounds. AB - OBJECTIVES: Establishing a high-value care (HVC) culture within an institution requires a multidisciplinary commitment and participation. Bedside rounds provide an ideal environment for role modeling and learning behaviors that promote an HVC culture. However, little is understood regarding the types of HVC discussions that take place at the bedside and who participates in those discussions. METHODS: A prospective observational study at a tertiary-care, university affiliated, free-standing children's hospital. The prevalence of HVC discussions was captured by using the HVC Rounding Tool, a previously developed instrument with established validity evidence. For each observed HVC discussion, raters recorded who initiated the discussion and a description of the topic. RESULTS: Raters observed 660 patient encounters over 59 separate dates. Of all patient encounters, 29% (191 of 660; 95% confidence interval: 26%-33%) included at least 1 observed HVC discussion. The attending physician or fellow initiated 41% of all HVC discussions, followed by residents or medical students (31%), families (12%), and nurses (7%). CONCLUSIONS: Despite a recent focus on improving health care value and educating trainees in the practice of HVC, our study demonstrated that bedside discussions of HVC are occurring with a limited frequency at our institution and that attending physicians initiate the majority of discussions. The capacity of the nonphysician team members to contribute to establishing and sustaining an HVC culture may be underused. Multi-institutional studies are necessary to determine if this is a national trend and whether discussions have an impact on patient outcomes and hospital costs. PMID- 29437834 TI - Impaired Production and Diurnal Regulation of Vascular RvDn-3 DPA Increase Systemic Inflammation and Cardiovascular Disease. AB - RATIONALE: Diurnal mechanisms are central to regulating host responses. Recent studies uncovered a novel family of mediators termed as specialized proresolving mediators that terminate inflammation without interfering with the immune response. OBJECTIVE: Herein, we investigated the diurnal regulation of specialized proresolving mediators in humans and their role in controlling peripheral blood leukocyte and platelet activation. METHODS AND RESULTS: Using lipid mediator profiling and healthy volunteers, we found that plasma concentrations of n-3 docosapentaenoic acid-derived D-series resolvins (RvDn-3 DPA) were regulated in a diurnal manner. The production and regulation of these mediators was markedly altered in patients at risk of myocardial infarct. These changes were associated with decreased 5-lipoxygenase expression and activity, as well as increased systemic adenosine concentrations. We also found a significant negative correlation between plasma RvDn-3 DPA and markers of platelet, monocyte, and neutrophil activation, including CD63 and CD11b. Incubation of RvDn-3 DPA with peripheral blood from healthy volunteers and patients with cardiovascular disease significantly and dose-dependently decreased platelet and leukocyte activation. Furthermore, administration of RvD5n-3 DPA to ApoE-/- (apolipoprotein E deficient) mice significantly reduced platelet-leukocyte aggregates, vascular thromboxane B2 concentrations, and aortic lesions. CONCLUSIONS: These results demonstrate that peripheral blood RvDn-3 DPA are diurnally regulated in humans, and dysregulation in the production of these mediators may lead to cardiovascular disease. PMID- 29437837 TI - Confronting the Hidden Curriculum of High-Value Care Education. PMID- 29437835 TI - Network Analysis to Risk Stratify Patients With Exercise Intolerance. AB - RATIONALE: Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking. OBJECTIVE: Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance. METHODS AND RESULTS: Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011-2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|>0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to P<9.5e-46 for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pVo2) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements (P<0.01). Compared with a probabilistic model, including 23 independent predictors of pVo2 and pVo2 itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold (P<0.0001; 95% CI, 2.2-8.1) and 2.8-fold (P=0.0018; 95% CI, 1.5-5.2) increase in hazard for age- and pVo2-adjusted all cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort. CONCLUSIONS: Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pVo2 that predict hospitalization in patients with exercise intolerance. PMID- 29437839 TI - 2017 Year-End Metrics. PMID- 29437841 TI - Improving Evaluation of Dental Hygiene Students' Cultural Competence with a Mixed Methods Approach. AB - Most dental hygiene educational programs include cultural competence education, but may not evaluate student outcomes. The aim of this study was to design and implement a mixed-methods evaluation to measure dental hygiene students' progression toward cultural competence. Two cohorts consisting of consecutive classes in one U.S. dental hygiene program participated in the study. A total of 47 dental hygiene students (100% response rate) completed self-assessments to measure their attitudes and knowledge at three time points between 2014 and 2016. Mean scores were calculated for three domains: Physical Environment, Communication, and Values. Qualitative analysis of the students' cultural diversity papers was also conducted to further evaluate students' knowledge and skills. Bennett's five-level conceptual framework was used to code phrases or sentences to place students in the general categories of ethnocentric or ethno relative. The quantitative and qualitative results yielded different outcomes for Cohort 1, but not for Cohort 2. The Cohort 1 students assessed themselves statistically significantly lower over time in one of the three measured domains. However, the Cohort 2 students assessed themselves as statistically significantly more culturally competent in all three domains. Qualitative results placed 72% of Cohort 1 students and 83% of Cohort 2 students in the more desirable ethno relative category. Since quantitative methods consisting of student self assessments may not adequately measure students' cultural competence, adding qualitative methods to measure skills specific to patient care in this study added a robust dimension to evaluating this complex dental hygiene student competence. PMID- 29437838 TI - Probing Dominant Negative Behavior of Glucocorticoid Receptor beta through a Hybrid Structural and Biochemical Approach. AB - Glucocorticoid receptor beta (GRbeta) is associated with glucocorticoid resistance via dominant negative regulation of GRalpha. To better understand how GRbeta functions as a dominant negative inhibitor of GRalpha at a molecular level, we determined the crystal structure of the ligand binding domain of GRbeta complexed with antagonist RU-486. The structure reveals that RU-486 binds in the same ligand binding pocket as in GRalpha and the unique C-terminal amino acids of GRbeta are mostly disordered. Binding energy analysis suggests that these C terminal residues of GRbeta do not contribute to RU-486 binding. Intriguingly, the GRbeta/RU-486 complex binds corepressor peptide with similar affinity as GRalpha/RU-486 complex, despite the lack of helix 12. Our biophysical and biochemical analysis reveals that in the presence of RU-486, GRbeta is found in a conformation that favors corepressor binding, potentially antagonizing GRalpha function. This study thus presents an unexpected molecular mechanism by which GRbeta could repress transcription. PMID- 29437842 TI - Relationship Between Dental Hygiene Students' Performance in an Oral Radiology Course and the National Board Dental Hygiene Examination: A Retrospective Study. AB - Dental hygiene students' performance in oral radiology courses may give an early indication of their readiness prior to taking the National Board Dental Hygiene Examination (NBDHE). The aim of this study was to determine the relationship between dental hygiene students' performance in an oral radiology lecture course and their performance on the NBDHE. Data were collected for all 117 dental hygiene students at Texas A&M University College of Dentistry from 2006 to 2009 who took the NBDHE during their second year of the program. Their final grades and scores on three written section examinations in an oral radiology course taken in their first year were compared with their overall NBDHE scores and raw scores on the oral radiology and case study sections. Moderate correlations (0.30.05). There were no opposite attitudes or contrasts found between the two groups with regards to PBL. The strongest themes expressed by both groups were that PBL should not be used as the sole method of instruction and that students needed a solid foundation in the subject prior to engaging in PBL. PMID- 29437847 TI - Dental Students' Perceived Clinical Competence in Prosthodontics: Comparison of Traditional and Problem-Based Learning Methodologies. AB - The aim of this study was to compare the perceived competence for treating prosthodontic patients of two samples of fourth-year dental students: those educated using traditional methodologies and those educated using problem-based learning (PBL). Two cohorts of fourth-year dental students at a dental school in Spain were surveyed: the traditional methods cohort (n=46) was comprised of all students in academic years 2012 and 2013, and the PBL cohort (n=57) was comprised of all students in academic years 2014 and 2015. Students in both cohorts reported the number of prosthodontic treatments they carried out per year and their perceived level of competence in performing such treatments. The results showed that the average number of treatments performed was similar for the two cohorts, except the number of metal-based removable partial dentures was significantly higher for students in the traditional (0.8+/-1.0) than the PBL (0.4+/-0.6) cohort. The level of perceived competence to treat complete denture patients for the combined cohorts was significantly higher (7.3+/-1.1) than that for partial acrylic dentures (6.7+/-1.5) and combined dentures (5.7+/-1.3). Students' clinical competence in prosthodontics mainly depended on number of treatments performed as the operator as well as the assistant. Students in the traditional methods cohort considered themselves to be significantly more competent at treating patients for removable partial and fixed prostheses (7.8+/ 1.1 and 7.6+/-1.1, respectively) than did students in the PBL cohort (6.4+/-1.5 and 6.6+/-1.5, respectively). Overall, however, the study found that practical experiences were more important than the teaching method used to achieve students' perceived competence. PMID- 29437848 TI - New decision formulas for predicting endotracheal tube depth in children: analysis of neck CT images. AB - INTRODUCTION: The purpose of this study was to construct a prediction model for endotracheal tube depth using neck CT images. METHODS: A retrospective image review was conducted that included patients who had undergone neck CT. Using sagittal neck CT images, we calculated the length between upper incisor and mid trachea and then derived the model via regression analysis. The model was validated externally using chest radiographs of patients who had undergone endotracheal intubation. We compared performance of our model with that of other methods (Broselow tape and APLS formula) via Bland-Altman analysis and the percentage of estimations within 10% of the measured values. RESULTS: A total of 1111 children were included in this study. The tube depth obtained from CT images was linearly related to body weight (tube depth (cm)=5.5+0.5*body wt (kg)) in children younger than 1 year and to height (tube depth (cm)=3+0.1*height (cm)) in children older than 1 year. External validation demonstrated that our new model showed better agreement with the desired tube depth than Broselow tape and APLS formula. The mean differences in children younger than 1 year were 0.61 cm and 1.24 cm for our formula and Broselow tape, respectively. The mean differences in children older than 1 year were -0.43 cm, -1.98 and -1.64 cm for our formula, Broselow tape and APLS formula, respectively. The percentages of estimates within 10% of the measured values were 52.7% and 35.8% for our formula and Broselow tape in children younger than 1 year, respectively, and 54.3%, 33.8% and 37.2% for our formula, Broselow tape and APLS formula in children older than 1 year, respectively (P<0.01). CONCLUSION: Our new formula is useful and more accurate than the currently available methods. PMID- 29437849 TI - Vibrio fischeri DarR Directs Responses to d-Aspartate and Represents a Group of Similar LysR-Type Transcriptional Regulators. AB - Mounting evidence suggests that d-amino acids play previously underappreciated roles in diverse organisms. In bacteria, even d-amino acids that are absent from canonical peptidoglycan (PG) may act as growth substrates, as signals, or in other functions. Given these proposed roles and the ubiquity of d-amino acids, the paucity of known d-amino-acid-responsive transcriptional control mechanisms in bacteria suggests that such regulation awaits discovery. We found that DarR, a LysR-type transcriptional regulator (LTTR), activates transcription in response to d-Asp. The d-Glu auxotrophy of a Vibrio fischerimurI::Tn mutant was suppressed, with the wild-type PG structure maintained, by a point mutation in darR This darR mutation resulted in the overexpression of an adjacent operon encoding a putative aspartate racemase, RacD, which compensated for the loss of the glutamate racemase encoded by murI Using transcriptional reporters, we found that wild-type DarR activated racD transcription in response to exogenous d-Asp but not upon the addition of l-Asp, l-Glu, or d-Glu. A DNA sequence typical of LTTR-binding sites was identified between darR and the divergently oriented racD operon, and scrambling this sequence eliminated activation of the reporter in response to d-Asp. In several proteobacteria, genes encoding LTTRs similar to DarR are linked to genes with predicted roles in d- and/or l-Asp metabolism. To test the functional similarities in another bacterium, darR and racD mutants were also generated in Acinetobacter baylyi In V. fischeri and A. baylyi, growth on d Asp required the presence of both darR and racD Our results suggest that multiple bacteria have the ability to sense and respond to d-Asp.IMPORTANCE d-Amino acids are prevalent in the environment and are generated by organisms from all domains of life. Although some biological roles for d-amino acids are understood, in other cases, their functions remain uncertain. Given the ubiquity of d-amino acids, it seems likely that bacteria will initiate transcriptional responses to them. Elucidating d-amino acid-responsive regulators along with the genes they control will help uncover bacterial uses of d-amino acids. Here, we report the discovery of DarR, a novel LTTR in V. fischeri that mediates a transcriptional response to environmental d-Asp and underpins the catabolism of d-Asp. DarR represents the founding member of a group of bacterial homologs that we hypothesize control aspects of aspartate metabolism in response to d-Asp and/or to d-Asp-containing peptides. PMID- 29437850 TI - Targeting the HUbeta Protein Prevents Porphyromonas gingivalis from Entering into Preexisting Biofilms. AB - The oral cavity is home to a wide variety of bacterial species, both commensal, such as various streptococcal species, and pathogenic, such as Porphyromonas gingivalis, one of the main etiological agents of periodontal disease. Our understanding of how these bacteria ultimately cause disease is highly dependent upon understanding how they coexist and interact with one another in biofilm communities and the mechanisms by which biofilms are formed. Our research has demonstrated that the DNABII family of DNA-binding proteins are important components of the extracellular DNA (eDNA)-dependent matrix of bacterial biofilms and that sequestering these proteins via protein-specific antibodies results in the collapse of the biofilm structure and release of the resident bacteria. While the high degree of similarity among the DNABII family of proteins has allowed antibodies derived against specific DNABII proteins to disrupt biofilms formed by a wide range of bacterial pathogens, the DNABII proteins of P. gingivalis have proven to be antigenically distinct, allowing us to determine if we can use anti P. gingivalis HUbeta antibodies to specifically target this species for removal from a mixed-species biofilm. Importantly, despite forming homotypic biofilms in vitro, P. gingivalis must enter preexisting biofilms in vivo in order to persist within the oral cavity. The data presented here indicate that antibodies derived against the P. gingivalis DNABII protein, HUbeta, reduce by half the amount of P. gingivalis organisms entering into preexisting biofilm formed by four oral streptococcal species. These results support our efforts to develop methods for preventing and treating periodontal disease.IMPORTANCE Periodontitis is one of the most prevalent chronic infections, affecting 40 to 50% of the population of the United States. The root cause of periodontitis is the presence of bacterial biofilms within the gingival space, with Porphyromonas gingivalis being strongly associated with the development of the disease. Periodontitis also increases the risk of secondary conditions and infections such as atherosclerosis and infective endocarditis caused by oral streptococci. To induce periodontitis, P. gingivalis needs to incorporate into preformed biofilms, with oral streptococci being important binding partners. Our research demonstrates that targeting DNABII proteins with an antibody disperses oral streptococcus biofilm and prevents P. gingivalis entry into oral streptococcus biofilm. These results suggest potential therapeutic treatments for endocarditis caused by streptococci as well as periodontitis. PMID- 29437851 TI - Mechanistic Features of the Enterococcal pCF10 Sex Pheromone Response and the Biology of Enterococcus faecalis in Its Natural Habitat. AB - Conjugative transfer of plasmids in enterococci is promoted by intercellular communication using peptide pheromones. The regulatory mechanisms that control transfer have been extensively studied in vitro However, the complicated systems that regulate the spread of these plasmids did not evolve in the laboratory test tube, and remarkably little is known about this form of signaling in the intestinal tract, the primary niche of these organisms. Because the evolution of Enterococcus faecalis strains and their coresident pheromone-inducible plasmids, such as pCF10, have occurred in the gastrointestinal (GI) tract, it is important to consider the functions controlled by pheromones in light of this ecology. This review summarizes our current understanding of the pCF10-encoded pheromone response. We consider how selective pressures in the natural environment may have selected for the complex and very tightly regulated systems controlling conjugation, and we pay special attention to the ecology of enterococci and the pCF10 plasmid as a gut commensal. We summarize the results of recent studies of the pheromone response at the single-cell level, as well as those of the first experiments demonstrating a role for pheromone signaling in plasmid transfer and in GI tract competitive fitness. These results will serve as a foundation for further in vivo studies that could lead to novel interventions to reduce opportunistic infections and the spread of antibiotic resistance. PMID- 29437852 TI - An N-terminal Retention Module Anchors the Giant Adhesin LapA of Pseudomonas fluorescens at the Cell Surface: A Novel Sub-family of Type I Secretion Systems. AB - LapA of Pseudomonas fluorescens Pf0-1 belongs to a diverse family of cell surface associated bacterial adhesins that are secreted via the type-1 secretion system (T1SS). We previously reported that the periplasmic protease LapG cleaves the N terminus of LapA at a canonical dialanine motif to release the adhesin from the cell surface under conditions unfavorable to biofilm formation, thus decreasing biofilm formation. Here, we characterize LapA as the first type 1 secreted substrate that does not follow the "one-step" rule of T1SS. Rather, a novel N terminal element, called the retention module (RM), localizes LapA at the cell surface as a secretion intermediate. Our genetic, biochemical, and molecular modeling analysis support a model wherein LapA is tethered to the cell surface through its T1SS outer membrane TolC-like pore, LapE, until LapG cleaves LapA in the periplasm. We further demonstrate this unusual retention strategy is likely conserved among LapA-like proteins, and reveals a new subclass of T1SS ABC transporters involved in transporting this group of surface-associated, LapA-like adhesins. These studies demonstrate a novel cell surface retention strategy used throughout the Proteobacteria and highlight a previously unappreciated flexibility of function for T1SS.Importance. Bacteria have evolved multiple secretion strategies to interact with their environment. For many bacteria, the secretion of cell surface associated adhesins is key for initiating contact with a preferred substratum to facilitate biofilm formation. Our work demonstrates that P. fluorescens uses a previously unrecognized secretion strategy to retain the giant adhesin LapA at its cell surface. Further, we identify likely LapA-like adhesins in various pathogenic and commensal Proteobacteria and provide phylogenetic evidence that these adhesins are secreted by a new subclass of T1SS ABC transporters. PMID- 29437853 TI - Cyclic stretch-induced Crp3 sensitizes vascular smooth muscle cells to apoptosis during vein arterialization remodeling. AB - Vein graft failure limits the long-term patency of the saphenous vein used as a conduit for coronary artery bypass graft. Early graft adaptation involves some degree of intima hyperplasia to sustain the hemodynamic stress, but the progress to occlusion in some veins remains unclear. We have demonstrated that stretch induced up-regulation of cysteine and glycine-rich protein 3 (Crp3) in rat jugular vein and human saphenous vein in response to arterialization. Here, we developed a Crp3-KO rat to investigate the role of Crp3 in vascular remodeling. After 28 days jugular vein arterialization, the intima layer was 3-fold thicker in the Crp3-KO that showed comparable smooth muscle cells (SMC) proliferation but an absence of early apoptosis observed in the wild-type rat (WT). We then investigated the role of Crp3 in early integrin-mediated signaling apoptosis in isolated jugular SMC. Interestingly, under basal conditions, ceramide treatment failed to induce apoptosis in both WT and Crp3-KO SMC. Under stretch, Crp3 expression increased in WT SMC and ceramide induced apoptosis. Immunoblotting analysis indicated that ceramide stretch-induced apoptosis in SMC is accompanied by a decrease in the phosphorylation status of both Fak and Akt, leading to an increase in Bax expression and caspase-3 cleavage. In contrast, ceramide failed to decrease Fak and Akt phosphorylation in Crp3-KO SMC and, therefore, there was no downstream induction of Bax expression and effector caspase-3 cleavage. Taken together, we provide evidence that stretch-induced Crp3 modulates vein remodeling in response to arterialization by sensitizing SMC to apoptosis. PMID- 29437854 TI - BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial to-Mesenchymal Transition. AB - Transcriptional programs in embryogenesis and cancer, such as the epithelial-to mesenchymal transition (EMT), ensure cellular plasticity, an essential feature of carcinoma progression. As effectors of signal transduction, the bromodomain and extraterminal (BET) proteins are well suited to support plasticity because they function as co-activators or co-repressors of mammalian transcriptomes. Here, using both hormone-sensitive and triple-negative breast cancer (TNBC) model systems, we systematically altered EMT transcriptional profiles by manipulating individual BET proteins and found that BRD2 positively regulates EMT, whereas BRD3 and BRD4 repress this program. Knockdown of individual BET proteins revealed independent transcriptional networks that differed from each other and from the small-molecule pan-BET inhibitor JQ1, which previously had been misleadingly asserted to be BRD4-selective. Available small-molecule pan-BET inhibitors, proposed as antiproliferative agents in cancer clinical trials, obscure these biological differences. Transcriptional profiling reveals that individual BET proteins, inhibited separately, engage in and control EMT through unique processes.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/4/580/F1.large.jpg Mol Cancer Res; 16(4); 580-6. (c)2018 AACR. PMID- 29437855 TI - Identifying the role of complement in triggering neuroinflammation after traumatic brain injury. AB - The complement system is implicated in promoting acute secondary injury after traumatic brain injury (TBI), but its role in chronic post-traumatic neuropathology remains unclear. Using various injury-site targeted complement inhibitors that block different complement pathways and activation products, we investigated how complement is involved in neurodegeneration and chronic neuroinflammation after TBI in a clinically relevant setting of complement inhibition. The current paradigm is that complement propagates post-TBI neuropathology predominantly through the terminal membrane attack complex (MAC), but the focus has been on acute outcomes. Following controlled cortical impact in adult male mice, we demonstrate that while inhibition of the MAC (with CR2-CD59) reduces acute deficits, inhibition of C3 activation is required to prevent chronic inflammation and ongoing neuronal loss. Activation of C3 triggered a sustained degenerative mechanism of microglial and astrocyte activation, reduced dendritic and synaptic density, and inhibited neuroblast migration several weeks after TBI. Moreover, inhibiting all complement pathways (with CR2-Crry), or only the alternative complement pathway (with CR2-fH), provided similar and significant improvements in chronic histological, cognitive and functional recovery, indicating a key role for the alternative pathway in propagating chronic post-TBI pathology. Although we confirm a role for the MAC in acute neuronal loss after TBI, this study shows that upstream products of complement activation generated predominantly via the alternative pathway propagate chronic neuroinflammation, thus challenging the current concept that the MAC represents a therapeutic target for treating TBI. A humanized version of CR2fH has been shown to be safe and non-immunogenic in clinical trials.Significance StatementComplement, and specifically the terminal membrane attack complex, has been implicated in secondary injury and neuronal loss after TBI. However, we demonstrate here that upstream complement activation products, generated predominantly via the alternative pathway, are responsible for propagating chronic inflammation and injury following CCI. Chronic inflammatory microgliosis is triggered by sustained complement activation after CCI, and is associated with chronic loss of neurons, dendrites and synapses, a process that continues to occur even 30 days after initial impact. Acute and injury-site targeted inhibition of the alternative pathway significantly improves chronic outcomes, and together these findings modify the conceptual paradigm for targeting the complement system to treat TBI. PMID- 29437857 TI - H2AFX and MDC1 promote maintenance of genomic integrity in male germ cells. AB - In somatic cells, H2afx and Mdc1 are close functional partners in DNA repair and damage response. However, it is not known whether they are also involved in the maintenance of genome integrity in meiosis. By analyzing chromosome dynamics in H2afx-/- spermatocytes, we found that the synapsis of autosomes and X-Y chromosomes was impaired in a fraction of cells. Such defects correlated with an abnormal recombination profile. Conversely, Mdc1 was dispensable for the synapsis of the autosomes and played only a minor role in X-Y synapsis, compared with the action of H2afx This suggested that those genes have non-overlapping functions in chromosome synapsis. However, we observed that both genes play a similar role in the assembly of MLH3 onto chromosomes, a key step in crossover formation. Moreover, we show that H2afx and Mdc1 cooperate in promoting the activation of the recombination-dependent checkpoint, a mechanism that restrains the differentiation of cells with unrepaired DSBs. This occurs by a mechanism that involves P53. Overall, our data show that, in male germ cells, H2afx and Mdc1 promote the maintenance of genome integrity.This article has an associated First Person interview with the first author of the paper. PMID- 29437856 TI - Noise-induced dysregulation of Quaking RNA binding proteins contributes to auditory nerve demyelination and hearing loss. AB - Noise exposure causes auditory nerve (AN) degeneration and hearing deficiency, though the proximal biological consequences are not entirely understood. Most AN fibers and spiral ganglion neurons are ensheathed by myelinating glia that provide insulation and ensure rapid transmission of nerve impulses from the cochlea to the brain. Here we show that noise exposure administered to mice of either sex rapidly affects myelinating glial cells, causing molecular and cellular consequences that precede nerve degeneration. This response is characterized by demyelination, inflammation and widespread expression changes in myelin-related genes, including the RNA splicing regulator Quaking (QKI) and numerous QKI target genes. Analysis of mice deficient in QKI revealed that QKI production in cochlear glial cells is essential for proper myelination of spiral ganglion neurons and AN fibers, and for normal hearing. Our findings implicate QKI dysregulation as a critical early component in the noise response, influencing cochlear glia function that leads to AN demyelination and, ultimately, hearing deficiency.SIGNIFICANCE STATEMENTAuditory glia cells ensheath a majority of spiral ganglion neurons with myelin, protect auditory neurons and allow for fast conduction of electrical impulses along the auditory nerve. Here we show that noise exposure causes glial dysfunction leading to myelin abnormality and altered expression of numerous genes in the auditory nerve, including QKI, a gene implicated in regulating myelination. Study of a conditional mouse model that specifically depleted QKI in glia showed that QKI deficiency alone was sufficient to elicit myelin-related abnormality and auditory functional declines. These results establish QKI as a key molecular target in the noise response and a causative agent in hearing loss. PMID- 29437859 TI - Health Disparities Facing Transgender and Gender Nonconforming Youth Are Not Inevitable. PMID- 29437858 TI - Coarse-grained molecular dynamics simulations reveal lipid access pathways in P glycoprotein. AB - P-glycoprotein (P-gp) exports a broad range of dissimilar compounds, including drugs, lipids, and lipid-like molecules. Because of its substrate promiscuity, P gp is a key player in the development of cancer multidrug resistance. Although P gp is one of the most studied ABC transporters, the mechanism by which its substrates access the cavity remains unclear. In this study, we perform coarse grained molecular dynamics simulations to explore possible lipid access pathways in the inward-facing conformation of P-gp embedded in bilayers of different lipid compositions. In the inward-facing orientation, only lipids from the lower leaflet access the cavity of the transporter. We identify positively charged residues at the portals of P-gp that favor lipid entrance to the cavity, as well as lipid-binding sites at the portals and within the cavity, which is in good agreement with previous experimental studies. This work includes several examples of lipid pathways for phosphatidylcholine and phosphatidylethanolamine lipids that help elucidate the molecular mechanism of lipid binding in P-gp. PMID- 29437860 TI - Antibiotic Prophylaxis for Children With Sickle Cell Anemia. AB - BACKGROUND: Children with sickle cell anemia (SCA) are at increased risk for invasive pneumococcal disease; antibiotic prophylaxis significantly reduces this risk. We calculated the proportion of children with SCA who received >=300 days of antibiotic prophylaxis and identified predictors of such receipt. METHODS: Children aged 3 months to 5 years with SCA were identified by the presence of 3 or more Medicaid claims with a diagnosis of SCA within a calendar year (2005 2012) in Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. Receipt of antibiotics was identified through claims for filled prescriptions. The outcome, receipt of >=300 days of antibiotics, was assessed annually by using varying classifications of antibiotics. By using logistic regression with generalized estimating equations, we estimated the odds of receiving >=300 days of antibiotics, with potential predictors of age, sex, year, state, and health services use. RESULTS: A total of 2821 children contributed 5014 person-years. Overall, only 18% of children received >=300 days of antibiotics. Each additional sickle cell disease-related outpatient visit (odds ratio = 1.01, 95% confidence interval: 1.01-1.02) and well-child visit (odds ratio = 1.08, 95% confidence interval: 1.02-1.13) was associated with incrementally increased odds of receiving >=300 days of antibiotics. CONCLUSIONS: Despite national recommendations and proven lifesaving benefit, antibiotic prophylaxis rates are low among children with SCA. Numerous health care encounters may offer an opportunity for intervention; in addition, such interventions likely need to include social factors that may affect the ability for a child to receive and adhere to antibiotic prophylaxis. PMID- 29437861 TI - Health and Care Utilization of Transgender and Gender Nonconforming Youth: A Population-Based Study. AB - BACKGROUND: Transgender and gender nonconforming (TGNC) adolescents have difficulty accessing and receiving health care compared with cisgender youth, yet research is limited by a reliance on small and nonrepresentative samples. This study's purpose was to examine mental and physical health characteristics and care utilization between youth who are TGNC and cisgender and across perceived gender expressions within the TGNC sample. METHODS: Data came from the 2016 Minnesota Student Survey, which consisted of 80 929 students in ninth and 11th grade (n = 2168 TGNC, 2.7%). Students self-reported gender identity, perceived gender expression, 4 health status measures, and 3 care utilization measures. Chi squares and multiple analysis of covariance tests (controlling for demographic covariates) were used to compare groups. RESULTS: We found that students who are TGNC reported significantly poorer health, lower rates of preventive health checkups, and more nurse office visits than cisgender youth. For example, 62.1% of youth who are TGNC reported their general health as poor, fair, or good versus very good or excellent, compared with 33.1% of cisgender youth (chi2 = 763.7, P < .001). Among the TGNC sample, those whose gender presentation was perceived as very congruent with their birth-assigned sex were less likely to report poorer health and long-term mental health problems compared with those with other gender presentations. CONCLUSIONS: Health care utilization differs between TGNC versus cisgender youth and across gender presentations within TGNC youth. With our results, we suggest that health care providers should screen for health risks and identify barriers to care for TGNC youth while promoting and bolstering wellness within this community. PMID- 29437862 TI - Structure and Functions of Pediatric Aerodigestive Programs: A Consensus Statement. AB - Aerodigestive programs provide coordinated interdisciplinary care to pediatric patients with complex congenital or acquired conditions affecting breathing, swallowing, and growth. Although there has been a proliferation of programs, as well as national meetings, interest groups and early research activity, there is, as of yet, no consensus definition of an aerodigestive patient, standardized structure, and functions of an aerodigestive program or a blueprint for research prioritization. The Delphi method was used by a multidisciplinary and multi institutional panel of aerodigestive providers to obtain consensus on 4 broad content areas related to aerodigestive care: (1) definition of an aerodigestive patient, (2) essential construct and functions of an aerodigestive program, (3) identification of aerodigestive research priorities, and (4) evaluation and recognition of aerodigestive programs and future directions. After 3 iterations of survey, consensus was obtained by either a supermajority of 75% or stability in median ranking on 33 of 36 items. This included a standard definition of an aerodigestive patient, level of participation of specific pediatric disciplines in a program, essential components of the care cycle and functions of the program, feeding and swallowing assessment and therapy, procedural scope and volume, research priorities and outcome measures, certification, coding, and funding. We propose the first consensus definition of the aerodigestive care model with specific recommendations regarding associated personnel, infrastructure, research, and outcome measures. We hope that this may provide an initial framework to further standardize care, develop clinical guidelines, and improve outcomes for aerodigestive patients. PMID- 29437863 TI - Associations between socioeconomic status and chronic kidney disease: a meta analysis. AB - BACKGROUND: Socioeconomic status (SES) has long been conjectured to be associated with the incidence and progression of chronic kidney disease (CKD), but few studies have examined this quantitatively. This meta-analysis aims to fill this gap. METHODS: A systematic literature review was performed using Medline and EMBASE to identify observational studies on associations between SES and incidence and progression of CKD, published between 1974 and March 2017. Individual results were meta-analysed using a random effects model, in line with Meta-analysis of Observational Studies in Epidemiology guidelines. RESULTS: In total, 43 articles met our inclusion criteria. CKD prevalence was associated with several indicators of SES, particularly lower income (OR 1.34, 95% CI (1.18 to 1.53), P<0.001; I2=73.0%, P=0.05); lower education (OR 1.21, 95% CI (1.11 to 1.32), P<0.001; I2=45.20%, P=0.034); and lower combined SES (OR 2.18, 95% CI (1.64 to 2.89), P<0.001; I2=0.0%, P=0.326). Lower levels of income, occupation and combined SES were also significantly associated with progression to end-stage renal disease (risk ratio (RR) 1.24, 95% CI (1.12 to 1.37), P<0.001; I2=66.6%, P=0.006; RR 1.05, 95% CI (1.01 to 1.09), P=0.012; I2=0.0%, P=0.796; and RR 1.39, 95% CI (1.09 to 1.79), P=0.009; I2=74.2%, P=0.009). Subgroup analyses generally confirmed these results, except in a few cases, such as an inverse association related to particular socioeconomic backgrounds and where results were adjusted by more disease-related risk factors. CONCLUSION: Lower income was most closely associated with prevalence and progression of CKD, and lower education was significantly associated with its prevalence. Evidence for other indicators was inconclusive. PMID- 29437864 TI - Chronic kidney disease mortality trends in selected Central America countries, 1997-2013: clues to an epidemic of chronic interstitial nephritis of agricultural communities. AB - BACKGROUND: In Central America, chronic interstitial nephritis of agricultural communities (CINAC) has reached epidemic proportions. Clusters of cases have been described in several farming communities. Its aetiology remains uncertain and a controversy exists on its key triggers, among them the heat stress-dehydration mechanism and the toxic exposure to agrochemicals. METHODS: This study analysed the mortality pattern and trend of chronic kidney disease code N18 (CKD-N18) according to the International Statistical Classification of Diseases and Related Health Problems-10th Revision, the proxy and the underlying cause of death, in four selected Central American countries from 1997 to 2013. In addition, we used exponential regression to retrospectively model the likely onset and prior trajectory of the epidemic. RESULTS: Between 1997 and 2013, CKD-N18 mortality accounting 47 885 deaths (31% were female), 19 533 of which occurred below 60 years of age (26% female). The excess of mortality starts as early as 10-14 years of age for both boys and girls. El Salvador and Nicaragua, with mortality rates between 9-fold and 12-fold higher than reference countries, were the most affected. Statistical modelling suggests that the epidemic commenced around the mid-1970s, coinciding with important changes in modes of agricultural production. CONCLUSIONS: This study provides the most comprehensive mortality analysis of this epidemic published to date and confirms an excess of CKD-N18 mortality and its relation with the epidemic of CINAC. The overall trends and the mortality pattern among women, children and adolescents suggest that the heat stress dehydration hypothesis cannot fully explain this epidemic and that other environmental factors, more likely agricultural practices and agrochemicals, may be causally involved. PMID- 29437865 TI - Associations of dyslipidaemia and lipid-lowering treatment with risk of postoperative cognitive dysfunction: a systematic review and meta-analysis. AB - BACKGROUND: Lipid imbalance is linked to age-related cognitive impairment, but its role in postoperative cognitive dysfunction (POCD) is unknown. Here, we present a systematic review and meta-analysis on dyslipidaemia, lipid-lowering treatment and POCD risk. METHODS: PubMed, Ovid SP and Cochrane databases were searched for longitudinal studies that reported on associations of any measure of dyslipidaemia and/or lipid-lowering treatment with POCD as relative risks (RRs) or ORs. Fixed-effects inverse variance models were used to combine effects. RESULTS: Of 205 articles identified in the search, 17 studies on 2725 patients (grand mean age 67 years; mean age range 61-71 years) with follow-up periods of 1 day to 4 years (median 7 days; IQR 1-68 days) were included. Studies focused almost exclusively on hypercholesterolaemia as a measure of dyslipidaemia and on statins as lipid-lowering treatment. Across 12 studies on hypercholesterolaemia, we found no association with POCD risk (RR 0.93; 95% CI 0.80 to 1.08; P=0.34). Statin use before surgery was associated with a reduced POCD risk across eight studies (RR 0.81; 95% CI 0.67 to 0.98; P=0.03), but data on treatment duration were lacking. CONCLUSION: Statin users appear to be at reduced risk of POCD although hypercholesterolaemia per se may not be associated with POCD risk. Trial studies are needed to evaluate the usefulness of statins in POCD prevention. PMID- 29437866 TI - How to use sequence analysis for life course epidemiology? An example on HIV positive Sub-Saharan migrants in France. AB - BACKGROUND: Life course epidemiology is now an established field in social epidemiology; in sociodemography, the quantitative analysis of biographies recently experienced significant trend from event history analysis to sequence analysis. The purpose of this article is to introduce and adapt this methodology to a social epidemiology question, taking the example of the impact of HIV diagnosis on Sub-Saharan migrants' residential trajectories in the Paris region. METHODS: The sample consists of 640 migrants born in Sub-Saharan Africa receiving HIV care. They were interviewed in healthcare facilities in the Paris region within the PARCOURS project, conducted from 2012 to 2013, using life event history calendars, which recorded year by year their health, family and residential histories. We introduce a two-step methodological approach consisting of (1) sequence analysis by optimal matching to build a typology of migrants' residential pathways before and after diagnosis, and (2) a Cox model of the probability to experience changes in the residential situation. RESULTS: The seven-clusters typology shows that for a majority, the HIV diagnosis did not entail changes in residential situation. However 30% of the migrants experienced a change in their residential situation at time of diagnosis. The Cox model analysis reveals that this residential change was in fact moving in with one's partner (HR 2.99, P<0.000) rather than network rejection. CONCLUSION: This original combination of sequence analysis and Cox models is a powerful process that could be applied to other themes and constitutes a new approach in the life course epidemiology toolbox. TRIAL REGISTRATION NUMBER: NCT02566148. PMID- 29437867 TI - Evidence for genetic anticipation in vonHippel-Lindau syndrome. AB - BACKGROUND: von Hippel-Lindau (vHL) syndrome is a rare autosomal-dominant disorder that confers a lifelong risk for developing both benign and malignant tumours in multiple organs. Recent evidence suggests that vHL may exhibit genetic anticipation (GA). The aim of this study was to determine if GA occurs in vHL, and if telomere shortening may be a factor in GA. METHODS: A retrospective chart review of vHL families seen at The Hospital for Sick Children between 1984 and 2016 was performed. Age of onset (AOO, defined as the age of first physician diagnosed vHL-related manifestation) was confirmed for 96 patients from 20 unrelated families (80 clinically affected and 16 unaffected carriers). Flow FISH(flow cytometry sorting of cells whose telomeres are labeled by Fluorescence In Situ Hybridization) was used to measure mean telomere length of six white blood cell subtypes from 14 known VHL pathogenic variant carriers. RESULTS: The median AOO for generations I, II and III were 32.5, 22.5 and 12.0 years, respectively. The differences in the AOO between generations were highly significant using a Cox proportional hazards model (P=6.00*10-12). Telomere lengths were significantly different for granulocytes and natural killer lymphocytes of patients with vHL compared with age-matched controls. For six vHL parent-child pairs, median white blood cell telomere lengths between parent and child were not significantly different. CONCLUSIONS: Our results suggest that vHL telomere abnormalities may be primarily somatic in origin rather than a cause of GA. As tumour development exhibits GA in our cohort, vHL surveillance guidelines may need to account for a patient's generational position within a vHL pedigree. PMID- 29437868 TI - Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study. AB - BACKGROUND: Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. METHODS: In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. RESULTS: 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (+/-15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (beta: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. CONCLUSIONS: Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta. PMID- 29437871 TI - Gut microbiota modulate T cell trafficking into human colorectal cancer. AB - OBJECTIVE: Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers. DESIGN: Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing. RESULTS: CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival. CONCLUSIONS: Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues. PMID- 29437870 TI - CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity. AB - OBJECTIVE: Metabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) mouse models commonly exhibit strong steatosis in tumour cells as seen in human steatohepatitic HCC (SH-HCC), which may reflect a characteristic metabolic alteration. DESIGN: Non-tumour and HCC tissues obtained from diethylnitrosamine injected mice fed either a normal or a high-fat diet (HFD) were subjected to comprehensive metabolome analysis, and the significance of obesity-mediated metabolic alteration in hepatocarcinogenesis was evaluated. RESULTS: The extensive accumulation of acylcarnitine species was seen in HCC tissues and in the serum of HFD-fed mice. A similar increase was found in the serum of patients with NASH-HCC. The accumulation of acylcarnitine could be attributed to the downregulation of carnitine palmitoyltransferase 2 (CPT2), which was also seen in human SH-HCC. CPT2 downregulation induced the suppression of fatty acid beta oxidation, which would account for the steatotic changes in HCC. CPT2 knockdown in HCC cells resulted in their resistance to lipotoxicity by inhibiting the Src mediated JNK activation. Additionally, oleoylcarnitine enhanced sphere formation by HCC cells via STAT3 activation, suggesting that acylcarnitine accumulation was a surrogate marker of CPT2 downregulation and directly contributed to hepatocarcinogenesis. HFD feeding and carnitine supplementation synergistically enhanced HCC development accompanied by acylcarnitine accumulation in vivo. CONCLUSION: In obesity-driven and NASH-driven HCC, metabolic reprogramming mediated by the downregulation of CPT2 enables HCC cells to escape lipotoxicity and promotes hepatocarcinogenesis. PMID- 29437872 TI - Mathematical and Experimental Validation of Flux Dialysis Method: An Improved Approach to Measure Unbound Fraction for Compounds with High Protein Binding and Other Challenging Properties. AB - A flux dialysis method to measure unbound fraction (fu) of compounds with high protein binding and other challenging properties was tested and validated. This method is based on the principle that the initial flux rate of a compound through a size-excluding dialysis membrane is proportional to the product of the compound initial concentration, fu, and unbound dialysis membrane permeability (Pmem). Therefore, fu can be determined from the initial concentration and flux rate, assuming membrane Pmem is known. Compound initial flux rates for 14 compounds were determined by dialyzing human plasma containing compound (donor side) versus compound-free plasma (receiver side) and measuring the rate of compound appearance into the receiver side. Eleven compounds had known fu values obtained from conventional methods (ranging from 0.000013 to 0.22); three compounds (bedaquiline, lapatinib, and pibrentasvir) had previously qualified fu values (e.g., <0.001).Pmem estimated from flux rates and known fu values did not meaningfully differ among the compounds and were consistent with previously published values, indicating that Pmem is a constant for the dialysis membrane. This Pmem constant and the individual compound flux rates were used to calculate fu values. The flux dialysis fu values for the 11 compounds were in good agreement with their reported fu values (all within 2.5-fold; R2 = 0.980), confirming the validity of the method. Furthermore, the flux dialysis method allowed discrete fu to be estimated for the three compounds with previously qualified fu Theoretical and experimental advantages of the flux dialysis method over other dialysis-based protein binding methods are discussed. PMID- 29437873 TI - Brain Distribution of a Novel MEK Inhibitor E6201: Implications in the Treatment of Melanoma Brain Metastases. AB - Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and mitogen-activated protein/extracellular signal-regulated kinase (MEK) has been identified to be an important target. E6201 is a potent synthetic small-molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the blood-brain barrier on the central nervous system (CNS) exposure of E6201. In vitro studies utilizing transfected Madin-Darby canine kidney II (MDCKII) cells indicate that E6201 is not a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp). In vivo studies also suggest a minimal involvement of P-gp and Bcrp in E6201's brain distribution. The total concentrations in brain were higher than in plasma, resulting in a brain-to-plasma AUC ratio (Kp) of 2.66 in wild-type mice. The brain distribution was modestly enhanced in Mdr1a/b-/-, Bcrp1-/-, and Mdr1a/b-/ Bcrp1-/- knockout mice. The nonspecific binding of E6201 was higher in brain compared with plasma. However, free-drug concentrations in brain following 40 mg/kg intravenous dose reach levels that exceed reported in vitro half-maximal inhibitory concentration (IC50) values, suggesting that E6201 may be efficacious in inhibiting MEK-driven brain tumors. The brain distribution characteristics of E6201 make it an attractive targeted agent for clinical testing in MBM, glioblastoma, and other CNS tumors that may be effectively targeted with inhibition of MEK signaling. PMID- 29437874 TI - Comparison of Species and Cell-Type Differences in Fraction Unbound of Liver Tissues, Hepatocytes, and Cell Lines. AB - Fraction unbound (fu) of liver tissue, hepatocytes, and other cell types is an essential parameter used to estimate unbound liver drug concentration and intracellular free drug concentration. fu,liver and fu,cell are frequently measured in multiple species and cell types in drug discovery and development for various applications. A comparison study of 12 matrices for fu,liver and fu,cell of hepatocytes in five different species (mouse, rat, dog, monkey, and human), as well as fu,cell of Huh7 and human embryonic kidney 293 cell lines, was conducted for 22 structurally diverse compounds with the equilibrium dialysis method. Using an average bioequivalence approach, our results show that the average difference in binding to liver tissue, hepatocytes, or different cell types was within 2 fold of that of the rat fu,liver Therefore, we recommend using rat fu,liver as a surrogate for liver binding in other species and cell types in drug discovery. This strategy offers the potential to simplify binding studies and reduce cost, thereby enabling a more effective and practical determination of fu for liver tissues, hepatocytes, and other cell types. In addition, fu under hepatocyte stability incubation conditions should not be confused with fu,cell, as one is a diluted fu and the other is an undiluted fu Cell density also plays a critical role in the accurate measurement of fu,cell. PMID- 29437869 TI - Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine. AB - Immunotherapy strategies targeting immune checkpoints such as the CTLA4 and CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) T cell coreceptor pathways are revolutionising oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg, HLA genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine. PMID- 29437875 TI - Interindividual Differences in the Expression of ATP-Binding Cassette and Solute Carrier Family Transporters in Human Skin: DNA Methylation Regulates Transcriptional Activity of the Human ABCC3 Gene. AB - The identification of drug transporters expressed in human skin and interindividual differences in gene expression is important for understanding the role of drug transporters in human skin. In the present study, we evaluated the expression of ATP-binding cassette (ABC) and solute carrier (SLC) transporters using human skin tissues. In skin samples, ABCC3 was expressed at the highest levels, followed by SLCO3A1, SLC22A3, SLC16A7, ABCA2, ABCC1, and SLCO2B1. Among the quantitated transporters, ABCC3 accounted for 20.0% of the total mean transporter mRNA content. The expression of ABCC3 mRNA showed large interindividual variability (9.5-fold). None of the single nucleotide polymorphisms tested (-1767G>A, -1328G>A, -1213C>G, -897delC, -260T>A, and 211C>T) in the promoter region of the ABCC3 gene showed a significant change in ABCC3 mRNA levels. ABCC3 expression levels negatively correlated with the methylation status of the CpG island (CGI) located approximately 10 kilobase pairs upstream of ABCC3 (Rs: -0.323, P < 0.05). The reporter gene assay revealed a significant increase in transcriptional activity in the presence of CGI. ABCC3 mRNA was upregulated in HaCaT cells by the demethylating agent 5-aza-2' deoxycytidine. Furthermore, the deletion of the region surrounding CGI using the clustered regularly interspaced short palindromic repeat/Cas9 system resulted in significantly lower ABCC3 mRNA levels than those in control clones in HaCaT cells. Herein, we demonstrated large interindividual differences in the expression of drug transporters in human skin. CGI may function as an enhancer of the transcription of ABCC3, and methylation levels in CGI contribute to the variability of ABCC3 expression in human skin. PMID- 29437876 TI - Subarachnoid gadolinium following angiography-induced cortical blindness [corrected]. PMID- 29437877 TI - How many people have been bitten by dogs? A cross-sectional survey of prevalence, incidence and factors associated with dog bites in a UK community. AB - BACKGROUND: Dog bite studies are typically based on hospital records and may be biased towards bites requiring significant medical treatment. This study investigated true dog bite prevalence and incidence at a community-level and victim-related risk factors, in order to inform policy and prevention. METHODS: A cross-sectional study of a community of 1280 households in Cheshire, UK, surveyed 694 respondents in 385 households. Data included dog ownership and bite history, demographics, health and personality (Ten Item Personality Inventory (TIPI) brief measure). Multivariable logistic regression modelled risk factors for having ever been bitten by a dog, accounting for clustering of individuals within households. RESULTS: A quarter of participants (24.78%, 95% CI 21.72 to 28.13) reported having ever been bitten by a dog during their lifetime, with only a third of bites described requiring further medical treatment and 0.6% hospital admission. Incidence of dog bites was 18.7 (11.0-31.8) per 1000 population per year. Males were 1.81 times more likely to have been bitten in their lifetime than females (95% CI 1.20 to 2.72, P=0.005). Current owners of multiple dogs were 3.3 times more likely (95% CI 1.13 to 9.69, P=0.03) to report having been bitten than people not currently owning a dog. Regarding all bites described, most commonly people were bitten by a dog that they had never met before the incident (54.7%). Individuals scoring higher in emotional stability had a lower risk of having ever been bitten (OR=0.77 for 1 point change in scale between 1 and 7, 95% CI 0.66 to 0.9, P=0.001). CONCLUSION: This study suggests that the real burden of dog bites is considerably larger than those estimated from hospital records. Further, many bites do not require medical treatment and hospital-based bite data are not representative of bites within the wider population. Victim personality requires further investigation and potential consideration in the design of bite prevention schemes. PMID- 29437878 TI - Essential Role of Polo-like Kinase 1 (Plk1) Oncogene in Tumor Growth and Metastasis of Tamoxifen-Resistant Breast Cancer. AB - The most common therapy for estrogen receptor-positive breast cancer is antihormone therapy, such as tamoxifen. However, acquisition of resistance to tamoxifen in one third of patients presents a serious clinical problem. Polo-like kinase 1 (Plk1) is a key oncogenic regulator of completion of G2-M phase of the cell cycle. We assessed Plk1 expression in five chemoresistant cancer cell types and found that Plk1 and its downstream phosphatase Cdc25c were selectively overexpressed in tamoxifen-resistant MCF-7 (TAMR-MCF-7) breast cancer cells. Real time monitoring of cell proliferation also showed that TAMR-MCF-7 cells were more sensitive to inhibition of cell proliferation by the ATP-competitive Plk1 inhibitor BI2536 than were the parent MCF-7 cells. Moreover, BI2536 suppressed expression of epithelial-mesenchymal transition marker proteins and 3D spheroid formation in TAMR-MCF-7 cells. Using TAMR-MCF-7 cell-implanted xenograft and spleen-liver metastasis models, we showed that BI2536 inhibited tumor growth and metastasis in vivo Our results suggest that Plk1 could be a novel target for the treatment of tamoxifen-resistant breast cancer. Mol Cancer Ther; 17(4); 825-37. (c)2018 AACR. PMID- 29437879 TI - Characterizing the Potency and Impact of Carbon Ion Therapy in a Primary Mouse Model of Soft Tissue Sarcoma. AB - Carbon ion therapy (CIT) offers several potential advantages for treating cancers compared with X-ray and proton radiotherapy, including increased biological efficacy and more conformal dosimetry. However, CIT potency has not been characterized in primary tumor animal models. Here, we calculate the relative biological effectiveness (RBE) of carbon ions compared with X-rays in an autochthonous mouse model of soft tissue sarcoma. We used Cre/loxP technology to generate primary sarcomas in KrasLSL-G12D/+; p53fl/fl mice. Primary tumors were irradiated with a single fraction of carbon ions (10 Gy), X-rays (20 Gy, 25 Gy, or 30 Gy), or observed as controls. The RBE was calculated by determining the dose of X-rays that resulted in similar time to posttreatment tumor volume quintupling and exponential growth rate as 10 Gy carbon ions. The median tumor volume quintupling time and exponential growth rate of sarcomas treated with 10 Gy carbon ions and 30 Gy X-rays were similar: 27.3 and 28.1 days and 0.060 and 0.059 mm3/day, respectively. Tumors treated with lower doses of X-rays had faster regrowth. Thus, the RBE of carbon ions in this primary tumor model is 3. When isoeffective treatments of carbon ions and X-rays were compared, we observed significant differences in tumor growth kinetics, proliferative indices, and immune infiltrates. We found that carbon ions were three times as potent as X rays in this aggressive tumor model and identified unanticipated differences in radiation response that may have clinical implications. Mol Cancer Ther; 17(4); 858-68. (c)2018 AACR. PMID- 29437881 TI - Curcumin exerts a protective effect against premature ovarian failure in mice. AB - This study was designed to investigate the protective effect of curcumin against d-galactose (d-gal)-induced premature ovarian failure (POF) in mice. A mouse POF model was induced by subcutaneous injection of d-gal (200 mg/kg/day) daily for 42 days. Mice in the curcumin group received both d-gal treatment and intraperitoneal injection of curcumin (100 mg/kg/day) for 42 days. Ovarian function, oxidative stress and apoptosis were evaluated. The P, E2 and SOD levels were higher, and the FSH, LH and MDA levels were significantly lower in the curcumin group than those in the d-gal group. The proportion of primordial follicles was also significantly higher in the curcumin group than that in the d gal group. In addition, curcumin treatment after d-gal administration resulted in significantly lower Sod2, Cat, 8-OhdG, 4-HNE, NTY and senescence-associated protein P16 expression levels, higher Amh expression levels and less apoptosis in granulosa cells than was observed in the d-gal group. Moreover, the p-Akt, Nrf2 and HO-1 protein expression levels were significantly higher and the apoptosis related cleaved caspase-3 and -9 protein expression levels were markedly lower in the curcumin group than in the d-gal group. In conclusion, curcumin effectively inhibited d-gal-induced oxidative stress, apoptosis and ovarian injury via a mechanism involving the Nrf2/HO-1 and PI3K/Akt signaling pathways, suggesting that curcumin is a potential protective agent against POF. PMID- 29437882 TI - Decidual cell regulation of trophoblast is altered in pregnancies at risk of pre eclampsia. AB - Successful implantation and placentation are dependent on the interaction between decidual stromal cells (DSC) and extravillous trophoblast (EVT) cells. The extent of trophoblast invasion relies on communication between the placenta and maternal decidua. The cyclical process of decidualisation induces a transformation of endometrial fibroblasts to secretory DSC; these secreted products have many functions including the control of trophoblast invasion. Inadequate trophoblast invasion and remodelling of the uterine vessels (the spiral arteries) are associated with pregnancy disorders such as pre-eclampsia. Uterine artery Doppler resistance index (RI) in the first trimester of pregnancy can be used as a proxy measure of remodelling. DSC were isolated from pregnancies with normal (normal RI) or impaired (high RI) spiral artery remodelling. Following isolation, DSC were re-decidualised using cAMP and MPA and secretion of the decidualisation markers IGFBP-1 and prolactin assessed. We examined the impact of DSC-secreted factors on trophoblast cell function, using the EVT cell line SGHPL-4. We demonstrated that DSC exposed to decidual factors were able to re-decidualise in vitro and that the chemoattraction of trophoblasts by DSC is impaired in pregnancies with high RI. This study provides new insights into the role that DSC play in regulating EVT functions during the first trimester of pregnancy. This is the first study to demonstrate that DSC from pregnancies with impaired vascular remodelling in the first trimester secrete factors that inhibit the directional movement of trophoblast cells. This finding may be important in understanding aberrant trophoblast invasion in pregnancies where vascular remodelling is impaired. PMID- 29437884 TI - Beckwith-Wiedemann Syndrome: Partnership in the Diagnostic Journey of a Rare Disorder. PMID- 29437883 TI - Cerebrospinal Fluid Reference Values for Young Infants Undergoing Lumbar Puncture. AB - OBJECTIVES: To determine age-specific reference values and quantify age-related changes for cerebrospinal fluid (CSF) white blood cell (WBC) counts and protein and glucose concentrations in infants <=60 days of age. METHODS: This multicenter, cross-sectional study included infants <=60 days old with CSF cultures and complete CSF profiles obtained within 24 hours of presentation. Those with conditions suspected or known to cause abnormal CSF parameters (eg, meningitis) and those with a hospital length of stay of >72 hours were excluded. Reference standards were determined for infants <=28 days of age and 29 to 60 days of age by using the third quartile +1.5 interquartile range for WBC and protein and the first quartile -1.5 interquartile range for glucose. CSF parameter centile curves based on age were calculated by using the LMST method. RESULTS: A total of 7766 patients were included. CSF WBC counts were higher in infants <=28 days of age (upper bound: 15 cells/mm3) than in infants 29 to 60 days of age (upper bound: 9 cells/mm3; P < .001). CSF protein concentrations were higher in infants <=28 days of age (upper bound: 127 mg/dL) than in infants 29 to 60 days of age (upper bound: 99 mg/dL; P < .001). CSF glucose concentrations were lower in infants <=28 days of age (lower bound: 25 mg/dL) than in infants 29 to 60 days of age (lower bound: 27 mg/dL; P < .001). CONCLUSIONS: The age-specific CSF WBC count, protein concentration, and glucose concentration reference values identified in this large, multicenter cohort of infants can be used to interpret the results of lumbar puncture in infants <=60 days of age. PMID- 29437885 TI - Association of different antiplatelet therapies with mortality after primary percutaneous coronary intervention. AB - OBJECTIVES: Prasugrel and ticagrelor both reduce ischaemic endpoints in high-risk acute coronary syndromes, compared with clopidogrel. However, comparative outcomes of these two newer drugs in the context of primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) remains unclear. We sought to examine this question using the British Cardiovascular Interventional Society national database in patients undergoing primary PCI for STEMI. METHODS: Data from January 2007 to December 2014 were used to compare use of P2Y12 antiplatelet drugs in primary PCI in >89 000 patients. Statistical modelling, involving propensity matching, multivariate logistic regression (MLR) and proportional hazards modelling, was used to study the association of different antiplatelet drug use with all-cause mortality. RESULTS: In our main MLR analysis, prasugrel was associated with significantly lower mortality than clopidogrel at both 30 days (OR 0.87, 95% CI 0.78 to 0.97, P=0.014) and 1 year (OR 0.89, 95% CI 0.82 to 0.97, P=0.011) post PCI. Ticagrelor was not associated with any significant differences in mortality compared with clopidogrel at either 30 days (OR 1.07, 95% CI 0.95 to 1.21, P=0.237) or 1 year (OR 1.058, 95% CI 0.96 to 1.16, P=0.247). Finally, ticagrelor was associated with significantly higher mortality than prasugrel at both time points (30 days OR 1.22, 95% CI 1.03 to 1.44, P=0.020; 1 year OR 1.19 95% CI 1.04 to 1.35, P=0.01). CONCLUSIONS: In a cohort of over 89 000 patients undergoing primary PCI for STEMI in the UK, prasugrel is associated with a lower 30-day and 1-year mortality than clopidogrel and ticagrelor. Given that an adequately powered comparative randomised trial is unlikely to be performed, these data may have implications for routine care. PMID- 29437880 TI - Molecular regulation of follicle-stimulating hormone synthesis, secretion and action. AB - Follicle-stimulating hormone (FSH) plays fundamental roles in male and female fertility. FSH is a heterodimeric glycoprotein expressed by gonadotrophs in the anterior pituitary. The hormone-specific FSHbeta-subunit is non-covalently associated with the common alpha-subunit that is also present in the luteinizing hormone (LH), another gonadotrophic hormone secreted by gonadotrophs and thyroid stimulating hormone (TSH) secreted by thyrotrophs. Several decades of research led to the purification, structural characterization and physiological regulation of FSH in a variety of species including humans. With the advent of molecular tools, availability of immortalized gonadotroph cell lines and genetically modified mouse models, our knowledge on molecular mechanisms of FSH regulation has tremendously expanded. Several key players that regulate FSH synthesis, sorting, secretion and action in gonads and extragonadal tissues have been identified in a physiological setting. Novel post-transcriptional and post translational regulatory mechanisms have also been identified that provide additional layers of regulation mediating FSH homeostasis. Recombinant human FSH analogs hold promise for a variety of clinical applications, whereas blocking antibodies against FSH may prove efficacious for preventing age-dependent bone loss and adiposity. It is anticipated that several exciting new discoveries uncovering all aspects of FSH biology will soon be forthcoming. PMID- 29437886 TI - Secondary mitral regurgitation (part 2): deliberations on mitral surgery and transcatheter repair. AB - Secondary mitral regurgitation (MR) develops as a consequence of postinfarction remodelling of the ventricle or other causes of left ventricular (LV) dilatation and dysfunction. The presence of MR amplifies the poor prognosis of the failing ventricle, but it has not been established whether the adverse outcomes stem from the MR or whether the MR is simply a marker of progressive LV dysfunction. In this article, an attempt will be made to clarify the clinical impact of mitral surgery and transcatheter repair in patients with secondary MR. Observational studies indicate symptomatic improvement, but the results of randomised trials are mixed. Furthermore, neither mitral surgery nor transcatheter repair consistently leads to reversal of the adverse LV remodelling. There is, however, general agreement that these procedures do not have a salutary effect on survival. Certainly mitral surgery and transcatheter repair can substantially reduce the mitral regurgitant flow, but inconsistencies and uncertainties regarding clinical outcomes persist in the published literature. Some such problems could be resolved by utilisation of more accurate and reproducible imaging modalities in randomised studies of patients who are most likely to benefit from a reduction in the regurgitant volume-namely those with the most severe MR. PMID- 29437887 TI - Preventing stroke in patients with heart failure: why are patients losing out? PMID- 29437888 TI - Changing the Game for Hand Hygiene Conversations. PMID- 29437889 TI - Roles of prefrontal cortex and mediodorsal thalamus in task engagement and behavioral flexibility. AB - Behavioral tasks involving auditory cues activate inhibitory neurons within auditory cortex, leading to a reduction in the amplitude of auditory evoked response potentials (ERPs). One hypothesis is that this process -- termed 'task engagement'- may enable context-dependent behaviors. Here we set out to determine 1) whether the medial prefrontal cortex (mPFC) plays a role in task engagement, and 2) how task engagement relates to the context-dependent processing of auditory cues in male and female mice performing a decision making task that can be guided by either auditory or visual cues. We found that, in addition to auditory ERP suppression, task-engagement is associated with increased mPFC activity and an increase in theta band (4-7 Hz) synchronization between the mPFC and auditory cortex. Optogenetically inhibiting the mPFC eliminates the task engagement-induced auditory ERP suppression, while also preventing mice from switching between auditory and visual cue-based rules. However, mPFC inhibition, which eliminates task engagement-induced auditory ERP suppression, did not prevent mice from making decisions based on auditory cues. Furthermore, a more specific manipulation - selective disruption of mPFC outputs to the mediodorsal (MD) thalamus - is sufficient to prevent switching between auditory and visual rules, but does not affect auditory ERPs. Based on these findings we conclude that: (1) the mPFC contributes to both task engagement and behavioral flexibility; (2) mPFC-MD projections are important for behavioral flexibility but not task engagement; (3) task engagement, evidenced by the suppression of cortical responses to sensory input, is not required for sensory-cue guided decision making.SIGNIFICANCE STATEMENTWhen rodents perform choice-selection tasks based on sensory cues, neural responses to these cues are modulated as compared to task-free conditions. Here we demonstrate that this phenomenon depends on the prefrontal cortex, and thus represents a form of "top-down" regulation. However, we also show that this phenomenon is not critical for task performance, as rodents can make decisions based on specific sensory cues even when the task dependent modulation of responses to those cues is abolished. Furthermore, disrupting one specific set of prefrontal outputs impairs rule switching but not the task-dependent modulation of sensory responses. These results show that the prefrontal cortex comprises multiple circuits that mediate dissociable functions related to behavioral flexibility and sensory processing. PMID- 29437892 TI - Overlapping Role of SCYL1 and SCYL3 in Maintaining Motor Neuron Viability. AB - Members of the SCY1-like (SCYL) family of protein kinases are evolutionarily conserved and ubiquitously expressed proteins characterized by an N-terminal pseudokinase domain, centrally located HEAT repeats, and an overall disorganized C-terminal segment. In mammals, 3 family members encoded by genes Scyl1, Scyl2, and Scyl3 have been described. Studies have pointed to a role for SCYL1 and SCYL2 in regulating neuronal function and viability in mice and humans, but little is known about the biological function of SCYL3. Here, we show that the biochemical and cell biological properties of SCYL3 are similar to those of SCYL1 and both proteins work in conjunction to maintain motor neuron viability. Specifically, although lack of Scyl3 in mice has no apparent effect on embryogenesis and postnatal life, it accelerates the onset of the motor neuron disorder caused by Scyl1 deficiency. Growth abnormalities, motor dysfunction, hindlimb paralysis, muscle wasting, neurogenic atrophy, motor neuron degeneration, and loss of large caliber axons in peripheral nerves occurred at an earlier age in Scyl1/Scyl3 double-deficient mice than in Scyl1-deficient mice. Disease onset also correlated with the mislocalization of TDP-43 in spinal motor neurons, suggesting that SCYL1 and SCYL3 regulate TDP-43 proteostasis. Together, our results demonstrate an overlapping role for SCYL1 and SCYL3 in vivo and highlight the importance the SCYL family of proteins in regulating neuronal function and survival. Only male mice were used in this study.SIGNIFICANCE STATEMENTSCYL1 and SCYL2, members of the SCY1-like family of pseudokinases, have well-established roles in neuronal function. Herein, we uncover the role of SCYL3 in maintaining motor neuron viability. Although targeted disruption of Scyl3 in mice had little or no effect on embryonic development and postnatal life, it accelerated disease onset associated with the loss of Scyl1, a novel motor neuron disease gene in humans. Scyl1 and Scyl3 double-deficient mice had neuronal defects characteristic of amyotrophic lateral sclerosis, including TDP-43 pathology, at an earlier age than did Scyl1-deficient mice. Thus, we show that SCYL1 and SCYL3 play overlapping roles in maintaining motor neuronal viability in vivo and confirm that SCYL family members are critical regulators of neuronal function and survival. PMID- 29437891 TI - Abstract memory representations in the ventromedial prefrontal cortex and hippocampus support concept generalization. AB - Memory function involves both the ability to remember details of individual experiences and the ability to link information across events to create new knowledge. Prior research has identified the ventromedial prefrontal cortex (VMPFC) and the hippocampus as important for integrating across events in service of generalization in episodic memory. The degree to which these memory integration mechanisms contribute to other forms of generalization, such as concept learning, is unclear. The present study used a concept-learning task in humans (both sexes) coupled with model-based fMRI to test whether VMPFC and hippocampus contribute to concept generalization, and whether they do so by maintaining specific category exemplars or abstract category representations. Two formal categorization models were fit to individual subject data: a prototype model that posits abstract category representations and an exemplar model that posits category representations based on individual category members. Latent variables from each of these models were entered into neuroimaging analyses to determine whether VMPFC and the hippocampus track prototype or exemplar information during concept generalization. Behavioral model fits indicated that almost three quarters of the subjects relied on prototype information when making judgments about new category members. Paralleling prototype dominance in behavior, correlates of the prototype model were identified in VMPFC and the anterior hippocampus with no significant exemplar correlates. These results indicate that the VMPFC and portions of the hippocampus play a broad role in memory generalization and that they do so by representing abstract information integrated from multiple events.SIGNIFICANCE STATEMENTWhether people represent concepts as a set of individual category members or by deriving generalized concept representations abstracted across exemplars has been debated. In episodic memory, generalized memory representations have been shown to arise through integration across events supported by the ventromedial prefrontal cortex (VMPFC) and hippocampus. The current study combined formal categorization models with fMRI data analysis to show that the VMPFC and anterior hippocampus represent abstract prototype information during concept generalization, contributing novel evidence of generalized concept representations in the brain. Results indicate that VMPFC-hippocampal memory integration mechanisms contribute to knowledge generalization across multiple cognitive domains, with the degree of abstraction of memory representations varying along the long axis of the hippocampus. PMID- 29437890 TI - Brain transcriptome databases: a user's guide. AB - Transcriptional programs instruct the generation and maintenance of diverse subtypes of neural cells, establishment of distinct brain regions, formation and function of neural circuits, and ultimately behavior. Spatiotemporal and cell type-specific analyses of the transcriptome, the sum total of all RNA transcripts in a cell or an organ, can provide insights into the role of genes in brain development and function, and their potential contribution to disorders of the brain. In the previous decade, advances in sequencing technology and funding from the National Institutes of Health and private foundations for large-scale genomics projects have led to a growing collection of brain transcriptome databases. These valuable resources provide rich and high-quality datasets with spatiotemporal, cell type-specific, and single-cell precision. Most importantly, many of these databases are publicly available via user-friendly web interface, making the information accessible to individual scientists without the need for advanced computational expertise. Here, we highlight key publicly available brain transcriptome databases, summarize the tissue sources and methods used to generate the data, and discuss their utility for neuroscience research. PMID- 29437893 TI - Selective Mineralocorticoid Receptor Cofactor Modulation as Molecular Basis for Finerenone's Antifibrotic Activity. AB - Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in chronic heart failure. Novel nonsteroidal MRAs are currently developed and need to be pharmacologically characterized in comparison to classical steroidal MRAs. A mouse model of cardiac fibrosis induced by short-term isoproterenol injection was used to compare the nonsteroidal MRA finerenone and the steroidal MRA eplerenone in equi-efficient systemic MR blocking dosages. Molecular mechanisms were studied in MR-expressing H9C2/MR+ cardiomyocytes and in MR transcriptional cofactor binding assays. Both MRAs significantly inhibited an isoproterenol mediated increase of left ventricular mass. Isoproterenol-induced cardiac fibrosis and macrophage invasion were potently blocked by finerenone, whereas eplerenone had no significant effect. Speckle tracking echocardiography revealed a significant improvement of global longitudinal peak strain by finerenone, an effect less prominent with eplerenone. Antifibrotic actions of finerenone were accompanied by a significant inhibition of profibrotic cardiac TNX (tenascin-X) expression, a regulation absent with eplerenone. Finally, we show a higher potency/efficacy and inverse agonism of finerenone versus eplerenone in MR transcriptional cofactor binding assays indicating differential MR cofactor modulation by steroidal and nonsteroidal MRAs. This study demonstrates that the nonsteroidal MRA finerenone potently prevents cardiac fibrosis and improves strain parameters in mice. Cardiac antifibrotic actions of finerenone may result from the inhibition of profibrotic TNX gene expression mediated by differential MR cofactor binding. Selective MR cofactor modulation provides a molecular basis for distinct (pre)-clinical actions of nonsteroidal and steroidal MRAs. PMID- 29437894 TI - Genetic Susceptibility to Hypertension-Induced Renal Injury. PMID- 29437895 TI - Blood Pressure Profile 1 Year After Severe Preeclampsia. AB - Preeclampsia increases the long-term risk of cardiovascular disease, possibly through occurrence of hypertension after delivery, such as masked hypertension, night-time hypertension, and an adverse systolic night-to-day blood pressure (BP) ratio. These types of hypertension are often unnoticed and can only be detected with ambulatory BP monitoring (ABPM). We aimed to determine hypertension prevalence and 24-hour BP pattern with ABPM and office BP measurements in women 1 year after severe preeclampsia. This is a retrospective cohort study. As part of a follow-up program after severe preeclampsia, 200 women underwent ABPM and an office BP measurement 1 year after delivery. We calculated hypertension prevalence (sustained hypertension, masked hypertension, and white-coat hypertension) and systolic night-to-day BP ratio (dipping pattern). Medical files and questionnaires provided information on preexisting hypertension and antihypertensive treatment. One year after delivery, 41.5% of women had hypertension (sustained hypertension, masked hypertension, or white-coat hypertension) with ABPM. Masked hypertension was most common (17.5%), followed by sustained hypertension (14.5%) and white-coat hypertension (9.5%). With sheer office BP measurement, only 24.0% of women would have been diagnosed hypertensive. Forty-six percent of women had a disadvantageous dipping pattern. Hypertension is common 1 year after experiencing severe preeclampsia. Masked hypertension and white-coat hypertension are risk factors for future cardiovascular disease and can only be diagnosed with ABPM. Therefore, ABPM should be offered to all these women at high risk of developing hypertension and possibly future cardiovascular disease. PMID- 29437897 TI - TLR9 (Toll-Like Receptor 9) Agonist Suppresses Angiogenesis by Differentially Regulating VEGFA (Vascular Endothelial Growth Factor A) and sFLT1 (Soluble Vascular Endothelial Growth Factor Receptor 1) in Preeclampsia. AB - Preeclampsia is a common pregnancy-specific disorder characterized by elevated blood pressure and proteinuria. Activation of the maternal immune system and impaired placental angiogenesis are thought to contribute to the pathogenesis of preeclampsia. TLR9 (Toll-like receptor 9) plays a role in innate immunity, defending the organism against infection. The purpose of this study was to determine whether TLR9 inhibits angiogenesis at the fetomaternal interface under conditions of preeclampsia. We confirmed the downregulation of VEGFA (vascular endothelial growth factor A) and upregulation of TLR9 and sFLT1 (soluble vascular endothelial growth factor receptor 1) in placentas from preeclamptic women. Then, we established a mouse model with preeclampsia-like symptoms using the synthetic TLR9 agonist CpG (cytidine-phosphate-guanosine)-ODN (oligodeoxynucleotide; ODN1826). We observed the downregulation of VEGFA and the upregulation of sFLT1 in placentas from the preeclampsia-like animal model and in trophoblasts treated with CpG-ODN (ODN2006). In addition, silencing TLR9 promoted the migration and invasion of HTR8/SVneo cells. In conclusion, TLR9 is capable of robustly suppressing angiogenesis by differentially regulating the expression of VEGFA and sFLT1 at the fetomaternal interface, potentially contributing to the development of preeclampsia. PMID- 29437896 TI - Susceptibility to Hypertensive Renal Disease in the Spontaneously Hypertensive Rat Is Influenced by 2 Loci Affecting Blood Pressure and Immunoglobulin Repertoire. AB - High blood pressure exerts its deleterious effects on health largely through acceleration of end-organ diseases. Among these, progressive loss of renal function is particularly important, not only for the direct consequences of kidney damage but also because loss of renal function is associated with amplification of other adverse cardiovascular outcomes. Genetic susceptibility to hypertension and associated end-organ disease is non-Mendelian in both humans and in a rodent model, the spontaneously hypertensive rat (SHR). Here, we report that hypertensive end-organ disease in the inbred SHR-A3 line is attributable to genetic variation in the immunoglobulin heavy chain on chromosome 6. This variation coexists with variation in a 10 Mb block on chromosome 17 that contains genetic variation in 2 genes involved in immunoglobulin Fc receptor signaling. Substitution of these genomic regions into the SHR-A3 genome from the closely related, but injury-resistant, SHR-B2 line normalizes both biomarker and histological measures of renal injury. Our findings indicate that genetic variation leads to a contribution by immune mechanisms hypertensive end-organ injury and that, in this rat model, disease is influenced by differences in germ line antibody repertoire. PMID- 29437898 TI - Should Maternal Hemodynamics Guide Antihypertensive Therapy in Preeclampsia? PMID- 29437899 TI - Prognostic value and clinicopathological significance of serum- and tissue-based cytokeratin 18 express level in breast cancer: a meta-analysis. AB - Cytokeratin 18 (CK18), a type I cytokeratin of the intermediate filament family, has been associated with the prognosis of cancer patients for decades. However, its exact role in predicting the clinical outcome of breast cancer remains controversial. To comprehensively investigated the prognostic value of CK18 in breast cancer, a systematically meta-analysis was conducted to explore the association between CK18 expression and overall survival. Literature collection was conducted by retrieving electronic databases Pubmed, Cochrane Library, Web of Science, EMBASE, and OVID completely (up to January 1, 2017). Nine relevant studies with 4857 cases assessing the relationship between CK18 high expression and the outcome of breast cancer patients were enrolled in our analysis. The results indicated that the high level of CK18 expression was significantly associated with overall survival of breast cancer patients via a specimen depended manner. Reports which used serum to detect the expression of CK18 predicted a poor outcome of breast cancer (HR = 1.24, 95%CI: 1.11-1.38, P<0.0001), while studies which used tissue as specimen indicated a reverse result (HR = 0.71, 95%CI: 0.60-0.84, P<0.00001). Moreover, overexpression of CK18 was highly relevant to advanced clinicopathological parameters of breast cancer, such as progesterone receptor, human epidermal growth factor receptor-2, tumor size, tumor stage, nodal status, and tumor grade. Taken together, the present study demonstrated that CK18 might be served as a novel biomarker to predict clinicopathological features and the outcome of breast cancer. PMID- 29437900 TI - Identification of a Novel Mutation in the ABCA4 Gene in a Chinese Family with Retinitis Pigmentosa Using Exome Sequencing. AB - Retinitis pigmentosa (RP) is a group of hereditary, degenerative retinal disorders characterized by progressive retinal dysfunction, outer retina cell loss, and retinal tissue atrophy. It eventually leads to tunnel vision and legal, or total blindness. Here we aimed to reveal the causal gene and mutation contributing to the development of autosomal recessive RP (arRP) in a consanguineous family. A novel homozygous mutation, c.4845delT (p.K1616Rfs*46), in the ATP-binding cassette subfamily A member 4gene ( ABCA4 ) was identified. It may reduce ABCA4 protein activity, leading to progressive degeneration of both rod and cone photoreceptors. The study extends the arRP genotypic spectrum and confirms a genotype-phenotype relationship. This study may also disclose some new clues for RP genetic causes and pathogenesis, as well as clinical and genetic diagnosis. The research findings may contribute to improvement in clinical care, therapy, genetic screening, and counseling. PMID- 29437901 TI - Vitamin D deficiency in relation to the poor functional outcomes in nondiabetic patients with ischemic stroke. AB - To assess the hypothesis that vitamin D, reflected by 25-hydroxyvitamin D (25(OH) D) would be associated with higher risk of poor functional outcomes amongst nondiabetic stroke patients. The present study was conducted in Nanchang, China. Serum concentration of 25(OH) D and National Institutes of Health Stroke Scale (NIHSS) were measured at the time of admission. Functional outcome was measured by modified Rankin scale (mRS) at 1 year after admission. Multivariate analyses were performed using logistic regression models. The cut point of 25(OH) D level for vitamin D deficiency was 20 ng/ml. In the present study, 266 nondiabetic subjects with stroke were included; 149 out of the 266 patients were defined as vitamin D deficiency (56%). The poor outcome distribution across the 25(OH) D quartiles ranged between 64% (first quartile) and 13% (fourth quartile). In those 149 patients with vitamin D deficiency, 75 patients were defined as poor functional outcomes, giving a prevalence rate of 50% (95% confidence interval (CI): 42-58%). In multivariate analysis models, for vitamin D deficiency, the adjusted risk of poor functional outcomes and mortality increased by 220% (odds ratio (OR): 3.2; 95% CI: 1.7-4.2, P<0.001) and 290% (OR: 3.9; 95% CI: 2.1-5.8, P<0.001), respectively. Vitamin D deficiency is associated with an increased risk of poor functional outcome events in Chinese nondiabetic stroke individuals. PMID- 29437902 TI - Maternal resveratrol consumption and its programming effects on metabolic health in offspring mechanisms and potential implications. AB - A growing body of evidence has clearly demonstrated that maternal nutrition can strongly determine the susceptibility to the development of metabolic diseases in offspring. With the increasing prevalence of maternal overweight, obesity, and gestational diabetes mellitus, it yields enormous burden for individual and public health. Interventions during pregnancy have been proven to be challenging, with limited efficacy and low compliance. Resveratrol, as a natural polyphenolic compound, has a wide-range of beneficial properties, including potent antiobesogenic, antiatherosclerotic, and antidiabetic effects. However, the role of maternal resveratrol intake on metabolic health in offspring has not been extensively investigated. Therefore, the aim of this study was to review the effects of maternal resveratrol supplementation on metabolic health in offspring and its potential mechanisms. PMID- 29437903 TI - Bioinformatics analysis of microRNAs related to blood stasis syndrome in diabetes mellitus patients. AB - In traditional Chinese medicine (TCM), blood stasis syndrome (BSS) is mainly manifested by the increase of blood viscosity, platelet adhesion rate and aggregation, and the change of microcirculation, resulting in vascular endothelial injury. It is an important factor in the development of diabetes mellitus (DM). The aim of the present study was to screen out the potential candidate microRNAs (miRNAs) in DM patients with BSS by high-throughput sequencing (HTS) and bioinformatics analysis. Human umbilical vein endothelial cells (HUVECs) were incubated with 10% human serum to establish models of DM with BSS, DM without BSS (NBS), and normal control (NC). Total RNA of each sample was extracted and sequenced by the Hiseq2000 platform. Differentially expressed miRNAs (DE-miRNAs) were screened between samples and compared with known changes in mRNA abundance. Target genes of miRNAs were predicted by softwares. Gene Ontology (GO) and pathway enrichment analysis of the target genes were conducted. According to the significantly enriched GO annotations and pathways (P-value <= 0.001), we selected the key miRNAs of DM with BSS. It showed that the number of DE-miRNAs in BSS was 32 compared with non-blood stasis syndrome (NBS) and NC. The potential candidate miRNAs were chosen from GO annotations in which target genes were significantly enriched (-log10 (P-value) > 5), which included miR-140-5p, miR-210, miR-362-5p, miR-590-3p, and miR-671-3p. The present study screened out the potential candidate miRNAs in DM patients with BSS by HTS and bioinformatics analysis. The miRNAs will be helpful to provide valuable suggestions on clinical studies of DM with BSS at the gene level. PMID- 29437904 TI - A computational study for rational HIV-1 non-nucleoside reverse transcriptase inhibitor selection and the discovery of novel allosteric pockets for inhibitor design. AB - HIV drug resistant mutations that render the current Highly Active Anti Retroviral Therapy (HAART) cocktail drugs ineffective are increasingly reported. To study the mechanisms of these mutations in conferring drug resistance, we computationally analyzed 14 reverse transcriptase (RT) structures of HIV-1 on the following parameters: drug-binding pocket volume, allosteric effects caused by the mutations, and structural thermal stability. We constructed structural correlation-based networks of the mutant RT-drug complexes and the analyses support the use of efavirenz (EFZ) as the first-line drug, given that cross resistance is least likely to develop from EFZ-resistant mutations. On the other hand, rilpivirine (RPV)-resistant mutations showed the highest cross-resistance to the other non-nucleoside RT inhibitors. With significant drug cross-resistance associated with the known allosteric drug-binding site, there is a need to identify new allosteric druggable sites in the structure of RT. Through computational analyses, we found such a novel druggable pocket on the HIV-1 RT structure that is comparable with the original allosteric drug site, opening the possibility to the design of new inhibitors. PMID- 29437905 TI - The response of nucleus pulposus cell senescence to static and dynamic compressions in a disc organ culture. AB - Mechanical stimuli obviously affect disc nucleus pulposus (NP) biology. Previous studies have indicated that static compression exhibits detrimental effects on disc biology compared with dynamic compression. To study disc NP cell senescence under static compression and dynamic compression in a disc organ culture, porcine discs were cultured and subjected to compression (static compression: 0.4 MPa for 4 h once per day; dynamic compression: 0.4 MPa at a frequency of 1.0 Hz for 4 h once per day) for 7 days using a self-developed mechanically active bioreactor. The non-compressed discs were used as controls. Compared with the dynamic compression, static compression significantly promoted disc NP cell senescence, reflected by the increased senescence-associated beta-galactosidase (SA-beta-Gal) activity, senescence-associated heterochromatic foci (SAHF) formation and senescence markers expression, and the decreased telomerase (TE) activity and NP matrix biosynthesis. Static compression accelerates disc NP cell senescence compared with the dynamic compression in a disc organ culture. The present study provides that acceleration of NP cell senescence may be involved in previously reported static compression-mediated disc NP degenerative changes. PMID- 29437906 TI - Cardiac troponin for predicting all-cause mortality in patients with acute ischemic stroke: a meta-analysis. AB - Cardiac troponins are specific biomarkers of cardiac injury. However, the prognostic usefulness of cardiac troponin in patients with acute ischemic stroke is still controversial. The objective of this meta-analysis was to investigate the association of cardiac troponin elevation with all-cause mortality in patients with acute ischemic stroke. PubMed and Embase databases were searched for relevant studies up to April 31, 2017. All observational studies reporting an association of baseline cardiac troponin-T (cTnT) or troponin-I (cTnI) elevation with all-cause mortality risk in patients with acute ischemic stroke were included. Pooled adjusted risk ratio (RR) and corresponding 95% confidence interval (CI) were obtained using a random effect model. Twelve studies involving 7905 acute ischemic stroke patients met our inclusion criteria. From the overall pooled analysis, patients with elevated cardiac troponin were significantly associated with increased risk of all-cause mortality (RR: 2.53; 95% CI: 1.83 3.50). The prognostic value of cardiac troponin elevation on all-cause mortality risk was stronger (RR: 3.54; 95% CI: 2.09-5.98) during in-hospital stay. Further stratified analysis showed elevated cTnT (RR: 2.36; 95% CI: 1.47-3.77) and cTnI (RR: 2.79; 95% CI: 1.68-4.64) level conferred the similar prognostic value of all cause mortality. Acute ischemic stroke patients with elevated cTnT or cTnI at baseline independently predicted an increased risk of all-cause mortality. Determination of cardiac troponin on admission may aid in the early death risk stratification in these patients. PMID- 29437907 TI - Mitochondrial versus nuclear gene expression and membrane protein assembly: The case of subunit 2 of yeast cytochrome c oxidase. AB - Deletion of the yeast mitochondrial gene COX2, encoding subunit 2 (mtCox2) of cytochrome c oxidase (CcO), results in a respiratory-incompetent Deltacox2 strain. For a cytosol-synthesized Cox2 to restore respiratory growth, it must carry the W56R mutation (cCox2W56R). Nevertheless, only a fraction of cCox2W56R is matured in mitochondria, allowing ~60% steady-state accumulation of CcO. This can be attributed either to the point mutation or to an inefficient biogenesis of cCox2W56R We generated a strain expressing the mutant protein mtCox2W56R inside mitochondria which should follow the canonical biogenesis of mitochondria-encoded Cox2. This strain exhibited growth rates, CcO steady-state levels, and CcO activity similar to the wild-type; therefore the efficiency of Cox2 biogenesis is the limiting step for a successful allotopic expression. Upon co-expression of cCox2W56R and mtCox2, each protein assembled into CcO independently from its genetic origin resulting in a mixed population of CcO with most complexes containing the mtCox2 version. Notably, the presence of the mtCox2 enhances cCox2W56R incorporation. We provide proof of principle that an allotopically expressed Cox2 may complement a phenotype due to a mutant mitochondrial COX2 gene. These results are relevant to develop a rational design of genes for allotopic expression intended to treat human mitochondrial diseases. PMID- 29437908 TI - A Quality-Improvement Initiative to Reduce NICU Transfers for Neonates at Risk for Hypoglycemia. AB - BACKGROUND AND OBJECTIVE: Neonatal hypoglycemia is a common problem, often requiring management in the NICU. Nonpharmacologic interventions, including early breastfeeding and skin-to-skin care (SSC), may prevent hypoglycemia and the need to escalate care. Our objective was to maintain mother-infant dyads in the mother infant unit by decreasing hypoglycemia resulting in NICU transfer. METHODS: Inborn infants >=35 weeks' gestation with at least 1 risk factor for hypoglycemia were included. Using quality-improvement methodology, a bundle for at-risk infants was implemented, which included a protocol change focusing on early SSC, early feeding, and obtaining a blood glucose measurement in asymptomatic infants at 90 minutes. The primary outcome was the overall transfer rate of at-risk infants to the NICU. Secondary outcomes were related to protocol adherence. Balancing measures, including the rate of symptomatic hypoglycemia and sepsis evaluations, were monitored. Statistical process control charts using standard interpretation rules were used to monitor for improvement in key aims. RESULTS: For infants at risk for hypoglycemia, the NICU transfer rate decreased from 17% to 3% overall. Documented early feeding and SSC in at-risk newborns increased. The percent of at-risk infants transferred to the NICU who did not require intravenous dextrose decreased from 5% at baseline to 0.7% after intervention. There were no adverse outcomes observed in the period before or after the intervention. CONCLUSIONS: The implementation of a quality-improvement intervention promoting SSC and early feeding in at-risk infants was associated with a decreased rate of transfer to the NICU for hypoglycemia. PMID- 29437909 TI - When Lightning Strikes Twice in Pediatrics: Case Report and Review of Recurrent Myocarditis. AB - Myocarditis is an important but incompletely understood cause of cardiac dysfunction. Children with fulminant myocarditis often require inotropic or mechanical circulatory support, and researchers in some studies suggest that up to 42% of children who die suddenly have evidence of myocarditis. Recurrent myocarditis is extremely rare, and the vast majority of reported cases involve adult patients. Pediatric providers who suspect a recurrence of myocarditis have limited evidence to guide patient management because the literature in this domain is sparse. Here we present a unique, illustrative pediatric case of recurrent myocarditis. A 14-year-old boy presented for the second time in 2 years with a clinical history strongly suggestive of myocarditis. Although myocarditis was suggested in the results of cardiac MRI, no pathogen was identified during his first presentation. During his second episode of myocarditis, parvovirus was confirmed by polymerase chain reaction testing of an endomyocardial specimen that also met Dallas criteria for myocarditis. With each presentation, he had decreased ventricular function that subsequently normalized. To the best of our knowledge, there are no reports of recurrent myocarditis in children in whom the diagnosis was confirmed by using MRI and/or biopsy data. Reviewing this distinctive case and the existing literature may help characterize this entity and raise awareness among care providers. PMID- 29437912 TI - New hallmark of hepatocellular carcinoma, early hepatocellular carcinoma and high grade dysplastic nodules on Gd-EOB-DTPA MRI in patients with cirrhosis: a new diagnostic algorithm. AB - OBJECTIVE: Many improvements have been made in diagnosing hepatocellular carcinoma (HCC), but the radiological hallmarks of HCC have remained the same for many years. We prospectively evaluated the imaging criteria of HCC, early HCC and high-grade dysplastic nodules (HGDNs) in patients under surveillance for chronic liver disease, using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) MRI and diffusion-weighted imaging. DESIGN: Our study population included 420 nodules >1 cm in 228 patients. The MRI findings of each nodule were collected in all sequences/phases. The diagnosis of HCC was made according to the American Association for the Study of Liver Diseases (AASLD) criteria; all atypical nodules were diagnosed using histology. RESULTS: A classification and regression tree was developed using three MRI findings which were independently significant correlated variables for early HCC/HCC, and the best sequence of their application in a new diagnostic algorithm (hepatobiliary hypointensity, arterial hyperintensity and diffusion restriction) was suggested. This algorithm demonstrated, both in the entire study population and for nodules <=2 cm, higher sensitivity (96% [95% CI 93.5% to 97.6%] and 96.6% [95% CI 93.9% to 98.5%], P<0.001, respectively) and slightly lower specificity (91.8% [95% CI 88.6% to 94.1%], P=0.063, and 92.7% [95% CI 88.9% to 95.4%], P=0.125, respectively) than those of the AASLD criteria. Our new diagnostic algorithm also showed a very high sensitivity (94.7%; 95% CI 92% to 96.6%) and specificity (99.3%; 95% CI 97.7% to 99.8%) in classifying HGDN. CONCLUSION: Our new diagnostic algorithm demonstrated significantly higher sensitivity and comparable specificity than those of the AASLD imaging criteria for HCC in patients with cirrhosis evaluated using Gd-EOB DTPA MRI, even for lesions <=2 cm. Moreover, this diagnostic algorithm allowed evaluating other lesions which could arise in a cirrhotic liver, such as early HCC and HGDN. PMID- 29437911 TI - Developing a core outcome set for fistulising perianal Crohn's disease. AB - OBJECTIVE: Lack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn's disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD. DESIGN: Candidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback from their panel (in the second round) and all participants (in the third round) to allow refinement of their scores. RESULTS: A total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study.The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion). CONCLUSION: A fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care. PMID- 29437910 TI - Modern diagnosis of GERD: the Lyon Consensus. AB - Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD in isolation, but are of value in determining need for further investigation. Conclusive evidence for reflux on oesophageal testing include advanced grade erosive oesophagitis (LA grades C and D), long-segment Barrett's mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET) >6% on ambulatory pH or pH impedance monitoring. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal AET <4% and <40 reflux episodes on pH-impedance monitoring off proton pump inhibitors. Reflux symptom association on ambulatory reflux monitoring provides supportive evidence for reflux triggered symptoms, and may predict a better treatment outcome when present. When endoscopy and pH or pH-impedance monitoring are inconclusive, adjunctive evidence from biopsy findings (histopathology scores, dilated intercellular spaces), motor evaluation (hypotensive lower oesophageal sphincter, hiatus hernia and oesophageal body hypomotility on high-resolution manometry) and novel impedance metrics (baseline impedance, postreflux swallow-induced peristaltic wave index) can add confidence for a GERD diagnosis; however, diagnosis cannot be based on these findings alone. An assessment of anatomy, motor function, reflux burden and symptomatic phenotype will therefore help direct management. Future GERD management strategies should focus on defining individual patient phenotypes based on the level of refluxate exposure, mechanism of reflux, efficacy of clearance, underlying anatomy of the oesophagogastric junction and psychometrics defining symptomatic presentations. PMID- 29437913 TI - Comparison of different histological indexes in the assessment of UC activity and their accuracy regarding endoscopic outcomes and faecal calprotectin levels. AB - OBJECTIVE: Histological remission is being increasingly acknowledged as a therapeutic endpoint in patients with UC. The work hereafter described aimed to evaluate the concordance between three histological classification systems-Geboes Score (GS), Nancy Index (NI) and RobartsHistopathologyIndex (RHI), as well as to evaluate their association with the endoscopic outcomes and the faecal calprotectin (FC) levels. DESIGN: Biopsy samples from 377 patients with UC were blindly evaluated using GS, NI and RHI. The results were compared with the patients' Mayo Endoscopic Score and FC levels. RESULT: GS, NI and RHI have a good concordance concerning the distinction between patients in histological remission or activity. RHI was particularly close to NI, with 100% of all patients classified as being in remission with NI being identified as such with RHI and 100% of all patients classified as having activity with RHI being identified as such with NI. These scores could also predict the Mayo Endoscopic Score and the FC levels, with their sensitivity and specificity levels depending on the chosen cut-offs. Moreover, higher FC levels were statistically associated with the presence of neutrophils in the epithelium, as well as with ulceration or erosion of the intestinal mucosa. CONCLUSIONS: GS, NI and RHI histopathological scoring systems are comparable in what concerns patients' stratification into histological remission/activity. Additionally, FC levels are increased when neutrophils are present in the epithelium and the intestinal mucosa has erosions or ulcers. The presence of neutrophils in the epithelium is, indeed, the main marker of histological activity. PMID- 29437914 TI - Gastrointestinal ultrasound in inflammatory bowel disease: an underused resource with potential paradigm-changing application. AB - Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework. PMID- 29437915 TI - CYP4X1 Inhibition by Flavonoid CH625 Normalizes Glioma Vasculature through Reprogramming TAMs via CB2 and EGFR-STAT3 Axis. AB - Tumor-associated macrophages (TAMs) are pivotal effector cells in angiogenesis. Here, we tested whether CYP4X1 inhibition in TAMs by flavonoid CH625 prolongs survival and normalizes glioma vasculature. CH625 was selected against the CYP4X1 3D model by virtual screening and showed inhibitory activity on the CYP4X1 catalytic production of 14,15-EET-EA in the M2-polarized human peripheral blood mononuclear cells (IC50 = 16.5 MUM). CH625 improved survival and reduced tumor burden in the C6 and GL261 glioma intracranial and subcutaneous model. In addition, CH625 normalized vasculature (evidenced by a decrease in microvessel density and HIF-1alpha expression and an increase in tumor perfusion, pericyte coverage, and efficacy of temozolomide therapy) accompanied with the decreased secretion of 14,15-EET-EA, VEGF, and TGF-beta in the TAMs. Furthermore, CH625 attenuated vascular abnormalization and immunosuppression induced by coimplantation of GL261 cells with CYP4X1high macrophages. In vitro TAM polarization away from the M2 phenotype by CH625 inhibited proliferation and migration of endothelial cells, enhanced pericyte migration and T cell proliferation, and decreased VEGF and TGF-beta production accompanied with the downregulation of CB2 and EGFR-dependent downstream STAT3 expression. These effects were reversed by overexpression of CYP4X1 and STAT3 or exogenous addition of 14,15-EET-EA, VEGF, TGF-beta, EGF, and CB2 inhibitor AM630. These results suggest that CYP4X1 inhibition in TAMs by CH625 prolongs survival and normalizes tumor vasculature in glioma via CB2 and EGFR-STAT3 axis and may serve as a novel therapeutic strategy for human glioma. PMID- 29437916 TI - Mobility shift of beta-dystroglycan as a marker of GMPPB gene-related muscular dystrophy. AB - BACKGROUND: Defects in glycosylation of alpha-dystroglycan (alpha-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of alpha-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes. METHODS: We describe clinical, genetic and biochemical findings of 21 patients with GMPPB-associated dystroglycanopathy. RESULTS: We report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (beta-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormal N-linked glycosylation of beta-DG. CONCLUSIONS: Our data demonstrate that a change in beta-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in GMPPB. PMID- 29437917 TI - Colocalization and Disposition of Cellulosomes in Clostridium clariflavum as Revealed by Correlative Superresolution Imaging. AB - Cellulosomes are multienzyme complexes produced by anaerobic, cellulolytic bacteria for highly efficient breakdown of plant cell wall polysaccharides. Clostridium clariflavum is an anaerobic, thermophilic bacterium that produces the largest assembled cellulosome complex in nature to date, comprising three types of scaffoldins: a primary scaffoldin, ScaA; an adaptor scaffoldin, ScaB; and a cell surface anchoring scaffoldin, ScaC. This complex can contain 160 polysaccharide-degrading enzymes. In previous studies, we proposed potential types of cellulosome assemblies in C. clariflavum and demonstrated that these complexes are released into the extracellular medium. In the present study, we explored the disposition of the highly structured, four-tiered cell-anchored cellulosome complex of this bacterium. Four separate, integral cellulosome components were subjected to immunolabeling: ScaA, ScaB, ScaC, and the cellulosome's most prominent enzyme, GH48. Imaging of the cells by correlating scanning electron microscopy and three-dimensional (3D) superresolution fluorescence microscopy revealed that some of the protuberance-like structures on the cell surface represent cellulosomes and that the components are highly colocalized and organized by a defined hierarchy on the cell surface. The display of the cellulosome on the cell surface was found to differ between cells grown on soluble or insoluble substrates. Cell growth on microcrystalline cellulose and wheat straw exhibited dramatic enhancement in the amount of cellulosomes displayed on the bacterial cell surface.IMPORTANCE Conversion of plant biomass into soluble sugars is of high interest for production of fermentable industrial materials, such as biofuels. Biofuels are a very attractive alternative to fossil fuels, both for recycling of agricultural wastes and as a source of sustainable energy. Cellulosomes are among the most efficient enzymatic degraders of biomass known to date, due to the incorporation of a multiplicity of enzymes into a potent, multifunctional nanomachine. The intimate association with the bacterial cell surface is inherent in its efficient action on lignocellulosic substrates, although this property has not been properly addressed experimentally. The dramatic increase in cellulosome performance on recalcitrant feedstocks is critical for the design of cost-effective processes for efficient biomass degradation. PMID- 29437918 TI - Prevalence of Infection-Competent Serogroup 6 Legionella pneumophila within Premise Plumbing in Southeast Michigan. AB - Coinciding with major changes to its municipal water system, Flint, MI, endured Legionnaires' disease outbreaks in 2014 and 2015. By sampling premise plumbing in Flint in the fall of 2016, we found that 12% of homes harbored legionellae, a frequency similar to that in residences in neighboring areas. To evaluate the genetic diversity of Legionella pneumophila in Southeast Michigan, we determined the sequence type (ST) and serogroup (SG) of the 18 residential isolates from Flint and Detroit, MI, and the 33 clinical isolates submitted by hospitals in three area counties in 2013 to 2016. Common to one environmental and four clinical samples were strains of L. pneumophila SG1 and ST1, the most prevalent ST worldwide. Among the Flint premise plumbing isolates, 14 of 16 strains were of ST367 and ST461, two closely related SG6 strain types isolated previously from patients and corresponding environmental samples. Each of the representative SG1 clinical strains and SG6 environmental isolates from Southeast Michigan infected and survived within macrophage cultures at least as well as a virulent laboratory strain, as judged by microscopy and by enumerating CFU. Likewise, 72 h after infection, the yield of viable-cell counts increased >100-fold for each of the representative SG1 clinical isolates, Flint premise plumbing SG6 ST367 and -461 isolates, and two Detroit residential isolates. We verified by immunostaining that SG1-specific antibody does not cross-react with the SG6 L. pneumophila environmental strains. Because the widely used urinary antigen diagnostic test does not readily detect non-SG1 L. pneumophila, Legionnaires' disease caused by SG6 L. pneumophila is likely underreported worldwide.IMPORTANCEL. pneumophila is the leading cause of disease outbreaks associated with drinking water in the United States. Compared to what is known of the established risks of colonization within hospitals and hotels, relatively little is known about residential exposure to L. pneumophila One year after two outbreaks of Legionnaires' disease in Genesee County, MI, that coincided with damage to the Flint municipal water system, our multidisciplinary team launched an environmental surveillance and laboratory research campaign aimed at informing risk management strategies to provide safe public water supplies. The most prevalent L. pneumophila strains isolated from residential plumbing were closely related strains of SG6. In laboratory tests of virulence, the SG6 environmental isolates resembled SG1 clinical strains, yet they are not readily detected by the common diagnostic urinary antigen test, which is specific for SG1. Therefore, our study complements the existing epidemiological literature indicating that Legionnaires' disease due to non-SG1 strains is underreported around the globe. PMID- 29437919 TI - Physiological Heterogeneity Triggers Sibling Conflict Mediated by the Type VI Secretion System in an Aggregative Multicellular Bacterium. AB - A hallmark of social microorganisms is their ability to engage in complex and coordinated behaviors that depend on cooperative and synchronized actions among many cells. For instance, myxobacteria use an aggregation strategy to form multicellular, spore-filled fruiting bodies in response to starvation. One barrier to the synchronization process is physiological heterogeneity within clonal populations. How myxobacteria cope with these physiological differences is poorly understood. Here, we investigated the interactions between closely related but physiologically distinct Myxococcus xanthus populations. We used a genetic approach to create amino acid auxotrophs and tested how they interact with a parental prototroph strain. Importantly, we found that auxotrophs were killed by their prototroph siblings when the former were starved for amino acids but not when grown on rich medium or when both strains were starved. This antagonism depended on the type VI secretion system (T6SS) as well as gliding motility; in particular, we identified the effector-immunity pair (TsxEI) as the mediator of this killing. This sibling antagonism resulted from lower levels of the TsxI immunity protein in the starved population. Thus, when starving auxotrophs were mixed with nonstarving prototrophs, the auxotrophs were susceptible to intoxication by the TsxE effector delivered by the T6SS from the prototrophs. Furthermore, our results suggested that homogeneously starving populations have reduced T6SS activity and, therefore, do not antagonize each other. We conclude that heterogeneous populations of M. xanthus use T6SS-dependent killing to eliminate starving or less-fit cells, thus facilitating the attainment of homeostasis within a population and the synchronization of behaviors.IMPORTANCE Social bacteria employ elaborate strategies to adapt to environmental challenges. One means to prepare for unpredictable changes is for clonal populations to contain individuals with diverse physiological states. These subpopulations will differentially respond to new environmental conditions, ensuring that some cells will better adapt. However, for social bacteria physiological heterogeneity may impede the ability of a clonal population to synchronize their behaviors. By using a highly cooperative and synchronizable model organism, M. xanthus, we asked how physiological differences between interacting siblings impacted their collective behaviors. Physiological heterogeneity was experimentally designed such that one population starved while the other grew when mixed. We found that these differences led to social conflict where more-fit individuals killed their less-fit siblings. For the first time, we report that the T6SS nanoweapon mediates antagonism between siblings, resulting in myxobacterial populations becoming more synchronized to conduct social behaviors. PMID- 29437921 TI - Expanding Primary Metabolism Helps Generate the Metabolic Robustness To Facilitate Antibiotic Biosynthesis in Streptomyces. AB - The expansion of the genetic repertoire of an organism by gene duplication or horizontal gene transfer (HGT) can aid adaptation. Streptomyces bacteria are prolific producers of bioactive specialized metabolites that have adaptive functions in nature and have found extensive utility in human medicine. While the biosynthesis of these specialized metabolites is directed by dedicated biosynthetic gene clusters, little attention has been focused on how these organisms have evolved robustness in their genomes to facilitate the metabolic plasticity required to provide chemical precursors for biosynthesis during the complex metabolic transitions from vegetative growth to specialized metabolite production and sporulation. Here, we examine genetic redundancy in actinobacteria and show that specialized metabolite-producing bacterial families exhibit gene family expansion in primary metabolism. Focusing on a gene duplication event, we show that the two pyruvate kinases in the genome of Streptomyces coelicolor arose by an ancient duplication event and that each has evolved altered enzymatic kinetics, with Pyk1 having a 20-fold-higher kcat than Pyk2 (4,703 s-1 compared to 215 s-1, respectively), and yet both are constitutively expressed. The pyruvate kinase mutants were also found to be compromised in terms of fitness compared to wild-type Streptomyces These data suggest that expanding gene families can help maintain cell functionality during metabolic perturbation such as nutrient limitation and/or specialized metabolite production.IMPORTANCE The rise of antimicrobial-resistant infections has prompted a resurgence in interest in understanding the production of specialized metabolites, such as antibiotics, by Streptomyces The presence of multiple genes encoding the same enzymatic function is an aspect of Streptomyces biology that has received little attention; however, understanding how the metabolic expansion influences these organisms can help enhance production of clinically useful molecules. Here, we show that expanding the number of pyruvate kinases enables metabolic adaptation, increases strain fitness, and represents an excellent target for metabolic engineering of industrial specialized metabolite-producing bacteria and the activation of cryptic specialized metabolites. PMID- 29437920 TI - Genomic Analysis of Hospital Plumbing Reveals Diverse Reservoir of Bacterial Plasmids Conferring Carbapenem Resistance. AB - The hospital environment is a potential reservoir of bacteria with plasmids conferring carbapenem resistance. Our Hospital Epidemiology Service routinely performs extensive sampling of high-touch surfaces, sinks, and other locations in the hospital. Over a 2-year period, additional sampling was conducted at a broader range of locations, including housekeeping closets, wastewater from hospital internal pipes, and external manholes. We compared these data with previously collected information from 5 years of patient clinical and surveillance isolates. Whole-genome sequencing and analysis of 108 isolates provided comprehensive characterization of blaKPC/blaNDM-positive isolates, enabling an in-depth genetic comparison. Strikingly, despite a very low prevalence of patient infections with blaKPC-positive organisms, all samples from the intensive care unit pipe wastewater and external manholes contained carbapenemase-producing organisms (CPOs), suggesting a vast, resilient reservoir. We observed a diverse set of species and plasmids, and we noted species and susceptibility profile differences between environmental and patient populations of CPOs. However, there were plasmid backbones common to both populations, highlighting a potential environmental reservoir of mobile elements that may contribute to the spread of resistance genes. Clear associations between patient and environmental isolates were uncommon based on sequence analysis and epidemiology, suggesting reasonable infection control compliance at our institution. Nonetheless, a probable nosocomial transmission of Leclercia sp. from the housekeeping environment to a patient was detected by this extensive surveillance. These data and analyses further our understanding of CPOs in the hospital environment and are broadly relevant to the design of infection control strategies in many infrastructure settings.IMPORTANCE Carbapenemase-producing organisms (CPOs) are a global concern because of the morbidity and mortality associated with these resistant Gram-negative bacteria. Horizontal plasmid transfer spreads the resistance mechanism to new bacteria, and understanding the plasmid ecology of the hospital environment can assist in the design of control strategies to prevent nosocomial infections. A 5-year genomic and epidemiological survey was undertaken to study the CPOs in the patient-accessible environment, as well as in the plumbing system removed from the patient. This comprehensive survey revealed a vast, unappreciated reservoir of CPOs in wastewater, which was in contrast to the low positivity rate in both the patient population and the patient-accessible environment. While there were few patient-environmental isolate associations, there were plasmid backbones common to both populations. These results are relevant to all hospitals for which CPO colonization may not yet be defined through extensive surveillance. PMID- 29437922 TI - Staphylococcus aureus HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis. AB - Staphylococcus aureus is responsible for a significant amount of devastating disease. Its ability to colonize the host and cause infection is supported by a variety of proteins that are dependent on the cofactor heme. Heme is a porphyrin used broadly across kingdoms and is synthesized de novo from common cellular precursors and iron. While heme is critical to bacterial physiology, it is also toxic in high concentrations, requiring that organisms encode regulatory processes to control heme homeostasis. In this work, we describe a posttranscriptional regulatory strategy in S. aureus heme biosynthesis. The first committed enzyme in the S. aureus heme biosynthetic pathway, glutamyl-tRNA reductase (GtrR), is regulated by heme abundance and the integral membrane protein HemX. GtrR abundance increases dramatically in response to heme deficiency, suggesting a mechanism by which S. aureus responds to the need to increase heme synthesis. Additionally, HemX is required to maintain low levels of GtrR in heme-proficient cells, and inactivation of hemX leads to increased heme synthesis. Excess heme synthesis in a DeltahemX mutant activates the staphylococcal heme stress response, suggesting that regulation of heme synthesis is critical to reduce self-imposed heme toxicity. Analysis of diverse organisms indicates that HemX is widely conserved among heme-synthesizing bacteria, suggesting that HemX is a common factor involved in the regulation of GtrR abundance. Together, this work demonstrates that S. aureus regulates heme synthesis by modulating GtrR abundance in response to heme deficiency and through the activity of the broadly conserved HemX.IMPORTANCEStaphylococcus aureus is a leading cause of skin and soft tissue infections, endocarditis, bacteremia, and osteomyelitis, making it a critical health care concern. Development of new antimicrobials against S. aureus requires knowledge of the physiology that supports this organism's pathogenesis. One component of staphylococcal physiology that contributes to growth and virulence is heme. Heme is a widely utilized cofactor that enables diverse chemical reactions across many enzyme families. S. aureus relies on many critical heme-dependent proteins and is sensitive to excess heme toxicity, suggesting S. aureus must maintain proper intracellular heme homeostasis. Because S. aureus provides heme for heme-dependent enzymes via synthesis from common precursors, we hypothesized that regulation of heme synthesis is one mechanism to maintain heme homeostasis. In this study, we identify that S. aureus posttranscriptionally regulates heme synthesis by restraining abundance of the first heme biosynthetic enzyme, GtrR, via heme and the broadly conserved membrane protein HemX. PMID- 29437923 TI - Adjustments to Photosystem Stoichiometry and Electron Transfer Proteins Are Key to the Remarkably Fast Growth of the Cyanobacterium Synechococcus elongatus UTEX 2973. AB - At the genome level, Synechococcus elongatus UTEX 2973 (Synechococcus 2973) is nearly identical to the model cyanobacterium Synechococcus elongatus PCC 7942 (Synechococcus 7942) with only 55 single nucleotide differences separating the two strains. Despite the high similarity between the two strains, Synechococcus 2973 grows three times faster, accumulates significantly more glycogen, is tolerant to extremely high light intensities, and displays higher photosynthetic rates. The high homology between the two strains provides a unique opportunity to examine the factors that lead to increased photosynthetic rates. We compared the photophysiology of the two strains and determined the differences in Synechococcus 2973 that lead to increased photosynthetic rates and the concomitant increase in biomass production. In this study, we identified inefficiencies in the electron transport chain of Synechococcus 7942 that have been alleviated in Synechococcus 2973. Photosystem II (PSII) capacity is the same in both strains. However, Synechococcus 2973 exhibits a 1.6-fold increase in PSI content, a 1.5-fold increase in cytochrome b6f content, and a 2.4-fold increase in plastocyanin content on a per cell basis. The increased content of electron carriers allows a higher flux of electrons through the photosynthetic electron transport chain, while the increased PSI content provides more oxidizing power to maintain upstream carriers ready to accept electrons. These changes serve to increase the photosynthetic efficiency of Synechococcus 2973, the fastest growing cyanobacterium known.IMPORTANCE As the global population increases, the amount of arable land continues to decrease. To prevent a looming food crisis, crop productivity per acre must increase. A promising target for improving crop productivity is increasing the photosynthetic rates in crop plants. Cyanobacteria serve as models for higher plant photosynthetic systems and are an important test bed for improvements in photosynthetic productivity. In this study, we identified key factors that lead to improved photosynthetic efficiency and increased production of biomass of a cyanobacterium. We suggest that the findings presented herein will give direction to improvements that may be made in other photosynthetic organisms to improve photosynthetic efficiency. PMID- 29437924 TI - Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses. AB - Extracellular vesicles (EVs) or exosomes have been implicated in the pathophysiology of infections and cancer. The negative regulatory factor (Nef) encoded by simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) plays a critical role in the progression to AIDS and impairs endosomal trafficking. Whether HIV-1 Nef can be loaded into EVs has been the subject of controversy, and nothing is known about the connection between SIV Nef and EVs. We find that both SIV and HIV-1 Nef proteins are present in affinity-purified EVs derived from cultured cells, as well as in EVs from SIV-infected macaques. Nef positive EVs were functional, i.e., capable of membrane fusion and depositing their content into recipient cells. The EVs were able to transfer Nef into recipient cells. This suggests that Nef readily enters the exosome biogenesis pathway, whereas HIV virions are assembled at the plasma membrane. It suggests a novel mechanism by which lentiviruses can influence uninfected and uninfectable, i.e., CD4-negative, cells.IMPORTANCE Extracellular vesicles (EVs) transfer biologically active materials from one cell to another, either within the adjacent microenvironment or further removed. EVs also package viral RNAs, microRNAs, and proteins, which contributes to the pathophysiology of infection. In this report, we show that both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) incorporate the virus-encoded Nef protein into EVs, including EVs circulating in the blood of SIV-infected macaques and that this presents a novel mechanism of Nef transfer to naive and even otherwise non infectable cells. Nef is dispensable for viral replication but essential for AIDS progression in vivo Demonstrating that Nef incorporation into EVs is conserved across species implicates EVs as novel mediators of the pathophysiology of HIV. It could help explain the biological effects that HIV has on CD4-negative cells and EVs could become biomarkers of disease progression. PMID- 29437925 TI - Layered Structure and Complex Mechanochemistry Underlie Strength and Versatility in a Bacterial Adhesive. AB - While designing synthetic adhesives that perform in aqueous environments has proven challenging, microorganisms commonly produce bioadhesives that efficiently attach to a variety of substrates, including wet surfaces. The aquatic bacterium Caulobacter crescentus uses a discrete polysaccharide complex, the holdfast, to strongly attach to surfaces and resist flow. The holdfast is extremely versatile and has impressive adhesive strength. Here, we used atomic force microscopy in conjunction with superresolution microscopy and enzymatic assays to unravel the complex structure of the holdfast and to characterize its chemical constituents and their role in adhesion. Our data support a model whereby the holdfast is a heterogeneous material organized as two layers: a stiffer nanoscopic core layer wrapped into a sparse, far-reaching, flexible brush layer. Moreover, we found that the elastic response of the holdfast evolves after surface contact from initially heterogeneous to more homogeneous. From a composition point of view, besides N-acetyl-d-glucosamine (NAG), the only component that had been identified to date, our data show that the holdfast contains peptides and DNA. We hypothesize that, while polypeptides are the most important components for adhesive force, the presence of DNA mainly impacts the brush layer and the strength of initial adhesion, with NAG playing a primarily structural role within the core. The unanticipated complexity of both the structure and composition of the holdfast likely underlies its versatility as a wet adhesive and its distinctive strength. Continued improvements in understanding of the mechanochemistry of this bioadhesive could provide new insights into how bacteria attach to surfaces and could inform the development of new adhesives.IMPORTANCE There is an urgent need for strong, biocompatible bioadhesives that perform underwater. To strongly adhere to surfaces and resist flow underwater, the bacterium Caulobacter crescentus produces an adhesive called the holdfast, the mechanochemistry of which remains undefined. We show that the holdfast is a layered structure with a stiff core layer and a polymeric brush layer and consists of polysaccharides, polypeptides, and DNA. The DNA appears to play a role in the structure of the brush layer and initial adhesion, the peptides in adhesive strength, and the polysaccharides in the structure of the core. The complex, multilayer organization and diverse chemistry described here underlie the distinctive adhesive properties of the holdfast and will provide important insights into the mechanisms of bacterial adhesion and bioadhesive applications. PMID- 29437926 TI - CCCTC-Binding Factor Acts as a Heterochromatin Barrier on Herpes Simplex Viral Latent Chromatin and Contributes to Poised Latent Infection. AB - Herpes simplex virus 1 (HSV-1) establishes latent infection in neurons via a variety of epigenetic mechanisms that silence its genome. The cellular CCCTC binding factor (CTCF) functions as a mediator of transcriptional control and chromatin organization and has binding sites in the HSV-1 genome. We constructed an HSV-1 deletion mutant that lacked a pair of CTCF-binding sites (CTRL2) within the latency-associated transcript (LAT) coding sequences and found that loss of these CTCF-binding sites did not alter lytic replication or levels of establishment of latent infection, but their deletion reduced the ability of the virus to reactivate from latent infection. We also observed increased heterochromatin modifications on viral chromatin over the LAT promoter and intron. We therefore propose that CTCF binding at the CTRL2 sites acts as a chromatin insulator to keep viral chromatin in a form that is poised for reactivation, a state which we call poised latency.IMPORTANCE Herpes simplex virus 1 (HSV-1) is a human pathogen that persists for the lifetime of the host as a result of its ability to establish latent infection within sensory neurons. The mechanism by which HSV-1 transitions from the lytic to latent infection program is largely unknown; however, HSV-1 is able to coopt cellular silencing mechanisms to facilitate the suppression of lytic gene expression. Here, we demonstrate that the cellular CCCTC-binding factor (CTCF)-binding site within the latency associated transcript (LAT) region is critical for the maintenance of a specific local chromatin structure. Additionally, loss of CTCF binding has detrimental effects on the ability to reactivate from latent infection. These results argue that CTCF plays a critical role in epigenetic regulation of viral gene expression to establish and/or maintain a form of latent infection that can reactivate efficiently. PMID- 29437927 TI - The Viscoelastic Properties of the Fungal Cell Wall Allow Traffic of AmBisome as Intact Liposome Vesicles. AB - The fungal cell wall is a critically important structure that represents a permeability barrier and protective shield. We probed Candida albicans and Cryptococcus neoformans with liposomes containing amphotericin B (AmBisome), with or without 15-nm colloidal gold particles. The liposomes have a diameter of 60 to 80 nm, and yet their mode of action requires them to penetrate the fungal cell wall to deliver amphotericin B to the cell membrane, where it binds to ergosterol. Surprisingly, using cryofixation techniques with electron microscopy, we observed that the liposomes remained intact during transit through the cell wall of both yeast species, even though the predicted porosity of the cell wall (pore size, ~5.8 nm) is theoretically too small to allow these liposomes to pass through intact. C. albicans mutants with altered cell wall thickness and composition were similar in both their in vitro AmBisome susceptibility and the ability of liposomes to penetrate the cell wall. AmBisome exposed to ergosterol deficient C. albicans failed to penetrate beyond the mannoprotein-rich outer cell wall layer. Melanization of C. neoformans and the absence of amphotericin B in the liposomes were also associated with a significant reduction in liposome penetration. Therefore, AmBisome can reach cell membranes intact, implying that fungal cell wall viscoelastic properties are permissive to vesicular structures. The fact that AmBisome can transit through chemically diverse cell wall matrices when these liposomes are larger than the theoretical cell wall porosity suggests that the wall is capable of rapid remodeling, which may also be the mechanism for release of extracellular vesicles.IMPORTANCE AmBisome is a broad-spectrum fungicidal antifungal agent in which the hydrophobic polyene antibiotic amphotericin B is packaged within a 60- to 80-nm liposome. The mode of action involves perturbation of the fungal cell membrane by selectively binding to ergosterol, thereby disrupting membrane function. We report that the AmBisome liposome transits through the cell walls of both Candida albicans and Cryptococcus neoformans intact, despite the fact that the liposome is larger than the theoretical cell wall porosity. This implies that the cell wall has deformable, viscoelastic properties that are permissive to transwall vesicular traffic. These observations help explain the low toxicity of AmBisome, which can deliver its payload directly to the cell membrane without unloading the polyene in the cell wall. In addition, these findings suggest that extracellular vesicles may also be able to pass through the cell wall to deliver soluble and membrane bound effectors and other molecules to the extracellular space. PMID- 29437929 TI - Ketamine alters lateral prefrontal oscillations in a rule-based working memory task. AB - Acute administration of N-methyl-D-aspartate receptor (NMDAR) antagonists in healthy humans and animals produces working memory deficits similar to those observed in schizophrenia. However, it is unclear whether they also lead to altered low-frequency (<=60Hz) neural oscillatory activities similar to those associated with schizophrenia during working memory processes. Here we recorded local field potentials (LFPs) and single unit activity from the lateral prefrontal cortex (LPFC) of three male rhesus macaque monkeys while they performed a rule-based prosaccade and antisaccade working memory task, both before and after systemic injections of a subanesthetic dose (<=0.7mg/kg) of ketamine. Accompanying working-memory impairment, ketamine enhanced the low gamma band (30-60Hz) and dampened the beta band (13-30Hz) oscillatory activities in the LPFC during both delay periods and inter-trial intervals. It also increased task related alpha-band activities, likely reflecting compromised attention. Beta-band oscillations may be especially relevant to working memory processes, as stronger beta power weakly but significantly predicted shorter saccadic reaction time. Also in beta band, ketamine reduced the performance-related oscillation as well as the rule information encoded in the spectral power. Ketamine also reduced rule information in the spike-field phase consistency in almost all frequencies up to 60Hz. Our findings support NMDAR antagonists in non-human primates as a meaningful model for altered neural oscillations and synchrony, which reflect a disorganized network underlying the working memory deficits in schizophrenia.SIGNIFICANCE STATEMENTLow doses of ketamine-an NMDA receptor blocker-produce working memory deficits similar to those observed in schizophrenia. In the LPFC, a key brain region for working memory, we found that ketamine altered neural oscillatory activities in similar ways that differentiate schizophrenic patients and healthy subjects, during both task and non-task periods. Ketamine induced stronger gamma (30-60Hz) and weaker beta (13-30Hz) oscillations, reflecting local hyperactivity and reduced long-range communications. Furthermore, ketamine reduced performance-related oscillatory activities, as well as the rule information encoded in the oscillations and in the synchrony between single cell activities and oscillations. The ketamine model helps link the molecular and cellular basis of neural oscillatory changes to the working memory deficit in schizophrenia. PMID- 29437928 TI - Exploring the Antimicrobial Action of Quaternary Amines against Acinetobacter baumannii. AB - Quaternary amine compounds (QAC) are potent antimicrobials used to prevent the spread of pathogenic bacteria. While they are known for their membrane-damaging properties, QAC action has been suggested to extend beyond the surface to intracellular targets. Here we characterize the range of action of the QAC biocide benzalkonium chloride (BZK) against the bacterial pathogen Acinetobacter baumannii At high concentrations, BZK acts through membrane disruption, but at low concentrations we show that wide-spread protein aggregation is associated with BZK-induced cell death. Resistance to BZK is found to develop through ribosomal protein mutations that protect A. baumannii against BZK-induced protein aggregation. The multifunctional impact of BZK led us to discover that alternative QAC structures, with low human toxicity, retain potent action against multidrug-resistant A. baumannii, Staphylococcus aureus, and Clostridium difficile and present opportunities for their development as antibiotics.IMPORTANCE Quaternary amine compounds (QACs) are widely used to prevent the spread of bacterial pathogens, but our understanding of their mode of action is incomplete. Here we describe disruption of bacterial proteostasis as an unrecognized action of QAC antimicrobial action and uncover the potential of diverse QAC structures to act as multitarget antibiotics. PMID- 29437931 TI - Families' Experiences With Pediatric Family-Centered Rounds: A Systematic Review. AB - CONTEXT: Family-centered rounding (FCR) is of increasing importance in pediatric medicine. Although researchers have begun to understand the effect of FCR on providers and systematic health care outcomes, we provide a systematic review of the literature regarding families' experiences with FCR. OBJECTIVE: To systematically review patient and family experiences with pediatric FCR. DATA SOURCES: Our data sources included PubMed, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Scopus, and Embase. STUDY SELECTION: Inclusion criteria included publication in a peer-reviewed journal between January 2007 and February 2017, written in the English language, pediatric population (patients 0 21 years), and specific measurement of a families' experience with FCR. DATA EXRACTION: Data extracted were sample size, participating medical unit, measures of family experience, and overall results of family experience. RESULTS: Twenty eight studies were included. It is unclear whether participation in FCR increases family satisfaction compared with standard rounds; however, families report a strong desire to participate in FCR. Family benefits of FCR included increased understanding of information and confidence in the medical team, as well as reduced parental anxiety. LIMITATIONS: There were only 2 studies in which researchers examined pediatric patients' experiences with FCR, and literature on the communication needs of non-English-speaking families was also limited. CONCLUSIONS: Overall, it is suggested that families positively perceive their experience with FCR, although more research is needed to determine if satisfaction is greater in FCR versus standard rounds as well as to better understand different perspectives of adolescent patients and non-English-speaking families. PMID- 29437930 TI - Bottom-up and top-down factors differentially influence stimulus representations across large-scale attentional networks. AB - Visual attention is thought to be supported by three large-scale frontoparietal networks: the frontoparietal control network (FPCN), the dorsal attention network (DAN), and the ventral attention network (VAN). The traditional view is that these networks support visual attention by biasing and evaluating sensory representations in visual cortical regions. However, recent evidence suggests that frontoparietal regions actively represent perceptual stimuli. Here, we assessed how perceptual stimuli are represented across large-scale frontoparietal and visual networks. Specifically, we tested whether representations of stimulus features across these networks are differentially sensitive to bottom-up and top down factors. In a pair of pattern-based fMRI studies, male and female human subjects made perceptual decisions about face images that varied along two independent dimensions: gender and affect. Across studies, we interrupted bottom up visual input using backward masks. Within studies, we manipulated which stimulus features were goal-relevant (i.e., whether gender or affect was relevant) and task switching (i.e., whether the goal on the current trial matched the goal on the prior trial). We found that stimulus features could be reliably decoded from all four networks and, importantly, that sub-regions within each attentional network maintained coherent representations. Critically, the different attentional manipulations (interruption, goal relevance, task switching) differentially influenced feature representations across networks. Namely, whereas visual interruption had a relatively greater influence on representations in visual regions, goal relevance and task switching had a relatively greater influence on representations in frontoparietal networks. Thus, large-scale brain networks can be dissociated according to how attention influences the feature representations that they maintain.SIGNIFICANCE STATEMENTVisual attention is supported by multiple frontoparietal attentional networks. However, it remains unclear how stimulus features are represented within these networks and how they are influenced by attention. Here we assessed feature representations in four large-scale networks using a perceptual decision making paradigm in which we manipulated top-down and bottom-up factors. We found that top-down manipulations such as goal relevance and task switching modulated feature representations in attentional networks, whereas bottom-up manipulations such as interruption of visual processing had a relatively stronger influence on feature representations in visual regions. Together, these findings indicate that attentional networks actively represent stimulus features and that representations within different large-scale networks are influenced by different forms of attention. PMID- 29437932 TI - Recommended Childhood and Adolescent Immunization Schedules: United States, 2018. PMID- 29437933 TI - Well-Appearing Newborn With a Vesiculobullous Rash at Birth. AB - A term, appropriate-for-gestational-age, male infant born via normal spontaneous vaginal delivery presented at birth with a full-body erythematous, vesiculobullous rash. He was well-appearing with normal vital signs and hypoglycemia that quickly resolved. His father had a history of herpes labialis. His mother had an episode of herpes zoster during pregnancy and a prolonged rupture of membranes that was adequately treated. The patient underwent a sepsis workup, including 2 attempted but unsuccessful lumbar punctures, and was started on broad-spectrum antibiotics and acyclovir, given concerns about bacterial or viral infection. The rash evolved over the course of several days. Subsequent workup, with particular attention to his history and presentation, led to his diagnosis. PMID- 29437934 TI - Morphological characteristics associated with the rupture risk of mirror posterior communicating artery aneurysms. AB - OBJECTIVE: Patient related clinical factors and intracranial aneurysms (IAs) at different locations may lead to statistical bias when investigating the rupture risk of IAs. Thus the purpose of this study was to identify the morphological parameters that are related to the rupture of mirror posterior communicating artery aneurysms (PComAAs). METHODS: Between August 2011 and July 2017, 68 patients with mirror PComAAs and aneurysmal subarachnoid hemorrhage were diagnosed by CT angiography at three medical centers. Morphological characteristics for PComAAs included bifurcation, shape, neck width, width, depth, maximum size, flow angle, parent vessel diameter, aspect ratio (AR), depth/width ratio, bottleneck factor, and size ratio (SR). Multiple logistic regression analysis was performed to determine the independent risk factors for rupture. Receiver operating characteristic curve analysis was performed to obtain the optimal thresholds. RESULTS: AR (OR 5.623) and SR (OR 5.570) were more commonly observed in the ruptured cohort. The threshold values of AR and SR were 0.98 and 1.21, respectively. CONCLUSIONS: Mirror PComAAs are a useful model to investigate the rupture risk of PComAAs. AR (>=0.98) and SR (>=1.21) are better predictors of ruptured PComAAs. PMID- 29437935 TI - The Barrel vascular reconstruction device for endovascular coiling of wide-necked intracranial aneurysms: a multicenter, prospective, post-marketing study. AB - BACKGROUND AND PURPOSE: The Barrel vascular reconstruction device (Barrel VRD) is a novel stent with design features that allow endovascular coiling of wide-necked bifurcation aneurysms while preserving adjacent branches, without necessitating dual stent implantation. This study aimed to assess the safety and effectiveness of the Barrel VRD at 12-month follow-up. MATERIALS AND METHODS: The Barrel VRD trial is a prospective, multicenter, observational post-marketing registry evaluating the use of the Barrel VRD for treatment of wide-necked bifurcation aneurysms. The primary effectiveness endpoint was successful aneurysm treatment measured by digital subtraction angiography with a Raymond-Roy occlusion grade of 1 or 2 in the absence of retreatment, parent artery stenosis (>50%), or target aneurysm rupture at 12 months. The primary safety endpoint was the absence of neurological death or major stroke at 12 months. RESULTS: Twenty patients were enrolled from December 2013 to December 2014. The device was implanted in 19 patients with 19 aneurysms (8 middle cerebral artery, 4 anterior communicating artery, 1 internal carotid artery terminus, 4 basilar artery aneurysms; mean dome height 5.7+/-1.91 mm; mean neck length 4.8+/-1.35 mm, mean dome-to-neck ratio 1.6+/-2.0). Coiling was performed in all cases. The primary effectiveness endpoint was achieved in 78.9% of subjects (15/19; 12 complete occlusions, 3 neck remnants), and the primary safety endpoint was 5.3% (1/19). CONCLUSIONS: This prospective study demonstrates that the Barrel VRD device resulted in ~80% occlusion rates and ~5% rates of neurological complications at 1 year after endovascular treatment of wide-necked bifurcation intracranial aneurysms. REGISTERED CLINICAL TRIAL: NCT02125097;Results. PMID- 29437936 TI - Ventilatory response to exercise in cardiopulmonary disease: the role of chemosensitivity and dead space. AB - The lungs and heart are irrevocably linked in their oxygen (O2) and carbon dioxide (CO2) transport functions. Functional impairment of the lungs often affects heart function and vice versa The steepness with which ventilation (V'E) rises with respect to CO2 production (V'CO2 ) (i.e. the V'E/V'CO2 slope) is a measure of ventilatory efficiency and can be used to identify an abnormal ventilatory response to exercise. The V'E/V'CO2 slope is a prognostic marker in several chronic cardiopulmonary diseases independent of other exercise-related variables such as peak O2 uptake (V'O2 ). The V'E/V'CO2 slope is determined by two factors: 1) the arterial CO2 partial pressure (PaCO2 ) during exercise and 2) the fraction of the tidal volume (VT) that goes to dead space (VD) (i.e. the physiological dead space ratio (VD/VT)). An altered PaCO2 set-point and chemosensitivity are present in many cardiopulmonary diseases, which influence V'E/V'CO2 by affecting PaCO2 Increased ventilation-perfusion heterogeneity, causing inefficient gas exchange, also contributes to the abnormal V'E/V'CO2 observed in cardiopulmonary diseases by increasing VD/VT During cardiopulmonary exercise testing, the PaCO2 during exercise is often not measured and VD/VT is only estimated by taking into account the end-tidal CO2 partial pressure (PETCO2 ); however, PaCO2 is not accurately estimated from PETCO2 in patients with cardiopulmonary disease. Measuring arterial gases (PaO2 and PaCO2 ) before and during exercise provides information on the real (and not "estimated") VD/VT coupled with a true measure of gas exchange efficiency such as the difference between alveolar and arterial O2 partial pressure and the difference between arterial and end-tidal CO2 partial pressure during exercise. PMID- 29437937 TI - Indoor bacteria and asthma in adults: a multicentre case-control study within ECRHS II. AB - Both protective and adverse effects of indoor microbial exposure on asthma have been reported, but mostly in children. To date, no study in adults has used non targeted methods for detection of indoor bacteria followed by quantitative confirmation.A cross-sectional study of 198 asthmatic and 199 controls was conducted within the European Community Respiratory Health Survey (ECRHS) II. DNA was extracted from mattress dust for bacterial analysis using denaturing gradient gel electrophoresis (DGGE). Selected bands were sequenced and associations with asthma confirmed with four quantitative PCR (qPCR) assays.15 out of 37 bands detected with DGGE, which had at least a suggestive association (p<0.25) with asthma, were sequenced. Of the four targeted qPCRs, Clostridium cluster XI confirmed the protective association with asthma. The association was dose dependent (aOR 0.43 (95% CI 0.22-0.84) for the fourth versus first quartile, p for trend 0.009) and independent of other microbial markers. Few significant associations were observed for the three other qPCRs used.In this large international study, the level of Clostridium cluster XI was independently associated with a lower risk of prevalent asthma. Results suggest the importance of environmental bacteria also in adult asthma, but need to be confirmed in future studies. PMID- 29437938 TI - Detection of human cytomegalovirus in bronchoalveolar lavage of intensive care unit patients. PMID- 29437939 TI - Evolution of respiratory function in Duchenne muscular dystrophy from childhood to adulthood. AB - In Duchenne muscular dystrophy (DMD), it is still to be determined if specific timepoints can be identified during the natural evolution of respiratory dysfunction from childhood to adulthood and if scoliosis, steroid therapy and nocturnal noninvasive mechanical ventilation (NIMV) have any effect on it.In a 7 year retrospective study performed on 115 DMD patients (6-24 years), evaluated once or twice per year, with 574 visits in total, evolution mean curves of spirometry, lung volumes, spontaneous breathing and thoraco-abdominal pattern (measured by optoelectronic plethysmography) parameters were obtained by nonlinear regression model analysis.While predicted values of forced vital capacity, forced expiratory volume in 1 s, and peak expiratory flow decline continuously since childhood, during spontaneous breathing the following parameters become significantly different than normal in sequence: abdominal contribution to tidal volume (lower after 14.8 years), tidal volume (lower after 17.2 years), minute ventilation (lower after 18.1 years) and respiratory rate (higher after 22.1 years). Restrictive lung pattern and diaphragmatic impairment are exacerbated by scoliosis severity, slowed by steroids treatment and significantly affected by NIMV.Spirometry, lung volumes, breathing pattern and thoraco-abdominal contributions show different evolution curves over time. Specific timepoints of respiratory impairment are identified during disease progression. These should be considered when defining outcome measures in clinical trials and treatment strategies in DMD. PMID- 29437940 TI - The effect of text messaging on latent tuberculosis treatment adherence: a randomised controlled trial. AB - There is limited high-quality evidence available to inform the use of text messaging to improve latent tuberculosis infection (LTBI) treatment adherence.We performed a parallel, randomised controlled trial at two sites to assess the effect of a two-way short message service on LTBI adherence. We enrolled adults initiating LTBI therapy from June 2012 to September 2015 in British Columbia, Canada. Participants were randomised in a 1:1 ratio to standard LTBI treatment (control) or standard LTBI treatment plus two-way weekly text messaging (intervention). The primary outcome was treatment completion, defined as taking >=80% prescribed doses within 12 months (isoniazid) or 6 months (rifampin) of enrolment. The trial was unblinded except for the data analyst.A total of 358 participants were assigned to the intervention (n=170) and control (n=188) arms. In intention-to-treat analysis, the proportion of participants completing LTBI therapy in the intervention and control arms was 79.4% and 81.9%, respectively (RR 0.97, 95% CI 0.88-1.07; p=0.550). Results were similar for pre-specified secondary end-points, including time-to-completion of LTBI therapy, completion of >90% of prescribed LTBI doses and health-related quality of life.Weekly two-way text messaging did not improve LTBI completion rates compared to standard LTBI care; however, completion rates were high in both treatment arms. PMID- 29437941 TI - Intravenous magnesium sulfate for acute wheezing in young children: a randomised double-blind trial. AB - Magnesium sulfate has been shown to be an effective treatment in older children with asthma exacerbations, but it has not been investigated in acute severe virus induced wheezing in young children.The study enrolled 61 children aged 6 months to 4 years. Inclusion criteria were severe wheezing, classified as a score of >=6 points as assessed by the Respiratory Distress Assessment Instrument (RDAI) after initial treatment with salbutamol, and the symptoms of acute viral infection. The children were randomly allocated to receive either an infusion of magnesium sulfate (40 mg.kg-1) or 0.9% sodium chloride as a placebo infusion for 20 min. Primary outcome measure was mean change in RDAI scores from baseline to 6 h after the treatment.Change in the severity of wheezing from baseline to 6 h after the treatment, as measured by mean+/-sd RDAI scores, was 4.7+/-2.6 in the magnesium sulfate group and 4.2+/-4.2 in the placebo group (difference 0.5, 95% CI -1.3 to 2.3, p=0.594).Intravenous magnesium sulfate was ineffective in treating acute severe virus-induced wheezing in young children, in contrast to the previous efficacy demonstrated in older children. PMID- 29437942 TI - E-cigarette vapour enhances pneumococcal adherence to airway epithelial cells. AB - E-cigarette vapour contains free radicals with the potential to induce oxidative stress. Since oxidative stress in airway cells increases platelet-activating factor receptor (PAFR) expression, and PAFR is co-opted by pneumococci to adhere to host cells, we hypothesised that E-cigarette vapour increases pneumococcal adhesion to airway cells.Nasal epithelial PAFR was assessed in non-vaping controls, and in adults before and after 5 min of vaping. We determined the effect of vapour on oxidative stress-induced, PAFR-dependent pneumococcal adhesion to airway epithelial cells in vitro, and on pneumococcal colonisation in the mouse nasopharynx. Elemental analysis of vapour was done by mass spectrometry, and oxidative potential of vapour assessed by antioxidant depletion in vitroThere was no difference in baseline nasal epithelial PAFR expression between vapers (n=11) and controls (n=6). Vaping increased nasal PAFR expression. Nicotine-containing and nicotine-free E-cigarette vapour increased pneumococcal adhesion to airway cells in vitro Vapour-stimulated adhesion in vitro was attenuated by the PAFR blocker CV3988. Nicotine-containing E-cigarette vapour increased mouse nasal PAFR expression, and nasopharyngeal pneumococcal colonisation. Vapour contained redox-active metals, had considerable oxidative activity, and adhesion was attenuated by the antioxidant N-acetyl cysteine.This study suggests that E-cigarette vapour has the potential to increase susceptibility to pneumococcal infection. PMID- 29437943 TI - Macitentan in pulmonary hypertension due to left ventricular dysfunction. AB - The MELODY-1 study evaluated macitentan for pulmonary hypertension because of left heart disease (PH-LHD) in patients with combined post- and pre-capillary PH.63 patients with PH-LHD and diastolic pressure gradient >=7 mmHg and pulmonary vascular resistance (PVR) >3WU were randomised to macitentan 10 mg (n=31) or placebo (n=32) for 12 weeks. The main end-point assessed a composite of significant fluid retention (weight gain >=5% or >=5 kg because of fluid overload or parenteral diuretic administration) or worsening in New York Heart Association functional class from baseline to end of treatment. Exploratory end-points included changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) and haemodynamics at week 12.Seven macitentan-treated and four placebo-treated patients experienced significant fluid retention/worsening functional class; treatment difference, 10.08% (95% CI -15.07-33.26; p=0.34). The difference, driven by the fluid retention component, was apparent within the first month. At week 12, versus placebo, the macitentan group showed no change in PVR, mean right atrial pressure or pulmonary arterial wedge pressure; a non-significant increase in cardiac index (treatment effect 0.4 (95% CI 0.1-0.7) L.min-1.m-2) and decrease in NT-proBNP (0.77 (0.55-1.08)) was observed. Adverse events and serious adverse events were numerically more frequent with macitentan versus placebo.Macitentan treated patients were quantitatively more likely to experience significant fluid retention versus placebo. Macitentan resulted in no significant changes in any exploratory end-points. PMID- 29437944 TI - Emphysema and extrapulmonary tissue loss in COPD: a multi-organ loss of tissue phenotype. AB - We tested whether emphysema progression accompanies enhanced tissue loss in other body compartments in 1817 patients from the ECLIPSE chronic obstructive pulmonary disease (COPD) cohort.Clinical and selected systemic biomarker measurements were compared in subjects grouped by quantitative tomography scan emphysema quartiles using the percentage of low attenuation area (LAA%). Lowest and highest quartile patients had amino-acid metabolomic profiles. We related LAA% to 3 years decline in lung function (forced expiratory volume in 1 s (FEV1)), body mass index (BMI), fat-free mass index (FFMI) and exacerbations, hospitalisations and mortality rates.Participants with more baseline emphysema had lower FEV1, BMI and FFMI, worse functional capacity, and less cardiovascular disease but more osteoporosis. Systemic C-reactive protein and interleukin-6 levels were similar among groups, but club cell protein 16 was higher and interleukin-8, surfactant protein D and soluble receptor for advanced glycation end product were lower with more emphysema. Metabolomics differed between extreme emphysema quartiles. Patients with more emphysema had accelerated FEV1, BMI and FFMI decline and more exacerbations, hospitalisations and mortality.COPD patients with more emphysema undergo excessive loss of pulmonary and extrapulmonary tissue, which is probably related to abnormal tissue maintenance. Because of worse clinical outcomes, we propose this subgroup be named the multi-organ loss of tissue (MOLT) COPD phenotype. PMID- 29437945 TI - A comparison of linezolid lung tissue concentrations among patients with drug resistant tuberculosis. PMID- 29437946 TI - Should gatifloxacin be included in the model list of essential medicines? PMID- 29437947 TI - Variation in incidence trends of malignant pleural mesothelioma in Europe. PMID- 29437948 TI - The great breathlessness of cardiopulmonary diseases. PMID- 29437949 TI - On Don Quixote and pink puffers: multi-organ loss of tissue COPD. PMID- 29437950 TI - Will we be singing a different tune on combined post- and pre-capillary pulmonary hypertension? PMID- 29437951 TI - Heat shock protein-90 toward theranostics: a breath of fresh air in idiopathic pulmonary fibrosis. PMID- 29437952 TI - Septal cholinergic neurons gate hippocampal output to entorhinal cortex via oriens lacunosum moleculare interneurons. AB - Neuromodulation of neural networks, whereby a selected circuit is regulated by a particular modulator, plays a critical role in learning and memory. Among neuromodulators, acetylcholine (ACh) plays a critical role in hippocampus dependent memory and has been shown to modulate neuronal circuits in the hippocampus. However, it has remained unknown how ACh modulates hippocampal output. Here, using in vitro and in vivo approaches, we show that ACh, by activating oriens lacunosum moleculare (OLM) interneurons and therefore augmenting the negative-feedback regulation to the CA1 pyramidal neurons, suppresses the circuit from the hippocampal area CA1 to the deep-layer entorhinal cortex (EC). We also demonstrate, using mouse behavior studies, that the ablation of OLM interneurons specifically impairs hippocampus-dependent but not hippocampus-independent learning. These data suggest that ACh plays an important role in regulating hippocampal output to the EC by activating OLM interneurons, which is critical for the formation of hippocampus-dependent memory. PMID- 29437953 TI - SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice. AB - Solute carrier family 39, member 14 (SLC39A14) is a transmembrane transporter that can mediate the cellular uptake of zinc, iron, and manganese (Mn). Studies of Slc39a14 knockout (Slc39a14-/-) mice have documented that SLC39A14 is required for systemic growth, hepatic zinc uptake during inflammation, and iron loading of the liver in iron overload. The normal physiological roles of SLC39A14, however, remain incompletely characterized. Here, we report that Slc39a14-/- mice spontaneously display dramatic alterations in tissue Mn concentrations, suggesting that Mn is a main physiological substrate for SLC39A14. Specifically, Slc39a14-/- mice have abnormally low Mn levels in the liver coupled with markedly elevated Mn concentrations in blood and most other organs, especially the brain and bone. Radiotracer studies using 54Mn reveal that Slc39a14-/- mice have impaired Mn uptake by the liver and pancreas and reduced gastrointestinal Mn excretion. In the brain of Slc39a14-/- mice, Mn accumulated in the pons and basal ganglia, including the globus pallidus, a region susceptible to Mn-related neurotoxicity. Brain Mn accumulation in Slc39a14-/- mice was associated with locomotor impairments, as assessed by various behavioral tests. Although a low-Mn diet started at weaning was able to reverse brain Mn accumulation in Slc39a14-/- mice, it did not correct their motor deficits. We conclude that SLC39A14 is essential for efficient Mn uptake by the liver and pancreas, and its deficiency results in impaired Mn excretion and accumulation of the metal in other tissues. The inability of Mn depletion to correct the motor deficits in Slc39a14-/- mice suggests that the motor impairments represent lasting effects of early-life Mn exposure. PMID- 29437955 TI - Field study of charitable giving reveals that reciprocity decays over time. AB - We examine how reciprocity changes over time by studying a large quasiexperiment in the field. Specifically, we analyze administrative data from a university hospital system. The data include information about over 18,000 donation requests made by the hospital system via mail to a set of its former patients in the 4 months after their first hospital visit. We exploit quasiexperimental variation in the timing of solicitation mailings relative to patient hospital visits and find that an extra 30-day delay between the provision of medical care and a donation solicitation decreases the likelihood of a donation by 30%. Our findings have important implications for models of economic behavior, which currently fail to incorporate reciprocity's sensitivity to time. The fact that reciprocal behavior decays rapidly as time passes also suggests the importance of capitalizing quickly on opportunities to benefit from a quid pro quo. PMID- 29437954 TI - T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable. AB - HIV controllers (HCs) are individuals who can naturally control HIV infection, partially due to potent HIV-specific CD8+ T cell responses. Here, we examined the hypothesis that superior function of CD8+ T cells from HCs is encoded by their T cell receptors (TCRs). We compared the functional properties of immunodominant HIV-specific TCRs obtained from HLA-B*2705 HCs and chronic progressors (CPs) following expression in primary T cells. T cells transduced with TCRs from HCs and CPs showed equivalent induction of epitope-specific cytotoxicity, cytokine secretion, and antigen-binding properties. Transduced T cells comparably, albeit modestly, also suppressed HIV infection in vitro and in humanized mice. We also performed extensive molecular dynamics simulations that provided a structural basis for similarities in cytotoxicity and epitope cross-reactivity. These results demonstrate that the differential abilities of HIV-specific CD8+ T cells from HCs and CPs are not genetically encoded in the TCRs alone and must depend on additional factors. PMID- 29437956 TI - Spatial patterns of tree yield explained by endogenous forces through a correspondence between the Ising model and ecology. AB - Spatial patterning of periodic dynamics is a dramatic and ubiquitous ecological phenomenon arising in systems ranging from diseases to plants to mammals. The degree to which spatial correlations in cyclic dynamics are the result of endogenous factors related to local dynamics vs. exogenous forcing has been one of the central questions in ecology for nearly a century. With the goal of obtaining a robust explanation for correlations over space and time in dynamics that would apply to many systems, we base our analysis on the Ising model of statistical physics, which provides a fundamental mechanism of spatial patterning. We show, using 5 y of data on over 6,500 trees in a pistachio orchard, that annual nut production, in different years, exhibits both large scale synchrony and self-similar, power-law decaying correlations consistent with the Ising model near criticality. Our approach demonstrates the possibility that short-range interactions can lead to long-range correlations over space and time of cyclic dynamics even in the presence of large environmental variability. We propose that root grafting could be the common mechanism leading to positive short-range interactions that explains the ubiquity of masting, correlated seed production over space through time, by trees. PMID- 29437957 TI - Normal aging induces A1-like astrocyte reactivity. AB - The decline of cognitive function occurs with aging, but the mechanisms responsible are unknown. Astrocytes instruct the formation, maturation, and elimination of synapses, and impairment of these functions has been implicated in many diseases. These findings raise the question of whether astrocyte dysfunction could contribute to cognitive decline in aging. We used the Bac-Trap method to perform RNA sequencing of astrocytes from different brain regions across the lifespan of the mouse. We found that astrocytes have region-specific transcriptional identities that change with age in a region-dependent manner. We validated our findings using fluorescence in situ hybridization and quantitative PCR. Detailed analysis of the differentially expressed genes in aging revealed that aged astrocytes take on a reactive phenotype of neuroinflammatory A1-like reactive astrocytes. Hippocampal and striatal astrocytes up-regulated a greater number of reactive astrocyte genes compared with cortical astrocytes. Moreover, aged brains formed many more A1 reactive astrocytes in response to the neuroinflammation inducer lipopolysaccharide. We found that the aging-induced up regulation of reactive astrocyte genes was significantly reduced in mice lacking the microglial-secreted cytokines (IL-1alpha, TNF, and C1q) known to induce A1 reactive astrocyte formation, indicating that microglia promote astrocyte activation in aging. Since A1 reactive astrocytes lose the ability to carry out their normal functions, produce complement components, and release a toxic factor which kills neurons and oligodendrocytes, the aging-induced up-regulation of reactive genes by astrocytes could contribute to the cognitive decline in vulnerable brain regions in normal aging and contribute to the greater vulnerability of the aged brain to injury. PMID- 29437958 TI - Superinfection Exclusion between Two High-Risk Human Papillomavirus (HPV) Types During a Co-Infection. AB - Superinfection exclusion is a common phenomenon whereby a single cell is unable to be infected by two types of the same pathogen. Superinfection exclusion has been described for various viruses including vaccinia virus, measles virus, hepatitis C virus, influenza A virus, and human immunodeficiency virus. Additionally, the mechanism of exclusion has been observed at various steps in the viral life cycle including attachment, entry, viral genomic replication, transcription, and exocytosis. Human papillomavirus is the causative agent of cervical cancer. Recent epidemiological studies indicate that up to 50% women who are HPV+ are infected with more than one HPV type. However, no mechanism of superinfection exclusion has ever been identified for HPV. Here, we show that superinfection exclusion exists during a HPV co-infection and that it occurs on the cell surface during the attachment/entry phase of the viral lifecycle. Additionally, we are able to show that the minor capsid protein, L2, plays a role in this exclusion. This study shows, for the first time, that superinfection exclusion occurs during HPV co-infections and describes a potential molecular mechanism through which it occurs.IMPORTANCE Superinfection exclusion is a phenomenon whereby one cell is unable to be infected by multiple related pathogens. It has been described for many viruses and has been shown to occur at various points in the viral lifecycle. HPV is the causative agent of cervical cancer and is involved in other anogenital and orphopharyngeal cancers. Recent epidemiological research has shown that up to 50% of HPV positive individuals harbor more than one type of HPV. We investigated the interaction between two high-risk HPV types, HPV16 and HPV18 during a co-infection. We present data that HPV16 is able to block, or exclude, HPV18 on the cell surface during a co infection. This exclusion is, in part, due to differences in the HPV minor capsid protein, L2. This report provides, for the first time, evidence of superinfection exclusion for HPV and leads to a better understanding of the complex interactions between multiple HPV types during co-infections. PMID- 29437959 TI - The Unstructured Paramyxovirus Nucleocapsid Protein Tail Domain Modulates Viral Pathogenesis through Regulation of Transcriptase Activity. AB - The paramyxovirus replication machinery comprises the viral large (L) protein and phosphoprotein (P-protein) in addition to the nucleocapsid (N) protein, which encapsidates the single-stranded RNA genome. Common to paramyxovirus N proteins is a C-terminal tail (Ntail). The mechanistic role and relevance for virus replication of the structurally disordered central Ntail section are unknown. Focusing initially on members of the Morbillivirus genus, a series of measles virus (MeV) and canine distemper virus (CDV) N proteins were generated with internal deletions in the unstructured tail section. N proteins with large tail truncations remained bioactive in mono- and polycistronic minireplicon assays and supported efficient replication of recombinant viruses. Bioactivity of Ntail mutants extended to N proteins derived from highly pathogenic Nipah virus. To probe an effect of Ntail truncations on viral pathogenesis, recombinant CDVs were analyzed in a lethal CDV/ferret model of morbillivirus disease. The recombinant viruses displayed different stages of attenuation ranging from ameliorated clinical symptoms to complete survival of infected animals, depending on the molecular nature of the Ntail truncation. Reinfection of surviving animals with pathogenic CDV revealed robust protection against a lethal challenge. The highly attenuated virus was genetically stable after ex vivo passaging and recovery from infected animals. Mechanistically, gradual viral attenuation coincided with stepwise altered viral transcriptase activity in infected cells. These results identify the central Ntail section as a determinant for viral pathogenesis and establish a novel platform to engineer gradual virus attenuation for next generation paramyxovirus vaccine design.IMPORTANCE Investigating the role of the paramyxovirus N protein tail domain (Ntail) in virus replication, we demonstrated in this study that the structurally disordered central Ntail region is a determinant for viral pathogenesis. We show that internal deletions in this Ntail region of up to 55 amino acids in length are compatible with efficient replication of recombinant viruses in cell culture but result in gradual viral attenuation in a lethal canine distemper virus (CDV)/ferret model. Mechanistically, we demonstrate a role of the intact Ntail region in the regulation of viral transcriptase activity. Recombinant viruses with Ntail truncations induce protective immunity against lethal challenge of ferrets with pathogenic CDV. This identification of the unstructured central Ntail domain as a nonessential paramyxovirus pathogenesis factor establishes a foundation for harnessing Ntail truncations for vaccine engineering against emerging and reemerging members of the paramyxovirus family. PMID- 29437960 TI - Silencing Retinoid X Receptor Alpha Expression Enhances Early-Stage Hepatitis B Virus Infection In Cell Cultures. AB - Multiple steps of the life cycle of hepatitis B virus (HBV) are known to be coupled to hepatic metabolism. However, the details of involvement of the hepatic metabolic milieu in HBV infection remain incompletely understood. Hepatic lipid metabolism is controlled by a complicated transcription factor network centered on retinoid X receptor alpha (RXRalpha). Here, we report that RXRalpha negatively regulates HBV infection at an early stage in cell cultures. The RXR-specific agonist bexarotene inhibits HBV in HepG2 cells expressing the sodium taurocholate cotransporting polypeptide (NTCP) (HepG2-NTCP), HepaRG cells, and primary Tupaia hepatocytes (PTHs); reducing RXRalpha expression significantly enhanced HBV infection in the cells. Transcriptome sequencing (RNA-seq) analysis of HepG2-NTCP cells with a disrupted RXRalpha gene revealed that reduced gene expression in arachidonic acid (AA)/eicosanoid biosynthesis pathways, including the AA synthases phospholipase A2 group IIA (PLA2G2A), is associated with increased HBV infection. Moreover, exogenous treatment of AA inhibits HBV infection in HepG2 NTCP cells. These data demonstrate that RXRalpha is an important cellular factor in modulating HBV infection and implicate the participation of AA/eicosanoid biosynthesis pathways in the regulation of HBV infection.IMPORTANCE Understanding how HBV infection is connected with hepatic lipid metabolism may provide new insights into virus infection and its pathogenesis. By a series of genetic studies in combination with transcriptome analysis and pharmacological assays, we here investigated the role of cellular retinoid X receptor alpha (RXRalpha), a crucial transcription factor for controlling hepatic lipid metabolism, in de novo HBV infection in cell cultures. We found that silencing of RXRalpha resulted in elevated HBV covalently closed circular DNA (cccDNA) formation and viral antigen production, while activation of RXRalpha reduced HBV infection efficiency. Our results also showed that silencing phospholipase A2 group IIA (PLA2G2A), a key enzyme of arachidonic acid (AA) synthases, enhanced HBV infection efficiency in HepG2-NTCP cells and that exogenous AA treatment reduced de novo HBV infection in the cells. These findings unveil RXRalpha as an important cellular factor in modulating HBV infection and may point to a new strategy for host-targeted therapies against HBV. PMID- 29437961 TI - Hepatitis B virus DNA integration occurs early in the viral life cycle in an in vitro infection model via NTCP-dependent uptake of enveloped virus particles. AB - Chronic infection by the Hepatitis B Virus (HBV) is the major contributor to liver disease worldwide. Though HBV replicates via a nuclear episomal DNA (cccDNA), integration of HBV DNA into the host cell genome is regularly observed in the liver of infected patients. While reported as a pro-oncogenic alteration, the mechanism(s) and timing of HBV DNA integration are not well-understood, chiefly due to the lack of in vitro infection models that have detectable integration events. Here, we have established an in vitro system in which integration can be reliably detected following HBV infection. We measured HBV DNA integration using inverse nested PCR in primary human hepatocytes, HepaRG-NTCP, HepG2-NTCP, and Huh7-NTCP cells after HBV infection. Integration was detected in all cell types at a rate of >1 per 10000 cells, with the most consistent detection in Huh7-NTCP cells. Integration rate remained stable between 3 and 9 days post-infection. HBV DNA integration was efficiently blocked by treatment with 200nM of the HBV entry inhibitor Myrcludex B, but not with 10MUM Tenofovir, 100U Interferon alpha, or 1MUM of the capsid assembly inhibitor GLS4. This suggests integration of HBV DNA occurs immediately after infection of hepatocytes and is likely independent of de novo HBV replication in this model. Site analysis revealed that HBV DNA integrations were distributed over the entire human genome. Further, integrated HBV DNA sequences were consistent with double-stranded linear HBV DNA being the major precursor. Thus, we have established an in vitro system to interrogate the mechanisms of HBV DNA integration.ImportanceHepatitis B Virus (HBV) is a common blood-borne pathogen and, following a chronic infection, can cause liver cancer and liver cirrhosis. Integration of HBV DNA into the host genome occurs in all known members of the hepadnaviridae family, despite this form not being necessary for viral replication. HBV DNA integration has been reported to drive liver cancer formation and persistence of virus infection. However, when and the mechanism(s) by which HBV DNA integration occurs is not clear. Here, we have developed and characterized an in vitro system to reliably detect HBV DNA integrations that result from a true HBV infection event and that closely resemble those found in patient tissues. Using this model, we show that integration already occurs when the infection is first established. Importantly, we provide here a system to analyze molecular factors involved in HBV integration, which can be used to develop strategies to halt its formation. PMID- 29437962 TI - Shigella Phages Isolated during a Dysentery Outbreak Reveal Uncommon Structures and Broad Species Diversity. AB - In 2016, Michigan experienced the largest outbreak of shigellosis, a type of bacillary dysentery caused by Shigella spp., since 1988. Following this outbreak, we isolated 16 novel Shigella-infecting bacteriophages (viruses that infect bacteria) from environmental water sources. Most well-known bacteriophages infect the common laboratory species Escherichia coli and Salmonella enterica, and these phages have built the foundation of molecular and bacteriophage biology. Until now, comparatively few bacteriophages were known to infect Shigella spp., which are close relatives of E. coli We present a comprehensive analysis of these phages' host ranges, genomes, and structures, revealing genome sizes and capsid properties that are shared by very few previously described phages. After sequencing, a majority of the Shigella phages were found to have genomes of an uncommon size, shared by only 2% of all reported phage genomes. To investigate the structural implications of this unusual genome size, we used cryo-electron microscopy to resolve their capsid structures. We determined that these bacteriophage capsids have similarly uncommon geometry. Only two other viruses with this capsid structure have been described. Since most well-known bacteriophages infect Escherichia or Salmonella, our understanding of bacteriophages has been limited to a subset of well-described systems. Continuing to isolate phages using nontraditional strains of bacteria can fill gaps that currently exist in bacteriophage biology. In addition, the prevalence of Shigella phages during a shigellosis outbreak may suggest a potential impact of human health epidemics on local microbial communities.IMPORTANCEShigella spp. bacteria are causative agents of dysentery and affect more than 164 million people worldwide every year. Despite the need to combat antibiotic-resistant Shigella strains, relatively few Shigella-infecting bacteriophages have been described. By specifically looking for Shigella-infecting phages, this work has identified new isolates that (i) may be useful to combat Shigella infections and (ii) fill gaps in our knowledge of bacteriophage biology. The rare qualities of these new isolates emphasize the importance of isolating phages on "nontraditional" laboratory strains of bacteria to more fully understand both the basic biology and diversity of bacteriophages. PMID- 29437963 TI - Induction of Genotype Cross-Reactive, Hepatitis C Virus-Specific, Cell-Mediated Immunity in DNA-Vaccinated Mice. AB - A universal hepatitis C virus (HCV) vaccine should elicit multiantigenic, multigenotypic responses, which are more likely to protect against challenge with the range of genotypes and subtypes circulating in the community. A vaccine cocktail and vaccines encoding consensus HCV sequences are attractive approaches to achieve this goal. Consequently, in a series of mouse vaccination studies, we compared the immunogenicity of a DNA vaccine encoding a consensus HCV nonstructural 5B (NS5B) protein to that of a cocktail of DNA plasmids encoding the genotype 1b (Gt1b) and Gt3a NS5B proteins. To complement this study, we assessed responses to a multiantigenic cocktail regimen by comparing a DNA vaccine cocktail encoding Gt1b and Gt3a NS3, NS4, and NS5B proteins to a single genotype NS3/4/5B DNA vaccine. To thoroughly evaluate in vivo cytotoxic T lymphocyte (CTL) and T helper (Th) cell responses against Gt1b and Gt3a HCV peptide-pulsed target cells, we exploited a novel fluorescent-target array (FTA). FTA and enzyme-linked immunosorbent spot (ELISpot) analyses collectively indicated that the cocktail regimens elicited higher responses to Gt1b and Gt3a NS5B proteins than those with the consensus vaccine, while the multiantigenic DNA cocktail significantly increased the responses to NS3 and NS5B compared to those elicited by the single-genotype vaccines. Thus, a DNA cocktail vaccination regimen is more effective than a consensus vaccine or a monovalent vaccine at increasing the breadth of multigenotypic T cell responses, which has implications for the development of vaccines for communities where multiple HCV genotypes circulate.IMPORTANCE Despite the development of highly effective direct-acting antivirals (DAA), infections with hepatitis C virus (HCV) continue, particularly in countries where the supply of DAA is limited. Furthermore, patients who eliminate the virus as a result of DAA therapy can still be reinfected. Thus, a vaccine for HCV is urgently required, but the heterogeneity of HCV strains makes the development of a universal vaccine difficult. To address this, we developed a novel cytolytic DNA vaccine which elicits robust cell-mediated immunity (CMI) to the nonstructural (NS) proteins in vaccinated animals. We compared the immune responses against genotypes 1 and 3 that were elicited by a consensus DNA vaccine or a DNA vaccine cocktail and showed that the cocktail induced higher levels of CMI to the NS proteins of both genotypes. This study suggests that a universal HCV vaccine can most readily be achieved by use of a DNA vaccine cocktail. PMID- 29437964 TI - In Vitro Measles Virus Infection of Human Lymphocyte Subsets Demonstrates High Susceptibility and Permissiveness of both Naive and Memory B Cells. AB - Measles is characterized by a transient immune suppression, leading to an increased risk of opportunistic infections. Measles virus (MV) infection of immune cells is mediated by the cellular receptor CD150, expressed by subsets of lymphocytes, dendritic cells, macrophages, and thymocytes. Previous studies showed that human and nonhuman primate memory T cells express higher levels of CD150 than naive cells and are more susceptible to MV infection. However, limited information is available about the CD150 expression and relative susceptibility to MV infection of B-cell subsets. In this study, we assessed the susceptibility and permissiveness of naive and memory T- and B-cell subsets from human peripheral blood or tonsils to in vitro MV infection. Our study demonstrates that naive and memory B cells express CD150, but at lower frequencies than memory T cells. Nevertheless, both naive and memory B cells proved to be highly permissive to MV infection. Furthermore, we assessed the susceptibility and permissiveness of various functionally distinct T and B cells, such as helper T (TH) cell subsets and IgG- and IgA-positive memory B cells, in peripheral blood and tonsils. We demonstrated that TH1TH17 cells and plasma and germinal center B cells were the subsets most susceptible and permissive to MV infection. Our study suggests that both naive and memory B cells, along with several other antigen experienced lymphocytes, are important target cells of MV infection. Depletion of these cells potentially contributes to the pathogenesis of measles immune suppression.IMPORTANCE Measles is associated with immune suppression and is often complicated by bacterial pneumonia, otitis media, or gastroenteritis. Measles virus infects antigen-presenting cells and T and B cells, and depletion of these cells may contribute to lymphopenia and immune suppression. Measles has been associated with follicular exhaustion in lymphoid tissues in humans and nonhuman primates, emphasizing the importance of MV infection of B cells in vivo However, information on the relative susceptibility of B-cell subsets is scarce. Here, we compared the susceptibility and permissiveness to in vitro MV infection of human naive and memory T- and B-cell subsets isolated from peripheral blood or tonsils. Our results demonstrate that both naive and memory B cells are more permissive to MV infection than T cells. The highest infection levels were detected in plasma cells and germinal center B cells, suggesting that infection and depletion of these populations contribute to reduced host resistance. PMID- 29437965 TI - CTCF Binding Sites in the Herpes Simplex Virus 1 Genome Display Site-Specific CTCF Occupation, Protein Recruitment, and Insulator Function. AB - There are seven conserved CTCF binding domains in the herpes simplex virus 1 (HSV 1) genome. These binding sites individually flank the latency-associated transcript (LAT) and the immediate early (IE) gene regions, suggesting that CTCF insulators differentially control transcriptional domains in HSV-1 latency. In this work, we show that two CTCF binding motifs in HSV-1 display enhancer blocking in a cell-type-specific manner. We found that CTCF binding to the latent HSV-1 genome was LAT dependent and that the quantity of bound CTCF was site specific. Following reactivation, CTCF eviction was dynamic, suggesting that each CTCF site was independently regulated. We explored whether CTCF sites recruit the polycomb-repressive complex 2 (PRC2) to establish repressive domains through a CTCF-Suz12 interaction and found that Suz12 colocalized to the CTCF insulators flanking the ICP0 and ICP4 regions and, conversely, was removed at early times postreactivation. Collectively, these data support the idea that CTCF sites in HSV-1 are independently regulated and may contribute to lytic-latent HSV-1 control in a site-specific manner.IMPORTANCE The role of chromatin insulators in DNA viruses is an area of interest. It has been shown in several beta- and gammaherpesviruses that insulators likely control the lytic transcriptional profile through protein recruitment and through the formation of three dimensional (3D) chromatin loops. The ability of insulators to regulate alphaherpesviruses has been understudied to date. The alphaherpesvirus HSV-1 has seven conserved insulator binding motifs that flank regions of the genome known to contribute to the establishment of latency. Our work presented here contributes to the understanding of how insulators control transcription of HSV 1. PMID- 29437966 TI - Herpes Simplex Virus 1 Dramatically Alters Loading and Positioning of RNA Polymerase II on Host Genes Early in Infection. AB - Herpes simplex virus 1 (HSV-1) transcription is mediated by cellular RNA Polymerase II (Pol II). Recent studies investigating how Pol II transcription of host genes is altered after HSV-1 are conflicting. ChIP-seq studies suggest Pol II is almost completely removed from host genes at 4 hours post infection (hpi), while 4SU labeling experiments show that host transcription termination is extended at 7 hpi implying a significant amount of Pol II remains associated with host genes in infected cells. To address this discrepancy, we used precision nuclear run on (PRO-seq) to determine the location of Pol II to single base pair resolution in combination with quantitative, reverse transcription PCR (qRTPCR) analysis 3 hpi. HSV-1 decreased Pol II on approximately 2/3 of cellular genes, but increased Pol II on others. For more than 85% of genes for which transcriptional termination could be statistically assessed, Pol II was displaced to positions downstream of the normal termination zone suggesting extensive termination defects. Pol II amounts at the promoter, promoter-proximal pause site, and gene body were also modulated in a gene-specific manner. qRTPCR of selected RNAs showed that HSV-1 induced extension of the termination zone strongly correlated with decreased RNA and mRNA accumulation. However, HSV-1 induced increases of Pol II occupancy on genes without termination zone extension correlated with increased cytoplasmic mRNA. Functional grouping of genes with increased Pol II occupancy suggested an upregulation of exosome secretion, and downregulation of apoptosis, both of which are potentially beneficial to virus production.ImportanceThis study provides a map of RNA polymerase II location on host genes after infection with HSV-1 with greater detail than previous ChIP-seq studies and rectifies discrepancies between ChIP-seq data and 4SU labeling experiments with HSV-1. The data shows the effects a given change in RNA Pol II location on host genes has on the abundance of different RNA types, including nuclear, polyadenylated mRNA and cytoplasmic, polyadenylated mRNA. It gives a clearer understanding of how HSV-1 augments host transcription of some genes to provide an environment favorable to HSV-1 replication. PMID- 29437967 TI - Immunogenicity of NYVAC Prime-Protein Boost Human Immunodeficiency Virus Type 1 Envelope Vaccination and Simian-Human Immunodeficiency Virus Challenge of Nonhuman Primates. AB - A preventive human immunodeficiency virus type 1 (HIV-1) vaccine is an essential part of the strategy to eradicate AIDS. A critical question is whether antibodies that do not neutralize primary isolate (tier 2) HIV-1 strains can protect from infection. In this study, we investigated the ability of an attenuated poxvirus vector (NYVAC) prime-envelope gp120 boost to elicit potentially protective antibody responses in a rhesus macaque model of mucosal simian-human immunodeficiency virus (SHIV) infection. NYVAC vector delivery of a group M consensus envelope, trivalent mosaic envelopes, or a natural clade B isolate B.1059 envelope elicited antibodies that mediated neutralization of tier 1 viruses, cellular cytotoxicity, and phagocytosis. None of the macaques made neutralizing antibodies against the tier 2 SHIV SF162P3 used for mucosal challenge. Significant protection from infection was not observed for the three groups of vaccinated macaques compared to unvaccinated macaques, although binding antibody to HIV-1 Env correlated with decreased viremia after challenge. Thus, NYVAC Env prime-gp120 boost vaccination elicited polyfunctional, nonneutralizing antibody responses with minimal protective activity against tier 2 SHIV mucosal challenge.IMPORTANCE The antibody responses that confer protection against HIV-1 infection remain unknown. Polyfunctional antibody responses correlated with time to infection in previous macaque studies. Determining the ability of vaccines to induce these types of responses is critical for understanding how to improve upon the one efficacious human HIV-1 vaccine trial completed thus far. We characterized the antibody responses induced by a NYVAC-protein vaccine and determined the protective capacity of polyfunctional antibody responses in an R5, tier 2 mucosal SHIV infection model. PMID- 29437968 TI - Induction of Interferon Kappa in Human Papillomavirus 16 Infection by Transforming Growth Factor Beta-Induced Promoter Demethylation. AB - Persistent high-risk human papillomavirus (HPV) infection is the major causal factor in cervical and other anogenital cancers. Because there are currently no therapeutics capable of preventing neoplastic progression of HPV infections, understanding the mechanisms of HPV-mediated persistence, including immune evasion, is a major research priority. The multifunctional growth factor transforming growth factor beta (TGFbeta) has been shown to inhibit expression of early viral transcripts from cells harboring integrated HPV genomes or cells infected with retroviruses expressing HPV oncoproteins. However, the mechanism of TGFbeta-induced inhibition has not been fully defined. In this study, we have observed a previously uncharacterized ability of TGFbeta to repress the differentiation-induced upregulation of late HPV16 gene expression. In addition, interferon kappa (IFN-kappa), a keratinocyte-specific, constitutively expressed cytokine suppressed by differentiation, can be transcriptionally induced by TGFbeta1. TGFbeta-mediated IFN-kappa transcription only occurs in cells containing HPV16, and this is due to TGFbeta1-mediated reversal of HPV-induced methylation of the IFN-kappa promoter through active DNA demethylation mediated by thymine DNA glycosylase (TDG). This novel interaction between growth factor and innate immune signaling may shed light on the mechanisms of HPV persistence and how the virus manipulates both immune and growth factor signaling to promote its life cycle.IMPORTANCE Persistent infection by high-risk HPVs is the primary risk factor for development of HPV-induced cancers. Persistence involves viral evasion of the immune response, including the IFN response. HPV is also known to suppress TGFbeta signaling, which inhibits viral gene expression. Here, we show that the TGFbeta and IFN pathways are interrelated in the context of HPV16 infection through the upregulation of IFN-kappa by TGFbeta. The ability of TGFbeta to induce IFN-kappa promoter demethylation and transcriptional activation provides a new explanation for why HPV has evolved mechanisms to inhibit TGFbeta in infected cells. PMID- 29437969 TI - Monoclonal antibodies against occludin completely prevented hepatitis C virus infection in a mouse model. AB - Hepatitis C virus (HCV) entry into host cells is a multistep process requiring various host factors, including the tight junction protein occludin (OCLN), which has been shown to be essential for HCV infection in in vitro cell culture systems. However, it remains unclear whether OCLN is an effective and safe target for HCV therapy, owing to the lack of binders that can recognize the intact extracellular loop domains of OCLN and prevent HCV infection. In this study, we successfully generated four rat anti-OCLN monoclonal antibodies (mAbs) by genetic immunization method and unique cell differential screening. These four mAbs bound to human OCLN with a very high affinity (Kd < 1 nM). One mAb recognized the second loop of human and mouse OCLN, whereas the three other mAbs recognized the first loop of human OCLN. All mAbs inhibited HCV infection in Huh7.5.1-8 cells in a dose-dependent manner, without apparent cytotoxicity. Additionally, the anti OCLN mAbs prevented both cell-free HCV infection and cell-to-cell HCV transmission. Kinetic studies with anti-OCLN and anti-claudin-1 (CLDN1) mAbs demonstrated that OCLN interacts with HCV after CLDN1 in the internalization step. Two selected mAbs completely inhibited HCV infection in human liver chimeric mice, without apparent adverse effects. Therefore, OCLN would be an appropriate host target for anti-HCV entry inhibitors, and anti-OCLN mAbs may be promising candidates for novel anti-HCV agents, particularly in combination with direct-acting HCV antiviral agents.IMPORTANCE Hepatitis C virus (HCV) entry into host cells is thought to be a very complex process involving various host entry factors, such as the tight junction proteins claudin-1 and occludin (OCLN). In this study, we developed novel functional monoclonal antibodies (mAbs) that recognize intact extracellular domains of OCLN, which is essential for HCV entry into host cells. The established mAbs against OCLN, which had a very high affinity and selectivity for intact OCLN, strongly inhibited HCV infection both in vitro and in vivo Using these anti-OCLN mAbs, we found that OCLN is necessary for the later stages of HCV entry. These anti-OCLN mAbs are likely to be very useful for understanding the OCLN-mediated HCV entry mechanism and might be promising candidates for novel HCV entry inhibitors. PMID- 29437970 TI - A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid. AB - Polyamides have been shown to bind double-stranded DNA by complementing the curvature of the minor groove and forming various hydrogen bonds with DNA. Several polyamide molecules have been found to have potent antiviral activities against papillomavirus, a double-stranded DNA virus. By analogy, we reason that polyamides may also interact with the structured RNA bound in the nucleocapsid of a negative-strand RNA virus. Vesicular stomatitis virus (VSV) was selected as a prototype virus to test this possibility since its genomic RNA encapsidated in the nucleocapsid forms a structure resembling one strand of an A-form RNA duplex. One polyamide molecule, UMSL1011, was found to inhibit infection of VSV. To confirm that the polyamide targeted the nucleocapsid, a nucleocapsid-like particle (NLP) was incubated with UMSL1011. The encapsidated RNA in the polyamide treated NLP was protected from thermo-release and digestion by RNase A. UMSL1011 also inhibits viral RNA synthesis in the intracellular activity assay for the viral RNA-dependent RNA polymerase. The crystal structure revealed that UMSL1011 binds the structured RNA in the nucleocapsid. The conclusion of our studies is that the RNA in the nucleocapsid is a viable antiviral target of polyamides. Since the RNA structure in the nucleocapsid is similar in all negative-strand RNA viruses, polyamides may be optimized to target the specific RNA genome of a negative-strand RNA virus, such as respiratory syncytial virus and Ebola virus.IMPORTANCE Negative-strand RNA viruses (NSVs) include several life threatening pathogens, such as rabies virus, respiratory syncytial virus, and Ebola virus. There are no effective antiviral drugs against these viruses. Polyamides offer an exceptional opportunity because they may be optimized to target each NSV. Our studies on vesicular stomatitis virus, an NSV, demonstrated that a polyamide molecule could specifically target the viral RNA in the nucleocapsid and inhibit viral growth. The target specificity of the polyamide molecule was proved by its inhibition of thermo-release and RNA nuclease digestion of the RNA bound in a model nucleocapsid, and a crystal structure of the polyamide inside the nucleocapsid. This encouraging observation provided the proof-of-concept rationale for designing polyamides as antiviral drugs against NSVs. PMID- 29437971 TI - N-Terminomics TAILS Identifies Host Cell Substrates of Poliovirus and Coxsackievirus B3 3C Proteinases That Modulate Virus Infection. AB - Enteroviruses encode proteinases that are essential for processing of the translated viral polyprotein. In addition, viral proteinases also target host proteins to manipulate cellular processes and evade innate antiviral responses to promote replication and infection. Although some host protein substrates of enterovirus proteinases have been identified, the full repertoire of targets remains unknown. We used a novel quantitative in vitro proteomics-based approach, termed terminal amine isotopic labeling of substrates (TAILS), to identify with high confidence 72 and 34 new host protein targets of poliovirus and coxsackievirus B3 (CVB3) 3C proteinases (3Cpros) in HeLa cell and cardiomyocyte HL-1 cell lysates, respectively. We validated a subset of candidate substrates that are targets of poliovirus 3Cproin vitro including three common protein targets, phosphoribosylformylglycinamidine synthetase (PFAS), hnRNP K, and hnRNP M, of both proteinases. 3Cpro-targeted substrates were also cleaved in virus infected cells but not noncleavable mutant proteins designed from the TAILS identified cleavage sites. Knockdown of TAILS-identified target proteins modulated infection both negatively and positively, suggesting that cleavage by 3Cpro promotes infection. Indeed, expression of a cleavage-resistant mutant form of the endoplasmic reticulum (ER)-Golgi vesicle-tethering protein p115 decreased viral replication and yield. As the first comprehensive study to identify and validate functional enterovirus 3Cpro substrates in vivo, we conclude that N terminomics by TAILS is an effective strategy to identify host targets of viral proteinases in a nonbiased manner.IMPORTANCE Enteroviruses are positive-strand RNA viruses that encode proteases that cleave the viral polyprotein into the individual mature viral proteins. In addition, viral proteases target host proteins in order to modulate cellular pathways and block antiviral responses in order to facilitate virus infection. Although several host protein targets have been identified, the entire list of proteins that are targeted is not known. In this study, we used a novel unbiased proteomics approach to identify ~100 novel host targets of the enterovirus 3C protease, thus providing further insights into the network of cellular pathways that are modulated to promote virus infection. PMID- 29437972 TI - Susceptibility of Primary Human Choroid Plexus Epithelial Cells and Meningeal Cells to Infection by JC Virus. AB - JC polyomavirus (JCPyV) establishes a lifelong persistence in roughly half the human population worldwide. The cells and tissues that harbor persistent virus in vivo are not known, but renal tubules and other urogenital epithelial cells are likely candidates as virus is shed in the urine of healthy individuals. In an immunosuppressed host, JCPyV can become reactivated and cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system. Recent observations indicate that JCPyV may productively interact with cells in the choroid plexus and leptomeninges. To further study JCPyV infection in these cells, primary human choroid plexus epithelial cells and meningeal cells were challenged with virus, and their susceptibility to infection was compared to the human glial cell line, SVG-A. We found that JCPyV productively infects both choroid plexus epithelial cells and meningeal cells in vitro Competition with the soluble receptor fragment LSTc reduced virus infection in these cells. Treatment of cells with neuraminidase also inhibited both viral infection and binding. Treatment with the serotonin receptor antagonist, ritanserin, reduced infection in SVG-A and meningeal cells. We also compared the ability of wild-type and sialic acid-binding mutant pseudoviruses to transduce these cells. Wild-type pseudovirus readily transduced all three cell types, but pseudoviruses harboring mutations in the sialic acid-binding pocket of the virus failed to transduce the cells. These data establish a novel role for choroid plexus and meninges in harboring virus that likely contributes not only to meningoencephalopathies but also to PML.IMPORTANCE JCPyV infects greater than half the human population worldwide and causes central nervous system disease in patients with weakened immune systems. Several recent reports have found JCPyV in the choroid plexus and leptomeninges of patients with encephalitis. Due to their role in forming the blood-cerebrospinal fluid barrier, the choroid plexus and leptomeninges are also poised to play roles in virus invasion of brain parenchyma, where infection of macroglial cells leads to the development of progressive multifocal leukoencephalopathy, a severely debilitating and often fatal infection. In this paper we show for the first time that primary choroid plexus epithelial cells and meningeal cells are infected by JCPyV, lending support to the association of JCPyV with meningoencephalopathies. These data also suggest that JCPyV could use these cells as reservoirs for the subsequent invasion of brain parenchyma. PMID- 29437973 TI - RNA Binding Protein RBM38 Regulates Expression of the 11-Kilodalton Protein of Parvovirus B19, Which Facilitates Viral DNA Replication. AB - Human parvovirus B19 (B19V) expresses a single precursor mRNA (pre-mRNA), which undergoes alternative splicing and alternative polyadenylation to generate 12 viral mRNA transcripts that encode two structural proteins (VP1 and VP2) and three nonstructural proteins (NS1, 7.5-kDa protein, and 11-kDa protein). Splicing at the second 5' donor site (D2 site) of the B19V pre-mRNA is essential for the expression of VP2 and the 11-kDa protein. We previously identified that cis acting intronic splicing enhancer 2 (ISE2) that lies immediately after the D2 site facilitates the recognition of the D2 donor for its efficient splicing. In this study, we report that ISE2 is critical for the expression of the 11-kDa viral nonstructural protein. We found that ISE2 harbors a consensus RNA binding motif protein 38 (RBM38) binding sequence, 5'-UGUGUG-3'. RBM38 is expressed during the middle stage of erythropoiesis. We first confirmed that RBM38 binds specifically with the ISE2 element in vitro The knockdown of RBM38 significantly decreases the level of spliced mRNA at D2 that encodes the 11-kDa protein but not that of the D2-spliced mRNA that encodes VP2. Importantly, we found that the 11 kDa protein enhances viral DNA replication and virion release. Accordingly, the knockdown of RBM38 decreases virus replication via downregulating 11-kDa protein expression. Taken together, these results suggest that the 11-kDa protein facilitates B19V DNA replication and that RBM38 is an essential host factor for B19V pre-mRNA splicing and for the expression of the 11-kDa protein.IMPORTANCE B19V is a human pathogen that can cause fifth disease, arthropathy, anemia in immunocompromised patients and sickle cell disease patients, myocarditis, and hydrops fetalis in pregnant women. Human erythroid progenitor cells (EPCs) are most susceptible to B19V infection and fully support viral DNA replication. The exclusive tropism of B19V for erythroid-lineage cells is dependent not only on the expression of viral receptors and coreceptors on the cell surface but also on the intracellular host factors that support B19V replication. Our present study shows that B19V uses a host factor, RNA binding motif protein 38 (RBM38), for the processing of its pre-mRNA during virus replication. Specifically, RBM38 interacts with the intronic splicing enhancer 2 (ISE2) element of B19V pre-mRNA and promotes 11-kDa protein expression, thereby regulating the 11-kDa protein mediated augmentation of B19V replication. The identification of this novel host pathogen interaction will provide mechanistic insights into B19V replication and aid in finding new targets for anti-B19V therapeutics. PMID- 29437974 TI - HAVCR1 (CD365) and Its Mouse Ortholog Are Functional Hepatitis A Virus (HAV) Cellular Receptors That Mediate HAV Infection. AB - The hepatitis A virus (HAV) cellular receptor 1 (HAVCR1), classified as CD365, was initially discovered as an HAV cellular receptor using an expression cloning strategy. Due to the lack of HAV receptor-negative replication-competent cells, it was not possible to fully prove that HAVCR1 was a functional HAV receptor. However, biochemistry, classical virology, and epidemiology studies further supported the functional role of HAVCR1 as an HAV receptor. Here, we show that an anti-HAVCR1 monoclonal antibody that protected African green monkey kidney (AGMK) cells against HAV infection only partially protected monkey Vero E6 cells and human hepatoma Huh7 cells, indicating that these two cell lines express alternative yet unidentified HAV receptors. Therefore, we focused our work on AGMK cells to further characterize the function of HAVCR1 as an HAV receptor. Advances in clustered regularly interspaced short palindromic repeat/Cas9 technology allowed us to knock out the monkey ortholog of HAVCR1 in AGMK cells. The resulting AGMK HAVCR1 knockout (KO) cells lost susceptibility to HAV infection, including HAV-free viral particles (vpHAV) and exosomes purified from HAV-infected cells (exo-HAV). Transfection of HAVCR1 cDNA into AGMK HAVCR1 KO cells restored susceptibility to vpHAV and exo-HAV infection. Furthermore, transfection of the mouse ortholog of HAVCR1, mHavcr1, also restored the susceptibility of AGMK HAVCR1 KO cells to HAV infection. Taken together, our data clearly show that HAVCR1 and mHavcr1 are functional HAV receptors that mediate HAV infection. This work paves the way for the identification of alternative HAV receptors to gain a complete understanding of their interplay with HAVCR1 in the cell entry and pathogenic processes of HAV.IMPORTANCE HAVCR1, an HAV receptor, is expressed in different cell types, including regulatory immune cells and antigen presenting cells. How HAV evades the immune response during a long incubation period of up to 4 weeks and the mechanism by which the subsequent necroinflammatory process clears the infection remain a puzzle that most likely involves the HAV-HAVCR1 interaction. Based on negative data, a recent paper from the S. M. Lemon and W. Maury laboratories (A. Das, A. Hirai-Yuki, O. Gonzalez Lopez, B. Rhein, S. Moller-Tank, R. Brouillette, L. Hensley, I. Misumi, W. Lovell, J. M. Cullen, J. K. Whitmire, W. Maury, and S. M. Lemon, mBio 8:e00969 17, 2017, https://doi.org/10.1128/mBio.00969-17) suggested that HAVCR1 is not a functional HAV receptor, nor it is it required for HAV infection. However, our data, based on regain of the HAV receptor function in HAVCR1 knockout cells transfected with HAVCR1 cDNA, disagree with their findings. Our positive data show conclusively that HAVCR1 is indeed a functional HAV receptor and lays the ground for the identification of alternative HAV receptors and how they interact with HAVCR1 in cell entry and the pathogenesis of HAV. PMID- 29437975 TI - Differential Delivery of Genomic Double-Stranded RNA Causes Reovirus Strain Specific Differences in Interferon Regulatory Factor 3 Activation. AB - Serotype 3 (T3) reoviruses induce substantially more type 1 interferon (IFN-I) secretion than serotype 1 (T1) strains. However, the mechanisms underlying differences in IFN-I production between T1 and T3 reoviruses remain undefined. Here, we found that differences in IFN-I production between T1 and T3 reoviruses correlate with activation of interferon regulatory factor 3 (IRF3), a key transcription factor for the production of IFN-I. T3 strain rsT3D activated IRF3 more rapidly and to a greater extent than the T1 strain rsT1L, in simian virus 40 (SV40) immortalized endothelial cells (SVECs). Differences in IRF3 activation between rsT1L and rsT3D were observed in the first hours of infection and were independent of de novo viral RNA and protein synthesis. NF-kappaB activation mirrored IRF3 activation, with rsT3D inducing more NF-kappaB activity than rsT1L. We also found that IRF3 and NF-kappaB are activated in a mitochondrial antiviral signaling protein (MAVS)-dependent manner. rsT1L does not suppress IRF3 activation, as IRF3 phosphorylation could be induced in rsT1L-infected cells. Transfected rsT1L and rsT3D RNA induced IRF3 phosphorylation, indicating that genomic RNA from both strains has the capacity to activate IRF3. Finally, bypassing the normal route of reovirus entry by transfecting in vitro-generated viral cores revealed that rsT1L and rsT3D core particles induced equivalent IRF3 activation. Taken together, our findings indicate that entry-related events that occur after outer capsid disassembly, but prior to deposition of viral cores into the cytoplasm, influence the efficiency of IFN-I responses to reovirus. This work provides further insight into mechanisms by which nonenveloped viruses activate innate immune responses.IMPORTANCE Detection of viral nucleic acids by the host cell triggers type 1 interferon (IFN-I) responses, which are critical for containing and clearing viral infections. Viral RNA is sensed in the cytoplasm by cellular receptors that initiate signaling pathways, leading to the activation of interferon regulatory factor 3 (IRF3) and NF-kappaB, key transcription factors required for IFN-I induction. Serotype 3 (T3) reoviruses induce significantly more IFN-I than serotype 1 (T1) strains. In this work, we found that differences in IFN-I production by T1 and T3 reoviruses correlate with differential IRF3 activation. Differences in IRF3 activation are not caused by a blockade of the IRF3 activation by a T1 strain. Rather, differences in events during the late stages of viral entry determine the capacity of reovirus to activate host IFN-I responses. Together, our work provides insight into mechanisms of IFN-I induction by nonenveloped viruses. PMID- 29437976 TI - Laser Adjuvant-Assisted Peptide Vaccine Promotes Skin Mobilization of Dendritic Cells and Enhances Protective CD8+ TEM and TRM Cell Responses against Herpesvirus Infection and Disease. AB - There is an urgent need for chemical-free and biological-free safe adjuvants to enhance the immunogenicity of vaccines against widespread viral pathogens, such as herpes simplex virus 2 (HSV-2), that infect a large proportion of the world human population. In the present study, we investigated the safety, immunogenicity, and protective efficacy of a laser adjuvant-assisted peptide (LAP) vaccine in the B6 mouse model of genital herpes. This LAP vaccine and its laser-free peptide (LFP) vaccine analog contain the immunodominant HSV-2 glycoprotein B CD8+ T cell epitope (HSV-gB498-505) covalently linked with the promiscuous glycoprotein D CD4+ T helper cell epitope (HSV-gD49-89). Prior to intradermal delivery of the LAP vaccine, the lower-flank shaved skin of B6 or CD11c/eYFP transgenic mice received a topical skin treatment with 5% imiquimod cream and then was exposed for 60 s to a laser, using the FDA-approved nonablative diode. Compared to the LFP vaccine, the LAP vaccine (i) triggered mobilization of dendritic cells (DCs) in the skin, which formed small spots along the laser-treated areas, (ii) induced phenotypic and functional maturation of DCs, (iii) stimulated long-lasting HSV-specific effector memory CD8+ T cells (TEM cells) and tissue-resident CD8+ T cells (TRM cells) locally in the vaginal mucocutaneous tissues (VM), and (iv) induced protective immunity against genital herpes infection and disease. As an alternative to currently used conventional adjuvants, the chemical- and biological-free laser adjuvant offers a well tolerated, simple-to-produce method to enhance mass vaccination for widespread viral infections.IMPORTANCE Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect a large proportion of the world population. There is an urgent need for chemical-free and biological-free safe adjuvants that would advance mass vaccination against the widespread herpes infections. The present study demonstrates that immunization with a laser-assisted herpes peptide vaccine triggered skin mobilization of dendritic cells (DCs) that stimulated strong and long-lasting HSV-specific effector memory CD8+ T cells (TEM cells) and tissue resident CD8+ T cells (TRM cells) locally in the vaginal mucocutaneous tissues. The induced local CD8+ T cell response was associated with protection against genital herpes infection and disease. These results draw attention to chemical- and biological-free laser adjuvants as alternatives to currently used conventional adjuvants to enhance mass vaccination for widespread viral infections, such as those caused by HSV-1 and HSV-2. PMID- 29437977 TI - Differential Contribution of RNA Interference Components in Response to Distinct Fusarium graminearum Virus Infections. AB - The mechanisms of RNA interference (RNAi) as a defense response against viruses remain unclear in many plant-pathogenic fungi. In this study, we used reverse genetics and virus-derived small RNA profiling to investigate the contributions of RNAi components to the antiviral response against Fusarium graminearum viruses 1 to 3 (FgV1, -2, and -3). Real-time reverse transcription-quantitative PCR (qRT PCR) indicated that infection of Fusarium graminearum by FgV1, -2, or -3 differentially induces the gene expression of RNAi components in F. graminearum Transcripts of the DICER-2 and AGO-1 genes of F. graminearum (FgDICER-2 and FgAGO 1) accumulated at lower levels following FgV1 infection than following FgV2 or FgV3 infection. We constructed gene disruption and overexpression mutants for each of the Argonaute and dicer genes and for two RNA-dependent RNA polymerase (RdRP) genes and generated virus-infected strains of each mutant. Interestingly, mycelial growth was significantly faster for the FgV1-infected FgAGO-1 overexpression mutant than for the FgV1-infected wild type, while neither FgV2 nor FgV3 infection altered the colony morphology of the gene deletion and overexpression mutants. FgV1 RNA accumulation was significantly decreased in the FgAGO-1 overexpression mutant. Furthermore, the levels of induction of FgAGO-1, FgDICER-2, and some of the FgRdRP genes caused by FgV2 and FgV3 infection were similar to those caused by hairpin RNA-induced gene silencing. Using small RNA sequencing analysis, we documented different patterns of virus-derived small interfering RNA (vsiRNA) production in strains infected with FgV1, -2, and -3. Our results suggest that the Argonaute protein encoded by FgAGO-1 is required for RNAi in F. graminearum, that FgAGO-1 induction differs in response to FgV1, -2, and -3, and that FgAGO-1 might contribute to the accumulation of vsiRNAs in FgV1 infected F. graminearumIMPORTANCE To increase our understanding of how RNAi components in Fusarium graminearum react to mycovirus infections, we characterized the role(s) of RNAi components involved in the antiviral defense response against Fusarium graminearum viruses (FgVs). We observed differences in the levels of induction of RNA silencing-related genes, including FgDICER-2 and FgAGO-1, in response to infection by three different FgVs. FgAGO-1 can efficiently induce a robust RNAi response against FgV1 infection, but FgDICER genes might be relatively redundant to FgAGO-1 with respect to antiviral defense. However, the contribution of this gene in the response to the other FgV infections might be small. Compared to previous studies of Cryphonectria parasitica, which showed dicer-like protein 2 and Argonaute-like protein 2 to be important in antiviral RNA silencing, our results showed that F. graminearum developed a more complex and robust RNA silencing system against mycoviruses and that FgDICER-1 and FgDICER-2 and FgAGO-1 and FgAGO-2 had redundant roles in antiviral RNA silencing. PMID- 29437978 TI - WDR5 Facilitates Human Cytomegalovirus Replication by Promoting Capsid Nuclear Egress. AB - WD repeat-containing protein 5 (WDR5) is essential for assembling the VISA associated complex to induce a type I interferon antiviral response to Sendai virus infection. However, the roles of WDR5 in DNA virus infections are not well described. Here, we report that human cytomegalovirus exploits WDR5 to facilitate capsid nuclear egress. Overexpression of WDR5 in fibroblasts slightly enhanced the infectious virus yield. However, WDR5 knockdown dramatically reduced infectious virus titers with only a small decrease in viral genome replication or gene expression. Further investigation of late steps of viral replication found that WDR5 knockdown significantly impaired formation of the viral nuclear egress complex and induced substantially fewer infoldings of the inner nuclear membrane. In addition, fewer capsids were associated with these infoldings, and there were fewer capsids in the cytoplasm. Restoration of WDR5 partially reversed these effects. These results suggest that WDR5 knockdown impairs the nuclear egress of capsids, which in turn decreases virus titers. These findings reveal an important role for a host factor whose function(s) is usurped by a viral pathogen to promote efficient replication. Thus, WDR5 represents an interesting regulatory mechanism and a potential antiviral target.IMPORTANCE Human cytomegalovirus (HCMV) has a large (~235-kb) genome with over 170 open reading frames and exploits numerous cellular factors to facilitate its replication. HCMV infection increases protein levels of WD repeat-containing protein 5 (WDR5) during infection, overexpression of WDR5 enhances viral replication, and knockdown of WDR5 dramatically attenuates viral replication. Our results indicate that WDR5 promotes the nuclear egress of viral capsids, the depletion of WDR5 resulting in a significant decrease in production of infectious virions. This is the first report that WDR5 favors HCMV, a DNA virus, replication and highlights a novel target for antiviral therapy. PMID- 29437980 TI - Temporal-prefrontal cortical network for discrimination of valuable objects in long-term memory. AB - Remembering and discriminating objects based on their previously learned values are essential for goal-directed behaviors. While the cerebral cortex is known to contribute to object recognition, surprisingly little is known about its role in retaining long-term object-value associations. To address this question, we trained macaques to arbitrarily associate small or large rewards with many random fractal objects (>100) and then used fMRI to study the long-term retention of value-based response selectivity across the brain. We found a pronounced long term value memory in core subregions of temporal and prefrontal cortex where, several months after training, fractals previously associated with high reward ("good" stimuli) elicited elevated fMRI responses compared with those associated with low reward ("bad" stimuli). Similar long-term value-based modulation was also observed in subregions of the striatum, amygdala, and claustrum, but not in the hippocampus. The value-modulated temporal-prefrontal subregions showed strong resting-state functional connectivity to each other. Moreover, for areas outside this core, the magnitude of long-term value responses was predicted by the strength of resting-state functional connectivity to the core subregions. In separate testing, free-viewing gaze behavior indicated that the monkeys retained stable long-term memory of object value. These results suggest an implicit and high-capacity memory mechanism in the temporal-prefrontal circuitry and its associated subcortical regions for long-term retention of object-value memories that can guide value-oriented behavior. PMID- 29437979 TI - Functional Role of N-Linked Glycosylation in Pseudorabies Virus Glycoprotein gH. AB - Many viral envelope proteins are modified by asparagine (N)-linked glycosylation, which can influence their structure, physicochemical properties, intracellular transport, and function. Here, we systematically analyzed the functional relevance of N-linked glycans in the alphaherpesvirus pseudorabies virus (PrV) glycoprotein H (gH), which is an essential component of the conserved core herpesvirus fusion machinery. Upon gD-mediated receptor binding, the heterodimeric complex of gH and gL activates gB to mediate fusion of the viral envelope with the host cell membrane for viral entry. gH contains five potential N-linked glycosylation sites at positions 77, 162, 542, 604, and 627, which were inactivated by conservative mutations (asparagine to glutamine) singly or in combination. The mutated proteins were tested for correct expression and fusion activity. Additionally, the mutated gH genes were inserted into the PrV genome for analysis of function during virus infection. Our results demonstrate that all five sites are glycosylated. Inactivation of the PrV-specific N77 or the conserved N627 resulted in significantly reduced in vitro fusion activity, delayed penetration kinetics, and smaller virus plaques. Moreover, substitution of N627 greatly affected transport of gH in transfected cells, resulting in endoplasmic reticulum (ER) retention and reduced surface expression. In contrast, mutation of N604, which is conserved in the Varicellovirus genus, resulted in enhanced in vitro fusion activity and viral cell-to-cell spread. These results demonstrate a role of the N-glycans in proper localization and function of PrV gH. However, even simultaneous inactivation of all five N-glycosylation sites of gH did not severely inhibit formation of infectious virus particles.IMPORTANCE Herpesvirus infection requires fusion of the viral envelope with cellular membranes, which involves the conserved fusion machinery consisting of gB and the heterodimeric gH/gL complex. The bona fide fusion protein gB depends on the presence of the gH/gL complex for activation. Viral envelope glycoproteins, such as gH, usually contain N-glycans, which can have a strong impact on their folding, transport, and functions. Here, we systematically analyzed the functional relevance of all five predicted N-linked glycosylation sites in the alphaherpesvirus pseudorabies virus (PrV) gH. Despite the fact that mutation of specific sites affected gH transport, in vitro fusion activity, and cell-to-cell spread and resulted in delayed penetration kinetics, even simultaneous inactivation of all five N-glycosylation sites of gH did not severely inhibit formation of infectious virus particles. Thus, our results demonstrate a modulatory but nonessential role of N-glycans for gH function. PMID- 29437983 TI - Genetics of Intracranial Aneurysms. PMID- 29437982 TI - Anxiety After Stroke: The Importance of Subtyping. AB - BACKGROUND AND PURPOSE: Anxiety after stroke is common and disabling. Stroke trialists have treated anxiety as a homogenous condition, and intervention studies have followed suit, neglecting the different treatment approaches for phobic and generalized anxiety. Using diagnostic psychiatric interviews, we aimed to report the frequency of phobic and generalized anxiety, phobic avoidance, predictors of anxiety, and patient outcomes at 3 months poststroke/transient ischemic attack. METHODS: We followed prospectively a cohort of new diagnosis of stroke/transient ischemic attack at 3 months with a telephone semistructured psychiatric interview, Fear Questionnaire, modified Rankin Scale, EuroQol-5D5L, and Work and Social Adjustment Scale. RESULTS: Anxiety disorder was common (any anxiety disorder, 38 of 175 [22%]). Phobic disorder was the predominant anxiety subtype: phobic disorder only, 18 of 175 (10%); phobic and generalized anxiety disorder, 13 of 175 (7%); and generalized anxiety disorder only, 7 of 175 (4%). Participants with anxiety disorder reported higher level of phobic avoidance across all situations on the Fear Questionnaire. Younger age (per decade increase in odds ratio, 0.64; 95% confidence interval, 0.45-0.91) and having previous anxiety/depression (odds ratio, 4.38; 95% confidence interval, 1.94-9.89) were predictors for anxiety poststroke/transient ischemic attack. Participants with anxiety disorder were more dependent (modified Rankin Scale score 3-5, [anxiety] 55% versus [no anxiety] 29%; P<0.0005), had poorer quality of life on EQ-5D5L, and restricted participation (Work and Social Adjustment Scale: median, interquartile range, [anxiety] 19.5, 10-27 versus [no anxiety] 0, 0-5; P<0.001). CONCLUSIONS: Anxiety after stroke/transient ischemic attack is predominantly phobic and is associated with poorer patient outcomes. Trials of anxiety intervention in stroke should consider the different treatment approaches needed for phobic and generalized anxiety. PMID- 29437981 TI - Second-Generation Hydrogel Coils for the Endovascular Treatment of Intracranial Aneurysms: A Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: Endovascular embolization of intracranial aneurysms with hydrogel-coated coils lowers the risk of major recurrence, but technical limitations (coil stiffness and time restriction for placement) have prevented their wider clinical use. We aimed to assess the efficacy of softer, second generation hydrogel coils. METHODS: A randomized controlled trial was conducted at 22 centers in France and Germany. Patients aged 18 to 75 years with untreated ruptured or unruptured intracranial aneurysms measuring 4 to 12 mm in diameter were eligible and randomized (1:1 using a web-based system, stratified by rupture status) to coiling with either second-generation hydrogel coils or bare platinum coils. Assist devices were allowed as clinically required. Independent imaging core laboratory was masked to allocation. Primary end point was a composite outcome measure including major aneurysm recurrence, aneurysm retreatment, morbidity that prevented angiographic controls, and any death during treatment and follow-up. Data were analyzed as randomized. RESULTS: Randomization began on October 15, 2009, and stopped on January 31, 2014, after 513 patients (hydrogel, n=256; bare platinum, n=257); 20 patients were excluded for missing informed consent and 9 for treatment-related criteria. Four hundred eighty-four patients (hydrogel, n=243; bare platinum, n=241) were included in the analysis; 208 (43%) were treated for ruptured aneurysms. Final end point data were available for 456 patients. Forty-five out of 226 (19.9%) patients in the hydrogel group and 66/230 (28.7%) in the control group had an unfavorable composite primary outcome, giving a statistically significant reduction in the proportion of an unfavorable composite primary outcome with hydrogel coils-adjusted for rupture status-of 8.4% (95% confidence interval, 0.5-16.2; P=0.036). Adverse and serious adverse events were evenly distributed between groups. CONCLUSIONS: Our results suggest that endovascular coil embolization with second-generation hydrogel coils may reduce the rate of unfavorable outcome events in patients with small- and medium-sized intracranial aneurysms. CLINICAL TRIAL REGISTRATION: URL: https://www.drks.de/drks_web/. Unique identifier: DRKS00003132. PMID- 29437984 TI - Differences in experiences of barriers to STI testing between clients of the internet-based diagnostic testing service GetCheckedOnline.com and an STI clinic in Vancouver, Canada. AB - OBJECTIVES: Internet-based STI testing programmes may overcome barriers posed by in-clinic testing, though uptake could reflect social gradients. The role these services play in comparison to clinical testing services is unknown. We compared experiences of testing barriers between STI clinic clients to clients of GetCheckedOnline.com (GCO; where clients take a printed lab form to a lab). METHODS: Our 10-month cross-sectional study was conducted after GCO was promoted to STI clinic clients and men who have sex with men (MSM). Clinic and GCO clients completed an online survey assessing testing barriers and facilitators; responses were compared using bivariate analysis (level of significance P<0.01; significant results below). RESULTS: Compared with 321 clinic clients, the 73 GCO clients were more likely to be older (median 35 vs 30 years), MSM (45% vs 16%), be testing routinely (67% vs 39%), have delayed testing for any reason (76% vs 54%) and due to clinic distance (28% vs 9%), report delays due to wait times (50% vs 17%), embarrassment with testing (16% vs 6%), discomfort discussing sexual health where they usually go for testing (39% vs 22%), as well as discomfort discussing sexual history with (19% vs 5%) and fearing judgement from (30% vs 15%) any healthcare provider. GCO clients were less likely to have found clinic hours convenient (59% vs 77%) and clinic appointments easy to make (49% vs 66%), and more likely to report long wait times (50% vs 17%). We found no differences in technology skills/use. CONCLUSIONS: In this urban setting, an internet-based testing service effectively engaged individuals experiencing testing barriers, with few social gradients in uptake. While some testing barriers could be addressed through increasing access to clinical services, others require social and structural changes, highlighting the importance of internet-based STI testing services to increasing test uptake. PMID- 29437986 TI - The Shifting Transcriptional Response of Maize Smut Fungus. PMID- 29437985 TI - Comparing the characteristics of users of an online service for STI self-sampling with clinic service users: a cross-sectional analysis. AB - OBJECTIVES: Online services for self-sampling at home could improve access to STI testing; however, little is known about those using this new modality of care. This study describes the characteristics of users of online services and compares them with users of clinic services. METHODS: We conducted a cross-sectional analysis of routinely collected data on STI testing activity from online and clinic sexual health services in Lambeth and Southwark between 1January 2016 and 31March 2016. Activity was included for chlamydia, gonorrhoea, HIV and syphilis testing for residents of the boroughs aged 16 years and older. Logistic regression models were used to explore potential associations between type of service use with age group, gender, ethnic group, sexual orientation, positivity and Index of Multiple Deprivation (IMD) quintiles. We used the same methods to explore potential associations between return of complete samples for testing with age group, gender, ethnic group, sexual orientation and IMD quintiles among online users. RESULTS: 6456 STI tests were carried out by residents in the boroughs. Of these, 3582 (55.5%) were performed using clinic services and 2874 (44.5%) using the online service. In multivariate analysis, online users were more likely than clinic users to be aged between 20 and 30 years, female, white British, homosexual or bisexual, test negative for chlamydia or gonorrhoea and live in less deprived areas. Of the individuals that ordered a kit from the online service, 72.5% returned sufficient samples. In multivariate analysis, returners were more likely than non-returners to be aged >20 years and white British. CONCLUSION: Nearly half (44.5%) of all basic STI testing was done online, although the characteristics of users of clinic and online services differed and positivity rates for those using the online service for testing were lower. Clinics remain an important point of access for some groups. PMID- 29437987 TI - Cell Cycle Regulation by Chlamydomonas Cyclin-Dependent Protein Kinases. PMID- 29437988 TI - MAC3A and MAC3B, Two Core Subunits of the MOS4-Associated Complex, Positively Influence miRNA Biogenesis. AB - MAC3A and MAC3B are conserved U-box-containing proteins in eukaryotes. They are subunits of the MOS4-associated complex (MAC) that plays essential roles in plant immunity and development in Arabidopsis thaliana However, their functional mechanisms remain elusive. Here, we show that Arabidopsis MAC3A and MAC3B act redundantly in microRNA (miRNA) biogenesis. Lack of both MAC3A and MAC3B in the mac3b mac3b double mutant reduces the accumulation of miRNAs, causing elevated transcript levels of miRNA targets. mac3a mac3b also decreases the levels of primary miRNA transcripts (pri-miRNAs). However, MAC3A and MAC3B do not affect the promoter activity of genes encoding miRNAs (MIR genes), suggesting that they may not affect MIR transcription. This result, together with the fact that MAC3A associates with pri-miRNAs in vivo, indicates that MAC3A and MAC3B may stabilize pri-miRNAs. Furthermore, we find that MAC3A and MAC3B interact with the DCL1 complex that catalyzes miRNA maturation, promote DCL1 activity, and are required for the localization of HYL1, a component of the DCL1 complex. Besides MAC3A and MAC3B, two other MAC subunits, CDC5 and PRL1, also function in miRNA biogenesis. Based on these results, we propose that MAC functions as a complex to control miRNA levels through modulating pri-miRNA transcription, processing, and stability. PMID- 29437989 TI - Galactoglycerolipid Lipase PGD1 Is Involved in Thylakoid Membrane Remodeling in Response to Adverse Environmental Conditions in Chlamydomonas. AB - Photosynthesis occurs in the thylakoid membrane, where the predominant lipid is monogalactosyldiacylglycerol (MGDG). As environmental conditions change, photosynthetic membranes have to adjust. In this study, we used a loss-of function Chlamydomonas reinhardtii mutant deficient in the MGDG-specific lipase PGD1 (PLASTID GALACTOGLYCEROLIPID DEGRADATION1) to investigate the link between MGDG turnover, chloroplast ultrastructure, and the production of reactive oxygen species (ROS) in response to different adverse environmental conditions. The pgd1 mutant showed altered MGDG abundance and acyl composition and altered abundance of photosynthesis complexes, with an increased PSII/PSI ratio. Transmission electron microscopy showed hyperstacking of the thylakoid grana in the pgd1 mutant. The mutant also exhibited increased ROS production during N deprivation and high light exposure. Supplementation with bicarbonate or treatment with the photosynthetic electron transport blocker DCMU protected the cells against oxidative stress in the light and reverted chlorosis of pgd1 cells during N deprivation. Furthermore, exposure to stress conditions such as cold and high osmolarity induced the expression of PGD1, and loss of PGD1 in the mutant led to increased ROS production and inhibited cell growth. These findings suggest that PGD1 plays essential roles in maintaining appropriate thylakoid membrane composition and structure, thereby affecting growth and stress tolerance when cells are challenged under adverse conditions. PMID- 29437991 TI - A think tank of JT, by JT and for JT. PMID- 29437990 TI - GRF-interacting factor1 Regulates Shoot Architecture and Meristem Determinacy in Maize. AB - Plant architecture results from a balance of indeterminate and determinate cell fates. Cells with indeterminate fates are located in meristems, comprising groups of pluripotent cells that produce lateral organs. Meristematic cells are also found in intercalary stem tissue, which provides cells for internodes, and at leaf margins to contribute to leaf width. We identified a maize (Zea mays) mutant that has a defect in balancing determinacy and indeterminacy. The mutant has narrow leaves and short internodes, suggesting a reduction in indeterminate cells in the leaf and stem. In contrast, the mutants fail to control indeterminacy in shoot meristems. Inflorescence meristems are fasciated, and determinate axillary meristems become indeterminate. Positional cloning identified growth regulating factor-interacting factor1 (gif1) as the responsible gene. gif1 mRNA accumulates in distinct domains of shoot meristems, consistent with tissues affected by the mutation. We determined which GROWTH REGULATING FACTORs interact with GIF1 and performed RNA-seq analysis. Many genes known to play roles in inflorescence architecture were differentially expressed in gif1 Chromatin immunoprecipitation identified some differentially expressed genes as direct targets of GIF1. The interactions with these diverse direct and indirect targets help explain the paradoxical phenotypes of maize GIF1. These results provide insights into the biological functions of gif1. PMID- 29437992 TI - 'The industry must be inconspicuous': Japan Tobacco's corruption of science and health policy via the Smoking Research Foundation. AB - OBJECTIVE: To investigate how and why Japan Tobacco, Inc. (JT) in 1986 established the Smoking Research Foundation (SRF), a research-funding institution, and to explore the extent to which SRF has influenced science and health policy in Japan. METHODS: We analysed documents in the Truth Tobacco Industry Documents archive, along with recent Japanese litigation documents and published documents. RESULTS: JT's effort to combat effective tobacco control was strengthened in the mid-1980s, following privatisation of the company. While remaining under the protection of Japan's Ministry of Finance, the semiprivatised company lost its 'access to politicos', opening up a perceived need for collaboration with global cigarette makers. One solution, arrived at through clandestine planning with American companies, was to establish a third-party organisation, SRF, with the hope of capturing scientific and medical authority for the industry. Guarded by powerful people in government and academia, SRF was launched with the covert goal of influencing tobacco policy both inside and outside Japan. Scholars funded by SRF have participated in international conferences, national advisory committees and tobacco litigation, in most instances helping the industry to maintain a favourable climate for the continued sale of cigarettes. CONCLUSIONS: Contrary to industry claims, SRF was never meant to be independent or neutral. With active support from foreign cigarette manufacturers, SRF represents the expansion into Asia of the denialist campaign that began in the USA in 1953. PMID- 29437993 TI - High prevalence of gait abnormalities in pugs. AB - The objective of this prospective study was to determine the prevalence of gait abnormalities in a cohort of Swedish pugs by using an owner-based questionnaire targeting signs of gait abnormality and video footage showing the dog's gait. This study also evaluated associated conditions of abnormal gait, including other health disorders prevalent in the breed. Five hundred and fifty (550) pugs registered in the Swedish Kennel Club, of one, five and eight years of age, in 2015 and 2016, were included in the study. Gait abnormalities were reported in 30.7 per cent of the responses. In the majority of cases, the character of the described gait indicated a neurological cause for the gait abnormality. An association was observed between abnormal gait and age, with gait abnormalities being significantly more common in older pugs (P=0.004). An association was also found between abnormal gait and dyspnoea, with dyspnoea being significantly more common in pugs with gait abnormalities (P<0.0001). This study demonstrated that the prevalence of gait abnormalities was high in the Swedish pug breed and increased with age. Future studies on the mechanisms behind these gait abnormalities are warranted. PMID- 29437994 TI - Metabolic profiling of visceral adipose tissue from obese subjects with or without metabolic syndrome. AB - Obesity represents one of the most complex public health challenges and has recently reached epidemic proportions. Obesity is also considered to be primarily responsible for the rising prevalence of metabolic syndrome, defined as the coexistence in the same individual of several risk factors for atherosclerosis, including dyslipidemia, hypertension and hyperglycemia, as well as for cancer. Additionally, the presence of three of the five risk factors (abdominal obesity, low high-density lipoprotein cholesterol, high triglycerides, high fasting glucose and high blood pressure) characterizes metabolic syndrome, which has serious clinical consequences. The current study was conducted in order to identify metabolic differences in visceral adipose tissue (VAT) collected from obese (body mass index 43-48) human subjects who were diagnosed with metabolic syndrome, obese individuals who were metabolically healthy and nonobese healthy controls. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analyses were used to obtain the untargeted VAT metabolomic profiles of 481 metabolites belonging to all biochemical pathways. Our results indicated consistent increases in oxidative stress markers from the pathologically obese samples in addition to subtle markers of elevated glucose levels that may be consistent with metabolic syndrome. In the tissue derived from the pathologically obese subjects, there were significantly elevated levels of plasmalogens, which may be increased in response to oxidative changes in addition to changes in glycerolphosphorylcholine, glycerolphosphorylethanolamine glycerolphosphorylserine, ceramides and sphingolipids. These data could be potentially helpful for recognizing new pathways that underlie the metabolic vascular complications of obesity and may lead to the development of innovative targeted therapies. PMID- 29437995 TI - Inverse Drug Screening of Bioelectric Signaling and Neurotransmitter Roles: Illustrated Using a Xenopus Tail Regeneration Assay. AB - Xenopus embryos and larvae are an ideal model system in which to study the interplay between genetics, physiology, and anatomy in the control of structure and function. An important emerging field is the study of bioelectric signaling, the exchange of ion- and neurotransmitter-mediated messages among all types of cells (not just nerve and muscle cells), in the regulation of growth and form during embryogenesis, regeneration, and cancer. To facilitate the mechanistic investigation of bioelectric events in vivo, it is necessary to identify the endogenous signaling machinery involved in any patterning process of interest. This protocol uses the tail regeneration assay in Xenopus to perform an inverse drug screen; tiers of known compounds are used to probe the involvement of increasingly specific classes of bioelectric and neurotransmitter machinery. By using a hierarchical approach, large classes of targets are ruled out in early rounds, focusing attention on progressively narrower sets of proteins. Such a screen avoids many of the limitations of a molecular-genetic targeting approach and provides a rapid and efficient way to focus on specific targets. Usually, <10 experiments are needed to determine whether bioelectrics and/or neurotransmitter signaling are involved in the process of interest. This protocol describes the strategy in the context of a semiquantitative analysis of tail regeneration but can be applied to any assay in Xenopus or other small aquatic model system (e.g., zebrafish). Given the ever-increasing toolkit of chemical genetics, such screens represent a powerful and versatile methodology for probing the physiological circuits underlying pattern regulation. PMID- 29437996 TI - Assembly of Spindles and Asters in Xenopus Egg Extracts. AB - Here, we provide methods for assembly of mitotic spindles and interphase asters in Xenopus laevis egg extract, and compare them to spindles and asters in the egg and zygote. Classic "cycled" spindles are made by adding sperm nuclei to metaphase-arrested cytostatic factor (CSF) extract and inducing entry into interphase extract to promote nucleus formation and DNA replication. Interphase nuclei are then converted to cycled spindles arrested in metaphase by addition of CSF extract. Kinetochores assemble in this reaction and these spindles can segregate chromosomes. CSF spindles are made by addition of sperm nuclei to CSF extract. They are less physiological and lack functional kinetochores but suffice for some applications. Large interphase asters are prepared by addition of artificial centrosomes or sperm nuclei to actin-intact egg extract. These asters grow rapidly to hundreds of microns in radius by branching microtubule nucleation at the periphery, so the aster as a whole is a network of short, dynamic microtubules. They resemble the sperm aster after fertilization, and the asters that grow out of the poles of the mitotic spindle at anaphase. When interphase asters grow into each other they interact and assemble aster interaction zones at their shared boundary. These zones consist of a line (in extract) or disc (in zygotes) of antiparallel microtubule bundles coated with cytokinesis midzone proteins. Interaction zones block interpenetration of microtubules from the two asters, and signal to the cortex to induce cleavage furrows. Their reconstitution in extract allows dissection of the biophysics of spatially regulated cytokinesis signaling. PMID- 29437997 TI - Fluorescence In Situ Hybridization of Cryosectioned Xenopus Oocytes. AB - Xenopus laevis oocytes are widely used to study mechanisms of RNA function and biogenesis. While the large size of Xenopus oocytes is amenable to both biochemical and imaging approaches, the relative opacity of the yolk-rich cytoplasm has limited high-resolution imaging of endogenous RNAs. Here, we present a protocol that combines multi-probe fluorescence in situ hybridization with cryosectioning to provide a highly sensitive means of imaging endogenous oocyte RNAs. PMID- 29437998 TI - Preparation of Cellular Extracts from Xenopus Eggs and Embryos. AB - Cell-free cytoplasmic extracts prepared from Xenopus eggs have been used extensively to recapitulate and characterize intracellular events in vitro. Egg extracts can be induced to transit the cell cycle and reconstitute assembly of dynamic structures including the interphase nucleus and the mitotic spindle. In this protocol, methods are described for preparing crude cytoplasmic extracts from Xenopus eggs and embryos that are arrested in metaphase of the cell cycle. The basic protocol uses unfertilized Xenopus laevis eggs, which are crushed by centrifugation in the presence of EGTA to preserve the natural cytostatic factor (CSF) activity that maintains high levels of Cdk1/cyclin B kinase and metaphase arrest. In the second method, the basic procedure is adapted for Xenopus tropicalis eggs with minor modifications to accommodate differences in frog size, timing of egg laying, and temperature and salt sensitivity. The third variation takes advantage of the synchronous divisions of fertilized X. laevis eggs to generate extracts from embryos, which are arrested in metaphase by the addition of nondegradable cyclin B and an inhibitor of the anaphase-promoting complex (APC) that together stabilize Cdk1/cyclin B kinase activity. Because they are obtained in much smaller amounts and their cell cycles are less perfectly synchronized, extracts prepared from embryos are less robust than egg extracts. X. laevis egg extracts have been used to study a wide range of cellular processes. In contrast, X. tropicalis egg extracts and X. laevis embryo extracts have been used primarily to characterize molecular mechanisms regulating spindle and nuclear size. PMID- 29437999 TI - Microfluidic Encapsulation of Demembranated Sperm Nuclei in Xenopus Egg Extracts. AB - The cell-free nature of Xenopus egg extract makes it a uniquely tractable experimental model system. The extract, effectively unconfined cytoplasm, allows the direct and relatively straight-forward addition of purified proteins and other reagents, a characteristic that renders the system amenable to many biochemical and cell biological manipulations. Accessibility to the system also facilitates the direct physical manipulation and probing of biological structures, in turn enabling mechanical properties of intracellular assemblies and organelles, such as the mitotic spindle and nucleus, to be measured. Recently, multiphase microfluidics have been combined with Xenopus egg extracts to encapsulate discrete cytoplasmic volumes. Described here is a protocol detailing the use of multiphase microfluidic devices to encapsulate sperm nuclei within extract droplets of defined size and shape. This protocol can also be applied more generally to encapsulation of microbeads and other particles. PMID- 29438000 TI - Isolation and Demembranation of Xenopus Sperm Nuclei. AB - The inherent experimental advantages of intact amphibian eggs have been exploited for several decades to advance our understanding of fundamental developmental processes and the cell cycle. Characterization of these processes at the molecular level has been greatly advanced by the use of cell-free extracts, which permit the development of biochemically tractable approaches. Demembranated Xenopus laevis sperm nuclei have been used with cell-free extracts to recapitulate cell cycle progression and to control the cell cycle state of the egg extract. This system has become an invaluable and widely used tool for studies of cell cycle regulation and many downstream events. Here, we describe a protocol, derived in part from other published protocols and modified over time, for the preparation of Xenopus sperm nuclei that can be used in a variety of in vitro assays. PMID- 29438001 TI - Association between shiftwork and the risk of colorectal cancer in females: a population-based case-control study. AB - OBJECTIVE: Research indicates that shiftwork may be associated with increased risks of adverse health outcomes, including some cancers. However, the evidence of an association between shiftwork and colorectal cancer risk is limited and inconclusive. Further, while several possible pathways through which shiftwork might result in cancer have been proposed, few studies have taken these factors into account. We investigated the association between two types of shiftwork (graveyard shiftwork and early-morning shiftwork) and six mechanistic shiftwork variables (including light at night and phase shift) and the risk of colorectal cancer among females in an Australian population-based case-control study. Graveyard shiftwork was the primary exposure of interest. METHODS: Participants (350 cases and 410 controls) completed a lifetime occupational history, and exposure to each of the eight shiftwork variables was assigned to participants through a job exposure matrix. We used logistic regression to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI) for the association between different shiftwork variables and the risk of colorectal cancer, adjusting for potential demographic, lifestyle and medical confounders. RESULTS: Working in an occupation involving long-term exposure (>7.5 years) to graveyard shiftwork was not associated with colorectal cancer risk (adjusted OR 0.95, 95% CI 0.57 to 1.58). Similarly, no increased risks of colorectal cancer were seen for any of the other seven shiftwork variables examined. CONCLUSIONS: No evidence of an increased risk of colorectal cancer among females who had worked in occupations involving shiftwork was observed in this study. PMID- 29438002 TI - A Microdose PET Study of the Safety, Immunogenicity, Biodistribution, and Radiation Dosimetry of 18F-FB-A20FMDV2 for Imaging the Integrin alphavbeta6. AB - The alphavbeta6 integrin is involved in the pathogenesis of cancer and fibrosis. A radiolabeled 20-amino-acid alphavbeta6-binding peptide, derived from the foot and mouth virus (NAVPNLRGDLQVLAQKVART [A20FMDV2]), has been developed to image alphavbeta6 levels preclinically. This study was designed to translate these findings into a clinical PET imaging protocol to measure the expression of alphavbeta6 in humans. Methods: Preclinical toxicology was undertaken, and a direct immunoassay was developed for 4-fluorobenzamide (FB)-A20FMDV2. Four healthy human subjects (2 male and 2 female) received a single microdose of 18F FB-A20FMDV2 followed by a multibed PET scan of the whole body over more than 3 h. Results: There were no findings in the preclinical toxicology assessments, and no anti-A20FMDV2 antibodies were detected before or after dosing with the PET ligand. The mean and SD of the administered mass of 18F-FB-A20FMDV2 was 8.7 +/- 4.4 MUg (range, 2.7-13.0 MUg). The mean administered activity was 124 +/- 20 MBq (range, 98-145 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the subjects. No significant changes in vital signs, laboratory study results, or electrocardiography results were observed. Uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, kidneys, ureters, and bladder. Time-activity curves indicated that the highest activity was in the bladder content, followed by the kidneys, small intestine, stomach, liver, spleen, thyroid, and gallbladder. The largest component of the residence times was the voided urine, followed by muscle, bladder, and liver. Using the mean residence time over all subjects as input to OLINDA/EXM, the effective dose was determined to be 0.0217 mSv/MBq; using residence times from single subjects gave an SD of 0.0020 mSv/MBq from the mean. The critical organ was the urinary bladder, with an absorbed dose of 0.18 mGy/MBq. Conclusion:18F-FB-A20FMDV2 successfully passed toxicology criteria, showed no adverse effects in this first-in-humans study, and has an effective dose that enables multiple scans in a single subject. PMID- 29438003 TI - Lymphoscintigraphy of Chylous Anomalies: Chylothorax, Chyloperitoneum, Chyluria, and Lymphangiomatosis-15-Year Experience in a Pediatric Setting and Review of the Literature. AB - In the pediatric setting, lymphoscintigraphy is used mostly for the evaluation of lymphedema. Only a few cases of chylous anomalies and lymphatic malformations imaged with lymphoscintigraphy have been reported in the literature. The aim of this study was to review the use of lymphoscintigraphy in those pathologies. Methods: All lymphoscintigraphy studies performed for chylous anomalies between 2001 and 2017 in our hospital were retrospectively reviewed. The results were correlated to clinical and radiologic findings. Lymphoscintigraphy consisted of sequential imaging after injection of 3.7-9.25 MBq (100-250 MUCi) of 99mTc filtered sulfur colloid at the level of the feet or hands. Results: Twenty-five studies were performed on 21 patients. Fourteen studies were obtained for the evaluation of chylothorax. Eleven were performed for chyloperitoneum, chyluria, chylopericardium, exudative enteropathy, or lymphangiomatosis. Ten studies were positive for lymphatic leakage, and 1 had uncertain results. After correlation with radiologic findings and follow-up, there were 7 true-negative and 5 false negative results (previous 67Ga-interfering activity in 1, injection in only the hands in 3, and a low-fat diet in 1). One study became positive after injection in the feet, and another became positive after a switch to a high-fat diet. Conclusion: Lymphoscintigraphy is a useful tool for imaging lymphatic anomalies in children. Suggestions to optimize results include placing the patient on a high-fat diet, withholding octreotide, injecting the 4 extremities, and imaging with SPECT/CT. PMID- 29438004 TI - Incremental Value of SPECT/CT in the Detection of Femoral Head Viability in Slipped Capital Femoral Epiphysis. AB - In this article, we discuss the role of 99mTc-methylene diphosphonate SPECT/CT in 2 cases of slipped capital femoral epiphysis. We describe the incremental value of SPECT/CT in determining the viability of the femoral head and the implications in management of patients with slipped epiphysis. PMID- 29438005 TI - Maximum-Likelihood Expectation-Maximization Algorithm Versus Windowed Filtered Backprojection Algorithm: A Case Study. AB - Filtered backprojection (FBP) algorithms reduce image noise by smoothing the image. Iterative algorithms reduce image noise by noise weighting and regularization. It is believed that iterative algorithms are able to reduce noise without sacrificing image resolution, and thus iterative algorithms, especially maximum-likelihood expectation maximization (MLEM), are used in nuclear medicine to replace FBP algorithms. Methods: This short paper uses counter examples to show that this belief is not true. We compare image noise variance for FBP and MLEM reconstructions having the same spatial resolution. Results: The truth is that although MLEM suppresses image noise, it does so by sacrificing image resolution as well; the performance of windowed FBP may be better than that of MLEM in our case study. Conclusion: The myth of the superiority of iterative algorithms is caused by comparing them with conventional FBP instead of with windowed FBP. However, we do not intend to generalize the comparison results to imply which algorithm is more favorable. PMID- 29438006 TI - Statistics Refresher for Molecular Imaging Technologists, Part 2: Accuracy of Interpretation, Significance, and Variance. AB - This article is the second part of a continuing education series reviewing basic statistics that nuclear medicine and molecular imaging technologists should understand. In this article, the statistics for evaluating interpretation accuracy, significance, and variance are discussed. Throughout the article, actual statistics are pulled from the published literature. We begin by explaining 2 methods for quantifying interpretive accuracy: interreader and intrareader reliability. Agreement among readers can be expressed simply as a percentage. However, the Cohen kappa-statistic is a more robust measure of agreement that accounts for chance. The higher the kappa-statistic is, the higher is the agreement between readers. When 3 or more readers are being compared, the Fleiss kappa-statistic is used. Significance testing determines whether the difference between 2 conditions or interventions is meaningful. Statistical significance is usually expressed using a number called a probability (P) value. Calculation of P value is beyond the scope of this review. However, knowing how to interpret P values is important for understanding the scientific literature. Generally, a P value of less than 0.05 is considered significant and indicates that the results of the experiment are due to more than just chance. Variance, standard deviation (SD), confidence interval, and standard error (SE) explain the dispersion of data around a mean of a sample drawn from a population. SD is commonly reported in the literature. A small SD indicates that there is not much variation in the sample data. Many biologic measurements fall into what is referred to as a normal distribution taking the shape of a bell curve. In a normal distribution, 68% of the data will fall within 1 SD, 95% will fall within 2 SDs, and 99.7% will fall within 3 SDs. Confidence interval defines the range of possible values within which the population parameter is likely to lie and gives an idea of the precision of the statistic being measured. A wide confidence interval indicates that if the experiment were repeated multiple times on other samples, the measured statistic would lie within a wide range of possibilities. The confidence interval relies on the SE. PMID- 29438007 TI - BEST PRACTICES IN MOLECULAR BREAST IMAGING: A GUIDE FOR TECHNOLOGISTS. AB - Molecular breast imaging (MBI) technologists are required to possess a combination of nuclear medicine skills and mammographic positioning techniques. Currently, no formal programs offer this type of hybrid technologist training. The purpose of this perspective is to provide a best practices guide for technologists performing MBI. Familiarity with best practices may aid in obtaining high-quality MBI examinations by decreasing the likelihood of image artifacts, positioning problems and other factors that contribute to false negative or false positive findings. PMID- 29438008 TI - PET Radiopharmaceuticals: What's new, what's reimbursed, and what's next? AB - The field of molecular imaging is undergoing a period of growth and expansion. Of the ten FDA-approved PET imaging agents, six have been approved since 2012. As we enter 2018, we await the approval of a targeted radionuclide therapy, 177Lu DOTATATE. The approval of agents such as 11C-choline represented a paradigm shift in radiopharmaceutical drug development. This shift has illuminated a path to approval for similar agents and demonstrated the importance of molecular imaging in determining effective treatment strategies in serious diseases. This is a review of approval history of PET agents with a summary of how to use the newest agents in your clinic. Then, a look to the not-so-distant future to see what agents we may be using to image and treat patients with serious illnesses. The promise of personalized medicine is within our grasp. PMID- 29438009 TI - Are you afraid to write a manuscript? If so, then a Brief Communication might be right for you. PMID- 29438010 TI - Nuclear Medicine and Resources for Patients: How Complex Are Online Patient Educational Materials? AB - The Internet is a major source of health care information for patients. The American Medical Association and the National Institutes of Health recommend that consumer health care websites be written at a third- to seventh-grade level. The purpose of this study was to evaluate the level of readability of patient education websites pertaining to nuclear medicine. Methods: We searched for 10 terms on Google, collected the top 10 links for each term, and analyzed their level of readability using 10 well-established readability scales. Results: Collectively, the 99 articles were written at a grade level of 11.8 (SD, 3.4). Only 5 of the 99 articles were written at the third- to seventh-grade level recommended by the National Institutes of Health and the American Medical Association. Conclusion: There is a clear discordance between the readability level of nuclear medicine-related imaging terms and the National Institutes of Health and American Medical Association guidelines. This discordance may have a negative impact on patient understanding, contributing to poor health outcomes. PMID- 29438011 TI - Grking the Smoothened signal. AB - The kinase GRK2 has been linked to the clinically important Hedgehog (HH) signaling pathway, where it is paradoxically required for signal transduction yet also promotes internalization and degradation of the critical HH signal transducer Smoothened. Two reports by Li et al and Pusapati et al in this issue of Science Signaling provide new insights into the role of GRK2 in HH signaling. PMID- 29438012 TI - Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases. AB - Hedgehog (Hh) induces signaling by promoting the reciprocal trafficking of its receptor Patched (Ptc) and the signal transducer Smoothened (Smo), which is inhibited by Ptc, at the cell surface. We identified Smurf family E3 ubiquitin ligases as essential for Smo ubiquitylation and cell surface clearance and demonstrated that Smurf family members mediate the reciprocal trafficking of Ptc and Smo in Drosophila melanogaster G protein-coupled receptor kinase 2 (Gprk2) mediated phosphorylation of Smurf promoted Smo ubiquitylation by increasing the recruitment of Smurf to Smo, whereas protein kinase A (PKA)-mediated phosphorylation of Smo caused Smurf to dissociate from Smo, thereby inhibiting Smo ubiquitylation. Smo and Ptc competed for the same pool of Smurf family E3 ubiquitin ligases, and Hh promoted Ptc ubiquitylation and degradation by disrupting the association of Smurf family E3 ubiquitin ligases with Smo and stimulating their binding to Ptc. Our study identifies the E3 ubiquitin ligases that target Smo and provides insight into how Hh regulates the reciprocal trafficking of its receptor and signal transducer. PMID- 29438013 TI - The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function. AB - Shortening and removal of the polyadenylate [poly(A)] tail of mRNA, a process called deadenylation, is a key step in mRNA decay that is mediated through the CCR4-NOT (carbon catabolite repression 4-negative on TATA-less) complex. In our investigation of the regulation of mRNA deadenylation in the heart, we found that this complex was required to prevent cell death. Conditional deletion of the CCR4 NOT complex components Cnot1 or Cnot3 resulted in the formation of autophagic vacuoles and cardiomyocyte death, leading to lethal heart failure accompanied by long QT intervals. Cnot3 bound to and shortened the poly(A) tail of the mRNA encoding the key autophagy regulator Atg7. In Cnot3-depleted hearts, Atg7 expression was posttranscriptionally increased. Genetic ablation of Atg7, but not Atg5, increased survival and partially restored cardiac function of Cnot1 or Cnot3 knockout mice. We further showed that in Cnot3-depleted hearts, Atg7 interacted with p53 and modulated p53 activity to induce the expression of genes encoding cell death-promoting factors in cardiomyocytes, indicating that defects in deadenylation in the heart aberrantly activated Atg7 and p53 to promote cell death. Thus, mRNA deadenylation mediated by the CCR4-NOT complex is crucial to prevent Atg7-induced cell death and heart failure, suggesting a role for mRNA deadenylation in targeting autophagy genes to maintain normal cardiac homeostasis. PMID- 29438016 TI - What's happening in Neurology(r). PMID- 29438014 TI - G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog. AB - The morphogen Sonic Hedgehog (SHH) patterns tissues during development by directing cell fates in a concentration-dependent manner. The SHH signal is transmitted across the membrane of target cells by the heptahelical transmembrane protein Smoothened (SMO), which activates the GLI family of transcription factors through a mechanism that is undefined in vertebrates. Using CRISPR-edited null alleles and small-molecule inhibitors, we systematically analyzed the epistatic interactions between SMO and three proteins implicated in SMO signaling: the heterotrimeric G protein subunit GalphaS, the G protein-coupled receptor kinase 2 (GRK2), and the GalphaS-coupled receptor GPR161. Our experiments uncovered a signaling mechanism that modifies the sensitivity of target cells to SHH and consequently changes the shape of the SHH dose-response curve. In both fibroblasts and spinal neural progenitors, the loss of GPR161, previously implicated as an inhibitor of basal SHH signaling, increased the sensitivity of target cells across the entire spectrum of SHH concentrations. Even in cells lacking GPR161, GRK2 was required for SHH signaling, and Galphas, which promotes the activation of protein Kinase A (PKA), antagonized SHH signaling. We propose that the sensitivity of target cells to Hedgehog morphogens, and the consequent effects on gene expression and differentiation outcomes, can be controlled by signals from G protein-coupled receptors that converge on Galphas and PKA. PMID- 29438015 TI - Unraveling the CNOT: A new player in the autophagy-cell death nexus. AB - Autophagy plays a context-dependent role in cardiac homeostasis. In this issue of Science Signaling, Yamaguchi et al delineate a role for CCR4-NOT-mediated mRNA deadenylation in preventing the autophagy factor Atg7 from coactivating p53 mediated transcription of cell death genes in the heart. PMID- 29438017 TI - What's happening in Neurology(r)Clinical Practice. PMID- 29438018 TI - What's happening in Neurology(r)Genetics. PMID- 29438019 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29438020 TI - What's happening in Innovations in Care Delivery. PMID- 29438021 TI - Burnout, wellness, and the future of our profession. PMID- 29438022 TI - A clue for familial mitochondrial disorder: Discovering a vintage painting. PMID- 29438023 TI - Teaching NeuroImages: Intracranial foreign body reaction after endovascular procedures. PMID- 29438024 TI - Editors' note: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. PMID- 29438025 TI - Reader response: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. PMID- 29438026 TI - Reader response: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB consortium. PMID- 29438027 TI - Reader response: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. PMID- 29438028 TI - Reader response: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. PMID- 29438029 TI - Author response: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. PMID- 29438030 TI - Clinical Reasoning: Importance of clinical phenomenology in the era of genetic testing. PMID- 29438031 TI - Pearls & Oy-sters: Persistent elevation of serum carcinoembryonic antigen in secretory meningioma. PMID- 29438032 TI - Teaching Video NeuroImages: Delayed hemibody myorhythmia and palatal myoclonus after vertebrobasilar stroke. PMID- 29438033 TI - A Repulsive Environment Induces Neurodegeneration of Midbrain Dopaminergic Neurons. PMID- 29438034 TI - C1QTNF3 in the murine ovary and its function in folliculogenesis. AB - C1q/tumor necrosis factor-related protein 3 (C1QTNF3) is a novel adipokine with modulating effects on metabolism, inflammation and the cardiovascular system. C1QTNF3 expression levels in the sera and omental adipose tissues of women with PCOS are low compared to control subjects. However, the expression and function of C1QTNF3 in the ovary has not previously been examined. Here, we assessed the expression patterns of C1qtnf3 in the ovary and explored its role in folliculogenesis. The C1qtnf3 transcript abundance was higher in large follicles than in small follicles and was under the influence of gonadotropin. C1QTNF3 was detected mainly in the granulosa cells and oocytes of growing follicles and modestly in the granulosa cells of atretic follicles and in luteal cells. Excess androgen significantly decreased C1QTNF3 expression in the ovaries in vivo and in granulosa cells in vitro Recombinant C1QTNF3 protein accelerated the weight gain of ovarian explants and the growth of preantral follicles induced by follicle stimulating hormone (FSH) in vitro The stimulatory effect of C1QTNF3 on ovarian growth was accompanied by the initiation of AKT, mTOR, p70S6K and 4EBP1 phosphorylation, an increase in CCND2 expression and a reduction in cleaved CASP3 levels. Moreover, the addition of C1QTNF3 accelerated proliferation and reduced activated CASP3/7 activity in granulosa cells. In vivo, the ovarian intrabursal administration of the C1QTNF3 antibody delayed gonadotropin-induced antral follicle development. Taken together, our data demonstrate that C1QTNF3 is an intraovarian factor that promotes follicle growth by accelerating proliferation, decelerating apoptosis and promoting AKT/mTOR phosphorylation. PMID- 29438035 TI - Early experience with a temporary bridging device (Comaneci) in the endovascular treatment of ruptured wide neck aneurysms. AB - BACKGROUND: The difficulties in obtaining complete and stable endovascular occlusion are most evident for ruptured aneurysms exhibiting a wide neck and unfavorable geometric features. The aim of our study was to present our experience with the Comaneci temporary bridging device in ruptured wide neck aneurysms. METHODS: From May to July 2017, 29 ruptured aneurysms underwent endovascular embolization with the Comaneci device. Angiographic and clinical results were retrospectively analyzed. RESULTS: 29 ruptured intracranial aneurysms from different locations were included. Successful embolization was achieved in all lesions; complete post-procedure occlusion was seen in 25 (86%) cases. Insufficient embolization or neck remnant was observed in four cases (13.7%). Complications probably related, directly related, or indirectly related to the device occurred in 3.44% of patients (1/29 patients). At least one angiographic follow-up was performed in each of the 29 cases. The 12 month follow up examination has yet to be done. CONCLUSION: The Comaneci device offers a new promising and reliable technique that can safely support aneurysm coiling occlusion even in a rupture environment. However, long term monitoring of patients treated by this device is mandatory. PMID- 29438036 TI - Cervical ICA pseudo-occlusion on single phase CTA in patients with acute terminal ICA occlusion: what is the mechanism and can delayed CTA aid diagnosis? AB - BACKGROUND: Single-phase CT angiography (CTA) forms the basis of hyperacute stroke imaging but many patients with terminal internal carotid artery (ICA) occlusion exhibit a pseudo-occlusion of the cervical ICA whereby a column of unopacified blood mimics a tandem cervical ICA lesion. We aimed to investigate the utility of a delayed phase acquisition to aid identification of a pseudo occlusion and investigated the mechanism for this imaging artefact. METHODS: Thirteen patients with a pseudo-occlusion were compared with 13 patients without. CT, CTA, and digital subtraction angiographic images were reviewed by two interventional neuroradiologists for extension of thrombus into the ophthalmic segment, filling of the posterior communicating artery and ophthalmic artery, and for extension of contrast beyond the cervical segment and outline of the proximal clot surface by contrast on delayed imaging performed at 40 or 80 s. RESULTS: Those with a pseudo-occlusion demonstrated more frequent thrombus extension into the ophthalmic segment (100% vs 23%, P=0.0001), less frequent filling of the posterior communicating artery (15% vs 85%, P=0.0012), and less frequent filling of the ophthalmic artery (15% vs 92%, P=0.0002) compared with those without a pseudo-occlusion. Delayed CTA imaging showed contrast beyond the cervical segment and meeting the proximal clot face in 2/11 patients. Each of these two patients showed patency of the posterior communicating artery origin. CONCLUSION: Thrombus extension into the ophthalmic segment and patency of the posterior communicating artery and ophthalmic artery seem to govern whether a patient with a terminal ICA occlusion exhibits a pseudo-occlusion. Delayed imaging was of limited value in identification of a pseudo-occlusion. PMID- 29438038 TI - Blood-ocular barrier leakage: Further evidence for remote effects following ischemic stroke. PMID- 29438037 TI - Tau-negative amnestic dementia masquerading as Alzheimer disease dementia. AB - OBJECTIVE: To describe the phenomenon of tau-negative amnestic dementia mimicking Alzheimer disease (AD) clinically and radiologically and to highlight the importance of biomarkers in AD research. METHODS: Eight participants with amnestic mild cognitive impairment or AD dementia were evaluated by a behavioral neurologist and had a standardized neuropsychological battery performed. All participants completed structural (MRI) and molecular (amyloid and tau PET) imaging. AD-signature thickness and adjusted hippocampal volume served as structural biomarkers, while standardized uptake value ratios (SUVRs) from validated regions of interest for amyloid and tau PET were used to determine molecular biomarker status. RESULTS: All participants were thought to have AD as the primary driver of their symptoms before any PET imaging. All participants had hippocampal atrophy, and 2 participants fell below the AD-signature thickness cutoff for elderly controls (2.57), with a further 3 falling below the more stringent cutoff based on young controls (2.67). Four participants were amyloid positive (SUVR >1.42), and all were tau negative (SUVR <1.33). CONCLUSIONS: The participants presented here were clinically impaired, with structural imaging evidence of neurodegeneration, in the absence of any significant tau accumulation. Therefore, AD is unlikely as a cause of their clinical presentation and neurodegenerative imaging findings. Several implications are discussed, including the need to establish amyloid and tau positivity in N+ participants before enrolling them in trials of disease-modifying therapy agents for AD. PMID- 29438040 TI - Maternal and fetal risks of natalizumab exposure in utero: A fine balance. PMID- 29438039 TI - Blood-ocular barrier disruption in patients with acute stroke. AB - OBJECTIVE: Prompted by the unexpected finding of gadolinium leakage into ocular structures (GLOS) in acute stroke patients, we studied the frequency and nature of this finding in 167 patients. METHODS: Patients were selected who had an MRI with gadolinium at baseline and another MRI with fluid-attenuated inversion recovery (FLAIR) imaging at 2 and/or 24 hours later. GLOS was detected as lack of vitreous and/or aqueous fluid suppression on postcontrast FLAIR images. RESULTS: GLOS, evident on postcontrast FLAIR MRI, occurred in 127/167 (76%) patients: 86/109 (79%) patients treated with tissue plasminogen activator and 41/58 (71%) who were untreated. At 2 hours after administration of the contrast, GLOS was more common in the aqueous chamber alone, occurring in 67% of patients, compared to the vitreous chamber alone, seen in 6% of patients; it occurred in both chambers in 27% of patients. At 24 hours, GLOS was present in 121/162 (75%) patients, always involving the vitreous chamber, but also affecting the aqueous chamber in 6% of cases. Vitreous GLOS at 24 hours was associated with increasing age (p = 0.002) and a higher burden of cerebral white matter hyperintensities (p = 0.017). Patients with rapid diffuse GLOS, defined as GLOS involving both chambers at 2 hours, had larger infarcts (p = 0.022) and a higher degree of blood brain barrier permeability (p = 0.025). CONCLUSIONS: We found GLOS to be common in patients with acute stroke; delayed GLOS was a marker for chronic vascular disease. The mechanism for acute GLOS remains uncertain but may be a remote effect of acute cerebral injury on the blood-ocular barrier. PMID- 29438043 TI - Selective cognitive impairment and hyposmia in p.A53T SNCA PD vs typical PD. AB - OBJECTIVE: To evaluate nonmotor symptoms in early SNCA/p.A53T Parkinson disease (PD) (A53T PD) compared to typical PD (tPD). METHODS: The presence of hyposmia, neuropsychiatric, dysautonomic, and sleep disturbances was assessed by standardized questionnaires and validated scales in 18 patients with A53T PD and 18 patients with tPD, matched for age, sex, and disease duration. All patients were enrolled into the Parkinson's Progression Markers Initiative study. RESULTS: The levodopa equivalent daily dose was higher in the A53T PD (p = 0.018) group vs the tPD group. Scores on the University of Pennsylvania Smell Identification Test (p = 0.001), Benton Judgement of Line Orientation test (p = 0.001), Letter Number Sequencing Test (p = 0.002), and phonemic verbal fluency (p = 0.002) were lower in the A53T PD group vs the tPD group. In contrast, overall cognition, verbal memory, and semantic fluency were similar between groups. CONCLUSION: The observed selective cognitive impairment reflecting frontal-parietal network dysfunction, together with impaired olfaction, define a set of nonmotor dysfunctions related to A53T PD. These results have implications for the prognosis of patients with A53T PD. Moreover, as the archetypal alpha synucleinopathy, such results may give insights into tPD. PMID- 29438041 TI - Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. AB - OBJECTIVE: To assess the risk of disease reactivation during pregnancy after natalizumab suspension in women with multiple sclerosis (MS). METHODS: Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents through a 2-factor repeated measures analysis. Predictors of disease activity were assessed through stepwise multivariable logistic regression models. RESULTS: A total of 92 pregnancies were tracked in 83 women receiving natalizumab. Among these pregnancies, 74 in 70 women resulted in live births, with a postpartum follow-up of at least 1 year, and were compared with 350 previously published pregnancies. Relapse rate during and after pregnancy was higher in women treated with natalizumab (p < 0.001). In multivariable analysis, longer natalizumab washout period was the only predictor of relapse occurrence during pregnancy (p = 0.001). Relapses in the postpartum year were related to relapses during pregnancy (p = 0.019) and early reintroduction of disease-modifying drugs (DMD; p = 0.021). Disability progression occurred in 16.2% of patients and was reduced by early reintroduction of DMD (p = 0.024). CONCLUSIONS: Taken as a whole, our findings indicate that the combination of avoiding natalizumab washout and the early resumption of DMD after delivery could be the best option in the perspective of maternal risk. This approach must take into account possible fetal risks that need to be discussed with the mother and require further investigation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in women with MS, the risk of relapses during pregnancy is higher in those who had been using natalizumab as compared to those who had been using interferon-beta or no treatment. PMID- 29438044 TI - Impairment of cross-modality of vision and olfaction in Parkinson disease. AB - OBJECTIVE: To determine whether Parkinson disease (PD) affects cross-modal function of vision and olfaction because it is known that PD impairs various cognitive functions, including olfaction. METHODS: We conducted behavioral experiments to identify the influence of PD on cross-modal function by contrasting patient performance with age-matched normal controls (NCs). We showed visual effects on the strength and preference of odor by manipulating semantic connections between picture/odorant pairs. In addition, we used brain imaging to identify the role of striatal presynaptic dopamine transporter (DaT) deficits. RESULTS: We found that odor evaluation in participants with PD was unaffected by visual information, while NCs overestimated smell when sniffing odorless liquid while viewing pleasant/unpleasant visual cues. Furthermore, DaT deficit in striatum, for the posterior putamen in particular, correlated to few visual effects in participants with PD. CONCLUSIONS: These findings suggest that PD impairs cross-modal function of vision/olfaction as a result of posterior putamen deficit. This cross-modal dysfunction may serve as the basis of a novel precursor assessment of PD. PMID- 29438042 TI - In vivo [18F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease. AB - OBJECTIVE: To determine whether specific patterns of [18F]-AV-1451 tau-PET retention are observed in patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD). METHODS: In vivo [18F]-AV-1451 PET neuroimaging was performed in 5 patients with sporadic CJD (median age, 66 years [63-74]), and results were compared to cognitively normal (CN) persons (n = 44; median age, 68 years [63 74]) and to participants with very mild Alzheimer disease (AD) dementia (n = 8; median age, 77 years [63-90]). Autopsy was completed in all patients with CJD, confirming the clinical diagnosis and permitting characterization of AD neuropathologic change (ADNC). RESULTS: All patients with CJD presented with rapidly progressive dementia, typical magnetic resonance brain imaging changes, and elevated CSF total tau (median = 6,519; range = 1,528-13,240 pg/mL). Death occurred within 9 months of symptom onset, with a median 1 month (0.2-3.3) interval from [18F]-AV-1451 PET to autopsy. No unique pattern of [18F]-AV-1451 retention was observed on visual inspection. Summary standardized uptake value ratios in patients with CJD (1.17, 1.08-1.36) were indistinguishable from CN persons (1.14, 0.84-1.54; p = 0.6), and well below those of participants with AD (2.23, 1.60-3.04; p <= 0.01). [18F]-AV-1451 retention in patients with CJD and CN persons was similar in brain areas frequently affected in AD and CJD. Neuropathologic analysis confirmed the clinical diagnosis in all patients with CJD. Four patients with CJD also had low-level ADNC (A1B1C0); one patient had intermediate-level ADNC (A2B2C1/2). CONCLUSION: Increased [18F]-AV-1451 retention was not observed in patients with rapidly progressive dementia due to sporadic CJD. The [18F]-AV-1451 PET tracer maintains good specificity for paired helical tau filaments associated with AD dementia. PMID- 29438045 TI - Double-target DBS for essential tremor: 8-contact lead for cZI and Vim aligned in the same trajectory. PMID- 29438046 TI - Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. AB - OBJECTIVE: To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA). METHODS: Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed. RESULTS: A total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.9-8.5, p < 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-beta (IFN-beta) was associated with lower length and weight of the babies (p < 0.001). CONCLUSION: Our results showed that natalizumab exposure to up 12 weeks of gestation is associated with an increased risk of SA, although within the limits expected in the general population, whereas the risk of CA needs further investigation. Taking into account the high risk of disease reactivation after natalizumab suspension, pregnancy could be planned continuing natalizumab while strictly monitoring conception. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in women with MS, natalizumab exposure increases the risk of spontaneous abortion as compared to IFN-beta-exposed or untreated patients (OR 3.9, 95% CI 1.9-8.5). PMID- 29438047 TI - Ethylene Exerts Species-Specific and Age-Dependent Control of Photosynthesis. PMID- 29438048 TI - Hydrogen Sulfide Increases Production of NADPH Oxidase-Dependent Hydrogen Peroxide and Phospholipase D-Derived Phosphatidic Acid in Guard Cell Signaling. AB - Hydrogen sulfide (H2S) is an important gaseous signaling molecule in plants that participates in stress responses and development. l-Cys desulfhydrase 1, one of the enzymatic sources of H2S in plants, participates in abscisic acid-induced stomatal closure. We combined pharmacological and genetic approaches to elucidate the involvement of H2S in stomatal closure and the interplay between H2S and other second messengers of the guard cell signaling network, such as hydrogen peroxide (H2O2) and phospholipase D (PLD)-derived phosphatidic acid in Arabidopsis (Arabidopsis thaliana). Both NADPH oxidase isoforms, respiratory burst oxidase homolog (RBOH)D and RBOHF, were required for H2S-induced stomatal closure. In vivo imaging using the cytosolic ratiometric fluorescent biosensor roGFP2-Orp1 revealed that H2S stimulates H2O2 production in Arabidopsis guard cells. Additionally, we observed an interplay between H2S and PLD activity in the regulation of reactive oxygen species production and stomatal movement. The PLDalpha1 and PLDdelta isoforms were required for H2S-induced stomatal closure, and most of the H2S-dependent H2O2 production required the activity of PLDalpha1. Finally, we showed that H2S induced increases in the PLDdelta-derived phosphatidic acid levels in guard cells. Our results revealed the involvement of H2S in the signaling network that controls stomatal closure, and suggest that H2S regulates NADPH oxidase and PLD activity in guard cells. PMID- 29438050 TI - Parasite-mediated microhabitat segregation between congeneric hosts. AB - Parasite-mediated competition can shape community structure and host distribution. If two species compete for resources, parasites may indirectly change the outcome of competition. We tested the role of a trematode parasite in mediating microhabitat use by congeneric isopods Austridotea annectens and Austridotea lacustris Although both isopods share resources, they rarely co-occur in the same discrete microhabitats. We set up mesocosms with and without competition and/or parasites to examine the role of parasites in host distribution and habitat segregation. Austridotea annectens showed a clear preference for one microhabitat type regardless of competition or parasitic infection. By contrast, A. lacustris showed little habitat selection in the absence of competition, but favoured sandy habitats in the presence of uninfected A. annectens and rocky habitats when competing with infected A. annectens Our results suggest that parasites in one species affect the distribution of another species, and mediate competition between these species. We demonstrated the impacts of a parasite on the microhabitat use of its host's competitor. This also represents an example of a super-extended phenotype, where a parasite affects the phenotype of a non-host. PMID- 29438049 TI - Oncoprotein AEG-1 is an endoplasmic reticulum RNA-binding protein whose interactome is enriched in organelle resident protein-encoding mRNAs. AB - Astrocyte elevated gene-1 (AEG-1), an oncogene whose overexpression promotes tumor cell proliferation, angiogenesis, invasion, and enhanced chemoresistance, is thought to function primarily as a scaffolding protein, regulating PI3K/Akt and Wnt/beta-catenin signaling pathways. Here we report that AEG-1 is an endoplasmic reticulum (ER) resident integral membrane RNA-binding protein (RBP). Examination of the AEG-1 RNA interactome by HITS-CLIP and PAR-CLIP methodologies revealed a high enrichment for endomembrane organelle-encoding transcripts, most prominently those encoding ER resident proteins, and within this cohort, for integral membrane protein-encoding RNAs. Cluster mapping of the AEG-1/RNA interaction sites demonstrated a normalized rank order interaction of coding sequence >5' untranslated region, with 3' untranslated region interactions only weakly represented. Intriguingly, AEG-1/membrane protein mRNA interaction sites clustered downstream from encoded transmembrane domains, suggestive of a role in membrane protein biogenesis. Secretory and cytosolic protein-encoding mRNAs were also represented in the AEG-1 RNA interactome, with the latter category notably enriched in genes functioning in mRNA localization, translational regulation, and RNA quality control. Bioinformatic analyses of RNA-binding motifs and predicted secondary structure characteristics indicate that AEG-1 lacks established RNA binding sites though shares the property of high intrinsic disorder commonly seen in RBPs. These data implicate AEG-1 in the localization and regulation of secretory and membrane protein-encoding mRNAs and provide a framework for understanding AEG-1 function in health and disease. PMID- 29438051 TI - Successful escape of bombardier beetles from predator digestive systems. AB - Some prey animals can escape from the digestive systems of predators after being swallowed. To clarify the ecological factors that determine the success of such an escape, we investigated how the bombardier beetle Pheropsophus jessoensis escapes from two toad species, Bufo japonicus and Btorrenticola, under laboratory conditions. Pheropsophus jessoensis ejects a hot chemical spray from the tip of the abdomen when it is attacked. Although all toads swallowed the bombardier beetles, 43% of the toads vomited the beetles 12-107 min after swallowing them. All the vomited beetles were still alive and active. Our experiment showed that Pjessoensis ejected hot chemicals inside the toads, thereby forcing the toads to vomit. Large beetles escaped more frequently than small beetles, and small toads vomited the beetles more frequently than large toads. Our results demonstrate the importance of the prey-predator size relationship in the successful escape of prey from inside a predator. PMID- 29438052 TI - Current indirect fitness and future direct fitness are not incompatible. AB - In primitively eusocial insects, many individuals function as workers despite being capable of independent reproduction. Such altruistic behaviour is usually explained by the argument that workers gain indirect fitness by helping close genetic relatives. The focus on indirect fitness has left open the question of whether workers are also capable of getting direct fitness in the future in spite of working towards indirect fitness in the present. To investigate this question, we recorded behavioural profiles of all wasps on six naturally occurring nests of Ropalidia marginata, and then isolated all wasps in individual plastic boxes, giving them an opportunity to initiate nests and lay eggs. We found that 41% of the wasps successfully did so. Compared to those that failed to initiate nests, those that did were significantly younger, had significantly higher frequency of self-feeding behaviour on their parent nests but were not different in the levels of work performed in the parent nests. Thus ageing and poor feeding, rather than working for their colonies, constrain individuals for future independent reproduction. Hence, future direct fitness and present work towards gaining indirect fitness are not incompatible, making it easier for worker behaviour to be selected by kin selection or multilevel selection. PMID- 29438053 TI - Social cues trigger differential immune investment strategies in a non-social insect, Tenebrio molitor. AB - Social immunization (SI) is a horizontal transfer of immunity that protects naive hosts against infection following exposure to infected nestmates. While mainly documented in eusocial insects, non-social species also share similar ecological features which favour the development of group-level immunity. Here, we investigate SI in Tenebrio molitor by pairing naive females with a pathogen challenged conspecific for 72 h before measuring a series of immune and fitness traits. We found no evidence for SI, as beetles who cohabited with a live pathogen-challenged conspecific were not better protected against bacterial challenge. However, exposure to a heat-killed-bacteria-challenged conspecific appeared to increase pathogen tolerance, which manifested in differential fitness investment. Our results together suggest that T. molitor do respond to immune related cues in the social environment, despite not showing a classic immunization response as predicted. PMID- 29438054 TI - Geomagnetic field influences upward movement of young Chinook salmon emerging from nests. AB - Organisms use a variety of environmental cues to orient their movements in three dimensional space. Here, we show that the upward movement of young Chinook salmon (Oncorhynchus tshawytscha) emerging from gravel nests is influenced by the geomagnetic field. Fish in the ambient geomagnetic field travelled farther upwards through substrate than did fish tested in a field with the vertical component inverted. This suggests that the magnetic field is one of several factors that influences emergence from the gravel, possibly by serving as an orientation cue that helps fish determine which way is up. Moreover, our work indicates that the Oncorhynchus species are sensitive to the magnetic field throughout their life cycles, and that it guides their movements across a range of spatial scales and habitats. PMID- 29438056 TI - One-Tube Isolation of DNA from Mouse Tails. AB - This protocol describes a variation of a simple method for isolation of DNA from mouse tails that uses commercially available gel-barrier tubes to eliminate the tedious transfer of samples during serial extractions with organic solvents. This variant is useful when processing very large numbers of samples. PMID- 29438055 TI - Persistence of an extracellular systemic infection across metamorphosis in a holometabolous insect. AB - Organisms with complex life cycles can differ markedly in their biology across developmental life stages. Consequently, distinct life stages can represent drastically different environments for parasites. This difference is especially striking with holometabolous insects, which have dramatically different larval and adult life stages, bridged by a complete metamorphosis. There is no a priori guarantee that a parasite infecting the larval stage would be able to persist into the adult stage. In fact, to our knowledge, transstadial transmission of extracellular pathogens has never been documented in a host that undergoes complete metamorphosis. We tested the hypothesis that a bacterial parasite originally sampled from an adult host could infect a larva, then survive through metamorphosis and persist into the adult stage. As a model, we infected the host Drosophila melanogaster with a horizontally transmitted, extracellular bacterial pathogen, Providencia rettgeri We found that this natural pathogen survived systemic infection of larvae (L3) and successfully persisted into the adult host. We then discuss how it may be adaptive for bacteria to transverse life stages and even minimize virulence at the larval stage in order to benefit from adult dispersal. PMID- 29438057 TI - Complement-Dependent Cytotoxicity Assay. AB - A useful feature of therapeutic antibodies is the ability to kill the cells to which they bind. Antibodies are capable of mediating cell killing in a variety of ways. Apoptosis, complement-mediated mechanisms, and antibody-dependent cellular cytotoxicity are all effects that can be assayed to characterize lead antibody candidates. Extensive, multidose characterizations of a series of candidates can be performed in a short amount of time using assays developed for high-throughput flow cytometry systems. Antibodies that contain the Fc portion of the human IgG1 can activate complement-mediated cell death. One way in which they do this is via direct complement killing of tumor cells by the membrane attack complex, a process usually called complement-dependent cytotoxicity. PMID- 29438058 TI - Assessment of Antibody-Dependent Cellular Cytotoxicity by Flow Cytometry. AB - A useful feature of therapeutic antibodies is the ability to kill the cells to which they bind. Antibodies are capable of mediating cell killing in a variety of ways. Apoptosis, complement-mediated mechanisms, and antibody-dependent cellular cytotoxicity (ADCC) are all effects that can be assayed to characterize lead antibody candidates. Extensive, multidose characterizations of a series of candidates can be performed in a short amount of time using assays developed for high-throughput flow cytometry systems. Antibodies that contain the Fc portion of the human IgG1 can activate complement-mediated killing. In the ADCC method described here, cytotoxicity is mediated mostly by natural killer (NK) cells. Thus, if an antibody binds to its target on the surface of a tumor cell, Fc receptors on the surface of the NK cells (effector cells) recognize the bound antibody. This leads to the release of cytotoxic granules containing perforin, granzymes, and interferon gamma, a cytokine that can stimulate other cells of the immune system such as T cells. PMID- 29438059 TI - Electroporation of Postimplantation Mouse Embryos In Utero. AB - Gene transfer by electroporation is possible in mouse fetuses within the uterus. As described in this protocol, the pregnant female is anesthetized, the abdominal cavity is opened, and the uterus with the fetuses is exteriorized. A solution of plasmid DNA is injected through the uterine wall directly into the fetus, typically into a cavity like the brain ventricle, guided by fiber optic illumination. Electrodes are positioned on the uterus around the region of the fetus that was injected, and electrical pulses are delivered. The uterus is returned to the abdominal cavity, the body wall is sutured closed, and the female is allowed to recover. The manipulated fetuses can then be collected and analyzed at various times after the electroporation. This method allows experimental access to later-stage developing mouse embryos. PMID- 29438060 TI - Preparation of Antisense Oligonucleotides to Inhibit miRNA Function. AB - This protocol is used to design antisense oligonucleotides (ASOs) for specific inhibition of miRNA function in cultured cells. The incorporation of 2'-O-methyl modifications in ASOs enhances their potency and resistance to degradation, whereas 3'-terminal cholesterol-conjugation facilitates delivery of ASOs into cells. PMID- 29438061 TI - Inhibiting miRNA Function by Antisense Oligonucleotides in Cultured Mammalian Cells. AB - Methods for transfecting antisense oligonucleotides (ASOs) into mammalian cells for suppression of miRNA function are described in this protocol. The effects of ASOs on the miRNA are evaluated by measuring the protein level of the putative miRNA target or the activity of a reporter bearing a 3' untranslated region (3' UTR) derived from the putative miRNA target. PMID- 29438062 TI - Inhibiting miRNA Function by Antisense Oligonucleotides in Drosophila S2 Cells. AB - This protocol describes methods to transfect antisense oligonucleotides (ASOs) into Drosophila S2 cells for suppression of miRNA function. The effects of ASOs on the miRNA are evaluated by measuring the protein level of the putative miRNA target or the activity of a reporter bearing a 3' UTR derived from the putative miRNA target. PMID- 29438063 TI - Caring for Escherichia coli. AB - The bacterial strain E. coli K-12 has played an indisputably important role over the past century-in biology overall and in molecular biology in particular. Strains of E. coli (either untransformed or transformed with a plasmid) are usually sent through the mail as agar stab cultures. All strains must be validated as soon as they enter the laboratory, before they are used in experiments. This protocol provides guidelines for validation and storage of E. coli and plasmids. PMID- 29438064 TI - Buffers. AB - Biological reactions work well only within a narrow concentration range of hydrogen ions. Paradoxically, however, many of these reactions themselves generate or consume protons. Buffers are substances that undergo reversible protonation within a particular pH range and therefore maintain the concentration of hydrogen ions within acceptable limits. This introduction describes standard buffers used in molecular cloning, including Tris buffers, Good buffers, and phosphate buffers. PMID- 29438065 TI - Cytosolic carnitine acetyltransferase as a source of cytosolic acetyl-CoA: a possible mechanism for regulation of cardiac energy metabolism. AB - The role of carnitine acetyltransferase (CrAT) in regulating cardiac energy metabolism is poorly understood. CrAT modulates mitochondrial acetyl-CoA/CoA (coenzyme A) ratios, thus regulating pyruvate dehydrogenase activity and glucose oxidation. Here, we propose that cardiac CrAT also provides cytosolic acetyl-CoA for the production of malonyl-CoA, a potent inhibitor of fatty acid oxidation. We show that in the murine cardiomyocyte cytosol, reverse CrAT activity (RCrAT, producing acetyl-CoA) is higher compared with the liver, which primarily uses ATP citrate lyase to produce cytosolic acetyl-CoA for lipogenesis. The heart displayed a lower RCrAT Km for CoA compared with the liver. Furthermore, cytosolic RCrAT accounted for 4.6 +/- 0.7% of total activity in heart tissue and 12.7 +/- 0.2% in H9C2 cells, while highly purified heart cytosolic fractions showed significant CrAT protein levels. To investigate the relationship between CrAT and acetyl-CoA carboxylase (ACC), the cytosolic enzyme catalyzing malonyl CoA production from acetyl-CoA, we studied ACC2-knockout mouse hearts which showed decreased CrAT protein levels and activity, associated with increased palmitate oxidation and acetyl-CoA/CoA ratio compared with controls. Conversely, feeding mice a high-fat diet for 10 weeks increased cardiac CrAT protein levels and activity, associated with a reduced acetyl-CoA/CoA ratio and glucose oxidation. These data support the presence of a cytosolic CrAT with a low Km for CoA, favoring the formation of cytosolic acetyl-CoA, providing an additional source to the classical ATP-citrate lyase pathway, and that there is an inverse relation between CrAT and the ratio of acetyl-CoA/CoA as evident in conditions affecting the regulation of cardiac energy metabolism. PMID- 29438066 TI - Cardiomyocyte diffusible redox mediators control Trypanosoma cruzi infection: role of parasite mitochondrial iron superoxide dismutase. AB - Chagas disease (CD), caused by the protozoa Trypanosoma cruzi, is a chronic illness in which parasites persist in the host-infected tissues for years. T. cruzi invasion in cardiomyocytes elicits the production of pro-inflammatory mediators [TNF-alpha, IL-1beta, IFN-gamma; nitric oxide (.NO)], leading to mitochondrial dysfunction with increased superoxide radical (O2.-), hydrogen peroxide (H2O2) and peroxynitrite generation. We hypothesize that these redox mediators may control parasite proliferation through the induction of intracellular amastigote programmed cell death (PCD). In this work, we show that T. cruzi (CL-Brener strain) infection in primary cardiomyocytes produced an early (24 h post infection) mitochondrial dysfunction with H2O2 generation and the establishment of an oxidative stress evidenced by FoxO3 activation and target host mitochondrial protein expression (MnSOD and peroxiredoxin 3). TNF-alpha/IL 1beta-stimulated cardiomyocytes were able to control intracellular amastigote proliferation compared with unstimulated cardiomyocytes. In this condition leading to oxidant formation, an enhanced number of intracellular apoptotic amastigotes were detected. The ability of H2O2 to induce T. cruzi PCD was further confirmed in the epimastigote stage of the parasite. H2O2 treatment induced parasite mitochondrial dysfunction together with intra-mitochondrial O2.- generation. Importantly, parasites genetically engineered to overexpress mitochondrial Fe-superoxide dismutase (Fe-SODA) were more infective to TNF alpha/IL-1beta-stimulated cardiomyocytes with less apoptotic amastigotes; this result underscores the role of this enzyme in parasite survival. Our results indicate that cardiomyocyte-derived diffusible mediators are able to control intracellular amastigote proliferation by triggering T. cruzi PCD and that parasite Fe-SODA tilts the process toward survival as part of an antioxidant based immune evasion mechanism. PMID- 29438067 TI - Functional role of highly conserved residues of the N-terminal tail and first transmembrane segment of a P4-ATPase. AB - The P4 family of P-type ATPases (P4-ATPases) plays an important role in maintaining phospholipid asymmetry in eukaryotic cell membranes. Leishmania miltefosine transporter (LMT) is a plasma membrane (PM) P4-ATPase that catalyses translocation into the parasite of the leishmanicidal drug miltefosine as well as phosphatidylcholine and phosphatidylethanolamine analogues. In the present study, we analysed the role, in LMT, of a series of highly conserved amino acids previously undescribed in the N-terminal region of P4-ATPases. Seven residues were identified and, according to an LMT structural model, five were located in the cytosolic N-terminal tail (Asn58, Ile60, Lys64, Tyr65 and Phe70) and the other two (Pro72 and Phe79) in the first transmembrane segment (TM1). Alanine scanning mutagenesis analysis showed that N58A, Y65A and F79A mutations caused a considerable reduction in the LMT translocase activity. These mutations did not affect protein expression levels. We generated additional mutations in these three residues to assess the influence of the conservation degree on LMT translocase activity. Some of these mutations reduced expression levels without affecting the interaction between LMT and its CDC50 subunit, LRos3. Conserved and non-conserved mutations in the invariant residue Asn58 drastically reduced the translocase activity. Consequently, Asn58 may be necessary to achieve optimal catalytic LMT activity as previously described for the potentially equivalent Asn39 of the sarco/endoplasmic reticulum Ca2+-ATPase isoform 1a (SERCA1a). Additionally, conservation of a hydrophobic residue at position 79 is crucial for LMT stability. PMID- 29438069 TI - Sugar Coating the Phloem Sieve Element Wall. PMID- 29438068 TI - The Dynamic Plant: Capture, Transformation, and Management of Energy. PMID- 29438070 TI - Successfully reducing newborn asphyxia in the labour unit in a large academic medical centre: a quality improvement project using statistical process control. AB - BACKGROUND: A safe delivery is part of a good start in life, and a continuous focus on preventing harm during delivery is crucial, even in settings with a good safety record. In January 2013, the labour unit at Copenhagen University Hospital, Hvidovre, undertook a quality improvement (QI) project to prevent asphyxia and reduced the percentage of newborns with asphyxia by 48%. METHODS: The change theory consisted of two primary elements: (1) the clinical content, including three clinical bundles of evidence-based care, a 'delivery bundle', an 'oxytocin bundle' and a 'vacuum extraction bundle'; (2) an implementation theory, including improving skills in interpretation of cardiotocography, use of QI methods and participation in a national learning network. The Model for Improvement and Deming's system of profound knowledge were used as a methodological framework. Data on compliance with the care bundles and the number of deliveries between newborns with asphyxia (Apgar <7 after 5 min or pH <7) were analysed using statistical process control. RESULTS: Compliance with all three clinical care bundles improved to 95% or more, and the percentages of newborns with pH <7 and Apgar <7 after 5 min were reduced by 48% and 31%, respectively. In general, the QI approach strengthened multidisciplinary teamwork, systematised workflow and structured communication around the deliveries. Changes included making a standard memo in the medical record, the use of a bedside whiteboard, bedside handovers, shared decisions with a peer when using an oxytocin infusion and the use of a checklist before vacuum extractions. CONCLUSION: This QI project illustrates how aspects of patient safety, such as the prevention of asphyxia, can be improved using QI methods to more reliably implement best practice, even in high-performing systems. PMID- 29438071 TI - Chronic obstructive pulmonary disease and the risk of 12 cardiovascular diseases: a population-based study using UK primary care data. AB - Risks for cardiovascular diseases (CVDs) other than myocardial infarction and stroke in the general COPD population are not well quantified. We used a matched cohort study design and Cox regression to estimate relative risks for 12 separate CVDs in a large population-based cohort of patients with COPD over a 12-year period. Associations between COPD and individual CVDs were heterogeneous, with the highest relative risks observed for heart failure and diseases of the arterial circulation (in excess of 2.5 for those aged 64-75 years). Relative risks declined with increasing age but for most CVD outcomes remained unchanged over the study period. PMID- 29438073 TI - Stroke Self-Management Support Improves Survivors' Self-Efficacy and Outcome Expectation of Self-Management Behaviors. AB - BACKGROUND AND PURPOSE: Evidence shows self-management programs are associated with improved recovery outcomes. This article reports on the effectiveness of a new nurse-led self-efficacy-based stroke self-management program. METHODS: A randomized controlled trial of participants recruited from 3 acute stroke units was conducted. The intervention group received the 4-week stroke self-management program. The control group received usual care. All participants were assessed at baseline and 8 weeks after randomization. Data were analyzed using generalized estimating equations. Outcomes included self-efficacy, outcome expectation, and satisfaction with performance of self-management behaviors. RESULTS: One hundred twenty-eight participants were randomized with mean age, 67.46 years (SD, 11.95); 59% men; and mean duration poststroke, 45 days (SD, 26.16). At 8 weeks of follow up in the intention-to-treat population, the intervention group improved significantly in self-efficacy (95% confidence interval, 2.55-12.45; P<0.01), outcome expectation (95% confidence interval, 5.47-14.01; P<0.01), and satisfaction with performance of self-management behaviors (95% confidence interval, 3.38-13.87; P<0.01) compared with the control. Similar results were obtained at 8 weeks of follow-up in the per-protocol population. CONCLUSIONS: The stroke self-management program improved survivors' self-efficacy, outcome expectation, and satisfaction with performance of self-management behaviors. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02112955. PMID- 29438072 TI - Using a network organisational architecture to support the development of Learning Healthcare Systems. AB - The US National Academy of Sciences has called for the development of a Learning Healthcare System in which patients and clinicians work together to choose care, based on best evidence, and to drive discovery as a natural outgrowth of every clinical encounter to ensure innovation, quality and value at the point of care. However, the vision of a Learning Healthcare System has remained largely aspirational. Over the last 13 years, researchers, clinicians and families, with support from our paediatric medical centre, have designed, developed and implemented a network organisational model to achieve the Learning Healthcare System vision. The network framework aligns participants around a common goal of improving health outcomes, transparency of outcome measures and a flexible and adaptive collaborative learning system. Team collaboration is promoted by using standardised processes, protocols and policies, including communication policies, data sharing, privacy protection and regulatory compliance. Learning methods include collaborative quality improvement using a modified Breakthrough Series approach and statistical process control methods. Participants observe their own results and learn from the experience of others. A common repository (a 'commons') is used to share resources that are created by participants. Standardised technology approaches reduce the burden of data entry, facilitate care and result in data useful for research and learning. We describe how this organisational framework has been replicated in four conditions, resulting in substantial improvements in outcomes, at scale across a variety of conditions. PMID- 29438074 TI - Lacunar Infarcts, but Not Perivascular Spaces, Are Predictors of Cognitive Decline in Cerebral Small-Vessel Disease. AB - BACKGROUND AND PURPOSE: Cerebral small-vessel disease is a major cause of cognitive impairment. Perivascular spaces (PvS) occur in small-vessel disease, but their relationship to cognitive impairment remains uncertain. One reason may be difficulty in distinguishing between lacunes and PvS. We determined the relationship between baseline PvS score and PvS volume with change in cognition over a 5-year follow-up. We compared this to the relationship between baseline lacune count and total lacune volume with cognition. In addition, we examined change in PvS volume over time. METHODS: Data from the prospective SCANS study (St Georges Cognition and Neuroimaging in Stroke) of patients with symptomatic lacunar stroke and confluent leukoaraiosis were used (n=121). Multimodal magnetic resonance imaging was performed annually for 3 years and neuropsychological testing annually for 5 years. Lacunes were manually identified and distinguished from PvS. PvS were rated using a validated visual rating scale, and PvS volumes calculated using T1-weighted images. Linear mixed-effect models were used to determine the impact of PvS and lacunes on cognition. RESULTS: Baseline PvS scores or volumes showed no association with cognitive indices. No change was detectable in PvS volumes over the 3 years. In contrast, baseline lacunes associated with all cognitive indices and predicted cognitive decline over the 5 year follow-up. CONCLUSIONS: Although a feature of small-vessel disease, PvS are not a predictor of cognitive decline, in contrast to lacunes. This study highlights the importance of carefully differentiating between lacunes and PvS in studies investigating vascular cognitive impairment. PMID- 29438075 TI - Response by Yoshimura et al to Letter Regarding Article, "Randomized Controlled Trial of Early Versus Delayed Statin Therapy in Patients With Acute Ischemic Stroke: ASSORT Trial (Administration of Statin on Acute Ischemic Stroke Patient)". PMID- 29438076 TI - Response by Park and Bae to Letter Regarding Article, "One-Year Outcomes After Minor Stroke or High-Risk Transient Ischemic Attack: Korean Multicenter Stroke Registry Analysis". PMID- 29438077 TI - Stroke Risk Factors Unique to Women. PMID- 29438079 TI - Letter by Moris et al Regarding Article, "One-Year Outcomes After Minor Stroke or High-Risk Transient Ischemic Attack: Korean Multicenter Stroke Registry Analysis". PMID- 29438078 TI - Preeclampsia: Association With Posterior Reversible Encephalopathy Syndrome and Stroke. PMID- 29438080 TI - Thrombus Neutrophil Extracellular Traps Content Impair tPA-Induced Thrombolysis in Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Neutrophil Extracellular Traps (NETs) are DNA extracellular networks decorated with histones and granular proteins produced by activated neutrophils. NETs have been identified as major triggers and structural factors of thrombosis. A recent study designated extracellular DNA threads from NETs as a potential therapeutic target for improving tissue-type plasminogen activator (tPA)-induced thrombolysis in acute coronary syndrome. The aim of this study was to assess the presence of NETs in thrombi retrieved during endovascular therapy in patients with acute ischemic stroke (AIS) and their impact on tPA induced thrombolysis. METHODS: We analyzed thrombi from 108 AIS patients treated with endovascular therapy. Thrombi were characterized by hematoxylin/eosin staining, immunostaining, and ex vivo enzymatic assay. Additionally, we assessed ex vivo the impact of deoxyribonuclease 1 (DNAse 1) on thrombolysis of AIS thrombi. RESULTS: Histological analysis revealed that NETs contributed to the composition of all AIS thrombi especially in their outer layers. Quantitative measurement of thrombus NETs content was not associated with clinical outcome or AIS pathogenesis but correlated significantly with endovascular therapy procedure length and device number of passes. Ex vivo, recombinant DNAse 1 accelerated tPA induced thrombolysis, whereas DNAse 1 alone was ineffective. CONCLUSIONS: This study suggests that thrombus NETs content may be responsible for reperfusion resistance, including mechanical or pharmacological approaches with intravenous tPA, irrespectively of their etiology. The efficacy of a strategy involving an administration of DNAse 1 in addition to tPA should be explored in the setting of AIS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02907736. PMID- 29438082 TI - Letter by Scheitz et al Regarding Article, "Randomized Controlled Trial of Early Versus Delayed Statin Therapy in Patients With Acute Ischemic Stroke: ASSORT Trial (Administration of Statin on Acute Ischemic Stroke Patient)". PMID- 29438081 TI - Microvasospasms After Experimental Subarachnoid Hemorrhage Do Not Depend on Endothelin A Receptors. AB - BACKGROUND AND PURPOSE: Perturbations in cerebral microcirculation (eg, microvasospasms) and reduced neurovascular communication determine outcome after subarachnoid hemorrhage (SAH). ET-1 (endothelin-1) and its receptors have been implicated in the pathophysiology of large artery spasms after SAH; however, their role in the development of microvascular dysfunction is currently unknown. Here, we investigated whether inhibiting ETA (endothelin A) receptors can reduce microvasospasms after experimentally induced SAH. METHODS: SAH was induced in male C57BL/6 mice by filament perforation of the middle cerebral artery. Three hours after SAH, a cranial window was prepared and the pial and parenchymal cerebral microcirculation was measured in vivo using two-photon microscopy before, during, and after administration of the ETA receptor inhibitor clazosentan. In separate experiments, the effect of clazosentan treatment on neurological outcome was measured 3 days after SAH. RESULTS: Clazosentan treatment had no effect on the number or severity of SAH-induced cerebral microvasospasms nor did it affect neurological outcome. CONCLUSIONS: Our results indicate that ETA receptors, which mediate large artery spasms after SAH, do not seem to play a role in the development of microarterial spasms, suggesting that posthemorrhagic spasms are mediated by distinct mechanisms in large and small cerebral vessels. Given that cerebral microvessel dysfunction is a key factor for outcome after SAH, further research into the mechanisms that underlie posthemorrhagic microvasospasms is urgently needed. PMID- 29438083 TI - Stroke in Women: Recognizing Opportunities for Prevention and Treatment. PMID- 29438084 TI - Polygenic Risk for Depression Increases Risk of Ischemic Stroke: From the Stroke Genetics Network Study. AB - BACKGROUND AND PURPOSE: Although depression is a risk factor for stroke in large prospective studies, it is unknown whether these conditions have a shared genetic basis. METHODS: We applied a polygenic risk score (PRS) for major depressive disorder derived from European ancestry analyses by the Psychiatric Genomics Consortium to a genome-wide association study of ischemic stroke in the Stroke Genetics Network of National Institute of Neurological Disorders and Stroke. Included in separate analyses were 12 577 stroke cases and 25 643 controls of European ancestry and 1353 cases and 2383 controls of African ancestry. We examined the association between depression PRS and ischemic stroke overall and with pathogenic subtypes using logistic regression analyses. RESULTS: The depression PRS was associated with higher risk of ischemic stroke overall in both European (P=0.025) and African ancestry (P=0.011) samples from the Stroke Genetics Network. Ischemic stroke risk increased by 3.0% (odds ratio, 1.03; 95% confidence interval, 1.00-1.05) for every 1 SD increase in PRS for those of European ancestry and by 8% (odds ratio, 1.08; 95% confidence interval, 1.04 1.13) for those of African ancestry. Among stroke subtypes, elevated risk of small artery occlusion was observed in both European and African ancestry samples. Depression PRS was also associated with higher risk of cardioembolic stroke in European ancestry and large artery atherosclerosis in African ancestry persons. CONCLUSIONS: Higher polygenic risk for major depressive disorder is associated with increased risk of ischemic stroke overall and with small artery occlusion. Additional associations with ischemic stroke subtypes differed by ancestry. PMID- 29438085 TI - Building Cross-Disciplinary Research Collaborations. PMID- 29438086 TI - Impact of Conventional Stroke Risk Factors on Stroke in Women: An Update. PMID- 29438087 TI - Focused Update of Sex Differences in Patient Reported Outcome Measures After Stroke. PMID- 29438090 TI - Fertility Preservation in Leukemia. PMID- 29438089 TI - Stable Accumulation of Photosystem II Requires ONE-HELIX PROTEIN1 (OHP1) of the Light Harvesting-Like Family. AB - The cellular functions of two Arabidopsis (Arabidopsis thaliana) one-helix proteins, OHP1 and OHP2 (also named LIGHT-HARVESTING-LIKE2 [LIL2] and LIL6, respectively, because they have sequence similarity to light-harvesting chlorophyll a/b-binding proteins), remain unclear. Tagged null mutants of OHP1 and OHP2 (ohp1 and ohp2) showed stunted growth with pale-green leaves on agar plates, and these mutants were unable to grow on soil. Leaf chlorophyll fluorescence and the composition of thylakoid membrane proteins revealed that ohp1 deletion substantially affected photosystem II (PSII) core protein function and led to reduced levels of photosystem I core proteins; however, it did not affect LHC accumulation. Transgenic ohp1 plants rescued with OHP1-HA or OHP1-Myc proteins developed a normal phenotype. Using these tagged OHP1 proteins in transgenic plants, we localized OHP1 to thylakoid membranes, where it formed protein complexes with both OHP2 and High Chlorophyll Fluorescence244 (HCF244). We also found PSII core proteins D1/D2, HCF136, and HCF173 and a few other plant specific proteins associated with the OHP1/OHP2-HCF244 complex, suggesting that these complexes are early intermediates in PSII assembly. OHP1 interacted directly with HCF244 in the complex. Therefore, OHP1 and HCF244 play important roles in the stable accumulation of PSII. PMID- 29438088 TI - PROHIBITIN3 Forms Complexes with ISOCHORISMATE SYNTHASE1 to Regulate Stress Induced Salicylic Acid Biosynthesis in Arabidopsis. AB - Salicylic acid (SA) is a major defense signal in plants. In Arabidopsis (Arabidopsis thaliana), the chloroplast-localized isochorismate pathway is the main source of SA biosynthesis during abiotic stress or pathogen infections. In the first step of the pathway, the enzyme ISOCHORISMATE SYNTHASE1 (ICS1) converts chorismate to isochorismate. An unknown enzyme subsequently converts isochorismate to SA. Here, we show that ICS1 protein levels increase during UV-C stress. To identify proteins that may play roles in SA production by regulating ICS1, we analyzed proteins that coimmunoprecipitated with ICS1 via mass spectrometry. The ICS1 complexes contained a large number of peptides from the PROHIBITIN (PHB) protein family, with PHB3 the most abundant. PHB proteins have diverse biological functions that include acting as scaffolds for protein complex formation and stabilization. PHB3 was reported previously to localize to mitochondria. Using fractionation, protease protection, and live imaging, we show that PHB3 also localizes to chloroplasts, where ICS1 resides. Notably, loss of PHB3 function led to decreased ICS1 protein levels in response to UV-C stress. However, ICS1 transcript levels remain unchanged, indicating that ICS1 is regulated posttranscriptionally. The phb3 mutant displayed reduced levels of SA, the SA-regulated protein PR1, and hypersensitive cell death in response to UV-C and avirulent strains of Pseudomonas syringae and, correspondingly, supported increased growth of P. syringae The expression of a PHB3 transgene in the phb3 mutant complemented all of these phenotypes. We suggest a model in which the formation of PHB3-ICS1 complexes stabilizes ICS1 to promote SA production in response to stress. PMID- 29438091 TI - A Phase I Dose-Escalation Study of Clofarabine in Patients with Relapsed or Refractory Low-Grade or Intermediate-Grade B-Cell or T-Cell Lymphoma. AB - LESSONS LEARNED: Clofarabine can be active in relapsed and refractory lymphoid malignancies on a weekly dosing schedule.Responses were seen in patients with T cell lymphomas, including cutaneous T-cell lymphoma, but not in patients with aggressive B-cell lymphomas. BACKGROUND: Clofarabine is a second-generation purine nucleoside analog currently approved for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. In adults, clofarabine has been investigated in several phase I and II trials as a single agent and in combination for relapsed or refractory acute leukemia. These studies have shown that clofarabine has activity and an acceptable safety profile in patients with hematological malignancies. In this phase I dose escalation trial, clofarabine was evaluated in patients with relapsed or refractory, low-grade or intermediate grade, B-cell or T-cell lymphoma. METHODS: The starting dose of 10 mg/m2 per week was administered intravenously (IV) for 3 consecutive weeks every 28 days, and doses were escalated in cohorts of three. The study objectives were to determine the maximum tolerated dose (MTD), characterize and quantify the toxicity profile, and determine the overall response rate of clofarabine administered once a week for 3 weeks and repeated every 4 weeks. Eligible patients were over the age of 18, had a histologically confirmed low-grade or intermediate-grade B-cell or T cell lymphoma, and must have previously been treated with one standard chemotherapy regimen, excluding single-agent rituximab. The primary objectives included in statistical analyses were MTD, toxicity, and overall response rate (ORR). Four patients were enrolled in cohort 1 (clofarabine 10 mg/m2), four in cohort 2 (clofarabine 15 mg/m2), three in cohort 3 (clofarabine 20 mg/m2), two in cohort 4 (clofarabine 30 mg/m2), and one in cohort 5 (clofarabine 40 mg/m2) (Table 2). RESULTS: MTD was not reached in the study. The most common toxicity observed was myelosuppression. A total of four (29%) patients experienced grade 3 leukopenia, with three (21%) patients experiencing grade 4 neutropenia. The myelosuppression was not considered to be a dose-limiting toxicity, as it resolved within 7 days.Fourteen patients were enrolled: 10 patients with T-cell non-Hodgkin lymphoma (NHL) and 4 patients with B-cell NHL (see Table 1). All 14 patients received at least one dose of clofarabine and were evaluable for response. One patient with cutaneous T-cell lymphoma (CTCL) had a partial response; five (36%) had stable disease, and eight patients (57%) had no response. The one patient with a response had stage III erythroderma and was treated in the 10 mg/m2 cohort; a nodal complete response by positron emission tomography scan was observed with a partial response of the skin. CONCLUSION: In this study, weekly administration of clofarabine was demonstrated to be safe and associated with minimal hematologic toxicity at doses ranging from 10-40 mg/m2. In prior studies when dosed daily for 5 consecutive days, the MTD was shown to be 4 mg/m2. Weekly dosing within this dose range did not result in dose modifications, and the MTD was not reached. Clinical efficacy was observed in one patient with CTCL who was treated in the lowest-dose cohort. PMID- 29438092 TI - Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with Carboplatin, Paclitaxel, and Bevacizumab for First-Line Nonsquamous Non Small Cell Lung Cancer. AB - LESSONS LEARNED: The lack of efficacy associated with anti-EGFL7 combined with standard bevacizumab and chemotherapy in this phase II trial in non-small cell lung carcinoma is consistent with the lack of benefit observed in colorectal carcinoma, highlighting the challenge of enhancing the efficacy of VEGF inhibition in unselected populations.Future efforts with agents like anti-EGFL7 should be guided by advances in pharmacodynamic and predictive biomarker development for antiangiogenic agents. BACKGROUND: Epidermal growth factor-like domain 7 (EGFL7) is an extracellular matrix-associated protein that is upregulated during angiogenesis and supports endothelial cell survival. This phase II trial evaluated the efficacy of the anti-EGFL7 antibody, parsatuzumab, in combination with bevacizumab plus platinum-based therapy for advanced or recurrent nonsquamous non-small cell lung cancer (NS-NSCLC). METHODS: Patients (n = 104) were randomized to either placebo or parsatuzumab (600 mg) in combination with bevacizumab (15 mg/kg) and carboplatin/paclitaxel, administered on day 1 of each 21-day cycle. Carboplatin and paclitaxel were administered for up to six cycles. Bevacizumab and parsatuzumab/placebo were administered for a maximum of 24 months. RESULTS: The progression-free survival (PFS) hazard ratio (HR) was 1.7 (95% confidence interval [CI], 1.0-2.8; p = .047). The median PFS was 6.7 months for the parsatuzumab arm versus 8.1 months for the placebo arm. The hazard ratio for overall survival (OS) was 1.1 (95% CI, 0.5-2.2; p = .847). The objective response rate (ORR) was 29% in the parsatuzumab arm and 56% in the placebo arm. Overall safety and tolerability were consistent with the established toxicity profile of bevacizumab. CONCLUSION: There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line NS-NSCLC. PMID- 29438093 TI - FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations. AB - : On June 22, 2017, the Food and Drug Administration expanded indications for dabrafenib and trametinib to include treatment of patients with metastatic non small cell lung cancer (NSCLC) harboring BRAF V600E mutations. Approval was based on results from an international, multicenter, multicohort, noncomparative, open label trial, study BRF113928, which sequentially enrolled 93 patients who had received previous systemic treatment for advanced NSCLC (Cohort B, n = 57) or were treatment-naive (Cohort C, n = 36). All patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily. In Cohort B, overall response rate (ORR) was 63% (95% confidence interval [CI] 49%-76%) with response durations >=6 months in 64% of responders. In Cohort C, ORR was 61% (95% CI 44% 77%) with response durations >=6 months in 59% of responders. Results were evaluated in the context of the Intergroupe Francophone de Cancerologie Thoracique registry and a chart review of U.S. electronic health records at two academic sites, characterizing treatment outcomes data for patients with metastatic NSCLC with or without BRAF V600E mutations. The treatment effect of dabrafenib 150 mg twice daily was evaluated in 78 patients with previously treated BRAF mutant NSCLC, yielding an ORR of 27% (95% CI 18%-38%), establishing that dabrafenib alone is active, but that the addition of trametinib is necessary to achieve an ORR of >40%. The most common adverse reactions (>=20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. IMPLICATIONS FOR PRACTICE: The approvals of dabrafenib and trametinib, administered concurrently, provide a new regimen for the treatment of a rare subset of non-small cell lung cancer (NSCLC) and demonstrate how drugs active for treatment of BRAF-mutant tumors in one setting predict efficacy and can provide supportive evidence for approval in another setting. The FDA also approved the first next-generation sequencing oncology panel test for simultaneous assessment of multiple actionable mutations, which will facilitate selection of optimal, personalized therapy. The test was shown to accurately and reliably select patients with NSCLC with the BRAF V600E mutation for whom treatment with dabrafenib and trametinib is the optimal treatment. PMID- 29438094 TI - Anti-EGFR Therapy in Small Bowel Adenocarcinoma. PMID- 29438095 TI - Early Steps in the Value of Cancer Care-Many Paths Remain Unexplored. PMID- 29438096 TI - FDA Approval Summary: Lenalidomide as Maintenance Therapy After Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma. AB - : On February 22, 2017, the U.S. Food and Drug Administration (FDA) granted approval for the use of lenalidomide as maintenance therapy after autologous hematopoietic stem cell transplantation (auto-HSCT) for patients with multiple myeloma. The approval was based on evidence from two randomized, blinded trials of maintenance lenalidomide versus placebo in patients with myeloma who had undergone auto-HSCT along with a third trial of lenalidomide versus no therapy. Each of the trials demonstrated superior progression-free survival for the patients treated with lenalidomide. The effect on overall survival was mixed, with one trial showing longer overall survival and another showing no effect. Subgroup analysis suggested better results for patients with International Staging System stage I or II disease compared with stage III disease. Safety evaluation did not reveal any new safety concerns. More second primary malignancies were observed in the lenalidomide arm compared with the placebo arm. The FDA concluded that lenalidomide maintenance showed a favorable benefit-to risk ratio when used as maintenance therapy after auto-HSCT. IMPLICATIONS FOR PRACTICE: Prior to this approval, there were no U.S. Food and Drug Administration approved maintenance therapies for patients with multiple myeloma (MM) who have undergone autologous hematopoietic stem cell transplantation (auto-HSCT). Maintenance therapy with lenalidomide after auto-HSCT in patients with MM demonstrated an approximately 15- to 18-month advantage in progression-free survival compared with placebo at the time of the primary analysis. Patients treated with lenalidomide also appeared to have a survival advantage compared with patients treated with placebo. Because of the high rate of relapse of MM in patients following auto-HSCT and because MM is a serious and often fatal disease, these results appear to be clinically meaningful. PMID- 29438097 TI - Rapamycin for lymphangioleiomyomatosis: optimal timing and optimal dosage. PMID- 29438098 TI - Sustained antiviral effects and clearance of hepatitis surface antigen after combination therapy with entecavir and pegylated interferon in chronic hepatitis B. AB - BACKGROUND: Although the efficacy of combination therapy with lamivudine or tenofovir and pegylated interferon (PEG-IFN) has been reported in patients with chronic hepatitis B (CHB), the long-term effect of the combination based on the observation of clinical course remains to be clarified. We previously reported the efficacy of combination therapy with entecavir (ETV) and PEG-IFN. Here, we investigated the long-term effect of this combination in patients with CHB. METHODS: We administered both ETV and PEG-IFN-alpha2a or -2b simultaneously to 26 patients with HBV genotype C infection. Treatment was continued for 48 weeks followed by 24 weeks of observation period; we examined the virological and biochemical responses. We also analysed characteristics related to the post treatment relapse. Finally, we investigated the long-term therapeutic effects. RESULTS: Average reduction of intra-hepatic cccDNA level was 1.2 log copies/MUg at the completion of administration. Pretreatment hepatitis B surface antigen (HBsAg) level with more than 3.5 log U/ml was identified as a predictive factor for relapse. Furthermore, the cumulative rates of HBsAg-negative patients at 1, 3 and 5 years after the completion of administration were 3.8, 8.4 and 15%, respectively (mean follow-up period: 4.8 years). CONCLUSIONS: Baseline HBsAg level with more than 3.5 log U/ml is a useful predictor for relapse 24 weeks after the completion of administration in patients treated with combination therapy. Combination with ETV and PEG-IFN could be an option for treatment of CHB patients especially in those with baseline HBsAg levels of less than 3.5 log U/ml. PMID- 29438099 TI - Thermal transport characterization of stanene/silicene heterobilayer and stanene bilayer nanostructures. AB - Recently, stanene and silicene based nanostructures with low thermal conductivity have incited noteworthy interest due to their prospect in thermoelectrics. Aiming at the possibility of extracting lower thermal conductivity, in this study, we have proposed and modeled stanene/silicene heterobilayer nanoribbons, a new heterostructure and subsequently characterized their thermal transport by using an equilibrium molecular dynamics simulation. In addition, the thermal transport in bilayer stanene is also studied and compared. We have computed the thermal conductivity of the stanene/silicene and bilayer stanene nanostructures to characterize their thermal transport phenomena. The studied nanostructures show good thermal stability within the temperature range of 100-600 K. The room temperature thermal conductivities of pristine 10 nm * 3 nm stanene/silicene hetero-bilayer and stanene bilayer are estimated to be 3.63 +/- 0.27 W m-1 K-1 and 1.31 +/- 0.34 W m-1 K-1, respectively, which are smaller than that of silicene, graphene and some other 2D monolayers as well as heterobilayers such as stanene/graphene and silicene/graphene. In the temperature range of 100-600 K, the thermal conductivity of our studied bilayer nanoribbons decreases with an increase in the temperature. Furthermore, we have investigated the dependence of our estimated thermal conductivity on the size of the considered nanoribbons. The thermal conductivities of both the nanoribbons are found to increase with an increase in the width of the structure. The thermal conductivity shows a similar increasing trend with the increase in the ribbon length, as well. Our results suggest that, the low thermal conductivity of our studied bilayer structures can be further decreased by nanostructuring. The significantly low thermal conductivity of the stanene/silicene heterobilayer and stanene bilayer nanoribbons realized in our study would provide a good insight and encouragement into their appealing prospect in the thermoelectric applications. PMID- 29438100 TI - Electrode quenching control for highly efficient CsPbBr3 perovskite light emitting diodes via surface plasmon resonance and enhanced hole injection by Au nanoparticles. AB - Compared to organic-inorganic hybrid metal halide perovskites, all-inorganic cesium lead halides (e.g, CsPbBr3) hold greater promise in being emissive materials for light-emitting diodes owing to their superior optoelectronic properties as well as their higher stabilities. However, there is still considerable potential for breakthroughs in the current efficiency of CsPbBr3 perovskite light-emitting diodes (PeLEDs). Electrode quenching is one of the main problems limiting the current efficiency of PeLEDs when poly(3,4 ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS) is used as the hole injection layer. In this work, electrode quenching control was realized via incorporating Au NPs into PEDOT:PSS. As a result, the CsPbBr3 PeLEDs realized an improvement in maximum luminescence ranging from ~2348 to ~7660 cd m-2 (~226% enhancement) and current efficiency from 1.65 to 3.08 cd A-1 (~86% enhancement). Such substantial enhancement of the electroluminescent performance can be attributed to effective electrode quenching control at the PEDOT:PSS/CsPbBr3 perovskite interface via the combined effects of local surface plasma resonance coupling and enhanced hole transportation in the PEDOT:PSS layer by Au nanoparticles. PMID- 29438101 TI - A depth-encoding PET detector that uses light sharing and single-ended readout with silicon photomultipliers. AB - Detectors with depth-encoding capability and good timing resolution are required to develop high-performance whole-body or total-body PET scanners. In this work, depth-encoding PET detectors that use light sharing between two discrete crystals and single-ended readout with silicon photomultipliers (SiPMs) were manufactured and evaluated. The detectors consisted of two unpolished 3 * 3 * 20 mm3 LYSO crystals with different coupling materials between them and were read out by Hamamatsu 3 * 3 mm2 SiPMs with one-to-one coupling. The ratio of the energy of one SiPM to the total energy of two SiPMs was used to measure the depth of interaction (DOI). Detectors with different coupling materials in-between the crystals were measured in the singles mode in an effort to obtain detectors that can provide good DOI resolution. The DOI resolution and energy resolution of three types of detector were measured and the timing resolution was measured for the detector with the best DOI and energy resolution. The optimum detector, with 5 mm optical glue, a 9 mm triangular ESR and a 6 mm rectangular ESR in-between the unpolished crystals, provides a DOI resolution of 2.65 mm, an energy resolution of 10.0% and a timing resolution of 427 ps for events of E > 400 keV. The detectors simultaneously provide good DOI and timing resolution, and show great promise for the development of high-performance whole-body and total body PET scanners. PMID- 29438102 TI - Gold-carbon dots for the intracellular imaging of cancer-derived exosomes. AB - As a novel fluorescent nanomaterial, gold-carbon quantum dots (GCDs) possess high biocompatibility and can be easily synthesized by a microwave-assisted method. Owing to their small sizes and unique optical properties, GCDs can be applied to imaging of biological targets, such as cells, exosomes and other organelles. In this study, GCDs were used for fluorescence imaging of exosomes. Tumor-specific antibodies are attached to the GCDs, forming exosome specific nanoprobes. The nanoprobes can label exosomes via immuno-reactions and thus facilitate fluorescent imaging of exosomes. When incubated with live cells, exosomes labeled with the nanoprobes can be taken up by the cells. The intracellular experiments confirmed that the majority of exosomes were endocytosed by cells and transported to lysosomes. The manner by which exosomes were taken up and the intracellular distribution of exosomes are unaffected by the GCDs. The experimental results successfully demonstrated that the presented nanoprobe can be used to study the intrinsic intracellular behavior of tumor derived exosomes. We believe that the GCDs based nanoprobe holds a great promise in the study of exosome related cellular events, such as cancer metastasis. PMID- 29438103 TI - Synthesis and catalytic activity of electrospun NiO/NiCo2O4 nanotubes for CO and acetaldehyde oxidation. AB - NiO/NiCo2O4 nanotubes with a diameter of approximately 100 nm are synthesized using Ni and Co precursors via electro-spinning and subsequent calcination processes. The tubular structure is confirmed via transmission electron microscopy imaging, whereas the structures and elemental compositions of the nanotubes are determined using x-ray diffraction, energy dispersive x-ray spectroscopy, and x-ray photoelectron spectroscopy. N2 adsorption isotherm data reveal that the surface of the nanotubes consists of micropores, thereby resulting in a significantly higher surface area (~20 m2 g-1) than expected for a flat-surface structure (<15 m2 g-1). Herein, we present a study of the catalytic activity of our novel NiO/NiCo2O4 nanotubes for CO and acetaldehyde oxidation. The catalytic activity of NiO/NiCo2O4 is superior to Pt below 100 degrees C for CO oxidation. For acetaldehyde oxidation, the total oxidation activity of NiO/NiCo2O4 for acetaldehyde is comparable with that of Pt. Coexistence of many under-coordinated Co and Ni active sites in our structure is suggested be related to the high catalytic activity. It is suggested that our novel NiO/NiCo2O4 tubular structures with surface microporosity can be of interest for a variety of applications, including the catalytic oxidation of harmful gases. PMID- 29438104 TI - Programmable and functional electrothermal bimorph actuators based on large-area anisotropic carbon nanotube paper. AB - Electro-active polymer (EAP) actuators, such as electronic, ionic and electrothermal (ET) actuators, have become an important branch of next-generation soft actuators in bionic robotics. However, most reported EAP actuators could realize only simple movements, being restricted by the small area of flexible electrodes and simple designs. We prepared large-area flexible electrodes of high anisotropy, made of oriented carbon nanotube (CNT) paper, and carried out artful graphic designs and processing on the electrodes to make functional ET bimorph actuators which can realize large bending deformations (over 220 degrees , curvature > 1.5 cm-1) and bionic movements driven by electricity. The anisotropy of CNT paper benefits electrode designs and multiform actuations for complex actuators. Based on the large-area CNT paper, more interesting and functional actuators can be designed and prepared which will have practical applications in the fields of artificial muscles, complicated actuations, and soft and bionic robotics. PMID- 29438106 TI - Optimized fan-shaped chiral metamaterial as an ultrathin narrow-band circular polarizer at visible frequencies. AB - Chiral metamaterials have the great ability to manipulate the circular polarizations of light, which can be utilized to build ultrathin circular polarizers. Here we build a narrow-band circular polarizer at visible frequencies based on plasmonic fan-shaped chiral nanostructures. In order to achieve the best optical performance, we systematically investigate how different fabrication factors affect the chiral optical response of the fan-shaped chiral nanostructures, including incident angle of vapor depositions, nanostructure thickness, and post-deposition annealing. The optimized fan-shaped nanostructures show two narrow bands for different circular polarizations with the maximum extinction ratios 7.5 and 6.9 located at wavelength 687 nm and 774 nm, respectively. PMID- 29438105 TI - Magnetic resonance and photoacoustic imaging of brain tumor mediated by mesenchymal stem cell labeled with multifunctional nanoparticle introduced via carotid artery injection. AB - OBJECTIVE: To evaluate the feasibility of visualizing bone marrow-derived human mesenchymal stem cells (MSCs) labeled with a gold-coated magnetic resonance (MR) active multifunctional nanoparticle and injected via the carotid artery for assessing the extent of MSC homing in glioma-bearing mice. MATERIALS AND METHODS: Nanoparticles containing superparamagnetic iron oxide coated with gold (SPIO@Au) with a diameter of ~82 nm and maximum absorbance in the near infrared region were synthesized. Bone marrow-derived MSCs conjugated with green fluorescent protein (GFP) were successfully labeled with SPIO@Au at 4 MUg ml-1 and injected via the internal carotid artery in six mice bearing orthotopic U87 tumors. Unlabeled MSCs were used as a control. The ability of SPIO@Au-loaded MSCs to be imaged using MR and photoacoustic (PA) imaging at t = 0 h, 2 h, 24 h, and 72 h was assessed using a 7 T Bruker Biospec experimental MR scanner and a Vevo LAZR PA imaging system with a 5 ns laser as the excitation source. Histological analysis of the brain tissue was performed 72 h after MSC injection using GFP fluorescence, Prussian blue staining, and hematoxylin-and-eosin staining. RESULTS: MSCs labeled with SPIO@Au at 4 MUg ml-1 did not exhibit cell death or any adverse effects on differentiation or migration. The PA signal in tumors injected with SPIO@Au loaded MSCs was clearly more enhanced post-injection, as compared with the tumors injected with unlabeled MSCs at t = 72 h. Using the same mice, T2-weighted MR imaging results taken before injection and at t = 2 h, 24 h, and 72 h were consistent with the PA imaging results, showing significant hypointensity of the tumor in the presence of SPIO@Au-loaded MSCs. Histological analysis also showed co-localization of GFP fluorescence and iron, thereby confirming that SPIO@Au labeled MSCs continue to carry their nanoparticle payloads even at 72 h after injection. CONCLUSIONS: Our results demonstrated the feasibility of tracking carotid artery-injected SPIO@Au-labeled MSCs in vivo via MR and PA imaging. PMID- 29438108 TI - STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion. AB - Immune evasion and the suppression of antitumor responses during cancer progression are considered hallmarks of cancer and are typically attributed to tumor-derived factors. Although the molecular basis for the crosstalk between tumor and immune cells is an area of active investigation, whether host-specific germline variants can dictate immunosuppressive mechanisms has remained a challenge to address. A commonly occurring germline mutation (c.1162G>A/rs351855 G/A) in the FGFR4 (CD334) gene enhances signal transducer and activator of transcription 3 (STAT3) signaling and is associated with poor prognosis and accelerated progression of multiple cancer types. Here, using rs351855 SNP knockin transgenic mice and Fgfr4-knockout mice, we reveal the genotype-specific gain of immunological function of suppressing the CD8/CD4+FOXP3+CD25+ regulatory T cell ratio in vivo. Furthermore, using knockin transgenic mouse models for lung and breast cancers, we establish the host-specific, tumor-extrinsic functions of STAT3-enhancing germline variants in impeding the tumor infiltration of CD8 T cells. Thus, STAT3-enhancing germline receptor variants contribute to immune evasion through their pleiotropic functions in immune cells. PMID- 29438109 TI - Racial Differences in Sepsis Mortality at U.S. Academic Medical Center-Affiliated Hospitals. AB - OBJECTIVES: To determine the racial disparities in severe sepsis hospitalizations and outcomes in U.S. academic medical center-affiliated hospitals. DESIGN: Retrospective analysis of sepsis hospitalizations. SETTINGS: U.S. academic medical center-affiliated hospitals participating in Vizient Consortium from 2012 to 2014. PATIENTS: Sepsis hospitalizations using International Classification of Diseases, Ninth revision, discharge diagnoses codes defined by the Angus method. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared rates of sepsis hospitalization, ICU admission, organ dysfunction, and hospital mortality between blacks and whites. We repeated the analyses stratified by community-acquired, healthcare-associated, and hospital-acquired sepsis subtypes. Of 10,244,780 hospitalizations in our cohort, 1,114,386 (10.9%) had sepsis. Sepsis subtypes included community-acquired sepsis (61.8%), healthcare-associated sepsis (23.8%), and hospital-acquired sepsis (14.4%). Although the proportion of discharges with sepsis was lower for blacks than whites (106.72 vs 109.43 per 1,000 hospitalizations; p < 0.001), the proportion of black sepsis hospitalizations was higher for individuals greater than 30 years old. Blacks exhibited lower adjusted sepsis hospital mortality than whites (odds ratio, 0.85; 95% CI, 0.84-0.86). The adjusted odds of hospital mortality following community-acquired, healthcare associated, and hospital-acquired sepsis were lower for blacks than whites. CONCLUSIONS: In this current series of hospital discharges at U.S. academic medical center-affiliated hospitals, blacks exhibited lower adjusted rates of sepsis hospitalizations and mortality than whites. PMID- 29438107 TI - Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes. AB - Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes (T1D), the DQ8 molecule is common, confers significant disease risk, and is involved in disease pathogenesis. We hypothesized that blocking DQ8 antigen presentation would provide therapeutic benefit by preventing recognition of self-peptides by pathogenic T cells. We used the crystal structure of DQ8 to select drug-like small molecules predicted to bind structural pockets in the MHC antigen-binding cleft. A limited number of the predicted compounds inhibited DQ8 antigen presentation in vitro, with 1 compound preventing insulin autoantibody production and delaying diabetes onset in an animal model of spontaneous autoimmune diabetes. An existing drug with a similar structure, methyldopa, specifically blocked DQ8 in patients with recent-onset T1D and reduced inflammatory T cell responses to insulin, highlighting the relevance of blocking disease-specific MHC class II antigen presentation to treat autoimmunity. PMID- 29438110 TI - The Randomized Educational Acute Respiratory Distress Syndrome Diagnosis Study: A Trial to Improve the Radiographic Diagnosis of Acute Respiratory Distress Syndrome. AB - OBJECTIVES: Radiographic criteria for acute respiratory distress syndrome have been criticized for poor reliability. Our objective was to test an educational intervention to improve the radiographic identification of acute respiratory distress syndrome by participants in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure study. DESIGN: Randomized controlled trial. SETTINGS: Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure study centers. SUBJECTS: Study coordinators in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure study. INTERVENTIONS: Participants were randomized to either an online training module followed by a test module (intervention) or test module followed by training module (control). MEASUREMENTS AND MAIN RESULTS: The primary outcome was the number of radiographs correctly identified as meeting criteria for acute respiratory distress syndrome on an online test module (out of 11). Prespecified secondary analyses included a comparison of agreement between the groups and subgroup analyses by profession, age, years of experience, and stated familiarity with diagnostic criteria for acute respiratory distress syndrome. Four-hundred sixty-three study participants consented to participate. There was no effect of the intervention on correct answers by participants (proportion correct 58% [intervention] vs 56% [control]; p = 0.15), or in any subgroup analyses. Overall agreement between raters was 0.296 for the intervention and 0.272 for the control (p < 0.001). CONCLUSIONS: Participant recognition of radiographic criteria for acute respiratory distress syndrome was low, with poor agreement. This was not impacted by an educational intervention designed to improve accuracy of identification of radiographic criteria for acute respiratory distress syndrome. PMID- 29438111 TI - Comparison of Transplant Waitlist Outcomes for Pediatric Candidates Supported by Ventricular Assist Devices Versus Medical Therapy. AB - OBJECTIVES: Ventricular assist devices have gained popularity in the management of refractory heart failure in children listed for heart transplantation. Our primary aim was to compare the composite endpoint of all-cause pretransplant mortality and loss of transplant eligibility in children who were treated with a ventricular assist device versus a medically managed cohort. DESIGN: This was a retrospective cohort analysis. SETTINGS: Data were obtained from the Scientific Registry of Transplant Recipients. PATIENTS: The at-risk population (n = 1,380) was less than 18 years old, either on a ventricular assist device (605 cases) or an equivalent-severity, intensively medically treated group (referred to as MED, 775 cases). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The impact of ventricular assist devices was estimated via Cox proportional hazards regression (hazard ratio), dichotomizing 1-year outcomes to "poor" (22%: 193 deaths, 114 too sick) versus all others (940 successful transplants, 41 too healthy, 90 censored), while adjusting for conventional risk factors. Among children 0-12 months old, ventricular assist device was associated with a higher risk of poor outcomes (hazard ratio, 2.1; 95% CI, 1.5-3.0; p < 0.001). By contrast, ventricular assist device was associated with improved outcomes for ages 12-18 (hazard ratio, 0.3; 95% CI, 0.1-0.7; p = 0.003). For candidates 1-5 and 6-11 years old, there were no differences in outcomes between the ventricular assist device and MED groups (hazard ratio, 0.8 and 1.0, p = 0.43 and 0.9). The interaction between ventricular assist devices and age group was strongly significant (p < 0.001). CONCLUSIONS: This is a comparative study of ventricular assist devices versus medical therapy in children. Age is a significant modulator of waitlist outcomes for children with end-stage heart failure supported by ventricular assist device, with the impact of ventricular assist devices being more beneficial in adolescents. PMID- 29438112 TI - Executive functioning and daily living of individuals with chronic stroke: measurement and implications. AB - Deficits in executive functioning (EF) are often still present at the chronic stage after stroke, which may negatively impact independent living. The objectives of this study were (a) to characterize the EF and independence in daily living of community-dwelling individuals with chronic stroke by using pen and-paper and performance-based EF assessments, (b) to explore correlations between scores detected by different EF assessments and (c) to assess the correlations between EF and independence in basic activities of daily living (BADL) and instrumental activities of daily living (IADL). This cross-sectional study included 50 (30 men and 20 women) community-dwelling individuals [mean (SD) age 59.8 (9.3)] with chronic stroke. Participants were overall independent in basic activities of daily living, without significant cognitive impairment. Participants underwent EF assessment using two pen-and-paper tools: Trail Making Test, Zoo Map subtest from the Behavioral Assessment of Dysexecutive Syndrome and two performance-based tools; EF Route-Finding Task and bill-paying subtest from the Executive Functions Performance Test. BADL, IADL, depressive symptoms, gait speed and upper extremity motor impairment were also assessed. Participants demonstrated mild to moderate EF deficits with moderate significant correlations between the scores of various EF assessments. Participants varied in their independence in IADL, and EF was significantly correlated to independence in BADL and IADL (-0.3150%) morphologic component they contained (adenocarcinoma, diffuse infiltrative carcinoma, mucinous carcinoma) and "mixed" carcinoma if none predominated. Cases with unusual morphology were assigned to a "special subtypes" group ("rare" tumors). Correlation of overall survival and staining patterns was carried out. Adenocarcinomas comprised 43.6% (n=51), diffuse infiltrative carcinomas 28.2% (n=33), mucinous carcinomas 6% (n=7), mixed carcinomas 6%, and "rare/other" carcinomas 16.2% (n=19) of the 117 muscle invasive carcinoma cases. High tumor stage was associated with worse overall survival at multivariate analysis (P=0.000, log-rank). Higher cathepsin E and cyclin-dependent kinase 1 expression was associated with worse overall survival on univariate analysis (log-rank; P=0.050 and 0.001, respectively). Mismatch repair defects were seen in adenocarcinomas and "rare" tumors with MLH1 silencing. These above-mentioned points can lead to the differentiation of metabolic and phenotypic features per gastric carcinoma subtype and may help design targeted approaches. PMID- 29438114 TI - Validity and Reliability of the Frontotemporal Dementia Rating Scale (FTD-FRS) for the Progression and Staging of Dementia in Brazilian Patients. AB - INTRODUCTION: Few studies on instruments for staging frontotemporal dementia (FTD) have been conducted. OBJECTIVE: The objective of this study was to analyze the factor structure, internal consistency, reliability, and convergent validity of the Brazilian version of the Frontotemporal Dementia Rating Scale (FTD-FRS). METHODS: A total of 97 individuals aged 40 years and above with >2 years' education took part in the study, 31 patients diagnosed with behavioral variant FTD (bvFTD), 8 patients with primary progressive aphasia, 28 with Alzheimer disease, 8 with mild cognitive impairment, and a control group of 22 healthy subjects. The FTD-FRS was completed by family members or caregivers, and Neurologists completed the 8-item Clinical Dementia Rating for Frontotemporal Lobar Degeneration (CDR-FTLD) scale (6 original domains plus Language and Behavior). The Alzheimer disease and FTD patients had equivalent disease severity level. RESULTS: The internal consistency of the FTD-FRS, estimated by Cronbach alpha, was 0.975 whereas test-retest reliability was 0.977. Scree plot and exploratory factor (Varimax rotation) analyses revealed the existence of 4 factors, with eigenvalues >1, which together explained 77.13% of the total variance with values of 1.28 to 17.52. The domains of the Brazilian version of the FTD-FRS scale correlated with the domains of the CDR-FTLD. CONCLUSIONS: The present study is the first to document the factorial structure of the FTD-FRS and its convergent validity with the CDR-FTLD. These tools are key to determine dementia severity in FTD. The Brazilian FTD-FRS demonstrated adequate psychometric properties for use in Brazil. This instrument may contribute to disease staging in FTD and may help to document intervention-related changes. PMID- 29438115 TI - Standardizing a federally qualified health center's preventive care processes: Use of failure modes and effects analysis. AB - : A multisite federally qualified health center used a Failure Modes and Effects Analysis to identify and correct potential challenges to the implementation of the proactive office encounter model. This model is designed to proactively identify and close preventive care gaps through electronic medical record use, new workflows, and staff training. PMID- 29438116 TI - Analysis of Football Injuries by Position Group in Division I College Football: A 5-Year Program Review. AB - OBJECTIVE: The purpose of this study was to evaluate injury characteristics by position groups. DESIGN: Prospective, observational study. SETTING: A single, major Division I collegiate football program. PARTICIPANTS: All players on a collegiate football program each fall regular season. INDEPENDENT VARIABLES: Exposure to Division I collegiate football and position groups. MAIN OUTCOME MEASURES: Injury rates (IRs) per 1000 athlete exposures (AEs) and injury rate ratios (IRRs) were calculated and analyzed for all monitored injury variables, which included time in the season, body part, type of injury, game and practice injuries, mechanism of injury, and type of exposure. RESULTS: During the 2012 to 2016 fall regular seasons, there were 200 reported injuries sustained from 48 615 AE. The overall 5-year IR was 4.11 per 1000 AEs (3.57-4.72 95% confidence intervals). Skill players sustained the highest IR in the preseason (IR, 7.56) compared with line (IR, 4.26) and other (IR, 4.10) position groups. In addition, skill players demonstrated a significantly higher IRR compared with the line (IRR, 1.75, P < 0.05) and other (IRR, 1.85, P < 0.05) position groups. CONCLUSIONS: Skill players sustained most of their injuries in the preseason, whereas the linemen and other position groups suffered most of their injuries in the first half of the regular season. Skill players demonstrated a significantly higher IR in preseason, noncontact mechanism injuries, and injuries to the upper leg and thigh compared with line and other position groups. Efforts to reduce soft-tissue muscle strains in skill players targeting the preseason may provide one of the best opportunities to significantly decrease current football IRs, whereas efforts to reduce contact exposures may have the greatest effect on concussions and contact mechanism injuries for the other position group. There were no significant differences in IRs between position groups and type of exposure. PMID- 29438117 TI - Small bowel tumours: update in diagnosis and management. AB - PURPOSE OF REVIEW: The aim of this study was to summarize the role of recently developed diagnostic techniques in the diagnosis and management of patients with small bowel tumours (SBTs). RECENT FINDINGS: Recent studies show that the overall SBT incidence is increasing. The introduction of small bowel dedicated diagnostic tools [i.e. capsule endoscopy, device-assisted enteroscopy (DAE), computed tomography (CT) and MRI-enterography] might partially explain this trend. In patients with SBT, DAE might represent an ideal tool by coupling careful mucosal inspection with sampling capability. Unfortunately, DAE is an invasive procedure and seldom allows complete small bowel evaluation in a single setting. Therefore, DAE is more often used in clinical practice as confirmatory tool, when other less invasive and readily available tests (i.e. capsule endoscopy or radiological tests) identify relevant findings. Nevertheless, in patients with SBT, capsule endoscopy is burdened by an increased risk of capsule retention and/or missing proximal small bowel lesions, whereas dedicated cross-sectional imaging techniques often identify nonspecific findings of limited clinical significance. SUMMARY: Despite recent technical improvements, in patients with SBT, the result of a single diagnostic procedure is often insufficient to provide a definite diagnosis. A balanced combination of different tests allows reaching a final diagnosis and drive further management. PMID- 29438118 TI - NSAIDs and the small bowel. AB - PURPOSE OF REVIEW: The review describes the effects of NSAID gastrointestinal toxicity on the small bowel, wherein injury is as prevalent as in the gastroduodenum. This is well documented by capsule endoscopy, which also provides an endoscopic endpoint for novel treatment strategies. RECENT FINDINGS: Appreciation of the prevalence of NSAID enteropathy has grown with capsule endoscopy and the use of composite end points that include obscure haemoglobin decreases in clinical studies. Along with dual cyclo-oxygenase isoform inhibition, gram-negative antigen presentation plays a role in the pathogenesis of NSAID enteropathy. The concomitant use of proton pump inhibitor (PPI) agents with both selective and nonselective NSAIDs in gastroduodenal protection exacerbates endoscopic enteropathy, which is thought to be due to intestinal dysbiosis. Strategies for small bowel mucosal protection include prostaglandin repletion and augmenting the intestinal flora. SUMMARY: NSAID- related enteropathy is common and often presents subclinically. The most common presentation is anaemia, which may be less common in those on cyclo-oxygenase (COX)-2 inhibitors than nonselective NSAIDs. PPI use worsens NSAID enteropathy with more occult bleeding and ulceration and has been linked to gram-negative intestinal dysbiosis. If NSAID cessation is not possible, COX-2 inhibition without PPI therapy should be considered in patients with upper gastrointestinal risk factors. Mucoprotective agents such as misoprostol and rebamipide show promise and probiotics may have a future role. PMID- 29438119 TI - Liver disease in patients with cystic fibrosis. AB - PURPOSE OF REVIEW: The aim of this study was to provide an overview of the current understanding of the pathophysiology, diagnosis and management of cystic fibrosis-liver disease (CFLD). RECENT FINDINGS: CFLD has a variety of manifestations. Previously, it was thought that patients progressed from mild cholestatic disease to cirrhosis to decompensated cirrhosis with portal hypertension. Newer evidence suggests that some patients may develop cirrhosis while others develop noncirrhotic portal hypertension. Advances in our understanding of the pathophysiology of disease necessitate modifications to the current diagnostic criteria. Both fibroscan and noninvasive biomarkers can be used to identify patients with cirrhosis and portal hypertension. Ursodeoxycholic acid remains the mainstay of therapy despite a paucity of rigorous studies supporting its use. Novel therapeutic agents such as CF transmembrane conductance regulator (CFTR) modulators and potentiators are encouraging but need to be evaluated specifically in CFLD. SUMMARY: A better understanding of the pathophysiology of disease is critical to developing more disease-specific diagnostics and therapeutics. PMID- 29438120 TI - MiSight Assessment Study Spain: Adverse Events, Tear Film Osmolarity, and Discontinuations. AB - OBJECTIVES: To assess the relative clinical success of MiSight contact lenses (CLs) (study group) and distance single-vision (SV) spectacles (control group) in children in terms of adverse events (AEs), discontinuations, and tear film osmolarity over a 2-year period. METHODS: Seventy-four subjects aged 8 to 12 with myopia of -0.75 to -4.00 D and astigmatism less than 1.00 D were randomly assigned to MiSight CLs or SV groups. Subjects were monitored at 6-month intervals over the course of 24 months and advised to report to the clinic immediately should AEs occur. Adverse events were categorized as serious, significant, and nonsignificant. Discontinuation was defined as cessation of participation in the study. RESULTS: Forty-four children were corrected with MiSight CLs and 33 with SV spectacles. No serious or significant AEs were found in any of the participants in either group. Two nonsignificant AEs were found in MiSight group, corresponding to a foreign body on the cornea in two children. There were five discontinuations in MiSight group, one because of change of residence and four because of unwillingness to use the CL. There were no discontinuations in SV group. Neither group showed any significant changes in osmolarity data over the 24 months of follow-up (P>=0.05). CONCLUSIONS: No clinically serious events were observed in either group. Our results show that correct use of MiSight CLs is a safe option for myopia correction. The success of this treatment requires a combination of proper lens fitting, good adherence to routine follow-ups, and timely treatment of complications. PMID- 29438121 TI - Comparison of the Lotrafilcon B and Comfilcon A Silicone Hydrogel Bandage Contact Lens on Postoperative Ocular Discomfort After Photorefractive Keratectomy. AB - OBJECTIVES: To compare the lotrafilcon B and comfilcon A silicone hydrogel bandage contact lenses after photorefractive keratectomy (PRK). METHODS: One hundred twenty eyes of 60 patients who underwent PRK were included in this randomized clinical trial study. In the end of the surgery, the lotrafilcon B (Air Optix; Ciba Vision, Duluth, GA) was used in one eye and the comfilcon A (Biofinity; Coopervision, Fairport, NY) was used in the fellow eye randomly. Pain and discomfort were assessed on the first and third day after surgery by visual analogue scale. RESULTS: The mean pain score was 3.75+/-3.32 and 4.47+/-3.60 on the first day (P=0.253) and 3.63+/-3.48 and 4.16+/-3.60 on the third day (P=0.416) after the use of the lotrafilcon B and comfilcon A, respectively. The results showed no significant difference between the two groups (P=0.823). The mean score of foreign body sensation was 4.31+/-3.38 and 5.49+/-3.04 on the first day (P=0.045) and 4.44+/-3.34 and 5.13+/-3.23 on the third day (P=0.250) after the use of the lotrafilcon B and comfilcon A, respectively. The comfilcon A lens caused a more severe foreign body sensation only on the first day. There was no significant difference in photophobia, epiphora, and blurred vision between the two lenses (P>0.05). CONCLUSIONS: Both lotrafilcon B and comfilcon A silicone hydrogel bandage contact lenses reduce clinical symptoms after PRK effectively. We found no difference in pain control and discomfort between them. However, the patients using the lotrafilcon B lens showed less foreign body sensation on the first day postoperatively. PMID- 29438122 TI - Corneal and Anterior Chamber Morphology in Human Immunodeficiency Virus-1 Infected Patients Without Opportunistic Infections. AB - OBJECTIVES: To evaluate corneal and anterior chamber morphology as measured by Pentacam HR in human immunodeficiency virus (HIV)-infected patients without opportunistic infections and to search for signs of accelerated aging. METHODS: This prospective study included 41 eyes of 41 HIV-1-infected patients (study group) and 50 eyes of 50 healthy subjects (control group). Specular microscope and Pentacam HR were used for corneal and anterior chamber morphology evaluation. Corneal endothelial cell density (CECD), hexagonal cell ratio, coefficient of variation, corneal thickness, density and volume, maximum keratometry, anterior chamber volume (ACV), and anterior chamber depth (ACD) measurements were recorded for analysis. RESULTS: The mean CD4 count was 428.3+/-231.9 (36-950) cells/mL, and the time since diagnosis was 27.5+/-34.1 months in the study group. The difference in anterior segment parameters was not significantly different between the study and the control groups (P>0.05). Age significantly correlated with CECD (r=-0.436, P=0.004), ACV (r=-0.570, P<0.001), ACD (r=-0.471, P=0.002), and corneal density (r=0.424, P=0.006) in the study group, whereas it did not show a significant correlation with any ocular parameters in the control group (Pearson correlation). CONCLUSION: Corneal density, CECD, ACV, and ACD showed significant correlation with age in HIV-1-infected patients. Further studies are needed to show whether ocular parameters may serve as useful tools to monitor HIV-related accelerated aging. PMID- 29438123 TI - Relationships Between Meibomian Gland Loss and Age, Sex, and Dry Eye. AB - PURPOSE: This study evaluated relationships between meibomian gland loss (MGL) and age, sex, and dry eye. METHODS: Dry eye and MGL of the lower eyelid was evaluated from 112 randomly selected subjects (66 women; mean age 62.8; SD +/ 15.7; and age range: 19-89 years) from Horst Riede GmbH, Weinheim, Germany. In addition, subjects were grouped into dry eye and non-dry eye by the Ocular Surface Disease Index (OSDI) score, lid-parallel conjunctival folds and non invasive break-up time. Symptoms were evaluated by the OSDI. Meibography of the lower eyelid was performed using a Cobra camera (bon Optic, Lubeck, Germany), and images were analyzed by its digital grading tool. Data were analyzed by backward, multiple regression analyses and Pearson correlation. RESULTS: Analyzing all subjects, multiple regression analyses detected that age and dry eye status (dry eye diagnosis or OSDI) but not sex were significantly related to MGL. In both, non-dry eye (n=66) and dry eye subjects (n=46), dry eye status (OSDI) but not age or sex was significantly related to MGL. Ocular Surface Disease Index scores were significantly correlated with MGL, but this correlation was stronger among all subjects (Pearson correlation; r=0.536, P<0.001) and dry eye group subjects (r=0.520, P<0.001) than in non-dry eye group subjects (r=0.275, P=0.014). CONCLUSIONS: Dry eye group subjects showed significantly increased MGL of the lower eyelid. Age and dry eye status were related to MGL of the lower eyelid, but sex was not; dry eye status was the dominant factor. PMID- 29438124 TI - Friendly Faces: Characteristics of Children and Adolescents With Repeat Visits to a Specialized Child Psychiatric Emergency Program. AB - OBJECTIVES: Pediatric mental health emergency department (ED) visits continue to rise with 19% to 62% of youth presenting to the ED ultimately returning for a mental health-related complaint. To better understand the needs of children returning to the ED, this study examines the clinical, demographic, and environmental factors associated with revisits to a dedicated child psychiatric ED. METHODS: Clinical factors, home environment, and mental health service utilization of 885 children presenting to a dedicated child psychiatric ED over a 1-year period were abstracted by retrospective chart review. Bivariate analyses comparing demographic and clinical characteristics for children with and without revisits and a multivariable logistic regression were performed. RESULTS: Of the children presenting to the ED, 186 (21.0%) had at least 1 revisit in the subsequent 180 days. Thirty-one percent of initial visits presented as urgent, 55% presented as emergent. Children presenting with more severe symptoms at their initial visit were more likely to return within 6 months. Female gender, suicidal and disruptive behavioral symptomatology, and a diagnosis of oppositional defiant disorder were associated with repeat visits. Children with mental health system involvement were more likely to have revisits than those who were "treatment naive." CONCLUSIONS: Revisits to the ED are driven by both clinical factors, including severity and psychosocial complexity, and barriers to accessing services. Addressing the problem of return ED visits will require the development of a robust mental health service system that is accessible to children and families of all socioeconomic levels. PMID- 29438125 TI - Presumed Systemic Inflammatory Response Syndrome in the Pediatric Emergency Department. AB - OBJECTIVE: The aim of this study was to examine the incidence and outcomes of patients presenting with systemic inflammatory response syndrome (SIRS) in the pediatric emergency department (PED). METHODS: This was a descriptive, retrospective cohort study of all patients from birth to 18 years presenting to the PED of a single center on 16 days distributed over 1 year. The presence of presumed SIRS (pSIRS, defined as noncore temperature measurement and cell count when clinically indicated) and sepsis was determined for all study patients. Patients were followed up for 1 week. RESULTS: The incidence of pSIRS was 15.3% (216/1416). Suspected or proven infection was present in 37.1% (n = 525) of the study population and 76.4% (n = 165) with pSIRS, with no cases of severe sepsis or septic shock. Sensitivity and specificity of pSIRS for predicting infection were 31.4% (95% confidence interval [CI], 27.5%-35.6%) and 94.3% (95% CI, 92.5% 95.7%), respectively. Although patients with pSIRS had a relative risk of 2.4 (95% CI, 1.6-3.5; P < 0.0001) for admission, 74% were discharged home with no subsequent PED visits. Of defined sepsis cases, 75% were discharged home without return. CONCLUSIONS: Presumed SIRS and sepsis are relatively common in the PED. Use of pSIRS to screen for sepsis risks missing infection, whereas using pSIRS in the current sepsis definition results in overinclusion of nonsevere illness. PMID- 29438126 TI - Sonographic Evaluation and Monitoring of Pneumoperitoneum After Air Enema Reduction for Intussusception. AB - Abdominal radiography and computed tomography scans are standard tests to diagnose pneumoperitoneum. With the growing availability of point-of-care ultrasound, pneumoperitoneum may be diagnosed in settings without easy access to radiography or computed tomography, such as in overcrowded emergency departments or resource-poor environments. The use of point-of-care ultrasound to diagnose or monitor pneumoperitoneum has been described in adult but not pediatric patients. We present a case of point-of-care ultrasound detection of pneumoperitoneum and monitoring for tension pneumoperitoneum, after failed air enema reduction for intussusception in an infant. PMID- 29438127 TI - Osteoarthritis pain. Recent advances and controversies. AB - PURPOSE OF REVIEW: Osteoarthritis is one of the most frequent causes of chronic pain. Because there is no causal treatment of osteoarthritis, sufficient pain control is of uppermost importance but often not met. The review reports recent advances and controversies in our understanding of osteoarthritis pain and its treatment. RECENT FINDINGS: Osteoarthritis pain is determined by processes at different levels. An important local factor of pain generation in the joint is inflammation such as synovitis, and neuropathic components of osteoarthritis pain are being discussed. Neuroplastic changes in the nociceptive system such as peripheral and central sensitization facilitate pain processing. Osteoarthritis pain may also be aggravated by general factors such as metabolic changes and diabetes mellitus, genetic and psychological factors. The review will also address mediators involved in osteoarthritis pain and treatment options. SUMMARY: Recent research is increasing our understanding of osteoarthritis pain by elucidating local factors in the joint which cause pain, by showing neuroplastic changes in the nociceptive system and by addressing the significance of general factors in pain such as metabolic changes. The weight of such factors may determine the pain pattern in individual patients. PMID- 29438128 TI - Toxins in pain. AB - PURPOSE OF REVIEW: Pain is a distressing protective sensory experience warning of actual or potential tissue damage. Natural toxins have evolved to exploit pain and related neuronal pathways to facilitate prey capture and for defence, often producing either numbness, paralysis or intense pain by selectively modulating ion channels and receptors in pain pathways. Understanding how toxins modulate pain pathways can enhance our understanding of the physiological and pathological basis of pain. RECENT FINDINGS: Toxins continue to provide a rich source of unique pharmacological tools and novel drug leads to treat severe neurological disorders, including chronic pain. Recently discovered toxins that selectively modulate Nav1.7 and Nav1.1 have helped unravel their involvement in pain signalling. SUMMARY: Toxins have evolved to induce or inhibit pain by targeting a broad range of ion channels and receptors, including NaV, CaV, KV, TRP, ASIC, P2X, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, N-methyl-D aspartate, NET and GPCRs. These toxins bind to specific sites to stimulate or inhibit the activity of these membrane proteins. Toxins continue to yield some of the most exciting leads for developing novel nonopioid analgesics. PMID- 29438129 TI - Central and peripheral processes in headache. AB - PURPOSE OF REVIEW: Migraine is an extremely incapacitating collection of neurological symptoms that usually includes a severe, throbbing, recurring pain on one side of the head. The World Health Organization ranks migraine as the third most prevalent disease and the seventh commonest primary pain condition in the world. Trigeminovascular-mediated central sensitization has been implicated in the development of migraine symptoms including pain following light touch. This review explores the activation and sensitization of the brain systems that have emerged from recent studies and that contribute to migraine. RECENT FINDINGS: A number of pathophysiological mechanisms have been implicated in the development of migraine and other primary headache disorders. Neuroimaging techniques used to identify both structural and functional features of the brain in migraineurs have helped identify brain regions that are active during or in between migraine attacks, with particular emphasis on those areas relevant to pain pathways, including the hypothalamus and periaqueductal grey. SUMMARY: Several key studies have helped address the long-standing debate over whether migraine originates from vascular or neuronal dysfunction and now support that migraine is a neurological disorder. However, a complete understanding of the central nervous system dysfunction underlying this condition has yet to be elucidated. PMID- 29438130 TI - Blood Culture and Pleural Fluid Culture Yields in Pediatric Empyema Patients: A Retrospective Review, 1996-2016. AB - Empyema is a complication of community-acquired pneumonia. We conducted a retrospective analysis of empyema patients discharged from 1996 to 2016, examining culture results according to timing of antibiotic administration. Blood culture decreased from 45% to 4% after antibiotics, and pleural fluid culture yield decreased from 67% to 30%. More than half of methicillin-resistant Staphylococcus aureus cases occurred from 2011 to 2016. PMID- 29438132 TI - Successful Combination Therapy of Liposomal Amphotericin B and Caspofungin for Disseminated Fusariosis in a Pediatric Patient With Acute Lymphoblastic Leukemia. AB - Disseminated fusariosis is a fatal infection in immunocompromised hosts. However, the optimal antifungal treatment for disseminated fusariosis has not yet been established. We report a case of disseminated fusariosis after chemotherapy for acute lymphoblastic leukemia, presenting with multiple skin, lung and kidney lesions and cerebrospinal fluid invasion. The combination therapy of liposomal amphotericin B and caspofungin resolved disseminated fusariosis successfully. PMID- 29438131 TI - Improved Neurodevelopment After Initiation of Antiretroviral Therapy in Human Immunodeficiency Virus-infected Children. AB - BACKGROUND: Late human immunodeficiency virus (HIV) diagnosis after severe co morbidity remains common in resource-limited settings. Neurodevelopmental recovery during antiretroviral therapy (ART) for late-diagnosed children is understudied. We determined 6-month neurodevelopmental trajectories in HIV infected children initiating ART during hospitalization. METHODS: HIV-infected children initiated ART after HIV diagnosis during hospitalization in Kenya. The Malawi Developmental Assessment Tool was administered after clinical stabilization within 1 month and at 6 months post-ART initiation. Baseline versus 6-month Z scores for each developmental domain were compared; cofactors for change in Z scores were evaluated using linear regression. RESULTS: Among 74 children, median age was 1.7 years (interquartile range, 0.8-2.4) and median Z scores for gross motor, fine motor, social and language domains were -1.34, 1.04, -0.53 and -0.95, respectively. At baseline, children with higher plasma viremia had lower social Z scores (P = 0.008). Better nourished (weight-for-age Z score [WAZ] >=-2) children had higher Z scores in all developmental domains (all P values <=0.05). After 6 months on ART (n = 58), gross and fine motor Z scores improved significantly (mean change 0.39; P = 0.007 and 0.43; P = 0.001, respectively), but social and language did not. Children with better immune and growth response to ART had higher gains in gross motor (0.05 per unit-gain CD4%; P = 0.04; 0.34 per unit-gain WAZ; P = 0.006 and 0.44 per unit-gain height-for-age Z score; P = 0.005), social (0.37 per unit-gain WAZ; P = 0.002) and language (0.25 per unit-gain height-for-age Z score; P = 0.01). CONCLUSIONS: Children had significant neurodevelopmental gains during 6 months of ART, and children with better growth and immune recovery had greater improvement. Prompt commencement of ART may improve neurodevelopment in addition to immunity and growth. PMID- 29438133 TI - Accuracy of ultrasound exam performed by emergency medicine versus radiology residents in the diagnosis of acute appendicitis. AB - BACKGROUND: Although the traditional approach to the diagnosis of acute appendicitis (AA) is using clinical methods, experience has shown that strict reliance on clinical data can lead to mismanagement or unnecessary surgery. OBJECTIVE: The objective of this study was to determine the total agreement of ultrasound (US) results in AA performed by emergency medicine (EM) versus radiology residents in emergency department. PATIENTS AND METHODS: In this cross sectional study, 121 patients with AA suspicion underwent an US exam by both trained EM and radiology residents in emergency department. The training course for EM residents consisted of attending an 8-h-workshop and then practicing an US exam on real patients within a 2-month period. The gold standards were either histopathologic or follow-up results. Total agreement of the results in both specialties was compared. RESULTS: There were 67 men and 54 women, with a mean age of 33.6+/-16.1 years (18.2-88.7 years). Fifty-four (44.6%) patients underwent surgery with the initial diagnosis of AA and the rest were evaluated by follow ups. On the basis of our gold standards, the diagnosis was finally confirmed in 46 (38%) cases. There was a high total agreement in AA diagnosis [96% agreement, kappa=0.90; 95% confidence interval (CI)=0.81-0.99] between the two groups. The specificity and sensitivity of EM and radiology groups were 99% (95% CI=93-100), 63% (95% CI=48-77), 97% (95% CI=91-100), and 72% (95% CI=57-84), respectively. CONCLUSION: US has a high diagnostic specificity in patients suspected of having AA and EM residents can perform this modality as accurately as radiologists after training in the emergency setting. PMID- 29438134 TI - Better compliance with triage criteria in trauma would reduced costs with maintained patient safety. AB - OBJECTIVE: To evaluate trauma triage criteria in terms of compliance, undertriage, and overtriage and identify risk factors for mistriage. METHODS: In a retrospective cohort study, all consecutive trauma patients at a University Hospital in Sweden in 2012 were included. Patients were stratified into three groups on the basis of trauma team activation (full trauma team, limited trauma team, and no trauma team). Case records were reviewed for mechanism of injury, vital signs, and injuries. Compliance with alert criteria was evaluated and injury severity score combined with the Matrix method was used for assessment of overtriage and undertriage. RESULTS: A total of 1424 trauma patients were included in the study. Seventy-three (5.1%) patients activated a full trauma team, 732 (51.4%) a limited trauma team, and 619 (43.5%) did not activate any trauma team. Undertriage was 2.7% [95% confidence interval (CI): 1.9-3.8%] and overtriage was 34.2% (95% CI: 23.5-46.3%) in the complete cohort. Compliance with 'trauma triage criteria' was assessed by comparing actual alerts with what was estimated to be the correct alert levels on the basis of prehospital case records. Compliance with full trauma team criteria was 80% (68-88%), limited trauma team was 54% (51-58%), and no trauma team was 79% (76-82%). Assuming full compliance with trauma criteria, the Matrix method resulted in an undertriage of 2.3% (95% CI: 1.6-3.3%) and an overtriage of 42.6% (95% CI: 32.4-53.2%). CONCLUSION: The overtriage and undertriage in this study is in line with the recommendations of the American College of Surgeons Committee on Trauma. However, better compliance with trauma alert criteria would result in fewer trauma team activations without affecting patient safety.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 29438135 TI - Assessment of prognostic performance of Albumin-Bilirubin, Child-Pugh, and Model for End-stage Liver Disease scores in patients with liver cirrhosis complicated with acute upper gastrointestinal bleeding. AB - OBJECTIVE: The Albumin-Bilirubin (ALBI) score was developed recently to assess the severity of liver dysfunction. We aimed to assess its prognostic performance in patients with liver cirrhosis complicated with upper gastrointestinal bleeding (UGIB) while comparing it with Child-Pugh (CP) and Model for End-stage Liver Disease (MELD) scores. PATIENTS AND METHODS: This was a retrospective unicentric study, including consecutive adult patients with cirrhosis admitted for UGIB between January 2011 and November 2015. Clinical, analytical, and endoscopic variables were assessed and ALBI, CP, and MELD scores at admission were calculated. RESULTS: This study included 111 patients. During the first 30 days of follow-up, 12 (10.8%) patients died, and during the first year of follow-up, another 10 patients died (first-year mortality of 19.8%).On comparing the three scores, for in-stay and 30-day mortality, only the ALBI score showed statistically significant results, with an area under the curve (AUC) of 0.80 (P<0.01) for both outcomes. For first-year mortality, AUC for ALBI, CP, and MELD scores were 0.71 (P<0.01), 0.64 (P<0.05), and 0.66 (P=0.02), respectively, whereas for global mortality, AUC were 0.75 (P<0.01), 0.72 (P<0.01), and 0.72 (P<0.01), respectively. On comparing the AUC of the three scores, no significant differences were found in first-year mortality and global mortality. CONCLUSION: In our series, the ALBI score accurately predicted both in-stay and 30-day mortality, whereas CP and MELD scores could not predict these outcomes. All scores showed a fair prognostic prediction performance for first-year and global mortality. These results suggest that the ALBI score is particularly useful in the assessment of short-term outcomes, with a better performance than the most commonly used scores. PMID- 29438136 TI - Risk factors for low bone mineral density in pediatric inflammatory bowel disease: the positive role of physical activity. AB - OBJECTIVE: In pediatric inflammatory bowel disease (IBD), the prevalence of low bone mineral density (BMD) and bone fractures and the relationship between these are still debated. Our aim was to report data from a cohort of pediatric patients with IBD. PATIENTS AND METHODS: Cross-sectional assessment of growth and BMD [(dual-energy x-ray absorptiometry (DXA)] and retrospective chart review were performed to report the lifetime prevalence of bone fractures and clinical associations with patients' data. RESULTS: We examined 216 patients with IBD, 8 25 years old (median: 14 years). Low BMD was found in 12.5% (spine) and 27% (total body). Multiple regression analysis showed that BMD was predicted by Z scores for height and weight at DXA. History of menstrual irregularities and nasogastric tube feedings was associated with lower BMD, whereas physical activity and higher Z-score for height at DXA were associated with higher BMD.The prevalence of lifetime fractures was 11.8%. Patients with a history of fractures had lower Z-scores for spine BMD (-1.20 vs. -0.69, P=0.020) and total-body BMD ( 1.30 vs. -0.75, P=0.014) compared with those without a history of fractures. Patients with spine BMD Z-score of up to -2 SD score had significantly increased prevalence of fractures compared with those with Z-score more than -2 SD score (28 vs. 10%, P=0.015). CONCLUSION: This study provides further insight into risk factors for low BMD in pediatric IBD. Novel findings were the association between low BMD and fractures, and the positive relationship between BMD and physical activity. PMID- 29438137 TI - Visualization of Myocardial Infarction in Postmortem Multiphase Computed Tomography Angiography: A Feasibility Study. AB - Recent studies have indicated that multiphase postmortem computed tomography angiography (MPMCTA) allows detection of a pathological enhancement of the myocardium in regions that correlate with the localization of the infarction at histology. The aim of this study was to verify this hypothesis by examining MPMCTA images in cases of myocardial infarction. Therefore, we investigated 10 autopsy cases where death was attributed to myocardial infarction or which showed cardiovascular pathology. As a control group, we selected 10 cases of non-natural (namely, not cardiac) death. The MPMCTA was performed in both groups to ascertain whether a pathological enhancement could be observed. We detected a myocardial enhancement in all cardiac death cases, in the same region that showed infarction at histology. No enhancement was observed in control cases. These results have important implications in the routine management of sudden cardiac death cases. In fact, MPMCTA can not only orient about the cause of death before autopsy, but can especially help to identify affected regions for guiding and improving the sampling for microscopic examination. PMID- 29438138 TI - Fatal Road Traffic Vehicle Collisions With Pedestrian Victims: Forensic Postmortem Computed Tomography and Autopsy Correlation. AB - Fatal car-to-pedestrian collisions regularly appear in the forensic pathologist's routine, particularly in places of extended urbanization. Postmortem computed tomography has gained an exceptional role to supplement autopsy worldwide, giving information that is supplementary or complimentary to conventional autopsy. In this retrospective study, a total number of 320 findings in a series of 21 pedestrians fatally hit by cars and trucks of both postmortem computed tomography and autopsy were correlated. According to our results, it is best to combine both methods to give well-founded answers to questions pertaining to both collision reconstruction and cause of death. PMID- 29438139 TI - Optimizing Pulmonary Embolism Computed Tomography in the Age of Individualized Medicine: A Prospective Clinical Study. AB - PURPOSE: The aim of the study was to simultaneously optimize contrast media (CM) injection and scan parameters for the individual patient during computed tomography pulmonary angiography (CTPA). METHODS: In this study (NCT02611115), 235 consecutive patients suspected of having pulmonary embolism were prospectively enrolled. Automated kV selection software on a third-generation multidetector computed tomography adapted tube voltage to the individual patient, based on scout scans. The contrast injection protocol was adapted to both patient body weight and kV-setting selection via a predefined formula, based on previous research. Injection data were collected from a contrast media and radiation dose monitoring software. Attenuation was measured in Hounsfield units (HU) in the pulmonary trunk (PT); attenuation values 200 HU or greater were considered diagnostic. Subjective image quality was assessed by using a 4-point Likert scale at the level of the PT, lobar, segmental, and subsegmental arteries. Results between groups were reported as mean +/- SD. RESULTS: Two hundred twenty-two patients (94%) were scanned at a kV setting below 100 kV: n = 108 for 70 kV, n = 82 for 80 kV, and n = 32 for 90 kV. Mean CM bolus volume (in milliliters) and total iodine load (in grams of iodine) for 70 to 90 kV were as follows: 24 +/- 3 mL and 7 +/- 1 g I, 29 +/- 4 mL and 9 +/- 2 g I, and 38 +/- 4 mL and 11 +/- 1 g I, respectively. Mean flow rates (in milliliters per second) and iodine delivery rates (in grams of iodine per second) were 3.0 +/- 0.4 mL/s and 0.9 +/- 0.1 g I/s (70 kV), 3.6 +/- 0.4 mL/s and 1.0 +/- 0.1 g I/s (80 kV), and 4.7 +/- 0.5 mL/s and 1.3 +/- 0.1 g I/s (90 kV). Mean radiation doses were 1.3 +/- 0.3 mSv at 70 kV, 1.7 +/- 0.4 mSv at 80 kV, and 2.2 +/- 0.6 mSv at 90 kV. Mean vascular attenuation in the PT for each kV group was as follows: 397 +/- 101 HU for 70 kV, 398 +/- 96 HU for 80 kV, and 378 +/- 100 HU for 90 kV, P = 0.59. Forty-six patients (21%) showed pulmonary embolism on the CTPA. One scan (90 kV) showed nondiagnostic segmental pulmonary arteries, and 5% of subsegmental arteries were of nondiagnostic image quality. All other segments were considered diagnostic excellent subjective image quality. CONCLUSIONS: Simultaneously optimizing both CM injections and kV settings to the individual patient in CTPA results in diagnostic attenuation with on average 24 to 38 mL of CM volume and a low radiation dose for most patients. This individualized protocol may help overcome attenuation-variation problems between patients and kV settings in CTPA. PMID- 29438140 TI - Cost-effectiveness of a Ceramide-Infused Skin Barrier Versus a Standard Barrier: Findings From a Long-Term Cost-effectiveness Analysis. AB - PURPOSE: To assess the cost-effectiveness of a ceramide-infused skin barrier (CIB) versus other skin barriers (standard of care) among patients who have undergone ostomy creation. DESIGN: Cost-effectiveness analysis, based on a decision-analytic model that was estimated using data from the ADVOCATE (A Study Determining Variances in Ostomy Skin Conditions And The Economic Impact) trial, which investigated stoma-related healthcare costs over 12 weeks among patients who recently underwent fecal ostomy, and from other sources. SUBJECTS AND SETTING: Analysis was based on a hypothetical cohort of 1000 patients who recently underwent fecal ostomy; over a 1-year period, 500 patients were assumed to use CIB and 500 were assumed to use standard of care. METHODS: We adapted a previous economic model to estimate expected 1-year costs and outcomes among persons with a new ostomy assumed to use CIB versus standard of care. Outcomes of interest included peristomal skin complications (PSCs) (up to 2 during the 1-year period of interest) and quality-adjusted life days (QALDs); QALDs vary from 1, indicating a day of perfect health to 0, indicating a day with the lowest possible health (deceased). Subjects were assigned QALDs on a daily basis, with the value of the QALD on any given day based on whether the patient was experiencing a PSC. Costs included those related to skin barriers, ostomy accessories, and care of PSCs. The incremental cost-effectiveness of CIB versus standard of care was estimated as the incremental cost per PSC averted and QALD gained, respectively; net monetary benefit of CIB was also estimated. All analyses were run using the perspective of an Australian payer. RESULTS: On a per patient basis, use of CIB was expected over a 1-year period to result in 0.16 fewer PSCs, an additional 0.35 QALDs, and a savings of A$180 (Australian dollars, US $137) in healthcare costs all versus standard of care. Management with CIB provided a net monetary benefit (calculated as the product of maximum willingness to pay for 1 QALD times additional QALDs with CIB less the incremental cost of CIB) of A$228 (US $174). Probabilistic sensitivity analysis was also completed; it revealed that 97% of model runs resulted in fewer expected PSCs with CIB; 92% of these runs resulted in lower expected costs with CIB. CONCLUSIONS: Findings suggest that the CIB is a cost-effective skin barrier for persons living with an ostomy. PMID- 29438141 TI - Single-antigen Bead Assays to Define Unacceptable Antigen Mismatches? PMID- 29438142 TI - Self-efficacy and Patient-Reported Pain. PMID- 29438143 TI - Identifying Pain and Effects on Quality of Life from Chronic Wounds Secondary to Lower-Extremity Vascular Disease: An Integrative Review. AB - GENERAL PURPOSE: To provide information to enable better assessment and management of patients with lower extremity vascular disease (LEVD) chronic wound pain. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After completing this continuing education activity, you will be able to: ABSTRACT: A lack of wound pain validation and provider understanding about the effect of pain on quality of life are the biggest barriers to pain management for patients with chronic wound pain. There is also a need for a holistic, validated pain assessment tool for these patients. This is an integrative review of the literature intended to identify gaps in pain identification and (re)assessment for patients with chronic wounds related to lower-extremity vascular disease. PMID- 29438144 TI - Long-term Scar Quality after Treatment of Standardized Partial-Thickness Skin Graft Donor Sites. AB - BACKGROUND: The long-term aesthetic appearance of scars is of great importance to patients. Biobrane (Smith and Nephew, Fort Worth, Texas), a biosynthetic skin dressing, is a successfully established dressing for the treatment of superficial wounds. A new silk barrier dressing (Dressilk; Prevor, Moulin de Verville, France) has also shown good results in wound healing. This study evaluated the long-term scar quality of superficial wounds treated with these dressings. METHODS: From February 2012 to May 2013, 11 patients with burns in need of skin grafting received donor site treatment. Study authors dressed 2 adjacent, standardized, partial-thickness skin graft donor sites on each participant with Biobrane or Dressilk. Scar formation on both treated areas was compared 24 months after initial application using subjective and objective assessment methods. RESULTS: Independent of treatment, the majority of the patients described scar quality similar to normal skin using subjective and objective evaluation tools. However, for scar perfusion, significantly lower oxygen saturation was shown in both treated areas compared with untreated skin. CONCLUSIONS: Comparatively, the 2 wound dressings showed similar results, making silk dressings an interesting alternative to biosynthetic ones. PMID- 29438145 TI - Dramatic Reduction in Hospital-Acquired Pressure Injuries Using a Pink Paper Reminder System. AB - OBJECTIVE: The goal of this quality improvement project was to reduce the number of hospital-acquired pressure injuries (HAPIs) by flagging extremely high-risk patients with a pink paper reminder system and implementing a pressure injury prevention order set. METHODS: The pink paper reminder system is an innovative, cost-neutral, simple approach to identify patients at highest risk of pressure injury development who meet specific criteria. There are 2 steps to this intervention. First, study authors developed a new risk assessment tool, the pink paper criteria. When a patient met the specified criteria, a pink piece of paper titled "SKIN AT RISK" in a large font was hung at the head of his/her bed to reinforce preventive strategies. Next, a set of pressure injury preventive measures was ordered. PATIENTS: This quality improvement project included all adult hospitalized patients of all specialties based in 2 Kaiser Permanente hospitals. RESULTS: There was a 67% reduction in HAPI incidences following the initiation of the pink paper reminder system, from a mean rate of 1.2 to 0.4 incidence of HAPIs per 1000 patient-days measured over 4 years. CONCLUSIONS: Identifying and flagging patients who are at extremely high risk of pressure injuries and implementing an order set of pressure injury preventive measures dramatically reduced the rate of HAPIs per 1000 patient-days. PMID- 29438146 TI - The Characterization of Plantar Skin Across Environmental Condition and Time. AB - OBJECTIVE: In the presence of pathologic conditions such as diabetes or neuropathy and activity-related forces, the plantar surface of the foot is a common place for skin breakdown. With this risk, foundational knowledge of typical plantar skin behavior is needed. The purpose of this study was to characterize the plantar skin properties (tangential stiffness, normal compliance, and thickness) across environmental condition and time. DESIGN AND SETTING: Nonexperimental laboratory design. PATIENTS: Sixteen individuals participated (age range, 19-78 years; mean age, 48.5 +/- 19.23 years; mean body mass index, 31.5 +/- 7.61 kg/m). MAIN OUTCOME MEASURES: Tangential stiffness, normal compliance, and thickness were assessed with the Tissue Interrogation Device (TID), Myotonometer, and ultrasound, respectively. Measurements were taken at 5 anatomic locations over 4 visits across a day (morning and afternoon), week, and month. Measurements were taken in standard (20 degrees C to 24 degrees C, 35%-50% relative humidity) and shoe conditions (32 degrees C, 66% relative humidity). MAIN RESULTS: Tangential stiffness (P = .000), normal compliance (P = .000), and thickness (epidermis, P = .000; dermis, P = .044) all varied by location. No main effect differences were noted across visits or environment across devices. Reliability varied across visits. CONCLUSIONS: All 3 skin properties were found to vary across location and people. Given skin property consistency over time and device reliability, it is reasonable to take and compare measurements within a week. Environmental conditions should be reported and controlled in research assessing plantar skin. PMID- 29438148 TI - Are You Prepared to Use -X {EPSU} and -59 Modifiers? PMID- 29438147 TI - Ulcerated Basal Cell Carcinomas Masquerading as Venous Leg Ulcers. AB - BACKGROUND: Nonmelanoma skin cancers rarely arise from venous leg ulcers (VLUs). Although basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer, its association with lower-extremity ulcers is not as frequently reported as other malignancies. OBJECTIVE: To report a case series of biopsy-proven BCC from lower-extremity ulcers of patients who presented at a multispecialty wound clinic. METHODS: Four male patients (mean age, 82.75 years) with 4 chronic VLUs (duration ranging from 2 months to 10 years) underwent a biopsy of their ulcerative lesions. RESULTS: Histologic examination of the specimens revealed 4 cases of BCC. All of the lesions were surgically excised, followed by split thickness skin graft (n = 2) or healing by secondary intention (n = 2). All of the patients remained healed at follow-up ranging from 15 to 27 months, except for 1 patient who opted for conservative management and had not completely healed at 14 months' follow-up. CONCLUSIONS: Biopsies are warranted for any VLU with documented stalled healing following 3 months of standard of care. One biopsy is performed at the periphery of the ulcer and another at the base in order to rule out the presence of malignant transformation because of BCC, squamous cell carcinoma, sarcoma, melanoma, lymphoma, or metastases. PMID- 29438149 TI - 100 Years of Bedsores: How Much Have We Learned? AB - Just over 100 years ago, an article was published describing a plan to treat decubitus ulcers that can shed light upon medical progress and current practices. Key prevention and treatment elements included a dedicated ward, staff continuity, frequent position changes and special surfaces, cleanliness, disinfectants, and dressing changes. The necessity of resource allocation and interdisciplinary collaboration was acknowledged. This article sheds light on not only how much we have learned, but also how far we have to go. PMID- 29438150 TI - Understanding Your Documentation Requirements. PMID- 29438152 TI - Is it Possible for Late-Onset Schizophrenia to Masquerade as Manganese Psychosis? PMID- 29438151 TI - Identifying Pain and Effects on Quality of Life from Chronic Wounds Secondary to Lower-Extremity Vascular Disease: An Integrative Review. PMID- 29438153 TI - Reoccurring Injury, Chronic Health Conditions, and Behavioral Health: Gender Differences in the Causes of Workers' Compensation Claims. AB - OBJECTIVE: The aim of this study was o examine how work and nonwork health related factors contribute to workers' compensation (WC) claims by gender. METHODS: Workers (N = 16,926) were enrolled in the Pinnacol Assurance Health Risk Management study, a multiyear, longitudinal research program assessing small and medium-sized enterprises in Colorado. Hypotheses were tested using gender stratified logistic regression models. RESULTS: For both women and men, having incurred a prior WC claim increased the odds of a future claim. The combination of incurring a prior claim and having metabolic health conditions resulted in lower odds of a future claim. Behavioral health risk factors increased the odds of having a claim more so among women than among men. CONCLUSION: This study provides data to support multifactorial injury theories, and the need for injury prevention efforts that consider workplace conditions as well as worker health. PMID- 29438154 TI - How Many Paid Sick Days Are Enough? AB - OBJECTIVE: This study analyzes the relationship between number of paid sick days and reported preventive health care service usage among older US workers. METHODS: Using a 2014 cross-section of 3235 US workers age 49 to 57 from the National Longitudinal Survey of Youth, this study is the first to measure paid sick leave as an ordinal variable in an effort to refine our understanding of sick leave, and identify the ideal range of sick days necessary for people to access preventive health care services. RESULTS: We find workers with 10 or more paid sick days have increased odds of reporting five different preventive health care services. CONCLUSION: To support worker and public health, policy planners may want to consider the number of paid sick days that are needed before changes in preventive service use are observed. PMID- 29438155 TI - A "Sit Less, Walk More" Workplace Intervention for Office Workers: Long-Term Efficacy of a Quasi-Experimental Study. AB - OBJECTIVE: This study tested the maintenance outcomes of a 3-month Sit Less, Walk More (SLWM) workplace intervention for office workers compared with usual care at 12 months from the baseline. METHOD: A quasi-experimental study was conducted in two workplaces. The intervention group (n = 51) received multi-component intervention and the comparison group (n = 50) received newsletters only. The outcomes of the study (self-reported psychosocial, physical activity, sitting, and lost productivity; objectively measured cardiometabolic biomarkers) were compared at baseline, 3, and 12 months. RESULTS: Generalized estimating equations analyses found that the intervention group had significant improvements in self regulation for sitting less and moving more (P = 0.017), walking (P = 0.003), weight (P = 0.013), waist circumference (P = 0.002), and insulin (P = 0.000) at 12 months compared with the comparison group. CONCLUSION: The SLWM intervention was effective in improving self-regulation, walking, and some cardiometabolic biomarkers in office workers. PMID- 29438156 TI - Anxiety Sensitivity Physical and Cognitive Concerns in Relation to Smoking oriented Cognition: An Examination Among Treatment-seeking Adults Who Smoke. AB - OBJECTIVES: Elevated levels of anxiety sensitivity (AS; fear of anxiety and internal sensations) is highly common among adults who smoke, and contributes to several maladaptive smoking beliefs and behaviors. AS is comprised of 3 empirically established factors, relating to fears of social concerns, fears of physical symptoms, and fears of cognitive dyscontrol. Relatively few studies have examined how these 3 subscales pertain to smoking processes. The aim of the present investigation was to examine, among treatment-seeking adults who smoke, the interactive effects of AS-physical and cognitive concerns in relation to: perceived barriers to smoking cessation; smoking-related negative reinforcement expectancies; and smoking-related avoidance and inflexibility. METHODS: Participants included 470 adults who smoke (47.8% female; mean age 37.2, SD 13.5), who were recruited to participate in a smoking-cessation treatment study. At the baseline assessment, participants completed self-report measures, including the Anxiety Sensitivity Index-3, Barriers to Cessation Scale, Smoking Consequences Questionnaire, and Avoidance and Inflexibility Scale. RESULTS: Results indicated that after controlling for the effects of sex, cigarette dependence, alcohol problems, tobacco-related medical illness, current axis 1 disorder, and AS-social concerns, a significant interaction emerged, such that the association between AS-cognitive concerns and the studied smoking-based cognitions were stronger among lower levels of AS-physical concerns (but not higher physical concerns). CONCLUSIONS: The current findings suggest that it may be beneficial to provide specialized smoking-cessation interventions for certain subgroups of adults who smoke, such as those with different AS profiles, to promote healthier beliefs about quitting. PMID- 29438157 TI - Effects of Varenicline Alone and in Combination With Low-dose Naltrexone on Alcohol-primed Smoking in Heavy-drinking Tobacco Users: A Preliminary Laboratory Study. AB - OBJECTIVES: Heavy-drinking tobacco users are less likely to successfully quit smoking than their moderate-drinking counterparts, even when they are prescribed smoking cessation medication. One strategy for improving treatment outcomes in this subgroup of tobacco users may be to combine medication therapies to target both alcohol and tobacco use simultaneously. Adding naltrexone to frontline smoking cessation treatments may improve treatment outcomes in this group. METHOD: This double-blind, placebo-controlled human laboratory study examined the effects of varenicline (2 mg/d) and varenicline (2 mg/d), combined with a low dose of naltrexone (25 mg/d) on alcohol-primed smoking behavior in a laboratory model of smoking relapse in heavy-drinking tobacco users (n = 30). Participants attended a laboratory session and received an alcohol challenge (target breath alcohol concentration = 0.030 g/dL). They completed a smoking delay task that assessed their ability to resist smoking followed by an ad libitum smoking phase (primary outcomes). They also provided ratings of subjective drug effects and craving, and carbon monoxide levels were measured after smoking (secondary outcomes). RESULTS: Participants receiving varenicline monotherapy delayed smoking longer and smoked fewer cigarettes than those on placebo. Participants receiving varenicline + low-dose naltrexone did not delay smoking longer than those receiving varenicline alone. Participants in both active medication arms smoked fewer cigarettes ad libitum than those receiving placebo. CONCLUSIONS: Varenicline can improve smoking outcomes even after an alcohol prime, supporting its use in heavy drinkers who wish to quit smoking. Findings did not support increased efficacy of combined varenicline + low-dose naltrexone relative to varenicline monotherapy. PMID- 29438158 TI - Intensive Care Unit Enhanced Recovery Pathway for Patients Undergoing Orthotopic Liver Transplants Recipients: A Prospective, Observational Study. AB - BACKGROUND: Liver transplant recipients continue to have high perioperative resource utilization and prolonged length of stay despite improvements in perioperative care. Enhanced recovery pathways have been shown in other surgical populations to produce reductions in hospital resource utilization. METHODS: A prospective, observational study was performed to examine the effect of an enhanced recovery pathway for postoperative care after liver transplantation. Outcomes from patients undergoing liver transplantation from November 1, 2013, to October 31, 2014, managed by the pathway were compared to transplant recipients from the year before pathway implementation. Multivariable regression analysis was used to assess the association of the clinical pathway on clinical outcomes. RESULTS: The intervention and control groups included 141 and 106 patients, respectively. There were no demographic differences between the control and intervention group including no differences between the length of surgery and cold ischemic time. Median intensive care unit length of stay was reduced from 4.4 to 2.6 days (P < .001). The intervention group had a higher likelihood of earlier discharge (hazard ratio [95% CI], 2.01 [1.55-2.62]; P < .001), and a 69% and 65% lower odds of receiving a plasma (P < .001) or packed red blood cell (P < .001) transfusion. There was no significant effect on hospital mortality (P = .40), intensive care unit readmission rates (P = .75), or postoperative infections (urinary traction infections: P = .09; pneumonia: P = .27). CONCLUSIONS: An enhanced recovery pathway focused on milestone-based elements of intensive care unit management and predetermined management triggers including hemodynamic goals, fluid therapy, perioperative antibiotics, glycemic control, and standardized transfusion triggers led to reductions in intensive care unit length of stay without an increase in perioperative complications. PMID- 29438160 TI - Editorial of Hidden Costs of Hospitalization After Firearm Injury: National Analysis of Different Hospital Readmission. PMID- 29438159 TI - Surveying the Literature: Synopsis of Recent Key Publications. PMID- 29438161 TI - 25-Hydroxyvitamin D serum levels and melanoma risk: a case-control study and evidence synthesis of clinical epidemiological studies. AB - There is accumulating evidence that the vitamin D pathway may play a role in melanoma. The aim of this study was to investigate the association between 25 hydroxyvitamin D [25(OH)D] serum levels and the risk of cutaneous melanoma. A case-control study with 137 incident cases of melanoma (serum samples collected at the time of diagnosis) and 99 healthy controls (serum samples collected between October and April) was carried out and evaluated in the framework of an evidence synthesis of clinical epidemiological studies on the topic to facilitate comparisons and summarize the scientific evidence produced so far. There was a statistically significant difference in the median levels of serum vitamin D between melanoma patients and healthy controls (18.0 vs. 27.8 ng/ml, P<0.001). Among melanoma patients, 66.2%, compared with 15.2% of healthy controls, had vitamin D deficiency (<=20 ng/ml), whereas vitamin D sufficiency (>=30 ng/ml) was observed in only 7.4% of melanoma patients and in 37.4% of the healthy controls (P<0.001). A multivariate model including age, sex, and BMI showed a statistically significant inverse association between melanoma and vitamin D sufficiency versus deficiency (odds ratio=0.04; 95% confidence interval: 0.02 0.10, P<0.001). Also, vitamin D insufficiency versus deficiency was significantly inversely associated with melanoma (odds ratio=0.13; 95% confidence interval: 0.06-0.27, P<0.001). These results suggest that both deficient and insufficient serum levels of vitamin D are associated with melanoma and that a trend seems to be present with a reduced risk of melanoma when vitamin D approaches normal values. PMID- 29438162 TI - Serum glucose and insulin and risk of cancers of the breast, endometrium, and ovary in postmenopausal women. AB - Limited evidence suggests that hyperinsulinemia may contribute to the risk of breast, endometrial, and, possibly, ovarian cancer. The aim of this study was to assess the association of serum glucose and insulin with risk of these cancers in postmenopausal women, while taking into account potential confounding and modifying factors. We studied 21 103 women with fasting baseline insulin and glucose measurements in a subsample of the Women's Health Initiative. The subsample was composed of four studies within Women's Health Initiative with different selection and sampling strategies. Over a mean of 14.7 years of follow up, 1185 breast cancer cases, 156 endometrial cancer cases, and 130 ovarian cancer cases were diagnosed. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) by quartile of glucose or insulin. Serum insulin was positively associated with breast cancer risk (multivariable-adjusted HR for highest vs. lowest quartile 1.41, 95% CI: 1.16 1.72, Ptrend<0.0003), and glucose and insulin were associated with roughly a doubling of endometrial cancer risk (for glucose: HR: 2.00, 95% CI: 1.203.35, Ptrend=0.01; for insulin: HR: 2.39, 95% CI: 1.32-4.33, Ptrend=0.008). These associations remained unchanged or were slightly attenuated after mutual adjustment, adjustment for serum lipids, and assessment of possible reverse causation. Glucose and insulin showed no association with ovarian cancer. Our findings provide support for a role of insulin-related pathways in the etiology of cancers of the breast and endometrium. However, because of the unrepresentative nature of the sample, our results need confirmation in other populations. PMID- 29438163 TI - The interplay between tuberculosis and systemic lupus erythematosus. AB - PURPOSE OF REVIEW: Tuberculosis (TB) is a millenarian chronic infection and, yet, remains a major global health problem. The interaction between systemic lupus erythematosus (SLE) and TB is complex, as one seems to be a risk factor for the development of the other. SLE patients are more likely to develop TB, that is more frequently extrapulmonary, with more extensive pulmonary involvement, and with a higher relapse rate. RECENT FINDINGS: Different studies suggest that TB is more prevalent in SLE patients and that TB may actually be a risk factor for the development of the disease. Molecular and epidemiological data suggest that TB may be involved in the pathogenesis of SLE. SUMMARY: We reviewed the most relevant aspects of TB infection in SLE patients, including the burden of TB, its role in inducing flare and its perpetuation, risk evaluation and prevention, and pearls and pitfalls when assessing extrapulmonary TB in SLE patients. We conclude that a high suspicion of TB in SLE patients from endemic countries should be kept in mind, especially in those with nephritis and high cumulative doses of corticosteroids. PMID- 29438164 TI - The autoimmune ecology: an update. AB - PURPOSE OF REVIEW: The autoimmune ecology refers to the interactions between individuals and their environment leading to a breakdown in immune tolerance and, therefore, to the development of one or more autoimmune diseases in such an individual. Herein, an update is offered on four specific factors associated with autoimmune diseases, namely, vitamin D, smoking, alcohol and coffee consumption from the perspective of exposome and metabolomics. RECENT FINDINGS: Smoking is associated with an increased risk for most of the autoimmune diseases. Carbamylation of proteins as well as NETosis have emerged as possible new pathophysiological mechanisms for rheumatoid arthritis. Low-to-moderate alcohol consumption seems to decrease the risk of systemic lupus erythematosus and rheumatoid arthritis, and studies of vitamin have suggested a beneficial effect on these conditions. Coffee intake appears to be a risk factor for type 1 diabetes mellitus and rheumatoid arthritis and a protective factor for multiple sclerosis and primary biliary cholangitis. SUMMARY: Recent studies support the previously established positive associations between environmental factors and most of the autoimmune diseases. Nevertheless, further studies from the perspective of metabolomics, proteomics and genomics will help to clarify the effect of environment on autoimmune diseases. PMID- 29438165 TI - Histologic Features of Gastrointestinal Tract Biopsies in IgA Vasculitis (Henoch Schonlein Purpura). AB - Immunoglobulin A (IgA) vasculitis or Henoch-Schonlein purpura (HSP) typically occurs in the pediatric population, although rare cases also occur in adults. Gastrointestinal (GI) involvement is common. The "classic" histologic finding in IgA vasculitis (HSP) is leukocytoclastic vasculitis (LCV); other histologic features in biopsies of IgA vasculitis (HSP) have only been rarely described. The pathology archival files at our institution were searched for GI biopsies from patients with IgA vasculitis (HSP). Slides were retrieved and histologic and clinical features were reviewed. We identified 16 patients with IgA vasculitis (HSP) with a GI biopsy series, including both adult and pediatric patients. The most common histologic abnormality was lamina propria hemorrhage (all cases) with many cases also showing lamina propria fibrin deposition with red cell sludging and nuclear debris (7 cases). Twelve of the 16 duodenal biopsies had acute duodenitis; 3 of which were severe and erosive. Several also had an eosinophilic infiltrate. Seven of the 9 jejunal and/or ileal biopsies had acute jejunitis or ileitis. An acute colitis or proctitis was observed in 9/12 colorectal biopsies. Four biopsies contained LCV; in each of these cases, the involved vessels were small capillaries within the lamina propria. Only 1 biopsy contained deeper submucosal vessels, but they were uninvolved. Sites involved by LCV included the colorectum (2 cases), colorectum and terminal ileum, terminal ileum only, duodenum, and jejunum (1 case each). All patients presented with abdominal pain; 13/16 developed a rash, 1 following the index biopsy. Other presenting symptoms included diarrhea and/or hematochezia (8 cases), nausea/vomiting (5 cases), and intussusception (1 case). Four patients had concurrent skin biopsies showing LCV; only 1 of these patients had LCV on GI biopsy. Indications for biopsy included nonspecific presenting symptoms, absence of rash at presentation, and/or failure to respond adequately to steroid therapy. Biopsies are commonly performed in patients with or without suspected IgA vasculitis (HSP) to rule out infection, inflammatory bowel disease, and less commonly, vasculitis. In general, vasculitis is not commonly observed in GI biopsies of patients with IgA vasculitis (HSP), and the spectrum of findings includes neutrophilic infiltrate within the small bowel and colon, with the duodenum most commonly affected. While the clinical and histologic findings may mimic early inflammatory bowel disease, the presence of predominant small bowel involvement, especially erosive duodenitis, should raise suspicion for IgA vasculitis (HSP). Biopsies should be obtained before steroid therapy is initiated, if possible. PMID- 29438166 TI - Noninferiority Diagnostic Value, but Also Economic and Turnaround Time Advantages From Digital Pathology. PMID- 29438167 TI - INSM1 is a Sensitive and Specific Marker of Neuroendocrine Differentiation in Head and Neck Tumors. AB - The head and neck is the site of a wide and sometimes bewildering array of neuroendocrine (NE) tumors. Although recognition of NE differentiation may be necessary for appropriate tumor classification and treatment, traditional NE markers such as synaptophysin, chromogranin, and CD56 are not always sufficiently sensitive or specific to make this distinction. Insulinoma-associated protein 1 (INSM1) is a novel transcription factor that has recently demonstrated excellent sensitivity and specificity for NE differentiation in various anatomic sites, but has not yet been extensively evaluated in tumors of the head and neck. We performed INSM1 immunohistochemistry on NE tumors (n=97) and non-NE tumors (n=626) across all histologic grades and anatomic subsites of the head and neck. INSM1 was positive in all types of head and neck NE tumors evaluated here (99.0% sensitivity), including middle ear adenoma, pituitary adenoma, paraganglioma, medullary thyroid carcinoma, olfactory neuroblastoma, small cell carcinoma, large cell NE carcinoma, and sinonasal teratocarcinosarcoma. Notably, it was positive in the vast majority of high-grade NE malignancies (95.8% sensitivity). INSM1 also was negative in almost all non-NE tumors (97.6% specificity) with the highest rates of reactivity in alveolar rhabdomyosarcoma and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1 (SMARCB1)-deficient sinonasal carcinoma. These findings confirm that INSM1 may be used as a standalone first-line marker of NE differentiation for tumors of the head and neck. PMID- 29438168 TI - Utility of CK7 Versus p16 as a Prognostic Biomarker in CIN 2. AB - Cervical intraepithelial neoplasia (CIN) 2 is an equivocal diagnosis, with p16 immunohistochemical positivity currently recommended for diagnostic confirmation. Biomarkers characteristic of squamocolumnar junction cells were recently found to be positive in almost all CIN 2 and CIN 3. CIN 1 lesions which express squamocolumnar junction markers (in particular cytokeratin 7 [CK7]) are associated with a higher rate of subsequent high-grade squamous intraepithelial lesion, suggesting that CK7 may be a useful prognostic biomarker for CIN 1. We sought to determine the utility of CK7 as a prognostic biomarker in the setting of morphologic CIN 2, and to compare this to the utility of p16 in this setting. We performed CK7 immunohistochemical on 116 cases originally diagnosed as CIN 2. Of these, 68.1% were p16 and 90.5% were CK7. A total of 19.5% of patients had a subsequent diagnosis of CIN 3 on biopsy or excision; the index CIN 2 lesion was CK7 in all of these cases (sensitivity 100%) and p16 in all but 1 (21/22; sensitivity 95.5%). The specificity of p16 (37.4%) and CK7 (8.0%) for predicting subsequent CIN 3 were significantly different (P<0.001). While p16 expression was significantly associated with subsequent CIN 3 (P=0.002), CK7 expression was not (P=0.202). We conclude that CK7, unlike p16, is not useful as a prognostic biomarker in CIN 2. While it is still promising as a prognostic marker in CIN 1, additional studies are needed to determine optimal staining/interpretation criteria. PMID- 29438169 TI - Superficial Solitary Fibrous Tumor: A Series of 26 Cases. AB - While superficial (cutaneous/subcutaneous) solitary fibrous tumor (SFT) have been described, definitive diagnosis is difficult due to overlapping features with other tumors. We describe the largest series to date of superficial SFT. For inclusion, SFT had to arise in dermis or subcutis. Twenty-six cases were identified. Patients ranged from 16 to 80 years (mean, 47 y) with a marked female predominance (19 F; 7 M). Tumors involved the head (11), thigh (7), back (3), shoulder (2), upper arm (1), ankle (1), and great toe (1). Mean size was 2.9 cm (range, 1.0 to 7.0 cm). The majority (n=19) had typical histologic features (cellular SFT) with irregular fascicles of spindled cells, staghorn-like blood vessels, and variable amounts of collagen. Necrosis was evident in 3 cases (all <25%). Mitotic activity ranged from 0 to 10 mitotic figures/10 high-power fields (mean, 2 mitotic figures/10 high-power fields). Seventeen of the 18 were positive for STAT6, whereas 21/22 expressed CD34. All were low risk (23/23) by proposed criteria (Demicco and colleagues), including 2 cases with malignant histology. Three could not be risk stratified due to lack of information on tumor size. Follow-up, available on 7 cases, showed no recurrence/metastasis (mean follow-up, 100 mo; range, 2 to 241 mo). Cutaneous SFT are more common in women and most often involve the head. They are usually low risk by proposed criteria and appear to behave in an indolent manner, though larger studies are needed to confirm this. Recognition that SFT may present as a superficial mass will avoid misclassification as other CD34-positive neoplasms that frequently arise in the skin and subcutaneous tissue. PMID- 29438170 TI - Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) Syndrome and Carcinoid Tumors With/Without NECH: A Clinicopathologic, Radiologic, and Immunomolecular Comparison Study. AB - The diagnostic criteria of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are not well defined, and DIPNECH can be mistaken for carcinoids associated with neuroendocrine cell hyperplasia (NECH). In this study, we compared clinical, radiologic, histologic, immunohistochemical, and molecular features of DIPNECH and isolated carcinoids with/without NECH. The study population included 151 cases (77 female patients and 74 male patients), 19 with DIPNECH and 132 with carcinoids with/without NECH. None of the cases displayed molecular alterations or anaplastic lymphoma kinase expression. Compared with individuals with carcinoids with/without NECH, patients with DIPNECH were more likely to be female individuals (P<0.0001), nonsmokers (P=0.021), and symptomatic, and to have an obstructive/mixed respiratory defect, peripheral location of the lesions, and air trapping (P<0.0001) on chest computed tomography, and constrictive bronchiolitis on histology (P<0.0001). Among immunohistochemical markers, DIPNECH was associated with higher expression of thyroid transcription factor-1, CD10, and gastrin-releasing peptide/bombesin-like peptide (P<0.0001). Yet, when a purely histopathologic definition of DIPNECH was applied, 40% of isolated carcinoids also met the diagnostic criteria for DIPNECH, even in the absence of symptoms and/or radiologic abnormalities. Therefore, as DIPNECH represents a distinct clinical syndrome, we suggest the term DIPNECH be limited to cases presenting with respiratory symptoms, functional and/or radiologic abnormalities, and constrictive bronchiolitis on histology. PMID- 29438171 TI - Analysis of the Histologic Features Associated With Interobserver Variation in Idiopathic Pulmonary Fibrosis. AB - The histologic manifestation of idiopathic pulmonary fibrosis (IPF) is usual interstitial pneumonia (UIP), which is a good prognostic determinant of survival compared with other histologic interstitial lung disease patterns. According to the current international guidelines, the histologic features of suspected IPF/UIP are divided into 4 categories: UIP, probable UIP, possible UIP, and not UIP pattern. Four pulmonary pathologists who were blinded to clinicoradiologic information reevaluated 50 surgical lung biopsies (83.3%), 6 lung explant (10.0%), and 4 autopsy samples (6.7%) from the FinnishIPF registry (N=60) using the current diagnostic guidelines. Additional histologic features atypical for UIP were also evaluated and compared with clinicora-diologic information. The interobserver agreement of pathologists was examined by Cohen kappa (kappa) coefficient; the survival of the patients was estimated with Kaplan-Meier curves. The histologic reevaluation indicated that 38 of 60 patients (63.3%) had definite UIP. Inflammation was the most common additional histologic finding (15/60, 25.0%). The interobserver agreement on histologic diagnosis ranged from slight (kappa=0.044) to substantial (kappa=0.779). The interobserver agreement varied extensively with regard to the presence of giant cells. The observed histologic features displayed no association with radiologic patterns or survival. Definite UIP and honeycombing findings in high-resolution computed tomography correlated with poor prognosis. A high level of interobserver variability was observed between pathologists, even in this well-defined cohort of IPF patients, which highlights the importance of multidisciplinary decision making in IPF diagnostics and stresses the need for a reassessment of the histologic criteria. PMID- 29438172 TI - Gastric Carcinomas With Lymphoid Stroma: An Evaluation of the Histopathologic and Molecular Features. AB - Gastric carcinoma with lymphoid stroma is an uncommon variant enriched for mutually exclusive Epstein-Barr virus (EBV) positivity and mismatch repair (MMR) deficiency. We performed this study to evaluate molecular alterations in this morphologically homogeneous subtype and compare them with 295 conventional gastric cancers analyzed in The Cancer Genome Atlas study. We identified 31 study cases and subjected them to in situ hybridization for EBV-encoded RNAs and assessment for MMR status. Immunostains for PD-L1, beta-catenin, and HER2 were performed; extracted DNA was sequenced with a Comprehensive Cancer Panel. Most study patients were older adult men with stage I or II disease (76%). Tumors were classified as EBV/MMR-proficient (MMR-P) (n=7), EBV/MMR deficient (n=12), and EBV/MMR-P (n=12). EBV/MMR-P tumors were usually located in the proximal stomach (83%) and showed heterogenous growth patterns with glandular differentiation (83%). Tumors in all groups showed numerous tumor infiltrating lymphocytes and PD L1 expression, infrequent nuclear beta-catenin accumulation (10%), and lacked both membranous HER2 staining and HER2 amplification. EBV/MMR-deficient tumors showed significantly higher tumor mutation burden (P=0.001) and KRAS alterations (56%) compared with EBV/MMR-P tumors (9%, P=0.05). TP53 variants were more common among EBV/MMR-P tumors (82%) compared with EBV/MMR proficient (0%, P=0.01) and EBV/MMR-deficient (11%, P<0.01) tumors. Alterations in KRAS, ARID1A, PIK3CA, and TP53 followed similar patterns of distribution compared with The Cancer Genome Atlas dataset. We conclude that gastric carcinomas with lymphoid stroma show a spectrum of molecular changes and frequent PD-L1 expression, raising the possibility that this subgroup of tumors may be susceptible to checkpoint inhibitors and/or agents that target receptor tyrosine kinase-mediated signaling. PMID- 29438173 TI - Fallopian Tube Mucosal Involvement in Cervical Gastric-type Adenocarcinomas: Report of a Series With Discussion of the Distinction From Synchronous In Situ Tubal Lesions. AB - Cervical gastric-type adenocarcinomas are aggressive non-human papillomavirus related carcinomas with a propensity for extracervical spread, including unusual sites such as the omentum, peritoneum, and ovary. We report 7 cases of cervical gastric-type adenocarcinoma with fallopian tube involvement predominantly in the form of mucosal colonization without underlying invasion. As far as we are aware, this has not been previously described and this report adds to the literature regarding metastatic neoplasms, which may exhibit tubal mucosal involvement and mimic an in situ lesion at this site. In all cases, there was associated ovarian involvement and in 6 of 7 cases, there was endometrial colonization. We speculate that the fallopian tube (and ovarian) involvement is secondary to transuterine spread. Given the occasional occurrence of multifocal gastric-type glandular lesions (benign or malignant) involving different sites in the female genital tract, we discuss the distinction between synchronous independent and metastatic lesions. PMID- 29438174 TI - Presence or Absence of Significant HPVE4 Expression in High-grade Anal Intraepithelial Neoplasia With p16/Ki-67 Positivity Indicates Distinct Patterns of Neoplasia: A Study Combining Immunohistochemistry and Laser Capture Microdissection PCR. AB - Progression of anal intraepithelial neoplasia (AIN) involves transition from productive to transforming human papillomavirus (HPV) infection. Grading aims to distinguish productive low-grade AIN from high-grade anal intraepithelial neoplasia (HGAIN) with risk of cancer. We describe immunohistochemical patterns in AIN adding a novel marker for initiation of the productive phase of the HPV life cycle (panHPVE4) to those for cell cycle activity (Ki-67) and transforming activity of HPVE7 gene (p16). We studied 67 anal biopsies for suspected anal neoplasia (17 normal, 15 AIN1, 20 AIN2, 15 AIN3) from 54 men who have sex with men at New York Presbyterian Hospital, USA. Two pathologists generated consensus AIN and immunogrades. Whole tissue and laser capture microdissection samples from multiple HPV-infected biopsies were tested for HPV with SPF10-PCR-DEIA-LiPA25, version 1. (Para)basal Ki-67 expression distinguished normal from AIN (>=lower third Ki-67) with sensitivity 0.92 and specificity 1.0. Ki-67 did not distinguish grades of AIN. Null/patchy p16 versus diffuse >=lower-third patterns discriminated HGAIN (sensitivity, 1.0; specificity, 0.84). There was marked heterogeneity in E4 expression within HGAIN. Most AIN2 (14/20) was E4 versus 0/15 AIN3 (sensitivity, 0.70; specificity 1.0). HPV was detected in 63 (94%) biopsies, with 49 (77.8%) high-risk HPV. HPV16 was the most frequent (13%). Multiple HPV genotypes were found in 15 (24%) biopsies and laser capture microdissection polymerase chain reaction confirmed specific HPV types in E4 +/- AIN. Although Ki 67 discriminated AIN and p16 HGAIN, E4/p16 staining shows that most AIN2 is different from transformed AIN3 in showing both entry into productive HPV infection and transforming activity. PMID- 29438175 TI - Effect of Fascia Penetration on Sensory Nerve Conduction in the Superficial Radial Nerve. AB - PURPOSE: The aim of this study was to identify the effects of fascia penetration on superficial radial sensory nerve action potential amplitude. METHODS: The penetration point (PP) at which the nerve penetrated the brachioradialis fascia and became superficial was observed using ultrasonography. The sensory nerve action potential amplitude was measured at five points: the penetration point, 2 and 4 cm proximal to the PP, and 2 and 4 cm distal to the PP. RESULTS: The sensory nerve action potential amplitude at the penetration point and at 2 and 4 cm distal to the PP was significantly larger than that at 2 and 4 cm proximal to the PP. The largest amplitude was obtained 2 cm distal to the PP. CONCLUSIONS: The sensory nerve action potential of the superficial radial nerve changes significantly around the fascia penetration point. PMID- 29438176 TI - Disinhibited Blink Reflex Recovery Is Related to Lateral Trunk Flexion in Parkinson Disease. AB - PURPOSE: Lateral trunk flexion is often observed in patients with Parkinson disease (PD) and causes poor quality of life. Asymmetrical function of the basal ganglia is believed to be the main cause of lateral trunk flexion, and dysfunction of the basal ganglia facilitates the blink reflex by disinhibiting the spinal trigeminal nucleus. Our aim was to investigate whether a disinhibited blink reflex recovery curve (BRrc) was associated with lateral trunk flexion in PD patients. METHODS: We enrolled 21 PD patients, including 11 with marked lateral trunk flexion (F-PD) and 10 with normal posture (N-PD), and 10 normal controls. Blink reflex recovery curves at interstimulus intervals of 200, 300, and 500 ms were compared between F-PD, N-PD, and normal controls. RESULTS: The BRrc in F-PD patients was more disinhibited than in N-PD patients and controls, and this disinhibition was asymmetrical. CONCLUSIONS: The asymmetrically disinhibited BRrc in F-PD patients was associated with lateral trunk flexion. This is the first neurophysiological study of patients with PD with abnormal posture. Examination of the BRrc may permit early detection of asymmetrical basal ganglia dysfunction that can eventually cause lateral trunk flexion. PMID- 29438177 TI - EEG Factors After Pediatric Cardiac Arrest. AB - PURPOSE: We aimed to determine whether conventional standardized EEG features could be consolidated into a more limited number of factors and whether the derived factor scores changed during the acute period after pediatric cardiac arrest. METHODS: Children resuscitated after cardiac arrest underwent conventional continuous EEG monitoring. The EEG was scored in 12-hour epochs for up to 72-hours after return of circulation by an electroencephalographer using standardized critical care EEG terminology. We performed a polychoric factor analysis to determine whether numerous observed EEG features could be represented by a smaller number of derived factors. Linear mixed-effects regression models and heat maps evaluated whether the factor scores remained stable across epochs. RESULTS: We performed EEG monitoring in 89 consecutive children, which yielded 453 EEG segments. We identified two factors, which were not correlated. The background features were factor loaded with the features continuity, voltage, and frequency. The intermittent features were factor loaded with the features of seizures, periodic patterns, and interictal discharges. Factor scores were calculated for each EEG segment. Linear, mixed-effect, regression results indicated that the factor scores did not change over time for the background features factor (coefficient, 0.18; 95% confidence interval, 0.04-0.07; P = 0.52) or the intermittent features factor (coefficient, -0.003; 95% confidence interval, -0.02 to 0.01; P = 0.70). However, heat maps showed that some individual subjects did experience factor score changes over time, particularly if they had medium initial factor scores. CONCLUSIONS: Subsequent studies assessing whether EEG is informative for neurobehavioral outcomes after pediatric cardiac arrest could combine numerous EEG features into two factors, each reflecting multiple background and intermittent features. Furthermore, the factor scores would be expected to remain stable during the acute period for most subjects. PMID- 29438178 TI - Treatment of pancreatic cancer with intravenous vitamin C: a case report. AB - Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and is often discovered at an advanced stage with few therapeutic options. Current conventional regimens for PDA are associated with significant morbidity, decreased quality of life, and a considerable financial burden. As a result, some patients turn to integrative medicine therapies as an alternate option after a diagnosis of PDA. Intravenous pharmacologic ascorbic acid (PAA) is one such treatment. The use of PAA has been passionately debated for many years, but more recent rigorous scientific research has shown that there are significant blood concentration differences when ascorbic acid is given parenterally when compared to oral dosing. This pharmacologic difference appears to be critical for its role in oncology. Here, we report the use of PAA in a patient with poorly differentiated stage IV PDA as an exclusive chemotherapeutic regimen. The patient survived nearly 4 years after diagnosis, with PAA as his sole treatment, and he achieved objective regression of his disease. He died from sepsis and organ failure from a bowel perforation event. This case illustrates the possibility of PAA to effectively control tumor progression and serve as an adjunct to standard of care PDA chemotherapy regimens. Our patient's experience with PAA should be taken into consideration, along with previous research in cell, animal, and clinical experiments to design future treatment trials. PMID- 29438180 TI - The National Conference for Nurse Practitioners: Sunshine, sessions, and CE. PMID- 29438179 TI - A novel small molecular STAT3 inhibitor, 5Br-6b, induces apoptosis and inhibits migration in colorectal cancer cells. AB - Signal transducers and activators of transcription 3 (STAT3) represent a transcription factor that is constitutively activated in various cancers. Numerous studies have shown that STAT3 plays crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and suppression of antitumor host immune response in the tumor microenvironment. In this study, we investigated a novel inhibitor, called -6b, to target STAT3 in colorectal cancer cells. The influence of 5Br-6b on the proliferation of colorectal cell lines SW480 and HCT116 was evaluated using an 3-(4, 5-dimethylthiazolyl)-2 and 5 diphenyltetrazolium bromide assay. We detected cell apoptosis after the treatment of 5Br-6b by flow cytometry. In addition, 5Br-6b caused the cleavage of caspase-3 and decreased the expression of Bcl-2. Cancer cell invasion and migration were measured by transwell and wound-healing assay. The potential mechanism was evaluated by western blotting and immunofluorescence. The results show that 5Br 6b inhibits the activation of STAT3, and decreases the expression of its target genes that regulate cell proliferation, migration, and apoptosis. Thus, 5Br-6b is a promising therapeutic drug candidate for colorectal cancer by inhibiting persistent STAT3 signaling. PMID- 29438181 TI - ADHD: From childhood to young adulthood. AB - Attention-deficit hyperactivity disorder (ADHD) affects approximately 11% of children between the ages of 4 and 17 years. This article discusses performing a comprehensive assessment for ADHD, the use of validated tools to make an accurate diagnosis, physical exam findings that may be suggestive of certain conditions, and ADHD treatment options. PMID- 29438182 TI - ADHD: From childhood to young adulthood. PMID- 29438184 TI - Adolescent use of electronic nicotine delivery systems. PMID- 29438183 TI - Adolescent use of electronic nicotine delivery systems. AB - Use of electronic nicotine delivery systems is flourishing among adolescents. The long-term effects have not been fully determined; however, literature suggests there is potential for significant harm. Providers must be aware of usage trends, device safety, and product knowledge. Adolescents should be evaluated through routine screening, and cessation counseling should be initiated. PMID- 29438185 TI - Detection and management of atrial fibrillation using remote monitoring. AB - Atrial fibrillation (AF) is the most common dysrhythmia encountered in the United States. Symptoms may be similar to those of other cardiac conditions, which can delay the timely detection, diagnosis, and management of AF. This article provides an overview of AF and modalities used in remote monitoring. PMID- 29438186 TI - Peanut allergy reduction in high-risk pediatric patients. AB - The prevalence of food allergies has doubled in the past 10 years. Peanut allergies are a significant public health issue and are the primary reason for food-related anaphylactic reactions that result in death. Evidence supports that early introduction of the peanut protein (or in combination with immunotherapy) to the highly allergic may safely desensitize patients, which could lead to less adverse allergic reactions and alter allergy management overall. PMID- 29438187 TI - The role of race in clinical decision making. AB - Is race/ethnicity useful in clinical decision making? This article uses a case example to discuss the role of race/ethnicity in clinical decision making, how racial/ethnic categories were developed, potential problems of using racial/ethnic categories, and the difference between risk factors and risk markers. The authors make the argument that using a patient's race/ethnicity in clinical decision making often results in a missed or incorrect diagnosis. PMID- 29438188 TI - Lamotrigine rash: Benign allergy or severe adverse reaction? PMID- 29438189 TI - Good Samaritan laws: Will I be protected if I help? PMID- 29438191 TI - The Association Between Depressive Symptoms and N-Terminal Pro-B-Type Natriuretic Peptide With Functional Status in Patients With Heart Failure. AB - BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and depressive symptoms are each associated with functional status in patients with heart failure (HF), but their association together with functional status has not been examined. OBJECTIVE: The aim of this study was to determine whether functional status scores differ as a function of depressive symptoms and NT-proBNP levels considered together. METHODS: We studied 284 patients with HF who were divided into 4 groups based on the median split of NT-proBNP levels and cut point for depressive symptoms (Beck Depression Inventory >= 14): (1) low NT-proBNP of 562.5 pg/mL or less without depressive symptoms, (2) low NT-proBNP of 562.5 pg/mL or less with depressive symptoms, (3) high NT-proBNP of greater than 562.5 pg/mL without depressive symptoms, and (4) high NT-proBNP of greater than 562.5 pg/mL with depressive symptoms. The Duke Activity Status Index was used to assess functional status. RESULTS: Nonlinear regression demonstrated that patients without depressive symptoms were more than twice as likely to have higher (better) functional status scores than patients with depressive symptoms regardless of NT-proBNP levels after controlling for age, gender, prescribed antidepressants, and body mass index. Functional status levels of patients with low NT-proBNP did not differ from those with high NT-proBNP in the presence of depressive symptoms. CONCLUSION: When examined together, depressive symptoms rather than NT-proBNP levels predicted functional status. CLINICAL IMPLICATIONS: Adequate treatment of depressive symptoms may lead to better functional status regardless of HF severity. PMID- 29438192 TI - Changes in Health Insurance Coverage Associated With the Affordable Care Act Among Adults With and Without a Cancer History: Population-based National Estimates. AB - BACKGROUND: The Affordable Care Act (ACA) improved health care coverage accessibility by expanding Medicaid eligibility, creating insurance Marketplaces, and subsidizing premiums. We examine coverage changes associated with ACA implementation, comparing adults with and without a cancer history. METHODS: We included nonelderly adults from the 2012 to 2015 National Health Interview Survey. Using information on state Medicaid policies (2013), expansion decisions (2015), family structure, income, insurance offers, and current coverage, we assigned adults in all 4 years to mutually exclusive eligibility categories including: Medicaid-eligible pre-ACA; expansion eligible for Medicaid; and Marketplace premium subsidy eligible. Linear probability regressions estimated pre-post (2012-2013 vs. 2014-2015) coverage changes by eligibility category, stratified by cancer history. RESULTS: The uninsured rate for cancer survivors decreased from 12.4% to 7.7% (P<0.001) pre-post ACA implementation. Relative to income >400% of the federal poverty guideline, the uninsured rate for cancer survivors decreased by an adjusted 8.4 percentage points [95% confidence interval (CI), 1.3-15.6] among pre-ACA Medicaid eligible; 16.7 percentage points (95% CI, 9.0-24.5) among expansion eligible, and 11.3 percentage points (95% CI, -0.8 to 23.5, with a trend P=0.069) for premium subsidy eligible. Decreases in uninsured among expansion-eligible adults without a cancer history [9.7 percentage points (95% CI, 7.4-12.0), were smaller than for cancer survivors (with a trend, P=0.086)]. Despite coverage gains, ~528,000 cancer survivors and 19.1 million without a cancer history remained uninsured post-ACA, yet over half were eligible for Medicaid or subsidized Marketplace coverage. CONCLUSIONS: ACA implementation was associated with large coverage gains in targeted expansion groups, including cancer survivors, but additional progress is needed. PMID- 29438194 TI - Teaching Patient-Centered Care Through the Veterans History Project. AB - Determining the best ways to teach military culture and the veteran experience to nursing students and new nurses is an essential component in developing a culturally sensitive nursing workforce. The purpose of this article is to describe a theory-driven, experiential learning approach to integrating the Veterans History Project into the curricula for a postbaccalaureate nurse residency program. Participants acknowledged that this educational project better prepared them to care for the veteran population. PMID- 29438193 TI - Defining and Assessing Geriatric Risk Factors and Associated Health Care Utilization Among Older Adults Using Claims and Electronic Health Records. AB - BACKGROUND: Using electronic health records (EHRs), in addition to claims, to systematically identify patients with factors associated with adverse outcomes (geriatric risk) among older adults can prove beneficial for population health management and clinical service delivery. OBJECTIVE: To define and compare geriatric risk factors derivable from claims, structured EHRs, and unstructured EHRs, and estimate the relationship between geriatric risk factors and health care utilization. RESEARCH DESIGN: We performed a retrospective cohort study of patients enrolled in a Medicare Advantage plan from 2011 to 2013 using both administrative claims and EHRs. We defined 10 individual geriatric risk factors and a summary geriatric risk index based on diagnosed conditions and pattern matching techniques applied to EHR free text. The prevalence of geriatric risk factors was estimated using claims, structured EHRs, and structured and unstructured EHRs combined. The association of geriatric risk index with any occurrence of hospitalizations, emergency department visits, and nursing home visits were estimated using logistic regression adjusted for demographic and comorbidity covariates. RESULTS: The prevalence of geriatric risk factors increased after adding unstructured EHR data to structured EHRs, compared with those derived from structured EHRs alone and claims alone. On the basis of claims, structured EHRs, and structured and unstructured EHRs combined, 12.9%, 15.0%, and 24.6% of the patients had 1 geriatric risk factor, respectively; 3.9%, 4.2%, and 15.8% had >=2 geriatric risk factors, respectively. Statistically significant association between geriatric risk index and health care utilization was found independent of demographic and comorbidity covariates. For example, based on claims, estimated odds ratios for having 1 and >=2 geriatric risk factors in year 1 were 1.49 (P<0.001) and 2.62 (P<0.001) in predicting any occurrence of hospitalizations in year 1, and 1.32 (P<0.001) and 1.34 (P=0.003) in predicting any occurrence of hospitalizations in year 2. CONCLUSIONS: The results demonstrate the feasibility and potential of using EHRs and claims for collecting new types of geriatric risk information that could augment the more commonly collected disease information to identify and move upstream the management of high-risk cases among older patients. PMID- 29438195 TI - Incidence of new hepatitis C virus infection is still increasing in French MSM living with HIV. AB - OBJECTIVE: High hepatitis C virus (HCV) treatment uptake combined with effective direct-acting antiviral-based regimens resulted in a dramatic decline of HCV infection in French people living with HIV (PLWH). We assessed the yearly incidence of new HCV infection in PLWH enrolled in the large French Dat'AIDS cohort from 2012 to 2016 with a specific focus on MSM. METHODS: The incidence of new HCV infection was determined yearly in HCV-negative PLWH with serological follow-up during 2012-2016. The incidence of HCV reinfection was determined in patients who were cured of a previous infection. RESULTS: Among 40 714 PLWH, HCV status was available in 38 217 (94%). A total of 5557 PLWH (15%) were HCV infected at first time-point, 82% of whom were cured of HCV by the end of 2016. Among 21 519 HCV-negative PLWH with serological follow-up (63 449 patient-years), 219 first HCV infections occurred (MSM: 188, others: 31). Similarly, among 3406 patients who were cured of a previous infection (10 602 patient-years), 73 reinfections occurred (MSM: 51, others: 22). From 2012 to 2016, the incidence of a first infection in MSM rose from 0.5 to 0.92% patient-years, whereas the incidence or reinfection remained stable (2.52-2.90% patient-years). CONCLUSION: Despite a high HCV treatment uptake and cure rate, the incidence of first HCV infection regularly increased in French HIV-positive MSM between 2012 and 2016. The incidence of reinfection fluctuated but remained constantly higher than the incidence of first infection, suggesting that a subgroup of MSM pursued high-risk practices following cure of a first infection. PMID- 29438196 TI - Antiretroviral drug concentrations in hair are associated with virologic outcomes among young people living with HIV in Tanzania. AB - OBJECTIVE: We assessed the relationship of self-reported adherence versus antiretroviral therapy (ART) concentrations in hair with virologic outcomes among young people living with HIV. DESIGN: This was a cross-sectional study that enrolled young people living with HIV age 11-24 years, who attended a youth HIV clinic in Moshi, Tanzania. METHODS: ART adherence was assessed by self-report, drug concentration in hair samples, and plasma HIV-1 RNA measurements. Those with virologic failure, defined as plasma HIV-1 RNA more than 400 copies/ml, had genotypic resistance assessed. Receiver operating characteristic curves were used to evaluate ART-concentration threshold cutoffs for virologic suppression, after excluding those with known high-level resistance mutations. RESULTS: Among 280 young people enrolled, 227 were included in the final analysis. Seventy-two (32%) self-reported inadequate adherence and 91 (40%) had virologic failure. Hair ART concentration (P < 0.001), but not self-reported adherence (P = 0.53), was associated with virologic outcome. Sixty-seven (74%) of those with virologic failure had resistance testing performed, of whom 60% had high-level resistance. Receiver operating characteristic curves demonstrated moderate or high classification performance for association with virologic suppression with specific hair ART-concentration cutoffs for lopinavir (1.8 ng/mg), efavirenz (1.04 ng/mg), and nevirapine (33.2 ng/mg). CONCLUSION: Hair ART-concentrations were significantly associated with virologic outcomes among young people living with HIV. ART-concentration thresholds associated with virologic suppression are proposed. Hair analysis may provide a noninvasive, cost-effective adherence assessment tool in settings with limited second and third-line treatment options. PMID- 29438197 TI - Elevated liver stiffness is linked to increased biomarkers of inflammation and immune activation in HIV/hepatitis C virus-coinfected patients. AB - OBJECTIVES: Immune dysregulation is a hallmark of HIV and hepatitis C virus (HCV) infections. We aimed to evaluate the relationship between liver stiffness measurement (LSM) and biomarkers of T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy in HIV/HCV-coinfected patients. DESIGN: Cross-sectional study. METHODS: We studied 238 HIV/HCV coinfected patients, 32 healthy controls, and 39 HIV-monoinfected patients. Patients were stratified according to LSM into four groups: less than 12.5, 12.5 25, 25-40, and more than 40 kPa. T-cell subsets were measured using flow cytometry and plasma biomarkers using immunoassays. RESULTS: HIV/HCV-coinfected patients had higher biomarker levels of immune activation in peripheral blood [T cell activation (CD4CD38 and CD8CD38), bacterial translocation (soluble CD14), inflammation [IL-1b, IL-6, IL-8, IL-18, IFN-gamma-inducible protein 10 (IP-10)] endothelial dysfunction [soluble vascular cell adhesion molecule 1 (sVCAM1), soluble intercellular cell adhesion molecule 1 (sICAM1), and soluble tumor necrosis factor receptor 1 (sTNFR1)], and coagulopathy (plasminogen activator inhibitor-1)] than healthy controls and HIV-monoinfected patients. Moreover, in HIV/HCV-coinfected patients, a direct relationship between LSM and immune activation [T-cell activation (CD8CD38 bacterial translocation (lipopolysaccharide), inflammation (IL-8, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] was found. Subsequently, patients were stratified into different fibrosis stages, finding that patients with cirrhosis who had LSM at least 40 kPa showed higher biomarker values of immune activation [T-cell activation (CD4CD38 and CD8CD38), bacterial translocation (lipopolysaccharide), inflammation (IL-8, IL-6, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] than patients from the other three groups (<12.5, 12.5-25, and 25-40 kPa). CONCLUSION: T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy increased with the severity of liver fibrosis in HIV/HCV-coinfected patients, particularly in patients who had LSM at least 40 kPa. PMID- 29438199 TI - Changes in cerebral function parameters with maraviroc-intensified antiretroviral therapy in treatment naive HIV-positive individuals. AB - BACKGROUND: Maraviroc-intensified antiretroviral therapy (ART) may be associated with cognitive benefits. METHODS: Therapy-naive, cognitively asymptomatic, HIV positive individuals were randomly allocated on a 1 : 1 basis to standard ART (Arm1: tenofovir-emtricitabine and atazanavir/ritonavir) or maraviroc intensified ART (Arm2: abacavir-lamivudine and darunavir/ritonavir/maraviroc). Over 48 weeks, detailed assessments of cognitive function tests were undertaken and cerebral metabolites measured using proton magnetic resonance spectroscopy. Our primary endpoint was mean change in cognitive function across treatment arms with factors associated with cognitive function changes also assessed. RESULTS: Of 60 individuals randomized (30 Arm1 and 30 Arm2), 58 were men and 44 of white ethnicity. Treatment groups had similar disease characteristics including overall mean (SD) baseline CD4 cell count 428 (209) and 414 (229) cells/MUl, Arms1 and 2, respectively. At week 48, plasma HIV RNA was less than 50 copies/ml in 55 of 56 of those completing study procedures. Cognitive function improved over 48 weeks [mean change z-score (SD) 0.16 (0.09) Arm1 and 0.25 (0.08) Arm2, P = 0.96 for differences between study arms]. A greater increase in frontal grey matter N acetyl aspartate/creatine ratio was observed in Arm1 [ratio change of 0.071 (SD 0.16)] versus Arm2 [change -0.097 (SD 0.18), P = 0.009], although this was not associated with changes in cognitive function (P = 0.17). CONCLUSION: Maraviroc intensified ART had no demonstrable benefit on cognitive function in individuals initiating ART. Greater improvement in neuronal metabolites (N-acetyl aspartate/creatine) was observed with standard ART. Future work should focus on maraviroc-intensified ART in individuals with cognitive impairment. PMID- 29438198 TI - The association of C-reactive protein with subclinical cardiovascular disease in HIV-infected and HIV-uninfected women. AB - OBJECTIVE: HIV is a cardiovascular disease (CVD) risk factor. However, CVD risk is often underestimated in HIV-infected women. C-reactive protein (CRP) may improve CVD prediction in this population. We examined the association of baseline plasma CRP with subclinical CVD in women with and without HIV. DESIGN: Retrospective cohort study. METHODS: A total of 572 HIV-infected and 211 HIV uninfected women enrolled in the Women's Interagency HIV Study underwent serial high-resolution B-mode carotid artery ultrasonography between 2004 and 2013 to assess carotid intima-media thickness (CIMT) and focal carotid artery plaques. We used multivariable linear and logistic regression models to assess the association of baseline high (>=3 mg/l) high-sensitivity (hs) CRP with baseline CIMT and focal plaques, and used multivariable linear and Poisson regression models for the associations of high hsCRP with CIMT change and focal plaque progression. We stratified our analyses by HIV status. RESULTS: Median (interquartile range) hsCRP was 2.2 mg/l (0.8-5.3) in HIV-infected, and 3.2 mg/l (0.9-7.7) in HIV-uninfected, women (P = 0.005). There was no statistically significant association of hsCRP with baseline CIMT [adjusted mean difference 3.5 MUm (95% confidence interval:-19.0 to 12.1)] or focal plaques [adjusted odds ratio: 1.31 (0.67-2.67)], and no statistically significant association of hsCRP with CIMT change [adjusted mean difference 11.4 MUm (-2.3 to 25.1)]. However, hsCRP at least 3 mg/l was positively associated with focal plaque progression in HIV-uninfected [adjusted rate ratio: 5.97 (1.46-24.43)], but not in HIV-infected [adjusted rate ratio: 0.81 (0.47-1.42)] women (P = 0.042 for interaction). CONCLUSION: In our cohort of women with similar CVD risk factors, higher baseline hsCRP is positively associated with carotid plaque progression in HIV-uninfected, but not HIV-infected, women, suggesting that subclinical CVD pathogenesis may be different HIV-infected women. PMID- 29438200 TI - Switching from abacavir to tenofovir disoproxil fumarate is associated with rises in soluble glycoprotein VI, suggesting changes in platelet-collagen interactions. AB - OBJECTIVES: Altered platelet function has been proposed as an underlying mechanism to explain increased risk of myocardial infarction in people living with HIV associated with use of the nucleoside reverse transcriptase inhibitor abacavir (ABC). We aimed to examine changes in platelet biomarkers in people living with HIV switching from ABC. METHODS: In a prospective, 48-week substudy of virally suppressed HIV-1-positive subjects randomized to remain on ABC/lamivudine (ABC/3TC) or switch to tenofovir disoproxil fumarate/emtricitabine, we measured soluble glycoprotein VI (sGPVI), soluble P selectin, soluble CD40 ligand and von Willebrand factor in plasma collected over time and assessed differences using mixed effect models. RESULTS: Of 312 randomized participants, 310 were included in the analysis. Mean (SD) age 46.4 (9.3) years, 262 (85%) men and 201 (65%) white. At baseline, there was no significant between-group difference in sGPVI [tenofovir disoproxil fumarate/emtricitabine 3.75 (0.25) versus ABC/3TC 3.61 (0.22) ng/ml, P = 0.69]. Greater increases in sGPVI from baseline to week 48 occurred in those switched from ABC/3TC (effect size +0.57 ng/ml; 95% confidence interval, 0.2-0.94; P = 0.003). There was no significant baseline difference or change overtime in soluble P-selectin, soluble CD40 ligand or von Willebrand factor between groups. CONCLUSION: The significant increases in sGPVI that occur with a switch from ABC/3TC are suggestive of changes in platelet function centred on platelet/collagen interactions and potentially represent an underlying mechanism to explain increased risk of myocardial infarction with ABC. PMID- 29438201 TI - Location of the Septoaponeurosis Junction Relative to the Tarsal Plate in Upper Eyelids. AB - The aim of this study was to measure the location of the septoaponeurosis junction relative to the tarsal plate in the upper eyelids of Koreans through a histologic study.Thirty-four upper eyelids from 34 Korean adult cadavers (mean age, 77.8 years) were used. Sagittal sections on the midpupillary line were made, and 10-MUm-thick sections were prepared and stained with hematoxylin-eosin and Masson trichrome. Under a magnifying loupe with a scale, the height of the tarsal plate (HTP), thickness of the tarsal plate (TTP), distance from the lid margin to the septoaponeurosis junction (MJD), and distance from the upper border of the tarsal plate to the septoaponeurosis junction (TJD) were measured.The mean HTP was 8.09 +/- 1.68 mm (range: 4.0-0.8 mm). The mean TTP was 1.52 +/- 1.56 mm (range: 0.8-3.0 mm). The mean MJD was 9.18 +/- 2.69 mm (range: 2.5-13.0 mm). The mean TJD was 1.1 +/- 2.6 mm (range: -5.5-7.0 mm). In 25 (73.5%) of the 34 eyelids, the SAJ (1.1 +/- 2.6 mm) was above the upper border of the tarsal plate (UTP); however, in 9 (26.5%) of the 34 eyelids, below the UTP. The greater the HTP, the greater the MJD was (y=0.620x+4.166, P = 0.024 [linear regression analysis]). However, there was no significant correlation between the HTP and TJD (P = 0.155 [correlation analysis]).The results of this study provide a useful guide for performing operations involving the orbital septum and levator aponeurosis. PMID- 29438202 TI - Endoscopic Modified Medial Maxillectomy for Fungal Ball of the Hypoplastic Maxillary Sinus With Bony Hypertrophy. AB - Sinus fungal ball is defined as noninvasive chronic rhino-sinusitis with a clump of mold in the paranasal sinuses, typically affecting the maxillary sinus. Fairly good outcomes of endoscopic surgery have been reported where the ball is removed through the antrostomy. However, the affected sinus tends to have a smaller cavity and thicker bony walls. As such, it is often challenging to maintain a window size that is sufficient to control possible recurrence. The endoscopic modified medial maxillectomy procedure was applied to a 61-year old and a 70-year old female patient with maxillary sinus fungal ball. Using this method, we created a much larger inferior meatal antrostomy without difficulty. The window provided us with an endoscopic view of the whole sinus and complete eradication of the lesion. Endoscopic modified medial maxillectomy is useful as a surgical procedure for maxillary sinus fungal ball and should be considered for better outcomes. PMID- 29438203 TI - Does Periosteal Graft Combined With Platelet-Rich Plasma Enhance the Healing of Bone Defect? AB - INTRODUCTION: This study investigated the effect of periosteal graft + platelet rich plasma (PRP) combination on facial bone defect healing. METHODS: Five millimeter critical sized defects in zygomatic arches of 12 adult New Zealand rabbits were created. Rabbits were randomly divided into 3 groups: First group (control group): bone defects of left zygomatic arches of 6 rabbits were wrapped with a silicone tube. Second group (periosteal graft group): bone defects of left zygomatic arches of 6 rabbits were wrapped with periosteal graft. Third group (experimental group): bone defects of right zygomatic arches of 12 rabbits were wrapped with periosteal graft-PRP combination. New bone formation was evaluated at 8th and 16th weeks. One rabbit was sacrificed at 8th week. Remaining 11 rabbits were imaged with 3-dimensional computed tomography (CT) at 16th week; then, zygomatic arches were removed for micro-CT and histologic examinations. RESULTS: Three-dimensional CT analysis at 16th week revealed no significant difference between groups regarding new bone formation (P = 0.232). Micro-CT analysis of new regenerated bone at 16th week displayed significant differences between groups 1 and 3 regarding mean bone volume (BV, mm) (P = 0.028) and mean bone mineral density (BMD, mm) (P = 0.001). There was no difference between groups 2 and 3 or between groups 1 and 2, regarding BV or BMD. Histological Bone Regeneration Scorings at 16th week displayed significant difference between groups (P = 0.015). Negative correlation between 3-dimensional CT and histologic results (r = 0.120); positive correlations between BV/BMD values in micro-CT and histologic results (r = 0.524 and r = 0.456) were found. CONCLUSIONS: By enhancing bone formation capacity of periosteal grafts, periosteal graft-PRP combination provided bone formation having more volume and density comparing with silicone tube application. PMID- 29438204 TI - Effects of Hyaluronic Acid and Hydroxyapatite/Beta-tricalcium Phosphate in Combination on Bone Regeneration of a Critical-size Defect in an Experimental Model. AB - Hyaluronic acid (HyA) is an outstanding new product in the field of oral and maxillofacial surgery. The aim of this study was to evaluate the effects of HyA on bone regeneration in critical-size calvarial defects. Twenty-four female Sprague-Dawley rats were used in the present study. In each rat, 4 critical-size defects received different treatments: no treatment (control); HyA; Graft; and HyA + Graft combination. New bone formation, defect closure, inflammation, vascular proliferation, immature bone formation, mature bone formation, and bone marrow existence were investigated based on histological findings. The healing parameters related to bone formation (new bone formation, defect closure, immature bone formation) were significantly higher in the HyA group compared with the control group. However, HyA alone was unable to induce sufficient bone regeneration compared with treatments involving graft materials (Graft and HyA + Graft). In the Graft and HyA + Graft groups, prominent enhancement of all healing parameters was noted. The present results demonstrate that HyA alone did not adequately enhance bone regeneration in critical-size defects. Moreover, addition of HyA to a biphasic alloplastic graft material did not result in improved regeneration compared with the graft material alone. PMID- 29438205 TI - Evaluation of Postoperative Stability After Open Reduction and Internal Fixation of Zygomaticomaxillary Complex Fractures Using Cone Beam Computed Tomography Analysis. AB - The aim of this study was to evaluate whether the amount of fracture displacement affects postoperative stability of isolated zygomaticomaxillary complex fractures and to determine whether the 1-point fixation method is as stable as 2- or 3 point fixation methods. The authors investigated 14 patients with 1-point fixation in the zygomaticomaxillary area (group A), 14 patients with 2-point fixation in the zygomaticomaxillary and frontozygomatic area (group B), and 13 patients with 3-point fixation in the zygomaticomaxillary, frontozygomatic, and infraorbital rim area (group C). Stability of the reduced zygomaticomaxillary complex was assessed by comparing immediate postoperative cone beam computed tomography images with those obtained at least 3 months later. Preoperatively, the total mean displacement was 3.79 +/- 1.36 mm in group A, 3.43 +/- 0.89 mm in group B, and 3.86 +/- 1.57 mm in group C. The total postoperative orbital and screw changes were 0.91 +/- 0.18 and 0.72 +/- 0.08 mm, respectively, in group A; 0.92 +/- 0.19 and 0.68 +/- 0.09 mm, respectively, in group B; and 0.91 +/- 0.11 and 0.66 +/- 0.10 mm, respectively, in group C. There were no significant relationships between postoperative stability and amount of fracture displacement in any of the 3 groups, or between the 3 groups (P > 0.05). There was little difference in postoperative stability between the 3 groups. Hence, the amount of displacement is not a very important consideration when deciding the fixation method, including the number and location of miniplates applied for fixation. PMID- 29438206 TI - Surgical Outcome After Less "Rigid" Fixation in Open Cranial Vault Remodeling for Craniosynostosis. AB - : : Open cranial vault remodeling techniques require rigid fixation with hardware such as plates and screws; however, complications can occur. The purpose of this study was to assess the surgical outcome after open reconstruction for craniosynostosis with less rigid fixation using nonabsorbable suture. METHODS: Retrospective review of patients who underwent open craniofacial reconstruction for craniosynostosis at the Hospital Kuala Lumpur between January 2011 and December 2016 were performed. Demographic data, surgical complications, and postoperative aesthetic outcomes and reoperations were evaluated using Whitaker classification. Statistical analyses were performed using SPSS. RESULTS: Thirty four (n = 34) cases were included in this review consisting of 16 males and 18 females (ratio 1:1.25). Sixteen patients were syndromic with multiple suture synostoses: Apert syndrome (n = 8), Crouzon syndrome (n = 6), and Muenke's syndrome (n = 2). Eighteen patients were nonsyndromic: isolated single-suture craniosynostosis (n = 12) and multiple suture involvement (n = 6). Mean age of presentation was 17.4 months (4-16 months) with mean age of surgery of 23.8 months (6-68 months). Mean length of surgery was 6.1 hours (range 3-10 hours) and mean length of hospital stay was 10 days (mean 7-20 days). Mean duration of follow-up was 2.2 years (6 month-4 years). There were a total of 9 complications postoperatively: massive blood loss (n = 4), seroma (n = 2), exposure keratitis (n = 1), hand extravasation (n = 1), and occipital sore (n = 1). Analysis showed multiple suture craniosynostoses were associated with longer operative times (4.3 hours vs 6.5 hours, P = 0.0082 < 0.05) and higher blood transfusion (170 mL vs 275 mL, P = 0.0274 < 0.05). Older age was also associated with higher blood transfusion (135.5 mL; <12 months vs 250.2 mL; 12-24 months vs 302.1 mL; >24 months of age, P = 0.00059). Patients were categorized as 88.2% (n = 30) Whitaker I and II and 11.8% (n = 4) Whitaker III and IV. Reoperation rates were 2.9% (n = 1). Whitaker III and IV class were higher among patients with syndromic synostosis, unicoronal and multiple suture synostoses. CONCLUSIONS: Our technique of open cranial reconstruction with nonabsorbable suture nylon 2/0 as sole method of fixation has resulted in good aesthetic outcome with low reoperations and complications rate. Longer follow-up is needed to ascertain our long-term results. PMID- 29438207 TI - Facial Fracture-Associated Blindness. AB - INTRODUCTION: Yet uncommon, blindness is a potential associated injury of facial fractures. METHODS: Epidemiology, mechanisms, fracture types, and outcome of facial fractures-associated blindness in a 10-year period are retrospectively reviewed. RESULTS: Out of 907 facial fractures patients, 10 had blindness, giving a frequency of 1.1%. There were 9 men and 1 woman whom age range was 6 to 59 years (mean: 31.2 years). Intentional injury patients were significantly the most at risk of blindness (P = 0.02). In all the patients, the fracture involved at least 1 of the orbit walls. Risk of blindness was significantly higher in naso fronto-orbito-ethmoidal complex fractures (P = 0.03). The vision loss was recorded in 13 eyes (unilateral in 7 patients and bilateral in 3). Its predominant mechanism was a globe rupture or perforation, recorded in 8 eyes. A treatment with intention to improve the vision was attempted in 1 patient only. None of the patients had vision recovery. DISCUSSION: The findings of this study commend comprehensive ophthalmologic evaluation in any patient with an orbit wall fracture. PMID- 29438208 TI - Power-Assisted Particulate Bone Grafting Effectively Prevents Osseous Defects After Cranial Vault Reconstruction. AB - BACKGROUND: Cranial vault reconstruction (CVR) is the gold standard in the operative treatment of craniosynostosis. Full thickness osseous defects (FTOD) of the calvaria have been observed in 5% to 15% patients after CVR, with higher rates cited in the fronto-orbital advancement (FOA) subset. Particulate bone graft (PBG) harvested manually has been shown to decrease FTOD after FOA from 24% to 5.5%. The authors used a modified technique using a powered craniotome, with the hypothesis that the technique would also improve outcomes. METHODS: A retrospective review was performed of patients who underwent CVR for craniosynostosis between 2004 and 2014. Patient demographics, diagnosis, age, operative details, and postoperative care were reviewed in detail. Categorical, nonparametric variables were compared by Fisher exact tests. RESULTS: A total of 135 patients met inclusion criteria. The most common diagnoses were metopic (n = 41), sagittal (n = 33), and unilateral coronal craniosynostosis (n = 31); 65% (n = 88) underwent FOA, 29% (n = 39) underwent single-stage total vault reconstruction, and 6% (n = 8) had a posterior vault reconstruction. CVR was performed without PBG in 95 patients and with PBG in 40 patients. Without PBG, FTOD were discovered on clinical examination in 18% of patients (n=17): 11 presented with subcentimeter defects, while 6 had larger defects requiring revision cranioplasty (6% operative revision rate). Among those receiving PBG, 1 patient presented a subcentimeter FTOD (2.5% FTOD incidence and 0% operative revision rate). CONCLUSION: Particulate bone graft harvested with a powered device decreases the rate of FTOD and reoperation rate after CVR for craniosynostosis. PMID- 29438209 TI - An Unusual Complication of Bone Wax Utilization. AB - Bone wax is a commonly used hemostatic agent with minimal complications. Some of the known complications include inflammation, granuloma formation, infection, and impaired osteogenesis. Several clinical reports of bone wax migration have also been reported. In this paper, the authors present a rare patient of bone wax migration intracranially in a 6-year-old patient who initially underwent craniotomy for the evacuation of subdural hematoma and repair of depressed skull fracture. The patient then underwent craniotomy scalp scar revision several months later. Postoperatively he developed short-term memory loss, apraxia, and word finding difficulties. The imaging findings were consistent with the presence of a foreign body centered in the posterior aspect of the left middle temporal gyrus, which was surgically removed and found to be bone wax. The patient recovered well with complete improvement of his neurologic symptoms. PMID- 29438210 TI - Hemangioma of the Hard Palate in an Elderly Patient as a Life-Threatening Surgical Emergency. AB - Hemangiomas of the head and neck are common benign tumors usually in childhood. They are rarely seen in hard palate. The authors present a geriatric patient with abundant hemorrhage due to a capillary hemangioma of the hard palate. Management and treatment approaches of this rare, urgent, and life-threatening situation is discussed. PMID- 29438211 TI - Seasonal Variation of Epistaxis in Germany. AB - AIM: The goal of the present study was to analyze the seasonal variation of epistaxis in ear, nose, and throat (ENT) practices in Germany in 2016. METHODS: The present study sample included patients who received a first epistaxis diagnosis from physicians in 114 ENT practices in Germany between January 2016 and December 2016. The number of epistaxis patients per practice was calculated for each month. A logistic regression model, adjusted for age and sex, was used to calculate the association between epistaxis diagnosis and the month. RESULTS: The authors found a total of 15,523 patients with epistaxis in 114 ENT practices. Of these patients, 55.9% were men and the mean age was 47.8 +/- 27.6 years. The highest number of epistaxis patients was found in February (14.89 patients per practice) and the lowest in August (7.22 patients per practice). The age- and sex adjusted risk of epistaxis was significantly higher in the months of February (OR = 1.32), March (OR = 1.37), April (OR = 1.34), May (OR = 1.35), and December (OR = 1.33) compared with August. CONCLUSIONS: The presentation of patients with epistaxis at German ENT practices shows a marked seasonal variation with a low in the summer, an increase in fall and winter, and a peak in February, March, and April. PMID- 29438212 TI - Maxillo-Mandibular Reconstruction in Pediatric Patients: How To Do It? AB - Maxillo-mandibular reconstruction in pediatric patients involves particular functional and cosmetic implications. Attention is required for the craniofacial growth over time, involvement of the permanent dentition, facial symmetry, and donor site morbidity. Our aim is to identify the best reconstructive options for maxilla-mandibular defects in children (<18 years) based on our experience with 25 pediatric patients. We believe that reconstruction has to be performed at the same time as resection in pediatric patients. Local flaps should be reserved for cases of maxillary defects because of malignant neoplasms, which ultimately have poor prognosis. In cases of large mandibular defects, radiotherapy is eventually required. When the condition of the soft tissues is poor (because of previous surgery, etc), free flaps potentially represent the best options. Nevertheless, in patients younger than 5 years old (with no damaged tissues), reconstruction with rib grafts should be performed, and the use of titanium plates should be reserved for very select cases (such as temporary reconstruction in toddlers). PMID- 29438213 TI - New Nitric Oxide Donor NCX 1443: Therapeutic Effects on Pulmonary Hypertension in the SAD Mouse Model of Sickle Cell Disease. AB - Nitric oxide (NO) donors may be useful for treating pulmonary hypertension (PH) complicating sickle cell disease (SCD), as endogenous NO is inactivated by hemoglobin released by intravascular hemolysis. Here, we investigated the effects of the new NO donor NCX1443 on PH in transgenic SAD mice, which exhibit mild SCD without severe hemolytic anemia. In SAD and wild-type (WT) mice, the pulmonary pressure response to acute hypoxia was similar and was abolished by 100 mg/kg NCX1443. The level of PH was also similar in SAD and WT mice exposed to chronic hypoxia (9% O2) alone or with SU5416 and was similarly reduced by daily NCX1443 gavage. Compared with WT mice, SAD mice exhibited higher levels of HO-1, endothelial NO synthase, and PDE5 but similar levels of lung cyclic guanosine monophosphate. Cultured pulmonary artery smooth muscle cells from SAD mice grew faster than those from WT mice and had higher PDE5 protein levels. Combining NCX1443 and a PDE5 inhibitor suppressed the growth rate difference between SAD and WT cells and induced a larger reduction in hypoxic PH severity in SAD than in WT mice. By amplifying endogenous protective mechanisms, NCX1443 in combination with PDE5 inhibition may prove useful for treating PH complicating SCD. PMID- 29438214 TI - NcRNAs in CAVD: a review of recent studies. AB - Calcific aortic valve disease (CAVD) is the most common heart valve disorder in human populations. Nevertheless, there are presently no effective means for its prevention and treatment. It is therefore critical to comprehensively define key mechanisms of the disease. A major focus of cardiovascular research has been characterization of how regulation of gene expression maintains healthy physiologic status of the component tissues of the system and how derangements of gene regulation may become pathological. Recently, substantial evidence has emerged, that non-coding RNAs (ncRNAs), which are an enormous and versatile class of regulatory elements, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have roles in onset and prognosis of CAVD. Authors of the present report have therefore here provided a summary of the current understanding of contributions made by ncRNAs major features of CAVD. It is anticipated that this article will serve as a valuable guide to research strategy in this field and may additionally provide both researchers and clinicians with an expanded range of CAVD-associated biomarkers. PMID- 29438215 TI - Rutaecarpine Suppresses Proliferation and Promotes Apoptosis of Human Pulmonary Artery Smooth Muscle Cells in Hypoxia Possibly Through HIF-1alpha-Dependent Pathways. AB - PURPOSE: The aim of this study is to investigate the potential roles of Rutaecarpine (Rut) in hypoxia-induced human pulmonary artery smooth muscle cells (HPASMCs) model. METHODS: HPASMCs were cultured with or without hypoxia followed by Rut administration. Cytotoxicity and cell proliferation were assessed by CCK-8 and Cell counting method. Flow cytometry was used for the measurement of cell apoptosis rates. The mRNA expression of hypoxia-induced factor (HIF)-1alpha and protein levels of HIF-1alpha, p53, p21, erythropoietin, and vascular endothelial growth factor were determined by quantitative real-time polymerase chain reaction and Western blot, respectively. RESULTS: Rut inhibited the proliferation of HPASMCs with IC50 value of 43.5 MUmol.L. Hypoxia significantly increased proliferation and decreased apoptosis in HPASMCs, whereas Rut rescued this phenomenon at the appropriate concentration. Meanwhile, Rut effectively decreased the protein and mRNA expressions of HIF-1alpha. Knockdown of HIF-1alpha expression by small interfering RNA (siRNA) significantly enhanced the proapoptotic effect rather than antiproliferation effect of Rut in HPASMCs. Moreover, Rut simultaneously reduced proliferating cell nuclear antigen protein expression, whereas increased p53 and p21 protein levels. However, no significant difference was observed in the protein levels of vascular endothelial growth factor and erythropoietin. CONCLUSIONS: Our results demonstrated that Rut exerted protective effects on HPASMCs against hypoxia partly through the HIF-1alpha dependent signaling pathway. PMID- 29438216 TI - Open letter to journal editors on: International Consensus Radiochemistry Nomenclature Guidelines. PMID- 29438217 TI - Suppressed thyroglobulin performs better than stimulated thyroglobulin in defining an excellent response in patients with differentiated thyroid cancer. AB - PURPOSE: According to the American Thyroid Association guidelines in 2015, both an unstimulated thyroglobulin (u-Tg) below 0.2 ng/ml and a stimulated thyroglobulin (s-Tg) below 1.0 ng/ml were required along with negative imaging findings to define an excellent response. This study aimed to investigate whether a u-Tg below 0.2 ng/ml coincides with a s-Tg below 1 ng/ml. PATIENTS AND METHODS: A total of 290 patients with nonmetastatic differentiated thyroid cancer were retrospectively evaluated with a median follow-up of 36 months. The levels of s Tg were observed in patients whose u-Tg levels were below 0.2 ng/ml after radioiodine therapy, and risk factors associated with the increase of s-Tg to above 1 ng/ml from below 0.2 ng/ml were analyzed. RESULTS: In total, 52.8% (153/290) of the patients achieved a u-Tg below 0.2 ng/ml 3 months after remnant ablation, most of whom (83.7%, 128/153) also achieved a s-Tg below 1 ng/ml. A total of 25 (16.3%) patients had an increased s-Tg above 1 ng/ml. A comparative analysis showed no significant difference between patients who showed an increase in thyroglobulin from below 0.2 ng/ml to above 1 ng/ml and those who did not. In a subgroup analysis assessing the influence of thyrotropin (thyroxin-stimulating hormone) on s-Tg, we enrolled 43 patients with at least two s-Tg measurements. We found that a higher level of thyroxin-stimulating hormone (118.23+/-30.72 vs. 59.99+/-26.12 uIU/ml) increased the s-Tg in 88.4% patients (P=0.00), which led to more patients (18.6-30.2%) with an increased s-Tg (to above 1 ng/ml) after thyroxin withdrawal. CONCLUSION: Assessment of the level of u-Tg might be a better parameter to use for defining excellent response as u-Tg is more stable, convenient, economical, and is not associated with hypothyroidism as a side effect. PMID- 29438218 TI - Full-endoscopic Uniportal Odontoidectomy and Decompression of the Anterior Cervicomedullary Junction Using the Retropharyngeal Approach. AB - STUDY DESIGN: A study of a series of consecutive full-endoscopic uniportal decompressions of the anterior craniocervical junction with retropharyngeal approach. OBJECTIVE: The aim of this study was to evaluate the direct anterior decompression of the craniocervical junction in patients with bulbomedullary compression using a full-endoscopic uniportal technique via an anterolateral retropharyngeal approach. SUMMARY OF BACKGROUND DATA: Acute or progressive myelopathy may necessitate direct anterior decompression of the craniocervical junction and odontoidectomy. Different techniques with individual advantages and disadvantages can be used. In addition to the gold standard - the transoral approach - there is increasing experience with the endoscopic transnasal technique. Other alternative procedures are also being developed. METHODS: Between 2013 and 2016, eight patients with basilar impression, retrodental pannus, or retrodental infection were operated in the full-endoscopic uniportal technique with a retropharyngeal approach. Anterior decompression of the bulbomedullary junction with odontoidectomy was performed. All patients additionally underwent posterior stabilization. Imaging and clinical data were collected in follow-up examinations for 1 year. RESULTS: The bulbomedullary junction was adequately decompressed. No problems due to swelling of pharyngeal soft tissue occurred. One patient required revision due to secondary bleeding. No other complications were observed. All patients had a good clinical outcome with stable regression of the myelopathy symptoms and/or healing of the infection. The imaging follow-up showed sufficient decompression of bone and soft tissue in all cases. No evidence was found of increasing instability or failure of posterior fusion. CONCLUSION: In the operated patients, the full-endoscopic uniportal surgical technique with anterior retropharyngeal approach was found to be a sufficient and minimally invasive method with the known advantages of an endoscopic procedure under continuous irrigation. It should not be viewed only as competition for other surgical techniques - due to its individual technical parameters, it can also be considered to be an alternative or complementary procedure. LEVEL OF EVIDENCE: 4. PMID- 29438219 TI - Bibliometric Analysis of Gender Authorship Trends and Collaboration Dynamics Over 30 Years of Spine 1985 to 2015. AB - STUDY DESIGN: A bibliometric analysis. OBJECTIVE: The aim of this article was to study bibliometric changes over the last 30 years of Spine. These trends are important regarding academic publication productivity. SUMMARY OF BACKGROUND DATA: Inflation in authorship number and other bibliometric variables has been described in the scientific literature. The issue of author gender is taking on increasing importance, as efforts are being made to close the gender gap. METHODS: From 1985 to 2015, 10-year incremental data for several bibliometric variables were collected, including author gender. Standard bivariate statistical analyses were performed. Trends over time were assessed by the Cochran linear trend. A P < 0.05 was considered statistically significant. RESULTS: Inclusion criteria were met for 1566 manuscripts. The majority of the manuscripts were from North America (51.2%), Europe (25.2%), and Asia (20.8%). The number of manuscripts, authors, countries, pages, and references all increased from 1985 to 2015. There was a slight increase in female first authors over time (17.5% to 18.4%, P = 0.048). There was no gender change over time for corresponding authors (14.3% to 14.0%, P = 0.29). There was an 88% increase in the percentage of female first authors having male corresponding authors (P = 0.00004), and a 123% increase in male first authors having female corresponding authors (P = 0.0002). The 14% to 18% of female authors in Spine is higher than the ~5% female membership of the Scoliosis Research Society and North American Spine Society. CONCLUSION: Manuscripts in Spine over the past 30 years have shown a significant increase in the number of authors, collaborating institutions and countries, printed pages, references, and number of times each manuscript was cited. There has been a mild increase in female first authorship, but none in corresponding authorship. Increases in female authorship will likely require recruitment of more females into the discipline rather than providing females in the discipline with authorship opportunities. LEVEL OF EVIDENCE: N/A. PMID- 29438220 TI - Commentary Regarding "Caregiver Perceptions and Health-Related Quality-of-Life Changes in Cerebral Palsy Patients After Spinal Arthrodesis". PMID- 29438221 TI - Plasma Concentration of Biomarkers Reflecting Endothelial Cell- and Glycocalyx Damage are Increased in Patients With Suspected ST-Elevation Myocardial Infarction Complicated by Cardiogenic Shock. AB - BACKGROUND: Mortality in ST-elevation myocardial infarction (STEMI) patients developing cardiogenic shock (CS) during hospitalization is high. Catecholamines, ischemia, and inflammation (parameters present in CS) affect the endothelium. We hypothesized that plasma level of biomarkers reflecting endothelial damage would be associated with CS and mortality. METHODS: In 96% of 1467 consecutive patients with suspected STEMI, biomarkers reflecting endothelial cell- (soluble thrombomodulin, sTM) and glycocalyx- (syndecan-1) damage were measured on admission. Patients were stratified by CS development or not. CS-Patients were substratified by CS on admission (admission-CS), CS developed in the catheterization laboratory (cath. lab.-CS), or late CS. RESULTS: STEMI patients with admission-CS (n = 85) and cath.lab.-CS (n = 25) had higher levels of sTM and syndecan-1 compared with no-CS patients (n = 1,299). Late CS-patients (n = 58) had higher levels of sTM (median (25th; 75th percentile) 8.8 (7.0; 11.6) vs. 7.4 (6.0; 9.0) ng/mL, P = 0.0004) but not Syndecan-1 (P = 0.26) compared with no-CS patients. sTM was, however, not independently associated with late CS development (OR (95% CI) 1.07 (0.99-1.16), P = 0.09). Patients with the highest level of sTM and syndecan-1 had the highest 30-day mortality (Plogrank<0.0001). However, neither sTM nor Syndecan-1 was independently associated with 30-day mortality (HR (95% CI) sTM: 1.06 (0.996-1.12), P = 0.07; Syndecan-1: 1.04 (0.99-1.08), P = 0.12). CONCLUSION: Patients with suspected STEMI patients and admission CS/cath.lab.-CS had elevated admission levels of sTM and Syndecan-1 compared with no CS patients. Patients developing late CS had higher sTM plasma concentration compared with patients without shock. However, the biomarker levels were not independently associated with late CS and mortality. PMID- 29438222 TI - High CRP Levels After Critical Illness are Associated With an Increased Risk of Rehospitalization. AB - PURPOSE: Chronic inflammation, even at subclinical levels, is associated with adverse long-term outcome. PATIENTS AND METHODS: In this prospective, observational study, 66 critically ill patients surviving to hospital discharge were included. C-reactive protein (CRP) levels were determined at hospital discharge, 1, 2, and 6 weeks after hospital discharge. All the patients were repeatedly screened for adverse events resulting in rehospitalization or death for 1.5 years. RESULTS: After hospital discharge, over two-thirds of the patients exhibited elevated CRP levels (>2.0 mg/L). During the first week, CRP decreased compared with hospital discharge (P < 0.001) but did not change after week 1 (P = 0.67). Age (P = 0.24), surgical status (P = 0.95), or sepsis (P = 0.77) did not influence the CRP course. The latter differed between patients with (n = 15) and without (n = 51) adverse events (P = 0.003). CRP levels of patients without adverse events persistently decreased after hospital discharge (P = 0.03), whereas those of patients with adverse events did not (P = 0.86) but rebounded early. CONCLUSIONS: Plasma CRP levels in critically ill patients decreased during the first week after hospital discharge but remained unchanged during the subsequent 5 weeks. Over two-thirds of the patients exhibited elevated CRP levels compatible with chronic sub-clinical inflammation. Persistently elevated CRP levels after hospital discharge are associated with higher risk of rehospitalization. PMID- 29438223 TI - Knockdown of Tfpi-Anchored Endothelial Cells Exacerbates Lipopolysaccharide Induced Acute Lung Injury via NF-kappaB Signaling Pathway. AB - BACKGROUND: As activation of the coagulation system is both a consequence and contributor to acute lung injury (ALI), pulmonary coagulopathy has become a potential target for therapeutic intervention in ALI patients. We investigated the effects and possible mechanisms of endothelial cell (EC)-anchored tissue factor pathway inhibitor (TFPI) on lipopolysaccharide (LPS)-induced ALI in mice. METHODS: To assess the effect of endothelial cell-anchored TFPI deletion on ALI indices, TFPI knockout (cKO) mice were generated. Mice were instilled by direct intra-tracheal injection LPS for the preparation of an ALI model. Evans Blue Dye (EBD) was injected intravenously 2 h prior to animal sacrifice (48 h post-LPS). Lungs were fixed for histopathology and the prepared tissue was homogenized or used to extract bronchoalveolar lavage fluid (BALF) or detect EBD concentration. TFPI knock down mice with ALI were compared to wild-type (WT) mice with ALI to assess the effect of TFPI on endothelial barrier function and inflammation. RESULTS: TFPI deletion markedly exacerbated LPS histopathological changes in lung, and the LPS changes in protein, EBD extravasation, pro-inflammatory cytokines TNFalpha, IL-1beta and IL-6 in BALF in lung. The number and infiltration of white blood cells (WBCs) from BALF and lung tissue of TFPI cKO mice with LPS-challenged ALI was increased compared to WT mice with LPS challenged ALI. We also found further increased TLR4 and NF-kappaB activation and additional expression of VCAM-1 and reduction of ACE2 expression in TFPI cKO+LPS mice compared with WT+LPS mice. CONCLUSION: Endothelial-specific TFPI deficiency promoted LPS-induced pulmonary inflammation and endothelial barrier permeability possibly via toll-like receptor 4 (TLR4)- mediated NF-kappaB signaling pathway activation.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0. PMID- 29438224 TI - Erlotinib Protects LPS-Induced Acute Lung Injury in Mice by Inhibiting EGFR/TLR4 Signaling Pathway. AB - Epidermal growth factor receptor (EGFR) has been reported to initiate the inflammatory response, but its activation in lipopolysaccharide (LPS)-induced murine model of acute lung injury (ALI) remains unclear. In this study, we investigated the role of EGFR in the LPS-induced murine model of ALI and explored whether its inhibitor erlotinib could affect the progression of lung injury. We first detected the phosphorylated EGFR (p-EGFR)/EGFR ratio at different time points after LPS stimulation, and then different concentrations of erlotinib were used to treat mice at 1 h before LPS stimulation and collected samples at the time point of the highest p-EGFR/EGFR ratio. Lung injury indicators were detected and compared among groups. EGFR and toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-kappaB) signal transduction factors, including p-EGFR, p-AKT, p ERK1/2, p-p65, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL 1beta), were measured with western blot. We found that the mice challenged with LPS suffered from the most serious lung injury at 24 h after LPS stimulation when the p-EGFR/EGFR ratio was relatively the highest. Erlotinib significantly diminished LPS-induced exudation of total cells, neutrophils, and proteins in BALF. Both the ELISA and western blot results showed that erlotinib attenuated the expression of TNF-alpha and IL-1beta in LPS-induced ALI in mice. Inhibition of EGFR by erlotinib downregulated the expression of p-p65 protein level as well as blocked the activation of AKT and ERK1/2 signaling pathway. Taken together, erlotinib alleviated the LPS-induced ALI in a dose-dependent manner by suppressing EGFR activation and downregulating the NF-kappaB-mediated secretion of proinflammatory cytokines. PMID- 29438226 TI - Racial differences in presentations and predictors of acute pain after motor vehicle collision. AB - African Americans experience a greater burden of acute pain than non-Hispanic white individuals across of variety of acute medical conditions, but it is unknown whether this is the case after trauma. We evaluated pain, pain-related characteristics (eg, peritraumatic distress), and analgesic treatment in 2 cohorts of individuals (African American [n = 931] and non-Hispanic white [n = 948]) presenting to the emergency department (ED) after a motor vehicle collision. We performed a propensity-matched analysis (n = 796 in each group) to assess racial differences in acute pain in the ED. In multivariable models conducted within the matched sample, race was associated with moderate to severe axial pain (odds ratio [OR] 3.2; 95% confidence interval [CI]: 2.1-5.0, P < 0.001) and higher average numerical rating scale scores (1.3; 95% CI: 1.1-1.6; P < 0.001). After adjustment for pain and other covariates, non-Hispanic white patients were more likely to receive an opioid analgesic in the ED (OR 2.0; 95% CI: 1.4-3.0, P < 0.001) or at discharge (OR 4.9; 95% CI: 3.4-7.1, P < 0.001) and also less likely to receive an NSAID in the ED (OR 0.54; 95% CI: 0.38-0.78; P = 0.001) or at discharge (0.31; 95% CI: 0.43-0.84). Racial differences in the severity of acute posttraumatic pain after a motor vehicle collision are not explained by factors such as socioeconomic status or crash characteristics. Despite a higher burden of acute pain, African Americans were less likely to receive opioid analgesics and more likely to receive NSAIDs. Further work is needed to understand the relationship between pain severity, disparities in analgesic treatment, and longer term outcomes, such as post-motor vehicle collision chronic pain. PMID- 29438225 TI - Traits associated with central pain augmentation in the Knee Pain In the Community (KPIC) cohort. AB - This study aimed to identify self-report correlates of central pain augmentation in individuals with knee pain. A subset of participants (n = 420) in the Knee Pain and related health In the Community (KPIC) baseline survey undertook pressure pain detection threshold (PPT) assessments. Items measuring specific traits related to central pain mechanisms were selected from the survey based on expert consensus, face validity, item association with underlying constructs measured by originating host questionnaires, adequate targeting, and PPT correlations. Pain distribution was reported on a body manikin. A "central pain mechanisms" factor was sought by factor analysis. Associations of items, the derived factor, and originating questionnaires with PPTs were compared. Eight self-report items measuring traits of anxiety, depression, catastrophizing, neuropathic-like pain, fatigue, sleep disturbance, pain distribution, and cognitive impact were identified as likely indices of central pain mechanisms. Pressure pain detection thresholds were associated with items representing each trait and with their originating scales. Pain distribution classified as "pain below the waist additional to knee pain" was more strongly associated with low PPT than were alternative classifications of pain distribution. A single factor, interpreted as "central pain mechanisms," was identified across the 8 selected items and explained variation in PPT (R = 0.17) better than did any originating scale (R = 0.10-0.13). In conclusion, including representative items within a composite self-report tool might help identify people with centrally augmented knee pain. PMID- 29438227 TI - Sensitization of transient receptor potential vanilloid 4 and increasing its endogenous ligand 5,6-epoxyeicosatrienoic acid in rats with monoiodoacetate induced osteoarthritis. AB - Transient receptor potential vanilloid 4 (TRPV4) receptor modulates pain, and this has been noted in several animal models. However, the involvement of TRPV4 in osteoarthritic (OA) pain remains poorly understood. This study assessed the functional changes in TRPV4 and the expression of its endogenous ligand 5,6 epoxyeicosatrienoic acid (5,6-EET) in a rat monoiodoacetate (MIA)-induced OA pain model (MIA rats). Monoiodoacetate-treated rats showed reduced grip strength as compared to sham-treated rats, and this loss in function could be recovered by the intraarticular administration of a TRPV4 antagonist (HC067047 or GSK2193874). By contrast, the intraarticular administration of the TRPV4 agonist, GSK1016790A, increased the pain-related behaviors in MIA rats but not in sham rats. TRPV4 expression was not increased in knee joints of MIA rats; however, the levels of phosphorylated TRPV4 at Ser824 were increased in dorsal root ganglion neurons. In addition, 5,6-EET was increased in lavage fluids from the knee joints of MIA rats and in meniscectomy-induced OA pain model rats. 5,6-EET and its metabolite were also detected in synovial fluids from patients with OA. In conclusion, TRPV4 was sensitized in the knee joints of MIA rats through phosphorylation in dorsal root ganglion neurons, along with an increase in the levels of its endogenous ligand 5,6-EET. The analgesic effects of the TRPV4 antagonist in the OA pain model rats suggest that TRPV4 may be a potent target for OA pain relief. PMID- 29438228 TI - Antitumor effect of the Newcastle disease viral hemagglutinin-neuraminidase gene is expressed through an oncolytic adenovirus effect in osteosarcoma cells. AB - Newcastle disease virus (NDV) can specifically kill cancer cells and has less toxicity to normal cells. The hemagglutinin-neuraminidase (HN) protein is an important structural protein in NDV pathogenesis and has been postulated as a promising candidate for antitumor therapy. The aim of this study was to investigate the anticancer potential of recombinant adenovirus Ad-HN-PEG3p-E1a. An MTS assay was performed to determine viral proliferation after viral infection, the data showed that the proliferation ability of osteosarcoma cells decreased, whereas there was no significant change in normal hepatic cells. DAPI and Annexin V experiments showed that osteosarcoma cells were killed because of apoptosis, active oxygen content, and augmented mitochondrial membrane potential loss. Caspase Activity Assay Kits were used to detect the caspase-3 activities of the treated OS-732 for increased expression. Western blot analysis showed that cytochrome C increased significantly and apoptosis of the virus was confirmed in tumor cells. In-vivo experiments show that NDV has an inhibitory effect on tumor growth. The recombinant adenovirus, which is composed of a HN protein and progressive increment promoter PEG3p, could inhibit the growth of OS-732 and promote the apoptosis of tumor cells. However, there was no clear relationship with normal cell (L02) apoptosis. PMID- 29438235 TI - Lyin' with a Lion: Deceptive Advertising for "Vitalized Air" Anesthetics. PMID- 29438233 TI - Searching for Quality: Hip Fractures and Type of Anesthesia. PMID- 29438237 TI - Slocum's Cocaine "Surprise" for Johnson Pillmore, M.D. PMID- 29438238 TI - Images in Anesthesiology: Intraoral Lipomas. PMID- 29438236 TI - Eucaine Lactate from H. K. Mulford Company of Philadelphia. PMID- 29438239 TI - From Malaysia and Spain: The Liebig Company Peppers the World with Capsaicin. PMID- 29438241 TI - Does the Brachial Artery Lack Effective Collaterals? PMID- 29438240 TI - "Frozen Air" Anesthetics in St. Louis by Columbia Dental Parlors. PMID- 29438242 TI - In Reply. PMID- 29438243 TI - Effect of Spinal versus General Anesthesia in Study Comparing Three Methods of Using Local Anesthetics to Achieve Post-knee Arthroplasty Pain. PMID- 29438244 TI - In Reply. PMID- 29438245 TI - "A Message in the Bottle". PMID- 29438246 TI - Impact of Weaning from Mechanical Ventilation: The Importance of Pleural Effusions and Their Effect on Pulmonary Vascular Resistance. PMID- 29438248 TI - In Reply. PMID- 29438247 TI - Accurate Quantification of Pleural Effusion and Cofactors Affecting Weaning Failure. PMID- 29438249 TI - One Size Fits All for Stress-dose Steroids. PMID- 29438250 TI - In Reply. PMID- 29438251 TI - Volume Responsiveness Alone Is Not an Indication for Volume Administration! PMID- 29438252 TI - Goal-directed Hemodynamic Therapy: Neither for Anyone, Neither the Same for Everyone. PMID- 29438253 TI - In Reply. PMID- 29438254 TI - Statin Therapy before Cardiac Surgery: Neutral or Detrimental Effects? PMID- 29438255 TI - Neurocritical Care Needs Predictive Scores That Succeed at Predicting Failure as Well as They Predict Success. PMID- 29438256 TI - In Reply. PMID- 29438257 TI - Recent insights into vascular development from studies in zebrafish. AB - PURPOSE OF REVIEW: Zebrafish has provided a powerful platform to study vascular biology over the past 25 years, owing to their distinct advantages for imaging and genetic manipulation. In this review, we summarize recent progress in vascular biology with particular emphasis on vascular development in zebrafish. RECENT FINDINGS: The advent of transcription activator-like effector nuclease and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 genome-editing technologies has dramatically facilitated reverse genetic approaches in zebrafish, as in other models. Here, we highlight recent studies on vascular development in zebrafish which mainly employed forward or reverse genetics combined with high-resolution imaging. These studies have advanced our understanding of diverse areas in vascular biology, including transcriptional regulation of endothelial cell differentiation, endothelial cell signaling during angiogenesis and lymphangiogenesis, vascular bed-specific developmental mechanisms, and perivascular cell recruitment. SUMMARY: The unique attributes of the zebrafish model have allowed critical cellular and molecular insights into fundamental mechanisms of vascular development. Knowledge acquired through recent zebrafish work further advances our understanding of basic mechanisms underlying vascular morphogenesis, maintenance, and homeostasis. Ultimately, insights provided by the zebrafish model will help to understand the genetic, cellular, and molecular underpinnings of human vascular malformations and diseases. PMID- 29438258 TI - Contribution of resident and recruited macrophages in vascular physiology and pathology. AB - PURPOSE OF REVIEW: Macrophages are generally believed to originate entirely from the bone marrow; however, this paradigm is challenged by the discovery of yolk sac-derived resident macrophages. Here, we provide an overview of recent advances in the ontogeny and function of resident macrophages. RECENT FINDINGS: Macrophage precursors from three distinct embryonic sources (yolk sac, fetal liver and bone marrow) are found to colonize various tissues via the blood circulation early during embryogenesis until shortly after birth. They differentiate into distinct long-lived resident macrophages in response to the expression of tissue-specific transcription factors. Resident macrophages are proficient at taking up tissue specific cellular debris and consequently acquire tissue-specific imprints. They are primarily involved in homeostasis but can also support the functionality of various tissues. Under pathological settings, dysregulation of resident macrophages can promote disease progression. SUMMARY: Resident macrophages maintain themselves via in-situ proliferation under steady state. Following injury, bone marrow monocytes can contribute to the resident macrophage pool in adult animal. Embryonically and postnatally derived resident macrophages are similar but not identical: the former are more efficient at efferocytosis, whereas the latter are more competent at host defense. Thus, specific targeting of these two different resident macrophage populations may lead to better therapeutic strategies. PMID- 29438259 TI - Band 3 function and dysfunction in a structural context. AB - PURPOSE OF REVIEW: Current research on the human band 3 glycoprotein, the red cell chloride/bicarbonate anion exchanger (AE1), is highlighted and placed within a structural context. RECENT FINDINGS: The determination of the crystal structure of the membrane domain of human band 3, the founding member of the solute carrier 4 (SLC4) family of bicarbonate transporters, is a major breakthrough toward understanding the mechanism of action of this membrane transport protein, its interaction with partner proteins, and how mutations linked to disease affect its ability to fold and function. SUMMARY: Band 3 contains 14 transmembrane segments arranged in a 7+7 transmembrane inverted repeat topology common to all members of the SLC4 family and the unrelated SLC26 anion transporter family. A functional feature of this fold is the presence of a core and a gate domain: the core domain contains two short transmembrane helices (TM3 and 10) that face each other in the middle of the membrane with the positive N-terminal helix dipoles creating the anion-binding site, whereas the gate domain forms the dimer interface. During transport, the movement of these two domains relative to each other provides the intracellular and extracellular compartments with alternating access to the central anion-binding site. PMID- 29438260 TI - Endothelial cell biology of Endoglin in hereditary hemorrhagic telangiectasia. AB - PURPOSE OF REVIEW: Mutations in the Endoglin (Eng) gene, an auxiliary receptor in the transforming growth factor beta (TGFbeta)-superfamily signaling pathway, are responsible for the human vascular disorder hereditary hemorrhagic telangiectasia (HHT) type 1, characterized in part by blood vessel enlargement. A growing body of work has uncovered an autonomous role for Eng in endothelial cells. We will highlight the influence of Eng on distinct cellular behaviors, such as migration and shape control, which are ultimately important for the assignment of proper blood vessel diameters. RECENT FINDINGS: How endothelial cells establish hierarchically ordered blood vessel trees is one of the outstanding questions in vascular biology. Mutations in components of the TGFbeta-superfamily of signaling molecules disrupt this patterning and cause arteriovenous malformations (AVMs). Eng is a TGFbeta coreceptor enhancing signaling through the type I receptor Alk1. Recent studies identified bone morphogenetic proteins (BMPs) 9 and 10 as the primary ligands for Alk1/Eng. Importantly, Eng potentiated Alk1 pathway activation downstream of hemodynamic forces. New results furthermore revealed how Eng affects endothelial cell migration and cell shape control in response to these forces, thereby providing new avenues for our understanding of AVM cause. SUMMARY: We will discuss the interplay of Eng and hemodynamic forces, such as shear stress, in relation to Alk1 receptor activation. We will furthermore detail how this signaling pathway influences endothelial cell behaviors important for the establishment of hierarchically ordered blood vessel trees. Finally, we will provide an outlook how these insights might help in developing new therapies for the treatment of HHT. PMID- 29438261 TI - Is Nonarteritic Ischemic Optic Neuropathy Due to Choroidal Compression of the Prelaminar Neurovascular Compartment of the Optic Nerve Head? PMID- 29438262 TI - Impact of the Elimination of Consultation Codes on Neuro-Ophthalmology in the United States. PMID- 29438263 TI - Validity and Acceptance of Color Vision Testing on Smartphones. AB - BACKGROUND: Ishihara color plates (ICP) are the most commonly used color vision test (CVT) worldwide. With the advent of new technologies, attempts have been made to streamline the process of CVT. As hardware and software evolve, smartphone-based testing modalities may aid ophthalmologists in performing more efficient ophthalmic examinations. We assess the validity of smartphone color vision testing (CVT) by comparing results using the Eye Handbook (EHB) CVT application with standard Ishihara color plates (ICP). METHODS: Prospective case control study of subjects 18 years and older with visual acuity of 20/100 or better at 14 inches. The study group included patients with any ocular pathology. The color vision deficient (CVD) group was patients who failed more than 2 plates. The control group had no known ocular pathology. CVT was performed with both ICP and EHB under standardized background illuminance. Eleven plates were tested with each modality. Validity of EHB CVT and acceptance of EHB CVT were analyzed. Statistical analyses were performed using Bland-Altman plot with limits of agreement (LOA) at the 95th percentile of differences in score, independent samples t tests with 95% confidence interval (CI), and Pearson chi tests. RESULTS: The Bland-Altman plot showed agreement between correct number of plates in EHB and ICP for the study subjects (bias, -0.25; LOA, -1.92 to 1.42). Agreement was also observed between the correct number of plates in EHB and ICP for the controls (bias, -0.01; LOA, -0.61 to 0.59) and CVD (bias, -0.50; LOA, 4.64 to 3.64) subjects. The sensitivity of EHB was 0.92 (95% CI 0.76-1.07) and the specificity of EHB was 1.00 (95% CI 1.00-1.00). Fifty-nine percent preferred EHB, 12% preferred ICP, and 29% had no preference. CONCLUSIONS: In healthy controls and patients with ocular pathology, there was an agreement of CVT results comparing EHB with ICP. Overall, the majority preferred EHB to ICP. These findings demonstrate that further testing is required to understand and improve the validity of smartphone CVT in subjects with ocular pathology. PMID- 29438264 TI - Multiple Sclerosis: Eyes on the Future. PMID- 29438265 TI - Keep Your Eyes Wide Open: On Visual- and Vision-Related Measurements to Better Understand Multiple Sclerosis Pathophysiology. AB - BACKGROUND: Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is multifaceted. It manifests as acute episodes as well as an accumulative chronic disability; myelin involvement as well as axonal damage; local as well as global effects; and disease load elements as well as compensatory mechanisms. The visual system, with its clear structural organization and relatively direct reflection of damage, may serve as an appropriate model to study MS. METHODS: In recent years, we have witnessed a blossoming in the field of visual measures in MS. Because it is impossible to cover all different aspects of these measures, we chose to focus on several hot topics in MS literature and shed light on them through studies conducted in the visual system. RESULTS: We argue that numerous methods can be used to study axonal and demyelinating aspects of the disease. Although optical coherence tomography and static visual functions better reflect the axonal aspects of the disease, conduction velocity as measured by visual-evoked potential latencies and dynamic visual function mirrors myelin levels. We also posit that the classic disease load parameters cannot be the only means by which we assess a patient's condition. Novel imaging methods such as diffusion tensor imaging and functional magnetic resonance imaging can be used to assess the global effects of local damage on neighboring white matter and compensatory abilities of the brain. CONCLUSIONS: There have been great advances in therapeutic research in MS. However, the stratification of patients according to their prognosis and predictive outcomes in response to treatment is still in its infancy. The many facets of MS make it difficult to piece all the data together into one cohesive conclusion for the individual patient. The visual system, with our ability to assess both structure and function, offers a promising opportunity to study both pathophysiologic mechanisms and novel therapies. PMID- 29438266 TI - New Ways of "Seeing" the Mechanistic Heterogeneity of Multiple Sclerosis Plaque Pathogenesis. AB - BACKGROUND: Over the past few decades, we have witnessed a transformation with respect to the principles and pathobiological underpinnings of multiple sclerosis (MS). From the traditional rubric of MS as an inflammatory and demyelinating disorder restricted to central nervous system (CNS) white matter, our contemporary view has evolved to encompass a broader understanding of the variable mechanisms that contribute to tissue injury, in a disorder now recognized to affect white and grey matter compartments. EVIDENCE ACQUISITION: A constellation of inflammation, ion channel derangements, bioenergetic supply: demand mismatches within the intra-axonal compartment, and alterations in the dynamics and oximetry of blood flow in CNS tissue compartments are observed in MS. These findings have raised questions regarding how histopathologic heterogeneity may influence the diverse clinical spectrum of MS; and, accordingly, how individual treatment needs vary from 1 patient to the next. RESULTS: We are now on new scaffolding in MS; one that promises to translate key clinical and laboratory observations to the application of emerging patient centered therapies. CONCLUSIONS: This review highlights our current knowledge of the underlying disease mechanisms in MS, explores the inflammatory and neurodegenerative consequences of tissue damage, and examines physiologic factors that contribute to bioenergetic homeostasis within the CNS of affected patients. PMID- 29438267 TI - Clinical significance of visually equivocal amyloid PET findings from the Alzheimer's Disease Neuroimaging Initiative cohort. AB - To evaluate the clinical and imaging characteristics of patients with visually equivocal amyloid PET images, patients from the Alzheimer's Disease Neuroimaging Initiative cohort who had fluorine-18-florbetapir PET scans both at baseline and 24 months were selected. Five nuclear medicine physicians visually assessed the PET images and classified them as either positive or negative. Images not reaching a majority agreement were classified as equivocal. Among a total of 379 patients, the number of patients in each fluorine-18-florbetapir PET negative/equivocal/positive categories was 218 (57.5%), 32 (8.4%), and 129 (34.0%). Eight to 9% of patients with normal cognition (N=12/141), mild cognitive impairment (N=20/214), and no Alzheimer's disease (N=0/24) showed equivocal PET finding for each. In negative/equivocal/positive groups, positive cerebrospinal fluid Abeta1-42 was observed in 25.7, 81.5, and 98.3%, respectively. Baseline standardized uptake value ratios of fluorine-18-florbetapir PET were 0.75+/-0.05, 0.86+/-0.09, and 1.01+/-0.09, respectively [F(2, 376)=603.547; P<0.001]. After 24 months of follow-up, the standardized uptake value ratios increased by 0.81+/ 2.62, 2.81+/-2.90, and 2.17+/-3.66%, respectively [F(2, 376)=7.905, P<0.05 vs. the negative group]. Among mild cognitive impairment patients, the equivocal group showed a more rapid decline in glucose metabolism than the negative group [5.52+/-5.36 vs. 0.67+/-4.45; F(2, 122)=9.028, P<0.01]. 8.4% of the patients in this study showed a visually equivocal result of amyloid PET. These patients showed a moderate amount of amyloid accumulation and a rapid rate of accumulation. PMID- 29438268 TI - Endocytosis of Red Blood Cell Microparticles by Pulmonary Endothelial Cells is Mediated By Rab5. AB - Microparticles are submicron vesicles shed from aging erythrocytes as a characteristic feature of the red blood cell (RBC) storage lesion. Exposure of pulmonary endothelial cells to RBC-derived microparticles promotes an inflammatory response, but the mechanisms underlying microparticle-induced endothelial cell activation are poorly understood. In the present study, cultured murine lung endothelial cells (MLECs) were treated with microparticles isolated from aged murine packed RBCs or vehicle. Microparticle-treated cells demonstrated increased expression of the adhesion molecules ICAM and E-selectin, as well as the cytokine, IL-6. To identify mechanisms that mediate these effects of microparticles on MLECs, cells were treated with microparticles covalently bound to carboxyfluorescein succinimidyl ester (CFSE) and cellular uptake of microparticles was quantified via flow cytometry. Compared with controls, there was a greater proportion of CFSE-positive MLECs from 15 min up to 24 h, suggesting endocytosis of the microparticles by endothelial cells. Colocalization of microparticles with lysosomes was observed via immunofluorescence, indicating endocytosis and endolysosomal trafficking. This process was inhibited by endocytosis inhibitors. SiRNA knockdown of Rab5 signaling protein in endothelial cells resulted in impaired microparticle uptake as compared with nonsense siRNA treated cells, as well as an attenuation of the inflammatory response to microparticle treatment. Taken together, these data suggest that endocytosis of RBC-derived microparticles by lung endothelial cells results in endothelial cell activation. This response seems to be mediated, in part, by the Rab5 signaling protein. PMID- 29438270 TI - Women's Health Initiative and rate of hormone use: a study that impacted a whole generation. PMID- 29438269 TI - The effects of stair climbing on arterial stiffness, blood pressure, and leg strength in postmenopausal women with stage 2 hypertension. AB - OBJECTIVE: Menopause is accompanied by a progressive arterial stiffening associated with increases in blood pressure (BP) and decline in muscular function. It is crucial to prevent or reduce the negative effects of menopause on vascular and muscular function by implementing appropriate lifestyle interventions, such as exercise training. We examined the effects of a stair climbing (SC) regimen on arterial stiffness (pulse wave velocity [PWV]), BP, and leg strength in postmenopausal women with stage 2 hypertension. METHODS: Using a parallel experimental design, participants were randomly assigned to either SC (n = 21) or nonexercising control group (n = 20) for 12 weeks. Participants in the SC group trained 4 d/wk, climbing 192 steps 2 to 5 times/d. Participants' brachial-to-ankle PWV (baPWV), BP, and leg strength were measured at baseline and after 12 weeks of their assigned intervention. RESULTS: There was a significant group by time interaction (P < 0.05) for baPWV, and systolic BP (SBP) and diastolic BP (DBP) which significantly decreased (P < 0.05), and leg strength which significantly increased (P < 0.05) after SC compared with no changes in the control. The changes in baPWV were correlated with changes in SBP (r = 0.66, P < 0.05) and leg strength (r = -0.47, P < 0.05). CONCLUSIONS: SC led to reductions in arterial stiffness, BP, and increases in leg strength in stage 2 hypertensive postmenopausal women. The decrease in arterial stiffness partially explained the improvements in SBP and leg strength. SC may be an effective intervention in the prevention and treatment of menopause/aging-related vascular complications and muscle weakness. PMID- 29438271 TI - Efficacy of misoprostol before diagnostic hysteroscopy in postmenopausal women: a randomized clinical trial. AB - OBJECTIVE: To evaluate pain and determine the efficacy of misoprostol, compared with placebo, for postmenopausal women before diagnostic hysteroscopy. METHODS: This randomized, double-blind, placebo-controlled clinical trial included 158 postmenopausal women who received either 200 MUg of misoprostol or placebo through the vaginal route before diagnostic hysteroscopy (79 women/group). The primary outcome was pain assessment (presence and intensity) during the four steps of hysteroscopy: cervical grasping with a Pozzi tenaculum forceps immediately before hysteroscopy, during hysteroscopy, during performance of the endometrial biopsy, and postprocedure. The secondary outcomes were duration of the procedure, need for additional cervical dilatation, complications, and adverse effects. RESULTS: Mean ages of the women were 62 +/- 8.2 years and 60 +/- 7.3 years in the misoprostol and placebo groups, respectively. Abnormal bleeding (misoprostol group, 45.6%; placebo, 43%) and endometrial thickening (54.4% in the misoprostol group and 57% in the placebo group) were the most common indications for the examination in both groups (P = 0.49). There was no significant difference between groups in the pain intensity of the four steps of the procedure. The duration of hysteroscopy was similar in both groups (misoprostol group, 2.5 +/- 2.7 minutes; placebo, 2.1 +/- 1.6 minutes; P = 0.43). Additional cervical dilatation was needed in 11 women in the misoprostol group versus 9 in the placebo group (P = 0.63). In both groups, there was no significant difference in terms of complications. Adverse effects were reported by 25.3% of women using misoprostol (vaginal bleeding, 11.3%; cramping, 12.6%; diarrhea, 2.5%; 1 woman reported both vaginal bleeding and cramping). In the placebo group, only 2.5% of women developed adverse effects (P < 0.0001). CONCLUSION: Misoprostol does not reduce pain intensity, the duration of the procedure, or need for additional cervical dilatation, and causes more adverse effects when used in postmenopausal women before diagnostic hysteroscopy. PMID- 29438272 TI - Cardiovascular risk after withdrawal of hormone therapy. PMID- 29438273 TI - Novel Phage Display-Derived Anti-Abrin Antibodies Confer Post-Exposure Protection against Abrin Intoxication. AB - Abrin toxin is a type 2 ribosome inactivating glycoprotein isolated from the seeds of Abrus precatorius (jequirity pea). Owing to its high toxicity, relative ease of purification and accessibility, it is considered a biological threat agent. To date, there is no effective post-exposure treatment for abrin poisoning and passive immunization remains the most effective therapy. However, the effectiveness of anti-abrin monoclonal antibodies for post-exposure therapy following abrin intoxication has not been demonstrated. The aim of this study was to isolate high affinity anti-abrin antibodies that possess potent toxin neutralization capabilities. An immune scFv phage-display library was constructed from an abrin-immunized rabbit and a panel of antibodies (six directed against the A subunit of abrin and four against the B subunit) was isolated and expressed as scFv-Fc antibodies. By pair-wise analysis, we found that these antibodies target five distinct epitopes on the surface of abrin and that antibodies against all these sites can bind the toxin simultaneously. Several of these antibodies (namely, RB9, RB10, RB28 and RB30) conferred high protection against pulmonary intoxication of mice, when administered six hours post exposure to a lethal dose of abrin. The data presented in this study demonstrate for the first time the efficacy of monoclonal antibodies in treatment of mice after pulmonary intoxication with abrin and promote the use of these antibodies, one or several, for post-exposure treatment of abrin intoxication. PMID- 29438274 TI - Activity of Salvia dolomitica and Salvia somalensis Essential Oils against Bacteria, Molds and Yeasts. AB - Essential oils (EOs) from Salvia dolomitica and Salvia somalensis, widely employed in the cosmetic and perfume industry, were analyzed for composition and tested against bacterial and fungal pathogens isolated from clinical and environmental specimens. The analyses were carried out against Staphylococcus aureus, Staphylococcus pseudointermedius, Pseudomonas aeruginosa, Escherichia coli, Streptococcus canis, Streptococcus pyogenes, Klebsiella pneumoniae, Proteus mirabilis, Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes, Aspergillus niger, Aspergillus flavus, Candida albicans, Candida krusei, Mucor sp. and Trichothecium roseum. Both EOs showed similar percentages of total monoterpenes and sesquiterpene hydrocarbons. The main constituents were 1,8 cineole and beta-caryophyllene in S. dolomitica and bornyl acetate and camphor in S. somalensis. The selected EOs have no relevant antifungal or antibacterial activities if compared to conventional drugs. PMID- 29438275 TI - Hydrogel-Based Fluorescent Dual pH and Oxygen Sensors Loaded in 96-Well Plates for High-Throughput Cell Metabolism Studies. AB - In this study, we developed fluorescent dual pH and oxygen sensors loaded in multi-well plates for in-situ and high-throughput monitoring of oxygen respiration and extracellular acidification during microbial cell growth for understanding metabolism. Biocompatible PHEMA-co-PAM materials were used as the hydrogel matrix. A polymerizable oxygen probe (OS2) derived from PtTFPP and a polymerizable pH probe (S2) derived from fluorescein were chemically conjugated into the matrix to solve the problem of the probe leaching from the matrix. Gels were allowed to cure directly on the bottom of 96-well plates at room-temperature via redox polymerization. The influence of matrix's composition on the sensing behaviors was investigated to optimize hydrogels with enough robustness for repeatable use with good sensitivity. Responses of the dual sensing hydrogels to dissolved oxygen (DO) and pH were studied. These dual oxygen-pH sensing plates were successfully used for microbial cell-based screening assays, which are based on the measurement of fluorescence intensity changes induced by cellular oxygen consumption and pH changes during microbial growth. This method may provide a real-time monitoring of cellular respiration, acidification, and a rapid kinetic assessment of multiple samples for cell viability as well as high-throughput drug screening. All of these assays can be carried out by a conventional plate reader. PMID- 29438276 TI - Printing Smart Designs of Light Emitting Devices with Maintained Textile Properties. AB - To maintain typical textile properties, smart designs of light emitting devices are printed directly onto textile substrates. A first approach shows improved designs for alternating current powder electroluminescence (ACPEL) devices. A configuration with the following build-up, starting from the textile substrate, was applied using the screen printing technique: silver (10 um)/barium titanate (10 um)/zinc-oxide (10 um) and poly(3,4 ethylenedioxythiophene)poly(styrenesulfonate) (10 um). Textile properties such as flexibility, drapability and air permeability are preserved by implementing a pixel-like design of the printed layers. Another route is the application of organic light emitting devices (OLEDs) fabricated out of following layers, also starting from the textile substrate: polyurethane or acrylate (10-20 um) as smoothing layer/silver (200 nm)/poly(3,4 ethylenedioxythiophene)poly(styrenesulfonate) (35 nm)/super yellow (80 nm)/calcium/aluminum (12/17 nm). Their very thin nm-range layer thickness, preserving the flexibility and drapability of the substrate, and their low working voltage, makes these devices the possible future in light-emitting wearables. PMID- 29438277 TI - A response to the Comment on Tomaskova et al. Mortality in Miners with Coal Workers' Pneumoconiosis in the Czech Republic in the Period 1992-2013. Int. J. Environ. Res. Public Health, 2017, 14, 269 by the Author Mei Yong. AB - At first, we would like to thank Mei Yong for the comments on our article Mortality in Miners with Coal-Workers' Pneumoconiosis in the Czech Republic in the Period 1992-2013 [...]. PMID- 29438278 TI - Towards Efficient Wireless Body Area Network Using Two-Way Relay Cooperation. AB - The fabrication of lightweight, ultra-thin, low power and intelligent body-borne sensors leads to novel advances in wireless body area networks (WBANs). Depending on the placement of the nodes, it is characterized as in/on body WBAN; thus, the channel is largely affected by body posture, clothing, muscle movement, body temperature and climatic conditions. The energy resources are limited and it is not feasible to replace the sensor's battery frequently. In order to keep the sensor in working condition, the channel resources should be reserved. The lifetime of the sensor is very crucial and it highly depends on transmission among sensor nodes and energy consumption. The reliability and energy efficiency in WBAN applications play a vital role. In this paper, the analytical expressions for energy efficiency (EE) and packet error rate (PER) are formulated for two-way relay cooperative communication. The results depict better reliability and efficiency compared to direct and one-way relay communication. The effective performance range of direct vs. cooperative communication is separated by a threshold distance. Based on EE calculations, an optimal packet size is observed that provides maximum efficiency over a certain link length. A smart and energy efficient system is articulated that utilizes all three communication modes, namely direct, one-way relay and two-way relay, as the direct link performs better for a certain range, but the cooperative communication gives better results for increased distance in terms of EE. The efficacy of the proposed hybrid scheme is also demonstrated over a practical quasi-static channel. Furthermore, link length extension and diversity is achieved by joint network channel (JNC) coding the cooperative link. PMID- 29438280 TI - Synthesis of Graphite Oxide with Different Surface Oxygen Contents Assisted Microwave Radiation. AB - Graphite oxide is synthesized via oxidation reaction using oxidant compounds that have lattice defects by the incorporation of unlike functional groups. Herein, we report the synthesis of the graphite oxide with diverse surface oxygen content through three (B, C, D) different modified versions of the Hummers method assisted microwave radiation compared with the conventional graphite oxide sample obtained by Hummers method (A). These methods allow not only the production of graphite oxide but also reduced graphene oxide, without undergoing chemical, thermal, or mechanical reduction steps. The values obtained of C/O ratio were ~2, 3.4, and ~8.5 for methodologies C, B, and D, respectively, indicating the presence of graphite oxide and reduced graphene oxide, according to X-ray photoelectron spectroscopy. Raman spectroscopy of method D shows the fewest structural defects compared to the other methodologies. The results obtained suggest that the permanganate ion produces reducing species during graphite oxidation. The generation of these species is attributed to a reversible reaction between the permanganate ion with pi electrons, ions, and radicals produced after treatment with microwave radiation. PMID- 29438281 TI - IFN-Gamma-Dependent and Independent Mechanisms of CD4+ Memory T Cell-Mediated Protection from Listeria Infection. AB - While CD8+ memory T cells can promote long-lived protection from secondary exposure to intracellular pathogens, less is known regarding the direct protective mechanisms of CD4+ T cells. We utilized a prime/boost model in which mice are initially exposed to an acutely infecting strain of lymphocytic choriomeningitis virus (LCMV), followed by a heterologous rechallenge with Listeria monocytogenes recombinantly expressing the MHC Class II-restricted LCMV epitope, GP61-80 (Lm-gp61). We found that heterologous Lm-gp61 rechallenge resulted in robust activation of CD4+ memory T cells and that they were required for rapid bacterial clearance. We further assessed the relative roles of TNF and IFNgamma in the direct anti-bacterial function of CD4+ memory T cells. We found that disruption of TNF resulted in a complete loss of protection mediated by CD4+ memory T cells, whereas disruption of IFNgamma signaling to macrophages results in only a partial loss of protection. The protective effect mediated by CD4+ T cells corresponded to the rapid accumulation of pro-inflammatory macrophages in the spleen and an altered inflammatory environment in vivo. Overall, we conclude that protection mediated by CD4+ memory T cells from heterologous Listeria challenge is most directly dependent on TNF, whereas IFNgamma only plays a minor role. PMID- 29438279 TI - Recent Updates on Treatment of Ocular Microbial Infections by Stem Cell Therapy: A Review. AB - Ocular microbial infection has emerged as a major public health crisis during the past two decades. A variety of causative agents can cause ocular microbial infections; which are characterized by persistent and destructive inflammation of the ocular tissue; progressive visual disturbance; and may result in loss of visual function in patients if early and effective treatments are not received. The conventional therapeutic approaches to treat vision impairment and blindness resulting from microbial infections involve antimicrobial therapy to eliminate the offending pathogens or in severe cases; by surgical methods and retinal prosthesis replacing of the infected area. In cases where there is concurrent inflammation, once infection is controlled, anti-inflammatory agents are indicated to reduce ocular damage from inflammation which ensues. Despite advances in medical research; progress in the control of ocular microbial infections remains slow. The varying level of ocular tissue recovery in individuals and the incomplete visual functional restoration indicate the chief limitations of current strategies. The development of a more extensive therapy is needed to help in healing to regain vision in patients. Stem cells are multipotent stromal cells that can give rise to a vast variety of cell types following proper differentiation protocol. Stem cell therapy shows promise in reducing inflammation and repairing tissue damage on the eye caused by microbial infections by its ability to modulate immune response and promote tissue regeneration. This article reviews a selected list of common infectious agents affecting the eye; which include fungi; viruses; parasites and bacteria with the aim of discussing the current antimicrobial treatments and the associated therapeutic challenges. We also provide recent updates of the advances in stem cells studies on sepsis therapy as a suggestion of optimum treatment regime for ocular microbial infections. PMID- 29438282 TI - Toll-Like Receptors: Regulators of the Immune Response in the Human Gut. AB - Toll-like receptors (TLRs) are powerful molecular regulators by which the immune system may "sense" the environment and protect the host from pathogens or endogenous threats. In mammalian cells, several TLRs were identified with a tissue and cell type-specific distribution. Understanding the functions of specific TLRs is crucial for the development and discovery of compounds useful to maintaining or re-establishing homeostasis in the gastrointestinal tract (GIT). Due to their relevance in regulating the inflammatory response in the GIT, we will focus here on TLR2, TLR4, and TLR5. In particular, we describe (a) the molecular pathways activated by the stimulation of these receptors with their known bacterial ligands; (b) the non-bacterial ligands known to interact directly with TLR2 and TLR4 and their soluble forms. The scope of this minireview is to highlight the importance of bacterial and non-bacterial compounds in affecting the gut immune functions via the activation of the TLRs. PMID- 29438283 TI - New Insights into the Tumor Microenvironment Utilizing Protein Array Technology. AB - The tumor microenvironment (TME) is a considerably heterogeneous niche, which is created by tumor cells, the surrounding tumor stroma, blood vessels, infiltrating immune cells, and a variety of associated stromal cells. Intercellular communication within this niche is driven by soluble proteins synthesized by local tumor and stromal cells and include chemokines, growth factors, interferons, interleukins, and angiogenic factors. The interaction of tumor cells with their microenvironment is essential for tumorigenesis, tumor progression, growth, and metastasis, and resistance to drug therapy. Protein arrays enable the parallel detection of hundreds of proteins in a small amount of biological sample. Recent data have demonstrated that the application of protein arrays may yield valuable information regarding the structure and functional mechanisms of the TME. In this review, we will discuss protein array technologies and their applications in TME analysis to discern pathways involved in promoting the tumorigenic phenotype. PMID- 29438284 TI - Enhancing the Bioconversion of Azelaic Acid to Its Derivatives by Response Surface Methodology. AB - Azelaic acid (AzA) and its derivatives have been known to be effective in the treatment of acne and various cutaneous hyperpigmentary disorders. The esterification of azelaic acid with lauryl alcohol (LA) to produce dilaurylazelate using immobilized lipase B from Candida antarctica (Novozym 435) is reported. Response surface methodology was selected to optimize the reaction conditions. A well-fitting quadratic polynomial regression model for the acid conversion was established with regards to several parameters, including reaction time and temperature, enzyme amount, and substrate molar ratios. The regression equation obtained by the central composite design of RSM predicted that the optimal reaction conditions included a reaction time of 360 min, 0.14 g of enzyme, a reaction temperature of 46 degrees C, and a molar ratio of substrates of 1:4.1. The results from the model were in good agreement with the experimental data and were within the experimental range (R2 of 0.9732).The inhibition zone can be seen at dilaurylazelate ester with diameter 9.0+/-0.1 mm activities against Staphylococcus epidermidis S273. The normal fibroblasts cell line (3T3) was used to assess the cytotoxicity activity of AzA and AzA derivative, which is dilaurylazelate ester. The comparison of the IC50 (50% inhibition of cell viability) value for AzA and AzA derivative was demonstrated. The IC50 value for AzA was 85.28 MUg/mL, whereas the IC50 value for AzA derivative was more than 100 MUg/mL. The 3T3 cell was still able to survive without any sign of toxicity from the AzA derivative; thus, it was proven to be non-toxic in this MTT assay when compared with AzA. PMID- 29438285 TI - MicroRNA-31 and MicroRNA-155 Are Overexpressed in Ulcerative Colitis and Regulate IL-13 Signaling by Targeting Interleukin 13 Receptor alpha-1. AB - Interleukin-13 (IL-13) is an important Type 2 T helper (Th2) cytokine, controlling biological functions in epithelium and has been linked to asthma, atopic dermatitis and ulcerative colitis (UC). Interleukin-13 signals through IL 13 receptor alpha-1 (IL13RA1 (gene) and IL13Ralpha1 (protein)), a receptor that can be regulated by microRNAs (miRs). MicroRNAs are small non-coding single stranded RNAs with a role in several pathologies. However, their relevance in the pathophysiology of UC, a chronic inflammatory condition of the colonic mucosa, is poorly characterised. Here, we determined the expression of IL13Ralpha1 in UC, its potential regulation by miRs and the subsequent effect on IL-13 signalling. Inflamed mucosa of UC patients showed decreased mRNA and protein expression of IL13RA1 when compared to healthy controls. We show that miR-31 and miR-155 are upregulated in inflamed UC mucosa and that both directly target the 3' untranslated region of IL13RA1 mRNA. Transfection of miR-31 and miR-155 mimics reduced the expression of IL13RA1 mRNA and protein, and blocked IL-13-dependent phosphorylation of signal transducer and activator of transcription 6 (STAT6) in HT-29 cells, a gut epithelium cell line. Interleukin-13 activation of suppressor of cytokine signaling 1 (SOCS1) and eotaxin-3 (CCL26) expression was also diminished. MicroRNA-31/microRNA-155 mimics also downregulated IL13RA1 in ex vivo human inflamed UC biopsies. We propose that miR-31 and miR-155 have an important role in limiting IL-13 signalling in UC disease. PMID- 29438286 TI - HDPE/Chitosan Blends Modified with Organobentonite Synthesized with Quaternary Ammonium Salt Impregnated Chitosan. AB - In this study, blends based on a high density polyethylene (HDPE) and chitosan (CS) were successfully prepared by melt processing, in a laboratory internal mixer. The CS biopolymer content effect (up to maximum of 40%), and, the addition of bentonite clay modified with quaternary ammonium salt (CTAB) impregnated chitosan as a compatibilizing agent, on the properties of the blends was analyzed by Fourier transform-infrared spectroscopy (FT-IR), wide angle X-ray diffraction (WAXD), differential scanning calorimetry (DSC), thermogravimetric analyses (TG), tensile strength, and scanning electron microscopy (SEM). The use of clay modified with CTAB impregnated chitosan, employing a method developed here, improved the compatibility of HDPE with chitosan, and therefore the thermal and some of the mechanical properties were enhanced, making HDPE/chitosan blends suitable candidates for food packaging. It was possible to obtain products of synthetic polymer, HDPE, with natural polymer, chitosan, using a method very used industrially, with acceptable and more friendly properties to the environment, when compared to conventional synthetic polymers. In addition, due to the possibility of impregnated chitosan with quaternary ammonium salt exhibit higher antibacterial activity than neat chitosan, the HDPE/chitosan/organobentonite blends may be potentially applied in food containers to favor the preservation of food for a longer time in comparison to conventional materials. PMID- 29438287 TI - Serum Lycopene Concentrations and Associations with Clinical Outcomes in a Cohort of Maternal-Infant Dyads. AB - Oxidative stress has been associated with adverse neonatal outcomes, and many carotenoids, including lycopene, potentially have antioxidant properties. The objective of this analysis was to explore the associations between serum lycopene concentrations, including lycopene isomers, and maternal-newborn outcomes. Maternal and cord blood samples were collected in 180 mother-infant pairs. Serum of total lycopene as well as the cis- and trans-isomers concentrations were measured using HPLC (High Performance Liquid Chromatography). Descriptive statistics were calculated; Spearman coefficients were used to assess correlations between maternal and cord concentrations. The relationship between lycopene concentration and outcomes were evaluated with linear and logistic regression models, with adjustment for relevant confounders. A p <= 0.05 was considered statistically significant. Maternal and cord serum lycopene concentrations were positively correlated for total lycopene (r = 0.30, p < 0.0001), cis-lycopene (r = 0.29, p = 0.0002); and trans-lycopene (r = 0.32, p < 0.0001). Maternal concentrations of cis-lycopene were significantly lower in mothers whose infants developed respiratory distress syndrome compared to those who did not (0.336 +/- 0.171 vs. 0.445 +/- 0.238 umol/L, p = 0.04) and also in mothers whose babies were admitted to the newborn intensive care unit compared to those who were not (0.380 +/- 0.202 vs. 0.458 +/- 0.244 umol/L, p = 0.04). Conversely, cord concentrations of trans-lycopene were significantly higher in infants who developed RDS (Respiratory Distress Syndrome) (0.023 +/- 0.012 vs. 0.016 +/- 0.012, p = 0.007 for RDS vs. no RDS), and a similar pattern was seen NICU admission (0.023 +/- 0.016 vs. 0.015 +/- 0.009 umol/L for NICU (Newborn Intensive Care Unit) admission vs. no NICU admission, p = 0.007). Maternal concentrations of total and cis-lycopene were positively associated with infant birth weight, length and head circumference after adjustment for relevant confounders. As serum carotenoids, including lycopene, are modifiable by diet, future research determining the clinical impact of these compounds is warranted. PMID- 29438288 TI - Probiotic Properties of Exopolysaccharide-Producing Lactobacillus Strains Isolated from Tempoyak. AB - Tempoyak is a functional Malaysian food (an acid-fermented condiment) which is produced from the pulp of the durian (Durio zibethinus) fruit. The current study aimed to isolate and identify potential exopolysaccharide (EPS)-producing Lactobacillus strains from tempoyak for potential use as probiotics. Seven isolates (DUR2, DUR4, DUR5, DUR8, DUR12, DUR18, and DUR20) out of 44 were able to produce EPS, and exhibited resistance to acid and bile salt compared to the reference strains Lactobacillus rhmnosus (ATCC53103) and L. plantarum (ATCC8014). The seven isolated strains belonged to five different species-L. plantarum, L. fermentum, L. crispatus, L. reuteri, and L. pentosus-which were identified using API 50 CHL and 16S rRNA gene sequences (Polymerase chain reaction, PCR - based). The seven strains displayed different ability to produce EPS (100-850 mg/L). Isolates exhibited a high survivability to acid (pH 3.0), bile salts (0.3%), and gastrointestinal tract model (<70%). Results showed that the auto-aggregation and cell surface hydrophobicity ranged from 39.98% to 60.09% and 50.80% to 80.53%, respectively, whereas, the highest co-aggregation value (66.44%) was observed by L. fermentum (DUR8) with Pseudomonas aeruginosa. The isolates showed good inhibitory activity against tested pathogens, high antioxidant activity (32.29% to 73.36%), and good ability to reduce cholesterol (22.55% to 75.15%). Thus, the seven tested strains have value as probiotics. PMID- 29438289 TI - Qualitative Analysis of E-Liquid Emissions as a Function of Flavor Additives Using Two Aerosol Capture Methods. AB - This work investigates emissions sampling methods employed for qualitative identification of compounds in e-liquids and their resultant aerosols to assess what capture methods may be sufficient to identify harmful and potentially harmful constituents present. Three popular e-liquid flavors (cinnamon, mango, vanilla) were analyzed using qualitative gas chromatography-mass spectrometry (GC MS) in the un-puffed state. Each liquid was also machine-puffed under realistic use flow rate conditions and emissions were captured using two techniques: filter pads and methanol impingers. GC-MS analysis was conducted on the emissions captured using both techniques from all three e-liquids. The e-liquid GC-MS analysis resulted in positive identification of 13 compounds from the cinnamon flavor e-liquid, 31 from mango, and 19 from vanilla, including a number of compounds observed in all e-liquid experiments. Nineteen compounds were observed in emissions which were not present in the un-puffed e-liquid. Qualitative GC-MS analysis of the emissions samples identify compounds observed in all three samples: e-liquid, impinge, and filter pads, and each subset thereof. A limited number of compounds were observed in emissions captured with impingers, but were not observed in emissions captured using filter pads; a larger number of compounds were observed on emissions collected from the filter pads, but not those captured with impingers. It is demonstrated that sampling methods have different sampling efficiencies and some compounds might be missed using only one method. It is recommended to investigate filter pads, impingers, thermal desorption tubes, and solvent extraction resins to establish robust sampling methods for emissions testing of e-cigarette emissions. PMID- 29438291 TI - The Effect of N-Terminal Domain Removal towards the Biochemical and Structural Features of a Thermotolerant Lipase from an Antarctic Pseudomonas sp. Strain AMS3. AB - Lipase plays an important role in industrial and biotechnological applications. Lipases have been subject to modification at the N and C terminals, allowing better understanding of lipase stability and the discovery of novel properties. A thermotolerant lipase has been isolated from Antarctic Pseudomonas sp. The purified Antarctic AMS3 lipase (native) was found to be stable across a broad range of temperatures and pH levels. The lipase has a partial Glutathione-S transferase type C (GST-C) domain at the N-terminal not found in other lipases. To understand the influence of N-terminal GST-C domain on the biochemical and structural features of the native lipase, the deletion of the GST-C domain was carried out. The truncated protein was successfully expressed in E. coli BL21(DE3). The molecular weight of truncated AMS3 lipase was approximately ~45 kDa. The number of truncated AMS3 lipase purification folds was higher than native lipase. Various mono and divalent metal ions increased the activity of the AMS3 lipase. The truncated AMS3 lipase demonstrated a similarly broad temperature range, with the pH profile exhibiting higher activity under alkaline conditions. The purified lipase showed a substrate preference for a long carbon chain substrate. In addition, the enzyme activity in organic solvents was enhanced, especially for toluene, Dimethylsulfoxide (DMSO), chloroform and xylene. Molecular simulation revealed that the truncated lipase had increased structural compactness and rigidity as compared to native lipase. Removal of the N terminal GST-C generally improved the lipase biochemical characteristics. This enzyme may be utilized for industrial purposes. PMID- 29438290 TI - Mining and Development of Novel SSR Markers Using Next Generation Sequencing (NGS) Data in Plants. AB - Microsatellites, or simple sequence repeats (SSRs), are one of the most informative and multi-purpose genetic markers exploited in plant functional genomics. However, the discovery of SSRs and development using traditional methods are laborious, time-consuming, and costly. Recently, the availability of high-throughput sequencing technologies has enabled researchers to identify a substantial number of microsatellites at less cost and effort than traditional approaches. Illumina is a noteworthy transcriptome sequencing technology that is currently used in SSR marker development. Although 454 pyrosequencing datasets can be used for SSR development, this type of sequencing is no longer supported. This review aims to present an overview of the next generation sequencing, with a focus on the efficient use of de novo transcriptome sequencing (RNA-Seq) and related tools for mining and development of microsatellites in plants. PMID- 29438292 TI - Diversity and Antimicrobial Resistance Genotypes in Non-Typhoidal Salmonella Isolates from Poultry Farms in Uganda. AB - Non-typhoidal Salmonella (NTS) are foodborne pathogens of global public health significance. The aim of this study was to subtype a collection of 85 NTS originating from poultry farms in Uganda, and to evaluate a subgroup of phenotypically resistant isolates for common antimicrobial resistance genes and associated integrons. All isolates were subtyped by pulsed-field gel electrophoresis (PFGE). Phenotypically resistant isolates (n = 54) were screened by PCR for the most relevant AMR genes corresponding to their phenotypic resistance pattern, and all 54 isolates were screened by PCR for the presence of integron class 1 and 2 encoding genes. These genes are known to commonly encode resistance to ampicillin, tetracycline, ciprofloxacin, trimethoprim, sulfonamide and chloramphenicol. PFGE revealed 15 pulsotypes representing 11 serotypes from 75 isolates, as 10 were non-typable. Thirty one (57.4%) of the 54 resistant isolates carried at least one of the seven genes (blaTEM-1,cmlA, tetA, qnrS,sul1,dhfrI,dhfrVII) identified by PCR and six (11%) carried class 1 integrons. This study has shown that a diversity of NTS-clones are present in Ugandan poultry farm settings, while at the same time similar NTS-clones occur in different farms and areas. The presence of resistance genes to important antimicrobials used in human and veterinary medicine has been demonstrated, hence the need to strengthen strategies to combat antimicrobial resistance at all levels. PMID- 29438293 TI - Neuroprotective Effects of neuroEPO Using an In Vitro Model of Stroke. AB - Erythropoietin (EPO) is a glycoprotein initially identified as a hormone synthesized and secreted by the kidney that regulates erythropoiesis. EPO, and a group of its derivatives, are being evaluated as possible neuroprotective agents in cerebral ischemia. The objective of this study, using an in vitro model, was to determine how neuroEPO-which is a variant of EPO with a low sialic acid content-protects neurons from the toxic action of glutamate. Primary neuronal cultures were obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a medium containing 100 uM glutamate for 15 min. After this time, a new medium containing 100 ng of neuroEPO/mL was added. Morphological cell change was assessed by phase-contrast microscopy. Oxidative stress was analysed by measuring antioxidant and oxidant activity. After 24 h, the treatment with 100 ng of neuroEPO/mL showed a significant (p < 0.01) decrease in mortality, compared to cells treated with glutamate alone. neuroEPO treatment decreased mortality and tended to reproduce the morphological characteristics of the control. The oxidative stress induced by glutamate is reduced after neuroEPO treatment. These results confirm that neuroEPO has a protective effect against neuronal damage induced by excitotoxicity, improving antioxidant activity in the neuron, and protecting it from oxidative stress. PMID- 29438294 TI - First Diagnosed Case of Camelpox Virus in Israel. AB - An outbreak of a disease in camels with skin lesions was reported in Israel during 2016. To identify the etiological agent of this illness, we employed a multidisciplinary diagnostic approach. Transmission electron microscopy (TEM) analysis of lesion material revealed the presence of an orthopox-like virus, based on its characteristic brick shape. The virus from the skin lesions successfully infected chorioallantoic membranes and induced cytopathic effect in Vero cells, which were subsequently positively stained by an orthopox-specific antibody. The definite identification of the virus was accomplished by two independent qPCR, one of which was developed in this study, followed by sequencing of several regions of the viral genome. The qPCR and sequencing results confirmed the presence of camelpox virus (CMLV), and indicated that it is different from the previously annotated CMLV sequence available from GenBank. This is the first reported case of CMLV in Israel, and the first description of the isolated CMLV subtype. PMID- 29438295 TI - Patient-Centered Communication. AB - As the population ages, morbidity and mortality associated with chronic disease will increase. Some patient-centered improvements have been made in health care services, but optimal health has not been fully realized. Only when pharmacists have a holistic understanding of an individual patient, including their experience of illness and medication, can they effectively assess appropriateness, safety, efficacy, and adherence to medications and develop realistic treatment plans. When patients are involved in their care, they are better able to manage complex chronic conditions by understanding and adhering to their plan of care. Pharmacists can enable patients to participate fully using patient-centered communication. There are relatively few published articles on patient-centered communication specific to pharmacists, but the Calgary-Cambridge guide and Four Habits model have applicability to pharmacy practice. The Patient Centered Communication Tools (PaCT), created for use in pharmacy education and loosely based on the Four Habits model, can assist pharmacists in developing their patient-centered communication skills. Lastly, best practices for patient centered communication in pharmacy practice are described. PMID- 29438296 TI - Natural Occurrence of Nivalenol, Deoxynivalenol, and Deoxynivalenol-3-Glucoside in Polish Winter Wheat. AB - The presence of mycotoxins in cereal grain is a very important food safety factor. The occurrence of "masked" mycotoxins has been intensively investigated in recent years. In this study, the occurrence of nivalenol, deoxynivalenol-3 glucoside, and deoxynivalenol in 92 samples of winter wheat from Polish cultivars was determined. The frequency of the occurrence of deoxynivalenol and nivalenol in the samples was 83% and 70%, respectively. The average content of the analytes was: for deoxynivalenol 140.2 ug/kg (10.5-1265.4 ug/kg), for nivalenol 35.0 ug/kg (5.1-372.5 ug/kg). Deoxynivalenol-3-glucoside, the formation of which is connected with the biotransformation pathway in plants, was present in 27% of tested wheat samples; its average content was 41.9 ug/kg (15.8-137.5 ug/kg). The relative content of deoxynivalenol-3-glucoside (DON-3G) compared to deoxynivalenol (DON) in positive samples was 4-37%. Despite the high frequency of occurrence of these mycotoxins, the quality of wheat from the 2016 season was good. The maximum content of DON, as defined in EU regulations (1250 ug/kg), was exceeded in only one sample. Nevertheless, the presence of a glycosidic derivative of deoxynivalenol can increase the risk to food safety, as it can be hydrolyzed by intestinal microflora. PMID- 29438297 TI - Fenofibrate Nanocrystals Embedded in Oral Strip-Films for Bioavailability Enhancement. AB - The aim of the present study was to make a fenofibrate (FNB) nanocrystal (NC) by wet media milling, characterizations and formulates into oral strip-films (OSFs). Mechanical properties, redispersion study, and solid-state characterizations results suggested that reduction of drug crystal size at nanoscale and incorporation into OSFs does not affect the solid-state properties of the drug. In vitro dissolution kinetics showed enhanced dissolution rate was easily manipulated by changing the thickness of the OSF. In situ UV-imaging was used to monitor drug dissolution qualitatively and quantitatively in real time. Results confirm that the intrinsic dissolution rates and surface drug concentration measured with this device were in agreement with the USP-IV dissolution profiles. In vivo pharmacokinetics in rabbits showed a significant difference in the pharmacokinetics parameter (1.4 fold increase bioavailability) of FNB NC-loaded OSFs as compared to the marketed formulation "Tricor" and as-received (pristine) drug. This approach of drug nanocrystallization and incorporation into OSFs may have significant applications in cost-effective tools for bioavailability enhancement of FNB. PMID- 29438298 TI - The Effects of the WNT-Signaling Modulators BIO and PKF118-310 on the Chondrogenic Differentiation of Human Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs) are multipotent cells, mainly from bone marrow, and an ideal source of cells in bone and cartilage tissue engineering. A study of the chondrogenic differentiation of MSCs is of particular interest for MSCs-based cartilage regeneration. In this study, we aimed to optimize the conditions for the chrondogenic differentiation of MSCs by regulating WNT signaling using the small molecule WNT inhibitor PKF118-310 and activator BIO. Human mesenchymal stem cells (hMSCs) were isolated from bone marrow aspirates and cultured in hMSCs proliferation medium. Pellet culture was subsequently established for three dimensional chondrogenic differentiation of 5 weeks. WNT signaling was increased by the small molecule glycogen synthase kinase-3 inhibitor 6-bromoindirubin-3 oxim (BIO) and decreased by the WNT inhibitor PKF118-310 (PKF). The effects of BIO and PKF on the chondrogenesis of hMSCs was examined by real-time PCR, histological methods, and ELISA. We found that activation of canonical WNT signaling by BIO significantly downregulated the expression of cartilage-specific genes SOX9, COL2A1, and ACAN, and matrix metalloproteinase genes MMP1/3/9/13, but increased ADAMTS 4/5. Inhibition of WNT signaling by PKF increased the expression of SOX9, COL2A1, ACAN, and MMP9, but decreased MMP13 and ADAMTS4/5. In addition, a high level of WNT signaling induced the expression of hypertrophic markers COL10A1, ALPL, and RUNX2, the dedifferentiation marker COL1A1, and glycolysis genes GULT1 and PGK1. Deposition of glycosaminoglycan (GAG) and collagen type II in the pellet matrix was significantly lost in the BIO-treated group and increased in the PKF-treated group. The protein level of COL10A1 was also highly induced in the BIO group. Interestingly, BIO decreased the number of apoptotic cells while PKF significantly induced apoptosis during chondrogenesis. The natural WNT antagonist DKK1 and the protein level of MMP1 in the pellet culture medium were decreased after PKF treatment. All of these chondrogenic effects appeared to be mediated through the canonical WNT signaling pathway, since the target gene Axin2 and other WNT members, such as TCF4 and beta-catenin, were upregulated by BIO and downregulated by PKF, respectively, and BIO induced nuclear translocation of beta-catenin while PKF inhibited beta-catenin translocation into the nucleus. We concluded that addition of BIO to a chondrogenic medium of hMSCs resulted in a loss of cartilage formation, while PKF induced chondrogenic differentiation and cartilage matrix deposition and inhibited hypertrophic differentiation. However, BIO promoted cell survival by inhibiting apoptosis while PKF induced cell apoptosis. This result indicates that either an overexpression or overinhibition of WNT signaling to some extent causes harmful effects on chondrogenic differentiation. Cartilage tissue engineering could benefit from the adjustment of the critical level of WNT signaling during chondrogenesis of hMSC. PMID- 29438299 TI - The Antioxidant and Xanthine Oxidase Inhibitory Activity of Plumeria rubra Flowers. AB - Plumeria rubra Linn of the family Apocynaceae is locally known in Malaysia as "Kemboja". It has been used by local traditional medicine practitioners for the treatment of arthritis-related disease. The LCMS/MS analysis of the methanol extract of flowers (PR-ME) showed that it contains 3-O-caffeyolquinic acid, 5 caffeoquinic acid, 1,3-dicaffeoquinic acid, chlorogenic acid, citric acid, 3,3-di O-methylellagic acid, kaempferol-3-O-glucoside, kaempferol-3-rutinoside, kaempferol, quercetin 3-O-alpha-l-arabinopyranoside, quercetin, quinic acid and rutin. The flower PR-ME contained high amounts of phenol and flavonoid at 184.632 mg GAE/g and 203.2.2 mg QE/g, respectively. It also exhibited the highest DPPH, FRAP, metal chelating, hydrogen peroxide, nitric oxide superoxide radical scavenging activity. Similarly, the XO inhibitory activity in vitro assay possesses the highest inhibition effects at an IC50 = 23.91 MUg/mL. There was no mortality or signs of toxicity in rats at a dose of 4 g/kg body weight. The administration of the flower PR-ME at doses of 400 mg/kg to the rats significantly reduced serum uric acid 43.77%. Similarly, the XO activity in the liver was significantly inhibited by flower PR-ME at doses of 400 mg/kg. These results confirm that the flower PR-ME of P. rubra contains active phytochemical compounds as detected in LCMS/MS that contribute to the inhibition of XO activity in vitro and in vivo in reducing acid uric level in serum and simultaneously scavenging the free radical to reduce the oxidative stress. PMID- 29438300 TI - Compact Hip-Force Sensor for a Gait-Assistance Exoskeleton System. AB - In this paper, we propose a compact force sensor system for a hip-mounted exoskeleton for seniors with difficulties in walking due to muscle weakness. It senses and monitors the delivered force and power of the exoskeleton for motion control and taking urgent safety action. Two FSR (force-sensitive resistors) sensors are used to measure the assistance force when the user is walking. The sensor system directly measures the interaction force between the exoskeleton and the lower limb of the user instead of a previously reported force-sensing method, which estimated the hip assistance force from the current of the motor and lookup tables. Furthermore, the sensor system has the advantage of generating torque in the walking-assistant actuator based on directly measuring the hip-assistance force. Thus, the gait-assistance exoskeleton system can control the delivered power and torque to the user. The force sensing structure is designed to decouple the force caused by hip motion from other directional forces to the sensor so as to only measure that force. We confirmed that the hip-assistance force could be measured with the proposed prototype compact force sensor attached to a thigh frame through an experiment with a real system. PMID- 29438301 TI - Ultrasensitive Determination of Malathion Using Acetylcholinesterase Immobilized on Chitosan-Functionalized Magnetic Iron Nanoparticles. AB - A renewable, disposable, low cost, and sensitive sensor for the detection of organophosphorus pesticides was constructed by immobilizing the acetylcholinesterase enzyme (AChE), via glutaraldehyde, on magnetic iron nanoparticles (Fe3O4) previously synthesized and functionalized with chitosan (CS). The sensor was denoted AChE/CS/Fe3O4. The magnetic nanoparticles were characterized by Fourier transform infrared spectroscopy and transmission electron microscopy. Acetylthiocholine (ATCh) was incubated with AChE/CS/Fe3O4 and attached to a screen-printed electrode using a magnet. The oxidation of thiocholine (from ATCh hydrolysis) was monitored at an applied potential of +0.5 V vs. Ag/AgCl(KClsat) in 0.1 mol L-1 phosphate buffer solution (pH 7.5) as the supporting electrolyte. A mixture of the pesticide malathion and ATCh was investigated using the same procedure, and the results were compared and expressed as inhibition percentages. For determination of malathion, the proposed sensor presented a linear response in the range from 0.5 to 20 nmol L-1 (R = 0.9942). The limits of detection (LOD) and quantification (LOQ) were 0.3 and 0.8 nmol L-1, respectively. Real samples were also investigated, with recovery values of 96.0% and 108.3% obtained for tomato and pond water samples, respectively. The proposed sensor is a feasible option for malathion detection, offering a linear response, good sensitivity, and a low detection limit. PMID- 29438302 TI - Synthesis, Characterization, and Performance Evaluation of Sulfur-Containing Diphenylamines Based on Intramolecular Synergism. AB - To obtain novel structural antioxidants that have different antioxidant mechanisms, four 2-(alkylthio)-N-(4-(phenylamino)phenyl)acetamides 2a-d as dual functional antioxidants are designed, synthesized, and confirmed by 1H-NMR, FTIR, MS, and elemental analysis. The antioxidant behavior of compounds 2a-d as additives of base oil triisodecyl trimellitate (TIDTM) is evaluated by non isothermal and isothermal DSC analyses. The results showed all compounds can greatly increase the incipient oxidation temperature (IOT) and oxidation induction time (OIT) of TIDTM, especially, compound 2c exhibited an OIT value of 72.5 min at 230 degrees C, which is almost 28 times the length of TIDTM. Moreover, compounds 2a-d do not affect the tribological performance of TIDTM. The mechanism of antioxidants involved an intramolecular synergism are proposed. This work demonstrates compound 2c can be used as a novel potential antioxidant additive of TIDTM; in addition, it would inspire the emergence of highly potent antioxidants with different antioxidant mechanisms. PMID- 29438304 TI - Protective Performance of Polyaniline-Sulfosalicylic Acid/Epoxy Coating for 5083 Aluminum. AB - Epoxy coatings incorporating different content of sulfosalicylic acid doped polyaniline (PANI-SSA) have been investigated for corrosion protection of 5083 aluminum alloy in 3.5% NaCl solution. The performance of the coatings is studied using a combination of electrochemical impedance spectroscopy (EIS), open circuit potential (OCP), gravimetric tests, adhesion tests, scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The results demonstrate that the content of PANI-SSA not only affects the coating compactness and the transportation of aggressive medium, but also has a significant influence on the based aluminum. The coating with 2 wt. % PANI-SSA exhibits the best corrosion inhibition due to its good protective properties and the formation of a complete PANI-SSA induced oxide layer. PMID- 29438306 TI - Comparative Analysis of Chemical Composition, Antioxidant Activity and Quantitative Characterization of Some Phenolic Compounds in Selected Herbs and Spices in Different Solvent Extraction Systems. AB - This study evaluated the efficacy of various organic solvents (80% acetone, 80% ethanol, 80% methanol) and distilled water for extracting antioxidant phenolic compounds from turmeric, curry leaf, torch ginger and lemon grass extracts. They were analyzed regarding the total phenol and flavonoid contents, antioxidant activity and concentration of some phenolic compounds. Antioxidant activity was determined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay and the ferric reducing antioxidant power (FRAP) assay. Quantification of phenolic compounds was carried out using high-performance liquid chromatography (HPLC). All the extracts possessed antioxidant activity, however, the different solvents showed different efficiencies in the extraction of phenolic compounds. Turmeric showed the highest DPPH values (67.83-13.78%) and FRAP (84.9-2.3 mg quercetin/g freeze-dried crude extract), followed by curry leaf, torch ginger and lemon grass. While 80% acetone was shown to be the most efficient solvent for the extraction of total phenolic compounds from turmeric, torch ginger and lemon grass (221.68, 98.10 and 28.19 mg GA/g freeze dried crude extract, respectively), for the recovery of phenolic compounds from curry leaf (92.23 mg GA/g freeze dried crude extract), 80% ethanol was the most appropriate solvent. Results of HPLC revealed that the amount of phenolic compounds varied depending on the types of solvents used. PMID- 29438307 TI - Thermally Optimized Polarization-Maintaining Photonic Crystal Fiber and Its FOG Application. AB - In this paper, we propose a small-diameter polarization-maintaining solid-core photonic crystal fiber. The coating diameter, cladding diameter and other key parameters relating to the thermal properties were studied. Based on the optimized parameters, a fiber with a Shupe constant 15% lower than commercial photonic crystal fibers (PCFs) was fabricated, and the transmission loss was lower than 2 dB/km. The superior thermal stability of our fiber design was proven through both simulation and measurement. Using the small-diameter fiber, a split high precision fiber optic gyro (FOG) prototype was fabricated. The bias stability of the FOG was 0.0023 degrees /h, the random walk was 0.0003 degrees / h , and the scale factor error was less than 1 ppm. Throughout a temperature variation ranging from -40 to 60 degrees C, the bias stability was less than 0.02 degrees /h without temperature compensation which is notably better than FOG with panda fiber. As a result, the PCF FOG is a promising choice for high precision FOG applications. PMID- 29438305 TI - The Crosstalk between Nrf2 and Inflammasomes. AB - The Nrf2 (nuclear factor E2-related factor or nuclear factor (erythroid-derived 2)-like 2) transcription factor is a key player in cytoprotection and activated in stress conditions caused by reactive oxygen species (ROS) or electrophiles. Inflammasomes represent central regulators of inflammation. Upon detection of various stress factors, assembly of the inflamasome protein complex results in activation and secretion of proinflammatory cytokines. In addition, inflammasome activation causes pyroptosis, a lytic form of cell death, which supports inflammation. There is growing evidence of a crosstalk between the Nrf2 and inflammasome pathways at different levels. For example, Nrf2 activating compounds inhibit inflammasomes and consequently inflammation. This review summarizes what is known about the complex and predominantly antagonistic relationship of both stress-activated pathways. PMID- 29438303 TI - Cytoskeletons in the Closet-Subversion in Alphaherpesvirus Infections. AB - Actin filaments, microtubules and intermediate filaments form the cytoskeleton of vertebrate cells. Involved in maintaining cell integrity and structure, facilitating cargo and vesicle transport, remodelling surface structures and motility, the cytoskeleton is necessary for the successful life of a cell. Because of the broad range of functions these filaments are involved in, they are common targets for viral pathogens, including the alphaherpesviruses. Human tropic alphaherpesviruses are prevalent pathogens carried by more than half of the world's population; comprising herpes simplex virus (types 1 and 2) and varicella-zoster virus, these viruses are characterised by their ability to establish latency in sensory neurons. This review will discuss the known mechanisms involved in subversion of and transport via the cytoskeleton during alphaherpesvirus infections, focusing on protein-protein interactions and pathways that have recently been identified. Studies on related alphaherpesviruses whose primary host is not human, along with comparisons to more distantly related beta and gammaherpesviruses, are also presented in this review. The need to decipher as-yet-unknown mechanisms exploited by viruses to hijack cytoskeletal components-to reveal the hidden cytoskeletons in the closet will also be addressed. PMID- 29438308 TI - Diversification of Secondary Metabolite Biosynthetic Gene Clusters Coincides with Lineage Divergence in Streptomyces. AB - We have identified Streptomyces sister-taxa which share a recent common ancestor and nearly identical small subunit (SSU) rRNA gene sequences, but inhabit distinct geographic ranges demarcated by latitude and have sufficient genomic divergence to represent distinct species. Here, we explore the evolutionary dynamics of secondary metabolite biosynthetic gene clusters (SMGCs) following lineage divergence of these sister-taxa. These sister-taxa strains contained 310 distinct SMGCs belonging to 22 different gene cluster classes. While there was broad conservation of these 22 gene cluster classes among the genomes analyzed, each individual genome harbored a different number of gene clusters within each class. A total of nine SMGCs were conserved across nearly all strains, but the majority (57%) of SMGCs were strain-specific. We show that while each individual genome has a unique combination of SMGCs, this diversity displays lineage-level modularity. Overall, the northern-derived (NDR) clade had more SMGCs than the southern-derived (SDR) clade (40.7 +/- 3.9 and 33.8 +/- 3.9, mean and S.D., respectively). This difference in SMGC content corresponded with differences in the number of predicted open reading frames (ORFs) per genome (7775 +/- 196 and 7093 +/- 205, mean and S.D., respectively) such that the ratio of SMGC:ORF did not differ between sister-taxa genomes. We show that changes in SMGC diversity between the sister-taxa were driven primarily by gene acquisition and deletion events, and these changes were associated with an overall change in genome size which accompanied lineage divergence. PMID- 29438309 TI - Progress and Challenges of Ultrasonic Testing for Stress in Remanufacturing Laser Cladding Coating. AB - Stress in laser cladding coating is an important factor affecting the safe operation of remanufacturing components. Ultrasonic testing has become a popular approach in the nondestructive evaluation of stress, because it has the advantages of safety, nondestructiveness, and online detection. This paper provides a review of ultrasonic testing for stress in remanufacturing laser cladding coating. It summarizes the recent research outcomes on ultrasonic testing for stress, and analyzes the mechanism of ultrasonic testing for stress. Remanufacturing laser cladding coating shows typical anisotropic behaviors. The ultrasonic testing signal in laser cladding coating is influenced by many complex factors, such as microstructure, defect, temperature, and surface roughness, among others. At present, ultrasonic testing for stress in laser cladding coating can only be done roughly. This paper discusses the active mechanism of micro/macro factors in the reliability of stress measurement, as well as the impact of stress measurement on the quality and safety of remanufacturing components. Based on the discussion, this paper proposes strategies to nondestructively, rapidly, and accurately measure stress in remanufacturing laser cladding coating. PMID- 29438310 TI - Stability of Porcine Epidemic Diarrhea Virus on Fomite Materials at Different Temperatures. AB - Indirect transmission of porcine epidemic diarrhea virus (PEDV) ensues when susceptible animals contact PEDV-contaminated fomite materials. Although the survival of PEDV under various pHs and temperatures has been studied, virus stability on different fomite surfaces under varying temperature conditions has not been explored. Hence, we evaluated the survival of PEDV on inanimate objects routinely used on swine farms such as styrofoam, rubber, plastic, coveralls, and other equipment. The titer of infectious PEDV at 4 degrees C decreased by only 1 to 2 log during the first 5 days, and the virus was recoverable for up to 15 days on Styrofoam, aluminum, Tyvek(r) coverall, cloth, and plastic. However, viral titers decreased precipitously when stored at room temperature; no virus was detectable after one day on all materials tested. A more sensitive immunoplaque assay was able to detect virus from Styrofoam, metal, and plastic at 20 days post application, representing a 3-log loss of input virus on fomite materials. Recovery of infectious PEDV from Tyvek(r) coverall and rubber was above detection limit at 20 days. Our findings indicate that the type of fomite material and temperatures impact PEDV stability, which is important in understanding the nuances of indirect transmission and epidemiology of PEDV. PMID- 29438311 TI - Effects of Dried Blood Spot Storage on Lipidomic Analysis. AB - During the lipidomic analysis of red blood cell membranes, the distribution and percentage ratios of the fatty acids are measured. Since fatty acids are the key constituents of cell membranes, by evaluating their quantities it possible to understand the general health of the cells and to obtain health indicators of the whole organism. However, because the analysis is precise, it is necessary to ensure that the blood does not undergo significant variations between the point of collection and analysis. The composition of the blood may vary dramatically weeks after collection, hence, here an attempt is made to stabilize these complex matrixes using antioxidants deposited on the paper cards on which the blood itself is deposited. PMID- 29438312 TI - Thermal Decomposition Behavior of Hydroxytyrosol (HT) in Nitrogen Atmosphere Based on TG-FTIR Methods. AB - The thermal decomposition behavior of olive hydroxytyrosol (HT) was first studied using thermogravimetry (TG). Cracked chemical bond and evolved gas analysis during the thermal decomposition process of HT were also investigated using thermogravimetry coupled with infrared spectroscopy (TG-FTIR). Thermogravimetry Differential thermogravimetry (TG-DTG) curves revealed that the thermal decomposition of HT began at 262.8 degrees C and ended at 409.7 degrees C with a main mass loss. It was demonstrated that a high heating rate (over 20 K.min-1) restrained the thermal decomposition of HT, resulting in an obvious thermal hysteresis. Furthermore, a thermal decomposition kinetics investigation of HT indicated that the non-isothermal decomposition mechanism was one-dimensional diffusion (D1), integral form g(x) = x2, and differential form f(x) = 1/(2x). The four combined approaches were employed to calculate the activation energy (E = 128.50 kJ.mol-1) and Arrhenius preexponential factor (ln A = 24.39 min-1). In addition, a tentative mechanism of HT thermal decomposition was further developed. The results provide a theoretical reference for the potential thermal stability of HT. PMID- 29438313 TI - Polysiloxane/Polystyrene Thermo-Responsive and Self-Healing Polymer Network via Lewis Acid-Lewis Base Pair Formation. AB - The use of thermo-reversible Lewis Pair (LP) interactions in the formation of transient polymer networks is still greatly underexplored. In this work, we describe the synthesis and characterization of polydimethylsiloxane/polystyrene (PDMS/PS) blends that form dynamic Lewis acid-Lewis base adducts resulting in reversible crosslinks. Linear PS containing 10 mol % of di-2-thienylboryl pendant groups randomly distributed was obtained in a two-step one-pot functionalization reaction from silyl-functionalized PS, while ditelechelic PDMS with pyridyl groups at the chain-termini was directly obtained via thiol-ene "click" chemistry from commercially available vinyl-terminated PDMS. The resulting soft gels, formed after mixing solutions containing the PDMS and PS polymers, behave at room temperature as elastomeric solid-like materials with very high viscosity (47,300 Pa.s). We applied rheological measurements to study the thermal and time dependence of the viscoelastic moduli, and also assessed the reprocessability and self-healing behavior of the dry gel. PMID- 29438314 TI - Reduction of Hexavalent Chromium and Detection of Chromate Reductase (ChrR) in Stenotrophomonas maltophilia. AB - An Gram negative strain of S. maltophilia, indigenous to environments contaminated by Cr(VI) and identified by biochemical methods and 16S rRNA gene analysis, reduced chromate by 100%, 98-99% and 92% at concentrations in the 10 70, 80-300, and 500 mg/L range, respectively at pH 7 and temperature 37 degrees C. Increasing concentrations of Cr(VI) in the medium lowered the growth rate but could not be directly correlated with the amount of Cr(VI) reduced. The strain also exhibited multiple resistance to antibiotics and tolerance and resistance to various heavy metals (Ni, Zn and Cu), with the exception of Hg. Hexavalent chromium reduction was mainly associated with the soluble fraction of the cell evaluated with crude cell-free extracts. A protein of molecular weight around 25 kDa was detected on SDS-PAGE gel depending on the concentration of hexavalent chromium in the medium (0, 100 and 500 mg/L). In silico analysis in this contribution, revealed the presence of the chromate reductase gene ChrR in S. maltophilia, evidenced through a fragment of around 468 bp obtained experimentally. High Cr(VI) concentration resistance and high Cr(VI) reducing ability of the strain make it a suitable candidate for bioremediation. PMID- 29438316 TI - Regulation of Programmed Death Ligand 1 (PD-L1) Expression in Breast Cancer Cell Lines In Vitro and in Immunodeficient and Humanized Tumor Mice. AB - Programmed death ligand 1 (PD-L1) expression is an efficient strategy of tumor cells to escape immunological eradiation. However, only little is known about the factors that affect the cellular expression levels. Here we assessed the PD-L1 expression on different breast cancer cell lines under standard in vitro culture conditions and as a function of Epirubicin or Paclitaxel treatment. Moreover, we evaluated the expression in immunodeficient tumor mice as well as in humanized tumor mice (i.e., in the presence of a human immune system). We found highest PD L1 levels in JIMT-1 and MDA-MB-231 cells. Epirubicin treatment caused a decrease and Paclitaxel treatment an increased PD-L1 expression in MDA-MB-231 cells. In addition, we identified nuclear PD-L1 in MDA-MB-231 cells. All in vivo transplanted breast cancer cell lines downregulated PD-L1 expression compared to their in vitro counterpart. Neither the gene copy number nor the presence of human immune system in humanized tumor mice had an effect on the PD-L1 content. We demonstrate that the degree of PD-L1 expression amongst breast cancer cell lines varies considerably. In addition, cytotoxic treatments and other extrinsic parameters differentially affect the expression. Hence, further investigations including in vivo evaluations are necessary to understand PD-L1 regulation for advanced breast cancer stratification. PMID- 29438315 TI - Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors. AB - BACKGROUND: Heat shock protein 90 (HSP90) is a well-known target for cancer therapy. In a previous work, some of us have reported a series of 3-aryl naphtho[2,3-d]isoxazole-4,9-diones as inhibitors of HSP90. METHODS: In the present work, various compounds with new chromenopyridinone and thiochromenopyridinone scaffolds were synthesized as potential HSP90 inhibitors. Their binding affinity to HSP90 was studied in vitro. Selected compounds (5 and 8) were further studied in various tumor cell lines regarding their potential to cause cell growth inhibition, alter the cell cycle profile, inhibit proliferation, and induce apoptosis. Their effect on HSP90 client protein levels was also confirmed in two cell lines. Finally, the antitumor activity of compound 8 was studied in A431 squamous cell carcinoma xenografts in nude mice. RESULTS: Our results indicated that treatment with compounds 5 and 8 decreased the proliferation of tumor cell lines and compound 8 induced apoptosis. In addition, these two compounds were able to downregulate selected proteins known as "clients" of HSP90. Finally, treatment of xenografted mice with compound 5 resulted in a considerable dose-dependent inhibition of tumor growth. CONCLUSIONS: Our results show that two new compounds with a chromenopyridinone and thiochromenopyridinone scaffold are promising putative HSP90 inhibitors causing tumor cell growth inhibition. PMID- 29438317 TI - Polynomial Phase Estimation Based on Adaptive Short-Time Fourier Transform. AB - Polynomial phase signals (PPSs) have numerous applications in many fields including radar, sonar, geophysics, and radio communication systems. Therefore, estimation of PPS coefficients is very important. In this paper, a novel approach for PPS parameters estimation based on adaptive short-time Fourier transform (ASTFT), called the PPS-ASTFT estimator, is proposed. Using the PPS-ASTFT estimator, both one-dimensional and multi-dimensional searches and error propagation problems, which widely exist in PPSs field, are avoided. In the proposed algorithm, the instantaneous frequency (IF) is estimated by S-transform (ST), which can preserve information on signal phase and provide a variable resolution similar to the wavelet transform (WT). The width of the ASTFT analysis window is equal to the local stationary length, which is measured by the instantaneous frequency gradient (IFG). The IFG is calculated by the principal component analysis (PCA), which is robust to the noise. Moreover, to improve estimation accuracy, a refinement strategy is presented to estimate signal parameters. Since the PPS-ASTFT avoids parameter search, the proposed algorithm can be computed in a reasonable amount of time. The estimation performance, computational cost, and implementation of the PPS-ASTFT are also analyzed. The conducted numerical simulations support our theoretical results and demonstrate an excellent statistical performance of the proposed algorithm. PMID- 29438318 TI - Touch Locating and Stretch Sensing Studies of Conductive Hydrogels with Applications to Soft Robots. AB - Soft robots possess great potential in environmental adaptations, while their environmental sensing abilities are critical. Conductive hydrogels have been suggested to possess sensing abilities. However, their application in soft robots is lacking. In this work, we fabricated a soft and stretchable gel material, introduced its sensing mechanisms, and developed a measurement setup. Both experimental and simulation studies indicate strong nonlinearity of touch locating on a square touch panel with Cartesian coordinates. To simplify the touch locating, we proposed a touch locating system based on round touch panels with polar coordinates. Mathematical calculations and finite element method (FEM) simulations showed that in this system the locating of a touch point was only determined by its polar radius. This was verified by experimental studies. As a resistor, a gel strip's resistance increases with stretching. To demonstrate their applications on soft robots, a 3D printed three-fingered soft gripper was employed with gel strips attached. During finger bending for rod grasping, the resistances of the gel strips increased, indicating stretching of the soft material. Furthermore, the strain and stress of a gel strip increased with a decrease of the rod diameter. These studies advance the application of conductive hydrogels on soft robots. PMID- 29438319 TI - A Holistic Approach to the Evaluation of the Montado Ecosystem Using Proximal Sensors. AB - The Montado is a silvo-pastoral system characterized by open canopy woodlands with natural or cultivated grassland in the undercover and grazing animals. The aims of this study were to present several proximal sensors with potential to monitor relevant variables in the complex montado ecosystem and demonstrate their application in a case study designed to evaluate the effect of trees on the pasture. This work uses data collected between March and June 2016, at peak of dryland pasture production under typical Mediterranean conditions, in twenty four sampling points, half under tree canopy (UTC) and half outside tree canopy (OTC). Correlations were established between pasture biomass and capacitance measured by a commercial probe and between pasture quality and normalized difference vegetation index (NDVI) measured by a commercial active optical sensor. The interest of altimetric and apparent soil electrical conductivity maps as the first step in the implementation of precision agriculture projects was demonstrated. The use of proximal sensors to monitor soil moisture content, pasture photosynthetically active radiation and temperature helped to explain the influence of trees on pasture productivity and quality. The significant and strong correlations obtained between capacitance and pasture biomass and between NDVI and pasture nutritive value (in terms of crude protein, CP and neutral detergent fibre, NDF) can make an important contribution to determination of key components of pasture productivity and quality and implementation of site specific pasture management. Animal tracking demonstrated its potential to be an important tool for understanding the interaction between various factors and components that interrelate in the montado ecosystem and to support grazing management decisions. PMID- 29438320 TI - A Method on Dynamic Path Planning for Robotic Manipulator Autonomous Obstacle Avoidance Based on an Improved RRT Algorithm. AB - In a future intelligent factory, a robotic manipulator must work efficiently and safely in a Human-Robot collaborative and dynamic unstructured environment. Autonomous path planning is the most important issue which must be resolved first in the process of improving robotic manipulator intelligence. Among the path planning methods, the Rapidly Exploring Random Tree (RRT) algorithm based on random sampling has been widely applied in dynamic path planning for a high dimensional robotic manipulator, especially in a complex environment because of its probability completeness, perfect expansion, and fast exploring speed over other planning methods. However, the existing RRT algorithm has a limitation in path planning for a robotic manipulator in a dynamic unstructured environment. Therefore, an autonomous obstacle avoidance dynamic path-planning method for a robotic manipulator based on an improved RRT algorithm, called Smoothly RRT (S RRT), is proposed. This method that targets a directional node extends and can increase the sampling speed and efficiency of RRT dramatically. A path optimization strategy based on the maximum curvature constraint is presented to generate a smooth and curved continuous executable path for a robotic manipulator. Finally, the correctness, effectiveness, and practicability of the proposed method are demonstrated and validated via a MATLAB static simulation and a Robot Operating System (ROS) dynamic simulation environment as well as a real autonomous obstacle avoidance experiment in a dynamic unstructured environment for a robotic manipulator. The proposed method not only provides great practical engineering significance for a robotic manipulator's obstacle avoidance in an intelligent factory, but also theoretical reference value for other type of robots' path planning. PMID- 29438323 TI - Robust Object Tracking Based on Motion Consistency. AB - Object tracking is an important research direction in computer vision and is widely used in video surveillance, security monitoring, video analysis and other fields. Conventional tracking algorithms perform poorly in specific scenes, such as a target with fast motion and occlusion. The candidate samples may lose the true target due to its fast motion. Moreover, the appearance of the target may change with movement. In this paper, we propose an object tracking algorithm based on motion consistency. In the state transition model, candidate samples are obtained by the target state, which is predicted according to the temporal correlation. In the appearance model, we define the position factor to represent the different importance of candidate samples in different positions using the double Gaussian probability model. The candidate sample with highest likelihood is selected as the tracking result by combining the holistic and local responses with the position factor. Moreover, an adaptive template updating scheme is proposed to adapt to the target's appearance changes, especially those caused by fast motion. The experimental results on a 2013 benchmark dataset demonstrate that the proposed algorithm performs better in scenes with fast motion and partial or full occlusion compared to the state-of-the-art algorithms. PMID- 29438322 TI - The Application of NHEJ-CRISPR/Cas9 and Cre-Lox System in the Generation of Bivalent Duck Enteritis Virus Vaccine against Avian Influenza Virus. AB - Duck-targeted vaccines to protect against avian influenza are critically needed to aid in influenza disease control efforts in regions where ducks are endemic for highly pathogenic avian influenza (HPAI). Duck enteritis virus (DEV) is a promising candidate viral vector for development of vaccines targeting ducks, owing to its large genome and narrow host range. The clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 system is a versatile gene-editing tool that has proven beneficial for gene modification and construction of recombinant DNA viral vectored vaccines. Currently, there are two commonly used methods for gene insertion: non-homologous end-joining (NHEJ) and homology directed repair (HDR). Owing to its advantages in efficiency and independence from molecular requirements of the homologous arms, we utilized NHEJ-dependent CRISPR/Cas9 to insert the influenza hemagglutinin (HA) antigen expression cassette into the DEV genome. The insert was initially tagged with reporter green fluorescence protein (GFP), and a Cre-Lox system was later used to remove the GFP gene insert. Furthermore, a universal donor plasmid system was established by introducing double bait sequences that were independent of the viral genome. In summary, we provide proof of principle for generating recombinant DEV viral vectored vaccines against the influenza virus using an integrated NHEJ CRISPR/Cas9 and Cre-Lox system. PMID- 29438321 TI - The Intersection of HPV Epidemiology, Genomics and Mechanistic Studies of HPV Mediated Carcinogenesis. AB - Of the ~60 human papillomavirus (HPV) genotypes that infect the cervicovaginal epithelium, only 12-13 "high-risk" types are well-established as causing cervical cancer, with HPV16 accounting for over half of all cases worldwide. While HPV16 is the most important carcinogenic type, variants of HPV16 can differ in their carcinogenicity by 10-fold or more in epidemiologic studies. Strong genotype phenotype associations embedded in the small 8-kb HPV16 genome motivate molecular studies to understand the underlying molecular mechanisms. Understanding the mechanisms of HPV genomic findings is complicated by the linkage of HPV genome variants. A panel of experts in various disciplines gathered on 21 November 2016 to discuss the interdisciplinary science of HPV oncogenesis. Here, we summarize the discussion of the complexity of the viral-host interaction and highlight important next steps for selected applied basic laboratory studies guided by epidemiological genomic findings. PMID- 29438324 TI - Thermoauxetic Behavior of Composite Structures. AB - This paper presents a study of new two-dimensional composite structures with respect to their thermomechanical properties. The investigated structures are based on very well-known auxetic geometries-i.e., the anti-tetrachiral and re entrant honeycomb-modified by additional linking elements, material which is highly sensitive to changes of temperature. The study shows that temperature can be used as a control parameter to tune the value of the effective Poisson's ratio, which allows, in turn, changing its value from positive to negative, according to the temperature applied. The study shows that such thermoauxetic behavior applies both to composites with voids and those completely filled with material. PMID- 29438325 TI - Untargeted Metabolomics Profiling of an 80.5 km Simulated Treadmill Ultramarathon. AB - Metabolomic profiling of nine trained ultramarathon runners completing an 80.5 km self-paced treadmill-based time trial was carried out. Plasma samples were obtained from venous whole blood, collected at rest and on completion of the distance (post-80.5 km). The samples were analyzed by using high-resolution mass spectrometry in combination with both hydrophilic interaction (HILIC) and reversed phase (RP) chromatography. The extracted putatively identified features were modeled using Simca P 14.1 software (Umetrics, Umea, Sweden). A large number of amino acids decreased post-80.5 km and fatty acid metabolism was affected with an increase in the formation of medium-chain unsaturated and partially oxidized fatty acids and conjugates of fatty acids with carnitines. A possible explanation for the complex pattern of medium-chain and oxidized fatty acids formed is that the prolonged exercise provoked the proliferation of peroxisomes. The peroxisomes may provide a readily utilizable form of energy through formation of acetyl carnitine and other acyl carnitines for export to mitochondria in the muscles; and secondly may serve to regulate the levels of oxidized metabolites of long chain fatty acids. This is the first study to provide evidence of the metabolic profile in response to prolonged ultramarathon running using an untargeted approach. The findings provide an insight to the effects of ultramarathon running on the metabolic specificities and alterations that may demonstrate cardio protective effects. PMID- 29438326 TI - Chlorinated Azaphilone Pigments with Antimicrobial and Cytotoxic Activities Isolated from the Deep Sea Derived Fungus Chaetomium sp. NA-S01-R1. AB - Four novel compounds, chaephilone C (1), chaetoviridides A-C (2-4), were obtained from the culture of a deep sea derived fungus Chaetomium sp. NA-S01-R1, together with four known compounds-chaetoviridin A (5), chaetoviridine E (6), chaetomugilin D (7) and cochliodone A (8). Their structures, including absolute configurations, were assigned based on NMR, MS and time-dependent density functional theory (TD-DFT) ECD calculations. A plausible biogenetic pathway for compounds 1-3 was proposed. Compounds 2 and 3 exhibited antibacterial activities against Vibrio rotiferianus and Vibrio vulnificus. Compounds 1, 3 and 4 displayed similar anti-methicillin resistant Staphylococcus aureus (anti-MRSA) activities in comparison to chloramphenicol. Compound 2 showed the most potent cytotoxic activities towards the Hep G2 cell and compounds 1 and 3 demonstrated relatively stronger cytotoxic activities than the other compounds against the HeLa cell. PMID- 29438327 TI - Carbon-Based Nanomaterials/Allotropes: A Glimpse of Their Synthesis, Properties and Some Applications. AB - Carbon in its single entity and various forms has been used in technology and human life for many centuries. Since prehistoric times, carbon-based materials such as graphite, charcoal and carbon black have been used as writing and drawing materials. In the past two and a half decades or so, conjugated carbon nanomaterials, especially carbon nanotubes, fullerenes, activated carbon and graphite have been used as energy materials due to their exclusive properties. Due to their outstanding chemical, mechanical, electrical and thermal properties, carbon nanostructures have recently found application in many diverse areas; including drug delivery, electronics, composite materials, sensors, field emission devices, energy storage and conversion, etc. Following the global energy outlook, it is forecasted that the world energy demand will double by 2050. This calls for a new and efficient means to double the energy supply in order to meet the challenges that forge ahead. Carbon nanomaterials are believed to be appropriate and promising (when used as energy materials) to cushion the threat. Consequently, the amazing properties of these materials and greatest potentials towards greener and environment friendly synthesis methods and industrial scale production of carbon nanostructured materials is undoubtedly necessary and can therefore be glimpsed as the focal point of many researchers in science and technology in the 21st century. This is based on the incredible future that lies ahead with these smart carbon-based materials. This review is determined to give a synopsis of new advances towards their synthesis, properties, and some applications as reported in the existing literatures. PMID- 29438329 TI - Novel Conjugated Polymers Prepared by Direct (Hetero) arylation: An Eco-Friendly Tool for Organic Electronics. AB - The phthalimide (PhI) moiety has been attracting more attention as an excellent acceptor building block in donor-acceptor (D-A) conjugated polymers. In this paper; three D-A conjugated polymers with or without thiocarbonyl moieties are successfully prepared by the direct (hetero)-arylation polymerization (DHAP), which is an atom efficient and facile synthetic strategy to obtain polymer materials. Compared with the traditional carbon-carbon coupling reactions, this method possesses more advantages, including: fewer synthetic steps, avoidance of the preparation of the organometallic reagents, higher atom economy and fewer toxic byproducts, better compatibility with chemically sensitive functional groups and so on. All three of these designed PhI-based polymers exhibited favourable optoelectronic and thermal performance. The optical, thermodynamic and electrochemical properties of the synthesized polymers were systematically investigated using ultraviolet-visible (UV-vis) spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and cyclic voltammetry (CV). The results of these three polymers indicated that thionation of the carbonyl was a highly effective methods to improve the properties of PhI-based polymers; and provided impetus for the development of thionated PhI derivatives for organic electronic applications. PMID- 29438330 TI - Are Kazakhstani Women Satisfied with Antenatal Care? Implementing the WHO Tool to Assess the Quality of Antenatal Services. AB - Women's satisfaction is a part of the quality assurance process with potential to improve antenatal health services. The objective of this study was to assess the prevalence of women's satisfaction with antenatal care in an urban Kazakhstani setting and investigate associated factors. A total of 1496 women who delivered in all maternity clinics from 6 February through 11 July 2013 in Semey, East Kazakhstan, filled out a standardized pretested questionnaire on satisfaction with antenatal care. Independent associations between dissatisfaction and its correlates were studied by logistic regression. Ninety percent of the women were satisfied with the antenatal care. Women who were dissatisfied had lower education. These women would have preferred more checkups, shorter intervals between checkups, more time with care providers, and shorter waiting times. The overall dissatisfaction was associated with long waiting times and insufficient information on general health in pregnancy, results of laboratory tests, treatment during pregnancy, and breastfeeding. Although most of the women in the study setting were satisfied with the new antenatal care model, we identified the main sources of dissatisfaction that should be addressed. Given that Semey is a typical Kazakhstani city, the results can be generalized to other Kazakhstani urban settings. PMID- 29438328 TI - DNA Tumor Virus Regulation of Host DNA Methylation and Its Implications for Immune Evasion and Oncogenesis. AB - Viruses have evolved various mechanisms to evade host immunity and ensure efficient viral replication and persistence. Several DNA tumor viruses modulate host DNA methyltransferases for epigenetic dysregulation of immune-related gene expression in host cells. The host immune responses suppressed by virus-induced aberrant DNA methylation are also frequently involved in antitumor immune responses. Here, we describe viral mechanisms and virus-host interactions by which DNA tumor viruses regulate host DNA methylation to evade antiviral immunity, which may contribute to the generation of an immunosuppressive microenvironment during cancer development. Recent trials of immunotherapies have shown promising results to treat multiple cancers; however, a significant number of non-responders necessitate identifying additional targets for cancer immunotherapies. Thus, understanding immune evasion mechanisms of cancer-causing viruses may provide great insights for reversing immune suppression to prevent and treat associated cancers. PMID- 29438331 TI - Meta-Prediction of MTHFR Gene Polymorphisms and Air Pollution on the Risk of Hypertensive Disorders in Pregnancy Worldwide. AB - Hypertensive disorders in pregnancy (HDP) are devastating health hazards for both women and children. Both methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and air pollution can affect health status and result in increased risk of HDP for women. The major objective of this study was to investigate the effect of MTHFR polymorphisms, air pollution, and their interaction on the risk of HDP by using meta-predictive analytics. We searched various databases comprehensively to access all available studies conducted for various ethnic populations from countries worldwide, from 1997 to 2017. Seventy-one studies with 8064 cases and 13,232 controls for MTHFR C677T and 11 studies with 1425 cases and 1859 controls for MTHFR A1298C were included. MTHFR C677T homozygous TT (risk ratio (RR) = 1.28, p < 0.0001) and CT plus TT (RR = 1.07, p = 0.0002) were the risk genotypes, while wild-type CC played a protective role (RR = 0.94, p = 0.0017) for HDP. The meta-predictive analysis found that the percentage of MTHFR C677T TT plus CT (p = 0.044) and CT (p = 0.043) genotypes in the HDP case group were significantly increased with elevated levels of air pollution worldwide. Additionally, in countries with higher air pollution levels, the pregnant women with wild-type CC MTHFR 677 had a protection effect against HDP (p = 0.014), whereas, the homozygous TT of MTHFR C677T polymorphism was a risk genotype for developing HDP. Air pollution level is an environmental factor interacting with increased MTHFR C677T polymorphisms, impacting the susceptibility of HDP for women. PMID- 29438332 TI - Diaphragmatic Palsy. AB - The diaphragm is the primary muscle of respiration, and its weakness can lead to respiratory failure. Diaphragmatic palsy can be caused by various causes. Injury to the phrenic nerve during thoracic surgeries is the most common cause for diaphragmatic palsy. Depending on the cause, the symptoms of diaphragmatic palsies vary from completely asymptomatic to disabling dyspnea requiring mechanical ventilation. On pulmonary function tests, there will be a decrease in the maximum respiratory muscle power. Spirometry shows reduced lung functions and a significant drop of lung function in supine position is typical of diaphragmatic palsy. Diaphragmatic movements with respiration can be directly visualized by fluoroscopic examination. Currently, this test is being replaced by bedside thoracic ultrasound examination, looking at the diaphragmic excursion with deep breathing or sniffing. This test is found to be equally efficient, and without risks of ionizing radiation of fluoroscope. Treatment of diaphragmatic palsy depends on the cause. Surgical approach of repair of diaphragm or nonsurgical approach of noninvasive ventilation has been tried with good success. Overall prognosis of diaphragmatic palsy is good, except when it is related to neuromuscular degeneration conditions. PMID- 29438333 TI - Cocoa Farmers' Compliance with Safety Precautions in Spraying Agrochemicals and Use of Personal Protective Equipment (PPE) in Cameroon. AB - The inability of farmers to comply with essential precautions in the course of spraying agrochemicals remains a policy dilemma, especially in developing countries. The objectives of this paper were to assess compliance of cocoa farmers with agrochemical safety measures, analyse the factors explaining involvement of cocoa farmers in the practice of reusing agrochemical containers and wearing of personal protective equipment (PPE). Data were collected with structured questionnaires from 667 cocoa farmers from the Centre and South West regions in Cameroon. Data analyses were carried out with Probit regression and Negative Binomial regression models. The results showed that average cocoa farm sizes were 3.55 ha and 2.82 ha in South West and Centre regions, respectively, and 89.80% and 42.64% complied with manufacturers' instructions in the use of insecticides. Eating or drinking while spraying insecticides and fungicides was reported by 4.20% and 5.10% of all farmers in the two regions, respectively. However, 37.78% and 57.57% of all farmers wore hand gloves and safety boots while spraying insecticides in the South West and Centre regions of Cameroon, respectively. In addition, 7.80% of all the farmers would wash agrochemical containers and use them at home, while 42.43% would wash and use them on their farms. Probit regression results showed that probability of reusing agrochemical containers was significantly influenced (p < 0.05) by region of residence of cocoa farmers, gender, possession of formal education and farming as primary occupation. The Negative Binomial regression results showed that the log of number PPE worn was significantly influenced (p < 0.10) by region, marital status, attainment of formal education, good health, awareness of manufacturers' instructions, land area and contact index. It was among others concluded that efforts to train farmers on the need to be familiar with manufacturers' instructions and use PPE would enhance their safety in the course of spraying agrochemicals. PMID- 29438334 TI - Changing the Paradigm in Public Health and Disability through a Knowledge Translation Center. AB - People with disabilities are a health disparity population that face many barriers to health promotion opportunities in their communities. Inclusion in public health initiatives is a critical approach to address the health disparities that people with disabilities experience. The National Center on Health, Physical Activity and Disability (NCHPAD) is tackling health disparities in the areas of physical activity, healthy nutrition, and healthy weight management. Using the NCHPAD Knowledge Adaptation, Translation, and Scale-up Framework, NCHPAD is systematically facilitating, monitoring, and evaluating inclusive programmatic, policy, systems, and environmental (PPSE) changes in communities and organizations at a local and national level. Through examples we will highlight the importance of adapting knowledge, facilitating uptake, developing strategic partnerships and building community capacity that ultimately creates sustainable, inclusive change. PMID- 29438335 TI - Factors Influencing Abortion Decision-Making Processes among Young Women. AB - Background: Decision-making about if and how to terminate a pregnancy is a dilemma for young women experiencing an unwanted pregnancy. Those women are subject to sociocultural and economic barriers that limit their autonomy and make them vulnerable to pressures that influence or force decisions about abortion. Objective: The objective of this study was to explore the individual, interpersonal and environmental factors behind the abortion decision-making process among young Mozambican women. Methods: A qualitative study was conducted in Maputo and Quelimane. Participants were identified during a cross-sectional survey with women in the reproductive age (15-49). In total, 14 women aged 15 to 24 who had had an abortion participated in in-depth interviews. A thematic analysis was used. Results: The study found determinants at different levels, including the low degree of autonomy for women, the limited availability of health facilities providing abortion services and a lack of patient-centeredness of health services. Conclusions: Based on the results of the study, the authors suggest strategies to increase knowledge of abortion rights and services and to improve the quality and accessibility of abortion services in Mozambique. PMID- 29438336 TI - Measurement of a 3D Ultrasonic Wavefield Using Pulsed Laser Holographic Microscopy for Ultrasonic Nondestructive Evaluation. AB - In ultrasonic array imaging, 3D ultrasonic wavefields are normally recorded by an ultrasonic piezo array transducer. Its performance is limited by the configuration and size of the array transducer. In this paper, a method based on digital holographic interferometry is proposed to record the 3D ultrasonic wavefields instead of the array transducer, and the measurement system consisting of a pulsed laser, ultrasonic excitation, and synchronization and control circuit is designed. A consecutive sequence of holograms of ultrasonic wavefields are recorded by the system. The interferograms are calculated from the recorded holograms at different time sequence. The amplitudes and phases of the transient ultrasonic wavefields are recovered from the interferograms by phase unwrapping. The consecutive sequence of transient ultrasonic wavefields are stacked together to generate 3D ultrasonic wavefields. Simulation and experiments are carried out to verify the proposed technique, and preliminary results are presented. PMID- 29438337 TI - Patch Transporter: Incentivized, Decentralized Software Patch System for WSN and IoT Environments. AB - [-12]In the complicated settings of WSN (Wireless Sensor Networks) and IoT (Internet of Things) environments, keeping a number of heterogeneous devices updated is a challenging job, especially with respect to effectively discovering target devices and rapidly delivering the software updates. In this paper, we convert the traditional software update process to a distributed service. We set an incentive system for faithfully transporting the patches to the recipient devices. The incentive system motivates independent, self-interested transporters for helping the devices to be updated. To ensure the system correctly operates, we employ the blockchain system that enforces the commitment in a decentralized manner. We also present a detailed specification for the proposed protocol and validate it by model checking and simulations for correctness. PMID- 29438338 TI - Feasibility Assessment of a Fine-Grained Access Control Model on Resource Constrained Sensors. AB - Upcoming smart scenarios enabled by the Internet of Things (IoT) envision smart objects that provide services that can adapt to user behavior or be managed to achieve greater productivity. In such environments, smart things are inexpensive and, therefore, constrained devices. However, they are also critical components because of the importance of the information that they provide. Given this, strong security is a requirement, but not all security mechanisms in general and access control models in particular are feasible. In this paper, we present the feasibility assessment of an access control model that utilizes a hybrid architecture and a policy language that provides dynamic fine-grained policy enforcement in the sensors, which requires an efficient message exchange protocol called Hidra. This experimental performance assessment includes a prototype implementation, a performance evaluation model, the measurements and related discussions, which demonstrate the feasibility and adequacy of the analyzed access control model. PMID- 29438339 TI - Measuring Device for Air Speed in Macroporous Media and Its Application Inside Apple Storage Bins. AB - In cold storage facilities of fruit and vegetables, airflow is necessary for heat removal. The design of storage facilities influences the air speed in the surrounding of the product. Therefore, knowledge about airflow next to the product is important to plan the layout of cold stores adapted to the requirements of the products. A new sensing device (ASL, Air speed logger) is developed for omnidirectional measurement of air speed between fruit or vegetables inside storage bins or in bulk. It consists of four interconnected plastic spheres with 80 mm diameter each, adapted to the size of apple fruit. In the free space between the spheres, silicon diodes are fixed for the airflow measurement based on a calorimetric principle. Battery and data logger are mounted inside the spheres. The device is calibrated in a wind tunnel in a measuring range of 0-1.3 m/s. Air speed measurements in fruit bulks on laboratory scale and in an industrial fruit store show air speeds in gaps between fruit with high stability at different airflow levels. Several devices can be placed between stored products for determination of the air speed distribution inside bulks or bin stacks in a storage room. PMID- 29438340 TI - Encapsulation of Multiple Microalgal Cells via a Combination of Biomimetic Mineralization and LbL Coating. AB - The encapsulation of living cells is appealing for its various applications to cell-based sensors, bioreactors, biocatalysts, and bioenergy. In this work, we introduce the encapsulation of multiple microalgal cells in hollow polymer shells of rhombohedral shape by the following sequential processes: embedding of microalgae in CaCO3 crystals; layer-by-layer (LbL) coating of polyelectrolytes; and removal of sacrificial crystals. The microcapsule size was controlled by the alteration of CaCO3 crystal size, which is dependent on CaCl2/Na2CO3 concentration. The microalgal cells could be embedded in CaCO3 crystals by a two step process: heterogeneous nucleation of crystal on the cell surface followed by cell embedment by the subsequent growth of crystal. The surfaces of the microalgal cells were highly favorable for the crystal growth of calcite; thus, micrometer-sized microalgae could be perfectly occluded in the calcite crystal without changing its rhombohedral shape. The surfaces of the microcapsules, moreover, could be decorated with gold nanoparticles, Fe3O4 magnetic nanoparticles, and carbon nanotubes (CNTs), by which we would expect the functionalities of a light-triggered release, magnetic separation, and enhanced mechanical and electrical strength, respectively. This approach, entailing the encapsulation of microalgae in semi-permeable and hollow polymer microcapsules, has the potential for application to microbial-cell immobilization for high biomass-concentration cultivation as well as various other bioapplications. PMID- 29438341 TI - Characterization of TTN Novex Splicing Variants across Species and the Role of RBM20 in Novex-Specific Exon Splicing. AB - Titin (TTN) is a major disease-causing gene in cardiac muscle. Titin (TTN) contains 363 exons in human encoding various sizes of TTN protein due to alternative splicing regulated mainly by RNA binding motif 20 (RBM20). Three isoforms of TTN protein are produced by mutually exclusive exons 45 (Novex 1), 46 (Novex 2), and 48 (Novex 3). Alternatively splicing in Novex isoforms across species and whether Novex isoforms are associated with heart disease remains completely unknown. Cross-species exon comparison with the mVISTA online tool revealed that exon 45 is more highly conserved across all species than exons 46 and 48. Importantly, a conserved region between exons 47 and 48 across species was revealed for the first time. Reverse transcript polymerase chain reaction (RT PCR) and DNA sequencing confirmed a new exon named as 48' in Novex 3. In addition, with primer pairs for Novex 1, a new truncated form preserving introns 44 and 45 was discovered. We discovered that Novex 2 is not expressed in the pig, mouse, and rat with Novex 2 primer pairs. Unexpectedly, three truncated forms were identified. One TTN variant with intron 46 retention is mainly expressed in the human and frog heart, another variant with co-expression of exons 45 and 46 exists predominantly in chicken and frog heart, and a third with retention of introns 45 and 46 is mainly expressed in pig, mouse, rat, and chicken. Using Rbm20 knockout rat heart, we revealed that RBM20 is not a splicing regulator of Novex variants. Furthermore, the expression levels of Novex variants in human hearts with cardiomyopathies suggested that Novexes 2 and 3 could be associated with dilated cardiomyopathy (DCM) and/or arrhythmogenic right ventricular cardiomyopathy (ARVC). Taken together, our study reveals that splicing diversity of Novex exons across species and Novex variants might play a role in cardiomyopathy. PMID- 29438342 TI - Phytochemical Analysis, Antioxidant and Antimicrobial Activities of Helichrysum arenarium (L.) Moench. and Antennaria dioica (L.) Gaertn. Flowers. AB - Antennaria dioica (L.) Gaertn. and Helichrysum arenarium (L.) Moench. are two species of the Asteraceae family, known in Romanian traditional medicine for their diuretic, choleretic, and anti-inflammatory properties. The aim of the present study was to evaluate the phenolic and sterolic composition of flowers from the two species and to assess their antioxidant, antibacterial and antifungal properties. LC-MS analyses were performed on methanolic, ethanolic and 70% v/v ethanolic extracts, before and after acid hydrolysis, and revealed high amounts of polyphenols. Chlorogenic acid was found as the main compound for the flowers of A. dioica (502.70 +/- 25.11 mg/100 g d.w.), while quercitrin was dominant in H. arenarium (424.28 +/- 21.21 mg/100 g d.w.) in 70% v/v ethanolic extracts before hydrolysis. Antioxidant capacity assays showed an important antioxidant potential, which can be correlated with the determined polyphenolic compounds, showing the 70% v/v ethanolic extracts of the two species as being the most effective antioxidant samples for the DPPH assay. Antibacterial and antifungal assays confirm a modest biological potential for the same extract of both species. Results obtained in the present study bring important data and offer scientific evidence on the chemical composition and on the biological activities of the flowers belonging to the two species. PMID- 29438343 TI - Development of an mHealth Application for Women Newly Diagnosed with Osteoporosis without Preceding Fractures: A Participatory Design Approach. AB - mHealth is a useful tool to improve health outcome within chronic disease management. However, mHealth is not implemented in the field of postmenopausal osteoporosis even though it is a major worldwide health challenge. Therefore, this study aims to design and develop an mHealth app to support women in self management of osteoporosis when they are diagnosed without preceding fractures. Participatory design is conducted in three phases. Based on identified needs in the first phase, a prototype is designed and developed in an iterative process in the second phase before the mHealth app is tested in the third phase. This paper focuses on the user activities in phase two and describes how a team of researchers, women, physicians, healthcare professionals, and app designers are involved in the participatory design process. The study shows that participatory design is a viable approach when developing an mHealth app for women with asymptomatic osteoporosis. Results obtained from the workshops and laboratory tests demonstrate the importance of feedback from users in the iterative process, as well as the participation of users and app designers in workshops and laboratory tests to enable mutual learning when developing new mHealth solutions. The regular member-checks and involvement of users helped to identify challenges associated with providing healthcare services through an app. PMID- 29438344 TI - Evaluation of a Multichannel Non-Contact ECG System and Signal Quality Algorithms for Sleep Apnea Detection and Monitoring. AB - Sleep-related conditions require high-cost and low-comfort diagnosis at the hospital during one night or longer. To overcome this situation, this work aims to evaluate an unobtrusive monitoring technique for sleep apnea. This paper presents, for the first time, the evaluation of contactless capacitively-coupled electrocardiography (ccECG) signals for the extraction of sleep apnea features, together with a comparison of different signal quality indicators. A multichannel ccECG system is used to collect signals from 15 subjects in a sleep environment from different positions. Reference quality labels were assigned for every 30-s segment. Quality indicators were calculated, and their signal classification performance was evaluated. Features for the detection of sleep apnea were extracted from capacitive and reference signals. Sleep apnea features related to heart rate and heart rate variability achieved high similarity to the reference values, with p-values of 0.94 and 0.98, which is in line with the more than 95% beat-matching obtained. Features related to signal morphology presented lower similarity with the reference, although signal similarity metrics of correlation and coherence were relatively high. Quality-based automatic classification of the signals had a maximum accuracy of 91%. Best-performing quality indicators were based on template correlation and beat-detection. Results suggest that using unobtrusive cardiac signals for the automatic detection of sleep apnea can achieve similar performance as contact signals, and indicates clinical value of ccECG. Moreover, signal segments can automatically be classified by the proposed quality metrics as a pre-processing step. Including contactless respiration signals is likely to improve the performance and provide a complete unobtrusive cardiorespiratory monitoring solution; this is a promising alternative that will allow the screening of more patients with higher comfort, for a longer time, and at a reduced cost. PMID- 29438345 TI - A Comparative Analysis of Climate-Risk and Extreme Event-Related Impacts on Well Being and Health: Policy Implications. AB - There are various climate risks that are caused or influenced by climate change. They are known to have a wide range of physical, economic, environmental and social impacts. Apart from damages to the physical environment, many climate risks (climate variability, extreme events and climate-related hazards) are associated with a variety of impacts on human well-being, health, and life supporting systems. These vary from boosting the proliferation of vectors of diseases (e.g., mosquitos), to mental problems triggered by damage to properties and infrastructure. There is a great variety of literature about the strong links between climate change and health, while there is relatively less literature that specifically examines the health impacts of climate risks and extreme events. This paper is an attempt to address this knowledge gap, by compiling eight examples from a set of industrialised and developing countries, where such interactions are described. The policy implications of these phenomena and the lessons learned from the examples provided are summarised. Some suggestions as to how to avert the potential and real health impacts of climate risks are made, hence assisting efforts to adapt to a problem whose impacts affect millions of people around the world. All the examples studied show some degree of vulnerability to climate risks regardless of their socioeconomic status and need to increase resilience against extreme events. PMID- 29438346 TI - Sjogren-Like Lacrimal Keratoconjunctivitis in Germ-Free Mice. AB - Commensal bacteria play an important role in the formation of the immune system but their role in the maintenance of immune homeostasis at the ocular surface and lacrimal gland remains poorly understood. This study investigated the eye and lacrimal gland phenotype in germ-free and conventional C57BL/6J mice. Our results showed that germ-free mice had significantly greater corneal barrier disruption, greater goblet cell loss, and greater total inflammatory cell and CD4+ T cell infiltration within the lacrimal gland compared to the conventionally housed group. A greater frequency of CD4+IFN-gamma+ cells was observed in germ-free lacrimal glands. Females exhibited a more severe phenotype compared to males. Adoptive transfer of CD4+ T cells isolated from female germ-free mice into RAG1KO mice transferred Sjogren-like lacrimal keratoconjunctivitis. Fecal microbiota transplant from conventional mice reverted dry eye phenotype in germ-free mice and decreased CD4+IFN-gamma+ cells to levels similar to conventional C57BL/6J mice. These findings indicate that germ-free mice have a spontaneous lacrimal keratoconjunctivitis similar to that observed in Sjogren syndrome patients and demonstrate that commensal bacteria function in maintaining immune homeostasis on the ocular surface. Thus, manipulation of intestinal commensal bacteria has the potential to become a novel therapeutic approach to treat Sjogren Syndrome. PMID- 29438348 TI - Molecular-Assisted Pollen Grain Analysis Reveals Spatiotemporal Origin of Long Distance Migrants of a Noctuid Moth. AB - Pollen grains are regularly used as markers to determine an insect's movement patterns or host (plant) feeding behavior, yet conventional morphology-based pollen grain analysis (or palynology) encounters a number of important limitations. In the present study, we combine conventional analytical approaches with DNA meta-barcoding to identify pollen grains attached to migrating adults of the turnip moth, Agrotis segetum (Lepidoptera: Noctuidae) in Northeast China. More specifically, pollen grains were dislodged from 2566 A. segetum long distance migrants captured on Beihuang Island (Bohai Sea) and identified to many (plant) species level. Pollen belonged to 26 families of plants, including Fagaceae, Oleaceae, Leguminosae, Asteraceae, Pinaceae and Rosaceae, including common species such as Citrus sinensis, Olea europaea, Ligustrum lucidum, Robinia pseudoacacia, Castanopsis echinocarpa, Melia azedarach and Castanea henryi. As the above plants are indigenous to southern climes, we deduce that A. segetum forage on plants in those locales prior to engaging in northward spring migration. Our work validates the use of DNA-assisted approaches in lepidopteran pollination ecology research and provides unique and valuable information on the adult feeding range and geographical origin of A. segetum. Our findings also enable targeted (area-wide) pest management interventions or guide the future isolation of volatile attractants. PMID- 29438347 TI - Mitochondrial Dynamics in Basal and Stressful Conditions. AB - The historical role of mitochondria resides in converting the energy released during the oxidation of macromolecules (carbohydrates, lipids and proteins) into adenosine tri-phosphate, a major form of chemically stored energy which sustains cell growth and homeostasis. Beyond this role in bioenergetics regulation, mitochondria play a role in several other cellular processes including lipid metabolism, cellular calcium homeostasis, autophagy and immune responses. Furthermore, mitochondria are highly dynamic organelles: as all other cellular endomembranes, they are continuously moving along cytoskeleton, and, most importantly, they constantly interact one with each other by membrane tethering, fusion and fission. This review aims to highlight the tight correlation between the morphodynamics of mitochondria and their biological function(s), in physiological as well as stress conditions, in particular nutrient deprivation, pathogen attack and some human diseases. Finally, we emphasize some crosstalk between the fusion/fission machinery and the autophagy pathway to ending on some speculative hypothesis to inspire future research in the field. PMID- 29438349 TI - ON the Nature of Ionic Liquid Gating of La2-xSrxCuO4. AB - Ionic liquids have recently been used as means of modulating the charge carrier properties of cuprates. The mechanism behind it, however, is still a matter of debate. In this paper we report experiments on ionic liquid gated ultrathin La2 xSrxCuO4 films. Our results show that the electrostatic part of gating has limited influence in the conductance of the cuprate in the gate voltage range of 0 to - 2 V. A non-electrostatic mechanism takes over for gate voltages below - 2 V. This mechanism most likely changes the oxygen concentration of the film. The results presented are in line with previous X-ray based studies on ionic liquid gating induced oxygenation of the cuprate materials YBa2Cu3O7-x and La2-xSrxCuO4. PMID- 29438350 TI - Work Stress Interventions in Hospital Care: Effectiveness of the DISCovery Method. AB - Effective interventions to prevent work stress and to improve health, well-being, and performance of employees are of the utmost importance. This quasi experimental intervention study presents a specific method for diagnosis of psychosocial risk factors at work and subsequent development and implementation of tailored work stress interventions, the so-called DISCovery method. This method aims at improving employee health, well-being, and performance by optimizing the balance between job demands, job resources, and recovery from work. The aim of the study is to quantitatively assess the effectiveness of the DISCovery method in hospital care. Specifically, we used a three-wave longitudinal, quasi-experimental multiple-case study approach with intervention and comparison groups in health care work. Positive changes were found for members of the intervention groups, relative to members of the corresponding comparison groups, with respect to targeted work-related characteristics and targeted health, well-being, and performance outcomes. Overall, results lend support for the effectiveness of the DISCovery method in hospital care. PMID- 29438351 TI - Bioconversion of Tyrosine and Tryptophan Derived Biogenic Amines by Neuropathogenic Bacteria. AB - The biochemical potential of pathogenic bacteria may cause alteration in the neurophysiological environment; consequently, neuroendocrine and immune responses of the host are modulated by endogenously produced metabolic products of neuropathogenic bacteria. The present study was designed to detect the derived biogenic amines in spent culture media of Bacillus cereus (Bc), Clostridium tetani (Ct), Listeria monocytogenes (Lm), and Neisseria meningitidis (Nm). Overnight grown culture in different culture media i.e., Nutrient broth (NB), Luria basal broth (LB), Brain Heart Infusion broth (BHI), and human serum supplemented RPMI 1640 medium (RPMI) were used to prepare filter-sterilized, cell free cultural broths (SCFBs) and subjected to high performance liquid chromatography with electrochemical detection (HPLC-EC) along with the control SCFBs. Comparative analysis of biogenic amines in neuropathogenic bacterial SCFBs with their respective control (SCFB) revealed the complete degradation of dopamine (DA) into its metabolic products by Bc, Ct, and Nm, whereas Lm showed negligible degradation of DA. A relatively high concentration of 5-hydroxyindol acetic acid (5HIAA) by Bc in NB and LB indicated the tryptophan metabolism by the serotonin (5HT) pathway. Our study suggests that microbial endocrinology could help unravel new perspectives to the progression of infectious diseases. PMID- 29438352 TI - The Financial Implications of a Well-Hidden and Ignored Chronic Lyme Disease Pandemic. AB - 1 million people are predicted to get infected with Lyme disease in the USA in 2018. Given the same incidence rate of Lyme disease in Europe as in the USA, then 2.4 million people will get infected with Lyme disease in Europe in 2018. In the USA by 2050, 55.7 million people (12% of the population) will have been infected with Lyme disease. In Europe by 2050, 134.9 million people (17% of the population) will have been infected with Lyme disease. Most of these infections will, unfortunately, become chronic. The estimated treatment cost for acute and chronic Lyme disease for 2018 for the USA is somewhere between 4.8 billion USD and 9.6 billion USD and for Europe somewhere between 10.1 billion EUR and 20.1 billion EUR. If governments do not finance IV treatment with antibiotics for chronic Lyme disease, then the estimated government cost for chronic Lyme disease for 2018 for the USA is 10.1 billion USD and in Europe 20.1 billion EUR. If governments in the USA and Europe want to minimize future costs and maximize future revenues, then they should pay for IV antibiotic treatment up to a year even if the estimated cure rate is as low as 25%. The cost for governments of having chronic Lyme patients sick in perpetuity is very large. PMID- 29438353 TI - Qualitative and Quantitative Detection of PrPSc Based on the Controlled Release Property of Magnetic Microspheres Using Surface Plasmon Resonance (SPR). AB - Prion protein (PrPSc) has drawn widespread attention due to its pathological potential to prion diseases. In this work, we constructed a novel surface plasmon resonance (SPR) detection assay involving magnetic microspheres (MMs) and its controlled release property, for selective capture, embedding, concentration, and SPR detection of PrPSc with high sensitivity and specificity. Aptamer-modified magnetic particles (AMNPs) were used to specifically capture PrPSc. Amphiphilic copolymer was used to embed the labeled PrPSc and form magnetic microspheres to isolate PrPSc from the external environment. Static magnetic and alternating magnetic fields were used to concentrate and control release the embedded PrPSc, respectively. Finally, the released AMNPs-labeled PrPSc was detected by SPR which was equipped with a bare gold sensing film. A good linear relationship was obtained between SPR responses and the logarithm of PrPSc concentrations over a range of 0.01-1000 ng/mL. The detection sensitivity for PrPSc was improved by 10 fold compared with SPR direct detection format. The specificity of the present biosensor was also determined by PrPC and other reagents as controls. This proposed approach could also be used to isolate and detect other highly pathogenic biomolecules with similar structural characteristics by altering the corresponding aptamer in the AMNPs conjugates. PMID- 29438354 TI - Nutritional Quality of School Meals in France: Impact of Guidelines and the Role of Protein Dishes. AB - In France, school meals must comply with 15 frequency criteria (FC) expressed as nutritional requirements (e.g., "starters containing more than 15% fat served no more than four times out of 20") in a series of 20 consecutive meals. The objective was to assess, for the first time, the nutritional impact of complying with French school food FC. Based on 40 series of meals actually served in primary schools ("observed series"), several scenarios (1600 series per scenario) of compliance or non-compliance with FC were simulated, and nutritional quality was assessed via the mean adequacy ratio (MAR/2000 kcal). In the observed series, only 9.7 FC on average (range 4-14) were fulfilled. In the simulated series: (i) MAR was positively associated with FC compliance level, with the highest MAR obtained with complete compliance; (ii) MAR decreased when meat or fish-based dishes were replaced by dishes without meat or fish; and (iii) removing the protein dish without replacement led to the lowest MAR. This study demonstrates that French school food guidelines ensure good nutritional quality of food services. It also shows that generalizing the service of meals without meat or fish would deteriorate overall nutritional quality, highlighting the need to define the composition of vegetarian dishes and their frequency of service to children. PMID- 29438355 TI - Efficacy of an Optimised Bacteriophage Cocktail to Clear Clostridium difficile in a Batch Fermentation Model. AB - Clostridium difficile infection (CDI) is a major cause of infectious diarrhea. Conventional antibiotics are not universally effective for all ribotypes, and can trigger dysbiosis, resistance and recurrent infection. Thus, novel therapeutics are needed to replace and/or supplement the current antibiotics. Here, we describe the activity of an optimised 4-phage cocktail to clear cultures of a clinical ribotype 014/020 strain in fermentation vessels spiked with combined fecal slurries from four healthy volunteers. After 5 h, we observed ~6-log reductions in C. difficile abundance in the prophylaxis regimen and complete C. difficile eradication after 24 h following prophylactic or remedial regimens. Viability assays revealed that commensal enterococci, bifidobacteria, lactobacilli, total anaerobes, and enterobacteria were not affected by either regimens, but a ~2-log increase in the enterobacteria, lactobacilli, and total anaerobe abundance was seen in the phage-only-treated vessel compared to other treatments. The impact of the phage treatments on components of the microbiota was further assayed using metagenomic analysis. Together, our data supports the therapeutic application of our optimised phage cocktail to treat CDI. Also, the increase in specific commensals observed in the phage-treated control could prevent further colonisation of C. difficile, and thus provide protection from infection being able to establish. PMID- 29438356 TI - Ent-Clerodane Diterpenes from the Bark of Croton oligandrus Pierre ex Hutch. and Assessment of Their Cytotoxicity against Human Cancer Cell Lines. AB - New clerodane diterpenes, 12-epi-megalocarpodolide D (2) and an epimeric mixture of crotonolins A (3) and B (4), were isolated from the bark of Croton oligandrus following a bioassay-guided isolation protocol. Known compounds, megalocarpodolide D (1), 12-epi-crotocorylifuran (5), cluytyl-ferulate (6), hexacosanoyl- ferulate (7), vanillin (8), acetyl-aleuritolic acid (9) and lupeol (10), were also isolated. The structures of the isolated compounds (1-10) were elucidated by spectroscopic means. The cytotoxicity of compounds 1-10 was assessed against A549, MCF7, PC3 and PNT2 cell lines using the MTT assay. Compounds 1 and 2 showed moderate levels of activity against both A549 and MCF7 cells with 1 being the most active with IC50 values of 63.8 +/- 13.8 and 136.2 +/ 22.7 uM against A549 and MCF7 cells, respectively. The epimeric mixture of 3 and 4 was moderately active against A549 and PC3 cells (IC50 = 128.6 +/- 31.0 and 111.2 +/- 2.9 uM, respectively). PMID- 29438357 TI - Small Molecules: Therapeutic Application in Neuropsychiatric and Neurodegenerative Disorders. AB - In recent years, an increasing number of studies have been published, focusing on the potential therapeutic use of small catalytic agents with strong biological properties. So far, most of these works have only regarded specific clinical fields, such as oncology, infectivology and general pathology, in particular with respect to the treatment of significant inflammatory processes. However, interesting data on possible therapeutic applications of small molecules for the treatment of neuropsychiatric and neurodegenerative illnesses are emerging, especially with respect to the possibility to modulate the cellular redox state. Indeed, a crucial role of redox dysregulation in the pathogenesis of these disorders has been widely demonstrated by both pre-clinical and clinical studies, being the reduction of the total amount of free radicals a promising novel therapeutic approach for these diseases. In this review, we focused our interest on studies published during the last ten years reporting therapeutic potential of small molecules for the treatment of neuropsychiatric and neurodegenerative disorders, also based on the biological efficiency of these compounds in detecting intracellular disturbances induced by increased production of reactive oxygen species. PMID- 29438359 TI - Effects of 17beta-Estradiol on Mitophagy in the Murine MC3T3-E1 Osteoblast Cell Line is Mediated via G Protein-Coupled Estrogen Receptor and the ERK1/2 Signaling Pathway. AB - BACKGROUND Osteoporosis is associated with 17beta-estradiol deficiency. The G protein-coupled receptor 30 (GPR30) is known to be an estrogen-responsive receptor, but its role in the degradation of mitochondria in osteoblasts by autophagy, or mitophagy, remains unclear. The aim of this in vitro study was to evaluate the effects of 17beta-estradiol, GPR30, and its signaling pathway, on mitophagy in the murine MC3T3-E1 osteoblast cell line. MATERIAL AND METHODS In the murine MC3T3-E1 osteoblast cell line, cells were treated with 17beta estradiol, or G15, a selective GPR30 antagonist, or U0126, a mitogen-activated protein (MAP) kinase (ERK1/2) inhibitor, or with vehicle as control. The expression of GPR30 was determined by Western blot, reverse transcription polymerase chain reaction (RT-PCR), and confocal immunofluorescence imaging. Cell morphology and mitochondrial autophagosomes were identified using transmission electron microscopy (TEM). Phosphorylation of the mitophagy markers, heat shock protein 60 (Hsp60), translocase of outer membrane (Tom)20, and microtubule associated protein 1A/1B-light chain 3 (LC3) were determined by Western blot, and cell proliferation was determined using the bromodeoxyuridine (BrdU) assay. RESULTS The optimum concentration of 17beta-estradiol that resulted in GPR30 expression in MC3T3-E1 cells was 10^-7 M, which led to the accumulation of mitochondrial autophagosomes and increased protein phosphorylation levels of Hsp60, Tom20, and LC3. In cells pretreated with G15 or U0126, 17b-estradiol treatment did not increase mitophagy in MC3T3-E1 cells. CONCLUSIONS In murine osteoblasts cultured in vitro, treatment with 17beta-estradiol resulted in the expression of GPR30 and enhanced mitophagy through the GPR30 and ERK1/2 signaling pathway. PMID- 29438360 TI - An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma. AB - This corrects the article DOI: 10.1038/bjc.2017.85. PMID- 29438358 TI - Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins. AB - Plant Ribosome-inactivating proteins (RIPs) including the type I RIP Saporin have been used for the construction of Immunotoxins (ITxs) obtained via chemical conjugation of the toxic domain to whole antibodies or by generating genetic fusions to antibody fragments/targeting domains able to direct the chimeric toxin against a desired sub-population of cancer cells. The high enzymatic activity, stability and resistance to conjugation procedures and especially the possibility to express recombinant fusions in yeast, make Saporin a well-suited tool for anti cancer therapy approaches. Previous clinical work on RIPs-based Immunotoxins (including Saporin) has shown that several critical issues must be taken into deeper consideration to fully exploit their therapeutic potential. This review focuses on possible combinatorial strategies (chemical and genetic) to augment Saporin-targeted toxin efficacy. Combinatorial approaches may facilitate RIP escape into the cytosolic compartment (where target ribosomes are), while genetic manipulations may minimize potential adverse effects such as vascular-leak syndrome or may identify T/B cell epitopes in order to decrease the immunogenicity following similar strategies as those used in the case of bacterial toxins such as Pseudomonas Exotoxin A or as for Type I RIP Bouganin. This review will further focus on strategies to improve recombinant production of Saporin-based chimeric toxins. PMID- 29438361 TI - A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424. AB - BACKGROUND: Src is involved in cancer invasion and metastasis. AZD0424, an oral inhibitor of Src and ABL1, has shown evidence of anti-tumour activity in pre clinical studies. METHODS: A phase Ia, dose escalation study was performed to assess the safety of continuous oral dosing with AZD0424 in advanced solid tumours. Secondary objectives included investigation of AZD0424 pharmacokinetics, effect on Src activity using markers of bone turnover, and anti-tumour activity. RESULTS: 41 patients were treated; 34 received AZD0424 once-daily at doses ranging from 5 mg to 150 mg, and 7 received 40 mg bi-daily 41.5% of patients experienced at least one AZD0424-related adverse event that was Grade 3-5 in severity, with patients treated at doses above 60 mg per day experiencing multiple treatment-related toxicities. The most commonly observed AZD0424-related adverse events were nausea, fatigue, anorexia and alopecia. Cmax and AUC increased linearly with dose and the mean+/-standard deviation t1/2 was 8.4+/-2.8 h. Clear evidence of Src target inhibition was seen at doses ?20 mg per day. No responses were observed and 7 patients (17.1%) achieved stable disease lasting 6 weeks or more. CONCLUSIONS: AZD0424 displayed no evidence of efficacy as monotherapy despite a clear pharmacodynamic effect. Further evaluation of AZD0424 monotherapy in patients with solid tumours is not recommended. PMID- 29438362 TI - Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array. AB - This corrects the article DOI: 10.1038/bjc.2016.50. PMID- 29438363 TI - CD9-positive exosomes from cancer-associated fibroblasts stimulate the migration ability of scirrhous-type gastric cancer cells. AB - This corrects the article DOI: 10.1038/bjc.2017.85. PMID- 29438364 TI - Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium. AB - This corrects the article DOI: 10.1038/bjc.2017.231. PMID- 29438366 TI - IKKalpha is required in the intestinal epithelial cells for tumour stemness. AB - BACKGROUND: Colorectal cancer is a common cause of death in developed countries. Progression from adenoma to invasive carcinoma requires accumulation of mutations starting with the Adenomatous Polyposis Coli (Apc) gene. NF-kappaB signalling is a key element in cancer, mainly related to the activity of IKKbeta. IKKalpha kinase also participates in this process by mechanisms that are primarily unknown. METHODS: We generated a compound mouse model with mutation in Apc and lacking intestinal epithelial IKKalpha, produced intestinal organoids and tumour spheroids with different genetic backgrounds, and performed immunohistochemistry and RNA-seq analysis. RESULTS: Deficiency of IKKalpha prevents adenoma formation, with adenomas lacking IKKalpha showing reduced proliferation. In contrast, IKKalpha status did not affect normal intestinal function. The same divergent phenotype was found in the organoid-spheroid model. We also found that epithelial IKKalpha controls stemness, proliferation and apoptosis-related expression. CONCLUSIONS: IKKalpha is a potential therapeutic target for Apc mutant colorectal cancer patients. PMID- 29438365 TI - Strategies for clinical development of monoclonal antibodies beyond first-in human trials: tested doses and rationale for dose selection. AB - BACKGROUND: Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined. METHODS: We identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results. RESULTS: In the 37 dose-escalation NFIHTs, the RP2D indication was still poorly defined. In phase II-III NFIHTs (n=103 on 37 mAbs), the FIHT RP2D was the only dose tested for five mAbs. For 16 mAbs, only doses different from the FIHT RP2D or the maximum administered dose (MAD) were tested and the dose selection rationale infrequently indicated. In the 60 RTs on 27 FDA approved mAbs with available FIHT, the FIHT RP2D was tested only for two mAbs, and RT doses were much lower than the FIHT MAD. CONCLUSIONS: The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published articles and not based on FIHT data. PMID- 29438369 TI - Reply to 'Comment on '30 years follow-up and increased risks of breast cancer and leukaemia after long-term low-dose-rate radiation exposure''. PMID- 29438367 TI - Randomised study shows that repeated self-sampling and HPV test has more than two fold higher detection rate of women with CIN2+ histology than Pap smear cytology. AB - This corrects the article DOI: 10.1038/bjc.2017.85. PMID- 29438368 TI - Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients. AB - This corrects the article DOI: 10.1038/bjc.2017.85. PMID- 29438370 TI - Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAFV600 mutation-positive melanoma. AB - BACKGROUND: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAFV600-mutated melanoma. An analysis of health-related quality of life (HRQOL) from coBRIM is reported. METHODS: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ?1 time point thereafter constituted the analysis population. Change from baseline ?10 points was considered clinically meaningful. RESULTS: Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ?10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment. CONCLUSIONS: In patients with advanced/metastatic BRAFV600-mutated melanoma, treatment with C+V maintained HRQOL compared with P+V, with superior efficacy. PMID- 29438371 TI - A new panel of pancreatic cancer biomarkers discovered using a mass spectrometry based pipeline. AB - This corrects the article DOI: 10.1038/bjc.2017.85. PMID- 29438372 TI - A phase I trial of the gamma-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. AB - BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by gamma-secretase inhibitors has been shown to be effective in pre clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a gamma secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds. PMID- 29438373 TI - Anlotinib as a third-line therapy in patients with refractory advanced non-small cell lung cancer: a multicentre, randomised phase II trial (ALTER0302). AB - BACKGROUND: Anlotinib (AL3818) is a novel multitarget tyrosine kinase inhibitor, inhibiting tumour angiogenesis and proliferative signalling. The objective of this study was to assess the safety and efficacy of third-line anlotinib for patients with refractory advanced non-small-cell lung cancer (RA-NSCLC). METHODS: Eligible patients were randomised 1 : 1 to receive anlotinib (12 mg per day, per os; days 1-14; 21 days per cycle) or a placebo. The primary end point was progression-free survival (PFS). RESULTS: A total of 117 eligible patients enrolled from 13 clinical centres in China were analysed in the full analysis set. No patients received immune check-point inhibitors and epidermal growth factor receptor status was unknown in 60.7% of the population. PFS was better with anlotinib compared with the placebo (4.8 vs 1.2 months; hazard ratio (HR)=0.32; 95% confidence interval (CI), 0.20-0.51; P<0.0001), as well as overall response rate (ORR) (10.0%; 95% CI, 2.4-17.6% vs 0%; 95% CI, 0-6.27%; P=0.028). The median overall survival (OS) was 9.3 months (95% CI, 6.8-15.1) for the anlotinib group and 6.3 months (95% CI, 4.3-10.5) for the placebo group (HR=0.78; 95% CI, 0.51-1.18; P=0.2316). Adverse events were more frequent in the anlotinib than the placebo group. The percentage of grade 3-4 treatment-related adverse events was 21.67% in the anlotinib group. CONCLUSIONS: Anlotinib as a third-line treatment provided significant PFS benefits to patients with RA-NSCLC when compared with the placebo, and the toxicity profiles showed good tolerance. PMID- 29438374 TI - Comment on '30 years follow-up and increased risks of breast cancer and leukaemia after long-term low-dose-rate radiation exposure'. PMID- 29438375 TI - Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel. AB - BACKGROUND: Colorectal cancer (CRC) screening might be improved by using a measure of prior risk to modulate screening intensity or the faecal immunochemical test threshold. Intermediate molecular biomarkers could aid risk prediction by capturing both known and unknown risk factors. METHODS: We sampled normal bowel mucosa from the proximal colon, distal colon and rectum of 317 individuals undergoing colonoscopy. We defined cases as having a personal history of colorectal polyp(s)/cancer, and controls as having no history of colorectal neoplasia. Molecular analyses were performed for: telomere length (TL); global methylation; and the expression of genes in molecular pathways associated with colorectal tumourigenesis. We also calculated a polygenic risk score (PRS) based on CRC susceptibility polymorphisms. RESULTS: Bowel TL was significantly longer in cases than controls, but was not associated with blood TL. PRS was significantly and independently higher in cases. Hypermethylation showed a suggestive association with case:control status. No gene or pathway was differentially expressed between cases and controls. Gene expression often varied considerably between bowel locations. CONCLUSIONS: PRS and bowel TL (but not blood TL) may be clinically-useful predictors of CRC risk. Sample collection to assess these biomarkers is feasible in clinical practice, especially where population screening uses flexible sigmoidoscopy or colonoscopy. PMID- 29438376 TI - Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer. AB - This corrects the article DOI: 10.1038/bjc.2017.43. PMID- 29438377 TI - Modeling the spread of the Zika virus using topological data analysis. AB - Zika virus (ZIKV), a disease spread primarily through the Aedes aegypti mosquito, was identified in Brazil in 2015 and was declared a global health emergency by the World Health Organization (WHO). Epidemiologists often use common state-level attributes such as population density and temperature to determine the spread of disease. By applying techniques from topological data analysis, we believe that epidemiologists will be able to better predict how ZIKV will spread. We use the Vietoris-Rips filtration on high-density mosquito locations in Brazil to create simplicial complexes, from which we extract homology group generators. Previously epidemiologists have not relied on topological data analysis to model disease spread. Evaluating our model on ZIKV case data in the states of Brazil demonstrates the value of these techniques for the improved assessment of vector borne diseases. PMID- 29438378 TI - Multi-stability with ambiguous visual stimuli in Drosophila orientation behavior. AB - It is widely accepted for humans and higher animals that vision is an active process in which the organism interprets the stimulus. To find out whether this also holds for lower animals, we designed an ambiguous motion stimulus, which serves as something like a multi-stable perception paradigm in Drosophila behavior. Confronted with a uniform panoramic texture in a closed-loop situation in stationary flight, the flies adjust their yaw torque to stabilize their virtual self-rotation. To make the visual input ambiguous, we added a second texture. Both textures got a rotatory bias to move into opposite directions at a constant relative angular velocity. The results indicate that the fly now had three possible frames of reference for self-rotation: either of the two motion components as well as the integrated motion vector of the two. In this ambiguous stimulus situation, the flies generated a continuous sequence of behaviors, each one adjusted to one or another of the three references. PMID- 29438379 TI - Advancing the immunoaffinity platform AFFIRM to targeted measurements of proteins in serum in the pg/ml range. AB - There is a great need for targeted protein assays with the capacity of sensitive measurements in complex samples such as plasma or serum, not the least for clinical purposes. Proteomics keeps generating hundreds of biomarker candidates that need to be transferred towards true clinical application through targeted verification studies and towards clinically applicable analysis formats. The immunoaffinity assay AFFIRM (AFFInity sRM) combines the sensitivity of recombinant single chain antibodies (scFv) for targeted protein enrichment with a specific mass spectrometry readout through selected reaction monitoring (SRM) in an automated workflow. Here we demonstrate a 100 times improved detection capacity of the assay down to pg/ml range through the use of oriented antibody immobilization to magnetic beads. This was achieved using biotin-tagged scFv coupled to streptavidin coated magnetic beads, or utilizing the FLAG tag for coupling to anti-FLAG antibody coated magnetic beads. An improved multiplexing capacity with an 11-plex setup was also demonstrated compared to a previous 3 plex setup, which is of great importance for the analysis of panels of biomarker targets. PMID- 29438380 TI - The number of measurements needed to obtain high reliability for traits related to enzymatic activities and photosynthetic compounds in soybean plants infected with Phakopsora pachyrhizi. AB - Asian rust affects the physiology of soybean plants and causes losses in yield. Repeatability coefficients may help breeders to know how many measurements are needed to obtain a suitable reliability for a target trait. Therefore, the objectives of this study were to determine the repeatability coefficients of 14 traits in soybean plants inoculated with Phakopsora pachyrhizi and to establish the minimum number of measurements needed to predict the breeding value with high accuracy. Experiments were performed in a 3x2 factorial arrangement with three treatments and two inoculations in a random block design. Repeatability coefficients, coefficients of determination and number of measurements needed to obtain a certain reliability were estimated using ANOVA, principal component analysis based on the covariance matrix and the correlation matrix, structural analysis and mixed model. It was observed that the principal component analysis based on the covariance matrix out-performed other methods for almost all traits. Significant differences were observed for all traits except internal CO2 concentration for the treatment effects. For the measurement effects, all traits were significantly different. In addition, significant differences were found for all Treatment x Measurement interaction traits except coumestrol, chitinase and chlorophyll content. Six measurements were suitable to obtain a coefficient of determination higher than 0.7 for all traits based on principal component analysis. The information obtained from this research will help breeders and physiologists determine exactly how many measurements are needed to evaluate each trait in soybean plants infected by P. pachyrhizi with a desirable reliability. PMID- 29438381 TI - Monitoring tumor response to the vascular disrupting agent CKD-516 in a rabbit VX2 intramuscular tumor model using PET/MRI: Simultaneous evaluation of vascular and metabolic parameters. AB - OBJECTIVES: To determine whether the CKD-516 produces a significant change in vascular and metabolic parameters in PET/MRI. MATERIALS AND METHODS: With institutional Animal Care and Use Committee approval, 18 VX2 carcinoma tumors implanted in bilateral back muscles of 9 rabbits were evaluated. Serial PET/MRI were performed before, 4 hours after and 1-week after vascular disrupting agent, CKD-516 at a dose of 0.7 mg/kg (treated group, n = 10) or saline (control group, n = 8) administration. PET/MRI-derived parameters and their interval changes were compared between the treated and control group by using the linear mixed model. Each parameter within each group was also compared by using the linear mixed model. RESULTS: Changes of the volume transfer coefficient (Ktrans) and the initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) in the treated group were significantly larger compared with those in the control group at 4-hour follow-up (mean, -39.91% vs. -6.04%, P = 0.018; and 49.71% vs. +6.23%, P = 0.013). Change of metabolic tumor volume (MTV) in the treated group was significantly smaller compared with that in the control group at 1-week follow-up (mean, +118.34% vs. +208.87%, P = 0.044). Serial measurements in the treated group revealed that Ktrans and iAUC decreased at 4-hour follow-up (P < 0.001) and partially recovered at 1-week follow-up (P = 0.001 and 0.024, respectively). MTV increased at a 4-hour follow-up (P = 0.038) and further increased at a 1-week follow-up (P < 0.001), while total lesion glycolysis (TLG) did not show a significant difference between the time points. SUVmax and SUVmean did not show significant interval changes between time points (P > 0.05). CONCLUSIONS: PET/MRI is able to monitor the changes of vascular and metabolic parameters at different time points simultaneously, and confirmed that vascular changes precede the metabolic changes by VDA, CKD-516. PMID- 29438382 TI - Predicting mortality in extremely low birth weight infants: Comparison between gestational age, birth weight, Apgar score, CRIB II score, initial and lowest serum albumin levels. AB - We explored GA, BW, Apgar score, CRIB II score, and serum albumin levels as univariate predictors of mortality in extremely low birth weight infants. Medical records of 564 extremely low birth weight infants were reviewed retrospectively. The infants were grouped as survivors (group I), expired <= 7th postnatal day (group II), and expired > 7th postnatal day (group III). The predictive value for mortality of gestational age, birth weight, Apgar scores at 1 and 5 min, clinical risk index for babies II score, and first and lowest serum albumin levels was assessed by calculating the associated area under the curve (AUC) in receiver operating characteristic (ROC) curves. The overall survival and mortality rates of groups I, II, and III were 81.0% (457/564), 7.6% (43/564), and 11.4% (64/564), respectively. Birth weight, Apgar scores at 1 and 5 min, and first serum albumin levels were significantly higher, while the clinical risk index for babies II score was significantly lower in group I when compared to groups II and III. Gestational age and lowest serum albumin level in group I were significantly higher than group III, but not group II. However, gestational age, birth weight, and clinical risk index for babies II score showed gestational age dependent variations regardless of survival or mortality. Apgar score at 5 min (0.756) and lowest serum albumin level (0.771) demonstrated the highest AUC of the ROC curve in predicting mortality in group II and III, respectively. In conclusion, Apgar score at 5 min and lowest serum albumin level were the most effective predictors for mortality in extremely low birth weight infants during <= 7th and > 7th postnatal days, respectively. PMID- 29438383 TI - Comparative genomic analysis of mollicutes with and without a chaperonin system. AB - The GroE chaperonin system, which comprises GroEL and GroES, assists protein folding in vivo and in vitro. It is conserved in all prokaryotes except in most, but not all, members of the class of mollicutes. In Escherichia coli, about 60 proteins were found to be obligatory clients of the GroE system. Here, we describe the properties of the homologs of these GroE clients in mollicutes and the evolution of chaperonins in this class of bacteria. Comparing the properties of these homologs in mollicutes with and without chaperonins enabled us to search for features correlated with the presence of GroE. Interestingly, no sequence based features of proteins such as average length, amino acid composition and predicted folding/disorder propensity were found to be affected by the absence of GroE. Other properties such as genome size and number of proteins were also found to not differ between mollicute species with and without GroE. Our data suggest that two clades of mollicutes re-acquired the GroE system, thereby supporting the view that gaining the system occurred polyphyletically and not monophyletically, as previously debated. Our data also suggest that there might have been three isolated cases of lateral gene transfer from specific bacterial sources. Taken together, our data indicate that loss of GroE does not involve crossing a high evolutionary barrier and can be compensated for by a small number of changes within the few dozen client proteins. PMID- 29438384 TI - A tale of two mixotrophic chrysophytes: Insights into the metabolisms of two Ochromonas species (Chrysophyceae) through a comparison of gene expression. AB - Ochromonas spp. strains CCMP1393 and BG-1 are phagotrophic phytoflagellates with different nutritional strategies. Strain CCMP1393 is an obligate phototroph while strain BG-1 readily grows in continuous darkness in the presence of bacterial prey. Growth and gene expression of strain CCMP1393 were investigated under conditions allowing phagotrophic, mixotrophic, or phototrophic nutrition. The availability of light and bacterial prey led to the differential expression of 42% or 45-59% of all genes, respectively. Data from strain CCMP1393 were compared to those from a study conducted previously on strain BG-1, and revealed notable differences in carbon and nitrogen metabolism between the 2 congeners under similar environmental conditions. Strain BG-1 utilized bacterial carbon and amino acids through glycolysis and the tricarboxylic acid cycle, while downregulating light harvesting and carbon fixation in the Calvin cycle when both light and bacteria were available. In contrast, the upregulation of genes related to photosynthesis, light harvesting, chlorophyll synthesis, and carbon fixation in the presence of light and prey for strain CCMP1393 implied that this species is more phototrophic than strain BG-1, and that phagotrophy may have enhanced phototrophy. Cellular chlorophyll a content was also significantly higher in strain CCMP1393 supplied with bacteria compared to those without prey. Our results thus point to very different physiological strategies for mixotrophic nutrition in these closely related chrysophyte species. PMID- 29438385 TI - Variability in metagenomic samples from the Puget Sound: Relationship to temporal and anthropogenic impacts. AB - Whole-metagenome sequencing (WMS) has emerged as a powerful tool to assess potential public health risks in marine environments by measuring changes in microbial community structure and function in uncultured bacteria. In addition to monitoring public health risks such as antibiotic resistance determinants, it is essential to measure predictors of microbial variation in order to identify natural versus anthropogenic factors as well as to evaluate reproducibility of metagenomic measurements.This study expands our previous metagenomic characterization of Puget Sound by sampling new nearshore environments including the Duwamish River, an EPA superfund site, and the Hood Canal, an area characterized by highly variable oxygen levels. We also resampled a wastewater treatment plant, nearshore and open ocean sites introducing a longitudinal component measuring seasonal and locational variations and establishing metagenomics sampling reproducibility. Microbial composition from samples collected in the open sound were highly similar within the same season and location across different years, while nearshore samples revealed multi-fold seasonal variation in microbial composition and diversity. Comparisons with recently sequenced predominant marine bacterial genomes helped provide much greater species level taxonomic detail compared to our previous study. Antibiotic resistance determinants and pollution and detoxification indicators largely grouped by location showing minor seasonal differences. Metal resistance, oxidative stress and detoxification systems showed no increase in samples proximal to an EPA superfund site indicating a lack of ecosystem adaptation to anthropogenic impacts. Taxonomic analysis of common sewage influent families showed a surprising similarity between wastewater treatment plant and open sound samples suggesting a low-level but pervasive sewage influent signature in Puget Sound surface waters. Our study shows reproducibility of metagenomic data sampling in multiple Puget Sound locations while establishing baseline measurements of antibiotic resistance determinants, pollution and detoxification systems. Combining seasonal and longitudinal data across these locations provides a foundation for evaluating variation in future studies. PMID- 29438387 TI - Genetic association study of NLRP1, CARD, and CASP1 inflammasome genes with chronic Chagas cardiomyopathy among Trypanosoma cruzi seropositive patients in Bolivia. AB - About 20-30% of people infected with Chagas disease present with chronic Chagas cardiomyopathy (CCC), the most serious and frequent manifestation of the disease, while others remain asymptomatic and often do not experience Chagas-specific mortality. It is not currently well understood what causes these differential disease outcomes, but a genetic predisposition within the host could play an important role. This study examined variants in the NLRP1, CARD, and CASP1 inflammasome genes among 62 T. cruzi seropositive patients from Bolivia (38 cases with CCC and 24 asymptomatic controls) to uncover associations with CCC. All subjects underwent a complete medical examination including electrocardiogram (EKG) and echocardiogram. After genotype calling and quality control filtering with exclusion of 3 cases and 3 controls, association analysis was performed across 76 directly genotyped SNPs in NLRP1, CARD, and CASP1 genes, adjusting for age, sex, and population stratification. One SNP (rs11651270; Bonferroni corrected p = 0.036) corresponding to a missense mutation in NLPR1 was found to be significant after adjustment for multiple testing, and a suggestive association was seen in CARD11 (rs6953573; Bonferroni-corrected p = 0.060). Although limited by sample size, the study results suggest variations in the inflammasome, particularly in NLRP1 and CARD11, may be associated with CCC. PMID- 29438388 TI - Ancient DNA analysis of Indigenous rockfish use on the Pacific Coast: Implications for marine conservation areas and fisheries management. AB - Rockfish (Sebastes spp.) are a common marine fish in nearshore and continental shelf environments in the North Pacific Ocean. They are frequently identified in coastal archaeological sites in western North America; however, the morphological similarity of rockfish species limits conventional zooarchaeological identifications to the genus level. This study applies ancient DNA analysis to 96 archaeological rockfish specimens from four sites on separate islands in an archipelago on western Vancouver Island, British Columbia, Canada. Two of the archaeological sites are located within a marine protected area specifically designed to facilitate the recovery of inshore rockfish populations; two sites are located outside this boundary and remain subject to considerable fishing pressure. Using mitochondrial 16S and control region DNA sequences, we identify at least twelve different rockfish species utilized during the past 2,500 years. Identification of rockfish at closely spaced and contemporaneously occupied sites confirms that a variety of Sebastes species were consistently exploited at each site, with more exposed areas having a higher number of species present. Identification results indicate that four of the twelve species did not occur within the conservation area boundary and, instead, were found in sites where commercial and recreational fishing continues to be permitted. This study demonstrates that ancient DNA identifications of archaeological assemblages can complement and expand perspective on modern day fisheries conservation and management in this National Park Reserve and First Nations ancestral territory. PMID- 29438386 TI - Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators. AB - Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20 fold increased parasite load, they could be still protected from ECM if they received DOX from day 4-6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions. PMID- 29438389 TI - A chance-constrained stochastic approach to intermodal container routing problems. AB - We consider a container routing problem with stochastic time variables in a sea rail intermodal transportation system. The problem is formulated as a binary integer chance-constrained programming model including stochastic travel times and stochastic transfer time, with the objective of minimising the expected total cost. Two chance constraints are proposed to ensure that the container service satisfies ship fulfilment and cargo on-time delivery with pre-specified probabilities. A hybrid heuristic algorithm is employed to solve the binary integer chance-constrained programming model. Two case studies are conducted to demonstrate the feasibility of the proposed model and to analyse the impact of stochastic variables and chance-constraints on the optimal solution and total cost. PMID- 29438390 TI - Correction: Acoustic differentiation and behavioral response reveals cryptic species within Buergeria treefrogs (Anura, Rhacophoridae) from Taiwan. AB - [This corrects the article DOI: 10.1371/journal.pone.0184005.]. PMID- 29438391 TI - Hearing impairment increases the risk of distal radius, hip, and spine fractures: A longitudinal follow-up study using a national sample cohort. AB - OBJECTIVE: Hearing impairment has been suggested to increase the risk of falls. However, most previous studies were conducted in an older population without classification of the fracture regions. This study aimed to delineate the risk of each fracture type in all age populations. METHODS: The Korean National Health Insurance Service-National Sample Cohort was collected from 2002 to 2013. A total of 4,854 severe hearing-impaired and 1,354 profound hearing-impaired participants were matched for age, group, sex, income group, and region of residence with 19,416 and 5,416 control participants, respectively. The fracture diagnosis was based on the International Classification of Disease (ICD-10) codes as follows: distal radius fracture (S525), hip fracture (S720, S721, S722), and spine fracture (S220, S32). Crude (simple) and adjusted hazard ratios (HRs) for each fracture associated with severe or profound hearing impairment were analyzed using the Cox proportional hazard model. RESULTS: The severe hearing-impaired group had an increased risk of distal radius fracture, hip fracture, and spine fracture compared with the control group (adjusted HR = 1.67, 95% CI = 1.38-2.03, P < 0.001 for hip fracture). The profound hearing-impaired group had an increased risk of hip and spine fracture (adjusted HR = 2.21, 95% CI = 1.44-3.39, P < 0.001 for hip fracture). CONCLUSION: The risk of distal radius fracture, hip fracture, and spine fracture was increased in the severe hearing-impaired group compared with the control group. PMID- 29438392 TI - Highly conserved extended haplotypes of the major histocompatibility complex and their relationship to multiple sclerosis susceptibility. AB - OBJECTIVE: To determine the relationship between highly-conserved extended haplotypes (CEHs) in the major histocompatibility complex (MHC) and MS susceptibility. BACKGROUND: Among the ~200 MS-susceptibility regions, which are known from genome-wide analyses of single nucleotide polymorphisms (SNPs), the MHC accounts for roughly a third of the currently explained variance and the strongest MS-associations are for certain Class II alleles (e.g., HLA-DRB1*15:01; HLA-DRB1*03:01; and HLA-DRB1*13:03), which frequently reside on CEHs within the MHC. DESIGN/METHODS: Autosomal SNPs (441,547) from 11,376 MS cases and 18,872 controls in the WTCCC dataset were phased. The most significant MS associated SNP haplotype was composed of 11 SNPs in the MHC Class II region surrounding the HLA DRB1 gene. We also phased alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, and HLA DQB1 loci. This data was used to probe the relationship between CEHs and MS susceptibility. RESULTS: We phased a total of 59,884 extended haplotypes (HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DQB1 and SNP haplotypes) from 29,942 individuals. Of these, 10,078 unique extended haplotypes were identified. The 10 most common CEHs accounted for 22% (13,302) of the total. By contrast, the 8,446 least common extended haplotypes also accounted for approximately 20% (12,298) of the total. This extreme frequency-disparity among extended haplotypes necessarily complicates interpretation of reported disease-associations with specific HLA alleles. In particular, the HLA motif HLA-DRB1*15:01~HLA-DQB1*06:02 is strongly associated with MS risk. Nevertheless, although this motif is almost always found on the a1 SNP haplotype, it can rarely be found on others (e.g., a27 and a36), and, in these cases, it seems to have no apparent disease-association (OR = 0.7; CI = 0.3-1.3 and OR = 0.7; CI = 0.2-2.2, respectively). Furthermore, single copy carriers of the a1 SNP-haplotype without this HLA motif still have an increased disease risk (OR = 2.2; CI = 1.2-3.8). In addition, even among the set of CEHs, which carry the Class II motif of HLA-DRB1*15:01~HLA-DQB1*06:02~a1, different CEHs have differing strengths in their MS-associations. CONCLUSIONS: The MHC in diverse human populations consists, primarily, of a very small collection of very highly-selected CEHs. Our findings suggest that the MS-association with the HLA DRB1*15:01~HLA-DQB1*06:02 haplotype may be due primarily to the combined attributes of the CEHs on which this particular HLA-motif often resides. PMID- 29438393 TI - Hyperspectral measurements of immature Lucilia sericata (Meigen) (Diptera: Calliphoridae) raised on different food substrates. AB - Immature Lucilia sericata (Meigen) raised on beef liver, beef heart, pork liver and pork heart at a mean temperature of 20.6 degrees C took a minimum of 20 days to complete development. Minimum development time differences within stages were observed between the meat types (pork/beef), but not the organ types (liver/heart). Daily hyperspectral measurements were conducted and a functional regression was completed to examine the main effects of meat and organ type on daily spectral measurements. The model examined post feeding larval spectral measurements of insects raised on beef liver alone, the effect of those raised on pork compared with those raised on beef, the effect of those raised on heart compared with those raised on liver and the interactional effect of those raised on pork heart compared with those raised on beef liver. The analyses indicated that the spectral measurements of post feeding L. sericata raised on pork and beef organs (liver and heart) are affected by the meat and organ type. PMID- 29438394 TI - Prenatal exposure to preeclampsia is associated with accelerated height gain in early childhood. AB - BACKGROUND: Preeclampsia is associated with low birth weight, both because of increased risks of preterm and of small-for-gestational-age (SGA) births. Low birth weight is associated with accelerated childhood height gain and cardiovascular diseases later in life. The aim was to investigate if prenatal exposure to preeclampsia is associated with accelerated childhood height gain, also after adjustments for SGA-status and gestational age at birth. METHODS: In a cohort of children prenatally exposed to preeclampsia (n = 865) or unexposed (n = 22,898) we estimated height gain between birth and five years of age. The mean difference in height gain between exposed and unexposed children was calculated and adjustments were done with linear regression models. RESULTS: Children exposed to preeclampsia were on average born shorter than unexposed. Exposed children grew on average two cm more than unexposed from birth to five years of age. After adjustments for maternal characteristics including socioeconomic factors, height, body mass index (BMI) and diabetes, as well as for parents smoking habits, infant's breastfeeding and childhood obesity, the difference was 1.6 cm (95% CI 1.3-1.9 cm). Further adjustment for SGA birth only slightly attenuated this estimate, but adjustment for gestational age at birth decreased the estimate to 0.5 cm (95% CI 0.1-0.7 cm). CONCLUSION: Prenatal exposure to preeclampsia is associated with accelerated height gain in early childhood. The association seemed independent on SGA-status, but partly related to shorter gestational age at birth. PMID- 29438396 TI - Children's peer violence perpetration and victimization: Prevalence and associated factors among school children in Afghanistan. AB - BACKGROUND: Child peer violence is a global problem and seriously impacts children's physical and psychological health, and their education outcomes. There are few research studies on children's peer violence available in South Asian countries, particularly in Afghanistan. This paper describes the prevalence of children's peer violence perpetration and victimization and associated factors among school children in Afghanistan. METHODS: A total of 770 children were recruited into a baseline study conducted as part of an intervention evaluation in 11 schools (seven girls' and four boys' schools). All children were interviewed with a questionnaire developed for the study. The main outcome is a three-level peer violence variable consisting of (a) no violence, (b) victimization only, or (c) perpetration (with or without victimization). Peer violence victimization was measured through the Multidimensional Peer Victimization Scale, and peer violence perpetration was measured through an adjusted version of the same scale with wording changed to measure perpetration. RESULTS: 49.7% of boys and 43.3% of girls reported having experienced more than one instance of violence victimization in the past month, and 31.7% of boys and 17.6% of girls disclosed perpetration of more than one instance of violence in the past month, with considerable overlap found between experience of victimization and perpetration, particularly among boys. Multinomial models of factors associated with peer violence show that for boys, food insecurity was associated with perpetration of peer violence but not with victimization, and experiencing corporal punishment at school in the last month was significantly associated with both peer victimization and perpetration. For girls, food insecurity, more depressive symptoms and experiencing any beating at home were associated with both violence victimization and perpetration. Having a disability was associated with victimization only, and having witnessed their father fighting and experiencing any kind of corporal punishment were associated with peer violence perpetration only. DISCUSSION: Peer violence in Afghanistan is linked to food insecurity, exposure of children to witnessing family violence, and children's experience of physical violence at home and corporal punishment at school. School-based settings provide an important platform for interventions to reduce and prevent peer violence; however, such interventions may benefit from broader violence-prevention initiatives conducted at the community level. PMID- 29438395 TI - Recognition of sites of functional specialisation in all known eukaryotic protein kinase families. AB - The conserved function of protein phosphorylation, catalysed by members of protein kinase superfamily, is regulated in different ways in different kinase families. Further, differences in activating triggers, cellular localisation, domain architecture and substrate specificity between kinase families are also well known. While the transfer of gamma-phosphate from ATP to the hydroxyl group of Ser/Thr/Tyr is mediated by a conserved Asp, the characteristic functional and regulatory sites are specialized at the level of families or sub-families. Such family-specific sites of functional specialization are unknown for most families of kinases. In this work, we systematically identify the family-specific residue features by comparing the extent of conservation of physicochemical properties, Shannon entropy and statistical probability of residue distributions between families of kinases. An integrated discriminatory score, which combines these three features, is developed to demarcate the functionally specialized sites in a kinase family from other sites. We achieved an area under ROC curve of 0.992 for the discrimination of kinase families. Our approach was extensively tested on well-studied families CDK and MAPK, wherein specific protein interaction sites and substrate recognition sites were successfully detected (p-value < 0.05). We also find that the known family-specific oncogenic driver mutation sites were scored high by our method. The method was applied to all known kinases encompassing 107 families from diverse eukaryotic organisms leading to a comprehensive list of family-specific functional sites. Apart from other uses, our method facilitates identification of specific protein interaction sites and drug target sites in a kinase family. PMID- 29438397 TI - Capacity of non-invasive hepatic fibrosis algorithms to replace transient elastography to exclude cirrhosis in people with hepatitis C virus infection: A multi-centre observational study. AB - INTRODUCTION: Achievement of the 2030 World Health Organisation (WHO) global hepatitis C virus (HCV) elimination targets will be underpinned by scale-up of testing and use of direct-acting antiviral treatments. In Australia, despite publically-funded testing and treatment, less than 15% of patients were treated in the first year of treatment access, highlighting the need for greater efficiency of health service delivery. To this end, non-invasive fibrosis algorithms were examined to reduce reliance on transient elastography (TE) which is currently utilised for the assessment of cirrhosis in most Australian clinical settings. MATERIALS AND METHODS: This retrospective and prospective study, with derivation and validation cohorts, examined consecutive patients in a tertiary referral centre, a sexual health clinic, and a prison-based hepatitis program. The negative predictive value (NPV) of seven non-invasive algorithms were measured using published and newly derived cut-offs. The number of TEs avoided for each algorithm, or combination of algorithms, was determined. RESULTS: The 850 patients included 780 (92%) with HCV mono-infection, and 70 (8%) co-infected with HIV or hepatitis B. The mono-infected cohort included 612 men (79%), with an overall prevalence of cirrhosis of 16% (125/780). An 'APRI' algorithm cut-off of 1.0 had a 94% NPV (95%CI: 91-96%). Newly derived cut-offs of 'APRI' (0.49), 'FIB 4' (0.93) and 'GUCI' (0.5) algorithms each had NPVs of 99% (95%CI: 97-100%), allowing avoidance of TE in 40% (315/780), 40% (310/780) and 40% (298/749) respectively. When used in combination, NPV was retained and TE avoidance reached 54% (405/749), regardless of gender or co-infection. CONCLUSIONS: Non-invasive algorithms can reliably exclude cirrhosis in many patients, allowing improved efficiency of HCV assessment services in Australia and worldwide. PMID- 29438398 TI - Proteomics analysis identified peroxiredoxin 2 involved in early-phase left ventricular impairment in hamsters with cardiomyopathy. AB - Given the hypothesis that inflammation plays a critical role in the progression of cardiovascular diseases, the aim of the present study was to identify new diagnostic and prognostic biomarkers of myocardial proteins involved in early phase cardiac impairment, using proteomics analysis. Using the two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with MALDI-TOF/TOF tandem mass spectrometry, we compared differences in the expression of proteins in the whole left ventricles between control hamsters, dilated cardiomyopathic hamsters (TO-2), and hypertrophy cardiomyopathic hamsters (Bio14.6) at 6 weeks of age (n = 6, each group). Proteomic analysis identified 10 protein spots with significant alterations, with 7 up-regulated and 3 down-regulated proteins in the left ventricles of both TO-2 and Bio 14.6 hamsters, compared with control hamsters. Of the total alterations, peroxiredoxin 2 (PRDX2) showed significant upregulation in the left ventricles of TO-2 and Bio 14.6 hamsters. Our data suggest that PRDX2, a redox regulating molecule, is involved in early-phase left ventricular impairment in hamsters with cardiomyopathy. PMID- 29438399 TI - Early visual ERPs show stable body-sensitive patterns over a 4-week test period. AB - Event-related potential (ERP) studies feature among the most cited papers in the field of body representation, with recent research highlighting the potential of ERPs as neuropsychiatric biomarkers. Despite this, investigation into how reliable early visual ERPs and body-sensitive effects are over time has been overlooked. This study therefore aimed to assess the stability of early body sensitive effects and visual P1, N1 and VPP responses. Participants were asked to identify pictures of their own bodies, other bodies and houses during an EEG test session that was completed at the same time, once a week, for four consecutive weeks. Results showed that amplitude and latency of early visual components and their associated body-sensitive effects were stable over the 4-week period. Furthermore, correlational analyses revealed that VPP component amplitude might be more reliable than VPP latency and specific electrode sites might be more robust indicators of body-sensitive cortical activity than others. These findings suggest that visual P1, N1 and VPP responses, alongside body-sensitive N1/VPP effects, are robust indications of neuronal activity. We conclude that these components are eligible to be considered as electrophysiological biomarkers relevant to body representation. PMID- 29438400 TI - Nocturnal insomnia symptoms and stress-induced cognitive intrusions in risk for depression: A 2-year prospective study. AB - Nearly half of US adults endorse insomnia symptoms. Sleep problems increase risk for depression during stress, but the mechanisms are unclear. During high stress, individuals having difficulty falling or staying asleep may be vulnerable to cognitive intrusions after stressful events, given that the inability to sleep creates a period of unstructured and socially isolated time in bed. We investigated the unique and combined effects of insomnia symptoms and stress induced cognitive intrusions on risk for incident depression. 1126 non-depressed US adults with no history of DSM-5 insomnia disorder completed 3 annual web-based surveys on sleep, stress, and depression. We examined whether nocturnal insomnia symptoms and stress-induced cognitive intrusions predicted depression 1y and 2y later. Finally, we compared depression-risk across four groups: non-perseverators with good sleep, non-perseverators with insomnia symptoms, perseverators with good sleep, and perseverators with insomnia symptoms. Insomnia symptoms (beta = .10-.13, p < .001) and cognitive intrusions (beta = .19-.20, p < .001) predicted depression severity 1y and 2y later. Depression incidence across 2 years was 6.2%. Perseverators with insomnia had the highest rates of depression (13.0%), whereas good sleeping non-perseverators had the lowest rates (3.3%, Relative Risk = 3.94). Perseverators with sleep latency >30 m reported greater depression than good sleeping perseverators (t = 2.09, p < .04). Cognitive intrusions following stress creates a depressogenic mindset, and nocturnal wakefulness may augment the effects of cognitive arousal on depression development. Poor sleepers may be especially vulnerable to cognitive intrusions when having difficulty initiating sleep. As treatable behaviors, nighttime wakefulness and cognitive arousal may be targeted to reduce risk for depression in poor sleepers. PMID- 29438402 TI - Haiku: New paradigm for the reverse genetics of emerging RNA viruses. AB - Reverse genetics is key technology for producing wild-type and genetically modified viruses. The ISA (Infectious Subgenomic Amplicons) method is a recent versatile and user-friendly reverse genetics method to rescue RNA viruses. The main constraint of its canonic protocol was the requirement to produce (e.g., by DNA synthesis or fusion PCR) 5' and 3' modified genomic fragments encompassing the human cytomegalovirus promoter (pCMV) and the hepatitis delta virus ribozyme/simian virus 40 polyadenylation signal (HDR/SV40pA), respectively. Here, we propose the ultimately simplified "Haiku" designs in which terminal pCMV and HDR/SV40pA sequences are provided as additional separate DNA amplicons. This improved procedure was successfully applied to the rescue of a wide range of viruses belonging to genera Flavivirus, Alphavirus and Enterovirus in mosquito or mammalian cells using only standard PCR amplification techniques and starting from a variety of original materials including viral RNAs extracted from cell supernatant media or animal samples. We also demonstrate that, in specific experimental conditions, the presence of the HDR/SV40pA is not necessary to rescue the targeted viruses. These ultimately simplified "Haiku" designs provide an even more simple, rapid, versatile and cost-effective tool to rescue RNA viruses since only generation of overlapping amplicons encompassing the entire viral genome is now required to generate infectious virus. This new approach may completely modify our capacity to obtain infectious RNA viruses. PMID- 29438401 TI - Systemic and vascular inflammation in an in-vitro model of central obesity. AB - Metabolic disorders due to over-nutrition are a major global health problem, often associated with obesity and related morbidities. Obesity is peculiar to humans, as it is associated with lifestyle and diet, and so difficult to reproduce in animal models. Here we describe a model of human central adiposity based on a 3-tissue system consisting of a series of interconnected fluidic modules. Given the causal link between obesity and systemic inflammation, we focused primarily on pro-inflammatory markers, examining the similarities and differences between the 3-tissue model and evidence from human studies in the literature. When challenged with high levels of adiposity, the in-vitro system manifests cardiovascular stress through expression of E-selectin and von Willebrand factor as well as systemic inflammation (expressing IL-6 and MCP-1) as observed in humans. Interestingly, most of the responses are dependent on the synergic interaction between adiposity and the presence of multiple tissue types. The set-up has the potential to reduce animal experiments in obesity research and may help unravel specific cellular mechanisms which underlie tissue response to nutritional overload. PMID- 29438403 TI - Release of transcriptional repression through the HCR promoter region confers uniform expression of HWP1 on surfaces of Candida albicans germ tubes. AB - The mechanisms that fungi use to co-regulate subsets of genes specifically associated with morphogenic states represent a basic unsolved problem in fungal biology. Candida albicans is an important model of fungal differentiation both for rapid interconversion between yeast and hyphal growth forms and for white/opaque switching mechanisms. The Sundstrom lab is interested in mechanisms regulating hypha-specific expression of adhesin genes that are critical for C. albicans hyphal growth phenotypes and pathogenicity. Early studies on hypha specific genes such as HWP1 and ALS3 reported 5' intergenic regions that are larger than those typically found in an average promoter and are associated with hypha-specific expression. In the case of HWP1, activation and repression involves a 368 bp region, denoted the HWP1 control region (HCR), located 1410 bp upstream of its transcription start site. In previous work we showed that HCR confers developmental regulation to a heterologous ENO1 promoter, indicating that HCR by itself contains sufficient information to couple gene expression to morphology. Here we show that the activation and repression mediated by HCR are localized to distinct HCR regions that are targeted by the transcription factors Nrg1p and Efg1p. The finding that Efg1p mediates both repression via HCR under yeast morphological conditions and activation conditions positions Efg1p as playing a central role in coupling HWP1 expression to morphogenesis through the HCR region. These localization studies revealed that the 120 terminal base pairs of HCR confer Efg1p-dependent repressive activity in addition to the Nrg1p repressive activity mediated by DNA upstream of this subregion. The 120 terminal base pair subregion of HCR also contained an initiation site for an HWP1 transcript that is specific to yeast growth conditions (HCR-Y) and may function in the repression of downstream DNA. The detection of an HWP1 mRNA isoform specific to hyphal growth conditions (HWP1-H) showed that morphology-specific mRNA isoforms occur under both yeast and hyphal growth conditions. Similar results were found at the ALS3 locus. Taken together, these results, suggest that the long 5' intergenic regions upstream of hypha-specific genes function in generating mRNA isoforms that are important for morphology-specific gene expression. Additional complexity in the HWP1 promoter involving HCR-independent activation was discovered by creating a strain lacking HCR that exhibited variable HWP1 expression during hyphal growth conditions. These results show that while HCR is important for ensuring uniform HWP1 expression in cell populations, HCR independent expression also exists. Overall, these results elucidate HCR dependent mechanisms for coupling HWP1-dependent gene expression to morphology uniformly in cell populations and prompt the hypothesis that mRNA isoforms may play a role in coupling gene expression to morphology in C. albicans. PMID- 29438404 TI - Xylem specific activation of 5' upstream regulatory region of two NAC transcription factors (MusaVND6 and MusaVND7) in banana is regulated by SNBE-like sites. AB - Deposition of secondary cell wall in the xylem elements is controlled by a subgroup of NAC (NAM, ATAF, CUC) family, known as vascular-related NAC transcription factors (VNDs). In the present study, we analyzed the 5' upstream regulatory region of two banana NAC transcription factors (MusaVND6 and MusaVND7) for tissue specific expression and presence of 19-bp secondary-wall NAC binding element (SNBE)-like motifs. Transgenic banana plants of Musa cultivar Rasthali harboring either PMusaVND7::GUS or PMusaVND6::GUS showed specific GUS (beta-D Glucuronidase) activity in cells of the xylem tissue. Approximately 1.2kb promoter region of either MusaVND6 or MusaVND7 showed presence of at least two SNBE-like motifs. This 1.2kb promoter region was retarded in a gel shift assay by three banana VND protein (VND1,VND2 and VND3). The banana VND1-VND3 could also retard the mobility of isolated SNBE-like motifs of MusaVND6 or MusaVND7 in a gel shift assay. Transcript levels of MusaVND6 and MusaVND7 were elevated in transgenic banana overexpressing either banana VND1, VND2 or VND3. Present study suggested a probable regulation of banana VND6 and VND7 expression through direct interaction of banana VND1- VND3 with SNBE-like motifs. Our study also indicated two promoter elements for possible utilization in cell wall modifications in plants especially banana, which is being recently considered as a potential biofuel crop. PMID- 29438405 TI - Multiplatform plasma metabolic and lipid fingerprinting of breast cancer: A pilot control-case study in Colombian Hispanic women. AB - Breast cancer (BC) is a highly heterogeneous disease associated with metabolic reprogramming. The shifts in the metabolome caused by BC still lack data from Latin populations of Hispanic origin. In this pilot study, metabolomic and lipidomic approaches were performed to establish a plasma metabolic fingerprint of Colombian Hispanic women with BC. Data from 1H-NMR, GC-MS and LC-MS were combined and compared. Statistics showed discrimination between breast cancer and healthy subjects on all analytical platforms. The differentiating metabolites were involved in glycerolipid, glycerophospholipid, amino acid and fatty acid metabolism. This study demonstrates the usefulness of multiplatform approaches in metabolic/lipid fingerprinting studies to broaden the outlook of possible shifts in metabolism. Our findings propose relevant plasma metabolites that could contribute to a better understanding of underlying metabolic shifts driven by BC in women of Colombian Hispanic origin. Particularly, the understanding of the up regulation of long chain fatty acyl carnitines and the down-regulation of cyclic phosphatidic acid (cPA). In addition, the mapped metabolic signatures in breast cancer were similar but not identical to those reported for non-Hispanic women, despite racial differences. PMID- 29438406 TI - Comparison between influenza coded primary care consultations and national influenza incidence obtained by the General Practitioners Sentinel Network in Portugal from 2012 to 2017. AB - Influenza is associated with severe illness, death, and economic burden. Sentinel surveillance systems have a central role in the community since they support public health interventions. This study aimed to describe and compare the influenza-coded primary care consultations with the reference index of influenza activity used in Portugal, General Practitioners Sentinel Network, from 2012 to 2017. An ecological time-series study was conducted using weekly R80-coded primary care consultations (according to the International Classification of Primary Care-2), weekly influenza-like illness (ILI) incidence rates from the General Practitioners Sentinel Network and Goldstein Index (GI). Good accordance between these three indicators was observed in the characterization of influenza activity regarding to start and length of the epidemic period, intensity of influenza activity, and influenza peak. A high correlation (>0.75) was obtained between weekly ILI incidence rates and weekly number of R80-coded primary care consultations during all five studied seasons. In 3 out of 5 seasons this correlation increased when weekly ILI incidence rates were multiplied for the percentage of influenza positive cases. A cross-correlation between weekly ILI incidence rates and the weekly number of R80-coded primary care consultations revealed that there was no lag between the rate curves of influenza incidence and the number of consultations in the 2012/13 and 2013/14 seasons. In the last three seasons, the weekly influenza incidence rates detected the influenza epidemic peak for about a week earlier. In the last season, the GI anticipated the detection of influenza peak for about a two-week period. Sentinel networks are fundamental elements in influenza surveillance that integrate clinical and virological data but often lack representativeness and are not able to provide regional and age groups estimates. Given the good correlation between weekly ILI incidence rate and weekly number of R80 consultations, primary care consultation coding system may be used to complement influenza surveillance data, namely, to monitor regional influenza activity. In the future, it would be interesting to analyse concurrent implementation of both surveillance systems with the integration of all available information. PMID- 29438407 TI - The complete mitochondrial genome of Somanniathelphusa boyangensis and phylogenetic analysis of Genus Somanniathelphusa (Crustacea: Decapoda: Parathelphusidae). AB - In this study, the authors first obtained the mitochondrial genome of Somanniathelphusa boyangensis. The results showed that the mitochondrial genome is 17,032bp in length, included 13 protein-coding genes, 2 rRNAs genes, 22 tRNAs genes and 1 putative control region, and it has the characteristics of the metazoan mitochondrial genome A+T bias. All tRNA genes display the typical clover leaf secondary structure except tRNASer(AGN), which has lost the dihydroxyuridine arm. The GenBank database contains the mitochondrial genomes of representatives of approximately 22 families of Brachyura, comprising 56 species, including 4 species of freshwater crab. The authors established the phylogenetic relationships using the maximum likelihood and Bayesian inference methods. The phylogenetic relationship indicated that the molecular taxonomy of S. boyangensis is consistent with current morphological classification, and Parathelphusidae and Potamidae are derived within the freshwater clade or as part of it. In addition, the authors used the COX1 sequence of Somanniathelphusa in GenBank and the COX1 sequence of S. boyangensis to estimated the divergence time of this genus. The result displayed that the divergence time of Somanniathelphusa qiongshanensis is consistent with the separation of Hainan Island from mainland China in the Beibu Gulf, and the divergence time for Somanniathelphusa taiwanensis and Somanniathelphusa amoyensis is consistent with the separation of Taiwan Province from Mainland China at Fujian Province. These data indicate that geologic events influenced speciation of the genus Somanniathelphusa. PMID- 29438408 TI - Thermal resilience may shape population abundance of two sympatric congeneric Cotesia species (Hymenoptera: Braconidae). AB - Basal and plasticity of thermal tolerance determine abundance, biogeographical patterns and activity of insects over spatial and temporal scales. For coexisting stemborer parasitoids, offering synergistic impact for biological control, mismatches in thermal tolerance may influence their ultimate impact in biocontrol programs under climate variability. Using laboratory-reared congeneric parasitoid species Cotesia sesamiae Cameron and Cotesia flavipes Cameron (Hymenoptera: Braconidae), we examined basal thermal tolerance to understand potential impact of climate variability on their survival and limits to activity. We measured upper- and lower -lethal temperatures (ULTs and LLTs), critical thermal limits [CTLs] (CTmin and CTmax), supercooling points (SCPs), chill-coma recovery time (CCRT) and heat knock-down time (HKDT) of adults. Results showed LLTs ranging -5 to 5 degrees C and -15 to -1 degrees C whilst ULTs ranged 35 to 42 degrees C and 37 to 44 degrees C for C. sesamiae and C. flavipes respectively. Cotesia flavipes had significantly higher heat tolerance (measured as CTmax), as well as cold tolerance (measured as CTmin) relative to C. sesamiae (P<0.0001). While SCPs did not vary significantly (P>0.05), C. flavipes recovered significantly faster following chill-coma and had higher HKDT compared to C. sesamiae. The results suggest marked differential basal thermal tolerance responses between the two congeners, with C. flavipes having an advantage at both temperature extremes. Thus, under predicted climate change, the two species may differ in phenologies and biogeography with consequences on their efficacy as biological control agents. These results may assist in predicting spatio-temporal activity patterns which can be used in integrated pest management programs under climate variability. PMID- 29438409 TI - The effect of transient oxygenation on stem cell mobilization and ischemia/reperfusion heart injury. AB - For general anesthesia, pre-oxygenation is routinely performed prior to intubation. It is well-known that ischemic/hypoxic preconditioning induces stem cell mobilization and protects against ischemia/reperfusion (I/R) injury. In this study, we investigated the effect of transient oxygenation on stem cell mobilization and I/R injury of the heart. Mice were exposed to 100% oxygen for 5 or 20 minutes. We evaluated the number of c-kit+ stem/progenitor cells and the levels of SDF-1alpha and VEGF in peripheral blood at 1, 3, 6, and 24 hours after oxygenation. We also induced I/R injury of the heart at 3 hours post-oxygenation for 5 minutes and then examined stem cell recruitment and fibrotic changes in the heart 3 or 14 days later. The number of c-kit+ cells in peripheral blood was significantly increased at 1 or 24 hours after oxygenation for either 5 or 20 minutes. Oxygenation for 5 or 20 minutes did not significantly change the SDF 1alpha level measured in plasma. However, the plasma VEGF level was decreased at 3 hours post-oxygenation for 20 minutes (p = 0.051). Oxygenation for 5 minutes did not significantly alter the fibrotic area or cell apoptosis. Although oxygenation for 5 minutes increased the number of c-kit+ cells in hearts damaged by I/R injury, this difference was not significant between groups due to large variation between individuals (p = 0.14). Although transient oxygenation induces stem cell mobilization, it does not appear to protect against I/R injury of the heart in mice. PMID- 29438410 TI - A new prediction model for operative time of flexible ureteroscopy with lithotripsy for the treatment of renal stones. AB - This study aimed to develop a prediction model for the operative time of flexible ureteroscopy (fURS) for renal stones. We retrospectively evaluated patients with renal stones who had been treated successfully and had stone-free status determined by non-contrast computed tomography (NCCT) 3 months after fURS and holmium laser lithotripsy between December 2009 and September 2014 at a single institute. Correlations between possible factors and the operative time were analyzed using Spearman's correlation coefficients and a multivariate linear regression model. The P value < 0.1 was used for entry of variables into the model and for keeping the variables in the model. Internal validation was performed using 10,000 bootstrap resamples. Flexible URS was performed in 472 patients, and 316 patients were considered to have stone-free status and were enrolled in this study. Spearman's correlation coefficients showed a significant positive relationship between the operation time and stone volume (rho = 0.417, p < 0.001), and between the operation time and maximum Hounsfield units (rho = 0.323, p < 0.001). A multivariate assessment with forced entry and stepwise selection revealed six factors to predict the operative time of fURS: preoperative stenting, stone volume, maximum Hounsfield unit, surgeon experience, sex, and sheath diameter. Based on this finding, we developed a model to predict operative time of fURS. The coefficient of determination (R2) in this model was 0.319; the mean R2 value for the prediction model was 0.320 +/- 0.049. To our knowledge, this is the first report of a model for predicting the operative time of fURS treatment of renal stones. The model may be used to reliably predict operative time preoperatively based on patient characteristics and the surgeons' experience, plan staged URS, and avoid surgical complications. PMID- 29438411 TI - Evaluation of a mid-career investigator career development award: Assessing the ability of OppNet K18 awardees to obtain NIH follow-on research funding. AB - The National Institutes of Health (NIH) K18 award mechanism provides funded opportunities for established investigators to gain knowledge in fields outside of their primary disciplines, but outcomes associated with these awards have not been evaluated to date. NIH's Basic Behavioral and Social Sciences Opportunity Network (OppNet) is one of the few initiatives that has used this award mechanism. We explored how the unique features of K18 awards affect the ability of recipients to obtain follow-on NIH research funding. We compared outcomes (ability to obtain follow-on funding and interval between receipt of the primary award and receipt of the first follow-on award) associated with OppNet K18 awards to findings from evaluations of other NIH career development (K) awards, which usually target early-career investigators. We hypothesized that K18 award recipients might be (1) more successful than are other K award recipients in obtaining follow-on NIH research funding due to their career experience or (2) less successful due to the competing demands of other projects. By analyzing follow-on NIH research awards and interview data, we found that OppNet K18 award recipients were at least as successful as were other K award recipients in obtaining follow-on funding and may have been more successful by certain measures. K18 awards produce their outcomes with a lower investment per investigator than do other K awards, suggesting continued or enhanced use of the mechanism. PMID- 29438412 TI - Tissue distribution and subcellular localizations determine in vivo functional relationship among prostasin, matriptase, HAI-1, and HAI-2 in human skin. AB - The membrane-bound serine proteases prostasin and matriptase and the Kunitz-type protease inhibitors HAI-1 and HAI-2 are all expressed in human skin and may form a tightly regulated proteolysis network, contributing to skin pathophysiology. Evidence from other systems, however, suggests that the relationship between matriptase and prostasin and between the proteases and the inhibitors can be context-dependent. In this study the in vivo zymogen activation and protease inhibition status of matriptase and prostasin were investigated in the human skin. Immunohistochemistry detected high levels of activated prostasin in the granular layer, but only low levels of activated matriptase restricted to the basal layer. Immunoblot analysis of foreskin lysates confirmed this in vivo zymogen activation status and further revealed that HAI-1 but not HAI-2 is the prominent inhibitor for prostasin and matriptase in skin. The zymogen activation status and location of the proteases does not support a close functional relation between matriptase and prostasin in the human skin. The limited role for HAI-2 in the inhibition of matriptase and prostasin is the result of its primarily intracellular localization in basal and spinous layer keratinocytes, which probably prevents the Kunitz inhibitor from interacting with active prostasin or matriptase. In contrast, the cell surface expression of HAI-1 in all viable epidermal layers renders it an effective regulator for matriptase and prostasin. Collectively, our study suggests the importance of tissue distribution and subcellular localization in the functional relationship between proteases and protease inhibitors. PMID- 29438413 TI - Spatial overlap links seemingly unconnected genotype-matched TB cases in rural Uganda. AB - INTRODUCTION: Incomplete understanding of TB transmission dynamics in high HIV prevalence settings remains an obstacle for prevention. Understanding where transmission occurs could provide a platform for case finding and interrupting transmission. METHODS: From 2012-2015, we sought to recruit all adults starting TB treatment in a Ugandan community. Participants underwent household (HH) contact investigation, and provided names of social contacts, sites of work, healthcare and socializing, and two sputum samples. Mycobacterium tuberculosis culture-positive specimens underwent 24-loci MIRU-VNTR and spoligotyping. We sought to identify epidemiologic links between genotype-matched cases by analyzing social networks and mapping locations where cases reported spending >=12 hours over the one-month pre-treatment. Sites of spatial overlap (<=100m) between genotype-matched cases were considered potential transmission sites. We analyzed social networks stratified by genotype clustering status, with cases linked by shared locations, and compared network density by location type between clustered vs. non-clustered cases. RESULTS: Of 173 adults with TB, 131 (76%) were enrolled, 108 provided sputum, and 84/131 (78%) were MTB culture-positive: 52% (66/131) tested HIV-positive. Of 118 adult HH contacts, 105 (89%) were screened and 3 (2.5%) diagnosed with active TB. Overall, 33 TB cases (39%) belonged to 15 distinct MTB genotype-matched clusters. Within each cluster, no cases shared a HH or reported shared non-HH contacts. In 6/15 (40%) clusters, potential epidemiologic links were identified by spatial overlap at specific locations: 5/6 involved health care settings. Genotype-clustered TB social networks had significantly greater network density based on shared clinics (p<0.001) and decreased density based on shared marketplaces (p<0.001), compared to non clustered networks. CONCLUSIONS: In this molecular epidemiologic study, links between MTB genotype-matched cases were only identifiable via shared locations, healthcare locations in particular, rather than named contacts. This suggests most transmission is occurring between casual contacts, and emphasizes the need for improved infection control in healthcare settings in rural Africa. PMID- 29438414 TI - Perfluoroalkyl substances and changes in body weight and resting metabolic rate in response to weight-loss diets: A prospective study. AB - BACKGROUND: The potential endocrine-disrupting effects of perfluoroalkyl substances (PFASs) have been demonstrated in animal studies, but whether PFASs may interfere with body weight regulation in humans is largely unknown. This study aimed to examine the associations of PFAS exposure with changes in body weight and resting metabolic rate (RMR) in a diet-induced weight-loss setting. METHODS AND FINDINGS: In the 2-year POUNDS Lost randomized clinical trial based in Boston, Massachusetts, and Baton Rouge, Louisiana, that examined the effects of energy-restricted diets on weight changes, baseline plasma concentrations of major PFASs were measured among 621 overweight and obese participants aged 30-70 years. Body weight was measured at baseline and 6, 12, 18, and 24 months. RMR and other metabolic parameters, including glucose, lipids, thyroid hormones, and leptin, were measured at baseline and 6 and 24 months. Participants lost an average of 6.4 kg of body weight during the first 6 months (weight-loss period) and subsequently regained an average of 2.7 kg of body weight during the period of 6-24 months (weight regain period). After multivariate adjustment, baseline PFAS concentrations were not significantly associated with concurrent body weight or weight loss during the first 6 months. In contrast, higher baseline levels of PFASs were significantly associated with a greater weight regain, primarily in women. In women, comparing the highest to the lowest tertiles of PFAS concentrations, the multivariate-adjusted mean weight regain (SE) was 4.0 (0.8) versus 2.1 (0.9) kg for perfluorooctanesulfonic acid (PFOS) (Ptrend = 0.01); 4.3 (0.9) versus 2.2 (0.8) kg for perfluorooctanoic acid (PFOA) (Ptrend = 0.007); 4.7 (0.9) versus 2.5 (0.9) kg for perfluorononanoic acid (PFNA) (Ptrend = 0.006); 4.9 (0.9) versus 2.7 (0.8) kg for perfluorohexanesulfonic acid (PFHxS) (Ptrend = 0.009); and 4.2 (0.8) versus 2.5 (0.9) kg for perfluorodecanoic acid (PFDA) (Ptrend = 0.03). When further adjusted for changes in body weight or thyroid hormones during the first 6 months, results remained similar. Moreover, higher baseline plasma PFAS concentrations, especially for PFOS and PFNA, were significantly associated with greater decline in RMR during the weight-loss period and less increase in RMR during the weight regain period in both men and women. Limitations of the study include the possibility of unmeasured or residual confounding by socioeconomic and psychosocial factors, as well as possible relapse to the usual diet prior to randomization, which could have been rich in foods contaminated by PFASs through food packaging and also dense in energy. CONCLUSIONS: In this diet-induced weight-loss trial, higher baseline plasma PFAS concentrations were associated with a greater weight regain, especially in women, possibly explained by a slower regression of RMR levels. These data illustrate a potential novel pathway through which PFASs interfere with human body weight regulation and metabolism. The possible impact of environmental chemicals on the obesity epidemic therefore deserves attention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00072995. PMID- 29438415 TI - Longitudinal changes in telomere length and associated genetic parameters in dairy cattle analysed using random regression models. AB - Telomeres cap the ends of linear chromosomes and shorten with age in many organisms. In humans short telomeres have been linked to morbidity and mortality. With the accumulation of longitudinal datasets the focus shifts from investigating telomere length (TL) to exploring TL change within individuals over time. Some studies indicate that the speed of telomere attrition is predictive of future disease. The objectives of the present study were to 1) characterize the change in bovine relative leukocyte TL (RLTL) across the lifetime in Holstein Friesian dairy cattle, 2) estimate genetic parameters of RLTL over time and 3) investigate the association of differences in individual RLTL profiles with productive lifespan. RLTL measurements were analysed using Legendre polynomials in a random regression model to describe TL profiles and genetic variance over age. The analyses were based on 1,328 repeated RLTL measurements of 308 female Holstein Friesian dairy cattle. A quadratic Legendre polynomial was fitted to the fixed effect of age in months and to the random effect of the animal identity. Changes in RLTL, heritability and within-trait genetic correlation along the age trajectory were calculated and illustrated. At a population level, the relationship between RLTL and age was described by a positive quadratic function. Individuals varied significantly regarding the direction and amount of RLTL change over life. The heritability of RLTL ranged from 0.36 to 0.47 (SE = 0.05 0.08) and remained statistically unchanged over time. The genetic correlation of RLTL at birth with measurements later in life decreased with the time interval between samplings from near unity to 0.69, indicating that TL later in life might be regulated by different genes than TL early in life. Even though animals differed in their RLTL profiles significantly, those differences were not correlated with productive lifespan (p = 0.954). PMID- 29438416 TI - Diastereoselective synthesis of chiral 1,3-cyclohexadienals. AB - A novel approach to the production of chiral 1,3-cyclohexadienals has been developed. The organocatalysed asymmetric reaction of different beta disubstituted-alpha,beta-unsaturated aldehydes with a chiral alpha,beta unsaturated aldehyde in the presence of a Jorgensen-Hayashi organocatalyst provides easy and stereocontrolled access to the cyclohexadienal backbone. This method allows for the synthesis of potential photoprotective chiral 1,3 cyclohexadienals and extra extended conjugation compounds in a simple manner. PMID- 29438417 TI - Visualizing the intercity correlation of PM2.5 time series in the Beijing-Tianjin Hebei region using ground-based air quality monitoring data. AB - The Beijing-Tianjin-Hebei area faces a severe fine particulate matter (PM2.5) problem. To date, considerable progress has been made toward understanding the PM2.5 problem, including spatial-temporal characterization, driving factors, and health effects. However, little research has been done on the dynamic interactions and relationships between PM2.5 concentrations in different cities in this area. To address the research gap, this study discovered a phenomenon of time-lagged intercity correlations of PM2.5 time series and proposed a visualization framework based on this phenomenon to visualize the interaction in PM2.5 concentrations between cities. The visualizations produced using the framework show that there are significant time-lagged correlations between the PM2.5 time series in different cities in this area. The visualizations also show that the correlations are more significant in colder months and between cities that are closer, and that there are seasonal changes in the temporal order of the correlated PM2.5 time series. Further analysis suggests that the time-lagged intercity correlations of PM2.5 time series are most likely due to synoptic meteorological variations. We argue that the visualizations demonstrate the interactions of air pollution between cities in the Beijing-Tianjin-Hebei area and the significant effect of synoptic meteorological conditions on PM2.5 pollution. The visualization framework could help determine the pathway of regional transportation of air pollution and may also be useful in delineating the area of interaction of PM2.5 pollution for impact analysis. PMID- 29438419 TI - Some aspects of entomological determinants of Phlebotomus orientalis in highland and lowland visceral leishmaniasis foci in northwestern Ethiopia. AB - Visceral leishmaniasis (VL) is one of the major public health problems in northwest Ethiopia, mainly in Libo-Kemkem and Metema districts, where Phlebotomus orientalis is the most probable vector of the disease. The aim of this study was to determine the physiological age, host preference and vectorial potential of P. orientalis in the highland and lowland foci of the region. Sand flies were collected using CDC light traps between May 2011 and April 2012 in Libo-Kemkem and October 2012 and September 2013 in Metema from household compounds, farm field and mixed forest. Females belonging to Phlebotomus were dissected for physiological age determination and Leishmania detection and isolation. Leishmania infections in sand flies were investigated using molecular methods. Freshly fed Phlebotomus females were tested to identify blood meal sources using PCR-RLB and ELISA. A total of 1149 (936 from Libo-Kemkem and 213 from Metema) blood unfed female P. orientalis were dissected for age determination. The parity rate was 45.6% and 66.2% in Libo-Kemkem and Metema, respectively. None of 798 female P. orientalis dissected (578 from Libo-Kemkem and 220 from Metema) was infected with Leishmania parasites. A total of 347 P. orientalis specimens collected from Libo-Kemkem were processed using PCR, of which 10 (2.8%) specimens were found with DNA of Leishmania spp. Of a total 491 freshly fed female P. orientalis analyzed for blood meal origins by RLB-PCR and ELISA, 57.6% (67.8% from Libo-Kemkem and 49.8% from Metema) were found to contain bovine blood while 4.9% (3.7% from Libo-Kemkem and 5.7% from Metema) were of human blood. In conclusion, the present study showed parity difference between the two populations of P. orientalis and that both populations have strong zoophilic behavior. Based on the presented evidences, the species is strongly implicated as a vector of kala-azar in both areas. Therefore, vector control should be a component of a strategy to manage visceral leishmaniasis in both study areas. PMID- 29438418 TI - Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet. AB - During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC-fed males, and were only slightly changed in HFC diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT. PMID- 29438420 TI - Endogenous salicylic acid shows different correlation with baicalin and baicalein in the medicinal plant Scutellaria baicalensis Georgi subjected to stress and exogenous salicylic acid. AB - Salicylic acid (SA) is synthesized via the phenylalanine lyase (PAL) and isochorismate synthase (ICS) pathways and can influence the stress response in plants by regulating certain secondary metabolites. However, the association between SA and particular secondary metabolites in the Chinese medicinal plant Scutellaria baicalensis Georgi is unclear. To elucidate the association between SA and the secondary metabolites baicalin and baicalein, which constitute the primary effective components of S. baicalensis, we subjected seedlings to drought and salt stress and exogenous SA treatment in a laboratory setting and tested the expression of PAL and ICS, as well as the content of free SA (FSA), total SA (TSA), baicalin, and baicalein. We also assessed the correlation of FSA and TSA with PAL and ICS, and with baicalin and baicalein accumulation, respectively. The results indicated that both FSA and TSA were positively correlated with PAL, ICS, and baicalin, but negatively correlated with baicalein. The findings of this study improve our understanding of the manner in which SA regulates secondary metabolites in S. baicalensis. PMID- 29438421 TI - A parallel spatiotemporal saliency and discriminative online learning method for visual target tracking in aerial videos. AB - Visual tracking in aerial videos is a challenging task in computer vision and remote sensing technologies due to appearance variation difficulties. Appearance variations are caused by camera and target motion, low resolution noisy images, scale changes, and pose variations. Various approaches have been proposed to deal with appearance variation difficulties in aerial videos, and amongst these methods, the spatiotemporal saliency detection approach reported promising results in the context of moving target detection. However, it is not accurate for moving target detection when visual tracking is performed under appearance variations. In this study, a visual tracking method is proposed based on spatiotemporal saliency and discriminative online learning methods to deal with appearance variations difficulties. Temporal saliency is used to represent moving target regions, and it was extracted based on the frame difference with Sauvola local adaptive thresholding algorithms. The spatial saliency is used to represent the target appearance details in candidate moving regions. SLIC superpixel segmentation, color, and moment features can be used to compute feature uniqueness and spatial compactness of saliency measurements to detect spatial saliency. It is a time consuming process, which prompted the development of a parallel algorithm to optimize and distribute the saliency detection processes that are loaded into the multi-processors. Spatiotemporal saliency is then obtained by combining the temporal and spatial saliencies to represent moving targets. Finally, a discriminative online learning algorithm was applied to generate a sample model based on spatiotemporal saliency. This sample model is then incrementally updated to detect the target in appearance variation conditions. Experiments conducted on the VIVID dataset demonstrated that the proposed visual tracking method is effective and is computationally efficient compared to state-of-the-art methods. PMID- 29438422 TI - In vivo evaluation of insect wax for hair growth potential. AB - Insect wax is secreted by Ericerus pela Chavanness. It has been traditionally used to treat hair loss in China, but few reports have been published on the hair growth-promoting effect of insect wax. In this work, we examined the hair growth promoting effects of insect wax on model animals. Different concentrations of insect wax were topically applied to the denuded backs of mice, and 5% minoxidil was applied topically as a positive control. We found that insect wax significantly promoted hair growth in a dose-dependent manner, 45% and 30% insect wax both induced hair to regrow, while less visible hair growth was observed in blank controls on the 16th day. The experimental areas treated with 45% and 30% insect wax exhibited significant differences in hair scores compared to blank controls, and hair lengths in the 45% and 30% insect wax group was significantly longer than in blank controls on the 16th and 20th days. There were no new hair follicles forming in the treated areas, and the hair follicles were prematurely converted to the anagen phase from the telogen phase in experimental areas treated with 45% and 30% insect wax. Both 45% and 30% insect wax upregulated vascular endothelial growth factor expression. The results indicated that 45% and 30% insect wax showed hair growth-promoting potential approximately as potent as 5% minoxidil by inducing the premature conversion of telogen-to-anagen and by prolonging the mature anagen phase rather than increasing the number of hair follicles, which was likely related to the upregulation of VEGF expression. The dissociative policosanol in insect wax was considered the key ingredient most likely responsible for the hair growth promoting potential. PMID- 29438423 TI - Immature platelet fraction and thrombopoietin in patients with liver cirrhosis: A cohort study. AB - BACKGROUND AND AIMS: Thrombocytopenia occurs frequently in patients with cirrhosis. The immature platelet fraction (IPF%) is measured to differentiate the causes of thrombocytopenia. To date the relevance of thrombopoietin (TPO) in the context of cirrhosis is unknown. The aim of our study was to investigate the cause of thrombocytopenia in patients with liver cirrhosis by measuring IPF%, TPO and spleen size. In addition we examined the use of IPF% to evaluate the severity of cirrhosis and its complications. METHODS: Overall, we included 88 in-patients with cirrhosis in our study. The collected data comprises current health status, blood parameters, severity of cirrhosis evaluated by Child-Pugh score and MELD score, spleen diameter, ascites and esophageal varices. The IPF% was measured using an automatic hematology analyzer. TPO was measured with ELISA. RESULTS: IPF% (p = 0.003) and spleen diameter (p = 0.001) were significantly higher in patients with thrombocytopenia. There was no significant difference in TPO between patients with and without thrombocytopenia. The mean values of IPF% varied significantly (p = 0.044) in Child-Pugh stages. IPF% was significantly (p = 0.005) elevated in patients with esophageal varices. Moreover, IPF% higher than 3.85% displayed sensitivity of 76.6% and specificity of 52.4% with an area under receiver operating curve characteristics of 0.669 for the presence of esophageal varices. CONCLUSION: On closer examination of the three compartments known to have an influence on platelet count splenomegaly seems to be the major cause of thrombocytopenia in patients with cirrhosis according to current knowledge. Higher IPF% in patients with thrombocytopenia indicates peripheral consumption of platelets. The relation between spleen diameter and platelet count indicates the spleen to be the major place of platelets' consumption. TPO did not differ between patients with and without thrombocytopenia. Furthermore, we cannot exclude an influence of impaired thrombopoietin synthesis on platelet counts. The association between IPF% and platelet count suggests that there is physiological regulation of platelets in patients with cirrhosis. In our study IPF% is associated with esophageal varices and the stage of cirrhosis. Further studies are needed to confirm these results. PMID- 29438424 TI - Vestibular schwannomas: Accuracy of tumor volume estimated by ice cream cone formula using thin-sliced MR images. AB - PURPOSE: We estimated the volume of vestibular schwannomas by an ice cream cone formula using thin-sliced magnetic resonance images (MRI) and compared the estimation accuracy among different estimating formulas and between different models. METHODS: The study was approved by a local institutional review board. A total of 100 patients with vestibular schwannomas examined by MRI between January 2011 and November 2015 were enrolled retrospectively. Informed consent was waived. Volumes of vestibular schwannomas were estimated by cuboidal, ellipsoidal, and spherical formulas based on a one-component model, and cuboidal, ellipsoidal, Linskey's, and ice cream cone formulas based on a two-component model. The estimated volumes were compared to the volumes measured by planimetry. Intraobserver reproducibility and interobserver agreement was tested. Estimation error, including absolute percentage error (APE) and percentage error (PE), was calculated. Statistical analysis included intraclass correlation coefficient (ICC), linear regression analysis, one-way analysis of variance, and paired t tests with P < 0.05 considered statistically significant. RESULTS: Overall tumor size was 4.80 +/- 6.8 mL (mean +/-standard deviation). All ICCs were no less than 0.992, suggestive of high intraobserver reproducibility and high interobserver agreement. Cuboidal formulas significantly overestimated the tumor volume by a factor of 1.9 to 2.4 (P <= 0.001). The one-component ellipsoidal and spherical formulas overestimated the tumor volume with an APE of 20.3% and 29.2%, respectively. The two-component ice cream cone method, and ellipsoidal and Linskey's formulas significantly reduced the APE to 11.0%, 10.1%, and 12.5%, respectively (all P < 0.001). CONCLUSION: The ice cream cone method and other two component formulas including the ellipsoidal and Linskey's formulas allow for estimation of vestibular schwannoma volume more accurately than all one-component formulas. PMID- 29438426 TI - Optimization of robustness of interdependent network controllability by redundant design. AB - Controllability of complex networks has been a hot topic in recent years. Real networks regarded as interdependent networks are always coupled together by multiple networks. The cascading process of interdependent networks including interdependent failure and overload failure will destroy the robustness of controllability for the whole network. Therefore, the optimization of the robustness of interdependent network controllability is of great importance in the research area of complex networks. In this paper, based on the model of interdependent networks constructed first, we determine the cascading process under different proportions of node attacks. Then, the structural controllability of interdependent networks is measured by the minimum driver nodes. Furthermore, we propose a parameter which can be obtained by the structure and minimum driver set of interdependent networks under different proportions of node attacks and analyze the robustness for interdependent network controllability. Finally, we optimize the robustness of interdependent network controllability by redundant design including node backup and redundancy edge backup and improve the redundant design by proposing different strategies according to their cost. Comparative strategies of redundant design are conducted to find the best strategy. Results shows that node backup and redundancy edge backup can indeed decrease those nodes suffering from failure and improve the robustness of controllability. Considering the cost of redundant design, we should choose BBS (betweenness-based strategy) or DBS (degree based strategy) for node backup and HDF(high degree first) for redundancy edge backup. Above all, our proposed strategies are feasible and effective at improving the robustness of interdependent network controllability. PMID- 29438425 TI - Treatment with silver nitrate versus topical steroid treatment for umbilical granuloma: A non-inferiority randomized control trial. AB - OBJECTIVE: The aim of this prospective multicenter randomized controlled trial was to compare the efficacy of silver nitrate cauterization against that of topical steroid ointment in the treatment of neonatal umbilical granuloma. METHODS: An open-label, non-inferiority randomized controlled trial was conducted from January 2013 to January 2016. The primary endpoint for the silver nitrate cauterization and topical steroid ointment groups was the healing rate after 2 weeks of treatment, applying a non-inferiority margin of 10%. The healing rate was evaluated until completion of 3 weeks of treatment. RESULTS: Participants comprised 207 neonates with newly diagnosed umbilical granuloma, randomized to receive silver nitrate cauterization (n = 104) or topical steroid ointment (n = 103). Healing rates after 2 weeks of treatment were 87.5% (91/104) in the silver nitrate cauterization and 82% (82/100) in the topical steroid ointment group group. The difference between groups was -5.5% (95% confidence interval, -19.1%, 8.4%), indicating that the non-inferiority criterion was not met. After 3 weeks of treatment, the healing rate with topical steroid ointment treatment was almost identical to that of silver nitrate cauterization (94/104 [90.4%] vs. 91/100 [91.0%]; 0.6% [-13.2 to 14.3]). No major complications occurred in either group. CONCLUSIONS: This study did not establish non-inferiority of topical steroid ointment treatment relative to silver nitrate cauterization, presumably due to lower healing rates than expected leading to an underpowered trial. However, considering that silver nitrate cauterization carries a distinct risk of chemical burns and that the overall efficacy of topical steroid ointment treatment is similar to that of silver nitrate cauterization, topical steroid ointment might be considered as a good alternative in the treatment of neonatal umbilical granuloma due to its safety and simplicity. To clarify non-inferiority, a larger study is needed. PMID- 29438427 TI - Climate-dependence of ecosystem services in a nature reserve in northern China. AB - Evaluation of ecosystem services has become a hotspot in terms of research focus, but uncertainties over appropriate methods remain. Evaluation can be based on the unit price of services (services value method) or the unit price of the area (area value method). The former takes meteorological factors into account, while the latter does not. This study uses Kunyu Mountain Nature Reserve as a study site at which to test the effects of climate on the ecosystem services. Measured data and remote sensing imagery processed in a geographic information system were combined to evaluate gas regulation and soil conservation, and the influence of meteorological factors on ecosystem services. Results were used to analyze the appropriateness of the area value method. Our results show that the value of ecosystem services is significantly affected by meteorological factors, especially precipitation. Use of the area value method (which ignores the impacts of meteorological factors) could considerably impede the accuracy of ecosystem services evaluation. Results were also compared with the valuation obtained using the modified equivalent value factor (MEVF) method, which is a modified area value method that considers changes in meteorological conditions. We found that MEVF still underestimates the value of ecosystem services, although it can reflect to some extent the annual variation in meteorological factors. Our findings contribute to increasing the accuracy of evaluation of ecosystem services. PMID- 29438428 TI - How will climate change affect endangered Mediterranean waterbirds? AB - Global warming and direct anthropogenic impacts, such as water extraction, largely affect water budgets in Mediterranean wetlands, thereby increasing wetland salinities and isolation, and decreasing water depths and hydroperiods (duration of the inundation period). These wetland features are key elements structuring waterbird communities. However, the ultimate and net consequences of these dynamic conditions on waterbird assemblages are largely unknown. We combined regular sampling of waterbird presence through one annual cycle with in situ data on relevant environmental predictors of waterbird distribution to model habitat selection for 69 species in a typical Mediterranean wetland network in southwestern Spain. Species associations with environmental features were subsequently used to predict changes in habitat suitability for each species under three climate change scenarios (encompassing changes in environmental predictors that ranged from 10% to 50% change as predicted by regional climatic models). Waterbirds distributed themselves unevenly throughout environmental gradients and water salinity was the most important gradient structuring the distribution of the community. Environmental suitability for the guilds of diving birds and vegetation gleaners will decline in future climate scenarios, while many small wading birds will benefit from changing conditions. Resident species and those that breed in this wetland network will also be more negatively impacted than those using this area for wintering or stopover. We provide a tool that can be used in a horizon-scanning framework to identify emerging issues in waterbird conservation and to anticipate suitable management actions. PMID- 29438429 TI - Choosing important health outcomes for comparative effectiveness research: An updated systematic review and involvement of low and middle income countries. AB - BACKGROUND: Core outcome sets (COS) comprise a minimum set of outcomes that should be measured and reported in all trials for a specific health condition. The COMET (Core Outcome Measures in Effectiveness Trials) Initiative maintains an up to date, publicly accessible online database of published and ongoing COS. An annual systematic review update is an important part of this process. METHODS: This review employed the same, multifaceted approach that was used in the original review and the previous two updates. This approach has identified studies that sought to determine which outcomes/domains to measure in clinical trials of a specific condition. This update includes an analysis of the inclusion of participants from low and middle income countries (LMICs) as identified by the OECD, in these COS. RESULTS: Eighteen publications, relating to 15 new studies describing the development of 15 COS, were eligible for inclusion in the review. Results show an increase in the use of mixed methods, including Delphi surveys. Clinical experts remain the most common stakeholder group involved. Overall, only 16% of the 259 COS studies published up to the end of 2016 have included participants from LMICs. CONCLUSION: This review highlights opportunities for greater public participation in COS development and the involvement of stakeholders from a wider range of geographical settings, in particular LMICs. PMID- 29438430 TI - Unravelling the bioherbicide potential of Eucalyptus globulus Labill: Biochemistry and effects of its aqueous extract. AB - In the worldwide search for new strategies in sustainable weed management, the use of plant species able to produce and release phytotoxic compounds into the environment could be an effective alternative to synthetic herbicides. Eucalyptus globulus Labill. is known to be a source of biologically active compounds responsible for its phytotoxic and allelopathic properties. Our previous results demonstrated the bioherbicide potential of eucalyptus leaves incorporated into the soil as a green manure, probably through the release of phytotoxins into the soil solution. Thus, the aims of this study were to understand the phytotoxicity of the eucalyptus leaves aqueous extract applied in pre- and post-emergence, and to identify and quantify its potentially phytotoxic water-soluble compounds. The effects were tested on the germination and early growth of the model target species Lactuca sativa and Agrostis stolonifera, and on physiological parameters of L. sativa adult plants after watering or spraying application. Dose-response curves and ED50 and ED80 values for eucalyptus aqueous extracts revealed pre emergence inhibitory effects on both target species, effects being comparable to the herbicide metolachlor. While spraying treatment reduced the aerial and root biomass and increased the dry weight/fresh weight ratio of lettuce adult plants, watering application reduced protein contents and chlorophyll concentrations with respect to control, reflecting different modes of action depending on the site of phytotoxin entry. Via HPLC analyses, a total of 8 phenolic compounds (chlorogenic, two rho-coumaric derivatives, ellagic, hyperoside, rutin, quercitrin, and kaempferol 3-O-glucoside) and other 5 low weight organic acids (citric, malic, shikimic, succinic and fumaric acids) were obtained from aqueous extract, the latter being identified for the first time in E. globulus. Despite some phytotoxic effects were found on lettuce adult plants, the use of eucalyptus aqueous extract would be discarded in post-emergence, whereas it was promising as a pre-emergence bioherbicide. PMID- 29438431 TI - Novel animal model for Achilles tendinopathy: Controlled experimental study of serial injections of collagenase in rabbits. AB - Our goal was to develop a novel technique for inducing Achilles tendinopathy in animal models which more accurately represents the progressive histological and biomechanical characteristic of chronic Achilles tendinopathy in humans. In this animal research study, forty-five rabbits were randomly assigned to three groups and given bilateral Achilles injections. Low dose (LD group) (n = 18) underwent a novel technique with three low-dose (0.1mg) injections of collagenase that were separated by two weeks, the high dose group (HD) (n = 18) underwent traditional single high-dose (0.3mg) injections, and the third group were controls (n = 9). Six rabbits were sacrificed from each experimental group (LD and HD) at 10, 12 and 16 weeks. Control animals were sacrificed after 16 weeks. Histological and biomechanical properties were then compared in all three groups. At 10 weeks, Bonar score and tendon cross sectional area was highest in HD group, with impaired biomechanical properties compared to LD group. At 12 weeks, Bonar score was higher in LD group, with similar biomechanical findings when compared to HD group. After 16 weeks, Bonar score was significantly increased for both LD group (11,8+/-2,28) and HD group (5,6+/-2,51), when compared to controls (2+/-0,76). LD group showed more pronounced histological and biomechanical findings, including cross sectional area of the tendon, Young's modulus, yield stress and ultimate tensile strength. In conclusion, Achilles tendinopathy in animal models that were induced by serial injections of low-dose collagenase showed more pronounced histological and biomechanical findings after 16 weeks than traditional techniques, mimicking better the progressive and chronic characteristic of the tendinopathy in humans. PMID- 29438432 TI - Cross detection for odor of metabolic waste between breast and colorectal cancer using canine olfaction. AB - Although several studies have been performed to detect cancer using canine olfaction, none have investigated whether canine olfaction trained to the specific odor of one cancer is able to detect odor related to other unfamiliar cancers. To resolve this issue, we employed breast and colorectal cancer in vitro, and investigated whether trained dogs to odor related to metabolic waste from breast cancer are able to detect it from colorectal cancer, and vice versa. The culture liquid samples used in the cultivation of cancerous cells (4T1 and CT26) were employed as an experimental group. Two different breeds of dogs were trained for the different cancer odor each other. The dogs were then tested using a double-blind method and cross-test to determine whether they could correctly detect the experimental group, which contains the specific odor for metabolic waste of familiar or unfamiliar cancer. For two cancers, both dogs regardless of whether training or non-training showed that accuracy was over 90%, and sensitivity and specificity were over 0.9, respectively. Through these results, it was verified that the superior olfactory ability of dogs can discriminate odor for metabolic waste of cancer cells from it of benign cells, and that the specific odor for metabolic waste of breast cancer has not significant differences to it of colorectal cancer. That is, it testifies that metabolic waste between breast and colorectal cancer have the common specific odor in vitro. Accordingly, a trained dogs for detecting odor for metabolic waste of breast cancer can perceive it of colorectal cancer, and vice versa. In order to the future work, we will plan in vivo experiment for the two cancers and suggest research as to what kind of cancers have the common specific odor. Furthermore, the relationship between breast and colorectal cancer should be investigated using other research methods. PMID- 29438434 TI - Seasonal dynamics of the juvenile fish community structure in the Maowei Sea mangroves. AB - More than 50% of Chinese mangroves were lost between 1950 and 2000 to habitat destruction, prompting an urge for conservation. To assess the importance of the protected Maowei Gulf mangrove estuary for fish population assemblage in the Beibu Gulf (China), we studied species composition and abundance of juvenile fish (including larvae) from July 2012 to June 2013. A total of 11 691 specimens were collected, which belonged to 24 species and 15 families. Six perciform species constituted 93% of the total sample. Pseudogobius javanicus (53.29%) was the dominant species from August to November, Omobranchus elegans (28.49%) from April to July, non-identified species in December and January, and Liza carinata in February and March. A number of commercially important fish species were also identified. Abundance was the highest in summer/early autumn (max 162.4 in Sep), and lowest in winter/early spring (Mar = 4.5). Diversity (H') and richness (Dma) indices (both max. in May: 1.67 and 1.95 respectively) were generally positively correlated with tide and temperature, and negatively with salinity. Seasonal variations play a more important role in the fish assemblage structure than tidal rhythm, with differences particularly pronounced between colder and warmer months. Despite the prominent seasonal differences in abiotic factors, this study indicates that Maowei mangroves provide habitat and food for juvenile fish throughout the year and thus are indispensable for the fish diversity in the Beibu Gulf. PMID- 29438433 TI - Attempts to grow human noroviruses, a sapovirus, and a bovine norovirus in vitro. AB - Noroviruses (NoVs) and Sapoviruses (SaVs) are enteric caliciviruses that have been detected in multiple mammalian species, including humans. Currently, efficient cell culture systems have been established only for murine NoVs and porcine SaV Cowden strain. Establishment of an efficient in vitro cell culture system for other NoVs and SaVs remains challenging; however, human NoV (HuNoV) replication in 3D cultured Caco-2 cells and a clone of Caco-2 cells, C2BBe1, human enteroids and in human B cells has been reported. In this study, we tested various cells and culture conditions to grow HuNoVs and a human SaV (HuSaV) to test the possibility of the propagation in different cells and culture conditions. We also attempted to grow a bovine NoV (BoNoV) in ex vivo organ cultures. We did not observe significant RNA level increases for HuSaV and BoNoV under our test conditions. HuNoV RNA levels increased to a maximum of ~600-fold in long-term Caco-2 cells that were cultured for 1-2 months in multi-well plates and inoculated with HuNoV-positive and bacteria-free human stool suspensions using serum-free medium supplemented with the bile acid, GCDCA. However, this positive result was inconsistent. Our results demonstrated that HuNoVs, BoNoV and HuSaV largely failed to grow in vitro under our test conditions. Our purpose is to share our findings with other researchers with the goal to develop efficient, reproducible simplified and cost-effective culture systems for human and animal NoVs and SaVs in the future. PMID- 29438435 TI - Population-based validation of a German version of the Brief Resilience Scale. AB - Smith and colleagues developed the Brief Resilience Scale (BRS) to assess the individual ability to recover from stress despite significant adversity. This study aimed to validate the German version of the BRS. We used data from a population-based (sample 1: n = 1.481) and a representative (sample 2: n = 1.128) sample of participants from the German general population (age >= 18) to assess reliability and validity. Confirmatory factor analyses (CFA) were conducted to compare one- and two-factorial models from previous studies with a method-factor model which especially accounts for the wording of the items. Reliability was analyzed. Convergent validity was measured by correlating BRS scores with mental health measures, coping, social support, and optimism. Reliability was good (alpha = .85, omega = .85 for both samples). The method-factor model showed excellent model fit (sample 1: chi2/df = 7.544; RMSEA = .07; CFI = .99; SRMR = .02; sample 2: chi2/df = 1.166; RMSEA = .01; CFI = 1.00; SRMR = .01) which was significantly better than the one-factor model (Deltachi2(4) = 172.71, p < .001) or the two-factor model (Deltachi2(3) = 31.16, p < .001). The BRS was positively correlated with well-being, social support, optimism, and the coping strategies active coping, positive reframing, acceptance, and humor. It was negatively correlated with somatic symptoms, anxiety and insomnia, social dysfunction, depression, and the coping strategies religion, denial, venting, substance use, and self-blame. To conclude, our results provide evidence for the reliability and validity of the German adaptation of the BRS as well as the unidimensional structure of the scale once method effects are accounted for. PMID- 29438436 TI - Assessment of coronary vascular function with cardiac PET in relation to serum uric acid. AB - BACKGROUND: Elevated serum uric acid (SUA) levels have been independently associated with cardiovascular disease. Stress myocardial perfusion positron emission tomography (PET) allows for measurement of absolute myocardial blood flow (MBF) and quantification of global left ventricular coronary flow reserve (CFR). A CFR <2.0 is considered impaired coronary vascular function, and it is associated with increased cardiovascular risk. We evaluated the relationship between SUA and PET-measured markers of coronary vascular function. METHODS: We studied adults undergoing a stress myocardial perfusion PET on clinical grounds (1/2006-3/2014) who also had >=1 SUA measurement within 180 days from the PET date. Multivariable linear regression estimated the association between SUA and PET-derived MBF and CFR. We also stratified analyses by diabetes status. RESULTS: We included 382 patients with mean (SD) age of 68.4 (12.4) years and mean (SD) SUA level of 7.2 (2.6) mg/dl. 36% were female and 29% had gout. Median [IQR] CFR was reduced at 1.6 [1.2, 2.0] and median [IQR] stress MBF was 1.5 [1.1, 2.1] ml/min/g. In the adjusted analysis, SUA was inversely associated with stress MBF (beta = -0.14, p = 0.01) but not with CFR. Among patients without diabetes (n = 215), SUA had a negative association with CFR (beta = -0.15, p = 0.02) and stress MBF (beta = -0.19, p = 0.01) adjusting for age, sex, extent of myocardial scar and ischemia, serum creatinine and gout. In diabetic patients (n = 167), SUA was not associated with either CFR or MBF. CONCLUSIONS: In this cross-sectional study, higher SUA is modestly associated with worse CFR and stress MBF among patients without diabetes. PMID- 29438438 TI - Priority Queue Based Reactive Buffer Management Policy for Delay Tolerant Network under City Based Environments. AB - Delay Tolerant Network (DTN) multi-copy routing protocols are privileged to create and transmit multiple copies of each message that causes congestion and some messages are dropped. This process is known as reactive drop because messages were dropped re-actively to overcome buffer overflows. The existing reactive buffer management policies apply a single metric to drop source, relay and destine messages. Hereby, selection to drop a message is dubious because each message as source, relay or destine may have consumed dissimilar magnitude of network resources. Similarly, DTN has included time to live (ttl) parameter which defines lifetime of message. Hence, when ttl expires then message is automatically destroyed from relay nodes. However, time-to-live (ttl) is not applicable on messages reached at their destinations. Moreover, nodes keep replicating messages till ttl expires even-though large number of messages has already been dispersed. In this paper, we have proposed Priority Queue Based Reactive Buffer Management Policy (PQB-R) for DTN under City Based Environments. The PQB-R classifies buffered messages into source, relay and destine queues. Moreover, separate drop metric has been applied on individual queue. The experiment results prove that proposed PQB-R has reduced number of messages transmissions, message drop and increases delivery ratio. PMID- 29438437 TI - A novel LPL intronic variant: g.18704C>A identified by re-sequencing Kuwaiti Arab samples is associated with high-density lipoprotein, very low-density lipoprotein and triglyceride lipid levels. AB - The role interethnic genetic differences play in plasma lipid level variation across populations is a global health concern. Several genes involved in lipid metabolism and transport are strong candidates for the genetic association with lipid level variation especially lipoprotein lipase (LPL). The objective of this study was to re-sequence the full LPL gene in Kuwaiti Arabs, analyse the sequence variation and identify variants that could attribute to variation in plasma lipid levels for further genetic association. Samples (n = 100) of an Arab ethnic group from Kuwait were analysed for sequence variation by Sanger sequencing across the 30 Kb LPL gene and its flanking sequences. A total of 293 variants including 252 single nucleotide polymorphisms (SNPs) and 39 insertions/deletions (InDels) were identified among which 47 variants (32 SNPs and 15 InDels) were novel to Kuwaiti Arabs. This study is the first to report sequence data and analysis of frequencies of variants at the LPL gene locus in an Arab ethnic group with a novel "rare" variant (LPL:g.18704C>A) significantly associated to HDL (B = 0.181; 95% CI (-0.357, -0.006); p = 0.043), TG (B = 0.134; 95% CI (0.004-0.263); p = 0.044) and VLDL (B = 0.131; 95% CI (-0.001-0.263); p = 0.043) levels. Sequence variation in Kuwaiti Arabs was compared to other populations and was found to be similar with regards to the number of SNPs, InDels and distribution of the number of variants across the LPL gene locus and minor allele frequency (MAF). Moreover, comparison of the identified variants and their MAF with other reports provided a list of 46 potential variants across the LPL gene to be considered for future genetic association studies. The findings warrant further investigation into the association of g.18704C>A with lipid levels in other ethnic groups and with clinical manifestations of dyslipidemia. PMID- 29438439 TI - Mother to child transmission of HIV in Brazil: Data from the "Birth in Brazil study", a national hospital-based study. AB - AIMS: to estimate the mother to child transmission (MTCT) of HIV among infected pregnant women identified in the "Birth in Brazil" study and to evaluate care practices provided in order to identify missed opportunities at preventing the MTCT of HIV infection in the country. METHODS: Descriptive study using data obtained from the consultation of different databases: the "Birth in Brazil" study database and the Brazilian National Information Systems (NIS) databases. We used cases of pregnant women infected with HIV identified in the "Birth in Brazil" study, and cases of AIDS in children under 5 years old identified in the NIS, to estimate the MTCT of HIV infection in the country, with a 95% confidence interval. We also estimated the HIV cascade (HIV diagnosis; use of antiretroviral treatment (ART) during pregnancy, labour, and for the newborn; adequate care during childbirth considering viral load at birth; and no breastfeeding) using data from the same sources. RESULTS: MTCT of HIV of 2.0% (95% CI 0.3%-13.8%). At birth, 84.0% of HIV infected woman showed a positive HIV diagnosis, 74.9% received combined ART during pregnancy, 80.7% received ART during childbirth, 77.1% received adequate care during childbirth, 86.8% of newborns received ART within the first 24 hours after birth, and 2.8% of newborns were breastfed. Considering all steps, 61.3% of the women (95% CI 48.3%-72.8%) received all available medical interventions. In the analysis restricted to women identified in the NIS, 65.3% (95% CI 48.0%-79.3%) of HIV infected women received all available medical interventions. CONCLUSION: Brazil has healthcare policies that guarantee free access to tests, ART and substitutes for maternal milk. However, missed opportunities to prevent MTCT of HIV were identified in at least one-third of women and may be making it difficult to reach HIV-elimination targets especially in the less developed country regions. PMID- 29438441 TI - Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates expression of low density lipoprotein (LDL) receptors via receptor internalization and subsequent lysosomal degradation. Thus, an anti-PCSK9 antibody is well known as an anti hyperlipidemia drug. Here, we aimed to develop vaccine for a long-term treatment of dyslipidemia targeted to PCSK9. In This study, we designed a peptide vaccine for mouse PCSK-9, which consisted of short peptides conjugated to keyhole limpet hemocyanin (KLH) as a carrier protein. Vaccines were administered to male apolipoprotein E (ApoE) deficient mice with adjuvants and significantly elicited an antibody response against PCSK9. The PCSK9 vaccines were administered to mice three times in 2-week intervals, and antibody titers and lipoprotein levels were evaluated up to 24 weeks after the first immunization to determine the therapeutic effect. Anti-PCSK9 antibody titers reached peak levels 6 weeks after the first immunization, and theses titers were maintained for up to 24 weeks. Decreased plasma levels of total cholesterol, very low-density lipoprotein (VLDL), and chylomicron (CM) were maintained for up to 24 weeks. Immunized mice exhibited a significant increase in cell-surface LDL receptor expression. Stimulation with KLH, but not PCSK9, induced the production of INF-gamma and interleukin-4 (IL-4), as determined with ELISPOT assays, thus indicating that PCSK9 vaccine did not elicit T-cell activation in our vaccine system. The present anti-PCSK9 vaccine induced long-lasting anti-PCSK9 antibody production and improved lipoprotein profiles. Thus, anti-PCSK9 vaccine could become a new option for the treatment of dyslipidemia as a long-acting therapy in future. PMID- 29438440 TI - Identification and characterization of MYH9 locus for high efficient gene knock in and stable expression in mouse embryonic stem cells. AB - Targeted integration of exogenous genes into so-called safe harbors/friend sites, offers the advantages of expressing normal levels of target genes and preventing potentially adverse effects on endogenous genes. However, the ideal genomic loci for this purpose remain limited. Additionally, due to the inherent and unresolved issues with the current genome editing tools, traditional embryonic stem (ES) cell-based targeted transgenesis technology is still preferred in practical applications. Here, we report that a high and repeatable homologous recombination (HR) frequency (>95%) is achieved when an approximate 6kb DNA sequence flanking the MYH9 gene exon 2 site is used to create the homology arms for the knockout/knock-in of diverse nonmuscle myosin II (NM II) isoforms in mouse ES cells. The easily obtained ES clones greatly facilitated the generation of multiple NM II genetic replacement mouse models, as characterized previously. Further investigation demonstrated that though the targeted integration site for exogenous genes is shifted to MYH9 intron 2 (about 500bp downstream exon 2), the high HR efficiency and the endogenous MYH9 gene integrity are not only preserved, but the expected expression of the inserted gene(s) is observed in a pre-designed set of experiments conducted in mouse ES cells. Importantly, we confirmed that the expression and normal function of the endogenous MYH9 gene is not affected by the insertion of the exogenous gene in these cases. Therefore, these findings suggest that like the commonly used ROSA26 site, the MYH9 gene locus may be considered a new safe harbor for high-efficiency targeted transgenesis and for biomedical applications. PMID- 29438442 TI - The siRNA-mediated knockdown of GluN3A in 46C-derived neural stem cells affects mRNA expression levels of neural genes, including known iGluR interactors. AB - For years, GluN3A was solely considered to be a dominant-negative modulator of NMDARs, since its incorporation into receptors alters hallmark features of conventional NMDARs composed of GluN1/GluN2 subunits. Only recently, increasing evidence has accumulated that GluN3A plays a more diversified role. It is considered to be critically involved in the maturation of glutamatergic synapses, and it might act as a molecular brake to prevent premature synaptic strengthening. Its expression pattern supports a putative role during neural development, since GluN3A is predominantly expressed in early pre- and postnatal stages. In this study, we used RNA interference to efficiently knock down GluN3A in 46C-derived neural stem cells (NSCs) both at the mRNA and at the protein level. Global gene expression profiling upon GluN3A knockdown revealed significantly altered expression of a multitude of neural genes, including genes encoding small GTPases, retinal proteins, and cytoskeletal proteins, some of which have been previously shown to interact with GluN3A or other iGluR subunits. Canonical pathway enrichment studies point at important roles of GluN3A affecting key cellular pathways involved in cell growth, proliferation, motility, and survival, such as the mTOR pathway. This study for the first time provides insights into transcriptome changes upon the specific knockdown of an NMDAR subunit in NSCs, which may help to identify additional functions and downstream pathways of GluN3A and GluN3A-containing NMDARs. PMID- 29438443 TI - Visual discrimination of screen-detected persistent from transient subsolid nodules: An observer study. AB - PURPOSE: To evaluate whether, and to which extent, experienced radiologists are able to visually correctly differentiate transient from persistent subsolid nodules from a single CT examination alone and to determine CT morphological features to make this differentiation. MATERIALS AND METHODS: We selected 86 transient and 135 persistent subsolid nodules from the National Lung Screening Trial (NLST) database. Four experienced radiologists visually assessed a predefined list of morphological features and gave a final judgment on a continuous scale (0-100). To assess observer performance, area under the receiver operating characteristic (ROC) curve was calculated. Statistical differences of morphological features between transient and persistent lesions were calculated using Chi-square. Inter-observer agreement of morphological features was evaluated by percentage agreement. RESULTS: Forty-nine lesions were excluded by at least 2 observers, leaving 172 lesions for analysis. On average observers were able to differentiate transient from persistent subsolid nodules >= 10 mm with an area under the curve of 0.75 (95% CI 0.67-0.82). Nodule type, lesion margin, presence of a well-defined border, and pleural retraction showed significant differences between transient and persistent lesions in two observers. Average pair-wise percentage agreement for these features was 81%, 64%, 47% and 89% respectively. Agreement for other morphological features varied from 53% to 95%. CONCLUSION: The visual capacity of experienced radiologists to differentiate persistent and transient subsolid nodules is moderate in subsolid nodules larger than 10 mm. Performance of the visual assessment of CT morphology alone is not sufficient to generally abandon a short-term follow-up for subsolid nodules. PMID- 29438444 TI - Systems genomics study reveals expression quantitative trait loci, regulator genes and pathways associated with boar taint in pigs. AB - Boar taint is an offensive odour and/or taste from a proportion of non-castrated male pigs caused by skatole and androstenone accumulation during sexual maturity. Castration is widely used to avoid boar taint but is currently under debate because of animal welfare concerns. This study aimed to identify expression quantitative trait loci (eQTLs) with potential effects on boar taint compounds to improve breeding possibilities for reduced boar taint. Danish Landrace male boars with low, medium and high genetic merit for skatole and human nose score (HNS) were slaughtered at ~100 kg. Gene expression profiles were obtained by RNA-Seq, and genotype data were obtained by an Illumina 60K Porcine SNP chip. Following quality control and filtering, 10,545 and 12,731 genes from liver and testis were included in the eQTL analysis, together with 20,827 SNP variants. A total of 205 and 109 single-tissue eQTLs associated with 102 and 58 unique genes were identified in liver and testis, respectively. By employing a multivariate Bayesian hierarchical model, 26 eQTLs were identified as significant multi-tissue eQTLs. The highest densities of eQTLs were found on pig chromosomes SSC12, SSC1, SSC13, SSC9 and SSC14. Functional characterisation of eQTLs revealed functions within regulation of androgen and the intracellular steroid hormone receptor signalling pathway and of xenobiotic metabolism by cytochrome P450 system and cellular response to oestradiol. A QTL enrichment test revealed 89 QTL traits curated by the Animal Genome PigQTL database to be significantly overlapped by the genomic coordinates of cis-acting eQTLs. Finally, a subset of 35 cis-acting eQTLs overlapped with known boar taint QTL traits. These eQTLs could be useful in the development of a DNA test for boar taint but careful monitoring of other overlapping QTL traits should be performed to avoid any negative consequences of selection. PMID- 29438445 TI - CRISPR/Cas9 in Leishmania mexicana: A case study of LmxBTN1. AB - Leishmania parasites cause human cutaneous, mucocutaneous and visceral leishmaniasis. Several studies proposed involvement of certain genes in infectivity of these parasites based on differential mRNA expression data. Due to unusual gene expression mechanism, functions of such genes must be further validated experimentally. Here, we investigated a role of one of the putative virulence factors, LmxM.22.0010-encoded BTN1 (a protein involved in Batten disease in humans), in L. mexicana infectivity. Due to the incredible plasticity of the L. mexicana genome, we failed to obtain a complete knock-out of LmxM.22.0010 using conventional recombination-based approach even after ablating four alleles of this gene. To overcome this, we established a modified CRISPR Cas9 system with genomic expression of Cas9 nuclease and gRNA. Application of this system allowed us to establish a complete BTN1 KO strain of L. mexicana. The mutant strain did not show any difference in growth kinetics and differentiation in vitro, as well as in the infectivity for insect vectors and mice hosts. Based on the whole-transcriptome profiling, LmxM.22.0010-encoded BTN1 was considered a putative factor of virulence in Leishmania. Our study suggests that ablation of LmxM.22.0010 does not influence L. mexicana infectivity and further illustrates importance of experimental validation of in silico-predicted virulence factors. Here we also describe the whole genome sequencing of the widely used model isolate L. mexicana M379 and report a modified CRISPR/Cas9 system suitable for complete KO of multi-copy genes in organisms with flexible genomes. PMID- 29438446 TI - A thioredoxin-dependent peroxiredoxin Q from Corynebacterium glutamicum plays an important role in defense against oxidative stress. AB - Peroxiredoxin Q (PrxQ) that belonged to the cysteine-based peroxidases has long been identified in numerous bacteria, but the information on the physiological and biochemical functions of PrxQ remain largely lacking in Corynebacterium glutamicum. To better systematically understand PrxQ, we reported that PrxQ from model and important industrial organism C. glutamicum, encoded by the gene ncgl2403 annotated as a putative PrxQ, played important roles in adverse stress resistance. The lack of C. glutamicum prxQ gene resulted in enhanced cell sensitivity, increased ROS accumulation, and elevated protein carbonylation levels under adverse stress conditions. Accordingly, PrxQ-mediated resistance to adverse stresses mainly relied on the degradation of ROS. The physiological roles of PrxQ in resistance to adverse stresses were corroborated by its induced expression under adverse stresses, regulated directly by the stress-responsive ECF-sigma factor SigH. Through catalytical kinetic activity, heterodimer formation, and bacterial two-hybrid analysis, we proved that C. glutamicum PrxQ catalytically eliminated peroxides by exclusively receiving electrons from thioredoxin (Trx)/thioredoxin reductase (TrxR) system and had a broad range of oxidizing substrates, but a better efficiency for peroxynitrite and cumene hydroperoxide (CHP). Site-directed mutagenesis confirmed that the conserved Cys49 and Cys54 are the peroxide oxidation site and the resolving Cys residue, respectively. It was also discovered that C. glutamicum PrxQ mainly existed in monomer whether under its native state or functional state. Based on these results, a catalytic model of PrxQ is being proposed. Moreover, our result that C. glutamicum PrxQ can prevent the damaging effects of adverse stresses by acting as thioredoxin-dependent monomeric peroxidase could be further applied to improve the survival ability and robustness of the important bacterium during fermentation process. PMID- 29438451 TI - The hard road to data interpretation: 3 or 6 months of adjuvant chemotherapy for patients with stage III colon cancer? AB - Background: Six months of adjuvant oxaliplatin-based chemotherapy is standard for patients with stage III colon cancer following surgery. However, oxaliplatin is associated with peripheral neurotoxicity which worsens over treatment duration. Consequently, a shorter treatment duration, if equally effective, would be extremely beneficial. A pooled analysis of data for 12 834 stage III colon cancer patients, from six randomised phase III trials of adjuvant therapy, the International Duration Evaluation of Adjuvant chemotherapy study, was carried out and the results presented at the ASCO Annual Meeting 2017. To clarify the potential impact of these results on clinical practice, ESMO decided to sponsor a special session at their 2017 Annual Meeting dedicated to achieving a more meaningful interpretation of the results. Methods: Medical oncologists from Europe, the United States and Asia selected for their involvement in the trials, together with an independent statistician and an independent clinician, were invited to provide their independent interpretations of the results and contribute to a moderated panel discussion. The pooled analysis evaluated the non inferiority of 3 versus 6 months of adjuvant FOLFOX/CAPOX therapy but not the non inferiority of 3 months CAPOX versus 6 months FOLFOX therapy. Results: There was strong evidence of an interaction between the choice of regimen (CAPOX or FOLFOX) and duration of treatment. Patients were classified as either 'fighters' or 'fatalists', and 3-month CAPOX was considered standard for patients classified as fatalists even if they had high-risk disease. However, patients classified as 'fighters' would only receive 3 months of CAPOX if they had low-risk disease but would always receive 6 months of CAPOX/FOLFOX if they had T4 disease. The panel was split on whether they would advocate 3 or 6 months CAPOX therapy based on high-risk N2 disease. Conclusions: The main drivers of the duration of treatment were choice of regimen and patient attitude, with risk, based mainly on T4 stage, having less influence. PMID- 29438452 TI - Early-life predictors of future multi-morbidity: results from the Hertfordshire Cohort. AB - Background: multi-morbidity is an increasing challenge in western medicine and has the potential to impact patients' quality of life, treatment options and compliance with medications. The aim of this study was to identify the early-life predictors of long-term multi-morbidity in an historical cohort, the Hertfordshire Cohort Study (HCS). Methods: perinatal and infant health records were kept on all children born in Hertfordshire between 1931 and 1939. Participants who were still alive in 1998 were recruited to the HCS and data collected on major chronic diseases. They were subsequently followed up in the Clinical Outcomes Study (COS), and data recorded on all major illnesses since HCS, as well as current medications. Ordinal logistic regression analysed the association between early-life factors and the number of morbidities in these two surveys as well as medication count. Results: a total of 2299 participants had data in COS, 1131 (49%) were female, median age (interquartile range) at recruitment to HCS was 66 (64-68) years. Higher rates of childhood illnesses were significantly associated with future multi-morbidity (multivariate odds ratio (OR) (95% confidence interval (CI)) 1.15 (1.06, 1.25)) and higher medication counts at COS (multivariate OR (95%CI) 1.14 (1.06, 1.23)). Conclusions: children who experience more illnesses at a young age may be prone to develop multi morbidity in later life. PMID- 29438454 TI - Comparative Efficacy of Antihypertensive Agents in Salt-Sensitive Hypertensive Patients: A Network Meta-Analysis. AB - BACKGROUND: Salt-sensitive hypertension (SSH) is an intermediate inherited phenotype of essential hypertension as well as being an independent risk factor for cardiovascular disease. However, effective medications for the treatment of SSH have not been clarified. This study was to compare the efficacious of different classes of antihypertensive agents combined with salt intake on the reduction of blood pressure (BP) in patients with SSH. METHODS: We used sources as PubMed, EMBASE, Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), CNKI, and WANFANG database from inception to November 2016. Studies that compared the efficacy of 2 or more antihypertensive agents or placebos in adult salt-sensitive hypertensive patients were included. The outcomes included variations in mean arterial blood pressure, systolic and diastolic blood pressure. RESULTS: Twenty-five studies were involved in this meta analysis. A calcium channel blocker (CCB) with hydrochlorothiazide and moderate salt intake was significantly the most efficacious in comparison with placebo (standardized mean differences (SMD), 95% credibility intervals (CI): 26.66, 12.60 to 40.16), angiotensin receptor blockers (ARBs) (SMD, 95% CI: 22.94, 5.26 to 40.51), and the other interventions for patients with SSH and no concomitant diseases. For SSH patients who were obese, CCB with metformin and moderate salt intake would decrease blood pressure with 17.90 mm Hg. CONCLUSIONS: For SSH patients with no concomitant diseases, CCB combined with hydrochlorothiazide and moderate salt intake was optimal in reducing BP, while CCB combined with metformin and moderate salt intake was the most efficacious at reducing BP in SSH patients with coexisting obesity. PMID- 29438453 TI - The role of silicon in plant biology: a paradigm shift in research approach. AB - Background: Silicon (Si) is known to have numerous beneficial effects on plants, alleviating diverse forms of abiotic and biotic stress. Research on this topic has accelerated in recent years and revealed multiple effects of Si in a range of plant species. Available information regarding the impact of Si on plant defence, growth and development is fragmented, discipline-specific, and usually focused on downstream, distal phenomena rather than underlying effects. Accordingly, there is a growing need for studies that address fundamental metabolic and regulatory processes, thereby allowing greater unification and focus of current research across disciplines. Scope and Conclusions: Silicon is often regarded as a plant nutritional 'non-entity'. A suite of factors associated with Si have been recently identified, relating to plant chemistry, physiology, gene regulation and interactions with other organisms. Research to date has typically focused on the impact of Si application upon plant stress responses. However, the fundamental, underlying mechanisms that account for the manifold effects of Si in plant biology remain undefined. Here, the known effects of Si in higher plants relating to alleviation of both abiotic and biotic stress are briefly reviewed and the potential importance of Si in plant primary metabolism is discussed, highlighting the need for a unifying research framework targeting common underlying mechanisms. The traditional approach of discipline-specific work on single stressors in individual plant species is currently inadequate. Thus, a holistic and comparative approach is proposed to assess the mode of action of Si between plant trait types (e.g. C3, C4 and CAM; Si accumulators and non-accumulators) and between biotic and abiotic stressors (pathogens, herbivores, drought, salt), considering potential pathways (i.e. primary metabolic processes) highlighted by recent empirical evidence. Utilizing genomic, transcriptomic, proteomic and metabolomic approaches in such comparative studies will pave the way for unification of the field and a deeper understanding of the role of Si in plants. PMID- 29438455 TI - Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies. AB - An association between vitamin D and attention deficit hyperactivity disorder (ADHD) has been proposed by several researchers in recent years; however, the investigations have led to inconsistent results. The present study was conducted to summarize the published observational data on the relation between vitamin D status and the likelihood of ADHD. Online databases, including PubMed, the ISI Web of Science, Google Scholar, and Scopus, were checked up to June 2017 for relevant observational studies. A random-effects model was incorporated to summarize the study results. Out of 2770 retrieved articles, 13 observational studies (9 case-control or cross-sectional studies and 4 prospective studies) were eligible for inclusion in the systematic review and meta-analysis. Analysis of the 10,334 children and adolescents who attended the 9 case-control or cross sectional studies revealed that children with ADHD have lower serum concentrations of 25-hydroxyvitamin D than do healthy children (weighted mean difference: -6.75 ng/mL; 95% CI: -9.73, -3.77 ng/mL; I2 = 94.9%]. Five case control studies reported the OR for developing ADHD based on vitamin D status; the meta-analysis of their data revealed that lower vitamin D status is significantly associated with the likelihood of ADHD (OR: 2.57; 95% CI: 1.09, 6.04; I2 = 84.3%). Furthermore, the meta-analysis of prospective studies conducted in 4137 participants indicated that perinatal suboptimal vitamin D concentrations are significantly associated with a higher risk of ADHD in later life (RR: 1.40; 95% CI: 1.09, 1.81; I2 = 0.0%). It should be noted that the association found in prospective studies was sensitive to one of the included investigations. The present review provides evidence supporting the relation between vitamin D deficiency and ADHD. However, the overall effect sizes are small, and therefore the association should be considered equivocal at this time. Further prospective cohort studies and community-based intervention trials are highly recommended to better elucidate the causal association. PMID- 29438456 TI - Choline. PMID- 29438458 TI - The Problem of Curcumin and Its Bioavailability: Could Its Gastrointestinal Influence Contribute to Its Overall Health-Enhancing Effects? AB - Curcumin, from the spice turmeric, exhibits anti-inflammatory, antioxidant, anticancer, antiviral, and neurotrophic activity and therefore holds promise as a therapeutic agent to prevent and treat several disorders. However, a major barrier to curcumin's clinical efficacy is its poor bioavailability. Efforts have therefore been dedicated to developing curcumin formulations with greater bioavailability and systemic tissue distribution. However, it is proposed in this review that curcumin's potential as a therapeutic agent may not solely rely on its bioavailability, but rather its medicinal benefits may also arise from its positive influence on gastrointestinal health and function. In this review, in vitro, animal, and human studies investigating the effects of curcumin on intestinal microbiota, intestinal permeability, gut inflammation and oxidative stress, anaphylactic response, and bacterial, parasitic, and fungal infections are summarized. It is argued that positive changes in these areas can have wide ranging influences on both intestinal and extraintestinal diseases, and therefore presents as a possible mechanism behind curcumin's therapeutic efficacy. PMID- 29438459 TI - Dietary Supplements with Antiplatelet Activity: A Solution for Everyone? AB - Dietary supplements can have beneficial effects on a number of risk factors for cardiovascular diseases, and interest in the use of nonpharmacologic nutraceutical-based treatments for cardiovascular disorders is growing. The aim of this review is to present the role of dietary supplements with antiplatelet activity in the prophylaxis and treatment of cardiovascular disorders. In addition, this paper describes their effects on another very important element of hemostasis-blood coagulation. However, because controlled human clinical experiments are too limited to clearly identify the antiplatelet and anticoagulant properties of dietary supplements, used alone or in combination with classical antiplatelet therapy (e.g., with aspirin), most information in this article is based on in vitro studies. Therefore, it cannot be unequivocally stated whether dietary supplements are universally safe and bring benefits to all. Some authors suggest that blood platelet count and function should be monitored in patients taking such supplements, especially before and after surgery, as well as other hemostasis parameters such as coagulation times. PMID- 29438460 TI - Practical Dietary Recommendations for the Prevention and Management of Nonalcoholic Fatty Liver Disease in Adults. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. In the absence of effective pharmacotherapies, clinical guidelines focus primarily on weight loss to treat this condition. Established consensus, evidence-based, and clinical dietary recommendations for NAFLD are currently lacking. The aim of this paper is to provide evidence-based practical dietary recommendations for the prevention and management of NAFLD in adults. A literature review focusing on established principles for the development of clinical practice recommendations was employed using the following criteria: based on substantial evidence, ensures risk minimization, is flexible for an individual patient approach, and is open to further modification as evidence emerges. The Practice-based Evidence in Nutrition classification system was used to grade these principles. Five key dietary recommendations were developed: 1) follow traditional dietary patterns, such as the Mediterranean diet; 2) limit excess fructose consumption and avoid processed foods and beverages with added fructose; 3) PUFAs, especially long-chain omega-3 rich foods and MUFAs, should replace SFAs in the diet; 4) replace processed food, fast food, commercial bakery goods, and sweets with unprocessed foods high in fiber, including whole grains, vegetables, fruits, legumes, nuts, and seeds; and 5) avoid excess alcohol consumption. Improving diet quality may reduce the incidence and progression of NAFLD and associated risk factors. Many of the benefits are likely to result from the collective effect of dietary patterns. High-quality research-in particular, randomized clinical trials assessing dietary interventions that focus on liver specific endpoints-are needed as a priority. PMID- 29438461 TI - Backpack Programs and the Crisis Narrative of Child Hunger-A Critical Review of the Rationale, Targeting, and Potential Benefits and Harms of an Expanding but Untested Model of Practice. AB - In recent years, school-based food backpack programs (BPPs) have come into national prominence as a response to a perceived crisis of child hunger in America. Distributing bags of free food directly to schoolchildren for their own personal consumption each weekend, BPPs bring together private donors, faith communities, and public schools around an intuitively appealing project: children are hungry, and so we give them food. Perhaps because of their intuitive appeal, BPPs have expanded rapidly, without rigorous evaluation to determine their impacts on children, families, and schools. This Perspective aims to open up thinking about BPPs, first articulating the implicit conceptual model that undergirds BPPs, drawing on documentation offered by major program providers and on our own experience working with several schools implementing BPPs, to provide a window into what BPPs do and how and why they do it. We focus in particular on how the crisis narrative of child hunger has shaped the BPP model and on the related interplay between public sympathy and the neoliberal climate in which structural solutions to family poverty are eschewed. We then assess the BPP model in light of existing knowledge, concluding that BPPs fit poorly with the needs of the majority of children living in food-insecure households in the United States and consequently put children at risk of negative consequences associated with worry, shame, stigma, and disruptions to family functioning. Finally, we provide recommendations for practice and research, emphasizing the importance of 1) responding to children's actual needs throughout program implementation, 2) avoiding unnecessary risks by effective targeting of services to only those children who need them, and 3) rigorously evaluating program outcomes and unintended consequences to determine whether, even for the small number of US children who experience hunger, the benefits of the BPP model outweigh its psychosocial costs. PMID- 29438462 TI - Butyrate: A Double-Edged Sword for Health? AB - Butyrate, a four-carbon short-chain fatty acid, is produced through microbial fermentation of dietary fibers in the lower intestinal tract. Endogenous butyrate production, delivery, and absorption by colonocytes have been well documented. Butyrate exerts its functions by acting as a histone deacetylase (HDAC) inhibitor or signaling through several G protein-coupled receptors (GPCRs). Recently, butyrate has received particular attention for its beneficial effects on intestinal homeostasis and energy metabolism. With anti-inflammatory properties, butyrate enhances intestinal barrier function and mucosal immunity. However, the role of butyrate in obesity remains controversial. Growing evidence has highlighted the impact of butyrate on the gut-brain axis. In this review, we summarize the present knowledge on the properties of butyrate, especially its potential effects and mechanisms involved in intestinal health and obesity. PMID- 29438463 TI - Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. AB - Background: Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. Methods and materials: Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non inferiority margin of 1.48, then with a margin of 1.25. Results: Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade>=3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). Conclusions: DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.gov: NCT01839773. PMID- 29438464 TI - Intragenerational Social Mobility and Changes in Blood Pressure: Longitudinal Analysis From the ELSA-Brasil Study. AB - BACKGROUND: During the past 4 decades, the highest worldwide blood pressure (BP) levels have shifted from high-income countries to low- and middle-income countries. We investigated the association of intragenerational social mobility with changes in BP and also with the incidence of hypertension over a 4-year follow-up. METHODS: Data for 6,529 baseline participants from ELSA-Brasil born between 1938 and 1975 were used. Based on a social mobility matrix, occupational social mobility was defined as the change in occupational social class between participants' first occupation and current occupation (stable high; upward; downward; stable low). Incident hypertension was defined as systolic blood pressure (SBP) >= 140 mm Hg or diastolic blood pressure (DBP) >= 90 mm Hg or use of antihypertensive medication. Hypertensive participants at baseline were excluded. Mixed effects regression models were used. RESULTS: Compared to the stable high group, the downwardly mobile group showed a higher increase over time in both SBP (beta = 1.49, 95% CI 0.60; 2.37) and DBP (beta = 0.96, 95% CI 0.32; 1.59) after adjustments for background characteristics and also proximal risk factors such as health-related behaviors and body mass index as time-dependent covariates, and diabetes. In contrast, upward mobility had no influence on BP changes (beta = 0.67, 95% CI -0.07; 1.41 for SBP, and beta = 0.47, 95% CI -0.05; 1.00 for DBP). Social mobility was not associated with the incidence of hypertension. CONCLUSIONS: We showed socioeconomic inequalities in BP progression over the life course. The longitudinal changes in BP varied by social mobility groups in the context of low- and middle-income countries, where high BP has become most prevalent. PMID- 29438465 TI - Does Stromal Vascular Fraction Ensure a Higher Survival in Autologous Fat Grafting for Breast Augmentation? A Volumetric Study Using 3-Dimensional Laser Scanning. AB - Background: Cell-assisted lipotransfer (CAL) has been considered a promising technique for promoting adipogenesis and angiogenesis in fat grafts. Objectives: The author sought to objectively analyze the change of breast volume in patients who underwent stromal vascular fraction (SVF)-enriched fat grafting for breast augmentation and compared the clinical results with those who underwent conventional fat grafting without SVF by using 3D laser scanning. Methods: From April 2015 to March 2016, 105 patients who underwent traditional fat grafting without SVF enrichment for breast augmentation were assigned to group A and served as the control. The other 101 patients who underwent SVF-enriched fat grafting for breast augmentation were assigned to group B. The charts of these patients were retrospectively reviewed. Results: The survival rate of the transplanted fat was 67.9% in group A and 68.7% in group B at 12 months after the operation. Postoperative complication rate was 3.8% in group A and 5.9% in group B. The differences were statistically insignificant. Conclusions: SVF does not ensure a higher survival rate in autologous fat grafting for breast augmentation. Considering the potential drawbacks of adipose-derived stem cells (ADSC) and the extra cost of the consumables, in particular the need for harvesting larger amount of fat which could be reserved for additional fat grafting at a later time to achieve even better improvement, the results of this study do not support the use of SVF in autologous fat grafting for breast augmentation in terms of graft survival and postoperative complications. PMID- 29438466 TI - Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing. AB - Background: Oropharyngeal squamous cell carcinomas (OPSCCs) are traditionally caused by smoking and excessive alcohol consumption. However, in the last decades high-risk human papillomavirus (HPV) infections play an increasingly important role in tumorigenesis. HPV-driven OPSCCs are known to have a more favorable prognosis, which has led to important and marked changes in the recently released TNM-8. In this 8th edition, OPSCCs are divided based on p16 immunostaining, with p16 overexpression as surrogate marker for the presence of HPV. The aims of this study are to evaluate TNM-8 on a Dutch consecutive cohort of patients with p16 positive OPSCC and to determine the relevance of additional HPV DNA testing. Patients and methods: All OPSCC patients without distant metastases at diagnosis and treated with curative intent at VU University Medical Center (2000-2015) and Erasmus Medical Center (2000-2006) were included (N = 1204). HPV status was determined by p16 immunostaining followed by HPV DNA PCR on the p16 immunopositive cases. We compared TNM-7 and TNM-8 using the Harrell's C index. Results: In total, 388 of 1204 (32.2%) patients were p16-immunopositive. In these patients, TNM-8 had a markedly better predictive prognostic power than TNM-7 (Harrell's C index 0.63 versus 0.53). Of the 388 p16-positive OPSCCs, 48 tumors (12.4%) were HPV DNA-negative. This subgroup had distinct demographic, clinical and morphologic characteristics and showed a significantly worse five-year overall survival compared with the HPV DNA-positive tumors (P < 0.001). Conclusions: TNM-8 has a better predictive prognostic power than TNM-7 in patients with p16-positive OPSCC. However, within p16-positive OPSCCs, there is an HPV DNA-negative subgroup with distinct features and a worse overall survival, indicating the importance to perform additional HPV DNA testing when predicting prognosis and particularly for selecting patients for de-intensified treatment regimens. PMID- 29438467 TI - Prophylactic Antimicrobial Therapy for Acute Aspiration Pneumonitis. AB - Background: Prophylactic antimicrobial therapy is frequently prescribed for acute aspiration pneumonitis, with the intent of preventing the development of aspiration pneumonia. However, few clinical studies have examined the benefits and harms of this practice. Methods: A retrospective cohort study design was used to compare outcomes of patients with aspiration pneumonitis who received prophylactic antimicrobial therapy with those managed with supportive care only during the initial 2 days following macroaspiration. The primary outcome was in hospital mortality within 30 days. Secondary outcomes included transfer to critical care and antimicrobial therapy received between days 3 and 14 following macroaspiration including escalation of therapy and antibiotic-free days. Results: Among 1483 patients reviewed, 200 met the case definition for acute aspiration pneumonitis, including 76 (38%) who received prophylactic antimicrobial therapy and 124 (62%) who received supportive management only. After adjusting for patient-level predictors, antimicrobial prophylaxis was not associated with any improvement in mortality (odds ratio, 0.9; 95% confidence interval [CI], 0.4-1.7; P = .7). Patients receiving prophylactic antimicrobial therapy were no less likely to require transfer to critical care (5% vs 6%; P = .7) and subsequently received more frequent escalation of antibiotic therapy (8% vs 1%; P = .002) and fewer antibiotic-free days (7.5 vs 10.9; P < .0001). Conclusions: Prophylactic antimicrobial therapy for patients with acute aspiration pneumonitis does not offer clinical benefit and may generate antibiotic selective pressures that results in the need for escalation of antibiotic therapy among those who develop aspiration pneumonia. PMID- 29438468 TI - Varietal Resistance Against the Rice Water Weevil in Field and Greenhouse Studies. AB - The resistance of commercial rice (Oryza sativa L.) varieties widely grown in Louisiana was assessed against the rice water weevil, Lissorhoptrus oryzophilus Kuschel (Coleoptera: Curculionidae), the major insect pest of rice in the United States, in a 5-yr field study that included conventional inbred, herbicide tolerant, and hybrid varieties. Resistance was evaluated by comparing densities of immature rice water weevils (larvae and pupae) in root-soil core samples taken at two time points after flooding. Randomized block experiments were conducted in two different locations to enable identification of potentially resistant varieties over diverse environments. There were small but significant differences in the resistance of commercial varieties over the 5-yr field study. The variety 'Jefferson' was found to support larval densities 6-70% lower than other varieties, while 'Jupiter' often supported higher larval densities. Greenhouse experiments evaluated adult preference for oviposition and survivorship of larvae on different varieties. Females exhibited limited ovipositional preference for varieties: numbers of weevil eggs per plant differed significantly among varieties in choice tests but not in no-choice tests, while first instar densities in both choice and no-choice tests showed no significant differences among varieties. Analysis of data from both choice and no-choice tests showed that numbers of late instars and pupae differed significantly among varieties, suggesting presence of antibiosis in some cultivars. Our results suggest that none of the varieties tested possess high levels of resistance to rice water weevil infestation, although 'Jupiter' appears to be more susceptible than other varieties and 'Jefferson' appears to be somewhat more resistant. PMID- 29438469 TI - Reply to Horowitz. PMID- 29438470 TI - Use of clinical risk stratification in non-ST elevation acute coronary syndromes: an analysis from the CONCORDANCE registry. AB - Aims: There is little information on clinical risk stratification (CRS) compared to objective risk tools in patients with non-ST elevation acute coronary syndromes (NSTEACS). We quantified CRS use, its agreement with Global Registry of Acute Coronary Events (GRACE) risk scores (GRS), and association with outcomes. Methods and results: Data were extracted from the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events (CONCORDANCE), a multi-centre NSTEACS registry. From February 2009 to December 2015, 4512 patients from 41 sites were included. Predictors of CRS use and association with treatment were identified, CRS-GRS agreement determined and prediction of in-hospital and 6-month mortality compared. Clinical risk stratification was documented in 21% of patients. Family history of coronary disease was the only independent predictor of CRS use [odds ratio (OR) 1.23, 95% confidence interval (95% CI) 1.04-1.45]; electrocardiogram changes (OR 0.8, 95% CI 0.68-0.96), elevated biomarkers (OR 0.59, 95% CI 0.48-0.73), dementia (OR 0.56, 95% CI 0.36-0.84), and an urban hospital setting (OR 0.41, 95% CI 0.19 0.89) were independent negative predictors. A treatment-risk paradox was observed: high CRS risk patients received less anticoagulation (79% vs. 88%, P = 0.001) and angiography (83% vs. 71%, P < 0.001). CRS-GRS agreement was poor (kappa coefficient = 0.034) and CRS less predictive for in-hospital (c-statistic 0.54 vs. 0.87, P < 0.001) and 6-month (c-statistic 0.55 vs. 0.74, P < 0.01) mortality. Conclusion: In Australia, CRS does not guide treatment, correlate with GRS or predict outcomes. This study suggests the need for greater awareness and integration of validated tools such as the GRACE score to optimally direct treatment and potentially improve outcomes. PMID- 29438471 TI - Severity of Chagasic Cardiomyopathy Is Associated With Response to a Novel Rapid Diagnostic Test for Trypanosoma cruzi TcII/V/VI. AB - Background: Trypanosoma cruzi causes Chagas disease in the Americas. The outcome of infection ranges from lifelong asymptomatic status to severe disease. Relationship between T. cruzi lineage (TcI-TcVI) infection history and prognosis is not understood. We previously described peptide-based lineage-specific enzyme linked immunosorbent assay (ELISA) with trypomastigote small surface antigen (TSSA). Methods: A novel rapid diagnostic test (RDT; Chagas Sero K-SeT) that incorporates a peptide that corresponds to the TSSA II/V/VI common epitope was developed and validated by comparison with ELISA. Patients from Bolivia and Peru, including individuals with varying cardiac pathology, and matched mothers and neonates, were then tested using Chagas Sero K-SeT. Results: Chagas Sero K-SeT and ELISA results, with a Bolivian subset of cardiac patients, mothers, and neonates, were in accord. In adult chronic infections (n = 121), comparison of severity class A (no evidence of Chagas cardiomyopathy) with class B (electrocardiogram suggestive of Chagas cardiomyopathy) and class C/D (decreased left ventricular ejection fraction; moderate/severe Chagas cardiomyopathy) revealed a statistically significant increase in Chagas Sero K-SeT reactivity with increasing severity (chi2 for trend, 7.39; P = .007). In Peru, Chagas Sero K SeT detected the sporadic TcII/V/VI infections. Conclusions: We developed a low cost RDT that can replace ELISA for identification of TSSA II/V/VI immunoglobulin G. Most importantly, we show that response to this RDT is associated with severity of Chagas cardiomyopathy and thus may have prognostic value. Repeated challenge with T. cruzi infection may both exacerbate disease progression and boost the immune response to the TSSApep-II/V/VI epitope. PMID- 29438472 TI - Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. AB - Although first identified over 70 years ago, Klinefelter syndrome (KS) continues to pose substantial diagnostic challenges, as many patients are still misdiagnosed, or remain undiagnosed. In fact, as few as 25% of patients with KS are accurately diagnosed and most of these diagnoses are not made until adulthood. Classic characteristics of KS include small testes, infertility, hypergonadothropic hypogonadism, and cognitive impairment. However, the pathophysiology behind KS is not well understood, although genetic effects are also thought to play a role. For example, recent developments in genetics and genomics point to a fundamental change in our understanding of KS, with global epigenetic and RNA expression changes playing a central role for the phenotype. KS is also associated with more general health markers, including higher morbidity and mortality rates and lower socioeconomic status (which likely affect both morbidity and mortality). In addition, hypogonadism is associated with greater risk of metabolic syndrome, type 2 diabetes, cardiovascular disease, breast cancer, and extragonadal germ cell tumors. Medical treatment typically focuses on testosterone replacement therapy (TRT), although the effects of this therapy have not been studied rigorously, and future studies need to evaluate the effects of TRT on metabolic risk and neurocognitive outcomes. This review presents a comprehensive interdisciplinary examination of recent developments in genetic, endocrine, and neurocognitive science, including the study of animal models. It provides a number of recommendations for improving the effectiveness of research and clinical practice, including neonatal KS screening programs, and a multidisciplinary approach to KS treatment from childhood until senescence. PMID- 29438474 TI - Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: a systematic review and meta-analyses. AB - Introduction: The association of lifestyle factors with molecular pathological subtypes of colorectal cancer (CRC), such as microsatellite instability (MSI), could provide further knowledge about the colorectal carcinogenic process. The aim of this review was to evaluate possible associations between lifestyle factors and risk of sporadic CRC by MSI status. Methods: PubMed and Web of Science were searched for studies investigating the association between alcohol, body mass index, dietary fiber, hormone replacement therapy (HRT), non-steroidal anti-inflammatory drugs, physical activity, red meat, smoking, or statin use, with MSI-high (MSI-H) and microsatellite stable (MSS) CRC. Meta-analyses were carried out to calculate summary relative risks (sRR). Results: Overall, 31 studies reporting on the association between lifestyle factors and CRC according to MSI status were included in this review. Ever smoking was associated with MSI H (sRR = 1.62; 95% CI: 1.40-1.88) and MSS/MSI-low CRC (sRR = 1.10; 95% CI: 1.01 1.20), but the association was significantly stronger for MSI-H CRC. The use of HRT was associated with a 20% decrease (sRR = 0.80; 95% CI: 0.73-0.89) in the risk of MSS CRC, but was not associated with MSI-H CRC. An increase in body mass index per 5 kg/m2 was equally associated with MSS and MSI-H CRC (sRR = 1.22, in both cases), but was statistically significant for MSS CRC only (95% CI: 1.11 1.34 and 0.94-1.58, respectively). Limited evidence for associations between other lifestyle factors and CRC by MSI status exists. Conclusions: Lifestyle factors, such as HRT and smoking are differentially associated with the risk of MSI-H and MSS CRC. Further research on associations of lifestyle factors and CRC subtypes is necessary to provide a better understanding of the CRC disease pathway. PMID- 29438473 TI - In Uncontrolled Diabetes, Hyperglucagonemia and Ketosis Result From Deficient Leptin Action in the Parabrachial Nucleus. AB - Growing evidence implicates neurons that project from the lateral parabrachial nucleus (LPBN) to the hypothalamic ventromedial nucleus (VMN) in a neurocircuit that drives counterregulatory responses to hypoglycemia, including increased glucagon secretion. Among LPBN neurons in this circuit is a subset that expresses cholecystokinin (LPBNCCK neurons) and is tonically inhibited by leptin. Because uncontrolled diabetes is associated with both leptin deficiency and hyperglucagonemia, and because intracerebroventricular (ICV) leptin administration reverses both hyperglycemia and hyperglucagonemia in this setting, we hypothesized that deficient leptin inhibition of LPBNCCK neurons drives activation of this LPBN->VMN circuit and thereby results in hyperglucagonemia. Here, we report that although bilateral microinjection of leptin into the LPBN does not ameliorate hyperglycemia in rats with streptozotocin-induced diabetes mellitus (STZ-DM), it does attenuate the associated hyperglucagonemia and ketosis. To determine if LPBN leptin signaling is required for the antidiabetic effect of ICV leptin in STZ-DM, we studied mice in which the leptin receptor was selectively deleted from LPBNCCK neurons. Our findings show that although leptin signaling in these neurons is not required for the potent antidiabetic effect of ICV leptin, it is required for leptin-mediated suppression of diabetic hyperglucagonemia. Taken together, these findings suggest that leptin-mediated effects in animals with uncontrolled diabetes occur through actions involving multiple brain areas, including the LPBN, where leptin acts specifically to inhibit glucagon secretion and associated ketosis. PMID- 29438475 TI - Detecting Infections Rapidly and Easily for Candidemia Trial, Part 2 (DIRECT2): A Prospective, Multicenter Study of the T2Candida Panel. AB - Background: Blood cultures are approximately 50% sensitive for diagnosing invasive candidiasis. The T2Candida nanodiagnostic panel uses T2 magnetic resonance and a dedicated instrument to detect Candida directly within whole blood samples. Methods: Patients with Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, or Candida krusei candidemia were identified at 14 centers using diagnostic blood cultures (dBCs). Follow-up blood samples were collected concurrently for testing by T2Candida and companion cultures (cBCs). T2Candida results are reported qualitatively for C. albicans/C. tropicalis, C. glabrata/C. krusei, and C. parapsilosis. T2Candida and cBCs were positive if they detected a species present in the dBC. Results: Median time between collection of dBC and T2Candida/cBC samples in 152 patients was 55.5 hours (range, 16.4-148.4). T2Candida and cBCs were positive in 45% (69/152) and 24% (36/152) of patients, respectively (P < .0001). T2Candida clinical sensitivity was 89%, as positive results were obtained in 32/36 patients with positive cBCs. Combined test results were both positive (T2+/cBC+), 21% (32/152); T2+/cBC-, 24% (37/152); T2-/cBC+, 3% (4/152); and T2-/cBC-, 52% (79/152). Prior antifungal therapy, neutropenia, and C. albicans candidemia were independently associated with T2Candida positivity and T2+/cBC- results (P values < .05). Conclusions: T2Candida was sensitive for diagnosing candidemia at the time of positive blood cultures. In patients receiving antifungal therapy, T2Candida identified bloodstream infections that were missed by cBCs. T2Candida may improve care by shortening times to Candida detection and species identification compared to blood cultures, retaining sensitivity during antifungal therapy and rendering active candidemia unlikely if results are negative. Clinical Trials Registration: NCT01525095. PMID- 29438476 TI - Influence of Winter Cover Crop Mulch on Arthropods in a Reduced Tillage Cucurbit System. AB - Winter cover crop mulches can diversify agricultural habitats and provide a range of benefits for crop production and pest management. Here we report the influence of strip tilled winter cover crop mulches on arthropod abundance in organic vegetable plots. Crookneck squash (Cucurbita pepo L.; Cucurbitales: Cucurbitaceae) was direct seeded into mowed and strip tilled barley (Hordeum vulgare L.; Poales: Poaceae), crimson clover (Trifolium incarnatum L.; Fabales: Fabaceae), a barley + crimson clover mixture, or a no-cover crop control. Arthropods on squash plants were assessed weekly using visual counts. Seed predation was assessed using weed seed arenas. In 2013, mixed species cover crops produced the most ground cover, fewest weeds, and largest squash plants, but herbivore and predator abundance were not correlated with any of those factors. In 2014, mixed species cover crops again produced the most ground cover and fewest weeds, but the largest squash plants were found in no-cover crop control plots, which also had the highest herbivore abundance per plant. Predator and herbivore abundance were positively correlated with squash plant size in 2014. There were no differences in seed predation across treatments. Differences in ground cover biomass and weed presence between the 2 yr may have contributed to differences in squash plant quality and subsequent herbivore abundance between seasons. Results suggest that arthropods on plants responded largely indirectly to cover crops through host plant quality. Results are interpreted in light of overall costs and benefits of cover cropping. PMID- 29438477 TI - What We Do and Do Not Know About Women and Kidney Diseases; Questions Unanswered and Answers Unquestioned: Reflection on World Kidney Day and International Woman's Day. PMID- 29438478 TI - Corrigendum to: 'Scaffold-free trachea regeneration by tissue engineering with bio-3D printing' [Interact CardioVasc Thorac Surg 2018]?. PMID- 29438479 TI - Novel Tn916-like elements confer aminoglycoside/macrolide co-resistance in clinical isolates of Streptococcus gallolyticus ssp. gallolyticus. AB - Background: Streptococcus gallolyticus ssp. gallolyticus (Sgg) is a commensal bacterium and an opportunistic pathogen. In humans it has been clinically associated with the incidence of colorectal cancer (CRC) and epidemiologically recognized as an emerging cause of infective endocarditis (IE). The standard therapy of Sgg includes the administration of a penicillin in combination with an aminoglycoside. Even though penicillin-resistant isolates have still not been reported, epidemiological studies have shown that this microbe is a reservoir of multiple acquired genes, conferring resistance to tetracyclines, aminoglycosides, macrolides and glycopeptides. However, the underlying antibiotic resistance mobilome of Sgg remains poorly understood. Objectives: To investigate the mobile genetic basis of antibiotic resistance in multiresistant clinical Sgg. Methods: Isolate NTS31106099 was recovered from a patient with IE and CRC at Nantes University Hospital, France and studied by Illumina WGS and comparative genomics. Molecular epidemiology of the identified mobile element(s) was performed using antibiotic susceptibility testing (AST), PCR, PFGE and WGS. Mobility was investigated by PCR and filter mating. Results: Two novel conjugative transposons, Tn6263 and Tn6331, confer aminoglycoside/macrolide co-resistance in clinical Sgg. They display classical family Tn916/Tn1545 modular architecture and harbour an aph(3')-III->sat4->ant(6)-Ia->erm(B) multiresistance gene cluster, related to pRE25 of Enterococcus faecium. These and/or closely related elements are highly prevalent among genetically heterogeneous clinical isolates of Sgg. Conclusions: Previously unknown Tn916-like mobile genetic elements conferring aminoglycoside/macrolide co-resistance make Sgg, collectively with other gut Firmicutes such as enterococci and eubacteria, a potential laterally active reservoir of these antibiotic resistance determinants among the mammalian gastrointestinal microbiota. PMID- 29438480 TI - Human trophoblast epithelial-mesenchymal transition in abnormally invasive placenta. AB - Differentiation of first trimester human placental cytotrophoblast (CTB) from an anchorage-dependent epithelial phenotype into the mesenchymal-like invasive extravillous trophoblast (EVT) is crucial in the development of the maternal fetal interface. We showed previously that differentiation of first trimester CTB to EVT involves an epithelial-mesenchymal transition (EMT). Here we compare the epithelial-mesenchymal characteristics of CTB and EVT derived from normal third trimester placenta or placenta previa versus abnormally invasive placenta (AIP). CTB and EVT were isolated from normal term placenta or placenta previa following Caesarean section and EVT from AIP following Caesarean hysterectomy. Cell identity was validated by measurement of cytokeratin-7 and HLA-G. Comparing normal term CTB with EVT from normal term placenta or placenta previa for differential expression analysis of genes associated with the EMT showed changes in >70% of the genes probed. While demonstrating a mesenchymal phenotype relative to CTB, many of the gene expression changes in third trimester EVT were reduced relative to the first trimester EVT. We suggest that third trimester EVT are in a more constrained, metastable state compared to first trimester equivalents. By contrast, EVT from AIP demonstrate characteristics that are more mesenchymal than normal third trimester EVT, placing them closer to first trimester EVT on the EMT spectrum, consistent with a more invasive phenotype. PMID- 29438481 TI - Mortality reduction from quitting smoking in Hong Kong: population-wide proportional mortality study. AB - Background: The effects of smoking cessation might be different in different populations. Proportional mortality studies of all deaths, relating the certified cause to retrospectively determined smoking habits, have helped assess the hazards of smoking in Hong Kong, and further analyses can help assess the effects of prolonged cessation (although not of recent cessation, as life-threatening disease can itself cause cessation, particularly in old age). Methods: The LIMOR study sought the certified causes of all deaths in 1998, and interviewed 81% of families at death registries to determine the decedent's smoking history. Cases were deaths from pre-defined diseases of interest (N = 15 356); controls were deaths from pre-defined non-smoking-related diseases (N = 5023). Case vs control odds ratios for ex-smokers vs smokers were calculated by age-, sex- and education standardized logistic regression. These are described as mortality rate ratios (RRs), with a group-specific confidence interval (CI). Results: For the aggregate of all deaths from any of the diseases of interest at ages 35-69 years, the RRs for current smoking, quitting 0-4, 5-9 or 10+ years ago and never-smoking were, respectively, RR = 1 (95% CI 0.86-1.17), 0.91 (0.73-1.14), 0.71 (0.49-1.02), 0.66 (0.50-0.87) and 0.43 (0.37-0.48). Younger age of quitting (25-44 or 45-64) appeared to be associated with greater protection: RR = 0.58 (0.38-0.88) and 0.71 (0.54-0.93), respectively. These patterns were less clear at older ages, particularly for death from emphysema. Conclusions: Longer durations of smoking cessation are associated with progressively lower mortality rates from the diseases of interest. For sustainable monitoring of tobacco-attributed mortality, approximate years since last smoked should be recorded during death registration. PMID- 29438482 TI - The lipodystrophic hotspot lamin A p.R482W mutation deregulates the mesodermal inducer T/Brachyury and early vascular differentiation gene networks. AB - The p.R482W hotspot mutation in A-type nuclear lamins causes familial partial lipodystrophy of Dunnigan-type (FPLD2), a lipodystrophic syndrome complicated by early onset atherosclerosis. Molecular mechanisms underlying endothelial cell dysfunction conferred by the lamin A mutation remain elusive. However, lamin A regulates epigenetic developmental pathways and mutations could perturb these functions. Here, we demonstrate that lamin A R482W elicits endothelial differentiation defects in a developmental model of FPLD2. Genome modeling in fibroblasts from patients with FPLD2 caused by the lamin A R482W mutation reveals repositioning of the mesodermal regulator T/Brachyury locus towards the nuclear center relative to normal fibroblasts, suggesting enhanced activation propensity of the locus in a developmental model of FPLD2. Addressing this issue, we report phenotypic and transcriptional alterations in mesodermal and endothelial differentiation of induced pluripotent stem cells we generated from a patient with R482W-associated FPLD2. Correction of the LMNA mutation ameliorates R482W associated phenotypes and gene expression. Transcriptomics links endothelial differentiation defects to decreased Polycomb-mediated repression of the T/Brachyury locus and over-activation of T target genes. Binding of the Polycomb repressor complex 2 to T/Brachyury is impaired by the mutated lamin A network, which is unable to properly associate with the locus. This leads to a deregulation of vascular gene expression over time. By connecting a lipodystrophic hotspot lamin A mutation to a disruption of early mesodermal gene expression and defective endothelial differentiation, we propose that the mutation rewires the fate of several lineages, resulting in multi-tissue pathogenic phenotypes. PMID- 29438483 TI - Statin Use and Risks of Influenza-Related Outcomes Among Older Adults Receiving Standard-Dose or High-Dose Influenza Vaccines Through Medicare During 2010-2015. AB - Background: Statins are used to reduce cardiovascular disease risk. Recent studies suggest that statin use may be associated with an increased influenza risk among influenza vaccinees. We used Medicare data to evaluate associations between statins and risks of influenza-related encounters among vaccinees. Methods: In this retrospective cohort study, we identified Medicare beneficiaries aged > 65 years who received high-dose (HD) or standard-dose (SD) influenza vaccines at pharmacies from 2010-2011 through 2014-2015. Statin users were matched to nonusers by vaccine type, demographics, prior medical encounters, and comorbidities. We used multivariable Poisson models to estimate associations between statin use around the time of vaccination and risk of influenza-related encounters. Study outcomes included influenza-related office visits with a rapid test followed by dispensing of oseltamivir and influenza-related hospitalizations (including emergency room visits) during high influenza circulation periods. Results: The study included 1403651 statin users matched to nonusers. Cohorts were well balanced, with standardized mean differences <=0.03 for all measured covariates. For statin users compared to nonusers, the adjusted relative risk was 1.086 (95% confidence interval [CI], 1.025-1.150) for influenza-related visits and 1.096 (95% CI, 1.013-1.185) for influenza-related hospitalizations. The risk difference ranged from -0.02 to 0.23 for influenza-related visits and from -0.04 to 0.13 for hospitalizations, depending on season severity. Results were similar for HD and SD vaccinees and for nonsynthetic and synthetic statin users. Conclusions: Among 2.8 million Medicare beneficiaries, these results suggest that statin use around the time of vaccination does not substantially affect the risk of influenza-related medical encounters among older adults. PMID- 29438484 TI - Undetected Infection by Maize Bushy Stunt Phytoplasma Enhances Host-Plant Preference to Dalbulus maidis (Hemiptera: Cicadellidae). AB - Vector-borne plant pathogenic bacteria can induce changes in infected plants favoring the insect vector behavior and biology. The study aimed to determine the effect of maize bushy stunt phytoplasma (MBSP) postinoculation period on the host plant preference and transmission efficiency by the corn leafhopper, Dalbulus maidis DeLong & Wolcott, 1923 (Hemiptera: Cicadellidae). In a series of choice tests, D. maidis preference was measured as settling and oviposition on healthy maize plants versus infected maize plants showing early disease symptoms, advanced symptoms, or no symptoms. Finally, transmission efficiency of D. maidis was measured when the vector previously acquired the phytoplasma from asymptomatic source plants at different postinoculation periods. D. maidis adults preferred to settle and to oviposit on healthy than on symptomatic infected plants with advanced disease symptoms, and preferred asymptomatic plants over symptomatic ones. MBSP transmission by D. maidis was positively correlated with the postinoculation period of the source plant. Results suggest an MBSP modulation for D. maidis preference on asymptomatic infected maize plants in the early stages of the crop, allowing the pathogen an undetected transmission. PMID- 29438485 TI - Lower than expected elevated tricuspid regurgitant jet velocity in adults with sickle cell disease in Nigeria. AB - Background: Cardiopulmonary disease is a major cause of morbidity and mortality in persons with sickle cell disease (SCD). Tricuspid regurgitant jet velocity (TRJV) and predicted forced expiratory volume in 1 s (FEV1%) predicted are independently associated with death in SCD. The goal of this study was to determine the prevalence of elevated TRJV and the association, if any, between TRJV and FEV1% predicted among persons with sickle cell anaemia (SCA) in Nigeria. Methods: Using a cross-sectional design, we enrolled 100 adult Nigerians (>=15 y) with SCA. We screened participants using Doppler echocardiogram to determine their TRJV and assessed their lung function with spirometry. Results: The prevalence of elevated TRJV was 6%, with 74% of participants having low FEV1% predicted (<70%). TRJV was negatively correlated with FEV1%, but this finding was not statistically significant (Spearman's rho=-0.0263, p=0.8058). Conclusions: We found a low prevalence of elevated TRJV and a trend in association between TRJV and FEV1% predicted in Nigerian adults with SCA. Our findings underscore the need to explore further the relationship between SCD and cardiopulmonary disease in adults. PMID- 29438486 TI - The role of the food industry in health: lessons from tobacco? AB - Introduction: In this review, we highlight poor diet as the biggest risk factor for non-communicable diseases. We examine the denial tactics used by the food industry, how they reflect the tactics previously used by the tobacco industry, and how campaigners can use this knowledge to achieve future public health successes. Sources of data: Data sources are wide ranging, notably publications relating to public health, obesity and processed food, the effectiveness hierarchy and food industry denialism tactics. Areas of agreement: Global burden of disease analyses consistently demonstrate that poor diet produces a bigger burden of non-communicable disease than tobacco, alcohol and inactivity put together. The lessons learnt from the tobacco control experience of successfully fighting the tobacco industry can be applied to other industries including processed food and sugary drinks. Areas of controversy: Tackling obesity and poor diet is a more complex issue than tobacco. Food industries continue to promote weak or ineffective policies such as voluntary reformulation, and resist regulation and taxation. However, the UK food industry now faces increasing pressure from professionals, public and politicians to accept reformulation and taxes, or face more stringent measures. Growing points and areas timely for developing research: The rise in childhood and adult obesity needs to be arrested and then reversed. Unhealthy processed food and sugary drinks are a major contributing factor. There is increasing interest in the tactics being used by the food industry to resist change. Advocacy and activism will be essential to counter these denialism tactics and ensure that scientific evidence is translated into effective regulation and taxation. PMID- 29438487 TI - Successful derivation of human trophoblast stem cells. PMID- 29438488 TI - Cardioprotection by ischemic postconditioning and cyclic guanosine monophosphate elevating agents involves cardiomyocyte nitric oxide-sensitive guanylyl cyclase. AB - Aims: It has been suggested that the nitric oxide-sensitive guanylyl cyclase (NO GC)/cyclic guanosine monophosphate (cGMP)-dependent signalling pathway affords protection against cardiac damage during acute myocardial infarction (AMI). It is, however, not clear whether the NO-GC/cGMP system confers its favourable effects through a mechanism located in cardiomyocytes (CMs). The aim of this study was to evaluate the infarct-limiting effects of the endogenous NO-GC in CMs in vivo. Methods and results: Ischemia/reperfusion (I/R) injury was evaluated in mice with a CM-specific deletion of NO-GC (CM NO-GC KO) and in control siblings (CM NO-GC CTR) subjected to an in vivo model of AMI. Lack of CM NO-GC resulted in a mild increase in blood pressure but did not affect basal infarct sizes after I/R. Ischemic postconditioning (iPost), administration of the phosphodiesterase-5 inhibitors sildenafil and tadalafil as well as the NO-GC activator cinaciguat significantly reduced the amount of infarction in control mice but not in CM NO GC KO littermates. Interestingly, NS11021, an opener of the large-conductance and Ca2+-activated potassium channel (BK), an important downstream effector of cGMP/cGKI in the cardiovascular system, protects I/R-exposed hearts of CM NO-GC proficient and deficient mice. Conclusions: These findings demonstrate an important role of CM NO-GC for the cardioprotective signalling following AMI in vivo. CM NO-GC function is essential for the beneficial effects on infarct size elicited by iPost and pharmacological elevation of cGMP; however, lack of CM NO GC does not seem to disrupt the cardioprotection mediated by the BK opener NS11021. PMID- 29438489 TI - Transient Anosmia Induces Depressive-like and Anxiolytic-like Behavior and Reduces Amygdalar Corticotropin-Releasing Hormone in a ZnSO4-Induced Mouse Model. AB - Olfactory loss is known to affect both mood and quality of life. Transient anosmia was induced in mice to study the resulting changes in mood, behavior, and on a molecular level. Transient anosmia was induced by a single intranasal instillation of ZnSO4 in BALB/c mice. Hematoxylin and eosin (HE) staining, and potato chip finding test were performed to confirm olfactory loss. Tail suspension, forced swim, and splash tests were performed to evaluate depression related behavior; while the open field, and elevated plus maze tests were used to evaluate anxiety-related behavior. The mRNA levels of amygdalar corticotropin releasing hormone (CRH) and hypothalamic glucocorticoid receptor (GR) were quantified using real-time PCR to confirm relevant molecular change. Olfactory loss was confirmed 1-2.5 weeks after induction, and this loss was subsequently reversed over time. The results of the behavioral tests indicated increased depression-like and reduced anxiety-like behavior at week 1. Accordingly, PCR data identified decreased amygdalar CRH expression at week 1. These results suggest that transient anosmia induces both depressive and anxiolytic behavior as a result of decreased amygdalar CRH in a mouse model of anosmia. PMID- 29438490 TI - Detection of novel metabolite for Roxadustat doping by global metabolomics. AB - Roxadustat (FG-4592, Rox) is a stabilizer for hypoxia-inducible transcription factors (HIFs), which induce production of the erythroid growth factor erythropoietin, and has been listed by the World Anti-Doping Agency as a prohibited substance for athletes since 2011. Although the detection technologies for Rox and its glucuronide-conjugated metabolite (Rox-Gluc) have been developed exploiting triple quadrupole mass spectrometry (MS/MS), the production of metabolites from Rox in the human body remains to be clarified. Here, we established a protocol for the detection of unknown metabolites in plasma and urine samples from Rox-doping mice by global metabolomics using an ultra high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). We identified methylated Rox (Rox-Methyl), a novel metabolite, and Rox-Gluc in mouse urine by principal component analysis and orthogonal partial least squares discriminant analysis based on detected features by UHPLC QTOF/MS analysis. The estimated pharmacokinetic parameters of Rox-Methyl and Rox Gluc in mouse plasma showed similar profiles to that of Rox and both compounds showed similar biological activities. Of note, Rox-Methyl showed shorter half life than Rox-Gluc in vivo, implying the easy escape from anti-doping screen. These results demonstrate that the global metabolomics method introduced in this study will contribute to the identification and detection of HIF-analog doping. PMID- 29438491 TI - New insights on a NGF-mediated pathway to induce ovulation in rabbits (Oryctolagus cuniculus). AB - To investigate the ovulatory mechanisms triggered by raw semen (RS) in rabbits, we examined the expression of nerve growth factor (NGF)-a supposed ovulation inducing factor (OIF)-and cognate receptors in anterior pituitary, ovary, and cervix as well as plasma NGF and luteinizing hormone (LH) concentrations. Six does/group were sham-inseminated with sterile saline (PBS), naturally mated (NM), inseminated with RS alone or after lumbar anesthesia (ARS), or treatment with COX inhibitors (CIRS). Immunohistochemistry revealed positive signals for NGF and receptors in all tissues. RT-PCR confirmed the presence of the target transcripts in the same tissues, except NTRK1 in the cervix. Circulating NGF concentrations rose 3- to 6-fold (P < 0.01) 15 min after semen deposition into the genital tract of NM, RS, and ARS rabbits and remained sustained thereafter. Circulating NGF was 4-fold lower (P < 0.01) in CIRS than in RS does indicating that NGF is mainly synthesized by the uterus. A concomitant rise of LH and NGF concentrations was found in 83.3%, 50.0%, and 16.7% of NM, RS, and CIRS does, respectively, but not in ARS (despite high NGF circulating levels). Seminal plasma NGF concentration was 151.9 +/- 9.25 MUg/mL. The ovulatory responses were 0%, 83.3%, 66.7%, 16.7%, and 0% in PBS, NM, RS, ARS, and CIRS groups, respectively. Present data confirm that, although RS may induce ovulation via endocrine mechanisms through binding to NGF receptors in the ovary, a novel OIF-mediated neural mechanism facilitates ovulation in rabbits. PMID- 29438492 TI - Can stress make you relax? PMID- 29438494 TI - Artificial intelligence in drug combination therapy. AB - Currently, the development of medicines for complex diseases requires the development of combination drug therapies. It is necessary because in many cases, one drug cannot target all necessary points of intervention. For example, in cancer therapy, a physician often meets a patient having a genomic profile including more than five molecular aberrations. Drug combination therapy has been an area of interest for a while, for example the classical work of Loewe devoted to the synergism of drugs was published in 1928-and it is still used in calculations for optimal drug combinations. More recently, over the past several years, there has been an explosion in the available information related to the properties of drugs and the biomedical parameters of patients. For the drugs, hundreds of 2D and 3D molecular descriptors for medicines are now available, while for patients, large data sets related to genetic/proteomic and metabolomics profiles of the patients are now available, as well as the more traditional data relating to the histology, history of treatments, pretreatment state of the organism, etc. Moreover, during disease progression, the genetic profile can change. Thus, the ability to optimize drug combinations for each patient is rapidly moving beyond the comprehension and capabilities of an individual physician. This is the reason, that biomedical informatics methods have been developed and one of the more promising directions in this field is the application of artificial intelligence (AI). In this review, we discuss several AI methods that have been successfully implemented in several instances of combination drug therapy from HIV, hypertension, infectious diseases to cancer. The data clearly show that the combination of rule-based expert systems with machine learning algorithms may be promising direction in this field. PMID- 29438496 TI - The Adiponectin Paradox in the Elderly: Associations with Body Composition, Physical Functioning, and Mortality. AB - Background: To determine if adiponectin levels are associated with weight loss, low muscle mass, and physical functioning among the elderly and to determine independent associations with incident disability and death. Methods: Included were 3,044 participants from the Health, Aging and Body Composition Study who had whole-body dual energy absorptiometry performed to evaluate appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2), CT measures of thigh muscle density, weight histories, estimates of physical functioning, and adiponectin levels at enrollment. Associations between adiponectin levels and body composition, weight loss, and physical functioning were assessed in multivariable linear regression models. Associations between adiponectin and incident disability and mortality were assessed in mediation analyses, adjusting for other factors. Results: Greater adiponectin at baseline was independently associated with low FMI Z-Score, lower waist circumference, low ALMI Z-Score, low muscle density, a history of weight loss, and poor physical functioning (all p<0.05). Greater adiponectin levels (per SD) were associated with incident disability [HR: 1.14 (1.08, 1.20) p<0.001] and greater mortality [HR: 1.17 (1.10, 1.25) p<0.001] in models adjusting for demographic factors, adiposity, and comorbid conditions. The association was completely attenuated and no longer significant (all p>0.05) when adjusting for body composition, muscle density, weight loss, and physical functioning at baseline. Conclusions: Greater serum adiponectin levels are associated with historical weight loss, low skeletal muscle mass, low muscle density, and poor physical functioning. High adiponectin is associated with a greater risk of incident disability and death, but not independently of these factors. PMID- 29438495 TI - Collaborative, pooled and harmonized study designs for epidemiologic research: challenges and opportunities. AB - Collaborative study designs (CSDs) that combine individual-level data from multiple independent contributing studies (ICSs) are becoming much more common due to their many advantages: increased statistical power through large sample sizes; increased ability to investigate effect heterogeneity due to diversity of participants; cost-efficiency through capitalizing on existing data; and ability to foster cooperative research and training of junior investigators. CSDs also present surmountable political, logistical and methodological challenges. Data harmonization may result in a reduced set of common data elements, but opportunities exist to leverage heterogeneous data across ICSs to investigate measurement error and residual confounding. Combining data from different study designs is an art, which motivates methods development. Diverse study samples, both across and within ICSs, prompt questions about the generalizability of results from CSDs. However, CSDs present unique opportunities to describe population health across person, place and time in a consistent fashion, and to explicitly generalize results to target populations of public health interest. Additional analytic challenges exist when analysing CSD data, because mechanisms by which systematic biases (e.g. information bias, confounding bias) arise may vary across ICSs, but multidisciplinary research teams are ready to tackle these challenges. CSDs are a powerful tool that, when properly harnessed, permits research that was not previously possible. PMID- 29438497 TI - New Molecular Method for Detection of Candidemia, but Don't Forget the Blood Cultures. PMID- 29438493 TI - Estrogen in the male: a historical perspective. AB - Estrogens have traditionally been considered female hormones. Nevertheless, the presence of estrogen in males has been known for over 90 years. Initial studies suggested that estrogen was deleterious to male reproduction because exogenous treatments induced developmental abnormalities. However, demonstrations of estrogen synthesis in the testis and high concentrations of 17beta-estradiol in rete testis fluid suggested that the female hormone might have a function in normal male reproduction. Identification of estrogen receptors and development of biological radioisotope methods to assess estradiol binding revealed that the male reproductive tract expresses estrogen receptor extensively from the neonatal period to adulthood. This indicated a role for estrogens in normal development, especially in efferent ductules, whose epithelium is the first in the male reproductive tract to express estrogen receptor during development and a site of exceedingly high expression. In the 1990s, a paradigm shift occurred in our understanding of estrogen function in the male, ushered in by knockout mouse models where estrogen production or expression of its receptors was not present. These knockout animals revealed that estrogen's main receptor (estrogen receptor 1 [ESR1]) is essential for male fertility and development of efferent ductules, epididymis, and prostate, and that loss of only the membrane fraction of ESR1 was sufficient to induce extensive male reproductive abnormalities and infertility. This review provides perspectives on the major discoveries and developments that led to our current knowledge of estrogen's importance in the male reproductive tract and shaped our evolving concept of estrogen's physiological role in the male. PMID- 29438498 TI - chromswitch: a flexible method to detect chromatin state switches. AB - Summary: Chromatin state plays a major role in controlling gene expression, and comparative analysis of ChIP-seq data is key to understanding epigenetic regulation. We present chromswitch, an R/Bioconductor package to integrate epigenomic data in a defined window of interest to detect an overall switch in chromatin state. Chromswitch accurately classifies a benchmarking dataset, and when applied genome-wide, the tool successfully detects chromatin changes that result in brain-specific expression. Availability and implementation: Chromswitch is implemented as an R package available from Bioconductor at https://bioconductor.org/packages/chromswitch. All data and code for reproducing the analysis presented in this paper are available at https://doi.org/10.5281/zenodo.1101260. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29438499 TI - Ksp1-dependent phosphorylation of eIF4G modulates post-transcriptional regulation of specific mRNAs under glucose deprivation conditions. AB - Post-transcriptional regulation is an important mechanism for modulating gene expression and is performed by numerous mRNA-binding proteins. To understand the mechanisms underlying post-transcriptional regulation, we investigated the phosphorylation status of 32 mRNA-binding proteins under glucose deprivation conditions in Saccharomyces cerevisiae. We identified 17 glucose-sensitive phosphoproteins and signal pathways implicated in their phosphorylation. Notably, phosphorylation of the eukaryotic translation initiation factor 4G (eIF4G) was regulated by both the Snf1/AMPK pathway and the target of rapamycin complex 1 (TORC1) pathway. The serine/threonine protein kinase Ksp1 has previously been suggested to be a downstream effector of TORC1, but its detailed function has rarely been discussed. We identified that Snf1/AMPK and TORC1 signalings converge on Ksp1, which phosphorylates eIF4G under glucose deprivation conditions. Ksp1 dependent phosphorylation of eIF4G regulates the degradation of specific mRNAs (e.g. glycolytic mRNAs and ribosomal protein mRNAs) under glucose deprivation conditions likely through the recruitment of Dhh1. Taken together, our results suggest that Ksp1 functions as a novel modulator of post-transcriptional regulation in yeast. PMID- 29438501 TI - Occupational radiation exposure in the electrophysiology laboratory with a focus on personnel with reproductive potential and during pregnancy: A European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart rhythm Society (HRS). PMID- 29438500 TI - Diffusion radiomics as a diagnostic model for atypical manifestation of primary central nervous system lymphoma: development and multicenter external validation. AB - Background: Radiomics is a rapidly growing field in neuro-oncology, but studies have been limited to conventional MRI, and external validation is critically lacking. We evaluated technical feasibility, diagnostic performance, and generalizability of a diffusion radiomics model for identifying atypical primary central nervous system lymphoma (PCNSL) mimicking glioblastoma. Methods: A total of 1618 radiomics features were extracted from diffusion and conventional MRI from 112 patients (training set, 70 glioblastomas and 42 PCNSLs). Feature selection and classification were optimized using a machine-learning algorithm. The diagnostic performance was tested in 42 patients of internal and external validation sets. The performance was compared with that of human readers (2 neuroimaging experts), cerebral blood volume (90% histogram cutoff, CBV90), and apparent diffusion coefficient (10% histogram, ADC10) using the area under the receiver operating characteristic curve (AUC). Results: The diffusion radiomics was optimized with the combination of recursive feature elimination and a random forest classifier (AUC 0.983, stability 2.52%). In internal validation, the diffusion model (AUC 0.984) showed similar performance with conventional (AUC 0.968) or combined diffusion and conventional radiomics (AUC 0.984) and better than human readers (AUC 0.825-0.908), CBV90 (AUC 0.905), or ADC10 (AUC 0.787) in atypical PCNSL diagnosis. In external validation, the diffusion radiomics showed robustness (AUC 0.944) and performed better than conventional radiomics (AUC 0.819) and similar to combined radiomics (AUC 0.946) or human readers (AUC 0.896 0.930). Conclusion: The diffusion radiomics model had good generalizability and yielded a better diagnostic performance than conventional radiomics or single advanced MRI in identifying atypical PCNSL mimicking glioblastoma. PMID- 29438502 TI - Genomic Architecture of the Two Cold-Adapted Genera Exiguobacterium and Psychrobacter: Evidence of Functional Reduction in the Exiguobacterium antarcticum B7 Genome. AB - Exiguobacterium and Psychrobacter are bacterial genera with several cold-adapted species. These extremophiles are commonly isolated from the same habitats in Earth's cryosphere and have great ecological and biotechnological relevance. Thus, through comparative genomic analyses, it was possible to understand the functional diversity of these psychrotrophic and psychrophilic species and present new insights into the microbial adaptation to cold. The nucleotide identity between Exiguobacterium genomes was >90%. Three genomic islands were identified in the E. antarcticum B7 genome. These islands contained genes involved in flagella biosynthesis and chemotaxis, as well as enzymes for carotenoid biosynthesis. Clustering of cold shock proteins by Ka/Ks ratio suggests the occurrence of a positive selection over these genes. Neighbor joining clustering of complete genomes showed that the E. sibiricum was the most closely related to E. antarcticum. A total of 92 genes were shared between Exiguobacterium and Psychrobacter. A reduction in the genomic content of E. antarcticum B7 was observed. It presented the smallest genome size of its genus and a lower number of genes because of the loss of many gene families compared with the other genomes. In our study, eight genomes of Exiguobacterium and Psychrobacter were compared and analysed. Psychrobacter showed higher genomic plasticity and E. antarcticum B7 presented a large decrease in genomic content without changing its ability to grow in cold environments. PMID- 29438504 TI - Potentially inappropriate medication and hospitalization/emergency department visits among the elderly in Korea. AB - Objective: To investigate the association between potentially inappropriate medicine (PIM) use, defined using the American Geriatric Society (AGS) 2012 Beers criteria, and the risk of hospitalization or emergency department (ED) visits in elderly patients, and to examine the most frequently used PIMs among patients with adverse outcomes. Design/Setting: This was a retrospective study using National Health Insurance claims data from 2010 to 2012. Intervention(s): Elderly patients who took PIMs are compared to those who were not taking PIMs. Study participants: Elderly patients (n = 79 552) who visited medical institutions in Jeju Island during 2011. Main outcome measure: Hospitalization and ED visits were evaluated according to whether the patients took PIMs during the study period. The most frequent medications used by the PIM group were also investigated. Results: The likelihood of hospitalization was higher in older patients who took at least one PIM than in those who were not taking PIMs during the study period (odds ratio 2.25, 95% confidence interval 2.09-2.44). Patients taking PIMs were more likely to visit EDs (odds ratio 1.59, 95% confidence interval 1.50-1.67). Among patients who were hospitalized or visited EDs, 45.5% had taken at least one PIM on that day. The most commonly used PIMs included chlorpheniramine maleate, diazepam, metoclopramide HCl and diclofenac sodium. Conclusion: Our findings indicate that PIM use can lead to negative health consequences, providing further evidence of the inappropriateness of these medications. Thus, pharmaceutical policies regarding PIM use may need to be implemented for elderly adults in Korea. PMID- 29438503 TI - Lineage specific transcription factors and epigenetic regulators mediate TGFbeta dependent enhancer activation. AB - During neurogenesis, dynamic developmental cues, transcription factors and histone modifying enzymes regulate the gene expression programs by modulating the activity of neural-specific enhancers. How transient developmental signals coordinate transcription factor recruitment to enhancers and to which extent chromatin modifiers contribute to enhancer activity is starting to be uncovered. Here, we take advantage of neural stem cells as a model to unravel the mechanisms underlying neural enhancer activation in response to the TGFbeta signaling. Genome-wide experiments demonstrate that the proneural factor ASCL1 assists SMAD3 in the binding to a subset of enhancers. Once located at the enhancers, SMAD3 recruits the histone demethylase JMJD3 and the remodeling factor CHD8, creating the appropriate chromatin landscape to allow enhancer transcription and posterior gene activation. Finally, to analyze the phenotypical traits owed to cis regulatory regions, we use CRISPR-Cas9 technology to demonstrate that the TGFbeta responsive Neurog2 enhancer is essential for proper neuronal polarization. PMID- 29438505 TI - Assimilation of cyanide and cyano-derivatives by Pseudomonas pseudoalcaligenes CECT5344: from omic approaches to biotechnological applications. AB - Mining, jewellery and metal-processing industries use cyanide for extracting gold and other valuable metals, generating large amounts of highly toxic wastewater. Biological treatments may be a clean alternative under the environmental point of view to the conventional physical or chemical processes used to remove cyanide and related compounds from these industrial effluents. Pseudomonas pseudoalcaligenes CECT5344 can grow under alkaline conditions using cyanide, cyanate or different nitriles as the sole nitrogen source, and is able to remove up to 12 mM total cyanide from a jewellery industry wastewater that contains cyanide free and complexed to metals. Complete genome sequencing of this bacterium has allowed the application of transcriptomic and proteomic techniques, providing a holistic view of the cyanide biodegradation process. The complex response to cyanide by the cyanotrophic bacterium P. pseudoalcaligenes CECT5344 and the potential biotechnological applications of this model organism in the bioremediation of cyanide-containing industrial residues are reviewed. PMID- 29438506 TI - DNA repair activity of Fe(II)/2OG-dependent dioxygenases affected by low iron level in Saccharomyces cerevisiae. AB - Iron deprivation induces transcription of genes required for iron uptake, and transcription factor Aft1 and Aft2 mediate this by regulating transcriptional program in Saccharomyces cerevisiae. Iron-dependent Fe(II) and 2-oxoglutarate dependent dioxygenase family proteins are involved in various cellular pathways including DNA alkylation damage repair. Whether Aft1/Aft2 are required for DNA alkylation repair is currently unknown. In this report, we have analyzed DNA alkylation repair under iron-deprived condition. Saccharomyces cerevisiae Tpa1 is a member of Fe(II) and 2-oxoglutarate-dependent dioxygenase family, and we show that deletion of AFT1 and AFT2 genes affects Tpa1 function resulting in sensitivity to alkylating agent methyl methane sulfonate (MMS). Deletion of AFT1 and AFT2 along with base excision repair pathway DNA glycosylase MAG1 renders the aft1Deltaaft2Deltamag1Delta mutant highly sensitive to MMS. We have further studied effect of iron depletion by replacing S. cerevisiae Tpa1 with Escherichia coli AlkB and human AlkBH3. We observed that the activity of AlkB and AlkBH3 is also diminished similarly when present in aft1Deltaaft2Delta background as evident by sensitivity to MMS. PMID- 29438507 TI - Bacterial density rather than diversity correlates with hatching success across different avian species. AB - Bacterial communities within avian nests are considered an important determinant of egg viability, potentially selecting for traits that confer embryos with protection against trans-shell infection. A high bacterial density on the eggshell increases hatching failure, whether this effect could be due to changes in bacterial community or just a general increase in bacterial density. We explored this idea using intra- and interspecific comparisons of the relationship between hatching success and eggshell bacteria characterized by culture and molecular techniques (fingerprinting and high-throughput sequencing). We collected information for 152 nests belonging to 17 bird species. Hatching failures occurred more frequently in nests with higher density of aerobic mesophilic bacteria on their eggshells. Bacterial community was also related to hatching success, but only when minority bacterial operational taxonomic units were considered. These findings support the hypothesis that bacterial density is a selective agent of embryo viability, and hence a proxy of hatching failure only within species. Although different avian species hold different bacterial densities or assemblages on their eggs, the association between bacteria and hatching success was similar for different species. This result suggests that interspecific differences in antibacterial defenses are responsible for keeping the hatching success at similar levels in different species. PMID- 29438508 TI - Harnessing the power of communities: career networking strategies for bioscience PhD students and postdoctoral researchers. AB - With an ever more competitive global labour market, coupled with an ever increasing population of PhD-qualified graduates, the ability to communicate effectively and build strategic connections with others can be advantageous in the job-search process. Whether in pursuit of a tenure-track or non-academic position, many postdoctoral researchers and PhD students will benefit from networking as early as possible to enhance their career prospects. Sometimes viewed cynically as 'using people' or dismissed as 'the old boy network,' the ability to make meaningful connections and build relationships can be more valuable than other job-related skills in order to gain entry to, and progress within, many professions. This mini-review highlights the positive influence of networking and how bioscience PhD students and postdoctoral researchers can harness the power of communities to achieve career success. It is argued that those who make connections and promote personal patronage through networking can gain an advantage over their contemporaries. A summary of key theories and research studies that underpin the practice of networking provides credence to these assertions, which are further substantiated with examples pertinent to the academic community. Although primarily focussed on the biosciences, much of the content is applicable to other scientists at a similar career stage. PMID- 29438509 TI - DOSE DISTRIBUTION IN A BREAST UNDERGOING MAMMOGRAPHY BASED ON A 3D DETAILED BREAST MODEL FOR CHINESE WOMEN. AB - Not only the mean glandular dose (MGD) but also the glandular dose distribution is important in describing the radiation exposure to breast in mammography. For a more precise knowledge of the absorbed dose distribution in the breast, experimental measurements with thermoluminescence dosemeter and Monte Carlo simulations with Geant4 were performed in this study. The experimental measurements with homogeneous physical breast phantoms were used to validate Monte Carlo simulations of homogeneous mathematical breast models undergoing mammography. Then a 3D detailed breast model with a compressed breast thickness of 4 cm and a glandular content of 50%, which has been constructed in previous work, was used to study the absorbed dose distribution inside the breast undergoing mammography. Furthermore, the effects of the glandular tissue distribution on MGD were studied by reversing the breast model in head-toe direction to get a breast model with a different distribution of glandular tissues. PMID- 29438511 TI - Prediction of ischaemic stroke in non-valvular atrial fibrillation if advanced echocardiography plays the game. PMID- 29438510 TI - Diagnostic accuracy of 2-hydroxyglutarate magnetic resonance spectroscopy in newly diagnosed brain mass and suspected recurrent gliomas. AB - Background: Isocitrate dehydrogenase (IDH) mutations result in abnormal accumulation of 2-hydroxyglutarate (2HG) in gliomas that can be detected by MRS. We examined the diagnostic accuracy of 2HG single-voxel spectroscopy (SVS) and chemical shift imaging (CSI) in both newly diagnosed and posttreatment settings. Methods: Long echo time (97 ms) SVS and CSI were acquired in 85 subjects, including a discovery cohort of 39 patients who had postoperative residual or recurrent glioma with confirmed IDH-mutation status and 6 normal volunteers, a prospective preoperative validation cohort of 24 patients with newly diagnosed brain mass, and a prospective recurrent-lesion validation cohort of 16 previously treated IDH-mutant glioma patients with suspected tumor recurrence. The optimal thresholds for both methods in diagnosing IDH status were determined by receiver operating characteristic analysis in the discovery cohort and then applied to the 2 validation cohorts to assess the diagnostic performance. Results: The optimal 2HG/creatine thresholds of SVS and 75th percentile CSI for IDH mutations were 0.11 and 0.23, respectively. When applied to the validation sets, the sensitivity, specificity, and accuracy in distinguishing IDH-mutant gliomas in the preoperative cohort were 85.71%, 100.00%, and 94.12% for SVS, and 100.00%, 69.23%, and 81.82% for CSI, respectively. In the recurrent-lesion cohort, the sensitivity, specificity, and accuracy for discriminating IDH-positive recurrent gliomas were 40.00%, 62.50%, and 53.85% for SVS, and 66.67%, 100.00%, and 86.67% for CSI, respectively. Conclusions: 2HG MRS provides diagnostic utility for IDH mutant gliomas both preoperatively and at time of suspected tumor recurrence. SVS has a better diagnostic performance for untreated IDH-mutant gliomas, whereas CSI demonstrates greater performance in identifying recurrent tumors. PMID- 29438512 TI - Patients' and Surgeons' Perceptions of Social Media's Role in the Decision Making for Primary Aesthetic Breast Augmentation. AB - Background: Social media (SoMe) has evolved to be a platform that patients use to seek information prior to an operation, share perioperative and postoperative journey, provide feedback, offer and receive support. While there have been studies looking at the evolution and usage of SoMe either by patients or by surgeons, there is no information that compares its usefulness for both the groups. Objectives: The aim of this study was to compare the views held by patients and surgeons, towards social media and other internet resources, in relation to one commonly performed operation. Methods: A questionnaire was presented to 648 consecutive patients who attended our clinic for consultation for primary breast augmentation from September 2016 to March 2017. A separate "surgeons' questionnaire" was answered by a group of 138 plastic surgeons who were either practicing in branches of our clinic, had previously done fellowship with us, or were visiting the clinic. Results: All 138 surgeons and 648 patients responded to the questionnaire. A total of 91.4% of patients said that they had searched online and 61.4% had searched in specific online groups for information on breast augmentation. A total of 88.9% of patients had specifically looked for clinical photographs and 73.4% had specifically searched for unfavorable reviews of the surgeon. In comparison, 72.5% of surgeons thought that over three quarters of patients gather information on the internet while only 20.3% thought that over three quarters of patients use social media for their information. A total of 52.5% of surgeons have noticed that social media affected their consultations. Conclusions: With the evolution of the internet and related technologies, the role of social media continues to increase. While patients use social media to help make their decisions, it is not the only deciding factor. Surgeons appear to underestimate the patients' use of these technologies. There is concern in each group about the amount of inaccurate information on the social media. This underlines the importance of providing factual, evidence-based information to the patients. PMID- 29438513 TI - The HMGB protein Ixr1 interacts with Ssn8 and Tdh3 involved in transcriptional regulation. AB - Ixr1 is a Saccharomyces cerevisiae transcriptional factor that extensively regulates the response to hypoxia and controls other important cellular functions and DNA repair. During aerobic growth, the Ixr1 repressor function is predominant on regulated promoters of hypoxic genes, although activator effects are also observed on other genes. During hypoxia, Ixr1 expression increases and the number of genes activated by Ixr1 also increase. In this work we demonstrate that the NH2-terminal region of Ixr1 is involved in transcriptional activation. We also present the first analysis about Ixr1 interactions with three factors that have been previously identified as important players in the yeast hypoxic response, Cyc8, Tup1 and Ssn8; results demonstrate that only Ssn8 binds to Ixr1. We have also looked for other Ixr1-binding proteins associated with transcriptional regulation, by co-purification and mass spectrometry identification. Tdh3, a protein involved in transcriptional silencing, is among the new identified Ixr1 binding proteins. Differential phosphorylation of Ixr1 is found when comparing aerobic and hypoxic yeast growth. Implication of these results in transcriptional regulation mediated by Ixr1 is discussed. PMID- 29438514 TI - Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP). PMID- 29438515 TI - Diabetes and long-term outcomes of ischaemic stroke: findings from Get With The Guidelines-Stroke. AB - Aims: There is a paucity of data on the influence of diabetes on long-term outcomes after ischaemic stroke (IS). We assessed whether outcomes after IS differ between patients with and without diabetes. Methods and results: Patients aged >=65 years (n = 409 060) in Get With The Guidelines-Stroke (nationwide registry of stroke patients from 1690 sites in the USA) were followed for 3 years post-discharge. The outcomes of interest were mortality, cardiovascular and non cardiovascular hospitalizations, heart failure (HF), and recurrence of IS/transient ischaemic attack (TIA). Patients with diabetes (29.6%) were younger and had more comorbidities. At 3 years post-discharge after IS, diabetes was associated with higher risks of adverse outcomes: all-cause mortality [cumulative incidence 46.0% vs. 44.2%, absolute difference (AD) 1.8%; adjusted hazard ratio (aHR) 1.24, 95% confidence interval 1.23-1.25], all-cause readmission (71.3% vs. 63.7%, AD 7.6%; aHR 1.22, 1.21-1.23), composite of mortality and all-cause readmission (84.1% vs. 79.3%, AD 4.8%; aHR 1.21, 1.20-1.22), composite of mortality and cardiovascular readmission (69.5% vs. 64.3%, AD 5.2%; aHR 1.19, 1.18-1.20), IS/TIA readmission (15.9% vs. 13.3%, AD 2.6%; aHR 1.18, 1.16-1.20), HF readmission (10.3% vs. 6.4%, AD 3.9%; aHR 1.60, 1.56-1.64), non-cardiovascular readmission (58.3% vs. 50.3%, AD 8.0%; aHR 1.28, 1.26-1.29), and non-IS/TIA readmission (67.6% vs. 59.7%, AD 7.9%; aHR 1.23, 1.22-1.25). Accounting for the initial severity of stroke using the National Institute of Health Stroke Scale as well as using propensity score matching method as a sensitivity analysis, did not modify the results. Conclusion: Among older IS patients diabetes was associated with increased risks of death, cardiovascular and non-cardiovascular hospitalizations, HF, and IS/TIA recurrence. PMID- 29438516 TI - Are trained delivery assistants better than non-trained personnel in practicing essential newborn care in home deliveries? Evidence from a nationally representative survey in Bangladesh. AB - Background: In Bangladesh, the neonatal mortality rate has remained relatively high at 23 deaths per 1000 live births. Consistent adoption of essential newborn care (ENC) practices should lower this rate significantly. This study assessed whether the presence of skilled birth attendants (SBAs) in home deliveries improved ENC practices in Bangladesh. Methods: Data from the Bangladesh Demographic and Health Survey 2014 on mothers who reported home birth in the previous 3 y was utilized (n=2761 out of 4904 total births). SBAs include all types of healthcare providers who have received formal training in obstetric care. A generalized structural equation model was used to explore factors affecting (1) utilization of antenatal care, (2) choice of birth attendants and (3) adoption of ENC practices. Results: One-quarter (25.7%) of home births were delivered by an SBA. SBAs performed ENC practices more often than traditional birth attendants (thermal care, 15.0% of skilled deliveries vs 10.1% of unskilled; cord care, 71.6% vs 62.9%; early breastfeeding, 63.9% vs 58.6%). The presence of an SBA during delivery resulted in a greater likelihood of receiving ENC practices. Conclusion: Although SBAs performed the recommended activities at a higher rate than the unskilled across all outcomes, the proportion of SBAs performing ENC practices is still low. It is important for policymakers to identify strategies to improve the effectiveness of SBAs in home deliveries. PMID- 29438517 TI - Genome editing in Kluyveromyces and Ogataea yeasts using a broad-host-range Cas9/gRNA co-expression plasmid. AB - While CRISPR-Cas9-mediated genome editing has transformed yeast research, current plasmids and cassettes for Cas9 and guide-RNA expression are species specific. CRISPR tools that function in multiple yeast species could contribute to the intensifying research on non-conventional yeasts. A plasmid carrying a pangenomic origin of replication and two constitutive expression cassettes for Cas9 and ribozyme-flanked gRNAs was constructed. Its functionality was tested by analyzing inactivation of the ADE2 gene in four yeast species. In two Kluyveromyces species, near-perfect targeting (>=96%) and homologous repair (HR) were observed in at least 24% of transformants. In two Ogataea species, Ade- mutants were not observed directly after transformation, but prolonged incubation of transformed cells resulted in targeting efficiencies of 9% to 63% mediated by non-homologous end joining (NHEJ). In an Ogataea parapolymorpha ku80 mutant, deletion of OpADE2 mediated by HR was achieved, albeit at low efficiencies (<1%). Furthermore the expression of a dual polycistronic gRNA array enabled simultaneous interruption of OpADE2 and OpYNR1 demonstrating flexibility of ribozyme-flanked gRNA design for multiplexing. While prevalence of NHEJ prevented HR-mediated editing in Ogataea, such targeted editing was possible in Kluyveromyces. This broad-host range CRISPR/gRNA system may contribute to exploration of Cas9-mediated genome editing in other Saccharomycotina yeasts. PMID- 29438519 TI - Convergent Evolution of Human-Isolated H7N9 Avian Influenza A Viruses. AB - Background: Avian influenza A virus H7N9 has caused 5 epidemic waves of human infections in China since 2013. Avian influenza A viruses may face strong selection to adapt to novel conditions when establishing themselves in humans. In this study, we sought to determine whether adaptive evolution had occurred in human-isolated H7N9 viruses. Methods: We evaluated all available genomes of H7N9 avian influenza A virus. Maximum likelihood trees were separately reconstructed for all 8 genes. Signals of positive selection and convergent evolution were then detected on branches that lead to changes in host tropism (from avian to human). Results: We found that 3 genes had significant signals of positive selection (all of them P < .05). In addition, we detected 34 sites having significant signals for parallel evolution in 8 genes (all of them P < .05), including 7 well-known sites (Q591K, E627K, and D701N in PB2 gene; R156K, V202A, and L244Q in HA; and R289K in NA) that play roles in crossing species barriers for avian influenza A viruses. Conclusion: Our study suggests that, during infection in humans, H7N9 viruses have undergone adaptive evolution to adapt to their new host environment and that the sites where parallel evolution occurred might play roles in crossing species barriers and respond to the new selection pressures arising from their new host environments. PMID- 29438518 TI - Obesity and High-Fat Diet Induce Distinct Changes in Placental Gene Expression and Pregnancy Outcome. AB - Obese women are at high risk of pregnancy complications, including preeclampsia, miscarriage, preterm birth, stillbirth, and neonatal death. In the current study, we aimed to determine the effects of obesity on pregnancy outcome and placental gene expression in preclinical mouse models of genetic and nutritional obesity. The leptin receptor (LepR) null-reactivatable (LepRloxTB), LepR-deficient (Leprdb/+), and high-fat diet (HFD)-fed mice were assessed for fertility, pregnancy outcome, placental morphology, and placental transcriptome using standard quantitative polymerase chain reaction (qPCR) and qPCR arrays. The restoration of fertility of LepRloxTB was performed by stereotaxic delivery of adeno-associated virus-Cre into the hypothalamic ventral premammillary nucleus. Fertile LepRloxTB females were morbidly obese, whereas the wild-type mice-fed HFD showed only a mild increase in body weight. Approximately 80% of the LepRloxTB females had embryo resorptions (~40% of the embryos). In HFD mice, the number of resorptions was not different from controls fed a regular diet. Placentas of resorbed embryos from obese mice displayed necrosis and inflammatory infiltrate in the labyrinth and changes in the expression of genes associated with angiogenesis and inflammation (e.g., Vegfa, Hif1a, Nfkbia, Tlr3, Tlr4). In contrast, placentas from embryos of females on HFD showed changes in a different set of genes, mostly associated with cellular growth and response to stress (e.g., Plg, Ang, Igf1, Igfbp1, Fgf2, Tgfb2, Serpinf1). Sexual dimorphism in gene expression was only apparent in placentas from obese LepRloxTB mice. Our findings indicate that an obese environment and HFD have distinct effects on pregnancy outcome and the placental transcriptome. PMID- 29438520 TI - Advancing Pediatric Antibacterial Drug Development: A Critical Need to Reinvent our Approach. AB - The Clinical Trials Transformation Initiative convened with several groups in the pediatric antibacterial drug development community with the goal of identifying challenges and recommending ways to improve current practice. Attention to 5 major areas hold the promise of making new antibiotics available for use in children as soon as possible after they are approved for use in adults. PMID- 29438521 TI - Leydig cell dysfunction is associated with post-transcriptional deregulation of CYP17A1 in men with Sertoli cell-only syndrome. AB - STUDY QUESTION: Is the expression of steroidogenic enzyme 17alpha Hydroxylase/17,20-Lyase (CYP17A1) down-regulated in Leydig cells (LCs) of men with spermatogenic failure and compensated impairment of LC function, i.e. a low testosterone to LH (T/LH) ratio? SUMMARY ANSWER: Although the transcriptional expression of CYP17A1 is increased, its protein expression is decreased, in isolated LCs of men with spermatogenic failure and reduced serum T/LH. WHAT IS KNOWN ALREADY: Primary spermatogenic defects have been associated with functional and morphological abnormalities of LCs, characterized by decreased serum testosterone (T) levels, decreased T/LH, increased 17beta-estradiol (E2) and E2/T ratio, and larger clusters of LCs (LC hyperplasia). CYP17A1 is a key enzyme in the testosterone pathway and has been implicated in the steroidogenic lesion produced by E2 stimulation. STUDY DESIGN, SIZE, DURATION: We studied 18 azoospermic patients with Sertoli cell-only syndrome (SCOS) and signs of LC dysfunction (cases) and 10 obstructive azoospermic/oligozoospermic men with normal spermatogenesis (controls). The SCOS patients were sub-grouped into 9 cases with T/LH <2 and 9 cases with T/LH >=2. All of the men underwent testicular biopsy for sperm retrieval at the Reproductive Unit of a University Hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: The transcriptional expression of CYP17A1 and SF-1 (steroidogenic factor 1) was quantified by SYBR(r)Green-based qPCR in LCs isolated by laser capture microdissection (LCM), and relative expression to the control pool was assessed. CYP17A1 protein expression was semi quantified by indirect immunofluorescence (IFI) using Image-Pro Plus v7.0 (Media Cybernetics) in testicular tissue. FSH and LH serum concentrations, and serum and intratesticular T (ITT) and E2 (ITE2) were measured by IRMA and RIA, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: Relative CYP17A1 mRNA expression was increased in cases with T/LH <2 compared to cases with T/LH >=2, by a mean of 3.3-fold (P = 0.002). No corresponding increase in protein expression was found; in fact, CYP17A1 immunostaining intensity assessed by the Integrated Optical Density (IOD) parameter was lower in the cases with T/LH <2 compared to controls (P = 0.008). Relative SF-1 mRNA expression was similar in both case subgroups. CYP17A1 mRNA expression correlated with ITE2 and intratesticular E2/T (r = 0.536; P = 0.026 and r = 0.542; P = 0.016, respectively), while an inverse association was observed for ITE2 and protein level expression (r = -0.421; P = 0.05). LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: We should interpret the results of the semi quantification of immunofluorescent staining by Image-Pro Plus software with caution, because it is a semi-quantitative method that may have certain difficulties regarding the disposition of protein in the cells. However, it is not influenced by variations in the number of cells that express the protein, as could be the case of western blot analysis in testicular tissue. WIDER IMPLICATIONS OF THE FINDINGS: Dysfunctional LCs of men with SCOS show post transcriptional deregulation of CYP17A1, with increased mRNA and decreased protein expression, which may be modulated by increased ITE2 levels. In addition, transcriptional expression of CYP17A1 was not associated with changes in SF-1 mRNA expression. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Fund for Scientific and Technological Development (FONDECYT) of Chile to A.C. [grant number 1120176]. The authors declare no conflict of interest. PMID- 29438523 TI - Reconsidering Treatment of Community-Acquired Pneumonia: Are Macrolides Plus beta Lactams Essential? PMID- 29438522 TI - RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study. AB - Background: RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort. Patients and methods: Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal kappa coefficient of 0.7, reflecting acceptable concordance (precision +/- 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary. Results: From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the kappa coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the kappa coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06 0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers. Conclusion: This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients. Clinical Trial registration: Clinicaltrials.gov, NCT02502656. PMID- 29438524 TI - Elevated Cyclic AMP Inhibits Mycobacterium tuberculosis-Stimulated T-cell IFN gamma Secretion Through Type I Protein Kinase A. AB - Cyclic adenosine monophosphate (cAMP) is critical in immune regulation, and its role in tuberculosis infection remains unclear. We determined the levels of cAMP in peripheral blood mononuclear cells (PBMC) from tuberculosis patients and the mechanisms for cAMP suppression of IFN-gamma production. PBMC from tuberculosis patients contained significantly elevated cAMP than latent tuberculosis infected subjects (LTBI), with an inverse correlation with IFN-gamma production. Consistent with this, the expression of cAMP response element binding protein (CREB), activating transcription factor (ATF)-2 and c-Jun were reduced in tuberculosis patients compared with LTBI. PKA type I specific cAMP analogs inhibited Mtb-stimulated IFN-g production by PBMC through suppression of Mtb induced IFN-gamma promoter binding activities of CREB, ATF-2, and c-Jun and also miR155, the target miRNA of these transcription factors. Neutralizing both IL-10 and TGF-beta1 or supplementation of IL-12 restored cAMP-suppressed IFN-g production. We conclude that increased cAMP inhibits IFN-g production through PKA type I pathway in tuberculosis infection. PMID- 29438526 TI - Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy for Glioblastoma of the Corpus Callosum. AB - BACKGROUND: Glioblastoma of the corpus callosum is particularly difficult to treat, as the morbidity of surgical resection generally outweighs the potential survival benefit. Laser interstitial thermal therapy (LITT) is a safe and effective treatment option for difficult to access malignant gliomas of the thalamus and insula. OBJECTIVE: To assess the safety and efficacy of LITT for the treatment of glioblastoma of the corpus callosum. METHODS: We performed a multicenter retrospective analysis of prospectively collected data. The primary endpoint was the safety and efficacy of LITT as a treatment for glioblastoma of the corpus callosum. Secondary endpoints included tumor coverage at thermal damage thresholds, median survival, and change in Karnofsky Performance Scale score 1 mo after treatment. RESULTS: The study included patients with de novo or recurrent glioblastoma of the corpus callosum (n = 15). Mean patient age was 54.7 yr. Mean pretreatment Karnofsky Performance Scale score was 80.7 and there was no significant difference between subgroups. Mean tumor volume was 18.7 cm3. Hemiparesis occurred in 26.6% of patients. Complications were more frequent in patients with tumors >15 cm3 (RR 6.1, P = .009) and were associated with a 32% decrease in survival postLITT. Median progression-free survival, survival postLITT, and overall survival were 3.4, 7.2, and 18.2 mo, respectively. CONCLUSION: LITT is a safe and effective treatment for glioblastoma of the corpus callosum and provides survival benefit comparable to subtotal surgical resection with adjuvant chemoradiation. LITT-associated complications are related to tumor volume and can be nearly eliminated by limiting the procedure to tumors of 15 cm3 or less. PMID- 29438525 TI - Immunization of Malaria-Preexposed Volunteers With PfSPZ Vaccine Elicits Long Lived IgM Invasion-Inhibitory and Complement-Fixing Antibodies. AB - Background: The assessment of antibody responses after immunization with radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (Sanaria PfSPZ Vaccine) has focused on IgG isotype antibodies. Here, we aimed to investigate if P. falciparum sporozoite binding and invasion inhibitory IgM antibodies are induced following immunization of malaria preexposed volunteers with PfSPZ Vaccine. Methods: Using serum from volunteers immunized with PfSPZ, we measured vaccine-induced IgG and IgM antibodies to P. falciparum circumsporozoite protein (PfCSP) via ELISA. Function of this serum as well as IgM antibody fractions was measured via in vitro in an inhibition of sporozoite invasion assay. These IgM antibody fractions were also measured for binding to sporozoites by immunofluorescence assay and complement fixation on whole sporozoites. Results: We found that in addition to anti-PfCSP IgG, malaria preexposed volunteers developed anti-PfCSP IgM antibodies after immunization with PfSPZ Vaccine and that these IgM antibodies inhibited P. falciparum sporozoite invasion of hepatocytes in vitro. These IgM plasma fractions also fixed complement to whole P. falciparum sporozoites. Conclusions: This is the first finding that PfCSP and P. falciparum sporozoite-binding IgM antibodies are induced following immunization of PfSPZ Vaccine in malaria-preexposed individuals and that IgM antibodies can inhibit P. falciparum sporozoite invasion into hepatocytes in vitro and fix complement on sporozoites. These findings indicate that the immunological assessment of PfSPZ Vaccine-induced antibody responses could be more sensitive if they include parasite-specific IgM in addition to IgG antibodies. Clinical Trials Registration: NCT02132299. PMID- 29438527 TI - Effects of Hospital Practice Patterns for Antibiotic Administration for Pneumonia on Hospital Lengths of Stay and Costs. AB - Background: Hospital practice patterns vary for switching from intravenous to oral antibiotics for community-acquired pneumonia in pediatric patients, but it is unknown how these practice patterns affect hospital lengths of stay and costs. Methods: We conducted a retrospective study of 78673 pediatric patients (aged 3 months to 17 years) hospitalized for community-acquired pneumonia. Analyses were performed with data from the Pediatric Health Information System between 2007 and 2016, including discharge data from 48 freestanding children's hospitals. Patients who received antibiotics used to treat aspiration pneumonia and patients with a complex chronic condition were excluded to focus the study on uncomplicated cases. We modeled hospital practice patterns using hospital-level averages for the last day of service on which patients received antibiotics intravenously or first day of service on which patients received antibiotics orally. Results: We found that a 1-day decrease in the hospital-level average last day of service on which a patient received antibiotics intravenously reduced the average length of stay by 0.58 day (95% confidence interval [CI], -0.69 to 0.47 day) and average cost by $1332 (95% CI, -$2363 to -$300). Results were similar when hospital practice patterns were modeled using the average first day of service on which a patient received antibiotics orally. These reductions in lengths of stay and costs were not associated with a difference in 30-day readmission rates. Conclusions: Given the reductions in lengths of stay and costs without sacrificing patient outcomes (readmissions), antimicrobial stewardship programs could target provider education on the duration of intravenous antibiotic therapy as a way to reduce resource utilization. PMID- 29438528 TI - Maintenance of Certification: Perceptions and Attitudes of Neurosurgeons. AB - Assuring clinical competence throughout the career of a neurosurgeon is of paramount importance for patient safety. We present the first comprehensive survey of all neurosurgeons board certified through the American Board of Neurological Surgery (ABNS) to evaluate perceptions of Maintenance of Certification (MOC). We administered a validated, online, confidential survey to 4899 neurosurgeons (2435 ABNS diplomates participating in MOC, 1440 diplomates certified prior to 1999 [time-unlimited certificates], and 1024 retired diplomates). We received 1449 responses overall (30% response rate). Our study found that most respondents believe that neurosurgeons should be required to participate in continuing professional improvement following initial board certification (75%). Most believe that specialty boards, working in conjunction with specialty societies, should require diplomates to participate in programs meant to promote continuous professional development (73%). The majority of respondents (76%) believed that self-assessment tests constituted a meaningful professional development activity, in addition to periodic case log reviews (33%) or quality improvement projects (32.6%). A plurality of respondents (44%) do not feel that the MOC process as currently structured provides them with value. There were no differences between those who were "grandfathered" and those who actively participate in MOC and no differences between those in private practice versus those in academics. The ABNS is cognizant of diplomate concerns and is actively developing new MOC paradigms to ensure that the process achieves both the goals of meeting the public interest and assuring that the quality of American neurosurgery remains exemplary. PMID- 29438530 TI - Hypertrophic obstructive cardiomyopathy: what, when, why, for whom? AB - Hypertrophic cardiomyopathy is the most common genetic cardiovascular disorder and is associated with symptoms of heart failure and increased risk of sudden cardiac death. The most common condition is obstruction of the left ventricular outflow tract. Surgical septal myectomy and alcohol septal ablation are the 2 accepted modes of septal reduction therapy and are indicated when there are advanced symptoms and a peak left ventricular outflow gradient >=50 mmHg. Advantages of alcohol septal ablation are limited groin approach, reduction of obstruction of the left ventricular outflow tract and functional improvement, but there are higher chances for intracardiac device implantation and residual obstruction. Septal myectomy offers very low mortality, absolute and immediate resolution of obstruction of the left ventricular outflow tract and survival comparative to a matched general population with almost negligible residual obstruction. It is recommended that patients with obstructive hypertrophic cardiomyopathy should be treated at experienced centres. PMID- 29438529 TI - A CsMYB6-CsTRY module regulates fruit trichome initiation in cucumber. AB - Fruit epidermal features such as the number and size of trichomes or spines are important fruit quality traits in cucumber production. Little is known about the molecular mechanisms underlying fruit spine formation in cucumber. Here, we report functional characterization of the cucumber CsMYB6 gene, which encodes a MIXTA-like MYB transcription factor that plays an important role in regulating fruit trichome development. Spatial-temporal expression analyses revealed high level expression of CsMYB6 in the epidermis of cucumber ovaries during fruit spine initiation, which was similar to the expression of CsTRY, a homolog of the Arabidopsis TRY gene that also plays a key role in trichome development. Overexpression of CsMYB6 and CsTRY in cucumber and Arabidopsis revealed that CsMYB6 and CsTRY act as negative regulators of trichome initiation in both species, and that CsMYB6 acted upstream of CsTRY in this process. CsMYB6 was found to bind to the three MYB binding sites inside the promoter region of CsTRY, and protein-protein interaction assays suggested that CsTRY also directly interacted with CsMYB6 protein. The results also revealed conserved and divergent roles of CsMYB6 and its Arabidopsis homolog AtMYB106 in trichome development. Collectively, our results reveal a novel mechanism in which the CsMYB6-CsTRY complex negatively regulates fruit trichome formation in cucumber. PMID- 29438531 TI - Characteristics of Follicular Variant Papillary Thyroid Carcinoma in a Pediatric Cohort. AB - Context: In adults, noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) is considered a low risk for metastasis and persistent/recurrent disease. Objective: The goal of this study was to assess the clinical, sonographic, and histopathologic features of FVPTC in a pediatric cohort. Design: A retrospective review of subjects <19 years of age with papillary thyroid carcinoma (PTC) who underwent thyroidectomy between January 2010 and July 2015. Setting: Multidisciplinary academic referral center. Patients: Patients with FVPTC, defined as a tumor >=1 cm in the largest dimension with predominant follicular growth, complete lack of well-formed papillae, and nuclear features of PTC. Main Outcome Measures: Tumor size and location, presence of a tumor capsule, capsule and vascular invasion, lymph node invasion, and distant metastasis. Results: Eighteen patients with FVPTC were identified from a case cohort of 110 patients with PTC. On histopathology, 13 (72%) had unifocal nodules and 14 (78%) had completely encapsulated FVPTC. Capsule invasion was frequent (nine of 14; 64%), and vascular invasion was found in one-third of patients (six of 18; 33%). No lymph node metastases were found in the 13 patients (72%) who had a central neck lymph node dissection. One patient with vascular invasion had distant metastases. Conclusion: When strictly defined, FVPTC in pediatric patients has a low risk for bilateral disease and metastasis. Prospective studies are needed to confirm whether lobectomy with surveillance is sufficient to achieve remission in pediatric patients with low-risk FVPTC. PMID- 29438532 TI - A Child With Intermittent Headaches and Eosinophilic Meningitis. PMID- 29438533 TI - Implication of Nilgai Antelope (Artiodactyla: Bovidae) in Reinfestations of Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) in South Texas: A Review and Update. AB - The Cattle Fever Tick Eradication Program was the first parasite eradication program of veterinary importance in the United States and is considered to be one of the greatest disease eradication programs of all time. The program's utilization of pasture vacation and dipping of cattle in acaricide has been extremely successful for controlling Rhipicephalus (Boophilus) microplus (Canestrini) and R. (B.) annulatus (Say), collectively known as cattle fever ticks, on cattle along the Texas border with Mexico for decades. However, the increase of white-tailed deer, Odocoileus virginianus (Zimmermann), populations in South Texas over the last 50 yr has compromised the success of the program. R. (B.) microplus and R. (B.) annulatus infestation data have confirmed that O. virginianus can support the maintenance and movement of both species of cattle fever tick within the permanent quarantine or buffer zone in South Texas along the Rio Grande, and also in the cattle fever tick-free area north and east of the buffer zone. Over the last two decades, increasing populations of exotic nilgai antelope, Boselaphus tragocamelus (Pallas), in South Texas have further complicated cattle fever tick eradication efforts. Historical cattle fever tick infestation data, host source data, and geographical data support the continued role of O. virginianus in maintaining reinfestations of R. (B.) microplus and R. (B.) annulatus in South Texas as well as the increasing role of nilgai antelope in cattle fever tick maintenance and dispersal. PMID- 29438534 TI - Both in vivo FSH depletion and follicular exposure to Gonadotrophin-releasing hormone analogues in vitro are not effective to prevent follicular depletion during chemotherapy in mice. AB - STUDY QUESTION: Does fertility preservation using gonadotrophin-releasing hormone (GnRH) analogues during chemotherapy act through a direct effect on the ovary or through inhibition of FSH secretion? SUMMARY ANSWER: The absence of FSH in vivo and the direct exposition of ovarian follicles to GnRH analogues in vitro did not prevent chemotherapy-induced ovarian damage. WHAT IS KNOWN ALREADY: The potential mechanisms of action of GnRH analogues in protecting ovaries against chemotherapy damage remain poorly understood. We previously showed that GnRH analogues have a limited inhibitory effect on gonadotropin secretion and follicular growth in mice. STUDY DESIGN SIZE, DURATION: Mouse models were developed to independently evaluate (i) the indirect effect of FSH depletion on chemotherapy-induced ovarian damage using Fshb-deficient (-/-) mice to mimic the profound inhibition of FSH secretion during GnRH analogues treatment and (ii) the direct in vitro effect of GnRH agonist and antagonist in follicles exposed to chemotherapy using a follicular culture system. PARTICIPANTS/MATERIALS, SETTING, METHODS: To assess the indirect effect of GnRH analogues through FSH inhibition, Fshb-/- mice were treated with 1 IU pregnant mare serum gonadotropin (control group) or saline (study group) for 7 days and with cyclophosphamide (200 mg/kg) on Day 5. Ovaries were collected 48 h post-cyclophosphamide to evaluate ovarian reserve, cellular apoptosis and proliferation. To evaluate the direct effects of GnRH analogues on growing follicles, isolated preantral follicles from prepubertal mice were cultured in vitro for 13 days with 1 MUM GnRH analogues and 20 MUM of 4 hydroperoxycyclophosphamide or not at Day 4. Oocytes were matured by adding epidermal growth factor (EGF)/hCG on Day 12. Follicular development, follicular survival, oocyte maturation rates, cAMP production, and steroidogenesis were evaluated. To assess the direct GnRH analogues effects on follicular reserve, whole neonatal ovaries were cultured in vitro under the same conditions for 2 days. Ovaries were processed 24 h post-chemotherapy for ovarian reserve, cellular apoptosis and proliferation analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Cyclophosphamide induced a significant follicular loss of more than 50% in Fshb-/ mice regardless of previous treatment with gonadotropins and no difference was observed in cell proliferation or apoptosis. In vitro experiments on growing follicles showed that 4-hydroperoxycyclophosphamide significantly decreased preantral follicle survival and maturation rates (55% and 37%, respectively) and delayed follicular development, regardless of the presence of GnRH analogues. Chemotherapy reduced granulosa cell numbers in all groups, while no change in cAMP production/106 granulosa cells was observed. Similarly, 4 hydroperoxycyclophosphamide induced apoptosis and significant follicular loss in cultured neonatal ovaries irrespective of GnRH analogues exposure. LIMITATIONS REASONS FOR CAUTION: As ovarian GnRH receptors expression differs in humans and mice, further studies are needed to validate our results in human ovaries. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that ovarian damage occurred even in the absence of FSH, suggesting that inhibition of the pituitary gonadal axis is not involved in ovarian protection during GnRH analogues treatment. Using in vitro models, no evidence for direct protective effect of GnRH analogues against cyclophosphamide metabolite damage was observed. At present, clinical efficiency of GnRH analogues to prevent chemotherapy-induced ovarian damage remains highly debated and these experimental results reinforced the question as they did not bring evidence of direct or indirect mechanisms of protection. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by the Belgian FNRS, 'Le Fonds Emile DEFAY', and 'La Fondation Rose et Jean Hoguet'. Authors have no conflict of interest to declare. PMID- 29438535 TI - Discrepancies in national time trends of outpatient antibiotic utilization using different measures: a population-based study in France. AB - Objectives: To assess time trends of outpatient antibiotic utilization using different measures and explore their discrepancies. Methods: Based on French sales data from the IQVIA SDM database, 2009-16, we assessed time trends in outpatient antibiotic utilization using PrID, DID, PID and SID (defined as the number of prescriptions, DDDs, packages and standard units per 1000 inhabitants per day, respectively). We explored discrepancies between trends in PrID and DID by modelling the number of DDDs per prescription. Results: Outpatient antibiotic utilization (n = 538.2 million projected prescriptions) decreased in terms of PrID, PID and SID (-10%, -8% and -8%, respectively; negative regression slopes; P < 0.01), but remained stable according to DID (+2%; slope 0.009; P = 0.4). The number of DDDs per prescription increased over time (+14%; slope 0.019; P < 0.001). The proportions of amoxicillin and amoxicillin/clavulanate were positively associated with the number of DDDs per prescription (adjusted coefficients 0.10 and 0.15, respectively; both P < 0.05), as well as the proportion of adult and hospital prescriptions (adjusted coefficients 0.07 and 0.05, respectively; both P < 0.05). The discrepancy between DID and PrID disappeared when the DDD of amoxicillin was increased to values higher than the current DDD. Conclusions: Time trends in outpatient antibiotic utilization expressed as PrID, DID, PID and SID provided conflicting results. We caution against using DID alone when monitoring antibiotic utilization. Instead, we recommend monitoring both DID and PrID as they provide different types of relevant information, especially when studying trends at a national level. PMID- 29438536 TI - Evaluation of Xpert MTB/RIF Assay for Diagnosis of Tuberculosis in Children. AB - Introduction: Childhood tuberculosis (TB) is now a global priority. With the advent of Xpert MTB/RIF, more TB cases in children are being reported. This study was undertaken to evaluate the performance of Xpert in diagnosis of pulmonary and extra-pulmonary TB in children. Methods: Specimens from 171 suspected TB cases in children aged <15 years were tested with Xpert, culture and smear microscopy in the Department of Microbiology, Institute of Medical Sciences, India. Results: The specimens included 106 gastric aspirates, 51 cerebrospinal fluids, 8 induced sputum and 6 lymph node aspirates. Xpert detected Mycobacterium tuberculosis in 19 cases (14 pulmonary and 5 extra-pulmonary), 7 of which were rifampicin resistant. Sensitivity, specificity, positive predictive value and negative predictive value of Xpert compared with culture were 88.89, 98.04, 84.21 and 98.68%, respectively. The sensitivity was 100% in children aged 1-5 years and 6 10 years and in gastric aspirates. Conclusion: Xpert is an efficient diagnostic tool in childhood tuberculosis. PMID- 29438537 TI - Irrigation and Grass Cover Effects on Pupal Survival Rates in Soil and Adult Emergence Patterns of Rhagoletis indifferens (Diptera: Tephritidae). AB - Western cherry fruit fly, Rhagoletis indifferens (Curran; Diptera: Tephritidae), occurs in unmanaged cherries (Prunus spp.) across dry climates in Washington State and other regions in western United States and Canada. To help explain the fly's distribution in arid climates, we determined the effects of adding water to bare and grass-covered soils on pupal survival rates and adult emergence patterns of R. indifferens in central Washington. Water was added ('irrigated') or not to bare soil and grass-covered soil in cylinders pressed into the ground. Larvae were added to cylinders and pupal survival and adult fly emergence determined over three seasons. Irrigating bare soil had no effect on pupal survival or adult emergence, but in grass-covered soil, irrigation increased pupal survival (15.2 17.0% vs 6.7-9.5%) and adult emergence (2 of 3 yr, 12.8 and 24.1 vs 1.1 and 11.6%; no difference in 1 yr). Pupal survival was greater in bare (24.5-47.7%) than grass-covered soil (6.7-17.0%). Moisture was higher in irrigated than unirrigated treatments but within irrigated treatments, moisture in bare versus grass-covered soil did not differ. In both irrigated and unirrigated treatments, humidity in soil 5 cm below the surface where many pupae reside was >60%, including during summers. Results suggest R. indifferens pupae tolerate unirrigated soils during summer because soil moisture and high humidity there can prevent desiccation, contributing to the fly's wide distribution and abundance in dry climates, and that dry, grass-covered soils or mulch barriers in mid- and late-summer could reduce fly survival under some conditions. PMID- 29438538 TI - Testing the Role of the Red Queen and Court Jester as Drivers of the Macroevolution of Apollo Butterflies. AB - In macroevolution, the Red Queen (RQ) model posits that biodiversity dynamics depend mainly on species-intrinsic biotic factors such as interactions among species or life-history traits, while the Court Jester (CJ) model states that extrinsic environmental abiotic factors have a stronger role. Until recently, a lack of relevant methodological approaches has prevented the unraveling of contributions from these 2 types of factors to the evolutionary history of a lineage. Herein, we take advantage of the rapid development of new macroevolution models that tie diversification rates to changes in paleoenvironmental (extrinsic) and/or biotic (intrinsic) factors. We inferred a robust and fully sampled species-level phylogeny, as well as divergence times and ancestral geographic ranges, and related these to the radiation of Apollo butterflies (Parnassiinae) using both extant (molecular) and extinct (fossil/morphological) evidence. We tested whether their diversification dynamics are better explained by an RQ or CJ hypothesis, by assessing whether speciation and extinction were mediated by diversity-dependence (niche filling) and clade-dependent host-plant association (RQ) or by large-scale continuous changes in extrinsic factors such as climate or geology (CJ). For the RQ hypothesis, we found significant differences in speciation rates associated with different host-plants but detected no sign of diversity-dependence. For CJ, the role of Himalayan-Tibetan building was substantial for biogeography but not a driver of high speciation, while positive dependence between warm climate and speciation/extinction was supported by continuously varying maximum-likelihood models. We find that rather than a single factor, the joint effect of multiple factors (biogeography, species traits, environmental drivers, and mass extinction) is responsible for current diversity patterns and that the same factor might act differently across clades, emphasizing the notion of opportunity. This study confirms the importance of the confluence of several factors rather than single explanations in modeling diversification within lineages. PMID- 29438539 TI - SURVEY OF IMAGING TECHNOLOGY AND PATIENT DOSE RECORDING PRACTICE IN DEVELOPING COUNTRIES. AB - A survey was conducted through the International Atomic Energy Agency (IAEA) to assess the use of older imaging technologies and availability of dose information in radiography, computed tomography (CT), mammography and interventional machines. Responses from 55 countries indicated 55.8% having non-digital radiography systems, only 9.1% having all systems that are digital (CR and DR), nearly one-third (36.4%) still use calcium tungstate screens in radiography cassettes and only 16.9% having all mammography systems as digital. On the dose features, not all CT machines provide CTDI, DLP values directly as only about half (50.6%) stated all machines having CTDI and DLP display, nearly half (46.8%) indicated the absence of KAP meters in radiography systems. Only 53.2% stated all angiography machines having DAP/KAP display. Only about a quarter (23.4%) having picture archiving and communication system in all hospitals in the country. Nearly one-third (36.4%) have no difficulty in maintaining patient identification number while sending dose data. PMID- 29438540 TI - Influence of sleep restriction on weight loss outcomes associated with caloric restriction. AB - Study Objectives: To examine the effects of moderate sleep restriction (SR) on body weight, body composition, and metabolic variables in individuals undergoing caloric restriction (CR). Methods: Overweight or obese adults were randomized to an 8 week caloric restriction (CR) regimen alone (n = 15) or combined with sleep restriction (CR + SR) (n = 21). All participants were instructed to restrict daily calorie intake to 95 per cent of their measured resting metabolic rate. Participants in the CR + SR group were also instructed to reduce time in bed on five nights and to sleep ad libitum on the other two nights each week. Results: The CR + SR group reduced sleep by 57 +/- 36 min per day during SR days and increased sleep by 59 +/- 38 min per day during ad libitum sleep days, resulting in a sleep reduction of 169 +/- 75 min per week. The CR and CR + SR groups lost similar amounts of weight, lean mass, and fat mass. However, the proportion of total mass lost as fat was significantly greater (p = 0.016) in the CR group. This proportion was greater than body fat percentage at baseline for the CR (p = 0.0035), but not the CR + SR group. Resting respiratory quotient was reduced (p = 0.033) only in CR, and fasting leptin concentration was reduced only in CR + SR (p = 0.029). Conclusions: Approximately 1 hr of SR on five nights a week led to less proportion of fat mass loss in individuals undergoing hypocaloric weight loss, despite similar weight loss. SR may adversely affect changes in body composition and "catch-up" sleep may not completely reverse it. Clinical trial registration: ClinicalTrials.gov (NCT02413866). PMID- 29438542 TI - Discovery and development of new antibacterial drugs: learning from experience? AB - Antibiotic (antibacterial) resistance is a serious global problem and the need for new treatments is urgent. The current antibiotic discovery model is not delivering new agents at a rate that is sufficient to combat present levels of antibiotic resistance. This has led to fears of the arrival of a 'post-antibiotic era'. Scientific difficulties, an unfavourable regulatory climate, multiple company mergers and the low financial returns associated with antibiotic drug development have led to the withdrawal of many pharmaceutical companies from the field. The regulatory climate has now begun to improve, but major scientific hurdles still impede the discovery and development of novel antibacterial agents. To facilitate discovery activities there must be increased understanding of the scientific problems experienced by pharmaceutical companies. This must be coupled with addressing the current antibiotic resistance crisis so that compounds and ultimately drugs are delivered to treat the most urgent clinical challenges. By understanding the causes of the failures and successes of the pharmaceutical industry's research history, duplication of discovery programmes will be reduced, increasing the productivity of the antibiotic drug discovery pipeline by academia and small companies. The most important scientific issues to address are getting molecules into the Gram-negative bacterial cell and avoiding their efflux. Hence screening programmes should focus their efforts on whole bacterial cells rather than cell-free systems. Despite falling out of favour with pharmaceutical companies, natural product research still holds promise for providing new molecules as a basis for discovery. PMID- 29438541 TI - Molecular characterization of Giardia lamblia in children less than 5 years of age with diarrhoea attending the Bengo General Hospital, Angola. AB - Background: Giardia lamblia is a pathogenic intestinal protozoan with high prevalence in developing countries, especially among children. Molecular characterization has revealed the existence of eight assemblages, with A and B being more commonly described in human infections. Despite its importance, to our knowledge this is the first published molecular analysis of G. lamblia assemblages in Angola. Methods: The present study aimed to identify the assemblages of G. lamblia in children with acute diarrhoea presenting at the Bengo General Hospital, Angola. A stool sample was collected and microscopy and immunochromatographic tests were used. DNA was extracted and assemblage determination was performed through amplification of the gene fragment ssu-rRNA (175 bp) and beta-giardin (511 bp) through polymerase chain reaction and DNA sequencing. Results: Of the 16 stool samples screened, 12 were successfully sequenced. Eleven isolates were assigned to assemblage B and one to assemblage A. Subassemblage determination was not possible for assemblage B, while the single isolate assigned to assemblage A was identified as belonging to subassemblage A3. Conclusion: This study provides information about G. lamblia assemblages in Bengo Province, Angola and may contribute as a first step in understanding the molecular epidemiology of this protozoan in the country. GenBank accession numbers for the ssur-RNA gene: MF479750, MF479751, MF479752, MF479753, MF479754, MF479755, MF479756, MF479757, MF479758, MF479759, MF479760, MF479761. GenBank accession numbers for the beta-giardin gene: MF565378, MF565379, MF565380, MF565381. PMID- 29438543 TI - Curcumin attenuates heat-stress-induced oxidant damage by simultaneous activation of GSH-related antioxidant enzymes and Nrf2-mediated phase II detoxifying enzyme systems in broiler chickens. AB - The object of this study was to investigate the effect of curcumin on modulating the glutathione (GSH)-related antioxidant enzymes and antioxidant responses via NF-E2-related factor 2 (Nrf2) signaling pathway in heat-stressed broiler chickens. A total of 400 one-day-old male Arbor Acres broiler chicks was reared in an environmentally controlled room. At 21 d, broiler chicks were divided into 5 treatment groups and were fed one of 4 diets under 2 temperature conditions: 22 degrees C + a basal diet (CON treatment); 34 degrees C for 8 h (0900-1700) + a basal diet supplemented with 0, 50, 100, or 200 mg/kg curcumin (HS, CMN1, CMN2, and CMN3 treatments, respectively). The heat treatment lasted for 20 consecutive days. The results showed that heat stress significantly increased (P < 0.05) the weekly rectal temperature and average head and feet temperature. Compared to the HS treatment, feed conversion was significantly decreased (P < 0.05) in CMN1 and CMN2 treatments. CMN1 administration significantly improved (P < 0.05) the pH24 of muscle. The abnormal changes of serum malonaldehyde and corticosterone concentrations were prevented (P < 0.05) by curcumin. Mitochondrial GSH concentration in the liver was significantly increased (P < 0.05) in CMN1 and CMN2 treatments compared with the HS treatment. The CMN1, CMN2, and CMN3 supplementations significantly increased (P < 0.05) gamma-GCL, GSH-Px, and GST activities. Curcumin significantly increased (P < 0.05) the expression of Nrf2, HO-1, and gamma-GCLc in the liver as compared to the CON diet. The expression of Cu/ZnSOD and CAT were increased (P < 0.05) by feeding CMN2, respectively, as compared to the HS treatment. It was concluded that curcumin supplementation enhanced the resistance of broilers to heat stress, as evidenced by reversing the FC, increasing the GSH content and GSH-related enzyme activities, and inducing the expression of Nrf2 and Nrf2-mediated phase II detoxifying enzyme genes. PMID- 29438545 TI - Commentary on: Surgical Management of Penile Lesions Secondary to Foreign Body Reaction: A Case Report and Systematic Review. PMID- 29438544 TI - Emergence and control of linezolid-resistant Staphylococcus epidermidis in an ICU of a German hospital. AB - Objectives: To investigate an outbreak of linezolid-resistant Staphylococcus epidermidis (LRSE) in an interdisciplinary ICU, linezolid consumption and infection control measures taken. Methods: Routine surveillance of nosocomial infections revealed colonization and infection with LRSE affecting 14 patients during a 15 month period. LRSE isolates were analysed with respect to their clonal relatedness, antimicrobial susceptibility, the presence of cfr and/or mutations in the 23S rRNA, rplC, rplD and rplV genes. cfr plasmids were characterized by Illumina sequencing. Medical records were reviewed and antibiotic consumption was determined. Results: Molecular typing identified the presence of three different LRSE clusters: PFGE type I/ST168 (n = 5), PFGE type II/ST5 (n = 10) and PFGE type III/ST2 (n = 1). Ten strains harboured the cfr gene; we also detected mutations in the respective ribosomal protein genes. WGS revealed an almost identical 39 kb cfr plasmid obtained from strains of different genetic background (ST2, ST5, ST168) that shows high similarity to the recently published LRSE plasmid p12-02300. Due to an increase in the number of patients treated for infections with MRSA, a significant increase in linezolid usage was noted from January to July 2014 (from 5.55 to 20.41 DDDs/100 patient-days). Conclusions: Here, we report the molecular epidemiology of LRSE in an ICU. Our results suggest the selection of resistant mutants under linezolid treatment as well as the spread of cfr-carrying plasmids. The reduction of linezolid usage and the strengthening of contact precautions proved to be effective infection control measures. PMID- 29438546 TI - High-Intensity Ultrasound Treatment for Vincristine-Induced Neuropathic Pain. AB - BACKGROUND: Vincristine is a commonly used chemotherapeutic agent that results in debilitating untreatable peripheral neuropathy. OBJECTIVE: To determine the effects of pulsed high-intensity focused ultrasound (HIFU) on sensory thresholds in a validated vincristine-induced neuropathy (VIN) rodent model. METHODS: VIN was induced and mechanical allodynia was confirmed by nociceptive testing. von Frey fibers and Randall-Sellito test were used as measures of innocuous and noxious mechanical thresholds, respectively, and the hot plate test for thermal thresholds. Tests were performed before VIN, after 2 wk of vincristine, at 24, 48, 72, and 120 h after HIFU applied to the left L5 dorsal root ganglia at 3 Watts for 3 min. Comparisons were made between a VIN cohort who underwent HIFU, a VIN cohort who underwent sham HIFU, and naive rodents who underwent HIFU. RESULTS: VIN HIFU rats had significantly increased mechanical thresholds at 24 h (P < .001), 48 h (P = .008), 72 h (P = .003), and 120 h (P = .03) after treatment, when compared to pre-HIFU thresholds. Furthermore, at 24 and 48 h following treatment, VIN HIFU rats had significantly higher innocuous and noxious mechanical thresholds and thermal thresholds than VIN sham HIFU rats (P < .001). Thresholds were not altered in naive rodents who underwent HIFU. Histological data of L5 dorsal root ganglia of VIN HIFU rats suggest that transient cellular edema resolves by 48 h. CONCLUSION: Our data suggest that HIFU increases mechanical and thermal thresholds in VIN rodents. Whether HIFU can preclude the development of reduced thresholds in the VIN model warrants further study. PMID- 29438547 TI - Effectiveness of general practitioner online training and an information booklet for parents on antibiotic prescribing for children with respiratory tract infection in primary care: a cluster randomized controlled trial. AB - Objectives: Antibiotics are too often prescribed in childhood respiratory tract infection (RTI), despite limited effectiveness, potential side effects and bacterial resistance. We aimed to reduce antibiotic prescribing for children with RTI by online training for general practitioners (GPs) and information for parents. Methods: A pragmatic cluster randomized controlled trial in primary care. The intervention consisted of online training for GPs and an information booklet for parents. The primary outcome was the antibiotic prescription rate for children presenting with RTI symptoms, as registered by GPs. Secondary outcomes were number of reconsultations within the same disease episode, consultations for new episodes, hospital referrals and pharmacy-dispensed antibiotic courses for children. This trial was registered at the Dutch Trial Register (NTR), registration number: NTR4240. Results: After randomization, GPs from a total of 32 general practices registered 1009 consultations. An antibiotic was prescribed in 21% of consultations in the intervention group, compared with 33% in the usual care group, controlled for baseline prescribing (rate ratio 0.65, 95% CI 0.46 0.91). The probability of reconsulting during the same RTI episode did not differ significantly between the intervention and control groups, and nor did the numbers of consultations for new episodes and hospital referrals. In the intervention group antibiotic dispensing was 32 courses per 1000 children/year lower than the control group, adjusted for baseline prescribing (rate ratio 0.78, 95% CI 0.66-0.92). The numbers and proportion of second-choice antibiotics did not differ significantly. Conclusions: Concise, feasible, online GP training, with an information booklet for parents, showed a relevant reduction in antibiotic prescribing for children with RTI. PMID- 29438548 TI - Descriptive sensory and instrumental texture profile analysis of woody breast in marinated chicken. AB - The broiler industry is currently experiencing a muscle anomaly referred to as "woody breast," and the effect of different cooking methods on the marination properties of severe woody breast (SWB) has not yet been reported. This study compared the texture attributes of marinated (injected) normal (NOR) and SWB using a convection oven and a flat-top grill. The objectives were 1) to develop and validate a descriptive texture attribute panel with 6 trained panelists using a 16-point scale and 2) to evaluate the instrumental texture profile analysis (TPA) using a texture analyzer. Sixty-four NOR and SWB were obtained from a commercial facility. Fillet color (L*, a*, b*) and pH were measured before marination. In each of 2 trials, the breast muscles were injected in bulk with 15% brine (0.48 STPP, 0.55% NaCl, final concentration), and marinade retention was determined after 20 minutes. The meat was vacuum packaged, stored at -20 degrees C (7 d sensory; 29 d TPA) and then thawed (4 degrees C, 24 h). Fillets were cooked to 73 degrees C on a flat-top grill (176 degrees C) or in an oven (176 degrees C), and cook loss % was determined. Panelist samples (2 * 2 cm) and TPA samples (4 * 2 cm) were cut into 3 pieces. Color and pH were higher for SWB than NOR fillets (P < 0.05). Marinade retention was 83.21% for NOR meat and 59.23% for SWB meat. The flat-top grill method resulted in higher cook loss than oven (P < 0.05). SWB had higher cook loss when compared to NOR (P < 0.05). Sensory texture descriptors springiness, hardness, denseness, cohesiveness, fracturability, fibrousness, crunchiness, and chewiness were higher for SWB than NOR fillets (P < 0.05). TPA attributes also showed higher values for SWB compared to NOR (P < 0.05). No differences in texture were found between the grill and oven for sensory and TPA attributes. In summary, marinated SWB has significant texture differences when compared to NOR, regardless of cooking method. PMID- 29438549 TI - New Lessons for Addressing Article 12. PMID- 29438550 TI - Hypoxia Promotes Ectopic Adhesion Ability of Endometrial Stromal Cells via TGF beta1/Smad Signaling in Endometriosis. AB - Hypoxia plays a vital role in the progression of endometriosis. Additionally, integrin-mediated aberrant adhesion is also essential for establishment of endometriotic lesions. In this study, we sought to determine the function of hypoxia in integrin-mediated adhesion of endometrial stromal cells (ESCs) in endometriosis. The expressions of adhesion molecule integrins (integrin alpha5, integrin alphaV, integrin beta3, and integrin beta5) were determined in 15 normal endometria and 15 paired eutopic and ectopic endometria by immunohistochemistry. Thirteen primary ESCs from patients with peritoneal endometriosis in the proliferative phase were cultured under a hypoxic (1% O2) or normoxic (21% O2) environment, and the expression levels of hypoxia-inducible factor (HIF)-1alpha, transforming growth factor (TGF)-beta1, and integrins were detected by quantitative reverse transcription polymerase chain reaction and western blot. The alteration of integrins in endometriotic mouse models were also explored. Our results demonstrated that HIF-1alpha and integrins were highly expressed in ESCs of endometriotic lesions compared with ESCs of eutopic and normal endometrium. Hypoxia treatment significantly increased ESC adhesion abilities and integrin expression, which were positively correlated with TGF-beta1 expression. Both TGF beta1 and hypoxia enhanced ESC adhesion properties, whereas hypoxia combined with TGF-beta1 receptor inhibitor inhibited ESC adhesion. Knockdown of HIF-1alpha attenuated TGF-beta1/Smad signaling activation and integrin expression and reduced ESC adhesion. Higher expression levels of HIF-1alpha, TGF-beta1, and integrins were detected in endometriotic cysts from mice models. Our findings provide a novel insight of endometriosis that the hypoxic microenvironment stimulates ESCs to produce excessive TGF-beta1 and activates the TGF-beta1/Smad signaling pathway, thus enhancing integrin expression and the adhesion ability of ESCs. PMID- 29438551 TI - Coiling Versus Microsurgical Clipping in the Treatment of Unruptured Middle Cerebral Artery Aneurysms: A Meta-Analysis. AB - BACKGROUND: Open microsurgical clipping of unruptured intracranial aneurysms has long been the gold standard, yet advancements in endovascular coiling techniques have begun to challenge the status quo. OBJECTIVE: To compare endovascular coiling with microsurgical clipping among adults with unruptured middle cerebral artery aneurysms (MCAA) by conducting a meta-analysis. METHODS: A systematic search was conducted from January 2011 to October 2015 to update a previous meta analysis. All studies that reported unruptured MCAA in adults treated by microsurgical clipping or endovascular coiling were included and cumulatively analyzed. RESULTS: Thirty-seven studies including 3352 patients were included. Using the random-effects model, pooled analysis of 11 studies of microsurgical clipping (626 aneurysms) revealed complete aneurysmal obliteration in 94.2% of cases (95% confidence interval [CI] 87.6%-97.4%). The analysis of 18 studies of endovascular coiling (759 aneurysms) revealed complete obliteration in 53.2% of cases (95% CI: 45.0%-61.1%). Among clipping studies, 22 assessed neurological outcomes (2404 aneurysms), with favorable outcomes in 97.9% (95% CI: 96.8% 98.6%). Among coiling studies, 22 examined neurological outcomes (826 aneurysms), with favorable outcomes in 95.1% (95% CI: 93.1%-96.5%). Results using the fixed effect models were not materially different. CONCLUSION: This updated meta analysis demonstrates that surgical clipping for unruptured MCAA remains highly safe and efficacious. Endovascular treatment for unruptured MCAAs continues to improve in efficacy and safety; yet, it results in lower rates of occlusion. PMID- 29438552 TI - Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations. AB - Context: Most girls with Turner syndrome (TS) have hypergonadotropic hypogonadism and need hormonal replacement for induction of puberty and then for maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The optimal estrogen replacement regimen is still being studied. Evidence Acquisition: We conducted a systematic search of PubMed for studies related to TS and puberty. Evidence Synthesis: The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at age 11 to 12 years, with dose increases over 2 to 3 years. Initiation with low-dose estradiol (E2) is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. For adults who have undergone pubertal development, we suggest transdermal estrogen and oral progestin and discuss other approaches. We discuss linear growth, lipids, liver function, blood pressure, neurocognition, socialization, and bone and uterine health as related to hormonal replacement. Conclusion: Evidence supports the effectiveness of starting pubertal estrogen replacement with low-dose transdermal E2. When transdermal E2 is unavailable or the patient prefers, evidence supports use of oral micronized E2 or an intramuscular preparation. Only when these are unavailable should ethinyl E2 be prescribed. We recommend against the use of conjugated estrogens. Once progestin is added, many women prefer the ease of use of a pill containing both an estrogen and a progestin. The risks and benefits of different types of preparations, with examples, are discussed. PMID- 29438553 TI - RNAi-Mediated Knockdown of vATPase Subunits Affects Survival and Reproduction of Bed Bugs (Hemiptera: Cimicidae). AB - The common bed bug, Cimex lectularius L. (Hemiptera: Cimicidae) has resurged as one of the most troublesome household pests affecting people across the globe. Bed bug infestations have increased in recent years primarily due to the evolution of insecticide resistance and the insect's ability to hitchhike with travelers. vATPases are one of the most evolutionarily conserved holoenzymes in eukaryotes, which are mainly involved in proton transport across the plasma membranes and intracellular organelles. RNA interference (RNAi) has been developed as a promising tool for insect control. In this study, we used RNAi as an approach to knock down subunits A and E of the vATPase gene of bed bugs. Delivery of 0.2 ug/insect of dsRNA specific to vATPase-A and vATPase-E into female bed bugs dramatically impaired the laying and viability of eggs over time. Injection of the vATPase-E dsRNA decreased survival of the bed bugs over 30 d. Our results also showed that the knockdown of mRNA is highly effective and persistent up to 30 d post injection. This research demonstrated that silencing of the two vATPase subunits A and E offers a potential strategy to suppress bed bug populations. PMID- 29438554 TI - MICROWAVE DIATHERMY IN PHYSIOTHERAPY: INTRODUCTION AND EVALUATION OF A QUALITY CONTROL PROCEDURE. AB - Microwave diathermies (MWDs) are electromagnetic (EM) radiation emitting systems that are used by physiotherapists for thermotherapy treatment. Although this form of therapy is widely available in most physiotherapy units worldwide, management of the equipment is not obligatory addressed either by clinical engineers or medical physicists. A novel quality control (QC) protocol for MWD equipment, examining mechanical, electrical and electronic condition, the power output and EM radiation distribution in the electrotherapy room, was used during a national QC survey. The results of the survey revealed serious concerns about the safety of users and coexisting patients. The proposed approach could result in the introduction of EM-screened rooms, ensuring that MWD users and other persons in the vicinity will not be exposed to EM radiation over reference levels. International bodies could develop specific directives for EM radiation exposure in Physiotherapy Units, to conform to the proposed acceptance and functioning criteria for MDWs. PMID- 29438555 TI - Autophagy-related gene ATG13 is involved in control of xylose alcoholic fermentation in the thermotolerant methylotrophic yeast Ogataea polymorpha. AB - Lignocellulosic biomass belongs to main sustainable renewable sources for global energy supply. One of the main challenges in the conversion of saccharified lignocellulosic biomass into bioethanol is the utilization of xylose, since lignocellulosic feedstocks contain a significant amount of this pentose. The non conventional thermotolerant yeast Ogataea polymorpha naturally ferments xylose to ethanol at elevated temperatures (45 degrees C). Studying the molecular mechanisms of regulation of xylose metabolism is a promising way toward increased xylose conversion to ethanol. Insertional mutagenesis was applied to yeast O. polymorpha to identify genes involved in regulation of xylose fermentation. An insertional mutant selected as 3-bromopyruvate resistant strain possessed 50% increase in ethanol production as compared to the parental strain. Increase in ethanol production was caused by disruption of an autophagy-related gene ATG13. Involvement of Atg13 in regulation of xylose fermentation was confirmed by deletion of that gene. The atg13Delta strain also produced an elevated amount of ethanol from xylose. Insertion in ATG13 gene did not disrupt HORMA domain and did not lead to defects in autophagy whereas knock out of this gene impaired autophagy process. We suggest that Atg13 plays two different functions and its role in regulation of xylose fermentation differs from that in autophagy. PMID- 29438556 TI - Physical Performance Trajectories and Mortality among Older Mexican Americans. AB - Background: We sought to identify distinct trajectory classes of physical performance in Mexican Americans aged 75 years and older, and to examine whether these trajectories predict mortality. Methods: We used 4 waves of Hispanic Established Populations for Epidemiologic Studies of the Elderly (H-EPESE) data for adults 75 years and older from 2004-5 to 2013. Latent growth curve analysis was used to identify distinct trajectory classes. Multinomial logistic regression analysis was used to examine the association between baseline characteristics and the newly constructed trajectories. Cox proportional hazards regression models examined the hazard of mortality as a function of Short Physical Performance Battery (SPPB) trajectories. Results: The study follow-up period was approximately 9.5-years. 1411 adults were successfully classified into 3 (low declining, high-declining, and high-stable) physical performance trajectory classes. Depressive symptoms (RRR=1.94, 95%CI= 1.17-3.22), diabetes (RRR=2.44, 95%CI=1.63-3.65), number of other comorbid health conditions (RRR=1.40, 95%CI=1.16-1.68) and obesity (RRR=2.83, 95%CI=1.67-4.80), increased the relative risk of classification into the low, relative to high-stable trajectory class. Male gender and foreign-born status significantly reduced risk of classification in the low-declining and high-declining trajectory classes. We observed a statistically significant association between low-declining (HR=3.01, 95%CI=2.34 3. 87) and high-declining (HR=1.64, 95%CI=1.32-2.03) trajectories and increased risk of mortality. Conclusions: Differences in mortality across physical performance trajectory classes suggests that these physical performance classes represent differences in underlying disease progression, and thus differences in mortality risk among older Mexican Americans, which warrants additional research to better understand differential physical performance trajectories and their effects on morbidity and mortality in heterogeneous aging populations. PMID- 29438557 TI - Is drug-induced hepatitis related to the severity of tuberculous meningitis? AB - Background: Drug-induced hepatitis (DIH) occurs more commonly in tuberculous meningitis (TBM) than non-CNS tuberculosis. We evaluate DIH in TBM and its relationship with disease severity and surrogate markers of stress. Methods: Sixty-seven patients with TBM were included prospectively. The diagnosis of DIH was based on five times elevation of alanine amino transferase (ALT) in asymptomatic and three times in symptomatic patients, serum bilirubin 1.5 mg/dL or more occurring after 3 days of antitubercular drugs without any other cause of liver dysfunction; and improvement in liver function upon drug withdrawal. Stage of TBM, Glasgow Coma Scale (GCS) score, signs of raised intracranial pressure (ICP), ESR, C-reactive protein (CRP), systemic inflammatory response syndrome (SIRS), serum cortisol and MRI findings were noted on admission and during DIH. Results: A total of 32.8% (22/67) patients with TBM developed DIH that was associated with worsening in GCS score (p=0.01), stage TBM (p=0.02), SIRS parameters (p=0.04), ESR (p=0.04) and CRP (p<0.01) compared with their baseline. Stage of TBM independently predicted DIH (OR=0.42, 95% CI, 0.18-1.0; p=0.04)]. Drug-induced hepatitis occurred with paradoxical worsening in 11 patients and had higher mortality (32% vs 7%; p=0.01). Conclusion: DIH occurred in 32.8% (22/67) of patients with TBM, and was related to the severity of TBM and possibly to the accompanying 'physiological stress'. PMID- 29438558 TI - KMgene: a unified R package for gene-based association analysis for complex traits. AB - Summary: In this report, we introduce an R package KMgene for performing gene based association tests for familial, multivariate or longitudinal traits using kernel machine (KM) regression under a generalized linear mixed model framework. Extensive simulations were performed to evaluate the validity of the approaches implemented in KMgene. Availability and implementation: http://cran.r project.org/web/packages/KMgene. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29438560 TI - HIITE: HIV-1 incidence and infection time estimator. AB - Motivation: Around 2.1 million new HIV-1 infections were reported in 2015, alerting that the HIV-1 epidemic remains a significant global health challenge. Precise incidence assessment strengthens epidemic monitoring efforts and guides strategy optimization for prevention programs. Estimating the onset time of HIV-1 infection can facilitate optimal clinical management and identify key populations largely responsible for epidemic spread and thereby infer HIV-1 transmission chains. Our goal is to develop a genomic assay estimating the incidence and infection time in a single cross-sectional survey setting. Results: We created a web-based platform, HIV-1 incidence and infection time estimator (HIITE), which processes envelope gene sequences using hierarchical clustering algorithms and informs the stage of infection, along with time since infection for incident cases. HIITE's performance was evaluated using 585 incident and 305 chronic specimens' envelope gene sequences collected from global cohorts including HIV-1 vaccine trial participants. HIITE precisely identified chronically infected individuals as being chronic with an error less than 1% and correctly classified 94% of recently infected individuals as being incident. Using a mixed-effect model, an incident specimen's time since infection was estimated from its single lineage diversity, showing 14% prediction error for time since infection. HIITE is the first algorithm to inform two key metrics from a single time point sequence sample. HIITE has the capacity for assessing not only population-level epidemic spread but also individual-level transmission events from a single survey, advancing HIV prevention and intervention programs. Availability and implementation: Web-based HIITE and source code of HIITE are available at http://www.hayounlee.org/software.html. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29438559 TI - Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA. AB - Reactive oxygen species (ROS) are formed in mitochondria during electron transport and energy generation. Elevated levels of ROS lead to increased amounts of mitochondrial DNA (mtDNA) damage. We report that levels of M1dG, a major endogenous peroxidation-derived DNA adduct, are 50-100-fold higher in mtDNA than in nuclear DNA in several different human cell lines. Treatment of cells with agents that either increase or decrease mitochondrial superoxide levels leads to increased or decreased levels of M1dG in mtDNA, respectively. Sequence analysis of adducted mtDNA suggests that M1dG residues are randomly distributed throughout the mitochondrial genome. Basal levels of M1dG in mtDNA from pulmonary microvascular endothelial cells (PMVECs) from transgenic bone morphogenetic protein receptor 2 mutant mice (BMPR2R899X) (four adducts per 106 dG) are twice as high as adduct levels in wild-type cells. A similar increase was observed in mtDNA from heterozygous null (BMPR2+/-) compared to wild-type PMVECs. Pulmonary arterial hypertension is observed in the presence of BMPR2 signaling disruptions, which are also associated with mitochondrial dysfunction and oxidant injury to endothelial tissue. Persistence of M1dG adducts in mtDNA could have implications for mutagenesis and mitochondrial gene expression, thereby contributing to the role of mitochondrial dysfunction in diseases. PMID- 29438561 TI - Can We Predict Psychosis Outside the Clinical High-Risk State? A Systematic Review of Non-Psychotic Risk Syndromes for Mental Disorders. AB - Recent evidence has suggested that psychosis could develop not only in people at clinical high risk for psychosis (CHR-P) but also in those with clinical risk syndromes for emergent nonpsychotic mental disorders. The proportion of people with these clinical risk syndromes who will develop psychosis rather than to other nonpsychotic mental disorders is undetermined. Electronic databases were searched for studies reporting on clinical risk syndromes for the development of emergent nonpsychotic mental disorders. Incidence of emerging psychotic and nonpsychotic mental disorders defined on the ICD or DSM. Of a total of 9 studies relating to 3006 nonpsychotic at-risk individuals were included. Within prospective studies (n = 4, sample = 1051), the pooled incidence of new psychotic disorders across these clinical risk syndromes was of 12.9 per 1000 person-years (95% CI: 4.3 to 38.6) and that of nonpsychotic disorders (n = 3, sample = 538) was of 43.5 per 1000 person-years (95% CI: 30.9 to 61.3). Psychotic disorders may emerge outside the CHR-P paradigm, from clinical risk syndromes for incident nonpsychotic disorders, albeit at lower rates than in the CHR-P group. The clinical risk syndromes for emerging nonpsychotic disorders may exhibit a pluripotential risk of developing several types of mental disorders compared with CHR-P. If substantiated by future research, the current findings suggest that it may be useful to move beyond the current strategy of identifying individuals meeting CHR-P criteria only. PMID- 29438562 TI - Randomized Controlled Trial of the Safety and Immunogenicity of Revaccination With Tetanus-Diphtheria-Acellular Pertussis Vaccine (Tdap) in Adults 10 Years After a Previous Dose. AB - Background: Reduced-antigen-content tetanus, diphtheria, and acellular pertussis (Tdap) vaccine is recommended in many countries for boosting immunity in adolescents and adults. Although immunity to these antigens wanes with time, currently available Tdap products are not labeled for repeat administration in the United States. Methods: We performed an observer-blinded, randomized controlled trial in 1330 adults aged 18 to <65 years who received either the Tdap (n = 1002) or tetanus-diphtheria (Td) (n = 328) vaccine 8 to 12 years after a dose of Tdap vaccine administered previously. Solicited adverse events following immunization were documented for 7 days after vaccination, and serious adverse events and adverse events of medical significance were documented for 6 months after vaccination. Levels of antibodies against component vaccine antigens were measured before and 1 month after vaccination. Results: A solicited adverse event was reported by 87.7% of Tdap and 88.0% of Td vaccine recipients. We found no significant differences in the rates of injection-site reactions, systemic reactions, or serious adverse events between the vaccine groups. A robust antibody response to each pertussis antigen in the Tdap-vaccinated group was found; postvaccination-to-prevaccination geometric mean antibody concentration ratios were 8:1 (pertussis toxoid), 5.9 (filamentous hemagglutinin), 6.4 (pertactin), and 5.2 (fimbriae 2 and 3). Postvaccination geometric mean concentrations of tetanus antibody (4.20 and 4.74 IU/mL, respectively) and diphtheria antibody (10.1 and 12.6 IU/mL, respectively) were similar in the Tdap and Td groups, and the rates of seroprotection against tetanus and diphtheria were >99% in both groups. Conclusions: A second dose of Tdap vaccine in adults approximately 10 years after a previous dose was well tolerated and immunogenic. These data might facilitate consideration of providing Tdap booster doses to adults. PMID- 29438564 TI - ERRATUM FOR "alpha7-Nicotinic Acetylcholine Receptor Agonist Ameliorates Nicotine Plus High-Fat Diet-Induced Hepatic Steatosis in Male Mice by Inhibiting Oxidative Stress and Stimulating AMPK Signaling". PMID- 29438563 TI - New concepts in anammox processes for wastewater nitrogen removal: recent advances and future prospects. AB - The discovering of anaerobic ammonium oxidation (anammox) process led to the development of autotrophic nitrogen removal systems for the treatment of effluents with low C:N rate. The anammox processes provide an efficient way to remove high concentrations of ammonium compounds from industrial and urban wastewater and covert them to dinitrogen. Nevertheless, recently obtained results suggest new ways for research on autotrophic nitrogen removal system including possibility for low temperature operation, adaptation to high organic matter loads and antibiotics inhibition effect. For these reasons, the prevalence and spatial distribution of anammox communities in autotrophic nitrogen removal wastewater treatment technologies, as well as their role in formation of fixed biofilms, are reviewed here in order to illustrate the present and future significance of these microorganisms in environmental biotechnology. PMID- 29438565 TI - Diabetes and ischaemic stroke: a deadly association. PMID- 29438566 TI - A Theoretical Model of Resource-Oriented Music Therapy with Informal Hospice Caregivers during Pre-Bereavement. AB - Background: Over the past decade, caregiver pre-bereavement has received increased scholarly and clinical attention across multiple healthcare fields. Pre bereavement represents a nascent area for music therapy to develop best practices in and an opportunity to establish clinical relevancy in the interdisciplinary team. Objective: This study was an exploratory inquiry into the role of music therapy with pre-bereaved informal hospice caregivers. This study intended to articulate (a) what pre-bereavement needs are present for informal hospice caregivers, (b) which of those needs were addressed in music, and (c) the process by which music therapy addressed those needs. Methods: A constructivist grounded theory methodology using situational analysis was used. We interviewed 14 currently bereaved informal hospice caregivers who had participated in music therapy with the care recipient. Results: Analysis resulted in a theoretical model of resource-oriented music therapy promoting caregiver resilience. The resource, caregivers' stable caring relationships with care recipients through their pre-illness identities (i.e., spouse, parent, or child), is amplified through music therapy. Engagement with this resource mediates the risk of increased care burden and results in resilience fostering purposefulness and value in caregiving. Conclusions: Resource-oriented music therapy provides a unique clinical avenue for supporting caregivers through pre-bereavement, and was acknowledged by caregivers as a unique and integral hospice service. Within this model, caregivers are better positioned to develop meaning from the experience of providing care through the death of a loved one. PMID- 29438567 TI - Determination of the Baseline Susceptibility of European Populations of Cydia pomonella (Lepidoptera: Tortricidae) to Chlorantraniliprole and the Role of Cytochrome P450 Monooxygenases. AB - The codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae), is the key pest on pome fruit and walnut orchards worldwide. Its resistance to available insecticides has been widely reported. Chlorantraniliprole is an anthranilic diamide that was introduced in European countries in 2008-2009 and acts by activating the insect's ryanodine receptors. The aims of this study were to determine the baseline susceptibility of European populations of C. pomonella to chlorantraniliprole, to establish the discriminant concentrations (DC) to check the possible development of resistance, and to know the role of cytochrome P450 monooxygenases (P450) in the possible susceptibility decrease of field populations to the insecticide. Ten field populations from Spain along with others were used to calculate the baseline response of larvae to chlorantraniliprole incorporated into the diet. A pooled probit line was calculated, and three DC were established: 0.3 mg a.i./kg (close to the LC50), 1.0 mg a.i./kg (close to the LC90), and 10 mg a.i./kg diets (threefold the LC99). The DC were used to test the susceptibility of 27 field populations from France, Germany, Hungary, Italy, and Spain. The corrected mortality observed in all cases ranged within the expected interval, even with Spanish populations that showed between 12.1 and 100.0% of individuals with high P450 activity. However, the mortality caused by the DC0.3 decreased as the mean P450 activity increased. Field populations resistant to other insecticides were susceptible to chlorantraniliprole. The determined baseline codling moth susceptibility is a valuable reference for tracking possible future alterations in the efficacy of the insecticide. PMID- 29438569 TI - THE SCREENING INDOOR RADON AND PRELIMINARY STUDY OF INDOOR THORON CONCENTRATION LEVELS IN KUWAIT. AB - Indoor measurements of radon and thoron in Kuwait were conducted during the years 2015 and 2016. In this study, 65 dwellings were selected for the long-term radon thoron survey using passive nuclear track monitors. The monitors (at least one) were used at various locations in the dwellings for 83-306 days. Some measurements were also repeated at the same locations in different seasons. This current study is a preliminary thoron survey with relatively small sample size. The results showed that the range of thoron concentration was from below the lower limit of detection to 35 Bq m-3, whereas the range of radon concentration was within 10-202 Bq m-3. Furthermore, 22% of the radon results exceeded the WHO radon reference level of 100 Bq m-3. The analysis of variance showed a correlation between indoor radon concentration and the season. However, the thoron measurements were rather limited and the values were low. In addition, the relationship was investigated between radon and thoron concentrations involving the floor levels and the type of ventilation systems used. PMID- 29438568 TI - Haemodynamic assessment and support in sepsis and septic shock in resource limited settings. AB - Background: Recommendations for haemodynamic assessment and support in sepsis and septic shock in resource-limited settings are largely lacking. Methods: A task force of six international experts in critical care medicine, all of them members of the Global Intensive Care Working Group of the European Society of Intensive Care Medicine and with extensive bedside experience in resource-limited intensive care units, reviewed the literature and provided recommendations regarding haemodynamic assessment and support, keeping aspects of efficacy and effectiveness, availability and feasibility and affordability and safety in mind. Results: We suggest using capillary refill time, skin mottling scores and skin temperature gradients; suggest a passive leg raise test to guide fluid resuscitation; recommend crystalloid solutions as the initial fluid of choice; recommend initial fluid resuscitation with 30 ml/kg in the first 3 h, but with extreme caution in settings where there is a lack of mechanical ventilation; recommend against an early start of vasopressors; suggest starting a vasopressor in patients with persistent hypotension after initial fluid resuscitation with at least 30 ml/kg, but earlier when there is lack of vasopressors and mechanical ventilation; recommend using norepinephrine (noradrenaline) as a first-line vasopressor; suggest starting an inotrope with persistence of plasma lactate >2 mmol/L or persistence of skin mottling or prolonged capillary refill time when plasma lactate cannot be measured, and only after initial fluid resuscitation; suggest the use of dobutamine as a first-line inotrope; recommend administering vasopressors through a central venous line and suggest administering vasopressors and inotropes via a central venous line using a syringe or infusion pump when available. Conclusion: Recommendations for haemodynamic assessment and support in sepsis and septic shock in resource-limited settings have been developed by a task force of six international experts in critical care medicine with extensive practical experience in resource-limited settings. PMID- 29438570 TI - DOSIMETRIC ASPECTS OF OPTIMIZATION OF PROTECTION IN IRAN INDUSTRIAL RADIOGRAPHY PRACTICE. AB - According to the worldwide reports, industrial radiography is one of the highest risk radiation practices due to handling high activity sources. Therefore, an optimization of protection along with appropriate investigation level and/or dose constraint is required to achieve appropriate radiological safety. This research, presents some statistical aspects of this optimization using frequency distributions and percentiles of individual recorded dose of industrial radiographers from the years 2002 to 2016 in Iran. The results show that, considering an investigation level of 4 mSv for bimonthly monitoring periods, 3 7% of population of workers has been investigated during these years. Moreover, an overall reduction on average annual and collective doses is observed, despite of the relative increasing in the number of workers. Since the frequency of periodical recorded dose at lower dose range (e.g. <4 mSv) causes greater impacts on the reduction of collective dose than the higher ranges, a retrospective average dose of non-investigated workers can also be substitute with a constant value as a dose constraint. It can be concluded that all the past measures of regulatory body and attempts of the employers have been effective improving the radiological protection in this practice in Iran. However, establishing a dose constraint seems to be essential to continue and improve this optimization of protection. PMID- 29438571 TI - Use of non-vitamin K oral anticoagulants in people with atrial fibrillation and diabetes mellitus. AB - AIMS: To examine the efficacy and safety of non-vitamin K oral anticoagulants in people with both atrial fibrillation and diabetes mellitus. METHODS: We reviewed efficacy and safety data from the warfarin-controlled phase III non-vitamin K oral anticoagulants trials (ARISTOTLE, RE-LY, ROCKET-AF, ENGAGE AF-TIMI 48) and their post hoc analyses with regard to diabetes status. We also reviewed the updated literature regarding this population. RESULTS: At baseline 20-40% of the participants in the phase III non-vitamin K oral anticoagulants trials had diabetes mellitus at baseline. This population, in comparison with those without diabetes, was more likely to have other comorbidities, such as hypertension and coronary artery disease; thus, their cardiovascular risk was higher. Participants with diabetes had higher rates of stroke and systemic embolism than participants without diabetes. This risk was decreased using non-vitamin K oral anticoagulants, with no significant interaction by diabetic status or the specific drug used. Overall, compared with warfarin, non-vitamin K oral anticoagulants were safe and reduced the incidence of major bleeding in people with atrial fibrillation and diabetes, although the results varied with the different non-vitamin K oral anticoagulants. CONCLUSIONS: The efficacy and safety of non-vitamin K oral anticoagulants compared with warfarin generally extend to participants with diabetes mellitus, although dedicated randomized trials or real world data are lacking. PMID- 29438572 TI - Hypertriglyceridaemic-waist phenotype and risk of diabetes in people with impaired fasting glucose in primary care: a cohort study. AB - AIM: We aimed to determine the prospective association between baseline triglyceridaemic-waist phenotypes and diabetic mellitus incidence in individuals with impaired fasting glucose seen in primary care. METHODS: A cohort of 1101 participants (84.4% of the recruited individuals) with impaired fasting glucose were recruited from three primary care clinics during regular follow-ups to monitor their chronic conditions. Baseline triglyceridaemic-waist phenotypes were divided into four groups: (1) normal waistline and triglyceride level (n = 252); (2) isolated central obesity (n = 518); (3) isolated high triglyceride level (n = 80); and (4) central obesity with high triglyceride level (i.e. hypertriglyceridaemic-waist phenotype) (n = 251). The presence of diabetes at follow-up was determined by fasting plasma glucose (>= 7.0 mmol/l) and/or 2-h 75 g oral glucose tolerance test (>= 11.1 mmol/l) and/or HbA1c (47.5 mmol/mol; >= 6.5%) according to American Diabetes Association diagnostic criteria. Multivariable Cox proportional hazards regressions were established to assess the impact of different triglyceridaemic-waist phenotypes on time to diabetes onset. RESULTS: After a mean follow-up period of 6.5 months (sd 4.7 months), the number of diabetes cases was significantly higher in the group with hypertriglyceridaemic-waist phenotype (52.2%) compared with the other three phenotype groups (group 1: 28.2%; group 2: 34.6%; group 3: 30.0%). Only the hypertriglyceridaemic-waist phenotype showed an increased risk of developing diabetes (hazard ratio 1.581, 95% CI 1.172-2.134; P = 0.003) compared with the group with normal waistline and triglyceride level after controlling for confounders. CONCLUSIONS: The combination of central obesity and hypertriglyceridaemia is associated with > 50% risk of progression to diabetes within 6 months among individuals with impaired fasting glucose seen in primary care. PMID- 29438573 TI - What is your diagnosis? Nasopharyngeal mass in a mixed breed dog. PMID- 29438574 TI - Protective effects of an extract of the freshwater microalga Scenedesmus rubescens on UV-irradiated skin cells. AB - BACKGROUND: Skin ageing results from intrinsic but also extrinsic factors of which UV irradiation is a main cause. It is hence of interest to have means to protect skin from UV irradiation-induced damage. We selected an extract of the freshwater microalga Scenedesmus rubescens and assessed its potential to protect skin from photoageing caused by UV irradiation. METHODS: Skin cells in vitro and ex vivo were analysed for markers of UV irradiation-induced photodamage such as decreased viability, decreased collagen content, hyperpigmentation and sunburn cells. RESULTS: We found that a dry extract of the microalga Scenedesmus rubescens was able to suppress cellular signs of ageing induced by UV irradiation. It enhanced dermal fibroblast viability, rescued dermal collagen content, inhibited the formation of sunburn cells and inhibited tyrosinase activity. CONCLUSION: An extract of Scenedesmus rubescens showed broad activity against markers of UV irradiation-induced cutaneous ageing. It may therefore be used as a preventive or regenerative agent for anti-ageing strategies. PMID- 29438575 TI - Primary care professionals providing non-urgent care in hospital emergency departments. AB - BACKGROUND: In many countries emergency departments (EDs) are facing an increase in demand for services, long waits, and severe crowding. One response to mitigate overcrowding has been to provide primary care services alongside or within hospital EDs for patients with non-urgent problems. However, it is unknown how this impacts the quality of patient care and the utilisation of hospital resources, or if it is cost-effective. This is the first update of the original Cochrane Review published in 2012. OBJECTIVES: To assess the effects of locating primary care professionals in hospital EDs to provide care for patients with non urgent health problems, compared with care provided by regularly scheduled emergency physicians (EPs). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (the Cochrane Library; 2017, Issue 4), MEDLINE, Embase, CINAHL, PsycINFO, and King's Fund, from inception until 10 May 2017. We searched ClinicalTrials.gov and the WHO ICTRP for registered clinical trials, and screened reference lists of included papers and relevant systematic reviews. SELECTION CRITERIA: Randomised trials, non-randomised trials, controlled before after studies, and interrupted time series studies that evaluated the effectiveness of introducing primary care professionals to hospital EDs attending to patients with non-urgent conditions, as compared to the care provided by regularly scheduled EPs. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified four trials (one randomised trial and three non-randomised trials), one of which is newly identified in this update, involving a total of 11,463 patients, 16 general practitioners (GPs), 9 emergency nurse practitioners (NPs), and 69 EPs. These studies evaluated the effects of introducing GPs or emergency NPs to provide care to patients with non-urgent problems in the ED, as compared to EPs for outcomes such as resource use. The studies were conducted in Ireland, the UK, and Australia, and had an overall high or unclear risk of bias. The outcomes investigated were similar across studies, and there was considerable variation in the triage system used, the level of expertise and experience of the medical practitioners, and type of hospital (urban teaching, suburban community hospital). Main sources of funding were national or regional health authorities and a medical research funding body.There was high heterogeneity across studies, which precluded pooling data. It is uncertain whether the intervention reduces time from arrival to clinical assessment and treatment or total length of ED stay (1 study; 260 participants), admissions to hospital, diagnostic tests, treatments given, or consultations or referrals to hospital-based specialist (3 studies; 11,203 participants), as well as costs (2 studies; 9325 participants), as we assessed the evidence as being of very low-certainty for all outcomes.No data were reported on adverse events (such as ED returns and mortality). AUTHORS' CONCLUSIONS: We assessed the evidence from the four included studies as of very low-certainty overall, as the results are inconsistent and safety has not been examined. The evidence is insufficient to draw conclusions for practice or policy regarding the effectiveness and safety of care provided to non-urgent patients by GPs and NPs versus EPs in the ED to mitigate problems of overcrowding, wait times, and patient flow. PMID- 29438576 TI - Shifting the focus - the primary role of IL-23 in psoriasis and other inflammatory disorders. AB - Insights into the pathophysiology of autoimmune inflammatory diseases including psoriasis have advanced considerably in recent years, and in parallel, so too have the available treatment options. Current clinical paradigms for the treatment of psoriasis have evolved to include targeted biologic therapies, starting with tumour necrosis factor-alpha (TNF-alpha) inhibitors and later, agents targeting interleukin (IL)-12/23 and IL-17. The most recent evidence suggests that IL-23 might be an even more potent target for the effective treatment of psoriasis and other autoimmune inflammatory disorders. This review will describe recent developments leading to the current understanding of the key role of IL-23 as a 'master regulator' of autoimmune inflammation and the clinical evidence for agents that specifically target this modulator in the context of treating psoriasis, spondyloarthropathy and inflammatory bowel disease. PMID- 29438577 TI - A BAHD acyltransferase catalyzing 19-O-acetylation of tabersonine derivatives in roots of Catharanthus roseus enables combinatorial synthesis of monoterpene indole alkaloids. AB - While the characterization of the biosynthetic pathway of monoterpene indole alkaloids (MIAs) in leaves of Catharanthus roseus is now reaching completion, only two enzymes from the root counterpart dedicated to tabersonine metabolism have been identified to date, namely tabersonine 19-hydroxylase (T19H) and minovincine 19-O-acetyltransferase (MAT). Albeit the recombinant MAT catalyzes MIA acetylation at low efficiency in vitro, we demonstrated that MAT was inactive when expressed in yeast and in planta, suggesting an alternative function for this enzyme. Therefore, through transcriptomic analysis of periwinkle adventitious roots, several other BAHD acyltransferase candidates were identified based on the correlation of their expression profile with T19H and found to localize in small genomic clusters. Only one, named tabersonine derivative 19-O acetyltransferase (TAT) was able to acetylate the 19-hydroxytabersonine derivatives from roots, such as minovincinine and horhammericine, following expression in yeast. Kinetic studies also showed that the recombinant TAT was specific for root MIAs and displayed an up to 200-fold higher catalytic efficiency than MAT. In addition, gene expression analysis, protein subcellular localization and heterologous expression in Nicotiana benthamiana were in agreement with the prominent role of TAT in acetylation of root-specific MIAs, thereby redefining the molecular determinants of the root MIA biosynthetic pathway. Finally, identification of TAT provided a convenient tool for metabolic engineering of MIAs in yeast enabling efficiently mixing different biosynthetic modules spatially separated in the whole plant. This combinatorial synthesis associating several enzymes from Catharanthus roseus resulted in the conversion of tabersonine in tailor-made MIAs bearing both leaf and root-type decorations. PMID- 29438578 TI - Individual heterogeneity and early life conditions shape growth in a freshwater top predator. AB - Body size can have profound impacts on survival, movement, and reproductive schedules shaping individual fitness, making growth a central process in ecological and evolutionary dynamics. Realized growth is the result of a complex interplay between life history schedules, individual variation, and environmental influences. Integrating all of these aspects into growth models is methodologically difficult, depends on the availability of repeated measurements of identifiable individuals, and consequently represents a major challenge in particular for natural populations. Using a unique 30-yr time series of individual length measurements inferred from scale year rings of wild brown trout, we develop a Bayesian hierarchical model to estimate individual growth trajectories in temporally and spatially varying environments. We reveal a gradual decrease in average juvenile growth, which has carried over to adult life and contributed to decreasing sizes observed at the population level. Commonly studied environmental drivers like temperature and water flow did not explain much of this trend and overall persistent and among-year individual variation dwarfed temporal variation in growth patterns. Our model and results are relevant to a wide range of questions in ecology and evolution requiring a detailed understanding of growth patterns, including conservation and management of many size-structured populations. PMID- 29438579 TI - Consequences of relying on statistical significance: Some illustrations. AB - BACKGROUND: Despite regular criticisms of null hypothesis significance testing (NHST), a focus on testing persists, sometimes in the belief to get published and sometimes encouraged by journal reviewers. This paper aims to demonstrate known key limitations of NHST using simple nontechnical illustrations. DESIGN: The first illustration is based on simulated data of 20 000 studies that compare two groups for an outcome event. The true effect size (difference in event rates) and sample size (20-100 per group) were varied. The second illustration used real data from a meta-analysis on alpha-blockers for the treatment of ureteric stones. RESULTS: The simulations demonstrated the large between-study variability in P values (range between <.0001 and 1 for most simulation conditions). A focus on statistically significant effects (P < .05), notably in small to moderate samples, led to strongly overestimated effect sizes (up to 240%) and many false positive conclusions, that is statistically significant effects that were, in fact, true null effects. Effect sizes also exerted strong between-study variability, but confidence intervals accounted for this: the interval width decreased with larger sample size, and the percentage of intervals that contained the true effect size was accurate across simulation conditions. Reducing alpha level, as recently suggested, reduced false-positive conclusions but strongly increased the overestimation of significant effects (up to 320%). CONCLUSIONS: Researchers and journals should abandon statistical significance as a pivotal element in most scientific publications. Confidence intervals around effect sizes are more informative, but should not merely be reported to comply with journal requirements. PMID- 29438580 TI - Drug Self-Delivery Systems Based on Hyperbranched Polyprodrugs towards Tumor Therapy. AB - Amphiphilic hyperbranched polyprodrugs (DOX-S-S-PEG) with drug repeat units in hydrophobic core linked by disulfide bonds were developed as drug self-delivery systems for cancer therapy. The hydroxyl groups and the amine group in doxorubicin (DOX) were linked by 3,3'-dithiodipropanoic acid as hydrophobic hyperbranched cores, then amino-terminated polyethylene glycol monomethyl ether (mPEG-NH2 ) as hydrophilic shell was linked to hydrophobic cores to form amphiphilic and glutathione (GSH)-responsive micelle of hyperbranched polyprodrugs. The amphiphilic micelles can be disrupted under GSH (1 mg mL-1 ) circumstance. Cell viability of A549 cells and 293T cells was evaluated by CCK-8 and Muse Annexin V & Dead Cell Kit. The disrupted polyprodrugs maintained drug activity for killing tumor cells. Meanwhile, the undisrupted polyprodrugs possessed low cytotoxicity to normal cells. The cell uptake experiments showed that the micelles of DOX-S-S-PEG were taken up by A549 cells and distributed to cell nuclei. Thus, the drug self-delivery systems with drug repeat units in hydrophobic cores linked by disulfide bonds showed significant special advantages: 1) facile one-pot synthesis; 2) completely without toxic or non degradable polymers; 3) DOX itself functions as fluorescent labeled molecule and self-delivery carrier; 4) drug with inactive form in hyperbranched cores and low cytotoxicity to normal cells. These advantages make them excellent drug self delivery systems for potential high efficient cancer therapy. PMID- 29438581 TI - Curcumin-Functionalized Ag/Ag2 O Nanocomposites: Efficient Visible-Light Z-scheme Photocatalysts. AB - Curcumin-functionalized Ag/Ag2 O (c-Ag/Ag2 O) nanocomposites with varying proportions of curcumin and Ag/Ag2 O were prepared by a simple one pot green synthesis protocol in aqueous medium. The plasmonic band undergoes slight redshift, broadening and decrease in intensity with increase in the proportion of Ag2 O formed. These composite nanoparticles were found to be efficient visible light photocatalysts for aerobic oxidation of methyl orange and rhodamine B (RhB). Functionalization by curcumin significantly enhanced the photocatalytic activity with good reusability. The photocatalytic oxidation rate showed super linear increase with light intensity because of localized surface plasmon resonance (LSPR)-induced strong near field. The trapping experiments confirmed that superoxide radicals were the main active species responsible for the degradation reaction. A plasmonic Z-scheme photocatalytic mechanism is proposed to explain the possible charge transfer and separation behavior of electron-hole pairs among Ag, Ag2 O and curcumin under visible-light irradiation. PMID- 29438583 TI - Issue Highlights-March 2018. PMID- 29438582 TI - Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics. AB - Muraymycins are a subclass of antimicrobially active uridine-derived natural products. Biological data on several muraymycin analogues have been reported, including some inhibitory in vitro activities toward their target protein, the bacterial membrane enzyme MraY. However, a structure-activity relationship (SAR) study on naturally occurring muraymycins based on such in vitro data has been missing so far. In this work, we report a detailed SAR investigation on representatives of the four muraymycin subgroups A-D using a fluorescence-based in vitro MraY assay. For some muraymycins, inhibition of MraY with IC50 values in the low-picomolar range was observed. These inhibitory potencies were compared with antibacterial activities and were correlated to modelling data derived from a previously reported X-ray crystal structure of MraY in complex with a muraymycin inhibitor. Overall, these results will pave the way for the development of muraymycin analogues with optimized properties as antibacterial drug candidates. PMID- 29438584 TI - Regional regulation of focal adhesion kinase after concentric and eccentric loading is related to remodelling of human skeletal muscle. AB - AIMS: We assessed focal adhesion kinase (FAK) response to concentric (CON) vs eccentric (ECC) resistance training (RT) at two vastus lateralis (VL) sites, and the relationships between FAK, muscle protein synthesis (MPS) and morphological remodelling. METHODS: Six young males trained both legs unilaterally 3 times/week for 8 weeks; one leg performed CON RT, the contralateral performed ECC RT. Muscle biopsies were collected after training from VL mid-belly (MID) and distal (distal) sites at 0, 4, 8 weeks. Focal adhesion kinase content and activation were evaluated by immunoblotting. MPS was assessed by deuterium oxide tracer; morphological adaptations were evaluated by ultrasound and DXA. RESULTS: pY397 FAK 8 weeks levels were ~4-fold greater after ECC at the distal site compared to CON (P < .05); pY397FAK to total FAK ratio was greater in ECC vs CON at 4 (~2.2 fold, P < .05) and 8 weeks (~9-fold, P < .001) at the distal site. Meta-vinculin was found transiently increased at 4 weeks at the distal site only after ECC RT. ECC presented greater fascicle length (Lf) increases (10.5% vs 4%), whereas CON showed greater in pennation angle (PA) changes (12.3% vs 2.1%). MPS did not differ between exercise types or muscle sites at all time points. distal pY397 FAK and pY397-FAK/FAK values correlated to changes in Lf at 8 weeks (r = .76, P < .01 and r = .66, P < .05 respectively). CONCLUSION: Focal adhesion kinase phosphorylation was greater at 8 weeks after ECC RT and was muscle region specific. FAK activity correlated to contraction-dependent architectural remodelling, suggesting a potential role of FAK in orienting muscle structural changes in response to distinct mechanical stimuli. PMID- 29438585 TI - Photoanode for Aqueous Dye-Sensitized Solar Cells based on a Novel Multicomponent Thin Film. AB - Most of the dye-sensitized solar cells (DSSCs) developed so far use organic electrolytes and water-sensible sensitizers. The search for aqueous DSSCs, a promising technology for solar-energy conversion, implies finding materials that are stable in aqueous solution. In this study, Prussian blue (PB) was utilized as an innovative sensitizer in a photoanode for DSSCs and a novel synthetic approach to a carbon nanotubes/TiO2 /PB nanocomposite thin film was developed. The photoresponse was evaluated in a total aqueous electrolyte, and photocurrents of 600 MUA cm-2 were achieved. PMID- 29438586 TI - Progression and treatment rates using an active surveillance protocol incorporating image-guided baseline biopsies and multiparametric magnetic resonance imaging monitoring for men with favourable-risk prostate cancer. AB - OBJECTIVE: To assess early outcomes since the introduction of an active surveillance (AS) protocol incorporating multiparametric magnetic resonance imaging (mpMRI)-guided baseline biopsies and image-based surveillance. PATIENTS AND METHODS: A new AS protocol mandating image-guided baseline biopsies, annual mpMRI and 3-monthly prostate-specific antigen (PSA) testing, but which retained protocol re-biopsies, was tested. Pathological progression, treatment conversion and triggers for non-protocol biopsy were recorded prospectively. RESULTS: Data from 157 men enrolled in the AS protocol (median age 64 years, PSA 6.8 ng/mL, follow-up 39 months) were interrogated. A total of 12 men (7.6%) left the AS programme by choice. Of the 145 men who remained, 104 had re-biopsies either triggered by a rise in PSA level, change in mpMRI findings or by protocol. Overall, 23 men (15.9%) experienced disease progression; pathological changes were observed in 20 men and changes in imaging results were observed in three men. Of these 23 men, 17 switched to treatment, giving a conversion rate of 11.7% (<4% per year). Of the 20 men with pathological progression, this was detected in four of them after a PSA increase triggered a re-biopsy, while in 10 men progression was detected after an mpMRI change. Progression was detected in six men, however, solely after a protocol re-biopsy without prior PSA or mpMRI changes. Using PSA and mpMRI changes alone to detect progression was found to have a sensitivity and specificity of 70.0% and 81.7%, respectively. CONCLUSION: Our AS protocol, with thorough baseline assessment and imaging-based surveillance, showed low rates of progression and treatment conversion. Changes in mpMRI findings were the principle trigger for detecting progression by imaging alone or pathologically; however, per protocol re-biopsy still detected a significant number of pathological progressions without mpMRI or PSA changes. PMID- 29438587 TI - Managing penetrating renal trauma: experience from two major trauma centres in the UK. AB - OBJECTIVES: To present our series of patients with penetrating renal trauma treated at two urban major trauma centres and to discuss the contemporary management of such injuries. METHODS: We reviewed prospective urological trauma databases for all patients presenting with penetrating renal trauma between January 2005 and October 2016. Patient demographics, clinical characteristics, imaging, management and follow-up data were analysed. RESULTS: Over the 11-year period, 63 patients presented with penetrating renal injuries. The vast majority of patients were male (n = 61; 96.8%), with a mean (range) age of 27.4 (14-71) years. Injuries were equally common on either side (31 left, 32 right). The most common mechanism of injury was stabbing (n = 55; 87.3%), followed by gunshot (n = 7; 11.1%) and crossbow injuries (n = 1; 1.6%). All patients underwent contrast enhanced computed tomography. Using the American Association for the Surgery of Trauma renal injury grading system, 11 (17.5%) had grade II, 26 (41.3%) had grade III and 26 (41.3%) had grade IV injury. The most common associated injuries were thoracic (n = 23; 36.5%), liver (n = 11; 17.5%), splenic (n = 10; 15.9%), gastrointestinal tract (n = 8; 12.7%) and musculoskeletal (n = 6; 9.5%). At presentation, 16 patients (25.4%) were haemodynamically unstable. The majority of patients did not require blood transfusion (n = 56; 88.9%), while transfusion of >5 units was rare (n = 4; 6.3%). Fifty-two patients (82.5%) were managed by observation alone, while 10 (15.9%) underwent emergency angiography and embolization. Patients with grade IV injury were more likely to require embolization than those with grade III injury; however, the difference was not significant (26.9% vs 15.4%; P = 0.29). One patient (1.6%) underwent retroperitoneal exploration of their renal injury and was managed conservatively. Eight patients underwent laparotomy for other visceral injuries while their renal injury was managed conservatively. Renal artery pseudoaneurysm developed in five patients (7.9%) and one patient (1.6%) developed renal arteriovenous malformation. No patients underwent nephrectomy and no mortality was reported. CONCLUSIONS: The vast majority of patients with penetrating renal injuries can be safely managed non-operatively in this setting. Selective renal artery embolization is an effective option for patients in an unstable condition, with excellent outcomes. Associated thoracic or visceral injuries requiring operative management are common in penetrating renal trauma, while urologists should limit or have a high threshold for surgical intervention. PMID- 29438588 TI - Aerobic Oxidation Catalysis by a Molecular Barium Vanadium Oxide. AB - Aerobic catalytic oxidations are promising routes to replace environmentally harmful oxidants with O2 in organic syntheses. Here, we report a molecular barium vanadium oxide, [Ba4 (dmso)14 V14 O38 (NO3 )] (={Ba4 V14 }) as viable homogeneous catalyst for a series of oxidation reactions in N,N-dimethyl formamide solution under oxygen (8 bar). Starting from the model compound 9,10-dihydroanthracene, we report initial dehydrogenation/ aromatization leading to anthracene formation; this intermediate is subsequently oxidized by stepwise oxygen transfer, first giving the mono-oxygenated anthrone and then the di-oxygenated target product, anthraquinone. Comparative reaction analyses using the Neumann catalyst [PV2 Mo10 O40 ]5- as reference show that oxygen diffusion into the reaction mixture is the rate-limiting step, resulting in accumulation of the reduced catalyst species. This allows us to propose improved reactor designs to overcome this fundamental challenge for aerobic oxidation catalysis. PMID- 29438589 TI - British Association of Urological Surgeons (BAUS) consensus document for the management of male genital emergencies - penile fracture. AB - Male genital emergencies relating to the penis and scrotum are rare and require prompt investigation and surgical intervention. Clinicians are often unfamiliar with the management of these conditions and may not work in a specialist centre with on-site expertise in genitourethral surgery. The aim of these consensus statements is to provide best practice guidance for urological surgeons based in the UK which are developed by an expert consensus. Penile fracture is a rare emergency and in most cases requires prompt exploration and repair to prevent erectile dysfunction and penile curvature. PMID- 29438590 TI - Hybrid transanal resection of a near-circumferential large, low rectal polyp - a video vignette. PMID- 29438591 TI - Restoration of eastern oyster populations with positive density dependence. AB - Positive density dependence (i.e., Allee effects) can create a threshold of population states below which extinction of the population occurs. The existence of this threshold, which can often be a complex, multi-dimensional surface, rather than a single point, is of particular importance in degraded populations for which there is a desire for successful restoration. Here, we incorporated positive density dependence into a closed, size- and age-structured integral projection model parameterized with empirical data from an eastern oyster, Crassostrea virginica, population in Pamlico Sound, North Carolina, USA. To understand the properties of the threshold surface, and implications for restoration, we introduced a general method based on a linearization of the threshold surface at its unique, unstable equilibrium. We estimated the number of oysters of a particular age (i.e., stock enhancement), or the surface area of dead shell substrate required (i.e., habitat enhancement) to move a population from an extinction trajectory to a persistence trajectory. The location of the threshold surface was strongly affected by changes in the amount of local larval retention. Traditional stock enhancement with oysters <1 yr old (i.e., spat) required three times as many oysters relative to stock enhancement with oysters between ages 3 and 7 yr old, while the success of habitat enhancement depended upon the initial size distribution of the population. The methodology described here demonstrates the importance of considering positive density dependence in oyster populations, and also provides insights into effective management and restoration strategies when dealing with a high dimensional threshold separating extinction and persistence. PMID- 29438592 TI - Are all gonadotrophin-releasing hormone agonists equivalent for the treatment of prostate cancer? A systematic review. AB - To review direct comparative studies of the gonadotrophin-releasing hormone (GnRH) agonists goserelin, triptorelin, and leuprorelin for the treatment of prostate cancer, and identify whether there are meaningful clinical differences between these agents. In June 2017, the following searches were performed independently by two reviewers in PubMed: (i) 'prostate cancer' and 'triptorelin' and 'leuprorelin', (ii) 'prostate cancer' and 'triptorelin' and 'goserelin', and (iii) 'prostate cancer' and 'goserelin' and 'leuprorelin', without time restriction. Duplicates were deleted. Relevant conference abstracts were also screened. A total of 16 direct comparative trials were identified: 12 reported on efficacy outcomes, four on safety/tolerability, and five on the convenience of administration/user perceptions. These studies are restricted in terms of patient numbers, formulations assessed, and endpoints measured; none were adequately powered for survival outcome measures. Studies reporting on efficacy endpoints did not show major differences in the ability of these GnRH agonists to reduce levels of testosterone or prostate-specific antigen. Some studies suggest differences in short- or long-term testosterone control, the rate of injection site adverse events, and patient/healthcare professional perceptions, but definitive conclusions cannot be drawn from the existing evidence. Few direct comparative trials of GnRH agonists have been conducted. Whilst GnRH agonists provide a similar castration effect, there is not enough evidence to show that GnRH agonists are equivalent. PMID- 29438593 TI - What happens to the unsuccessful spermatozoa? AB - To study apoptosis as a functional pathway in mature spermatozoa and apoptosis correlated to the acrosome reaction via the intracellular calcium concentration, semen samples from 27 healthy human donors were treated with inducers of apoptosis (betulinic acid, thapsigargin), inducers of the acrosome reaction (thapsigargin, calcium ionophore) or hydrogen peroxide to produce reactive oxygen species with and without prior incubation with a calcium chelator. Computer assisted sperm analysis, flow cytometry, and transmission electron microscopy were performed to analyze changes in the acrosomal status and in apoptotic features. Betulinic acid, thapsigargin, and the calcium ionophore treatment resulted in an increased number of sperm cells with caspase 9 and caspase 3 activation, disrupted mitochondrial membrane potential, and a reacted acrosome. Sperm motility was decreased in all cases. Transmission electron analyses showed ultra-morphological changes, such as membrane integrity, membrane blebbing, the formation of head vacuoles, defects of the nuclear envelope, nuclear fragmentation, and the acrosome reaction. Acrosome reaction and apoptotic features decreased due to the reduction in intracellular calcium by the calcium chelator NP-EGTA, AM. Therefore, apoptotic cell death in acrosome-reacted sperm cells mediated by high intracellular calcium levels is possible. PMID- 29438594 TI - Gold-Copper Aerogels with Intriguing Surface Electronic Modulation as Highly Active and Stable Electrocatalysts for Oxygen Reduction and Borohydride Oxidation. AB - We, for the first time, report the successful synthesis of self-assembled AuCu aerogels by a one-pot kinetically controlled approach. A startling electronic modulation effect of Cu on Au was observed across the entire alloy composition range, for which the optimal upshift of the d-band center for the highest activities was 0.24 eV. Owing to the combination of a nanoporous architecture and a robust electronic effect, the Au52 Cu48 aerogels exhibited better catalytic performance for the oxygen reduction reaction (ORR) and the direct borohydride oxidation reaction (BOR) than commercial Pt/C catalysts. The specific and mass ORR activities were 4.5 and 6.3 times higher, respectively, on the Au52 Cu48 aerogels than on Pt/C with negligible activity decay even after 10 000 cycles and a duration of 40 000 s. For the BOR, the Au52 Cu48 aerogels also exhibited far better selectivity and activity than Pt/C. The new AuCu aerogels show great potential as a promising alternative for Pt-based catalysts in fuel cells. PMID- 29438595 TI - Effects of Early Alcohol Exposure on Functional Organization and Microstructure of a Visual-Tactile Integrative Circuit. AB - BACKGROUND: Children with fetal alcohol spectrum disorders (FASD) often have deficits associated with multisensory processing. Because ethanol (EtOH) disrupts activity-dependent neuronal plasticity, a process that is essential for refining connections during cortical development, we hypothesize that early alcohol exposure results in alterations in multisensory cortical networks, which could explain the multisensory processing deficits seen in FASD. Here, we use a gyrencephalic animal model to test the prediction that early alcohol exposure alters the functional connectivity and microstructural features of the rostral posterior parietal cortex (PPr), a visual-tactile integrative area. METHODS: Ferrets were exposed to moderate doses of EtOH during the brain growth spurt period. Functional connectivity and microstructural features were assessed using resting-state functional magnetic resonance imaging and ex vivo diffusion kurtosis imaging (DKI), respectively, when the animals reached juvenile age and adulthood, respectively. RESULTS: While the whole brain volume was smaller in alcohol-treated animals, the relative size of the frontal brain area was larger when compared to control animals. Altered functional connectivity was observed in alcohol-treated animals, where increased connectivity was observed between PPr and the region that provides its major visual inputs (the caudal portion of the parietal cortex), but not with the region that provides its major somatosensory inputs (tertiary somatosensory cortex). DKI revealed reduced microstructural tissue complexity in all investigated sensory areas of alcohol-treated animals. CONCLUSIONS: In this study, we observed alterations in cortical functional connectivity and microstructural integrity in a cortical area involved in multisensory processing in a ferret FASD model. These findings indicate an alteration in cortical networks that may be related to the multisensory processing deficiencies observed in FASD. PMID- 29438596 TI - Early Discontinuation of Montelukast Treatment; A Danish Nationwide Utilization Study. AB - Montelukast, a leukotriene receptor antagonist, was marketed in 1998 as an oral supplementary treatment to patients with mild to moderate asthma. The aim of this study was to describe the early discontinuation pattern among montelukast users in Denmark in the period of 1 March 1998 to 31 December 2016, and to identify demographic characteristics possibly associated with early discontinuation. This nationwide drug utilization study was based on data collected from three nationwide Danish registers. All montelukast users who redeemed at least one prescription in the study period were identified. Early discontinuation was defined as failing to fill a second prescription for montelukast within at least a year after the initial montelukast prescription. Among 135,271 included montelukast users, 47,480 (35%) discontinued the use of montelukast after a single redeemed prescription. The trend in early discontinuation increased throughout the years. The most predominant demographic risk factors for early discontinuation were prescription for only nasal topical anti-allergic treatment up to a year prior to montelukast initiation [adjusted odds ratio (OR) 2.25; 95% confidence interval (CI) 2.13-2.38], as well as suspected off-label use (adjusted OR 2.02; 95% CI 1.97-2.08). Several risk factors were associated with a decreased risk of early discontinuation; most pronounced was a prescription of inhaled corticosteroids within a year up to montelukast initiation [adjusted OR 0.47 (95% CI 0.46-0.49)]. Early discontinuation was more pronounced after patent expiry in 2012 [adjusted OR 1.42 (95% CI 1.38-1.45)]. In conclusion, we found that early montelukast discontinuation increased during the last 19 years. Appropriateness of the treatment indication as estimated by concomitant prescription of adequate inhalation therapy was associated with a low risk of early discontinuation. A more pronounced early discontinuation was observed after patent expiry in 2012, which could reflect a more liberal approach to montelukast prescription. PMID- 29438597 TI - Personally tailored activities for improving psychosocial outcomes for people with dementia in long-term care. AB - BACKGROUND: People with dementia who are being cared for in long-term care settings are often not engaged in meaningful activities. Offering them activities which are tailored to their individual interests and preferences might improve their quality of life and reduce challenging behaviour. OBJECTIVES: ? To assess the effects of personally tailored activities on psychosocial outcomes for people with dementia living in long-term care facilities.? To describe the components of the interventions.? To describe conditions which enhance the effectiveness of personally tailored activities in this setting. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, on 16 June 2017 using the terms: personally tailored OR individualized OR individualised OR individual OR person-centred OR meaningful OR personhood OR involvement OR engagement OR engaging OR identity. We also performed additional searches in MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science (ISI Web of Science), ClinicalTrials.gov, and the World Health Organization (WHO) ICTRP, to ensure that the search for the review was as up to date and as comprehensive as possible. SELECTION CRITERIA: We included randomised controlled trials and controlled clinical trials offering personally tailored activities. All interventions included an assessment of the participants' present or past preferences for, or interests in, particular activities as a basis for an individual activity plan. Control groups received either usual care or an active control intervention. DATA COLLECTION AND ANALYSIS: Two authors independently checked the articles for inclusion, extracted data and assessed the methodological quality of included studies. For all studies, we assessed the risk of selection bias, performance bias, attrition bias and detection bias. In case of missing information, we contacted the study authors. MAIN RESULTS: We included eight studies with 957 participants. The mean age of participants in the studies ranged from 78 to 88 years and in seven studies the mean MMSE score was 12 or lower. Seven studies were randomised controlled trials (three individually randomised, parallel group studies, one individually randomised cross-over study and three cluster-randomised trials) and one study was a non-randomised clinical trial. Five studies included a control group receiving usual care, two studies an active control intervention (activities which were not personally tailored) and one study included both an active control and usual care. Personally tailored activities were mainly delivered directly to the participants; in one study the nursing staff were trained to deliver the activities. The selection of activities was based on different theoretical models but the activities did not vary substantially.We found low-quality evidence indicating that personally tailored activities may slightly improve challenging behaviour (standardised mean difference (SMD) -0.21, 95% confidence interval (CI) -0.49 to 0.08; I2 = 50%; 6 studies; 439 participants). We also found low-quality evidence from one study that was not included in the meta-analysis, indicating that personally tailored activities may make little or no difference to general restlessness, aggression, uncooperative behaviour, very negative and negative verbal behaviour (180 participants). There was very little evidence related to our other primary outcome of quality of life, which was assessed in only one study. From this study, we found that quality of life rated by proxies was slightly worse in the group receiving personally tailored activities (moderate-quality evidence, mean difference (MD) -1.93, 95% CI -3.63 to -0.23; 139 participants). Self-rated quality of life was only available for a small number of participants, and there was little or no difference between personally tailored activities and usual care on this outcome (low-quality evidence, MD 0.26, 95% CI -3.04 to 3.56; 42 participants). We found low-quality evidence that personally tailored activities may make little or no difference to negative affect (SMD -0.02, 95% CI -0.19 to 0.14; I2 = 0%; 6 studies; 589 participants). We found very low quality evidence and are therefore very uncertain whether personally tailored activities have any effect on positive affect (SMD 0.88, 95% CI 0.43 to 1.32; I2 = 80%; 6 studies; 498 participants); or mood (SMD -0.02, 95% CI -0.27 to 0.23; I2 = 0%; 3 studies; 247 participants). We were not able to undertake a meta-analysis for engagement and the sleep-related outcomes. We found very low quality evidence and are therefore very uncertain whether personally tailored activities improve engagement or sleep-related outcomes (176 and 139 participants, respectively). Two studies that investigated the duration of the effects of personally tailored activities indicated that the intervention effects persisted only during the delivery of the activities. Two studies reported information about adverse effects and no adverse effects were observed. AUTHORS' CONCLUSIONS: Offering personally tailored activities to people with dementia in long-term care may slightly improve challenging behaviour. Evidence from one study suggested that it was probably associated with a slight reduction in the quality of life rated by proxies, but may have little or no effect on self-rated quality of life. We acknowledge concerns about the validity of proxy ratings of quality of life in severe dementia. Personally tailored activities may have little or no effect on negative affect and we are uncertain whether they improve positive affect or mood. There was no evidence that interventions were more likely to be effective if based on one specific theoretical model rather than another. Our findings leave us unable to make recommendations about specific activities or the frequency and duration of delivery. Further research should focus on methods for selecting appropriate and meaningful activities for people in different stages of dementia. PMID- 29438599 TI - Fatal Adverse Event with Dabigatran in Elderly Patient with Reduced Kidney Function. AB - An elderly man with decreased kidney function was admitted to hospital with gastrointestinal bleeding. After remaining stable for 2 days in hospital, he became haemodynamically unstable and an adverse effect of dabigatran was suspected, but efforts to treat the patient failed and the following morning he passed away. In conjunction with the autopsy, blood samples from his hospital stay were analysed for dabigatran, revealing the highest concentration (6400 ng/mL) apparently reported to date. Supra-therapeutic dosing was, however, never suspected. Dabigatran is largely excreted through the kidneys. A possible cause of the high dabigatran concentrations could be a rapid decrease in kidney function that seemingly occurred over a period of 2 months, sometime between his initiation of treatment (eGFR 51-55 mL/min/1.73 m2 ) and subsequent hospital admission (eGFR 31 mL/min/1.73 m2 ). The increasing dabigatran concentrations in the patient was, however, not apparent to the prescribing doctor, as therapeutic drug monitoring of dabigatran is not recommended in current guidelines and no such analyses were performed. There may be a need to evaluate blood concentrations of dabigatran, in the light of the reported differences in interindividual concentrations, along with the increased risks of thromboembolic events with lower concentrations and major bleeding events with higher concentrations. Functional assays to assess concentrations of dabigatran in blood have been developed and are available in some hospitals to be used in suspected overdoses or before emergency surgeries. Methods to determine concentrations of dabigatran specifically have also been developed and can additionally be used for therapeutic drug monitoring in an outpatient setting, especially in high-risk individuals. PMID- 29438598 TI - Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature. AB - TMEM16A is essential for Ca2+ -activated Cl- conductance in vascular smooth muscle. The importance of TMEM16A for agonist-induced vascular constriction and blood pressure control is, however, under debate. Previous studies suggested that TMEM16A might have a complex cellular function beyond being essential for the Ca2+ -activated Cl- conductance, for example modulation of Ca2+ channel expression. Mice with constitutive, smooth muscle-specific expression of siRNA directed against Tmem16a (transgenic mice, TG) were generated. Isometric constrictions of isolated aorta, mesenteric, femoral and tail arteries from TG mice were compared with wild-types. Protein expression was analysed by Western blots. Blood pressure and heart rate were studied telemetrically. Significant TMEM16A down-regulation was seen in aorta and tail arteries, while no changes were detected in mesenteric and femoral arteries. Contractile responses of mesenteric and femoral arteries from TG and wild-type mice were not different. Aorta from TG mice showed reduced agonist-induced constriction, while their responses to elevated K+ were unchanged. Tail arteries from TG mice also constricted less to adrenergic stimulation than wild-types. Surprisingly, tail arteries from TG mice constricted less to elevated K+ too and were more sensitive to nifedipine-induced relaxation. Consistently, TMEM16A down-regulation in tail arteries was associated with reduction in CACNA1C protein (i.e. vascular L-type Ca2+ channel) expression. No differences in blood pressure and heart rate between the groups were seen. This study suggests a complex contribution of TMEM16A in vascular function. We suggest that TMEM16A modulates arterial contractility, at least in part, indirectly via regulation of CACNA1C expression. PMID- 29438600 TI - International consensus statement on allergy and rhinology: allergic rhinitis executive summary. AB - BACKGROUND: The available allergic rhinitis (AR) literature continues to grow. Critical evaluation and understanding of this literature is important to appropriately utilize this knowledge in the care of AR patients. The International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR) has been produced as a multidisciplinary international effort. This Executive Summary highlights and summarizes the findings of the comprehensive ICAR:AR document. METHODS: The ICAR:AR document was produced using previously described methodology. Specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: Over 100 individual topics related to AR diagnosis, pathophysiology, epidemiology, disease burden, risk factors, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR were addressed in the comprehensive ICAR:AR document. Herein, the Executive Summary provides a synopsis of these findings. CONCLUSION: In the ICAR:AR critical review of the literature, several strengths were identified. In addition, significant knowledge gaps exist in the AR literature where current practice is not based on the best quality evidence; these should be seen as opportunities for additional research. The ICAR:AR document evaluates the strengths and weaknesses of the AR literature. This Executive Summary condenses these findings into a short summary. The reader is also encouraged to consult the comprehensive ICAR:AR document for a thorough description of this work. PMID- 29438601 TI - Open access: is there a predator at the door? PMID- 29438603 TI - From Early Radiographic Knee Osteoarthritis to Joint Arthroplasty: Determinants of Structural Progression and Symptoms. AB - OBJECTIVE: To assess structural progression in knees with no/mild radiographic osteoarthritis (OA) (i.e., Kellgren/Lawrence [K/L] grades 0-2) that will undergo knee replacement during a 5-year period; to assess differences in structural damage on magnetic resonance imaging (MRI) in knees with no/mild radiographic OA versus those with severe radiographic OA (i.e., K/L grades 3 and 4) at baseline; and to assess differences in pain levels between those groups. METHODS: All participants who underwent knee replacement from baseline to 60 months were drawn from the Osteoarthritis Initiative. MRIs were assessed for bone marrow lesions (BMLs), Hoffa synovitis, and effusion synovitis (i.e., hyperintensity signal changes in the fat pad and abnormal amount of capsular distension due to intraarticular joint fluid and/or synovial thickening) at baseline and at the time point before knee replacement (T0). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score (KOOS) pain were used for pain characterization. WOMAC activities of daily living and KOOS quality of life were applied to characterize functional status of the included participants. Logistic regression was used to assess the association of no/mild radiographic OA with these MRI features and pain. RESULTS: Based on inclusion criteria, 181 knees were selected. Participants were predominantly female (57.8%) with a mean age of 64.4 years. A total of 51 knees (28.2%) had no/mild radiographic OA at baseline. Of these, 51.0% progressed to severe radiographic OA. No/mild radiographic OA knees showed higher odds of BMLs in the patellofemoral joint at baseline (odds ratio [OR] 7.92 [95% confidence interval (95% CI) 3.45-18.16]) and T0 (OR 9.44 [95% CI 4.00-22.28]) compared to severe radiographic OA knees. In addition, no/mild radiographic OA knees were associated with change from no pain to pain from baseline to T0 (adjusted OR 5.48 [95% CI 1.25-24.00]). CONCLUSION: More than half of the knees with no/mild radiographic OA before knee replacement progressed to severe radiographic OA during 4 years of follow-up. BMLs in the patellofemoral joint were more often seen among knees that had no/mild radiographic OA. Worsening pain status may contribute to knee replacement in knees with no/mild radiographic OA. PMID- 29438604 TI - Increased Burden of Psychiatric Disorders in Rheumatoid Arthritis. AB - OBJECTIVE: We estimated the incidence and prevalence of depression, anxiety disorder, bipolar disorder, and schizophrenia in a population-based cohort with rheumatoid arthritis (RA) as compared to an age-, sex-, and geographically matched cohort without RA. METHODS: Using population-based administrative health data from Manitoba, Canada, we identified persons with incident RA between 1989 and 2012, and a cohort from the general population matched 5:1 on year of birth, sex, and region of residence. We applied validated algorithms for depression, anxiety disorder, bipolar disorder, and schizophrenia to determine the annual incidence of these conditions after the diagnosis of RA, and their lifetime and annual period prevalence. We compared findings between cohorts using negative binomial regression models. RESULTS: We identified 10,206 incident cases of RA and 50,960 matched individuals. After adjustment for age, sex, socioeconomic status, region of residence, number of physician visits, and year, the incidence of depression was higher in the RA cohort over the study period (incidence rate ratio [IRR] 1.46 [95% confidence interval (95% CI) 1.35-1.58]), as was the incidence of anxiety disorder (IRR 1.24 [95% CI 1.15-1.34]) and bipolar disorder (IRR 1.21 [95% CI 1.00-1.47]). The incidence of schizophrenia did not differ between groups (IRR 0.96 [95% CI 0.61-1.50]). Incidence rates of psychiatric disorders declined minimally over time. The lifetime and annual period prevalence of depression and anxiety disorder were also higher in the RA than in the matched cohort over the study period. CONCLUSION: The incidence and prevalence of depression, anxiety disorder, and bipolar disorder are elevated in the RA population as compared to a matched population. PMID- 29438602 TI - International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis. AB - BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding. PMID- 29438605 TI - Understanding the Factors That Influence Risk Tolerance Among Minority Women: A Qualitative Study. AB - OBJECTIVE: To explore the factors that influence risk tolerance among women from different racial/ethnic groups. METHODS: In-depth individual interviews of non Hispanic African American, non-Hispanic white, and Hispanic women ages 20-45 years were conducted by a trained interviewer using a semi-structured interview guide to elicit the factors that influence risk tolerance among minority women. The interviews were audiotaped and professionally transcribed, with a final sample size of 36 determined by thematic saturation. The members of the research team used open coding to review and develop a list of codes, which was modified as new codes emerged. A final list of 35 codes was applied to the transcripts and combined into broader themes. RESULTS: The study included 30.6% non-Hispanic African American, 33.3% non-Hispanic white, and 36.1% Hispanic women, with a mean +/- SD age of 34.8 +/- 6.8 years. Several major themes explaining risk aversion among minority women emerged: discrepancies in quality of health care, perceived prejudice, lack of knowledge and education, medication beliefs, risk perception, and constrained resources. The latter was discussed most frequently. CONCLUSION: While our findings identify several concerns that may be addressed through implementation of more effective communication strategies by medical providers, they also highlight that disparities are strongly influenced by the complex ways financial and social constraints impact health care decisions of minority women. PMID- 29438606 TI - Experience and Context Shape Patient and Clinician Goals For Treatment of Rheumatoid Arthritis: A Qualitative Study. AB - OBJECTIVE: Alignment of patient and clinician goals, which is central to effective patient-centered care, has been linked to improved patient experience and outcomes but has not been explored in rheumatoid arthritis (RA). The aim of this study was to analyze goal conceptualization among RA patients and clinicians. METHODS: Seven focus groups and 1 semi-structured interview were conducted with RA patients and clinicians who were recruited from 4 rheumatology clinics. An interview guide was developed to explore goal concordance related to RA treatment. Researchers utilized a concurrent deductive-inductive data analysis approach. RESULTS: Nineteen patients (mean age 55 years, 74% female, 32% non white, and 26% Spanish-speaking) and 18 clinicians (44% trainees, 44% female, 28% non-white) participated. Across clinician and patient focus groups, the 2 identified domains were patient knowledge of RA and psychosocial dynamics (stress) in RA treatment. Within the knowledge domain, 3 themes emerged: RA knowledge for informed choice, RA knowledge to ensure adherence and medication safety, and clinician assumption of patient inability to interpret information. Within the second domain of RA and stress, 2 themes emerged: patient illness experience informs treatment context in ways that are not shared by clinicians, and the impact of patient-clinician communication and decision-making on goal concordance. CONCLUSION: Knowledge is a shared goal, but RA patients and clinicians hold divergent attitudes towards this goal. While knowledge is integral to self-management and effective shared decision-making, mismatches in attitudes may lead to suboptimal communication. Tools to support patient goal directed RA care may promote high quality patient-centered care and result in reduced disparities. PMID- 29438607 TI - Improved Gout Outcomes in Primary Care Using a Novel Disease Management Program: A Pilot Study. AB - OBJECTIVE: To pilot a primary care gout management improvement intervention. METHODS: Two large primary care sites were selected: 1 underwent the intervention, the other, a control, underwent no intervention. The intervention consisted of engagement of intervention-site staff, surveys of provider performance improvement preferences, and onsite live and enduring online education. Electronic health record reminders were constructed. Both the intervention and control sites had 3 quality measures assessed monthly: the percentage of gout patients treated with urate-lowering therapy, the percentage of treated patients monitored with serum urate, and the percentage of treated patients at target serum urate <=6.0 mg/dl. The intervention-site providers received monthly reports comparing their measures against their peers. RESULTS: By 6 months, the intervention site significantly improved all 3 gout performance measures. The percentage treated increased from 54.4% to 61.1% (odds ratio [OR] 1.19 [95% confidence interval (95% CI) 1.08-1.31]; P < 0.001), the percentage monitored increased from 56.1% to 79.2% (OR 1.52 [95% CI 1.24-1.87]; P < 0.001), and the percentage at goal increased from 26.85% to 43.3% (OR 1.43 [95% CI 1.16 1.77]; P < 0.001). At 6 months after intervention, gout patients at the intervention site were more likely to be monitored (79.2% versus 53.4% [OR 3.54 (95% CI 2.30-5.45)]; P < 0.001) and at goal (43.3% versus 28.3% [OR 1.99 (95% CI 1.33-2.96)]; P < 0.001) than control-site patients. Numbers treated did not significantly improve over the control site. CONCLUSION: A pilot multifaceted gout management program can significantly improve primary care gout management performance. PMID- 29438608 TI - Clinician and Patient Views About Self-Management Support in Arthritis: A Cross Sectional UK Survey. AB - OBJECTIVE: To establish receipt and provision of self-management support for patients with inflammatory arthritis in the UK, and to establish whether receipt of self-management support is associated with patient's knowledge, skills, and confidence to self-manage. METHODS: Questionnaires for patients and health care professionals were sent to members and associates of the National Rheumatoid Arthritis Society. Patients completed the Patient Activation Measure (PAM), and questions about receipt of self-management support. Health care professionals completed the Clinician Support PAM and questions about provision of self management support. RESULTS: A total of 886 patients and 117 health care professionals completed the survey. Only 15% of patients had attended a structured self-management program. More than half of the patients reported having the skills, confidence, and knowledge to self-manage, and this skill set was associated with receipt of self-management support that was embedded in routine care. All health care professionals felt that patients should be actively involved in their own care, but 60% were unable to offer structured self management support. Health care professionals reported engaging in more embedded self-management support than patients reported receiving in routine care. CONCLUSION: Only a small proportion of patients with arthritis have attended a structured support program. Although health care professionals report engaging in self-management support embedded in routine care, patients do not necessarily agree, and these differences could impact the experience of patients with arthritis. When embedded self-management support does occur, it is a significant predictor of patients' knowledge, skills, and confidence to self-manage, as opposed to attendance at a structured program. PMID- 29438609 TI - Additive Mixing and Conformal Coating of Noniridescent Structural Colors with Robust Mechanical Properties Fabricated by Atomization Deposition. AB - Artificial structural colors based on short-range-ordered amorphous photonic structures (APSs) have attracted great scientific and industrial interest in recent years. However, the previously reported methods of self-assembling colloidal nanoparticles lack fine control of the APS coating and fixation on substrates and poorly realize three-dimensional (3D) conformal coatings for objects with irregular or highly curved surfaces. In this paper, atomization deposition of silica colloidal nanoparticles with poly(vinyl alcohol) as the additive is proposed to solve the above problems. By finely controlling the thicknesses of APS coatings, additive mixing of noniridescent structural colors is easily realized. Based on the intrinsic omnidirectional feature of atomization, a one-step 3D homogeneous conformal coating is also readily realized on various irregular or highly curved surfaces, including papers, resins, metal plates, ceramics, and flexible silk fabrics. The vivid coatings on silk fabrics by atomization deposition possess robust mechanical properties, which are confirmed by rubbing and laundering tests, showing great potential in developing an environmentally friendly coloring technique in the textile industry. PMID- 29438610 TI - Compact Plasmonic Blackbody for Cancer Theranosis in the Near-Infrared II Window. AB - We have developed a class of blackbody materials, i. e., hyperbranched Au plasmonic blackbodies (AuPBs), of compact sizes (<50 nm). The AuPBs were prepared in a seedless and surfactant-free approach based on the use of mussel-inspired dopamine. Strong intraparticle plasmonic coupling among branches in close proximity leads to intense and uniform broadband absorption across 400-1350 nm. The blackbody absorption imparts the compact AuPB with a superior photothermal efficiency of >80% and closely matched photothermal activity in the first near infrared (NIR-I) and the second near-infrared (NIR-II) spectral windows, making it a rare broadband theranostic probe for integrated photoacoustic imaging and photothermal therapy (PTT). Our comparative study, using the same probe, has demonstrated that the improved PTT outcome of NIR-II over NIR-I primarily results from its higher maximum permission exposure (MPE) rather than the deeper tissue penetration favored by longer wavelengths. The compact plasmonic broadband nanoabsorbers with tailored surface properties hold potential for a wide spectrum of light-mediated applications. PMID- 29438611 TI - Vinylboronic Acids as Efficient Bioorthogonal Reactants for Tetrazine Labeling in Living Cells. AB - Bioorthogonal chemistry can be used for the selective modification of biomolecules without interfering with any other functionality present in the cell. The tetrazine ligation is very suitable as a bioorthogonal reaction because of its selectivity and high reaction rates with several alkenes and alkynes. Recently, we described vinylboronic acids (VBAs) as novel hydrophilic bioorthogonal moieties that react efficiently with dipyridyl- s-tetrazines and used them for protein modification in cell lysate. It is not clear, however, whether VBAs are suitable for labeling experiments in living cells because of the possible coordination with, for example, vicinal carbohydrate diols. Here, we evaluated VBAs as bioorthogonal reactants for labeling of proteins in living cells using an irreversible inhibitor of the proteasome and compared the reactivity to that of an inhibitor containing norbornene, a widely used reactant for the tetrazine ligation. No large differences were observed between the VBA and norbornene probes in a two-step labeling approach with a cell-penetrable fluorescent tetrazine, indicating that the VBA gives little or no side reactions with diols and can be used efficiently for protein labeling in living cells. PMID- 29438612 TI - High-Affinity Peptidomimetic Inhibitors of the DCN1-UBC12 Protein-Protein Interaction. AB - The Cullin-RING ligases (CRLs) regulate the turnover of approximately 20% of the proteins in mammalian cells and are emerging therapeutic targets in human diseases. The activation of CRLs requires the neddylation of their cullin subunit, which is controlled by an activation complex consisting of Cullin-RBX1 UBC12-NEDD8-DCN1. Herein, we describe the design, synthesis, and evaluation of peptidomimetics targeting the DCN1-UBC12 protein-protein interaction. Starting from a 12-residue UBC12 peptide, we have successfully obtained a series of peptidomimetic compounds that bind to DCN1 protein with KD values of <10 nM. Determination of a cocrystal structure of a potent peptidomimetic inhibitor complexed with DCN1 provides the structural basis for their high-affinity interaction. Cellular investigation of one potent DCN1 inhibitor, compound 36 (DI 404), reveals that it effectively and selectively inhibits the neddylation of cullin 3 over other cullin members. Further optimization of DI-404 may yield a new class of therapeutics for the treatment of human diseases in which cullin 3 CRL plays a key role. PMID- 29438613 TI - Comparative CHARMM and AMOEBA Simulations of Lanthanide Hydration Energetics and Experimental Aqueous-Solution Structures. AB - The accurate understanding of metal ion hydration in solutions is a prerequisite for predicting stability, reactivity, and solubility. Herein, additive CHARMM force field parameters were developed to enable molecular dynamics simulations of lanthanide (Ln) speciation in water. Quantitatively similar to the much more resource-intensive polarizable AMOEBA potential, the CHARMM simulations reproduce the experimental hydration free energies and correlations in the first shell (Ln oxygen distance and hydration number). Comparisons of difference pair distribution functions obtained from the two simulation approaches with those from high-energy X-ray scattering experiments reveal good agreement of first coordination sphere correlations for the Lu3+ ion (CHARMM only), but further improvement to both approaches is required to reproduce the broad, non-Gaussian distribution seen from the La3+ experiment. Second-coordination sphere comparisons demonstrate the importance of explicitly including an anion in the simulation. This work describes the usefulness of less resource-intensive additive potentials in some complex chemical systems such as solution environments where multiple interactions have similar energetics. In addition, 3 dimensional descriptions of the La3+ and Lu3+ coordination geometries are extracted from the CHARMM simulations and generally discussed in terms of potential improvements to solute-structure modeling within solution environments. PMID- 29438615 TI - Synthesis and Properties of Alternating Polypeptoids and Polyampholytes as Protein-Resistant Polymers. AB - Alternating polypeptoids are particularly appealing because alternating sequence may impart highly ordered structure and special functions, while their simple synthesis still remains a key challenge. We describe that natural amino acid monomers can be polymerized via Ugi reaction in a step-growth fashion as an AA' BB' system, which leads to alternating polypeptoids with molecular weight up to 15 kg/mol. These alternating polypeptoids are thermally responsive and exhibit cloud points ( Tcp) between 27 and 37 degrees C. Importantly, the marriage of high functionality of amino acids with Ugi reaction also enables the preparation of polypeptoids encoding both protected amino and carboxyl groups in the side chains with alternating arrangement. The cleavage of the protecting groups leads to alternating polyampholytes without any compositional drift. Such alternating polyampholytes not only exhibit high water solubility (>100 mg/mL) but also demonstrate the ability to resist aggregation with proteins. Moreover, the cell viability measurements reveal that these materials have minimal cytotoxicity to HeLa cells. Overall, this study offers us a simple way to prepare a variety of polypeptoids and polyampholytes as new protein-resistant materials for bioapplications. PMID- 29438614 TI - Molecular Dynamics Simulations with Quantum Mechanics/Molecular Mechanics and Adaptive Neural Networks. AB - Direct molecular dynamics (MD) simulation with ab initio quantum mechanical and molecular mechanical (QM/MM) methods is very powerful for studying the mechanism of chemical reactions in a complex environment but also very time-consuming. The computational cost of QM/MM calculations during MD simulations can be reduced significantly using semiempirical QM/MM methods with lower accuracy. To achieve higher accuracy at the ab initio QM/MM level, a correction on the existing semiempirical QM/MM model is an attractive idea. Recently, we reported a neural network (NN) method as QM/MM-NN to predict the potential energy difference between semiempirical and ab initio QM/MM approaches. The high-level results can be obtained using neural network based on semiempirical QM/MM MD simulations, but the lack of direct MD samplings at the ab initio QM/MM level is still a deficiency that limits the applications of QM/MM-NN. In the present paper, we developed a dynamic scheme of QM/MM-NN for direct MD simulations on the NN predicted potential energy surface to approximate ab initio QM/MM MD. Since some configurations excluded from the database for NN training were encountered during simulations, which may cause some difficulties on MD samplings, an adaptive procedure inspired by the selection scheme reported by Behler [ Behler Int. J. Quantum Chem. 2015 , 115 , 1032 ; Behler Angew. Chem., Int. Ed. 2017 , 56 , 12828 ] was employed with some adaptions to update NN and carry out MD iteratively. We further applied the adaptive QM/MM-NN MD method to the free energy calculation and transition path optimization on chemical reactions in water. The results at the ab initio QM/MM level can be well reproduced using this method after 2-4 iteration cycles. The saving in computational cost is about 2 orders of magnitude. It demonstrates that the QM/MM-NN with direct MD simulations has great potentials not only for the calculation of thermodynamic properties but also for the characterization of reaction dynamics, which provides a useful tool to study chemical or biochemical systems in solution or enzymes. PMID- 29438616 TI - Polymer Assembly Encapsulation of Lanthanide Nanoparticles as Contrast Agents for In Vivo Micro-CT. AB - Despite recent technological advancements in microcomputed tomography (micro-CT) and contrast agent development, preclinical contrast agents are still predominantly iodine-based. Higher contrast can be achieved when using elements with higher atomic numbers, such as lanthanides; lanthanides also have X-ray attenuation properties that are ideal for spectral CT. However, the formulation of lanthanide-based contrast agents at the high concentrations required for vascular imaging presents a significant challenge. In this work, we developed an erbium-based contrast agent that meets micro-CT imaging requirements, which include colloidal stability upon redispersion at high concentrations, evasion of rapid renal clearance, and circulation times of tens of minutes in small animals. Through systematic studies with poly(ethylene glycol) (PEG)-poly(propylene glycol), PEG-polycaprolactone, and PEG-poly(l-lactide) (PLA) block copolymers, the amphiphilic block copolymer PEG114-PLA53 was identified to be ideal for encapsulating oleate-coated lanthanide-based nanoparticles for in vivo intravenous administration. We were able to synthesize a contrast agent containing 100 mg/mL of erbium that could be redispersed into colloidally stable particles in saline after lyophilization. Contrast enhancement of over 250 HU was achieved in the blood pool for up to an hour, thereby meeting the requirements of live animal micro-CT. PMID- 29438617 TI - Construction of Bioactive and Reinforced Bioresorbable Nanocomposites by Reduced Nano-Graphene Oxide Carbon Dots. AB - Bioactive and reinforced poly(epsilon-caprolactone) (PCL) films were constructed by incorporation of cellulose derived reduced nanographene oxide (r-nGO) carbon nanodots. Two different microwave-assisted reduction routes in superheated water were utilized to obtain r-nGO and r-nGO-CA. For the latter, a green reducing agent caffeic acid (CA), was incorporated in the reduction process. The materials were extruded and compression molded to obtain proper dispersion of the carbon nanodots in the polymer matrix. FTIR results revealed favorable interactions between r-nGO-CA and PCL that improved the dispersion of r-nGO-CA. r-nGO, and r nGO-CA endorsed PCL with several advantageous functionalities including improved storage modulus and creep resistance. The considerable increase in storage modulus demonstrated that the carbon nanodots had a significant reinforcing effect on PCL. The PCL films with r-nGO-CA were also evaluated for their osteobioactivity and cytocompatibility. Bioactivity was demonstrated by formation of hydroxyapatite (HA) minerals on the surface of r-nGO-CA loaded nanocomposites. At the same time, the good cytocompatibility of PCL was retained as illustrated by the good cell viability to MG63 osteoblast-like cells giving promise for bone tissue engineering applications. PMID- 29438618 TI - Autodetachment from Vibrationally Excited Vinylidene Anions. AB - Slow electron velocity-map imaging of the cryogenically cooled H2CC- anion reveals a strong dependence of its high-resolution photoelectron spectrum on detachment photon energy in two specific ranges, from 4000 to 4125 cm-1 and near 5020 cm-1. This effect is attributed to vibrational excitation of the anion followed by autodetachment to H2CC + e-. In the lower energy range, the electron kinetic energy (eKE) distributions are dominated by two features that occur at constant eKEs of 114(3) and 151.9(14) cm-1 rather than constant electron binding energies, as is typically seen for direct photodetachment. These features are attributed to DeltaJ = DeltaK = 0 autodetachment transitions from two vibrationally excited anion states. The higher energy resonance autodetaches to neutral eigenstates with amplitude in the theoretically predicted shallow well lying along the vinylidene-acetylene isomerization coordinate. Calculations provide assignments of all autodetaching anion states and show that the observed autodetachment is facilitated by an intersection of the anion and neutral surfaces. PMID- 29438619 TI - Plasmon-Enhanced Catalysis: Distinguishing Thermal and Nonthermal Effects. AB - In plasmon-enhanced heterogeneous catalysis, illumination accelerates reaction rates by generating hot carriers and hot surfaces in the constituent nanostructured metals. In order to understand how photogenerated carriers enhance the nonthermal reaction rate, the effects of photothermal heating and thermal gradients in the catalyst bed must be confidently and quantitatively characterized. This is a challenging task considering the conflating effects of light absorption, heat transport, and reaction energetics. Here, we introduce a methodology to distinguish the thermal and nonthermal contributions from plasmon enhanced catalysts, demonstrated by illuminated rhodium nanoparticles on oxide supports to catalyze the CO2 methanation reaction. By simultaneously measuring the total reaction rate and the temperature gradient of the catalyst bed, the effective thermal reaction rate may be extracted. The residual nonthermal rate of the plasmon-enhanced reaction is found to grow with a superlinear dependence on illumination intensity, and its apparent quantum efficiency reaches ~46% on a Rh/TiO2 catalyst at a surface temperature of 350 degrees C. Heat and light are shown to work synergistically in these reactions: the higher the temperature, the higher the overall nonthermal efficiency in plasmon-enhanced catalysis. PMID- 29438620 TI - Leakiness of Pinned Neighboring Surface Nanobubbles Induced by Strong Gas-Surface Interaction. AB - The stability of two neighboring surface nanobubbles on a chemically heterogeneous surface is studied by molecular dynamics (MD) simulations of binary mixtures consisting of Lennard-Jones (LJ) particles. A diffusion equation-based stability analysis suggests that two nanobubbles sitting next to each other remain stable, provided the contact line is pinned, and that their radii of curvature are equal. However, many experimental observations seem to suggest some long-term kind of ripening or shrinking of the surface nanobubbles. In our MD simulations we find that the growth/dissolution of the nanobubbles can occur due to the transfer of gas particles from one nanobubble to another along the solid substrate. That is, if the interaction between the gas and the solid is strong enough, the solid-liquid interface can allow for the existence of a "tunnel" which connects the liquid-gas interfaces of the two nanobubbles to destabilize the system. The crucial role of the gas-solid interaction energy is a nanoscopic element that hitherto has not been considered in any macroscopic theory of surface nanobubbles and may help to explain experimental observations of the long term ripening. PMID- 29438621 TI - Explicit Solvation Matters: Performance of QM/MM Solvation Models in Nucleophilic Addition. AB - Nucleophilic addition onto a carbonyl moiety is strongly affected by solvent, and correctly simulating this solvent effect is often beyond the capability of single scale quantum mechanical (QM) models. This work explores multiscale approaches for the description of the reversible and highly solvent-sensitive nucleophilic N|...C?O bond formation in an Me2N-(CH2)3-CH?O molecule. In the first stage of this work, we rigorously compare and test four recent quantum mechanical/molecular mechanical (QM/MM) explicit solvation models, employing a QM description of water molecules in spherical regions around both the oxygen and the nitrogen atom of the solute. The accuracy of the models is benchmarked against a reference QM simulation, focusing on properties of the solvated Me2N (CH2)3-CH?O molecule in its ring-closed form. In the second stage, we select one of the models (continuous adaptive QM/MM) and use it to obtain a reliable free energy profile for the N|...C bond formation reaction. We find that the dual sphere approach allows the model to accurately account for solvent reorganization along the entire reaction path. In contrast, a simple microsolvation model cannot adapt to the changing conditions and provides an incorrect description of the reaction process. PMID- 29438623 TI - Interdisciplinary Dissertation Research Among Public Health Doctoral Trainees, 2003-2015. AB - OBJECTIVES: Given the call for more interdisciplinary research in public health, the objectives of this study were to (1) examine the correlates of interdisciplinary dissertation completion and (2) identify secondary fields most common among interdisciplinary public health graduates. METHODS: We analyzed pooled cross-sectional data from 11 120 doctoral graduates in the Survey of Earned Doctorates, 2003-2015. The primary outcome was interdisciplinary dissertation completion. Covariates included primary public health field, sociodemographic characteristics, and institutional attributes. RESULTS: From 2003 to 2015, a total of 4005 of 11 120 (36.0%) doctoral graduates in public health reported interdisciplinary dissertations, with significant increases observed in recent years. Compared with general public health graduates, graduates of environmental health (odds ratio [OR] = 1.74; P < .001) and health services administration (OR = 1.38; P < .001) doctoral programs were significantly more likely to report completing interdisciplinary dissertation work, whereas graduates from biostatistics (OR = 0.51; P < .001) and epidemiology (OR = 0.76; P < .001) were less likely to do so. Completing an interdisciplinary dissertation was associated with being male, a non-US citizen, a graduate of a private institution, and a graduate of an institution with high but not the highest level of research activity. Many secondary dissertation fields reported by interdisciplinary graduates included other public health fields. CONCLUSION: Although interdisciplinary dissertation research among doctoral graduates in public health has increased in recent years, such work is bounded in certain fields of public health and certain types of graduates and institutions. Academic administrators and other stakeholders may use these results to inform greater interdisciplinary activity during doctoral training and to evaluate current and future collaborations across departments or schools. PMID- 29438624 TI - Lessons from Cancer: Subcellular Drug Targeting of Mitochondrial HSP90 in Pulmonary Arterial Hypertension. PMID- 29438625 TI - Biomechanical Evaluation of a Single- Versus Double-Tunnel Coracoclavicular Ligament Reconstruction With Acromioclavicular Stabilization for Acromioclavicular Joint Injuries. AB - BACKGROUND: An anatomic double-tunnel (DT) reconstruction technique has been widely adopted to reconstruct the ruptured coracoclavicular (CC) ligaments seen with high-grade acromioclavicular (AC) joint injuries. However, the anatomic DT reconstruction has been associated with the risk of clavicle fractures, which may be problematic, particularly for contact athletes. Purpose/Hypothesis: The purpose was to compare a single-tunnel (ST) CC ligament reconstruction for AC joint injuries with the native state as well as with the more established anatomic DT CC ligament reconstruction. The hypothesis was that ST CC ligament reconstruction would demonstrate biomechanical properties similar to those of the native state and the DT CC ligament reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: Eighteen fresh-frozen human cadaveric shoulders (9 matched pairs) with mean +/- SD age of 55.5 +/- 8.5 years underwent biomechanical testing. One specimen of each matched pair underwent a ST CC ligament reconstruction and the second, a DT CC ligament reconstruction. The ST and DT CC ligament reconstruction techniques involved a 5-mm distal clavicle excision, avoided coracoid drilling, and utilized a 3.0-mm suture anchor to fix the excess lateral limb to reconstruct the superior AC joint capsule. The ST CC ligament reconstruction technique additionally included a 1.3-mm suture tape to help avoid a sawing effect, as well as a dog-bone button over the clavicular tunnel to increase stability of the construct. All specimens were tested to 70 N in 3 directions (superior, anterior, and posterior) in the intact and reconstructed states. The ultimate load, yield load, stiffness, and mode of failure of the reconstructed specimens were tested. RESULTS: There were no significant differences in translation at 70 N in the superior ( P = .31), anterior ( P = .56), and posterior ( P = .35) directions between the ST CC ligament reconstruction and the intact state. The ultimate load to failure, yield load, and stiffness in the ST and DT groups were also not significantly different. There were no distal clavicle fractures in load-to-failure testing in the ST or DT group. CONCLUSION: In this biomechanical study, ST CC ligament reconstruction demonstrates biomechanical properties comparable to the intact state. Additionally, use of the ST CC ligament reconstruction shows biomechanical properties similar to the DT CC ligament reconstruction technique while theoretically posing less risk of clavicle fracture. CLINICAL RELEVANCE: This study suggests that the ST CC ligament reconstruction has biomechanical properties equivalent to the DT CC ligament reconstruction with less theoretical risk of clavicle fracture. PMID- 29438622 TI - AMOEBA Polarizable Atomic Multipole Force Field for Nucleic Acids. AB - The AMOEBA polarizable atomic multipole force field for nucleic acids is presented. Valence and electrostatic parameters were determined from high-level quantum mechanical data, including structures, conformational energy, and electrostatic potentials, of nucleotide model compounds. Previously derived parameters for the phosphate group and nucleobases were incorporated. A total of over 35 MUs of condensed-phase molecular dynamics simulations of DNA and RNA molecules in aqueous solution and crystal lattice were performed to validate and refine the force field. The solution and/or crystal structures of DNA B-form duplexes, RNA duplexes, and hairpins were captured with an average root-mean squared deviation from NMR structures below or around 2.0 A. Structural details, such as base pairing and stacking, sugar puckering, backbone and chi-torsion angles, groove geometries, and crystal packing interfaces, agreed well with NMR and/or X-ray. The interconversion between A- and B-form DNAs was observed in ethanol-water mixtures at 328 K. Crystal lattices of B- and Z-form DNA and A-form RNA were examined with simulations. For the RNA tetraloop, single strand tetramers, and HIV TAR with 29 residues, the simulated conformational states, 3 J coupling, nuclear Overhauser effect, and residual dipolar coupling data were compared with NMR results. Starting from a totally unstacked/unfolding state, the rCAAU tetranucleotide was folded into A-form-like structures during ~1 MUs molecular dynamics simulations. PMID- 29438627 TI - Genome-Wide Association Study in Acute Respiratory Distress Syndrome. Finding the Needle in the Haystack to Advance Our Understanding of Acute Respiratory Distress Syndrome. PMID- 29438626 TI - Reactive cold plasma particles generate oxidative stress in yeast but do not trigger apoptosis. AB - Interactions of living cells with cold plasma of electrical discharges affect cell physiology, often resulting in the loss of viability. However, the mechanisms involved in cell killing are poorly understood, and dissection of cellular pathways or structures affected by plasma using simple eukaryotic models is needed. Using selected genetic mutants of yeast (Saccharomyces cerevisiae), we investigated the role of oxidative stress and yeast apoptosis in plasma-induced cell killing. Increased sensitivity of yeast strains deficient in superoxide dismutases indicated that reactive oxygen species generated in the plasma are among the most prominent factors involved in killing of yeast cells. In mutant strains with a deletion of the key components of yeast apoptotic pathway, the sensitivity of cells towards the plasma treatment remained unaffected. Yeast apoptosis, thus, does not appear to play a significant role in plasma-induced cell killing of yeast. PMID- 29438628 TI - Rotator Cuff Repair in Adolescent Athletes. AB - BACKGROUND: Rotator cuff tears are rare injuries in adolescents but cause significant morbidity if unrecognized. Previous literature on rotator cuff repairs in adolescents is limited to small case series, with few data to guide treatment. HYPOTHESIS: Adolescent patients would have excellent functional outcome scores and return to the same level of sports participation after rotator cuff repair but would have some difficulty with returning to overhead sports. STUDY DESIGN: Case series; Level of evidence 4. METHODS: A retrospective search of the practice's billing records identified all patients participating in at least 1 sport who underwent rotator cuff repair between 2006 and 2014 with an age <18 years at the time of surgery and a minimum follow-up of 2 years. Clinical records were evaluated for demographic information, and telephone follow-up was obtained regarding return to play, performance, other surgery and complications, a numeric pain rating scale (0-10) for current shoulder pain, American Shoulder and Elbow Surgeons (ASES) Shoulder Assessment Form, and the Western Ontario Rotator Cuff Index. RESULTS: Thirty-two consecutive adolescent athletes (28 boys and 4 girls) with a mean age of 16.1 years (range, 13.2-17.9 years) met inclusion criteria. Twenty-nine patients (91%) had a traumatic event, and 27 of these patients (93%) had no symptoms before the trauma. The most common single tendon injury was to the supraspinatus (21 patients, 66%), of which 2 were complete tendon tears, 1 was a bony avulsion of the tendon, and 18 were high-grade partial tears. Fourteen patients (56%) underwent single-row repair of their rotator cuff tear, and 11 (44%) underwent double-row repair. All subscapularis injuries were repaired in open fashion, while all other tears were repaired arthroscopically. Twenty-seven patients (84%) completed the outcome questionnaires at a mean 6.2 years after surgery (range, 2-10 years). The mean ASES score was 93 (range, 65 100; SD = 9); mean Western Ontario Rotator Cuff Index, 89% (range, 60%-100%; SD = 13%); and mean numeric pain rating, 0.3 (range, 0-3; SD = 0.8). Overall, 25 patients (93%) returned to the same level of play or higher. Among overhead athletes, 13 (93%) were able to return to the same level of play, but 8 (57%) were forced to change positions. There were no surgical complications, but 2 patients did undergo a subsequent operation. CONCLUSION: Surgical repair of high grade partial-thickness and complete rotator cuff tears yielded successful outcomes among adolescents, with excellent functional outcomes at midterm follow up. However, overhead athletes may have difficulty playing the same position after surgery. PMID- 29438629 TI - Corrigendum. AB - Webber, E., & Watkins, A. L. (2017). Evolution of a profession: The role of accreditation in lactation education. Journal of Human Lactation, 33(4), 740-744. (Original DOI: 10.1177/0890334417711893). PMID- 29438630 TI - Isoform-specific role of Na/K-ATPase alpha1 in skeletal muscle. AB - The distribution of Na/K-ATPase alpha-isoforms in skeletal muscle is unique, with alpha1 as the minor (15%) isoform and alpha2 comprising the bulk of the Na/K ATPase pool. The acute and isoform-specific role of alpha2 in muscle performance and resistance to fatigue is well known, but the isoform-specific role of alpha1 has not been as thoroughly investigated. In vitro, we reported that alpha1 has a role in promoting cell growth that is not supported by alpha2. To assess whether alpha1 serves this isoform-specific trophic role in the skeletal muscle, we used Na/K-ATPase alpha1-haploinsufficient (alpha1+/-) mice. A 30% decrease of Na/K ATPase alpha1 protein expression without change in alpha2 induced a modest yet significant decrease of 10% weight in the oxidative soleus muscle. In contrast, the mixed plantaris and glycolytic extensor digitorum longus weights were not significantly affected, likely because of their very low expression level of alpha1 compared with the soleus. The soleus mass reduction occurred without change in total Na/K-ATPase activity or glycogen metabolism. Serum analytes including K+, fat tissue mass, and exercise capacity were not altered in alpha1+/ mice. The impact of alpha1 content on soleus muscle mass is consistent with a Na/K-ATPase alpha1-specific role in skeletal muscle growth that cannot be fulfilled by alpha2. The preserved running capacity in alpha1+/- is in sharp contrast with previously reported consequences of genetic manipulation of alpha2. Taken together, these results lend further support to the concept of distinct isoform-specific functions of Na/K-ATPase alpha1 and alpha2 in skeletal muscle. PMID- 29438632 TI - Neonatal nutritional programming impairs adiponectin effects on energy homeostasis in adult life of male rats. AB - Neonatal nutritional changes induce long-lasting effects on energy homeostasis. Adiponectin influences food intake and body weight. The aim of this study was to investigate the effects of neonatal nutritional programming on the central stimulation of adiponectin. Male Wistar rats were divided on postnatal (PN) day 3 in litters of 3 (small litter, SL), 10 (normal litter, NL), or 16 pups/dam (large litter, LL). We assessed body weight gain for 60 days, adiponectin concentration, and white adipose tissue weight. We examined the response of SL, NL, and LL rats on body weight gain, food intake, oxygen consumption (Vo2), respiratory exchange ratio (RER), calorimetry, locomotor activity, phosphorylated-AMP-activated protein kinase (AMPK) expression in the hypothalamus, and uncoupling protein (UCP)-1 in the brown adipose tissue after central stimulus with adiponectin. After weaning, SL rats maintained higher body weight gain despite similar food intake compared with NL rats. LL rats showed lower body weight at weaning, with a catch up afterward and higher food intake. Both LL and SL groups had decreased plasma concentrations of adiponectin at PN60. SL rats had increased white adipose tissue. Central injection of adiponectin decreased body weight and food intake and increased Vo2, RER, calorimetry, p-AMPK and UCP- 1 expression in NL rats, but it had no effect on SL and LL rats, compared with the respective vehicle groups. In conclusion, neonatal under- and overfeeding induced an increase in body weight gain in juvenile and early adult life. Unresponsiveness to central effects of adiponectin contributes to the imbalance of the energy homeostasis in adult life induced by neonatal nutritional programming. PMID- 29438631 TI - Plasma endocannabinoid levels in lean, overweight, and obese humans: relationships to intestinal permeability markers, inflammation, and incretin secretion. AB - Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation; however, little is known of these effects in humans. This study aimed to 1) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl- sn-glycerol (2-AG), and OEA in humans; and 2) examine relationships to intestinal permeability, inflammation markers, and incretin hormone secretion. Twenty lean, 18 overweight, and 19 obese participants underwent intraduodenal Intralipid infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumor necrosis factor alpha (TNFalpha), glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and Toll-like receptor 4 (TLR4) (by RT-PCR) were assessed. Fasting plasma AEA was increased in obese compared with lean and overweight patients ( P < 0.05), with no effect of BMI group or ID lipid infusion on plasma 2-AG or OEA. Duodenal expression of IAP and ZO-1 was reduced in obese compared with lean ( P < 0.05), and these levels related negatively to plasma AEA ( P < 0.05). The iAUC for AEA was positively related to iAUC GIP ( r = 0.384, P = 0.005). Obese individuals have increased plasma AEA and decreased duodenal expression of ZO-1 and IAP compared with lean and overweight subjects. The relationships between plasma AEA with duodenal ZO-1, IAP, and GIP suggest that altered endocannabinoid signaling may contribute to changes in intestinal permeability, inflammation, and incretin release in human obesity. PMID- 29438633 TI - Experiences and Perspectives About Breastfeeding in "Public": A Qualitative Exploration Among Normal-Weight and Obese Mothers. AB - BACKGROUND: Women face societal and cultural barriers to breastfeeding. These challenges have been investigated in international studies and U.S. public opinion polls; however, mothers' experiences with breastfeeding in public in the United States remain unexplored. Research aim: The aim of this study was to describe the experiences of obese and normal-weight women with breastfeeding in public in central New York. METHODS: Pregnant women ( N = 26) in central New York who intended to breastfeed and were either normal weight or obese were enrolled during their third trimester. A longitudinal, qualitative study was conducted to obtain information about women's experiences from birth through 3 to 6 months postpartum. Interviews were audio recorded, transcribed, and verified for accuracy. Transcripts were analyzed iteratively using conventional content analysis. RESULTS: The concept of "public" was situational rather than a set of physical places; women experienced challenges while breastfeeding around others in private locations that were indistinguishable from those they encountered in places typically considered public. Women experienced social and physical awkwardness including perceived lack of acceptability, fear of confrontation, exposure, and positioning difficulties. They used strategies to reduce awkwardness, for example, being "discreet" and minimizing breastfeeding around other people. Obese women experienced similar challenges but to a greater degree than normal-weight women. CONCLUSION: "Breastfeeding around others" described mother's experiences more accurately than "breastfeeding in public" and was experienced as awkward both socially and physically, particularly by obese women. Strategies are needed to normalize breastfeeding in the United States and to prepare mothers for the challenges of breastfeeding around others. PMID- 29438635 TI - Twenty-Year Follow-up Study Comparing Operative Versus Nonoperative Treatment of Anterior Cruciate Ligament Ruptures in High-Level Athletes. AB - BACKGROUND: An anterior cruciate ligament (ACL) rupture has major consequences at midterm follow-up, with an increasing chance of developing an old knee in a young patient. The long-term (>=20 years) effects of the operative and nonoperative treatment of ACL ruptures are still unclear. PURPOSE: To compare the long-term treatment outcomes of operative versus nonoperative treatment of ACL ruptures in high-level athletes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Fifty patients with an ACL rupture were eligible for participation, and they were treated either nonoperatively (n = 25) in 1992, consisting of structured rehabilitation and lifestyle adjustments, or operatively (n = 25) between 1994 and 1996 with an arthroscopic transtibial bone-patellar tendon-bone technique. The patients in the nonoperative group were drawn from those who responded well to 3 months of nonoperative treatment, whereas the patients in the operative group were drawn from those who had persistent instability after 3 months of nonoperative treatment. Both groups were pair-matched and assessed at 10- and 20 year follow-up regarding radiological knee osteoarthritis, functional outcomes (Lysholm, International Knee Documentation Committee [IKDC], Tegner, Knee injury and Osteoarthritis Outcome Score), meniscal status, and knee stability (KT-1000 arthrometer, pivot-shift test, Lachman test, 1-legged hop test). RESULTS: All 50 patients (100%) were included in the current study for follow-up. After 20 years, we found knee osteoarthritis in 80% of the operative group compared with 68% of the nonoperative group ( P = .508). There was no difference between groups regarding functional outcomes and meniscectomy performed. The median IKDC subjective score was 81.6 (interquartile range [IQR], 59.8-89.1) for the operative group and 78.2 (IQR, 61.5-92.0) for the nonoperative group ( P = .679). Regarding the IKDC objective score, 21 patients (84%) in the operative group had a normal or near normal score (A and B) compared with 5 patients (20%) in the nonoperative group ( P < .001). The pivot-shift test finding was negative in 17 patients (68%) versus 3 patients (13%) for the operative and nonoperative groups, respectively ( P < .001), and the Lachman test finding was negative in 12 patients (48%) versus 1 patient (4%), respectively ( P = .002). CONCLUSION: In this retrospective pair-matched follow-up study, we found that after 20-year follow-up, there was no difference in knee osteoarthritis between operative versus nonoperative treatment when treatment was allocated on the basis of a patient's response to 3 months of nonoperative treatment. Although knee stability was better in the operative group, it did not result in better subjective and objective functional outcomes. PMID- 29438636 TI - MJA editor-in-chief Prof Nick Talley wins top honour. PMID- 29438634 TI - Regulating Cannabis Manufacturing: Applying Public Health Best Practices from Tobacco Control. AB - State legalization and regulation of cannabis, despite continued federal illegality, is a massive shift in regulatory approach. Manufactured cannabis, including concentrates, extracts, edibles, tinctures, topicals and other products, has received less attention than more commonly used dried flower, but represents emerging regulatory challenges due to additives, potency, consumption methods, and abuse and misuse potential. In November 2017, the California Department of Public Health (CDPH) released initial cannabis manufacturing regulations as part of a new state regulatory structure. As the largest U.S. medical cannabis market (and largest legal adult use market in the world beginning in 2018), California's regulatory approach will potentially influence national and global policy. Comparing CDPH's initial regulations to tobacco control best practices reveals that, while the regulations recognize the need to protect public health, prioritizing public health over business interests requires stronger approaches to labeling, packaging, and product formulations. Based on tobacco best practices, we recommend that cannabis regulations incorporate large and proportionately sized informational labels, a prominent universal cannabis symbol, rotating and pictorial health warnings, mandatory plain packaging, a comprehensive ban on characterizing flavors and addictive additives, and strict limits on the potency of inhalable products and those easily confused with non-cannabis products. PMID- 29438637 TI - Population attributable fractions of perinatal outcomes for nulliparous women associated with overweight and obesity, 1990-2014. AB - OBJECTIVE: To examine the prevalence across 25 years of overweight and obesity among nulliparous Australian women during early pregnancy; to estimate the proportions of adverse perinatal outcomes attributable to overweight and obesity in this population. DESIGN: Cohort study; retrospective analysis of electronic maternity data. Setting, participants: 42 582 nulliparous women with singleton pregnancies giving birth at the Royal Prince Alfred Hospital, an urban teaching hospital in Sydney, January 1990 - December 2014. MAIN OUTCOME MEASURES: Maternal body mass index (BMI), socio-demographic characteristics, and selected maternal, birth and neonatal outcomes; the proportion of adverse perinatal outcomes that could be averted by reducing the prevalence of overweight and obesity in women prior to first pregnancies (population attributable fraction, PAF). RESULTS: The prevalence of overweight among nulliparous pregnant women increased from 12.7% (1990-1994) to 16.4% (2010-2014); the prevalence of obesity rose from 4.8% to 7.3% in the same period, while the proportion with normal range BMIs fell from 73.5% to 68.2%. The PAFs for key adverse maternal and neonatal outcomes increased across the study period; during 2010-2014, 23.8% of pre-eclampsia, 23.4% of fetal macrosomia, and 17.0% of gestational diabetes were attributable to overweight and obesity. Were overweight and obese women to have moved down one BMI category during 2010-2014, 19% of pre-eclampsia, 15.9% of macrosomia, 14.2% of gestational diabetes, 8.5% of caesarean deliveries, 7.1% of low for gestational age birthweight, 6.8% of post partum haemorrhage, 6.5% of admissions to special care nursery, 5.8% of prematurity, and 3.8% of fetal abnormality could have been averted. CONCLUSIONS: Over the past 25 years, the proportions of adverse perinatal outcomes attributable to overweight and obesity have risen with the increasing prevalence of maternal overweight and obesity. A substantial proportion of these outcomes might be averted with obesity prevention strategies that reduce pre-pregnancy maternal weight. PMID- 29438639 TI - The other source of government funding for medical research that needs reform. PMID- 29438640 TI - Choosing Wisely Australia: changing behaviour in health care. PMID- 29438641 TI - Compassion and evidence in prescribing cannabinoids: a perspective from the Royal Australasian College of Physicians. PMID- 29438642 TI - Understanding epidemiology and its contribution to public health. PMID- 29438643 TI - Encephalopathy after chocolate consumption. PMID- 29438644 TI - The value of food fortification as a public health intervention. PMID- 29438645 TI - Maternal overweight and obesity: where to from here? PMID- 29438646 TI - Administrative encounters in general practice: low value or hidden value care? AB - OBJECTIVE: To determine the frequency of general practice administrative encounters, and to determine whether they represent low value care. DESIGN: Secondary analysis of data from the Bettering Evaluation and Care of Health (BEACH) dataset. SETTING: 1 568 100 GP-patient encounters in Australia, 2000-01 to 2015-16. PARTICIPANTS: An annual nationally representative random sample of about 1000 GPs, who each recorded the details of 100 consecutive encounters with patients. MAIN OUTCOME MEASURES: Proportions of general practice encounters that were potentially low value care encounters (among the patient's reasons for the encounter was at least one administrative, medication, or referral request) and potentially low value care only encounters (such reasons were the sole reason for the encounter). For 2015-16, we also examined other health care provided by GPs at these encounters. RESULTS: During 2015-16, 18.5% (95% CI, 17.7-19.3%) of 97 398 GP-patient encounters were potentially low value care request encounters; 7.4% (95% CI, 7.0-7.9%) were potentially low value care only encounters. Administrative work was requested at 3.8% (95% CI, 3.5-4.0%) of GP visits, 35.4% of which were for care planning and coordination, 33.5% for certification, and 31.2% for other reasons. Medication requests were made at 13.1% (95% CI, 12.4 13.7%) of encounters; other health care was provided at 57.9% of medication request encounters, counselling, advice or education at 23.4%, and pathology testing was ordered at 16.7%. Referrals were requested at 2.8% (95% CI, 1.7-3.0%) of visits, at 69.4% of which additional health care was provided. The problems managed most frequently at potentially low value care only encounters were chronic diseases. CONCLUSION: Most patients requested certificates, medications and referrals in the context of seeking help for other health needs. Additional health care, particularly for chronic diseases, was provided at most GP administrative encounters. The MBS Review should consider the hidden value of these encounters. PMID- 29438647 TI - Iodine adequacy in Tasmania sustained after 7 years of mandatory bread fortification. PMID- 29438648 TI - Managing menopausal symptoms after cancer: an evidence-based approach for primary care. AB - Impaired ovarian function and menopausal symptoms are common after cancer treatment. Menopausal symptoms often occur at an earlier age in women with cancer, and may be more severe than in natural menopause; they may be the most persistent and troubling sequelae of cancer. A third of female patients with cancer report dissatisfaction with the quality and length of physician-patient discussions about reproductive health, including menopause. Systemic menopausal hormone therapy is the most effective treatment for menopausal symptoms, but it is not suitable for all patients after cancer - where it is unsuitable, alternative effective non-hormonal treatments are available. Effective pharmacological agents available to treat vasomotor symptoms include selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, clonidine and gabapentin. There is increasing evidence supporting cognitive behavioural therapy for the treatment of vasomotor symptoms, in self-help or group settings. Vaginal atrophy can be treated with vaginal (topical) oestrogen with minimal systemic absorption; topical vaginal lubricants may help with vaginal dryness and dyspareunia, with some evidence suggesting that silicone based products may be more effective than water-based ones. Bone health may be impaired in post-menopausal women with cancer or in cancer survivors, particularly in women with treatment-related menopause or in women receiving anti oestrogen therapies; this should be managed in addition to menopausal symptoms. Primary care physicians should be aware of the troublesome and ongoing nature of menopausal symptoms after cancer, should discuss them with all patients after cancer treatment, and should consider treatment or referral to a specialist for appropriate management. PMID- 29438649 TI - Cannabis for paediatric epilepsy: challenges and conundrums. AB - Research is expanding for the use of cannabidiol as an anticonvulsant drug. The mechanism of cannabidiol in paediatric epilepsy is unclear but is thought to play a role in modulation of synaptic transmission. Evidence for its efficacy in treating epilepsy is limited but growing, with a single pharmaceutical company funded randomised double-blind controlled trial in children with Dravet syndrome. Progress towards the use of medicinal cannabinoids incorporates a complex interplay of social influences and political and legal reform. Access to unregistered but available cannabidiol in Australia outside of clinical trials and compassionate access schemes is state dependent and will require Therapeutic Goods Administration approval, although the cost may be prohibitive. Further clinical trials are needed to clearly define efficacy and safety, particularly long term. PMID- 29438650 TI - Updated evidence-based clinical practice guidelines for the diagnosis and management of melanoma: definitive excision margins for primary cutaneous melanoma. AB - INTRODUCTION: Definitive management of primary cutaneous melanoma consists of surgical excision of the melanoma with the aim of curing the patient. The melanoma is widely excised together with a safety margin of surrounding skin and subcutaneous tissue, after the diagnosis and Breslow thickness have been established by histological assessment of the initial excision biopsy specimen. Sentinel lymph node biopsy should be discussed for melanomas >= 1 mm thickness (>= 0.8 mm if other high risk features) in which case lymphoscintigraphy must be performed before wider excision of the primary melanoma site. The 2008 evidence based clinical practice guidelines for the management of melanoma (http://www.cancer.org.au/content/pdf/HealthProfessionals/ClinicalGuidelines/Clin calPracticeGuidelines-ManagementofMelanoma.pdf) are currently being revised and updated in a staged process by a multidisciplinary working party established by Cancer Council Australia. The guidelines for definitive excision margins for primary melanomas have been revised as part of this process. Main recommendations: The recommendations for definitive wide local excision of primary cutaneous melanoma are: melanoma in situ: 5-10 mm margins invasive melanoma (pT1) <= 1.0 mm thick: 1 cm margins invasive melanoma (pT2) 1.01-2.00 mm thick: 1-2 cm margins invasive melanoma (pT3) 2.01-4.00 mm thick: 1-2 cm margins invasive melanoma (pT4) > 4.0 mm thick: 2 cm margins Changes in management as a result of the guideline: Based on currently available evidence, excision margins for invasive melanoma have been left unchanged compared with the 2008 guidelines. However, melanoma in situ should be excised with 5-10 mm margins, with the aim of achieving complete histological clearance. Minimum clearances from all margins should be assessed and stated. Consideration should be given to further excision if necessary; positive or close histological margins are unacceptable. PMID- 29438651 TI - Premature deaths of nursing home residents: an epidemiological analysis. PMID- 29438652 TI - Premature deaths of nursing home residents: an epidemiological analysis. PMID- 29438653 TI - Stereochemical study of mouse muscone receptor MOR215-1 and vibrational theory based on statistical physics formalism. AB - In the biosensor system, olfactory receptor sites could be activated by odorant molecules and then the biological interactions are converted into electrical signals by a signal transduction cascade that leads the toopening of ion channels, generating a current that leads into the cilia and depolarizes the membrane. The aim of this paper is to present a new investigation that allows determining the olfactory band using a monolayer adsorption with identical sites modeling which may also describe the static and the dynamic sensitivities through the expression of the olfactory response. Moreover, knowing the size of receptor site in olfactory sensory neurons provides valuable information about the relationship between molecular structure and biological activity. The determination of microreceptors and mesoreceptors is mostly carried out via physical adsorption and the radius is calculated using the Kelvin equation. The mean values of radius obtained from the maximum of the receptor size distributions peaks are 4 nm for l-muscone and 6 nm for d-muscone. PMID- 29438654 TI - The Significance of Repeat Cultures in the Treatment of Severe Fungal Keratitis. AB - PURPOSE: To identify fungal keratitis patients who are at risk of a poor outcome and may benefit from closer follow-up or more aggressive treatment. DESIGN: Secondary analysis of randomized clinical trial data. METHODS: We compared the clinical outcomes of patients who had positive 6-day fungal cultures with those who did not, using backward stepwise regression with covariates for all baseline clinical characteristics. SUBJECTS: Patients presenting with a smear-positive filamentous fungal ulcer and visual acuity of 20/400 or worse, and who subsequently had a 6-day fungal culture performed at the Aravind Eye Care system (India), Lumbini Eye Hospital (Nepal), or Bharatpur Eye Hospital (Nepal). MAIN OUTCOME MEASURES: The primary outcome is rate of corneal perforation and/or the need for therapeutic penetrating keratoplasty. Secondary outcomes include 3-month best spectacle-corrected visual acuity (BSCVA), 3-month infiltrate and/or scar size, and rate of re-epithelialization. RESULTS: Patients who tested positive at their 6-day culture had twice the hazard of experiencing a corneal perforation or the need for therapeutic penetrating keratoplasty (P = .002) than those who tested negative, even after controlling for baseline ulcer characteristics. These patients also had on average 0.26 logMAR lines worse BSCVA at 3 months (P = .001). Culture positivity at day 6 was not a statistically significant predictor of 3-month infiltrate/scar-size (-0.24 mm1; P = .45) or time to re epithelialization (hazard ratio = .81; P = .31). CONCLUSIONS: Here we identify a uniquely valuable clinical tool, day 6 culture results, for the treatment of severe fungal keratitis. Risk stratification based on repeat culture positivity is an objective way to assess response to medical therapy and identify patients who are at high risk of a poor clinical outcome. This establishes a new standard of care for severe fungal keratitis management. PMID- 29438655 TI - Short-Term Neurodevelopmental Outcome in Children Born With High-Risk Congenital Lung Lesions. AB - BACKGROUND: This study sought to evaluate neurodevelopmental outcome in survivors of high-risk congenital lung lesions (CLLs) who underwent prenatal intervention or postnatal surgery within the first month of life. METHODS: Forty-five high risk CLL survivors underwent assessment using the Bayley Scales of Infant Development, 3rd Edition between July 2004 and December 2016. Scores were grouped as average, at-risk, and delayed based on SD intervals. Correlations between outcome and risk factors were analyzed by Fisher's exact test or two-sided t test as appropriate, with significant p values <0.05. RESULTS: Open prenatal intervention was required in 13 (28.9%) children (fetal surgical resection, n = 4 , ex utero intrapartum treatment, n = 9), whereas 32 (71.1%) children had respiratory distress postnatally and required resection within the first month of life. Mean age at follow-up was 19.3 +/- 10.3 months. Mean composite scores were within the expected average range. A total of 62.2% scored within the average range for all domains. At-risk scores were found in 26.7% of children in at least one domain, and 11.1% had delays in at least one domain. Neurodevelopmental outcome was similar between treatment groups. Prolonged ventilator support and neonatal intensive care unit stay, need for supplemental oxygen at day of life 30, gastroesophageal reflux disease, and delayed enteral feeding were associated with neurologic delays (all p < 0.05). CONCLUSIONS: Neurodevelopmental scores for high-risk CLL survivors in infancy and toddlerhood are age appropriate. Neither fetal intervention nor the need for postnatal resection within the first month of life increases the risk of delays. Surrogate markers of a complicated neonatal course are predictive of adverse outcome. PMID- 29438656 TI - Postoperative Radiotherapy for Oral Squamous Cell Carcinoma With Histologic Risk Factors: Are We Over-Treating? AB - PURPOSE: The role of postoperative radiotherapy (PORT) remains controversial for patients with low-risk oral squamous cell carcinoma (OSCC) and adverse histologic features. The aim of this study was to examine the survival benefits in the role of PORT, when compared with surgery alone, among these patients. MATERIALS AND METHODS: In this systematic review, relevant published literature was identified in the PubMed database and eligible studies were included. Predictor variables were perineural invasion (PNI), lymphovascular invasion, and unfavorable grade. The primary outcomes were patient survival and recurrence rates. Because of the heterogeneity and insufficiency of the reported data, quantitative meta-analysis was precluded. Qualitative analysis and pooled analysis on overall survival were performed for study patients. RESULTS: Six eligible studies were included, with a median study period of 10 years. All studies evaluated the role of PORT in pN0 OSCC patients with PNI, and 3 studies evaluated the role of PORT in patients with PNI in isolation. Overall, study patients had similar treatment outcomes between the PORT and non-PORT groups. In the pooled analysis of 325 patients, PORT was not associated with an improved overall survival rate compared with surgery alone (70.3% vs 80.2%, P = .059). CONCLUSIONS: No evidence was found to support the application of PORT given the indication of histologic risk factors alone. The prescription of PORT for PNI, lymphovascular invasion, and unfavorable grading among otherwise low-risk OSCC needs to be approached with caution to avoid the unnecessary harm of radiation exposure. PMID- 29438657 TI - Biocompatibility and Efficiency of Biodegradable Magnesium-Based Plates and Screws in the Facial Fracture Model of Beagles. AB - PURPOSE: A biodegradable magnesium alloy system has been developed as a substitute for conventional plates and screws made of titanium or absorbable polymer. However, previous studies were limited to small animal experiments using screws or wires. In the present study, we preliminarily evaluated the biocompatibility and effectiveness of human standard-size biodegradable magnesium based plates and screws in facial fractures of beagles. MATERIALS AND METHODS: Fracture lines were created bilaterally in the zygomatic arches of 6 beagles. They were fixed in situ with plates and screws made of magnesium alloy mixed with calcium and zinc (experimental group) or absorbable polymer (control group). Laboratory testing, radiologic imaging, histologic analysis, and mechanical testing were performed 4 weeks postoperatively. RESULTS: Inflammatory reactions were not significantly increased in any animal. Mechanical testing showed greater ultimate load and structural stiffness in the experimental group. In the histologic analysis, the void area and bone regeneration area were increased in the experimental, and the implant area and soft tissue area were increased in the control group. Radiologically, 3-dimensional micro-computed tomography showed no differences in the bone gap area between the 2 groups. A temporary increase in hydrogen gas around the magnesium implants regressed spontaneously and did not affect bone healing significantly. CONCLUSIONS: Magnesium-based biodegradable plates and screws showed good biocompatibility and offered considerable stability for fixating facial bone fractures in the early bone-healing process. These results show the possibilities for the future development of magnesium alloy plates and screws for craniomaxillofacial fixation in humans. PMID- 29438658 TI - Functional Capacity in Adults With Cerebral Palsy: Lower Limb Muscle Strength Matters. AB - OBJECTIVE: To investigate the relation between lower limb muscle strength, passive muscle properties, and functional capacity outcomes in adults with cerebral palsy (CP). DESIGN: Cross-sectional study. SETTING: Tertiary institution biomechanics laboratory. PARTICIPANTS: Adults with spastic-type CP (N=33; mean age, 25y; range, 15-51y; mean body mass, 70.15+/-21.35kg) who were either Gross Motor Function Classification System (GMFCS) level I (n=20) or level II (n=13). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Six-minute walk test (6MWT) distance (m), lateral step-up (LSU) test performance (total repetitions), timed up-stairs (TUS) performance (s), maximum voluntary isometric strength of plantar flexors (PF) and dorsiflexors (DF) (Nm.kg-1), and passive ankle joint and muscle stiffness. RESULTS: Maximum isometric PF strength independently explained 61% of variance in 6MWT performance, 57% of variance in LSU test performance, and 50% of variance in TUS test performance. GMFCS level was significantly and independently related to all 3 functional capacity outcomes, and age was retained as a significant independent predictor of LSU and TUS test performance. Passive medial gastrocnemius muscle fascicle stiffness and ankle joint stiffness were not significantly related to functional capacity measures in any of the multiple regression models. CONCLUSIONS: Low isometric PF strength was the most important independent variable related to distance walked on the 6MWT, fewer repetitions on the LSU test, and slower TUS test performance. These findings suggest lower isometric muscle strength contributes to the decline in functional capacity in adults with CP. PMID- 29438659 TI - What Factors Are Associated With the Recovery of Autonomy After a Hip Fracture? A Prospective, Multicentric Cohort Study. AB - OBJECTIVE: To identify the factors associated with recovering autonomy in activities of daily living (ADL) in patients who have had a hip fracture. DESIGN: A prospective cohort study. SETTING: The orthopedic and orthogeriatric departments of 2 regional hospitals. PARTICIPANTS: Patients (N=742) aged >=65 years with a diagnosis of fragility hip fracture. MAIN OUTCOME MEASURES: The level of autonomy at 4 months was assessed using the ADL scale. RESULTS: The median score on the ADL scale at 4 months was 3 (interquartile range, 5). Half of the population was unable to recover their prefracture autonomy levels. The following were found to be risk factors: increasing age (B=.02, P<.001); an elevated number of comorbidities (B=.044, P=.005); a lower level of prefracture autonomy (B=.087, P<.001); more frequent use of an antidecubitus mattress (B=.211, P<.001); an increased number of days with disorientation (B=.002, P=.012); failure to recover deambulation (B=.199, P<.001); an increased number of days with diapers (B=.003, P<.001), with a urinary catheter (B=.03, P<.001), and with bed rails (B=.001, P=.014); and a nonintensive care pathway (B=.199, P=.014). CONCLUSIONS: Recovery of deambulation, treatment of disorientation and management of incontinence are modifiable factors significantly associated with the functional recovery of autonomy. PMID- 29438660 TI - Reliability of hunger-related assessments during 24-hour fasts and their relationship to body composition and subsequent energy compensation. AB - Many diets employ regular periods of fasting that extend beyond a typical overnight fast (i.e. intermittent fasting [IF]). Evaluation of acute fasting responses provides information concerning the potential theoretical rationale for IF. The purpose of the present investigation was to assess the test-retest reliability of hunger-related variables during 24-hour fasts and the relationship between these variables and body composition, as well as subsequent energy intake (EI) after fasting. Eleven participants (6 F, 5 M) completed two 24-hour fasts after being provided a 3-day standardized weight-maintenance diet. From 16 to 24 h of fasting, participants were directly observed and provided hourly assessments of hunger, desire to eat (DTE), prospective food consumption (PFC), fullness and energy. After the fast, participants were allowed ad libitum food consumption, and compensation was calculated as EI relative to weight-maintenance energy needs. Test-retest reliability for hunger-related assessments at particular durations of fasting was evaluated using intraclass correlation coefficients (ICC), changes in dependent variables were evaluated using ANOVA with repeated measures, and relationships between variables were explored using bivariate correlations. At 16 h of fasting, the ICCs for all hunger-related assessments were statistically significant (r = 0.67-0.91; p <= 0.05). However, as the fast progressed, reliability varied substantially. When averaged across the nine measurements, the ICCs were: 0.81 (fullness), 0.74 (PFC), 0.67 (energy), 0.44 (DTE) and 0.36 (hunger). Body fat percentage was significantly correlated with changes in PFC (r = 0.62, p = 0.04), hunger (r = 0.66, p = 0.03), DTE (r = 0.71, p = 0.02), and fullness (r = -0.63, p = 0.04), but not energy (r = -0.16, p = 0.64). Average EI compensation was only 60% of weight-maintenance needs, but substantial variability was observed (7 to 110% compensation). Compensation was significantly correlated with changes in PFC (r = 0.72, p = 0.01), hunger (r = 0.63, p = 0.04) and DTE (r = 0.60, p = 0.05), but not fullness (r = 0.58, p = 0.06) or energy (r = 0.35, p = 0.29). Compensation and body fat percentage were not correlated (r = 0.03, p = 0.94). The percent of energy intake from fat and protein increased after the fast (29.9 to 37.3% and 13.8 to 16.8%; p < 0.05), while the percent of energy intake from carbohydrate decreased (56.4 to 46.0%; p = 0.02). These results may have implications for IF programs. It is possible that the implementation of multiple "test fasts," in which subjective variables and subsequent energy intake are evaluated, could be used to identify candidates who may be more likely to benefit from an IF program. PMID- 29438661 TI - Early life socioeconomic status associates with interleukin-6 responses to acute laboratory stress in adulthood. AB - It is proposed that environmental exposures in early life influence immune programming. Specifically, socioeconomic disadvantage is thought to program an immune phenotype that is prone to inflammation and associated with increased risk for inflammatory disease later in life. Existing literature shows an inverse association of early childhood socioeconomic status (SES) with adult levels of systemic inflammation. Here, we extend that literature to examine whether early childhood SES also relates to the magnitude of inflammatory response to acute psychological stress in adulthood. Healthy volunteers (N = 110; 40-58 years; 59% female; 90% white) performed a laboratory stress protocol, with blood samples drawn at the end of a 30-min baseline, a 5-min speech task, and a 30-min recovery to assess interleukin (IL)-6 stress responses. An early childhood SES index was derived from reports of parental home and vehicle ownership, and number of bedrooms per child in the home across ages 1-2, 3-4, and 5-6. Regressions adjusted for current age, sex, race, and BMI showed that lower SES at age 1-2 was associated with larger IL-6 stress responses in adulthood (DeltaR2 = 0.05, beta = -0.24, p = .03). This association was independent of adult SES and task-evoked affective responses. No association was found between SES at ages 3-4 or 5-6 and IL-6 responses. These results provide initial evidence for a link between disadvantage in the first 2 years of life and heightened inflammatory response to stress in adulthood; this link may contribute to the increased disease risk that accompanies being raised in disadvantaged socioeconomic circumstances. PMID- 29438663 TI - Cloning and functional characterization of three new pheromone receptors from the diamondback moth, Plutella xylostella. AB - The highly specialized olfactory receptor neurons (ORNs) on the antennae of male moths can recognize blends of several pheromone components. In previous studies, a total of six candidate pheromone receptor (PR) genes were cloned and functionally characterized in the diamondback moth, Plutella xylostella. In the present work, we report on three novel candidate pheromone receptor genes: PxylOR8, PxylOR41, and PxylOR45 in the same species. Gene expression analysis revealed that PxylOR8 is specifically expressed in female adult antennae, while PxylOR41 and PxylOR45 are expressed in antennae in both sexes, but with a male bias. In situ hybridization revealed that PxylOR8, PxylOR41 and PxylOR45 are localized in long trichoid sensilla. Functional analyses on the three pheromone receptor genes were then performed using the heterologous expression system of Xenopus oocytes. PxylOR41 was tuned to two minor pheromone components Z9-14:Ac, Z9-14:OH, and their analog Z9-14:Ald. PxylOR8 and PxylOR45 did not respond to any tested pheromone components and analogs. These results may contribute to clarifying how pheromone detection works in P. xylostella. PMID- 29438662 TI - Alendronate augments lipid A-induced IL-1beta release and Smad3/NLRP3/ASC dependent cell death. AB - Alendronate (ALN) is a nitrogen-containing bisphosphonate (NBP) that inhibits bone resorption. NBPs have inflammatory side effects, and ALN augments bacteria induced interleukin (IL)-1beta production. The present study aimed to examine whether ALN induces pyroptosis, a form of cell death associated with IL-1beta release, in macrophage-like J774.1 cells incubated with lipid A, a component of gram-negative bacteria. Pretreatment of J774.1 cells with ALN increased lipid A induced IL-1beta production and cell death, but not IL-6 and TNF-alpha production. Ac-YVAD-CHO, a caspase-1 inhibitor, inhibited ALN-augmented IL-1beta production induced by lipid A, although it did not affect ALN-induced cell death. Moreover, Ac-IETD-CHO, a caspase-8 inhibitor, and Z-VAD-FMK, a pan-caspase inhibitor, did not inhibit ALN-induced cell death, suggesting that the effects of ALN are exerted independently of caspase activation. We also demonstrate that a Smad3 inhibitor (SIS3) suppressed ALN-augmented IL-1beta production. Moreover, SIS3 attenuated ALN-augmented release of LDH and caspase-1. These results suggest that ALN augments IL-1beta production, cell death, and caspase-1 release in a manner dependent on Smad3. We then investigated whether ALN-augmented IL-1beta production and cell death are dependent on apoptosis-associated speck-like protein containing a CARD (ASC) and NOD-like receptor pyrin domain containing-3 (NLRP3), which are associated with Smad3 activation. Both anti-ASC and anti-NLRP3 antibodies suppressed ALN-induced cell death and caspase-1 release, but only anti ASC antibody inhibited ALN-augmented IL-1beta production. Our findings suggest that ALN-augmented IL-1beta production and cell death require Smad3 and ASC activation, and that SIS3 and anti-ASC antibodies may serve as palliative agents for necrotizing inflammatory diseases caused by ALN. PMID- 29438664 TI - FAT10 attenuates hypoxia-induced cardiomyocyte apoptosis by stabilizing caveolin 3. AB - FAT10, a member of the ubiquitin-like-modifier family of proteins, plays a cardioprotective role in response to hypoxic/ischemic injury. Caveolin-3 (Cav-3), a muscle-specific caveolin family member, is involved in cardiomyocyte apoptosis. However, the link between FAT10 and Cav-3 in ischemic cardiomyocytes is unclear. In the present study, we found that both FAT10 and Cav-3 were upregulated in ischemic myocardial tissues and in hypoxic cardiomyocytes. Furthermore, our results demonstrated that FAT10 inhibits hypoxia-induced cardiomyocyte apoptosis by increasing Cav-3 expression. Importantly, following myocardial infarction, knockout of FAT10 aggravated cardiac dysfunction and increased cardiomyocyte apoptosis by reducing Cav-3 expression. Additionally, Cav-3 was degraded by the ubiquitin-proteasome system (UPS) in cardiomyocytes. Mechanistically, we found that FAT10 stabilizes Cav-3 expression by inhibiting ubiquitination-mediated degradation in cardiomyocytes. Together, these findings revealed a novel role of FAT10 in protection against ischemia-induced injury via stabilization of Cav-3, providing evidence that the FAT10/Cav-3 axis may be a potential therapeutic target for patients with ischemic heart conditions. PMID- 29438665 TI - Cartilage intermediate layer protein-1 alleviates pressure overload-induced cardiac fibrosis via interfering TGF-beta1 signaling. AB - Cardiac fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins in the myocardium and results in decreased ventricular compliance and diastolic dysfunction. Cartilage intermediate layer protein-1 (CILP-1), a novel identified cardiac matricellular protein, is upregulated in most conditions associated with cardiac remodeling, however, whether CILP-1 is involved in pressure overload-induced fibrotic response is unknown. Here, we investigated whether CILP-1 was critically involved in the fibrotic remodeling induced by pressure overload. Western blot analysis and immunofluorescence staining showed that CILP-1 was predominantly detected in cardiac myocytes and to a less extent in the interstitium. In isolated adult mouse ventricular myocytes and nonmyocytes, CILP-1 was found to be mainly synthesized by myocytes. CILP-1 expression in left ventricles was upregulated in C57BL/6 mice undergoing transverse aortic constriction (TAC). Myocardial CILP-1 knockdown aggravated whereas CILP-1 overexpression attenuated TAC-induced ventricular remodeling and dysfunction, as measured by echocardiography test, morphological examination, and gene expressions of fibrotic molecules. Incubation of cardiac fibroblasts with the conditioned medium containing full-length, N-terminal, or C-terminal CILP-1 inhibited transforming growth factor (TGF)-beta1-induced Smad3 phosphorylation and the subsequent profibrotic events. We first demonstrated that C-terminal CILP 1 increased Akt phosphorylation, promoted the interaction between Akt and Smad3, and suppressed Smad3 phosphorylation. Blockade of PI3K-Akt pathway attenuated the inhibitory effect of C-CILP-1 on TGF-beta1-induced Smad3 activation. We conclude that CILP-1 is a novel ECM protein possessing anti-fibrotic ability in pressure overload-induced fibrotic remodeling. This anti-fibrotic effect of CILP-1 attributes to interfering TGF-beta1 signaling through its N- and C- terminal fragments. PMID- 29438666 TI - An alternative DNA extraction method for detection of Blastocystis spp. in human fecal samples. AB - Polymerase chain reaction (PCR) is an effective technique for diagnosis of Blastocystis infection. Notably, DNA isolation procedure is extremely critical for the PCR step. In the present study, a recently described extraction procedure, named as the "sand method" was modified and adapted for isolation of Blastocystis DNA. To evaluate its efficacy, the current method and QIAamp DNA Stool Mini Kit (Qiagen) were applied to fresh human stool samples. Our results indicated that, the mean DNA concentrations obtained by the sand method and the commercial kit were 48 and 55 ng/MUl, respectively. Also, no DNA inhibitors were detected in two methods. The sand method was capable of detecting 16 parasites per 50 mg feces. DNA samples extracted by both methods were subjected to PCR. Blastocystis spp. were detected in 11 (31.4%) of 35 samples, and perfect agreement (kappa: 1.000) was found between the PCR-sand method and PCR-commercial kit method. The samples that were detected positive by PCR-sand method were successfully sequenced, and Blastocystis subtypes (STs) were identified as ST3, ST2 and ST1. In conclusion, the present study indicates that the sand method provides a simple, rapid and inexpensive procedure for reliable extraction of Blastocystis DNA from stool samples. PMID- 29438667 TI - Reply. PMID- 29438668 TI - Reply. PMID- 29438669 TI - Trans-suppression of host CDH3 and LOXL4 genes during Cryptosporidium parvum infection involves nuclear delivery of parasite Cdg7_FLc_1000 RNA. AB - Intestinal infection by Cryptosporidium parvum causes significant alterations in the gene expression profile in host epithelial cells. Previous studies demonstrate that a panel of parasite RNA transcripts of low protein-coding potential are delivered into infected host cells and may modulate host gene transcription. Using in vitro models of human intestinal cryptosporidiosis, we report here that trans-suppression of the cadherin 3 (CDH3) and lysyl oxidase like 4 (LOXL4) genes in human intestinal epithelial cells following C. parvum infection involves host delivery of the Cdg7_FLc_1000 RNA, a C. parvum RNA that has been previously demonstrated to be delivered into the nuclei of infected host cells. Downregulation of CDH3 and LOXL4 genes was detected in host epithelial cells following C. parvum infection or in cells expressing the parasite Cdg7_FLc_1000 RNA. Knockdown of Cdg7_FLc_1000 attenuated the trans-suppression of CDH3 and LOXL4 genes in host cells induced by infection. Interestingly, Cdg7_FLc_1000 was detected to be recruited to the promoter regions of both CDH3 and LOXL4 gene loci in host cells following C. parvum infection. Host delivery of Cdg7_FLc_1000 promoted the PH domain zinc finger protein 1 (PRDM1)-mediated H3K9 methylation associated with trans-suppression in the CDH3 gene locus, but not the LOXL4 gene. Therefore, our data suggest that host delivery of Cdg7_FLc_1000 causes CDH3 trans-suppression in human intestinal epithelial cells following C. parvum infection through PRDM1-mediated H3K9 methylation in the CDH3 gene locus, whereas Cdg7_FLc_1000 induces trans-suppression of the host LOXL4 gene through H3K9/H3K27 methylation-independent mechanisms. PMID- 29438670 TI - Phylogenetic and environmental DNA insights into emerging aquatic parasites: implications for risk management. AB - Species translocation leads to disease emergence in native species of considerable economic importance. Generalist parasites are more likely to be transported, become established and infect new hosts, thus their risk needs to be evaluated. Freshwater systems are particularly at risk from parasite introductions due to the frequency of fish movements, lack of international legislative controls for non-listed pathogens and inherent difficulties with monitoring disease introductions in wild fish populations. Here we used one of the world's most invasive freshwater fish, the topmouth gudgeon, Pseudorasbora parva, to demonstrate the risk posed by an emergent generalist parasite, Sphaerothecum destruens. Pseudorasbora parva has spread to 32 countries from its native range in China through the aquaculture trade and has introduced S. destruens to at least five of these. We systematically investigated the spread of S. destruens through Great Britain and its establishment in native fish communities through a combination of phylogenetic studies of the host and parasite and a novel environmental DNA detection assay. Molecular approaches confirmed that S. destruens is present in 50% of the P. parva communities tested and was also detected in resident native fish communities but in the absence of notable histopathological changes. We identified specific P. parva haplotypes associated with S. destruens and evaluated the risk of disease emergence from this cryptic fish parasite. We provide a framework that can be applied to any aquatic pathogen to enhance detection and help mitigate future disease risks in wild fish populations. PMID- 29438672 TI - The effects of theta burst stimulation (TBS) targeting the prefrontal cortex on executive functioning: A systematic review and meta-analysis. AB - Theta burst stimulation (TBS) is a highly efficient repetitive transcranial magnetic stimulation (rTMS) variant employed in experimental and clinical treatment paradigms. Despite widespread usage of TBS targeting the prefrontal cortex (PFC), there has been no systematic review of the evidence linking TBS protocols to changes in task performance on common measures of prefrontal function in general, and executive functions specifically. A systematic review of the literature was conducted using PsycINFO, PubMed, Web of Science and Scopus databases to identify articles examining the effects of TBS targeting the PFC on executive function task performance. Both the up-regulating (intermittent theta burst stimulation; iTBS) and down-regulating (continuous theta burst stimulation; cTBS) variants of TBS were considered. 32 (29 cTBS; 8 iTBS) studies met the inclusion criteria. Participants (n = 759; 51.41% female) were primarily young adults (Mage = 26), with one study examining the effects of cTBS and iTBS in older adults. Results from individual studies were converted to Hedge's g and random-effects models were used to estimate the overall effect size for each protocol. Age, biological sex, and control methodology were examined as potential moderators of the cTBS effect on executive function test performance. Findings indicated a- reliable attentuating effect of cTBS on executive function task performance (g = -.244, Z = -5.920, p < .001); this effect was relatively uniform across included studies (Q= 24.178, p = .838, I2 = 0). Although no significant moderators of the cTBS effect were identified, laterality sub analyses indicated that the magnitude of the effect was significantly higher (Mdiff = .213, Zdiff = 2.546, p = .011) for left-sided (g = -.358, Z = -5.816, p < .001) relative to right-sided (g = -.145, Z = -2.552, p = .011) PFC stimulation. A systematic review of iTBS studies revealed variability in reliability of effects though most were in the theorized direction. TBS protocols appear to be effective in modulating prefrontal cortical excitability in previously theorized directions. PMID- 29438671 TI - The Structure of the Biofilm-controlling Response Regulator BfmR from Acinetobacter baumannii Reveals Details of Its DNA-binding Mechanism. AB - The rise of drug-resistant bacterial infections coupled with decreasing antibiotic efficacy poses a significant challenge to global health care. Acinetobacter baumannii is an insidious, emerging bacterial pathogen responsible for severe nosocomial infections aided by its ability to form biofilms. The response regulator BfmR, from the BfmR/S two-component system, is the master regulator of biofilm initiation in A. baumannii and is a tractable therapeutic target. Here we present the structure of A. baumannii BfmR using a hybrid approach combining X-ray crystallography, nuclear magnetic resonance spectroscopy, chemical crosslinking mass spectrometry, and molecular modeling. We also show that BfmR binds the previously proposed bfmRS promoter sequence with moderate affinity. While BfmR shares many traits with other OmpR/PhoB family response regulators, some unusual properties were observed. Most importantly, we observe that when phosphorylated, BfmR binds this promoter sequence with a lower affinity than when not phosphorylated. All other OmpR/PhoB family members studied to date show an increase in DNA-binding affinity upon phosphorylation. Understanding the structural and biochemical mechanisms of BfmR will aid in the development of new antimicrobial therapies. PMID- 29438673 TI - Distribution of nitric oxide synthase in the rock cavy (Kerodon rupestris) brain I: The diencephalon. AB - Nitric oxide (NO) is a highly soluble and membrane-permeable neurotransmitter, so it does not need to be packed in vesicles or have a membrane receptor. In the nervous system, NO is synthesized by the neuronal form of the nitric oxide synthase (NOS) enzyme and has been considered as a local neurotransmitter. NOS distribution is widespread in the nervous system of various vertebrate species, which may explain its participation in many functions such as memory, blood pressure regulation and sexual behavior. Here we used immunohistochemistry against NOS and NADPH diaphorase histochemistry to map the distribution of NO in the diencephalon of the rock cavy (Kerodon rupestris), a rodent endemic to the Brazilian Northeast. Rock cavy has crepuscular habits and is adapted to ecological conditions such as heat and scarcity of water and food. This study found that NOS distribution was more concentrated in the hypothalamus of this animal. Among the hypothalamic nuclei, the median preoptic, supraoptic, paraventricular nucleus of the hypothalamus, ventromedial nucleus of the hypothalamus, ventral and dorsal premammillary nucleus, supramammillary nucleus, lateral mammillary nucleus and dorsal hypothalamic nucleus had the largest collections of NOS immunoreactive (NOS-ir) neurons. Some nuclei of the thalamus and epithalamus such as the paraventricular nucleus of the thalamus, the ventral lateral geniculate nucleus, the medial geniculate nucleus and the lateral habenula showed NOS-ir neurons. This distribution is similar to that described in other rodents, indicating that NO also has an important role in rock cavy's physiology. PMID- 29438674 TI - Molecular characterization of inhibin-A: Structure and expression analysis in Clarias batrachus. AB - The inhibins are disulphide-linked heterodimeric glycoproteins that belong to the TGFbeta superfamily. Inhibins have been well studied in mammals but the information about their structure and function is very limited in lower vertebrates. The aim of the present study was to characterize inhibin-A and to understand its receptor binding interaction, and to evaluate its biological function in Clarias batrachus. Structure prediction of inhibin-A revealed two glycosylation sites on inhibin-alpha (Asp262 and Asn334). Docking of inhibin-A with its receptor; betaglycan and Act RIIA showed that residues Ser321, Gly324 and Leu325 of inhibin-alpha are involved in high affinity binding with betaglycan while inhibin-betaA bound to Act RIIA by forming hydrogen bonds. The mRNA transcript analysis of various tissues indicated the presence of higher to moderate expression of inhibin-alpha and inhibin-betaA in the gonads and the extra-gonadal tissues. Further, stage specific expression showed decreased levels of inhibin-alpha in the gonads during the annual reproductive cycles. Inhibin betaA, activin-betaB and Act RIIA increased in the brain during spawning while FSHr increased in the gonads during the preparatory phase. Our study provides molecular, structural and functional insights of inhibin-A for the first time in C. batrachus. PMID- 29438676 TI - Stress-induced cellular responses in immunogenic cell death: Implications for cancer immunotherapy. AB - Cancer is evading the host's defense mechanisms leading to avoidance of immune destruction. During tumor progression, immune-evading cancer cells arise due to selective pressure from the hypoxic and nutrient-deprived microenvironment. Thus, therapies aiming at re-establishing immune destruction of pathological cells constitute innovating anti-cancer strategies. Accumulating evidence suggests that selected conventional chemotherapeutic drugs increase the immunogenicity of stressed and dying cancer cells by triggering a form of cell death called immunogenic cell death (ICD), which is characterized by the release of danger associated molecular patterns (DAMPs). In this review, we summarize the effects of ICD inducers on DAMP signaling leading to adjuvanticity and antigenicity. We will discuss the associated stress response pathways that cause the release of DAMPs leading to improved immune recognition and their relevance in cancer immunotherapy. Our aim is to highlight the contribution of adaptive immunity to the long-term clinical benefits of anticancer treatments and the properties of immune memory that can protect cancer patients against relapse. PMID- 29438675 TI - Involvement of matrix metalloproteinases (MMP-2, -7, -9) and their tissue inhibitors (TIMP-2, -3) in the regression of chicken postovulatory follicles. AB - The study was undertaken to examine mRNA expression and localization of selected matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), and the activity of MMPs in chicken postovulatory follicles (POFs) during their apoptotic regression. Apoptotic cells and apoptosis-related caspase expression and activity were examined as well. Chickens were sacrificed 2 h and 21 h after ovulation, and five POFs (POF1 to POF5) were isolated from the ovaries. It was found that the number of apoptotic cells (TUNEL-positive) increased along with follicle regression. The relative expression (RQ) of caspase-2, -3, -8 and -9 mRNA increased (P < 0.05) in POF5, while the activity of all examined caspases elevated gradually (approximately 80-150%) reaching the highest level in POF3, and then slowly decreased to the value noted in POF1 (P < 0.05 - P < 0.001). Real time polymerase chain reaction revealed different expression of MMP-2, -7, -9 and TIMP-2 and -3 on mRNA levels, and activity assay showed the changes in activity of MMP-2 and -9 in the POFs. Regression of the follicles was accompanied predominantly by an increase in the relative expression of MMP-2, and a decrease in TIMP-2 and -3 mRNAs (P < 0.05 - P < 0.001). The activity levels of MMP-2 and 9 showed pronounced changes during the examined period. During follicle regression elevated activity of MMP-2 and -9 was found (P < 0.05 - P < 0.001). Immunohistochemistry demonstrated tissue- and follicle-dependent immunoreactivity of the examined members of the MMP system. In summary, the results showing the apoptotic regression-related changes as well as tissue-dependent differences in the expression of selected MMPs and TIMPs, and activity of MMP-2 and MMP-9, point to the significance that these molecules might participate in the complex orchestration of chicken POF regression. PMID- 29438677 TI - Autophagy inducers in cancer. AB - Autophagy is a complex, physiological process devoted to degrade and recycle cellular components. Proteins and organelles are first phagocytized by autophagosomes, then digested in lysosomes, and finally recycled to be utilized again during cellular metabolism. Moreover, autophagy holds an important role in the physiopathology of several diseases. In cancer, excellent works demonstrated the dual functions of autophagy in tumour biology: autophagy activation can promote cancer cells survival (protective autophagy), or contribute to cancer cell death (cytotoxic/nonprotective autophagy). A better understanding of the dichotomy roles of autophagy in cancer biology can help to identify or design new drugs able to induce/enhance (or block) autophagic flux. These features will necessary be tissue-dependent and confined to a specific time of treatment. The intent of this review is to focus on the different potentialities of autophagy inducers in cancer prevention versus therapy in order to elicit a desirable clinical response. Few promising synthetic and natural compounds have been identified and the pros and cons of their role in autophagy regulation is reviewed here. In the complex framework of autophagy modulation, "connecting the dots" is not a simple work and the lack of clinical studies further complicates the scenario, but the final goal to obtain clinically relevant autophagy inducers can reveal an unexpected landscape. PMID- 29438678 TI - Characterization of santalene synthases using an inorganic pyrophosphatase coupled colorimetric assay. AB - We developed a colorimetric assay using yeast inorganic pyrophosphatase (IPP1) as a coupling enzyme to measure the activities of terpene synthases. IPP1 hydrolyzes pyrophosphate, the byproduct of terpene synthase catalyzed reactions, into orthophosphate, which can then be quantitated by reacting with molybdic acid to form a blue color compound. As a proof of concept, this method was used to quantitatively characterize three santalene synthases, SaSSy and SspiSSy involved in sandalwood oil biosynthesis, and a phylogenetically distant SanSyn from Clausena lansium. Our study provided the kinetic parameters of all three santalene synthases and demonstrated the validity of the enzyme couple colorimetric assay by the comparison of this assay with the existing GC-MS (Gas Chromatography-Mass Spectrometry) method. PMID- 29438679 TI - Discovery of novel bacterial toxins by genomics and computational biology. AB - Hundreds and hundreds of bacterial protein toxins are presently known. Traditionally, toxin identification begins with pathological studies of bacterial infectious disease. Following identification and cultivation of a bacterial pathogen, the protein toxin is purified from the culture medium and its pathogenic activity is studied using the methods of biochemistry and structural biology, cell biology, tissue and organ biology, and appropriate animal models, supplemented by bioimaging techniques. The ongoing and explosive development of high-throughput DNA sequencing and bioinformatic approaches have set in motion a revolution in many fields of biology, including microbiology. One consequence is that genes encoding novel bacterial toxins can be identified by bioinformatic and computational methods based on previous knowledge accumulated from studies of the biology and pathology of thousands of known bacterial protein toxins. Starting from the paradigmatic cases of diphtheria toxin, tetanus and botulinum neurotoxins, this review discusses traditional experimental approaches as well as bioinformatics and genomics-driven approaches that facilitate the discovery of novel bacterial toxins. We discuss recent work on the identification of novel botulinum-like toxins from genera such as Weissella, Chryseobacterium, and Enteroccocus, and the implications of these computationally identified toxins in the field. Finally, we discuss the promise of metagenomics in the discovery of novel toxins and their ecological niches, and present data suggesting the existence of uncharacterized, botulinum-like toxin genes in insect gut metagenomes. PMID- 29438680 TI - Ischemia-reperfusion injury alters skin microvascular responses to local heating of the index finger. AB - BACKGROUND: Ischemia-reperfusion (IR) injury impairs microcirculatory function by reducing nitric oxide (NO) bioavailability and increasing sympathetic tone. This study non-invasively examined the effects of acute upper limb IR injury on local thermal hyperemia (LTH) in glabrous and non-glabrous finger skin. MATERIALS AND METHODS: In ten healthy males, LTH was examined twice (~7-10 d apart) for each skin type on the index finger using laser-Doppler flowmetry in a counterbalanced design with either 1) 20 min ischemia, followed by reperfusion (ISCH) or 2) time matched control (SHAM). LTH tests were performed using a standard heating protocol (33-42 degrees C at 1 degrees C.20 s-1 + 20 min at 44 degrees C) and baseline, initial peak, nadir, delayed plateau and maximal heating phases were identified as well as vasodilatory onset time and time to initial peak. Cutaneous vasomotion was evaluated using spectral analysis and comparing absolute and normalized wavelet amplitudes between conditions for both skin types at baseline and during LTH. RESULTS: In non-glabrous skin, IR injury delayed the vasodilatory onset of local heating by 27.4 [11.3, 43.4] s (p = 0.004) and attenuated cutaneous vasodilation during the initial peak and sustained heating by -44.5 [ 73.0, -15.9] PU (p = 0.003) and -34.4 [-62.9, -5.8] PU (p = 0.020), respectively. Analysis of normalized wavelet amplitudes in non-glabrous skin identified impaired microvascular function at baseline via NO-dependent mechanisms (-3.64 [ 7.22, -0.05] %, p = 0.047), and during LTH via respiratory influences (-2.83 [ 5.39, -0.21] %, p = 0.031). In glabrous skin, IR injury delayed vasodilatory onset time by 24.9 [1.1, 67.6] s (p = 0.042). The vasodilatory response to sustained local skin heating in glabrous skin was increased following IR injury (+56.3 [15.1, 116.5], p = 0.012), however, this was not evident when accounting for differences in blood pressure between conditions. Additionally, no other differences in vasodilatory or vasomotor functions were observed in this skin type between conditions (all, p > 0.05). CONCLUSIONS: The current IR model elicits impaired cutaneous vasodilatory responses to local heating in young males, primarily in non-glabrous skin, and may be useful for exploring mechanisms of IR-injury and for testing potential countermeasures in otherwise healthy humans. PMID- 29438681 TI - The diagnostic value of five serum tumor markers for patients with cholangiocarcinoma. AB - OBJECTIVE: To assess the clinical significance and diagnostic value of the single and combined detection of five tumor markers in patients with cholangiocarcinoma. METHODS: In total, 296 patients with biliary tract disease who were diagnosed and received treatment at Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University (17113011) during April 2011 to Dec 2017 were chosen for this study. Patients were divided into a cholangiocarcinoma group and a benign biliary tract disease group. Serum was collected from the patients, and the concentrations of AFP, CEA, CA125, CA19-9, CA72-4 and total bilirubin (TBIL) were tested. BM SPSS Statistics 22.0 was used to analyze the data. Receiver-operating characteristic (ROC) curves for the single and combined detection of five tumor markers were generated, and the sensitivity, specificity, and area under ROC curve (AUC) were calculated. RESULTS: The concentrations of serum tumor markers in the cholangiocarcinoma group were higher than those in the benign biliary tract disease group. The AUCs for the single detections of the AFP, CEA, CA125, CA19-9, CA72-4 were 0.654, 0.808, 0.772, 0.833, and 0.743, and the optimal cutoffs were 2.58 ng/mL, 2.85 ng/mL, 23.85 U/mL, 46.75 U/mL, and 2.46 U/mL respectively. The combined detection of CEA, CA125 and CA19-9 had great diagnostic value. Its AUC was 0.888, its sensitivity was 85.1%, and its specificity was 83.1%. CONCLUSIONS: The levels of CEA, CA125, CA19-9 and CA72-4 had a different diagnostic value for cholangiocarcinoma, and combined serum CEA, CA125 and CA19-9 would have the best clinical diagnostic effect of cholangiocarcinoma. PMID- 29438682 TI - Serum and dietary zinc and copper in Iranian girls. AB - OBJECTIVE: Girls with micronutrient deficiencies may have impaired growth and development, and furthermore this may also impact on their childbearing. We have investigated the relationship between serum zinc and copper concentrations, dietary zinc and copper intake and anthropometric and demographic parameters, and cardiovascular risk factors, in 408 girls living in northeastern Iran. METHODS: A total of 408 healthy girls, aged 12-18 years old, were included in our study. Serum zinc and copper concentrations were measured by flame atomic absorption (Varian AA240FS) and zinc and copper intake were assessed using a 3-day dietary record. RESULTS: There was a weak correlation between serum and dietary zinc intake (r = 0.117, p = 0.018). The correlation between serum and dietary copper approached significance (r = -0.094, p = 0.056). The mean serum zinc and copper concentrations were 14.61 +/- 2.71 MUmol/L and 19.48 +/- 8.01 MUmol/L respectively. Height, total cholesterol (TC) and low-density lipoprotein (LDL) were positively correlated with serum copper concentration. Subjects with high serum copper concentrations (>24 MUmol/L) were found to have a significantly higher fasting blood glucose (FBG) compared to subjects with normal, or low serum copper concentrations (p = 0.033). Girls who were in the 5th percentile or greater for height were found to have higher serum copper concentrations than girls in other height categories. CONCLUSION: There was a weak relationship between dietary and serum concentrations of zinc. Copper status was associated with anthropometric and biochemical parameters, including FBG and lipid profile. Further studies are required to define the role of copper in metabolic health. PMID- 29438683 TI - Management of the American cockroach's oothecae: The potential of entomopathogenic fungi control. AB - The Periplaneta americana species is an annoyance to man, causing allergies and damage to clothes and documents. It has the ability to spread pathogens and requires control measures. Control with natural enemies is less aggressive and can currently be applied with less risk than other techniques, such as chemical control, which is the main method used worldwide to control its post-embryonic stages. The potential microbial control of nymphs and adults of this pest has been shown, but little is known about its oothecae. There are isolates of fungal species that can be used to achieve this aim, but they may have innate differences in their virulence and ability to spread. This study aimed to identify fungal isolates JAB 68 and IBCB 35 through genetic sequencing of the ITS1-5.8S-ITS2 region, analyze their ability to synthesize chitinase, and investigate and compare their aggressiveness against P. americana oothecae and their influence on nymph eclosion. Fungal suspensions were inoculated into minimal medium containing glucose (control) as the sole carbon source and 1% colloidal chitin to determine the chitinolytic activity on the 4th, 7th and 10th days and sporulation on the 10th day. To obtain mortality, extrusion and the compiled number of hatched nymphs, oothecae were sprayed with suspensions of the isolates as follows: T1 - no application; T2 - aqueous solution of Tween 80(r) 0.1% (vehicle suspension for treatments T3 to T8); T3 - 2 * 109 conidia/mL of the JAB 68 isolate; T4 - 2 * 108 con./mL of the JAB 68 isolate; T5 - 2 * 107 con./mL of the JAB 68 isolate; T6 - 2 * 109 con./mL of the IBCB 35 isolate; T7 - 2 * 108 con./mL of the IBCB 35 isolate; T8 - 2 * 107 con./mL of the IBCB 35 isolate. The JAB 68 and IBCB 35 isolates were identified as belonging to the species Metarhizium anisopliae and Beauveria bassiana, respectively. Chitinolytic activity and extrusion were good parameters for evaluating the fungi's action on oothecal control. The most aggressive entomopathogen was M. anisopliae isolate JAB 68, with shorter time for fungus extrusion at a concentration of 2 * 107 con./mL. B. bassiana reduced the number of hatched nymphs at a concentration of 2 * 108 con./mL. Both fungi are capable of infecting and killing P. americana's oothecae and reducing the number of nymphs hatched. PMID- 29438684 TI - Post-infectious bronchiolitis obliterans in children: is general quality of life the right measure? PMID- 29438685 TI - Maternal restrictive feeding practices for child weight control and associated characteristics. AB - OBJECTIVE: To identify associations between maternal restrictive feeding practices for child weight control and sociodemographic, behavioral, dietetic, and anthropometric characteristics. METHODS: Cross-sectional study with mothers of children aged 2-8 years. Maternal feeding practices were measured by the Comprehensive Feeding Practices Questionnaire, in private schools in Brazil. Bivariate and multivariate associations were performed, using nonparametric analyses to estimate odds ratios and significance levels. RESULTS: Maternal restrictive feeding practices for weight control were independently associated with the mother's perception of her child being a little overweight/overweight/obese (OR=4.61, p=0.001), greater concern about the child's overweight (OR=2.61, p<0.001), child's overweight/obesity/severe obesity (OR= 2.18, p<0.001), and the child's greater intake of ultra-processed foods (OR=1.40, p=0.026). CONCLUSION: In this study, the risk variables identified for the use of the maternal restrictive feeding practices to control the child's weight can be used to provide education and guidance interventions in health and education networks directed to groups with similar characteristics to those of the studied population. PMID- 29438686 TI - Evaluation of nonalcoholic fatty liver disease using magnetic resonance in obese children and adolescents. AB - OBJECTIVE: To determine the frequency of nonalcoholic fatty liver disease using nuclear magnetic resonance as a noninvasive method. METHODOLOGY: This was a cross sectional study conducted on 50 children and adolescents followed up at an outpatient obesity clinic. The subjects were submitted to physical examination, laboratory tests (transaminases, liver function tests, lipid profile, glycemia, and basal insulin) and abdominal nuclear magnetic resonance (calculation of hepatic, visceral, and subcutaneous fat). RESULTS: Nonalcoholic fatty liver disease was diagnosed in 14 (28%) participants, as a severe condition in eight (percent fat >18%), and as non-severe in four (percent fat from 9% to 18%). Fatty liver was associated with male gender, triglycerides, AST, ALT, AST/ALT ratio, and acanthosis nigricans. Homeostasis model assessment of insulin resistance and metabolic syndrome did not show an association with fatty liver. CONCLUSION: The frequency of nonalcoholic fatty liver disease in the present population of children and adolescents was lower than that reported in the international literature. It is suggested that nuclear magnetic resonance is an imaging exam that can be applied to children and adolescents, thus representing an effective noninvasive tool for the diagnosis of nonalcoholic fatty liver disease in this age range. However, further national multicenter studies with longitudinal design are needed for a better analysis of the correlation between nonalcoholic fatty liver disease and its risk factors, as well as its consequences. PMID- 29438687 TI - Increased ApoB/ApoA1 ratio is associated with excess weight, body adiposity, and altered lipid profile in children. AB - OBJECTIVE: To investigate ApoB/ApoA1 ratio and its association with cardiovascular risk factors in children. METHODS: Cross-sectional study with 258 children aged 8 and 9 years old, enrolled in all urban schools in the city of Vicosa-MG. Anthropometric and body composition assessment, as well as biochemical profile of the children was performed. Socioeconomic variables and sedentary lifestyle were evaluated through a semi-structured questionnaire. RESULTS: Many children had excess weight (35.2%), abdominal adiposity (10.5%), and body fat (15.6%), as well as increased ApoB/ApoA1 ratio (14.7%), total cholesterol (51.8%), and triglycerides (19.8%). Children with excess weight and total and central fat had a higher prevalence of having a higher ApoB/ApoA1 ratio, as well as those with atherogenic lipid profile (increased LDL-c and triglycerides and low HDL-c). A direct association was found between the number of cardiovascular risk factors and the ApoB/ApoA1 ratio (p=0.001), regardless of age and income. CONCLUSION: The increased ApoB/ApoA1 ratio was associated with excess weight, body adiposity (total and central), and altered lipid profile in children. Children with a higher number of cardiovascular risk factors had higher ApoB/ApoA1 ratio, in both genders. PMID- 29438688 TI - Neomorphic ERalpha Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery. AB - In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis. PMID- 29438689 TI - Glycans Pave the Way for Immunotherapy in Triple-Negative Breast Cancer. AB - The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD L1 with a drug-conjugated antibody opens new avenues for treatment. PMID- 29438690 TI - c-Raf in KRas Mutant Cancers: A Moving Target. AB - Therapies for KRas cancers remain a major clinical need. In the current issue of Cancer Cell, Sanclemente and coworkers in Mariano Barbacid's group validate c-Raf as a prime target for these cancers. c-Raf ablation caused regression of advanced KRasG12V/Trp53 tumors, without obvious systemic toxicity and without affecting MAPK signaling. PMID- 29438691 TI - HIPPO Stampede in Nerve Sheath Tumors. AB - Current therapies for malignant peripheral nerve sheath tumors (MPNSTs) are ineffective. The study by Wu et al. in this issue of Cancer Cell provides evidence that the HIPPO pathway is overactive in human MPNSTs and that combined modulation of LATS1/2-YAP/TAZ and PDGFR signaling in Schwann cells reduces MPNST growth. PMID- 29438692 TI - An Epigenetic Switch: From Senescent Melanocytes to Malignant Melanoma (and Back). AB - Oncogene-induced senescence is an important barrier during melanomagenesis. In this issue of Cancer Cell, Yu et al. show how elevated expression of structurally unrelated H3K9 demethylases disables senescence and constitutes a liability that can be exploited to restore senescence in melanoma by pharmacological inhibition of these epigenetic regulators. PMID- 29438693 TI - Cellular Pliancy and the Multistep Process of Tumorigenesis. AB - Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis. PMID- 29438694 TI - Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations. AB - Estrogen receptor alpha (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER+) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic targets. PMID- 29438695 TI - Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD L1. AB - Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring beta-1,3-N acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces a potent cell-killing effect as well as a bystander-killing effect on adjacent cancer cells lacking PD-L1 expression without any detectable toxicity. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy. PMID- 29438697 TI - Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors. AB - Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition in vitro and in vivo, which reverses aberrant gene expression induced by Ezh2 inactivation. PMID- 29438698 TI - Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors. PMID- 29438699 TI - DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk. AB - Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence associated hypermethylation mainly involves metabolic regulators and appears early in proliferating "near-senescent" cells, which can be immortalized but are refractory to transformation. Importantly, a subset of transformation-associated hypermethylated developmental genes exhibits highest methylation gains at all age associated cancer risk states across tissue types. These epigenetic changes favoring cell self-renewal and survival, arising during tissue aging, are fundamentally important for stratifying cancer risk and concepts for cancer prevention. PMID- 29438696 TI - The Integrated Genomic Landscape of Thymic Epithelial Tumors. AB - Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy. PMID- 29438701 TI - Chronic ethanol consumption increases vascular oxidative stress and the mortality induced by sub-lethal sepsis: Potential role of iNOS. AB - We hypothesized that long-term ethanol consumption would increase the mortality and aggravate the deleterious effects of sub-lethal cecal ligation and puncture (SL-CLP) in the vasculature by inducing the expression of inducible nitric oxide (NO) synthase (iNOS). Male C57BL/6J wild-type (WT) or iNOS-deficient mice (iNOS-/ ) were treated with ethanol (20% v/v) for 12 weeks and then subjected to SL-CLP. Mice were killed 24 h post-operatively or followed six days for survival. Septic ethanol-treated mice showed a higher mortality than septic WT mice. However, septic iNOS-deficient mice treated with ethanol showed a decreased mortality rate when compared to ethanol-treated WT mice. Ethanol and SL-CLP augmented superoxide anion (O2-) generation in the mesenteric arterial bed (MAB) of both WT and iNOS deficient mice. Treatment with ethanol and SL-CLP enhanced lipoperoxidation in the MAB of WT, but not iNOS-deficient mice. SL-CLP enhanced nitrate/nitrite (NOx) concentrations in the MAB of WT, but not iNOS-deficient mice. Both, ethanol and SL-CLP increased TNF-alpha and IL-6 levels in the MAB. Treatment with ethanol as well as SL-CLP up-regulated the expression of iNOS in the MAB of WT mice. The major finding of our study is that chronic ethanol consumption increases the mortality induced by SL-CLP and that iNOS plays a role in such response. Although ethanol led to vascular alterations, it did not aggravate the vascular injury induced by SL-CLP. Finally, iNOS mediated the increase in oxidative stress and pro-inflammatory cytokines induced by SL-CLP in the vasculature. PMID- 29438700 TI - Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma. AB - Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. We show here that structurally distinct H3K9-active demethylases-the lysine-specific demethylase-1 (LSD1) and several Jumonji C domain-containing moieties (such as JMJD2C)-disable senescence and permit Ras/Braf-evoked transformation. In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis. A large subset of established melanoma cell lines and primary human melanoma samples presented with a collective upregulation of related and unrelated H3K9 demethylase activities, whose targeted inhibition restored senescence, even in Braf inhibitor-resistant melanomas, evoked secondary immune effects and controlled tumor growth in vivo. PMID- 29438702 TI - The cytogenetic effects of silibinin alone and in combination with methotrexate in mouse bone marrow. AB - The use of herbal drugs for disease treatment has increased worldwide. Flavonolignan silibinin, the major biologically active component of milk thistle (Silybum marianum), has various biological effects. This study is designed to evaluate the cytogenetic effects of flavonolignan silibinin in mouse bone marrow cells alone and in combination with methotrexate. In this study, the cytogenetic effects of flavonolignan silibinin were observed in mouse bone marrow cells after five days of treatment with a single intraperitoneal (IP) dose of either 50, 100 or 150 mg/kg body weight of silibinin hemisuccinate (SHS), alone or in combination with a single dose of 20 mg/kg methotrexate (MTX). The end-points were chromosomal aberrations (CAs) and a mitotic index (MI) study 24 h after the last dose. SHS (100 mg/kg or 150 mg/kg) could significantly reduce the MI (P < 0.05) in a dose-dependent manner. CAs significantly increased when SHS was administered at 150 mg/kg. Moreover, the MI significantly increased when SHS was administered prior to MTX at 50 mg/kg or 100 mg/kg. However, the MI was further reduced at a dose of 150 mg/kg. Additionally, SHS could significantly reduce the CAs that were induced by MTX. As a conclusion, Silibinin has a weak clastogenic effect, and in combination with MTX, it can enhance MTX's inhibitory effect on the MI and reduce CAs in bone marrow cells. This finding may direct attention to the beneficial effects of using SHS in chemotherapeutic approaches. PMID- 29438703 TI - Etizolam attenuates the reduction in cutaneous temperature induced in mice by exposure to synthetic predator odor. AB - Anxiety- and stress-related disorders can be debilitating psychiatric conditions in humans. To prevent or ameliorate these conditions, reliable animal models are needed to evaluate the effects of anxiolytic drugs. Previously, we found that a mixture of three pyrazine analogues (P-mix) that were present at high levels in wolf urine induced fear-related responses in mice, rats and deer. A change in cutaneous temperature was shown to be induced by acute stress simultaneously with changes in heart rate, arterial pressure and freezing behavior, raising the possibility that cutaneous temperature could be used as an index of stress. In the present study, using infrared thermography, we showed that exposure of mice to P-mix induced a decrease in cutaneous temperature. We then examined the dose dependent effects of an anxiolytic drug, etizolam (0-20 mg/kg), on the temperature decrease. Pre-administration of etizolam (5 mg/kg or higher) inhibited the P-mix-induced decrease in cutaneous temperature. Exposure to P-mix induced Fos-immunoreactivity, a marker of neuronal excitation, at the mouse amygdala and hypothalamus, and etizolam (5 mg/kg) attenuated that immunoreactivity. The present results suggested that the measurement of cutaneous P-mix-induced temperature changes in mice could be used as an animal model for evaluating the effects of anxiolytic drugs. PMID- 29438704 TI - Nicorandil inhibits mechanical allodynia induced by paclitaxel by activating opioidergic and serotonergic mechanisms. AB - Recently, we demonstrated that nicorandil exhibits activities in models of inflammatory and nociceptive pain. In the present study, we extended this investigation by evaluating the effects of nicorandil in models of neuropathic pain induced by paclitaxel or nerve injury in mice. Four intraperitoneal (i.p.) injections of paclitaxel (2 mg/kg.day, cumulative dose 8 mg/kg) or chronic constriction injury (CCI) of the sciatic nerve induced a long lasting mechanical allodynia. Per os (p.o.) administration of two doses of nicorandil (50, 100 and 150 mg/kg) on the 14th day after the first paclitaxel injection attenuated the mechanical allodynia. Equimolar doses of nicotinamide (86.7 mg/kg, p.o.) or nicotinic acid (87.7 mg/kg, p.o.) were devoid of effect. Mechanical allodynia induced by CCI was also attenuated by p.o. administration of two doses of nicorandil (150 mg/kg) on the 14th day after nerve injury. Nicorandil (50, 100 and 150 mg/kg, p.o.) did not affect motor activity. The antinociceptive activity of nicorandil in the model of mechanical allodynia induced by paclitaxel was partially attenuated by naltrexone (5 and 10 mg/kg, i.p.) or cyproheptadine (5 and 10 mg/kg, i.p.), but not by glibenclamide (20 and 40 mg/kg, p.o.). Concluding, nicorandil exhibits activity in experimental models of neuropathic pain when mechanical allodynia is fully established. Activation of opioidergic and serotonergic pathways mediates the antinociceptive activity of nicorandil. It is unlikely that this activity requires biotransformation to nicotinamide or nicotinic acid. Nicorandil should be further evaluated aiming to identify a new alternative in the pharmacological management of neuropathic pain. PMID- 29438705 TI - Protective effect of hydroxysafflor yellow A alone or in combination with acetylglutamine on cerebral ischemia reperfusion injury in rat: A PET study using 18F-fuorodeoxyglucose. AB - Hydroxysafflor yellow A (HSYA) and acetylglutamine (NAG) are extensively applied in the treatment of brain injury. In this study, we investigated the neuroprotective effect and underlying mechanism of HSYA alone or together with NAG using a rat model of cerebral ischemia reperfusion injury. Male Sprague Dawley (SD) rats (n = 5) were intraperitoneally injected with 5, 10, 20 mg/kg HSYA, 300 mg/kg NAG and 10 mg/kg HSYA+300 mg/kg NAG after the onset of reperfusion and once each day for the following 7 days. After assessing the neurological deficit and infarct volume, we used 18F-FDG-PET to evaluate the regional cerebral metabolic rate of glucose consumption, immunohistochemical analysis to detect the expression of GFAP, NGF, Bcl-2, Bax, caspase-3 and ICAM-1 in brain tissue at day 7 after cerebral I/R injury. Meanwhile, the mRNA levels of ICAM-1, IL-1beta, TNF-alpha and NF-kappaB were determined by qRT-PCR, the protein levels of Bcl-2, Bax and caspase-3 were detected by western blot. The results indicated that HSYA significantly up-regulated glucose metabolism, improved neurological function, decreased cerebral infarction volume. HSYA alone or together with NAG attenuated apoptosis and inflammation by up-regulating GFAP, NGF and Bcl-2 expression, suppressing the expression of Bax, caspase-3 and ICAM 1, IL-1beta, TNF-alpha and NF-kappaB. These finding suggested that HSYA exerted neuroprotection against cerebral I/R injury by modulating inflammation and apoptosis process, and HSYA in combination with NAG possessed a synergetic effect on protecting cerebral I/R brain injury. PMID- 29438707 TI - Reply by Authors. PMID- 29438706 TI - A novel role of the antitumor agent tricyclodecan-9-yl-xanthogenate as an open channel blocker of KCNQ1/KCNE1. AB - Tricyclodecan-9-yl-xanthogenate (D609) is widely known for its antitumor and antiviral properties via the inhibition of phosphatidylcholine-specific phospholipase C and sphingomyelin synthase. Previously, we found that chronic application of D609 suppressed the K+ channel, KCNQ1/KCNE1, more drastically than expected from its actions on the enzymes, suggesting a direct action of D609 on the channel. Here, we aimed to test this possibility by studying the affinity, specificity, and mechanisms of D609 on KCNQ1/KCNE1. The effect of D609 on KCNQ1/KCNE1 was studied using an in vitro expression system and in native cells, using electrophysiological techniques. We found that D609 rapidly and reversibly inhibited KCNQ1/KCNE1 channels expressed in human embryonic kidney 293 T (HEK293T) cells, in a concentration-dependent manner with a high affinity. D609 neither suppressed endogenous K+ currents in HEK293T cells, nor inhibited the sustained and transient K+ currents of mouse neostriatal neurons, but blocked a KCNQ1/KCNE1-like current in neostriatal neurons. D609 potently blocked IKs, the cardiac KCNQ1/KCNE1 channel, in guinea pig cardiac muscle cells. The action of D609 on KCNQ1/KCNE1 depended on the usage of the channel, suggesting that D609 binds to the channel in the open state. We identified D609 as a potent and specific open channel blocker of KCNQ1/KCNE1. Because KCNQ1/KCNE1 is highly expressed in the heart, the inner ear and the pancreas, D609, when used as an antitumor or antiviral drug, may affect the function of a number of organs in vivo even when used at low concentrations. PMID- 29438708 TI - Editorial Comment. PMID- 29438710 TI - Analysis of T cell receptor repertoire in monozygotic twins concordant and discordant for chronic hepatitis B infection. AB - Due to their identical inheritance and shared surroundings, identical twins have been the recommended group for studying the susceptibility and prognosis of diseases. Here, CD8+ T cell receptor beta (TCRbeta) chains were analyzed by high throughput sequencing in three pairs of healthy identical twins and chronic hepatitis B patients. The data showed a high level of similarity in the TCR repertoire of each pair in terms of average TCR Vbeta segment expression and frequency of the complementary determining region 3 (CDR3) pattern and skewed or oligoclonal clonotypes. Notably, the level of similarity in TCR Vbeta expression between the twins appeared to be independent of the consistency or inconsistency of chronic HBV infection, although the detailed CDR3 pattern and frequency were related to disease prognosis. There were more immunodominant clonotypes in patients with HBV antigen seroconversion, which showed an increased abundance. These immunodominant clonotypes may be used as favorable prognostic biomarkers and potential targets for immunotherapy. Thus, delineating the CD8+ T cell repertoire of identical twins with concordant chronic viral infections provides a promising means to screen protective TCR genes for immunotherapy. PMID- 29438711 TI - Detection of substrate binding of a collagen-specific molecular chaperone HSP47 in solution using fluorescence correlation spectroscopy. AB - Heat shock protein 47 kDa (HSP47), an ER-resident and collagen-specific molecular chaperone, recognizes collagenous hydrophobic amino acid sequences (Gly-Pro-Hyp) and assists in secretion of correctly folded collagen. Elevated collagen production is correlated with HSP47 expression in various diseases, including fibrosis and keloid. HSP47 knockdown ameliorates liver fibrosis by inhibiting collagen secretion, and inhibition of the interaction of HSP47 with procollagen also prevents collagen secretion. Therefore, a high-throughput system for screening of drugs capable of inhibiting the interaction between HSP47 and collagen would aid the development of novel therapies for fibrotic diseases. In this study, we established a straightforward method for rapidly and quantitatively measuring the interaction between HSP47 and collagen in solution using fluorescence correlation spectroscopy (FCS). The diffusion rate of HSP47 labeled with Alexa Fluor 488 (HSP47-AF), a green fluorescent dye, decreased upon addition of type I or III collagen, whereas that of dye-labeled protein disulfide isomerase (PDI) or bovine serum albumin (BSA) did not, indicating that specific binding of HSP47 to collagen could be detected using FCS. Using this method, we calculated the dissociation constant of the interaction between HSP47 and collagen. The binding ratio between HSP47-AF and collagen did not change in the presence of sodium chloride, confirming that the interaction was hydrophobic in nature. In addition, we observed dissociation of collagen from HSP47 at low pH and re-association after recovery to neutral pH. These observations indicate that this system is appropriate for detecting the interaction between HSP47 and collagen, and could be applied to high-throughput screening for drugs capable of suppressing and/or curing fibrosis. PMID- 29438713 TI - Synergistic tumoricidal effect of combined hPD-L1 vaccine and HER2 gene vaccine. AB - Immunotherapy is gathering momentum as a kind of important therapy for cancer patients. However, monotherapies have limited efficacy in improving outcomes and benefit only in a small subset of patients. Combination therapies targeting multiple pathways often can augment an immune response to improve survival further. Here, the tumoricidal effects of the dual hPD-L1(human programmed cell death ligand 1) vaccination/HER2(human epidermal growth factor receptor 2) gene vaccination immunotherapy against the established HER2-expressed cancers were observed. Animals treated with combination therapy using hPD-L1 vaccine and HER2 gene vaccine had significantly improved survival in a mammary carcinoma model. We observed an increase in tumor growth inhibition following treatment. The percentage of the tumor-free mice (%) was much higher in the combined PD-L1/HER2 group. Furthermore, under the tumor-burden condition, hPD-L1 vaccine enhanced humoral immunity of HER2 gene vaccine. And the combination treatment increased the IFN-gamma-producing effector T cells. Additionally, splenocytes from the combined PD-L1/HER2 group immunized mice possessed higher CTL activity. Notably, vaccination with combination therapy induced a significant decrease in the percentage of CD4+CD25+ Treg cells. Collectively, these data demonstrate that PD L1/HER2 gene vaccine combination therapy synergistically generates marked tumoricidal effects against established HER2-expressing cancers. PMID- 29438712 TI - Lipid metabolism and lipophagy in cancer. AB - The tumor microenvironment can be hypoxic, acidic, and deficient in nutrients, thus causing the metabolism of tumor cells as well as the neighboring stromal cells to be remodelled to facilitate tumor survival, proliferation, and metastasis. Abnormal tumor lipid metabolism is a fairly new field, which has received attention in the past few years. Cross-talk between tumor cells and tumor-associated stromal cells modulates the high metabolic needs of the tumor. Fatty acid turnover is high in tumor cells to meet the energy as well as synthetic requirements of the growing tumor. Lipolysis of lipids stored in lipid droplets was earlier considered to be solely carried out by cytosolic lipases. However recent studies demonstrate that lipophagy (autophagic degradation of lipids by acidic lipases) serves as an alternate pathway for the degradation of lipid droplets. Involvement of lipophagy in lipid turnover makes it a crucial player in tumorigenesis and metastasis. In this review we discuss the metabolic reprogramming of tumor cells with special focus on lipid metabolism. We also address the lipid turnover machinery in the tumor cell, especially the lipophagic pathway. Finally, we integrate the current understanding of lipophagy with tumor lipid metabolism. PMID- 29438714 TI - Quaternary structure influences the peroxidase activity of peroxiredoxin 3. AB - Peroxiredoxins are abundant peroxidase enzymes that are key regulators of the cellular redox environment. A major subgroup of these proteins, the typical 2-Cys peroxiredoxins, can switch between dimers and decameric or dodecameric rings, during the catalytic cycle. The necessity of this change in quaternary structure for function as a peroxidase is not fully understood. In order to explore this, human peroxiredoxin 3 (Prx3) protein was engineered to form both obligate dimers (S75E Prx3) and stabilised dodecameric rings (S78C Prx3), uncoupling structural transformations from the catalytic cycle. The obligate dimer, S75E Prx3, retained catalytic activity towards hydrogen peroxide, albeit significantly lower than the wildtype and S78C proteins, suggesting an evolutionary advantage of having higher order self-assemblies. PMID- 29438715 TI - Perceived child eating behaviours and maternal migrant background. AB - The Child Eating Behaviour Questionnaire (CEBQ) is a well-established instrument in the study of obesity-related eating behaviours among children. However, research using the CEBQ in multicultural samples is limited. This study aims to identify and examine differences in child eating behaviours as reported by Swedish-born and non-Swedish-born mothers living in Sweden. Mothers (n = 1310, 74 countries of origin, mean age 36.5 years, 63.6% with higher education, 29.2% with overweight or obesity) of children aged 3-8 years (mean age 4.8 years, 18.1% with overweight or obesity) completed the CEBQ. Responses were analysed using CEBQ subscales Food Responsiveness, Emotional Overeating, Enjoyment of Food, and Desire to Drink, clustering into Food Approach, and subscales Satiety Responsiveness, Slowness in Eating, Emotional Undereating, and Food Fussiness, clustering into Food Avoidance. Data were compared across seven regional groups, divided by maternal place of birth: (1) Sweden (n = 941), (2) Nordic and Western Europe (n = 68), (3) Eastern and Southern Europe (n = 97), (4) the Middle East and North Africa (n = 110), (5) East, South and Southeast Asia (n = 52), (6) Sub Saharan Africa (n = 16), and (7) Central and South America (n = 26). Crude, partly and fully adjusted linear regression models controlled for child's age, gender and weight status, and mother's education, weight status and concern about child weight. The moderation effect of maternal concern about child weight was examined through interaction analyses. Results showed that while Food Approach and Food Avoidance behaviours were associated with maternal migrant background, associations for Food Fussiness were limited. Notably, mothers born in the Middle East and North Africa reported higher frequencies of both Food Approach (except for Enjoyment of Food) and Food Avoidance. The study highlights the importance of examining how regionally-specific maternal migrant background affects mothers' perceptions of child eating behaviours. PMID- 29438716 TI - Cholinergic tone in ventral tegmental area: Functional organization and behavioral implications. AB - The ventral tegmental area (VTA), a pivotal brain region of the mesocorticolimbic dopaminergic system, is substantially innervated and modulated by cholinergic projections from the pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus. In this review, we focus mainly on the current findings on VTA cholinergic compositions and functions, including VTA cholinergic innervations and synaptic connectivity, acetylcholine receptor expression and functional characteristics, cholinergic modulation of neuronal activity and dopamine efflux, cholinergic modulation of VTA-mediated behaviors such as reward and addiction, stress and depression, locomotion, etc. Taken together, these findings indicate that cholinergic transmission to the VTA plays an important role in modulation of the VTA circuit, which is implicated in regulation of multiple behaviors. PMID- 29438717 TI - The association of HLA-B27 and Klebsiella pneumoniae in ankylosing spondylitis: A systematic review. AB - Ankylosing spondylitis (AS) is a chronic inflammatory arthritis of unknown origin. Its autoimmune origin has been suggested but never proven. Several reports have implicated K. pneumoniae as a triggering or perpetuating factor in AS; and the HLA-B27 antigen has also been found in association with AS. But there is no satisfactory explanation of why the presence of HLA-B27 predisposes to AS and the precise role played by K. pneumoniae in the disease has not yet been clarified. However, various studies have shown that the results of molecular, immunological, and microbiological studies could establish the link between K. pneumoniae infections and HLA-B27 in the aetiopathogenesis of AS. In this review, we have examined the evidence linking the interaction between K. pneumoniae infections and HLA-B27 in AS, and tried to exploit the possible mechanisms by which K. pneumoniae infections might induce pathologic processes to develop novel diagnostic criteria. Finally, we have also summarized some dietary regimens that could be helpful in the therapeutic management of AS patients. PMID- 29438718 TI - Safety, potential biotechnological and probiotic properties of bacteriocinogenic Enterococcus lactis strains isolated from raw shrimps. AB - The aims of this study are to isolate new bacteriocinogenic lactic acid bacterial strains from white (Penaeus vannamei) and pink (Palaemon serratus) raw shrimps and evaluate their technological and probiotic potentialities. Seven strains were selected, among fifty active isolates, as producing interesting antimicrobial activity. Identified as Enterococcus lactis, these isolates were able to produce enterocins A, B and/or P. The safety aspect, assessed by microbiological and molecular tests, demonstrated that the strains were susceptible to relevant antibiotics such as vancomycin, negative for haemolysin and gelatinase activities, and did not harbour virulence and antibiotic resistance genes. The assessment of potential probiotic and technological properties showed a low or no lipolytic activity, moderate milk-acidifying ability, high reducing power, proteolytic activity and tolerance to bile (P < 0.05) and good autoaggregation and coaggregation capacities. Two strains designated as CQ and C43 exhibiting high enzymatic activities and bile salt hydrolase activity were found to display high survival under simulated in vitro oral cavity and gastrointestinal tract conditions caused by presence of lysozyme, pepsin, pancreatin, bile salts and acidic pH. This study highlights safe Enterococcus lactis strains with great technological and probiotic potentials for future application as new starter, adjunct, protective or probiotic cultures in food industry. PMID- 29438719 TI - A multi-step approach for testing non-toxic amphiphilic antifouling coatings against marine microfouling at different levels of biological complexity. AB - Marine biofouling on artificial surfaces such as ship hulls or fish farming nets causes enormous economic damage. The time for the developmental process of antifouling coatings can be shortened by reliable laboratory assays. For designing such test systems, it is important that toxic effects can be excluded, that multiple parameters can be addressed simultaneously and that mechanistic aspects can be included. In this study, a multi-step approach for testing antifouling coatings was established employing photoautotrophic biofilm formation of marine microorganisms in micro- and mesoscoms. Degree and pattern of biofilm formation was determined by quantification of chlorophyll fluorescence. For the microcosms, co-cultures of diatoms and a heterotrophic bacterium were exposed to fouling-release coatings. For the mesocosms, a novel device was developed that permits parallel quantification of a multitude of coatings under defined conditions with varying degrees of shear stress. Additionally, the antifouling coatings were tested for leaching of potential compounds and finally tested in sea trials. This multistep-approach revealed that the individual steps led to consistent results regarding antifouling activity of the coatings. Furthermore, the novel mesocosm system can be employed for advanced antifouling analysis including metagenomic approaches for determination of microbial diversity attaching to different coatings under changing shear forces. PMID- 29438720 TI - Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia: A genome wide epigenetic analysis. AB - Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line K562, on active (histone H3 lysine 9 acetylation, H3K9ac and histone H3 lysine 4 tri-methylation, H3K4me3) and repressive (histone H3 lysine 9 tri methylation, H3K9me3) histone marks by Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). Both selenite and MSA had major effects on histone marks but the effects of MSA were more pronounced. Gene ontology analysis revealed that selenite affected genes involved in response to oxygen and hypoxia, whereas MSA affected distinct gene sets associated with cell adhesion and glucocorticoid receptors, also apparent by global gene expression analysis using RNA sequencing. The correlation to adhesion was functionally confirmed by a significantly weakened ability of MSA treated cells to attach to fibronectin and linked to decreased expression of integrin beta 1. A striking loss of cellular adhesion was also confirmed in primary patient AML cells. Recent strategies to enhance the cytotoxicity of chemotherapeutic drugs by disrupting the interaction between leukemic and stromal cells in the bone marrow are of increasing interest; and organic selenium compounds like MSA might be promising candidates. In conclusion, these results provide new insight on the mechanism of action of selenium compounds, and will be of value for the understanding, usage, and development of new selenium compounds as anticancer agents. PMID- 29438721 TI - Changes in left ventricular systolic and diastolic function on serial echocardiography after out-of-hospital cardiac arrest. AB - AIM: Reversible myocardial dysfunction is common after out-of-hospital cardiac arrest (OHCA). The aim of this study was to determine if changes on serial transthoracic echocardiography (TTE) can predict long-term mortality in OHCA subjects. METHODS: This is a single-center historical cohort study of OHCA subjects undergoing targeted temperature management who received >1 TTE during hospitalization. Two-dimensional and Doppler parameters of systolic and diastolic function were compared between paired TTE. Univariate analysis was used to determine associations between TTE parameters and all-cause mortality. RESULTS: Fifty-nine patients were included; mean age was 59.4 +/- 11.2 years (75% male). Initial rhythm was shockable in 90%. Initial TTE was done a median of 10.4 h after admission and repeat TTE was done 5.7 +/- 4.1 days later. Between TTE studies, there were significant increases in left ventricular ejection fraction (LVEF, from 32% to 43%), cardiac output, stroke volume, and other Doppler-derived hemodynamic parameters, while systemic vascular resistance decreased (all p < 0.001). Systolic function and hemodynamic parameters on initial TTE were not associated with follow-up mortality. Patients who died during follow-up (n = 16, 27%) had smaller increases in LVEF and cardiac output-derived hemodynamic parameters than long-term survivors (p < 0.05). CONCLUSIONS: Significant changes in systolic function and hemodynamic parameters occur on serial Doppler TTE after OHCA, consistent with reversible post-arrest myocardial dysfunction. The magnitude of those changes is greater in long-term survivors, emphasizing that the degree of recovery from post-arrest myocardial dysfunction may be more important than its initial severity. PMID- 29438722 TI - Vitamin D3 signaling and breast cancer: Insights from transgenic mouse models. AB - The biologically active form of vitamin D3 (1,25(OH)2D) regulates epithelial cell differentiation, proliferation, and apoptosis, lending weight to clinical evidence linking vitamin D3 insufficiency to breast cancer incidence and mortality. Local dysregulation of vitamin D3 metabolism has been identified in patients with breast cancer, implying that disruption of 1,25(OH)2D signaling may contribute to breast cancer development in an autocrine or paracrine manner. Mouse mammary glands express the critical enzymes responsible for 1,25(OH)2D synthesis (Cyp2r1 and Cyp27b1), degradation (Cyp24a1), as well as the vitamin D3 receptor (Vdr), and genetically modified mouse models have revealed a great deal about the role of vitamin D3 in cancer initiation and progression. Ablation of Vdr or Cyp27b1 in murine models of mammary cancer reduces the anti-tumor effects of vitamin D3, while elevation of Cyp24a1 levels increases degradation of 1,25(OH)2D, leading to diminished anti-tumor effects. This review discusses the recent transgenic mouse models of vitamin D3 metabolism and the Vdr signaling network, and how these contribute to mammary gland development, and cancer tumorigenesis and progression. Collectively, these mouse models have helped clarify mechanisms of action of vitamin D3 signaling and suggest that activation or restoration of the vitamin D3 regulated pathway is a potential approach for human breast cancer prevention. PMID- 29438723 TI - Discovery and development of ODM-204: A Novel nonsteroidal compound for the treatment of castration-resistant prostate cancer by blocking the androgen receptor and inhibiting CYP17A1. AB - We report the discovery of a novel nonsteroidal dual-action compound, ODM-204, that holds promise for treating patients with castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer characterised by high androgen receptor (AR) expression and persistent activation of the AR signaling axis by residual tissue androgens. For ODM-204, has a dual mechanism of action. The compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting CYP17A1, the prerequisite enzyme for the formation of dihydrotestosterone (DHT) and testosterone (T), and by blocking AR with high affinity and specificity. In our study, ODM-204 inhibited the proliferation of androgen-dependent VCaP and LNCaP cells in vitro and reduced significantly tumour growth in a murine VCaP xenograft model in vivo. Intriguingly, after a single oral dose of 10-30 mg/kg, ODM-204 dose-dependently inhibited adrenal and testicular steroid production in sexually mature male cynomolgus monkeys. Similar results were obtained in human chorionic gonadotropin-treated male rats. In rats, leuprolide acetate-mediated (LHRH agonist) suppression of the circulating testosterone levels and decrease in weights of androgen-sensitive organs was significantly and dose-dependently potentiated by the co-administration of ODM 204. ODM-204 was well tolerated in both rodents and primates. Based on our data, ODM-204 could provide an effective therapeutic option for men with CRPC. PMID- 29438724 TI - Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling. AB - The aim of this study is to develop nanosuspension of carvedilol (CRV) by wet media milling. Concentration of polymeric stabilizer (hydroxypropyl cellulose-HPC SL), milling speed and size of milling beads were identified as critical formulation and process parameters and their effect on CRV particle size after 60 min of milling was assessed using a Box-Behnken experimental design. Optimized nanosuspension was solidified using spray drying and freeze drying and subjected to solid state characterization. Low stabilizer concentration (10%), low milling speed (300 rpm) with small milling beads (0.1 mm) were found as optimal milling conditions. Crystal lattice simulation identified potential slip plane within CRV crystals, where fractures are the most likely to occur. Calculated mechanical properties of CRV crystal indicates that low energy stress is sufficient to initiate fracture, if applied in the correct direction, explaining the advantage of using smaller milling beads. Only spray dried nanosuspension redispersed to original nanoparticles, while particle agglomeration during freeze drying prevented sample redispersion. Wet milling and spray drying did not induce polymorphic transition of CRV, while there is indication of polymorphic transition during freeze drying, making spray drying as the preferred solidification method. PMID- 29438725 TI - Photostabilization strategies of photosensitive drugs. AB - PURPOSE: Several active compounds are sensitive to light, especially to the ultraviolet radiation (UV-R) leading to their degradation or modification, with lost or decrease of their biological activity. The aim of this study was to perform a systematic review regarding photostabilization strategies used on health products and perform a critical appraisal of their effectiveness. RESULTS: The bibliographic search identified 2261 results and merely 40 studies met the selection criteria. Of these, 85% referred to encapsulation strategies, 10% to antioxidants and 5% to the use of solar filters. Cyclodextrins (CD's) were the most used encapsulation systems (32.5%) followed by liposomes and lipid nanoparticles (each 17.5%), microparticles (15%) and polymeric nanoparticles (10%). The most effective were found to be liposomes and lipid nanoparticles. However, the different methodological conditions used limit the true relevance of this finding. CONCLUSIONS: A gold standard strategy suitable for all compounds cannot be proposed. Instead, case-by-case evaluation, supported on the photodegradation mechanism is recommended. Systematic studies that compare different photostabilization strategies undertaken with the same irradiation conditions are also needed. PMID- 29438726 TI - Floating liquid crystalline molecularly imprinted polymer coated carbon nanotubes for levofloxacin delivery. AB - Liquid crystalline molecularly imprinted polymers (LC-MIPs) were low cross linking MIPs (5-20 mol%) by introducing a LC monomer into the MIP polymerization system to keep the shape of the imprinted cavities due to additional interactions between the mesogenic groups. The multiwalled carbon nanotubes (MWCNTs) coated LC MIP (MWCNT@LC-MIP) was the first fabricated as a novel floating interaction controlled DDS. The synthesis was achieved by adding 9-vinylanthracene to obtain the high-density vinyl group functionalized MWCNTs firstly, and then polymerization of LC MIPs was performed on the surface of MWCNTs using a mixture of methacrylic acid, ethylene glycol dimethacrylate, and 4-methyl phenyl dicyclohexyl ethylene (LC monomer) with levofloxacin (LVF) as model template drug. Both template/functional monomer ratio and levels of crosslinker were optimized to obtain the best imprinting factor. Characterizations of polymer were investigated by the transmission electron microscope, nitrogen adsorption, thermogravimetric analysis, Fourier transform infrared spectra and floating behavior studies. The imprinting effect was confirmed by the adsorption isotherms, adsorption kinetics and effect of selectivity. In vitro release studies were examined by the LVF-loaded MWCNT@LC-MIP and the control samples, MWCNT@LC-NIP, MWCNT@MIP, MWCNT@NIP and the bare MWCNT using acetonitrile as the dissolute medium. The release profiles showed an obvious zero-order release of LVF from MWCNT@LC-MIP, which exhibited 3.8 MUg/h of the release rate with duration of about 20 h. In vivo pharmacokinetic study displayed the relative bioavailability of the gastro-floating MWCNT@LC-MIP was 578.9%, whereas only 58.0% of MWCNT@MIP and 11.7% of the bared MWCNT. As a conclusion, MWCNT@LC-MIP showed potentials for oral administration by the innovative combination of floating and controlled release properties. PMID- 29438727 TI - Is cohorting the only solution to control carbapenemase-producing Enterobacteriaceae outbreaks? A single-centre experience. AB - BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) are a major health issue. Cohorting may help to control spread of CPEs in hospitals, but is expensive and hard to implement. AIM: To identify ward variables associated with CPE in-hospital transmission in a hospital where cohorting has never been implemented. METHODS: Cohort prospective study, comparing 14-consecutive-day periods regarding in-hospital transmission. Each period met the two following conditions: (i) CPE carriers/infected admitted for >=48 h; (ii) 80% of relative contact patients were screened at least twice. Periods (a) with no acquired CPE case among relative contact patients were compared to periods (b) during which one or more CPE case acquisition was identified. Variables potentially associated with CPE transmission were assessed: colonization pressure, caregiver:patient ratio, hand hygiene compliance, hydro-alcoholic product consumption, antibiotic consumption, and infection control team (ICT) involvement on the ward. FINDINGS: Sixty-eight periods of two consecutive weeks were included, 18 (26.5%) included at least one CPE case acquisition. By multivariate analysis, colonization pressure (odds ratio: 1.12; 95% confidence interval: 1.0-1.25; P = 0.042) and antibiotic consumption (2.41; 1.02-5.66; P = 0.044) were associated with CPE in hospital transmission. Caregiver:patient ratio potentiated both these variables, suggesting a role for understaffing in CPE transmission. CONCLUSION: Understanding ward variables associated with CPE spread can help design suitable solutions. Colonization pressure and antibiotic consumption seems to be driving in-hospital transmission, along with caregiver:patient ratio. In presence of high colonization pressure, dedicated healthcare workers for managing CPE patients should be implemented. Co-ordination between ICT and antimicrobial stewardship team is also crucial to prevent CPE spread. PMID- 29438728 TI - Long-term early life adverse experience impairs responsiveness to exteroceptive stimuli in adult rats. AB - It has been shown that early life traumatic events strongly alter the physiology and behavior in adult rats. In the present study, the effect of postnatal stressor on the spontaneous behavior of adult male rats was evaluated. A method of positive habituation based on a detailed analysis of behavioral patterns and attention of animals to a stimulus object was used. Twenty-four dams and twenty four of their male progeny were used. Pups were divided into three groups (n = 8): controls (C); maternal social stressor (S); maternal social and physical stressors (SW). Animals (postnatal day 70-80) were individually placed in the open field arena in two habituation sessions with a 24-h delay between them (Test day 1 and Test day 2). Before the start of third session (Test day 3) a solid object was fixed in the center of the arena. Each test lasted 10 min. Our results showed the habituation effect in both stressed-groups. Although there were no significant differences in the number of investigations of the novel object among all tested groups, stress-exposed rats spent less time investigating the object. In conclusion, our findings indicate that long-term neonatal stress may impair an animal's ability to sustain attention to stimuli. PMID- 29438729 TI - Hyaluronan chemistries for three-dimensional matrix applications. AB - Hyaluronan is a ubiquitous constituent of mammalian extracellular matrices and, because of its excellent intrinsic biocompatibility and chemical modification versatility, has been widely employed in a multitude of biomedical applications. In this article, we will survey the approaches used to tailor hyaluronan to specific needs of tissue engineering, regenerative and reconstructive medicine and overall biomedical research. We will also describe recent examples of applications in these broader areas, such as 3D cell culture, bioprinting, organoid biofabrication, and precision medicine that are facilitated by the use of hyaluronan as a biomaterial. PMID- 29438730 TI - Human Vdelta3+ gammadelta T cells induce maturation and IgM secretion by B cells. AB - This study tested the hypothesis that the Vdelta3 subset of human gammadelta T cells, like their Vdelta2 counterparts, can influence differentiation, antibody secretion and cytokine production by B cells. Vdelta3 T cells constitute a minor subset of peripheral blood lymphocytes but are enriched in the liver and gut and are expanded in patients with cytomegalovirus activation and B cell chronic lymphocytic leukemia. They have been reported to include MHC class I and CD1d restricted cells. Like Vdelta2 T cells, they are capable of maturing dendritic cells into cytokine-producing antigen presenting cells, making them potential targets for dendritic cell-based immunotherapies. Since it is unknown if Vdelta3 T cells can also provide B cell help, we investigated if Vdelta3 T cells can promote B cell differentiation, antibody secretion and cytokine production in vitro. Vdelta3 T cells were sorted from healthy human blood and expanded using phytohemagglutinin and cultured with freshly isolated human B cells. We found that Vdelta3 T cells and B cells reciprocally induced expression of maturation markers CD40, CD86 and HLA-DR but not TH1, TH2 or TH17 cytokines. Furthermore, Vdelta3 T cells promoted the release of IgM, but not IgG, IgA or IgE by B cells. These data demonstrate, for the first time, a reciprocal activating relationship between Vdelta3 T cells and B cells, which could prove a useful target for cellular immunotherapy. PMID- 29438731 TI - Neuroprotective effect of the group III mGlu receptor agonist ACPT-I after ischemic stroke in rats with essential hypertension. AB - Our previous studies have shown that ACPT-I [(1S, 3R,4S)-1-aminocyclopentane 1,2,4-tricarboxylic acid], a blood-brain barrier permeable agonist of group III metabotropic glutamate (mGlu) receptors, was neuroprotective against middle cerebral artery occlusion/reperfusion (MCAO/R) in normotensive rats. Preclinical studies are typically performed on healthy animals, whereas stroke patients predominately exhibit comorbidities, such as hypertension; therefore, in the present study, we investigated the effect of ACPT-I in spontaneously hypertensive rats (SHR) after MCAO/R. We examined the potential neuroprotective action of ACPT I (30 mg/kg) when administered during occlusion or reperfusion via the assessment of not only the brain infarction volume but also motor (CatWalk gait analysis and open field test) and sensorimotor (vibrissae-evoked forelimb-placing test) functions following MCAO/R. We determined that ACPT-I not only reduced the cortico-striatal infarction but also improved several gait parameters (run speed, run and stand durations, swing speed and stride length) and mobility when administered 30 min after the start of the occlusion or 30 min after the start of reperfusion. Moreover, the sensorimotor function was improved in hypertensive rats treated with ACPT-I during occlusion. In conclusion, the current findings provide further evidence for the neuroprotective effects of ACPT-I against ischemic damage. These findings may have clinical implications because hypertension is an important risk factor for ischemic stroke. PMID- 29438732 TI - Charge, size distribution and hydrophobicity of viruses: Effect of propagation and purification methods. AB - Two virus propagation methods (in broth and on double agar overlay) and three purification procedures (PEG precipitation, centrifugal diafiltration and CsCl density gradient centrifugation) were comparatively evaluated using MS2 and P22 bacteriophages as model viruses. The prepared stocks were characterized in terms of electrophoretic mobility as a function of pH, particle size distribution, surface tension components and the overall hydrophobicity of the virus, as well as the percentage of infectious and total virus recovered. The obtained data were used to rank the purification methods according to six criteria of likely practical relevance. Regardless of the purification method applied, virus propagation in broth media resulted in higher purity virus stocks as the growth on double agar overlay introduced difficult-to-remove residual agar. CsCl density gradient centrifugation gave the highest quality bacteriophage suspensions, recovered infectious P22 at least as efficiently as the other two purification methods and selected for intact P22 virions over damaged ones. The impurities remaining in the virus suspension after PEG precipitation and centrifugal diafiltration broadened the size distribution and interfered with electrophoretic mobility measurements. The residual impurities had a major impact on the free energy of virus-virus interfacial interaction (the quantitative measure of virus hydrophobicity/hydrophilicity) leading to an incorrect determination of P22 bacteriophage as hydrophilic. The trends in measured physicochemical properties can be rationalized by considering impurity-coated virions as permeable soft particles. PMID- 29438733 TI - Pre-validation of an in vitro skin irritation test for medical devices using the reconstructed human tissue model EpiDermTM. AB - Assessment of dermal irritation is an essential component of the safety evaluation of medical devices. Reconstructed human epidermis (RhE) models have replaced rabbit skin irritation testing for neat chemicals and their mixtures (OECD Test Guideline 439). However, this guideline cannot be directly applied to the area of medical devices (MD) since their non-toxicity assessment is largely based on the testing of MD extracts that may have very low irritation potential. Therefore, the RhE-methods previously validated with neat chemicals needed to be modified to reflect the needs for detection of low levels of potential irritants. A protocol employing RhE EpiDerm was optimized in 2013 using known irritants and spiked polymers (Casas et al., 2013, TIV). In 2014 and 2015 MatTek In Vitro Life Science Laboratories (IVLSL) and RIVM assessed the transferability of the assay. After the successful transfer and standardization of the protocol, 17 laboratories were trained in the use of the protocol in the preparation for the validation. Laboratories produced data with 98% agreement of predictions for the selected references and controls. We conclude that a modified RhE skin irritation test has the potential to address the skin irritation potential of the medical devices. Standardization and focus on the technical issues is essential for accurate prediction. PMID- 29438734 TI - Impaired PARP activity in response to the beta-adrenergic receptor agonist isoproterenol. AB - Psychological stress has been associated with DNA damage, thus increasing the risk of numerous diseases including cancer. Here, we investigate the effect of acute and chronic stress on poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage and DNA repair initiator. In order to mimic the chronic release of epinephrine, human peripheral blood mononuclear cells (PBMCs) were treated repeatedly with the sympathomimetic drug isoproterenol. We found significant induction of DNA strand breaks that remained unrepaired 24 h after ex vivo incubation. Isoproterenol-induced DNA strand breaks could be partially prevented by pre-treatment with the beta-adrenergic receptor antagonist propranolol. Furthermore, the level of PARP-1 protein and PARP activity decreased and the levels of the PARP substrate nicotinamide adenine dinucleotide (NAD+) and of adenosine triphosphate (ATP), necessary to replenish NAD+ pools, were lowered by isoproterenol treatment. In conclusion our data provide novel insights into the mechanisms of isoproterenol-induced genotoxicity linking beta-adrenergic stimulation and PARP-1. PMID- 29438735 TI - High-intensity stretch-shortening contraction training modifies responsivity of skeletal muscle in old male rats. AB - Utilization of high-intensity resistance training to counter age-related sarcopenia is currently debated because of the potential for maladaptation when training design is inappropriate. Training design is problematic because the influence of various loading variables (e.g. contraction mode, repetition number, and training frequency) is still not well characterized at old age. To address this in a precisely controlled manner, we developed a rodent model of high intensity training consisting of maximally-activated stretch-shortening contractions (SSCs), contractions typical during resistance training. With this model, we determined that at old age, high-repetition SSC training (80 SSCs: 8 sets of 10 repetitions) performed frequently (i.e. 3 days per week) for 4.5 weeks induced strength deficits with no muscle mass gain while decreasing frequency to 2 days per week promoted increases in muscle mass and muscle quality (i.e. performance normalized to muscle mass). This finding confirmed the popular notion that decreasing training frequency has a robust effect with age. Meanwhile, the influence of other loading variables remains contentious. The aim of the present study was to assess muscle adaptation following modulation of contraction mode and repetition number during high-intensity SSC training. Muscles of young (3 month old) and old (30 month old) male rats were exposed to 4.5 weeks of low repetition static training of 4 (i.e. 4 sets of one repetition) isometric (ISO) contractions 3 days per week or a more moderate-repetition dynamic training of 40 SSCs (i.e. 4 sets of 10 repetitions) 3 days per week. For young rats, performance and muscle mass increased regardless of training protocol. For old rats, no muscle mass adaptation was observed for 4 ISO training while 40 SSC training induced muscle mass gain without improvement in muscle quality, an outcome distinct from modulating training frequency. Muscle mass gain for old rats was accompanied by decreased protein levels of tumor necrosis factor alpha, a mediator of age-related chronic inflammatory signaling, to young levels. These findings suggest that while dynamic high-intensity training with a moderate number of repetitions has a limited capacity for altering muscle quality, such training is a viable strategy for countering age-related inflammatory signaling and modifying muscle mass. PMID- 29438736 TI - Toxic elements in hair and in vitro fertilization outcomes: A prospective cohort study. AB - We analysed the association between the concentration of four toxic elements (As, Cd, Hg and Pb) and diverse reproductive outcomes in a cohort of 194 women with fertility disorders undergoing IVF in a public hospital. Concentration in hair specimens was explored as biomarker of exposure during the three months prior to oocyte retrieval. The proportion of negative results, especially regarding pregnancy and birth outcomes, is remarkable. However, we found that the probability of mature oocytes was inversely associated with the concentration of Hg in hair (RR = 0.81, 95% CI: 0.70-0.95) and directly associated with that of Pb (RR = 1.18, 95% CI: 1.03-1.35). These findings provide insights for future research on the links between heavy metal concentrations and IVF outcomes. PMID- 29438737 TI - Neurogenesis and sexual behavior. AB - Different conditions induce proliferation, migration and integration of new neurons in the adult brain. This process of neurogenesis is a clear example of long lasting plastic changes in the brain of different species. Sexual behavior is a motivated behavior that is crucial for the survival of the species, but an individual can spend all his life without displaying sexual behavior. In the present review, we briefly describe some of the effects of pheromones on neurogenesis. We review in detail studies describing the effects of sexual behavior in both males and females on proliferation, migration and integration of new cells and neurons. It will become evident that most of the studies have been done in rodents, assessing the effects of this behavior on neurogenesis within the dentate gyrus of the hippocampus and in the subventricular zone - rostral migratory stream - olfactory bulb system. PMID- 29438738 TI - The AMPK-PGC-1alpha signaling axis regulates the astrocyte glutathione system to protect against oxidative and metabolic injury. AB - Neurons are highly sensitive to metabolic and oxidative injury, but endogenous astrocyte mechanisms have a critical capacity to provide protection from these stresses. We previously reported that the master regulator PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha) is necessary for retinal astrocytes to mount effective injury responses, with particular regard to oxidative stress. Yet, this pathway has not been well studied in glia. PGC-1alpha is a transcriptional co-activator that is dysregulated in a variety of neurodegenerative diseases. It functions as a master regulator of cellular bioenergetics, with the ability to regulate tissue specific responses. A key inducer of PGC-1alpha signaling is adenosine monophosphate-activated kinase (AMPK). Thus, the AMPK-PGC-1alpha signaling axis coordinates metabolic and oxidative damage responses in the central nervous system (CNS). Here we report that AMPK selectively regulates expression of GCLM (glutamate cysteine ligase modulatory subunit) in astrocytes, but not neurons, through PGC-1alpha activation. Glutamate cysteine ligase (GCL) is the rate limiting enzyme in the biosynthesis of glutathione (GSH); a critical antioxidant and detoxifying peptide in the CNS. Through this mechanism we describe PGC-1alpha-dependent induction of GSH synthesis and antioxidant activity in astrocytes, and in the rodent retina in vivo. Furthermore, we demonstrate that therapeutic agonism of this pathway with the AMP mimetic, AICAR, rescues GSH levels in vivo, while reducing RGC death and astrocyte reactivity, following retinal ischemia/reperfusion injury. This mechanism presents a novel strategy for enhancing protective astrocyte antioxidant capacity in the CNS. PMID- 29438739 TI - Factors influencing degradation of trichloroethylene by sulfide-modified nanoscale zero-valent iron in aqueous solution. AB - Sulfide-modified nanoscale zero-valent iron (S/NZVI) has been considered as an efficient material to degrade trichloroethylene (TCE) in groundwater. However, some critical factors influencing the dechlorination of TCE by S/NZVI have not been investigated clearly. In this study, the effects of Fe/S molar ratio, initial pH, dissolved oxygen and particle aging on TCE dechlorination by S/NZVI (using dithionite as sulfidation reagent) were studied. Besides, the feasibility of reactivation of the aged-NZVI by sulfidation treatment was looked into. The results show that the Fe/S molar ratio and initial pH significantly influenced the TCE dechlorination, and a higher TCE dechlorination was observed at Fe/S molar ratio of ~60 under alkaline condition. Spectroscopic analyses demonstrate that the enhanced TCE dechlorination was associated with the presence of FeS on the surface of S/NZVI. Dissolved oxygen had little effect on TCE dechlorination by S/NZVI, revealing that the FeS layer could be able to alleviate the surface passivation of NZVI caused by oxidation. Aging of S/NZVI up to 10-20 d only slightly decreased the dechlorination efficiency of TCE. Although an obvious drop in dechorination efficiency was observed for the S/NZVI aged for 30 d, it still exhibited a higher reactivity than the bare NZVI. This indicates that sulfidation of NZVI did prolong its lifetime. Additionally, sulfidation treatment was used to reactivate the aged NZVI, and the results show that the reactivated NZVI even had higher reactivity than the fresh NZVI, suggesting that sulfidation treatment would be a promising method to reactivate the aged NZVI. PMID- 29438740 TI - Adult hippocampal MeCP2 preserves the genomic responsiveness to learning required for long-term memory formation. AB - MeCP2 is required both during postnatal neurodevelopment and throughout the adult life for brain function. Although it is well accepted that MeCP2 in the maturing nervous system is critical for establishing normal development, the functions of MeCP2 during adulthood are poorly understood. Particularly, the requirement of hippocampal MeCP2 for cognitive abilities in the adult is not studied. To characterize the role of MeCP2 in adult neuronal function and cognition, we used a temporal and region-specific disruption of MeCP2 expression in the hippocampus of adult male mice. We found that MeCP2 is required for long-term memory formation and that it controls the learning-induced transcriptional response of hippocampal neurons required for memory consolidation. Furthermore, we uncovered MeCP2 functions in the adult hippocampus that may underlie cognitive integrity. We showed that MeCP2 maintains the developmentally established chromatin configuration and epigenetic landscape of CA1 neurons throughout the adulthood, and that it regulates the expression of neuronal and immune-related genes in the adult hippocampus. Overall, our findings identify MeCP2 as a maintenance factor in the adult hippocampus that preserves signal responsiveness of the genome and allows for integrity of cognitive functions. This study provides new insight into how MeCP2 maintains adult brain functions, but also into the mechanisms underlying the cognitive impairments observed in RTT patients and highlights the understudied role of DNA methylation interpretation in adult cognitive processes. PMID- 29438741 TI - Different mechanisms underlie stress-induced changes in plasticity and metaplasticity in the prefrontal cortex of juvenile and adult animals: Emotional induced metaplasticity in the prefrontal cortex. AB - Metaplasticity is the dynamic regulation of the ability to induce activity dependent synaptic plasticity and is governed by the prior history of the synapses. Previous reports by others and us have shown that behavioral stress induces a form of emotional metaplasticity that affects the ability to induce LTP in the subiculum-medial prefrontal cortex pathway, which depends on NMDA receptors (NMDAr). However, studies addressing the effects of stress on LTP and metaplasticity have mainly focused on the adult animal. Here we compared the effects of exposure to stress on the induction of LTP in adult and juvenile animals and examined whether a low dose of NMDAr antagonist (MK801) that does not affect LTP per se would differentially affect stress-induced metaplasticity in adult and juvenile animals. Our findings show that exposure to the elevated platform differentially affects the induction of LTP in adult and juvenile animals. Specifically, whereas exposure to stress resulted in impaired LTP in adult animals, it resulted in enhanced LTP in juvenile animals. Similarly, while MK801 failed to inhibit the induction of LTP in both age groups, it resulted in inhibition of stress-induced enhanced LTP in juvenile animals, but did not affect stress-induced impaired LTP in adult animals. Taken together, these findings demonstrate that emotional metaplasticity is differently dependent on NMDAr in adult and juvenile animals that may stem from developmental differences in the NMDA receptor representation. These results further confirm that the mechanisms of plasticity following stress are distinctive in the two groups of age. PMID- 29438742 TI - A novel high-resolution multilocus sequence typing of Giardia intestinalis Assemblage A isolates reveals zoonotic transmission, clonal outbreaks and recombination. AB - Molecular epidemiology and genotyping studies of the parasitic protozoan Giardia intestinalis have proven difficult due to multiple factors, such as low discriminatory power in the commonly used genotyping loci, which has hampered molecular analyses of outbreak sources, zoonotic transmission and virulence types. Here we have focused on assemblage A Giardia and developed a high resolution assemblage-specific multilocus sequence typing (MLST) method. Analyses of sequenced G. intestinalis assemblage A genomes from different sub-assemblages identified a set of six genetic loci with high genetic variability. DNA samples from both humans (n = 44) and animals (n = 18) that harbored Giardia assemblage A infections, were PCR amplified (557-700 bp products) and sequenced at the six novel genetic loci. Bioinformatic analyses showed five to ten-fold higher levels of polymorphic sites than what was previously found among assemblage A samples using the classic genotyping loci. Phylogenetically, a division of two major clusters in assemblage A became apparent, separating samples of human and animal origin. A subset of human samples (n = 9) from a documented Giardia outbreak in a Swedish day-care center, showed full complementarity at nine genetic loci (the six new and the standard BG, TPI and GDH loci), strongly suggesting one source of infection. Furthermore, three samples of human origin displayed MLST profiles that were phylogenetically more closely related to MLST profiles from animal derived samples, suggesting zoonotic transmission. These new genotyping loci enabled us to detect events of recombination between different assemblage A isolates but also between assemblage A and E isolates. In summary, we present a novel and expanded MLST strategy with significantly improved sensitivity for molecular analyses of virulence types, zoonotic potential and source tracking for assemblage A Giardia. PMID- 29438743 TI - Detection and molecular characterization of enteric viruses in children with acute gastroenteritis in Northern Italy. AB - Enteric viral infections are a major concern for public health, and viral acute gastroenteritis is the principal cause of pediatric morbidity and mortality worldwide, mostly in developing countries. The purpose of this study was to determine the prevalence of different enteric viruses detected in a pediatric population with acute gastroenteritis symptoms, and to characterize the strains detected. Stools were collected from children, aged from 2 months to 15 years old, admitted to one of the main hospitals of Northern Italy, between November 2015 and October 2016. Stools were tested for nine enteric viruses (adenovirus, rotavirus A, norovirus, astrovirus, sapovirus, enterovirus, parechovirus, bocavirus and aichivirus) by molecular methods. Furthermore, rotavirus, norovirus and adenovirus were deeply characterized by nucleotide sequencing and phylogenetic analysis. A total of 151 out of 510 (29.6%) stools analyzed resulted positive for at least one of the enteric virus investigated. The most common virus detected was rotavirus A (53/151, 35.1%), followed by norovirus (39/151, 25.8%), adenovirus (35/151, 23.1%), sapovirus (9/151, 6%), enterovirus (5/151, 3.3%), astrovirus (5/151, 3.3%), parechovirus (4/151, 2.6%) and bocavirus (1/151, 0.6%). Aichi virus was not detected in any sample. Co-infections were detected in 12 out of 510 faecal samples (2.3%). These data improved the knowledge of the enteric viruses circulating in children in Northern Italy. In fact, besides rotavirus, adenovirus and norovirus, several viruses circulated across the whole year in the pediatric population object of this study. The introduction of specific viral diagnosis in our clinical setting will improve patient care by reducing unnecessary use of antibiotics addressing the right etiologic diagnosis. PMID- 29438744 TI - Lipopolysaccharide interferes with the use of the human Cell Line Activation Test to determine the allergic potential of proteins. AB - It was believed that high molecular weight molecules including proteins cannot penetrate the skin. However, protein penetration through disrupted/ruptured skin has been reported recently, thus carrying the potential for inducing an allergic response. We used the human Cell Line Activation Test (h-CLAT), an in vitro skin sensitization test, to assess the allergic potential of proteins by measuring levels of CD86 and CD54 in the human monocytic leukemia cell line THP-1. Six allergens including ovalbumin (OVA) and human serum albumin (HSA; negative control) upregulated CD86 and/or CD54; a false-positive result was obtained using HSA. This was caused by lipopolysaccharide (LPS) contamination. Naturally derived materials often include LPS at various concentrations and may influence protein induction of CD86 and CD54. Additionally, polymyxin B, an LPS inhibitor, could not completely overcome the effect of LPS. Therefore, if test proteins contain >=0.1 EU/mL LPS, their allergenic potency will not be assessed accurately using h CLAT. These data show that naturally occurring materials or those derived from living organisms should be evaluated for their LPS content. It is important to confirm the applicability of in vitro methods such as h-CLAT for assessing the allergenic potency of naturally occurring proteins; our findings can be a foundation for future studies. PMID- 29438745 TI - An automated epifluorescence microscopy imaging assay for the identification of phospho-AKT level modulators in breast cancer cells. AB - AKT is an enzyme of the PI3K/pAKT pathway, regulating proliferation and cell survival. High basal levels of active, phosphorylated AKT (pAKT) are associated with tumor progression and therapeutic resistance in some breast cancer subtypes, including HER2 positive breast cancers. Various stimuli can increase pAKT levels and elevated basal pAKT levels are a feature of PTEN-deficient breast cancer cell lines. The aim of this study was to develop an assay able to identify modulators of pAKT levels using an automated epifluorescence microscope and high content analysis. To develop this assay, we used HCC-1569, a PTEN-deficient, HER2 overexpressing breast cancer cell line with elevated basal pAKT levels. HCC-1569 cells were treated with a selective pharmacological inhibitor of AKT (MK-2206) to reduce basal pAKT levels or EGF to increase pAKT levels. Immunofluorescence images were acquired using an automated epifluorescence microscope and integrated intensity of cytoplasmic pAKT staining was calculated using high content analysis software. Mean and median integrated cytoplasmic intensity were normalized using fold change and standard score to assess assay quality and to identify most robust data analysis. The highest z' factor was achieved for median data normalization using the standard score method (z' = 0.45). Using our developed assay we identified the calcium homeostasis regulating proteins TPRV6, STIM1 and TRPC1 as modulators of pAKT levels in HCC-1569 cells. Calcium signaling controls a diverse array of cellular processes and some calcium homeostasis regulating proteins are involved in modulating pAKT levels in cancer cells. Thus, these identified hits present promising targets for further assessment. PMID- 29438746 TI - Longitudinal changes in MR T1rho/T2 signal of meniscus and its association with cartilage T1p/T2 in ACL-injured patients. AB - OBJECTIVE: To evaluate the longitudinal changes in meniscal T1rho/T2 signal post reconstruction in patients with acute anterior cruciate ligament (ACL) injury and to investigate the association with T1rho/T2 signal in articular knee cartilage. METHOD: In this prospective study, knees of 37 patients with ACL-injury and reconstruction in addition to 13 healthy controls were scanned using magnetic resonance imaging (MRI) T1rho/T2 mapping. Quantitative analysis of the meniscus was performed in the anterior/posterior horns of lateral/medial meniscus fourteen sub-compartments of cartilage spanning the medial/lateral area of the tibia and femoral condyles. Meniscus T1rho/T2 signals were compared between injured, contralateral and control knees at baseline, 6-months, 1-year and 2-years using t tests for cross-sectional comparisons and a mixed model for longitudinal comparisons. Pearson-partial correlations between meniscal and cartilage T1rho/T2 were evaluated. RESULTS: There was a significant decrease of T1rho/T2 signal in the posterior horn of lateral meniscus (PHLAT) of injured knees during a 2-year period. In the posterior horn of medial meniscus (PHMED), T1rho/T2 signal of injured knees was significantly elevated at all time points post-reconstruction compared to contralateral and control knees. Within injured knees, PHMED T1rho/T2 signal showed significant positive correlations with medial tibia (MT) cartilage T1rho/T2 signal at all time points. CONCLUSION: A significant decrease in PHLAT T1rho/T2 signal by 2-years suggests potential tissue recovery after ACL-injury. Elevated T1rho/T2 signal in the PHMED of injured knees at 2-years correlating with knee cartilage T1rho/T2 signal elevations suggests involvement of the PHMED in subacute cartilage degeneration after ACL-injury and reconstruction. PMID- 29438747 TI - In-flow protein immobilization monitored by magnetic resonance imaging. AB - Protein immobilization is a key enabling technology for flow biocatalysis. For this purpose, many different immobilization protocols and characterization techniques have been developed in recent decades. However, examples where proteins are directly immobilized on ready-to-use reactors are scarce, likely due to the lack of analytical tools to monitor in-flow protein immobilization in a non-invasive manner. Here, we have for the first time exploited Magnetic Resonance Imaging (MRI) to characterize in-flow protein immobilization on pre packed bed columns. This concept was demonstrated by in-flow immobilization of a green fluorescence protein. MRI analysis revealed that both the protein concentration of the flushed solution and flow rate play key roles in controlling the spatial organization of the protein across the packed-bed reactor. This analytical tool coupled to in-flow protein immobilization has been expanded to more industrially relevant enzymes, such as the lipase from Thermomyces lanuginosus, achieving a ready-to-use reactor packed with a heterogeneous biocatalyst with high activity (up to 3000 U * g-1) and high stability (75% residual activity after 1 h incubation at 60 degrees C). Introducing new analytical tools during the fabrication of heterogeneous biocatalysts will contribute to make the process of immobilizing proteins on solid carriers more rational than currently is. PMID- 29438748 TI - Neuregulin 1 discovered as a cleavage target for the HCV NS3/4A protease by a microfluidic membrane protein array. AB - The hepatitis C virus (HCV) non-structural protein 3 (NS3) is essential for HCV maturation. The NS3/4A protease is a target for several HCV treatments and is a well-known target for HCV drug discovery. The protein is membrane associated and thus probably interacts with other membrane proteins. However, the vast majority of known NS3 host partners are soluble proteins rather than membrane proteins, most likely due to lack of appropriate platforms for their discovery. Utilization of an integrated microfluidics platform enables analysis of membrane proteins in their native form. We screened over 2800 membrane proteins for interaction with NS3 and 90 previously unknown interactions were identified. Of these, several proteins were selected for validation by co-immunoprecipitation and for NS3 proteolytic activity. Bearing in mind the considerable number of interactions formed, together with the popularity of NS3/4A protease as a drug target, it was striking to note its lack of proteolytic activity. Only a single protein, Neuregulin1, was observed to be cleaved, adding to the 3 known NS3/4A cleavage targets. Neuregulin1 participates in neural proliferation. Recent studies have shown its involvement in HCV infection and hepatocellular carcinoma. We showed that NS3/4A triggers an increase in neuregulin1 mRNA levels in HCV infected cells. Despite this increase, its protein concentration is decreased due to proteolytic cleavage. Additionally, its EGF-like domain levels were increased, possibly explaining the ErbB2 and EGFR upregulation in HCV infected cells. The newly discovered protein interactions may provide insights into HCV infection mechanisms and potentially provide new therapeutic targets against HCV. PMID- 29438749 TI - Protective effects of total alkaloids from Dendrobium crepidatum against LPS induced acute lung injury in mice and its chemical components. AB - Dendrobium crepidatum was one of the sources of Herba Dendrobii, a famous and precious traditional Chinese medicine. Indolizine-type alkaloids are the main characteristic ingredients of D. crepidatum, which possesses a variety of changeable skeletons. In the present study, we found that the total alkaloids of D. crepidatum (TAD) can inhibit the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated macrophages and showed protective effects against LPS-induced acute lung injury (ALI) in mice through downregulating the TLR4-mediated MyD88/MAPK signaling pathway. Further phytochemical study showed that six previously undescribed indolizine-type compounds, including a racemic mixture (dendrocrepidine A-E) were isolated from TAD. Meanwhile, dendrocrepidine F was separated into a pair of enantiomers by a chiral chromatography, and their absolute configurations were assigned by single-crystal X-ray diffraction analysis. The isomer (-)-dendrocrepidine F showed higher anti-inflammatory effects by inhibiting NO production in LPS-treated macrophages with an IC50 value of 13.3 MUM. Taken together, indolizine-type alkaloids are the active components of D. crepidatum through downregulating the TLR4-mediated pathway, indicating some kind of therapy of TAD for ALI treatment. PMID- 29438750 TI - Chemical and rheological properties of polysaccharides from litchi pulp. AB - Litchi polysaccharide (LP) was extracted from litchi pulp. Its chemical composition, microstructure, zeta potential, flow and viscoelastic behavior were investigated. LP contained uronic acid (41.18%), neutral sugar (42.23%), and protein (2.72%). The monosaccharide composition was mostly arabinose, galactose, and a small amount of mannose, rhamnose and glucose. Scanning electron microscopy (SEM) showed LP was porous network structure. LP concentration had no effect on its zeta potential value while salts reduced them. LP showed shear-thinning behavior during the tested shear rate range. The power-law model was used to evaluate the flow behavior of LP; both its flow behavior index and consistency index changed with different concentrations. The viscosity of LP increased under acidic conditions (pH2-4), but was stable with heat treatment. The LP dispersion displayed as a liquid viscoelastic behavior in 1% and 2% concentrations and behaved as an elastic gel at 3% concentration as well as the addition of NaCl and CaCl2. PMID- 29438751 TI - Developing lignin-based bio-nanofibers by centrifugal spinning technique. AB - Lignin-based nanofibers were produced via centrifugal spinning from lignin thermoplastic polyurethane polymer blends. The most suitable process parameters were chosen by optimization of the rotational speed, nozzle diameter and spinneret-to-collector distance using different blend ratios of the two polymers at different total polymer concentrations. The basic characteristics of polymer solutions were enlightened by their viscosity and surface tension. The morphology of the fibers produced was characterized by SEM, while their thermal properties by DSC and TG analysis. Multiply regression was used to determine the parameters that have higher impact on the fiber diameter. It was possible to obtain thermally stable lignin/polyurethane nanofibers with diameters below 500nm. From the aspect of spinnability, 1:1 lignin/TPU contents were shown to be more feasible. On the other side, the most suitable processing parameters were found to be angular velocity of 8500rpm for nozzles of 0.5mm diameter and working distance of 30cm. PMID- 29438752 TI - Design and evaluation of chitosan/poly(l-lactide)/pectin based composite scaffolds for cartilage tissue regeneration. AB - Poor regenerative potential of cartilage tissue due to the avascular nature and lack of supplementation of reparative cells impose an important challenge in recent medical practice towards development of artificial extracellular matrix with enhanced neo-cartilage tissue regeneration potential. Chitosan (CH), poly (l lactide) (PLLA), and pectin (PC) compositions were tailored to generate polyelectrolyte complex based porous scaffolds using freeze drying method and crosslinked by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), N hydroxysuccinimide (NHS) solution containing chondroitin sulfate (CS) to mimic the composition as well as architecture of the cartilage extracellular matrix (ECM). The physical, chemical, thermal, and mechanical behaviors of developed scaffolds were done. The scaffolds were porous with homogeneous pore structure with pore size 49-170MUm and porosities in the range of 79 to 84%. Fourier transform infrared study confirmed the presence of polymers (CH, PLLA and PC) within the scaffolds. The crystallinity of the scaffold was examined by the X-ray diffraction studies. Furthermore, scaffold shows suitable swelling property, moderate biodegradation and hemocompatibility in nature and possess suitable mechanical strength for cartilage tissue regeneration. MTT assay, GAG content, and attachment of chondrocyte confirmed the regenerative potential of the cell seeded scaffold. The histopathological analysis defines the suitability of scaffold for cartilage tissue regeneration. PMID- 29438753 TI - Antidiabetic activities of polysaccharides from Anoectochilus roxburghii and Anoectochilus formosanus in STZ-induced diabetic mice. AB - Six polysaccharides were extracted from different parts (whole plants, roots and leaves) of Anoectochilus roxburghii and Anoectochilus formosanus (ARPs, ARPs-1, ARPs-2, AFPs, AFPs-1 and AFPs-2). Their primary characteristics were identified and their antidiabetic activities were evaluated in STZ-induced diabetic mice. Root polysaccharides (ARPs-1and AFPs-1) and leaf polysaccharides (ARPs-2 and AFPs 2) were distinct from each other in terms of the Mws, monosaccharide compositions and functional groups. Notably, the primary structures of ARPs and AFPs were similar to those of ARPs-1and AFPs-1, respectively. In animal experiment, after feeding with polysaccharides samples, the body weight, blood glucose, glycogen, insulin, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), malondiadehyde (MDA) and antioxidant enzyme activities in liver and kidney of mice were tested to investigate the antidiabetic activities. All polysaccharides exhibited varying antidiabetic activities (antihyperglycemic, antioxidant and antihyperlipidemic activities), which were closely related to their primary characteristics. Furthermore, root polysaccharides with higher Mws and glucose content in both A. roxburghii and A. formosanus, exhibited better antidiabetic activities than leaf polysaccharides, and ARPs which showed the best antidiabetic activities had the potential to be used as functional food or medicine for diabetes treatment. PMID- 29438754 TI - MnO2-deposited lignin-based carbon nanofiber mats for application as electrodes in symmetric pseudocapacitors. AB - Low-cost, high-performance electrodes are highly attractive for practical supercapacitor applications. MnO2-deposited carbon nanofiber mats (MnO2-CNFMs) are prepared for use as binder-free supercapacitor electrodes. MnO2 is deposited on the mats in situ by hydrothermally decomposing aqueous KMnO4, leading to the formation of nanocrystals of MnO2. The MnO2-CNFM electrode produced with 38.0MUmol KMnO4 (this electrode) shows a high specific capacitance of ~171.6F.g-1 at a scan rate of 5mV.s-1. Moreover, a symmetric supercapacitor with the electrode exhibits a specific capacitance of 67.0F.g-1, an energy density of 6.0Wh.kg-1 and a power density of 160W.kg-1 at a special current of 0.1A.g-1. Further, the symmetric supercapacitor displays excellent cycling stability, retains approximately 99% of the capacitance after 1000cycles. The simplicity and ease of preparation of the MnO2-CNFMs as well as their suitability for use in coin-type supercapacitor cells make them ideal for application in cost-effective and high-performance electrodes for supercapacitors. PMID- 29438755 TI - The combined effect of formulation and pH on properties of polyethylene oxide composite fiber containing egg albumen protein. AB - The aim of this work was to elucidate the influence of egg white albumen (EA) protein loaded on the electrospinning of PEO solutions under different concentrations and pHs conditions. Properties of the electrospun fiber mats, such as morphology, thermal properties, and wettability were analyzed. In addition, rheological behavior of the polymer solutions was measured to explain the electrospinnability for fiber formation. The rheological results showed that the addition of EA protein affects the molecular entanglement required to electrospin PEO, being able to incorporate up to 75wt% EA protein. The diameter of most of the PEO/EA fibers was in the range of 200-400nm. When comparing the effect of concentration and pH of the electrospinning solution, the morphology of the fibers was found to be mainly affected by the second one. FTIR analysis of the blend fibers confirmed the presence of the protein and revealed that the secondary structure changed with pH. From a thermodynamic point of view, the EA protein and PEO showed a high degree of mutual incompatibility. The presence of EA protein influenced PEO polymer thermal behavior, lowering its melting point and decreasing the quantity of PEO crystallites. All the PEO/EA electrospun fiber mats showed rapid water absorption, which increased as PEO concentration became higher, and similarly, when lowering protein concentration. PMID- 29438756 TI - Rapid improvement of prurigo nodularis with cyclosporine treatment. PMID- 29438757 TI - Comparative effectiveness of targeted immunomodulators for the treatment of moderate-to-severe plaque psoriasis: A systematic review and network meta analysis. AB - BACKGROUND: The comparative effectiveness of available targeted immunomodulators for moderate-to-severe psoriasis has not been evaluated. OBJECTIVE: To evaluate the comparative effectiveness of targeted immunomodulators for adults with moderate-to-severe plaque psoriasis. METHODS: Systematic literature review of placebo-controlled and head-to-head randomized trials of 8 targeted immunomodulators that evaluated clinical benefits or harm. The primary outcome was a 75% improvement on the Psoriasis Area and Severity Index. We also conducted a network meta-analysis adjusted for placebo response to perform indirect comparisons between agents. RESULTS: In the network meta-analysis, the targeted immunomodulators ordered by increasing relative risk (demonstrating greater likelihood) of achieving a 75% improvement on the Psoriasis Area and Severity Index relative to placebo were as follows: apremilast (6.2), etanercept (9.6), adalimumab (13.0), ustekinumab (14.0), secukinumab (15.4), infliximab (16.2), brodalumab (17.3), and ixekizumab (17.9). Ixekizumab, brodalumab, and infliximab were all statistically superior to ustekinumab, adalimumab, etanercept, and apremilast; results were similar to those of head-to-head studies where data were available. LIMITATIONS: Much of the evidence is short-term (covering 10-16 weeks); limited direct comparisons. CONCLUSIONS: The interleukin 17A inhibitors are more effective in achieving clearance than ustekinumab, and they are generally more effective than etanercept, adalimumab, and apremilast. PMID- 29438758 TI - Global burden of urticaria: Insights from the 2016 Global Burden of Disease Study. PMID- 29438759 TI - The staining of clothing by sunscreens: A pilot study. PMID- 29438760 TI - Impact of a smartphone application on skin self-examination rates in patients who are new to total body photography: A randomized controlled trial. PMID- 29438761 TI - Rethinking biotin therapy for hair, nail, and skin disorders. PMID- 29438762 TI - The impact of underlying disease state on outcomes in patients with pyoderma gangrenosum: A national survey. AB - BACKGROUND: Whether the underlying disease affects the outcomes in pyoderma gangrenosum (PG) is unclear. OBJECTIVES: To determine the impact of comorbid disease associations and concomitant procedural treatments on patient outcomes in hospitalizations of patients with PG. METHODS: A cross-sectional analysis of the National Inpatient Sample for hospitalizations of patients with PG from the years 2002 to 2011, analyzing in-hospital mortality rate and health care resource utilization. RESULTS: Inflammatory bowel disease was the most frequent comorbid association, followed by inflammatory arthritis, hematologic malignancies/dyscrasia, and vasculitis. Multivariable modeling showed that vasculitis and hematologic malignancy/dyscrasia, when compared with inflammatory bowel disease, were associated with a 4-fold to 6-fold increased risk of in hospital mortality and increasing health care resource utilization. Inpatient procedural interventions, including skin grafts, biopsies, and debridement, did not affect mortality and were associated with an increased length of stay. LIMITATIONS: The database does not account for outpatient follow-up; additionally, there was a low rate of coded comorbid conditions. CONCLUSIONS: Comprehensive evaluation to determine the underlying comorbidity for patients with PG is important for patient risk stratification. PMID- 29438763 TI - Whole-exome sequencing reveals differences between nail apparatus melanoma and acral melanoma. PMID- 29438764 TI - A technique for more precise distinction between catagen and telogen human hair follicles ex vivo. PMID- 29438766 TI - In-office compounding of lidocaine-epinephrine: An option for anesthesia preparation before skin biopsy. PMID- 29438765 TI - Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib: A 32 week open-label extension study with optional narrow-band ultraviolet B. PMID- 29438769 TI - Patient satisfaction and preference for absorbable versus nonabsorbable sutures for linear repairs. PMID- 29438767 TI - Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts. AB - BACKGROUND: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management, OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of recommendations. METHODS: A preliminary survey, based on the European Dermatology Forum (EDF) and the European Academy of Dermatology and Venereology (EADV) guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology (AAD) conference. A second survey was sent following the meeting to more experts to achieve greater international consensus. RESULTS: The 39 experts participated in the first round of the Delphi-survey while 54 from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II based on Delphi results and meeting discussion. LIMITATIONS: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first line therapy option for moderate to severe pemphigus. PMID- 29438768 TI - Commentary: Skin cancer in the military. PMID- 29438770 TI - Ascertainment of asthma prognosis using natural language processing from electronic medical records. PMID- 29438771 TI - Chronic inducible urticaria: A systematic review of treatment options. AB - BACKGROUND: Chronic inducible urticaria (CindU) is a condition characterized by the appearance of recurrent wheals, angioedema, or both as a response to specific and reproducible triggers. OBJECTIVE: We sought to systematically assess evidence on the efficacy and safety of treatment options for CindU. Results were used to inform the 2017 update of "The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria." METHODS: Randomized controlled trials and controlled intervention studies were searched systematically in various databases. Included studies were evaluated with the Cochrane Risk of Bias tool. Where possible, results from single studies were meta analyzed, applying the Mantel-Haenszel approach by using a random-effects model (Der Simonian-Laird). RESULTS: We identified 30 studies that included patients with cold urticaria, symptomatic dermographism, delayed-pressure urticaria, or cholinergic urticaria. No studies on other forms of CindU were eligible. Risk of bias was often rated as unclear or high. Overall, second-generation antihistamines were more effective than placebo, and available data indicate that updosing might be effective. Omalizumab proved effective in patients with symptomatic dermographism, who did not respond to antihistamines. Detailed results are given for each type of CindU. CONCLUSIONS: The available evidence is limited by small samples, heterogeneous efficacy outcomes, and poor reporting quality in many of the included studies. The findings are congruent with the suggested stepwise approach to treating CindUs. However, the data do not allow for drawing specific conclusions for specific subtypes of CindU. PMID- 29438773 TI - Peroxisomal disorders: Improved laboratory diagnosis, new defects and the complicated route to treatment. AB - Peroxisomes catalyze a number of essential metabolic functions of which fatty acid alpha- and beta-oxidation, ether phospholipid biosynthesis, glyoxylate detoxification and bile acid synthesis are the most important. The key role of peroxisomes in humans is exemplified by the existence of a group of peroxisomal disorders, caused by mutations in > 30 different genes which code for proteins with a role in either peroxisome biogenesis or one of the metabolic pathways in peroxisomes. Technological advances in laboratory methods at the metabolite-, enzyme-, and molecular level have not only allowed the identification of new peroxisomal disorders but also new phenotypes associated with already identified genetic defects thus extending the clinical spectrum. Unfortunately, progress in the field of pathogenesis and treatment has lagged behind although there are certainly new and hopeful developments with respect to X-linked adrenoleukodystrophy and hyperoxaluria type 1. PMID- 29438772 TI - Lumen area change (Delta Lumen) between inspiratory and expiratory multidetector computed tomography as a measure of severe outcomes in asthmatic patients. AB - BACKGROUND: Quantitative computed tomographic (QCT) biomarkers of airway morphology hold potential for understanding and monitoring regional airway remodeling in asthmatic patients. OBJECTIVE: We sought to determine whether the change in airway lumen area between total lung capacity (TLC) and functional residual capacity (FRC) lung volumes measured from CT imaging data was correlated with severe outcomes in asthmatic patients. METHODS: We studied 152 asthmatic patients (90 female and 62 male patients) and 33 healthy subjects (12 female and 21 male subjects) using QCT. Postprocessing of airways at generations 1 to 5 (1 = trachea) was performed for wall area percentage, wall thickness percentage (WT%), lumen area at baseline total lung capacity (LATLC), lumen area at baseline functional residual capacity (LAFRC), and low attenuation area at FRC. A new metric (reflecting remodeling, distal air trapping, or both), Delta Lumen, was determined as follows: Percentage difference in lumen area (LATLC - LAFRC)/LATLC * 100. RESULTS: Postprocessing of 4501 airway segments was performed (3681 segments in the 152 patients with asthma and 820 segments in the 33 healthy subjects; range, 17-28 segments per subject). Delta Lumen values were negatively correlated with WT% and low attenuation area (P < .01) in asthmatic patients. Delta Lumen values were significantly lower for airway generations 3 to 5 (segmental airways) in subjects undergoing hospitalization because of exacerbation and in patients with refractory asthma requiring treatment with systemic corticosteroids. WT% and low attenuation area were positively and Delta Lumen values were negatively associated with systemic corticosteroid treatment (P < .05), suggesting that a reduced Delta Lumen value is a potential outcome biomarker in patients with severe asthma. CONCLUSION: Reduced Delta Lumen value in the central airways measured by using QCT is a promising exploratory biomarker of unstable refractory asthma that warrants further study. PMID- 29438774 TI - Palliative effects of Moringa olifera ethanolic extract on hemato-immunologic impacts of melamine in rats. AB - Melamine (MEL) is a widespread food contaminant and adulterant. Moringa olifera is a widely known medicinal plant with various pharmacological properties. Herein, this study aimed to investigate, for the first time, the probable protective or therapeutic role of M. olifera ethanolic extract (MOE) against MEL induced hemato-immune toxic hazards. Fifty Sprague Dawely male rats were orally treated with distilled water, MOE (800 mg/kg bw), MEL (700 mg/kg bw), MOE/MEl or MOE + MEl. Erythrogram and leukogram profiling were evaluated to assess hematological status. Innate immune functions were evaluated via measuring lysozyme levels, nitric oxide concentration, and bactericidal activity of phagocytes. Serum immunoglobulin levels were estimated as indicators of humoral immunity. Histologic and immunohistochemical evaluations of splenic tissues were also performed. The results indicated that MEL caused a significant decline in RBC, Hb, PCV, total WBC, neutrophil, lymphocyte, phagocytes bactericidal activity, lysozyme activity, nitric oxide, total IgM and IgG levels. Also, MEL induced various pathologic lesions in the spleen with strong expression of CD4 and CD8 positive cells. MOE significantly counteracted the former anaemic, leucopenic, innate and humoral depressant effects of MEL particularly at co exposure. In conclusion, these findings revealed that MOE could be candidate therapy against MEL hemato-immunotoxic impacts. PMID- 29438775 TI - Detoxifying effect of pyridoxine on acetaminophen-induced hepatotoxicity via suppressing oxidative stress injury. AB - The detoxifying effect of pyridoxine against acetaminophen (APAP)-induced hepatotoxicity was investigated. HepG2 cells were co-treated with APAP and pyridoxine to compare with betaine or methionine for 24 h. LDH, ALT and AST activities were measured to determine direct cells damage in vitro and in vivo. Lipid peroxidation, antioxidant enzymes activity, and glutathione level were measured. Cytochrome c releaseand procaspase-3, cleaved caspase-3, Bcl-2, or Bax protein levels were measured to determine APAP-induced apoptotic cell death. Pyridoxine treatment significantly increased cell viability and decreased leakage of LDH activity against APAP-induced hepatotoxicity in HepG2 cells. ALT and AST activities were dose-dependently reduced by pyridoxine treatment compared to APAP treated group. Significant increases in activities of GST and GPx were observed after co-treatment with APAP and pyridoxine. Although APAP-induced Nrf2 and HO-1 expression levels were gradually reduced in HepG2 cells by pyridoxine treatment, induction of antioxidant enzymes activities were dose-dependently increased. These protected effects of pyridoxine against APAP-induced hepatoxicity were closely associated with suppression of APAP-induced oxidative stress and apoptotic cell death in HepG2 cells. These data indicated that the protective action of pyridoxine against hepatic cell injuries was involved in the direct antioxidant activity which provides a pivotal mechanism for its potential hepatoprotective action. PMID- 29438776 TI - Quercetin ameliorates HFD-induced NAFLD by promoting hepatic VLDL assembly and lipophagy via the IRE1a/XBP1s pathway. AB - The consumption of a quercetin-rich diet has been well-established as a feasible method against non-alcoholic fatty liver disease (NAFLD); however, the molecular mechanisms underlying the progression of NAFLD and its intervention by quercetin remain largely obscure. Male Sprague-Dawley rats fed high-fat diet (HFD), and HepG2 cells stimulated with free fatty acid, were treated with quercetin and various pharmacological reagents to explore the effect of signaling pathways involved in endoplasmic reticulum stress on very low-density lipoprotein (VLDL) assembly and lipophagy. Quercetin intake decreased hepatic TG content by 39%, with a 1.5-fold increase in VLDL, and up-regulated spliced X-box binding protein 1 (XBP1s) expression compared with the HFD group. Thapsigargin or STF-083010 (an IRE1alpha endonuclease inhibitor) decreased VLDL content in a dose-dependent manner, partially counteracting the protective effects of quercetin, 4-PBA or APY 29 (an IRE1alpha endonuclease activator). Additionally, microsomal TG-transfer protein complex expression was increased with quercetin-treated and down regulated by STF-083010. Moreover, quercetin increased co-localization of lysosomes with lipid droplets (LDs) accompanied by decreased p62 accumulation. STF-083010 partially abolished the effect of quercetin on LDs autophagy in an mTOR-independent manner. Collectively, these findings demonstrate that hepatic VLDL assembly and lipophagy are the main targets of quercetin against NAFLD via the IRE1a/XBP1s pathway. PMID- 29438777 TI - The differential roles of PEA15 phosphorylations in reactive astrogliosis and astroglial apoptosis following status epilepticus. AB - Up to this day, the roles of PEA15 expression and its phosphorylation in seizure related events have not been still unclear. In the present study, we found that PEA15 was distinctly phosphorylated in reactive astrocytes and apoptotic astrocytes in the rat hippocampus following LiCl-pilocarpine-induced status epilepticus (SE, a prolonged seizure activity). PEA15-serine (S) 104 phosphorylation was up-regulated in reactive astrocytes following SE, although PEA15 expression and its S116 phosphorylation were unaltered. Bisindolylmaleimide (BIM), a protein kinase C (PKC) inhibitor, attenuated SE-induced reactive astrogliosis, but phorbol 12-myristate 13-acetate (PMA, a PKC activator) aggravated it. Unlike reactive astrocytes, PEA15-S116 phosphorylation was reduced in apoptotic astrocytes. However, PEA15 expression and its S104 phosphorylation were unchanged in apoptotic astrocyte. Neither BIM nor PMA affected SE-induced astroglial apoptosis. PEA15 expression and its phosphorylations were not relevant to SE-induced CA1 neuronal death. These findings indicate that PEA15-S104 and S116 phosphorylations may play a role in reactive astrogliosis and prevention of astroglial apoptosis, respectively. Therefore, we suggest that the selective manipulation of PEA15 phosphorylations may regulate apoptotic and/or proliferative signals in astrocytes. PMID- 29438778 TI - Gamma oscillations in the entorhinal-hippocampal circuit underlying memory and dementia. AB - Gamma oscillations that occur within the entorhinal cortex-hippocampal circuitry play important roles in the formation and retrieval of memory in healthy brains. Recent studies report that gamma oscillations are impaired in the entorhinal hippocampal circuit of Alzheimer's disease (AD) patients and AD animal models. Here we review the latest advancements in studies of entorhinal-hippocampal gamma oscillations in healthy memory and dementia. This review is especially salient for readers in Alzheimer's research field not familiar with in vivo electrophysiology. Recent studies have begun to show a causal link between gamma oscillations and AD pathology, suggesting that gamma oscillations may even offer a plausible future therapeutic target. PMID- 29438779 TI - Down-regulation of miRNA-320c promotes tumor growth and metastasis and predicts poor prognosis in human glioma. AB - Emerging studies show that dysregulated miRNAs are implicated in tumorigenesis and progression of various cancers. MiRNA-320c, an important member of miRNA-320 family, was characterized as a new candidate miRNA that suppressed the development of colorectal cancer and bladder cancer. However, the function of miRNA-320c in human glioma remained unclear. Here, we found that miRNA-320c was significantly down-regulated in glioma tissues in contrast with normal brain tissues, being tightly related to clinical stage of glioma by qRT-PCR. Moreover, Kaplan-Meier analysis demonstrated that patients with low miRNA-320c expression had a shorter survival. Multivariate Cox regression analysis indicated that miRNA 320c could serve as an independent poor prognostic factor for patients with glioma. Functionally, overexpression of miRNA-320c could dramatically inhibit glioma cell proliferation, migration and invasion, as well as promote apoptosis. Further analysis indicated that overexpression of miRNA-320c dramatically led to the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells by suppressing the expression of G1/S transition key regulators, such as Cyclin D1 and CDK6. Additionally, up-regulation of miRNA-320c could significantly impair migration and invasion of glioma cells via reducing the expression of MMP2, MMP9, N-cadherin and Integrin beta1. Collectively, our data revealed that miRNA-320c played a crucial role in the carcinoma processes of glioma and might serve as a new prognosis biomarker and therapeutic target of glioma. PMID- 29438780 TI - Modulation of central endocannabinoid system results in gastric mucosal protection in the rat. AB - : Previous findings showed that inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), degrading enzymes of anandamide (2-AEA) and 2 arachidonoylglycerol (2-AG), reduced the nonsteroidal anti-inflammatory drug induced gastric lesions. The present study aimed to investigate: i./whether central or peripheral mechanism play a major role in the gastroprotective effect of inhibitors of FAAH, MAGL and AEA uptake, ii./which peripheral mechanism(s) may play a role in mucosal protective effect of FAAH, MAGL and uptake inhibitors. METHODS: Gastric mucosal damage was induced by acidified ethanol. Gastric motility was measured in anesthetized rats. Catalepsy and the body temperature were also evaluated. Mucosal calcitonin gene-related peptide (CGRP), somatostatin concentrations and superoxide dismutase (SOD) activity were measured. The compounds were injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). RESULTS: 1. URB 597, JZL184 (inhibitors of FAAH and MAGL) and AM 404 (inhibitor of AEA uptake) decreased the mucosal lesions significantly given either i.c.v. or i.p. 2. URB 937, the peripherally restricted FAAH inhibitor failed to exert significant action injected i.p. 3. Ethanol-induced decreased levels of mucosal CGRP and somatostatin were reversed by URB 597, JZL 184 and AM 404, the decreased SOD activity was elevated significantly by URB 597 and JZL 184. 4. Neither compounds given i.c.v. influenced gastric motility, elicited catalepsy, or hypothermia. CONCLUSION: Elevation of central endocannabinoid levels by blocking their degradation or uptake via stimulation of mucosal defensive mechanisms resulted in gastroprotective action against ethanol-induced mucosal injury. These findings might suggest that central endocannabinoid system may play a role in gastric mucosal defense and maintenance of mucosal integrity. PMID- 29438781 TI - Neurobiological links between depression and AD: The role of TGF-beta1 signaling as a new pharmacological target. AB - In the last several years a large number of studies have demonstrated the neurobiological and clinical continuum between depression and Alzheimer's disease (AD). Depression is a risk factor for the development of AD, and the presence of depressive symptoms significantly increases the conversion of Mild Cognitive Impairment (MCI) into AD. Common pathophysiological events have been identified in depression and AD, including neuroinflammation with an aberrant Tumor Necrosis Factor-alpha (TNF-alpha) signaling, and an impairment of Brain-Derived Neurotrophic Factor (BDNF) and Transforming-Growth-Factor-beta1 (TGF-beta1) signaling. TGF-beta1 is an anti-inflammatory cytokine that exerts neuroprotective effects against amyloid-beta (Abeta)-induced neurodegeneration, and it has a key role in memory formation and synaptic plasticity. TGF-beta1 plasma levels are reduced in major depressed patients (MDD), correlate with depression severity, and significantly contribute to treatment resistance in MDD. The deficit of Smad dependent TGF-beta1 signaling is also an early event in AD pathogenesis, which contributes to inflammaging and cognitive decline in AD. A long-term treatment with antidepressants such as selective-serotonin-reuptake inhibitors (SSRIs) is known to reduce the risk of AD in patients with depression and, SSRIs, such as fluoxetine, increase the release of TGF-beta1 from astrocytes and exert relevant neuroprotective effects in experimental models of AD. We propose the TGF-beta1 signaling pathway as a common pharmacological target in depression and AD, and discuss the potential rescue of TGF-beta1 signaling by antidepressants as a way to prevent the transition from depression to AD. PMID- 29438782 TI - Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: Involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors. AB - Semicarbazide-sensitive amine oxidase (SSAO) produces tissue irritants by deamination of primary amines, which activate transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly on nociceptors. Since there are no data about its functions in pain, we studied the effects and mechanisms of action of our novel SSAO inhibitor and dual TRPA1/TRPV1 antagonist multi-target drug SZV 1287 in different pain models. Acute chemonociception was induced by TRPV1 and TRPA1 activation (resiniferatoxin and formalin, respectively), chronic arthritis by K/BxN serum transfer, traumatic mononeuropathy by sciatic nerve ligation. SZV 1287 (20 mg/kg i.p.) was investigated in C57BL/6J wildtype (WT), TRPA1- (TRPA1-/-) and TRPV1-deficient (TRPV1-/-) mice. Paw mechanonociception was measured by aesthesiometry, thermonociception by hot plate, nocifensive behavior by licking duration, volume by plethysmometry, myeloperoxidase activity by luminescence and plasma extravasation by fluorescence imaging, glia activation in pain-related brain regions by immunohistochemistry. SZV 1287 significantly inhibited both TRPA1 and TRPV1 activation-induced acute chemonociception and hyperalgesia. In K/BxN arthritis, daily SZV 1287 injections significantly decreased hyperalgesia, L4-L6 spinal dorsal horn microgliosis, edema and myeloperoxidase activity. SZV 1287 evoked antihyperalgesic and anti-edema effects were absent in TRPV1-/-, and remarkably reduced in TRPA1-/- mice. In contrast, myeloperoxidase-inhibitory effect was absent in TRPA1-/-, but not in TRPV1-/- animals. Acute SZV 1287 administration resulted in approximately 50% significant reduction of neuropathic hyperalgesia 7 days after nerve ligation, which was not observed in either TRPA1 /- or TRPV1-/- mice. SZV 1287 inhibits chronic inflammatory and neuropathic pain via TRPV1 and TRPA1/TRPV1 activation, respectively, highlighting its drug developmental potential. PMID- 29438783 TI - Construction of a high-efficiency cloning system using the Golden Gate method and I-SceI endonuclease for targeted gene replacement in Bacillus anthracis. AB - To investigate gene function in Bacillus anthracis, a high-efficiency cloning system is required with an increased rate of allelic exchange. Golden Gate cloning is a molecular cloning strategy allowing researchers to simultaneously and directionally assemble multiple DNA fragments to construct target plasmids using type IIs restriction enzymes and T4 DNA ligase in the same reaction system. Here, a B. anthracis S-layer protein EA1 allelic exchange vector was successfully constructed using the Golden Gate method. No new restriction sites were introduced into this knockout vector, and seamless assembly of the DNA fragments was achieved. To elevate the efficiency of homologous recombination between the allelic exchange vector and chromosomal DNA, we introduced an I-SceI site into the allelic exchange vector. The eag gene was successfully knocked out in B. anthracis using this vector. Simultaneously, the allelic exchange vector construction method was developed into a system for generating B. anthracis allelic exchange vectors. To verify the effectiveness of this system, some other allelic exchange vectors were constructed and gene replacements were performed in B. anthracis. It is speculated that this gene knockout vector construction system and high-efficiency targeted gene replacement using I-SceI endonuclease can be applied to other Bacillus spp. PMID- 29438784 TI - Novel antibody-cytokine fusion proteins featuring granulocyte-colony stimulating factor, interleukin-3 and interleukin-4 as payloads. AB - Neutrophils can strongly influence disease activity in cancer and in chronic inflammation. Here, we report for the first time the construction and characterization of antibody-fusion proteins featuring granulocyte-colony stimulating factor and interleukin-3 as payloads capable of enhancing neutrophil activity and a novel antibody-interleukin-4 fusion protein with neutrophil inhibitory potential. We used the F8 antibody specific to the alternatively spliced extra domain A (EDA) of fibronectin as a targeting agent, since the cognate antigen is strongly upregulated in diseases characterized by angiogenesis. The fusion proteins GCSF-F8, F8-IL3 and F8-IL4-F8, were cloned, expressed, and their targeting ability assessed, exhibiting preferential tumor uptake with tumor:blood ratios at 24 h after injection of 3.3, 18.2 and 27.3, respectively. In F9 tumor bearing-mice GCSF-F8 and F8-IL3 did not provide a therapeutic benefit, while F8-IL4-F8 showed a potent tumor growth retardation. In the collagen-induced model of arthritis, GCSF-F8 and F8-IL3 induced a worsening of the disease, while F8-IL4-F8 slowed arthritis progression but, surprisingly, exhibited substantial toxicity when used in combination with dexamethasone. Collectively, the results indicate that the novel fusion proteins could be expressed and efficiently delivered to the site of disease. However, they were not superior to other antibody-cytokine fusions previously described by our laboratory. PMID- 29438785 TI - Low-molecular weight keratins with anti-skin aging activity produced by anaerobic digestion of poultry feathers with Fervidobacterium islandicum AW-1. AB - Bioactive peptides contribute to various cellular processes including improved skin physiology. Hence, bioactive keratins have attracted considerable attention as active cosmetic ingredients for skin health. Here, we obtained low molecular weight (LMW) keratins from native chicken feathers by anaerobic digestion with an extremely thermophilic bacterium Fervidobacterium islandicum AW-1, followed by stepwise fractionation through ultrafiltration. To assess the effects of the feather keratins on skin health, we performed in vitro and ex vivo assays to investigate their inhibitory effects on matrix metalloproteinases (MMPs). As results, LMW feather keratins marginally inhibited collagenase, elastase, and radical scavenging activities. On the other hand, LMW feather keratins significantly suppressed the expression of ultraviolet B (UVB)-induced MMP-1 and MMP-13 in human dermal fibroblasts. Furthermore, phospho-kinase antibody array revealed that LMW feather keratins suppressed UVB-induced phosphorylation of Akts, c-Jun N-terminal kinases 1, p38 beta, and RSK2, but not ERKs in human dermal fibroblast. Overall, these results suggest that LMW feather keratins are potential candidates as cosmeceutical peptides for anti-skin aging. PMID- 29438786 TI - Sphenoid Mucocele with Intracranial Extension: An Anatomic Perspective. AB - BACKGROUND: Isolated sphenoid mucoceles are rare, but because of their close proximity to important vasculonervous structures, local extension may result in serious consequences. CASE DESCRIPTION: A 47-year-old patient presented with headaches, meningismus, and a left homonymous lateral hemianopia. We report the atypical evolution of a posttraumatic sphenoid mucocele invading the sellar region and extending into the subarachnoid space with compression of the right optic tract, and we describe its surgical management. Further, with the aid of cadaveric specimens, we aim to analyze the precise pathway followed by the expanding collection from an anatomic perspective. CONCLUSIONS: Anatomic knowledge of the sellar and parasellar regions is the key to understand the process of how sphenoid mucoceles may extend intracranially. Early endoscopic drainage with a large sphenoidotomy allows favorable outcomes and prevents serious consequences. PMID- 29438788 TI - Cerebellar Peduncle Localized Oligodendroglioma: Case Report and Review of the Literature. AB - BACKGROUND: Oligodendrogliomas constitute 5% of all primary brain tumors and are the third most common cancer among intracranial tumors. More than 90% of oligodendrogliomas have supratentorial localization. Oligodendrogliomas arising in cerebellar peduncle are substantially rare, <1%. Up to now, 6 oligodendroglioma cases with cerebellar peduncle localization have been presented. We aimed to discuss our World Health Organization grade II oligodendroglioma case, which originated from cerebellar peduncle in the light of literature. CASE DESCRIPTION: We report a case of 43-year-old woman. Her complaints were headache, perioral numbness and gait abnormality. Magnetic resonance imaging revealed cyst-like well-demarcated lesion localized in right cerebellar peduncle. Tumor excision was performed by turning around the tumor. CONCLUSION: It should be kept in mind that oligodendrogliomas may be present as cerebellar peduncle localized tumors. PMID- 29438787 TI - S2 Alar-Iliac Screw Insertion: Technical Note with Pictorial Guide. AB - BACKGROUND: The S2 alar-iliac (S2AI) screw is a modification of the iliac fixation technique using the space between the neuroforamina of S1 and S2 as an insertion point to fix the sacrum to the ilium. To our knowledge, an anatomic review of the S2AI technique has not been described and the insertion point is vague and angles differ in reports from the literature. The purpose of the current anatomic illustration is to provide step-by-step techniques with fluoroscopic imaging to help confirm the safe placement of S2AI screws. METHODS: The procedure was performed on the left and rights sides of a fresh, frozen, and thawed predissected male cadaver in a surgical training facility through a standard posterior midline exposure for placement of the S2AI screws. All screws were placed by a fellowship-trained spine surgeon and an attending spine surgeon. RESULTS: The specimen was placed prone, and a midline incision begun at the L4 or L5 spinous process. Using the anteroposterior and inlet views, the S1 dorsal sacral foramen, the S1 endplate, and the sacroiliac joint can be identified. The insertion point is 10 mm laterally between the S1 and S2 foramina and near to the sacroiliac joint. Aim toward the anterior inferior iliac spine is ensured by using a 30 degrees -40 degrees lateral angulation in the transverse plane and 20 degrees -30 degrees caudal angulation in the sagittal plane depending on the sacral angulation. Using lateral fluoroscopy, the acetabulum and greater sciatic notch can be identified and screw misplacement can be avoided. The screw length is measured and is usually between 60 and 90 mm (8- to 9-mm diameter). An elevator is used to identify the outer sacral cortex. Anteroposterior, obturator outlet, and teardrop views are used to ensure correct screw insertion. CONCLUSIONS: Fluoroscopic guidance is crucial for optimal S2AI screw placement. Using the described technique allows a safe and correct insertion of the S2AI screw. PMID- 29438789 TI - "Suspended Posterior Tubercle of Atlas" with Atlantoaxial Dislocation. AB - INTRODUCTION: Congenital anomaly of the C1 posterior arch is a well-known entity and is often associated with atlantoaxial dislocation. However, a well-formed C1 posterior tubercle with absence of the remaining posterior arch is rare. Such unusual anomalies pose a surgical challenge as trying to delineate the arch early in the course of surgery could be potentially dangerous. We discuss here a similar case of C1 posterior arch defect with atlantoaxial dislocation and its management. CASE REPORT: A 17-year-old female presented with progressive spastic quadriparesis and neck pain. Evaluation revealed atlantoaxial dislocation with the presence of a well-formed posterior C1 tubercle in the absence of the rest of the posterior arch. C1-C2 joints were opened, and lateral masses were fused in reduced position. Intraoperatively, a posterior C1 tubercle was found suspended from the lateral masses by fibrous bands. The surgical nuances have been discussed. CONCLUSION: Presence of posterior tubercle alone with aplasia of the posterior arch results from a persistent posterior ossification center with nonextension of lateral ossification centers. In the presence of the C1 posterior fibrous arch, the joint spaces must be exposed first before attempting to delineate the posterior arch. This will prevent inadvertent injury to the vertebral artery and dura. PMID- 29438790 TI - Cervical Spinal Fusion: 16-Year Trends in Epidemiology, Indications, and In Hospital Outcomes by Surgical Approach. AB - BACKGROUND: The rate of cervical spinal fusion has been increasing significantly. However, there is a paucity of literature describing trends based on surgical approach using complete population databases. We investigated the approach-based trends in epidemiology, indications, and in-hospital outcomes of cervical spinal fusion. METHODS: New York's Statewide Planning and Research Cooperative System database was queried to identify patients who underwent primary subaxial cervical fusion from 1997 to 2012. Demographic and clinical information was obtained. Subgroup analyses were performed based on surgical approach: anterior (A), posterior (P), and circumferential (C). RESULTS: A total of 87,045 cervical fusions were included. Over the study period, the population-adjusted annual fusion rate increased from 23.7 to 50.6 per 100,000 population (P < 0.001). A fusion was most common (85.2%), followed by P (12.3%), and C (2.5%). Mean ages were 49.8 +/- 11.9, 59.9 +/- 15.2, and 55.1 +/- 14.5 years (P < 0.001), respectively. Although rates remained steady among younger patients, they increased for older patients. Overall, degenerative conditions were the predominant indications for surgery and increased in rate over time. The mean length of stay was: A, 3.1 +/- 10.5; P, 9.1 +/- 14.1; and C, 14.1 +/- 22.5 days (P < 0.001). Rates of in-hospital complications were A, 3.0%; P, 10.5%; and C, 18.9% (P < 0.001), and mortality was A, 0.3%, P, 1.8%, and C, 2.5% (P < 0.001). CONCLUSIONS: The rate of subaxial spinal fusions increased 114% from 1997 to 2012 in New York State. Rates remained stable in younger patients but increased in the older population. Preoperative indications and postoperative courses differed significantly among the various approaches, with patients undergoing anterior fusion having better short-term outcomes. PMID- 29438791 TI - Necessity of Repeat Computed Tomography Imaging in Isolated Mild Traumatic Subarachnoid Hemorrhage. AB - BACKGROUND: The standard of care for mild isolated traumatic subarachnoid hemorrhage (itSAH) involves serial head computed tomography (CT) examinations at dedicated time intervals to monitor neurologic status and hemorrhagic progression. Considering recent evidence questioning such an aggressive monitoring protocol, this study aimed to assess the necessity of repeat head CT imaging in managing itSAH. METHODS: All patients who presented to our academic institution with mild traumatic brain injury were evaluated. Patients >=18 years of age presenting with mild, blunt itSAH (Glasgow Coma Scale [GCS] score 13-15) were included. Patients with significant polytrauma or coagulopathy were excluded. Patient demographics (age and sex), imaging results (CT progression), and outcomes (final GCS score, discharge status, interventions, and 30-day readmission) were all recorded. RESULTS: Of 190 cases identified for inclusion, 58 (30.5%) met all study criteria (age, 59.5 +/- 18.0 y; 30 men). Five (8.6%) patients presented with repeat CT progression, with none reporting 30-day readmission or adverse event on follow-up. Comparison of cases with and without CT progression found no meaningful differences in age or sex. Of the 3 patients readmitted, none demonstrated CT progression, and cause of readmission was unrelated to head trauma in all cases. Two patients demonstrated clinical deterioration (final GCS score <14), and neither case showed progression on CT, was readmitted, or received neurosurgical intervention of any kind. CONCLUSIONS: Our findings suggest that serial CT imaging has little efficacy in changing mild itSAH management and is poorly correlated with clinical progression. A less aggressive management protocol may be more appropriate for managing this patient population. PMID- 29438792 TI - The First Neurosurgery Boot Camp in Southeast Asia: Evaluating Impact on Knowledge and Regional Collaboration in Yangon, Myanmar. AB - BACKGROUND: For the first time in Southeast Asia, a Fundamentals of Neurosurgery Boot Camp was held at the University of Medicine 1 in Yangon, Myanmar, February 24-26, 2017. The aim of this course was to teach and train fundamental skills to neurosurgery residents. METHODS: The Myanmar Neurosurgical Society, Foundation for International Education in Neurosurgery, Society for Neurological Surgeons, The University of Medicine 1 in Yangon, Myanmar, and the Henry Ford Department of Neurosurgery developed a 2-day resident training course. Day 1 activities consisted of lectures by faculty, small group case discussions, and industry supported demonstrations of surgical techniques. Day 2 activities consisted of hands-on skill stations for common neurosurgical procedures with each station supervised by attending faculty. Written evaluations were distributed before the meeting, immediately after the meeting, and 6 months after the meeting. RESULTS: Boot camp attendees included 40 residents and 24 neurosurgical faculty from Myanmar, Cambodia, Nepal, Singapore, South Korea, Thailand, and Vietnam. There were 35 evaluations completed before the boot camp, 34 completed immediately after boot camp, and 20 completed 6 months after boot camp. Knowledge of participants improved from 62.75% before boot camp to 71.50% 6 months after boot camp (P = 0.046). CONCLUSIONS: Boot camps provide fundamental didactic and technical exposure to trainees in developed and developing countries and help standardize training in basic neurosurgical competencies, while exposing local faculty to important teaching methods. This model provides a sustainable solution to educational needs and demonstrates to local neurosurgeons how they can take ownership of the educational process. PMID- 29438793 TI - Transvertebral Bone Graft and Augmentation Versus Posterior Spinal Instrumentation in the Treatment of Simple Thoracolumbar Compression Fractures. AB - OBJECTIVE: This retrospective cohort study was performed to investigate clinical efficacy of TBGA compared with pedicle screw fixation (PSF). METHODS: A total of 86 eligible patients with single-level simple thoracolumbar compression fracture (TLCF) received TBGA (n = 41) or PSF (n = 45) from January 2013 to July 2015. The patients were evaluated using plain radiography, computed tomography, and magnetic resonance imaging preoperatively. The radiologic examinations were performed at each time point postoperatively. Clinical status was assessed using the Oswestry Disability Index (ODI) and visual analog scale (VAS) scores. In addition, anterior vertebral body height (AVBH), kyphosis angle (KA), radiologic adjacent segment pathology (RASP), and complication rates were also compared between the 2 groups. The average follow-up period of patients was 26.1 months. RESULTS: Significant clinical improvements in ODI, VAS, AVBH, and KA were achieved in both TBGA and PSF groups after surgery, respectively (P < 0.05). There was no statistical difference in improvements of ODI and VAS between the TBGA and PSF groups (P > 0.05). Similarly, improvements of AVBH and KA showed no statistical difference between the 2 groups (P > 0.05). In addition, the rates of RASP and complications in PSF group were significantly higher than the TBGA group during the follow-up period (P < 0.05). CONCLUSIONS: TBGA can achieve satisfactory clinical effects in treatment of simple TLCF. TBGA involves shorter operative time, less blood loss, lower RASP, and lower complication rates and could be more suitable for the surgical treatment of simple TLCF. PMID- 29438794 TI - Discrete multi-physics simulations of diffusive and convective mass transfer in boundary layers containing motile cilia in lungs. AB - In this paper, the mass transfer coefficient (permeability) of boundary layers containing motile cilia is investigated by means of discrete multi-physics. The idea is to understand the main mechanisms of mass transport occurring in a ciliated-layer; one specific application being inhaled drugs in the respiratory epithelium. The effect of drug diffusivity, cilia beat frequency and cilia flexibility is studied. Our results show the existence of three mass transfer regimes. A low frequency regime, which we called shielding regime, where the presence of the cilia hinders mass transport; an intermediate frequency regime, which we have called diffusive regime, where diffusion is the controlling mechanism; and a high frequency regime, which we have called convective regime, where the degree of bending of the cilia seems to be the most important factor controlling mass transfer in the ciliated-layer. Since the flexibility of the cilia and the frequency of the beat changes with age and health conditions, the knowledge of these three regimes allows prediction of how mass transfer varies with these factors. PMID- 29438795 TI - Independent suboesophageal neuronal innervation of the defense gland and longitudinal muscles in the stick insect (Peruphasma schultei) prothorax. AB - This study investigates the neuroanatomy of the defense gland and a related muscle in the stick insect Peruphasma schultei with axonal tracing and histological sections. The gland is innervated by three neurons through the Nervus anterior of the suboesophageal ganglion (SOG), the ipsilateral neuron (ILN), the contralateral neuron (CLN) and the prothoracic intersegmental neuron (PIN). The ILN has a large soma which is typical for motoneurons that cause fast contraction of large muscles and its dendrites are located in motor-sensory and sensory neuropile areas of the SOG. The CLN might be involved in the coordination of bilateral or unilateral discharge as its neurites are closely associated to the ILN of the contralateral gland. Close to the ejaculatory duct of the gland lies a dorsal longitudinal neck muscle, musculus pronoto-occipitalis (Idlm2), which is likely indirectly involved in gland discharge by controlling neck movements and, therefore, the direction of discharge. This muscle is innervated by three ventral median neurons (VMN). Thus, three neuron types (ILN, CLN, and PIN) innervate the gland muscle directly, and the VMNs could aid secretion indirectly. The cytoanatomy of motorneurons innervating the defense gland and neck muscle are discussed regarding the structure and functions of the neuropile in the SOG. As a basis for the neuroanatomical study on the defense gland we assembled a map of the SOG in Phasmatodea. PMID- 29438796 TI - Validation of assessment of intraoral digital photography for evaluation of dental restorations in clinical research. AB - OBJECTIVES: The aim of this study was to investigate the validity of assessment of intraoral digital photography in the evaluation of dental restorations. METHODS: Intraoral photographs of anterior and posterior restorations were classified based on FDI criteria according to the need for intervention: no intervention, repair and replacement. Evaluations were performed by an experienced expert in restorative dentistry (gold standard evaluator) and 3 trained dentists (consensus). The clinical inspection was the reference standard method. The prevalence of failures was explored. Cohen's kappa statistic was used. Validity was accessed by sensitivity, specificity, likelihood ratio and predictives values. RESULTS: Higher prevalence of failed restorations intervention was identified by the intraoral photography (17.7%) in comparison to the clinical evaluation (14.1%). Moderate agreement in the diagnosis of total failures was shown between the methods for the gold standard evaluator (kappa = 0.51) and consensus of evaluators (kappa = 0.53). Gold standard evaluator and consensus showed substantial and moderate agreement for posterior restorations (kappa = 0.61; 0.59), and fair and moderate agreement for anterior restorations (kappa = 0.36; 0.43), respectively. The accuracy was 84.8% in the assessment by intraoral photographs. Sensitivity and specificity values of 87.5% and 89.3% were found. CONCLUSIONS: Under the limits of this study, the assessment of digital photography performed by intraoral camera is an indirect diagnostic method valid for the evaluation of dental restorations, mainly in posterior teeth. This method should be employed taking into account the higher detection of defects provided by the images, which are not always clinically relevant. PMID- 29438797 TI - Association of alcohol dehydrogenase 1C gene *1/*2 polymorphism with alcohol Dependence(AD) in Turkey: A meta-analysis. AB - Previous studies have investigated the association between ADH1C *1/*2 polymorphism and alcohol dependence (AD), but have yielded controversial results in Turkey. Therefore, in an effort to illustrate whether ADH1C *1/*2 polymorphism is associated with AD risk in Turkish population, we used meta analysis to synthetically evaluate the effect of ADH1C *1/*2 polymorphism on AD. Publications were identified by searching in PubMed and EMBASE databases. Four eligible studies involving 400 controls and 421 cases were included in this study. Overall, there is a significant association between ADH1C *1/*2 polymorphism and AD risk in the allelic model (OR = 1.66, 95% CI = 1.05-2.62, P = 0.03) and recessive model (OR = 1.72, 95% CI = 1.14-2.58, P = 0.01), while no significance was discovered in the dominant genetic model, homozygote model and heterozygotemodel. No publication bias was indicated from Begg's and Egger's test. Our meta-analysis results suggested that a potential relationship between ADH1C *1/*2 polymorphism and AD risk in Turkish population. Further studies are confirmed to resolve this question about the etiological mechanisms of the correlation. PMID- 29438798 TI - Short-term fasting decreases excitatory synaptic inputs to ventromedial tuberoinfundibular dopaminergic neurons and attenuates their activity in male mice. AB - Tuberoinfundibular dopaminergic (TIDA) neurons in the arcuate nucleus (ARC) of the hypothalamus play a role in inhibiting prolactin (PRL) secretion from the anterior pituitary. PRL is involved in a variety of behaviors, including feeding. Consequently, we hypothesized that fasting might reduce the activity of TIDA neurons, which might alter PRL secretion. However, direct examinations of TIDA neuron activity are difficult. Recently, transgenic mice were generated that expressed green fluorescent protein (GFP) under the control of the rat tyrosine hydroxylase gene. We first determined that GFP in the dorsomedial ARC was a reliable marker of TIDA neurons. Then, we performed electrophysiology and immunocytochemistry in GFP-labeled TIDA neurons to examine whether different feeding conditions could change their activity. Eight-week-old male mice were fed or fasted for 24 h. After sacrifice, we prepared acutely isolated brain slices for conducting whole-cell voltage-clamp recordings. TIDA neurons were identified with fluorescence microscopy. The mean amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced in fasting mice compared to fed mice, but different feeding conditions did not affect the mean mEPSC intervals. This result suggested that fasting reduced the number of excitatory synaptic inputs to TIDA neurons. To determine whether a reduction in excitatory synaptic inputs would cause a reduction in TIDA neuron activity, we examined the effect of 24-h fasting on c-Fos expression in the ARC. We found that fasting significantly reduced the number of Fos-positive TIDA neurons. In addition, serum PRL levels were significantly increased. Taken together, the present findings suggested that short-term fasting attenuated TIDA neuron activity. PMID- 29438799 TI - Lig4-4 selectively inhibits TREK-1 and plays potent neuroprotective roles in vitro and in rat MCAO model. AB - Two-pore domain potassium channel TREK-1 was known to play an important role in neuroprotection, especially in acute cerebral ischemia. In the present study we found that 3-(nitromethyl) isobenzofuran-1(3H)-one (lig4-4) could robustly inhibit TREK-1 currents with an IC50 of 2.06 MUM. However, the IC50 of lig4-4 for other ion channel subtypes such as Kv2.1, Kv1.5, Kv3.1, hERG and neuronal Na+ and Ca2+ channels were more than 30 MUM, suggesting a specific inhibition of TREK-1 channel. MTT assay showed that lig4-4 significantly enhanced cell viability of cultured neurons under the condition of oxygen and glucose deprivation followed by reoxygenation (OGD/R). Annexin V/Propidium Iodide apoptosis assay also demonstrated that lig4-4 obviously reduced cell apoptosis in OGD/R-injured neurons. Western blotting results indicated that OGD/R-induced up-regulation of cleaved-caspase-3 expression and down-regulation of Bcl-2 could be notably reversed by lig4-4. The in vivo study showed that after oral administration of lig4-4 at 50 mg/kg, the infarct volume in middle cerebral artery occlusion (MCAO) rat model reduced from a vehicle control of 38.8% to 28%. Both in vitro and in vivo studies suggested that inhibition of TREK-1 with lig4-4 might produce a neuroprotective effect against cerebral ischemia. In conclusion, we demonstrated that lig4-4 selectively inhibited TREK-1 and protected brain from cerebral ischemic injury. The mechanisms might relate to block TREK-1 and inhibit neuronal apoptosis by modulating the expressions of Bcl-2 and cleaved-caspase-3. PMID- 29438800 TI - Intracellular pH Regulation in iPSCs-derived Astrocytes from Subjects with Chronic Mountain Sickness. AB - Chronic Mountain Sickness (CMS) occurs in high-altitude residents with major neurological symptoms such as migraine headaches, dizziness and cognitive deficits. Recent work demonstrated that highlanders have increased intracellular pH (pHi) in their brain cells, perhaps for the sake of adaptation to hypoxemia and help to facilitate glycolysis, DNA synthesis, and cell cycle progression. Since there are well adapted (non-CMS) and maladapted (CMS) high-altitude dwellers, it is not clear whether pHi is differently regulated in these two high altitude populations. In this work, we obtained induced pluripotent stem cell (iPSC)-derived astrocytes from both CMS and non-CMS highlanders who live in the Peruvian Andes (>14,000 ft) and studied pHi regulation in these astrocytes using pH-sensitive dye BCECF. Our results show that the steady-state pHi (ss pHi) is lower in CMS astrocytes compared with non-CMS astrocytes. In addition, the acid extrusion following an acid loading is faster and the pHi dependence of H+ flux rate becomes steeper in CMS astrocytes. Furthermore, the Na+ dependency of ss pHi is stronger in CMS astrocytes and the Na+/H+ exchanger (NHE) inhibitors blunted the acid extrusion in both CMS and non-CMS astrocytes. We conclude that (a) NHE contributes to the ss pHi stabilization and mediates active acid extrusion during the cytosolic acidosis in highlanders; (b) acid extrusion becomes less pHi sensitive in non-CMS (versus CMS) astrocytes which may prevent NHE from over activated in the hypoxia-induced intracellular acidosis and render the non-CMS astrocytes more resistant to hypoxemia challenges. PMID- 29438802 TI - Endocannabinoid Signaling in Embryonic Neuronal Motility and Cell-Cell Contact - Role of mGluR5 and TRPC3 Channels. AB - Cell-cell communication plays a central role in the guidance of migrating neuronal precursor cells during the development of the cerebral cortex. Endocannabinoids (eCBs) have previously been shown to be one of the central factors regulating neuronal migration. In this study the effects of eCBs on different parameters, expected to affect embryonic cortical neuronal motility have been analyzed in neurosphere-derived neuroblasts using time-lapse microscopy. Increased endogenous production of the endocannabinoid 2-arachidonyl glycerol (2-AG) causes bursts of neuroblast motility. The neuroblasts move longer distances and show a low frequency of turning, and the number of neuron-neuron contacts are reduced. Similar changes occur interfering with the function of the metabotropic glutamate receptor 5 (mGluR5) or its transducer canonical transient receptor potential channel 3 (TRPC3) or the neuregulin receptor ErbB4. Blocking of 2-AG production reverses these effects. The data suggest that eCB-regulated neuronal motility is controlled by mGluR5/TRPC3 activity possibly via NRG/ErbB4 signaling. PMID- 29438801 TI - Specific Activity Features in the Forced Swim Test: Brain Neurotrophins and Development of Stress-induced Depressive-like Behavior in Rats. AB - Selective vulnerability or resilience to mood disorders is related to individual differences or personality. In the present study forced swim test (FST) was used as a tool for division of male rats according to their immobility behavior. The animals were subjected to a chronic unpredictable mild stress (CUS). Depressive like behavior and modifications in brain neurotrophin system of were examined after CUS exposure. The low immobile (LI) and high immobile (HI) rats demonstrated elusive differences in expression of BDNF ExVI mRNA and TrkA mRNA which was higher in the hippocampus and frontal cortex, respectively, of HI rats as compared to LI animals. Exposure to CUS resulted in development of depressive like phenotype and increased anxiety in both subgroups; however, immobility in FST specifically decreased in the initially HI animals. In hippocampus of stressed LI rats, the contents of total BDNF mRNA decreased. In hippocampus of stressed HI rats, the content of TrkA mRNA increased whereas in frontal cortex, the content of BDNF exon I mRNA decreased in both LI and HI rats. The levels of BDNF ExIX and ExI as well TrkB mRNAs were higher in the hippocampus of HI rats as compared to LI rats. In general, the response of hippocampus to CUS was much more expressed as compared to frontal cortex. Thus, initially different stress coping strategies of rats in the FST (HI, LI) were associated with the development of similar behavioral phenotypes after chronic unpredictable stress; however, these phenotypes were associated with different alterations in neurotrophin systems of the brain. PMID- 29438803 TI - Sleep State Dependence of Optogenetically evoked Responses in Neuronal Nitric Oxide Synthase-positive Cells of the Cerebral Cortex. AB - Slow-wave activity (SWA) in the electroencephalogram during slow-wave sleep (SWS) varies as a function of sleep-wake history. A putative sleep-active population of neuronal nitric oxide synthase (nNOS)-containing interneurons in the cerebral cortex, defined as such by the expression of Fos in animals euthanized after protracted deep sleep, may be a local regulator of SWA. We investigated whether electrophysiological responses to activation of these cells are consistent with their role of a local regulator of SWA. Using a Cre/loxP strategy, we targeted the population of nNOS interneurons to express the light-activated cation channel Channelrhodopsin2 and the histological marker tdTomato in mice. We then performed histochemical and optogenetic studies in these transgenic mice. Our studies provided histochemical evidence of transgene expression and electrophysiological evidence that the cerebral cortex was responsive to optogenetic manipulation of these cells in both anesthetized and behaving mice. Optogenetic stimulation of the cerebral cortex of animals expressing Channelrhodopsin2 in nNOS interneurons triggered an acute positive deflection of the local field potential that was followed by protracted oscillatory events only during quiet wake and slow wave sleep. The response during wake was maximal when the electroencephalogram (EEG) was in a negative polarization state and abolished when the EEG was in a positive polarization state. Since the polarization state of the EEG is a manifestation of slow-wave oscillations in the activity of underlying pyramidal neurons between the depolarized (LFP negative) and hyperpolarized (LFP positive) states, these data indicate that sleep-active cortical neurons expressing nNOS function in sleep slow-wave physiology. PMID- 29438804 TI - Axonal Activation of the Unfolded Protein Response Promotes Axonal Regeneration Following Peripheral Nerve Injury. AB - Adult mammalian peripheral neurons have an intrinsic regrowth capacity in response to axonal injury. The induction of calcium ion (Ca2+) oscillations at an injured site is critical for the regulation of regenerative responses. In polarized neurons, distal axonal segments contain a well-developed endoplasmic reticulum (ER) network that is responsible for Ca2+ homeostasis. Although these characteristics implicate the relevance among injury-induced Ca2+ dynamics, axonal ER-derived signaling, and regenerative responses propagated along the axons, the details are not fully understood. In the present study, we found that Ca2+ release from the axonal ER was accelerated in response to injury. Additionally, axonal injury-dependent Ca2+ release from the ER activated unfolded protein response (UPR) signaling at injured sites. Inhibition of axonal UPR signaling led to fragmentation of the axonal ER and disrupted growth cone formation, suggesting that activation of axonal UPR branches following axonal injury promotes regeneration via regulation of ER reconstruction and formation of growth cones. Our studies revealed that local activation of axonal UPR signaling by injury-induced Ca2+ release from the ER is critical for regeneration. These findings provide a new concept for the link between injury-induced signaling at a distant location and regulation of organelle and cytoskeletal formation in the orchestration of axonal regeneration. PMID- 29438805 TI - The correlation between National Health Service trusts' clinical trial activity and both mortality rates and care quality commission ratings: a retrospective cross-sectional study. AB - OBJECTIVES: Evidence supporting the notion that clinical research activity in itself is of benefit to organisations as a whole is inconclusive. In the recent past, a positive association between research activity and reduced mortality has been shown. This study aimed to ascertain if clinical research activity is associated with established organisational outcome measures. STUDY DESIGN: Retrospective cross-sectional study. METHODS: For 129 English National Health Service hospital Trusts, National Institute for Health Research study activity data, Summary Hospital-level Mortality Indicator (SHMI) scores and Care Quality Commission (CQC) ratings were collected. Research activity was controlled for Trust size by dividing it by clinical staffing levels. Multiple linear regression and Spearman correlation analyses were performed. RESULTS: Although there is a significant association between the number of studies and participants with both SHMI score and CQC rating, one particular variable is correlated more significantly than others: the number of participants recruited into interventional studies. It shows a significant correlation with better CQC ratings (standardised coefficient beta 0.26, P-value 0.003) and lower SHMI scores (standardised coefficient beta -0.50, P-value 0.001). CONCLUSIONS: The mortality related results corroborate with other published data showing a correlation between increased research and reduced deaths. Furthermore, there is also a statistically significant association between clinical trials activity and improved CQC ratings. However, these tie-ins are predominantly driven by the number of participants in interventional research rather than observational research activity. PMID- 29438806 TI - Initiation of the zygotic genetic program in the ascidian embryo. AB - In embryos of ascidians, which are invertebrate chordates, the expression of a small number of genes from the zygotic genome begins between the 8- and 16-cell stages. They are considered the first zygotic genes to be expressed under the direct control of maternal factors. The initial transcriptional quiescence before the 8-cell stage is essential for establishing differential gene expression patterns between the animal and vegetal hemispheres, because these hemispheres are first segregated into distinct blastomeres at the 8-cell stage. While the mechanisms of this transcriptional silencing have not been understood, the mechanism by which maternal factors cooperatively establish the first differential gene expression patterns has been well understood. Here, we review the initial processes that occur until the 16-cell stage in ascidian embryos. PMID- 29438807 TI - Lymphocyte integration of complement cues. AB - We address current data, views and puzzles on the emerging topic of regulation of lymphocytes by complement proteins or fragments. Such regulation is believed to take place through complement receptors (CR) and membrane complement regulators (CReg) involved in cell function or protection, respectively, including intracellular signalling. Original observations in B cells clearly support that complement cues through CR improve their performance. Other lymphocytes likely integrate complement-derived signals, as most lymphoid cells constitutively express or regulate CR and CReg upon activation. CR-induced signals, particularly by anaphylatoxins, clearly regulate lymphoid cell function. In contrast, data obtained by CReg crosslinking using antibodies are not always confirmed in human congenital deficiencies or knock-out mice, casting doubts on their physiological relevance. Unsurprisingly, human and mouse complement systems are not completely homologous, adding further complexity to our still fragmentary understanding of complement-lymphocyte interactions. PMID- 29438808 TI - Effect of tiotropium on spontaneous expiratory flow-volume curves during exercise in GOLD 1-2 COPD. AB - This substudy of a large, randomized, controlled trial (NCT01072396) examined tiotropium (18 MUg qd) effects on dynamic hyperinflation during constant work rate treadmill exercise. Areas-under-the-spontaneous expiratory flow-volume (SEFV)-curves were compared in 20 COPD patients and 16 age-matched untreated controls, using rectangular area ratio (RAR) between peak intrabreath and end expiratory flow. Seven patients exhibited SEFV curve concavity with RAR <= 0.5 (RARlow) in >=1 test without tiotropium; (mean +/- SD FEV1: 1.60 +/- 0.59 L; 63.4 +/- 14.0%predicted). In RARlow patients, tiotropium increased end-exercise inspiratory capacity (IC, 2.10 +/- 0.05 vs. 1.89 +/- 0.05 L, tiotropium vs. placebo; p = 0.045) and RAR (0.57 +/- 0.02 vs. 0.53 +/- 0.02; p < 0.001). Patients without SEFV curve concavity with RAR > 0.5 (n = 13; RARhigh), had higher screening FEV1 (2.15 +/- 0.47 L; 79.6 +/- 10.1%predicted) versus RARlow patients and no difference in end-exercise IC and RAR between tiotropium and placebo (IC: 2.24 +/- 0.03 vs. 2.17 +/- 0.03 L; RAR: 0.63 +/- 0.005 vs. 0.62 +/- 0.005). RAR and%predicted IC at peak exercise were positively correlated in RARlow patients (R2 = 0.43, p = 0.0002). Tiotropium increased exercise RAR in GOLD 1-2 patients with SEFV curve concavity. PMID- 29438809 TI - Flow visualization through particle image velocimetry in realistic model of rhesus monkey's upper airway. AB - Studies concerning inhalation toxicology and respiratory drug-delivery systems require biological testing involving experiments performed on animals. Particle image velocimetry (PIV) is an effective in vitro technique that reveals detailed inhalation flow patterns, thereby assisting analyses of inhalation exposure to various substances. A realistic model of a rhesus-monkey upper airway was developed to investigate flow patterns in its oral and nasal cavities through PIV experiments performed under steady-state constant inhalation conditions at various flow rates-4, 10, and 20 L/min. Flow rate of the fluid passing through the inlet into the trachea was measured to obtain characteristic flow mechanisms, and flow phenomena in the model were confirmed via characterized flow fields. It was observed that increase in flow rate leads to constant velocity profiles in upper and lower trachea regions. It is expected that the results of this study would contribute to future validation of studies aimed at developing in silico models, especially those involving computational fluid dynamic (CFD) analysis. PMID- 29438810 TI - Nasal high-frequency oscillatory ventilation inhibits gastroesophageal reflux in the neonatal period. AB - Nasal high-frequency oscillatory ventilation (nHFOV) in neonates is increasingly considered due to enhanced alveolar ventilation, absence of patient-ventilator asynchrony and lessened ventilator-induced lung injury. Although any type of non invasive respiratory support can lead to gastric distension via esophageal air passage and thus promote gastroesophageal refluxes (GERs), we have shown that nasal continuous positive airway pressure (CPAP; 6 cmH2O) and intermittent positive pressure ventilation (15/4 cmH2O) conversely inhibit GERs in lambs. The current objective was to test the hypothesis that nHFOV also inhibits GERs compared to spontaneous ventilation without respiratory support. Eight lambs underwent five hours of polysomnographic and esophageal multichannel intraluminal impedance pHmetry recordings to assess GERs and air passage into the esophagus, with and without nHFOV (mean airway pressure = 8 cmH2O, oscillation frequency = 8 Hz, amplitude ~ 20 cmH2O and I:E = 1:2). Results revealed that GERs were decreased with nHFOV (p = .03), despite an increase in gas-containing swallows (p = .01). In conclusion, similarly to nasal CPAP and intermittent positive pressure ventilation, nHFOV inhibits GERs in newborn lambs. PMID- 29438811 TI - Is cough important in acute exacerbations of COPD? AB - Chronic obstructive pulmonary disease is predicted to become the 4th leading cause of death worldwide by 2030. The natural history of the disease includes progressive symptoms punctuated by acute exacerbations during which symptoms rapidly deteriorate. The resulting disability places significant burden on health and social care systems. Cough is the second most common symptom reported by COPD patients, is a source of significant distress and is associated with adverse outcomes. We discuss the importance of cough in COPD, its mechanism and the relationship between cough and COPD exacerbations. We review the literature and present original data relating to the investigation of cough during COPD exacerbation, its associations and potential benefits of cough monitoring. PMID- 29438812 TI - Hyperoxia-induced regulation of cough reflex and its effect after antioxidant supplementation. AB - Hyperoxia-induced lung injury is well known in animal and human studies. The respiratory epithelium including sensory nerve endings is a major target for oxidative injury that manifested in lung function changes including cough. On the basis of available information we supposed that hyperoxia alone or in combination with primary lung tissue injury should have a damaging effect on lungs, including the airway nerve endings with the changes in the sensitivity of the central and peripheral neuronal pathways regulating cough. We have previously demonstrated that long-term exposure to 100% oxygen inhibits the cough reflex in cat. This review article summarizes the effect of hyperoxia on the cough reflex in guinea pig model using different concentrations of oxygen and different time of exposure. We also present information on the potential role of antioxidants in reversal of the detrimental effects of hyperoxia on coughing and additional analysis of experiments from previously published studies were obtained and analysed for the cough reflex sensitivity. PMID- 29438813 TI - Temporal variations and spatial distributions of heavy metals in a wastewater irrigated soil-eggplant system and associated influencing factors. AB - Heavy metal pollution in farmlands is highly concerned as crops' easy-uptake of heavy metal can ultimately affect consumers. In order to offer suggestions on cultivating safe quality vegetable, specifically eggplant which is widely consumed for its nutritional value and antioxidant activity, a field study was undertaken to investigate the temporal variations and spatial distributions of heavy metals in a wastewater-irrigated soil-eggplant system. In the present study, eggplants were planted in the farmlands of Weichuan village (WC) (relatively unpolluted field), Liangzhuang village (LZ) (moderately polluted field) and Minqin village (MQ) (seriously polluted field) to elucidate their temporal uptake processes of heavy metals described by the sigmoid model. Eggplant tissues from severely polluted farmlands were found with higher heavy metal concentrations and lower yields compared with other two groups. What is more, 25 farmlands along the Dongdagou stream (heavy metals polluted stream) were chosen to analyze the spatial distribution of heavy metals in soils and eggplants. Heavy metal concentrations in eggplants decreased with the decline of heavy metal concentrations in soil from upstream (pollution source) to downstream. Moreover, several methods were employed to assess bioavailability of heavy metals in soils. All the bioavailable heavy metals were found in linear positive correlations with heavy metal concentrations. Meanwhile, linear correlations were found between heavy metals in soils and eggplants. At last, redundancy analysis was used to investigate the effects of soil properties (pH, organic matter and texture of soils) and heavy metals on eggplants' uptake. The results indicated that soil heavy metals had a dominant impact on their accumulations in eggplant fruit, with a variance contribution of 78.0%, while soil properties had a regulatory effect, with a variance contribution of 5.2%. PMID- 29438814 TI - Inter-visit variability of conjunctival microvascular hemodynamic measurements in healthy and diabetic retinopathy subjects. AB - Conjunctival microcirculation imaging provides a non-invasive means for detecting hemodynamic alterations due to systemic and ocular diseases. However, reliable longitudinal monitoring of hemodynamic changes due to disease progression requires establishment of measurement variability over time. The purpose of the current study was to determine inter-visit variability of conjunctival microvascular hemodynamic measurements in non-diabetic control (NC, N = 7) and diabetic retinopathy (DR, N = 10) subjects. Conjunctival microvascular imaging was performed during 2 visits, which were 17 +/- 12 weeks apart. Images were analyzed to determine vessel diameter (D), axial blood velocity (V), blood flow (Q), wall shear rate (WSR) and wall shear stress (WSS). The inter-visit variability was determined based on mean inter-visit differences. In NC, inter visit variability of D, V, Q, WSR and WSS were 0.2 +/- 0.5 MUm, -0.01 +/- 0.16 mm/s, -8 +/- 46 pl/s, -3 +/- 46 s-1 and -0.01 +/- 0.10 dyne/cm2, respectively. Inter-visit variability of D, V, Q, WSR and WSS were beyond the normal 95% confidence limits in 60%, 20%, 40%, 20% and 20% of DR subjects, respectively. The variability of hemodynamic measurements over time was established in non-diabetic subjects, suggestive of the potential of the method for detecting longitudinal changes due to progression of DR. PMID- 29438815 TI - New onset squamous cell carcinoma in previous split-thickness skin graft donor site. AB - INTRODUCTION: Marjolin' s ulcer, an aggressive ulcerating squamous cell carcinoma, is a well-known phenomenon that occurs in chronically inflamed or scarred tissue; however, squamous cell carcinoma arising in the acute setting after tissue trauma - specifically autograft donor harvest sites for burns - is a rare, but notable event. METHODS: This case series describes three instances of squamous cell carcinoma diagnosed in split-thickness skin graft donor sites in the immediate post-operative period. Charts were reviewed in detail after at least 9 months follow-up from identification of the tumor. Detailed descriptions of each case are included. A discussion of the literature on this rare entity is included as well. RESULTS: In the three cases discussed, all were characterized clinically as painful masses arising in a recently healed donor site. Two were managed surgically with adherence to oncologic principals. One lesion regressed or fell off spontaneously. With at least 9 months follow-up, there was no evidence of recurrence. CONCLUSIONS: Very few cases of acute neoplasm in donor sites have been described in the literature. Presently, there is no dominant theory as to how these lesions arise; however, this is an entity that burn care providers, world wide should be aware of, with a low threshold for oncologic evaluation if suspected. PMID- 29438816 TI - The effect of tranexamic acid in unilateral and bilateral total knee arthroplasty in the South Asian population: A retrospective cohort study. AB - INTRODUCTION: Together with evidence of higher bleeding tendencies, the vulnerability of the South-Asian population to anemia secondary to a higher prevalence of hemoglobinopathies and micronutrient deficiencies merits further exploration of the effects of tranexamic acid on this population. Additionally, limited access to self-care facilities and certain sociocultural beliefs and practices may not be conducive to a speedy recovery from surgical complications. The aim of this study is to investigate the effects of intraoperative administration of tranexamic acid during total knee arthroplasty when considering the South-Asian population. METHODOLOGY: Medical record files of 355 patients who underwent total knee arthroplasty (2007-2015) were reviewed to collect data regarding patient characteristics, surgical variables and post-operative complications. Unilateral and Bilateral total knee arthroplasty were studied separately. Analysis was done using t-test, Mann-Whitney U test, chi-square and Fisher's exact square where appropriate. The threshold for significance was p < 0.05. RESULTS: The study showed that for unilateral surgery, tranexamic acid caused a significant reduction in estimated blood loss (p-value=0.011), total operative time, calculated blood loss, and hemoglobin change (p-value<0.001) whereas in bilateral surgery, tranexamic acid only caused a significant reduction in calculated blood loss (p-value < 0.001) and hemoglobin change (p-value=0.001). Interestingly, in those who received tranexamic acid vs. those who did not, there was a significant increase in length of hospital stay (p<0.001) and special care unit admissions (p-value=0.033) in unilateral and bilateral surgery respectively. CONCLUSIONS: Although tranexamic acid effectively reduces intraoperative blood loss, it does not have an effect on the need for post-operative blood transfusions. The increased length of stay and special care unit admissions associated with tranexamic acid use should be explored further to reveal the complete safety profile of tranexamic acid administration in the South-Asian population during total knee arthroplasty. PMID- 29438817 TI - The outcomes and complications of pancreaticoduodenectomy (Whipple procedure): Cross sectional study. AB - BACKGROUND: Pancreaticoduodenectomy (PD) is one of the most difficult and complex surgery that carries a high rate of major complications, including delayed gastric emptying (DGE), pancreatic fistula, bleeding, intra-abdominal collection, and pulmonary complications. In this study, we have tried to demonstrate the outcomes, and rates of complications from patients who had undergone this procedure by our surgical team. MATERIALS AND METHODS: This retrospective study has been constructed on 98 patients who underwent pancreaticoduodenectomy from May 2010 to November 2017 in three different hospitals of the Sulaimanyah governorate in the Kurdistan region of Iraq by the same surgical team. Data was collected from the medical records of patients. A preoperative work up had done for all patients, including those who are necessary for anesthesia fitness and those for staging assessment. None of the operated patients received any types of neoadjuvant therapy. RESULT: Out of all 98 patients who underwent PD, the most common complication was wound infection (23.5%), followed by pancreatic leak (21.4%). The pulmonary complication rate was 17.3%, while the intra-abdominal collection rate was 12.2%. In 12.2% of our patients we faced postoperative bleeding, with five patients having to be reopened for this reason. About 77.3% of patients that underwent preoperative ERCP had difficult bile duct dissection. There was an association between preoperative ERCP and difficult bile duct dissection (P Value < 0.001). CONCLUSION: Outcomes of our surgical team compared to the published data of some other centers. Preoperative ERCP seems to make difficulty in bile duct dissection during PD. PMID- 29438818 TI - Small and large airway reactions to osmotic stimuli in asthma and chronic idiopathic cough. AB - BACKGROUND: Chronic cough is a common symptom and related to several pulmonary, airway and heart diseases. When all likely medical explanations for the coughing are excluded, there remains a large group of patients with chronic coughing, which is mostly a cough reflex easily triggered by environmental irritants and noxious stimuli. The main aim of this study was to improve the diagnostic ability to differentiate chronic idiopathic cough (CIC) from asthma. METHODS: Twenty three patients with CIC, 16 patients with mild asthma and 21 control participants were included. The study consisted of three randomised bronchial provocations with osmotic stimuli: mannitol, eucapnic dry air and hypertonic saline. At each provocation lung function was assessed by spirometry and impulse oscillometry (IOS). RESULTS: In a comparison of the groups, while the FEV1 measurements did not differ, the CIC group had increased airway resistance and reactance after provocation with hypertonic saline compared to the control subjects. After mannitol provocation the patients with asthma had significantly increased airway resistance compared to the controls and from eucapnic dry air provocations these patients had a significant reduction in spirometry values and increased airway resistance compared to both the patients with CIC and the controls. CONCLUSION: The asthma group reacted in a predictable way with impaired lung function from osmotic provocations, whereas the patients with CIC demonstrated peripheral airway changes from hypertonic saline, also known to be a noxious stimulus. The IOS method uncovers differences between patients with CIC and control participants that contribute to our ability to provide a correct diagnosis. PMID- 29438819 TI - Diagnostic yield of standard-wake and sleep EEG recordings. AB - OBJECTIVE: To investigate whether Posterior Dominant Rhythm (PDR) can be reliably assessed in sleep-EEG recordings and to investigate the diagnostic yield of standard-wake and sleep-recordings. METHODS: EEG recordings of 303 consecutive patients aged 18-88 years were analyzed. All patients had both standard-wake and sleep-recordings, including patients who had abnormal standard recordings. Melatonin was used in 6% of sleep EEGs, and sleep deprivation in 94%. The mean duration of sleep was 41 min. We measured the PDR frequency in standard and sleep recordings, both before and after sleep. We compared the diagnostic yield of standard-wake and sleep EEG recordings. RESULTS: Compared to standard EEG, sleep recordings showed a significantly lower PDR frequency, both when measured before and after sleep (p < 0.001). One-hundred-fifty-six patients (51%) had normal standard recordings, and 35 of them (22%) had abnormal findings in the sleep recording. One-hundred-forty-seven patients had abnormal standard recordings and in 16 of them (11%) these abnormalities were not present in sleep-recording. CONCLUSIONS: PDR is significantly slower in the wake periods of sleep-recordings, compared to standard wake recordings. SIGNIFICANCE: Sleep and standard wake recordings are complementary. PMID- 29438820 TI - Intraoperative hippocampal electrocorticography frequently captures electrographic seizures and correlates with hippocampal pathology. AB - OBJECTIVE: Relationship between electrographic seizures on hippocampal electrocorticography (IH-ECoG) and presence/type of hippocampal pathology remains unclear. METHODS: IH-ECoG was recorded for 10-20 min from the ventricular surface of the hippocampus following removal of the temporal neocortex in 40 consecutive patients. Correlation between intraoperative hippocampal seizures and preoperative MRI, hippocampal histopathology, and EEG from invasive monitoring was determined. RESULTS: IH-ECoG captured electrographic seizures in 15/40 patients (in 8/23 with abnormal hippocampal signal on MRI and 7/17 patients without MRI abnormality). Hippocampal neuronal loss was observed in 22/40 (Group 1), while 18/40 had no significant neuronal loss (Group 2). In Group 1, 4/22 had seizures on IH-ECoG, while 11/18 had electrographic seizures in Group 2. In 24/40 patients who underwent prolonged extraoperative intracranial EEG (IC-EEG) recording, hippocampal seizures were captured in 14. Of these, 7 also had seizures during IH-ECoG. In 10/24 IC-EEG patients without seizures, 3 had seizures on IH-ECoG. CONCLUSIONS: IH-ECoG frequently captures spontaneous electrographic seizures. These are more likely to occur in patients with pathologic processes that do not disrupt/infiltrate hippocampus compared to patients with intractable epilepsy associated with disrupted hippocampal architecture. SIGNIFICANCE: Intraoperative hippocampal seizures may result from deafferentation from the temporal neocortex and disinhibition of the perforant pathway. PMID- 29438821 TI - Molecular characterisation of extended-spectrum beta-lactamase-producing Gram negative bacterial isolates from surgical wounds of patients at a hospital in North Central Nigeria. AB - OBJECTIVES: This study aimed to characterise extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacterial isolates from patients with surgical site infections (SSIs) at a tertiary healthcare facility in Abuja, Nigeria. METHODS: Consecutive, non-duplicate wound swabs were collected over a 3-month period from wounds of patients with SSI and were cultured appropriately. Bacterial isolates were identified using rapid identification kits. The modified agar disk diffusion method was used for antimicrobial susceptibility testing, and phenotypic ESBL activity of the isolates was determined using the double-disk synergy test (DDST). PCR was thereafter used for molecular characterisation of the isolates. RESULTS: A total of 57.1% (20/35) of the bacterial isolates were Gram-negative, with Pseudomonas aeruginosa (7/20; 35.0%) being the most prevalent. The isolates exhibited varying degree of antimicrobial resistance, with resistance as high as 100% for ampicillin and amoxicillin. Phenotypic ESBL production was observed in 65.0% (13/20) of the Gram-negative bacterial isolates. DNA analysis revealed that 61.5%, 53.8% and 38.5% of the isolates harboured blaSHV, blaCTX-M and blaTEM genes, respectively, with 30.8% of the isolates co harbouring blaSHV and blaCTX-M. Similarly, 23.1% of the isolates harboured blaSHV and blaTEM, whilst 15.4% harboured blaCTX-M and blaTEM. However, none of the investigated isolates harboured a blaOXA gene. CONCLUSION: The prevalence of ESBL genes among Gram-negative SSI pathogens is high. This calls for an urgent need to review infection control policies and antimicrobial prescription patterns as well as increased surveillance of ESBLs as the possibility of an epidemic outbreak of multidrug-resistant pathogens in the hospital is high. PMID- 29438822 TI - Intermediate-calcium based cementitious materials prepared by MSWI fly ash and other solid wastes: hydration characteristics and heavy metals solidification behavior. AB - Municipal solid waste incineration (MSWI) fly ash is a by-product of garbage incineration power generation, and its disposal is currently a world problem because it contains over standard heavy metals. This research aims to solidify the heavy metals in MSWI fly ash and make it to be utilizable construction materials under the guidance of intermediate-calcium cementitious materials (ICCM), and meanwhile figure out the solidification and hydration mechanism. The hydration characteristics of ICCM were characterized by XRD, FTIR, 29Si MAS-NMR and SEM techniques, and the environmental properties are investigated by TCLP and EPMA. The results indicate that the optimal ratio of (CaO + MgO)/(SiO2 + Al2O3) for ICCM is at the range of 0.76-0.88. The compressive strengths of ICCM reach the 42.5R normal Portland cement level, and the leaching concentrations of heavy metals meet the Chinese integrated wastewater discharge standard GB 8978-1996. As predominant hydration products, ettringite, hydrocalumite and amorphous C-S-H gel are principally responsible for the strength development of ICCM, and the (Ca + Mg)/(Si + Al) ratio at 0.88 has the best polymerized structure. The heavy metals are well solidified through combining with the C-S-H gel or absorbed in the hydration pastes. This paper provides an effective solution to use the MSWI fly ash in building material. PMID- 29438823 TI - Biodegradation of bispyribac sodium by a novel bacterial consortium BDAM: Optimization of degradation conditions using response surface methodology. AB - Bispyribac sodium (BS), is a selective, systemic and post emergent herbicide used to eradicate grasses and broad leaf weeds. Extensive use of this herbicide has engendered serious environmental concerns. Hence it is important to develop strategies for bioremediation of BS in a cost effective and environment friendly way. In this study a bacterial consortium named BDAM, comprising three novel isolates Achromobacter xylosoxidans (BD1), Achromobacter pulmonis (BA2), and Ochrobactrum intermedium (BM2), was developed by virtue of its potential for degradation of BS. Different culture conditions (temperature, pH and inoculum size) were optimized for degradation of BS by the consortium BDAM and the mutual interactions of these parameters were analysed using a 23 full factorial central composite design (CCD) based on Response Surface Methodology (RSM). The optimal values for temperature, pH and inoculum size were found to be 40 degrees C, 8 and 0.4 g/L respectively to achieve maximum degradation of BS (85.6%). Moreover, the interactive effects of these parameters were investigated using three dimensional surface plots in terms of maximum fitness function. Importantly, it was concluded that the newly developed consortium is a potential candidate for biodegradation of BS in a safe, cost-effective and environmentally friendly manner. PMID- 29438824 TI - Low bone toughness in the TallyHO model of juvenile type 2 diabetes does not worsen with age. AB - Fracture risk increases as type 2 diabetes (T2D) progresses. With the rising incidence of T2D, in particular early-onset T2D, a representative pre-clinical model is needed to study mechanisms for treating or preventing diabetic bone disease. Towards that goal, we hypothesized that fracture resistance of bone from diabetic TallyHO mice decreases as the duration of diabetes increases. Femurs and lumbar vertebrae were harvested from male, TallyHO mice and male, non-diabetic SWR/J mice at 16weeks (n>=12 per strain) and 34weeks (n>=13 per strain) of age. As is characteristic of this model of juvenile T2D, the TallyHO mice were obese and hyperglycemic at an early age (5weeks and 10weeks of age, respectively). The femur mid-shaft of TallyHO mice had higher tissue mineral density and larger cortical area, as determined by micro-computed tomography, compared to the femur mid-shaft of SWR/J mice, irrespective of age. As such, the diabetic rodent bone was structurally stronger than the non-diabetic rodent bone, but the higher peak force endured by the diaphysis during three-point (3pt) bending was not independent of the difference in body weight. Upon accounting for the structure of the femur diaphysis, the estimated toughness at 16weeks and 34weeks was lower for the diabetic mice than for non-diabetic controls, but neither toughness nor estimated material strength and resistance to crack growth (3pt bending of contralateral notched femur) decreased as the duration of hyperglycemia increased. With respect to trabecular bone, there were no differences in the compressive strength of the L6 vertebral strength between diabetic and non diabetic mice at both ages despite a lower trabecular bone volume for the TallyHO than for the SWR/J mice at 34weeks. Amide I sub-peak ratios as determined by Raman Spectroscopy analysis of the femur diaphysis suggested a difference in collagen structure between diabetic and non-diabetic mice, although there was not a significant difference in matrix pentosidine between the groups. Overall, the fracture resistance of bone in the TallyHO model of T2D did not progressively decrease with increasing duration of hyperglycemia. However, given the variability in hyperglycemia in this model, there were correlations between blood glucose levels and certain structural properties including peak force. PMID- 29438825 TI - Tracing compartment exchange by NMR diffusometry: Water in lithium-exchanged low silica X zeolites. AB - The two-region model for analyzing signal attenuation in pulsed field gradient (PFG) NMR diffusion studies with molecules in compartmented media implies that, on their trajectory, molecules get from one region (one type of compartment) into the other one with a constant (i.e. a time-invariant) probability. This pattern has proved to serve as a good approach for considering guest diffusion in beds of nanoporous host materials, with the two regions ("compartments") identified as the intra- and intercrystalline pore spaces. It is obvious, however, that the requirements of the application of the two-region model are not strictly fulfilled given the correlation between the covered diffusion path lengths in the intracrystalline pore space and the probability of molecular "escape" from the individual crystallites. On considering water diffusion in lithium-exchanged low silica X zeolite, we are now assuming a different position since this type of material is known to offer "traps" in the trajectories of the water molecules. Now, on attributing the water molecules in the traps and outside of the traps to these two types of regions, we perfectly comply with the requirements of the two region model. We do, moreover, benefit from the option of high-resolution measurements owing to the combination of magic angle spinning (MAS) with PFG NMR. Data analysis via the two-region model under inclusion of the influence of nuclear magnetic relaxation yields satisfactory agreement between experimental evidence and theoretical estimates. Limitations in accuracy are shown to result from the fact that mass transfer outside of the traps is too complicated for being adequately reflected by simple Fick's laws with but one diffusivity. PMID- 29438826 TI - Morphometric analyses of small accessory liver lobes using radiological imaging. AB - AIM: To investigate the prevalence and morphometric characteristics of small accessory liver lobes using computed tomography (CT) and magnetic resonance (MR) images. MATERIAL AND METHODS: The study population comprised 3269 patients (1671 men and 1598 women; mean age, 67.1 +/- 15.2 years) who had undergone abdominal CT examination. Small accessory liver lobes were identified after verification of their continuity with the liver parenchyma on CT images. Their imaging characteristics were analyzed and presented. RESULTS: Thirty-five small accessory liver lobes in 33 patients (1.01%; 25 men and 8 women, 71.0 +/- 11.7 years) were identified. Thirty-one patients (93.9%) had solitary lesions most frequently identified on liver segment 6 (80.0%) with the mean size 9.6 +/- 4.8 mm. These showed iso (62.9%), hyper (28.6%), or hypoattenuation (8.6%) on unenhanced CT. Enhanced CT images were available for 29 lesions. Enhancement of 12 lesions (41.4%) was similar to that of the liver parenchyma, whereas 17 lesions (58.6%) showed poor enhancement. MR images were available for 10 lesions, which showed hyperintensity (50.0%) on T2-weighted images and poor enhancement (50.0%). The characteristics of other lesions were similar to those of the liver parenchyma. During observation (mean, 77.0 months; n = 29), 19 lesions remained the same size (65.5%), 5 new lesions increased size (17.2%), and 5 showed reduced size (17.2%). CONCLUSION: Small accessory liver lobes, commonly located on segment 6, were frequently observed and did not necessarily show the same findings as the liver parenchyma. Time-dependent morphological changes were observed in approximately one-third of the lesions. PMID- 29438827 TI - Give music therapy a chance in post-stroke rehabilitation. PMID- 29438828 TI - Bi-clustering of metabolic data using matrix factorization tools. AB - Metabolic phenotyping technologies based on Nuclear Magnetic Spectroscopy (NMR) and Mass Spectrometry (MS) generate vast amounts of unrefined data from biological samples. Clustering strategies are frequently employed to provide insight into patterns of relationships between samples and metabolites. Here, we propose the use of a non-negative matrix factorization driven bi-clustering strategy for metabolic phenotyping data in order to discover subsets of interrelated metabolites that exhibit similar behaviour across subsets of samples. The proposed strategy incorporates bi-cross validation and statistical segmentation techniques to automatically determine the number and structure of bi clusters. This alternative approach is in contrast to the widely used conventional clustering approaches that incorporate all molecular peaks for clustering in metabolic studies and require a priori specification of the number of clusters. We perform the comparative analysis of the proposed strategy with other bi-clustering approaches, which were developed in the context of genomics and transcriptomics research. We demonstrate the superior performance of the proposed bi-clustering strategy on both simulated (NMR) and real (MS) bacterial metabolic data. PMID- 29438829 TI - Thermophoresis for characterizing biomolecular interaction. AB - The study of biomolecular interactions is crucial to get more insight into the biological system. The interactions of protein-protein, protein-nucleic acids, protein-sugars, nucleic acid-nucleic acids and protein-small molecules are supporting therapeutics and technological developments. Recently, the development in a large number of analytical techniques for characterizing biomolecular interactions reflect the promising research investments in this field. In this review, microscale thermophoresis technology (MST) is presented as an analytical technique for characterizing biomolecular interactions. Recent years have seen much progress and several applications established. MST is a powerful technique in quantitation of binding events based on the movement of molecules in microscopic temperature gradient. Simplicity, free solutions analysis, low sample volume, short analysis time, and immobilization free are the MST advantages over other competitive techniques. A wide range of studies in biomolecular interactions have been successfully carried out using MST, which tend to the versatility of the technique to use in screening binding events in order to save time, cost and obtained high data quality. PMID- 29438830 TI - Sample and substrate preparation for exploring living neurons in culture with quantitative-phase imaging. AB - Quantitative-phase imaging (QPI) has recently emerged as a powerful new quantitative microscopy technique suitable for the noninvasive exploration of the structure and dynamics of transparent specimens, including living cells in culture. Indeed, the quantitative-phase signal (QPS), induced by transparent living cells, can be detected with a nanometric axial sensitivity, and contains a wealth of information about both cell morphology and content. However, QPS is also sensitive to various sources of experimental noise. In this chapter, we emphasize how to properly and specifically measure the cell-mediated QPS in a wet lab environment, when measuring with a digital holographic microscope (DHM). First, we present the substrate-requisite characteristics for properly achieving such cell-mediated QPS measurements at single-cell level. Then, we describe how quantitative-phase digital holographic microscopy (QP-DHM) can be used to numerically process holograms and subsequently reshape wavefronts in association with post-processing algorithms, thereby allowing for highly stable QPS obtainable over extended periods of time. Such stable QPS is a prerequisite for exploring the dynamics of specific cellular processes. We also describe experimental procedures that make it possible to extract important biophysical cellular parameters from QPS including absolute cell volume, transmembrane water permeability, and the movements of water in and out of the cell. To illustrate how QP-DHM can reveal the dynamics of specific cellular processes, we show how the monitoring of transmembrane water movements can be used to resolve the neuronal network dynamics at single-cell level. This is possible because QPS can measure the activity of electroneutral cotransports, including NKCC1 and KCC2, during a neuronal firing mediated by glutamate, the main excitatory neurotransmitter in the brain. Finally, we added a supplemental section, with more technical details, for readers who are interested in troubleshooting live cell QP-DHM. PMID- 29438831 TI - Thread- paper, and fabric enzyme-linked immunosorbent assays (ELISA). AB - Enzyme-linked immunosorbent assay (ELISA) is an immunological assay commonly used to measure antibodies, antigens, proteins, and glycoproteins in biological samples. While the procedure is routine and straightforward, there are a number of variables (reagent selection, volume measurement, temperature, and time) that if not carefully considered, can affect the test outcome. Herein, we describe the development of microfluidic thread/paper-based analytical devices (uTPAD), microfluidic fabric-based analytical devices (uFAD), and microfluidic thread based analytical devices (uTAD) as new platforms for ELISA. The quantitative detection of biotinylated goat anti-mouse IgG (system one) and rabbit IgG (system two) antibodies via colorimetric analysis is detailed. We explain the design and fabrication of the devices and the step-by-step protocol for the ELISA. A comparison between the techniques is described and the results obtained from them elucidated. PMID- 29438832 TI - Temperature controlled ionic liquid aqueous two phase system combined with affinity capillary electrophoresis for rapid and precise pharmaceutical-protein binding measurements. AB - Temperature controlled ionic liquid aqueous two phase system (ILATPS) was used to improve the precision of pharmaceutical-AGP (human alpha (alpha1)-acid glycoprotein) binding measurements by affinity capillary electrophoresis (ACE). The effect of different types of short-chain alkyl imidazolium ILs within the concentration range of 10.0-1000.0 MUmol L-1 on a propranolol (PRO)-AGP model was firstly investigated by ILATPS/ACE system. Use of 100.0 MUmol L-1 1-butyl-3 methylimidazolium chloride (BMImCl) in 67.0 mmol L-1 potassium phosphate buffer (pH 7.4) containing low concentrations of AGP (5.0-100.0 umol L-1) gave the highest precision value (2.98 +/- 0.14 * 105 L/mol) which is in concord with the reported one (3.00 * 105) under similar experimental conditions. The proposed BMImCl/phosphate solution was a unique temperature controlled system to preserve AGP activity during the pre-analysis and within ACE measurements under lab conditions for about 30 days. This period could be prolonged by converting the one-phase solution into biphasic solution at 4 degrees C storage temperature and again it could get rapidly back into one-phase by raising the temperature with gentle shaking. This behavior could be attributed to the electrostatic interaction and pi-pi interaction between BMIm cations and negatively charged AGP ions (pI = 2.7). Moreover, the compatibility of ILATPS with ACE has been the critical factor to avoid precipitation of salts formed by anion exchange in the running buffer. The current ILATPS/ACE system was further used to rapidly and precisely estimate the binding constants of anticancer drugs methotrexate (MTX) and vinblastine (VBL) with human AGP. The obtained binding values have been in good agreements with their findings by high performance affinity chromatography (HPAC). This ILATP/ACE system could similarly be applied to improve the precision of other proteins binding measurements with consuming a small amount of protein and with shortening ACE analysis time. PMID- 29438833 TI - Recording 13C-15N HMQC 2D sparse spectra in solids in 30 s. AB - We propose a dipolar HMQC Hadamard-encoded (D-HMQC-Hn) experiment for fast 2D correlations of abundant nuclei in solids. The main limitation of the Hadamard methods resides in the length of the encoding pulses, which results from a compromise between the selectivity and the sensitivity due to losses. For this reason, these methods should mainly be used with sparse spectra, and they profit from the increased separation of the resonances at high magnetic fields. In the case of the D-HMQC-Hn experiments, we give a simple rule that allows directly setting the optimum length of the selective pulses, versus the minimum separation of the resonances in the indirect dimension. The demonstration has been performed on a fully 13C,15N labelled f-MLF sample, and it allowed recording the build-up curves of the 13C-15N cross-peaks within 10 min. However, the method could also be used in the case of less sensitive samples, but with more accumulations. PMID- 29438834 TI - Two-site jumps in dimethyl sulfone studied by one- and two-dimensional 17O NMR spectroscopy. AB - Polycrystalline dimethyl sulfone is studied using central-transition oxygen-17 exchange NMR. The quadrupolar and chemical shift tensors are determined by combining quantum chemical calculations with line shape analyses of rigid-lattice spectra measured for stationary and rotating samples at several external magnetic fields. Quantum chemical computations predict that the largest principal axes of the chemical shift anisotropy and electrical field gradient tensors enclose an angle of about 73 degrees . This prediction is successfully tested by comparison with absorption spectra recorded at three different external magnetic fields. The experimental one-dimensional motionally narrowed spectra and the two-dimensional exchange spectrum are compatible with model calculations involving jumps of the molecules about their two-fold symmetry axis. This motion is additionally investigated by means of two-time stimulated-echo spectroscopy which allows for a determination of motional correlation functions over a wider temperature range than previously reported using carbon and deuteron NMR. On the basis of suitable second-order quadrupolar frequency distributions, sin-sin stimulated-echo amplitudes are calculated for a two-site model in the limit of vanishing evolution time and compared with experimental findings. The present study thus establishes oxygen-17 NMR as a powerful method that will be particularly useful for the study of solids and liquids devoid of nuclei governed by first-order anisotropies. PMID- 29438835 TI - Structural MRI correlates of cognitive function in multiple sclerosis. AB - BACKGROUND: Cognitive impairment (CI) has been associated with numerous magnetic resonance imaging (MRI) indices in multiple sclerosis (MS) patients. In this study we investigated the association of a large set of 2D and 3D MRI markers with cognitive function in MS. METHODS: A sample of 61 RRMS patients (mean age 41.8 +/- 10.6 years old, 44 women, mean disease duration 137.9 +/- 83.9 months) along with 51 age and gender matched healthy controls was used in this cross sectional study. Neuropsychological and other tests, along with a large set of 2D/3D MRI evaluations were made. RESULTS: 44.3% of patients had CI. CI patients had more disability, physical fatigue than non-CI patients and more psychological distress than non-CI patients and HCs. Also, CI patients had significantly larger third ventricle width and volume, smaller coprus callosum index and larger lesion volume than non-CI patients. These MRI markers also significantly predicted cognitive scores after adjusting for age and education, explaining about 30.6% of the variance of the total cognitive score. CONCLUSIONS: Selected linear and volumetric MRI indices predict cognitive function in MS. Future studies should expand these results by exploring longitudinal changes and producing normative data. PMID- 29438836 TI - MOG-antibody demyelinating diseases: a case of post-partum severe rhombencephalitis and transverse myelitis. AB - INTRODUCTION: Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) associated disorders present with a spectrum of clinical pictures including brainstem involvement. CASE REPORT: A patient with the sudden onset of a post-partum severe rhombencephalitis causing respiratory failure (12 years after a mild transverse myelitis). Despite the aggressive clinical course, she had an impressive recovery after plasmapheresis, and no further relapses on immunosuppression. CONCLUSION: MOG-IgG disorders could relapse several years after onset and involve brainstem. Good prognosis is possible after treatment. PMID- 29438837 TI - A modified multiscale peak alignment method combined with trilinear decomposition to study the volatile/heat-labile components in Ligusticum chuanxiong Hort - Cyperus rotundus rhizomes by HS-SPME-GC/MS. AB - Head Space/Solid Phase Micro-Extraction (HS-SPME) coupled with Gas Chromatography/Mass Spectrometer (GC/MS) was used to determine the volatile/heat labile components in Ligusticum chuanxiong Hort - Cyperus rotundus rhizomes. Facing co-eluting peaks in k samples, a trilinear structure was reconstructed to obtain the second-order advantage. The retention time (RT) shift with multi channel detection signals for different samples has been vital in maintaining the trilinear structure, thus a modified multiscale peak alignment (mMSPA) method was proposed in this paper. The peak position and peak width of representative ion profile were firstly detected by mMSPA using Continuous Wavelet Transform with Haar wavelet as the mother wavelet (Haar CWT). Then, the raw shift was confirmed by Fast Fourier Transform (FFT) cross correlation calculation. To obtain the optimal shift, Haar CWT was again used to detect the subtle deviations and be amalgamated in calculation. Here, to ensure there is no peaks shape alternation, the alignment was performed in local domains of data matrices, and all data points in the peak zone were moved via linear interpolation in non-peak parts. Finally, chemical components of interest in Ligusticum chuanxiong Hort - Cyperus rotundus rhizomes were analyzed by HS-SPME-GCMS and mMSPA-alternating trilinear decomposition (ATLD) resolution. As a result, the concentration variation between herbs and their pharmaceutical products can provide a scientific basic for the quality standard establishment of traditional Chinese medicines. PMID- 29438838 TI - Selenium distribution in the Chinese environment and its relationship with human health: A review. AB - This paper reviewed the Se in the environment (including total Se in soil, water, plants, and food), the daily Se intake and Se content in human hair were also examined to elucidate Se distribution in the environment and its effects on human health in China. Approximately 51% of China is Se deficiency in soil, compared with 72% in the survey conducted in 1989. Low Se concentrations in soil, water, plants, human diet and thus human hair were found in most areas of China. The only significant difference was observed between Se-rich and Se-excessive areas for Se contents in water, staple cereal, vegetables, fruits, and animal-based food, no remarkable contrast was found among other areas (p>0.05). This study also demonstrated that 39-61% of Chinese residents have lower daily Se intakes according to WHO/FAO recommended value (26-34MUg/day). Further studies should focus on thoroughly understanding the concentration, speciation, and distribution of Se in the environment and food chain to successfully utilize Se resources, remediate Se deficiency, and assess the Se states and eco-effects on human health. PMID- 29438839 TI - Sirtuin7 has an oncogenic potential via promoting the growth of cholangiocarcinoma cells. AB - Accumulating evidence indicates that sirtuin7 (SIRT7) plays an oncogenic role in the main types of liver cancer, hepatocellular carcinoma (HCC). Nevertheless, the clinical significance of SIRT7 and its role in cholangiocarcinoma (CCA) is largely undiscovered. Here, we found that SIRT7 displayed higher expression in CCA tissues compared to intrahepatic normal bile duct and surrounding liver tissues based on The Cancer Genome Atlas (TCGA) data. Our data further confirmed that SIRT7 was overexpressed in CCA patient tissues and cell lines. Clinical analysis revealed that high SIRT7 expression was correlated with large tumor size and advanced tumor-node-metastasis (TNM) stage. Furthermore, SIRT7 overexpression independently predicted poor prognosis of CCA patients. Functionally, we demonstrated that SIRT7 knockdown suppressed proliferation and cell cycle progression of HUCCT1 cells in vitro and in vivo. SIRT7 restoration promoted the growth of QBC-939 cells. Mechanistically, SIRT7 reduced p21 expression and increased the levels of Cyclin D1 and cyclin dependent kinase 2 (CDK2) in CCA cells. Furthermore, microRNA-125b-5p (miR-125b-5p) was recognized as a direct negative regulator of SIRT7 and reduced SIRT7 abundance in CCA cells. Notably, miR-125b-5p restoration showed similar effects to SIRT7 knockdown on the growth of CCA cells. Taken together, we demonstrate for the first time that miR-125b-5p regulation of SIRT7 functions as an oncogene and a potential prognostic biomarker in CCA. PMID- 29438840 TI - Efficacy and safety of combined low doses of either diclofenac or celecoxib with gabapentin versus their single high dose in treatment of neuropathic pain in rats. AB - Neuropathic pain is a worldwide health problem with no consensus regarding its optimal therapy. This study compared the analgesic effect and gastric, hepatic, and renal safety of combined low doses of diclofenac and celecoxib with gabapentin versus their individual high doses in the treatment of neuropathic pain in rats. Left sciatic nerve ligation was used as neuropathic pain model. Rats were allocated into 7 groups (7 rats for each): sham control; model group (received vehicle); Gaba-group (received gabapentin (100 mg/kg /day); Diclo 10 group (received diclofenac (10 mg/kg); Cele 10-group (received celecoxib (10 mg/kg/day); Gaba + Diclo 5 (receivedgabapentin(100 mg/kg /day) plus diclofenac (5 mg/kg); Gaba + Cele 5 (received gabapentin (100 mg/kg/day) plus celecoxib (5 mg/kg)). The analgesic effect was assessed using both hot plate and acetone tests. The impact of the used drugs on peptic ulcer index, liver enzymes, and serum urea and creatinine was evaluated, along with histopathological examination and oxidative stress parameters. Combination therapy of low dose of either diclofenac or celecoxib, with gabapentin showed higher analgesic effect compared with their individual high doses as indicated by prolonged response time in hot plate test and decreased frequency of paw withdrawal in acetone test. Their effect was associated with gentle effect on gastric mucosa, renal and hepatic integrity and oxidative stress parameters. In conclusion, the use of combined low doses of either diclofenac or celecoxib with gabapentin is better than high dose monotherapy regarding both the efficacy and safety. PMID- 29438841 TI - Anti-migraine and anti-depression activities of Tianshu capsule by mediating Monoamine oxidase. AB - BACKGROUND: Tianshu capsule(TSC)is a Chinese patent medicine. It's widely used to treat migraine clinically in China. AIM OF THE STUDY: In the present study, we investigated anti-migraine and anti-depression activities of TSC using in vivo animal models together with in vitro studies to investigate the mechanism of action. MATERIALS AND METHODS: Nitroglycerin (NTG) -induced migraine rat model, rat was given a subcutaneous injection of the NTG suspension (10 mg/kg) once a week for 5 weeks. Behavioral observation was carried out and brain tissues were sampled to determine levels of 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine (NE), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B) and tyrosine hydroxylase (TH) by ELISA, in order to evaluate the effect of TSC on migraine progression. Tail suspension test and forced swim test were carried in order to evaluate the effect of TSC on depression progression. RESULTS: TSC treatments decreased scratch head times significantly in a rat migraine model. Meanwhile, TSC suppressed activities of MAO-A and MAO-B, up-regulated 5-HT, DA and NE expressions in brain tissues. Tail suspension test showed a decrease of immobility time in TSC groups. Furthermore, TSC increased climb times, up regulated activities of 5-HT, DA and NE in forced swim test mice. Additionally, TSC could attenuate the reduction of 5-HT, DA and NE induced by corticosterone in primary neuronal cells. CONCLUSION: TSC could effectively prevent depression, one of the most frequent comorbidities in migraine. It may provide a new target for treating migraine. PMID- 29438842 TI - Supramolecular nanofibers of dexamethasone derivatives to form hydrogel for topical ocular drug delivery. AB - The low bioavailability exhibits by conventional ocular formulation owing to rapid precorneal clearance and lower corneal permeability can be overcame by the application of the gelling system. In the present study, a prodrug supramolecular hydrogel derived from succinated dexamethasone (Dex-SA) was fabricated using a pH hydrolytic strategy and explored as a "self-delivery" system for ophthalmic drugs. The self-assembled Dex-SA supramolecular hydrogel exhibited a typical nano fibrous microstructure and was thixotropic. Both dexamethasone (Dex) and Dex-SA prodrug sustainably released from Dex-SA supramolecular hydrogel in a period of 120 h in vitro release study, and the initial pH value of hydrogel significantly influence on the release ratio of Dex/Dex-SA. Furthermore, the lyophilized Dex-SA supramolecular hydrogel displayed long-term stability without causing any apparent hydrolysis of Dex-SA at -20 degrees C over 30 day and quickly re-formed a hydrogel after dissolving into aqueous solution. The formed Dex-SA supramolecular hydrogel had lower cytotoxicity than Dex at drug concentration up to 2.5 mM, and exhibited a comparable anti-inflammatory efficacy to a Dex sodium phosphate (Dexp) aqueous solution in lipopolysaccharide-activated RAW264.7 macrophages. Topical instillation of the Dex-SA supramolecular hydrogel showed excellent intraocular biocompatibility and it was not an irritant in rabbit eyes. More importantly, the Dex-SA supramolecular hydrogel provided a prolonged precorneal retention and significantly enhanced the ocular bioavailability over Dexp aqueous solution after topical instillation. Overall, this work illustrates an effective approach for the development of prodrug supramolecular hydrogels to extend the precorneal retention and enhance ocular bioavailability of drugs after topical instillation. PMID- 29438843 TI - Probing the reproducibility of quantitative estimates of structural connectivity derived from global tractography. AB - As quantitative measures derived from fiber tractography are increasingly being used to characterize the structural connectivity of the brain, it is important to establish their reproducibility. However, no such information is as yet available for global tractography. Here we provide the first comprehensive analysis of the reproducibility of streamline counts derived from global tractography as quantitative estimates of structural connectivity. In a sample of healthy young adults scanned twice within one week, within-session and between-session test retest reproducibility was estimated for streamline counts of connections based on regions of the AAL atlas using the intraclass correlation coefficient (ICC) for absolute agreement. We further evaluated the influence of the type of head coil (12 versus 32 channels) and the number of reconstruction repetitions (reconstructing streamlines once or aggregated over ten repetitions). Factorial analyses demonstrated that reproducibility was significantly greater for within- than between-session reproducibility and significantly increased by aggregating streamline counts over ten reconstruction repetitions. Using a high-resolution head-coil incurred only small beneficial effects. Overall, ICC values were positively correlated with the streamline count of a connection. Additional analyses assessed the influence of different selection variants (defining fuzzy versus no fuzzy borders of the seed mask; selecting streamlines that end in versus pass through a seed) showing that an endpoint-based variant using fuzzy selection provides the best compromise between reproducibility and anatomical specificity. In sum, aggregating quantitative indices over repeated estimations and higher numbers of streamlines are important determinants of test-retest reproducibility. If these factors are taken into account, streamline counts derived from global tractography provide an adequately reproducible quantitative measure that can be used to gauge the structural connectivity of the brain in health and disease. PMID- 29438844 TI - Top-down expectation effects of food labels on motivation. AB - Labels on food packages inform our beliefs, shaping our expectations of food properties, such as its expected taste and healthiness. These beliefs can influence the processing of caloric rewards beyond objective sensory properties and have the potential to impact decision making. However, no studies, within or beyond the food domain, have assessed how written information, such as food labels, affect implicit motivation to obtain rewards, even though choices in daily life might be strongly driven by implicit motivational biases. We investigated how written information affects implicit motivation to obtain caloric rewards in healthy young adults. We used food labels (high- and low calorie), associated with an identical fruit-flavored sugar-sweetened beverage, to study motivation for caloric rewards during fMRI. In a joystick task, hungry participants (N = 31) were instructed to make fast approach or avoid movements to earn the cued beverages. Behaviorally, we found a general approach bias, which was stronger for the beverage that was most preferred during a subsequent choice test, i.e., the one labeled as low-calorie. This behavioral effect was accompanied by increased BOLD signal in the sensorimotor cortex during the response phase of the task for the preferred, low-calorie beverage compared with the non-preferred, high-calorie beverage. During the anticipation phase, the non preferred, high-calorie beverage label elicited stronger fMRI signal in the right ventral anterior insula, a region associated with aversion and taste intensity, than the preferred, low-calorie label. Together, these data suggest that high calorie labeling can increase avoidance of beverages and reduce neural activity in brain regions associated with motor control. In conclusion, we show effects of food labeling on fMRI responses during anticipation and subsequent motivated action and on behavior, in the absence of objective taste differences, demonstrating the influence of written information on implicit biases. These findings contribute to our understanding of implicit biases in real-life eating behavior. PMID- 29438845 TI - "Brain over body"-A study on the willful regulation of autonomic function during cold exposure. AB - The defense of body temperature against environmental thermal challenges is a core objective of homeostatic regulation governed by the autonomic nervous system. Autonomous mechanisms of thermoregulation are only weakly affected by top down modulation, allowing only transient tolerance for extreme cold. There is however, anecdotal evidence of a unique set of individuals known for extreme cold tolerance. Here we present a case study of a 57-year old Dutch national, Wim Hof, the so-called "Iceman", with the ability to withstand frequent prolonged periods of extreme cold exposure based on the practice of a self-developed technique involving a combination of forced breathing, cold exposure and meditation (collectively referred to as the Wim Hof Method, henceforth "WHM"). The relative contributions of the brain and the periphery that endow the Iceman with these capabilities is unknown. To investigate this, we conducted multi-modal imaging assessments of the brain and the periphery using a combination of fMRI and PET/CT imaging. Thermoregulatory defense was evoked by subjecting the Iceman (and a cohort of typical controls) to a fMRI paradigm designed to generate periods of mild hypothermia interspersed by periods of return to basal core body temperature. fMRI was acquired in two separate sessions: in a typical (passive) state and following the practice of WHM. In addition, the Iceman also underwent a whole body PET/CT imaging session using the tracers C11-hydroxyephedrine (HED) and 18F-fluorodeoxyglucose (FDG) during both thermoneutral and prolonged mild cold conditions. This acquisition allowed us to determine changes in sympathetic innervation (HED) and glucose consumption (FDG) in muscle and fat tissues in the absence of the WHM. fMRI analyses indicated that the WHM activates primary control centers for descending pain/cold stimuli modulation in the periaqueductal gray (PAG), possibly initiating a stress-induced analgesic response. In addition, the WHM also engages higher-order cortical areas (left anterior and right middle insula) that are uniquely associated with self-reflection, and which facilitate both internal focus and sustained attention in the presence of averse (e.g. cold) external stimuli. However, the activation of brown adipose tissue (BAT) was unremarkable. Finally, forceful respiration results in increased sympathetic innervation and glucose consumption in intercostal muscle, generating heat that dissipates to lung tissue and warms circulating blood in the pulmonary capillaries. Our results provide compelling evidence for the primacy of the brain (CNS) rather than the body (peripheral mechanisms) in mediating the Iceman's responses to cold exposure. They also suggest the compelling possibility that the WHM might allow practitioners to develop higher level of control over key components of the autonomous system, with implications for lifestyle interventions that might ameliorate multiple clinical syndromes. PMID- 29438846 TI - Six genes of ompA family shuffling for development of polyvalent vaccines against Vibrio alginolyticus and Edwardsiella tarda. AB - Polyvalent vaccines against more than one species of pathogens are especially important due to the complex ecosystem in aquaculture. We have previously shown that the development of polyvalent vaccines by shuffling six ompA genes from different bacteria with V. parahaemolyticus VP0764 primers. Here, we used the same 6 genes, V. alginolyticus VA0764 and VA1186, V. parahaemolyticus VP0764 and VP1186, E. tarda ompA and E. coli ompA, but with E. tarda ompA primers to develop new polyvalent vaccines. By this approach, we identified 7 potential polyvalent vaccines that were effective against both V. alginolyticus and E. tarda infections. Furthermore, the innate immunity triggered by the vaccines were also explored in three groups, no protection (group I), protection against V. alginolyticus (group II), and protection against both V. alginolyticus and E. tarda (group III). The transcription of IL-1beta, IL-6, IL-8, C3b and NF-kB were significantly increased in group II and group III but not group I, where the expression level of group III was higher than group II. In addition, differential activities of succinate dehydrogenase were detected among the three groups. These results indicate the expansion of polyvalent vaccine reservoir with the same shuffling genes but different primers, and promote the understanding of the mechanisms of polyvalent vaccines based on vaccine-induced innate immunity. PMID- 29438847 TI - Assessment of the effects of sulfated polysaccharides extracted from the red seaweed Irish moss Chondrus crispus on the immune-stimulant activity in mussels Mytilus spp. AB - Seaweeds contain a number of health enhancing and antimicrobial bioactive compounds including sulfated polysaccharides (SP). In the present study, SP extracted from a European red seaweed Irish moss Chondrus crispus was chemically analyzed, SP content extracted and the immune-response effect on wild Irish mussels Mytilus spp. investigated for the first time. A high percent yield of SP was extracted from C. crispus and the immune-stimulant activity of SP was assessed in a laboratory trial with mussels exposed to three different treatments of low (10 MUg mL-1), medium (20 MUg mL-1) and high (50 MUg mL-1) SP dose concentrations and a control mussel group with no exposure to SP. An initial mussel sample was processed prior to the trial commencing and mussels were subsequently sampled on Days 1, 2, 3, 4, 7, and 10 post SP exposure. Both cell, humoral and immune related gene responses including haemocyte cell viability, haemocyte counts, lysozyme activity and expression of immune related genes (defensin, mytimycin and lysozyme mRNA) were assessed. No mussel mortalities were observed in either the treated or non-treated groups. Mussels exposed with SP showed an increase in haemocyte cell viability and the total number of haemocytes compared to control mussels. Lysozyme activity was also higher in treated mussels. Additionally, up-regulated expression of defensin, mytimycin and lysozyme mRNA was observed in SP treated mussels shortly after exposure (on Days 1, 2, and 3) to SP. These results indicate that a high quality yield of SP can be readily extracted from C. crispus and more importantly based on the animal model used in this study, SP extracted from C. crispus can rapidly induce health enhancing activities in Mytilus spp. at a cellular, humoral and molecular level and with a prolonged effect up to ten days post treatment. PMID- 29438848 TI - Effect of nitrite exposure on the antioxidant enzymes and glutathione system in the liver of bighead carp, Aristichthys nobilis. AB - Nitrite (NO2-) can cause oxidative stress in aquatic animal when it accumulates in the organism, resulting in different toxic effects on fish. In the present study, we investigated the effects of nitrite exposure on the antioxidant enzymes and glutathione system in the liver of Bighead carp (Aristichthys nobilis). Fish [Initial average weight: (180.05 +/- 0.092) g] were exposed to 48.634 mg/L nitrite for 96 h, and a subsequent 96 h for the recovery test. Fish livers were collected to assay antioxidant enzymes activity, hepatic structure and expression of genes after 0 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h of exposure and12 h, 24 h, 48 h, 72 h, 96 h of recovery. The results showed that the activity of glutathione peroxidase (GSH-Px), glutathione S-transferase (GST), and glutathione reductase (GR) increased significantly in the early stages of nitrite exposure. The study also showed that nitrite significantly up-regulated the mRNA levels of glutathione peroxidase (GSH-Px), glutathione S-transferase (GST), and glutathione reductase (GR) after 6, 48, and 72 h of exposure respectively. Nitrite also increased the formation of malondialdehyde (MDA), oxidized glutathione (GSSG), and the activity of catalase (CAT). Nitrite was observed to reduce the activity of superoxide dismutase (SOD) and the level of glutathione (GSH). In the recovery test, GSH and the GSSG recovered but did not return to pre-stress levels. The results suggested that the glutathione system played important roles in nitrite induced oxidative stress in fish. The bighead carp responds to oxidative stress by enhancing the activity of GSH-Px, GST, GR and up-regulating the expression level of GSH-Px, GST, GR, a whilst simultaneously maintaining the dynamic balance of GSH/GSSG. CAT was also indispensable. They could reduce the degree of lipid peroxidation, and ultimately protect the body from oxidative damage. PMID- 29438849 TI - Association between histological alterations in the thymus and sudden infant death syndrome. AB - INTRODUCTION: Sudden infant death syndrome (SIDS) involves the death of an infant during the first year of life and it is among the leading causes of infant mortality worldwide. One hypothesis regarding the pathogenesis of SIDS is that it results from a combination of three independent factors: endogenous vulnerability, a critical time window during postnatal development, and exogenous stressors. This hypothesis is known as the "triple-risk model". METHODS: In this study, we used an immunohistological approach to compare the cellular microenvironments of thymuses from 19 infants whose sudden death was classified as SIDS and a control group, which consisted of thymuses from age-matched children undergoing surgery for various congenital heart defects. We hypothesized that morphological signs of stress-related thymic involution would be present. RESULTS: Based on our observations, we found evidence that the proliferation and maturation of T-lymphocytes in the thymuses of infants with SIDS were suppressed. We observed enhanced macrophage activity, suggesting an increase in the apoptosis of lymphocytes and decrease in number of thymic dendritic cells and myoid cells. Significant apoptosis of thymic lymphocytes without cell regeneration typically leads to atrophy of the thymus. All cellular events we observed resemble the initial stage of stress-related thymic involution. CONCLUSION: These results support the "triple-risk model," suggesting that certain exogenous stressors might be involved in the pathogenesis of SIDS. This was probably not recognized during the autopsies of infants who died suddenly. PMID- 29438850 TI - Secreted protein extract analyses present the plant pathogen Alternaria alternata as a suitable industrial enzyme toolbox. AB - : Lignocellulosic plant biomass is the most abundant carbon source in the planet, which makes it a potential substrate for biorefinery. It consists of polysaccharides and other molecules with applications in pharmaceutical, food and feed, cosmetics, paper and textile industries. The exploitation of these resources requires the hydrolysis of the plant cell wall, which is a complex process. Aiming to discover novel fungal natural isolates with lignocellulolytic capacities, a screening for feruloyl esterase activity was performed in samples taken from different metal surfaces. An extracellular enzyme extract from the most promising candidate, the natural isolate Alternaria alternata PDA1, was analyzed. The feruloyl esterase activity of the enzyme extract was characterized, determining the pH and temperature optima (pH 5.0 and 55-60 degrees C, respectively), thermal stability and kinetic parameters, among others. Proteomic analyses derived from two-dimensional gels allowed the identification and classification of 97 protein spots from the extracellular proteome. Most of the identified proteins belonged to the carbohydrates metabolism group, particularly plant cell wall degradation. Enzymatic activities of the identified proteins (beta-glucosidase, cellobiohydrolase, endoglucanase, beta-xylosidase and xylanase) of the extract were also measured. These findings confirm A. alternata PDA1 as a promising lignocellulolytic enzyme producer. SIGNIFICANCE: Although plant biomass is an abundant material that can be potentially utilized by several industries, the effective hydrolysis of the recalcitrant plant cell wall is not a straightforward process. As this hydrolysis occurs in nature relying almost solely on microbial enzymatic systems, it is reasonable to infer that further studies on lignocellulolytic enzymes will discover new sustainable industrial solutions. The results included in this paper provide a promising fungal candidate for biotechnological processes to obtain added value from plant byproducts and analogous substrates. Moreover, the proteomic analysis of the secretome of a natural isolate of Alternaria sp. grown in the presence of one of the most used vegetal substrates on the biofuels industry (sugar beet pulp) sheds light on the extracellular enzymatic machinery of this fungal plant pathogen, and can be potentially applied to developing new industrial enzymatic tools. This work is, to our knowledge, the first to analyze in depth the secreted enzyme extract of the plant pathogen Alternaria when grown on a lignocellulosic substrate, identifying its proteins by means of MALDI-TOF/TOF mass spectrometry and characterizing its feruloyl esterase, cellulase and xylanolytic activities. PMID- 29438851 TI - Redox responses are preserved across muscle fibres with differential susceptibility to aging. AB - : Age-related loss of muscle mass and function is associated with increased frailty and loss of independence. The mechanisms underlying the susceptibility of different muscle types to age-related atrophy are not fully understood. Reactive oxygen species (ROS) are recognised as important signalling molecules in healthy muscle and redox sensitive proteins can respond to intracellular changes in ROS concentrations modifying reactive thiol groups on Cysteine (Cys) residues. Conserved Cys residues tend to occur in functionally important locations and can have a direct impact on protein function through modifications at the active site or determining protein conformation. The aim of this work was to determine age related changes in the redox proteome of two metabolically distinct murine skeletal muscles, the quadriceps a predominantly glycolytic muscle and the soleus which contains a higher proportion of mitochondria. To examine the effects of aging on the global proteome and the oxidation state of individual redox sensitive Cys residues, we employed a label free proteomics approach including a differential labelling of reduced and reversibly oxidised Cys residues. Our results indicate the proteomic response to aging is dependent on muscle type but redox changes that occur primarily in metabolic and cytoskeletal proteins are generally preserved between metabolically distinct tissues. BIOLOGICAL SIGNIFICANCE: Skeletal muscle containing fast twitch glycolytic fibres are more susceptible to age related atrophy compared to muscles with higher proportions of oxidative slow twitch fibres. Contracting skeletal muscle generates reactive oxygen species that are required for correct signalling and adaptation to exercise and it is also known that the intracellular redox environment changes with age. To identify potential mechanisms for the distinct response to age, this article combines a global proteomic approach and a differential labelling of reduced and reversibly oxidised Cysteine residues in two metabolically distinct skeletal muscles, quadriceps and soleus, from adult and old mice. Our results indicate that the global proteomic changes with age in skeletal muscles are dependent on fibre type. However, redox specific changes are preserved across muscle types and accompanied with a reduction in the number of redox sensitive Cysteine residues. PMID- 29438852 TI - Transcriptome analysis to assess the cholestatic hepatotoxicity induced by Polygoni Multiflori Radix: Up-regulation of key enzymes of cholesterol and bile acid biosynthesis. AB - : Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. However, PMR-associated hepatotoxicity is becoming a safety issue. Cholestasis often occurs in PMR-induced hepatotoxicity in clinical medicine, but the exact mechanism is not completely understood. An RNA-Seq method was employed, in the present study, to explore the molecular mechanism of cholestatic liver injury induced by PMR, characterized by the hepatic transcriptional response in rats exposed to 1 and 20 g/kg PMR for 90 days. Pathological changes seen in rat livers exposed to PMR included increased bile ducts in portal areas and biliary epithelial cell hyperplasia, which were accompanied by the elevation of serum biochemistries. Dose-dependent increases in the expression of 14 transcripts encoding enzymes involved in the cholesterol biosynthetic pathway were identified. Furthermore, cholesterol 7-alpha hydroxylase (Cyp7a1), a rate limiting enzyme in the synthesis of bile acids (BAs) from cholesterol, was found to be upregulated by PMR treatment. Protein analysis by western blot suggested that expression of 3-hydroxy-3-methylglutaryl CoA reductase (Hmgcr) and Cyp7a1 were increased in a dose-dependent manner. Collectively, the present study demonstrates that PMR upregulates key enzymes for biosynthesis of cholesterol and BA, which poses the risk of cholestatic liver injury. SIGNIFICANCE: To the best of our knowledge, this is the first transcriptome analysis to highlight the main molecular changes occurring in rats chronic exposed to PMR. We have identified 39 specific differentially expressed genes (DEGs) that were present in various comparisons. A total of 14 of these altered gene transcripts were associated with cholesterol biosynthesis. Another factor of great importance in our opinion seemed to be the enhancement of bile acid (BA) biosynthesis, which were closely linked to cholesterol biosynthesis or metabolism. Our findings suggested that the disturbance on balance of BA formation and elimination might lead to a BA overload in hepatocytes, thereby resulting in liver injury. PMID- 29438853 TI - Gastric ulceration and perforation secondary to large trichobezoar - A case report describing the role of magnetic resonance imaging in diagnosis. AB - INTRODUCTION: Trichotillomania and trichotillophagia can result in huge intraluminal coagulations of hair. Rarely, these can present with gastric perforation. This work has been reported in line with the SCARE criteria (Agha et al., 2016) [1]. PRESENTATION OF CASE: We report the case of a 15 year old girl who attended the emergency department with abdominal pain and vomiting. Ultrasound abdomen and pelvis identified free fluid within the pelvis concerning for inflammatory bowel disease. A subsequent magnetic resonance enterography (MRE) demonstrated a giant gastric trichobezoar which resulted in gastric perforation necessitating laparotomy and gastrotomy. The patient recovered well from the surgery and was reviewed by the psychiatry service prior to discharge. DISCUSSION: Trichobezoar is a challenging diagnosis and as clinician, we must always include it in our differential diagnosis. The clinical presentation, signs and symptoms depend on the size of the trichobezoar and the presence of complications. Management is almost always surgical. CONCLUSION: This case illustrates the infrequent perforation risk of gastric bezoars and the important role of magnetic resonance imaging in diagnosis, particularly in a population who must not be exposed to excessive radiation. PMID- 29438854 TI - Thrombosis of the spleno-mesentiric portal axis following laparoscopic sleeve gastrectomy: A rare case report. AB - INTRODUCTION: Mesenteric, splenic and portal veins thrombosis (MSPVT) is uncommon complication after sleeve gastrectomy. CASE REPORT: A 38-year-old female underwent laparoscopic sleeve gastrectomy (LSG) for the treatment of morbid obesity, presented 4weeks later with epigastric pain. Computed tomography (CT) scan revealed superior mesenteric, splenic and the portal veins thrombosis. CONCLUSION: MSPVT is a rare presentation after laparoscopic sleeve gastrectomy, which requires early diagnosis and management and it should be included in the differential diagnosis for unexplained abdominal symptoms after laparoscopic sleeve gastrectomy. PMID- 29438855 TI - True aneurysm of the proximal occipital artery: Case report. AB - INTRODUCTION: True aneurysms of the proximal occipital artery are rare, may cause neurological symptoms due to compression of the hypoglossal nerve and their resection may be technically demanding. PRESENTATION OF CASE: The case of an aneurysm of the proximal occipital artery causing discomfort and tongue deviation by compression on the hypoglossal nerve is reported. Postoperative course after resection was followed by complete regression of symptoms. CONCLUSION: Surgical resection, as standard treatment of aneurysms of the occipital artery, with the eventual technical adjunct of intubation by the nose is effective in durably relieving symptoms and preventing aneurysm-related complication. PMID- 29438856 TI - The surgical management of dysphagia secondary to diffuse idiopathic skeletal hyperostosis. AB - OBJECTIVE: This study reviews the management pathway and surgical outcomes of patients referred to and operated on at a tertiary neurosurgical centre, for dysphagia associated with anterolateral cervical hyperostosis (ACH) in diffuse idiopathic skeletal hyperostosis (DISH). PATIENTS & METHODS: Electronic patient records for 6 patients who had undergone anterior cervical osteophytectomy for dysphagia secondary to ACH were reviewed. ACH diagnosis was made by an Ear, Nose and Throat (ENT) specialist and patients were referred to a neurosurgical-led multidisciplinary team (MDT) for review. A senior radiologist performed imaging measurements and vertebral level localization was confirmed via barium-swallow video-fluoroscopy. Speech and language therapists (SLTs) determined the suitability of pre-operative conservative management. Patients were followed-up post-operatively with clinical and radiological assessments. RESULTS: 6 patients (Male to female ratio, 6:0; mean age, 59 years) were referred to a tertiary neurosurgical centre with DISH related dysphagia, an average of 25 months after ENT review (range, 14-36 months) between 2005 and 2016. The vertebral levels implicated in dysphagia ranged from C2 to T1 with a median of 4 vertebral levels involved. The most frequently affected vertebral levels were C4-6 (all 6 patients). The average antero-posterior height (as measured on axial images) of the most prominent osteophyte was 15.9 mm (range 12.0-20.0 mm). Patients underwent elective cervical osteophytectomy on average 10.8 months after neurosurgical review (range, 3-36 months). One patient had a post-operative haematoma needing evacuation and prolonged hospital stay. The average duration of follow-up was 42.3 months. All our patients maintained good symptomatic resolution without osteophyte recurrence. CONCLUSIONS: All our patients experienced significant and sustained clinical improvement. Anterior cervical osteophytectomy consistently leads to improvement in symptomatic ACH patients without recurrence. Early referral to a neurosurgical multi-disciplinary team (MDT) is indicated in ACH related dysphagia, once conservative management has failed. PMID- 29438857 TI - Modelling the growth of Listeria monocytogenes in Mediterranean fish species from aquaculture production. AB - Over the last couple of decades, several studies have evaluated growth dynamics of L. monocytogenes in lightly processed and ready-to-eat (RTE) fishery products mostly consumed in Nordic European countries. Other fish species from aquaculture production are of special interest since their relevant consumption patterns and added value in Mediterranean countries, such as sea bream and sea bass. In the present study, the growth of L. monocytogenes was evaluated in fish-based juice (FBJ) by means of optical density (OD) measurements in a temperature range 2-20 degrees C under different atmosphere conditions (i.e. reduced oxygen and aerobic). The Baranyi and Roberts model was used to estimate the maximum growth rate (MUmax) from the observed growth curves. The effect of storage temperature on MUmax was modelled using the Ratkowsky square root model. The developed models were validated using experimental growth data for L. monocytogenes in sea bream and sea bass fillets stored under static and dynamic temperature conditions. Overall, models developed in FBJ provided fail-safe predictions for L. monocytogenes growth. For the model generated under reduced oxygen conditions, bias and accuracy factor for growth rate predictions were 1.15 and 1.25, respectively, showing good performance to adequately predict L. monocytogenes growth in Mediterranean fish products. The present study provides validated predictive models for L. monocytogenes growth in Mediterranean fish species to be used in microbial risk assessment and shelf-life studies. PMID- 29438858 TI - Molybdenum diselenide nanosheet/carbon nanofiber heterojunctions: Controllable fabrication and enhanced photocatalytic properties with a broad-spectrum response from visible to infrared light. AB - Molybdenum diselenide nanosheet/carbon nanofiber (MoSe2/CNF) heterojunctions have been successfully obtained by a facile two-step synthesis route combining an electrospinning technique and solvothermal method. The results show that MoSe2 nanosheets distributed evenly on the carbon nanofibers without aggregation, and the loading amount of MoSe2 could be well controlled by adjusting the reactant concentrations during the solvothermal process for the fabrication of the MoSe2/CNF heterojunctions. The as-prepared MoSe2/CNF heterojunctions exhibited higher photocatalytic activity than pure MoSe2 for the degradation of Rhodamine B (RhB) under visible and infrared light irradiation. The normalized rate constant for the MoSe2/CNF heterojunctions was nearly 3.2 times and 1.6 times higher than that of pure MoSe2 under visible light and infrared light (1.5 W, 980 nm laser) irradiation, respectively. The enhanced photocatalytic activity might be attributed to the formation of heterojunctions, which could improve the separation of photogenerated electrons and holes at the MoSe2/CNF heterojunctions interface. In addition, MoSe2/CNF heterojunctions could be efficiently separated from the solution by sedimentation due to their ultralong one-dimensional and self-supporting structure. Such MoSe2/CNF heterojunctions with a broad-spectrum response photocatalytic performance might have potential applications in water treatment. PMID- 29438859 TI - Enhanced photoluminescence properties of a carbon dot system through surface interaction with polymeric nanoparticles. AB - HYPOTHESIS: Carbon dot systems are highly surface sensitive fluorescent nanomaterials. In the presence of specific molecules or ions, the fluorescence properties can be strongly influenced. Often their fluorescent properties are activated or strongly enhanced through passivation agents such as polymer coatings. While several passivating polymers have been directly attached to the carbon dot systems, the interaction of carbon dot systems with the polymer surface of colloids has not been investigated as a way to activate or enhance the photoluminescent properties. Here, we show for the first time that the interaction of carbon dot systems with polymer colloids can strongly enhance the fluorescent properties of the carbon dot systems. EXPERIMENTS: To introduce carbon dot - polymer nanoparticle interactions, carbon dots are either generated directly in a microwave assisted synthesis in the presence of negatively charged polystyrene nanoparticles (in situ) or synthesized in the microwave separately and mixed afterwards with polymer nanoparticles (mixing). For the carbon dot system synthesis, chitosan, 1,2-ethylenediamine, and acetic acid are used as precursors. The produced carbon dot - polymer nanoparticle system are characterized by scanning electron microscopy, transmission electron microscopy, and flow cytometry measurements, and their interaction is assessed by fluorescence spectroscopy and fluorescence lifetime measurements. FINDINGS: We show that depending on the synthesis route (in situ or mixing), the carbon dot systems are either covalently attached (in situ) or electrostatically bound (mixing) to the surface of the nanoparticles. Regardless of the preparation methods of the investigated carbon dot - polymer nanoparticle system and the interaction (chemical or physical) with the surface, the fluorescence intensity is strongly enhanced and the fluorescence lifetime prolonged. These findings indicate a stabilization of the radiative trap states of carbon dot systems through interaction with the surface of the particles. PMID- 29438860 TI - Hole transport layer based on conjugated polyelectrolytes for polymer solar cells. AB - We demonstrate the conjugated polyelectrolytes (CPEs) as efficient hole transport layer (HTL) of polymer solar cells. Replacing poly(3,4-ethylenedioxy thiophene):poly(styrenesulfonate) (PEDOT:PSS) with a CPEs with narrow bandgap results in both improvements in device efficiency and stability. In spite of their narrow bandgap, thin CPE films (thickness of ~30 nm) enable sufficient light absorption within the active layer. Enhancement of device efficiency is attributed to low surface roughness, high transmittance in visible region, and reduced charge transfer resistance. Compared to the device with PEDOT:PSS, pH neutral nature of CPEs may enhance device stability under ambient condition. PMID- 29438861 TI - Synthesis of spherical and cubic magnetic iron oxide nanocrystals at low temperature in air. AB - Synthesis of magnetite nanocrystals typically requires harsh reaction conditions, including high reaction pressures and/or temperatures, to obtain morphology controlled nanocrystals like cubic magnetite nanocrystals. We report the synthesis of cubic magnetite nanocrystals with a size of 9 nm at reaction temperatures less than 100 degrees C in air. The synthesized magnetite nanocubes exhibited uniform size and highly crystalline nature. In addition, we synthesized size-controlled spherical magnetite nanocrystals in the size range of 2.5 nm to 9 nm by modifying the reaction conditions. PMID- 29438862 TI - Fabrication of nano copper oxide evenly patched on cubic sodium tantalate for oriented photocatalytic reduction of carbon dioxide. AB - A synthetic process was exploited to fabricate patchy CuO evenly planted on cubic NaTaO3 for photocatalytically reducing CO2 in isopropanol. The nano patches of CuO with about 15 nm in size were uniformly distributed on the surface of NaTaO3 via a phase-transfer protocol and solvothermal synthesis. The crystal phase, morphology, composition, optical absorption and charge separation of as-prepared CuO-NaTaO3 were characterized by XRD, SEM, TEM, EDX, XPS, UV-Vis and PL. The results of photocatalytic reduction of CO2 confirmed that the CuO patched NaTaO3 possessed better ability to separate charge carriers and selectively reduce CO2 to methanol than CuO directly loaded NaTaO3 using the traditional liquid phase reduction procedure after comparing the methanol yields. Furthermore, 5 wt% CuO patched NaTaO3 led to the highest methanol yield of 1302.22 MUmol g-1 h-1. A redox mechanism was proposed and illustrated in a schematic diagram. PMID- 29438863 TI - Controlling pore size of activated carbon through self-activation process for removing contaminants of different molecular sizes. AB - Self-activation was employed for the manufacturing of activated carbon (AC) using kenaf core fibers, which is more environmentally friendly and cost-effective than the conventional physical/chemical activations. It makes the use of the gases emitted from the thermal treatment to activate the converted carbon itself. The mechanism was illustrated by the Fourier transform infrared spectroscopy and mass spectrometry analysis of the emitted gases, showing that CO2 served as an activating agent. The AC from self-activation presented high performance, for instance, the Brunauer-Emmett-Teller surface area was up to 2296 m2 g-1, Using the Density Functional Theory (DFT), the pore volume (PV) was determined to be 1.876 cm3 g-1. Linear relations of PVDFT-micropore/iodine number, and PVDFT mesopore/tannin value were established, indicating a strong relationship between the pore structure of AC and its adsorbing preference. Adsorption results for copper (II) and rhodamine 6G also indicated that the pore size of AC should be designed based on the molecular size of the contaminants. PMID- 29438864 TI - Evaluation of nonionic surfactant modified montmorillonite as mycotoxins adsorbent for aflatoxin B1 and zearalenone. AB - This work aims at exploring the potential of nonionic surfactant octylphenol polyoxyethylene ether (OP-10) modified montmorillonites (NMts) as mycotoxins adsorbent. The resulting NMts has different structural configurations, organic carbon contents, surface hydrophobicity and textural properties at different surfactant loadings. The prepared NMts were used for adsorption of polar aflatoxin B1 (AFB1) and weak polar zearalenone (ZER) in both single and binary contaminate systems by simulating conditions of gastrointestinal tract. The adsorption capacities of NMts to AFB1 and ZER increased up to 2.78 and 8.54 mg/g respectively from 0.51 and 0.00 mg/g of raw montmorillonite (Mt). High adsorption capacities of NMts to AFB1 and ZER could be reached at low surfactant loadings. There was little decrease from pH of 3.5 to 6.5 but became negligible with increasing the surfactant loadings. In binary-contaminate adsorption system, the adsorption of ZER was obviously affected by the existence of AFB1, while ZER had little effect on the adsorption process of AFB1 due to different adsorption mechanism. This study demonstrates that NMts could be a promising adsorbent for simultaneous detoxification of polar and non-polar mycotoxins. PMID- 29438865 TI - Fabrication of hierarchical porous nickel based metal-organic framework (Ni-MOF) constructed with nanosheets as novel pseudo-capacitive material for asymmetric supercapacitor. AB - Hierarchical porous nickel based metal-organic framework (Ni-MOF) constructed with nanosheets is fabricated by a facile hydrothermal process with the existence of trimesic acid and nickel ions. Various structures of Ni-MOFs can be obtained through adjusting the molar ratio of trimesic acid and nickel ion, the obtained hierarchical porous Ni-MOF exhibits optimal porous structure, which also possesses largest specific surface area. The hierarchical porous structure constructed with nanosheets can supply more active sites for electrochemical reactions to realize the excellent electrochemical properties, thus the hierarchical porous Ni-MOF reveals an outstanding specific capacitance of 1057 F/g at current density of 1 A/g, and delivers high specific capacitance of 649 F/g at current density of 30 A/g, indicating that it exhibits good rate capability of 63.4% even up to 30 A/g. The hierarchical porous Ni-MOF keeps 70% of its original value up to 2 500 charge-discharge cycles at the current density of 10 A/g. Furthermore, asymmetric supercapacitors (ASCs) were assembled based on hierarchical porous Ni-MOF and activated carbon (AC), the ASCs reveal specific capacitance of 87 F/g at current density of 0.5 A/g, and exhibit high energy density of 21.05 Wh/kg and power density of 6.03 kW/kg. Additionally, the tandem ASCs can light up a red LED. The hierarchical porous Ni-MOF exhibits promising applications in high performance supercapacitors. PMID- 29438866 TI - A Comparison of graphene hydrogels modified with single-walled/multi-walled carbon nanotubes as electrode materials for capacitive deionization. AB - Capacitive deionization (CDI) is a technology used to remove salt from brackish water, and it is an energy-saving, low-cost method compared with other methods, such as reverse osmosis, multi-stage ash distillation and electrodialysis. In this paper, three-dimensional (3D) graphene hydrogels modified with single-walled carbon nanotubes (SWCNTs) or multi-walled carbon nanotubes (MWCNTs) were synthesized by a one-step water bath method to increase the conductivity of materials and reduce the aggregation of the graphene sheets. The CDI performance differences between the two materials were compared and discussed. The results suggested that SWCNTs/rGO had a higher electrosorption capacity (48.73 mg/g) than MWCNTs/rGO, and this was attributed to its high specific surface area (308.37 m2/g), specific capacity (36.35 F/g), and smaller charge transfer resistance compared with those of the MWCNTs/rGO electrode. The results indicate SWCNTs/rGO is a promising and suitable material for CDI technology and we provide basic guidance for further CNTs/graphene composite research. PMID- 29438867 TI - Evaluation of the microscopic distribution of florfenicol in feed pellets for salmon by Fourier Transform infrared imaging and multivariate analysis. AB - Fourier Transform infrared imaging and multivariate analysis were used to identify, at the microscopic level, the presence of florfenicol (FF), a heavily used antibiotic in the salmon industry, supplied to fishes in feed pellets for the treatment of salmonid rickettsial septicemia (SRS). The FF distribution was evaluated using Principal Component Analysis (PCA) and Augmented Multivariate Curve Resolution with Alternating Least Squares (augmented MCR-ALS) on the spectra obtained from images with pixel sizes of 6.25 MUm * 6.25 MUm and 1.56 MUm * 1.56 MUm, in different zones of feed pellets. Since the concentration of the drug was 3.44 mg FF/g pellet, this is the first report showing the powerful ability of the used of spectroscopic techniques and multivariate analysis, especially the augmented MCR-ALS, to describe the FF distribution in both the surface and inner parts of feed pellets at low concentration, in a complex matrix and at the microscopic level. The results allow monitoring the incorporation of the drug into the feed pellets. PMID- 29438868 TI - Investigation of the reverse effect of Danhong injection on doxorubicin-induced cardiotoxicity in H9c2 cells: Insight by LC-MS based non-targeted metabolomic analysis. AB - Although Danhong injection (DHI) has been clearly shown to attenuate ischemic myocardial injury and improve heart function, there is no research regarding its role in doxorubicin (DOX)-induced cardiomyopathy. In this study, we aimed to investigate the reverse effect of DHI on DOX-induced cardiotoxicity in H9c2 cells. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated that DHI had no cytotoxicity towards the relevant cell line unless the concentration was as high as 50 MUL/mL. The satisfactory cardioprotective effect of DHI exerted at the concentration of 10 MUL/mL, which agreed well with the result of real-time cell viability assay. Then non-targeted metabolomics based on LC-MS was employed to characterize metabolic alterations in DOX-induced cells with DHI treatment. Multivariate analysis, including PCA and PLS-DA, revealed 31 altered metabolites after DOX treatment that were primarily related to the disturbance of amino acids and nucleotides metabolism. While DHI could intervene in some disturbed metabolic pathways, such as the metabolism of arginine, glutathione (GSH), pantothenic acid, cytidine, inosine and 5'-methylthioadenosine. These results suggested that DHI exerted the therapeutic effect by improving energy metabolism and attenuating oxidative stress. The present study can lay a foundation for further research on the promising therapeutic effect of DHI in managing DOX-induced cardiotoxicity. PMID- 29438869 TI - Building mindfulness bottom-up: Meditation in natural settings supports open monitoring and attention restoration. AB - Mindfulness courses conventionally use effortful, focused meditation to train attention. In contrast, natural settings can effortlessly support state mindfulness and restore depleted attention resources, which could facilitate meditation. We performed two studies that compared conventional training with restoration skills training (ReST) that taught low-effort open monitoring meditation in a garden over five weeks. Assessments before and after meditation on multiple occasions showed that ReST meditation increasingly enhanced attention performance. Conventional meditation enhanced attention initially but increasingly incurred effort, reflected in performance decrements toward the course end. With both courses, attentional improvements generalized in the first weeks of training. Against established accounts, the generalized improvements thus occurred before any effort was incurred by the conventional exercises. We propose that restoration rather than attention training can account for early attentional improvements with meditation. ReST holds promise as an undemanding introduction to mindfulness and as a method to enhance restoration in nature contacts. PMID- 29438870 TI - Controlled preparation of MoS2/PbBiO2I hybrid microspheres with enhanced visible light photocatalytic behaviour. AB - Novel MoS2/PbBiO2I hybrid microspheres were controllably synthesized via the ionic liquid 1-hexyl-3-methylimidazolium iodide ([Hmim]I) assisted solvothermal method. The morphologies, structures, optical and electronic properties of the materials were explored by XRD, XPS, SEM, TEM, DRS, EIS and photocurrent analysis. The photocatalytic activity of MoS2/PbBiO2I was evaluated by the degradation of rhodamine B (RhB), antibiotic agent ciprofloxacin (CIP) and bisphenol A (BPA) under visible light irradiation. The photodegradation results showed that the activity of MoS2/PbBiO2I was higher than that of pure PbBiO2I because of suitable band alignment, a larger specific surface area, an enhanced light absorption region, and stronger photocurrent intensity arising from the interface interaction between MoS2 and PbBiO2I. The 1.0 wt% MoS2/PbBiO2I showed the best photocatalytic performance. Electron spin resonance (ESR) experiments and free radical trapping experiments showed that the superoxide radicals (O2-) and holes (h+) were determined to be the main active species for the photocatalysis process. A possible mechanism was presented based on the detection and analysis results. PMID- 29438871 TI - Red cell distribution width as a predictor of 1-year survival in ischemic stroke patients treated with intravenous thrombolysis. AB - INTRODUCTION: Red cell distribution width (RDW) has been found to be a prognostic marker in vascular diseases. Increased RDW predicted mortality and outcome after ischemic stroke however, the underlying mechanisms are unclear. Our study aimed to clarify the relation of RDW with stroke severity and 1-year survival. MATERIAL AND METHODS: Single-centre retrospective cohort study based on a prospective database of consecutive patients with acute anterior circulation ischemic stroke treated with intravenous thrombolysis (IVT) in a 9-year period. Clinical characteristics were collected from the registry. Additional information, namely pre-IVT RDW, was retrieved from individual patient records. Information concerning survival during the first year after stroke was collected from the national Health Data Platform. RESULTS: 602 patients were included. Patients in the higher RDW quartiles were older, and more frequently presented hypertension and cardioembolic etiology. RDW was higher in patients who presented early infection and a positive correlation was found between RDW and C-reactive protein. RDW was not associated with admission severity of stroke, neurological status 24 h after stroke or occurrence of symptomatic intracranial hemorrhage (sICH). Patients in the higher quartiles of RDW presented a lower 1-year survival (p < 0.001). After stepwise adjustment for variables of interest, including severity of ischemic stroke, sICH, and response to IVT, RDW remained a predictor of 1-year survival, specifically in patients >=75 years and in patients with early post-stroke infection. CONCLUSIONS: RDW is a predictor of 1-year survival in patients with ischemic stroke treated with IVT, specifically in older patients and those who develop early infection, and its prediction value is independent from stroke severity and response to IVT. PMID- 29438872 TI - Evidence for contemporary plant mitoviruses. AB - Mitoviruses have small RNA(+) genomes, replicate in mitochondria, and have been shown to infect only fungi to date. For this report, sequences that appear to represent nearly complete plant mitovirus genomes were recovered from publicly available transcriptome data. Twenty of the refined sequences, 2684-2898 nt long and derived from 10 different species of land plants, appear to encompass the complete coding regions of contemporary plant mitoviruses, which furthermore constitute a monophyletic cluster within genus Mitovirus. Complete coding sequences of several of these viruses were recovered from multiple transcriptome (but not genome) studies of the same plant species and also from multiple plant tissues. Crop plants among implicated hosts include beet and hemp. Other new results suggest that such genuine plant mitoviruses were immediate ancestors to endogenized mitovirus elements now widespread in land plant genomes. Whether these mitoviruses are wholly cryptic with regard to plant health remains to be investigated. PMID- 29438873 TI - Interactive associations of parental support, demands, and psychological control, over adolescents' beliefs about the legitimacy of parental authority. AB - The present study examined the relationship between parental support, demand, psychological control and adolescents' beliefs about the legitimacy of parental authority for personal and multifaceted issues in a sample of 1342 Chilean adolescents (M = 16.38, SD = 1.24, age range 14-20). Results from multiple regression analyses separated by age indicated that demand was positively associated with adolescents' beliefs about the legitimacy of parental authority for personal and multifaceted issues and that psychological control was negatively associated with adolescents' legitimacy beliefs concerning personal issues. Furthermore, parental support moderated the relationship between parental demand and adolescents' beliefs about parental legitimacy for personal and multifaceted issues: those who display high levels of demand showed stronger beliefs about parental legitimacy at high level of support. These results support the interactive effect of parental support and demand on adolescent development. PMID- 29438874 TI - Gender differences in pathways from child physical and sexual abuse to adolescent risky sexual behavior among high-risk youth. AB - This study investigated gender differences in the roles of internalizing and externalizing symptoms and substance use as pathways linking child physical and sexual abuse to risky sexual behavior among youth at risk of maltreatment. Path analysis was performed with 862 adolescents drawn from Longitudinal Studies of Child Abuse and Neglect. Four waves of data collected in the United States were used: childhood physical and sexual abuse experiences (from ages 0-12) were assessed by Child Protective Services reports, internalizing and externalizing symptoms were measured at age 14, substance use was measured at age 16, and risky sexual behavior was measured at age 18. Physical abuse was directly associated with risky sexual behavior in boys but not girls. For girls, physical abuse had a significant indirect effect on risky sexual behavior via externalizing symptoms. Gender-focused preventive intervention strategies may be effective in reducing risky sexual behavior among at-risk adolescents. PMID- 29438875 TI - How do post-divorce paternal and maternal family trajectories relate to adolescents' subjective well-being? AB - Previous research on adolescents' well-being has focused mainly on the differences between married and divorced families. Recently, interest has shifted towards the cumulative effects of the various family transitions experienced by children. To contribute to this literature, we investigate the relationship of maternal and paternal family trajectories following divorce with adolescents' well-being by analyzing two dyadic subsamples of the 'Divorce in Flanders' study: mothers-adolescents (n = 515) and fathers-adolescents (n = 365). Results from the sequence analyses and structural equation models show that adolescents' well being was lower if their mothers were in less stable partnership situations, namely if they had never repartnered, were in a LAT (living apart together) relationship or had had several relationships since their divorce. For fathers, the opposite result was found: adolescents' well-being was lower when their fathers were in seemingly stable partnership situations, i.e. if they had remarried or begun living with a new partner since their divorce. PMID- 29438876 TI - Off the top of my head: Malleability and stability in natural categories. AB - Previous research has found that category representations are highly malleable knowledge structures, varying widely across different contexts and individuals. However, it has also been found that such malleability does not apply equally to all types of category information. The present research further investigates the representational malleability versus stability of natural taxonomic categories. Using perceptual fluency as means to induce malleability, we explored whether malleability is moderated by the degree of typicality of category information. In the first experiment, we found that fluency-based malleability only occurs for non-typical category information. In follow-up experiments, we investigated the boundary conditions under which such fluency-based malleability occurs. Namely, in Experiment 2, we showed that the effect of fluency on non-typical features disappeared when there is a sensory modality mismatch between study and test phases. Finally, in Experiment 3, we demonstrated that this effect reappears in the modality mismatch condition when participants are given a response deadline. The implications of these findings to current theories of category representation and the perceptual fluency literature are discussed. PMID- 29438877 TI - Assessing the influence of sound parameters on crossmodal cuing in different regions of space. AB - To date, crossmodal spatial cuing research has primarily investigated spatial attention modulated by the positioning of auditory cues, without addressing the question of the role played by sound parameters such as intensity change, waveform structure, or duration. Therefore in the present study, we investigated exogenous spatial cuing following the presentation of auditory cues having different intensity profiles (looming or receding), waveforms (triangular structured waveform or white noise), and durations (250 ms or 500 ms). Auditory cues were presented from one of four locations (front-left, front-right, rear left, or rear-right). The participants had to make speeded elevation discrimination responses to visual targets presented from the front (on the left or right). The magnitude of the cuing effect was larger following the presentation of a structured looming auditory cue than a structured receding cue. On the other hand, there was no statistical difference between the magnitude of the cuing effect in the looming and in the receding intensity profiles when white noise cues were used. Such findings are consistent with previous reports. Furthermore, the magnitude of the cuing effect was larger when the cues were presented from the front than from the rear. On the contrary, other recent findings showed that the presentation of a 100 ms constant-intensity auditory cue exogenously oriented visual attention to the cued hemifield, regardless of whether the cues were presented from the front or rear. Therefore, the findings reported here demonstrated that sound parameters can modulate the exogenous orienting of crossmodal spatial attention. PMID- 29438878 TI - Crushing hope: Short term responses to tragedy vary by hopefulness. AB - This paper explores the consequences of hopefulness when the environment changes. Much literature has documented the importance of a positive outlook in pursuing investments in health and education that pay off in the future. A question that has received less attention is whether a positive outlook creates resilience in the face of setbacks or whether a positive outlook may be a disadvantage in extreme circumstances, especially when there is a large mismatch between expectations and reality. This paper uses the coincidental interview schedule of the Add Health data (N = 15,024) around the terrorist attack of September 11, 2001 to examine interactions with this environmental shock and previously elicited measures of hopefulness. The results suggest that increases in depressive symptoms following the attack are concentrated among those young adults who initially expressed the most hopefulness in the future as teenagers. PMID- 29438879 TI - Bio-inspired redox-cycling antimicrobial film for sustained generation of reactive oxygen species. AB - Open wounds and burns are prone to infection and there remains considerable interest in developing safe and effective mechanisms to confer antimicrobial activities to wound dressings. We report a biomimetic wound dressing for the in situ and sustained generation of reactive oxygen species (ROS). Specifically, we fabricate a catechol-modified chitosan film that mimics features of the melanin capsule generated during an insect immune response to infection. We use an electrochemical reverse engineering approach to demonstrate that this catechol chitosan film possesses redox-activities and can be repeatedly oxidized and reduced. In vitro tests demonstrate that this film catalyzes the transfer of electrons from physiological reductant ascorbate to O2 for sustained ROS generation, and confers ascorbate-dependent antimicrobial activities. In vivo antimicrobial experiment with a rat subcutaneous model indicates the catechol chitosan film at reduced state inhibits the bacterial growth and alleviates the infection of the incisions. Open wound healing tests with a mouse model indicate that the catechol-chitosan film suppresses the bacterial population at the wound site, induces less inflammation and promotes wound healing. We envision this biomimetic approach for the sustained, localized and in situ generation of ROS could provide new opportunities for wound management by protecting against pathogen infection and potentially even enlisting ROS-mediated wound healing mechanisms. PMID- 29438880 TI - Glucose & oxygen exhausting liposomes for combined cancer starvation and hypoxia activated therapy. AB - Starvation therapy to slow down the tumor growth by cutting off its energy supply has been proposed to be an alternative therapeutic strategy for cancer treatment. Herein, glucose oxidase (GOx) is loaded into stealth liposomes and act as the glucose and oxygen elimination agent to trigger the conversion of glucose and oxygen into gluconic acid and H2O2. Such liposome-GOx after intravenous injection with effective tumor retention is able to exhaust glucose and oxygen within the tumor, producing cytotoxic H2O2 and enhancing hypoxia, as vividly visualized by non-invasive in vivo photoacoustic imaging. By further combination treatment with stealth liposomes loaded with banoxantrone dihydrochloride (AQ4N), a hypoxia activated pro-drug, a synergistically enhanced tumor growth inhibition effect is achieved in the mouse model of 4T1 tumor. Hence, by combining starvation therapy and hypoxia-activated therapy tactfully utilizing liposomal nanocarriers to co deliver both enzymes and prodrugs, an innovative strategy is presented in this study for effective cancer treatment. PMID- 29438881 TI - Crosstalk between core-multishell nanocarriers for cutaneous drug delivery and antigen-presenting cells of the skin. AB - Owing their unique chemical and physical properties core-multishell (CMS) nanocarriers are thought to underlie their exploitable biomedical use for a topical treatment of skin diseases. This highlights the need to consider not only the efficacy of CMS nanocarriers but also the potentially unpredictable and adverse consequences of their exposure thereto. As CMS nanocarriers are able to penetrate into viable layers of normal and stripped human skin ex vivo as well as in in vitro skin disease models the understanding of nanoparticle crosstalk with components of the immune system requires thorough investigation. Our studies highlight the biocompatible properties of CMS nanocarriers on Langerhans cells of the skin as they did neither induce cytotoxicity and genotoxicity nor cause reactive oxygen species (ROS) or an immunological response. Nevertheless, CMS nanocarriers were efficiently taken up by Langerhans cells via divergent endocytic pathways. Bioimaging of CMS nanocarriers by fluorescence lifetime imaging microscopy (FLIM) and flow cytometry indicated not only a localization within the lysosomes but also an energy-dependent exocytosis of unmodified CMS nanocarriers into the extracellular environment. PMID- 29438882 TI - Comparative evaluation of cell- and serum-derived exosomes to deliver immune stimulators to lymph nodes. AB - To determine whether exosomes are efficient carriers for immune stimulating molecules into lymph nodes, comparative studies of exosomes (EXOs) derived from different origins (cells and serums) in terms of physicochemical properties and delivery efficiency were performed. Serum-derived EXOs were of a preferable size and generated higher yields than RAW264.7 cell-derived exosomes (RAW-EXO). In particular, fetal bovine serum-derived exosomes (bo-EXO), with a size below 50 nm, were delivered not only to surface zones (subcapsular sinus (SCS) macrophage zone) but also to inner paracortex zones (T cell zone) of lymph nodes, which allowed an efficient delivery of immune stimulating molecules to antigen presenting cells and T cells. The encapsulation of immune stimulating biomolecules (monophosphoryl lipid A (MPLA) and CpG oligodeoxynucleotides (CpG ODN)) within EXOs greatly increased intracellular delivery to macrophages via phagocytic pathways, which induced higher TNF-alpha and IL-6 secretion than free MPLA and free CpG ODN. MPLA-incorporated exosomes activated and differentiated T cells after subcutaneous injection, which elevated cytokine IFN-gamma and TNF alpha induction for CD3+ T cells. Taken together, bo-EXOs might serve as efficient carrier systems of immune stimulators to lymph nodes for desired immune responses. PMID- 29438883 TI - Gradient nano-engineered in situ forming composite hydrogel for osteochondral regeneration. AB - Fabrication of anisotropic osteochondral-mimetic scaffold with mineralized subchondral zone and gradient interface remains challenging. We have developed an injectable semi-interpenetrating network hydrogel construct with chondroitin sulfate nanoparticles (ChS-NPs) and nanohydroxyapatite (nHA) (~30-90 nm) in chondral and subchondral hydrogel zones respectively. Mineralized subchondral hydrogel exhibited significantly higher osteoblast proliferation and alkaline phosphatase activity (p < 0.05). Osteochondral hydrogel exhibited interconnected porous structure and spatial variation with gradient interface of nHA and ChS NPs. Microcomputed tomography (MUCT) demonstrated nHA gradation while rheology showed predominant elastic modulus (~930 Pa) at the interface. Co-culture of osteoblasts and chondrocytes in gradient hydrogels showed layer-specific retention of cells and cell-cell interaction at the interface. In vivo osteochondral regeneration by biphasic (nHA or ChS) and gradient (nHA + ChS) hydrogels was compared with control using rabbit osteochondral defect after 3 and 8 weeks. Complete closure of defect was observed in gradient (8 weeks) while defect remained in other groups. Histology demonstrated collagen and glycosaminoglycan deposition in neo-matrix and presence of hyaline cartilage characteristic matrix, chondrocytes and osteoblasts. MUCT showed mineralized neo tissue formation, which was confined within the defect with higher bone mineral density in gradient (chondral: 0.42 +/- 0.07 g/cc, osteal: 0.64 +/- 0.08 g/cc) group. Further, biomechanical push-out studies showed significantly higher load for gradient group (378 +/- 56 N) compared to others. Thus, the developed nano engineered gradient hydrogel enhanced hyaline cartilage regeneration with subchondral bone formation and lateral host-tissue integration. PMID- 29438886 TI - The influence of motives on alcohol- and sex-related behaviors among female college students. AB - PURPOSE: Although previous studies have elucidated associations between motivations for drinking and sex as they relate to risky health outcomes among female college students, the utility of cross-domain motives (i.e., alcohol motives predicting sex-related outcomes and vice versa) in the prediction of specific alcohol- and sex-related behaviors has yet to be examined. The current study examined relations between drinking and sex motives with multiple risky alcohol- and sex-related outcomes (i.e., alcohol consumption, alcohol-related problems, alcohol consumption prior to sexual intercourse, number of sexual partners [vaginal, oral, anal], and emergency contraception use). PROCEDURES: Multiple structural equation models were used to examine univariate and multivariate associations among drinking and sex motives and specific outcomes in a sample of female undergraduates with lifetime histories of alcohol use and sexual activity (N = 436; 77% White, 21% Hispanic). RESULTS: Findings indicated differential associations between motives and specific outcomes across univariate versus multivariate analyses. Multivariate models indicated greater endorsement of enhancement and less endorsement of intimacy sex motives were significantly associated with heavy drinking and alcohol-related problems, whereas alcohol motives were less reliably linked to sex-related outcomes. When considered simultaneously, sex motives accounted for more variance in some alcohol outcomes relative to certain drinking motives. CONCLUSIONS: Cross-domain motives may be useful in predicting risky outcomes among female college students. Research implications include the importance of examining motive-behavior relations in univariate and multivariate contexts. Clinical implications include cross-domain motive assessment and use of emotion regulation strategies to reduce emotionally motivated maladaptive alcohol- and sex-related behaviors. PMID- 29438884 TI - Sprouting angiogenesis induces significant mechanical heterogeneities and ECM stiffening across length scales in fibrin hydrogels. AB - Matrix stiffness is a well-established instructive cue in two-dimensional cell cultures. Its roles in morphogenesis in 3-dimensional (3D) cultures, and the converse effects of cells on the mechanics of their surrounding microenvironment, have been more elusive given the absence of suitable methods to quantify stiffness on a length-scale relevant for individual cell-extracellular matrix (ECM) interactions. In this study, we applied traditional bulk rheology and laser tweezers-based active microrheology to probe mechanics across length scales during the complex multicellular process of capillary morphogenesis in 3D, and further characterized the relative contributions of neovessels and supportive stromal cells to dynamic changes in stiffness over time. Our data show local ECM stiffness was highly heterogeneous around sprouting capillaries, and the variation progressively increased with time. Both endothelial cells and stromal support cells progressively stiffened the ECM, with the changes in bulk properties dominated by the latter. Interestingly, regions with high micro stiffness did not necessarily correlate with remodeled regions of high ECM density as shown by confocal reflectance microscopy. Collectively, these findings, especially the large spatiotemporal variations in local stiffness around cells during morphogenesis in soft 3D fibrin gels, underscore that characterizing ECM mechanics across length scales. provides an opportunity to attain a deeper mechanobiological understanding of the microenvironment's roles in cell fate and tissue patterning. PMID- 29438885 TI - The positive effects of secreting cytokines IL-17 and IFN-gamma on the early stage differentiation and negative effects on the calcification of primary osteoblasts in vitro. AB - OBJECTIVE: Interleukin-17 (IL-17) and interferon-gamma (IFN-gamma) are all pro inflammatory cytokines produced by specific subsets of T-cells and are also considered crucial regulators in bone remodeling, but their effects on osteogenesis have not been carefully studied. So, this study aimed to investigate the effects of secreting cytokines IL-17 and IFN-gamma on the osteogenesis of primary osteoblasts and to clarify the potential roles of the related Janus activated kinase 2 (JAK2) and downstream signal transducer and activator of transcription 3 (STAT3) signaling pathway in bone remodeling. METHODS: The proliferation of osteoblasts was evaluated by MTT assay. Osteogenic activity was tested by alkaline phosphatase (ALP) activity assay and alizarin red staining. The mRNA levels of ALP, osteocalcin, osteoprotegerin (OPG), Runt-related transcription factor 2 (Runx2) and receptor activator of nuclear factor-kappa B ligand (RANKL) were also measured by real-time quantitative PCR. The JAK2-STAT3 pathway was evaluated by Western blot. RESULTS: Osteoblasts showed no obvious proliferation when treated with IL-17 and/or IFN-gamma, but higher ALP activities were observed in primary osteoblasts treated with IL-17 or IL-17 + IFN-gamma in induction medium. We also found that IL-17 could promote the gene expression of Alp, Runx2, Osteocalcin, Opg, and Rankl, while IFN-gamma might attenuate this effect. Nevertheless, IL-17 and IFN-gamma exhibited an inhibitory effect on the calcification of primary osteoblasts. We also found that IL-17 could directly facilitate RANKL expressions by JAK2-STAT3 pathway. CONCLUSION: The positive effects of IL-17 and IFN-gamma on the early-stage differentiation and the negative effects on the calcification of murine calvarial osteoblasts contribute to our understanding of the role and interaction of inflammatory factors in the bone remodeling and as fundamental mechanisms involved in the destruction of alveolar bone. PMID- 29438889 TI - Recent progress in potential anti-hepatitis B virus agents: Structural and pharmacological perspectives. AB - Hepatitis B virus (HBV) infections affect about 240 million patients worldwide and increase the risk of liver cirrhosis and hepatocellular carcinoma. It is estimated that about 686 thousand people died annually of liver damage resulted from HBV infections. At present, two classes of antiviral drugs have been approved by the Food and Drug Administration (FDA) for the treatment of hepatitis B, immunomodulators (interferon [IFN]-a and pegylated-interferon [PEG-IFN]-a) and nucleos(t)ide analogs (lamivudine, telbivudine, adefovir, tenofovir [TDF], and entecavir [ETV]). However, it still remains a daunting challenge for curing HBV, because of the low sustained response rates (20-30%) and many side effects of IFN and peg-IFN. Although nucleoside analogues are well tolerated and exhibit an early and potent antiviral effect, the selection of resistant mutants and nephrotoxicity during long-term therapy limit their use. Here, we focus on summarizing the currently approved anti-HBV drugs and characterization of novel HBV inhibitors and analysing their structures, targets, anti-HBV effects and mechanisms of action, which may shed new light on the discovery of small compounds as potential anti-HBV drugs for treatment of HBV. PMID- 29438888 TI - Tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one scaffold derivatives: Synthesis and biological evaluation as selective BuChE inhibitors. AB - BuChE inhibitors play important roles in treatment of patients with advanced Alzheimer's disease (AD). A series of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin 5(6H)-one derivatives were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. Some derivatives showed selective BuChE inhibitory activity, which was influenced by the volumes of the substituted groups at the C6 position and halogen substituents at the benzene ring of tricyclic scaffold. Among them, compounds 3f and 3o with dihalogen and 6 ethyl substituent showed the most potent activity (IC50 = 2.95, 2.04 MUM, and mixed-type, non-competitive inhibition against BuChE, respectively). Eutomer (6R) 3o exhibited better BuChE inhibitory activity than (6S)-3o. Compound 3o exhibited nontoxic, good ADMET properties, and remarkable neuroprotective activity. Docking studies revealed the same binding orientation within the active site of target enzyme. Compound 3o was nicely bound to BuChE via three hydrogen bonds, one Alkyl interaction and three Pi-Alkyl interactions. The selective BuChE inhibitors had a potential use in progressive neurodegenerative disorder. PMID- 29438887 TI - Is the Fagerstrom test for nicotine dependence invariant across secular trends in smoking? A question for cross-birth cohort analysis of nicotine dependence. AB - BACKGROUND: The Fagerstrom Test for Nicotine Dependence (FTND), a derivation of the Fagerstrom Tolerance Questionnaire, was first published in 1991. The FTND remains one of the most widely used measures of nicotine dependence for studying genetic and epidemiological risk factors and the likelihood of smoking cessation. However, it is unclear whether secular trends in patterns of smoking alter the psychometric properties of the FTND and its interpretation. METHODS: We examined measurement invariance in the lifetime and current FTND scores across birth cohorts using participants drawn from six study samples (N = 13,775). RESULTS: We found significant (p < 0.05) measurement non-invariance in means and factor loadings of most FTND items by birth cohort, but effect sizes, ranging from r2 = 0.0001 to r2 = 0.0035, indicated that less than 0.5% of the model variance was explained by the measurement non-invariance for each factor loading. To assess its impact, we regressed the lifetime FTND latent variable on well-established factors associated with nicotine dependence (quitting smoking and the nicotinic acetylcholine receptor gene [CHRNA5] variant rs16969968, separately), and we observed that the regression coefficients were unchanged between models with and without adjustment for measurement non-invariance. CONCLUSIONS: These findings suggest that possible FTND non-invariance that occurs across study samples of various birth years has a negligible impact on study results. PMID- 29438890 TI - Flavonoids from Chinese bayberry leaves induced apoptosis and G1 cell cycle arrest via Erk pathway in ovarian cancer cells. AB - Ovarian cancer is one of the leading causes of death related to the female reproductive system in western countries. Adverse side effects and resistance to platinum based chemotherapy have become the major obstacles for ovarian cancer treatment. Natural products have gained great attention in cancer treatment in recent years. Chinese bayberry leaves flavonoids (BLF) containing rich content of myricitrin (myricetin 3-O-rhamnoside) and a part of quercetrin (quercetin 3 rhamnoside) inhibited the growth of an ovarian cancer cell line A2780/CP70. Such inhibitory effects might be due to the induction of apoptosis and G1 cell cycle arrest. BLF treatment increased the expression of cleaved caspase-3 and -7 and induced apoptosis via a Erk-dependent caspase-9 activation intrinsic apoptotic pathway by up-regulating the pro-apoptotic proteins (Bad and Bax) and down regulating the anti-apoptotic proteins (Bcl-xL and Bcl-2), which were also in consistency with the results from Hoechst 33342 staining and flow cytometry analysis. Furthermore, by reducing the expression of cyclin D1 and CDK4 and p Erk, BLF elevated the distribution of G1 phase in cell cycle and thus caused G1 cell cycle arrest. Overall, these results indicated that BLPs could be a valuable resource of natural compound for ovarian cancer treatment. PMID- 29438891 TI - Synthesis and pharmacological evaluation of 6,7-dimethoxy-1,2,3,4 tetrahydroisoquinoline derivatives as sigma-2 receptor ligands. AB - Increasing evidences have implicated that sigma-2 receptor is a biomarker and significantly over-expressed in many proliferative cancer cells with no or low expression in normal cells. Sigma-2 receptor selective ligands have been successfully used as valuable tools to study its pharmacological functions, tumor imaging, and cancer therapeutics or adjuvants. 6,7-Dimethoxy-1,2,3,4 tetrahydroisoquinolinylalkyl benzamides are among a few categories of structures that have demonstrated high affinities and selectivities for sigma-2 receptor and been used extensively as study tools in various tumor imaging and therapy. As a continuous effort, we have synthesized a new series of 6,7-dimethoxy-1,2,3,4 tetrahydroisoquinoline derivatives and evaluated their affinities for both sigma 1 and sigma-2 receptors. Most of these newly developed analogs showed good to excellent binding affinities for sigma-2 receptor with no or low affinities for sigma-1 receptor. In particular, compounds 3b, 3e, 4b, and 4e demonstrated Ki values of 5-6 nM affinities and excellent selectivities for sigma-2 receptor. In addition, these analogs also demonstrated moderate anticancer activities against human liver Huh-7 tumor cells and human esophagus KYSE-140 cancer cells. But their cytotoxicities seem not to be correlated with their sigma-2 receptor affinities. PMID- 29438892 TI - Influences of dissolved organic matters on tetracyclines transport in the process of struvite recovery from swine wastewater. AB - Due to the extensive existence of tetracyclines (TCs), struvite (MgNH4PO4.6H2O) recovery from swine wastewater will pose TCs-pharmacological threats to the agricultural planting and environment. This study investigated the influences of dissolved organic matters (DOM), as an important medium in the wastewater, on TCs transport during struvite recovery from swine wastewater. Compared to TCs concentrations of 1.49-2.16 MUg/g in the solids obtained from synthetic wastewater, the existence of DOM significantly enhanced TCs contents in the products with the values of 360-742 MUg/g. DOM was fractionated into four size fractions with different molecular weight cut-off, i.e. FDOM1 (30 kDa-0.45 MUm), FDOM2 (5-30 kDa), FDOM3 (1-5 kDa) and FDOM4 (<1 kDa). Results revealed that the destabilization and aggregation of FDOM1 and FDOM2 contributed major roles to TCs transport from the aqueous phase to the solid products. Meanwhile, the hydrolysis of certain parts of FDOM1 and FDOM2 led to the aqueous TCs re-partition among various DOM constituents, which presented a false appearance that FDOM4 with smaller molecular weight posed significant influences on TCs transport. Increasing pH values from 8.5 to 10.5 resulted with a stepwise increase of precipitated DOM, thereby enhancing TCs concentrations from 94.5 to 292.4 MUg/g to 627.2-825.0 MUg/g in the recovered solids. The outcomes provide a better understanding on the capability of DOM on TCs transport and abatement in the phosphate recovery process. PMID- 29438893 TI - Cryptosporidium species and subtypes in animals inhabiting drinking water catchments in three states across Australia. AB - As part of long-term monitoring of Cryptosporidium in water catchments serving Western Australia, New South Wales (Sydney) and Queensland, Australia, we characterised Cryptosporidium in a total of 5774 faecal samples from 17 known host species and 7 unknown bird samples, in 11 water catchment areas over a period of 30 months (July 2013 to December 2015). All samples were initially screened for Cryptosporidium spp. at the 18S rRNA locus using a quantitative PCR (qPCR). Positives samples were then typed by sequence analysis of an 825 bp fragment of the 18S gene and subtyped at the glycoprotein 60 (gp60) locus (832 bp). The overall prevalence of Cryptosporidium across the various hosts sampled was 18.3% (1054/5774; 95% CI, 17.3-19.3). Of these, 873 samples produced clean Sanger sequencing chromatograms, and the remaining 181 samples, which initially produced chromatograms suggesting the presence of multiple different sequences, were re-analysed by Next- Generation Sequencing (NGS) to resolve the presence of Cryptosporidium and the species composition of potential mixed infections. The overall prevalence of confirmed mixed infection was 1.7% (98/5774), and in the remaining 83 samples, NGS only detected one species of Cryptosporidium. Of the 17 Cryptosporidium species and four genotypes detected (Sanger sequencing combined with NGS), 13 are capable of infecting humans; C. parvum, C. hominis, C. ubiquitum, C. cuniculus, C. meleagridis, C. canis, C. felis, C. muris, C. suis, C. scrofarum, C. bovis, C. erinacei and C. fayeri. Oocyst numbers per gram of faeces (g-1) were also determined using qPCR, with medians varying from 6021 61,064 across the three states. The significant findings were the detection of C. hominis in cattle and kangaroo faeces and the high prevalence of C. parvum in cattle. In addition, two novel C. fayeri subtypes (IVaA11G3T1 and IVgA10G1T1R1) and one novel C. meleagridis subtype (IIIeA18G2R1) were identified. This is also the first report of C. erinacei in Australia. Future work to monitor the prevalence of Cryptosporidium species and subtypes in animals in these catchments is warranted. PMID- 29438894 TI - Novel edge treatment method for improving the transmission reconstruction quality in Tomographic Gamma Scanning. AB - Tomographic Gamma Scanning (TGS) is a method used for the nondestructive assay of radioactive wastes. In TGS, the actual irregular edge voxels are regarded as regular cubic voxels in the traditional treatment method. In this study, in order to improve the performance of TGS, a novel edge treatment method is proposed that considers the actual shapes of these voxels. The two different edge voxel treatment methods were compared by computing the pixel-level relative errors and normalized mean square errors (NMSEs) between the reconstructed transmission images and the ideal images. Both methods were coupled with two different interative algorithms comprising Algebraic Reconstruction Technique (ART) with a non-negativity constraint and Maximum Likelihood Expectation Maximization (MLEM). The results demonstrated that the traditional method for edge voxel treatment can introduce significant error and that the real irregular edge voxel treatment method can improve the performance of TGS by obtaining better transmission reconstruction images. With the real irregular edge voxel treatment method, MLEM algorithm and ART algorithm can be comparable when assaying homogenous matrices, but MLEM algorithm is superior to ART algorithm when assaying heterogeneous matrices. PMID- 29438895 TI - Piriformospora indica cell wall extract as the best elicitor for asiaticoside production in Centella asiatica (L.) Urban, evidenced by morphological, physiological and molecular analyses. AB - Vascular plants synthesise a multitude of organic molecules or phytochemicals, referred to as "secondary metabolites". These molecules are involved in a variety of roles in the life span of plants, ranging from structural ones to protection. Centella asiatica (L.) Urban has probably been used since prehistoric times and has been reported to have been used for various medicinal and cosmetic purposes. The plant contains several active constituents, of which the most important is asiaticoside, a triterpenoid. Asiaticoside content in C. asiatica can be enhanced by the use of biotic elicitors like Piriformospora indica. P. indica has been used as a model to study the mechanisms and evolution of mutualistic symbiosis. P. indica is similar to Arbuscular Mycorrhizal (AM) fungi in terms of plant growth promotional effects. The autoclaved fraction from P. indica (PiCWE) was found to be the most active fraction in promoting the plant biomass and asiaticoside content. To date, there are no reports on the potential role of PiCWE in enhancement of asiaticoside over the control and P. indica colonized plants, which was evidenced by the differential expression of key genes involved and final asiaticoside content along with the determination of phytohormones. Moreover, differential expression of selected miRNAs in PiCWE - C. asiatica root interactions over the control and P. indica treated C. asiatica leaf samples was also scrutinized. The important consequence of induction with PiCWE was the significant enhancement of asiaticoside in the PiCWE induced plants in comparison with the asiaticoside content in control and P. indica-C. asiatica interaction. In addition, the role of miRNAs in C. asiatica - PiCWE would enable more in-depth studies for deciphering the molecular and physiological mechanisms of the association and regulation of PiCWE - C. asiatica interactions. PMID- 29438896 TI - Transcriptomic profiling reveals pigment regulation during peanut testa development. AB - Although peanut (Arachis hypogaea L.) is one of the most important edible oil crops globally, pigments present in the testa influence both the processing efficiency and the quality of the oil. In peanut, polymeric phenolic compounds are present in the episperm rather than in the endothelium and their levels increase during ripening; therefore, to better understand testa development, and especially the accumulation of pigments, RNA-Seq was applied to elucidate the mechanisms underlying the regulation of peanut testae at three different developmental stages (i.e., at 20 days after flowering - 20DAF - and at 40DAF and 60DAF). A total of 5452 differentially expressed unigenes (DEGs) were obtained encompassing these three stages; comparative results showed that phenylpropanoid biosynthesis, phenylalanine metabolism, flavonoid biosynthesis, and plant hormone signal transduction comprised the principal KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways expressed during peanut testa development. Further studies revealed that the expression patterns of the flavonoid biosynthesis pathway genes PAL, C4H, CHS, and CHI (early biosynthetic genes - EBGs) were consistent with the accumulation of testa pigments. Thus, the results of this study demonstrate that EBGs, as well as the homologs of AtMYB111 (i.e., c35101_g4 and c37398_g2), are likely the principal regulators of testa pigment accumulation; the gene database assembled here is therefore a sequencing resource for future research and provides a foundation for understanding the regulation of pink testa pigmentation in peanuts. PMID- 29438897 TI - Association between habitual tryptophan intake and depressive symptoms in young and middle-aged women. AB - BACKGROUND: The intake of tryptophan, the precursor of serotonin, is assumed to affect serotonin availability and depression onset. Nevertheless, a definitive relationship between dietary tryptophan intake and depressive symptoms has not been established. We examined the association between tryptophan intake and depressive symptoms screened in a group of 4272 first-year female dietetic students and 3651 their mothers. METHODS: Dietary tryptophan intake during the preceding month was assessed with a validated, self-administered diet history questionnaire. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) using two cutoff scores: CES-D score >= 16 and CES-D score >= 19 (the optimal cutoff score for Japanese people). The multivariate adjusted prevalence ratio (PR) and 95% confidence interval (CI) for depressive symptoms were calculated using Poisson regression analysis. RESULTS: The prevalence of depressive symptoms (CES-D score >= 16) was 50.0% for young women and 26.5% for middle-aged women. The adjusted PR (95% CI) for depressive symptoms in the highest versus lowest quintile of tryptophan intake was 0.84 (0.75, 0.93) in young women (P for trend < 0.0001) and 0.83 (0.64, 1.01) in middle-aged women (P for trend < 0.0001). These associations were stable even when depressive symptoms were defined as a CES-D score >= 19. LIMITATIONS: This is a cross-sectional study. Depressive symptoms were assessed using a self reported questionnaire. CONCLUSIONS: This cross-sectional study showed that a higher tryptophan intake was independently associated with a lower prevalence of depressive symptoms in young Japanese women. PMID- 29438898 TI - Current and ideal skin tone: Associations with tanning behavior among sexual minority men. AB - Sexual minority men have high rates of skin cancer, yet little is known about skin cancer risk behaviors in this population. It was hypothesized that current skin tone would moderate the association between darker ideals and tanning behaviors. Data were collected online from 231 sexual minority men in San Diego, United States of America, with a mean age of 24.66 (SD = 5.44). Ideal and current skin tone ratings and indoor and outdoor tanning behaviors were assessed. Darker ideals were significantly associated with increased indoor and outdoor tanning. The effect of darker ideals on tanning was strongest among individuals with lighter current skin tone, indicating a significant interaction. Sexual minority men whose perceived skin tone did not match their ideal were more likely to engage in skin cancer risk behaviors. Future skin cancer prevention programs aimed at sexual minority men may consider techniques that modify ideal skin tone internalization. PMID- 29438899 TI - Elemental mercury neurotoxicity and clinical recovery of function: A review of findings, and implications for occupational health. AB - This paper assessed approximately 30 studies, mostly involving occupationally exposed subjects, concerning the extent to which those who developed elemental mercury (Hg)-induced central and/or peripheral neurotoxicities from chronic or acute exposures recover functionality and/or performance. While some recovery occurred in the vast majority of cases, the extent of such recoveries varied considerably by individual and endpoint. Factors accounting for the extensive inter-individual variation in toxicity and recovery were not specifically assessed such as age, gender, diet, environmental enrichment, chelation strategies and dose-rate. While the data indicate that psychomotor endpoints often show substantial and relatively rapid (i.e., 2-6 months) recovery and that neuropsychological endpoints display slower and less complete recovery, generalizations are difficult due to highly variable study designs, use of different endpoints measured between studies, different Hg exposures based on blood/urine concentrations and Hg dose-rates, the poor capacity for replicating findings due to the unpredictable/episodic nature of harmful exposures to elemental Hg, and the inconsistency of the initiation of studies after induced toxicities and the differing periods of follow up during recovery periods. Finally, there is strikingly limited animal model literature on the topic of recovery/reversibility of elemental Hg toxicity, a factor which significantly contributes to the overall marked uncertainties for predicting the rate and magnitude of recovery and the factors that affect it. PMID- 29438900 TI - Sperm quality biomarkers complement reproductive and endocrine parameters in investigating environmental contaminants in common carp (Cyprinus carpio) from the Lake Mead National Recreation Area. AB - Lake Mead National Recreational Area (LMNRA) serves as critical habitat for several federally listed species and supplies water for municipal, domestic, and agricultural use in the Southwestern U.S. Contaminant sources and concentrations vary among the sub-basins within LMNRA. To investigate whether exposure to environmental contaminants is associated with alterations in male common carp (Cyprinus carpio) gamete quality and endocrine- and reproductive parameters, data were collected among sub-basins over 7 years (1999-2006). Endpoints included sperm quality parameters of motility, viability, mitochondrial membrane potential, count, morphology, and DNA fragmentation; plasma components were vitellogenin (VTG), 17beta-estradiol, 11-keto-testosterone, triiodothyronine, and thyroxine. Fish condition factor, gonadosomatic index, and gonadal histology parameters were also measured. Diminished biomarker effects were noted in 2006, and sub-basin differences were indicated by the irregular occurrences of contaminants and by several associations between chemicals (e.g., polychlorinated biphenyls, hexachlorobenzene, galaxolide, and methyl triclosan) and biomarkers (e.g., plasma thyroxine, sperm motility and DNA fragmentation). By 2006, sex steroid hormone and VTG levels decreased with subsequent reduced endocrine disrupting effects. The sperm quality bioassays developed and applied with carp complemented endocrine and reproductive data, and can be adapted for use with other species. PMID- 29438901 TI - Role of radical pairs and feedback in weak radio frequency field effects on biological systems. AB - Radio frequency electromagnetic fields (RF) have been shown to modify the concentrations of the radical O2-, H2O2 and cancer cell growth rates at exposure levels below those that cause significant heating. Reactive oxygen species (ROS) are both signaling molecules and species that can do damage, depending on timing, location and concentrations. We briefly look at some mechanisms by which electromagnetic fields can modify the concentrations of ROS and some of the feedback and repair processes that lead to variable biological effects. Of particular interest are the role of radical pairs and their spins, which have received considerable attention recently, and the role of feedback in biological systems, to which less attention has been paid. PMID- 29438903 TI - Mechanosensing at integrin-mediated cell-matrix adhesions: from molecular to integrated mechanisms. AB - Integrin-mediated adhesions between cells and the extracellular matrix are fundamental for cell function, and one of their main roles is to sense and respond to mechanical force. Here we discuss the different mechanisms that can confer mechanosensitivity to adhesions. We first address molecular mechanisms mediated by force-induced changes in molecular properties, such as binding dynamics or protein conformation. Then, we discuss recent evidence on how these mechanisms are integrated with cellular and extracellular parameters such as myosin and actin activity, membrane tension, and ECM properties, endowing cells with an exquisite ability to both detect and respond to physical and mechanical cues from their environment. PMID- 29438902 TI - Secret handshakes: cell-cell interactions and cellular mimics. AB - Cell-cell junctions, acting as 'secret handshakes', mediate cell-cell interactions and make multicellularity possible. Work over the previous century illuminated key players comprising these junctions including the cadherin superfamily, nectins, CAMs, connexins, notch/delta, lectins, and eph/Ephrins. Recent work has focused on elucidating how interactions between these complex and often contradictory cues can ultimately give rise to large-scale organization in tissues. This effort, in turn, has enabled bioengineering advances such as cell mimetic interfaces that allow us to better probe junction biology and to develop new biomaterials. This review details exciting, recent developments in these areas as well as providing both historical context and a discussion of some topical challenges and opportunities for the future. PMID- 29438904 TI - Actin, microtubule, septin and ESCRT filament remodeling during late steps of cytokinesis. AB - Cytokinesis is the process by which a mother cell is physically cleaved into two daughter cells. In animal cells, cytokinesis begins with the contraction of a plasma membrane-associated actomyosin ring that is responsible for the ingression of a cleavage furrow. However, the post-furrowing steps of cytokinesis are less understood. Here, we highlight key recent findings that reveal a profound remodeling of several classes of cytoskeletal elements and cytoplasmic filaments (septins, microtubules, actin and ESCRT) in the late steps of cytokinesis. We review how this remodeling is required first for the stabilization of the intercellular bridge connecting the daughter cells and then for the steps leading up to abscission. New players regulating the abscission (NoCut) checkpoint, which delays abscission via cytoskeleton and ESCRT remodeling in response to various cytokinetic stresses, will also be emphasized. Altogether, the latest discoveries reveal a crucial role for posttranslational modifications of the cytoskeleton (actin oxidation, septin SUMOylation) and an unexpected requirement of ESCRT-III polymer dynamics for successful abscission. PMID- 29438905 TI - Induction of systemic inflammation by hyaluronan and hsp70 in women with pre eclampsia. AB - Pre-eclampsia (PE) is a human pregnancy syndrome with abnormal activation of the innate immune response. The study evaluated the involvement of molecular structures called damage-associated molecular patterns (DAMPs), such as hyaluronan (HA) and heat shock proteins (Hsp) on NLRP1 and NLRP3 inflammasomes activation in peripheral blood monocytes. Twenty pre-eclamptic women, 20 normotensive pregnant women (NT) and 20 non-pregnant women (NP) were studied. Enzyme immunoassay was employed for the determination of HA, Hsp70 and High mobility group Box 1 (HMGB1) in plasma, as well as for the detection of Interleukin-1beta (IL-1beta), IL-18 and tumor necrosis factor alpha (TNF-alpha) in the supernatant of monocytes cultured with or without HA and Hsp70. The inflammasomes induction was evaluated by the quantification of mRNA for NLRP1, NLRP3, caspase-1, IL-1beta, IL-18, HMGB1 and TNF-alpha by qPCR in monocyte culture. The results showed significantly higher plasma levels of HA, Hsp70 and HMGB1 in pre-eclamptic women than in NT and NP women. Monocytes from women with PE showed endogenous activation of NLRP1 and NLRP3 inflammasomes, and expressed high amounts of IL-1beta, IL-18, HMGB1 and TNF-alpha. The stimulation of monocytes with HA increased the gene expression of NLRP1, NLRP3, caspase-1, TNF alpha, IL-1beta, HMGB1 and IL-18 and the production of IL-1beta in pre-eclamptic women. Monocytes cultured with Hsp70 produced elevated levels of IL-1beta and TNF alpha through a mechanism independent of inflammasomes activation. These results suggest the participation of these DAMPs in the systemic inflammatory response that is characteristic of PE. PMID- 29438906 TI - Alteration in the serum concentrations of FGF19, FGFR4 and betaKlotho in patients with thyroid cancer. AB - INTRODUCTION: betaKlotho (betaKL) is known to act as co-receptor for fibroblast growth factor receptor 4 (FGFR4) which is the main cognate receptor for fibroblast growth factor 19 (FGF19). Dysregulation of this FGF19/FGFR4/betaKL signaling axis has been implicated in the pathogenesis of several cancers. However, its role in the pathogenesis of thyroid cancer has not been determined. MATERIALS AND METHODS: The aim of this study was to assess FGF19, FGFR4 and betaKL concentrations in a group of 36 patients with papillary thyroid cancer (PTC), 11 patients with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and a group of 19 subjects with multinodular nontoxic goiter (MNG). The control group consisted of 20 healthy volunteers. Serum FGF19, FGFR4 and betaKL concentrations were measured using specific ELISA methods. RESULTS: Significantly lower concentrations of betaKL and higher concentrations of FGF19 were found in patients with PTC, FTC and ATC as compared with MNG group and controls. An elevation of FGFR4 serum concentration was observed in all thyroid cancer groups in comparison to MNG group and controls; however, in FTC group it was statistically insignificant. A positive correlation was found between betaKL and FGFR4 concentrations in PTC patients. The levels of betaKL, FGF19 and FGFR4 did not differ significantly between MNG group and healthy controls. CONCLUSIONS: Our results indicate that a disrupted FGF19/FGFR4/betaKL signaling pathway may play a role in the development of thyroid cancers. However, further studies are needed to elucidate the molecular mechanism of the neoplastic transition of thyroid epithelial cells. PMID- 29438908 TI - In situ monitoring of PTHLH secretion in neuroblastoma cells cultured onto nanoporous membranes. AB - In this work, we propose for the first time the use of anodic aluminum oxide (AAO) nanoporous membranes for in situ monitoring of parathyroid hormone-like hormone (PTHLH) secretion in cultured human cells. The biosensing system is based on the nanochannels blockage upon immunocomplex formation, which is electrically monitored through the voltammetric oxidation of Prussian blue nanoparticles (PBNPs). Models evaluated include a neuroblastoma cell line (SK-N-AS) and immortalized keratinocytes (HaCaT) as a control of high PTHLH production. The effect of total number of seeded cells and incubation time on the secreted PTHLH levels is assessed, finding that secreted PTHLH levels range from approximately 60 to 400 ng/mL. Moreover, our methodology is also applied to analyse PTHLH production following PTHLH gene knockdown upon transient cell transfection with a specific silencing RNA (siRNA). Given that inhibition of PTHLH secretion reduces cell proliferation, survival and invasiveness in a number of tumors, our system provides a powerful tool for the preclinical evaluation of therapies that regulate PTHLH production. This nanoporous membrane - based sensing technology might be useful to monitor the active secretion of other proteins as well, thus contributing to characterize their regulation and function. PMID- 29438907 TI - Tongue exercise and ageing effects on morphological and biochemical properties of the posterior digastric and temporalis muscles in a Fischer 344 Brown Norway rat model. AB - OBJECTIVE: This study sought to examin effects of age and tongue exercise on the posterior digastric (opener) and the temporalis (closer). We hypothesized 1) age would result in differing morphological (cross sectional area) and biochemical (myosin heavy chain isoform) components of these muscles; 2) tongue exercise would result in coactivation of these muscles inducing a decrease in age-related differences between age groups. DESIGN: Young adult (9 months) and old (32 months) Fischer 344 Brown Norway rats were randomized into a tongue exercise or control group. Post-training, posterior digastric and temporalis muscles were harvested and analyzed using: 1) Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) to assess percent myosin heavy chain (MyHC) content; 2) Immunohistochemical staining to determine cross sectional area (CSA). RESULTS: A larger proportion of slowly contracting MyHC isoforms in the posterior digastric and temporalis muscles were found in old. No significant main effects for age or exercise in fiber size were found in posterior digastric muscle. An interaction between age and exercise for temporalis cross sectional area indicated the old exercise group had smaller average cross sectional area than all other groups. CONCLUSIONS FINDINGS: suggest that: 1) Increasing age induces biochemical changes in muscles of the jaw, specifically showing an increase the proportion of slower contracting MyHC isoforms; 2) Increasing age and tongue exercise induce a reduction in muscle fiber cross sectional area in the temporalis muscle only. However, continued study of these cranial muscle systems is warranted to better understand these changes that occur with age and exercise. PMID- 29438909 TI - Correlation of sex ratio at birth with health and socioeconomic indicators. AB - INTRODUCTION: The sex ratio at birth (male divided by total live births: M/T) has been mooted as a potential sentinel health indicator. Several metrics indicate individual countries' health and socioeconomic status. In this study, in all available countries (where such data was accessible), M/T and these indicators were compared in order to ascertain whether better (vis-a-vis health and socioeconomic status) levels of these indicators were associated with higher M/T in available countries. METHODS: The following were obtained (by country) from various sources: M/T, infant mortality rate, under 5 years mortality rate, fertility rate, Human Development Index, gross domestic product per capita, life expectancy for both sexes, females, males, as well as both sexes Health Adjusted Life Expectancy (HALE). Pearson correlation was performed comparing M/T and these indicators. RESULTS: Despite weak correlation values, all except for the Human Development Index (HDI) correlated with M/T at statistically significant levels. DISCUSSION: A decrease in mortality and an increase in life expectancy and GDP/capita are indicators of socioeconomic wellbeing. In this study, mortality was negatively correlated with M/T. Life expectancy and GDP/capita were both positively correlated with M/T, indicating that M/T may also serve as a surrogate health indicator, and incidentally, also supporting the Trivers-Willard hypothesis. Improving economies lead to increasing education, which in turns tends to lower fertility rate in association with a declining M/T. In conclusion, the global correlation of health and socioeconomic indicators with M/T suggests that M/T may be a useful sentinel health indicator. PMID- 29438910 TI - Is there a generalized timing impairment in Autism Spectrum Disorders across time scales and paradigms? AB - Individuals with ASD have abnormal motor and perceptual functions that do not currently form diagnostic criteria of ASD, but nevertheless may affect everyday behaviour. Temporal processing seems to be one of such non-diagnostic yet impaired domains, although the lack of systematic studies testing different aspects of timing in the same sample of participants prevents a conclusive assessment of whether there is a generalized temporal deficit in ASD associated with diagnostic symptoms. 17 children diagnosed with ASD and 18 typically developing age- and IQ-matched controls carried out a set of motor and perceptual timing tasks: free tapping, simultaneity judgment, auditory duration discrimination, and verbal duration estimation. Parents of participants filled in a questionnaire assessing the sense and management of time. Children with ASD showed faster and more variable free tapping than controls. Auditory duration discrimination thresholds were higher in the ASD group than controls in a sub second version of the task, while there were no group differences in a supra second discrimination of intervals. Children with ASD showed more variable thresholds of simultaneity judgment, and they received lower parental scores for their sense and management of time. No group differences were observed in the verbal duration estimation task in the minute-range. Different timing functions were correlated in the ASD group but not among controls, whilst several timing measures correlated with ASD symptoms. We conclude that children with ASD show a broad range of abnormalities in temporal processing tasks including motor timing, perceptual timing, and temporal perspective. PMID- 29438911 TI - Biomechanical assessment of dynamic balance: Specificity of different balance tests. AB - Dynamic balance is vitally important for most sports and activities of daily living, so the assessment of dynamic stability has become an important issue. In consequence, a large number of balance tests have been developed. However, it is not yet known whether these tests (i) measure the same construct and (ii) can differentiate between athletes with different balance expertise. We therefore studied three common dynamic balance tests: one-leg jump landings, Posturomed perturbations and simulated forward falls. Participants were 24 healthy young females in regular training in either gymnastics (n = 12) or swimming (n = 12). In each of the tests, the participants were instructed to recover balance as quickly as possible. Dynamic stability was computed by time to stabilization and margin of stability, deduced from force plates and motion capture respectively. Pearson's correlations between the dynamic balance tests found no significant associations between the respective dynamic stability measures. Furthermore, independent t-tests indicated that only jump landings could properly distinguish between both groups of athletes. In essence, the different dynamic balance tests applied did not measure the same construct but rather task-specific skills, each of which depends on multifactorial internal and external constraints. Our study therefore contradicts the traditional view of considering balance as a general ability, and reinforces that dynamic balance measures are not interchangeable. This highlights the importance of selecting appropriate balance tests. PMID- 29438912 TI - Spatial and temporal analysis center of pressure displacement during adolescence: Clinical implications of developmental changes. AB - This study aimed to provide insight into the development of postural control abilities in youth. A total of 276 typically developing adolescents (155 males, 121 females) with a mean age of 13.23 years (range of 7.11-18.80) were recruited for participation. Subjects performed two-minute quiet standing trials in bipedal stance on a force plate. Center of pressure (COP) trajectories were quantified using Sample Entropy (SampEn) in the anterior-posterior direction (SampEn-AP), SampEn in the medial-lateral direction (SampEn-ML), and Path Length (PL) measures. Three separate linear regression analyses were conducted to predict the relationship between age and each of the response variables after adjusting for individuals' physical characteristics. Linear regression models showed an inverse relationship between age and entropy measures after adjusting for body mass index. Results indicated that chronological age was predictive of entropy and path length patterns. Specifically, older adolescents exhibited center of pressure displacement (smaller path length) and less complex, more regular center of pressure displacement patterns (lower SampEn-AP and SampEn-ML values) compared to the younger children. These findings support prior studies suggesting that developmental changes in postural control abilities may continue throughout adolescence and into adulthood. PMID- 29438913 TI - Evaluation of caffeine effects on biochemical and genotoxic biomarkers in the neotropical freshwater teleost Prochilodus lineatus. AB - Caffeine is often found in aquatic environments, leading to concerns regarding its adverse consequences for aquatic biota. Biochemical and genotoxic biomarkers were analysed in juveniles of Prochilodus lineatus to evaluate the effects of caffeine. Fish were exposed to caffeine (0.3, 3 and 30 MUg L-1) for either 24 h or 168 h. Longer exposure to caffeine resulted in a significant reduction in the activity of the phase I biotransformation enzyme ethoxyresorufin-O-deethylase (EROD) in the brain but a significant increase in the liver. Changes in glutathione content (GSH), glutathione S-transferase (GST) activity, and lipid peroxidation were not found in the liver and brain of fish exposed to caffeine. DNA damage in erythrocytes were also not found. These results show that caffeine may interfere with the biotransformation mechanism of P. lineatus after 168 h exposure, but it does not generate sufficient changes to trigger a state of oxidative stress. PMID- 29438914 TI - Microwave-assisted catalytic pyrolysis of moso bamboo for high syngas production. AB - Microwave-assisted pyrolysis of moso bamboo with the activated carbon-supported iron(III) ion catalyst was carried out with the aim of obtaining high quality and quantity syngas(H2 + CO). The effect of the catalyst on moso bomboo pyrolysis involving the temperature-rising characteristics, product distribution, tar conversion and gas compositions were investigated. The results indicated that the catalyst improved the microwave-absorption capability and increased the maximum reaction temperatures. The formation of gases was promoted by the catalyst mainly at the expense of the tar, indicating the catalyst had an excellent activity for the tar conversion .The catalyst had the positive influence on the formation of syngas with the maximum content reaching up to 81.14 vol% with H2/CO being 1.04 and inhibited the production of CH4 and CO2. The loading of iron(III) ion into activated carbon exerted a significant influence on bamboo pyrolysis. The addition of the catalyst increased the thermal efficiency of the reaction system. PMID- 29438915 TI - Ammonia-oxidizing bacteria dominate ammonia oxidation in a full-scale wastewater treatment plant revealed by DNA-based stable isotope probing. AB - A full-scale wastewater treatment plant (WWTP) with three separate treatment processes was selected to investigate the effects of seasonality and treatment process on the community structures of ammonia-oxidizing archaea (AOA) and bacteria (AOB). And then DNA-based stable isotope probing (DNA-SIP) was applied to explore the active ammonia oxidizers. The results of high-throughput sequencing indicated that treatment processes varied AOB communities rather than AOA communities. AOA slightly outnumbered AOB in most of the samples, whose abundance was significantly correlated with temperature. DNA-SIP results showed that the majority of AOB amoA gene was labeled by 13C-substrate, while just a small amount of AOA amoA gene was labeled. As revealed by high-throughput sequencing of heavy DNA, Nitrosomonadaceae-like AOB, Nitrosomonas sp. NP1, Nitrosomonas oligotropha and Nitrosomonas marina were the active AOB, and Nitrososphaera viennensis dominated the active AOA. The results indicated that AOB, not AOA, dominated active ammonia oxidation in the test WWTP. PMID- 29438916 TI - Pressurized entrained-flow pyrolysis of microalgae: Enhanced production of hydrogen and nitrogen-containing compounds. AB - Pressurized entrained-flow pyrolysis of Chlorella vulgaris microalgae was investigated. The impact of pressure on the yield and composition of pyrolysis products were studied. The results showed that the concentration of H2 in bio-gas increased sharply with increasing pyrolysis pressure, while those of CO, CO2, CH4, and C2H6 were dramatically decreased. The concentration of H2 reached 88.01 vol% in bio-gas at 900 degrees C and 4 MPa. Higher pressures promoted the hydrogen transfer to bio-gas. The bio-oils derived from pressurized pyrolysis were rich in nitrogen-containing compounds and PAHs. The highest concentration of nitrogen-containing compounds in bio-oil was achieved at 800 degrees C and 1 MPa. Increasing pyrolysis pressure promoted the formation of nitrogen-containing compounds such as indole, quinoline, isoquinoline and phenanthridine. Higher pyrolysis pressures led to increased sphericity, enhanced swelling, and higher carbon order of bio-chars. Pressurized pyrolysis of biomass has a great potential for poly-generation of H2, nitrogen containing compounds and bio-char. PMID- 29438917 TI - Rapid start-up of a nitritation granular reactor using activated sludge as inoculum at the influent organics/ammonium mass ratio of 2/1. AB - Partial oxidation of ammonium to nitrite is a pre- and crucial step to achieve shortcut biological nitrogen removal from ammonium-rich wastewater. In the present study, a nitritation granular reactor using activated sludge as inoculum was started up in a sequencing batch reactor (SBR) at a fixed influent C/N ratio of 2:1. Variations in the reactor performance, functional bacteria activities, sludge morphology and bacterial community structure were investigated. Results showed the formation of compact granules was achieved in 55 days, and a stable nitrite accumulation rate of 0.68 kg N.m-3.d-1 was maintained in the following period. With a rapid growth of granular size, the total nitrogen removal by simultaneous nitritation/denitritation was progressively increased to 50%. In sludge granulation, the significant enrichment of r-strategist ammonium oxidizing bacteria (Nitrosomonas) was identified. Additionally, both high free ammonia concentration and extra nitrite competition by heterotrophic denitrifiers were critical to suppress nitrite oxidizing bacteria effectively. PMID- 29438918 TI - Wheat straw fractionation by ethanol-water mixture: Optimization of operating conditions and comparison with diluted sulfuric acid pre-treatment. AB - The fractionation of wheat straw by ethanol-water (EW) pre-treatment was studied regarding its main operating conditions: time, temperature, L/S ratio and ethanol percentage were optimized by using an orthogonal experimental design (Taguchi). Afterwards, diluted sulfuric acid (DSA) hydrolysis and EW treatments have been compared in terms of energy consumption and yield of a cellulosic solid residue able to be enzymatically hydrolyzed to glucose. Experimental results show that temperature is the only variable of EW with a significant effect on the quality of the pretreated solids. EW pre-treatment of wheat straw is more effective than DSA hydrolysis due to its higher capacity of delignification. Moreover, a high glucose yield (80%) can be obtained by enzymatic hydrolysis of a solid pretreated with a moderate energy input EW (160 degrees C, 45 min) while wheat straw needs of a higher energy input during DSA to produce a similar yield of glucose after saccharification. PMID- 29438919 TI - Perspectives for the microbial production of methyl propionate integrated with product recovery. AB - A new approach was studied for bio-based production of methyl propionate, a precursor of methyl methacrylate. Recombinant E. coli cells were used to perform a cascade reaction in which 2-butanol is reduced to butanone using alcohol dehydrogenase, and butanone is oxidized to methyl propionate and ethyl acetate using a Baeyer-Villiger monooxygenase (BVMO). Product was removed by in situ stripping. The conversion was in line with a model comprising product formation and stripping kinetics. The maximum conversion rates were 1.14 g-butanone/(L h), 0.11 g-ethyl acetate/(L h), and 0.09 g-methyl propionate/(L h). The enzyme regioselectivity towards methyl propionate was 43% of total ester. Starting from biomass-based production of 2-butanol, full-scale ester production with conventional product purification was calculated to be competitive with petrochemical production if the monooxygenase activity and regioselectivity are enhanced, and the costs of bio-based 2-butanol are minimized. PMID- 29438920 TI - Rewiring the microbe-electrode interfaces with biologically reduced graphene oxide for improved bioelectrocatalysis. AB - The aim of this work was to study biologically reduced graphene oxide (RGO) for engineering the surface architecture of the bioelectrodes to improve the performance of Bioelectrochemical System (BES). Gluconobacter roseus mediates the reduction of graphene oxide (GO). The RGO modified bioelectrodes produced a current density of 1 mA/cm2 and 0.69 mA/cm2 with ethanol and glucose as substrates, respectively. The current density of RGO modified electrodes was nearly 10-times higher than the controls. This study, for the first time, reports a new strategy to improve the yield as well as efficiency of the BES by wrapping and wiring the electroactive microorganisms to the electrode surfaces using RGO. This innovative wrapping approach will decrease the loss of electrons in the microbe-electrolyte interfaces as well as increase the electron transfer rates at the microorganism-electrode interfaces. PMID- 29438921 TI - Obsessions in Schizophrenia: A need for reconsideration? PMID- 29438922 TI - Delusional infestation successfully controlled with typical antipsychotic depot injection: An illustrative case report. PMID- 29438923 TI - Need for evaluation of underlying dysfunctional cognition in problem drinkers. PMID- 29438924 TI - Chemotherapy is administered to a minority of hospitalized patients with diffuse large B-cell lymphoma and is associated with less likelihood of death during hospitalization. AB - BACKGROUND: While treatment of DLBCL is largely outpatient, some patients require planned or unplanned admissions for chemotherapy, new diagnosis, relapse, or toxicity. We examined risk factors for receipt of inpatient chemotherapy and death during hospitalization. METHODS: We analyzed data from the 2012-2013 HCUP NIS. We identified patient and hospital characteristics that were associated with chemotherapy administration and death. RESULTS: Chemotherapy was given in 3260/11,150 (29.2%) of hospitalizations. Younger age, urban teaching hospitals, fewer chronic conditions, male sex, non-Medicare insurance, and "less likelihood of dying" were associated with chemotherapy. Chemotherapy portended lower odds of death; older age and longer hospitalizations were associated with increased odds of death. CONCLUSION: We identified socio-demographics and clinical characteristics associated with inpatient chemotherapy in DLBCL patients. Chemotherapy is associated with lower odds of death during hospitalization, suggesting that most chemotherapy is given appropriately to non-critically ill patients. Clinical acuity is a stronger predictor of death than socio demographics. PMID- 29438925 TI - Exploring determinants of care-seeking behaviour of oral cancer patients in India: A qualitative content analysis. AB - BACKGROUND: A major public health concern in India is the high morbidity and mortality rates of oral cancer because of late diagnosis. Among the several determinants of this late diagnosis, the most important is the healthcare-seeking behaviour of the oral cancer patients. The aim of this study was to explore the care-seeking behaviour and its determinants among oral cancer patients. METHODS: A face-to-face in-depth interview was conducted among 70 oral cancer patients using a semi-structured questionnaire, and qualitative content analysis of the results was performed. RESULTS: All the patients had squamous-cell carcinoma and none had attended any screening programme. The most common site affected was the buccal mucosa with a non-healing wound. Most of the patients contacted a doctor available nearby; only 7% of patients consulted a dentist. Only one patient approached a traditional healer. The median patient delay was 30 (4-365) days and the professional delay was 40 (4-650) days. Enablers included determinants such as increasing symptoms (80%), influence of the society (74%), fear (10%), and social media (3%). The main barriers were lack of awareness (97%), hope that the lesion will heal spontaneously (90%), lack of perception of seriousness (64%), financial constraints (55%), provider switching (47%), and missed diagnosis (44%). CONCLUSION: The care-seeking path among oral cancer patients is complex, customised, and influenced by multiple patient-related and system-related factors. PMID- 29438926 TI - Slip points of subcutaneous adipose tissue lipids do not predict beef marbling score or percent intramuscular lipid. AB - We hypothesized that slip points of subcutaneous (s.c.) adipose tissue lipids would predict USDA beef marbling scores or percent intramuscular lipid (%IML). M. longissimus dorsi (LD) muscle and s.c. adipose tissue from 79 feedlot-finished Angus steers were analyzed for lipid slip point, %IML, and fatty acid composition. The s.c. monounsaturated:saturated fatty acid (MUFA:SFA) ratio and s.c. lipid slip points were highly correlated (R2 = 0.557; P < 0.001), but the correlation between s.c. lipid slip point and LD lipid MUFA:SFA ratio was low (R2 = 0.112; P < 0.01). Similarly, there was a low correlation between LD lipid slip point and s.c. lipid slip point (R2 = 0.185; P < 0.001). Neither USDA marbling score nor %IML were correlated with s.c. lipid slip point (R2 = 0.001; P > 0.05). These data indicate s.c. adipose tissue lipid slip point did not predict USDA marbling scores or %IML in the conventionally fed Angus steers of this study. PMID- 29438927 TI - Extraction of hazardous metals from green liquor dregs by ethylenediaminetetraacetic acid. AB - Green liquor dregs are the major inorganic solid side stream of kraft pulp mills which contain environmentally hazardous metals. The presence of hazardous metals in this industrial residue brings statutory limits for its landfilling, although they are not easily mobilized from the solid phase. In this study, the chelating agent ethylenediaminetetraacetic acid (EDTA) is utilized to extract hazardous metals such as Cd, Pb and Zn from green liquor dregs. Furthermore, the influence of EDTA on the removal of Ca as the main mineral nutrient present in the green liquor dregs is studied. The effect of parameters such as EDTA dosage, L/S ratio and contact time on the removal rate of the elements is investigated. In addition, the experimental data are fitted to the Elovich model and the pseudo first-order model to describe the desorption kinetics. The results show that 59 wt% of Cd, 13 wt% of Co, 62 wt% of Cu, 3 wt% of Mn, 12 wt% of Ni, 43 wt% of Pb, 16 wt% of Zn, and less than 1 wt% of Ca were extracted from green liquor dregs with EDTA dosage of 0.035 gEDTA salt/gdregs and the L/S ratio of 6.25 ml/g. The current study opens up new possibilities to use the green liquor dregs for improving the soil fertility instead of landfilling. PMID- 29438928 TI - Trees are all around us: Farmers' management of wood pastures in the light of a controversial policy. AB - Wood pastures are some of the most species-rich environments found in Europe and therefore essential habitats for biodiversity conservation. Society also puts faith in multiple values of trees, ranging from climate change mitigation to socio-cultural traditions. Therefore, the seemingly arbitrary tree density limit for pasture environments imposed by the EU through its Common Agricultural Policy (CAP) threatened both biological and societal values. In this study on farmers' perspectives, we target the effects of the CAP tree density limit on management of wood pastures in a low-intensively managed agricultural landscape of southern Sweden. The case of simplifying nature by using simple number limitations was used as an entry point in semi-structured, open-ended, interviews with farmers and officials about their view on trees and pasture management in relation to policy directives. The interviews showed that the policy incentive shifted the management focus from grazing quality to the number of trees and that farmers are willing to cut in order to get subsidies and timber revenues, however not unreflectingly. Farmers had high knowledge about the wide ranging social, cultural and natural values of trees, and are often themselves as good regulators of tree management as policies intend to be. Our study reveals many difficulties in managing the complex relations within landscapes with simplified legal measures, opening up for further discussion about improving policy instruments to preserve both social and biological values of wood pastures. However, although the tree density limit has been criticised on many points related to biodiversity conservation, this study shows that other values linked to pasture trees, e.g. the aesthetic values and their importance as shelter for grazing animals, could be an argument to actually keep the focus on trees as indicators of pasture management quality. We suggest that trees in general and wood-pastures in particular therefore are good starting points, or boundary-objects, for collaboration between production and conservation interests of farming and environmental management. PMID- 29438929 TI - Performance evaluation of five Mediterranean species to optimize ecosystem services of green roofs under water-limited conditions. AB - Rapid urban growth in Mediterranean cities has become a serious environmental concern. Due to this expansion, which covers adjacent horizontal ground, a critical deficit of green areas has been increasing. Moreover, irrigation is considered an important issue since water is one of the most limiting natural resources all over the world. The main objective of this study was to perform a long-term experiment to assess five Mediterranean species for extensive green roof implementation in Mediterranean-climate conditions. Brachypodium phoenicoides, Crithmum maritimum, Limonium virgatum, Sedum sediforme and Sporobolus pungens were grown in experimental modules under well-watered and water-limited conditions (irrigation at 50% and 25% ET0, respectively). Plant growth and cover, relative appearance, color evolution and water use were determined periodically for two years. Shoot and root biomass were quantified at the end of the experimental period. The effects of the irrigation treatments and seasonal changes were assessed to identify the advantages and disadvantages of each species according to their environmental performance. All species survived and showed adequate esthetic performance and plant cover during the experiment. S. sediforme registered the lowest variation of relative appearance along the experiment, the highest biomass production and the lowest water consumption. Nevertheless, B. phoenicoides appeared to be an interesting alternative to S. sediforme, showing high esthetic performance and water consumption throughout the rainy season, suggesting a potential role of this species in stormwater regulation related with runoff reduction. S. pungens performed well in summer but presented poor esthetics during winter. PMID- 29438930 TI - Engagement takes a (fishing) village to manage a resource: Principles and practice of effective stakeholder engagement. PMID- 29438931 TI - Aggregating the response in time series regression models, applied to weather related cardiovascular mortality. AB - In environmental epidemiology studies, health response data (e.g. hospitalization or mortality) are often noisy because of hospital organization and other social factors. The noise in the data can hide the true signal related to the exposure. The signal can be unveiled by performing a temporal aggregation on health data and then using it as the response in regression analysis. From aggregated series, a general methodology is introduced to account for the particularities of an aggregated response in a regression setting. This methodology can be used with usually applied regression models in weather-related health studies, such as generalized additive models (GAM) and distributed lag nonlinear models (DLNM). In particular, the residuals are modelled using an autoregressive-moving average (ARMA) model to account for the temporal dependence. The proposed methodology is illustrated by modelling the influence of temperature on cardiovascular mortality in Canada. A comparison with classical DLNMs is provided and several aggregation methods are compared. Results show that there is an increase in the fit quality when the response is aggregated, and that the estimated relationship focuses more on the outcome over several days than the classical DLNM. More precisely, among various investigated aggregation schemes, it was found that an aggregation with an asymmetric Epanechnikov kernel is more suited for studying the temperature mortality relationship. PMID- 29438932 TI - The serum concentrations of perfluoroalkyl compounds were inversely associated with growth parameters in 2-year old children. AB - The relationship between the serum concentrations of perfluoroalkyl compounds (PFCs) and growth parameters was investigated in 2-year-old Korean children. The study included 361 children aged 2years (192 boys and 169 girls; 22-27months), born at term appropriate-for-gestational-age, who visited between 2012 and 2013. Growth parameters of height and weight, and serum samples were collected from 2 year-old children. Four PFCs (perfluorohexane sulfonic acid [PFHxS], perfluorooctane sulfonic acid [PFOS], perfluorooctanoic acid [PFOA], and perfluorononanoic acid [PFNA]), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), and perfluoroheptanoic acid (PFHpA) were detected in >99, 93.4, 89.8, and 74.2% of the serum samples, respectively. The duration of breastfeeding was positively associated with the serum concentrations of ln-transformed PFHxS, PFOS, PFHpA, PFOA, PFNA, PFDA, and PFUnDA (all P<0.001). Height at 2years of age was inversely related to PFHxS, PFOS, PFOA, PFNA, and PFDA concentrations (adjusted beta per ln unit [95% confidence interval, CI]: 0.84 [-1.26, -0.42], -0.77 [-1.27, -0.15], -0.91 [-1.36, -0.47], -0.48 [-1.40, 0.51], and -0.44 [-0.77, -0.10] cm, respectively), after adjusting for age, sex, and midparental height. Weight at 2years of age was inversely associated with PFNA (adjusted beta per ln unit [95% CI]: -0.32 [-0.48, -0.15] kg), after adjusting for age, sex, and parental BMI. In conclusion, the serum concentrations of PFCs were inversely associated with growth parameters in 2-year-old children. PMID- 29438933 TI - Assessment of Cr pollution in tributary sediment cores in the Three Gorges Reservoir combining geochemical baseline and in situ DGT. AB - The mobility and transfer of trace metals in sediments are vital to understanding trace metals environmental behavior in water environment. However, as a predominant aquatic carcinogen, an effective method for assessing the release and deposition for Cr at the sediment-water interface (SWI) is still not clearly understood. Here we established a comprehensive methodology to evaluate the release risk of Cr at the SWI combining regional geochemical baseline (RGB) and diffusive gradients in thin films (DGT). Sediment cores and water samples were collected in the two tributaries and mainstream of the Three Gorges Reservoir, which is the world's largest man-made hydroelectric station. Results showed that the calculated Cr carcinogenic risks in surface water did not exceed US EPA maximum recommended level. The RGB of Cr (85.53 +/- 14.44 mg/kg) were calculated and the differentials between Cr concentration and RGB in surface sediments showed the average anthropogenic contribution rate was 6.03% and the upstream of Meixi River (MX-S) and mainstream were influenced by anthropogenic activities. The net diffusive flux using DGT showed that Cr in the midstream of Caotang River and MX had the potential to move upwards into the overlying water. Furthermore, combining the results of differential (Cr concentration vs. RGB) and the net flux, MX-S was the only site with a risk of Cr release. To the best of our knowledge, this study is the first attempt to combine RGB and DGT to scientifically assess metal release at SWI and provided a new perspective to comprehensively assess metal pollution in water environment. PMID- 29438934 TI - Dynamic energy budget models in ecological risk assessment: From principles to applications. AB - In ecological risk assessment of chemicals, hazard identification and hazard characterisation are most often based on ecotoxicological tests and expressed as summary statistics such as No Observed Effect Concentrations or Lethal Concentration values and No Effect Concentrations. Considerable research is currently ongoing to further improve methodologies to take into account toxico kinetic aspects in toxicological assessments, extrapolations of toxic effects observed on individuals to population effects and combined effects of multiple chemicals effects. In this context, the principles of the Dynamic Energy Budget (DEB), namely the conserved allocation of energy to different life-supporting processes in a wide variety of different species, have been applied successfully to the development of a number of DEB models. DEB models allow the incorporation of effects on growth, reproduction and survival within one consistent framework. This review aims to discuss the principles of the DEB theory together with available DEB models, databases available and applications in ecological risk assessment of chemicals for a wide range of species and taxa. Future perspectives are also discussed with particular emphasis on ongoing research efforts to develop DEB models as open source tools to further support the research and regulatory community to integrate quantitative biology in ecotoxicological risk assessment. PMID- 29438935 TI - Functional graphene oxide membrane preparation for organics/inorganic salts mixture separation aiming at advanced treatment of refractory wastewater. AB - Some refractory organic matters or soluble microbial products remained in the effluents of refractory organic wastewater after biological secondary treatment and need an advanced treatment before final disposal. Graphene oxide (GO) was known to have potential to be the next generation membrane material. The functional organics/inorganic salts separation GO membrane preparation and application in wastewater advanced treatment could reduce energy or chemicals consumption and avoid organics/inorganic salts mixed concentrate waste problems after nanofiltration or reverse osmosis. In this study, we developed a novelty GO membrane aiming at advanced purification of organic matters in the secondary effluents of refractory organic wastewater and avoiding the organics/inorganic salts mixed concentrate waste problem. The influence of preparation conditions including pore size of support membrane, the number of GO layers and the applied pressure was investigated. It was found that for organics/inorganic salts mixture separation membrane preparation, the rejection and flux would achieve balance for the support membrane at a pore size of ~0.1MUm and the number of GO layers of has an optimization value (~10 layers). A higher assemble pressure (~10bar) contributed to the acquisition of a higher rejection efficiency and lower roughness membrane. This as prepared GO membrane was applied to practical secondary effluent of a chemical synthesis pharmaceuticals wastewater. A good organic matter rejection efficiency (76%) and limited salt separation (<14%) was finally obtained. These results can promote the practical application of GO membrane and the resourcelized treatment of industrial wastewater. PMID- 29438936 TI - Combined seven miRNAs for early hepatocellular carcinoma detection with chronic low-dose exposure to microcystin-LR in mice. AB - Aberrant miRNA expression has been detected in various tumor tissues, which may be considered as a marker for early cancer diagnosis. One miRNA has multiple downstream target genes, which can be regulated by multiple upstream other miRNAs. Hence, this dynamic regulation is likely characterized by volatility, and thus, finding the appropriate time point for tests becomes essential for the use of miRNAs as an early marker of tumor diagnosis. In this study, we established a chronic liver cancer progression model in mice by using low doses of the harmful substance microcystin-LR (MC-LR). On the basis of miRNAs microarray assay, we further tested seven miRNAs that showed characteristic expression changes in pre hepatocarcinogenesis. Our results showed that the levels of four miRNAs (miR-122 5p, miR-125-5p, miR-199a-5p, and miR-503-5p) decreased dramatically, whereas those of two miRNAs (miR-222-5p and miR-590-5p) increased significantly in the early stages, which were all accompanied by an increase in atypia of hepatocytes. MiR-490-5p was a sensitive molecular, suitable only for evaluation of pathological changes in young mice. Therefore the combination the seven of miRNAs for a set may prove to be an effective method in healthy assessment of environmental toxicants for detection of hepatocarcinogenesis caused by hazardous materials. PMID- 29438937 TI - Arbuscular mycorrhizal fungi alleviate the heavy metal toxicity on sunflower (Helianthus annuus L.) plants cultivated on a heavily contaminated field soil at a WEEE-recycling site. AB - An 8-week pot experiment was conducted to investigate the growth and responses of sunflower (Helianthus annuus L.) to arbuscular mycorrhizal (AM) fungal inoculations on a heavily heavy metal (HM)-contaminated (H) soil and a lightly HM enriched (L) soil, both of which were collected from a waste electrical and electronic equipment (WEEE)-recycling site. Compared with the L soil, the H soil induced significantly larger (P<0.05) concentrations of Cd, Cu, Pb, Cr, Zn and Ni in sunflower (except for root Cr and shoot Ni), which impaired the thylakoid lamellar folds in leaves. The biomasses and P concentrations of shoots and roots, as well as the total P acquisitions per pot were all significantly decreased (P<0.05). Both Funneliformis mosseae (Fm) and F. caledonium (Fc) inoculation significantly increased (P<0.05) root mycorrhizal colonization. For the L soil, AM fungal inoculations had no significant effects on the soil-plant system, except for a decrease of soil pH and increases of soil available P and DTPA extractable Zn concentrations with the Fm-inoculated treatment. For the H soil, however, AM fungal inoculations significantly increased (P<0.05) the biomasses and P concentrations of shoots and roots, as well as the total P acquisitions per pot, and significantly reduced (P<0.05) the concentrations of HMs in shoots (except for Cu and Pb with Fm- and Fc- inoculated treatments, respectively) and alleviated the toxicity symptoms of HMs in thylakoid structure of leaves. AM fungal inoculations in the H soil also significantly increased (P<0.05) the shoot uptake of HMs (except for Cr), and tended to decrease the total concentrations of HMs in soils. This suggests the potential application of AM fungi for both reducing HM stress and promoting phytoextraction of HM-contaminated soils caused by WEEE recycling. PMID- 29438938 TI - Th17 cells regulate the production of CXCL1 in breast cancer. AB - Recently, the link between inflammation and cancer has been targeted for the prevention or treatment of malignant tumours. We aimed to investigate the relationship between Th17 cells and CXCL1 in breast cancer and the biological effects of CXCL1 on breast cancer. In vivo, the Th17 cell frequency in the peripheral blood was determined by flow cytometry. Secretion of IL-17 and CXCL1 in the blood serum was determined by enzyme-linked immunosorbent assay (ELISA). Expression of IL-17A and CXCL1 mRNA was determined by qRT-PCR. In vitro, the effects of Th17/CXCL1 during breast cancer were assessed in the human breast cancer cell lines MCF-7 and MDA-MB-231. Cell proliferation was measured using the CCK8 assay. Cell invasion and migration ability were assessed using a transwell cell invasion and wound- healing assay. In vivo, Th17 cells and CXCL1 were increased in breast cancer patients. Moreover, their changes were correlated in breast cancer cells. Th17 cells upregulate the production of CXCL1 during breast cancer progression. CXCL1, which is produced by breast cancer cells, can promote cancer growth and development, and may also point to a specific histogenetic pathway. PMID- 29438939 TI - AT-RVD1 repairs mouse lung after cigarette smoke-induced emphysema via downregulation of oxidative stress by NRF2/KEAP1 pathway. AB - Long-term exposure to cigarette smoke (CS) results in alveolar parenchyma destruction due to chronic inflammatory response and the imbalance between oxidants and antioxidants, and proteases and antiproteases. Emphysema is the main symptom of chronic obstructive pulmonary disease. Current treatment focuses on relieving respiratory symptoms, and inflammation resolution failure is an important pathophysiological element of the disease. Specialized pro-resolving mediators (SPMs) synthesized endogenously during resolution processes demonstrated beneficial effects in murine models of airway inflammation. Here, we aimed to test the SPM AT-RvD1 in a murine model of CS-induced emphysema. AT-RvD1 restored elastic fibers and lung morphology, with reduction in MMP-3, neutrophils, and myeloperoxidase activity and increases in macrophages and IL-10 levels. AT-RvD1 also decreased levels of oxidative stress markers and ROS via upregulation of the Nrf2/Keap1 pathway. Therefore, we suggest that AT-RvD1 causes pro-resolutive action in our murine model of CS-induced emphysema by upregulation of the Nrf2/Keap1 pathway. PMID- 29438940 TI - Functional paper-based SERS substrate for rapid and sensitive detection of Sudan dyes in herbal medicine. AB - There has been an increasing demand for rapid and sensitive techniques for the identification of Sudan compounds that emerged as the most often illegally added fat-soluble dyes in herbal medicine. In this report, we have designed and fabricated a functionalized filter paper consisting of gold nanorods (GNRs) and mono-6-thio-cyclodextrin (HS-beta-CD) as a surface-enhanced Raman spectroscopy (SERS) substrate, in which the GNR provides sufficient SERS enhancement, and the HS-beta-CD with strong chemical affinity toward GNR provides the inclusion compound to capture hydrophobic molecules. Moreover, the CD-GNR were uniformly assembled on filter paper cellulose through the electrostatic adsorption and hydrogen bond, so that the CD-GNR paper-based SERS substrate (CD-GNR-paper) demonstrated higher sensitivity for the determination of Sudan III (0.1MUM) and Sudan IV (0.5MUM) than GNRs paper-based SERS substrate (GNR-paper), with high stability after the storage in the open air for 90days. Importantly, CD-GNR-paper can effectively collect the Sudan dyes from illegally adulterated onto samples of Resina Draconis with a simple operation, further open up new exciting opportunity for SERS detection of more compounds illegally added with high sensitivity and fast signal responses. PMID- 29438941 TI - Detection of malachite green in fish based on magnetic fluorescent probe of CdTe QDs/nano-Fe3O4@MIPs. AB - A magnetic fluorescent probe of CdTe QDs/nano-Fe3O4@MIPs was prepared using CdTe QDs and Fe3O4 nanoparticles as co-nucleus and molecularly imprinted polymers (MIPs) as specific recognition sites based on a reverse microemulsion method. With the specific enrichment and magnetic separation properties, the probe of CdTe QDs/nano-Fe3O4@MIPs was used to detect malachite green (MG) in fish samples. The TEM analysis showed that the particles of CdTe QDs/nano-Fe3O4@MIPs were spherical with average diameter around 53nm, and a core-shell structure was well shaped with several Fe3O4 nanoparticles and CdTe QDs embedded in each of the microsphere. Quick separation of the probes from solutions could be realized with a magnet, indicating the excellent magnetic property of CdTe QDs/nano-Fe3O4@MIPs. The probe exhibited high specific adsorption towards MG and excellent fluorescence emission at lambdaem 598nm. The fluorescence of CdTe QDs/nano Fe3O4@MIPs could be linearly quenched by MG at the concentrations from 0.025 to 1.5MUmolL-1. The detection limit was 0.014MUmolL-1. The average recovery of spiked MG in fish samples was 105.2%. The result demonstrated that the as prepared CdTe QDs/nano-Fe3O4@MIPs could be used as a probe to the detection of trace MG in fish samples. PMID- 29438942 TI - Leach of the weathering crust elution-deposited rare earth ore for low environmental pollution with a combination of (NH4)2SO4 and EDTA. AB - High concentration of ammonium sulfate, a typical leaching agent, was often used in the mining process of the weathering crust elution-deposited rare earth ore. After mining, a lot of ammonia nitrogen and labile heavy metal fractions were residual in tailings, which may result in a huge potential risk to the environment. In this study, in order to achieve the maximum extraction of rare earth elements and reduce the labile heavy metal, extraction effect and fraction changes of lanthanum (La) and lead (Pb) in the weathering crust elution-deposited rare earth ore were studied by using a compound agent of (NH4)2SO4-EDTA. The extraction efficiency of La was more than 90% by using 0.2% (NH4)2SO4-0.005 M EDTA, which was almost same with that by using 2.0% (NH4)2SO4 solution. In contrast, the extraction efficiency of Pb was 62.3% when use 0.2% (NH4)2SO4-0.005 M EDTA, which is much higher than that (16.16%) achieved by using 2.0% (NH4)2SO4 solution. The released Pb fractions were mainly acid extractable and reducible fractions, and the content of reducible fraction being leached accounted for 70.45% of the total reducible fraction. Therefore, the use of 0.2% (NH4)2SO4 0.005 M EDTA can not only reduce the amount of (NH4)2SO4, but also decrease the labile heavy metal residues in soil, which provides a new way for efficient La extraction with effective preventing and controlling environmental pollution in the process of mining the weathering crust elution-deposited rare earth ore. PMID- 29438943 TI - Perfluoroalkylsulfonic and carboxylic acids in earthworms (Eisenia fetida): Accumulation and effects results from spiked soils at PFAS concentrations bracketing environmental relevance. AB - Effects of perfluorobutanesulfonic acid (PFBS), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluoroheptanoic acid (PFHpA) on earthworms (Eisenia fetida) in soils contaminated with these compounds at 0.1, 1, 10, 1,000, and 100,000 MUg kg-1 dry weight, covering concentration levels found in background, biosolid-amended, and facility-surrounding soils, were investigated. Earthworms were exposed to spiked soil for 21 days. Concentrations of these compounds in earthworms after 21-d exposure ranged from below detection to 127 mg kg-1 wet weight with the rank order of PFNA > PFHxS > PFHpA > PFBS; no mortality of earthworms was observed in all treatments including controls, except PFBS at 1,000 MUg kg-1 and all PFASs at 100,000 MUg kg-1. The highest weight loss (29%) was observed for earthworms exposed to PFNA at 100,000 MUg kg-1, which was significantly different from all other treatments except PFHpA at 100,000 MUg kg 1. These results are expected to fill some data gaps in toxicity of PFASs in terrestrial environments and provide helpful information on the potential for trophic transport of PFASs from soil to higher organisms. PMID- 29438944 TI - Equilibrium biopartitioning of organic anions - A case study for humans and fish. AB - In this work we combine partition coefficients between water and membrane lipid, storage lipid, the plasma protein albumin as well as structural protein with the tissue dependent fraction of the respective phases in order to obtain a clearer picture on the relevance of various biological tissues for the bioaccumulation of 31 organic anions. Most of the partition coefficients are based on experimental data, supplemented by some predicted ones. The data suggest that the plasma protein, albumin, will be the major sorption matrix in mammals. Only small fractions of the studied chemicals will occur freely dissolved in an organism. For the investigated acids with pKa <5, partitioning is dominated by the ionic species rather than the corresponding neutral species. Bioconcentration in fish is not expected to occur for many of these acids unless pH in the aqueous environment is low or specific sorption mechanisms are relevant. In contrast, biomagnification in terrestrial mammals would be expected for most organic anions if they are not sufficiently metabolized. We conclude that sorption is important for the toxicokinetics of ionizable organic chemicals and the dominating sorbing matrices are quite different from those for neutral species. PMID- 29438945 TI - Bisphenol A and dibutyl phthalate affect the expression of juxtacrine signaling factors in rat testis. AB - The study was designed to examine the effects of model plastic derived compounds, bisphenol A (BPA) and dibutyl phthalate (DBP), on juxtacrine communication in adult rat testis, by evaluating the expression of Notch pathway components. Testicular explant were exposed in vitro to BPA (5 * 10-6 M, 2.5 * 10-5 M, 5 * 10 5 M) or DBP (10-6 M, 10-5 M, 10-4 M) for 24 h. To determine the expression of Notch1, Dll4, Hey1, Hes1 and Hey5 real-time RT-PCR was used. Protein levels and localization of NOTCH1 receptor, its ligand DLL4 as well as HEY1, HES1 and HEY5 factors were detected by western blot analysis and immunohistochemistry, respectively. Upregulation of Notch1, Dll4 and Hey1 at the mRNA and protein level was demonstrated in testis explants after BPA and DBP treatment (p < 0.05; p < 0.01; p < 0.001). Hes5 expression decreased after BPA (p < 0.05; p < 0.01; p < 0.001), whereas Hes1 expression was not altered by either BPA or DBP. Tested chemicals altered immunoexpression of activated NOTCH1, DLL4, HEY1 and HES5 both in seminiferous epithelium and interstitial tissue, exerting differential effects on particular cell types. In conclusion, BPA and DBP affect Notch signaling pathway in rat testis, which indicates that juxtacrine communication is a potential target for the action of plastic derived compounds in male gonad. PMID- 29438946 TI - The effect of hazardous pollutants from coal combustion activity: Phytotoxicity assessment of aqueous soil extracts. AB - Airborne fly ash and related hazardous particles derived from coal combustion contaminate soil and groundwater, negatively affecting ecosystems. The aim of this study was chemical and toxicological evaluation of aqueous extracts of soil collected from the vicinity of a coal-fired Plomin power plant (PPP), using Lemna (Lemna minor L.) bioassay and additional biochemical indicators - photosynthetic pigments, lipid peroxidation, antioxidative enzymes and glutathione. Topsoil samples were collected from distances of 200, 300, 400 and 800 m from the PPP in accordance with the prevailing SW wind direction. Elevated levels of polycyclic aromatic hydrocarbons (up to 15,765 ng L-1) and potentially toxic trace elements were detected in the Plomin soil extracts (PEs) in comparison to control soil extract (CE). Trace elements accumulated in L. minor were mostly in accordance with their concentrations in PEs. The results demonstrate that PEs induced significant growth inhibition and other phytotoxic effects. Those effects can be related to damage caused by increased production of reactive oxygen species and impaired antioxidant levels. The connection among the phytotoxicity, a distribution of analyzed contaminants, and distances from the PPP is clearly established. PMID- 29438947 TI - Pretreatment of anaerobic digester samples by hydrochloric acid for solution state 1H and 13C NMR spectroscopic characterization of organic matter. AB - Pretreatment of anaerobic digester samples by hydrochloric acid (HCl) resulted in removal of Fe-based mineral and coordination compounds, attenuating their interferences with solution-state nuclear magnetic resonance (NMR) spectroscopic characterization of the solid phase organic matter. Substrate (influent) and digestate (effluent) samples from two full-scale anaerobic digesters, designated CD (co-digester) and SSD (sewage sludge digester), were investigated. Pretreatment of CD samples with 0.2-2.0 mol l-1 HCl and pretreatment of SSD samples with 1.0-3.0 mol l-1 HCl removed 96-100% and 76-80% of total Fe, respectively. Pretreatment declined overall paramagnetic characteristics of digestate samples, manifested by 50% (CD) and 70% (SSD) decrease in electron paramagnetic resonance signal intensities. As a result, meaningful solution-state 1H,13C heteronuclear single quantum coherence and 1H NMR spectra of DMSO-d6 soluble organic matter could be acquired. Sample pretreatment with the lowest concentration of HCl resulted in alteration of C:N ratios in solid phase, likely due to removal of labile organic and inorganic C- and N-containing compounds, while elevating the HCl concentration did not further change the C:N ratios. Furthermore, sample pretreatment increased the solubility of carbohydrates and proteins in DMSO-d6, enabling the detection of NMR resonances from certain structural units of carbohydrates (e.g. anomeric O2CH) and proteins (e.g. CHalpha in amino acids). Both attenuation of the paramagnetic matrix as well as an enhanced solubility of carbohydrate and protein fractions of the samples in DMSO d6 solvent contributed to an improved molecular characterization of anaerobic digester samples by solution-state NMR analysis. PMID- 29438948 TI - Isolation and characterization of a quinclorac-degrading Actinobacteria Streptomyces sp. strain AH-B and its implication on microecology in contaminated soil. AB - Quinclorac, a highly selective auxin herbicide, is widely used for controlling weeds in rice field. However, the residual quinclorac is toxic to many crops, vegetables, and aquatic animals, resulting in one of the major problems in crop rotation. Here, we investigated the degradation of quinclorac by strain AH-B, which was isolated from long-term quinclorac-contaminated soil using continuous circulating fluidized bed reactor and subjected to atmospheric and room temperature plasma mutation. Morphological examination, 16S rRNA gene sequencing, and phylogenetic analysis revealed that strain AH-B was Streptomyces sp. The quinclorac degradation efficiency of AH-B in liquid medium was 97.2% after 18 days when the initial quinclorac concentration was 20 mg L-1. The degradation products were 3-chloro-7-methoxy-8-quinoline-carboxylic, 3-chloro-7-methyl-8 quinoline-carboxylic, 3-chloro-7-oxyethyl-8-quinoline-carboxylic, and 3,7 dichloro-6-methyl-8-quinoline-carboxylic. The inoculum size, initial quinclorac concentration, pH, and temperature were found to affect quinclorac degradation efficiency of AH-B. High-performance liquid chromatography-electrospray ionization tandem mass spectrometry analysis revealed that quinclorac degradation by AH-B produced many products. In soil with initial quinclorac content of 1 mg kg-1 dry soil, addition of AH-B resulted in 87.5% quinclorac degradation after 42 days, while that in the control (without AH-B) was 22.4%. Furthermore, microecological analysis using next-generation sequencing of 16S rRNA geneshowed that some bacterial species, such as Bacterioides and Proteobacteria, could survive in quinclorac-contaminated soil, while some bacteria, such as Firmicutes, were very sensitive to quinclorac. Besides, some fungal species, such as Basidiomycota, could also survive quinclorac-contamination. After 42 days, the diversity of bacteria and fungi in soil treated with AH-B was higher than that in the control, implying that bioaugmentation with strain AH-B could reduce quinclorac toxicity to microorganisms in soil. PMID- 29438949 TI - Biosorption of heavy metals by obligate halophilic fungi. AB - The presence of heavy metals in the environment poses a serious threat to human health. Remediation of this problem using microorganisms has been widely researched to find a sustainable solution. Obligate halophilic fungi comprising Aspergillus flavus, Aspergillus gracilis, Aspergillus penicillioides (sp. 1), Aspergillus penicillioides (sp. 2), Aspergillus restrictus and Sterigmatomyces halophilus were used for the biosorption of cadmium, copper, ferrous, manganese, lead and zinc. The metals were supplemented as salts in potato dextrose broth for the growth of obligate halophilic fungi and incubated for 14 days. The supernatant and biomass were obtained by the acid digestion method. The biosorption was screened by atomic absorption spectroscopy. All tested fungi showed moderate to high adsorption of heavy metals, amongst which A. flavus and S. halophilus showed the best average adsorption of all heavy metals studied, with an average of 86 and 83%, respectively. On average, Fe and Zn are best removed from the liquid media of obligate halophilic fungi, with an average of 85 and 84%, respectively. This pioneering study of biosorption by obligate halophilic fungi using inexpensive media in stagnant conditions provides a cost effective environmental solution for the removal of heavy metals. PMID- 29438950 TI - Inorganic mercury (Hg2+) accumulation in autotrophic and mixotrophic planktonic protists: Implications for Hg trophodynamics in ultraoligotrophic Andean Patagonian lakes. AB - Microbial assemblages are typical of deep ultraoligotrophic Andean Patagonian lakes and comprise picoplankton and protists (phytoflagellates and mixotrophic ciliates), having a central role in the C cycle, primary production and in the incorporation of dissolved inorganic mercury (Hg2+) into lake food webs. In this study we evaluated the mechanisms of Hg2+ incorporation in hetero- and autotrophic bacteria, in the autotrophic dinoflagellate (Gymnodinium paradoxum) and in two mixotrophic ciliates (Stentor araucanus and Ophrydium naumanni) dominating the planktonic microbial assemblage. The radioisotope 197Hg was used to trace the Hg2+ incorporation in microbiota. Hg uptake was analyzed as a function of cell abundance (BCF: bioconcentration factor), cell surface (SCF: surface concentration factor) and cell volume (VCF: volume concentration factor). Overall, the results obtained showed that these organisms incorporate substantial amounts of dissolved Hg2+ passively (adsorption) and actively (bacteria consumption or attachment), displaying different Hg internalization and therefore, varying potential for Hg transfer. Surface area and quality, and surface:volume ratio (S:V) control the passive uptake in all the organisms. Active incorporation depends on bacteria consumption in the mixotrophic ciliates, or on bacteria association to surface in the autotrophic dinoflagellate. Hg bioaccumulated by pelagic protists can be transferred to higher trophic levels through plankton and fish feeding, regenerated to the dissolved phase by excretion, and/or transferred to the sediments by particle sinking. In ultraoligotrophic Andean Patagonian lakes, picoplankton and planktonic protists are key components of lake food webs, linking the pelagic and benthic Hg pathways, and thereby playing a central role in Hg trophodynamics. PMID- 29438951 TI - Enhanced reactivity of nZVI embedded into supermacroporous cryogels for highly efficient Cr(VI) and total Cr removal from aqueous solution. AB - Novel supermacroporous PSA-nZVI composites with nanoscale zero-valent iron particles (nZVI) embedded into poly (sodium acrylate) (PSA) cryogels were synthesized through ion exchange followed by in-situ reduction. The magnetic composites were evaluated for material characterizations and their efficiency for Cr(VI) and total Cr removal from aqueous medium in batch experiments. PSA-nZVI composites with high nZVI loading capacity up to 128.70 mg Fe/g PSA were obtained, and the interconnected macroporous structure of PSA cryogel remained unaltered with nZVI uniformly distributed on PSA cryogel as determined by TGA, SEM, TEM, XRD and XPS analyses. PSA-nZVI composites showed faster reaction rate than free nZVI both for Cr(VI) and total Cr removal, suggesting no mass transfer resistance and the enhanced reactivity of nZVI in PSA carrier. PSA-nZVI composites exhibited much more remarkable performance for Cr(VI) and total Cr removal than free nZVI particles in high removal capacity and broad pH application range (pH 4-10). The reaction mechanisms were also elucidated with XPS analyses before and after Cr(VI) reduction reactions. These results demonstrate that PSA cryogel acts as an excellent carrier and shows multiple functions in nZVI particle dispersion, pH buffering and oxidation resistance in addition to immobilizing nZVI particles from release. PMID- 29438952 TI - Macroplastic and microplastic contamination assessment of a tropical river (Saigon River, Vietnam) transversed by a developing megacity. AB - Both macroplastic and microplastic contamination levels were assessed for the first time in a tropical river estuary system, i.e. the Saigon River, that traverses a developing South East Asian megacity, i.e. Ho Chi Minh City, Vietnam. The analysis of floating debris collected daily on the Nhieu Loc - Thi Nghe canal by the municipal waste management service shows that the plastic mass percentage represents 11-43%, and the land-based plastic debris entering the river was estimated from 0.96 to 19.91 g inhabitant-1 d-1, namely 350 to 7270 g inhabitant 1 yr-1. Microplastics were assessed in the Saigon River and in four urban canals by sampling bulk water for anthropogenic fiber analysis and 300 MUm mesh size plankton net exposition for fragment analysis. Fibers and fragments are highly concentrated in this system, respectively 172,000 to 519,000 items m-3 and 10 to 223 items m-3. They were found in various colors and shapes with smallest size and surface classes being predominant. The macroplastics and fragments were mainly made of polyethylene and polypropylene while the anthropogenic fibers were mainly made of polyester. The relation between macroplastic and microplastic concentrations, waste management, population density and water treatment are further discussed. PMID- 29438953 TI - Abiotic formation of organoiodine compounds by manganese dioxide induced iodination of dissolved organic matter. AB - Iodination of dissolved organic matter (DOM) initiated by manganese oxide may represent an important source of organoiodine compounds (OICs) for iodide containing waters. Here, Suwannee River natural organic matter was selected as model DOM, the OICs formation in simulated freshwater samples from iodinated DOM induced by manganese oxide (delta-MnO2) was investigated at different pHs and concentrations of iodide and delta-MnO2 by using negative ion electrospray ionization coupled with Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR MS). While no OIC was observed in DOM control samples without delta-MnO2, hundreds of OICs were detected in the presence of delta-MnO2, suggesting the enhanced role of delta-MnO2 played in DOM iodination. The relative abundance was defined as the value of dividing the peak intensity of OICs by the highest m/z peak intensity constantly occurred in each mass spectrum, and selected as a parameter for partly reflecting the real level of OICs. The relative abundance of most OICs were around or greater than 1%, and several OICs with higher relative abundance were identified as diiodo-5-hydroxy-4-cyclopentene 1,3-dione, diiodomethane and diiodoacetic acid. The numbers of the formed OICs increased with the increase concentrations of iodide/delta-MnO2 and the decrease of pH, and nearly all OICs formed at lower levels of iodide/delta-MnO2 and/or higher pH were overlapped by that at higher levels of iodide/delta-MnO2 and/or lower pH, indicating the reliability of FT-ICR MS analysis techniques and data processing method. The OICs were formed mainly from the iodination of typical lignin-like and tannin-like compounds, as well as the precursor compounds with higher relative abundance through substitution reactions. Our findings demonstrate that the OICs formation by delta-MnO2-initiated DOM iodination should receive more attention and the concentration, exact structure and toxicity of the OICs need to be further investigated. PMID- 29438954 TI - Dietary intake and urinary metals among pregnant women in the Pacific Northwest. AB - Pregnancy is a period when the mother and her offspring are susceptible to the toxic effects of metals. We investigated associations of intake of frequently consumed foods with urinary metals concentrations among pregnant women in the Pacific Northwest. We measured urinary cadmium (U-Cd), arsenic (U-As) and molybdenum (U-Mo) concentrations from spot urine samples in early pregnancy (15 weeks of gestation, on average) among 558 women from Seattle and Tacoma, Washington. We assessed periconceptional dietary intake using a semi-quantitative food frequency questionnaire (FFQ). We also determined early pregnancy zinc concentrations in serum. Statistical analyses involved multivariable linear regression models, adjusted for smoking status, age, race/ethnicity, multivitamin and supplement use, education, estimated total energy intake, and gravidity. The geometric mean and range in MUg/g creatinine for U-Cd, U-As and U-Mo were 0.29 (0.1-8.2), 18.95 (3-550), and 72.1 (15-467), respectively. U-Cd was positively associated with dietary zinc intake (P-value = 0.004) and serum zinc (P value<0.001) while it was negatively associated with coffee intake (P-value = 0.03). U-As was positively associated with dietary fish [(Lean fish, fatty fish, shellfish and non-fried fish) (P-values<0.01)], selenium (P-value = 0.004), zinc (P-value = 0.017), vegetables (P-value = 0.004), and low-fat yogurt (P-value = 0.03). Women who reported higher intake of dietary magnesium (Mg)(P-value = 0.04), insoluble fiber (P-value = 0.03), and low-fat yogurt (P-value = 0.04) had higher U-Mo concentrations. Our study suggests that vegetables, fish, fiber and yogurt might be significant dietary sources of metals. Future studies aimed at investigating the risk of exposure to metals from other various food sources among reproductive-age and pregnant women are needed. PMID- 29438955 TI - Long-term increase in secondary exposure to anticoagulant rodenticides in European polecats Mustela putorius in Great Britain. AB - As a result of legal protection and population recovery, European polecats (Mustela putorius) in Great Britain are expanding into areas associated with greater usage of second-generation anticoagulant rodenticides (SGARs). We analysed polecat livers collected from road casualties from 2013 to 2016 for residues of five SGARs. We related variation in residues to polecat traits and potential exposure pathways, by analysing stable isotopes of carbon (delta13C) and nitrogen (delta15N) in their whiskers. 54 of 68 (79%) polecats had detectable residues of at least one SGAR. Bromadiolone (71%) was the most frequently detected compound, followed by difenacoum (53%) and brodifacoum (35%). Applying historical limits of detection to allow comparison between these new data and previous assessments, we show that in the 25 years from 1992 to 2016 inclusive, the rate of detection of SGARs in polecats in Britain has increased by a factor of 1.7. The probability of SGAR detection was positively related to increasing values of delta15N, suggesting that polecats feeding at a higher trophic level were more likely to be exposed. Total concentrations of SGARs in polecats with detectable residues were higher in polecats collected in arable compared to pastoral habitats, and in the west compared to the east of Britain. The number of compounds detected and total concentrations of SGARs increased with polecat age. There was no evidence of regional or seasonal variation in the probability of detecting SGARs, suggesting that the current risk of exposure to SGARs does not vary seasonally and has increased (from that in the 1990s) throughout the polecat's range. We recommend quantification of current practices in rodenticide usage, particularly in the light of recent regulatory changes, to enable assessment and mitigation of the risks of secondary exposure to rodenticides in non-target wildlife. PMID- 29438957 TI - Trump marches to wrong beat. PMID- 29438956 TI - The long and short of doubling down: polyploidy, epigenetics, and the temporal dynamics of genome fractionation. AB - We consider the rapidly advancing discipline of plant evolutionary genomics, with a focus on the evolution of polyploid genomes. In many lineages, polyploidy is followed by 'biased fractionation', the unequal loss of genes from ancestral progenitor genomes. Mechanistically, it has been proposed that biased fractionation results from changes in the epigenetic landscape near genes, likely mediated by transposable elements. These epigenetic changes result in unequal gene expression between duplicates, establishing differential fitness that leads to biased gene loss with respect to ancestral genomes. We propose a unifying conceptual framework and a set of testable hypotheses based on this model, relating genome size, the proximity of transposable elements to genes, epigenetic reprogramming, chromatin accessibility, and gene expression. PMID- 29438958 TI - Infographic. Can standardised clinical examination of athletes with acute groin injuries predict the presence and location of MRI findings? PMID- 29438959 TI - Retrospective analysis of the national impact of industrial action by English junior doctors in 2016. AB - OBJECTIVES: To examine the impacts of the four episodes of industrial action by English junior doctors in early 2016. DESIGN: Descriptive retrospective study of admitted patient care, accident and emergency (A&E) and outpatient activity in English hospitals. SETTING: All hospitals across England. PARTICIPANTS: All patients who attended A&E or outpatient appointments or those who were admitted to hospital during the 3-week period surrounding each of the four strikes (12 January, 10 February, 9-10 March and 26-27 April, excluding weekends). MAIN OUTCOME MEASURES: Raw numbers and percentage changes of outpatient appointments and cancellations, A&E visits, admitted patients and all inhospital mortality on strike days compared with patient activity on the same weekday in the weeks before and after the strikes. RESULTS: There were 3.4 million admissions, 27 million outpatient appointments and 3.4 million A&E attendances over the four 3 week periods analysed. Across the four strikes, there were 31 651 fewer admissions (-9.1%), 23 895 fewer A&E attendances (-6.8%) and 173 462 fewer outpatient appointments (-6.0%) than expected. Additionally, 101 109 more outpatient appointments were cancelled by hospitals than expected (+52%). The 26 27 April strike, where emergency services were also affected, showed the largest impacts on regular service. Mortality did not measurably increase on strike days. Regional analysis showed that services in the Yorkshire and the Humber region were disproportionately more affected by the industrial action. CONCLUSIONS: Industrial action by junior doctors during early 2016 caused a significant impact on the provision of healthcare provided by English hospitals. We also observed regional variations in how these strikes affected providers. PMID- 29438960 TI - How I treat myelodysplastic syndromes of childhood. AB - Pediatric myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders with an annual incidence of 1 to 4 cases per million, accounting for less than 5% of childhood hematologic malignancies. MDSs in children often occur in the context of inherited bone marrow failure syndromes, which represent a peculiarity of myelodysplasia diagnosed in pediatric patients. Moreover, germ line syndromes predisposing individuals to develop MDS or acute myeloid leukemia have recently been identified, such as those caused by mutations in GATA2, ETV6, SRP72, and SAMD9/SAMD9-L Refractory cytopenia of childhood (RCC) is the most frequent pediatric MDS variant, and it has specific histopathologic features. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many children with MDSs and is routinely offered to all patients with MDS with excess of blasts, to those with MDS secondary to previously administered chemoradiotherapy, and to those with RCC associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. Immune-suppressive therapy may be a treatment option for RCC patients with hypocellular bone marrow and the absence of monosomy 7 or a complex karyotype, although the response rate is lower than that observed in severe aplastic anemia, and a relevant proportion of these patients will subsequently need HSCT for either nonresponse or relapse. PMID- 29438961 TI - Allele-selective RUNX1 binding regulates P1 blood group status by transcriptional control of A4GALT. AB - P1 and Pk are glycosphingolipid antigens synthesized by the A4GALT-encoded alpha1,4-galactosyltransferase, using paragloboside and lactosylceramide as acceptor substrates, respectively. In addition to the compatibility aspects of these histo-blood group molecules, both constitute receptors for multiple microbes and toxins. Presence or absence of P1 antigen on erythrocytes determines the common P1 (P1+Pk+) and P2 (P1-Pk+weak) phenotypes. A4GALT transcript levels are higher in P1 individuals and single-nucleotide polymorphisms (SNPs) in noncoding regions of A4GALT, particularly rs5751348, correlate with P1/P2 status. Despite these recent findings, the molecular mechanism underlying these phenotypes remains elusive. The In(Lu) phenotype is caused by Kruppel-like factor 1 (KLF1) haploinsufficiency and shows decreased P1 levels on erythrocytes. We therefore hypothesized KLF1 regulates A4GALT expression. Intriguingly, P1 specific sequences including rs5751348 revealed potential binding sites for several hematopoietic transcription factors, including KLF1. However, KLF1 binding did not explain P1 -specific shifts in electrophoretic mobility-shift assays and small interfering RNA silencing of KLF1 did not affect A4GALT transcript levels. Instead, protein pull-down experiments using P1 but not P2 oligonucleotide probes identified runt-related transcription factor 1 (RUNX1) by mass spectrometry. Furthermore, RUNX1 binds P1 alleles selectively, and knockdown of RUNX1 significantly decreased A4GALT transcription. These data indicate that RUNX1 regulates A4GALT and thereby the expression of clinically important glycosphingolipids implicated in blood group incompatibility and host-pathogen interactions. PMID- 29438962 TI - The Little Prince: is not a glimpse into the world of autism. PMID- 29438964 TI - Private company criticised over exaggerated screening claims. PMID- 29438963 TI - Health professionals' and coroners' views on less invasive perinatal and paediatric autopsy: a qualitative study. AB - OBJECTIVE: To assess health professionals' and coroners' attitudes towards non minimally and minimally invasive autopsy in the perinatal and paediatric setting. METHODS: A qualitative study using semistructured interviews. Data were analysed thematically. RESULTS: Twenty-five health professionals (including perinatal/paediatric pathologists and anatomical pathology technologists, obstetricians, fetal medicine consultants and bereavement midwives, intensive care consultants and family liaison nurses, a consultant neonatologist and a paediatric radiologist) and four coroners participated. Participants viewed less invasive methods of autopsy as a positive development in prenatal and paediatric care that could increase autopsy rates. Several procedural and psychological benefits were highlighted including improved diagnostic accuracy in some circumstances, potential for faster turnaround times, parental familiarity with imaging and laparoscopic approaches, and benefits to parents and faith groups who object to invasive approaches. Concerns around the limitations of the technology such not reaching the same levels of certainty as full autopsy, unsuitability of imaging in certain circumstances, the potential for missing a diagnosis (or misdiagnosis) and de-skilling the workforce were identified. Finally, a number of implementation issues were raised including skills and training requirements for pathologists and radiologists, access to scanning equipment, required computational infrastructure, need for a multidisciplinary approach to interpret results, cost implications, equity of access and acceptance from health professionals and hospital managers. CONCLUSION: Health professionals and coroners viewed less invasive autopsy as a positive development in perinatal and paediatric care. However, to inform implementation a detailed health economic analysis and further exploration of parental views, particularly in different religious groups, are required. PMID- 29438966 TI - Review condemns treatment of trust staff who blew whistle on poor care. PMID- 29438967 TI - Children could keep the healthcare community on its toes. PMID- 29438968 TI - CD38 pretargeted RIT of B-cell tumors. PMID- 29438965 TI - Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases. AB - ERBB2 amplification has been identified in ~5% of KRAS wild-type colorectal cancers (CRCs). A recent clinical trial showed response to HER2-directed therapy in a subset of ERBB2-amplified metastatic CRCs resistant to chemotherapy and EGFR directed therapy. With the aim of better understanding mechanisms of resistance to HER2-directed and EGFR-directed therapies, we report the complete molecular characterization of two cases of ERBB2-amplified CRC. PCR-free whole-genome sequencing was used to identify mutations, copy-number alterations, structural variations, and losses of heterozygosity. ERBB2 copy number was also measured by fluorescence in situ hybridization. Single-stranded mRNA sequencing was used for gene expression profiling. Immunohistochemistry and protein mass spectrometry were used to quantify HER2 protein expression. The cases showed ERBB2 copy number of 86 and 92, respectively. Both cases were immunohistochemically positive for HER2 according to CRC-specific scoring criteria. Fluorescence in situ hybridization and protein mass spectrometry corroborated significantly elevated ERBB2 copy number and abundance of HER2 protein. Both cases were microsatellite stable and without mutation of RAS pathway genes. Additional findings included altered expression of PTEN, MET, and MUC1 and mutation of PIK3CA The potential effects of the molecular alterations on sensitivity to EGFR and HER2-directed therapies were discussed. Identification of ERBB2 amplification in CRC is necessary to select patients who may respond to HER2-directed therapy. An improved understanding of the molecular characteristics of ERBB2-amplified CRCs and their potential mechanisms of resistance will be useful for future research into targeted therapies and may eventually inform therapeutic decision-making. PMID- 29438969 TI - ENLightening YEATS in antagonizing polycomb repression. PMID- 29438971 TI - Syphilitic lymphadenitis with abscess formation involving cervical lymph nodes. PMID- 29438970 TI - Myosin IIa signal von Willebrand factor release. PMID- 29438972 TI - Interference of hyperleukocytosis in red blood cell count. PMID- 29438973 TI - Wong RSM, Saleh MN, Khelif A, et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017;130(23):2527-2536. PMID- 29438974 TI - Martin-Pardillos A, Tsaalbi-Shtylik A, Chen S, et al. Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions. Blood. 2017;130(13):1523-1534. PMID- 29438975 TI - Person-Centered Integrated Care for Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND AND OBJECTIVES: The effectiveness of person-centered integrated care strategies for CKD is uncertain. We conducted a systematic review and meta analysis of randomized, controlled trials to assess the effect of person-centered integrated care for CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to April of 2016), and selected randomized, controlled trials of person-centered integrated care interventions with a minimum follow-up of 3 months. Random-effects meta-analysis was used to assess the effect of person centered integrated care. RESULTS: We included 14 eligible studies covering 4693 participants with a mean follow-up of 12 months. In moderate quality evidence, person-centered integrated care probably had no effect on all-cause mortality (relative risk [RR], 0.86; 95% confidence interval [95% CI], 0.68 to 1.08) or health-related quality of life (standardized mean difference, 0.02; 95% CI, -0.05 to 0.10). The effects on renal replacement therapy (RRT) (RR, 1.00; 95% CI, 0.65 to 1.55), serum creatinine levels (mean difference, 0.59 mg/dl; 95% CI, -0.38 to 0.36), and eGFR (mean difference, 1.51 ml/min per 1.73 m2; 95% CI, -3.25 to 6.27) were very uncertain. Quantitative analysis suggested that person-centered integrated care interventions may reduce all-cause hospitalization (RR, 0.38; 95% CI, 0.15 to 0.95) and improve BP control (RR, 1.20; 95% CI, 1.00 to 1.44), although the certainty of the evidence was very low. CONCLUSIONS: Person-centered integrated care may have little effect on mortality or quality of life. The effects on serum creatinine, eGFR, and RRT are uncertain, although person centered integrated care may lead to fewer hospitalizations and improved BP control. PMID- 29438976 TI - Role of upstream stimulatory factor 2 in glutamate dehydrogenase gene transcription. AB - Glutamate dehydrogenase (Gdh) plays a central role in ammonia detoxification by catalysing reversible oxidative deamination of l-glutamate into alpha ketoglutarate using NAD+ or NADP+ as cofactor. To gain insight into transcriptional regulation of glud, the gene that codes for Gdh, we isolated and characterised the 5' flanking region of glud from gilthead sea bream (Sparus aurata). In addition, tissue distribution, the effect of starvation as well as short- and long-term refeeding on Gdh mRNA levels in the liver of S. aurata were also addressed. 5'-Deletion analysis of glud promoter in transiently transfected HepG2 cells, electrophoretic mobility shift assays, chromatin immunoprecipitation (ChIP) and site-directed mutagenesis allowed us to identify upstream stimulatory factor 2 (Usf2) as a novel factor involved in the transcriptional regulation of glud Analysis of tissue distribution of Gdh and Usf2 mRNA levels by reverse transcriptase-coupled quantitative real-time PCR (RT-qPCR) showed that Gdh is mainly expressed in the liver of S. aurata, while Usf2 displayed ubiquitous distribution. RT-qPCR and ChIP assays revealed that long-term starvation down regulated the hepatic expression of Gdh and Usf2 to similar levels and reduced Usf2 binding to glud promoter, while refeeding resulted in a slow but gradual restoration of both Gdh and Usf2 mRNA abundance. Herein, we demonstrate that Usf2 transactivates S. aurata glud by binding to an E-box located in the proximal region of glud promoter. In addition, our findings provide evidence for a new regulatory mechanism involving Usf2 as a key factor in the nutritional regulation of glud transcription in the fish liver. PMID- 29438977 TI - Post-transcriptional Regulation of UGT2B10 Hepatic Expression and Activity by Alternative Splicing. AB - The detoxification enzyme UDP-glucuronosyltransferase UGT2B10 is specialized in the N-linked glucuronidation of many drugs and xenobiotics. Preferred substrates possess tertiary aliphatic amines and heterocyclic amines, such as tobacco carcinogens and several antidepressants and antipsychotics. We hypothesized that alternative splicing (AS) constitutes a means to regulate steady-state levels of UGT2B10 and enzyme activity. We established the transcriptome of UGT2B10 in normal and tumoral tissues of multiple individuals. The highest expression was in the liver, where 10 AS transcripts represented 50% of the UGT2B10 transcriptome in 50 normal livers and 44 hepatocellular carcinomas. One abundant class of transcripts involves a novel exonic sequence and leads to two alternative (alt.) variants with novel in-frame C termini of 10 or 65 amino acids. Their hepatic expression was highly variable among individuals, correlated with canonical transcript levels, and was 3.5-fold higher in tumors. Evidence for their translation in liver tissues was acquired by mass spectrometry. In cell models, they colocalized with the enzyme and influenced the conjugation of amitriptyline and levomedetomidine by repressing or activating the enzyme (40%-70%; P < 0.01) in a cell context-specific manner. A high turnover rate for the alt. proteins, regulated by the proteasome, was observed in contrast to the more stable UGT2B10 enzyme. Moreover, a drug-induced remodeling of UGT2B10 splicing was demonstrated in the HepaRG hepatic cell model, which favored alt. variants expression over the canonical transcript. Our findings support a significant contribution of AS in the regulation of UGT2B10 expression in the liver with an impact on enzyme activity. PMID- 29438978 TI - A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing. AB - TDP-43 is an RNA-binding protein active in splicing that concentrates into membraneless ribonucleoprotein granules and forms aggregates in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Although best known for its predominantly disordered C-terminal domain which mediates ALS inclusions, TDP-43 has a globular N-terminal domain (NTD). Here, we show that TDP-43 NTD assembles into head-to-tail linear chains and that phosphomimetic substitution at S48 disrupts TDP-43 polymeric assembly, discourages liquid-liquid phase separation (LLPS) in vitro, fluidizes liquid-liquid phase separated nuclear TDP-43 reporter constructs in cells, and disrupts RNA splicing activity. Finally, we present the solution NMR structure of a head-to-tail NTD dimer comprised of two engineered variants that allow saturation of the native polymerization interface while disrupting higher-order polymerization. These data provide structural detail for the established mechanistic role of the well-folded TDP-43 NTD in splicing and link this function to LLPS. In addition, the fusion-tag solubilized, recombinant form of TDP-43 full-length protein developed here will enable future phase separation and in vitro biochemical assays on TDP-43 function and interactions that have been hampered in the past by TDP-43 aggregation. PMID- 29438979 TI - Mitochondrial tyrosyl-DNA phosphodiesterase 2 and its TDP2S short isoform. AB - Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs abortive topoisomerase II cleavage complexes. Here, we identify a novel short isoform of TDP2 (TDP2S) expressed from an alternative transcription start site. TDP2S contains a mitochondrial targeting sequence, contributing to its enrichment in the mitochondria and cytosol, while full-length TDP2 contains a nuclear localization signal and the ubiquitin associated domain in the N-terminus. Our study reveals that both TDP2 isoforms are present and active in the mitochondria. Comparison of isogenic wild-type (WT) and TDP2 knockout (TDP2-/-/-) DT40 cells shows that TDP2-/-/- cells are hypersensitive to mitochondrial-targeted doxorubicin (mtDox), and that complementing TDP2-/-/- cells with human TDP2 restores resistance to mtDox. Furthermore, mtDox selectively depletes mitochondrial DNA in TDP2-/-/- cells. Using CRISPR-engineered human cells expressing only the TDP2S isoform, we show that TDP2S also protects human cells against mtDox. Finally, lack of TDP2 in the mitochondria reduces the mitochondria transcription levels in two different human cell lines. In addition to identifying a novel TDP2S isoform, our report demonstrates the presence and importance of both TDP2 isoforms in the mitochondria. PMID- 29438980 TI - Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study. AB - OBJECTIVE: To determine if trimethoprim use for urinary tract infection (UTI) is associated with an increased risk of acute kidney injury, hyperkalaemia, or sudden death in the general population. DESIGN: Cohort study. SETTING: UK electronic primary care records from practices contributing to the Clinical Practice Research Datalink linked to the Hospital Episode Statistics database. PARTICIPANTS: Adults aged 65 and over with a prescription for trimethoprim, amoxicillin, cefalexin, ciprofloxacin, or nitrofurantoin prescribed up to three days after a primary care diagnosis of UTI between April 1997 and September 2015. MAIN OUTCOME MEASURES: The outcomes were acute kidney injury, hyperkalaemia, and death within 14 days of a UTI treated with antibiotics. RESULTS: Among a cohort of 1 191 905 patients aged 65 and over, 178 238 individuals were identified with at least one UTI treated with antibiotics, comprising a total of 422 514 episodes of UTIs treated with antibiotics. The odds of acute kidney injury in the 14 days following antibiotic initiation were higher following trimethoprim (adjusted odds ratio 1.72, 95% confidence interval 1.31 to 2.24) and ciprofloxacin (1.48, 1.03 to 2.13) compared with amoxicillin. The odds of hyperkalaemia in the 14 days following antibiotic initiation were only higher following trimethoprim (2.27, 1.49 to 3.45) compared with amoxicillin. However, the odds of death within the 14 days following antibiotic initiation were not higher with trimethoprim than with amoxicillin: in the whole population the adjusted odds ratio was 0.90 (95% confidence interval 0.76 to 1.07) while among users of renin-angiotensin system blockers the odds of death within 14 days of antibiotic initiation was 1.12 (0.80 to 1.57). The results suggest that, for 1000 UTIs treated with antibiotics among people 65 and over, treatment with trimethoprim instead of amoxicillin would result in one to two additional cases of hyperkalaemia and two admissions with acute kidney injury, regardless of renin-angiotensin system blockade. However, for people taking renin-angiotensin system blockers and spironolactone treatment with trimethoprim instead of amoxicillin there were 18 additional cases of hyperkalaemia and 11 admissions with acute kidney injury. CONCLUSION: Trimethoprim is associated with a greater risk of acute kidney injury and hyperkalaemia compared with other antibiotics used to treat UTIs, but not a greater risk of death. The relative risk increase is similar across population groups, but the higher baseline risk among those taking renin-angiotensin system blockers and potassium-sparing diuretics translates into higher absolute risks of acute kidney injury and hyperkalaemia in these groups. PMID- 29438981 TI - Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling. AB - Mitochondrial abundance is dynamically regulated and was previously shown to be increased by Wnt/beta-catenin signaling. Pgam5 is a mitochondrial phosphatase which is cleaved by the rhomboid protease presenilin-associated rhomboid-like protein (PARL) and released from membranes after mitochondrial stress. In this study, we show that Pgam5 interacts with the Wnt pathway component axin in the cytosol, blocks axin-mediated beta-catenin degradation, and increases beta catenin levels and beta-catenin-dependent transcription. Pgam5 stabilized beta catenin by inducing its dephosphorylation in an axin-dependent manner. Mitochondrial stress triggered by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment led to cytosolic release of endogenous Pgam5 and subsequent dephosphorylation of beta-catenin, which was strongly diminished in Pgam5 and PARL knockout cells. Similarly, hypoxic stress generated cytosolic Pgam5 and led to stabilization of beta-catenin, which was abolished by Pgam5 knockout. Cells stably expressing cytosolic Pgam5 exhibit elevated beta-catenin levels and increased mitochondrial numbers. Our study reveals a novel mechanism by which damaged mitochondria might induce replenishment of the mitochondrial pool by cell intrinsic activation of Wnt signaling via the Pgam5-beta-catenin axis. PMID- 29438983 TI - Plasma MicroRNA Clusters in Human Left Ventricular Remodeling: A Biomarker and Discovery Platform. PMID- 29438982 TI - MicroRNAs Associated With Reverse Left Ventricular Remodeling in Humans Identify Pathways of Heart Failure Progression. AB - BACKGROUND: Plasma extracellular RNAs have recently garnered interest as biomarkers in heart failure (HF). Most studies in HF focus on single extracellular RNAs related to phenotypes and outcomes, and few describe their functional roles. We hypothesized that clusters of plasma microRNAs (miRNAs) associated with left ventricular (LV) remodeling in human HF would identify novel subsets of genes involved in HF in animal models. METHODS AND RESULTS: We prospectively measured circulating miRNAs in 64 patients with systolic HF (mean age, 64.8 years; 91% men; median LV ejection fraction, 26%) with serial echocardiography (10 months apart) during medical therapy. We defined LV reverse remodeling as a 15% reduction in LV end-systolic volume index. Using principal components analysis, we identified a component associated with LV reverse remodeling (odds ratio=3.99; P=0.01) that provided risk discrimination for LV reverse remodeling superior to a clinical model (C statistic, 0.58 for a clinical model versus 0.71 for RNA-based model). Using network bioinformatics, we uncovered genes not previously widely described in HF regulated simultaneously by >2 miRNAs. We observed increased myocardial expression of these miRNAs during HF development in animals, with downregulation of target gene expression, suggesting coordinate miRNA-mRNA regulation. Target mRNAs were involved in autophagy, metabolism, and inflammation. CONCLUSIONS: Plasma miRNAs associated with LV reverse remodeling in humans are dysregulated in animal HF and target clusters of genes involved in mechanisms implicated in HF. A translational approach integrating human HF, bioinformatics, and model systems may uncover novel pathways involved in HF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00351390. PMID- 29438984 TI - Bawa-Garba to appeal High Court ruling and may challenge manslaughter conviction. PMID- 29438985 TI - Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer. AB - The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Here, we show that nilotinib, a clinically approved drug for chronic myeloid leukaemia, strongly inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining beta-catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines. Collectively, our results indicate that the targeting DDR1 kinase activity with nilotinib may be beneficial for patients with mCRC. PMID- 29438986 TI - Phospholipid transfer protein: its impact on lipoprotein homeostasis and atherosclerosis. AB - Phospholipid transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development in humans; however, we still do not quite understand the mechanisms. In mouse models, PLTP overexpression induces atherosclerosis, while its deficiency reduces it. Thus, mouse models were used to explore the mechanisms. In this review, I summarize the major progress made in the PLTP research field and emphasize its impact on lipoprotein metabolism and atherosclerosis, as well as its regulation. PMID- 29438987 TI - Interaction of lecithin:cholesterol acyltransferase with lipid surfaces and apolipoprotein A-I-derived peptides. AB - LCAT is an enzyme responsible for the formation of cholesteryl esters from unesterified cholesterol (UC) and phospholipid (PL) molecules in HDL particles. However, it is poorly understood how LCAT interacts with lipoproteins and how apoA-I activates it. Here we have studied the interactions between LCAT and lipids through molecular simulations. In addition, we studied the binding of LCAT to apoA-I-derived peptides, and their effect on LCAT lipid association-utilizing experiments. Results show that LCAT anchors itself to lipoprotein surfaces by utilizing nonpolar amino acids located in the membrane-binding domain and the active site tunnel opening. Meanwhile, the membrane-anchoring hydrophobic amino acids attract cholesterol molecules next to them. The results also highlight the role of the lid-loop in the lipid binding and conformation of LCAT with respect to the lipid surface. The apoA-I-derived peptides from the LCAT-activating region bind to LCAT and promote its lipid surface interactions, although some of these peptides do not bind lipids individually. The transfer free-energy of PL from the lipid bilayer into the active site is consistent with the activation energy of LCAT. Furthermore, the entry of UC molecules into the active site becomes highly favorable by the acylation of SER181. PMID- 29438988 TI - Flavopiridol Inhibits TGF-beta-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2. AB - Transforming growth factor-beta (TGF-beta) is a pleiotropic growth factor implicated in the development of atherosclerosis for its role in mediating glycosaminoglycan (GAG) chain hyperelongation on the proteoglycan biglycan, a phenomenon that increases the binding of atherogenic lipoproteins in the vessel wall. Phosphorylation of the transcription factor Smad has emerged as a critical step in the signaling pathways that control the synthesis of biglycan, both the core protein and the GAG chains. We have used flavopiridol, a well-known cyclin dependent kinase inhibitor, to study the role of linker region phosphorylation in the TGF-beta-stimulated synthesis of biglycan. We used radiosulfate incorporation and SDS-PAGE to assess proteoglycan synthesis, real-time polymerase chain reaction to assess gene expression, and chromatin immunoprecipitation to assess the binding of Smads to the promoter region of GAG Synthesizing genes. Flavopiridol blocked TGF-beta-stimulated synthesis of mRNA for the GAG synthesizing enzymes, and chondroitin 4-sulfotransferase (C4ST-1), chondroitin sulfate synthase-1 (ChSy-1) and TGF-beta-mediated proteoglycans synthesis as well as GAG hyperelongation. Flavopiridol blocked TGF-beta-stimulated Smad2 phosphorylation at both the serine triplet and the isolated threonine residue in the linker region. The binding of Smad to the promoter region of the C4ST-1 and ChSy-1 genes was stimulated by TGF-beta, and this response was blocked by flavopiridol, demonstrating that linker region phosphorylated Smad can pass to the nucleus and positively regulate transcription. These results demonstrate the validity of the kinases, which phosphorylate the Smad linker region as potential therapeutic target(s) for the development of an agent to prevent atherosclerosis. PMID- 29438989 TI - Mitotic Phosphorylation of SENP3 Regulates DeSUMOylation of Chromosome-Associated Proteins and Chromosome Stability. AB - Progression of mitotic cell cycle and chromosome condensation and segregation are controlled by posttranslational protein modifications such as phosphorylation and SUMOylation. However, how SUMO isopeptidases (SENP) regulate cell mitotic procession is largely unknown. Here, we demonstrate that precise phosphorylation of SENP3 during mitosis suppresses SENP3 deSUMOylation activity towards chromosome-associated proteins, including topoisomerase IIalpha (TopoIIalpha). Cyclin B-dependent kinases 1 and protein phosphatase 1alpha were identified as the kinase and phosphatase in control of mitotic SENP3 phosphorylation, respectively. SENP3 phosphorylation decreased its interaction with TopoIIalpha, resulting in reduced SENP3 deSUMOylation activity on TopoIIalpha. Furthermore, we observed mitotic arrest, increased chromosome instability, and promotion of tumorigenesis in cells expressing a nonphosphorylatable SENP3 mutant. These data show that SENP3 phosphorylation plays a crucial role in regulating the SUMOylation of chromosome-associated proteins and chromosome stability in mitosis.Significance: Phosphorylation of SENP3 regulates SUMOylation of chromosome-associated proteins to maintain genomic stability during mitosis. Cancer Res; 78(9); 2171-8. (c)2018 AACR. PMID- 29438990 TI - Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis. AB - Targeting of steroidogenic enzymes (e.g., abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here, we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacologic inhibition of LRH-1 activity attenuated LRH-1-mediated androgen deprivation and anti-androgen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management.Significance: These findings not only demonstrate the significant role of the nuclear receptor LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. Cancer Res; 78(9); 2205-18. (c)2018 AACR. PMID- 29438991 TI - Genetic Hitchhiking and Population Bottlenecks Contribute to Prostate Cancer Disparities in Men of African Descent. AB - Prostate cancer incidence and mortality rates in African and African American men are greatly elevated compared with other ethnicities. This disparity is likely explained by a combination of social, environmental, and genetic factors. A large number of susceptibility loci have been reported by genome-wide association studies (GWAS), but the contribution of these loci to prostate cancer disparities is unclear. Here, we investigated the population structure of 68 previously reported GWAS loci and calculated genetic disparity contribution statistics to identify SNPs that contribute the most to differences in prostate cancer risk across populations. By integrating GWAS results with allele frequency data, we generated genetic risk scores for 45 African and 19 non-African populations. Tests of natural selection were used to assess why some SNPs have large allele frequency differences across populations. We report that genetic predictions of prostate cancer risks are highest for West African men and lowest for East Asian men. These differences may be explained by the out-of-Africa bottleneck and natural selection. A small number of loci appear to drive elevated prostate cancer risks in men of African descent, including rs9623117, rs6983267, rs10896449, rs10993994, and rs817826. Although most prostate cancer-associated loci are evolving neutrally, there are multiple instances where alleles have hitchhiked to high frequencies with linked adaptive alleles. For example, a protective allele at 2q37 appears to have risen to high frequency in Europe due to selection acting on pigmentation. Our results suggest that evolutionary history contributes to the high rates of prostate cancer in African and African American men.Significance: A small number of genetic variants cause an elevated risk of prostate cancer in men of West African descent. Cancer Res; 78(9); 2432 43. (c)2018 AACR. PMID- 29438992 TI - Nonlinear Regression Improves Accuracy of Characterization of Multiplexed Mass Spectrometric Assays. AB - The need for assay characterization is ubiquitous in quantitative mass spectrometry-based proteomics. Among many assay characteristics, the limit of blank (LOB) and limit of detection (LOD) are two particularly useful figures of merit. LOB and LOD are determined by repeatedly quantifying the observed intensities of peptides in samples with known peptide concentrations and deriving an intensity versus concentration response curve. Most commonly, a weighted linear or logistic curve is fit to the intensity-concentration response, and LOB and LOD are estimated from the fit. Here we argue that these methods inaccurately characterize assays where observed intensities level off at low concentrations, which is a common situation in multiplexed systems. This manuscript illustrates the deficiencies of these methods, and proposes an alternative approach based on nonlinear regression that overcomes these inaccuracies. We evaluated the performance of the proposed method using computer simulations and using eleven experimental data sets acquired in Data-Independent Acquisition (DIA), Parallel Reaction Monitoring (PRM), and Selected Reaction Monitoring (SRM) mode. When the intensity levels off at low concentrations, the nonlinear model changes the estimates of LOB/LOD upwards, in some data sets by 20-40%. In absence of a low concentration intensity leveling off, the estimates of LOB/LOD obtained with nonlinear statistical modeling were identical to those of weighted linear regression. We implemented the nonlinear regression approach in the open-source R based software MSstats, and advocate its general use for characterization of mass spectrometry-based assays. PMID- 29438993 TI - Identification of progesterone receptor membrane component-1 as an interaction partner and possible regulator of fatty acid 2-hydroxylase. AB - The fatty acid 2-hydroxylase (FA2H) is essential for synthesis of 2-hydroxylated fatty acids in myelinating and other cells, and deficiency of this enzyme causes a complicated form of hereditary spastic paraplegia also known as fatty acid hydroxylase-associated neurodegeneration. Despite its important role in sphingolipid metabolism, regulation of FA2H and its interaction with other proteins involved in the same or other metabolic pathways is poorly understood. To identify potential interaction partners of the enzyme, quantitative mass spectrometry using stable isotope labeling of cells was combined with formaldehyde cross-linking and proximity biotinylation, respectively. Besides other enzymes involved in sphingolipid synthesis and intermembrane transfer of ceramide, and putative redox partners of FA2H, progesterone receptor membrane component-1 (PGRMC1) and PGRMC2 were identified as putative interaction partners. These two related heme-binding proteins are known to regulate several cytochrome P450 enzymes. Bimolecular fluorescence complementation experiments confirmed the interaction of FA2H with PGRMC1. Moreover, the PGRMC1 inhibitor AG-205 significantly reduced synthesis of hydroxylated ceramide and glucosylceramide in FA2H-expressing cells. This suggests that PGRMC1 may regulate FA2H activity, possibly through its heme chaperone activity. PMID- 29438994 TI - DRUID: a pipeline for transcriptome-wide measurements of mRNA stability. AB - Control of messenger RNA (mRNA) stability is an important aspect of gene regulation. The gold standard for measuring mRNA stability transcriptome-wide uses metabolic labeling, biochemical isolation of labeled RNA populations, and high-throughput sequencing. However, difficult normalization procedures have inhibited widespread adoption of this approach. Here, we present DRUID (for determination of rates using intron dynamics), a new computational pipeline that is robust, easy to use, and freely available. Our pipeline uses endogenous introns to normalize time course data and yields reproducible half-lives, even with data sets that were otherwise unusable. DRUID can handle data sets from a variety of organisms, spanning yeast to humans, and we even applied it retroactively on published data sets. We anticipate that DRUID will allow broad application of metabolic labeling for studies of transcript stability. PMID- 29438995 TI - Genomic Context Analysis of de Novo STXBP1 Mutations Identifies Evidence of Splice Site DNA-Motif Associated Hotspots. AB - Mutations within STXBP1 have been associated with a range of neurodevelopmental disorders implicating the pleotropic impact of this gene. Although the frequency of de novo mutations within STXBP1 for selective cohorts with early onset epileptic encephalopathy is more than 1%, there is no evidence for a hotspot within the gene. In this study, we analyzed the genomic context of de novo STXBP1 mutations to examine whether certain motifs indicated a greater risk of mutation. Through a comprehensive context analysis of 136 de novo/rare mutation (SNV/Indels) sites in this gene, strikingly 26.92% of all SNV mutations occurred within 5bp upstream or downstream of a 'GTA' motif (P < 0.0005). This implies a genomic context modulated mutagenesis. Moreover, 51.85% (14 out of 27) of the 'GTA' mutations are splicing compared to 14.70% (20 out of 136) of all reported mutations within STXBP1 We also noted that 11 of these 14 'GTA' associated mutations are de novo in origin. Our analysis provides strong evidence of DNA motif modulated mutagenesis for STXBP1 de novo splicing mutations. PMID- 29438997 TI - Doxorubicin-induced DNA Damage Causes Extensive Ubiquitination of Ribosomal Proteins Associated with a Decrease in Protein Translation. AB - Protein posttranslational modifications (PTMs) play a central role in the DNA damage response. In particular, protein phosphorylation and ubiquitination have been shown to be essential in the signaling cascade that coordinates break repair with cell cycle progression. Here, we performed whole-cell quantitative proteomics to identify global changes in protein ubiquitination that are induced by DNA double-strand breaks. In total, we quantified more than 9,400 ubiquitin sites and found that the relative abundance of ~10% of these sites was altered in response to DNA double-strand breaks. Interestingly, a large proportion of ribosomal proteins, including those from the 40S as well as the 60S subunit, were ubiquitinated in response to DNA damage. In parallel, we discovered that DNA damage leads to the inhibition of ribosome function. Taken together, these data uncover the ribosome as a major target of the DNA damage response. PMID- 29438996 TI - Global Identification of Small Ubiquitin-related Modifier (SUMO) Substrates Reveals Crosstalk between SUMOylation and Phosphorylation Promotes Cell Migration. AB - Proteomics studies have revealed that SUMOylation is a widely used post translational modification (PTM) in eukaryotes. However, how SUMO E1/2/3 complexes use different SUMO isoforms and recognize substrates remains largely unknown. Using a human proteome microarray-based activity screen, we identified over 2500 proteins that undergo SUMO E3-dependent SUMOylation. We next constructed a SUMO isoform- and E3 ligase-dependent enzyme-substrate relationship network. Protein kinases were significantly enriched among SUMOylation substrates, suggesting crosstalk between phosphorylation and SUMOylation. Cell based analyses of tyrosine kinase, PYK2, revealed that SUMOylation at four lysine residues promoted PYK2 autophosphorylation at tyrosine 402, which in turn enhanced its interaction with SRC and full activation of the SRC-PYK2 complex. SUMOylation on WT but not the 4KR mutant of PYK2 further elevated phosphorylation of the downstream components in the focal adhesion pathway, such as paxillin and Erk1/2, leading to significantly enhanced cell migration during wound healing. These studies illustrate how our SUMO E3 ligase-substrate network can be used to explore crosstalk between SUMOylation and other PTMs in many biological processes. PMID- 29438998 TI - Hydroxychloroquine: A Physiologically-Based Pharmacokinetic Model in the Context of Cancer-Related Autophagy Modulation. AB - Hydroxychloroquine (HCQ) is a lysosomotropic autophagy inhibitor being used in over 50 clinical trials either alone or in combination with chemotherapy. Pharmacokinetic (PK) and pharmacodynamic (PD) studies with HCQ have shown that drug exposure in the blood does not correlate with autophagy inhibition in either peripheral blood mononuclear cells or tumor tissue. To better explain this PK/PD disconnect, a PBPK was developed for HCQ describing the tissue-specific absorption, distribution, metabolism, and excretion as well as lysosome-specific sequestration. Using physiologic and biochemical parameters derived from literature or obtained experimentally, the model was first developed and validated in mice, and then adapted to simulate human HCQ exposure in whole blood and urine through allometric scaling and species-specific parameter modification. The human model accurately simulated average steady-state concentrations (Css) of those observed in five different HCQ combination clinical trials across seven different doses, which was then expanded by comparison of the Css distribution in a virtual human population at this range of doses. Value of this model lies in its ability to simulate HCQ PK in patients while accounting for PK modification by combination treatment modalities, drug concentrations at the active site in the lysosome under varying pH conditions, and exposure in tissues where toxicity is observed. PMID- 29438999 TI - Characteristics of Single-Loop Macroreentrant Biatrial Tachycardia Diagnosed by Ultrahigh-Resolution Mapping System. AB - BACKGROUND: Biatrial tachycardia (BiAT) is a rare form of atrial macroreentrant tachycardia, in which both atria form a critical part of the circuit. We aimed to identify the characteristics and precise circuits of single-loop macroreentrant BiATs. METHODS AND RESULTS: We identified 8 patients (median age, 59.5 years old) with 9 BiATs in a cohort of 336 consecutive patients from 2 institutions who had undergone AT catheter ablation using an automatic ultrahigh-resolution mapping system. Seven of the 8 patients had a history of persistent AF ablation, including septal or anterior left atrium ablation before developing BiAT. One of the 8 patients had a history of an atrial septal patch closure with a massively enlarged right atrium. Nine ATs (median cycle length, 334 ms; median 12 561 points in the left atrium; 8814 points in the right atrium) were diagnosed as single-loop macroreentrant BiATs. We observed 3 types of BiAT (1) BiAT with a perimitral and peritricuspid reentrant circuit (n=3), (2) BiAT using the right atrium septum and a perimitral circuit (n=3), and (3) BiAT using only the left atrium and right atrium septum (n=3). Catheter ablation successfully terminated 8 of the 9 BiATs. CONCLUSIONS: All patients who developed BiAT had an electric obstacle on the anteroseptal left atrium, primarily from prior ablation lesions. In this situation, mapping of both atria should be considered during AT. Because 3 types of single-loop BiAT were observed, ablation strategies should be adjusted to the type of BiAT circuit. PMID- 29439000 TI - Endo-/Epicardial Catheter Ablation of Atrial Fibrillation: Feasibility, Outcome, and Insights Into Arrhythmia Mechanisms. AB - BACKGROUND: Until today, catheter interventional mapping and ablation of atrial fibrillation (AF) has been limited to the right and left atrial endocardium. We report feasibility, electrophysiological findings, and clinical outcome using a combined endo-/epicardial catheter approach for mapping and ablation of AF. METHODS AND RESULTS: Fifty-nine patients with permanence of pulmonary vein isolation and further symptomatic recurrences of paroxysmal AF, persistent AF, or atrial tachycardia underwent reablation using biatrial endo-/epicardial mapping and ablation. Identification of arrhythmia substrates and selection of ablation strategy were based on sinus rhythm voltage mapping. Using continuous monitoring and a 3-month blanking period, freedom from AF/atrial tachycardia >=2 minutes was defined as primary end point. In all patients, endo-/epicardial mapping and ablation was feasible using standard technologies of catheter access, 3 dimensional mapping, and radiofrequency ablation. Epicardial mapping and ablation did not add procedural risks. Exclusively epicardial low voltage substrates were found in 14% of the patients. For the first time, novel epicardial conduction abnormalities located in the epicardial fiber network were described in human AF patients (19% of the cohort). Epicardial ablation was needed in 80% of the patients. Over 23+/-10 months of follow-up freedom from arrhythmia recurrences measured 73%. CONCLUSIONS: Catheter-based endo-/epicardial mapping and ablation of AF was feasible and safe. Epicardial mapping provided new insights into AF mechanisms. Epicardial ablation increased transmurality of ablation lesions. Clinical outcome in this cohort of complex AF patients was favorable, indicating potential further development of current AF treatment. PMID- 29439001 TI - The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non-cell autonomous mechanisms. AB - Developmental genes contribute to cancer, as reported for the homeobox gene Cdx2 playing a tumor suppressor role in the gut. In this study, we show that human colon cancers exhibiting the highest reduction in CDX2 expression belong to the serrated subtype with the worst evolution. In mice, mosaic knockout of Cdx2 in the adult intestinal epithelium induces the formation of imperfect gastric-type metaplastic lesions. The metaplastic knockout cells do not spontaneously become tumorigenic. However, they induce profound modifications of the microenvironment that facilitate the tumorigenic evolution of adjacent Cdx2-intact tumor-prone cells at the surface of the lesions through NF-kappaB activation, induction of inducible nitric oxide synthase, and stochastic loss of function of Apc This study presents a novel paradigm in that metaplastic cells, generally considered as precancerous, can induce tumorigenesis from neighboring nonmetaplastic cells without themselves becoming cancerous. It unveils the novel property of non-cell autonomous tumor suppressor gene for the Cdx2 gene in the gut. PMID- 29439002 TI - Cost analysis of the CTLB Study, a multitherapy antenatal education programme to reduce routine interventions in labour. AB - OBJECTIVE: To assess whether the multitherapy antenatal education 'CTLB' (Complementary Therapies for Labour and Birth) Study programme leads to net cost savings. DESIGN: Cost analysis of the CTLB Study, using analysis of outcomes and hospital funding data. METHODS: We take a payer perspective and use Australian Refined Diagnosis-Related Group (AR-DRG) cost data to estimate the potential savings per woman to the payer (government or private insurer). We consider scenarios in which the intervention cost is either borne by the woman or by the payer. Savings are computed as the difference in total cost between the control group and the study group. RESULTS: If the cost of the intervention is not borne by the payer, the average saving to the payer was calculated to be $A808 per woman. If the payer covers the cost of the programme, this figure reduces to $A659 since the average cost of delivering the programme was $A149 per woman. All these findings are significant at the 95% confidence level. Significantly more women in the study group experienced a normal vaginal birth, and significantly fewer women in the study group experienced a caesarean section. The main cost saving resulted from the reduced rate of caesarean section in the study group. CONCLUSION: The CTLB antenatal education programme leads to significant savings to payers that come from reduced use of hospital resources. Depending on which perspective is considered, and who is responsible for covering the cost of the programme, the net savings vary from $A659 to $A808 per woman. Compared with the average cost of birth in the control group, we conclude that the programme could lead to a reduction in birth-related healthcare costs of approximately 9%. TRIAL REGISTRATION NUMBER: ACTRN12611001126909. PMID- 29439004 TI - Assessing the nutrient intake of a low-carbohydrate, high-fat (LCHF) diet: a hypothetical case study design. AB - OBJECTIVE: The low-carbohydrate, high-fat (LCHF) diet is becoming increasingly employed in clinical dietetic practice as a means to manage many health-related conditions. Yet, it continues to remain contentious in nutrition circles due to a belief that the diet is devoid of nutrients and concern around its saturated fat content. This work aimed to assess the micronutrient intake of the LCHF diet under two conditions of saturated fat thresholds. DESIGN: In this descriptive study, two LCHF meal plans were designed for two hypothetical cases representing the average Australian male and female weight-stable adult. National documented heights, a body mass index of 22.5 to establish weight and a 1.6 activity factor were used to estimate total energy intake using the Schofield equation. Carbohydrate was limited to <130 g, protein was set at 15%-25% of total energy and fat supplied the remaining calories. One version of the diet aligned with the national saturated fat guideline threshold of <10% of total energy and the other included saturated fat ad libitum. PRIMARY OUTCOMES: The primary outcomes included all micronutrients, which were assessed using FoodWorks dietary analysis software against national Australian/New Zealand nutrient reference value (NRV) thresholds. RESULTS: All of the meal plans exceeded the minimum NRV thresholds, apart from iron in the female meal plans, which achieved 86%-98% of the threshold. Saturated fat intake was logistically unable to be reduced below the 10% threshold for the male plan but exceeded the threshold by 2 g (0.6%). CONCLUSION: Despite macronutrient proportions not aligning with current national dietary guidelines, a well-planned LCHF meal plan can be considered micronutrient replete. This is an important finding for health professionals, consumers and critics of LCHF nutrition, as it dispels the myth that these diets are suboptimal in their micronutrient supply. As with any diet, for optimal nutrient achievement, meals need to be well formulated. PMID- 29439006 TI - 'Reversing type 2 diabetes starts with ignoring the guidelines': education from Dr Sarah Hallberg's TEDx talk. PMID- 29439007 TI - Rise of a new superpower: health and China's global trade ambitions. PMID- 29439003 TI - Impact of red and processed meat and fibre intake on treatment outcomes among patients with chronic inflammatory diseases: protocol for a prospective cohort study of prognostic factors and personalised medicine. AB - INTRODUCTION: Chronic inflammatory diseases (CIDs) are frequently treated with biological medications, specifically tumour necrosis factor inhibitors (TNFi)). These medications inhibit the pro-inflammatory molecule TNF alpha, which has been strongly implicated in the aetiology of these diseases. Up to one-third of patients do not, however, respond to biologics, and lifestyle factors are assumed to affect treatment outcomes. Little is known about the effects of dietary lifestyle as a prognostic factor that may enable personalised medicine. The primary outcome of this multidisciplinary collaborative study will be to identify dietary lifestyle factors that support optimal treatment outcomes. METHODS AND ANALYSIS: This prospective cohort study will enrol 320 patients with CID who are prescribed a TNFi between June 2017 and March 2019. Included among the patients with CID will be patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis), rheumatic disorders (rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis), inflammatory skin diseases (psoriasis, hidradenitis suppurativa) and non-infectious uveitis. At baseline (pretreatment), patient characteristics will be assessed using patient-reported outcome measures, clinical assessments of disease activity, quality of life and lifestyle, in addition to registry data on comorbidity and concomitant medication(s). In accordance with current Danish standards, follow-up will be conducted 14-16 weeks after treatment initiation. For each disease, evaluation of successful treatment response will be based on established primary and secondary endpoints, including disease-specific core outcome sets. The major outcome of the analyses will be to detect variability in treatment effectiveness between patients with different lifestyle characteristics. ETHICS AND DISSEMINATION: The principle goal of this project is to improve the quality of life of patients suffering from CID by providing evidence to support dietary and other lifestyle recommendations that may improve clinical outcomes. The study is approved by the Ethics Committee (S 20160124) and the Danish Data Protecting Agency (2008-58-035). Study findings will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences. TRIAL REGISTRATION NUMBER: NCT03173144; Pre-results. PMID- 29439005 TI - Randomised controlled trial using a theory-based m-health intervention to improve physical activity and sleep health in adults: the Synergy Study protocol. AB - INTRODUCTION: There is a need to reduce physical inactivity and poor sleep health in the adult population to decrease chronic disease rates and the associated burden. Given the high prevalence of these risk behaviours, effective interventions with potential for wide reach are warranted. METHODS AND ANALYSIS: The aim of this two-arm RCT will be to test the effect of a three month personalised mobile app intervention on two main outcomes: minutes of moderate-to vigorous-intensity physical activity and overall sleep quality. In addition, between-group changes in health-related quality of life and mental health status will be assessed as secondary outcomes. The pre-specified mediators and moderators include social cognitive factors, the neighbourhood environment, health (BMI, depression, anxiety, stress), sociodemographic factors (age, gender, education) and app usage. Assessments will be conducted after three months (primary endpoint) and six months (follow-up). The intervention will provide access to a specifically developed mobile app, through which participants can set goals for active minutes, daily step counts, resistance training, sleep times and sleep hygiene practice. The app also allows participants to log their behaviours daily and view progress bars as well as instant feedback in relation to goals. The personalised support system will consist of weekly summary reports, educational and instructional materials, prompts on disengagement and weekly facts. ETHICS AND DISSEMINATION: The Human Research Ethics Committee of The University of Newcastle, Australia granted full approval: H-2016-0181. This study will assess the efficacy of a combined behaviour intervention, mechanisms of behaviour change and gather high-quality process data, all of which will help refine future trials. Dissemination of findings will include publication in a peer-reviewed journal and presentation at national or international conferences. Participants will receive a plain English summary report of results. TRIAL REGISTRATION NUMBER: ACTRN12617000376347; Pre-results. PMID- 29439008 TI - PD-1 and PD-L1 expression in thymic epithelial tumours and non-neoplastic thymus. AB - AIMS: We explored the relationships between programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression and the pathological and clinical features of thymic epithelial tumours and thymic hyperplasia. METHODS: We evaluated PD-1 and PDL-1 expressions within epithelial and microenvironmental components in thymic epithelial tumours (n=44) and thymic hyperplasias (n=8), immunohistochemically. We compared the results with demographic, clinical and histopathological features of the cases. RESULTS: We found 48% epithelial expression and 82.7% microenvironment expression for PD-1 and 11.5% epithelial expression and 34.6% microenvironment expression for PD-L1. There was no PD-1 expression, in either the epithelial or microenvironment, in the thymic hyperplasia group. PD-1 and PD-L1 positivity was more significant in thymic epithelial tumours than thymic hyperplasia. Patients with PD-1-positive microenvironments exhibited significantly shorter mean estimated survival time than their negative counterparts. CONCLUSION: These findings suggest that anti-PD 1 and anti-PD-L1 therapies may benefit patients due to high release of PD-1 and PD-L1 in thymic epithelial tumours. PMID- 29439009 TI - HER2 testing of gastro-oesophageal adenocarcinoma: a commentary and guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Committee. AB - The use of biologics targeted to the human epidermal growth factor receptor 2 (HER2) protein is the latest addition to the armamentarium used to fight advanced gastric or gastro-oesophageal junction adenocarcinoma. The decision to treat with the biologic trastuzumab is completely dependent on HER2 testing of tumour tissue. In 2017, the College of American Pathologists, American Society for Clinical Pathology and the American Society of Clinical Oncology jointly published guidelines for HER2 testing and clinical decision making in gastro oesophageal adenocarcinoma. The Association of Clinical Pathologists Molecular Pathology and Diagnostics Committee has issued the following document as a commentary of these guidelines and, in parallel, to provide guidance on HER2 testing in National Health Service pathology departments within the UK. This guidance covers issues related to case selection, preanalytical aspects, analysis and interpretation of such HER2 testing. PMID- 29439010 TI - Breast Cancer Blood Flow and Metabolism on Dual-Acquisition 18F-FDG PET: Correlation with Tumor Phenotype and Neoadjuvant Chemotherapy Response. AB - Early changes in tumor glucose metabolism (SUVmax) and in tumor blood flow (BF) have been evaluated separately for monitoring breast cancer response to neoadjuvant chemotherapy (NAC). This study used a single 18F-FDG dual-acquisition PET examination to simultaneously assess these two imaging features and to determine whether they correlate with the same pretherapy tumor phenotypic features and whether they are comparable or complementary in predicting pathologic complete response (pCR). Methods: This prospective study included 150 women with breast cancer and an indication for NAC. A 2-min chest-centered dynamic PET acquisition was performed at the time of 18F-FDG injection, followed by a delayed static PET acquisition 90 min later. Tumor BF was calculated from the dynamic acquisition using a validated first-pass model, and tumor SUVmax was calculated from the delayed acquisition. This dual acquisition was repeated after the first cycle of NAC to measure early changes in tumor BF and SUVmaxResults: A weak correlation was found between SUVmax and BF at baseline (r = 0.22; P = 0.006). A high baseline SUVmax was associated with all biologic markers of tumor aggressiveness, including the triple-negative breast cancer subtype (P < 0.0001). In contrast, a high baseline BF was associated only with obesity (P = 0.002). The change in SUVmax (mean, -44.6% +/- 27.4%) varied depending on the Scarff-Bloom Richardson grade, overexpression of human epidermal growth factor receptor 2 (HER2-positive), and lack of hormone receptor expression (P = 0.04, P < 0.001, and P = 0.01, respectively). BF (mean change, -26.9% +/- 54.3%) showed a drastic reduction only in HER2-positive subtypes (-58.7% +/- 30.0%), supporting the antiangiogenic effect of trastuzumab. Changes in SUVmax outperformed changes in BF for predicting pCR in all tumor subtypes: the areas under the curve for change in SUVmax were 0.82, 0.65, and 0.90 in the triple-negative, HER2-positive, and luminal subtypes, respectively. Conclusion: Of the two biologic hallmarks of cancer evaluated in this study, a reduction in tumor glucose metabolism was more accurate than a reduction in tumor BF for predicting pCR in the different subtypes of breast cancer. PMID- 29439011 TI - Measurement of Brown Adipose Tissue Activity Using Microwave Radiometry and 18F FDG PET/CT. AB - The aim of this study was to evaluate the operating characteristics of a microwave radiometry system in the noninvasive assessment of activated and nonactivated brown adipose tissue (BAT) and normal-tissue temperatures, reflecting metabolic activity in healthy human subjects. The radiometry data were compared with 18F-FDG PET/CT images in the same subjects. Methods: Microwave radiometry and 18F-FDG PET/CT were sequentially performed on 19 participants who underwent a cold intervention to maximize BAT activation. The cold intervention involved the participants' intermittently placing their feet on an ice block while sitting in a cool room. Participants exhibiting BAT activity qualitatively on PET/CT were scanned again with both modalities after undergoing a BAT minimization protocol (exposure to a warm room and a 20-mg dose of propranolol). Radiometry was performed every 5 min for 2 h before PET/CT imaging during both the warm and the cold interventions. A grid of 15-20 points was drawn on the participant's upper body (data were collected at each point), and a photograph was taken for comparison with PET/CT images. Results: PET/CT identified increased signal consistent with BAT activity in 11 of 19 participants. In 10 of 11 participants with active BAT, radiometry measurements collected during the cold study were modestly, but significantly, higher on points located over areas of active BAT on PET/CT than on points not exhibiting BAT activity (P < 0.01). This difference lessened during the warm studies: 7 of 11 participants showed radiometry measurements that did not differ significantly between the same set of points. The mean radiometry result collected during BAT maximization was 33.2 degrees C +/- 1.5 degrees C at points designated as active and 32.7 degrees C +/- 1.3 degrees C at points designated as inactive (P < 0.01). Conclusion: Passive microwave radiometry was shown to be feasible and, with substantial improvements, has the potential to noninvasively detect active brown adipose tissue without a radiotracer injection. PMID- 29439012 TI - Immediate Postablation 18F-FDG Injection and Corresponding SUV Are Surrogate Biomarkers of Local Tumor Progression After Thermal Ablation of Colorectal Carcinoma Liver Metastases. AB - The aim of this study was to determine whether intraprocedural 18F-FDG PET/CT can be used as a predictor of local tumor progression after percutaneous ablation of colorectal liver metastases. Methods: In this institutional review board-approved prospective study, 39 patients (19 men and 20 women; median age, 56 y) underwent split-dose 18F-FDG PET/CT-guided ablation followed by immediate biopsy and contrast-enhanced CT imaging of the ablation zone. Binary categorization of biopsy tissues was performed on the basis of the presence of only nonviable coagulation necrosis or viable tumor cells. Minimum ablation margin measurements from contrast-enhanced CT imaging were categorized as 0 mm, 1-4 mm, 5-9 mm, or greater than or equal to 10 mm. SUVs were obtained from PET/CT imaging, and SUV ratios were calculated from 3-dimensional regions of interest located in the ablation zone and surrounding normal liver. All predictive variables (biopsy, minimum margin distance, and SUV ratio) were evaluated as predictors of time to local tumor progression identified on imaging using competing-risks regression models (uni- and multivariate analyses). Results: A total of 62 consecutive ablations were evaluated. The mean SUV ratio was significantly higher for viable tumor-positive immediate postablation biopsies (n = 10) than for tumor-negative biopsies (n = 52) (85.8 +/- 92.2 vs. 42.3 +/- 45.5) (P = 0.03) and for a minimum margin size of less than 5 mm (n = 15) than for a minimum margin size of greater than or equal to 5 mm (n = 47) (78.5 +/- 99.1 vs. 38.3 +/- 78.5) (P = 0.01). After a median follow-up period of 22.5 (range, 7-52) months, 23 of 62 ablated tumors showed local tumor progression (37.1%). The local tumor progression rate was significantly higher for viable tumor-positive biopsies (8/10) than for negative biopsies (15/52) (80% vs. 29%) (P = 0.001) and for a minimum margin size of less than 5 mm (9/15) than for a minimum margin size of greater than or equal to 10 mm (2/15) (60% vs. 13%) (P = 0.02) but not 5-9 mm (37.5%; 12/32) (P = 0.5). In a competing-risks analysis, biopsy results (P = 0.07) and the minimum margin size (P = 0.08) were borderline significant, but the SUV ratio was not (P = 0.22). However, for negative biopsy ablations, the minimum margin size and SUV ratio were predictive imaging factors for local tumor progression; subdistribution hazard ratios were 0.564 (0.325-0.978) (P = 0.04) and 1.005 (1.001-1.009) (P = 0.005), respectively. Conclusion: The SUV ratio and minimum margin size can independently predict colorectal metastasis local tumor progression after liver ablation when there are no viable tumor cells on immediate postablation biopsies. PMID- 29439013 TI - Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid-Mediated Pretargeting: In Vivo Proof of Principle. AB - Affibody molecules are small proteins engineered using a nonantibody scaffold. Radiolabeled Affibody molecules are excellent imaging probes, but their application to radionuclide therapy has been prevented by high renal reabsorption. The aim of this study was to test the hypothesis that Affibody based peptide nucleic acid (PNA)-mediated pretargeted therapy of human epidermal growth factor receptor 2 (HER2)-expressing cancer extends survival without accompanying renal toxicity. Methods: A HER2-targeting Affibody molecule ligated with an AGTCGTGATGTAGTC PNA hybridization probe (ZHER2:342-SR-HP1) was used as the primary pretargeting agent. A complementary AGTCGTGATGTAGTC PNA conjugated to the chelator DOTA and labeled with the radionuclide 177Lu (177Lu-HP2) was used as the secondary agent. The influence of different factors on pretargeting was investigated. Experimental radionuclide therapy in mice bearing SKOV-3 xenografts was performed in 6 cycles separated by 7 d. Results: Optimal tumor targeting was achieved when 16 MBq/3.5 MUg (0.65 nmol) of 177Lu-HP2 was injected 16 h after injection of 100 MUg (7.7 nmol) of ZHER2:342-SR-HP1. The calculated absorbed dose to tumors was 1,075 mGy/MBq, whereas the absorbed dose to kidneys was 206 mGy/MBq and the absorbed dose to blood (surrogate of bone marrow) was 4 mGy/MBq. Survival of mice was significantly longer (P < 0.05) in the treatment group (66 d) than in the control groups treated with the same amount of ZHER2:342-SR-HP1 only (37 d), the same amount and activity of 177Lu-HP2 only (32 d), or phosphate-buffered saline (37 d). Conclusion: The studied pretargeting system can deliver an absorbed dose to tumors appreciably exceeding absorbed doses to critical organs, making Affibody-based PNA-mediated pretargeted radionuclide therapy highly attractive. PMID- 29439014 TI - Reply: Cerebrospinal Fluid, Hyposmia, and Dementia in Alzheimer Disease: Insights from Dynamic PET and a Hypothesis. PMID- 29439015 TI - Respiratory Motion Compensation for PET/CT with Motion Information Derived from Matched Attenuation-Corrected Gated PET Data. AB - Respiratory motion degrades the detection and quantification capabilities of PET/CT imaging. Moreover, mismatch between a fast helical CT image and a time averaged PET image due to respiratory motion results in additional attenuation correction artifacts and inaccurate localization. Current motion compensation approaches typically have 3 limitations: the mismatch among respiration-gated PET images and the CT attenuation correction (CTAC) map can introduce artifacts in the gated PET reconstructions that can subsequently affect the accuracy of the motion estimation; sinogram-based correction approaches do not correct for intragate motion due to intracycle and intercycle breathing variations; and the mismatch between the PET motion compensation reference gate and the CT image can cause an additional CT-mismatch artifact. In this study, we established a motion correction framework to address these limitations. Methods: In the proposed framework, the combined emission-transmission reconstruction algorithm was used for phase-matched gated PET reconstructions to facilitate the motion model building. An event-by-event nonrigid respiratory motion compensation method with correlations between internal organ motion and external respiratory signals was used to correct both intracycle and intercycle breathing variations. The PET reference gate was automatically determined by a newly proposed CT-matching algorithm. We applied the new framework to 13 human datasets with 3 different radiotracers and 323 lesions and compared its performance with CTAC and non attenuation correction (NAC) approaches. Validation using 4-dimensional CT was performed for one lung cancer dataset. Results: For the 10 18F-FDG studies, the proposed method outperformed (P < 0.006) both the CTAC and the NAC methods in terms of region-of-interest-based SUVmean, SUVmax, and SUV ratio improvements over no motion correction (SUVmean: 19.9% vs. 14.0% vs. 13.2%; SUVmax: 15.5% vs. 10.8% vs. 10.6%; SUV ratio: 24.1% vs. 17.6% vs. 16.2%, for the proposed, CTAC, and NAC methods, respectively). The proposed method increased SUV ratios over no motion correction for 94.4% of lesions, compared with 84.8% and 86.4% using the CTAC and NAC methods, respectively. For the 2 18F-fluoropropyl-(+) dihydrotetrabenazine studies, the proposed method reduced the CT-mismatch artifacts in the lower lung where the CTAC approach failed and maintained the quantification accuracy of bone marrow where the NAC approach failed. For the 18F FMISO study, the proposed method outperformed both the CTAC and the NAC methods in terms of motion estimation accuracy at 2 lung lesion locations. Conclusion: The proposed PET/CT respiratory event-by-event motion-correction framework with motion information derived from matched attenuation-corrected PET data provides image quality superior to that of the CTAC and NAC methods for multiple tracers. PMID- 29439016 TI - PSMA-Targeted Radionuclide Therapy and Salivary Gland Toxicity: Why Does It Matter? PMID- 29439017 TI - Comparative Dosimetry for 68Ga-DOTATATE: Impact of Using Updated ICRP Phantoms, S Values, and Tissue-Weighting Factors. AB - The data that have been used in almost all calculations of MIRD S value absorbed dose and effective dose are based on stylized anatomic computational phantoms and tissue-weighting factors adopted by the International Commission on Radiological Protection (ICRP) in its publication 60. The more anatomically realistic phantoms that have recently become available are likely to provide more accurate effective doses for diagnostic agents. 68Ga-DOTATATE is a radiolabeled somatostatin analog that binds with high affinity to somatostatin receptors, which are overexpressed in neuroendocrine tumors and can be used for diagnostic PET/CT-based imaging. Several studies have reported effective doses for 68Ga-DOTATATE using the stylized Cristy-Eckerman (CE) phantoms from 1987; here, we present effective dose calculations using both the ICRP 60 and more updated formalisms. Methods: Whole body PET/CT scans were acquired for 16 patients after 68Ga-DOTATATE administration. Contours were drawn on the CT images for spleen, liver, kidneys, adrenal glands, brain, heart, lungs, thyroid gland, salivary glands, testes, red marrow (L1-L5), muscle (right thigh), and whole body. Dosimetric calculations were based on the CE phantoms and the more recent ICRP 110 reference-voxel phantoms. Tissue-weighting factors from ICRP 60 and ICRP 103 were used in effective dose calculations for the CE phantoms and ICRP 110 phantoms, respectively. Results: The highest absorbed dose coefficients (absorbed dose per unit activity) were, in descending order, in the spleen, pituitary gland, kidneys, adrenal glands, and liver. For ICRP 110 phantoms with tissue-weighting factors from ICRP 103, the effective dose coefficient was 0.023 +/- 0.003 mSv/MBq, which was significantly lower than the 0.027 +/- 0.005 mSv/MBq calculated for CE phantoms with tissue-weighting factors from ICRP 60. One of the largest differences in estimated absorbed dose coefficients was for the urinary bladder wall, at 0.040 +/- 0.011 mGy/MBq for ICRP 110 phantoms compared with 0.090 +/- 0.032 mGy/MBq for CE phantoms. Conclusion: This study showed that the effective dose coefficient was slightly overestimated for CE phantoms, compared with ICRP 110 phantoms using the latest tissue-weighting factors from ICRP 103. The more detailed handling of electron transport in the latest phantom calculations gives significant differences in estimates of the absorbed dose to stem cells in the walled organs of the alimentary tract. PMID- 29439018 TI - Xpert MTB/RIF as add-on test to microscopy in a low tuberculosis incidence setting. PMID- 29439019 TI - Haemodynamics to predict outcome in pulmonary hypertension due to left heart disease: a meta-analysis. PMID- 29439021 TI - Are inhaled corticosteroids prescribed rationally in primary ciliary dyskinesia? PMID- 29439022 TI - Comparison of different staging methods for COPD in predicting outcomes. AB - Chronic obstructive pulmonary disease (COPD) is commonly staged according to the percentage of predicted forced expiratory volume in 1 s (FEV1 % pred), but other methods have been proposed. In this study we compared the performance of seven staging methods in predicting outcomes.We retrospectively studied 296 COPD outpatients. For each patient the disease severity was staged by separately applying the following methods: the criteria proposed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), quartiles of FEV1 % pred and z-score of FEV1, quartiles and specified cut-off points of the ratio of FEV1 over height squared ((FEV1.Ht-2)A and (FEV1.Ht-2)B, respectively), and quartiles of the ratio of FEV1 over height cubed (FEV1.Ht-3) and of FEV1 quotient (FEV1Q). We evaluated the performance of these methods in predicting the risks of severe acute exacerbation and all-cause mortality.Overall, staging based on the reference independent FEV1Q performed best in predicting the risks of severe acute exacerbation (including frequent exacerbation) and mortality, followed by (FEV1.Ht-2)B The performance of staging methods could also be influenced by the choice of cut-off values. Future work using large and ethnically diverse populations to refine and validate the cut-off values would enhance the prediction of outcomes. PMID- 29439020 TI - Impact of immunosuppression on incidence, aetiology and outcome of ventilator associated lower respiratory tract infections. AB - The aim of this planned analysis of the prospective multinational TAVeM database was to determine the incidence, aetiology and impact on outcome of ventilator associated lower respiratory tract infections (VA-LRTI) in immunocompromised patients.All patients receiving mechanical ventilation for >48 h were included. Immunocompromised patients (n=663) were compared with non-immunocompromised patients (n=2297).The incidence of VA-LRTI was significantly lower among immunocompromised than among non-immunocompromised patients (16.6% versus 24.2%; sub-hazard ratio 0.65, 95% CI 0.53-0.80; p<0.0001). Similar results were found regarding ventilator-associated tracheobronchitis (7.3% versus 11.6%; sub-hazard ratio 0.61, 95% CI 0.45-0.84; p=0.002) and ventilator-associated pneumonia (9.3% versus 12.7%; sub-hazard ratio 0.72, 95% CI 0.54-0.95; p=0.019). Among patients with VA-LRTI, the rates of multidrug-resistant bacteria (72% versus 59%; p=0.011) and intensive care unit mortality were significantly higher among immunocompromised than among non-immunocompromised patients (54% versus 30%; OR 2.68, 95% CI 1.78-4.02; p<0.0001). In patients with ventilator-associated pneumonia, mortality rates were higher among immunocompromised than among non immunocompromised patients (64% versus 34%; p<0.001).Incidence of VA-LRTI was significantly lower among immunocompromised patients, but it was associated with a significantly higher mortality rate. Multidrug-resistant pathogens were more frequently found in immunocompromised patients with VA-LRTI. PMID- 29439023 TI - Hippocampal ripples down-regulate synapses. AB - The specific effects of sleep on synaptic plasticity remain unclear. We report that mouse hippocampal sharp-wave ripple oscillations serve as intrinsic events that trigger long-lasting synaptic depression. Silencing of sharp-wave ripples during slow-wave states prevented the spontaneous down-regulation of net synaptic weights and impaired the learning of new memories. The synaptic down-regulation was dependent on the N-methyl-d-aspartate receptor and selective for a specific input pathway. Thus, our findings are consistent with the role of slow-wave states in refining memory engrams by reducing recent memory-irrelevant neuronal activity and suggest a previously unrecognized function for sharp-wave ripples. PMID- 29439024 TI - Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. AB - Diurnal gene expression patterns underlie time-of-the-day-specific functional specialization of tissues. However, available circadian gene expression atlases of a few organs are largely from nocturnal vertebrates. We report the diurnal transcriptome of 64 tissues, including 22 brain regions, sampled every 2 hours over 24 hours, from the primate Papio anubis (baboon). Genomic transcription was highly rhythmic, with up to 81.7% of protein-coding genes showing daily rhythms in expression. In addition to tissue-specific gene expression, the rhythmic transcriptome imparts another layer of functional specialization. Most ubiquitously expressed genes that participate in essential cellular functions exhibit rhythmic expression in a tissue-specific manner. The peak phases of rhythmic gene expression clustered around dawn and dusk, with a "quiescent period" during early night. Our findings also unveil a different temporal organization of central and peripheral tissues between diurnal and nocturnal animals. PMID- 29439025 TI - Thermal proximity coaggregation for system-wide profiling of protein complex dynamics in cells. AB - Proteins differentially interact with each other across cellular states and conditions, but an efficient proteome-wide strategy to monitor them is lacking. We report the application of thermal proximity coaggregation (TPCA) for high throughput intracellular monitoring of protein complex dynamics. Significant TPCA signatures observed among well-validated protein-protein interactions correlate positively with interaction stoichiometry and are statistically observable in more than 350 annotated human protein complexes. Using TPCA, we identified many complexes without detectable differential protein expression, including chromatin associated complexes, modulated in S phase of the cell cycle. Comparison of six cell lines by TPCA revealed cell-specific interactions even in fundamental cellular processes. TPCA constitutes an approach for system-wide studies of protein complexes in nonengineered cells and tissues and might be used to identify protein complexes that are modulated in diseases. PMID- 29439027 TI - Phosphoric acid as a precursor to chemicals traditionally synthesized from white phosphorus. AB - White phosphorus, generated in the legacy thermal process for phosphate rock upgrading, has long been the key industrial intermediate for the synthesis of phosphorus-containing chemicals, including herbicides, flame-retardants, catalyst ligands, battery electrolytes, pharmaceuticals, and detergents. In contrast, phosphate fertilizers are made on a much larger scale from phosphoric acid, obtained by treating phosphate rock with sulfuric acid. Dehydration of phosphoric acid using sodium chloride gives trimetaphosphate, and here we report that trichlorosilane, primarily used for the production of high-purity silicon, reduces trimetaphosphate to the previously unknown bis(trichlorosilyl)phosphide anion. This anion offers an entry point to value-added organophosphorus chemicals such as primary and secondary alkyl phosphines, and thus to organophosphinates, and can also be used to prepare phosphine gas and the hexafluorophosphate anion, all previously available only downstream from white phosphorus. PMID- 29439026 TI - Rev-erbalpha dynamically modulates chromatin looping to control circadian gene transcription. AB - Mammalian physiology exhibits 24-hour cyclicity due to circadian rhythms of gene expression controlled by transcription factors that constitute molecular clocks. Core clock transcription factors bind to the genome at enhancer sequences to regulate circadian gene expression, but not all binding sites are equally functional. We found that in mice, circadian gene expression in the liver is controlled by rhythmic chromatin interactions between enhancers and promoters. Rev-erbalpha, a core repressive transcription factor of the clock, opposes functional loop formation between Rev-erbalpha-regulated enhancers and circadian target gene promoters by recruitment of the NCoR-HDAC3 co-repressor complex, histone deacetylation, and eviction of the elongation factor BRD4 and the looping factor MED1. Thus, a repressive arm of the molecular clock operates by rhythmically modulating chromatin loops to control circadian gene transcription. PMID- 29439028 TI - Draft Genome Sequence of Anaerobic Fermentative Bacterium Anaeromicrobium sediminis DY2726D. AB - Here, we report the draft genome sequence of Anaeromicrobium sediminis DY2726D, isolated from a west Pacific Ocean sediment sample. The genome comprises 4,710,590 bp in 56 contigs, with a G+C content of 31.2%. A total of 3,811 protein coding sequences were predicted. The genome annotation revealed that DY2726D may represent a marine type of Clostridiaceae. PMID- 29439029 TI - Complete Genome Sequence of a Recombinant NADC30-Like Strain, SCnj16, of Porcine Reproductive and Respiratory Syndrome Virus in Southwestern China. AB - The NADC30-like strains of porcine reproductive and respiratory syndrome virus (PRRSV) are characterized by a 131-amino-acid deletion in nonstructural protein 2 (NSP2). Here, we report the complete genome sequence of a recombinant NADC30-like PRRSV strain, SCnj16, that exhibits the molecular marker of the Chinese highly pathogenic PRRSV (HP-PRRSV) in NSP2. PMID- 29439030 TI - Near-Complete Genome Sequences of Several New Norovirus Genogroup II Genotypes. AB - We report here the near-complete genome sequences of 13 norovirus strains detected in stool samples from patients with acute gastroenteritis from Bangladesh, Ecuador, Guatemala, Peru, Nicaragua, and the United States that are classified into one existing (genotype II.22 [GII.22]), 3 novel (GII.23, GII.24 and GII.25), and 3 tentative novel (GII.NA1, GII.NA2, and GII.NA3) genotypes. PMID- 29439031 TI - Draft Genome Sequence of the Endophyte Paenibacillus sp. Strain GM2FR Isolated from Festuca rubra. AB - Here, we report the 7.4-Mb draft genome sequence of Paenibacillus sp. strain GM2FR, an endophytic bacterium isolated from aerial plant tissues of Festuca rubra L. Genome analysis revealed 6,652 coding gene sequences and several gene clusters involved in plant growth promotion, such as that for the siderophore bacillibactin. PMID- 29439032 TI - Complete Genome Sequence of the Circular Extrachromosomal Element of Naegleria gruberi Strain EGB Ribosomal DNA. AB - The circular extrachromosomal element of Naegleria gruberi strain EGB was linearized, molecularly cloned, and fully sequenced. The sequence comprises 14,007 bp and encodes the organism's rRNA genes, two potential open reading frames, and numerous repeated sequence regions. PMID- 29439033 TI - Genome Sequence of Serratia marcescens subsp. sakuensis Strain K27, a Marine Bacterium Isolated from Sponge (Haliclona amboinensis). AB - Serratia marcescens subsp. sakuensis strain K27 was isolated from sponge (Haliclona amboinensis). The genome of this strain consists of 5,325,727 bp, with 5,140 open reading frames (ORFs), 3 rRNAs, and 67 tRNAs. It contains genes for the production of amylases, lipases, and proteases. Gene clusters for the biosynthesis of nonribosomal peptides and thiopeptide were also identified. PMID- 29439034 TI - Complete Genome Sequences of Three Fish-Associated Streptococcus agalactiae Isolates. AB - The whole-genome sequences are described here for three group B Streptococcus (GBS) (S. agalactiae) serotype Ib isolates obtained from tilapia (Oreochromis niloticus) farmed at sites in Honduras, Costa Rica, and the United States. The bacteria were isolated from the brains of fish displaying signs of streptococcosis. PMID- 29439035 TI - Draft Genome Sequence of Burkholderia sp. Strain WAC0059, a Bacterium Isolated from the Medicinal Fungus Antrodia cinnamomea. AB - Burkholderia sp. strain WAC0059 was isolated from a fruiting body of the medicinal fungus Antrodia cinnamomea collected in Taiwan. Here, we report the draft genome sequence of this bacterium to facilitate the investigation of its biology. PMID- 29439036 TI - Draft Genome Sequence of an Active Heterotrophic Nitrifier-Denitrifier, Cupriavidus pauculus UM1. AB - Here, we present the draft genome sequence of Cupriavidus pauculus UM1, a metal resistant heterotrophic nitrifier-denitrifier capable of synthesizing nitrite from pyruvic oxime. The size of the genome is 7,402,815 bp with a GC content of 64.8%. This draft assembly consists of 38 scaffolds. PMID- 29439037 TI - Draft Genome Sequence of the Siderophore-Degrading Soil Bacterium Mesorhizobium loti Strain LU. AB - Here, we present the draft genome of Mesorhizobium loti strain LU, a soil bacterium capable of degrading the trihydroxamate siderophore deferrioxamine B to its constituent monohydroxamic acids. Genome size was 6,399,828 bp, with a GC content of 61.5%. This draft genome consists of 35 scaffolds, with an N50 of 389,921 bp. PMID- 29439038 TI - Draft Genome Sequence of a Polymyxin B-Resistant Sequence Type 195 Clinical Isolate of Acinetobacter baumannii from India. AB - Acinetobacter baumannii has emerged as a troublesome nosocomial pathogen worldwide. We report here the draft genome sequence of polymyxin B-resistant sequence type 195 (ST195) A. baumannii strain GU71, isolated from a tertiary care hospital in the city of Guwahati, Assam, India. PMID- 29439039 TI - Complete Genome Sequence of the Myoviral Bacteriophage YS35, Which Causes the Lysis of a Multidrug-Resistant Pseudomonas aeruginosa Strain. AB - The lytic bacteriophage YS35, which is capable of lysing multidrug-resistant Pseudomonas aeruginosa strains, was isolated from a sewage sample. Here, we describe the complete genome sequence of this myoviral bacteriophage, which contains 93,296 bp of double-stranded DNA and has a 49.4% G+C content. PMID- 29439040 TI - Complete Genome Sequence of a Novel Recombinant GII.P16-GII.1 Norovirus Associated with a Gastroenteritis Outbreak in Shandong Province, China, in 2017. AB - We report here the complete genome sequence of a novel recombinant GII.P16-GII.1 norovirus identified from eight fecal samples collected during an acute gastroenteritis outbreak in Jinan, Shandong Province, China, in 2017. The virus had nucleotide identities of 99% and 91% in the ORF1 and ORF2 genes of related strains, respectively. PMID- 29439041 TI - Complete Genome Sequence of the Novel Cellulolytic, Anaerobic, Thermophilic Bacterium Herbivorax saccincola Type Strain GGR1, Isolated from a Lab Scale Biogas Reactor as Established by Illumina and Nanopore MinION Sequencing. AB - The cellulolytic bacterium Herbivorax saccincola strain GGR1, which represents the type strain of this species, was isolated from the in vivo enriched cellulose binding community of a lab scale thermophilic biogas reactor. Here, we report the complete genome sequence of H. saccincola GGR1T, the first isolated member of the genus Herbivorax. PMID- 29439042 TI - Draft Genome Sequence of Bacillus altitudinis Strain KL4, Isolated from Bottom Sediments in Lake Krotovaya Lyaga (Novosibirsk Region, Russia). AB - The Bacillus altitudinis strain KL4 was isolated from bottom sediments in Lake Krotovaya Lyaga (Novosibirsk Region, Russia, 53.7 degrees N, 77.9 degrees E). The sequenced and annotated genome is 3,738,419 bp long and carries 3,909 genes. PMID- 29439043 TI - Complete Genome Sequence of Beak and Feather Disease Virus Isolated from an African Grey Parrot in China in 2017. AB - The complete nucleotide (nt) sequence of beak and feather disease virus (BFDV) was determined. The viral genome consists of 1,991 nt, including an 870-nt open reading frame 1 (ORF1), a 744-nt ORF2, a conserved stem-loop structure, and the second hairpin. This is the first reported detection of BFDV in an infected African grey parrot in China. PMID- 29439044 TI - Draft Genome Sequence of Rhodococcus sp. Strain M8, Which Can Degrade a Broad Range of Nitriles. AB - Rhodococcus sp. strain M8 is a nitrile-degrading bacterium isolated from acrylonitrile-contaminated sites. This strain produces the enzymes for sequential nitrile degradation, cobalt-type nitrile hydratase, and amidase in large amounts. Its draft genome sequence, announced here, has an estimated size of 6.3 Mbp. PMID- 29439045 TI - Draft Whole-Genome Sequences of Zhihengliuella halotolerans La12 and Microbacterium kitamiense Sa12, Strains with Cellulase Activity, Isolated from the Qinghai-Tibetan Plateau. AB - We report the complete genome sequences of cellulolytic strains Zhihengliuella halotolerans La12 and Microbacterium kitamiense Sa12, which were isolated from soil samples collected from the Qinghai-Tibetan Plateau in Western China. The final assemblies of La12 and Sa12 comprise 3,712,694 bp, with over 111 contigs, and 3,830,439 bp, with over 39 contigs, respectively. PMID- 29439046 TI - Draft Genome Sequences of Acinetobacter and Bacillus Strains Isolated from Spacecraft-Associated Surfaces. AB - We report here the draft genome sequences of four strains isolated from spacecraft-associated surfaces exhibiting increased resistance to stressors such as UV radiation and exposure to H2O2 The draft genomes of strains 1P01SCT, FO 92T, 50v1, and 2P01AA had sizes of 5,500,894 bp, 4,699,376 bp, 3,174,402 bp, and 4,328,804 bp, respectively. PMID- 29439047 TI - Genome Sequence of the Necrotrophic Plant Pathogen Alternaria brassicicola Abra43. AB - Alternaria brassicicola causes dark spot (or black spot) disease, which is one of the most common and destructive fungal diseases of Brassicaceae spp. worldwide. Here, we report the draft genome sequence of strain Abra43. The assembly comprises 29 scaffolds, with an N50 value of 2.1 Mb. The assembled genome was 31,036,461 bp in length, with a G+C content of 50.85%. PMID- 29439048 TI - Genomic Sequence of a Swine Pasivirus Type 1 Strain Identified in U.S. Swine. AB - We report for the first time in the United States the identification of a swine pasivirus (SPaV) strain with a genomic sequence identity of less than 80% to other SPaVs reported in Europe and China, using a next-generation sequencing (NGS) technique in sow tissues collected from an animal study conducted in 2001, suggesting virus circulation in domestic swine. PMID- 29439049 TI - Draft Genome Sequence of Endozoicomonas acroporae Strain Acr-14T, Isolated from Acropora Coral. AB - A lacuna exists in our understanding of the genetic makeup of Endozoicomonas bacteria, due to scarcity of genome sequences. We report here the first draft genome sequence of Endozoicomonas acroporae Acr-14, a type strain isolated from the coral Acropora This sequence will foster an understanding of the genetic makeup and role of hosts in shaping gene repertoires. PMID- 29439050 TI - Draft Genome Sequence of Cyanobacterium sp. Strain HL-69, Isolated from a Benthic Microbial Mat from a Magnesium Sulfate-Dominated Hypersaline Lake. AB - The complete genome sequence of Cyanobacterium sp. strain HL-69 consists of 3,155,247 bp and contains 2,897 predicted genes comprising a chromosome and two plasmids. The genome is consistent with a halophilic nondiazotrophic phototrophic lifestyle, and this organism is able to synthesize most B vitamins and produces several secondary metabolites. PMID- 29439051 TI - Complete Genome Sequence of Industrial Dairy Strain Streptococcus thermophilus DGCC 7710. AB - We report here the complete genome sequence of Streptococcus thermophilus DGCC 7710. S. thermophilus is widely used in industrial dairy production. PMID- 29439052 TI - Complete Genome Sequence of a Recombinant Porcine Epidemic Diarrhea Virus Strain, CH/JXJA/2017, Isolated in Jiangxi, China, in 2017. AB - The full-length genome sequence of a variant of porcine epidemic diarrhea virus (PEDV), that of strain CH/JXJA/2017, was highly homologous to CH/ZMDZY/11, a highly virulent Chinese PEDV strain. CH/JXJA/2017 had a distant relationship with the attenuated CV777 vaccine strain, but the insertion sites of the S1 gene were similar to those of the recombinant strain of CH/ZMDZY/11. PMID- 29439053 TI - Complete Genome Sequence of a Human Metapneumovirus Isolate Collected in Brazil. AB - Here, we present the complete genome sequence of a human metapneumovirus isolate collected from a hospitalized infant suffering from acute respiratory disease. This is the first complete genome sequence of human metapneumovirus originating from Brazil. PMID- 29439054 TI - Draft Genome Sequence of Acidithiobacillus sp. Strain SH, a Marine Acidophilic Sulfur-Oxidizing Bacterium. AB - We announce here the genome sequence of a marine acidophilic sulfur-oxidizing bacterium, Acidithiobacillus sp. strain SH. The bacterium has potential for use in bioleaching of sulfide ores from seawater and contains a noble gene for thiosulfate quinone oxidoreductase in addition to specific genes for the oxidation of reduced inorganic sulfur compounds. PMID- 29439055 TI - Complete Genome Sequence and Methylome Analysis of Bacillus caldolyticus NEB414. AB - Bacillus caldolyticus NEB414 is the original source strain for the restriction enzyme BclI. Its complete sequence and full methylome were determined using single-molecule real-time sequencing. PMID- 29439056 TI - Complete Genome Sequence of the Nonheterocystous Cyanobacterium Pseudanabaena sp. ABRG5-3. AB - We report here the complete sequences of the main genome (4.8 Mb) and seven plasmids of the semifilamentous, nonheterocystous cyanobacterium Pseudanabaena sp. ABRG5-3, a strain isolated from a pond in Japan. These data are expected to enhance our understanding of the Pseudanabaena subclade near the root of cyanobacterial diversity. PMID- 29439057 TI - Association of fetuin-A with incident type 2 diabetes: results from the MONICA/KORA Augsburg study and a systematic meta-analysis. AB - OBJECTIVE: We investigated the association of circulating fetuin-A with incident T2D particularly examining potential sex differences. Additionally, we determined whether putative associations were independent of subclinical inflammation, adiponectin and liver fat content. DESIGN: Case-cohort study plus systematic meta analysis. METHODS: We investigated the association between baseline fetuin-A levels and incident T2D in the MONICA/KORA Augsburg study using Cox proportional hazards analyses. Furthermore, we conducted a systematic review within PubMed and EMBASE and pooled association estimates of eligible studies with the MONICA/KORA Augsburg data using a DerSimonian-Laird random effects model. RESULTS: Within MONICA/KORA Augsburg, 930 participants developed incident T2D (median follow-up: 14 years). We observed a significant association between fetuin-A and T2D risk after multivariable adjustment including C-reactive protein and adiponectin. The strength of the association was similar in males and females (P value for sex interaction >0.55). Seven eligible published studies were identified in addition to the MONICA/KORA Augsburg study for the meta-analysis. The pooled hazard ratio (95% CI) for incident T2D per 1 standard deviation (s.d.) increment of fetuin-A was 1.24 (1.14-1.34) for the multivariable adjusted model. Our sex-stratified meta-analysis yielded relative risk estimates per 1 s.d. of 1.19 (1.04-1.38) in males and 1.29 (1.15-1.46) in females. Further individual adjustment for subclinical inflammation, adiponectin and liver fat content had almost no impact on the strength of the association. CONCLUSIONS: Higher fetuin-A levels are associated with incident T2D in both males and females independently of subclinical inflammation, adiponectin and liver fat content. PMID- 29439058 TI - Autoimmune necrotising myopathy and HMGCR antibodies. AB - Statins lower serum cholesterol concentrations by inhibiting the enzyme 3-hydroxy 3-methylglutaryl-coenzyme A reductase (HMGCR). Muscle side effects are relatively common and include asymptomatic elevation of serum creatine kinase (CK), myalgia, proximal muscle weakness and rhabdomyolysis. More recently, a subset of cases of immune-mediated necrotising myopathy has been found to have antibodies against HMGCR. It is often an aggressive and debilitating myopathy and has a complex pathogenesis characterised by fibre necrosis, usually with minimal associated inflammation. Not all such patients are taking statins. The general consensus is that best treatment involves withdrawing the statin and giving immunosuppressive and immunomodulatory treatment. We describe three cases of HMGCR-related immune mediated necrotising myopathy, detailing their clinical course and subsequent management, illustrating the spectrum of this disorder. PMID- 29439059 TI - Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): impact on the reclassification of thyroid nodules. AB - The 2017 edition of the WHO book on Classification of Tumours of Endocrine Organs includes a new section entitled 'Other encapsulated follicular-patterned thyroid tumours', in which the newly created NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) is identified and described in detail. Despite deleting the word 'carcinoma' from its name, NIFTP is not a benign tumor either and is best regarded as a neoplasm with 'very low malignant potential'. The main goal of the introduction of NIFTP category is to prevent overdiagnosis and overtreatment. Sampling constraints, especially when dealing with heterogeneous and/or large nodules, and difficulties in the invasiveness evaluation, are the major weaknesses of the histological characterization of NIFTP. At the cytological level, NIFTP can be separated from classic papillary carcinoma (cPTC) but not from encapsulated, invasive follicular variant PTC. The impact of NIFTP individualization for cytopathology is the drop of rates of malignancy for each Bethesda category in general and for indeterminate categories in particular. The biggest impact will be seen in institutions with a high frequency of FVPTC. The introduction of NIFTP has changed the utility of predictive values of molecular tests because RAS mutations and PAX8-PPARg rearrangements are frequently detected in NIFTP. This turns less promising the application of mutation detection panels as indicators of malignancy and will probably contribute to switch to a rule-out approach of molecular testing. Selection for surgery will go on being determined by a combined detection of clinical, cytological and ultrasound suspicious features. PMID- 29439060 TI - The long and the short of it - a perspective on peptidergic regulation of circuits and behaviour. AB - Neuropeptides are the most diverse class of chemical modulators in nervous systems. They contribute to extensive modulation of circuit activity and have profound influences on animal physiology. Studies on invertebrate model organisms, including the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, have enabled the genetic manipulation of peptidergic signalling, contributing to an understanding of how neuropeptides pattern the output of neural circuits to underpin behavioural adaptation. Electrophysiological and pharmacological analyses of well-defined microcircuits, such as the crustacean stomatogastric ganglion, have provided detailed insights into neuropeptide functions at a cellular and circuit level. These approaches can be increasingly applied in the mammalian brain by focusing on circuits with a defined and identifiable sub-population of neurons. Functional analyses of neuropeptide systems have been underpinned by systematic studies to map peptidergic networks. Here, we review the general principles and mechanistic insights that have emerged from these studies. We also highlight some of the challenges that remain for furthering our understanding of the functional relevance of peptidergic modulation. PMID- 29439061 TI - Correction: Elucidating mechanisms for insect body size: partial support for the oxygen-dependent induction of moulting hypothesis (doi: 10.1242/jeb.166157). PMID- 29439062 TI - Correction: Hormesis-like effect of mild larval crowding on thermotolerance in Drosophila flies (doi: 10.1242/jeb.169342). PMID- 29439064 TI - Interventions that enhance health services for parents and infants to improve child development and social and emotional well-being in high-income countries: a systematic review. AB - BACKGROUND: Experiences in the first 1000 days of life have a critical influence on child development and health. Health services that provide support for families need evidence about how best to improve their provision. METHODS: We systematically reviewed the evidence for interventions in high-income countries to improve child development by enhancing health service contact with parents from the antenatal period to 24 months postpartum. We searched 15 databases and trial registers for studies published in any language between 01 January 1996 and 01 April 2016. We also searched 58 programme or organisation websites and the electronic table of contents of eight journals. RESULTS: Primary outcomes were motor, cognitive and language development, and social-emotional well-being measured to 39 months of age (to allow the interventions time to produce demonstrable effects). Results were reported using narrative synthesis due to the variation in study populations, intervention design and outcome measurement. 22 of the 12 986 studies identified met eligibility criteria. Using Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group criteria, the quality of evidence overall was moderate to low. There was limited evidence for intervention effectiveness: positive effects were seen in 1/6 studies for motor development, 4/11 for language development, 4/8 for cognitive development and 3/19 for social-emotional well-being. However, most studies showing positive effects were at high/unclear risk of bias, within-study effects were inconsistent and negative effects were also seen. Intervention content and intensity varied greatly, but this was not associated with effectiveness. CONCLUSIONS: There is insufficient evidence that interventions currently available to enhance health service contacts up to 24 months postpartum are effective for improving child development. There is an urgent need for robust evaluation of existing interventions and to develop and evaluate novel interventions to enhance the offer to all families. PROSPERO REGISTRATION NUMBER: CRD42015015468. PMID- 29439063 TI - New techniques, applications and perspectives in neuropeptide research. AB - Neuropeptides are one of the most diverse classes of signaling molecules and have attracted great interest over the years owing to their roles in regulation of a wide range of physiological processes. However, there are unique challenges associated with neuropeptide studies stemming from the highly variable molecular sizes of the peptides, low in vivo concentrations, high degree of structural diversity and large number of isoforms. As a result, much effort has been focused on developing new techniques for studying neuropeptides, as well as novel applications directed towards learning more about these endogenous peptides. The areas of importance for neuropeptide studies include structure, localization within tissues, interaction with their receptors, including ion channels, and physiological function. Here, we discuss these aspects and the associated techniques, focusing on technologies that have demonstrated potential in advancing the field in recent years. Most identification and structural information has been gained by mass spectrometry, either alone or with confirmations from other techniques, such as nuclear magnetic resonance spectroscopy and other spectroscopic tools. While mass spectrometry and bioinformatic tools have proven to be the most powerful for large-scale analyses, they still rely heavily on complementary methods for confirmation. Localization within tissues, for example, can be probed by mass spectrometry imaging, immunohistochemistry and radioimmunoassays. Functional information has been gained primarily from behavioral studies coupled with tissue-specific assays, electrophysiology, mass spectrometry and optogenetic tools. Concerning the receptors for neuropeptides, the discovery of ion channels that are directly gated by neuropeptides opens up the possibility of developing a new generation of tools for neuroscience, which could be used to monitor neuropeptide release or to specifically change the membrane potential of neurons. It is expected that future neuropeptide research will involve the integration of complementary bioanalytical technologies and functional assays. PMID- 29439065 TI - Protocol for a prospective, school-based standardisation study of a digital social skills assessment tool for children: The Paediatric Evaluation of Emotions, Relationships, and Socialisation (PEERS) study. AB - BACKGROUND: Humans are by nature a social species, with much of human experience spent in social interaction. Unsurprisingly, social functioning is crucial to well-being and quality of life across the lifespan. While early intervention for social problems appears promising, our ability to identify the specific impairments underlying their social problems (eg, social communication) is restricted by a dearth of accurate, ecologically valid and comprehensive child direct assessment tools. Current tools are largely limited to parent and teacher ratings scales, which may identify social dysfunction, but not its underlying cause, or adult-based experimental tools, which lack age-appropriate norms. The present study describes the development and standardisation of Paediatric Evaluation of Emotions, Relationships, and Socialisation (PEERS(r)), an iPad based social skills assessment tool. METHODS: The PEERS project is a cross sectional study involving two groups: (1) a normative group, recruited from early childhood, primary and secondary schools across metropolitan and regional Victoria, Australia; and (2) a clinical group, ascertained from outpatient services at The Royal Children's Hospital Melbourne (RCH). The project aims to establish normative data for PEERS(r), a novel and comprehensive app-delivered child-direct measure of social skills for children and youth. The project involves recruiting and assessing 1000 children aged 4.0-17.11 years. Assessments consist of an intellectual screen, PEERS(r) subtests, and PEERS-Q, a self-report questionnaire of social skills. Parents and teachers also complete questionnaires relating to participants' social skills. Main analyses will comprise regression based continuous norming, factor analysis and psychometric analysis of PEERS(r) and PEERS-Q. ETHICS AND DISSEMINATION: Ethics approval has been obtained through the RCH Human Research Ethics Committee (34046), the Victorian Government Department of Education and Early Childhood Development (002318), and Catholic Education Melbourne (2166). Findings will be disseminated through international conferences and peer-reviewed journals. Following standardisation of PEERS(r), the tool will be made commercially available. PMID- 29439066 TI - Effect of an increased dosage of statins on spinal degenerative joint disease: a retrospective cohort study. AB - OBJECTIVES: It has been proven that statin can protect synovial joints from developing osteoarthritis through its anti-inflammatory effects. However, studies on the effect of statins on spinal degenerative joint diseases are few and limited to in vitro studies. Therefore, we investigated the relationship between the statin dosage and the development of spinal degenerative joint diseases. DESIGN: A retrospective cohort study. SETTING: Patients registered in Taiwan National Health Insurance Research Database. PARTICIPANTS: Patients aged 40-65 years old from 2001 to 2010 were included. Those who received statin treatment before 2001, were diagnosed with spinal degenerative joint diseases or received any spinal surgery before 2004 or had any spinal trauma before 2011 were excluded. A total of 7238 statin users and 164 454 non-users were identified and followed up for the next 7 years to trace the development of spinal degenerative joint disease. OUTCOME MEASURES: The incident rate of spinal degenerative joint diseases and HRs among the groups treated with different statin dosages. RESULTS: A higher dosage of statins was associated with a significantly lower risk of developing spinal degenerative joint disease in patients with hypercholesterolaemia. Compared with the group receiving less than 5400 mg of a statin, the HR of the 11 900-28 000 mg group was 0.83 (95% CI 0.70 to 0.99), and that of the group receiving more than 28 000 mg was 0.81 (95% CI 0.68 to 0.97). Results of subgroup analysis showed a significantly lower risk in men, those aged 50-59 years and those with a monthly income less than US$600. CONCLUSIONS: Our study's findings clearly indicated that a higher dosage of statins can reduce the incidence of spinal degenerative joint disease in patients with hypercholesterolaemia, and it can be beneficial for people with a higher risk of spine degeneration. PMID- 29439067 TI - Economic burden of schizophrenia in Italy: a probabilistic cost of illness analysis. AB - OBJECTIVES: Schizophrenia is a chronic, debilitating psychiatric disease with highly variable treatment pathways and consequent economic impacts on resource utilisation. The aim of the study was to estimate the economic burden of schizophrenia in Italy for both the societal and Italian National Healthcare perspective. METHODS: A probabilistic cost of illness model was applied. A systematic literature review was carried out to identify epidemiological and economic data. Direct costs were calculated in terms of drugs, hospitalisations, specialist services, residential and semiresidential facilities. Indirect costs were calculated on the basis of patients' and caregivers' loss of productivity. In addition, the impact of disability compensation was taken into account using a database from the Italian National Social Security Institute -Italy (INPS). RESULTS: Overall, 303 913 prevalent patients with schizophrenia were estimated. Of these, 212 739 (70%) were diagnosed and 175 382 (82%) were treated with antipsychotics. The total economic burden was estimated at ?2.7 billion (95% CI ?1771.93 to ?3988.65), 50.5% due to indirect costs and 49.5% to direct costs. Drugs corresponded to 10% of direct costs and hospitalisations (including residential and semiresidential facilities) accounted for 81%. CONCLUSIONS: This study highlighted that indirect costs and hospitalisations (including residential and semiresidential facilities) play a major role within the expenses associated with schizophrenia in Italy, and this may be considered as a tool for public decision-makers. PMID- 29439068 TI - Does high-carbohydrate intake lead to increased risk of obesity? A systematic review and meta-analysis. AB - OBJECTIVES: The present study aimed to test the association between high and low carbohydrate diets and obesity, and second, to test the link between total carbohydrate intake (as a percentage of total energy intake) and obesity. SETTING, PARTICIPANTS AND OUTCOME MEASURES: We sought MEDLINE, PubMed and Google Scholar for observation studies published between January 1990 and December 2016 assessing an association between obesity and high-carbohydrate intake. Two independent reviewers selected candidate studies, extracted data and assessed study quality. RESULTS: The study identified 22 articles that fulfilled the inclusion and exclusion criteria and quantified an association between carbohydrate intake and obesity. The first pooled strata (high-carbohydrate versus low-carbohydrate intake) suggested a weak increased risk of obesity. The second pooled strata (increasing percentage of total carbohydrate intake in daily diet) showed a weak decreased risk of obesity. Both these pooled strata estimates were, however, not statistically significant. CONCLUSIONS: On the basis of the current study, it cannot be concluded that a high-carbohydrate diet or increased percentage of total energy intake in the form of carbohydrates increases the odds of obesity. A central limitation of the study was the non-standard classification of dietary intake across the studies, as well as confounders like total energy intake, activity levels, age and gender. Further studies are needed that specifically classify refined versus unrefined carbohydrate intake, as well as studies that investigate the relationship between high fat, high unrefined carbohydrate-sugar diets. PROSPERO REGISTRATION NUMBER: CRD42015023257. PMID- 29439069 TI - Moving towards a better path? A mixed-method examination of China's reforms to remedy medical corruption from pharmaceutical firms. AB - OBJECTIVES: Few studies have systematically examined the effects of the existing regulations for alleviating corruption in China. This study assesses the effectiveness of China's reforms to curb medical corruption. METHODS: We used mixed methods for the evaluation of existing countermeasures. First, qualitative informant interviews based on the Donabedian model were conducted to obtain experts' evaluation of various kinds of countermeasures. Second, using data from 'China Judgements Online', we analysed the trend of occurrence and the characteristics of the medical corruption cases in recent years to reflect the overall effects of these countermeasures in China. RESULTS: Since 1990s, China has implemented three main categories of countermeasures to oppose medical corruption: fines and criminal penalties, health policy regulations, and reporting scheme policy. Information from the interviews showed that first the level of fines and criminal penalties for medical corruption behaviours may not be sufficient. Second, health policy regulations are also insufficient. Although the National Reimbursement Drug List and Essential Drug List were implemented, they were incomplete and created additional opportunities for corruption. Moreover, the new programme that centralised the purchase of pharmaceuticals found that most purchasing committees were not independent, and the selection criteria for bidding lacked scientific evidence. Third, the reporting scheme for commercial bribery records by the health bureau was executed poorly. In addition, quantitative online data showed no obvious decrease of institutional medical corruption in recent years, and most criminals have been committing crimes for a long time before getting detected, which further demonstrated the low effectiveness of the above countermeasures. CONCLUSIONS: Although existing countermeasures have exerted certain effects according to Chinese experts, more rigorous legislation and well-functioning administrative mechanisms are needed. Fundamentally, financial incentives for hospitals/physicians and the health insurance system should be improved. PMID- 29439070 TI - Cross-sectional analysis of the prevalence and predictors of statin utilisation in Ireland with a focus on primary prevention of cardiovascular disease. AB - OBJECTIVE: To describe the prevalence of statin utilisation by people aged over 50 years in Ireland and the factors associated with the likelihood of using a statin, focusing particularly on those using statins for primary prevention of cardiovascular disease (CVD). METHODS: This is a cross-sectional analysis of cardiovascular risk and sociodemographic factors associated with statin utilisation from wave 1 of The Irish Longitudinal Study on Ageing. A hierarchy of indications for statin utilisation, consisting of eight mutually exclusive levels of CVD-related diagnoses, was created. Participants were assigned one level of indication. The prevalence of statin utilisation was calculated. The likelihood that an individual was using a statin was estimated using a multivariable logistic regression model, controlling for cardiovascular risk and sociodemographic factors. RESULTS: In this nationally representative sample (n=5618) of community-dwelling participants aged 50 years and over, 1715 (30.5%) were taking statins. Of these, 65.0% (57.3% of men and 72.7% of women) were doing so for the primary prevention of CVD. Thus, almost two-thirds of those taking statins did so for primary prevention and there was a notable difference between women and men in this regard. We also found that statin utilisation was highest among those with a prior history of CVD and was significantly associated with age (compared with the base category 50-64 years; 65-74 years OR 1.38 (95% CI 1.16 to 1.65); 75+ OR 1.33 (95% CI 1.04 to 1.69)), living with a spouse or partner (compared with the base category living alone; OR 1.35 (95% CI 1.10 to 1.65)), polypharmacy (OR 1.74 (95% CI 1.39 to 2.19)) and frequency of general practitioner visits (compared with the base category 0 visits per year; 1-2 visits OR 2.46 (95% CI 1.80 to 3.35); 3-4 visits OR 3.24 (95% CI 2.34 to 4.47); 5 6 visits OR 2.98 (95% CI 2.08 to 4.26); 7+ visits OR 2.51 (95% CI 1.73 to 3.63)), even after controlling for clinical need. There was no association between using statins and gender, education, income, social class, health insurance status, location or Systematic Coronary Risk Evaluation (SCORE) risk in the multivariable analysis. CONCLUSION: Statin utilisation among those with no history of CVD accounted for almost two-thirds of all statin use, in part reflecting the high proportion of the population with no history of CVD, although utilisation rates were highest among those with a history of CVD. PMID- 29439071 TI - Ten-year inhospital mortality trends for patients with trauma in Japan: a multicentre observational study. AB - OBJECTIVES: Trauma is one of the main causes of death in Japan, and treatments and prognoses of these injuries are constantly changing. We therefore aimed to investigate a 10-year trend (2004-2013) in inhospital mortality among patients with trauma in Japan. DESIGN: Multicentre observational study. SETTING: Japanese nationwide trauma registry (the Japan Trauma Data Bank) data. PARTICIPANTS: All patients with trauma whose Injury Severity Score (ISS) were 3 and above, who were aged 15 years or older, and whose mechanisms of injury (MOI) were blunt and penetrating between 2004 and 2013 (n=90 833). OUTCOME MEASURES: A 10-year trend in inhospital mortality. RESULTS: Inhospital mortality for all patients with trauma significantly decreased over the study decade in our Cochran-Armitage test (P<0.001). Similarly, inhospital mortality for patients with ISS 16 or more and patients who scored 50% or better on the Trauma and Injury Severity Score (TRISS) probability of survival scale significantly decreased (P<0.001). In addition, the OR for inhospital mortality of these three patient groups decreased yearly after adjusting for age, gender, MOI, ISS, Glasgow Coma Scale, systolic blood pressure and respiratory rate on hospital arrival in multivariable logistic regression analyses. Furthermore, inhospital mortality for patient with blunt trauma significantly decreased in injury mechanism-stratified Mantel-extension testing (P<0.001). Finally, multivariable logistic regression analyses showed that the OR for inhospital mortality of patients with ISS 16 and over decreased each year after adding and adjusting for means of transportation and usage of whole-body CT. CONCLUSION: Inhospital mortality for patients with trauma in Japan significantly decreased during the study decade after adjusting for patient characteristics, injury severity and the response environment after injury. PMID- 29439072 TI - 'Because my brain isn't as active as it should be, my eyes don't always see': a qualitative exploration of the stress process for those living with posterior cortical atrophy. AB - OBJECTIVES: To explore the stress process for individuals living with posterior cortical atrophy (PCA) and their families. DESIGN: A qualitative study using in depth semi-structured dyadic and individual interviews with people living with a diagnosis of PCA and a family carer. Interview transcripts were thematically analysed. SETTING: Participants' homes. PARTICIPANTS: 20 individuals in the mild to moderate stages of PCA and 20 family carers. FINDINGS: Three major themes were identified: (1) the diagnostic journey: mostly an unsettling and convoluted process, owing to the early age of onset, rarity and atypical symptom profile of PCA. (2) Interactions with the physical environment: profound difficulties with functional and leisure activities were usually compensated for with adaptations maximising familiarity or simplicity. (3) Implications within the psychosocial environment: symptoms impacted individuals' sense of independence and identity and required reallocations of roles and responsibilities. Ongoing uncertainties and the progressive nature of PCA caused most dyads to take a 'one day at a time' approach to coping. Relatively well-preserved insight and memory were a benefit and burden, as individuals shared the illness experience with family members and also compared their current situation to pre-diagnosis. The experience was framed by background and contextual factors and understood within an ever-changing temporal context. CONCLUSION: The stress process in PCA is characterised by uncertainty and unpredictability from diagnosis through to ongoing management. The provision of tailored information about cortical visual problems and associated functional difficulties, time-sensitive environmental adaptations to help those with PCA to identify what and where things are and psychosocial interventions for the marital/family unit as a whole would be useful to improve both functional status and psychological well-being. Future research exploring (1) stress and coping in the later stages of PCA and (2) the nature and impact of visual impairment(s) in typical Alzheimer's disease would be worthwhile. PMID- 29439073 TI - Characteristics of medical disputes arising from dental practice in Guangzhou, China: an observational study. AB - OBJECTIVES: Doctor-patient conflict is a phenomenon that has become one of the major social problems affecting China's medical system today. This study aimed to analyse the nature of medical dispute incidents arising from dental practice, discover the related factors that may have incited such disputes and explore measures whereby the incidents of patients' conflicts towards dentists can be reduced. METHODS: A survey conducted in six public hospitals in Guangzhou, one of the largest cities in China, showed that more than two million patients received dental treatment between 2008 and 2012. chi2 test and binary logistic regression analysis were used to identify statistically significant differences in incident rates. RESULTS: In a total of more than two million outpatients, 541 reported dental disputes and lodged complaints with the medical service centre. Male patients reported higher dispute rates than did females (chi2=9.74, P<0.01). Binary logistic regression analysis further showed that disputes developed into conflicts depending on five factors: patient gender, dental specialty, cause of dispute, mode of payment and resolution duration. CONCLUSIONS: Gender, specialties, cause of dispute, mode of payment and resolution duration are associated with the incidence of dental conflicts, suggesting that medical quality is positively correlated to dental disputes, the coverage of stomatology in medical insurance should be expanded and detailed negotiation system should be developed for resolving dental disputes. PMID- 29439074 TI - Major determinant of the occurrence of pacing-induced cardiomyopathy in complete atrioventricular block: a multicentre, retrospective analysis over a 15-year period in South Korea. AB - OBJECTIVES: The predictors of pacing-induced cardiomyopathy (PICM) for complete atrioventricular block (CAVB) have not yet been defined. The aim of this study was to investigate the major determinant of the occurrence of PICM. SETTING: This is a multicentre, retrospective analysis of CAVB from tertiary referral centres in Daejeon, South Korea. PARTICIPANTS: A cohort of 900 consecutive patients with an implanted pacemaker was collected from December 2001 to August 2015. Of these, a total of 130 patients with CAVB with pacing-dependent rhythm who underwent ECG and echocardiogram before and after implantation were analysed for the occurrence of PICM. OUTCOME MEASURES: Cox proportional hazards models evaluated the determinant of PICM by ECG, device parameters and echocardiogram over a mean of 4.5 years. RESULTS: PICM was observed in 16.1% (n=21) of all patients with CAVB (age, 64+/-11 years; male, 36.2%). The preimplant left ventricular (LV) ejection fraction (66%+/-9% vs 66%+/-8%) and non-apical pacing (40.4% vs 33.3%) were similar; however, the native QRS duration (124+/-34 ms vs 149+/-32 ms) and the paced QRS duration (pQRSd) (139+/-29 ms vs 167+/-28 ms) were significantly different between the two groups. The postimplant LV ejection fraction (61%+/-7% vs 31%+/-8%) was also significantly different at the end of follow-up. A pQRSd significantly correlated with PICM (HR 1.05, 95% CI 1.02 to 1.09, P=0.001). A pQRSd with a cut-off value of above 140 ms had a sensitivity of 95% while a pQRSd with a cut-off value of above 167 ms had a specificity of 90% for PICM. CONCLUSION: In patients with CAVB with pacing-dependent rhythm, regardless of the pacing site, the pQRSd is a major determinant of the occurrence of PICM. PMID- 29439075 TI - Adult psychosocial outcomes of men and women who were looked-after or adopted as children: prospective observational study. AB - OBJECTIVE: To investigate whether men and women who were looked-after (in public care) or adopted as children are at increased risk of adverse psychological and social outcomes in adulthood. DESIGN, SETTING: Prospective observational study using the Avon Longitudinal Study of Parents and Children, which recruited pregnant women and their male partners in and around Bristol, UK in the early 1990s. PARTICIPANTS: 8775 women and 3654 men who completed questionnaires at recruitment (mean age: women 29; men 32) and 5 years later. EXPOSURE: Childhood public care status: looked-after; adopted; not looked-after or adopted (reference group). OUTCOMES: Substance use (alcohol, cannabis, tobacco) prepregnancy and 5 years later; if ever had addiction; anxiety and depression during pregnancy and 5 years later; if ever had mental health problem; social support during pregnancy; criminal conviction. RESULTS: For women, 2.7% were adopted and 1.8% had been looked-after; for men, 2.4% and 1.4%, respectively. The looked-after group reported the poorest outcomes overall, but this was not a universal pattern, and there were gender differences. Smoking rates were high for both the looked-after (men 47%, women 58%) and adopted (men 44%, women 40%) groups relative to the reference group (both 28%). The looked-after group were at increased risk of a high depression score (men: 26% vs 11%, OR 2.9 (95% CI 1.5 to 5.6); women: 24% vs 9%, 3.4 (2.2 to 5.0)). A high anxiety score was reported by 10% of the reference women, compared with 26% of those looked-after (3.0 (2.0 to 4.5)) and 17% of those adopted (1.8 (1.2 to 2.6)). Looked-after men and women reported the lowest social support, while criminal convictions and addiction were highest for looked after men. Adjustment for adult socioeconomic position generally attenuated associations for the looked-after group. CONCLUSIONS: The needs of those who experience public care as children persist into adulthood. Health and social care providers should recognise this. PMID- 29439076 TI - Cohort profile: 'Centenari a Trieste' (CaT), a study of the health status of centenarians in a small defined area of Italy. AB - PURPOSE: Centenarians, a segment of the population which some 50 years ago comprised only a few individuals, now count thousands in many countries, and demographic projections forecast that this growth will continue. The study of this new population will give us new information on extreme longevity and help prepare for their health and social needs. The aim of the Centenari a Trieste study is to describe the health and health service use by centenarians, with specific focus on cognitive status. PARTICIPANTS: This is a population-based study of centenarians living in the province of Trieste (Italy), a small area with a high prevalence of centenarians and a close network of health and social services, which makes it possible to conduct a study. Consenting individuals were visited by a clinician, tested by neuropsychologists and also gave a sample of their blood. Administrative data were retrieved as well. FINDINGS TO DATE: Of the 163 centenarians, 70 could be contacted and participated in the study. The main reasons for non-participation were impossibility to contact the subject (70) and death (20). Centenarians were mostly women (90%), tended to live in a nursing home (60%) and were generally severely functionally impaired (Barthel Index <50: 61%). Data from the administrative database showed that about one out of five needed hospitalisation in the preceding year and more than three out of four had at least one drug prescription. FUTURE PLANS: In 2017, we started a new wave of the study enrolling people who had just become centenarian and reassessing subjects already seen; we hope to extend this recruitment in the next years. Subjects are now examined also by cardiologists and dental specialists. We are collecting further different biological specimens to investigate new hypotheses on the cognitive function of the centenarians. PMID- 29439077 TI - Impact of the New Cooperative Medical Scheme on the trend of catastrophic health expenditure in Chinese rural households: results from nationally representative surveys from 2003 to 2013. AB - OBJECTIVE: To evaluate the trend of catastrophic health expenses (CHE) for inpatient care in relation to the commencement of the New Cooperative Medical Scheme (NCMS) in rural China from 2003 to 2013, and the roles of NCMS in protecting affected households from CHE. METHODS: We assessed the 10-year trend of the incidence and severity of CHE in rural households with hospitalised members using data from the Chinese National Health Services Survey. Generalised estimating equations were used to estimate the OR and 95% CI of the association between incidence rates of CHE ([Formula: see text]) and NCMS reimbursement. RESULTS: The incidence and severity of CHE after NCMS reimbursement both decreased and their changes increased rapidly from 2003 to 2013. After adjustment of the covariates, [Formula: see text] before reimbursement was significantly higher than that after reimbursement, and the OR (95% CI) was 1.50 (1.24 to 1.81), 1.79 (1.69 to 1.90) and 2.94 (2.77 to 3.11) in 2003, 2008 and 2013, respectively. CONCLUSION: The incidence and severity of CHE both reduced after NCMS reimbursements in each year. Excluding some confounding factors, [Formula: see text] was significantly associated with NCMS reimbursement. NCMS partly protected the rural households with hospitalised members from CHE. However, the inequalities between different income groups still existed. [Formula: see text] in rural households with hospitalised members was still rather high in 2003, 2008 and 2013 even though they were covered by NCMS. This study will provide suggestions for further reforms in China and guidance for other low-income/middle income countries. PMID- 29439078 TI - New mechanism to identify cost savings in English NHS prescribing: minimising 'price per unit', a cross-sectional study. AB - BACKGROUND: Minimising prescription costs while maintaining quality is a core element of delivering high-value healthcare. There are various strategies to achieve savings, but almost no research to date on determining the most effective approach. We describe a new method of identifying potential savings due to large national variations in drug cost, including variation in generic drug cost, and compare these with potential savings from an established method (generic prescribing). METHODS: We used English National Health Service (NHS) Digital prescribing data, from October 2015 to September 2016. Potential cost savings were calculated by determining the price per unit (eg, pill, millilitre) for each drug and dose within each general practice. This was compared against the same cost for the practice at the lowest cost decile to determine achievable savings. We compared these price-per-unit savings to the savings possible from generic switching and determined the chemicals with the highest savings nationally. A senior pharmacist manually assessed whether a random sample of savings were practically achievable. RESULTS: We identified a theoretical maximum of L410 million of savings over 12 months. L273 million of these savings were for individual prescribing changes worth over L50 per practice per month (mean annual saving L33 433 per practice); this compares favourably with generic switching, where only L35 million of achievable savings were identified. The biggest savings nationally were on glucose blood testing reagents (L12 million), fluticasone propionate (L9 million) and venlafaxine (L8 million). Approximately half of all savings were deemed practically achievable. DISCUSSION: We have developed a new method to identify and enable large potential cost savings within NHS community prescribing. Given the current pressures on the NHS, it is vital that these potential savings are realised. Our tool enabling doctors to achieve these savings is now launched in pilot form at OpenPrescribing.net. However, savings could potentially be achieved more simply through national policy change. PMID- 29439079 TI - Primary outcome switching among drug trials with and without principal investigator financial ties to industry: a cross-sectional study. AB - OBJECTIVES: To determine the relationship between manufacturer-related financial ties among investigators of published drug trials and rates of discrepant registered and published primary trial outcomes. DESIGN: Cross-sectional study. SETTING: Human subjects drug trials published in 'core clinical' MEDLINE journals in 2013. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary study endpoint was the presence of a prospectively registered, clearly defined primary outcome that matched the published primary outcome for each included trial. Secondary outcomes included assessments of registration timing and quality, and the impact of outcome discrepancies between registration and publication on the statistical significance of the included trials. RESULTS: Of 192 included trials, 134 (70%) were positive and 58 (30%) were negative. Financial ties were present between first or last authors and drug manufacturers for 130 trials (68%), of which 78% were positive, versus 53% of trials with no financial ties that were positive. Clearly defined, prospectively registered outcomes that matched the published outcomes were present in just 76 of the 192 trials (40%). After adjusting for study start date and sample size, the observed relationship between investigator financial ties and the presence of a match between prospectively registered and published primary outcomes was of borderline statistical significance (OR 2.12, 95% CI 0.998 to 4.50). Studies with financial ties present were more likely than studies without ties to have been prospectively registered (78%vs48%, P<0.001) and were more likely to have prospectively registered a clearly defined primary outcome(62%vs35%, P<0.001). CONCLUSIONS: Less than half of the trials in this cohort were prospectively registered with a clear primary outcome that was consistent with the primary outcome reported in the published manuscript. The presence of investigator financial ties was associated with higher quality registration practices, though this association diminished after adjusting for factors that impact registration quality. PMID- 29439080 TI - Risk factors for difficult peripheral venous cannulation in hospitalised patients. Protocol for a multicentre case-control study in 48 units of eight public hospitals in Spain. AB - INTRODUCTION: Patients with difficult venous access experience undesirable effects during healthcare, such as delayed diagnosis and initiation of treatment, stress and pain related to the technique and reduced satisfaction. This study aims to identify risk factors with which to model the appearance of difficulty in achieving peripheral venous puncture in hospital treatment. METHODS AND ANALYSIS: Case-control study. We will include adult patients requiring peripheral venous cannulation in eight public hospitals, excluding those in emergency situations and women in childbirth or during puerperium. The nurse who performs the technique will record in an anonymised register variables related to the intervention. Subsequently, a researcher will extract the health variables from the patient's medical history. Patients who present one of the following conditions will be assigned to the case group: two or more failed punctures, need for puncture support, need for central access after failure to achieve peripheral access, or decision to reject the technique. The control group will be obtained from records of patients who do not meet the above conditions. It has been stated a minimum sample size of 2070 patients, 207 cases and 1863 controls.A descriptive analysis will be made of the distribution of the phenomenon. The variables hypothesised to be risk factors for the appearance of difficult venous cannulation will be studied using a logistic regression model. ETHICS AND DISSEMINATION: The study was funded in January 2017 and obtained ethical approval from the Research Ethics Committee of the Balearic Islands. Informed consent will be obtained prior to data collection. Results will be published in a peer reviewed scientific journal. PMID- 29439081 TI - Long-term trends of liver cancer mortality by gender in urban and rural areas in China: an age-period-cohort analysis. AB - OBJECTIVES: To provide an up-to-date overview of long-term trends of liver cancer mortality and evaluate the effects attributable to age, period and cohort in Chinese population stratified by gender and urban/rural areas. METHODS: Population and liver cancer mortality data were obtained based on the Disease Surveillance Points in China from 1991 to 2014. To examine the time trends of liver cancer mortality by gender in urban and rural areas in China, Joinpoint analysis was used to estimate the annual per cent change. The intrinsic estimator, a method of age-period-cohort analysis to estimate age, period and cohort effects simultaneously, was used to analyse the underlying mechanisms for liver cancer mortality trends in the aforementioned four groups. RESULTS: We observed a significant decline in liver cancer mortality for urban men (average annual per cent change (AAPC)=-1.1%, P<0.05) and urban women (AAPC=-1.4%, P<0.05), while the liver cancer mortality remained stable for rural men (AAPC= 0.1%, P>0.05) and rural women (AAPC=-0.9%, P>0.05). Compared with the 15-19 age group, the liver cancer mortality risk of the 85 and above age group increased 65 and 42 times for urban and rural men, and 102 and 70 times for urban and rural women. From the 1990-1994 period to the 2005-2009 period, the risk increased 56% and 92% for urban and rural men, and 30% and 74% for urban and rural women. Compared with period and cohort effects, age effects were the most influential factor in liver cancer mortality. CONCLUSIONS: As the status of ageing population in China gets worse, the burden caused by liver cancer mortality could still be a great challenge for China in the future. The disparity of liver cancer mortality trends between urban and rural residents can be attributed to period effects, referring to the unequal medical levels and resources between urban and rural areas. PMID- 29439082 TI - Association of common comorbidities with osteonecrosis: a nationwide population based case-control study in Denmark. AB - OBJECTIVE: To examine recent time trends in the incidence of osteonecrosis (ON) in Denmark and to investigate different common comorbidities association with ON in a population-based setting. METHODS: Using Danish medical databases, we included all patients with a first-time hospital diagnosis of ON during 1995 2012. Each ON case was matched with 10 randomly selected population control subjects from general population. For all participants, we obtained a complete hospital history of comorbidities included in the CharlsonComorbidity Index 5 years preceding the inclusion date. RESULTS: 4107 ON cases and 41 063 controls were included. The incidence of ON increased from 3.9 in 1995 to 5.5 in 2012 per 100 000 inhabitants. Solid cancer was the most common comorbidity, associated with an adjusted OR (aOR) for ON of 2.0 (95% CI 1.7 to 2.2). For advanced metastatic cancer, leukaemia and lymphoma, aORs of ON were 3.4 (95% CI 2.5 to 4.5), 4.3 (95% CI 2.7 to 7.0) and 5.8 (95% CI 4.3 to 7.8), respectively. Among other chronic conditions, aORs were 3.5 (95% CI 3.0 to 4.1) for connective tissue diseases and 2.3 (95% CI 2.0 to 2.7) for chronic pulmonary diseases. aORs were also increased at 2.8 (95% CI 1.9 to 4.1) and 4.5 (95% CI 2.5 to 8.2) for mild and moderate-to-severe liver disease, respectively, and 4.2 (95% CI 3.4 to 5.2) for renal disease. CONCLUSION: This large population-based study provides evidence for an increasing ON incidence in the general population and documents an association between several common comorbid conditions and risk of ON. PMID- 29439083 TI - Psychological Outcomes following a nurse-led Preventative Psychological Intervention for critically ill patients (POPPI): protocol for a cluster randomised clinical trial of a complex intervention. AB - INTRODUCTION: Acute psychological stress, as well as unusual experiences including hallucinations and delusions, are common in critical care unit patients and have been linked to post-critical care psychological morbidity such as post traumatic stress disorder (PTSD), depression and anxiety. Little high-quality research has been conducted to evaluate psychological interventions that could alleviate longer-term psychological morbidity in the critical care unit setting. Our research team developed and piloted a nurse-led psychological intervention, aimed at reducing patient-reported PTSD symptom severity and other adverse psychological outcomes at 6 months, for evaluation in the POPPI trial. METHODS AND ANALYSIS: This is a multicentre, parallel group, cluster-randomised clinical trial with a staggered roll-out of the intervention. The trial is being carried out at 24 (12 intervention, 12 control) NHS adult, general, critical care units in the UK and is evaluating the clinical effectiveness and cost-effectiveness of a nurse-led preventative psychological intervention in reducing patient-reported PTSD symptom severity and other psychological morbidity at 6 months. All sites deliver usual care for 5 months (baseline period). Intervention group sites are then trained to carry out the POPPI intervention, and transition to delivering the intervention for the rest of the recruitment period. Control group sites deliver usual care for the duration of the recruitment period. The trial also includes a process evaluation conducted independently of the trial team. ETHICS AND DISSEMINATION: This protocol was reviewed and approved by the National Research Ethics Service South Central - Oxford B Research Ethics Committee (reference: 15/SC/0287). The first patient was recruited in September 2015 and results will be disseminated in 2018. The results will be presented at national and international conferences and published in peer reviewed medical journals. TRIAL REGISTRATION NUMBER: ISRCTN53448131; Pre-results. PMID- 29439084 TI - Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case-control pharmacokinetic study. AB - INTRODUCTION: Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response. The aim of this study is to characterise the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in T2DM versus non-T2DM subjects following the administration of a cocktail of probe drug substrates. METHODS AND ANALYSIS: This single-centre clinical study proposes the first detailed characterisation of T2DM impacts on major CYP450 drug-metabolising enzyme activities. We intend to recruit 42 patients with controlled T2DM (A1C<=7%), 42 patients with uncontrolled T2DM (A1C>7%) and 42 non-diabetic control subjects. The primary objective is to determine and compare major CYP450 activities in patients with T2DM versus non diabetic subjects by dosing in plasma and urine probe drug substrates and metabolites following the oral administration of a drug cocktail: caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4/5). Secondary objectives will evaluate the influence of variables such as glycaemia, insulinaemia, genetic polymorphisms and inflammation. The value of an endogenous biomarker of CYP3A activity is also evaluated. The first patient was recruited in May 2015 and patients will be enrolled up to completion of study groups. ETHICS AND DISSEMINATION: Approval was obtained from the ethic review board of the CHUM research centre (Montreal, Canada). TRIAL REGISTRATION NUMBER: NCT02291666. PMID- 29439086 TI - Using photography to enhance GP trainees' reflective practice and professional development. AB - The capacity and the commitment to reflect are integral to the practice of medicine and are core components of most general practitioners (GP) training programmes. Teaching through the humanities is a growing area within medical education, but one which is often considered a voluntary 'add-on' for the interested doctor. This article describes an evaluation of a highly innovative pedagogical project which used photography as a means to enhance GP trainees' reflective capacity, self-awareness and professional development. Photography was used as a tool to develop GP trainees' skills in recognising and articulating the attitudes, feelings and values that might impact on their clinical work and to enhance their confidence in their ability to deal with these concerns/issues. We submit that photography is uniquely well suited for facilitating insight and self reflection because it provides the ability to record 'at the touch of a button' those scenes and images to which our attention is intuitively drawn without the need for-or the interference of-conscious decisions. This allows us the opportunity to reflect later on the reasons for our intuitive attraction to these scenes. These photography workshops were a compulsory part of the GP training programme and, despite the participants' traditional scientific backgrounds, the results clearly demonstrate the willingness of participants to accept-even embrace-the use of art as a tool for learning. The GP trainees who took part in this project acknowledged it to be beneficial for both their personal and professional development. PMID- 29439085 TI - IDEA intervention to prevent depressive symptoms and promote well-being in early stage dementia: protocol for a randomised controlled feasibility study. AB - OBJECTIVE: Depressive symptoms are common among people with dementia, impacting quality of life and cognitive and functional decline. Currently, little is known about the acceptability and feasibility of psychological interventions for people with mild dementia, with recent reviews identifying the need for further evidence. Developing and evaluating psychological interventions to prevent and treat these symptoms is, therefore, an important clinical and research priority. This protocol describes a study testing the acceptability and feasibility of a manual-based behavioural activation (BA) intervention for preventing and treating depressive symptoms in people with mild dementia. The aim of this study is to explore the feasibility of conducting a pragmatic multicentre randomised controlled trial of clinical effectiveness of an eight-session intervention. The Intervention to prevent Depressive symptoms and promote well-being in EArly-stage dementia (IDEA) programme supports people with dementia and their family carers in identifying and scheduling enjoyable and meaningful activities. METHODS AND ANALYSIS: Sixty people who have received a diagnosis of dementia of any type in the last 6 months will be recruited via memory clinics. Further criteria are a Mini-Mental State Examination score of >=20, and a family carer who can assist with the intervention. Consenting participants will be randomised in a ratio of 2:1 to BA or to treatment as usual. Analyses will estimate parameters such as rates of recruitment, retention and number of sessions completed. Questionnaires measuring depressive symptoms and quality of life for both the person with dementia and their carer will be completed at baseline, 3 and 6 months. Qualitative interviews will explore acceptability of the intervention, study procedures and experiences of the sessions. ETHICS AND DISSEMINATION: This study received a favourable ethical opinion from the London Camberwell St Giles Research Ethics Committee (16/LO/0540). We will disseminate findings at key conferences, the Alzheimer's Society and University College London websites and local stakeholder events. TRIAL REGISTRATION NUMBER: ISRCTN75503960; Pre-results. PMID- 29439087 TI - High Constitutive Activity Accounts for the Combination of Enhanced Direct Activation and Reduced Potentiation in Mutated GABAA Receptors. AB - GABAA receptors activated by the transmitter GABA are potentiated by several allosterically acting drugs, including the intravenous anesthetic propofol. Propofol can also directly activate the receptor, albeit at higher concentrations. Previous functional studies have identified amino acid residues whose substitution reduces potentiation of GABA-activated receptors by propofol while enhancing the ability of propofol to directly activate the receptor. One interpretation of such observations is that the mutation has specific effects on the sites or processes involved in potentiation or activation. We show here that divergent effects on potentiation and direct activation can be mediated by increased constitutive open probability in the mutant receptor without any specific effect on the interactions between the allosteric drug and the receptor. By simulating GABAA receptor activity using the concerted transition model, we demonstrate that the predicted degree of potentiation is reduced as the level of constitutive activity increases. The model further predicts that a potentiating effect of an allosteric modulator is a computable value that depends on the level of constitutive activity, the amplitude of the response to the agonist, and the amplitude of the direct activating response to the modulator. Specific predictions were confirmed by electrophysiological data from the binary alpha1beta3 and concatemeric ternary beta2alpha1gamma2L+beta2alpha1 GABAA receptors. The corollaries of reduced potentiation due to increased constitutive activity are isobolograms that conform to simple additivity and a loss of separation between the concentration-response relationships for direct activation and potentiation. PMID- 29439088 TI - Metabolic effects of short-term caloric restriction in mice with reduced insulin gene dosage. AB - Caloric restriction (CR) is the only environmental intervention with robust evidence that it extends lifespan and delays the symptoms of aging, but its mechanisms are incompletely understood. Based on the prolonged longevity of knockout models, it was hypothesized that the insulin-IGF pathway could be a target for developing a CR mimic. This study aimed to test whether CR has additive effects on glucose homeostasis and beta-cell function in mice with reduced insulin gene dosage. To study models with a range of basal insulin levels, wild-type C57BL/6J and mice on an Ins2-/- background, were put on 8 weeks of 40% CR at various ages. Both male and female mice rapidly lost weight due to a reduced WAT mass. Glucose tolerance was improved and fasting glucose levels were reduced by CR in both wild type and 45- and 70-week-old Ins2-/- mice. The effects of CR and reduced insulin on glucose tolerance were non-additive in 20-week-old mice. Interestingly, mice on CR generally exhibited an inability to further depress blood glucose after insulin injection, pointing to possible alterations in insulin sensitivity. In conclusion, our results demonstrate that CR can cause weight loss in the context of reduced insulin production, but that CR-improved glucose homeostasis does not occur near the 'insulin floor' in young mice. Collectively, these data shed further light on the relationships between CR, insulin and glucose homeostasis. PMID- 29439089 TI - Yellow (577 nm) micropulse laser versus half-dose verteporfin photodynamic therapy in eyes with chronic central serous chorioretinopathy: results of the Pan American Collaborative Retina Study (PACORES) Group. AB - PURPOSE: To compare the functional and anatomical outcomes of eyes with chronic central serous chorioretinopathy treated with yellow micropulse (MP) laser versus half-dose verteporfin photodynamic therapy (PDT). METHODS: This is a multicentre, retrospective comparative study of 92 eyes treated with yellow MP laser (duty cycle of 5%, zero spacing between spots, spot size varied from 100 to 200 um, power varied from 320 to 660 mW, and the pulse burst duration was 200 ms) and 67 eyes treated with PDT (half-dose verteporfin (3 mg/m2) infused over 10 min), followed by laser activation for 83 s. Spot sizes varied from 400 to 2000 um. RESULTS: In the MP group, at 12 months of follow-up, the mean best corrected visual acuity (BCVA) improved from the logarithm of the minimum angle of resolution (logMAR) of 0.41+/-0.27 at baseline to 0.21+/-0.26 (P<0.0001), 48.9% (45/92) of eyes had an improvement of >=3 lines of BCVA from baseline, 48.9% (45/92) of eyes remained within 2 lines of baseline BCVA, and only 2.2% (2/92) of eyes lost >=3 lines of BCVA from baseline. In the PDT group, at 12 months of follow-up, the mean BCVA changed from logMAR of 0.50+/-0.34 at baseline to 0.47+/ 0.34 (P=0.89), 19% (13/67) of eyes had an improvement of >=3 lines of BCVA from baseline, 73% (49/67) of eyes remained within 2 lines of baseline BCVA, and 7% (5/67) of eyes lost >=3 lines of BCVA from baseline. There were no adverse events attributable to the yellow MP laser treatment. One eye in the PDT group developed choroidal neovascularisation, which was treated with three intravitreal bevacizumab injections. CONCLUSIONS: Both PDT and MP are effective in restoring the macular anatomy. In places where PDT is not available, yellow MP laser may be an adequate treatment alternative. PMID- 29439090 TI - Blindness, low vision and cataract surgery outcome among adults in Hohhot of Inner Mongolia: a Rapid Assessment of Avoidable Blindness (RAAB) study. AB - BACKGROUND: To determine the prevalence and causes of visual impairment (VI), and to describe the characteristics of cataract surgery coverage and related barriers among adults aged >=50 years residing in Hohhot, Inner Mongolia. METHODS: A population-based cross-sectional study was performed. Presenting visual acuity (PVA) was measured using the Rapid Assessment of Avoidable Blindness (RAAB) methodology. All VI cases were defined using the WHO definition, based on the PVA of the better-seeing eye. Details on history of cataract surgery and barriers to cataract surgery were also obtained using a standardised questionnaire. RESULTS: Of 4500 eligible individuals, 3985 (88.6% response rate) were examined. The age standardised prevalence of moderate VI (PVA <6/18 to >=6/60) was 5.4% (95% CI 4.6% to 6.3%), and severe VI (PVA <6/60 to >=3/60) was 0.9% (95% CI 0.6% to 1.3%). The age-standardised prevalence of blindness (PVA <3/60) was 1.2% (95% CI 0.8% to 1.6%). Uncorrected refractive error (40.1%) and cataract (37.9%) were the leading causes of overall VI. Cataract (34.9%) was the leading cause of blindness. Among individuals with blindness, cataract surgical coverage was 80.7%. Among individuals with blindness due to cataract, the main barriers to cataract surgery were lack of awareness (38.1%). CONCLUSIONS: The age standardised prevalence rate of blindness in Hohhot was lower compared with other RAAB studies in China. Cataract was the leading cause of blindness. These findings provide useful information for the planning of public healthcare services in Inner Mongolia. PMID- 29439091 TI - Evaluation of galectin-1 and galectin-3 as prospective biomarkers in keratoconus. AB - AIMS: To evaluate the expression of beta-galactoside-binding proteins galectin (Gal)-1 and Gal-3 in patients with keratoconus (KC) and postcorneal collagen cross-linking (CXL) treatment in vitro. METHODS: Tear fluid, cornea samples and conjunctival impression cytology specimens from control and KC patients were used to evaluate Gal-1 and Gal-3 expressions. Primary keratocytes were isolated by collagenase digestion from surgically removed corneas of five normal or KC human corneal buttons and cultured in Dulbecco's modified eagle medium/Ham's F12 medium supplemented with 2% fetal bovine serum. These cells were evaluated under two experimental conditions: control and submitted to the application of ultraviolet A light and riboflavin 0.1% (CXL) for 30 min. RESULTS: Patients with KC displayed increased levels of Gal-1 and Gal-3 in conjunctival epithelial cells compared with control. Furthermore, KC corneas were associated with intense expression of Gal-1 in the stroma, released by keratocytes. Ultrastructural analysis of keratocytes showed a marked increase of endogenous Gal-3 levels, but not Gal-1, in KC. In vitro, CXL induced significant release of Gal-1 in keratocyte supernatants (116+/-18 ng/mL, P<0.05) and decreased inflammatory biomarkers as interleukin (IL)-6, IL-8, matrix metalloproteinase (MMP)-2 and MMP-9. Gal-3 levels were not detected in the keratocyte supernatants. CONCLUSION: Gal-1 and Gal-3 represent new interesting KC biomarkers as revealed by their different expression patterns in KC and control corneal samples. CXL has an immunosuppressive effect on keratocytes by reducing the release of cytokines and MMPs and increased expression of anti-inflammatory protein Gal-1. PMID- 29439093 TI - Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment. AB - Polycystic ovarian syndrome (PCOS) is a common reproductive disorder frequently associated with a substantial risk factor for ovarian hyperstimulation syndrome (OHSS). Dopamine receptor 2 (D2) agonists, like cabergoline (Cb2), have been used to reduce the OHSS risk. However, lutein granulosa cells (LGCs) from PCOS patients treated with Cb2 still show a deregulated dopaminergic tone (decreased D2 expression and low dopamine production) and increased vascularization compared to non-PCOS LGCs. Therefore, to understand the PCOS ovarian physiology, it is important to explore the mechanisms that underlie syndrome based on the therapeutic effects of Cb2. Here, LGCs from non-PCOS and PCOS patients were cultured with hCG in the absence/presence of Cb2 (n = 12). Subsequently, a transcriptomic-paired design that compared untreated vs treated LGCs within each patient was performed. After transcriptomic analysis, functions and genes were prioritized by systems biology approaches and validated by RT-qPCR. We identified that similar functions were altered in both PCOS and non-PCOS LGCs treated with Cb2; however, PCOS-treated LGCs exhibited more significant changes than non-PCOS. Among the prioritized functions, dopaminergic synapse, vascular endothelial growth factor (VEGF) signaling, apoptosis and ovarian steroidogenesis were highlighted. Finally, network modeling showed CASP9, VEGFA, AKT1, CREB, AIF, MAOA, MAPK14 and BMAL1 as key genes implicated in these pathways in Cb2 response, which might be potential biomarkers for further studies in PCOS. PMID- 29439092 TI - Serum Sodium and Cognition in Older Community-Dwelling Men. AB - BACKGROUND AND OBJECTIVES: Mild hyponatremia is a common finding in older adults; however, the association of lower serum sodium with cognition in older adults is currently unknown. We determined whether lower normal serum sodium is associated with cognitive impairment and risk of cognitive decline in community-dwelling older men. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Five thousand four hundred thirty-five community-dwelling men aged >=65 years who participated in Osteoporotic Fractures in Men, a cohort study with a median follow-up for cognitive function of 4.6 years, were included in this analysis. Multivariable logistic regression was used to examine the association between baseline fasting serum sodium levels and the odds of prevalent cognitive impairment (cross sectional analysis; modified Mini-Mental Status [3MS] score <1.5 SD [<84] below or Trail Making Test Part B time >1.5 SD above the mean [>223 seconds]) and cognitive decline (prospective analysis [n=3611]; decrease in follow-up 3MS score or increase in Trails B time >1.5 SD of the mean score/time change [>9 or >67 seconds]). RESULTS: Participants were aged 74+/-6 years with a fasting mean serum sodium level of 141+/-3 mmol/L. Fifteen percent (n=274), 12% (n=225), and 13% (n=242) had prevalent cognitive impairment in tertiles 1, 2, and 3, respectively. After adjustment, lower serum sodium was associated with prevalent cognitive impairment (tertile 1 [126-140 mmol/L] versus tertile 2 [141-142 mmol/L], odds ratio [OR], 1.30; 95% confidence interval [95% CI], 1.06 to 1.61). Fourteen percent (n=159), 10% (n=125), and 13% (n=159) had cognitive decline in tertiles 1, 2, and 3, respectively. Lower serum sodium was also associated with cognitive decline (tertile 1 versus tertile 2, OR, 1.37; 95% CI, 1.06 to 1.77). Tertile 3 (143-153 mmol/L) was additionally associated with cognitive decline. Results were similar in sensitivity analyses according to clinical cut-offs and by quartiles. CONCLUSIONS: In community-dwelling older men, serum sodium between 126-140, and 126-140 or 143-153 mmol/L, are independently associated with prevalent cognitive impairment and cognitive decline, respectively. PMID- 29439094 TI - Uterine and placental distribution of selected extracellular matrix (ECM) components in the dog. AB - For many years, modifications of the uterine extracellular matrix (ECM) during gestation have not been considered as critical for successful canine (Canis lupus familiaris) pregnancy. However, previous reports indicated an effect of free floating blastocysts on the composition of the uterine ECM. Here, the expression of selected genes involved in structural functions, cell-to-cell communication and inhibition of matrix metalloproteinases were targeted utilizing qPCR and immunohistochemistry. We found that canine free-floating embryos affect gene expression of FN1, ECM1 and TIMP4 This seems to be associated with modulation of trophoblast invasion, and proliferative and adhesive functions of the uterus. Although not modulated at the beginning of pregnancy, the decrease of structural ECM components (i.e. COL1, -3, -4 and LAMA2) from pre-implantation toward post implantation at placentation sites appears to be associated with softening of the tissue in preparation for trophoblast invasion. The further decrease of these components at placentation sites at the time of prepartum luteolysis seems to be associated with preparation for the release of fetal membranes. Reflecting a high degree of communication, intercellular cell adhesion molecules are induced following placentation (Cx26) or increase gradually toward prepartum luteolysis (Cx43). The spatio-temporal expression of TIMPs suggests their active involvement in modulating fetal invasiveness, and together with ECM1, they appear to protect deeper endometrial structures from trophoblast invasion. With this, the dog appears to be an interesting model for investigating placental functions in other species, e.g. in humans in which Placenta accreta appears to share several similarities with canine subinvolution of placental sites (SIPS). In summary, the canine uterine ECM is only moderately modified in early pregnancy, but undergoes vigorous reorganization processes in the uterus and placenta following implantation. PMID- 29439095 TI - Post-Hospital Discharge Care: A Retrospective Cohort Study Exploring the Value of Pharmacist-Enhanced Care and Describing Medication-Related Problems. AB - BACKGROUND Medication-related problems occur at high rates during care transitions. Evidence suggests that pharmacists are well-suited to identify and resolve medication-related problems during hospital admission and at discharge. Additional evidence is needed to understand the impact of face-to-face pharmacist visits in primary care after discharge. The purpose of the study was to describe medication-related problems found during face-to-face pharmacist visits in a medical home after hospital discharge.METHODS A retrospective cohort study was conducted within an academic primary care center staffed by family medicine trained physicians that evaluated patients who attended a hospital follow-up visit with pharmacist-enhanced care (N = 86) versus usual care (N = 86). The primary objective was to describe medication-related problems identified by pharmacists using a modified individualized Medication Assessment and Planning tool for patients receiving pharmacist-enhanced care. Secondary analyses were also conducted to compare 30-day and 60-day hospital readmission and emergency department visit rates in those exposed to pharmacist-enhanced care versus those who were not.RESULTS At baseline, the mean hospitalizations in the prior year were 1.1 +/- 1.7 (pharmacist-enhanced care) and 0.76 +/- 1.2 (usual care), indicating a low initial readmission risk. Of patients receiving pharmacist enhanced care, 97.7% were found to have at least 1 medication-related problem, with an average of 4.36 medication-related problems per patient. The 30-day readmission rate was lower, but not significantly different between groups (8.1% for pharmacist-enhanced care versus 12.8% for usual care; adjusted odds ratio (OR), 0.47; 95% confidence interval (CI), 0.16-1.36).LIMITATIONS Limitations include the retrospective cohort study design and small sample size. Medication related problems were identified and collected prospectively during pharmacist visits.CONCLUSION Medication-related problems are ubiquitous after hospital discharge. Larger prospective studies will be needed to understand the potential value of pharmacist-enhanced care during hospital follow-up visits on readmission rates in low-risk patient populations receiving care within a primary care medical home. PMID- 29439096 TI - North Carolina Medical Student Views on Abortion. AB - BACKGROUND Abortion is a controversial yet common procedure within the United States and North Carolina. Although much effort has been directed at understanding the views of physicians and the general public, the views of medical students on abortion are understudied. This study examines the views of medical students at different stages in training on abortion at a public institution, the University of North Carolina at Chapel Hill School of Medicine.METHODS We surveyed incoming, second year, fourth year, and leave-of absence medical students at the University of North Carolina at Chapel Hill about their views on abortion. We utilized an IRB-approved, anonymous online Qualtrics based, cross-sectional survey during the spring of 2014.RESULTS We received 315 responses (58% response rate) from 98 incoming (54.5%), 126 second year (70.0%), and 91 fourth year and leave-of-absence (49.2%) students. The majority of students, regardless of stage of training, felt abortion was morally acceptable (incoming 64.3%, second year 74.0%, and fourth year and leave-of-absence 70.0%). Of the students who found abortion to be acceptable, second year (80.9%) and fourth year and leave-of-absence (85.5%) students found second-trimester abortion more acceptable than incoming students (57.15%, P = .002); second year students (42.2%) had greater acceptability of third-trimester abortions compared to incoming (26.2%) and fourth year and leave-of-absence students (22.2%; P = .03). Religiosity and Republican political affiliation were associated with more conservative views on abortion (P = .002); however, gender or intention to enter into an obstetrics/gynecology residency were not.LIMITATIONS Our study reflects views from a single institution, the University of North Carolina at Chapel Hill School of Medicine. This limits the generalizability of our findings to the greater population of medical students across the country.CONCLUSION Despite the controversy surrounding abortion, our work suggests that medical students at the University of North Carolina at Chapel Hill School of Medicine have accepting views of abortion. PMID- 29439097 TI - Keeping Up With Cost. PMID- 29439098 TI - The Cost of Health Care in North Carolina. AB - Health care costs in North Carolina are substantial, costing $72.1 billion, or 15.2% of state gross domestic product in 2014. The purpose of this issue is to explore the causes of increased health care costs from a variety of perspectives and highlight current policy attempts to slow costs. PMID- 29439099 TI - Addressing the Root Cause: Rising Health Care Costs and Social Determinants of Health. AB - The United States is the only high-income country that does not have publicly financed universal health care, yet it has one of the world's highest public health care expenditures. This financial outlay is not bringing the desired result in health outcomes because the root cause is not being addressed: solving the systematic disparities and social determinants that lead to poor health and health inequities. Targeting resources for the most vulnerable populations and linking health care plans with community-based organizations to address social determinants of health at the outset is a cost-effective means of preventing expensive chronic illnesses and health inequities. PMID- 29439100 TI - Cultivating New Directions: The Changing Role of Tobacco in North Carolina's Economy. AB - Citing potential economic harm to the state, the tobacco industry has a history of opposing tobacco control efforts in North Carolina. This commentary discusses the changing role of tobacco in North Carolina's economy, argues that tobacco control causes little economic harm to the state, and explores development of alternative industries. PMID- 29439101 TI - Can Consumers Be Smarter Health Care Shoppers in the Quest for Cost Containment? AB - Lawmakers, health plans, and employers are increasingly shifting a greater portion of health care costs onto consumers in hopes that increased price sensitivity will make them become better health care shoppers. However, health care consumerism offers limited potential for system-wide cost containment and presents significant pitfalls for patients. PMID- 29439102 TI - How Relevant Do We Want to Be? PMID- 29439103 TI - Ask Early and Ask Often: How Discussing Costs Could Save Your Patient's Life. AB - Out-of-pocket spending continues to increase, particularly in cancer care. High out-of-pocket expenditures are associated with increased psychosocial distress, lower adherence, and higher mortality. In order to improve cancer-related outcomes, we must come up with interventions directed at reducing cancer-related financial toxicity. In this article, we highlight the most promising interventions. PMID- 29439104 TI - Costs at the End of Life: Perspectives for North Carolina. AB - Many elders require supportive services, with many costs covered by Medicaid. Once terminal illness sets in, palliative care and hospice may help control cost while ensuring quality. This commentary reviews trends in cost at the end of life and describes selected strategies to improve patient-centered care in North Carolina. PMID- 29439105 TI - The Multi-Billion Dollar Drug-Sensitive Spending Opportunity. AB - Chronic diseases increase utilization and avoidable drug-sensitive spending, but little is done to optimize medication use and drive value. Value-based approaches to health care financing should shift focus to drug-sensitive spending to balance patient access and quality improvement with cost containment. PMID- 29439106 TI - Rural Health Care Costs: Are They Higher and Why Might They Differ from Urban Health Care Costs? AB - Do health care costs differ between rural and urban populations, and if so, why might that be? Rural Americans are more vulnerable than their urban counterparts, which could lead us to suspect rural health care costs are higher. However, the answer may differ depending on how costs are measured and who is paying. PMID- 29439107 TI - The North Carolina State Health Plan for Teachers and State Employees: Strategies in Creating Financial Stability While Improving Member Health. AB - The North Carolina State Health Plan provides health care coverage to more than 700,000 members, including teachers, state employees, retirees, current and former lawmakers, state university and community college personnel, and their dependents. The State Health Plan is a division of the North Carolina Department of State Treasurer, self-insured, and exempt from the Employee Retirement Income Security Act as a government-sponsored plan. With health care costs rising at rates greater than funding, the Plan must take measures to stem cost growth while ensuring access to quality health care. The Plan anticipates focusing on strategic initiatives that drive results and cost savings while improving member health to protect the Plan's financial future. PMID- 29439108 TI - Hard Promises: Has the ACA Made Health Care More Affordable? PMID- 29439109 TI - Toward Value in Health Care: Perspectives, Priorities, and Policy. AB - The goal of value-based care is simple: deliver care that improves the health of patients at the lowest possible cost. In recent years, concerns about health care value have led to the emergence of multiple value-based frameworks for decision making. This commentary describes how the concept of value is defined for different stakeholders, discusses the impact of the value-based movement, and offers perspective on future directions for prioritization and policymaking. PMID- 29439110 TI - Running the Numbers: Aging and Cost of Health Care in North Carolina. PMID- 29439111 TI - Spotlight on the Safety Net: Charlotte Center for Legal Advocacy. PMID- 29439112 TI - Three Ways to Transform Worksite Wellness Programs. PMID- 29439114 TI - Correction: Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma. PMID- 29439113 TI - Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment. AB - OBJECTIVE: Hodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics. DESIGN: 54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS/BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111). RESULTS: KRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, p<0.001). Loss of MLH1/PMS2 staining and MLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome. CONCLUSIONS: We have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment. PMID- 29439117 TI - The pericyte-glia interface at the blood-brain barrier. AB - The cerebrovasculature is a multicellular structure with varying rheological and permeability properties. The outer wall of the brain capillary endothelium is enclosed by pericytes and astrocyte end feet, anatomically assembled to guarantee barrier functions. We, here, focus on the pericyte modifications occurring in disease conditions, reviewing evidence supporting the interplay amongst pericytes, the endothelium, and glial cells in health and pathology. Deconstruction and reactivity of pericytes and glial cells around the capillary endothelium occur in response to traumatic brain injury, epilepsy, and neurodegenerative disorders, impacting vascular permeability and participating in neuroinflammation. As this represents a growing field of research, addressing the multicellular reorganization occurring at the outer wall of the blood-brain barrier (BBB) in response to an acute insult or a chronic disease could disclose novel disease mechanisms and therapeutic targets. PMID- 29439116 TI - Brr6 and Brl1 locate to nuclear pore complex assembly sites to promote their biogenesis. AB - The paralogous Brr6 and Brl1 are conserved integral membrane proteins of the nuclear envelope (NE) with an unclear role in nuclear pore complex (NPC) biogenesis. Here, we analyzed double-degron mutants of Brr6/Brl1 to understand this function. Depletion of Brr6 and Brl1 caused defects in NPC biogenesis, whereas the already assembled NPCs remained unaffected. This NPC biogenesis defect was not accompanied by a change in lipid composition. However, Brl1 interacted with Ndc1 and Nup188 by immunoprecipitation, and with transmembrane and outer and inner ring NPC components by split yellow fluorescent protein analysis, indicating a direct role in NPC biogenesis. Consistently, we found that Brr6 and Brl1 associated with a subpopulation of NPCs and emerging NPC assembly sites. Moreover, BRL1 overexpression affected NE morphology without a change in lipid composition and completely suppressed the nuclear pore biogenesis defect of nup116Delta and gle2Delta cells. We propose that Brr6 and Brl1 transiently associate with NPC assembly sites where they promote NPC biogenesis. PMID- 29439118 TI - Understanding novel mechanisms of microbial pathogenesis in chronic lung disease: implications for new therapeutic targets. AB - Airway infections are considered as one of the vital factors driving the pathophysiology of chronic lung disease with significant influences on disease trajectory. Opportunistic lung microbes in diseased conditions induce excessive exacerbations and contribute to airflow limitation. Though there has been considerable amount of information that ascertains their links with airway inflammation, the intricate interaction in clinical conditions are poorly understood and requires further deciphering. Current therapeutic interventions for such pathologies are few and lack the ability to modulate underlying dysfunctional immunity as well as suppress the excessive infectious conditions. Thus, in this Commentary we provide a focused outlook on the mechanisms involved in microbial infestation in lung diseases and provides important information on new therapeutic interventions including the potential role of Resolvins and their derivatives as alternative therapeutic agents in combating such multifaceted pathological mechanisms. PMID- 29439119 TI - A kinetic account for amphetamine-induced monoamine release. AB - The plasmalemmal monoamine transporters for dopamine, norepinephrine, and serotonin (SERT) are targets for amphetamines. In vivo, amphetamines elicit most, if not all, of their actions by triggering monoamine efflux. This is thought to be accomplished by an amphetamine-induced switch from the forward-transport to the substrate-exchange mode. The mechanism underlying this switch has remained elusive; available kinetic models posit that substrates and cosubstrate Na+ ions bind either in a random or in a sequential order. Neither can account for all reported experimental observations. We used electrophysiological recordings to interrogate crucial conformational transitions associated with the binding of five different substrates (serotonin, para-chloroamphetamine, and the high affinity naphthyl-propan-amines PAL-287, PAL-1045, and PAL-1046) to human SERT expressed in HEK293 cells; specifically, we determined the relaxation kinetics of SERT from a substrate-loaded to a substrate-free state at various intracellular and extracellular Na+ concentrations. These rates and their dependence on intracellular and extracellular Na+ concentrations differed considerably between substrates. We also examined the effect of K+ on substrate affinity and found that K+ enhanced substrate dissociation. A kinetic model was developed, which allowed for random, but cooperative, binding of substrate and Na+ (or K+). The synthetic data generated by this model recapitulated the experimental observations. More importantly, the cooperative binding model accounted for the releasing action of amphetamines without any digression from alternating access. To the best of our knowledge, this model is the first to provide a mechanistic framework for amphetamine-induced monoamine release and to account for the findings that some substrates are less efficacious than others in promoting the substrate-exchange mode. PMID- 29439120 TI - Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE. AB - BACKGROUND AND PURPOSE: Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2* weighted imaging on 7T MR imaging. MATERIALS AND METHODS: Brain MR imaging using T1-weighted MP2RAGE at 500-MUm isotropic resolution, T2*-weighted gradient-echo, and T2*-weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry. RESULTS: MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P < .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P < .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical (r = 0.86, P < .001) and leukocortical lesion volume (r = 0.70, P < .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage. CONCLUSIONS: A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications. PMID- 29439121 TI - Brain Imaging in Cases with Positive Serology for Dengue with Neurologic Symptoms: A Clinicoradiologic Correlation. AB - BACKGROUND AND PURPOSE: Dengue is a common arboviral disease, which uncommonly involves the brain. There has been a recent surge in dengue cases and dengue related deaths in tropical countries. The aim of this study was to describe brain imaging findings in patients with dengue infection having neurologic symptoms. MATERIALS AND METHODS: Thirty-five patients with positive serology for dengue with CNS symptoms undergoing imaging of the brain were included in the study. Clinical, laboratory, and imaging parameters were assessed and correlated to poor outcome. RESULTS: A Glasgow Coma Scale score of <=12 at presentation, clinical classification of severe-type dengue, and the presence of acute renal failure were associated with poor outcome. Imaging parameters associated with poor outcome were involvement of the thalami and cerebellar peduncles and the presence of diffusion restriction and hemorrhagic foci in the brain parenchyma. CONCLUSIONS: Although not specific, dengue infection has imaging findings that can be used to narrow down the differential list and help in prognostication. PMID- 29439123 TI - Endovascular Thrombectomy in Wake-Up Stroke and Stroke with Unknown Symptom Onset. AB - BACKGROUND AND PURPOSE: Mechanical thrombectomy in acute ischemic stroke within 6 hours of symptom onset is effective and safe. However, in many patients, information on the beginning of symptoms is not available. Patients can be divided into those with wake-up stroke and daytime-unwitnessed stroke. Evidence on outcome and complications after mechanical thrombectomy in wake-up stroke and daytime-unwitnessed stroke is rare. A potential beneficial effect of mechanical thrombectomy in selected patients with wake-up stroke or daytime-unwitnessed stroke is suspected. MATERIALS AND METHODS: We analyzed 1073 patients with anterior circulation stroke undergoing mechanical thrombectomy between 2010 and 2016. Patients with wake-up stroke and daytime-unwitnessed stroke were compared with controls receiving mechanical thrombectomy as the standard of care. We assessed good functional outcome (mRS <= 2 at 3 months), mortality rates, and frequencies of symptomatic intracranial hemorrhage. Subgroup analyses tried to detect influences of patient selection via further imaging modalities (MR imaging, CTP; wake-up stroke [advanced], daytime-unwitnessed stroke [advanced]) on outcome and safety. RESULTS: There was no significant difference in good functional outcome between patients with wake-up stroke and controls (35.9% versus 38.3%, P = .625). Outcome in patients with daytime-unwitnessed stroke was inferior compared with controls (27.3%, P = .007). Groups did not differ in all cause mortality at day 90 (P = .224) and the rate of symptomatic intracranial hemorrhage (P = .292). Advanced imaging improved the frequency of good functional outcome (non-wake-up stroke [advanced] versus wake-up stroke [advanced]: OR, 2.92; 95% CI, 1.32-6.45; non-daytime-unwitnessed stroke [advanced] versus daytime unwitnessed stroke [advanced]: OR, 2.09; 95% CI, 1.03-4.25) with an additional reduction in all-cause mortality (non-daytime-unwitnessed stroke [advanced] versus daytime-unwitnessed stroke [advanced]: OR, 0.42; 95% CI, 0.20-0.88). CONCLUSIONS: Mechanical thrombectomy in selected patients with wake-up stroke allows a good functional outcome comparable with that of controls. Outcome after mechanical thrombectomy in daytime-unwitnessed stroke seems to be inferior compared with that in controls. Advanced imaging modalities may increase the frequency of good functional outcome in both patients with wake-up stroke and daytime-unwitnessed stroke. PMID- 29439122 TI - Iron-Insensitive Quantitative Assessment of Subcortical Gray Matter Demyelination in Multiple Sclerosis Using the Macromolecular Proton Fraction. AB - BACKGROUND AND PURPOSE: Fast macromolecular proton fraction mapping is a recent quantitative MR imaging method for myelin assessment. The objectives of this study were to evaluate the macromolecular proton fraction as a measure of demyelination in subcortical GM structures in multiple sclerosis and assess a potential relationship between demyelination and excess iron deposition using the macromolecular proton fraction and T2* mapping. MATERIALS AND METHODS: Macromolecular proton fraction and T2* maps were obtained from 12 healthy controls, 18 patients with relapsing-remitting MS, and 12 patients with secondary progressive MS using 3T MR imaging. Parameter values in the caudate nucleus, globus pallidus, putamen, substantia nigra, and thalamus were compared between groups and correlated to clinical data. RESULTS: The macromolecular proton fraction in all subcortical structures and T2* in the globus pallidus, putamen, and caudate nucleus demonstrated a significant monotonic decrease from controls to patients with relapsing-remitting MS and from those with relapsing-remitting MS to patients with secondary-progressive MS. The macromolecular proton fraction in all subcortical structures significantly correlated with the Expanded Disability Status Scale and MS Functional Composite scores with absolute Pearson correlation coefficient (r) values in a range of 0.4-0.6. Significant correlations (r = -0.4 to -0.6) were also identified between the macromolecular proton fraction and the 9-Hole Peg Test, indicating a potential relationship with nigrostriatal pathway damage. Among T2* values, weak significant correlations with clinical variables were found only in the putamen. The macromolecular proton fraction did not correlate with T2* in any of the studied anatomic structures. CONCLUSIONS: The macromolecular proton fraction provides an iron-insensitive measure of demyelination. Myelin loss in subcortical GM structures in MS is unrelated to excess iron deposition. Subcortical GM demyelination is more closely associated with the disease phenotype and disability than iron overload. PMID- 29439124 TI - Dual-Energy CT in Hemorrhagic Progression of Cerebral Contusion: Overestimation of Hematoma Volumes on Standard 120-kV Images and Rectification with Virtual High Energy Monochromatic Images after Contrast-Enhanced Whole-Body Imaging. AB - BACKGROUND AND PURPOSE: In patients with hemorrhagic contusions, hematoma volumes are overestimated on follow-up standard 120-kV images obtained after contrast enhanced whole-body CT. We aimed to retrospectively determine hemorrhagic progression of contusion rates on 120-kV and 190-keV images derived from dual energy CT and the magnitude of hematoma volume overestimation. MATERIALS AND METHODS: We retrospectively analyzed admission and follow-up CT studies in 40 patients with hemorrhagic contusions. After annotating the contusions, we measured volumes from admission and follow-up 120-kV and 190-keV images using semiautomated 3D segmentation. Bland-Altman analysis was used for hematoma volume comparison. RESULTS: On 120-kV images, hemorrhagic progression of contusions was detected in 24 of the 40 patients, while only 17 patients had hemorrhagic progression of contusions on 190-keV images (P = .008). Hematoma volumes were systematically overestimated on follow-up 120-kV images (9.68 versus 8 mm3; mean difference, 1.68 mm3; standard error, 0.37; P < .001) compared with 190-keV images. There was no significant difference in volumes between admission 120-kV and 190-keV images. Mean and median percentages of overestimation were 29% (95% CI, 18-39) and 22% (quartile 3 - quartile 1 = 36.8), respectively. CONCLUSIONS: The 120-kV images, which are comparable with single-energy CT images, significantly overestimated the hematoma volumes, hence the rate of hemorrhagic progression of contusions, after contrast-enhanced whole-body CT. Hence, follow up of hemorrhagic contusions should be performed on dual-energy CT, and 190-keV images should be used for the assessment of hematoma volumes. PMID- 29439125 TI - Evaluation of Leptomeningeal Contrast Enhancement Using Pre-and Postcontrast Subtraction 3D-FLAIR Imaging in Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Leptomeningeal contrast enhancement is found in patients with multiple sclerosis, though reported rates have varied. The use of 3D-fluid attenuated inversion recovery pre- and postcontrast subtraction imaging may more accurately determine the frequency of leptomeningeal contrast enhancement. The purpose of this study was to investigate the frequency of leptomeningeal contrast enhancement using the pre- and postcontrast subtraction approach and to evaluate 3 different methods of assessing the presence of leptomeningeal contrast enhancement. MATERIALS AND METHODS: We enrolled 258 consecutive patients with MS (212 with relapsing-remitting MS, 32 with secondary-progressive MS, and 14 with clinically isolated syndrome) who underwent both pre- and 10-minute postcontrast 3D-FLAIR sequences after a single dose of gadolinium injection on 3T MR imaging. The analysis included leptomeningeal contrast-enhancement evaluation on 3D-FLAIR postcontrast images in native space (method A), on pre- and postcontrast 3D-FLAIR images in native space (method B), and on pre-/postcontrast 3D-FLAIR coregistered and subtracted images (method C, used as the criterion standard). RESULTS: In total, 51 (19.7%) patients with MS showed the presence of leptomeningeal contrast enhancement using method A; 39 (15.1%), using method B; and 39 (15.1%), using method C (P = .002). Compared with method C as the criterion standard, method A showed 89.8% sensitivity and 92.7% specificity, while method B showed 84.6% sensitivity and 97.3% specificity (P < .001) at the patient level. Reproducibility was the highest using method C (kappa agreement, r = 088, P < .001). The mean time to analyze the 3D-FLAIR images was significantly lower with method C compared with methods A and B (P < .001). CONCLUSIONS: 3D-FLAIR postcontrast imaging offers a sensitive method for detecting leptomeningeal contrast enhancement in patients with MS. However, the use of subtraction imaging helped avoid false-positive cases, decreased reading time, and increased the accuracy of leptomeningeal contrast-enhancement foci detection in a clinical routine. PMID- 29439126 TI - Mechanical thrombectomy of acute ischemic stroke with a new intermediate aspiration catheter: preliminary results. AB - BACKGROUND AND PURPOSE: To report clinical and procedural outcomes of acute ischemic stroke patients after endovascular treatment with the new thromboaspiration catheter AXS Catalyst 6. METHODS: Patients with anterior and posterior circulation stroke were selected. Successful reperfusion defined as a Thrombolysis in Cerebral Infarction (TICI) score >=2 b and 3-month functional independence defined as a modified Rankin Scale (mRS) <=2 were the main efficacy outcomes. Symptomatic intracranial hemorrhage and mortality were the main safety outcomes. RESULTS: 107 patients were suitable for analysis. Mean age was 73.18+/ 12.62 year and median baseline NIHSS was 17 (range: 3-32). The most frequent site of occlusion was the middle cerebral artery (MCA) (60.7%). 76.6% of patients were treated with AXS Catalyst 6 alone without the need for rescue devices or thromboaspiration catheters. Successful reperfusion was achieved in 84.1%, functional independence in 47.6%, symptomatic intracranial hemorrhage occurred in 3.7%, and mortality in 21.4%. CONCLUSIONS: Endovascular treatment with AXS Catalyst 6 proved to be safe, technically feasible, and effective. Comparison analyses with other devices for mechanical thrombectomy are needed. PMID- 29439127 TI - ELVO: an operational definition. PMID- 29439128 TI - Comparison of Proteomic Quantification Approaches for Hepatic Drug Transporters: Multiplexed Global Quantitation Correlates with Targeted Proteomic Quantitation. AB - Targeted protein quantification using liquid chromatography-tandem mass spectrometry with stable isotope-labeled standards is recognized as the gold standard of practice for protein quantification. Such assays, however, can only cover a limited number of proteins, and developing targeted methods for larger numbers of proteins requires substantial investment. Alternatively, large-scale global proteomic experiments along with computational methods such as the "total protein approach" (TPA) have the potential to provide extensive protein quantification. In this study, we compared the TPA-based quantitation of seven major hepatic uptake transporters in four human liver tissue samples using global proteomic data obtained from two multiplexed tandem mass tag experiments (performed in two independent laboratories) to the quantitative data from targeted proteomic assays. The TPA-based quantitation of these hepatic transporters [sodium-taurocholate cotransporting polypeptide (NTCP/SLC10A1), organic anion transporter 2 (OAT2/SLC22A7), OAT7/SLC22A9, organic anion transporting polypeptide 1B1 (OATP1B1/SLCO1B1), OATP1B3/SLCO1B3, OATP2B1/SLCO2B1, and organic cation transporter (OCT1/SLC22A1)] showed good-to-excellent correlations (Pearson r = 0.74-1.00) to the targeted data. In addition, the values were similar to those measured by targeted proteomics with 71% and 86% of the data sets falling within 3-fold of the targeted data. A comparison of the TPA based quantifications of enzyme abundances to available literature data showed that the majority of the enzyme quantifications fell within the reference data intervals. In conclusion, these results demonstrate the capability of multiplexed global proteomic experiments to detect differences in protein expression between samples and provide reasonable estimations of protein expression levels. PMID- 29439129 TI - Simultaneous Assessment In Vitro of Transporter and Metabolic Processes in Hepatic Drug Clearance: Use of a Media Loss Approach. AB - Hepatocyte drug depletion-time assays are well established for determination of metabolic clearance in vitro. The present study focuses on the refinement and evaluation of a "media loss" assay, an adaptation of the conventional depletion assay involving centrifugation of hepatocytes prior to sampling, allowing estimation of uptake in addition to metabolism. Using experimental procedures consistent with a high throughput, a selection of 12 compounds with a range of uptake and metabolism characteristics (atorvastatin, cerivastatin, clarithromycin, erythromycin, indinavir, pitavastatin, repaglinide, rosuvastatin, saquinavir, and valsartan, with two control compounds-midazolam and tolbutamide) were investigated in the presence and absence of the cytochrome P450 inhibitor 1 aminobenzotriazole and organic anion transporter protein inhibitor rifamycin SV in rat hepatocytes. Data were generated simultaneously for a given drug, and provided, through the use of a mechanistic cell model, clearance terms characterizing metabolism, active and passive uptake, together with intracellular binding and partitioning parameters. Results were largely consistent with the particular drug characteristics, with active uptake, passive diffusion, and metabolic clearances ranging between 0.4 and 777, 3 and 383, and 2 and 236 MUl/min per milligram protein, respectively. The same experiments provided total and unbound drug cellular partition coefficients ranging between 3.8 and 254 and 2.3 and 8.3, respectively, and intracellular unbound fractions between 0.014 and 0.263. Following in vitro-in vivo extrapolation, the lowest prediction bias was noted using uptake clearance, compared with metabolic clearance or apparent clearance from the media loss assay alone. This approach allows rapid and comprehensive characterization of hepatocyte drug disposition valuable for prediction of hepatic processes in vivo. PMID- 29439130 TI - Limb- and Person-Level Risk Factors for Lower-Limb Amputation in the Prospective Seattle Diabetic Foot Study. AB - OBJECTIVE: Diabetes is the leading cause of nontraumatic lower-limb amputations in the U.S., but no research has prospectively examined associations between limb specific measurements and amputation risk among patients without foot ulcer. We investigated amputation risk by limb in relation to the same limb- and person level factors. RESEARCH DESIGN AND METHODS: We conducted a 22-year prospective study among 1,461 male patients with diabetes without foot ulcer (mean age 62.4 years), with 2,893 lower limbs among subjects recruited between 1990 and 2002 from one Department of Veterans Affairs general internal medicine clinic. The following information was collected: demographic, lifestyle, and diabetes characteristics; visual acuity; kidney function (estimated glomerular filtration rate [eGFR]); and lower-limb measurements including presence of Charcot deformity, sensory neuropathy by 10-g monofilament, dorsal foot transcutaneous oximetry (TcPO2) at 44 degrees C, and ankle-brachial index (ABI). RESULTS: Over 25,735 limb-years, 136 amputations occurred. A multivariable Cox model identified multiple independent risk factors: sensory neuropathy (hazard ratio 3.09 [95% CI 2.02-4.74]), ABI <=0.5 vs. >0.9 to <1.3 (3.98 [2.31-6.85]), ABI >=1.3 vs. >0.9 to <1.3 (2.20 [1.18-4.09]), 1-SD decrease in eGFR (1.18 [1.00-1.38]), poor vision (1.70 [1.05-2.73]), body weight in 21.4-kg increments (0.78 [0.61-0.98]), and age >70 years vs. <57 years (0.13 [0.04-0.38]). Although TcPO2 was not significantly associated with amputation overall, TcPO2 <26 mmHg significantly predicted a higher risk in the ABI >=1.3 category. CONCLUSIONS: Arterial disease and neuropathy emerged as the only limb-specific risk factors for amputation, but these and several person-level factors may be amenable to prevention or treatment interventions to potentially reduce diabetic amputation risk. PMID- 29439131 TI - Doctors' behaviour is as important as their clinical skills, say medical leaders. PMID- 29439132 TI - GTL1 and DF1 regulate root hair growth through transcriptional repression of ROOT HAIR DEFECTIVE 6-LIKE 4 in Arabidopsis. AB - How plants determine the final size of growing cells is an important, yet unresolved, issue. Root hairs provide an excellent model system with which to study this as their final cell size is remarkably constant under constant environmental conditions. Previous studies have demonstrated that a basic helix loop helix transcription factor ROOT HAIR DEFECTIVE 6-LIKE 4 (RSL4) promotes root hair growth, but how hair growth is terminated is not known. In this study, we demonstrate that a trihelix transcription factor GT-2-LIKE1 (GTL1) and its homolog DF1 repress root hair growth in Arabidopsis Our transcriptional data, combined with genome-wide chromatin-binding data, show that GTL1 and DF1 directly bind the RSL4 promoter and regulate its expression to repress root hair growth. Our data further show that GTL1 and RSL4 regulate each other, as well as a set of common downstream genes, many of which have previously been implicated in root hair growth. This study therefore uncovers a core regulatory module that fine tunes the extent of root hair growth by the orchestrated actions of opposing transcription factors. PMID- 29439134 TI - Self-organizing periodicity in development: organ positioning in plants. AB - Periodic patterns during development often occur spontaneously through a process of self-organization. While reaction-diffusion mechanisms are often invoked, other types of mechanisms that involve cell-cell interactions and mechanical buckling have also been identified. Phyllotaxis, or the positioning of plant organs, has emerged as an excellent model system to study the self-organization of periodic patterns. At the macro scale, the regular spacing of organs on the growing plant shoot gives rise to the typical spiral and whorled arrangements of plant organs found in nature. In turn, this spacing relies on complex patterns of cell polarity that involve feedback between a signaling molecule - the plant hormone auxin - and its polar, cell-to-cell transport. Here, we review recent progress in understanding phyllotaxis and plant cell polarity and highlight the development of new tools that can help address the remaining gaps in our understanding. PMID- 29439135 TI - Mapping human development at single-cell resolution. AB - Human development is regulated by spatiotemporally restricted molecular programmes and is pertinent to many areas of basic biology and human medicine, such as stem cell biology, reproductive medicine and childhood cancer. Mapping human development has presented significant technological, logistical and ethical challenges. The availability of established human developmental biorepositories and the advent of cutting-edge single-cell technologies provide new opportunities to study human development. Here, we present a working framework for the establishment of a human developmental cell atlas exploiting single-cell genomics and spatial analysis. We discuss how the development atlas will benefit the scientific and clinical communities to advance our understanding of basic biology, health and disease. PMID- 29439133 TI - The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse. AB - Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The pma mutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of Limk1 by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans. PMID- 29439137 TI - Clubfoot: Limk1 hits a nerve. PMID- 29439136 TI - Notch and steroid signalling carve out a niche. PMID- 29439138 TI - A plug for vascular integrity. PMID- 29439139 TI - Resveratrol attenuates mechanical compression-induced nucleus pulposus cell apoptosis through regulating the ERK1/2 signaling pathway in a disc organ culture. AB - BACKGROUND: Nucleus pulposus (NP) cell apoptosis is a typical feature within the degenerative disc. High magnitude compression significantly promotes NP cell apoptosis. Several studies have indicated that resveratrol has protective effects on disc cell's normal biology. OBJECTIVE: The present study aims to investigate whether resveratrol can attenuate mechanical overloading-induced NP cell apoptosis in a disc organ culture. METHODS: Isolated porcine discs were cultured in culture chambers of a mechanically active perfusion bioreactor and subjected to a relatively high magnitude compression (1.3 MPa at a frequency of 1.0 Hz for 2 h once per day) for 7 days. Different concentrations (50 and 100 MUM) of resveratrol were added into the culture medium to observe the protective effects of resveratrol against NP cell apoptosis under mechanical compression. The noncompressed discs were used as controls. RESULTS: Similar with the previous studies, this high magnitude compression significantly promoted NP cell apoptosis, reflected by the increased number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining-positive NP cells and enzyme (caspase-9 and caspase-3) activity, the up-regulated expression of proapoptotic molecules (Bax and caspase-3/cleaved caspase-3), and down-regulated expression of antiapoptotic molecule (Bcl-2). However, resveratrol partly attenuated NP cell apoptosis under this high magnitude compression in a dose-dependent manner. Additionally, though the ERK1/2 pathway was significantly activated in the mechanical compression group, resveratrol partly attenuated activation of the ERK1/2 pathway under mechanical compression in a dose-dependent manner. CONCLUSION: Resveratrol attenuates mechanical overloading-induced NP cell apoptosis in a dose-dependent manner, and inhibiting activation of the ERK1/2 pathway may be one potential mechanism behind this regulatory process. PMID- 29439140 TI - Image processing for cryogenic transmission electron microscopy of symmetry mismatched complexes. AB - Cryogenic transmission electron microscopy (cryo-TEM) is a high-resolution biological imaging method, whereby biological samples, such as purified proteins, macromolecular complexes, viral particles, organelles and cells, are embedded in vitreous ice preserving their native structures. Due to sensitivity of biological materials to the electron beam of the microscope, only relatively low electron doses can be applied during imaging. As a result, the signal arising from the structure of interest is overpowered by noise in the images. To increase the signal-to-noise ratio, different image processing-based strategies that aim at coherent averaging of signal have been devised. In such strategies, images are generally assumed to arise from multiple identical copies of the structure. Prior to averaging, the images must be grouped according to the view of the structure they represent and images representing the same view must be simultaneously aligned relatively to each other. For computational reconstruction of the three dimensional structure, images must contain different views of the original structure. Structures with multiple symmetry-related substructures are advantageous in averaging approaches because each image provides multiple views of the substructures. However, the symmetry assumption may be valid for only parts of the structure, leading to incoherent averaging of the other parts. Several image processing approaches have been adapted to tackle symmetry mismatched substructures with increasing success. Such structures are ubiquitous in nature and further computational method development is needed to understanding their biological functions. PMID- 29439141 TI - CRISPR/Cas9-mediated mosaic mutation of SRY gene induces hermaphroditism in rabbits. AB - Hermaphroditism is a rare disorder that affects sexual development, resulting in individuals with both male and female sexual organs. Hermaphroditism is caused by anomalies in genes regulating sex determination, gonad development, or expression of hormones and their receptors during embryonic development during sexual differentiation. SRY is a sex-determination gene on the Y chromosome that is responsible for initiating male sex determination in mammals. In this study, we introduced CRISPR/Cas9-mediated mutations in the high-mobility-group (HMG) region of the rabbit SRY As expected, SRY-mutant chimeric rabbits were diagnosed with hermaphroditism, characterized by possessing ovotestis, testis, ovary and uterus simultaneously. Histopathology analysis revealed that the testicular tissue was immature and lacked spermatogenic cells, while the ovarian portion appeared normal and displayed follicles at different stages. This is the first report of a rabbit hermaphroditism model generated by the CRISPR/Cas9 system. This novel rabbit model could advance our understanding of the pathogenesis of hermaphroditism, and identify novel therapies for human clinical treatment of hermaphroditism. PMID- 29439142 TI - Genome-wide differential expression profiling of mRNAs and lncRNAs associated with prolificacy in Hu sheep. AB - Reproductive ability, especially prolificacy, impacts sheep profitability. Hu sheep, a unique Chinese breed, is recognized for its high prolificacy (HP), early sexual maturity, and year-round estrus. However, little is known about the molecular mechanisms underlying HP in Hu sheep. To explore the potential mRNAs and long non-coding RNAs (lncRNAs) involved in Hu sheep prolificacy, we performed an ovarian genome-wide analysis of mRNAs and lncRNAs during the follicular stage using Hu sheep of HP (litter size = 3; three consecutive lambings) and low prolificacy (LP, litter size = 1; three consecutive lambings). Plasma luteinizing hormone (LH) concentration was higher in the HP group than in the LP group (P<0.05) during the follicular stage. Subsequently, 76 differentially expressed mRNAs (DE-mRNAs) and five differentially expressed lncRNAs (DE-lncRNAs) were identified by pairwise comparison; quantitative real-time PCR (qRT-PCR) analysis of ten randomly selected DE genes (mRNA and lncRNA) were consistent with the sequencing results. Gene Ontology (GO) analysis of DE-mRNAs revealed significant enrichment in immune response components, actin filament severing and phagocytosis. Pathway enrichment analysis of DE-mRNAs indicated a predominance of immune function pathways, including phagosomes, lysosomes, and antigen processing. We constructed a co-expression network of DE-mRNAs and mRNA-lncRNAs, with C1qA, CD53, cathepsin B (CTSB), CTSS, TYROBP, and AIF1 as the hub genes. Finally, the expression of lysosomal protease cathepsin genes, CTSB and cathepsin D (CTSD), were significantly up-regulated in sheep ovaries in the HP group compared with the LP group (P<0.05). These differential mRNAs and lncRNAs may provide information on the molecular mechanisms underlying sheep prolificacy. PMID- 29439143 TI - Anarchy in the UPR: A Ca2+-insensitive PKC inhibits SERCA activity to promote ER stress. AB - Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in Western countries, and is linked to the development of liver cancer and Type 2 diabetes (T2D). It is strongly associated with obesity, but the dysregulation of liver lipid storage is not fully understood. Fatty acid oversupply to hepatocytes can establish a vicious cycle involving diminished protein folding, endoplasmic reticulum (ER) stress, insulin resistance and further lipogenesis. This commentary discusses the recent findings of Lai et al. published in Bioscience Reports, that implicate protein kinase C delta (PKCdelta) activation by fatty acids in the inhibition of the SERCA Ca2+ pump, resulting in reduced ER Ca2+ loading and protein misfolding. PKCdelta therefore represents a target for the treatment of both steatosis and insulin resistance, key to the prevention of NAFLD and T2D. PMID- 29439144 TI - Coronary computed tomography angiography detection of short- and long-term outcomes after heart valve surgery with high risk cardiovascular patients. AB - Coronary computed tomography angiography (CCTA) is a promising alternative technique to detect significant coronary artery lesions in high-risk cardiovascular patients with left ventricular dysfunction (left ventricular ejection fractions < 40%) referred for elective valve surgery, while little research about the use of CCTA to detect the outcomes of heart valve surgery was performed. Forty-six consecutive high-risk cardiovascular patients with the New York Heart Association (NYHA) classification were retrospectively studied. Immediate, 10-week, 20-week, and 40-week outcomes after heart valve surgery were assessed with CCTA. Patients' average age at the time of surgery was 73 years, with the majority being male (54.35%). Among the CCTA parameters detected after 10, 20, and 40 weeks after heart valve surgery, only segment involvement score (SIS) did reach statistical significance when compared with baseline levels. The cumulative mortality rate at 10, 20, and 40 weeks were 19.56%, 30.43%, and 39.13% respectively. It can be seen that the early death is mainly due to complications, and with the time-lapse of surgery, the impact of complications on death is gradually eliminated. CCTA might be a useful tool to detect the outcomes of short and long-term outcomes after heart valve surgery with high risk cardiovascular patients, and SIS level is associated with the short- and long-term outcomes. PMID- 29439146 TI - GMC responds to concerns raised by Bawa-Garba case. PMID- 29439145 TI - Association between the ABCA1 rs1800977 polymorphism and susceptibility to type 2 diabetes mellitus in a Chinese Han population. AB - ATP-binding cassette transporter A1 (ABCA1) is associated with serum high-density lipoprotein (HDL) levels. Several studies have demonstrated that individuals with a high HDL cholesterol level have a reduced risk of incident type 2 diabetes mellitus (T2DM). Therefore, we conducted a case-control study including 508 T2DM patients and 614 controls to explore the association between the ABCA1 rs1800977 polymorphism and T2DM risk in a Chinese Han population. Genotyping was performed using matrix-assisted laser desorption/lionization time-of-flight mass spectrometry. Our results indicate that the TT genotype of the rs1800977 polymorphism was associated with a decreased risk of T2DM compared to the CC genotype. The T allele of the rs1800977 polymorphism was also related with a decreased risk of T2DM. There was no significant association between clinical parameters (HDL, low-density lipoprotein, cholesterol, body mass index, and age) and rs1800977 polymorphism genotypes. In conclusion, the ABCA1 rs1800977 polymorphism may contribute to the development of T2DM. However, larger studies with more diverse ethnic populations are needed to confirm these results. PMID- 29439147 TI - Antisense Inhibition of Protein Tyrosine Phosphatase 1B With IONIS-PTP-1BRx Improves Insulin Sensitivity and Reduces Weight in Overweight Patients With Type 2 Diabetes. AB - OBJECTIVE: To evaluate safety and efficacy of IONIS-PTP-1BRx, a second-generation 2'-O-methoxyethyl antisense inhibitor of protein tyrosine phosphatase 1B, as add on therapy in overweight patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea therapy. RESEARCH DESIGN AND METHODS: In this phase II, double-blind, randomized, placebo-controlled, multicenter trial, overweight and obese patients (BMI >=27 kg/m2) with type 2 diabetes (HbA1c >=7.5% [58 mmol/mol] and <=10.5% [91 mmol/mol]) on a stable dose of metformin alone or with sulfonylurea were randomized 2:1 to IONIS-PTP-1BRx 200 mg (n = 62) or placebo (n = 30) once weekly for 26 weeks. RESULTS: Mean baseline HbA1c was 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol) in placebo and active treatment, respectively. At week 27, IONIS-PTP-1BRx reduced mean HbA1c levels by -0.44% ( 4.8 mmol/mol; P = 0.074) from baseline and improved leptin (-4.4 ng/mL; P = 0.007) and adiponectin (0.99 MUg/mL; P = 0.026) levels compared with placebo. By week 36, mean HbA1c was significantly reduced (-0.69% [-7.5 mmol/mol]; P = 0.034) and accompanied by reductions in fructosamine (-33.2 MUmol/L; P = 0.005) and glycated albumin (-1.6%; P = 0.031) versus placebo. Despite both treatment groups receiving similar lifestyle counseling, mean body weight significantly decreased from baseline to week 27 with IONIS-PTP-1BRx versus placebo (-2.6 kg; P = 0.002) independent of HbA1c reduction (R2 = 0.0020). No safety concerns were identified in the study. CONCLUSIONS: Compared with placebo, IONIS-PTP-1BRx treatment for 26 weeks produced prolonged reductions in HbA1c, improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight-reducing effect. PMID- 29439149 TI - Pediatric dog bites: a population-based profile. AB - BACKGROUND: Previous studies have identified risk factors for dog bites in children, but use data from individual trauma centers, with limited generalizability. This study identifies a population risk profile for pediatric dog bites using the National Trauma Data Bank. We hypothesized that the population at risk was younger boys, that such bites occur at home, are moderately severe, and are on the face or neck. METHODS: For this retrospective cross-sectional study, a sample of 7912 children 17 years old and younger with International Classification of Diseases (ICD)-9 event code E906.0, for dog bites, were identified. Datasets from 2007 to 2014 were used. Data included patient's gender, age, ICD-9 primary and location E-codes, AIS body region and AIS severity. RESULTS: Most children were 6-12 years old and female, but a similar number fell into the narrower range of 0-2 years old. Injuries in the younger group frequently occurred at home, on the face and head, and with minor severity. Age of the child predicts the location of incident (P<0.001), the severity of injury (P<0.001) and the body region of the injury (P<0.001). Body region of the injury predicted its severity (P<0.001). DISCUSSION: Younger children are more likely to receive dog bites, and bites incurred are likely of greater severity. Children this young cannot yet be taught how to properly interact with a dog. CONCLUSIONS: Dog bites are a significant source of morbidity for children. Based on the population risk factors profile generated, this study recommends targeting live dog education towards the parents of young children. PMID- 29439148 TI - Biodiversity of CS-proteoglycan sulphation motifs: chemical messenger recognition modules with roles in information transfer, control of cellular behaviour and tissue morphogenesis. AB - Chondroitin sulphate (CS) glycosaminoglycan chains on cell and extracellular matrix proteoglycans (PGs) can no longer be regarded as merely hydrodynamic space fillers. Overwhelming evidence over recent years indicates that sulphation motif sequences within the CS chain structure are a source of significant biological information to cells and their surrounding environment. CS sulphation motifs have been shown to interact with a wide variety of bioactive molecules, e.g. cytokines, growth factors, chemokines, morphogenetic proteins, enzymes and enzyme inhibitors, as well as structural components within the extracellular milieu. They are therefore capable of modulating a panoply of signalling pathways, thus controlling diverse cellular behaviours including proliferation, differentiation, migration and matrix synthesis. Consequently, through these motifs, CS PGs play significant roles in the maintenance of tissue homeostasis, morphogenesis, development, growth and disease. Here, we review (i) the biodiversity of CS PGs and their sulphation motif sequences and (ii) the current understanding of the signalling roles they play in regulating cellular behaviour during tissue development, growth, disease and repair. PMID- 29439150 TI - Myelodysplastic Syndrome Splicing Factor Mutations Induce R-Loops. AB - Mutations in SRSF2 and U2AF35 trigger replication stress and ATR activation via R loop formation. PMID- 29439151 TI - MYCN Amplification Promotes Enhancer Invasion in Neuroblastoma. AB - Excess MYCN binds noncanonical enhancers as well as promoters to drive tumor specific gene expression. PMID- 29439152 TI - SLFN11 Blocks DNA Replication Independently of ATR Activity. AB - SLFN11 inhibits replication in response to DNA damage or cell cycle checkpoint inhibition. PMID- 29439153 TI - AR Inhibition Achieves Responses in AR+ Triple-Negative Breast Cancer. AB - The AR inhibitor enzalutamide achieved responses in patients with advanced TNBC in a phase II trial. PMID- 29439154 TI - Tumorigenic Colonic Bacteria May Promote Early Neoplasia. AB - Colonic biofilms may accelerate tumorigenesis in patients with familial adenomatous polyposis (FAP). PMID- 29439155 TI - GMC accepts another test as proof of language skills. PMID- 29439157 TI - From the unfolded protein response to metabolic diseases - lipids under the spotlight. AB - The unfolded protein response (UPR) is classically viewed as a stress response pathway to maintain protein homeostasis at the endoplasmic reticulum (ER). However, it has recently emerged that the UPR can be directly activated by lipid perturbation, independently of misfolded proteins. Comprising primarily phospholipids, sphingolipids and sterols, individual membranes can contain hundreds of distinct lipids. Even with such complexity, lipid distribution in a cell is tightly regulated by mechanisms that remain incompletely understood. It is therefore unsurprising that lipid dysregulation can be a key factor in disease development. Recent advances in analysis of lipids and their regulators have revealed remarkable mechanisms and connections to other cellular pathways including the UPR. In this Review, we summarize the current understanding in UPR transducers functioning as lipid sensors and the interplay between lipid metabolism and ER homeostasis in the context of metabolic diseases. We attempt to provide a framework consisting of a few key principles to integrate the different lines of evidence and explain this rather complicated mechanism. PMID- 29439158 TI - Image co-localization - co-occurrence versus correlation. AB - Fluorescence image co-localization analysis is widely utilized to suggest biomolecular interaction. However, there exists some confusion as to its correct implementation and interpretation. In reality, co-localization analysis consists of at least two distinct sets of methods, termed co-occurrence and correlation. Each approach has inherent and often contrasting strengths and weaknesses. Yet, neither one can be considered to always be preferable for any given application. Rather, each method is most appropriate for answering different types of biological question. This Review discusses the main factors affecting multicolor image co-occurrence and correlation analysis, while giving insight into the types of biological behavior that are better suited to one approach or the other. Further, the limits of pixel-based co-localization analysis are discussed in the context of increasingly popular super-resolution imaging techniques. PMID- 29439156 TI - Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD. AB - Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), Aim2 deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates. In bone marrow chimera studies, UUO induced substantially more tubular injury and IL-1beta cleavage in Aim2-/- or WT mice that received WT bone marrow than in WT mice that received Aim2-/- bone marrow. Intravital microscopy of the kidney in LysM(gfp/gfp) mice 5-6 days after UUO demonstrated the significant recruitment of GFP+ proinflammatory macrophages that crawled along injured tubules, engulfed DNA from necrotic cells, and expressed active caspase-1. DNA uptake occurred in large vacuolar structures within recruited macrophages but not resident CX3CR1+ renal phagocytes. In vitro, macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1beta, as well as the formation of AIM2+ ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNaseI attenuated the increase in IL-1beta levels, confirming that DNA was the principal damage associated molecular pattern in this process. Therefore, the activation of the AIM2 inflammasome by DNA from necrotic cells drives a proinflammatory phenotype that contributes to chronic injury in the kidney. PMID- 29439159 TI - Dual role for LAP2alpha in progeria cell proliferation. PMID- 29439160 TI - Co-occurrence of depressive symptoms and executive dysfunction after stroke: associations with brain pathology and prognosis. AB - OBJECTIVE: To examine, first, whether the co-occurrence of executive dysfunction (ED) and poststroke depression (PSD) shows different associations with neuroimaging markers and the course of depression and executive function, and second, whether it is associated with a different course on other cognitive domains and quality of life. METHODS: The present study included 245 stroke patients (35.9% female, mean age 67.5 years (SD=11.9). All patients completed neuropsychological and neuropsychiatric assessment 3 months poststroke, which were repeated at 6-month and 12-month follow-up. A subset (n=186) received 3 Tesla brain MRI at baseline to evaluate lesion-related imaging markers, white matter hyperintensity volume, global brain atrophy and total cerebral small vessel disease burden. RESULTS: Patients with 'depression-executive dysfunction syndrome' (DES) showed higher white matter hyperintensity volumes compared with all other groups and more frequently showed left-sided lesions compared with ED only and PSD only. They also had more frequently old infarcts and higher total cerebral small vessel disease burden compared with PSD only and patients with neither ED nor PSD, and more global brain atrophy compared with PSD only. Longitudinal analyses showed that patients with DES had a more chronic course of depressive symptoms relative to PSD only, and a stable pattern of worse cognitive performance similar to patients with ED only. CONCLUSIONS: The co-occurrence of ED and PSD is associated with a worse prognosis of depression, persistent cognitive impairment and a higher amount of vascular and degenerative brain pathology. Future studies are needed to examine whether these patients represent a more severe subtype within the PSD spectrum. CLINICAL TRIAL REGISTRATION: NCT02585349;Results. PMID- 29439161 TI - Meaning of psychiatric symptoms in frontotemporal dementia. PMID- 29439162 TI - Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort. AB - OBJECTIVE: To assess disease burden of chemotherapy-induced peripheral neuropathy (CIPN), which is a common dose-limiting side effect of neurotoxic chemotherapy. Late effects of CIPN may increase with improved cancer survival. METHODS: Olmsted County, Minnesota residents receiving neurotoxic chemotherapy were identified and CIPN was ascertained via text searches of polyneuropathy symptoms in the medical record. Clinical records were queried to collect data on baseline characteristics, risk factors, signs and symptoms of CIPN, medications, impairments and International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes for all subjects. RESULTS: A total of 509 individuals with incident exposure to an inclusive list of neurotoxic chemotherapy agents between 2006 and 2008 were identified. 268 (52.7%) of these individuals were determined to have CIPN. The median time from incident exposure to first documented symptoms was 71 days. Patients with CIPN received a neuropathy ICD-9 diagnosis in only 37 instances (13.8%). Pain symptoms and use of pain medications were observed more often in patients with CIPN. Five-year survival was greater in those with CIPN (55.2%) versus those without (36.1%). Those with CIPN surviving greater than 5 years (n=145) continued to have substantial impairments and were more likely to be prescribed opioids than those without CIPN (OR 2.0, 1.06-3.69). CONCLUSIONS: Results from our population-based study are consistent with previous reports of high incidence of CIPN in the first 2 years following incident exposure to neurotoxic chemotherapeutic agents, and its association with significant pain symptomatology and accompanied long-term opioid use. Increased survival following exposure to neurotoxic chemotherapy and its long-term disease burden necessitates further study among survivors. PMID- 29439163 TI - The cognitive profile of behavioural variant FTD and its similarities with ALS: a systematic review and meta-analysis. AB - Approximately 30% of patients with amyotrophic lateral sclerosis (ALS) have cognitive impairment and 8%-14% fulfil the criteria for behavioural variant frontotemporal dementia (bv-FTD). The cognitive profiles of ALS and bv-FTD have been reported to be comparable, but this has never been systematically investigated. We aimed to determine the cognitive profile of bv-FTD and examine its similarities with that of ALS, to provide evidence for the existence of a cognitive disease continuum encompassing bv-FTD and ALS. We therefore systematically reviewed neuropsychological studies on bv-FTD patients and healthy volunteers. Neuropsychological tests were divided in 10 cognitive domains and effect sizes were calculated for all domains and compared with the cognitive profile of ALS by means of a visual comparison and a Pearson's r correlation coefficient. We included 120 studies, totalling 2425 bv-FTD patients and 2798 healthy controls. All cognitive domains showed substantial effect sizes, indicating cognitive impairment in bv-FTD patients compared to healthy controls. The cognitive domains with the largest effect sizes were social cognition, verbal memory and fluency (1.77-1.53). The cognitive profiles of bv-FTD and ALS (10 cognitive domains, 1287 patients) showed similarities on visual comparison and a moderate correlation 0.58 (p=0.13). When social cognition, verbal memory, fluency, executive functions, language and visuoperception were considered, i.e. the cognitive profile of ALS, Pearson's r was 0.73 (p=0.09), which raised to 0.92 (p=0.03), when language was excluded in this systematic analysis of patients with a non-language subtype of FTD. The cognitive profile of bv-FTD consists of deficits in social cognition, verbal memory, fluency and executive functions and shows similarities with the cognitive profile of ALS. These findings support a cognitive continuum encompassing ALS and bv-FTD. PMID- 29439165 TI - Auditory Input Shapes Tonotopic Differentiation of Kv1.1 Expression in Avian Cochlear Nucleus during Late Development. AB - Tonotopic differentiation is fundamental for signal processing in the auditory system. However, when and how this differentiation arises remain elusive. We addressed this issue using electrophysiology and immunohistochemistry in nucleus magnocellularis of chickens of both sexes, which is known to differ in the expression of Kv1.1 channels depending on characteristic frequency (CF). Just after hearing onset (embryonic day 12-14), Kv1 current gradually increased to a slightly larger extent in neurons with higher CF, causing a tonotopic difference of Kv1 current before hatch. However, after hatch, a much larger increase of Kv1 current occurred, particularly in higher-CF neurons, due to an augmentation of Kv1.1 expression at the plasma membrane. This later change in expression led to the large tonotopic difference of Kv1 current characteristic of mature animals. Attenuation of auditory input by inducing conductive or sensorineural hearing loss around hatch suppressed the differentiation in a level-dependent manner. Moreover, elevation of auditory input during embryonic periods could not reproduce the differentiation, suggesting that the capacity of neurons to drive Kv1.1 expression via auditory input develops in a cell-specific manner, thus underlying the frequency-specific expression of the channel within the nucleus. The results indicated that the tonotopic differentiation of Kv1.1 in nucleus magnocellularis is partially determined before hatch, but largely driven by afferent input after hatch. Our results highlight the importance of neuronal capacity for sound to drive ion channel expression as well as the level of auditory experience in the frequency tuning of brainstem auditory circuits.SIGNIFICANCE STATEMENT Tuning-frequency-specific expression of ion channels is a prerequisite for auditory system function, but its underlying mechanisms remain unclear. Here, we revealed in avian cochlear nucleus that the expression of Kv1.1 became more dependent on auditory input at a late period of maturation in neurons tuned to higher-frequency sound, leading to frequency specific Kv1.1 expression. Attenuation of auditory input during this period suppressed the differentiation in a level-dependent manner, whereas elevation of input in earlier periods could not reproduce the differentiation. Thus, the capacity of neurons to drive Kv1.1 expression via auditory input develops in a cell-specific manner and directs differentiation, highlighting the importance of neuronal character as well as the level of input in the frequency tuning of auditory circuits. PMID- 29439164 TI - Human Sensorimotor Cortex Control of Directly Measured Vocal Tract Movements during Vowel Production. AB - During speech production, we make vocal tract movements with remarkable precision and speed. Our understanding of how the human brain achieves such proficient control is limited, in part due to the challenge of simultaneously acquiring high resolution neural recordings and detailed vocal tract measurements. To overcome this challenge, we combined ultrasound and video monitoring of the supralaryngeal articulators (lips, jaw, and tongue) with electrocorticographic recordings from the cortical surface of 4 subjects (3 female, 1 male) to investigate how neural activity in the ventral sensory-motor cortex (vSMC) relates to measured articulator movement kinematics (position, speed, velocity, acceleration) during the production of English vowels. We found that high-gamma activity at many individual vSMC electrodes strongly encoded the kinematics of one or more articulators, but less so for vowel formants and vowel identity. Neural population decoding methods further revealed the structure of kinematic features that distinguish vowels. Encoding of articulator kinematics was sparsely distributed across time and primarily occurred during the time of vowel onset and offset. In contrast, encoding was low during the steady-state portion of the vowel, despite sustained neural activity at some electrodes. Significant representations were found for all kinematic parameters, but speed was the most robust. These findings enabled by direct vocal tract monitoring demonstrate novel insights into the representation of articulatory kinematic parameters encoded in the vSMC during speech production.SIGNIFICANCE STATEMENT Speaking requires precise control and coordination of the vocal tract articulators (lips, jaw, and tongue). Despite the impressive proficiency with which humans move these articulators during speech production, our understanding of how the brain achieves such control is rudimentary, in part because the movements themselves are difficult to observe. By simultaneously measuring speech movements and the neural activity that gives rise to them, we demonstrate how neural activity in sensorimotor cortex produces complex, coordinated movements of the vocal tract. PMID- 29439166 TI - Induction and relief of curiosity elicit parietal and frontal activity. AB - Curiosity is a basic biological drive, but little is known about its behavioral and neural mechanisms. We can be curious about several types of information. On the one hand, curiosity is a function of the expected value of information, serving primarily to help us maximize reward. On the other hand, curiosity can be a function of the uncertainty of information, helping us to update what we know. In the current studies, we aimed to disentangle the contribution of information uncertainty and expected value of rewards to curiosity in humans of either sex. To this end, we designed a lottery task in which uncertainty and expected value of trial outcomes were manipulated independently, and examined how neural activity and behavioral measures of curiosity were modulated by these factors. Curiosity increased linearly with increased outcome uncertainty, both when curiosity was explicitly probed as well as when it was implicitly tested by people's willingness to wait. Increased expected value, however, did not strongly relate to these curiosity measures. Neuroimaging results showed greater BOLD response with increasing outcome uncertainty in parietal cortex at the time of curiosity induction. Outcome updating when curiosity was relieved resulted in an increased signal in the insula, orbitofrontal cortex and parietal cortex. Furthermore, the insula showed a linear increase corresponding to the size of the information update. These results suggest that curiosity is monotonically related to the uncertainty about one's current world model, the induction and relief of which are associated with activity in parietal and insular cortices respectively.SIGNIFICANCE STATEMENTHumans are curious by nature. When you hear your phone beep, you probably feel the urge to check the message right away, even though the message itself likely doesn't give you a direct reward. In this study, we demonstrated that curiosity can be driven by outcome uncertainty, irrespective of reward. The induction of curiosity was accompanied by increased activity in the parietal cortex, whereas the information update at the time of curiosity relief was associated with activity in insular cortex. These findings advance our understanding of the behavioral and neural constituents of curiosity, which lies at the core of human information-seeking and serves to optimize the individual's current world-model. PMID- 29439168 TI - Visual Aversive Learning Compromises Sensory Discrimination. AB - Aversive learning is thought to modulate perceptual thresholds, which can lead to overgeneralization. However, it remains undetermined whether this modulation is domain specific or a general effect. Moreover, despite the unique role of the visual modality in human perception, it is unclear whether this aspect of aversive learning exists in this modality. The current study was designed to examine the effect of visual aversive outcomes on the perception of basic visual and auditory features. We tested the ability of healthy participants, both males and females, to discriminate between neutral stimuli, before and after visual learning. In each experiment, neutral stimuli were associated with aversive images in an experimental group and with neutral images in a control group. Participants demonstrated a deterioration in discrimination (higher discrimination thresholds) only after aversive learning. This deterioration was measured for both auditory (tone frequency) and visual (orientation and contrast) features. The effect was replicated in five different experiments and lasted for at least 24 h. fMRI neural responses and pupil size were also measured during learning. We showed an increase in neural activations in the anterior cingulate cortex, insula, and amygdala during aversive compared with neutral learning. Interestingly, the early visual cortex showed increased brain activity during aversive compared with neutral context trials, with identical visual information. Our findings imply the existence of a central multimodal mechanism, which modulates early perceptual properties, following exposure to negative situations. Such a mechanism could contribute to abnormal responses that underlie anxiety states, even in new and safe environments.SIGNIFICANCE STATEMENT Using a visual aversive-learning paradigm, we found deteriorated discrimination abilities for visual and auditory stimuli that were associated with visual aversive stimuli. We showed increased neural activations in the anterior cingulate cortex, insula, and amygdala during aversive learning, compared with neutral learning. Importantly, similar findings were also evident in the early visual cortex during trials with aversive/neutral context, but with identical visual information. The demonstration of this phenomenon in the visual modality is important, as it provides support to the notion that aversive learning can influence perception via a central mechanism, independent of input modality. Given the dominance of the visual system in human perception, our findings hold relevance to daily life, as well as imply a potential etiology for anxiety disorders. PMID- 29439167 TI - Combinatorial Effects of Alpha- and Gamma-Protocadherins on Neuronal Survival and Dendritic Self-Avoidance. AB - The clustered protocadherins (Pcdhs) comprise 58 cadherin-related proteins encoded by three tandemly arrayed gene clusters, Pcdh-alpha, Pcdh-beta, and Pcdh gamma (Pcdha, Pcdhb, and Pcdhg, respectively). Pcdh isoforms from different clusters are combinatorially expressed in neurons. They form multimers that interact homophilically and mediate a variety of developmental processes, including neuronal survival, synaptic maintenance, axonal tiling, and dendritic self-avoidance. Most studies have analyzed clusters individually. Here, we assessed functional interactions between Pcdha and Pcdhg clusters. To circumvent neonatal lethality associated with deletion of Pcdhgs, we used Crispr-Cas9 genome editing in mice to combine a constitutive Pcdha mutant allele with a conditional Pcdhg allele. We analyzed roles of Pcdhas and Pcdhgs in the retina and cerebellum from mice (both sexes) lacking one or both clusters. In retina, Pcdhgs are essential for survival of inner retinal neurons and dendritic self-avoidance of starburst amacrine cells, whereas Pcdhas are dispensable for both processes. Deletion of both Pcdha and Pcdhg clusters led to far more dramatic defects in survival and self-avoidance than Pcdhg deletion alone. Comparisons of an allelic series of mutants support the conclusion that Pcdhas and Pcdhgs function together in a dose-dependent and cell-type-specific manner to provide a critical threshold of Pcdh activity. In the cerebellum, Pcdhas and Pcdhgs also cooperate to mediate self-avoidance of Purkinje cell dendrites, with modest but significant defects in either single mutant and dramatic defects in the double mutant. Together, our results demonstrate complex patterns of redundancy between Pcdh clusters and the importance of Pcdh cluster diversity in postnatal CNS development.SIGNIFICANCE STATEMENT The formation of neural circuits requires diversification and combinatorial actions of cell surface proteins. Prominent among them are the clustered protocadherins (Pcdhs), a family of ~60 neuronal recognition molecules. Pcdhs are encoded by three closely linked gene clusters called Pcdh-alpha, Pcdh beta, and Pcdh-gamma. The Pcdhs mediate a variety of developmental processes, including neuronal survival, synaptic maintenance, and spatial patterning of axons and dendrites. Most studies to date have been limited to single clusters. Here, we used genome editing to assess interactions between Pcdh-alpha and Pcdh gamma gene clusters. We examined two regions of the CNS, the retina and cerebellum and show that the 14 alpha-Pcdhs and 22 gamma-Pcdhs act synergistically to mediate neuronal survival and dendrite patterning. PMID- 29439170 TI - Extending Our Reach-Will Telemedicine Get Us There? PMID- 29439169 TI - Cochrane corner: complete versus culprit-only revascularisation in ST segment elevation myocardial infarction with multivessel disease. PMID- 29439171 TI - Letter to the Editor: Chicken Noodle Soup (Capsule) for the Soul? PMID- 29439172 TI - Inflammatory Myofibroblastic Tumor Driven by Novel NUMA1-ALK Fusion Responds to ALK Inhibition. AB - Inflammatory myofibroblastic tumors (IMTs) are soft tissue neoplasms with rare metastatic potential. Approximately half of IMTs are positive for an ALK rearrangement, and ALK inhibitors have been used successfully in the treatment of IMTs with a variety of ALK fusions. This report describes a 21-year-old woman with an aggressive, metastatic IMT with a novel NUMA1-ALK fusion that showed a dramatic response to the ALK inhibitors crizotinib and alectinib. To our knowledge, this report provides the first published description of an IMT with a NUMA1-ALK fusion. The patient's aggressive IMT responded favorably to crizotinib and alectinib, suggesting that ALK inhibitors may be effective in IMT with NUMA1 ALK fusions. We review published reports of ALK-driven IMTs that have received ALK inhibitor therapy and suggest characteristics that may be associated with favorable response to treatment. We also discuss the strengths and limitations of immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing in the diagnosis and management of IMTs. PMID- 29439173 TI - NCCN Guidelines Insights: T-Cell Lymphomas, Version 2.2018. AB - Natural killer (NK)/T-cell lymphomas are a rare and distinct subtype of non Hodgkin's lymphomas. NK/T-cell lymphomas are predominantly extranodal and most of these are nasal type, often localized to the upper aerodigestive tract. Because extranodal NK/T-cell lymphomas (ENKL) are rare malignancies, randomized trials comparing different regimens have not been conducted to date and standard therapy has not yet been established for these patients. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with ENKL as outlined in the NCCN Guidelines for T-Cell Lymphomas. PMID- 29439174 TI - Description of Venous Thromboembolism in Hospitalized Patients With Metastatic Cancer: A National Sample. AB - Background: This study aimed to determine patient-, tumor-, and hospital-level characteristics associated with venous thromboembolism (VTE), and to assess the impact of VTE on in-hospital mortality and length of hospital stay in hospitalized patients with metastatic cancer. Methods: Using the Nationwide Inpatient Sample database, a cross-sectional analysis was performed of patients aged >=18 years with at least 1 diagnosis of primary solid tumor and subsequent secondary or metastatic tumor between 2008 and 2013. Results: Among 850,570 patients with metastatic cancer, 6.6% were diagnosed with VTE. A significant trend for increasing VTE rates were observed from 2008 to 2013 (5.7%-7.2%; P<.0001). Using an adjusted multilevel hierarchical regression model, higher odds of VTE were seen among women (odds ratio [OR], 1.04; 95% CI, 1.02-1.06), black versus white patients (OR, 1.14; 95% CI, 1.11-1.18), and those with an Elixhauser comorbidity index score of >=3 (OR, 2.50; 95% CI, 2.38-2.63). Hospital-level correlates of VTE included treatment in a teaching hospital (OR, 1.05; 95% CI, 1.01-1.11) and an urban location (OR, 1.18; 95% CI, 1.09-1.27), and admission to hospitals in the Northeast (OR, 1.16; 95% CI, 1.08-1.24) and West (OR, 1.09; 95% CI, 1.03-1.16) versus the South. Patients with metastasis to the liver, brain, or respiratory organs and those with multiple (>=2) metastatic sites had higher odds of VTE, whereas those with metastasis to lymph nodes and genital organs had lower odds. Patients diagnosed with versus without VTE had higher odds of in-hospital mortality (OR, 1.50; 95% CI, 1.38-1.63) and prolonged hospital stay (OR, 1.65; 95% CI, 1.57-1.73). Conclusions: The frequency of VTE in patients with metastatic cancer is increasing. Patient characteristics, hospital factors, and site of metastasis independently predict the occurrence of VTE and allow for better stratification of patients with cancer according to their VTE risk. PMID- 29439175 TI - The AJCC 8th Edition Staging System for Soft Tissue Sarcoma of the Extremities or Trunk: A Cohort Study of the SEER Database. AB - Background: The AJCC recently published the 8th edition of its cancer staging system. Significant changes were made to the staging algorithm for soft tissue sarcoma (STS) of the extremities or trunk, including the addition of 2 additional T (size) classifications in lieu of tumor depth and grouping lymph node metastasis (LNM) with distant metastasis as stage IV disease. Whether these changes improve staging system performance is questionable. Patients and Methods: This retrospective cohort analysis of 21,396 adult patients with STS of the extremity or trunk in the SEER database compares the AJCC 8th edition staging system with the 7th edition and a newly proposed staging algorithm using a variety of statistical techniques. The effect of tumor size on disease-specific survival was assessed by flexible, nonlinear Cox proportional hazard regression using restricted cubic splines and fractional polynomials. Results: The slope of covariate-adjusted log hazards for sarcoma-specific survival decreases for tumors >8 cm in greatest dimension, limiting prognostic information contributed by the new T4 classification in the AJCC 8th edition. Anatomic depth independently provides significant prognostic information. LNM is not equivalent to distant, non-nodal metastasis. Based on these findings, an alternative staging system is proposed and demonstrated to outperform both AJCC staging schemes. The analyses presented also disclose no evidence of improved clinical performance of the 8th edition compared with the previous edition. Conclusions: The AJCC 8th edition staging system for STS is no better than the previous 7th edition. Instead, a proposed staging system based on histologic grade, tumor size, and anatomic depth shows significantly higher predictive accuracy, with higher model concordance than either AJCC staging system. Changes to existing staging systems should improve the performance of prognostic models. Until such improvements are documented, AJCC committees should refrain from modifying established staging schemes. PMID- 29439176 TI - Skeletal Muscle Quality Beyond Average Muscle Attenuation: A Proposal of Skeletal Muscle Phenotypes to Predict Short-Term Survival in Patients With Endometrial Cancer. AB - Background: Increasing evidence links sarcopenia and cancer prognosis, but limited data have focused on whether and to what extent muscle radiodensity can impact cancer outcomes. This study was conducted to investigate whether skeletal muscle mass, when divided into subranges of low or high radiodensity, improves prediction of short-term survival in patients with endometrial cancer (EC). Four skeletal muscle phenotypes were proposed to assess which is the best predictor of 1-year mortality. Methods: Patients with EC who had CT images available within 30 days before treatment (n=208) were enrolled in a retrospective cohort. CT images at the third lumbar vertebra (L3) were used to assess overall skeletal muscle index (SMI), which was then divided into subranges of radiation attenuation: low- and high-radiodensity SMI. The average muscle radiation attenuation (AMA) was also assessed. SMI and AMA were categorized as below or above the median and as below or above 30 Hounsfield units (HU), respectively, to construct 4 skeletal muscle phenotypes: "high SMI + high AMA"; "low SMI + high AMA"; "high SMI + low AMA"; and "low SMI + low AMA". One-year survival was evaluated using the Kaplan Meier method and Cox multiple regression analysis. Results: All of the skeletal muscle parameters, except the SMI, were significantly associated with shorter 1 year survival. The skeletal muscle phenotype of "low SMI + low AMA" showed the strongest association with 1-year mortality (hazard ratio, 5.36; 95% CI, 1.70 16.51). Conclusions: The additional value of classifying the skeletal muscle into subranges of radiodensity should be explored in the future. Evaluating the impact of skeletal muscle phenotypes on cancer prognosis is promising and must be assessed in further studies. PMID- 29439177 TI - Real-World Impact of a Decision Support Tool on Colony-Stimulating Factor Use and Chemotherapy-Induced Febrile Neutropenia Among Patients With Breast Cancer. AB - Background: White blood cell colony-stimulating factors (CSFs) decrease the incidence of chemotherapy-induced febrile neutropenia (FN). Widespread use of CSFs that is not guideline-concordant has been reported. Among patients with breast cancer receiving chemotherapy, the ability of evidence-based decision support tools to promote risk-appropriate reductions in CSF use without increased incidence of FN has not been examined. Methods: A retrospective cohort design and US commercial claims data were used. The impact of CSF decision support was analyzed among women with breast cancer receiving first-cycle chemotherapy from April 1, 2013, to March 30, 2015. The tool was implemented as part of a prior authorization process in 9 states starting July 1, 2014. Patients were assigned to intervention (ie, states where the decision support tool had been implemented) or nonintervention states (ie, 39 states where the tool had not been implemented). CSF use and subsequent incidence of FN were compared using difference-in-difference (DID) regressions adjusting for baseline differences in FN risk factors such as comorbidities and various infections. Results: The study sample of 7,224 patients (intervention states: pre-implementation, 1,991 and post implementation, 2,010; nonintervention states: pre-implementation, 1,569 and post implementation, 1,654) showed no significant difference in risk factors. Before and after implementation, a significant decrease in the proportion of patients with CSF use was observed in the intervention states (75% to 69%) compared with no significant change in the nonintervention (72% to 71%) states (DID, -5.4%; 95% CI, -6.0% to -4.7%; P=.006). No significance increase in FN incidence occurred in intervention (5.0% to 5.5%) and nonintervention (5.4% to 4.8%) states (DID, 0.2%; 95% CI, -0.20 to 0.30; P=.78). Similar results were obtained in subgroups by comorbidities and in sensitivity analyses by claims-based FN definitions. Conclusions: CSF use decreased modestly after implementation of the decision support tool, with no observed changes in FN rates. Such tools can reduce practice variation to improve care standards. PMID- 29439178 TI - Uterine Neoplasms, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology. AB - Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately two-thirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations. PMID- 29439179 TI - Evolving Roles of Histologic Evaluation and Molecular/Genomic Profiling in the Management of Endometrial Cancer. AB - Endometrial cancers are the most common gynecologic malignancies. The staging of endometrial cancer has evolved from a clinical-based system to a comprehensive surgical-pathologic approach that allows for better risk stratification and treatment planning. Over the past few years, use of NCCN's sentinel lymph node (SLN) mapping algorithm for the surgical staging of endometrial cancer has gained significant acceptance and is now commonly applied in many practices. However, pathologic evaluation of prognostic factors is beset by challenges, including the reproducibility of histologic classification and FIGO's grading, as well as the questionable clinical significance of low-volume tumor in SLNs. With the revelation of major genomic classes of endometrial cancer comes the potential for improved, reproducible, and prognostically relevant classification schemes, which integrate traditional pathologic parameters with genomic findings, to aid in treatment decisions. Pathologic identification of new variants of endometrial cancer, such as undifferentiated carcinoma, continues to advance the phenotypic spectrum of these tumors, spurring genomic and functional studies to further characterize their mechanistic underpinnings and potentially reveal new avenues for treatment. In the era of precision medicine, pathologic assessment of biomarkers (eg, mismatch repair proteins) and recognition of phenotypes that are amenable to specific targeted therapies (such as POLE-mutated tumors) have become integral to the management of women with endometrial carcinoma. PMID- 29439180 TI - Secondary Neoplasms of the Female Lower Genital Tract After Hematopoietic Cell Transplantation. AB - Hematopoietic cell transplantation (HCT) results in long-term survival (>=10 years) in 85% of patients who survive transplant-related complications within the first 2 years posttransplant. Transplant survivors, however, are at an increased risk of chronic health conditions compared with the general population, including the emergence of secondary malignant neoplasms. In particular, female transplant survivors may face a greater risk of lower genital tract (cervical, vulvar, or vaginal) neoplasms due to chronic immune dysregulation in the peritransplant and posttransplant environment. Persistent immune suppression may facilitate the carcinogenesis of human papillomavirus (HPV), the causative agent of nearly all cervical cancers and most vulvar and vaginal cancers. Nevertheless, the risk of these cancers has not been sufficiently quantified in female transplant survivors. Small clinical studies have shown that the rate of cervical cytological abnormalities increases after allogeneic HCT, but large population based studies have not consistently demonstrated an increased risk of secondary cervical cancer after transplant compared with the general population; the risk of developing secondary vulvar or vaginal cancer after transplant remains unclear. A better understanding of the natural history of HPV-associated lower genital tract neoplasms and their transplant-related risk factors would help delineate optimal long-term follow-up protocols in this population. In this systematic review, we summarize the current literature on this topic and discuss the implications for cervical cancer screening and vaccination in female transplant recipients. PMID- 29439184 TI - A novel variant Glanzmann thrombasthenia due to co-inheritance of a loss- and a gain-of-function mutation of ITGB3: evidence of a dominant effect of gain-of function mutations. PMID- 29439183 TI - The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis. AB - Systemic mastocytosis is a complex disease defined by abnormal growth and accumulation of neoplastic mast cells in various organs. Most patients exhibit a D816V-mutated variant of KIT, which confers resistance against imatinib. Clinical problems in systemic mastocytosis arise from mediator-related symptoms and/or organ destruction caused by malignant expansion of neoplastic mast cells and/or other myeloid cells in various organ systems. DCC-2618 is a spectrum-selective pan KIT and PDGFRA inhibitor which blocks KIT D816V and multiple other kinase targets relevant to systemic mastocytosis. We found that DCC-2618 inhibits the proliferation and survival of various human mast cell lines (HMC-1, ROSA, MCPV-1) as well as primary neoplastic mast cells obtained from patients with advanced systemic mastocytosis (IC50 <1 MUM). Moreover, DCC-2618 decreased growth and survival of primary neoplastic eosinophils obtained from patients with systemic mastocytosis or eosinophilic leukemia, leukemic monocytes obtained from patients with chronic myelomonocytic leukemia with or without concomitant systemic mastocytosis, and blast cells obtained from patients with acute myeloid leukemia. Furthermore, DCC-2618 was found to suppress the proliferation of endothelial cells, suggesting additional drug effects on systemic mastocytosis-related angiogenesis. Finally, DCC-2618 was found to downregulate IgE-mediated histamine release from basophils and tryptase release from mast cells. Together, DCC-2618 inhibits growth, survival and activation of multiple cell types relevant to advanced systemic mastocytosis. Whether DCC-2618 is effective in vivo in patients with advanced systemic mastocytosis is currently under investigation in clinical trials. PMID- 29439186 TI - Severe hemolysis and transfusion reactions after treatment with BGB-3111 and PD-1 antibody for Waldenstrom macroglobulinemia. PMID- 29439187 TI - Lethal neonatal bone marrow failure syndrome with multiple congenital abnormalities, including limb defects, due to a constitutional deletion of 3' MECOM. PMID- 29439185 TI - Extracellular vesicles in the hematopoietic microenvironment. AB - Self-renewal and differentiation are defining characteristics of hematopoietic stem and progenitor cells, and their balanced regulation is central to lifelong function of both blood and immune systems. In addition to cell-intrinsic programs, hematopoietic stem and progenitor cell fate decisions are subject to extrinsic cues from within the bone marrow microenvironment and systemically. Yet, many of the paracrine and endocrine mediators that shape hematopoietic function remain to be discovered. Extracellular vesicles serve as evolutionarily conserved, constitutive regulators of cell and tissue homeostasis, with several recent reports supporting a role for extracellular vesicles in the regulation of hematopoiesis. We review the physiological and pathophysiological effects that extracellular vesicles have on bone marrow compartmental function while highlighting progress in understanding vesicle biogenesis, cargo incorporation, differential uptake, and downstream effects of vesicle internalization. This review also touches on the role of extracellular vesicles in hematopoietic stem and progenitor cell fate regulation and recent advances in therapeutic and diagnostic applications of extracellular vesicles in hematologic disorders. PMID- 29439188 TI - Incidence and risk factors for relapses in HIV-associated non-Hodgkin lymphoma as observed in the German HIV-related lymphoma cohort study. AB - Outcome of HIV-infected patients with AIDS-related lymphomas has improved during recent years. However, data on incidence, risk factors, and outcome of relapses in AIDS-related lymphomas after achieving complete remission are still limited. This prospective observational multicenter study includes HIV-infected patients with biopsy- or cytology-proven malignant lymphomas since 2005. Data on HIV infection and lymphoma characteristics, treatment and outcome were recorded. For this analysis, AIDS-related lymphomas patients in complete remission were analyzed in terms of their relapse- free survival and potential risk factors for relapses. In total, 254 of 399 (63.7%) patients with AIDS-related lymphomas reached a complete remission with their first-line chemotherapy. After a median follow up of 4.6 years, 5-year overall survival of the 254 patients was 87.8% (Standard Error 3.1%). Twenty-nine patients relapsed (11.4%). Several factors were independently associated with a higher relapse rate, including an unclassifiable histology, a stage III or IV according to the Ann Arbor Staging System, no concomitant combined antiretroviral therapy during chemotherapy and R CHOP-based compared to more intensive chemotherapy regimens in Burkitt lymphomas. In conclusion, complete remission and relapse rates observed in our study are similar to those reported in HIV-negative non-Hodgkin lymphomas. These data provide further evidence for the use of concomitant combined antiretroviral therapy during chemotherapy and a benefit from more intensive chemotherapy regimens in Burkitt lymphomas. Modifications to the chemotherapy regimen appear to have only a limited impact on relapse rate. PMID- 29439189 TI - Socioeconomic inequality in recovery from poor physical and mental health in mid life and early old age: prospective Whitehall II cohort study. AB - BACKGROUND: Few studies have examined the influence of socioeconomic status on recovery from poor physical and mental health. METHODS: Prospective study with four consecutive periods of follow-up (1991-2011) of 7564 civil servants (2228 women) recruited while working in London. Health was measured by the Short-Form 36 questionnaire physical and mental component scores assessed at beginning and end of each of four rounds. Poor health was defined by a score in the lowest 20% of the age-sex-specific distribution. Recovery was defined as changing from a low score at the beginning to a normal score at the end of the round. The analysis took account of retirement status, health behaviours, body mass index and prevalent chronic disease. RESULTS: Of 24 001 person-observations in the age range 39-83, a total of 8105 identified poor physical or mental health. Lower grade of employment was strongly associated with slower recovery from poor physical health (OR 0.73 (95% CI 0.59 to 0.91); trend P=0.002) in age, sex and ethnicity-adjusted analyses. The association was halved after further adjustment for health behaviours, adiposity, systolic blood pressure (SBP) and serum cholesterol (OR 0.85 (0.68 to 1.07)). In contrast, slower recovery from poor mental health was associated robustly with low employment grade even after multiple adjustment (OR 0.74 (0.59 to 0.93); trend P=0.02). CONCLUSIONS: Socioeconomic inequalities in recovery from poor physical health were explained to a considerable extent by health behaviours, adiposity, SBP and serum cholesterol. These risk factors explained only part of the gradient in recovery for poor mental health. PMID- 29439190 TI - Disparities in injury morbidity among young adults in the USA: individual and contextual determinants. AB - BACKGROUND: Injuries have been recognised as important public health concerns, particularly among adolescents and young adults. Few studies have examined injuries using a multilevel perspective that addresses individual socioeconomic status (SES) and health behaviours and local socioeconomic conditions in early adolescence. We offer a conceptual framework incorporating these various components. METHODS: We test our conceptual framework using population data from the National Longitudinal Study of Adolescent Health Wave 4 when respondents were young adults and linked them to contextual level data from when they were middle schoolers. We use logistic and multilevel regression models to examine self reported injury risk in young adults by sex (n=14 356). RESULTS: Logistic regression models showed that men were more likely to experience serious injuries than women (OR 1.75, P<0.0001), but SES and health behaviours operated differently by sex. In stratified models, men with lower education had consistently higher injury risk, while only women with some college had increased injury risk (OR 1.40, P=0.0089) than college graduates. Low household income (OR 1.54, P=0.0011) and unemployment (OR 1.50, P=0.0008) increased female injury risk, but was non-significant for men. Alcohol consumption increased injury risk for both sexes, while only female smokers had elevated injury risk (OR 1.38, P=0.0154). In multilevel models, significant county-level variation was only observed for women. Women living in disadvantaged neighbourhoods during adolescence had increased injury risk (OR 1.001, P<0.0001). CONCLUSIONS: These findings highlight the importance of investigating mechanisms that link early life contextual conditions to early adult SES and health behaviours and their linkage to injury risk, particularly for women. PMID- 29439191 TI - How consistent are associations between maternal and paternal education and child growth and development outcomes across 39 low-income and middle-income countries? AB - BACKGROUND: Maternal and paternal education are associated with improved early child outcomes. However, less is known about how these relative associations compare for preschool children's growth versus development outcomes; and across country contexts. METHODS: We analysed data from 89 663 children aged 36 to 59 months in 39 low-income and middle-income countries (LMICs). We used linear regression models with country fixed effects to estimate the joint associations between maternal and paternal education and children's growth and development outcomes. Additionally, we examined the variability in these relationships by each country and within subgroups of countries. RESULTS: In the pooled sample, maternal and paternal education were independently associated with 0.37 (95% CI 0.33 to 0.41) and 0.20 (95% CI 0.16 to 0.24) higher height-for-age z-scores, and 0.31 (95% CI 0.29 to 0.34) and 0.16 (95% CI 0.14 to 0.18) higher Early Childhood Development Index z-scores, respectively (comparing secondary or higher to no education). Associations were stronger for maternal education than paternal education but comparable between child outcomes. In country-specific regressions, we found the most heterogeneity in the associations between maternal education and children's growth; and between paternal education and children's development. Subgroup analyses suggested that these associations may be systematically patterned by country-level adult illiteracy, infant mortality and food insecurity. CONCLUSION: Our findings highlight variability in the statistical significance and magnitude of the associations between caregivers' education and children's outcomes. Further research is needed to understand the sources of variation that may promote or constrain the benefits of caregivers' education for children's early health and development in LMICs. PMID- 29439192 TI - Teenage pregnancy and mental health beyond the postpartum period: a systematic review. AB - BACKGROUND: Teenage mothers are at increased risk for adverse social outcomes and short-term health problems, but long-term impacts on mental health are poorly understood. The aims of our systematic review were to determine the association between teenage pregnancy and mental health beyond the postpartum period, critically appraise the literature's quality and guide future research. METHODS: We systematically searched MEDLINE, Embase, PsycINFO, CINAHL, Scopus and Web of Science from inception to June 2017 for peer-reviewed articles written in English or French. Data were collected using a modified Cochrane Data Extraction Form. Study quality was assessed using the Effective Public Health Practice Project critical appraisal tool. Heterogeneity of studies permitted only a qualitative synthesis. RESULTS: Nine quantitative studies comprising the results from analyses of 11 cohorts met our criteria and were rated as strong (n=5), moderate (n=2) or weak (n=2). Three cohorts found a statistically significant association between teenage pregnancy and poor long-term mental health after adjustment, three found a statistically significant association before but not after adjustment and five did not find a statistically significant association. Studies observed varying degrees of attenuation after considering social context. Studies with statistically significant findings tended to comprise earlier cohorts, with outcomes measured at older ages. CONCLUSIONS: The association between teenage pregnancy and mental health beyond the postpartum period remains unclear. Future studies should employ age-period-cohort frameworks to disentangle effects of normative patterns and stress accumulation. Social factors are important in determining long-term mental health of teenage mothers and should be prioritised in prevention and intervention strategies. PMID- 29439193 TI - Cardiovascular health among the Czech population at the beginning of the 21st century: a 12-year follow-up study. AB - BACKGROUND: In the late 1980s, Czechia was among the countries which had the highest cardiovascular mortality in the world. In spite of enormous improvements since that time, there are still large opportunities in further improving cardiovascular health. METHODS: Based on the Czech Health, Alcohol and Psychosocial Factors in Eastern Europe sample (n=8449 at baseline, 12 years of follow-up, 494 cardiovascular disease (CVD) deaths up to 2015-events), the impact of selected covariates such as education, smoking habits, high blood pressure, blood cholesterol level, diabetes, obesity, physical activity and binge drinking and their multifactorial effects on cardiovascular mortality was evaluated by Cox regression. In addition, population attributable fractions (PAFs) were used to quantify the impact of these factors on CVD mortality in the population. RESULTS: Education was found as the strongest determinant of CVD mortality (primary vs university, HR 2.77, P<0.001; PAF=50.5%). CVD risk was two times higher for persons with diabetes compared with those without (HR 2.02, P<0.001, PAF=23.2%). Furthermore, significant factors found were smoking (smoker vs non-smoker, HR 1.91, P<0.001; PAF=26.5%), high blood pressure (HR 1.73, P<0.001; PAF=35.3%) and physical inactivity (none vs sufficient, HR 1.60, P<0.001; PAF=22.9%). Conversely, the effect of obesity was low (HR 1.29, P value =0.020), and binge drinking and high blood cholesterol level were not significant at all. CONCLUSIONS: Education had the largest impact on cardiovascular mortality among the Czech population. More than 50% of CVD death would be prevented if the whole population had the same risk values as the highest educated population. Reducing disparities in health related to education should benefit from attention to cardiovascular health literacy. PMID- 29439195 TI - Letter by Bennis et al Regarding Article, "Cerebral Near-Infrared Spectroscopy: A Potential Approach for Thrombectomy Monitoring". PMID- 29439194 TI - Quality of Life Is Poorer for Patients With Stroke Who Require an Interpreter: An Observational Australian Registry Study. AB - BACKGROUND AND PURPOSE: In multicultural Australia, some patients with stroke cannot fully understand, or speak, English. Language barriers may reduce quality of care and consequent outcomes after stroke, yet little has been reported empirically. METHODS: An observational study of patients with stroke or transient ischemic attack (2010-2015) captured from 45 hospitals participating in the Australian Stroke Clinical Registry. The use of interpreters in hospitals, which is routinely documented, was used as a proxy for severe language barriers. Health Related Quality of Life was assessed using the EuroQoL-5 dimension-3 level measured 90 to 180 days after stroke. Logistic regression was undertaken to assess the association between domains of EuroQoL-5 dimension and interpreter status. RESULTS: Among 34 562 registrants, 1461 (4.2%) required an interpreter. Compared with patients without interpreters, patients requiring an interpreter were more often women (53% versus 46%; P<0.001), aged >=75 years (68% versus 51%; P<0.001), and had greater access to stroke unit care (85% versus 78%; P<0.001). After accounting for patient characteristics and stroke severity, patients requiring interpreters had comparable discharge outcomes (eg, mortality, discharged to rehabilitation) to patients not needing interpreters. However, these patients reported poorer Health-Related Quality of Life (visual analogue scale coefficient, -9; 95% CI, -12.38, -5.62), including more problems with self care (odds ratio: 2.22; 95% CI, 1.82, 2.72), pain (odds ratio: 1.84; 95% CI, 1.52, 2.34), anxiety or depression (odds ratio: 1.60; 95% CI, 1.33, 1.93), and usual activities (odds ratio: 1.62; 95% CI, 1.32, 2.00). CONCLUSIONS: Patients requiring interpreters reported poorer Health Related Quality of Life after stroke/transient ischemic attack despite greater access to stroke units. These findings should be interpreted with caution because we are unable to account for prestroke Health Related Quality of Life. Further research is needed. PMID- 29439196 TI - Reduced Intravoxel Incoherent Motion Microvascular Perfusion Predicts Delayed Cerebral Ischemia and Vasospasm After Aneurysm Rupture. AB - BACKGROUND AND PURPOSE: Proximal artery vasospasm and delayed cerebral ischemia (DCI) after cerebral aneurysm rupture result in reduced cerebral perfusion and microperfusion and significant morbidity and mortality. Intravoxel incoherent motion (IVIM) magnetic resonance imaging extracts microvascular perfusion information from a multi-b value diffusion-weighted sequence. We determined whether decreased IVIM perfusion may identify patients with proximal artery vasospasm and DCI. METHODS: We performed a pilot retrospective cohort study of patients with ruptured cerebral aneurysms. Consecutive patients who underwent a brain magnetic resonance imaging with IVIM after ruptured aneurysm treatment were included. Patient demographic, treatment, imaging, and outcome data were determined by electronic medical record review. Primary outcome was DCI development with proximal artery vasospasm that required endovascular treatment. Secondary outcomes included mortality and clinical outcomes at 6 months. RESULTS: Sixteen patients (11 females, 69%; P=0.9) were included. There were no differences in age, neurological status, or comorbidities between patients who subsequently underwent endovascular treatment of DCI (10 patients; DCI+ group) and those who did not (6 patients; DCI- group). Compared with DCI- patients, DCI+ patients had decreased IVIM perfusion fraction f (0.09+/-0.03 versus 0.13+/-0.01; P=0.03), reduced diffusion coefficient D (0.82+/-0.05 versus 0.92+/-0.07*10-3 mm2/s; P=0.003), and reduced blood flow-related parameter fD* (1.18+/-0.40 versus 1.83+/-0.40*10-3 mm2/s; P=0.009). IVIM pseudodiffusion coefficient D* did not differ between DCI- (0.011+/-0.002) and DCI+ (0.013+/-0.005 mm2/s; P=0.4) patients. No differences in mortality or clinical outcome were identified. CONCLUSIONS: Decreased IVIM perfusion fraction f and blood flow-related parameter fD* correlate with DCI and proximal artery vasospasm development after cerebral aneurysm rupture. PMID- 29439197 TI - Reply to Kennedy: Historical evidence supports remarkable breaking wave heights. PMID- 29439198 TI - Reported extreme wave heights off Ireland are artifacts. PMID- 29439199 TI - Liprin-alpha3 controls vesicle docking and exocytosis at the active zone of hippocampal synapses. AB - The presynaptic active zone provides sites for vesicle docking and release at central nervous synapses and is essential for speed and accuracy of synaptic transmission. Liprin-alpha binds to several active zone proteins, and loss-of function studies in invertebrates established important roles for Liprin-alpha in neurodevelopment and active zone assembly. However, Liprin-alpha localization and functions in vertebrates have remained unclear. We used stimulated emission depletion superresolution microscopy to systematically determine the localization of Liprin-alpha2 and Liprin-alpha3, the two predominant Liprin-alpha proteins in the vertebrate brain, relative to other active-zone proteins. Both proteins were widely distributed in hippocampal nerve terminals, and Liprin-alpha3, but not Liprin-alpha2, had a prominent component that colocalized with the active-zone proteins Bassoon, RIM, Munc13, RIM-BP, and ELKS. To assess Liprin-alpha3 functions, we generated Liprin-alpha3-KO mice by using CRISPR/Cas9 gene editing. We found reduced synaptic vesicle tethering and docking in hippocampal neurons of Liprin-alpha3-KO mice, and synaptic vesicle exocytosis was impaired. Liprin alpha3 KO also led to mild alterations in active zone structure, accompanied by translocation of Liprin-alpha2 to active zones. These findings establish important roles for Liprin-alpha3 in active-zone assembly and function, and suggest that interplay between various Liprin-alpha proteins controls their active-zone localization. PMID- 29439201 TI - Impact of local symmetry breaking on the physical properties of tetrahedral liquids. AB - Water and silica are the most important materials with local tetrahedral symmetry. They have similar crystalline polymorphs and exhibit anomalous density maximum in the liquid state. However, water and silica also show very different characteristics. For instance, the density of water varies much more sharply than that of liquid silica near the maximum as temperature changes. More notably, silica is a very good glass-former, but water is an extremely poor one. The physical origins of these similarities and differences still remain elusive, due to the lack of a microscopic understanding of the structural ordering in these two important liquids. Here, by accessing microscopic structural information by computer simulations, we reveal that local translational symmetry breaking is responsible for the density anomalies. On the other hand, the difference in the degree of local orientational symmetry breaking between water and silica, which originates from the difference in their bonding nature, causes not only the difference in the sharpness of density anomalies, but also their distinct glass forming abilities. Our work not only shows the crucial roles of local translational and orientational symmetry breaking in the physical properties of the two extremely important materials, water and silica, but also provides a unified scenario applicable for other tetrahedral liquids such as Si, Ge, C, BeF2, and GeO2. PMID- 29439200 TI - Capping protein regulates actin dynamics during cytokinetic midbody maturation. AB - During cytokinesis, a cleavage furrow generated by actomyosin ring contraction is restructured into the midbody, a platform for the assembly of the abscission machinery that controls the final separation of daughter cells. The polymerization state of F-actin is important during assembly, ingression, disassembly, and closure of the contractile ring and for the cytoskeletal remodeling that accompanies midbody formation and progression to abscission. Actin filaments must be cleared from the abscission sites before the final cut can take place. Although many conserved proteins interact with and influence the polymerization state of actin filaments, it is poorly understood how they regulate cytokinesis in higher eukaryotes. We report here that the actin capping protein (CP), a barbed end actin binding protein, participates in the control of actin polymerization during later stages of cytokinesis in human cells. Cells depleted of CP furrow and form early midbodies, but they fail cytokinesis. Appropriate recruitment of the ESCRT-III abscission machinery to the midbody is impaired, preventing the cell from progressing to the abscission stage. To generate actin filaments of optimal length, different actin nucleators, such as formins, balance CP's activity. Loss of actin capping activity leads to excessive accumulation of formin-based linear actin filaments. Depletion of the formin FHOD1 results in partial rescue of CP-induced cytokinesis failure, suggesting that it can antagonize CP activity during midbody maturation. Our work suggests that the actin cytoskeleton is remodeled in a stepwise manner during cytokinesis, with different regulators at different stages required for successful progression to abscission. PMID- 29439202 TI - Compartmentalization of antagonistic Ca2+ signals in developing cochlear hair cells. AB - During a critical developmental period, cochlear inner hair cells (IHCs) exhibit sensory-independent activity, featuring action potentials in which Ca2+ ions play a fundamental role in driving both spiking and glutamate release onto synapses with afferent auditory neurons. This spontaneous activity is controlled by a cholinergic input to the IHC, activating a specialized nicotinic receptor with high Ca2+ permeability, and coupled to the activation of hyperpolarizing SK channels. The mechanisms underlying distinct excitatory and inhibitory Ca2+ roles within a small, compact IHC are unknown. Making use of Ca2+ imaging, afferent auditory bouton recordings, and electron microscopy, the present work shows that unusually high intracellular Ca2+ buffering and "subsynaptic" cisterns provide efficient compartmentalization and tight control of cholinergic Ca2+ signals. Thus, synaptic efferent Ca2+ spillover and cross-talk are prevented, and the cholinergic input preserves its inhibitory signature to ensure normal development of the auditory system. PMID- 29439205 TI - Inhaled Nitric Oxide in Extremely Premature Neonates With Respiratory Distress Syndrome. AB - BACKGROUND: Inhaled nitric oxide (iNO) is increasingly prescribed to extremely premature neonates with respiratory distress syndrome (RDS). Most of this off label use occurs during the first week of life. We studied this practice, hypothesizing that it would not be associated with improved survival. METHODS: We queried the Pediatrix Medical Group Clinical Data Warehouse to identify all neonates born at 22 to 29 weeks' gestation from 2004 to 2014. In our study sample, we included singletons who required mechanical ventilation for treatment of RDS and excluded those with anomalies. The primary outcome was death before discharge. Through a sequential risk set approach, each patient who received iNO during the first 7 days of life ("case patient") was matched by using propensity scores to a patient who had not received iNO at a chronological age before the case patient's iNO initiation age (defined as the index age for the matched pair). The association between iNO status and in-hospital mortality was evaluated in a Cox proportional hazards regression model by using age as the time scale with patients entering the risk set at their respective index age. RESULTS: Among 37 909 neonates in our study sample, we identified 993 (2.6%) who received iNO. The 2 matched cohorts each contained 971 patients. We did not observe a significant association between iNO exposure and mortality (hazard ratio, 1.08; 95% confidence interval, 0.94-1.25; P = .29). CONCLUSIONS: Off-label prescription of iNO is not associated with reduced in-hospital mortality among extremely premature neonates with RDS. PMID- 29439203 TI - Single-bacterial genomics validates rich and varied specialized metabolism of uncultivated Entotheonella sponge symbionts. AB - Marine sponges are prolific sources of unique bioactive natural products. The sponge Theonella swinhoei is represented by several distinct variants with largely nonoverlapping chemistry. For the Japanese chemotype Y harboring diverse complex polyketides and peptides, we previously provided genomic and functional evidence that a single symbiont, the filamentous, multicellular organism "Candidatus Entotheonella factor," produces almost all of these compounds. To obtain further insights into the chemistry of "Entotheonella," we investigated another phylotype, "Candidatus Entotheonella serta," present in the T. swinhoei WA sponge chemotype, a source of theonellamide- and misakinolide-type compounds. Unexpectedly, considering the lower chemical diversity, sequencing of individual bacterial filaments revealed an even larger number of biosynthetic gene regions than for Ca E. factor, with virtually no overlap. These included genes for misakinolide and theonellamide biosynthesis, the latter assigned by comparative genomic and metabolic analysis of a T. swinhoei chemotype from Israel, and by biochemical studies. The data suggest that both compound families, which were among the earliest model substances to study bacterial producers in sponges, originate from the same bacterium in T. swinhoei WA. They also add evidence that metabolic richness and variability could be a more general feature of Entotheonella symbionts. PMID- 29439206 TI - Inhaled Nitric Oxide for Preterm Infants: What Can Change Our Practice? PMID- 29439204 TI - hMENA is a key regulator in endothelin-1/beta-arrestin1-induced invadopodial function and metastatic process. AB - Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by beta-arrestin1 (beta-arr1) driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of beta-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression. ET-1R activation by ET-1 up-regulates expression of hMENA/hMENADeltav6 isoforms through beta-arr1, restricted to mesenchymal-like invasive SOC cells. The interaction of beta-arr1 with hMENA/hMENADeltav6 triggered by ET-1 leads to activation of RhoC and cortactin, recruitment of membrane type 1-matrix metalloprotease, and invadopodia maturation, thereby enhancing cell plasticity, transendothelial migration, and the resulting spread of invasive cells. The treatment with the ET-1R antagonist macitentan impairs the interaction of beta-arr1 with hMENA and inhibits invadopodial maturation and tumor dissemination in SOC orthotopic xenografts. Finally, high ETAR/hMENA/beta arr1 gene expression signature is associated with a poor prognosis in SOC patients. These data define a pivotal function of hMENA/hMENADeltav6 for ET 1/beta-arr1-induced invadopodial activity and ovarian cancer progression. PMID- 29439208 TI - Swisher Sweets 'Artist Project': using musical events to promote cigars. PMID- 29439207 TI - A Casino goes smoke free: a longitudinal study of secondhand and thirdhand smoke pollution and exposure. AB - BACKGROUND: Secondhand smoke (SHS) in US casinos is common, but little is known about the residue of tobacco smoke pollutants left behind in dust and on surfaces, commonly referred to as thirdhand smoke (THS). We examined SHS and THS pollution and exposure before and during a casino smoking ban and after smoking resumed. METHODS: A casino was visited nine times over a 15-month period to collect dust, surface and air samples in eight locations. Finger wipe and urine samples were collected from non-smoking confederates before and after a 4-hour casino visit. Samples were analysed for markers of SHS and THS pollution and exposure. RESULTS: Exceptionally high levels of THS were found in dust and on surfaces. Although the smoking ban led to immediate improvements in air quality, surface nicotine levels were unchanged and remained very high for the first month of the smoking ban. Surface nicotine decreased by 90% after 1 month (P<0.01), but nicotine and tobacco-specific nitrosamines in dust decreased more slowly, declining by 90% only after 3 months (P<0.01). Exposure was significantly reduced after the ban, but the benefits of the ban were reversed after smoking resumed. CONCLUSIONS: Long-term smoking in a casino creates deep THS reservoirs that persist for months after a smoking ban. A complete smoking ban immediately improves air quality and significantly reduces exposure to SHS and THS. However, THS reservoirs contribute to continued low-level exposure to toxicants. To accelerate the effect of smoking bans, remediation efforts should address specific THS reservoirs, which may require intensive cleaning as well as replacement of carpets, furniture and building materials. PMID- 29439209 TI - Two B-Box Proteins Regulate Photomorphogenesis by Oppositely Modulating HY5 through their Diverse C-Terminal Domains. AB - The Arabidopsis (Arabidopsis thaliana) BBX family comprises several positive and negative regulators of photomorphogenesis. BBX24, a member of BBX structural group IV, acts as a negative regulator of photomorphogenesis, whereas another member from the same group, BBX21, is a positive regulator. The molecular basis for the functional diversity shown by these related BBX family members is unknown. Using domain-swap lines, we show that the C-terminal regions of BBX24 and BBX21 specify their function. Because both BBX21 and BBX24 work in close association with HY5, we hypothesized that these proteins differentially regulate the levels or activity of HY5 to fulfill their opposite roles. We show that BBX21 can regulate HY5 post-transcriptionally and the two proteins can coordinate to promote photomorphogenesis. By contrast, BBX24 interferes with the binding of HY5 to the promoter of an anthocyanin biosynthetic gene, possibly by heterodimerizing with HY5 and preventing it from binding DNA. Our finding that both BBX21 and BBX24 regulate HY5 activity post-transcriptionally, in opposite ways, suggests that closely related B-box proteins execute contrasting functions through differential regulation of HY5. PMID- 29439210 TI - Mycorrhiza-Triggered Transcriptomic and Metabolomic Networks Impinge on Herbivore Fitness. AB - Symbioses between plants and mycorrhizal fungi are ubiquitous in ecosystems and strengthen the plants' defense against aboveground herbivores. Here, we studied the underlying regulatory networks and biochemical mechanisms in leaves induced by ectomycorrhizae that modify herbivore interactions. Feeding damage and oviposition by the widespread poplar leaf beetle Chrysomela populi were reduced on the ectomycorrhizal hybrid poplar Populus * canescens Integration of transcriptomics, metabolomics, and volatile emission patterns via mass difference networks demonstrated changes in nitrogen allocation in the leaves of mycorrhizal poplars, down-regulation of phenolic pathways, and up-regulation of defensive systems, including protease inhibitors, chitinases, and aldoxime biosynthesis. Ectomycorrhizae had a systemic influence on jasmonate-related signaling transcripts. Our results suggest that ectomycorrhizae prime wounding responses and shift resources from constitutive phenol-based to specialized protective compounds. Consequently, symbiosis with ectomycorrhizal fungi enabled poplars to respond to leaf beetle feeding with a more effective arsenal of defense mechanisms compared with nonmycorrhizal poplars, thus demonstrating the importance of belowground plant-microbe associations in mitigating aboveground biotic stress. PMID- 29439211 TI - Comparative Analysis of Arabidopsis Ecotypes Reveals a Role for Brassinosteroids in Root Hydrotropism. AB - Plant roots respond to soil moisture gradients and remodel their growth orientation toward water through hydrotropism, a process vital for acclimation to a changing soil environment. Mechanisms underlying the root hydrotropic response, however, remain poorly understood. Here, we examined hydrotropism in 31 Arabidopsis (Arabidopsis thaliana) ecotypes collected from different parts of the world and grown along moisture gradients in a specially designed soil-simulation system. Comparative transcriptome profiling and physiological analyses were carried out on three selected ecotypes, Wassilewskija (Ws), Columbia (Col-0) (strongly hydrotropic), Col-0 (moderately hydrotropic), and C24 (weakly hydrotropic), and in mutant lines with altered root hydrotropic responses. We show that H+ efflux, Ca2+ influx, redox homeostasis, epigenetic regulation, and phytohormone signaling may contribute to root hydrotropism. Among phytohormones, the role of brassinosteroids (BRs) was examined further. In the presence of an inhibitor of BR biosynthesis, the strong hydrotropic response observed in Ws was reduced. The root H+ efflux and primary root elongation also were inhibited when compared with C24, an ecotype that showed a weak hydrotropic response. The BR insensitive mutant bri1-5 displayed higher rates of root growth inhibition and root curvature on moisture gradients in vertical or oblique orientation when compared with wild-type Ws. We also demonstrate that BRI1 (a BR receptor) interacts with AHA2 (a plasma membrane H+-ATPase) and that their expression patterns are highly coordinated. This synergistic action may contribute to the strong hydrotropism observed in Ws. Our results suggest that BR-associated H+ efflux is critical in the hydrotropic response of Arabidopsis roots. PMID- 29439212 TI - Oxidation of Translation Factor EF-Tu Inhibits the Repair of Photosystem II. AB - The repair of photosystem II (PSII) is particularly sensitive to oxidative stress and the inhibition of repair is associated with oxidative damage to the translational elongation system in the cyanobacterium Synechocystis sp. PCC 6803. However, the molecular mechanisms underlying this inhibition are unknown. We previously demonstrated in vitro that EF-Tu, a translation factor that delivers aminoacyl-tRNA to the ribosome, is inactivated by reactive oxygen species via oxidation of the Cys residue Cys-82. In this study, we examined the physiological role of the oxidation of EF-Tu in Synechocystis Under strong light, EF-Tu was rapidly oxidized to yield oxidized monomers in vivo. We generated a Synechocystis transformant that expressed mutated EF-Tu in which Cys-82 had been replaced with a Ser residue. Under strong light, the de novo synthesis of proteins that are required for PSII repair, such as D1, was enhanced in the transformant and photoinhibition of PSII was alleviated. However, photodamage to PSII, measured in the presence of lincomycin, was similar between the transformant and wild-type cells, suggesting that expression of mutated EF-Tu might enhance the repair of PSII. Alleviating photoinhibition through mutation of EF-Tu did not alter cell growth under strong light, perhaps due to the enhanced production of reactive oxygen species. These observations suggest that the oxidation of EF-Tu under strong light inhibits PSII repair, resulting in the stimulation of photoinhibition. PMID- 29439214 TI - Programming gene and engineered-cell therapies with synthetic biology. AB - Gene and engineered-cell therapies promise to treat diseases by genetically modifying cells to carry out therapeutic tasks. Although the field has had some success in treating monogenic disorders and hematological malignancies, current approaches are limited to overexpression of one or a few transgenes, constraining the diseases that can be treated with this approach and leading to potential concerns over safety and efficacy. Synthetic gene networks can regulate the dosage, timing, and localization of gene expression and therapeutic activity in response to small molecules and disease biomarkers. Such "programmable" gene and engineered-cell therapies will provide new interventions for incurable or difficult-to-treat diseases. PMID- 29439213 TI - A Genetic Network for Systemic RNA Silencing in Plants. AB - Non-cell autonomous RNA silencing can spread from cell to cell and over long distances in animals and plants. However, the genetic requirements and signals involved in plant mobile gene silencing are poorly understood. Here, we identified a DICER-LIKE2 (DCL2)-dependent mechanism for systemic spread of posttranscriptional RNA silencing, also known as posttranscriptional gene silencing (PTGS), in Nicotiana benthamiana Using a suite of transgenic DCL RNAi lines coupled with a GFP reporter, we demonstrated that N. benthamiana DCL1, DCL2, DCL3, and DCL4 are required to produce microRNAs and 22, 24, and 21nt small interfering RNAs (siRNAs), respectively. All investigated siRNAs produced in local incipient cells were present at low levels in distal tissues. Inhibition of DCL2 expression reduced the spread of gene silencing, while suppression of DCL3 or DCL4 expression enhanced systemic PTGS. In contrast to DCL4 RNAi lines, DCL2 DCL4 double-RNAi lines developed systemic PTGS similar to that observed in DCL2 RNAi. We further showed that the 21 or 24 nt local siRNAs produced by DCL4 or DCL3 were not involved in long-distance gene silencing. Grafting experiments demonstrated that DCL2 was required in the scion to respond to the signal, but not in the rootstock to produce/send the signal. These results suggest a coordinated DCL genetic pathway in which DCL2 plays an essential role in systemic PTGS in N. benthamiana, while both DCL4 and DCL3 attenuate systemic PTGS. We discuss the potential role of 21, 22, and 24 nt siRNAs in systemic PTGS. PMID- 29439215 TI - War and peace in the nuclear age. PMID- 29439216 TI - News at a glance. PMID- 29439217 TI - Design for U.S. exascale computer takes shape. PMID- 29439218 TI - China's planned exascale computer threatens Summit's position at the top. PMID- 29439219 TI - Psychiatrists begin to map genetic architecture of mental disorders. PMID- 29439220 TI - Use of cholera vaccines expands, raising hopes. PMID- 29439221 TI - Gene therapy field hit by fresh safety concern. PMID- 29439223 TI - As polar ozone mends, UV shield closer to equator thins. PMID- 29439222 TI - Tobacco giant's research largesse ignites controversy. PMID- 29439224 TI - The happiness project. PMID- 29439225 TI - China's AI imperative. PMID- 29439226 TI - An indoor chemical cocktail. PMID- 29439227 TI - Toward an optically controlled brain. PMID- 29439228 TI - Cholesterol crystals impede nerve repair. PMID- 29439229 TI - How hummingbirds stay nimble on the wing. PMID- 29439230 TI - When quantum optics meets topology. PMID- 29439231 TI - Revising concepts about adult stem cells. PMID- 29439232 TI - Superradiators created atom by atom. PMID- 29439233 TI - Open data sharing and the Global South-Who benefits? PMID- 29439234 TI - Bialowieza Forest: Political stands. PMID- 29439235 TI - Bialowieza Forest: Logging data lacking. PMID- 29439236 TI - Transport expansion threatens the Arctic. PMID- 29439237 TI - Morphology, muscle capacity, skill, and maneuvering ability in hummingbirds. AB - How does agility evolve? This question is challenging because natural movement has many degrees of freedom and can be influenced by multiple traits. We used computer vision to record thousands of translations, rotations, and turns from more than 200 hummingbirds from 25 species, revealing that distinct performance metrics are correlated and that species diverge in their maneuvering style. Our analysis demonstrates that the enhanced maneuverability of larger species is explained by their proportionately greater muscle capacity and lower wing loading. Fast acceleration maneuvers evolve by recruiting changes in muscle capacity, whereas fast rotations and sharp turns evolve by recruiting changes in wing morphology. Both species and individuals use turns that play to their strengths. These results demonstrate how both skill and biomechanical traits shape maneuvering behavior. PMID- 29439238 TI - Live imaging of neurogenesis in the adult mouse hippocampus. AB - Neural stem and progenitor cells (NSPCs) generate neurons throughout life in the mammalian hippocampus. We used chronic in vivo imaging and followed genetically labeled individual NSPCs and their progeny in the mouse hippocampus for up to 2 months. We show that NSPCs targeted by the endogenous Achaete-scute homolog 1 (Ascl1) promoter undergo limited rounds of symmetric and asymmetric divisions, eliciting a burst of neurogenic activity, after which they are lost. Further, our data reveal unexpected asymmetric divisions of nonradial glia-like NSPCs. Cell fates of Ascl1-labeled lineages suggest a developmental-like program involving a sequential transition from a proliferative to a neurogenic phase. By providing a comprehensive description of lineage relationships, from dividing NSPCs to newborn neurons integrating into the hippocampal circuitry, our data offer insight into how NSPCs support life-long hippocampal neurogenesis. PMID- 29439239 TI - A topological quantum optics interface. AB - The application of topology in optics has led to a new paradigm in developing photonic devices with robust properties against disorder. Although considerable progress on topological phenomena has been achieved in the classical domain, the realization of strong light-matter coupling in the quantum domain remains unexplored. We demonstrate a strong interface between single quantum emitters and topological photonic states. Our approach creates robust counterpropagating edge states at the boundary of two distinct topological photonic crystals. We demonstrate the chiral emission of a quantum emitter into these modes and establish their robustness against sharp bends. This approach may enable the development of quantum optics devices with built-in protection, with potential applications in quantum simulation and sensing. PMID- 29439240 TI - Light amplification by seeded Kerr instability. AB - Amplification of femtosecond laser pulses typically requires a lasing medium or a nonlinear crystal. In either case, the chemical properties of the lasing medium or the momentum conservation in the nonlinear crystal constrain the frequency and the bandwidth of the amplified pulses. We demonstrate high gain amplification (greater than 1000) of widely tunable (0.5 to 2.2 micrometers) and short (less than 60 femtosecond) laser pulses, up to intensities of 1 terawatt per square centimeter, by seeding the modulation instability in an Y3Al5O12 crystal pumped by femtosecond near-infrared pulses. Our method avoids constraints related to doping and phase matching and therefore can occur in a wider pool of glasses and crystals even at far-infrared frequencies and for single-cycle pulses. Such amplified pulses are ideal to study strong-field processes in solids and highly excited states in gases. PMID- 29439241 TI - Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics. AB - Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy. PMID- 29439244 TI - My climate change crisis. PMID- 29439243 TI - Atomic structures of low-complexity protein segments reveal kinked beta sheets that assemble networks. AB - Subcellular membraneless assemblies are a reinvigorated area of study in biology, with spirited scientific discussions on the forces between the low-complexity protein domains within these assemblies. To illuminate these forces, we determined the atomic structures of five segments from protein low-complexity domains associated with membraneless assemblies. Their common structural feature is the stacking of segments into kinked beta sheets that pair into protofilaments. Unlike steric zippers of amyloid fibrils, the kinked sheets interact weakly through polar atoms and aromatic side chains. By computationally threading the human proteome on our kinked structures, we identified hundreds of low-complexity segments potentially capable of forming such interactions. These segments are found in proteins as diverse as RNA binders, nuclear pore proteins, and keratins, which are known to form networks and localize to membraneless assemblies. PMID- 29439245 TI - Downregulation of SPINK13 Promotes Metastasis by Regulating uPA in Ovarian Cancer Cells. AB - BACKGROUND/AIMS: Ovarian cancer (OC) is the fifth leading cause of cancer-related death in women, and it is difficult to diagnose at an early stage. The purpose of this study was to explore the prognostic biological markers of OC. METHODS: Univariate Cox regression analysis was used to identify genes related to OC prognosis from the Cancer Genome Atlas(TCGA) database. Immunohistochemistry was used to analyse the level of SPINK13 in OC and normal tissues. Cell proliferation, apoptosis and invasion were performed using MTT assay, flow cytometric analysis and Transwell assay, respectively. RESULTS: We identified the Kazal-type serine protease inhibitor-13 (SPINK13) gene related to OC prognosis from the Cancer Genome Atlas (TCGA) database by univariate Cox regression analysis. Overexpression of SPINK13 was associated with higher overall survival rate in OC patients. Immunohistochemistry showed that the level of SPINK13 protein was significantly lower in OC tissues than in normal tissues (P < 0.05).In vitro experiments showed that the overexpression of SPINK13 inhibited cellular proliferation and promoted apoptosis. Moreover, SPINK13 inhibited cell migration and epithelial to mesenchymal transition (EMT). SPINK13 was found to inhibit the expression of urokinase-type plasminogen activator (uPA), while recombinant uPA protein could reverse the inhibitory effect of SPINK13 on OC metastasis. CONCLUSION: These results indicate that SPINK13 functions as a tumour suppressor. The role of SPINK13 in cellular proliferation, apoptosis and migration is uPA dependent, and SPINK13 may be used as a potential biomarker for diagnosis and targeted therapy in OC. PMID- 29439242 TI - Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. AB - The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity. PMID- 29439246 TI - Cyclic Mechanical Stretch Induced Smooth Muscle Cell Changes in Cerebral Aneurysm Progress by Reducing Collagen Type IV and Collagen Type VI Levels. AB - BACKGROUND/AIMS: Cerebral aneurysm growth is characterized by continuous structural weakness of local smooth muscle cells, though the mechanism is unclear. In this study, we examine protein changes in cerebral aneurysm and human brain vascular smooth muscle cells after cyclic mechanical stretch. We further explore the relationship between the smooth muscle cell changes and reductions in the levels of collagen types IV and VI. METHODS: Saccular cerebral aneurysms (n=10) were collected, and temporal artery samples were used as controls. Quantitative proteomics were analyzed and histopathological changes were examined. Smooth muscle cells were cultured in a flexible silicone chamber and subjected to 15% cyclic mechanical stretch. The effect of stretch on the cell viability, function, gene and protein expression were further studied for the understanding the molecular mechanism of aneurysm development. RESULTS: Proteomics analysis revealed 92 proteins with increased expression and 88 proteins with decreased expression compared to the controls (p<0.05). KEGG pathway analysis showed that the change in focal adhesion and extracellular matrix-receptor interaction, suggesting the involvement of collagen type IV and VI. The aneurysm tissue exhibited fewer smooth muscle cells and lower levels of collagen type IV and VI. Human brain vascular smooth muscle cell culture showed spindle-like cells and obvious smooth muscle cell layer. Cell proteomics analysis showed that decreased expression of 118 proteins and increased expression of 32 proteins in smooth muscle cells after cyclic mechanical stretch. KEGG pathway analysis indicated that focal adhesion and ECM-receptor interaction were involved. After cyclic mechanical stretch, collagen type IV and IV expression were decreased. Moreover, the stretch induced MMP-1 and MMP-3 expression elevation. CONCLUSION: We demonstrated that collagen type IV and VI were decreased in cerebral aneurysms and continuous cyclic mechanical stretch induced smooth muscle cell changes. Smooth muscle cell protection provides an additional therapeutic option to prevent the growth of cerebral aneurysms. PMID- 29439247 TI - Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies? AB - Alzheimer disease (AD) is a progressive neurodegenerative disorder mainly characterized by cognitive deficits and neuropathological changes such as Tau lesions and amyloid plaques, but also associated with non-cognitive symptomatology. Metabolic and neuroendocrine abnormalities, such as alterations in body weight, brain insulin impairments, and lower brain glucose metabolism, which often precede clinical diagnosis, have been extensively reported in AD patients. However, the origin of these symptoms and their relation to pathology and cognitive impairments remain misunderstood. Insulin is a hormone involved in the control of energy homeostasis both peripherally and centrally, and insulin resistant state has been linked to increased risk of dementia. It is now well established that insulin resistance can exacerbate Tau lesions, mainly by disrupting the balance between Tau kinases and phosphatases. On the other hand, the emerging literature indicates that Tau protein can also modulate insulin signalling in the brain, thus creating a detrimental vicious circle. The following review will highlight our current understanding of the role of insulin in the brain and its relation to Tau protein in the context of AD and tauopathies. Considering that insulin signalling is prone to be pharmacologically targeted at multiple levels, it constitutes an appealing approach to improve both insulin brain sensitivity and mitigate brain pathology with expected positive outcome in terms of cognition. PMID- 29439248 TI - Transient Receptor Potential Vanilloid 4 Activation-Induced Increase in Glycine Activated Current in Mouse Hippocampal Pyramidal Neurons. AB - BACKGROUND/AIMS: Glycine plays an important role in regulating hippocampal inhibitory/ excitatory neurotransmission through activating glycine receptors (GlyRs) and acting as a co-agonist of N-methyl-d-aspartate-type glutamate receptors. Activation of transient receptor potential vanilloid 4 (TRPV4) is reported to inhibit hippocampal A-type gamma-aminobutyric acid receptor, a ligand gated chloride ion channel. GlyRs are also ligand-gated chloride ion channels and this paper aimed to explore whether activation of TRPV4 could modulate GlyRs. METHODS: Whole-cell patch clamp recording was employed to record glycine activated current (IGly) and Western blot was conducted to assess GlyRs subunits protein expression. RESULTS: Application of TRPV4 agonist (GSK1016790A or 5,6 EET) increased IGly in mouse hippocampal CA1 pyramidal neurons. This action was blocked by specific antagonists of TRPV4 (RN-1734 or HC-067047) and GlyR (strychnine), indicating that activation of TRPV4 increases strychnine-sensitive GlyR function in mouse hippocampal pyramidal neurons. GSK1016790A-induced increase in IGly was significantly attenuated by protein kinase C (PKC) (BIM II or D-sphingosine) or calcium/calmodulin-dependent protein kinase II (CaMKII) (KN 62 or KN-93) antagonists but was unaffected by protein kinase A or protein tyrosine kinase antagonists. Finally, hippocampal protein levels of GlyR alpha1 alpha2, alpha3 and beta subunits were not changed by treatment with GSK1016790A for 30 min or 1 h, but GlyR alpha2, alpha3 and beta subunits protein levels increased in mice that were intracerebroventricularly (icv.) injected with GSK1016790A for 5 d. CONCLUSION: Activation of TRPV4 increases GlyR function and expression, and PKC and CaMKII signaling pathways are involved in TRPV4 activation-induced increase in IGly. This study indicates that GlyRs may be effective targets for TRPV4-induced modulation of hippocampal inhibitory neurotransmission. PMID- 29439249 TI - Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability. AB - BACKGROUND/AIMS: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. METHODS: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL 18Ralpha and p-Smad3 were measured by Weston blotting. RESULTS: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4+ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. CONCLUSION: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease. PMID- 29439250 TI - Hoxa5 Promotes Adipose Differentiation via Increasing DNA Methylation Level and Inhibiting PKA/HSL Signal Pathway in Mice. AB - BACKGROUND/AIMS: Impaired adipogenesis may be the underlying cause in the development of obesity and type II diabetes. Mechanistically, the family of Homeobox transcription factors is implicated in the regulation of adipocyte fate. Hoxa5 is highly expressed in adipocytes, and its mRNA expression is decreased during differentiation. However, the function of Hoxa5 in adipose tissue has been poorly understood. The aim of this study is to unveil the role of Hoxa5 on adipocyte differentiation and its underlying mechanisms. METHODS: Quantitative real-time PCR (qPCR) and western blot were performed to determine Hoxa5 expression in primary adipocytes and in adipose tissues from mice. Lipid accumulation was evaluated by bodipy staining. Dual luciferase assay was applied to explore the transcription factor of Hoxa5 and the transcriptional target gene modulated by Hoxa5. All measurements were performed at least for three times at least. RESULTS: A significant reduction of Hoxa5 expression was observed in adipose tissue of High Fat Diet (HFD) induced obesity mice. We determined Hoxa5 increased adipocytes differentiation and mitochondrial biogenesis in adipocytes in vitro. CEBPbeta was determined a transcription factor of Hoxa5 and inhibited methylation level of Hoxa5 by combining on the promoter of Hoxa5. Importantly, we found Fabp4, a known positive regulator of adipocytes differentiation, was transcriptional activation by Hoxa5. In addition, Hoxa5 promotes adipocytes differentiation by inhibiting PKA/HSL pathway. CONCLUSION: Our study demonstrated the promoting role of Hoxa5 in adipocytes differentiation and therefore bringing a new therapeutic mean to the treatment of obesity and type II diabetes. PMID- 29439251 TI - Low Cerebral Oxygenation Is Associated with Cognitive Impairment in Chronic Hemodialysis Patients. AB - BACKGROUND/AIMS: High rates of cognitive impairment (CI) are an alarming problem in patients undergoing chronic hemodialysis (HD). Its pathophysiology remains unclear and there are indications that brain ischemia might be one of the key causes. Cerebral tissue oxygenation, as measured by near-infrared spectroscopy, is known to be decreased in HD patients. However, it is unknown whether CI is associated or not associated with lower cerebral oxygenation in these patients. The primary aim of our study was to probe this possible association. Our secondary aim was to assess other factors possibly related to cerebral ischemia and CI. METHODS: Thirty-nine patients treated by chronic HD were included in this cross-sectional study. All measurements were performed before the initiation of an HD session. The Montreal Cognitive Assessment (MoCA) was administered according to published recommendations. Regional saturation of oxygen (rSO2) of the left frontal lobe was measured using the INVOS 5100C device. Basic medical history and laboratory data were recorded, and handgrip strength was analyzed. We used the unpaired t test to compare the rSO2 and other variables between cognitively normal patients (MoCA score >=26) and those who displayed CI (MoCA score <26). Multiple linear regression analysis was used to adjust for principal confounders. RESULTS: Cognitively impaired patients had lower brain rSO2 values compared to cognitively normal patients (48 +/- 9 vs. 57 +/- 10%, p = 0.01). Among other variables, higher red cell distribution width (15.8 +/- 1.9 vs. 13.8 +/- 1.6%, p = 0.01) and lower hand grip strength (49.2 +/- 23.3 vs. 99.3 +/- 31.4 lbs, p < 0.001) also displayed a significant association with CI. The relation between rSO2 and MoCA score was significant after adjustment for age and gender (p = 0.007). CONCLUSION: Decreased brain oxygenation is associated with weaker cognitive performance in patients undergoing chronic HD. Further understanding the causes of cerebral ischemia in HD patients could lead to the prevention of cognitive decline in this population. PMID- 29439252 TI - Psychosocial Pretreatment Predictors of Weight Control: A Systematic Review Update. AB - OBJECTIVE: Systematically identifying pretreatment characteristics that predict successful weight management is important to improve intervention efficacy and clinical practice. This study provides a comprehensive update of a 2005 review on pretreatment predictors of successful weight management. METHODS: Results of 37 recent original studies from peer-reviewed journals were merged with the results from the 2005 review. A critical appraisal of the 66 studies included was provided, and meta-analyses were performed when feasible. RESULTS: Fewer previous weight loss attempts were the most consistent pretreatment predictor of successful weight management, although with a small effect size. Importantly, several variables were identified as non-significant predictors of weight loss, showing trivial effects (e.g., eating self-efficacy). Many psychosocial factors remain too little studied to allow reliable conclusions regarding their predictive value. CONCLUSION: Previous dieting attempts were identified as the soundest predictor of successful weight management. Several factors, previously considered barriers to successful weight management and now identified as non predictors, require more investigation given the limitations identified in this review. Importantly, due to a comparably thin empirical basis for many predictors, further research is essential to move the field forward. Implications of the current state of research and necessary steps to improve intervention efficacy and clinical practice are discussed. PMID- 29439253 TI - Positive Iron Balance in Chronic Kidney Disease: How Much is Too Much and How to Tell? AB - BACKGROUND: Regulation of body iron occurs at cellular, tissue, and systemic levels. In healthy individuals, iron absorption and losses are minimal, creating a virtually closed system. In the setting of chronic kidney disease and hemodialysis (HD), increased iron losses, reduced iron absorption, and limited iron availability lead to iron deficiency. Intravenous (IV) iron therapy is frequently prescribed to replace lost iron, but determining an individual's iron balance and stores can be challenging and imprecise, contributing to uncertainty about the long-term safety of IV iron therapy. SUMMARY: Patients on HD receiving judicious doses of IV iron are likely to be in a state of positive iron balance, yet this does not appear to confer an overt risk for clinically relevant iron toxicity. The concomitant use of iron with erythropoiesis-stimulating agents, the use of maintenance iron dosing regimens, and the reticuloendothelial distribution of hepatic iron deposition likely minimize the potential for iron toxicity in patients on HD. Key Messages: Because no single diagnostic test can, at present, accurately assess iron status and risk for toxicity, clinicians need to take an integrative approach to avoid iron doses that impose excessive exposure while ensuring sufficient replenishment of iron stores capable of overcoming hepcidin blockade and allowing for effective erythropoiesis. PMID- 29439254 TI - Inhibition of Suicidal Erythrocyte Death by Indirubin-3'-Monoxime. AB - BACKGROUND/AIMS: Qing Dai is a prized traditional Chinese medicine whose major component, indirubin, and its derivative, indirubin-3'-monoxime (IDM), have inhibitory effects on the growth of many human tumor cells and pronounced anti leukemic activities. However, the effects of IDM on mature human erythrocytes are unclear. This study aimed to evaluate the potential impact of IDM on erythrocytes and the mechanisms underlying that impact. METHODS: Utilizing flow cytometry and confocal laser scanning microscopy, phosphatidylserine exposure at the cell surface was estimated by annexin V-fluorescein isothiocyanate (FITC). The relative cell size, expressed in arbitrary units, was evaluated by forward scatter in a flow cytometer. Fluo-3 fluorescence was used to bewrite changes in cytosolic Ca2+ activity, reactive oxygen species (ROS) formation was assessed by 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence, and ceramide abundance was evaluated by FITC-conjugated specific antibodies. RESULTS: The 24-h exposure of human erythrocytes to IDM (12 uM) significantly decreased the percentage of annexin V-binding erythrocytes and the intracellular calcium concentration ([Ca2+]i). IDM (3-12 uM) did not significantly modify the ceramide level or DCFH-DA fluorescence. Energy depletion (removal of glucose for 24 hours) significantly increased annexin V binding and Fluo-3 fluorescence and diminished forward scatter, and these effects were significantly mitigated by IDM (12 uM). Moreover, the Ca2+ ionophore ionomycin (1 uM, 60 min) and oxidative stress (30 min exposure to 0.05 mM tert-butyl hydroperoxide, t-BHP) similarly triggered eryptosis, which was also significantly suppressed by IDM. CONCLUSIONS: IDM is a novel inhibitor of suicidal erythrocyte death following ionomycin treatment, t BHP treatment and energy depletion. Thus, IDM may counteract anemia and impairment of microcirculation, at least in part, by inhibition of Ca2+ entry into erythrocytes. PMID- 29439255 TI - Co-Upregulation of 14-3-3zeta and P-Akt is Associated with Oncogenesis and Recurrence of Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: 14-3-3zeta is involved in the regulation of PI3K/Akt pathway which is closely associated with carcinogenesis. However, the clinical significance of combined detection of 14-3-3zeta and p-Akt in hepatocellular carcinoma (HCC) remains unclear. METHODS: Two-hundred pairs of HCC and adjacent liver specimens were subjected to tissue microarray. The association of 14-3 3zeta and p-Akt levels with the postoperative survival and recurrence in HCC patients was analyzed with univariate and multivariate methods. Moreover, the effects of 14-3-3zeta overexpression on the growth of HCC and the expressions of p-Akt and HIF-1alpha were assessed in a xenograft mouse model. RESULTS: Elevated levels of 14-3-3zeta and p-Akt were detected in HCC and a positive correlation between the levels of 14-3-3zeta and p-Akt was verified. HCC patients with satellite nodules, microvascular invasion, portal vein tumor thrombosis, poor tumor differentiation and an advanced tumor stage tended to have higher levels of 14-3-3zeta and p-Akt. In addition, the postoperative 3-, 5-, and 7-year overall survival rates in HCC patients with 14-3-3zetahigh and p-Akthigh were significantly lower compared with those with 14-3-3zetalow and p-Aktlow, and the cumulative recurrence rate in HCC patients with 14-3-3zetahigh and p-Akthigh was significantly higher than that in those with 14-3-3zetalow and p-Aktlow. The multivariate Cox proportional hazard analysis indicated that concomitant upregulation of 14-3-3zeta and p-Akt was an independent factor that predicted poor survival and high recurrence in HCC patients. Furthermore, animal experiment showed that overexpression of 14-3-3zeta accelerated the growth of HCC xenograft tumors and induced the expressions of p-Akt and HIF-1alpha in vivo. CONCLUSION: Co-upregulation of 14-3-3zeta and p-Akt predicts poor prognosis in patients with HCC, and 14-3-3zeta-induced activation of the Akt signaling pathway contributes to HCC progression. PMID- 29439256 TI - Chromosome Nomenclature and Cytological Characterization of Sacred Lotus. AB - Sacred lotus is a basal eudicot plant that has been cultivated in Asia for over 7,000 years for its agricultural, ornamental, religious, and medicinal importance. A notable characteristic of lotus is the seed longevity. Extensive endeavors have been devoted to dissect its genome assembly, including the variety China Antique, which germinated from a 1,300-year-old seed. Here, cytogenetic markers representing the 10 largest megascaffolds, which constitute approximately 70% of the lotus genome assembly, were developed. These 10 megascaffolds were then anchored to the corresponding lotus chromosomes by fluorescence in situ hybridization using these cytogenetic markers, and a set of chromosome-specific cytogenetic markers that could unambiguously identify each of the 8 chromosomes was generated. Karyotyping was conducted, and a nomenclature based on chromosomal length was established for the 8 chromosomes of China Antique. Comparative karyotyping revealed relatively conserved chromosomal structures between China Antique and 3 modern cultivars. Interestingly, significant variations in the copy number of 45S rDNA were detected between China Antique and modern cultivars. Our results provide a comprehensive view on the chromosomal structure of sacred lotus and will facilitate further studies and the genome assembly of lotus. PMID- 29439257 TI - Assessing Extracellular Volume in Hemodialysis Patients Using Intradialytic Blood Pressure Slopes. AB - BACKGROUND/AIMS: Extracellular volume (ECV) overload is a mortality risk factor in hemodialysis patients, but no standard approach exists to objectively assess this clinically. We aimed to quantify relationships between slopes of repeated intradialytic blood pressure (BP) measurements and ECV. METHODS: In a cross sectional study of 71 hemodialysis patients, we calculated BP slopes from all intradialytic measurements using Gaussian regression. We measured extracellular and total body water (TBW) with bioimpedance spectroscopy. We analyzed unconditional and conditional associations between BP slope and volume metrics with mixed linear models and sensitivity analyses using non-linear intradialytic BP trajectory. RESULTS: Mean systolic intradialytic BP slope (IBPS) was -0.06 (0.1) mm Hg/min. Post-dialysis extracellular water (ECW)/weight was the volume metric mostly strongly associated with slope (r = 0.34, p = 0.007 for unconditional analysis; beta = 1.45, p = 0.001 for conditional analysis). Among subjects with post-dialysis systolic BP >=130 mm Hg, the association strengthened (r = 0.40, p = 0.006; beta = 1.42, p = 0.003). ECV was more strongly associated with the BP slope than with pre-dialysis, post-dialysis, or delta systolic BP (r = -0.07, 0.19, 0.28; p = 0.6, 0.1, 0.03). In nonlinear models, BP trajectory also had the strongest association with post-dialysis ECW/body weight (p < 0.001). CONCLUSIONS: In hypertensive hemodialysis patients, measurements of ECV excess are more strongly associated with IBPSs than with pre-dialysis, post-dialysis, or change in systolic BP. Among varying volume metrics, post-dialysis ECW/weight has the strongest association with these slopes. Determining IBPS is a novel method to optimize clinical assessment of ECV in hemodialysis patients. PMID- 29439258 TI - Bone Marrow Cell Therapy on 1,2-Dimethylhydrazine (DMH)-Induced Colon Cancer in Rats. AB - BACKGROUND/AIMS: Stem cell based therapies are being under focus due to their possible role in treatment of various tumors. Bone marrow stem cells believed to have anticancer potential and are preferred for their activities by stimulating the immune system, migration to the site of tumor and ability for inducting apoptosis in cancer cells. The current study was aimed to investigate the tumor suppressive effects of bone marrow cells (BMCs) in 1,2-dimethylhydrazine (DMH) induced colon cancer in rats. METHODS: The rats were randomly allocated into four groups: control, BMCs alone, DMH alone and BMCs with DMH. BMCs were injected intrarectally while DMH was injected subcutaneously at 20 mg/kg body weight once a week for 15 weeks. Histopathological examination and gene expression of survivin, beta-catenin and multidrug resistance-1 (MDR-1) by real-time reverse transcription-polymerase chain reaction (RT-PCR) in rat colon tissues. This is in addition to oxidative stress markers in colon were performed across all groups. RESULTS: The presence of aberrant crypt foci was reordered once histopathological examination of colon tissue from rats which received DMH alone. Administration of BMCs into rats starting from zero-day of DMH injection improved the histopathological picture which showed a clear improvement in mucosal layer, few inflammatory cells infiltration periglandular and in the lamina propria. Gene expression in rat colon tissue demonstrated that BMCs down-regulated survivin, beta-catenin, MDR-1 and cytokeratin 20 genes expression in colon tissues after colon cancer induction. Amelioration of the colon status after administration of MSCs has been evidenced by a major reduction of lipid peroxidation, nitric oxide, and increasing of glutathione content and superoxide dismutase along with catalase activities. CONCLUSION: Our findings demonstrated that BMCs have tumor suppressive effects in DMH-induced colon cancer as evidenced by down-regulation of survivin, beta-catenin, and MDR-1 genes and enhancing the antioxidant activity. PMID- 29439259 TI - Downregulation of PRAME Suppresses Proliferation and Promotes Apoptosis in Hepatocellular Carcinoma Through the Activation of P53 Mediated Pathway. AB - BACKGROUND/AIMS: The expression of PRAME and its role in hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to examine the functional role of PRAME in HCC development and exploring the molecular mechanism. METHODS: We first detected PRAME expression in 96 human HCC tissue samples and correlated with clinicopathological characteristics and prognosis of the patients. We then established stable HCC cell lines with PRAME overexpression and knockdown followed by functional analysis in vitro. Further, we examined the relationship between PRAME and p53 pathway in vitro by using Western blotting. Finally, PRAME expression was detected to evaluate its correlation with p-p53 and p53 pathway related apoptotic proteins in xenograft tumor mouse model using immunohistochemistry. RESULTS: PRAME expression was significantly higher in HCC tissues than in adjacent non-tumor tissues and their expression was positively correlated with alpha fetoprotein levels and tumor size. In addition, PRAME expression was associated with AJCC stage and is a potential biomarker of poor prognosis regarding 5-year overall survival in HCC. In vitro studies, we found that PRAME expression was higher in HCC cell lines than in normal hepatic cell line. Inhibited cell proliferation and increased cell apoptosis was observed in PRAME knockdown HCC cells. Futher, increased cell apoptosis was correlated with the proportion of cells in G0/G1 stage, activated p53 mediated apoptosis, and increased cyclin p21 expression. Xenograft analysis in nude mice also found that PRAME knockdown inhibited tumorigenesis while PRAME overexpression had opposite effect. CONCLUSIONS: In HCC, PRAME serves as a potential biomarker for poor prognosis and novel therapeutic target in treating this cancer. PRAME is a potential biomarker of poor prognosis in HCC. PRAME surpresses HCC cell death in vitro and in vivo by regulating p53 apoptotic signaling and may serve as a potential therapeutic target in HCC. PMID- 29439260 TI - Nephrocalcinosis in Amelogenesis Imperfecta Caused by the FAM20A Mutation. AB - BACKGROUND/AIMS: Enamel-renal syndrome is characterized by nephrocalcinosis, enamel defects, gingival hyperplasia and eruption failures. It has been recently identified that recessive mutations in the FAM20A gene result in amelogenesis imperfecta (AI)-gingival fibromatosis. The aim of this research to determine whether AI patients with known -FAM20A mutations also have nephrocalcinosis. METHODS: Complete oral and radiological examinations were performed for all participating family members. Renal examinations were performed using ultrasound. RESULTS: The teeth were evaluated for severe loss, and multiple eruption failures were evident from the clinical and radiological examinations. Unexpected extensive and fast crown resorption was found by radiological examination. Renal ultrasound revealed bilateral nephrocalcinosis in both affected individuals. Recessive FAM20A mutations can cause nephrocalcinosis in addition to the oral phenotype. CONCLUSION: AI patients with similar clinical phenotypes and FAM20A mutations should be examined for nephropathy even if they lack pertinent symptoms. Nephrology referral is warranted for patients who have clinical phenotypes related to AI-gingival fibromatosis even if they are not symptomatic. PMID- 29439262 TI - Erratum. PMID- 29439263 TI - What We Do and Do Not Know about Women and Kidney Diseases; Questions Unanswered and Answers Unquestioned: Reflection on World Kidney Day and International Women's Day. AB - Chronic kidney disease affects approximately 10% of the world's adult population: it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women's health and specifically their kidney health, on the community and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those learnings more broadly. Girls and women, who make up approximately 50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care, and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, but also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to have an impact on women, with profound consequences for child bearing, and on the fetus. Women have different complications on dialysis than men, and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women, kidney health, and kidney disease, and what we might learn in the future to improve outcomes worldwide. PMID- 29439261 TI - Metabolomics Reveals Protection of Resveratrol in Diet-Induced Metabolic Risk Factors in Abdominal Muscle. AB - BACKGROUND/AIMS: Abdominal obesity is recognized as the main reason of metabolic syndrome, which is closely related to disordered skeletal and/or abdominal muscle metabolic functions. Metabolomics is a comprehensive assessment system in biological metabolites. The aim of our present study is to investigate the diet induced metabolic risk factors by metabolic in the abdominal muscles and clarify the relationship between atheroprotective effects of Resveratrol (Rev) and abdominal muscles metabolic components during the development of atherosclerosis. METHODS: The mice were randomly divided into three groups including normal group (N), high fat diet (HFD or H) group and high fat diet with Rev treated group (HR). GC-MS combined with pattern recognition approaches were employed to obtain comprehensive metabolic signatures and related differential metabolites after 24 week HFD feeding. Oil Red O staining and Electron microscopy technology (EMT) were employed to detect the size of fatty plaques and intracellular lipid accumulation, respectively. RESULTS: The result indicated that 22 types of metabolites in the abdominal muscles were obviously altered by HFD feeding group. Moreover, Rev treatment obviously increased 11 different kinds of metabolites, most of which were involved in the carbohydrate, amino acid and lipid metabolisms. Importantly, these elevated different metabolites were involved in pathways mainly related to galactose metabolism, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism in abdominal muscles. Oil Red O staining and Electron microscopy showed less lipid accumulation in the lesions and decreased intracellular lipid deposition in the foam cells in HR group. CONCLUSIONS: We concluded that Rev produced a beneficial effect partially by modulating multiple metabolism pathways and metabolites in the abdominal muscles, which may provide a new protective mechanism of Rev on the progression of atherosclerosis. These notably changed metabolites might be potential biomarkers or therapeutic targets during development of metabolic syndrome and atherosclerosis. PMID- 29439266 TI - Effect of the Opioid Crisis on the Donor Pool for Kidney Transplantation: An Analysis of National Kidney Deceased Donor Trends from 2010-2016. AB - BACKGROUND: The opioid crisis has led to a dramatic increase in the number of drug overdose deaths in the United States. Little is known about the effect of the opioid crisis on the kidney transplant donor pool, particularly on hepatitis C virus (HCV)-infected donors. METHODS: This is a retrospective analysis of the data from the Organ Procurement and Transplantation Network from 2010 to 2016. We determined the changes in characteristics of kidney transplant donors and evaluated which changes may be directly related to the opioid crisis. RESULTS: Between 2010 and 2016, we found a 26% increase in overall donors, including a 277% increase in the number of donors who died from drug overdose. Nineteen percent of donors who died of drug overdose had HCV infection. Donors who die from drug overdose and donors with HCV infection are younger, less likely to have diabetes or hypertension, and have favorable kidney donor profile index scores compared to average donors. Despite these favorable characteristics, HCV-infected donors appear to be notably underutilized, with substantially lower kidneys per donor being transplanted compared to HCV uninfected donors. CONCLUSION: The opioid crisis in the United States has substantially altered the kidney donor pool. Strategies to increase utilization of all potentially viable kidneys for transplant are needed, particularly in this era of new, highly effective, direct acting antiviral therapy for HCV infection. PMID- 29439265 TI - Natural History of Vertebrobasilar Dolichoectatic and Fusiform Aneurysms: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Vertebrobasilar non-saccular and dolichoectatic aneurysms (VBDA) are a rare type of aneurysm and are generally associated with poor prognosis. In order to better characterize the natural history of VBDAs, we performed a systematic review and meta-analysis of the literature to determine rates of mortality, growth, rupture, ischemia, and intraparenchymal hemorrhage. MATERIALS AND METHODS: We searched the literature for longitudinal natural history studies of VBDA patients reporting clinical and imaging outcomes. Studied outcomes included annualized rates of growth, rupture, ischemic stroke, intracerebral hemorrhage (ICH), and mortality. We also studied the association between aneurysm morphology (dolichoectatic versus fusiform) and natural history. Meta-analysis was performed using a random-effects model using summary statistics from included studies. RESULTS: Fifteen studies with 827 patients and 5,093 patient-years were included. The overall annual mortality rate among patients with VBDAs was 13%/year (95% CI 8-19). Patients with fusiform aneurysms had a higher mortality rate than those with dolichoectatic aneurysms, but this did not reach statistical significance (12 vs. 8%, p = 0.11). The overall growth rate was 6%/year (95% CI 4-13). Patients with fusiform aneurysms had higher growth rates than those with dolichoectatic aneurysms (12 vs. 3%, p < 0.0001). The overall rupture rate was 3%/year (95% CI 1-5). Patients with fusiform aneurysms had higher rupture rates than those with dolichoectatic aneurysms (3 vs. 0%, p < 0.0001). The overall rate of ischemic stroke was 6%/year (95% CI 4-9). Patients with dolichoectatic aneurysms had higher ischemic stroke rates than those with fusiform aneurysms, but this did not reach statistical significance (8 vs. 4%, p = 0.13). The overall rate of ICH was 2%/year (95% CI 0-8) with no difference in rates between dolichoectatic and fusiform aneurysms (2 vs. 2%, p = 0.65). CONCLUSION: In general, the natural history of -VBDAs is poor. However, dolichoectatic and fusiform -VBDAs appear to have distinct natural histories with substantially higher growth and rupture associated with fusiform aneurysms. These findings suggest that these aneurysms should be considered separate entities. Further studies on the natural history of vertebrobasilar dolichoectatic and fusiform aneurysms with more complete follow-up are needed to better understand the risk factors for progression of these aneurysms. PMID- 29439264 TI - Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine. AB - The respiratory tract is faced daily with 10,000 L of inhaled air. While the majority of air contains harmless environmental components, the pulmonary immune system also has to cope with harmful microbial or sterile threats and react rapidly to protect the host at this intimate barrier zone. The airways are endowed with a broad armamentarium of cellular and humoral host defense mechanisms, most of which belong to the innate arm of the immune system. The complex interplay between resident and infiltrating immune cells and secreted innate immune proteins shapes the outcome of host-pathogen, host-allergen, and host-particle interactions within the mucosal airway compartment. Here, we summarize and discuss recent findings on pulmonary innate immunity and highlight key pathways relevant for biomarker and therapeutic targeting strategies for acute and chronic diseases of the respiratory tract. PMID- 29439267 TI - Radiation Exposure during Ureterorenoscopy and Laser Lithotripsy: An Analysis of Stone Characteristics. AB - INTRODUCTION AND OBJECTIVES: Stone formers often have a chronic exposure to significant quantities of ionising radiation from radiological investigations and interventions. Predicting radiation exposure would allow the clinician to quantify expected cumulative radiation and find strategies to minimise exposure. We evaluated radiation exposure during ureteroscopy and laser lithotripsy (URS + LL) for a single stone episode and correlated the results to stone characteristics. METHOD: Data was collected retrospectively for all patients undergoing URS + LL in our institution over a 1 year period. Patients with multiple stones, staghorn stones or incomplete stone clearance were excluded to simplify the analysis. Patient characteristics, fluoroscopy data and stone characteristics were recorded. RESULTS: We included 302 consecutive patients in the study. The majority of stones were located in the renal calyces/pelvis (54%) with the rest located in the upper (18%), middle (13%) and lower ureter (15%). Mean stone diameter was 9.9 mm (range 4-30 mm). Mean radiation exposure time during URS + LL was 44 s (range 12-119 s) with a mean total radiation exposure of 7.5 milligray (mGy; range 1.2-29.7 mGy). Renal stones were associated with 27% higher radiation exposure compared to ureteral stones (8.3 vs. 6.7 mGy; p = 0.02). There was a positive correlation between stone diameter and radiation exposure (Spearman's correlation coefficient rho = 0.28; p < 0.001). Stones with diameter greater than 10 mm were associated with 37% higher radiation exposure compared to smaller stones (9.1 vs. 6.6 mGy; p < 0.001). CONCLUSION: There is a direct correlation between stone burden, as well as location, and radiation exposure during URS + LL. Clinicians should consider strategies to reduce total radiation exposure in recurrent stone formers at risk of high radiation exposure by limiting screening time, using pulsed rather than continuous fluoroscopy, management with primary URS + LL, or using ultrasound guidance. PMID- 29439268 TI - Posterior Hyaloid Dissection: Let's Make It Easy with Blue. AB - PURPOSE: Our aim is to present in this online supplementa ry video (see www.karger.com/doi/10.1159/000486348) an easy new surgical technique using blue dye to dissect the posterior hyaloid when performing pars plana vitrectomy. PROCEDURES: Dual-Blue stain is injected in vitreous cavity just after central vitrectomy is performed. The distribution of the blue stain will allow us to know if there is a posterior vitreous detachment or not ("blue lake fashion" or "blue jelly fashion," respectively) and as an excellent visualization of the vitreous fibers is accomplished, dissection of the posterior hyaloid can be performed without difficulty. RESULTS: This procedure allows a much more simple, fast, and safe dissection of posterior hyaloid even for an inexperienced vitreoretinal surgeon. The cleavage plane between the retina and the posterior hyaloid is easily differentiated. CONCLUSIONS: A more controlled and easy dissection of posterior hyaloid during vitrectomy is accomplished with this simple technique without adding any extra cost. Message of the paper: An easy technique that allows a much easier dissection of the posterior hyaloid during vitrectomy improving visualization and decreasing risks. No extra cost, nor time is needed. PMID- 29439269 TI - The Predictive Value of Amplitude-Integrated Electroencephalography in Preterm Infants for IQ and Other Neuropsychological Outcomes at Early School Age. AB - BACKGROUND: Amplitude-integrated electroencephalography (aEEG) is used increasingly in neonatal intensive care and seems helpful in predicting outcomes at the age of 2 years. OBJECTIVES: To determine whether early aEEG patterns in preterm infants are equally useful in predicting outcomes at early school age. METHODS: We recorded aEEG in 41 preterms (gestational age 26.0-32.9 weeks) at a median postnatal age of 9.7 h (IQR 7.0-25.3) and in 43 preterms on median day 8 (IQR 7-9). We assessed aEEG by pattern recognition and calculated the means of the aEEG amplitude centiles. At a median of 7.39 years, i.e., early school age, we assessed their motor, cognitive, and behavioral outcomes. RESULTS: Depressed aEEG patterns were not associated with poorer outcomes. Cyclicity directly after birth was associated with a higher total IQ (mean 104 vs. 97, p = 0.05) and higher scores on visual perception (mean percentile 57.1 vs. 40.1, p = 0.049) and visual memory (mean percentile 34.5 vs. 19.1, p = 0.090). We found some associations between the aEEG amplitude centiles and cognitive outcomes, but none for motor or behavioral outcomes. There was an increased risk of abnormal scores on long-term verbal memory in cases of the lower 5th and 50th aEEG amplitude centiles directly after birth. The odds ratios were 0.65 (95% CI 0.42-0.99, p = 0.040) and 0.71 (95% CI 0.52-0.96, p = 0.025), respectively. CONCLUSIONS: In relatively healthy preterm infants the value of aEEG in predicting neuropsychological outcomes at early school age is limited. The presence of cyclicity directly after birth tends to be associated with better cognition. PMID- 29439270 TI - Should We Use Sentence- or Text-Level Tasks to Measure Oral Language Proficiency in Year-One Students following Whole-Class Intervention? AB - AIMS: To compare students' oral language proficiency on sentence- versus text level tasks at school entry and following tier 1 intervention in their first year of formal schooling. METHODS: 104 students participated in this study. Participants were part of a broader longitudinal study and were enrolled at 3 low socioeconomic, linguistically diverse Australian primary schools. Tasks were administered to all students at the beginning and end of the school year. Performance on the sentence-level task, the Renfrew Action Picture Test (RAPT), was analysed for information and grammar as per the test manual. Performance on the text-level task, the Profile of Oral Narrative Ability, was analysed for measures of story length, mean length of utterance, grammatical accuracy, number of different words, and story quality. RESULTS: Results showed that both tasks are sensitive to measure progress following tier 1 intervention. However, RAPT concern status was not related to oral narrative concern status. Furthermore, if only the RAPT task had been used, between 11 and 21% of students performing below expectations in oral narrative would not have been identified. CONCLUSION: It is recommended that the assessment of oral language proficiency of students from culturally diverse, low socioeconomic backgrounds goes beyond the sentence level and includes an oral narrative retell task. PMID- 29439271 TI - Normative Basal Values of Hormones and Proteins of Gonadal and Adrenal Functions from Birth to Adulthood. AB - In clinical practice, it is fundamental to compare the results of hormonal examinations obtained in the laboratory with reliable reference values. This is particularly difficult when faced with rare conditions, such as disorders of sex development, where not routinely assayed peptide hormones as well as intermediate steroid metabolites are often needed and local reliable reference values are not available. There are considerable differences among techniques and assays used in clinical and research laboratories. In fact, laboratory hormonology is undergoing a critical transition between techniques for quantitative determination: established immunoassays and mass spectrometry. Harmonizing results from different laboratories is a major challenge along the path leading to the establishment of consensus reference intervals for steroid hormones. Most of the efforts are being concentrated on testosterone, with very encouraging results being provided by the harmonization of liquid chromatography-tandem mass spectrometry results. However, this goal is still far from being achieved for the other steroid and small-molecule hormones, and a much more challenging perspective is foreseeable for protein hormones. In addition to technical issues, the importance of the definition and of the characterization of the reference population as well as sampling and processing methodology should not be underestimated, as these aspects may impact on hormonal axis and compound stability. The aim of the present review is to provide a comprehensive overview of the circulating reference values in basal condition of the hormones and proteins involved in sex development reported to date in the peer-reviewed literature. We present a series of tables where we have collected the reference intervals for each specific hormone and protein. PMID- 29439272 TI - Need of Emergency Surgery in Elderly Patients with Upper Gastrointestinal Bleeding: Survival Analysis during 2009-2015. AB - BACKGROUND/AIMS: The role of emergency surgery is decreasing in the treatment of patients with upper gastrointestinal bleeding (UGIB). We investigated the need of urgent surgery and outcome of elderly UGIB patients who often have cardiovascular comorbidities with antithrombotic medication. METHODS: All consecutive adult patients who received emergency treatment for suspected gastrointestinal bleeding between January 2009 and December 2011 were registered in an electronic database (n = 1,643). A total of 569 patients with a first-time UGIB were identified, of whom 282 were >=70 years old. Age-specific incidence rates, risk factors for bleeding and need of endoscopic or emergency surgery were studied. Long-term mortality was compared to age-adjusted control subjects (n = 569) without bleeding. RESULTS: The age-specific incidence of UGIB increased from 156 to 401 cases per 100,000 inhabitants from age 60-69 to 80-89 years, respectively. Cardiovascular comorbidities and antithrombotic therapies (acetosalicylic acid 51 vs. 27%; warfarins 25 vs. 11%) related to UGIB were more common in patients over than under 70 years of age (p < 0.0001). Early endoscopic therapy was successful in over 95% of patients, whereas emergency surgery was needed only in 6 (2%) patients >=70 years old. Hospital mortality (7.8%) was acceptable in these patients, but the 5-year mortality (40%) was significantly higher than in controls (20%, p < 0.001). CONCLUSION: Today, emergency surgery is seldom needed in the patients with UGIB. In comparison to the age-matched control population, long-term survival was significantly lower after UGIB in the elderly. PMID- 29439273 TI - Effects of Diet on Telomere Length: Systematic Review and Meta-Analysis. AB - BACKGROUND: The goal of this systematic review and meta-analysis is to determine the effect of diet on telomere length. METHODS: We searched the following databases: MEDLINE, Embase, LILACS, CINAHL, ISI Web of Science, and Scopus, as well as the Cochrane Central Register of Controlled Trials and the National Institutes of Health, from inception to December 2016. Articles that assessed effects of diet on telomere length were included. RESULTS: A total of 2,128 studies were identified, 30 were read in full, and 7 were systematically reviewed. Five RCTs were included in the meta-analysis, covering 9 diets; a total of 533 participants were included. Study heterogeneity (I2) was 89%, and differences were not identified regarding average telomere lengths (mean difference 1.06; 95% CI -1.53 to 3.65). CONCLUSION: The available evidence suggests that there is no effect of diet on telomere length, but the strong heterogeneity in the type and duration of dietary interventions does not allow any final statement on the absence of an effect of diet on telomere length. PMID- 29439274 TI - Relation of Paraoxonase 1 Activity with Biochemical Variables, Brachial Artery Intima-Media Thickness in Patients with Diabetes with or without Obesity. AB - AIM: The sodium-sparing effect of insulin leads to increase in total sodium pool of the body which is a chronic stimulus for atrial natriuretic peptide (ANP). In our study we aimed to determine the relationship between ANP and microvascular complications of diabetes. METHODS: 60 patients, 30-70 years old, with the diagnosis of type 2 diabetes mellitus (DM) are enrolled into the study. Patients with a chronic disease other than DM are excluded. Blood samples for routine biochemical tests are taken after at least 12 h fasting at 8-9 am. Blood samples for glucose and insulin levels are taken 2 h after a standard meal. Blood tubes with EDTA are used for ANP levels. The microvascular complications of the patients are evaluated. RESULTS: 32 of the patients had microvascular complications. Age, BMI, waist and hip circumferences, and ANP levels were significantly higher in the group with microvascular complications. There were no significant differences in waist-to-hip ratio, blood glucose, HbA1c, fasting insulin, postprandial insulin, fasting HOMA, postprandial HOMA as well as sodium, potassium, magnesium, calcium and lipid levels between the two groups. When the relationship between ANP and obesity, retinopathy, neuropathy, nephropathy, diabetes time, HbA1c, or sex are evaluated separately, the only significant parameters related to ANP were obesity and retinopathy. CONCLUSION: In our study we have found that there was a significant relationship between ANP levels and microvascular complications of diabetes. Future studies are needed to show if ANP is the stimulus of microvascular complication development/progression or only an epiphenomenon. PMID- 29439275 TI - Is Enhanced One-Stage Hepatectomy a Safe and Feasible Alternative to the Two Stage Hepatectomy in the Setting of Multiple Bilobar Colorectal Liver Metastases? A Comparative Analysis between Two Pioneering Centers. AB - BACKGROUND: Two-stage hepatectomy (TSH) is the present standard for multiple bilobar colorectal metastases (CLM). As alternative, ultrasound-guided one-stage hepatectomy (E-OSH) has been proposed even for deep-located nodules to compare TSH and E-OSH. METHODS: All consecutive TSH at the Paul Brousse Hospital and E OSH at the Humanitas Research Hospital were considered. The inclusion criteria were >=6 CLM, >=3 CLM in the left liver, and >=1 lesion with vascular contact. A total of 74 TSH and 35 E-OSH were compared. RESULTS: The 2 groups had similar characteristics. Drop-out rate of TSH was 40.5%. In comparison with the cumulated hepatectomies of TSH, E-OSH had lower blood loss (500 vs. 1,100 mL, p = 0.009), overall morbidity (37.1 vs. 70.5%, p = 0.003), severe morbidity (14.3 vs. 36.4%, p = 0.04), and liver-specific morbidity (22.9 vs. 40.9%, p = 0.02). R0 resection rate was similar between groups. E-OSH and completed TSH had similar overall survival (5-year 38.2 vs. 31.8%), recurrence-free survival (3-year 17.6 vs. 17.7%), and recurrence sites. CONCLUSIONS: E-OSH is a safe alternative to TSH for multiple bilobar deep-located CLM. Whenever feasible, E-OSH should even be considered the preferred option because it has excellent safety and oncological outcomes equivalent to completed TSH, without the drop-out risk. PMID- 29439276 TI - Mannose-Binding Lectin2 Gene Polymorphism and IgG4 in Membranous Nephropathy. AB - BACKGROUND: Idiopathic membranous nephropathy (IMN) has been linked to the lectin pathway, IgG4 and genetic susceptibility. We investigated the frequency of mannose-binding lectin2 (MBL2) gene polymorphisms and the serum ratio of IgG4 in patients with membranous nephropathy (MN). METHODS: Polymorphisms in the exon 1 of the MBL2 gene (codons 52, 54, and 57) and single base polymorphisms at positions -550 (HL) and -221 (XY) in the promoter region were evaluated in 60 patients compared to a control group (CG) of 101 blood donors. It established the frequency of polymorphisms and the serum ratio of IgG4 comparing 2 etiologies of MN: idiopathic (35 patients) and secondary to systemic lupus erythematosus (25 patients). RESULTS: Patients with MN had a 2.54-fold higher probability (95% CI 1.51-4.31) of carrying the O alelle, exon 1 variant, and 11.16-fold higher probability (95% CI 4.77-28.41) of having A/O genotype when compared to CG. The frequency of polymorphisms in the promoter region was similar between the groups. Combined genotypes generally related to the defective production of MBL (YA/O, XA/O and O/O) were more frequent in patients with MN (OR 7.11; 95% CI 2.69 21.27), when compared to controls. The median of serum ratio IgG4 was 5% for idiopathic MN and 3% for lupus MN patients (p = 0.016). CONCLUSIONS: Our data suggests that MBL2 polymorphisms may be associated with the activation of the lectin pathway by IgG4 subclass antibodies in MN. PMID- 29439277 TI - Inhibitors in Nonsevere Hemophilia A: What Is Known and Searching for the Unknown. AB - Nonsevere hemophilia A (NSHA) is an inherited X-linked bleeding disorder, caused by mutations of the F8 gene, leading to decreases of clotting factor VIII (FVIII) levels to 1 to 40 IU/dL. Desmopressin is the first therapeutic option for NSHA, but 40 to 50% of patients fail to attain adequate postinfusion FVIII levels. Thus, in these cases, FVIII concentrates remain the mainstay of treatment. The development of neutralizing FVIII antibodies (inhibitors) is a major challenge with replacement therapy. In contrast to severe disease, NSHA patients have a lifelong risk of inhibitor development. Recent data indicate that inhibitors are associated with a deterioration of clinical outcome, illustrated by an increase in bleeding and mortality rate. F8 genotype is an important risk factor for inhibitor occurrence together with surgical interventions and a high dose of FVIII concentrate. Adequate prevention and treatment of inhibitors in NSHA patients is limited by a lack of understanding of the underlying immunological mechanisms. Elucidation of the immunology driving inhibitor development is required to identify high-risk patients, to understand the association between clinical risk factors and inhibitor occurrence, and to provide the opportunity to develop new preventive and therapeutic strategies. PMID- 29439278 TI - Delineation of the extent of early gastric cancer by magnifying narrow-band imaging and chromoendoscopy: a multicenter randomized controlled trial. AB - BACKGROUND: Accurate delineation of tumor margins is necessary for curative resection of early gastric cancer (EGC). The objective of this multicenter, randomized, controlled study was to compare the accuracy with which magnifying narrow-band imaging (M-NBI) and indigo carmine chromoendoscopy delineate EGC margins. METHODS: Patients with EGC >= 10 mm undergoing endoscopic or surgical resection were enrolled. The oral-side margins of the lesions were first evaluated with conventional white-light endoscopy in both groups and then delineated by either chromoendoscopy or M-NBI. Biopsies were taken from noncancerous and cancerous mucosa, each at 5 mm from the margin. Accurate delineation was judged to have been achieved when the histological findings in all biopsy samples were consistent with endoscopic diagnoses. The primary end point was the difference in rate of accurate delineation between the two techniques. RESULTS: Data on 343 patients were analyzed. The accurate delineation rate (95 % confidence interval) was 85.7 % (80.4 - 91.0) in the chromoendoscopy group (n = 168), and 88.0 % (83.2 - 92.8) in the M-NBI group (n = 175; P = 0.63). Lower third tumor location (odds ratio [OR] 2.9; P = 0.01), nonflat macroscopic type (OR 4.4; P < 0.01), and high diagnostic confidence (OR 3.6; P < 0.001) were associated with accurate delineation, whereas use of M-NBI was not (OR 1.2; P = 0.39). Even after adjustment for identified confounders, the difference in accurate delineation between the groups was not significant (OR 1.0; P = 0.82). CONCLUSIONS: M-NBI does not offer superior delineation of EGC margins compared with chromoendoscopy; the two methods appear to be clinically equivalent. PMID- 29439279 TI - [Comorbid Mental Disorders in Gastroenterology and Hepatology: Prevalence and Psychosocial Needs in Tertiary Care]. AB - BACKGROUND: In the field of gastroenterology and hepatology, associations and interactions with comorbid mental disorders are often described, but there is currently a lack of methodologically high-quality studies on prevalence and the need for care. The aim of the study was to take account of this shortcoming. METHODS: Prospective, monocentric, cross-sectional study of a representative sample of inpatients at a university hospital. A total of 308 participants were examined for the presence of 8 frequent psychological syndromes with a validated questionnaire (PHQ-D). In addition, 63 participants were examined for the presence of mental disorders according to ICD-10 with a diagnostic interview (SKID-I) that covers a wider range of diagnoses. The need for psychosocial care was raised from the perspective of internal medicine practitioners and psychosomatic experts. RESULTS: The prevalence for at least 1 mental syndrome in the questionnaire sample (PHQ-D excl. PHQ-15) was 39.6%, in 23.8% of whom more than one syndrome was present. The most frequent were depressive and anxiety syndromes. There were significant differences in the various subgroups (sex, type and severity of the somatic disease). The 4-week prevalence for any mental disorder in the interview sample (SKID-I) was 52.4%. Affective and somatoform disorders as well as adaptation disorders were dominant. The need for psychosocial care was reported in 23.1% by the practitioners and in 30.2% by the experts. CONCLUSIONS: Patients with gastroenterological-hepatological tertiary care have a high prevalence of treatment-related psychological syndromes or disorders. In comparison with the reference data of the Robert Koch Institute on the 12-month prevalence of mental disorders among the general population in Germany, the proportion of current mental disorders is almost twice as high (52.7 vs. 27.1%, p<0.001). To cover the need for care, the provision of psychosomatic liaison services and the strengthening of psychosomatic basic care in gastroenterology/hepatology should be established. PMID- 29439280 TI - [Adherence to Immunosuppressive Medication Following Organ Transplantation]. AB - Organ transplantation is the best and to some extent only option for many patients with chronic organ failure. Usually after successful transplantation patients experience a significant improvement of their condition. Nevertheless, they are not cured but still chronically ill. Living with an organ transplant requires consequent immunosuppression intake, regular physician visits and following the recommendations regarding infection prevention. These factors are important to secure a long transplant survival. Especially non-adherence to immunosuppressants is known as a risk factor for transplant rejection. There are several reasons for non-adherent behavior. However identifying the individual motivations is crucial for addressing them correctly. The aim of this article is to give an overview of factors influencing adherence, to introduce options to assess adherence and to present ways to improve adherence. Randomized-controlled intervention studies are presented and on that basis recommendations for clinical practice are derived. PMID- 29439281 TI - [German Prevention Programs for Eating Disorders - A Systematic Review]. AB - In the past years a considerable amount of primary and secondary prevention programs for eating disorders was developed in German speaking countries. However, up to now there has been no systematic review of contents and evaluation studies. The main objective of the present systematic review is to identify and outline German prevention programs for eating disorders. This should facilitate the selection of appropriate and effective interventions for medical experts, other professionals and teachers. A systematic literature research was conducted and 22 German-language primary and secondary prevention programs were identified. Half of them were evaluated. The programs were conducted either in school, on the internet or in a group setting. The findings show that throughout almost all programs a reduction in weight and shape concerns and drive for thinness as well as an increase of (body) self-esteem could be observed in either the total sample or the high-risk sample. However, programs were inconsistently effective in reducing disordered eating behavior in the target population. All studies were effective in reducing at least one risk factor. Overall, higher effect sizes were found for secondary prevention programs than for primary prevention programs. Lastly, limitations of the studies and suggestions for future prevention efforts are discussed. PMID- 29439282 TI - Programmatic and Administrative Barriers to High-Risk Infant Follow-Up Care. AB - OBJECTIVE: This article characterizes programmatic features of a population based network of high-risk infant follow-up programs and identifies potential challenges associated with attendance from the providers' perspective. STUDY DESIGN: A web-based survey of high-risk infant follow-up program directors, coordinators, and providers of a statewide high-risk infant follow-up system. Frequencies and percentages were used to describe the survey responses. RESULTS: Of the 68 high-risk infant follow-up programs in California, 56 (82%) responded to the survey. The first visit no-show rate between 10 and 30% was estimated by 44% of programs with higher no-show rates for subsequent visits. Common strategies to remind families of appointments were phone calls and mailings. Most programs (54%) did not have a strategy to help families who lived distant to the high-risk infant follow-up clinic. CONCLUSION: High-risk infant follow-up programs may lack resources and effective strategies to enhance follow-up, particularly for those living at a distance. PMID- 29439283 TI - Replacement therapy for coronary artery bypass surgery in patients with hemophilia A and B. AB - There are only a few cases of patients with hemophilia A and B who have undergone coronary artery bypass surgery. High levels of replacement therapy with factor concentrate either with bolus or continuous infusion are usually required pre operatively and during the first post-operative days in order to maintain the coagulation deficient factor levels greater than 80% of normal. Heparinization during cardiopulmonary bypass appears to be safe and intra-operative blood salvage using cell saver techniques reduce the need for transfusions. PMID- 29439284 TI - Reply. PMID- 29439285 TI - Implantation of a sutureless bioprosthesis without guiding sutures in a heavily calcified aortic root. PMID- 29439286 TI - Evidence flowers: An innovative, visual method of presenting "best evidence" summaries to health professional and lay audiences. AB - BACKGROUND & AIMS: Barriers to dissemination and engagement with evidence pose a threat to implementing evidence-based medicine. Understanding, retention, and recall can be enhanced by visual presentation of information. The aim of this exploratory research was to develop and evaluate the accessibility and acceptability of visual summaries for presenting evidence syntheses with multiple exposures or outcomes to professional and lay audiences. METHODS: "Evidence flowers" were developed as a visual method of presenting data from 4 case scenarios: 2 complex evidence syntheses with multiple outcomes, Cochrane reviews, and clinical guidelines. Petals of evidence flowers were coloured according to the GRADE evidence rating system to display key findings and recommendations from the evidence summaries. Application of evidence flowers was observed during stakeholder workshops. Evaluation and feedback were conducted via questionnaires and informal interviews. RESULTS: Feedback from stakeholders on the evidence flowers collected from workshops, questionnaires, and interviews was encouraging and helpful for refining the design of the flowers. Comments were made on the content and design of the flowers, as well as the usability and potential for displaying different types of evidence. CONCLUSIONS: Evidence flowers are a novel and visually stimulating method for presenting research evidence from evidence syntheses with multiple exposures or outcomes, Cochrane reviews, and clinical guidelines. To promote access and engagement with research evidence, evidence flowers may be used in conjunction with other evidence synthesis products, such as (lay) summaries, evidence inventories, rapid reviews, and clinical guidelines. Additional research on potential adaptations and applications of the evidence flowers may further bridge the gap between research evidence and clinical practice. PMID- 29439287 TI - Demonstration of improved tissue integration and angiogenesis with an elastic, estradiol releasing polyurethane material designed for use in pelvic floor repair. AB - AIMS: Pelvic organ prolapse and stress urinary incontinence affect 40-50% of postmenopausal women worldwide. Polypropylene meshes have been extensively used for the surgical intervention of these disorders; however, these meshes can lead to severe complications in some patients. The need for synthetic materials more suited for use in pelvic floor repair is widely accepted. This study aims to develop an electrospun 17-beta-estradiol releasing polyurethane (PU) scaffold that not only provides the appropriate mechanical support but can also stimulate new extracellular matrix (ECM) production and angiogenesis. METHODS: PU scaffolds with and without 17-beta-estradiol (25 and 50 mg/g) were prepared by blend electrospinning. Mechanical properties of scaffolds were assessed by uniaxial cyclic and non-cyclic testing. The viability and ECM production of human adipose derived mesenchymal stem cells (hADMSCs) cultured on 17-beta-estradiol releasing PU scaffolds was evaluated. Angiogenic potential of estradiol releasing scaffolds was demonstrated by using an ex ovo chick chorioallantoic membrane (CAM) assay. RESULTS: The inclusion of estradiol in PU scaffolds did not change the ultrastructure but it significantly increased the ultimate tensile strength of scaffolds. hADMSCs on estradiol-releasing PU scaffolds showed more ECM production. The CAM assay revealed a significantly higher angiogenic potential of estradiol-releasing PU scaffolds with an additive effect seen when hADMSCs cultured on estradiol scaffolds. Histological examination of CAM tissue sections showed extensive cellular infiltration and a good tissue integration for all constructed scaffolds. CONCLUSIONS: This study shows the angiogenic potential of estradiol-releasing PU scaffolds with appropriate strength and elasticity desirable to support the pelvic floor. PMID- 29439288 TI - Childhood pneumothorax in Birt-Hogg-Dube syndrome: A cohort study and review of the literature. AB - BACKGROUND: Birt-Hogg-Dube syndrome (BHD) is an autosomal dominantly inherited cancer predisposition syndrome associated with an increased risk of spontaneous pneumothorax (SP) and renal cell carcinoma in the adult population. Recent studies suggest that BHD accounts for up to 10% of all SP in adults and BHD in children with SP have been reported. METHODS: To explore to what extent BHD is the cause of childhood pneumothorax, we studied a Danish BHD cohort consisting of 109 cases from 22 families. Clinical data was gathered by review of medical records. A systematic literature search concerning childhood and adolescence pneumothorax in BHD was performed and identified publications reviewed. RESULTS: In our cohort, three of 109 BHD cases experienced childhood pneumothorax, corresponding to a prevalence of 3%. Reviewing the literature, data regarding more than 800 BHD cases were covered. Only seven previously published cases of childhood pneumothorax in BHD were identified. CONCLUSION: Our findings suggest that BHD is likely the cause of a larger subset of childhood pneumothoraces than hitherto recognized. Awareness of BHD as a cause of childhood pneumothorax needs to be raised to provide patients and relatives with the possibility of specialized management of SP and regular renal cancer surveillance. PMID- 29439289 TI - Switching From Reference Adalimumab to SB5 (Adalimumab Biosimilar) in Patients With Rheumatoid Arthritis: Fifty-Two-Week Phase III Randomized Study Results. AB - OBJECTIVE: The 24-week equivalent efficacy and comparable safety results of the biosimilar SB5 and reference adalimumab (ADA) from the phase III randomized study in patients with moderate-to-severe rheumatoid arthritis (RA) have been reported previously. We undertook this transition study to evaluate patients who switched from ADA to SB5 or who continued to receive SB5 or ADA up to 52 weeks. METHODS: In this phase III study, patients were initially randomized 1:1 to receive SB5 or ADA (40 mg subcutaneously every other week). At 24 weeks, patients receiving ADA were rerandomized 1:1 to continue with ADA (ADA/ADA group) or to switch to SB5 (ADA/SB5 group) up to week 52; patients receiving SB5 continued with SB5 for 52 weeks (SB5 group). Efficacy, safety, and immunogenicity were evaluated up to 52 weeks. RESULTS: The full analysis set population consisted of 542 patients (269 in the SB5 group, 273 in the ADA overall group [patients who were randomized to receive ADA at week 0], 125 in the ADA/SB5 group, and 129 in the ADA/ADA group). The percentages of patients meeting the American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response) at week 24 were maintained after the transition from ADA to SB5, and these response rates were comparable across treatment groups throughout the study. ACR20 response rates ranged from 73.4% to 78.8% at week 52. Radiographic progression was minimal and comparable across treatment groups. The safety profile and the incidence of antidrug antibodies were comparable across treatment groups after transition. CONCLUSION: SB5 was well tolerated over 1 year in patients with RA, with efficacy, safety, and immunogenicity comparable to those of ADA. Switching from ADA to SB5 had no treatment-emergent issues such as increased adverse events, increased immunogenicity, or loss of efficacy. PMID- 29439290 TI - Review: Cell Death, Nucleic Acids, and Immunity: Inflammation Beyond the Grave. AB - Cells of the innate immune system are rigged with sensors that detect nucleic acids derived from microbes, especially viruses. It has become clear that these same sensors that respond to nucleic acids derived from damaged cells or defective intracellular processing are implicated in triggering diseases such as lupus and arthritis. The ways in which cells die and the concomitant presence of proteins and peptides that allow nucleic acids to re-enter cells profoundly influence innate immune responses. In this review, we briefly discusses different types of programmed necrosis, such as pyroptosis, necroptosis, and NETosis, and explains how nucleic acids can engage intracellular receptors and stimulate inflammation. Host protective mechanisms that include compartmentalization of receptors and nucleases as well as the consequences of nuclease deficiencies are explored. In addition, proximal and distal targets in the nucleic acid stimulation of inflammation are discussed in terms of their potential amenability to therapy for the attenuation of innate immune activation and disease pathogenesis. PMID- 29439291 TI - Neurobiologic Features of Fibromyalgia Are Also Present Among Rheumatoid Arthritis Patients. AB - OBJECTIVE: Many patients with rheumatoid arthritis (RA) report pain despite excellent control of inflammation with immunotherapies. Variable degrees of coexisting fibromyalgia (FM) may explain this disparity. FM has been characterized by aberrant brain functional connectivity, especially between the default mode network (DMN) and insula. We undertook this study to test the hypothesis that RA patients with the highest 2011 American College of Rheumatology FM survey criteria scores-a continuous measure of the degree of FM also known as "fibromyalgianess" (FMness)-would demonstrate functional connectivity abnormalities similar to those in FM. METHODS: RA patients underwent an 11-minute functional connectivity magnetic resonance imaging (MRI) brain scan and a clinical evaluation which included a measure of FMness. Brain networks were isolated from functional connectivity MRI data. Individual patient network-to whole brain connectivity analyses were then conducted, followed by group-level regression, which correlated the connectivity of each network with FMness. Results were significant on the cluster level with a family-wise error (FWE) rate P value less than 0.05 derived from an uncorrected voxel-level P value less than 0.001. RESULTS: A total of 54 patients participated (mean age 54.9 years, 75.9% women, mean FMness score 13.2 [range 1-29]). From the whole brain analyses, a single significant positive correlation between DMN connectivity to the left mid/posterior insula and FMness (r = 0.58, FWE-corrected P = 0.001) was demonstrated. CONCLUSION: RA patients who have increased levels of FMness appear to share neurobiologic features consistently observed in FM patients. This study is the first to provide neuroimaging evidence that RA is a mixed pain state, with many patients' symptoms being related to the central nervous system rather than to classic inflammatory mechanisms. PMID- 29439292 TI - Augmented Th17 Differentiation Leads to Cutaneous and Synovio-Entheseal Inflammation in a Novel Model of Psoriatic Arthritis. AB - OBJECTIVE: To introduce a novel preclinical animal model of psoriatic arthritis (PsA) in R26Stat3Cstopfl/fl CD4Cre mice, and to investigate the role of Th17 cytokines in the disease pathogenesis. METHODS: We characterized a novel murine model of Th17-driven cutaneous and synovio-entheseal disease directed by T cell specific expression of a hyperactive Stat3 allele. By crossing R26Stat3Cstopfl/fl CD4Cre mice onto an interleukin-22 (IL-22)-knockout background or treating the mice with a neutralizing antibody against IL-17, we interrogated how these Th17 cytokines could contribute to the pathogenesis of PsA. RESULTS: R26Stat3Cstopfl/fl CD4Cre mice developed acanthosis, hyperkeratosis, and parakeratosis of the skin, as well as enthesitis/tendinitis and periarticular bone erosion in different joints, accompanied by osteopenia. T cell-specific expression of a hyperactive Stat3C allele was found to drive the augmented Th17 response in these animals. Careful characterization of the mouse bone marrow revealed an increase in osteoclast progenitor (OCP) and RANKL-producing cells, which contributed to the osteopenia phenotype observed in the mutant animals. Abrogation of the Th17 cytokines IL-17 or IL-22 improved both the skin and bone phenotype in R26Stat3Cstopfl/fl CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP and RANKL expression on stromal cells. CONCLUSION: Perturbation of the IL-23/Th17 axis instigates Th17-mediated inflammation in R26Stat3Cstopfl/fl CD4Cre mice, leading to cutaneous and synovio-entheseal inflammation and bone pathologic features highly reminiscent of human PsA. Both IL-17A and IL-22 produced by Th17 cells appear to play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes PsA. PMID- 29439293 TI - Editorial: STATus of STAT3 in Psoriatic Arthritis. PMID- 29439294 TI - Interrupted Time Series Needed to Analyze Effects of Propoxyphene Withdrawal From Market and Health Outcome Trend Estimates: Comment on the Article by Curtis et al. PMID- 29439296 TI - New Guidelines for Managing Hypertension - Lower is Better. PMID- 29439297 TI - State of South Dakota's Child: 2017. AB - There was a slight decrease in 2016 from 2015 in the total number of live births in South Dakota, but it was the fifth consecutive year that there were more than 12,000 newborns in the state. Nearly one-quarter of South Dakota's births represent minority populations mirroring what is observed nationally. Infant mortality in South Dakota dropped to its lowest ever rate per 1,000 live births (4.8) in 2016. Fewer births of less than 500 g newborns, increased survival of very low birth weight newborns, and a decrease in deaths due to congenital anomalies contributed to this low mortality rate. Though there is little progress observed in decreasing the trend in rate of sudden unexpected infant death (SUID), 2016 brought a decrease in the rate of these deaths from a previous spike in 2015. While positive indicators are observed in the 2016 data, South Dakota's mean mortality rate of 6.6 for 2012-16 is statistically higher than the U.S. rate of 5.8 for 2014. Further, consistent with previous trends, the South Dakota mean 2012-16 mortality rate for minority infants (11.8) was significantly higher than that for white infants (5.1). These observations are discussed with strategies to prevent infant deaths. PMID- 29439298 TI - A Rare Cause of Pancreatic Head Mass: Metastatic Prostate Cancer - A Case Report and Review of Literature. AB - Metastases to the pancreas account for less than 5 percent of all malignancies affecting the pancreas. The most common secondary malignancy of the pancreas is renal cell carcinoma. We report a patient presented with abdominal pain and weight loss. Computed tomography (CT) imaging showed pancreatic head mass. Biopsy from the mass showed prostate metastasis after 13 years from radical prostatectomy and Leuprolide therapy. This case demonstrates a rare location for prostate metastasis which was the pancreas. To our knowledge there are only six cases reported in literature. Due to increased long-term survival of prostate cancer patients, the frequency of metastases to the pancreas will likely increase. Therefore, clinicians need to be aware the pancreatic tumor may be secondary to an extrapancreatic malignancy. PMID- 29439299 TI - Recurrent In-stent Restenosis in the Area of Previous Stent Fracture: A Management Dilemma. AB - Drug eluting stents (DES) have been increasingly being used for treatment of coronary artery disease (CAD) and have been shown to be very effective in prevention of primary in-stent restenosis (ISR). However DES have been increasingly associated with acute to subacute risk of stent fractures (SF). There is also a paucity of data about different management strategies for SF, especially in the long term. We present a case of recurrent ISR in an area of previous acute SF at the touchdown of saphenous venous graft (SVG) to first diagonal artery (D1). In our knowledge this is the first case reported of recurrent ISR due to prior acute stent fracture in a saphenous venous graft. It presents an interesting management dilemma with multiple layers of stent in the area of recurrent ISR which was managed with balloon angioplasty with good results. PMID- 29439300 TI - AngioVac System Used as an Adjunct Treatment for Intra-Cardiac Lead and Valvular Vegetations. AB - Infections are known complications of cardiovascular implantable electronic devices (CIEDs). We describe a case of a 62-year-old male who presented with pulseless electrical activity (PEA) cardiac arrest and respiratory failure. He had a history of cardiac resynchronization device and defibrillator (CRT-D) implantation for nonischemic cardiomyopathy. After resuscitation, he was found to have methicillin sensitive Staphylococcus aureus (MSSA) bacteremia on blood culture and large vegetations on the CRT-D lead and tricuspid valve found on echocardiography. The patient underwent extraction of the leads, but several large vegetations were present adherent to the tricuspid valve on intra-cardiac ultrasound (ICE). Due to comorbidities, the patient was not a candidate for surgical removal of these vegetations. Thus, he underwent percutaneous extraction of tricuspid and right atrial vegetations with the AngioVac device. PMID- 29439295 TI - Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis. AB - OBJECTIVE: Currently, there are no reliable biomarkers for predicting therapeutic response in patients with rheumatoid arthritis (RA). The synovium may unlock critical information for determining efficacy, since a reduction in the numbers of sublining synovial macrophages remains the most reproducible biomarker. Thus, a clinically actionable method for the collection of synovial tissue, which can be analyzed using high-throughput strategies, must become a reality. This study was undertaken to assess the feasibility of utilizing synovial biopsies as a precision medicine-based approach for patients with RA. METHODS: Rheumatologists at 6 US academic sites were trained in minimally invasive ultrasound-guided synovial tissue biopsy. Biopsy specimens obtained from patients with RA and synovial tissue from patients with osteoarthritis (OA) were subjected to histologic analysis, fluorescence-activated cell sorting, and RNA sequencing (RNA seq). An optimized protocol for digesting synovial tissue was developed to generate high-quality RNA-seq libraries from isolated macrophage populations. Associations were determined between macrophage transcriptional profiles and clinical parameters in RA patients. RESULTS: Patients with RA reported minimal adverse effects in response to synovial biopsy. Comparable RNA quality was observed from synovial tissue and isolated macrophages between patients with RA and patients with OA. Whole tissue samples from patients with RA demonstrated a high degree of transcriptional heterogeneity. In contrast, the transcriptional profile of isolated RA synovial macrophages highlighted different subpopulations of patients and identified 6 novel transcriptional modules that were associated with disease activity and therapy. CONCLUSION: Performance of synovial tissue biopsies by rheumatologists in the US is feasible and generates high-quality samples for research. Through the use of cutting-edge technologies to analyze synovial biopsy specimens in conjunction with corresponding clinical information, a precision medicine-based approach for patients with RA is attainable. PMID- 29439301 TI - Safe and Effective Triglyceride-Lowering Therapy for Hypertriglyceridemia Associated Pancreatitis: Insulin Mono-therapy in a Non-Diabetic Patient. AB - This report was prepared to describe a case in which insulin monotherapy was efficacious for the management of hypertriglyceridemia-associated pancreatitis (HGTP) in a patient who was not diabetic. Currently, there are no definite clinical guidelines or standards of practice for nondiabetic HGTP. Apart from insulin infusion, other regimens include plasmapheresis and heparin administration, both of which carry significant risks. We reported a case of a non-diabetic male with HTGP (triglyceride greater than 3,000 mg/dL) who was successfully managed with an insulin infusion. This resulted in achieving a level below 1,000 mg/dL within 28 hours of the initiation of therapy. The patient was discharged without additional incident in 72 hours. We believe that insulin monotherapy for HGTP is efficacious in non-diabetic patients and should be the regimen of choice. PMID- 29439302 TI - Pediatric Viral Myocarditis - A Review. AB - Pediatric myocarditis is a common pediatric illness most commonly secondary to a preceding viral infection. It is a leading cause of acquired heart failure, cardiomyopathy, and cardiac transplantation in pediatrics. Due to the variability in presentation, the diagnosis is often unrecognized until later in the disease course. It should be considered in the differential diagnosis of all children presenting with respiratory distress, since this is the most common presentation. Imagining modalities, such as cardiac magnetic resonance imaging have become a useful diagnostic tool in recent years; however, endomyocardial biopsy remains the gold standard diagnostic test. Treatment of viral myocarditis is mainly supportive, with debatable role of anti-inflammatory, immunosuppressing immunomodulators and anti-viral therapy. Although, the outcome is generally favorable, delay in supportive care may be associated with a worse prognosis. We focus on the clinical presentation, review diagnostic and treatment options of viral myocarditis. PMID- 29439304 TI - Quality Focus: Small Providers Benefit in Quality Payment Program Year Two. PMID- 29439303 TI - Depression and Pregnancy: Treatment Considerations. PMID- 29439306 TI - Pediatric residents' attitudes towards and experiences with collaboration with primary and secondary schools in the United States. PMID- 29439307 TI - Ultrasound combined transcutaneous electrical nerve stimulation (UltraTENS) versus phonophoresis of piroxicam (PhP) in symptomatic knee osteoarthritis: A randomized double-blind, controlled trial. AB - BACKGROUND: Ultrasound combined with transcutaneous electrical nerve stimulation (UltraTENS) and phonophoresis of piroxicam (PhP) are combined modality therapy that frequently used in musculoskeletal pain including knee osteoarthritis (OA). But it is lack of a good clinical trial to prove and compare their effects. OBJECTIVE: To compare the effects of UltraTENS with PhP on mild to moderate degree of symptomatic knee OA. METHODS: Sixty-one patients (55 women), mean age of 63.4 +/- 8.1 y, 50-90 mm VAS of knee pain and Kellgren-Lawrence score of grade I-III were randomly allocated into UltraTENS and PhP (N = 31 and 30, respectively). The UltraTENS group received a combined ultrasound with TENS program and a non-drug gel, whereas the PhP group got an ultrasound program with piroxicam gel and sham TENS. All patients were treated for a total of 10 sessions, consisting of five times per week and 10 min per session. Before and after treatment, patients were evaluated knee pain by using the 100-mm VAS and functional performance by Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index. RESULTS: The UltraTENS and PhP groups experienced considerable improvement in both VAS and total WOMAC scores post-treatment (P< 0.001). The PhP had better VAS of pain and WOMAC scores but no statistical significance. CONCLUSIONS: Results show that UltraTENS and PhP were effective for relieving pain and improve functionality knee OA without significant differences between their effects. PMID- 29439305 TI - Strategic application of radiotherapy for hepatocellular carcinoma. AB - With increasing clinical use, radiotherapy (RT) has been considered reliable and effective method for hepatocellular carcinoma (HCC) treatment, depending on extent of disease and patient characteristics. RT for HCC can improve therapeutic outcomes through excellent local control, downstaging, conversion from unresectable to resectable status, and treatments of unresectable HCCs with vessel invasion or multiple intrahepatic metastases. In addition, further development of modern RT technologies, including image-guided radiotherapy (IGRT), intensity-modulated radiotherapy (IMRT), and stereotactic body radiotherapy, has expanded the indication of RT. An essential feature of IGRT is that it allows image guidance therapy through in-room images obtained during radiation delivery. Compared with 3D-conformal RT, distinctions of IMRT are inverse treatment planning process and use of a large number of treatment fields or subfields, which provide high precision and exquisitely conformal dose distribution. These modern RT techniques allow more precise treatment by reducing inter- and intra-fractional errors resulting from daily changes and irradiated dose at surrounding normal tissues. More recently, particle therapy has been actively investigated to improve effectiveness of RT. This review discusses modern RT strategies for HCC, as well as optimal selection of RT in multimodal approach for HCC. PMID- 29439308 TI - Comparison of musculoskeletal pain distribution, quality of life and hopelessness level in mothers with disabled children in different ambulation levels. AB - OBJECTIVE: The aim of this study was to compare the musculoskeletal pain distribution, quality of life, and the hopelessness level in mothers with disabled children in different ambulation levels. METHODS: This study included a total of 177 mothers (mean age: 36.1 +/- 6.5 years) of children with disabilities. The mothers were divided into 3 different groups according to the ambulation level of their disabled children: Ambulatory children (Group 1), partially ambulatory children (Group 2) and non-ambulatory children (Group 3). Musculoskeletal pain distribution (body diagram) and pain intensity (The Visual Analogue Scale), four quality of life parameters (The Centers for Disease Control and Prevention Health-Related Quality of Life -4 Questionnaire) and hopelessness level (Beck Hopelessness Scale) were evaluated in all mothers. RESULTS: The results of our study showed that musculoskeletal pain was most common (79.1%) in the mothers of disabled children. The frequency and severity of back, shoulder and elbow pain in the mothers, number of activity limitation days and hopelessness level were found to increase significantly as the ambulation level in the child decreased (p< 0.05). CONCLUSIONS: The risk of musculoskeletal pain, participation in daily life and hopelessness level in the mothers increased as the ambulation level of the disabled children decreased. PMID- 29439309 TI - The relationships between shoulder pain, range of motion, and disability in patients with shoulder dysfunction. AB - BACKGROUND: Shoulder dysfunction is a major cause of musculoskeletal pain in general population. A variety of shoulder disorders can cause a reduction in shoulder range of motion and subsequent disability. OBJECTIVE: To investigate the relationship between the shoulder pain, range of motion, and disability in patients with shoulder dysfunction. METHODS: Sixty-four patients (49 men and 15 women) with shoulder disorders with a varying diagnosis including, adhesive capsulitis, rotator cuff injury, impingement syndrome, acromio-clavicular pain, and instability, participated in this cross-sectional study. Participants were asked to report the shoulder pain intensity and level of disability on a numerical rating scale (NRS) and the shoulder pain and disability index (SPADI), respectively. In addition, the active shoulder range of motion was evaluated. RESULTS: The Spearman rank correlation coefficient was used to investigate the association between the shoulder pain, range of motion, and disability. A good negative correlation found between the shoulder abduction, flexion, and rotation range of motion with the NRS score (rho =-0.710 to -0.747). A moderate negative correlation found between the extension and the NRS score (rho =-0.643). A good negative correlation found between abduction and the SPADI total score (rho = 0.714). A moderate negative correlation found between the shoulder flexion and rotation range of motion with the SPADI total score (rho =-0.547 to -0.694). A fair negative correlation found between the extension and the SPADI total score (rho =-0.495). A moderated positive correlation found between the NRS and the SPADI total score (rho = 0.667). CONCLUSIONS: The flexion, abduction, and rotation ROMs were most significantly associated with severity of pain and the physical disability in patients with shoulder dysfunction. Further, longitudinal studies are required to confirm these results. PMID- 29439310 TI - LncRNA AB073614 induces epithelial- mesenchymal transition of colorectal cancer cells via regulating the JAK/STAT3 pathway. AB - BACKGROUND: LncRNAs are involved in the metastasis and recurrence of human tumors, including colorectal cancer (CRC). We previously reported that lncRNA AB073614 promotes tumor proliferation and metastasis and predicted a poor clinical outcome of CRC patients. Herein, we investigated the underlying mechanism of lncRNA AB073614-related metastasis in CRC. MATERIAL AND METHODS: The expression of lncRNA AB073614 in CRC tissues were evaluated by quantitative real time PCR (qRT-PCR). Transwell assay was performed to detect the effects of lncRNA AB073614 on cell migration and invasion. Epithelial-mesenchymal transition (EMT) molecular markers and Janus kinase/signal transducer and activator of transcription (JAK/STAT3) pathway proteins expression levels were detected by Western blot and Immunofluorescence. RESULTS: We confirmed that lncRNA AB073614 was highly expressed in the colorectal cancer tissues. LncRNA AB073614 knockdown in SW480 and HCT116 cells significantly promoted the protein expression levels of E-cadherin and Occludin, and decreased the expressions of N-cadherin and Vimentin, then further decreased the cell migration and invasion ability. Interestingly, the expression of phosphorylated STAT3 was also down-regulated. Furthermore, SW480 and HCT116 cells were transfected with lncRNA AB073614 vector and treated with a JAK inhibitor, AT9283. The results showed that lncRNA AB073614 regulated EMT through JAK-STAT3 signaling pathway. CONCLUSION: All these results indicate that lncRNA AB073614 can induce the expression of EMT cell markers and regulate the process of EMT of CRC cells through regulating the JAK/STAT3 pathway activation. PMID- 29439311 TI - Overexpression of YTHDF1 is associated with poor prognosis in patients with hepatocellular carcinoma. AB - In China, hepatocellular carcinoma (HCC) is the most commonly diagnosed cancer and the leading cause of cancer death in men, followed by lung and stomach cancer. There was an urgent need to identify novel prognostic biomarkers for HCC. We explored the expression pattern of m6A related proteins in HCC tissues by using TCGA in this study. We found that the m6A 'reader' YTHDF1 was significantly upregulated in HCC and was positive correlated with pathology stage. Kaplan-Meier analysis showed that Lower YTHDF1 expression level was associated with better survival of HCC patients. Furthermore, we performed GO and KEGG pathway analysis of YTHDF1 co-expressed genes and found YTHDF1 played an important role in regulating HCC cell cycle progression and metabolism. We believed that this study will provide a potential new therapeutic and prognostic target for HCC. PMID- 29439312 TI - Predictive value of excision repair cross- complementation group 1 expression in locoregionally advanced nasopharyngeal carcinoma receiving cisplatin-based concurrent chemoradiotherapy. AB - BACKGROUND: Cisplatin-based concurrent chemoradiotherapy is recommended for nasopharyngeal carcinoma (NPC) at advanced stages. Excision repair cross complementation group 1 (ERCC1) plays an important function in the repair of DNA damage that is a critical process of chemo- and radiotherapy. OBJECTIVE: This study aimed to investigate the clinical significance of ERCC1 expression in NPC treated with cisplatin-based concurrent chemoradiotherapy in locoregionally advanced NPC. METHODS: The expression level of ERCC1 and its association with clinicopathological characteristics in 205 locoregionally advanced NPC patients receiving cisplatin-based concurrent chemoradiotherapy were analyzed retrospectively. RESULTS: The correlation analysis revealed that the treatment sensitive patients displayed dramatically lower ERCC1 expression than treatment resistant cases did. Furthermore, the Kaplan-Meier plots revealed lower ERCC1 expression was significantly associated with better survival. Multivariate analysis further showed that the ERCC1 expression was an independent predictor of NPC patients' survival. CONCLUSIONS: ERCC1 expression might be a useful predictive marker in patients with locoregionally advanced NPC receiving cisplatin-based concurrent chemoradiotherapy. PMID- 29439313 TI - Expression analysis of AFAP1-AS1 and AFAP1 in breast cancer. AB - Long non-coding RNAs (lncRNA) constitute a significant percentage of RNAs with no translation to proteins. Their participation in fundamental aspects of cell physiology as well as their dysregulation in a number of pathologic conditions such as cancer have been documented. Among lncRNAs is actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) whose elevated expression levels have been demonstrated in different cancers. In the in the present study we evaluated expression levels of AFAP1-AS1 and its antisense protein coding gene AFAP1 in breast cancer samples compare with adjacent non-cancerous tissues (ANCTs) as well as breast cancer cell lines with special focus on the assessment of the association between their transcript levels and patients' clinicopathological data. AFAP1-AS1 has shown significant up-regulation in both MDA-MB-231 and MCF-7 compared with control sample. AFAP1-AS1 has been shown to be expressed in all of tumor tissues but 76% (39 out of 51) ANCTs. AFAP1 expression was not significantly different between tumor samples and ANCTs. AFAP1-AS1 has been demonstrated to be significantly up-regulated in tumor tissues compared with ANCTs (fold change = 4.65, P= 0.028). No significant correlation has been detected between the levels of these two transcripts in tumor tissues (R=2 0.081) or ANCTs (R=2 0.115). No significant associations have been found between expression levels of these genes and patients' characteristics. However, both genes were significantly down-regulated in Ki-67 negative tumor samples. The observed up-regulation of AFAP1-AS1 in tumor samples compared with ANCTs implies its involvement in breast cancer pathogenesis and potentiates it as a biomarker or therapeutic target. PMID- 29439314 TI - Effects of MALAT1 on proliferation and apo- ptosis of human non-small cell lung cancer A549 cells in vitro and tumor xenograft growth in vivo by modulating autophagy. AB - OBJECTIVE: To explore the ability of MALAT1 to influence non-small cell lung cancer (NSCLC) A549 cells in vitro and tumor xenograft growth in vivo by modulating autophagy. METHODS: LncRNA MALAT-1 in normal HBE cells and human NSCLC cells was measured. A549 cells were treated with si-MALAT-1, negative control and si-MALAT-1 + rapamycin. The mRNA levels of MALAT-1, P62 and LC3 was determined by the qRT-PCR and the protein levels of autophagy-related proteins by the western blotting. The CCK8 assay was performed for cell proliferation, the scratch test for cell migration, the Transwell assay for cell invasion, and the flow cytometry for cell cycle and apoptosis. Tumor xenograft in nude mice is performed to test tumorigenesis of the transfected A549 cells. RESULTS: The expression level of MALAT-1 in A549, SPC-A-1 and NCI-H460 cells was increased compared to HBE cells. And A549 with a high expression level of MALAT-1 were selected for cell transfection. si-MALAT-1 decreased cell proliferation, migration, invasion, and LC3-II/LC3-I ratio, reduced cell cycle progression, and increased cell apoptosis and P62 protein expression. No significant difference was found between A549 cells and A549 cells transfected with si-MALAT-1 + RAPA, A549 cells transfected with NC and A549 cells transfected with si-MALAT-1 + RAPA. Nude mice injected with A549 cells transfected with si-MALAT-1 had smallest tumor on size and weight among other nude mice. CONCLUSION: Downregulation of MALAT1 may promote apoptosis and suppress proliferation, migration and invasion of human NSCLC A549 cells by inhibiting autophagy, thereby suppressing the development of NSCLC. PMID- 29439315 TI - Downregulated miR-217 expression predicts a poor outcome in acute myeloid leukemia. AB - BACKGROUND: Circulating microRNAs (miRNAs) play an essential role in the development and progression of acute myeloid leukemia (AML). However, the clinical value of serum miR-217 in AML remained poorly known. OBJECTIVE: This study aimed to explore the clinical significance of serum miR-217 in AML. METHODS: Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed to detect miR-217 levels in the blood samples obtained from 89 AML patients and 60 healthy controls. RESULTS: The results showed that miR-217 expression was significantly decreased in AML patients compared to controls. Likewise, serum miR-217 levels were greatly downregulated in the AML patients with poor risk cytogenetic. ROC analysis demonstrated that serum miR-217 could effectively differentiate AML patients from normal controls. Also, miR-217 expression was markedly increased in patients achieving complete remission after their treatment. In addition, low miR-217 expression was associated with aggressive clinical features. Moreover, Kaplan-Meier analysis showed that AML patients with low miR-217 expression tended to have shorter overall survival and disease free survival. In the multivariate analysis stratified for prognostic parameters, miR-217 was proved to be an independent prognostic indicator. CONCLUSIONS: Collectively, miR-217 was identified as an independent marker for the diagnosis and prognosis of AML. PMID- 29439316 TI - Correlation of IGFBP-6 expression with apoptosis and migration of colorectal carcinoma cells. AB - Colorectal cancer (CRC) is one of the most common malignant tumors in digestive tract. Previous study found close correlation between insulin-like growth factor binding proteins (IGFBPs) and occurrence of multiple tumors. This study aims to analyze the effects of IGFBP6 on the apoptosis and migration of tumor cells, and to investigate underlying mechanism. HCT-116 or SW480 cell was cultured with 1.0 mg/l, 10 mg/l and 100 mg/l IGFBP-6. MTT assay was employed to test the proliferation activity of tumor cells after differential treatment. The cell cycle of tumor cells was detected by flow cytometry, while Transwell assay was used to quantify the invasion and migration of tumor cells after IGFBP-6 intervention. In experimental group with IGFPB-6 application, the proliferation rate of HCG-116 or SW480 cells was gradually decreased with higher concentrations of IGFBP-6 (p< 0.05). The ratio of cells at G0/G1 phase was increased while S phase and G2/M phase ratio were all decreased with IGFPB-6. With further elevated concentration of IGFPB-6, there was more potency of higher G0/G1 ratio and lower S phase or G2/M phase (p< 0.05). Both invasion and migration ability of HCT-116 or SW480 cells in experimental group were decreased. With elevated IGFBP-6 concentration, cell invasion and migration were further weakened (p< 0.05).IGFBP 6 could inhibit invasion and migration of colorectal carcinoma cells possibly via inhibiting proliferation activity and arresting cell cycle of HCT-116 or SW480 cells. PMID- 29439317 TI - Lumbar sympathectomy reduces vascular permeability, possibly through decreased adenosine receptor A2a expression in the hind plantar skin of rats. AB - BACKGROUND: The effect of lumbar sympathectomy for the treatment of lower limb ischemia remains a matter of controversy. METHODS: Sprague-Dawley rats were subjected to lumbar sympathectomy, after which Evans blue dye was injected into the hind plantar skin. Extravasation of dye was measured and compared with rats undergoing sham operation. Hind plantar skin was processed for HE staining, immunohistochemistry, and Western blot. RESULTS: In sympathectomized rats, blue stained areas in hind plantar skin and concentrations of Evans blue were significantly less than that of sham sympathectomy (control) rats, both 2 weeks and 3 months after surgery. Expression of prostaglandin E2, bradykinin, bradykinin B2 receptor, and adenosine triphosphate were not significantly different between the sympathectomized and control groups. Adenosine receptor A2a expression was significantly reduced in the sympathectomized group both 2 weeks and 3 months after surgery. CONCLUSION: Vascular permeability in the hind plantar skin of rats decreases following lumbar sympathectomy, possibly via reduced expression of adenosine receptor A2a. PMID- 29439318 TI - The effect of three different surgical techniques for colon anastomosis on regional postoperative microperfusion: Laser Doppler Flowmetry study in pigs. AB - BACKGROUND: The optimal surgical approach to reconnecting bowel ends safely after resection is of great importance. OBJECTIVES: This project is focused on assessment of the perianastomotic microcirculation quality in the short postoperative period when using three different anastomosis techniques in experimental animal. METHODS: The experimental study involved 27 young female domestic pigs divided into three subgroups of 9 animals according to each surgical method of anastomosis construction in the sigmoid colon region: by manual suture, by stapler, or by gluing. Blood microcirculation in the anastomosis region was monitored using Laser Doppler Flowmetry (LDF). Anastomosis healing was evaluated by macroscopic and histological examination. RESULTS: Evaluation of the microcirculation in the anastomosis region showed the smallest decrease in perfusion values in animals reconstructed by suturing (Delta= 38.01%). A significantly more profound drop was observed postoperatively after stapling or gluing (Delta= -52.42% and Delta= -59.53%, respectively). All performed anastomoses healed without any signs of tissue and function pathology. CONCLUSIONS: Sewing, stapling, and gluing techniques for bowel anastomosis each have a different effect on regional microcirculation during 120 min. postoperatively. Nevertheless, the final results of anastomosis healing were found without of any pathology in all experimental animals managed by above mentioned anastomotic techniques. PMID- 29439319 TI - In memory of Prof. Dr. Holger Schmid-Schonbein. PMID- 29439320 TI - Of patents and patent disputes - The TNFalpha patent files. Part 2: Enbrel, Remicade, Cimzia and Simponi. AB - This article is the second part of a trilogy that discusses IP issues related to anti-Tumor Necrosis factor alpha (TNFalpha) biologics. TNFalpha is the world's most valuable target, with accumulated sales of TNFalpha biologics of 34 bn USD in 2014. While in the first part of this trilogy, Humira was discussed, this second parts discusses the patent strategies of Enbrel, Remicade, Cimzia and Simponi. PMID- 29439321 TI - Knowledge, attitude, and practice of HIV/AIDS among workers at China first highway engineering Company at Bilibila Sokota Road Project, Sokota, Ethiopia. AB - OBJECTIVE: The aim of this study was to assess Bilbila Sokota Road Project workers' knowledge, attitude and practice on HIV/AIDS in China first highway engineering Company. METHODS: A cross sectional Survey was conducted among workers in China first high way engineering Company at Bilbila Sokota road project, Sokota, Ethiopia. Fifty-five workers were taken from project site/company. Data was collected using a validated self-administrated standardized questionnaire on Knowledge, attitude and practice including behavioral change regarding HIV/AIDS. Descriptive statistics and multivariate and bivaraite logistic regression were employed. Data were analyzed using SPSS version 20 statistical soft ware. P-value < 0.05 was used as a significant difference. RESULT: Among the 54 workers' who participated in the study, most (96.3%) had ever heard of the diseases HIV/AIDS. The majority 32 (59.3%) of participants were respond that mass media. Followed by NGOs (29.6%). Thirty-three (61.1%) of the study participant were believed that HIV + mother infect their unborn child and 12 (22.2%) were not believed. Forty-six (85.2%) of participants had knew about how to use a condom correctly. Meanwhile, 40 (74.1%) were agreed that is acceptable for single men or women to use condom. Furthermore, Only 18 (33.3%) of them had used condom during last two time's sexual intercourse with other partners. Twenty-Seven (50%) of participants did not feel about their risk of becoming infected with HIV or another sexually transmitted infection. But, 10 (18.5%) were feel they are at risk of becoming infected with HIV or another sexually transmitted infection in study area. Mean knowledge scores was significantly difference by source of information on sexual health do workers' think most credible at their work place (P= 0.014) in the Company However, there was no any significantly difference by all components of attitude and practice toward to HIV/AIDS (P> 0.05). CONCLUSION: The findings shown that participants had ever heard about HIV/AIDS. Only Mass media and NGOs were used as the major source of information about HIV/AIDS. This implies it may be lack of further health education and training about all source of information regarding HIV/AIDS. HIV/AIDS prevention and control training and health education efforts should be intensified to improve the attitude and practice workers in china first highway engineering company at Bilbila Sokota Road Project. PMID- 29439322 TI - Cerebrospinal Fluid Biomarkers are Differentially Related to Structural and Functional Changes in Dementia of the Alzheimer's Type. AB - The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer's type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks. PMID- 29439323 TI - Interrelationship between the Levels of C9orf72 and Amyloid-beta Protein Precursor and Amyloid-beta in Human Cells and Brain Samples. AB - A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-beta (Abeta) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-beta protein precursor (AbetaPP) resulted in increased levels of secreted AbetaPP fragments and Abeta, while levels of AbetaPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AbetaPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AbetaPP fragments or Abeta remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Abeta42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AbetaPP processing, but warrant further studies to clarify the underlying mechanisms. PMID- 29439324 TI - Altered Expression of Urea Cycle Enzymes in Amyloid-beta Protein Precursor Overexpressing PC12 Cells and in Sporadic Alzheimer's Disease Brain. AB - Urea cycle enzymes may play important yet poorly characterized roles in Alzheimer's disease (AD). Our previous results showed that amyloid-beta (Abeta) affects urea cycle enzymes in rat pheochromocytoma (PC12) cells. The aim of the present study was to investigate the changes in arginases, other urea cycle enzymes, and nitric oxide synthases (NOSs) in PC12 cells transfected with AbetaPP bearing the double 'Swedish' mutation (APPsw, K670M/N671L) and in postmortem sporadic AD brain hippocampus; the mutation intensifies Abeta production and strongly associates with AD neuropathology. mRNA expression was analyzed using real-time PCR in cell cultures and DNA microarrays in hippocampal CA1 area of human AD brains. Arginase activity was measured spectrophotometrically, and arginine, ornithine, and citrulline levels by high-performance liquid chromatography. Our data demonstrated that the expression and activity of arginases (Arg1 and Arg2), as well as the expression of argininosuccinate synthase (Ass) were significantly reduced in APPsw cells compared to control. However, argininosuccinate lyase (Asl) was upregulated in APPsw cells. Real-time PCR analysis revealed significant elevation of neuronal nitric oxide synthase (Nnos) mRNA in APPsw cells, without changes in the endothelial Enos, whereas inducible Inos was undetectable. The changes were found to follow closely those observed in the human hippocampal CA1 region of sporadic AD brains. The changes in enzyme expression were accompanied in APPsw cells by significantly elevated citrulline, ornithine, and arginine. Our findings demonstrate that AbetaPP/Abeta alters arginine metabolism and induces a shift of cellular homeostasis that may support the oxidative/nitrosative stress observed in AD. PMID- 29439325 TI - Prediction and Early Detection of Alzheimer's Dementia: Professional Disclosure Practices and Ethical Attitudes. AB - BACKGROUND: Biomarker-supported testing for preclinical and prodromal Alzheimer's disease (AD) finds its way into clinical practice. Professional attitudes and practices regarding disclosure and ethical issues are controversial in many countries. OBJECTIVES: Against this background, the objective was to survey the actual practice and the attitudes of physicians in German hospitals and memory clinics in order to explore possible practical insecurities and ethical concerns. METHODS: A detailed survey with 37 items was conducted among medical professionals at German hospitals and memory clinics (n = 108). Analyses were performed using SPSS 21.0 (IBM). Findings were based on frequency and percentage distribution. RESULTS: Nearly half of the respondents stated that persons with mild cognitive impairment and pathological cerebrospinal fluid biomarkers were informed they had or would soon develop AD. While 81% acknowledged a 'right not to know', 75% said that results were always communicated. A majority agreed there was a benefit of prediction or later life planning [end-of-life, financial, family, housing (73-75%)] but also expected high psychological stress (82%) and self-stigmatization (70%) for those tested. CONCLUSIONS: There is considerable heterogeneity and insecurity regarding prediction and early detection in the context of AD in Germany. Information of professionals and standardization of professional testing and disclosure practices are needed. PMID- 29439326 TI - Is There a Characteristic Clinical Profile for Patients with Dementia and Sundown Syndrome? AB - BACKGROUND: Sundown syndrome (SS) is the onset or worsening of behavioral symptoms in the evening in patients with dementia. OBJECTIVE: To identify the differential clinical profile of patients with dementia who present SS. METHODS: A cross-sectional, case-control observational study was conducted by retrospectively reviewing the medical records of patients with dementia in a specialized Memory Unit. We compared the characteristics of patients with and without SS, including sociodemographic variables, etiology, and severity of the dementia, behavioral symptoms, sleep disorders (considering insomnia and hypersomnia), other diseases and treatments employed. We identified the factors related to SS and conducted a logistic regression analysis to establish a predictive nomogram. RESULTS: Of the 216 study patients with dementia, 41 (19%) had SS. There was a predominance of women (2.4:1), advanced age (p = 0.0001), dependence (p < 0.0001), institutionalization (p < 0.0001), caregiver burden (p < 0.0001), anxiety (p < 0.0001), delirium (p < 0.0001), hallucinations (p < 0.0001), wandering (p < 0.0001), Lewy body dementia (p = 0.05), higher Global Deterioration Scale score (GDS; p < 0.0001), and sleep disorders (p < 0.0001). The multivariate analysis revealed that age (p = 0.048), GDS score (p = 0.01), and the presence of insomnia or hypersomnia (p < 0.0001) independently defined the presence of SS. We established a predictive nomogram for developing SS in patients with dementia, with a predictive capacity of 80.1%. CONCLUSION: In our study, age, a higher score on the GDS, and the presence of insomnia or hypersomnia are differential clinical characteristics of patients with SS. We defined a nomogram that helps predicting the occurrence of SS in patients with dementia. PMID- 29439327 TI - Stabilized Low-n Amyloid-beta Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat. AB - BACKGROUND: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-beta oligomers (Abetao). These small soluble Abetao, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. OBJECTIVE: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-beta1-42 oligomers (Abetao1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. METHODS: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Abetao1-42 (10MUL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1beta, IL-6, TNF alpha), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). RESULTS: Acute ICV administration of Abetao1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. CONCLUSION: Taken together the results suggest that acute administration of soluble low-n Abetao may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology. PMID- 29439328 TI - Impact of Total Knee Arthroplasty with General Anesthesia on Brain Networks: Cognitive Efficiency and Ventricular Volume Predict Functional Connectivity Decline in Older Adults. AB - Using resting state functional magnetic resonance imaging (RS-fMRI), we explored: 1) pre- to post-operative changes in functional connectivity in default mode, salience, and central executive networks after total knee arthroplasty (TKA) with general anesthesia, and 2) the contribution of cognitive/brain reserve metrics these resting state functional declines. Individuals age 60 and older electing unilateral total knee arthroplasty (TKA; n = 48) and non-surgery peers with osteoarthritis (n = 45) completed baseline cognitive testing and baseline and post-surgery (post-baseline, 48-h post-surgery) brain MRI. We acquired cognitive and brain estimates for premorbid (vocabulary, reading, education, intracranial volume) and current (working memory, processing speed, declarative memory, ventricular volume) reserve. Functional network analyses corrected for pain severity and pain medication. The surgery group declined in every functional network of interest (p < 0.001). Relative to non-surgery peers, 23% of surgery participants declined in at least one network and 15% of the total TKA sample declined across all networks. Larger preoperative ventricular volume and lower scores on preoperative metrics of processing speed and working memory predicted default mode network connectivity decline. Premorbid cognitive and premorbid brain reserve did not predict decline. Within 48 hours after surgery, at least one fourth of the older adult sample showed significant functional network decline. Metrics of current brain status (ventricular volume), working memory, and processing speed predicted the severity of default mode network connectivity decline. These findings demonstrate the relevance of preoperative cognition and brain integrity on acute postoperative functional network change. PMID- 29439329 TI - Subtle Cognitive Impairment and Alzheimer's Disease-Type Pathological Changes in Cerebrospinal Fluid are Common Among Neurologically Healthy Subjects. AB - BACKGROUND: The neuropathology of Alzheimer's disease (AD) has previously been shown to be rather common among the elderly. OBJECTIVE: The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOEE4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population. METHODS: This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOEE4 status were analyzed. RESULTS: Of the studied subjects, 8.6% (n = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance. CONCLUSION: AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes. PMID- 29439330 TI - Hypoxia-Induced Signaling Activation in Neurodegenerative Diseases: Targets for New Therapeutic Strategies. AB - For the maintenance of cellular homeostasis and energy metabolism, an uninterrupted supply of oxygen (O2) is routinely required in the brain. However, under the impaired level of O2 (hypoxia) or reduced blood flow (ischemia), the tissues are not sufficiently oxygenated, which triggers disruption of cellular homeostasis in the brain. Hypoxia is known to have a notable effect on controlling the expression of proteins involved in a broad range of biological processes varying from energy metabolism, erythropoiesis, angiogenesis, neurogenesis to mitochondrial trafficking and autophagy, thus facilitating neuronal cells to endure in deprived O2. On the contrary, hypoxia to the brain is a major source of morbidity and mortality in humans culminating in cognitive impairment, gradual muscle weakness, loss of motor activity, speech deficit, and paralysis as well as other pathological consequences. Further, hypoxia resulting in reduced O2 deliveries to brain tissues is supposed to cause neurodegeneration in both in vivo and in vitro models. Similarly, chronic exposure to hypoxia has also been reportedly involved in defective vessel formation. Such vascular abnormalities lead to altered blood flow, reduced nutrient delivery, and entry of otherwise restricted infiltrates, thereby limiting O2 availability to the brain and causing neurological disabilities. Moreover, the precise mechanistic role played by hypoxia in mediating key processes of the brain and alternatively, in triggering pathological signals associated with neurodegeneration remains mysterious. Therefore, this review elucidates the intricate role played by hypoxia in modulating crucial processes of the brain and their severity in neuronal damage. Additionally, the involvement of numerous pharmacological approaches to compensate hypoxia-induced neuronal damage has also been addressed, which may be considered as a potential therapeutic approach in hypoxia-mediated neurodegeneration. PMID- 29439332 TI - Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models. AB - Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer's disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR). Long-term activation of the UPR mediates neuronal dysfunction in AD. We hypothesized that the UPR is impacted in a mouse model of DS. To test this, we performed gene and protein expression analysis of ER stress markers in the Ts65Dn mouse model of DS at 3, 9, and 18 months. We identified activation of the PERK pathway in Ts65Dn DS mice at 3 months of age compared to euploid controls. We also determined that the early and overt UPR activation decreased with age, the UPR signal was significantly reduced by 18 months. Our data suggest that UPR activation in DS mouse models occurs early before consistent brain neurodegeneration and might be an essential contributor to dys-proteostasis. PMID- 29439334 TI - What Do We Know About Behavioral Crises in Dementia? A Systematic Review. AB - BACKGROUND: Behavioral crises in dementia are represented by a wide variety of symptoms, regularly require external intervention from professionals, and are reported as a risk factor for hospital admission. Little is known about the factors that are associated with them. OBJECTIVE: To determine the factors associated with dementia-related behavioral crises. METHODS: We searched MEDLINE, CINAHL, PsycINFO, EMBASE, and AMED databases. An additional lateral search including reference lists was conducted. Two researchers screened all records for potential eligibility. Narrative synthesis was used to bring together the findings. RESULTS: Out of the 5,544 records identified, 24 articles (18 distinct studies) met the eligibility criteria. Aggression and agitation were the most common behaviors present at crises. Delusions, wandering/absconding, and hallucinations were also key behaviors contributing to crises. Behavioral crises predominantly happened in the severe stages of dementia (according to MMSE scores), in people with dementia residing in their own homes and in long-term care, and were the catalyst for admissions to psychiatric inpatient settings, specialist-care units, long-term care settings, or for referrals to psychiatric community services. Lack of consistency in assessment of behavior, and management of agitation/aggression in dementia crises were evident. CONCLUSION: Interventions to reduce the likelihood of people with dementia-related behaviors reaching crisis point need to focus on both family and care home settings and incorporate aggression and agitation management. Future research should focus on determining the factors that could be addressed to prevent behavioral crises and the interventions and models of care that may help to prevent crises. PMID- 29439333 TI - Risk of Conversion to Dementia in a Mild Behavioral Impairment Group Compared to a Psychiatric Group and to a Mild Cognitive Impairment Group. AB - BACKGROUND: There is insufficient available information on behavioral changes in the absence of cognitive impairment as factors increasing the risk of conversion to dementia. OBJECTIVE: To observe and analyze patients with mild behavioral impairment (MBI), mild cognitive impairment (MCI), and a psychiatry group (PG) to compare the risk of progression to dementia. METHODS: From 677 initially assessed >=60-year-old patients, a series of 348 patients was studied for a five-year period until censoring or conversion to dementia: 96 with MBI, 87 with MCI, and 165 with general psychiatry disorders, including 4 subgroups: Anxiety, Depression, Psychosis and Others. All patients were assessed with clinical, psychiatric, neurological, neuropsychological, and neuroimaging studies. RESULTS: From 348 patients, 126 evolved to dementia (36.2%). Conversion was significantly higher in MBI (71.5%), followed by the MCI-MBI overlap (59.6%) and MCI (37.8%) groups, compared to PG (13.9%) (Log-rank p < 0.001). MCI patients mostly converted to Alzheimer's dementia, while MBI converted to frontotemporal dementia and Lewy body dementia. Patients in PG converted to Lewy body dementia and frontotemporal dementia. CONCLUSION: Conversion to dementia is significantly higher in patients with neuropsychiatric symptoms. The MBI concept generates a new milestone in the refining of diagnosis of neurodegenerative diseases and the possibility of creating neuropsychiatric profiles. Its earlier identification will allow new possibilities for therapeutic intervention. PMID- 29439331 TI - Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer's Disease Pathology and Neuronal Damage. AB - Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer's disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n = 173). CSF samples were analyzed for markers of AD pathology (Abeta42, phosphorylated tau [p tau], sAbetaPPbeta) or neuronal damage (total tau; neurofilament light chain) (n = 147). Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1beta levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1beta, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF Abeta42. Higher CSF sAbetaPPbeta levels were associated with higher plasma markers only (IL-8; MCP 1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1beta were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF Abeta42 modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage. PMID- 29439336 TI - Memory Binding Test Predicts Incident Dementia: Results from the Einstein Aging Study. AB - BACKGROUND: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI. OBJECTIVE: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study. METHODS: As a sub-study in the Einstein Aging Study, 309 participants age>=70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of<=17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:<=24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:<=12). RESULTS: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p = 0.006). MBT TIP remained a significant predictor of dementia (p = 0.0002) when adjusting for FCSRT-FR or CR-L1. CONCLUSIONS: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis. PMID- 29439335 TI - Abnormalities of Resting State Cortical EEG Rhythms in Subjects with Mild Cognitive Impairment Due to Alzheimer's and Lewy Body Diseases. AB - The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) score was matched between the ADMCI and DLBMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test the clinical validity of these rsEEG markers. PMID- 29439338 TI - Multi-Parametric Classification of Vascular Cognitive Impairment and Dementia: The Impact of Diverse Cerebrovascular Injury Biomarkers. AB - Vascular cognitive impairment and dementia (VCID) is a diagnostic term applied to cognitively impaired individuals with heterogeneous cerebrovascular conditions affecting large and/or small vessels. Individual biomarkers have been identified as instrumental in relating VCID to specific underlying pathologies to better characterize this syndrome. Emerging research to refine panels of biomarkers will increase classification sensitivity and specificity. Refined VCID clustering based on the severity and pathology of vascular injury will permit the development of optimal prevention and treatment strategies. Here, we review recently reported data concerning the diversity of VCID-related pathology and attempts for VCID clustering based on biomarkers obtained from different sets of measurements. We discuss three major sets of biomarkers: 1) neuroimaging biomarkers, 2) neuropsychological performance measures, and 3) biochemical markers in current VCID clustering. Finally, we highlight the effect of blood brain barrier health on cerebrovascular disease trajectory. PMID- 29439337 TI - Utility of the LIBRA Index in Relation to Cognitive Functioning in a Clinical Health Seeking Sample. AB - BACKGROUND: Dementia prevalence is expected to increase substantially over the next few decades. Since there is currently no cure for dementia available, there is an urgent need for the early identification of individuals at high risk for dementia, so that primary and secondary prevention strategies can be implemented. Recently, the LIfestyle for BRAin health (LIBRA) index was developed as a new dementia risk algorithm. It specifically focuses on modifiable risk and protective factors that can be targeted in midlife. OBJECTIVE: The objective of this study was to evaluate the LIBRA index in relation to markers of cognitive functioning in a clinical, health-seeking sample of community-based older adults. METHODS: 484 participants (mean age 62.7 years) were recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney. Participants underwent comprehensive clinical and neuropsychological assessment and completed a self report survey pack. Participants were rated via consensus as having either subjective cognitive complaints (SCC) or meeting criteria for mild cognitive impairment (MCI). The LIBRA score was calculated based on 11 available risk and protective factors. RESULTS: 65.4% of the sample met criteria for MCI. People with MCI showed a significantly higher LIBRA score compared to people with SCC. Furthermore, multiple cognitive domains, in particular executive functioning, were associated with a higher LIBRA score, with stronger correlations in people with MCI. CONCLUSION: The LIBRA index might be a useful tool to determine lifestyle-attributable risk of cognitive decline in an older health-seeking population, including people with MCI. PMID- 29439339 TI - Plasma Antioxidant Status in Patients with Alzheimer's Disease and Cognitively Intact Elderly: A Meta-Analysis of Case-Control Studies. AB - Serum antioxidants may afford neuroprotection against Alzheimer's disease (AD) via correction of the pro-oxidative imbalance but findings reported have been inconsistent. We compared the pooled mean difference in serum levels of ten dietary antioxidants between patients with AD and cognitively intact controls from 52 studies in meta-analyses using random-effects models. Patients with AD had significantly lower plasma levels of alpha-carotene, beta-carotene, lycopene, lutein, vitamin A, C, and E, and uric acid. No significant difference was observed for plasma levels of beta-cryptoxanthin and zeaxanthin. Considerable heterogeneity was detected across studies. The lower serum levels of dietary antioxidants from the carotene and vitamin subclasses observed in individuals with AD suggest reduced systemic availability of these subclasses in this prevalent form of dementia. To our knowledge, these are the first meta-analyses to demonstrate lower serum lycopene and to evaluate beta-cryptoxanthin, lutein, and zeaxanthin levels in AD. In light of the significant heterogeneity detected across studies, caution should be exercised in the interpretation of the data and therapeutic intervention approaches considered through supplementation measures. Our data may better inform interventions to improve antioxidant status in a condition of major public health importance. PMID- 29439340 TI - Implementation of an Occupational Therapy Program for Alzheimer's Disease Patients in France: Patients' and Caregivers' Perspectives. AB - BACKGROUND: The French National Alzheimer Plan 2008-2012 created specialized Alzheimer teams, which provide up to 15 sessions of cognitive rehabilitation in the patient's home for 3 months. Sessions are conducted by an occupational therapist and a gerontological nursing assistant. OBJECTIVES: As the patient's experience is one determinant of successful implementation, we explored the usefulness of these teams as viewed by the patient and his or her main caregiver. METHODS: Thirteen patients and their caregiver, previously assisted by a specialized Alzheimer team, were individually given semi-structured interviews (n = 26, duration 20 to 180 minutes). RESULTS: Our study showed that although patients and caregiver had no initial expectations, most of them appreciated the support provided by the specialized Alzheimer teams. Patients valued the "human" component, and favored interventions that improved quality of life over those intended to maintain functional capacities. Caregivers observed improved mood and behavior in patients. Those involved in sessions felt empowered by contact with a specialized Alzheimer team. We discuss how patients' and caregivers' feedback influenced the implementation process through comprehensive use of the five dimensions of the RE-AIM framework. CONCLUSION: Whereas intervention by specialized Alzheimer teams was largely accepted by health care professionals, patients, and caregivers, its effectiveness is questioned in view of its deviation from the evidence-based model. Interviews with patients and caregivers shed light on some reasons for this deviation, as what they value in the intervention differs from the functional focus of the model. PMID- 29439341 TI - Reproducibility of Alzheimer's Disease Cerebrospinal Fluid-Biomarker Measurements under Clinical Routine Conditions. AB - Analysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of the-art differential diagnosis of dementias. Dementia due to Alzheimer's disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181 Tau (pTau) and low CSF amyloid-beta42 (Abeta42). Discrepancies in the laboratory analysis of human materials are well known and much effort has been put into harmonization procedures. In this study, we measured CSF biomarkers of more than 100 patients obtained under clinical routine conditions in two different clinical laboratories. The CSF biomarker levels obtained from the two different sites were significantly correlated: R2 = 0.7129 (tTau, p < 0.001), 0.7914 (pTau, p < 0.001), 0.5078 (Abeta42, p < 0.001), 0.5739 (Abeta40, p < 0.001), and 0.4308 (Abeta42/40, p < 0.001). However, the diagnostic classifications of the Abeta42, tTau, and pTau levels of identical subjects into normal versus pathological range made by the two different sites showed substantial discrepancies (31.5%, 29.6%, and 25.0% discordant cases, respectively). Applying Abeta42/40, instead of CSF Abeta42 alone, lead to a reduction of the discordant cases to 16.8%. Our findings suggest that CSF Abeta42/40 can outperform Abeta42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical routine. Thus, we recommend the inclusion of Abeta42/40 as a CSF biomarker in the diagnostic procedure. PMID- 29439342 TI - Circulatory Levels of Toxic Metals (Aluminum, Cadmium, Mercury, Lead) in Patients with Alzheimer's Disease: A Quantitative Meta-Analysis and Systematic Review. AB - BACKGROUND: Environmental exposure to toxic metals has been postulated to play a role in the pathophysiological processes of Alzheimer's disease (AD). However, the circulatory levels of toxic metals in AD patients are not consistent in previous studies. OBJECTIVE: To systematically assess levels of toxic metals (aluminum, mercury, cadmium, lead) in the circulation (blood, serum/plasma) of AD patients and controls. METHODS: PubMed, Web of Science, Science Direct, Cochrane Library, and the China National Knowledge Infrastructure (CNKI) were systematically searched to identify studies published up to January 1, 2017. Meta analyses were performed using random-effects models and the pooled standardized mean difference (SMD) were reported with 95% confidence intervals (CI). RESULTS: We identified 17, 7, 8, and 10 studies for aluminum, mercury, cadmium, and lead, respectively. Meta-analyses showed significantly elevated circulatory levels of aluminum (SMD = 1.08, 95% CI: 0.66, 1.50), mercury (SMD = 0.55, 95% CI, 0.15, 0.95), and cadmium (SMD = 0.62, 95% CI: 0.12, 1.11), whereas lower levels of lead (SMD = -0.23, 95% CI: -0.38, -0.07) in AD patients than in controls. Publication bias was only observed for aluminum studies, but the "trim and fill" analysis showed that the publication bias did not alter the direction of the effect. Sensitivity analyses showed no studies from the pooled analysis changed the results. CONCLUSION: Compared to controls, circulatory levels of aluminum, mercury, and cadmium are significantly higher but the levels of lead were reduced in AD patients. These findings suggest that elevated aluminum, mercury, and cadmium in the circulation, especially in serum may play a role in the progression of AD. PMID- 29439344 TI - Low Accuracy of Brief Cognitive Tests in Tracking Longitudinal Cognitive Decline in an Asian Elderly Cohort. AB - BACKGROUND: Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition. OBJECTIVE: To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments. METHODS: Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z scores on the battery were derived and used to assess overall and significant (>=0.5 standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported. RESULTS: The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64-0.78] & 0.73 [0.66-0.80] for overall decline; 0.78 [0.70-0.85] & 0.80 [0.73-0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively). CONCLUSION: There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change. PMID- 29439343 TI - Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease. AB - The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-beta. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-beta pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD. PMID- 29439345 TI - Joint Assessment of Quantitative 18F-Florbetapir and 18F-FDG Regional Uptake Using Baseline Data from the ADNI. AB - Joint analysis of amyloid and metabolic PET patterns across healthy, mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects was performed using baseline 18F-florbetapir and 18F-FDG PET of 684 subjects from the ADNI (251 normal, 204 stable MCI, 85 AD converters, and 144 AD). Correlation between regional amyloid and metabolic uptake was measured and predictive value of PET profile regarding AD conversion in cognitively impaired subjects was assessed using survival analysis and support vector machine classification (SVM). The highest correlations were found in the temporal cortex, precuneus, and posterior cingulum. With respect to normal controls, amyloid load increase was diffuse and early in MCI subjects, whereas metabolism decrease occurred later and predominated in temporo-parietal, precuneus, and cingulate cortices. Five-year AD conversion rates in cognitively impaired subjects were 5%, 22%, 42%, and 78% in amyloid-/FDG-, amyloid-/FDG+, amyloid+/FDG-, and amyloid+/FDG+ subjects respectively (mean follow-up 37+/-14 months). Using SVM, the combination of ADAS cog score, amyloid PET, and FDG PET yielded better performance in predicting AD conversion (77% accuracy; 58% positive predictive value; 88% negative predictive value) than ADAS-cog (72%; 52%; 86%), amyloid PET (72%; 52%; 87%), and FDG PET (67%; 47%; 84%). This study attests the complementary value of amyloid and FDG PET in MCI assessment and the efficiency of combined cognitive, amyloid, and metabolic scores to predict AD conversion. PMID- 29439346 TI - Chinese Herbal Medicine for Vascular Dementia: A Systematic Review and Meta Analysis of High-Quality Randomized Controlled Trials. AB - BACKGROUND: Vascular dementia (VaD) is the second common form of dementia and Chinese herbal medicine (CHM) has been used for aging-related disorders for thousands of years. However, there is still a lack of scientific evidence using CHM for VaD. OBJECTIVE: To conduct a systematic review to assess the current evidence available for the effectiveness and safety of CHM for VaD. METHODS: Six databases were searched for high-quality randomized-controlled clinical trials that met the requirements of at least 4 of the 7 domains of the Cochrane risk of bias tool from their inception to February 2017. RevMan 5.3 was applied for data analysis. RESULTS: Forty studies with 42 comparisons and 3,572 individuals were included. The studies investigated the CHM versus placebo (n = 4), CHM versus western conventional treatment (WCT) (n = 36), and CHM plus WCT versus WCT (n = 2). Meta-analysis showed that CHM for VaD could improve Mini-Mental State Examination (MMSE), the Activities of Daily Living, Hasegawa's dementia scale, and clinical effective rate but had statistically similar effect based on Blessed Behavior Scale (BBS) outcome when compared with WCTs. When compared with placebo, CHMs were more beneficial in improving MMSE but showed no significant difference in BBS scores. CHM as adjuvant therapy exerted an additive anti-VaD benefit on MMSE scores. The participants of CHM group had fewer adverse events than that of the placebo group or WCT group. CONCLUSION: The findings of the present study support, at least to an extent, that CHM can be recommended for routine use for treatment of VaD. PMID- 29439347 TI - Quantifying the Diagnostic Pathway for Patients with Cognitive Impairment: Real World Data from Seven European and North American Countries. AB - To ensure that patients with dementia and their caregivers receive appropriate treatment and support, early diagnosis is essential but remains challenging. Real world data from a multi-national, cross-sectional survey of physicians and their patients were analyzed to quantify the diagnostic pathway for dementia, including a focus on severity of patients' cognitive impairment (CI) at the time of symptom onset, referral and subsequent diagnosis. Data were collected for 7,620 patients with CI. Most patients saw a healthcare professional within 1 year of first symptoms and received a diagnosis within 3-7 months of initial consultation. However, only 20% of patients received a diagnosis before their disease progressed beyond the prodromal stage and 23.5% already had moderate CI at diagnosis. These findings show that the goal of identifying and diagnosing CI at the earliest stages of disease is, for many patients, not achieved. Efforts toward public awareness and proactive, earlier detection and intervention, must be maintained-indeed where possible invigorated. PMID- 29439349 TI - Comparing the Electronic and Standard Versions of the Montreal Cognitive Assessment in an Outpatient Memory Disorders Clinic: A Validation Study. AB - The Montreal Cognitive Assessment (MoCA) has become widely used as a brief test of cognitive function in patients with neurological disease. More convenient application of the MoCA might increase its use and enhance its utility. An electronic version of the MoCA has recently been developed. To establish validity of the electronic version (eMoCA), discrepancy scores, concordance correlation coefficients (CCC), and root mean squared differences (RMSD) were calculated between each administration method in a sample of 43 new adult patients presenting with primary memory complaints. The CCC was 0.84 and the RMSD was 2.27, with 76% of the sample having a difference score within 2 points. Overall, this study establishes adequate convergent validity between the MoCA and eMoCA among an adult population presenting with memory concerns. PMID- 29439350 TI - Early Tau Burden Correlates with Higher Rate of Atrophy in Transentorhinal Cortex. AB - Neurofibrillary tangle (NFT) pathology is linked to neurodegeneration in the medial temporal lobe (MTL). Using a tailored pipeline, we correlated atrophy rate, as measured from retrospective longitudinal MRI, with NFT burden, measured from 18F-AV-1451 PET, within MTL regions of earliest NFT pathology. In amyloid beta positive but not amyloid-beta negative individuals, we found significant correlation between 18F-AV-1451 uptake and atrophy rate that was strongest in the transentorhinal cortex, the first region with NFT pathology. This supports the role of NFTs in driving neurodegeneration and the utility of 18F-AV-1451 PET and structural measurement of transentorhinal cortex in tracking early tau-mediated disease progression. PMID- 29439348 TI - Evolvability of Amyloidogenic Proteins in Human Brain. AB - Currently, the physiological roles of amyloidogenic proteins (APs) in human brain, such as amyloid-beta and alpha-synuclein, are elusive. Given that many APs arose by gene duplication and have been resistant against the pressures of natural selection, APs may be associated with some functions that are advantageous for survival of offspring. Nonetheless, evolvability is the sole physiological quality of APs that has been characterized in microorganisms such as yeast. Since yeast and human brain may share similar strategies in coping with diverse range of critical environmental stresses, the objective of this paper was to discuss the potential role of evolvability of APs in aging-associated neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Given the heterogeneity of APs in terms of structure and cytotoxicity, it is argued that APs might be involved in preconditioning against diverse stresses in human brain. It is further speculated that these stress-related APs, most likely protofibrillar forms, might be transmitted to offspring via the germline, conferring preconditioning against forthcoming stresses. Thus, APs might represent a vehicle for the inheritance of the acquired characteristics against environmental stresses. Curiously, such a characteristic of APs is reminiscent of Charles Darwin's 'gemmules', imagined molecules of heritability described in his pangenesis theory. We propose that evolvability might be a physiological function of APs during the reproductive stage and neurodegenerative diseases could be a by-product effect manifested later in aging. Collectively, our evolvability hypothesis may play a complementary role in the pathophysiology of APs with the conventional amyloid cascade hypothesis. PMID- 29439351 TI - Relationship of Area of Soft Drusen in Retina with Cerebral Amyloid-beta Accumulation and Blood Amyloid-beta Level in the Elderly. AB - BACKGROUND: Histopathological studies have confirmed that soft drusen contains amyloid-beta (Abeta). OBJECTIVE: To examine the relationship between the area of soft drusen in the macular area and cerebral Abeta accumulation or plasma Abeta level in elderly persons without dementia. METHODS: Fourteen consecutive patients (18 eyes) aged >=50 years with macular soft drusen were studied prospectively. From color fundus photographs, the area of soft drusen (pixel) within a 6,000 MUm diameter with the macula as center was measured. Standard uptake value ratio (SUVR) was obtained from positron emission tomography using florbetapir, which indicates the ratio of cerebral cortical-to-cerebellar Abeta accumulation. Ratio of plasma Abeta1-42 to Abeta1-40 level was calculated. RESULTS: Mean age was 73.3+/-7.6 years. The soft drusen area was 4.32+/-2.42 mm2. The SUVR was 1.08+/ 0.15. Plasma Abeta1-42/Abeta1-40 ratio was 0.17+/-0.08. When SUVR >=1.10 was defined as positive and <1.10 as negative, the soft drusen area in SUVR-positive patients (6.19+/-1.14 mm2) was significantly (p = 0.0043) larger than that in SUVR-negative patients (3.13+/-2.27 mm2). Multivariate regression analysis showed that SUVR positivity correlated with soft drusen area (p = 0.0484) and with Voxel based Specific Regional Analysis System for Alzheimer's Disease score (p = 0.0360). However, there was no correlation with gender (p = 0.1921), age (p = 0.2361), Alzheimer's Disease Assessment Scale score (p = 0.6310), Mini-Mental State Examination score (p = 0.4246), or plasma Abeta1-42/Abeta1-40 ratio (p = 0.8398). CONCLUSION: Among elderly persons without dementia, the area of soft drusen was larger in those with more extensive cerebral Abeta accumulation. The area of soft drusen may be a biomarker of cerebral Abeta accumulation. PMID- 29439352 TI - Linking Atrial Fibrillation with Alzheimer's Disease: Epidemiological, Pathological, and Mechanistic Evidence. AB - Many studies have shown a relationship between atrial fibrillation (AF) and vascular dementia. AF is a major risk factor for stroke, and stroke is the greatest risk factor for vascular dementia. However, the relationship between Alzheimer's disease (AD), the leading cause of dementia, and AF remains unclear. At least four epidemiological studies have reported AF significantly raises the risk of AD 1.5- to 2.5-fold. Chronic cerebral hypoperfusion, resulting from persistent AF, could explain the link as hypoperfusion may mechanistically exacerbate amyloid-beta (Abeta) neuropathology, such as senile plaques and amyloid angiopathy, by upregulating Abeta-producing enzymes and lowering Abeta clearance efficiency. In addition, hypoperfusion may exacerbate tau pathology directly through upregulation of tau-phosphorylating enzymes and indirectly via the amyloid cascade. However, most neuropathological studies do not support the direct link between AD pathology and AF but rather suggests vascular neuropathology is related to, or coexistent with, AF and lowers the threshold for clinically-evident AD. Vascular neuropathology may thus mediate the link between AD and AF. From a treatment perspective, an observational study has shown that catheter ablation is associated with less incidence of AD in AF patients, suggesting rhythm-control suppresses hypoperfusion-induced AD neuropathology. In addition, rate-control may lower the rate of cognitive decline in cognitively impaired elderly subjects with AF. Further studies are warranted to clarify the mechanisms underlying the linkage between AF and AD. However, anticoagulation and rhythm-/rate-control against AF may hold promise even for AD patients. PMID- 29439353 TI - Evaluating Peripersonal Space through the Functional Transcranial Doppler: Are We Paving the Way for Early Detecting Mild Cognitive Impairment to Dementia Conversion? AB - BACKGROUND: Identifying the patients with mild cognitive impairment (MCI) who may develop dementia (MDC) is challenging. The study of peripersonal space (PPS) by using functional transcranial Doppler (fTCD) could be used for this purpose. OBJECTIVE: To identify changes in cerebral blood flow (CBF) during motor tasks targeting PPS, which can predict MDC. METHODS: We evaluated the changes in CBF in 22 patients with MCI and 23 with dementia [Alzheimer's disease (AD) and vascular dementia (VaD)] during a motor task (passive mobilization, motor imagery, and movement observation) in which the hand of the subject moved forward and backward the face. RESULTS: CBF increased when the hand approached the face and decreased when the hand moved from the face in the healthy controls (HCs). CBF changed were detectable only in patients with MCI but not in those with the AD and those who were MDC after 8-month follow-up. On the other hand, the patients with VaD presented a paradoxical response to the motor task (i.e., a decrease of CBF rather than an increase, as observed in HCs and MCI). Therefore, we found a modulation of PPS-related CBF only in HCs and patients with stable MCI (at the 8 month follow-up). CONCLUSIONS: fTCD may allow preliminarily differentiating and following-up the patients with MCI and MDC, thus allowing the physician to plan beforehand more individualized cognitive rehabilitative training. PMID- 29439354 TI - Effects of Gender and Other Confounding Factors on Leptin Concentrations in Alzheimer's Disease: Evidence from the Combined Analysis of 27 Case-Control Studies. AB - Leptin, as a link between fat mass and the brain, has been reported to be associated with gender. The gender differences in leptin levels between Alzheimer's disease (AD) and healthy elderly controls are inconclusive so far. To quantitatively summarize the leptin data available from female and male patients with AD, we searched PubMed and EMBASE for articles published from inception to July 20, 2017. Data were extracted from 27 studies, consisting of 3,014 participants. The pooled results showed that the overall leptin levels were lower in AD (Hedges' g = -0.481; p = 0.002) than in controls, and the leptin levels in whole blood and serum were decreased with moderate and large effect sizes (g = 0.677, -0.839; respectively; both of p-values <0.001) in AD compared with controls. In blood, there were significantly lower concentrations of leptin in female AD than in female controls (g = -0.590; p = 0.014), but not in male case control group (g = -0.666; p = 0.067). Meta-regression analysis demonstrated that the decreased extent of leptin levels in AD paralleled the degree of the severity of dementia symptoms, as well as the alterations of body mass index (p-values <=0.002). The findings provide strong evidence that 1) the blood concentrations of leptin are lower in female AD patients than in female controls; and 2) the greater the severity of dementia symptoms, the greater the decreases in the blood leptin levels. But more future investigations on the blood leptin levels in male AD patients is warranted. PMID- 29439356 TI - Frontal Cortex Epigenetic Dysregulation During the Progression of Alzheimer's Disease. AB - Although the frontal cortex plays an important role in cognitive function and undergoes neuronal dysfunction in Alzheimer's disease (AD), the factors driving these cellular alterations remain unknown. Recent studies suggest that alterations in epigenetic regulation play a pivotal role in this process in AD. We evaluated frontal cortex histone deacetylase (HDAC) and sirtuin (SIRT) levels in tissue obtained from subjects with a premortem diagnosis of no-cognitive impairment (NCI), mild cognitive impairment (MCI), mild to moderate AD (mAD), and severe AD (sAD) using quantitative western blotting. Immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a decrease in sAD compared to NCI. HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in MCI and mAD, but not in sAD compared to NCI. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to NCI. HDAC1 levels negatively correlated with perceptual speed, while SIRT1 positively correlated with perceptual speed, episodic memory, global cognitive score, and Mini-Mental State Examination. HDAC1 positively, while SIRT1 negatively correlated with cortical neurofibrillary tangle counts. These findings suggest that dysregulation of epigenetic proteins contribute to neuronal dysfunction and cognitive decline in the early stage of AD. PMID- 29439355 TI - Expression Profiling of Cytokine, Cholinergic Markers, and Amyloid-beta Deposition in the APPSWE/PS1dE9 Mouse Model of Alzheimer's Disease Pathology. AB - BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disease, is associated with dysfunction of the olfactory and the entorhinal cortex of the brain that control memory and cognitive functions and other daily activities. Pro inflammatory cytokines, amyloid-beta (Abeta), and the cholinergic system play vital roles in the pathophysiology of AD. However, the role of changes in cholinergic system components, Abeta accumulation, and cytokines in both the olfactory and entorhinal cortex is not known clearly. OBJECTIVE: The present study is aimed to evaluate the changes of cholinergic system components, Abeta accumulation, and cytokines in both the olfactory bulb (OB) and entorhinal cortex (EC) of young and aged APPSWE/PS1dE9 transgenic (Tg) mice. METHODS: We have explored the changes of cholinergic system components, Abeta accumulation, and expression profiling of cytokines in the OB and EC of aged APPswe transgenic mice and age-matched wild type mice using quantitative Real-Time PCR assays and immunohistochemistry techniques. RESULTS: In aged Tg mice, a significant increase of expression of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and chemokine MCP1 (p < 0.001, p < 0.001, and p = 0.001, respectively) and a significant reduction of nAChRalpha4 (p = 0.048) and AChE (p = 0.023) was observed when compared with age-matched wild type mice. Higher levels of AChE and BuChE are expressed in OB and EC of the APPSWE/PS1dE9 of Tg mice. Abeta accumulation was observed in OB and EC of the APPSWE/PS1dE9 of Tg mice. CONCLUSION: The study demonstrates the expression profiling of pro-inflammatory cytokines and cholinergic markers as well as Abeta accumulation in OB and EC of the APPSWE/PS1dE9 Tg mice. Moreover, the study also demonstrated that the APPSWE/PS1dE9 Tg mice can be useful as a mouse model to understand the role of pro-inflammatory cytokines and cholinergic markers in pathophysiology of AD. PMID- 29439357 TI - Dale Schenk One Year Anniversary: Fighting to Preserve the Memories. AB - It has been a year since we lost Dale Schenk on September 30, 2016. Dale's visionary work resulted in the remarkable discovery in 1999 that an experimental amyloid-beta (Abeta) vaccine reduced the neurodegeneration in a transgenic model of Alzheimer's disease (AD). Following Dale's seminal work, several active and passive immunotherapies have since been developed and tested in the clinic for AD, Parkinson's disease (PD), and other neurodegenerative disorders. Here we provide a brief overview of the current state of development of immunotherapy for AD, PD, and other neurodegenerative disorders in the context of this anniversary. The next steps in the development of immunotherapies will require combinatorial approaches mixing antibodies against various targets (e.g., Abeta, alpha-syn, Tau, and TDP43) with small molecules that block toxicity, aggregation, inflammation, and promote cell survival. PMID- 29439358 TI - Improvement in activities of daily living after visual training in patients with homonymous visual field defects using Goal Attainment Scaling. AB - BACKGROUND: Stroke is the most common cause of homonymous visual field defects (HVFDs). Yet, there is no standard protocol for composing a rehabilitation program. OBJECTIVE: In this study we assess ADL gain of visual training for vision restoration in HVFD patients by means of Goal Attainment Scaling. METHODS: Thirty-five patients trained two predefined regions of the visual field successively at home. In each region we compared the effects of both training rounds, one of which was thus 'directed' and the other 'undirected'. Visual fields were measured with Humphrey and Goldmann perimetry. QoL was assessed with three stroke-related questionnaires and ADL with Goal Attainment Scaling (GAS). RESULTS: Visual training improved the visual field for both Goldmann (ECSG = 5.82+/-0.94 mm; p = <0.001; n = 31) and Humphrey (0.79+/-0.20 dB; p = <0.001; n = 28) perimetry. All standardized stroke questionnaires were significantly improved after training (p < 0.039; n = 29), but showed no significant relation with either type of field improvement (p > 0.359). About 75% of the patients improved on their (personalized) GAS score. Interestingly, after both training rounds the GAS score increased in proportion to the extent of visual field improvement, for Goldmann border shift (p = 0.042; r = 0.38; n = 29) but not for Humphrey sensitivity increase (p = 0.337; r = 0.192; n = 28). Multiple regression revealed that GAS score was linearly related to the directed training component for Humphrey perimetry, but not for undirected training. CONCLUSION: Together these data suggest that (1) visual training aimed at vision restoration leads to visual field improvement and (2) the extent of visual field improvement is linearly related to the improvement of personal activities of daily living as evaluated by means of GAS. In conclusion, a personalized evaluation to assess treatment success showed the clinical significance of a visual training for vision restoration. PMID- 29439359 TI - Effects of combining high- and low-frequency repetitive transcranial magnetic stimulation on upper limb hemiparesis in the early phase of stroke. AB - BACKGROUND: Both high-frequency repetitive transcranial magnetic stimulation (HF rTMS) and low-frequency rTMS (LF-rTMS) are reported to benefit upper limb motor function rehabilitation in patients with stroke. However, the efficacy of combining LF- and HF-rTMS (LF-HF rTMS) has not been adequately explored, especially in the early phase of stroke. OBJECTIVE: To compare the effects of LF- and LF-HF rTMS on the upper limb motor function in the early phase post stroke. METHODS: Sixty-two patients were randomly assigned to three groups: LF-rTMS group (1 Hz rTMS to the contralesional hemisphere), LF-HF rTMS group (1 Hz rTMS to the contralesional hemisphere followed by 10 Hz rTMS to the lesional hemisphere) and sham group. The patients received the same conventional rehabilitation accompanied with sessions of rTMS for 15 consecutive days. The upper limb motor function was evaluated using the Fugl-Meyer Assessment (FMA) and the Wolf Motor Function Test (WMFT) before the first session, after the last session, and at 3 months after the last session. RESULTS: All patients finished the study without any adverse reaction. Three groups exhibited improvement in terms of the FMA score and the log WMFT time at the end of the treatment and 3 months later. Better improvement was found in the LF-HF rTMS group than in the LF-rTMS and sham groups. CONCLUSION: The results indicated that both LF- and LF-HF rTMS were effective in promoting upper limb motor recovery in patients with acute stroke. Combining HF- and LF-rTMS protocol in the present study is tolerable and more beneficial for motor improvement than the unilateral use of LF-rTMS alone. PMID- 29439360 TI - Aerobic rehabilitation program for improving muscle function in Parkinson's disease. AB - BACKGROUND: Parkinson's Disease (PD) is characterized by progressive and disabling symptoms. An impaired oxidative metabolism efficiency was supposed to be involved in the systemic impairment. Rehabilitative treatment represents a valid tool in promoting skeletal muscle's adaptations, even if no solid studies on muscle metabolic features are still available. OBJECTIVE: To evaluate the efficiency of skeletal muscle oxidative metabolism in PD patients in comparison with age-matched controls and test the role of an intensive aerobic treatment on muscle oxidative metabolism and its clinical effects. METHODS: 60 PD patients and 32 age-matched healthy controls participated. Haematic lactate values were detected during and after a submaximal incremental exercise on treadmill. The number of steps completed during the exercise was recorded. From these patients 10 underwent to an intensive aerobic treatment on treadmill (4 sessions/week for 4 weeks). Haematic lactate values and functional scales were recorded before (T0) and after (T1) treatment. RESULTS: At rest no significant difference in hematic lactate values between PD and control subjects was found. Lactate blood levels were significantly higher (p < 0,001) after the aerobic exercise test in PD patients compared to controls. These values remained higher at any time during recovery period (p < 0,001). No significant relationship between lactate values and the number of completed steps was found. After the rehabilitation treatment haematic value of lactate showed a significant reduction (p < 0,05) at 0, 5 and 10 minutes of recovery period with a normalization of value at 30'. All functional scales showed an improvement trend at T1, in particular Berg Balance Scale and 6 Meter Walking Test showed a significant reduction (p < 0,001 and p < 0,05 respectively). CONCLUSION: Our data clearly show an impaired muscle oxidative efficiency in PD subjects. The intensive rehabilitation program on treadmill showed a beneficial effect on muscle oxidative metabolism, endurance and balance, confirming the focal role of rehabilitation in PD patients. PMID- 29439361 TI - Voluntary contraction enhances spinal reciprocal inhibition induced by patterned electrical stimulation in patients with stroke. AB - BACKGROUND: Reciprocal inhibition (RI) may be important for recovering locomotion after stroke. Patterned electrical stimulation (PES) can modulate RI in a manner that could be enhanced by voluntary muscle contraction (VC). OBJECTIVE: To investigate whether VC enhances the PES-induced spinal RI in patients with stroke. METHODS: Twelve patients with chronic stroke underwent three 20 min tasks, each on different days: (1) PES (10 pulses, 100 Hz every 2 s) applied to the common peroneal nerve; (2) VC consisting of isometric contraction of the affected-side tibialis anterior muscle; (3) PES combined with VC (PES + VC). RI from the tibialis anterior to the soleus muscle was assessed before, immediately after, and 10, 20, and 30 min after the task. RESULTS: Compared to the baseline, PES + VC significantly increased the changes in reciprocal inhibition at immediately after and 10 min after the task. PES alone significantly increased this change immediately after the task, while VC alone showed no significant increase. CONCLUSION: VC enhanced the PES-induced plastic changes in RI in patients with stroke. This effect can potentially increase the success rate of newer neurorehabilitative approaches in achieving functional recovery after stroke. PMID- 29439362 TI - Effects of transcranial direct current stimulation on walking ability after stroke: A systematic review and meta-analysis. AB - BACKGROUND: As a promising technique, transcranial direct current stimulation (tDCS) has gained so much attention in its potential effects on functional recovery of lower limb following stroke. However, individual studies have yielded inconsistent or conflicting results. OBJECTIVE: To investigate the efficacy and safety of tDCS for the functional recovery of lower limb following stroke reported in the randomized controlled trials by using a meta-analysis. METHODS: MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science, CENTRAL, and Physiotherapy Evidence Database was comprehensively searched for randomized controlled trials published until April 2017 that investigated the effects of tDCS on lower limb function. Main outcomes included walking speed, walking endurance, mobility, balance function, muscle strength of lower limb and adverse events. RESULTS: A total of 10 trials (n = 194) met the inclusion criteria. Meta-analysis demonstrated a significant effect of tDCS on mobility (SMD 0.44, 95% CI: 0.01 to 0.87, P = 0.04) and muscle strength of lower limb (SMD 1.54, 95% CI: 0.29 to 2.78, P = 0.02). No significant effects were found in walking speed (SMD 0.39, 95% CI: -0.06 to 0.85, P = 0.09), walking endurance (SMD 0.28, 95% CI: -0.28 to 0.84, P = 0.33) and balance function (SMD 0.44, 95% CI: -0.06 to 0.94, P = 0.08). CONCLUSION: tDCS might have beneficial effects on improving mobility and muscle strength of lower limb among individuals with stroke. Future studies with larger sample sizes and an adequate follow-up period are needed. PMID- 29439363 TI - Effects of posture and coactivation on corticomotor excitability of ankle muscles. AB - BACKGROUND: The use of transcranial magnetic stimulation (TMS) to evaluate corticomotor excitability of lower limb (LL) muscles can provide insights about neuroplasticity mechanisms underlying LL rehabilitation. However, to date, a majority of TMS studies have focused on upper limb muscles. Posture-related activation is an important under-investigated factor influencing corticomotor excitability of LL muscles. OBJECTIVE: The purpose of this study was to evaluate effects of posture and background activation on corticomotor excitability of ankle muscles. METHODS: Fourteen young neurologically-unimpaired participants (26.1+/-4.1 years) completed the study. TMS-evoked motor evoked potentials (MEPs) were recorded from the tibialis anterior (TA) and soleus during 4 conditions - standing, standing coactivation, sitting, and sitting coactivation. TA and soleus MEP amplitudes were compared during: (1) standing versus sitting;(2) standing coactivation (standing while activating both TA and soleus) versus sitting coactivation; and (3) standing coactivation versus standing. For each comparison, background EMG for TA and soleus were matched. Trial-to-trial coefficient of variation of MEP amplitude and coil-positioning errors were additional dependent variables. RESULTS: No differences were observed in TA or soleus MEP amplitudes during standing versus sitting. Compared to sitting coactivation, larger MEPs were observed during standing coactivation for soleus but not TA. Compared to standing, the standing coactivation task demonstrated larger MEPs and reduced trial-to-trial MEP variability. CONCLUSION: Our findings suggest that incorporation of measurements in standing in future TMS studies may provide novel insights into neural circuits controlling LL muscles. Standing and standing coactivation tasks may be beneficial for obtaining functionally-relevant neuroplasticity assessments of LL musculature. PMID- 29439364 TI - Enhancement of motor learning by focal intermittent theta burst stimulation (iTBS) of either the primary motor (M1) or somatosensory area (S1) in healthy human subjects. AB - BACKGROUND: Motor rehabilitation after brain damage relies on motor re-learning as induced by specific training. Non-invasive brain stimulation (NIBS) can alter cortical excitability and thereby has a potential to enhance subsequent training induced learning. Knowledge about any priming effects of NIBS on motor learning in healthy subjects can help to design targeted therapeutic applications in brain damaged subjects. OBJECTIVE: To examine whether complex motor learning in healthy subjects can be enhanced by intermittent theta burst stimulation (iTBS) to primary motor or sensory cortical areas. METHODS: Eighteen young healthy subjects trained eight different arm motor tasks (arm ability training, AAT) once a day for 5 days using their left non-dominant arm. Except for day 1 (baseline), training was performed after applying an excitatory form of repetitive transcranial magnetic stimulation (iTBS) to either (I) right M1 or (II) S1, or (III) sham stimulation to the right M1. Subjects were randomly assigned to conditions I, II, or III. RESULTS: A principal component analysis of the motor behaviour data suggested eight independent motor abilities corresponding to the 8 trained tasks. AAT induced substantial motor learning across abilities with generalisation to a non-trained test of finger dexterity (Nine-Hole-Peg-Test, NHPT). Participants receiving iTBS (to either M1 or S1) showed better performance with the AAT tasks over the period of training compared to sham stimulation as well as a bigger improvement with the generalisation task (NHPT) for the trained left hand after training completion. CONCLUSION: Priming with an excitatory repetitive transcranial magnetic stimulation as iTBS of either M1 or S1 can enhance motor learning across different sensorimotor abilities. PMID- 29439366 TI - The potential dual role of transcallosal inhibition in post-stroke motor recovery. AB - Up to now, the mechanism of motor impairment and recovery after stroke has been thought to be based on the interhemispheric competition model. According to this model, which assumes that suppressing the excitability of contralesional hemisphere will enhance recovery by reducing transcallosal inhibition (TCI) of the stroke hemisphere, many clinical trials used non-invasive brain stimulation to improve motor function. Despite some positive findings, meta-analysis shows an important source of variability in the results, questioning whether the interhemispheric competition model would be exhaustive enough to explain the positive results or whether other mechanisms could explain the motor effects of inhibitory stimulation in the contralesional hemisphere. The goal of this study was to review the relationship between increased TCI and motor impairment after stroke.A systematic review of clinical studies investigating TCI through transcranial magnetic stimulation (TMS) in stroke patients and the relationship of this metric with motor recovery was then performed. After a literary search in PubMed eleven articles were included. The potential role of several covariates was examined and discussed.Overall, the importance of TCI as a putative mechanism for stimulation of the contralesional hemisphere seems to depend on the baseline motor function. In other words, from evidence coming mostly from chronic patients, modulation of abnormal TCI seems to be useful for patients with good motor function and less important in patients with poor motor function. TCI seems to be negatively correlated with mirror movements of the paretic hand. It can be inferred that suppressing the activity of the contralesional hemisphere could be beneficial for patients with good residual motor function and strong TCI, but not for those with poor motor function and weak TCI. Baseline motor function and measure of TCI should be taken into account for stratification of patients in clinical trials and for the design of customized treatment. PMID- 29439365 TI - Adaptive motor cortex plasticity following grip reconstruction in individuals with tetraplegia. AB - BACKGROUND: Tendon transfer is a surgical technique for restoring upper limb motor control in patients with cervical spinal cord injuries (SCI), and offers a rare window into cortical neuroplasticity following regained arm and hand function. OBJECTIVE: Here, we aimed to examine neuroplasticity mechanisms related to re-established voluntary motor control of thumb flexion following tendon transfer. METHODS: We used functional Magnetic Resonance Imaging (fMRI) to test the hypothesis that restored limb control following tendon transfer is mediated by activation of that limb's area of the primary motor cortex. We examined six individuals with tetraplegia who underwent right-sided surgical grip reconstruction at Sahlgrenska University Hospital, Sweden. All were right-handed males, with a SCI at the C6 or C7 level, and a mean age of 40 years (range = 31 48). The average number of years elapsed since the SCI was 13 (range = 6-26). Six right-handed gender- and age-matched control subjects were included (mean age 39 years, range = 29-46). Restoration of active thumb flexion in patients was achieved by surgical transfer of one of the functioning elbow flexors (brachioradialis), to the paralyzed thumb flexor (flexor pollicis longus). We studied fMRI responses to isometric right-sided elbow flexion and key pinch, and examined the cortical representations within the left hemisphere somatomotor cortex a minimum of one year after surgery. RESULTS: Cortical activations elicited by elbow flexion did not differ in topography between patients and control participants. However, in contrast to control participants, patients' cortical thumb flexion activations were not topographically distinct from their elbow flexion activations. CONCLUSION: This result speaks against a topographic reorganization in which the thumb region regains thumb control following surgical tendon transfer. Instead, our findings suggest a neuroplastic mechanism in which motor cortex resources previously dedicated to elbow flexion adapt to control the thumb. PMID- 29439367 TI - snRPN controls the ability of neurons to regenerate axons. AB - BACKGROUND: Retinal ganglion cells (RGCs) of mammals lose the ability to regenerate injured axons during postnatal maturation, but little is known about the underlying molecular mechanisms. OBJECTIVE: It remains of particular importance to understand the mechanisms of axonal regeneration to develop new therapeutic approaches for nerve injuries. METHODS: Retinas from newborn to adult monkeys (Callithrix jacchus)1 were obtained immediately after death and cultured in vitro. Growths of axons were monitored using microscopy and time-lapse video cinematography. Immunohistochemistry, Western blotting, qRT-PCR, and genomics were performed to characterize molecules associated with axonal regeneration and growth. A genomic screen was performed by using retinal explants versus native and non-regenerative explants obtained from eye cadavers on the day of birth, and hybridizing the mRNA with cross-reacting cDNA on conventional human microarrays. Followed the genomic screen, siRNA experiments were conducted to identify the functional involvement of identified candidates. RESULTS: Neuron-specific human ribonucleoprotein N (snRPN) was found to be a potential regulator of impaired axonal regeneration during neuronal maturation in these animals. In particular, up-regulation of snRPN was observed during retinal maturation, coinciding with a decline in regenerative ability. Axon regeneration was reactivated in snRPN knockout retinal ex vivo explants of adult monkey. CONCLUSION: These results suggest that coordinated snRPN-driven activities within the neuron-specific ribonucleoprotein complex regulate the regenerative ability of RGCs in primates, thereby highlighting a potential new role for snRPN within neurons and the possibility of novel postinjury therapies. PMID- 29439369 TI - Repetitive sessions of tDCS to improve naming in post-stroke aphasia: Insights from an individual patient data (IPD) meta-analysis. AB - OBJECTIVES: Small clinical trials reported that repetitive sessions of tDCS could improve naming abilities in post-stroke aphasia. However, systematic meta analyses found no effect, but all of these analyses pooled data from both single and repetitive sessions at the group level. The aim of this paper was to perform a meta-analysis based on individual patient data to explore the effects of repetitive tDCS sessions on naming in post-stroke aphasia and in prespecified subgroups. METHODS: We searched for published sham-controlled trials using the keywords "aphasia OR language" AND "transcranial direct current stimulation OR tDCS" AND "stroke". We computed an active and sham improvement ratio by dividing the difference between naming scores after and before the active or sham sessions, respectively, by the total number of picture items. Because of heterogeneity (I2 = 66%, p: 0.002), we used random-effects models to estimate the standardized mean difference (SMD) for the naming outcome. We then analyzed subgroups according to number of sessions, polarity, side/location of the active electrode, post-stroke delay, aphasia severity and comprehension disorders. RESULTS: Seven eligible studies were identified, including 68 chronic stroke patients. tDCS was beneficial on naming ability (35% +/-34% in the active vs. 25% +/-37% in the sham condition). An SMD of 0.8 (95% CI: 0.27-1.33) was found for the naming outcome. Additionally, there was a dose-dependent effect (5 vs. >5 sessions). We also demonstrated a prevalence of anodal vs. cathodal condition and left vs. right targeting electrode. Finally, repetitive sessions were beneficial regardless of the severity of aphasia, comprehension disorders or post-stroke delay. CONCLUSION: Repetitive sessions of tDCS are likely to be valuable in enhancing naming accuracy in post-stroke aphasia. PMID- 29439368 TI - Systemic administration of donepezil attenuates the efficacy of environmental enrichment on neurobehavioral outcome after experimental traumatic brain injury. AB - BACKGROUND: The acetylcholinesterase inhibitor (AChEI) donepezil (DON) is recommended as a potential treatment for cognition after clinical traumatic brain injury (TBI) and therefore may be prescribed as an adjunct therapy during rehabilitation. However, a dose-response study evaluating DON after a controlled cortical impact (CCI) injury in rats did not reveal cognitive benefits. OBJECTIVE: The aim of this study was to determine the effect of DON on behavioral and histological outcome when combined with environmental enrichment (EE), a preclinical model of neurorehabilitation. It was hypothesized that the combined treatments would produce a synergistic effect yielding improved recovery over neurorehabilitation alone. METHODS: Isoflurane-anesthetized adult male rats received a CCI or sham injury and then were randomly assigned to EE or standard (STD) housing plus systemic injections of DON (0.25 mg/kg) or vehicle (VEH; 1.0 mL/kg saline) once daily for 19 days beginning 24 hr after injury. Function was assessed by established motor and cognitive tests on post-injury days 1-5 and 14 19, respectively. Cortical lesion volume was quantified on day 19. RESULTS: DON was ineffective when administered alone. In contrast, EE conferred significant motor and cognitive benefits, and reduced cortical lesion volume vs. STD (p < 0.05). Combining the therapies weakened the efficacy of rehabilitation as revealed by diminished motor and cognitive recovery in the TBI+EE+DON group vs. the TBI+EE+VEH group (p < 0.05). CONCLUSION: These data replicate previous findings showing that EE is beneficial and DON is ineffective after CCI and add to the literature a novel and unpredicted finding that supports neither the hypothesis nor the use of DON for TBI. Investigation of other AChEIs after CCI injury is necessary to gain further insight into the value of this therapeutic strategy. PMID- 29439370 TI - The biomechanical analysis of three-dimensional distal radius fracture model with different fixed splints. AB - BACKGROUND: The distal radius fracture is one of the common clinical fractures. At present, there are no reports regarding application of the finite element method in studying the mechanism of Colles fracture and the biomechanical behavior when using splint fixation. OBJECTIVE: To explore the mechanism of Colles fracture and the biomechanical behavior when using different fixed splints. METHODS: Based on the CT scanning images of forearm for a young female volunteer, by using model construction technology combined with RPOE and ANSYS software, a 3-D distal radius fracture forearm finite element model with a real shape and bioactive materials is built. The material tests are performed to obtain the mechanical properties of the paper-based splint, the willow splint and the anatomical splint. The numerical results are compared with the experimental results to verify the correctness of the presented model. Based on the verified model, the stress distribution of different tissues are analyzed. Finally, the clinical tests are performed to observe and verify that the anatomical splint is the best fit for human body. RESULTS: Using the three kinds of splints, the transferred bone stress focus on the distal radius and ulna, which is helpful to maintain the stability of fracture. Also the stress is accumulated in the distal radius which may be attributed to flexion position. Such stress distribution may be helpful to maintain the ulnar declination. By comparing the simulation results with the experimental observations, the anatomical splint has the best fitting to the limb, which can effectively avoid the local compression. CONCLUSION: The anatomical splint is the most effective for fixing and curing the fracture. The presented model can provide theoretical basis and technical guide for further investigating mechanism of distal radius fracture and clinical application of anatomical splint. PMID- 29439371 TI - Automated triage parameters estimation from ECG. AB - Low-cost biosensors combined with low-cost portable devices can be very useful in time critical situations of mass casualties, when fast triage procedure must be attained. A methodology that uses ECG to derive the vital parameters (heart rate and respiratory rate) needed for the triage procedure is presented and it is aimed to leverage affordable low-cost equipment that can be easily utilized by urgent medical units or even volunteers in events of considerable number of injured civilians. The methodology relies on selected well-known and published algorithms for heart rate and respiratory rate derivation from a given ECG signal. It consists of methods for R-wave detection, kurtosis computation, smoothing, and finding peaks. The proposed approach is shown to offer a good trade-off between the accurate measurement of the parameters and their fast derivation. It has been evaluated by using a publicly available database. Its robustness is measured in terms of accuracy estimation, showing a sensitivity of 0.87 for heart rate and 0.74 for respiratory rate, a sensitivity of 0.76 considering the triage process and an average-case execution time of 0.02 seconds, making it suitable for real-time applications. PMID- 29439372 TI - Work-related threats and violence in human service sectors: The importance of the psycho-social work environment examined in a multilevel prospective study. AB - BACKGROUND: Threats and violence at work are major concerns for employees in many human service sectors. The prevention of work-related violence is a major challenge for employees and management. OBJECTIVE: The purpose of this study was to identify prospective associations between psycho-social work environment and work-related threats and violence in four high risk human service sectors. METHODS: Questionnaire data was collected from 3011 employees working at psychiatric wards, in the elder sector, in the Prison and Probation Service and at Special Schools. Associations between psycho-social work environment and work related violence and threats were then studied using a one-year follow-up design and multilevel logistic regression analyses. RESULTS: The analyses showed that quantitative demands, high emotional demands, low level of influence over own work-situation, low predictability, low rewards at work, low role clarity, many role conflicts, many work-family conflicts and low organizational justice had statistically significant associations with high levels of work-related threats. Furthermore, high emotional demands, low predictability, low role clarity, many role conflicts, many work-family conflicts, low supervisor quality and low support from nearest supervisor had statistically significant associations with high levels of work-related violence. Finally, across the four sectors both similar and different associations between psycho-social work environment and work-related violence and threats were found. CONCLUSION: The results of the study underline the importance of including the psycho-social work environment as a supplement to existing violence prevention methods and interventions aimed at reducing work-related violence and threats. PMID- 29439373 TI - Factors associated with high physical exertion during manual lifting: Cross sectional study among 200 blue-collar workers. AB - BACKGROUND: High physical exertion during work is a risk factor for back pain and long-term sickness absence. OBJECTIVE: To investigate which factors are associated with physical exertion during manual lifting. METHODS: From 14 workplaces across Denmark, 200 blue-collar workers reported perceived physical exertion (Borg-CR10) during manual lifting from floor to table height of 5, 10, 20 and 30 kg at the beginning and end of the working day. The workers also responded to a questionnaire and went through testing of isometric back muscle strength. Associations were modelled using logistic regression analysis controlled for various confounders. The outcome was dichotomized into low (0-4) and high (5-10) physical exertion. RESULTS: Gender (OR 8.57 [95% CI 4.46-16.46] for women), load (OR 4.22 [95% CI 3.58-4.97] for each 5-kg increase), back muscle strength (OR 0.43 [95% CI 0.23-0.83] for high), and back pain intensity (OR 2.80 [95% CI 1.43-5.48] for high) were associated with high perceived physical exertion. Age, smoking, Body Mass Index (BMI), and time of the day were not associated with physical exertion. CONCLUSIONS: Gender, load, back muscle strength and back pain influence physical exertion during manual lifting in blue collar workers. These factors should be considered when planning work with manual lifting for individual workers. PMID- 29439375 TI - Burnout and work-related stress in Italian rehabilitation professionals: A comparison of physiotherapists, speech therapists and occupational therapists. AB - BACKGROUND: Healthcare workers are exposed to work related stresses that significantly increase their risk of burnout. OBJECTIVE: To evaluate and compare burnout and work related stress levels in three categories of health professionals: physiotherapists, speech therapists and occupational therapists. METHODS: A convenience sample of 391 health professionals participated, including 210 physiotherapists, 101 speech therapists and 80 occupational therapists. We collected general socio-demographic information and administered the standardized Italian version of the Maslach Burnout Inventory (MBI) and the Health and Safety Executive (HSE) Management Standards Indicator Tool. RESULTS: We found the proportion of professionals with high-risk scores in the three dimensions of the MBI to be as follows: Emotional Exhaustion 32%, Depersonalisation 13% and Personal Accomplishment 9%. Overall, 14% of participants were at high risk of burnout. No significant differences were found between the three professional categories. Five subscales of the HSE were associated with burnout: Control (p < 0.01), Management support (p < 0.01), Relationship (p < 0.05), Role (p < 0.01), and Change (p < 0.05). CONCLUSIONS: Like all health care workers, rehabilitation professionals are at a high risk of burnout. There are common mechanisms underlying burnout in the different professional groups investigated. Further research in occupational health in rehabilitation settings is needed to prevent burnout. PMID- 29439374 TI - Important exposure controls for protection against antineoplastic agents: Highlights for oncology health care workers. AB - BACKGROUND: A great number of antineoplastic drugs (ANPDs) are used globally in cancer treatment. Due to their adverse health effects, occupational exposure to ANPDs is considered a potential health risk to health care workers. OBJECTIVE: The current study aimed to evaluate safe-handling practices of ANPDs, exposure controls, and adverse health implications for health care providers exposed to ANDPs. METHODS: Prevention measures, including engineering, administrative, and work practice controls, as well as personal protective equipment (PPE), were recorded daily through a questionnaire for six weeks. Acute adverse health effects experienced by health care workers were also documented. RESULTS: The implemented exposure controls for preparation, administration, cleaning, and waste disposal were not in accordance with the safe handling guidelines. Central nervous system disorders (26.33%) were the most frequent acute adverse effects reported by health care workers. A significant correlation was found between the number of experienced adverse effects and handling characteristics, including the number of preparations (r = 0.38, p < 0.05), dose, and the number of prepared drugs (r = 0.46, p < 0.01 and 0.39, p < 0.05), and working hours in different locations of oncology setting for six weeks (preparation room: r = 0.38, P < 0.05, treatment room: r = 0.46, P < 0.01, patient room: r = 0.63, P < 0.01, and station: r = 0.68, P < 0.01). CONCLUSIONS: Due to inadequate control measures, oncology health care workers were in danger of exposure to ANPDs and experienced acute adverse health effects. Implementation of appropriate exposure controls is required to prevent occupational exposure to ANPDs. PMID- 29439376 TI - Should we consider steps with variable height for a safer stair negotiation in older adults? AB - BACKGROUND: Effects of exercise on foot clearances are important. In older adults variations in foot clearances during walking may lead to a fall, but there is a lack of information concerning stair negotiation in older adults. Whether a condition of post exercise changes foot clearances between steps of a staircase in older adults still unknown. OBJECTIVE: To determine differences in clearances when older adults negotiate different steps of a staircase before and after a session of aerobic exercise. METHODS: Kinematics data from 30 older adults were acquired and the toe and heel clearances were determined for each step. Clearances were compared between the steps. RESULTS: Smaller clearances were found at the highest step during ascending and descending, which was not changed by exercise. Smaller clearances suggest higher risk of tripping at the top of the staircase, regardless of exercise. CONCLUSION: A smaller step at the top of a short flight of stairs could reduce chances of tripping in older adults. It suggests that steps with variable height could make stair negotiation safer in older adults. This hypothesis should be tested in further studies. PMID- 29439377 TI - Recovery, work-life balance and work experiences important to self-rated health: A questionnaire study on salutogenic work factors among Swedish primary health care employees. AB - BACKGROUND: There is a lack of information on positive work factors among health care workers. OBJECTIVE: To explore salutogenic work-related factors among primary health care employees. METHOD: Questionnaire to all employees (n = 599) from different professions in public and private primary health care centers in one health care district in Sweden. The questionnaire, which had a salutogenic perspective, included information on self-rated health from the previously validated SHIS (Salutogenic Health Indicator Scale), psychosocial work environment and experiences, recovery, leadership, social climate, reflection and work-life balance. RESULTS: The response rate was 84%. A multivariable linear regression model, with SHIS as the dependent variable, showed three significant predictors. Recovery had the highest relationship to SHIS (beta= 0.34), followed by experience of work-life balance (beta= 0.25) and work experiences (beta= 0.20). Increased experience of recovery during working hours related to higher self-rated health independent of recovery outside work. CONCLUSION: Individual experiences of work, work-life balance and, most importantly, recovery seem to be essential areas for health promotion. Recovery outside the workplace has been studied previously, but since recovery during work was shown to be of great importance in relation to higher self-rated health, more research is needed to explore different recovery strategies in the workplace. PMID- 29439378 TI - The experience of seeking, gaining and maintaining employment after traumatic spinal cord injury and the vocational pathways involved. AB - BACKGROUND: Vocational potential in people with spinal cord injury (SCI) are unrealised with rates of employment substantially lower than in the labour force participation of the general population and the pre-injury employment rates. OBJECTIVES: To understand the experience and pathway of people achieving employment outcome after traumatic spinal cord injury by; classifying participants into employment outcome groups of stable, unstable and without employment; identifying pre and post-injury pathways for participants in each group and, exploring the experiences of people of seeking, gaining and maintaining employment. METHODS: Thirty-one participants were interviewed. Mixed methods approach including interpretive phenomenological analysis and vocational pathway mapping of quantitative data. RESULTS: The most common pathway identified was from study and work pre-injury to stable employment post-injury. Four super ordinate themes were identified from the interpretive phenomenological analysis; expectations of work, system impacts, worker identity and social supports. Implications for clinical practice include fostering cultural change, strategies for system navigation, promotion of worker identity and optimal use of social supports. CONCLUSIONS: The findings increase insight and understanding of the complex experience of employment after spinal cord injury. There is opportunity to guide experimental research, policy development and education concerning the complexity of the return to work experience and factors that influence pathways. PMID- 29439379 TI - Cross-cultural adaptation and validation of the Depression, Anxiety and Stress Scale-21 (DASS-21) in the Korean working population. AB - BACKGROUND: In this study, we developed a new Korean translation for the shortened version of the Depression, Anxiety, and Stress Scale (DASS-21) and examined its psychometric properties in a Korean working population. OBJECTIVE: To develop a new Korean version of the DASS-21 and test its psychometric properties specific to the Korean working population. METHODS: The DASS-21 was translated to the Korean language in accordance with scientific guidelines for cross-cultural adaptation. A total of 228 general workers from Korea then completed the newly translated version of the DAS S-21 and its psychometric properties were evaluated. RESULTS: Most of the questionnaire items were correctly loaded on the proposed scales of the original questionnaire. Excellent internal consistency and measurement consistency over a one week interval were obtained for all scales (Cronbach's alpha; 0.87, 83, and 83, and ICC (2, 1); 0.84, 0.94, and 0.89 for depression, anxiety and stress scales, respectively). All three scales were negatively associated with the level of life satisfaction (p < 0.05). CONCLUSIONS: The new Korean version of DASS-21 has shown excellent validity and reliability of measurement in the Korean working population. Organizations investigating the prominent health issue of affective disorders in Korean workers can use this instrument with confidence. PMID- 29439380 TI - Community service coordination for minority clients with disabilities: 10-step guidelines. AB - Although many resources are available to rehabilitation counselors to utilizing community resources for minority clients with disabilities, guidelines specific to service allocation are not easily available. The purpose of this article is to provide rehabilitation counselors with a simple, modifiable service allocation template for this purpose. A 10-step referral making process with real-world examples is presented. Special attention is given to ways in which counselors can appropriately allocate and monitor services when working with minority clients, followed by a case study demonstrating how the model may be applied. PMID- 29439381 TI - Managers' attitudes to their older employees: A cross-sectional study. AB - BACKGROUND: Societal interest in enabling older workers to prolong their working life has increased in recent years due to demographic change. Managers have a key role in extending working life among employees, because they control the organisation, work environment and potential measures enabling older workers to extend their working life. OBJECTIVE: To examine managers' attitudes to their older workers. METHOD: A cross-sectional study based on a questionnaire answered by 905 managers working in different municipal departments in Sweden. RESULTS: Managers' attitude to their older workers' retirement time appeared to be associated with their own retirement planning. Managers who themselves wanted to work beyond 66 years considered it more important to keep older workers beyond that age than managers planning to retire at 66. The managers reported that older people were more careful, possessed experiences, skills and life knowledge that were useful in the workplace and helped guide new employees and younger employees. On the other hand, the majority of managers agreed with the stereotypical claim that older people are slower, resistant to change, less well educated and hostile to technology. CONCLUSION: The study stated that the managers' attitude to their own retirement planning affected their attitude to the retirement age for their older employees. This is important to consider in the debate of delayed retirement, and to perform activities and incentives in the society to change those attitudes if more people should get the possibility to an extended working life. Additional, almost 50% of the managers surveyed recognised possible measures for adapting work tasks to suit their ageing employees. However, only 5% of managers reported the existence of organisational measures targeted at promoting a sustainable work situation for older employees in their municipal department. The managers were interested in retaining older employees mainly if those older employees had some specific skills that were needed by the department, and not in general. PMID- 29439382 TI - The impact of occupational splash, sharps and needlestick injuries (SSNIs) on the quality of life of healthcare workers in a Kenyan university hospital. AB - BACKGROUND: Infection as a consequence of splash sharps and needlestick injuries (SSNIs) is a hazard faced by healthcare workers. Little is known about the impact this has on quality of life particularly in countries where the risk of infection is high. OBJECTIVE: This study aims to describe the impact SSNIs have on the quality of life of healthcare workers in Kenya, where blood borne illness prevalence is high. METHODS: A hospital-wide survey of a facility in Nairobi was conducted. Data was collected online from at risk healthcare workers using Burckhardt and Anderson's Quality of Life Scale (QOLS) and a 10-item symptoms questionnaire. RESULTS: Of the 416 participants, 192 (46.2%) had experienced SSNIs. Their mean QOLS scores were considerably lower than that predicted for a healthy population. The relationship between symptoms and QOLS scores showed a strong positive correlation (Pearson's r = 0.753). Tests of association between QOLS scores and SSNI type, anti-retroviral (ARV) drug use, educational level and staff cadre revealed significant association (p < 0.05). However, on key demographic variables, the association was non-dependent, indicating that the impact was felt similarly by many staff. CONCLUSIONS: SSNIs clearly impact on healthcare workers quality of life. Hospital management should ensure measures are taken to reduce SSNIs and provide appropriate personal protection equipment. For staff experiencing an SSNI, psychological wellbeing should be assessed and appropriate expert help provided. PMID- 29439383 TI - Thermal Behavior and Structural Study of SiO2/Poly(epsilon-caprolactone) Hybrids Synthesized via Sol-Gel Method. AB - SiO2-based organic-inorganic hybrids (OIHs) are versatile materials whose properties may change significantly because of their thermal treatment. In fact, after their preparation at low temperature by the sol-gel method, they still have reactive silanol groups due to incomplete condensation reactions that can be removed by accelerating these processes upon heating them in controlled experimental conditions. In this study, the thermal behavior of pure SiO2 and four SiO2-based OIHs containing increasing amount (6, 12, 24 and 50 wt %) of poly(epsilon-caprolactone) (PCL) has been studied by simultaneous thermogravimetry (TG) and differential scanning calorimetry (DSC). The FTIR analysis of the gas mixture evolved at defined temperatures from the samples submitted to the TG experiments identified the mechanisms of thermally activated processes occurring upon heating. In particular, all samples already release ethanol at low temperature. Moreover, thermal degradation of PCL takes place in the richest-PCL sample, leading to 5-hexenoic acid, H2O, CO2, CO and epsilon caprolactone. After the samples' treatment at 450, 600 and 1000 degrees C, the X ray diffraction (XRD) spectra revealed that they were still amorphous, while the presence of cristobalite is found in the richest-PCL material. PMID- 29439384 TI - Antibody Responses to Marburg Virus in Egyptian Rousette Bats and Their Role in Protection against Infection. AB - Egyptian rousette bats (ERBs) are reservoir hosts for the Marburg virus (MARV). The immune dynamics and responses to MARV infection in ERBs are poorly understood, and limited information exists on the role of antibodies in protection of ERBs against MARV infection. Here, we determine the duration of maternal immunity to MARV in juvenile ERBs, and evaluate the duration of the antibody response to MARV in bats naturally or experimentally infected with the virus. We further explore whether antibodies in previously naturally exposed bats is fully protective against experimental reinfection with MARV. Maternal immunity was lost in juvenile ERBs by 5 months of age. Antibodies to MARV remained detectable in 67% of experimentally infected bats approximately 4 months post inoculation (p.i.), while antibodies to MARV remained present in 84% of naturally exposed bats at least 11 months after capture. Reinfection of seropositive ERBs with MARV produced an anamnestic response from day 5 p.i. Although PCR-defined viremia was present in 73.3% of reinfected ERBs, replicating virus was recovered from the serum of only one bat on day 3 p.i. The negative PCR results in the salivary glands, intestines, bladders and reproductive tracts of reinfected bats, and the apparent absence of MARV in the majority of swabs collected from these bats suggest that reinfection may only play a minor role in the transmission and maintenance of MARV amongst ERBs in nature. PMID- 29439386 TI - Towards Phosphate Detection in Hydroponics Using Molecularly Imprinted Polymer Sensors. AB - An interdigitated electrode sensor was designed and microfabricated for measuring the changes in the capacitance of three phosphate selective molecularly imprinted polymer (MIP) formulations, in order to provide hydroponics users with a portable nutrient sensing tool. The MIPs investigated were synthesised using different combinations of the functional monomers methacrylic acid (MAA) and N allylthiourea, against the template molecules diphenyl phosphate, triethyl phosphate, and trimethyl phosphate. A cross-interference study between phosphate, nitrate, and sulfate was carried out for the MIP materials using an inductance, capacitance, and resistance (LCR) meter. Capacitance measurements were taken by applying an alternating current (AC) with a potential difference of 1 V root mean square (RMS) at a frequency of 1 kHz. The cross-interference study demonstrated a strong binding preference to phosphate over the other nutrient salts tested for each formulation. The size of template molecule and length of the functional monomer side groups also determined that a short chain functional monomer in combination with a template containing large R-groups produced the optimal binding site conditions when synthesising a phosphate selective MIP. PMID- 29439385 TI - ALV Integration-Associated Hypomethylation at the TERT Promoter Locus. AB - Avian leukosis virus (ALV) is a simple retrovirus that can induce B-cell lymphoma in chicken(s) and other birds by insertional mutagenesis. The promoter region of telomerase reverse transcriptase (TERT) has been identified as an important integration site for tumorigenesis. Tumors with TERT promoter integrations are associated with increased TERT expression. The mechanism of this activation is still under investigation. We asked whether insertion of proviral DNA perturbs the epigenome of the integration site and, subsequently, impacts the regulation of neighboring genes. DNA cytosine methylation, which generally acts to suppress transcription, is one major form of epigenetic regulation. In this study, we examine allele-specific methylation patterns of genomic DNA from chicken tumors by bisulfite sequencing. We observed that alleles with TERT promoter integrations are associated with decreased methylation in the host genome near the site of integration. Our observations suggest that insertion of ALV in the TERT promoter region may induce expression of TERT through inhibition of maintenance methylation in the TERT promoter region. PMID- 29439387 TI - The Macular Carotenoids are Associated with Cognitive Function in Preadolescent Children. AB - The macular carotenoids lutein (L) and zeaxanthin (Z) are obtained via diet and accumulate in the central retina where they are referred to as macular pigment. The density of this biomarker (macular pigment optical density; MPOD) has been positively correlated with cognitive functioning via measures of global cognition, processing speed, and visual-spatial abilities, among others. Although improvements in cognitive function have been found in adults, much less is known about how L and Z intake may support or improve cognitive functioning during periods of rapid developmental change, such as childhood and pre-adolescence. This study examined the relationship between MPOD and cognitive functioning in 51 7-13-year-old children (51% female). MPOD was measured using heterochromatic flicker photometry (HFP) optimized for this age group. Cognitive function was assessed using the Woodcock-Johnson III (composite standard scores were obtained for Brief Intellectual Ability, Verbal Ability, Cognitive Efficiency, Processing Speed, and Executive Processes). In this sample, MPOD was significantly related to Executive Processes, r(47) = 0.288, p < 0.05, and Brief Intellectual Ability, r(47) = 0.268, p < 0.05. The relationship to Cognitive Efficiency was positive and trending but not significant, r(49) = 0.206, p = 0.074. In general, these data are consistent with those of adults showing a link between higher carotenoid status and improved cognitive functioning. PMID- 29439388 TI - Inhibitory Effect of Flavonolignans on the P2Y12 Pathway in Blood Platelets. AB - Adenosine diphosphate (ADP) is the major platelet agonist, which is important in the shape changes, stability, and growth of the thrombus. Platelet activation by ADP is associated with the G protein-coupled receptors P2Y1 and P2Y12. The pharmacologic blockade of the P2Y12 receptor significantly reduces the risk of peripheral artery disease, myocardial infarction, ischemic stroke, and vascular death. Recent studies demonstrated the inhibition of ADP-induced blood platelet activation by three major compounds of the flavonolignans group: silybin, silychristin, and silydianin. For this reason, the aim of the current work was to verify the effects of silybin, silychristin, and silydianin on ADP-induced physiological platelets responses, as well as mechanisms of P2Y12-dependent intracellular signal transduction. We evaluated the effect of tested flavonolignans on ADP-induced blood platelets' aggregation in platelet-rich plasma (PRP) (using light transmission aggregometry), adhesion to fibrinogen (using the static method), and the secretion of PF-4 (using the ELISA method). Additionally, using the double labeled flow cytometry method, we estimated platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. We demonstrated a dose-dependent reduction of blood platelets' ability to perform ADP-induced aggregation, adhere to fibrinogen, and secrete PF-4 in samples treated with flavonolignans. Additionally, we observed that all of the tested flavonolignans were able to increase VASP phosphorylation in blood platelets samples, which is correlated with P2Y12 receptor inhibition. All of these analyses show that silychristin and silybin have the strongest inhibitory effect on blood platelet activation by ADP, while silydianin also inhibits the ADP pathway, but to a lesser extent. The results obtained in this study clearly demonstrate that silybin, silychristin, and silydianin have inhibitory properties against the P2Y12 receptor and block ADP-induced blood platelet activation. PMID- 29439389 TI - Early-Life Exposure to Non-Nutritive Sweeteners and the Developmental Origins of Childhood Obesity: Global Evidence from Human and Rodent Studies. AB - Non-nutritive sweeteners (NNS) are increasingly consumed by children and pregnant women around the world, yet their long-term health impact is unclear. Here, we review an emerging body of evidence suggesting that early-life exposure to NNS may adversely affect body composition and cardio-metabolic health. Some observational studies suggest that children consuming NNS are at increased risk for obesity-related outcomes; however, others find no association or provide evidence of confounding. Fewer studies have examined prenatal NNS exposure, with mixed results from different analytical approaches. There is a paucity of RCTs evaluating NNS in children, yielding inconsistent results that can be difficult to interpret due to study design limitations (e.g., choice of comparator, multifaceted interventions). The majority of this research has been conducted in high-income countries. Some rodent studies demonstrate adverse metabolic effects from NNS, but most have used extreme doses that are not relevant to humans, and few have distinguished prenatal from postnatal exposure. Most studies focus on synthetic NNS in beverages, with few examining plant-derived NNS or NNS in foods. Overall, there is limited and inconsistent evidence regarding the impact of early life NNS exposure on the developmental programming of obesity and cardio metabolic health. Further research and mechanistic studies are needed to elucidate these effects and inform dietary recommendations for expectant mothers and children worldwide. PMID- 29439390 TI - Pathogenicity Islands Distribution in Non-O157 Shiga Toxin-Producing Escherichia coli (STEC). AB - Shiga toxin-producing Escherichia coli (STEC) are foodborne pathogens associated with outbreaks and hemolytic-uremic syndrome. Cattle and meat foods are the main reservoir and infection source, respectively. Pathogenicity islands (PAIs) play an important role in STEC pathogenicity, and non-locus of the enterocyte effacement(LEE) effector (nle) genes present on them encode translocated substrates of the type III secretion system. A molecular risk assessment based on the evaluation of the nle content has been used to predict which STEC strains pose a risk to humans. The goal was to investigate the distribution of the PAIs OI (O-island)-36 (nleB2, nleC, nleH1-1, nleD), OI-57 (nleG2-3, nleG5-2, nleG6-2), OI-71 (nleA, nleF, nleG, nleG2-1, nleG9, nleH1-2) and OI-122 (ent/espL2, nleB, nleE, Z4321, Z4326, Z4332, Z4333) among 204 clinical, food and animal isolates belonging to 52 non-O157:H7 serotypes. Differences in the frequencies of genetic markers and a wide spectrum of PAI virulence profiles were found. In most LEE negative strains, only module 1 (Z4321) of OI-122 was present. However, some unusual eae-negative strains were detected, which carried other PAI genes. The cluster analysis, excluding isolates that presented no genes, defined two major groups: eae-negative (determined as seropathotypes (SPTs) D, E or without determination, isolated from cattle or food) and eae-positive (mostly identified as SPTs B, C, or not determined). PMID- 29439391 TI - Application of Nanoparticle Technology to Reduce the Anti-Microbial Resistance through beta-Lactam Antibiotic-Polymer Inclusion Nano-Complex. AB - Biocompatible polymeric materials with potential to form functional structures in association with different therapeutic molecules have a high potential for biological, medical and pharmaceutical applications. Therefore, the capability of the inclusion of nano-Complex formed between the sodium salt of poly(maleic acid alt-octadecene) and a beta-lactam drug (ampicillin trihydrate) to avoid the chemical and enzymatic degradation and enhance the biological activity were evaluated. PAM-18Na was produced and characterized, as reported previously. The formation of polymeric hydrophobic aggregates in aqueous solution was determined, using pyrene as a fluorescent probe. Furthermore, the formation of polymer-drug nano-complexes was characterized by Differential Scanning Calorimetry-DSC, viscometric, ultrafiltration/centrifugation assays, zeta potential and size measurements were determined by dynamic light scattering-DLS. The PAM-18Na capacity to avoid the chemical degradation was studied through stress stability tests. The enzymatic degradation was evaluated from a pure beta-lactamase, while the biological degradation was determined by different beta-lactamase producing Staphylococcus aureus strains. When ampicillin was associated with PAM-18Na, the half-life time in acidic conditions increased, whereas both the enzymatic degradation and the minimum inhibitory concentration decreased to a 90 and 75%, respectively. These results suggest a promissory capability of this polymer to protect the beta-lactam drugs against chemical, enzymatic and biological degradation. PMID- 29439392 TI - The Uncertain Geographic Context Problem in the Analysis of the Relationships between Obesity and the Built Environment in Guangzhou. AB - Traditionally, static units of analysis such as administrative units are used when studying obesity. However, using these fixed contextual units ignores environmental influences experienced by individuals in areas beyond their residential neighborhood and may render the results unreliable. This problem has been articulated as the uncertain geographic context problem (UGCoP). This study investigates the UGCoP through exploring the relationships between the built environment and obesity based on individuals' activity space. First, a survey was conducted to collect individuals' daily activity and weight information in Guangzhou in January 2016. Then, the data were used to calculate and compare the values of several built environment variables based on seven activity space delineations, including home buffers, workplace buffers (WPB), fitness place buffers (FPB), the standard deviational ellipse at two standard deviations (SDE2), the weighted standard deviational ellipse at two standard deviations (WSDE2), the minimum convex polygon (MCP), and road network buffers (RNB). Lastly, we conducted comparative analysis and regression analysis based on different activity space measures. The results indicate that significant differences exist between variables obtained with different activity space delineations. Further, regression analyses show that the activity space delineations used in the analysis have a significant influence on the results concerning the relationships between the built environment and obesity. The study sheds light on the UGCoP in analyzing the relationships between obesity and the built environment. PMID- 29439393 TI - Low-Cost Wireless Temperature Measurement: Design, Manufacture, and Testing of a PCB-Based Wireless Passive Temperature Sensor. AB - Low-cost wireless temperature measurement has significant value in the food industry, logistics, agriculture, portable medical equipment, intelligent wireless health monitoring, and many areas in everyday life. A wireless passive temperature sensor based on PCB (Printed Circuit Board) materials is reported in this paper. The advantages of the sensor include simple mechanical structure, convenient processing, low-cost, and easiness in integration. The temperature sensitive structure of the sensor is a dielectric-loaded resonant cavity, consisting of the PCB substrate. The sensitive structure also integrates a patch antenna for the transmission of temperature signals. The temperature sensing mechanism of the sensor is the dielectric constant of the PCB substrate changes with temperature, which causes the resonant frequency variation of the resonator. Then the temperature can be measured by detecting the changes in the sensor's working frequency. The PCB-based wireless passive temperature sensor prototype is prepared through theoretical design, parameter analysis, software simulation, and experimental testing. The high- and low-temperature sensing performance of the sensor is tested, respectively. The resonant frequency decreases from 2.434 GHz to 2.379 GHz as the temperature increases from -40 degrees C to 125 degrees C. The fitting curve proves that the experimental data have good linearity. Three repetitive tests proved that the sensor possess well repeatability. The average sensitivity is 347.45 KHz / C from repetitive measurements conducted three times. This study demonstrates the feasibility of the PCB-based wireless passive sensor, which provides a low-cost temperature sensing solution for everyday life, modern agriculture, thriving intelligent health devices, and so on, and also enriches PCB product lines and applications. PMID- 29439395 TI - Effectiveness and Safety of a Probiotic-Mixture for the Treatment of Infantile Colic: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial with Fecal Real-Time PCR and NMR-Based Metabolomics Analysis. AB - INTRODUCTION: To investigate the effectiveness and the safety of a probiotic mixture (Vivomixx(r), Visbiome(r), DeSimone Formulation(r); Danisco-DuPont, Madison, WI, USA) for the treatment of infantile colic in breastfed infants, compared with a placebo. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in exclusively breastfed infants with colic, randomly assigned to receive a probiotic-mixture or a placebo for 21 days. A structured diary of gastrointestinal events of the infants was given to the parents to complete. Samples of feces were also collected to evaluate microbial content and metabolome using fecal real-time polymerase chain reaction (qPCR) and Nuclear magnetic resonance (NMR)-based analysis. Study registered at ClinicalTrials.gov (NCT01869426). RESULTS: Fifty-three exclusively-breastfed infants completed three weeks of treatment with a probiotic-mixture (n = 27) or a placebo (n = 26). Infants receiving the probiotic-mixture had less minutes of crying per day throughout the study by the end of treatment period (68.4 min/day vs. 98.7 min/day; p = 0.001). A higher rate of infants from the probiotic-mixture group responded to treatment (defined by reduction of crying times of >=50% from baseline), on day 14, 12 vs. 5 (p = 0.04) and on day 21, 26 vs. 17 (p = 0.001). A higher quality of life, assessed by a 10-cm visual analogue scale, was reported by parents of the probiotic-mixture group on day 14, 7.1 +/- 1.2 vs. 7.7 +/- 0.9 (p = 0.02); and on day 21, 6.7 +/- 1.6 vs. 5.9 +/- 1.0 (p = 0.001). No differences between groups were found regarding anthropometric data, bowel movements, stool consistency or microbiota composition. Probiotics were found to affect the fecal molecular profile. No adverse events were reported. CONCLUSIONS: Administration of a probiotic-mixture appears safe and reduces inconsolable crying in exclusively breastfed infants. PMID- 29439396 TI - Functional Magnetic Mesoporous Silica Microparticles Capped with an Azo Derivative: A Promising Colon Drug Delivery Device. AB - Magnetic micro-sized mesoporous silica particles were used for the preparation of a gated material able to release an entrapped cargo in the presence of an azo reducing agent and, to some extent, at acidic pH. The magnetic mesoporous microparticles were loaded with safranin O and the external surface was functionalized with an azo derivative 1 (bearing a carbamate linkage) yielding solid S1. Aqueous suspensions of S1 at pH 7.4 showed negligible safranin O release due to the presence of the bulky azo derivative attached onto the external surface of the inorganic scaffold. However, in the presence of sodium dithionite (azoreductive agent), a remarkable safranin O delivery was observed. At acidic pH, a certain safranin O release from S1 was also found. The pH triggered safranin O delivery was ascribed to the acid-induced hydrolysis of the carbamate moiety that linked the bulky azo derivatives onto the mesoporous inorganic magnetic support. The controlled release behavior of S1 was also tested using a model that simulated the gastro intestinal tract. PMID- 29439394 TI - Carbonic Anhydrase IX (CAIX), Cancer, and Radiation Responsiveness. AB - Carbonic anhydrase IX has been under intensive investigation as a therapeutic target in cancer. Studies demonstrate that this enzyme has a key role in pH regulation in cancer cells, allowing these cells to adapt to the adverse conditions of the tumour microenviroment. Novel CAIX inhibitors have shown efficacy in both in vitro and in vivo pre-clinical cancer models, adversely affecting cell viability, tumour formation, migration, invasion, and metastatic growth when used alone. In co-treatments, CAIX inhibitors may enhance the effects of anti-angiogenic drugs or chemotherapy agents. Research suggests that these inhibitors may also increase the response of tumours to radiotherapy. Although many of the anti-tumour effects of CAIX inhibition may be dependent on its role in pH regulation, recent work has shown that CAIX interacts with several of the signalling pathways involved in the cellular response to radiation, suggesting that pH-independent mechanisms may also be an important basis of its role in tumour progression. Here, we discuss these pH-independent interactions in the context of the ability of CAIX to modulate the responsiveness of cancer to radiation. PMID- 29439397 TI - Re-Arrangements in the Cytoplasmic Distribution of Small RNAs Following the Maternal-to-Zygotic Transition in Drosophila Embryos. AB - Small ribonucleic acids (RNAs) are known to regulate gene expression during early development. However, the dynamics of interaction between small RNAs and polysomes during this process is largely unknown. To investigate this phenomenon, 0-1 h and 7-8 h Drosophila melanogaster embryos were fractionated on sucrose density gradients into four fractions based on A254 reading (1) translationally inactive messenger ribonucleoprotein (mRNP), (2) 60S, (3) monosome, and (4) polysome. Comparative analysis of deep-sequencing reads from fractionated and un fractionated 0-1 h and 7-8 h embryos revealed development-specific co sedimentation pattern of small RNAs with the cellular translation machinery. Although most micro RNAs (miRNAs) did not have a specific preference for any state of the translational machinery, we detected fraction-specific enrichment of a few miRNAs such as dme-miR-1-3p, -184-3p, 5-5p and 263-5p. More interestingly, we observed changes in the subcellular location of a subset of miRNAs in fractionated embryos despite no measurable difference in their amount in unfractionated embryos. Transposon-derived endo small interfering RNAs (siRNAs) were over-expressed in 7-8 h embryos and associated mainly with the mRNP fraction. In contrast, transposon-derived PIWI-interacting RNAs (piRNA), which were more abundant in 0-1 h embryos, co-sedimented primarily with the polysome fractions. These results suggest that there appears to be a complex interplay among the small RNAs with respect to their polysome-cosedimentation pattern during early development in Drosophila melanogaster. PMID- 29439398 TI - A Real-Time Wireless Sweat Rate Measurement System for Physical Activity Monitoring. AB - There has been significant research on the physiology of sweat in the past decade, with one of the main interests being the development of a real-time hydration monitor that utilizes sweat. The contents of sweat have been known for decades; sweat provides significant information on the physiological condition of the human body. However, it is important to know the sweat rate as well, as sweat rate alters the concentration of the sweat constituents, and ultimately affects the accuracy of hydration detection. Towards this goal, a calorimetric based flow rate detection system was built and tested to determine sweat rate in real time. The proposed sweat rate monitoring system has been validated through both controlled lab experiments (syringe pump) and human trials. An Internet of Things (IoT) platform was embedded, with the sensor using a Simblee board and Raspberry Pi. The overall prototype is capable of sending sweat rate information in real time to either a smartphone or directly to the cloud. Based on a proven theoretical concept, our overall system implementation features a pioneer device that can truly measure the rate of sweat in real time, which was tested and validated on human subjects. Our realization of the real-time sweat rate watch is capable of detecting sweat rates as low as 0.15 uL/min/cm2, with an average error in accuracy of 18% compared to manual sweat rate readings. PMID- 29439399 TI - Synthesis and Fluorescent Property Study of Novel 1,8-Naphthalimide-Based Chemosensors. AB - A series of novel mono- and di-substituted N-n-butyl-1,8-naphthalimide derivatives were synthesized simultaneously via a three-step reaction. The single crystal structure of N-n-butyl-4-[N',N'-bis(2',4'-dichlorobenzoyl)ethylamino]-1,8 naphthalimide (3f) was determined. The UV-vis and fluorescence properties of compound 3f were investigated. The 3f showed highly selective and sensitive fluorescence changes response towards Pb2+. A titration of monomer with Pb2+ ion was performed. When Pb2+ ion concentration increased from 0 to 10 eq., the fluorescent intensity of 3f decreased from 199.97 to 48.21. The pH effect on 3f showed that it is stable in a wide range of pH. The results indicated that 3f might be a probe molecule for Pb2+. PMID- 29439400 TI - Use of Ultrasound in Reconditioning by Welding of Tools Used in the Process of Regenerating Rubber. AB - Addressing the problem of reconditioning large parts is of particular importance, due to their value and to the fact that the technologies for their reconditioning are very complex. The tools used to refine regenerated rubber which measure 660 mm in diameter and 2130 mm in length suffer from a rather fast dimensional wear. Within this research, the authors looked for a welding reconditioning procedure that would allow a very good adhesion between the deposited material layer and the base material. In this regard, the MAG (Metal Active Gas) welding process was used, but the ultrasonic activation of the welding process was also considered. Thus, the wire used for welding was activated considering a variation of the frequency of ultrasounds in the range f = 18-22 kHz respectively of the oscillation amplitude A = 30-60 MUm. Under these conditions it was found that the presence of ultrasonic waves during the welding cladding process results in uniform deposition of hard carbons at the grain boundary and in the elimination of any existing oxides on the deposition surface, but at the same time increases the adhesion between the base material and the additional material, all of which positively influence the wear and corrosion resistance of the tools used to refine the regenerated rubber. PMID- 29439401 TI - Achieving Crossed Strong Barrier Coverage in Wireless Sensor Network. AB - Barrier coverage has been widely used to detect intrusions in wireless sensor networks (WSNs). It can fulfill the monitoring task while extending the lifetime of the network. Though barrier coverage in WSNs has been intensively studied in recent years, previous research failed to consider the problem of intrusion in transversal directions. If an intruder knows the deployment configuration of sensor nodes, then there is a high probability that it may traverse the whole target region from particular directions, without being detected. In this paper, we introduce the concept of crossed barrier coverage that can overcome this defect. We prove that the problem of finding the maximum number of crossed barriers is NP-hard and integer linear programming (ILP) is used to formulate the optimization problem. The branch-and-bound algorithm is adopted to determine the maximum number of crossed barriers. In addition, we also propose a multi-round shortest path algorithm (MSPA) to solve the optimization problem, which works heuristically to guarantee efficiency while maintaining near-optimal solutions. Several conventional algorithms for finding the maximum number of disjoint strong barriers are also modified to solve the crossed barrier problem and for the purpose of comparison. Extensive simulation studies demonstrate the effectiveness of MSPA. PMID- 29439403 TI - Improving Health Care Management in Primary Care for Homeless People: A Literature Review. AB - BACKGROUND: Homeless people have poorer health status than the general population. They need complex care management, because of associated medical troubles (somatic and psychiatric) and social difficulties. We aimed to describe the main characteristics of the primary care programs that take care of homeless people, and to identify which could be most relevant. METHODS: We performed a literature review that included articles which described and evaluated primary care programs for homeless people. RESULTS: Most of the programs presented a team based approach, multidisciplinary and/or integrated care. They often proposed co located services between somatic health services, mental health services and social support services. They also tried to answer to the specific needs of homeless people. Some characteristics of these programs were associated with significant positive outcomes: tailored primary care organizations, clinic orientation, multidisciplinary team-based models which included primary care physicians and clinic nurses, integration of social support, and engagement in the community's health. CONCLUSIONS: Primary health care programs that aimed at taking care of the homeless people should emphasize a multidisciplinary approach and should consider an integrated (mental, somatic and social) care model. PMID- 29439402 TI - Mammarenaviral Infection Is Dependent on Directional Exposure to and Release from Polarized Intestinal Epithelia. AB - Mammarenavirusesare single-stranded RNA viruses with a bisegmented ambisense genome. Ingestion has been shown as a natural route of transmission for both Lassa virus (LASV) and Lymphocytic choriomeningitis virus (LCMV). Due to the mechanism of transmission, epithelial tissues are among the first host cells to come in contact with the viruses, and as such they potentially play a role in spread of virus to naive hosts. The role of the intestinal epithelia during arenavirus infection remains to be uncharacterized. We have utilized a well established cell culture model, Caco-2, to investigate the role of intestinal epithelia during intragastric infection. We found that LCMV-Armstrong, LCMV-WE, and Mopeia (MOPV) release infectious progeny via similar patterns. However, the reassortant virus, ML-29, containing the L segment of MOPV and S segment of LASV, exhibits a unique pattern of viral release relative to LCMV and MOPV. Furthermore, we have determined attachment efficacy to Caco-2 cells is potentially responsible for observed replication kinetics of these viruses in a polarized Caco-2 cell model. Collectively, our data shows that viral dissemination and interaction with intestinal epithelia may be host, tissue, and viral specific. PMID- 29439404 TI - High-Fat-Diet-Induced Obesity Produces Spontaneous Ventricular Arrhythmias and Increases the Activity of Ryanodine Receptors in Mice. AB - Ventricular arrhythmias are a common cause of sudden cardiac death, and their occurrence is higher in obese subjects. Abnormal gating of ryanodine receptors (RyR2), the calcium release channels of the sarcoplasmic reticulum, can produce ventricular arrhythmias. Since obesity promotes oxidative stress and RyR2 are redox-sensitive channels, we investigated whether the RyR2 activity was altered in obese mice. Mice fed a high fat diet (HFD) became obese after eight weeks and exhibited a significant increase in the occurrence of ventricular arrhythmias. Single RyR2 channels isolated from the hearts of obese mice were more active in planar bilayers than those isolated from the hearts of the control mice. At the molecular level, RyR2 channels from HFD-fed mice had substantially fewer free thiol residues, suggesting that redox modifications were responsible for the higher activity. Apocynin, provided in the drinking water, completely prevented the appearance of ventricular arrhythmias in HFD-fed mice, and normalized the activity and content of the free thiol residues of the protein. HFD increased the expression of NOX4, an isoform of NADPH oxidase, in the heart. Our results suggest that HFD increases the activity of RyR2 channels via a redox-dependent mechanism, favoring the appearance of ventricular arrhythmias. PMID- 29439405 TI - Cholecalciferol Additively Reduces Serum Parathyroid Hormone Levels in Severe Secondary Hyperparathyroidism Treated with Calcitriol and Cinacalcet among Hemodialysis Patients. AB - We evaluated the improvement of intact parathyroid hormone (iPTH) levels and bone parameters by supplementing nutritional vitamin D (cholecalciferol) to combined calcimimetic (cinacalcet) and active vitamin D analog (calcitriol) among severe secondary hyperparathyroidism (SHPT) hemodialysis (HD) patients. A randomized, controlled open-label study was undertaken in 60 HD patients with serum iPTH > 1000 pg/mL or persistently high iPTH >= 600 pg/mL even after >3 months of calcitriol (3 MUg/week). The study group received oral cholecalciferol (5000 IU/ day) and the control group received a placebo. All patients received fixed dose cinacalcet (30 mg/day, orally) and calcitriol. Calcitriol was reduced if iPTH <= 300 pg/mL and cinacalcet was withdrawn if serum iPTH was persistently low (iPTH <= 300 pg/mL) for 4 weeks after the reduction of calcitriol. A significantly lower iPTH level was noted from the 20th week in the study group compared to the placebo group, and the target iPTH <= 300 pg/mL was achieved at the 24th week in the study group. Most patients achieved serum 25-(OH)D3 >= 30 ng/mL in the study group. Nearly 40% of study patients gained >10% improvement in femoral neck (FN) bone mineral density (BMD). We conclude that cholecalciferol additively reduced serum iPTH levels, improved 25-(OH)D3 levels and improved FN BMD when used together with cinacalcet/calcitriol in severe SHPT HD patients. PMID- 29439407 TI - Quantification and Variability Analysis of Lignin Optical Properties for Colour Dependent Industrial Applications. AB - Lignin availability has increased significantly due to the commercialization of several processes for recovery and further development of alternatives for integration into Kraft pulp mills. Also, progress in lignin characterization, understanding of its chemistry as well as processing methods have resulted in the identification of novel lignin-based products and potential derivatives, which can serve as building block chemicals. However, all these have not led to the successful commercialization of lignin-based chemicals and materials. This is because most analyses and characterizations focus only on the technical suitability and quantify only the composition, functional groups present, size and morphology. Optical properties, such as the colour, which influences the uptake by users for diverse applications, are neither taken into consideration nor analysed. This paper investigates the quantification of lignin optical properties and how they can be influenced by process operating conditions. Lignin extraction conditions were also successfully correlated to the powder colour. About 120 lignin samples were collected and the variability of their colours quantified with the CIE L*a*b* colour space. In addition, a robust and reproducible colour measurement method was developed. This work lays the foundation for identifying chromophore molecules in lignin, as a step towards correlating the colour to the functional groups and the purity. PMID- 29439406 TI - Site-Specific Cleavage by Topoisomerase 2: A Mark of the Core Centromere. AB - In addition to its roles in transcription and replication, topoisomerase 2 (topo 2) is crucial in shaping mitotic chromosomes and in ensuring the orderly separation of sister chromatids. As well as its recruitment throughout the length of the mitotic chromosome, topo 2 accumulates at the primary constriction. Here, following cohesin release, the enzymatic activity of topo 2 acts to remove residual sister catenations. Intriguingly, topo 2 does not bind and cleave all sites in the genome equally; one preferred site of cleavage is within the core centromere. Discrete topo 2-centromeric cleavage sites have been identified in alpha-satellite DNA arrays of active human centromeres and in the centromere regions of some protozoans. In this study, we show that topo 2 cleavage sites are also a feature of the centromere in Schizosaccharomyces pombe, the metazoan Drosophila melanogaster and in another vertebrate species, Gallus gallus (chicken). In vertebrates, we show that this site-specific cleavage is diminished by depletion of CENP-I, an essential constitutive centromere protein. The presence, within the core centromere of a wide range of eukaryotes, of precise sites hypersensitive to topo 2 cleavage suggests that these mark a fundamental and conserved aspect of this functional domain, such as a non-canonical secondary structure. PMID- 29439408 TI - Flow Control in Wells Turbines for Harnessing Maximum Wave Power. AB - Oceans, and particularly waves, offer a huge potential for energy harnessing all over the world. Nevertheless, the performance of current energy converters does not yet allow us to use the wave energy efficiently. However, new control techniques can improve the efficiency of energy converters. In this sense, the plant sensors play a key role within the control scheme, as necessary tools for parameter measuring and monitoring that are then used as control input variables to the feedback loop. Therefore, the aim of this work is to manage the rotational speed control loop in order to optimize the output power. With the help of outward looking sensors, a Maximum Power Point Tracking (MPPT) technique is employed to maximize the system efficiency. Then, the control decisions are based on the pressure drop measured by pressure sensors located along the turbine. A complete wave-to-wire model is developed so as to validate the performance of the proposed control method. For this purpose, a novel sensor-based flow controller is implemented based on the different measured signals. Thus, the performance of the proposed controller has been analyzed and compared with a case of uncontrolled plant. The simulations demonstrate that the flow control-based MPPT strategy is able to increase the output power, and they confirm both the viability and goodness. PMID- 29439409 TI - Cancer Targeting and Drug Delivery Using Carbon-Based Quantum Dots and Nanotubes. AB - Currently cancer treatment is in large part non-specific with respect to treatment. Medication is often harsh on patients, whereby they suffer several undesired side effects as a result. Carbon-based nanoparticles have attracted attention in recent years due to their ability to act as a platform for the attachment of several drugs and/or ligands. Relatively simple models are often used in cancer research, wherein carbon nanoparticles are conjugated to a ligand that is specific to an overexpressed receptor for imaging and drug delivery in cancer treatment. These carbon nanoparticles confer unique properties to the imaging or delivery vehicle due to their nontoxic nature and their high fluorescence qualities. Chief among the ongoing research within carbon-based nanoparticles emerge carbon dots (C-dots) and carbon nanotubes (CNTs). In this review, the aforementioned carbon nanoparticles will be discussed in their use within doxorubicin and gemcitabine based drug delivery vehicles, as well as the ligand-mediated receptor specific targeted therapy. Further directions of research in current field are also discussed. PMID- 29439411 TI - Bioactive Compounds in Cornelian Cherry Vinegars. AB - We analyzed the effect of Cornelian cherry varieties differing in fruit color ('Yantaryi'-yellow fruits, 'Koralovyi'-coral fruits, 'Podolski'-red fruits) and the production method on the physicochemical and antioxidative properties of Cornelian cherry vinegars, and on their content of iridoids and polyphenols. Acetic fermentation was conducted by two methods: I) single-stage (spontaneous) acetic fermentation, without inoculation with microorganisms, and II) two-stage fermentation in which the first stage involved the use of Saccharomyces bayanus Safspirit fruit yeast for alcoholic fermentation, and the second one included spontaneous acetic fermentation. Acetic acid, glycerol, individual iridoids, phenolic acids, flavonols, and anthocyanins were quantified by a high-performance liquid chromatography (HPLC) method. The antioxidative activity was determined based on the following tests: 2,2-Diphenyl-2-picryl-hydrazyl (DPPH*), 2,2'-Azino bis(3-ethylbenzo-thiazoline-6-sulfonic acid (ABTS*+), and ferric reducing antioxidant power (FRAP), while the total polyphenols content was determined using the Folin-Ciocialteu (F-C) reagent test. Both the Cornelian cherry variety and vinegar production method affected the antioxidative properties as well as concentrations of iridoids and polyphenols in the finished product. The concentration of total polyphenols (F-C) in vinegars ranged from 326.60 to 757.27 mg gallic acids equivalents (GAE)/100 mL vinegar, whereas the antioxidative activity assayed with the DPPH* and FRAP methods was the highest in the vinegars produced from the coral and red varieties of Cornelian cherry with the two-stage method. Loganic acid predominated among the identified iridoids, reaching a concentration of 185.07 mg loganic acid (LA)/100 mL in the vinegar produced in the two-stage fermentation from the coral-fruit variety. Caffeoylquinic acid derivatives were the main representatives among the identified phenolic compounds. The results of this study demonstrate Cornelian cherry vinegars to be rich sources of biologically-active iridoids and phenolic compounds with antioxidative properties. PMID- 29439412 TI - Congenital Vomer Agenesis: A Rare and Poorly Understood Condition Revealed by Cone Beam CT. AB - Isolated congenital vomer agenesis is a very rare and poorly understood condition. In the context of dental work-up by cone-beam computed tomography (CBCT), the explored volume of the facial bones occasionally reveals incidental abnormalities. We report the case of a 13-year old Caucasian female who underwent CBCT for the pre-treatment evaluation of primary failure of tooth eruption affecting the permanent right upper and inferior molars. CBCT depicted a large defect of the postero-inferior part of the nasal septum without associated soft tissue abnormality and without cranio-facial malformation or cleft palate. In the absence of a history of trauma, chronic inflammatory sinonasal disease, neoplasia and drug abuse, a posterior nasal septum defect warrants the diagnosis of vomer agenesis. A discussion of this condition and of salient CBCT features is provided. PMID- 29439410 TI - Potential Antitumor Activity of 2-O-alpha-d-Glucopyranosyl-6-O-(2 Pentylheptanoyl)-l-Ascorbic Acid. AB - Intravenous administration of high-dose ascorbic acid (AA) has been reported as a treatment for cancer patients. However, cancer patients with renal failure cannot receive this therapy because high-dose AA infusion can have side effects. To solve this problem, we evaluated the antitumor activity of a lipophilic stable AA derivative, 2-O-alpha-d-glucopyranosyl-6-O-(2-pentylheptanoyl)-l-ascorbic acid (6 bOcta-AA-2G). Intravenous administration of 6-bOcta-AA-2G suppressed tumor growth in colon-26 tumor-bearing mice more strongly than did AA, even at 1/10 of the molar amount of AA. Experiments on the biodistribution and clearance of 6-bOcta AA-2G and its metabolites in tumor-bearing mice showed that 6-bOcta-AA-2G was hydrolyzed to 6-O-(2-propylpentanoyl)-l-ascorbic acid (6-bOcta-AA) slowly to yield AA, and the results suggested that this characteristic metabolic pattern is responsible for making the antitumor activity of 6-bOcta-AA-2G stronger than that of AA and that the active form of 6-bOcta-AA-2G showing antitumor activity is 6 bOcta-AA. In in vitro experiments, the oxidized form of 6-bOcta-AA as well as 6 bOcta-AA showed significant cytotoxicity, while the oxidized forms of ascorbic acid showed no cytotoxicity at all, suggesting that the antitumor activity mechanism of 6-bOcta-AA-2G is different from that of AA and that the antitumor activity is due to the reduced and oxidized form of 6-bOcta-AA. The findings suggest that 6-bOcta-AA-2G is a potent candidate as an alternative drug to intravenous high-dose AA. PMID- 29439413 TI - Performance Analysis of Diversity-Controlled Multi-User Superposition Transmission for 5G Wireless Networks. AB - In this paper, we propose a novel low-complexity multi-user superposition transmission (MUST) technique for 5G downlink networks, which allows multiple cell-edge users to be multiplexed with a single cell-center user. We call the proposed technique diversity-controlled MUST technique since the cell-center user enjoys the frequency diversity effect via signal repetition over multiple orthogonal frequency division multiplexing (OFDM) sub-carriers. We assume that a base station is equipped with a single antenna but users are equipped with multiple antennas. In addition, we assume that the quadrature phase shift keying (QPSK) modulation is used for users. We mathematically analyze the bit error rate (BER) of both cell-edge users and cell-center users, which is the first theoretical result in the literature to the best of our knowledge. The mathematical analysis is validated through extensive link-level simulations. PMID- 29439414 TI - An IoT-Based Gamified Approach for Reducing Occupants' Energy Wastage in Public Buildings. AB - Conserving energy amenable to the activities of occupants in public buildings is a particularly challenging objective that includes associating energy consumption to particular individuals and providing them with incentives to alter their behavior. This paper describes a gamification framework that aims to facilitate achieving greater energy conservation in public buildings. The framework leverages IoT-enabled low-cost devices, to improve energy disaggregation mechanisms that provide energy use and-consequently-wastage information at the device, area and end-user level. The identified wastages are concurrently targeted by a gamified application that motivates respective behavioral changes combining team competition, virtual rewards and life simulation. Our solution is being developed iteratively with the end-users' engagement during the analysis, design, development and validation phases in public buildings located in three different countries: Luxembourg (Musee National d'Histoire et d'Art), Spain (EcoUrbanBuilding, Institut Catala d'Energia headquarters, Barcelona) and Greece (General Secretariat of the Municipality of Athens). PMID- 29439416 TI - Experimental Investigations on Subsequent Yield Surface of Pure Copper by Single Sample and Multi-Sample Methods under Various Pre-Deformation. AB - Using copper thin-walled tubular specimens, the subsequent yield surfaces under pre-tension, pre-torsion and pre-combined tension-torsion are measured, where the single-sample and multi-sample methods are applied respectively to determine the yield stresses at specified offset strain. The rule and characteristics of the evolution of the subsequent yield surface are investigated. Under the conditions of different pre-strains, the influence of test point number, test sequence and specified offset strain on the measurement of subsequent yield surface and the concave phenomenon for measured yield surface are studied. Moreover, the feasibility and validity of the two methods are compared. The main conclusions are drawn as follows: (1) For the single or multi-sample method, the measured subsequent yield surfaces are remarkably different from cylindrical yield surfaces proposed by the classical plasticity theory; (2) there are apparent differences between the test results from the two kinds of methods: the multi sample method is not influenced by the number of test points, test order and the cumulative effect of residual plastic strain resulting from the other test point, while those are very influential in the single-sample method; and (3) the measured subsequent yield surface may appear concave, which can be transformed to convex for single-sample method by changing the test sequence. However, for the multiple-sample method, the concave phenomenon will disappear when a larger offset strain is specified. PMID- 29439415 TI - Current Application of Capillary Electrophoresis in Nanomaterial Characterisation and Its Potential to Characterise the Protein and Small Molecule Corona. AB - Due to the increasing use and production of nanomaterials (NMs), the ability to characterise their physical/chemical properties quickly and reliably has never been so important. Proper characterisation allows a thorough understanding of the material and its stability, and is critical to establishing dose-response curves to ascertain risks to human and environmental health. Traditionally, methods such as Transmission Electron Microscopy (TEM), Field Flow Fractionation (FFF) and Dynamic Light Scattering (DLS) have been favoured for size characterisation, due to their wide-availability and well-established protocols. Capillary Electrophoresis (CE) offers a faster and more cost-effective solution for complex dispersions including polydisperse or non-spherical NMs. CE has been used to rapidly separate NMs of varying sizes, shapes, surface modifications and compositions. This review will discuss the literature surrounding the CE separation techniques, detection and NM characteristics used for the analysis of a wide range of NMs. The potential of combining CE with mass spectrometry (CE-MS) will also be explored to further expand the characterisation of NMs, including the layer of biomolecules adsorbed to the surface of NMs in biological or environmental compartments, termed the acquired biomolecule corona. CE offers the opportunity to uncover new/poorly characterised low abundance and polar protein classes due to the high ionisation efficiency of CE-MS. Furthermore, the possibility of using CE-MS to characterise the poorly researched small molecule interactions within the NM corona is discussed. PMID- 29439417 TI - Recent Advances in Antibacterial and Antiendotoxic Peptides or Proteins from Marine Resources. AB - Infectious diseases caused by Gram-negative bacteria and sepsis induced by lipopolysaccharide (LPS) pose a major threat to humans and animals and cause millions of deaths each year. Marine organisms are a valuable resource library of bioactive products with huge medicinal potential. Among them, antibacterial and antiendotoxic peptides or proteins, which are composed of metabolically tolerable residues, are present in many marine species, including marine vertebrates, invertebrates and microorganisms. A lot of studies have reported that these marine peptides and proteins or their derivatives exhibit potent antibacterial activity and antiendotoxic activity in vitro and in vivo. However, their categories, heterologous expression in microorganisms, physicochemical factors affecting peptide or protein interactions with bacterial LPS and LPS-neutralizing mechanism are not well known. In this review, we highlight the characteristics and anti-infective activity of bifunctional peptides or proteins from marine resources as well as the challenges and strategies for further study. PMID- 29439418 TI - Small RNAs of Haloferax mediterranei: Identification and Potential Involvement in Nitrogen Metabolism. AB - Small RNAs have been studied in detail in domains Bacteria and Eukarya but, in the case of the domain Archaea, the knowledge is scarce and the physiological function of these small RNAs (sRNAs) is still uncertain. To extend the knowledge of sRNAs in the domain Archaea and their possible role in the regulation of the nitrogen assimilation metabolism in haloarchaea, Haloferax mediterranei has been used as a model microorganism. The bioinformatic approach has allowed for the prediction of 295 putative sRNAs genes in the genome of H. mediterranei, 88 of which have been verified by means of RNA-Sequencing (RNA-Seq). The secondary structure of these sRNAs and their possible targets have been identified. Curiously, some of them present as possible target genes relating to nitrogen assimilation, such as glutamate dehydrogenase and the nitrogen regulatory PII protein. Analysis of RNA-Seq data has also revealed differences in the expression pattern of 16 sRNAs according to the nitrogen source. Consequently, RNomic and bioinformatic approaches used in this work have allowed for the identification of new sRNAs in H. mediterranei, some of which show different expression patterns depending on the nitrogen source. This suggests that these sRNAs could be involved in the regulation of nitrogen assimilation and can constitute an important gene regulatory network. PMID- 29439419 TI - Immunoconjugates for Osteosarcoma Therapy: Preclinical Experiences and Future Perspectives. AB - Osteosarcoma (OS) is an aggressive osteoid-producing tumor of mesenchymal origin, which represents the most common primary bone malignancy. It is characterized by a complex and frequently uncertain etiology. The current standard care for high grade OS treatment is neoadjuvant chemotherapy, followed by surgery and post operative chemotherapy. In order to ameliorate survival rates of patients, new therapeutic approaches have been evaluated, mainly immunotherapy with antibody drug conjugates or immunoconjugates. These molecules consist of a carrier (frequently an antibody) joined by a linker to a toxic moiety (drug, radionuclide, or toxin). Although several clinical trials with immunoconjugates have been conducted, mainly in hematological tumors, their potential as therapeutic agents is relatively under-explored in many types of cancer. In this review, we report the immunoconjugates directed against OS surface antigens, considering the in vitro and in vivo studies. To date, several attempts have been made in preclinical settings, reporting encouraging results and demonstrating the validity of the idea. The clinical experience with glembatumumab vedotin may provide new insights into the real efficacy of antibody-drug conjugates for OS therapy, possibly giving more information about patient selection. Moreover, new opportunities could arise from the ongoing clinical trials in OS patients with unconjugated antibodies that could represent future candidates as carrier moieties of immunoconjugates. PMID- 29439420 TI - An Overview of Chemical Profiles, Antioxidant and Antimicrobial Activities of Commercial Vegetable Edible Oils Marketed in Japan. AB - This study analyzed chemical components and investigated the antioxidant and antimicrobial activities of fourteen vegetable edible oils marketed in Japan. High-performance liquid chromatography (HPLC) was used to identify and quantify principal phenolic acids and flavonoids. In the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, sunflower, safflower, canola, soybean, Inca inchi, sesame, and rice bran showed markedly greater activity, whilst the percentage of lipid peroxidation inhibition (LPI%) in sunflower, canola, cotton, grape, flax, perilla, Inca inchi, perillartine, and rice bran were significantly higher than other oils. Maximum total phenol content (TPC) was recorded in flax, followed by perillartine, rice bran, and perilla, whereas total flavonoid content (TFC) was the greatest in Inca inchi and sesame. Benzoic acid was the most common constituent, followed by vanillic acid, p-hydroxybenzoic acid, ferulic acid, and p-coumaric acid. On the other hand, luteolin was the most abundant flavonoid, followed by esculetin, myricetin, isoquercetin, and kaempferol, while fisetin was detected only in sunflower. In general, all of the edible oils showed antimicrobial activity, but the growth inhibition of Staphylococcus aureus and Escherichia coli of cotton, grape, chia, sesame, and rice bran were greater than other oils. PMID- 29439421 TI - The Effect of Ginger Juice Processing on the Chemical Profiles of Rhizoma coptidis. AB - Rhizoma coptidis (RC) has been used as an herbal medicine in China for over one thousand years, and it was subjected to specific processing before use as materia medica. Processing is a pharmaceutical technique that aims to enhance the efficacy and/or reduce the toxicity of crude drugs according to traditional Chinese medicine theory. In this study, the chemical profiles of RC, ginger juice processed RC (GRC), and water processed RC (WRC) was determined to reveal the mechanism of processing of RC. UPLC-QTOF-MS analysis of methanol extract of RC, GRC, and WRC has been conducted to investigate the effect of processing on the composition of RC. HPLC-PDA was used to determine the variance of total alkaloids and seven alkaloids of RC during the processing. The volatiles of RC, GRC and ginger juice were separated by distillation, the change of volatiles content was recorded and analyzed, and the qualitative analysis of the volatiles was carried out using GC-MS. The microstructures of RC, GRC and WRC were observed using a light microscope. Results showed that ginger juice/water processing had limited influence on the composition of RC's methanol extract, but significant influence on the content of some alkaloids in RC. Ginger juice processing significantly increased (p < 0.05) the volatiles content of RC and changed the volatiles composition obviously. Processing also had an influence on the microstructure of RC. This research comprehensively revealed the mechanism of ginger juice processing of RC. PMID- 29439422 TI - Separation and Purification of Fructo-Oligosaccharide by High-Speed Counter Current Chromatography Coupled with Precolumn Derivatization. AB - High-speed counter-current chromatography (HSCCC) coupled with precolumn derivatization was developed for isolating and purifying fructo-oligosaccharides (FOSs). Firstly, the total FOSs were precolumn derivatized and then separated by high-speed counter-current chromatography (HSCCC) with two-phase solvent system petroleum ether-n-butanol-methanol-water (3:2:1:4, v/v). Secondly, the obtained compounds were deacetylated and the fructo-oligosaccharides (FOSs) with high purity were obtained. Their structures were identified by mass spectrometry (MS) and nuclear magnetic resonance (NMR). This research successfully established a novel strategy for separation and purification of FOS. There is no doubt that the application of the research will be beneficial for the quantitative and qualitative analysis of products containing FOSs. PMID- 29439423 TI - A Railway Track Geometry Measuring Trolley System Based on Aided INS. AB - Accurate measurement of the railway track geometry is a task of fundamental importance to ensure the track quality in both the construction phase and the regular maintenance stage. Conventional track geometry measuring trolleys (TGMTs) in combination with classical geodetic surveying apparatus such as total stations alone cannot meet the requirements of measurement accuracy and surveying efficiency at the same time. Accurate and fast track geometry surveying applications call for an innovative surveying method that can measure all or most of the track geometric parameters in short time without interrupting the railway traffic. We provide a novel solution to this problem by integrating an inertial navigation system (INS) with a geodetic surveying apparatus, and design a modular TGMT system based on aided INS, which can be configured according to different surveying tasks including precise adjustment of slab track, providing tamping measurements, measuring track deformation and irregularities, and determination of the track axis. TGMT based on aided INS can operate in mobile surveying mode to significantly improve the surveying efficiency. Key points in the design of the TGMT's architecture and the data processing concept and workflow are introduced in details, which should benefit subsequent research and provide a reference for the implementation of this kind of TGMT. The surveying performance of proposed TGMT with different configurations is assessed in the track geometry surveying experiments and actual projects. PMID- 29439424 TI - A COTS-Based Portable System to Conduct Accurate Substance Concentration Measurements. AB - Traditionally, electrochemical procedures aimed at determining substance concentrations have required a costly and cumbersome laboratory environment. Specialized equipment and personnel obtain precise results under complex and time consuming settings. Innovative electrochemical-based sensors are emerging to alleviate this difficulty. However, they are generally scarce, proprietary hardware and/or software, and focused only on measuring a restricted range of substances. In this paper, we propose a portable, flexible, low-cost system, built from commercial off-the-shelf components and easily controlled, using open source software. The system is completed with a wireless module, which enables the transmission of measurements to a remote database for their later processing. A well-known PGSTAT100 Autolab device is employed to validate the effectiveness of our proposal. To this end, we select ascorbic acid as the substance under consideration, evaluating the reliability figure and obtaining the calibration curves for both platforms. The final outcomes are shown to be feasible, accurate, and repeatable. PMID- 29439427 TI - Potential and Limitations of an Improved Method to Produce Dynamometric Wheels. AB - A new methodology for the estimation of tyre-contact forces is presented. The new procedure is an evolution of a previous method based on harmonic elimination techniques developed with the aim of producing low cost dynamometric wheels. While the original method required stress measurement in many rim radial lines and the fulfillment of some rigid conditions of symmetry, the new methodology described in this article significantly reduces the number of required measurement points and greatly relaxes symmetry constraints. This can be done without compromising the estimation error level. The reduction of the number of measuring radial lines increases the ripple of demodulated signals due to non eliminated higher order harmonics. Therefore, it is necessary to adapt the calibration procedure to this new scenario. A new calibration procedure that takes into account angular position of the wheel is completely described. This new methodology is tested on a standard commercial five-spoke car wheel. Obtained results are qualitatively compared to those derived from the application of former methodology leading to the conclusion that the new method is both simpler and more robust due to the reduction in the number of measuring points, while contact forces' estimation error remains at an acceptable level. PMID- 29439425 TI - Inappropriate Use of Medication by Elderly, Polymedicated, or Multipathological Patients with Chronic Diseases. AB - The growth of the aging population leads to the increase of chronic diseases, of the burden of multimorbility, and of the complexity polypharmacy. The prevalence of medication errors rises in patients with polypharmacy in primary care, and this is a major concern to healthcare systems. This study reviews the published literature on the inappropriate use of medicines in order to articulate recommendations on how to reduce it in chronic patients, particularly in those who are elderly, polymedicated, or multipathological. A systematic review of articles published from January 2000 to October 2015 was performed using MEDLINE, EMBASE, PsychInfo, Scopus, The Cochrane Library, and Index Medicus databases. We selected 80 studies in order to analyse the content that addressed the question under consideration. Our literature review found that half of patients know what their prescribed treatment is; that most of elderly people take five or more medications a day; that in elderly, polymedicated people, the probability of a medication error occurring is higher; that new tools have been recently developed to reduce errors; that elderly patients can understand written information but the presentation and format is an important factor; and that a high percentage of patients have remaining doubts after their visit. Thus, strategies based on the evidence should be applied in order to reduce medication errors. PMID- 29439426 TI - Special Protein Molecules Computational Identification. AB - Computational identification of special protein molecules is a key issue in understanding protein function. It can guide molecular experiments and help to save costs. I assessed 18 papers published in the special issue of Int. J. Mol. Sci., and also discussed the related works. The computational methods employed in this special issue focused on machine learning, network analysis, and molecular docking. New methods and new topics were also proposed. There were in addition several wet experiments, with proven results showing promise. I hope our special issue will help in protein molecules identification researches. PMID- 29439428 TI - Monitoring Walker Assistive Devices: A Novel Approach Based on Load Cells and Optical Distance Measurements. AB - This paper presents a measurement system intended to monitor the usage of walker assistive devices. The goal is to guide the user in the correct use of the device in order to prevent risky situations and maximize comfort. Two risk indicators are defined: one related to force unbalance and the other related to motor incoordination. Force unbalance is measured by load cells attached to the walker legs, while motor incoordination is estimated by synchronizing force measurements with distance data provided by an optical sensor. The measurement system is equipped with a Bluetooth link that enables local supervision on a computer or tablet. Calibration and experimental results are included in the paper. PMID- 29439429 TI - Plane Wave SH0 Piezoceramic Transduction Optimized Using Geometrical Parameters. AB - Structural health monitoring is a prominent alternative to the scheduled maintenance of safety-critical components. The nondispersive nature as well as the through-thickness mode shape of the fundamental shear horizontal guided wave mode (SH 0 ) make it a particularly attractive candidate for ultrasonic guided wave structural health monitoring. However, plane wave excitation of SH 0 at a high level of purity remains challenging because of the existence of the fundamental Lamb modes (A 0 and S 0 ) below the cutoff frequency thickness product of high-order modes. This paper presents a piezoelectric transducer concept optimized for plane SH 0 wave transduction based on the transducer geometry. The transducer parameter exploration was initially performed using a simple analytical model. A 3D multiphysics finite element model was then used to refine the transducer design. Finally, an experimental validation was conducted with a 3D laser Doppler vibrometer system. The analytical model, the finite element model, and the experimental measurement showed excellent agreement. The modal selectivity of SH 0 within a 20 ? beam opening angle at the design frequency of 425 kHz in a 1.59 mm aluminum plate was 23 dB, and the angle of the 6 dB wavefront was 86 ? . PMID- 29439431 TI - Experimental Investigation of Multi-mode Fiber Laser Cutting of Cement Mortar. AB - This study successfully applied multi-mode laser cutting with the variation of the laser cutting speed to cement mortar for the first time. The effects of the amount of silica sand in the cement mortar on laser cutting are tested and analyzed. The kerf width and penetration depth of the specimens after laser cutting are investigated. As the laser cutting speed increases, the penetration depth decreases for both cement paste and cement mortar, whereas the kerf width becomes saturated and increases, respectively, for cement paste and cement mortar. Cross sections of the specimens are compared with illustrations. Top-view images of the cement mortar with indicators of the physical characteristics, such as re-solidification, burning, and cracks are examined, and the possible causes of these characteristics are explained. The optical absorption rates of cement based materials are quantified at wide ranges of wavelength to compare the absorption rates in accordance with the materials compositions. The chemical composition variation before and after laser cutting is also compared by EDX (Energy Dispersive X-Ray) analysis. In addition to these observations, material removal mechanisms for cement mortar are proposed. PMID- 29439430 TI - Gender Difference and Spatial Heterogeneity in Local Obesity. AB - This study asks if there is gender-specific spatial heterogeneity in local obesity. By using the 2015 Korea Community Health Survey and employing spatial analyses, this study found that there is considerable gender-specific spatial heterogeneity in local obesity rates. More specifically, we found that: (1) local obesity rates are more spatially dependent for women than for men; (2) environmental factors, in general, have stronger effects on local obesity rates for women than for men; (3) environmental factors have more spatially varying effects on local obesity rates for women than for men. Based on these findings, we suggest that policies for obesity prevention should not be based on the assumption of spatial homogeneity and gender indifference, but rather should be refined based on gender-specific spatial heterogeneity in local obesity. PMID- 29439432 TI - Complex Formation of Resorufin and Resazurin with Beta-Cyclodextrins: Can Cyclodextrins Interfere with a Resazurin Cell Viability Assay? AB - Resazurin (or Alamar Blue) is a poorly fluorescent dye. During the cellular reduction of resazurin, its highly fluorescent product resorufin is formed. Resazurin assay is a commonly applied method to investigate viability of bacterial and mammalian cells. In this study, the interaction of resazurin and resorufin with beta-cyclodextrins was investigated employing spectroscopic and molecular modeling studies. Furthermore, the influence of beta-cyclodextrins on resazurin-based cell viability assay was also tested. Both resazurin and resorufin form stable complexes with the examined beta-cyclodextrins (2.0-3.1 * 103 and 1.3-1.8 * 103 L/mol were determined as binding constants, respectively). Cells were incubated for 30 and 120 min and treated with resazurin and/or beta cyclodextrins. Our results suggest that cyclodextrins are able to interfere with the resazurin-based cell viability assay that presumably results from the following mechanisms: (1) inhibition of the cellular uptake of resazurin and (2) enhancement of the fluorescence signal of the formed resorufin. PMID- 29439433 TI - Multiple Mycotoxins in Rice: Occurrence and Health Risk Assessment in Children and Adults of Punjab, Pakistan. AB - Mycotoxin contamination in rice can create a health risk for the consumers. In this study, the measurement of 23 mycotoxins in rice samples (n = 180) was performed using a validated LC-MS/MS method. A food frequency questionnaire was used to get rice consumption data for the assessment of mycotoxin dietary exposure, before calculating the health risk in adults and children of north and south regions of the Pakistani Punjab province. The prevalence of aflatoxin B1 (56%), aflatoxin B2 (48%), nivalenol (28%), diacetoxyscirpenol (23%), fumonisin B1 (42%), zearalenone (15%), HT-2 toxin (10%), deoxynivalenol (8%), and ochratoxin A (6%) was estimated in samples with a mean concentration range between 0.61 and 22.98 ug/kg. Aflatoxin degradation by traditional Pakistani cooking recipes was evaluated and observed to be 41-63%. The dietary exposure to aflatoxins exceeded the tolerable daily intake at all levels, and ochratoxin A and zearalenone posed health risk at high contamination and high consumption levels. The margin of aflatoxin B1 exposure ranged between 10 and 69 in adults and 10 and 62 in children. The mean cancer risk by aflatoxin B1 exposure was 0.070 (adults) and 0.071 (children) cases/year/100,000 people in South Punjab population, and 0.122 (adults) and 0.127 (children) cases/year/100,000 people in North Punjab population. This study will provide new insights for the planning and management of mycotoxins in Pakistan. PMID- 29439434 TI - Genome-Wide Identification, Characterization, and Expression Profiling of Glutathione S-Transferase (GST) Family in Pumpkin Reveals Likely Role in Cold Stress Tolerance. AB - Plant growth and development can be adversely affected by cold stress, limiting productivity. The glutathione S-transferase (GST) family comprises important detoxifying enzymes, which play major roles in biotic and abiotic stress responses by reducing the oxidative damage caused by reactive oxygen species. Pumpkins (Cucurbitamaxima) are widely grown, economically important, and nutritious; however, their yield can be severely affected by cold stress. The identification of putative candidate genes responsible for cold-stress tolerance, including the GST family genes, is therefore vital. For the first time, we identified 32 C. maxima GST (CmaGST) genes using a combination of bioinformatics approaches and characterized them by expression profiling. These CmaGST genes represent seven of the 14 known classes of plant GSTs, with 18 CmaGSTs categorized into the tau class. The CmaGSTs were distributed across 13 of pumpkin's 20 chromosomes, with the highest numbers found on chromosomes 4 and 6. The large number of CmaGST genes resulted from gene duplication; 11 and 5 pairs of CmaGST genes were segmental- and tandem-duplicated, respectively. In addition, all CmaGST genes showed organ-specific expression. The expression of the putative GST genes in pumpkin was examined under cold stress in two lines with contrasting cold tolerance: cold-tolerant CP-1 (C. maxima) and cold-susceptible EP-1 (Cucurbita moschata). Seven genes (CmaGSTU3, CmaGSTU7, CmaGSTU8, CmaGSTU9, CmaGSTU11, CmaGSTU12, and CmaGSTU14) were highly expressed in the cold-tolerant line and are putative candidates for use in breeding cold-tolerant crop varieties. These results increase our understanding of the cold-stress-related functions of the GST family, as well as potentially enhancing pumpkin breeding programs. PMID- 29439435 TI - Synchronization, Attention and Transformation: Multidimensional Exploration of the Aesthetic Experience of Contemporary Dance Spectators. AB - The co-presence of bodies in intersubjective situations can give rise to processes of kinesthetic empathy and physiological synchronization, especially in the context of dance: the body and attention of the spectators are oriented towards the dancers. In this study, we investigate the processes of "body-mind" resonance between a choreography and its spectators, and more specifically the lasting impact of this resonance post-performance. We then explore the relation between the observed effects and subjective measures of attention. The study focuses on the work of the French choreographer Myriam Gourfink, who develops a unique movement, based on the slower breathing of dancers: the breathing generates an extremely slow movement without rhythmic ruptures. Phenomenological studies of her work report changes in temporal perception and changes in bodily attentional states. We made use of two cognitive tasks in order to quantify this change in temporal perception: Spontaneous Motor Tempo (SMT) and Apparent Motion effect (AM) before and after a 40-min live performance. Subjective reports were collected at the end of the performance. Physiological data were recorded before and after the performance. We performed a control experiment with a choreography of a distinctly different quality of movement. Post-Gourfink performance, we observed a significant deceleration of SMT and a decrease in its variability, while AM was reported with longer temporal intervals. Neither of these effects was observed in the control condition. Furthermore, an increase in perception of AM was correlated with a slower breathing rate after the performance. Correlations with subjective reports suggest a link between changes in cognitive and physiological dynamics and the degree of absorption of the spectators in the performance. In addition, these changes were related to specific reported attentional dispositions that we interpret as a form of attentional resonance. The ensemble of the results suggests an expansion of the "specious present" that is related to the slowing of physiological rhythms, and an attentional resonance between spectators and the choreography. The intricate relation we observed between inter-personal resonance and temporal cognition, foregrounds the notion of shared present as a neurophenomenological construct. PMID- 29439437 TI - Sub-THz Imaging Using Non-Resonant HEMT Detectors. AB - Plasma waves in gated 2-D systems can be used to efficiently detect THz electromagnetic radiation. Solid-state plasma wave-based sensors can be used as detectors in THz imaging systems. An experimental study of the sub-THz response of II-gate strained-Si Schottky-gated MODFETs (Modulation-doped Field-Effect Transistor) was performed. The response of the strained-Si MODFET has been characterized at two frequencies: 150 and 300 GHz: The DC drain-to-source voltage transducing the THz radiation (photovoltaic mode) of 250-nm gate length transistors exhibited a non-resonant response that agrees with theoretical models and physics-based simulations of the electrical response of the transistor. When imposing a weak source-to-drain current of 5 MUA, a substantial increase of the photoresponse was found. This increase is translated into an enhancement of the responsivity by one order of magnitude as compared to the photovoltaic mode, while the NEP (Noise Equivalent Power) is reduced in the subthreshold region. Strained-Si MODFETs demonstrated an excellent performance as detectors in THz imaging. PMID- 29439436 TI - Chondrogenic Differentiation of Defined Equine Mesenchymal Stem Cells Derived from Umbilical Cord Blood for Use in Cartilage Repair Therapy. AB - Cartilage engineering is a new strategy for the treatment of cartilage damage due to osteoarthritis or trauma in humans. Racehorses are exposed to the same type of cartilage damage and the anatomical, cellular, and biochemical properties of their cartilage are comparable to those of human cartilage, making the horse an excellent model for the development of cartilage engineering. Human mesenchymal stem cells (MSCs) differentiated into chondrocytes with chondrogenic factors in a biomaterial appears to be a promising therapeutic approach for direct implantation and cartilage repair. Here, we characterized equine umbilical cord blood-derived MSCs (eUCB-MSCs) and evaluated their potential for chondrocyte differentiation for use in cartilage repair therapy. Our results show that isolated eUCB-MSCs had high proliferative capacity and differentiated easily into osteoblasts and chondrocytes, but not into adipocytes. A three-dimensional (3D) culture approach with the chondrogenic factors BMP-2 and TGF-beta1 potentiated chondrogenic differentiation with a significant increase in cartilage-specific markers at the mRNA level (Col2a1, Acan, Snorc) and the protein level (type II and IIB collagen) without an increase in hypertrophic chondrocyte markers (Col10a1 and Mmp13) in normoxia and in hypoxia. However, these chondrogenic factors caused an increase in type I collagen, which can be reduced using small interfering RNA targeting Col1a2. This study provides robust data on MSCs characterization and demonstrates that eUCB-MSCs have a great potential for cartilage tissue engineering. PMID- 29439439 TI - Efficient Deployment of Key Nodes for Optimal Coverage of Industrial Mobile Wireless Networks. AB - In recent years, industrial wireless networks (IWNs) have been transformed by the introduction of mobile nodes, and they now offer increased extensibility, mobility, and flexibility. Nevertheless, mobile nodes pose efficiency and reliability challenges. Efficient node deployment and management of channel interference directly affect network system performance, particularly for key node placement in clustered wireless networks. This study analyzes this system model, considering both industrial properties of wireless networks and their mobility. Then, static and mobile node coverage problems are unified and simplified to target coverage problems. We propose a novel strategy for the deployment of clustered heads in grouped industrial mobile wireless networks (IMWNs) based on the improved maximal clique model and the iterative computation of new candidate cluster head positions. The maximal cliques are obtained via a double-layer Tabu search. Each cluster head updates its new position via an improved virtual force while moving with full coverage to find the minimal inter cluster interference. Finally, we develop a simulation environment. The simulation results, based on a performance comparison, show the efficacy of the proposed strategies and their superiority over current approaches. PMID- 29439440 TI - A Maximum Feasible Subsystem for Globally Optimal 3D Point Cloud Registration. AB - In this paper, a globally optimal algorithm based on a maximum feasible subsystem framework is proposed for robust pairwise registration of point cloud data. Registration is formulated as a branch-and-bound problem with mixed-integer linear programming. Among the putative matches of three-dimensional (3D) features between two sets of range data, the proposed algorithm finds the maximum number of geometrically correct correspondences in the presence of incorrect matches, and it estimates the transformation parameters in a globally optimal manner. The optimization requires no initialization of transformation parameters. Experimental results demonstrated that the presented algorithm was more accurate and reliable than state-of-the-art registration methods and showed robustness against severe outliers/mismatches. This global optimization technique was highly effective, even when the geometric overlap between the datasets was very small. PMID- 29439441 TI - Thermal Properties of SiOC Glasses and Glass Ceramics at Elevated Temperatures. AB - In the present study, the effect of the chemical and phase composition on the thermal properties of silicon oxide carbides (SiOC) has been investigated. Dense monolithic SiOC materials with various carbon contents were prepared and characterized with respect to their thermal expansion, as well as thermal conductivity. SiOC glass has been shown to exhibit low thermal expansion (e.g., ca. 3.2 * 10-6 K-1 for a SiOC sample free of segregated carbon) and thermal conductivity (ca. 1.5 W/(m?K)). Furthermore, it has been observed that the phase separation, which typically occurs in SiOC exposed to temperatures beyond 1000 1200 degrees C, leads to a decrease of the thermal expansion (i.e., to 1.83 * 10 6 K-1 for the sample above); whereas the thermal conductivity increases upon phase separation (i.e., to ca. 1.7 W/(m?K) for the sample mentioned above). Upon adjusting the amount of segregated carbon content in SiOC, its thermal expansion can be tuned; thus, SiOC glass ceramics with carbon contents larger than 10-15 vol % exhibit similar coefficients of thermal expansion to that of the SiOC glass. Increasing the carbon and SiC content in the studied SiOC glass ceramics leads to an increase in their thermal conductivity: SiOC with relatively large carbon and silicon carbides (SiC) volume fractions (i.e., 12-15 and 20-30 vol %, respectively) were shown to possess thermal conductivities in the range from 1.8 to 2.7 W/(m?K). PMID- 29439438 TI - RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution. AB - RNA dependent RNA polymerase (RdRp) is one of the most versatile enzymes of RNA viruses that is indispensable for replicating the genome as well as for carrying out transcription. The core structural features of RdRps are conserved, despite the divergence in their sequences. The structure of RdRp resembles that of a cupped right hand and consists of fingers, palm and thumb subdomains. The catalysis involves the participation of conserved aspartates and divalent metal ions. Complexes of RdRps with substrates, inhibitors and metal ions provide a comprehensive view of their functional mechanism and offer valuable insights regarding the development of antivirals. In this article, we provide an overview of the structural aspects of RdRps and their complexes from the Group III, IV and V viruses and their structure-based phylogeny. PMID- 29439442 TI - A Survey on Data Storage and Information Discovery in the WSANs-Based Edge Computing Systems. AB - In the post-Cloud era, the proliferation of Internet of Things (IoT) has pushed the horizon of Edge computing, which is a new computing paradigm with data are processed at the edge of the network. As the important systems of Edge computing, wireless sensor and actuator networks (WSANs) play an important role in collecting and processing the sensing data from the surrounding environment as well as taking actions on the events happening in the environment. In WSANs, in network data storage and information discovery schemes with high energy efficiency, high load balance and low latency are needed because of the limited resources of the sensor nodes and the real-time requirement of some specific applications, such as putting out a big fire in a forest. In this article, the existing schemes of WSANs on data storage and information discovery are surveyed with detailed analysis on their advancements and shortcomings, and possible solutions are proposed on how to achieve high efficiency, good load balance, and perfect real-time performances at the same time, hoping that it can provide a good reference for the future research of the WSANs-based Edge computing systems. PMID- 29439443 TI - EDDA: An Efficient Distributed Data Replication Algorithm in VANETs. AB - Efficient data dissemination in vehicular ad hoc networks (VANETs) is a challenging issue due to the dynamic nature of the network. To improve the performance of data dissemination, we study distributed data replication algorithms in VANETs for exchanging information and computing in an arbitrarily connected network of vehicle nodes. To achieve low dissemination delay and improve the network performance, we control the number of message copies that can be disseminated in the network and then propose an efficient distributed data replication algorithm (EDDA). The key idea is to let the data carrier distribute the data dissemination tasks to multiple nodes to speed up the dissemination process. We calculate the number of communication stages for the network to enter into a balanced status and show that the proposed distributed algorithm can converge to a consensus in a small number of communication stages. Most of the theoretical results described in this paper are to study the complexity of network convergence. The lower bound and upper bound are also provided in the analysis of the algorithm. Simulation results show that the proposed EDDA can efficiently disseminate messages to vehicles in a specific area with low dissemination delay and system overhead. PMID- 29439445 TI - Two New Triterpenoids from the Roots of Codonopsis pilosula. AB - Pseudolarolides U and V, two new triterpenoids, and four biogenetically related compounds, pseudolarolides E, F, K, and P were isolated from the roots of Codonopsis pilosula (Campanulaceae). Their structures were determined by spectroscopic data. The regulation of Sirtuin 1 (SIRT1) activity by all the isolated compounds was evaluated. PMID- 29439444 TI - Comparative Membrane-Associated Proteomics of Three Different Immune Reactions in Potato. AB - Plants have evolved different types of immune reactions but large-scale proteomics about these processes are lacking, especially in the case of agriculturally important crop pathosystems. We have established a system for investigating PAMP-triggered immunity (PTI) and two different effector-triggered immunity (ETI; triggered by Avr2 or IpiO) responses in potato. The ETI responses are triggered by molecules from the agriculturally important Phytophthora infestans interaction. To perform large-scale membrane protein-based comparison of these responses, we established a method to extract proteins from subcellular compartments in leaves. In the membrane fractions that were subjected to quantitative proteomics analysis, we found that most proteins regulated during PTI were also regulated in the same way in ETI. Proteins related to photosynthesis had lower abundance, while proteins related to oxidative and biotic stress, as well as those related to general antimicrobial defense and cell wall degradation, were found to be higher in abundance. On the other hand, we identified a few proteins-for instance, an ABC transporter-like protein-that were only found in the PTI reaction. Furthermore, we also identified proteins that were regulated only in ETI interactions. These included proteins related to GTP binding and heterotrimeric G-protein signaling, as well as those related to phospholipase signaling. PMID- 29439446 TI - The T2238C Human Atrial Natriuretic Peptide Molecular Variant and the Risk of Cardiovascular Diseases. AB - Atrial natriuretic peptide (ANP) is a cardiac hormone which plays important functions to maintain cardio-renal homeostasis. The peptide structure is highly conserved among species. However, a few gene variants are known to fall within the human ANP gene. The variant rs5065 (T2238C) exerts the most substantial effects. The T to C transition at the 2238 position of the gene (13-23% allele frequency in the general population) leads to the production of a 30-, instead of 28-, amino-acid-long alpha-carboxy-terminal peptide. In vitro, CC2238/alphaANP increases the levels of reactive oxygen species and causes endothelial damage, vascular smooth muscle cells contraction, and increased platelet aggregation. These effects are achieved through the deregulated activation of type C natriuretic peptide receptor, the consequent inhibition of adenylate cyclase activity, and the activation of Gialpha proteins. In vivo, endothelial dysfunction and increased platelet aggregation are present in human subjects carrying the C2238/alphaANP allele variant. Several studies documented an increased risk of stroke and of myocardial infarction in C2238/alphaANP carriers. Recently, an incomplete response to antiplatelet therapy in ischemic heart disease patients carrying the C2238/alphaANP variant and undergoing percutaneous coronary revascularization has been reported. In summary, the overall evidence supports the concept that T2238C/ANP is a cardiovascular genetic risk factor that needs to be taken into account in daily clinical practice. PMID- 29439447 TI - Sensor-Oriented Path Planning for Multiregion Surveillance with a Single Lightweight UAV SAR. AB - In the surveillance of interested regions by unmanned aerial vehicle (UAV), system performance relies greatly on the motion control strategy of the UAV and the operation characteristics of the onboard sensors. This paper investigates the 2D path planning problem for the lightweight UAV synthetic aperture radar (SAR) system in an environment of multiple regions of interest (ROIs), the sizes of which are comparable to the radar swath width. Taking into account the special requirements of the SAR system on the motion of the platform, we model path planning for UAV SAR as a constrained multiobjective optimization problem (MOP). Based on the fact that the UAV route can be designed in the map image, an image based path planner is proposed in this paper. First, the neighboring ROIs are merged by the morphological operation. Then, the parts of routes for data collection of the ROIs can be located according to the geometric features of the ROIs and the observation geometry of UAV SAR. Lastly, the route segments for ROIs surveillance are connected by a path planning algorithm named the sampling-based sparse A* search (SSAS) algorithm. Simulation experiments in real scenarios demonstrate that the proposed sensor-oriented path planner can improve the reconnaissance performance of lightweight UAV SAR greatly compared with the conventional zigzag path planner. PMID- 29439448 TI - Rapid Screening of Cadmium in Rice and Identification of Geographical Origins by Spectral Method. AB - The accuracy, repeatability and detection limits of the energy-dispersive X-ray fluorescence (XRF) spectrometer used in this study were tested to verify its suitability for rapid screening of cadmium in samples. Concentrations of cadmium in rice grain samples were tested by the XRF spectrometer. The results showed that the apparatus had good precision around the national limit value (0.2 mg/kg). Raman spectroscopy has been analyzed in the discrimination of rice grain samples from different geographical origins within China. Scanning time has been discussed in order to obtain better Raman features of rice samples. A total of 31 rice samples were analyzed. After spectral data pre-treatment, principal component analysis (PCA), K-means clustering (KMC), hierarchical clustering (HC) and support vector machine (SVM) were performed to discriminate origins of rice samples. The results showed that the geographical origins of rice could be classified using Raman spectroscopy combined with multivariate analysis. PMID- 29439449 TI - Metabolic Effects of FecB Gene on Follicular Fluid and Ovarian Vein Serum in Sheep (Ovis aries). AB - The FecB gene has been discovered as an important gene in sheep for its high relationship with the ovulation rate, but its regulatory mechanism remains unknown. In the present study, liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were adopted to detect the metabolic effects of FecB gene in follicular fluid (FF) and ovarian vein serum (OVS) in Small Tail Han (STH) sheep. ANOVA and random forest statistical methods were employed for the identification of important metabolic pathways and biomarkers. Changes in amino acid metabolism, redox environment, and energy metabolism were observed in FF from the three FecB genotype STH ewes. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) showed that metabolic effects of FecB gene are more pronounced in FF than in OVS. Therefore, the difference of the metabolic profile in FF is also affected by the FecB genotypes. In Spearman correlation analysis, key metabolites (e.g., glucose 6-phosphate, glucose 1-phosphate, aspartate, asparagine, glutathione oxidized (GSSG), cysteine-glutathione disulfide, gamma-glutamylglutamine, and 2 hydrosybutyrate) in ovine FF samples showed a significant correlation with the ovulation rate. Our findings will help to explain the metabolic mechanism of high prolificacy ewes and benefit fertility identification. PMID- 29439450 TI - Synthesis of alpha-Fe2O3 and Fe-Mn Oxide Foams with Highly Tunable Magnetic Properties by the Replication Method from Polyurethane Templates. AB - Open cell foams consisting of Fe and Fe-Mn oxides are prepared from metallic Fe and Mn powder precursors by the replication method using porous polyurethane (PU) templates. First, reticulated PU templates are coated by slurry impregnation. The templates are then thermally removed at 260 degrees C and the debinded powders are sintered at 1000 degrees C under N2 atmosphere. The morphology, structure, and magnetic properties are studied by scanning electron microscopy, X-ray diffraction and vibrating sample magnetometry, respectively. The obtained Fe and Fe-Mn oxide foams possess both high surface area and homogeneous open-cell structure. Hematite (alpha-Fe2O3) foams are obtained from the metallic iron slurry independently of the N2 flow. In contrast, the microstructure of the FeMn based oxide foams can be tailored by adjusting the N2 flow. While the main phases for a N2 flow rate of 180 L/h are alpha-Fe2O3 and FeMnO3, the predominant phase for high N2 flow rates (e.g., 650 L/h) is Fe2MnO4. Accordingly, a linear magnetization versus field behavior is observed for the hematite foams, while clear hysteresis loops are obtained for the Fe2MnO4 foams. Actually, the saturation magnetization of the foams containing Mn increases from 5 emu/g to 52 emu/g when the N2 flow rate (i.e., the amount of Fe2MnO4) is increased. The obtained foams are appealing for a wide range of applications, such as electromagnetic absorbers, catalysts supports, thermal and acoustic insulation systems or wirelessly magnetically-guided porous objects in fluids. PMID- 29439451 TI - Wogonin Suppresses the Activity of Matrix Metalloproteinase-9 and Inhibits Migration and Invasion in Human Hepatocellular Carcinoma. AB - As one of the major active ingredients in Radix Scutellariae, wogonin has been shown to be associated with various pharmacological activities on cancer cell growth, apoptosis, and cell invasion and migration. Here, we demonstrated that wogonin may harbor potential anti-metastatic activities in hepatocarcinoma (HCC). The anti-metastasis potential of wogonin and its underlying mechanisms were evaluated by ligand-protein docking approach, surface plasmon resonance assay, and in vitro gelatin zymography studies. Our results showed that wogonin (100 MUM, 50 MUM) suppressed MHCC97L and PLC/PRF/5 cells migration and invasion in vitro. The docking approach and surface plasmon resonance assay indicated that the potential binding affinity between wogonin and matrix metalloproteinase-9 (MMP-9) may lead to inhibition of MMP-9 activity and further leads to suppression of tumor metastasis. This conclusion was further verified by Western blot results and gelatin zymography analysis. Wogonin might be a potent treatment option for disrupting the tumor metastasis that favors HCC development. The potential active targets from computational screening integrated with biomedical study may help us to explore the molecular mechanism of herbal medicines. PMID- 29439452 TI - Interaction Multipath in Through-the-Wall Radar Imaging Based on Compressive Sensing. AB - Clutters caused by multipath have been widely researched in through-the-wall radar imaging (TWRI). The existing research work of multipath only consider reflections from the wall, while in the condition of a small scene, with the increasing number of targets, multipath from targets to targets, named interaction multipath, usually generates ghosts, which degrades the performance of TWRI. In order to mitigate the effect of interaction multipath, considering fast data acquisition and measurement reduction, we made use of the propagation characteristic of interaction multipath to build the sparse model of the target scene and developed a compressive sensing (CS)-based method, which is referred to as 'interaction CS'. For the number of point targets increasing from 5-8, intensive evaluation and direct comparison of the imaging results with existing methods are conducted to show that the proposed interaction CS performs better at ghost suppression in the same condition of the signal-to-noise ratio (SNR). PMID- 29439453 TI - Probing Contaminant-Induced Alterations in Chlorophyll Fluorescence by AC Dielectrophoresis-Based 2D-Algal Array. AB - The investigation of contaminant impact on algae requires rapid and reliable cell collection and optical detection. The capability of alternative current (AC) dielectrophoresis (DEP) collection of whole cell arrays with combined fluorescence microscopy detection to follow the alterations of chlorophyll fluorescence during environmental contaminant exposure was explored. The application of an AC-field of 100 V cm-1, 100 Hz for 30 min to capture and immobilize the cells of green alga Chlamydomonas reinhardtii in two-dimensional (2D) arrays does not induce changes in chlorophyll fluorescence. The results demonstrate that DEP-based 2D-arrays allow non-invasive detection of chlorophyll fluorescence change upon exposure to high concentrations of copper oxide nanoparticles and ionic copper. These results were in agreement with data obtained by flow cytometry used as a comparative method. The tool was also applied to follow the effect of a number of ubiquitous contaminants such as inorganic mercury, methylmercury, and diuron. However, a statistically significant short-term effect was observed only for mercury. Overall, DEP-based 2D-arrays of algal cells with fluorescence detection appear to be suitable for stain-free probing the effects on the photosynthetic microorganisms in highly polluted environment. PMID- 29439454 TI - Synthesis of Large-Scale Single-Crystalline Monolayer WS2 Using a Semi-Sealed Method. AB - As a two-dimensional semiconductor, WS2 has attracted great attention due to its rich physical properties and potential applications. However, it is still difficult to synthesize monolayer single-crystalline WS2 at larger scale. Here, we report the growth of large-scale triangular single-crystalline WS2 with a semi sealed installation by chemical vapor deposition (CVD). Through this method, triangular single-crystalline WS2 with an average length of more than 300 um was obtained. The largest one was about 405 MUm in length. WS2 triangles with different sizes and thicknesses were analyzed by optical microscope and atomic force microscope (AFM). Their optical properties were evaluated by Raman and photoluminescence (PL) spectra. This report paves the way to fabricating large scale single-crystalline monolayer WS2, which is useful for the growth of high quality WS2 and its potential applications in the future. PMID- 29439455 TI - Carotenoids-Antioxidant Properties. AB - The carotenoid group of pigments are ubiquitous in nature and more than 600 different carotenoids have been identified and characterized [1].[...]. PMID- 29439456 TI - Epinephrine in Anaphylaxis: Preclinical Study of Pharmacokinetics after Sublingual Administration of Taste-Masked Tablets for Potential Pediatric Use. AB - Epinephrine is a life-saving treatment in anaphylaxis. In community settings, a first-aid dose of epinephrine is injected from an auto-injector (EAI). Needle phobia highly contributes to EAI underuse, leading to fatalities-especially in children. A novel rapidly-disintegrating sublingual tablet (RDST) of epinephrine was developed in our laboratory as a potential alternative dosage form. The aim of this study was to evaluate the sublingual bioavailability of epinephrine 30 mg as a potential pediatric dose incorporated in our novel taste-masked RDST in comparison with intramuscular (IM) epinephrine 0.15 mg from EAI, the recommended and only available dosage form for children in community settings. We studied the rate and extent of epinephrine absorption in our validated rabbit model (n = 5) using a cross-over design. The positive control was IM epinephrine 0.15 mg from an EpiPen Jr(r). The negative control was a placebo RDST. Tablets were placed under the tongue for 2 min. Blood samples were collected at frequent intervals and epinephrine concentrations were measured using HPLC with electrochemical detection. The mean +/- SEM maximum plasma concentration (Cmax) of 16.7 +/- 1.9 ng/mL at peak time (Tmax) of 21 min after sublingual epinephrine 30 mg did not differ significantly (p > 0.05) from the Cmax of 18.8 +/- 1.9 ng/mL at a Tmax of 36 min after IM epinephrine 0.15 mg. The Cmax of both doses was significantly higher than the Cmax of 7.5 +/- 1.7 ng/mL of endogenous epinephrine after placebo. These taste-masked RDSTs containing a 30 mg dose of epinephrine have the potential to be used as an easy-to-carry, palatable, non-invasive treatment for anaphylactic episodes for children in community settings. PMID- 29439457 TI - Immune Landscape of Breast Cancers. AB - Breast cancer is a very heterogeneous disease, both at a molecular and a histological level. Five intrinsic subtypes were initially identified-Luminal-A, Luminal-B, HER2+, Triple negative/basal like (TNBC) and normal like-subsequently expanded to seven (Basal-like-1 and 2, mesenchymal, mesenchymal stem-like, luminal androgen receptor, immuno-modulatory and unstable). Although genetic and epigenetic changes are key pathogenic events, the immune system plays a substantial role in promoting progression and metastasis. This review will discuss the extent to which immune cells can be detected within the tumor microenvironment, as well as their prognostic role and relationship with the microbiome, with an emphasis on TNBC. PMID- 29439458 TI - Carrier-Free Microspheres of an Anti-Cancer Drug Synthesized via a Sodium Catalyst for Controlled-Release Drug Delivery. AB - There are several challenges involved in the development of effective anti-cancer drugs, including accurate drug delivery without toxic side effects. Possible systemic toxicity and the rapid biodegradation of drug carriers are potential risks in the use of carriers for drug-delivery formulations. Therefore, the carrier-free drug delivery of an anti-cancer drug is desirable. Herein, 4-amino-2 benzyl-6-methylpyrimidine (ABMP) was synthesized via a new method using a sodium catalyst, and proved to be effective in inducing breast cancer cell (MDA-MB-231) apoptosis. Moreover, the transparent amorphous state solid of ABMP was demonstrated to have a slow-release property in phosphate buffer solution (PBS). Microspheres of ABMP were prepared with diameters in the range of 5-15 MUm. The slow-release property of the ABMP microspheres indicated their potential use for controlled-release drug delivery. We believe that microspheres of ABMP have potential as a new kind of carrier-free anti-cancer drug delivery system. PMID- 29439460 TI - Investigation of Surface Morphology of 6H-SiC Irradiated with He+ and H2+ Ions. AB - Light ion implantation is one of the important procedures of smart cut for SiC based semiconductor fabrication. This work investigated the surface morphologies and microstructures of single crystal 6H-SiC irradiated by one or both of H2+ and He+ ions at room temperature and then annealed at specific temperatures. Blisters evolved from the coalescence of H nanocracks were formed in the H2+ and He++H2+ irradiated sample surface, while circular ripples originated from the pressure release of helium bubbles after high temperature annealing were formed in the He+ irradiated sample surface. The lateral radius a of the blisters in the irradiated sample with low H2+ fluence was larger than that in the irradiated sample with high H2+ fluence and with He++H2+ ions. About 8-58% of implanted H atoms contributed to the formation of the blisters. Compared with other irradiated samples, the ratio of w0/a and the density of the blisters in the He++H2+ irradiated samples were largest. The stress field of the blisters was simulated using finite element method and the inner pressure in the blisters was also calculated. The corresponding mechanism was analyzed and discussed. PMID- 29439459 TI - Natural Contamination with Mycotoxins Produced by Fusarium graminearum and Fusarium poae in Malting Barley in Argentina. AB - Two of the most common species of toxin-producing Fusarium contaminating small cereal grains are Fusarium graminearum and F. poae; with both elaborating diverse toxins, especially deoxynivalenol (DON) and nivalenol (NIV), respectively. The objective of our work during the 2012-2014 growing seasons was to screen crops for the most commonly isolated Fusarium species and to quantify DON and NIV toxins in natural malting-barley samples from different producing areas of Argentina. We identified 1180 Fusarium isolates in the 119 samples analyzed, with 51.2% being F. graminearum, 26.2% F. poae and 22.6% other species. We found high concentrations of mycotoxins, at maximum values of 12 MUg/g of DON and 7.71 MUg/g of NIV. Of the samples, 23% exhibited DON at an average of 2.36 MUg/g, with 44% exceeding the maximum limits (average of 5.24 MUg/g); 29% contained NIV at an average of 2.36 MUg/g; 7% contained both DON and NIV; and 55% were without DON or NIV. Finally, we report the mycotoxin contamination of the grain samples produced by F. graminearum and F. poae, those being the most frequent Fusarium species present. We identified the main Fusarium species affecting natural malting-barley grains in Argentina and documented the presence of many samples with elevated concentrations of DON and NIV. To our knowledge, the investigation reported here was the first to quantify the contamination by Fusarium and its toxins in natural samples of malting barley in Argentina. PMID- 29439461 TI - Early Diagnosis to Improve the Poor Prognosis of Pancreatic Cancer. AB - Pancreatic cancer (PC) has a poor prognosis due to delayed diagnosis. Early diagnosis is the most important factor for improving prognosis. For early diagnosis of PC, patients with clinical manifestations suggestive of PC and high risk for developing PC need to be selected for examinations for PC. Signs suggestive of PC (e.g., symptoms, diabetes mellitus, acute pancreatitis, or abnormal results of blood examinations) should not be missed, and the details of risks for PC (e.g., familial history of PC, intraductal mucin producing neoplasm, chronic pancreatitis, hereditary pancreatitis, or life habit) should be understood. Multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) can be performed for diagnosing PC, but the diagnostic ability of these examinations for PC is limited. Endoscopic diagnostic procedures, such as endoscopic ultrasonography, including fine-needle aspiration, and endoscopic retrograde pancreatocholangiography, including Serial Pancreatic-juice Aspiration Cytologic Examination (SPACE), could be recommended for a detailed examination to diagnose pancreatic carcinoma earlier. PMID- 29439462 TI - Physicochemical Properties and Oxidative Storage Stability of Milled Roselle (Hibiscus sabdariffa L.) Seeds. AB - Milled Roselle (Hibiscus sabdariffa L.) seeds of the UMKL cultivar were analyzed for proximate composition, water and oil absorption capacity, and the influence of storage conditions on storage stability. The storage stability was determined under four types of conditions: light/oxygen (air) (LO), light/nitrogen (LN), darkness/oxygen (air) (DO), and darkness/nitrogen (DN) while monitoring for seven consecutive months. During the storage period, the formation of volatiles was determined using dynamic headspace sampling and Gas Chromatography-Mass Spectrometry (GC-MS) analysis. In total, 85 volatiles were identified, mainly aldehydes, alcohols, ketones, furans, and acids indicating lipid oxidation. It is recommended that milled Roselle seeds should be flushed with nitrogen and stored in darkness. Under these conditions, the seeds can be stored for at least three months without changes in volatile profile. This is important to ensure the good quality of milled Roselle seeds for further commercialization. PMID- 29439463 TI - Compliance with Dietary Guidelines Varies by Weight Status: A Cross-Sectional Study of Australian Adults. AB - Population surveys have rarely identified dietary patterns associated with excess energy intake in relation to risk of obesity. This study uses self-reported food intake data from the validated Commonwealth Scientific and Industrial Research Organisation (CSIRO) Healthy Diet Score survey to examine whether apparent compliance with dietary guidelines varies by weight status. The sample of 185,951 Australian adults were majority female (71.8%), with 30.2%, 35.3% and 31.0% aged between 18-30, 31-50 and 51-70 years respectively. Using multinomial regression, in the adjusted model controlling for gender and age, individuals in the lowest quintile of diet quality were almost three times more likely to be obese than those in the highest quintile (OR 2.99, CI: 2.88:3.11; p < 0.001). The differential components of diet quality between normal and obese adults were fruit (difference in compliance score 12.9 points out of a possible 100, CI: 12.3:13.5; p < 0.001), discretionary foods (8.7 points, CI: 8.1:9.2; p < 0.001), and healthy fats (7.7 points, CI: 7.2:8.1; p < 0.001). Discretionary foods was the lowest scoring component across all gender and weight status groups, and are an important intervention target to improve diet quality. This study contributes to the evidence that diet quality is associated with health outcomes, including weight status, and will be useful in framing recommendations for obesity prevention and management. PMID- 29439464 TI - A Descriptive Longitudinal Study of Changes in Vape Shop Characteristics and Store Policies in Anticipation of the 2016 FDA Regulations of Tobacco Products, Including E-Cigarettes. AB - After proposing the "Deeming Rule" in 2014, the U.S. Food and Drug Administration (FDA) began regulating the manufacturing, marketing, and sales of electronic cigarette (e-cigarette) products as tobacco products in 2016. The current study conducted vape shop store observations and surveyed Los Angeles-area shop employees (assessing their beliefs, awareness, and perceptions of e-cigarettes and related FDA regulations) at two time points one year apart to better understand what vape shop retailers would do given FDA's soon-to-be-enacted Deeming Rule. The study also compared retailer beliefs/awareness/actions and store characteristics immediately after the Deeming Rule proposal versus a year after the Rule had been proposed, right before its enactment. Two data collection waves occurred before the Deeming Rule enactment, with Year 1 surveying 77 shops (2014) and Year 2 surveying 61 shops (2015-2016). Between the data collection points, 16 shops had closed. Among the shops that were open at both time points, the majority (95% in Year 1; 74% in Year 2) were aware of some FDA regulations or other policies applying to vape shops. However, overall awareness of FDA regulations and state/local policies governing e-cigarettes significantly decreased from Year 1 to Year 2. At both time points, all shops offered customers free puffs of nicotine-containing e-liquids (prohibited by the then upcoming Deeming Rule). Perceptions of e-cigarette safety also significantly decreased between the years. Exploring vape shop retailer perceptions and store policies (i.e., free puffs/samples displays, perceptions of e-cigarette safety, etc.) over time will help the FDA assess the needs of the vape shop community and develop more effective retailer education campaigns and materials targeted to increase compliance with the newly enacted regulations. PMID- 29439465 TI - Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival. AB - Inherited point mutations in collagen II in humans affecting mainly cartilage are broadly classified as chondrodysplasias. Most mutations occur in the glycine (Gly) of the Gly-X-Y repeats leading to destabilization of the triple helix. Arginine to cysteine substitutions that occur at either the X or Y position within the Gly-X-Y cause different phenotypes like Stickler syndrome and congenital spondyloepiphyseal dysplasia (SEDC). We investigated the consequences of arginine to cysteine substitutions (X or Y position within the Gly-X-Y) towards the N and C terminus of the triple helix. Protein expression and its secretion trafficking were analyzed. Substitutions R75C, R134C and R704C did not alter the thermal stability with respect to wild type; R740C and R789C proteins displayed significantly reduced melting temperatures (Tm) affecting thermal stability. Additionally, R740C and R789C were susceptible to proteases; in cell culture, R789C protein was further cleaved by matrix metalloproteinases (MMPs) resulting in expression of only a truncated fragment affecting its secretion and intracellular retention. Retention of misfolded R740C and R789C proteins triggered an ER stress response leading to apoptosis of the expressing cells. Arginine to cysteine mutations towards the C-terminus of the triple helix had a deleterious effect, whereas mutations towards the N-terminus of the triple helix (R75C and R134C) and R704C had less impact. PMID- 29439466 TI - Analysis of Peptide Ligand Specificity of Different Insect Adipokinetic Hormone Receptors. AB - Adipokinetic hormone (AKH) is a highly researched insect neuropeptide that induces the mobilization of carbohydrates and lipids from the fat body at times of high physical activity, such as flight and locomotion. As a naturally occurring ligand, AKH has undergone quite a number of amino acid changes throughout evolution, and in some insect species multiple AKHs are present. AKH acts by binding to a rhodopsin-like G protein-coupled receptor, which is related to the vertebrate gonadotropin-releasing hormone receptors. In the current study, we have cloned AKH receptors (AKHRs) from seven different species, covering a wide phylogenetic range of insect orders: the fruit fly, Drosophila melanogaster, and the yellow fever mosquito, Aedes aegypti (Diptera); the red flour beetle, Tribolium castaneum, and the large pine weevil, Hylobius abietis (Coleoptera); the honeybee, Apis mellifera (Hymenoptera); the pea aphid, Acyrthosiphon pisum (Hemiptera); and the desert locust, Schistocerca gregaria (Orthoptera). The agonistic activity of different insect AKHs, including the respective endogenous AKHs, at these receptors was tested with a bioluminescence-based assay in Chinese hamster ovary cells. All receptors were activated by their endogenous ligand in the nanomolar range. Based on our data, we can refute the previously formulated hypothesis that a functional AKH signaling system is absent in the beneficial species, Apis mellifera. Furthermore, our data also suggest that some of the investigated AKH receptors, such as the mosquito AKHR, are more selective for the endogenous (conspecific) ligand, while others, such as the locust AKHR, are more promiscuous and can be activated by AKHs from many other insects. This information will be of high importance when further analyzing the potential use of AKHRs as targets for developing novel pest control agents. PMID- 29439468 TI - On the Temporal Stability of Analyte Recognition with an E-Nose Based on a Metal Oxide Sensor Array in Practical Applications. AB - The paper deals with a functional instability of electronic nose (e-nose) units which significantly limits their real-life applications. Here we demonstrate how to approach this issue with example of an e-nose based on a metal oxide sensor array developed at the Karlsruhe Institute of Technology (Germany). We consider the instability of e-nose operation at different time scales ranging from minutes to many years. To test the e-nose we employ open-air and headspace sampling of analyte odors. The multivariate recognition algorithm to process the multisensor array signals is based on the linear discriminant analysis method. Accounting for the received results, we argue that the stability of device operation is mostly affected by accidental changes in the ambient air composition. To overcome instabilities, we introduce the add-training procedure which is found to successfully manage both the temporal changes of ambient and the drift of multisensor array properties, even long-term. The method can be easily implemented in practical applications of e-noses and improve prospects for device marketing. PMID- 29439467 TI - Blood Mitochondrial DNA Content in HIV-Exposed Uninfected Children with Autism Spectrum Disorder. AB - Long-term outcomes of perinatal exposure to maternal antiretroviral therapy in HIV-exposed uninfected (HEU) children are unknown. However, both HIV antiretroviral therapy and autism spectrum disorder (ASD) have been associated with mitochondrial alterations. Leukocyte mitochondrial DNA (mtDNA) content can serve as a marker for mitochondrial dysfunction. In this cross-sectional, nested case-control study, HEU children with ASD were matched approximately 1:3 on age, sex, and ethnicity to HEU children without ASD, HIV-unexposed uninfected (HUU) controls, and HUU children with ASD. Leukocyte mtDNA content was measured using quantitative PCR. Among 299 HEU in this study, 14 (4.7%) were diagnosed with ASD, which is higher than the general population prevalence estimates. HEU children without ASD and HUU children with ASD had higher mtDNA content than HUU controls. HEU children with ASD had significantly higher mtDNA content than all other study groups. Our results suggest a clear association between elevated leukocyte mtDNA content and both HEU and ASD status. This may implicate mitochondrial dysfunction as a contributor to the high ASD prevalence observed in our cohort. PMID- 29439469 TI - Determination of Non-Transferrin Bound Iron, Transferrin Bound Iron, Drug Bound Iron and Total Iron in Serum in a Rats after IV Administration of Sodium Ferric Gluconate Complex by Simple Ultrafiltration Inductively Coupled Plasma Mass Spectrometric Detection. AB - A rapid, sensitive and specific ultrafiltration inductively-coupled plasma mass spectrometry (UF-ICP-MSICP-MS) method was developed and validated for the quantification of non-transferrin bound iron (NTBI), transferrin bound iron (TBI), drug bound iron (DI) and total iron (TI) in the same rat serum sample after intravenous (IV) administration of iron gluconate nanoparticles in sucrose solution (Ferrlecit(r)). Ultrafiltration with a 30 kDa molecular cut-off filter was used for sample cleanup. Different elution solvents were used to separate each form of iron from sample serum. Isolated fractions were subjected to inductively-coupled mass spectrometric analysis after microwave digestion in 4% nitric acid. The reproducibility of the method was evaluated by precision and accuracy. The calibration curve demonstrated linearity from 5-500 ng/mL with a regression (r2) of more than 0.998. This method was effectively implemented to quantify rat pharmacokinetic study samples after intravenous administration of Ferrlecit(r). The method was successfully applied to a pharmacokinetic (PK) study of Ferrlecit in rats. The colloidal iron followed first order kinetics with half life of 2.2 h and reached background or pre-dose levels after 12 h post-dosing. The drug shown a clearance of 0.31 mL/min/kg and volume of distribution of 0.05 L/kg. 19.4 +/- 2.4 mL/h/kg. PMID- 29439471 TI - From Concept to Commerce: Developing a Successful Fungal Endophyte Inoculant for Agricultural Crops. AB - The development of endophyte inoculants for agricultural crops has been bedevilled by the twin problems of a lack of reliability and consistency, with a consequent lack of belief among end users in the efficacy of such treatments. We have developed a successful research pipeline for the production of a reliable, consistent and environmentally targeted fungal endophyte seed-delivered inoculant for barley cultivars. Our approach was developed de novo from an initial concept to source candidate endophyte inoculants from a wild relative of barley, Hordeum murinum (wall barley). A careful screening and selection procedure and extensive controlled environment testing of fungal endophyte strains, followed by multi year field trials has resulted in the validation of an endophyte consortium suitable for barley crops grown on relatively dry sites. Our approach can be adapted for any crop or environment, provided that the set of first principles we have developed is followed. Here, we report how we developed the successful pipeline for the production of an economically viable fungal endophyte inoculant for barley cultivars. PMID- 29439470 TI - Melatonin Alleviates High Temperature-Induced Pollen Abortion in Solanum lycopersicum. AB - Melatonin is a pleiotropic signal molecule that plays critical roles in regulating plant growth and development, as well as providing physiological protections against various environmental stresses. Nonetheless, the mechanisms for melatonin-mediated pollen thermotolerance remain largely unknown. In this study, we report that irrigation treatment with melatonin (20 uM) effectively ameliorated high temperature-induced inactivation of pollen and inhibition of pollen germination in tomato (Solanum lycopersicum) plants. Melatonin alleviated reactive oxygen species production in tomato anthers under high temperature by the up-regulation of the transcription and activities of several antioxidant enzymes. Transmission electron micrograph results showed that high temperature induced pollen abortion is associated with a premature degeneration of the tapetum cells and the formation of defective pollen grains with degenerated nuclei at the early uninuclear microspore stage, whilst melatonin protected degradation of organelles by enhancing the expression of heat shock protein genes to refold unfolded proteins and the expression of autophagy-related genes and formation of autophagosomes to degrade denatured proteins. These findings suggest a novel function of melatonin to protect pollen activity under high temperature and support the potential effects of melatonin on reproductive development of plants. PMID- 29439472 TI - Snacking Patterns in Children: A Comparison between Australia, China, Mexico, and the US. AB - Snacking is common in children and influenced by many factors. The aim of this study is to provide insight of both common and country-specific characteristics of snacking among 4-13 year old children. We analyzed snacking prevalence, energy and nutrient contributions from snacking across diverse cultures and regions, represented by Australia, China, Mexico, and the US using data from respective national surveys. We found that the highest prevalence of snacking was in Australia and the US (over 95%) where snacking provided one-third and one-quarter of total energy intake (TEI), respectively, followed by Mexico (76%, provided 15% TEI) and China (65%, provided 10% TEI). Compared to 4-8 year-olds, the consumption of fruits and milk was lower in 9-13 year-old children, with a trend of increasing savory snacks consumption in China, Mexico, and the US. The nutrient density index of added sugars and saturated fat was higher, especially in Australia, Mexico, and the US. Results suggested that snacking could be an occasion to promote fruit and vegetable consumption in all countries, especially for older children. Snacking guidelines should focus on reducing consumption of snacks high in saturated fat and added sugars for Australia, Mexico, and the US, whereas improving dairy consumption is important in China. PMID- 29439473 TI - Determination of Proteinaceous Selenocysteine in Selenized Yeast. AB - A method for the quantitation of proteinaceous selenocysteine (SeCys) in Se-rich yeast was developed. The method is based on the reduction of the Se-Se and S-Se bridges with dithiotretiol, derivatization with iodoacetamide (carbamidomethylation), followed by HPLC-ICP MS. The chromatographic conditions were optimized for the total recovery of the proteinaceous selenocysteine, the minimum number of peaks in the chromatogram (reduction of derivatization products of other Se-species present) and the baseline separation. A typical chromatogram of a proteolytic digest of selenized yeast protein consisted of up to five peaks (including SeMet, carbamidomethylated (CAM)-SeCys, and Se(CAM)2) identified by retention time matching with available standards and electrospray MS. Inorganic selenium non-specifically attached to proteins and selenomethionine could be quantified (in the form of Se(CAM)2) along with SeCys. Selenocysteine, selenomethionine, inorganic selenium, and the water soluble-metabolite fraction accounted for the totality of selenium species in Se-rich yeast. PMID- 29439474 TI - Bacterial Heterologous Expression System for Reconstitution of Chloroplast Inner Division Ring and Evaluation of Its Contributors. AB - Plant chloroplasts originate from the symbiotic relationship between ancient free living cyanobacteria and ancestral eukaryotic cells. Since the discovery of the bacterial derivative FtsZ gene-which encodes a tubulin homolog responsible for the formation of the chloroplast inner division ring (Z ring)-in the Arabidopsis genome in 1995, many components of the chloroplast division machinery were successively identified. The knowledge of these components continues to expand; however, the mode of action of the chloroplast dividing system remains unknown (compared to bacterial cell division), owing to the complexities faced in in planta analyses. To date, yeast and bacterial heterologous expression systems have been developed for the reconstitution of Z ring-like structures formed by chloroplast FtsZ. In this review, we especially focus on recent progress of our bacterial system using the model bacterium Escherichia coli to dissect and understand the chloroplast division machinery-an evolutionary hybrid structure composed of both bacterial (inner) and host-derived (outer) components. PMID- 29439475 TI - Partial Discharge Monitoring on Metal-Enclosed Switchgear with Distributed Non Contact Sensors. AB - Metal-enclosed switchgear, which are widely used in the distribution of electrical energy, play an important role in power distribution networks. Their safe operation is directly related to the reliability of power system as well as the power quality on the consumer side. Partial discharge detection is an effective way to identify potential faults and can be utilized for insulation diagnosis of metal-enclosed switchgear. The transient earth voltage method, an effective non-intrusive method, has substantial engineering application value for estimating the insulation condition of switchgear. However, the practical application effectiveness of TEV detection is not satisfactory because of the lack of a TEV detection application method, i.e., a method with sufficient technical cognition and analysis. This paper proposes an innovative online PD detection system and a corresponding application strategy based on an intelligent feedback distributed TEV wireless sensor network, consisting of sensing, communication, and diagnosis layers. In the proposed system, the TEV signal or status data are wirelessly transmitted to the terminal following low-energy signal preprocessing and acquisition by TEV sensors. Then, a central server analyzes the correlation of the uploaded data and gives a fault warning level according to the quantity, trend, parallel analysis, and phase resolved partial discharge pattern recognition. In this way, a TEV detection system and strategy with distributed acquisition, unitized fault warning, and centralized diagnosis is realized. The proposed system has positive significance for reducing the fault rate of medium voltage switchgear and improving its operation and maintenance level. PMID- 29439476 TI - Virus-Like-Vaccines against HIV. AB - Protection against chronic infections has necessitated the development of ever more potent vaccination tools. HIV seems to be the most challenging foe, with a remarkable, poorly immunogenic and fragile surface glycoprotein and the ability to overpower the cell immune system. Virus-like-particle (VLP) vaccines have emerged as potent inducers of antibody and helper T cell responses, while replication-deficient viral vectors have yielded potent cytotoxic T cell responses. Here, we review the emerging concept of merging these two technologies into virus-like-vaccines (VLVs) for the targeting of HIV. Such vaccines are immunologically perceived as viruses, as they infect cells and produce VLPs in situ, but they only resemble viruses, as the replication defective vectors and VLPs cannot propagate an infection. The inherent safety of such a platform, despite robust particle production, is a distinct advantage over live-attenuated vaccines that must balance safety and immunogenicity. Previous studies have delivered VLVs encoded in modified Vaccinia Ankara vectors and we have developed the concept into a single-reading adenovirus-based technology capable of eliciting robust CD8+ and CD4+ T cells responses and trimer binding antibody responses. Such vaccines offer the potential to display the naturally produced immunogen directly and induce an integrated humoral and cellular immune response. PMID- 29439478 TI - Bacterial Microbiota of Rice Roots: 16S-Based Taxonomic Profiling of Endophytic and Rhizospheric Diversity, Endophytes Isolation and Simplified Endophytic Community. AB - Rice is currently the most important food crop in the world and we are only just beginning to study the bacterial associated microbiome. It is of importance to perform screenings of the core rice microbiota and also to develop new plant microbe models and simplified communities for increasing our understanding about the formation and function of its microbiome. In order to begin to address this aspect, we have performed a 16S rDNA taxonomic bacterial profiling of the rhizosphere and endorhizosphere of two high-yield rice cultivars-Pionero 2010 FL and DANAC SD20A-extensively grown in Venezuela in 2014. Fifteen putative bacterial endophytes were then isolated from surface-sterilized roots and further studied in vitro and in planta. We have then performed inoculation of rice seedlings with a simplified community composed by 10 of the isolates and we have tracked them in the course of 30 days in greenhouse cultivation. The results obtained suggest that a set was able to significantly colonize together the rice endorhizospheres, indicating possible cooperation and the ability to form a stable multispecies community. This approach can be useful in the development of microbial solutions for a more sustainable rice production. PMID- 29439477 TI - A Practical Review of the Emerging Direct Anticoagulants, Laboratory Monitoring, and Reversal Agents. AB - Millions of patients in the United States use anticoagulation for a variety of indications, such as the prevention of stroke in those with atrial fibrillation (AF) and the treatment and prevention of venous thrombosis. For over six decades warfarin was the only available oral anticoagulant, but now several DOACs are available and their use has become more prevalent in recent years. In spite of this increased use, many physicians remain reluctant to prescribe DOACs due to concerns about bleeding and reversibility. PMID- 29439480 TI - Appropriate Handling, Processing and Analysis of Blood Samples Is Essential to Avoid Oxidation of Vitamin C to Dehydroascorbic Acid. AB - Vitamin C (ascorbate) is the major water-soluble antioxidant in plasma and its oxidation to dehydroascorbic acid (DHA) has been proposed as a marker of oxidative stress in vivo. However, controversy exists in the literature around the amount of DHA detected in blood samples collected from various patient cohorts. In this study, we report on DHA concentrations in a selection of different clinical cohorts (diabetes, pneumonia, cancer, and critically ill). All clinical samples were collected into EDTA anticoagulant tubes and processed at 4 degrees C prior to storage at -80 degrees C for subsequent analysis by HPLC with electrochemical detection. We also investigated the effects of different handling and processing conditions on short-term and long-term ascorbate and DHA stability in vitro and in whole blood and plasma samples. These conditions included metal chelation, anticoagulants (EDTA and heparin), and processing temperatures (ice, 4 degrees C and room temperature). Analysis of our clinical cohorts indicated very low to negligible DHA concentrations. Samples exhibiting haemolysis contained significantly higher concentrations of DHA. Metal chelation inhibited oxidation of vitamin C in vitro, confirming the involvement of contaminating metal ions. Although EDTA is an effective metal chelator, complexes with transition metal ions are still redox active, thus its use as an anticoagulant can facilitate metal ion-dependent oxidation of vitamin C in whole blood and plasma. Handling and processing blood samples on ice (or at 4 degrees C) delayed oxidation of vitamin C by a number of hours. A review of the literature regarding DHA concentrations in clinical cohorts highlighted the fact that studies using colourimetric or fluorometric assays reported significantly higher concentrations of DHA compared to those using HPLC with electrochemical detection. In conclusion, careful handling and processing of samples, combined with appropriate analysis, is crucial for accurate determination of ascorbate and DHA in clinical samples. PMID- 29439479 TI - Zinc and Skin Disorders. AB - The skin is the third most zinc (Zn)-abundant tissue in the body. The skin consists of the epidermis, dermis, and subcutaneous tissue, and each fraction is composed of various types of cells. Firstly, we review the physiological functions of Zn and Zn transporters in these cells. Several human disorders accompanied with skin manifestations are caused by mutations or dysregulation in Zn transporters; acrodermatitis enteropathica (Zrt-, Irt-like protein (ZIP)4 in the intestinal epithelium and possibly epidermal basal keratinocytes), the spondylocheiro dysplastic form of Ehlers-Danlos syndrome (ZIP13 in the dermal fibroblasts), transient neonatal Zn deficiency (Zn transporter (ZnT)2 in the secretory vesicles of mammary glands), and epidermodysplasia verruciformis (ZnT1 in the epidermal keratinocytes). Additionally, acquired Zn deficiency is deeply involved in the development of some diseases related to nutritional deficiencies (acquired acrodermatitis enteropathica, necrolytic migratory erythema, pellagra, and biotin deficiency), alopecia, and delayed wound healing. Therefore, it is important to associate the existence of mutations or dysregulation in Zn transporters and Zn deficiency with skin manifestations. PMID- 29439481 TI - Review of Gallium-68 PSMA PET/CT Imaging in the Management of Prostate Cancer. AB - Over 90% of prostate cancers over-express prostate specific membrane antigen (PSMA) and these tumor cells may be accurately targeted for diagnosis by 68Ga PSMA-positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) imaging. This novel molecular imaging modality appears clinically to have superseded CT, and appears superior to MR imaging, for the detection of metastatic disease. 68Ga PSMA PET/CT has the ability to reliably stage prostate cancer at presentation and can help inform an optimal treatment approach. Novel diagnostic applications of 68Ga-PSMA PET/CT include guiding biopsy to improve sampling accuracy, and guiding surgery and radiotherapy. In addition to facilitating the management of metastatic castrate resistant prostate cancer (mCRPC), 68Ga-PSMA can select patients who may benefit from targeted systemic radionuclide therapy. 68Ga-PSMA is the diagnostic positron-emitting theranostic pair with the beta emitter Lutetium-177 PSMA (177Lu-PSMA) and alpha-emitter Actinium-225 PSMA (225Ac-PSMA) which can both be used to treat PSMA-avid metastases of prostate cancer in the molecular tumor-targeted approach of theranostic nuclear oncology. PMID- 29439482 TI - Ecdysonelactones, Ecdysteroids from the Tropical Eastern Pacific Zoantharian Antipathozoanthus hickmani. AB - Despite a large occurrence, especially over the Pacific Ocean, the chemical diversity of marine invertebrates belonging to the order Zoantharia is largely underexplored. For the two species of the genus Antipathozoanthus no chemical study has been reported so far. The first chemical investigation of Antipathozoanthus hickmani collected at the Marine Protected Area "El Pelado", Santa Elena, Ecuador, led to the isolation of four new ecdysteroid derivatives named ecdysonelactones. The structures of ecdysonelactones A-D (1-4) were determined based on their spectroscopy data, including 1D and 2D NMR and HRMS. The four compounds of this family of ecdysteroids feature an unprecedented gamma lactone fused at the C-2/C-3 position of ring A. These derivatives exhibited neither antimicrobial nor cytotoxic activities. PMID- 29439484 TI - Experience of Nurses in Hemodialysis Care: A Phenomenological Study. AB - This study aimed to describe the experiences of nurses in hemodialysis care. In this phenomenological study, purposive sampling began and continued until data saturation. The research environment was the Hemodialysis unit. Data was collected through semi-structured interviews. Finally, two main classes and four sub-classes were identified, including factors effective on care (inhibitors and facilitators) and care outcomes (the negative effects of care on the nurse and the positive effects of care on the patient), and "challenging care" as the main theme. As the results show, nurses suffer from several physical and mental harm, and this harm even extends to their family environment, and their families are indirectly affected by the negative effects of this care. Therefore, strengthening management approaches to eliminate the inhibitor factors is essential in order to prevent nurses' burnout or quitting while improving the quality of care provided by them. PMID- 29439483 TI - Anti-Cancer Activities of Diterpenoids Derived from Euphorbia fischeriana Steud. AB - Euphorbia fischeriana Steud is an essential oriental folk medicine used for healing cancer, edema and tuberculosis. Recently, its anticancer activitity has attracted more attention. A volume of research has indicated that diterpenoids are the major anticancer active constituents from this medicinal herb. In this review, we aimed to provide a summary of the promising anticancer diterpenoids from this plant; many diterpenoids mentioned in this article are newly discovered diterpenoids. According to the carbon skeleton and substituents, they can be classified into eight subtypes: ent-abietane, daphnane, tigliane, ingenane, ent atisane, ent-rosane, ent-kaurane, and lathyrane. Futhermore, their key anticancer mechanisms and protein targets of these compounds will be discussed. These natural diterpenoids could provide a reservoir for drug discovery. PMID- 29439485 TI - Effect of Laser Remelting on Friction-Wear Behaviors of Cold Sprayed Al Coatings in 3.5% NaCl Solution. AB - A cold sprayed Al coating on S355 structural steel was processed using a laser remelting (LR). The surface and cross-section morphologies, chemical compositions, and phases of as-obtained Al coating before and after LR were analyzed using a scanning electronic microscope (SEM), energy dispersive spectrometer (EDS), and X-ray diffractometer (XRD), respectively, and their hardness was measured using a micro-hardness tester. The friction-wear behaviors of Al coating before and after LR in 3.5% NaCl solution were conducted to simulate the sand and gravel scouring on its surface in seawater, the effects of wear loads and speeds on the tribological properties of Al coating were analyzed, and the wear mechanisms under different wear loads and speeds were also discussed. The results show that the Al coating after LR is primarily composed of an Al phase and its hardness is 104.66 HV, increasing 54.70 HV than the cold sprayed Al coating. The average coefficient of friction (COF) of cold sprayed Al coating at the wear load of 0.5, 1.0 and 1.5 N is 0.285, 0.239, and 0.435, respectively, while that after LR is 0.243, 0.227, and 0.327, respectively, decreased by 14.73%, 5.02% and 24.83% compared to the cold sprayed Al coating. The wear rate of cold sprayed Al coating at the wear load of 0.5, 1.0 and 1.5 N is 1.60 * 10-4, 2.36 * 10-4, and 2.40 * 10-4 mm3/m.N, respectively, while that after LR is 1.59 * 10-4, 1.70 * 10-4, and 1.94 * 10-4 mm3/m.N, respectively, decreased by 1%, 32%, and 23%, respectively, indicating that LR has high anti friction performance. Under the wear load action of 1.0 N, the average COF of laser remelted Al coating at the wear speeds of 300, 400 and 500 times/min is 0.294, 0.279, and 0.239, respectively, and the corresponding wear rate is 1.06 * 10-4, 1.24 * 10-4, and 1.70 * 10-4 mm3/m.N, respectively. The wear mechanism of cold sprayed Al coating is primarily corrosion wear at the loads of 0.5 and 1.0 N, and that at the load of 1.5 N is abrasive wear and fatigue wear; while that after LR is abrasive wear and fatigue wear, with no corrosion wear, showing that LR improves its corrosion and wear resistance. PMID- 29439486 TI - Biosorption of Cadmium by Non-Toxic Extracellular Polymeric Substances (EPS) Synthesized by Bacteria from Marine Intertidal Biofilms. AB - Cadmium is a major heavy metal found in polluted aquatic environments, mainly derived from industrial production processes. We evaluated the biosorption of solubilized Cd2+ using the extracellular polymeric substances (EPS) produced by Bacillus sp. MC3B-22 and Microbacterium sp. MC3B-10 (Microbactan); these bacteria were originally isolated from intertidal biofilms off the coast of Campeche, Mexico. EPS were incubated with different concentrations of cadmium in ultrapure water. Residual Cd2+ concentrations were determined by Inductive Coupled Plasma Optic Emission Spectrometry and the maximum sorption capacity (Qmax) was calculated according to the Langmuir model. EPS were characterized by X-ray photoelectron spectroscopy (XPS) before and after sorption. The Qmax of Cd2+ was 97 mg g-1 for Microbactan and 141 mg g-1 for MC3B-22 EPS, these adsorption levels being significantly higher than previously reported for other microbial EPS. In addition, XPS analysis revealed changes in structure of EPS after biosorption and showed that amino functional groups contributed to the binding of Cd2+, unlike other studies that show the carbohydrate fraction is responsible for this activity. This work expands the current view of bacterial species capable of synthesizing EPS with biosorbent potential for cadmium and provides evidence that different chemical moieties, other than carbohydrates, participate in this process. PMID- 29439487 TI - Alternative Splicing as a Target for Cancer Treatment. AB - Alternative splicing is a key mechanism determinant for gene expression in metazoan. During alternative splicing, non-coding sequences are removed to generate different mature messenger RNAs due to a combination of sequence elements and cellular factors that contribute to splicing regulation. A different combination of splicing sites, exonic or intronic sequences, mutually exclusive exons or retained introns could be selected during alternative splicing to generate different mature mRNAs that could in turn produce distinct protein products. Alternative splicing is the main source of protein diversity responsible for 90% of human gene expression, and it has recently become a hallmark for cancer with a full potential as a prognostic and therapeutic tool. Currently, more than 15,000 alternative splicing events have been associated to different aspects of cancer biology, including cell proliferation and invasion, apoptosis resistance and susceptibility to different chemotherapeutic drugs. Here, we present well established and newly discovered splicing events that occur in different cancer-related genes, their modification by several approaches and the current status of key tools developed to target alternative splicing with diagnostic and therapeutic purposes. PMID- 29439488 TI - A Physical Health Profile of Youths Living with a "Hikikomori" Lifestyle. AB - A cross-sectional study was designed to understand the impacts of "hikikomori" lifestyle on physical health. A total of 104 eligible hikikomori cases were recruited from the social services network of Hong Kong with a mean age of 19.02 +/- 3.62 (ranged 13-31) year-old, and had completed the set of questionnaires and a series of anthropometric and physical health measurements. Despite SF36 score of 84.0 indicated good physical functioning in general, participants were lived sedentarily with high incidence of hypertension at 15.4% and prehypertension at 31.7%. Occurrence of hypertension and prehypertension in cases living as hikikomori >6 months were 3 times and 1.5 times higher than those newly onset cases, respectively. The blood pressure levels were correlated with age and all obesity index parameters measured including waist circumference and body mass index. Results also observed a shift of body weight from underweight to overweight and obesity along the hikikomori duration. Half of the hypertensive cases involved the elevation of systolic blood pressure, which suggested higher odds of cardiovascular complications. In conclusion, the hikikomori lifestyle could be a risk behavior that may harm the younger generation physically by promoting obesity and hypertension and probably other chronic illnesses. PMID- 29439489 TI - The Low-Renin Hypertension Phenotype: Genetics and the Role of the Mineralocorticoid Receptor. AB - A substantial proportion of patients with hypertension have a low or suppressed renin. This phenotype of low-renin hypertension (LRH) may be the manifestation of inherited genetic syndromes, acquired somatic mutations, or environmental exposures. Activation of the mineralocorticoid receptor is a common final mechanism for the development of LRH. Classically, the individual causes of LRH have been considered to be rare diseases; however, recent advances suggest that there are milder and "non-classical" variants of many LRH-inducing conditions. In this regard, our understanding of the underlying genetics and mechanisms accounting for LRH, and therefore, potentially the pathogenesis of a large subset of essential hypertension, is evolving. This review will discuss the potential causes of LRH, with a focus on implicated genetic mechanisms, the expanding recognition of non-classical variants of conditions that induce LRH, and the role of the mineralocorticoid receptor in determining this phenotype. PMID- 29439490 TI - Chemical Sensor Systems and Associated Algorithms for Fire Detection: A Review. AB - Indoor fire detection using gas chemical sensing has been a subject of investigation since the early nineties. This approach leverages the fact that, for certain types of fire, chemical volatiles appear before smoke particles do. Hence, systems based on chemical sensing can provide faster fire alarm responses than conventional smoke-based fire detectors. Moreover, since it is known that most casualties in fires are produced from toxic emissions rather than actual burns, gas-based fire detection could provide an additional level of safety to building occupants. In this line, since the 2000s, electrochemical cells for carbon monoxide sensing have been incorporated into fire detectors. Even systems relying exclusively on gas sensors have been explored as fire detectors. However, gas sensors respond to a large variety of volatiles beyond combustion products. As a result, chemical-based fire detectors require multivariate data processing techniques to ensure high sensitivity to fires and false alarm immunity. In this paper, we the survey toxic emissions produced in fires and defined standards for fire detection systems. We also review the state of the art of chemical sensor systems for fire detection and the associated signal and data processing algorithms. We also examine the experimental protocols used for the validation of the different approaches, as the complexity of the test measurements also impacts on reported sensitivity and specificity measures. All in all, further research and extensive test under different fire and nuisance scenarios are still required before gas-based fire detectors penetrate largely into the market. Nevertheless, the use of dynamic features and multivariate models that exploit sensor correlations seems imperative. PMID- 29439491 TI - Exogenous Melatonin Mitigates Acid Rain Stress to Tomato Plants through Modulation of Leaf Ultrastructure, Photosynthesis and Antioxidant Potential. AB - Acid rain (AR) is a serious global environmental issue causing physio morphological changes in plants. Melatonin, as an indoleamine molecule, has been known to mediate many physiological processes in plants under different kinds of environmental stress. However, the role of melatonin in acid rain stress tolerance remains inexpressible. This study investigated the possible role of melatonin on different physiological responses involving reactive oxygen species (ROS) metabolism in tomato plants under simulated acid rain (SAR) stress. SAR stress caused the inhibition of growth, damaged the grana lamella of the chloroplast, photosynthesis, and increased accumulation of ROS and lipid peroxidation in tomato plants. To cope the detrimental effect of SAR stress, plants under SAR condition had increased both enzymatic and nonenzymatic antioxidant substances compared with control plants. But such an increase in the antioxidant activities were incapable of inhibiting the destructive effect of SAR stress. Meanwhile, melatonin treatment increased SAR-stress tolerance by repairing the grana lamella of the chloroplast, improving photosynthesis and antioxidant activities compared with those in SAR-stressed plants. However, these possible effects of melatonin are dependent on concentration. Moreover, our study suggests that 100-MUM melatonin treatment improved the SAR-stress tolerance by increasing photosynthesis and ROS scavenging antioxidant activities in tomato plants. PMID- 29439492 TI - An Improved Quadrilateral Fitting Algorithm for the Water Column Contribution in Airborne Bathymetric Lidar Waveforms. AB - In this paper, an improved method based on a mixture of Gaussian and quadrilateral functions is presented to process airborne bathymetric LiDAR waveforms. In the presented method, the LiDAR waveform is fitted to a combination of three functions: one Gaussian function for the water surface contribution, another Gaussian function for the water bottom contribution, and a new quadrilateral function to fit the water column contribution. The proposed method was tested on a simulated dataset and a real dataset, with the focus being mainly on the performance of retrieving bottom response and water depths. We also investigated the influence of the parameter settings on the accuracy of the bathymetry estimates. The results demonstrate that the improved quadrilateral fitting algorithm shows a superior performance in terms of low RMSE and a high detection rate in the water depth and magnitude retrieval. What's more, compared with the use of a triangular function or the existing quadrilateral function to fit the water column contribution, the presented method retrieved the least noise and the least number of unidentified waveforms, showed the best performance in fitting the return waveforms, and had consistent fitting goodness for all different water depths. PMID- 29439495 TI - Active Electro-Location of Objects in the Underwater Environment Based on the Mixed Polarization Multiple Signal Classification Algorithm. AB - This article proposes a novel active localization method based on the mixed polarization multiple signal classification (MP-MUSIC) algorithm for positioning a metal target or an insulator target in the underwater environment by using a uniform circular antenna (UCA). The boundary element method (BEM) is introduced to analyze the boundary of the target by use of a matrix equation. In this method, an electric dipole source as a part of the locating system is set perpendicularly to the plane of the UCA. As a result, the UCA can only receive the induction field of the target. The potential of each electrode of the UCA is used as spatial-temporal localization data, and it does not need to obtain the field component in each direction compared with the conventional fields-based localization method, which can be easily implemented in practical engineering applications. A simulation model and a physical experiment are constructed. The simulation and the experiment results provide accurate positioning performance, with the help of verifying the effectiveness of the proposed localization method in underwater target locating. PMID- 29439494 TI - Listeriolysin O Causes ENaC Dysfunction in Human Airway Epithelial Cells. AB - Pulmonary permeability edema is characterized by reduced alveolar Na+ uptake capacity and capillary barrier dysfunction and is a potentially lethal complication of listeriosis. Apical Na+ uptake is mainly mediated by the epithelial sodium channel (ENaC) and initiates alveolar liquid clearance. Here we examine how listeriolysin O (LLO), the pore-forming toxin of Listeria monocytogenes, impairs the expression and activity of ENaC. To that purpose, we studied how sub-lytic concentrations of LLO affect negative and positive regulators of ENaC expression in the H441 airway epithelial cell line. LLO reduced expression of the crucial ENaC-alpha subunit in H441 cells within 2 h and this was preceded by activation of PKC-alpha, a negative regulator of the channel's expression. At later time points, LLO caused a significant reduction in the phosphorylation of Sgk-1 at residue T256 and of Akt-1 at residue S473, both of which are required for full activation of ENaC. The TNF-derived TIP peptide prevented LLO-mediated PKC-alpha activation and restored phospho-Sgk-1-T256. The TIP peptide also counteracted the observed LLO-induced decrease in amiloride sensitive Na+ current and ENaC-alpha expression in H441 cells. Intratracheally instilled LLO caused profound pulmonary edema formation in mice, an effect that was prevented by the TIP peptide; thus indicating the therapeutic potential of the peptide for the treatment of pore-forming toxin-associated permeability edema. PMID- 29439496 TI - UAV-Assisted Dynamic Clustering of Wireless Sensor Networks for Crop Health Monitoring. AB - In this study, a crop health monitoring system is developed by using state of the art technologies including wireless sensors and Unmanned Aerial Vehicles (UAVs). Conventionally data is collected from sensor nodes either by fixed base stations or mobile sinks. Mobile sinks are considered a better choice nowadays due to their improved network coverage and energy utilization. Usually, the mobile sink is used in two ways: either it goes for random walk to find the scattered nodes and collect data, or follows a pre-defined path established by the ground network/clusters. Neither of these options is suitable in our scenario due to the factors like dynamic data collection, the strict targeted area required to be scanned, unavailability of a large number of nodes, dynamic path of the UAV, and most importantly, none of these are known in advance. The contribution of this paper is the formation of dynamic runtime clusters of field sensors by considering the above mentioned factors. Furthermore a mechanism (Bayesian classifier) is defined to select best node as cluster head. The proposed system is validated through simulation results, lab and infield experiments using concept devices. The obtained results are encouraging, especially in terms of deployment time, energy, efficiency, throughput and ease of use. PMID- 29439493 TI - Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies. AB - Isocitrate dehydrogenases 1 and 2 (IDH1,2), the key Krebs cycle enzymes that generate NADPH reducing equivalents, undergo heterozygous mutations in >70% of low- to mid-grade gliomas and ~20% of acute myeloid leukemias (AMLs) and gain an unusual new activity of reducing the alpha-ketoglutarate (alpha-KG) to D-2 hydroxyglutarate (D-2HG) in a NADPH-consuming reaction. The oncometabolite D-2HG, which accumulates >35 mM, is widely accepted to drive a progressive oncogenesis besides exacerbating the already increased oxidative stress in these cancers. More importantly, D-2HG competes with alpha-KG and inhibits a large number of alpha-KG-dependent dioxygenases such as TET (Ten-eleven translocation), JmjC domain-containing KDMs (histone lysine demethylases), and the ALKBH DNA repair proteins that ultimately lead to hypermethylation of the CpG islands in the genome. The resulting CpG Island Methylator Phenotype (CIMP) accounts for major gene expression changes including the silencing of the MGMT (O6-methylguanine DNA methyltransferase) repair protein in gliomas. Glioma patients with IDH1 mutations also show better therapeutic responses and longer survival, the reasons for which are yet unclear. There has been a great surge in drug discovery for curtailing the mutant IDH activities, and arresting tumor proliferation; however, given the unique and chronic metabolic effects of D-2HG, the promise of these compounds for glioma treatment is uncertain. This comprehensive review discusses the biology, current drug design and opportunities for improved therapies through exploitable synthetic lethality pathways, and an intriguing oncometabolite-inspired strategy for primary glioblastoma. PMID- 29439498 TI - Advances in Targeted Pesticides with Environmentally Responsive Controlled Release by Nanotechnology. AB - Pesticides are the basis for defending against major biological disasters and important for ensuring national food security. Biocompatible, biodegradable, intelligent, and responsive materials are currently an emerging area of interest in the field of efficient, safe, and green pesticide formulation. Using nanotechnology to design and prepare targeted pesticides with environmentally responsive controlled release via compound and chemical modifications has also shown great potential in creating novel formulations. In this review, special attention has been paid to intelligent pesticides with precise controlled release modes that can respond to micro-ecological environment changes such as light sensitivity, thermo-sensitivity, humidity sensitivity, soil pH, and enzyme activity. Moreover, establishing intelligent and controlled pesticide release technologies using nanomaterials are reported. These technologies could increase pesticide-loading, improve the dispersibility and stability of active ingredients, and promote target ability. PMID- 29439497 TI - Dual Roles of Ascidian Chondromodulin-1: Promoting Cell Proliferation Whilst Suppressing the Growth of Tumor Cells. AB - Chondromodulin-1 (ChM-1) is an extracellular matrix protein that plays crucial roles in tumor cell growth and angiogenesis in vertebrates and humans. ChM-1 is highly expressed in the invertebrate Ciona savignyi, a marine ascidian chosen as a model. The effect of the recombinant Ciona mature ChM-1 peptide (Cs-mChM-1) on cell proliferation, migration and angiogenesis was evaluated on cultured cells. The results revealed that low concentrations of Cs-mChM-1 (12.5 nM) promoted osteoblastic cell (MC3T3-E1) growth and protected cells from H2O2-induced damage. However, a higher concentration of Cs-mChM-1 (i.e., 500 nM) not only suppressed both growth and migration of tumor cells, including human cervical cancer (HeLa) cells and human neuroblastoma (SH-SY5Y) cells, but also significantly inhibited proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs). The expression levels of cyclinD1 and mitogen-activated protein kinase 1 (MAPK1) were slightly increased in Cs-mChM-1 treated MC3T3-E1 cells, whereas these genes decreased in treated HeLa cells, SH-SY5Y cells and HUVECs. This result indicates that Cs-mChM-1 modifies cell behavior by regulating cell cycle and cell adhesion. Thus, the present results reveal that recombinant peptides of ChM-1 from invertebrates can play a dual role in cell proliferation and migration of different cell types. The inhibition effects on tumor cell growth and angiogenesis indicate potential pharmaceutical applications for recombinant Cs mChM-1. PMID- 29439499 TI - Canaloplasty in Corticosteroid-Induced Glaucoma. Preliminary Results. AB - PURPOSE: to present the mid-term results of canaloplasty in a small cohort of corticosteroid glaucoma patients. MATERIAL AND METHODS: Nine eyes from seven patients with various types of corticosteroid glaucoma in maximum medical therapy underwent canaloplasty. Patients underwent complete ophthalmic examination every six months. Success was defined as: post-operative intraocular pressure (IOP) <= 21 mmHg and <= 16 mmHg without ("complete success"), and with/without medical treatment ("qualified success"). The IOP reduction had to be >= 20. The number of medications before and after surgery was considered. The follow-up mean period was 32.7 +/- 20.8 months (range 14-72 months). RESULTS: The pre-operative mean IOP was 30.7 +/- 7.2 mmHg (range: 24-45). The mean IOP at 6 and 12-month follow up was 13.1 +/- 2.6 mmHg, and 13.7 +/- 1.9 mmHg, respectively. Qualified and complete success at 6 and 12 months was 100% for both of the two definitions. The number of medications used preoperatively and at the 12-month follow-up was 4.3 +/- 0.7, and 0.2 +/- 1.0, respectively. No serious complication was observed. CONCLUSIONS: The mid-term results of canaloplasty in patients with corticosteroid induced glaucoma appear to be very promising. Canaloplasty should be considered as a possible alternative to filtering surgery in this form of glaucoma, when medical therapy is not sufficient to maintain the IOP within reasonable limits. PMID- 29439500 TI - Skin Lesion Analysis towards Melanoma Detection Using Deep Learning Network. AB - Skin lesions are a severe disease globally. Early detection of melanoma in dermoscopy images significantly increases the survival rate. However, the accurate recognition of melanoma is extremely challenging due to the following reasons: low contrast between lesions and skin, visual similarity between melanoma and non-melanoma lesions, etc. Hence, reliable automatic detection of skin tumors is very useful to increase the accuracy and efficiency of pathologists. In this paper, we proposed two deep learning methods to address three main tasks emerging in the area of skin lesion image processing, i.e., lesion segmentation (task 1), lesion dermoscopic feature extraction (task 2) and lesion classification (task 3). A deep learning framework consisting of two fully convolutional residual networks (FCRN) is proposed to simultaneously produce the segmentation result and the coarse classification result. A lesion index calculation unit (LICU) is developed to refine the coarse classification results by calculating the distance heat-map. A straight-forward CNN is proposed for the dermoscopic feature extraction task. The proposed deep learning frameworks were evaluated on the ISIC 2017 dataset. Experimental results show the promising accuracies of our frameworks, i.e., 0.753 for task 1, 0.848 for task 2 and 0.912 for task 3 were achieved. PMID- 29439502 TI - An Improved Pansharpening Method for Misaligned Panchromatic and Multispectral Data. AB - Numerous pansharpening methods were proposed in recent decades for fusing low spatial-resolution multispectral (MS) images with high-spatial-resolution (HSR) panchromatic (PAN) bands to produce fused HSR MS images, which are widely used in various remote sensing tasks. The effect of misregistration between MS and PAN bands on quality of fused products has gained much attention in recent years. An improved method for misaligned MS and PAN imagery is proposed, through two improvements made on a previously published method named RMI (reduce misalignment impact). The performance of the proposed method was assessed by comparing with some outstanding fusion methods, such as adaptive Gram-Schmidt and generalized Laplacian pyramid. Experimental results show that the improved version can reduce spectral distortions of fused dark pixels and sharpen boundaries between different image objects, as well as obtain similar quality indexes with the original RMI method. In addition, the proposed method was evaluated with respect to its sensitivity to misalignments between MS and PAN bands. It is certified that the proposed method is more robust to misalignments between MS and PAN bands than the other methods. PMID- 29439501 TI - The Roles of Mitochondrion in Intergenomic Gene Transfer in Plants: A Source and a Pool. AB - Intergenomic gene transfer (IGT) is continuous in the evolutionary history of plants. In this field, most studies concentrate on a few related species. Here, we look at IGT from a broader evolutionary perspective, using 24 plants. We discover many IGT events by assessing the data from nuclear, mitochondrial and chloroplast genomes. Thus, we summarize the two roles of the mitochondrion: a source and a pool. That is, the mitochondrion gives massive sequences and integrates nuclear transposons and chloroplast tRNA genes. Though the directions are opposite, lots of likenesses emerge. First, mitochondrial gene transfer is pervasive in all 24 plants. Second, gene transfer is a single event of certain shared ancestors during evolutionary divergence. Third, sequence features of homologies vary for different purposes in the donor and recipient genomes. Finally, small repeats (or micro-homologies) contribute to gene transfer by mediating recombination in the recipient genome. PMID- 29439503 TI - Roadside Survey of Ants on Oahu, Hawaii. AB - Hawaii is home to over 60 ant species, including five of the six most damaging invasive ants. Although there have been many surveys of ants in Hawaii, the last island-wide hand-collection survey of ants on Oahu was conducted in 1988-1994. In 2012, a timed hand-collection of ants was made at 44 sites in a systematic, roadside survey throughout Oahu. Ants were identified and species distribution in relation to elevation, precipitation and soil type was analyzed. To assess possible convenience sampling bias, 15 additional sites were sampled further from roads to compare with the samples near roads. Twenty-four species of ants were found and mapped; Pheidole megacephala (F.), Ochetellus glaber (Mayr), and Technomyrmex difficilis Forel were the most frequently encountered ants. For six ant species, a logistic regression was performed with elevation, average annual precipitation, and soil order as explanatory variables. O. glaber was found in areas with lower precipitation around Oahu. Paratrechina longicornis (Latrielle) and Tetramorium simillimum (Smith, F.) were found more often in lower elevations and in areas with the Mollisol soil order. Elevation, precipitation, and soil type were not significant sources of variation for P. megacephala, Plagiolepis alluaudi Emery, and T. difficilis. P. megacephala was associated with fewer mean numbers of ants where it occurred. Ant assemblages near and far from roads did not significantly differ. Many species of ants remain established on Oahu, and recent invaders are spreading throughout the island. Mapping ant distributions contributes to continued documentation and understanding of these pests. PMID- 29439504 TI - Comparing the Potential of Multispectral and Hyperspectral Data for Monitoring Oil Spill Impact. AB - Oil spills from offshore drilling and coastal refineries often cause significant degradation of coastal environments. Early oil detection may prevent losses and speed up recovery if monitoring of the initial oil extent, oil impact, and recovery are in place. Satellite imagery data can provide a cost-effective alternative to expensive airborne imagery or labor intensive field campaigns for monitoring effects of oil spills on wetlands. However, these satellite data may be restricted in their ability to detect and map ecosystem recovery post-spill given their spectral measurement properties and temporal frequency. In this study, we assessed whether spatial and spectral resolution, and other sensor characteristics influence the ability to detect and map vegetation stress and mortality due to oil. We compared how well three satellite multispectral sensors: WorldView2, RapidEye and Landsat EMT+, match the ability of the airborne hyperspectral AVIRIS sensor to map oil-induced vegetation stress, recovery, and mortality after the DeepWater Horizon oil spill in the Gulf of Mexico in 2010. We found that finer spatial resolution (3.5 m) provided better delineation of the oil-impacted wetlands and better detection of vegetation stress along oiled shorelines in saltmarsh wetland ecosystems. As spatial resolution become coarser (3.5 m to 30 m) the ability to accurately detect and map stressed vegetation decreased. Spectral resolution did improve the detection and mapping of oil impacted wetlands but less strongly than spatial resolution, suggesting that broad-band data may be sufficient to detect and map oil-impacted wetlands. AVIRIS narrow-band data performs better detecting vegetation stress, followed by WorldView2, RapidEye and then Landsat 15 m (pan sharpened) data. Higher quality sensor optics and higher signal-to-noise ratio (SNR) may also improve detection and mapping of oil-impacted wetlands; we found that resampled coarser resolution AVIRIS data with higher SNR performed better than either of the three satellite sensors. The ability to acquire imagery during certain times (midday, low tide, etc.) or a certain date (cloud-free, etc.) is also important in these tidal wetlands; WorldView2 imagery captured at high-tide detected a narrower band of shoreline affected by oil likely because some of the impacted wetland was below the tideline. These results suggest that while multispectral data may be sufficient for detecting the extent of oil-impacted wetlands, high spectral and spatial resolution, high-quality sensor characteristics, and the ability to control time of image acquisition may improve assessment and monitoring of vegetation stress and recovery post oil spills. PMID- 29439505 TI - The Complete Chloroplast Genome of a Key Ancestor of Modern Roses, Rosa chinensis var. spontanea, and a Comparison with Congeneric Species. AB - Rosa chinensis var. spontanea, an endemic and endangered plant of China, is one of the key ancestors of modern roses and a source for famous traditional Chinese medicines against female diseases, such as irregular menses and dysmenorrhea. In this study, the complete chloroplast (cp) genome of R. chinensis var. spontanea was sequenced, analyzed, and compared to congeneric species. The cp genome of R. chinensis var. spontanea is a typical quadripartite circular molecule of 156,590 bp in length, including one large single copy (LSC) region of 85,910 bp and one small single copy (SSC) region of 18,762 bp, separated by two inverted repeat (IR) regions of 25,959 bp. The GC content of the whole genome is 37.2%, while that of LSC, SSC, and IR is 42.8%, 35.2% and 31.2%, respectively. The genome encodes 129 genes, including 84 protein-coding genes (PCGs), 37 transfer RNA (tRNA) genes, and eight ribosomal RNA (rRNA) genes. Seventeen genes in the IR regions were found to be duplicated. Thirty-three forward and five inverted repeats were detected in the cp genome of R. chinensis var. spontanea. The genome is rich in SSRs. In total, 85 SSRs were detected. A genome comparison revealed that IR contraction might be the reason for the relatively smaller cp genome size of R. chinensis var. spontanea compared to other congeneric species. Sequence analysis revealed that the LSC and SSC regions were more divergent than the IR regions within the genus Rosa and that a higher divergence occurred in non-coding regions than in coding regions. A phylogenetic analysis showed that the sampled species of the genus Rosa formed a monophyletic clade and that R. chinensis var. spontanea shared a more recent ancestor with R. lichiangensis of the section Synstylae than with R. odorata var. gigantea of the section Chinenses. This information will be useful for the conservation genetics of R. chinensis var. spontanea and for the phylogenetic study of the genus Rosa, and it might also facilitate the genetics and breeding of modern roses. PMID- 29439506 TI - Bryonolic Acid Blocks Cancer Cell Clonogenicity and Invasiveness through the Inhibition of Fatty Acid: Cholesteryl Ester Formation. AB - Bryonolic acid (BrA) is a pentacyclic triterpene present in several plants used in African traditional medicine such as Anisophyllea dichostyla R. Br. Here we investigated the in vitro anticancer properties of BrA. We report that BrA inhibits acyl-coA: cholesterol acyl transferase (ACAT) activity in rat liver microsomes in a concentration-dependent manner, blocking the biosynthesis of the cholesterol fatty acid ester tumour promoter. We next demonstrated that BrA inhibits ACAT in intact cancer cells with an IC50 of 12.6 +/- 2.4 uM. BrA inhibited both clonogenicity and invasiveness of several cancer cell lines, establishing that BrA displays specific anticancer properties. BrA appears to be more potent than the other pentacyclic triterpenes, betulinic acid and ursolic acid studied under similar conditions. The inhibitory effect of BrA was reversed by exogenous addition of cholesteryl oleate, showing that ACAT inhibition is responsible for the anticancer effect of BrA. This report reveals new anticancer properties for BrA. PMID- 29439507 TI - An Unsupervised Change Detection Method Using Time-Series of PolSAR Images from Radarsat-2 and GaoFen-3. AB - The traditional unsupervised change detection methods based on the pixel level can only detect the changes between two different times with same sensor, and the results are easily affected by speckle noise. In this paper, a novel method is proposed to detect change based on time-series data from different sensors. Firstly, the overall difference image of the time-series PolSAR is calculated by omnibus test statistics, and difference images between any two images in different times are acquired by Rj test statistics. Secondly, the difference images are segmented with a Generalized Statistical Region Merging (GSRM) algorithm which can suppress the effect of speckle noise. Generalized Gaussian Mixture Model (GGMM) is then used to obtain the time-series change detection maps in the final step of the proposed method. To verify the effectiveness of the proposed method, we carried out the experiment of change detection using time series PolSAR images acquired by Radarsat-2 and Gaofen-3 over the city of Wuhan, in China. Results show that the proposed method can not only detect the time series change from different sensors, but it can also better suppress the influence of speckle noise and improve the overall accuracy and Kappa coefficient. PMID- 29439508 TI - Advances in Heparins and Related Research. An Epilogue. AB - The discovery of heparin in 1916 by Jay McLean, a medical student at Johns Hopkins University, not only provided a universal anticoagulant, but also laid the foundation for the discipline of hemostasis and thrombosis[...]. PMID- 29439510 TI - Fatigue Behavior of Porous Ti-6Al-4V Made by Laser-Engineered Net Shaping. AB - The fatigue behavior and fracture mechanisms of additively manufactured Ti-6Al-4V specimens are investigated in this study. Three sets of testing samples were fabricated for the assessment of fatigue life. The first batch of samples was built by using Laser-Engineered Net Shaping (LENS) technology, a Direct Energy Deposition (DED) method. Internal voids and defects were induced in a second batch of samples by changing LENS machine processing parameters. Fatigue performance of these samples is compared to the wrought Ti-6Al-4V samples. The effects of machine-induced porosity are assessed on mechanical properties and results are presented in the form of SN curves for the three sets of samples. Fracture mechanisms are examined by using Scanning Electron Microscopy (SEM) to characterize the morphological characteristics of the failure surface. Different fracture surface morphologies are observed for porous and non-porous specimens due to the combination of head write speed and laser power. Formation of defects such as pores, unmelted regions, and gas entrapments affect the failure mechanisms in porous specimens. Non-porous specimens exhibit fatigue properties comparable with that of the wrought specimens, but porous specimens are found to show a tremendous reduced fatigue strength. PMID- 29439509 TI - Dietary Inflammatory Index and Cardiovascular Risk and Mortality-A Meta-Analysis. AB - Diet and chronic inflammation have been suggested to be risk factors in the development of cardiovascular disease (CVD) and related mortality. The possible link between the inflammatory potential of diet measured through the Dietary Inflammatory Index (DII(r)) and CVD has been investigated in several populations across the world. The aim of this study was to conduct a meta-analysis on studies exploring this association. Data from 14 studies were eligible, of which two were case-control, eleven were cohort, and one was cross-sectional. Results from the random-effects meta-analysis showed a positive association between increasing DII, indicating a pro-inflammatory diet, and CVD. Individuals in the highest versus the lowest (reference) DII category showed a 36% increased risk of CVD incidence and mortality, with moderate evidence of heterogeneity (relative risk (RR) = 1.36, 95% confidence interval (CI): 1.19, 1.57; heterogeneity index I2 = 69%, p < 0.001). When analyzed as a continuous variable, results showed an increased risk of CVD risk and mortality of 8% for each one-point increase in the DII score. Results remained unchanged when analyses were restricted to the prospective studies. Results of our meta-analysis support the importance of adopting a healthier anti-inflammatory diet for preventing CVD incidence and related mortality. In conclusion, a pro-inflammatory diet is associated with increased risk of CVD and CVD mortality. These results further substantiate the utility of DII as tool to characterize the inflammatory potential of diet and to predict CVD incidence and mortality. PMID- 29439511 TI - Comparison of Ultem 9085 Used in Fused Deposition Modelling (FDM) with Polytherimide Blends. AB - Polyetherimide (PEI) blends modified by either polycarbonate (PC) or polyethylene terephthalate glycol-modified (PETG) were prepared. The latter modifier (PETG) was an industrial grade widely used for fused deposition modelling (FDM) printing. PEI blends were compared to Ultem 9085, which is the standard PEI grade for FDM printing in advanced applications. All the blends were thoroughly characterized in terms of their rheological, morphological, thermomechanical and tensile properties. Ultem 9085 showed improved rheology for processing over standard PEI. PEI/PC blends with 10 wt % of modifier developed here closely matched the viscosity behavior of Ultem 9085. On the other hand, the blends with low PC content (i.e., less than 20 wt %) outperformed Ultem 9085 in terms of thermal and tensile properties. When PETG was added, similar tensile properties to Ultem 9085 were found. The immiscibility for PC contents higher than 20 wt % deteriorated the tensile properties, making it less attractive for applications, although melt viscosity decreased further for increasing PC contents. PMID- 29439512 TI - The Influence of Inflammation and Nerve Damage on the Neurochemical Characterization of Calcitonin Gene-Related Peptide-Like Immunoreactive (CGRP-LI) Neurons in the Enteric Nervous System of the Porcine Descending Colon. AB - The enteric nervous system (ENS), localized in the wall of the gastrointestinal tract, regulates the functions of the intestine using a wide range of neuronally active substances. One of them is the calcitonin gene-related peptide (CGRP), whose participation in pathological states in the large intestine remains unclear. Therefore, the aim of this study was to investigate the influence of inflammation and nerve damage using a double immunofluorescence technique to neurochemically characterize CGRP-positive enteric nervous structures in the porcine descending colon. Both pathological factors caused an increase in the percentage of CGRP-positive enteric neurons, and these changes were the most visible in the myenteric plexus after nerve damage. Moreover, both pathological states change the degree of co-localization of CGRP with other neurochemical factors, including substance P, the neuronal isoform of nitric oxide synthase, galanin, cocaine- and amphetamine-regulated transcript peptide and vesicular acetylcholine transporter. The character and severity of these changes depended on the pathological factor and the type of enteric plexus. The obtained results show that CGRP-positive enteric neurons are varied in terms of neurochemical characterization and take part in adaptive processes in the descending colon during inflammation and after nerve damage. PMID- 29439513 TI - Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation. AB - Phospholipase A2s (PLA2) is a major component of snake venom with diverse pathologic toxicities and, therefore, a potential target for antivenom therapy. Varespladib was initially designed as an inhibitor of mammal PLA2s, and was recently repurposed to a broad-spectrum inhibitor of PLA2 in snake venom. To evaluate the protective abilities of varespladib to hemorrhage, myonecrosis, and systemic toxicities that are inflicted by different crude snake venoms, subcutaneous ecchymosis, muscle damage, and biochemical variation in serum enzymes derived from the envenomed mice were determined, respectively. Varespladib treatment showed a significant inhibitory effect to snake venom PLA2, which was estimated by IC50 in vitro and ED50 in vivo. In animal models, the severely hemorrhagic toxicity of D. acutus and A. halys venom was almost fully inhibited after administration of varespladib. Moreover, signs of edema in gastrocnemius muscle were remarkably attenuated by administration of varespladib, with a reduced loss of myonecrosis and desmin. Serum levels of creatine kinase, lactate dehydrogenase isoenzyme 1, aspartate transaminase, and alanine transaminase were down-regulated after treatment with varespladib, which indicated the protection to viscera injury. In conclusion, varespladib may be a potential first-line drug candidate in snakebite envenomation first aid or clinical therapy. PMID- 29439514 TI - Electrochemical Preparation of Polyaniline Nanowires with the Used Electrolyte Solution Treated with the Extraction Process and Their Electrochemical Performance. AB - Electrochemical polymerization of aniline is one of the most promising methods to prepare polyaniline (PANI) materials. However, during this process, the electrolyte solution must be replaced after electropolymerization of a certain time because of the generation and the accumulation of the by-products, which have significant effects on the morphology, purity and properties of PANI products. Treatment and recycling of the used electrolyte solution are worthwhile to study to reduce the high treatment cost of the used electrolyte solution containing aniline and its polymerization by-products. Here, the composition of the used electrolyte solution was separated and determined by high performance liquid chromatography coupled with diode array detection (HPLC-DAD) in the range of ultraviolet and visible (UV-Vis) light. The analysis results revealed that the used electrolyte solution consisted of aniline, p-hydroquinone (HQ), p benzoquinone (BQ), co-oligomers of aniline and p-benzoquinone (CAB) and acid. Then, n-octanol and 2-octanone were selected as extracts to remove HQ, BQ and CAB from the used electrolyte solution. Following that, the recycled electrolyte solution was prepared by adjusting the concentration of aniline and acid of the aqueous phase, and the electrochemical polymerization process was conducted. Finally, the obtained PANI was characterized by scanning electron microscope (SEM) and electrochemical methods. The experimental results clearly demonstrate that the morphology and specific capacitance of PANI produced from the recycled electrolyte solution can be recovered completely. This research paves the way for reusing the used electrolyte solution for aniline electrochemical polymerization. PMID- 29439515 TI - Report of the Signal Transduction Society Meeting 2017-Metabolism in Health and Disease. AB - The annual "Joint Meeting Signal Transduction-Receptors, Mediators and Genes" of the Signal Transduction Society (STS) aims to be an interdisciplinary forum for researchers who share a common interest in deciphering signal transduction pathways in normal or transformed cells, in health and disease, in humans and animal models, or in plants or bacteria. The special focus of the 21st annual Joint Meeting, which took place from 8-10 November 2017 in Weimar, was the topic "Metabolism in Health and Disease" and covered multiple aspects of this highly exciting and fast developing research field. Invited keynote speakers introduced the impact of metabolism on tumor immunology, immune cell signaling, and posttranslational modifications in three specific workshops to the audience. Various other aspects of signal transduction were intensively discussed in five additional workshops. Here, we give an overview of the various workshops and further aspects of the scientific program. PMID- 29439516 TI - Expression of Pluripotency Genes in Chondrocyte-Like Cells Differentiated from Human Induced Pluripotent Stem Cells. AB - Human induced pluripotent stem cells (hiPSCs) constitute an important breakthrough in regenerative medicine, particularly in orthopedics, where more effective treatments are urgently needed. Despite the promise of hiPSCs only limited data on in vitro chondrogenic differentiation of hiPSCs are available. Therefore, we compared the gene expression profile of pluripotent genes in hiPSC derived chondrocytes (ChiPS) to that of an hiPSC cell line created by our group (GPCCi001-A). The results are shown on heatmaps and plots and confirmed by Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) analysis. Unlike the ChiPS, our GPCCi001-A cells maintained their pluripotency state during long-term culture, thus demonstrating that this cell line was comprised of stable, fully pluripotent hiPSCs. Moreover, these chondrocyte-like cells not only presented features that are characteristic of chondrocytes, but they also lost their pluripotency, which is an important advantage in favor of using this cell line in future clinical studies. PMID- 29439517 TI - Hyperglycemia Alters the Structure and Hemodynamics of the Developing Embryonic Heart. AB - Congenital heart defects (CHDs) represent the most common form of human birth defects; approximately one-third of heart defects involve malformations of the outflow tract (OFT). Maternal diabetes increases the risk of CHD by 3-5 fold. During heart organogenesis, little is known about the effects of hyperglycemia on hemodynamics, which are critical to normal heart development. Heart development prior to septation in the chick embryo was studied under hyperglycemic conditions. Sustained hyperglycemic conditions were induced, raising the average plasma glucose concentration from 70 mg/dL to 180 mg/dL, akin to the fasting plasma glucose of a patient with diabetes. The OFTs were assessed for structural and hemodynamic alterations using optical coherence tomography (OCT), confocal microscopy, and microcomputed tomography. In hyperglycemic embryos, the endocardial cushions of the proximal OFT were asymmetric, and the OFTs curvature and torsion were significantly altered. The blood flow velocity through the OFT of hyperglycemic embryos was significantly decreased, including flow reversal in 30% of the cardiac cycle. Thus, hyperglycemia at the onset of gestation results in asymmetric proximal endocardial cushions, abnormal OFT curvature, and altered hemodynamics in the developing heart. If present in humans, these results may identify early developmental alterations that contribute to the increased risk for cardiac malformations in babies from diabetic mothers. PMID- 29439518 TI - The Neuroprotective Effects of Cinnamic Aldehyde in an MPTP Mouse Model of Parkinson's Disease. AB - Cinnamic aldehyde (CA), a key flavor compound in cinnamon essential oil, has been identified as an anti-oxidant, anti-angiogenic, and anti-inflammatory material. Recently, the neuroprotective effects of CA have been reported in various neurodegenerative disorders, including Parkinson's disease (PD). In neurons, autophagy is tightly regulated, and consequently, the dysregulation of autophagy may induce neurodegenerative disorders. In the present study, we found that the selective dopaminergic neuronal death in the substantia nigra of 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models was prevented by CA. Stimulation of microtubule-associated protein light chain 3 (LC3) puncta mediated by MPTP treatment was decreased by CA. Moreover, down-regulated p62 in the substantia nigra of MPTP mice was increased by administration of CA. Finally, we showed that blockage of autophagy using autophagy inhibitors protected the 1 methyl-4-phenylpyridinium (MPP+)-mediated death of BE(2)-M17 cells. Together these results suggest that CA has a neuroprotective effect in a PD model and that inhibition of autophagy might be a promising therapeutic target for PD. PMID- 29439519 TI - Biochemical Mechanism of Rhododendrol-Induced Leukoderma. AB - RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol (RD))-a skin-whitening ingredient was reported to induce leukoderma in some consumers. We have examined the biochemical basis of the RD-induced leukoderma by elucidating the metabolic fate of RD in the course of tyrosinase-catalyzed oxidation. We found that the oxidation of racemic RD by mushroom tyrosinase rapidly produces RD-quinone, which gives rise to secondary quinone products. Subsequently, we confirmed that human tyrosinase is able to oxidize both enantiomers of RD. We then showed that B16 cells exposed to RD produce high levels of RD-pheomelanin and protein-SH adducts of RD-quinone. Our recent studies showed that RD-eumelanin-an oxidation product of RD-exhibits a potent pro-oxidant activity that is enhanced by ultraviolet-A radiation. In this review, we summarize our biochemical findings on the tyrosinase-dependent metabolism of RD and related studies by other research groups. The results suggest two major mechanisms of cytotoxicity to melanocytes. One is the cytotoxicity of RD-quinone through binding with sulfhydryl proteins that leads to the inactivation of sulfhydryl enzymes and protein denaturation that leads to endoplasmic reticulum stress. The other mechanism is the pro oxidant activity of RD-derived melanins that leads to oxidative stress resulting from the depletion of antioxidants and the generation of reactive oxygen radicals. PMID- 29439521 TI - Stabilization of Immobilized Lipases by Intense Intramolecular Cross-Linking of Their Surfaces by Using Aldehyde-Dextran Polymers. AB - Immobilized enzymes have a very large region that is not in contact with the support surface and this region could be the target of new stabilization strategies. The chemical amination of these regions plus further cross-linking with aldehyde-dextran polymers is proposed here as a strategy to increase the stability of immobilized enzymes. Aldehyde-dextran is not able to react with single amino groups but it reacts very rapidly with polyaminated surfaces. Three lipases-from Thermomyces lanuginosus (TLL), Rhizomucor miehiei (RML), and Candida antarctica B (CALB)-were immobilized using interfacial adsorption on the hydrophobic octyl-Sepharose support, chemically aminated, and cross-linked. Catalytic activities remained higher than 70% with regard to unmodified conjugates. The increase in the amination degree of the lipases together with the increase in the density of aldehyde groups in the dextran-aldehyde polymer promoted a higher number of cross-links. The sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of those conjugates demonstrates the major role of the intramolecular cross-linking on the stabilization of the enzymes. The highest stabilization was achieved by the modified RML immobilized on octyl-Sepharose, which was 250-fold more stable than the unmodified conjugate. The TLL and the CALB were 40-fold and 4-fold more stable than the unmodified conjugate. PMID- 29439520 TI - In Vitro and In Vivo Antioxidant Activities of the Flowers and Leaves from Paeonia rockii and Identification of Their Antioxidant Constituents by UHPLC-ESI HRMSn via Pre-Column DPPH Reaction. AB - The genus Paeonia, also known as the "King of Flowers" in China, is an important source of traditional Chinese medicine (TCM). Plants of this genus have been used to treat a range of cardiovascular and gynecological diseases. However, the potential pharmacological activity of one particular species, Paeonia rockii, has not been fully investigated. In the first part of the present study, 2,2-diphenyl 1-picrylhydrazyl (DPPH), 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS), reducing power assays, and metal ion chelating assays were used to investigate the in vitro antioxidant activities of Paeonia rockii. In the second portion of the study, a mouse model of d-galactose-induced aging was used to validate the antioxidant effects of the flowers from Paeonia rockii in vivo. Lastly, potential antioxidant constituents were screened and identified by ultra high pressure liquid chromatography and electrospray ionization coupled with high resolution mass spectrometry (UHPLC-ESI-HRMSn) combined with the DPPH assay. Results indicated that the flowers and leaves exhibited stronger antioxidant activity than ascorbic acid in vitro. The therapeutic effect of Paeoniarockii was determined in relation to the levels of biochemical indicators, such as 8-iso prostaglandin F2alpha (8-iso PGF2alpha) in the serum, superoxide dismutase (SOD), protein carbonyl, malondialdehyde (MDA), and glutathione (GSH) in the liver and brain, after daily intra-gastric administration of different concentrations of extracts (100, 200 and 400 mg/kg) for three weeks. The levels of 8-iso PGF2alpha (p < 0.01) and protein carbonyl groups (p < 0.01) were significantly reduced, whereas those of SOD (p < 0.05) had significantly increased, indicating that components of the flowers of Paeonia rockii had favorable antioxidant activities in vivo. Furthermore, UHPLC-ESI-HRMSn, combined with pre-column DPPH reaction, detected 25 potential antioxidant compounds. Of these, 18 compounds were tentatively identified, including 11 flavonoids, four phenolic acids, two tannins, and one monoterpene glycoside. This study concluded that the leaves and flowers from Paeonia rockii possess excellent antioxidant properties, highlighting their candidacy as "new" antioxidants, which can be utilized therapeutically to protect the body from diseases caused by oxidative stress. PMID- 29439522 TI - Unusual Electrical Transport Driven by the Competition between Antiferromagnetism and Ferromagnetism in Antiperovskite Mn3Zn1-xCoxN. AB - The magnetic, electrical transport and thermal expansion properties of Mn3Zn1 xCoxN (x = 0.2, 0.4, 0.5, 0.7, 0.9) have been systematically investigated. Co doping in Mn3ZnN complicates the magnetic interactions, leading to a competition between antiferromagnetism and ferromagnetism. Abrupt resistivity jump phenomenon and negative thermal expansion behavior, both associated with the complex magnetic transition, are revealed in all studied cases. Furthermore, semiconductor-like transport behavior is found in sample x = 0.7, distinct from the metallic behavior in other samples. Below 50 K, resistivity minimum is observed in samples x = 0.4, 0.7, and 0.9, mainly caused by e-e scattering mechanism. We finally discussed the strong correlation among unusual electrical transport, negative thermal expansion and magnetic transition in Mn3Zn1-xCoxN, which allows us to conclude that the observed unusual electrical transport properties are attributed to the shift of the Fermi energy surface entailed by the abrupt lattice contraction. PMID- 29439523 TI - The Influences of Soybean Agglutinin and Functional Oligosaccharides on the Intestinal Tract of Monogastric Animals. AB - Soybean agglutinin (SBA) is a non-fiber carbohydrate-related protein and the main anti-nutritional factor that exists in soybean or soybean products. SBA possesses a specific binding affinity for N-glyphthalide-d-galactosamine or galactose and has a covalently linked oligosaccharide chain. SBA mediates negative effects on animal intestinal health by influencing the intestinal structure, barrier function, mucosal immune system, and the balance of the intestinal flora. Functional oligosaccharides are non-digestible dietary oligosaccharides that are commonly applied as prebiotics since the biological effects of the functional oligosaccharides are to increase the host health by improving mucosal structure and function, protecting the integrity of the intestinal structure, modulating immunity, and balancing the gastrointestinal microbiota. The purpose of this review is to describe the structure and anti-nutritional functions of SBA, summarize the influence of SBA and functional oligosaccharides on the intestinal tract of monogastric animals, and emphasize the relationship between SBA and oligosaccharides. This review provides perspectives on applying functional oligosaccharides for alleviating the anti-nutritional effects of SBA on the intestinal tract. PMID- 29439524 TI - PM Origin or Exposure Duration? Health Hazards from PM-Bound Mercury and PM-Bound PAHs among Students and Lecturers. AB - This study assessed inhalation exposure to particulate matter (PM1)-bound mercury (Hgp) and PM1-bound polycyclic aromatic hydrocarbons (PAHs) among university students. For this purpose, simultaneous indoor (I) and outdoor (O) measurements were taken from two Polish technical universities (in Gliwice and Warsaw) located in distinct areas with respect to ambient concentrations and major sources of PM. The indoor geometric mean concentrations of Hgp were found to be 1.46 pg.m-3 and 6.38 pg.m-3 in Warsaw and Gliwice, while the corresponding outdoor concentrations were slightly lower at 1.38 pg.m-3 and 3.03 pg.m-3, respectively. A distinct pattern was found with respect to PAH concentrations with estimated I/O values of 22.2 ng.m-3/22.5 ng.m-3 in Gliwice and 10.9 ng.m-3/11.12 ng.m-3 in Warsaw. Hazard quotients (HQs) as a result of exposure to Hgp for students aged 21 ranged from 3.47 * 10-5 (Warsaw) to 1.3 * 10-4 (Gliwice) in terms of reasonable maximum exposure (RME). The non-cancer human health risk value related to Hgp exposure was thus found to be below the acceptable risk level value of 1.0 given by the US EPA. Daily exposure values for lecture hall occupants, adjusted to the benzo(a)pyrene (BaP) toxicity equivalent (BaPeq), were 2.9 and 1.02 ng.m-3 for the Gliwice and Warsaw students, respectively. The incremental lifetime cancer risk (ILCR) values with respect to exposure to PM1-bound PAHs during the students' time of study were 5.49 * 10-8 (Warsaw) and 1.43 * 10-7 (Gliwice). Thus, students' exposure to indoor PAHs does not lead to increased risk of lung cancer. PMID- 29439525 TI - Detection and Enhancement of Ketocarotenoid Accumulation in the Newly Isolated Sarcinoid Green Microalga Chlorosarcinopsis PY02. AB - The sarcinoid alga PY02 is a newly isolated soil alga native to western Thailand. In this study PY02 is described, the carotenoid profile of the green and red forms of the algal cells are compared, and the effect of nitrogen reduction and media volume on ketocarotenoid production are reported. Partial sequences of the genes from elongation factor Tu (tufA) and 18S rRNA reveal that the alga is from the Chlorosarcinopsis genus. Growth studies demonstrated that Chlorosarcinopsis PY02 is capable of photoautotrophic, heterotrophic and mixotrophic growth. A gradual change in colony colour from green to red was observed over a period of four weeks under mixotrophic conditions. Pigment analysis of lyophilized red cells using ultrahigh performance liquid chromatography (UPLC) with Photo Diode Array Detection (PDA), showed for the first time that an alga from the genus Chlorosarcinopsis is capable of producing ketocarotenoids such as adonixanthin and 3-OH-echinenone, with canthaxanthin as the dominant pigment. Interestingly, a reduction of nitrogen in the medium exerts a positive effect on the rate of colour change from one month to less than seven days. Enhancements of the canthaxanthin content from 520 to 1504 or 1427 ug.gDW-1 were detected under 50% and 10% nitrogen content, respectively. An increase of 16% in biomass production of PY02 was unexpectedly detected from a 50% nitrogen reduction under mixotrophic culture. Notably, in liquid mixotrophic media with volumes of 15, 30 and 60 mL, the lowest volume produced a significantly higher biomass and canthaxanthin content. PMID- 29439527 TI - Decoration of Cotton Fibers with a Water-Stable Metal-Organic Framework (UiO-66) for the Decomposition and Enhanced Adsorption of Micropollutants in Water. AB - We report on the successful functionalization of cotton fabrics with a water stable metal-organic framework (MOF), UiO-66, under mild solvothermal conditions (80 degrees C) and its ability to adsorb and degrade water micropollutants. The functionalized cotton samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). UiO-66 crystals grew in a uniform and conformal manner over the surface of the cotton fibers. The cotton fabrics functionalized with UiO-66 frameworks exhibited an enhanced uptake capacity for methylchlorophenoxypropionic acid (MCPP), a commonly used herbicide. The functionalized fabrics also showed photocatalytic activity, demonstrated by the degradation of acetaminophen, a common pharmaceutical compound, under simulated sunlight irradiation. These results indicate that UiO-66 can be supported on textile substrates for filtration and photocatalytic purposes and that these substrates can find applications in wastewater decontamination and micropollutant degradation. PMID- 29439526 TI - The Effect of Oligofructose-Enriched Inulin on Faecal Bacterial Counts and Microbiota-Associated Characteristics in Celiac Disease Children Following a Gluten-Free Diet: Results of a Randomized, Placebo-Controlled Trial. AB - Celiac disease (CD) is associated with intestinal microbiota alterations. The administration of prebiotics could be a promising method of restoring gut homeostasis in CD. The aim of this study was to evaluate the effect of prolonged oligofructose-enriched inulin (Synergy 1) administration on the characteristics and metabolism of intestinal microbiota in CD children following a gluten-free diet (GFD). Thirty-four paediatric CD patients (mean age 10 years; 62% females) on a GFD were randomized into two experimental groups receiving Synergy 1 (10 g/day) or placebo (maltodextrin; 7 g/day) for 3 months. The quantitative gut microbiota characteristics and short-chain fatty acids (SCFAs) concentration were analysed. In addition, side effects were monitored. Generally, the administration of Synergy 1 in a GFD did not cause any side effects. After the intervention period, Bifidobacterium count increased significantly (p < 0.05) in the Synergy 1 group. Moreover, an increase in faecal acetate and butyrate levels was observed in the prebiotic group. Consequently, total SCFA levels were 31% higher than at the baseline. The presented trial shows that Synergy 1 applied as a supplement of a GFD had a moderate effect on the qualitative characteristics of faecal microbiota, whereas it stimulated the bacterial metabolite production in CD children. PMID- 29439528 TI - Chemical Sensing Applications of ZnO Nanomaterials. AB - Recent advancement in nanoscience and nanotechnology has witnessed numerous triumphs of zinc oxide (ZnO) nanomaterials due to their various exotic and multifunctional properties and wide applications. As a remarkable and functional material, ZnO has attracted extensive scientific and technological attention, as it combines different properties such as high specific surface area, biocompatibility, electrochemical activities, chemical and photochemical stability, high-electron communicating features, non-toxicity, ease of syntheses, and so on. Because of its various interesting properties, ZnO nanomaterials have been used for various applications ranging from electronics to optoelectronics, sensing to biomedical and environmental applications. Further, due to the high electrochemical activities and electron communication features, ZnO nanomaterials are considered as excellent candidates for electrochemical sensors. The present review meticulously introduces the current advancements of ZnO nanomaterial-based chemical sensors. Various operational factors such as the effect of size, morphologies, compositions and their respective working mechanisms along with the selectivity, sensitivity, detection limit, stability, etc., are discussed in this article. PMID- 29439530 TI - Analysis of the High-Frequency Content in Human QRS Complexes by the Continuous Wavelet Transform: An Automatized Analysis for the Prediction of Sudden Cardiac Death. AB - BACKGROUND: Fragmentation and delayed potentials in the QRS signal of patients have been postulated as risk markers for Sudden Cardiac Death (SCD). The analysis of the high-frequency spectral content may be useful for quantification. METHODS: Forty-two consecutive patients with prior history of SCD or malignant arrhythmias (patients) where compared with 120 healthy individuals (controls). The QRS complexes were extracted with a modified Pan-Tompkins algorithm and processed with the Continuous Wavelet Transform to analyze the high-frequency content (85 130 Hz). RESULTS: Overall, the power of the high-frequency content was higher in patients compared with controls (170.9 vs. 47.3 103nV2Hz-1; p = 0.007), with a prolonged time to reach the maximal power (68.9 vs. 64.8 ms; p = 0.002). An analysis of the signal intensity (instantaneous average of cumulative power), revealed a distinct function between patients and controls. The total intensity was higher in patients compared with controls (137.1 vs. 39 103nV2Hz-1s-1; p = 0.001) and the time to reach the maximal intensity was also prolonged (88.7 vs. 82.1 ms; p < 0.001). DISCUSSION: The high-frequency content of the QRS complexes was distinct between patients at risk of SCD and healthy controls. The wavelet transform is an efficient tool for spectral analysis of the QRS complexes that may contribute to stratification of risk. PMID- 29439532 TI - A Quick Surgical Treatment of Conjunctivochalasis Using Radiofrequencies. AB - The purpose of our study is to present a quick surgical procedure for the treatment of Conjunctivochalasis (CCH) and to evaluate its effectiveness. Thirty consecutive patients, in whom CCH was diagnosed on clinical examination, were investigated for the presence of symptoms of dry eye. The 60 eyes were evaluated according to their symptomatology and the 40 symptomatic eyes were grouped in two stages using the LIPCOF (stage 1, one small fold; stage 2, more than two folds but not higher than the tear meniscus) classification and included in the study. After a subconjunctival injection of lidocaine 20 mg/mL, a medium frequency alternating current (RF) was used, adjusted in low power. With a wide tip, redundant conjunctiva was ablated leaving space between the ablations. Postoperative treatment included eye oint.gentamicin 0.3% with dexamethasone 0.03% three times a day for 5 days. At postoperative day 10, conjunctival edema had subsided and conjunctival epithelium was intact after fluorescein staining. Symptoms had improved in all patients. During follow-up, no complication was detected. Mild conjunctival hyperemia was present in all cases but resolved with standard postoperative medications. To conclude, CCh treatment with RF appears to be a safe, quick, and effective surgical technique. Operation time is less than 10 min and can be performed in an outpatient clinic. PMID- 29439531 TI - Chemopreventive Effect of Aster glehni on Inflammation-Induced Colorectal Carcinogenesis in Mice. AB - Although Aster glehni is a common dietary herb that has various bioactivities, including anti-diabetic, anti-adipogenic, and anti-inflammatory effects, A. glehni has not been studied in colon cancer. Therefore, we hypothesized the chemopreventive effects of an ethanol extract of A. glehni (AG) on azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated cancer (CAC) in mice. In this study, we found that treatment with AG significantly attenuated the AOM/DSS-induced enlargement of the spleen and shortening of the colon. In addition, colonic tumor formation, colonic damage, and increased muscle thickness were significantly reduced in AOM/DSS-induced mice fed AG. Treatment with AG also reduced intestinal interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha production and decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein expression in mice with AOM/DSS-induced CAC. Furthermore, AG reduced nuclear factor (NF)-kappaB activation via phosphorylation and degradation of inhibitor of kappa Balpha (IkappaBalpha), leading to inhibition of NF-kappaB p65 nuclear translocation. It also downregulated the expression of NF-kappaB-related proteins, including the B-cell lymphoma 2 (Bcl-2) family and inhibitors of apoptosis proteins (IAPs), in mice with AOM/DSS-induced CAC. Taken together, these findings suggest that the treatment with AG inhibited colitis-associated colon carcinogenesis in mice, and this chemopreventive effect was strongly mediated by suppression of the NF-kappaB signaling pathway, indicating that AG could be a promising protective agent against CAC. PMID- 29439529 TI - Impact of DNA and RNA Methylation on Radiobiology and Cancer Progression. AB - Radiotherapy is a well-established regimen for nearly half the cancer patients worldwide. However, not all cancer patients respond to irradiation treatment, and radioresistance is highly associated with poor prognosis and risk of recurrence. Elucidation of the biological characteristics of radioresistance and development of effective prognostic markers to guide clinical decision making clearly remain an urgent medical requirement. In tumorigenic and radioresistant cancer cell populations, phenotypic switch is observed during the course of irradiation treatment, which is associated with both stable genetic and epigenetic changes. While the importance of epigenetic changes is widely accepted, the irradiation triggered specific epigenetic alterations at the molecular level are incompletely defined. The present review provides a summary of current studies on the molecular functions of DNA and RNA m6A methylation, the key epigenetic mechanisms involved in regulating the expression of genetic information, in resistance to irradiation and cancer progression. We additionally discuss the effects of DNA methylation and RNA N6-methyladenosine (m6A) of specific genes in cancer progression, recurrence, and radioresistance. As epigenetic alterations could be reversed by drug treatment or inhibition of specific genes, they are also considered potential targets for anticancer therapy and/or radiotherapy sensitizers. The mechanisms of irradiation-induced alterations in DNA and RNA m6A methylation, and ways in which this understanding can be applied clinically, including utilization of methylation patterns as prognostic markers for cancer radiotherapy and their manipulation for anticancer therapy or use as radiotherapy sensitizers, have been further discussed. PMID- 29439533 TI - Molecular and Functional Properties of Protein Fractions and Isolate from Cashew Nut (Anacardium occidentale L.). AB - Some molecular and functional properties of albumin (83.6% protein), globulin (95.5% protein), glutelin (81.3% protein) as well as protein isolate (80.7% protein) from cashew nut were investigated. These proteins were subjected to molecular (circular dichroism, gel electrophoresis, scanning electron microscopy) and functional (solubility, emulsification, foaming, water/oil holding capacity) tests. Cashew nut proteins represent an abundant nutrient with well-balanced amino acid composition and could meet the requirements recommended by FAO/WHO. SDS-PAGE pattern indicated cashew nut proteins were mainly composed of a polypeptide with molecular weight (MW) of 53 kDa, which presented two bands with MW of 32 and 21 kDa under reducing conditions. The far-UV CD spectra indicated that cashew proteins were rich in beta-sheets. The surface hydrophobicity of the protein isolate was higher than that of the protein fractions. In pH 7.0, the solubility of protein fractions was above 70%, which was higher than protein isolate at any pH. Glutelin had the highest water/oil holding capacity and foaming properties. Protein isolate displayed better emulsifying properties than protein fractions. In summary, cashew nut kernel proteins have potential as valuable nutrition sources and could be used effectively in the food industry. PMID- 29439534 TI - Chemical and Microbial Quality of Groundwater in Siloam Village, Implications to Human Health and Sources of Contamination. AB - Due to inaccessibility of potable water, rural communities drill boreholes within their homesteads despite vulnerability to groundwater contamination and associated health risks. This study assessed the quality of groundwater, identified potential sources of contamination and potential human health risks in Siloam Village, South Africa. Statistical difference between similar water quality parameters at different sites was determined at a significance level (alpha) of 0.05. Water quality parameters with serious potential health effects on human beings were correlated with selected water quality parameters to understand the nature of correlation and possible sources of contamination. Fluorides and nitrates had excessively high concentrations associated with tooth damage and pronounced skeletal fluorosis, and methaemoglobinaemia in infants and mucous membrane irritation in adults, respectively. There were statistically significant differences between means of most water quality parameters. Contrasting correlation of fluoride with calcium and pH indicated the need to further identify local sources and fluoride control mechanisms. Correlation of nitrate with chloride mostly indicated that faecal contamination is the potential source of high nitrates in groundwater. This requires further verification. Presence of total coliforms and E. coli in most boreholes indicated potential presence of faecal contamination. The need to educate borehole owners' on possible strategies to minimise groundwater pollution was identified. PMID- 29439535 TI - Bioactivity Assessment of Indian Origin-Mangrove Actinobacteria against Candida albicans. AB - Actinobacteria is found to have a potent metabolic activity against pathogens. The present study reveals the assessment of potent antifungal secondary metabolites from actinobacteria isolated from Indian marine mangrove sediments. The samples were collected from the coastal regions of Muthupet, Andaman and the Nicobar Islands. Identification was carried out using 16S rRNA analysis and biosynthetic genes (Polyketide synthase type I/II and Non-ribosomal peptide synthase) were screened. Actinobacteria were assayed for their antifungal activity against 16 clinical Candida albicans and the compound analysis was performed using gas chromatography-mass spectrometry GC-MS. The 31 actinobacterial strains were isolated and 16S rRNA gene sequencing revealed that this ecosystem is rich on actinobacteria, with Streptomyces as the predominant genus. The PCR based screening of biosynthetic genes revealed the presence of PKS I in six strains, PKS-II in four strains and NRPS in 11 strains. The isolated actinobacteria VITGAP240 and VITGAP241 (two isolates) were found to have a potential antifungal activity against all the tested C. albicans. GC-MS results revealed that the actinobacterial compounds were belonging to heterocyclic, polyketides and peptides. Overall, the strains possess a wide spectrum of antifungal properties which affords the production of significant bioactive metabolites as potential antibiotics. PMID- 29439536 TI - What Are the Main Drivers of Young Consumers Purchasing Traditional Food Products? European Field Research. AB - In this research, the attitude of European young adults (age 18 to 30 years) regarding their consumption of local and traditional products was examined. The survey was conducted on a sample of 836 consumers from seven European countries (Greece, Bulgaria, Romania, Slovenia, Croatia, Denmark and France). Data collection was made by distributing a developed questionnaire through social media and university mail services. Principal Component Analysis (PCA) was used to identify consumer perception comparing the overall sample with two subsets (consumers from Eastern and Western European countries). Six major factors were revealed: consumer behavior, uncertainty about health issues, cost, influence of media and friends and availability in store. Young adults had a positive attitude to local and traditional food products, but they expressed insecurity about health issues. Cost factor had less of an influence on interviewees from Eastern European countries than those from the overall sample (3rd and 5th factor accordingly). Influence of close environment was a different factor in Eastern countries compared to Western ones, for which it was common to see an influence from media. Females and older people (25-30 years old) have fewer doubts about Traditional Food Products, while media have a high influence on consumers' decisions. The aim of this survey was to identify the consumer profiles of young adults and create different promotion strategies of local and traditional products among the two groups of countries. PMID- 29439537 TI - A Randomized Controlled Trial to Investigate the Effectiveness of the Prevention of Aspiration Pneumonia Using Recommendations for Swallowing Care Guided by Ultrasound Examination. AB - Prevention for aspiration pneumonia requires assessment of aspiration and adequate swallowing care. This randomized controlled trial aimed to investigate the effectiveness of ultrasound examination and recommendations for swallowing care for the reduction of aspiration and pharyngeal post-swallow residue as compared with standard swallowing care. Twenty-three participants were randomized to the intervention group and 23 to the control group. The intervention consisted of four ultrasound examinations during mealtimes and recommendations for swallowing care every 2 weeks during an 8 week period. No recommendations concerning swallowing care based on ultrasound examinations were provided to the control group. The frequency of aspiration or residue was defined as x/y * 100% when aspiration or residue were detected x times from y times concerning the total ultrasound measurements. The proportion of the residents with reduced frequency of aspiration which was detected by ultrasonography at eight weeks were 4.3% in the intervention group and 0% in the control group. The median reduction in the frequency of aspiration and residue in the intervention group was 31%, and that in the control group was 11%. In conclusion, swallowing care guided by frequent ultrasound examinations during mealtimes had a trend of reducing the frequency of aspiration and residue during an 8-week period in individuals relative to standard swallowing care alone. PMID- 29439538 TI - The Physical Clogging of the Landfill Leachate Collection System in China: Based on Filtration Test and Numerical Modelling. AB - Clogging of the leachate collection system (LCS) has been a common operation problem in municipal solid waste (MSW) landfills in China, which can result in high water levels that threaten the safety of landfill operations. To determine the cause of failure in an LCS, raw leachate from a municipal solid waste transfer station was collected and the high content of particulate matter was characterized. Based on the parameters obtained in a filtration test, a numerical simulation was performed to estimate the influence of particle deposition on drainage system clogging. The results showed that LCSs were confronted with the risk of clogging due to the deposition of particulate matter resulting from the higher concentration of total suspended solids (TSS level > 2200 mg L-1) and larger particle size (>30% TSS particles > 15 MUm) in the leachate. On one hand, the non-woven geotextile, as the upper layer of the LCS, retained most particulate matter of large diameters, reducing its hydraulic conductivity to approximately 10-8 to 10-9 m s-1 after 1-2 years of operation and perching significant leachate above it (0.6-0.7 m). On the other hand, the geotextile prevented the gravel layer from physically clogging and minimized the leachate head above the bottom liner. Therefore, the role of geotextile should be balanced to optimize the LCS in MSW landfills in China. PMID- 29439540 TI - An Architecture Framework for Orchestrating Context-Aware IT Ecosystems: A Case Study for Quantitative Evaluation ?. AB - With the emergence of various forms of smart devices and new paradigms such as the Internet of Things (IoT) concept, the IT (Information Technology) service areas are expanding explosively compared to the provision of services by single systems. A new system operation concept that has emerged in accordance with such technical trends is the IT ecosystem. The IT ecosystem can be considered a special type of system of systems in which multiple systems with various degrees of autonomy achieve common goals while adapting to the given environment. The single systems that participate in the IT ecosystem adapt autonomously to the current situation based on collected data from sensors. Furthermore, to maintain the services supported by the whole IT ecosystem sustainably, the configuration of single systems that participate in the IT ecosystem also changes appropriately in accordance with the changed situation. In order to support the IT ecosystem, this paper proposes an architecture framework that supports dynamic configuration changes to achieve the goal of the whole IT ecosystem, while ensuring the autonomy of single systems through the collection of data from sensors so as to recognize the situational context of individual participating systems. For the feasibility evaluation of the proposed framework, a simulated example of an IT ecosystem for unmanned forest management was constructed, and the quantitative evaluation results are discussed in terms of the extent to which the proposed architecture framework can continuously provide sustainable services in response to diverse environmental context changes. PMID- 29439539 TI - Force Modeling, Identification, and Feedback Control of Robot-Assisted Needle Insertion: A Survey of the Literature. AB - Robot-assisted surgery is of growing interest in the surgical and engineering communities. The use of robots allows surgery to be performed with precision using smaller instruments and incisions, resulting in shorter healing times. However, using current technology, an operator cannot directly feel the operation because the surgeon-instrument and instrument-tissue interaction force feedbacks are lost during needle insertion. Advancements in force feedback and control not only help reduce tissue deformation and needle deflection but also provide the surgeon with better control over the surgical instruments. The goal of this review is to summarize the key components surrounding the force feedback and control during robot-assisted needle insertion. The literature search was conducted during the middle months of 2017 using mainstream academic search engines with a combination of keywords relevant to the field. In total, 166 articles with valuable contents were analyzed and grouped into five related topics. This survey systemically summarizes the state-of-the-art force control technologies for robot-assisted needle insertion, such as force modeling, measurement, the factors that influence the interaction force, parameter identification, and force control algorithms. All studies show force control is still at its initial stage. The influence factors, needle deflection or planning remain open for investigation in future. PMID- 29439541 TI - The Effect of Active Creation on Psychological Health: A Feasibility Study on (Therapeutic) Mechanisms. AB - Creation is an important part of many interventions in creative arts therapies (art, music, dance, and drama therapy). This active part of art-making in arts therapies has not yet been closely investigated. The present study commits to this field of research using a mixed-methods design to investigate the effects of active creation on health-related psychological outcomes. In an artistic inquiry within an experimental design, N = 44 participants engaged in active art-making for eight minutes in the presence of the researcher (first author) with a choice of artistic materials: paper and colors for drawing and writing, musical instruments, space for moving or performing. Before and after the creation, participants completed a well-being, a self-efficacy and an experience of creation scale, and in addition found their own words to express the experiences during the activity. We hypothesized that the experience of empowerment, freedom, impact, and creativity (Experience of Creation Scale) mediates the positive effect of active creation on the outcomes of self-efficacy and well-being, and evaluated this assumption with a mediation analysis. Results suggest that the effect of active creation on both self-efficacy and well-being is significantly mediated by the Experience of Creation Scale. This article focuses on the quantitative side of the investigation. During the process, qualitative and quantitative results were triangulated for a more valid evaluation and jointly contribute to the emerging theory frame of embodied aesthetics. PMID- 29439542 TI - Update on the Non-Pharmacological Management of Stroke Prevention in Patients with Atrial Fibrillation. AB - Non-surgical left atrial appendage occlusion has emerged as an alternative to anticoagulant therapy in the management of stroke risk in patients with atrial fibrillation. This review reports on some of the more common devices that are currently being used to manage patients in this challenging group. PMID- 29439543 TI - Patient-Centered Care in Breast Cancer Genetic Clinics. AB - With advances in breast cancer (BC) gene panel testing, risk counseling has become increasingly complex, potentially leading to unmet psychosocial needs. We assessed psychosocial needs and correlates in women initiating testing for high genetic BC risk in clinics in France and Germany, and compared these results with data from a literature review. Among the 442 counselees consecutively approached, 212 (83%) in France and 180 (97%) in Germany, mostly BC patients (81% and 92%, respectively), returned the 'Psychosocial Assessment in Hereditary Cancer' questionnaire. Based on the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) BC risk estimation model, the mean BC lifetime risk estimates were 19% and 18% in France and Germany, respectively. In both countries, the most prevalent needs clustered around the "living with cancer" and "children-related issues" domains. In multivariate analyses, a higher number of psychosocial needs were significantly associated with younger age (b = 0.05), higher anxiety (b = 0.78), and having children (b = 1.51), but not with country, educational level, marital status, depression, or loss of a family member due to hereditary cancer. These results are in line with the literature review data. However, this review identified only seven studies that quantitatively addressed psychosocial needs in the BC genetic counseling setting. Current data lack understandings of how cancer risk counseling affects psychosocial needs, and improves patient-centered care in that setting. PMID- 29439544 TI - Clearly Transparent Nanopaper from Highly Concentrated Cellulose Nanofiber Dispersion Using Dilution and Sonication. AB - Nanopaper prepared from holocellulose pulp is one of the best substrates for flexible electronics because of its high thermal resistance and high clear transparency. However, the clearness of nanopaper decreases with increasing concentration of the starting cellulose nanofiber dispersion-with the use of a 2.2 wt % dispersion, for example-resulting in translucent nanopaper with a high haze of 44%. To overcome this problem, we show that the dilution of this high concentration dispersion with water followed by sonication for 10 s reduces the haze to less than 10% while maintaining the high thermal resistance of the nanopaper. Furthermore, the combination of water dilution and a short sonication treatment improves the clearness of the nanopaper, which would translate into cost savings for the transportation and storage of this highly concentrated cellulose nanofiber dispersion. Finally, we demonstrate the improvement of the electrical conductivity of clear transparent nanopaper prepared from an initially high-concentration dispersion by dropping and heating silver nanowire ink on the nanopaper. These achievements will pave the way toward the realization of the mass production of nanofiber-based flexible devices. PMID- 29439545 TI - Graphene Modified TiO2 Composite Photocatalysts: Mechanism, Progress and Perspective. AB - Graphene modified TiO2 composite photocatalysts have drawn increasing attention because of their high performance. Some significant advancements have been achieved with the continuous research, such as the corresponding photocatalytic mechanism that has been revealed. Specific influencing factors have been discovered and potential optimizing methods are proposed. The latest developments in graphene assisted TiO2 composite photocatalysts are abstracted and discussed. Based on the primary reasons behind the observed phenomena of these composite photocatalysts, probable development directions and further optimizing strategies are presented. Moreover, several novel detective technologies-beyond the decomposition test-which can be used to judge the photocatalytic performances of the resulting photocatalysts are listed and analyzed. Although some objectives have been achieved, new challenges still exist and hinder the widespread application of graphene-TiO2 composite photocatalysts, which deserves further study. PMID- 29439546 TI - Toxicity of Urban PM10 and Relation with Tracers of Biomass Burning. AB - The chemical composition of particles varies with space and time and depends on emission sources, atmospheric chemistry and weather conditions. Evidence suggesting that particles differ in toxicity depending on their chemical composition is growing. This in vitro study investigated the biological effects of PM10 in relation to PM-associated chemicals. PM10 was sampled in ambient air at an urban traffic site (Borgerhout) and a rural background location (Houtem) in Flanders (Belgium). To characterize the toxic potential of PM10, airway epithelial cells (Beas-2B cells) were exposed to particles in vitro. Different endpoints were studied including cell damage and death (cell viability) and the induction of interleukin-8 (IL-8). The mutagenic capacity was assessed using the Ames II Mutagenicity Test. The endotoxin levels in the collected samples were analyzed and the oxidative potential (OP) of PM10 particles was evaluated by electron paramagnetic resonance (EPR) spectroscopy. Chemical characteristics of PM10 included tracers for biomass burning (levoglucosan, mannosan and galactosan), elemental and organic carbon (EC/OC) and polycyclic aromatic hydrocarbons (PAHs). Most samples displayed dose-dependent cytotoxicity and IL-8 induction. Spatial and temporal differences in PM10 toxicity were seen. PM10 collected at the urban site was characterized by increased pro-inflammatory and mutagenic activity as well as higher OP and elevated endotoxin levels compared to the background area. Reduced cell viability (-0.46 < rs < -0.35, p < 0.01) and IL 8 induction (-0.62 < rs < -0.67, p < 0.01) were associated with all markers for biomass burning, levoglucosan, mannosan and galactosan. Furthermore, direct and indirect mutagenicity were associated with tracers for biomass burning, OC, EC and PAHs. Multiple regression analyses showed levoglucosan to explain 16% and 28% of the variance in direct and indirect mutagenicity, respectively. Markers for biomass burning were associated with altered cellular responses and increased mutagenic activity. These findings may indicate a role of biomass burning in the observed adverse health effect of particulate matter. PMID- 29439547 TI - Prostaglandin D2-Mediated DP2 and AKT Signal Regulate the Activation of Androgen Receptors in Human Dermal Papilla Cells. AB - Prostaglandin D2 (PGD2) and prostaglandin D2 receptor 2 (DP2) is known to be an important factor in androgenetic alopecia (AGA). However, the effect of PGD2 in human dermal papilla cells (hDPCs) is not fully understood. The function of PGD2 induced expression of the androgen receptor (AR), DP2, and AKT (protein kinase B) signal were examined by using real time-PCR (qRT-PCR), western blot analysis, immunocytochemistry (ICC), and siRNA transfection system. PGD2 stimulated AR expression and AKT signaling through DP2. PGD2 stimulated AR related factors (transforming growth factor beta 1 (TGFbeta1), Creb, lymphoid enhancer binding factor 1 (LEF1), and insulin-like growth factor 1, (IGF-1)) and AKT signaling (GSK3beta and Creb) on the AR expression in hDPCs. However, these factors were down-regulated by DP2 antagonist (TM30089) and AKT inhibitor (LY294002) as well as DP2 knockdown in hDPCs decreased AR expression and AKT signaling. Finally, we confirmed that PGD2 stimulates the expression of AR related target genes, and that AKT and its downstream substrates are involved in AR expression on hDPCs. Taken together, our data suggest that PGD2 promotes AR and AKT signal via DP2 in hDPCs, thus, PGD2 and DP2 signal plays a critical role in AR expression. These findings support the additional explanation for the development of AGA involving PGD2-DP2 in hDPCs. PMID- 29439548 TI - Detection of HPV16 in Esophageal Cancer in a High-Incidence Region of Malawi. AB - This study was designed to explore the role of human papillomavirus (HPV) in esophageal squamous cell carcinoma (ESCC). Fifty-five patients receiving diagnostic upper gastrointestinal endoscopy at Zomba Central Hospital or Queen Elizabeth Hospital in Blantyre (Malawi) in 2010, were included in our study. Formalin-fixed paraffin-embedded biopsies were collected for histopathological diagnosis. HPV DNA was detected using multiplex Quantitative PCR (qPCR) and in situ hybridization (ISH). p16INK4a staining served as a surrogate marker for HPV oncogene activity. Cell proliferation was determined by Ki-67 staining. Human immunodeficiency virus (HIV) status was evaluated by serology. Data on the consumption of alcohol and tobacco, and history of tuberculosis (TBC), oral thrush, and Herpes zoster, were obtained by questionnaire. Forty patients displayed ESCC, three displayed dysplastic epithelium, and 12 displayed normal epithelium. HPV16 was detected in six ESCC specimens and in one dysplastic lesion. Among HPV-positive patients, viral load varied from 0.001 to 2.5 copies per tumor cell. HPV DNA presence could not be confirmed by ISH. p16INK4a positivity correlated with the presence of HPV DNA (p = 0.03). Of particular note is that the Ki-67 proliferation index, in areas with diffuse nuclear or cytoplasmatic p16INK4a staining >=50%, was significantly higher in HPV-positive tumors compared to the corresponding p16INK4a stained areas of HPV-negative tumors (p = 0.004). HPV infection in ESCC was not associated with the consumption of tobacco or alcohol, but there were significantly more patients drinking locally brewed alcohol among HPV-positive tumor patients compared to non-tumor patients (p = 0.02) and compared to HPV-negative tumor patients (p = 0.047). There was no association between HIV infection, history of TBC, Herpes zoster, oral thrush, or HPV infection, in ESCC patients. Our indirect evidence for viral oncogene activity is restricted to single tumor cell areas, indicative of the role of HPV16 in the development of ESCC. The inhomogeneous presence of the virus within the tumor is reminiscent of the "hit and run" mechanism discussed for beta HPV types, such as HPV38. PMID- 29439549 TI - Enlightening Butterfly Conservation Efforts: The Importance of Natural Lighting for Butterfly Behavioral Ecology and Conservation. AB - Light is arguably the most important abiotic factor for living organisms. Organisms evolved under specific lighting conditions and their behavior, physiology, and ecology are inexorably linked to light. Understanding light effects on biology could not be more important as present anthropogenic effects are greatly changing the light environments in which animals exist. The two biggest anthropogenic contributors changing light environments are: (1) anthropogenic lighting at night (i.e., light pollution); and (2) deforestation and the built environment. I highlight light importance for butterfly behavior, physiology, and ecology and stress the importance of including light as a conservation factor for conserving butterfly biodiversity. This review focuses on four parts: (1) Introducing the nature and extent of light. (2) Visual and non visual light reception in butterflies. (3) Implications of unnatural lighting for butterflies across several different behavioral and ecological contexts. (4). Future directions for quantifying the threat of unnatural lighting on butterflies and simple approaches to mitigate unnatural light impacts on butterflies. I urge future research to include light as a factor and end with the hopeful thought that controlling many unnatural light conditions is simply done by flipping a switch. PMID- 29439550 TI - Cytotoxic and Antimicrobial Compounds from the Marine-Derived Fungus, Penicillium Species. AB - The organic extract of liquid cultures of the marine-derived Penicillium sp. was investigated. Fractionation of the extracts of the fungus led to the purification and identification of two new compounds, penicillatides A (1) and B (2), together with the previously reported cyclo(R-Pro-S-Phe) (3) and cyclo(R-Pro-R-Phe) (4). The structures of compounds 1-4 were assigned by extensive interpretation of their NMR and high-resolution mass spectrometry (HRMS). The antiproliferative and cytotoxic activities of the compounds against three human cancer cell lines as well as their antimicrobial activity against several pathogens were evaluated. Compounds 2-4 displayed variable cytotoxic and antimicrobial activities. PMID- 29439551 TI - Preliminary Investigation of Poly-Ether-Ether-Ketone Based on Fused Deposition Modeling for Medical Applications. AB - Poly-ether-ether-ketone (PEEK) fabricated by fused deposition modeling for medical applications was evaluated in terms of mechanical strength and in vitro cytotoxicity in this study. Orthogonal experiments were firstly designed to investigate the significant factors on tensile strength. Nozzle temperature, platform temperature, and the filament diameter were tightly controlled for improved mechanical strength performance. These sensitive parameters affected the interlayer bonding and solid condition in the samples. Fourier transform infrared (FTIR) spectrometry analysis was secondly conducted to compare the functional groups in PEEK granules, filaments, and printed parts. In vitro cytotoxicity test was carried out at last, and no toxic substances were introduced during the printing process. PMID- 29439553 TI - Magnetic Characterization of Direct-Write Free-Form Building Blocks for Artificial Magnetic 3D Lattices. AB - Three-dimensional (3D) nanomagnetism, where spin configurations extend into the vertical direction of a substrate plane allow for more complex, hierarchical systems and the design of novel magnetic effects. As an important step towards this goal, we have recently demonstrated the direct-write fabrication of freestanding ferromagnetic 3D nano-architectures of ferromagnetic CoFe in shapes of nano-tree and nano-cube structures by means of focused electron beam induced deposition. Here, we present a comprehensive characterization of the magnetic properties of these structures by local stray-field measurements using a high resolution micro-Hall magnetometer. Measurements in a wide range of temperatures and different angles of the externally applied magnetic field with respect to the surface plane of the sensor are supported by corresponding micromagnetic simulations, which explain the overall switching behavior of in part rather complex magnetization configurations remarkably well. In particular, the simulations yield coercive and switching fields that are in good quantitative correspondence with the measured coercive and switching fields assuming a bulk metal content of 100 at % consisting of bcc Co 3 Fe. We show that thermally unstable magnetization states can be repetitively prepared and their lifetime controlled at will, a prerequisite to realizing dynamic and thermally-active magnetic configurations if the building blocks are to be used in lattice structures. PMID- 29439552 TI - Proteinaceous Regulators and Inhibitors of Protein Tyrosine Phosphatases. AB - Proper control of the phosphotyrosine content in signal transduction proteins is essential for normal cell behavior and is lost in many pathologies. Attempts to normalize aberrant tyrosine phosphorylation levels in disease states currently involve either the application of small compounds that inhibit tyrosine kinases (TKs) or the addition of growth factors or their mimetics to boost receptor-type TK activity. Therapies that target the TK enzymatic counterparts, the multi enzyme family of protein tyrosine phosphatases (PTPs), are still lacking despite their undisputed involvement in human diseases. Efforts to pharmacologically modulate PTP activity have been frustrated by the conserved structure of the PTP catalytic core, providing a daunting problem with respect to target specificity. Over the years, however, many different protein interaction-based regulatory mechanisms that control PTP activity have been uncovered, providing alternative possibilities to control PTPs individually. Here, we review these regulatory principles, discuss existing biologics and proteinaceous compounds that affect PTP activity, and mention future opportunities to drug PTPs via these regulatory concepts. PMID- 29439554 TI - Pilot Study on Mass Spectrometry-Based Analysis of the Proteome of CD34+CD123+ Progenitor Cells for the Identification of Potential Targets for Immunotherapy in Acute Myeloid Leukemia. AB - Targeting of leukemic stem cells with specific immunotherapy would be an ideal approach for the treatment of myeloid malignancies, but suitable epitopes are unknown. The comparative proteome-level characterization of hematopoietic stem and progenitor cells from healthy stem cell donors and patients with acute myeloid leukemia has the potential to reveal differentially expressed proteins which can be used as surface-markers or as proxies for affected molecular pathways. We employed mass spectrometry methods to analyze the proteome of the cytosolic and the membrane fraction of CD34 and CD123 co-expressing FACS-sorted leukemic progenitors from five patients with acute myeloid leukemia. As a reference, CD34+CD123+ normal hematopoietic progenitor cells from five healthy, granulocyte-colony stimulating factor (G-CSF) mobilized stem cell donors were analyzed. In this Tandem Mass Tag (TMT) 10-plex labelling-based approach, 2070 proteins were identified with 171 proteins differentially abundant in one or both cellular compartments. This proof-of-principle-study demonstrates the potential of mass spectrometry to detect differentially expressed proteins in two compartment fractions of the entire proteome of leukemic stem cells, compared to their non-malignant counterparts. This may contribute to future immunotherapeutic target discoveries and individualized AML patient characterization. PMID- 29439555 TI - Theoretical Insight into the Biodegradation of Solitary Oil Microdroplets Moving through a Water Column. AB - In the aftermath of oil spills in the sea, clouds of droplets drift into the seawater column and are carried away by sea currents. The fate of the drifting droplets is determined by natural attenuation processes, mainly dissolution into the seawater and biodegradation by oil-degrading microbial communities. Specifically, microbes have developed three fundamental strategies for accessing and assimilating oily substrates. Depending on their affinity for the oily phase and ability to proliferate in multicellular structures, microbes might either attach to the oil surface and directly uptake compounds from the oily phase, or grow suspended in the aqueous phase consuming solubilized oil, or form three dimensional biofilms over the oil-water interface. In this work, a compound particle model that accounts for all three microbial strategies is developed for the biodegradation of solitary oil microdroplets moving through a water column. Under a set of educated hypotheses, the hydrodynamics and solute transport problems are amenable to analytical solutions and a closed-form correlation is established for the overall dissolution rate as a function of the Thiele modulus, the Biot number and other key parameters. Moreover, two coupled ordinary differential equations are formulated for the evolution of the particle size and used to investigate the impact of the dissolution and biodegradation processes on the droplet shrinking rate. PMID- 29439556 TI - Mindfulness-Based Baduanjin Exercise for Depression and Anxiety in People with Physical or Mental Illnesses: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: we used a quantitative method to systematically synthesize the emerging literature and critically evaluate the effects of Baduanjin on depression and anxiety in people with physical or mental illnesses. Additionally, we determined if the number of total Baduanjin training sessions is associated with decreased anxiety and depression levels. METHODS: both English and Chinese databases were searched for potential studies published between January 1982 and October 2017. The eligible randomized controlled trials were considered for meta analysis. Effect size (Hedge's g) was computed for the pooled effects while the random-effect model was set. For moderator analysis; Subgroup meta-analysis for categorical variables and meta-regression for continuous variables were performed. RESULTS: the aggregated result has shown a significant benefit in favour of Baduanjin on anxiety (Hedge's g = -0.99; CI -1.63 to -0.74) and depression (Hedge's g = -1.07; CI -1.3 to -0.83). For continuous potential moderators; meta-regression indicated a significant effect for total hours in Baduanjin practice (beta = -0.0053; 95% CI -0.009 to -0.0014; p = 0.008). With regard to depression; meta-regression indicated a significant effect for total sessions of Baduanjin practice (beta = -0.0023; 95% CI -0.006 to -0.0004; p = 0.028). CONCLUSIONS: the encouraging findings indicate the efficacy of Baduanjin exercise in reducing depression and anxiety symptoms in people with physical or mental illnesses. However; the results should be interpreted with caution because of existing methodological limitations (e.g., high risk of bias; Baduanjin combined with other behavioral interventions; and heterogeneity of control groups). PMID- 29439557 TI - A Novel Ship Detection Method Based on Gradient and Integral Feature for Single Polarization Synthetic Aperture Radar Imagery. AB - With the rapid development of remote sensing technologies, SAR satellites like China's Gaofen-3 satellite have more imaging modes and higher resolution. With the availability of high-resolution SAR images, automatic ship target detection has become an important topic in maritime research. In this paper, a novel ship detection method based on gradient and integral features is proposed. This method is mainly composed of three steps. First, in the preprocessing step, a filter is employed to smooth the clutters and the smoothing effect can be adaptive adjusted according to the statistics information of the sub-window. Thus, it can retain details while achieving noise suppression. Second, in the candidate area extraction, a sea-land segmentation method based on gradient enhancement is presented. The integral image method is employed to accelerate computation. Finally, in the ship target identification step, a feature extraction strategy based on Haar-like gradient information and a Radon transform is proposed. This strategy decreases the number of templates found in traditional Haar-like methods. Experiments were performed using Gaofen-3 single-polarization SAR images, and the results showed that the proposed method has high detection accuracy and rapid computational efficiency. In addition, this method has the potential for on-board processing. PMID- 29439558 TI - pH-Triggered Peptide Self-Assembly for Targeting Imaging and Therapy toward Angiogenesis with Enhanced Signals. AB - Mild acidic environment and angiogenesis are two typical characteristics of tumor. The specific response toward both lower pH and angiogenesis may enhance the targeting ability both for drug and diagnostic probe delivery. Herein, we present a kind of dual responding self-assembled nanotransformation material that is tumor angiogenesis targeting and pH triggered based on amphiphilic conjugation between peptides (STP) and aromatic molecules (tetraphenylethylene (TPE)). The morphology of the self-assembled peptide conjugates is responsibly changed from nanoparticles in neutral condition to nanofibers in acidic condition, which "turn on" the in vivo targeting imaging and accelerate the efficient drug delivery and in vivo therapy. On the basis of the well-controlled nanotransformation both in vitro and in vivo, we envisioned the successful demonstration of the responding materials would open a new avenue in turn on targeting imaging diagnostics and specific cancer therapeutics. PMID- 29439559 TI - Microporous Porphyrin Networks Mimicking a Velvet Worm Surface and Their Enhanced Sensitivities toward Hydrogen Chloride and Ammonia. AB - This work shows that the functions of microporous organic network materials can be enhanced through engineering of the material structure. Mimicking the surface structure of velvet worms, we prepared the aligned 1D structure (rod) of microporous porphyrin networks by the Sonogashira coupling of tetrakis(4 ethynylphenyl)porphyrin with 1,4-diiodobenzene in an anodic aluminum oxide plate. The length of the 1D structure was controlled in the range of 1-5 MUm. The velvet worm surface-like microporous porphyrin networks (Velvet-MPNs) showed higher sensitivities to hydrogen chloride and ammonia gases by up to ~14 and 4.6 times, respectively, compared with a control MPN material without rods. PMID- 29439560 TI - Multiscale Simulation of Protein Hydration Using the SWINGER Dynamical Clustering Algorithm. AB - To perform computationally efficient concurrent multiscale simulations of biological macromolecules in solution, where the all-atom (AT) models are coupled to supramolecular coarse-grained (SCG) solvent models, previous studies resorted to modified AT water models, such as the bundled-simple point charge (SPC) models, that use semiharmonic springs to restrict the relative movement of water molecules within a cluster. Those models can have a significant impact on the simulated biomolecules and can lead, for example, to a partial unfolding of a protein. In this work, we employ the recently developed alternative approach with a dynamical clustering algorithm, SWINGER, which enables a direct coupling of original unmodified AT and SCG water models. We perform an adaptive resolution molecular dynamics simulation of a Trp-Cage miniprotein in multiscale water, where the standard SPC water model is interfaced with the widely used MARTINI SCG model, and demonstrate that, compared to the corresponding full-blown AT simulations, the structural and dynamic properties of the solvated protein and surrounding solvent are well reproduced by our approach. PMID- 29439561 TI - Enhanced Proton Conductivity of Sulfonated Hybrid Poly(arylene ether ketone) Membranes by Incorporating an Amino-Sulfo Bifunctionalized Metal-Organic Framework for Direct Methanol Fuel Cells. AB - Novel side-chain-type sulfonated poly(arylene ether ketone) (SNF-PAEK) containing naphthalene and fluorine moieties on the main chain was prepared in this work, and a new amino-sulfo-bifunctionalized metal-organic framework (MNS, short for MIL-101-NH2-SO3H) was synthesized via a hydrothermal technology and postmodification. Then, MNS was incorporated into a SNF-PAEK matrix as an inorganic nanofiller to prepare a series of organic-inorganic hybrid membranes (MNS@SNF-PAEK-XX). The mechanical property, methanol resistance, electrochemistry, and other properties of MNS@SNF-PAEK-XX hybrid membranes were characterized in detail. We found that the mechanical strength and methanol resistances of these hybrid membranes were improved by the formation of an ionic cross-linking structure between -NH2 of MNS and -SO3H on the side chain of SNF PAEK. Particularly, the proton conductivity of these hybrid membranes increased obviously after the addition of MNS. MNS@SNF-PAEK-3% exhibited the proton conductivity of 0.192 S.cm-1, which was much higher than those of the pristine membrane (0.145 S.cm-1) and recast Nafion (0.134 S.cm-1) at 80 degrees C. This result indicated that bifunctionalized MNS rearranged the microstructure of hybrid membranes, which could accelerate the transfer of protons. The hybrid membrane (MNS@SNF-PAEK-3%) showed a better direct methanol fuel cell performance with a higher peak power density of 125.7 mW/cm2 at 80 degrees C and a higher open-circuit voltage (0.839 V) than the pristine membrane. PMID- 29439562 TI - Ion Channel Sensing: Are Fluctuations the Crux of the Matter? AB - The nonselective cation channel TRPV1 is responsible for transducing noxious stimuli into action potentials propagating through peripheral nerves. It is activated by temperatures greater than 43 degrees C, while remaining completely nonconductive at temperatures lower than this threshold. The origin of this sharp response, which makes TRPV1 a biological temperature sensor, is not understood. Here we used molecular dynamics simulations and free energy calculations to characterize the molecular determinants of the transition between nonconductive and conductive states. We found that hydration of the pore and thus ion permeation depends critically on the polar character of its molecular surface: in this narrow hydrophobic enclosure, the motion of a polar side-chain is sufficient to stabilize either the dry or wet state. The conformation of this side-chain is in turn coupled to the hydration state of four peripheral cavities, which undergo a dewetting transition at the activation temperature. PMID- 29439564 TI - Origins of Stereoselectivity in Mannich Reactions Catalyzed by Chiral Vicinal Diamines. AB - The origins of the enantio- and diastereoselectivities in the Mannich reactions between aldehydes and ketimines catalyzed by chiral vicinal diamines have been determined by density functional theory calculations and distortion-interaction analysis. Computational results indicate a strong energetic preference for hydrogen-bonded nine-membered cyclic transition states. The favored transition states involve eight heavy atoms in the crown (chair-chair) conformation using the nomenclature of the analogous cyclic hydrocarbons. Energetic discrimination in the chirality-imparting step arises from pseudogauche-butane-type interactions in the disfavored transition states, as well as steric clashes between the N-Boc protecting group and the ammonium N-substituents. PMID- 29439563 TI - Co-Compartmentation of Terpene Biosynthesis and Storage via Synthetic Droplet. AB - Traditional bioproduct engineering focuses on pathway optimization, yet is often complicated by product inhibition, downstream consumption, and the toxicity of certain products. Here, we present the co-compartmentation of biosynthesis and storage via a synthetic droplet as an effective new strategy to improve the bioproduct yield, with squalene as a model compound. A hydrophobic protein was designed and introduced into the tobacco chloroplast to generate a synthetic droplet for terpene storage. Simultaneously, squalene biosynthesis enzymes were introduced to chloroplasts together with the droplet-forming protein to co compartmentalize the biosynthesis and storage of squalene. The strategy has enabled a record yield of squalene at 2.6 mg/g fresh weight without compromising plant growth. Confocal fluorescent microscopy imaging, stimulated Raman scattering microscopy, and droplet composition analysis confirmed the formation of synthetic storage droplet in chloroplast. The co-compartmentation of synthetic storage droplet with a targeted metabolic pathway engineering represents a new strategy for enhancing bioproduct yield. PMID- 29439565 TI - Quasi-SMILES-Based Nano-Quantitative Structure-Activity Relationship Model to Predict the Cytotoxicity of Multiwalled Carbon Nanotubes to Human Lung Cells. AB - Quantitative structure-activity relationship (QSAR) models for nanomaterials (nano-QSAR) were developed to predict the cytotoxicity of 20 different types of multiwalled carbon nanotubes (MWCNTs) to human lung cells by using quasi-SMILES. The optimal descriptors, recorded as quasi-SMILES, were encoded to represent the physicochemical properties and experimental conditions for the MWCNTs from 276 data records collected from previously published studies. The quasi-SMILES used to build the optimal descriptors were (i) diameter, (ii) length, (iii) surface area, (iv) in vitro toxicity assay, (v) cell line, (vi) exposure time, and (vii) dose. The model calculations were performed by using the Monte Carlo method and computed with CORAL software ( www.insilico.eu/coral ). The quasi-SMILES-based nano-QSAR model provided satisfactory statistical results ( R2 for internal validation data sets: 0.60-0.80; R2pred for external validation data sets: 0.81 0.88). The model showed potential for use in the estimation of human lung cell viability after exposure to MWCNTs with the following properties: diameter, 12-74 nm; length, 0.19-20.25 MUm; surface area, 11.3-380.0 m2/g; and dose, 0-200 ppm. PMID- 29439567 TI - Fluorescent-Cavity Host: An Efficient Probe to Study Supramolecular Recognition Mechanisms. AB - Using fluorometry to study the interactions between guests and host cavities is often challenging, especially for hosts with small cavities because the fluorophore may not be close to the binding site. Therefore, it is critical to overcome this hurdle to broaden the applicability of fluorometry in supramolecular chemistry. Herein, we designed a fluorescent-cavity host (H1) by conjugating the binding site of a pillar[5]arene cavity and studied its host guest recognition mechanism in the cavity. Distinct fluorescent responses of H1 were observed for cyano homologues: the fluorescence was enhanced for succinonitrile but quenched for malononitrile. Such an unusual phenomenon with such subtle difference in guest structure was attributed to the different host guest interactions induced by the subtle difference of guest locations within the H1 cavity. Our results indicate that developing fluorescent-cavity hosts as probes will provide a powerful and insightful way to explore the exquisite detail of host-guest recognition, self-assembly, and molecular machinery. PMID- 29439566 TI - Incorporation of Nonproteinogenic Amino Acids in Class I and II Lantibiotics. AB - Lantibiotics are ribosomally synthesized and post-translationally modified peptide natural products that contain thioether cross-links formed by lanthionine and methyllanthionine residues. They exert potent antimicrobial activity against Gram-positive bacteria. We herein report production of analogues of two lantibiotics, lacticin 481 and nisin, that contain nonproteinogenic amino acids using two different strategies involving amber stop codon suppression technology. These methods complement recent alternative approaches to incorporate nonproteinogenic amino acids into lantibiotics. PMID- 29439568 TI - Lessons Learned from Luminous Luciferins and Latent Luciferases. AB - Compared to the broad palette of fluorescent molecules, there are relatively few structures that are competent to support bioluminescence. Here, we focus on recent advances in the development of luminogenic substrates for firefly luciferase. The scope of this light-emitting chemistry has been found to extend well beyond the natural substrate and to include enzymes incapable of luciferase activity with d-luciferin. The broadening range of luciferin analogues and evolving insight into the bioluminescent reaction offer new opportunities for the construction of powerful optical reporters of use in live cells and animals. PMID- 29439569 TI - Thylakoid Containing Artificial Cells for the Inhibition Investigation of Light Driven Electron Transfer during Photosynthesis. AB - The fabrication of artificial cells containing nature components is challenging. Herein we construct a thylakoid containing artificial cell (TA-cell) by forming multicompartmental structure inside giant unilamellar vesicles (GUVs) using osmotic stress. The thylakoids are selectively loaded inside each compartment in GUVs to mimic "chloroplast". The TA-cells are able to carry out photosynthesis upon light on. The TA-cells keep their 50% functionality of electron transfer for 12 days, which is twice of those of free thylakoids. Using TA-cells the inhibition of 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) and heavy metal ions (Hg2+, Cu2+, Cd2+, Pb2+ and Zn2+) on the electron transfer process in TA-cells is systematically investigated. Their half maximal inhibitory concentration (IC50) values are 36.23 +/- 1.87, 0.02 +/- 0.01, 0.42 +/- 0.08, 0.82 +/- 0.12, 1.97 +/- 0.21, and 4.08 +/- 0.18 MUM, respectively. Hg2+ is the most toxic ion for the photosynthesis process among these five heavy metal ions. This biomimetic system can be expanded to study other processes during the photosynthesis. The TA-cells pave a way to fabricate more complicated nature component containing artificial cells. PMID- 29439570 TI - Enhanced Sampling of Molecular Dynamics Simulations of a Polyalanine Octapeptide: Effects of the Periodic Boundary Conditions on Peptide Conformation. AB - We investigate the problem of artifacts caused by the periodic boundary conditions (PBC) used in molecular simulation studies. Despite the long history of simulations with PBCs, the existence of measurable artifacts originating from PBCs applied to inherently nonperiodic physical systems remains controversial. Specifically, these artifacts appear as differences between simulations of the same system but with different simulation-cell sizes. Earlier studies have implied that, even in the simple case of a small model peptide in water, sampling inefficiency is a major obstacle to understanding these artifacts. In this study, we have resolved the sampling issue using the replica exchange molecular dynamics (REMD) enhanced-sampling method to explore PBC artifacts. Explicitly solvated zwitterionic polyalanine octapeptides with three different cubic-cells, having dimensions of L = 30, 40, and 50 A, were investigated to elucidate the differences with 64 replica * 500 ns REMD simulations using the AMBER parm99SB force field. The differences among them were not large overall, and the results for the L = 30 and 40 A simulations in the conformational free energy landscape were found to be very similar at room temperature. However, a small but statistically significant difference was seen for L = 50 A. We observed that extended conformations were slightly overstabilized in the smaller systems. The origin of these artifacts is discussed by comparison to an electrostatic calculation method without PBCs. PMID- 29439571 TI - Characterized in Vitro Metabolism Kinetics of Alkyl Organophosphate Esters in Fish Liver and Intestinal Microsomes. AB - Tris(2-butoxyethyl) phosphate (TBOEP) and tris( n-butyl) phosphate (TNBP) are the most commonly used alkyl organophosphate esters (alkyl-OPEs), and they increasingly accumulate in organisms and create potential health hazards. This study examined the metabolism of TNBP and TBOEP in Carassius carassius liver and intestinal microsomes and the production of their corresponding monohydroxylated and dealkylated metabolites. After 140 min of incubation with fish liver microsomes, the rapid depletion of TNBP and TBOEP were both best fitted to the Michaelis-Menten model (at administrated concentrations ranging from 0.5 to 200 MUM), with a CLint (intrinsic clearance) of 3.1 and 3.9 MUL.min-1.mg-1 protein, respectively. But no significant ( P > 0.05) biotransformation was observed for these compounds in intestinal microsomes at any administrated concentrations. In fish liver microsomes assay, bis(2-butoxyethyl) hydroxyethyl phosphate (BBOEHEP) and bis(2-butoxyethyl) 3-hydroxyl-2-butoxyethyl phosphate (3-OH-TBOEP) were the most abundant metabolites of TBOEP, and dibutyl-3-hydroxybutyl phosphate (3-OH TNBP) was the predominant metabolite of TNBP. Similarly, the apparent Vmax values (maximum metabolic rate) of BBOEHEP and 3-OH-TNBP were also respectively highest among those of other metabolites. Further inhibition studies were conducted to identify the specific cytochrome P450 (CYP450) isozymes involved in the metabolism of TNBP and TBOEP in liver microsomes. It was confirmed that CYP3A4 and CYP1A were the significant CYP450 isoforms catalyzing the metabolism of TNBP and TBOEP in fish liver microsomes. Overall, this study emphasized the importance of hydroxylated metabolites as biomarkers for alkyl-OPEs exposure, and further research is needed to validate the in vivo formation and toxicological implications of these metabolites. PMID- 29439572 TI - Surface Hopping Dynamics beyond Nonadiabatic Couplings for Quantum Coherence. AB - Description of correct electron-nuclear couplings is crucial in modeling of nonadiabatic dynamics. Within traditional semiclassical or mixed quantum classical dynamics, the coupling between quantum electronic states and classical nuclear trajectories is governed by nonadiabatic coupling vectors coupled to classical nuclear momenta. This enables us to develop a very powerful nonadiabatic dynamics algorithm, namely, surface hopping dynamics, which can describe the splitting of nuclear wave packets and detailed balance. Despite its efficiency and practicality, it suffers from the lack of quantum decoherence due to incorrect accounts for the electron-nuclear coupling. Here we present a new surface hopping algorithm based on the exact electron-nuclear correlation from the exact factorization of molecular wave functions. This algorithm demands comparable computational costs to existing surface hopping methods. Numerical simulations with two-state models and a multidimensional multistate realistic molecule show that the electron-nuclear coupling beyond the nonadiabatic coupling terms can describe the quantum coherence properly. PMID- 29439573 TI - Impact of Changes in Oil and Gas Production Activities on Air Quality in Northeastern Oklahoma: Ambient Air Studies in 2015-2017. AB - A total of three ground-based ambient air studies were conducted in February through March of 2015, 2016, and 2017 at the Phillips 66 Research Center in northeastern Oklahoma. C2-C12 nonmethane hydrocarbons (NMHCs) were measured using whole-air sampling and gas chromatography-mass spectrometry. In 2016 and 2017, online methane and ethane measurements were also conducted. Strong methane-ethane correlation identified oil and gas (O&G) upstream and midstream operations to be the primary methane source. C2-C5 alkanes were the dominant NMHCs whose average mixing ratio peaked in 2016 before dropping in 2017. This observation is attributed to regional O&G upstream operations, which peaked in 2015. Mean mixing ratios of C2-C5 alkanes ranged from 0.99 to 16.99 ppb. Measured ratios of i-C5/ n C5 were 0.97 +/- 0.03, 1.18 +/- 0.04, and 1.06 +/- 0.02 in 2015, 2016, and 2017, respectively, indicating that O&G upstream and midstream operations were their primary source. Photochemical age was estimated using observed ratio between hexane and propane. Emission ratios of NMHCs at zero photochemical age were calculated, which resembled the composition reported in the literature for natural gas field condensate tank flashing. Back-trajectory analysis showed that hydrocarbon-rich plumes came from the south and west directions, where O&G upstream and midstream operations are abundant. High OH reactivity values were calculated from C2-C6 alkanes mixing ratios, with the average reactivity for the 3 years being 1.55, 1.88, and 1.16 s-1. This indicates that VOC emissions from O & G operations may contribute to ozone production. PMID- 29439574 TI - Model-Based Evaluation of N2O Production Pathways in the Anammox-Enriched Granular Sludge Cultivated in a Sequencing Batch Reactor. AB - A mechanistic model was developed as an extension of the Activated Sludge Model No. 1 to describe three nitrous oxide (N2O) production pathways in a laboratory scale anammox-enriched granular sequencing batch reactor. Heterotrophic denitrification and two processes mediated by ammonia oxidizing bacteria (AOB), that is, ammonia (NH4+) oxidation via hydroxylamine (NH2OH) and autotrophic denitrification, were considered. A systematic model calibration and validation protocol was developed to obtain a unique set of kinetic parameters in the extended model. The dynamic nitrate (NO3-), nitrite (NO2-), NH4+ and N2O behaviors were accurately predicted (R2 >= 0.81) under five different nitrogen loading conditions. The predicted N2O production factor ranged from 1.7 to 2.9%. The model-based analysis also revealed the dominant N2O production mechanisms in terms of the actual process conditions, that is, NH4+ oxidation via NH2OH when only NH4+ was supplied, heterotrophic denitrification when only NO2- was supplied, and a shift of the dominant mechanism when a mixture of NH4+ and NO2- was supplied. PMID- 29439575 TI - Density-Dependent Formulation of Dispersion-Repulsion Interactions in Hybrid Multiscale Quantum/Molecular Mechanics (QM/MM) Models. AB - Mixed multiscale quantum/molecular mechanics (QM/MM) models are widely used to explore the structure, reactivity, and electronic properties of complex chemical systems. Whereas such models typically include electrostatics and potentially polarization in so-called electrostatic and polarizable embedding approaches, respectively, nonelectrostatic dispersion and repulsion interactions are instead commonly described through classical potentials despite their quantum mechanical origin. Here we present an extension of the Tkatchenko-Scheffler semiempirical van der Waals (vdWTS) scheme aimed at describing dispersion and repulsion interactions between quantum and classical regions within a QM/MM polarizable embedding framework. Starting from the vdWTS expression, we define a dispersion and a repulsion term, both of them density-dependent and consistently based on a Lennard-Jones-like potential. We explore transferable atom type-based parametrization strategies for the MM parameters, based on either vdWTS calculations performed on isolated fragments or on a direct estimation of the parameters from atomic polarizabilities taken from a polarizable force field. We investigate the performance of the implementation by computing self-consistent interaction energies for the S22 benchmark set, designed to represent typical noncovalent interactions in biological systems, in both equilibrium and out-of equilibrium geometries. Overall, our results suggest that the present implementation is a promising strategy to include dispersion and repulsion in multiscale QM/MM models incorporating their explicit dependence on the electronic density. PMID- 29439576 TI - Modeling Nonreactive Molecule-Surface Systems on Experimentally Relevant Time and Length Scales: Dynamics and Conductance of Polyfluorene on Au(111). AB - We propose a computationally efficient strategy to accurately model nonreactive molecule-surface interactions that adapts density functional theory calculations with the Tkatchenko-Scheffler scheme for van der Waals interactions into a simple classical force field. The resulting force field requires just two adjustable parameters per atom type that are needed to capture short-range and polarization interactions. The developed strategy allows for classical molecular dynamics simulation of molecules on surfaces with the accuracy of high-level electronic structure methods but for system sizes (103 to 107 atoms) and timescales (picoseconds to microseconds) that go well beyond what can be achieved with first principles methods. Parameters for H, sp2 C, and O on Au(111) are developed and employed to atomistically model experiments that measure the conductance of a single polyfluorene on Au(111) as a continuous function of its length. The simulations qualitatively capture both the gross and fine features of the observed conductance decay during initial junction elongation and lead to a revised atomistic understanding of the experiment. PMID- 29439577 TI - Removing Water Vapor Interference in Peroxy Radical Chemical Amplification with a Large Diameter Nafion Dryer. AB - The chemical amplification (PERCA) method has been widely used for measuring peroxy radical concentrations in the troposphere. The accuracy and sensitivity of the method is critically dependent on the chain length (CL)-that is, the number of radical amplification cycles. However, CL decreases strongly with higher relative humidity (RH). So far, there does not appear to be a method to overcome this impact. Here we report the development of a Nafion dryer based dual-channel PERCA instrument. The large diameter Nafion dryer efficiently removes water vapor in milliseconds and minimally affects the sample. The low losses of peroxy radicals on the Nafion membrane make it an attractive tool for raising the CL, and thereby the measurement accuracy and sensitivity of PERCA systems. The reported instrument demonstrates this promising and simple method to minimize water vapor interference. PMID- 29439578 TI - Guest Back-Folding: A Molecular Design Strategy That Produces a Deep-Red Fluorescent Host/Guest Pair with Picomolar Affinity in Water. AB - One of the major goals of modern supramolecular chemistry, with important practical relevance in many technical fields, is the development of synthetic host/guest partners with ultrahigh affinity and selectivity in water. Currently, most association pairs exhibit micromolar affinity or weaker, and there are very few host/guest systems with Ka > 109 M-1, apparently due to a barrier imposed by enthalpy/entropy compensation. This present study investigated the threading of a water-soluble tetralactam cyclophane by a deep-red fluorescent squaraine guest with flanking polyethylene glycol chains, an association process that is dominated by a highly favorable enthalpic driving force. A squaraine structure was rationally designed to permit guest back-folding as a strategy to greatly expand the hydrophobic surface area that could be buried upon complexation. Guided by computational modeling, an increasing number of N-benzyl groups were appended to the squaraine core, so that, after threading, the aromatic rings could fold back and stack against the cyclophane periphery. The final design iteration exhibited an impressive combination of fluorescence and supramolecular properties, including ratiometric change in deep-red emission, picomolar affinity ( Ka = 5.1 * 1010 M-1), and very rapid threading ( kon = 7.9 * 107 M-1 s-1) in water at 25 degrees C. Similar excellent behavior was observed in serum solution. A tangible outcome of this study is a new cyclophane/squaraine association pair that will be a versatile platform for many different types of fluorescence-based imaging and diagnostics applications. From a broader perspective, guest back-folding of aromatic groups is a promising new supramolecular stabilization strategy to overcome enthalpy/entropy compensation and produce ultrahigh affinity [2]pseudorotaxane complexes in water and biological media. PMID- 29439579 TI - Introduction: Posttranslational Protein Modification. PMID- 29439581 TI - Association Between Dementia Severity and Recommended Lifestyle Changes: A Retrospective Cohort Study. AB - OBJECTIVE: Early diagnosis of dementia leads to early treatment which is beneficial to patients and the community. We reviewed initial evaluations from the Spectrum Health Medical Group Neurocognitive Clinic (SHMGNC) to evaluate dementia stage at the time of diagnosis. METHODS: We retrospectively reviewed 110 randomly chosen initial evaluations from September 2008 to December 2015 at the SHMGNC. Patients underwent a neurological examination, Montreal Cognitive Assessment, and a battery of neuropsychological testing. RESULTS: Of all, 78.9% had moderate or severe dementia at diagnosis. The SHMGNC recommended lifestyle changes (medication assistance, financial assistance, driving restrictions, and institutional care) in 75.8% of patients with dementia. The severity of dementia was associated with the number of lifestyle changes recommended. Cohabitation with a caregiver did not lead to an early diagnosis of dementia. CONCLUSIONS: Patients are not undergoing evaluation at the onset of the dementia process. Diagnosis is delayed. Home-based, patient-centered care may improve early screening and detection of dementia. PMID- 29439582 TI - Diversity of HIV-1 in Aquitaine, Southwestern France, 2012-2016. AB - We have estimated the prevalence of the different viral subtypes between January 2012 and December 2016 in HIV-1-infected patients of the Aquitaine region (southwest part of France) who had a routine HIV-1 genotype resistance testing (GRT) centralized at the Bordeaux University Hospital. GRT was performed on viral RNA (1,784 samples) before treatment initiation or at failure, whereas proviral DNA was used as template (1,420 samples) in the event of a treatment switch in patients with viral load below 50 copies/mL. Pol and integrase sequences were obtained; subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) were assigned by combining the results of SCUEAL, REGA, COMET, and HIV BLAST. Globally, subtype B was predominant with 71.7%, whereas non-B subtypes accounted for 28.3%. Within the non-B viruses, CRF02_AG was the most prominent (11.6%) followed by non-B non-URF (13.5%), A, CRF01_AE, G, CRF06_cpx, F, C, D, H, J, and finally URF (3.2%). The analysis of the two compartments separately showed that RNA exhibits higher percentages of non-B viruses than DNA. This study reveals a high degree of diversity of HIV-1 non-B subtype strains in Aquitaine, with an increasing prevalence of CRF02_AG and URF in the population investigated for viral RNA, that is, including more recently detected HIV-1-infected patients. Future studies should attempt to identify the transmission clusters while paying special attention to URF, since they seem to be increasing in the population and could potentially host CRF. PMID- 29439583 TI - Identification of a Novel HIV-1 Recombinant Form (B/C) in Men Who Have Sex with Men in Shaanxi, China. AB - Many new circulating recombinant forms (CRFs) and unique recombinant forms (URFs) of HIV-1 have been found in men who have sex with men (MSM) in recent years, in China. In this study, a unique HIV-1 recombinant genome (SN153) was characterized from an HIV-positive male infected through homosexual behavior in Shaanxi, China. The mosaic pattern had a complex intersubtype recombinant structure with six breakpoints, with three subtype C segments inserted into subtype B backbone. And three similar breakpoints with CRF07_BC were observed in the pol gene. The identification of the new URF suggested the genetic complexity of the HIV epidemic among MSM in Shaanxi province and the urgent need for epidemiological surveillance and their origin of the new recombination forms. PMID- 29439584 TI - Palliative Care Educational Interventions for Prelicensure Health-Care Students: An Integrative Review. AB - To provide adequate care, students from all health-care professions require education regarding palliative and end-of-life (EOL) care prior to entering professional practice. In particular, students need proper training to be equal members of interprofessional teams providing palliative and EOL care. However, limited information is currently available about the effectiveness of educational interventions relating to palliative and EOL care. Thus, an assessment of educational interventions to utilize in providing this education is warranted. The purpose of this integrative review was to critically evaluate the impact of palliative or EOL care interventional studies on learning outcomes for prelicensure health-care students. Articles published from 2001 to present that utilizied palliative or EOL care educational interventions for prelicensure students from any health-care profession and also evaluated preidentified learning outcomes were included in the review. The final sample comprised 34 articles. Four studies utilized interprofessional interventions, whereas the remaining taught students from a single profession. Trends in sample sizes, teaching interventions, learning outcomes, and outcome measures are discussed. Teaching interventions reviewed were primarily focused on student learning outcomes specific to knowledge and attitudes. Future studies should implement interprofessional educational interventions, utilize reliable and valid outcome measures, and evaluate their impact on different learning outcomes, such as self efficacy, comfort, and communication. PMID- 29439585 TI - Psychometric properties of questionnaires and diagnostic measures for autism spectrum disorders in adults: A systematic review. AB - Accurately diagnosing autism spectrum disorders in adulthood can be challenging. Structured questionnaires and diagnostic measures are frequently used to assist case recognition and diagnosis. This study reviewed research evidence on structured questionnaires and diagnostic measures published since the National Institute for Health and Care Excellence evidence update. The Cochrane library, Medline, Embase and PsycINFO were searched. In all, 20 studies met inclusion criteria. Sensitivity and specificity of structured questionnaires were best for individuals with previously confirmed autism spectrum disorder diagnoses and reduced in participants referred for diagnostic assessments, with discrimination of autism spectrum disorder from mental health conditions especially limited. For adults with intellectual disability, diagnostic accuracy increased when a combination of structured questionnaires were used. Evidence suggests some utility of diagnostic measures in identifying autism spectrum disorder among clinic referrals, although specificity for diagnosis was relatively low. In mental health settings, the use of a single structured questionnaire is unlikely to accurately identify adults without autism spectrum disorder or differentiate autism spectrum disorder from mental health conditions. This is important as adults seeking an autism spectrum disorder diagnostic assessment are likely to have co-existing mental health conditions. Robust autism spectrum disorder assessment tools specifically for use in adult diagnostic health services in the presence of co-occurring mental health and neurodevelopmental disorders are a research priority. PMID- 29439586 TI - Pulling back the curtain: Issues in conducting an intervention study with transition-aged youth with autism spectrum disorder and their families. AB - The transition from high school to adulthood is difficult for youth with autism spectrum disorder and their families. Recognizing these challenges, there is a small but emerging body of literature testing interventions to improve the transition process. But there are many challenges in performing intervention research that have yet to be fully addressed. We discuss issues that should be considered when conducting interventions with individuals with autism spectrum disorder to improve the transition to adulthood, drawing from our study of a parent training to facilitate access to adult services during the transition years. Issues covered include (1) timing (when is an intervention most effective?), (2) mode of delivery (what is the best way to present information?), (3) outcomes (how can intervention outcomes be accurately measured?), (4) target population (who is the intervention designed to help?), and (5) level of intervention (who should the intervention target?). Our answers, though preliminary, show the need to be flexible, to adopt a trial-and-error stance, and to listen to the needs-both explicit and implicit-of youth with autism spectrum disorder and their parents as they navigate the difficult transition from adolescence to adulthood. PMID- 29439587 TI - Clinical management of pediatric achalasia. AB - INTRODUCTION: Achalasia is a rare esophageal motility disorder. Much of the literature is based on the adult population. In adults, guidance of therapeutic approach by manometric findings has led to improvement in patient outcome. Promising results have been achieved with novel therapies such as PerOral Endoscopic Myotomy (POEM). Areas covered: In this review, we provide an overview of the novel diagnostic and therapeutic tools for achalasia management and in what way they will relate to the future management of pediatric achalasia. We performed a PubMed and EMBASE search of English literature on achalasia using the keywords 'children', 'achalasia', 'pneumatic dilation', 'myotomy' and 'POEM'. Cohort studies < 10 cases and studies describing patients >= 20 years were excluded. Data regarding patient characteristics, treatment outcome and adverse events were extracted and presented descriptively, or pooled when possible. Expert commentary: Available data report that pneumatic dilation and laparoscopic Heller's myotomy are effective in children, with certain studies suggesting lower success rates in pneumatic dilation. POEM is increasingly used in the pediatric setting with promising short-term results. Gastro-esophageal reflux disease (GERD) may occur post-achalasia intervention due to disruption of the LES and therefore requires diligent follow-up, especially in children treated with POEM. PMID- 29439589 TI - Measurement properties of the Dutch Unite Rhumatologique des Affections de la Main and its ability to measure change due to Dupuytren's disease progression compared with the Michigan Hand outcomes Questionnaire. AB - : Data of a prospective longitudinal cohort study including 233 Dupuytren's patients was used to determine: (1) whether the Unite Rhumatologique des Affections de la Main scale and Michigan Hand outcomes Questionnaire can detect change in hand function due to Dupuytren's disease progression and to compare their abilities; (2) the concurrent validity, reliability, responsiveness and interpretability of the Dutch Unite Rhumatologique des Affections de la Main. The Unite Rhumatologique des Affections de la Main and Michigan Hand outcomes Questionnaire had comparable measurement properties, and were both able to distinguish participants with disease progression from those without progression (resp. U = 1252.5, p = 0.008, and U = 1086.0, p < 0.001), but only at a group level. Individual cases of progression could not be detected using these outcome measures, as indicated by the fact that the smallest detectable change was larger than the minimal important change, and area under the receiver operating curve (AUC) values of 0.75 for Michigan Hand outcomes Questionnaire and 0.67 for Unite Rhumatologique des Affections de la Main. LEVEL OF EVIDENCE: II. PMID- 29439590 TI - Adapting and pilot testing the Healthy Love HIV and sexually transmitted infection prevention intervention with African, Caribbean and Black women in community-based settings in Toronto, Canada. AB - We adapted the Healthy Love Workshop (HLW), an HIV prevention workshop for African American women in the United States, for African, Caribbean and Black (ACB) women in Toronto, Canada. We conducted a pilot study with ACB women ( n = 80) in ten community-based settings with pre-test (T1), post-test (T2) and three month follow-up (T3) surveys. Mixed-effect regression results indicated significant increases in condom use self-efficacy and sexually transmitted infection (STI) knowledge scores from T1 to T3. Qualitative feedback revealed increased STI knowledge, confidence using condoms and suggestions for future HLWs. Findings highlight the promise of the adapted HLW for HIV/STI prevention with ACB women in Canada. PMID- 29439591 TI - Assessment of effectiveness and safety of biosimilar infliximab (CT-P13) in a real-life setting for treatment of patients with active rheumatoid arthritis or ankylosing spondylitis. AB - OBJECTIVE: To assess the effectiveness and safety of infliximab biosimilar, CT P13, administered in a real-life setting to adult patients with active rheumatoid arthritis (RA) or ankylosing spondylitis (AS). METHODS: This multi-center, non interventional, observational study was conducted in Bulgaria, the Czech Republic, and Romania. A total of 151 patients with severe active RA (n = 81) or AS (n = 70) were enrolled and treated with CT-P13 for 24 weeks, according to current medical recommendations. Effectiveness was assessed using the 4-item Disease Activity Score 28 with C-reactive protein (DAS28-CRP) for RA patients, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS patients. Safety was assessed by withdrawals and adverse events (AEs). RESULTS: A total of 129 patients (RA: 67; AS: 62) were included in the effectiveness analysis. CT-P13 treatment significantly improved DAS28-CRP scores at 12 and 24 weeks (p = .0001 vs baseline for both timepoints) in patients with RA and BASDAI scores at 12 and 24 weeks (p = .0001 vs baseline for both timepoints) in patients with AS. CRP levels were significantly reduced at 12 and 24 weeks (p = .0001 vs baseline for both timepoints). Among 713 infusions, 34 AEs were reported (4.8% of infusions), of which 11 were considered related to CT-P13 treatment. Two of seven serious AEs were considered possibly (hepatocellular injury) or definitely (dyspnoea due to allergic infusion reaction) treatment-related. Eight patients discontinued CT-P13 due to AEs and four patients were withdrawn due to therapeutic failure. CONCLUSIONS: CT-P13 was effective and safe in a real-life setting in patients with active RA or AS. PMID- 29439592 TI - Parental Self-Efficacy: A Concept Analysis Related to Teen Parenting and Implications for School Nurses. AB - Levels of parental self-efficacy are correlated with both positive and negative care delivery and developmental outcomes for parents and their infants. School nurses are in a unique position to facilitate parenting self-efficacy in teen parents. Using the concept analysis framework of Walker and Avant, parental self efficacy is analyzed and elucidated to distinguish the concept's defining attributes, antecedents, consequences, and empirical referents. The operational definition of parental self-efficacy arising from this concept review is an individual's belief that he or she is capable of integrating and executing the knowledge and skills necessary to parent their infant. Model, borderline, related, and contrary cases are presented, along with implications for school nursing practice. School nurses are ideally situated to assist teen parents with parental self-efficacy realization tasks. PMID- 29439593 TI - Bleeding Risks in Patients on Percutaneous Ventricular Assist Devices Receiving Two Different Dextrose Concentrations of Heparinized Purge Solution: A Case Series. AB - BACKGROUND: The Impella manufacturer has changed its recommendation for the diluent of the heparinized purge solution from 20% dextrose (D20) to 5% dextrose (D5). This reduced viscosity may result in increased purge solution infusion rates and unfractionated heparin (UFH) exposure. Increased UFH exposure could potentially cause increased bleeding events and may necessitate reduction in UFH concentration in the purge solution. Our objective was to evaluate anticoagulation for patients on Impella pumps receiving heparinized purge solution with D20 or D5 diluents. METHODS: This retrospective cohort analysis evaluated patients requiring Impella support outside of the cardiac catheterization lab. The primary outcome evaluated the number of patients with at least one supratherapeutic activated partial thromboplastin time (aPTT) while receiving heparinized purge solution alone without systemic UFH. Secondary outcomes included heparin concentration changes made to the purge solution, bleeding, and thrombotic events. RESULTS: Twelve patients received Impella support for an average of 37 hours (range, 10.8-89.6). Four patients received D20 and 8 patients received D5 purge solution. Five patients had at least one supratherapeutic aPTT while receiving heparinized purge solution alone without additional systemic UFH. All 5 patients were in the D5 group. Of these 5 patients, 3 required purge heparin concentration decreases and 3 had bleeding events. No patients had pump thrombosis. CONCLUSION: D5 purge solution with heparin 50 units/mL may increase the risk of supratherapeutic aPTTs, leading to increased bleeding. Decreasing heparin to 25 units/mL as a standard in purge solution may decrease these risks; however, protection against thrombosis remains unknown. PMID- 29439594 TI - Editorial Comment on: American Urological Association Antibiotic Best Practice Statement and Ureteroscopy: Does Antibiotic Stewardship Help? by Greene et al. PMID- 29439595 TI - Serum uric acid levels and outcome during admission in acute ischaemic stroke, depending on renal function. AB - BACKGROUND: The relationship between serum uric acid (SUA) levels and stroke is controversial. The discrepancies in the results could be due to the uneven setting of comorbidity. It is known that hyperuricaemia increases in parallel with the decline in renal function; however, there are few studies that adjust for renal disease. AIM: To investigate the relationship between SUA levels in the acute phase of ischaemic stroke according to the presence or absence of chronic kidney disease and clinical outcomes during admission. METHODS: Retrospective cross-sectional analysis of patients recruited through a unicentric stroke registry. The sample was divided according to its quartiles of SUA. Renal disease was defined based on the haematocrit, urea and Gender (HUGE) formula. The outcome was determined by the National Institutes of Health Stroke Scale (NIHSS) score. Statistically robust methods were used with R (version 3.3.2). RESULTS: A total of 412 patients (53.8% male) were analysed. The NIHSS score decreased as the SUA levels increased (p < 0.0009). Robust linear regression analysis showed a significant association between quantitative SUA levels and NIHSS score (p < 0.0003), even when patients were categorized according to renal function (p < 0.05). In an adjusted multivariate model, SUA levels showed an independent protective effect on the severity of stroke (OR = 0.67, 95% CI 0.51-0.88, p = 0.004). CONCLUSIONS: Our results support the hypothesis that hyperuricaemia plays a protective role in the prognosis of stroke, independently from renal function, and that even in patients with chronic kidney disease, it remains as a protective agent. PMID- 29439596 TI - Do Investments in Mental Health Systems Result in Greater Use of Mental Health Services? National Trends in Mental Health Service Use (MHSU) in the Canadian Military and Comparable Canadian Civilians, 2002-2013. AB - BACKGROUND: Mental disorders constitute a significant public health problem worldwide. Ensuring that those who need mental health services access them in an appropriate and timely manner is thus an important public health priority. We used data from 4 cross-sectional, nationally representative population health surveys that employed nearly identical methods to compare MHSU trends in the Canadian military versus comparable civilians. METHOD: The surveys were all conducted by Statistics Canada, approximately a decade apart (Military-2002, Military-2013, Civilian-2002, and Civilian-2012). The sample size for the pooled data across the surveys was 35,984. Comparisons across the 4 surveys were adjusted for differences in need in the 2 populations at the 2 time points. RESULTS: Our findings suggested that first, in the Canadian military, there was a clear and consistent pattern of improvement (i.e., increase) in MHSU over the past decade across a variety of provider types. The magnitudes of the changes were large, representing an absolute increase of 7.15% in those seeking any professional care, corresponding to an 84% relative increase. Second, in comparable Canadian civilians, MHSU remained either unchanged or increased only slightly. Third, the increases in MHSU over time were consistently greater in the military than in the comparable civilian sample. CONCLUSIONS: Our findings point to advantages with respect to MHSU of the military mental health system over the civilian system in Canada; these advantages have widened substantially over time. These findings speak strongly to the potential impact of analogous changes in other health systems, both military and civilian. PMID- 29439597 TI - Editorial Comment on: Crowdsourcing Evaluation of Ureteroscopic Videos Using the Post-Ureteroscopic Lesion Scale to Assess Ureteral Injury by Kaler et al. PMID- 29439599 TI - How is children's weight status assessed for early identification of overweight and obesity? - Narrative review of programs for weight status assessment. AB - Assessment of a child's weight status is the first step in the management of childhood overweight and obesity. We reviewed routine assessment programs to inform early and routine identification of childhood overweight and obesity to address this global health issue. Twelve electronic databases were searched (Scopus, Web of Science, Wiley, ScienceDirect, PsycINFO, PsycARTICLES, PsycEXTRA, CINAHL, Primary Search, MEDLINE, ERIC, Academic Search Elite) for universal programs for weight status assessment of children aged 4-12 in Organization for Economic Co-operation and Development - countries, which included more than one assessment and parents receiving feedback. Of 1638 papers found via database searches, and 18 additional records identified through other sources, 26 were included. Reference to five countries' programs for weight status assessment was found in the results: Australia, Sweden, the Netherlands, the United Kingdom and the United States. All of these programs were implemented in a school setting. Lack of services, stakeholder collaboration, parental awareness and engagement and government funding need to be improved for this health check to be undertaken as a part of an ongoing program. This review is about the implementation of similar programs. Early identification of risk for overweight and obesity allows families that require help to connect with available health services. PMID- 29439600 TI - Initial Experience With the Outback Catheter for Targeted Reentry During Subintimal Angioplasty of the Infragenicular Arteries. AB - PURPOSE: To report use of the Outback reentry device for targeted distal reentry during subintimal recanalization of chronic total occlusions (CTOs) in the infragenicular arteries. METHODS: During an 18-month period, the Outback device was applied in 10 patients (mean age 71.8+/-18.8 years; 8 men) to achieve reentry at the infragenicular segment following either unsuccessful spontaneous reentry after subintimal crossing of a CTO or when a targeted reentry was desired. The mean occlusion length was 117.5+/-101.0 mm. Technical (device) success, overall procedure success, and reentry accuracy are reported, along with any major or minor complications. RESULTS: The device was technically successful in achieving reentry in 9 of 10 cases; overall procedure success was achieved in 8 owing to heavy calcifications in a distal posterior tibial artery and a distal popliteal artery. The reentry accuracy was 10.8+/-14.6 mm. There were no major complications and only 3 minor sequelae, including 2 dissections and 1 small perforation; all were treated successfully with stenting. CONCLUSION: The Outback device has a high technical success rate in achieving targeted true lumen reentry in infragenicular subintimal angioplasty when spontaneous reentry is not possible or a targeted reentry is desirable. PMID- 29439598 TI - Diabetes Activates Periodontal Ligament Fibroblasts via NF-kappaB In Vivo. AB - Diabetes mellitus increases periodontitis and pathogenicity of the oral microbiome. To further understand mechanisms through which diabetes affects periodontitis, we examined its impact on periodontal ligament fibroblasts in vivo and in vitro. Periodontitis was induced by inoculation of Porphyromonas gingivalis and Fusobacterium nucleatum in normoglycemic and diabetic mice. Diabetes, induced by multiple low-dose injections of streptozotocin increased osteoclast numbers and recruitment of neutrophils to the periodontal ligament, which could be accounted for by increased CXC motif chemokine 2 (CXCL2) and receptor activator of nuclear factor kappa B ligand (RANKL) expression by these cells. Diabetes also stimulated a significant increase in nuclear factor kappa B (NF-kappaB) expression and activation in periodontal ligament (PDL) fibroblasts. Surprisingly, we found that PDL fibroblasts express a 2.3-kb regulatory unit of Col1alpha1 (collagen type 1, alpha 1) promoter typical of osteoblasts. Diabetes enhanced CXCL2 and RANKL expression in PDL fibroblasts was rescued in transgenic mice with lineage-specific NF-kappaB inhibition controlled by this regulatory element. In vitro, high glucose increased NF-kappaB transcriptional activity, NF kappaB nuclear localization, and RANKL expression in PDL fibroblasts, which was reduced by NF-kappaB inhibition. Thus, diabetes induces changes in PDL fibroblast gene expression that can enhance neutrophil recruitment and bone resorption, which may be explained by high glucose-induced NF-kappaB activation. Furthermore, PDL fibroblasts express a regulatory element in vivo that is typical of committed osteoblasts. PMID- 29439601 TI - A new class of agents for estrogen-receptor-positive breast cancer. PMID- 29439602 TI - A Correction Method of a Binary Classifier Applied to Multi-Label Pairwise Models. AB - In the paper, the problem of multi-label (ML) classification using the label pairwise (LPW) scheme is addressed. For this approach, the method of correction of binary classifiers which constitute the LPW ensemble is proposed. The correction is based on a probabilistic (randomized) model of a classifier that assesses the local class-specific probabilities of correct classification and misclassification. These probabilities are determined using the original concepts of a randomized reference classifier (RRC) and a local soft confusion matrix. Additionally, two special cases that deal with imbalanced labels and double labeled instances are considered. The proposed methods were evaluated using 29 benchmark datasets. In order to assess the efficiency of the introduced models and the proposed correction scheme, they were compared against original binary classifiers working in the LPW ensemble. The comparison was performed using four different ML evaluation measures: macro and micro-averaged [Formula: see text] loss, zero-one loss and Hamming loss. Moreover, relations between classification quality and the characteristics of ML datasets such as average imbalance ratio or label density were investigated. The experimental study reveals that the correction approaches significantly outperform the reference method in terms of zero-one loss and Hamming loss. PMID- 29439603 TI - Sgemaglutide in type 2 diabetes - is it the best glucagon-like peptide 1 receptor agonist (GLP-1R agonist)? AB - INTRODUCTION: Glucagon-like peptide-1 (GLP-1) is produced by the gut, and in a glucose-dependent manner stimulates insulin secretion while inhibiting glucagon secretion, reduces appetite and energy intake, and delays gastric emptying. The GLP-1R agonist semaglutide has recently been registered to treat type 2 diabetes. Area covered: This review is of semaglutide in type 2 diabetes, and considers which properties of this GLP-1R agonist, may be responsible for its clinical outcome benefits . Expert opinion: The pharmacokinetics of semaglutide make it ideal for once-weekly dosing. SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) showed that semaglutide 0.5 or 1 mg subcutaneously once-weekly reduced cardiovascular outcomes in subjects with type 2 diabetes and cardiovascular disease or risk, mean age 65 years, baseline HbA1c 8.7% and mean body weight of 92 kg. Although, semaglutide may be a useful drug in this population, it increased retinopathy to a small extent and this needs further investigation. Also, it is not known whether semaglutide will improve cardiovascular outcomes in other populations including those with lower ages, HbA1c values, and body weights similar to those included in the unsuccessful clinical outcome trials with the GLP-1R agonists, lixisenatide and exenatide. PMID- 29439604 TI - Acceptability of non-speculum clinician sampling for cervical screening in older women: A qualitative study. AB - OBJECTIVES: One reason that women over age 50 report avoiding cervical screening is increased discomfort postmenopause. This study aimed to explore the acceptability of human papillomavirus testing on clinician-collected vaginal samples without a speculum ('non-speculum') for cervical screening among older women. METHODS: Thirty-eight women in England aged 50-64 with a range of cervical screening experience ('up-to-date' n = 17, 'overdue screening' n = 18, 'never screened' n = 3) were identified via a recruitment agency. Women participated in focus groups or interviews about the potential for using clinician-collected samples without a speculum. Discussions were analysed using Framework Analysis. RESULTS: The two main themes identified were women's perceptions of the speculum and attitudes towards non-speculum screening. Many women reported negative experiences with the speculum, including increased pain after the menopause. Women generally had positive attitudes towards non-speculum clinician sampling and felt it would be a less intrusive option, but expressed concern that it could be less accurate than screening with a speculum. Women who were 'up-to-date' preferred conventional screening, while overdue and never screened women welcomed the option to be screened without a speculum. CONCLUSIONS: Human papillomavirus testing on non-speculum clinician-collected vaginal samples could be an acceptable alternative cervical screening method for older women. Offering this approach could increase screening uptake in older women who find conventional cervical screening to be less acceptable with ageing or the menopause. PMID- 29439606 TI - Editorial Comment on: Percutaneous Nephrolithotomy and Spina Bifida: Complex Stone Surgery? by Mitchell et al. PMID- 29439605 TI - Microglial Inflammasome Activation in Penetrating Ballistic-Like Brain Injury. AB - Penetrating traumatic brain injury (PTBI) is a significant cause of death and disability in the United States. Inflammasomes are one of the key regulators of the interleukin (IL)-1beta mediated inflammatory responses after traumatic brain injury. However, the contribution of inflammasome signaling after PTBI has not been determined. In this study, adult male Sprague-Dawley rats were subjected to sham procedures or penetrating ballistic-like brain injury (PBBI) and sacrificed at various time-points. Tissues were assessed by immunoblot analysis for expression of IL-1beta, IL-18, and components of the inflammasome: apoptosis associated speck-like protein containing a caspase-activation and recruitment domain (ASC), caspase-1, X-linked inhibitor of apoptosis protein (XIAP), nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3), and gasdermin-D (GSDMD). Specific cell types expressing inflammasome proteins also were evaluated immunohistochemically and assessed quantitatively. After PBBI, expression of IL-1beta, IL-18, caspase-1, ASC, XIAP, and NLRP3 peaked around 48 h. Brain protein lysates from PTBI animals showed pyroptosome formation evidenced by ASC laddering, and also contained increased expression of GSDMD at 48 h after injury. ASC-positive immunoreactive neurons within the perilesional cortex were observed at 24 h. At 48 h, ASC expression was concentrated in morphologically activated cortical microglia. This expression of ASC in activated microglia persisted until 12 weeks following PBBI. This is the first report of inflammasome activation after PBBI. Our results demonstrate cell-specific patterns of inflammasome activation and pyroptosis predominantly in microglia, suggesting a sustained pro-inflammatory state following PBBI, thus offering a therapeutic target for this type of brain injury. PMID- 29439607 TI - Septic Shock Following Surgical Decompression of Obstructing Ureteral Stones: A Prospective Analysis. AB - PURPOSE: To investigate risk factors for septic shock and death in patients with obstructive pyelonephritis due to ureteral stone, who underwent urinary tract decompression. PATIENTS AND METHODS: We prospectively enrolled patients who presented at the emergency department of our institution with clinical signs of pyelonephritis, Systemic Inflammatory Response Syndrome (SIRS), and obstructive ureteral stone confirmed by computed tomography scan. Forty patients that underwent urinary tract decompression were included. Demographical, medical, and laboratorial characteristics were recorded; antibiotic regimen and time from presentation to decompression were compared between patients with septic complications. RESULTS: Septic shock and death occurred in 6 (15%) and 2 (5%) patients, respectively. Gender, age, and comorbidities were not associated with septic complications. Urinary culture was negative in 40% of the cohort and the most prevalent pathogen was Escherichia coli. Administration of antibiotics other than third-generation cephalosporin was associated with septic shock (p = 0.02). There was no difference between groups regarding the time of antibiotics use (p = 0.63) and time from presentation to urinary tract decompression (p = 0.07). Patients with leukocyte count above 15.6 * 103/MUL had 2.2-fold greater risk of having septic shock (p = 0.027). CONCLUSIONS: We failed to find an association between time of antibiotic use or delayed urinary tract decompression and occurrence of septic complications; antibiotic choice was determinant of prognosis. Elevated serum leukocytes could be used as a trigger to indicate prompt surgical intervention. PMID- 29439608 TI - A review of ustekinumab in the treatment of psoriatic arthritis. AB - Psoriatic arthritis is an inflammatory arthritis associated with psoriasis. The IL-23/IL-17 axis is an important pathway in the development of psoriatic disease. Ustekinumab is a fully human monoclonal IgG1 antibody that binds to the p40 subunit of IL-12 and IL-23, which, in turn, inhibits downstream signaling pathways. PSUMMIT-1 and PSUMMIT-2 are two pivotal Phase III trials demonstrating global improvement in primary and secondary outcomes including inhibition of radiographic progression. Therapeutic benefit of ustekinumab for synovitis appears independent of previous disease modifying antirheumatic disease or anti TNF exposure. At present, the data support the use of ustekinumab in the treatment of psoriatic arthritis after the failure of NSAIDs and conventional disease modifying antirheumatic diseases as an alternative to, or after failure of an anti-TNF agent. PMID- 29439609 TI - BRAF and RAS Mutational Status in Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and Invasive Subtype of Encapsulated Follicular Variant of Papillary Thyroid Carcinoma in Korea. AB - BACKGROUND: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an indolent thyroid tumor previously known as noninvasive subtype of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). The absence of BRAFV600E mutations has been considered characteristic of NIFTPs. However, a recent study from Korea found that 28.6% of NIFTPs harbored a BRAF mutation. This study evaluated BRAF and RAS mutations in NIFTPs and invasive subtype of EFVPTCs. METHODS: This study enrolled 32 patients with NIFTP and 48 with invasive EFVPTC. BRAF, NRAS, HRAS, and KRAS mutations were evaluated by direct sequencing using DNA from fresh-frozen tissues and formalin-fixed, paraffin-embedded tissue samples. RESULTS: The primary tumor size of NIFTP was smaller than that of invasive EFVPTC (median 2.8 cm vs. 3.2 cm; p = 0.03). Cervical lymph node metastases were found in only four (8%) patients with invasive EFVPTC. There was no BRAF mutation in NIFTPs, whereas invasive EFVPTCs had three (6%) BRAFV600E mutations and one (2%) BRAFK601E mutation. RAS mutations were detected in 15 (47%) NIFTPs and 22 (46%) invasive EFVPTCs. NRAS mutations in codon 61 were the most common mutations in NIFTPs (34%) and invasive EFVPTCs (27%). There was no significant difference in the frequency of RAS mutations between the two groups. CONCLUSIONS: There was no BRAF mutation in any of the NIFTPs. RAS mutations, particularly mutations in codon 61 of NRAS, were the most common mutations in both NIFTPs and invasive EFVPTCs. The presence of a RAS mutation is not helpful for preoperative differentiation between NIFTPs and invasive EFVPTCs. PMID- 29439610 TI - Outpatient Procedural Sedation of Patients With Autism Spectrum Disorders for Magnetic Resonance Imaging of the Brain Using Propofol. AB - OBJECTIVE: To quantify the number of personnel, time to induce and complete sedation using propofol for outpatient magnetic resonance imaging (MRI) of the brain, and the frequency of serious adverse events (SAEs) in children with autism spectrum disorder (ASD) compared with children without ASD. RESULTS: Baseline characteristics were the same between both groups. Overall sedation success was 99%. Although most children were sedated with <=3 providers, 10% with ASD needed >=4 providers (P = .005). The duration of sedation was less for the ASD group compared with the non-ASD group (49 minutes vs 56 minutes, P = .005). There was no difference in SAE frequency between groups (ASD 14% vs non-ASD 16%, P = .57). CONCLUSION: Children with ASD can be sedated for brain MRI using propofol with no increased frequency of SAEs compared with children without ASD. Sedation teams should anticipate that 10% of children with ASD may need additional personnel before propofol induction. PMID- 29439611 TI - Do not underestimate the femoral pseudoaneurysm. AB - In addition to haematoma and arteriovenous fistula, the iatrogenic pseudoaneurysm is a common complication of vascular access that is caused by a perforation in the arterial wall. Iatrogenic pseudoaneurysms can progress in size and lead to rupture and active bleeding. Over the previous few decades, therapeutic methods have evolved from surgical repair to less invasive options, such as ultrasound guided compression therapy (UGCT) and ultrasound-guided thrombin injection (UGTI). This paper presents an overview of the diagnostic and treatment modalities used in femoral pseudoaneurysms as well as a comprehensive summary of previous studies that analysed the success and complication rates of UGCT and UGTI. PMID- 29439612 TI - A Nomogram Based on the Characteristics of Metastatic Lymph Nodes to Predict Papillary Thyroid Carcinoma Recurrence. AB - BACKGROUND: The extent of metastatic lymph node (LN) invasion was not considered in the postoperative stratification of the recurrence risk of papillary thyroid carcinoma (PTC) in the 2015 American Thyroid Association (ATA) guidelines, and the recommended risk stratification cannot be applied to individuals. A nomogram based on these risk factors was developed based on the risk factors to predict individual recurrence risk. METHODS: Data from 1788 PTC patients at the West China Hospital and 306 cases from the Shang Jin Nan Fu Hospital between August 2013 and July 2015 were included in this study. The 1788 cases were randomized into two groups-the training set (896 cases) and the testing set (896 cases)-and 306 cases were used as the external evaluation set. RESULTS: Univariate and multivariate analyses identified the following independent prognostic factors associated with recurrence in the three independent sets and the combined set (p < 0.01): LN invasion in the capsule or organ, more than five metastatic LNs, and a largest metastatic LN diameter >3 cm. Importantly, PTC patients showed significantly different recurrence rates depending on the extent of LN invasion in the three sets and in the combined set (p < 0.001). The nomogram was developed based on the risk factors in the training set and was validated in the independent testing and validation sets. CONCLUSION: The largest LN metastasis diameter, number of metastatic LNs, and the extent of extranodal invasion had significant prognostic value for predicting the risk of recurrence. Based on the characteristics of the thyroidal PTC lesion and metastatic LNs, the nomogram showed good prediction of recurrence in individual PTC patients. PMID- 29439613 TI - Occurrence of Endocrine and Thyroid Cancers Among Alaska Native People, 1969 2013. AB - BACKGROUND: Nationwide, the incidence of thyroid cancer is lower among American Indian/Alaska Native (AI/AN) people than among U.S. whites (USW). However, little is known about the incidence of thyroid or other endocrine cancers specifically among Alaska Native (AN) people. METHODS: Data were examined from the National Cancer Institute's Surveillance, Epidemiology, and End Results Alaska Native Tumor Registry on endocrine cancers diagnosed among AN people from 1969-2013, with a specific focus on thyroid cancers. Frequencies of endocrine cancers by site and also of thyroid cancers by histology, size, and stage at diagnosis were evaluated. Distributions were compared to USW (Surveillance, Epidemiology, and End Results 9 Registries) using the chi-square test. Five-year average annual age adjusted incidence rates of thyroid cancers were calculated, stratified by histology, age, and five-year period of diagnosis, and compared to those observed among USW. Five-year cause-specific survival was evaluated using cause of death data from the National Death Index Plus from the National Center for Health Statistics. RESULTS: During the 45-year period (1969-2013), 224 endocrine cancers were diagnosed among AN people, of which 210 (94%) were thyroid cancers. Compared to USW, AN people were diagnosed at a slightly younger age, had a higher proportion of thyroid cancers diagnosed with a size of 20-40 mm, and a larger proportion of patients with regional metastases. More than 85% of AN thyroid cancers were of papillary histology. The incidence of thyroid cancers was similar between AN people and USW, and appeared to increase among AN people over the period of surveillance. Finally, five-year cause-specific survival rate was 100% for papillary carcinoma patients and 86.3% [confidence interval 54.7-96.5] for follicular thyroid cancer patients. CONCLUSIONS: This study is the first report of endocrine cancers and the first detailed examination of thyroid cancer among AN people. The incidence of thyroid cancer was similar among AN people and USW. However, compared to USW, AN people appear to be at risk for diagnosis at a younger age, larger size, and higher stage. Further research is needed to explore the causes of these differences. PMID- 29439614 TI - Effect of Thyroglobulin Autoantibodies on the Metabolic Clearance of Serum Thyroglobulin. AB - BACKGROUND: In order to establish whether thyroglobulin autoantibodies (TgAb) influence the metabolic clearance of thyroglobulin (Tg) in humans, serum Tg and TgAb were correlated shortly after radioiodine (131I) treatment. METHODS: Samples were collected from 30 consecutive patients undergoing 131I activity for Graves' hyperthyroidism at the time of treatment and every 15 days thereafter, up to 90 days. Tg and TgAb were measured by immunometric assays (functional sensitivities: 0.1 ng/mL and 8 IU/mL). RESULTS: Tg was detectable in all patients at day 0. Tg concentrations rose from a mean of 33.2 ng/mL [confidence interval (CI) 17.8-61.0 ng/mL] at day 0 to a mean of 214.6 ng/mL [CI 116.9-393.4 ng/mL] at day 30 and then steadily decreased, reaching the lowest concentration at day 90 (M = 10.9 ng/mL [CI 5.5-20.9 ng/mL]). Compared to their levels at day 0 (M = 23.6 IU/mL [CI 10.5-52.9 IU/mL]), TgAb remained stable through day 15 and then gradually increased up to a mean of 116.6 IU/mL [CI 51.9-262.2 IU/mL] at day 90. Patients were then split into two groups according to their TgAb status at day 0: undetectable (<8 IU/mL; 9 patients) or detectable (>=8 IU/mL; 21 patients) TgAb. Compared to the other cohort, patients with detectable TgAb showed significantly lower Tg concentrations at day 0 (M = 20.3 ng/mL [CI 10.1-40.2 ng/mL] vs. M = 101.8 ng/mL [CI 36.6-279.8 ng/mL]), similar at day 15, lower levels at day 30 (M = 146.5 ng/mL [CI 74.3-287.8 ng/mL] vs. M = 514.8 ng/mL [CI 187.8-1407.9 ng/mL]), at day 45 (M = 87.5 ng/mL [CI 43.1-176.6 ng/mL] vs. M = 337.9 ng/mL [CI 120.1 947.0 ng/mL]), at day 60 (M = 61.6 ng/mL [CI 31.0-121.4 ng/mL] vs. M = 255.8 ng/mL [CI 79.0-823.8 ng/mL]), and at day 75 (M = 24.5 ng/mL [CI 11.9-49.2 ng/mL] vs. M = 249.5 ng/mL [CI 63.5-971.1 ng/mL]), and similar levels at day 90. Patients with detectable TgAb showed a lower (M = 182.5 ng/mL [CI 92.0-361.0 ng/mL] vs. M = 514.8 ng/mL [CI 187.8-1407.9 ng/mL]) and an earlier (day 15 vs. day 30) peak of Tg. The mean Tg concentration was lower in patients with detectable TgAb than in those with undetectable TgAb (area under the curve: 17,340 +/- 16,481 ng/mL vs. 36,883 +/- 44,625 ng/mL; p = 0.02). CONCLUSIONS: TgAb influence the changes in Tg concentrations observed immediately after 131I treatment, inducing lower levels and an earlier peak of Tg. These observations indicate that TgAb significantly influence the metabolic clearance of Tg, supporting the concept that their interference in the measurement of Tg is mainly due to an in vivo effect. PMID- 29439615 TI - Gender-Based Violence Against Transgender People in the United States: A Call for Research and Programming. AB - Gender-based violence (GBV) is an umbrella term for any harm that is perpetrated against a person's will and that results from power inequalities based on gender roles. Most global estimates of GBV implicitly refer only to the experiences of cisgender, heterosexually identified women, which often comes at the exclusion of transgender and gender nonconforming (trans) populations. Those who perpetrate violence against trans populations often target gender nonconformity, gender expression or identity, and perceived sexual orientation and thus these forms of violence should be considered within broader discussions of GBV. Nascent epidemiologic research suggests a high burden of GBV among trans populations, with an estimated prevalence that ranges from 7% to 89% among trans populations and subpopulations. Further, 165 trans persons have been reported murdered in the United States between 2008 and 2016. GBV is associated with multiple poor health outcomes and has been broadly posited as a component of syndemics, a term used to describe an interaction of diseases with underlying social forces, concomitant with limited prevention and response programs. The interaction of social stigma, inadequate laws, and punitive policies as well as a lack of effective GBV programs limits access to and use of GBV prevention and response programs among trans populations. This commentary summarizes the current body of research on GBV among trans populations and highlights areas for future research, intervention, and policy. PMID- 29439616 TI - Physical Abuse, Emotional Abuse, and Neglect and Childhood Behavior Problems: A Meta-Analysis of Studies in Mainland China. AB - The relationship between three types of child maltreatment, including physical abuse, emotional abuse and neglect, and childhood behavior problems in Mainland China, has not been systematically examined. This meta-analysis reviewed findings from 42 studies conducted in 98,749 children in Mainland China and analyzed the pooled effect sizes of the associations between child maltreatment and childhood behavior problems, heterogeneity in study findings, and publication bias. In addition, this study explored cross-study similarities/differences by comparing the pooled estimates with findings from five existing meta-analyses. Equivalent small-to-moderate effect sizes emerged in the relationships between the three types of maltreatment and child externalizing and internalizing behaviors, except that emotional abuse related more to internalizing than externalizing behaviors. Considerable heterogeneity exists among the 42 studies. Weak evidence suggests that child gender and reporter of emotional abuse may moderate the strengths of the relationships between child maltreatment and behavior problems. No indication of publication bias emerged. Cross-study comparisons show that the pooled effect sizes in this meta-analysis are about equal to those reported in the five meta analyses conducted in child and adult populations across the world. Findings urge relevant agencies in Mainland China to build an effective child protection system to prevent child maltreatment. PMID- 29439617 TI - Low-Density Lipoprotein Receptor-Related Protein 6 Is Essential for Trophoblast Survival and Invasion. AB - Remodeling of maternal spiral artery after the implantation of embryo relies on tightly regulated trophoblast functions and is pivotal to ensure the success of pregnancy. Low-density lipoprotein receptor-related protein 6 (LRP6) is implicated in angiogenesis and several vascular diseases, but its function in trophoblast regulation is still not fully understood. We aimed to investigate the involvement of LRP6 in trophoblast functions during maternal spiral artery remodeling. HTR-8/SVneo cells, a trophoblast cell line, were employed to examine the impact of LRP6 knockdown on proliferation, apoptosis, and migration, as well as invasion and tube formation. Expression of matrix metalloproteinases (MMPs), angiogenic factors placental growth factor (PlGF), and vascular endothelial growth factor (VEGF), as well as activation of canonical Wnt/beta-catenin signaling pathway, which was involved in artery remodeling process, was also analyzed. Lipoprotein receptor-related protein 6 knockdown suppressed proliferation, migration, invasion, and tube formation, as well as induced apoptosis in HTR-8/SVneo cells. In addition, LRP6 knockdown also significantly decreased expression of MMPs, PlGF, and VEGF and activation of Wnt/beta-catenin signaling pathway. Lipoprotein receptor-related protein 6 might positively regulate the remodeling of the maternal artery through both endovascular formation and trophoblast invasion. PMID- 29439618 TI - Effect of Prolonged GnRH Agonist Downregulation on ICSI Outcome in Patients With Endometriomas of Less Than 5 cm: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effect of prolonged Gonadotropin releasing hormone (GnRH) agonist downregulation in patients with endometriomas of less than 5 cm on the outcome of the proceeding Intracytoplasmic sperm injection (ICSI) trial. METHODS: In a randomized controlled trial at a university teaching hospital, 90 patients indicated for ICSI and having unilateral single endometrioma of less than 5 cm in diameter were randomized into 2 groups. Group A (45 patients) received the standard long protocol; whereas group B (45 patients) received 3 consecutive Intramuscular (IM) injections of triptorelin 3.75 mg 28 days apart followed by the standard long protocol 28 days after the last injection. RESULTS: There were no significant differences in the clinical and hormonal characteristics between the 2 groups. All ICSI cycle characteristics including number of retrieved oocytes, fertilized oocytes, and transferred embryos were also not significantly different. However, patients who received prolonged GnRH agonist therapy showed significantly higher chemical ( P = .011), clinical ( P = .018), and ongoing ( P = .028) pregnancy rates. CONCLUSION: Prolonged GnRH agonist downregulation improves the pregnancy rates in patients with small endometriomas undergoing ICSI. PMID- 29439619 TI - Elevated CD14++CD16+ Monocytes in Hyperhomocysteinemia-Associated Insulin Resistance in Polycystic Ovary Syndrome. AB - BACKGROUND:: Hyperhomocysteinemia, chronic low-grade inflammation, and insulin resistance are predominant features in women with polycystic ovary syndrome (PCOS). CD14++CD16+ inflammatory monocytes are elevated in cardiovascular diseases and diabetes, in which inflammation is one of the pathogenesis. We aimed to determine whether homocysteine levels are associated with monocyte subtypes or insulin resistance in women with PCOS. METHODS:: A cross-sectional study was conducted between December 2014 and June 2015 at Peking University Third Hospital. Among 196 Chinese patients with PCOS enrolled, 102 had homocysteine levels >=10 umol/L and 94 exhibited normal homocysteine levels. Monocyte surface markers and related cytokines were detected in peripheral blood samples using a flow cytometry, and data on insulin resistance and homocysteine levels were collected. RESULTS:: Our results showed that fasting insulin and homeostasis model assessment indices that reflect the severity of insulin resistance were increased in the hyperhomocysteinemia PCOS group. Simple linear regression analysis revealed that homocysteine level is one of the influence factors of insulin resistance in PCOS. Compared with the normal homocysteine group, patients with hyperhomocysteinemia had increased numbers of CD14++CD16+ inflammatory monocyte in their peripheral blood and elevated plasma levels of interleukin 1beta and interleukin-6, 2 typical cytokines secreted by the inflammatory monocytes. Unlike CD14+CD16++ nonclassical monocytes, CD14++CD16+ inflammatory monocytes are characterized by high expression of Human leukocyte antigen-antigen D related (HLA-DR). CONCLUSIONS:: Our findings indicate that CD14++CD16+ inflammatory monocytes are associated with hyperhomocysteinemia and insulin resistance in patients with PCOS. Notably, CD14++CD16+ monocytes may contribute to the pathogenesis of insulin resistance in women with PCOS. PMID- 29439620 TI - Acute Drug Effects on the Human Placental Tissue: The Development of a Placental Murine Xenograft Model. AB - OBJECTIVE:: A pilot study was conducted to establish a human placental xenograft, which could serve as a model to evaluate the effect of toxic exposures during pregnancy. STUDY DESIGN:: The protocol consisted of engraftment of third trimester human placental tissue in immunocompromised mice, after induction of a pseudo-pregnancy state by ovariectomy and progesterone supplementation. To validate the model, the placental tissue before and after engraftment was examined by immunohistochemistry, fluorescence-activated cell sorting (FACS), single-nucleotide polymorphism (SNP) genotyping, and whole transcriptome sequencing (WTSS). The human chorion gonadotropin (hCG) production in serum and urine was examined by enzyme-linked immunosorbent assay. RESULTS:: Microscopic evaluation of the placental tissue before and after engraftment revealed a stable morphology and preserved histological structure of the human tissue. Viable trophoblast was present after engraftment and remained stable over time. Vascularization and hormonal secretion (hCG) were present till 3 weeks after engraftment. Thirty-one SNPs were equally present, and there was a stable expression level for 56 451 genes evaluated by whole transcriptome sequencing. CONCLUSION:: Although this human placental xenograft model cannot copy the unique uterine environment in which the placenta develops and interacts between the mother and the fetus, it could be a suitable tool to evaluate the acute impact and adaptive processes of the placental tissue to environmental changes. PMID- 29439621 TI - Biofluid Metabolomics in Preterm Birth Research. AB - This article presents an account of the research carried out so far in the use of metabolomics to find biomarkers of preterm birth (PTB) in fetal, maternal, and newborn biofluids. Metabolomic studies have employed mainly nuclear magnetic resonance spectroscopy or mass spectrometry-based methodologies to analyze, on one hand, prenatal biofluids (amniotic fluid, maternal urine/maternal blood, cervicovaginal fluid) to identify predictive biomarkers of PTB, and on the other hand, biofluids collected at or after birth (amniotic fluid, umbilical cord blood, newborn urine, and newborn blood, maternal blood, or breast milk) to assess and follow up the health status of PTB babies. Besides advancing on the biochemical knowledge of PTB metabolism mainly during the in utero period and at birth, the work carried out has also helped to identify important requirements related to experimental design and analytical protocol that need to be addressed, if translation of these biomarkers to the clinic is to be envisaged. An outlook of possible future developments for the translation of laboratory results to the clinic is presented. PMID- 29439622 TI - Caloric Restriction Dramatically Stalls Lesion Growth in Mice With Induced Endometriosis. AB - Caloric restriction (CR) has been demonstrated to have many health-beneficial effects in many species, but whether CR can impede the development of endometriosis is unknown. To test the hypothesis that CR can impede the growth of endometriotic lesions and fibrogenesis, we conducted 2 experiments. In experiment 1, 20 female Balb/C mice were randomly assigned to either ad libitum (AL) group that was fed AL or to CR group that was fed 30% less calories than that of AL mice. Two weeks after the implementation of the dietary intervention, endometriosis was induced by intraperitoneal injection of endometrial fragments. Two weeks after the induction, all mice were sacrificed and their lesion samples were evaluated. In experiment 2, another 20 mice were used and CR was implemented 2 weeks after induction of endometriosis and lasted for 4 weeks. Caloric restriction instituted before the induction of endometriosis reduced the lesion weight by 88.5%, whereas CR implemented well after lesions were established reduced the lesion weight by 93.0%. In both cases, CR significantly increased staining levels of markers of autophagy but reduced proliferation, angiogenesis, steroidogenesis, and fibrosis in lesions as compared with the AL group. Consequently, CR, instituted either before or after the induction of endometriosis, dramatically curbs the growth of endometriotic lesions and fibrogenesis through multiple mechanisms. Caloric restriction and CR mimetics, a family of compounds mimicking the beneficial effect of CR, even when instituted well after lesions are established, may stall the development of endometriosis. Given the scarcity in research on how lifestyle can impact on the development of endometriosis, our study should hopefully stimulate more research in this area. PMID- 29439623 TI - Aspirin Ameliorates Preeclampsia Induced by a Peroxisome Proliferator-Activated Receptor Antagonist. AB - Reduced expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in the placenta was found in women with severe preeclampsia. Aspirin is currently used as the only recommended intervention in pregnancies for prevention of preeclampsia. In this study, we aimed to investigate whether aspirin could attenuate PPARgamma inhibitor (T0070907)-induced preeclampsia and its impact on expression of PPARgamma. Sixty Sprague-Dawley rats were used and treated with different doses of aspirin (0, 1, and 1.5 mg/kg) in presence or absence of PPARgamma antagonist, T0070907. We found that mean arterial blood pressure was significantly reduced by aspirin treatment in T0070907-exposed rats. T0070907 exposure also led to significant decrease in fetal weight and increase in placental weights. However, 1.5 mg/kg of aspirin reversed these effects of T0070907. Additionally, aspirin also reversed T0070907-induced changes in the levels of thromboxane B2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, and matrix metalloproteinase 2 in both maternal blood and placental tissue. The increased messenger RNA and protein levels of Cox1 and Cox2 induced by T0070907 were markedly reduced by aspirin treatment. Importantly, T0070907 repressed both transcriptional and translational levels of PPARgamma, which were reversed by aspirin. In conclusion, this study suggests that aspirin prevented the occurrence of preeclampsia, which is possibly through enhancing both transcriptional and translational levels of PPARgamma. PMID- 29439624 TI - Telepractice delivery of family-centred early intervention for children who are deaf or hard of hearing: A scoping review. AB - Introduction The use of telepractice, a method of delivering services through telecommunications technologies that provides two-way, synchronous audio and video signals in real-time, is becoming increasingly commonplace in early childhood education and intervention for children who are deaf or hard of hearing. Although the use of telepractice has been validated in the health sector as a viable and effective alternative to in-person service provision, evidence to support its use in the delivery of family-centred early intervention is still emerging. The purpose of this scoping review was to describe the current use of telepractice in the delivery of family-centred early childhood intervention for children who are deaf or hard of hearing, and their families. Method The review followed the framework outlined by the Joanna Briggs Institute (2015), including an iterative three-step search strategy. Specific inclusion criteria and data extraction fields were outlined in advance. Results A total of 23 peer-reviewed publications were included in the review. Most publications (70%) provided anecdotal evidence of the challenges and benefits associated with telepractice. The remaining publications (30%) reported on research studies evaluating the effectiveness of early intervention delivered through telepractice. Of the 23 included papers, 18 viewed the use of telepractice positively while the remaining 5 reported mixed conclusions and the need for more data. Discussion Current evidence in the literature indicates that telepractice can be an effective model for delivering family-centred early intervention for children who are deaf or hard of hearing. However, more research is needed to substantiate the use of telepractice as a viable alternative to traditional in-person services, rather than being seen as supplemental to such services. PMID- 29439625 TI - ? PMID- 29439626 TI - ? PMID- 29439627 TI - ? PMID- 29439628 TI - ? PMID- 29439629 TI - ? PMID- 29439630 TI - ? PMID- 29439631 TI - ? PMID- 29439632 TI - ? PMID- 29439633 TI - ? PMID- 29439634 TI - ? PMID- 29439635 TI - ? PMID- 29439636 TI - ? PMID- 29439637 TI - ? PMID- 29439638 TI - ? PMID- 29439639 TI - Thrombin Generation Biomarkers Decline With Parenteral Anticoagulation-An Overlooked Means of Anticoagulation Monitoring? AB - Anticoagulation therapy is administered to patients to prevent or stop thrombin generation in vivo. Although plasma tests of in vivo thrombin generation have been available for more than 2 decades, they are not routinely used in clinical trials or practice to monitor anticoagulation therapy. We observed a fall in one such marker, the D-dimer antigen, in patients receiving anticoagulation therapy. We therefore conducted a systematic review of the medical literature to document the change in serum biomarkers of thrombin generation following the initiation of anticoagulation therapy. Using a defined search strategy, we screened PubMed and Embase citations and identified full-length articles published in English. Eighteen articles containing serial changes in 1 of 3 markers of thrombin generation (D-dimer antigen, thrombin-antithrombin complexes, and prothrombin fragment 1+2 antigen levels) in the 14 days following the initiation of anticoagulation were identified. Even though the assays used varied considerably, each of the 3 markers of thrombin generation declined in the initial period of anticoagulation therapy, with changes evident as early as 1 day after beginning therapy. These observations provide a rationale for further exploration of these markers as measures of the adequacy of anticoagulation using classic as well as novel anticoagulants. Particular patient groups that would benefit from additional means of monitoring anticoagulation therapy are discussed. PMID- 29439640 TI - An Evaluation of Hemostatic Abnormalities in Patients With Hemophilia According to the Activated Partial Thromboplastin Time Waveform. AB - The usefulness of the waveform of activated partial thromboplastin time (APTT) in various diseases has been evaluated in recent years. The APTT waveform was examined in patients with hemophilia and patients positive for lupus anticoagulant (LA). The correlation with the FVIII activity was highest for the height of acceleration peak. The peak time of acceleration, velocity, and 1/2 fibrin formation, and the width of acceleration and velocity were significantly long and the height of acceleration was significantly low in patients with hemophilia. The height of velocity was significantly low in patients with hemophilia with inhibitor. There were no significant differences in the APTT waveform between patients with hemophilia and patients with LA, but the peak of acceleration and 1/2 fibrin formation were significantly longer and the height of acceleration and velocity were significantly lower in patients with hemophilia with inhibitor than in the patients with LA. Wave changes in the APTT were observed in all 22 patients positive for LA, while a biphasic waveform was observed in patients with hemophilia with FVIII activity <10.0%. The APTT waveform is useful for the analysis of hemostatic abnormalities in patients with hemophilia. PMID- 29439641 TI - Methylenetetrahydrofolate Reductase Gene Polymorphism (C677T) as a Risk Factor for Arterial Thrombosis in Georgian Patients. AB - Methylenetetrahydrofolate reductase ( MTHFR) gene polymorphism (C677T)] is a well recognized genetic risk factor for venous thrombosis; however, its association with arterial thrombosis is still under debate. Herein, we evaluated the prevalence of MTHFR C677T polymorphism in Georgian patients in comparison with healthy individuals and its association with arterial thrombosis. We enrolled 214 participants: 101 with arterial thrombosis (71.3% males; mean age: 66.3 +/- 12.1 years) and 113 controls (67.3% males; mean age: 56.6 +/- 11.3 years). Genomic DNA was extracted from dry blood spot on Whatman filter paper. Polymerase chain reaction was performed to determine MTHFR C677T polymorphism. Frequency of C677T allele polymorphism in controls was 21.2%, which corresponded to heterozygous and homozygous stage frequencies of 35.4% and 3.5%, respectively. In patient group, an allelic frequency of 33.2% was found, which corresponded to the presence of 48.5% of heterozygous and 8.9% of homozygous individuals. Comparing the frequency of mutated alleles between the 2 groups, a significantly high frequency of mutated alleles was found in patient group ( P < .05). In conclusion, high frequency of MTHFR C677T polymorphism found in arterial thrombosis patient group suggests that this polymorphism might increase the risk of arterial thrombosis in Georgian patients. PMID- 29439643 TI - A Look Into the Promising World of Selective Progesterone Receptor Modulators. PMID- 29439642 TI - Dental Restorative Materials Based on Thiol-Michael Photopolymerization. AB - Step-growth thiol-Michael photopolymerizable resins, constituting an alternative chemistry to the current methacrylate-based chain-growth polymerizations, were developed and evaluated for use as dental restorative materials. The beneficial features inherent to anion-mediated thiol-Michael polymerizations were explored, such as rapid photocuring, low stress generation, ester content tunability, and improved mechanical performance in a moist environment. An ester-free tetrafunctional thiol and a ultraviolet-sensitive photobase generator were implemented to facilitate thiol-Michael photopolymerization. Thiol-Michael resins of varied ester content were fabricated under suitable light activation. Polymerization kinetics and shrinkage stress were determined with Fourier transform infrared spectroscopy coupled with tensometery measurements. Thermomechanical properties of new materials were evaluated by dynamic mechanical analysis and in 3-point bending stress-strain experiments. Photopolymerization kinetics, polymerization shrinkage stress, glass transition temperature, flexural modulus, flexural toughness, and water sorption/solubility were compared between different thiol-Michael systems and the BisGMA/TEGDMA control. Furthermore, the mechanical performance of 2 thiol-Michael composites and a control composite were compared before and after extensive conditioning in water. All photobase catalyzed thiol-Michael polymerization matrices achieved >90% conversion with a dramatic reduction in shrinkage stress as compared with the unfilled dimethacrylate control. One prototype of ester-free thiol-Michael formulations had significantly better water uptake properties than the BisGMA/TEGDMA control system. Although exhibiting relatively lower Young's modulus and glass transition temperatures, highly uniform thiol-Michael materials achieved much higher toughness than the BisGMA/TEGDMA control. Moreover, low-ester thiol-Michael composite systems show stable mechanical performance even after extensive water treatment. Although further resin/curing methodology optimization is required, the photopolymerized thiol-Michael prototype resins can now be recognized as promising candidates for implementation in composite dental restorative materials. PMID- 29439644 TI - Potential HIV-1 fusion inhibitors mimicking gp41-specific broadly neutralizing antibody 10E8: In silico discovery and prediction of antiviral potency. AB - An integrated computational approach to in silico drug design was used to identify novel HIV-1 fusion inhibitor scaffolds mimicking broadly neutralizing antibody (bNab) 10E8 targeting the membrane proximal external region (MPER) of the HIV-1 gp41 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb 10E8 active towards the gp41 MPER segment, (ii) shape and pharmacophore-based identification of the 10E8-mimetic candidates by a web oriented virtual screening platform pepMMsMIMIC, (iii) high-throughput docking of the identified compounds with the gp41 MPER peptide, and (iv) molecular dynamics simulations of the docked structures followed by binding free energy calculations. As a result, eight hits-able to mimic pharmacophore properties of bNAb 10E8 by specific and effective interactions with the MPER region of the HIV 1 protein gp41 were selected as the most probable 10E8-mimetic candidates. Similar to 10E8, the predicted compounds target the critically important residues of a highly conserved hinge region of the MPER peptide that provides a conformational flexibility necessary for its functioning in cell-virus membrane fusion process. In light of the data obtained, the identified small molecules may present promising HIV-1 fusion inhibitor scaffolds for the design of novel potent antiviral drugs. PMID- 29439645 TI - Introduction to the 9th Young Scientists School on Systems Biology and Bioinformatics (SBB'2017). PMID- 29439646 TI - The influence of functional polymorphic positions of HLA-DRbeta1 molecules on risk for South Indian systemic lupus erythematosus patients. AB - The aim of this case-control study was to investigate the association of human leukocyte antigen (HLA) Class II alleles with the susceptibility and phenotypic heterogeneity in systemic lupus erythematosus (SLE) in South Indian patients. A total of 439 individuals (212 SLE cases and 227 age- and ethnicity-matched controls) were included in the study. The genotyping of HLA-DRbeta1 and - DQbeta1 was conducted by the PCR-SSP method. HLA-DRbeta1*07 was significantly associated with SLE (OR: 2.02; 95% CI: 1.34-3.04, p = 1.50 * 10-4, pc = 1.95 * 10-3), whereas the DRbeta1*14 allele was negatively associated with SLE (OR: 0.49; 95% CI: 0.31-0.76, p = 1.70 * 10-2, pc = 0.221). In addition, the HLA-DRbeta1*07/15 genotype tended to be positively associated with SLE (OR: 3.23, 95% CI: 1.57 6.63, p = 0.0009). Amino acid residues residing in the peptide-binding pocket of HLA-DRbeta1 play a significant role in peptide recruitment and antigen presentation. Our results demonstrated that amino acid glycine 11 (OR: 2.11, 95% CI: 1.42-3.12, pc = 0.00093), tyrosine 13 (OR: 2.11, 95% CI: 1.42-3.12, pc = 0.00062) and glutamine 74 (OR: 2.11, 95% CI: 1.42-3.12, pc = 0.00077) showed a significant positive association with SLE. Certain haplotype combinations, DRB1*07-DQbeta1*03 (OR: 2.21; 95% CI:1.29-3.79, pc = 0.06, p = 0.00036) and DRbeta1*07-DQbeta1*05 (OR: 2.51, 95% CI: 1.34-4.71, pc = 0.07, p = 0.00039), had positive associations whereas DRbeta1*14-DQbeta1*03 (OR: 0.14, 95% CI: 0.061 0.36, pc = 2.34 * 10-5, p = 1.30 * 10-6) were found to have a significant negative association with SLE. So far, the present study is the first attempt to investigate the association of HLA-DRbeta1 and - DQbeta1 allele, genotype and haplotype combinations with the risk of SLE in South Indian patients. In conclusion, the HLA-DRbeta1*07 allele is associated with risk of SLE whereas a protective association of HLA-DRbeta1*14 alleles with SLE was observed. PMID- 29439647 TI - Combination of ofatumumab and fresh frozen plasma in hypocomplementemic systemic lupus erythematosus: a case report. PMID- 29439648 TI - Effect of 12 weeks of once-daily tiotropium/olodaterol on exercise endurance during constant work-rate cycling and endurance shuttle walking in chronic obstructive pulmonary disease. AB - BACKGROUND: The TORRACTO(r) study evaluated the effects of tiotropium/olodaterol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease (COPD) after 12 weeks of treatment. METHODS: The effects of once-daily tiotropium/olodaterol (2.5/5 and 5/5 MUg) on endurance time during constant work rate cycle ergometry (CWRCE) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Endurance time during the endurance shuttle walk test (ESWT) after 6 and 12 weeks of treatment was also evaluated in a subset of patients. RESULTS: A total of 404 patients received treatment, with 165 participating in the ESWT substudy. A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks (primary endpoint) with tiotropium/olodaterol 5/5 ug [14% ( p = 0.02)] but not with tiotropium/olodaterol 2.5/5 ug [9% ( p = 0.14)] versus placebo. In the ESWT substudy, a trend to improvement in endurance time during ESWT after 12 weeks (key secondary endpoint) was observed with tiotropium/olodaterol 5/5 ug [21% ( p = 0.055)] and tiotropium/olodaterol 2.5/5 ug [21% ( p = 0.056)] versus placebo. CONCLUSION: Tiotropium/olodaterol 5/5 ug improved endurance time during cycle ergometry versus placebo, with a strong tendency to also improve walking endurance time. [ ClinicalTrials.gov identifier: NCT01525615.]. PMID- 29439649 TI - FuSpot: a web-based tool for visual evaluation of fusion candidates. AB - BACKGROUND: Gene fusions often occur in cancer cells and in some cases are the main driver of oncogenesis. Correct identification of oncogenic gene fusions thus has implications for targeted cancer therapy. Recognition of this potential has led to the development of a myriad of sequencing-based fusion detection tools. However, given the same input, many of these detectors will find different fusion points or claim different sets of supporting data. Furthermore, the rate at which these tools falsely detect fusion events in data varies greatly. This discrepancy between tools underscores the fact that computation algorithms still cannot perfectly evaluate evidence; especially when provided with small amounts of supporting data as is typical in fusion detection. We assert that when evidence is provided in an easily digestible form, humans are more proficient in identifying true positives from false positives. RESULTS: We have developed a web tool that, given the genomic coordinates of a candidate fusion breakpoint, will extract fusion and non-fusion reads adjacent to the fusion point from partner transcripts, and color code reads by transcript origin and read orientation for ease of intuitive inspection by the user. Fusion partner transcript read alignments are performed using a novel variant of the Smith-Waterman algorithm. CONCLUSIONS: Combined with dynamic filtering parameters, the visualization provided by our tool introduces a powerful new investigative step that allows researchers to comprehensively evaluate fusion evidence. Additionally, this allows quick identification of false positives that may deceive most fusion detectors, thus eliminating unnecessary gene fusion validation. We apply our visualization tool to publicly available datasets and provide examples of true as well as false positives reported by open source fusion detection tools. PMID- 29439650 TI - A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD); however, the natural course of disease progression is heterogeneous between patients. This study aimed to develop a natural history model of ADPKD that predicted progression rates and long-term outcomes in patients with differing baseline characteristics. METHODS: The ADPKD Outcomes Model (ADPKD-OM) was developed using available patient-level data from the placebo arm of the Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Study (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948). Multivariable regression equations estimating annual rates of ADPKD progression, in terms of total kidney volume (TKV) and estimated glomerular filtration rate, formed the basis of the lifetime patient-level simulation model. Outputs of the ADPKD-OM were compared against external data sources to validate model accuracy and generalisability to other ADPKD patient populations, then used to predict long-term outcomes in a cohort matched to the overall TEMPO 3:4 study population. RESULTS: A cohort with baseline patient characteristics consistent with TEMPO 3:4 was predicted to reach ESRD at a mean age of 52 years. Most patients (85%) were predicted to reach ESRD by the age of 65 years, with many progressing to ESRD earlier in life (18, 36 and 56% by the age of 45, 50 and 55 years, respectively). Consistent with previous research and clinical opinion, analyses supported the selection of baseline TKV as a prognostic factor for ADPKD progression, and demonstrated its value as a strong predictor of future ESRD risk. Validation exercises and illustrative analyses confirmed the ability of the ADPKD-OM to accurately predict disease progression towards ESRD across a range of clinically-relevant patient profiles. CONCLUSIONS: The ADPKD-OM represents a robust tool to predict natural disease progression and long-term outcomes in ADPKD patients, based on readily available and/or measurable clinical characteristics. In conjunction with clinical judgement, it has the potential to support decision-making in research and clinical practice. PMID- 29439651 TI - Serum and blood based biomarkers for lung cancer screening: a systematic review. AB - BACKGROUND: Lung cancer is the second most common cancer and the leading cause of cancer death for both men and women. Although low-dose CT (LDCT) is recommended for lung cancer screening in high-risk populations and may decrease lung cancer mortality, there is a need to improve the accuracy of lung cancer screening to decrease over-diagnosis and morbidity. Blood and serum-based biomarkers, including EarlyCDT-lung and microRNA based biomarkers, are promising adjuncts to LDCT in lung cancer screening. We evaluated the diagnostic performance of EarlyCDT-lung, micro-RNA signature classifier (MSC), and miR-test, and their impact on lung cancer-related mortality and all-cause mortality. METHODS: References were identified using searches of PubMed, EMBASE, and Ovid Medline(r) from January 2000 to November 2015. Phase three or greater studies in the English language evaluating the diagnostic performance of EarlyCDT-lung, MSC, and miR test were selected for inclusion. RESULTS: Three phase 3 studies were identified, one evaluating EarlyCDT-lung, one evaluating miR-Test, and one evaluating MSC respectively. No phase 4 or 5 studies were identified. All three biomarker assays show promise for the detection of lung cancer. MSC shows promise when used in conjunction with LDCT for lung cancer detection, achieving a positive likelihood ratio of 18.6 if both LDCT and MSC are positive, and a negative likelihood ratio of 0.03 if both LDCT and MSC are negative. However, there is a paucity of high quality studies that can guide clinical implementation. CONCLUSIONS: There is currently no high quality evidence to support or guide the implementation of these biomarkers in clinical practice. Reports of further research at stages four and five for these, and other promising methods, is required. PMID- 29439652 TI - Advantages of a multi-state approach in surgical research: how intermediate events and risk factor profile affect the prognosis of a patient with locally advanced rectal cancer. AB - BACKGROUND: Standard survival analysis fails to give insight into what happens to a patient after a first outcome event (like first relapse of a disease). Multi state models are a useful tool for analyzing survival data when different treatments and results (intermediate events) can occur. Aim of this study was to implement a multi-state model on data of patients with rectal cancer to illustrate the advantages of multi-state analysis in comparison to standard survival analysis. METHODS: We re-analyzed data from the RCT FOGT-2 study by using a multi-state model. Based on the results we defined a high and low risk reference patient. Using dynamic prediction, we estimated how the survival probability changes as more information about the clinical history of the patient becomes available. RESULTS: A patient with stage UICC IIIc (vs UICC II) has a higher risk to develop distant metastasis (DM) or both DM and local recurrence (LR) if he/she discontinues chemotherapy within 6 months or between 6 and 12 months, as well as after the completion of 12 months CTx with HR 3.55 (p = 0.026), 5.33 (p = 0.001) and 3.37 (p < 0.001), respectively. He/she also has a higher risk to die after the development of DM (HR 1.72, p = 0.023). Anterior resection vs. abdominoperineal amputation means 63% risk reduction to develop DM or both DM and LR (HR 0.37, p = 0.003) after discontinuation of chemotherapy between 6 and 12 months. After development of LR, a woman has a 4.62 times higher risk to die (p = 0.006). A high risk reference patient has an estimated 43% 5 year survival probability at start of CTx, whereas for a low risk patient this is 79%. After the development of DM 1 year later, the high risk patient has an estimated 5-year survival probability of 11% and the low risk patient one of 21%. CONCLUSIONS: Multi-state models help to gain additional insight into the complex events after start of treatment. Dynamic prediction shows how survival probabilities change by progression of the clinical history. PMID- 29439653 TI - Unexplained chronic liver disease in Ethiopia: a cross-sectional study. AB - BACKGROUND: Hepatitis B virus (HBV) infection is assumed to be the major cause of chronic liver disease (CLD) in sub-Saharan Africa. The contribution of other aetiological causes of CLD is less well documented and hence opportunities to modulate other potential risk factors are being lost. The aims of this study were to explore the aetiological spectrum of CLD in eastern Ethiopia and to identify plausible underlying risk factors for its development. METHODS: A cross-sectional study was undertaken between April 2015 and April 2016 in two public hospitals in Harar, eastern Ethiopia. The study population comprised of consenting adults with clinical and radiological evidence of chronic liver disease. The baseline evaluation included: (i) a semi-structured interview designed to obtain information about the ingestion of alcohol, herbal medicines and local recreational drugs such as khat (Catha edulis); (ii) clinical examination; (iii) extensive laboratory testing; and, (iv) abdominal ultrasonography. RESULTS: One hundred-and-fifty patients with CLD (men 72.0%; median age 30 [interquartile range 25-40] years) were included. CLD was attributed to chronic HBV infection in 55 (36.7%) individuals; other aetiological agents were identified in a further 12 (8.0%). No aetiological factors were identified in the remaining 83 (55.3%) patients. The overall prevalence of daily khat use was 78.0%, while alcohol abuse, defined as > 20 g/day in women and > 30 g/day in men, was rare (2.0%). Histological features of toxic liver injury were observed in a subset of patients with unexplained liver injury who underwent liver biopsy. CONCLUSION: The aetiology of CLD in eastern Ethiopia is largely unexplained. The widespread use of khat in the region, together with histopathological findings indicating toxic liver injury, suggests an association which warrants further investigation. PMID- 29439655 TI - High-fat diet aggravates postoperative cognitive dysfunction in aged mice. AB - BACKGROUND: Silent Information Regulator 1 (Sirt1) and apoptosis play key roles in postoperative cognitive dysfunction (POCD). Consuming a high-fat diet (HFD), a prevalent type of diet in modern society, has been increasingly recognized as contributing to neurodegenerative diseases. Although Sirt1 and apoptosis are significant responders to HFD in the brain, little is known regarding the functional correlations between HFD and POCD. METHODS: Thirty-two aged C57BL/6 male mice were randomly divided into 2 groups: an ad libitum (AL) group (fed a regular diet) and high-fat diet (HF) group (fed a high-fat diet). After 8 weeks, the animals were divided into four sub-groups: an ad libitum control (ALC) group, ad libitum surgery (ALS) group, high-fat diet control (HFC) group, and high-fat diet surgery (HFS) group. The ALS and HFS groups were exposed to 3% sevoflurane in 33% oxygen for 3 h and were subsequently subjected to exploratory surgery to establish the POCD model. The ALC and HFC groups were treated with 33% oxygen for 3 h without surgery. After 48 h, the learning and memory abilities of mice in each group were tested using the Morris water maze (MWM). The expression levels of Sirt1, Bcl-2, Bax and caspase-3 cleaved were detected by western blot. RESULTS: The MWM and western blotting results showed that the learning and memory abilities were decreased in the HFC group compared with the ALC group. The learning and memory abilities and the expression of Sirt1 in the hippocampus in the HFS group were significantly decreased compared with the other groups. A significant decrease in Sirt1 expression was also observed in the HFC group compared with the ALS group. The level of Bcl-2 was lower in the HFS group than in the HFC and ALC groups. The expression levels of caspase-3 cleaved and Bax increased in the HFS group compared with the HFC group. Moreover, the expression of caspase-3 cleaved was higher in the HFC group than in the ALS group. CONCLUSION: HFD can aggravate POCD in aged C57BL/6 mice, an effect that may be related to the inhibition expression of Sirt1 and the promotion of neuronal apoptosis. PMID- 29439654 TI - Prospective study on human fecal carriage of Enterobacteriaceae possessing mcr-1 and mcr-2 genes in a regional hospital in Hong Kong. AB - BACKGROUND: Human fecal carriage of Enterobacteriaceae possessing mobilized colistin resistance genes (mcr-1 and mcr-2) remains obscure in Hong Kong. As part of routine surveillance on emerging antibiotic resistance, we conducted a prospective study on this topic in a regional hospital in Hong Kong. METHODS: From October 31 to November 25, 2016, all fecal specimens submitted for routine analysis were included in this surveillance study. These comprised 672 consecutive routine fecal specimens collected from 616 individuals. Fecal specimens were screened for colistin-resistant Enterobacteriaceae by culture based method, and the presence of mcr-1 and mcr-2 genes in resistant isolates was identified by polymerase chain reaction and Sanger sequencing. Whole genome sequencing (WGS) of mcr-1-possessing Escherichia coli strains was facilitated using Illumina(r) MiSeq(r) followed by sequence analysis with appropriate bioinformatics tools. RESULTS: Fourteen mcr-1-positive E. coli strains were isolated from 14 separate individuals (2.08% of total fecal specimens), with 9 of them being asymptomatic, healthy clients coming for health assessment. No mcr-2 possessing Enterobacteriaceae was identified. Colistin minimum inhibitory concentrations of these mcr-1-positive isolates ranged from 2 to 4 MUg/mL. All these isolates were susceptible to carbapenems with 2 being extended spectrum beta-lactamase producers. WGS data revealed that these isolates belonged to at least 12 different sequence types (STs) and possessed diversified plasmid replicons, virulence and acquired antibiotic resistance genes. Further study on an E. coli ST201 strain (Pasteur scheme) revealed coexistence of 47,818-bp IncP-1 and 33,309-bp IncX4 types of mcr-1 plasmids, which was a combination of stability and high transmissibility. CONCLUSIONS: To the best of our knowledge, this is the first study on human fecal carriage of Enterobacteriaceae possessing mcr-1 and mcr-2 genes in Hong Kong. Our data further revealed asymptomatic carriage of mcr 1-possessing Enterobacteriaceae by both patients and healthy individuals. This is alarming considering wide diversity and high transmissibility of mcr-1 plasmids, which potentially facilitate emergence of pan-drug-resistant bacteria in future infection. This also highlights the importance of surveillance on emerging antibiotic resistance, especially for patients under intensive care. PMID- 29439656 TI - Genetic diversity and ex situ conservation of Loropetalum subcordatum, an endangered species endemic to China. AB - BACKGROUND: Loropetalum subcordatum is an endangered species endemic to China that is characterized by narrow distribution, small population size, and delayed fertilization. However, the genetic diversity of the entire extant natural and ex situ populations has not been assessed to date. In this study, we evaluated the genetic diversity and structure of six natural populations and a single ex situ population (the only known ex situ population of L. subcordatum) using sequence related amplified polymorphism data. RESULTS: In total, 553 reliable DNA bands, of which 359 (63.28%) were polymorphic, were amplified by polymerase chain reaction with combinations of 15 primers. Low average gene diversity within populations and high genetic differentiation were detected in L. subcordatum. A Mantel test demonstrated that there was a positive correlation between genetic and geographic distances, indicating that significant genetic divergence was likely the result of geographic isolation among natural populations. Furthermore, based on genetic structure patterns, populations of L. subcordatum were divided into three clusters. Group 1 was composed of specimens from Libo, Guizhou Province (GZ) and Huanjiang, Guangxi Zhuang Autonomous Region (GX). Group 2 was composed of Mt. Wuguishan, Guangdong Province (GD). Group 3 was composed of three populations in Hong Kong Special Administrative Region. Additionally, clonal reproduction probably existed in GD population. According to the genetic information analysis and field survey, the ex situ population did not match its source population (GD) in terms of genetics, and its habitat was different from the original natural habitat. We observed that a few individual GD seeds were needed to improve ZS ex situ in the future. CONCLUSIONS: Compared to previous SRAP-based studies of endangered plants, L. subcordatum had extremely low average gene diversity within populations and high genetic differentiation among populations. At present, the unique ex situ population has not been successful due to non-representative samples being taken, a smaller population size, and man made changes in habitat. Potential strategies are suggested to improve the conservation of this species. PMID- 29439657 TI - Effects of procyanidin on cardiomyocyte apoptosis after myocardial ischemia reperfusion in rats. AB - BACKGROUND: This study is aimed at investigating the effects of procyanidin on cardiomyocyte apoptosis of myocardial ischemia/reperfusion (I/R) injury in rats. METHODS: Sprague-Dawley rats were randomly assigned into four groups: control group (normal saline), ischemic group (normal saline), procyanidin low-dose group (procyanidin 50 mg/kg/day) and procyanidin high-dose group (procyanidin 100 mg/kg/day) by intragastric administration for 2 weeks. After last administration, myocardial I/R model was induced by ligating left anterior descending artery for 30 min followed by 120 min of perfusion. The activity of serum creatine kinase mb isoenzyme (CK-MB) was detected after experiment. The content of reactive oxygen species (ROS) was determined by ROS fluorescent probe dihydroethidium; the expressions of p53, Caspase-9, Caspase-3, Bcl-2 and Bax were determined by western blotting; myocardial apoptosis was measured by the method of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. RESULTS: Compared with control group, the contents of serum CK-MB, ROS, the expressions of p53, Caspase-9, Caspase-3 and Bax increased significantly in ischemic group, the Bcl-2 expression, Bcl-2/Bax ratio decreased and the cardiomyocyte apoptosis index increased (p < 0.05); compared with ischemic group, the content of CK-MB, ROS, the expressions of p53, Caspase-9, Caspase-3 and Bax decreased, the Bcl-2 expression, Bcl-2/Bax ratio increased and the cardiomyocyte apoptosis index decreased in procyanidin group (p < 0.05). CONCLUSIONS: Procyanidin can reduce cardiomyocyte apoptosis after I/R. This beneficial effect is partially dependant on decreased ROS, p53, Caspase-9, Caspase-3 and Bax, as well as increased Bcl-2 and Bcl-2/Bax ratio. PMID- 29439658 TI - High fidelity hypothermic preservation of primary tissues in organ transplant preservative for single cell transcriptome analysis. AB - BACKGROUND: High-fidelity preservation strategies for primary tissues are in great demand in the single cell RNAseq community. A reliable method would greatly expand the scope of feasible multi-site collaborations and maximize the utilization of technical expertise. When choosing a method, standardizability and fidelity are important factors to consider due to the susceptibility of single cell RNAseq analysis to technical noise. Existing approaches such as cryopreservation and chemical fixation are less than ideal for failing to satisfy either or both of these standards. RESULTS: Here we propose a new strategy that leverages preservation schemes developed for organ transplantation. We evaluated the strategy by storing intact mouse kidneys in organ transplant preservative solution at hypothermic temperature for up to 4 days (6 h, 1, 2, 3, and 4 days), and comparing the quality of preserved and fresh samples using FACS and single cell RNAseq. We demonstrate that the strategy effectively maintained cell viability, transcriptome integrity, cell population heterogeneity, and transcriptome landscape stability for samples after up to 3 days of preservation. The strategy also facilitated the definition of the diverse spectrum of kidney resident immune cells, to our knowledge the first time at single cell resolution. CONCLUSIONS: Hypothermic storage of intact primary tissues in organ transplant preservative maintains the quality and stability of the transcriptome of cells for single cell RNAseq analysis. The strategy is readily generalizable to primary specimens from other tissue types for single cell RNAseq analysis. PMID- 29439659 TI - Validation of genotype imputation in Southeast Asian populations and the effect of single nucleotide polymorphism annotation on imputation outcome. AB - BACKGROUND: Imputation involves the inference of untyped single nucleotide polymorphisms (SNPs) in genome-wide association studies. The haplotypic reference of choice for imputation in Southeast Asian populations is unclear. Moreover, the influence of SNP annotation on imputation results has not been examined. METHODS: This study was divided into two parts. In the first part, we applied imputation to genotyped SNPs from Southeast Asian populations from the Pan-Asian SNP database. Five percent of the total SNPs were removed. The remaining SNPs were applied to imputation with IMPUTE2. The imputed outcomes were verified with the removed SNPs. We compared imputation references from Chinese and Japanese haplotypes from the HapMap phase II (HMII) and the complete set of haplotypes from the 1000 Genomes Project (1000G). The second part was imputation accuracy and yield in Thai patient dataset. Half of the autosomal SNPs was removed to create Set 1. Another dataset, Set 2, was then created where we switched which half of the SNPs were removed. Both Set 1 and Set 2 were imputed with HMII to create a complete imputed SNPs dataset. The dataset was used to validate association testing, SNPs annotation and imputation outcome. RESULTS: The accuracy was highest for all populations when using the HMII reference, but at the cost of a lower yield. Thai genotypes showed the highest accuracy over other populations in both HMII and 1000G panels, although accuracy and yield varied across chromosomes. Imputation was tested in a clinical dataset to compare accuracy in gene-related regions, and coding regions were found to have a higher accuracy and yield. CONCLUSIONS: This work provides the first evidence of imputation reference selection for Southeast Asian studies and highlights the effects of SNP locations respective to genes on imputation outcome. Researchers will need to consider the trade-off between accuracy and yield in future imputation studies. PMID- 29439660 TI - The impact of down-regulated SK3 expressions on Hirschsprung disease. AB - BACKGROUND: Some Hirschsprung's disease (HSCR) patients showed persistent bowel symptoms following an appropriately performed pull-through procedure. The mechanism is presumed to be down-regulated small-conductance calcium-activated potassium channel 3 (SK3) expression in the HSCR ganglionic intestines. We aimed to investigate the SK3 expression's impact in HSCR patients after a properly performed pull-through surgery in an Indonesian population, a genetically distinct group within Asia. METHODS: We assessed SK3 gene expression in both the ganglionic and aganglionic colon of HSCR patients and controls colon by quantitative real-time polymerase chain reaction (RT-PCR). RESULTS: We ascertained fourteen sporadic HSCR patients and six anorectal malformation patients as controls. Quantitative RT-PCR showed that the SK3 expression was significantly lower (23-fold) in the ganglionic colon group compared to the control group (9.9 +/- 4.6 vs. 5.4 +/- 3.4; p = 0.044). The expression of SK3 in the aganglionic colon group was also significantly lower (43-fold) compared to the control group (10.8 +/- 4.4 vs. 5.4 +/- 3.4; p = 0.015). CONCLUSION: Our study shows that the down-regulated SK3 expression in ganglionic intestines might contribute to the persistent bowel symptoms following a properly performed pull through surgery in Indonesian HSCR patients. Furthermore, this study is the first report of SK3 expression in a sample population of Asian ancestry. PMID- 29439661 TI - Genome-wide scan for commons SNPs affecting bovine leukemia virus infection level in dairy cattle. AB - BACKGROUND: Bovine leukemia virus (BLV) infection is omnipresent in dairy herds causing direct economic losses due to trade restrictions and lymphosarcoma related deaths. Milk production drops and increase in the culling rate are also relevant and usually neglected. The BLV provirus persists throughout a lifetime and an inter-individual variation is observed in the level of infection (LI) in vivo. High LI is strongly correlated with disease progression and BLV transmission among herd mates. In a context of high prevalence, classical control strategies are economically prohibitive. Alternatively, host genomics studies aiming to dissect loci associated with LI are potentially useful tools for genetic selection programs tending to abrogate the viral spreading. The LI was measured through the proviral load (PVL) set-point and white blood cells (WBC) counts. The goals of this work were to gain insight into the contribution of SNPs (bovine 50KSNP panel) on LI variability and to identify genomics regions underlying this trait. RESULTS: We quantified anti-p24 response and total leukocytes count in peripheral blood from 1800 cows and used these to select 800 individuals with extreme phenotypes in WBCs and PVL. Two case-control genomic association studies using linear mixed models (LMMs) considering population stratification were performed. The proportion of the variance captured by all QC passed SNPs represented 0.63 (SE +/- 0.14) of the phenotypic variance for PVL and 0.56 (SE +/- 0.15) for WBCs. Overall, significant associations (Bonferroni's corrected -log10p > 5.94) were shared for both phenotypes by 24 SNPs within the Bovine MHC. Founder haplotypes were used to measure the linkage disequilibrium (LD) extent (r2 = 0.22 +/- 0.27 at inter-SNP distance of 25-50 kb). The SNPs and LD blocks indicated genes potentially associated with LI in infected cows: i.e. relevant immune response related genes (DQA1, DRB3, BOLA-A, LTA, LTB, TNF, IER3, GRP111, CRISP1), several genes involved in cell cytoskeletal reorganization (CD2AP, PKHD1, FLOT1, TUBB5) and modelling of the extracellular matrix (TRAM2, TNXB). Host transcription factors (TFs) were also highlighted (TFAP2D; ABT1, GCM1, PRRC2A). CONCLUSIONS: Data obtained represent a step forward to understand the biology of BLV-bovine interaction, and provide genetic information potentially applicable to selective breeding programs. PMID- 29439662 TI - Comparative genome analysis of 52 fish species suggests differential associations of repetitive elements with their living aquatic environments. AB - BACKGROUND: Repetitive elements make up significant proportions of genomes. However, their roles in evolution remain largely unknown. To provide insights into the roles of repetitive elements in fish genomes, we conducted a comparative analysis of repetitive elements of 52 fish species in 22 orders in relation to their living aquatic environments. RESULTS: The proportions of repetitive elements in various genomes were found to be positively correlated with genome sizes, with a few exceptions. More importantly, there appeared to be specific enrichment between some repetitive element categories with species habitat. Specifically, class II transposons appear to be more abundant in freshwater bony fish than in marine bony fish when phylogenetic relationship is not considered. In contrast, marine bony fish harbor more tandem repeats than freshwater species. In addition, class I transposons appear to be more abundant in primitive species such as cartilaginous fish and lamprey than in bony fish. CONCLUSIONS: The enriched association of specific categories of repetitive elements with fish habitats suggests the importance of repetitive elements in genome evolution and their potential roles in fish adaptation to their living environments. However, due to the restriction of the limited sequenced species, further analysis needs to be done to alleviate the phylogenetic biases. PMID- 29439663 TI - SALP, a new single-stranded DNA library preparation method especially useful for the high-throughput characterization of chromatin openness states. AB - BACKGROUND: Next-generation sequencing (NGS) is fundamental to the current biological and biomedical research. Construction of sequencing library is a key step of NGS. Therefore, various library construction methods have been explored. However, the current methods are still limited by some shortcomings. RESULTS: This study developed a new NGS library construction method, Single strand Adaptor Library Preparation (SALP), by using a novel single strand adaptor (SSA). SSA is a double-stranded oligonucleotide with a 3' overhang of 3 random nucleotides, which can be efficiently ligated to the 3' end of single strand DNA by T4 DNA ligase. SALP can be started with any denatured DNA fragments such as those sheared by Tn5 tagmentation, enzyme digestion and sonication. When started with Tn5-tagmented chromatin, SALP can overcome a key limitation of ATAC-seq and become a high-throughput NGS library construction method, SALP-seq, which can be used to comparatively characterize the chromatin openness state of multiple cells unbiasly. In this way, this study successfully characterized the comparative chromatin openness states of four different cell lines, including GM12878, HepG2, HeLa and 293T, with SALP-seq. Similarly, this study also successfully characterized the chromatin openness states of HepG2 cells with SALP-seq by using 105 to 500 cells. CONCLUSIONS: This study developed a new NGS library construction method, SALP, by using a novel kind of single strand adaptor (SSA), which should has wide applications in the future due to its unique performance. PMID- 29439664 TI - Heart rate-defined sustained attention in infants at risk for autism. AB - BACKGROUND: Although aberrant visual attention has been identified in infants at high familial risk for autism, the developmental emergence of atypical attention remains unclear. Integrating biological measures of attention into prospective high-risk infant studies may inform more nuanced developmental trajectories, clarifying the onset and course of atypical attention and potentially advancing early screening or treatment protocols. Heart rate-defined sustained attention (HRDSA) is a well-validated biological measure of attentional engagement that, in non-clinical infant populations, provides incremental information about attentional engagement beyond looking behaviors alone. The present study aimed to examine the characteristics and clinical correlates of HRDSA in high-risk infants, informing whether HRDSA may operate as a promising biological measure of attention and clinical symptoms in this population. METHODS: We examined age related patterns of HRDSA during a passive looking task in 5- to 14-month-old high-risk infant siblings of children with autism (n = 21) compared to low-risk controls (n = 21), with most participants contributing multiple assessments. Emergent autism features were measured using the Autism Diagnostic Observation Schedule at 24 months. Primary dependent variables included the proportion of time in behavioral attention, proportion of time in HRDSA, and average heart rate deceleration during HRDSA. For each variable, we used nested multilevel models to examine whether attention differed by group, as well as whether attention predicted emergent autism features among high-risk infant siblings. RESULTS: As expected, HRDSA served as a global biological measure of attention in high-risk infants, predicting greater variability in group risk status than behavioral looking alone. Among high-risk infants, more severe ASD features were also associated with increasingly shallow heart rate deceleration during HRDSA across development, suggesting abnormal qualities of HRDSA may inform individual differences within this population. CONCLUSIONS: These preliminary findings provide initial evidence that HRDSA may offer a sensitive, affordable, and portable biological measure of attention that may enhance understanding of atypical attention in high-risk infants. Using this method, we also provide initial evidence that atypical patterns of heart activity previously reported in children and adults with autism may emerge in the first year of life, warranting further study of how HRDSA may specifically inform attention profiles in ASD. PMID- 29439665 TI - Metagenomic analysis of microbial community and function involved in cd contaminated soil. AB - BACKGROUND: Soil contaminated with the heavy metal Cadmium (Cd) is a widespread problem in many parts of the world. Based on metagenomic analysis, we investigated the functional potential and structural diversity of the microbial community in Cd-contaminated and non-contaminated soil samples and we explored the associated metabolic pathway network in cluster of orthologous groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: The results showed that microorganisms in these soils were quite abundant, and many of them possessed numerous physiological functions. However, Cd-contamination has the potential to reduce the microbial diversity and further alter the community structure in the soil. Notably, function analysis of the crucial microorganisms (e. g. Proteobacteria, Sulfuricella and Thiobacillus) indicated that these bacteria and their corresponding physiological functions were important for the community to cope with Cd pollution. The COG annotation demonstrated that the predominant category was the microbial metabolism cluster in both soil samples, while the relative abundance of metabolic genes was increased in the Cd contaminated soil. The KEGG annotation results exhibited that the non contaminated soil had more genes, pathways, modules, orthologies and enzymes involved in metabolic pathways of microbial communities than the Cd-contaminated soil. The relative abundance of some dominant KEGG pathways increased in the Cd contaminated soil, and they were mostly enriched to the metabolism, biosynthesis and degradation of amino acids, fatty acids and nucleotides, which was related to Cd tolerance of the microorganisms. CONCLUSIONS: Cd-contamination can decrease the taxonomic species of microbes in soil and change the soil microbial composition. The functional pathways involved in the soil change with microbial structure variation, many of which are related to the heavy metal tolerance of soil microbes. The Cd-contaminated soil microbes is a potential resource for exploring cadmium resistant or tolerant bacteria. PMID- 29439666 TI - Prevalence and causes of low vision and blindness in an elderly population in Nepal: the Bhaktapur retina study. AB - BACKGROUND: This study aims to explore the prevalence and causes of low vision and blindness focused on retinal disease in a population above 60 years in Nepal. METHODS: Two thousand one hundred subjects were enrolled in a population-based cross-sectional study. History, presenting and best corrected visual acuity after subjective refraction, anterior and posterior segment examinations was obtained in detail. RESULTS: Among the total subjects, 1860 (88.57%) had complete information. Age varies from 60 to 95 (mean age: 69.64 +/- 7.31) years. Low vision and blindness in both eyes at presentation was found in 984 (52.90%, 95% confidence interval (CI): 50.60-55.19) and 36 (1.94%, 95% CI: 1.35-2.66) subjects respectively. After best correction, bilateral low vision and blindness was found in 426 (22.92%, 95% CI: 21.01-24.88), and 30 (1.61%, 95% CI: 0.10-2.30) subjects respectively. As compared to 60-69 years old, risk of visual impairment was four times higher (95% CI:3.26-5.58) in the 70-79 year olds and 14 times higher (95% CI: 9.72-19.73) in the age group 80 years and above. Major causes of bilateral low vision were cataract (68.07%), followed by retinal disorders (28.64%), and for blindness; retinal disorders (46.66%), followed by cataract (43.33%). Illiteracy was significantly associated with visual impairment. CONCLUSION: Among the elderly population, prevalence of visual impairment was high. Refractive error, cataract and retinal disorders were the major cause of low vision. Screening the population at the age 60 years and above, focused on cataract and posterior segment diseases, providing glasses and timely referral can help reduce visual impairment. PMID- 29439667 TI - Impact of PKCepsilon downregulation on autophagy in glioblastoma cells. AB - BACKGROUND: Several efforts have been focused on identification of pathways involved in malignancy, progression, and response to treatment in Glioblastoma (GB). Overexpression of PKCepsilon was detected in histological samples from GB, anaplastic astrocytoma, and gliosarcoma and is considered an important marker of negative disease outcome. In multiple studies on GB, autophagy has been shown as a survival mechanism during cellular stress, contributing to resistance against anti-cancer agents. The main object of this research was to determine the influence of PKCepsilon downregulation on the expression of genes involved in autophagy pathways in glioblastoma cell lines U-138 MG and U-118 MG with high PKCepsilon level. METHODS: We conducted siRNA-mediated knockdown of PKCepsilon in glioblastoma cell lines and studied the effects of autophagy pathway. The expression of autophagy-related genes was analyzed using qPCR and Western blot analysis was carried out to assess protein levels. Immunostaining was used to detect functional autophagic maturation process. RESULTS: We found that these cell lines exhibited a high basal expression of autophagy-related genes. Our results suggest that the loss of PKCepsilon contributes to the downregulation of genes involved in autophagy pathways. Moreover, most of the changes we observed in Western blot analysis and endogenous immunofluorescence experiments confirmed dysfunction of autophagy programs. We found that knockdown of PKCepsilon induced a decrease in the expression of Beclin1, Atg5, PI3K, whereas the expression of other autophagy-related proteins mTOR and Bcl2 was increased. Treatment of control siRNA glioma cells with rapamycin-induced autophagosome formation and increase in LC3-II level and caused a decrease in the expression of p62. Additionally, PKCepsilon siRNA caused a diminution in the Akt phosphorylation at Ser473 and in the protein level in both cell lines. Moreover, we observed reduction in the adhesion of glioblastoma cells, accompanied by the decrease in total FAK protein level and phosphorylation. CONCLUSIONS: Effects of down regulation of PKCepsilon in glioma cells raised the possibility that the expression of PKCepsilon is essential for the autophagic signal transduction pathways in these cells. Thus, our results identify an important role of PKCepsilon in autophagy and may, more importantly, identifyit as a novel therapeutic target. PMID- 29439668 TI - HIPECT4: multicentre, randomized clinical trial to evaluate safety and efficacy of Hyperthermic intra-peritoneal chemotherapy (HIPEC) with Mitomycin C used during surgery for treatment of locally advanced colorectal carcinoma. AB - BACKGROUND: Local relapse and peritoneal carcinomatosis (PC) for pT4 colon cancer is estimated in 15,6% and 36,7% for 12 months and 36 months from surgical resection respectively, achieving a 5 years overall survival of 6%. There are promising results using prophylactic HIPEC in this group of patients, and it is estimated that up to 26% of all T4 colon cancer could benefit from this treatment with a minimal morbidity. Adjuvant HIPEC is effective to avoid the possibility of peritoneal seeding after surgical resection. Taking into account these results and the cumulative experience in HIPEC use, we will lead a randomized controlled trial to determine the effectiveness and safety of adjuvant treatment with HIPEC vs. standard treatment in patients with colon cancer at high risk of peritoneal recurrence (pT4). METHODS/DESIGN: The aim of this study is to determine the effectiveness and safety of adjuvant HIPEC in preventing the development of PC in patients with colon cancer with a high risk of peritoneal recurrence (cT4). This study will be carried out in 15 Spanish HIPEC centres. Eligible for inclusion are patients who underwent curative resection for cT4NxM0 stage colon cancer. After resection of the primary tumour, 200 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously after the primary resection. Mitomycin C will be used as chemotherapeutic agent, for 60 min at 42-43 degrees C. Primary endpoint is loco regional control (LC) in months and the rate of loco-regional control (%LC) at 12 months and 36 months after resection. DISCUSSION: We assumed that adjuvant HIPEC will reduce the expected absolute risk of peritoneal recurrence from 36% to 18% at 36 months for T4 colon-rectal carcinoma. TRIAL REGISTRATION: NCT02614534 ( clinicaltrial.gov ) Nov-2015. PMID- 29439669 TI - A novel miR-375-HOXB3-CDCA3/DNMT3B regulatory circuitry contributes to leukemogenesis in acute myeloid leukemia. AB - BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies due to sophisticated genetic mutations and epigenetic dysregulation. MicroRNAs (miRNAs), a class of small non-coding RNAs, are important regulators of gene expression in all biological processes, including leukemogenesis. Recently, miR-375 has been reported to be a suppressive miRNA in multiple types of cancers, but its underlying anti-leukemia activity in AML is largely unknown. METHODS: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure the expression of miR-375 and HOXB3 in leukemic cells and normal controls. Targets of miR-375 were confirmed by western blot and luciferase assay. Phenotypic effects of miR-375 overexpression and HOXB3 knockdown were assessed using viability (trypan blue exclusion assay), colony formation/replating, as well as tumor xenograft assays in vivo. RESULTS: The expression of miR-375 was substantially decreased in leukemic cell lines and primary AML blasts compared with normal controls, because DNA hypermethylation of precursor-miR-375 (pre-miR 375) promoter was discovered in leukemic cells but not in normal controls. Lower expression of miR-375 predicted poor outcome in AML patients. Furthermore, forced expression of miR-375 not only decreased proliferation and colony formation in leukemic cells but also reduced xenograft tumor size and prolonged the survival time in a leukemia xenograft mouse model. Mechanistically, overexpression of miR 375 reduced HOXB3 expression and repressed the activity of a luciferase reporter through binding 3'-untranslated regions (3'-UTR) of HOXB3 mRNA. Overexpression of HOXB3 partially blocked miR-375-induced arrest of proliferation and reduction of colony number, suggesting that HOXB3 plays an important role in miR-375-induced anti-leukemia activity. Knockdown of HOXB3 by short hairpin RNAs reduced the expression of cell division cycle associated 3 (CDCA3), which decreased cell proliferation. Furthermore, HOXB3 induced DNA methyltransferase 3B (DNMT3B) expression to bind in the pre-miR-375 promoter and enhanced DNA hypermethylation of pre-miR-375, leading to the lower expression of miR-375. CONCLUSIONS: Collectively, we have identified a miR-375-HOXB3-CDCA3/DNMT3B regulatory circuitry which contributes to leukemogenesis and suggests a therapeutic strategy of restoring miR-375 expression in AML. PMID- 29439670 TI - Phase I study of an active immunotherapy for asymptomatic phase Lymphoplasmacytic lymphoma with DNA vaccines encoding antigen-chemokine fusion: study protocol. AB - BACKGROUND: There is now a renewed interest in cancer vaccines. Patients responding to immune checkpoint blockade usually bear tumors that are heavily infiltrated by T cells and express a high load of neoantigens, indicating that the immune system is involved in the therapeutic effect of these agents; this finding strongly supports the use of cancer vaccine strategies. Lymphoplasmacytic lymphoma (LPL) is a low grade, incurable disease featuring an abnormal proliferation of Immunoglobulin (Ig)-producing malignant cells. Asymptomatic patients are currently managed by a "watchful waiting" approach, as available therapies provide no survival advantage if started before symptoms develop. Idiotypic determinants of a lymphoma surface Ig, formed by the interaction of the variable regions of heavy and light chains, can be used as a tumor-specific marker and effective vaccination using idiotypes was demonstrated in a positive controlled phase III trial. METHODS: These variable region genes can be cloned and used as a DNA vaccine, a delivery system holding tremendous potential for streamlining vaccine production. To increase vaccination potency, we are targeting antigen-presenting cells (APCs) by fusing the antigen with a sequence encoding a chemokine (MIP-3alpha), which binds an endocytic surface receptor on APCs. Asymptomatic phase LPL is an excellent model to test our vaccine since patients have not received chemotherapeutics that interfere with innate immune function and have low tumor burden. We are evaluating the safety of this next generation DNA vaccine in a first-in-human clinical trial currently enrolling asymptomatic LPL patients. To elucidate the mode of action of this vaccine, we will assess its ability to generate tumor-specific immune responses and examine changes in the immune profile of both the peripheral blood and bone marrow. DISCUSSION: This vaccine could shift the current paradigm of clinical management for patients with asymptomatic LPL and inform development of other personalized approaches. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01209871; registered on September 24, 2010. PMID- 29439671 TI - Treatment using oxaliplatin and S-1 adjuvant chemotherapy for pathological stage III gastric cancer: a multicenter phase II study (TOSA trial) protocol. AB - BACKGROUND: Recent studies demonstrated the efficacy of S-1-based adjuvant chemotherapy administered for six months after curative surgery for stage III gastric cancer; however, it is unproven whether this type of combination chemotherapy is more effective than the standard adjuvant chemotherapy of S-1 for one year. METHODS: This multicenter phase II study evaluate the efficacy and safety of adjuvant chemotherapy using S-1 plus oxaliplatin followed by S-1 for up to one year for curatively resected stage III gastric cancer in patients aged over 20 years. Treatment initially comprises oral fluoropyrimidine S-1 (80 mg/m2) administered twice daily for the first 2 weeks of a 3-week cycle. On day 1 of a second 3-week cycle, patients will receive 100 mg/m2 of intravenous oxaliplatin followed by 80 mg/m2 of S-1 (maximum 8 cycles). Then, the patients will receive 80 mg/m2 of S-1 daily for 4 weeks, followed by 2 weeks of no chemotherapy. This 6 week cycle will be repeated during the first year after surgery. The primary endpoint is relapse-free survival for 3 years and secondary endpoints are safety, including the incidence of adverse events, and grading of neuropathy with each treatment cycle. The planned sample size of 75 patients is appropriate for this trial. The data will be analyzed on an intention-to-treat basis, assuming a two sided test with a 5% level of significance. DISCUSSION: In contrast to previous trials, the current study involves administration of S-1 until one year after surgery in addition to prior S-1 plus oxaliplatin, and is the first study to evaluate the safety and efficacy of S-1 plus oxaliplatin followed by S-1 for up to one year in patients with curatively resected stage III gastric cancer. TRIAL REGISTRATION: This trial is registered in the University Hospital Medical Information Network's Clinical Trials Registry (UMIN-CTR) registration number, R000029656 ( https://upload.umin.ac.jp/cgi-open bin/ctr_e/ctr_view.cgi?recptno=R000029656 ). Registered January 24, 2017. PMID- 29439672 TI - Renal manifestations of tuberous sclerosis complex: patients' and parents' knowledge and routines for renal follow-up - a questionnaire study. AB - BACKGROUND: Renal angiomyolipomas (AMLs) are a major clinical feature in patients with tuberous sclerosis complex (TSC). Spontaneous bleeding can be life threatening, and appropriate information and proper surveillance and management are important to limit morbidity and mortality. Because TSC is a rare disease, patients are at risk of suboptimal medical management. Our aim was to investigate patients' and parents' knowledge about renal angiomyolipomas (AMLs) in Tuberous Sclerosis Complex (TSC) and to identify current routines for renal follow-up. METHODS: A questionnaire survey was initiated by the French Reference Centre on TSC. It was distributed in France through university hospitals and the patients' association (2009-2011), and to patients registered by the Norwegian National Centre for Rare Epilepsy-Related Disorders (2013-2014). Contingency tables with Chi-Square test for independence (with Yates Continuity Correction) and Pearson Chi-Square value were used for correlation statistics. RESULTS: We included 357 patients (France, n=257; Norway n=100). Most participants knew that TSC is associated with AMLs. However, 42 % did not know about the risk of AMLrelated bleeding, and 37 % had been informed about the risk of bleeding only after the age of 15 years. Furthermore, 14 % did not know whether they themselves or their child had AMLs. Patients had less knowledge than parents. Medical consultations and patient associations were the main sources of information. Among 30 % of patients, renal imaging was not received at all, or not conducted every 1-3 years, as recommended by current guidelines. Regular imaging was more frequent in patients with AMLs < 15 years, than in patients with AMLs >= 15 years. Ultrasound was the most frequently used imaging modality. CONCLUSIONS: Knowledge of renal AML in TSC patients and their parents was lower than expected, and follow-up by renal imaging was suboptimal for a substantial proportion of patients. Patients and parents should be informed about the risk and symptoms of renal bleeding, at the latest when the patient is 15 years. Monitoring the growth of AMLs should be standardized to comply with guidelines. Transition between adolescence and adulthood is a high-risk period and ensuring appropriate follow-up at this time is particularly important. PMID- 29439673 TI - IL-10+ NK and TGF-beta+ NK cells play negative regulatory roles in HIV infection. AB - BACKGROUND: Natural killer (NK) cells play cytotoxic roles by targeting tumor cells or virus infected cells, they also play regulatory roles by secreting cytokines and chemokines. Transforming growth factor (TGF)-beta and interleukin (IL)-10 are important immunosuppressive cytokines potentially related to the immune dysregulation that occurs in the infection of human immunodeficiency virus (HIV). NK cells are an important source of TGF-beta and a main early producer of IL-10 in response to viral infection. Here, we evaluated the percentages of IL 10+ and TGF-beta+ NK cells in HIV-infected patients relative to healthy controls (HCs). METHODS: Study participants (n = 63) included 31 antiretroviral treatment (ART)-naive HIV-infected patients, 17 ART-treated HIV-infected patients, and 15 HIV-negative HCs. Expression of IL-10 or TGF-beta in NK cells was examined by flow cytometry, and the influences of recombinant IL-10 (rIL-10) or recombinant TGF-beta (rTGF-beta) on NK cell function were investigated in vitro. RESULTS: Compared with HCs, ART-naive HIV-infected patients had increased percentages of IL-10+ (2.0% vs. 0.4%, p = 0.015) and TGF-beta+ (4.5% vs. 2.1%, p = 0.022) NK cells, and ART-treated patients also had a higher percentage of IL-10+ NK cells (2.5% vs. 0.4%, p = 0.002). The percentages of IL-10+ and TGF-beta+ NK cells were positively correlated (r = 0.388; p = 0.010). The results of in vitro experiments demonstrated that rIL-10 and rTGF-beta inhibited NK cell CD107a expression (p = 0.037 and p = 0.024, respectively), IFN-gamma secretion (p = 0.006, p = 0.016, respectively), and granzyme B release after stimulation (p = 0.014, p = 0.040, respectively). CONCLUSIONS: Our data suggest that the percentages of IL-10+ or TGF-beta+ NK cells are increased in HIV-infected patients, and that rIL-10 and/or rTGF-beta can inhibit NK cell functions in vitro, providing a potential therapeutic target for strategies aimed at combating HIV infection. PMID- 29439674 TI - Establishing a clinical phenotype for cachexia in end stage kidney disease - study protocol. AB - BACKGROUND: Surveys using traditional measures of nutritional status indicate that muscle wasting is common among persons with end-stage kidney disease (ESKD). Up to 75% of adults undergoing maintenance dialysis show some evidence of muscle wasting. ESKD is associated with an increase in inflammatory cytokines and can result in cachexia, with the loss of muscle and fat stores. At present, only limited data are available on the classification of wasting experienced by persons with ESKD. Individuals with ESKD often exhibit symptoms of anorexia, loss of lean muscle mass and altered energy expenditure. These symptoms are consistent with the syndrome of cachexia observed in other chronic diseases, such as cancer, heart failure, and acquired immune deficiency syndrome. While definitions of cachexia have been developed for some diseases, such as cardiac failure and cancer, no specific cachexia definition has been established for chronic kidney disease. The importance of developing a definition of cachexia in a population with ESKD is underscored by the negative impact that symptoms of cachexia have on quality of life and the association of cachexia with a substantially increased risk of premature mortality. The aim of this study is to determine the clinical phenotype of cachexia specific to individuals with ESKD. METHODS: A longitudinal study which will recruit adult patients with ESKD receiving haemodialysis attending a Regional Nephrology Unit within the United Kingdom. Patients will be followed 2 monthly over 12 months and measurements of weight; lean muscle mass (bioelectrical impedance, mid upper arm muscle circumference and tricep skin fold thickness); muscle strength (hand held dynamometer), fatigue, anorexia and quality of life collected. We will determine if they experience (and to what degree) the known characteristics associated with cachexia. DISCUSSION: Cachexia is a debilitating condition associated with an extremely poor outcome. Definitions of cachexia in chronic illnesses are required to reflect specific nuances associated with each disease. These discrete cachexia definitions help with the precision of research and the subsequent clinical interventions to improve outcomes for patients suffering from cachexia. The absence of a definition for cachexia in an ESKD population makes it particularly difficult to study the incidence of cachexia or potential treatments, as there are no standardised inclusion criteria for patients with ESKD who have cachexia. Outcomes from this study will provide much needed data to inform development and testing of potential treatment modalities, aimed at enhancing current clinical practice, policy and education. PMID- 29439675 TI - Screening key genes for abdominal aortic aneurysm based on gene expression omnibus dataset. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a common cardiovascular system disease with high mortality. The aim of this study was to identify potential genes for diagnosis and therapy in AAA. METHODS: We searched and downloaded mRNA expression data from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) from AAA and normal individuals. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, transcriptional factors (TFs) network and protein-protein interaction (PPI) network were used to explore the function of genes. Additionally, immunohistochemical (IHC) staining was used to validate the expression of identified genes. Finally, the diagnostic value of identified genes was accessed by receiver operating characteristic (ROC) analysis in GEO database. RESULTS: A total of 1199 DEGs (188 up-regulated and 1011 down-regulated) were identified between AAA and normal individual. KEGG pathway analysis displayed that vascular smooth muscle contraction and pathways in cancer were significantly enriched signal pathway. The top 10 up-regulated and top 10 down-regulated DEGs were used to construct TFs and PPI networks. Some genes with high degrees such as NELL2, CCR7, MGAM, HBB, CSNK2A2, ZBTB16 and FOXO1 were identified to be related to AAA. The consequences of IHC staining showed that CCR7 and PDGFA were up-regulated in tissue samples of AAA. ROC analysis showed that NELL2, CCR7, MGAM, HBB, CSNK2A2, ZBTB16, FOXO1 and PDGFA had the potential diagnostic value for AAA. CONCLUSIONS: The identified genes including NELL2, CCR7, MGAM, HBB, CSNK2A2, ZBTB16, FOXO1 and PDGFA might be involved in the pathology of AAA. PMID- 29439676 TI - Evolution of CYP2J19, a gene involved in colour vision and red coloration in birds: positive selection in the face of conservation and pleiotropy. AB - BACKGROUND: Exaggerated signals, such as brilliant colours, are usually assumed to evolve through antagonistic coevolution between senders and receivers, but the underlying genetic mechanisms are rarely known. Here we explore a recently identified "redness gene", CYP2J19, that is highly interesting in this context since it encodes a carotenoid-modifying enzyme (a C4 ketolase involved in both colour signalling and colour discrimination in the red (long wavelength) spectral region.) RESULTS: A single full-length CYP2J19 was retrieved from 43 species out of 70 avian genomes examined, representing all major avian clades. In addition, CYP2J19 sequences from 13 species of weaverbirds (Ploceidae), seven of which have red C4-ketocarotenoid coloration were analysed. Despite the conserved retinal function and pleiotropy of CYP2J19, analyses indicate that the gene has been positively selected throughout the radiation of birds, including sites within functional domains described in related CYP (cytochrome P450) loci. Analyses of eight further CYP loci across 25 species show that positive selection is common in this gene family in birds. There was no evidence for a change in selection pressure on CYP2J19 following co-option for red coloration in the weaverbirds. CONCLUSIONS: The results presented here are consistent with an ancestral conserved function of CYP2J19 in the pigmentation of red retinal oil droplets used for colour vision, and its subsequent co-option for red integumentary coloration. The cause of positive selection on CYP2J19 is unclear, but may be partly related to compensatory mutations related to selection at the adjacent gene CYP2J40. PMID- 29439677 TI - Trajectory of vitamin D status during pregnancy in relation to neonatal birth size and fetal survival: a prospective cohort study. AB - BACKGROUND: We investigated the associations between vitamin D status in early and late pregnancy with neonatal small for gestational age (SGA), low birth weight (LBW) and preterm delivery. Furthermore, associations between vitamin D status and pregnancy loss were studied. METHODS: Serum 25-hydroxyvitamin D (25OHD) was sampled in gestational week <= 16 (trimester 1 (T1), N = 2046) and > 31 (trimester 3 (T3), N = 1816) and analysed using liquid chromatography tandem mass spectrometry. Pregnant women were recruited at antenatal clinics in south west Sweden at latitude 57-58 degrees N. Gestational and neonatal data were retrieved from medical records. Multiple gestations and terminated pregnancies were excluded from the analyses. SGA was defined as weight and/or length at birth < 2 SD of the population mean and LBW as < 2500 g. Preterm delivery was defined as delivery < 37 + 0 gestational weeks and pregnancy loss as spontaneous abortion or intrauterine fetal death. Associations between neonatal outcomes and 25OHD at T1, T3 and change in 25OHD (T3-T1) were studied using logistic regression. RESULTS: T1 25OHD was negatively associated with pregnancy loss and 1 nmol/L increase in 25OHD was associated with 1% lower odds of pregnancy loss (OR 0.99, p = 0.046). T3 25OHD >= 100 nmol/L (equal to 40 ng/ml) was associated with lower odds of SGA (OR 0.3, p = 0.031) and LBW (OR 0.2, p = 0.046), compared to vitamin D deficiency (25OHD < 30 nmol/L, or 12 ng/ml). Women with a >= 30 nmol/L increment in 25OHD from T1 to T3 had the lowest odds of SGA, LBW and preterm delivery. CONCLUSIONS: Vitamin D deficiency in late pregnancy was associated with higher odds of SGA and LBW. Lower 25OHD in early pregnancy was only associated with pregnancy loss. Vitamin D status trajectory from early to late pregnancy was inversely associated with SGA, LBW and preterm delivery with the lowest odds among women with the highest increment in 25OHD. Thus, both higher vitamin D status in late pregnancy and gestational vitamin D status trajectory can be suspected to play a role in healthy pregnancy. PMID- 29439678 TI - Correlation between global methylation level of peripheral blood leukocytes and serum C reactive protein level modified by MTHFR polymorphism: a cross-sectional study. AB - BACKGROUND: Chronic inflammatory conditions are associated with higher tumor incidence through epigenetic and genetic alterations. Here, we focused on an association between an inflammation marker, C-reactive-protein (CRP), and global DNA methylation levels of peripheral blood leukocytes. METHODS: The subjects were 384 healthy Japanese women enrolled as the control group of a case-control study for breast cancer conducted from 2001 to 2005. Global DNA methylation was quantified by Luminometric Methylation Assay (LUMA). RESULTS: With adjustment for lifestyle-related factors, including folate intake, the global DNA methylation level of peripheral blood leukocytes was significantly but weakly increased by 0.43% per quartile category for CRP (P for trend = 0.010). Estimated methylation levels stratified by CRP quartile were 70.0%, 70.8%, 71.4%, and 71.3%, respectively. In addition, interaction between polymorphism of MTHFR (rs1801133, known as C677T) and CRP was significant (P for interaction = 0.046); the global methylation level was significantly increased by 0.61% per quartile category for CRP in the CT/TT group (those with the minor allele T, P for trend = 0.001), whereas no association was observed in the CC group (wild type). CONCLUSIONS: Our study suggests that CRP concentration is weakly associated with global DNA methylation level. However, this association was observed more clearly in individuals with the minor allele of the MTHFR missense SNP rs1801133. By elucidating the complex mechanism of the regulation of DNA methylation by both acquired and genetic factors, our results may be important for cancer prevention. PMID- 29439679 TI - Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India. AB - BACKGROUND: Maturity-onset diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. METHODS: In this study, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Further, we have analyzed exome data to identify putative MODY relevant variants in genes previously not implicated in MODY. Functional validation of MODY relevant variants was also performed. RESULTS: We found MODY 3 (HNF1A; 7.2%) to be most frequently mutated followed by MODY 12 (ABCC8; 3.3%). They together account for ~ 11% of the cases. In addition to known MODY genes, we report the identification of variants in RFX6, WFS1, AKT2, NKX6-1 that may contribute to development of MODY. Functional assessment of the NKX6-1 variants showed that they are functionally impaired. CONCLUSIONS: Our findings showed HNF1A and ABCC8 to be the most frequently mutated MODY genes in south India. Further we provide evidence for additional MODY relevant genes, such as NKX6-1, and these require further validation. PMID- 29439680 TI - Microtiter miniature shaken bioreactor system as a scale-down model for process development of production of therapeutic alpha-interferon2b by recombinant Escherichia coli. AB - BACKGROUND: Demand for high-throughput bioprocessing has dramatically increased especially in the biopharmaceutical industry because the technologies are of vital importance to process optimization and media development. This can be efficiently boosted by using microtiter plate (MTP) cultivation setup embedded into an automated liquid-handling system. The objective of this study was to establish an automated microscale method for upstream and downstream bioprocessing of alpha-IFN2b production by recombinant Escherichia coli. The extraction performance of alpha-IFN2b by osmotic shock using two different systems, automated microscale platform and manual extraction in MTP was compared. RESULTS: The amount of alpha-IFN2b extracted using automated microscale platform (49.2 MUg/L) was comparable to manual osmotic shock method (48.8 MUg/L), but the standard deviation was 2 times lower as compared to manual osmotic shock method. Fermentation parameters in MTP involving inoculum size, agitation speed, working volume and induction profiling revealed that the fermentation conditions for the highest production of alpha-IFN2b (85.5 MUg/L) was attained at inoculum size of 8%, working volume of 40% and agitation speed of 1000 rpm with induction at 4 h after the inoculation. CONCLUSION: Although the findings at MTP scale did not show perfect scalable results as compared to shake flask culture, but microscale technique development would serve as a convenient and low-cost solution in process optimization for recombinant protein. PMID- 29439681 TI - Associations between perceived stress, socioeconomic status, and health-risk behaviour in deprived neighbourhoods in Denmark: a cross-sectional study. AB - BACKGROUND: Previous studies have found that residents of deprived neighbourhoods have an increased risk of perceived stress compared to residents with similar sociodemographic and socioeconomic characteristics in non-deprived neighbourhoods. While stress may provide an explanatory pathway linking neighbourhood deprivation to health-risk behaviour, only limited research has been undertaken on whether perceived stress influences health-risk behaviour in deprived neighbourhoods. Moreover, it is uncertain whether perceived stress has a negative effect on the associations between socioeconomic status and health-risk behaviours in deprived neighbourhoods. The overall aim of this study was to compare perceived stress in deprived neighbourhood with that in the general population, and to examine whether perceived stress was associated with health risk behaviours (including their co-occurrence) in deprived neighbourhoods. A further aim was to examine whether perceived stress modified the associations between socioeconomic status and health-risk behaviours. METHODS: Four questions from the Perceived Stress Scale were used as indicators of perceived stress. Multiple logistic regression analyses were applied to cross-sectional data from 5113 adults living in 12 deprived neighbourhoods in Denmark. Data from 14,868 individuals from the nationally representative Danish Health and Morbidity Survey 2010 were used as a comparison group with regard to perceived stress. RESULTS: Residents of deprived neighbourhoods had higher odds of perceived stress than the general population. Associations between disposable income, economic deprivation, strain, and perceived stress were found in deprived neighbourhoods. Perceived stress was significantly associated with higher odds of health-risk behaviour, including a low intake of fruit or vegetables, daily smoking, physical inactivity, and the co-occurrence of health-risk behaviours, even after adjustment for demographic and socioeconomic characteristics. Perceived stress was more strongly associated with physical inactivity and having two or more health-risk behaviours among residents with medium/high socioeconomic status compared to residents with low socioeconomic status. CONCLUSIONS: Overall, the study showed a clear association between perceived stress and health-risk behaviour in deprived neighbourhoods. Future health promotion interventions targeting deprived neighbourhoods may benefit from incorporating stress reduction strategies to reduce health-risk behaviour. Further research is needed to fully understand the mechanism underlying the association between perceived stress and health-risk behaviour in deprived neighbourhoods. PMID- 29439682 TI - The factors affecting household transmission dynamics and community compliance with Ebola control measures: a mixed-methods study in a rural village in Sierra Leone. AB - BACKGROUND: Little is understood of Ebola virus disease (EVD) transmission dynamics and community compliance with control measures over time. Understanding these interactions is essential if interventions are to be effective in future outbreaks. We conducted a mixed-methods study to explore these factors in a rural village that experienced sustained EVD transmission in Kailahun District, Sierra Leone. METHODS: We reconstructed transmission dynamics using a cross-sectional survey conducted in April 2015, and cross-referenced our results with surveillance, burial, and Ebola Management Centre (EMC) data. Factors associated with EVD transmission were assessed with Cox proportional hazards regression. Following the survey, qualitative semi-structured interviews explored views of community informants and households. RESULTS: All households (n = 240; 1161 individuals) participated in the survey. 29 of 31 EVD probable/confirmed cases died (93.5% case fatality rate); six deaths (20.6%) had been missed by other surveillance systems. Transmission over five generations lasted 16 weeks. Although most households had <=5 members there was a significant increase in risk of Ebola in households with > 5 members. Risk of EVD was also associated with older age. Cases were spatially clustered; all occurred in 15 households. EVD transmission was better understood when the community experience started to concord with public health messages being given. Perceptions of contact tracing changed from invading privacy and selling people to ensuring community safety. Burials in plastic bags, without female attendants or prayer, were perceived as dishonourable. Further reasons for low compliance were low EMC survival rates, family perceptions of a moral duty to provide care to relatives, poor communication with the EMC, and loss of livelihoods due to quarantine. Compliance with response measures increased only after the second generation, coinciding with the implementation of restrictive by-laws, return of the first survivor, reduced contact with dead bodies, and admission of patients to the EMC. CONCLUSIONS: Transmission occurred primarily in a few large households, with prolonged transmission and a high death toll. Return of a survivor to the village and more effective implementation of control strategies coincided with increased compliance to control measures, with few subsequent cases. We propose key recommendations for management of EVD outbreaks based on this experience. PMID- 29439683 TI - Elevated central venous pressure is associated with increased mortality in pediatric septic shock patients. AB - BACKGROUND: Central venous pressure (CVP) is an important factor affecting capillary blood flow, and it is associated with poor outcomes in adult septic shock patients. However, whether a similar association exists in pediatric patients remains unclear. METHODS: We retrospectively analyzed data from patients admitted to our pediatric intensive care unit (PICU) between February 2009 and July 2015. Patients were divided into two groups-survivors and nonsurvivors according to 28-day mortality. The associations between (a) mortality and CVP at 6, 24, 48, and 72 h after initiating treatment for established septic shock was analyzed and (b) initial serum lactic acid levels and 6-h CVP. RESULTS: Two hundred twenty-six patients were included in this study, and the mortality rate was 29.6% (67 deaths, nonsurvivor group). Initial serum lactic acid levels, Pediatric Risk of Mortality (PRISM) III score, and Vasoactive-Inotropic Score (VIS) within 24 h after PICU admission were significantly higher in the nonsurvivors than in survivors (1.3 [0.9, 2.4] vs. 3.9 [1.6, 8.0] mmol/l, 11.0 [7.0, 15.0] vs. 17.0 [10.0, 21.5], 12.0 [7.0, 25.0] vs. 22.5 [8.0, 55.0], respectively with p-values < 0.001, < 0.001, and 0.009, respectively). In addition, compared to survivors, a greater percentage of nonsurvivors required mechanical ventilation (92.5% vs. 51.6%, p < 0.001) and showed a greater extent of fluid overload at 48 h after admission (3.9% vs. 1.9%, p = 0.006), along with higher 6-h CVP (10.0 [7.0, 16.0] vs. 8.0 [5.0, 11.0] mmHg, p < 0.001). Patient survival according to levels of CVP (CVP < 8 mmHg, CVP 8-12 mmHg, or CVP > 12 mmHg) showed that the CVP > 12-mmHg group had significantly greater mortality rates (50.0%, p = 0.002) than the other groups (21.3% and 27.5%). Furthermore, multivariate analysis identified significant associations of CVP > 12 mmHg, serum lactic acid levels, and the need for mechanical ventilation with mortality (OR: 2.74, 1.30, and 12.51, respectively; 95% CI: 1.11-6.72, 1.12-1.50, and 4.12 37.96, respectively). CONCLUSIONS: Elevated CVP is an independent risk factor for mortality in pediatric septic shock patients. PMID- 29439684 TI - Prediction of post-acute care demand in medical and neurological inpatients: diagnostic assessment of the post-acute discharge score - a prospective cohort study. AB - BACKGROUND: Early identification of patients requiring transfer to post-acute care (PAC) facilities shortens hospital stays. With a focus on interprofessional assessment of biopsychosocial risk, this study's aim was to assess medical and neurological patients' post-acute care discharge (PACD) scores on days 1 and 3 after hospital admission regarding diagnostic accuracy and effectiveness as an early screening tool. The transfer to PAC facilities served as the outcome ("gold standard"). METHODS: In this prospective cohort study, registered at ClinicalTrial.gov (NCT01768494) on January 2013, 1432 medical and 464 neurological patients (total n = 1896) were included consecutively between February and October 2013. PACD scores and other relevant data were extracted from electronic records of patient admissions, hospital stays, and interviews at day 30 post-hospital admission. To gauge the scores' accuracy, we plotted receiver operating characteristic (ROC) curves, calculated area under the curve (AUC), and determined sensitivity and specificity at various cut-off levels. RESULTS: Medical patients' day 1 and day 3 PACD scores accurately predicted discharge to PAC facilities, with respective discriminating powers (AUC) of 0.77 and 0.82. With a PACD cut-off of >=8 points, day 1 and 3 sensitivities were respectively 72.6% and 83.6%, with respective specificities of 66.5% and 70.0%. Neurological patients' scores showed lower accuracy both days: using the same cut off, respective day 1 and day 3 AUCs were 0.68 and 0.78, sensitivities 41.4% and 68.7% and specificities 81.4% and 83.4%. CONCLUSION: PACD scores at days 1 and 3 accurately predicted transfer to PAC facilities, especially in medical patients on day 3. To confirm and refine these results, PACD scores' value to guide discharge planning interventions and subsequent impact on hospital stay warrants further investigation. TRIAL REGISTRATION: ClinialTrials.gov Identifier, NCT01768494 . PMID- 29439685 TI - Morphological characteristics of the posterior malleolar fragment according to ankle fracture patterns: a computed tomography-based study. AB - BACKGROUND: The posterior malleolar fragment (PMF) of an ankle fracture can have various shapes depending on the injury mechanism. The purpose of this study was to evaluate the morphological characteristics of the PMF according to the ankle fracture pattern described in the Lauge-Hansen classification by using computed tomography (CT) images. METHODS: We retrospectively analyzed CT data of 107 patients (107 ankles) who underwent surgery for trimalleolar fracture from January 2012 to December 2014. The patients were divided into two groups: 76 ankles in the supination-external rotation (SER) stage IV group and 31 ankles in the pronation-external rotation (PER) stage IV group. The PMF type of the two groups was assessed using the Haraguchi and Jan Bartonicek classification. The cross angle (alpha), fragment length ratio (FLR), fragment area ratio (FAR), sagittal angle (theta), and fragment height (FH) were measured to assess the morphological characteristics of the PMF. RESULTS: The PMF in the SER group mainly had a posterolateral shape, whereas that in the PER group mainly had a posteromedial two-part shape or a large posterolateral triangular shape (P = 0.02). The average cross angle was not significantly different between the two groups (SER group = 19.4 degrees , PER group = 17.6 degrees ). The mean FLR and FH were significantly larger in the PER group than in the SER group (P = 0.024, P = 0.006). The mean fragment sagittal angle in the PER group was significantly smaller than that in the SER group (P = 0.017). CONCLUSIONS: With regard to the articular involvement, volume, and vertical nature, the SER-type fracture tends to have a smaller fragment due to the rotational force, whereas the PER-type fracture tends to have a larger fragment due to the combination of rotational and axial forces. PMID- 29439686 TI - Genetically encoded calcium indicator with NTnC-like design and enhanced fluorescence contrast and kinetics. AB - BACKGROUND: The recently developed genetically encoded calcium indicator (GECI), called NTnC, has a novel design with reduced size due to utilization of the troponin C (TnC) as a Ca2+-binding moiety inserted into the mNeonGreen fluorescent protein. NTnC binds two times less Ca2+ ions while maintaining a higher fluorescence brightness at the basal level of Ca2+ in neurons as compared with the calmodulin-based GECIs, such as GCaMPs. In spite of NTnC's high brightness, pH-stability, and high sensitivity to single action potentials, it has a limited fluorescence contrast (F-Ca2+/F+Ca2+) and slow Ca2+ dissociation kinetics. RESULTS: Herein, we developed a new NTnC-like GECI with enhanced fluorescence contrast and kinetics by replacing the mNeonGreen fluorescent subunit of the NTnC indicator with EYFP. Similar to NTnC, the developed indicator, named iYTnC2, has an inverted fluorescence response to Ca2+ (i.e. becoming dimmer with an increase of Ca2+ concentration). In the presence of Mg2+ ions, iYTnC2 demonstrated a 2.8-fold improved fluorescence contrast in vitro as compared with NTnC. The iYTnC2 indicator has lower brightness and pH-stability, but similar photostability as compared with NTnC in vitro. Stopped-flow fluorimetry studies revealed that iYTnC2 has 5-fold faster Ca2+ dissociation kinetics than NTnC. When compared with GCaMP6f GECI, iYTnC2 has up to 5.6-fold faster Ca2+ association kinetics and 1.7-fold slower dissociation kinetics. During calcium transients in cultured mammalian cells, iYTnC2 demonstrated a 2.7 fold higher fluorescence contrast as compared with that for the NTnC. iYTnC2 demonstrated a 4-fold larger response to Ca2+ transients in neuronal cultures than responses of NTnC. iYTnC2 response in neurons was additionally characterized using whole-cell patch clamp. Finally, we demonstrated that iYTnC2 can visualize neuronal activity in vivo in the hippocampus of freely moving mice using a nVista miniscope. CONCLUSIONS: We demonstrate that expanding the family of NTnC-like calcium indicators is a promising strategy for the development of the next generation of GECIs with smaller molecule size and lower Ca2+ ions buffering capacity as compared with commonly used GECIs. PMID- 29439687 TI - 3D analysis of Osteosyntheses material using semi-automated CT segmentation: a case series of a 4 corner fusion plate. AB - BACKROUND: Scaphoidectomy and midcarpal fusion can be performed using traditional fixation methods like K-wires, staples, screws or different dorsal (non)locking arthrodesis systems. The aim of this study is to test the Aptus four corner locking plate and to compare the clinical findings to the data revealed by CT scans and semi-automated segmentation. METHODS: This is a retrospective review of eleven patients suffering from scapholunate advanced collapse (SLAC) or scaphoid non-union advanced collapse (SNAC) wrist, who received a four corner fusion between August 2011 and July 2014. The clinical evaluation consisted of measuring the range of motion (ROM), strength and pain on a visual analogue scale (VAS). Additionally, the Disabilities of the Arm, Shoulder and Hand (QuickDASH) and the Mayo Wrist Score were assessed. A computerized tomography (CT) of the wrist was obtained six weeks postoperatively. After semi-automated segmentation of the CT scans, the models were post processed and surveyed. RESULTS: During the six-month follow-up mean range of motion (ROM) of the operated wrist was 60 degrees , consisting of 30 degrees extension and 30 degrees flexion. While pain levels decreased significantly, 54% of grip strength and 89% of pinch strength were preserved compared to the contralateral healthy wrist. Union could be detected in all CT scans of the wrist. While X-ray pictures obtained postoperatively revealed no pathology, two user related technical complications were found through the 3D analysis, which correlated to the clinical outcome. CONCLUSION: Due to semi automated segmentation and 3D analysis it has been proved that the plate design can keep up to the manufacturers' promises. Over all, this case series confirmed that the plate can compete with the coexisting techniques concerning clinical outcome, union and complication rate. PMID- 29439688 TI - Effects of substrate binding site residue substitutions of xynA from Bacillus amyloliquefaciens on substrate specificity. AB - BACKGROUND: The aromatic residues of xylanase enzyme, W187, Y124, W144, Y128 and W63 of substrate binding pocket from Bacillus amyloliquefaciens were investigated for their role in substrate binding by homology modelling and sequence analysis. These residues are highly conserved and play an important role in substrate binding through steric hindrance. The substitution of these residues with alanine allows the enzyme to accommodate nonspecific substrates. RESULTS: Wild type and mutated genes were cloned and overexpressed in BL21. Optimum pH and temperature of rBAxn exhibited pH 9.0 and 50 degrees C respectively and it was stable up to 215 h. Along with the physical properties of rBAxn, kinetic parameters (Km 19.34 +/- 0.72 mg/ml; kcat 6449.12 +/- 155.37 min- 1 and kcat/Km 333.83 +/- 6.78 ml min 1 mg- 1) were also compared with engineered enzymes. Out of five mutations, W63A, Y128A and W144A lost almost 90% activity and Y124A and W187A retained almost 40-45% xylanase activity. CONCLUSIONS: The site-specific single mutation, led to alteration in substrate specificity from xylan to CMC while in case of double mutant the substrate specificity was altered from xylan to CMC, FP and avicel, indicating the role of aromatic residues on substrate binding, catalytic process and overall catalytic efficiency. PMID- 29439689 TI - Acceptability of financial incentives for maintenance of weight loss in mid-older adults: a mixed methods study. AB - BACKGROUND: Health insurers worldwide implement financial incentive schemes to encourage health-related behaviours, including to facilitate weight loss. The maintenance of weight loss is a public health challenge, and as non-communicable diseases become more prevalent with increasing age, mid-older adults could benefit from programs which motivate weight loss maintenance. However, little is understood about their perceptions of using financial incentives to maintain weight loss. METHODS: We used mixed methods to explore the attitudes and views of participants who had completed an Australian weight loss and lifestyle modification program offered to overweight and obese health insurance members with weight-related chronic diseases, about the acceptability and usefulness of different types of financial incentives to support weight loss maintenance. An online survey was completed by 130 respondents (mean age = 64 years); and a further 28 participants (mean age = 65 years) attended six focus groups. RESULTS: Both independent samples of participants supported a formalised maintenance program. Online survey respondents reported that non-cash (85.2%) and cash (77%) incentives would be potentially motivating; but only 40.5% reported that deposit contracts would motivate weight loss maintenance. Results of in-depth discussions found overall low support for any type of financial incentive, but particularly deposit contracts and lotteries. Some participants expressed that improved health was of more value than a monetary incentive and that they felt personally responsible for their own health, which was at odds with the idea of financial incentives. Others suggested ongoing program and peer support as potentially useful for weight loss maintenance. CONCLUSIONS: If financial incentives are considered for mid-older Australian adults in the health insurance setting, program planners will need to balance the discordance between participant beliefs about the individual responsibility for health and their desire for external supports to motivate and sustain weight loss maintenance. PMID- 29439690 TI - A systematic review of the effects of acupuncture on xerostomia and hyposalivation. AB - BACKGROUND: Saliva is fundamental to our oral health and our well-being. Many factors can impair saliva secretion, such as adverse effects of prescribed medication, auto-immune diseases (for example Sjogren's syndrome) and radiotherapy for head and neck cancers. Several studies have suggested a positive effect of acupuncture on oral dryness. METHODS: Pubmed and Web of Science were electronically searched. Reference lists of the included studies and relevant reviews were manually searched. Studies that met the inclusion criteria were systematically evaluated. Two reviewers assessed each of the included studies to confirm eligibility and assessing the risk of bias. RESULTS: Ten randomized controlled trials investigating the effect of acupuncture were included. Five trials compared acupuncture to sham/placebo acupuncture. Four trials compared acupuncture to oral hygiene/usual care. Only one clinical trial used oral care sessions as control group. For all the included studies, the quality for all the main outcomes has been assessed as low. Although some publications suggest a positive effect of acupuncture on either salivary flow rate or subjective dry mouth feeling, the studies are inconclusive about the potential effects of acupuncture. CONCLUSIONS: Insufficient evidence is available to conclude whether acupuncture is an evidence-based treatment option for xerostomia/hyposalivation. Further well-designed, larger, double blinded trials are required to determine the potential benefit of acupuncture. Sample size calculations should be performed before before initiating these studies. PMID- 29439691 TI - What matters most: protocol for a randomized controlled trial of breast cancer surgery encounter decision aids across socioeconomic strata. AB - BACKGROUND: Breast cancer is the most commonly diagnosed malignancy in women. Mastectomy and breast-conserving surgery (BCS) have equivalent survival for early stage breast cancer. However, each surgery has different benefits and harms that women may value differently. Women of lower socioeconomic status (SES) diagnosed with early stage breast cancer are more likely to experience poorer doctor patient communication, lower satisfaction with surgery and decision-making, and higher decision regret compared to women of higher SES. They often play a more passive role in decision-making and are less likely to undergo BCS. Our aim is to understand how best to support women of lower SES in making decisions about early stage breast cancer treatments and to reduce disparities in decision quality across socioeconomic strata. METHODS: We will conduct a three-arm, multi-site randomized controlled superiority trial with stratification by SES and clinician level randomization. At four large cancer centers in the United States, 1100 patients (half higher SES and half lower SES) will be randomized to: (1) Option Grid, (2) Picture Option Grid, or (3) usual care. Interviews, field-notes, and observations will be used to explore strategies that promote the interventions' sustained use and dissemination. Community-Based Participatory Research will be used throughout. We will include women aged at least 18 years of age with a confirmed diagnosis of early stage breast cancer (I to IIIA) from both higher and lower SES, provided they speak English, Spanish, or Mandarin Chinese. Our primary outcome measure is the 16-item validated Decision Quality Instrument. We will use a regression framework, mediation analyses, and multiple informants analysis. Heterogeneity of treatment effects analyses for SES, age, ethnicity, race, literacy, language, and study site will be performed. DISCUSSION: Currently, women of lower SES are more likely to make treatment decisions based on incomplete or uninformed preferences, potentially leading to poorer decision quality, quality of life, and decision regret. This study hopes to identify solutions that effectively improve patient-centered care across socioeconomic strata and reduce disparities in decision and care quality. TRIAL REGISTRATION: NCT03136367 at ClinicalTrials.gov Protocol version: Manuscript based on study protocol version 2.2, 7 November 2017. PMID- 29439693 TI - Health insurance is important in improving maternal health service utilization in Tanzania-analysis of the 2011/2012 Tanzania HIV/AIDS and malaria indicator survey. AB - BACKGROUND: Maternal mortality rates vary significantly from region to region. Interventions such as early and planned antenatal care attendance and facility delivery with skilled health workers can potentially reduce maternal mortality rates. Several factors can be attributed to antenatal care attendance, or lack thereof, including the cost of health care services. The aim of this study was to examine the role of health insurance coverage in utilization of maternal health services in Tanzania. METHODS: Secondary data analysis was conducted on the nationally representative sample of men and women aged 15-49 years using the 2011/12 Tanzania HIV and Malaria Indicator Survey. It included 4513 women who had one or more live births within three years before the survey. The independent variable was health insurance coverage. Outcome variables included proper timing of the first antenatal care visit, completing the recommended number of antenatal care (ANC) visits, and giving birth under skilled worker. Data were analyzed both descriptively and using regression analyses to examine independent association of health insurance and maternal health services. RESULTS: Of 4513 women, only 281 (6.2%) had health insurance. Among all participants, only 16.9%, 7.1%, and 56.5%, respectively, made their first ANC visit as per recommendation, completed the recommended number of ANC visits, and had skilled birth assistance at delivery. A higher proportion of women with health insurance had a proper timing of 1st ANC attendance compared to their counterparts (27.0% vs. 16.0%, p < 0.001). Similar trend was for skilled birth attendance (77.6% vs. 55.1%, p < 0.001). After adjusting for other confounders and covariates, having health insurance was associated with proper timing of 1st ANC attendance (AOR = 1.89, p < 0.001) and skilled birth attendance (AOR = 2.01, p < 0.01). CONCLUSIONS: Health insurance coverage and maternal health services were low in this nationally representative sample in Tanzania. Women covered by health insurance were more likely to have proper timing of the first antenatal visit and receive skilled birth assistance at delivery. To improve maternal health, health insurance alone is however not enough. It is important to improve other pillars of health system to attain and sustain better maternal health in Tanzania and areas with similar contexts. PMID- 29439692 TI - Automated chart review utilizing natural language processing algorithm for asthma predictive index. AB - BACKGROUND: Thus far, no algorithms have been developed to automatically extract patients who meet Asthma Predictive Index (API) criteria from the Electronic health records (EHR) yet. Our objective is to develop and validate a natural language processing (NLP) algorithm to identify patients that meet API criteria. METHODS: This is a cross-sectional study nested in a birth cohort study in Olmsted County, MN. Asthma status ascertained by manual chart review based on API criteria served as gold standard. NLP-API was developed on a training cohort (n = 87) and validated on a test cohort (n = 427). Criterion validity was measured by sensitivity, specificity, positive predictive value and negative predictive value of the NLP algorithm against manual chart review for asthma status. Construct validity was determined by associations of asthma status defined by NLP-API with known risk factors for asthma. RESULTS: Among the eligible 427 subjects of the test cohort, 48% were males and 74% were White. Median age was 5.3 years (interquartile range 3.6-6.8). 35 (8%) had a history of asthma by NLP-API vs. 36 (8%) by abstractor with 31 by both approaches. NLP-API predicted asthma status with sensitivity 86%, specificity 98%, positive predictive value 88%, negative predictive value 98%. Asthma status by both NLP and manual chart review were significantly associated with the known asthma risk factors, such as history of allergic rhinitis, eczema, family history of asthma, and maternal history of smoking during pregnancy (p value < 0.05). Maternal smoking [odds ratio: 4.4, 95% confidence interval 1.8-10.7] was associated with asthma status determined by NLP API and abstractor, and the effect sizes were similar between the reviews with 4.4 vs 4.2 respectively. CONCLUSION: NLP-API was able to ascertain asthma status in children mining from EHR and has a potential to enhance asthma care and research through population management and large-scale studies when identifying children who meet API criteria. PMID- 29439694 TI - Cardiometabolic disorder reduces survival prospects more than suboptimal body mass index irrespective of age or gender: a longitudinal study of 377,929 adults in Taiwan. AB - BACKGROUND: The effect of cardio-metabolic profile on the relationship of body mass index (BMI) with mortality is unclear. The aim of this study was to explore association between BMI and mortality at all ages, taking account of cardio metabolic disorders. METHODS: We followed 377,929 individuals (>= 20 years), who registered for health checkups in 1996-2007, until 2008 and found 9490 deaths. From multivariable Cox proportional hazards models we estimated mortality hazard ratios (HR) for those in high blood pressure, hyperglycemia, high waist circumference, dyslipidemia, and different BMIs categories (the underweight [< 18.5 kg/m2], low normal weight [18.5-21.9 kg/m2], normal weight [22-23.9 kg/m2, the referent], overweight [24-26.9 kg/m2], obese1 [27-29.9 kg/m2], and obese2 [>= 30 kg/m2]). Population attributable risk (PAR) provided estimates of the population mortality burden attributable to high blood pressure, hyperglycemia, high waist circumference, dyslipidemia, and deviant BMIs. RESULTS: Higher blood pressure, hyperglycemia, high waist circumference, and dyslipidemia were significantly predictive of higher mortality for nearly all ages. Compared with the referent BMI, underweight (HR = 1.69, 95% confidence interval = 1.51-1.90) and low normal weight (HR = 1.19, 1.11-1.28) were significant mortality risks, while overweight (HR = 0.82, 0.76-0.89) and obese1 (HR = 0.88, 0.79-0.97) were protective against premature death. The mortality impact of obesity was largely attributable to cardio-metabolic profile and attenuated by age. The population mortality burden with high blood pressure (PAR = 7.29%), hyperglycemia (PAR = 5.15%), high waist circumference (PAR = 4.24%), and dyslipidemia (PAR = 5.66%) was similar to that in the underweight (PAR = 5.50%) or low normal weight (PAR = 6.04%) groups. Findings for non-smokers and by gender were similar. CONCLUSIONS: The effect of BMI on mortality varies with age and is affected by cardio metabolic status. Compared to any deviant BMI, abnormal cardio-metabolic status has a similar or even greater health impact at both the individual and population levels. PMID- 29439695 TI - Male partner involvement in increasing the uptake of infant antiretroviral prophylaxis/treatment in sub Saharan Africa: A systematic review and meta analysis. AB - BACKGROUND: Infant antiretroviral prophylaxis plays an important role towards ensuring the reduction of HIV transmission from mother to child in the postpartum period. However in sub Saharan Africa (SSA), the low level of involvement of male partners may hinder the uptake of such services by HIV positive mothers. We conducted a systematic review and meta-analysis to determine the impact of male partner involvement approaches on the uptake of infant antiretroviral prophylaxis in SSA. METHODS: In this systematic review and meta-analysis, Ovid Medline, Embase, PsycINFO, Cochrane library, ClinicalTrials.gov, Web of Science and Current Controlled Trials were searched from 1st December 2015 up until 30th March 2016. Only studies carried out in SSA that reported an approach used in involving male partners and the impact on the uptake of infant antiretroviral prophylaxis irrespective of the Language and date of publication were included. Odds ratios were extracted or calculated from studies and combined in a meta analysis using the statistical package Stata version 11.0. Forest plots were generated using the random effect model. RESULTS: From an initial 2316 non duplicate articles, 09 articles were included in the systematic review and meta analysis. The pooled unadjusted odds ratio was 2.09(95% CI: 1.31 to 3.36) while the unadjusted odds ratios for enhanced psychosocial interventions (02 studies pooled), complex community interventions (02 studies pooled), verbal encouragement (02 studies pooled) and invitation letters(03 pooled studies) were 3.48(95% CI: 1.42 to 8.53), 1.85(95%CI: 0.85 to 4.03), 2.37(95%CI: 1.22 to 4.61) and 1.81(95%CI: 0.64 to 5.14) respectively. I squared was 89.5%, p < 0.001 and the heterogeneity was not explained by any of the variables in meta-regression. CONCLUSION: There was stronger evidence for enhanced psychosocial intervention and verbal encouragement in increasing the uptake of infant prophylaxis. The high heterogeneity suggests more studies are needed to draw a definite inference from the meta-analysis. More studies with larger sample sizes that are conducted using similar methods are needed in the future. TRIAL REGISTRATION: Prospero registration number: 42016032673 . PMID- 29439696 TI - Evaluation of spray and oral delivery of Newcastle disease I2 vaccine in chicken reared by smallholder farmers in central Ethiopia. AB - BACKGROUND: Newcastle disease (ND) is a highly infectious disease causing considerable economic losses to poultry farmers worldwide. Conventional vaccine delivery methods are not suitable for smallholder and rural poultry producers, and thus appropriate vaccination methods need to be sought. This study was carried out with the main objective of evaluating the efficacy of ND I2 vaccine delivered via drinking water and spray under smallholder farmers' condition in Minjar-Shenkora district, central Ethiopia. Twenty households were randomly assigned to intervention and control groups. Chickens owned by the selected households were randomly assigned to one of the three intervention groups. Blood samples were collected regularly for antibody assay from individual chicken vaccinated with ND I2 vaccine using different routes. RESULTS: At baseline, there was no difference in antibody titer among the experimental groups. After the first and booster vaccinations, the three vaccinated groups had significantly higher antibody titer (P < 0.001) than the unvaccinated control group. Interestingly, there was no statistically significant difference in antibody titer among the vaccinated groups. Out of the 40 chicken in the unvaccinated control only 14 had antibody titter>= log23. Similarly 19/37 of chicken in the drinking water group, 19/37 of chicken in the eye drop group and 20/40 chicken in the spray group had antibody titer >= log23. Two weeks after the first vaccination the proportion of chicken with antibody titer >= log23 rose to 23/37, 30/37 and 29/40 in the group vaccinated via drinking water, eye drop and spray, respectively. The proportion remained low in unvaccinated group. Hundred percent of the vaccinated chicken survived after infection with the virulent ND virus (Alemaya strain); whereas only 40% survived from the unvaccinated control group. CONCLUSION: The results of this study showed that ND I2 vaccine administered via drinking water and spray under smallholder farmers' situation provoked protective antibody level similar to the eye drop method. The use of ND I2 vaccine could contribute to food security if used by rural poultry farmers properly. PMID- 29439697 TI - Trajectories of antidepressant medication use in individuals before and after being granted disability pension due to common mental disorders- a nationwide register-based study. AB - BACKGROUND: Early retirement caused by disability pension (DP) due to common mental disorders (CMDs) is frequent in European countries. Inadequate treatment, e.g., suboptimal antidepressant (AD) medication before DP can be crucial in such DP. This explorative study aimed to disentangle trajectories of AD based on defined daily dose (DDD) before and after granted DP, and to characterize the trajectories by socio-demographics and medical factors. METHODS: All 4642 individuals in Sweden aged 19-64 with incident DP due to CMD in 2009-2010 were included. Trajectories of annual DDDs of AD were analysed over a 6-year period by a group-based trajectory method. Associations between socio-demographic or medical factors and different trajectories were estimated by chi2-test and multinomial logistic regression. RESULTS: Five trajectories of ADs were identified. Three groups, comprising 34%, 34%, and 21% of the cohort, had constant AD levels before and after DP with mean annual DDDs of 29, 234, and 580, respectively. Two groups, each including 6% of the cohort, had increasing levels of DDDs, levelling off at around 1150 and 785 DDDs after DP. Particularly age, outpatient care due to mental diagnoses and DP diagnoses were significantly associated with different trajectories (p < 0.05). All the groups had a larger proportion of older individuals (> 50%, 45-64 years), except for the 'increasing low' group, where younger individuals were in majority (> 60%, 18-44 years), who more frequently exited labour market due to 'anxiety disorders', with lower education and more specialised healthcare before DP than the other groups. CONCLUSION: The heterogeneity among the five trajectory groups was partly explained by age, the severity of the mental disorder and the DP diagnoses. DDDs of ADs, though on different levels, varied marginally before and after granted DP in the majority. Moreover, AD levels were very low in one third of the individuals. Early identification and focus on the 'increasing low' group might be important in order to identify individuals at risk for further increase in annual DDDs of ADs even after granted DP, and might also contribute in prevention of DP. Further detailed research regarding different groups is warranted. PMID- 29439698 TI - A retrospective analysis of bone mineral status in patients requiring spinal surgery. AB - BACKGROUND: Impaired bone quality is associated with poor outcome of spinal surgery. The aim of the study was to assess the bone mineral status of patients scheduled to undergo spinal surgery and to report frequencies of bone mineral disorders. METHODS: We retrospectively analyzed the bone mineral status of 144 patients requiring spinal surgery including bone mineral density by dual-energy X ray absorptiometry (DXA) as well as laboratory data with serum levels of 25 hydroxyvitamin D (25-OH-D), parathyroid hormone, calcium, bone specific alkaline phosphate, osteocalcin, and gastrin. High-resolution peripheral quantitative computed tomography (HR-pQCT) was additionally performed in a subgroup of 67 patients with T-Score below - 1.5 or history of vertebral fracture. RESULTS: Among 144 patients, 126 patients (87.5%) were older than 60 years. Mean age was 70.1 years. 42 patients (29.1%) had suffered from a vertebral compression fracture. 12 previously undiagnosed vertebral deformities were detected in 12 patients by vertebral fracture assessment (VFA). Osteoporosis was present in 39 patients (27.1%) and osteopenia in 63 patients (43.8%). Only 16 patients (11.1%) had received anti-osteoporotic therapy, while 54 patients (37.5%) had an indication for specific anti-osteoporotic therapy but had not received it yet. The majority of patients had inadequate vitamin D status (73.6%) and 34.7% of patients showed secondary hyperparathyroidism as a sign for a significant disturbed calcium homeostasis. In a subgroup of 67 patients, severe vertebral deformities were associated with stronger deficits in bone microarchitecture at the distal radius compared to the distal tibia. CONCLUSIONS: This study shows that bone metabolism disorders are highly prevalent in elderly patients scheduled for spinal surgery. Vertebral deformities are associated with a predominant deterioration of bone microstructure at the distal radius. As impaired bone quality can compromise surgical outcome, we strongly recommend an evaluation of bone mineral status prior to operation and anti-osteoporotic therapy if necessary. PMID- 29439699 TI - Exposure to cooking oil fumes and chronic bronchitis in nonsmoking women aged 40 years and over: a health-care based study. AB - BACKGROUND: Little is known about the effect of exposure to cooking oil fumes (COFs) on the development of non-malignant respiratory diseases in nonsmoking women. This study investigated the relationship between exposure to COFs and chronic bronchitis in female Taiwanese non-smokers. METHODS: Searching the 1999 claims and registration records maintained by Taiwan's National Health Insurance Program, we identified 1846 women aged 40 years or older diagnosed as having chronic bronchitis (ICD-9 code: 491) at least twice in 1999 as potential study cases and 4624 women who had no diagnosis of chronic bronchitis the same year as potential study controls. We visited randomly selected women from each group in their homes, interviewed to collect related data including cooking habits and kitchen characteristics, and them a spirometry to collect FEV1 and FVC data between 2000 and 2009. RESULTS: After the exclusion of thirty smokers, the women were classified those with chronic bronchitis (n = 53), probable chronic bronchitis (n = 285), and no pulmonary disease (n = 306) based on physician diagnosis and American Thoracic Society criteria. Women who had cooked >= 21 times per week between the ages of 20 and 40 years old had a 4.73-fold higher risk of chronic bronchitis than those cooking < 14 times per week (95% CI = 1.65 13.53). Perceived kitchen smokiness was significantly associated with decreased FEV1 (- 137 ml, p = 0.021) and FEV1/FVC ratio (- 7.67%, p = 0.008). CONCLUSIONS: Exposure to COF may exacerbate the progression of chronic bronchitis in nonsmoking women. PMID- 29439700 TI - Ocular dimensions of the Chinese adolescents with keratoconus. AB - BACKGROUND: Adolescent KC is a special segment of the general KC population because an adolescents's eyes are still susceptible to blurred vision and optical defocus during the sensitive period of ocular and visual development. In the present study, we evaluated the ocular dimensions of 53 KC adolescents. METHODS: One hundred and six KC eyes of 53 (42 boys and 11 girls) KC adolescents (age 15.5 +/- 1.7 years, range 11 to 18) were involved in this retrospective study. The eye with more severe KC (Severe Group) of each patient was compared with their less affected eye (Mild Group). Optical axial length (OAL) was measured by optical coherence biometry (IOL-master). Central corneal thickness, anterior chamber depth (ACD), flat keratometry value, steep keratometry value, and maximum keratometry value were assessed with an anterior segment analyzer (Pentacam HR). Anterior segment length (ASL) was manually measured from the 25 scheimpflug images captured by the Pentacam HR with the mean value recorded. The posterior segment length (PSL) was calculated with the formula "PSL = OAL-ASL". RESULTS: The mean ACD, OAL, ASL, and PSL values of the Severe Group were 3.51 +/- 0.32 mm, 24.76 +/- 1.24 mm, 4.01 +/- 0.30 mm and 20.76 +/- 1.15 mm.While those of the Mild Group were 3.36 +/- 0.29 mm, 24.97 +/- 1.40 mm, 3.94 +/- 0.35 mm and 21.03 +/- 1.31 mm. The Severe Group has significantly higher ACD (t = 4.539, P < 0.001) value but lower OAL (t = - 3.120, P = 0.003) and PSL (t = - 4.537, P < 0.001) values when compared with those of the Mild Group. For the Severe Group, the Kmax values were significantly correlated with the SE values (R = - 0.385, P = 0.004), the ACD values (R = 0.375, P = 0.006), the ASL values (R = 0.308, P = 0.025) and the PSL values (R = - 0.317, P = 0.021), but not with the OAL values (R = - 0.220, P = 0.114). In the Mild Group, the Kmax values were negatively correlated with the SE (R = - 0.577, P < 0.001), OAL(R = - 0.533, P < 0.001), and PSL (R = - 0.523, P < 0.001) values, but not with ACD (R = - 0.110, P = 0.434) or ASL (R = - 0.182, P = 0.192) values. CONCLUSIONS: For adolescent KC, the more keratoconic eyes may be characterized by deeper ACD but shorter OAL and PSL, when compared with the less affected ones. PMID- 29439701 TI - Population attributable risk of key modifiable risk factors associated with non exclusive breastfeeding in Nigeria. AB - BACKGROUND: Non-exclusive breastfeeding (non-EBF) is a risk factor for many of the 2300 under-five deaths occurring daily in Nigeria - a developing country with approximately 40 million children. This study aimed to quantify and compare the attributable burden of key modifiable risk factors associated with non-EBF in Nigeria to inform strategic policy responses and initiatives. METHODS: Relative risk and exposure prevalence for selected modifiable risk factors were used to calculate population attributable fractions based on Nigeria Demographic and Health Surveys data for the period (1999-2013). Scenarios based on feasible impact of community-based interventions in reducing exposure prevalence were also considered to calculate comparative potential impact fractions. RESULTS: In Nigeria, an estimated 22.8% (95% Confidence Interval, CI: 9.2-37.0%) of non-EBF was attributable to primary and no maternal education; 24.7% (95% CI: 9.5-39.5%) to middle and poor household wealth, 9.7% (1.7-18.1%) to lower number (1-3) and no antenatal care visits; 18.8% (95% CI: 6.9-30.8%) to home delivery and 16.6% (95% CI: 3.0-31.3%) to delivery assisted by a non-health professional. In combination, more than half of all cases of non-EBF (64.5%; 95% CI: 50.0-76.4%) could be attributed to those modifiable risk factors. Scenarios based on feasible impacts of community-based approaches to improve health service access and human capacity suggest that an avoidable burden of non-EBF practice of approximately 11% (95% CI: -5.4; 24.7) is achievable. CONCLUSION: Key modifiable risk factors contribute significantly to non-EBF in Nigerian women. Community-based initiatives and appropriate socio-economic government policies that specifically consider those modifiable risk factors could substantially reduce non-EBF practice in Nigeria. PMID- 29439702 TI - BCG vaccination in southern rural Mozambique: an overview of coverage and its determinants based on data from the demographic and health surveillance system in the district of Manhica. AB - BACKGROUND: Over the past four decades, the World Health Organization established the Expanded Programme on Immunization (EPI) to foster universal access to all relevant vaccines for all children at risk. The success of this program has been undeniable, but requires periodic monitoring to ensure that coverage rates remain high. The aim of this study was to measure the BCG vaccination coverage in Manhica district, a high TB burden rural area of Southern Mozambique and to investigate factors that may be associated with BCG vaccination. METHODS: We used data from the Health and Demographic Surveillance System (HDSS) run by the Manhica Health Research Centre (CISM) in the district of Manhica. A questionnaire was added in the annual HDSS round visits to retrospectively collect the vaccination history of children under the age of 3 years. Vaccinations are registered in the National Health Cards which are universally distributed at birth. This information was collected for children born from 2011 to 2014. Data on whether a child was vaccinated for BCG were collected from these National Health Cards and/or BCG scar assessment. RESULTS: A total of 10,875 number of children were eligible for the study and 7903 presented the health card. BCG coverage was 97.4% for children holding a health card. A BCG-compatible scar was observed in 99.0% of all children and in 99.6% of children with recorded BCG in the card. A total of 93.4% of children had been vaccinated with BCG within their first 28 days of life. None of the factors analysed were found to be associated with lack of BCG vaccination except for living in the municipality of Maluana compared to living in the municipality of Manhica; (OR = 1.89, 95% CI: 1.18 3.00). Coverage for other EPI vaccines during the first year of life was similarly high, but decreased for subsequent doses. CONCLUSIONS: BCG coverage is high and timely administered. Almost all vaccinated infants develop scar, which is a useful proxy for monitoring BCG vaccine implementation. PMID- 29439703 TI - Characterizing the transcutaneous electrical recruitment of lower leg afferents in healthy adults: implications for non-invasive treatment of overactive bladder. AB - BACKGROUND: As a potential new treatment for overactive bladder (OAB), we investigated the feasibility of non-invasively activating multiple nerve targets in the lower leg. METHODS: In healthy participants, surface electrical stimulation (frequency = 20 Hz, pulse width = 200 MUs) was used to target the tibial nerve, saphenous nerve, medial plantar nerve, and lateral plantar nerve. At each location, the stimulation amplitude was increased to define the thresholds for evoking (1) cutaneous sensation, (2) target nerve recruitment and (3) maximum tolerance. RESULTS: All participants were able to tolerate stimulation amplitudes that were 2.1 +/- 0.2 (range = 2.0 to 2.4) times the threshold for activating the target nerve. CONCLUSIONS: Non-invasive electrical stimulation can activate neural targets at levels that are consistent with evoking bladder-inhibitory reflex mechanisms. Further work is needed to test the clinical effects of stimulating one or more neural targets in OAB patients. PMID- 29439704 TI - Novel patterns of physical activity in a large sample of preschool-aged children. AB - BACKGROUND: Moderate-to-vigorous physical activity (MVPA), shown to be associated with health benefits, is not well-characterized in preschool-aged children. MVPA is commonly described as a threshold amount to achieve. We examined a novel way to characterize MVPA patterns in preschool-aged children by gender and age. METHODS: Preschool-aged children from Nashville, TN and Minneapolis, MN wore triaxial accelerometers. Four distinct MVPA patterns were identified: isolated spurt (IS), isolated sustained activity (ISA), clustered spurt (CS), and clustered sustained activity (CSA). Multivariable linear regression models were used to test associations of gender and age with each pattern. RESULTS: One thousand one hundred thirty-one children (3.9 years old, 51% girls, 30% overweight, 11% obese, and 76% Hispanic) wore accelerometers for 12.9 (SD = 1.4) hours/day for 6.7 (SD = 0.7) days. Children spent 53% of wear time in sedentary behavior and 13% in MVPA. On average, boys and girls achieved > 90 min/day of MVPA (98.2 min, SD = 32.3). Most MVPA (80%) was obtained in spurt-like (IS and CS) MVPA; however, girls spent a higher proportion of MVPA in IS and CS, and lower proportion of time in CSA (all p < 0.001). Controlling for gender, an increase of 1-year in age corresponded to a 1.5% increase in CSA (p < 0.05). CONCLUSIONS: How MVPA was obtained varied depending on the gender and age of the child. On average, boys spent more time in sustained MVPA than girls and MVPA was more sustained in older children. Utilizing these patterns could inform PA practice and policy guidelines. TRIAL REGISTRATION: NCT01316653 , date of registration: March 3, 2011; NCT01606891, date of registration: May 23, 2012. PMID- 29439705 TI - Chronic morbidity, deprivation and primary medical care spending in England in 2015-16: a cross-sectional spatial analysis. AB - BACKGROUND: Primary care provides the foundation for most modern health-care systems, and in the interests of equity, it should be resourced according to local need. We aimed to describe spatially the burden of chronic conditions and primary medical care funding in England at a low geographical level, and to measure how much variation in funding is explained by chronic condition prevalence and other patient and regional factors. METHODS: We used multiple administrative data sets including chronic condition prevalence and management data (2014/15), funding for primary-care practices (2015-16), and geographical and area deprivation data (2015). Data were assigned to a low geographical level (average 1500 residents). We investigated the overall morbidity burden across 19 chronic conditions and its regional variation, spatial clustering and association with funding and area deprivation. A linear regression model was used to explain local variation in spending using patient demographics, morbidity, deprivation and regional characteristics. RESULTS: Levels of morbidity varied within and between regions, with several clusters of very high morbidity identified. At the regional level, morbidity was modestly associated with practice funding, with the North East and North West appearing underfunded. The regression model explained 39% of the variability in practice funding, but even after adjusting for covariates, a large amount of variability in funding existed across regions. High morbidity and, especially, rural location were very strongly associated with higher practice funding, while associations were more modest for high deprivation and older age. CONCLUSIONS: Primary care funding in England does not adequately reflect the contemporary morbidity burden. More equitable resource allocation could be achieved by making better use of routinely available information and big data resources. Similar methods could be deployed in other countries where comparable data are collected, to identify morbidity clusters and to target funding to areas of greater need. PMID- 29439706 TI - Use of 'eradication' in HIV cure-related research: a public health debate. AB - BACKGROUND: The landscape of Human Immunodeficiency Virus (HIV) research has changed drastically over the past three decades. With the remarkable success of antiretroviral treatment (ART) in decreasing AIDS-related mortality, some researchers have shifted their HIV research focus from treatment to cure research. The HIV cure research community often uses the term eradication to describe the science, and talks about eradicating the virus from the body. In public discourse, the term eradication could be conflated with disease eradication at the population level. In this paper, we call for a reframing of HIV cure research as control, as it is a more accurate descriptor and achievable goal in the foreseeable future. DISCUSSION: The properties of HIV are discordant with eradicability standards at both the individual level (as a clinical concept), and at the population level (as a public health concept). At the individual level, true eradication would necessitate absolute elimination of all latent HIV reservoirs from the body. Current HIV cure-related research strategies have proven unsuccessful at accurately quantifying, let alone eliminating these reservoirs. At the population level, eradication implies the permanent global reduction of HIV to zero new cases and to zero risk for future cases. Given the absence of an efficacious HIV vaccine and the impracticality and unethicality of eliminating animal reservoirs, global eradication of HIV is highly implausible. From a public health perspective, HIV eradication remains an elusive goal. CONCLUSION: The term 'eradication' is a misleading description of current HIV cure-related research. Instead, we call for the use of more realistic expressions such as 'sustained virologic HIV suppression (or control)' or 'management of HIV persistence' to describe HIV cure-related research. Using these terms reorients what HIV cure science can potentially achieve in the near future and avoids creating unrealistic expectations, particularly among the millions of people globally who live with HIV. PMID- 29439707 TI - Stereotactic Body Radiotherapy (SBRT) for liver metastasis - clinical outcomes from the international multi-institutional RSSearch(r) Patient Registry. AB - BACKGROUND: Stereotactic body radiotherapy (SBRT) is an emerging treatment option for liver metastases in patients unsuitable for surgery. We investigated factors associated with clinical outcomes for liver metastases treated with SBRT from a multi-center, international patient registry. METHODS: Patients with liver metastases treated with SBRT were identified in the RSSearch(r) Patient Registry. Patient, tumor and treatment characteristics associated with treatment outcomes were assessed. Dose fractionations were normalized to BED10. Overall survival (OS) and local control (LC) were evaluated using Kaplan Meier analysis and log rank test. RESULTS: The study included 427 patients with 568 liver metastases from 25 academic and community-based centers. Median age was 67 years (31-91 years). Colorectal adenocarcinoma (CRC) was the most common primary cancer. 73% of patients received prior chemotherapy. Median tumor volume was 40 cm3 (1.6-877 cm3), median SBRT dose was 45 Gy (12-60 Gy) delivered in a median of 3 fractions [1-5]. At a median follow-up of 14 months (1-91 months) the median overall survival (OS) was 22 months. Median OS was greater for patients with CRC (27 mo), breast (21 mo) and gynecological (25 mo) metastases compared to lung (10 mo), other gastro-intestinal (GI) (18 mo) and pancreatic (6 mo) primaries (p < 0.0001). Smaller tumor volumes (< 40 cm3) correlated with improved OS (25 months vs 15 months p = 0.0014). BED10 >= 100 Gy was also associated with improved OS (27 months vs 15 months p < 0.0001). Local control (LC) was evaluable in 430 liver metastases from 324 patients. Two-year LC rates was better for BED10 >= 100 Gy (77.2% vs 59.6%) and the median LC was better for tumors < 40 cm3 (52 vs 39 months). There was no difference in LC based on histology of the primary tumor. CONCLUSIONS: In a large, multi-institutional series of patients with liver metastasis treated with SBRT, reasonable LC and OS was observed. OS and LC depended on dose and tumor volume, while OS varied by primary tumor. Future prospective trials on the role of SBRT for liver metastasis from different primaries in the setting of multidisciplinary management including systemic therapy, is warranted. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01885299 . PMID- 29439708 TI - Possible relationship between fibrosis of IgG4-related thymitis and the profibrotic cytokines, transforming growth factor beta 1, interleukin 1 beta and interferon gamma: a case report. AB - BACKGROUND: IgG4-related disease often forms a mass and the affected lesion is clinically removed because the mass cannot be differentiated from a neoplasm. Affected lesions commonly occur in the pancreas, hepatobiliary tract, kidney, and retroperitoneum. However, the lesion rarely occurs in the thymus. A histological worldwide consensus of IgG4-related disease proposed that pathological diagnosis of IgG4-related disease should meet more than two of three major features: 1) dense lymphoplasmacytic infiltration with greater than 40% IgG4+/IgG+ plasma cells, 2) storiform fibrosis; and 3) obliterative phlebitis. Currently, fibrosis of IgG4-related disease is thought to be induced by profibrotic cytokines such as transforming growth factor beta 1 (TGFB1), interleukin 1 beta (IL1B) and interferon gamma (IFNG), which are secreted by regulatory T cells (Tregs) and CD4 positive cytotoxic T cells. However, it is unclear whether profibrotic cytokines are associated with the fibrosis seen in IgG4-related thymitis. Here we examined whether cytokines in the mass were increased compared with those in the surrounding thymus, and whether Tregs were present in the mass, using reverse transcription absolute quantitative polymerase chain reaction (RT-ab-qPCR) and immunohistochemistry. CASE PRESENTATION: A 70-year-old Japanese man contracted IgG4-letated thymitis. Histological and immunohistochemical analyses demonstrated his mass had massive fibrosis with a focally storiform pattern and lymphoplasmacytic infiltration with 40% IgG4+/IgG+ plasma cells, but not obliterative phlebitis. The mass was surrounded by atrophic thymus. We diagnosed the mass as IgG4-related thymitis. Immunohistochemically, Tregs were scattered throughout the mass. RT-ab-qPCR showed that messenger RNA expressions of TGFB1, IL1B and IFNG in the mass were 270-, 158- and 5.5- fold higher than in the surrounding thymus. His serum IgG4 level after surgery was within the normal range (83.4 mg/dl soon after surgery, 89.3 mg/dl 2 weeks after surgery). CONCLUSIONS: Our results suggested the profibrotic cytokines TGFB1, IL1B and IFNG induce fibrosis and that Tregs might produce some of these cytokines in IgG4 related thymitis as well as in the other affected lesions of IgG4-related disease. PMID- 29439709 TI - Association between single nucleotide polymorphism rs11057401 of CCDC92 gene and the risk of coronary heart disease (CHD). AB - BACKGROUND: Given that the CCDC92 (coiled-coil domain containing 92) was important in insulin resistance, we sought to investigate whether the CCDC92 rs825476 SNP is associated with the risk of CHD in Chinese Han population. METHODS: Rs11057401 was genotyped for 817 patients with CHD and 724 age- and sex matched controls using PCR-based Invader assay with the probe sets designed and synthesized by third wave. RESULTS: Patients were found to have a significantly higher frequency of AA than the controls (23.5% vs. 14.7%, OR = 1.60, p = 0.000), and the frequency of allele A was found to be remarkably higher in the patients than the controls (48.1% vs. 40.3%, OR = 1.19, p = 0.000). Multivariate logistic analysis showed that the incidence of CHD was positively correlated with hyperlipidemia, T2D and rs11057401 AA/AT genotypes. The FPG, TC, and ApoA1 levels in the CHD patients were different among the AA, AT and TT genotypes (P < 0.05), the A allele carriers had higher FPG, TC and lower ApoA1 levels than the A allele non-carriers (P < 0.05). CONCLUSION: The genotypic and allelic frequencies of the rs11057401 SNP were significantly different between the patients with CHD and controls. Subjects with AA genotype or A allele were associated with an increased risk of CHD. The AA/AT genotypes were also associated with increased serum FPG, TC and decreased ApoA1 in CHD. PMID- 29439710 TI - SeMet attenuates OTA-induced PCV2 replication promotion by inhibiting autophagy by activating the AKT/mTOR signaling pathway. AB - Porcine circovirus type 2 (PCV2) is recognized as the causative agent of porcine circovirus-associated diseases. PCV2 replication could be promoted by low doses of ochratoxin A (OTA) as in our previous study and selenium has been shown to attenuate PCV2 replication. However, the underlying mechanism remains unclear. The aim of the study was to investigate the effects of selenomethionine (SeMet), the major component of organic selenium, on OTA-induced PCV2 replication promotion and its potential mechanism. The present study demonstrates that OTA could promote PCV2 replication as measured by cap protein expression, viral titer, viral DNA copies and the number of infected cells. In addition, OTA could activate autophagy as indicated by up-regulated light chain 3 (LC3)-II and autophagy-related protein 5 expressions and autophagosome formation. Further, OTA could down-regulate p-AKT and p-mTOR expressions and OTA-induced autophagy was inhibited when insulin was applied. SeMet at 2, 4 and 6 MUM had significant inhibiting effects against OTA-induced PCV2 replication promotion. Furthermore, SeMet could attenuate OTA-induced autophagy and up-regulate OTA-induced p-AKT and p-mTOR expression inhibition. Rapamycin, an inhibitor of AKT/mTOR, could reverse the effects of SeMet on OTA-induced autophagy and the PCV2 replication promotion. In conclusion, SeMet could block OTA-induced PCV2 replication promotion by inhibiting autophagy by activating the AKT/mTOR pathway. Therefore, SeMet supplementation could be an effective prophylactic strategy against PCV2 infections and autophagy may be a potential marker to develop novel anti-PCV2 drugs. PMID- 29439711 TI - Liver resection surgery versus thermal ablation for colorectal LiVer MetAstases (LAVA): study protocol for a randomised controlled trial. AB - BACKGROUND: Although surgical resection has been considered the only curative option for colorectal liver metastases (CLM), thermal ablation has recently been suggested as an alternative curative treatment. A prospective randomised trial is required to define the efficacy of resection vs ablation for the treatment of colorectal liver metastases. METHODS: Design and setting: This is a multicentre, open, randomised controlled non-inferiority trial design with internal pilot and will be performed in tertiary liver centres in UK and The Netherlands. PARTICIPANTS: Eligible patients will be those with colorectal liver metastases at high surgical risk because of their age, co-morbidities or tumour burden and who would be suitable for liver resection or thermal ablation. INTERVENTION: Thermal ablation as per local policy. CONTROL: Surgical liver resection performed as per centre protocol. Co-interventions: Further chemotherapy will be offered to patients as per current practice. Outcomes Pilot study: Same as main study and in addition patients and clinicians' acceptability of the trial to assist in optimisation of recruitment. PRIMARY OUTCOME: Disease-free survival (DFS) at two years post randomisation. SECONDARY OUTCOMES: Overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, DFS measured from end of intervention. FOLLOW-UP: 24 months from randomisation; five-year follow-up for overall survival. SAMPLE SIZE: 330 patients to demonstrate non inferiority of thermal ablation. DISCUSSION: This trial will determine the effectiveness and cost-effectiveness of thermal ablation vs surgical resection for high-risk people with colorectal liver metastases, and guide the optimal treatment for these patients. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN52040363 . Registered on 9 March 2016. PMID- 29439712 TI - Trovafloxacin attenuates neuroinflammation and improves outcome after traumatic brain injury in mice. AB - BACKGROUND: Trovafloxacin is a broad-spectrum antibiotic, recently identified as an inhibitor of pannexin-1 (Panx1) channels. Panx1 channels are important conduits for the adenosine triphosphate (ATP) release from live and dying cells that enhances the inflammatory response of immune cells. Elevated extracellular levels ATP released upon injury activate purinergic pathways in inflammatory cells that promote migration, proliferation, phagocytosis, and apoptotic signals. Here, we tested whether trovafloxacin administration attenuates the neuroinflammatory response and improves outcomes after brain trauma. METHODS: The murine controlled cortical impact (CCI) model was used to determine whether in vivo delivery of trovafloxacin has anti-inflammatory and neuroprotective actions after brain trauma. Locomotor deficit was assessed using the rotarod test. Levels of tissue damage markers and inflammation were measured using western blot, qPCR, and immunofluorescence. In vitro assays were used to evaluate whether trovafloxacin blocks ATP release and cell migration in a chemotactic-stimulated microglia cell line. RESULTS: Trovafloxacin treatment of CCI-injured mice significantly reduced tissue damage markers and improved locomotor deficits. In addition, trovafloxacin treatment significantly reduced mRNA levels of several pro-inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), which correlates with an overall reduction in the accumulation of inflammatory cell types (neutrophils, microglia/macrophages, and astroglia) at the injury zone. To determine whether trovafloxacin exerted these effects by direct action on immune cells, we evaluated its effect on ATP release and cell migration using a chemotactic stimulated microglial cell line. We found that trovafloxacin significantly inhibited both ATP release and migration of these cells. CONCLUSION: Our results show that trovafloxacin administration has pronounced anti-inflammatory and neuroprotective effects following brain injury. These findings lay the foundation for future studies to directly test a role for Panx1 channels in pathological inflammation following brain trauma. PMID- 29439713 TI - Potassium permanganate cleansing is an effective sanitary method for the reduction of bacterial bioload on raw Coriandrum sativum. AB - OBJECTIVE: Raw vegetables including flowers, leaves, stems, and roots are important carriers of food borne pathogens. We evaluated the bacteriological contamination of unwashed coriander leaves, and effectiveness of cleansing with 0.1% potassium permanganate solution as decontamination method. RESULTS: Significant bacterial contamination including pathogens like Salmonella species and Aeromonas species were isolated from unwashed coriander leaves. Decontamination with 0.1% potassium permanganate was found to be more effective than three steps wash with sterile water. PMID- 29439714 TI - TFAP2C promotes stemness and chemotherapeutic resistance in colorectal cancer via inactivating hippo signaling pathway. AB - BACKGROUND: Aberrant expression of transcription Factor AP-2 Gamma (TFAP2C) has been reported to be implicated in malignant process of many cancers. The purpose of this study is to investigate the clinical significance and biological roles of TFAP2C in colorectal cancer (CRC). METHODS: TFAP2C expression was evaluated by real-time PCR, Western blot and immunohistochemistry (IHC) respectively in clinical CRC tissues. Statistical analysis was performed to explore the correlation between TFAP2C expression and clinicopathological features, and overall and progression-free survival in CRC patients. In vitro and in vivo assays were performed to assess the biological roles of TFAP2C in CRC cells. Western blot, luciferase and Chromatin immunoprecipitation (ChIP) assays were used to identify the underlying pathway mediating the biological roles of TFAP2C in CRC. RESULTS: TFAP2C is robustly upregulated in CRC tissues and cells, and high expression of TFAP2C correlates with advanced clinicopathological features, poor prognosis and disease progression in CRC patients. Furthermore, upregulating TFAP2C enhances spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and reduces the apoptosis induced by 5-fluorouracil in colorectal cancer cells in vitro, and promotes stemness and chemoresistance of CRC cells in vivo; while silencing TFAP2C yields an opposite effect. Importantly, downregulation of TFAP2C dramatically restores chemotherapeutic sensitivity of CRC cells to 5-FU in vivo. Our results further demonstrate that TFAP2C promotes stemness and chemoresistance of CRC cells to 5 FU by inhibiting Hippo signaling via transcriptionally upregulating ROCK1 and ROCK2 in CRC cells. CONCLUSION: Our findings indicate that TFAP2C may serve as a novel prognostic factor in CRC patients, and a therapeutic target for the treatment of CRC, suggesting that silencing TFAP2C in combination with 5-FU may be an effective therapeutic strategy to improve survival in CRC patients. PMID- 29439715 TI - Skene duct adenocarcinoma in a patient with an elevated serum prostate-specific antigen level: a case report. AB - BACKGROUND: Female urethral carcinoma is a very rare disease that accounts for 0.02% of malignant diseases in female patients. CASE PRESENTATION: A 70-year-old Asian Japanese woman with a urethral tumor was referred to our hospital to undergo further examination. Biopsy specimens showed urethral adenocarcinoma that was positive for prostate-specific antigen. Her serum prostate-specific antigen level before surgery was 34.4 ng/ml. Urethral tumor resection with pelvic lymph node resection was performed. Her serum prostate-specific antigen level decreased to < 0.01 ng/ml after surgery. CONCLUSIONS: We report a very rare case of Skene duct adenocarcinoma in a female patient with serum prostate-specific antigen elevation. PMID- 29439716 TI - Risk factors of lateral lymph node metastasis in cN0 papillary thyroid carcinoma. AB - BACKGROUND: Cervical lymph node metastasis of papillary thyroid carcinoma (PTC) is common. However, whether undergoing prophylactic central lymph node (CLN) dissection or lateral lymph node (LLN) dissections to prevent metastasis is still controversial. This study aimed to retrospectively investigate the risk factors of LLN metastasis in clinical lymph node-negative (cN0) PTC patients. METHODS: We retrospectively studied 783 lymph node-negative (cN0) PTC patients who underwent total thyroidectomy plus CLN dissection and LLN dissection. RESULTS: The rates of CLN and LLN metastases were 68.2 and 47.4%, respectively. Large tumor size (> 20 mm) had a fourfold higher risk of LLN metastasis compared with small tumor size (<= 20 mm; OR = 4.082, 95% CI 2.646-6.289; P = 0.001). Patients with tumor in the upper lobe had ~ 3-fold higher risk of LLN metastasis compared with patients with tumor in other locations (OR = 2.874, 95% CI 1.916-4.310; P = 0.001). Multifocality and extrathyroidal extension indicated a twofold higher risk of LLN metastasis. Having >= 2 CLN metastases dramatically increased the risk of LLN metastasis, compared with those with < 2 CLN metastases (OR = 6.536, 95% CI 4.630 9.259; P = 0.001). CONCLUSIONS: Large tumor size (> 20 mm), tumor located in the upper lobe, multifocality, extrathyroidal extension, and >= 2 CLN metastases may increase the risk of LLN metastasis in cN0 PTC patients. PMID- 29439718 TI - Assessing the reliability of the short form 12 (SF-12) health survey in adults with mental health conditions: a report from the wellness incentive and navigation (WIN) study. AB - BACKGROUND: Although Short Form (SF)-12 * 2(r) has been extensively studied and used as a valid measure of health-related quality of life in a variety of population groups, no systematic studies have described the reliability of the measure in patients with behavioral conditions or serious mental illness (SMI). METHODS AND RESULTS: We assessed the internal consistency, split-half reliability and annual test-retest correlations in a sample of 1587 participants with either a combination of physical and behavioral conditions or SMI. The Mosier's alpha was 0.70 for the Physical Composite Scale (PCS) and 0.69 for the Mental Health Composite Scale (MCS), indicating good internal consistency. We observed strong correlations between physical functioning, physical role and body pain scales (r = 0.55-0.56), and between social functioning, emotional role, and mental health (r = 0.53-0.58). We calculated split-half reliabilities to be 0.74 for physical functioning, 0.75 for physical role, 0.73 for emotional role and 0.65 for mental health respectively. We assessed the annual test-retest correlation using intraclass correlation (ICC) and found an ICC of 0.61 for PCS and 0.57 for MCS composite scores, adjusting for age, sex, race/ethnicity, and CRG. We found no decline in the correlations between baseline and the following study years until year 3. CONCLUSIONS: Our results encourage using SF-12v2(r) to assess health related quality of life in the Medicaid population with combined physical and behavioral conditions or similar cohorts. TRIAL REGISTRATION: The WIN study was registered with clinicaltrials.gov on April 22, 2015. TRIAL REGISTRATION NUMBER: NCT02440906 . Retrospectively registered. PMID- 29439717 TI - Dysregulated phosphorylation of Rab GTPases by LRRK2 induces neurodegeneration. AB - BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). Elevated kinase activity is associated with LRRK2 toxicity, but the substrates that mediate neurodegeneration remain poorly defined. Given the increasing evidence suggesting a role of LRRK2 in membrane and vesicle trafficking, here we systemically screened Rab GTPases, core regulators of vesicular dynamics, as potential substrates of LRRK2 and investigated the functional consequence of such phosphorylation in cells and in vivo. METHODS: In vitro LRRK2 kinase assay with forty-five purified human Rab GTPases was performed to identify Rab family proteins as substrates of LRRK2. We identified the phosphorylation site by tandem mass-spectrometry and confirmed it by assessing phosphorylation in the in vitro LRRK2 kinase assay and in cells. Effects of Rab phosphorylation on neurodegeneration were examined in primary cultures and in vivo by intracranial injection of adeno-associated viral vectors (AAV) expressing wild-type or phosphomutants of Rab35. RESULTS: Our screening revealed that LRRK2 phosphorylated several Rab GTPases at a conserved threonine residue in the switch II region, and by using the kinase-inactive LRRK2-D1994A and the pathogenic LRRK2 G2019S along with Rab proteins in which the LRRK2 site was mutated, we verified that a subset of Rab proteins, including Rab35, were authentic substrates of LRRK2 both in vitro and in cells. We also showed that phosphorylation of Rab regulated GDP/GTP-binding property in cells. Moreover, in primary cortical neurons, mutation of the LRRK2 site in several Rabs caused neurotoxicity, which was most severely induced by phosphomutants of Rab35. Furthermore, intracranial injection of the AAV-Rab35 -T72A or AAV-Rab35-T72D into the substantia nigra substantially induced degeneration of dopaminergic neurons in vivo. CONCLUSIONS: Here we show that a subset of Rab GTPases are authentic substrates of LRRK2 both in vitro and in cells. We also provide evidence that dysregulation of Rab phosphorylation in the LRRK2 site induces neurotoxicity in primary neurons and degeneration of dopaminergic neurons in vivo. Our study suggests that Rab GTPases might mediate LRRK2 toxicity in the progression of PD. PMID- 29439719 TI - MYL6B, a myosin light chain, promotes MDM2-mediated p53 degradation and drives HCC development. AB - BACKGROUND: Identification of novel MDM2 or p53 binding proteins may reveal undefined oncogenes, tumor suppressors, signaling pathways and possible treatment targets. METHODS: By means of immunoprecipitation and Mass Spectrometry analysis, we aimed to identify novel regulators of the MDM2-p53 pathway. We further clarified the impact of MYL6B on the p53 protein level and on the process of apoptosis. We also investigated the role of MYL6B in hepatocellular carcinoma by clone formation assay and by determining the correlation between its expression and prognosis of HCC patients. RESULTS: We identified a novel MDM2 and p53 binding protein, MYL6B. It is a myosin light chain that could bind myosin II heavy chains to form non-muscle myosin II holoenzymes (NMII). We found that MYL6B could facilitate the binding of MDM2 to p53, which consequently promotes the ubiquitination and degradation of p53 protein. We further proved that MYL6B exerts the suppression effect on p53 as part of NMII holoenzymes because inhibiting the ATPase activity of myosin II heavy chain largely blocked this effect. We also discovered that MYL6B is overexpressed in HCC tissues and linked to the bad prognosis of HCC patients. Knocking out of MYL6B dramatically suppressed the clonogenic ability and increased the apoptosis level of HCC cell lines. CONCLUSIONS: To summary, our results demonstrate that MYL6B is a putative tumor driver gene in HCC which could promote the degradation of p53 by enhancing its' MDM2-mediated ubiquitination. PMID- 29439721 TI - Real-time fluorescence loop-mediated isothermal amplification assay for direct detection of egg drop syndrome virus. AB - BACKGROUND: Egg drop syndrome (EDS), caused by the adenovirus "egg drop syndrome virus" (EDSV) causes severe economic losses through reduced egg production in breeder and layer flocks. The diagnosis of EDSV has been done by molecular tools since its complete genome sequence was identified. In order to enhance the capabilities of the real-time fluorescence loop-mediated isothermal amplification (RealAmp) assay, we aimed to apply the method for direct detection of the EDSV without viral DNA extraction. In order to detect the presence of the EDSV DNA, three pairs of primers were designed, from the conserved region of fiber gene of the EDSV. RESULTS: For our assay, test and control samples were directly used in the reaction mixture in 10-fold serial dilution. The target DNA was amplified at 65 degrees C, which yield positive results in a relatively short period of 40-45 min. The method reported in this study is highly sensitive as compared to polymerase chain reaction (PCR) and showed no sign of cross-reactivity or false positive results. The RealAmp accomplished specific identification of EDSV among a variety of poultry disease viruses. CONCLUSIONS: The direct RealAmp can be used to detect the presence of EDSV. As our result showed, the RealAmp method could be suitable for the direct detection of other DNA viruses. PMID- 29439720 TI - Plant-derived antivirals against hepatitis c virus infection. AB - Hepatitis C virus (HCV) infection is a worldwide public health burden and it is estimated that 185 million people are or have previously been infected worldwide. There is no effective vaccine for prevention of HCV infection; however, a number of drugs are available for the treatment of infection. The availability of direct acting antivirals (DAAs) has dramatically improved therapeutic options for HCV genotype 1. However, the high costs and potential for development of resistance presented by existing treatment demonstrate the need for the development of more efficient new antivirals, or combination of therapies that target different stages of the viral lifecycle. Over the past decades, there has been substantial study of compounds extracted from plants that have activity against a range of microorganisms that cause human diseases. An extensive variety of natural compounds has demonstrated antiviral action worldwide, including anti-HCV activity. In this context, plant-derived compounds can provide an alternative approach to new antivirals. In this review, we aim to summarize the most promising plant-derived compounds described to have antiviral activity against HCV. PMID- 29439722 TI - Tomatidine and analog FC04-100 possess bactericidal activities against Listeria, Bacillus and Staphylococcus spp. AB - BACKGROUND: Tomatidine (TO) is a plant steroidal alkaloid that possesses an antibacterial activity against the small colony variants (SCVs) of Staphylococcus aureus. We report here the spectrum of activity of TO against other species of the Bacillales and the improved antibacterial activity of a chemically-modified TO derivative (FC04-100) against Listeria monocytogenes and antibiotic multi resistant S. aureus (MRSA), two notoriously difficult-to-kill microorganisms. METHODS: Bacillus and Listeria SCVs were isolated using a gentamicin selection pressure. Minimal inhibitory concentrations (MICs) of TO and FC04-100 were determined by a broth microdilution technique. The bactericidal activity of TO and FC04-100 used alone or in combination with an aminoglycoside against planktonic bacteria was determined in broth or against bacteria embedded in pre formed biofilms by using the Calgary Biofilm Device. Killing of intracellular SCVs was determined in a model with polarized pulmonary cells. RESULTS: TO showed a bactericidal activity against SCVs of Staphylococcus aureus, Bacillus cereus, B. subtilis and Listeria monocytogenes with MICs of 0.03-0.12 MUg/mL. The combination of an aminoglycoside and TO generated an antibacterial synergy against their normal phenotype. In contrast to TO, which has no relevant activity by itself against Bacillales of the normal phenotype (MIC > 64 MUg/mL), the TO analog FC04-100 showed a MIC of 8-32 MUg/mL. Furthermore, FC04-100 showed a strong bactericidal activity against L. monocytogenes SCVs in kill kinetics experiments, while TO did not. The addition of FC04-100 (4 MUg/mL) to a cefalexin:kanamycin (3:2) combination improved the activity of the combination by 32 fold against cefalexin and kanamycin-resistant MRSA strains. In combination with gentamicin, FC04-100 also exhibited a strong bactericidal activity against biofilm-embedded S. aureus. Also, FC04-100 and TO showed comparable intracellular killing of S. aureus SCVs. CONCLUSIONS: Chemical modifications of TO allowed improvement of its antibacterial activity against prototypical S. aureus and of its bactericidal activity against L. monocytogenes. Antibacterial activities against such prominent pathogens could be useful to prevent Listeria contamination in the food chain or as treatment for MRSA infections. PMID- 29439723 TI - Is palindromic rheumatism amongst children a benign disease? AB - BACKGROUND: Palindromic rheumatism is an idiopathic, periodic arthritis characterized by multiple, transient, recurring episodes. Palindromic rheumatism is well-characterized in adults, but has never been reported in pediatric populations. The aim of this study was to characterize the clinical features and outcomes of a series of pediatric patients with palindromic rheumatism. METHODS: We defined clinical criteria for palindromic rheumatism and reviewed all clinical visits in three Pediatric Rheumatology centers in Israel from 2006through 2015, to identify patients with the disease. We collected retrospective clinical and laboratory data on patients who fulfilled the criteria, and reviewed their medical records in order to determine the proportion of patients who had developed juvenile idiopathic arthritis. RESULTS: Overall, 10 patients were identified. Their mean age at diagnosis was 8.3 +/- 4.5 years and the average follow-up was 3.8 +/- 2.7 years. The mean duration of attacks was 12.2 +/- 8.4 days. The most frequently involved joints were knees. Patients tested positive for rheumatoid factor in 20% of cases. One patient developed polyarticular juvenile idiopathic arthritis after three years of follow-up, six patients (60%) continued to have attacks at their last follow-up and only three children (30%) achieved long-term remission. CONCLUSIONS: Progression to juvenile idiopathic arthritis is rare amongst children with palindromic rheumatism and most patients continued to have attacks at their last follow-up. Longer follow-up periods are required to predict the long-term outcomes of pediatric patients with palindromic rheumatism. PMID- 29439724 TI - Lobulated esophageal schwannoma resected with concurrent approach from the thorax and cervix. AB - BACKGROUND: Esophageal schwannomas are rare esophageal submucosal tumors. We herein report a case of a lobulated esophageal schwannoma resected with concurrent approach from the thorax and cervix. CASE PRESENTATION: A 74-year-old woman visited our hospital with complaint of loss of consciousness, and a lobulated mediastinal tumor was discovered by chance in computed tomography. Upper gastrointestinal endoscopy showed a smooth elevated lesion at a position of 23-28 cm from the incisor teeth. A hypermetabolic appearance was noted on positron emission tomography. Based on these data, a gastrointestinal stromal tumor was suspected. The tumor was enucleated at the thoracic cavity while being pushed from the cervical incision. Pathological examination showed an esophageal schwannoma. CONCLUSIONS: We experienced a case of lobulated esophageal schwannoma with fluorodeoxyglucose accumulation. We resected the tumor with concurrent approach from the thorax and cervix. PMID- 29439725 TI - Natural progress of D-dimer following total joint arthroplasty: a baseline for the diagnosis of the early postoperative infection. AB - BACKGROUND: Early detection followed by prompt intervention is essential for the treatment of periprosthetic joint infection (PJI). D-dimer, a fibrin degradation product, characteristically changes rapidly during early postoperative period and has a short half-life. The aim of this prospective study was to measure postoperative change of D-dimer level after joint arthroplasty in conjunction with ESR and CRP. METHODS: ESR, CRP, and D-dimer levels were measured on the day before surgery, postoperative days 1, 2, 3, and 5 and weeks 2 and 6 in 65 patients who underwent elective primary total hip arthroplasty (38 hips in 38 patients) or total knee arthroplasty (27 knees in 27 patients). We compared perioperative changes of the three biomarkers. RESULTS: ESR level was elevated from postoperative day 1 and reached a peak level of 45 mm/h at postoperative day 5. The elevation persisted until postoperative week 6. CRP level was elevated from postoperative day 1 and reached a peak level of 10 mg/dl between postoperative day 2 and day 3. The CRP level was decreased to the normal level around postoperative week 2. D-dimer level was sharply elevated and peaked to 4.5 MUg/dl at postoperative day 1. At postoperative day 2, it decreased to baseline level. After then, it slowly elevated again and reached a second peak at postoperative week 2. CONCLUSION: D-dimer showed a more rapid rise and fall than ESR and CRP in very early postoperative period. The D-dimer test might be effective in early detection of PJI, if combined with levels of ESR and CRP. The postoperative change of D-dimer in our study can serve as a baseline for early diagnosis of PJI. PMID- 29439727 TI - Correction to: Adolescent Coordinated Transition (ACT) to improve health outcomes among young people living with HIV in Nigeria: study protocol for a randomized controlled trial. AB - CORRECTION: In the original publication [1] the figure captions of Figs. 2 and 3 were reversed. The correct version can be found in this Erratum. PMID- 29439726 TI - A novel CAV derived cell-penetrating peptide efficiently delivers exogenous molecules through caveolae-mediated endocytosis. AB - Cell-penetrating peptide (CPP) is a promising cargo for delivering bioactive molecules. In this study, the N terminus of VP1 from chicken anemia virus, designated as CVP1, was found to carry enriched arginine residues with alpha helix. By confocal imaging, flow cytometry and MTT assay, we identified CVP1 as a novel, safe and efficient CPP. CVP1-FITC peptide could entry different types of cells tested with dose dependence, but without cytotoxic effects. Compared with TAT-FITC peptide, the CVP1-FITC peptide showed much higher cell-penetrating activity. Moreover, CVP1 could successfully deliver beta-glycosidase, poly (I:C) and plasmid into HCT116 cells. Inhibitors and temperature sensitivity analysis further indicated that the cell-penetrating activity of CVP1 was based on ATP dependent and caveolae-mediated endocytosis. All these data demonstrate that CVP1 has efficient cell-penetrating activity and great potential for developing a novel delivery vector. PMID- 29439728 TI - Obesity stigma as a globalizing health challenge. AB - BACKGROUND: Based on studies conducted in the global north, it is well documented that those who feel stigmatized by overweight/obesity can suffer extreme emotional distress, be subject to (often legal and socially-acceptable) discrimination, and adjust diet and exercise behaviors. These lead to significant negative health impacts, including depression and further weight gain. To date, weight-related stigma has been conceptualized as a problem particular to the highest income, industrialized, historically thin-valorizing societies like the US, Australasia, and Western Europe. MAIN BODY: There is limited but highly suggestive evidence that obesity stigma is an emergent phenomenon that affects populations across the global south. Emergent evidence includes: implicit and explicit measures showing very high levels of weight stigma in middle and low income countries, complex ethnographic evidence of widespread anti-fat beliefs even where fat-positivity endures, the globalization of new forms of "fat talk," and evidence of the emotional and material damage of weight-related rejection or mistreatment even where severe undernutrition is still a major challenge. CONCLUSION: Recognizing weight stigma as a global health problem has significant implications for how public health conceives and implements appropriate responses to the growing "obesity epidemic" in middle and lower income settings. PMID- 29439729 TI - Application of Neural Networks for classification of Patau, Edwards, Down, Turner and Klinefelter Syndrome based on first trimester maternal serum screening data, ultrasonographic findings and patient demographics. AB - BACKGROUND: The usage of Artificial Neural Networks (ANNs) for genome-enabled classifications and establishing genome-phenotype correlations have been investigated more extensively over the past few years. The reason for this is that ANNs are good approximates of complex functions, so classification can be performed without the need for explicitly defined input-output model. This engineering tool can be applied for optimization of existing methods for disease/syndrome classification. Cytogenetic and molecular analyses are the most frequent tests used in prenatal diagnostic for the early detection of Turner, Klinefelter, Patau, Edwards and Down syndrome. These procedures can be lengthy, repetitive; and often employ invasive techniques so a robust automated method for classifying and reporting prenatal diagnostics would greatly help the clinicians with their routine work. METHODS: The database consisted of data collected from 2500 pregnant woman that came to the Institute of Gynecology, Infertility and Perinatology "Mehmedbasic" for routine antenatal care between January 2000 and December 2016. During first trimester all women were subject to screening test where values of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (beta-hCG) were measured. Also, fetal nuchal translucency thickness and the presence or absence of the nasal bone was observed using ultrasound. RESULTS: The architectures of linear feedforward and feedback neural networks were investigated for various training data distributions and number of neurons in hidden layer. Feedback neural network architecture out performed feedforward neural network architecture in predictive ability for all five aneuploidy prenatal syndrome classes. Feedforward neural network with 15 neurons in hidden layer achieved classification sensitivity of 92.00%. Classification sensitivity of feedback (Elman's) neural network was 99.00%. Average accuracy of feedforward neural network was 89.6% and for feedback was 98.8%. CONCLUSION: The results presented in this paper prove that an expert diagnostic system based on neural networks can be efficiently used for classification of five aneuploidy syndromes, covered with this study, based on first trimester maternal serum screening data, ultrasonographic findings and patient demographics. Developed Expert System proved to be simple, robust, and powerful in properly classifying prenatal aneuploidy syndromes. PMID- 29439730 TI - Resolvin D2 protects against cerebral ischemia/reperfusion injury in rats. AB - Cerebral ischemia/reperfusion (I/R) injury is a critical factor leading to a poor prognosis for ischemic stroke patients. omega-3 fatty acid supplements taken as part of a daily diet have been shown to improve the prognosis of patients with ischemic stroke. In this study, we aimed to investigate the potential effects of resolvin D2 (RvD2), a derivative of omega-3 fatty acids, and its possible advantage on cerebral I/R injury in rats. Cerebral I/R caused by middle cerebral artery occlusion and reperfusion (MCAO/R) was established in Sprague-Dawley rats. First, in rats fed a regular diet, the MCAO/R stimulus led to a significant decrease in endogenous production of RvD2. Exogenous supply of RvD2 via intraperitoneal injection reversed MCAO/R-induced brain injury, including infarction, inflammatory response, brain edema, and neurological dysfunction. Meanwhile, RvD2 reversed the MCAO/R-induced decrease in the protein level of GPR18, which has been identified as a receptor for RvD2, especially in neurons and brain microvascular endothelial cells (BMVECs). Furthermore, RvD2 exerted rescue effects on MCAO/R-induced neuron and BMVEC death. Moreover, GPR18 antagonist O-1918 could block the rescue effects of RvD2, possibly at least partially though the GPR18-ERK1/2-NOS signaling pathway. Finally, compared with omega-3 fatty acid supplements, RvD2 treatment had a better rescue effect on cerebral infarction, which may be due to the MCAO/R-induced decrease in 5 lipoxygense phosphorylation and subsequent RvD2 generation. In conclusion, compared with omega-3 fatty acids, RvD2 may be an optimal alternative and complementary treatment for ischemic stroke patients with recanalization treatment. PMID- 29439731 TI - MetaLonDA: a flexible R package for identifying time intervals of differentially abundant features in metagenomic longitudinal studies. AB - BACKGROUND: Microbial longitudinal studies are powerful experimental designs utilized to classify diseases, determine prognosis, and analyze microbial systems dynamics. In longitudinal studies, only identifying differential features between two phenotypes does not provide sufficient information to determine whether a change in the relative abundance is short-term or continuous. Furthermore, sample collection in longitudinal studies suffers from all forms of variability such as a different number of subjects per phenotypic group, a different number of samples per subject, and samples not collected at consistent time points. These inconsistencies are common in studies that collect samples from human subjects. RESULTS: We present MetaLonDA, an R package that is capable of identifying significant time intervals of differentially abundant microbial features. MetaLonDA is flexible such that it can perform differential abundance tests despite inconsistencies associated with sample collection. Extensive experiments on simulated datasets quantitatively demonstrate the effectiveness of MetaLonDA with significant improvement over alternative methods. We applied MetaLonDA to the DIABIMMUNE cohort ( https://pubs.broadinstitute.org/diabimmune ) substantiating significant early lifetime intervals of exposure to Bacteroides and Bifidobacterium in Finnish and Russian infants. Additionally, we established significant time intervals during which novel differentially relative abundant microbial genera may contribute to aberrant immunogenicity and development of autoimmune disease. CONCLUSION: MetaLonDA is computationally efficient and can be run on desktop machines. The identified differentially abundant features and their time intervals have the potential to distinguish microbial biomarkers that may be used for microbial reconstitution through bacteriotherapy, probiotics, or antibiotics. Moreover, MetaLonDA can be applied to any longitudinal count data such as metagenomic sequencing, 16S rRNA gene sequencing, or RNAseq. MetaLonDA is publicly available on CRAN ( https://CRAN.R-project.org/package=MetaLonDA ). PMID- 29439732 TI - A randomised controlled trial to test the effectiveness of decision training on assessors' ability to determine optimal fitness-to-drive recommendations for older or disabled drivers. AB - BACKGROUND: Driving licensing jurisdictions require detailed assessments of fitness-to-drive from occupational therapy driver assessors (OTDAs). We developed decision training based on the recommendations of expert OTDAs, to enhance novices' capacity to make optimal fitness-to-drive decisions. The aim of this research was to determine effectiveness of training on novice occupational therapists' ability to make fitness-to-drive decisions. METHODS: A double blind, parallel, randomised controlled trial was conducted to test the effectiveness of decision training on novices' fitness-to-drive recommendations. Both groups made recommendations on a series of 64 case scenarios with the intervention group receiving training after reviewing two thirds of the cases; the control group, at this same point, just received a message of encouragement to continue. Participants were occupational therapy students on UK and Australian pre registration programmes who individually took part online, following the website instructions. The main outcome of training was the reduction in mean difference between novice and expert recommendations on the cases. RESULTS: Two hundred eighty-nine novices were randomised into intervention; 166 completed the trial (70 in intervention; 96 in control). No statistical differences in scores were found pre-training. Post training, the control group showed no significant change in recommendations compared to the experts (t(96) = -.69; p = .5), whereas the intervention group exhibited a significant change (t(69) = 6.89; p < 0.001). For the intervention group, the mean difference compared with the experts' recommendations reduced with 95% CI from -.13 to .09. Effect size calculated at the post-training demonstrated a moderate effect (d = .69, r = .32). CONCLUSIONS: Novices who received the decision training were able to change their recommendations whereas those who did not receive training did not. Those receiving training became more able to identify drivers who were not fit-to drive, as measured against experts' decisions on the same cases. This research demonstrated that novice occupational therapists can be trained to make decisions more aligned to those of expert OTDAs. The decision training and cases have been launched as a free training resource at www.fitnesstodrive.com . This can be used by novice driver assessors to increase their skill to identify drivers who are, and are not fit-to-drive, potentially increasing international workforce capacity in this growing field of practice. PMID- 29439733 TI - Measuring empathy in pediatrics: validation of the Visual CARE measure. AB - BACKGROUND: Empathy is a key element of "Patient and Family Centered Care", a clinical approach recommended by the American Academy of Pediatrics. However, there is a lack of validated tools to evaluate paediatrician empathy. This study aimed to validate the Visual CARE Measure, a patient rated questionnaire measuring physician empathy, in the setting of a Pediatric Emergency Department (ED). METHODS: The empathy of physicians working in the Pediatric ED of the University Hospital of Udine, Italy, was assessed using an Italian translation of the Visual Care Measure. This test has three versions suited to different age groups: the 5Q questionnaire was administered to children aged 7-11, the 10Q version to those older than 11, and the 10Q-Parent questionnaire to parents of children younger than 7. The internal reliability, homogeneity and construct validity of the 5Q and 10Q/10Q-Parent versions of the Visual Care Measure, were separately assessed. The influence of family background on the rating of physician empathy and satisfaction with the clinical encounter was also evaluated. RESULTS: Seven physicians and 416 children and their parents were included in the study. Internal consistency measured by Cronbach's alpha was 0.95 for the 10Q/10Q-Parent versions and 0.88 for the 5Q version. The item-total correlation was > 0.75 for each item. An exploratory factor analysis showed that all the items load onto the first factor. Physicians' empathy scores correlated with patients' satisfaction for both the 10Q and 10Q-Parent questionnaires (Spearman's rho = 0.7189; p < 0.001) and for the 5Q questionnaire (Spearman's rho = 0.5968; p < 0,001). Trust in the consulting physician was lower among immigrant parents (OR 0.43. 95% CI 0.20-0.93). CONCLUSIONS: The Visual Care Measure is a reliable second-person test of physician empathy in the setting of a Pediatric Emergency Room. More studies are needed to evaluate the reliability of this instrument in other pediatric settings distinct from the Emergency Room and to further evaluate its utility in measuring the impact of communication and empathy training programmes for healthcare professionals working in pediatrics. PMID- 29439734 TI - Periodontitis in patients with cirrhosis: a cross-sectional study. AB - BACKGROUND: Many patients with cirrhosis have poor oral health but little is known on periodontitis, and its clinical significance is largely unknown. This study aimed to examine the prevalence and predictors of periodontitis, and evaluate the association of periodontitis with nutritional and systemic inflammation status. METHODS: 145 patients with cirrhosis were consecutively enrolled. Clinical, oral examination of plaque, pocket depth, clinical attachment level, and bleeding on probing was performed. Patients were categorized as having no-or-mild, moderate, or severe periodontitis. Predictors of severe periodontitis and the association with nutritional and systemic inflammation status were analyzed using univariable and multivariable logistic regression analyses. RESULTS: The large majority of patients had periodontitis, 46% of them severely and 39% moderately. Predictors of severe periodontitis included smoking (odds ratio (OR) 2.93, 95% confidence interval (CI) 1.29-6.63), brushing teeth twice daily (OR 0.30, 95% CI 0.11-0.79), and visiting the dentist annually (OR 3.51, 95% CI 1.22-10.81). Cirrhosis etiology or severity was not predictors of severe periodontitis. The patients with severe periodontitis had a higher nutritional risk score than patients with moderate, mild, or no periodontitis (3, interquartile range (IQR) 3-5 vs. 3, IQR 2-4, P = 0.02). CONCLUSIONS: Most cirrhosis patients had significant periodontitis, the severity of which was related to life style factors and was associated with higher nutrition risk score. Our results emphasize the need for further research to establish the effect of periodontitis on cirrhosis. PMID- 29439735 TI - Peripheral mononuclear blood cell apheresis in a preclinical ovine model. AB - BACKGROUND: Recent research has demonstrated that circulating peripheral blood mononuclear fractions (PBMC) containing haematopoietic stem (HSC)/progenitor cells have the potential to play a crucial role in regenerative medicine strategies. Work in our laboratory has shown that a peripheral blood mononuclear cell fraction (PBMC) enhances cartilage repair in an osteochondral defect model in sheep and has a significant effect on cells in the joint niche. In order to obtain PBMC rich blood containing HSCs for further studies, we have performed, for the first time, apheresis on adult sheep. RESULTS: Subcutaneous granulocyte colony stimulating factor (G-CSF) was used to mobilise white blood cells and continual flow apheresis was performed on 8 sheep under general anaesthetic. There were no observable side effects, although a marked tendency for blood clotting during the procedure was noted. The administration of G-CSF for 3 days increased the white blood cell (WBC) count in the peripheral blood from to 6.7 +/ 2.1 * 106/ml to 16.1 +/- 5.0 * 106/ml. Following apheresis, the WBC numbers in the apheretic product increased to 38.5 +/- 27.6 * 106/ml, comprised of a significant increase in neutrophils and PBMC (from 5.25 +/- 1.8 * 106/ml following G-CSF stimulation to 27.5 5 +/- 27.6 * 106/ml). There was a mean of 2.1% CD34 + ve cells and 95.5% CD45 + ve cells in the apheretic product. CONCLUSIONS: This study describes the administration of G-CSF and subsequent apheresis in adult sheep. The technique is safe when performed as described with no observable side effects. The technique permits collection of an increased WBC fraction containing neutrophils and PBMC in adult sheep. This apheretic product contains CD34 + ve cells, representing an HSC/progenitor population for use in in vivo and in vitro experiments. PMID- 29439736 TI - Clinical evaluation of two different protein content formulas fed to full-term healthy infants: a randomized controlled trial. AB - BACKGROUND: A high early protein intake is associated with rapid postnatal weight gain and altered body composition. We aimed to evaluate the safety of a low protein formula in healthy full-term infants. METHODS: A randomized controlled trial was conducted. A total of 118 infants were randomized to receive two different protein content formulas (formula A or formula B (protein content: 1.2 vs. 1.7 g/100 mL, respectively)) for the first 4 months of life. Anthropometry and body composition by air displacement plethysmography were assessed at enrolment and at two and 4 months. The reference group comprised 50 healthy, exclusively breastfed, full-term infants. RESULTS: Weight gain (g/day) throughout the study was similar between the formula groups (32.5 +/- 6.1 vs. 32.8 +/- 6.8) and in the reference group (30.4 +/- 5.4). The formula groups showed similar body composition but a different fat-free mass content from breastfed infants at two and 4 months. However, the formula A group showed a fat-free mass increase more similar to that of the breastfed infants. The occurrence of gastrointestinal symptoms or adverse events was similar between the formula groups. CONCLUSIONS: Feeding a low-protein content formula appears to be safe and to promote adequate growth, although determination of the long-term effect on body composition requires further study. TRIAL REGISTRATION: The present study was retrospectively registered in ClinicalTrials.gov (trial number: NCT03035721 on January 18, 2017). PMID- 29439737 TI - Variability of phenolic and alkaloid content in different plant parts of Carissa edulis Vahl and Zanthoxylum chalybeum Engl. AB - OBJECTIVE: The objective of the study was to investigate the relative abundance and effect of post-harvest treatment on total phenolics (TP) and total alkaloids in the leaves and bark of Carissa edulis and Zanthoxylum chalybeum, which would give an indication of the suitability of leaves as alternative sources of medicine in these plant species. RESULTS: Results indicated higher levels of total phenolics than total alkaloids in both of the species under both freezing and air drying conditions. While more alkaloids were found in leaves compared to bark, there was no difference in abundance of phenols between the plant parts of both species. Air drying preserved more TPs than freezing and the opposite was true for alkaloids. For sustainability, leaves are recommended as an alternative source of medicine instead of the preferred root or stem bark. However, the choice of whether to dry or freeze will depend on the specific compound of interest. Assessment of spatial variability of medicinal properties is highly recommended. PMID- 29439738 TI - Dietary inflammatory index: a potent association with cardiovascular risk factors among patients candidate for coronary artery bypass grafting (CABG) surgery. AB - BACKGROUND: Recently, the clinical importance of dietary inflammatory index (DII) in predicting the inflammatory potential of diet and its role in pathogenesis of several chronic disease including some types of cancers, osteoporosis, cardiovascular disease and renal disease has been proposed. However, its association with the disease severity and progression and cardio-metabolic risk factors among patients candidate for coronary artery bypass graft surgery (CABG) has not been evaluated yet. In the current study, the association of DII with cardiovascular risk factors among patients candidate for CABG has been investigated. METHODS: In the current cross-sectional study, 454 patients aged 35 80 years as candidates of CABG and hospitalized in Tehran Heart Center were enrolled. Anthropometric and demographic characteristics were obtained from all of the participants. Dietary intakes were evaluated with a semi-quantitative food frequency questionnaire (FFQ) and DII was calculated. Biochemical parameters including hemoglobin (Hb) A1C, serum lipids, albumin, creatinine and high sensitive C-reactive protein (hs-CRP), lipoprotein (a), creatinine, blood urea nitrogen (BUN), albumin and hematocrit (HCT) were also assessed by commercial laboratory methods. Left ventricular ejection- fraction, number of diseased vessels, New York Heart Association (NYHA) functional class and the European system for cardiac operative risk evaluation (EuroSCORE) were estimated for clinical assessment. One way analysis of variance and chi square tests were used for comparison of demographic parameters between groups. Beta estimates and 95% confidence intervals (CI) for the association between DII and clinical parameters were estimated using linear regression adjusted for the confounders. RESULTS: According to our findings, high DII scores were associated with higher age, lower body mass index (BMI), higher prevalence of diabetes and myocardial infarction (MI) and lower educational attainment (P < 0.05). Male patients in 4th and 3rd quartile of DII had significantly higher total cholesterol (TC), triglyceride (TG), albumin, creatinine, BUN and hs-CRP concentrations and lower high density lipoprotein cholesterol (HDL) concentrations compared with male patients in lower quartiles (P < 0.05). While in female patients, only lipoprotein (a) concentrations and hematocrit (HCT) percentage in the 4th and 2nd quartile were significantly higher than lower quartiles. EuroSCORE was also significantly higher in top quartiles of DII (P = 0.006). CONCLUSION: As shown in our results, DII was in a positive association with several cardiovascular risk factors. The higher inflammatory potential of diet denoted higher values of serum lipids, CRP and kidney function tests and higher EuroSCORE as a predictor of post-operative mortality. Therefore, DII can be demonstrated as a target of nutritional interventions for ameliorating the CVD risk factors among patients candidate for CABG especially in male patients. PMID- 29439739 TI - Sex difference in clot lysability and association to coronary artery calcification. AB - BACKGROUND: Incidence and prevalence of cardiovascular disease (CVD) differ between sexes, and women experience CVD later than men. Changes in fibrin clot lysability are associated with CVD, and the present study addresses sex differences in fibrin clot lysability in asymptomatic middle-aged individuals and the relation to coronary artery calcification (CAC). METHODS: Participants free of morbidities and medication, N = 163, were randomly chosen from a national registry among citizens, 50 or 60 years of age, and were followed for 5 years. CAC was determined by the Agatston (Ag) score both at baseline and at follow-up. Based on the changes in Ag, the population was divided into two groups: DeltaAg = 0 U or DeltaAg > 0 U. Fibrin clot analyses were based on turbidimetric methods. RESULTS: At baseline, 116 women and 97 men were included; 84 women and 79 men completed the 5-year follow-up (77%). Independently of covariates, women with DeltaAg > 0 had reduced mean (SD) fibrin lysability at follow-up, 40.2% (15.9), both in comparison to baseline, 47.8% (20.4), p = 0.001, to women with DeltaAg = 0 U, 51.2% (24.5), p = 0.028, and to men with DeltaAg > 0 U, 54.4% (21.0), p = 0.002. CONCLUSIONS: Fibrin clot lysability changes over time with considerable sex differences. Women with progression of CAC have reduced fibrin clot lysability compared to men, indicating a sex-specific association between morphological vessel wall changes and fibrin clot lysability. PMID- 29439740 TI - Effects on inequality in life expectancy from a social ecology perspective. AB - BACKGROUND: Inequality in life expectancy (ILE) is defined as inequality in the distribution of expected span of life-based on data from survival tables estimated using the Atkinson inequality index. ILE can be influenced by socio ecological indicators including the Gini coefficient, secondary education, output per worker, and old age pension. This study examined the effects on ILE from a social ecology perspective. METHODS: This analysis is based on ILE data from 108 countries obtained from the United Nations Development Programme. Data on socio ecological indicators were obtained from the United Nations database. The associations between socio-ecological indicators and ILE were assessed using correlation coefficients and multiple regression models. RESULTS: Significant correlations were evident between ILE and the following indicators from a socio ecological perspective: Gini coefficient (GC: r = 0.335, p = 0.001) as an indicator of income inequality, female population with at least some secondary education (FSE: r = - 0.757, p = 0.001), male population with at least some secondary education (MSE: r = - 0.741, p = 0.001), output per worker as a measure of labor productivity (OPW: r = - 0.714, p = 0.001), and number of old age pension recipients (OPR: r = - 0.641, p = 0.001). In multivariate regression, the ILE predictors were higher GC and lower levels of FSE, MSE, OPW, and OPR (R2 = 0.648, p < 0.001). CONCLUSIONS: Socio-ecological factors have an important effect on ILE. Policies that address ILE should consider targeted socio-ecological factors, such as the Gini coefficient of income inequality, that give a personal perspective of economic deprivation, attainment of at least a secondary education by both females and males that gives a social environment perspective, output per worker that indicates labor productivity, and the number of old age pension recipients that indicates social security from a public policy perspective. PMID- 29439742 TI - The chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of vascular smooth muscle cells. AB - BACKGROUND: Thrombomodulin (TM), a transmembrane glycoprotein highly expressed in endothelial cells (ECs), is a potent anticoagulant maintaining circulation homeostasis. Under inflammatory states, TM expression is drastically reduced in ECs while vascular smooth muscle cells (VSMCs) show a robust expression of TM. The functional role of TM in VSMCs remains elusive. METHODS: We examined the role of TM in VSMCs activities in human aortic VSMCs stimulated with platelet-derived growth factor-BB (PDGF-BB). Using rat embryonic aorta-derived A7r5 VSMCs which do not express TM, the role of the chondroitin sulfate (CS) moiety of TM in VSMCs was delineated with cells expressing wild-type TM and the CS-devoid TM mutant. RESULTS: Expression of TM enhanced cell migration and adhesion/spreading onto type I collagen, but had no effect on cell proliferation. Knocking down TM with short hairpin RNA reduced PDGF-stimulated adhesion and migration of human aortic VSMCs. In A7r5 cells, TM-mediated cell adhesion was eradicated by pretreatment with chondroitinase ABC which degrades CS moiety. Furthermore, the TM mutant (TMS490, 492A) devoid of CS moiety failed to increase cell adhesion, spreading or migration. Wild-type TM, but not TMS490, 492A, increased focal adhesion kinase (FAK) activation during cell adhesion, and TM-enhanced cell migration was abolished by a function-blocking anti-integrin beta1 antibody. CONCLUSION: Chondroitin sulfate modification is required for TM-mediated activation of beta1 integrin and FAK, thereby enhancing adhesion and migration activity of VSMCs. PMID- 29439741 TI - Antibiotic-mediated changes in the fecal microbiome of broiler chickens define the incidence of antibiotic resistance genes. AB - BACKGROUND: Antimicrobial agents have been widely used in animal farms to prevent and treat animal diseases and to promote growth. Antimicrobial agents may change the bacterial community and enhance the resistome in animal feces. We used metagenome-wide analysis to investigate the changes in bacterial community, variations in antibiotic resistance genes (ARGs), and their bacterial hosts in the feces of broiler chickens over a full-treatment course of chlortetracycline at low and therapeutic dose levels. RESULTS: The effects of chlortetracycline on resistome were dependent on the specific ARG subtypes and not simply the overall community-level ARGs. Therapeutic dose of chlortetracycline promoted the abundance of tetracycline resistance genes (tetA and tetW) and inhibited multidrug resistance genes (mdtA, mdtC, mdtK, ompR, and TolC). The therapeutic dose of chlortetracycline led to loss of Proteobacteria mainly due to the decrease of Escherichia/Shigella (from 72 to 58%). Inhibition of Escherichia by chlortetracycline was the primary reason for the decrease of genes resistant to multiple drugs in the therapeutic dose group. The ARG host Bifidobacterium were enriched due to tetW harbored by Bifidobacterium under chlortetracycline treatment. Escherichia was always the major host for multidrug resistance genes, whereas the primary host was changed from Escherichia to Klebsiella for aminoglycoside resistance genes with the treatment of therapeutic dose of chlortetracycline. CONCLUSIONS: We provided the first metagenomic insights into antibiotic-mediated alteration of ARG-harboring bacterial hosts at community-wide level in chicken feces. These results indicated that the changes in the structure of antibiotic-induced feces microbial communities accompany changes in the abundance of bacterial hosts carrying specific ARGs in the feces microbiota. These findings will help to optimize therapeutic schemes for the effective treatment of antibiotic resistant pathogens in poultry farms. Resistome variations in faecal microbiome of chickens exposed to chlortetracycline. PMID- 29439743 TI - Supportive supervision and constructive relationships with healthcare workers support CHW performance: Use of a qualitative framework to evaluate CHW programming in Uganda. AB - BACKGROUND: While evidence supports community health worker (CHW) capacity to improve maternal and newborn health in less-resourced countries, key implementation gaps remain. Tools for assessing CHW performance and evidence on what programmatic components affect performance are lacking. This study developed and tested a qualitative evaluative framework and tool to assess CHW team performance in a district program in rural Uganda. METHODS: A new assessment framework was developed to collect and analyze qualitative evidence based on CHW perspectives on seven program components associated with effectiveness (selection; training; community embeddedness; peer support; supportive supervision; relationship with other healthcare workers; retention and incentive structures). Focus groups were conducted with four high/medium-performing CHW teams and four low-performing CHW teams selected through random, stratified sampling. Content analysis involved organizing focus group transcripts according to the seven program effectiveness components, and assigning scores to each component per focus group. RESULTS: Four components, 'supportive supervision', 'good relationships with other healthcare workers', 'peer support', and 'retention and incentive structures' received the lowest overall scores. Variances in scores between 'high'/'medium'- and 'low'-performing CHW teams were largest for 'supportive supervision' and 'good relationships with other healthcare workers.' Our analysis suggests that in the Bushenyi intervention context, CHW team performance is highly correlated with the quality of supervision and relationships with other healthcare workers. CHWs identified key performance-related issues of absentee supervisors, referral system challenges, and lack of engagement/respect by health workers. Other less-correlated program components warrant further study and may have been impacted by relatively consistent program implementation within our limited study area. CONCLUSIONS: Applying process-oriented measurement tools are needed to better understand CHW performance-related factors and build a supportive environment for CHW program effectiveness and sustainability. Findings from a qualitative, multi-component tool developed and applied in this study suggest that factors related to (1) supportive supervision and (2) relationships with other healthcare workers may be strongly associated with variances in performance outcomes within a program. Careful consideration of supervisory structure and health worker orientation during program implementation are among strategies proposed to increase CHW performance. PMID- 29439745 TI - Some problems with non-inferiority tests in psychotherapy research: psychodynamic therapies as an example. AB - In virtually every field of medicine, non-inferiority trials and meta-analyses with non-inferiority conclusions are increasingly common. This non-inferiority approach has been frequently used by a group of authors favoring psychodynamic therapies (PDTs), concluding that PDTs are just as effective as cognitive behavioral therapies (CBT). We focus on these examples to exemplify some problems associated with non-inferiority tests of psychological treatments, although the problems also apply to psychopharmacotherapy research, CBT research, and others. We conclude that non-inferiority trials have specific risks of different types of validity problems, usually favoring an (erroneous) non-inferiority conclusion. Non-inferiority trials require the definition of non-inferiority margins, and currently used thresholds have a tendency to be inflationary, not protecting sufficiently against degradation. The use of non-inferiority approaches can lead to the astonishing result that one single analysis can suggest both, superiority of the comparator (here: CBT) and non-inferiority of the other treatment (here PDT) at the same time. We provide recommendations how to improve the quality of non-inferiority trials, and we recommend to consider them among other criteria when evaluating manuscripts examining non-inferiority trials. If psychotherapeutic families (such as PDT and CBT) differ on the number of investigating trials, and in the fields of clinical applications, and in other validity aspects mentioned above, conclusions about their general non-inferiority are no more than a best guess, typically expressing the favored approach of the lead author. PMID- 29439746 TI - Antimicrobial Stewardship Program Implementation of a Quality Improvement Intervention Using Real-Time Feedback and an Electronic Order Set for the Management of Staphylococcus aureus Bacteremia. AB - Antimicrobial stewardship programs can optimize the management of Staphylococcus aureus bacteremia by integrating information technology and microbiology laboratory resources. This study describes our experience implementing an intervention consisting of real-time feedback and the use of an electronic order set for the management of S. aureus bacteremia. Infect Control Hosp Epidemiol 2018;39:346-349. PMID- 29439744 TI - An investigation into closed-loop treatment of neurological disorders based on sensing mitochondrial dysfunction. AB - Dynamic feedback based closed-loop medical devices offer a number of advantages for treatment of heterogeneous neurological conditions. Closed-loop devices integrate a level of neurobiological feedback, which allows for real-time adjustments to be made with the overarching aim of improving treatment efficacy and minimizing risks for adverse events. One target which has not been extensively explored as a potential feedback component in closed-loop therapies is mitochondrial function. Several neurodegenerative and psychiatric disorders including Parkinson's disease, Major Depressive disorder and Bipolar disorder have been linked to perturbations in the mitochondrial respiratory chain. This paper investigates the potential to monitor this mitochondrial function as a method of feedback for closed-loop neuromodulation treatments. A generic model of the closed-loop treatment is developed to describe the high-level functions of any system designed to control neural function based on mitochondrial response to stimulation, simplifying comparison and future meta-analysis. This model has four key functional components including: a sensor, signal manipulator, controller and effector. Each of these components are described and several potential technologies for each are investigated. While some of these candidate technologies are quite mature, there are still technological gaps remaining. The field of closed-loop medical devices is rapidly evolving, and whilst there is a lot of interest in this area, widespread adoption has not yet been achieved due to several remaining technological hurdles. However, the significant therapeutic benefits offered by this technology mean that this will be an active area for research for years to come. PMID- 29439747 TI - Paediatric obstructive sleep apnoea: can our identification of surgical candidates be evidence-based? AB - BACKGROUND: Paediatric obstructive sleep apnoea is a common clinical condition managed by most ENT clinicians. However, despite the plethora of publications on the subject, there is wide variability, in the literature and in practice, on key aspects such as diagnostic criteria, the impact of co-morbidities and the indications for surgical correction. METHODS: A systematic review is presented, addressing four key questions from the available literature: (1) what is the evidence base for any definition of paediatric obstructive sleep apnoea?; (2) does it cause serious systemic illness?; (3) what co-morbidities influence the severity of paediatric obstructive sleep apnoea?; and (4) is there a medical answer? RESULTS AND CONCLUSION: There is a considerable lack of evidence regarding most of these fundamental questions. Notably, screening measures show low specificity and can be insensitive to mild obstructive sleep apnoea. There is a surprising lack of clarity in the definition (let alone estimate of severity) of sleep-disordered breathing, relying on what may be arbitrary test thresholds. Areas of potential research might include investigation of the mechanisms through which obstructive sleep apnoea causes co-morbidities, whether neurocognitive, behavioural, metabolic or cardiovascular, and the role of non-surgical management. PMID- 29439748 TI - Community treatment orders: an analysis of the first five years of use in England. AB - BACKGROUND: Community treatment orders (CTOs) were introduced in England in 2008. Aims To measure the rate of CTO use in England during the first 5 years following introduction. METHOD: The number of involuntary detentions and CTOs in National Health Service (NHS) hospital trusts was collected between 2009 and 2014. Rates of CTO use and the ratio of CTOs to detentions on admission were calculated, and how these varied between trusts. RESULTS: The number of new CTOs each year ranged between 3834 and 4647. The number subject to a CTO per 100 000 population increased from 6.4 in 2009/10 to 10.0 in 2013/14. There was variation between NHS trusts in the use of CTOs when compared with the number of involuntary detentions CONCLUSIONS: The number of patients on CTOs increased year on year. Those on forensic sections were more likely to be discharged on a CTO than those on civil sections. There was considerable variation in the pattern of use between hospitals. Declaration of interest None. PMID- 29439749 TI - Letter to the Editor: NMDA receptor autoimmunity in mania following HSV encephalitis. PMID- 29439750 TI - Differential neural reward mechanisms in treatment-responsive and treatment resistant schizophrenia. AB - BACKGROUND: The significant proportion of schizophrenia patients refractory to treatment, primarily directed at the dopamine system, suggests that multiple mechanisms may underlie psychotic symptoms. Reinforcement learning tasks have been employed in schizophrenia to assess dopaminergic functioning and reward processing, but these have not directly compared groups of treatment-refractory and non-refractory patients. METHODS: In the current functional magnetic resonance imaging study, 21 patients with treatment-resistant schizophrenia (TRS), 21 patients with non-treatment-resistant schizophrenia (NTR), and 24 healthy controls (HC) performed a probabilistic reinforcement learning task, utilizing emotionally valenced face stimuli which elicit a social bias toward happy faces. Behavior was characterized with a reinforcement learning model. Trial-wise reward prediction error (RPE)-related neural activation and the differential impact of emotional bias on these reward signals were compared between groups. RESULTS: Patients showed impaired reinforcement learning relative to controls, while all groups demonstrated an emotional bias favoring happy faces. The pattern of RPE signaling was similar in the HC and TRS groups, whereas NTR patients showed significant attenuation of RPE-related activation in striatal, thalamic, precentral, parietal, and cerebellar regions. TRS patients, but not NTR patients, showed a positive relationship between emotional bias and RPE signal during negative feedback in bilateral thalamus and caudate. CONCLUSION: TRS can be dissociated from NTR on the basis of a different neural mechanism underlying reinforcement learning. The data support the hypothesis that a favorable response to antipsychotic treatment is contingent on dopaminergic dysfunction, characterized by aberrant RPE signaling, whereas treatment resistance may be characterized by an abnormality of a non-dopaminergic mechanism - a glutamatergic mechanism would be a possible candidate. PMID- 29439751 TI - Impact of hepatitis B vaccination on acute hepatitis B epidemiology in European Union/European Economic Area countries, 2006 to 2014. AB - Hepatitis B prevention in European Union/European Economic Area (EU/EEA) countries relies on vaccination programmes. We describe the epidemiology of acute hepatitis B virus (HBV) at country and EU/EEA level during 2006-2014. Using a multi-level mixed-effects Poisson regression model we assessed differences in the acute HBV infection notification rates between groups of countries that started universal HBV vaccination before/in vs after 1995; implemented or not a catch-up strategy; reached a vaccine coverage >= 95% vs < 95% and had a hepatitis B surface antigen prevalence >= 1% vs < 1%. Joinpoint regression analysis was used to assess trends by groups of countries, and additional Poisson regression models to evaluate the association between three-dose HBV vaccine coverage and acute HBV infection notification rates at country and EU/EEA level. The EU/EEA acute HBV infection notification rate decreased from 1.6 per 100,000 population in 2006 to 0.7 in 2014. No differences (p > 0.05) were found in the acute HBV infection notification rates between groups of countries, while as vaccine coverage increased, such rates decreased (p < 0.01). Countries with universal HBV vaccination before 1995, a catch-up strategy, and a vaccine coverage >= 95% had significant decreasing trends (p < 0.01). Ending HBV transmission in Europe by 2030 will require high vaccine coverage delivered through universal programmes, supported, where appropriate, by catch-up vaccination campaigns. PMID- 29439752 TI - High transmissibility of norovirus among infants and school children during the 2016/17 season in Osaka, Japan. AB - The number of person-to-person transmitted norovirus cases (n = 4,712) in school children in Osaka, Japan, during 2016/17 was the largest since 2012/13. Norovirus outbreaks were reported by 101 schools including 53 nursery schools (1,927 cases), 18 kindergartens (1,086 cases) and 30 elementary schools (1,699 cases). The dominant genotype among outbreaks was GII.P16-GII.2 (57.4%; 58/101), followed by GII.P2-GII.2 (8.9%; 9/101) and GII.P7-GII.6 (5.9%; 6/101). GII.4 was not detected despite dominance in previous years. PMID- 29439753 TI - Genital Chlamydia trachomatis infections in young adults - a school-based bio behavioural study in urban areas, Poland, 2012 to 2015. AB - Context and AimOne of the most common sexually transmitted pathogens disproportionately affecting young people is Chlamydia trachomatis (CT). This study aimed to assess prevalence of CT among sexually active students (aged 18-19 years) in their final years of high school education in Warsaw and Krakow. Methods: The sample was selected from 61 clusters, each cluster representing one school. We described city, sex, type of school and their association with CT prevalence. To account for non-responders we applied inverse probability weighting. Results: Our study population consisted of 3,136 young adults eligible for CT screening, of whom 2,326 reported having had sexual intercourse within past 12 months. Of the 950 students who agreed to be tested, 39 were infected with CT. Weighted prevalence of CT was 3.9% (95% confidence interval (CI): 2.7 5.1); however, prevalence in the students in Warsaw (6.6%; 95% CI: 3.5-12.4) was six times higher (prevalence ratio (PR) = 5.9; 95% CI: 2.0-17.3) than in Krakow (1.1%; 95% CI: 0.5-2.6). In both settings, female students attending vocational technical schools were most affected; the prevalence in this group was more than five times higher (PR = 5.2; 95% CI: 1.7-15.6) compared with female peers in high schools and more than three times higher (PR = 3.3; 95% CI: 1.0-10.7) compared with male peers attending vocational-technical schools. Conclusion: Our study suggested prevalence of CT infection among young people in Poland comparable with the European average, supporting implementation of a CT control programme as recommended in international guidelines. PMID- 29439754 TI - Multiplex PCR for detection of plasmid-mediated colistin resistance determinants, mcr-1, mcr-2, mcr-3, mcr-4 and mcr-5 for surveillance purposes. AB - Background and aimPlasmid-mediated colistin resistance mechanisms have been identified worldwide in the past years. A multiplex polymerase chain reaction (PCR) protocol for detection of all currently known transferable colistin resistance genes (mcr-1 to mcr-5, and variants) in Enterobacteriaceae was developed for surveillance or research purposes. Methods: We designed four new primer pairs to amplify mcr-1, mcr-2, mcr-3 and mcr-4 gene products and used the originally described primers for mcr-5 to obtain a stepwise separation of ca 200 bp between amplicons. The primer pairs and amplification conditions allow for single or multiple detection of all currently described mcr genes and their variants present in Enterobacteriaceae. The protocol was validated testing 49 European Escherichia coli and Salmonella isolates of animal origin. Results: Multiplex PCR results in bovine and porcine isolates from Spain, Germany, France and Italy showed full concordance with whole genome sequence data. The method was able to detect mcr-1, mcr-3 and mcr-4 as singletons or in different combinations as they were present in the test isolates. One new mcr-4 variant, mcr-4.3, was also identified. Conclusions: This method allows rapid identification of mcr positive bacteria and overcomes the challenges of phenotypic detection of colistin resistance. The multiplex PCR should be particularly interesting in settings or laboratories with limited resources for performing genetic analysis as it provides information on the mechanism of colistin resistance without requiring genome sequencing. PMID- 29439755 TI - Computer-Assisted versus Oral-and-Written History Taking for the Prevention and Management of Cardiovascular Disease: a Systematic Review of the Literature. AB - BACKGROUND AND OBJECTIVES: CVD is an important global healthcare issue; it is the leading cause of global mortality, with an increasing incidence identified in both developed and developing countries. It is also an extremely costly disease for healthcare systems unless managed effectively. In this review we aimed to: - Assess the effect of computer-assisted versus oral-and-written history taking on the quality of collected information for the prevention and management of CVD. - Assess the effect of computer-assisted versus oral-and-written history taking on the prevention and management of CVD. METHODS: A systematic review of randomised controlled trials that included participants of 16 years or older at the beginning of the study, who were at risk of CVD (prevention) or were either previously diagnosed with CVD (management). We searched all major databases. We assessed risk of bias using the Cochrane Collaboration tool. RESULTS: Two studies met the inclusion criteria. One comparing the two methods of history-taking for the prevention of cardiovascular disease n = 75. The study shows that generally the patients in the experimental group underwent more laboratory procedures, had more biomarker readings recorded and/or were given (or had reviewed), more dietary changes than the control group. The other study compares the two methods of history-taking for the management of cardiovascular disease (n = 479). The study showed that the computerized decision aid appears to increase the proportion of patients who responded to invitations to discuss CVD prevention with their doctor. The Computer- Assisted History Taking Systems (CAHTS) increased the proportion of patients who discussed CHD risk reduction with their doctor from 24% to 40% and increased the proportion who had a specific plan to reduce their risk from 24% to 37%. DISCUSSION: With only one study meeting the inclusion criteria, for prevention of CVD and one study for management of CVD we did not gather sufficient evidence to address all of the objectives of the review. We were unable to report on most of the secondary patient outcomes in our protocol. CONCLUSIONS: We tentatively conclude that CAHTS can provide individually-tailored information about CVD prevention. However, further primary studies are needed to confirm these findings. We cannot draw any conclusions in relation to any other clinical outcomes at this stage. There is a need to develop an evidence base to support the effective development and use of CAHTS in this area of practice. In the absence of evidence on effectiveness, the implementation of computer-assisted history taking may only rely on the clinicians' tacit knowledge, published monographs and viewpoint articles. PMID- 29439756 TI - S100A4 Protein in Inflammatory Bowel Disease: Results of a Single Centre Prospective Study. AB - INTRODUCTION: The aim of our study was to assess association of serum S100A4 protein with ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Study included 118 subjects: 93 patients with CD, 16 with UC and 9 controls. In CD group, 20/93 patients had B1 phenotype, 19/93 B2, 20/93 B3 and 34/93 B2 + B3. L1 involvement was present in 15/93, L2 in 14/93 and L3 in 64/93 patients. Serum S100A4 concentration was investigated in peripheral venous blood samples by means of ELISA. RESULTS: Serum S100A4 was significantly higher in UC (158.6 +/- 56.2 ng/mL), p = 0.019 and in CD (154.4 +/- 52.1 ng/mL), p = 0.007 compared to controls (104.8 +/- 40.5 ng/mL). No difference in S100A4 was revealed between UC and CD, p > 0.05. Serum S100A4 in each CD subgroup (according to behaviour) was significantly higher compared to controls, p < 0.05. Serum S100A4 was significantly higher in L2 (144.6 +/- 44.2 ng/mL), p = 0.041 and in L3 (163.0 +/- 52.8 ng/mL), p = 0.002 compared to controls and in L3 compared to L1 (126.9 +/- 47.6 ng/mL), p = 0.017. CONCLUSION: Association of serum S100A4 protein with UC and CD was confirmed. In CD, disease behaviour did not influence serum concentration of S100A4 protein. In CD, higher levels of serum S100A4 were observed in patients with ileo-colonic and colonic involvement compared to those with isolated small bowel involvement. PMID- 29439757 TI - Comparative Evaluation of Effect of Nano-hydroxyapatite and 8% Arginine Containing Toothpastes in Managing Dentin Hypersensitivity: Double Blind Randomized Clinical Trial. AB - PURPOSE: This double blind randomized clinical trial was conducted with the purpose of evaluating the effects of Nano-hydroxyapatite toothpaste as compared to 8% Arginine containing toothpaste in the management of Dentin hypersensitivity (DH). METHOD AND MATERIALS: Patients (30 in each group) suffering from DH and eliciting a VAS score higher than 2 in air blast and tactile test were randomly allocated (block randomization) into either a group 1 (arginine toothpaste) or group 2 (nHA toothpaste). The primary outcome evaluated was the reduction of DH as measured by the electrical stimulus reading on the digital pulp tester. Current required for eliciting a VAS score of 2 was recorded before application of dentifrice. 1 cm of toothpaste was then expressed on the tooth surface for two minutes in each group and rinsed off. The electrical stimulus required to elicit a VAS score of 2 was recorded after 5 minutes, 1 week and 4 weeks. RESULTS: The desensitizing paste containing arginine provided a statistically significant reduction in DH and so did the paste containing nHA. Mean increase in amperage value (reduction in DH) was higher for nHA based than the arginine containing dentifrice. This difference was not statistically significant showing that both toothpastes are equally effective. CONCLUSIONS: The findings of the present study encourage the use of Nano-hydroxyapatite and arginine containing dentifrice as an effective desensitizing agent providing relief from symptoms 5 minutes after application and after 1 and 4 weeks. PMID- 29439758 TI - Bilateral Simultaneous Testicular Torsion in a Newborn: Report of a Case. AB - INTRODUCTION: Testicular torsion is a urological emergency. If not recognized in time, this condition may result in ischaemic injury and loss of testis. Simultaneous bilateral neonatal testicular torsion is extremely rare and is usually misdiagnosed. CASE REPORT: We report a case of a male newborn, who presented with bilateral scrotal swelling and redness of the scrotum. Doppler ultrasound supported the diagnosis of bilateral testicular torsion, with an absent blood flow signal on the right side and a weak signal on the left side. Testicular exploration through scrotal incision was performed and bilateral testicular torsion was found. Right testis was grossly gangrenous, and right orchiectomy was performed. Left testicle was dark but showed recovery after detorsion with some bleeding from incised tunica albugenia. Fixation of the left testicle was performed. At six month follow-up, the left testis showed signs of atrophy and hormonal assay showed very low testosterone and elevated LH and FSH, suggesting hypogonadism. CONCLUSIONS: Management of neonatal testicular torsion is a matter of controversy. Testicular torsion results into acute ischemia and urgent surgical exploration is the key point of management. Although the possibility of salvaging the involved testicles is usually very low it is hard to justify a passive approach to a bilateral torsion resulting in such a devastating condition as anorchia. PMID- 29439759 TI - A Rare History: an Intracranial Nail Present for Over a Half-Century. AB - We present a rare case of a patient with a persistent headache for many years found to have an intracranial nail present for nearly 65 years. The nail was found entering approximately 1 cm from the midline on the left side, passing below the superior sagittal sinus, with the tip 1.5 mm right of the frontal horn of the lateral ventricle. Treatment strategies designed to optimize outcome for intracranial foreign bodies and possible complications are discussed in this report. We also discuss the decision for surgical intervention for foreign bodies and the relevance of position of the foreign body. PMID- 29439760 TI - Rare Abdominal Wall Malformation: Case Report of Umbilical Cord Hernia. AB - The umbilical cord hernia is the rarest form of abdominal wall malformations, anatomically completely different from gastroschisis and omphalocele. It occurs due to the permanent physiological evisceration of abdominal organs into umbilical celom and persistence of a patent umbilical ring. The umbilical cord hernia is often mistaken for omphalocele and called "small omphalocele". Here we present a case of a female newborn with umbilical cord hernia treated in our Hospital. After preoperative examinations surgery was done on the second day of life. The abdominal wall was closed without tension. The aim of this article is to present the importance of the proper diagnose of these three entities and to stimulate academic community for the answer, is this umbilical cord hernia or small omphalocele. PMID- 29439761 TI - Amyand's Hernia: an Up-to-Date Review of the Literature. AB - Amyand's hernia is defined as an inguinal hernia, containing the appendix within the hernia sac. Incidence of this rare condition rises up to 1% (0.19-1.7%) of all inguinal hernia cases. Inflammation of the appendix within the inguinal sac is even rarer, as it corresponds to 0.1% (0.07-0.13%) of all Amyand's hernia cases. After a comprehensive review of the limited relevant literature, we aim through this review study to describe the pathophysiology of inflammation of the appendix - contained in the hernia sac - and present the latest data about the diagnostic approach and surgical treatment of Amyand's hernia. PMID- 29439763 TI - Manipulative Handling of Data. PMID- 29439762 TI - The Treatment of Temporomandibular Joint Dislocation. AB - BACKGROUND: The estimated incidence of temporomandibular joint dislocation in Germany is at least 25/100 000 per year. A correct diagnosis and the initiation of appropriate treatment without delay are essential if permanent damage to the joint is to be avoided. METHODS: This review is based on pertinent publications retrieved by a systematic search in the PubMed, Cochrane, Embase, and ZB Med databases. RESULTS: The initial search yielded 24 650 hits; duplicates were removed and 136 studies were chosen for further analysis. The diagnosis of temporomandibular joint dislocation is generally made clinically from the finding of a lower jaw that is fixed in the open position. Acute dislocations are manually repositioned at once. The most common method is Hippocratic repositioning, in which the physician's thumb is placed laterally next to the teeth and the other fingers are placed on the lower surface of the lower jaw. The physician then exerts pressure, first caudally, then dorsally. Repositioning is carried out in two steps. For dislocations that have been present for a longer time, manual repositioning may be ineffective and surgery may be needed. Recurrent dislocation can be treated in a minimally invasive way with botulinum toxin injections or autologous blood therapy. Surgery may be needed if these methods are ineffective. CONCLUSION: There have been no more than a few randomized, controlled trials of treatments for temporomandibular joint dislocation, in particular concerning minimally invasive and open surgical treatments, and therefore only limited evidence-based conclusions can be drawn. Nonetheless, the diagnostic and therapeutic standards that have been established in recent years have gained wide international acceptance. PMID- 29439764 TI - Inadequate Statistical Evaluation. PMID- 29439765 TI - No Primary Care Physician Available. PMID- 29439766 TI - Unclear Group Formation. PMID- 29439767 TI - In Reply. PMID- 29439768 TI - Better Care Possible. PMID- 29439769 TI - In Reply. PMID- 29439770 TI - Heterotopic Ossification in a Dialysis Patient. PMID- 29439771 TI - Osteoporotic Pelvic Fractures. AB - BACKGROUND: The estimated incidence of osteoporotic pelvic fractures among persons over age 60 in Germany is 224 per 100 000 persons per year, and rising. A number of surgical treatment options are available, but clinical long-term data are lacking. METHODS: This review is based on pertinent publications and guidelines retrieved by a selective literature search, and on the authors' clinical experience. RESULTS: Patients often report one or more relatively trivial traumatic incidents leading up to the fracture. They complain of pain in the hip, groin, or lower lumbar region, or of low back pain and sciatica. A new classification scheme entitled Fragility Fractures of the Pelvis (FFP) takes the morphology of the fracture into account and can be used as an aid to therapeutic decision-making (evidence level IV). The goal of treatment is early mobilization with adequate pain relief. Isolated anterior pelvic ring fractures (FFP I) and nondisplaced posterior pelvic ring fractures (FFP II) are usually stable and can be treated conservatively. Type III and IV injuries are unstable and should generally be treated surgically. CONCLUSION: Retrospective analyses have shown that osteoporotic pelvic fractures are associated with decreased mobility and independence and with a one-year mortality ranging from 9.5% to 27%. Prospective therapeutic trials are urgently needed. PMID- 29439772 TI - Stomatitis associated with mammalian target of rapamycin inhibition: A review of pathogenesis, prevention, treatment, and clinical implications for oral practice in metastatic breast cancer. AB - BACKGROUND: Patients with metastatic breast cancer may develop oral morbidities that result from therapeutic interventions. Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a common adverse event (AE), secondary to mTOR inhibitor therapy, that can have a negative impact on treatment adherence, quality of life, and health care costs. A multidisciplinary team approach is important to minimize mIAS and to maximize treatment benefits to patients with breast cancer. In this review, we discuss the pathophysiology, diagnosis, and natural history of mIAS. Current and new management strategies for the prevention and treatment of mIAS are described in the context of fostering a coordinated team care approach to optimizing patient care. TYPES OF STUDIES REVIEWED: The authors conducted a PubMed search from 2007 through 2017 using the terms "stomatitis," "mIAS," "everolimus," "mTOR," "metastatic breast cancer," and "oral care." They selected articles published in peer-reviewed journals that reported controlled trials and evidence-based guidelines. RESULTS: mIAS can be distinguished from mucositis caused by cytotoxic chemotherapy or radiotherapy on the basis of cause, clinical presentation, and treatment paradigms. Specific preventive and therapeutic management strategies can be implemented across the continuum of patient oral health care. PRACTICAL IMPLICATIONS: Oral health care providers are on the frontline of oral health care for patients with metastatic breast cancer and are uniquely positioned to provide patient education, advocate accurate reporting of mIAS, and support early identification, monitoring, and prompt intervention to mitigate the severity and duration of this manageable, potentially dose-limiting AE. PMID- 29439773 TI - Effect of an experimental desensitizing agent on reduction of bleaching-induced tooth sensitivity: A triple-blind randomized clinical trial. AB - BACKGROUND: In this randomized study, split-mouth, triple-blind clinical trial, the authors evaluated the efficacy of a desensitizing gel that contained 5% potassium nitrate and 5% glutaraldehyde applied before in-office bleaching with 35% hydrogen peroxide (HP). METHODS: Treatment with the desensitizing or placebo control gels was randomly assigned to one-half of the maxillary teeth of 42 patients in a split-mouth design. The desensitizing gels were applied and maintained in contact with the tooth enamel for 10 minutes, followed by 2 HP bleaching sessions separated by 1 week. The primary outcome variable was pain intensity assessed with a numeric rating scale and a visual analog scale. Color was evaluated by means of a digital spectrophotometer and a value-oriented shade guide. RESULTS: The difference in risk of developing tooth sensitivity between the desensitizing gel group (31.7%, 95% confidence interval [CI], 19.6 to 46.9) and the control group (70.7%; 95% CI, 55.5 to 82.3%) was statistically significant (P < .0001), as well as the difference in pain intensity in the first 24 hours (P < .001). No statistically significant difference was found in color change between teeth that received the desensitizing gel and those that received the placebo gel. CONCLUSIONS: Application of desensitizing gel that contained 5% potassium nitrate and 5% glutaraldehyde before HP whitening reduced the risk and severity of dental sensitivity, without altering the effectiveness of whitening. PRACTICAL IMPLICATIONS: A single application of desensitizing gel that contained 5% potassium nitrate and 5% glutaraldehyde can reduce tooth sensitivity after dental bleaching systems. PMID- 29439775 TI - Right ventricular fractional area of change is predictive of ventilator support days in trauma and burn patients. AB - Echocardiography has contributed to the care of critically ill patients but there remains a need for more publications about its association with outcomes to confirm its role. We conducted a retrospective review of trauma and burn patients that were admitted to our intensive care unit between 2015 and 2017 that underwent hemodynamic transesophageal echocardiography. Data collected included demographics, clinical and laboratory data. Right ventricle fractional area of change (RVFAC) measurements were performed on still mages obtained from mid esophageal four-chamber-view clips. There were 74 patients, mean age was 51 years, and were predominantly white and male. Linear regression was used to test for the association between RVFAC and clinical outcomes. Adjusting for age, injury mechanism and injury severity, higher RVFAC was significantly associated with lower ventilator days (p = 0.03). Conclusion, higher right ventricle systolic function is associated with a lower number of ventilator support days in critically injured trauma and burn patients. PMID- 29439774 TI - Panniculectomy after bariatric surgical weight loss: Analysis of complications and modifiable risk factors. AB - INTRODUCTION: Bariatric surgery results in massive weight loss, leaving many patients with redundant skin that can cause significant physical and psychosocial limitations. We sought to identify variables associated with postoperative complications and adjuncts associated with the mitigation of postoperative complications. METHODS: A retrospective review was performed of all post bariatric surgery patients who underwent panniculectomy over a 10-year period. RESULTS: Total 706 patients included. Overall complication rate was 56%: dehiscence (24%), surgical site infection (22%), seroma (18%), and post-operative bleeding (5%). Return to operating room rate was 12%. Significant factors were: BMI >26 (p < 0.01), fleur-de-lis panniculectomy (p < 0.01), concomitant hernia repair (p < 0.01). Multivariate regression analysis demonstrated ASA class >2 (OR 1.97, p < 0.05) and incision type (OR 1.64, p < 0.05) to be independent predictors of morbidity. CONCLUSION: High morbidity for post-bariatric panniculectomy is primarily local wound complications. Potentially modifiable factors that increase the complication risk profile include higher BMI, higher ASA class, and the use of fleur-de-lis incision. PMID- 29439776 TI - Clinical risk factors for the development of tardive dyskinesia. AB - BACKGROUND: Tardive dyskinesia (TD) is a severe condition that can affect almost 1 out of 4 patients on current or previous antipsychotic treatment, including both first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs). While two novel vesicular monoamine transporter inhibitors, deutetrabenazine and valbenazine, have shown acute efficacy for TD, the majority of patients do not remit, and TD appears to recur once treatment is withdrawn. Hence, prevention of TD remains a crucial goal. METHODS: We provide a clinically oriented overview of risk factors for TD, dividing them into patient-, illness- and treatment-related variables, as well as nonmodifiable and modifiable factors. RESULTS: Unmodifiable patient-related and illness-related risk factors for TD include older age, female sex, white and African descent, longer illness duration, intellectual disability and brain damage, negative symptoms in schizophrenia, mood disorders, cognitive symptoms in mood disorders, and gene polymorphisms involving antipsychotic metabolism and dopamine functioning. Modifiable comorbidity-related and treatment-related factors include diabetes, smoking, and alcohol and substance abuse, FGA vs SGA treatment, higher cumulative and current antipsychotic dose or antipsychotic plasma levels, early parkinsonian side effects, anticholinergic co-treatment, akathisia, and emergent dyskinesia. DISCUSSION: Clinicians using dopamine antagonists need to consider risk factors for TD to minimize TD and its consequences. PMID- 29439777 TI - Special issue on breast imaging: part 1. PMID- 29439778 TI - The importance of histological assessment after neoadjuvant therapy and the need for standardisation. AB - Neoadjuvant therapy is increasingly being recognised as a management option for patients with primary invasive breast carcinoma; this may take the form of primary endocrine treatment or primary chemotherapy. Surgical specimens from women treated with neoadjuvant treatments, particularly primary chemotherapy, may cause a challenge for the histopathologist in handling and interpretation and have, in the past, been sampled, evaluated, and reported in a non-standardised way. This limits comparison between clinical trials and potentially provides clinicians and patients with suboptimal prognostic information. We describe here some of the difficulties faced and the recommendations and standards now applied. PMID- 29439779 TI - Re: RCR audit of compliance with UK guidelines for the prevention and detection of acute kidney injury in adult patients undergoing iodinated contrast media injections for CT. PMID- 29439780 TI - Evolving imaging techniques for staging axillary lymph nodes in breast cancer. AB - The presence and extent of axillary nodal metastases at the time of breast cancer diagnosis is a critical factor in disease prognosis and plays a central role in deciding the best treatment for patients. Accurate assessment of the axilla is therefore an essential component in staging breast cancer. Over the years, axillary staging has evolved from surgical axillary lymph node dissection (ALND), with its numerous associated long-term complications, to the much less-radical surgical sentinel lymph node excision biopsy (SLNB), the current reference standard. In parallel, radiological staging of the axilla has become increasingly more useful as our knowledge and techniques have improved. Preoperative axillary ultrasound is used widely to stage patients with breast cancer, providing an evaluation of node morphology and allowing targeted biopsy of abnormal nodes. This is important in helping stratify which patients should proceed directly to ALND and which should undergo SLNB first. Grey-scale ultrasound on its own is not perfect and can over- and underestimate axillary disease. Newer ultrasound techniques such as elastography may help to improve diagnostic confidence when visually assessing axillary nodes; for example, in more accurately assessing the extent of axillary disease burden or in differentiating benign reactive nodes from malignant nodes in equivocal cases. The use of intradermal "microbubbles" has shown great promise in being able to locate and biopsy the sentinel lymph node under ultrasound guidance, and raises the possibility that in the future such techniques may obviate the need for surgical SLNB in select patient populations. PMID- 29439781 TI - Signaling pathways regulating pituitary functions. PMID- 29439782 TI - Using multilevel models to evaluate the influence of contextual factors on HIV/AIDS, sexually transmitted infections, and risky sexual behavior in sub Saharan Africa: a systematic review. AB - PURPOSE: To describe the use of multilevel models (MLMs) in evaluating the influence of contextual factors on HIV/AIDS, sexually transmitted infections (STIs), and risky sexual behavior (RSB) in sub-Saharan Africa. METHODS: Ten databases were searched through May 29, 2016. Two reviewers completed screening and full-text review. Studies examining the influence of contextual factors on HIV/AIDS, STIs, and RSB and using MLMs for analysis were included. The Quality Assessment Tool for Quantitative Studies was used to evaluate study quality. RESULTS: A total of 118 studies met inclusion criteria. Seventy-four studies focused on HIV/AIDS-related topics; 46 focused on RSB. No studies related to STIs other than HIV/AIDS met the eligibility criteria. Of five studies examining HIV serostatus and community socioeconomic factors, three found an association between poverty and measures of inequality and increased HIV prevalence. Among studies examining RSB, associations were found with numerous contextual factors, including poverty, education, and gender norms. CONCLUSIONS: Studies using MLMs indicate that several contextual factors, including community measures of socioeconomic status and educational attainment, are associated with a number of outcomes related to HIV/AIDS and RSB. Future studies using MLMs should focus on contextual-level interventions to strengthen the evidence base for causality. PMID- 29439783 TI - Geographic access to mammography facilities and frequency of mammography screening. AB - PURPOSE: To assess the association between geographic access to mammography facilities and women's mammography utilization frequency. METHODS: Using data from the population-based 1995-2007 Wisconsin Women's Health study, we used proportional odds and logistic regression to test whether driving times to mammography facilities and the number of mammography facilities within 10 km of women's homes were associated with mammography frequency among women aged 50-74 years and whether associations differed between Rural-Urban Commuting Areas and income and education groups. RESULTS: We found evidence for nonlinear relationships between geographic access and mammography utilization (nonlinear effects of driving times and facility density, P-values .01 and .005, respectively). Having at least one nearby mammography facility was associated with greater mammography frequency among urban women (1 vs. 0 facilities, odds ratio 1.26, 95% confidence interval, 1.09-1.47), with similar effects among rural women. Adding more facilities had decreasing marginal effects. Long driving times tended to be associated with lower mammography frequency. We found no effect modification by income, education, or urbanicity. In rural settings, mammography nonuse was higher, facility density smaller, and driving times to facilities were longer. CONCLUSIONS: Having at least one mammography facility near one's home may increase mammography utilization, with decreasing effects per each additional facility. PMID- 29439784 TI - Influence of physical activity, sedentary behavior, and diet quality in childhood on the incidence of internalizing and externalizing disorders during adolescence: a population-based cohort study. AB - PURPOSE: Studies among youth suggest that physical inactivity, sedentary behaviors, and poor diet quality are associated with poor mental health. Few population-based studies have investigated these relationships longitudinally. We examined the association between physical activity, sedentary behaviors, and diet quality in childhood and the incidence of internalizing and externalizing disorders throughout adolescence. METHODS: We linked health behavior survey data from 2003 among 10- to 11-year-old children across Nova Scotia, Canada, with administrative health care data from 2003 to 2011. Students' diet quality was assessed using the Harvard Food Frequency Questionnaire. Physical activity and sedentary behaviors were self-reported, and internalizing and externalizing disorders were diagnosed by a physician. We applied Cox regression to examine the associations of the health behaviors with the incidence of internalizing and externalizing disorders between 2003 and 2011. RESULTS: Of the 4861 participating students, 23.7% and 9.4% had a diagnosis of internalizing and externalizing disorders, respectively. The incidences of internalizing and externalizing disorders were higher among students who were less physically active and spent more time using computers and video games. CONCLUSIONS: These findings suggest that promoting an active lifestyle in childhood may contribute to the prevention of both internalizing and externalizing disorders during adolescence. PMID- 29439785 TI - ? PMID- 29439786 TI - ? PMID- 29439787 TI - [Body, autonomy and responsibility of the individual]. AB - The question 'Who does my body belong to?' may at first seem strange. However, it highlights the complexity concealed by the very fact of corporeity, the place of existence and encounter between others and oneself. PMID- 29439788 TI - [The human body, subject or object of rights?] AB - While the protection of the body is the primary vocation of law, legislation also aims to regulate any actions which may cause it harm. Such actions include care procedures. It is in this contradiction that the legal status of the human body lies, not without a certain amount of ambiguity. PMID- 29439789 TI - [Different old ages]. AB - There is no single form of ageing. Some people age in a sort of peaceful and happy continuity of their existence, while others are confronted with illness or bereavements which can weaken them considerably. Ageing therefore takes many different forms. Autonomy, social ties and quality of life are key factors in determining how someone ages. PMID- 29439790 TI - [Place and role of the body in Christianity]. AB - Christianity has always been opposed to dualistic models devaluing the human body. The human person is created in God's image to be resurrected on the last day; his or her body is worthy of respect. It is in the body, or more precisely through it, that the human person is called to glorify and reveal the presence of God, manifested in the love between human beings. PMID- 29439791 TI - [The representation of the body in Islam]. AB - Science and Islamic culture incorporate the sacred and the profane. For a Muslim, science must be useful for humanity, and scientists must take responsibility, commensurate with their knowledge, for the potential consequences of their research. In this context, questions relating to the body in Islam take into account the Quran, hadiths and elements of established precedents. PMID- 29439792 TI - [Considerations relating to the body in the Jewish religion]. AB - In the Jewish religion, the body is the receptacle of the soul, and both are connected. Created in God's image, the body must be respected by the caregiver and by the patient. Judaism imposes constraints, but these restrictions must be lifted if a person's life is in danger. PMID- 29439794 TI - [Touch and care, skills to develop in a team]. AB - The relationship with the body requires constant adjustment between the patient, the caregiver and the team. A learning organisation supporting the use of touch at the heart of care favours the therapeutic alliance with the patient and the inter-disciplinary implementation of this approach. PMID- 29439793 TI - [The caregiver's relationship with the sick body]. AB - The patient-caregiver relationship is also a 'body-to-body' relationship. It brings into play sensory perceptions generating a cognitive and emotional interpretation. Maintaining the proper distance enables caregivers to remain professional while controlling the risk of 'symbolic contamination' and emotional overflow. PMID- 29439795 TI - [Washing patients, a special relational moment]. AB - Of the different care procedures, washing is a special relational moment between the patient and the caregiver. However, depending on the approach taken by the caregiver, the hand which is washing can be considered by the patient as dehumanising, or, on the contrary, a symbol of respect and comfort. PMID- 29439796 TI - [Understanding the other's body, testimonies of student nurses]. AB - From their very first practical placement, student nurses are confronted with suffering and bodies which are wounded, fatigued and worn down by pain, disease or age. They learn, through their experience and the support provided by health professionals, that showing consideration for others means taking care of their body with the utmost respect, in order to preserve the patient's dignity. PMID- 29439797 TI - [The patient with a mutilated body, specific management]. AB - The mutilated body testifies to the physical and psychological metamorphosis which is imposed on the patient concerned and the caregiver. For the patient as well as the professionals around him or her, taking care of this body is not easy and requires full awareness of the challenges involved. PMID- 29439798 TI - [Refusal of care and respect of the body]. AB - Patients receive numerous care procedures which they may refuse for physical and/or psychological reasons, even if, sometimes, the consequences for them can be dramatic. Faced with this situation, caregivers are helpless. Only ethical reflection centred on their responsibility and their humanity can guide them towards the suitable attitude to adopt. PMID- 29439799 TI - ? PMID- 29439800 TI - [Occupational health in China, an emerging issue]. AB - In Chinese factories, the prevention of occupational illness is inadequate. Public authorities have only recently started to pay attention to the issue. Individual and collective protection measures need to be developed, employees made aware of the issues and controls improved. PMID- 29439801 TI - ? PMID- 29439802 TI - Feasibility and accuracy of computer-assisted individual drill guide template for minimally invasive lumbar pedicle screw placement trajectory. AB - OBJECTIVE: To discuss the feasibility and accuracy of a specific computer assisted individual drill guide template (CIDGT) for minimally invasive lumbar pedicle screw placement trajectory (MI-LPT) through a bovine cadaveric experimental study. DESIGN: A 3-D reconstruction model, including lumbar vertebras (L1-L5), was generated, and the optimal MI-LPTs were determined. A drill guide template with a surface made of the antitemplate of the vertebral surface, including the spinous process and the entry point vertebral surface, was created by reverse engineering and rapid prototyping techniques. Then, MI-LPTs were determined by the drill guide templates, and the trajectories made by K wires were observed by postoperative CT scan. SETTING: General Hospital of Shenyang Military Area Command of Chinese PLA. RESULTS: In total, 150 K-wires for MI-LPTs were successfully inserted into L1-L5. The required mean time and fluoroscopy times between fixation of the template to the spinous process, entry point vertebral surface, and insertion of the K-wires for minimally invasive lumbar pedicle screw placement trajectories into each vertebra were 79.4 +/- 15.0 s and 2.1 +/- 0.8 times. There were no significant differences between the preoperative plan and postoperative assessment in the distance from the puncture to the midline and inclination angles according to the different levels (P > 0.05, respectively). The mean deviation between the preoperative plan and postoperative assessment in the distance from the puncture to the midline and inclination angles were 0.8 +/- 0.5 mm and 0.9 +/- 0.5 degrees , respectively. CONCLUSIONS: The potential use of the novel CIDGT, which was based on the unique morphology of the lumbar vertebra to place minimally invasive lumbar pedicle screws, is promising and could prevent too much radiation exposure intraoperatively. PMID- 29439803 TI - A point of application study to determine the accuracy, precision and reliability of a low-cost balance plate for center of pressure measurement. AB - Changes in postural sway measured via force plate center of pressure have been associated with many aspects of human motor ability. A previous study validated the accuracy and precision of a relatively new, low-cost and portable force plate called the Balance Tracking System (BTrackS). This work compared a laboratory grade force plate versus BTrackS during human-like dynamic sway conditions generated by an inverted pendulum device. The present study sought to extend previous validation attempts for BTrackS using a more traditional point of application (POA) approach. Computer numerical control (CNC) guided application of ~155 N of force was applied five times to each of 21 points on five different BTrackS Balance Plate (BBP) devices with a hex-nose plunger. Results showed excellent agreement (ICC > 0.999) between the POAs and measured COP by the BBP devices, as well as high accuracy (<1% average percent error) and precision (<0.1 cm average standard deviation of residuals). The ICC between BBP devices was exceptionally high (ICC > 0.999) providing evidence of almost perfect inter device reliability. Taken together, these results provide an important, static corollary to the previously obtained dynamic COP results from inverted pendulum testing of the BBP. PMID- 29439804 TI - Ongoing and new challenges of our journal. PMID- 29439805 TI - [Qualitative and quantitative study of ophthalmologic consultation in France: A multicenter descriptive survey]. AB - This study aimed to precisely map current ophthalmologic consultation in France through systematic data collection in one consultation day. Nine ophthalmologic centers participated in the survey, performing 1148 observations of patients aged from 2 to 102 years old, with a mean of 55.12years old and a male/female distribution of 43.8 %/56.2 %. In general, the patients came in either spontaneously (28.8 %) or for follow-up (59.6 %). Emergency consultations comprised 5.7 % of all cases. Comorbidities or major risk factors were found. Most the patients already wore visual correction (82.6 %), mainly glasses (77.3 %). At the end of the consultation, 48.2 % received a prescription for new optical correction. During the interview, 53.3 % of patients reported visual symptoms, most frequently blurriness, distortion or loss of vision. 25.3 % of the patients experienced ocular symptoms such as pain, watery eyes or itching. An ophthalmic disease was the reason for the consultation in 77.1 % of all cases. Its management included medicinal and/or surgical treatment (45.6 % and10.5 % respectively). The necessary tests were performed on site the same day and only 2.6 % of the patients were given a prescription for additional testing to be performed elsewhere in a referral center. From a qualitatively and quantitatively representative sample, this survey describes ophthalmologic consultation in France today in terms of age, male/female distribution, reason for the visit, the proportion of visual correction and other diseases, diagnosis and treatment. PMID- 29439806 TI - Reply-Letter to the Editor - Smoking status is inversely associated with overall diet quality: Findings from the ORISCAV-LUX study. PMID- 29439807 TI - Could Notch signaling pathway be a potential therapeutic option in renal diseases? AB - Notch pathway regulates key processes in the kidney, involved in embryonic development and tissue damage. In many human chronic renal diseases a local activation of Notch pathway has been described, suggesting that several components of Notch pathway could be considered as biomarkers of renal damage. Experimental studies by genetic modulation of Notch components or pharmacological approaches by gamma-secretase inhibitors have demonstrated the role of this pathway in renal regeneration renal, podocyte apoptosis, proliferation and fibroblasts activation, and induction of epithelial to mesenchymal transition of tubular epithelial cells. Recent studies suggest an interaction between Notch and NF-kappaB pathway involved in the regulation of renal inflammatory process. On the other hand, there are some miRNAs that could regulate Notch components and down-stream responses. All these data suggest that Notch blockade could be a novel therapeutic option for renal diseases. PMID- 29439808 TI - Neuroradiologic correlation with aphasias. Cortico-subcortical map of language. AB - Aphasia is an acquired language disorder due to a cerebral lesion; it is characterized by errors in production, denomination, or comprehension of language. Although most aphasias are mixed, from a practical point of view they are classified into different types according to their main clinical features: Broca's aphasia, Wernicke's aphasia, conduction aphasia, transcortical aphasia, and alexia with or without agraphia. We present the clinical findings for the main subtypes of aphasia, illustrating them with imaging cases, and we provide an up-to-date review of the language network with images from functional magnetic resonance imaging and tractography. PMID- 29439809 TI - Optical coherence tomography angiography: Present or future in daily clinical practice? PMID- 29439810 TI - Differential expression of proteome in aqueous humor in patients with and without glaucoma. AB - OBJECTIVE: To determine quantitative and qualitative differences of aqueous humor proteome in patients with and without glaucoma. METHOD: Observational, descriptive and cross-sectional study of 12 patients (8 men; 4 women) with and without glaucoma. There are 3 groups of minority proteins with serum equimolar contribution of each of the patients. Specimens were obtained during cataract surgery from patients without glaucoma (performed with retrobulbar anaesthesia [cataract retrobulbar patient -CRP-;n=4] or topical [cataract topical patient CTP-; n=4]), or from patients with glaucoma (performed with retrobulbar anaesthesia [glaucoma retrobulbar patient -GRP-; n=4]). The humor proteome samples were frozen at -80 degrees C until processing by trypsin digestion to obtain tryptic peptides, and then performing liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to obtain the proteome and its differential expression between groups. Statistical analysis was performed using the SPSS v.17 program. RESULTS: The study included 12 patients, aged (mean+/-standard deviation) 74.50+/-9.53 years. Concentrations obtained: 0.48+/-0.25MUg/MUl for CRP, 0.28+/-0.04MUg/MUl for CTP, and 0.35+/-0.16MUg/MUl for GRP. A total of 309 proteins were identified, of which 205, 210, and 182 were in CRP, CTP, and GRP, respectively. A total of 114 proteins were common to all three groups, 50 were exclusive to CRP, 58 to CTP, and 27 to GRP. CONCLUSIONS: In this pilot study, a quantitative difference was found in the protein expression of humor among patients with glaucoma, there being 27 proteins unique to patients with glaucomatous disease. PMID- 29439811 TI - Discussion. PMID- 29439812 TI - Better candy for the false lumen. PMID- 29439813 TI - Question the unquestionable. PMID- 29439814 TI - Teaching operative cardiac surgery in the era of increasing patient complexity: Can it still be done? AB - OBJECTIVE: Teaching the next generation operative cardiac surgery while maintaining the highest level of patient care is an ever-increasing challenge given the growing proportion of patients with multiple comorbidities, the loss of more straightforward cases to percutaneous interventions, and the pressure of public reporting. No study to date has compared the outcomes of similar cases performed entirely ("skin-to-skin") by the resident with those performed entirely by the staff to confirm the safety of this practice. METHODS: A total of 100 consecutive cardiac cases performed skin-to-skin by the resident (group R) were matched by procedure 1:1 to nonconsecutive cases performed by a single attending surgeon (group A). Patients were excluded from the analysis if there was overlap in any portion of the procedure by the trainee or the attending. RESULTS: Patients in group A were similar to those in group R with respect to age, gender, body mass index, American Society of Anesthesiologists classification, left ventricular ejection fraction, and diabetes mellitus. Mean operative times were longer in group R (4.6 vs 2.7 hours, P < .001), as were cardiopulmonary bypass times (96 vs 50 minutes, P < .001) and aortic crossclamp times (78 vs 39 minutes, P < .001). There were no significant differences in red blood cell transfusions, reexplorations, stroke, length of stay, or wound infections. There were no in hospital or 30-day deaths. CONCLUSIONS: Our data indicate that trainees can be educated in operative surgery under the current paradigm, despite longer operative times, without sacrificing outcome quality. It is reasonable to expect academic programs to continue providing trainees significant experience as primary operating surgeons. PMID- 29439815 TI - Pleural Lymphoma Associated With Chronic Empyema. PMID- 29439816 TI - [Burden, empathy, and resilience in dependent people caregivers]. AB - OBJECTIVE: To analyse the differences in perceived burden between family caregivers who are users of patient associations and those who are not; to assess the relationship between burden, resilience, and empathy levels. METHOD: Retrospective ex post facto study of two groups, one of them quasi control. The sample was composed of 155 informal caregivers (28 men and 155 women); 109 of them were users of patient relatives' associations and 46 were not. Both descriptive and bivariate comparative analyses were carried out. RESULTS: Caregivers who were members of patient associations showed lower burden and empathy levels than those who were not. This highlighted that the higher their level of perceived burden, the lower their level of resilience. CONCLUSIONS: Belonging to carers' associations results in a lower level of perceived burden and a lower risk of developing compassion fatigue syndrome. PMID- 29439817 TI - Forearm Torque and Lifting Strength: Normative Data. AB - PURPOSE: To establish reference values for new methods designed to quantitatively measure forearm torque and lifting strength and to compare these values with grip strength. METHODS: A total of 499 volunteers, 262 males and 237 females, aged 15 to 85 (mean, 44) years, were tested for lifting strength and forearm torque with the Kern and Baseline dynamometers. These individuals were also tested for grip strength with a Jamar dynamometer. Standardized procedures were used and information about sex, height, weight, hand dominance, and whether their work involved high or low manual strain was collected. RESULTS: Men had approximately 70% higher forearm torque and lifting strength compared with females. Male subjects aged 26 to 35 years and female subjects aged 36 to 45 years showed highest strength values. In patients with dominant right side, 61% to 78% had a higher or equal strength on this side in the different tests performed. In patients with dominant left side, the corresponding proportions varied between 41% and 65%. There was a high correlation between grip strength and forearm torque and lifting strength. Sex, body height, body weight, and age showed a significant correlation to the strength measurements. In a multiple regression model sex, age (entered as linear and squared) could explain 51% to 63% of the total variances of forearm torque strength and 30% to 36% of lifting strength. CONCLUSIONS: Reference values for lifting strength and forearm torque to be used in clinical practice were acquired. Grip strength has a high correlation to forearm torque and lifting strength. Sex, age, and height can be used to predict forearm torque and lifting strength. Prediction equations using these variables were generated. CLINICAL RELEVANCE: Normative data of forearm torque and lifting strength might improve the quality of assessment of wrist and forearm disorders as well as their treatments. PMID- 29439818 TI - Judgment hurts: The psychological consequences of experiencing stigma in multiple sclerosis. AB - RATIONALE: People living with MS often report feeling stigmatized, but little research has examined the psychological impact of this, which is important considering the high prevalence of depression in this population. OBJECTIVES: The aim of this study was to assess, concurrently and prospectively, the association between stigma and depression in people living with MS. METHODS: Data were available from 5369 participants enrolled in the semi-annual survey conducted by the North American Research Committee on Multiple Sclerosis (NARCOMS). Participants reported their MS stigma and depression in the spring 2013 update survey (T1) and their depression again one year later (T2). Demographic and health-related covariates were also assessed. RESULTS: People experiencing higher levels of stigma reported more depression symptoms and were more likely to meet the threshold for clinical depression at both times, even controlling for covariates. Higher levels of stigma also predicted T2 depression, controlling for T1 depression (and covariates), suggesting a possible causal association. Greater psychosocial reserve, a composite of measures assessing participants' feelings of belonging, social support, and sense of control, attenuated the association between stigma and depression. CONCLUSIONS: Stigma is an important but understudied predictor of depression in people living with MS, but greater psychosocial reserve provides a buffer. PMID- 29439819 TI - Re: Optimal Settings for the Noncontact Holmium:YAG Stone Fragmentation Popcorn Technique. PMID- 29439821 TI - Re: Impact of Postoperative Radiotherapy in Men with Persistently Elevated Prostate-specific Antigen After Radical Prostatectomy for Prostate Cancer: A Long term Survival Analysis. PMID- 29439820 TI - Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. AB - BACKGROUND: Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. OBJECTIVE: To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations. DESIGN, SETTING, AND PARTICIPANTS: We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the impact of germline DNA-repair gene mutation status on >=50% and >=90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. RESULTS AND LIMITATIONS: Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p=0.061), PFS (HR 0.50; p=0.090), and OS (HR 0.28; p=0.059). In propensity score weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25-0.92; p=0.027), PFS (HR 0.52, 95% CI 0.28-0.98; p=0.044), and OS (HR 0.34, 95% CI 0.12-0.99; p=0.048), but not in men with non-BRCA/ATM germline mutations (all p>0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n=9) with BRCA/ATM mutations. CONCLUSIONS: Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations. PATIENT SUMMARY: Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide. PMID- 29439822 TI - Re: Management of the Urologic Sepsis Syndrome. PMID- 29439823 TI - Re: Acrylic stent to aid placement of footplate of palatal distractor during surgically-assisted rapid palatal expansion. PMID- 29439824 TI - Re: Wrong tooth extraction: an examination of "Never Event" data. PMID- 29439825 TI - Successful endoscopic extraction of dental prosthesis impacted in a sigmoid diverticulum. PMID- 29439826 TI - Radiation-induced leiomyosarcoma of the rectum after cervical cancer treatment. PMID- 29439827 TI - Refractory gastric variceal bleeding treated through endoscopic ultrasound-guided coiling and N-butyl-2-cyanoacrylate application. PMID- 29439828 TI - Consistent Long-Term Therapy of Neovascular Age-Related Macular Degeneration Managed by 50 or More Anti-VEGF Injections Using a Treat-Extend-Stop Protocol. AB - PURPOSE: To examine the clinical results for patients with neovascular age related macular degeneration (nAMD) who were managed with a treat-extend-stop (TES) protocol and received 50 or more injections of anti-vascular endothelial growth factor (VEGF) agents. DESIGN: Retrospective case study. PARTICIPANTS: Data for patients from a private retina practice meeting the following criteria were included: diagnosis of nAMD and having received 50 or more intravitreal injections of anti-VEGF agents. METHODS: The patients' baseline visual acuity (VA; obtained using Snellen charts and converted to Early Treatment Diabetic Retinopathy Study [ETDRS] letters), age, length of follow-up, anti-VEGF agents used, and interval between treatments were obtained. These data were examined through the 51st injection and at the last follow-up examination. Patients were excluded if they lost significant vision because of a diagnosis unrelated to AMD during therapy. MAIN OUTCOME MEASURES: Visual acuity and complications. RESULTS: Seventy-one eyes of 67 patients were identified who met inclusion criteria. The mean age of patients was 83.0 years. Women made up 58.2% of the study population, whereas men constituted 41.8%. The mean initial VA was 55.6 ETDRS letters. The mean duration of follow-up at the 51st visit for an injection was 6.5 years, and the mean duration of follow-up at the last visit was 8 years. The mean number of injections at final follow-up was 63.7. The mean interval between treatments at the 51st follow-up was 5.4 weeks, and the mean follow-up at the last examination was 6.4 weeks. Mean VA at the 51st injection was 65.3 letters, and the mean change from baseline was 9.7 letters (P < 0.001, Student paired t test). The mean vision gained at last follow-up was 8.7 letters from baseline (P < 0.001), or 64.3 letters. CONCLUSIONS: In this study, patients gained a mean of 2 ETDRS lines after 50 injections. This study had a mean follow-up of 8 years, and 35.2% of eyes had a 3-line or more gain in VA at the last follow-up examination. Patients who require consistent long-term anti-VEGF therapy, managed with a TES protocol, are likely able to maintain or improve their vision. PMID- 29439829 TI - Effects of dry needling trigger point therapy in the shoulder region on patients with upper extremity pain and dysfunction: a systematic review with meta analysis. AB - QUESTION: What is the effectiveness and what are the adverse effects. DESIGN: Systematic review with meta-analysis. PARTICIPANTS: Patients with shoulder or upper extremity pain or dysfunction. INTERVENTION: Trigger point dry needling (TDN) compared to control, another intervention or another needling technique. OUTCOME MEASURES: Primary outcome measures included shoulder or upper limb pain, shoulder or upper limb dysfunction. RESULTS: Eleven randomized trials involving 496 participants were appraised. There was very low evidence that trigger point dry needling of the shoulder region is effective for reducing pain and improving function in the short term. There is some evidence that needling both active and latent trigger points is more effective than needling an active trigger point alone for pain immediately and 1-week after treatment (SMD=-0.74, 95%CI=-1.2 to 0.3; and SMD=-1.0, 95%CI=-1.52 to -0.59). CONCLUSION: There is very low evidence to support the use of TDN in the shoulder region for treating patients with upper extremity pain or dysfunction. Two studies reported adverse effects to TDN interventions. Most common adverse effects included bruising, bleeding, and pain during or after treatment. Future studies are likely to change the estimates of the effectiveness of TDN for patients with upper extremity pain or dysfunction. PROSPERO: CRD42016045639. PMID- 29439830 TI - Unexpected finding in preanesthesia room. Large-sized faringeal cyst. PMID- 29439831 TI - Routine Invasive Versus Selective Invasive Strategy in Elderly Patients Older Than 75 Years With Non-ST-Segment Elevation Acute Coronary Syndrome: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To evaluate outcomes of routine invasive strategy (RIS) compared with selective invasive strategy (SIS) in elderly patients older than 75 years with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). METHODS: We systematically searched databases for randomized controlled trials (RCTs) between January 1, 1990, and October 1, 2016, comparing RIS with SIS for elderly patients (age>75 years) with NSTE-ACS. Random effects meta-analysis was conducted to estimate odds ratio (OR) with 95% CIs for composite of death or myocardial infarction (MI), and individual end points of all-cause death, cardiovascular (CV) death, MI, revascularization, and major bleeding. RESULTS: A total of 6 RCTs with 1887 patients were included in the final analysis. Compared with an SIS, RIS was associated with significantly decreased risk of the composite end point of death or MI (OR, 0.65; 95% CI, 0.51-0.83). Similarly, RIS led to a significant reduction in the risk of MI (OR, 0.51; 95% CI, 0.40-0.66) and need for revascularization (OR, 0.31; 95% CI, 0.11-0.91) compared with SIS. There were no significant differences between RIS and SIS in terms of all-cause death (OR, 0.85; 95% CI, 0.63-1.20), CV death (OR, 0.84; 95% CI, 0.61-1.15), and major bleeding (OR, 1.96; 95% CI, 0.97-3.97). CONCLUSION: In elderly patients older than 75 years with NSTE-ACS, RIS is superior to SIS for the composite end point (death or MI), primarily driven by reduced risk of MI. PMID- 29439832 TI - Factors Associated With Positive Margins in Women Undergoing Breast Conservation Surgery. AB - OBJECTIVE: To identify factors predicting positive margins at lumpectomy prompting intraoperative reexcision in patients with breast cancer treated at a large referral center. PATIENTS AND METHODS: We reviewed all breast cancer lumpectomy cases managed at our institution from January 1, 2012, through December 31, 2013. Associations between rates of positive margin and patient and tumor factors were assessed using chi2 tests and univariate and adjusted multivariate logistic regression, stratified by ductal carcinoma in situ (DCIS) or invasive cancer. RESULTS: We identified 382 patients who underwent lumpectomy for definitive surgical resection of breast cancer, 102 for DCIS and 280 for invasive cancer. Overall, 234 patients (61.3%) required intraoperative reexcision for positive margins. The reexcision rate was higher in patients with DCIS than in those with invasive disease (78.4% [80 of 102] vs 56.4% [158 of 280]; univariate odds ratio, 2.80; 95% CI, 1.66-4.76; P<.001). Positive margin rates did not vary by patient age, surgeon, estrogen receptor, progesterone receptor, or ERBB2 status of the tumor. Among the 280 cases of invasive breast cancer, the only factor independently associated with lower odds of margin positivity was seed localization vs no localization (P=.03). CONCLUSION: Ductal carcinoma in situ was associated with a higher rate of positive margins at lumpectomy than invasive breast cancer on univariate analysis. Within invasive disease, seed localization was associated with lower rates of margin positivity. PMID- 29439833 TI - [Ascites as first manifestation of superior mesenteric and portal vein thrombosis secondary to protein S deficiency]. PMID- 29439834 TI - [Treatment of type 2 diabetes mellitus in elderly patients]. AB - The prevalence of type 2 diabetes mellitus (DM2) increases markedly with age. Antidiabetic treatment and the objectives of glycaemic control in elderly patients with DM2 should be individualised according to their biopsychosocial characteristics. In elderly patients for whom the benefits of intensive antidiabetic treatment are limited, the basic objectives should be to improve the quality of life, preserve functionality and avoid adverse effects, especially hypoglycaemia. Treatment of DM2 in the elderly was the subject of a consensus document published in 2012 and endorsed by several Spanish scientific societies. Since then, new therapeutic groups and evidence have emerged that warrant an update to this consensus document. The present document focuses on the therapeutic aspects of DM2 in elderly patients, understood as being older than 75 years or frail. PMID- 29439835 TI - Low CD25 on autoreactive Tregs impairs tolerance via low dose IL-2 and antigen delivery. AB - Dendritic cell (DC)-mediated T cell tolerance deficiencies contribute to the pathogenesis of autoimmune diseases such as type 1 diabetes. Delivering self antigen to dendritic-cell inhibitory receptor-2 (DCIR2)+ DCs can delay but not completely block diabetes development in NOD mice. These DCIR2-targeting antibodies induce tolerance via deletion and anergy, but do not increase islet specific Tregs. Because low-dose IL-2 (LD-IL-2) administration can preferentially expand Tregs, we tested whether delivering islet-antigen to tolerogenic DCIR2+ DCs along with LD-IL-2 would boost islet-specific Tregs and further block autoimmunity. But, surprisingly, adding LD-IL-2 did not increase efficacy of DC targeted antigen to inhibit diabetes. Here we show the effects of LD-IL-2, with or without antigen delivery to DCIR2+ DCs, on both polyclonal and autoreactive Treg and conventional T cells (Tconv). As expected, LD-IL-2 increased total Tregs, but autoreactive Tregs required both antigen and IL-2 stimulation for optimal expansion. Also, islet-specific Tregs had lower CD25 expression and IL-2 sensitivity, while islet-specific Tconv had higher CD25 expression, compared to polyclonal populations. LD-IL-2 increased activation and expansion of Tconv, and was more pronounced for autoreactive cells after treatment with IL-2 + islet antigen. Therefore, LD-IL-2 therapy, especially when combined with antigen stimulation, may not optimally activate and expand antigen-specific Tregs in chronic autoimmune settings. PMID- 29439836 TI - Hospital variation and the impact of postoperative complications on the use of perioperative chemo(radio)therapy in resectable gastric cancer. Results from the Dutch Upper GI Cancer Audit. AB - BACKGROUND: Dutch national guidelines on the diagnosis and treatment of gastric cancer recommend the use of perioperative chemotherapy in patients with resectable gastric cancer. However, adjuvant chemotherapy is often not administered. The aim of this study was to evaluate hospital variation on the probability to receive adjuvant chemotherapy and to identify associated factors with special attention to postoperative complications. METHODS: All patients who received neoadjuvant chemotherapy and underwent an elective surgical resection for stage IB-IVa (M0) gastric adenocarcinoma between 2011 and 2015 were identified from a national database (Dutch Upper GI Cancer Audit). A multivariable linear mixed model was used to evaluate case-mix adjusted hospital variation and to identify factors associated with adjuvant therapy. RESULTS: Of all surgically treated gastric cancer patients who received neoadjuvant chemotherapy (n = 882), 68% received adjuvant chemo(radio)therapy. After adjusting for case-mix and random variation, a large hospital variation in the administration rates for adjuvant was observed (OR range 0.31-7.1). In multivariable analysis, weight loss, a poor health status and failure of neoadjuvant chemotherapy completion were strongly associated with an increased likelihood of adjuvant therapy omission. Patients with severe postoperative complications had a threefold increased likelihood of adjuvant therapy omission (OR 3.07 95% CI 2.04-4.65). CONCLUSION: Despite national guidelines, considerable hospital variation was observed in the probability of receiving adjuvant chemo(radio)therapy. Postoperative complications were strongly associated with adjuvant chemo(radio)therapy omission, underlining the need to further reduce perioperative morbidity in gastric cancer surgery. PMID- 29439837 TI - Factors affecting differences between birth weight of littermates (BWTD) and the effects of BWTD on lamb performance. AB - The objectives of this study were to determine factors affecting lamb birth weight (BWT) and differences between BWT of the largest and smallest littermates (BWTD) and to assess the relative importance of BWT and BWTD on lamb survival and growth to weaning. Records from twin (n = 5369) or triplet (n = 1664) litters born on pasture were utilised. Breeds included Coopworth, Romney, Perendale, composite and Texel. Ewe and sire breed, age and weight of the dam, sex, and number of lambs born (NLB) affected BWT. Neither embryo loss nor ovulation pattern (i.e. all ova released from one ovary or some from each) were associated with BWT. Dam weight and NLB affected BWTD but dam age, sire or dam breed did not. Loss of an embryo reduced BWTD, and BWTD was lower when the ewe ovulated from both ovaries versus only one ovary for twins, but not triplets. Whereas BWT was moderately heritable (h2 = 0.20), BWTD was not heritable (h2 = 0.003). Lamb survival was positively associated with BWT. Lambs with BWTD > 1.3 kg were less likely to survive (73.3%) than those from litters of smaller BWTD (range 82.8 85.7% survival). Growth rate of twin and triplet lambs was positively associated with BWT. Surprisingly, lambs from litters with moderately high BWTD had slightly greater (approximately 3%) growth rate than those from lambs of low to intermediate BWTD. Thus, while large BWTD were negatively associated with survival, BWT itself, which was moderately heritable, appeared to be a stronger driver of lamb survival and average daily gain. PMID- 29439838 TI - Evolutionary Mechanisms Shaping the Maintenance of Antibiotic Resistance. AB - Antibiotics target essential cellular functions but bacteria can become resistant by acquiring either exogenous resistance genes or chromosomal mutations. Resistance mutations typically occur in genes encoding essential functions; these mutations are therefore generally detrimental in the absence of drugs. However, bacteria can reduce this handicap by acquiring additional mutations, known as compensatory mutations. Genetic interactions (epistasis) either with the background or between resistances (in multiresistant bacteria) dramatically affect the fitness cost of antibiotic resistance and its compensation, therefore shaping dissemination of antibiotic resistance mutations. This Review summarizes current knowledge on the evolutionary mechanisms influencing maintenance of resistance mediated by chromosomal mutations, focusing on their fitness cost, compensatory evolution, epistasis, and the effect of the environment on these processes. PMID- 29439839 TI - Characterizing the clinical isolates of dermatophytes in Hamadan city, Central west of Iran, using PCR-RLFP method. AB - OBJECTIVE: Dermatophytosis is one of the most common mycotic infections, which considered as a public health problem in the major of countries. This study evaluated the molecular epidemiology of dermatophytosis in patients referred to Farshchian hospital in Hamadan city with PCR-RFLP method. MATERIALS AND METHODS: Four hundred and five specimens from clinically suspected patients of dermatophytosis were collected and analyzed by direct microscopic and culture. The isolates were identified by PCR-RFLP method using the MvaI restriction enzyme. RESULTS: Of the 405 specimens, 88 specimens were positive in direct examination and culture. Among the patients, 64.8% were males and35.2% females. Tinea pedis (31.8%) was the most common type of dermatophytosis followed by tinea corporis (22.7%), tinea cruris (20.5%), tinea capitis (10.2%), tinea manuum (5.7%), tinea faciei (4.6%) and tinea unguium (4.6%). Trichophyton interdigitale (36.4%) was the most common isolate followed by Trichophyton rubrum (27.3%), Epidermophyton floccosum (17%), Trichophyton tonsurans (11.4%), Microsporum canis (4.5%), Microsporum gypseum (2.3%) and Trichophyton benhamiae (1.1%). CONCLUSION: Our finding showed that the anthropophilic dermatophyte species causing dermatophytosis are increasing, and molecular methods are reliable assays for accurse identification of dermatophyte species in epidemiological studies. PMID- 29439840 TI - Randomized Trial Evaluating the Effectiveness of Coloring on Decreasing Anxiety Among Parents in a Pediatric Surgical Waiting Area. AB - : Anxiety is common among pediatric surgical patients and their parents. Numerous studies have examined interventions to reduce pediatric patients' anxiety; however, less is known about reducing parental anxiety. In other populations, producing art has been shown to significantly reduce anxiety. PURPOSE: This study aimed to determine whether parents' anxiety decreased after coloring while their child is in surgery. DESIGN AND METHODS: A block randomized controlled trial was conducted with a convenience sample of 106 parents of children who were having a scheduled surgery. Each day of data collection was randomized where all parents enrolled that day would either color a pre-drawn art template for 30min or would simply wait in the waiting room for 30min. The primary outcome measure was anxiety, measured by the 6-item short form of the Spielberger State Trait Anxiety Inventory (STAI). RESULTS: Parents' average anxiety score decreased from the initial measurement to the measurement 30min later in both the control group and the intervention group. The reduction in anxiety was significantly greater for those parents who participated in coloring during their wait (p<0.0001). CONCLUSIONS: Coloring is a creative, simple, low cost, and effective activity to reduce anxiety among parents in a pediatric surgical waiting area. PRACTICE IMPLICATIONS: Providing coloring materials and information about the benefits of coloring in pediatric surgery waiting areas is an easy to implement intervention to reduce parental anxiety. PMID- 29439841 TI - Investigation of cancer-associated fibroblasts and p62 expression in oral cancer before and after chemotherapy. AB - PURPOSE: The aim of this study is to investigate the expression of the autophagy protein p62 in oral squamous cell carcinoma (OSCC) cells before and after chemotherapy. We also detected cancer-associated fibroblasts (CAFs) in these OSCC samples to explore the roles of p62 and CAFs in chemotherapy. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expression of p62 and alpha SMA in 26 paired OSCC samples before and after chemotherapy. The relationships between clinicopathological features, clinical outcome and the expression of these proteins were analyzed. RESULTS: Our results indicated an increased stromal alpha-SMA expression after chemotherapy in OSCC samples. High p62 expression of OSCC cells closely correlated with stromal alpha-SMA expression after chemotherapy. Furthermore, the post-chemotherapy p62 expression was associated with the prognosis for OSCC patients. CONCLUSION: These results suggest that chemotherapy may increase CAFs in OSCC. High cytoplasmic p62 expression may serve as a poor prognostic marker for OSCC patients. PMID- 29439842 TI - Zinc supplementation plays a crucial role in T helper 9 differentiation in allogeneic immune reactions and non-activated T cells. AB - T helper (Th) 9 cells play a critical role in immune-mediated diseases, including allergic airway inflammation, autoimmune diseases, and cancer development. Thus, the promotion or suppression of Th9 cell differentiation, transcriptional control, and function is very important for a healthy immune system. Interestingly, T cell maturation, differentiation and function are highly dependent on the individuals' zinc status. This is especially seen in zinc deficient individuals as in the elderly population often suffering of autoimmunity and increased incidence of infections. In this regard, this study examines the impact of zinc supplementation in pharmacological doses on Th9 differentiation in two in vitro models: 1) in mixed lymphocyte cultures (MLC) displaying allogeneic activated T cells in graft versus host disease, and 2) on non-activated resting T cells in peripheral blood mononuclear cells (PBMC). On the one hand, zinc supplementation significantly diminishes IL-4-induced Th9 differentiation in MLC thereby ameliorating this pro-inflammatory allogeneic immunoreaction. On the other hand, Th9 cells are induced in resting T cells in PBMC hence triggering the immunological defense. Thus, zinc supplementation can be considered as useful additive to dampen unwanted allogeneic immunoreactions. Moreover, the pro-inflammatory immune defense in non-reactive T cells can be strengthened, which is a frequent issue in the elderly population having a weakened immune response against invading pathogens. PMID- 29439843 TI - Development and reliability of the rating of compensatory movements in upper limb prosthesis wearers during work-related tasks. AB - STUDY DESIGN: Reliability study. INTRODUCTION: Quantifying compensatory movements during work-related tasks may help to prevent musculoskeletal complaints in individuals with upper limb absence. PURPOSE OF THE STUDY: (1) To develop a qualitative scoring system for rating compensatory shoulder and trunk movements in upper limb prosthesis wearers during the performance of functional capacity evaluation tests adjusted for use by 1-handed individuals (functional capacity evaluation-one handed [FCE-OH]); (2) to examine the interrater and intrarater reliability of the scoring system; and (3) to assess its feasibility. METHODS: Movement patterns of 12 videotaped upper limb prosthesis wearers and 20 controls were analyzed. Compensatory movements were defined for each FCE-OH test, and a scoring system was developed, pilot tested, and adjusted. During reliability testing, 18 raters (12 FCE experts and 6 physiotherapists/gait analysts) scored videotapes of upper limb prosthesis wearers performing 4 FCE-OH tests 2 times (2 weeks apart). Agreement was expressed in % and kappa value. Feasibility (focus area's "acceptability", "demand," and "implementation") was determined by using a questionnaire. RESULTS: After 2 rounds of pilot testing and adjusting, reliability of a third version was tested. The interrater reliability for the first and second rating sessions were k = 0.54 (confidence interval [CI]: 0.52 0.57) and k = 0.64 (CI: 0.61-0.66), respectively. The intrarater reliability was k = 0.77 (CI: 0.72-0.82). The feasibility was good but could be improved by a training program. DISCUSSION: It seems possible to identify compensatory movements in upper limb prosthesis wearers during the performance of FCE-OH tests reliably by observation using the developed observational scoring system. CONCLUSIONS: Interrater reliability was satisfactory in most instances; intrarater reliability was good. Feasibility was established. PMID- 29439844 TI - Comparison of two approaches in achieving smoking abstinence among patients in an outpatient clinic: A Phase 2 randomized controlled trial. AB - OBJECTIVES: To compare the effectiveness of quitting immediately and cutting down to quit in promoting smoking abstinence among smokers in an outpatient clinic. METHODS: A total of 100 subjects were randomized into two groups, 50 in the quit immediately group, who received an intervention on abruptly quitting, and 50 in the cut down to quit group, who received an intervention on gradual reduction. All subjects were followed up at 6 and 12 months via telephone. The intention-to treat principle was used. RESULTS: At the 6-month follow-up, the self-reported quit rate of subjects in the quit immediately group was significantly higher than in the cut down to quit group (18.0% vs. 4.0%, p = 0.04). However, this difference was not significant at the 12-month follow-up (12.0% vs. 4.0%, p = 0.16). CONCLUSION: These data suggest that quitting immediately might be more effective than cutting down to quit at 6 months but not at 12 months. PRACTICE IMPLICATIONS: It is crucial to allow smokers to select quitting immediately or reducing the number of cigarettes smoked. Further studies are warranted to compare the effectiveness of various approaches for achieving smoking abstinence. PMID- 29439845 TI - Adequacy of information provided by healthcare professionals on vaccines: Results of a population survey in Spain. AB - OBJECTIVE: To describe the population who self-reported perceiving information on vaccines provided by health professionals as inadequate, and to analyze factors associated. METHODS: A Spanish nationwide representative health survey conducted in individuals >=18 in 2015 (N = 7 800) was used. Respondents were classified according to the question: 'Do you think that health professionals inform adequately to patients about the advantages and risks of vaccines prior to their administration? (yes/no/non-responders). The association with socio-demographic and health-related characteristics and with opinions/attitudes regarding vaccines were analyzed. RESULTS: 33.7% of respondents felt not adequately informed. These individuals had lower influenza vaccination coverage (16.0% vs. 24.1%), and were more distrustful of vaccines in general (8.4% vs. 3.3%) as well as regarding on the influenza vaccine (11.9% vs. 7.6%). Inadequate information was associated with female gender (aOR:1.21,95%CI:1.08-1.35), autochthonous origin (aOR:1.54,95%CI:1.27--1.87), household income <=600?/month (aOR:1.45,95%CI:1.10 1.91), poor self-perceived health (aOR:3.17,95%CI:1.36-7.39), and a lower satisfaction with the National Health Service and nurses (aOR:0.92,95%CI:0.89 0.95 and aOR:0.85,95%CI:0.82-0.88). CONCLUSION: A large proportion of the population considers that the information provided regarding vaccines is inadequate. This perception is associated with negative attitudes towards vaccination. PRACTICE IMPLICATIONS: Further studies are required to deepen our understanding of the problem and to enhance communication provided by healthcare professionals. PMID- 29439847 TI - The outcomes of central hepatectomy versus extended hepatectomy: a systematic review and meta-analysis. AB - BACKGROUND: Central hepatectomy (CH) is a relatively uncommon liver resection technique. It is generally perceived as a more complex operation than extended hepatectomies (EH), with potentially higher associated morbidity. The outcomes of CH compared with EH is not well defined and there is a need to reassess. METHODS: A systematic literature search was conducted in PubMed, MEDLINE, EMBASE and Web of Science according to PRISMA guidelines for studies on the treatment of liver tumours with CH published from 1972 until February 2017. Outcomes of patients undergoing CH were assessed and compared to those undergoing EH. RESULTS: 18 publications including 1380 CH were included for analysis. Mortality rates after CH ranged from 0 to 9%. There were 20 (1.4%) deaths after CH and the most common cause of death was post-hepatectomy liver failure (PHLF). Morbidity rates varied between 12 and 61% and 316 (23%) post-operative events were reported. Analysis of five comparative studies showed similar mortality between CH and EH groups (OR: 0.64, 95% CI = 0.24-1.70, p = 0.37). There were significantly fewer overall post operative complications in the CH group (OR: 0.38, 95% CI = 0.28-0.51, p < 0.001) and reduced PHLF was found in the CH group compared to EH (OR: 0.53, 95% CI = 0.29-0.98, p = 0.04). The rates of post-hepatectomy biliary complications were similar between groups (OR: 0.98, 95% CI = 0.51-1.88, p = 0.96). Mean length of stay (days) was shorter in the CH group (MD: -2.67, 95% CI = -4.93 to -0.41, p = 0.02). CONCLUSION: CH appears to have similar post-operative mortality rates compared to EH but is associated with fewer post-operative complications, including PHLF and shorter overall length of stay. PMID- 29439846 TI - Diagnostic challenge for the rare lysosomal storage disease: Late infantile GM1 gangliosidosis. AB - BACKGROUND: GM1 gangliosidosis is a rare lysosomal storage disorder caused by GLB1 mutations. Because of its extreme rarity and symptoms that overlap with other neurodegenerative diseases, its diagnosis is sometimes challenging, especially in the late infantile form with less severe phenotype. We aim to expand the clinical and genetic spectrum of late infantile GM1 gangliosidosis. METHODS: We confirmed a diagnosis of GM1 gangliosidosis based on GLB1 mutations and/or the deficiency of beta-galactosidase activity. We identified the first two cases by whole-exome sequencing, and then the other six cases by direct sequencing of GLB1 with enzyme analysis. RESULTS: All eight patients presented with developmental delay or regression during late infancy and later developed epilepsy, mostly intractable generalized tonic seizures. No clinical signs of storage disorders were noted except for skeletal abnormalities. Interestingly, we found aspartate transaminase (AST) elevations alone with normal alanine transaminase (ALT) levels in all patients. The recurrent mutation, p.D448V in GLB1, accounted for 50.0% of total alleles in our cohort. CONCLUSIONS: With a high index of clinical suspicion, skeletal survey and AST level would be important for early diagnosis of GM1 gangliosidosis. In addition, we would highlight the clinical usefulness of whole-exome sequencing in the diagnosis of non-classical presentation of ultra-rare neurodegenerative disease in children. PMID- 29439849 TI - Potential of metric homotopy between intensity and geometry information for multi modal 3D registration. AB - This paper focuses on a novel strategy increasing robustness with respect to local optima when using Mutual Information (MI) in multi-modal image registration. This is realized by integrating additional geometry information in the cost function. Hereby, the main innovation is a generalization of multi metric registration approaches by means of a metric homotopy. Particularly we realize a method which automatically determines the parameters of the metric homotopy. To construct the cost function independent of the choice of the optimizer, the weighting is defined as a function of one of the metrics instead of optimizer steps. In addition, a differentiable cost function is developed. In comparison to the commonly used technique to process an intensity based registration on different resolutions, the proposed method is three times faster with unchanged accuracy. It is also shown that in the presence of large landmark errors the proposed method outperforms an approach in accuracy in which both similarity functionals are applied one after the other. The method is evaluated on 3D multi-modal human brain data sets from the Retrospective Image Registration Evaluation Project (RIRE). The evaluation is performed using the evaluation website of the RIRE project to make the registration results of the proposed method easily comparable to other methods. Therefore, the presented results are also available online on the RIRE project page. PMID- 29439848 TI - Rare Prostatic Artery Origins and the Importance of Collateral Circulation in Prostate Artery Embolization: A Pictorial Essay. PMID- 29439850 TI - Distal vein patch use and limb events after infragenicular prosthetic bypasses. AB - OBJECTIVE: In the absence of suitable autologous vein, the use of prosthetic grafts for infragenicular bypasses in peripheral arterial disease has become standard practice. The purpose of this study was to investigate whether creating a vein patch at the distal anastomosis would further improve patency and freedom from major adverse limb events (MALEs). Furthermore, we sought to investigate whether the use of a distal vein patch (DVP) was associated with lower rates of acute limb ischemia (ALI) for those presenting with occluded prosthetic bypass graft. METHODS: The cases of all patients undergoing infragenicular prosthetic bypass grafts between January 2009 and July 2016 were retrospectively reviewed. Demographics of the patients, clinical data, and outcomes (graft patency and MALEs) were collected. Patients were compared according to treatment group (DVP vs no DVP). A Cox regression analysis was used to analyze follow-up results. RESULTS: During the study period, a total of 373 patients underwent infragenicular bypass at our institution; of those, 93 (24.9%) had prosthetic grafts (DVP, 39; no DVP, 54). Overall, 92 (98.9%) patients were male; the mean age was 63.3 +/- 6.6 years and did not differ between the two groups. Patients undergoing prosthetic bypass with DVP were more likely to have chronic obstructive pulmonary disease (38.5% vs 14.8%; P = .009) and less likely to have chronic kidney disease (2.6% vs 20.4%; P = .011). Follow-up data were available for all patients for a median of 7.8 months (range, 1-89 months). After adjustment for differences in demographics and clinical data between the two groups, when outcomes were analyzed, MALEs were significantly lower in the DVP group (35.9% vs 57.4%; odds ratio [OR], 0.4; 95% confidence interval [CI], 0.2 0.9; P = .041). Similarly, reintervention rates were significantly lower in the DVP group (30.8% vs 50.0%; OR, 0.4; 95% CI, 0.2-0.9; P = .044). There was a trend toward higher primary patency in the DVP group (46.2% vs 35.2%; OR, 1.5; 95% CI, 0.7-3.5; P = .206) and lower rates of ALI after bypass occlusion (30.0% vs 42.9%; OR, 0.6; 95% CI, 0.2-1.8; P = .345). A Cox regression time-to-event analysis revealed late separation of freedom from MALEs for DVP relative to no DVP (log rank, P = .269). CONCLUSIONS: In this evaluation of infragenicular prosthetic bypass grafts, the creation of a vein patch at the distal anastomosis was associated with lower reintervention rates and a trend toward improved primary patency and MALEs. Furthermore, for those presenting with occluded prosthetic bypass graft, the use of a DVP was associated with a trend toward lower rates of ALI. PMID- 29439851 TI - Bioelectroremediation of perchlorate and nitrate contaminated water: A review. AB - Fresh water is a fundamental source for humans, hence the recent shrinkage in freshwater and increase in water pollution are imperative problems that vigorously affect the people and the environment worldwide. The breakneck industrialization contributes to the procreation of substantial abundance of wastewater and its treatment becomes highly indispensable. Perchlorate and nitrate containing wastewaters poses a serious threat to human health and environment. Conventional biological treatment methods are expensive and also not effective for treating wastewater effectively and incapable of in situ bioremediation. Bioelectrochemical systems are emerging as a new technology platform for a sustainable removal of such contaminants from wastewater streams. This article reviews the state of art of bioelectroremediation of contaminated waters with perchlorate and nitrate. Different aspects of this technology such as configuration and design, mode of operation and type of substrate are considered in detail. PMID- 29439852 TI - Cognitive Screening at the Population Level: The Italian Health Examination Survey, 2008-2012. PMID- 29439853 TI - Frailty Predicts Incident Urinary Incontinence Among Hospitalized Older Adults-A 1-Year Prospective Cohort Study. AB - OBJECTIVES: The relationship between frailty and urinary incontinence (UI) remains highly complex. There is limited data on the impact of frailty on new onset UI among hospitalized older adults. Thus, we examined the ability of frailty to predict incident UI among them. DESIGN: Prospective cohort study. SETTING: Acute geriatric unit at a large teaching hospital. PARTICIPANTS: Older adults hospitalized for an acute medical illness. MEASUREMENTS: Premorbid frailty was defined as having 3 of 5 items, namely fatigue, resistance, ambulation, illnesses, and loss of weight (FRAIL scale). Data on demographics, comorbidities, severity of illness, and functional status were gathered. Premorbid UI and UI at discharge and 6 and 12 months after hospitalization were identified. Logistic regression analysis was performed to examine how well frailty predicted incident UI at discharge and at 6 and 12 months following hospitalization. The independent predictive value of UI on mortality was also examined. RESULTS: Among 210 participants (mean age 89.4 +/- 4.6 years; 69.5% female; 50.0% frail), UI was present in 47.6%, with a higher prevalence among frail individuals (64.8% vs 30.5%, P < .001). Incident UI was more common in frail participants (at discharge: 24.3% vs 9.6%, P = .038; 6 months: 43.2% vs 21.7%, P = .020; and 12 months: 56.8% vs 33.3%, P = .020). Death among UI patients increased over time following hospitalization (at discharge: 6.0% vs 1.8%, P = .114; 6 months: 32.0% vs 9.1%, P < .001; and 12 months: 42.0% vs 13.6%, P < .001). Premorbid UI independently predicted mortality [6 months: odds ratio (OR) 3.10, 95% confidence interval (CI) 1.34-7.17, P = .008; 12 months: OR 3.41, 95% CI 1.59-7.32, P = .002], adjusting for age, sex, severity of illness, and frailty. Frailty predicted incident UI and/or death over time (at discharge: OR 2.98, 95% CI 1.00 8.91, P = .050; 6 months: OR 2.86, 95% CI 1.13-7.24, P = .027; 12 months: OR 2.67, 95% CI 1.13-6.27, P = .025), adjusting for age, sex, and severity of illness. CONCLUSION: Frailty is associated with UI, and predicts incident UI and/or death, even up to 12 months following hospitalization. Hence, greater emphasis should be given to identifying and managing UI during hospitalization and after discharge, especially among frail older adults. PMID- 29439855 TI - Catechol-O-methyltransferase (COMT) genetic variants are associated with cognitive decline in patients with Parkinson's disease. AB - OBJECTIVE: Catechol-O-methyltransferase (COMT), an enzyme that catalyzes the degradation of dopamine, is necessary for both motor and cognitive functions. Few studies have examined the association between COMT variants and cognition in patients with Parkinson's disease (PD). METHODS: We assessed a cohort of 409 PD patients without dementia who were regularly followed for two years. The Unified Parkinson's Disease Rating Scale (UPDRS) and Mini-Mental State Examination (MMSE) were administered at baseline and during the follow-up. The genetic variants and haplotypes of COMT, including rs6267, rs6269, rs4633, rs4818, and rs4680, were examined. RESULTS: No association was observed between COMT genotypes and baseline cognitive function. After a mean follow-up period of 647.3 days, MMSE scores deteriorated with age. Cognitive decline correlated with age (P < 0.05) but not with the motor severity defined using UPDRS part III scores (P = 0.21). Kaplan-Meier survival analyses showed that PD patients carrying the G allele of the rs6269 variant and COMT haplotypes constituting the G allele of rs6269 showed a significantly more rapid decline in the MMSE scores over the follow-up period (log-rank test, P < 0.01). Cox proportional regression analysis adjusted for covariates revealed that among patients with PD, those carrying the high-COMT activity haplotype (G_C_C_G for rs6269, rs4633, rs4818, and rs4680) showed a high risk of cognitive decline (hazard ratio = 3.24; P = 0.02). CONCLUSION: Our findings suggest that the high-COMT activity haplotype is associated with cognitive decline in patients with PD. PMID- 29439854 TI - Rapid sensing of l-leucine by human and murine hypothalamic neurons: Neurochemical and mechanistic insights. AB - OBJECTIVE: Dietary proteins are sensed by hypothalamic neurons and strongly influence multiple aspects of metabolic health, including appetite, weight gain, and adiposity. However, little is known about the mechanisms by which hypothalamic neural circuits controlling behavior and metabolism sense protein availability. The aim of this study is to characterize how neurons from the mediobasal hypothalamus respond to a signal of protein availability: the amino acid l-leucine. METHODS: We used primary cultures of post-weaning murine mediobasal hypothalamic neurons, hypothalamic neurons derived from human induced pluripotent stem cells, and calcium imaging to characterize rapid neuronal responses to physiological changes in extracellular l-Leucine concentration. RESULTS: A neurochemically diverse subset of both mouse and human hypothalamic neurons responded rapidly to l-leucine. Consistent with l-leucine's anorexigenic role, we found that 25% of mouse MBH POMC neurons were activated by l-leucine. 10% of MBH NPY neurons were inhibited by l-leucine, and leucine rapidly reduced AGRP secretion, providing a mechanism for the rapid leucine-induced inhibition of foraging behavior in rodents. Surprisingly, none of the candidate mechanisms previously implicated in hypothalamic leucine sensing (KATP channels, mTORC1 signaling, amino-acid decarboxylation) were involved in the acute activity changes produced by l-leucine. Instead, our data indicate that leucine-induced neuronal activation involves a plasma membrane Ca2+ channel, whereas leucine induced neuronal inhibition is mediated by inhibition of a store-operated Ca2+ current. CONCLUSIONS: A subset of neurons in the mediobasal hypothalamus rapidly respond to physiological changes in extracellular leucine concentration. Leucine can produce both increases and decreases in neuronal Ca2+ concentrations in a neurochemically-diverse group of neurons, including some POMC and NPY/AGRP neurons. Our data reveal that leucine can signal through novel mechanisms to rapidly affect neuronal activity. PMID- 29439856 TI - The optimal age for epicutaneous sensitization following tape-stripping in BALB/c mice. AB - BACKGROUND: Direct contact of food proteins with eczematous lesions is thought to be the main cause of epicutaneous sensitization. To further investigate the development and pathogenesis of food allergy in vivo, a good mouse model of epicutaneous sensitization is needed. However, a fundamental problem in that regard is that the optimal age for epicutaneous sensitization of mice is unknown. In this study, we attempted to elucidate that optimal age. METHODS: Dorsal skin of wild-type BALB/c female mice (1, 3, 8 and 24 weeks old) was shaved, depilated and tape-stripped. A Finn chamber containing a 20-MUl-aliquot of 20-mg/ml (OVA) was applied to the tape-stripped skin on 3 consecutive days/week, for 3 weeks. The body temperature was measured after intraperitoneal OVA challenge. Serum OVA specific IgE titers and OVA-induced cytokine production by spleen cells were measured by ELISA. Dendritic cells (DCs) that migrated to the draining lymph nodes were quantified by FITC-labeled OVA and flow cytometry. The mRNA expression levels in the dorsal skin were measured by qPCR. RESULTS: A significant age dependent body temperature decline was observed after OVA challenge. The serum OVA-specific IgE titer, OVA-induced cytokine production (i.e., IL-4, IL-5 and IL 13) by spleen cells, and number of FITC-OVA-engulfing DCs increased with age. In addition, mRNA for IL-33, but not TSLP or IL-25, was significantly induced in the skin by tape-stripping and increased with age. CONCLUSIONS: Twenty-four-week-old mice showed the greatest DC migration, Th2 polarization, IgE production and body temperature decline. Skin-derived IL-33 is likely to play key roles in those changes. PMID- 29439858 TI - Combination therapies for patients with metastatic renal cell carcinoma. PMID- 29439857 TI - Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. AB - BACKGROUND: Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. METHODS: In this ongoing, open label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. FINDINGS: Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59.0-84.4) patients achieved an objective response (complete or partial response). INTERPRETATION: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). FUNDING: Pfizer Inc. PMID- 29439860 TI - Peripheral neuropathies and the vestibular system: Is there a role for vestibular rehabilitation? PMID- 29439859 TI - Effect of dexmedetomidine and xylazine followed by MK-467 on gastrointestinal microperfusion in anaesthetized horses. AB - OBJECTIVE: To compare the effects of MK-467 during isoflurane anaesthesia combined with xylazine or dexmedetomidine on global and gastrointestinal perfusion parameters. STUDY DESIGN: Prospective, randomized experimental trial. ANIMALS: A total of 15 warmblood horses. METHODS: Horses were divided into two groups for administration of either dexmedetomidine (D) or xylazine (X) for premedication (D: 3.5 MUg kg-1; X: 0.5 mg kg-1) and as constant rate infusion during isoflurane anaesthesia (D: 7 MUg kg-1 hour-1; X: 1 mg kg-1 hour-1). During anaesthesia, heart rate, mean arterial blood pressure (MAP), systemic vascular resistance index (SVRI) and cardiac index (CI) were measured. Microperfusion of the colon, jejunum and stomach was measured using laser Doppler flowmetry. After 2 hours of stabilization, MK-467 (250 MUg kg-1) was administered, and measurements were continued for another 90 minutes. For statistical analysis, the permutation test and Wilcoxon rank-sum test were used (p < 0.05). RESULTS: There were no differences in baseline measurements between groups. The MK-467 bolus resulted in a significant decrease in MAP (D: -58%; X: -48%) and SVRI (D: -68%; X: -65%) lasting longer in group D (90 minutes) compared to group X (60 minutes). While CI increased (D: +31%; X: +35%), microperfusion was reduced in the colon (D: -44%; X: -34%), jejunum (D: -26%; X: -33%) and stomach (D: -37%; X: -35%). CONCLUSIONS AND CLINICAL RELEVANCE: Alpha-2-agonist induced vasoconstriction was reversed by the MK-467 dose used, resulting in hypotension and rise in CI. Gastrointestinal microperfusion decreased, probably as a result of insufficient perfusion pressure. An infusion rate for MK-467 as well as an ideal agonist/antagonist ratio should be determined. PMID- 29439861 TI - Enhancement of glycosylation by stable co-expression of two sialylation-related enzymes on Chinese hamster ovary cells. AB - Sialic acid plays important roles in stabilization and modulation of the interaction of molecules and membranes in organisms. Due to its high electronegativity, sialic acid can promote binding effects of molecules and support the transportation of drugs and ions in cells. This also strengthens cells against degradation from glycosidases and proteases. Hence sialic acid helps glycoproteins extend their half-lives and bioactivity. On the other hand, Chinese hamster ovary (CHO) cells have been widely used as a workhorse in biopharmaceutical fields in part due to the similarity between their glycan properties and those in humans. Thus, a high sialylation produced by CHO host cell line is strongly desired. In this study, we simultaneously overexpressed two key sialylated-based enzymes human beta-galactoside alpha(2,6) sialyltransferase I and UDP-GlcNAc 2-epimerase/ManNAc kinase to achieve greater sialylation pattern produced host cells. The single-cell line thus-generated produced an approximately 41.6% higher level of total free sialic acid, and the glycan profiles showed a significant increase of more than 7-fold in the relative amount of total sialylated N-glycan as compared to the wild-type. These results demonstrated that co-expression of these two sialylated-based key enzymes yielded a cell line that effectively produced glycoproteins with superior sialylation and achievable human-like glycoforms. PMID- 29439862 TI - Measurement of psychological adjustment to diabetes with the diabetes acceptance scale. AB - AIMS: To develop a psychometric measure of diabetes acceptance. METHODS: An item pool was developed and pilot-tested using a sample of 220 people with diabetes; item selection resulted in the 20-item 'Diabetes Acceptance Scale (DAS)'. 606 people with diabetes were then cross-sectionally assessed with the DAS to evaluate its reliability, validity and clinical utility; concurrent measurements included diabetes-related coping (FQCI), diabetes distress (PAID-5), depressive symptoms (PHQ-9), quality of life (EQ-5D), self-management (DSMQ), glycaemic control (HbA1c) and complications. RESULTS: Internal reliability was high (Cronbach's alpha = 0.96). Factorial and criterion-related results supported validity. Higher diabetes acceptance scores correlated with more functional coping styles, lower distress and depression levels, higher treatment adherence, better glycaemic control and better quality of life (all P < .001). Persons with low diabetes acceptance (22% of the sample) were four times more likely to have HbA1c values over 9.0% (75 mmol/mol), two times more likely to be diagnosed with long-term complications and each over two times more likely to have had episodes of severe hypoglycaemia and ketoacidosis in the past year; the prevalence of major depression in this group was fivefold increased (all P < .05). CONCLUSIONS: The DAS is a reliable and valid tool to measure diabetes acceptance. It may help identify patients with significant problems of accepting diabetes, a putative high-risk group in need of tailored care and support. PMID- 29439863 TI - Towards the enhancement of body standing balance recovery by means of a wireless audio-biofeedback system. AB - Human maintain their body balance by sensorimotor controls mainly based on information gathered from vision, proprioception and vestibular systems. When there is a lack of information, caused by pathologies, diseases or aging, the subject may fall. In this context, we developed a system to augment information gathering, providing the subject with warning audio-feedback signals related to his/her equilibrium. The system comprises an inertial measurement unit (IMU), a data processing unit, a headphone audio device and a software application. The IMU is a low-weight, small-size wireless instrument that, body-back located between the L2 and L5 lumbar vertebrae, measures the subject's trunk kinematics. The application drives the data processing unit to feeding the headphone with electric signals related to the kinematic measures. Consequently, the user is audio-alerted, via headphone, of his/her own equilibrium, hearing a pleasant sound when in a stable equilibrium, or an increasing bothering sound when in an increasing unstable condition. Tests were conducted on a group of six older subjects (59y-61y, SD = 2.09y) and a group of four young subjects (21y-26y, SD = 2.88y) to underline difference in effectiveness of the system, if any, related to the age of the users. For each subject, standing balance tests were performed in normal or altered conditions, such as, open or closed eyes, and on a solid or foam surface. The system was evaluated in terms of usability, reliability, and effectiveness in improving the subject's balance in all conditions. As a result, the system successfully helped the subjects in reducing the body swaying within 10.65%-65.90%, differences depending on subjects' age and test conditions. PMID- 29439864 TI - Incidence and epidemiology of intussusception among children under 2 years of age in Chenzhou and Kaifeng, China, 2009-2013. AB - INTRODUCTION: In China, rotavirus is the leading cause of diarrhea hospitalizations among children aged <5 years. A locally manufactured rotavirus vaccine is available for private market use, but little is known about its coverage. Given the impending availability of newer rotavirus vaccines, we evaluated intussusception rates among children aged <2 years to better understand intussusception epidemiology for future vaccine safety monitoring. METHODS: We conducted a retrospective review at 4 hospitals in Chenzhou City of Hunan Province and Kaifeng City of Henan Province. We identified intussusception cases admitted during 2009-2013 by reviewing medical records with the ICD-10 discharge code for intussusception and extracting demographic and clinical information from the electronic clinical record systems. RESULTS: During 2009-2013, 1715 intussusception hospitalizations among 1,487,215 children aged <2 years occurred in both cities. The average annual intussusception hospitalization incidence was 112.9 per 100,000 children aged <2 years (181.8 per 100,000 children <1 year; 56 per 100,000 children 1 to <2 years). Intussusception incidence was low among infants aged <3 months and peaked at age 6-8 months. No clear seasonality was observed. Ultrasound was used to diagnose 95.9% of cases. Enema reduction was performed in 80% cases; 25% of cases in Chenzhou and 16% in Kaifeng required surgical intervention. No deaths were reported. The median time between symptom onset and admission was 1 day. CONCLUSIONS: This study provides information on intussusception incidence and epidemiology in two cities of China during 2009 2013. Monitoring intussusception rates in this population will be important in the post-rotavirus vaccine era. PMID- 29439865 TI - 13-Valent vaccine serotype pneumococcal community acquired pneumonia in adults in high clinical risk groups. AB - There is debate regarding the value of vaccinating adults with the 13-valent pneumococcal conjugate vaccine (PCV-13). This analysis was conducted to investigate the risk of PCV-13 serotype community acquired pneumonia (CAP) in hospitalised adults with co-morbid disease and risk factors for pneumococcal disease in the UK. Consecutive adults hospitalised (2008-2013) with a primary diagnosis of CAP, were recruited. Pneumococcal aetiology disease was identified by use of pneumococcal urinary antigen detection and serotype identification using a validated multiplex immunoassay or serum latex agglutination. Adults with PCV-13 serotype CAP were compared to those with non-PCV-13 serotype CAP. Of 2224 patients, PCV-13 serotype CAP was identified in 337 (15.2%) and non-PCV-13 serotype CAP in 250 (11.2%) individuals. Adults aged >=65 years with one or more clinical risk factors had a significantly lower risk of PCV-13 serotype CAP compared to those aged 16-64 years without clinical risk factors (aOR 0.61, 95%CI 0.41-0.92, p = .018). In a stacked-risk analysis, the presence of incremental clinical risk factors was associated with lower odds of PCV-13 disease (p for trend = .029) Adults with underlying chronic respiratory disease (aOR) 0.56, 95% CI 0.36-0.85, p = .007) and chronic kidney disease (aOR 0.48, 95% CI 0.25-0.92, p = .028) had significantly lower adjusted odds of PCV-13 compared to non-PCV-13 serotype CAP. This analysis suggests that in the UK, the burden of PCV13 disease is greater in adults outside the traditional 'at-risk' groups compared to adults in 'at-risk' groups. PMID- 29439866 TI - Mass media effect on vaccines uptake during silent polio outbreak. AB - BACKGROUND: During 2013, isolation of a wild type 1 poliovirus from routine sewage sample in Israel, led to a national OPV campaign. During this period, there was a constant cover of the outbreak by the mass media. AIMS: To investigate the association of media exposure and OPV and non-OPV vaccines uptake during the 2013 silent polio outbreak in Israel. METHODS: We received data on daily immunization rates during the outbreak period from the Ministry of Health (MoH). We conducted a multivariable time trend analysis to assess the association between daily media exposure and vaccines uptake. Analysis was stratified by ethnicity and socio-economic status (SES). RESULTS: During the MoH supplemental immunization activity, 138,799 OPV vaccines were given. There was a significant association between media exposure and OPV uptake, most prominent in a lag of 3-5 days from the exposure among Jews (R.R 1.79C.I 95% 1.32-2.41) and high SES subgroups (R.R 1.71C.I 95% 1.27-2.30). These subgroups also showed increased non OPV uptake in a lag of 3-5 days from the media exposure, in all vaccines except for MMR. Lower SES and non-Jewish subgroups did not demonstrate the same association. CONCLUSION: Our findings expand the understanding of public behaviour during outbreaks. The public response shows high variability within specific subgroups. These findings highlight the importance of tailored communication strategies for each subgroup. PMID- 29439867 TI - Safety and tolerability of a liquid bovine rotavirus pentavalent vaccine (LBRV PV) in adults. AB - BACKGROUND: Rotavirus Gastroenteritis (RVGE) is an important global public health problem. Recently a Lyophilized Pentavalent Human Bovine Reassortant Rotavirus vaccine (BRV-PV, Rotasiil) was licensed in India. A Liquid formulation of the same vaccine (LBRV-PV) was tested in a Phase I clinical trial. METHODS: Total 20 healthy adults were given a single oral dose of LBRV-PV and were followed for one month for safety outcomes: immediate reactions, solicited reactions, unsolicited adverse events and serious adverse events. RESULTS: All 20 adults completed the study without any major protocol deviations. No immediate reaction, solicited reactions and unsolicited adverse events were reported during the study. No clinically significant changes were seen in the vital parameters and safety laboratory test results. CONCLUSIONS: LBRV-PV developed in India was safe and well tolerated in adults. Further clinical development of this vaccine in infants should be undertaken. Trial Registration - CTRI/2015/11/006,384. PMID- 29439868 TI - In-depth genome analyses of viruses from vaccine-derived rabies cases and corresponding live-attenuated oral rabies vaccines. AB - Live-attenuated rabies virus strains such as those derived from the field isolate Street Alabama Dufferin (SAD) have been used extensively and very effectively as oral rabies vaccines for the control of fox rabies in both Europe and Canada. Although these vaccines are safe, some cases of vaccine-derived rabies have been detected during rabies surveillance accompanying these campaigns. In recent analysis it was shown that some commercial SAD vaccines consist of diverse viral populations, rather than clonal genotypes. For cases of vaccine-derived rabies, only consensus sequence data have been available to date and information concerning their population diversity was thus lacking. In our study, we used high-throughput sequencing to analyze 11 cases of vaccine-derived rabies, and compared their viral population diversity to the related oral rabies vaccines using pairwise Manhattan distances. This extensive deep sequencing analysis of vaccine-derived rabies cases observed during oral vaccination programs provided deeper insights into the effect of accidental in vivo replication of genetically diverse vaccine strains in the central nervous system of target and non-target species under field conditions. The viral population in vaccine-derived cases appeared to be clonal in contrast to their parental vaccines. The change from a state of high population diversity present in the vaccine batches to a clonal genotype in the affected animal may indicate the presence of a strong bottleneck during infection. In conclusion, it is very likely that these few cases are the consequence of host factors and not the result of the selection of a more virulent genotype. Furthermore, this type of vaccine-derived rabies leads to the selection of clonal genotypes and the selected variants were genetically very similar to potent SAD vaccines that have undergone a history of in vitro selection. PMID- 29439869 TI - Immunization with an adjuvanted low-energy electron irradiation inactivated respiratory syncytial virus vaccine shows immunoprotective activity in mice. AB - Respiratory syncytial virus (RSV) is a pathogen causing severe lower respiratory tract disease in infants and the elderly. In spite of the great need for a vaccine against RSV, currently there is no licensed product on the market. A very early vaccine candidate developed in the 1960s based on formaldehyde inactivation (FI) turned out to instead enhance the disease. Our novel inactivation method applied low-energy electron irradiation (LEEI) to produce a killed RSV vaccine. LEEI yielded inactivated virus particles with a reproducible virus antigen conservation above 70%, while FI resulted in highly variable antigen conservation. Immunization of mice with LEEI-RSV elicited a strong immune response, resulting in a drastic reduction in viral load upon challenge in two independent studies. These results have implications for the development of an RSV vaccine and should be validated in further preclinical and clinical studies. PMID- 29439870 TI - RTS,S malaria vaccine efficacy and immunogenicity during Plasmodium falciparum challenge is associated with HLA genotype. AB - Although RTS,S remains the most advanced malaria vaccine, the factors influencing differences in vaccine immunogenicity or efficacy between individuals or populations are still poorly characterised. The analyses of genetic determinants of immunogenicity have previously been restricted by relatively small sample sizes from individual trials. Here we combine data from six Phase II RTS,S trials and evaluate the relationship between HLA allele groups and RTS,S-mediated protection in controlled human malaria infections (CHMI), using multivariate logistic or linear regression. We observed significant associations between three allele groups (HLA-A*01, HLA-B*08, and HLA-DRB1*15/*16) and protection, while another three allele groups (HLA-A*03, HLA-B*53, and HLA-DRB1*07) were significantly associated with lack of protection. It is noteworthy that these 'protective' allele groups are thought to be at a lower prevalence in sub-Saharan African populations than in the UK or USA where these Phase II trials occurred. Taken together, the analyses presented here give an indication that HLA genotype may influence RTS,S-mediated protective efficacy against malaria infection. PMID- 29439871 TI - Dermaseptins as potential antirabies compounds. AB - Over the last 20 years, natural peptides playing a key role in defense mechanisms and innate immunity have been isolated from unicellular organisms. Amphibian skin secretes dermaseptins, 24-34 amino acids in length that have a wide antimicrobial spectrum incorporating yeast, fungi, protozoa, bacteria and enveloped viruses. The anti-rabies virus (RABV) activity of dermaseptins S3 (30aa) and S4 (28aa) from Phyllomedusa sauvagei has been investigated, and further dissected its molecular basis by comparing punctual mutation or deletion of S4 analogues. The results showed that: (1) S4 is more active than S3 against RABV infection, 89% versus 38% inhibition at 7.5 MUM; (2) the 5 NH2-aa of S4 are crucial for its inhibitory potential (S46-28 lost any inhibition) but the COOH terminus stabilizes the inhibitory potential (S41-16 showed only 23% inhibition at 7.5 MUM); (3) there is a correlation between viral inhibition and dermaseptin cytotoxicity, which remains however moderated for BSR cells (<=12% at 10 MUM). A single mutation in position 4 (S4M4K) slightly reduced cytotoxicity while keeping its antiviral activity, 97% at 7.5 MUM. S4 and S4M4K showed an antiviral activity in vitro when provided 1 h after infection. In vivo experiments in mice by intramuscular injection of non-toxic doses of dermaseptin S4M4K 1 h post infection by a lethal dose of RABV at the same site allowed more than 50% improvement in mice survival. This study highlights the potential interest of dermaseptins as non-expansive alternatives to rabies immunoglobulins for the treatment of rabies that continues to claim about 60,000 human lives per year worldwide, almost exclusively in developing countries. PMID- 29439872 TI - Effectiveness of acellular pertussis vaccine and evolution of pertussis incidence in the community of Madrid from 1998 to 2015. AB - INTRODUCTION: Pertussis is a communicable disease that primarily affects infants. Vaccination has led to an important reduction in the incidence of the disease, however, resurgence of the disease has been observed. This study aimed to analyze the incidence of pertussis and assess the vaccination effectiveness (VE) of different schedules of acellular pertussis vaccination in the community of Madrid. METHODS: Pertussis cases notified to the Mandatory Disease Reporting System from 1998 to 2015 were analyzed. Five comparison periods were created: 1998-2001 (reference), 2002-2005, 2006-2009, 2010-2012 and 2013-2015. The incidence ratio (IR) between inter-epidemic periods was analyzed using a Poisson regression. VE was calculated using the screening method. Vaccine status data were collected from the vaccine registry. RESULTS: In total, 3855 cases were notified. Inter-epidemic periods were observed every 3-4 years. The incidence increased (IR: 5.99, p < 0.05) in the 2013-2015 period, particularly among infants younger than 1 month (IR: 32.41, p < 0.05). Vaccination data were available in 89% of cases. For those receiving the last dose at <=6-month VE was 89.9% (95% confidence interval (CI): 87.3-92.0) after one year of follow-up, and 85.5% (95% CI: 82.4-88.1) after 11 years of follow-up. For those receiving the last dose at 18-months VE decreased from 98.8% (95% CI: 98.3-99.1) to 85.1% (95% CI: 81.9-87.7) in the same period, and for those receiving the last dose at 4 year VE decreased from 99.6% (95% CI: 99.3-99.7) to 79.3% (95% CI: 74.6-83.1). CONCLUSIONS: B. pertussis is circulating in our population, as shown by the epidemic peaks and increased incidence of pertussis in recent years. VE increased with the number of doses and decreased with the follow-up period. The effect of this and other vaccination strategies must be monitored to control the disease. PMID- 29439873 TI - Prevalence and factors associated with fatigue in female patients with systemic lupus erythematosus. AB - OBJECTIVE: To determine the prevalence of fatigue in our cohort as well as the factors to which it is associated, its relationship with demographic variables, vitamin D levels, treatment, systemic lupus erythematosus (SLE) symptoms and disease activity. METHODS: A cross-sectional study was carried out including 102 consecutive female patients with SLE (American College of Rheumatology 1997 criteria) who attended the Parc de Salut Mar between January 2012 and May 2014. Variables collected were: sociodemographic data, vitamin D supplementation, fatigue VAS, pharmacological treatment, main serological markers of SLE, and plasma levels of 25(OH)-vitD. The association between fatigue and the different variables was evaluated by the Spearman's Rho correlation coefficient for the continuous variables, the Mann-Whitney U test for the categorical and the Kruskal Wallis test for the seasons of the year. RESULTS: The fatigue variable was evaluated through a fatigue VAS with a mean score of 52.84 (range 0-100), a median of 59 and a standard deviation of 29.86. A statistically significant relationship was found between fatigue and age, MHAQ, SLICC, summer and photosensitivity. As for the relationship between fatigue and vitamin D insufficiency (defined as 25-(OH)-vitD<=30 levels), the sample was divided into patients receiving vitamin D supplements (n=60) and patients without supplements (n=40), finding a significant relationship in that last group. CONCLUSIONS: A statistically significant association was found between the presence of fatigue and age, MHAQ, SLICC, photosensitivity, fibromyalgia and summer, and with vitamin D insufficiency in the group of patients without supplements (n=40). PMID- 29439874 TI - Metahemoglobinemia in infants over one year. AB - BACKGROUND AND OBJECTIVES: Methaemoglobinaemia is a typical acute intoxication disorder in children under one year old. It is produced by excess nitrates which induce the haemoglobin's iron oxidation, preventing its adequate binding to oxygen. It is more frequent in infants due to its lower enzymatic activity. PATIENTS: Two cases of 15-month-old infants with methaemoglobinaemia after the intake of vegetables, atypical by the age of the patients and the initial severity in the first case that simulated a septic syndrome. Both cases evolved well with adequate oxygen therapy. CONCLUSIONS: Although the most frequent clinical manifestation is cyanosis associated with respiratory distress, methaemoglobinaemia can present with more severe and confusing symptoms. The main treatment is oxygen therapy at high concentrations and methylene blue as an intravenous antidote only in selected cases. The intake of vegetables is the main cause of this in infants, so it is important to give adequate information to parents about the consumption and preservation of these foods during the first year of life. PMID- 29439875 TI - Consensus document on the implementation of next generation sequencing in the genetic diagnosis of hereditary cancer. AB - Genetic diagnosis of hereditary cancer syndromes offers the opportunity to establish more effective predictive and preventive measures for the patient and their families. The ultimate objective is to decrease cancer morbidity and mortality in high genetic risk families. Next Generation Sequencing (NGS) offers an important improvement in the efficiency of genetic diagnosis, allowing an increase in diagnostic yield with a substantial reduction in response times and economic costs. Consequently, the implementation of this new technology is a great opportunity for improvement in the clinical management of affected families. The aim of these guidelines is to establish a framework of useful recommendations for planned and controlled implementation of NGS in the context of hereditary cancer. These will help to consolidate the strengths and opportunities offered by this technology, and minimise the weaknesses and threats which may derive from its use. The recommendations of international societies have been adapted to our environment, taking the Spanish context into account at organisational and juridical levels. Forty-one statements are grouped under six headings: clinical and diagnostic utility, informed consent and genetic counselling pre-test and post-test, validation of analytical procedures, results report, management of information and distinction between research and clinical context. This guide has been developed by the Spanish Association of Human Genetics (AEGH), the Spanish Society of Laboratory Medicine (SEQC-ML) and the Spanish Society of Medical Oncology (SEOM). PMID- 29439876 TI - Identification of Theileria fuliginosa-like species in Ixodes australiensis ticks from western grey kangaroos (Macropus fuliginosus) in Western Australia. AB - Piroplasms, including the genera Babesia and Theileria, are intra-erythrocytic protozoa that are generally transmitted by ticks and are the aetiological agents for piroplasmosis in animals, as well as humans, worldwide. In Australia, numerous studies have been conducted on piroplasms in domestic animals; however, less is known about these protozoa in ticks from native wildlife. The present study characterised piroplasms in Ixodes australiensis (n = 119) and Amblyomma triguttatum (n = 35) ticks collected from kangaroos in Western Australia (WA). Approximately 7.6% (9/119) (95% CI 2.8-12.2) of the I. australiensis ticks were positive for piroplasms using nested-PCR at the 18S rRNA locus, whereas no piroplasm 18S rDNA was detected in the A. triguttatum ticks. All sequences from I. australiensis ticks were identical. Using a 852 bp multiple nucleotide alignment at the 18S rRNA variable region, sequences shared 97.6%, 94.3%, 93.5% and 93.4% pairwise identity with Theileria fuliginosa, Theileria brachyuri, Theileria penicillata, and a Theileria sp. (K1), derived from a burrowing bettong or boodie (Bettongia lesueur), respectively. Phylogenetic analysis revealed that the Theileria sp. from I. australiensis clustered together in the marsupial associated Theileria group, with T. fuliginosa as closest sister species. Hence, we conclude that this is the first observation of T. fuliginosa-like species in I. australiensis ticks parasitising kangaroos in WA. PMID- 29439877 TI - Seizure reductions outlast DBS explantation. PMID- 29439878 TI - Thickness and an Altered miRNA Expression in the Epicardial Adipose Tissue Is Associated With Coronary Heart Disease in Sudden Death Victims. AB - INTRODUCTION AND OBJECTIVES: An increased epicardial adipose tissue (EAT) thickness has become a new risk factor for coronary heart disease (CHD). We aimed to study the role of EAT dysfunction as a CHD marker by focusing on its thickness and microRNA (miRNA) expression profile, and the potential factors possibly influencing them. METHODS: One hundred and fifty-five CHD sudden cardiac death victims and 84 non-CHD-sudden death controls were prospectively enrolled at autopsy. A representative subset underwent EAT thickness measurements and EAT miRNA expression profiling. RESULTS: Epicardial adipose tissue thickness was increased and allowed an accurate diagnosis of patient status (among other measurements, EAT score area under the curve 0.718, P < .001). Epicardial adipose tissue from patients showed 14 up- and 14 down-regulated miRNAs and miR-34a-3p, 34a-5p, -124-3p, -125a-5p, 628-5p, -1303 and -4286 were validated by quantitative real-time polymerase chain reaction. Patients exhibited higher EAT levels of miR 34a-3p and -34a-5p than controls (with a positive trend considering EAT from coronaries without stenosis, with stable stenosis and complicated plaques) and correlated with age only in controls. The mild positive correlation between liver and EAT miR-34a-5p levels in patients (r = 0.295, P = .020) dramatically increased in EAT from complicated plaques (r = 0.799, P = .017). Similar correlations were observed for high-sensitivity-C-reactive protein levels and miR 34a-5p levels both in EAT and liver extracts. CONCLUSIONS: Increased age independent levels of miR-34a-3p and -34a-5p characterize the EAT miRNA expression profile of CHD regardless of EAT thickness, anthropometric parameters, and the presence of underlying atherosclerotic plaques. PMID- 29439879 TI - Can Focal Therapy Replace Radical Therapy for Prostate Cancer? Against Focal Therapy. AB - Until prospective data demonstrate the oncologic efficacy of focal therapy for clinically significant, localized prostate cancer, it should be considered as experimental and only performed within the confines of a clinical trial. PMID- 29439881 TI - Prospective assessment of the frequency of low gradient severe aortic stenosis with preserved left ventricular ejection fraction: Critical impact of aortic flow misalignment and pressure recovery phenomenon. AB - BACKGROUND: The frequency of paradoxical low-gradient severe aortic stenosis (AS) varies widely across studies. The impact of misalignment of aortic flow and pressure recovery phenomenon on the frequency of low-gradient severe AS with preserved left ventricular ejection fraction (LVEF) has not been evaluated in prospective studies. AIMS: To investigate prospectively the impact of aortic flow misalignment by Doppler and lack of pressure recovery phenomenon correction on the frequency of low-gradient (LG) severe aortic stenosis (AS) with preserved LVEF. METHODS: Aortic jet velocities and mean pressure gradient (MPG) were obtained by interrogating all windows in 68 consecutive patients with normal LVEF and severe AS (aortic valve area [AVA] <=1cm2) on the basis of the apical imaging window alone (two-dimensional [2D] apical approach). Patients were classified as having LG or high-gradient (HG) AS according to MPG <40mmHg or >=40mmHg, and normal flow (NF) or low flow (LF) according to stroke volume index >35mL/m2 or <=35mL/m2, on the basis of the 2D apical approach, the multiview approach (multiple windows evaluation) and AVA corrected for pressure recovery. RESULTS: The proportion of LG severe AS was 57% using the 2D apical approach alone. After the multiview approach and correction for pressure recovery, the proportion of LG severe AS decreased from 57% to 13% (LF-LG severe AS decreased from 23% to 3%; NF LG severe AS decreased from 34% to 10%). As a result, 25% of patients were reclassified as having HG severe AS (AVA <=1cm2 and MPG >=40mmHg) and 19% as having moderate AS. Hence, 77% of patients initially diagnosed with LG severe AS did not have "true" LG severe AS when the multiview approach and the pressure recovery phenomenon correction were used. CONCLUSIONS: Aortic flow misevaluation, resulting from lack of use of multiple windows evaluation and pressure recovery phenomenon correction, accounts for a large proportion of incorrectly graded AS and considerable overestimation of the frequency of LG severe AS with preserved LVEF. PMID- 29439880 TI - Suppression of inducible nitric oxide synthase and tumor necrosis factor-alpha level by lycopene is comparable to methylprednisolone in acute pancreatitis. AB - BACKGROUND: Oxidative stress and inflammation may play a key role in the pathogenesis of acute pancreatitis (AP). Lycopene, a natural carotenoid, has antioxidant scavenger capacity and inhibits inflammation in many experimental models. AIM: The study was designed to investigate whether lycopene can ameliorate l-arginine-induced pancreatitis in rats and to elucidate the underlying molecular mechanisms of these effects. METHODS: Forty-eight adult male Wistar rats were divided into: control group (vehicle, orally, 10 days), AP group (3 g/kg l-arginine, single i.p. injection, on day 10th of the experiment), lycopene group (50 mg/kg) and methylprednisolone group (30 mg/kg). Lycopene and methylprednisolone were given orally, once daily for 10 days prior to l-arginine injection. Rats were sacrificed 24 h after l-arginine injection. Inflammation/oxidative stress and pancreatic markers were assessed. Pancreatic histopathological studies were done. RESULTS: Lycopene group showed a significant reduction in tumor necrosis factor alpha (TNF-alpha), myeloperoxidase activity, and down-regulation of inducible nitric oxide synthase (iNOS) gene expression. Pancreatic nitric oxide concentration was reduced and pancreatic GSH was increased in lycopene group. Serum alpha-amylase and lipase activities were reduced by lycopene treatment. The histology of pancreas was improved in lycopene group as well as methylprednisolone group. CONCLUSION: Lycopene prior treatment proved anti-inflammatory and antioxidant effects against AP rat model via different mechanisms. PMID- 29439882 TI - Radiation Therapy to Sites of Metastatic Disease as Part of Consolidation in High Risk Neuroblastoma: Can Long-term Control Be Achieved? AB - PURPOSE: As part of consolidative therapy in high-risk neuroblastoma, modern protocols recommend radiation therapy (RT) both to the primary site and to sites of metastatic disease that persist after induction chemotherapy. Although there are abundant data showing excellent local control (LC) with 21 Gy directed at the primary site, there are few data describing the feasibility and efficacy of RT directed at metastatic sites of disease as part of consolidation. METHODS AND MATERIALS: All patients with neuroblastoma who received RT to metastatic sites of disease as a part of consolidative therapy at a single institution between 2000 and 2015 were reviewed. Among 159 patients, 244 metastases were irradiated. RESULTS: The median follow-up period among surviving patients was 7.4 years. Over 85% of the irradiated metastases were treated with 21 Gy (range, 10.5-36 Gy). Tumor recurrence occurred in 43 of 244 irradiated metastases (18%). The 5-year LC rate of treated metastatic sites was 81%. Metastatic sites that cleared with induction chemotherapy had improved LC compared with sites with persistent uptake on metaiodobenzylguanidine scans (LC rate, 92% vs 67%; P < .0001). LC at irradiated metastatic sites did not differ based on total number of sites irradiated or site of disease irradiated (bone vs soft tissue). Patients with bulky, resistant disease who were treated with 30 to 36 Gy had worse LC (P = .02). However, on multivariate analysis, only persistence after induction chemotherapy remained a significant prognostic factor for LC (hazard ratio, 3.7; P < .0001). Patients who had LC at irradiated metastatic sites had improved overall survival compared with those who did not (overall survival rate, 71% vs 50%; P < .0001). CONCLUSIONS: Response to chemotherapy is an important prognostic factor for LC at irradiated metastatic sites in neuroblastoma. Overall, consolidative RT appears to be an effective modality of LC. Long-term disease control can be achieved with such an approach. PMID- 29439883 TI - Endoscopic Surgery for Delayed Sinonasal Complications of Radiation Therapy for Nasopharyngeal Carcinoma: A Subjective Outcome. AB - PURPOSE: Delayed sinonasal complications of radiation therapy include choanal stenosis, osteoradionecrosis, chronic sinusitis, and intranasal synechiae. Only sporadic cases on their surgical treatment have been reported, with equivocal results. METHODS AND MATERIALS: We performed a prospective case series of all patients who had been surgically treated for delayed sinonasal complications of radiation therapy in our institution during the past 10 years. The inclusion criteria required >=6 months of follow-up after surgery. The included patients were asked to complete a Sino-Nasal Outcome Test 16-item questionnaire preoperatively and 6 months after surgery. RESULTS: Nine patients with history of radiation therapy for nasopharyngeal carcinoma were included in our series. In all cases, partial or complete subjective improvement occurred. CONCLUSIONS: In select cases, endoscopic sinus surgery could be of benefit in the treatment of delayed sinonasal complications of radiation therapy. PMID- 29439884 TI - A Quantitative CT Imaging Signature Predicts Survival and Complements Established Prognosticators in Stage I Non-Small Cell Lung Cancer. AB - PURPOSE: Prognostic biomarkers are needed to guide the management of early-stage non-small cell lung cancer (NSCLC). This work aims to develop an image-based prognostic signature and assess its complementary value to existing biomarkers. METHODS AND MATERIALS: We retrospectively analyzed data of stage I NSCLC in 8 cohorts. On the basis of an analysis of 39 computed tomography (CT) features characterizing tumor and its relation to neighboring pleura, we developed a prognostic signature in an institutional cohort (n = 117) and tested it in an external cohort (n = 88). A third cohort of 89 patients with CT and gene expression data was used to create a surrogate genomic signature of the imaging signature. We conducted further validation using data from 5 gene expression cohorts (n = 639) and built a composite signature by integrating with the cell cycle progression (CCP) score and clinical variables. RESULTS: An imaging signature consisting of a pleural contact index and normalized inverse difference was significantly associated with overall survival in both imaging cohorts (P = .0005 and P = .0009). Functional enrichment analysis revealed that genes highly correlated with the imaging signature were related to immune response, such as lymphocyte activation and chemotaxis (false discovery rate < 0.05). A genomic surrogate of the imaging signature remained a significant predictor of survival when we adjusted for known prognostic factors (hazard ratio, 1.81; 95% confidence interval, 1.34-2.44; P < .0001) and stratified patients within subgroups as defined by stage, histology, or CCP score. A composite signature outperformed the genomic surrogate, CCP score, and clinical model alone (P < .01) regarding concordance index (0.70 vs 0.62-0.63). CONCLUSIONS: The proposed CT imaging signature reflects fundamental biological differences in tumors and predicts overall survival in patients with stage I NSCLC. When combined with established prognosticators, the imaging signature improves survival prediction. PMID- 29439885 TI - Early Tissue Effects of Stereotactic Body Radiation Therapy for Spinal Metastases. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) is a highly effective and potentially ablative treatment for complex spinal metastases. Recent data have suggested radiobiologic effects of SBRT that expand beyond the traditional concept of DNA damage. Antitumor immunity, vascular damage leading to tumor necrosis, and increased rates of tumor apoptosis have been implied; however, in human evidence remains scarce. The present study reports unique pathologic confirmation of SBRT-induced biological effects within spinal metastases treated with preoperative SBRT. METHODS AND MATERIALS: Ten patients with spinal metastases secondary to various solid tumors were treated with preoperative single-fraction SBRT (18 Gy) to the magnetic resonance imaging-defined macroscopic metastasis, followed by spinal stabilization within 24 hours. Perioperative samples of spinal metastases were obtained, and 6 patients also had a pre-SBRT biopsy specimen available for a matched comparison. The samples were stained for tumor necrosis on routine hematoxylin-eosin-stained slices and, subsequently, immunohistochemical staining for T cells (CD3+, CD4+, CD8+), natural killer cells (CD56+), endothelium (CD31+), and apoptotic activity (caspase-3). RESULTS: Perioperative biopsy specimens were obtained ~6 hours (range 4.5-7.5) or 21 hours (range 18.5-22.5) after SBRT. Necrosis was observed in 83% of the 21-hour post-SBRT samples (5 of 6) compared with 0% of pre-SBRT biopsies (0 of 6) and 6-hour post-SBRT biopsies (0 of 4). Tumor cell apoptosis had increased greatly in the 21-hour post-SBRT samples compared with before and 6 hours after SBRT. The CD31+ vessel counts decreased after SBRT, as did mitotic activity. Both of the renal cell metastases displayed major decreases in vessel density. Desmoplastic reaction was visible in 67% (4 of 6) of the pre-SBRT samples compared with 100% (10 of 10) the post-SBRT samples. The T-cell and natural killer cell counts were relatively unaffected. CONCLUSIONS: High-dose single-fraction SBRT induced tumor necrosis, desmoplasia, and tumor apoptosis and decreased tumor vessel density within 24 hours, even in renal cell metastases. The role of immune cells seems limited in this early phase. These first-in-human results imply direct vascular and DNA damage mechanisms important in the clinical efficacy specific to spinal SBRT. PMID- 29439886 TI - Patient Experiences and Clinician Views on the Role of Radiation Therapy for Ductal Carcinoma In Situ. AB - PURPOSE: To evaluate patient experiences with decisions regarding radiation therapy (RT) for ductal carcinoma in situ (DCIS), and to assess clinician views on the role of RT for DCIS with favorable features in the present era. METHODS AND MATERIALS: A sample of women with newly diagnosed breast cancer from the population-based Georgia and Los Angeles County Surveillance, Epidemiology, and End Results (SEER) registries were sent surveys approximately 2 months after undergoing breast-conserving surgery (BCS), with a 70% response rate. The analytic sample was limited to 538 respondents with unilateral DCIS. We also surveyed 761 surgeons and radiation oncologists treating breast cancer in those regions, of whom, 539 responded (71%). RESULTS: After BCS, 23% of patients omitted RT, with twice the rate of omission in Los Angeles County relative to Georgia (31% vs 16%; P < .001). The most common reasons for omitting RT were advice from a clinician that it was not needed (62%) and concern about side effects (24%). Cost and transportation were not reported as influential considerations. After covariate adjustment, low- and intermediate-grade disease (odds ratio [OR] 5.5, 95% confidence interval [CI] 2.5-12; and OR 3.2, 95% CI 1.7 6.1, respectively) and Los Angeles County SEER site (OR 4.3, 95% CI 2.3-8.2) were significantly associated with greater RT omission. Of the responding clinicians, 62% would discuss RT omission for a patient with DCIS with favorable features. Clinicians in Los Angeles County were more likely to discuss RT omission than were those in Georgia (67% vs 56%; P = .01). Approximately one third of clinicians would obtain the Oncotype DX DCIS score. CONCLUSIONS: The heterogeneity in RT omission after BCS for DCIS continues to be substantial, with systematic differences in provider opinions across the 2 regions we studied. Enhanced precision of recurrence estimates, guidance from professional organizations, and better communication are needed to improve the consistency of treatment in this controversial area. PMID- 29439887 TI - A challenge for mutation specific risk stratification in long QT syndrome type 1. AB - BACKGROUND: The relationship between mutation locations in KCNQ1 which is a major gene in long QT syndrome (LQTS) and phenotype has been analyzed and used for risk stratification. Mutations in the transmembrane region (TM) or cytoplasmic-loop (C loop) are associated with more frequent cardiac events than those in other regions. However, accumulation of LQTS type 1 (LQT1) patients poses the question of whether the location specific risk stratification is really effective. METHODS: The study cohort consisted of 67 KCNQ1 mutation carriers and 13 family members who were suspected as having LQTS due to sudden cardiac death or syncope from 36 unrelated families. The KCNQ1 mutations were L250H, V254M, H258P, and R259C located in segment 4-5 linker (C-loop), G269S, and S277L in segment 5 (TM). RESULTS: More than half of the patients with V254M or S277L suffered sudden cardiac death or syncope. In contrast, those with other mutations showed mild phenotype. In these two mutations related to severe phenotype, gender frequency and the age of onset were contrasting, 14 out of 23 patients with V254M were male, 19 out of 22 patients with S277L were female. In the patients we could confirm the age of onset, all of the patients with V254M showed symptoms at less than 15 years old, while 5 out of 12 patients with S277L suffered symptoms after 16 years old. CONCLUSION: Clinical characteristics were not specific for mutation locations but specific for respective mutations in our LQT1 patients. Patients should be evaluated by their own mutations to prevent severe cardiac events. PMID- 29439888 TI - [Editorial]. PMID- 29439889 TI - Hematuria in an Adult with Congenital Heart Disease. AB - BACKGROUND: Adults with congenital heart disease (CHD) in the United States now outnumber children with CHD, due in part to the improvement in surgical and medical management. This growing population may present postoperatively to the emergency department (ED) with nonspecific complaints from unforseen complications secondary to cardiac intervention. CASE REPORT: We describe a 39 year-old male who presented to the ED with hematuria and dysuria after he underwent percutaneous device ventricular septal defect (VSD) closure 10 days before. Upon initial evaluation, laboratory results confirmed a urinary tract infection and hematuria. Given persistent red discoloration of urine and easy fatigability, further investigation and re-evaluation found him to be anemic secondary to intravascular hemolysis. Cardiac catheterization showed residual shunting through the VSD device margins causing the hemolysis. Although this is a rare complication of VSD device closure, the patient's initial presentation of hematuria and dysuria presented a unique diagnostic challenge. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients with underlying CHD require emergency physicians to consider a multidisciplinary approach to properly diagnose and facilitate treatment. PMID- 29439890 TI - Brugada-Type Pattern on Electrocardiogram Associated with High-Dose Loperamide Abuse. AB - BACKGROUND: Loperamide has been increasing in popularity recently for its effects separate from treatment of diarrhea. In large doses or in combination with other agents, it can lead to desirable effects in the central nervous system. However, cardiotoxicity has been reported with its abuse. CASE REPORT: A 49-year-old male who had been chronically abusing loperamide was found to have Brugada-like changes on his electrocardiogram (ECG). He had no other clinical symptoms associated with Brugada syndrome and did not have similar findings on previous ECGs. After abstaining from further loperamide use during hospitalization, this pattern slowly resolved without clinically significant dysrthymias. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A patient with a history of loperamide abuse is at risk for cardiotoxicity. While other dysrhythmias are reported more commonly with loperamide abuse, Brugada-like ECG changes can occur and warrant appropriate consultation and prompt follow-up. PMID- 29439891 TI - Resuscitative Endovascular Balloon Occlusion of the Aorta Using a Low-Profile Device is Easy and Safe for Emergency Physicians in Cases of Life-Threatening Hemorrhage. AB - BACKGROUND: Bleeding from hemorrhagic shock can be immediately controlled by blocking the proximal part of the hemorrhagic point using either resuscitative thoracotomy for aortic cross-clamping or insertion of a large-caliber (10-14Fr) resuscitative endovascular balloon occlusion of the aorta (REBOA) device via the femoral artery. However, such methods are very invasive and have various complications. With recent progress in endovascular treatment, a low-profile REBOA device (7Fr) has been developed. OBJECTIVE: The objective of this study was to report our experience of this low-profile REBOA device and to evaluate the usefulness of emergency physician-operated REBOA in life-threatening hemorrhagic shock. METHODS: Ten patients with refractory hemorrhagic shock underwent REBOA using this device via the femoral artery. All REBOA procedures were performed by emergency physicians. The success rate of the insertion, vital signs, and REBOA related complications were evaluated. RESULTS: Median age was 54 years (interquartile range 33-78 years). The causes of hemorrhagic shock were trauma (n = 4; 1 blunt and 3 penetrating), ruptured abdominal aortic aneurysm (n = 3), and obstetric hemorrhage (n = 3). Two patients had cardiopulmonary arrest upon arrival. REBOA procedure was successful in all patients, and all became hemodynamically stable to undergo definitive interventions after REBOA. There were no REBOA-related complications. The mortality rate within 24 h and 30 days was 40%. CONCLUSIONS: This REBOA device was useful for emergency physicians in life-threatening hemorrhagic shock because of its ease in handling and low invasiveness. PMID- 29439892 TI - A Human Bite on the Scrotum: Case Report and Review of Management in the Emergency Department. AB - BACKGROUND: Human bites involving the genitalia rarely present to the emergency department (ED). They have the potential to cause life-threatening secondary infections as well as serious physical and functional damage. CASE REPORT: We report a case of an adult male who sustained a human bite to the scrotum, resulting in a ragged laceration on the anterior scrotum, with a devascularized flap and necrotic edges overlying the wound. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Human bites to the scrotum are rare and, hence, the experience of emergency physicians treating patients presenting with these injuries may be minimal. This puts patients at risk of underevaluation or suboptimal treatment. The rapid initiation of antibiotics in the ED and thorough wound debridement will prevent infections, aid healing, and lead to improved outcomes by preserving organ function and integrity. We therefore present a systematic approach to the management of patients with human bite to the scrotum in the ED. PMID- 29439893 TI - The State of Affairs for Cardiovascular Health Research in Indigenous Women in Canada: A Scoping Review. AB - Cardiovascular disease (CVD) is the leading cause of death among Indigenous peoples in Canada. As rates of CVD rise, the impacts among the growing population of Indigenous women will emerge as an important health issue. The objective of this scoping review was to advance the state of knowledge about cardiovascular health research in Indigenous women in Canada. Five databases and grey literature (non-peer reviewed works) were searched to identify all studies that reported on the prevalence, pathophysiology, diagnosis, treatment, or interventions for CVD among adult Indigenous women in Canada, including First Nations, Metis, and Inuit. Searching identified 3194 potential articles; 61 of which were included. The most commonly researched topics were the prevalence of CVD, hypertension, and dyslipidemia. Rates of CVD and associated mortality among Indigenous women appear to have surpassed those of their nonindigenous counterparts. Very little research has examined the pathophysiology, diagnosis, and treatment of CVD. Gaps in the research identified the need for sex-based analyses, comparison with nonindigenous women, comprehensive longitudinal data, assessment of diagnosis criteria, development and evaluation of cardiovascular health interventions, and a better understanding of the role of culture and traditions in the prevention and treatment of CVD among Indigenous women. Although comprehensive CVD data are lacking, rates of CVD among Indigenous women in Canada are rising and are nearing or surpassing those of nonindigenous women. This review serves as a call to action to seek further research on the pathophysiology, diagnosis, and treatment of CVD among Indigenous women from across Canada. PMID- 29439894 TI - Early Failure of Primary Total Hip Arthroplasty: Is Surgical Approach a Risk Factor? AB - BACKGROUND: In an era of innovation in surgical approaches for total hip arthroplasty (THA), there is concern for increasing trends of early failure. The purpose of this study is to evaluate the incidence of early failure of primary THA stratified by surgical approach. METHODS: A retrospective review was performed on consecutive primary THAs completed from 2007 to 2014 at a high volume center. THAs were stratified by surgical approach. Only the direct anterior (DAA) and posterior approaches (PA) were included. The primary outcome measure was early revision (<5 years). Descriptive statistics were performed using SAS software. RESULTS: In total, 6894 primary THAs performed between 2007 and 2014 were included. Across 2431 DAA THAs and 4463 PA THAs, there were 103 revisions overall. There was no difference in the overall revision rate for DAA THAs (1.69%) compared to PA THAs (1.39%) (P = .33). The DAA had a higher rate of early revisions for femoral component loosening compared to the PA (P = .0003). About 35.7% of DAA THAs were revised for femoral loosening compared to 8% for the PA (P = .0003). Early failure by femoral loosening occurred more often via the DAA in Dorr A bone (P = .03). The PA had a higher incidence of revision for instability (P = .04). There was no difference in modes of failure with regards to time to failure, acetabular loosening, early periprosthetic fracture, or infection. CONCLUSION: The DAA had a higher incidence of femoral loosening while PA had a higher mode of failure due to instability. Overall revision rates were not statistically different between approaches. PMID- 29439895 TI - Adding Value to Total Joint Arthroplasty Care in an Academic Environment: The Utah Experience. AB - BACKGROUND: Adding value in a university-based academic health care system provides unique challenges when compared to other health care delivery models. Herein, we describe our experience in adding value to joint arthroplasty care at the University of Utah, where the concept of value-based health care reform has become an embraced and driving force. METHODS: To improve the value, new resources were needed for care redesign, physician leadership, and engagement in alternative payment models. The changes that occurred at our institution are described. RESULTS: Real-time data and knowledgeable personnel working behind the scenes, while physicians provide clinical care, help move clinical pathway redesigns. Engaged physicians are essential to the successful implementation of value creation and care pathway redesign that can lead to improvements in value. An investment of money and resources toward added infrastructure and personnel is often needed to realize large-scale improvements. Alignment of providers, payers, and hospital administration, including by means of gainsharing programs, can lead to improvements. CONCLUSION: Although significant care pathway redesign efforts may realize substantial initial cost savings, savings may be asymptotic in nature, which calls into question the likely sustainability of programs that incentivize or penalize payments based on historical targets. PMID- 29439896 TI - High Failure Rates of Concomitant Periprosthetic Joint Infection and Extensor Mechanism Disruption. AB - BACKGROUND: Patients presenting with both chronic periprosthetic joint infection (PJI) and extensor mechanism disruption (EMD) pose a significant challenge. As there is little in the literature regarding outcomes of patients with concomitant PJI and EMD, we performed a multicenter study to evaluate the outcomes. METHODS: Sixty patients with concomitant diagnoses of PJI and EMD were evaluated from 5 institutions. Patient demographics, presentation type, surgical management, and outcomes including recurrent infections, final surgery, and ambulatory status were documented. RESULTS: Fifty-three of 60 patients had an attempted extensor mechanism reconstruction/repair (EMR) of which 12 (23%) were successful, averaging 3.5 (range, 2-7) intervening surgeries. Forty-one patients (77%) were considered failures with recurrence of infection as most common failure (80%); 26 ended in fusion, 10 in above knee amputation, 3 with chronic resection arthroplasty, and 2 with chronic spacers/EMD. Seven patients had no attempt at EMR but proceeded directly to fusion (n = 6) or amputation (n = 1). There was no statistical difference between groups that had success or failure of EMR in age, American Society of Anesthesiologists Physical Status Classification System, or body mass index. CONCLUSION: Our study demonstrates that concomitant EMD and PJI is a dreaded combination with poor outcomes regardless of treatment. Eradication of infection and reconstruction of the extensor mechanism often require numerous surgeries and despite great effort often end in failure. Consideration of early fusion or amputation may be preferable in some patients to avoid the morbidity and mortality of repeated surgeries. PMID- 29439897 TI - The Elusive P2X7 Macropore. AB - ATP, which is released under pathological conditions and is considered a damage associated molecular pattern (DAMP), activates P2X7 receptors (P2X7Rs), trimeric plasma membrane ion channels selective for small cations. P2X7Rs are partners in NOD-like receptor containing a pyrin (NLRP3) inflammasome activation and promoters of tumor cell growth. P2X7R overstimulation triggers the ATP-dependent opening of a nonselective plasma membrane pore, known as a 'macropore', which allows fluxes of large hydrophilic molecules. The pathophysiological functions of P2X7R are thought to be dependent on activation of this conductance pathway, yet its molecular identity is unknown. Recent reports show that P2X7R permeability to organic solutes is an early and intrinsic property of the channel itself. A better understanding of P2X7R-dependent changes in plasma membrane permeability will allow a rationale development of novel anti-inflammatory and anticancer drugs. PMID- 29439898 TI - Comments on "Compositional and functional variations of oral microbiota associated with the mutational changes in oral cancer" by Yang et al. PMID- 29439900 TI - Total syntheses and stereochemical reassignments of mollenines A and B. AB - Total syntheses of prenylated pyrrolidinoindoline alkaloids, (-)-mollenines A [( )-1'] and B (2'), were accomplished via three- and four-step sequences including a bioinspired indole prenylation reaction followed by dioxomorpholine ring formation. Then, the stereochemistry of mollenines A and B was reassigned to 3S,6S,14S,16S by analysis of spectroscopic data and chemical syntheses with different approaches along with the comparison of calculated and experimental ECD spectra. In addition, a thermodynamically controlled epimerization reaction on the dioxomorpholine ring was observed in our synthesis. PMID- 29439899 TI - High expression of class III beta-tubulin has no impact on functional cancer cell growth inhibition of a series of key vinblastine analogs. AB - Clinical association studies have implicated high expression of class III beta tubulin as a predictive factor for lower response rates and reduced overall survival in patients receiving tubulin binding drugs, most notably the taxanes. Because of the implications, we examined a series of key vinblastine analogs that emerged from our studies in functional cell growth inhibition assays for their sensitivity to high expression of class III beta-tubulin (human non-small cell lung cancer cell line A549 vs taxol-resistant A549-T24). Unlike taxol, vinblastine and a set of key analogs 3-10 did not exhibit any loss in sensitivity toward A549-T24. The results suggest that vinblastine and related analogs are not likely prone to resistance derived from high expression of class III beta-tubulin unlike the taxanes. Most significant are the results with 4-6, a subset of 20' amide vinblastine analogs. They match or exceed the potency of vinblastine and they display more potent activity against taxol-resistant A549-T24 than even wild type A549 cells (1.2-2-fold), complementing our prior observations that they also display no sensitivity to overexpression of Pgp (HCT116/VM46 vs HCT116) and are not subject to resistance derived from Pgp efflux. PMID- 29439901 TI - Development of a fluorescent probe for detection of citrulline based on photo induced electron transfer. AB - Peptidyl arginine deiminases (PADs) catalyze the post-translational deimination of peptidyl arginine residues to form citrulline residues. Aberrant citrullination of histones by one of the PAD isozymes, PAD4, is associated with various diseases, including rheumatoid arthritis, so high-throughput screening systems are needed to identify PAD4 inhibitors as chemical tools to investigate the role of PAD4, and as candidate therapeutic agents. Here, we utilized the addition-cyclization reaction between phenylglyoxal and citrulline under acidic conditions to design turn-on fluorescent probes for citrulline based on the donor excited photoinduced electron transfer (d-PeT) mechanism. Among several derivatives of phenylglyoxal bearing a fluorescent moiety, we found that FGME enabled detection of citrulline without a neutralization process, and we used it to establish a simple methodology for turn-on fluorescence detection of citrulline. PMID- 29439902 TI - MF-8, a novel promising arylpiperazine-hydantoin based 5-HT7 receptor antagonist: In vitro drug-likeness studies and in vivo pharmacological evaluation. AB - We report the in vitro drug-likeness studies and in vivo pharmacological evaluation for a new potent 5-HT7 receptor antagonist MF-8 (5-(4-fluorophenyl)-3 (2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylhydantoin). The in vitro tests showed good permeability, very good metabolic stability, low risk of drug-drug interactions and satisfying safety profile. Moreover, MF-8 showed excellent antidepressant-like activity in the forced swim test in rodents and promising anxiolytic-like activity in the four-plate test in mice. Regarding the potent affinity, high selectivity and antagonistic activity of MF-8 for the 5-HT7 receptor as well as excellent drug - like properties in vitro and confirmed in vivo pharmacological activity, MF-8 should be considered as a very significant molecule in the search for a new class of anti-depressant drugs. PMID- 29439903 TI - Antibacterial activities of mono-, di- and tri-substituted triphenylamine-based phosphonium ionic liquids. AB - We report the synthesis of new mono, di and tri phosphonium ionic liquids and the evaluation of their antibacterial activities on both Gram-positive and Gram negative bacteria from the ESKAPE-group. Among the molecules synthesized some of them reveal a strong bactericidal activity (MIC = 0.5 mg/L) for Gram-positive bacteria (including resistant strains) comparable to that of standard antibiotics. A comparative Gram positive and Gram negative antibacterial activities shows that the nature of counter-ion has no significant effects. Interestingly, the increase of phosphonium lateral chains (from 4 to 8 carbons) results in a decrease of antibacterial activities. However, the increase of the spacer length has a positive influence on the activity on both Gram-positive and Gram-negative bacteria except for E. aerogenes. Finally, the increased charge density has no effect on the Gram-positive antibacterial activities (MIC between 2 and 4 mg/L) but seems to attenuate (except for P. aeruginosa) the discrimination between Gram-positive and Gram-negative. Overall these results suggest a unique mechanism of action of these triphenylamine-phosphonium ionic liquid derivatives. PMID- 29439904 TI - Discovery of morpholine-based aryl sulfonamides as Nav1.7 inhibitors. AB - Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs. PMID- 29439905 TI - Three-dimensional intracranial middle cerebral artery aneurysm models for aneurysm surgery and training. AB - To develop a realistic model of middle cerebral artery (MCA) aneurysms using three-dimensional (3D) printing for surgical planning, research, and training of neurosurgical residents. This study included eight MCA aneurysm cases. The aneurysm together with the adjacent arteries and skull base were printed based on raw computed tomography angiography (CTA) data using a 3D printer with acrylonitrile-butadiene-styrene as the model material. The aneurysm models were used for surgical planning, and craniotomy and clipping practice by neurosurgical residents. Feedback was obtained using a survey. 3D aneurysm models were created for all seven MCA aneurysm patients. There was good agreement in the model aneurysm diameter, width, and neck and the CTA data, with no significant difference (p > 0.05) among the groups. The simulator was useful for choosing the clips to use before surgery. The average response to each of the survey questions was greater than 3.85 (range 3.0-5.0) on a five-point scale. The 3D printed MCA aneurysm models were accurate. Simulation and practice using the 3D models was useful for understanding the aneurysm structure and choosing the clips to use before surgery, especially for junior neurosurgeons. PMID- 29439906 TI - Dermoid cysts of the conus medullaris: Clinical review, case series and management strategies. AB - BACKGROUND: The management of dermoid cysts can be tedious as they have a tendency to recur, and respond poorly to chemotherapy and radiation. Management is especially difficult for tumors involving highly eloquent areas such as the conus medullaris. OBJECTIVE: We aim to provide a summary of the pathology, clinical presentation, and operative management strategies of dermoid cysts involving the conus medullaris. METHODS: Two clinical cases of dermoid cysts of the conus are presented, as well as a commented surgical video. RESULTS: A 33 year-old man with a history of cystic conus medullaris tumor presented with progressive low back pain and loss of bowel and bladder function. His magnetic resonance imaging (MRI) scan showed recurrence of his tumor with tethering of the spinal cord. He was taken for a midline myelotomy that drained yellowish keratinous fluid and decompressed the cyst. No aggressive attempt at complete resection of the cyst wall was undertaken. He made a complete recovery after surgery. A 25 year-old woman with a history of dermoid cyst of the conus that was previously treated surgically, presented with lower extremity weakness and debilitating pain. Her MRI showed significant recurrence of the cystic lesion. She was taken for a midline myelotomy and improved after surgery with complete resolution of her symptoms. CONCLUSION: Dermoid cysts of the conus medullaris are challenging to treat. Surgical control and restraint are key, especially when patients are young and could potentially fully recover and remain in remission for a period of years. PMID- 29439907 TI - Posterior spinal cord shift does not affect surgical outcomes after muscle preserving selective laminectomy. AB - Postoperative posterior spinal cord shift (PSS) has been considered a required radiographic endpoint of posterior decompression procedures. To achieve PSS, laminoplasty for cervical compressive myelopathy (CCM) has been consecutively performed on four or more laminae (C2-C7, C3-C7, or C3-C6). However, the clinical significance of PSS remains controversial. By selecting the surgically treated laminae, selective laminectomy (SL) can achieve adequate decompression without disturbing the extensor musculature and facet joints. The clinical features and radiological findings from 162 patients with CCM whose decompression included C4/5 level were investigated. The postoperative C2-C7 angle, PSS at C4/5 level, and laminectomy width were measured. Radiologic factors affecting PSS and the relationship between PSS and functional outcome were analyzed. Smaller PSS was observed in cases involving two or fewer consecutive laminectomies than in cases involving three or more consecutive laminectomies. The number of consecutive laminae (CLs) surgically treated and the postoperative C2-C7 angle correlated with PSS. Multiple linear regression analyses showed that the number of surgically treated CLs was the greatest predictor of PSS. No correlation was observed between PSS and the recovery rate (RR) of the Japanese Orthopaedic Association (JOA) score; RR of the JOA score was not affected even in patients with no PSS. PSS was affected by the number of CLs surgically treated and the postoperative C2-C7 angle. The magnitude of PSS never affected the RR of JOA score after SL. Therefore, for patients with CCM, PSS is not mandatory to obtain satisfactory functional recovery. PMID- 29439908 TI - Symptom-associated change of motor-related neuromagnetic fields in a patient with multiple sclerosis: A case report. AB - The objective of this study was to investigate functional abnormalities of the brain in a patient with multiple sclerosis (MS) by using magnetoencephalography (MEG) and a finger-tapping task. A 46-year-old woman that presented with motor weakness of left hand and was diagnosed with MS. Conventional magnetic resonance imaging demonstrated a white matter lesion with hyperintensity on T2-weighted images in the right motor area. MEG recordings were performed during the period of motor weakness and after clinical improvement. Neuromagnetic brain activation was elicited by a simple, visually cued finger movement. The Equivalent current dipole (ECD) strength of the movement-evoked field (MEF) in the affected hemisphere was significantly decreased relative to the unaffected hemisphere. After improvement in motor weakness, we found that the lower amplitude of the readiness field and decreased ECD strength of the MEF observed in affected hemisphere during motor weakness had recovered. Analysis of motor-related neuromagnetic fields revealed that MEG may be used to detect diffuse changes in the brain that are not observable by conventional imaging of white matter regions in MS. We further found that brain activities can change after improvement in motor weakness. PMID- 29439909 TI - Prediction of outcome in asphyxiated newborns treated with hypothermia: Is a MRI scoring system described before the cooling era still useful? AB - AIM: To determine whether an MRI scoring system, which was validated in the pre cooling era, can still predict the neurodevelopmental outcome of asphyxiated newborns treated with hypothermia at 2 years of age. PATIENTS AND METHOD: We conducted a retrospective cohort study of asphyxiated newborns treated with hypothermia. An MRI scoring system, which was validated in the pre-cooling era, was used to grade the severity of brain injury on the neonatal brain MRI. Their neurodevelopment was assessed around 2 years of age; adverse outcome included cerebral palsy, global developmental delay, and/or epilepsy. RESULTS: One hundred and sixty-nine newborns were included. Among the 131 newborns who survived and had a brain MRI during the neonatal period, 92% were evaluated around 2 years of age or later. Of these newborns, 37% displayed brain injury, and 23% developed an adverse outcome. Asphyxiated newborns treated with hypothermia who had an adverse outcome had a significantly higher MRI score (p <0.001) compared to those without an adverse outcome. CONCLUSION: An MRI scoring system that was validated before the cooling era is still able to reliably differentiate which of the asphyxiated newborns treated with hypothermia were more prone to develop an adverse outcome around 2 years of age. PMID- 29439910 TI - [Analysis of the refusal of the flu vaccination (REGRIVI study)]. AB - INTRODUCTION: The objective of this study is to determine the reasons for refusing the flu vaccination in the Primary Care Health Centre of Vilanova de Arousa, Spain, as well as to evaluate the flu vaccination coverage after an educational intervention. MATERIAL AND METHODS: A quasi-experimental before and after study was conducted after an educational intervention on a total of 73 people that included those Primary Care Health Centre patients from Vilanova de Arousa who had refused the flu vaccination in 2014, and who did not meet the exclusion criteria (death during 2014 and 2015 campaigns, non-acceptance of participation, vaccine registration mistakes, contraindication or no indication for the vaccine, inability to contact). After a brief educational intervention, vaccination data from those patients in the 2015 and 2016 campaigns were checked. A descriptive analysis of the variables under study was then carried out. Of the 73 patients initially included, 72 completed the study. RESULTS: The main reasons for refusing a vaccination were the concerns about the adverse effects and patient perception of good health. Vaccination coverage was 50.7% in 2015, and 48.6% in 2016. CONCLUSIONS: The reasons for refusing vaccination are approachable with a brief intervention since the refusal decreases by half in the long-term. PMID- 29439911 TI - [Effects of physical exercise in a population with systemic lupus erythematosus: A systematic review]. AB - This systematic review was aimed at analysing the existing scientific evidence regarding the effects of physical exercise on the symptomatology, disease activity, and fitness level in a population with systemic lupus erythematosus. Following the PRISMA checklist, a search was carried out on PubMed, PEDro, and Sportdiscus databases. The PEDro and MINORS checklists were used in order to identify the methodological quality of the studies selected. A total of 14 studies were found, of which 10 were randomised controlled trials, and 4 were comparative studies. The performance of physical exercise led to significant improvements in fitness and fatigue. No adverse effects were registered. None of the studies found reported positive effects on the disease activity. The obtained results imply that the performance of physical exercise is safe for people with systemic lupus erythematosus, although its benefits are reduced mainly to improvements in their fitness and perceived level of fatigue. PMID- 29439912 TI - [Pruritus and rivaroxaban]. PMID- 29439913 TI - [Proposal confirmation by spirometry of chronic obstructive pulmonary disease]. PMID- 29439914 TI - Sequence-specific DNA binding Pyrrole-imidazole polyamides and their applications. AB - Pyrrole-imidazole polyamides (Py-Im polyamides) are cell-permeable compounds that bind to the minor groove of double-stranded DNA in a sequence-specific manner without causing denaturation of the DNA. These compounds can be used to control gene expression and to stain specific sequences in cells. Here, we review the history, structural variations, and functional investigations of Py-Im polyamides. PMID- 29439915 TI - Probing biological activity through structural modelling of ligand-receptor interactions of 2,4-disubstituted thiazole retinoids. AB - Retinoids, such as all-trans-retinoic acid (ATRA), regulate cellular differentiation and signalling pathways in chordates by binding to nuclear retinoic acid receptors (RARalpha/beta/gamma). Polar interactions between receptor and ligand are important for binding and facilitating the non-polar interactions and conformational changes necessary for RAR-mediated transcriptional regulation. The constraints on activity and RAR-type specificity with respect to the structural link between the polar and non-polar functions of synthetic retinoids are poorly understood. To address this, predictions from in silico ligand-RAR docking calculations and molecular dynamics simulations for a small library of stable, synthetic retinoids (designated GZ series) containing a central thiazole linker structure and different hydrophobic region substituents, were tested using a ligand binding assay and a range of cellular biological assays. The docking analysis showed that these thiazole-containing retinoids were well suited to the binding pocket of RARalpha, particularly via a favorable hydrogen bonding interaction between the thiazole and Ser232 of RARalpha. A bulky hydrophobic region (i.e., present in compounds GZ23 and GZ25) was important for interaction with the RAR binding pockets. Ligand binding assays generally reflected the findings from in silico docking, and showed that GZ25 was a particularly strongly binding ligand for RARalpha/beta. GZ25 also exhibited higher activity as an inducer of neuronal differentiation than ATRA and other GZ derivatives. These data demonstrate that GZ25 is a stable synthetic retinoid with improved activity which efficiently regulates neuronal differentiation and help to define the key structural requirements for retinoid activity enabling the design and development of the next generation of more active, selective synthetic retinoids as potential therapeutic regulators of neurogenesis. PMID- 29439917 TI - How do anxiety affect CD34 and CD3 cells in allogeneic peripheral blood stem cell transplantation? AB - Allogeneic peripheral blood stem cells (PBHSCs) transplantation using apheresis is a curative method for malignant and non-malignant hematologic diseases. The aim of this study was to assess the possible effects of anxiety as well as other variables on PBHSCs apheresis success. In this cross-sectional study, different demographic and clinical data such as granulocyte-colony stimulating factor (G CSF) dosage, CD 34+ cells count (before apheresis), CD 34+, CD3+ cells count in apheresis product and also complete blood count were assessed. Furthermore, for evaluation of anxiety level in donors, the Beck's anxiety inventory (BAI) was administered. In this study, 111 donors were randomly enrolled after meeting inclusion and exclusion criteria. Results of BAI showed the mean score of 22.85 +/- 15.43 (mild to moderate anxiety) for the participants. According to the bootstrapped quantile regression analysis, a statistically significant linear association was found between CD34+ cell count and BAI score (P-value < 0.001) after adjusting for confounding variables. Moreover, the BAI score had a statistically significant effect on CD3+ cells count (P-value = 0.021) after adjusting for confounding variables. Taken together, results showed that anxiety affects both CD34+ and CD3+ cells count. Thus, the authors suggest that anxiety levels would be evaluated as well as other variables in donors in order to run a proper intervention by professionals. PMID- 29439916 TI - New histone demethylase LSD1 inhibitor selectively targets teratocarcinoma and embryonic carcinoma cells. AB - LSD1/KDM1 is a histone demethylase that preferentially removes methyl groups from the mono- and di-methylated lysine 4 in histone H3 (H3K4), key marks for active chromatin for transcriptional activation. LSD1 is essential for pluripotent embryonic stem cells and embryonic teratocarcinoma/carcinoma cells and its expression is often elevated in various cancers. We developed a new LSD1 inhibitor, CBB3001, which potently inhibited LSD1 activity both in vitro and in vivo. CBB3001 also selectively inhibited the growth of human ovarian teratocarcinoma PA-1 and mouse embryonic carcinoma F9 cells, caused the downregulation of pluripotent stem cell proteins SOX2 and OCT4. However, CBB3001 does not have significant inhibition on the growth of human colorectal carcinoma HCT116 cells or mouse fibroblast NIH3T3 cells that do not express these stem cell proteins. Our studies strongly indicate that CBB3001 is a specific LSD1 inhibitor that selectively inhibits teratocarcinoma and embryonic carcinoma cells that express SOX2 and OCT4. PMID- 29439918 TI - Short-term administration of recombinant human erythropoietin decreases B cell number in human peripheral blood. AB - OBJECTIVES: There are conflicting results on the influence of recombinant human erythropoietin (rHuEPO) administration to lymphocytes, especially to B cells. METHODS: We analyzed peripheral white blood cell (WBC) subsets in patients who received one bolus administration of rHuEPO. 119 autologous blood donors were enrolled in this study. Fourty-nine out of them were treated with rHuEPO. Blood samples were obtained before the first phlebotomy and one week later before the second one. By flow cytometry, we measured the numbers of WBC, lymphocytes, dendritic cells, CD4+ T cells, CD8+ T cells, natural killer (NK) cells, B cells, monocytes, and neutrophils, further details of B cell subsets. RESULTS: In the EPO-treatment group, absolute numbers of lymphocytes, especially CD8+ T cells, NK cells, and B cells, significantly decreased after rHuEPO administration. In B cell subsets, absolute numbers of naive B cells and IgD-CD27- B cells significantly decreased. Other B cell subsets, such as transitional B cells, memory B cells, and marginal zone B cells, also showed a decreasing trend. CONCLUSION: These findings suggest that a single administration of rHuEPO can influence human immune system via reduction of B cell number in peripheral blood. PMID- 29439919 TI - Solutions to technical challenges during therapeutic plasma exchange using the Spectra Optia on a 4 kilogram neonate. AB - Therapeutic plasma exchange (TPE) on severely ill neonates poses many technical challenges, including obtaining adequate vascular access. In addition, clinical challenges such as risk of hypotension and cardiovascular instability are more pronounced in these patients. We report an approach to successfully managing these challenges while performing TPE on a 4 kilogram neonate using the Spectra Optia and 22 G venous access. PMID- 29439920 TI - Stem cell mobilization kinetics in elderly patients with multiple myeloma. AB - In this study, we aimed to investigate whether the procedure and product kinetics differ according to age groups in advanced-age MM patients who underwent autologous HSCT. 59 patients who underwent autologous HSCT were retrospectively analyzed. Then, the patients were divided into two groups as 60-65 years and >=65 years. It was significantly lower in >=65 years group (p = 0.008) and proportionally, the procedure duration was also significantly shortened in this group (p = 0.013). Total number of collected CD34 positive stem cells was 6.20 * 106 (+/-3.83) in 60-65 years group while it was 5.51 * 106 (+/-2.48) in >=65 years group with no statistically significant difference (p = 0.825). In conclusion, there was no significant difference in terms of the number of collected CD34-positive stem cells in this study that investigates the mobilization data, procedure and product kinetics, we think that successful stem cell mobilization can be performed in appropriately selected patients regardless of age. PMID- 29439921 TI - Impact of organizational interventions on reducing inappropriate intravenous immunoglobulin (IVIG) usage: A systematic review and meta-analysis. AB - BACKGROUND: With increasing global use of intravenous immunoglobulin (IVIG), there is interest in its appropriate usage. Efforts to regulate IVIG usage have primarily taken the form of organizational interventions implemented in hospitals to monitor and improve physician prescribing. Similar interventions have proven effective in reducing the inappropriate and total hospital usage of other blood products, but their efficacy on IVIG use is less understood. Thus, we performed a systematic review of studies reporting the change in inappropriate IVIG use following such interventions in hospitals or regions. METHODS: A systematic search was carried out using MEDLINE and EMBASE (1966-June 2016) for English language studies if they 1) were primary research, 2) described an organizational intervention to target plasma, IVIG, or albumin, and 3) reported appropriateness of usage and total usage preand post-intervention. Review Manager v5.0 was utilized to perform a random-effects meta-analysis on eligible IVIG studies, where the risk ratio (RR) of inappropriate IVIG transfusion comparing pre- and postintervention periods was calculated with 95% confidence intervals (CI). RESULTS: Our search retrieved three retrospective cohort studies, where metaanalysis encompassing 2100 episodes of IVIG transfusion demonstrated no decrease in inappropriate IVIG use (RR 1.55, 95% CI 0.78-3.07). Heterogeneity between studies was considerable (I2 = 89%). CONCLUSION: Organizational interventions were ineffective at changing inappropriate IVIG use, but more high quality studies describing the effects of these interventions are required before any conclusions can be drawn. Futureresearch efforts should also be directed at evolving evidence-based IVIGguidelines to improve patient safety and burdens on healthcare systems. PMID- 29439922 TI - Increased precision of coronal plane outcomes in robotic-assisted total knee arthroplasty: A systematic review and meta-analysis. AB - BACKGROUND: Inaccuracy of component alignment in total knee arthroplasty adversely impacts outcomes. Robotic systems improve translation of pre-operative planning to intra-operative steps, theoretically resulting in greater accuracy and precision. In this study we systematically review literature data of alignment outcomes and apply meta-analysis methods to assess whether robotic assisted knee arthroplasty provides superior outcomes when compared to conventional knee prostheses. METHODS: A PRISMA compliant search comparing alignment outcomes in robotic vs conventional knee arthroplasty was performed. Primary outcome measures were; number of three degree outliers and mean deviation from a neutral post-operative mechanical axis. RESULTS: In total, from five studies reporting upon 402 knees, a post-operative mechanical axis malalignment of >3 degrees occurred in 1/181 (0.006%) of robotic knees, and 42/159 (26.4%) of conventional knees with a meta-analysis odds ratio of 0.04 (95% CI 0.01-0.14), p < 0.00001 favouring robotic-assisted instrumentation. Meta-analysis also demonstrated weighted mean differences of post-operative mechanical axis alignment to be significantly more accurate in the robotic knee group: mean difference -0.63 (95% CI: -1.18,-0.08), z = 2.25, p = 0.02. Sensitivity analysis with inclusion of only Level 1 studies showed similar findings. CONCLUSIONS: This systematic review and meta-analysis demonstrates clear evidence of increased accuracy of alignment in robotic-assisted knee arthroplasty with specific regard to reconstituting a neutral mechanical axis and minimising number of outliers in the coronal plane. Further studies and long term data is required in order to conclude on survivorship and functional outcomes. PMID- 29439923 TI - Less or more? Maternal requests that go against medical advice. AB - PROBLEM AND BACKGROUND: This study explores the experiences of Dutch midwives and gynaecologists with pregnant women who request more, less or no care during pregnancy and/or childbirth. METHODS: All Dutch midwives and (trainee) gynaecologists were invited to fill out a questionnaire specifically designed for the purposes of this study. Holistic midwives were analysed separately from regular community midwives. FINDINGS: Most maternity care providers in the Netherlands receive requests for less care than recommended at least once a year. The most frequently maternal requests were declining testing for gestational diabetes (66.3%), opting for a home birth in case of a high risk pregnancy (65.3%), and declining foetal monitoring during labour (39.6%). Holistic midwives are more convinced of an increasing demand for less care than community midwives (73.1% vs. 35.2%, p=<0.001). More community midwives than hospital staff reported to have declined one or more request for less care than recommended (48.6% vs. 27.9%, p=<0.001). The majority of hospital staff also receive at least one request for an elective caesarean section every year. DISCUSSION AND CONCLUSION: Requests for more and less care than indicated during pregnancy and childbirth are equally prevalent in this study. However, a request for less care is more likely to be declined than a request for more care. Counselling women who disagree with their care provider demands time. In case of requests for less care, second best care should be considered. PMID- 29439924 TI - Canada's evacuation policy for pregnant First Nations women: Resignation, resilience, and resistance. AB - BACKGROUND: Aboriginal peoples in Canada are comprised of First Nations, Metis, and Inuit. Health care services for First Nations who live on rural and remote reserves are mostly provided by the Government of Canada through the federal department, Health Canada. One Health Canada policy, the evacuation policy, requires all First Nations women living on rural and remote reserves to leave their communities between 36 and 38 weeks gestational age and travel to urban centres to await labour and birth. Although there are a few First Nations communities in Canada that have re-established community birthing and Aboriginal midwifery is growing, most First Nations communities are still reliant on the evacuation policy for labour and birthing services. In one Canadian province, Manitoba, First Nations women are evacuated to The Pas, Thompson, or Winnipeg but most - including all women with high-risk pregnancies - go to Winnipeg. AIM: To contribute scholarship that describes First Nations women's and community members' experiences and perspectives of Health Canada's evacuation policy in Manitoba. METHODS: Applying intersectional theory to data collected through 12 semi-structured interviews with seven women and five community members (four females, one male) in Manitoba who had experienced the evacuation policy. The data were analyzed thematically, which revealed three themes: resignation, resilience, and resistance. FINDINGS: The theme of resignation was epitomized by the quote, "Nobody has a choice." The ability to withstand and endure the evacuation policy despite poor or absent communication and loneliness informed of resilience. Resistance was demonstrated by women who questioned the necessity and requirement of evacuation for labour and birth. In one instance, resistance took the form of a planned homebirth with Aboriginal registered midwives. CONCLUSION: There is a pressing need to improve the maternity care services that First Nations women receive when they are evacuated out of their communities, particularly when understood from the specific legal and constitutional position of First Nations women in Manitoba. PMID- 29439925 TI - [Self-monitoring treatment program with oral vitamin K antagonists in paediatric patients]. PMID- 29439926 TI - Association of Single Nucleotide Polymorphisms of the MDM4 Gene With the Susceptibility to Breast Cancer in a Southeast Iranian Population Sample. AB - INTRODUCTION: The murine double minute 4 (MDM4) protein is a negative regulator of p53, and its upregulation has been observed in many tumor types. Previous literature suggested that genetic variations in the MDM4 gene are associated with risk of different cancers. The objective of the present study was to examine the effect of 3 common genetic variants of MDM4, rs4245739 A>C, rs11801299 G>A, and rs1380576 C>G, on the risk of breast cancer (BC) in a southeast Iranian population sample. PATIENTS AND METHODS: A total of 265 BC patients and 221 healthy women were included in this case-control study. We used polymerase chain reaction (PCR)-restriction fragment length polymorphism and tetra amplification refractory mutation system-PCR methods for detection of MDM4 polymorphisms. RESULTS: Our findings showed that rs1380576 C>G was associated with a reduced risk of BC using co-dominant (GC vs. CC: odds ratio [OR], 0.54; 95% confidence interval [CI], 0.34-0.84; P = .006; and GG vs. CC: OR, 0.49; 95% CI, 0.26-0.94; P = .044), dominant (CG+GG vs. CC: OR, 0.54; 95% CI, 0.35-0.82; P = .004), and allele models (G vs. C: OR, 0.74; 95% CI, 0.57-0.96; P = .025). However, our study failed to show any relationship between rs4245739 A>C and rs11801299 G>A variants and BC risk (P > .05). We also found no significant association between MDM4 variants and clinical characteristics of BC patients (P > .05). CONCLUSION: Our findings proposed that the MDM4 rs1380576 C>G polymorphism was a protective factor for BC risk in our population. Additional studies with larger sample sizes and diverse ethnicities are required to confirm our findings. PMID- 29439927 TI - Characterization of pharmacists' interventions in asthma management: A systematic review. AB - OBJECTIVE: Pharmacists have adopted an active role in asthma management. This review aimed to analyze the intervention dose, understood as the "amount of program delivered," and core components of the intervention provided by pharmacists in asthma management. DATA SOURCES: A literature search was conducted in December 2016 using PubMed. STUDY SELECTION: A 2-stage approach was used. At the first stage, systematic reviews of pharmacists' interventions in asthma management were identified. At the second stage, primary studies included in the systematic reviews were selected. DATA EXTRACTION: The DEPICT-2 (Descriptive Elements of Pharmacist Intervention Characterization Tool) was used for data extraction. In addition GINA (Global Initiative for Asthma) guidelines were used as a reference to classify the interventions' core components. RESULTS: Thirty one studies were included. In most of the studies, the pharmacist-patient intervention occurred at the community pharmacy setting (n = 22). The most common core components used in pharmacists' interventions were the provision of drug information and patient counseling (n = 27). Pharmacists' interventions frequently were targeted at assessing and improving the use of patient's inhaler technique (n = 27). Educational materials and written action plans were the materials most commonly used in the interventions (n = 20). The duration (n = 13) and the frequency (n = 16) of the intervention were the most frequent information about the intervention dose measure reported. CONCLUSION: Pharmacists' interventions in asthma management are complex. Structured educational programs and patient counseling appear to be the most frequent core components of pharmacists' interventions. Interventions were focused on providing information about the condition and on inhaler technique assessment and training. However, most studies failed to report the intervention dose sufficiently to be reproduced. The reporting of this indicator is crucial to ensure the reproducibility of the interventions assessed and their implementation in practice. (Registration number CRD42016029181.). PMID- 29439928 TI - Post-consumer plastic packaging waste in England: Assessing the yield of multiple collection-recycling schemes. AB - The European Commission (EC) recently introduced a 'Circular Economy Package', setting ambitious recycling targets and identifying waste plastics as a priority sector where major improvements are necessary. Here, the authors explain how different collection modalities affect the quantity and quality of recycling, using recent empirical data on household (HH) post-consumer plastic packaging waste (PCPP) collected for recycling in the devolved administration of England over the quarterly period July-September 2014. Three main collection schemes, as currently implemented in England, were taken into account: (i) kerbside collection (KS), (ii) household waste recycling centres (HWRCs) (also known as 'civic amenity sites'), and (iii) bring sites/banks (BSs). The results indicated that: (a) the contribution of KS collection scheme in recovering packaging plastics is higher than HWRCs and BBs, with respective percentages by weight (wt%) 90%, 9% and 1%; (b) alternate weekly collection (AWC) of plastic recyclables in wheeled bins, when collected commingled, demonstrated higher yield in KS collection; (c) only a small percentage (16%) of the total amount of post consumer plastics collected in the examined period (141 kt) was finally sent to reprocessors (22 kt); (c) nearly a third of Local Authorities (LAs) reported insufficient or poor data; and (d) the most abundant fractions of plastics that finally reached the reprocessors were mixed plastic bottles and mixed plastics. PMID- 29439929 TI - Pyrolysis and co-composting of municipal organic waste in Bangladesh: A quantitative estimate of recyclable nutrients, greenhouse gas emissions, and economic benefits. AB - Waste causes environmental pollution and greenhouse gas (GHG) emissions when it is not managed sustainably. In Bangladesh, municipal organic waste (MOW) is partially collected and landfilled. Thus, it causes deterioration of the environment urging a recycle-oriented waste management system. In this study, we propose a waste management system through pyrolysis of selective MOW for biochar production and composting of the remainder with biochar as an additive. We estimated the carbon (C), nitrogen (N), phosphorus (P) and potassium (K) recycling potentials in the new techniques of waste management. Waste generation of a city was calculated using population density and per capita waste generation rate (PWGR). Two indicators of economic development, i.e., gross domestic product (GDP) and per capita gross national income (GNI) were used to adopt PWGR with a projected contribution of 5-20% to waste generation. The projected PWGR was then validated with a survey. The waste generation from urban areas of Bangladesh in 2016 was estimated between 15,507 and 15,888 t day-1 with a large share (~75%) of organic waste. Adoption of the proposed system could produce 3936 t day-1 biochar blended compost with an annual return of US $210 million in 2016 while it could reduce GHG emission substantially (-503 CO2 e t-1 municipal waste). Moreover, the proposed system would able to recover ~46%, 54%, 54% and 61% of total C, N, P and K content in the initial waste, respectively. We also provide a projection of waste generation and nutrient recycling potentials for the year 2035. The proposed method could be a self-sustaining policy option for waste management as it would generate ~US$51 from each tonne of waste. Moreover, a significant amount of nutrients can be recycled to agriculture while contributing to the reduction in environmental pollution and GHG emission. PMID- 29439930 TI - Low Protein Intake in the Population: Low Risk of Kidney Function Decline but High Risk of Mortality. AB - OBJECTIVE: This population-based study investigated low protein intake, mortality, and kidney function decline. DESIGN: Observational longitudinal cohort study. SUBJECTS: Target cohort consisted of 4,679 adults participating in 1988 1992 and 2001-2007 examinations of the Gubbio Study (baseline and follow-up). Data collection included overnight urine urea nitrogen (UUN) and other variables at baseline, serum creatinine at baseline and follow-up, and mortality from baseline to follow-up. Three hundred seventy-two persons were excluded for missing data. UUN in the lowest 20% of the distribution was defined as low and used as index of low protein intake. Estimated glomerular filtration rate (eGFR, mL/minute * 1.73 m2) was used as kidney function index. INTERVENTION: None (observational study). MAIN OUTCOME MEASURE: Mortality and eGFR decline are the main outcome measures, and eGFR decline was defined as eGFR change from baseline to follow-up <= mean-1 standard deviation (Z-score <= -1). RESULTS: Eight hundred seventy-one deaths occurred over 15.9 +/- 4.0 years of observation (417 from cardiovascular disease and 276 from neoplastic disease). Low UUN associated with mortality (hazard ratio, HR = 1.31, 95% confidence interval, CI = 1.12/1.53) due to association with mortality from neoplastic disease (HR = 1.33, 95% CI = 1.02/1.76). Mortality-corrected follow-up response rate was 79.9% (n = 2845). Baseline to follow-up eGFR change was -9.9 +/- 10.1, and eGFR decline was found in 454 examinees. Low UUN associated with eGFR decline only in subgroup with baseline eGFR <90 (n = 1441, odds ratio = 0.44, 95% CI = 0.22/0.85). Low baseline eGFR interacted with the association between low UUN and eGFR decline (P = .024). CONCLUSION: Low protein intake predicted higher mortality in the whole population and lower incidence of eGFR decline only in subgroup with reduced kidney function. PMID- 29439931 TI - Does Low-Protein Diet Influence the Uremic Toxin Serum Levels From the Gut Microbiota in Nondialysis Chronic Kidney Disease Patients? AB - OBJECTIVES: To evaluate the effects of low-protein diet (LPD) on uremic toxins and the gut microbiota profile in nondialysis chronic kidney disease (CKD) patients. DESIGN AND METHODS: Longitudinal study with 30 nondialysis CKD patients (stage 3-4) undergoing LPD for 6 months. Adherence to the diet was evaluated based on the calculation of protein equivalent of nitrogen appearance from the 24 hour urine analysis. Good adherence to LPD was considered when protein intake was from 90% to 110% of the prescribed amount (0.6 g/kg/day). Food intake was analyzed by the 24-hour recall method. The anthropometric, biochemical and lipid profile parameters were measured according to standard methods. Uremic toxin serum levels (indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid) were obtained by reversed-phase high-performance liquid chromatography (RP-HPLC). Fecal samples were collected to evaluate the gut microbiota profile through polymerase chain reaction and denaturing gradient gel electrophoresis. Statistical analysis was performed by the SPSS 23.0 program software. RESULTS: Patients who adhered to the diet (n = 14) (0.7 +/- 0.2 g/kg/day) presented an improvement in renal function (nonsignificant) and reduction in total and low density lipoprotein cholesterol (183.9 +/- 48.5-155.7 +/- 37.2 mg/dL, P = .01; 99.4 +/- 41.3-76.4 +/- 33.2 mg/dL, P = .01, respectively). After 6 months of nutricional intervention, p-cresyl sulfate serum levels were reduced significantly in patients who adhered to the LPD (19.3 [9.6-24.7] to 15.5 [9.8 24.1] mg/L, P = .03), and in contrast, the levels were increased in patients who did not adhere (13.9 [8.0-24.8] to 24.3 [8.1-39.2] mg/L, P = .004). In addition, using the denaturing gradient gel electrophoresis technique, it was observed change in the intestinal microbiota profile after LPD intervention in both groups, and the number of bands was positively associated with protein intake (r = 0.44, P = .04). CONCLUSION: LPD seems be a good strategy to reduce the uremic toxins production by the gut microbiota in nondialysis CKD patients. PMID- 29439932 TI - In Vivo Imaging of Single Mammalian Cells in Development and Disease. AB - Live imaging has transformed biomedical sciences by enabling visualization and analysis of dynamic cellular processes as they occur in their native contexts. Here, we review key recent efforts applying in vivo optical imaging with single cell resolution to mammalian systems ranging from embryos to adult tissues and organs. We highlight insights into active processes regulating cell fate and morphogenesis during embryonic development, how neuronal circuitry and non neuronal cell types contribute to neurological functions, and how novel imaging based approaches enable the dissection of neurological disorders and cancer with high spatio-temporal resolution. The convergence of technical advancements in accessing, visualizing, and manipulating individual cells provides an unprecedented lens to probe mammalian cellular dynamics in vivo in both physiological and pathological states. PMID- 29439933 TI - A national survey on management of varicose veins in China. AB - OBJECTIVE: This study aimed to investigate the current clinical practice and management strategies for varicose veins among Chinese physicians in general and in specific case vignettes. METHODS: A questionnaire survey was conducted among 726 Chinese physicians who were attending the vascular surgery academic conferences during August 2016 to May 2017 in China. Physicians were eligible if they were familiar with several currently used treatment techniques for varicose veins. RESULTS: A total of 681 physicians from 527 hospitals in 29 provinces across China completed the questionnaire. Of them, 80.0% were vascular surgeons, 13.1% were general surgeons, and 6.9% were interventional radiologists. More than half (67.0%) of them had >5 years of experience in management of varicose veins. A third of the participants performed routine venography for patients with suspected varicose veins. Moreover, 87.5% believed that the patient's medical insurance would influence their choice of treatment modalities. Only 38.5% of the participants' departments could perform day surgery for varicose veins. The most common average hospitalization time was 4 to 7 days, with an average cost of 4000 to 8000 yuan per leg. In the basic case (Clinical, Etiology, Anatomy, and Pathophysiology classification C2,SEpAsPr2,3), 63.8% preferred traditional surgery for great saphenous vein reflux, followed by endovenous laser ablation (24.3%), radiofrequency ablation (5.6%), and ultrasound-guided foam sclerotherapy (3.1%). Physicians in coastal China were more likely to choose endovenous thermal ablation than those from western China (P < .05). In modified case vignettes complicated with hyperpigmentation and lipodermatosclerosis or ulceration, more participants chose traditional surgery for great saphenous vein (73.2% vs 63.8% [P < .001]; 75.9% vs 63.8% [P < .001]) compared with the basic case. Moreover, 31.9% preferred continuation of compression therapy for patients with varicose veins and deep venous reflux, and 65.4% preferred correction of iliac vein compression before treatment of varicose veins. Distributions of management strategies were significantly different between the basic and modified case vignettes (all P < .01). CONCLUSIONS: Both traditional surgery and minimally invasive techniques are used for patients with varicose veins in China, but traditional surgery is the mainstay of treatment for varying degrees of varicose veins. Related clinical factors, duplex ultrasound scan findings, medical insurance, and economy may have influenced the physicians' choice of treatment modality for varicose veins. PMID- 29439934 TI - Suppressed networks of inflammatory mediators characterize chronic venous insufficiency. AB - OBJECTIVE: Chronic venous insufficiency (CVI) affects 25 million adults in the United States. Little emphasis has been placed on inflammatory changes associated with CVI. We hypothesize that in patients with early to mid-stage benign varicose vein disease, differences in circulating inflammatory mediators will be manifested in blood draining the involved area vs circulating blood in control subjects. METHODS: Patients undergoing either endovenous ablation or sclerotherapy for Clinical, Etiology, Anatomy, and Pathophysiology clinical class 3 to 5 disease underwent phlebotomy from regional veins at the time of the procedure. The patient's age, gender, clinical class, duration of symptoms, presence of superficial truncal reflux by duplex ultrasound, and treatment modality were recorded. Plasma from patients and banked blood samples from healthy volunteers (HVs) were subjected to Luminex (EMD Millipore, Billerica, Mass) to evaluate the expression of an established panel of 20 inflammatory mediators. Mediator concentrations were compared between patients and HVs using Mann-Whitney U tests. Importantly, computational analysis allowed us to compare not only the panel of inflammatory mediators but also the inflammatory networks connecting these mediators to one another. Principal components were analyzed to assess network robustness in each group. RESULTS: CVI venous blood revealed significantly lower levels of monokine induced by gamma interferon, soluble interleukin (IL) 2 receptor alpha chain, IL-4, IL-6, IL-7, tumor necrosis factor alpha, eotaxin, and granulocyte-macrophage colony-stimulating factor than blood from controls. Inflammatory networks were significantly less complex and less robust in the CVI patients compared with HVs. Based on principal component analysis, responses among HVs were more varied than those of CVI patients. CONCLUSIONS: We demonstrate that patients with CVI have significant differences not only in blood-borne inflammatory mediators but also in the interconnectedness of these mediators with one another and in their principal inflammatory characteristics. Results suggest hypoinflammation in chronic nonhealing changes in CVI. These novel findings, if validated in larger cohorts, may help predict the risk of disease progression or response to therapy in the future and may guide mechanistic studies on tissue responses to CVI. PMID- 29439935 TI - Successful subcutaneous desensitization in a patient with allergy to ixekizumab. PMID- 29439936 TI - Use of pdC1-INH concentrate for long-term prophylaxis during pregnancy in hereditary angioedema with normal C1-INH. PMID- 29439937 TI - The revised Declaration of Geneva, 2017, and India's contradictory legal provisions. AB - The World Medical Association (WMA) provides ethical guidance to physicians through its Declarations, Resolutions and Statements. WMA first adopted its resolution on physician participation in capital punishment in 1981, which then amended in 2000 and 2008. The revised Declaration of Geneva was adopted by the World Medical Association General Assembly on October 14, 2017, in Chicago. WMA reaffirmed that it is unethical for physicians to participate in capital punishment, in any way, or during any step of the execution process, including its planning and the instruction and/or training of persons to perform executions. Indian Medical Association (IMA) is signatory to all these policies and resolutions since it is a founder member of WMA. Most other national and international associations of Medical and other health professionals also forbid participation of their members in capital punishment. PMID- 29439938 TI - Medical Council of India's amended qualifications for Indian medical teachers: Well intended, yet half-hearted. AB - The Medical Council of India (MCI) must be commended for its efforts to introduce definitive criteria for appointments and promotions for teachers in medical institutions. On June 8, 2017, the MCI issued a circular to amend the Minimum Qualifications for Teachers in Medical Institutions Regulations, 1998 (henceforth Regulations, 1998). The amendment clarifies the minimum qualifications required for various postgraduate teaching positions in medical colleges. It indicates MCI's sustained engagement with qualifications of teachers in medical colleges, with the aim of enhancing the quality of teaching and thereby the quality of medical professionals passing out. However, we believe that these efforts continue to be inadequate in addressing the varied issues that face medical education and the educators in India. PMID- 29439939 TI - Need for gender sensitive health system responses to violence against women and children. AB - Five years since Nirbhaya, and nearly as long since the Justice Verma Committee Report, amendments to the Criminal Law Amendment Act 2013, and the National guidelines and protocols on medico-legal care for survivors of sexual violence by the Ministry of Health and Family Welfare (MoHFW) 2014, we, concerned individuals, women's groups, health organisations, ethicists, and academicians, urgently demand the attention of the central and state governments - to the continuing injustice, violations and discrimination against survivors of gender based violence (GBV). PMID- 29439940 TI - Parenthood: Is the law in Nigeria fit for assisted reproductive technology? AB - This paper examines the legal aspects of parenthood and how it is, or could be, determined in Nigeria given the wide popularity and uptake of assisted reproductive technology (ART). It aims to establish whether the existing national laws can sufficiently protect the interests of the child who is born and of the consumers, with an emphasis on the determination of the status of the parents. It also identifies problems and proposes solutions with regard to the specific issue of establishing legal parenthood following the use of ART, either with or without state regulation. The paper concludes by recommending specific ART legislation that could help solve the problems, and advises Nigerian law-makers to pay attention to statutes from other jurisdictions as a guide. PMID- 29439941 TI - Role of Social Media in Diabetes Management in the Middle East Region: Systematic Review. AB - BACKGROUND: Diabetes is a major health care burden in the Middle East region. Social networking tools can contribute to the management of diabetes with improved educational and care outcomes using these popular tools in the region. OBJECTIVE: The objective of this review was to evaluate the impact of social networking interventions on the improvement of diabetes management and health outcomes in patients with diabetes in the Middle East. METHODS: Peer-reviewed articles from PubMed (1990-2017) and Google Scholar (1990-2017) were identified using various combinations of predefined terms and search criteria. The main inclusion criterion consisted of the use of social networking apps on mobile phones as the primary intervention. Outcomes were grouped according to study design, type of diabetes, category of technological intervention, location, and sample size. RESULTS: This review included 5 articles evaluating the use of social media tools in the management of diabetes in the Middle East. In most studies, the acceptance rate for the use of social networking to optimize the management of diabetes was relatively high. Diabetes-specific management tools such as the Saudi Arabia Networking for Aiding Diabetes and Diabetes Intelligent Management System for Iraq systems helped collect patient information and lower hemoglobin A1c (HbA1c) levels, respectively. CONCLUSIONS: The reviewed studies demonstrated the potential of social networking tools being adopted in regions in the Middle East to improve the management of diabetes. Future studies consisting of larger sample sizes spanning multiple regions would provide further insight into the use of social media for improving patient outcomes. PMID- 29439942 TI - Using Robots at Home to Support Patients With Chronic Obstructive Pulmonary Disease: Pilot Randomized Controlled Trial. AB - BACKGROUND: Socially assistive robots are being developed for patients to help manage chronic health conditions such as chronic obstructive pulmonary disease (COPD). Adherence to medication and availability of rehabilitation are suboptimal in this patient group, which increases the risk of hospitalization. OBJECTIVE: This pilot study aimed to investigate the effectiveness of a robot delivering telehealth care to increase adherence to medication and home rehabilitation, improve quality of life, and reduce hospital readmission compared with a standard care control group. METHODS: At discharge from hospital for a COPD admission, 60 patients were randomized to receive a robot at home for 4 months or to a control group. Number of hospitalization days for respiratory admissions over the 4-month study period was the primary outcome. Medication adherence, frequency of rehabilitation exercise, and quality of life were also assessed. Implementation interviews as well as benefit-cost analysis were conducted. RESULTS: Intention-to treat and per protocol analyses showed no significant differences in the number of respiratory-related hospitalizations between groups. The intervention group was more adherent to their long-acting inhalers (mean number of prescribed puffs taken per day=48.5%) than the control group (mean 29.5%, P=.03, d=0.68) assessed via electronic recording. Self-reported adherence was also higher in the intervention group after controlling for covariates (P=.04). The intervention group increased their rehabilitation exercise frequency compared with the control group (mean difference -4.53, 95% CI -7.16 to -1.92). There were no significant differences in quality of life. Of the 25 patients who had the robot, 19 had favorable attitudes. CONCLUSIONS: This pilot study suggests that a homecare robot can improve adherence to medication and increase exercise. Further research is needed with a larger sample size to further investigate effects on hospitalizations after improvements are made to the robots. The robots could be especially useful for patients struggling with adherence. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000259549; http://www.anzctr.org.au (Archived by WebCite at http://www.webcitation.org/6whIjptLS). PMID- 29439943 TI - Cognitive Style and Mobile E-Learning in Emergent Otorhinolaryngology-Head and Neck Surgery Disorders for Millennial Undergraduate Medical Students: Randomized Controlled Trial. AB - BACKGROUND: Electronic learning (e-learning) through mobile technology represents a novel way to teach emergent otorhinolaryngology-head and neck surgery (ORL-HNS) disorders to undergraduate medical students. Whether a cognitive style of education combined with learning modules can impact learning outcomes and satisfaction in millennial medical students is unknown. OBJECTIVE: The aim of this study was to assess the impact of cognitive styles and learning modules using mobile e-learning on knowledge gain, competence gain, and satisfaction for emergent ORL-HNS disorders. METHODS: This randomized controlled trial included 60 undergraduate medical students who were novices in ORL-HNS at an academic teaching hospital. The cognitive style of the participants was assessed using the group embedded figures test. The students were randomly assigned (1:1) to a novel interactive multimedia (IM) group and conventional Microsoft PowerPoint show (PPS) group matched by age, sex, and cognitive style. The content for the gamified IM module was derived from and corresponded to the textbook-based learning material of the PPS module (video lectures). The participants were unblinded and used fully automated courseware containing the IM or PPS module on a 7-inch tablet for 100 min. Knowledge and competence were assessed using multiple-choice questions and multimedia situation tests, respectively. Each participant also rated their global satisfaction. RESULTS: All of the participants (median age 23 years, range 22-26 years; 36 males and 24 females) received the intended intervention after randomization. Overall, the participants had significant gains in knowledge (median 50%, interquartile range [IQR]=17% 80%, P<.001) and competence (median 13%, IQR=0%-33%, P=.006). There were no significant differences in knowledge gain (40%, IQR=13%-76% vs 60%, IQR=20%-100%, P=.42) and competence gain (0%, IQR= -21% to 38% vs 25%, IQR=0%-33%, P=.16) between the IM and PPS groups. However, the IM group had a higher satisfaction score (8, IQR=6-9 vs 6, IQR=4-7, P=.01) compared with the PPS group. Using Friedman's two-way nonparametric analysis of variance, cognitive styles (field independent, field-intermediate, or field-dependent classification) and learning modules (IM or PPS) had significant effects on both knowledge gain (both adjusted P<.001) and satisfaction (both adjusted P<.001). CONCLUSIONS: Mobile e-learning is an effective modality to improve knowledge of emergent ORL-HNS in millennial undergraduate medical students. Our findings suggest the necessity of developing various modules for undergraduate medical students with different cognitive styles. TRIAL REGISTRATION: Clinicaltrials.gov NCT02971735; https://clinicaltrials.gov/ct2/show/NCT02971735 (Archived by WebCite at http://www.webcitation.org/6waoOpCEV). PMID- 29439944 TI - Digital Peer-Support Platform (7Cups) as an Adjunct Treatment for Women With Postpartum Depression: Feasibility, Acceptability, and Preliminary Efficacy Study. AB - BACKGROUND: Peer support is considered to be an important framework of support for mothers experiencing postpartum depression (PPD); however, some barriers exist that may limit its use including peer availability and mothers' lack of time due to child care. OBJECTIVE: This non-randomized study was designed to examine the feasibility, acceptance, and preliminary clinical outcomes of using 7 Cups of Tea (7Cups), a digital platform that delivers self-help tools and 24/7 emotional support delivered by trained volunteers, as an adjunct treatment for mothers diagnosed with PPD. METHODS: Mothers with PPD were referred during intake to the study coach who provided guidance about 7Cups. 7Cups features included self-help tools and chats with trained volunteers who had experienced a perinatal mood disorder in their past. Acceptability was measured by examining self-reports and user engagement with the program. The primary outcome was the Edinburgh Postnatal Depression Scale (EPDS) change score between pre- and postintervention at 2 months, as collected in usual care by clinicians blinded to the study questions. Using a propensity score matching to control for potential confounders, we compared women receiving 7Cups to women receiving treatment as usual (TAU). RESULTS: Participants (n=19) proactively logged into 7Cups for a median of 12 times and 175 minutes. Program use was mostly through the mobile app (median of mobile use 94%) and between 18:00 and 08:00 when clinicians are unavailable (68% of total program use time). Participants chatted with volunteers for a total of 3064 minutes and have indicated in their responses 0 instances in which they felt unsafe. Intent-to-treat analysis revealed that 7Cups recipients experienced significant decreases in EPDS scores (P<.001, Cohen d=1.17). No significant difference in EPDS decrease over time was found between 7Cups and TAU, yet the effect size was medium favoring 7Cups (P=.05, Cohen d=0.58). CONCLUSIONS: This study supports using a computerized method to train lay people, without any in-person guidance or screening, and engage them with patients diagnosed with mental illness as part of usual care. The medium effect size (d=0.58) favoring the 7Cups group relative to TAU suggests that 7Cups might enhance treatment outcomes. A fully powered trial has to be conducted to examine this effect. PMID- 29439945 TI - Work Addiction Test Questionnaire to Assess Workaholism: Validation of French Version. AB - BACKGROUND: Work addiction is a significant public health problem with a growing prevalence. The Work Addiction Risk Test (WART) is the gold standard questionnaire to detect workaholism. OBJECTIVE: The main objective of this study was to validate the French version of the WART. METHODS: Questionnaires were proposed to voluntary French workers using the WittyFit software. There were no exclusion criteria. The questionnaire was administered anonymously for initial validity testing and readministered one week later for test-retest reliability. We also assessed the workers' sociodemographic characteristics, as well as other measurements for external validity, such as stress, well-being, and coaddictions to tobacco, alcohol, and cannabis. Several psychometric properties of the French WART were explored: acceptability, reliability (internal consistency [Cronbach alpha coefficient] and reproducibility [Lin concordance coefficient]), construct validity (correlation coefficients and principal component analysis), and external validity (correlation coefficients). RESULTS: Among the 1580 workers using WittyFit, 187 (11.83%) agreed to complete the WART questionnaire. Of those, 128 completed the test-retest survey (68.4%). Acceptability found that all respondents had fully completed the questionnaire, with few floor or ceiling effects. Reliability was very good with a Cronbach alpha coefficient at .90 (internal consistency) and Lin concordance coefficient at .90 (95% CI .87-.94] with a difference on the retest of .04 (SD 4.9) (95% CI -9.6 to 9.7) (reproducibility). We identified three main dimensions (construct validity). Relationships between WART and stress and well-being confirmed its external validity. CONCLUSIONS: The French version of the WART is a valid and reliable instrument to assess work addiction with satisfactory psychometric properties. Used in occupational medicine, this tool would allow the diagnosis of work addiction and can be easily implemented in current practice. PMID- 29439946 TI - Mobile Phone Apps for Behavioral Interventions for At-Risk Drinkers in Australia: Literature Review. AB - BACKGROUND: The mobile technology era has ushered in the use of mobile phone apps for behavioral intervention for at-risk drinkers. OBJECTIVE: Our objective was to review recent research relevant to mobile phone apps that can be used for behavioral intervention for at-risk drinkers in Australia. METHODS: The inclusion criteria for this review were articles published in peer-reviewed journals from 2001 to 2017 with use of the search terms "smartphone application," "alcohol," "substance," "behavioural intervention," "electronic health," and "mobile health." RESULTS: In total, we identified 103 abstracts, screened 90 articles, and assessed 50 full-text articles that fit the inclusion criteria for eligibility. We included 19 articles in this review. CONCLUSIONS: This review highlighted the paucity of evidence-based and empirically validated research into effective mobile phone apps that can be used for behavioral interventions with at risk drinkers in Australia. PMID- 29439947 TI - Patient and Health System Experience With Implementation of an Enterprise-Wide Telehealth Scheduled Video Visit Program: Mixed-Methods Study. AB - BACKGROUND: Real-time video visits are increasingly used to provide care in a number of settings because they increase access and convenience of care, yet there are few reports of health system experiences. OBJECTIVE: The objective of this study is to report health system and patient experiences with implementation of a telehealth scheduled video visit program across a health system. METHODS: This is a mixed methods study including (1) a retrospective descriptive report of implementation of a telehealth scheduled visit program at one large urban academic-affiliated health system and (2) a survey of patients who participated in scheduled telehealth visits. Health system and patient-reported survey measures were aligned with the National Quality Forum telehealth measure reporting domains of access, experience, and effectiveness of care. RESULTS: This study describes implementation of a scheduled synchronous video visit program over an 18-month period. A total of 3018 scheduled video visits were completed across multiple clinical departments. Patient experiences were captured in surveys of 764 patients who participated in telehealth visits. Among survey respondents, 91.6% (728/795) reported satisfaction with the scheduled visits and 82.7% (628/759) reported perceived quality similar to an in-person visit. A total of 86.0% (652/758) responded that use of the scheduled video visit made it easier to get care. Nearly half (46.7%, 346/740) of patients estimated saving 1 to 3 hours and 40.8% (302/740) reported saving more than 3 hours of time. The net promoter score, a measure of patient satisfaction, was very high at 52. CONCLUSIONS: A large urban multihospital health system implemented an enterprise wide scheduled telehealth video visit program across a range of clinical specialties with a positive patient experience. Patients found use of scheduled video visits made it easier to get care and the majority perceived time saved, suggesting that use of telehealth for scheduled visits can improve potential access to care across a range of clinical scenarios with favorable patient experiences. PMID- 29439948 TI - Smartphone application for the general public (mobile app review). PMID- 29439949 TI - Lower limb biomechanics in femoroacetabular impingement syndrome: a systematic review and meta-analysis. AB - OBJECTIVE: (1) Identify differences in hip and pelvic biomechanics in patients with femoroacetabular impingement syndrome (FAIS) compared with controls during everyday activities (eg, walking, squatting); and (2) evaluate the effects of interventions on hip and pelvic biomechanics during everyday activities. DESIGN: Systematic review. DATA SOURCES: Medline, CINAHL, EMBASE, Scopus and SPORTDiscus until February 2017. METHODS: Primary aim: studies that investigated hip or pelvic kinematics and/or joint torques of everyday activities in patients with FAIS compared with the asymptomatic contralateral limb or a control group. Secondary aim: studies that evaluated effects of conservative or surgical interventions on patients with FAIS using pre-post or controlled clinical trial designs. Biomechanical data must have been collected using three-dimensional motion capture devices. Reporting quality was assessed using the Epidemiological Appraisal Instrument and data were pooled (standardised mean difference (SMD), 95% CI) where populations and primary outcomes were similar. RESULTS: Fourteen studies were included (11 cross-sectional and three pre/post intervention), varying between low and moderate reporting quality. Patients with FAIS walked with a lower: peak hip extension angle (SMD -0.40, 95% CI -0.71 to -0.09), peak internal rotation angle (-0.67, 95% CI -1.19 to -0.16) and external rotation joint torque (-0.71, 95% CI -1.07 to -0.35), and squatted to a lesser depth with no difference in hip flexion range. Pre/post intervention data were limited in number and quality, and to surgical cohorts. CONCLUSION: This review suggests that patients with FAIS may demonstrate hip biomechanical impairments during walking and squatting, with minimal literature available to comment on other tasks. CLINICAL RELEVANCE: The information presented in the review provides insight into the biomechanical differences associated with FAIS; however, the between-group differences were small to moderate. This information may aid in the development of management strategies for people with the condition. PROSPEROREGISTRATION NUMBER: CRD42016038677. PMID- 29439950 TI - Patients treated with oxaliplatin are at risk for thrombocytopenia caused by multiple drug-dependent antibodies. PMID- 29439953 TI - Challenges facing the benign hematology physician-scientist workforce: identifying issues of recruitment and retention. PMID- 29439952 TI - Paraoxonase-2 regulates coagulation activation through endothelial tissue factor. AB - Oxidative stress and inflammation of the vessel wall contribute to prothrombotic states. The antioxidative protein paraoxonase-2 (PON2) shows reduced expression in human atherosclerotic plaques and endothelial cells in particular. Supporting a direct role for PON2 in cardiovascular diseases, Pon2 deficiency in mice promotes atherogenesis through incompletely understood mechanisms. Here, we show that deregulated redox regulation in Pon2 deficiency causes vascular inflammation and abnormalities in blood coagulation. In unchallenged Pon2-/- mice, we find increased oxidative stress and endothelial dysfunction. Bone marrow transplantation experiments and studies with endothelial cells provide evidence that increased inflammation, indicated by circulating interleukin-6 levels, originates from Pon2 deficiency in the vasculature. Isolated endothelial cells from Pon2-/- mice display increased tissue factor (TF) activity in vitro. Coagulation times were shortened and platelet procoagulant activity increased in Pon2-/- mice relative to wild-type controls. Coagulation abnormalities of Pon2-/- mice were normalized by anti-TF treatment, demonstrating directly that TF increases coagulation. PON2 reexpression in endothelial cells by conditional reversal of the knockout Pon2 cassette, restoration in the vessel wall using bone marrow chimeras, or treatment with the antioxidant N-acetylcysteine normalized the procoagulant state. These experiments delineate a PON2 redox-dependent mechanism that regulates endothelial cell TF activity and prevents systemic coagulation activation and inflammation. PMID- 29439951 TI - Enhancer dysfunction in leukemia. AB - Hematopoietic cancers are often initiated by deregulation of the transcriptional machinery. Prominent among such regulators are the sequence-specific DNA-binding transcription factors (TFs), which bind to enhancer and promoter elements in the genome to control gene expression through the recruitment of cofactors. Remarkably, perturbing the function of even a single TF or cofactor can modulate the active enhancer landscape of a cell; conversely, knowledge of the enhancer configuration can be used to discover functionally important TFs in a given cellular process. Our expanding insight into enhancer function can be attributed to the emergence of genome-scale measurements of enhancer activity, which can be applied to virtually any cell type to expose regulatory mechanisms. Such approaches are beginning to reveal the abnormal enhancer configurations present in cancer cells, thereby providing a framework for understanding how transcriptional dysregulation can lead to malignancy. Here, we review the evidence for alterations in enhancer landscapes contributing to the pathogenesis of leukemia, a malignancy in which enhancer-binding proteins and enhancer DNA itself are altered via genetic mutation. We will also highlight examples of small molecules that reprogram the enhancer landscape of leukemia cells in association with therapeutic benefit. PMID- 29439954 TI - Fine-tuning of FOXO3A in cHL as a survival mechanism and a hallmark of abortive plasma cell differentiation. AB - We recently found that FOXO1 repression contributes to the oncogenic program of classical Hodgkin lymphoma (cHL). Interestingly, FOXO3A, another member of the FOXO family, was reported to be expressed in the malignant Hodgkin and Reed Sternberg cells of cHL at higher levels than in non-Hodgkin lymphoma subtypes. We thus aimed to investigate mechanisms responsible for the maintenance of FOXO3A as well as the potential role of FOXO3A in cHL. Here, we show that high FOXO3A levels in cHL reflect a B-cell-differentiation-specific pattern. In B cells, FOXO3A expression increases during the process of centroblast to plasma cell (PC) differentiation. FOXO3A levels in cHL were found higher than in germinal center B cells, but lower than in terminally differentiated PCs. This intermediate FOXO3A expression in cHL might manifest the "abortive PC differentiation" phenotype. This assumption was further corroborated by the finding that overexpression of FOXO3A in cHL cell lines induced activation of the master PC transcription factor PRDM1alpha. As factors attenuating FOXO3A expression in cHL, we identified MIR155 and constitutive activation of extracellular signal-regulated kinase. Finally, we demonstrate the importance of FOXO3A expression in cHL using an RNA interference approach. We conclude that tightly regulated expression of FOXO3A contributes to the oncogenic program and to the specific phenotype of cHL. PMID- 29439955 TI - Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. PMID- 29439956 TI - Species Identification and In Vitro Antifungal Susceptibility of Aspergillus terreus Species Complex Clinical Isolates from a French Multicenter Study. AB - Aspergillus section Terrei is a species complex currently comprised of 14 cryptic species whose prevalence in clinical samples as well as antifungal susceptibility are poorly known. The aims of this study were to investigate A. Terrei clinical isolates at the species level and to perform antifungal susceptibility analyses by reference and commercial methods. Eighty-two clinical A. Terrei isolates were collected from 8 French university hospitals. Molecular identification was performed by sequencing parts of beta-tubulin and calmodulin genes. MICs or minimum effective concentrations (MECs) were determined for 8 antifungal drugs using both EUCAST broth microdilution (BMD) methods and concentration gradient strips (CGS). Among the 79 A. Terrei isolates, A. terreus stricto sensu (n = 61), A. citrinoterreus (n = 13), A. hortai (n = 3), and A. alabamensis (n = 2) were identified. All strains had MICs of >=1 mg/liter for amphotericin B, except for two isolates (both A. hortai) that had MICs of 0.25 mg/liter. Four A. terreus isolates were resistant to at least one azole drug, including one with pan-azole resistance, yet no mutation in the CYP51A gene was found. All strains had low MECs for the three echinocandins. The essential agreements (EAs) between BMD and CGS were >90%, except for those of amphotericin B (79.7%) and itraconazole (73.4%). Isolates belonging to the A section Terrei identified in clinical samples show wider species diversity beyond the known A. terreus sensu stricto Azole resistance inside the section Terrei is uncommon and is not related to CYP51A mutations here. Finally, CGS is an interesting alternative for routine antifungal susceptibility testing. PMID- 29439957 TI - High Rate of Association of 16S rRNA Methylases and Carbapenemases in Enterobacteriaceae Recovered from Hospitalized Children in Angola. AB - Acquired 16S rRNA methylases (RMTases) conferring pan-drug resistance to aminoglycosides were searched among enterobacterial isolates recovered in Angola. A total of 36 hospitalized children were screened for rectal colonization using the Superaminoglycoside selective medium. Twenty-two pan-aminoglycoside-resistant enterobacterial isolates were recovered, all of which produced RMTases, i.e., RmtB, ArmA, and RmtC. Highly diverse genetic backgrounds were identified for Escherichia coli and Klebsiella pneumoniae isolates, most of which coproduced carbapenemases NDM-1 or NDM-5, respectively. PMID- 29439958 TI - Interaction between Toll-Like Receptor 9-CpG Oligodeoxynucleotides and Hepatitis B Virus Virions Leads to Entry Inhibition in Hepatocytes and Reduction of Alpha Interferon Production by Plasmacytoid Dendritic Cells. AB - We previously reported that Toll-like receptor 9 (TLR9)-CpG oligonucleotides could inhibit the establishment of hepatitis B virus (HBV) infections in hepatocytes. Our aim was to uncover the underlying mechanisms of this inhibition. HepaRG cells, RPMI-B lymphoblastoma cells, and primary plasmacytoid dendritic cells (pDCs) exposed to HBV and TLR9 ligands/agonists in various configurations were used. We observed an inhibition of HBV infection upon TLR9 stimulations only when agonist was applied during inoculation. This inhibition was independent of interleukin-6 (IL-6)/interferon-inducible protein 10 (IP-10) production as well as of TLR9 expression in hepatocytes. We further demonstrated an entry inhibition mechanism by showing a noncovalent binding of TLR9 agonist to HBV particles. Besides inhibiting HBV entry into hepatocytes, this biophysical interaction between HBV virions and TLR9 agonist was responsible for a reduction of alpha interferon (IFN-alpha) expression by pDCs. Interestingly, subviral particles composed of only HBsAg were able to genuinely inhibit the TLR9 pathway, without titrating TLR9 ligands. To conclude, our data suggest that synthetic TLR9-CpG oligonucleotides can strongly inhibit HBV entry by "coating" HBV virions and thereby preventing their interaction with cellular receptor. This titration effect of TLR9 agonist is also artifactually responsible for the inhibition of TLR9 engagement in pDCs, whereas a genuine inhibition of this innate pathway was confirmed with HBsAg subviral particles. PMID- 29439959 TI - In Vitro Activity of Lascufloxacin against Streptococcus pneumoniae with Mutations in the Quinolone Resistance-Determining Regions. AB - Lascufloxacin showed potent activity against Streptococcus pneumoniae with a GyrA or ParC mutation (first-step mutant). The frequency of selecting resistant strains tended to be lower for lascufloxacin than for levofloxacin and garenoxacin after drug exposure in first-step mutants but was similar in the comparison between lascufloxacin and moxifloxacin. The increase in MIC was smaller for lascufloxacin than for levofloxacin, garenoxacin, and moxifloxacin when clinical strains with only ParC mutations were exposed to the corresponding drug. PMID- 29439960 TI - Anidulafungin Pharmacokinetics in Ascites Fluid and Pleural Effusion of Critically Ill Patients. AB - Anidulafungin concentrations were quantified with high-pressure liquid chromatography (HPLC) and UV detection of the ascites fluid and pleural effusion of 10 adult critically ill patients. Samples were collected from ascites fluid and from pleural drains or during paracentesis and thoracentesis, respectively. Anidulafungin levels in ascites fluid (0.12 to 0.99 MUg/ml) and in pleural effusion (0.32 to 2.02 MUg/ml) were below the simultaneous levels in plasma (1.04 to 7.70 and 2.48 to 13.36 MUg/ml, respectively) and below the MIC values for several pathogenic Candida strains. PMID- 29439961 TI - In Vitro Activities of Omadacycline and Comparators against Anaerobic Bacteria. AB - Omadacycline (OMC), a broad-spectrum aminomethylcycline, has shown clinical efficacy in anaerobic acute bacterial skin and skin structure infections (ABSSSI) and in animal models of intra-abdominal anaerobic infections. Here, the in vitro activity of OMC against clinically relevant anaerobes was similar to that of tigecycline, with MIC90 values of 1 to 8 MUg/ml against Bacteroides spp., 0.5 MUg/ml against Clostridium difficile, Prevotella spp., and Porphyromonas asaccharolytica, 1 MUg/ml against Peptostreptococcus spp., and 16 MUg/ml against Clostridium perfringens. PMID- 29439962 TI - In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, against Clostridium difficile. AB - DS-2969b is a novel GyrB inhibitor that is currently under clinical development for the treatment of Clostridium difficile infection (CDI). In this study, the in vitro and in vivo activities of DS-2969b were evaluated. DS-2969b inhibited the supercoiling activity of C. difficile DNA gyrase. DS-2969b showed potent in vitro activity against C. difficile clinical isolates with a MIC90 of 0.06 MUg/ml, which was 2-, 32-, and 16-fold lower than the MIC90s of fidaxomicin, vancomycin, and metronidazole, respectively. DS-2969b did not select spontaneously resistant mutants of various C. difficile strains at 4* MIC, and the frequency of resistance development was less than 4.8 * 10-9 In a hamster CDI model, 5-day oral administration of DS-2969b conferred complete protection from recurrence and mortality at 0.3 mg/kg of body weight once a day, in contrast to a 50% survival rate with fidaxomicin at 3 mg/kg once a day and 0% with vancomycin at a 50 mg/kg/dose twice a day. Even a single oral administration of 1 mg/kg of DS-2969b in the CDI model exhibited 100% animal survival without recurrence. DS-2969b was also efficacious by 5-day subcutaneous administration in the CDI model. DS-2969b showed similar levels of fecal excretion after intravenous and oral administrations in rats. These data support further development of DS-2969b as a drug for oral and intravenous treatment of CDI. PMID- 29439963 TI - In Vitro Study of the Susceptibility of Clinical Isolates of Trichomonas vaginalis to Metronidazole and Secnidazole. AB - Nitroimidazoles (metronidazole [MTZ] and tinidazole [TNZ]) are the only drugs recommended for treatment of Trichomonas vaginalis infections. MTZ resistance occurs in 4% to 10% of cases of vaginal trichomoniasis (R. D. Kirkcaldy et al., Emerg Infect Dis 18:939-943, 2012; J. R. Schwebke and F. J. Barrientes, Antimicrob Agents Chemother 50:4209-4210, 2006) and TNZ resistance in 1% of cases (J. R. Schwebke and F. J. Barrientes, Antimicrob Agents Chemother 50:4209-4210, 2006). Emerging nitroimidazole-resistant trichomoniasis is concerning, because few alternatives to standard therapy exist. We assessed the prevalence of in vitro aerobic MTZ and secnidazole resistance among T. vaginalis isolates collected in 2015 to 2016 from 100 women in Birmingham, Alabama, with positive cultures. Archived specimens were treated with secnidazole or MTZ (0.2 to 400 MUg/ml) for 48 h, according to U.S. Centers for Disease Control and Prevention protocols. Ninety-six (96%) of the 100 clinical Trichomonas isolates tested demonstrated lower minimum lethal concentrations for secnidazole than for MTZ, suggesting that secnidazole has better in vitro activity than MTZ. PMID- 29439964 TI - Determinants of Extreme beta-Lactam Tolerance in the Burkholderia pseudomallei Complex. AB - Slow-growing bacteria are insensitive to killing by antibiotics, a trait known as antibiotic tolerance. In this study, we characterized the genetic basis of an unusually robust beta-lactam (meropenem) tolerance seen in Burkholderia species. We identified tolerance genes under three different slow-growth conditions by extensive transposon mutant sequencing (Tn-seq), followed by single mutant validation. There were three principal findings. First, mutations in a small number of genes reduced tolerance under multiple conditions. Most of the functions appeared to be specific to peptidoglycan synthesis and the response to its disruption by meropenem action rather than being associated with more general physiological processes. The top tolerance genes are involved in immunity toward a type VI toxin targeting peptidoglycan (BTH_I0069), peptidoglycan recycling (ldcA), periplasmic regulation by proteolysis (prc), and an envelope stress response (rpoE and degS). Second, most of the tolerance functions did not contribute to growth in the presence of meropenem (intrinsic resistance), indicating that the two traits are largely distinct. Third, orthologues of many of the top Burkholderia thailandensis tolerance genes were also important in Burkholderia pseudomallei Overall, these studies show that the determinants of meropenem tolerance differ considerably depending on cultivation conditions, but that there are a few shared functions with strong mutant phenotypes that are important in multiple Burkholderia species. PMID- 29439965 TI - Next-Generation Sequencing and Bioinformatics Protocol for Malaria Drug Resistance Marker Surveillance. AB - The recent advances in next-generation sequencing technologies provide a new and effective way of tracking malaria drug-resistant parasites. To take advantage of this technology, an end-to-end Illumina targeted amplicon deep sequencing (TADS) and bioinformatics pipeline for molecular surveillance of drug resistance in P. falciparum, called malaria resistance surveillance (MaRS), was developed. TADS relies on PCR enriching genomic regions, specifically target genes of interest, prior to deep sequencing. MaRS enables researchers to simultaneously collect data on allele frequencies of multiple full-length P. falciparum drug resistance genes (crt, mdr1, k13, dhfr, dhps, and the cytochrome b gene), as well as the mitochondrial genome. Information is captured at the individual patient level for both known and potential new single nucleotide polymorphisms associated with drug resistance. The MaRS pipeline was validated using 245 imported malaria cases that were reported to the Centers for Disease Control and Prevention (CDC). The chloroquine resistance crt CVIET genotype (mutations underlined) was observed in 42% of samples, the highly pyrimethamine-resistant dhpsIRN triple mutant in 92% of samples, and the sulfadoxine resistance dhps mutation SGEAA in 26% of samples. The mdr1 NFSND genotype was found in 40% of samples. With the exception of two cases imported from Cambodia, no artemisinin resistance k13 alleles were identified, and 99% of patients carried parasites susceptible to atovaquone proguanil. Our goal is to implement MaRS at the CDC for routine surveillance of imported malaria cases in the United States and to aid in the adoption of this system at participating state public health laboratories, as well as by global partners. PMID- 29439967 TI - Pharmacodynamics of Voriconazole for Invasive Pulmonary Scedosporiosis. AB - Scedosporium apiospermum is a medically important fungal pathogen that causes a wide range of infections in humans. There are relatively few antifungal agents that are active against Scedosporium spp. Little is known about the pharmacodynamics of voriconazole against Scedosporium Both static and dynamic in vitro models of invasive scedosporiosis were developed. Monoclonal antibodies that target a soluble cell wall antigen secreted by Scedosporium apiospermum were used to describe the pharmacodynamics of voriconazole. Mathematical pharmacokinetic-pharmacodynamic models were fitted to the data to estimate the drug exposure required to suppress the release of fungal antigen. The experimental results were bridged to humans using Monte Carlo simulation. All 3 strains of S. apiospermum tested invaded through the cellular bilayer of the in vitro models and liberated antigen. There was a concentration-dependent decline in the amount of antigen, with near maximal antifungal activity against all 3 strains being achieved with voriconazole at 10 mg/liter. Similarly, there was a drug exposure-dependent decline in the amount of circulating antigen in the dynamic model and complete suppression of antigen, with an area under the concentration-time curve (AUC) of approximately 80 mg . h/liter. A regression of the AUC/MIC versus the area under the antigen-time curve showed that a near maximal effect was obtained with an AUC/MIC of approximately 100. Monte Carlo simulation suggested that only isolates with an MIC of 0.5 mg/liter enabled pharmacodynamic targets to be achieved with a standard regimen of voriconazole. Isolates with higher MICs may need drug exposure targets higher than those currently recommended for other fungi. PMID- 29439966 TI - In Vitro and In Vivo Efficacy of a Novel and Long-Acting Fungicidal Azole, PC1244, on Aspergillus fumigatus Infection. AB - The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates (n = 96) with a MIC range of 0.016 to 0.25 MUg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 MUg/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14alpha-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 MUg/ml), especially Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 MUg/ml) which indicated that it was 8-fold more potent than voriconazole. In vivo, once-daily intranasal administration of PC1244 (3.2 to 80 MUg/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed in vivo effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans. PMID- 29439968 TI - Targeting the Nonmevalonate Pathway in Burkholderia cenocepacia Increases Susceptibility to Certain beta-Lactam Antibiotics. AB - The nonmevalonate pathway is the sole pathway for isoprenoid biosynthesis in Burkholderia cenocepacia and is possibly a novel target for the development of antibacterial chemotherapy. The goals of the present study were to evaluate the essentiality of dxr, the second gene of the nonmevalonate pathway, in B. cenocepacia and to determine whether interfering with the nonmevalonate pathway increases susceptibility toward antibiotics. To this end, a rhamnose-inducible conditional dxr knockdown mutant of B. cenocepacia strain K56-2 (B. cenocepacia K56-2dxr) was constructed, using a plasmid which enables the delivery of a rhamnose-inducible promoter in the chromosome. Expression of dxr is essential for bacterial growth; the growth defect observed in the dxr mutant could be complemented by expressing dxr in trans under the control of a constitutive promoter, but not by providing 2-C-methyl-d-erythritol-4-phosphate, the reaction product of DXR (1-deoxy-d-xylulose 5-phosphate reductoisomerase). B. cenocepacia K56-2dxr showed markedly increased susceptibility to the beta-lactam antibiotics aztreonam, ceftazidime, and cefotaxime, while susceptibility to other antibiotics was not (or was much less) affected; this increased susceptibility could also be complemented by in trans expression of dxr A similarly increased susceptibility was observed when antibiotics were combined with FR900098, a known DXR inhibitor. Our data confirm that the nonmevalonate pathway is essential in B. cenocepacia and suggest that combining potent DXR inhibitors with selected beta-lactam antibiotics is a useful strategy to combat B. cenocepacia infections. PMID- 29439969 TI - Comparative In Vitro Activity of Omadacycline against Dog and Cat Bite Wound Isolates. AB - Omadacycline was tested against 125 isolates recovered from infected cat and dog bites in humans. Its activity was similar to that of other compounds in the tetracycline class, and it was active against strains exhibiting tetracycline resistance. Against anaerobic isolates, resistance to tetracyclines was more prominent and omadacycline was the most active of the group. All isolates had omadacycline MICs of <1 MUg/ml, with the exception of Eikenella corrodens, which showed reduced susceptibility to the entire tetracycline group. PMID- 29439970 TI - In Vitro Assessment of Antifungal Drugs and Sulfamethoxazole-Trimethoprim against Clinical Isolates of Conidiobolus lamprauges. PMID- 29439971 TI - Sofosbuvir and Ribavirin Liver Pharmacokinetics in Patients Infected with Hepatitis C Virus. AB - Sofosbuvir and ribavirin exert their anti-hepatitis C virus (anti-HCV) activity following metabolic activation in the liver. However, intrahepatic concentrations of the pharmacologically active nucleotide metabolites in humans are poorly characterized due to the inaccessibility of tissue and technical challenges with measuring nucleotide levels. A clinical study assessing the efficacy of sofosbuvir and ribavirin administered prior to liver transplantation to prevent HCV recurrence provided a unique opportunity to quantify nucleotide concentrations in human liver. We analyzed nucleotides using high-performance liquid chromatography coupled to tandem mass spectrometry in liver tissue from 30 HCV-infected patients with hepatocellular carcinoma who were administered sofosbuvir (400 mg/day) and ribavirin (1,000 to 1,200 mg/day) for 3 to 52 weeks prior to liver transplantation. Median total hepatic metabolite concentrations (the sum of nucleoside and mono-, di-, and triphosphates) were 77.1 MUM for sofosbuvir and 361 MUM for ribavirin in patients on therapy at the time of transplantation. Ribavirin and sofosbuvir efficiently loaded the liver, with total hepatic metabolite concentrations exceeding maximal levels in plasma by approximately 30-fold. Ribavirin metabolite levels suggest that its monophosphate is in great excess of its inhibition constant for IMP dehydrogenase and that its triphosphate is approaching the binding constant for incorporation by the HCV NS5B RNA-dependent RNA polymerase. In accordance with the potent antiviral activity of sofosbuvir, these results demonstrate that the liver triphosphate levels achieved following sofosbuvir administration greatly exceed the inhibition constant for HCV NS5B. In conclusion, this study expands the quantitative understanding of the pharmacology of sofosbuvir and ribavirin by establishing efficient hepatic delivery in the clinic. (This study has been registered at ClinicalTrials.gov under identifier NCT01559844.). PMID- 29439972 TI - Probing the Mechanism of Inactivation of the FOX-4 Cephamycinase by Avibactam. AB - Ceftazidime-avibactam is a "second-generation" beta-lactam-beta-lactamase inhibitor combination that is effective against Enterobacteriaceae expressing class A extended-spectrum beta-lactamases, class A carbapenemases, and/or class C cephalosporinases. Knowledge of the interactions of avibactam, a diazabicyclooctane with different beta-lactamases, is required to anticipate future resistance threats. FOX family beta-lactamases possess unique hydrolytic properties with a broadened substrate profile to include cephamycins, partly as a result of an isoleucine at position 346, instead of the conserved asparagine found in most AmpCs. Interestingly, a single amino acid substitution at N346 in the Citrobacter AmpC is implicated in resistance to the aztreonam-avibactam combination. In order to understand how diverse active-site topologies affect avibactam inhibition, we tested a panel of clinical Enterobacteriaceae isolates producing blaFOX using ceftazidime-avibactam, determined the biochemical parameters for inhibition using the FOX-4 variant, and probed the atomic structure of avibactam with FOX-4. Avibactam restored susceptibility to ceftazidime for most isolates producing blaFOX; two isolates, one expressing blaFOX-4 and the other producing blaFOX-5, displayed an MIC of 16 MUg/ml for the combination. FOX-4 possessed a k2/K value of 1,800 +/- 100 M-1 . s-1 and an off rate (koff) of 0.0013 +/- 0.0003 s-1 Mass spectrometry showed that the FOX-4 avibactam complex did not undergo chemical modification for 24 h. Analysis of the crystal structure of FOX-4 with avibactam at a 1.5-A resolution revealed a unique characteristic of this AmpC beta-lactamase. Unlike in the Pseudomonas-derived cephalosporinase 1 (PDC-1)-avibactam crystal structure, interactions (e.g., hydrogen bonding) between avibactam and position I346 in FOX-4 are not evident. Furthermore, another residue is not observed to be close enough to compensate for the loss of these critical hydrogen-bonding interactions. This observation supports findings from the inhibition analysis of FOX-4; FOX-4 possessed the highest Kd (dissociation constant) value (1,600 nM) for avibactam compared to other AmpCs (7 to 660 nM). Medicinal chemists must consider the properties of extended-spectrum AmpCs, such as the FOX beta-lactamases, for the design of future diazabicyclooctanes. PMID- 29439973 TI - Phase 1 Study To Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Oral Doses of DS-2969b, a Novel GyrB Inhibitor, in Healthy Subjects. AB - DS-2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection (CDI). The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on the normal gastrointestinal microbiota of multiple daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled three sequential ascending-dose cohorts (60 mg, 200 mg, and 400 mg). In each cohort, subjects received an oral dose of DS 2969b or placebo (six subjects received DS-2969b, and two received placebo) each morning for 14 days. DS-2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS-2969b were mild and predominantly related to the gastrointestinal tract. DS-2969a (free form of DS-2969b) plasma concentrations increased with increasing doses; however, both the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) increased less than dose proportionally. In all cohorts, sufficient fecal levels of DS-2969a were achieved within 24 h following the administration of the first dose and maintained for at least 17 days. Following treatment with DS-2969b, clear reductions in the populations of Clostridium coccoides and Bifidobacterium groups were observed. However, populations of three other bacterial groups examined (Bacteroides fragilis, Clostridium leptum, and Prevotella) were not affected. Data from this study support and encourage the further development of DS-2969b as a novel treatment for CDI. PMID- 29439974 TI - A Proof-of-Concept Study of the Efficacy of Systemically Administered Polymyxins in Mouse Burn Wound Infection Caused by Multidrug-Resistant Gram-Negative Pathogens. AB - The efficacy of subcutaneously administered polymyxins against burn wound infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae was examined in a murine infection model. Subcutaneously administered colistin and polymyxin B (30 mg/kg thrice daily) achieved a >=2 log10 reduction in the bacterial load for P. aeruginosa and A. baumannii infections, whereas wound infections by K. pneumoniae were less responsive (<1 log10 reduction). This study highlights the potential therapeutic benefits of parenteral polymyxins for treating burn wound infections. PMID- 29439975 TI - pSTM6-275, a Conjugative IncHI2 Plasmid of Salmonella enterica That Confers Antibiotic and Heavy-Metal Resistance under Changing Physiological Conditions. AB - Detailed annotation of an IncHI2 plasmid, pSTM6-275, from Salmonella enterica serotype 1,4,5,12:i:- strain TW-Stm6 revealed a composite structure, including antimicrobial resistance genes on mobile genetic elements. The plasmid was thermosensitive for transfer to Escherichia coli and conferred reduced susceptibility to antibiotics, copper sulfate, and silver nitrate. Metal ion susceptibility was dependent on physiological conditions, giving an insight into the environments where this trait might confer a fitness advantage. PMID- 29439976 TI - Coexistence of Two blaNDM-5 Genes on an IncF Plasmid as Revealed by Nanopore Sequencing. AB - In a carbapenem-resistant Escherichia coli clinical isolate of sequence type 167, two copies of blaNDM-5 were found on a 144,225-bp IncF self-transmissible plasmid of the F36:A4:B- type. Both blaNDM-5 genes were located in 11,065-bp regions flanked by two copies of IS26 The two regions were identical in sequence but were present at different locations on the plasmid, suggesting a duplication of the same region. This study highlights the complex genetic contexts of blaNDM-5. PMID- 29439977 TI - Inactivation of Plasmepsins 2 and 3 Sensitizes Plasmodium falciparum to the Antimalarial Drug Piperaquine. AB - Dihydroartemisinin-piperaquine (DHA-PPQ), the current frontline artemisinin combination therapy used to treat Plasmodium falciparum malaria in multiple Southeast Asian countries, is now increasingly failing in Cambodia, where artemisinin resistance is nearly fixed, which suggests that PPQ resistance has emerged and is spreading rapidly in the Greater Mekong Subregion. Recent reports have shown that amplification of the genes encoding plasmepsins 2 and 3 is a molecular marker of PPQ resistance; however, whether these enzymes play a role in the mechanism of resistance is currently unknown. We show here that inactivating the genes encoding plasmepsin 2 or 3 individually in P. falciparum reference strain 3D7 results in hypersusceptibility to PPQ. Interestingly, no significant differences in the susceptibility to other antimalarials were observed, which suggests specific roles of plasmepsins 2 and 3 in PPQ susceptibility. The piperaquine hyper-sensitivity of the plasmepsin-2-and-3-inactivated lines provides direct evidence that these enzymes modulate parasite susceptibility to PPQ in the context of a single copy of PfMDR1 and independent of Kelch13 mutations conferring artemisinin resistance. PMID- 29439978 TI - Pharmacokinetics of 2,000 Milligram Ertapenem in Tuberculosis Patients. AB - Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC0-infinity) was 2,032 (1,751 to 2,346) mg . h/liter, the intercompartmental clearance (CL12) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment (V1) was 1.514 (1.064 to 2.210) liters. A more than dose-proportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time (f40% T>MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f40% T>MIC for most of the patients, and exploration in a phase 2 study can be advocated. PMID- 29439979 TI - Prediction Model for Antimalarial Activities of Hemozoin Inhibitors by Using Physicochemical Properties. AB - The rapid spread of strains of malaria parasites that are resistant to several drugs has threatened global malaria control. Hence, the aim of this study was to predict the antimalarial activity of chemical compounds that possess anti hemozoin-formation activity as a new means of antimalarial drug discovery. After the initial in vitro anti-hemozoin-formation high-throughput screening (HTS) of 9,600 compounds, a total of 224 hit compounds were identified as hemozoin inhibitors. These 224 compounds were tested for in vitro erythrocytic antimalarial activity at 10 MUM by using chloroquine-mefloquine-sensitive Plasmodium falciparum strain 3D7A. Two independent experiments were conducted. The physicochemical properties of the active compounds were extracted from the ChemSpider and SciFinder databases. We analyzed the extracted data by using Bayesian model averaging (BMA). Our findings revealed that lower numbers of S atoms; lower distribution coefficient (log D) values at pH 3, 4, and 5; and higher predicted distribution coefficient (ACD log D) values at pH 7.4 had significant associations with antimalarial activity among compounds that possess anti-hemozoin-formation activity. The BMA model revealed an accuracy of 91.23%. We report new prediction models containing physicochemical properties that shed light on effective chemical groups for synthetic antimalarial compounds and help with in silico screening for novel antimalarial drugs. PMID- 29439981 TI - The case for child health. PMID- 29439980 TI - Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy. AB - An increase in the incidence of rare but hard-to-treat invasive fungal pathogens as well as resistance to the currently available antifungal drugs calls for new broad-spectrum antifungals with a novel mechanism of action. Here we report the identification and characterization of two novel zinc-attenuating compounds, ZAC307 and ZAC989, which exhibit broad-spectrum in vitro antifungal activity and in vivo efficacy in a fungal kidney burden candidiasis model. The compounds were identified serendipitously as part of a drug discovery process aimed at finding novel inhibitors of the fungal plasma membrane proton ATPase Pma1. Based on their structure, we hypothesized that they might act as zinc chelators. Indeed, both fluorescence-based affinity determination and potentiometric assays revealed these compounds, subsequently termed zinc-attenuating compounds (ZACs), to have strong affinity for zinc, and their growth inhibitory effects on Candida albicans and Aspergillus fumigatus could be inactivated by the addition of exogenous zinc to fungal growth media. We determined the ZACs to be fungistatic, with a low propensity for resistance development. Gene expression analysis suggested that the ZACs interfere negatively with the expression of genes encoding the major components of the A. fumigatus zinc uptake system, thus supporting perturbance of zinc homeostasis as the likely mode of action. With demonstrated in vitro and in vivo antifungal activity, low propensity for resistance development, and a novel mode of action, the ZACs represent a promising new class of antifungal compounds, and their advancement in a drug development program is therefore warranted. PMID- 29439982 TI - PccD Regulates Branched-Chain Amino Acid Degradation and Exerts a Negative Effect on Erythromycin Production in Saccharopolyspora erythraea. AB - Branched-chain amino acid (BCAA) degradation is a major source of propionyl coenzyme A (propionyl-CoA), a key precursor of erythromycin biosynthesis in Saccharopolyspora erythraea In this study, we found that the bkd operon, responsible for BCAA degradation, was regulated directly by PccD, a transcriptional regulator of propionyl-CoA carboxylase genes. The transcriptional level of the bkd operon was upregulated 5-fold in a pccD gene deletion strain (DeltapccD strain) and decreased 3-fold in a pccD overexpression strain (WT/pIB pccD), demonstrating that PccD was a negative transcriptional regulator of the operon. The deletion of pccD significantly improved the DeltapccD strain's growth rate, whereas pccD overexpression repressed WT/pIB-pccD growth rate, in basic Evans medium with 30 mM valine as the sole carbon and nitrogen source. The deletion of gdhA1 and the BcdhE1 gene (genes in the bkd operon) resulted in lower growth rates of DeltagdhA1 and DeltaBcdhE1 strains, respectively, on 30 mM valine, further suggesting that the bkd operon is involved in BCAA degradation. Both bkd overexpression (WT/pIB-bkd) and pccD inactivation (DeltapccD strain) improve erythromycin production (38% and 64%, respectively), whereas the erythromycin production of strain WT/pIB-pccD was decreased by 48%. Lastly, we explored the applications of engineering pccD and bkd in an industrial high erythromycin-producing strain. pccD deletion in industrial strain S. erythraea E3 (E3pccD) improved erythromycin production by 20%, and the overexpression of bkd in E3DeltapccD (E3DeltapccD/pIB-bkd) increased erythromycin production by 39% compared with S. erythraea E3 in an industrial fermentation medium. Addition of 30 mM valine to industrial fermentation medium further improved the erythromycin production by 23%, a 72% increase from the initial strain S. erythraea E3.IMPORTANCE We describe a bkd operon involved in BCAA degradation in S. erythraea The genes of the operon are repressed by a TetR regulator, PccD. The results demonstrated that PccD controlled the supply of precursors for biosynthesis of erythromycin via regulating the BCAA degradation and propionyl CoA assimilation and exerted a negative effect on erythromycin production. The findings reveal a regulatory mechanism in feeder pathways and provide new strategies for designing metabolic engineering to increase erythromycin yield. PMID- 29439983 TI - Polyporales Brown Rot Species Fomitopsis pinicola: Enzyme Activity Profiles, Oxalic Acid Production, and Fe3+-Reducing Metabolite Secretion. AB - Basidiomycota fungi in the order Polyporales are specified to decomposition of dead wood and woody debris and thereby are crucial players in the degradation of organic matter and cycling of carbon in the forest ecosystems. Polyporales wood decaying species comprise both white rot and brown rot fungi, based on their mode of wood decay. While the white rot fungi are able to attack and decompose all the lignocellulose biopolymers, the brown rot species mainly cause the destruction of wood polysaccharides, with minor modification of the lignin units. The biochemical mechanism of brown rot decay of wood is still unclear and has been proposed to include a combination of nonenzymatic oxidation reactions and carbohydrate-active enzymes. Therefore, a linking approach is needed to dissect the fungal brown rot processes. We studied the brown rot Polyporales species Fomitopsis pinicola by following mycelial growth and enzyme activity patterns and generating metabolites together with Fenton-promoting Fe3+-reducing activity for 3 months in submerged cultures supplemented with spruce wood. Enzyme activities to degrade hemicellulose, cellulose, proteins, and chitin were produced by three Finnish isolates of F. pinicola Substantial secretion of oxalic acid and a decrease in pH were notable. Aromatic compounds and metabolites were observed to accumulate in the fungal cultures, with some metabolites having Fe3+-reducing activity. Thus, F. pinicola demonstrates a pattern of strong mycelial growth leading to the active production of carbohydrate- and protein-active enzymes, together with the promotion of Fenton biochemistry. Our findings point to fungal species-level "fine-tuning" and variations in the biochemical reactions leading to the brown rot type of wood decay.IMPORTANCEFomitopsis pinicola is a common fungal species in boreal and temperate forests in the Northern Hemisphere encountered as a wood-colonizing saprotroph and tree pathogen, causing a severe brown rot type of wood degradation. However, its lignocellulose-decomposing mechanisms have remained undiscovered. Our approach was to explore both the enzymatic activities and nonenzymatic Fenton reaction-promoting activities (Fe3+ reduction and metabolite production) by cultivating three isolates of F. pinicola in wood-supplemented cultures. Our findings on the simultaneous production of versatile enzyme activities, including those of endoglucanase, xylanase, beta glucosidase, chitinase, and acid peptidase, together with generation of low pH, accumulation of oxalic acid, and Fe3+-reducing metabolites, increase the variations of fungal brown rot decay mechanisms. Furthermore, these findings will aid us in revealing the wood decay proteomic, transcriptomic, and metabolic activities of this ecologically important forest fungal species. PMID- 29439985 TI - Variable membrane protein A of flavescence doree phytoplasma binds the midgut perimicrovillar membrane of Euscelidius variegatus and promotes adhesion to its epithelial cells. AB - Phytoplasmas are uncultivated plant pathogens and cell wall-less bacteria and are transmitted from plant to plant by hemipteran insects. Phytoplasmas' circulative propagative cycle in insects requires the crossing of the midgut and salivary glands, and primary adhesion to cells is an initial step towards the invasion process. The flavescence doree phytoplasma possesses a set of variable membrane proteins (Vmps) exposed to its surface, and this pathogen is suspected to interact with insect cells. The results showed that VmpA is expressed by the flavescence doree phytoplasma present in the midgut and salivary glands. Phytoplasmas cannot be cultivated at present, and no mutant can be produced to investigate the putative role of Vmps in the adhesion of phytoplasma to insect cells. To overcome this difficulty, we engineered the Spiroplasma citri mutant G/6, which lacks the adhesins ScARPs, for VmpA expression and used VmpA-coated fluorescent beads to determine if VmpA acts as an adhesin in ex vivo adhesion assays and in vivo ingestion assays. VmpA specifically interacted with Euscelidius variegatus insect cells in culture and promoted the retention of VmpA coated beads to the midgut of E. variegatus In this latest case, VmpA-coated fluorescent beads were localized and embedded in the perimicrovillar membrane of the insect midgut. Thus, VmpA functions as an adhesin that could be essential in the colonization of the insect by the FD phytoplasmas.Importance Phytoplasmas infect a wide variety of plants, ranging from wild plants to cultivated species, and are transmitted by different leafhoppers, planthoppers and psyllids. The specificity of the phytoplasma-insect vector interaction has a major impact on the phytoplasma plant host range. As entry into insect cells is an obligate process for phytoplasma transmission, the bacterial adhesion to insect cells is a key step. Thus, studying surface-exposed proteins of phytoplasma will help to identify the adhesins implicated in the specific recognition of insect vectors. In this study, it is shown that the membrane protein VmpA of the flavescence doree phytoplasma acts as an adhesin that is able to interact with cells of Euscelidius variegatus, the experimental vector of the FD phytoplasma. PMID- 29439984 TI - Comparative Genomics Shows That Mycobacterium ulcerans Migration and Expansion Preceded the Rise of Buruli Ulcer in Southeastern Australia. AB - Since 2000, cases of the neglected tropical disease Buruli ulcer, caused by infection with Mycobacterium ulcerans, have increased 100-fold around Melbourne (population 4.4 million), the capital of Victoria, in temperate southeastern Australia. The reasons for this increase are unclear. Here, we used whole-genome sequence comparisons of 178 M. ulcerans isolates obtained primarily from human clinical specimens, spanning 70 years, to model the population dynamics of this pathogen from this region. Using phylogeographic and advanced Bayesian phylogenetic approaches, we found that there has been a migration of the pathogen from the east end of the state, beginning in the 1980s, 300 km west to the major human population center around Melbourne. This move was then followed by a significant increase in M. ulcerans population size. These analyses inform our thinking around Buruli ulcer transmission and control, indicating that M. ulcerans is introduced to a new environment and then expands, rather than it being from the awakening of a quiescent pathogen reservoir.IMPORTANCE Buruli ulcer is a destructive skin and soft tissue infection caused by Mycobacterium ulcerans and is characterized by progressive skin ulceration, which can lead to permanent disfigurement and long-term disability. Despite the majority of disease burden occurring in regions of West and central Africa, Buruli ulcer is also becoming increasingly common in southeastern Australia. Major impediments to controlling disease spread are incomplete understandings of the environmental reservoirs and modes of transmission of M. ulcerans The significance of our research is that we used genomics to assess the population structure of this pathogen at the Australian continental scale. We have then reconstructed a historical bacterial spread and modeled demographic dynamics to reveal bacterial population expansion across southeastern Australia. These findings provide explanations for the observed epidemiological trends with Buruli ulcer and suggest possible management to control disease spread. PMID- 29439987 TI - Exponentially Increased Thermal Resistance of Salmonella spp. and Enterococcus faecium at Reduced Water Activity. AB - Salmonella spp. exhibit prolonged survivability and high tolerance to heat in low moisture foods. The reported thermal resistance parameters of Salmonella spp. in low-moisture foods appear to be unpredictable due to various unknown factors. We report here that temperature-dependent water activity (aw, treatment temperature) plays an important role in the sharply increased thermal resistance of Salmonella enterica serovar Enteritidis PT 30 and its potential surrogate Enterococcus faecium NRRL B-2354. In our study, silicon dioxide granules, as carriers, were separately inoculated with these two microorganisms and were heated at 80 degrees C with controlled relative humidity between 18 and 72% (resulting in corresponding aw,80 degrees C values for bacteria between 0.18 and 0.72) in custom-designed test cells. The inactivation kinetics of both microorganisms fitted a log-linear model (R2, 0.83 to 0.97). Reductions in the aw,80 degrees C values of bacterial cells exponentially increased the D80 degrees C (the time needed to achieve a 1-log reduction in a bacterial population at 80 degrees C) values for S Enteritidis and E. faecium on silicon dioxide. The log-linear relationship between the D80 degrees C values for each strain in silicon dioxide and its aw,80 degrees C values was also verified for organic wheat flour. E. faecium showed consistently higher D80 degrees C values than S Enteritidis over the aw,80 degrees C range tested. The estimated zaw (the change in aw,80 degrees C needed to change D80 degrees C by 1 log) values of S Enteritidis and E. faecium were 0.31 and 0.28, respectively. This study provides insight into the interpretation of Salmonella thermal resistance that could guide the development and validation of thermal processing of low-moisture foods.IMPORTANCE In this paper, we established that the thermal resistance of the pathogen S Enteritidis and its surrogate Enterococcus faecium, as reflected by D values at 80 degrees C, increases sharply with decreasing relative humidity in the environment. The log linear relationship between the D80 degrees C values of each strain in silicon dioxide and its aw,80 degrees C values was also verified for organic wheat flour. The results provide new quantitative insight into the way in which the thermal resistance of microorganisms changes in low-moisture systems, and they should aid in the development of effective thermal treatment strategies for pathogen control in low-moisture foods. PMID- 29439986 TI - Stress Response Protein BolA Influences Fitness and Promotes Salmonella enterica Serovar Typhimurium Virulence. AB - The intracellular pathogen Salmonella enterica serovar Typhimurium has emerged as a major cause of foodborne illness, representing a severe clinical and economic concern worldwide. The capacity of this pathogen to efficiently infect and survive inside the host depends on its ability to synchronize a complex network of virulence mechanisms. Therefore, the identification of new virulence determinants has become of paramount importance in the search of new targets for drug development. BolA-like proteins are widely conserved in all kingdoms of life. In Escherichia coli, this transcription factor has a critical regulatory role in several mechanisms that are tightly related to bacterial virulence. Therefore, in the present work we used the well-established infection model Galleria mellonella to evaluate the role of BolA protein in S Typhimurium virulence. We have shown that BolA is an important player in S Typhimurium pathogenesis. Specifically, the absence of BolA leads to a defective virulence capacity that is most likely related to the remarkable effect of this protein on S Typhimurium evasion of the cellular response. Furthermore, it was demonstrated that BolA has a critical role in bacterial survival under harsh conditions since BolA conferred protection against acidic and oxidative stress. Hence, we provide evidence that BolA is a determining factor in the ability of Salmonella to survive and overcome host defense mechanisms, and this is an important step in progress to an understanding of the pathways underlying bacterial virulence.IMPORTANCE BolA has been described as an important protein for survival in the late stages of bacterial growth and under harsh environmental conditions. High levels of BolA in stationary phase and under stresses have been connected with a plethora of phenotypes, strongly suggesting its important role as a master regulator. Here, we show that BolA is a determining factor in the ability of Salmonella to survive and overcome host defense mechanisms, and this is an important step in progress to an understanding of the pathways underlying bacterial virulence. This work constitutes a relevant step toward an understanding of the role of BolA protein and may have an important impact on future studies in other organisms. Therefore, this study is of utmost importance for understanding the genetic and molecular bases involved in the regulation of Salmonella virulence and may contribute to future industrial and public health care applications. PMID- 29439988 TI - Display of Recombinant Proteins on Bacterial Outer Membrane Vesicles by Using Protein Ligation. AB - The Escherichia coli virulence factor hemoglobin protease (Hbp) has been engineered into a surface display system that can be expressed to high density on live E. coli and Salmonella enterica serovar Typhimurium cells or derived outer membrane vesicles (OMVs). Multiple antigenic sequences can be genetically fused into the Hbp core structure for optimal exposure to the immune system. Although the Hbp display platform is relatively tolerant, increasing the number, size, and complexity of integrated sequences generally lowers the expression of the fused constructs and limits the density of display. This is due to the intricate mechanism of Hbp secretion across the outer membrane and the efficient quality control of translocation-incompetent chimeric Hbp molecules in the periplasm. To address this shortcoming, we explored the coupling of purified proteins to the Hbp carrier after its translocation across the outer membrane using the recently developed SpyTag/SpyCatcher protein ligation system. As expected, fusion of the small SpyTag to Hbp did not hamper display on OMVs. Subsequent addition of purified proteins fused to the SpyCatcher domain resulted in efficient covalent coupling to Hbp-SpyTag. Using in addition the orthogonal SnoopTag/SnoopCatcher system, multiple antigen modules could be coupled to Hbp in a sequential ligation strategy. Not only antigens proved suitable for Spy-mediated ligation but also nanobodies. Addition of this functionality to the platform might allow the targeting of live bacterial or OMV vaccines to certain tissues or immune cells to tailor immune responses.IMPORTANCE Outer membrane vesicles (OMVs) derived from Gram-negative bacteria attract increasing interest in the development of vaccines and therapeutic agents. We aim to construct a semisynthetic OMV platform for recombinant antigen presentation on OMVs derived from attenuated Salmonella enterica serovar Typhimurium cells displaying an adapted Escherichia coli autotransporter, Hbp, at the surface. Although this autotransporter accepts substantial modifications, its capacity with respect to the number, size, and structural complexity of the antigens genetically fused to the Hbp carrier is restricted. Here we describe the application of SpyCatcher/SpyTag protein ligation technology to enzymatically link antigens to Hbp present at high density in OMVs. Protein ligation was apparently unobstructed by the membrane environment and allowed a high surface density of coupled antigens, a property we have shown to be important for vaccine efficacy. The OMV coupling procedure appears versatile and robust, allowing fast production of experimental vaccines and therapeutic agents through a modular plug-and-display procedure. PMID- 29439989 TI - Phylogenetic Evidence for the Existence of Multiple Strains of Rickettsia parkeri in the New World. AB - The bacterium Rickettsia parkeri has been reported to infect ticks of the "Amblyomma maculatum species complex" in the New World, where it causes spotted fever illness in humans. In South America, three additional rickettsial strains, namely, Atlantic rainforest, NOD, and Parvitarsum, have been isolated from the ticks Amblyomma ovale, Amblyomma nodosum, and Amblyomma parvitarsum, respectively. These three strains are phylogenetically closely related to R. parkeri, Rickettsia africae, and Rickettsia sibirica Herein, we performed a robust phylogenetic analysis encompassing 5 genes (gltA, ompA, virB4, dnaA, and dnaK) and 3 intergenic spacers (mppE-pur, rrl-rrf-ITS, and rpmE-tRNAfMet) from 41 rickettsial isolates, including different isolates of R. parkeri, R. africae, R. sibirica, Rickettsia conorii, and strains Atlantic rainforest, NOD, and Parvitarsum. In our phylogenetic analyses, all New World isolates grouped in a major clade distinct from the Old World Rickettsia species (R. conorii, R. sibirica, and R. africae). This New World clade was subdivided into the following 4 clades: the R. parkerisensu stricto clade, comprising the type strain Maculatum 20 and all other isolates of R. parkeri from North and South America, associated with ticks of the A. maculatum species complex; the strain NOD clade, comprising two South American isolates from A. nodosum ticks; the Parvitarsum clade, comprising two South American isolates from A. parvitarsum ticks; and the strain Atlantic rainforest clade, comprising six South American isolates from the A. ovale species complex (A. ovale or Amblyomma aureolatum). Under such evidences, we propose that strains Atlantic rainforest, NOD, and Parvitarsum are South American strains of R. parkeriIMPORTANCE Since the description of Rickettsia parkeri infecting ticks of the "Amblyomma maculatum species complex" and humans in the New World, three novel phylogenetic close-related rickettsial isolates were reported in South America. Herein, we provide genetic evidence that these novel isolates, namely, strains Atlantic rainforest, NOD, and Parvitarsum, are South American strains of R. parkeri. Interestingly, each of these R. parkeri strains seems to be primarily associated with a tick species group, namely, R. parkerisensu stricto with the "Amblyomma maculatum species group," R. parkeri strain NOD with Amblyomma nodosum, R. parkeri strain Parvitarsum with Amblyomma parvitarsum, and R. parkeri strain Atlantic rainforest with the "Amblyomma ovale species group." Such rickettsial strain-tick species specificity suggests a coevolution of each tick-strain association. Finally, because R. parkerisensu stricto and R. parkeri strain Atlantic rainforest are human pathogens, the potential of R. parkeri strains NOD and Parvitarsum to be human pathogens cannot be discarded. PMID- 29439990 TI - Microbial rRNA Synthesis and Growth Compared through Quantitative Stable Isotope Probing with H218O. AB - Growing bacteria have a high concentration of ribosomes to ensure sufficient protein synthesis, which is necessary for genome replication and cellular division. To elucidate whether metabolic activity of soil microorganisms is coupled with growth, we investigated the relationship between rRNA and DNA synthesis in a soil bacterial community using quantitative stable isotope probing (qSIP) with H218O. Most soil bacterial taxa were metabolically active and grew, and there was no significant difference between the isotopic composition of DNA and RNA extracted from soil incubated with H218O. The positive correlation between 18O content of DNA and rRNA of taxa, with a slope statistically indistinguishable from 1 (slope = 0.96; 95% confidence interval [CI], 0.90 to 1.02), indicated that few taxa made new rRNA without synthesizing new DNA. There was no correlation between rRNA-to-DNA ratios obtained from sequencing libraries and the atom percent excess (APE) 18O values of DNA or rRNA, suggesting that the ratio of rRNA to DNA is a poor indicator of microbial growth or rRNA synthesis. Our results support the notion that metabolic activity is strongly coupled to cellular division and suggest that nondividing taxa do not dominate soil metabolic activity.IMPORTANCE Using quantitative stable isotope probing of microbial RNA and DNA with H218O, we show that most soil taxa are metabolically active and grow because their nucleic acids are significantly labeled with 18O. A majority of the populations that make new rRNA also grow, which argues against the common paradigm that most soil taxa are dormant. Additionally, our results indicate that relative sequence abundance-based RNA-to-DNA ratios, which are frequently used for identifying active microbial populations in the environment, underestimate the number of metabolically active taxa within soil microbial communities. PMID- 29439991 TI - Single-Molecule Tracking of DNA Translocases in Bacillus subtilis Reveals Strikingly Different Dynamics of SftA, SpoIIIE, and FtsA. AB - Like many bacteria, Bacillus subtilis possesses two DNA translocases that affect chromosome segregation at different steps. Prior to septum closure, nonsegregated DNA is moved into opposite cell halves by SftA, while septum-entrapped DNA is rescued by SpoIIIE. We have used single-molecule fluorescence microscopy and tracking (SMT) experiments to describe the dynamics of the two different DNA translocases, the cell division protein FtsA and the glycolytic enzyme phosphofructokinase (PfkA), in real time. SMT revealed that about 30% of SftA molecules move through the cytosol, while a fraction of 70% is septum bound and static. In contrast, only 35% of FtsA molecules are static at midcell, while SpoIIIE molecules diffuse within the membrane and show no enrichment at the septum. Several lines of evidence suggest that FtsA plays a role in septal recruitment of SftA: an ftsA deletion results in a significant reduction in septal SftA recruitment and a decrease in the average dwell time of SftA molecules. FtsA can recruit SftA to the membrane in a heterologous eukaryotic system, suggesting that SftA may be partially recruited via FtsA. Therefore, SftA is a component of the division machinery, while SpoIIIE is not, and it is otherwise a freely diffusive cytosolic enzyme in vivo Our developed SMT script is a powerful technique to determine if low-abundance proteins are membrane bound or cytosolic, to detect differences in populations of complex-bound and unbound/diffusive proteins, and to visualize the subcellular localization of slow and fast-moving molecules in live cells.IMPORTANCE DNA translocases couple the late events of chromosome segregation to cell division and thereby play an important role in the bacterial cell cycle. The proteins fall into one of two categories, integral membrane translocases or nonintegral translocases. We show that the membrane-bound translocase SpoIIIE moves slowly throughout the cell membrane in B. subtilis and does not show a clear association with the division septum, in agreement with the idea that it binds membrane-bound DNA, which can occur through cell division across nonsegregated chromosomes. In contrast, SftA behaves like a soluble protein and is recruited to the division septum as a component of the division machinery. We show that FtsA contributes to the recruitment of SftA, revealing a dual role of FtsA at the division machinery, but it is not the only factor that binds SftA. Our work represents a detailed in vivo study of DNA translocases at the single-molecule level. PMID- 29439992 TI - Deposition of Bacteria and Bacterial Spores by Bathroom Hot Air Hand Dryers. AB - Hot air hand dryers in multiple men's and women's bathrooms in 3 basic science research areas in an academic health center were screened for their deposition on plates of: i) total bacteria, some of which were identified; and ii) a kanamycin resistant Bacillus subtilis strain, PS533, spores of which are produced in large amounts in one basic science research laboratory. Plates exposed to hand dryer air for 30 seconds averaged 18-60 colonies/plate but interior hand dryer nozzle surfaces had minimal bacterial levels, plates exposed to bathroom air for 2 minutes with hand dryers off averaged <=1 colony, and plates exposed to bathroom air moved by a small fan for 20 minutes had averages of 15 and 12 colonies/plate in two buildings tested. Retrofitting hand dryers with HEPA filters reduced bacterial deposition by hand dryers ~4-fold, and potential human pathogens were recovered from plates exposed to hand dryer air whether or not a HEPA filter was present, and from bathroom air moved by a small fan. Spore-forming colonies, identified as B. subtilis PS533 averaged ~2.5-5% of bacteria deposited by hand dryers throughout basic research areas examined regardless of distance from the spore forming laboratory, and these were almost certainly deposited as spores. Comparable results were obtained when bathroom air was sampled for spores. These results indicate that many kinds of bacteria, including potential pathogens and spores, can be deposited on hands exposed to bathroom hand dryers, and that spores could be dispersed throughout buildings and deposited on hands by hand dryers.Importance While there is evidence that bathroom hand dryers can disperse bacteria from hands or deposit bacteria on surfaces, including recently washed hands, there is less information on: i) the organisms dispersed by hand dryers; ii) if hand dryers provide a reservoir of bacteria or simply blow large amounts of bacterially contaminated air; and iii) if bacterial spores are deposited on surfaces by hand dryers. Consequently, this study has implications for the control of opportunistic bacterial pathogens and spores in public environments including healthcare settings. Within a large building, potentially pathogenic bacteria including bacterial spores may travel between rooms, and subsequent bacterial/spore deposition by hand dryers is a possible mechanism for spread of infectious bacteria including spores of potential pathogens if present. PMID- 29439993 TI - Accumulation and Dissolution of Magnetite Crystals in a Magnetically Responsive Ciliate. AB - Magnetotactic bacteria (MTB) represent a group of microorganisms that are widespread in aquatic habitats and thrive at oxic-anoxic interfaces. They are able to scavenge high concentrations of iron thanks to the biomineralization of magnetic crystals in their unique organelles, the so-called magnetosome chains. Although their biodiversity has been intensively studied, their ecology and impact on iron cycling remain largely unexplored. Predation by protozoa was suggested as one of the ecological processes that could be involved in the release of iron back into the ecosystem. Magnetic protozoa were previously observed in aquatic environments, but their diversity and the fate of particulate iron during grazing are poorly documented. In this study, we report the morphological and molecular characterizations of a magnetically responsive MTB grazing protozoan able to ingest high quantities of MTB. This protozoan is tentatively identified as Uronema marinum, a ciliate known to be a predator of bacteria. Using light and electron microscopy, we investigated in detail the vacuoles in which the lysis of phagocytized prokaryotes occurs. We carried out high-resolution observations of aligned magnetosome chains and ongoing dissolution of crystals. Particulate iron in the ciliate represented approximately 0.01% of its total volume. We show the ubiquity of this interaction in other types of environments and describe different grazing strategies. These data contribute to the mounting evidence that the interactions between MTB and protozoa might play a significant role in iron turnover in microaerophilic habitats.IMPORTANCE Identifying participants of each biogeochemical cycle is a prerequisite to our understanding of ecosystem functioning. Magnetotactic bacteria (MTB) participate in iron cycling by concentrating large amounts of biomineralized iron minerals in their cells, which impacts their chemical environment at, or below, the oxic-anoxic transition zone in aquatic habitats. It was shown that some protozoa inhabiting this niche could become magnetic by the ingestion of magnetic crystals biomineralized by grazed MTB. In this study, we show that magnetic MTB grazers are commonly observed in marine and freshwater sediments and can sometimes accumulate very large amounts of particulate iron. We describe here different phagocytosis strategies, determined using magnetic particles from MTB as tracers after their ingestion by the protozoa. This study paves the way for potential scientific or medical applications using MTB grazers as magnetosome hyperaccumulators. PMID- 29439994 TI - Immediate effect of scalp acupuncture on the gait of patients with subacute intracerebral haemorrhage analysed by three-dimensional motion: secondary analysis of a randomised controlled trial. AB - OBJECTIVE: To investigate the immediate effect of scalp acupuncture on walking pattern, using three-dimensional gait analysis (3D-GA), among patients in the subacute stage of intracerebral haemorrhage (ICH). METHODS: A subset of 30 patients with subacute ICH participating in a recently published randomised controlled trial who were able to walk independently were assessed by 3D-GA before and immediately after scalp acupuncture treatment (treatment group) or no intervention (control group) and the results presented here as a secondary analysis. The acupuncture manipulation was repeated three times with an interval of 5 min. Spatiotemporal and kinematic parameters during walking were collected and analysed using a 3D motion analysis system. RESULTS: After treatment, there were significant differences between the treatment and control groups in the spatiotemporal parameters of step length, velocity and cadence (p<0.05) and double-limb support. No significant difference was found in step width. When kinematic parameters were evaluated, the treatment group showed a significantly decreased peak pelvic anterior tilt angle and an increased hip extension angle after scalp acupuncture treatment, whereas the control group demonstrated no temporal changes. There were no significant changes in any other kinematic parameters in either group. CONCLUSIONS: As the first exploratory study to investigate the effect of the scalp acupuncture on gait performance in patients with subacute ICH, this secondary analysis of a recent randomised trial suggested an immediate effect of treatment on spatiotemporal parameters. Improvement in gait pattern may be associated with a decreased anterior tilt of the pelvis and augmented hip joint motion during walking. TRIAL REGISTRATION NUMBER: ChiCTR-TRC 08000225; Post-results. PMID- 29439995 TI - Primary photodynamic therapy with verteporfin for pigmented posterior pole cT1a choroidal melanoma: a 3-year retrospective analysis. AB - AIMS: To investigate the outcomes of primary photodynamic therapy (PDT) for pigmented posterior pole cT1a choroidal melanoma. METHODS: Retrospective interventional consecutive case series of 26 patients (26 eyes) with pigmented posterior pole cT1a choroidal melanoma, who were treated with 3 sessions of PDT and followed-up thereafter. RESULTS: Included were 11 males and 15 females that presented at a median age of 66 years (mean: 64) with transformed naevi (n=11) or suspicious lesions (n=15) with >=3 risk factors for growth, with lipofuscin in all. In all cases, diagnosis was clinically based (no tissue biopsy). Tumour control was achieved in 16 (62%) patients in a median follow-up time of 29 months (mean: 27). Ten patients failed treatment by form of radial expansion, diagnosed in a median time of 13 months (mean: 12) from last treatment. By Kaplan-Meier analysis, success rate after 1, 2 and 3 years was 85%, 59% and 51%, respectively. On statistical analysis, number of suspicious features was found to be the only risk factor predicting failure (P=0.046). One patient developed macula-sparing branch retinal artery occlusion after treatment. Following PDT, subretinal fluid resolved in all cases and visual acuity significantly improved in all treatment success cases (P=0.043). There were no cases of metastatic spread. CONCLUSION: Primary PDT resulted in tumour regression of small, pigmented choroidal melanoma in 62% after a mean of 27 months. Treatment was more effective in tumours with three or less risk factors for growth, and resulted with fluid elimination and significant improvement in vision in treatment-success cases. PMID- 29439996 TI - Overestimation of hyperopia with autorefraction compared with retinoscopy under cycloplegia in school-age children. AB - AIM: To compare sphere and cylinder refraction values using retinoscopy and autorefraction under cycloplegic conditions in children. METHODS: This cross sectional study was carried out using multistage cluster sampling. The target population was children aged 6-12 years in Shahroud, a northern city in Iran. Examinations included measurements of visual acuity, subjective refraction and objective refraction. Objective refraction was measured with and without cycloplegia with a retinoscope and an autorefractometer. RESULTS: After applying the exclusion criteria, data from 5053 children were analysed. Spherical refraction results with autorefraction were significantly higher than results with retinoscopy (P<0.001). Refraction overestimation was significant in all age groups (P<0.0001). Comparison of differences in different spherical ametropia subgroups also showed a significant intermethod difference in all refractive states (P<0. 01). Overall, autorefraction tended to over plus hyperopics and under minus myopic cases compared with retinoscopy. The 95% limits of agreement for spherical values measured with the two techniques were -0.35 Diopter (D) to 0.50 D. The values of J0 and J45 vectors with autorefraction were significantly higher than those with retinoscopy (P<0.001). The 95% limits of agreement between the two methods for vectors J0 and J45 were -0.12 D to 0.15 D and -0.10 D to 0.11 D, respectively. CONCLUSION: Since the observed differences in spherical refraction and the cylindrical components obtained through retinoscopy and autorefraction are statistically significant, but clinically insignificant, and the two methods have a strong correlation and agreement, it can be concluded that autorefraction can be a suitable substitute for retinoscopy in children under cycloplegic conditions. PMID- 29439997 TI - Improving adherence to healthy dietary patterns, genetic risk, and long term weight gain: gene-diet interaction analysis in two prospective cohort studies. PMID- 29439998 TI - We need a review of all sepsis deaths, not the conviction of health professionals. PMID- 29439999 TI - M-CSF and GM-CSF monocyte-derived macrophages in systemic sclerosis: the two sides of the same coin? PMID- 29440000 TI - Assay variation in the detection of antinuclear antibodies in the sera of patients with established SLE. AB - OBJECTIVE: The expression of antinuclear antibodies (ANA) is considered almost constant in systemic lupus erythematosus (SLE), although recent experience has suggested that many subjects with SLE considered for clinical trials are ANA negative at screening. The objective of this study is to determine whether assay variation can influence ANA detection in patients with established SLE. METHODS: Sera from 103 patients with established SLE were tested using three different immunofluorescence assays (IFA) for ANA determination. ANA determinations were also performed by an ELISA and bead-based multiplex assay. RESULTS: With IFA kits, the frequency of ANA negativity varied from 5 to 23 of 103 samples (4.9% 22.3%). The ELISA and multiplex assays showed that 12 (11.7%) and 14 (13.6%) samples were negative, respectively. Samples positive in all assays differed from those with discordant assay results in the frequency of historical anti-double stranded DNA positivity and low complement levels at the time of blood sampling. DISCUSSION: These findings indicate that ANA negativity occurs in patients with established SLE although the frequency varies depending on the assay kit. Given the range of negativity with well-validated assays, these findings raise questions about whether ANA positivity should be employed to determine eligibility for clinical trials. PMID- 29440001 TI - Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors. AB - OBJECTIVE: To determine whether tumour necrosis factor inhibitor (TNFi) use is associated with an increased rate of incident malignancy compared with no TNFi use in the treatment of juvenile idiopathic arthritis (JIA), paediatric inflammatory bowel disease (pIBD) and paediatric plaque psoriasis (pPsO). METHODS: We performed a retrospective cohort study of administrative claims data from the USA from 2000 to 2014. Exposure to TNFi was considered permanent from the first observed exposure onward. The malignancy outcome was defined by diagnosis codes with evidence of cancer treatment. We calculated standardised incidence ratios (SIRs) comparing the observed number of malignancies to the expected numbers according to cancer surveillance data. We used multivariable Cox proportional hazards models to estimate adjusted HRs (aHRs) for incident malignancy. RESULTS: We identified 15 598 children with TNFi use and 73 839 children with no TNFi use (30 703 and 121 801 person-years of follow-up, respectively). We identified 15 malignancies among children with TNFi use (SIR 2.9 (1.6 to 4.9)) and 42 malignancies among children without TNFi use (SIR 2.1 (1.5 to 2.9)). The aHR was 1.58 (0.88 to 2.85) for TNFi use versus no TNFi use. In pIBD, TNFi use with thiopurine use was associated with a higher SIR (6.0 (1.2 to 17.5)) compared with TNFi use without thiopurine use (2.5 (0.7 to 6.4)). CONCLUSION: Children diagnosed with JIA, pIBD and pPsO had an increased rate of malignancy compared with the general population, but treatment with TNFi did not appear to significantly further increase the risk compared with no TNFi use. More data are needed about the long-term risks of TNFi use. PMID- 29440003 TI - Carillion's toll on NHS. PMID- 29440002 TI - Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide. AB - We studied the association between non-HLA donor characteristics (age, sex, donor recipient relationship, blood group [ABO] match, and cytomegalovirus [CMV] serostatus) and transplant outcomes after T-cell-replete HLA-haploidentical transplantation using posttransplantation cyclophosphamide (PT-Cy) in 928 adults with hematologic malignancy transplanted between 2008 and 2015. Siblings (n = 358) and offspring (n = 450) were the predominant donors, with only 120 patients having received grafts from parents. Although mortality risks were higher with donors aged 30 years or older (hazard ratio, 1.39; P < .0001), the introduction of patient age to the Cox regression model negated the effect of donor age. Two year survival adjusted for CMV seropositivity, disease, and disease risk index was lower in patients aged 55 to 78 years after transplantation of grafts from donors younger than 30 years (53%) or aged at least 30 years (46%) compared with younger patients who received grafts from donors younger than 30 years (61%) and at least 30 years (60%; P < .0001). Similarly, 2-year survival in patients aged 55 to 78 years was lower after transplantation of grafts from siblings (45%) or offspring (48%) compared with patients aged 18 to 54 years after transplantation of grafts from siblings (62%), offspring (58%), and parents (61%; P < .0001). Graft failure was higher after transplantation of grafts from parents (14%) compared with siblings (6%) or offspring (7%; P = .02). Other non-HLA donor characteristics were not associated with survival or graft failure. The current analyses suggest patient and disease, rather than non-HLA donor characteristics, predominantly influence survival in adults. PMID- 29440004 TI - Age at Menarche and Cardiometabolic Health: A Sibling Analysis in the Scottish Family Health Study. AB - BACKGROUND: Previous studies of age at menarche and cardiometabolic health report conflicting findings, and only a few could account for childhood characteristics. We aimed to estimate the associations of age at menarche with cardiovascular risk factors in unrelated women and within sister groups, under the assumption that within-sibship estimates will be better adjusted for shared genetics and early life environment. METHODS AND RESULTS: Our study included 7770 women, from 5984 sibships, participating in the GS:SFHS (Generation Scotland: Scottish Family Health Study). We used fixed- and between-effects linear regression to estimate the associations within sister groups and between unrelated individuals, respectively. Within sibships, the mean difference between sisters with early menarche (<=11 years) and sisters with menarche at 12 to 13 years was 1.73 mm Hg (95% confidence interval [CI], -0.41 to 3.86) for systolic blood pressure, 1.26 mm Hg (95% CI, -0.02 to 2.55) for diastolic blood pressure, -0.06 nmol/L (95% CI, -0.11 to -0.02) for high-density lipoprotein, 0.20 nmol/L (95% CI, 0.08-0.32) for non-high-density lipoprotein, -0.34% (95% CI, -1.98 to 1.30) for glucose, 1.60 kg/m2 (95% CI, 0.92-2.28) for body mass index, and 2.75 cm (95% CI, 1.06-4.44) for waist circumference. There was weak evidence of associations between later menarche (14-15 or >=16 years) and lower body mass index, waist circumference, and blood pressure. We found no strong evidence that estimates from within- and between-sibship analyses differed (all P values >0.1). The associations with other cardiovascular risk factors were attenuated after adjustment for adult body mass index. CONCLUSIONS: Our results suggest that confounding by shared familial characteristics is unlikely to be a major driver of the association between early menarche and adverse cardiometabolic health but do not exclude confounding by individual-level characteristics. PMID- 29440005 TI - Interaction Between the Sodium-Glucose-Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects. AB - BACKGROUND: Dapagliflozin inhibits the sodium-glucose-linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium-glucose-linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide. METHODS AND RESULTS: Healthy subjects (n=42) receiving a fixed diet with ~110 mmol.d-1 of Na+ were randomized to bumetanide (1 mg.d-1), dapagliflozin (10 mg.d-1), or both for 7 days, followed by 7 days of both. There were no meaningful pharmacokinetic interactions. Na+ excretion increased modestly with the first dose of dapagliflozin (22+/-6 mmol.d-1; P<0.005) but by more (P<0.005) with the first dose of bumetanide (74+/-7 mmol.d-1; P<0.005), which was not significantly different from both diuretics together (80+/-5 mmol.d-1; P<0.005). However, Na+ excretion with dapagliflozin was 190% greater (P<0.005) when added after 1 week of bumetanide (64+/-6 mmol.d-1), and Na+ excretion with bumetanide was 36% greater (P<0.005) when added after 1 week of dapagliflozin (101+/-8 mmol.d-1). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy (P<0.05). CONCLUSIONS: First-dose Na+ excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na+ excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide-induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00930865. PMID- 29440006 TI - ApoB/ApoA-I Ratio is Associated With Faster Hemodynamic Progression of Aortic Stenosis: Results From the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) Study. AB - BACKGROUND: Previous studies reported that middle-aged patients with atherogenic lipoprotein-lipid profile exhibit faster progression of aortic valve stenosis (AS). The ratio of apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) reflects the balance between atherogenic and anti-atherogenic lipoproteins. The aim of this study was to examine the association between apoB/apoA-I ratio and AS hemodynamic progression and to determine whether this association varies according to age. METHODS AND RESULTS: A total of 159 patients (66+/-13 years, 73% men) with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study. Hemodynamic progression of AS was determined by the change in peak aortic jet velocity (Vpeak) measured by Doppler echocardiography between baseline and 2-year follow-up. Patients in the top tertile of apoB/apoA-I ratio (>=0.62) had a faster progression rate of AS compared with those in the bottom/mid tertiles (Vpeak progression: 0.30 [0.09 0.49] versus 0.16 [0.01-0.36] m/s, P=0.02). There was a significant interaction (P=0.007) between apoB/apoA-I ratio and age. Among younger patients (ie, aged <70 years; median value of the cohort), those in the top tertile of apoB/apoA-I ratio had a 3.4-fold faster AS progression compared with those in the bottom/mid tertiles (Vpeak progression: 0.34 [0.13-0.69] versus 0.10 [-0.03-0.31] m/s, P=0.002), whereas there was no significant difference between tertiles in the subgroup of older patients (P=0.83). After comprehensive adjustment, higher apoB/apoA-I ratio was significantly associated with faster AS progression in the subset of younger patients (all, standardized beta>=0.36; P<=0.01). CONCLUSIONS: Higher apoB/apoA-I ratio is significantly associated with faster hemodynamic progression of AS in the younger patients. These findings suggest that atherogenic lipid factors may play a crucial role in the pathogenesis of AS in younger patients, but may be are less important in older patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01679431. PMID- 29440007 TI - Recommendations to Enhance Pediatric Cardiovascular Drug Development: Report of a Multi-Stakeholder Think Tank. PMID- 29440008 TI - Novel alpha-Actin Gene Mutation p.(Ala21Val) Causing Familial Hypertrophic Cardiomyopathy, Myocardial Noncompaction, and Transmural Crypts. Clinical Pathologic Correlation. AB - BACKGROUND: Mutations of alpha-actin gene (ACTC1) have been phenotypically related to various cardiac anomalies, including hypertrophic cardiomyopathy and dilated cardiomyopathy and left ventricular (LV) myocardial noncompaction. A novel ACTC mutation is reported as cosegregating for familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts. METHODS AND RESULTS: In an Italian family of 7 subjects, 4 aged 10 (II-1), 14 (II-2), 43 (I-4) and 46 years (I-5), presenting abnormal ECG changes, dyspnea and palpitation (II-2, I-4, and I-5), and recurrent cerebral ischemic attack (I-5), underwent 2-dimensional echo, cardiac magnetic resonance, Holter monitoring, and next-generation sequencing gene analysis. Patients II-2 and I-5 with ventricular tachycardia underwent a cardiac invasive study, including coronary with LV angiography and endomyocardial biopsy. In all the affected members, ECG showed right bundle branch block and left anterior hemiblock with age-related prolongation of QRS duration. Two-dimensional echo and cardiac magnetic resonance documented LV myocardial noncompaction in all and in I-4, I-5, and II-2 a progressive LV hypertrophy up to 22-mm maximal wall thickness. Coronary arteries were normal. LV angiography showed transmural crypts progressing to spongeous myocardial transformation with LV dilatation and dysfunction in the oldest subject. At histology and electron microscopy detachment of myocardiocytes were associated with cell and myofibrillar disarray and degradation of intercalated discs causing disanchorage of myofilaments to cell membrane. Next-generation sequencing showed in affected members an unreported p.(Ala21Val) mutation of ACTC. CONCLUSIONS: Novel p.(Ala21Val) mutation of ACTC1 causes myofibrillar and intercalated disc alteration leading to familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts. PMID- 29440009 TI - U-Shaped Association Between Serum Uric Acid Levels With Cardiovascular and All Cause Mortality in the Elderly: The Role of Malnourishment. AB - BACKGROUND: The link between elevated serum uric acid (SUA) levels and cardiovascular disease (CVD)-related mortality in the elderly population remains inconclusive. Nutritional status influences both SUA and CVD outcomes. Therefore, we investigated whether SUA-predicted mortality and the effect-modifying roles of malnourishment in older people. METHODS AND RESULTS: A longitudinal Taiwanese cohort including 127 771 adults 65 years and older participating in the Taipei City Elderly Health Examination Program from 2001 to 2010 were stratified by 1 mg/dL increment of SUA. Low SUA (<4 mg/dL) strata was categorized by malnourishment status defined as Geriatric Nutritional Risk Index <98, serum albumin <38 g/L, or body mass index <22 kg/m2. Study outcomes were all-cause and CVD-related mortality. Cox models were used to estimate hazard ratios (HRs) of mortality, after adjusting for 20 demographic and comorbid covariates. Over a median follow-up of 5.8 years, there were 16 439 all-cause and 3877 CVD-related deaths. Compared with the reference SUA strata of 4 to <5 mg/dL, all-cause mortality was significantly higher at SUA <4 mg/dL (HR, 1.16; 95% confidence interval, 1.07-1.25) and >=8 mg/dL (HR, 1.13; confidence interval, 1.06-1.21), with progressively elevated risks at both extremes. Similarly, increasingly higher CVD-related mortality was found at the SUA level <4 mg/dL (HR, 1.19; confidence interval, 1.00-1.40) and >=7 mg/dL (HR, 1.17; confidence interval, 1.04-1.32). Remarkably, among the low SUA (<4 mg/dL) strata, only malnourished participants had greater all-cause and CVD-related mortality. This modifying effect of malnourishment remained consistent across subgroups. CONCLUSIONS: SUA >=8 or <4 mg/dL independently predicts higher all-cause and CVD-related mortality in the elderly, particularly in those with malnourishment. PMID- 29440010 TI - Effect and Safety of Morphine Use in Acute Anterior ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Morphine is commonly used to treat chest pain during myocardial infarction, but its effect on cardiovascular outcome has never been directly evaluated. The aim of this study was to examine the effect and safety of morphine in patients with acute anterior ST-segment elevation myocardial infarction followed up for 1 year. METHODS AND RESULTS: We used the database of the CIRCUS (Does Cyclosporine Improve Outcome in ST Elevation Myocardial Infarction Patients) trial, which included 969 patients with anterior ST-segment elevation myocardial infarction, admitted for primary percutaneous coronary intervention. Two groups were defined according to use of morphine preceding coronary angiography. The composite primary outcome was the combined incidence of major adverse cardiovascular events, including cardiovascular death, heart failure, cardiogenic shock, myocardial infarction, unstable angina, and stroke during 1 year. A total of 554 (57.1%) patients received morphine at first medical contact. Both groups, with and without morphine treatment, were comparable with respect to demographic and periprocedural characteristics. There was no significant difference in major adverse cardiovascular events between patients who received morphine compared with those who did not (26.2% versus 22.0%, respectively; P=0.15). The all-cause mortality was 5.3% in the morphine group versus 5.8% in the no-morphine group (P=0.89). There was no difference between groups in infarct size as assessed by the creatine kinase peak after primary percutaneous coronary intervention (4023+/-118 versus 3903+/-149 IU/L; P=0.52). CONCLUSIONS: In anterior ST-segment elevation myocardial infarction patients treated by primary percutaneous coronary intervention, morphine was used in half of patients during initial management and was not associated with a significant increase in major adverse cardiovascular events at 1 year. PMID- 29440011 TI - Different Weight Histories and Risk of Incident Coronary Heart Disease and Stroke: Tehran Lipid and Glucose Study. AB - BACKGROUND: This study aimed to determine the association between different weight histories, including cumulative excess weight, cumulative excess waist circumference (WC), duration of general and central adiposity, current and maximum body mass index, and current and maximum WC, and incident coronary heart disease (CHD) and stroke. METHODS AND RESULTS: The study population consisted of 4398 adults aged >=40 years without CHD or stroke at baseline. Associations between different weight histories and CHD and stroke were determined by multivariable time-varying Cox regression models after adjustment for age, sex, and time-varying confounders. Further adjustment was also done for mediators (eg, diabetes mellitus, hypercholesterolemia, and hypertension). During median follow up of 13.9 years, 718 incident CHD and 158 stroke events were documented. Multivariable adjusted hazard ratios (HRs) were calculated in the sex and confounder adjusted model for CHD per 1-SD increase in cumulative excess weight (HR: 1.02; 95% confidence interval [CI], 0.96-1.07), cumulative excess WC (HR: 1.14; 95% CI, 1.04-1.24), duration of general adiposity (HR: 1.00; 95% CI, 0.92 1.08), duration of central adiposity (HR: 1.01; 95% CI, 0.93-1.09), current body mass index (HR: 1.03; 95% CI, 0.99-1.07), current WC (HR: 1.21; 95% CI, 1.11 1.32), maximum body mass index (HR: 1.01; 95% CI, 0.95-1.07), and maximum WC (HR: 1.17; 95% CI, 1.07-1.28). After further adjustment for mediators, current and maximum WC still showed a significant risk (HR: 1.13 [95% CI, 1.03-1.23] and 1.09 [95% CI, 1.00-1.20], respectively). Moreover, in the sex and confounder adjusted model, cumulative excess WC and maximum WC were associated with higher risk of stroke (hazard ratio: 1.21 [95% CI, 0.99-1.48] and 1.25 [95% CI, 1.02-1.55], respectively). CONCLUSIONS: Exposure to cumulative excess weight and cumulative excess WC confers little additional risk beyond their current and maximum values. Even current and maximum WC were associated with incident CHD in the presence of obesity mediators, and the latter was a significant predictor of stroke in the presence of confounders. PMID- 29440012 TI - Patterns of regional variation of opioid prescribing in primary care in England: a retrospective observational study. AB - BACKGROUND: Opioids are a widely prescribed class of drug with potentially harmful short-term and long-term side effects. There are concerns about the amounts of these drugs being prescribed in England given that they are increasingly considered ineffective in the context of long-term non-cancer pain, which is one of the major reasons for their prescription. AIM: To assess the amount and type of opioids prescribed in primary care in England, and patterns of regional variation in prescribing. DESIGN AND SETTING: Retrospective observational study using publicly available government data from various sources pertaining to opioids prescribed in primary practice in England and Indices of Social Deprivation. METHOD: Official government data were analysed for opioid prescriptions from August 2010 to February 2014. The total amount of opioid prescribed was calculated and standardised to allow for geographical comparisons. RESULTS: The total amount of opioid prescribed, in equivalent milligrams of morphine, increased (r = 0.48) over the study period. More opioids were prescribed in the north than in the south of England (r = 0.66, P<0.0001), and more opioids were prescribed in areas of greater social deprivation (r = 0.56, P<0.0001). CONCLUSION: Long-term opioid prescribing is increasing despite poor efficacy for non-cancer pain, potential harm, and incompatibility with best practice. Questions of equality of care arise from higher prescription rates in the north of England and in areas of greater social deprivation. A national registry of patients with high opioid use would improve patient safety for this high-risk demographic, as well as provide more focused epidemiological data regarding patterns of prescribing. PMID- 29440013 TI - The impact of new forms of large-scale general practice provider collaborations on England's NHS: a systematic review. AB - BACKGROUND: Over the past decade, collaboration between general practices in England to form new provider networks and large-scale organisations has been driven largely by grassroots action among GPs. However, it is now being increasingly advocated for by national policymakers. Expectations of what scaling up general practice in England will achieve are significant. AIM: To review the evidence of the impact of new forms of large-scale general practice provider collaborations in England. DESIGN AND SETTING: Systematic review. METHOD: Embase, MEDLINE, Health Management Information Consortium, and Social Sciences Citation Index were searched for studies reporting the impact on clinical processes and outcomes, patient experience, workforce satisfaction, or costs of new forms of provider collaborations between general practices in England. RESULTS: A total of 1782 publications were screened. Five studies met the inclusion criteria and four examined the same general practice networks, limiting generalisability. Substantial financial investment was required to establish the networks and the associated interventions that were targeted at four clinical areas. Quality improvements were achieved through standardised processes, incentives at network level, information technology-enabled performance dashboards, and local network management. The fifth study of a large-scale multisite general practice organisation showed that it may be better placed to implement safety and quality processes than conventional practices. However, unintended consequences may arise, such as perceptions of disenfranchisement among staff and reductions in continuity of care. CONCLUSION: Good-quality evidence of the impacts of scaling up general practice provider organisations in England is scarce. As more general practice collaborations emerge, evaluation of their impacts will be important to understand which work, in which settings, how, and why. PMID- 29440014 TI - Presenting the primary care team to the public: a qualitative exploration of general practice websites. AB - BACKGROUND: Increasing demand and expanded primary care provision, coupled with a reduced GP workforce, present challenges for primary care. New workforce models aim to reduce GP workload by directing patients to a variety of alternative clinicians. Concurrently, the principle of patient choice in relation to healthcare providers has gained prominence. It is, therefore, necessary to provide patients with sufficient information to negotiate access to appropriate primary healthcare professionals. AIM: To explore how practice websites present three exemplar healthcare professional groups (GPs, advanced nurse practitioners [ANPs], and practice nurses [PNs]) to patients and the implications for informing appropriate consultation choices. DESIGN AND SETTING: Qualitative thematic analysis of a sample of general practice websites. METHOD: In total, 79 accessible websites from a metropolitan district in the north of England were thematically analysed in relation to professional representation and signposting of the three identified professional groups. RESULTS: Information about each group was incomplete, inconsistent, and sometimes inaccurate across the majority of general practice websites. There was a lack of coherence and strategy in representation and direction of website users towards appropriate primary healthcare practitioners. CONCLUSION: Limited and unclear representation of professional groups on general practice websites may have implications for the direction of patients to the wider clinical healthcare team. Patients may not have appropriate information to make choices about consulting with different healthcare practitioners. This constitutes a missed opportunity to signpost patients to appropriate clinicians and enhance understanding of different professional roles. The potential for websites to disseminate information to the public is not being maximised. PMID- 29440015 TI - Self-rated worry in acute care telephone triage: a mixed-methods study. AB - BACKGROUND: Telephone triage is used to assess acute illness or injury. Clinical decision making is often assisted by triage tools that lack callers' perspectives. This study analysed callers' perception of urgency, defined as degree of worry in acute care telephone calls. AIM: To explore the caller's ability to quantify their degree of worry, the association between degree of worry and variables related to the caller, the effect of degree of worry on triage outcome, and the thematic content of the caller's worry. DESIGN AND SETTING: A mixed-methods study with simultaneous convergent design combining descriptive statistics and thematic analysis of 180 calls to a Danish out-of hours service. METHOD: The following quantitative data were measured: age of caller, sex, reason for encounter, symptom duration, triage outcome, and degree of worry (rated from 1 = minimally worried to 5 = extremely worried). Qualitative data consisted of audio-recorded telephone calls. RESULTS: Most callers (170 out of 180) were able to scale their worry when contacting the out-of-hours service (median = 3, interquartile range = 2-4, mean = 2.76). Degree of worry was associated with female sex (odds ratio [OR] 1.98, 95% CI = 1.13 to 3.45) and symptom duration (>24 hours: OR 2.01, 95% CI = 1.13 to 3.45) (reference <5 hours), but not with age or reason for encounter. A high degree of worry significantly increased the chance of being triaged to a face-to-face consultation. The thematic content of worry varied from emotions of feeling bothered to feeling distressed. Callers provided more contextual information when asked about their degree of worry. CONCLUSION: Callers were able to rate their degree of worry. The degree of worry scale is feasible for larger-scale studies if incorporating a patient-centred approach in out-of-hours telephone triage. PMID- 29440016 TI - Reducing inappropriate antibiotic prescribing for children in primary care: a cluster randomised controlled trial of two interventions. AB - BACKGROUND: Antibiotics are overprescribed for non-severe acute infections in children in primary care. AIM: To explore two different interventions that may reduce inappropriate antibiotic prescribing for non-severe acute infections. DESIGN AND SETTING: A cluster randomised, factorial controlled trial in primary care, in Flanders, Belgium. METHOD: Family physicians (FPs) enrolled children with non-severe acute infections into this study. The participants were allocated to one of four intervention groups according to whether the FPs performed: (1) a point-of-care C-reactive protein test (POC CRP); (2) a brief intervention to elicit parental concern combined with safety net advice (BISNA); (3) both POC CRP and BISNA; or (4) usual care (UC). Guidance on the interpretation of CRP was not provided. The main outcome was the immediate antibiotic prescribing rate. A mixed logistic regression was performed to analyse the data. RESULTS: In this study 2227 non-severe acute infections in children were registered by 131 FPs. In comparison with UC, POC CRP did not influence antibiotic prescribing, (adjusted odds ratio [AOR] 1.01, 95% confidence interval [CI] = 0.57 to 1.79). BISNA increased antibiotic prescribing (AOR 2.04, 95% CI = 1.19 to 3.50). In combination with POC CRP, this increase disappeared. CONCLUSION: Systematic POC CRP testing without guidance is not an effective strategy to reduce antibiotic prescribing for non-severe acute infections in children in primary care. Eliciting parental concern and providing a safety net without POC CRP testing conversely increased antibiotic prescribing. FPs possibly need more training in handling parental concern without inappropriately prescribing antibiotics. PMID- 29440017 TI - Patient involvement in diagnosing cancer in primary care: a systematic review of current interventions. AB - BACKGROUND: Patients can play a role in achieving an earlier diagnosis of cancer by monitoring and re-appraising symptoms after initially presenting to primary care. It is not clear what interventions exist, or what the components of an intervention to engage patients at this diagnostic stage are. AIM: The review had two aims: 1) to identify interventions that involve patients, and 2) to establish key components for engaging patients in the diagnosis of cancer in primary care at the post-presentation stage. DESIGN AND SETTING: Empirical studies and non empirical articles were identified searching Ovid MEDLINE, PsycINFO, and Embase databases, relevant journals, and available key author publication lists. METHOD: Abstracts and titles were screened against inclusion and exclusion criteria. Qualitative synthesis of empirical research and current opinion from across all articles was used to select, organise, and interpret findings. RESULTS: No interventions were found. Sixteen articles provided suggestions for potential interventions and components important at the post-presentation stage. Factors contributing to patients not always being engaged in assisting with diagnosis, strategies to foster patient involvement, and moderators and benefits to patients and health services (proximal and distal outcomes) were captured in a logic model. CONCLUSION: There is an absence of interventions involving patients during the post-presentation stage of the diagnostic process. Limited literature was drawn upon to identify potential barriers and facilitators for engaging patients at this diagnostic stage, and to establish possible mechanisms of change and measurable outcomes. Findings can direct future research and the development of interventions. PMID- 29440018 TI - Correction: Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016. PMID- 29440019 TI - Correction: Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. PMID- 29440033 TI - Trajectories of Long-Term Normal Fasting Plasma Glucose and Risk of Coronary Heart Disease: A Prospective Cohort Study. AB - BACKGROUND: Fasting plasma glucose (FPG) levels can vary over time and its longitudinal changing patterns may predict cardiometabolic risk. We aim to identify different trajectories of FPG in those who remained normoglycemic and investigate the association between trajectory groups and coronary heart disease risk in a large prospective cohort study. METHODS AND RESULTS: A total of 20 514 subjects between ages 20 and 80 years were included at baseline. All participants had maintained normal FPG throughout an average follow-up period of 5.8 years. We identified 3 distinct trajectories using a group-based trajectory model, labeled by initial value and changing pattern: low-increasing (n=12 694), high-increasing decreasing (n=5330), and high-decreasing-increasing (n=2490). The coronary heart disease incidence density among these 3 groups (3.00, 4.05, and 3.26 per 1000 person-years, respectively) was significantly different (P=0.038). The high increasing-decreasing group was characterized by a starting FPG of 4.80 mmol/L, and increased up to 5.42 mmol/L at age 55, then decreased thereafter. Treating the low-increasing group as the reference, the age- and sex-adjusted hazard ratio was 1.58 (95% confidence interval, 1.23-2.02) for the high-increasing-decreasing group by Cox proportional hazard regression. After adjustment for other potential confounding factors, the hazard ratio is 1.40 (95% confidence interval, 1.08 1.81). The association persisted after adjustment for baseline FPG, mean, or SD of FPG. CONCLUSIONS: Distinct trajectories of long-term normal FPG are associated with the development of coronary heart disease, which is independent of other metabolic factors including FPG levels. These findings have implications for intervention and prevention of coronary heart disease among individuals who are normoglycemic. PMID- 29440034 TI - Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults. AB - BACKGROUND: Global longitudinal strain (GLS), reflecting total shortening of the myocardium during the cardiac cycle, has emerged as a more precise myocardial function measure than left ventricular ejection fraction (LVEF). Longitudinal strain may be selectively affected in subclinical heart disease, even in the presence of normal LVEF. This study examines subclinical cardiac dysfunction, assessed by GLS and LVEF, and cognition among older adults. METHODS AND RESULTS: Vanderbilt Memory and Aging Project participants who were free of clinical dementia, stroke, and heart failure (n=318, 73+/-7 years, 58% male) completed neuropsychological assessment and cardiac magnetic resonance to quantify GLS and LVEF. Linear regression models related GLS and LVEF to neuropsychological performances, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and APOE*epsilon4 status. Models were repeated with a cardiac*cognitive diagnosis interaction term. Compromised GLS (reflected by higher values) related to worse naming (beta=-0.07, P=0.04), visuospatial immediate recall (beta=-0.83, P=0.03), visuospatial delayed recall (beta=-0.22, P=0.03), and verbal delayed recall (beta=-0.11, P=0.007). LVEF did not relate to worse performance on any measure (P>0.18). No diagnostic interactions were observed. CONCLUSIONS: Our study results are among the first to suggest that compromised GLS relates to worse episodic memory and language performance among older adults who are free of clinical dementia, stroke, and heart failure. Subclinical cardiac dysfunction may correlate with cognitive health in late life, even when LVEF remains normal. The results add to growing evidence that GLS may be a more sensitive and preferred method for quantifying subclinical changes in cardiac function. PMID- 29440035 TI - Readmissions Following a Hospitalization for Cardiovascular Events in Dialysis Patients: A Retrospective Cohort Study. AB - BACKGROUND: Hospitalization for cardiovascular disease (CVD) is common among patients receiving maintenance dialysis, but patterns of readmissions following cardiovascular events are underexplored. METHODS AND RESULTS: In this retrospective analysis of prevalent, Medicare-eligible patients receiving dialysis in 2012-2013, all live-discharge hospitalizations attributed to CVD were ascertained. Rates of all-cause, CVD-related, and non-CVD-related readmissions and death in the ensuing 10 and 30 days were calculated. Multinomial logistic modeling was used to assess the relationship between potential explanatory factors and outcomes of interest. Among 142 210 analyzed hospitalizations, mean age at time of index CVD hospitalization was 64.9+/-14.1 years; 50.4% of index hospitalizations were for women, and 41.4% were for white patients. Fully 15.6% and 34.2% of CVD hospitalizations resulted in readmission within 10 and 30 days, respectively; less than half of readmissions were CVD related (42.5%, 10 days; 43.1%, 30 days). Death within 30 days, regardless of readmission, occurred after 4.5% of index hospitalizations; 51.2% were attributed to CVD. Compared with ages 65 to 69 years, younger age tended to be associated with increased readmission risk (adjusted relative risk for ages 18-44 years: 1.55; 95% confidence interval, 1.48-1.63). Readmission risk did not differ between white and black patients, but risk of death without readmission was markedly lower for black patients (relative risk: 0.60; 95% confidence interval, 0.55-0.67). CONCLUSIONS: Roughly 1 in 3 CVD hospitalizations resulted in 30-day readmission; nearly 1 in 20 was followed by death within 30 days. Risk of death without readmission was higher for white than black patients, despite no difference in risk of readmission. PMID- 29440036 TI - Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent Cumulative Dose. AB - BACKGROUND: We have recently found that 3 repeated doses (12*106 each) of c kitPOS cardiac progenitor cells (CPCs) were markedly more effective than a single dose of 12*106 cells in alleviating postinfarction left ventricular dysfunction and remodeling. However, since the single-dose group received only one third of the total number of CPCs given to the multiple-dose group, it is unknown whether the superior therapeutic efficacy was caused by repeated treatments per se or by administration of a higher total number of CPCs. This issue has major clinical implications because multiple cell injections in patients pose significant challenges, which would be obviated by using 1 large injection. Accordingly, we determined whether the beneficial effects of 3 repeated CPC doses can be recapitulated by 1 large dose containing the same total number of cells. METHODS AND RESULTS: Rats with a 30-day-old myocardial infarction received 3 echo-guided intraventricular infusions, 35 days apart, of vehicle-vehicle-vehicle, 36*106 CPCs-vehicle-vehicle, or 3 equal doses of 12*106 CPCs. Infusion of a single, large dose of CPCs (36*106 cells) produced an initial improvement in left ventricular function, but no further improvement was observed after the second and third infusions (both vehicle). In contrast, each of the 3 doses of CPCs (12*106) caused a progressive improvement in left ventricular function, the cumulative magnitude of which was greater than with a single dose. Unlike the single dose, repeated doses reduced collagen content and immune cell infiltration. CONCLUSIONS: Three repeated doses of CPCs are superior to 1 dose even though the total number of cells infused is the same, possibly because of greater antifibrotic and anti-inflammatory actions. PMID- 29440037 TI - Persistent Inflammation, Stem Cell-Induced Systemic Anti-Inflammatory Effects, and Need for Repeated Stem Cell Injections: Critical Concepts Influencing Optimal Stem Cell Strategies for Treating Acute Myocardial Infarction and Heart Failure. PMID- 29440039 TI - Response to: 'Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis' by Lee and Song. PMID- 29440038 TI - Infographic: Injury and illness, the 2016 Olympic Games. PMID- 29440040 TI - Objectively measured physical activity, sedentary behaviour and all-cause mortality in older men: does volume of activity matter more than pattern of accumulation? AB - OBJECTIVES: To understand how device-measured sedentary behaviour and physical activity are related to all-cause mortality in older men, an age group with high levels of inactivity and sedentary behaviour. METHODS: Prospective population based cohort study of men recruited from 24 UK General Practices in 1978-1980. In 2010-2012, 3137 surviving men were invited to a follow-up, 1655 (aged 71-92 years) agreed. Nurses measured height and weight, men completed health and demographic questionnaires and wore an ActiGraph GT3x accelerometer. All-cause mortality was collected through National Health Service central registers up to 1 June 2016. RESULTS: After median 5.0 years' follow-up, 194 deaths occurred in 1181 men without pre-existing cardiovascular disease. For each additional 30 min in sedentary behaviour, or light physical activity (LIPA), or 10 min in moderate to vigorous physical activity (MVPA), HRs for mortality were 1.17 (95% CI 1.10 to 1.25), 0.83 (95% CI 0.77 to 0.90) and 0.90 (95% CI 0.84 to 0.96), respectively. Adjustments for confounders did not meaningfully change estimates. Only LIPA remained significant on mutual adjustment for all intensities. The HR for accumulating 150 min MVPA/week in sporadic minutes (achieved by 66% of men) was 0.59 (95% CI 0.43 to 0.81) and 0.58 (95% CI 0.33 to 1.00) for accumulating 150 min MVPA/week in bouts lasting >=10 min (achieved by 16% of men). Sedentary breaks were not associated with mortality. CONCLUSIONS: In older men, all activities (of light intensity upwards) were beneficial and accumulation of activity in bouts >=10 min did not appear important beyond total volume of activity. Findings can inform physical activity guidelines for older adults. PMID- 29440041 TI - Factors predicting the success of trabeculectomy bleb enhancement with needling. AB - BACKGROUND: Bleb needling is widely used to restore flow and lower intraocular pressure (IOP) in a failing trabeculectomy. We aimed to measure the safety and efficacy of needling in a large cohort and identify factors that were associated with success and failure. METHODS: This retrospective audit included all patients who underwent needling at Addenbrooke's Hospital, Cambridge over a 10-year period. Data were available on 91 patients (98% of patients identified), including 191 needlings on 96 eyes. Success was defined as IOP below 21 mm Hg or 16 mm Hg or 13 mm Hg consistently, without reoperation or glaucoma medication. Risk factors for failure were assessed by Cox proportional hazard regression and Kaplan-Meier curves. RESULTS: Success defined as IOP <16 mm Hg was 66.6% at 12 months and 53% at 3 years and success defined as IOP <21 mm Hg was 77.1% at 12 months and 73.1% at 3 years. Failure after needling was most common in the first 6 months. Factors that predicted failure were flat or fibrotic blebs (non functional) and no longer injected, while success was predicted by achieving a low IOP immediately after needling. No significant complications were identified. CONCLUSION: Needling was most successful soon after trabeculectomy, but resuscitation of a long-failed trabeculectomy had lower likelihood of success. The safety and efficacy compare favourably with alternative treatment approaches. PMID- 29440042 TI - Statistical approaches in published ophthalmic clinical science papers: a comparison to statistical practice two decades ago. AB - The aim of this study is to evaluate the current practice of statistical analysis of eye data in clinical science papers published in British Journal of Ophthalmology (BJO) and to determine whether the practice of statistical analysis has improved in the past two decades. All clinical science papers (n=125) published in BJO in January-June 2017 were reviewed for their statistical analysis approaches for analysing primary ocular measure. We compared our findings to the results from a previous paper that reviewed BJO papers in 1995. Of 112 papers eligible for analysis, half of the studies analysed the data at an individual level because of the nature of observation, 16 (14%) studies analysed data from one eye only, 36 (32%) studies analysed data from both eyes at ocular level, one study (1%) analysed the overall summary of ocular finding per individual and three (3%) studies used the paired comparison. Among studies with data available from both eyes, 50 (89%) of 56 papers in 2017 did not analyse data from both eyes or ignored the intereye correlation, as compared with in 60 (90%) of 67 papers in 1995 (P=0.96). Among studies that analysed data from both eyes at an ocular level, 33 (92%) of 36 studies completely ignored the intereye correlation in 2017, as compared with in 16 (89%) of 18 studies in 1995 (P=0.40). A majority of studies did not analyse the data properly when data from both eyes were available. The practice of statistical analysis did not improve in the past two decades. Collaborative efforts should be made in the vision research community to improve the practice of statistical analysis for ocular data. PMID- 29440044 TI - Acupuncture and in vitro fertilisation research: current and future directions. AB - BACKGROUND: Acupuncture is a common adjuvant treatment to support patients undergoing in vitro fertilisation (IVF). However, the impact of acupuncture and the different roles it can play in IVF remain unclear. OBJECTIVE: In this paper, we present an overview and critique of the current evidence on acupuncture's impact on IVF-related stress, describe harms, and propose future directions for investigation. CONCLUSION: Two to three acupuncture sessions performed on or around the day of embryo transfer are insufficient interventions to improve IVF birth outcomes but provide significant IVF-related stress reduction. Research investigating acupuncture to support IVF is heterogeneous and confounded by the lack of an appropriate comparator. However, evidence suggests several acupuncture sessions improve endometrial thickness, reduce stress, and improve patient satisfaction. Observational studies suggest more sessions are associated with increases in clinical pregnancy and live birth rates. An optimised acupuncture intervention with a reasonable comparator is necessary for future studies, with evidence-based guidance on technique and number of sessions. Acupuncture should not be rejected as an adjuvant therapy for IVF, but more studies are needed to clarify acupuncture's role in supporting IVF cycles. PMID- 29440043 TI - Acupuncture versus medication for pain management: a cross-sectional study of breast cancer survivors. AB - AIM OF THE STUDY: Breast cancer survivors who take aromatase inhibitors (AI) often suffer from chronic pain. Emerging evidence supports the use of acupuncture as an effective pain management strategy for this condition, but its acceptability among cancer survivors is unknown. We evaluated breast cancer survivors' preferences for acupuncture as compared with medication use and identified factors predictive of this preference. METHODS: We conducted a cross sectional study among breast cancer survivors who were currently, or had been, taking an AI. The primary outcome was degree of preference for acupuncture as compared with medication for pain management. We conducted multivariate logistic regression analyses to evaluate the effects of socioeconomic status (SES) factors and health beliefs on treatment preference. RESULTS: Among 592 participants, 160 (27.0%) preferred acupuncture, 153 (25.8%) preferred medication and 279 (47.1%) had no clear preference. In a multivariate analysis that only included SES, higher education and white race were significantly associated with greater preference for acupuncture. When health beliefs were added, SES effects were attenuated, while greater expectation of acupuncture's effect, lower perceived barriers to its use, higher social norm (endorsement from family members and healthcare professionals) related to acupuncture and higher holistic health beliefs were associated with greater preference for acupuncture. CONCLUSION: We found similar rates of preference for acupuncture versus medication among breast cancer survivors for pain management. Specific attitudes and beliefs predicted such preferences, highlighting the importance of a patient-centred approach to align patient beliefs and preferences with therapeutic options for more effective pain management. TRIAL REGISTRATION NUMBER: NCT01013337; Results. PMID- 29440046 TI - Assisted dying: it's time to poll UK doctors. PMID- 29440045 TI - Impact of acupuncture on antihistamine use in patients suffering seasonal allergic rhinitis: secondary analysis of results from a randomised controlled trial. AB - BACKGROUND: Seasonal allergic rhinitis (SAR) is a common disease that has detrimental effects on the quality of life (QoL) of affected individuals. Approximately 18% of patients try to alleviate their symptoms through acupuncture. The ACUSAR (ACUpuncture in Seasonal Allergic Rhinitis) study (ClinicalTrials.gov registration no. NCT00610584) assessed the impact of acupuncture on SAR, showing significant improvements in rhinitis-specific QoL (RQoL) and in rescue medication (RM) use. OBJECTIVE: A secondary analysis of SAR patients' use of antihistamine. METHODS: Patients were randomised into three study groups: acupuncture plus RM, sham acupuncture plus RM, and RM alone. The patients documented their medication use before and during the intervention period (8 weeks). The main outcome was the number of days with antihistamine use. Statistical analyses were conducted using parametric and non-parametric tests. The robustness of the results was tested by sensitivity analyses using non parametric bootstrapping. RESULTS: The data from 414 patients were analysed. The acupuncture group used antihistamines significantly less often compared with the other groups (acupuncture vs sham acupuncture: mean difference -4.49 days, p=0.01; acupuncture vs RM: mean difference -9.15 days, p<0.001). Approximately 38% of the acupuncture group did not use any antihistamine in contrast to only 16% in the RM group. The pre-post comparison suggested that the acupuncture patients did not need to increase the days of antihistamine use to alleviate their symptoms, unlike the other groups. CONCLUSIONS: Acupuncture appeared to significantly reduce the number of days of antihistamine use while improving RQoL and SAR symptoms; it can therefore be considered a valuable, additional treatment option for patients with SAR. TRIAL REGISTRATION NUMBER: NCT00610584; Post results. PMID- 29440047 TI - Wanted: a WhatsApp alternative for clinicians. PMID- 29440048 TI - Margaret McCartney: The NHS shouldn't have to pick up the bill for private screening tests. PMID- 29440049 TI - Withdrawn: Cutaneous larva migrans with pulmonaryinvolvement. PMID- 29440050 TI - Carer experience of end-of-life service provision: a social network analysis. AB - OBJECTIVE: To identify the position of formal service providers in the networks of those providing end-of-life care in the home from the perspective of the informal network. METHODS: Using third-generation social network analysis, this study examined the nature and strength of relationships of informal caring networks with formal service providers through individual carer interviews, focus groups of caring networks and outer network interviews. RESULTS: Service providers were usually highly valued for providing services, equipment, pain management and personalised care for the dying person plus support and advice to the principal carer about both caring tasks and negotiating the health system. However, formal service providers were positioned as marginal in the caring network. Analysis of the relative density of relationships within networks showed that whereas relationships among family and friends had similar density, relationships between service providers and family or friends were significantly lower. CONCLUSION: The results supported the Circles of Care model and mirror the perspective of formal service providers identified in previous research. The research raises questions about how formal and informal networks might be better integrated to increase their effectiveness for supporting in-home care. PMID- 29440051 TI - Cold forced open-water swimming: a natural intervention to improve postoperative pain and mobilisation outcomes? AB - Postoperative neuropathic pain exacerbated by movement is poorly understood and difficult to treat but a relatively common complication of surgical procedures such as endoscopic thoracic sympathectomy. Here, we describe a case of unexpected, immediate, complete and sustained remission of postoperative intercostal neuralgia after the patient engaged in an open-water swim in markedly cold conditions. Though an incidental chance association is possible, the clear temporal proximity linking the swim with pain remission makes a causal relationship possible. We discuss plausible mechanisms that may underlie the relationship and discuss the potential implications for postoperative pain management and patient-centred mobilisation. We recommend further evaluation of cold forced open-water swimming as a mobility-pain provocation challenge to see if the observed unexpectedly positive outcome can be replicated. With the poor response to traditional management, there is a need for novel, curative interventions for postoperative neuropathic pain and associated impaired mobility. PMID- 29440052 TI - Second letter to the GMC chair regarding Hadiza Bawa-Garba. PMID- 29440053 TI - Biology conference in Italy sparks criticism for including anti-vaccine speakers. PMID- 29440055 TI - "High holidays" are linked to increased risk of fatal traffic crashes. PMID- 29440056 TI - Surgeon is suspended for nine months for working without insurance for 12 days. PMID- 29440057 TI - The role of robotics in colorectal surgery. AB - Studies of laparoscopic approaches in colorectal surgery support the use of such methods. Compared with the open approach, laparoscopy reduces rates of postoperative complications and decreases length of stay, while providing equivalent oncologic outcomes. Nevertheless, much of colorectal surgery is still being performed by the open approach. This may be partly due to the technical challenges in performing laparoscopy, particularly when working in narrow spaces such as the pelvis. Moreover, some of the current literature has questioned the oncologic outcomes after laparoscopic surgery for rectal cancer. Robotic surgery has been heralded as the minimally invasive tool that can overcome these challenges. It has the advantages that it provides a three dimensional image, uses wristed instruments, and has a computer interface that allows for fluid and accurate movements. Overall, current evidence suggests that robotics is safe and feasible in colorectal surgery, and that short term and long term outcomes are comparable to those seen for laparoscopic approaches. Studies on the costs of robotic surgery show conflicting results, and this is arguably one of the biggest disadvantages of its use. Because robotic surgery is a relatively new technology, few large high quality studies are available. Most of the published studies in this area consist of retrospective reviews, case matched studies, and national database reviews. Large randomized prospective studies are needed to further support its use. PMID- 29440054 TI - Effects of changes in eating speed on obesity in patients with diabetes: a secondary analysis of longitudinal health check-up data. AB - OBJECTIVE: Few studies have examined the causal relationships between lifestyle habits and obesity. With a focus on eating speed in patients with type 2 diabetes, this study aimed to analyse the effects of changes in lifestyle habits on changes in obesity using panel data. METHODS: Patient-level panel data from 2008 to 2013 were generated using commercially available insurance claims data and health check-up data. The study subjects comprised Japanese men and women (n=59 717) enrolled in health insurance societies who had been diagnosed with type 2 diabetes during the study period. Body mass index (BMI) was measured, and obesity was defined as a BMI of 25 or more. Information on lifestyle habits were obtained from the subjects' responses to questions asked during health check-ups. The main exposure of interest was eating speed ('fast', 'normal' and 'slow'). Other lifestyle habits included eating dinner within 2 hours of sleeping, after dinner snacking, skipping breakfast, alcohol consumption frequency, sleep adequacy and tobacco consumption. A generalised estimating equation model was used to examine the effects of these habits on obesity. In addition, fixed effects models were used to assess these effects on BMI and waist circumference. RESULTS: The generalised estimating equation model showed that eating slower inhibited the development of obesity. The ORs for slow (0.58) and normal-speed eaters (0.71) indicated that these groups were less likely to be obese than fast eaters (P<0.001). Similarly, the fixed-effects models showed that eating slower reduced BMI and waist circumference. Relative to fast eaters, the coefficients of the BMI model for slow and normal-speed eaters were -0.11 and -0.07, respectively (P<0.001). DISCUSSION: Changes in eating speed can affect changes in obesity, BMI and waist circumference. Interventions aimed at reducing eating speed may be effective in preventing obesity and lowering the associated health risks. PMID- 29440059 TI - Doctors welcome push for parents to use pharmacies but urge caution in emergencies. PMID- 29440060 TI - Sixty seconds on . . . Xanax. PMID- 29440061 TI - Ticks transmitting Lyme disease are found in a third of Britain, mainly the south. PMID- 29440062 TI - My burning issues for 2018: increasing costs and training non-doctors. PMID- 29440063 TI - David Oliver: The Bawa-Garba case, doctors, and the GMC-what next? PMID- 29440064 TI - Follow-up for patients with metal-on-metal hip replacements: are the new MHRA recommendations justified? PMID- 29440068 TI - Molecular Characterization of Renal Cell Carcinoma: A Potential Three-MicroRNA Prognostic Signature. AB - Background: Aberrantly expressed miRNAs promote renal cell carcinoma (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, a consensus clinically significant miRNA signature has not been identified. To identify an miRNA signature for predicting clinical outcome in RCC patients, we used a four-pronged interconnected approach.Methods: Differentially expressed miRNAs were identified and analyzed in 113 specimens (normal kidney: 59; tumor: 54). miRNA profiling was performed in matched normal and tumor specimens from 8 patients and extended to 32 specimens. Seven aberrantly expressed miRNAs were analyzed by qPCR, and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in The Cancer Genome Atlas RCC dataset (n = 241).Results: Discovery phase identified miR-21, miR-142 3p, miR-142-5p, miR-150, and miR-155 as significantly upregulated (2-4-fold) and miR-192 and miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (<4 cm) from benign oncocytomas. In univariate and multivariate analyses, miRNA combinations (miR-21+194; miR-21+142-5p+194) significantly predicted metastasis and/or disease-specific mortality; miR-21+142-5p+194 (for metastasis): P = 0.0017; OR, 0.53; 95% confidence interval (CI), 0.75-0.33; 86.7% sensitivity; 82% specificity. In the TCGA dataset, combined biomarkers associated with metastasis and overall survival (miR-21+142-5p+194: P < 0.0001; OR, 0.37; 95% CI, 0.58-0.23).Conclusions: The interconnected discovery-validation approach identified a three-miRNA signature as a potential predictor of disease outcome in RCC patients.Impact: With 10% survival at 5 years, metastatic disease presents poor prognosis for RCC patients. The three-miRNA signature discovered and validated may potentially at an early stage detect and predict metastasis, to allow early intervention for improving patient prognosis. Cancer Epidemiol Biomarkers Prev; 27(4); 464-72. (c)2018 AACR. PMID- 29440066 TI - Data sharing and reanalysis of randomized controlled trials in leading biomedical journals with a full data sharing policy: survey of studies published in The BMJ and PLOS Medicine. AB - OBJECTIVES: To explore the effectiveness of data sharing by randomized controlled trials (RCTs) in journals with a full data sharing policy and to describe potential difficulties encountered in the process of performing reanalyses of the primary outcomes. DESIGN: Survey of published RCTs. SETTING: PubMed/Medline. ELIGIBILITY CRITERIA: RCTs that had been submitted and published by The BMJ and PLOS Medicine subsequent to the adoption of data sharing policies by these journals. MAIN OUTCOME MEASURE: The primary outcome was data availability, defined as the eventual receipt of complete data with clear labelling. Primary outcomes were reanalyzed to assess to what extent studies were reproduced. Difficulties encountered were described. RESULTS: 37 RCTs (21 from The BMJ and 16 from PLOS Medicine) published between 2013 and 2016 met the eligibility criteria. 17/37 (46%, 95% confidence interval 30% to 62%) satisfied the definition of data availability and 14 of the 17 (82%, 59% to 94%) were fully reproduced on all their primary outcomes. Of the remaining RCTs, errors were identified in two but reached similar conclusions and one paper did not provide enough information in the Methods section to reproduce the analyses. Difficulties identified included problems in contacting corresponding authors and lack of resources on their behalf in preparing the datasets. In addition, there was a range of different data sharing practices across study groups. CONCLUSIONS: Data availability was not optimal in two journals with a strong policy for data sharing. When investigators shared data, most reanalyses largely reproduced the original results. Data sharing practices need to become more widespread and streamlined to allow meaningful reanalyses and reuse of data. TRIAL REGISTRATION: Open Science Framework osf.io/c4zke. PMID- 29440069 TI - Therapeutic Opportunities in Eukaryotic Translation. AB - The ability to block biological processes with selective small molecules provides advantages distinct from most other experimental approaches. These include rapid time to onset, swift reversibility, ability to probe activities in manners that cannot be accessed by genetic means, and the potential to be further developed as therapeutic agents. Small molecule inhibitors can also be used to alter expression and activity without affecting the stoichiometry of interacting partners. These tenets have been especially evident in the field of translation. Small molecule inhibitors were instrumental in enabling investigators to capture short-lived complexes and characterize specific steps of protein synthesis. In addition, several drugs that are the mainstay of modern antimicrobial drug therapy are potent inhibitors of prokaryotic translation. Currently, there is much interest in targeting eukaryotic translation as decades of research have revealed that deregulated protein synthesis in cancer cells represents a targetable vulnerability. In addition to being potential therapeutics, small molecules that manipulate translation have also been shown to influence cognitive processes such as memory. In this review, we focus on small molecule modulators that target the eukaryotic translation initiation apparatus and provide an update on their potential application to the treatment of disease. PMID- 29440067 TI - Perilipin 3 Deficiency Stimulates Thermogenic Beige Adipocytes Through PPARalpha Activation. AB - Beige adipocytes can dissipate energy as heat. Elaborate communication between metabolism and gene expression is important in the regulation of beige adipocytes. Although lipid droplet (LD) binding proteins play important roles in adipose tissue biology, it remains unknown whether perilipin 3 (Plin3) is involved in the regulation of beige adipocyte formation and thermogenic activities. In this study, we demonstrate that Plin3 ablation stimulates beige adipocytes and thermogenic gene expression in inguinal white adipose tissue (iWAT). Compared with wild-type mice, Plin3 knockout mice were cold tolerant and displayed enhanced basal and stimulated lipolysis in iWAT, inducing peroxisome proliferator-activated receptor alpha (PPARalpha) activation. In adipocytes, Plin3 deficiency promoted PPARalpha target gene and uncoupling protein 1 expression and multilocular LD formation upon cold stimulus. Moreover, fibroblast growth factor 21 expression and secretion were upregulated, which was attributable to activated PPARalpha in Plin3-deficient adipocytes. These data suggest that Plin3 acts as an intrinsic protective factor preventing futile beige adipocyte formation by limiting lipid metabolism and thermogenic gene expression. PMID- 29440070 TI - Role of eIF2alpha Kinases in Translational Control and Adaptation to Cellular Stress. AB - A central mechanism regulating translation initiation in response to environmental stress involves phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha). Phosphorylation of eIF2alpha causes inhibition of global translation, which conserves energy and facilitates reprogramming of gene expression and signaling pathways that help to restore protein homeostasis. Coincident with repression of protein synthesis, many gene transcripts involved in the stress response are not affected or are even preferentially translated in response to increased eIF2alpha phosphorylation by mechanisms involving upstream open reading frames (uORFs). This review highlights the mechanisms regulating eIF2alpha kinases, the role that uORFs play in translational control, and the impact that alteration of eIF2alpha phosphorylation by gene mutations or small molecule inhibitors can have on health and disease. PMID- 29440072 TI - Alternative Perspectives on Students' Reasoning about Emergent Processes. PMID- 29440071 TI - Noninvasive Immunometabolic Cardiac Inflammation Imaging Using Hyperpolarized Magnetic Resonance. AB - RATIONALE: Current cardiovascular clinical imaging techniques offer only limited assessment of innate immune cell-driven inflammation, which is a potential therapeutic target in myocardial infarction (MI) and other diseases. Hyperpolarized magnetic resonance (MR) is an emerging imaging technology that generates contrast agents with 10- to 20 000-fold improvements in MR signal, enabling cardiac metabolite mapping. OBJECTIVE: To determine whether hyperpolarized MR using [1-13C]pyruvate can assess the local cardiac inflammatory response after MI. METHODS AND RESULTS: We performed hyperpolarized [1 13C]pyruvate MR studies in small and large animal models of MI and in macrophage like cell lines and measured the resulting [1-13C]lactate signals. MI caused intense [1-13C]lactate signal in healing myocardial segments at both day 3 and 7 after rodent MI, which was normalized at both time points after monocyte/macrophage depletion. A near-identical [1-13C]lactate signature was also seen at day 7 after experimental MI in pigs. Hyperpolarized [1-13C]pyruvate MR spectroscopy in macrophage-like cell suspensions demonstrated that macrophage activation and polarization with lipopolysaccharide almost doubled hyperpolarized lactate label flux rates in vitro; blockade of glycolysis with 2-deoxyglucose in activated cells normalized lactate label flux rates and markedly inhibited the production of key proinflammatory cytokines. Systemic administration of 2 deoxyglucose after rodent MI normalized the hyperpolarized [1-13C]lactate signal in healing myocardial segments at day 3 and also caused dose-dependent improvement in IL (interleukin)-1beta expression in infarct tissue without impairing the production of key reparative cytokines. Cine MRI demonstrated improvements in systolic function in 2-DG (2-deoxyglucose)-treated rats at 3 months. CONCLUSIONS: Hyperpolarized MR using [1-13C]pyruvate provides a novel method for the assessment of innate immune cell-driven inflammation in the heart after MI, with broad potential applicability across other cardiovascular disease states and suitability for early clinical translation. PMID- 29440073 TI - How Four Scientists Integrate Thermodynamic and Kinetic Theory, Context, Analogies, and Methods in Protein-Folding and Dynamics Research: Implications for Biochemistry Instruction. AB - To keep biochemistry instruction current and relevant, it is crucial to expose students to cutting-edge scientific research and how experts reason about processes governed by thermodynamics and kinetics such as protein folding and dynamics. This study focuses on how experts explain their research into this topic with the intention of informing instruction. Previous research has modeled how expert biologists incorporate research methods, social or biological context, and analogies when they talk about their research on mechanisms. We used this model as a guiding framework to collect and analyze interview data from four experts. The similarities and differences that emerged from analysis indicate that all experts integrated theoretical knowledge with their research context, methods, and analogies when they explained how phenomena operate, in particular by mapping phenomena to mathematical models; they explored different processes depending on their explanatory aims, but readily transitioned between different perspectives and explanatory models; and they explained thermodynamic and kinetic concepts of relevance to protein folding in different ways that aligned with their particular research methods. We discuss how these findings have important implications for teaching and future educational research. PMID- 29440074 TI - The Effects of Doctoral Teaching Development on Early-Career STEM Scholars' College Teaching Self-efficacy. AB - To help prepare future faculty in science, technology, engineering, and mathematics (STEM) to teach undergraduates, more research universities are offering teaching development (TD) programs to doctoral students who aspire to academic careers. Using social cognitive career theory, we examine the effects of TD programs on early-career STEM scholars' sense of self-efficacy as postsecondary teachers. In 2011, a survey questionnaire was administered to 2156 people who in 2009 were doctoral students in STEM departments at three U.S. research universities; 1445 responded (67%). Regression analysis revealed positive relationships between TD participation and participants' college teaching self-efficacy and positive interaction effects for women. These findings may be used to improve the quality and quantity of TD offerings and help them gain wider acceptance. PMID- 29440112 TI - SGLT2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis: A South Australian Clinical Case Series and Australian Spontaneous Adverse Event Notifications. PMID- 29440113 TI - Effect of A1C and Glucose on Postoperative Mortality in Noncardiac and Cardiac Surgeries. AB - OBJECTIVE: Hemoglobin A1c (A1C) is used in assessment of patients for elective surgeries because hyperglycemia increases risk of adverse events. However, the interplay of A1C, glucose, and surgical outcomes remains unclarified, with often only two of these three factors considered simultaneously. We assessed the association of preoperative A1C with perioperative glucose control and their relationship with 30-day mortality. RESEARCH DESIGN AND METHODS: Retrospective analysis on 431,480 surgeries within the Duke University Health System determined the association of preoperative A1C with perioperative glucose (averaged over the first 3 postoperative days) and 30-day mortality among 6,684 noncardiac and 6,393 cardiac surgeries with A1C and glucose measurements. A generalized additive model was used, enabling nonlinear relationships. RESULTS: A1C and glucose were strongly associated. Glucose and mortality were positively associated for noncardiac cases: 1.0% mortality at mean glucose of 100 mg/dL and 1.6% at mean glucose of 200 mg/dL. For cardiac procedures, there was a striking U-shaped relationship between glucose and mortality, ranging from 4.5% at 100 mg/dL to a nadir of 1.5% at 140 mg/dL and rising again to 6.9% at 200 mg/dL. A1C and 30-day mortality were not associated when controlling for glucose in noncardiac or cardiac procedures. CONCLUSIONS: Although A1C is positively associated with perioperative glucose, it is not associated with increased 30-day mortality after controlling for glucose. Perioperative glucose predicts 30-day mortality, linearly in noncardiac and nonlinearly in cardiac procedures. This confirms that perioperative glucose control is related to surgical outcomes but that A1C, reflecting antecedent glycemia, is a less useful predictor. PMID- 29440114 TI - Editor's Note. PMID- 29440115 TI - Phenotypic Spectrum of HCN4 Mutations: A Clinical Case. PMID- 29440117 TI - Fresh Frozen Plasma Transfusion Can Confound the Analysis of Circulating Cell Free DNA. PMID- 29440118 TI - The Enigma of Blood Pressure Measurement in Children with CKD. PMID- 29440116 TI - Improving Interpretation of Cardiac Phenotypes and Enhancing Discovery With Expanded Knowledge in the Gene Ontology. AB - BACKGROUND: A systems biology approach to cardiac physiology requires a comprehensive representation of how coordinated processes operate in the heart, as well as the ability to interpret relevant transcriptomic and proteomic experiments. The Gene Ontology (GO) Consortium provides structured, controlled vocabularies of biological terms that can be used to summarize and analyze functional knowledge for gene products. METHODS AND RESULTS: In this study, we created a computational resource to facilitate genetic studies of cardiac physiology by integrating literature curation with attention to an improved and expanded ontological representation of heart processes in the Gene Ontology. As a result, the Gene Ontology now contains terms that comprehensively describe the roles of proteins in cardiac muscle cell action potential, electrical coupling, and the transmission of the electrical impulse from the sinoatrial node to the ventricles. Evaluating the effectiveness of this approach to inform data analysis demonstrated that Gene Ontology annotations, analyzed within an expanded ontological context of heart processes, can help to identify candidate genes associated with arrhythmic disease risk loci. CONCLUSIONS: We determined that a combination of curation and ontology development for heart-specific genes and processes supports the identification and downstream analysis of genes responsible for the spread of the cardiac action potential through the heart. Annotating these genes and processes in a structured format facilitates data analysis and supports effective retrieval of gene-centric information about cardiac defects. PMID- 29440119 TI - Twenty-Four-Hour Ambulatory Blood Pressure versus Clinic Blood Pressure Measurements and Risk of Adverse Outcomes in Children with CKD. AB - BACKGROUND: and objectives Our objective was to determine whether clinic BPs (taken at either a single visit or two sequential visits) are inferior to ambulatory BPs in their ability to discriminate risk of adverse outcomes in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We included 513 participants of the CKD in Children Study who had clinic BPs and 24-hour ambulatory BP monitoring performed during similar timeframes. Predictors of interest were systolic BPs taken at a single visit or two repeated visits within a 1-year period compared with mean wake and sleep systolic ambulatory BPs. Outcomes were left ventricular hypertrophy and ESKD. We determined the ability for each BP parameter to provide risk discrimination using c statistics. RESULTS: During mean follow-up of 3.5 years, 123 participants developed ESKD. In cross sectional unadjusted analysis, every 0.1 increase in systolic BP index was associated with a 2.0 times higher odds of left ventricular hypertrophy (95% confidence interval, 1.5 to 2.8) by clinic BPs versus 1.8 times higher odds (95% confidence interval, 1.3 to 2.4) by ambulatory wake BP. The c statistic was highest for clinic BP (c=0.65; 95% confidence interval, 0.58 to 0.73) but similar to ambulatory wake BP (c=0.64; 95% confidence interval, 0.57 to 0.71) for the discrimination of left ventricular hypertrophy. In longitudinal unadjusted analysis, every 0.1 increase in systolic BP index was associated with a higher risk of ESKD using repeated clinic (hazard ratio, 1.5; 95% confidence interval, 1.3 to 1.8) versus ambulatory wake BP (hazard ratio, 1.6; 95% confidence interval, 1.3 to 2.0). Unadjusted c statistics were the same for wake (c=0.61; 95% confidence interval, 0.56 to 0.67) and clinic systolic BPs (c=0.61; 95% confidence interval, 0.55 to 0.66) for discriminating risk of ESKD. CONCLUSIONS: Clinic BPs taken in a protocol-driven setting are not consistently inferior to ambulatory BP in the discrimination of BP-related adverse outcomes in children with CKD. PMID- 29440120 TI - Financial Hardship after Hematopoietic Cell Transplantation: Lack of Impact on Survival. AB - Background: Financial hardship is a growing challenge for patients with blood cancer who undergo hematopoietic cell transplantation (HCT), and it is associated with poor patient-reported outcomes. In contrast, little is known about the potential impact of patient-reported financial hardship on post-HCT survival.Methods: We sought to describe the association of financial hardship with survival after HCT in a prospectively assembled cohort of patients from three large transplant centers (n = 325).Results: There was no association between financial hardship measures assessed at 6 months post-HCT and 1- or 2 year survival after HCT.Conclusions: Patient-reported financial distress after HCT does not seem to adversely affect post-HCT survival.Impact: When assessing the effectiveness of interventions to ameliorate familial financial burden among HCT, the focus should be on patient-reported outcomes rather than survival. Cancer Epidemiol Biomarkers Prev; 27(3); 345-7. (c)2018 AACR. PMID- 29440122 TI - Defining lineages in the human embryo. PMID- 29440121 TI - Risk of Dementia in Adults With Congenital Heart Disease: Population-Based Cohort Study. AB - BACKGROUND: More children with congenital heart disease (CHD) are surviving to adulthood, and CHD is associated with risk factors for dementia. We compared the risk of dementia in CHD adults to that of the general population. METHODS: In this cohort study, we used medical registries and a medical record review covering all Danish hospitals to identify adults with CHD diagnosed between 1963 and 2012. These individuals with CHD were followed from January 1, 1981, 30 years of age, or date of first CHD registration (index date for matched members of the general population cohort) until hospital diagnosis of dementia, death, emigration, or end of study (December 31, 2012). For each individual with CHD, we identified 10 members of the general population utilizing the Danish Civil Registration System matched on sex and birth year. We computed cumulative incidences and hazard ratios (HRs) of dementia, adjusting for sex and birth year. RESULTS: The cumulative incidence of dementia was 4% by 80 years of age in 10 632 adults with CHD (46% male). The overall HR comparing adults with CHD with the general population cohort was 1.6 (95% confidence interval [CI], 1.3-2.0). The HR among individuals with CHD without extracardiac defects was 1.4 (95% CI, 1.1 1.8). Adults with mild-to-moderate CHD had an HR of 1.5 (95% CI, 1.1-2.0), whereas the HR was 2.0 (95% CI, 1.2-3.3) for severe CHD, including univentricular hearts. The HR for early onset dementia (<65 years of age) was 2.6 (95% CI, 1.8 3.8), whereas the late-onset HR was 1.3 (95% CI, 1.0-1.8). CONCLUSIONS: CHD was associated with an increased risk of dementia compared with the general population, in particular for early onset dementia. Further understanding of dementia risk in the population with CHD is a potential target for future investigation. PMID- 29440123 TI - PORTRAIT (Patient-Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories): Overview of Design and Rationale of an International Prospective Peripheral Arterial Disease Study. AB - BACKGROUND: Health status outcomes, including symptoms, functional status, and quality of life, are critically important outcomes from patients' perspectives. The PORTRAIT study (Patient-Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories) was designed to prospectively define health status outcomes and examine associations between patients' characteristics and care to these outcomes among those presenting with new-onset or worsened claudication. METHODS AND RESULTS: PORTRAIT screened 3637 patients with an abnormal ankle-brachial index and new, or worsened, claudication symptoms from 16 peripheral arterial disease (PAD) specialty clinics in the United States, the Netherlands, and Australia between June 2, 2011, and December 3, 2015. Of the 1608 eligible patients, 1275 (79%) were enrolled. Before treatment, patients were interviewed to obtain their demographics, PAD symptoms and health status, psychosocial characteristics, preferences for shared decision making, socioeconomic, and cardiovascular risk factors. Patients' medical history, comorbidities, and PAD diagnostic information were abstracted from patients' medical records. Serial information about patients' health status, psychosocial, and lifestyle factors was collected at 3, 6, and 12 months by a core laboratory. Follow-up rates ranged from 84.2% to 91%. Clinical follow-up for PAD-related hospitalizations and major cardiovascular events is ongoing. CONCLUSIONS: PORTRAIT systematically collected serial PAD-specific health status data as a foundation for risk stratification, comparative effectiveness studies, and clinicians' adherence to quality-based performance measures. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01419080. PMID- 29440124 TI - SORCS1 and SORCS3 control energy balance and orexigenic peptide production. AB - SORCS1 and SORCS3 are two related sorting receptors expressed in neurons of the arcuate nucleus of the hypothalamus. Using mouse models with individual or dual receptor deficiencies, we document a previously unknown function of these receptors in central control of metabolism. Specifically, SORCS1 and SORCS3 act as intracellular trafficking receptors for tropomyosin-related kinase B to attenuate signaling by brain-derived neurotrophic factor, a potent regulator of energy homeostasis. Loss of the joint action of SORCS1 and SORCS3 in mutant mice results in excessive production of the orexigenic neuropeptide agouti-related peptide and in a state of chronic energy excess characterized by enhanced food intake, decreased locomotor activity, diminished usage of lipids as metabolic fuel, and increased adiposity, albeit at overall reduced body weight. Our findings highlight a novel concept in regulation of the melanocortin system and the role played by trafficking receptors SORCS1 and SORCS3 in this process. PMID- 29440126 TI - Adolescent with painful vesicular otitis and vertigo. PMID- 29440125 TI - Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells. AB - Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complementary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the six members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR-based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anticancer reagents. PMID- 29440127 TI - Ethics and patient and public involvement with children and young people. AB - Patient and public involvement (PPI) is important both in research and in quality improvement activities related to healthcare services . While PPI activities do not require formal ethical approval, they can raise a number of ethical concerns, through the introduction of complex technical medical concepts, challenging language or sensitive subject areas. There is very little published literature to guide ethical practice in this area. We have been conducting PPI with children and young people throughout a research study in paediatric palliative care. PPI started during the application process and continued to guide and shape the research as it progressed. Ethical issues can arise at any time in PPI work. Although many can be predicted and planned for, the nature of PPI means that researchers can be presented with ideas and concepts they had not previously considered, requiring reflexivity and a reactive approach. This paper describes how we considered and addressed the potential ethical issues of PPI within our research. The approach that emerged provides a framework that can be adapted to a range of contexts and will be of immediate relevance to researchers and clinicians who are conducting PPI to inform their work. PMID- 29440128 TI - A Quality Improvement Intervention to Improve Inpatient Pediatric Asthma Controller Accuracy. AB - OBJECTIVES: Our objective was to investigate if a rigorous quality improvement (QI) intervention could increase accuracy of pediatric asthma controller medications on discharge from an inpatient hospitalization. METHODS: Our interprofessional QI team developed interventions such as improving documentation and creating standardized language to ensure patients were discharged on an appropriate asthma controller medication and improve assessment of asthma symptom control. Each week of 2015-2016, the first 5 patients discharged with status asthmaticus from the pediatric wards were reviewed for documentation of the 6 asthma control questions and accuracy of the discharge controller therapy. Correct discharge medication was defined as being prescribed the age-appropriate medication and dose on the basis of baseline controller therapy, compliance with baseline medication, and responses to asthma control assessment. The weekly proportion of control questions that were accessed and correct controller medications that were prescribed were analyzed by using Nelson rules and interrupted time series. RESULTS: A total of 240 preintervention and 252 postintervention charts were reviewed. The primary outcome of the median proportion of patients discharged on appropriate controller therapy improved from 60% in preintervention data to 80% in the postintervention period. The process measure of proportion of asthma control questions that were assessed improved from 43% in the preintervention period to 98% by the final months of the intervention period. Both of these changes were statistically significant as per Nelson's rules and interrupted time series analyses (P = .02 and P < .001, respectively, for postintervention break). CONCLUSIONS: An interdisciplinary QI team successfully improved the accuracy of asthma controller therapy on discharge and the inpatient assessment of asthma control questions. PMID- 29440129 TI - Genomic Predictions and Genome-Wide Association Study of Resistance Against Piscirickettsia salmonis in Coho Salmon (Oncorhynchus kisutch) Using ddRAD Sequencing. AB - Piscirickettsia salmonis is one of the main infectious diseases affecting coho salmon (Oncorhynchus kisutch) farming, and current treatments have been ineffective for the control of this disease. Genetic improvement for P. salmonis resistance has been proposed as a feasible alternative for the control of this infectious disease in farmed fish. Genotyping by sequencing (GBS) strategies allow genotyping of hundreds of individuals with thousands of single nucleotide polymorphisms (SNPs), which can be used to perform genome wide association studies (GWAS) and predict genetic values using genome-wide information. We used double-digest restriction-site associated DNA (ddRAD) sequencing to dissect the genetic architecture of resistance against P. salmonis in a farmed coho salmon population and to identify molecular markers associated with the trait. We also evaluated genomic selection (GS) models in order to determine the potential to accelerate the genetic improvement of this trait by means of using genome-wide molecular information. A total of 764 individuals from 33 full-sib families (17 highly resistant and 16 highly susceptible) were experimentally challenged against P. salmonis and their genotypes were assayed using ddRAD sequencing. A total of 9,389 SNPs markers were identified in the population. These markers were used to test genomic selection models and compare different GWAS methodologies for resistance measured as day of death (DD) and binary survival (BIN). Genomic selection models showed higher accuracies than the traditional pedigree-based best linear unbiased prediction (PBLUP) method, for both DD and BIN. The models showed an improvement of up to 95% and 155% respectively over PBLUP. One SNP related with B-cell development was identified as a potential functional candidate associated with resistance to P. salmonis defined as DD. PMID- 29440130 TI - Cardiac magnetic resonance imaging of myocardial mass and fibrosis in primary aldosteronism. AB - BACKGROUND: Primary aldosteronism (PA) is associated with increased cardiovascular morbidity, presumably due to left ventricular (LV) hypertrophy and fibrosis. However, the degree of fibrosis has not been extensively studied. Cardiac magnetic resonance imaging (CMR) contrast enhancement and novel sensitive T1 mapping to estimate increased extracellular volume (ECV) are available to measure the extent of fibrosis. OBJECTIVES: To assess LV mass and fibrosis before and after treatment of PA using CMR with contrast enhancement and T1 mapping. METHODS: Fifteen patients with newly diagnosed PA (PA1) and 24 age- and sex matched healthy subjects (HS) were studied by CMR with contrast enhancement. Repeated imaging with a new scanner with T1 mapping was performed in 14 of the PA1 and 20 of the HS median 18 months after specific PA treatment and in additional 16 newly diagnosed PA patients (PA2). RESULTS: PA1 had higher baseline LV mass index than HS (69 (53-91) vs 51 (40-72) g/m2; P < 0.001), which decreased significantly after treatment (58 (40-86) g/m2; P < 0.001 vs baseline), more with adrenalectomy (n = 8; -9 g/m2; P = 0.003) than with medical treatment (n = 6; -5 g/m2; P = 0.075). No baseline difference was found in contrast enhancement between PA1 and HS. T1 mapping showed no increase in ECV as a myocardial fibrosis marker in PA. Moreover, ECV was lower in the untreated PA2 than HS 10 min post contrast, and in both PA groups compared with HS 20 min post-contrast. CONCLUSION: Specific treatment rapidly reduced LV mass in PA. Increased myocardial fibrosis was not found and may not represent a common clinical problem. PMID- 29440131 TI - Diagnostic accuracy and comparison of BIPSS in response to lysine vasopressin and hCRH. AB - CONTEXT: Bilateral inferior petrosal sinus sampling (BIPSS) using hCRH is currently considered the 'gold standard' test for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). Vasopressin is more potent than CRH to stimulate ACTH secretion as shown in animal studies; however, no comparative data of its use are available during BIPSS. OBJECTIVE: To study the diagnostic accuracy and comparison of hCRH and lysine vasopressin (LVP) stimulation during BIPSS. PATIENTS AND METHODS: 29 patients (27-Cushing's disease, 2-ectopic CS; confirmed on histopathology) underwent BIPSS and were included for the study. Patients were randomized to receive hCRH, 5 U LVP or 10 U LVP during BIPSS for ACTH stimulation. BIPSS and contrast-enhanced magnetic resonance imaging (CEMRI) were compared with intra-operative findings of trans-sphenoidal surgery (TSS) for localization and lateralization of the ACTH source. RESULTS: BIPSS correctly localized the source of ACTH excess in 29/29 of the patients with accuracy of 26/26 patients, using any of the agent, whereas sensitivity and PPV for lateralization with hCRH, 5 U LVP and 10 U LVP was seen in 10/10, 6/10; 10/10,8/10 and 7/7,6/7 patients respectively. Concordance of BIPSS with TSS was seen in 20/27, CEMRI with BIPSS in 16/24 and CEMRI with TSS in 18/24 of patients for lateralizing the adenoma. Most of the side effects were transient and were comparable in all the three groups. CONCLUSION: BIPSS using either hCRH or LVP (5 U or 10 U) confirmed the source of ACTH excess in all the patients, while 10 U LVP correctly lateralized the pituitary adenoma in three fourth of the patients. PMID- 29440133 TI - South Korea expands investigation into child author scandal. PMID- 29440132 TI - Treatment thresholds for intervention in posthaemorrhagic ventricular dilation: a randomised controlled trial. AB - OBJECTIVE: To compare a low versus a higher threshold for intervention in preterm infants with posthaemorrhagic ventricular dilatation. DESIGN: Multicentre randomised controlled trial (ISRCTN43171322). SETTING: 14 neonatal intensive care units in six countries. PATIENTS: 126 preterm infants <=34 weeks gestation with ventricular dilatation after grade III-IV haemorrhage were randomised to low threshold (LT) (ventricular index (VI) >p97 and anterior horn width (AHW) >6 mm) or higher threshold (HT) (VI>p97+4 mm and AHW >10 mm). INTERVENTION: Cerebrospinal fluid tapping by lumbar punctures (LPs) (max 3), followed by taps from a ventricular reservoir, to reduce VI, and eventually a ventriculoperitoneal (VP) shunt if stabilisation of the VI below the p97+4 mm did not occur. COMPOSITE MAIN OUTCOME MEASURE: VP shunt or death. RESULTS: 19 of 64 (30%) LT infants and 23 of 62 (37%) HT infants were shunted or died (P=0.45). A VP shunt was inserted in 12/64 (19%) in the LT and 14/62 (23%) infants in the HT group. 7/12 (58%) LT infants and 1/14 (7%) HT infants required shunt revision (P<0.01). 62 of 64 (97%) LT infants and 36 of 62 (58%) HT infants had LPs (P<0.001). Reservoirs were inserted in 40 of 64 (62%) LT infants and 27 of 62 (43%) HT infants (P<0.05). CONCLUSIONS: There was no significant difference in the primary composite outcome of VP shunt placement or death in infants with posthaemorrhagic ventricular dilatation who were treated at a lower versus a higher threshold for intervention. Infants treated at the lower threshold received more invasive procedures. Assessment of neurodevelopmental outcomes will provide further important information in assessing the risks and benefits of the two treatment approaches. PMID- 29440135 TI - Biomechanics of omnidirectional strikes in flat spiders. AB - Many ambush predators attack prey using rapid strikes, but these strikes are typically only anteriorly directed. However, a predator may attack laterally and posteriorly oriented prey if it can couple the strikes with rapid body reorientation. Here, we examined omnidirectional strikes in flattie spiders (Selenopidae), a group of sit-and-wait ambush predators found on open surfaces. These spiders attack prey throughout their entire peripheral range using rapid strikes that consist of rapid translation and rotation toward the prey. These spiders ambush with radially oriented, long, laterigrade legs in a ready-to-fire status. Once prey is detected, the spider maneuvers toward it using a single flexion of the legs closest to the prey, which is assisted by 0-3 extension strides by the contralateral legs. The within-stance joint actions by a few legs generate a large resultant force directed toward the prey and a large turning moment. Furthermore, the turning speed is enhanced by rapid midair leg adductions, which effectively reduce the spider's moment of inertia during angular acceleration. Our results demonstrate a novel hunting behavior with high maneuverability that is generated with effectively controlled reconfigurations of long, laterigrade legs. These results provide insights for understanding the diversity of animal legs and developing highly maneuverable multi-legged robots. PMID- 29440134 TI - Interobserver variation in the diagnosis of fibroepithelial lesions of the breast: a multicentre audit by digital pathology. AB - AIM: Fibroepithelial lesions (FELs) of the breast span a morphological continuum including lesions where distinction between cellular fibroadenoma (FA) and benign phyllodes tumour (PT) is difficult. The distinction is clinically important with FAs managed conservatively while equivocal lesions and PTs are managed with surgery. We sought to audit core biopsy diagnoses of equivocal FELs by digital pathology and to investigate whether digital point counting is useful in clarifying FEL diagnoses. METHOD: Scanned slide images from cores and subsequent excisions of 69 equivocal FELs were examined in a multicentre audit by eight pathologists to determine the agreement and accuracy of core needle biopsy (CNB) diagnoses and by digital point counting of stromal cellularity and expansion to determine if classification could be improved. RESULTS: Interobserver variation was high on CNB with a unanimous diagnosis from all pathologists in only eight cases of FA, diagnoses of both FA and PT on the same CNB in 15 and a 'weak' mean kappa agreement between pathologists (k=0.36). 'Moderate' agreement was observed on CNBs among breast specialists (k=0.44) and on excision samples (k=0.49). Up to 23% of lesions confidently diagnosed as FA on CNB were PT on excision and up to 30% of lesions confidently diagnosed as PT on CNB were FA on excision. Digital point counting did not aid in the classification of FELs. CONCLUSION: Accurate and reproducible diagnosis of equivocal FELs is difficult, particularly on CNB, resulting in poor interobserver agreement and suboptimal accuracy. Given the diagnostic difficulty, and surgical implications, equivocal FELs should be reported in consultation with experienced breast pathologists as a small number of benign FAs can be selected out from equivocal lesions. PMID- 29440136 TI - Problems in anticoagulation of a patient with antibiotic treatment for endocarditis: interaction of rifampicin and vitamin K antagonists. AB - The cytochrome P450 is a superfamily of isoenzymes that are responsible for the metabolism of many drugs. Significant changes in pharmacokinetics and drug interactions may be due to induction of hepatic cytochrome P450 enzymes. Rifampicin is a common inducer of CYP3A4. We report a case of a 57-year-old woman who was suspected for endocarditis and therefore treated with rifampicin. Due to previous mechanical aortic valve replacement, she also received phenprocoumon for anticoagulation. Although continuing anticoagulant therapy, antibiotic coadministration led to normal international normalised ratio (INR) level. Fifteen days after the treatment with rifampicin ended, INR returned to therapeutic level. PMID- 29440137 TI - Basilar artery fenestration: an unusual possible cause of ischaemic stroke? AB - Basilar artery fenestration is an uncommon congenital dysplasia and may be associated with ischaemic stroke. We present a case of a previously healthy 36 year-old man who presented with vertigo and vomiting. MRI showed posterior circulation territory infarction. High-resolution magnetic resonance angiography revealed a slit-like fenestration in the basilar artery. This patient had no traditional vascular risk factors or aetiology of cryptogenic stroke. The patient recovered from his neurological deficit after antiplatelet therapy and was given prophylactic aspirin therapy. There was no recurrence of symptoms after 12 months of follow-up. PMID- 29440138 TI - Rhabdomyolysis: a rare complication of Hashimoto's thyroiditis precipitated by statin therapy. AB - Hashimoto's thyroiditis (HT) or chronic lymphocytic thyroiditis is the most common form of primary hypothyroidism. Muscular manifestations like weakness, pain, stiffness and elevated muscle enzymes have been noticed in hypothyroidism. Statins are also known to cause myositis and rhabdomyolysis. This is a case of a middle-aged man, on statin therapy, who presented with severe muscle aches and pain and was found to have rhabdomyolysis. Further evaluation revealed an underlying HT as the culprit for his condition. He was managed with intravenous fluids and levothyroxine along with cessation of statins, following which he improved. PMID- 29440140 TI - Respiratory symptoms of an abdominal origin. PMID- 29440139 TI - Propionibacterium acnes and Staphylococcus epidermidis olecranon bursitis/osteomyelitis: a case involving surgical and antibiotic treatment. AB - This report describes a 63-year-old generally healthy male with septic olecranon bursitis caused by Propionibacterium acnes The patient sustained a small laceration after striking the posterior aspect of his left elbow on a metal railing when he was at a public swimming pool. We concluded that P. acnes was not initially detected because cultures were only kept for 5 days. Consequently, initial antibiotic treatment failed. P. acnes and Staphylococcus epidermidis grew in a subsequent tissue culture. The infection did not respond to intravenous vancomycin although soft-tissue debridements were done. This likely reflected the presence of olecranon osteomyelitis (seen on MRI scans) in addition to inadequate treatment with this antibiotic in the setting of a polymicrobial infection. Eventually, the infection was eradicated with multiple soft-tissue debridements in addition to the continuation of vancomycin with daily intravenous piperacillin/tazobactam that was added for the final 4 weeks of antibiotic treatment. PMID- 29440141 TI - How can positive and negative trainer feedback in the operating theatre impact a surgical trainee's confidence and well-being: a qualitative study in the north of England. AB - OBJECTIVE: To identify the perception of positive feedback (PF) and negative feedback (NF) provided by trainers in the operating theatre on surgical trainees' confidence and well-being. DESIGN: Narrative interview study. SETTING: Twelve hospitals that form part of one deanery within the UK. PARTICIPANTS: Maximum variation sampling of 15 higher general surgical trainees provided insight into how PF and NF from trainers in the operating theatre affect confidence and well being. METHODS: Narrative telephone interviews were conducted with general surgical trainees between April and June 2016. All interviews were recorded, transcribed and anonymised. Transcriptions were analysed using the five-step framework analysis by two independent researchers. RESULTS: Fifteen trainees (age 28-38 years) were interviewed (median interview time: 29 min). Thematic framework analysis identified nine themes within the data. PF, which included corrective feedback, helped the trainees to relax and seemed to enhance their operative performance. All trainees reported significant and unjustified NF, some of which would be defined as undermining and bullying. Many believed this to have a negative impact on their training with minimal educational benefit. Many trainees felt NF adversely affected their performance in the operating theatre with some expressing a wish to leave the profession as a consequence. CONCLUSION: Both PF and NF exist in the operating theatre. Both have an important influence on the trainee, their performance and career. PF, if specific, helped aid progression of learning, increased motivation and performance of surgical trainees. In contrast, NF was perceived to have detrimental effects on trainees' performance and their well-being and, in some, introduced a desire to pursue an alternative career. PMID- 29440142 TI - Overtesting and undertesting in primary care: a systematic review and meta analysis. AB - BACKGROUND: Health systems are currently subject to unprecedented financial strains. Inappropriate test use wastes finite health resources (overuse) and delays diagnoses and treatment (underuse). As most patient care is provided in primary care, it represents an ideal setting to mitigate waste. OBJECTIVE: To identify overuse and underuse of diagnostic tests in primary care. DESIGN: Systematic review and meta-analysis. DATA SOURCES AND ELIGIBILITY CRITERIA: We searched MEDLINE and Embase from January 1999 to October 2017 for studies that measured the inappropriateness of any diagnostic test (measured against a national or international guideline) ordered for adult patients in primary care. RESULTS: We included 357 171 patients from 63 studies in 15 countries. We extracted 103 measures of inappropriateness (41 underuse and 62 overuse) from included studies for 47 different diagnostic tests.The overall rate of inappropriate diagnostic test ordering varied substantially (0.2%-100%)%).17 tests were underused >50% of the time. Of these, echocardiography (n=4 measures) was consistently underused (between 54% and 89%, n=4). There was large variation in the rate of inappropriate underuse of pulmonary function tests (38%-78%, n=8).Eleven tests were inappropriately overused >50% of the time. Echocardiography was consistently overused (77%-92%), whereas inappropriate overuse of urinary cultures, upper endoscopy and colonoscopy varied widely, from 36% to 77% (n=3), 10%-54% (n=10) and 8%-52% (n=2), respectively. CONCLUSIONS: There is marked variation in the appropriate use of diagnostic tests in primary care. Specifically, the use of echocardiography (both underuse and overuse) is consistently poor. There is substantial variation in the rate of inappropriate underuse of pulmonary function tests and the overuse of upper endoscopy, urinary cultures and colonoscopy. PROSPERO REGISTRATION NUMBER: CRD42016048832. PMID- 29440144 TI - SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin-Rho GTPase-Hippo Pathways. AB - Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-alpha4beta1 integrin signaling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-Actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2 alpha5beta1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.Significance: Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/9/2305/F1.large.jpg Cancer Res; 78(9); 2305-17. (c)2018 AACR. PMID- 29440143 TI - Exploring the lived experience and chronic low back pain beliefs of English speaking Punjabi and white British people: a qualitative study within the NHS. AB - INTRODUCTION: Disabling chronic low back pain (CLBP) is associated with negative beliefs and behaviours, which are influenced by culture, religion and interactions with healthcare practitioners (HCPs). In the UK, HCPs encounter people from different cultures and ethnic backgrounds, with South Asian Indians (including Punjabis) forming the largest ethnic minority group. Better understanding of the beliefs and experiences of ethnic minorities with CLBP might inform effective management. OBJECTIVES: To explore the CLBP beliefs and experiences of English-speaking Punjabi and white British people living with CLBP, explore how beliefs may influence the lived experience of CLBP and conduct cross-cultural comparisons between the two groups. DESIGN: Qualitative study using semistructured interviews set within an interpretive description framework and thematic analysis. SETTING: A National Health Service hospital physiotherapy department, Leicester, UK. PARTICIPANTS: 10 CLBP participants (5 English-speaking Punjabi and 5 white British) purposively recruited from physiotherapy waiting lists. RESULTS: Participants from both groups held negative biomedical CLBP beliefs such as the 'spine is weak', experienced unfulfilling interactions with HCPs commonly due to a perceived lack of support and negative psychosocial dimensions of CLBP with most participants catastrophising about their CLBP. Specific findings to Punjabi participants included (1) disruption to cultural religious well-being, as well as (2) a perceived lack of understanding and empathy regarding their CLBP from the Punjabi community. In contrast to their white British counterparts, Punjabi participants reported initially using passive coping strategies; however, all participants reported a transition towards active coping strategies. CONCLUSION: CLBP beliefs and experiences, irrespective of ethnicity, were primarily biomedically orientated. However, cross-cultural differences included cultural-religious well-being, the community response to CLBP experienced by Punjabi participants and coping styles. These findings might help inform management of people with CLBP. PMID- 29440145 TI - The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1 Expression and Targeting Tumor-Initiating Cells. AB - Traditional treatments of small-cell lung cancer (SCLC) with cisplatin, a standard-of-care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TICs in SCLC, in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TICs. Combination of cisplatin and CBL0137 killed patient derived and murine SCLC cell lines synergistically. In response to CBL0137 alone, TICs were more sensitive than non-TICs, in part, because CBL0137 increased expression of the tumor suppressor NOTCH1 by abrogating the binding of negative regulator SP3 to the NOTCH1 promoter, and in part because treatment decreased the high expression of stem cell transcription factors. The combination of cisplatin and CBL0137 greatly reduced the growth of a patient-derived xenograft in mice and also the growth of a syngeneic mouse SCLC tumor. Thus, CBL0137 can be a highly effective drug against SCLC, especially in combination with cisplatin.Significance: These findings reveal a novel therapeutic regimen for SCLC, combining cisplatin with an inhibitor that preferentially targets tumor initiating cells. Cancer Res; 78(9); 2396-406. (c)2018 AACR. PMID- 29440146 TI - A DDX31/Mutant-p53/EGFR Axis Promotes Multistep Progression of Muscle-Invasive Bladder Cancer. AB - The p53 and EGFR pathways are frequently altered in bladder cancer, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle-invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31-bound mutp53/SP1 enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin in advanced MIBC, leading to EGFR-Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31/NCL interaction resulted in downregulation of EGFR/Akt signaling, eliciting an in vivo antitumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31/NCL formation may lead to potential treatment strategies for advanced MIBC.Significance: DDX31 cooperates with mutp53 and EGFR to promote progression of muscle invasive bladder cancer. Cancer Res; 78(9); 2233 47. (c)2018 AACR. PMID- 29440147 TI - The Balance Players of the Adaptive Immune System. AB - Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)-restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer. Vaccination against genetically stable cells with regular HLA expression is an attractive way to directly target immunosuppressive cells in addition to attracting proinflammatory cells into the tumor microenvironment. Importantly, vaccination toward IDO or PD-L1 to potentiate such T cells have proven safe, with minimal toxicity in the clinical phase I trials conducted thus far.Cancer Res; 78(6); 1379-82. (c)2018 AACR. PMID- 29440148 TI - Interventions in hospitalised patients with cancer: the importance of impending death awareness. AB - OBJECTIVES: Burdensome and futile interventions with the aim of prolonging life should be avoided in dying patients. However, current clinical practice has hardly been investigated.We examined the number and type of diagnostic and therapeutic medical interventions in hospitalised patients with cancer in their last days of life. In addition, we investigated if physician awareness of impending death affected the use of these interventions. METHODS: Questionnaire study and medical record study. Attending physicians of patients who died in a university hospital between January 2010 and June 2012 were asked whether they had been aware of the patient's impending death. The use of diagnostic and therapeutic interventions and medications was assessed by studying patients' charts. We included 131 patients. RESULTS: In the last 72 and 24 hours of life, 59% and 24% of the patients received one or more diagnostic interventions, respectively. Therapeutic interventions were provided to 47% and 31%. In the last 24 hours of life, patients received on average 5.8 types of medication.Awareness of a patient's impending death was associated with a significant lower use of diagnostic interventions (48% vs 69% in the last 72 hours; 11% vs 37% in the last 24 hours) and several medications that potentially prolong life (eg, antibiotics and cardiovascular medication). CONCLUSIONS: Many patients with cancer who die in hospital receive diagnostic and therapeutic interventions in the last days of life of which their advantages are questionable. To improve end-of-life care, medical care should be adapted. PMID- 29440149 TI - Cancer cachexia: rationale for the MENAC (Multimodal-Exercise, Nutrition and Anti inflammatory medication for Cachexia) trial. AB - : Cancer cachexia is a multifactorial syndrome characterised by an ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support alone. Cachexia has a high prevalence in cancer and a major impact on patient physical function, morbidity and mortality. Despite the consequences of cachexia, there is no licensed treatment for cachexia and no accepted standard of care. It has been argued that the multifactorial genesis of cachexia lends itself to therapeutic targeting through a multimodal treatment. Following a successful phase II trial, a phase III randomised controlled trial of a multimodal cachexia intervention is under way. Termed the MENAC trial (Multimodal-Exercise, Nutrition and Anti-inflammatory medication for Cachexia), this intervention is based on evidence to date and consists of non-steroidal anti-inflammatory drugs and eicosapentaenoic acid to reduce inflammation, a physical exercise programme using resistance and aerobic training to increase anabolism, as well as dietary counselling and oral nutritional supplements to promote energy and protein balance. Herein we describe the development of this trial. TRIAL REGISTRATION NUMBER: NCT02330926. PMID- 29440151 TI - Cost-effectiveness of mammography from a publicly funded health care system perspective. AB - BACKGROUND: The implementation of population-wide breast cancer screening programs has important budget implications. We evaluated the cost-effectiveness of various breast cancer screening scenarios in Canada from a publicly funded health care system perspective using an established breast cancer simulation model. METHODS: Breast cancer incidence, outcomes and total health care system costs (screening, investigation, diagnosis and treatment) for the Canadian health care environment were modelled. The model predicted costs (in 2012 dollars), life years gained and quality-adjusted life-years (QALYs) gained for 11 active screening scenarios that varied by age range for starting and stopping screening (40-74 yr) and frequency of screening (annual, biennial or triennial) relative to no screening. All outcomes were discounted. Marginal and incremental cost effectiveness analyses were conducted. One-way sensitivity analyses of key parameters assessed robustness. RESULTS: The lifetime overall costs (undiscounted) to the health care system for annual screening per 1000 women ranged from $7.4 million (for women aged 50-69 yr) to $10.7 million (40-74 yr). For biennial and triennial screening per 1000 women (aged 50-74 yr), costs were less, at about $6.1 million and $5.3 million, respectively. The incremental cost utility ratio varied from $36 981/QALY for triennial screening in women aged 50 69 versus no screening to $38 142/QALY for biennial screening in those aged 50-69 and $83 845/QALY for annual screening in those aged 40-74. INTERPRETATION: Our economic analysis showed that both benefits of mortality reduction and costs rose together linearly with the number of lifetime screens per women. The decision on how to screen is related mainly to willingness to pay and additional considerations such as the number of women recalled after a positive screening result. PMID- 29440150 TI - Night Shift Work, Genetic Risk, and Type 2 Diabetes in the UK Biobank. AB - OBJECTIVE: To examine the effects of past and current night shift work and genetic type 2 diabetes vulnerability on type 2 diabetes odds. RESEARCH DESIGN AND METHODS: In the UK Biobank, we examined associations of current (N = 272,214) and lifetime (N = 70,480) night shift work exposure with type 2 diabetes risk (6,770 and 1,191 prevalent cases, respectively). For 180,704 and 44,141 unrelated participants of European ancestry (4,002 and 726 cases, respectively) with genetic data, we assessed whether shift work exposure modified the relationship between a genetic risk score (comprising 110 single-nucleotide polymorphisms) for type 2 diabetes and prevalent diabetes. RESULTS: Compared with day workers, all current night shift workers were at higher multivariable-adjusted odds for type 2 diabetes (none or rare night shifts: odds ratio [OR] 1.15 [95% CI 1.05-1.26]; some nights: OR 1.18 [95% CI 1.05-1.32]; and usual nights: OR 1.44 [95% CI 1.19 1.73]), except current permanent night shift workers (OR 1.09 [95% CI 0.93 1.27]). Considering a person's lifetime work schedule and compared with never shift workers, working more night shifts per month was associated with higher type 2 diabetes odds (<3/month: OR 1.24 [95% CI 0.90-1.68]; 3-8/month: OR 1.11 [95% CI 0.90-1.37]; and >8/month: OR 1.36 [95% CI 1.14-1.62]; Ptrend = 0.001). The association between genetic type 2 diabetes predisposition and type 2 diabetes odds was not modified by shift work exposure. CONCLUSIONS: Our findings show that night shift work, especially rotating shift work including night shifts, is associated with higher type 2 diabetes odds and that the number of night shifts worked per month appears most relevant for type 2 diabetes odds. Also, shift work exposure does not modify genetic risk for type 2 diabetes, a novel finding that warrants replication. PMID- 29440152 TI - Protocol for validation of the 4AT, a rapid screening tool for delirium: a multicentre prospective diagnostic test accuracy study. AB - INTRODUCTION: Delirium is a severe neuropsychiatric syndrome of rapid onset, commonly precipitated by acute illness. It is common in older people in the emergency department (ED) and acute hospital, but greatly under-recognised in these and other settings. Delirium and other forms of cognitive impairment, particularly dementia, commonly coexist. There is a need for a rapid delirium screening tool that can be administered by a range of professional-level healthcare staff to patients with sensory or functional impairments in a busy clinical environment, which also incorporates general cognitive assessment. We developed the 4 'A's Test (4AT) for this purpose. This study's primary objective is to validate the 4AT against a reference standard. Secondary objectives include (1) comparing the 4AT with another widely used test (the Confusion Assessment Method (CAM)); (2) determining if the 4AT is sensitive to general cognitive impairment; (3) assessing if 4AT scores predict outcomes, including (4) a health economic analysis. METHODS AND ANALYSIS: 900 patients aged 70 or over in EDs or acute general medical wards will be recruited in three sites (Edinburgh, Bradford and Sheffield) over 18 months. Each patient will undergo a reference standard delirium assessment and will be randomised to assessment with either the 4AT or the CAM. At 12 weeks, outcomes (length of stay, institutionalisation and mortality) and resource utilisation will be collected by a questionnaire and via the electronic patient record. ETHICS AND DISSEMINATION: Ethical approval was granted in Scotland and England. The study involves administering tests commonly used in clinical practice. The main ethical issues are the essential recruitment of people without capacity. Dissemination is planned via publication in high impact journals, presentation at conferences, social media and the website www.the4AT.com. TRIAL REGISTRATION NUMBER: ISRCTN53388093; Pre-results. PMID- 29440153 TI - Does assistive technology contribute to social inclusion for people with intellectual disability? A systematic review protocol. AB - INTRODUCTION: The aim of this review is to answer the following question: Does assistive technology contribute to social inclusion for people with intellectual disability? Previous research on assistive technology has focused on socioeconomic impacts such as education, employment and access to healthcare by people with intellectual disability. There is a need to consolidate evidence on the interaction between intellectual disability, assistive technology, community living and social inclusion. METHODS AND ANALYSIS: The review will consider studies from all settings: geographical, socioeconomic and care (institutional and community care), published in English. Studies reported in other languages with abstracts in English will be included if they can be translated using Google Translate, otherwise such studies will be included in the appendix. The review will include both qualitative and quantitative studies. The intervention in this review refers to the use of assistive technology to promote community participation or interpersonal relationships (social inclusion) for people with intellectual disability. The outcomes will be behavioural and social benefits of using assistive technology by people with intellectual disability. Enhanced interpersonal relationships and community participation by people with intellectual disability. Data analysis will be in two phases. The first phase will involve analysis of individual study designs separately. The second phase will be narrative/thematic synthesis of all study groups. ETHICS: The review will not create any ethical or safety concerns. DISSEMINATION: At least one peer reviewed article in a leading journal such as the BMJ is planned. The findings will also be disseminated through a seminar session involving internal audience at Trinity College Dublin and within the Assistive Technologies for people with Intellectual Disability and Autism research programme. PROSPERO REGISTRATION NUMBER: CRD42017065447; Pre-results. PMID- 29440155 TI - Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov. AB - OBJECTIVES: This review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials. DESIGN: Review of adaptive design clinical trials in EMBASE, PubMed, Cochrane Registry of Controlled Clinical Trials, Web of Science and ClinicalTrials.gov. Phase I and seamless Phase I/II trials were excluded. Variables extracted from trials included basic study characteristics, adaptive design features, size and use of independent data monitoring committees (DMCs) and blinded interim analyses. We also examined use of the adaptive trials in new drug submissions to the Food and Drug Administration (FDA) and European Medicines Agency (EMA) and recorded regulators' experiences with adaptive designs. RESULTS: 142 studies met inclusion criteria. There has been a recent growth in publicly reported use of adaptive designs among researchers around the world. The most frequently appearing types of adaptations were seamless Phase II/III (57%), group sequential (21%), biomarker adaptive (20%), and adaptive dose-finding designs (16%). About one-third (32%) of trials reported an independent DMC, while 6% reported blinded interim analysis. We found that 9% of adaptive trials were used for FDA product approval consideration, and 12% were used for EMA product approval consideration. International regulators had mixed experiences with adaptive trials. Many product applications with adaptive trials had extensive correspondence between drug sponsors and regulators regarding the adaptive designs, in some cases with regulators requiring revisions or alterations to research designs. CONCLUSIONS: Wider use of adaptive designs will necessitate new drug application sponsors to engage with regulatory scientists during planning and conduct of the trials. Investigators need to more consistently report protections intended to preserve confidentiality and minimise potential operational bias during interim analysis. PMID- 29440154 TI - Outcomes comparison of different surgical strategies for the management of severe aortic valve stenosis: study protocol of a prospective multicentre European registry (E-AVR registry). AB - INTRODUCTION: Traditional and transcatheter surgical treatments of severe aortic valve stenosis (SAVS) are increasing in parallel with the improved life expectancy. Recent randomised controlled trials (RCTs) reported comparable or non inferior mortality with transcatheter treatments compared with traditional surgery. However, RCTs have the limitation of being a mirror of the predefined inclusion/exclusion criteria, without reflecting the 'real clinical world'. Technological improvements have recently allowed the development of minimally invasive surgical accesses and the use of sutureless valves, but their impact on the clinical scenario is difficult to assess because of the monocentric design of published studies and limited sample size. A prospective multicentre registry including all patients referred for a surgical treatment of SAVS (traditional, through full sternotomy; minimally invasive; or transcatheter; with both 'sutured' and 'sutureless' valves) will provide a 'real-world' picture of available results of current surgical options and will help to clarify the 'grey zones' of current guidelines. METHODS AND ANALYSIS: European Aortic Valve Registry is a prospective observational open registry designed to collect all data from patients admitted for SAVS, with or without coronary artery disease, in 16 cardiac surgery centres located in six countries (France, Germany, Italy, Spain, Switzerland and UK). Patients will be enrolled over a 2-year period and followed up for a minimum of 5 years to a maximum of 10 years after enrolment. Outcome definitions are concordant with Valve Academic Research Consortium-2 criteria and established guidelines. Primary outcome is 5-year all-cause mortality. Secondary outcomes aim at establishing 'early' 30-day all-cause and cardiovascular mortality, as well as major morbidity, and 'late' cardiovascular mortality, major morbidity, structural and non-structural valve complications, quality of life and echocardiographic results. ETHICS AND DISSEMINATION: The study protocol is approved by local ethics committees. Any formal presentation or publication of data will be considered as a joint publication by the participating physician(s) and will follow the recommendations of the International Committee of Medical Journal Editors for authorship. TRIAL REGISTRATION NUMBER: NCT03143361; Pre-results. PMID- 29440156 TI - Association between social health insurance and choice of hospitals among internal migrants in China: a national cross-sectional study. AB - OBJECTIVES: There is a tendency to pursue higher-level hospitalisation services in China, especially for internal migrants. This study aims to investigate the choices of hospitalisation services among internal migrants, and evaluate the association between social health insurance and hospitalisation choices. METHODS: Data were from a 2014 nationally representative cross-sectional sample of internal migrants aged 15-59 years in China. Descriptive analyses were used to perform the distribution of healthcare facility levels for hospitalisation services, and multinomial logistic regression was applied to examine the association between social health insurance and hospitalisation choices. RESULTS: Of the 6121 inpatient care users, only 11.50% chose the primary healthcare facilities for hospitalisation services, 44.91% chose the secondary hospitals and 43.59% preferred the tertiary hospitals. The choices presented large regional variations across the country. Compared with the uninsured, social health insurance had no statistically significant effect on patient choices of healthcare facility levels among internal migrants in China, whereas socioeconomic status was positively associated with the choices. CONCLUSIONS: Social health insurance had little influence on the hospital choice among the internal migrants. Thus, social health insurance should be consolidated and portable to enhance the proper incentive of health insurance on healthcare seeking behaviours. PMID- 29440157 TI - Is socioeconomic segregation of the poor associated with higher premature mortality under the age of 60? A cross-sectional analysis of survey data in major Indian cities. AB - OBJECTIVES: Although urbanisation is generally associated with poverty reduction in low-income and middle-income countries, it also results in increased socioeconomic segregation of the poor. Cities with higher levels of socioeconomic segregation tend to have higher mortality rates, although the evidence is based on ecological associations. The paper examines whether socioeconomic segregation of the poor is associated with higher under-60 years ('premature') mortality risk in Indian cities and whether this association is confounded by contextual and compositional sociodemographic and socioeconomic factors. SETTING AND PARTICIPANTS: A population representative sample of over one million from 39 427 households living in 1876 urban wards within 59 Indian districts (cities) from the third (2008) District Level Household Survey (DLHS-3). PRIMARY OUTCOME AND OTHER MEASURES: The outcome was any death under the age of 60 reported by households in the preceding 4years of the DLHS-3. Socioeconomic segregation, estimated at the district (city) level, was measured using an isolation index of the poor and the index of dissimilarity. RESULTS: Poor households living in cities where the poor were more isolated had higher probabilities of premature mortality than poor households living in cities where the poor were less isolated. In contrast, it did not matter whether rich households lived in more or less socioeconomically segregated cities. A 1 SD increase in the isolation index was associated with an absolute increase of 1.1% in the probability of premature mortality for the poorest households. CONCLUSION: Increasing segregation of the poor may result in higher premature mortality. As low-income and middle-income countries become increasingly urbanised, there is a risk that this may lead to increased segregation of the poor as well as increased premature mortality. PMID- 29440158 TI - Risk factors and between-hospital variation of caesarean section in Denmark: a cohort study. AB - OBJECTIVES: The aim of this study was to estimate the effects of risk factors on elective and emergency caesarean section (CS) and to estimate the between hospital variation of risk-adjusted CS proportions. DESIGN: Historical registry based cohort study. SETTINGS AND PARTICIPANTS: The study was based on all singleton deliveries in hospital units in Denmark from January 2009 to December 2012. A total of 226 612 births by 198 590 mothers in 29 maternity units were included. PRIMARY AND SECONDARY OUTCOME MEASURES: We estimated (1) OR of elective and emergency CS adjusted for several risk factors, for example, body mass index, parity, age and size of maternity unit and (2) risk-adjusted proportions of elective and emergency CS to evaluate between-hospital variation. RESULTS: The CS proportion was stable at 20%-21%, but showed wide variation between units, even in adjusted models. Large units performed significantly more elective CSs than smaller units, and the risk of emergency CS was significantly reduced compared with smaller units. Many of the included risk factors were found to influence the risk of CS. The most important risk factors were breech presentation and previous CS. Four units performed more CSs and one unit fewer CSs than expected. CONCLUSION: The main risk factors for elective CS were breech presentation and previous CS; for emergency CS they were breech presentation and cephalopelvic disproportion. The proportions of CS were stable during the study period. We found variation in risk-adjusted CS between hospitals in Denmark. Although exhaustive models were applied, the results indicated the presence of systematic variation between hospital units, which was unexpected in a small, well-regulated country such as Denmark. PMID- 29440159 TI - Multicentre study on capsular closure versus non-capsular closure during hip arthroscopy in Danish patients with femoroacetabular impingement (FAI): protocol for a randomised controlled trial. AB - INTRODUCTION: Hip arthroscopy has become a standard procedure in the treatment of hip joint pain not related to osteoarthritis or dysplasia in the young and active patient. There has been increasing focus on the contribution of the hip capsule to function and on stability following hip arthroscopy. It has been suggested that capsular closure after hip arthroscopy may prevent microinstability and macroinstability of the hip joint and reduce revision rate. However, it remains unknown whether capsular closure should be performed as a standard procedure when performing hip arthroscopies, especially in patients without additional risk factors for instability such as hypermobility or dysplasia of the hip. We hypothesised that capsular closure will lead to a superior outcome in hip arthroscopy for femoroacetabular impingement syndrome (FAIS) compared with non capsular closure. METHODS AND ANALYSIS: In this randomised controlled, multicentre trial, 200 patients scheduled for hip arthroscopy for FAIS will be cluster randomised into one of two groups (group I: hip arthroscopy without capsular closure, group II: hip arthroscopy combined with capsular closure). Inclusion criteria are: age between 18 years and 50 years and FAIS according to the Warwick agreement. Exclusion criteria are: previous hip surgery in either hip, previous conditions of Legg-Calve-Perthes or slipped capital femoral epiphysis, malignant disease, recent hip or pelvic fractures, arthritis, Ehlers Danlos or Marfan disease, recent (within 6 weeks) application of intra-articular corticosteroids, language problems of any kind, and radiological signs of osteoarthritis, acetabular dysplasia or acetabular retroversion. Surgery will be performed in Denmark at four centres by four surgeons, all performing an interportal capsulotomy and closure with at least two absorbable sutures. Patients in both groups, who are blinded for the intervention, will receive the same standardised rehabilitation programme. As primary outcome scores, HAGOS (sport) will be used with HAGOS (symptoms, pain, function in daily living, participation in physical activities and hip and/or groin-related quality of life), Hip Sports Activity Scale, short validated version of the International Hip Outcome Tool, EQ-5D, Visual Analogue Scale for pain, complications and reoperation rate as secondary outcome tools. Using HAGOS (sport) as primary outcome parameter the power analysis required a minimum of 84 individuals per group. Together with a clinical examination performed by the patient's surgeon 1 year after surgery, patient reported outcome measures will be completed preoperatively, as well as at 3 months, 1 year, 2 years and 5 years postoperatively. In addition, adverse effects will be recorded. ETHICS AND DISSEMINATION: The study is approved by the Central Denmark Region Committee on Biomedical research ethics. The results of this study will be presented at national and international congresses and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03158454; Pre-results. PMID- 29440160 TI - Interventions to increase access to or uptake of physical health screening in people with severe mental illness: a realist review. AB - OBJECTIVES: To identify and evaluate interventions aimed at increasing uptake of, or access to, physical health screening by adults with severe mental illness; to examine why interventions might work. DESIGN: Realist review. SETTING: Primary, secondary and tertiary care. RESULTS: A systematic search identified 1448 studies, of which 22 met the inclusion criteria. Studies were from Australia (n=3), Canada (n=1), Hong Kong (n=1), UK (n=11) and USA (n=6). The studies focused on breast cancer screening, infection preventive services and metabolic syndrome (MS) screening by targeting MS-related risk factors. The interventions could be divided into those focusing on (1) health service delivery changes (12 studies), using quality improvement, randomised controlled trial, cluster randomised feasibility trial, retrospective audit, cross-sectional study and satisfaction survey designs and (2) tests of tools designed to facilitate screening (10 studies) using consecutive case series, quality improvement, retrospective evaluation and pre-post audit study designs. All studies reported improved uptake of screening, or that patients had received screening they would not have had without the intervention. No estimation of overall effect size was possible due to heterogeneity in study design and quality. The following factors may contribute to intervention success: staff and stakeholder involvement in screening, staff flexibility when taking physical measurements (eg, using adapted equipment), strong links with primary care and having a pharmacist on the ward. CONCLUSIONS: A range of interventions may be effective, but better quality research is needed to determine any effect size. Researchers should consider how interventions may work when designing and testing them in order to target better the specific needs of this population in the most appropriate setting. Behaviour change interventions to reduce identified barriers of patient and health professional resistance to screening this population are required. Resource constraints, clarity over professional roles and better coordination with primary care need to be addressed. PMID- 29440162 TI - Sequelae of multidrug-resistant tuberculosis: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: The sequelae of multidrug-resistant tuberculosis (MDR-TB) are poorly understood and inconsistently reported. We will aim to assess the existing evidence for the clinical, psychological, social and economic sequelae of MDR-TB and to assess the health-related quality of life in patients with MDR-TB. METHODS AND ANALYSIS: We will perform a systematic review and meta-analysis of published studies reporting sequelae of MDR-TB. We will search PubMed, SCOPUS, ProQuest, Web of Science and PsychINFO databases up to 5 September 2017. MDR-TB sequelae will include any clinical, psychological, social and economic effects as well as health-related quality of life that occur after MDR-TB treatment or illness. Two researchers will screen the titles and abstracts of all citations identified in our search, extract data, and assess the scientific quality using standardised formats. Providing there is appropriate comparability in the studies, we will use a random-effects meta-analysis model to produce pooled estimates of MDR-TB sequelae from the included studies. We will stratify the analyses based on treatment regimen, comorbidities (such as HIV status and diabetes mellitus), previous TB treatment history and study setting. ETHICS AND DISSEMINATION: As this study will be based on published data, ethical approval is not required. The final report will be disseminated through publication in a peer-reviewed scientific journal and will also be presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42017073182. PMID- 29440161 TI - Clinician, patient and general public beliefs about diagnostic imaging for low back pain: protocol for a qualitative evidence synthesis. AB - INTRODUCTION: Little is known about how to reduce unnecessary imaging for low back pain. Understanding clinician, patient and general public beliefs about imaging is critical to developing strategies to reduce overuse. OBJECTIVE: To synthesise qualitative research that has explored clinician, patient or general public beliefs about diagnostic imaging for low back pain. METHODS AND ANALYSIS: We will perform a qualitative evidence synthesis of relevant qualitative research exploring clinician, patient and general public beliefs about diagnostic imaging for low back pain. Exclusions will be studies not using qualitative methods and studies not published in English. Studies will be identified using sensitive search strategies in MEDLINE, EMBASE, CINAHL, AMED and PsycINFO. Two reviewers will independently apply inclusion and exclusion criteria, extract data, and use the Critical Appraisal Skills Programme quality assessment tool to assess the quality of included studies. To synthesise the data we will use a narrative synthesis approach that involves developing a theoretical model, conducting a preliminary synthesis, exploring relations in the data, and providing a structured summary. We will code the data using NVivo. At least two reviewers will independently apply the thematic framework to extracted data. Confidence in synthesis findings will be evaluated using the GRADE Confidence in the Evidence from Reviews of Qualitative Research tool. ETHICS AND DISSEMINATION: Ethical approval is not required to conduct this review. We will publish the results in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42017076047. PMID- 29440163 TI - Severity and management of postabortion complications among women in Zimbabwe, 2016: a cross-sectional study. AB - OBJECTIVES: Abortion complications cause significant morbidity and mortality. We aimed to assess the severity and factors associated with abortion complications (induced or spontaneous), and the management of postabortion care (PAC) in Zimbabwe. DESIGN: Prospective, facility-based 28 day survey among women seeking PAC and their providers. SETTING: 127 facilities in Zimbabwe with the capacity to provide PAC, including all central and provincial hospitals, and a sample of primary health centres (30%), district/general/mission hospitals (52%), private (77%) and non-governmental organisation (NGO) (68%) facilities. PARTICIPANTS: 1002 women presenting with abortion complications during the study period. MAIN OUTCOME MEASURES: Severity of abortion complications and associated factors, delays in care seeking, and clinical management of complications. RESULTS: Overall, 59% of women had complications classified as mild, 19% as moderate, 19% as severe, 3% as near miss and 0.2% died. A median of 47 hours elapsed between experiencing complication and receiving treatment; many delays were due to a lack of finances. Women who were rural, younger, not in union, less educated, at later gestational ages or who had more children were significantly more likely to have higher severity complications. Most women were treated by doctors (91%). The main management procedure used was dilatation and curettage/dilatation and evacuation (75%), while 12% had manual vacuum aspiration (MVA) or electrical vacuum aspiration and 11% were managed with misoprostol. At discharge, providers reported that 43% of women received modern contraception. CONCLUSION: Zimbabwean women experience considerable abortion-related morbidity, particularly young, rural or less educated women. Abortion-related morbidity and concomitant mortality could be reduced in Zimbabwe by liberalising the abortion law, providing PAC in primary health centres, and training nurses to use medical evacuation with misoprostol and MVA. Regular in-service training on PAC guidelines with follow-up audits are needed to ensure compliance and availability of equipment, supplies and trained staff. PMID- 29440165 TI - Correction: Bluebelle study (phase A): a mixed-methods feasibility study to inform an RCT of surgical wound dressing strategies. PMID- 29440166 TI - Correction: Epidural analgesia in critically ill patients with acute pancreatitis: the multicentre randomised controlled EPIPAN study protocol. PMID- 29440167 TI - Correction: Study protocol for a randomised controlled trial: harmonising optimal strategy for treatment of coronary artery stenosis - coronary intervention with next-generation drug-eluting stent platforms and abbreviated dual antiplatelet therapy (HOST-IDEA) trial. PMID- 29440164 TI - Standard echocardiography versus handheld echocardiography for the detection of subclinical rheumatic heart disease: protocol for a systematic review. AB - INTRODUCTION: Rheumatic heart disease (RHD) is a preventable and treatable chronic condition which persists in many developing countries largely affecting impoverished populations. Handheld echocardiography presents an opportunity to address the need for more cost-effective methods of diagnosing RHD in developing countries, where the disease continues to carry high rates of morbidity and mortality. Preliminary studies have demonstrated moderate sensitivity as well as high specificity and diagnostic odds for detecting RHD in asymptomatic patients. We describe a protocol for a systematic review on the diagnostic performance of handheld echocardiography compared to standard echocardiography using the 2012 World Heart Federation criteria for diagnosing subclinical RHD. METHODS AND ANALYSIS: Electronic databases including PubMed, Scopus, Web of Science and EBSCOhost as well as reference lists and citations of relevant articles will be searched from 2012 to date using a predefined strategy incorporating a combination of Medical Subject Heading terms and keywords. The methodological validity and quality of studies deemed eligible for inclusion will be assessed against review specific Quality Assessment of Diagnostic Accuracy Studies 2 criteria and information on metrics of diagnostic accuracy and demographics extracted. Forest plots of sensitivity and specificity as well as scatter plots in receiver operating characteristic (ROC) space will be used to investigate heterogeneity. If possible, a meta-analysis will be conducted to produce summary results of sensitivity and specificity using the Hierarchical Summary ROC method. In addition, a sensitivity analysis will be conducted to investigate the effect of studies with a high risk of bias. ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review of previously published literature. The planned review will provide a summary of the diagnostic accuracy of handheld echocardiography. Results may feed into evidence-based guidelines and should the findings of this review warrant a change in clinical practice, a summary report will be disseminated among leading clinicians and healthcare professionals in the field. PROSPERO REGISTRATION NUMBER: CRD42016051261. PMID- 29440168 TI - FOXO Transcription Factors Both Suppress and Support Breast Cancer Progression. AB - FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function include proliferation, survival, redox homeostasis, and PI3K signaling, all of which must be carefully balanced for tumor cells to thrive.Significance: FOXO proteins are not solely tumor suppressors, but also support tumor growth and metastasis by regulating a multitude of cellular processes essential for tumorigenesis. Cancer Res; 78(9); 2356-69. (c)2018 AACR. PMID- 29440169 TI - Oncogenic Kinase-Induced PKM2 Tyrosine 105 Phosphorylation Converts Nononcogenic PKM2 to a Tumor Promoter and Induces Cancer Stem-like Cells. AB - The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Because oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas nonphosphorylated PKM2 is nononcogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed nontumorigenic tetramers in nontransformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phosphomimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem-like cell population by increasing Yes-associated protein (YAP) nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem-like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem-like cell properties.Significance: These findings reveal PKM2 promotes tumorigenesis by inducing cancer stem-like cell properties and clarify the paradox of PKM2's dichotomous functions in tumor progression. Cancer Res; 78(9); 2248-61. (c)2018 AACR. PMID- 29440170 TI - RSK Regulates PFK-2 Activity to Promote Metabolic Rewiring in Melanoma. AB - Metabolic reprogramming is a hallmark of cancer that includes increased glucose uptake and accelerated aerobic glycolysis. This phenotype is required to fulfill anabolic demands associated with aberrant cell proliferation and is often mediated by oncogenic drivers such as activated BRAF. In this study, we show that the MAPK-activated p90 ribosomal S6 kinase (RSK) is necessary to maintain glycolytic metabolism in BRAF-mutated melanoma cells. RSK directly phosphorylated the regulatory domain of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), an enzyme that catalyzes the synthesis of fructose-2,6-bisphosphate during glycolysis. Inhibition of RSK reduced PFKFB2 activity and glycolytic flux in melanoma cells, suggesting an important role for RSK in BRAF-mediated metabolic rewiring. Consistent with this, expression of a phosphorylation deficient mutant of PFKFB2 decreased aerobic glycolysis and reduced the growth of melanoma in mice. Together, these results indicate that RSK-mediated phosphorylation of PFKFB2 plays a key role in the metabolism and growth of BRAF mutated melanomas.Significance: RSK promotes glycolytic metabolism and the growth of BRAF-mutated melanoma by driving phosphorylation of an important glycolytic enzyme. Cancer Res; 78(9); 2191-204. (c)2018 AACR. PMID- 29440171 TI - Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer. AB - Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors.Significance: These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. Cancer Res; 78(9); 2383-95. (c)2018 AACR. PMID- 29440173 TI - Canine Research to Benefit Humans and Dogs Alike. AB - The Jackson Laboratory recently launched the Tallwood Canine Cancer Research Initiative, in which tumor samples from dogs will be collected to create patient derived xenografts in mice. These models, and their accompanying genome sequences, can then be shared with researchers around the world. The initiative's goal is to learn more about the biology of human cancers through comparative genomic analyses. PMID- 29440172 TI - A Distinct Oncogenerative Multinucleated Cancer Cell Serves as a Source of Stemness and Tumor Heterogeneity. AB - The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiologic stemness of the resulting cell populations. Here, we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy refractory ovarian tumors, which generate and gestate daughter generation Gn cells intracytoplasmically. Release of Gn cells occurred by ejection through crevices in the P1 cell membrane by body contractions or using a funiculus-like structure. These events characterized a not yet described mechanism of cell segregation. Maternal P1 cells were principally capable of surviving parturition events and continued to breed and nurture Gn progenies. In addition, P1 cells were competent to horizontally transmit offspring Gn cells into other specific proximal cells, injecting them to receptor R1 cells via cell-cell tunneling. This process represents a new mechanism used by tumor cells to invade surrounding tissues and ensure life cycles. In contrast to the pregnant P1 cells with low expression of stem cell markers despite their physiologic stemness, the first offspring generations of daughter G1 cells expressed high levels of ovarian cancer stem cell markers. Furthermore, both P1 and Gn cells overexpressed multiple human endogenous retroviral envelope proteins. Moreover, programmed death-ligand 1 and the immunosuppressive domain of the retroviral envelope proteins were also overexpressed in P1 cells, suggesting effective protection against the host immune system. Together, our data suggest that P1 oncogenerative cancer cells exhibit a not yet described cell biological mechanism of persistence and transmission of malignant cells in patients with advanced cancers.Significance: P1 oncogenerative cell entities express low levels of CSC markers, which are characteristic of their histological origin. Cancer Res; 78(9); 2318-31. (c)2018 AACR. PMID- 29440174 TI - Platelets Enhance Multiple Myeloma Progression via IL-1beta Upregulation. AB - Purpose: Tumor cell-platelet interactions contribute to tumor progression and metastasis in solid tumors. However, the role of platelets in hematological malignancies is not clear. We investigated the association of platelet activation status with clinical stages in multiple myeloma (MM) patients and explored the role of platelets in MM progression.Experimental Design: Platelets were obtained from healthy donors and MM patients. We examined platelet activation status in MM patients by flow cytometry and transmission electron microscopy. We also observed the enriched pathways that are involved with platelet activation in RNA sequencing of platelets. MM cell lines were used to assess the effect of platelets on MM cell proliferation in vitro and their engraftment in vivo RNA sequencing of MM cell lines was performed to explore molecular mechanisms underlying MM cell-platelet interaction and a CRISPR/Cas9 knockout approach was used for validation.Results: Platelets from MM patients were highly activated with disease progression. RNA sequencing of platelets revealed that genes involved in platelets were enriched in patients with smoldering MM (SMM) or MM. Platelets promoted MM cell proliferation in vitro and contributed to tumor engraftment in bone marrow in vivo RNA sequencing revealed that IL-1beta was upregulated in MM cell lines co-cultured with platelets, whereas IL-1beta knockout in MM cell lines abrogated the effects of platelets on MM cell proliferation and engraftment in vivoConclusions: Platelets from MM patients were highly activated with disease progression. IL-1beta is critical to platelet mediated MM progression and might be a potential target for MM treatment. Clin Cancer Res; 24(10); 2430-9. (c)2018 AACR. PMID- 29440176 TI - Targeting HSF1: A Prime Integrator of Proteotoxic Stress Response in Myeloma. AB - The HSF1 transcription factor is an integrator of the cellular stress response, and its expression has demonstrated poor prognosis in multiple myeloma. The novel anti-HSF1 small-molecule inhibitors CCT251236 and KRIB11 demonstrate in vitro and in vivo antimyeloma activity, representing a novel approach for targeting the heat shock response in myeloma. Clin Cancer Res; 24(10); 2237-8. (c)2018 AACRSee related article by Fok et al., p. 2395. PMID- 29440175 TI - Pan-Cancer Molecular Classes Transcending Tumor Lineage Across 32 Cancer Types, Multiple Data Platforms, and over 10,000 Cases. AB - Purpose: The Cancer Genome Atlas data resources represent an opportunity to explore commonalities across cancer types involving multiple molecular levels, but tumor lineage and histology can represent a barrier in moving beyond differences related to cancer type.Experimental Design: On the basis of gene expression data, we classified 10,224 cancers, representing 32 major types, into 10 molecular-based "classes." Molecular patterns representing tissue or histologic dominant effects were first removed computationally, with the resulting classes representing emergent themes across tumor lineages.Results: Key differences involving mRNAs, miRNAs, proteins, and DNA methylation underscored the pan-cancer classes. One class expressing neuroendocrine and cancer-testis antigen markers represented ~4% of cancers surveyed. Basal-like breast cancers segregated into an exclusive class, distinct from all other cancers. Immune checkpoint pathway markers and molecular signatures of immune infiltrates were most strongly manifested within a class representing ~13% of cancers. Pathway level differences involving hypoxia, NRF2-ARE, Wnt, and Notch were manifested in two additional classes enriched for mesenchymal markers and miR200 silencing.Conclusions: All pan-cancer molecular classes uncovered here, with the important exception of the basal-like breast cancer class, involve a wide range of cancer types and would facilitate understanding the molecular underpinnings of cancers beyond tissue-oriented domains. Numerous biological processes associated with cancer in the laboratory setting were found here to be coordinately manifested across large subsets of human cancers. The number of cancers manifesting features of neuroendocrine tumors may be much higher than previously thought, which disease is known to occur in many different tissues. Clin Cancer Res; 24(9); 2182-93. (c)2018 AACR. PMID- 29440177 TI - Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition. AB - Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT.Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT.Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%.Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932-43. (c)2018 AACR. PMID- 29440178 TI - Evaluation of Alteration in Hepatic and Intestinal BCRP Function In Vivo from ABCG2 c.421C>A Polymorphism Based on PBPK Analysis of Rosuvastatin. AB - Polymorphism c.421C>A in the ABCG2 gene is thought to reduce the activity of breast cancer resistance protein (BCRP), a xenobiotic transporter, although it is not clear which organ(s) contributes to the polymorphism-associated pharmacokinetic change. The aim of the present study was to estimate quantitatively the influence of c.421C>A on intestinal and hepatic BCRP activity using a physiologically based pharmacokinetic (PBPK) model of rosuvastatin developed from clinical data and several in vitro studies. Simultaneous fitting of clinical data for orally and intravenously administered rosuvastatin, obtained in human subjects without genotype information, was first performed with the PBPK model to estimate intrinsic clearance for hepatic elementary process. The fraction of BCRP activity in 421CA and 421AA (fca and faa values, respectively) with respect to that in 421CC subjects was then estimated based on extended clearance concepts and simultaneous fitting to oral administration data for the three genotypes (421CC, 421CA, and 421AA). On the assumption that c.421C>A affects both intestinal and hepatic BCRP, clinical data in each genotype were well reproduced by the model, and the estimated terminal half-life was compatible with the observed values. The assumption that c.421C>A affects only either intestinal or hepatic BCRP gave poorer agreement with observed values. The faa values obtained on the former assumption were 0.48-0.54. Thus, PBPK model analysis enabled quantitative evaluation of alteration in BCRP activity owing to c.421C>A, and BCRP activity in 421AA was estimated as half that in 421CC. PMID- 29440181 TI - A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2- Advanced Breast Cancer. AB - Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERalpha) and a potent and selective antagonist and degrader of ERalpha. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity.Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion "rolling 6" design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade >=3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up.Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER+/HER2- advanced breast cancer. Clin Cancer Res; 24(15); 3510-8. (c)2018 AACRSee related commentary by Jordan, p. 3480. PMID- 29440182 TI - Shedding Light on IDH1 Mutation in Gliomas. AB - IDH mutation is of central importance in the diagnosis and treatment of gliomas. Fourier-transform infrared spectroscopy, in combination with a supervised machine learning approach, can be used to detect metabolic alterations induced by IDH1 mutations in a fraction of the time of conventional techniques. Clin Cancer Res; 24(11); 2467-9. (c)2018 AACRSee related article by Uckermann et al., p. 2530. PMID- 29440179 TI - Role of c-Jun-N-Terminal Kinase in Pregnane X Receptor-Mediated Induction of Human Cytochrome P4503A4 In Vitro. AB - Cytochrome P450 CYP3A4 is the most abundant drug-metabolizing enzyme and is responsible for the metabolism of ~50% of clinically available drugs. Induction of CYP3A4 impacts the disposition of its substrates and leads to harmful clinical consequences, such as failure of therapy. To prevent such undesirable consequences, the molecular mechanisms of regulation of CYP3A4 need to be fully understood. CYP3A4 induction is regulated primarily by the xenobiotic nuclear receptor pregnane-X receptor (PXR). After ligand binding, PXR is translocated to the nucleus, where it binds to the CYP3A4 promoter and induces its gene expression. PXR function is modulated by phosphorylation(s) by multiple kinases. In this study, we determined the role of the c-Jun N-terminal kinase (JNK) in PXR mediated induction of CYP3A4 enzyme in vitro. Human liver carcinoma cells (HepG2) were transfected with CYP3A4 luciferase and PXR plasmids, followed by treatment with JNK inhibitor (SP600125; SP) and PXR activators rifampicin (RIF) or hyperforin. Our results indicate that SP treatment significantly attenuated PXR mediated induction of CYP3A4 reporter activity, as well as gene expression and enzyme activity. JNK knockdown by siRNA (targeting both JNK 1 and 2) also attenuated CYP3A4 induction by RIF. Interestingly, SP treatment attenuated JNK activation by RIF. Furthermore, treatment with RIF increased PXR nuclear levels and binding to the CYP3A4 promoter; SP attenuated these effects. This study shows that JNK is a novel mechanistic regulator of CYP3A4 induction by PXR. PMID- 29440180 TI - Resistance-promoting effects of ependymoma treatment revealed through genomic analysis of multiple recurrences in a single patient. AB - As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pregenomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies. A combination of high-depth whole-genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were used. Treatment with radiation and chemotherapies resulted in a substantial increase in mutational burden and diversification of the tumor subclonal architecture without eradication of the founding clone. Notable somatic alterations included a MEN1 driver, several epigenetic modifiers, and therapy-induced mutations that impacted multiple other cancer-relevant pathways and altered the neoantigen landscape. These genomic data provided new mechanistic insights into the genesis of ependymoma and pathways of resistance. They also revealed that radiation and chemotherapy were significant forces in shaping the increased subclonal complexity of each tumor recurrence while also failing to eradicate the founding clone. This raises the question of whether standard-of-care treatments have similar consequences in other patients with ependymoma and other types of brain tumors. If so, the perspective obtained by real-time genomic characterization of a tumor may be essential for making effective patient-specific and adaptive clinical decisions. PMID- 29440184 TI - Household air pollution and measures of blood pressure, arterial stiffness and central haemodynamics. AB - OBJECTIVE: We evaluated the exposure-response associations between personal exposure to air pollution from biomass stoves and multiple vascular and haemodynamic parameters in rural Chinese women. METHODS: We analysed the baseline information from a longitudinal study in southwestern China. Women's brachial and central blood pressure and pulse pressure, carotid-femoral pulse wave velocity and augmentation index, and their 48-hour personal exposures to fine particulate matter (PM2.5) and black carbon were measured in summer and winter. We evaluated the associations between exposure to air pollution and haemodynamic parameters using mixed-effects regression models adjusted for known cardiovascular risk factors. RESULTS: Women's (n=205, ages 27-86 years) exposures to PM2.5 and black carbon ranged from 14 ug/m3 to 1405 ug/m3 and 0.1-121.8 ug/m3, respectively. Among women aged >=50 years, increased PM2.5 exposure was associated with higher systolic (brachial: 3.5 mm Hg (P=0.05); central: 4.4 mm Hg (P=0.005)) and diastolic blood pressure (central: 1.3 mm Hg (P=0.10)), higher pulse pressure (peripheral: 2.5 mm Hg (P=0.05); central: 2.9 mm Hg (P=0.008)) and lower peripheral-central pulse pressure amplification (-0.007 (P=0.04)). Among younger women, the associations were inconsistent in the direction of effect and not statistically significant. Increased PM2.5 exposure was associated with no difference in pulse wave velocity and modestly higher augmentation index though the CI included zero (1.1%; 95% CI -0.2% to 2.4%). Similar associations were found for black carbon exposure. CONCLUSIONS: Exposure to household air pollution was associated with higher blood pressure and central haemodynamics in older Chinese women, with no associations observed with pulse wave velocity. PMID- 29440183 TI - Ambulatory blood pressure and long-term risk for atrial fibrillation. AB - OBJECTIVE: Data on the contribution of ambulatory blood pressure (ABP) components to the risk of developing atrial fibrillation (AF) are limited. We prospectively tested the hypothesis that ABP may represent a potentially modifiable risk factor for the development of AF in a European population study. METHODS: We recorded daytime blood pressure (BP) in 3956 subjects randomly recruited from the general population in five European countries. Of these participants, 2776 (70.2%) underwent complete 24-hour ABP monitoring. Median follow-up was 14 years. We defined daytime systolic BP load as the percentage BP readings above 135 mm Hg. The incidence of AF was assessed from ECGs obtained at baseline and follow-up and from records held by general practitioners and/or hospitals. RESULTS: Overall, during 58 810 person-years of follow-up, 143 participants experienced new-onset AF. In adjusted Cox models, each SD increase in baseline 24 hours, daytime and night-time systolic BP was associated with a 27% (P=0.0056), 22% (P=0.023) and 20% (P=0.029) increase in the risk for incident AF, respectively. Conventional systolic BP was borderline associated with the risk of AF (18%; P=0.06). As compared with the average population risk, participants in the lower quartile of daytime systolic BP load (<3%) had a 51% (P=0.0038) lower hazard for incident AF, whereas in the upper quartile (>38%), the risk was 46% higher (P=0.0094). CONCLUSIONS: Systolic ABP is a significant predictor of incident AF in a population-based cohort. We also observed that participants with a daytime systolic BP load >38% had significantly increased risk of incident AF. PMID- 29440185 TI - Differing associations for sport versus occupational physical activity and cardiovascular risk. AB - OBJECTIVES: We investigate the independent and interacting long-term associations of occupational physical activity (OPA) and sport physical activity (SpPA) with the incidence of coronary heart disease (CHD) and cardiovascular diseases (CVD; CHD plus ischaemic stroke) in North Italian male workers. METHODS: 3574 employed men aged 25-64 years, free of CVD at baseline, recruited in three population based and one factory-based cohorts, were included in the analysis. The Baecke Questionnaire was used to assess OPA and SpPA in 'minutes per week' of moderate or vigorous PA. We estimated the associations between different domains of PA and the endpoints, adjusting for major CVD risk factors, using Cox models. RESULTS: During a median follow-up of 14 years, 135 and 174 first CHD and CVD events, fatal and non-fatal, occurred. Compared with the intermediate OPA tertile, the HRs for CHD among low and high OPA workers were 1.66 (95% CI 1.06 to 2.59) and 1.18 (0.72 to 1.94), respectively (P value=0.07). Decreasing trends in CHD and CVD rates across increasing levels of SpPA were also found, with an HR for CVD of 0.68 (0.46 to 0.98) for intermediate/recommended SpPA compared with poor SpPA. We also found a statistically significant SpPA-OPA interaction, and the protective effect of SpPA was only found among sedentary workers, for both endpoints. Conversely, high OPA workers with intermediate/recommended SpPA levels had increased CHD and CVD rates compared with the poor SpPA category. CONCLUSIONS: Our results provide further evidence on the health paradox of OPA, with higher CVD rates among workers with intense PA at work. Moreover, the protective effect on CVDs of SpPA is prominent in sedentary workers, but it attenuates and even reverses in moderate and strenuous OPA workers. PMID- 29440186 TI - Long-Term Outcome of Substrate Modification in Ablation of Post-Myocardial Infarction Ventricular Tachycardia. AB - BACKGROUND: Long-term results of substrate modification for ablation of ventricular tachycardia (VT) have not been reported. We report long-term outcomes of substrate elimination targeting local abnormal ventricular activities (LAVA) for post-myocardial infarction VT. METHODS AND RESULTS: One hundred fifty-nine consecutive patients undergoing first ablation were included (65+/-11 years, 92% implantable cardioverter defibrillators, 54% storms, and 73% appropriate shocks). LAVA were identified in 92% and VT was inducible in 73%. Complete LAVA elimination and noninducibility after ablation were achieved in 64% and 85%. During a median follow-up of 47 months (interquartile range, 34-82), single procedure ventricular arrhythmia (VA)-free survival was 55% (10% storms and 19% shocks). The VA-free survival was 73%, 68%, 61%, 55%, and 49% after 1, 2, 3, 4, and 5 years, respectively. Complete LAVA elimination was associated with improved outcomes: VA-free survival of 82% at 1 year and 61% at 5 years. In the subgroup treated with multielectrode mapping and real-time image integration, VA-free survival was 86% and 65% at 1 year and 4 years, respectively. Including repeat procedures in 18% of pts (1.3+/-0.6 ablations/pt) outcomes improved to 69% VA free survival (2% storms and 9% shocks) during median 46-month follow-up. Overall survival was 91% at 1 year and 77% at 5 years of follow-up. CONCLUSIONS: In this monocentric study, substrate modification targeting LAVA for post-myocardial infarction VT resulted in a substantial reduction of VT storm and implantable cardioverter defibrillator shocks and up to 49% of patients free from arrhythmia at 5 years after a single procedure. Complete LAVA elimination, multielectrode mapping, and real-time integration were associated with improved VA-free survival. PMID- 29440188 TI - February 12th Question. PMID- 29440187 TI - Repolarization Heterogeneity Measured With T-Wave Area Dispersion in Standard 12 Lead ECG Predicts Sudden Cardiac Death in General Population. AB - BACKGROUND: We developed a novel electrocardiographic marker, T-wave area dispersion (TW-Ad), which measures repolarization heterogeneity by assessing interlead T-wave areas during a single cardiac cycle and tested whether it can identify patients at risk for sudden cardiac death (SCD) in the general population. METHODS AND RESULTS: TW-Ad was measured from standard digital 12-lead ECG in 5618 adults (46% men; age, 50.9+/-12.5 years) participating in the Health 2000 Study-an epidemiological survey representative of the Finnish adult population. Independent replication was performed in 3831 participants of the KORA S4 Study (Cooperative Health Research in the Region of Augsburg; 49% men; age, 48.7+/-13.7 years; mean follow-up, 8.8+/-1.1 years). During follow-up (7.7+/ 1.4 years), 72 SCDs occurred in the Health 2000 Survey. Lower TW-Ad was univariately associated with SCD (0.32+/-0.36 versus 0.60+/-0.19; P<0.001); it had an area under the receiver operating characteristic curve of 0.809. TW-Ad (<=0.46) conferred a hazard ratio of 10.8 (95% confidence interval, 6.8-17.4; P<0.001) for SCD; it remained independently predictive of SCD after multivariable adjustment for clinical risk markers (hazard ratio, 4.6; 95% confidence interval, 2.7-7.4; P<0.001). Replication analyses performed in the KORA S4 Study confirmed an increased risk for cardiac death (unadjusted hazard ratio, 5.5; 95% confidence interval, 3.2-9.5; P<0.001; multivariable adjusted hazard ratio, 1.9; 95% confidence interval, 1.1-3.5; P<0.05). CONCLUSION: Low TW-Ad, reflecting increased heterogeneity of repolarization, in standard 12-lead resting ECGs is a powerful and independent predictor of SCD in the adult general population. PMID- 29440189 TI - Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal? AB - Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints. Clin Cancer Res; 24(10); 2239 40. (c)2018 AACRSee related article by Mushti et al., p. 2268. PMID- 29440190 TI - A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma. AB - Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1 Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age dependence and predilection of RMC toward the right kidney.Significance: This perspective proposes an integrated and testable model of renal medullary carcinoma pathogenesis. Insights provided by this model can additionally inform other malignancies arising from the renal medulla and/or associated with loss of the SMARCB1 tumor suppressor gene. Clin Cancer Res; 24(9); 2044-9. (c)2018 AACR. PMID- 29440193 TI - American Heart Association Precision Medicine Platform. PMID- 29440194 TI - Upper Limits of Aerobic Power and Performance in Heart Transplant Recipients: Legacy Effect of Prior Endurance Training. PMID- 29440191 TI - Torso-Like Is a Component of the Hemolymph and Regulates the Insulin Signaling Pathway in Drosophila. AB - In Drosophila, key developmental transitions are governed by the steroid hormone ecdysone. A number of neuropeptide-activated signaling pathways control ecdysone production in response to environmental signals, including the insulin signaling pathway, which regulates ecdysone production in response to nutrition. Here, we find that the Membrane Attack Complex/Perforin-like protein Torso-like, best characterized for its role in activating the Torso receptor tyrosine kinase in early embryo patterning, also regulates the insulin signaling pathway in Drosophila We previously reported that the small body size and developmental delay phenotypes of torso-like null mutants resemble those observed when insulin signaling is reduced. Here we report that, in addition to growth defects, torso like mutants also display metabolic and nutritional plasticity phenotypes characteristic of mutants with impaired insulin signaling. We further find that in the absence of torso-like, the expression of insulin-like peptides is increased, as is their accumulation in insulin-producing cells. Finally, we show that Torso-like is a component of the hemolymph and that it is required in the prothoracic gland to control developmental timing and body size. Taken together, our data suggest that the secretion of Torso-like from the prothoracic gland influences the activity of insulin signaling throughout the body in Drosophila. PMID- 29440192 TI - Impact of anticoagulation therapy on valve haemodynamic deterioration following transcatheter aortic valve replacement. AB - OBJECTIVE: To evaluate the changes in transvalvular gradients and the incidence of valve haemodynamic deterioration (VHD) following transcatheter aortic valve replacement (TAVR), according to use of anticoagulation therapy. METHODS AND RESULTS: This multicentre study included 2466 patients (46% men; mean age 81+/-7 years) who underwent TAVR with echocardiography performed at 12-month follow-up. Anticoagulation therapy was used in 707 patients (28.7%) following TAVR (AC group). A total of 663 patients received vitamin K antagonists, and 44 patients received direct oral anticoagulants. A propensity score matching analysis was performed to adjust for intergroup (AC vs non-AC post-TAVR) differences. A total of 622 patients per group were included in the propensity-matched analysis. VHD was defined as a >=10 mm Hg increase in the mean transprosthetic gradient at follow-up (vs hospital discharge). The mean clinical follow-up was 29+/-18 months. The mean transvalvular gradient significantly increased at follow-up in the non-AC group within the global cohort (P=0.003), whereas it remained stable over time in the AC group (P=0.323). The incidence of VHD was significantly lower in the AC group (0.6%) compared with the non-AC group (3.7%, P<0.001), and these significant differences remained within the propensity-matched populations (0.6% vs 3.9% in the AC and non-AC groups, respectively, P<0.001). The occurrence of VHD did not associate with an increased risk of all-cause death (P=0.468), cardiovascular death (P=0.539) or stroke (P=0.170) at follow-up. CONCLUSIONS: The lack of anticoagulation therapy post-TAVR was associated with significant increments in transvalvular gradients and a greater risk of VHD. VHD was subclinical in most cases and did not associate with major adverse clinical events. Future randomised trials are needed to determine if systematic anticoagulation therapy post-TAVR would reduce the incidence of VHD. PMID- 29440195 TI - Hypertension, Genes, and Environment: Challenges for Prevention and Risk Prediction. PMID- 29440196 TI - Coronary Artery Calcium: If Measuring Once Is Good, Is Twice Better? PMID- 29440197 TI - Assessing Prognosis of Pulmonary Arterial Hypertension in the Therapeutic Era: Importance of Serial Hemodynamic Measurements. PMID- 29440198 TI - Developing a Clinical Approach to Air Pollution and Cardiovascular Health. AB - Nearly 3 billion people are exposed to household air pollution emitted from inefficient cooking and heating stoves, and almost the entire global population is exposed to detectable levels of outdoor air pollution from traffic, industry, and other sources. Over 3 million people die annually of ischemic heart disease or stroke attributed to air pollution, more than from traditional cardiac risk factors such as obesity, diabetes mellitus, or smoking. Clinicians have a role to play in reducing the burden of pollution-attributable cardiovascular disease. However, there currently exists no clear clinical approach to this problem. Here, we provide a blueprint for an evidence-based clinical approach to assessing and mitigating cardiovascular risk from exposure to air pollution. We begin with a discussion of the global burden of pollution-attributable cardiovascular disease, including a review of the mechanisms by which particulate matter air pollution leads to cardiovascular outcomes. Next, we offer a simple patient-screening tool using known risk factors for pollution exposure. We then discuss approaches to quantifying air pollution exposures and cardiovascular risk, including the development of risk maps for clinical catchment areas. We review a collection of interventions for household and outdoor air pollution, which clinicians can tailor to patients and populations at risk. Finally, we identify future research needed to quantify pollution exposures and validate clinical interventions. Overall, we demonstrate that clinicians can be empowered to mitigate the global burden of cardiovascular disease attributable to air pollution. PMID- 29440199 TI - Broad... Narrow... Broad QRS Tachycardia. PMID- 29440200 TI - Impact of Coronary Remodeling on Fractional Flow Reserve. PMID- 29440202 TI - Letter by Jin-shan and Xue-bin Regarding Article, "Physiology of Angina and Its Alleviation With Nitroglycerin: Insights From Invasive Catheter Laboratory Measurements During Exercise". PMID- 29440201 TI - Proefferocytic Therapy Promotes Transforming Growth Factor-beta Signaling and Prevents Aneurysm Formation. PMID- 29440203 TI - Response by Asrress et al to Letter Regarding Article, "Physiology of Angina and Its Alleviation With Nitroglycerin: Insights From Invasive Catheter Laboratory Measurements During Exercise". PMID- 29440204 TI - Letter by Galyfos and Filis Regarding Article, "Effect of Obesity and Underweight Status on Perioperative Outcomes of Congenital Heart Operations in Children, Adolescents, and Young Adults: An Analysis of Data From the Society of Thoracic Surgeons Database". PMID- 29440205 TI - Response by O'Byrne et al to Letter Regarding Article, "Effect of Obesity and Underweight Status on Perioperative Outcomes of Congenital Heart Operations in Children, Adolescents, and Young Adults: An Analysis of Data From the Society of Thoracic Surgeons Database". PMID- 29440206 TI - Correction to: Efficacy and Safety of a Pharmaco-Invasive Strategy With Half-Dose Alteplase Versus Primary Angioplasty in ST-Segment-Elevation Myocardial Infarction: EARLY-MYO Trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment-Elevation Myocardial Infarction). PMID- 29440207 TI - Correction: Predictors of HIV virological failure and drug resistance in Chinese patients after 48 months of antiretroviral treatment, 2008-2012: a prospective cohort study. PMID- 29440208 TI - Meta-analysis of self-reported health symptoms in 1990-1991 Gulf War and Gulf War era veterans. AB - OBJECTIVES: Across diverse groups of Gulf War (GW) veterans, reports of musculoskeletal pain, cognitive dysfunction, unexplained fatigue, chronic diarrhoea, rashes and respiratory problems are common. GW illness is a condition resulting from GW service in veterans who report a combination of these symptoms. This study integrated the GW literature using meta-analytical methods to characterise the most frequently reported symptoms occurring among veterans who deployed to the 1990-1991 GW and to better understand the magnitude of ill health among GW-deployed veterans compared with non-deployed GW-era veterans. DESIGN: Meta-analysis. METHODS: Literature databases were searched for peer-reviewed studies published from January 1990 to May 2017 reporting health symptom frequencies in GW-deployed veterans and GW-era control veterans. Self-reported health symptom data were extracted from 21 published studies. A binomial-normal meta-analytical model was used to determine pooled prevalence of individual symptoms in GW-deployed veterans and GW-era control veterans and to calculate combined ORs of health symptoms comparing GW-deployed veterans and GW-era control veterans. RESULTS: GW-deployed veterans had higher odds of reporting all 56 analysed symptoms compared with GW-era controls. Odds of reporting irritability (OR 3.21, 95% CI 2.28 to 4.52), feeling detached (OR 3.59, 95% CI 1.83 to 7.03), muscle weakness (OR 3.19, 95% CI 2.73 to 3.74), diarrhoea (OR 3.24, 95% CI 2.51 to 4.17) and rash (OR 3.18, 95% CI 2.47 to 4.09) were more than three times higher among GW-deployed veterans compared with GW-era controls. CONCLUSIONS: The higher odds of reporting mood-cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms among GW-deployed veterans compared with GW-era controls indicates these symptoms are important when assessing GW veteran health status. PMID- 29440209 TI - To what extent do hospitalised patients receive appropriate CT and MRI scans? Results of a cross-sectional study in Southern Italy. AB - OBJECTIVES: The aim of this study was to assess the frequency of appropriateness of inpatient CT and MRI scans performed in Southern Italy. METHODS: The study was carried out by retrospectively reviewing medical records of adult patients admitted between 1 January and 31 December 2012 in two hospitals. The evaluation of appropriateness was performed according to the American College of Radiology Appropriateness Criteria, which assigns a score between 1 and 9. RESULTS: Eight hundred and fifty-three medical records were reviewed. Six hundred and thirty nine patients received CT examinations and 256 received MRI examinations. Four hundred and ninety-six (77.6%) of the patient population had appropriate CT and 202 (78.9%) received appropriate MRI examinations. The appropriateness was associated with: a confirmation of the diagnostic hypothesis, only one examination performed during hospital stay, the anatomical scan region, with musculoskeletal system being the least appropriate anatomical scan region. Moreover, for CT examinations, appropriateness was also associated with no use of contrast agent. CONCLUSIONS: Our findings highlight the need to reduce inappropriate use of CT and MRI. The study showed that the tool used is reliable to measure the extent of appropriateness of diagnostic imaging for inpatient examinations. PMID- 29440210 TI - Factors associated with health literacy in multimorbid patients in primary care: a cross-sectional study in Switzerland. AB - OBJECTIVE: To identify factors associated with health literacy in multimorbid patients. DESIGN: A nationwide cross-sectional study in Switzerland. Univariate and multivariate linear regressions were calculated to identify variables associated with health literacy. A multiple imputation approach was used to deal with missing values. PARTICIPANTS: Multimorbid patients recruited in primary care settings (n=888), above 18 years old and suffering from at least 3 of 75 chronic conditions on a predefined list based on the International Classification of Primary Care 2. MAIN MEASURES: Health literacy was assessed using the European Health Literacy Survey project questionnaire (HLS-EU 6). This comprises six items scored from 1 to 4 (very difficult=1, fairly difficult=2, fairly easy=3, very easy=4), and the total health literacy score is computed as their mean. As we wished to understand the determinants associated with lower health literacy, the HLS-EU 6 score was the only dependent variable; all other covariates were considered independent. RESULTS: The mean health literacy score (SD) was 2.9 (0.5). Multivariate analyses found significant associations between low health literacy scores and treatment burden scores (beta=-0.004, 95% CI -0.006 to 0.002); marital status, predominantly the divorced group (beta=0.136, 95% CI 0.012 to 0.260); dimensions of the EuroQuol 5 Dimension 3 Level (EQ5D3L) quality of life assessment, that is, for moderate problems with mobility (beta=-0.086, 95% CI -0.157 to 0.016); and with moderate problems (beta=-0.129, 95% CI -0.198 to 0.060) and severe problems with anxiety/depression (beta=-0.343, 95% CI -0.500 to 0.186). CONCLUSIONS: Multimorbid patients with a high treatment burden, altered quality of life by problems with mobility, anxiety or depression, often also have low levels of health literacy. Primary care practitioners should therefore pay particular attention to these patients in their daily practice. PMID- 29440211 TI - Portuguese version of a stress and well-being evaluation tool (ASSET)at the workplace: validation of the psychometric properties. AB - OBJECTIVE: The main objective of this work was to translate the English version of ASSET (A Shortened Stress Evaluation Tool) into the Portuguese version and to validate its psychometric properties. Additionally, this work tested the convergent validity of the instrument. METHODS: The translation and retroversion were conducted by experts and submitted to the authors for approval. Within an observational, cross-sectional study, regarding mental health at the workplace, ASSET together with other scales was applied to a sample of 405 participants. The psychometric validity of the subscales was studied using confirmatory factorial analysis. RESULTS: The factorial structure of ASSET is globally supported by the results, with the Perceptions of Your Job and Attitudes Towards your Organisation subscales requiring slight adjustments in the item structure and the Your Health subscales replicating the original structure. The convergent validity also supports the ASSET, showing that all subscales are significantly correlated with variables used to test convergence. CONCLUSIONS: Globally, the results constitute an important contribution to ASSET and open the possibility of its usage among Portuguese-speaking countries. The results provide an evidence on the validity of the instrument and, in particular, of the mental and physical health subscales. PMID- 29440212 TI - Scoping review on the use of socially assistive robot technology in elderly care. AB - OBJECTIVE: With an elderly population that is set to more than double by 2050 worldwide, there will be an increased demand for elderly care. This poses several impediments in the delivery of high-quality health and social care. Socially assistive robot (SAR) technology could assume new roles in health and social care to meet this higher demand. This review qualitatively examines the literature on the use of SAR in elderly care and aims to establish the roles this technology may play in the future. DESIGN: Scoping review. DATA SOURCES: Search of CINAHL, Cochrane Library, Embase, MEDLINE, PsychINFO and Scopus databases was conducted, complemented with a free search using Google Scholar and reference harvesting. All publications went through a selection process, which involved sequentially reviewing the title, abstract and full text of the publication. No limitations regarding date of publication were imposed, and only English publications were taken into account. The main search was conducted in March 2016, and the latest search was conducted in September 2017. ELIGIBILITY CRITERIA: The inclusion criteria consist of elderly participants, any elderly healthcare facility, humanoid and pet robots and all social interaction types with the robot. Exclusions were acceptability studies, technical reports of robots and publications surrounding physically or surgically assistive robots. RESULTS: In total, 61 final publications were included in the review, describing 33 studies and including 1574 participants and 11 robots. 28 of the 33 papers report positive findings. Five roles of SAR were identified: affective therapy, cognitive training, social facilitator, companionship and physiological therapy. CONCLUSIONS: Although many positive outcomes were reported, a large proportion of the studies have methodological issues, which limit the utility of the results. Nonetheless, the reported value of SAR in elderly care does warrant further investigation. Future studies should endeavour to validate the roles demonstrated in this review. SYSTEMATIC REVIEW REGISTRATION: NIHR 58672. PMID- 29440213 TI - Does industry-sponsored education foster overdiagnosis and overtreatment of depression, osteoporosis and over-active bladder syndrome? An Australian cohort study. AB - OBJECTIVES: To investigate patterns of industry-sponsored educational events that focus on specific health conditions for which there are concerns about overdiagnosis and overtreatment. DESIGN AND SETTING: This retrospective cohort study examines publicly reported industry-sponsored events in Australia from October 2011 to September 2015 for three conditions potentially subject to overdiagnosis and overtreatment: depression, osteoporosis and overactive bladder. We used a database of transparency reports to identify events with a focus on depression, osteoporosis and overactive bladder and compared these with other sponsored events. We hypothesised that companies marketing treatments for each condition would sponsor related events and that target audiences would mainly work in primary care, reflecting a broad patient population. MAIN OUTCOME MEASURES: Event and attendee characteristics, sponsoring companies, related marketed treatments, cost-effectiveness ratings and dispensing rates. RESULTS: Over the study period, we identified 1567 events focusing on depression, 1375 on osteoporosis and 190 on overactive bladder (total n=3132, with 96 660 attendees). These events were attended by primary care doctors more often than sponsored events without a focus on these three conditions: relative risk (RR)=3.06 (95% CI 2.81 to 3.32) for depression, RR=1.48 (95% CI 1.41 to 1.55) for osteoporosis and RR=2.59 (95% CI 2.09 to 3.21) for overactive bladder. Servier, which markets agomelatine and AstraZeneca (quetiapine) sponsored 51.2% and 23.0% of depression events, respectively. Amgen and GlaxoSmithKline, which co-market denosumab, sponsored 49.5% of osteoporosis events and Astellas and Commonwealth Serum Laboratories (CSL) (mirabegron and solifenacin) sponsored 80.5% of overactive bladder events. CONCLUSIONS: This 4-year overview of industry-sponsored events on three overdiagnosed and overtreated conditions found that primary care clinicians were often targeted, dinner was often provided and that a few companies sponsored most events. In most cases, sponsors' products are not cost-effective choices for the specified condition. This pattern highlights the need for professional education to be free of commercial sponsorship. PMID- 29440214 TI - 'It has saved thousands of lives, so why change it?' Content analysis of objections to cervical screening programme changes in Australia. AB - OBJECTIVES: The incidence and mortality of cervical cancer have halved since introduction of the Australian cervical screening programme in 1991, involving 2 yearly Pap smears from ages 18-69 years. In 2017, the programme changed to 5- yearly primary human papillomavirus (HPV) testing for women aged 25-74 years. This study investigated reasons for opposition to the renewed screening programme within the open-ended comments of an online petition, 'Stop May 1st Changes to Pap Smears-Save Women's Lives', opposing the changes, which received over 70 000 signatures and almost 20 000 comments. METHODS: Content analysis of a random sample of 2000 comments, reflecting 10% of the 19 633 comments posted in February March 2017. RESULTS: Nineteen codes were identified, reflecting four themes: (1) valuing women's health and rights, (2) political statements, (3) concerns about healthcare funding cuts and (4) opposition to specific components of the new screening programme. The most prevalent codes were: placing value on women's health (33%), concerns about increasing screening intervals (17%) and opposition to the changes related to personal experiences with cervical cancer or cervical abnormalities (15%). Concern about the key change in technology (HPV testing instead of Pap smears) was expressed in less than 3% of comments, and some opposition to the changes from health professionals was noted. CONCLUSIONS: Screening changes within this selected group were perceived as threatening women's health, as a political policy created by male decision-makers and as a cost-cutting exercise. Many commenters were concerned about increased screening intervals and later screening onset, but little opposition was expressed regarding the testing technology itself. This analysis may inform public education and communication strategies for future changes to cervical screening programmes internationally, to pre-emptively address specific concerns about the changes. PMID- 29440215 TI - Does exposure to simulated patient cases improve accuracy of clinicians' predictive value estimates of diagnostic test results? A within-subjects experiment at St Michael's Hospital, Toronto, Canada. AB - OBJECTIVE: Clinicians often overestimate the probability of a disease given a positive test result (positive predictive value; PPV) and the probability of no disease given a negative test result (negative predictive value; NPV). The purpose of this study was to investigate whether experiencing simulated patient cases (ie, an 'experience format') would promote more accurate PPV and NPV estimates compared with a numerical format. DESIGN: Participants were presented with information about three diagnostic tests for the same fictitious disease and were asked to estimate the PPV and NPV of each test. Tests varied with respect to sensitivity and specificity. Information about each test was presented once in the numerical format and once in the experience format. The study used a 2 (format: numerical vs experience) * 3 (diagnostic test: gold standard vs low sensitivity vs low specificity) within-subjects design. SETTING: The study was completed online, via Qualtrics (Provo, Utah, USA). PARTICIPANTS: 50 physicians (12 clinicians and 38 residents) from the Department of Family and Community Medicine at St Michael's Hospital in Toronto, Canada, completed the study. All participants had completed at least 1 year of residency. RESULTS: Estimation accuracy was quantified by the mean absolute error (MAE; absolute difference between estimate and true predictive value). PPV estimation errors were larger in the numerical format (MAE=32.6%, 95% CI 26.8% to 38.4%) compared with the experience format (MAE=15.9%, 95% CI 11.8% to 20.0%, d=0.697, P<0.001). Likewise, NPV estimation errors were larger in the numerical format (MAE=24.4%, 95% CI 14.5% to 34.3%) than in the experience format (MAE=11.0%, 95% CI 6.5% to 15.5%, d=0.303, P=0.015). CONCLUSIONS: Exposure to simulated patient cases promotes accurate estimation of predictive values in clinicians. This finding carries implications for diagnostic training and practice. PMID- 29440216 TI - Fetal alcohol spectrum disorder and youth justice: a prevalence study among young people sentenced to detention in Western Australia. AB - OBJECTIVES: To estimate the prevalence of fetal alcohol spectrum disorder (FASD) among young people in youth detention in Australia. Neurodevelopmental impairments due to FASD can predispose young people to engagement with the law. Canadian studies identified FASD in 11%-23% of young people in corrective services, but there are no data for Australia. DESIGN: Multidisciplinary assessment of all young people aged 10-17 years 11 months and sentenced to detention in the only youth detention centre in Western Australia, from May 2015 to December 2016. FASD was diagnosed according to the Australian Guide to the Diagnosis of FASD. PARTICIPANTS: 99 young people completed a full assessment (88% of those consented; 60% of the 166 approached to participate); 93% were male and 74% were Aboriginal. FINDINGS: 88 young people (89%) had at least one domain of severe neurodevelopmental impairment, and 36 were diagnosed with FASD, a prevalence of 36% (95% CI 27% to 46%). CONCLUSIONS: This study, in a representative sample of young people in detention in Western Australia, has documented a high prevalence of FASD and severe neurodevelopmental impairment, the majority of which had not been previously identified. These findings highlight the vulnerability of young people, particularly Aboriginal youth, within the justice system and their significant need for improved diagnosis to identify their strengths and difficulties, and to guide and improve their rehabilitation. PMID- 29440217 TI - Using big data to improve cardiovascular care and outcomes in China: a protocol for the CHinese Electronic health Records Research in Yinzhou (CHERRY) Study. AB - INTRODUCTION: Data based on electronic health records (EHRs) are rich with individual-level longitudinal measurement information and are becoming an increasingly common data source for clinical risk prediction worldwide. However, few EHR-based cohort studies are available in China. Harnessing EHRs for research requires a full understanding of data linkages, management, and data quality in large data sets, which presents unique analytical opportunities and challenges. The purpose of this study is to provide a framework to establish a uniquely integrated EHR database in China for scientific research. METHODS AND ANALYSIS: The CHinese Electronic health Records Research in Yinzhou (CHERRY) Study will extract individual participant data within the regional health information system of an eastern coastal area of China to establish a longitudinal population-based ambispective cohort study for cardiovascular care and outcomes research. A total of 1 053 565 Chinese adults aged over 18 years were registered in the health information system in 2009, and there were 23 394 deaths from 1 January 2009 to 31 December 2015. The study will include information from multiple epidemiological surveys; EHRs for chronic disease management; and health administrative, clinical, laboratory, drug and electronic medical record (EMR) databases. Follow-up of fatal and non-fatal clinical events is achieved through records linkage to the regional system of disease surveillance, chronic disease management and EMRs (based on diagnostic codes from the International Classification of Diseases, tenth revision). The CHERRY Study will provide a unique platform and serve as a valuable big data resource for cardiovascular risk prediction and population management, for primary and secondary prevention of cardiovascular events in China. ETHICS AND DISSEMINATION: The CHERRY Study was approved by the Peking University Institutional Review Board (IRB00001052-16011) in April 2016. Results of the study will be disseminated through published journal articles, conferences and seminar presentations, and on the study website (http://www.cherry-study.org). PMID- 29440218 TI - Impact of renin-angiotensin system inhibitors on clinical outcomes and ventricular remodelling after transcatheter aortic valve implantation: rationale and design of the RASTAVI randomised multicentre study. AB - INTRODUCTION: Transcatheter aortic valve implantation (TAVI) as a treatment in severe aortic stenosis (AS) is an excellent alternative to conventional surgical replacement. However, long-term outcomes are not benign. Renin-angiotensin system (RAS) blockade has shown benefit in terms of adverse remodelling in severe AS and after surgical replacement. METHODS AND ANALYSIS: The RAS blockade after TAVI (RASTAVI) trial aims to detect if there is a benefit in clinical outcomes and ventricular remodelling with this therapeutic strategy following the TAVI procedure. The study has been designed as a randomised 1:1 open-label study that will be undertaken in 8 centres including 336 TAVI recipients. All patients will receive the standard treatment. The active treatment group will receive ramipril as well. Randomisation will be done before discharge, after signing informed consent. All patients will be followed up for 3 years. A cardiac magnetic resonance will be performed initially and at 1 year to assess ventricular remodelling, defined as ventricular dimensions, ejection fraction, ventricular mass and fibrosis. Recorded events will include cardiac death, admission due to heart failure and stroke. The RASTAVI Study will improve the management of patients after TAVI and may help to increase their quality of life, reduce readmissions and improve long-term survival in this scenario. ETHICS AND DISSEMINATION: All authors and local ethics committees have approved the study design. All patients will provide informed consent. Results will be published irrespective of whether the findings are positive or negative. TRIAL REGISTRATION NUMBER: NCT03201185. PMID- 29440219 TI - Wool-derived keratin dressings versus usual care dressings for treatment of slow healing venous leg ulceration: study protocol for a randomised controlled trial (Keratin4VLU). AB - INTRODUCTION: Keratins, filament-forming proteins found in vertebrate epithelium, are downregulated in slow-healing venous leg ulcers (VLU) compared with normal healing VLU. Laboratory and animal model research has suggested exogenous keratins increase expression of endogenous keratins. A non-randomised controlled trial of an exogenous keratin dressing reported increased healing in slow-healing VLU. To date, no randomised controlled trial has been done to verify these promising findings. METHODS AND ANALYSIS: The Keratin4VLU trial is a single blind, pragmatic, parallel group, randomised controlled trial of keratin dressings compared with usual care non-medicated dressings in patients with VLU where either (1) the ulcer area is greater than 5 cm2, (2) the ulcer has been present for more than 26 weeks or (3) both. All patients will receive compression therapy. The primary outcome is the proportion of patients with healed VLU at 24 weeks after randomisation as adjudicated by blinded review of an ulcer photograph. Secondary outcomes are time to healing, estimated change in ulcer area, change in health-related quality of life, agreement between blinded and unblinded assessors and adverse events. The analysis will be intention-to-treat on the primary and secondary outcomes (excepting health-related quality of life). ETHICS AND DISSEMINATION: The Keratin4VLU trial received ethical approval from the Northern A Health and Disability Ethics Committee. We plan to publish the results within 1 year of trial completion and will include the results on the trial registration page. TRIAL REGISTRATION NUMBER: NCT02896725; Pre-results. PMID- 29440221 TI - To endocycle or endomitose? An unusual cell cycle switch. PMID- 29440220 TI - Variant cell cycles regulated by Notch signaling control cell size and ensure a functional blood-brain barrier. AB - Regulation of cell size is crucial in development. In plants and animals two cell cycle variants are employed to generate large cells by increased ploidy: the endocycle and endomitosis. The rationale behind the choice of which of these cycles is implemented is unknown. We show that in the Drosophila nervous system the subperineurial glia (SPG) are unique in using both the endocycle and endomitosis to grow. In the brain, the majority of SPG initially endocycle, then switch to endomitosis during larval development. The Notch signaling pathway and the String Cdc25 phosphatase are crucial for the endocycle versus endomitosis choice, providing the means experimentally to change cells from one to the other. This revealed fundamental insights into the control of cell size and the properties of endomitotic cells. Endomitotic cells attain a higher ploidy and larger size than endocycling cells, and endomitotic SPG are necessary for the blood-brain barrier. Decreased Notch signaling promotes endomitosis even in the ventral nerve cord SPG that normally are mononucleate, but not in the endocycling salivary gland cells, revealing tissue-specific cell cycle responses. PMID- 29440222 TI - SQANTI: extensive characterization of long-read transcript sequences for quality control in full-length transcriptome identification and quantification. AB - High-throughput sequencing of full-length transcripts using long reads has paved the way for the discovery of thousands of novel transcripts, even in well annotated mammalian species. The advances in sequencing technology have created a need for studies and tools that can characterize these novel variants. Here, we present SQANTI, an automated pipeline for the classification of long-read transcripts that can assess the quality of data and the preprocessing pipeline using 47 unique descriptors. We apply SQANTI to a neuronal mouse transcriptome using Pacific Biosciences (PacBio) long reads and illustrate how the tool is effective in characterizing and describing the composition of the full-length transcriptome. We perform extensive evaluation of ToFU PacBio transcripts by PCR to reveal that an important number of the novel transcripts are technical artifacts of the sequencing approach and that SQANTI quality descriptors can be used to engineer a filtering strategy to remove them. Most novel transcripts in this curated transcriptome are novel combinations of existing splice sites, resulting more frequently in novel ORFs than novel UTRs, and are enriched in both general metabolic and neural-specific functions. We show that these new transcripts have a major impact in the correct quantification of transcript levels by state-of-the-art short-read-based quantification algorithms. By comparing our iso-transcriptome with public proteomics databases, we find that alternative isoforms are elusive to proteogenomics detection. SQANTI allows the user to maximize the analytical outcome of long-read technologies by providing the tools to deliver quality-evaluated and curated full-length transcriptomes. PMID- 29440223 TI - Enhancer transcription: what, where, when, and why? AB - Following the discovery of widespread enhancer transcription, enhancers and promoters have been found to be far more similar than previously thought. In this issue of Genes & Development, two studies (Henriques and colleagues [pp. 26-41] and Mikhaylichenko and colleagues [pp. 42-57]) shine new light on the transcriptional nature of promoters and enhancers in Drosophila Together, these studies support recent work in mammalian cells that indicates that most active enhancers drive local transcription using factors and mechanisms similar to those of promoters. Intriguingly, enhancer transcription is shown to be coordinated by SPT5- and P-TEFb-mediated pause-release, but the pause half-life is shorter, and termination is more rapid at enhancers than at promoters. Moreover, bidirectional transcription from promoters is associated with enhancer activity, lending further credence to models in which regulatory elements exist along a spectrum of promoter-ness and enhancer-ness. We propose a general unified model to explain possible functions of transcription at enhancers. PMID- 29440224 TI - Competent for commitment: you've got to have heart! AB - The mature heart is composed primarily of four different cell types: cardiac myocytes, endothelium, smooth muscle, and fibroblasts. These cell types derive from pluripotent progenitors that become progressively restricted with regard to lineage potential, giving rise to multipotent cardiac progenitor cells and, ultimately, the differentiated cell types of the heart. Recent studies have begun to shed light on the defining characteristics of the intermediary cell types that exist transiently during this developmental process and the extrinsic and cell autonomous factors that influence cardiac lineage decisions and cellular competence. This information will shape our understanding of congenital and adult cardiac disease and guide regenerative therapeutic approaches. In addition, cardiac progenitor specification can serve as a model for understanding basic mechanisms regulating the acquisition of cellular identity. In this review, we present the concept of "chromatin competence" that describes the potential for three-dimensional chromatin organization to function as the molecular underpinning of the ability of a progenitor cell to respond to inductive lineage cues and summarize recent studies advancing our understanding of cardiac cell specification, gene regulation, and chromatin organization and how they impact cardiac development. PMID- 29440225 TI - Adipokine expression and endothelial function in subclinical hypothyroidism rats. AB - The purpose of our study was to observe adipokine expression and endothelial function in subclinical hypothyroidism (sHT) rats and to determine whether levothyroxine (LT4) treatment affects these changes. Sixty-five male Wistar rats were randomly divided into five groups: the control group; sHT A, B and C groups and the sHT + T4 group. The sHT rats were induced by methimazole (MMI) and the sHT + T4 rats were administered LT4 treatment after 8 weeks of MMI administration. Thyroid function and lipid levels were measured using radioimmunoassays and enzymatic colorimetric methods, respectively. Serum adiponectin (APN), chemerin, TNF-alpha, endothelin (ET-1) and nitric oxide (NO) levels were measured using ELISA kits and a nitric-reductive assay. The expression of APN, chemerin and TNF-alpha in visceral adipose tissue (VAT) was measured in experimental rats using RT-PCR and Western blotting. Hematoxylin eosin (HE) staining was used to observe changes in adipose tissue. The sHT rats had significantly higher levels of thyroid-stimulating hormone (TSH), TNF-alpha, chemerin, ET-1, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and lower levels of APN and NO than those in control and sHT + T4 rats. Based on Pearson correlation analysis, the levels of chemerin, TNF-alpha, ET-1, LDL-C, TC and triglyceride (TG) were positively correlated with TSH, but APN and NO levels were negatively correlated with TSH. These findings demonstrated that high TSH levels contribute to the changes of adipokines and endothelial dysfunction in sHT, but LT4 treatment ameliorates those changes. PMID- 29440226 TI - A single nucleotide incorporation step limits human telomerase repeat addition activity. AB - Human telomerase synthesizes telomeric DNA repeats (GGTTAG)n onto chromosome ends using a short template from its integral telomerase RNA (hTR). However, telomerase is markedly slow for processive DNA synthesis among DNA polymerases. We report here that the unique template-embedded pause signal restricts the first nucleotide incorporation for each repeat synthesized, imparting a significantly greater KM This slow nucleotide incorporation step drastically limits repeat addition processivity and rate under physiological conditions, which is alleviated with augmented concentrations of dGTP or dGDP, and not with dGMP nor other nucleotides. The activity stimulation by dGDP is due to nucleoside diphosphates functioning as substrates for telomerase. Converting the first nucleotide of the repeat synthesized from dG to dA through the telomerase template mutation, hTR-51U, correspondingly shifts telomerase repeat addition activity stimulation to dATP-dependent. In accordance, telomerase without the pause signal synthesizes DNA repeats with extremely high efficiency under low dGTP concentrations and lacks dGTP stimulation. Thus, the first nucleotide incorporation step of the telomerase catalytic cycle is a potential target for therapeutic enhancement of telomerase activity. PMID- 29440227 TI - IRES-mediated translation of cofilin regulates axonal growth cone extension and turning. AB - In neuronal development, dynamic rearrangement of actin promotes axonal growth cone extension, and spatiotemporal translation of local mRNAs in response to guidance cues directs axonal growth cone steering, where cofilin plays a critical role. While regulation of cofilin activity is well studied, regulatory mechanism for cofilin mRNA translation in neurons is unknown. In eukaryotic cells, proteins can be synthesized by cap-dependent or cap-independent mechanism via internal ribosome entry site (IRES)-mediated translation. IRES-mediated translation has been reported in various pathophysiological conditions, but its role in normal physiological environment is poorly understood. Here, we report that 5'UTR of cofilin mRNA contains an IRES element, and cofilin is predominantly translated by IRES-mediated mechanism in neurons. Furthermore, we show that IRES-mediated translation of cofilin is required for both axon extension and axonal growth cone steering. Our results provide new insights into the function of IRES-mediated translation in neuronal development. PMID- 29440229 TI - A shot to the heart: a rare case of cardiac embolization. AB - : SummaryThis is a case report of intracardiac foreign bodies that gained access to the heart by migration from a peripheral vein. The case report describes the diagnostic findings on cardiac imaging and summarizes different approaches to management. LEARNING POINTS: Appearance of embolized cardiac missiles with reverberation and acoustic shadowing.Role of different imaging modalities in the diagnosis of intracardiac foreign bodies.Indications for surgical or transcatheter retrieval. PMID- 29440228 TI - AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress. AB - Although c-Myc is essential for melanocyte development, its role in cutaneous melanoma, the most aggressive skin cancer, is only partly understood. Here we used the NrasQ61KINK4a-/- mouse melanoma model to show that c-Myc is essential for tumor initiation, maintenance, and metastasis. c-Myc-expressing melanoma cells were preferentially found at metastatic sites, correlated with increased tumor aggressiveness and high tumor initiation potential. Abrogation of c-Myc caused apoptosis in primary murine and human melanoma cells. Mechanistically, c Myc-positive melanoma cells activated and became dependent on the metabolic energy sensor AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase that plays an important role in energy and redox homeostasis under stress conditions. AMPK pathway inhibition caused apoptosis of c-Myc-expressing melanoma cells, while AMPK activation protected against cell death of c-Myc-depleted melanoma cells through suppression of oxidative stress. Furthermore, TCGA database analysis of early-stage human melanoma samples revealed an inverse correlation between C-MYC and patient survival, suggesting that C-MYC expression levels could serve as a prognostic marker for early-stage disease. PMID- 29440230 TI - Plasma tau is increased in frontotemporal dementia. AB - BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is familial with mutations in GRN, MAPT and C9orf72 being the major genetic causes. Robust biomarkers of the underlying pathology are still lacking in FTD with no markers currently being able to distinguish those with tau and TDP 43 inclusions during life. METHODS: This study used an ultrasensitive single molecule methodology to measure plasma tau concentrations in 176 participants: 71 with bvFTD, 83 with PPA and 22 healthy controls. The patient group included 36 with pathogenic mutations in either MAPT (n=12), GRN (n=9) or C9orf72 (n=15). Group comparisons were performed between clinical and genetic groups and controls using a linear regression model with bias-corrected bootstrap CIs. Correlative analyses were performed to investigate associations with measures of disease severity and progression. RESULTS: Higher plasma tau concentrations were seen in bvFTD (mean 1.96 (SD 1.07) pg/mL) and PPA (2.65 (2.15) pg/mL) compared with controls (1.67 (0.50) pg/mL). Investigating the PPA group further showed significantly higher levels compared with controls in each of the PPA subtypes (non-fluent, semantic and logopenic variants, as well as a fourth group not meeting criteria for one of the three main variants). In the genetic groups, only the MAPT group had significantly increased concentrations (2.62 (1.39) pg/mL) compared with controls. No significant correlations were seen with cross sectional or longitudinal brain volumes, serum neurofilament light chain concentrations or disease duration. CONCLUSION: Plasma tau levels are increased in FTD in all clinical groups, but in the genetic subtypes only in MAPT mutations, the group of patients who definitively have tau pathology at postmortem. Future studies will be required in pathologically confirmed cohorts to investigate this association further, and whether plasma tau will be helpful in differentiating patients with FTD with tau from those with other pathologies. PMID- 29440231 TI - Ex vivo activity of cytotoxic drugs and targeted agents in small intestinal neuroendocrine tumors. AB - Small intestinal neuroendocrine tumors (SI-NETs) are generally considered resistant to systemic treatment. To date, predictive markers for drug activity are lacking. Tumor samples from 27 patients with SI-NETs were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinicopathological variables and pre-treatment biomarkers. For cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinum, gemcitabine and doxorubicin compared with CRC. For several of the targeted kinase inhibitors, SI-NET was among the most sensitive solid tumor types. CLL and ovarian cancer were generally the most sensitive tumor types to both cytotoxic drugs and protein kinase inhibitors. SI-NET was more sensitive to the mTOR inhibitor sirolimus than the other solid tumor types tested. Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors. Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo SI-NETs exhibit intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinicopathological factors and currently used biomarkers are not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NET. The great variability in drug sensitivity calls for individualized selection of therapy. PMID- 29440232 TI - Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers. AB - The human genome is 'pervasively transcribed' leading to a complex array of non coding RNAs (ncRNAs) that far outnumber coding mRNAs. ncRNAs have regulatory roles in transcription and post-transcriptional processes as well numerous cellular functions that remain to be fully described. Best characterized of the 'expanding universe' of ncRNAs are the ~22 nucleotide microRNAs (miRNAs) that base-pair to target mRNA's 3' untranslated region within the RNA-induced silencing complex (RISC) and block translation and may stimulate mRNA transcript degradation. Long non-coding RNAs (lncRNAs) are classified as >200 nucleotides in length, but range up to several kb and are heterogeneous in genomic origin and function. lncRNAs fold into structures that interact with DNA, RNA and proteins to regulate chromatin dynamics, protein complex assembly, transcription, telomere biology and splicing. Some lncRNAs act as sponges for miRNAs and decoys for proteins. Nuclear-encoded lncRNAs can be taken up by mitochondria and lncRNAs are transcribed from mtDNA. Both miRNAs and lncRNAs are dysregulated in endocrine cancers. This review provides an overview on the current understanding of the regulation and function of selected lncRNAs and miRNAs, and their interaction, in endocrine-related cancers: breast, prostate, endometrial and thyroid. PMID- 29440234 TI - Does Akkermansia muciniphila play a role in type 1 diabetes? PMID- 29440235 TI - Do patients with blunt thoracic aortic injury present to hospital with unstable vital signs? A systematic review and meta-analysis. AB - BACKGROUND: Blunt thoracic aortic injury (BTAI) is an uncommon diagnosis, usually developing as a consequence of high-impact acceleration-deceleration mechanisms. Timely diagnosis may enable early resuscitation and reduction of shear forces, essential to prevent worsening of the injury prior to definitive management. Death is commonly due to haemorrhagic shock, but clinical features may be absent until sudden and massive haemorrhage. OBJECTIVES: The aim of this systematic review was to determine the proportion of patients with BTAI who present with unstable vital signs. METHODS: Manuscripts were identified through a search of MEDLINE, EMBASE and the Cochrane Library databases, focusing on subject headings and keywords related to the aorta and trauma. Mechanisms of injury, haemodynamic status and mortality from the included manuscripts were reviewed. Meta-analysis of presenting haemodynamic status among a select group of similar papers was conducted. RESULTS: Nineteen studies were included, with five selected for meta analysis. Most reported cases of BTAI (80.0%-100%) were caused by road traffic incidents, with mortality consistently higher among initially unstable patients. There was statistically significant heterogeneity among the included studies (P<0.01). The pooled proportion of patients with haemodynamic instability in the setting of BTAI was 48.8% (95% CI 8.3 to 89.4). CONCLUSIONS: Normal vital signs do not rule out aortic injury. A high degree of clinical suspicion and liberal use of imaging is necessary to prevent missed or delayed diagnoses. PMID- 29440233 TI - Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma. AB - OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification and targeted therapy. However, these analyses were performed in bulk samples and focused on coding genes, which represent a small fraction of the genome. DESIGN: We developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA. RESULTS: We generated a catalogue of PDA-associated lncRNAs. We showed that lncRNAs define molecular subtypes with biological and clinical significance. We identified lncRNAs in genomic regions with SCNA and single nucleotide polymorphisms associated with lifetime risk of PDA and associated with clinical outcome using genomic and clinical data in PDA. Systems biology and experimental functional analysis of two epithelial lncRNAs (LINC00673 and FAM83H-AS1) suggest they regulate the transcriptional profile of pancreatic tumour samples and PDA cell lines. CONCLUSIONS: Our findings indicate that lncRNAs are associated with genetic marks of pancreatic cancer risk, contribute to the transcriptional regulation of neoplastic cells and provide an important resource to design functional studies of lncRNAs in PDA. PMID- 29440236 TI - The consequences of patient charges for prescription drugs in Canada: a cross sectional survey. AB - BACKGROUND: Many Canadians face substantial out-of-pocket charges for prescription drugs. Prior work suggests that this causes some patients to not take their medications as prescribed; however, we have little understanding of whether charges for prescription medicines lead patients to forego basic needs or to use more health care services. Our study aimed to quantify the consequences of patient charges for medicines in Canada. METHODS: As part of the 2016 Canadian Community Health Survey, we designed and fielded cross-sectional questions to 28 091 Canadians regarding prescription drug affordability, consequent use of health care services and trade-offs with other expenditures. We calculated weighted population estimates and proportions, and used logistic regression to determine which patient characteristics were associated with these behaviours. RESULTS: Overall, 5.5% (95% confidence interval 5.1%-6.0%) of Canadians reported being unable to afford 1 or more drugs in the prior year, representing 8.2% of those with at least 1 prescription. Drugs for mental health conditions were the most commonly reported drug class for cost-related nonadherence. About 303 000 Canadians had additional doctor visits, about 93 000 sought care in the emergency department, and about 26 000 were admitted to hospital at the population level. Many Canadians forewent basic needs such as food (about 730 000 people), heat (about 238 000) and other health care expenses (about 239 000) because of drug costs. These outcomes were more common among females, younger adults, Aboriginal peoples, those with poorer health status, those lacking drug insurance and those with lower income. INTERPRETATION: Out-of-pocket charges for medicines for Canadians are associated with foregoing prescription drugs and other necessities as well as use of additional health care services. Changes to protect vulnerable populations from drug costs might reduce these negative outcomes. PMID- 29440237 TI - Tension-dependent regulation of mammalian Hippo signaling through LIMD1. AB - Hippo signaling is regulated by biochemical and biomechanical cues that influence the cytoskeleton, but the mechanisms that mediate this have remained unclear. We show that all three mammalian Ajuba family proteins - AJUBA, LIMD1 and WTIP - exhibit tension-dependent localization to adherens junctions, and that both LATS family proteins, LATS1 and LATS2, exhibit an overlapping tension-dependent junctional localization. This localization of Ajuba and LATS family proteins is also influenced by cell density, and by Rho activation. We establish that junctional localization of LATS kinases requires LIMD1, and that LIMD1 is also specifically required for the regulation of LATS kinases and YAP1 by Rho. Our results identify a biomechanical pathway that contributes to regulation of mammalian Hippo signaling, establish that this occurs through tension-dependent LIMD1-mediated recruitment and inhibition of LATS kinases in junctional complexes, and identify roles for this pathway in both Rho-mediated and density dependent regulation of Hippo signaling. PMID- 29440239 TI - Follicular dendritic cell sarcoma of the duodenum: an extremely rare entity. AB - Extranodal follicular dendritic cell sarcoma (FDCS) is a very rare tumour, only reported in case reports and case series. It poses diagnostic and management challenge both to the clinician and pathologist. We present such a rare case of duodenal FDCS in a 56-year-old woman who was recently managed in our institution. Repeated pre surgical biopsies were non-diagnostic and the final diagnosis was made only after surgical excision of the tumour and with the help of histopathological and immunohistochemical studies. The patient had a complete en block resection of the tumour and was discharged home well 5 days postsurgery. To the best of our knowledge, this is the first case of FDCS reported arising from the duodenum. PMID- 29440238 TI - The physiological regulation of macropinocytosis during Dictyostelium growth and development. AB - Macropinocytosis is a conserved endocytic process used by Dictyostelium amoebae for feeding on liquid medium. To further Dictyostelium as a model for macropinocytosis, we developed a high-throughput flow cytometry assay to measure macropinocytosis, and used it to identify inhibitors and investigate the physiological regulation of macropinocytosis. Dictyostelium has two feeding states: phagocytic and macropinocytic. When cells are switched from phagocytic growth on bacteria to liquid media, the rate of macropinocytosis slowly increases, due to increased size and frequency of macropinosomes. Upregulation is triggered by a minimal medium containing three amino acids plus glucose and likely depends on macropinocytosis itself. The presence of bacteria suppresses macropinocytosis while their product, folate, partially suppresses upregulation of macropinocytosis. Starvation, which initiates development, does not of itself suppress macropinocytosis: this can continue in isolated cells, but is shut down by a conditioned-medium factor or activation of PKA signalling. Thus macropinocytosis is a facultative ability of Dictyostelium cells, regulated by environmental conditions that are identified here.This article has an associated First Person interview with the first author of the paper. PMID- 29440240 TI - Atypical presentation of atypical haemolytic uraemic syndrome. AB - A 17-year-old girl presented with fever, myalgia, vomiting for 1 month and oliguria and dyspnoea for 4 days. She was tachycardic,hypertensive, with pedal oedema and decreased breath sounds. She had high serum creatinine (3 mg/dL), anaemia, thrombocytopenia, leucocytosis and eosinophilia with schistocytes. Lactate dehydrogenase, transaminases were high , with low haptoglobin and high ferritin (5269 ng/mL). Complement C3/C4 and fibrinogen were normal. Urinalysis showed large blood and protein and stool studies were negative. Her ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was normal. Kidney biopsy showed acute interstitial nephritis (AIN) in addition to thrombotic angiopathy. The differentials - haemolytic uraemic syndrome (HUS), thrombotic thrombocytopenia (TTP) and haemophagocytic lymphohistiocytosis (HLH) were ruled out. Her genetic testing was abnormal for large CFHR1-CFHR3 homozygous deletion and heterozygous missense variant in exon 2 of DGKE making the diagnosis of atypical HUS. She received eculizumab and was discharged on oral steroids for AIN and biweekly eculizumab infusions with excellent recovery. PMID- 29440241 TI - 'If there were water we should stop and drink': neurofibromatosis presenting with diabetes insipidus. AB - A 58-year-old right-handed woman presented to our institution with a 1-month history of polydipsia and polyuria. She had a remote history of neurofibroma excision by dermatology and, on examination, was noted to meet the clinical diagnostic criteria for neurofibromatosis type 1. Laboratory investigations revealed hypernatraemia and elevated serum osmolality, accompanied by reduced urinary osmolality. A subsequent water deprivation test confirmed central diabetes insipidus, which responded to treatment with desmopressin. MRI of the brain showed pituitary enlargement, which raised the possibility of an underlying pituitary adenoma or, alternatively, lymphocytic hypophysitis. Both conditions have rarely been described in neurofibromatosis. PMID- 29440242 TI - Bilobed gallbladder: a rare congenital anomaly. AB - Bilobed gallbladder is a rare form of duplication of gallbladder. Preoperative diagnosis is important to avoid peroperative complications; however, it is also a challenge as imaging reports are often confounding. A case of bilobed gallbladder managed successfully laparoscopically is presented. PMID- 29440243 TI - Spontaneous pneumomediastinum. AB - Spontaneous pneumomediastinum is the presence of free air within the mediastinum that is not associated with trauma. It is a rare, self-limiting condition that can cause widespread subcutaneous surgical emphysema. We present the case of a 12 year-old boy who presented with widespread spontaneous surgical emphysema and pneumomediastinum, with no history of trauma or respiratory tract disease. We discuss our assessment of him and management with our multidisciplinary team (MDT), and whether radiological investigations including CT are helpful in such cases. In conclusion, we hypothesised that the child's coughing was the most likely cause of the tracheal rupture leading to the spontaneous surgical emphysema. Spontaneous pneumomediastinum in the paediatric patient is extremely rare. This case highlights how spontaneous pneumomediastinum can be successfully managed conservatively, and how MDT input can be helpful in guiding management in such unusual cases. PMID- 29440244 TI - Acute rheumatic fever presenting as complete heart block: report of an adolescent case and review of literature. AB - A 14-year-old boy suffering from chronic rheumatic heart disease came to the emergency department with recurrent episodes of presyncope and syncope. He was found to have complete heart block (CHB) and required temporary pacemaker insertion. Further workup revealed that CHB was secondary to acute rheumatic carditis. His atrioventricular (AV) conduction abnormalities recovered in a stepwise fashion over 5 days while he was being treated with corticosteroids, without the need for permanent pacemaker insertion. This case illustrates that acute rheumatic carditis can rarely present with advanced AV conduction block, which may be reversible. PMID- 29440245 TI - Pityriasis rubra pilaris: a rare inflammatory dermatosis. PMID- 29440246 TI - Calcitonin receptors are ancient modulators for rhythms of preferential temperature in insects and body temperature in mammals. AB - Daily body temperature rhythm (BTR) is essential for maintaining homeostasis. BTR is regulated separately from locomotor activity rhythms, but its molecular basis is largely unknown. While mammals internally regulate BTR, ectotherms, including Drosophila, exhibit temperature preference rhythm (TPR) behavior to regulate BTR. Here, we demonstrate that the diuretic hormone 31 receptor (DH31R) mediates TPR during the active phase in Drosophila DH31R is expressed in clock cells, and its ligand, DH31, acts on clock cells to regulate TPR during the active phase. Surprisingly, the mouse homolog of DH31R, calcitonin receptor (Calcr), is expressed in the suprachiasmatic nucleus (SCN) and mediates body temperature fluctuations during the active phase in mice. Importantly, DH31R and Calcr are not required for coordinating locomotor activity rhythms. Our results represent the first molecular evidence that BTR is regulated distinctly from locomotor activity rhythms and show that DH31R/Calcr is an ancient specific mediator of BTR during the active phase in organisms ranging from ectotherms to endotherms. PMID- 29440247 TI - KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis. AB - Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator KMT2D (MLL4) is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undifferentiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Genome-wide, KMT2D interacts with p63 and is enriched at its target enhancers. Depletion of KMT2D results in a broad loss of enhancer histone modifications H3 Lys 4 (H3K4) monomethylation (H3K4me1) and H3K27 acetylation (H3K27ac) as well as reduced expression of p63 target genes, including key genes involved in epithelial development and adhesion. Together, these results reveal a critical role for KMT2D in the control of epithelial enhancers and p63 target gene expression, including the requirement of KMT2D for the maintenance of epithelial progenitor gene expression and the coordination of proper terminal differentiation. PMID- 29440248 TI - Risk category system to identify pituitary adenoma patients with AIP mutations. AB - BACKGROUND: Predictive tools to identify patients at risk for gene mutations related to pituitary adenomas are very helpful in clinical practice. We therefore aimed to develop and validate a reliable risk category system for aryl hydrocarbon receptor-interacting protein (AIP) mutations in patients with pituitary adenomas. METHODS: An international cohort of 2227 subjects were consecutively recruited between 2007 and 2016, including patients with pituitary adenomas (familial and sporadic) and their relatives. All probands (n=1429) were screened for AIP mutations, and those diagnosed with a pituitary adenoma prospectively, as part of their clinical screening (n=24), were excluded from the analysis. Univariate analysis was performed comparing patients with and without AIP mutations. Based on a multivariate logistic regression model, six potential factors were identified for the development of a risk category system, classifying the individual risk into low-risk, moderate-risk and high-risk categories. An internal cross-validation test was used to validate the system. RESULTS: 1405 patients had a pituitary tumour, of which 43% had a positive family history, 55.5% had somatotrophinomas and 81.5% presented with macroadenoma. Overall, 134 patients had an AIP mutation (9.5%). We identified four independent predictors for the presence of an AIP mutation: age of onset providing an odds ratio (OR) of 14.34 for age 0-18 years, family history (OR 10.85), growth hormone excess (OR 9.74) and large tumour size (OR 4.49). In our cohort, 71% of patients were identified as low risk (<5% risk of AIP mutation), 9.2% as moderate risk and 20% as high risk (>=20% risk). Excellent discrimination (c-statistic=0.87) and internal validation were achieved. CONCLUSION: We propose a user-friendly risk categorisation system that can reliably group patients into high-risk, moderate risk and low-risk groups for the presence of AIP mutations, thus providing guidance in identifying patients at high risk of carrying an AIP mutation. This risk score is based on a cohort with high prevalence of AIP mutations and should be applied cautiously in other populations. PMID- 29440249 TI - Photobacterium damselae subsp. damselae, a generalist pathogen with unique virulence factors and high genetic diversity. AB - Photobacterium damselae subsp. damselae causes vibriosis in a variety of marine animals, including fish species of importance in aquaculture. It also may cause wound infections in humans that can progress into a fatal outcome. Two major virulence factors are encoded within the large conjugative plasmid pPHDD1: the phospholipase-D damselysin (Dly) and the pore-forming toxin Phobalysin P (PhlyP). The two toxins exert hemolytic and cytolytic activity in a synergistic manner. Albeit PhlyP has close homologues in many Vibrio species, it has unique features that differentiate it from related toxins. Dly phospholipase constitutes a singular trait of P. damselae subsp. damselae among the Vibrionaceae, although related toxins are found in members of the Aeromonadaceae Fish farm outbreaks can also be caused by plasmidless strains. Such observation led to the characterization of two ubiquitous, chromosome-encoded toxins with lesser cytolytic activity: the pore forming-toxin Phobalysin C (PhlyC) and the phospholipase-hemolysin PlpV. Special attention deserves the high genetic diversity of this pathogen, with a number of strain-specific features including the cell envelope polysaccharide synthesis clusters. Fish outbreaks are likely caused by multiclonal populations which contain both plasmidless and pPHDD1 harbouring isolates, and not by well-adapted clonal complexes. Still, among such a genetic heterogeneity, it is feasible to identify conserved weak points in the biology of this bacterium: the two-component regulatory system RstAB (CarSR) was found to be necessary for maximal production of virulence factors and its inactivation severely impaired virulence. PMID- 29440250 TI - Functional Overlap of hetP and hetZ in Regulation of Heterocyst Differentiation in Anabaena sp. Strain PCC 7120. AB - HetR plays a key role in regulation of heterocyst differentiation and patterning in Anabaena It directly regulates genes involved in heterocyst differentiation (such as hetP and hetZ), genes involved in pattern formation (patA), and many others. In this study, we investigated the functional relationship of hetP and hetZ and their role in HetR-dependent cell differentiation. Coexpression of hetP and hetZ from the promoter of ntcA, which encodes the global nitrogen regulator, enabled a hetR mutant to form heterocysts with low aerobic nitrogenase activity. Overexpression of hetZ restored heterocyst differentiation in a hetP mutant and vice versa. Overexpression of hetR restored heterocyst formation in either a hetP or a hetZ mutant but not in a hetZ hetP double mutant. The functional overlap of hetP and hetZ was further confirmed by reverse transcription-quantitative PCR (RT qPCR) and transcriptomic analyses of their effects on gene expression. In addition, yeast two-hybrid and pulldown assays showed the interaction of HetZ with HetR. HetP and HetZ are proposed as the two major factors that control heterocyst formation in response to upregulation of hetRIMPORTANCE Heterocyst forming cyanobacteria contribute significantly to N2 fixation in marine, freshwater, and terrestrial ecosystems. Formation of heterocysts enables this group of cyanobacteria to fix N2 efficiently under aerobic conditions. HetR, HetP, and HetZ are among the most important factors involved in heterocyst differentiation. We present evidence for the functional overlap of hetP and hetZ and for the key role of the HetR-HetP/HetZ circuit in regulation of heterocyst differentiation. The regulatory mechanism based on HetR, HetP, and HetZ is probably conserved in all heterocyst-forming cyanobacteria. PMID- 29440251 TI - The Transcriptional Regulator HlyU Positively Regulates Expression of exsA, Leading to Type III Secretion System 1 Activation in Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus is a marine bacterium that is globally recognized as the leading cause of seafood-borne gastroenteritis. V. parahaemolyticus uses various toxins and two type 3 secretion systems (T3SS-1 and T3SS-2) to subvert host cells during infection. We previously determined that V. parahaemolyticus T3SS-1 activity is upregulated by increasing the expression level of the master regulator ExsA under specific growth conditions. In this study, we set out to identify V. parahaemolyticus genes responsible for linking environmental and growth signals to exsA gene expression. Using transposon mutagenesis in combination with a sensitive and quantitative luminescence screen, we identify HlyU and H-NS as two antagonistic regulatory proteins controlling the expression of exsA and, hence, T3SS-1 in V. parahaemolyticus Disruption of hns leads to constitutive unregulated exsA gene expression, consistent with its known role in repressing exsA transcription. In contrast, genetic disruption of hlyU completely abrogated exsA expression and T3SS-1 activity. A V. parahaemolyticushlyU null mutant was significantly deficient for T3SS-1-mediated host cell death during in vitro infection. DNA footprinting studies with purified HlyU revealed a 56-bp protected DNA region within the exsA promoter that contains an inverted repeat sequence. Genetic evidence suggests that HlyU acts as a derepressor, likely by displacing H-NS from the exsA promoter, leading to exsA gene expression and appropriately regulated T3SS-1 activity. Overall, the data implicate HlyU as a critical positive regulator of V. parahaemolyticus T3SS-1-mediated pathogenesis.IMPORTANCE Many Vibrio species are zoonotic pathogens, infecting both animals and humans, resulting in significant morbidity and, in extreme cases, mortality. While many Vibrio species virulence genes are known, their associated regulation is often modestly understood. We set out to identify genetic factors of V. parahaemolyticus that are involved in activating exsA gene expression, a process linked to a type III secretion system involved in host cytotoxicity. We discover that V. parahaemolyticus employs a genetic regulatory switch involving H-NS and HlyU to control exsA promoter activity. While HlyU is a well-known positive regulator of Vibrio species virulence genes, this is the first report linking it to a transcriptional master regulator and type III secretion system paradigm. PMID- 29440252 TI - A Single Amino Acid Change in the Response Regulator PhoP, Acquired during Yersinia pestis Evolution, Affects PhoP Target Gene Transcription and Polymyxin B Susceptibility. AB - Yersinia pestis, the causative agent of plague, evolved from the closely related pathogen Yersinia pseudotuberculosis During its emergence, Y. pestis is believed to have acquired its unique pathogenic characteristics through numerous gene gains/losses, genomic rearrangements, and single nucleotide polymorphism (SNP) changes. One such SNP creates a single amino acid variation in the DNA binding domain of PhoP, the response regulator in the PhoP/PhoQ two-component system. Y. pseudotuberculosis and the basal human-avirulent strains of Y. pestis harbor glycines at position 215 of PhoP, whereas the modern human-virulent strains (e.g., KIM and CO92) harbor serines at this residue. Since PhoP plays multiple roles in the adaptation of Y. pestis to stressful host conditions, we tested whether this amino acid substitution affects PhoP activity or the ability of Y. pestis to survive in host environments. Compared to the parental KIM6+ strain carrying the modern allele of phoP (phoP-S215), a derivative carrying the basal allele (phoP-G215) exhibited slightly defective growth under a low-Mg2+ condition and decreased transcription of a PhoP target gene, ugd, as well as an ~8-fold increase in the susceptibility to the antimicrobial peptide polymyxin B. The phoP G215 strain showed no apparent defect in flea colonization, although a phoP-null mutant showed decreased flea infectivity in competition experiments. Our results suggest that the amino acid variation at position 215 of PhoP causes subtle changes in the PhoP activity and raise the possibility that the change in this residue have contributed to the evolution of increased virulence in Y. pestisIMPORTANCEY. pestis acquired a single nucleotide polymorphism (SNP) in phoP when the highly human-virulent strains diverged from less virulent basal strains, resulting in an amino acid substitution in the DNA binding domain of the PhoP response regulator. We show that Y. pestis carrying the modern phoP allele has an increased ability to induce the PhoP-regulated ugd gene and resist antimicrobial peptides compared to an isogenic strain carrying the basal allele. Given the important roles PhoP plays in host adaptation, the results raise an intriguing possibility that this amino acid substitution contributed to the evolution of increased virulence in Y. pestis Additionally, we present the first evidence that phoP confers a survival fitness advantage to Y. pestis inside the flea midgut. PMID- 29440253 TI - Structural Basis of a Thiol-Disulfide Oxidoreductase in the Hedgehog-Forming Actinobacterium Corynebacterium matruchotii. AB - The actinobacterium Corynebacterium matruchotii has been implicated in nucleation of oral microbial consortia leading to biofilm formation. Due to the lack of genetic tools, little is known about basic cellular processes, including protein secretion and folding, in this organism. We report here a survey of the C. matruchotii genome, which encodes a large number of exported proteins containing paired cysteine residues, and identified an oxidoreductase that is highly homologous to the Corynebacterium diphtheriae thiol-disulfide oxidoreductase MdbA (MdbACd). Crystallization studies uncovered that the 1.2-A resolution structure of C. matruchotii MdbA (MdbACm) possesses two conserved features found in actinobacterial MdbA enzymes, a thioredoxin-like fold and an extended alpha helical domain. By reconstituting the disulfide bond-forming machine in vitro, we demonstrated that MdbACm catalyzes disulfide bond formation within the actinobacterial pilin FimA. A new gene deletion method supported that mdbA is essential in C. matruchotii Remarkably, heterologous expression of MdbACm in the C. diphtheriae DeltamdbA mutant rescued its known defects in cell growth and morphology, toxin production, and pilus assembly, and this thiol-disulfide oxidoreductase activity required the catalytic motif CXXC. Altogether, the results suggest that MdbACm is a major thiol-disulfide oxidoreductase, which likely mediates posttranslocational protein folding in C. matruchotii by a mechanism that is conserved in ActinobacteriaIMPORTANCE The actinobacterium Corynebacterium matruchotii has been implicated in the development of oral biofilms or dental plaque; however, little is known about the basic cellular processes in this organism. We report here a high-resolution structure of a C. matruchotii oxidoreductase that is highly homologous to the Corynebacterium diphtheriae thiol-disulfide oxidoreductase MdbA. By biochemical analysis, we demonstrated that C. matruchotii MdbA catalyzes disulfide bond formation in vitro Furthermore, a new gene deletion method revealed that deletion of mdbA is lethal in C. matruchotii Remarkably, C. matruchotii MdbA can replace C. diphtheriae MdbA to maintain normal cell growth and morphology, toxin production, and pilus assembly. Overall, our studies support the hypothesis that C. matruchotii utilizes MdbA as a major oxidoreductase to catalyze oxidative protein folding. PMID- 29440254 TI - Expression of Pyridoxal 5'-Phosphate-Independent Racemases Can Reduce 2 Aminoacrylate Stress in Salmonella enterica. AB - The RidA protein (PF01042) from Salmonella enterica is a deaminase that quenches 2-aminoacrylate (2AA) and other reactive metabolites. In the absence of RidA, 2AA accumulates, damages cellular enzymes, and compromises the metabolic network. In vitro, RidA homologs from all domains of life deaminate 2AA, and RidA proteins from plants, bacteria, yeast, and humans complement the mutant phenotype of a ridA mutant strain of S. enterica In the present study, a methanogenic archaeon, Methanococcus maripaludis S2, was used to probe alternative mechanisms to restore metabolic balance. M. maripaludis MMP0739, which is annotated as an aspartate/glutamate racemase, complemented a ridA mutant strain and reduced the intracellular 2AA burden. The aspartate/glutamate racemase YgeA from Escherichia coli or S. enterica, when provided in trans, similarly restored wild-type growth to a ridA mutant. These results uncovered a new mechanism to ameliorate metabolic stress, and they suggest that direct quenching by RidA is not the only strategy to quench 2AA.IMPORTANCE 2-Aminoacrylate is an endogenously generated reactive metabolite that can damage cellular enzymes if not directly quenched by the conserved deaminase RidA. This study used an archaeon to identify a RidA independent mechanism to prevent metabolic stress caused by 2AA. The data suggest that a gene product annotated as an aspartate/glutamate racemase (MMP0739) produces a metabolite that can quench 2AA, expanding our understanding of strategies available to quench reactive metabolites. PMID- 29440255 TI - Increased Activity of Cystathionine beta-Lyase Suppresses 2-Aminoacrylate Stress in Salmonella enterica. AB - Reactive enamine stress caused by intracellular 2-aminoacrylate accumulation leads to pleiotropic growth defects in a variety of organisms. Members of the well-conserved RidA/YER057c/UK114 protein family prevent enamine stress by enhancing the breakdown of 2-aminoacrylate to pyruvate. In Salmonella enterica, disruption of RidA allows 2-aminoacrylate to accumulate and to inactivate a variety of pyridoxal 5'-phosphate-dependent enzymes by generating covalent bonds with the enzyme and/or cofactor. This study was initiated to identify mechanisms that can overcome 2-aminoacrylate stress in the absence of RidA. Multicopy suppressor analysis revealed that overproduction of the methionine biosynthesis enzyme cystathionine beta-lyase (MetC) (EC 4.4.1.8) alleviated the pleiotropic consequences of 2-aminoacrylate stress in a ridA mutant strain. Degradation of cystathionine by MetC was not required for suppression of ridA phenotypes. The data support a model in which MetC acts on a noncystathionine substrate to generate a metabolite that reduces 2-aminoacrylate levels, representing a nonenzymatic mechanism of 2-aminoacrylate depletion.IMPORTANCE RidA proteins are broadly conserved and have been demonstrated to deaminate 2-aminoacrylate and other enamines. 2-Aminoacrylate is generated as an obligatory intermediate in several pyridoxal 5'-phosphate-dependent reactions; if it accumulates, it damages cellular enzymes. This study identified a novel mechanism to eliminate 2 aminoacrylate stress that required the overproduction, but not the canonical activity, of cystathionine beta-lyase. The data suggest that a metabolite metabolite interaction is responsible for quenching 2-aminoacrylate, and they emphasize the need for emerging technologies to probe metabolism in vivo. PMID- 29440256 TI - Identification of Streptococcus gallolyticus subsp. gallolyticus (Biotype I) Competence-Stimulating Peptide Pheromone. AB - Streptococcus gallolyticus subsp. gallolyticus, a member of the group D streptococci, is normally found in the bovine rumen and human gut. It is an opportunistic pathogen that was recently determined to be a bacterial driver of colorectal cancer, in addition to causing other diseases, such as infective endocarditis, bacteremia, neonatal meningitis, and septicemia. As an emerging pathogen, not much is known about this bacterium, its virulence mechanisms, or its virulence regulatory pathways. Previous studies suggest that S. gallolyticus subsp. gallolyticus uses a ComRS pathway, one of many Streptococcus quorum sensing circuitries, for competence. However, thus far, the ubiquitous ComABCDE pathway has not been studied, nor has its regulatory role in S. gallolyticus subsp. gallolyticus We therefore sought to study the S. gallolyticus subsp. gallolyticus ComABCDE quorum-sensing pathway and have identified its peptide pheromone, which is termed the competence-stimulating peptide (CSP). We further determined that this peptide regulates the production of bacteriocin-like inhibitory substances (BLISs), a phenotype that has been linked with the ComABCDE pathway in both Streptococcus pneumoniae and Streptococcus mutans Our data show that S. gallolyticus subsp. gallolyticus TX20005 produces a 21-mer CSP signal, which differs from CSP signals of other Streptococcus species in that its active form begins three residues after the double-glycine leader signal of the ComC precursor peptide. Additionally, our data suggest that this peptide might not be related to competence induction, as opposed to CSP signaling peptides in other Streptococcus species. This study provides the first evidence that S. gallolyticus subsp. gallolyticus utilizes quorum sensing to eliminate competitors, presenting a potential pathway to target this emerging human pathogen.IMPORTANCEStreptococcus gallolyticus subsp. gallolyticus is an emerging human pathogen known as a causative agent of infective endocarditis, and recently, of colorectal cancer. In this work, we revealed a functional quorum sensing circuitry in S. gallolyticus subsp. gallolyticus, including the identification of the central signaling peptide pheromone, competence-stimulating peptide (CSP), and the regulatory role of this circuitry in the production of bacteriocin-like inhibitory substances (BLISs). This work uncovered a mechanism by which this bacterium outcompetes other bacterial species and thus provides a potential tool to study this opportunistic pathogen. PMID- 29440257 TI - Reduction of Spermidine Content Resulting from Inactivation of Two Arginine Decarboxylases Increases Biofilm Formation in Synechocystis sp. Strain PCC 6803. AB - The phototropic bacterium Synechocystis sp. strain PCC 6803 is able to adapt its morphology in order to survive in a wide range of harsh environments. Under conditions of high salinity, planktonic cells formed cell aggregates in culture. Further observations using crystal violet staining, confocal laser scanning microscopy, and field emission-scanning electron microscopy confirmed that these aggregates were Synechocystis biofilms. Polyamines have been implicated in playing a role in biofilm formation, and during salt stress the content of spermidine, the major polyamine in Synechocystis, was reduced. Two putative arginine decarboxylases, Adc1 and Adc2, in Synechocystis were heterologously expressed in Escherichia coli and purified. Adc2 had high arginine decarboxylase activity, whereas Adc1 was much less active. Disruption of the adc genes in Synechocystis resulted in decreased spermidine content and formation of biofilms even under nonstress conditions. Based on the characterization of the adc mutants, Adc2 was the major arginine decarboxylase whose activity led to inhibition of biofilm formation, and Adc1 contributed only minimally to the process of polyamine synthesis. Taken together, in Synechocystis the shift from planktonic lifestyle to biofilm formation was correlated with a decrease in intracellular polyamine content, which is the inverse relationship of what was previously reported in heterotroph bacteria.IMPORTANCE There are many reports concerning biofilm formation in heterotrophic bacteria. In contrast, studies on biofilm formation in cyanobacteria are scarce. Here, we report on the induction of biofilm formation by salt stress in the model phototrophic bacterium Synechocystis sp. strain PCC 6803. Two arginine decarboxylases (Adc1 and Adc2) possess function in the polyamine synthesis pathway. Inactivation of the adc1 and adc2 genes leads to biofilm formation even in the absence of salt. The shift from planktonic culture to biofilm formation is regulated by a decrease in spermidine content in Synechocystis This negative correlation between biofilm formation and polyamine content, which is the opposite of the relationship reported in other bacteria, is important not only in autotrophic but also in heterotrophic bacteria. PMID- 29440258 TI - Staphylococcal protein A contributes to persistent colonization of mice with Staphylococcus aureus. AB - Staphylococcus aureus persistently colonizes the nasopharynx of humans, which increases the risk for invasive diseases such as skin infection and bacteremia. Nasal colonization triggers IgG responses against staphylococcal surface antigens, however these antibodies cannot prevent subsequent colonization or disease. Here we describe S. aureus WU1, a multi-locus sequence type ST88 isolate, that persistently colonizes the nasopharynx of mice. We report that staphylococcal protein A (SpA) is required for persistence of S. aureus WU1 in the nasopharynx. Compared to animals colonized by wild-type S. aureus, mice colonized with the Deltaspa variant mount increased IgG responses against staphylococcal colonization determinants. Immunization of mice with a non toxigenic SpA variant, which cannot crosslink B cell receptors and divert antibody responses, elicits protein A-neutralizing antibodies that promote IgG responses against colonizing S. aureus and diminish pathogen persistence.IMPORTANCEStaphylococcus aureus persistently colonizes the nasopharynx of about a third of the human population, thereby promoting community and hospital-acquired infections. Antibiotics are currently used for decolonization of individuals at increased risk of infection. However, the efficacy of antibiotics is limited by recolonization and selection for drug resistant strains. Here we propose a model whereby staphylococcal protein A (SpA), a B cell superantigen, modifies host immune responses during colonization to support continued persistence of S. aureus in the nasopharynx. We show that this mechanism can be thwarted by vaccine-induced anti-SpA antibodies that promote IgG responses against staphylococcal antigens and diminish colonization. PMID- 29440259 TI - Three-step transcriptional priming that drives the commitment of multipotent progenitors toward B cells. AB - Stem cell fate is orchestrated by core transcription factors (TFs) and epigenetic modifications. Although regulatory genes that control cell type specification are identified, the transcriptional circuit and the cross-talk among regulatory factors during cell fate decisions remain poorly understood. To identify the "time-lapse" TF networks during B-lineage commitment, we used multipotent progenitors harboring a tamoxifen-inducible form of Id3, an in vitro system in which virtually all cells became B cells within 6 d by simply withdrawing 4 hydroxytamoxifen (4-OHT). Transcriptome and epigenome analysis at multiple time points revealed that ~10%-30% of differentially expressed genes were virtually controlled by the core TFs, including E2A, EBF1, and PAX5. Strikingly, we found unexpected transcriptional priming before the onset of the key TF program. Inhibition of the immediate early genes such as Nr4a2, Klf4, and Egr1 severely impaired the generation of B cells. Integration of multiple data sets, including transcriptome, protein interactome, and epigenome profiles, identified three representative transcriptional circuits. Single-cell RNA sequencing (RNA-seq) analysis of lymphoid progenitors in bone marrow strongly supported the three-step TF network model during specification of multipotent progenitors toward B-cell lineage in vivo. Thus, our findings will provide a blueprint for studying the normal and neoplastic development of B lymphocytes. PMID- 29440260 TI - Chromatin remodeler CHD7 regulates the stem cell identity of human neural progenitors. AB - Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE-neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS specific enhancers, which support the maintenance of the NE and CNS lineage identities. Furthermore, we found that BRN2 and SOX21 are downstream effectors of CHD7, which shapes cellular identities by enhancing a CNS-specific cellular program and indirectly repressing non-CNS-specific cellular programs. Based on our results, CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate NE and CNS lineage identities. PMID- 29440261 TI - Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming. AB - B-cell fate determination requires the action of transcription factors that operate in a regulatory network to activate B-lineage genes and repress lineage inappropriate genes. However, the dynamics and hierarchy of events in B-cell programming remain obscure. To uncouple the dynamics of transcription factor expression from functional consequences, we generated induction systems in developmentally arrested Ebf1-/- pre-pro-B cells to allow precise experimental control of EBF1 expression in the genomic context of progenitor cells. Consistent with the described role of EBF1 as a pioneer transcription factor, we show in a time-resolved analysis that EBF1 occupancy coincides with EBF1 expression and precedes the formation of chromatin accessibility. We observed dynamic patterns of EBF1 target gene expression and sequential up-regulation of transcription factors that expand the regulatory network at the pro-B-cell stage. A continuous EBF1 function was found to be required for Cd79a promoter activity and for the maintenance of an accessible chromatin domain that is permissive for binding of other transcription factors. Notably, transient EBF1 occupancy was detected at lineage-inappropriate genes prior to their silencing in pro-B cells. Thus, persistent and transient functions of EBF1 allow for an ordered sequence of epigenetic and transcriptional events in B-cell programming. PMID- 29440262 TI - A meiotic XPF-ERCC1-like complex recognizes joint molecule recombination intermediates to promote crossover formation. AB - Meiotic crossover formation requires the stabilization of early recombination intermediates by a set of proteins and occurs within the environment of the chromosome axis, a structure important for the regulation of meiotic recombination events. The molecular mechanisms underlying and connecting crossover recombination and axis localization are elusive. Here, we identified the ZZS (Zip2-Zip4-Spo16) complex, required for crossover formation, which carries two distinct activities: one provided by Zip4, which acts as hub through physical interactions with components of the chromosome axis and the crossover machinery, and the other carried by Zip2 and Spo16, which preferentially bind branched DNA molecules in vitro. We found that Zip2 and Spo16 share structural similarities to the structure-specific XPF-ERCC1 nuclease, although it lacks endonuclease activity. The XPF domain of Zip2 is required for crossover formation, suggesting that, together with Spo16, it has a noncatalytic DNA recognition function. Our results suggest that the ZZS complex shepherds recombination intermediates toward crossovers as a dynamic structural module that connects recombination events to the chromosome axis. The identification of the ZZS complex improves our understanding of the various activities required for crossover implementation and is likely applicable to other organisms, including mammals. PMID- 29440263 TI - Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization. AB - Insulin resistance, the failure to activate insulin signaling in the presence of ligand, leads to metabolic diseases, including type 2 diabetes. Physical activity and mechanical stress have been shown to protect against insulin resistance, but the molecular mechanisms remain unclear. Here, we address this relationship in the Drosophila larval fat body, an insulin-sensitive organ analogous to vertebrate adipose tissue and livers. We found that insulin signaling in Drosophila fat body cells is abolished in the absence of physical activity and mechanical stress even when excess insulin is present. Physical movement is required for insulin sensitivity in both intact larvae and fat bodies cultured ex vivo. Interestingly, the insulin receptor and other downstream components are recruited to the plasma membrane in response to mechanical stress, and this membrane localization is rapidly lost upon disruption of larval or tissue movement. Sensing of mechanical stimuli is mediated in part by integrins, whose activation is necessary and sufficient for mechanical stress-dependent insulin signaling. Insulin resistance develops naturally during the transition from the active larval stage to the immotile pupal stage, suggesting that regulation of insulin sensitivity by mechanical stress may help coordinate developmental programming with metabolism. PMID- 29440265 TI - Causal effects of the microbiota on immune-mediated diseases. AB - The mammalian immune system has evolved in the presence of a complex community of indigenous microorganisms that constitutively colonize all barrier surfaces. This intimate relationship has resulted in the development of a vast array of reciprocal interactions between the microbiota and the host immune system, particularly in the intestine, where the density and diversity of indigenous microbes are greatest. Alterations in the gut microbiota have been correlated with almost every known immunological disease, but in most cases, it remains unclear whether these changes are a cause or effect of the disease or merely a reflection of epidemiological differences between groups. Here, we review recent efforts to demonstrate a causal role for the microbiota in health and disease, outline experimental advances that have made these studies possible, and highlight how changes in microbial composition may influence immune system function. PMID- 29440264 TI - Centrobin controls primary ciliogenesis in vertebrates. AB - The BRCA2 interactor, centrobin, is a centrosomal protein that has been implicated in centriole duplication and microtubule stability. We used genome editing to ablate CNTROB in hTERT-RPE1 cells and observed an increased frequency of monocentriolar and acentriolar cells. Using a novel monoclonal antibody, we found that centrobin primarily localizes to daughter centrioles but also associates with mother centrioles upon serum starvation. Strikingly, centrobin loss abrogated primary ciliation upon serum starvation. Ultrastructural analysis of centrobin nulls revealed defective axonemal extension after mother centriole docking. Ciliogenesis required a C-terminal portion of centrobin that interacts with CP110 and tubulin. We also depleted centrobin in zebrafish embryos to explore its roles in an entire organism. Centrobin-depleted embryos showed microcephaly, with curved and shorter bodies, along with marked defects in laterality control, morphological features that indicate ciliary dysfunction. Our data identify new roles for centrobin as a positive regulator of vertebrate ciliogenesis. PMID- 29440266 TI - Essential immunologic orchestrators of intestinal homeostasis. AB - Over the past 25 years, substantial advances have been made in our understanding of the cellular and molecular pathways that are essential to maintain a state of health in the mammalian gastrointestinal tract, an organ that is densely colonized by both immune cells and trillions of microbes. Seminal studies in the 1990s identified that several cytokines, antigen-presentation molecules, and components of the T cell receptor were necessary to prevent the development of spontaneous intestinal inflammation in mice. Subsequent research revealed that these pathways orchestrate beneficial interactions with intestinal microbes, involve complex communication between innate and adaptive immune cells, and can be dysregulated in human inflammatory bowel disease. Here, we discuss how these early findings set the stage for numerous other advances and shaped our current knowledge of host-microbiota interactions and intestinal homeostasis in mammals. It is expected that continued investigation of these areas will define previously unknown immunologic mechanisms of tolerance and inflammation in the intestine that can be exploited to benefit human health. PMID- 29440267 TI - Differentiation of pathologic/neoplastic hypercortisolism (Cushing's syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo Cushing's syndrome): Letter to the Editor. PMID- 29440268 TI - Differentiation of pathologic/neoplastic hypercortisolism (Cushing syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as Pseudo-Cushing syndrome): response to Letter to the Editor. PMID- 29440270 TI - Correction: STAT4 and T-bet control follicular helper T cell development in viral infections. PMID- 29440269 TI - The MtDMI2-MtPUB2 Negative Feedback Loop Plays a Role in Nodulation Homeostasis. AB - DOES NOT MAKE INFECTION 2 (MtDMI2) is a Leu rich repeat-type receptor kinase required for signal transduction in the Medicago truncatula/Sinorhizobium meliloti symbiosis pathway. However, the mechanisms through which MtDMI2 participates in nodulation homeostasis are poorly understood. In this study, we identified MtPUB2-a novel plant U-box (PUB)-type E3 ligase-and showed that it interacts with MtDMI2. MtDMI2 and MtPUB2 accumulation were shown to be similar in various tissues. Roots of plants in which MtPUB2 was silenced by RNAi (MtPUB2 RNAi plants) exhibited impaired infection threads, fewer nodules, and shorter primary root lengths compared to those of control plants transformed with empty vector. Using liquid chromatography-tandem mass spectrometry, we showed that MtDMI2 phosphorylates MtPUB2 at Ser-316, Ser-421, and Thr-488 residues. When MtPUB2-RNAi plants were transformed with MtPUB2S421D , which mimics the phosphorylated state, MtDMI2 was persistently ubiquitinated and degraded by MtPUB2S421D, resulting in fewer nodules than observed in MtPUB2/MtPUB2-RNAi complemented plants. However, MtPUB2S421A /MtPUB2-RNAi-complemented plants showed no MtPUB2 ubiquitination activity, and their nodulation phenotype was similar to that of MtPUB2-RNAi plants transformed with empty vector. Further studies demonstrated that these proteins form a negative feedback loop of the prey (MtDMI2)-predator (MtPUB2) type. Our results suggest that the MtDMI2-MtPUB2 negative feedback loop, which displays crosstalk with the long-distance autoregulation of nodulation via MtNIN, plays an important role in nodulation homeostasis. PMID- 29440271 TI - Phosphorylated immunoreceptor tyrosine-based activation motifs and integrin cytoplasmic domains activate spleen tyrosine kinase via distinct mechanisms. AB - Spleen tyrosine kinase (Syk) is involved in cellular adhesion and also in the activation and development of hematopoietic cells. Syk activation induced by genomic rearrangement has been linked to certain T-cell lymphomas, and Syk inhibitors have been shown to prolong survival of patients with B-cell lineage malignancies. Syk is activated either by its interaction with a double phosphorylated immunoreceptor tyrosine-based activation motif (pITAM), which induces rearrangements in the Syk structure, or by the phosphorylation of specific tyrosine residues. In addition to its immunoreceptor function, Syk is activated downstream of integrin pathways, and integrins bind to the same region in Syk as does pITAM. However, it is unknown whether integrins and pITAM use the same mechanism to activate Syk. Here, using purified Syk protein and fluorescence based enzyme assay we investigated whether interaction of the integrin beta3 cytoplasmic domain with the Syk regulatory domain causes changes in Syk activity similar to those induced by pITAM peptides. We observed no direct Syk activation by soluble integrin peptide, and integrin did not compete with pITAM-induced activation even though at high concentrations, the integrin cytoplasmic domain peptide competed with Syk's substrate. However, clustered integrin peptides induced Syk activation, presumably via a transphosphorylation mechanism. Moreover, the clustered integrins also activated a Syk variant in which tyrosines were replaced with phenylalanine (Y348F/Y352F), indicating that clustered integrin-induced Syk activation involved other phosphorylation sites. In conclusion, integrin cytoplasmic domains do not directly induce Syk conformational changes and do not activate Syk via the same mechanism as pITAM. PMID- 29440272 TI - Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1. AB - Endogenous nitric oxide (NO) generated by inducible NO synthase (iNOS) promotes glioblastoma cell proliferation and invasion and also plays a key role in glioblastoma resistance to chemotherapy and radiotherapy. Non-ionizing photodynamic therapy (PDT) has anti-tumor advantages over conventional glioblastoma therapies. Our previous studies revealed that glioblastoma U87 cells up-regulate iNOS after a photodynamic challenge and that the resulting NO not only increases resistance to apoptosis but renders surviving cells more proliferative and invasive. These findings were largely based on the effects of inhibiting iNOS activity and scavenging NO. Demonstrating now that iNOS expression in photostressed U87 cells is mediated by NF-kappaB, we hypothesized that (i) recognition of acetylated lysine (acK) on NF-kappaB p65/RelA by bromodomain and extra-terminal (BET) protein Brd4 is crucial; and (ii) by suppressing iNOS expression, a BET inhibitor (JQ1) would attenuate the negative effects of photostress. The following evidence was obtained. (i) Like iNOS, Brd4 protein and p65-acK levels increased severalfold in photostressed cells. (ii) JQ1 at minimally toxic concentrations had no effect on Brd4 or p65-acK up-regulation after PDT but strongly suppressed iNOS, survivin, and Bcl-xL up-regulation, along with the growth and invasion spurt of PDT-surviving cells. (iii) JQ1 inhibition of NO production in photostressed cells closely paralleled that of growth/invasion inhibition. (iv) Finally, at 1% the concentration of iNOS inhibitor 1400W, JQ1 reduced post-PDT cell aggressiveness to a far greater extent. This is the first evidence for BET inhibitor targeting of iNOS expression in cancer cells and how such targeting can markedly improve therapeutic efficacy. PMID- 29440273 TI - Relationship between the dimerization of thyroglobulin and its ability to form triiodothyronine. AB - Thyroglobulin (TG) is the most abundant thyroid gland protein, a dimeric iodoglycoprotein (660 kDa). TG serves as the protein precursor in the synthesis of thyroid hormones tetraiodothyronine (T4) and triiodothyronine (T3). The primary site for T3 synthesis in TG involves an iodotyrosine acceptor at the antepenultimate Tyr residue (at the extreme carboxyl terminus of the protein). The carboxyl-terminal region of TG comprises a cholinesterase-like (ChEL) domain followed by a short unique tail sequence. Despite many studies, the monoiodotyrosine donor residue needed for the coupling reaction to create T3 at this evolutionarily conserved site remains unidentified. In this report, we have utilized a novel, convenient immunoblotting assay to detect T3 formation after protein iodination in vitro, enabling the study of T3 formation in recombinant TG secreted from thyrocytes or heterologous cells. With this assay, we confirm the antepenultimate residue of TG as a major T3-forming site, but also demonstrate that the side chain of this residue intimately interacts with the same residue in the apposed monomer of the TG dimer. T3 formation in TG, or the isolated carboxyl terminal region, is inhibited by mutation of this antepenultimate residue, but we describe the first substitution mutation that actually increases T3 hormonogenesis by engineering a novel cysteine, 10 residues upstream of the antepenultimate residue, allowing for covalent association of the unique tail sequences, and that helps to bring residues Tyr2744 from apposed monomers into closer proximity. PMID- 29440274 TI - Biological noise and positional effects influence cell stemness. AB - Biological (or cellular) noise is the random quantitative variability of proteins and other molecules in individual, genetically identical cells. As the result of biological noise in the levels of some transcription factors that determine a cell's differentiation status, differentiated cells may dedifferentiate to a stem cell state given a sufficiently long time period. Here, to provide direct evidence supporting this hypothesis, we used a live-cell monitoring system based on enhanced green fluorescent protein (eGFP) expression to continuously assess the "stemness" of individual human and murine malignant mesothelioma cells over a period of up to 3 months. Re-expression of the transcription factors, the top hierarchical stemness markers Sox2 (SRY-box 2) and Oct4 (octamer-binding transcription factor), monitored as cell eGFP expression was observed in a subpopulation of differentiated eGFP(-) malignant mesothelioma cells. However, we found that this transition was extremely rare. Of note, when it did occur, neighboring cells that were not direct descendants of a newly emerged eGFP(+) stem cell were more likely than non-neighboring cells to also become an eGFP(+) stem cell. This observation suggested a positional effect and led to a clustered "mosaic" reappearance of eGFP(+) stem cells. Moreover, stem cells reappeared even in cell cultures derived from one single differentiated eGFP(-) cell. On the basis of our experimental in vitro and in vivo findings, we developed a tumor growth model to predict the clustered localization of cancer stem cells within a tumor mass. PMID- 29440275 TI - Prior Percutaneous Coronary Intervention and Mortality in Patients Undergoing Surgical Myocardial Revascularization: Results From the E-CABG (European Multicenter Study on Coronary Artery Bypass Grafting) With a Systematic Review and Meta-Analysis. AB - BACKGROUND: The clinical impact of prior percutaneous coronary intervention (PCI) in patients requiring coronary artery bypass grafting (CABG) remains unsettled. We sought to determine whether prior PCI is associated with adverse outcome after CABG. METHODS AND RESULTS: Data from the prospective E-CABG (European Multicenter Study on Coronary Artery Bypass Grafting) conducted between January 2015 and March 2016 at 16 European centres were analyzed using propensity weighted methodology to adjust for confounding. A parallel systematic review/meta-analysis (MEDLINE, Embase, SCOPUS, and Cochrane Library) through September 2017 was accomplished. Of a total of 3641 adult patients included in the E-CABG study, 685 (19%) patients had a history of PCI. At multivariable level, prior PCI was not associated with an increased hospital mortality in both unweighted and weighted patient groups (odds ratio, 0.73; 95% confidence interval, 0.29-1.38; P=0.33 and odds ratio, 0.90; 95% confidence interval, 0.39-2.08; P=0.81, respectively). Subgroup analyses confirmed that prior PCI had no impact on hospital mortality and morbidity, including reexploration for bleeding, blood transfusion, hospital resource use, and neurological, renal, and cardiac complications. The systematic review provided a total of 71 366 individuals and showed a trend toward higher in hospital/30-day mortality (adjusted odds ratio, 1.30; 95% confidence interval, 0.99-1.70; I2=43.1%) in patients with prior PCI. CONCLUSIONS: Our prospective multicenter study showed that prior PCI was not associated with an increased risk of mortality or other adverse outcomes in patients undergoing CABG. In light of a trend toward increased mortality observed in the meta-analysis, further studies are needed to ascertain the prognostic impact of prior PCI in the outcome after CABG. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02319083. PMID- 29440276 TI - Accurate Depth of Radiofrequency-Induced Lesions in Renal Sympathetic Denervation Based on a Fine Histological Sectioning Approach in a Porcine Model. AB - BACKGROUND: Ablation lesion depth caused by radiofrequency-based renal denervation (RDN) was limited to <4 mm in previous animal studies, suggesting that radiofrequency-RDN cannot ablate a substantial percentage of renal sympathetic nerves. We aimed to define the true lesion depth achieved with radiofrequency-RDN using a fine sectioning method and to investigate biophysical parameters that could predict lesion depth. METHODS AND RESULTS: Radiofrequency was delivered to 87 sites in 14 renal arteries from 9 farm pigs at various ablation settings: 2, 4, 6, and 9 W for 60 seconds and 6 W for 120 seconds. Electric impedance and electrode temperature were recorded during ablation. At 7 days, 2470 histological sections were obtained from the treated arteries. Maximum lesion depth increased at 2 to 6 W, peaking at 6.53 (95% confidence interval, 4.27-8.78) mm under the 6 W/60 s condition. It was not augmented by greater power (9 W) or longer duration (120 seconds). There were statistically significant tendencies at 6 and 9 W, with higher injury scores in the media, nerves, arterioles, and fat. Maximum lesion depth was positively correlated with impedance reduction and peak electrode temperature (Pearson correlation coefficients were 0.59 and 0.53, respectively). CONCLUSIONS: Lesion depth was 6.5 mm for radiofrequency-RDN at 6 W/60 s. The impedance reduction and peak electrode temperature during ablation were closely associated with lesion depth. Hence, these biophysical parameters could provide prompt feedback during radiofrequency RDN procedures in the clinical setting. PMID- 29440277 TI - Percutaneous Catheter Interventions Followed by Coronary Artery Bypass Grafting: Primum Non Nocere. PMID- 29440279 TI - Impairment of PPARalpha and the Fatty Acid Oxidation Pathway Aggravates Renal Fibrosis during Aging. AB - Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys show significantly increased fibrosis with impaired kidney function, the mechanisms underlying the effects of aging on renal fibrosis have not been investigated. In this study, we investigated peroxisome proliferator-activated receptor alpha (PPARalpha) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPARalpha and the FAO pathway-associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPARalpha protein expression associated with increased expression of PPARalpha targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPARalpha expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF-beta-induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPARalpha-/- mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPARalpha signaling during aging aggravates renal fibrosis development, and targeting PPARalpha is useful for preventing age-associated CKD. PMID- 29440278 TI - Regulation of KATP Channel Trafficking in Pancreatic beta-Cells by Protein Histidine Phosphorylation. AB - Protein histidine phosphatase 1 (PHPT-1) is an evolutionarily conserved 14-kDa protein that dephosphorylates phosphohistidine. PHPT-1-/- mice were generated to gain insight into the role of PHPT-1 and histidine phosphorylation/dephosphorylation in mammalian biology. PHPT-1-/- mice exhibited neonatal hyperinsulinemic hypoglycemia due to impaired trafficking of KATP channels to the plasma membrane in pancreatic beta-cells in response to low glucose and leptin and resembled patients with congenital hyperinsulinism (CHI). The defect in KATP channel trafficking in PHPT-1-/- beta-cells was due to the failure of PHPT-1 to directly activate transient receptor potential channel 4 (TRPC4), resulting in decreased Ca2+ influx and impaired downstream activation of AMPK. Thus, these studies demonstrate a critical role for PHPT-1 in normal pancreatic beta-cell function and raise the possibility that mutations in PHPT-1 and/or TRPC4 may account for yet to be defined cases of CHI. PMID- 29440280 TI - Wnt9a Promotes Renal Fibrosis by Accelerating Cellular Senescence in Tubular Epithelial Cells. AB - Cellular senescence is associated with renal disease progression, and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. However, the underlying mechanism is unknown. We assessed the potential role of Wnt9a in tubular cell senescence and renal fibrosis. Compared with tubular cells of normal subjects, tubular cells of humans with a variety of nephropathies and those of several mouse models of CKD expressed high levels of Wnt9a that colocalized with the senescence-related protein p16INK4A Wnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and expression of p16INK4A Furthermore, ectopic expression of Wnt9a after ischemia-reperfusion injury (IRI) induced activation of beta-catenin and exacerbated renal fibrosis. Overexpression of Wnt9a exacerbated tubular senescence, evidenced by increased detection of p16INK4A expression and senescence-associated beta-galactosidase activity. Conversely, shRNA-mediated knockdown of Wnt9a repressed IRI-induced renal fibrosis in vivo and impeded the growth of senescent tubular epithelial cells in culture. Notably, Wnt9a-induced renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4A in the IRI mouse model. In a human proximal tubular epithelial cell line and primary renal tubular cells, Wnt9a remarkably upregulated levels of senescence-related p16INK4A, p19ARF, p53, and p21 and decreased the phosphorylation of retinoblastoma protein. Wnt9a also induced senescent tubular cells to produce TGF-beta1, which promoted proliferation and activation in normal rat kidney fibroblasts. Thus, Wnt9a drives tubular senescence and fibroblast activation. Furthermore, the Wnt9a-TGF-beta pathway appears to create a reciprocal activation loop between senescent tubular cells and activated fibroblasts that promotes and accelerates the pathogenesis of renal fibrosis. PMID- 29440282 TI - FIND: difFerential chromatin INteractions Detection using a spatial Poisson process. AB - Polymer-based simulations and experimental studies indicate the existence of a spatial dependency between the adjacent DNA fibers involved in the formation of chromatin loops. However, the existing strategies for detecting differential chromatin interactions assume that the interacting segments are spatially independent from the other segments nearby. To resolve this issue, we developed a new computational method, FIND, which considers the local spatial dependency between interacting loci. FIND uses a spatial Poisson process to detect differential chromatin interactions that show a significant difference in their interaction frequency and the interaction frequency of their neighbors. Simulation and biological data analysis show that FIND outperforms the widely used count-based methods and has a better signal-to-noise ratio. PMID- 29440281 TI - 3' UTR lengthening as a novel mechanism in regulating cellular senescence. AB - Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3' untranslated regions (3' UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3' UTRs and reduced gene expression. Genes that harbor longer 3' UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3' UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes. Mechanistically, splicing factor TRA2B bound to a core "AGAA" motif located in the alternative 3' UTR of Rras2, thereby reducing the RRAS2 protein level and causing senescence. Both proximal and distal poly(A) signals showed strong sequence conservation, highlighting the vital role of APA regulation during evolution. Our results revealed APA as a novel mechanism in regulating cellular senescence. PMID- 29440284 TI - Failure Is an Option: Using Errors as Teaching Opportunities. PMID- 29440283 TI - Evolution of neuropeptide signalling systems. AB - Neuropeptides are a diverse class of neuronal signalling molecules that regulate physiological processes and behaviour in animals. However, determining the relationships and evolutionary origins of the heterogeneous assemblage of neuropeptides identified in a range of phyla has presented a huge challenge for comparative physiologists. Here, we review revolutionary insights into the evolution of neuropeptide signalling that have been obtained recently through comparative analysis of genome/transcriptome sequence data and by 'deorphanisation' of neuropeptide receptors. The evolutionary origins of at least 30 neuropeptide signalling systems have been traced to the common ancestor of protostomes and deuterostomes. Furthermore, two rounds of genome duplication gave rise to an expanded repertoire of neuropeptide signalling systems in the vertebrate lineage, enabling neofunctionalisation and/or subfunctionalisation, but with lineage-specific gene loss and/or additional gene or genome duplications generating complex patterns in the phylogenetic distribution of paralogous neuropeptide signalling systems. We are entering a new era in neuropeptide research where it has become feasible to compare the physiological roles of orthologous and paralogous neuropeptides in a wide range of phyla. Moreover, the ambitious mission to reconstruct the evolution of neuropeptide function in the animal kingdom now represents a tangible challenge for the future. PMID- 29440285 TI - Nutrient Intake in the First Two Weeks of Life and Brain Growth in Preterm Neonates. AB - BACKGROUND: Optimizing early nutritional intake in preterm neonates may promote brain health and neurodevelopment through enhanced brain maturation. Our objectives were (1) to determine the association of energy and macronutrient intake in the first 2 weeks of life with regional and total brain growth and white matter (WM) maturation, assessed by 3 serial MRI scans in preterm neonates; (2) to examine how critical illness modifies this association; and (3) to investigate the relationship with neurodevelopmental outcomes. METHODS: Forty nine preterm neonates (21 boys, median [interquartile range] gestational age: 27.6 [2.3] weeks) were scanned serially at the following median postmenstrual weeks: 29.4, 31.7, and 41. The total brain, basal nuclei, and cerebellum were semiautomatically segmented. Fractional anisotropy was extracted from diffusion tensor imaging data. Nutritional intake from day of life 1 to 14 was monitored and clinical factors were collected. RESULTS: Greater energy and lipid intake predicted increased total brain and basal nuclei volumes over the course of neonatal care to term-equivalent age. Similarly, energy and lipid intake were significantly associated with fractional anisotropy values in selected WM tracts. The association of ventilation duration with smaller brain volumes was attenuated by higher energy intake. Brain growth predicted psychomotor outcome at 18 months' corrected age. CONCLUSIONS: In preterm neonates, greater energy and enteral feeding during the first 2 weeks of life predicted more robust brain growth and accelerated WM maturation. The long-lasting effect of early nutrition on neurodevelopment may be mediated by enhanced brain growth. Optimizing nutrition in preterm neonates may represent a potential avenue to mitigate the adverse brain health consequences of critical illness. PMID- 29440287 TI - Correction to: Angiotensin-(1-7) and Vascular Function: The Clinical Context. PMID- 29440288 TI - Correction to: Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARbeta/delta-Dependent Vasodilator Pathway. PMID- 29440289 TI - NEO212 Inhibits Migration and Invasion of Glioma Stem Cells. AB - Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10-fold more cytotoxic to glioma stem cells (GSC) than TMZ, and is active against TMZ resistant tumor cells. In this study, we show that NEO212 decreases migration and invasion of primary cultures of patient-derived GSCs, in both mesenchymal USC02 and proneural USC04 populations. The mechanism by which NEO212 reduces migration and invasion appears to be independent of its DNA alkylating effects, which cause cytotoxicity during the first hours of treatment, and is associated with a decrease in the FAK/Src signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases the production of matrix metalloproteinases MMP2 and MMP9, crucial for GSC invasion. Gene expression analysis of epithelial and mesenchymal markers suggests that NEO212 increases the expression of epithelial-like characteristics, suggesting a reversion of the epithelial-to-mesenchymal transition process. Furthermore, in an in vivo orthotopic glioma model, NEO212 decreases tumor progression by reducing invasion of GSCs, thereby increasing survival time of mice. These studies indicate that NEO212, in addition to cytotoxicity, can effectively reduce migration and invasion in GSCs, thus exhibiting significant clinical value in the reduction of invasion and malignant glioma progression. Mol Cancer Ther; 17(3); 625-37. (c)2018 AACR. PMID- 29440290 TI - A Spatio-Temporal Model of Macrophage-Mediated Drug Resistance in Glioma Immunotherapy. AB - The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment in driving the development of acquired drug resistance remain elusive, which significantly impedes effective clinical cancer treatment. Recent experimental studies have revealed a macrophage-mediated drug resistance mechanism in which the tumor microenvironment undergoes adaptation in response to macrophage-targeted colony-stimulating factor-1 receptor (CSF1R) inhibition therapy in gliomas. In this study, we developed a spatio-temporal model to quantitatively describe the interplay between glioma cells and CSF1R inhibitor targeted macrophages through CSF1 and IGF1 pathways. Our model was used to investigate the evolutionary kinetics of the tumor regrowth and the associated dynamic adaptation of the tumor microenvironment in response to the CSF1R inhibitor treatment. The simulation result obtained using this model was in agreement with the experimental data. The sensitivity analysis revealed the key parameters involved in the model, and their potential impacts on the model behavior were examined. Moreover, we demonstrated that the drug resistance is dose-dependent. In addition, we quantitatively evaluated the effects of combined CSFR inhibition and IGF1 receptor (IGF1R) inhibition with the goal of designing more effective therapies for gliomas. Our study provides quantitative and mechanistic insights into the microenvironmental adaptation mechanisms that operate during macrophage-targeted immunotherapy and has implications for drug dose optimization and the design of more effective combination therapies. Mol Cancer Ther; 17(4); 814-24. (c)2018 AACR. PMID- 29440291 TI - Small Molecule-Mediated Activation of RAS Elicits Biphasic Modulation of Phospho ERK Levels that Are Regulated through Negative Feedback on SOS1. AB - Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacologic modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here, we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS-mutant isoforms. We show that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant or after pretreatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time-dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of an S1178A SOS1 mutant. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated RAS-GTP levels over time in response to compound, as compared with the biphasic changes in RAS-GTP exhibited in cells expressing wild-type SOS1. These results suggest that small molecule targeting of SOS1 can elicit a biphasic modulation of RAS-GTP and phospho-ERK levels through negative feedback on SOS1 that regulates the interaction between SOS1 and GRB2. Mol Cancer Ther; 17(5); 1051-60. (c)2018 AACR. PMID- 29440292 TI - A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs). AB - Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared with those of the cross-linker. Thus, the improved in vivo tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment. Mol Cancer Ther; 17(3); 650-60. (c)2018 AACR. PMID- 29440293 TI - A Correlative Analysis of PD-L1, PD-1, PD-L2, EGFR, HER2, and HER3 Expression in Oropharyngeal Squamous Cell Carcinoma. AB - We explored potential associations of the PD-1/PD-L1/PD-L2 pathway with clinical characteristics, outcome, and expression of EGFR, HER2, HER3 in oropharyngeal squamous cell carcinoma (OPSCC) using an institutional database. Protein expression was assessed by IHC on tissue microarray sections (EGFR, HER2, HER3) or whole tissue sections (PD-1/PD-L1/PD-L2). Expression of EGFR, HER2, HER3, PD L1, and PD-L2 was quantified on tumor cells. Maximum density of PD-1 positive lymphocytes was measured on a scale of 0 to 4 within the tumor mass and peritumoral stroma. Associations between biomarkers and patient outcomes were tested using descriptive and inferential statistics, logistic regression, and Cox proportional hazards models. We analyzed tissue samples from 97 OPSCC cases: median age 59 years, p16+ (71%), male (83.5%), never smokers (18%), stage 3 to 4 disease (77%). Twenty-five percent of cases were PD-L1 positive. The proportion of PD-L1+ tumors was higher in p16+ (29%) than p16- OPSCC (11%, P = 0.047). There was no correlation between PD-L1, PD-L2, PD-1, EGFR, HER2, or HER3 expression. Positive PD-L1 status correlated with advanced nodal disease on multivariate analysis (OR 5.53; 95% CI, 1.06-28.77; P = 0.042). Negative PD-L2 expression was associated with worse survival (HR 3.99; 95% CI, 1.37-11.58; P = 0.011) in p16- OPSCC. Lower density of PD-1 positive lymphocytes in peritumoral stroma was associated with significantly increased risk of death on multivariate analysis (HR 3.17; 95% CI, 1.03-9.78; P = 0.045) after controlling for prognostic factors such as stage and p16 status. PD-L1 expression on tumor cells correlates with p16 status and advanced nodal status in OPSCC. PD-1 positive lymphocytes in peritumoral stroma serve as an independent prognostic factor for overall survival. Mol Cancer Ther; 17(3); 710-6. (c)2018 AACR. PMID- 29440294 TI - In Vitro and In Vivo Activity of IMGN853, an Antibody-Drug Conjugate Targeting Folate Receptor Alpha Linked to DM4, in Biologically Aggressive Endometrial Cancers. AB - Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FRalpha) expression in these biologically aggressive (type II) endometrial cancers and evaluate FRalpha as a targetable receptor for IMGN853 (mirvetuximab soravtansine). The expression of FRalpha was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FRalpha. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/patient-derived xenograft (PDX) models. Semiquantitative IHC analysis indicated that 41% of the USC patients overexpress FRalpha. Further, overexpression of FRalpha (i.e., 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared with control in 2+ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FRalpha showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FRalpha = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FRalpha, IMGN853 treatment showed complete resolution of tumors (P < 0.001). Treatment with IMGN853 in the USC PDX model (BIO(K)1), expressing 2+ FRalpha, induced twofold increase in median survival (P < 0.001). IMGN853 shows impressive antitumor activity in biologically aggressive FRalpha 2+ uterine cancers. These preclinical data suggest that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FRalpha may benefit from this treatment. Mol Cancer Ther; 17(5); 1003-11. (c)2018 AACR. PMID- 29440296 TI - PIM Kinases Are a Potential Prognostic Biomarker and Therapeutic Target in Neuroblastoma. AB - The majority of high-risk neuroblastoma patients are refractory to, or relapse on, current treatment regimens, resulting in 5-year survival rates of less than 50%. This emphasizes the urgent need to identify novel therapeutic targets. Here, we report that high PIM kinase expression is correlated with poor overall survival. Treatment of neuroblastoma cell lines with the pan-PIM inhibitors AZD1208 or PIM-447 suppressed proliferation through inhibition of mTOR signaling. In a panel of neuroblastoma cell lines, we observed a marked binary response to PIM inhibition, suggesting that specific genetic lesions control responses to PIM inhibition. Using a genome-wide CRISPR-Cas9 genetic screen, we identified NF1 loss as the major resistance mechanism to PIM kinase inhibitors. Treatment with AZD1208 impaired the growth of NF1 wild-type xenografts, while NF1 knockout cells were insensitive. Thus, our data indicate that PIM inhibition may be a novel targeted therapy in NF1 wild-type neuroblastoma. Mol Cancer Ther; 17(4); 849-57. (c)2018 AACR. PMID- 29440295 TI - MicroRNA-203 Inhibits Long Noncoding RNA HOTAIR and Regulates Tumorigenesis through Epithelial-to-mesenchymal Transition Pathway in Renal Cell Carcinoma. AB - This study aims to investigate the role of miR-203-HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration, and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly underexpressed, whereas HOTAIR was overexpressed in RCC cell lines and clinical specimens compared with normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathologic characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration, and invasion with an induction of apoptosis and cell cycle arrest. However, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico, RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203-HOTAIR interaction resulted in the inhibition of epithelial-to mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers), and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal marker), KLF4, and Nanog (stemness markers) was also observed. This is the first report demonstrating miR-203-mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis. Mol Cancer Ther; 17(5); 1061-9. (c)2018 AACR. PMID- 29440297 TI - MI130004, a Novel Antibody-Drug Conjugate Combining Trastuzumab with a Molecule of Marine Origin, Shows Outstanding In Vivo Activity against HER2-Expressing Tumors. AB - In the search for novel payloads to design new antibody-drug conjugates (ADC), marine compounds represent an interesting opportunity given their unique chemical features. PM050489 is a marine compound that binds beta-tubulin at a new site and disrupts the microtubule network, hence leading to mitotic aberrations and cell death. PM050489 has been conjugated to trastuzumab via Cys residues through a noncleavable linker, and the resulting ADC, named MI130004, has been studied. Analysis of MI130004 delivered data consistent with the presence of two molecules of PM050489 per antibody molecule, likely bound to both sides of the intermolecular disulfide bond connecting the antibody light and heavy chains. The antitumor activity of MI130004 was analyzed in vitro and in vivo in different cell lines of diverse tumor origin (breast, ovary, and gastric cancer) expressing different levels of HER2. MI130004 showed very high in vitro potency and good selectivity for tumor cells that overexpressed HER2. At the cellular level, MI130004 impaired tubulin polymerization, causing disorganization and disintegration of the microtubule network, which ultimately led to mitotic failure, mirroring the effect of its payload. Treatment with MI130004 in mice carrying histologically diverse tumors expressing HER2 induced a long-lasting antitumor effect with statistically significant inhibition of tumor growth coupled with increases in median survival time compared with vehicle or trastuzumab. These results strongly suggest that MI130004 is endowed with remarkable anticancer activity and confirm the extraordinary potential of marine compounds for the design of new ADCs. Mol Cancer Ther; 17(4); 786-94. (c)2018 AACR. PMID- 29440298 TI - Reduced expression of the Nodal co-receptor Oep causes loss of mesendodermal competence in zebrafish. AB - The activation of specific gene expression programs depends on the presence of the appropriate signals and the competence of cells to respond to those signals. Although it is well established that cellular competence is regulated in space and time, the molecular mechanisms underlying the loss of competence remain largely unknown. Here, we determine the time window during which zebrafish prospective ectoderm loses its ability to respond to Nodal signals, and show that this coincides with a decrease in the levels of the Nodal co-receptor One-eyed pinhead (Oep). Bypassing Oep using a photoactivatable receptor, or an Oep independent ligand, allows activation of Nodal target genes for an extended period of time. These results suggest that the reduced expression of Oep causes the loss of responsiveness to Nodal signals in the prospective ectoderm. Indeed, extending the presence of Oep prolongs the window of competence to respond to Nodal signals. Our findings suggest a simple mechanism in which the decreasing level of one component of the Nodal signaling pathway regulates the loss of mesendodermal competence in the prospective ectoderm. PMID- 29440299 TI - A molecular framework controlling style morphology in Brassicaceae. AB - Organ formation in multicellular organisms depends on the coordinated activities of regulatory components that integrate developmental and hormonal cues to control gene expression and mediate cell-type specification. For example, development of the Arabidopsis gynoecium is tightly controlled by distribution and synthesis of the plant hormone auxin. The functions of several transcription factors (TFs) have been linked with auxin dynamics during gynoecium development; yet how their activities are coordinated is not known. Here, we show that five such TFs function together to ensure polarity establishment at the gynoecium apex. The auxin response factor ETTIN (ARF3; herein, ETT) is a central component of this framework. Interaction of ETT with TF partners is sensitive to the presence of auxin and our results suggest that ETT forms part of a repressive gene-regulatory complex. We show that this function is conserved between members of the Brassicaceae family and that variation in an ETT subdomain affects interaction strengths and gynoecium morphology. These results suggest that variation in affinities between conserved TFs can lead to morphological differences and thus contribute to the evolution of diverse organ shapes. PMID- 29440300 TI - An evolutionarily conserved NIMA-related kinase directs rhizoid tip growth in the basal land plant Marchantia polymorpha. AB - Tip growth is driven by turgor pressure and mediated by the polarized accumulation of cellular materials. How a single polarized growth site is established and maintained is unclear. Here, we analyzed the function of NIMA related protein kinase 1 (MpNEK1) in the liverwort Marchantia polymorpha In the wild type, rhizoid cells differentiate from the ventral epidermis and elongate through tip growth to form hair-like protrusions. In Mpnek1 knockout mutants, rhizoids underwent frequent changes in growth direction, resulting in a twisted and/or spiral morphology. The functional MpNEK1-Citrine protein fusion localized to microtubule foci in the apical growing region of rhizoids. Mpnek1 knockouts exhibited increases in both microtubule density and bundling in the apical dome of rhizoids. Treatment with the microtubule-stabilizing drug taxol phenocopied the Mpnek1 knockout. These results suggest that MpNEK1 directs tip growth in rhizoids through microtubule organization. Furthermore, MpNEK1 expression rescued ectopic outgrowth of epidermal cells in the Arabidopsis thaliana nek6 mutant, strongly supporting an evolutionarily conserved NEK-dependent mechanism of directional growth. It is possible that such a mechanism contributed to the evolution of the early rooting system in land plants. PMID- 29440301 TI - Cyclical expression of GDNF is required for spermatogonial stem cell homeostasis. AB - In the murine testis, self-renewal of spermatogonial stem cells (SSCs) requires glial cell line-derived neurotrophic factor (GDNF) secreted from neighboring somatic cells. However, it not clear how GDNF promotes self-renewal in vivo or what downstream signaling pathways are required for SSC maintenance. We found that GDNF is normally expressed cyclically during spermatogenesis. Stage-specific ectopic expression of GDNF caused the accumulation of a GFRA1+ LIN28- Asingle population, which has enhanced SSC activity compared with wild type, suggesting that GDNF normally limits self-renewal to specific stages. Despite the increase in SSC cell number, EdU labeling during steady-stage spermatogenesis, and during recovery after busulfan-mediated spermatogonial depletion, indicated that GDNF promotes self-renewal by blocking differentiation and not by promoting proliferation. Increased GDNF signaling led to increased phosphorylation of AKT3 in undifferentiated spermatogonia, but not of AKT1 or AKT2, and was independent of RPS6 phosphorylation, suggesting that AKT3 functions in SSC self-renewal or progenitor cell expansion. PMID- 29440302 TI - Phosphorylation states change Otx2 activity for cell proliferation and patterning in the Xenopus embryo. AB - The homeodomain transcription factor Otx2 has essential roles in head and eye formation via the negative and positive regulation of its target genes, but it remains elusive how this dual activity of Otx2 affects cellular functions. In the current study, we first demonstrated that both exogenous and endogenous Otx2 are phosphorylated at multiple sites. Using Xenopus embryos, we identified three possible cyclin-dependent kinase (Cdk) sites and one Akt site, and analyzed the biological activities of phosphomimetic (4E) and nonphosphorylatable (4A) mutants for those sites. In the neuroectoderm, the 4E but not the 4A mutant downregulated the Cdk inhibitor gene p27xic1 (cdknx) and posterior genes, and promoted cell proliferation, possibly forming a positive-feedback loop consisting of Cdk, Otx2 and p27xic1 for cell proliferation, together with anteriorization. Conversely, the 4A mutant functioned as an activator on its own and upregulated the expression of eye marker genes, resulting in enlarged eyes. Consistent with these results, the interaction of Otx2 with the corepressor Tle1 is suggested to be phosphorylation dependent. These data suggest that Otx2 orchestrates cell proliferation, anteroposterior patterning and eye formation via its phosphorylation state. PMID- 29440303 TI - Mechanical strain regulates the Hippo pathway in Drosophila. AB - Animal cells are thought to sense mechanical forces via the transcriptional co activators YAP (or YAP1) and TAZ (or WWTR1), the sole Drosophila homolog of which is named Yorkie (Yki). In mammalian cells in culture, artificial mechanical forces induce nuclear translocation of YAP and TAZ. Here, we show that physiological mechanical strain can also drive nuclear localisation of Yki and activation of Yki target genes in the Drosophila follicular epithelium. Mechanical strain activates Yki by stretching the apical domain, reducing the concentration of apical Crumbs, Expanded, Kibra and Merlin, and reducing apical Hippo kinase dimerisation. Overexpressing Hippo kinase to induce ectopic activation in the cytoplasm is sufficient to prevent Yki nuclear localisation even in flattened follicle cells. Conversely, blocking Hippo signalling in warts clones causes Yki nuclear localisation even in columnar follicle cells. We find no evidence for involvement of other pathways, such as Src42A kinase, in regulation of Yki. Finally, our results in follicle cells appear generally applicable to other tissues, as nuclear translocation of Yki is also readily detectable in other flattened epithelial cells such as the peripodial epithelium of the wing imaginal disc, where it promotes cell flattening. PMID- 29440305 TI - Exposure to traffic-related air pollution and acute bronchitis in children: season and age as modifiers. AB - BACKGROUND: Acute bronchitis (AB) is one of the principal causes of childhood morbidity. Increasing number of studies has shown that air pollution is an important environmental contributor of respiratory disease. However, evidence so far is scarce regarding the effects of air pollution on childhood AB, and it also remains unclear how the risk of AB will change by season and age. METHODS: Data on hospital visits for AB in children, air pollution and meteorological factors from 1 January 2015 to 31 December 2016 were collected in Hefei, China. Time series analysis was applied to assess the short-term effects of traffic-related air pollution on childhood AB outpatient visits. A Poisson generalised linear regression model combined with a distributed lag non-linear model was used to estimate the relationships, controlling for long-term trends, seasonal patterns, meteorological factors and other possible confounders. RESULTS: We found that an IQR increase in concentrations of nitrogen dioxide, particulate matter <2.5 um and carbon monoxide significantly increased the daily hospital visits for childhood AB with 4-day cumulative effect estimates (relative risks: 1.03, 95% CI 1.01 to 1.05; 1.09, 95% CI 1.07 to 1.11; 1.07, 95% CI 1.05 to 1.09). Notably, the risk estimates during the cold season are pronounced; however, no significant association was observed during the warm season. Interestingly, children aged 6 14 years were more vulnerable to air pollutants than children aged less than 1 year and within 1-5 years. However, no gender difference was observed. CONCLUSION: A significant association of traffic-related air pollution and increased department visits for childhood AB was observed, notably in school-age children and during the cold season. PMID- 29440306 TI - Trends and determinants of the Flynn effect in cognitive functioning among older individuals in 10 European countries. AB - BACKGROUND: Although cognitive performance levels in old age have increased in most countries, recent evidence documents a slowing down or even decline in cohort gains in highly developed countries. The aim of this study was to assess trends and determinants in secular cohort gains in cognitive functioning among older individuals and whether cohort gains are levelling off in most advanced countries. METHODS: Data for individuals aged between 50 and 84 years from the Survey of Health, Ageing and Retirement in Europe in 10 European countries between 2004 and 2013 (n=92 739) were used to assess country and age-specific changes in immediate word recall. Multivariate random intercept models were used to assess associations between secular cohort changes in immediate word recall, initial performance levels and changes in country-level socio-demographic characteristics. RESULTS: Performance in immediate word recall improved in all countries between 2004 and 2013 (from 4.40 to 5.08 words, P<0.05). However, secular cohort gains were significantly smaller in countries with initially higher performance levels (coeff.=-0.554, 95% CI -0.682 to -0.426). Changes in socio-demographic and health conditions, including decreases in cardiovascular disease, physical activity and educational achievement, were associated with larger secular cohort gains. CONCLUSIONS: Results may either reflect that some countries are approaching the limits of cognitive plasticity, are slowing in their progress or that societal structures have not yet been optimised to improve cognitive abilities in midlife and beyond, or a combination of these interpretations. PMID- 29440304 TI - beta-Catenin maintains lung epithelial progenitors after lung specification. AB - The entire lung epithelium arises from SRY box 9 (SOX9)-expressing progenitors that form the respiratory tree and differentiate into airway and alveolar cells. Despite progress in understanding their initial specification within the embryonic foregut, how these progenitors are subsequently maintained is less clear. Using inducible, progenitor-specific genetic mosaic mouse models, we showed that beta-catenin (CTNNB1) maintains lung progenitors by promoting a hierarchical lung progenitor gene signature, suppressing gastrointestinal (GI) genes, and regulating NK2 homeobox 1 (NKX2.1) and SRY box 2 (SOX2) in a developmental stage-dependent manner. At the early, but not later, stage post lung specification, CTNNB1 cell-autonomously maintained normal NKX2.1 expression levels and suppressed ectopic SOX2 expression. Genetic epistasis analyses revealed that CTNNB1 is required for fibroblast growth factor (Fgf)/Kirsten rat sarcoma viral oncogene homolog (Kras)-mediated promotion of the progenitors. In silico screening of Eurexpress and translating ribosome affinity purification (TRAP)-RNAseq identified a progenitor gene signature, a subset of which depends on CTNNB1. Wnt signaling also maintained NKX2.1 expression and suppressed GI genes in cultured human lung progenitors derived from embryonic stem cells. PMID- 29440307 TI - Community group membership and multidimensional subjective well-being in older age. AB - BACKGROUND: It has been highlighted as a public health priority to identify ways of supporting well-being in older age to allow people to lead healthy and integrated lifestyles. This study explored whether membership in eight different sorts of community groups was associated with enhanced experienced, evaluative and eudemonic well-being among older adults. METHODS: We analysed data from 2548 adults aged 55+ drawn from the English Longitudinal Study of Aging. We used multivariate logistic and linear regression models to compare change in well being between baseline and follow-up 10 years later in relation to membership of different community groups while controlling for potential confounding variables. RESULTS: Membership in two types of community groups was associated with enhanced well-being: attending education, arts or music classes was longitudinally associated with lower negative affect (OR 0.73, CI 0.57 to 0.92) and life satisfaction (beta 0.55, CI 0.02 to 1.08) while church or religious group membership was longitudinally associated with lower negative affect (OR 0.79, CI 0.65 to 0.98) and higher positive affect (OR 1.54, CI 1.25 to 1.90). There was no evidence of reverse causality through cross-lagged analyses. However, just 17.4% and 24.6% of older adults were found to engage in these two types of community groups, respectively, and several demographic factors were identified as barriers to participation. CONCLUSIONS: Overall, this study suggests that education, arts or music classes and church or religious groups may support well-being in older age. Programmes to encourage engagement could be designed for older adults who may not normally access these community resources. PMID- 29440308 TI - Your health is your wealth: faith-based community action on the health of African migrant communities in Amsterdam. AB - The African migrant communities in Europe face many challenges including poor health outcomes. Migrant community leaders can play a crucial role in addressing the health needs of their community members. In this paper, we described Sub Saharan African migrant community leaders' action to improve the health of their faith-based community members in Amsterdam, the Netherlands. PMID- 29440309 TI - Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist-Induced Rat Models of Schizophrenia. AB - The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain penetrant PDE2A inhibitor, (N-{(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2 methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia. PMID- 29440312 TI - Symphony of the Regulators: How Do Plants Control Complex Responses to Environmental Signals? PMID- 29440310 TI - Asp1 Bifunctional Activity Modulates Spindle Function via Controlling Cellular Inositol Pyrophosphate Levels in Schizosaccharomyces pombe. AB - The generation of two daughter cells with the same genetic information requires error-free chromosome segregation during mitosis. Chromosome transmission fidelity is dependent on spindle structure/function, which requires Asp1 in the fission yeast Schizosaccharomyces pombe Asp1 belongs to the diphosphoinositol pentakisphosphate kinase (PPIP5K)/Vip1 family which generates high-energy inositol pyrophosphate (IPP) molecules. Here, we show that Asp1 is a bifunctional enzyme in vivo: Asp1 kinase generates specific IPPs which are the substrates of the Asp1 pyrophosphatase. Intracellular levels of these IPPs directly correlate with microtubule stability: pyrophosphatase loss-of-function mutants raised Asp1 made IPP levels 2-fold, thus increasing microtubule stability, while overexpression of the pyrophosphatase decreased microtubule stability. Absence of Asp1-generated IPPs resulted in an aberrant, increased spindle association of the S. pombe kinesin-5 family member Cut7, which led to spindle collapse. Thus, chromosome transmission is controlled via intracellular IPP levels. Intriguingly, identification of the mitochondrion-associated Met10 protein as the first pyrophosphatase inhibitor revealed that IPPs also regulate mitochondrial distribution. PMID- 29440311 TI - Heritable, allele-specific chromosomal looping between tandem promoters specifies promoter usage of SHC1. AB - Half of the genes in the human genome contain alternative promoters, some of which generate products with opposing functions. Aberrant silencing or activation of such alternative promoters is associated with multiple diseases including cancer, but little is known regarding the molecular mechanisms that control alternative promoter choice. The SHC1 gene encodes p46Shc/p52Shc and p66Shc, proteins oppositely regulating anchorage independent growth that are produced respectively by transcription initiated from the upstream and downstream tandem promoters of SHC1 Here we demonstrate that activation of these promoters is mutually exclusive on separate alleles in single primary endothelial cells in a heritable fashion, assuring expression of both transcripts by the cell. Peripheral blood lymphocytes that do not transcribe p66Shc transcribed p52Shc biallelically. This distinct monoallelic transcription pattern is established by allele-specific chromosomal looping between tandem promoters, which silences the upstream promoter. Our results reveal a new mechanism to control alternative promoter usage through higher order chromatin structure. PMID- 29440313 TI - Hold Me Closer: Meiotic Crossover Formation and FANCD2. PMID- 29440314 TI - SULFATION PATHWAYS: The steroid sulfate axis and its relationship to maternal behaviour and mental health. AB - Steroid hormones can exist in functionally dissociable sulfated and non-sulfated (free) forms and can exert profound effects on numerous aspects of mammalian physiology; the ratio of free-to-sulfated steroids is governed by the antagonistic actions of steroid sulfatase (STS) and sulfotransferase (SULT) enzymes. Here, I examine evidence from human and animal model studies, which suggests that STS and its major substrate (dehydroepiandrosterone sulfate, DHEAS) and product (DHEA) can influence brain function, behaviour and mental health, before summarising how the activity of this axis varies throughout mammalian pregnancy and the postpartum period. I then consider how the steroid sulfate axis might impact upon normal maternal behaviour and how its dysfunction might contribute towards risk of postpartum psychiatric illness. Understanding the biological substrates underlying normal and abnormal maternal behaviour will be important for maximising the wellbeing of new mothers and their offspring. PMID- 29440315 TI - JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study. AB - BACKGROUND: Pulmonary hypertension (PH) is a common disorder in patients with idiopathic pulmonary fibrosis (IPF) and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation (V)/perfusion (Q) mismatching and oxygen desaturation. Janus kinase type 2 (JAK2) is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown. OBJECTIVE: The study of JAK2 as potential target to treat PH in IPF. METHODS AND RESULTS: JAK2 expression was increased in pulmonary arteries (PAs) from IPF (n=10; 1.93-fold; P=0.0011) and IPF+PH (n=9; 2.65-fold; P<0.0001) compared with PA from control subjects (n=10). PA remodelling was evaluated in human pulmonary artery endothelial cells (HPAECs) and human pulmonary artery smooth muscle cells (HPASMCs) from patients with IPF in vitro treated with the JAK2 inhibitor JSI-124 or siRNA-JAK2 and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-JAK2 inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. JAK2 inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel (BKCa). JAK2 inhibition activated BKCa channels and reduced intracellular Ca2+. JSI-124 1 mg/kg/day, reduced bleomycin-induced lung fibrosis, PA remodelling, right ventricular hypertrophy, PA hypertension and V/Q mismatching in rats. The animal studies followed the ARRIVE guidelines. CONCLUSIONS: JAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH. PMID- 29440316 TI - Glial fibrillary acidic protein antibody-positive meningoencephalomyelitis. AB - Glial fibrillary acidic protein antibody-positive meningoencephalomyelitis is a newly described, possibly under-recognised, severe inflammatory condition of the nervous system. The clinical presentation is variable but most commonly is a combination of meningitis, encephalitis and myelitis; other manifestations may include seizures, psychiatric symptoms and tremor. There is a significant association with malignancies, often occult, and with other autoimmune conditions. Although the disease responds well to corticosteroids acutely, it typically relapses when these are tapered, and so patients need long-term immunosuppression. We report a young man presenting with subacute meningoencephalitis and subsequent myelitis, and discuss the typical presentation and management of this severe but treatable condition. PMID- 29440317 TI - Thioredoxin regulates G6PDH activity by changing redox states of OpcA in the nitrogen-fixing cyanobacterium Anabaena sp. PCC 7120. AB - Glucose 6-phosphate dehydrogenase (G6PDH) catalyzes the first reaction in the oxidative pentose phosphate pathway. In green plant chloroplasts, G6PDH is a unique redox-regulated enzyme, since it is inactivated under the reducing conditions. This regulation is accomplished using a redox-active cysteine pair, which is conserved in plant G6PDH. The inactivation of this enzyme under conditions of light must be beneficial to prevent release of CO2 from the photosynthetic carbon fixation cycle. In the filamentous, heterocyst-forming, nitrogen-fixing cyanobacterium Anabaena sp. PCC 7120 (Anabaena 7120), G6PDH plays a pivotal role in providing reducing power for nitrogenase, and its activity is also reported to be suppressed by reduction, though Anabaena G6PDH does not conserve the critical cysteines for regulation. Based on the thorough analyses of the redox regulation mechanisms of G6PDH from Anabaena 7120 and its activator protein OpcA, we found that m-type thioredoxin regulates G6PDH activity by changing the redox states of OpcA. Mass spectrometric analysis and mutagenesis studies indicate that Cys393 and Cys399 of OpcA are responsible for the redox regulation property of this protein. Moreover, in vivo analyses of the redox states of OpcA showed that more than half of the OpcA is present as an oxidized form, even under conditions of light, when cells are cultured under the nitrogen fixing conditions. This redox regulation of OpcA might be necessary to provide reducing power for nitrogenase by G6PDH in heterocysts even during the day. PMID- 29440320 TI - Left of bang interventions in trauma: some legal implications of military medical prophylaxis. AB - In the context of military medical care, Eisenstein and colleagues have introduced the notion 'left of bang intervention in trauma', which refers to interventions administered before trauma to reduce morbidity and mortality after injury. This paper responds to Eisenstein and colleagues' ethical analysis of such interventions, highlighting the difficulty in distinguishing between purely prophylactic and enhancing interventions. This response also addresses legal issues that arise from left of bang interventions under human rights law and the law of armed conflict, in particular the questions as to whether the consent of service members would need to be obtained and whether the adversary would as a consequence be authorised to resort to more injurious weapons. PMID- 29440318 TI - Monitoring the 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) modification in eukaryotic tRNAs via the gamma-toxin endonuclease. AB - The post-transcriptional modification of tRNA at the wobble position is a universal process occurring in all domains of life. In eukaryotes, the wobble uridine of particular tRNAs is transformed to the 5-methoxycarbonylmethyl-2 thiouridine (mcm5s2U) modification which is critical for proper mRNA decoding and protein translation. However, current methods to detect mcm5s2U are technically challenging and/or require specialized instrumental expertise. Here, we show that gamma-toxin endonuclease from the yeast Kluyveromyces lactis can be used as a probe for assaying mcm5s2U status in the tRNA of diverse eukaryotic organisms ranging from protozoans to mammalian cells. The assay couples the mcm5s2U dependent cleavage of tRNA by gamma-toxin with standard molecular biology techniques such as northern blot analysis or quantitative PCR to monitor mcm5s2U levels in multiple tRNA isoacceptors. The results gained from the gamma-toxin assay reveals the evolutionary conservation of the mcm5s2U modification across eukaryotic species. Moreover, we have used the gamma-toxin assay to verify uncharacterized eukaryotic Trm9 and Trm112 homologs that catalyze the formation of mcm5s2U. These findings demonstrate the use of gamma-toxin as a detection method to monitor mcm5s2U status in diverse eukaryotic cell types for cellular, genetic, and biochemical studies. PMID- 29440319 TI - Tudor staphylococcal nuclease is a structure-specific ribonuclease that degrades RNA at unstructured regions during microRNA decay. AB - Tudor staphylococcal nuclease (TSN) is an evolutionarily conserved ribonuclease in eukaryotes that is composed of five staphylococcal nuclease-like domains (SN1 SN5) and a Tudor domain. TSN degrades hyper-edited double-stranded RNA, including primary miRNA precursors containing multiple I*U and U*I pairs, and mature miRNA during miRNA decay. However, how TSN binds and degrades its RNA substrates remains unclear. Here, we show that the C. elegans TSN (cTSN) is a monomeric Ca2+ dependent ribonuclease, cleaving RNA chains at the 5'-side of the phosphodiester linkage to produce degraded fragments with 5'-hydroxyl and 3'-phosphate ends. cTSN degrades single-stranded RNA and double-stranded RNA containing mismatched base pairs, but is not restricted to those containing multiple I*U and U*I pairs. cTSN has at least two catalytic active sites located in the SN1 and SN3 domains, since mutations of the putative Ca2+-binding residues in these two domains strongly impaired its ribonuclease activity. We further show by small-angle X-ray scattering that rice osTSN has a flexible two-lobed structure with open to closed conformations, indicating that TSN may change its conformation upon RNA binding. We conclude that TSN is a structure-specific ribonuclease targeting not only single-stranded RNA, but also unstructured regions of double-stranded RNA. This study provides the molecular basis for how TSN cooperates with RNA editing to eliminate duplex RNA in cell defense, and how TSN selects and degrades RNA during microRNA decay. PMID- 29440321 TI - Targeting the MAPK Pathway in RAS Mutant Cancers. AB - Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this review, we highlight the challenges and opportunities in targeting KRAS mutant tumors through inhibition of mitogen-activated protein kinase (MAPK) signaling with conformation-specific kinase inhibitors. Through structural analysis and mechanistic studies with BRAF and mitogen-activated protein kinase (MEK) inhibitors, we describe how kinase-dependent and -independent functions of MAPK signaling components regulate KRAS-driven tumorigenesis and how these insights can be used to treat RAS mutant cancers with small molecule kinase inhibitors. PMID- 29440322 TI - Neurodegeneration in Progressive Multiple Sclerosis. AB - The neuron is the target of inflammatory demyelinating processes in multiple sclerosis (MS). In progressive MS, however, there is a gathering body of evidence indicating molecular changes within neuronal cell bodies. All of these molecular changes to intrinsic neurons converge on mitochondria, and the most reproduced change relates to mitochondrial respiratory chain complex deficiency. This compromise in the capacity to generate ATP in the neuronal cell body is coupled with an increased demand for energy by the demyelinated axon, which is particularly relevant to the long tracts such as corticospinal tracts with long projection axons. Recent work in our laboratory and that of our collaborators indicate limited reflection of the molecular changes that are intrinsic neurons in the experimental disease models. The mitochondrial changes within neuronal compartments are an under-recognized aspect of progressive MS and likely to offer novel targets for the improvement of neuronal function as well as neuroprotection. PMID- 29440323 TI - The Evolving Mechanisms of Action of Glatiramer Acetate. AB - Glatiramer acetate (GA) is a synthetic amino acid copolymer that is approved for treatment of relapsing remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS). GA reduces multiple sclerosis (MS) disease activity and has shown comparable efficacy with high-dose interferon-beta. The mechanism of action (MOA) of GA has long been an enigma. Originally, it was recognized that GA treatment promoted expansion of GA-reactive T-helper 2 and regulatory T cells, and induced the release of neurotrophic factors. However, GA treatment influences both innate and adaptive immune compartments, and it is now recognized that antigen-presenting cells (APCs) are the initial cellular targets for GA. The anti inflammatory (M2) APCs induced following treatment with GA are responsible for the induction of anti-inflammatory T cells that contribute to its therapeutic benefit. Here, we review studies that have shaped our current understanding of the MOA of GA. PMID- 29440324 TI - Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis A. AB - Hepatitis A virus (HAV) is transmitted by the fecal-oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute liver failure (ALF), but do not include progression to chronic hepatitis. Risk factors for severe acute hepatitis A are older age (>40 years) and preexisting liver disease. Some patients may show atypical clinical features such as relapsing hepatitis, prolonged cholestasis, or extrahepatic manifestations. Almost all hepatitis A patients spontaneously recover with supportive care. However, in the case of ALF (<1%), intensive care and urgent decision on liver transplantation are required. Liver injury during hepatitis A is not directly caused by HAV but is known to be caused by immune mediated mechanisms. In this review, the natural history and clinical manifestations of hepatitis A are described. In addition, mechanisms of immunopathogenesis in hepatitis A are discussed. PMID- 29440325 TI - Genetics of Multiple Sclerosis: An Overview and New Directions. AB - The contribution of genetic inheritance in multiple sclerosis was established early on. Although multiple sclerosis is not a Mendelian disease, its incidence and prevalence is higher in family members of affected individuals compared with the general population. Throughout the last decade, several small studies failed to identify any robust genetic associations besides the classic associations in the major histocompatibility complex region. During the past few years, genome wide association studies (GWAS) have revolutionized the genetics of multiple sclerosis, uncovering more than 200 implicated genetic loci. Here, we describe these main findings and discuss the new avenues that these discoveries lay open. PMID- 29440326 TI - Multiparametric MRI of intracranial aneurysms treated with the Woven EndoBridge (WEB): a case of Faraday's cage? AB - OBJECTIVE: To evaluate multiparametric MRI including non-contrast and contrast enhanced morphological and angiographic techniques for intracranial aneurysms treated with the single-layer Woven EndoBridge (WEB) embolization system applying simultaneous digital subtraction angiography (DSA) as the reference of standard. MATERIALS AND METHODS: We retrospectively identified all patients with incidental and acute ruptured intracranial aneurysms treated with a WEB device (WEB SL and WEB SLS) between March 2014 and June 2016 in our neurovascular center with early (within 7 days) postinterventional multiparametric MRI as well as mid-term (5-8 months) follow-up MRI and DSA available. Occlusion rates were recorded both in DSA and MR angiography (MRA). In MRI, signal intensities within the WEB as well as in the occluded dome distal to the WEB, if present, were measured by region-of interest (ROI) analysis. RESULTS: Twenty-five patients fulfilled the inclusion criteria. Rates of complete/adequate occlusion at mid-term follow-up were 84% with both MRA and DSA. A strong signal loss within the WEB was observed in all MR sequences at initial and follow-up examinations. ROI analysis did not reveal significant differences in non-contrast (P=0.946) and contrast-enhanced imaging (P=0.377). A T1-hyperintense thrombus in the non-WEB-carrying dome was a frequent observation. CONCLUSIONS: Signal intensity measurements in multiparametric MRI suggest that neither contrast-enhanced MRA nor morphological sequences are capable of revealing reliable information on the WEB lumen, presumably due to radio frequency shielding. MRI is therefore not suitable for confirming complete thrombus formation within the WEB. PMID- 29440327 TI - Cardiovascular effects among workers exposed to multiwalled carbon nanotubes. AB - OBJECTIVES: The increase in production of multiwalled carbon nanotubes (MWCNTs) has led to growing concerns about health risks. In this study, we assessed the association between occupational exposure to MWCNTs and cardiovascular biomarkers. METHODS: A cross-sectional study was performed among 22 workers of a company commercially producing MWCNTs (subdivided into lab personnel with low or high exposure and operators), and a gender and age-matched unexposed population (n=42). Exposure to MWCNTs and 12 cardiovascular markers were measured in participants' blood (phase I). In a subpopulation of 13 exposed workers and six unexposed workers, these measures were repeated after 5 months (phase II). We analysed associations between MWCNT exposure and biomarkers of cardiovascular risk, adjusted for age, body mass index, sex and smoking. RESULTS: We observed an upward trend in the concentration of endothelial damage marker intercellular adhesion molecule-1 (ICAM-1), with increasing exposure to MWCNTs in both phases. The operator category showed significantly elevated ICAM-1 geometric mean ratios (GMRs) compared with the controls (phase I: GMR=1.40, P=1.30E-3; phase II: GMR=1.37, P=0.03). The trends were significant both across worker categories (phase I: P=1.50E-3; phase II: P=0.01) and across measured GM MWCNT concentrations (phase I: P=3.00E-3; phase II: P=0.01). No consistent significant associations were found for the other cardiovascular markers. CONCLUSION: The associations between MWCNT exposure and ICAM-1 indicate endothelial activation and an increased inflammatory state in workers with MWCNT exposure. PMID- 29440328 TI - Evaluation of California's 'Tobacco 21' law. AB - INTRODUCTION: California's law raising the minimum tobacco sales age to 21 went into effect on 9 June 2016. This law, known as 'Tobacco 21' or 'T21', also expanded the definition of tobacco to include electronic smoking devices. This paper describes the T21 evaluation plan and initial evaluation results. METHODS: An evaluation plan and logic model were created to evaluate T21. A tobacco retailer poll was conducted 7 months after the law went into effect to assess awareness, support and implementation; an online survey of California adults was fielded to provide data on tobacco use and attitudinal changes before and after T21 implementation; and tobacco purchase surveys were conducted to assess the retailer violation rate (RVR). Multivariate models estimated the odds of RVR and odds of being aware, agreeing with and observing advertisements related to T21. RESULTS: Seven months after the T21 effective date, 98.6% of retailers were aware of the law and 60.6% supported the law. Furthermore, 66.2% of retailers agreed that people who start smoking before 21 would become addicted to tobacco products. The RVR using youth decoys under age 18 statistically decreased from 10.3% before T21 to 5.7% after T21 (P=0.002). Furthermore, the RVR using young adult decoys ages 18-19 was 14.2% (95% CI 9.3% to 19.1%) for traditional tobacco and 13.1% (95% CI 10.2% to 16.1%) for electronic smoking devices. CONCLUSIONS: Survey findings suggest that the high awareness and support for the law may have contributed to reducing illegal tobacco sales to youth under 18 and achieving widespread retailer conformity with the new law disallowing sales to young adults under 21. PMID- 29440329 TI - Accurately Predicting the Risk of Serious Maternal Morbidity in Preterm Preeclampsia: Can It Be Done? PMID- 29440330 TI - Assessment of the fullPIERS Risk Prediction Model in Women With Early-Onset Preeclampsia. AB - Early-onset preeclampsia is associated with severe maternal and perinatal complications. The fullPIERS model (Preeclampsia Integrated Estimate of Risk) showed both internal and external validities for predicting adverse maternal outcomes within 48 hours for women admitted with preeclampsia at any gestational age. This ability to recognize women at the highest risk of complications earlier could aid in preventing these adverse outcomes through improved management. Because the majority (~70%) of the women in the model development had late-onset preeclampsia, we assessed the performance of the fullPIERS model in women with early-onset preeclampsia to determine whether it will be useful in this subgroup of women with preeclampsia. Three cohorts of women admitted with early-onset preeclampsia between 2012 and 2016, from tertiary hospitals in Canada, the Netherlands, and United Kingdom, were used. Using the published model equation, the probability of experiencing an adverse maternal outcome was calculated for each woman, and model performance was evaluated based on discrimination, calibration, and stratification. The total data set included 1388 women, with an adverse maternal outcome rate of 7.3% within 48 hours of admission. The model had good discrimination, with an area under the receiver operating characteristic curve of 0.80 (95% confidence interval, 0.75-0.86), and a calibration slope of 0.68. The estimated likelihood ratio at the predicted probability of >=30% was 23.4 (95% confidence interval, 14.83-36.79), suggesting a strong evidence to rule in adverse maternal outcomes. The fullPIERS model will aid in identifying women admitted with early-onset preeclampsia in similar settings who are at the highest risk of adverse outcomes, thereby allowing timely and effective interventions. PMID- 29440331 TI - Dysregulated Pseudogene HK2P1 May Contribute to Preeclampsia as a Competing Endogenous RNA for Hexokinase 2 by Impairing Decidualization. AB - Preeclampsia is a pregnancy-specific hypertensive disorder, which seriously undermines the health of maternity and fetus. However, its cause and pathogenesis remain elusive. Flawed decidualization is considered to be related to preeclampsia. Increasing evidence indicates that long noncoding RNAs are correlated with a variety of diseases, including preeclampsia. In this study, we verified the expression of long noncoding RNA HK2P1 (hexokinase 2 pseudogene 1) and its cognate gene HK2 (hexokinase 2), which were found by our previous RNA sequencing analysis in the decidua of severe preeclampsia patients and matched control subjects. Besides that, we also investigated the function and the mechanism of HK2P1 and HK2 during decidualization. HK2 is the crucial enzyme involved in glycolysis. The HK2P1 and HK2 genes are homologous to each other. The results demonstrated that HK2P1, like HK2, stimulated the glucose uptake and lactate production of human endometrial stromal cells. In addition, HK2P1 and HK2 are indispensable for endometrial decidualization. Downregulated HK2P1 or HK2 inhibited human endometrial stromal cells proliferation and differentiation. Furthermore, there was a significant positive correlation between the expression of HK2P1 and HK2, and HK2P1 regulated the HK2 expression via competition for the shared miR-6887-3p. Taken together, our results indicated that the reduced expression of HK2P1 and HK2 may have contributed to the occurrence and development of preeclampsia by suppressing glycolysis and impairing decidualization. Our study would be helpful to understand the pathogenesis and the regulatory network of preeclampsia. PMID- 29440332 TI - Downregulated Serum 14, 15-Epoxyeicosatrienoic Acid Is Associated With Abdominal Aortic Calcification in Patients With Primary Aldosteronism. AB - Patients with primary aldosteronism (PA) have increased risk of target-organ damage, among which vascular calcification is an important indicator of cardiovascular mortality. 14, 15-Epoxyeicosatrienoic acid (14, 15-EET) has been shown to have beneficial effects in vascular remodeling. However, whether 14, 15 EET associates with vascular calcification in PA is unknown. Thus, we aimed to investigate the association between 14, 15-EET and abdominal aortic calcification (AAC) in patients with PA. Sixty-nine patients with PA and 69 controls with essential hypertension, matched for age, sex, and blood pressure, were studied. 14, 15-Dihydroxyeicosatrienoic acid (14, 15-DHET), the inactive metabolite from 14, 15-EET, was estimated to reflect serum 14, 15-EET levels. AAC was assessed by computed tomographic scanning. Compared with matched controls, the AAC prevalence was almost 1-fold higher in patients with PA (27 [39.1%] versus 14 [20.3%]; P=0.023), accompanied by significantly higher serum 14, 15-DHET levels (7.18+/ 4.98 versus 3.50+/-2.07 ng/mL; P<0.001). Plasma aldosterone concentration was positively associated with 14, 15-DHET (beta=0.444; P<0.001). Multivariable logistic analysis revealed that lower 14, 15-DHET was an independent risk factor for AAC in PA (odds ratio, 1.371; 95% confidence interval, 1.145-1.640; P<0.001), especially in young patients with mild hypertension and normal body mass index. In conclusion, PA patients exibited more severe AAC, accompanied by higher serum 14, 15-DHET levels. On the contrary, decreased 14, 15-EET was significantly associated with AAC prevalence in PA patients, especially in those at low cardiovascular risk. PMID- 29440333 TI - Non-tender recurrent scrotal cellulitis. PMID- 29440334 TI - Deep sedation for colonoscopy is unnecessary and wasteful. PMID- 29440335 TI - Age- and sex-specific Canadian utility norms, based on the 2013-2014 Canadian Community Health Survey. AB - BACKGROUND: Although many Canadian studies have provided disease-specific or patient group-specific utility scores, the utility score norms currently available for the general Canadian population are outdated. Canadian guideline recommendations for the economic evaluation of health technologies advocate for utilities reflecting those of the general population and for stratified analyses when results are heterogeneous; as such, there is also a need for age-, sex- and jurisdiction-specific utility score norms. METHODS: We used data from the 2013 2014 Canadian Community Health Survey. We used the Health Utilities Index Mark 3 to calculate utility scores. We estimated means (with 95% confidence intervals [CIs]) and medians (with interquartile ranges [IQRs]) for utility scores. In addition to Canadian-level measures, we stratified all utility score norms by respondents' age, sex, and province or territory of residence. We weighted respondents' answers and computed 95% CIs using sampling weights and bootstrap weights provided by Statistics Canada to extrapolate the study findings to the Canadian population. RESULTS: Respondents to the 2013-2014 Canadian Community Health Survey represented 30 014 589 community-dwelling Canadians 12 years of age and older (98% of the Canadian population); half of the respondents were female (50.6%), and the weighted average age was 44.8 (95% CI 44.7-44.9) years. The mean and median self-reported utility scores for Canadians were estimated at 0.863 (95% CI 0.861-0.865) and 0.927 (IQR 0.838-0.972), respectively. INTERPRETATION: This study provides utility score norms for several age-, sex-and jurisdiction specific strata in Canada. These results will be useful for future cost-utility analyses and could serve as benchmark values for comparisons with future studies. PMID- 29440336 TI - The genome, microbiome and evolutionary medicine. PMID- 29440337 TI - Pulmonary nodules as incidental findings. PMID- 29440338 TI - Placenta percreta. PMID- 29440339 TI - Thrombophilia testing in venous thromboembolism. PMID- 29440340 TI - The authors respond to "Thrombophilia testing in venous thromboembolism". PMID- 29440342 TI - Addressing physician burnout at the systems level. PMID- 29440341 TI - Validation of the Ottawa Subarachnoid Hemorrhage Rule in patients with acute headache. PMID- 29440343 TI - Is it ever ethical for doctors to diagnose patients they haven't examined? PMID- 29440344 TI - Nova Scotia doctors battle government over pay model. PMID- 29440345 TI - More supports for unmatched medical students coming soon. PMID- 29440348 TI - Correction: Ammonia excretion in aquatic invertebrates: new insights and questions (doi: 10.1242/jeb.169219). PMID- 29440346 TI - Drought Sensitivity of Norway Spruce at the Species' Warmest Fringe: Quantitative and Molecular Analysis Reveals High Genetic Variation Among and Within Provenances. AB - Norway spruce (Picea abies) is by far the most important timber species in Europe, but its outstanding role in future forests is jeopardized by its high sensitivity to drought. We analyzed drought response of Norway spruce at the warmest fringe of its natural range. Based on a 35-year old provenance experiment we tested for genetic variation among and within seed provenances across consecutively occurring strong drought events using dendroclimatic time series. Moreover, we tested for associations between ~1,700 variable SNPs and traits related to drought response, wood characteristics and climate-growth relationships. We found significant adaptive genetic variation among provenances originating from the species' Alpine, Central and Southeastern European range. Genetic variation between individuals varied significantly among provenances explaining up to 44% of the phenotypic variation in drought response. Varying phenotypic correlations between drought response and wood traits confirmed differences in selection intensity among seed provenances. Significant associations were found between 29 SNPs and traits related to drought, climate growth relationships and wood properties which explained between 11 and 43% of trait variation, though 12 of them were due to single individuals having extreme phenotypes of the respective trait. The majority of these SNPs are located within exons of genes and the most important ones are preferentially expressed in cambium and xylem expansion layers. Phenotype-genotype associations were stronger if only provenances with significant quantitative genetic variation in drought response were considered. The present study confirms the high adaptive variation of Norway spruce in Central and Southeastern Europe and demonstrates how quantitative genetic, dendroclimatic and genomic data can be linked to understand the genetic basis of adaptation to climate extremes in trees. PMID- 29440349 TI - Genetic tests in lymphatic vascular malformations and lymphedema. AB - Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as locus heterogeneity. The aim of this review is to provide a comprehensive clinical genetic description of lymphatic malformations and the techniques used for their diagnosis, and to propose a flowchart for genetic testing. Literature and database searches were performed to find conditions characterised by lymphatic malformations or the predisposition to lymphedema after surgery, to identify the associated genes and to find the guidelines and genetic tests currently used for the molecular diagnosis of these disorders. This search allowed us to identify several syndromes with lymphatic malformations that are characterised by a great heterogeneity of phenotypes, alleles and loci, and a high frequency of sporadic cases, which may be associated with somatic mutations. For these disorders, we found many diagnostic tests, an absence of harmonic guidelines for molecular diagnosis and well-established clinical guidelines. Targeted sequencing is the preferred method for the molecular diagnosis of lymphatic malformations. These techniques are easy to implement and have a good diagnostic success rates. In addition, they are relatively inexpensive and permit parallel analysis of all known disease-associated genes. The targeted sequencing approach has improved the diagnostic process, giving patients access to better treatment and, potentially, to therapy personalised to their genetic profiles. These new techniques will also facilitate the prenatal and early postnatal diagnosis of congenital lymphatic conditions and the possibility of early intervention. PMID- 29440347 TI - Thyroid hormone receptor localization in target tissues. AB - The thyroid hormone receptors, TRalpha1, TRbeta1 and other subtypes, are members of the nuclear receptor superfamily that mediate the action of thyroid hormone signaling in numerous tissues to regulate important physiological and developmental processes. Their most well-characterized role is as ligand dependent transcription factors; TRs bind thyroid hormone response elements in the presence or absence of thyroid hormone to facilitate the expression of target genes. Although primarily residing in the nucleus, TRalpha1 and TRbeta1 shuttle rapidly between the nucleus and cytoplasm. We have identified multiple nuclear localization signals and nuclear export signals within TRalpha1 and TRbeta1 that interact with importins and exportins, respectively, to mediate translocation across the nuclear envelope. More recently, enigmatic cytoplasmic functions have been ascribed to other TR subtypes, expanding the diversity of the cellular response to thyroid hormone. By integrating data on localization signal motifs, this review provides an overview of the complex interplay between TR's dynamic transport pathways and thyroid hormone signaling activities. We examine the variation in TR subtype response to thyroid hormone signaling, and what is currently known about regulation of the variety of tissue-specific localization patterns, including targeting to the nucleus, the mitochondria and the inner surface of the plasma membrane. PMID- 29440350 TI - Correction to: Correction: FOXP1-related intellectual disability syndrome: a recognisable entity. PMID- 29440351 TI - Th1, Th17, and Th1Th17 Lymphocytes during Tuberculosis: Th1 Lymphocytes Predominate and Appear as Low-Differentiated CXCR3+CCR6+ Cells in the Blood and Highly Differentiated CXCR3+/-CCR6- Cells in the Lungs. AB - Th1 lymphocytes are considered the main mediators of protection against tuberculosis (TB); however, their phenotypic characteristics and relationship with Th17 and Th1Th17 populations during TB are poorly understood. We have analyzed Th1, Th17, and Th1Th17 lymphocytes in the blood and pulmonary lesions of TB patients. The populations were identified based on the production of IFN-gamma and/or IL-17 and the coexpression of CXCR3 (X3) and CCR6 (R6). In the blood, IL 17+ and IFN-gamma+IL-17+ lymphocytes were barely detectable (median, <0.01% of CD4+ lymphocytes), whereas IFN-gamma+ lymphocytes predominated (median, 0.45%). Most IFN-gamma+ lymphocytes (52%) were X3+R6+, suggesting their "nonclassical" (ex-Th17) nature. In the lungs, IL-17+ and IFN-gamma+IL-17+ lymphocytes were more frequent (0.3%, p < 0.005), yet IFN-gamma+ cells predominated (11%). Phenotypically, lung CD4+ cells were X3+/loR6- The degree of differentiation of blood effector CD4+ lymphocytes (evaluated based on CD62L/CD27/CD28 coexpression) increased as follows: X3+R6+ < X3+R6- < X3-R6-, with X3-R6- cells being largely terminally differentiated CD62L-CD27-CD28- cells. Lung CD4+ lymphocytes were highly differentiated, recalling blood X3+/-R6- populations. Following in vitro stimulation with anti-CD3/anti-CD28 Abs, X3+R6+CD4+ lymphocytes converted into X3+R6- and X3-R6- cells. The results demonstrate that, during active TB, Th1 lymphocytes predominate in blood and lungs, document differences in X3/R6 expression by blood and lung CD4+ cells, and link the pattern of X3/R6 expression with the degree of cell differentiation. These findings add to the understanding of immune mechanisms operating during TB and are relevant for the development of better strategies to control it. PMID- 29440352 TI - c-Src-Dependent and -Independent Functions of Matk in Osteoclasts and Osteoblasts. AB - The non-receptor tyrosine kinase c-Src participates in bone metabolism by regulating the activities of both the bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we investigated whether megakaryocyte-associated tyrosine kinase (Matk), a potent inhibitor of c-Src, affects the functions of murine osteoclasts and osteoblasts. Results revealed that the formation of osteoclasts with actin rings was attenuated by Matk overexpression in osteoclast precursor cells but was enhanced by Matk knockdown. The inhibitory effect of Matk on osteoclasts was closely related with the inhibition of c-Src activity. Intriguingly, Matk overexpression in osteoblasts reduced bone nodule formation. Conversely, Matk knockdown increased osteoblast function. Most importantly, binding of Matk to Runx2 resulted in the inhibition of Runx2 translocation into the nucleus and downregulation of Runx2 target genes. Taken together, our findings demonstrated that Matk plays a critical role in bone metabolism by impairing the functions of osteoclasts and osteoblasts via distinct mechanisms involving inhibition of c-Src-dependent and -independent signaling pathways. PMID- 29440353 TI - Reciprocal Regulation of Glycolysis-Driven Th17 Pathogenicity and Regulatory T Cell Stability by Cdc42. AB - A balance between Th17 cells and regulatory T cells (Tregs) is important for host immunity and immune tolerance. The underlying molecular mechanisms remain poorly understood. Here we have identified Cdc42 as a central regulator of Th17/Treg balance. Deletion of Cdc42 in T cells enhanced Th17 differentiation but diminished induced Treg differentiation and suppressive function. Treg-specific deletion of Cdc42 decreased natural Tregs but increased effector T cells including Th17 cells. Notably, Cdc42-deficient Th17 cells became pathogenic associated with enhanced glycolysis and Cdc42-deficient Tregs became unstable associated with weakened glycolytic signaling. Inhibition of glycolysis in Cdc42 deficient Th17 cells diminished their pathogenicity and restoration of glycolysis in Cdc42-deficient Tregs rescued their instability. Intriguingly, Cdc42 deficiency in T cells led to exacerbated wasting disease in mouse models of colitis and Treg-specific deletion of Cdc42 caused early, fatal lymphoproliferative diseases. In summary, we show that Cdc42 is a bona fide regulator of peripheral tolerance through suppression of Th17 aberrant differentiation/pathogenicity and promotion of Treg differentiation/stability/function involving metabolic signaling and thus Cdc42 pathway might be harnessed in autoimmune disease therapy. PMID- 29440356 TI - Arterial diameter and the gender disparity in stroke thrombectomy outcomes. AB - BACKGROUND: Compared with males, females consistently fare worse following mechanical thrombectomy for large vessel ischemic strokes. Understanding why this gender disparity occurs may guide improvements in future treatment strategies. In this study, we aim to determine whether gender differences in cerebral arterial diameter correlate with clinical outcomes following stroke thrombectomy. METHODS: We performed an observational study of consecutive acute ischemic stroke patients undergoing mechanical thrombectomy at a single, urban tertiary care medical center. Catheter angiographic images were used to manually measure proximal segment arterial diameters in a standardized fashion. Medical record review was used to obtain relevant independent and dependent variables. RESULTS: Ninety two patients (42 females) between June 2013 and August 2016 met inclusion criteria. Internal carotid artery (ICA) terminus diameters for males and females were 3.08 mm (SD=0.46) and 2.81 mm (SD=0.45), respectively (P=0.01). M1 segment middle cerebral artery (MCA) diameters for males and females were 2.47 mm (SD=0.30) and 2.18 mm (SD=0.31), respectively (P<0.0001). 48% of patients in the upper MCA caliber tertile attained a favorable mRS 90 day value compared with 35% in each of the lower and middle tertiles (P=0.51). Larger MCA diameters correlated with favorable discharge disposition (P=0.21). CONCLUSIONS: These results provide limited evidence that males have larger cerebral arterial diameters than females and that larger arterial diameters may improve the odds for favorable clinical outcomes. If future studies validate these findings, arterial diameter may become a relevant variable in the design of improved thrombectomy strategies. PMID- 29440355 TI - The Antimicrobial Peptide CRAMP Is Essential for Colon Homeostasis by Maintaining Microbiota Balance. AB - Commensal bacteria are critical for physiological functions in the gut, and dysbiosis in the gut may cause diseases. In this article, we report that mice deficient in cathelin-related antimicrobial peptide (CRAMP) were defective in the development of colon mucosa and highly sensitive to dextran sulfate sodium (DSS) elicited colitis, as well as azoxymethane-mediated carcinogenesis. Pretreatment of CRAMP-/- mice with antibiotics markedly reduced the severity of DSS-induced colitis, suggesting CRAMP as a limiting factor on dysbiosis in the colon. This was supported by observations that wild-type (WT) mice cohoused with CRAMP-/- mice became highly sensitive to DSS-induced colitis, and the composition of fecal microbiota was skewed by CRAMP deficiency. In particular, several bacterial species that are typically found in oral microbiota, such as Mogibacterium neglectum, Desulfovibrio piger, and Desulfomicrobium orale, were increased in feces of CRAMP-/- mice and were transferred to WT mice during cohousing. When littermates of CRAMP+/- parents were examined, the composition of the fecal microbiota of WT pups and heterozygous parents was similar. In contrast, although the difference in fecal microbiota between CRAMP-/- and WT pups was small early on after weaning and single mouse housing, there was an increasing divergence with prolonged single housing. These results indicate that CRAMP is critical in maintaining colon microbiota balance and supports mucosal homeostasis, anti inflammatory responses, and protection from carcinogenesis. PMID- 29440358 TI - Environmental calcium and variation in yolk sac size influence swimming performance in larval lake sturgeon (Acipenser fulvescens). AB - In many animal species, performance in the early life stages strongly affects recruitment to the adult population; however, factors that influence early life history stages are often the least understood. This is particularly relevant for lake sturgeon, Acipenser fulvescens, living in areas where environmental calcium concentrations are declining, partly due to anthropogenic activity. As calcium is important for muscle contraction and fatigue resistance, declining calcium levels could constrain swimming performance. Similarly, swimming performance could be influenced by variation in yolk sac volume, because the yolk sac is likely to affect drag forces during swimming. Testing swimming performance of larval A. fulvescens reared in four different calcium treatments spanning the range of 4 132 mg l-1 [Ca2+], this study found no treatment effects on the sprint swimming speed. A novel test of volitional swimming performance, however, revealed reduced swimming performance in the low calcium environment. Specifically, volitionally swimming larvae covered a shorter distance before swimming cessation in the low calcium environment compared with the other treatments. Moreover, sprint swimming speed in larvae with a large yolk sac was significantly slower than in larvae with a small yolk sac, regardless of body length variation. Thus, elevated maternal allocation (i.e. more yolk) was associated with reduced swimming performance. Data suggest that larvae in low calcium environments or with a large yolk sac exhibit reduced swimming performance and could be more susceptible to predation or premature downstream drift. Our study reveals how environmental factors and phenotypic variation influence locomotor performance in a larval fish. PMID- 29440359 TI - Avian thermoregulation in the heat: phylogenetic variation among avian orders in evaporative cooling capacity and heat tolerance. AB - Little is known about the phylogenetic variation of avian evaporative cooling efficiency and heat tolerance in hot environments. We quantified thermoregulatory responses to high air temperature (Ta) in ~100-g representatives of three orders, namely, the African cuckoo (Cuculus gularis, Cuculiformes), lilac-breasted roller (Coracias caudatus, Coraciiformes) and Burchell's starling (Lamprotornis australis, Passeriformes). All three species initiated respiratory mechanisms to increase evaporative heat dissipation when body temperature (Tb) approached 41.5 degrees C in response to increasing Ta, with gular flutter observed in cuckoos and panting in rollers and starlings. Resting metabolic rate and evaporative water loss increased by quantitatively similar magnitudes in all three species, although maximum rates of evaporative water loss were proportionately lower in starlings. Evaporative cooling efficiency [defined as the ratio of evaporative heat loss (EHL) to metabolic heat production (MHP)] generally remained below 2.0 in cuckoos and starlings, but reached a maximum of ~3.5 in rollers. The high value for rollers reveals a very efficient evaporative cooling mechanism, and is similar to EHL/MHP maxima for similarly sized columbids which very effectively dissipate heat via cutaneous evaporation. This unexpected phylogenetic variation among the orders tested in the physiological mechanisms of heat dissipation is an important step toward determining the evolution of heat tolerance traits in desert birds. PMID- 29440354 TI - Csf1r-mApple Transgene Expression and Ligand Binding In Vivo Reveal Dynamics of CSF1R Expression within the Mononuclear Phagocyte System. AB - CSF1 is the primary growth factor controlling macrophage numbers, but whether expression of the CSF1 receptor differs between discrete populations of mononuclear phagocytes remains unclear. We have generated a Csf1r-mApple transgenic fluorescent reporter mouse that, in combination with lineage tracing, Alexa Fluor 647-labeled CSF1-Fc and CSF1, and a modified DeltaCsf1-enhanced cyan fluorescent protein (ECFP) transgene that lacks a 150 bp segment of the distal promoter, we have used to dissect the differentiation and CSF1 responsiveness of mononuclear phagocyte populations in situ. Consistent with previous Csf1r-driven reporter lines, Csf1r-mApple was expressed in blood monocytes and at higher levels in tissue macrophages, and was readily detectable in whole mounts or with multiphoton microscopy. In the liver and peritoneal cavity, uptake of labeled CSF1 largely reflected transgene expression, with greater receptor activity in mature macrophages than monocytes and tissue-specific expression in conventional dendritic cells. However, CSF1 uptake also differed between subsets of monocytes and discrete populations of tissue macrophages, which in macrophages correlated with their level of dependence on CSF1 receptor signaling for survival rather than degree of transgene expression. A double DeltaCsf1r-ECFP-Csf1r-mApple transgenic mouse distinguished subpopulations of microglia in the brain, and permitted imaging of interstitial macrophages distinct from alveolar macrophages, and pulmonary monocytes and conventional dendritic cells. The Csf1r-mApple mice and fluorescently labeled CSF1 will be valuable resources for the study of macrophage and CSF1 biology, which are compatible with existing EGFP-based reporter lines. PMID- 29440357 TI - Genetic Suppression of Basement Membrane Defects in Caenorhabditis elegans by Gain of Function in Extracellular Matrix and Cell-Matrix Attachment Genes. AB - Basement membranes are extracellular matrices essential for embryonic development in animals. Peroxidasins are extracellular peroxidases implicated in the unique sulfilimine cross-links between type IV basement membrane collagens. Loss of function in the Caenorhabditis elegans peroxidasin PXN-2 results in fully penetrant embryonic or larval lethality. Using genetic suppressor screening, we find that the requirement for PXN-2 in development can be bypassed by gain of function in multiple genes encoding other basement membrane components, or proteins implicated in cell-matrix attachment. We identify multiple alleles of let-805, encoding the transmembrane protein myotactin, which suppress phenotypes of pxn-2 null mutants and of other basement membrane mutants such as F spondin/spon-1 These let-805 suppressor alleles cause missense alterations in two pairs of FNIII repeats in the extracellular domain; they act dominantly and have no detectable phenotypes alone, suggesting they cause gain of function. We also identify suppressor missense mutations affecting basement membrane components type IV collagen (emb-9, let-2) and perlecan (unc-52), as well as a mutation affecting spectraplakin (vab-10), a component of the epidermal cytoskeleton. These suppressor alleles do not bypass the developmental requirement for core structural proteins of the basement membrane such as laminin or type IV collagen. In conclusion, putative gain-of-function alterations in matrix proteins or in cell-matrix receptors can overcome the requirement for certain basement membrane proteins in embryonic development, revealing previously unknown plasticity in the genetic requirements for the extracellular matrix. PMID- 29440360 TI - Avian thermoregulation in the heat: evaporative cooling capacity and thermal tolerance in two Australian parrots. AB - Avian orders differ in their thermoregulatory capabilities and tolerance of high environmental temperatures. Evaporative heat loss, and the primary avenue whereby it occurs, differs amongst taxa. Although Australian parrots (Psittaciformes) have been impacted by mass mortality events associated with extreme weather events (heat waves), their thermoregulatory physiology has not been well characterized. We quantified the upper limits to thermoregulation under extremely hot conditions in two Australian parrots: the mulga parrot (Psephotellus varius; ~55 g) and the galah (Eolophus roseicapilla; ~265 g). At air temperatures (Ta) exceeding body temperature (Tb), both species showed increases in Tb to maximum values around 43-44 degrees C, accompanied by rapid increases in resting metabolic rate above clearly defined upper critical limits of thermoneutrality and increases in evaporative water loss to levels equivalent to 700-1000% of baseline rates at thermoneutral Ta Maximum cooling capacity, quantified as the fraction of metabolic heat production dissipated evaporatively, ranged from 1.71 to 1.79, consistent with the known range for parrots, similar to the corresponding range in passerines, and well below the corresponding ranges for columbids and caprimulgids. Heat tolerance limit (the maximum Ta tolerated) ranged from 44 to 55 degrees C, similar to the range reported for passerines, but lower than that reported for columbids and caprimulgids. Our data suggest that heat tolerance in parrots is similar to that in passerines. We argue that understanding how thermoregulatory capacity and heat tolerance vary across avian orders is vital for predicting how climate change and the associated increase in frequency of extreme weather events may impact avian populations in the future. PMID- 29440361 TI - Defusing inflammasomes. AB - In this issue of JEM, Boucher et al. (https://doi.org/10.1084/jem.20172222) report isolation of active caspase-1 from macrophages after inflammasome activation. Surprisingly, they find that caspase-1 is quickly inactivated upon autoproteolytic processing. PMID- 29440363 TI - Metaplastic Cdx2-depleted cells can be very disruptive neighbors. AB - In this issue of JEM, Balbinot et al. (https://doi.org/10.1084/jem.20170934) describe an original mechanism where Cdx2 inactivation regulates intestinal metaplastic to neoplastic transition in a paracrine fashion. Surprisingly, the target cells are neighboring "normal" Cdx2-positive cells. PMID- 29440362 TI - Sustained Id2 regulation of E proteins is required for terminal differentiation of effector CD8+ T cells. AB - CD8+ T cells responding to infection differentiate into a heterogeneous population composed of progeny that are short-lived and participate in the immediate, acute response and those that provide long-lasting host protection. Although it is appreciated that distinct functional and phenotypic CD8+ T cell subsets persist, it is unclear whether there is plasticity among subsets and what mechanisms maintain subset-specific differences. Here, we show that continued Id2 regulation of E-protein activity is required to maintain the KLRG1hi CD8+ T cell population after lymphocytic choriomeningitis virus infection. Induced deletion of Id2 phenotypically and transcriptionally transformed the KLRG1hi "terminal" effector/effector-memory CD8+ T cell population into a KLRG1lo memory-like population, promoting a gene-expression program that resembled that of central memory T cells. Our results question the idea that KLRG1hi CD8+ T cells are necessarily terminally programmed and suggest that sustained regulation is required to maintain distinct CD8+ T cell states. PMID- 29440365 TI - Autoregulation and Virulence Control by the Toxin-Antitoxin System SavRS in Staphylococcus aureus. AB - Toxin-antitoxin (TA) systems play diverse physiological roles, such as plasmid maintenance, growth control, and persister cell formation, but their involvement in bacterial pathogenicity remains largely unknown. Here, we have identified a novel type II toxin-antitoxin system, SavRS, and revealed the molecular mechanisms of its autoregulation and virulence control in Staphylococcus aureus Electrophoretic mobility shift assay and isothermal titration calorimetry data indicated that the antitoxin SavR acted as the primary repressor bound to its own promoter, while the toxin SavS formed a complex with SavR to enhance the ability to bind to the operator site. DNase I footprinting assay identified the SavRS binding site containing a short and long palindrome in the promoter region. Further, mutation and DNase I footprinting assay demonstrated that the two palindromes were crucial for DNA binding and transcriptional repression. More interestingly, genetic deletion of the savRS system led to the increased hemolytic activity and pathogenicity in a mouse subcutaneous abscess model. We further identified two virulence genes, hla and efb, by real-time quantitative reverse transcription-PCR and demonstrated that SavR and SavRS could directly bind to their promoter regions to repress virulence gene expression. PMID- 29440364 TI - Rab6-dependent retrograde traffic of LAT controls immune synapse formation and T cell activation. AB - The adapter molecule linker for activation of T cells (LAT) orchestrates the formation of signalosomes upon T cell receptor (TCR) stimulation. LAT is present in different intracellular pools and is dynamically recruited to the immune synapse upon stimulation. However, the intracellular traffic of LAT and its function in T lymphocyte activation are ill defined. We show herein that LAT, once internalized, transits through the Golgi-trans-Golgi network (TGN), where it is repolarized to the immune synapse. This retrograde transport of LAT depends on the small GTPase Rab6 and the target soluble N-ethylmaleimide-sensitive factor attachment protein receptor (t-SNARE) Syntaxin-16, two regulators of the endosome to-Golgi/TGN retrograde transport. We also show in vitro in Syntaxin-16- or Rab6 silenced human cells and in vivo in CD4+ T lymphocytes of the Rab6 knockout mouse that this retrograde traffic controls TCR stimulation. These results establish that the retrograde traffic of LAT from the plasma membrane to the Golgi-TGN controls the polarized delivery of LAT at the immune synapse and T lymphocyte activation. PMID- 29440366 TI - Salmonella enterica Serovar Typhimurium Increases Functional PD-L1 Synergistically with Gamma Interferon in Intestinal Epithelial Cells via Salmonella Pathogenicity Island 2. AB - Nontyphoidal serovars of Salmonella enterica are pathogenic bacteria that are common causes of food poisoning. Whereas Salmonella mechanisms of host cell invasion, inflammation, and pathogenesis are mostly well established, a new possible mechanism of immune evasion is being uncovered. Programmed death ligand 1 (PD-L1) is an immunosuppressive membrane protein that binds to activated T cells via their PD-1 receptor and thereby halts their activation. PD-L1 expression plays an essential role in the immunological tolerance of self antigens but is also exploited for immune evasion by pathogen-infected cells and cancer cells. Here, we show for the first time that Salmonella infection of intestinal epithelial cells causes the induction of PD-L1. The increased expression of PD-L1 through Salmonella infection was seen in both human and rat intestinal epithelial cell lines. We determined that cellular invasion by the bacteria is necessary for PD-L1 induction, potentially indicating that Salmonella strains are delivering mediators from inside the host cell that trigger the increased PD-L1 expression. Using knockout mutants, we determined that this effect largely originates from the Salmonella pathogenicity island 2. We also show for the first time in any cell type that Salmonella combined with gamma interferon (IFN-gamma) causes a synergistic induction of PD-L1. Finally, we show that Salmonella plus IFN-gamma induction of PD-L1 decreased the cytokine production of activated T cells. Understanding Salmonella immune evasion strategies could generate new therapeutic targets and help to manipulate PD-L1 expression in other diseases. PMID- 29440367 TI - A Plasmodium Parasite with Complete Late Liver Stage Arrest Protects against Preerythrocytic and Erythrocytic Stage Infection in Mice. AB - Genetically attenuated malaria parasites (GAP) that arrest during liver stage development are powerful immunogens and afford complete and durable protection against sporozoite infection. Late liver stage-arresting GAP provide superior protection against sporozoite challenge in mice compared to early live stage arresting attenuated parasites. However, very few late liver stage-arresting GAP have been generated to date. Therefore, identification of additional loci that are critical for late liver stage development and can be used to generate novel late liver stage-arresting GAPs is of importance. We further explored genetic attenuation in Plasmodium yoelii by combining two gene deletions, PlasMei2 and liver-specific protein 2 (LISP2), that each cause late liver stage arrest with various degrees of infrequent breakthrough to blood stage infection. The dual gene deletion resulted in a synthetic lethal phenotype that caused complete attenuation in a highly susceptible mouse strain. P. yoeliiplasmei2-lisp2- arrested late in liver stage development and did not persist in livers beyond 3 days after infection. Immunization with this GAP elicited robust protective antibody responses in outbred and inbred mice against sporozoites, liver stages, and blood stages as well as eliciting protective liver-resident T cells. The immunization afforded protection against both sporozoite challenge and blood stage challenge. These findings provide evidence that completely attenuated late liver stage-arresting GAP are achievable via the synthetic lethal approach and might enable a path forward for the creation of a completely attenuated late liver stage-arresting P. falciparum GAP. PMID- 29440368 TI - Influence of Eimeria falciformis Infection on Gut Microbiota and Metabolic Pathways in Mice. AB - Coccidiosis, caused by different species of Eimeria parasites, is an economically important disease of poultry and livestock worldwide. Here we report previously unknown alterations in the gut microbes and metabolism of BALB/c mice infected with Eimeria falciformis Specifically, we observed a significant shift in the abundance of cecal bacteria and disrupted metabolism in parasitized animals. The relative abundances of Lachnospiraceae bacterium NK4A136, Ruminiclostridium, Alistipes, and Lactobacillus declined in response to E. falciformis infection, whereas Escherichia, Shigella, Helicobacter, Klebsiella, and Bacteroides were increased. Carbohydrate and amino acid metabolites in the serum samples of infected mice were significantly altered compared to naive controls. Levels of amino acids, including asparagine, histidine, l-cysteine, tryptophan, lysine, glycine, serine, alanine, proline, ornithine, methionine, and valine, decreased on day 7 postinfection before returning to baseline on day 14. In addition, increased levels of indolelactate and mannitol and a reduced amount of oxalic acid indicated impaired carbon metabolism upon parasitic infection. These data demonstrate that intestinal coccidial infection perturbs the microbiota and disrupts carbon and nitrogen metabolism. PMID- 29440369 TI - Fetal and Maternal Innate Immunity Receptors Have Opposing Effects on the Severity of Experimental Malaria in Pregnancy: Beneficial Roles for Fetus-Derived Toll-Like Receptor 4 and Type I Interferon Receptor 1. AB - Malaria in pregnancy (MiP) is a distinctive clinical form of Plasmodium infection and is a cause of placental insufficiency leading to poor pregnancy outcomes. Maternal innate immunity responses play a decisive role in the development of placental inflammation, but the action of fetus-derived factors in MiP outcomes has been overlooked. We investigated the role of the Tlr4 and Ifnar1 genes, taking advantage of heterogenic mating strategies to dissect the effects mediated by maternally and fetally derived Toll-like receptor 4 (TLR4) or type I interferon receptor 1 (IFNAR1). Using a mouse infection system displaying severe MiP outcomes, we found that the expressions of TLR4 and IFNAR1 in the maternal compartment take part in deleterious MiP outcomes, but their fetal counterparts patently counteract these effects. We uncovered that fetal TLR4 contributes to the in vitro uptake of infected erythrocytes by trophoblasts and to the innate immune response in the placenta, offering robust protection of fetus viability, but had no sensible impact on the placental parasite burden. In contrast, we observed that the expression of IFNAR1 in the fetal compartment was associated with a reduced placental parasite burden but had little beneficial effect on fetus outcomes. Furthermore, the downregulation of Ifnar1 expression in infected placentas and in trophoblasts exposed to infected erythrocytes indicated that the interferon-IFNAR1 pathway is involved in the trophoblast response to infection. This work unravels that maternal and fetal counterparts of innate immune pathways drive opposing responses in murine placental malaria and implicates the activation of innate receptors in fetal trophoblast cells in the control of placental infection and in the protection of the fetus. PMID- 29440370 TI - Virulence of the Melioidosis Pathogen Burkholderia pseudomallei Requires the Oxidoreductase Membrane Protein DsbB. AB - The naturally antibiotic-resistant bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a disease with stubbornly high mortality and a complex, protracted treatment regimen. The worldwide incidence of melioidosis is likely grossly underreported, though it is known to be highly endemic in northern Australia and Southeast Asia. Bacterial disulfide bond (DSB) proteins catalyze the oxidative folding and isomerization of disulfide bonds in substrate proteins. In the present study, we demonstrate that B. pseudomallei membrane protein disulfide bond protein B (BpsDsbB) forms a functional redox relay with the previously characterized virulence mediator B. pseudomallei disulfide bond protein A (BpsDsbA). Genomic analysis of diverse B. pseudomallei clinical isolates demonstrated that dsbB is a highly conserved core gene. Critically, we show that DsbB is required for virulence in B. pseudomallei A panel of B. pseudomalleidsbB deletion strains (K96243, 576, MSHR2511, MSHR0305b, and MSHR5858) were phenotypically diverse according to the results of in vitro assays that assess hallmarks of virulence. Irrespective of their in vitro virulence phenotypes, two deletion strains were attenuated in a BALB/c mouse model of infection. A crystal structure of a DsbB-derived peptide complexed with BpsDsbA provides the first molecular characterization of their interaction. This work contributes to our broader understanding of DSB redox biology and will support the design of antimicrobial drugs active against this important family of bacterial virulence targets. PMID- 29440371 TI - Antibiotics with Interleukin-15 Inhibition Reduce Joint Inflammation and Bone Erosions but Not Cartilage Destruction in Staphylococcus aureus-Induced Arthritis. AB - Staphylococcus aureus-induced arthritis causes rapid joint destruction, often leading to disabling joint damage despite antibiotics. We have previously shown that interleukin-15 (IL-15) inhibition without antibiotics is beneficial in S. aureus-induced arthritis. We therefore hypothesized that the inhibition of IL-15, in combination with antibiotics, might represent a useful therapy that would reduce inflammation and joint destruction but preserve the host's ability to clear the infection. Female wild-type C57BL/6 mice were intravenously inoculated with the toxic shock syndrome toxin 1 (TSST-1)-producing LS-1 strain of S. aureus with 0.8 * 108 CFU S. aureus LS-1/mouse. Three days later, treatment consisting of cloxacillin, followed by flucloxacillin, together with either anti-IL-15 antibodies (aIL-15ab) or control antibodies, was started. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. The addition of aIL-15ab to antibiotics in S. aureus-induced arthritis reduced synovitis and bone erosions compared to controls. The number of bone-resorbing osteoclasts in the joints was reduced, whereas cartilage destruction was not significantly altered. Importantly, the combination therapy did not adversely affect the clinical outcome of S. aureus-induced arthritis, such as survival or weight change, or compromise the host's ability to clear the infection. Since the clinical outcome of S. aureus-induced arthritis was not affected, the addition of aIL-15ab to antibiotics ought to be safe. Taken together, the combination of aIL 15ab and antibiotics is a beneficial, but not optimal, treatment of S. aureus induced arthritis since it reduces synovitis and bone erosions but has a limited effect on cartilage destruction. PMID- 29440372 TI - A Natural Mouse Model for Neisseria Colonization. AB - Commensals are important for the proper functioning of multicellular organisms. How a commensal establishes persistent colonization of its host is little understood. Studies of this aspect of microbe-host interactions are impeded by the absence of an animal model. We have developed a natural small animal model for identifying host and commensal determinants of colonization and of the elusive process of persistence. Our system couples a commensal bacterium of wild mice, Neisseria musculi, with the laboratory mouse. The pairing of a mouse commensal with its natural host circumvents issues of host restriction. Studies are performed in the absence of antibiotics, hormones, invasive procedures, or genetic manipulation of the host. A single dose of N. musculi, administered orally, leads to long-term colonization of the oral cavity and gut. All mice are healthy. Susceptibility to colonization is determined by host genetics and innate immunity. For N. musculi, colonization requires the type IV pilus. Reagents and powerful tools are readily available for manipulating the laboratory mouse, allowing easy dissection of host determinants controlling colonization resistance. N. musculi is genetically related to human-dwelling commensal and pathogenic Neisseria and encodes host interaction factors and vaccine antigens of pathogenic Neisseria Our system provides a natural approach for studying Neisseria-host interactions and is potentially useful for vaccine efficacy studies. PMID- 29440373 TI - Calcium supplementation in osteoporosis: useful or harmful? AB - Osteoporosis and fragility fractures are important social and economic problems worldwide and are due to both the loss of bone mineral density and sarcopenia. Indeed, fragility fractures are associated with increased disability, morbidity and mortality. It is known that a normal calcium balance together with a normal vitamin D status is important for maintaining well-balanced bone metabolism, and for many years, calcium and vitamin D have been considered crucial in the prevention and treatment of osteoporosis. However, recently, the usefulness of calcium supplementation (alone or with concomitant vitamin D) has been questioned, since some studies reported only weak efficacy of these supplementations in reducing fragility fracture risk. On the other hand, besides the gastrointestinal side effects of calcium supplements and the risk of kidney stones related to use of co-administered calcium and vitamin D supplements, other recent data suggested potential adverse cardiovascular effects from calcium supplementation. This debate article is focused on the evidence regarding both the possible usefulness for bone health and the potential harmful effects of calcium and/or calcium with vitamin D supplementation. PMID- 29440374 TI - MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art review. AB - Heart failure is a major cause of morbidity and mortality in type 2 diabetes. Type 2 diabetes contributes to the development of heart failure through a variety of mechanisms, including disease-specific myocardial structural, functional and metabolic changes. This review will focus on the contemporary contributions of state of the art non-invasive technologies to our understanding of diabetic cardiomyopathy, including data on cardiac disease phenotype, cardiac energy metabolism and energetic deficiency, ectopic and visceral adiposity, diabetic liver disease, metabolic modulation strategies and cardiovascular outcomes with new classes of glucose-lowering therapies. PMID- 29440376 TI - Demographically diverse crowds are typically not much wiser than homogeneous crowds. AB - Averaging independent numerical judgments can be more accurate than the average individual judgment. This "wisdom of crowds" effect has been shown with large, diverse samples, but the layperson wishing to take advantage of this may only have access to the opinions of a small, more demographically homogeneous "convenience sample." How wise are homogeneous crowds relative to diverse crowds? In simulations and survey studies, we demonstrate three necessary conditions under which small socially diverse crowds can outperform socially homogeneous crowds: Social identity must predict judgment, the effect of social identity on judgment must be at least moderate in size, and the average estimates of the social groups in question must "bracket" the truth being judged. Seven survey studies suggest that these conditions are rarely met in real judgment tasks. Comparisons between the performances of diverse and homogeneous crowds further confirm that social diversity can make crowds wiser but typically by a very small margin. PMID- 29440375 TI - Preoperative medical treatment in Cushing's syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN. AB - BACKGROUND: Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. OBJECTIVE: (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). PATIENTS AND METHODS: 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). RESULTS: Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups. CONCLUSIONS: PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results. PMID- 29440378 TI - Pathology after Chlamydia trachomatis infection is driven by nonprotective immune cells that are distinct from protective populations. AB - Infection with Chlamydia trachomatis drives severe mucosal immunopathology; however, the immune responses that are required for mediating pathology vs. protection are not well understood. Here, we employed a mouse model to identify immune responses required for C. trachomatis-induced upper genital tract pathology and to determine whether these responses are also required for bacterial clearance. In mice as in humans, immunopathology was characterized by extravasation of leukocytes into the upper genital tract that occluded luminal spaces in the uterus and ovaries. Flow cytometry identified these cells as neutrophils at early time points and CD4+ and CD8+ T cells at later time points. To determine what draws these cells to C. trachomatis-infected tissue, we measured the expression of 700 inflammation-related genes in the upper genital tract and found an up-regulation of many chemokines, including a node of interaction between CXCL9/10/11 and their common receptor CXCR3. Either depleting neutrophils or reducing T-cell numbers by CXCR3 blockade was sufficient to significantly ameliorate immunopathology but had no effect on bacterial burden, demonstrating that these responses are necessary for mucosal pathology but dispensable for C. trachomatis clearance. Therapies that specifically target these host responses may therefore prove useful in ameliorating C. trachomatis induced pathology without exacerbating infection or transmission. PMID- 29440377 TI - Efficient derivation of stable primed pluripotent embryonic stem cells from bovine blastocysts. AB - Embryonic stem cells (ESCs) are derived from the inner cell mass of preimplantation blastocysts. From agricultural and biomedical perspectives, the derivation of stable ESCs from domestic ungulates is important for genomic testing and selection, genome engineering, and modeling human diseases. Cattle are one of the most important domestic ungulates that are commonly used for food and bioreactors. To date, however, it remains a challenge to produce stable pluripotent bovine ESC lines. Employing a culture system containing fibroblast growth factor 2 and an inhibitor of the canonical Wnt-signaling pathway, we derived pluripotent bovine ESCs (bESCs) with stable morphology, transcriptome, karyotype, population-doubling time, pluripotency marker gene expression, and epigenetic features. Under this condition bESC lines were efficiently derived (100% in optimal conditions), were established quickly (3-4 wk), and were simple to propagate (by trypsin treatment). When used as donors for nuclear transfer, bESCs produced normal blastocyst rates, thereby opening the possibility for genomic selection, genome editing, and production of cattle with high genetic value. PMID- 29440380 TI - Comparative transcriptome analysis reveals distinct genetic modules associated with Helios expression in intratumoral regulatory T cells. AB - Regulatory T cells (Tregs) are key modulators of immune tolerance, capable of suppressing inflammatory immune responses and promoting nonlymphoid tissue homeostasis. Helios, a transcription factor (TF) that is selectively expressed by Tregs, has been shown to be essential for the maintenance of Treg lineage stability in the face of inflammatory conditions that include autoimmune disease and cancer. Helios-deficient Tregs within tumors acquire effector T cell function and contribute to immune responses against cancer. However, the underlying genetic basis of this Treg reprogramming is not well understood. Here, we report that Helios-deficient Tregs within the chronic inflammatory tumor microenvironment (TME) derepress genetic programs associated with T helper (Th) cell differentiation by up-regulating Th cell-associated TFs and effector cytokines. These genetic changes of Helios-deficient Tregs are most apparent in a Treg subpopulation with high affinity for self-antigens, as detected by both increased GITR/PD-1 expression and increased responsiveness to self-antigens. Their combined effects may promote a phenotype conversion of Tregs into effector T cells within the TME, where TCR engagement and costimulatory receptor expression by Tregs are increased. These data provide a genetic basis for the unstable phenotype of Helios-deficient Tregs within the inflammatory environment of tumors and suggest that immune milieu-dependent alterations in gene expression are a central feature of Treg conversion. PMID- 29440381 TI - Azo compounds as a family of organic electrode materials for alkali-ion batteries. AB - Organic compounds are desirable for sustainable Li-ion batteries (LIBs), but the poor cycle stability and low power density limit their large-scale application. Here we report a family of organic compounds containing azo group (N=N) for reversible lithiation/delithiation. Azobenzene-4,4'-dicarboxylic acid lithium salt (ADALS) with an azo group in the center of the conjugated structure is used as a model azo compound to investigate the electrochemical behaviors and reaction mechanism of azo compounds. In LIBs, ADALS can provide a capacity of 190 mAh g-1 at 0.5 C (corresponding to current density of 95 mA g-1) and still retain 90%, 71%, and 56% of the capacity when the current density is increased to 2 C, 10 C, and 20 C, respectively. Moreover, ADALS retains 89% of initial capacity after 5,000 cycles at 20 C with a slow capacity decay rate of 0.0023% per cycle, representing one of the best performances in all organic compounds. Superior electrochemical behavior of ADALS is also observed in Na-ion batteries, demonstrating that azo compounds are universal electrode materials for alkali-ion batteries. The highly reversible redox chemistry of azo compounds to alkali ions was confirmed by density-functional theory (DFT) calculations. It provides opportunities for developing sustainable batteries. PMID- 29440379 TI - Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models. AB - Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2. PMID- 29440382 TI - Germ-layer commitment and axis formation in sea anemone embryonic cell aggregates. AB - Robust morphogenetic events are pivotal for animal embryogenesis. However, comparison of the modes of development of different members of a phylum suggests that the spectrum of developmental trajectories accessible for a species might be far broader than can be concluded from the observation of normal development. Here, by using a combination of microsurgery and transgenic reporter gene expression, we show that, facing a new developmental context, the aggregates of dissociated embryonic cells of the sea anemone Nematostella vectensis take an alternative developmental trajectory. The self-organizing aggregates rely on Wnt signals produced by the cells of the original blastopore lip organizer to form body axes but employ morphogenetic events typical for normal development of distantly related cnidarians to re-establish the germ layers. The reaggregated cells show enormous plasticity including the capacity of the ectodermal cells to convert into endoderm. Our results suggest that new developmental trajectories may evolve relatively easily when highly plastic embryonic cells face new constraints. PMID- 29440383 TI - Reply to Ahluwalia et al.: Contributions of melatonin receptors are tissue dependent. PMID- 29440384 TI - Melatonin signaling in mitochondria extends beyond neurons and neuroprotection: Implications for angiogenesis and cardio/gastroprotection. PMID- 29440385 TI - A moment for compassion: emerging rhetorics in end-of-life care. AB - Compassion is an emotional response to the suffering of others. Once felt, it entails subsequent action to ameliorate their suffering. Recently, 'compassion' has become the flagship concept to be fostered in the delivery of end-of-life care, and a rallying call for social action and public health intervention. In this paper, we examine the emerging rhetorics of compassion as they relate to end of-life care and offer a critique of the expanding discourse around it. We argue that, even where individuals 'possess' compassion or are 'trained' in it, there are difficulties for compassion to flow freely, particularly within Western society. This relates to specific sociopolitical structural factors that include the sense of privacy and individualism in modern industrialised countries, highly professionalised closed health systems, anxiety about litigation on health and safety grounds, and a context of suspicion and mistrust within the global political scenario. We must then ask ourselves whether compassion can be created intentionally, without paying attention to the structural aspects of society. One consequence of globalisation is that countries in the global South are rapidly trying to embrace the features of modernity adopted by the global North. We argue that unrealistic assumptions have been made about the role of compassion in end of-life care and these idealist aspirations must be tempered by a more structural assessment of potential. Compassion that is not tied to to realistic action runs the risk of becoming empty rhetoric. PMID- 29440386 TI - The Primacy of Spatial Context in the Neural Representation of Events. AB - Some theories of episodic memory hypothesize that spatial context plays a fundamental role in episodic memory, acting as a scaffold on which episodes are constructed. A prediction based on this hypothesis is that spatial context should play a primary role in the neural representation of an event. To test this hypothesis in humans, male and female participants imagined events, composed of familiar locations, people, and objects, during an fMRI scan. We used multivoxel pattern analysis to determine the neural areas in which events could be discriminated based on each feature. We found that events could be discriminated according to their location in areas throughout the autobiographical memory network, including the parahippocampal cortex and posterior hippocampus, retrosplenial cortex, posterior cingulate cortex, precuneus, and medial prefrontal cortex. Events were also discriminable based on person and object features, but in fewer regions. Comparing classifier performance in regions involved in memory for scenes and events demonstrated that the location of an event was more accurately classified than the person or object involved. These results support theories that suggest that spatial context is a prominent defining feature of episodic memory.SIGNIFICANCE STATEMENT Remembered and imagined events are complex, consisting of many elements, including people, objects, and locations. In this study, we sought to determine how these types of elements differentially contribute to how the brain represents an event. Participants imagined events consisting of familiar locations, people, and objects (e.g., kitchen, mom, umbrella) while their brain activity was recorded with fMRI. We found that the neural patterns of activity in brain regions associated with spatial and episodic memory could distinguish events based on their location, and to some extent, based on the people and objects involved. These results suggest that the spatial context of an event plays an important role in how an event is represented in the brain. PMID- 29440387 TI - The soluble form of LOTUS inhibits Nogo receptor-mediated signaling by interfering with the interaction between Nogo receptor type 1 and p75 neurotrophin receptor. AB - Nogo receptor type 1 (NgR1) is known to inhibit neuronal regeneration in the CNS. We have previously identified lateral olfactory tract usher substance (LOTUS) interacts with NgR1 and inhibits its function by blocking its ligand binding. Therefore, LOTUS is expected to have therapeutic potential for the promotion of neuronal regeneration. However, it remains unknown whether the soluble form of LOTUS (s-LOTUS) also has an inhibitory action on NgR1 function as a candidate for therapeutic agents. Here, we show that s-LOTUS inhibits NgR1-mediated signaling by inhibiting the molecular interaction between NgR1 and its co-receptor p75 neurotrophin receptor (p75NTR). In contrast to the membrane-bound form of LOTUS, s-LOTUS did not block ligand binding to NgR1. However, we identified p75NTR as a novel LOTUS binding partner, and found that s-LOTUS suppressed the interaction between p75NTR and NgR1. s-LOTUS inhibited myelin-associated inhibitor (MAI) induced RhoA activation in murine cortical neurons. Functional analyses revealed that s-LOTUS inhibited MAI-induced growth cone collapse and neurite outgrowth inhibition in chick DRG neurons. In addition, while olfactory bulb (OB) neurons of lotus-KO mice are sensitive to MAI due to a lack of LOTUS expression, treatment with s-LOTUS inhibited MAI-induced growth cone collapse in these neurons. Finally, we observed that s-LOTUS promoted axonal regeneration in optic nerve crush injury of mice (either sex). These findings suggest that s-LOTUS inhibits NgR1-mediated signaling possibly by interfering with the interaction between NgR1 and p75NTR Thus, s-LOTUS may have potential as a therapeutic agent for neuronal regeneration in the damaged CNS.SIGNIFICANCE STATEMENTNogo receptor type 1 (NgR1) is a well-known receptor to inhibit neuronal regeneration in the CNS. Because the membrane-bound form of LOTUS antagonizes NgR1 through a cis-type molecular interaction between LOTUS and NgR1, the soluble form of LOTUS (s-LOTUS) is expected to be a therapeutic agent for neuronal regeneration. In our present study, we show that s-LOTUS inhibits the interaction between NgR1 and p75NTR, NgR1 ligand-induced RhoA activation, growth cone collapse and neurite outgrowth inhibition, and promotes axonal regeneration. Our results indicate that s-LOTUS inhibits NgR1-mediated signaling through a trans-type molecular interaction between LOTUS and NgR1, and therefore, s-LOTUS may have therapeutic potential for neuronal regeneration. PMID- 29440388 TI - Large Visual Stimuli Induce Two Distinct Gamma Oscillations in Primate Visual Cortex. AB - Recent studies have shown the existence of two gamma rhythms in the hippocampus subserving different functions but, to date, primate studies in primary visual cortex have reported a single gamma rhythm. Here, we show that large visual stimuli induce a slow gamma (25-45 Hz) in area V1 of two awake adult female bonnet monkeys and in the EEG of 15 human subjects (7 males and 8 females), in addition to the traditionally known fast gamma (45-70 Hz). The two rhythms had different tuning characteristics for stimulus orientation, contrast, drift speed, and size. Further, fast gamma had short latency, strongly entrained spikes and was coherent over short distances, reflecting short-range processing, whereas slow gamma appeared to reflect long-range processing. Together, two gamma rhythms can potentially provide better coding or communication mechanisms and a more comprehensive biomarker for diagnosis of mental disorders.SIGNIFICANCE STATEMENT Gamma rhythm has been associated with high-level cognitive functions such as attention and feature binding and has been reported to be abnormal in brain disorders such as autism and schizophrenia. Unlike previous studies that have shown a single gamma rhythm in the primate visual cortex, we found that large visual gratings induce two distinct gamma oscillations in both monkey LFP and human EEG. These rhythms, termed slow (25-45 Hz) and fast (45-70 Hz), exhibited distinct tuning preferences, latencies, and coherence profiles, potentially reflecting processing at two different ranges. Multiple gamma oscillations in visual cortex may provide a richer representation of external visual stimuli and could be used for developing brain-machine interfacing applications and screening tests for neuropsychiatric disorders. PMID- 29440389 TI - Antisense transcription-dependent chromatin signature modulates sense transcript dynamics. AB - Antisense transcription is widespread in genomes. Despite large differences in gene size and architecture, we find that yeast and human genes share a unique, antisense transcription-associated chromatin signature. We asked whether this signature is related to a biological function for antisense transcription. Using quantitative RNA-FISH, we observed changes in sense transcript distributions in nuclei and cytoplasm as antisense transcript levels were altered. To determine the mechanistic differences underlying these distributions, we developed a mathematical framework describing transcription from initiation to transcript degradation. At GAL1, high levels of antisense transcription alter sense transcription dynamics, reducing rates of transcript production and processing, while increasing transcript stability. This relationship with transcript stability is also observed as a genome-wide association. Establishing the antisense transcription-associated chromatin signature through disruption of the Set3C histone deacetylase activity is sufficient to similarly change these rates even in the absence of antisense transcription. Thus, antisense transcription alters sense transcription dynamics in a chromatin-dependent manner. PMID- 29440390 TI - High dietary fat and sucrose results in an extensive and time-dependent deterioration in health of multiple physiological systems in mice. AB - Obesity is associated with metabolic dysfunction, including insulin resistance and hyperinsulinemia, and with disorders such as cardiovascular disease, osteoporosis, and neurodegeneration. Typically, these pathologies are examined in discrete model systems and with limited temporal resolution, and whether these disorders co-occur is therefore unclear. To address this question, here we examined multiple physiological systems in male C57BL/6J mice following prolonged exposure to a high-fat/high-sucrose diet (HFHSD). HFHSD-fed mice rapidly exhibited metabolic alterations, including obesity, hyperleptinemia, physical inactivity, glucose intolerance, peripheral insulin resistance, fasting hyperglycemia, ectopic lipid deposition, and bone deterioration. Prolonged exposure to HFHSD resulted in morbid obesity, ectopic triglyceride deposition in liver and muscle, extensive bone loss, sarcopenia, hyperinsulinemia, and impaired short-term memory. Although many of these defects are typically associated with aging, HFHSD did not alter telomere length in white blood cells, indicating that this diet did not generally promote all aspects of aging. Strikingly, glucose homeostasis was highly dynamic. Glucose intolerance was evident in HFHSD-fed mice after 1 week and was maintained for 24 weeks. Beyond 24 weeks, however, glucose tolerance improved in HFHSD-fed mice, and by 60 weeks, it was indistinguishable from that of chow-fed mice. This improvement coincided with adaptive beta-cell hyperplasia and hyperinsulinemia, without changes in insulin sensitivity in muscle or adipose tissue. Assessment of insulin secretion in isolated islets revealed that leptin, which inhibited insulin secretion in the chow-fed mice, potentiated glucose-stimulated insulin secretion in the HFHSD-fed mice after 60 weeks. Overall, the excessive calorie intake was accompanied by deteriorating function of numerous physiological systems. PMID- 29440391 TI - SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis. AB - Heart failure is an aging-associated disease that is the leading cause of death worldwide. Sirtuin family members have been largely studied in the context of aging and aging-associated diseases. Sirtuin 2 (SIRT2) is a cytoplasmic protein in the family of sirtuins that are NAD+-dependent class III histone deacetylases. In this work, we studied the role of SIRT2 in regulating nuclear factor of activated T-cells (NFAT) transcription factor and the development of cardiac hypertrophy. Confocal microscopy analysis indicated that SIRT2 is localized in the cytoplasm of cardiomyocytes and SIRT2 levels are reduced during pathological hypertrophy of the heart. SIRT2-deficient mice develop spontaneous pathological cardiac hypertrophy, remodeling, fibrosis, and dysfunction in an age-dependent manner. Moreover, young SIRT2-deficient mice develop exacerbated agonist-induced hypertrophy. In contrast, SIRT2 overexpression attenuated agonist-induced cardiac hypertrophy in cardiomyocytes in a cell-autonomous manner. Mechanistically, SIRT2 binds to and deacetylates NFATc2 transcription factor. SIRT2 deficiency stabilizes NFATc2 and enhances nuclear localization of NFATc2, resulting in increased transcription activity. Our results suggest that inhibition of NFAT rescues the cardiac dysfunction in SIRT2-deficient mice. Thus, our study establishes SIRT2 as a novel endogenous negative regulator of NFAT transcription factor. PMID- 29440392 TI - Structure, function, and mechanism of the core circadian clock in cyanobacteria. AB - Circadian rhythms enable cells and organisms to coordinate their physiology with the cyclic environmental changes that come as a result of Earth's light/dark cycles. Cyanobacteria make use of a post-translational oscillator to maintain circadian rhythms, and this elegant system has become an important model for circadian timekeeping mechanisms. Composed of three proteins, the KaiABC system undergoes an oscillatory biochemical cycle that provides timing cues to achieve a 24-h molecular clock. Together with the input/output proteins SasA, CikA, and RpaA, these six gene products account for the timekeeping, entrainment, and output signaling functions in cyanobacterial circadian rhythms. This Minireview summarizes the current structural, functional and mechanistic insights into the cyanobacterial circadian clock. PMID- 29440393 TI - Granule-stored MUC5B mucins are packed by the non-covalent formation of N terminal head-to-head tetramers. AB - Most MUC5B mucin polymers in the upper airways of humans and pigs are produced by submucosal glands. MUC5B forms N-terminal covalent dimers that are further packed into larger assemblies because of low pH and high Ca2+ in the secretory granule of the mucin-producing cell. We purified the recombinant MUC5B N-terminal covalent dimer and used single-particle electron microscopy to study its structure under intracellular conditions. We found that, at intragranular pH, the dimeric MUC5B organized into head-to-head noncovalent tetramers where the von Willebrand D1-D2 domains hooked into each other. These N-terminal tetramers further formed long linear complexes from which, we suggest, the mucin domains and their C termini project radially outwards. Using conventional and video microscopy, we observed that, upon secretion into the submucosal gland ducts, a flow of bicarbonate-rich fluid passes the mucin-secreting cells. We suggest that this unfolds and pulls out the MUC5B assemblies into long linear threads. These further assemble into thicker mucin bundles in the glandular ducts before emerging at the gland duct opening. We conclude that the combination of intracellular packing of the MUC5B mucin and the submucosal gland morphology creates an efficient machine for producing linear mucin bundles. PMID- 29440394 TI - Structure-function analysis of manganese exporter proteins across bacteria. AB - Manganese (Mn) is an essential trace nutrient for organisms because of its role in cofactoring enzymes and providing protection against reactive oxygen species (ROS). Many bacteria require manganese to form pathogenic or symbiotic interactions with eukaryotic host cells. However, excess manganese is toxic, requiring cells to have manganese export mechanisms. Bacteria are currently known to possess two widely distributed classes of manganese export proteins, MntP and MntE, but other types of transporters likely exist. Moreover, the structure and function of MntP is not well understood. Here, we characterized the role of three structurally related proteins known or predicted to be involved in manganese transport in bacteria from the MntP, UPF0016, and TerC families. These studies used computational analysis to analyze phylogeny and structure, physiological assays to test sensitivity to high levels of manganese and ROS, and inductively coupled plasma-mass spectrometry (ICP-MS) to measure metal levels. We found that MntP alters cellular resistance to ROS. Moreover, we used extensive computational analyses and phenotypic assays to identify amino acids required for MntP activity. These negatively charged residues likely serve to directly bind manganese and transport it from the cytoplasm through the membrane. We further characterized two other potential manganese transporters associated with a Mn sensing riboswitch and found that the UPF0016 family of proteins has manganese export activity. We provide here the first phenotypic and biochemical evidence for the role of Alx, a member of the TerC family, in manganese homeostasis. It does not appear to export manganese, but rather it intriguingly facilitates an increase in intracellular manganese concentration. These findings expand the available knowledge about the identity and mechanisms of manganese homeostasis proteins across bacteria and show that proximity to a Mn-responsive riboswitch can be used to identify new components of the manganese homeostasis machinery. PMID- 29440395 TI - Fatty acid-binding protein 5 controls microsomal prostaglandin E synthase 1 (mPGES-1) induction during inflammation. AB - Fatty acid-binding proteins (FABPs) are intracellular lipid carriers that regulate inflammation, and pharmacological inhibition of FABP5 reduces inflammation and pain. The mechanism(s) underlying the anti-inflammatory effects associated with FABP5 inhibition is poorly understood. Herein, we identify a novel mechanism through which FABP5 modulates inflammation. In mice, intraplantar injection of carrageenan induces acute inflammation that is accompanied by edema, enhanced pain sensitivity, and elevations in proinflammatory cytokines and prostaglandin E2 (PGE2). Inhibition of FABP5 reduced pain, edema, cytokine, and PGE2 levels. PGE2 is a major eicosanoid that enhances pain in the setting of inflammation, and we focused on the mechanism(s) through which FABP5 modulates PGE2 production. Cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1) are enzymes up-regulated at the site of inflammation and account for the bulk of PGE2 biosynthesis. Pharmacological or genetic FABP5 inhibition suppressed the induction of mPGES-1 but not COX-2 in carrageenan-injected paws, which occurred predominantly in macrophages. The cytokine interleukin 1beta (IL 1beta) is a major inducer of mPGES-1 during inflammation. Using A549 cells that express FABP5, IL-1beta stimulation up-regulated mPGES-1 expression, and mPGES-1 induction was attenuated in A549 cells bearing a knockdown of FABP5. IL-1beta up regulates mPGES-1 via NF-kappaB, which activates the mPGES-1 promoter. Knockdown of FABP5 reduced the activation and nuclear translocation of NF-kappaB and attenuated mPGES-1 promoter activity. Deletion of NF-kappaB-binding sites within the mPGES-1 promoter abrogated the ability of FABP5 to inhibit mPGES-1 promoter activation. Collectively, these results position FABP5 as a novel regulator of mPGES-1 induction and PGE2 biosynthesis during inflammation. PMID- 29440396 TI - Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19. AB - Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate cyclin C (CycC)-dependent kinase 8 (CDK8) in Mediator, implicating impaired Mediator-associated CDK8 activity in the molecular pathogenesis of these clinically significant lesions. Notably, the CDK8 paralog CDK19 is also expressed in myometrium, and both CDK8 and CDK19 assemble into Mediator in a mutually exclusive manner, suggesting that CDK19 activity may also be germane to the pathogenesis of MED12 mutation-induced UFs. However, whether and how UF-linked mutations in MED12 affect CDK19 activation is unknown. Herein, we show that MED12 allosterically activates CDK19 and that UF-linked exon 2 mutations in MED12 disrupt its CDK19 stimulatory activity. Furthermore, we find that within the Mediator kinase module, MED13 directly binds to the MED12 C terminus, thereby suppressing an apparent UF mutation-induced conformational change in MED12 that otherwise disrupts its association with CycC-CDK8/19. Thus, in the presence of MED13, mutant MED12 can bind, but cannot activate, CycC CDK8/19. These findings indicate that MED12 binding is necessary but not sufficient for CycC-CDK8/19 activation and reveal an additional step in the MED12 dependent activation process, one critically dependent on MED12 residues altered by UF-linked exon 2 mutations. These findings confirm that UF-linked mutations in MED12 disrupt composite Mediator-associated kinase activity and identify CDK8/19 as prospective therapeutic targets in UFs. PMID- 29440397 TI - Sex bias in MHC I-associated shaping of the adaptive immune system. AB - HLA associations, T cell receptor (TCR) repertoire bias, and sex bias have independently been shown for many diseases. While some immunological differences between the sexes have been described, they do not fully explain bias in men toward many infections/cancers, and toward women in autoimmunity. Next-generation TCR variable beta chain (TCRBV) immunosequencing of 824 individuals was evaluated in a multiparametric analysis including HLA-A -B/MHC class I background, TCRBV usage, sex, age, ethnicity, and TCRBV selection/expansion dynamics. We found that HLA-associated shaping of TCRBV usage differed between the sexes. Furthermore, certain TCRBVs were selected and expanded in unison. Correlations between these TCRBV relationships and biochemical similarities in HLA-binding positions were different in CD8 T cells of patients with autoimmune diseases (multiple sclerosis and rheumatoid arthritis) compared with healthy controls. Within patients, men showed higher TCRBV relationship Spearman's rhos in relation to HLA-binding position similarities compared with women. In line with this, CD8 T cells of men with autoimmune diseases also showed higher degrees of TCRBV perturbation compared with women. Concerted selection and expansion of CD8 T cells in patients with autoimmune diseases, but especially in men, appears to be less dependent on high HLA-binding similarity than in CD4 T cells. These findings are consistent with studies attributing autoimmunity to processes of epitope spreading and expansion of low-avidity T cell clones and may have further implications for the interpretation of pathogenic mechanisms of infectious and autoimmune diseases with known HLA associations. Reanalysis of some HLA association studies, separating the data by sex, could be informative. PMID- 29440398 TI - Assembly of the membrane domain of ATP synthase in human mitochondria. AB - The ATP synthase in human mitochondria is a membrane-bound assembly of 29 proteins of 18 kinds. All but two membrane components are encoded in nuclear genes, synthesized on cytoplasmic ribosomes, and imported into the matrix of the organelle, where they are assembled into the complex with ATP6 and ATP8, the products of overlapping genes in mitochondrial DNA. Disruption of individual human genes for the nuclear-encoded subunits in the membrane portion of the enzyme leads to the formation of intermediate vestigial ATPase complexes that provide a description of the pathway of assembly of the membrane domain. The key intermediate complex consists of the F1-c8 complex inhibited by the ATPase inhibitor protein IF1 and attached to the peripheral stalk, with subunits e, f, and g associated with the membrane domain of the peripheral stalk. This intermediate provides the template for insertion of ATP6 and ATP8, which are synthesized on mitochondrial ribosomes. Their association with the complex is stabilized by addition of the 6.8 proteolipid, and the complex is coupled to ATP synthesis at this point. A structure of the dimeric yeast Fo membrane domain is consistent with this model of assembly. The human 6.8 proteolipid (yeast j subunit) locks ATP6 and ATP8 into the membrane assembly, and the monomeric complexes then dimerize via interactions between ATP6 subunits and between 6.8 proteolipids (j subunits). The dimers are linked together back-to-face by DAPIT (diabetes-associated protein in insulin-sensitive tissue; yeast subunit k), forming long oligomers along the edges of the cristae. PMID- 29440401 TI - Climate-change-driven accelerated sea-level rise detected in the altimeter era. AB - Using a 25-y time series of precision satellite altimeter data from TOPEX/Poseidon, Jason-1, Jason-2, and Jason-3, we estimate the climate-change driven acceleration of global mean sea level over the last 25 y to be 0.084 +/- 0.025 mm/y2 Coupled with the average climate-change-driven rate of sea level rise over these same 25 y of 2.9 mm/y, simple extrapolation of the quadratic implies global mean sea level could rise 65 +/- 12 cm by 2100 compared with 2005, roughly in agreement with the Intergovernmental Panel on Climate Change (IPCC) 5th Assessment Report (AR5) model projections. PMID- 29440400 TI - Rewiring Yarrowia lipolytica toward triacetic acid lactone for materials generation. AB - Polyketides represent an extremely diverse class of secondary metabolites often explored for their bioactive traits. These molecules are also attractive building blocks for chemical catalysis and polymerization. However, the use of polyketides in larger scale chemistry applications is stymied by limited titers and yields from both microbial and chemical production. Here, we demonstrate that an oleaginous organism (specifically, Yarrowia lipolytica) can overcome such production limitations owing to a natural propensity for high flux through acetyl CoA. By exploring three distinct metabolic engineering strategies for acetyl-CoA precursor formation, we demonstrate that a previously uncharacterized pyruvate bypass pathway supports increased production of the polyketide triacetic acid lactone (TAL). Ultimately, we establish a strain capable of producing over 35% of the theoretical conversion yield to TAL in an unoptimized tube culture. This strain also obtained an averaged maximum titer of 35.9 +/- 3.9 g/L with an achieved maximum specific productivity of 0.21 +/- 0.03 g/L/h in bioreactor fermentation. Additionally, we illustrate that a beta-oxidation-related overexpression (PEX10) can support high TAL production and is capable of achieving over 43% of the theoretical conversion yield under nitrogen starvation in a test tube. Next, through use of this bioproduct, we demonstrate the utility of polyketides like TAL to modify commodity materials such as poly(epichlorohydrin), resulting in an increased molecular weight and shift in glass transition temperature. Collectively, these findings establish an engineering strategy enabling unprecedented production from a type III polyketide synthase as well as establish a route through O-functionalization for converting polyketides into new materials. PMID- 29440399 TI - Structural studies of Acidianus tailed spindle virus reveal a structural paradigm used in the assembly of spindle-shaped viruses. AB - The spindle-shaped virion morphology is common among archaeal viruses, where it is a defining characteristic of many viral families. However, structural heterogeneity intrinsic to spindle-shaped viruses has seriously hindered efforts to elucidate the molecular architecture of these lemon-shaped capsids. We have utilized a combination of cryo-electron microscopy and X-ray crystallography to study Acidianus tailed spindle virus (ATSV). These studies reveal the architectural principles that underlie assembly of a spindle-shaped virus. Cryo electron tomography shows a smooth transition from the spindle-shaped capsid into the tubular-shaped tail and allows low-resolution structural modeling of individual virions. Remarkably, higher-dose 2D micrographs reveal a helical surface lattice in the spindle-shaped capsid. Consistent with this, crystallographic studies of the major capsid protein reveal a decorated four helix bundle that packs within the crystal to form a four-start helical assembly with structural similarity to the tube-shaped tail structure of ATSV and other tailed, spindle-shaped viruses. Combined, this suggests that the spindle-shaped morphology of the ATSV capsid is formed by a multistart helical assembly with a smoothly varying radius and allows construction of a pseudoatomic model for the lemon-shaped capsid that extends into a tubular tail. The potential advantages that this novel architecture conveys to the life cycle of spindle-shaped viruses, including a role in DNA ejection, are discussed. PMID- 29440402 TI - Light color acclimation is a key process in the global ocean distribution of Synechococcus cyanobacteria. AB - Marine Synechococcus cyanobacteria are major contributors to global oceanic primary production and exhibit a unique diversity of photosynthetic pigments, allowing them to exploit a wide range of light niches. However, the relationship between pigment content and niche partitioning has remained largely undetermined due to the lack of a single-genetic marker resolving all pigment types (PTs). Here, we developed and employed a robust method based on three distinct marker genes (cpcBA, mpeBA, and mpeW) to estimate the relative abundance of all known Synechococcus PTs from metagenomes. Analysis of the Tara Oceans dataset allowed us to reveal the global distribution of Synechococcus PTs and to define their environmental niches. Green-light specialists (PT 3a) dominated in warm, green equatorial waters, whereas blue-light specialists (PT 3c) were particularly abundant in oligotrophic areas. Type IV chromatic acclimaters (CA4-A/B), which are able to dynamically modify their light absorption properties to maximally absorb green or blue light, were unexpectedly the most abundant PT in our dataset and predominated at depth and high latitudes. We also identified populations in which CA4 might be nonfunctional due to the lack of specific CA4 genes, notably in warm high-nutrient low-chlorophyll areas. Major ecotypes within clades I-IV and CRD1 were preferentially associated with a particular PT, while others exhibited a wide range of PTs. Altogether, this study provides important insights into the ecology of Synechococcus and highlights the complex interactions between vertical phylogeny, pigmentation, and environmental parameters that shape Synechococcus community structure and evolution. PMID- 29440403 TI - Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/beta-catenin pathway. AB - Regulator of G protein signaling z1 (RGSz1), a member of the RGS family of proteins, is present in several networks expressing mu opioid receptors (MOPRs). By using genetic mouse models for global or brain region-targeted manipulations of RGSz1 expression, we demonstrated that the suppression of RGSz1 function increases the analgesic efficacy of MOPR agonists in male and female mice and delays the development of morphine tolerance while decreasing the sensitivity to rewarding and locomotor activating effects. Using biochemical assays and next generation RNA sequencing, we identified a key role of RGSz1 in the periaqueductal gray (PAG) in morphine tolerance. Chronic morphine administration promotes RGSz1 activity in the PAG, which in turn modulates transcription mediated by the Wnt/beta-catenin signaling pathway to promote analgesic tolerance to morphine. Conversely, the suppression of RGSz1 function stabilizes Axin2 Galphaz complexes near the membrane and promotes beta-catenin activation, thereby delaying the development of analgesic tolerance. These data show that the regulation of RGS complexes, particularly those involving RGSz1-Galphaz, represents a promising target for optimizing the analgesic actions of opioids without increasing the risk of dependence or addiction. PMID- 29440405 TI - Correction for Mano et al., Optimal run-and-tumble-based transportation of a Janus particle with active steering. PMID- 29440404 TI - Multivariate resting-state functional connectivity predicts response to cognitive behavioral therapy in obsessive-compulsive disorder. AB - Cognitive behavioral therapy (CBT) is an effective treatment for many with obsessive-compulsive disorder (OCD). However, response varies considerably among individuals. Attaining a means to predict an individual's potential response would permit clinicians to more prudently allocate resources for this often stressful and time-consuming treatment. We collected resting-state functional magnetic resonance imaging from adults with OCD before and after 4 weeks of intensive daily CBT. We leveraged machine learning with cross-validation to assess the power of functional connectivity (FC) patterns to predict individual posttreatment OCD symptom severity. Pretreatment FC patterns within the default mode network and visual network significantly predicted posttreatment OCD severity, explaining up to 67% of the variance. These networks were stronger predictors than pretreatment clinical scores. Results have clinical implications for developing personalized medicine approaches to identifying individual OCD patients who will maximally benefit from intensive CBT. PMID- 29440407 TI - In and out of glacial extremes by way of dust-climate feedbacks. AB - Mineral dust aerosols cool Earth directly by scattering incoming solar radiation and indirectly by affecting clouds and biogeochemical cycles. Recent Earth history has featured quasi-100,000-y, glacial-interglacial climate cycles with lower/higher temperatures and greenhouse gas concentrations during glacials/interglacials. Global average, glacial maxima dust levels were more than 3 times higher than during interglacials, thereby contributing to glacial cooling. However, the timing, strength, and overall role of dust-climate feedbacks over these cycles remain unclear. Here we use dust deposition data and temperature reconstructions from ice sheet, ocean sediment, and land archives to construct dust-climate relationships. Although absolute dust deposition rates vary greatly among these archives, they all exhibit striking, nonlinear increases toward coldest glacial conditions. From these relationships and reconstructed temperature time series, we diagnose glacial-interglacial time series of dust radiative forcing and iron fertilization of ocean biota, and use these time series to force Earth system model simulations. The results of these simulations show that dust-climate feedbacks, perhaps set off by orbital forcing, push the system in and out of extreme cold conditions such as glacial maxima. Without these dust effects, glacial temperature and atmospheric CO2 concentrations would have been much more stable at higher, intermediate glacial levels. The structure of residual anomalies over the glacial-interglacial climate cycles after subtraction of dust effects provides constraints for the strength and timing of other processes governing these cycles. PMID- 29440406 TI - Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. AB - Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell. PMID- 29440408 TI - The ZBED6-IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals. AB - A single nucleotide substitution in the third intron of insulin-like growth factor 2 (IGF2) is associated with increased muscle mass and reduced subcutaneous fat in domestic pigs. This mutation disrupts the binding of the ZBED6 transcription factor and leads to a threefold up-regulation of IGF2 expression in pig skeletal muscle. Here, we investigated the biological significance of ZBED6 IGF2 interaction in the growth of placental mammals using two mouse models, ZBED6 knock-out (Zbed6-/-) and Igf2 knock-in mice that carry the pig IGF2 mutation. These transgenic mice exhibit markedly higher serum IGF2 concentrations, higher growth rate, increased lean mass, and larger heart, kidney, and liver; no significant changes were observed for white adipose tissues. The changes in body and lean mass were most pronounced in female mice. The phenotypic changes were concomitant with a remarkable up-regulation of Igf2 expression in adult tissues. Transcriptome analysis of skeletal muscle identified differential expression of genes belonging to the extracellular region category. Expression analysis using fetal muscles indicated a minor role of ZBED6 in regulating Igf2 expression prenatally. Furthermore, transcriptome analysis of the adult skeletal muscle revealed that this elevated expression of Igf2 was derived from the P1 and P2 promoters. The results revealed very similar phenotypic effects in the Zbed6 knock-out mouse and in the Igf2 knock-in mouse, showing that the effect of ZBED6 on growth of muscle and internal organs is mediated through the binding site in the Igf2 gene. The results explain why this ZBED6 binding site is extremely well conserved among placental mammals. PMID- 29440409 TI - Monoterpenes are the largest source of summertime organic aerosol in the southeastern United States. AB - The chemical complexity of atmospheric organic aerosol (OA) has caused substantial uncertainties in understanding its origins and environmental impacts. Here, we provide constraints on OA origins through compositional characterization with molecular-level details. Our results suggest that secondary OA (SOA) from monoterpene oxidation accounts for approximately half of summertime fine OA in Centreville, AL, a forested area in the southeastern United States influenced by anthropogenic pollution. We find that different chemical processes involving nitrogen oxides, during days and nights, play a central role in determining the mass of monoterpene SOA produced. These findings elucidate the strong anthropogenic-biogenic interaction affecting ambient aerosol in the southeastern United States and point out the importance of reducing anthropogenic emissions, especially under a changing climate, where biogenic emissions will likely keep increasing. PMID- 29440410 TI - Ridding fMRI data of motion-related influences: Removal of signals with distinct spatial and physical bases in multiecho data. AB - "Functional connectivity" techniques are commonplace tools for studying brain organization. A critical element of these analyses is to distinguish variance due to neurobiological signals from variance due to nonneurobiological signals. Multiecho fMRI techniques are a promising means for making such distinctions based on signal decay properties. Here, we report that multiecho fMRI techniques enable excellent removal of certain kinds of artifactual variance, namely, spatially focal artifacts due to motion. By removing these artifacts, multiecho techniques reveal frequent, large-amplitude blood oxygen level-dependent (BOLD) signal changes present across all gray matter that are also linked to motion. These whole-brain BOLD signals could reflect widespread neural processes or other processes, such as alterations in blood partial pressure of carbon dioxide (pCO2) due to ventilation changes. By acquiring multiecho data while monitoring breathing, we demonstrate that whole-brain BOLD signals in the resting state are often caused by changes in breathing that co-occur with head motion. These widespread respiratory fMRI signals cannot be isolated from neurobiological signals by multiecho techniques because they occur via the same BOLD mechanism. Respiratory signals must therefore be removed by some other technique to isolate neurobiological covariance in fMRI time series. Several methods for removing global artifacts are demonstrated and compared, and were found to yield fMRI time series essentially free of motion-related influences. These results identify two kinds of motion-associated fMRI variance, with different physical mechanisms and spatial profiles, each of which strongly and differentially influences functional connectivity patterns. Distance-dependent patterns in covariance are nearly entirely attributable to non-BOLD artifacts. PMID- 29440411 TI - Experimental evidence of low-density liquid water upon rapid decompression. AB - Water is an extraordinary liquid, having a number of anomalous properties which become strongly enhanced in the supercooled region. Due to rapid crystallization of supercooled water, there exists a region that has been experimentally inaccessible for studying deeply supercooled bulk water. Using a rapid decompression technique integrated with in situ X-ray diffraction, we show that a high-pressure ice phase transforms to a low-density noncrystalline (LDN) form upon rapid release of pressure at temperatures of 140-165 K. The LDN subsequently crystallizes into ice-Ic through a diffusion-controlled process. Together with the change in crystallization rate with temperature, the experimental evidence indicates that the LDN is a low-density liquid (LDL). The measured X-ray diffraction data show that the LDL is tetrahedrally coordinated with the tetrahedral network fully developed and clearly linked to low-density amorphous ices. On the other hand, there is a distinct difference in structure between the LDL and supercooled water or liquid water in terms of the tetrahedral order parameter. PMID- 29440412 TI - Genetic resistance to purine nucleoside phosphorylase inhibition in Plasmodium falciparum. AB - Plasmodium falciparum causes the most lethal form of human malaria and is a global health concern. The parasite responds to antimalarial therapies by developing drug resistance. The continuous development of new antimalarials with novel mechanisms of action is a priority for drug combination therapies. The use of transition-state analog inhibitors to block essential steps in purine salvage has been proposed as a new antimalarial approach. Mutations that reduce transition-state analog binding are also expected to reduce the essential catalytic function of the target. We have previously reported that inhibition of host and P. falciparum purine nucleoside phosphorylase (PfPNP) by DADMe Immucillin-G (DADMe-ImmG) causes purine starvation and parasite death in vitro and in primate infection models. P. falciparum cultured under incremental DADMe ImmG drug pressure initially exhibited increased PfPNP gene copy number and protein expression. At increased drug pressure, additional PfPNP gene copies appeared with point mutations at catalytic site residues involved in drug binding. Mutant PfPNPs from resistant clones demonstrated reduced affinity for DADMe-ImmG, but also reduced catalytic efficiency. The catalytic defects were partially overcome by gene amplification in the region expressing PfPNP. Crystal structures of native and mutated PfPNPs demonstrate altered catalytic site contacts to DADMe-ImmG. Both point mutations and gene amplification are required to overcome purine starvation induced by DADMe-ImmG. Resistance developed slowly, over 136 generations (2136 clonal selection). Transition-state analog inhibitors against PfPNP are slow to induce resistance and may have promise in malaria therapy. PMID- 29440414 TI - Changing character of rainfall in eastern China, 1951-2007. AB - The topography and continental configuration of East Asia favor the year-round existence of storm tracks that extend thousands of kilometers from China into the northwestern Pacific Ocean, producing zonally elongated patterns of rainfall that we call "frontal rain events." In spring and early summer (known as "Meiyu Season"), frontal rainfall intensifies and shifts northward during a series of stages collectively known as the East Asian summer monsoon. Using a technique called the Frontal Rain Event Detection Algorithm, we create a daily catalog of all frontal rain events in east China during 1951-2007, quantify their attributes, and classify all rainfall on each day as either frontal, resulting from large-scale convergence, or nonfrontal, produced by local buoyancy, topography, or typhoons. Our climatology shows that the East Asian summer monsoon consists of a series of coupled changes in frontal rain event frequency, latitude, and daily accumulation. Furthermore, decadal changes in the amount and distribution of rainfall in east China are overwhelmingly due to changes in frontal rainfall. We attribute the "South Flood-North Drought" pattern observed beginning in the 1980s to changes in the frequency of frontal rain events, while the years 1994-2007 witnessed an uptick in event daily accumulation relative to the rest of the study years. This particular signature may reflect the relative impacts of global warming, aerosol loading, and natural variability on regional rainfall, potentially via shifting the East Asian jet stream. PMID- 29440413 TI - Intensity and duration of TCR signaling is limited by p38 phosphorylation of ZAP 70T293 and destabilization of the signalosome. AB - ZAP-70 is a tyrosine kinase that is essential for initiation of T cell antigen receptor (TCR) signaling. We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. Mutant T cells expressing ZAP-70 with an alanine substitution at this residue (ZAP-70T293A) had enhanced TCR proximal signaling and increased effector responses. Lack of ZAP 70T293 phosphorylation increased association of ZAP-70 with the TCR and prolonged the existence of TCR signaling microclusters. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex. PMID- 29440415 TI - Coprolites reveal ecological interactions lost with the extinction of New Zealand birds. AB - Over the past 50,000 y, biotic extinctions and declines have left a legacy of vacant niches and broken ecological interactions across global terrestrial ecosystems. Reconstructing the natural, unmodified ecosystems that preceded these events relies on high-resolution analyses of paleoecological deposits. Coprolites are a source of uniquely detailed information about trophic interactions and the behaviors, gut parasite communities, and microbiotas of prehistoric animal species. Such insights are critical for understanding the legacy effects of extinctions on ecosystems, and can help guide contemporary conservation and ecosystem restoration efforts. Here we use high-throughput sequencing (HTS) of ancient eukaryotic DNA from coprolites to reconstruct aspects of the biology and ecology of four species of extinct moa and the critically endangered kakapo parrot from New Zealand (NZ). Importantly, we provide evidence that moa and prehistoric kakapo consumed ectomycorrhizal fungi, suggesting these birds played a role in dispersing fungi that are key to NZ's natural forest ecosystems. We also provide the first DNA-based evidence that moa frequently supplemented their broad diets with ferns and mosses. Finally, we also find parasite taxa that provide insight into moa behavior, and present data supporting the hypothesis of coextinction between moa and several parasite species. Our study demonstrates that HTS sequencing of coprolites provides a powerful tool for resolving key aspects of ancient ecosystems and may rapidly provide information not obtainable by conventional paleoecological techniques, such as fossil analyses. PMID- 29440416 TI - Divergent biodiversity change within ecosystems. AB - The Earth's ecosystems are under unprecedented pressure, yet the nature of contemporary biodiversity change is not well understood. Growing evidence that community size is regulated highlights the need for improved understanding of community dynamics. As stability in community size could be underpinned by marked temporal turnover, a key question is the extent to which changes in both biodiversity dimensions (temporal alpha- and temporal beta-diversity) covary within and among the assemblages that comprise natural communities. Here, we draw on a multiassemblage dataset (encompassing vertebrates, invertebrates, and unicellular plants) from a tropical freshwater ecosystem and employ a cyclic shift randomization to assess whether any directional change in temporal alpha diversity and temporal beta-diversity exceeds baseline levels. In the majority of cases, alpha-diversity remains stable over the 5-y time frame of our analysis, with little evidence for systematic change at the community level. In contrast, temporal beta-diversity changes are more prevalent, and the two diversity dimensions are decoupled at both the within- and among-assemblage level. Consequently, a pressing research challenge is to establish how turnover supports regulation and when elevated temporal beta-diversity jeopardizes community integrity. PMID- 29440417 TI - Lupus-like autoimmune disease caused by a lack of Xkr8, a caspase-dependent phospholipid scramblase. AB - Apoptotic cells expose phosphatidylserine (PtdSer) on their cell surface and are recognized by macrophages for clearance. Xkr8 is a scramblase that exposes PtdSer in a caspase-dependent manner. Here, we found that among the three Xkr members with caspase-dependent scramblase activity, mouse hematopoietic cells express only Xkr8. The PtdSer exposure of apoptotic thymocytes, splenocytes, and neutrophils was strongly reduced when Xkr8 was absent. While wild-type apoptotic lymphocytes and neutrophils were efficiently engulfed in vitro by phagocytes expressing Tim4 and MerTK, Xkr8-deficient apoptotic cells were hardly engulfed by these phagocytes. Accordingly, the number of apoptotic thymocytes in the thymus and neutrophils in the peritoneal cavity of the zymosan-treated mice was significantly increased in Xkr8-deficient mice. The percentage of CD62Llo senescent neutrophils was increased in the spleen of Xkr8-null mice, especially after the treatment with granulocyte colony-stimulating factor. Xkr8-null mice on an MRL background showed high levels of autoantibodies, splenomegaly with high levels of effector CD4 T cells, and glomerulonephritis development with immune complex deposition at glomeruli. These results indicate that the Xkr8-mediated PtdSer exposure in apoptotic lymphocytes and aged neutrophils is essential for their clearance, and its defect activates the immune system, leading to lupus like autoimmune disease. PMID- 29440418 TI - Cu+-specific CopB transporter: Revising P1B-type ATPase classification. AB - The copper-transporting P1B-ATPases, which play a key role in cellular copper homeostasis, have been divided traditionally into two subfamilies, the P1B-1 ATPases or CopAs and the P1B-3-ATPases or CopBs. CopAs selectively export Cu+ whereas previous studies and bioinformatic analyses have suggested that CopBs are specific for Cu2+ export. Biochemical and spectroscopic characterization of Sphaerobacter thermophilus CopB (StCopB) show that, while it does bind Cu2+, the binding site is not the prototypical P1B-ATPase transmembrane site and does not involve sulfur coordination as proposed previously. Most important, StCopB exhibits metal-stimulated ATPase activity in response to Cu+, but not Cu2+, indicating that it is actually a Cu+ transporter. X-ray absorption spectroscopic studies indicate that Cu+ is coordinated by four sulfur ligands, likely derived from conserved cysteine and methionine residues. The histidine-rich N-terminal region of StCopB is required for maximal activity, but is inhibitory in the presence of divalent metal ions. Finally, reconsideration of the P1B-ATPase classification scheme suggests that the P1B-1- and P1B-3-ATPase subfamilies both comprise Cu+ transporters. These results are completely consistent with the known presence of only Cu+ within the reducing environment of the cytoplasm, which should eliminate the need for a Cu2+ P1B-ATPase. PMID- 29440420 TI - Companies' contribution to sustainability through global supply chains. AB - Global supply chains play a critical role in many of the most pressing environmental stresses and social struggles identified by the United Nations' Sustainable Development Goals (SDGs). Responding to calls from the global community, companies are adopting a variety of voluntary practices to improve the environmental and/or social management of their suppliers' activities. We develop a global survey of 449 publicly listed companies in the food, textile, and wood products sectors with annual reports in English to provide insight into how the private sector contributes to advancing the SDGs via such sustainable-sourcing practices. We find that while 52% of companies use at least one sustainable sourcing practice, these practices are limited in scope; 71% relates to only one or a few input materials and 60.5% apply to only first-tier suppliers. We also find that sustainable-sourcing practices typically address a small subset of the sustainability challenges laid out by the SDGs, primarily focusing on labor rights and compliance with national laws. Consistent with existing hypotheses, companies that face consumer and civil society pressure are associated with a significantly higher probability of adopting sustainable-sourcing practices. Our findings highlight the opportunities and limitations of corporate sustainable sourcing practices in addressing the myriad sustainability challenges facing our world today. PMID- 29440419 TI - Epitope-specific monoclonal antibodies to FSHbeta increase bone mass. AB - Pituitary hormones have long been thought solely to regulate single targets. Challenging this paradigm, we discovered that both anterior and posterior pituitary hormones, including FSH, had other functions in physiology. We have shown that FSH regulates skeletal integrity, and, more recently, find that FSH inhibition reduces body fat and induces thermogenic adipose tissue. A polyclonal antibody raised against a short, receptor-binding epitope of FSHbeta was found not only to rescue bone loss postovariectomy, but also to display marked antiobesity and probeiging actions. Questioning whether a single agent could be used to treat two medical conditions of public health importance--osteoporosis and obesity--we developed two further monoclonal antibodies, Hf2 and Mf4, against computationally defined receptor-binding epitopes of FSHbeta. Hf2 has already been shown to reduce body weight and fat mass and cause beiging in mice on a high fat diet. Here, we show that Hf2, which binds mouse Fsh in immunoprecipitation assays, also increases cortical thickness and trabecular bone volume, and microstructural parameters, in sham-operated and ovariectomized mice, noted on microcomputed tomography. This effect was largely recapitulated with Mf4, which inhibited bone resorption by osteoclasts and stimulated new bone formation by osteoblasts. These effects were exerted in the absence of alterations in serum estrogen in wild-type mice. We also reconfirm the existence of Fshrs in bone by documenting the specific binding of fluorescently labeled FSH, FSH-CH, in vivo. Our study provides the framework for the future development of an FSH-based therapeutic that could potentially target both bone and fat. PMID- 29440421 TI - National trends in drinking water quality violations. AB - Ensuring safe water supply for communities across the United States is a growing challenge in the face of aging infrastructure, impaired source water, and strained community finances. In the aftermath of the Flint lead crisis, there is an urgent need to assess the current state of US drinking water. However, no nationwide assessment has yet been conducted on trends in drinking water quality violations across several decades. Efforts to reduce violations are of national concern given that, in 2015, nearly 21 million people relied on community water systems that violated health-based quality standards. In this paper, we evaluate spatial and temporal patterns in health-related violations of the Safe Drinking Water Act using a panel dataset of 17,900 community water systems over the period 1982-2015. We also identify vulnerability factors of communities and water systems through probit regression. Increasing time trends and violation hot spots are detected in several states, particularly in the Southwest region. Repeat violations are prevalent in locations of violation hot spots, indicating that water systems in these regions struggle with recurring issues. In terms of vulnerability factors, we find that violation incidence in rural areas is substantially higher than in urbanized areas. Meanwhile, private ownership and purchased water source are associated with compliance. These findings indicate the types of underperforming systems that might benefit from assistance in achieving consistent compliance. We discuss why certain violations might be clustered in some regions and strategies for improving national drinking water quality. PMID- 29440422 TI - Climate for women in climate science: Women scientists and the Intergovernmental Panel on Climate Change. AB - The Intergovernmental Panel on Climate Change (IPCC) is an authoritative and influential source of reports on climate change. The lead authors of IPCC reports include scientists from around the world, but questions have been raised about the dominance of specific disciplines in the report and the disproportionate number of scholars from the Global North. In this paper, we analyze the as-yet unexamined issue of gender and IPCC authorship, looking at changes in gender balance over time and analyzing women's views about their experience and barriers to full participation, not only as women but also at the intersection of nationality, race, command of English, and discipline. Over time, we show that the proportion of female IPCC authors has seen a modest increase from less than 5% in 1990 to more than 20% in the most recent assessment reports. Based on responses from over 100 women IPCC authors, we find that many women report a positive experience in the way in which they are treated and in their ability to influence the report, although others report that some women were poorly represented and heard. We suggest that an intersectional lens is important: not all women experience the same obstacles: they face multiple and diverse barriers associated with social identifiers such as race, nationality, command of English, and disciplinary affiliation. The scientific community benefits from including all scientists, including women and those from the Global South. This paper documents barriers to participation and identifies opportunities to diversify climate science. PMID- 29440424 TI - Land-use and land-cover change shape the sustainability and impacts of protected areas. AB - Protected areas (PAs) remain the dominant policy to protect biodiversity and ecosystem services but have been shown to have limited impact when development interests force them to locations with lower deforestation pressure. Far less known is that such interests also cause widespread tempering, reduction, or removal of protection [i.e., PA downgrading, downsizing, and degazettement (PADDD)]. We inform responses to PADDD by proposing and testing a bargaining explanation for PADDD risks and deforestation impacts. We examine recent degazettements for hydropower development and rural settlements in the state of Rondonia in the Brazilian Amazon. Results support two hypotheses: (i) ineffective PAs (i.e., those where internal deforestation was similar to nearby rates) were more likely to be degazetted and (ii) degazettement of ineffective PAs caused limited, if any, additional deforestation. We also report on cases in which ineffective portions were upgraded. Overall our results suggest that enhancing PAs' ecological impacts enhances their legal durability. PMID- 29440423 TI - ATP synthase from Trypanosoma brucei has an elaborated canonical F1-domain and conventional catalytic sites. AB - The structures and functions of the components of ATP synthases, especially those subunits involved directly in the catalytic formation of ATP, are widely conserved in metazoans, fungi, eubacteria, and plant chloroplasts. On the basis of a map at 32.5-A resolution determined in situ in the mitochondria of Trypanosoma brucei by electron cryotomography, it has been proposed that the ATP synthase in this species has a noncanonical structure and different catalytic sites in which the catalytically essential arginine finger is provided not by the alpha-subunit adjacent to the catalytic nucleotide-binding site as in all species investigated to date, but rather by a protein, p18, found only in the euglenozoa. A crystal structure at 3.2-A resolution of the catalytic domain of the same enzyme demonstrates that this proposal is incorrect. In many respects, the structure is similar to the structures of F1-ATPases determined previously. The alpha3beta3-spherical portion of the catalytic domain in which the three catalytic sites are found, plus the central stalk, are highly conserved, and the arginine finger is provided conventionally by the alpha-subunits adjacent to each of the three catalytic sites found in the beta-subunits. Thus, the enzyme has a conventional catalytic mechanism. The structure differs from previous described structures by the presence of a p18 subunit, identified only in the euglenozoa, associated with the external surface of each of the three alpha-subunits, thereby elaborating the F1-domain. Subunit p18 is a pentatricopeptide repeat (PPR) protein with three PPRs and appears to have no function in the catalytic mechanism of the enzyme. PMID- 29440425 TI - Bryostatin-1 alleviates experimental multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory disorder targeting the central nervous system (CNS). The relapsing-remitting phase of MS is largely driven by peripheral activation of autoreactive T-helper (Th) 1 and Th17 lymphocytes. In contrast, compartmentalized inflammation within the CNS, including diffuse activation of innate myeloid cells, characterizes the progressive phase of MS, the most debilitating phase that currently lacks satisfactory treatments. Recently, bryostatin-1 (bryo-1), a naturally occurring, CNS-permeable compound with a favorable safety profile in humans, has been shown to act on antigen-presenting cells to promote differentiation of lymphocytes into Th2 cells, an action that might benefit Th1-driven inflammatory conditions such as MS. In the present study, we show that bryo-1 provides marked benefit in mice with experimental autoimmune encephalomyelitis (EAE), an experimental MS animal model. Preventive treatment with bryo-1 abolishes the onset of neurologic deficits in EAE. More strikingly, bryo-1 reverses neurologic deficits after EAE onset, even when treatment is initiated at a late stage of disease when peak adaptive immunity has subsided. Treatment with bryo-1 in vitro promotes an anti-inflammatory phenotype in antigen-presenting dendritic cells, macrophages, and to a lesser extent, lymphocytes. These findings suggest the potential for bryo-1 as a therapeutic agent in MS, particularly given its established clinical safety. Furthermore, the benefit of bryo-1, even in late treatment of EAE, combined with its targeting of innate myeloid cells suggests therapeutic potential in progressive forms of MS. PMID- 29440426 TI - STING-dependent translation inhibition restricts RNA virus replication. AB - In mammalian cells, IFN responses that occur during RNA and DNA virus infections are activated by distinct signaling pathways. The RIG-I-like-receptors (RLRs) bind viral RNA and engage the adaptor MAVS (mitochondrial antiviral signaling) to promote IFN expression, whereas cGAS (cGMP-AMP synthase) binds viral DNA and activates an analogous pathway via the protein STING (stimulator of IFN genes). In this study, we confirm that STING is not necessary to induce IFN expression during RNA virus infection but also find that STING is required to restrict the replication of diverse RNA viruses. The antiviral activities of STING were not linked to its ability to regulate basal expression of IFN-stimulated genes, activate transcription, or autophagy. Using vesicular stomatitis virus as a model, we identified a requirement of STING to inhibit translation during infection and upon transfection of synthetic RLR ligands. This inhibition occurs at the level of translation initiation and restricts the production of viral and host proteins. The inability to restrict translation rendered STING-deficient cells 100 times more likely to support productive viral infections than wild-type counterparts. Genetic analysis linked RNA sensing by RLRs to STING-dependent translation inhibition, independent of MAVS. Thus, STING has dual functions in host defense, regulating protein synthesis to prevent RNA virus infection and regulating IFN expression to restrict DNA viruses. PMID- 29440427 TI - Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A. AB - Bone metastatic lesions are classified as osteoblastic or osteolytic lesions. Prostate and breast cancer patients frequently exhibit osteoblastic-type and osteolytic-type bone metastasis, respectively. In metastatic lesions, tumor cells interact with many different cell types, including osteoblasts, osteoclasts, and mesenchymal stem cells, resulting in an osteoblastic or osteolytic phenotype. However, the mechanisms responsible for the modification of bone remodeling have not been fully elucidated. MicroRNAs (miRNAs) are transferred between cells via exosomes and serve as intercellular communication tools, and numerous studies have demonstrated that cancer-secreted miRNAs are capable of modifying the tumor microenvironment. Thus, cancer-secreted miRNAs can induce an osteoblastic or osteolytic phenotype in the bone metastatic microenvironment. In this study, we performed a comprehensive expression analysis of exosomal miRNAs secreted by several human cancer cell lines and identified eight types of human miRNAs that were highly expressed in exosomes from osteoblastic phenotype-inducing prostate cancer cell lines. One of these miRNAs, hsa-miR-940, significantly promoted the osteogenic differentiation of human mesenchymal stem cells in vitro by targeting ARHGAP1 and FAM134A Interestingly, although MDA-MB-231 breast cancer cells are commonly known as an osteolytic phenotype-inducing cancer cell line, the implantation of miR-940-overexpressing MDA-MB-231 cells induced extensive osteoblastic lesions in the resulting tumors by facilitating the osteogenic differentiation of host mesenchymal cells. Our results suggest that the phenotypes of bone metastases can be induced by miRNAs secreted by cancer cells in the bone microenvironment. PMID- 29440428 TI - Contribution of NIH funding to new drug approvals 2010-2016. AB - This work examines the contribution of NIH funding to published research associated with 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010-2016. We identified >2 million publications in PubMed related to the 210 NMEs (n = 131,092) or their 151 known biological targets (n = 1,966,281). Of these, >600,000 (29%) were associated with NIH-funded projects in RePORTER. This funding included >200,000 fiscal years of NIH project support (1985-2016) and project costs >$100 billion (2000-2016), representing ~20% of the NIH budget over this period. NIH funding contributed to every one of the NMEs approved from 2010-2016 and was focused primarily on the drug targets rather than on the NMEs themselves. There were 84 first-in-class products approved in this interval, associated with >$64 billion of NIH-funded projects. The percentage of fiscal years of project funding identified through target searches, but not drug searches, was greater for NMEs discovered through targeted screening than through phenotypic methods (95% versus 82%). For targeted NMEs, funding related to targets preceded funding related to the NMEs, consistent with the expectation that basic research provides validated targets for targeted screening. This analysis, which captures basic research on biological targets as well as applied research on NMEs, suggests that the NIH contribution to research associated with new drug approvals is greater than previously appreciated and highlights the risk of reducing federal funding for basic biomedical research. PMID- 29440429 TI - Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events. AB - The locus coeruleus (LC) is the principal origin of noradrenaline in the brain. LC integrity varies considerably across healthy older individuals, and is suggested to contribute to altered cognitive functions in aging. Here we test this hypothesis using an incidental memory task that is known to be susceptible to noradrenergic modulation. We used MRI neuromelanin (NM) imaging to assess LC structural integrity and pupillometry as a putative index of LC activation in both younger and older adults. We show that older adults with reduced structural LC integrity show poorer subsequent memory. This effect is more pronounced for emotionally negative events, in accord with a greater role for noradrenergic modulation in encoding salient or aversive events. In addition, we found that salient stimuli led to greater pupil diameters, consistent with increased LC activation during the encoding of such events. Our study presents novel evidence that a decrement in noradrenergic modulation impacts on specific components of cognition in healthy older adults. The findings provide a strong motivation for further investigation of the effects of altered LC integrity in pathological aging. PMID- 29440431 TI - Microstructural origin of resistance-strain hysteresis in carbon nanotube thin film conductors. AB - A basic need in stretchable electronics for wearable and biomedical technologies is conductors that maintain adequate conductivity under large deformation. This challenge can be met by a network of one-dimensional (1D) conductors, such as carbon nanotubes (CNTs) or silver nanowires, as a thin film on top of a stretchable substrate. The electrical resistance of CNT thin films exhibits a hysteretic dependence on strain under cyclic loading, although the microstructural origin of this strain dependence remains unclear. Through numerical simulations, analytic models, and experiments, we show that the hysteretic resistance evolution is governed by a microstructural parameter [Formula: see text] (the ratio of the mean projected CNT length over the film length) by showing that [Formula: see text] is hysteretic with strain and that the resistance is proportional to [Formula: see text] The findings are generally applicable to any stretchable thin film conductors consisting of 1D conductors with much lower resistance than the contact resistance in the high-density regime. PMID- 29440430 TI - POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation. AB - The Hippo signaling pathway is a master regulator of organ growth, tissue homeostasis, and tumorigenesis. The activity of the Hippo pathway is controlled by various upstream components, including Expanded (Ex), but the precise molecular mechanism of how Ex is regulated remains poorly understood. Here we identify Plenty of SH3s (POSH), an E3 ubiquitin ligase, as a key component of Hippo signaling in DrosophilaPOSH overexpression synergizes with loss of Kibra to induce overgrowth and up-regulation of Hippo pathway target genes. Furthermore, knockdown of POSH impedes dextran sulfate sodium-induced Yorkie-dependent intestinal stem cell renewal, suggesting a physiological role of POSH in modulating Hippo signaling. Mechanistically, POSH binds to the C-terminal of Ex and is essential for the Crumbs-induced ubiquitination and degradation of Ex. Our findings establish POSH as a crucial regulator that integrates the signal from the cell surface to negatively regulate Ex-mediated Hippo activation in Drosophila. PMID- 29440432 TI - PI5P4Kgamma functions in DTX1-mediated Notch signaling. AB - Notch signaling is an evolutionarily conserved pathway that is essential for development, where it controls processes ranging from cell differentiation to survival. Transport through endosomes is a critical step in regulating Notch signaling capacity, where the E3 ubiquitin ligase DTX1 is thought to control Notch1 intracellular transport decisions by direct receptor ubiquitination. However, how DTX1 regulates Notch1 transport within endosomes and the consequence of Notch1 ubiquitination by DTX1 remain unresolved. Here we demonstrate that DTX1 colocalizes with Notch1 on tubulovesicular recycling endosomes. We find that DTX1 silencing leads to enhanced Notch1 recycling from this compartment to the cell surface via a rab4a-mediated transport route. This, in turn, increases Notch1 cell-surface levels and enhances signaling. Surprisingly, we discovered that DTX1 depletion also elevates Notch1 activity mediated by a mutant form of the receptor that lacks lysine residues for ubiquitination, suggesting that DTX1 targets additional factors. Using an activity-based screen for ubiquitination targets, we identified multiple DTX1 substrates including PI5P4Kgamma, a lipid kinase involved in PI(4,5)P2 production. Immunolocalization analysis reveals that PI5P4Kgamma, like DTX1 and Notch1, is present on tubulovesicular recycling endosomes. However, in contrast to DTX1, Notch1 signaling is inhibited by pharmacological inactivation or siRNA depletion of PI5P4Kgamma. Moreover, loss of PI5P4Kgamma activity decreases Notch1 recycling rates and reduces receptor cell surface levels. Collectively, these findings argue that PI5P4Kgamma positively regulates the Notch pathway by promoting receptor recycling. Additionally, they support a model where DTX1 controls Notch1 endosomal sorting decisions by controlling PI5P4Kgamma-mediated production of PI(4,5)P2. PMID- 29440434 TI - The complexity of Neanderthal technology. PMID- 29440433 TI - Windowed Granger causal inference strategy improves discovery of gene regulatory networks. AB - Accurate inference of regulatory networks from experimental data facilitates the rapid characterization and understanding of biological systems. High-throughput technologies can provide a wealth of time-series data to better interrogate the complex regulatory dynamics inherent to organisms, but many network inference strategies do not effectively use temporal information. We address this limitation by introducing Sliding Window Inference for Network Generation (SWING), a generalized framework that incorporates multivariate Granger causality to infer network structure from time-series data. SWING moves beyond existing Granger methods by generating windowed models that simultaneously evaluate multiple upstream regulators at several potential time delays. We demonstrate that SWING elucidates network structure with greater accuracy in both in silico and experimentally validated in vitro systems. We estimate the apparent time delays present in each system and demonstrate that SWING infers time-delayed, gene-gene interactions that are distinct from baseline methods. By providing a temporal framework to infer the underlying directed network topology, SWING generates testable hypotheses for gene-gene influences. PMID- 29440435 TI - Unique parasite aDNA in moa coprolites from New Zealand suggests mass parasite extinctions followed human-induced megafauna extinctions. PMID- 29440436 TI - Stepping into the genetics of biological motion processing. PMID- 29440437 TI - Biodiversity may wax or wane depending on metrics or taxa. PMID- 29440438 TI - Throwing back the big ones saves a fishery from hot water. PMID- 29440440 TI - Classification and interaction in random forests. PMID- 29440439 TI - Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis. AB - RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNFalpha, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II. Ripk1K584R/K584R knockin mutant cells are resistant to RIPK1 kinase dependent apoptosis and necroptosis. The resistance of K584R cells, however, can be overcome by forced dimerization of RIPK1. Finally, we show that the K584R RIPK1 knockin mutation protects mice against TNFalpha-induced systematic inflammatory response syndrome. Our study demonstrates the role of RIPK1-DD in mediating RIPK1 dimerization and activation of its kinase activity during necroptosis and RIPK1-dependent apoptosis. PMID- 29440441 TI - Origami-inspired, on-demand deployable and collapsible mechanical metamaterials with tunable stiffness. AB - Origami has been employed to build deployable mechanical metamaterials through folding and unfolding along the crease lines. Deployable metamaterials are usually flexible, particularly along their deploying and collapsing directions, which unfortunately in many cases leads to an unstable deployed state, i.e., small perturbations may collapse the structure along the same deployment path. Here we create an origami-inspired mechanical metamaterial with on-demand deployability and selective collapsibility through energy analysis. This metamaterial has autonomous deployability from the collapsed state and can be selectively collapsed along two different paths, embodying low stiffness for one path and substantially high stiffness for another path. The created mechanical metamaterial yields load-bearing capability in the deployed direction while possessing great deployability and collapsibility. The principle in this work can be utilized to design and create versatile origami-inspired mechanical metamaterials that can find many applications. PMID- 29440442 TI - Digital signaling network drives the assembly of the AIM2-ASC inflammasome. AB - The AIM2-ASC inflammasome is a filamentous signaling platform essential for mounting host defense against cytoplasmic dsDNA arising not only from invading pathogens but also from damaged organelles. Currently, the design principles of its underlying signaling network remain poorly understood at the molecular level. We show here that longer dsDNA is more effective in inducing AIM2 assembly, its self-propagation, and downstream ASC polymerization. This observation is related to the increased probability of forming the base of AIM2 filaments, and indicates that the assembly discerns small dsDNA as noise at each signaling step. Filaments assembled by receptor AIM2, downstream ASC, and their joint complex all persist regardless of dsDNA, consequently generating sustained signal amplification and hysteresis. Furthermore, multiple positive feedback loops reinforce the assembly, as AIM2 and ASC filaments accelerate the assembly of nascent AIM2 with or without dsDNA. Together with a quantitative model of the assembly, our results indicate that an ultrasensitive digital circuit drives the assembly of the AIM2-ASC inflammasome. PMID- 29440443 TI - Reply to Van Meerbeek and Svenning, Emery, and Springmann et al.: Clarifying assumptions and objectives in evaluating effects of food system shifts on human diets. PMID- 29440444 TI - Causing confusion in the debate about the transition toward a more plant-based diet. PMID- 29440445 TI - Feedlot diet for Americans that results from a misspecified optimization algorithm. PMID- 29440446 TI - Without animals, US farmers would reduce feed crop production. PMID- 29440447 TI - A Human Genome-Wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1alpha XBP1 Activation. AB - Activation of the unfolded protein response (UPR) signaling pathways is linked to multiple human diseases, including cancer. The inositol-requiring kinase 1alpha (IRE1alpha)-X-box binding protein 1 (XBP1) pathway is the most evolutionarily conserved of the three major signaling branches of the UPR. Here, we performed a genome-wide siRNA screen to obtain a systematic assessment of genes integrated in the IRE1alpha-XBP1 axis. We monitored the expression of an XBP1-luciferase chimeric protein in which luciferase was fused in-frame with the spliced (active) form of XBP1. Using cells expressing this reporter construct, we identified 162 genes for which siRNA inhibition resulted in alteration in XBP1 splicing. These genes express diverse types of proteins modulating a wide range of cellular processes. Pathway analysis identified a set of genes implicated in the pathogenesis of breast cancer. Several genes, including BCL10, GCLM, and IGF1R, correlated with worse relapse-free survival (RFS) in an analysis of patients with triple-negative breast cancer (TNBC). However, in this cohort of 1,908 patients, only high GCLM expression correlated with worse RFS in both TNBC and non-TNBC patients. Altogether, our study revealed unidentified roles of novel pathways regulating the UPR, and these findings may serve as a paradigm for exploring novel therapeutic opportunities based on modulating the UPR.Implications: Genome wide RNAi screen identifies novel genes/pathways that modulate IRE1alpha-XBP1 signaling in human tumor cells and leads to the development of improved therapeutic approaches targeting the UPR.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/5/745/F1.large.jpg Mol Cancer Res; 16(5); 745-53. (c)2018 AACR. PMID- 29440449 TI - Impact of the Anticancer Drug NT157 on Tyrosine Kinase Signaling Networks. AB - The small-molecule drug NT157 has demonstrated promising efficacy in preclinical models of a number of different cancer types, reflecting activity against both cancer cells and the tumor microenvironment. Two known mechanisms of action are degradation of insulin receptor substrates (IRS)-1/2 and reduced Stat3 activation, although it is possible that others exist. To interrogate the effects of this drug on cell signaling pathways in an unbiased manner, we have undertaken mass spectrometry-based global tyrosine phosphorylation profiling of NT157 treated A375 melanoma cells. Bioinformatic analysis of the resulting dataset resolved 5 different clusters of tyrosine-phosphorylated peptides that differed in the directionality and timing of response to drug treatment over time. The receptor tyrosine kinase AXL exhibited a rapid decrease in phosphorylation in response to drug treatment, followed by proteasome-dependent degradation, identifying an additional potential target for NT157 action. However, NT157 treatment also resulted in increased activation of p38 MAPK alpha and gamma, as well as the JNKs and specific Src family kinases. Importantly, cotreatment with the p38 MAPK inhibitor SB203580 attenuated the antiproliferative effect of NT157, while synergistic inhibition of cell proliferation was observed when NT157 was combined with a Src inhibitor. These findings provide novel insights into NT157 action on cancer cells and highlight how globally profiling the impact of a specific drug on cellular signaling networks can identify effective combination treatments. Mol Cancer Ther; 17(5); 931-42. (c)2018 AACR. PMID- 29440450 TI - Pharmacokinetic Assessment of Cooperative Efflux of the Multitargeted Kinase Inhibitor Ponatinib Across the Blood-Brain Barrier. AB - A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multikinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and unbound (free) brain-to-plasma ratios were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp [Mdr1a/b(-/ )Bcrp1(-/-)] compared with the wild-type mice. The triple knockout mice had a greater than an additive increase in the brain exposure of ponatinib when compared with single knockout mice [Bcrp1(-/-) or Mdr1a/b(-/-)], suggesting functional compensation of transporter-mediated drug efflux. Based on the BBB model characterizing the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were approximately 15 fold higher in the wild-type compared with Mdr1a/b(-/-)Bcrp1(-/-) mice, resulting in a significant increase in the mean transit time (the average time spent by ponatinib in the brain in a single passage) in the absence of efflux transporters (P-gp and Bcrp). This study characterized transporter-mediated drug efflux from the brain, a process that reduces the duration and extent of ponatinib exposure in the brain and has critical implications for the use of targeted drug delivery for brain tumors. PMID- 29440448 TI - Establishment of Dimethyl Labeling-based Quantitative Acetylproteomics in Arabidopsis. AB - Protein acetylation, one of many types of post-translational modifications (PTMs), is involved in a variety of biological and cellular processes. In the present study, we applied both CsCl density gradient (CDG) centrifugation-based protein fractionation and a dimethyl-labeling-based 4C quantitative PTM proteomics workflow in the study of dynamic acetylproteomic changes in Arabidopsis. This workflow integrates the dimethyl chemical labeling with chromatography-based acetylpeptide separation and enrichment followed by mass spectrometry (MS) analysis, the extracted ion chromatogram (XIC) quantitation based computational analysis of mass spectrometry data to measure dynamic changes of acetylpeptide level using an in-house software program, named Stable isotope based Quantitation-Dimethyl labeling (SQUA-D), and finally the confirmation of ethylene hormone-regulated acetylation using immunoblot analysis. Eventually, using this proteomic approach, 7456 unambiguous acetylation sites were found from 2638 different acetylproteins, and 5250 acetylation sites, including 5233 sites on lysine side chain and 17 sites on protein N termini, were identified repetitively. Out of these repetitively discovered acetylation sites, 4228 sites on lysine side chain (i.e. 80.5%) are novel. These acetylproteins are exemplified by the histone superfamily, ribosomal and heat shock proteins, and proteins related to stress/stimulus responses and energy metabolism. The novel acetylproteins enriched by the CDG centrifugation fractionation contain many cellular trafficking proteins, membrane-bound receptors, and receptor-like kinases, which are mostly involved in brassinosteroid, light, gravity, and development signaling. In addition, we identified 12 highly conserved acetylation site motifs within histones, P-glycoproteins, actin depolymerizing factors, ATPases, transcription factors, and receptor-like kinases. Using SQUA-D software, we have quantified 33 ethylene hormone-enhanced and 31 hormone-suppressed acetylpeptide groups or called unique PTM peptide arrays (UPAs) that share the identical unique PTM site pattern (UPSP). This CDG centrifugation protein fractionation in combination with dimethyl labeling-based quantitative PTM proteomics, and SQUA-D may be applied in the quantitation of any PTM proteins in any model eukaryotes and agricultural crops as well as tissue samples of animals and human beings. PMID- 29440451 TI - Establishing Transcriptional Signatures to Differentiate PXR-, CAR-, and AhR Mediated Regulation of Drug Metabolism and Transport Genes in Cryopreserved Human Hepatocytes. AB - The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug-disposition genes via activation of nuclear receptors (NRs), such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR), remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR-/CAR-/AhR-specific drug-metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO), and AhR (omeprazole). Dose response for ligand-induced changes to 38 major human DMEs and critical hepatobiliary transporters were assessed using a custom gene expression array card. We identified novel differentially expressed drug disposition genes for PXR (?ABCB1/MDR1, CYP2C9, CYP2C19, and EPHX1, ?ABCB11), CAR [?sulfotransferase (SULT) 1E1, uridine glucuronosyl transferase (UGT) 2B4], and AhR (?SLC10A1/NTCP, SLCO1B1/OATP1B1], and coregulated genes (CYP1A1, CYP2B6, CYP2C8, CYP3A4, UGT1A1, UGT1A4). Subsequently, DME gene expression signatures were generated for known CYP3A4 inducers PF-06282999 and pazopanib. The former produced an induction signature almost identical to that of rifampin, suggesting activation of the PXR pathway, whereas the latter produced an expression signature distinct from those of PXR, CAR, or AhR, suggesting involvement of an alternate pathway(s). These results demonstrate that involvement of PXR/CAR/AhR can be identified via expression changes of signature DME/transporter genes. Inclusion of such signature genes could serve to simultaneously identify potential inducers and inhibitors, and the NRs involved in the transcriptional regulation, thus providing a more holistic and mechanism-based assessment of DDI risk for DMEs and transporters beyond conventional cytochrome P450 isoforms. PMID- 29440452 TI - Heartbeat: Is there any effective therapy for heart failure with preserved ejection fraction? PMID- 29440453 TI - Cochrane corner: interventions to improve adherence to lipid-lowering medication. PMID- 29440454 TI - Is traumatic intracranial haemorrhage a specific risk factor for atrial fibrillation? PMID- 29440455 TI - Authors' reply. PMID- 29440456 TI - Specific PKC betaII inhibitor: one stone two birds in the treatment of diabetic foot ulcers. AB - To explore whether or not inhibition of protein kinase C betaII (PKC betaII) stimulates angiogenesis as well as prevents excessive NETosis in diabetics thus accelerating wound healing. Streptozotocin (STZ, 60 mg/kg/day for 5 days, i.p.) was injected to induce type I diabetes in male ICR mice. Mice were treated with ruboxistaurin (30 mg/kg/day, orally) for 14 consecutive days. Wound closure was evaluated by wound area and number of CD31-stained capillaries. Peripheral blood flow cytometry was done to evaluate number of circulating endothelial progenitor cells (EPCs). NETosis assay and wound tissue immunofluorescence imaging were done to evaluate the percentage of neutrophils undergoing NETosis. Furthermore, the expression of PKC betaII, protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and histone citrullation (H3Cit) were determined in the wound by Western blot analysis. Ruboxistaurin accelerated wound closure and stimulated angiogenesis in diabetic mice. The number of circulating EPCs was increased significantly in ruboxistaurin treated diabetic mice. Moreover, ruboxistaurin treatment significantly decreases the percentages of H3Cit+ cells in both peripheral blood and wound areas. This prevented excess activated neutrophils forming an extracellular trap (NETs) formation. The expressions of phospho-Akt (p-Akt), phospho-eNOS (p-eNOS), and VEGF increased significantly in diabetic mice on ruboxistaurin treatment. The expressions of PKC betaII and H3Cit+, on the other hand, decreased with ruboxistaurin treatment. The results of the present study suggest that ruboxistaurin by inhibiting PKC betaII activation, reverses EPCs dysfunction as well as prevents exaggerated NETs formation in a diabetic mouse model; thereby accelerating the wound healing process. PMID- 29440458 TI - Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization. AB - Macrophages play essential roles in the generation and resolution of inflammation. Ischemia-reperfusion injury (IRI) triggers a systemic inflammatory response and leads to cellular injury and organ failure. During surgical procedures of the liver, such as hepatic resection and liver transplantation, IRI leads to the dysfunction of the liver. Rho-associated protein kinase (ROCK) inhibitors were reported protecting the liver from IRI. However, the systematic administration of ROCK inhibitors causes severe hypotension. Here, using Fasudil carried liposomes, we specifically inhibited the ROCK-II expression in Kupffer cells and blood monocytes. Through this macrophage/monocyte specific treatment of Fasudil, we successfully protected the liver from IRI by shifting Kupffer cells/monocytes from M1/classical to M2/patrolling phenotype in the liver and peripheral blood. Our finding provides novel insights into the macrophage/monocyte-specific drug delivery and the treatment of liver IRI. PMID- 29440457 TI - Liraglutide protects cardiac function in diabetic rats through the PPARalpha pathway. AB - Increasing evidence shows that diabetes causes cardiac dysfunction. We hypothesized that a glucagon-like peptide-1 analogue, liraglutide, would attenuate cardiac dysfunction in diabetic rats. Twenty-four Sprague Dawley (SD) rats were divided into 2 groups fed either a normal diet (normal, n = 6) or a high-fat diet (HFD, n = 18) for 4 weeks. Then, the HFD rats were injected with streptozotocin (STZ) to create a diabetic rat model. Diabetic rats were divided into 3 subgroups receiving vehicle (diabetic, n = 6), a low dose of liraglutide (Llirag, 0.2 mg/kg/day, n = 6) or a high dose of liraglutide (Hlirag, 0.4 mg/kg/day, n = 6). Metabolic parameters, systolic blood pressure, heart rate, left ventricular (LV) function, and whole genome expression of the heart were determined. Diabetic rats developed insulin resistance, increased blood lipid levels and oxidative stress, and impaired LV function, serum adiponectin, NO. Liraglutide improved insulin resistance, serum adiponectin, NO, heart rate and LV function and reduced blood triglyceride, total cholesterol levels and oxidative stress. Moreover, liraglutide increased heart Nr1h3 , Ppar-alpha and Srebp expression and reduced Dgat , and Angptl3 expression. Liraglutide prevented in cardiac dysfunction by activating the PPARalpha pathway to inhibit Dgat expression and oxidative stress in diabetic rats. PMID- 29440459 TI - miR-139-5p inhibits isoproterenol-induced cardiac hypertrophy by targetting c Jun. AB - Hypertrophic cardiomyopathy (HCM) is a serious monogenic disease characterized by cardiac hypertrophy, fibrosis, sudden cardiac death, and heart failure. Previously, we identified that miR-139-5p was down-regulated in HCM patients. However, the regulatory effects of miR-139-5p remain unclear. Thus, we investigated the role of miR-139-5p in the regulation of cardiac hypertrophy. The expression of miR-139-5p in left ventricular tissues in HCM patients and mice subjected to transverse aortic constriction (TAC) was significantly down regulated. Knockdown of miR-139-5p expression in neonatal rat cardiomyocytes (NRCMs) induced cardiomyocyte enlargement and increased atrial natriuretic polypeptide (ANP) expression. Overexpression of miR-139-5p antagonized isoproterenol (ISO)-induced cardiomyocyte enlargement and ANP/brain natriuretic peptide (BNP) up-regulation. More importantly, we found that c-Jun expression was inhibited by miR-139-5p in NRCMs. Knockdown of c-Jun expression significantly attenuated cardiac hypertrophy induced by miR-139-5p deprivation. Our data indicated that miR-139-5p was down-regulated in the hearts of HCM patients and that it inhibited cardiac hypertrophy by targetting c-Jun expression. PMID- 29440460 TI - Caspase-1 regulate AngII-induced cardiomyocyte hypertrophy via upregulation of IL 1beta. AB - Cardiac hypertrophy is a compensatory response to stress or stimuli, which results in arrhythmia and heart failure. Although multiple molecular mechanisms have been identified, cardiac hypertrophy is still difficult to treat. Pyroptosis is a caspase-1 dependent pro-inflammatory programmed cell death. Caspase-1 is involved in various types of diseases, including hepatic injury, cancers, and diabetes related complications. However, the exact role of caspase-1 in cardiac hypertrophy is yet to be discovered. The present study aimed to explore the possible role of caspase-1 in pathogenesis of cardiac hypertrophy. We established cardiac hypertrophy models both in vivo and in vitro to detect the expression of caspase-1 and IL-1beta. The results showed that caspase-1 and IL-1beta expression levels were significantly upregulated during cardiac hypertrophy. Subsequently, caspase-1 inhibitor was co-administered with angiotensin II (Ang II) in cardiomyocytes to observe whether it could attenuate cardiac hypertrophy. Results showed that caspase-1 attenuated the pro-hypertrophic effect of Ang II, which was related to the downregulation of caspase-1 and IL-1beta. In conclusion, our results provide a novel evidence that caspase-1 mediated pyroptosis is involved in cardiac hypertrophy, and the inhibition of caspase-1 will offer a therapeutic potential against cardiac hypertrophy. PMID- 29440461 TI - Blockade of glutamate receptor ameliorates lipopolysaccharide-induced sepsis through regulation of neuropeptides. AB - Glutamate receptors (N-methyl-d-aspartate receptor (NMDAR)) are expressed mainly in the central nervous system (CNS), but several potentially important exceptions are worth mentioning. Recently, NMDAR, a glutamate receptor, has been reported to be found in the lungs. NMDAR is activated in acute lung injury (ALI). Here, the present experiment was designed to examine whether NMDAR blockade (MK-801) ameliorates ALI through affecting neuropeptides in LPS-induced sepsis animal models. Male Kunming mice were divided into control group, LPS group, control + MK-801 group, and LPS + MK-801 group. Bronchoalveolar lavage fluid (BALF) was collected and evaluated. The lung histological pathology was assayed by immunocytochemistry staining. Western blot was used to measure PGP9.5, substance P (SP), and vasoactive intestinal polypeptide (VIP). Results showed that LPS induced mice animal models were ameliorated by co-treatment with the MK-801, an uncompetitive NMDAR antagonist. Moreover, the protective effects of MK-801 attributed to the increased secretion of VIP and decreased secretion of SP. The results of the present study indicated that the blockade of NMDAR may represent a promising therapeutic strategy for the treatment of sepsis-associated ALI through regulation of neuropeptides. PMID- 29440462 TI - miR-25 inhibits sepsis-induced cardiomyocyte apoptosis by targetting PTEN. AB - To investigate the regulatory mechanism of miR-25 in sepsis-induced cardiomyocyte apoptosis. Rats models of sepsis were established by cecal ligation and puncture (CLP). Lipopolysaccharide (LPS)-induced cardiomyocyte was used as an in vitro model of sepsis. The expressions of miR-25, tensin homolog deleted on chromosome 10 (PTEN), Toll-like receptors 4 (TLR4), and p-p65 were analyzed by quantitative real-time PCR (qRT-PCR) and Western blot, respectively. The levels of interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were detected by ELISA. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated d-UTP nick end labeling (TUNEL) assay. The relationship between miR-25 and PTEN was measured by luciferase reporter assays. MiR-25 expression in serum of CLP rats and LPS-induced cardiomyocyte was decreased, while the contents of TNF-alpha and IL-6 were increased. Moreover, the expressions of PTEN, TLR4, and p-p65 in LPS induced cardiomyocyte were significantly increased. Overexpression of miR-25 increased the survival rate of rats, inhibited LPS-increased cardiomyocyte apoptosis, reversed the increased expression of PTEN, TLR4, p-p65, TNF-alpha, and IL-6 induced by LPS. The luciferase assay demonstrated that PTEN was a target of miR-25. Additionally, pcDNA-PTEN reversed the inhibitory effect of miR-25 mimic on cardiomyocyte apoptosis, while TAK-242 (TLR-4 inhibitor) countered this effect. miR-25 reduced LPS-induced cardiomyocyte apoptosis by down-regulating PTEN/TLR4/NF-kappaB axis. PMID- 29440463 TI - Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma. AB - OBJECTIVES: Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90 RE, which elicits a sustained therapeutic response. DESIGN: Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE. RESULTS: TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8+ T cells, CD56+ NK cells and CD8+ CD56+ NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB+CD8+ T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-alpha on both the CD8+ and CD4+ T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1+/Tim-3+CD8+ T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs. CONCLUSION: High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment. PMID- 29440465 TI - Social networks as drivers of syphilis and HIV infection among young men who have sex with men. AB - OBJECTIVES: Syphilis and HIV epidemics overlap, yet little is known about combined network and behavioural factors that drive syphilis-HIV coinfection. Our study objective was to assess network contexts and sexual behaviours associated with syphilis-HIV co-infection and monoinfection among a particularly vulnerable subgroup: young Black men who have sex with men (YBMSM). To achieve this objective, we examined factors associated with coinfection by each subgroup as classified by syphilis-HIV infection status: (A) HIV monoinfected, (B) syphilis monoinfected and (C) neither syphilis infected nor HIV infected. In addition, we further identified the factors that are associated with HIV infection or syphilis monoinfection. METHODS: Data were collected from a sample of 365 YBMSM, aged 16 29 years, recruited through respondent-driven sampling between 2014 and 2016, in two cities with large HIV epidemics: Houston, TX, and Chicago, IL. We conducted a series of multinomial logistic regression models to predict coinfection, HIV monoinfection and syphilis monoinfection as a function of network and sexual behavioural factors. RESULTS: Coinfection was associated with having network members who are coinfected or HIV infected within one's social network. Syphilis monoinfection was associated with a higher number of social venues attended, and HIV monoinfection was associated with having more condomless top partners. CONCLUSION: Public health interventions that address the diagnosis and treatment of syphilis infection and ensure that those with syphilis are being tested for HIV may be promising in limiting the synergy of syphilis-HIV infections in onward transmission. Advancing HIV and syphilis prevention efforts in high-prevalence networks may allow prioritisation of limited resources. PMID- 29440467 TI - Fentanyl lozenge story part 2: from military procurement to package. AB - This paper describes the selection of fentanyl as a replacement for morphine as the United Kingdom Ministry of Defence's first-line battlefield analgesic agent. It is a detailed review of the 6 year journey from selection to eventual roll-out in October 2017. It concentrates on the procurement and governance process of the deployment of fentanyl for individual issue and self-use. It highlights the significant differences in military and civilian legislation, the specialist environment we work in and the safety concerns surrounding controlled drugs in the austere environment. The lessons learnt can be applied to other organisations working in specialist environments that are looking to improve patient care through novel or off-license techniques that meet legislative resistance. PMID- 29440468 TI - Systematic review of caregiver burden in spouses and partners providing informal care to wounded, injured or sick (WIS) military personnel. AB - INTRODUCTION: For the purposes of this review, caregivers are individuals who provide care that is typically unpaid and usually takes place at home. This systematic review aims to identify burden among spouses/partners caring for wounded, injured or sick military personnel and the factors associated with caregiver burden. METHODS: A systematic review was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Five electronic databases and relevant websites were searched. Two reviewers appraised the quality of the studies and carried out data extraction. RESULTS: Ten original papers were identified, of which eight were quantitative studies and two were qualitative. These papers highlighted the potential negative impact caregiving can have on spouses/partners and also some of the positive aspects of caring that can strengthen intimate relationships. CONCLUSIONS: Caring for an injured or ill military spouse or partner is a difficult task, compounded by the complexity of dealing with potentially both their physical and mental health problems. However, research has also identified some positive aspects of caring that can strengthen intimate relationships. PMID- 29440464 TI - Outcome measures in coeliac disease trials: the Tampere recommendations. AB - OBJECTIVE: A gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures. DESIGN: Based on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed. RESULTS: We comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease. CONCLUSION: Careful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry. PMID- 29440469 TI - Air-drop blood supply in the French Army. AB - BACKGROUND: Haemorrhagic shock remains the leading cause of preventable death in overseas and austere settings. Transfusion of blood components is critical in the management of this kind of injury. For French naval and ground military units, this supply often takes too long considering the short shelf-life of red blood cell concentrates (RBCs) and the limited duration of transport in cooling containers (five to six days). Air-drop supply could be an alternative to overcome these difficulties on the condition that air-drop does not cause damage to blood units. METHODS: After a period of study and technical development of packaging, four air-drops at medium and high altitudes were performed with an aircraft of the French Air Force. After this, one air-drop was carried out at medium altitude with 10 RBCs and 10 French lyophilised plasma (FLYP). A second air-drop was performed with a soldier carrying one FLYP unit at 12 000 feet. For these air-drops real blood products were used, and quality control testing and temperature monitoring were performed. RESULTS: The temperatures inside the containers were within the normal ranges. Visual inspection indicated that transfusion packaging and dumped products did not undergo deterioration. The quality control data on RBCs and FLYP, including haemostasis, suggested no difference before and after air-drop. DISCUSSION: The operational implementation of the air-drop of blood products seems to be one of the solutions for the supply of blood products in military austere settings or far forward on battlefield, allowing safe and early transfusion. PMID- 29440466 TI - Prevalence of Mycoplasma genitalium in different population groups: systematic review andmeta-analysis. AB - BACKGROUND: Mycoplasma genitalium is a common cause of non-gonococcal non chlamydial urethritis and cervicitis. Testing of asymptomatic populations has been proposed, but prevalence in asymptomatic populations is not well established. We aimed to estimate the prevalence of M. genitalium in the general population, pregnant women, men who have sex with men (MSM), commercial sex workers (CSWs) and clinic-based samples, METHODS: We searched Embase, Medline, IndMED, African Index Medicus and LILACS from 1 January 1991 to 12 July 2016 without language restrictions. We included studies with 500 participants or more. Two reviewers independently screened and selected studies and extracted data. We examined forest plots and conducted random-effects meta-analysis to estimate prevalence, if appropriate. Between-study heterogeneity was examined using the I2 statistic and meta-regression. RESULTS: Of 3316 screened records, 63 were included. In randomly selected samples from the general population, the summary prevalence was 1.3% (95% CI 1.0% to 1.8%, I2 41.5%, three studies, 9091 people) in countries with higher levels of development and 3.9% (95% CI 2.2 to 6.7, I2 89.2%, three studies, 3809 people) in countries with lower levels. Prevalence was similar in women and men (P=0.47). In clinic based samples, prevalence estimates were higher, except in asymptomatic patients (0.8%, 95% CI 0.4 to 1.4, I2 0.0%, three studies, 2889 people). Summary prevalence estimates were, in the following groups: pregnant women 0.9% (95% CI 0.6% to 1.4%, I2 0%, four studies, 3472 people), MSM in the community 3.2% (95% CI 2.1 to 5.1, I2 78.3%, five studies, 3012 people) and female CSWs in the community 15.9% (95% CI 13.5 to 18.9, I2 79.9%, four studies, 4006 people). DISCUSSION: This systematic review can inform testing guidelines for M. genitalium. The low estimated prevalence of M. genitalium in the general population, pregnant women and asymptomatic attenders at clinics does not support expansion of testing to these groups. REGISTRATION NUMBERS: PROSPERO: CRD42015020420. PMID- 29440470 TI - Case of venom ophthalmia following contact with Naja pallida: the red spitting cobra. AB - Venom ophthalmia is a condition that can be eyesight threatening. This article describes a case of venom ophthalmia due to the Naja pallida (red spitting cobra) and is aimed to educate readers regarding the management of an uncommon, yet important, pathology that deployed military personnel may encounter. Simple first steps can reduce the impact of the injury with copious irrigation of the eye being the key management step. Each step of the management, including what not to do, is discussed in order to educate and act as a guide to all deployed healthcare professionals. PMID- 29440472 TI - Response by Singfer and Defreyne to Letter Regarding Article, "Unruptured Brain Arteriovenous Malformations: Primary ONYX Embolization in ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-Eligible Patients". PMID- 29440471 TI - Clinical and Demographic Characteristics Associated With Suboptimal Primary Stroke and Transient Ischemic Attack Prevention: Retrospective Analysis. AB - BACKGROUND AND PURPOSE: Primary prevention of stroke and transient ischemic attack (TIA) is important to reduce the burden of these conditions; however, prescribing of prevention drugs is suboptimal. We aimed to identify individual clinical and demographic characteristics associated with potential missed opportunities for prevention therapy with lipid-lowering, anticoagulant, or antihypertensive drugs before stroke/TIA. METHODS: We analyzed anonymized electronic primary care records from a UK primary care database that covers 561 family practices. Patients with first-ever stroke/TIA, >=18 years, with diagnosis between January 1, 2009, and December 31, 2013, were included. Missed opportunities for prevention were defined as people with clinical indications for lipid-lowering, anticoagulant, or antihypertensive drugs but not prescribed these drugs before their stroke/TIA. Mixed-effect logistic regression models evaluated the relationship between missed opportunities and individual clinical/demographic characteristics. RESULTS: The inclusion criteria were met by 29 043 people with stroke/TIA. Patients with coronary heart disease, chronic kidney disease, peripheral arterial disease, or diabetes mellitus were at less risk of a missed opportunity for prescription of lipid-lowering and antihypertensive drugs. However, patients with a 10-year cardiovascular disease risk >=20% but without these diagnoses had increased risk of having a missed opportunity for prescription of lipid-lowering drugs or antihypertensive drugs. Women were less likely to be prescribed anticoagulants but more likely to be prescribed antihypertensive drugs. The elderly (>=85 years of age) were less likely to be prescribed all 3 prevention drugs, compared with people aged 75 to 79 years. CONCLUSIONS: Knowing the patient characteristics predictive of missed opportunities for stroke prevention may help primary care identify and appropriately manage these patients. Improving the management of these groups may reduce their risk and potentially prevent large number of future strokes and TIAs in the population. PMID- 29440473 TI - Letter by Liu and Chen Regarding Article, "Unruptured Brain Arteriovenous Malformations: Primary ONYX Embolization in ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-Eligible Patients". PMID- 29440474 TI - Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke. AB - BACKGROUND AND PURPOSE: MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia. METHODS: SHR (spontaneously hypertensive rats) and normotensive WKY (Wistar Kyoto) rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery via craniectomy, or transient occlusion of the middle cerebral artery by the intraluminal suture method. JZL184 or MJN110 was administered 60 minutes after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between days 1 to 28 by magnetic resonance imaging, histology, and behavioral tests. RESULTS: Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors. CONCLUSIONS: Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke. PMID- 29440475 TI - Characterization of the molecular crosstalk within the essential Grc3/Las1 pre rRNA processing complex. AB - Grc3 is an essential well-conserved eukaryotic polynucleotide kinase (PNK) that cooperates with the endoribonuclease Las1 to process the preribosomal RNA (rRNA). Aside from being dependent upon Las1 for coordinated kinase and nuclease function, little is known about Grc3 substrate specificity and the molecular mechanisms governing kinase activity. Here we characterize the kinase activity of Grc3 and identify key similarities and differences between Grc3 and other polynucleotide kinase family members. In contrast to other PNK family members, Grc3 has distinct substrate preference for RNA substrates in vitro. By disrupting conserved residues found at the Grc3 kinase active site, we identified specific residues required to support Grc3-directed Las1-mediated pre-rRNA cleavage in vitro and in vivo. The crosstalk between Grc3 and Las1 ensures the direct coupling of cleavage and phosphorylation during pre-rRNA processing. Taken together, our studies provide key insight into the polynucleotide kinase activity of the essential enzyme Grc3 and its molecular crosstalk with the endoribonuclease Las1. PMID- 29440477 TI - The man with two broken hips: neck of femur fracture with previous Girdlestone arthroplasty. PMID- 29440476 TI - Determination of the small RNA GcvB regulon in the Gram-negative bacterial pathogen Pasteurella multocida and identification of the GcvB seed binding region. AB - Pasteurella multocida is a Gram-negative bacterium responsible for many important animal diseases. While a number of P. multocida virulence factors have been identified, very little is known about how gene expression and protein production is regulated in this organism. Small RNA (sRNA) molecules are critical regulators that act by binding to specific mRNA targets, often in association with the RNA chaperone protein Hfq. In this study, transcriptomic analysis of the P. multocida strain VP161 revealed a putative sRNA with high identity to GcvB from Escherichia coli and Salmonella enterica serovar Typhimurium. High-throughput quantitative liquid proteomics was used to compare the proteomes of the P. multocida VP161 wild-type strain, a gcvB mutant, and a GcvB overexpression strain. These analyses identified 46 proteins that displayed significant differential production after inactivation of gcvB, 36 of which showed increased production. Of the 36 proteins that were repressed by GcvB, 27 were predicted to be involved in amino acid biosynthesis or transport. Bioinformatic analyses of putative P. multocida GcvB target mRNAs identified a strongly conserved 10 nucleotide consensus sequence, 5' AACACAACAT-3', with the central eight nucleotides identical to the seed binding region present within GcvB mRNA targets in E. coli and S. Typhimurium. Using a defined set of seed region mutants, together with a two-plasmid reporter system that allowed for quantification of sRNA-mRNA interactions, this sequence was confirmed to be critical for the binding of the P. multocida GcvB to the target mRNA, gltA. PMID- 29440479 TI - Reply to 'Influenza follicles and their buds as early diagnostic markers of influenza: typical images' and demonstration of lymphoid follicles in the posterior pharyngeal walls of patients with mycoplasmal pneumonia. PMID- 29440478 TI - Career specialty choices of UK medical graduates of 2015 compared with earlier cohorts: questionnaire surveys. AB - OBJECTIVE: To report the career specialty choices of UK medical graduates of 2015 one year after graduation and to compare these with the choices made at the same postgraduate stage by previous cohorts. DESIGN: National survey using online and postal questionnaires. SETTING: UK. PARTICIPANTS: UK-trained medical graduates. MAIN OUTCOME MEASURES: Grouped and individual specialty choices. RESULTS: The response rate was 41.3% (3040/7095). Among the graduates of 2015, general practice (27.8% of first choices) and hospital medical specialties (26.5%) were the most frequent first choices of long-term career. First choices for general practice declined among women from 36.1% for the 2005-2009 cohorts to 33.3% for the 2015 cohort, and among men from 22.4% for the 2005-2009 cohorts to 19.3% for the 2015 cohort. First choices for surgery declined among men (from 29.5% for the 2005-2009 cohorts to 21.7% for the 2015 cohort), but not among women (12.3% for the 2005-2009 cohorts and 12.5% for the 2015 cohort). There was an increase in the percentage of first choices for anaesthesia, psychiatry, radiology and careers outside medicine. Anaesthesia, oncology, paediatrics and radiology increased in popularity over time among men, but not among women. CONCLUSIONS: Career choices for general practice remain low. Other current shortage specialties, apart from radiology and psychiatry, are not showing an increase in the number of doctors who choose them. Large gender differences remain in the choices for some specialties. Further work is needed into the determinants of junior doctors' choices for shortage specialties and those with large gender imbalances. PMID- 29440480 TI - Trismus caused by paraneoplastic brainstem encephalitis. AB - We discuss the assessment and differential diagnoses of a middle-aged man who presented with trismus, double vision and behavioural problems. MRI scan of the brain was initially normal, but a month later showed high signal in the hippocampal region on fluid attenuated inversion recovery sequence (FLAIR) imaging. We suspected a paraneoplastic brainstem encephalitis because of his smoking history, rapidly progressive symptoms and abnormal brainstem signs. A positron emission tomography-CT scan identified abnormal subcarinal nodes, shown on biopsy to be metastatic small cell lung cancer. He is currently undergoing treatment with chemotherapy and radiotherapy. PMID- 29440482 TI - Successfully implementing Safety WalkRounds: secret sauce more than a magic bullet. PMID- 29440481 TI - Prospective evaluation of medication-related clinical decision support over-rides in the intensive care unit. AB - BACKGROUND: Clinical decision support (CDS) displayed in electronic health records has been found to reduce the incidence of medication errors and adverse drug events (ADE). Recent data suggested that medication-related CDS alerts were frequently over-ridden, often inappropriately. Patients in the intensive care unit (ICU) are at an increased risk of ADEs; however, limited data exist on the benefits of CDS in the ICU. This study aims to evaluate potential harm associated with medication-related CDS over-rides in the ICU. METHODS: This was a prospective observational study of adults admitted to any of six ICUs between July 2016 and April 2017 at our institution. Patients with provider-overridden CDS for dose (orders for scheduled frequency and not pro re nata), drug allergy, drug-drug interaction, geriatric and renal alerts (contraindicated medications for renal function or renal dosing) were included. The primary outcome was the appropriateness of over-rides, which were evaluated by two independent reviewers. Secondary outcomes included incidence of ADEs following alert over-ride and risk of ADEs based on over-ride appropriateness. RESULTS: A total of 2448 over-ridden alerts from 712 unique patient encounters met inclusion criteria. The overall appropriateness rate for over-rides was 81.6% and varied by alert type. More ADEs (potential and definite) were identified following inappropriate over-rides compared with appropriate over-rides (16.5 vs 2.74 per 100 over-ridden alerts, Fisher's exact test P<0.001). An adjusted logistic regression model showed that inappropriate over-rides were associated with an increased risk of ADEs (OR 6.14, 95% CI 4.63 to 7.71, P<0.001). CONCLUSIONS: Approximately four of five identified CDS over-rides were appropriately over-ridden, with the rate varying by alert type. However, inappropriate over-rides were six times as likely to be associated with potential and definite ADEs, compared with appropriate over-rides. Further efforts should be targeted at improving the positive predictive value of CDS such as by suppressing alerts that are appropriately over-ridden. PMID- 29440483 TI - Rigorous evaluations of evolving interventions: can we have our cake and eat it too? PMID- 29440484 TI - Synergistic and additive effect of retinoic acid in circumventing resistance to p53 restoration. AB - TP53 mutations occur in ~50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of p53R172H -mutant lymphomas, we identified retinoic acid receptor gamma (RARgamma) as an actionable target and demonstrated that pharmacological activation of RARgamma with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors. PMID- 29440485 TI - Reporter-nanobody fusions (RANbodies) as versatile, small, sensitive immunohistochemical reagents. AB - Sensitive and specific antibodies are essential for detecting molecules in cells and tissues. However, currently used polyclonal and monoclonal antibodies are often less specific than desired, difficult to produce, and available in limited quantities. A promising recent approach to circumvent these limitations is to employ chemically defined antigen-combining domains called "nanobodies," derived from single-chain camelid antibodies. Here, we used nanobodies to prepare sensitive unimolecular detection reagents by genetically fusing cDNAs encoding nanobodies to enzymatic or antigenic reporters. We call these fusions between a reporter and a nanobody "RANbodies." They can be used to localize epitopes and to amplify signals from fluorescent proteins. They can be generated and purified simply and in unlimited amounts and can be preserved safely and inexpensively in the form of DNA or digital sequence. PMID- 29440486 TI - Cooperative breeding and the evolutionary coexistence of helper and nonhelper strategies. PMID- 29440487 TI - Generic assembly patterns in complex ecological communities. AB - The study of ecological communities often involves detailed simulations of complex networks. However, our empirical knowledge of these networks is typically incomplete and the space of simulation models and parameters is vast, leaving room for uncertainty in theoretical predictions. Here we show that a large fraction of this space of possibilities exhibits generic behaviors that are robust to modeling choices. We consider a wide array of model features, including interaction types and community structures, known to generate different dynamics for a few species. We combine these features in large simulated communities, and show that equilibrium diversity, functioning, and stability can be predicted analytically using a random model parameterized by a few statistical properties of the community. We give an ecological interpretation of this "disordered" limit where structure fails to emerge from complexity. We also demonstrate that some well-studied interaction patterns remain relevant in large ecosystems, but their impact can be encapsulated in a minimal number of additional parameters. Our approach provides a powerful framework for predicting the outcomes of ecosystem assembly and quantifying the added value of more detailed models and measurements. PMID- 29440488 TI - Pivotal roles of PCNA loading and unloading in heterochromatin function. AB - In Saccharomyces cerevisiae, heterochromatin structures required for transcriptional silencing of the HML and HMR loci are duplicated in coordination with passing DNA replication forks. Despite major reorganization of chromatin structure, the heterochromatic, transcriptionally silent states of HML and HMR are successfully maintained throughout S-phase. Mutations of specific components of the replisome diminish the capacity to maintain silencing of HML and HMR through replication. Similarly, mutations in histone chaperones involved in replication-coupled nucleosome assembly reduce gene silencing. Bridging these observations, we determined that the proliferating cell nuclear antigen (PCNA) unloading activity of Elg1 was important for coordinating DNA replication forks with the process of replication-coupled nucleosome assembly to maintain silencing of HML and HMR through S-phase. Collectively, these data identified a mechanism by which chromatin reassembly is coordinated with DNA replication to maintain silencing through S-phase. PMID- 29440489 TI - Cryo-EM reconstruction of AlfA from Bacillus subtilis reveals the structure of a simplified actin-like filament at 3.4-A resolution. AB - Low copy-number plasmid pLS32 of Bacillus subtilis subsp. natto contains a partitioning system that ensures segregation of plasmid copies during cell division. The partitioning locus comprises actin-like protein AlfA, adaptor protein AlfB, and the centromeric sequence parN Similar to the ParMRC partitioning system from Escherichia coli plasmid R1, AlfA filaments form actin like double helical filaments that arrange into an antiparallel bipolar spindle, which attaches its growing ends to sister plasmids through interactions with AlfB and parN Because, compared with ParM and other actin-like proteins, AlfA is highly diverged in sequence, we determined the atomic structure of nonbundling AlfA filaments to 3.4-A resolution by cryo-EM. The structure reveals how the deletion of subdomain IIB of the canonical actin fold has been accommodated by unique longitudinal and lateral contacts, while still enabling formation of left handed, double helical, polar and staggered filaments that are architecturally similar to ParM. Through cryo-EM reconstruction of bundling AlfA filaments, we obtained a pseudoatomic model of AlfA doublets: the assembly of two filaments. The filaments are antiparallel, as required by the segregation mechanism, and exactly antiphasic with near eightfold helical symmetry, to enable efficient doublet formation. The structure of AlfA filaments and doublets shows, in atomic detail, how deletion of an entire domain of the actin fold is compensated by changes to all interfaces so that the required properties of polymerization, nucleotide hydrolysis, and antiparallel doublet formation are retained to fulfill the system's biological raison d'etre. PMID- 29440490 TI - Nuclear quantum effect with pure anharmonicity and the anomalous thermal expansion of silicon. AB - Despite the widespread use of silicon in modern technology, its peculiar thermal expansion is not well understood. Adapting harmonic phonons to the specific volume at temperature, the quasiharmonic approximation, has become accepted for simulating the thermal expansion, but has given ambiguous interpretations for microscopic mechanisms. To test atomistic mechanisms, we performed inelastic neutron scattering experiments from 100 K to 1,500 K on a single crystal of silicon to measure the changes in phonon frequencies. Our state-of-the-art ab initio calculations, which fully account for phonon anharmonicity and nuclear quantum effects, reproduced the measured shifts of individual phonons with temperature, whereas quasiharmonic shifts were mostly of the wrong sign. Surprisingly, the accepted quasiharmonic model was found to predict the thermal expansion owing to a large cancellation of contributions from individual phonons. PMID- 29440492 TI - Time-spliced X-ray diffraction imaging of magnetism dynamics in a NdNiO3 thin film. AB - Diffraction imaging of nonequilibrium dynamics at atomic resolution is becoming possible with X-ray free-electron lasers. However, there are unresolved problems with applying this method to objects that are confined in only one dimension. Here I show that reliable one-dimensional coherent diffraction imaging is possible by splicing together images recovered from different time delays in an optical pump X-ray probe experiment. The time and space evolution of antiferromagnetic order in a vibrationally excited complex oxide heterostructure is recovered from time-resolved measurements of a resonant soft X-ray diffraction peak. Midinfrared excitation of the substrate is shown to lead to a demagnetization front that propagates at a velocity exceeding the speed of sound, a critical observation for the understanding of driven phase transitions in complex condensed matter. PMID- 29440491 TI - Cryo-EM structure of the bacterial actin AlfA reveals unique assembly and ATP binding interactions and the absence of a conserved subdomain. AB - Bacterial actins are an evolutionarily diverse family of ATP-dependent filaments built from protomers with a conserved structural fold. Actin-based segregation systems are encoded on many bacterial plasmids and function to partition plasmids into daughter cells. The bacterial actin AlfA segregates plasmids by a mechanism distinct from other partition systems, dependent on its unique dynamic properties. Here, we report the near-atomic resolution electron cryo-microscopy structure of the AlfA filament, which reveals a strikingly divergent filament architecture resulting from the loss of a subdomain conserved in all other actins and a mode of ATP binding. Its unusual assembly interfaces and nucleotide interactions provide insight into AlfA dynamics, and expand the range of evolutionary variation accessible to actin quaternary structure. PMID- 29440493 TI - GABAergic inhibition of leg motoneurons is required for normal walking behavior in freely moving Drosophila. AB - Walking is a complex rhythmic locomotor behavior generated by sequential and periodical contraction of muscles essential for coordinated control of movements of legs and leg joints. Studies of walking in vertebrates and invertebrates have revealed that premotor neural circuitry generates a basic rhythmic pattern that is sculpted by sensory feedback and ultimately controls the amplitude and phase of the motor output to leg muscles. However, the identity and functional roles of the premotor interneurons that directly control leg motoneuron activity are poorly understood. Here we take advantage of the powerful genetic methodology available in Drosophila to investigate the role of premotor inhibition in walking by genetically suppressing inhibitory input to leg motoneurons. For this, we have developed an algorithm for automated analysis of leg motion to characterize the walking parameters of wild-type flies from high-speed video recordings. Further, we use genetic reagents for targeted RNAi knockdown of inhibitory neurotransmitter receptors in leg motoneurons together with quantitative analysis of resulting changes in leg movement parameters in freely walking Drosophila Our findings indicate that targeted down-regulation of the GABAA receptor Rdl (Resistance to Dieldrin) in leg motoneurons results in a dramatic reduction of walking speed and step length without the loss of general leg coordination during locomotion. Genetically restricting the knockdown to the adult stage and subsets of motoneurons yields qualitatively identical results. Taken together, these findings identify GABAergic premotor inhibition of motoneurons as an important determinant of correctly coordinated leg movements and speed of walking in freely behaving Drosophila. PMID- 29440494 TI - Execution of saccadic eye movements affects speed perception. AB - Due to the foveal organization of our visual system we have to constantly move our eyes to gain precise information about our environment. Doing so massively alters the retinal input. This is problematic for the perception of moving objects, because physical motion and retinal motion become decoupled and the brain has to discount the eye movements to recover the speed of moving objects. Two different types of eye movements, pursuit and saccades, are combined for tracking. We investigated how the way we track moving targets can affect the perceived target speed. We found that the execution of corrective saccades during pursuit initiation modifies how fast the target is perceived compared with pure pursuit. When participants executed a forward (catch-up) saccade they perceived the target to be moving faster. When they executed a backward saccade they perceived the target to be moving more slowly. Variations in pursuit velocity without corrective saccades did not affect perceptual judgments. We present a model for these effects, assuming that the eye velocity signal for small corrective saccades gets integrated with the retinal velocity signal during pursuit. In our model, the execution of corrective saccades modulates the integration of these two signals by giving less weight to the retinal information around the time of corrective saccades. PMID- 29440495 TI - High-order above-threshold dissociation of molecules. AB - Electrons bound to atoms or molecules can simultaneously absorb multiple photons via the above-threshold ionization featured with discrete peaks in the photoelectron spectrum on account of the quantized nature of the light energy. Analogously, the above-threshold dissociation of molecules has been proposed to address the multiple-photon energy deposition in the nuclei of molecules. In this case, nuclear energy spectra consisting of photon-energy spaced peaks exceeding the binding energy of the molecular bond are predicted. Although the observation of such phenomena is difficult, this scenario is nevertheless logical and is based on the fundamental laws. Here, we report conclusive experimental observation of high-order above-threshold dissociation of H2 in strong laser fields where the tunneling-ionized electron transfers the absorbed multiphoton energy, which is above the ionization threshold to the nuclei via the field driven inelastic rescattering. Our results provide an unambiguous evidence that the electron and nuclei of a molecule as a whole absorb multiple photons, and thus above-threshold ionization and above-threshold dissociation must appear simultaneously, which is the cornerstone of the nowadays strong-field molecular physics. PMID- 29440496 TI - CRISPR/Cas9 cleavages in budding yeast reveal templated insertions and strand specific insertion/deletion profiles. AB - Harnessing CRISPR-Cas9 technology provides an unprecedented ability to modify genomic loci via DNA double-strand break (DSB) induction and repair. We analyzed nonhomologous end-joining (NHEJ) repair induced by Cas9 in budding yeast and found that the orientation of binding of Cas9 and its guide RNA (gRNA) profoundly influences the pattern of insertion/deletions (indels) at the site of cleavage. A common indel created by Cas9 is a 1-bp (+1) insertion that appears to result from Cas9 creating a 1-nt 5' overhang that is filled in by a DNA polymerase and ligated. The origin of +1 insertions was investigated by using two gRNAs with PAM sequences located on opposite DNA strands but designed to cleave the same sequence. These templated +1 insertions are dependent on the X-family DNA polymerase, Pol4. Deleting Pol4 also eliminated +2 and +3 insertions, which are biased toward homonucleotide insertions. Using inverted PAM sequences, we also found significant differences in overall NHEJ efficiency and repair profiles, suggesting that the binding of the Cas9:gRNA complex influences subsequent NHEJ processing. As with events induced by the site-specific HO endonuclease, CRISPR Cas9-mediated NHEJ repair depends on the Ku heterodimer and DNA ligase 4. Cas9 events are highly dependent on the Mre11-Rad50-Xrs2 complex, independent of Mre11's nuclease activity. Inspection of the outcomes of a large number of Cas9 cleavage events in mammalian cells reveals a similar templated origin of +1 insertions in human cells, but also a significant frequency of similarly templated +2 insertions. PMID- 29440497 TI - Structural insights into the mechanism of inhibition of AHAS by herbicides. AB - Acetohydroxyacid synthase (AHAS), the first enzyme in the branched amino acid biosynthesis pathway, is present only in plants and microorganisms, and it is the target of >50 commercial herbicides. Penoxsulam (PS), which is a highly effective broad-spectrum AHAS-inhibiting herbicide, is used extensively to control weed growth in rice crops. However, the molecular basis for its inhibition of AHAS is poorly understood. This is despite the availability of structural data for all other classes of AHAS-inhibiting herbicides. Here, crystallographic data for Saccharomyces cerevisiae AHAS (2.3 A) and Arabidopsis thaliana AHAS (2.5 A) in complex with PS reveal the extraordinary molecular mechanisms that underpin its inhibitory activity. The structures show that inhibition of AHAS by PS triggers expulsion of two molecules of oxygen bound in the active site, releasing them as substrates for an oxygenase side reaction of the enzyme. The structures also show that PS either stabilizes the thiamin diphosphate (ThDP)-peracetate adduct, a product of this oxygenase reaction, or traps within the active site an intact molecule of peracetate in the presence of a degraded form of ThDP: thiamine aminoethenethiol diphosphate. Kinetic analysis shows that PS inhibits AHAS by a combination of events involving FAD oxidation and chemical alteration of ThDP. With the emergence of increasing levels of resistance toward front-line herbicides and the need to optimize the use of arable land, these data suggest strategies for next generation herbicide design. PMID- 29440498 TI - Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1. AB - The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes. PMID- 29440499 TI - Transcriptome dynamics at Arabidopsis graft junctions reveal an intertissue recognition mechanism that activates vascular regeneration. AB - The ability for cut tissues to join and form a chimeric organism is a remarkable property of many plants; however, grafting is poorly characterized at the molecular level. To better understand this process, we monitored genome-wide gene expression changes in grafted Arabidopsis thaliana hypocotyls. We observed a sequential activation of genes associated with cambium, phloem, and xylem formation. Tissues above and below the graft rapidly developed an asymmetry such that many genes were more highly expressed on one side than on the other. This asymmetry correlated with sugar-responsive genes, and we observed an accumulation of starch above the graft junction. This accumulation decreased along with asymmetry once the sugar-transporting vascular tissues reconnected. Despite the initial starvation response below the graft, many genes associated with vascular formation were rapidly activated in grafted tissues but not in cut and separated tissues, indicating that a recognition mechanism was activated independently of functional vascular connections. Auxin, which is transported cell to cell, had a rapidly elevated response that was symmetric, suggesting that auxin was perceived by the root within hours of tissue attachment to activate the vascular regeneration process. A subset of genes was expressed only in grafted tissues, indicating that wound healing proceeded via different mechanisms depending on the presence or absence of adjoining tissues. Such a recognition process could have broader relevance for tissue regeneration, intertissue communication, and tissue fusion events. PMID- 29440501 TI - What Have We Learned About Influenza Deaths in Children and How Can We Do Better? PMID- 29440500 TI - Adaptive evolution of genomically recoded Escherichia coli. AB - Efforts are underway to construct several recoded genomes anticipated to exhibit multivirus resistance, enhanced nonstandard amino acid (nsAA) incorporation, and capability for synthetic biocontainment. Although our laboratory pioneered the first genomically recoded organism (Escherichia coli strain C321.?A), its fitness is far lower than that of its nonrecoded ancestor, particularly in defined media. This fitness deficit severely limits its utility for nsAA-linked applications requiring defined media, such as live cell imaging, metabolic engineering, and industrial-scale protein production. Here, we report adaptive evolution of C321.?A for more than 1,000 generations in independent replicate populations grown in glucose minimal media. Evolved recoded populations significantly exceeded the growth rates of both the ancestral C321.?A and nonrecoded strains. We used next-generation sequencing to identify genes mutated in multiple independent populations, and we reconstructed individual alleles in ancestral strains via multiplex automatable genome engineering (MAGE) to quantify their effects on fitness. Several selective mutations occurred only in recoded evolved populations, some of which are associated with altering the translation apparatus in response to recoding, whereas others are not apparently associated with recoding, but instead correct for off-target mutations that occurred during initial genome engineering. This report demonstrates that laboratory evolution can be applied after engineering of recoded genomes to streamline fitness recovery compared with application of additional targeted engineering strategies that may introduce further unintended mutations. In doing so, we provide the most comprehensive insight to date into the physiology of the commonly used C321.?A strain. PMID- 29440502 TI - Influenza-Associated Pediatric Deaths in the United States, 2010-2016. AB - BACKGROUND: Influenza-associated pediatric deaths became a notifiable condition in the United States in 2004. METHODS: We analyzed deaths in children aged <18 years with laboratory-confirmed influenza virus infection reported to the Centers for Disease Control and Prevention during the 2010-2011 to 2015-2016 influenza seasons. Data were collected with a standard case report form that included demographics, medical conditions, and clinical diagnoses. RESULTS: Overall, 675 deaths were reported. The median age was 6 years (interquartile range: 2-12). The average annual incidence was 0.15 per 100 000 children (95% confidence interval: 0.14-0.16) and was highest among children aged <6 months (incidence: 0.66; 95% confidence interval: 0.53-0.82), followed by children aged 6-23 months (incidence: 0.33; 95% confidence interval: 0.27-0.39). Only 31% (n = 149 of 477) of children aged >=6 months had received any influenza vaccination. Overall, 65% (n = 410 of 628) of children died within 7 days after symptom onset. Half of the children (n = 327 of 654) had no preexisting medical conditions. Compared with children with preexisting medical conditions, children with none were younger (median: 5 vs 8 years old), less vaccinated (27% vs 36%), more likely to die before hospital admission (77% vs 48%), and had a shorter illness duration (4 vs 7 days; P < .05 for all). CONCLUSIONS: Each year, influenza-associated pediatric deaths are reported. Young children have the highest death rates, especially infants aged <6 months. Increasing vaccination among children, pregnant women, and caregivers of infants may reduce influenza-associated pediatric deaths. PMID- 29440503 TI - Learning From National and State Trends in Sudden Unexpected Infant Death. PMID- 29440504 TI - National and State Trends in Sudden Unexpected Infant Death: 1990-2015. AB - BACKGROUND: Sharp declines in sudden unexpected infant death (SUID) in the 1990s and a diagnostic shift from sudden infant death syndrome (SIDS) to unknown cause and accidental suffocation and strangulation in bed (ASSB) in 1999-2001 have been documented. We examined trends in SUID and SIDS, unknown cause, and ASSB from 1990 to 2015 and compared state-specific SUID rates to identify significant trends that may be used to inform SUID prevention efforts. METHODS: We used data from US mortality files to evaluate national and state-specific SUID rates (deaths per 100 000 live births) for 1990-2015. SUID included infants with an underlying cause of death, SIDS, unknown cause, or ASSB. To examine overall US rates for SUID and SUID subtypes, we calculated the percent change by fitting Poisson regression models. We report state differences in SUID and compared state specific rates from 2000-2002 to 2013-2015 by calculating the percent change. RESULTS: SUID rates declined from 154.6 per 100 000 live births in 1990 to 92.4 in 2015, declining 44.6% from 1990 to 1998 and 7% from 1999 to 2015. From 1999 to 2015, SIDS rates decreased 35.8%, ASSB rates increased 183.8%, and there was no significant change in unknown cause rates. SUID trends among states varied widely from 41.5 to 184.3 in 2000-2002 and from 33.2 to 202.2 in 2013-2015. CONCLUSIONS: Reductions in SUID rates since 1999 have been minimal, and wide variations in state-specific rates remain. States with significant declines in SUID rates might have SUID risk-reduction programs that could serve as models for other states. PMID- 29440505 TI - Cutting Edge: Divergent Requirement of T-Box Transcription Factors in Effector and Memory NK Cells. AB - The T-box transcription factors T-bet and Eomesodermin (Eomes) instruct discrete stages in NK cell development. However, their role in the immune response of mature NK cells against pathogens remains unexplored. We used an inducible deletion system to elucidate the cell-intrinsic role of T-bet and Eomes in mature NK cells during the course of mouse CMV infection. We show both T-bet and Eomes to be necessary for the expansion of virus-specific NK cells, with T-bet upregulation induced by IL-12 signaling and STAT4 binding to a conserved enhancer region upstream of the Tbx21 loci. Interestingly, our data suggest maintenance of virus-specific memory NK cell numbers and phenotype was dependent on T-bet, but not Eomes. These findings uncover a nonredundant and stage-specific influence of T-box transcription factors in the antiviral NK cell response. PMID- 29440506 TI - Carbon Monoxide Impairs CD11b+Ly-6Chi Monocyte Migration from the Blood to Inflamed Pancreas via Inhibition of the CCL2/CCR2 Axis. AB - Acute pancreatitis (AP) is a sterile inflammation, in which inflammatory monocytes (CD11b+Ly-6Chi) are recruited into the inflamed tissue at the onset of disease. Monocyte infiltration and activation at the site of inflammation are critical to the pathogenesis of AP. Our previous studies have shown a protective role for CO in AP, which is partially mediated by inhibition of macrophage activation via TLR4 signaling. In the current study, to gain a better understanding of CO's therapeutic effect, we further investigated whether CO could affect inflammatory monocyte trafficking during AP. In a mouse model of AP, we found that treatment with CO-releasing molecule-2 (CORM-2) impaired recruitment of inflammatory monocytes, but not that of neutrophils, from peripheral blood to inflamed pancreas. During the early stage of AP, a single dose of CORM-2 decreased pancreatic CCL2 and soluble ICAM-1 expression. In addition, using in vivo and in vitro experiments, we found that CORM-2 had the ability to inhibit CD11b+Ly-6Chi monocyte migration via blockade of CCR2 endocytosis. Notably, we showed that CORM-2 inhibited CCR2 endocytosis of inflammatory monocytes (CD14hiCD16-) from AP patients. Taken together, our results highlighted CO's effect on inflammatory monocyte trafficking, shedding additional light on its therapeutic potential in AP. PMID- 29440507 TI - Cutting Edge: Check Your Mice-A Point Mutation in the Ncr1 Locus Identified in CD45.1 Congenic Mice with Consequences in Mouse Susceptibility to Infection. AB - B6.SJL-Ptprca Pepcb /Boy (CD45.1) mice have been used in hundreds of congenic competitive transplants, with the presumption that they differ from C57BL/6 mice only at the CD45 locus. In this study, we describe a point mutation in the natural cytotoxicity receptor 1 (Ncr1) locus fortuitously identified in the CD45.1 strain. This point mutation was mapped at the 40th nucleotide of the Ncr1 locus causing a single amino acid mutation from cysteine to arginine at position 14 from the start codon, resulting in loss of NCR1 expression. We found that these mice were more resistant to CMV due to a hyper innate IFN-gamma response in the absence of NCR1. In contrast, loss of NCR1 increased susceptibility to influenza virus, a result that is consistent with the role of NCR1 in the recognition of influenza Ag, hemagglutinin. This work sheds light on potential confounding experimental interpretation when this congenic strain is used as a tool for tracking lymphocyte development. PMID- 29440508 TI - Cutting Edge: De Novo Glucocorticoid Synthesis by Thymic Epithelial Cells Regulates Antigen-Specific Thymocyte Selection. AB - Glucocorticoid (GC) signaling in thymocytes counters negative selection and promotes the generation of a self-tolerant yet Ag-responsive T cell repertoire. Whereas circulating GC are derived from the adrenals, GC are also synthesized de novo in the thymus. The significance of this local production is unknown. In this study we deleted 11beta-hydroxylase, the enzyme that catalyzes the last step of GC biosynthesis, in thymic epithelial cells (TEC) or thymocytes. Like GC receptor deficient T cells, T cells from mice lacking TEC-derived but not thymocyte derived GC proliferated poorly to alloantigen, had a reduced antiviral response, and exhibited enhanced negative selection. Strikingly, basal expression of GC responsive genes in thymocytes from mice lacking TEC-derived GC was reduced to the same degree as in GC receptor-deficient thymocytes, indicating that at steady state the majority of biologically active GC are paracrine in origin. These findings demonstrate the importance of extra-adrenal GC even in the presence of circulating adrenal-derived GC. PMID- 29440510 TI - Educated natural killer cells show dynamic movement of the activating receptor NKp46 and confinement of the inhibitory receptor Ly49A. AB - Educated natural killer (NK) cells have inhibitory receptors specific for self major histocompatibility complex (MHC) class I molecules and kill cancer cells more efficiently than do NK cells that do not have such receptors (hyporesponsive NK cells). The mechanism behind this functional empowerment through education has so far not been fully described. In addition, distinctive phenotypic markers of educated NK cells at the single-cell level are lacking. We developed a refined version of the image mean square displacement (iMSD) method (called iMSD carpet analysis) and used it in combination with single-particle tracking to characterize the dynamics of the activating receptor NKp46 and the inhibitory receptor Ly49A on resting educated versus hyporesponsive murine NK cells. Most of the NKp46 and Ly49A molecules were restricted to microdomains; however, individual NKp46 molecules resided in these domains for shorter periods and diffused faster on the surface of educated, compared to hyporesponsive, NK cells. In contrast, the movement of Ly49A was more constrained in educated NK cells compared to hyporesponsive NK cells. Either disrupting the actin cytoskeleton or adding cholesterol to the cells prohibited activating signaling, suggesting that the dynamics of receptor movements within the cell membrane are critical for the proper activation of NK cells. The faster and more dynamic movement of NKp46 in educated NK cells may facilitate a swifter response to interactions with target cells. PMID- 29440509 TI - The unfolded protein response regulator ATF6 promotes mesodermal differentiation. AB - ATF6 encodes a transcription factor that is anchored in the endoplasmic reticulum (ER) and activated during the unfolded protein response (UPR) to protect cells from ER stress. Deletion of the isoform activating transcription factor 6alpha (ATF6alpha) and its paralog ATF6beta results in embryonic lethality and notochord dysgenesis in nonhuman vertebrates, and loss-of-function mutations in ATF6alpha are associated with malformed neuroretina and congenital vision loss in humans. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated this hypothesis using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a small-molecule ATF6 agonist and, conversely, inhibited ATF6 using induced pluripotent stem cells from patients with ATF6 mutations. We found that ATF6 suppressed pluripotency, enhanced differentiation, and unexpectedly directed mesodermal cell fate. Our findings reveal a role for ATF6 during differentiation and identify a new strategy to generate mesodermal tissues through the modulation of the ATF6 arm of the UPR. PMID- 29440511 TI - Structural basis for the interaction between the cell polarity proteins Par3 and Par6. AB - Polarity is a fundamental property of most cell types. The Par protein complex is a major driving force in generating asymmetrically localized protein networks and consists of atypical protein kinase C (aPKC), Par3, and Par6. Dysfunction of this complex causes developmental abnormalities and diseases such as cancer. We identified a PDZ domain-binding motif in Par6 that was essential for its interaction with Par3 in vitro and for Par3-mediated membrane localization of Par6 in cultured cells. In fly embryos, we observed that the PDZ domain-binding motif was functionally redundant with the PDZ domain in targeting Par6 to the cortex of epithelial cells. Our structural analyses by x-ray crystallography and NMR spectroscopy showed that both the PDZ1 and PDZ3 domains but not the PDZ2 domain in Par3 engaged in a canonical interaction with the PDZ domain-binding motif in Par6. Par3 thus has the potential to recruit two Par6 proteins simultaneously, which may facilitate the assembly of polarity protein networks through multivalent PDZ domain interactions. PMID- 29440512 TI - Clinically detected non-aggressive lung cancers: implications for overdiagnosis and overtreatment in lung cancer screening. PMID- 29440513 TI - Imaging of native transcription factors and histone phosphorylation at high resolution in live cells. AB - Fluorescent labeling of endogenous proteins for live-cell imaging without exogenous expression of tagged proteins or genetic manipulations has not been routinely possible. We describe a simple versatile antibody-based imaging approach (VANIMA) for the precise localization and tracking of endogenous nuclear factors. Our protocol can be implemented in every laboratory allowing the efficient and nonharmful delivery of organic dye-conjugated antibodies, or antibody fragments, into different metazoan cell types. Live-cell imaging permits following the labeled probes bound to their endogenous targets. By using conventional and super-resolution imaging we show dynamic changes in the distribution of several nuclear transcription factors (i.e., RNA polymerase II or TAF10), and specific phosphorylated histones (gammaH2AX), upon distinct biological stimuli at the nanometer scale. Hence, considering the large panel of available antibodies and the simplicity of their implementation, VANIMA can be used to uncover novel biological information based on the dynamic behavior of transcription factors or posttranslational modifications in the nucleus of single live cells. PMID- 29440514 TI - SLAMF1 is required for TLR4-mediated TRAM-TRIF-dependent signaling in human macrophages. AB - Signaling lymphocytic activation molecule family 1 (SLAMF1) is an Ig-like receptor and a costimulatory molecule that initiates signal transduction networks in a variety of immune cells. In this study, we report that SLAMF1 is required for Toll-like receptor 4 (TLR4)-mediated induction of interferon beta (IFNbeta) and for killing of Gram-negative bacteria by human macrophages. We found that SLAMF1 controls trafficking of the Toll receptor-associated molecule (TRAM) from the endocytic recycling compartment (ERC) to Escherichia coli phagosomes. In resting macrophages, SLAMF1 is localized to ERC, but upon addition of E. coli, it is trafficked together with TRAM from ERC to E. coli phagosomes in a Rab11 dependent manner. We found that endogenous SLAMF1 protein interacted with TRAM and defined key interaction domains as amino acids 68 to 95 of TRAM as well as 15 C-terminal amino acids of SLAMF1. Interestingly, the SLAMF1-TRAM interaction was observed for human but not mouse proteins. Overall, our observations suggest that SLAMF1 is a new target for modulation of TLR4-TRAM-TRIF inflammatory signaling in human cells. PMID- 29440515 TI - Integrative studies of cultural evolution: crossing disciplinary boundaries to produce new insights. AB - Culture evolves according to dynamics on multiple temporal scales, from individuals' minute-by-minute behaviour to millennia of cultural accumulation that give rise to population-level differences. These dynamics act on a range of entities-including behavioural sequences, ideas and artefacts as well as individuals, populations and whole species-and involve mechanisms at multiple levels, from neurons in brains to inter-population interactions. Studying such complex phenomena requires an integration of perspectives from a diverse array of fields, as well as bridging gaps between traditionally disparate areas of study. In this article, which also serves as an introduction to the current special issue, we highlight some specific respects in which the study of cultural evolution has benefited and should continue to benefit from an integrative approach. We showcase a number of pioneering studies of cultural evolution that bring together numerous disciplines. These studies illustrate the value of perspectives from different fields for understanding cultural evolution, such as cognitive science and neuroanatomy, behavioural ecology, population dynamics, and evolutionary genetics. They also underscore the importance of understanding cultural processes when interpreting research about human genetics, neuroscience, behaviour and evolution.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440516 TI - Cultural transmission in an ever-changing world: trial-and-error copying may be more robust than precise imitation. AB - Cultural transmission facilitates the spread of behaviours within social groups and may lead to the establishment of stable traditions in both human and non human animals. The fidelity of transmission is frequently emphasized as a core component of cultural evolution and as a prerequisite for cumulative culture. Fidelity is often considered a synonym of precise copying of observed behaviours. However, while precise copying guarantees reliable transmission in an ideal static world, it may be vulnerable to realistic variability in the actual environment. Here, we argue that fidelity may be more naturally achieved when the social learning mechanisms incorporate trial-and-error; and that the robustness of social transmission is thereby increased. We employed a simple model to demonstrate how culture that is produced through exact copying is fragile in an (even slightly) noisy world. When incorporating a certain degree of trial-and error, however, cultures are more readily formed in a stochastic environment and are less vulnerable to rare ecological changes. We suggest that considering trial and-error learning as a stabilizing component of social transmission may provide insights into cultural evolution in a realistic, variable, world.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440517 TI - Enquire within: cultural evolution and cognitive science. AB - Cultural evolution and cognitive science need each other. Cultural evolution needs cognitive science to find out whether the conditions necessary for Darwinian evolution are met in the cultural domain. Cognitive science needs cultural evolution to explain the origins of distinctively human cognitive processes. Focusing on the first question, I argue that cultural evolutionists can get empirical traction on third-way cultural selection by rooting the distinction between replication and reconstruction, two modes of cultural inheritance, in the distinction between System 1 and System 2 cognitive processes. This move suggests that cultural epidemiologists are right in thinking that replication has higher fidelity than reconstruction, and replication processes are not genetic adaptations for culture, but wrong to assume that replication is rare. If replication is not rare, an important requirement for third-way cultural selection, one-shot fidelity, is likely to be met. However, there are other requirements, overlooked by dual-inheritance theorists when they conflate strong (Darwinian) and weak (choice) senses of 'cultural selection', including dumb choices and recurrent fidelity In a second excursion into cognitive science, I argue that these requirements can be met by metacognitive social learning strategies, and trace the origins of these distinctively human cognitive processes to cultural evolution. Like other forms of cultural learning, they are not cognitive instincts but cognitive gadgets.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440519 TI - High-magnitude innovators as keystone individuals in the evolution of culture. AB - Borrowing from the concept of keystone species in ecological food webs, a recent focus in the field of animal behaviour has been keystone individuals: individuals whose impact on population dynamics is disproportionally larger than their frequency in the population. In populations evolving culture, such may be the role of high-magnitude innovators: individuals whose innovations are a major departure from the population's existing behavioural repertoire. Their effect on cultural evolution is twofold: they produce innovations that constitute a 'cultural leap' and, once copied, their innovations may induce further innovations by conspecifics (socially induced innovations) as they explore the new behaviour themselves. I use computer simulations to study the coevolution of independent innovations, socially induced innovations and innovation magnitude, and show that while socially induced innovation is assumed here to be less costly than independent innovation, it does not readily evolve. When it evolves, it may in some conditions select against independent innovation and lower its frequency, despite it requiring independent innovation in order to operate; at the same time, however, it leads to much faster cultural evolution. These results confirm the role of high-magnitude innovators as keystones, and suggest a novel explanation for the low frequency of independent innovation.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440518 TI - The evolution of the capacity for language: the ecological context and adaptive value of a process of cognitive hijacking. AB - Language plays a pivotal role in the evolution of human culture, yet the evolution of the capacity for language-uniquely within the hominin lineage remains little understood. Bringing together insights from cognitive psychology, neuroscience, archaeology and behavioural ecology, we hypothesize that this singular occurrence was triggered by exaptation, or 'hijacking', of existing cognitive mechanisms related to sequential processing and motor execution. Observed coupling of the communication system with circuits related to complex action planning and control supports this proposition, but the prehistoric ecological contexts in which this coupling may have occurred and its adaptive value remain elusive. Evolutionary reasoning rules out most existing hypotheses regarding the ecological context of language evolution, which focus on ultimate explanations and ignore proximate mechanisms. Coupling of communication and motor systems, although possible in a short period on evolutionary timescales, required a multi-stepped adaptive process, involving multiple genes and gene networks. We suggest that the behavioural context that exerted the selective pressure to drive these sequential adaptations had to be one in which each of the systems undergoing coupling was independently necessary or highly beneficial, as well as frequent and recurring over evolutionary time. One such context could have been the teaching of tool production or tool use. In the present study, we propose the Cognitive Coupling hypothesis, which brings together these insights and outlines a unifying theory for the evolution of the capacity for language.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440520 TI - Assessing the relative impact of historical divergence and inter-group transmission on cultural patterns: a method from evolutionary ecology. AB - In the study of cultural evolution, observed among-group affinity patterns reflect the effects of processes such as mutation (e.g. innovation and copying error), between-group interaction (culture flow), drift and selection. As in biology, cultural affinity patterns are often spatially correlated, making it difficult to distinguish between the opposing geographically mediated forces of divergence and interaction, which cause groups to become more distinct or similar over time, respectively. Analogous difficulties are faced by evolutionary biologists examining the relationship between biological affinity and geography, particularly at lower taxonomic levels where the potential for gene flow between lineages is greatest. Tree models are generally used to assess the fit between affinity patterns and models of historical divergence. However, factors driving lineage divergence are often spatially mediated, resulting in tree models that are themselves geographically structured. Here, we showcase a simple method drawn from evolutionary ecology for assessing the relative impact of both geographically mediated processes simultaneously. We illustrate the method using global human craniometric diversity and material culture from the northern coast of New Guinea as example case studies. This method can be employed to quantify the relative importance of history (divergence) and geographically mediated between-group interaction (culture flow) in explaining observed cultural affinity patterns.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440521 TI - Using features of a Creole language to reconstruct population history and cultural evolution: tracing the English origins of Sranan. AB - Creole languages are formed in conditions where speakers from distinct languages are brought together without a shared first language, typically under the domination of speakers from one of the languages and particularly in the context of the transatlantic slave trade and European colonialism. One such Creole in Suriname, Sranan, developed around the mid-seventeenth century, primarily out of contact between varieties of English from England, spoken by the dominant group, and multiple West African languages. The vast majority of the basic words in Sranan come from the language of the dominant group, English. Here, we compare linguistic features of modern-day Sranan with those of English as spoken in 313 localities across England. By way of testing proposed hypotheses for the origin of English words in Sranan, we find that 80% of the studied features of Sranan can be explained by similarity to regional dialect features at two distinct input locations within England, a cluster of locations near the port of Bristol and another cluster near Essex in eastern England. Our new hypothesis is supported by the geographical distribution of specific regional dialect features, such as post vocalic rhoticity and word-initial 'h', and by phylogenetic analysis of these features, which shows evidence favouring input from at least two English dialects in the formation of Sranan. In addition to explicating the dialect features most prominent in the linguistic evolution of Sranan, our historical analyses also provide supporting evidence for two distinct hypotheses about the likely geographical origins of the English speakers whose language was an input to Sranan. The emergence as a likely input to Sranan of the speech forms of a cluster near Bristol is consistent with historical records, indicating that most of the indentured servants going to the Americas between 1654 and 1666 were from Bristol and nearby counties, and that of the cluster near Essex is consistent with documents showing that many of the governors and important planters came from the southeast of England (including London) (Smith 1987 The Genesis of the Creole Languages of Surinam; Smith 2009 In The handbook of pidgin and creole studies, pp. 98-129).This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440523 TI - Current and potential roles of archaeology in the development of cultural evolutionary theory. AB - Archaeology has much to contribute to the study of cultural evolution. Empirical data at archaeological timescales are uniquely well suited to tracking rates of cultural change, detecting phylogenetic signals among groups of artefacts, and recognizing long-run effects of distinct cultural transmission mechanisms. Nonetheless, these are still relatively infrequent subjects of archaeological analysis and archaeology's potential to help advance our understanding of cultural evolution has thus far been largely unrealized. Cultural evolutionary models developed in other fields have been used to interpret patterns identified in archaeological records, which in turn provides independent tests of these models' predictions, as demonstrated here through a study of late Prehistoric stone projectile points from the US Southwest. These tests may not be straightforward, though, because archaeological data are complex, often representing events aggregated over many years (or centuries or millennia), while processes thought to drive cultural evolution (e.g. biased learning) operate on much shorter timescales. To fulfil archaeology's potential, we should continue to develop models specifically tailored to archaeological circumstances, and explore ways to incorporate the rich contextual data produced by archaeological research.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440522 TI - Generative inference for cultural evolution. AB - One of the major challenges in cultural evolution is to understand why and how various forms of social learning are used in human populations, both now and in the past. To date, much of the theoretical work on social learning has been done in isolation of data, and consequently many insights focus on revealing the learning processes or the distributions of cultural variants that are expected to have evolved in human populations. In population genetics, recent methodological advances have allowed a greater understanding of the explicit demographic and/or selection mechanisms that underlie observed allele frequency distributions across the globe, and their change through time. In particular, generative frameworks often using coalescent-based simulation coupled with approximate Bayesian computation (ABC)-have provided robust inferences on the human past, with no reliance on a priori assumptions of equilibrium. Here, we demonstrate the applicability and utility of generative inference approaches to the field of cultural evolution. The framework advocated here uses observed population-level frequency data directly to establish the likely presence or absence of particular hypothesized learning strategies. In this context, we discuss the problem of equifinality and argue that, in the light of sparse cultural data and the multiplicity of possible social learning processes, the exclusion of those processes inconsistent with the observed data might be the most instructive outcome. Finally, we summarize the findings of generative inference approaches applied to a number of case studies.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440524 TI - Variation is the universal: making cultural evolution work in developmental psychology. AB - Culture is a human universal, yet it is a source of variation in human psychology, behaviour and development. Developmental researchers are now expanding the geographical scope of research to include populations beyond relatively wealthy Western communities. However, culture and context still play a secondary role in the theoretical grounding of developmental psychology research, far too often. In this paper, we highlight four false assumptions that are common in psychology, and that detract from the quality of both standard and cross cultural research in development. These assumptions are: (i) the universality assumption, that empirical uniformity is evidence for universality, while any variation is evidence for culturally derived variation; (ii) the Western centrality assumption, that Western populations represent a normal and/or healthy standard against which development in all societies can be compared; (iii) the deficit assumption, that population-level differences in developmental timing or outcomes are necessarily due to something lacking among non-Western populations; and (iv) the equivalency assumption, that using identical research methods will necessarily produce equivalent and externally valid data, across disparate cultural contexts. For each assumption, we draw on cultural evolutionary theory to critique and replace the assumption with a theoretically grounded approach to culture in development. We support these suggestions with positive examples drawn from research in development. Finally, we conclude with a call for researchers to take reasonable steps towards more fully incorporating culture and context into studies of development, by expanding their participant pools in strategic ways. This will lead to a more inclusive and therefore more accurate description of human development.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440525 TI - Evolutionary demography of age at last birth: integrating approaches from human behavioural ecology and cultural evolution. AB - Cultural evolutionary theory and human behavioural ecology offer different, but compatible approaches to understanding human demographic behaviour. For much of their 30 history, these approaches have been deployed in parallel, with few explicit attempts to integrate them empirically. In this paper, we test hypotheses drawn from both approaches to explore how reproductive behaviour responds to cultural changes among Mosuo agriculturalists of China. Specifically, we focus on how age at last birth (ALB) varies in association with temporal shifts in fertility policies, spatial variation and kinship ecologies. We interpret temporal declines in ALB as plausibly consistent with demographic front loading of reproduction in light of fertility constraints and later ages at last birth in matrilineal populations relative to patrilineal ones as consistent with greater household cooperation for reproductive purposes in the former. We find little evidence suggesting specific transmission pathways for the spread of norms regulating ALB, but emphasize that the rapid pace of change strongly suggests that learning processes were involved in the general decline in ALB over time. The different predictions of models we employ belie their considerable overlap and the potential for a synthetic approach to generate more refined tests of evolutionary hypotheses of demographic behaviour.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440526 TI - On the absence of a correlation between population size and 'toolkit size' in ethnographic hunter-gatherers. AB - In apparent contradiction to the theoretically predicted effect of population size on the quality/quantity of material culture, statistical analyses on ethnographic hunter-gatherers have shown an absence of correlation between population size and toolkit size. This has sparked a heated, if sometimes tangential, debate as to the usefulness of the theoretical models and as to what modes of cultural transmission humans are capable of and hunter-gatherers rely on. I review the directly relevant theoretical literature and argue that much of the confusion is caused by a mismatch between the theoretical variable and the empirical observable. I then confirm that a model incorporating the appropriate variable does predict a positive association between population size and toolkit size for random oblique, vertical, best-of-K, conformist, anticonformist, success bias and one-to-many cultural transmission, with the caveat that for all populations sampled, the population size has remained constant and toolkit size has reached the equilibrium for this population size. Finally, I suggest three theoretical scenarios, two of them involving variable population size, that would attenuate or eliminate this association and hence help to explain the empirical absence of correlation.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440527 TI - Divide and conquer: intermediate levels of population fragmentation maximize cultural accumulation. AB - Identifying the determinants of cumulative cultural evolution is a key issue in the interdisciplinary field of cultural evolution. A widely held view is that large and well-connected social networks facilitate cumulative cultural evolution because they promote the spread of useful cultural traits and prevent the loss of cultural knowledge through factors such as drift. This view stems from models that focus on the transmission of cultural information, without considering how new cultural traits actually arise. In this paper, we review the literature from various fields that suggest that, under some circumstances, increased connectedness can decrease cultural diversity and reduce innovation rates. Incorporating this idea into an agent-based model, we explore the effect of population fragmentation on cumulative culture and show that, for a given population size, there exists an intermediate level of population fragmentation that maximizes the rate of cumulative cultural evolution. This result is explained by the fact that fully connected, non-fragmented populations are able to maintain complex cultural traits but produce insufficient variation and so lack the cultural diversity required to produce highly complex cultural traits. Conversely, highly fragmented populations produce a variety of cultural traits but cannot maintain complex ones. In populations with intermediate levels of fragmentation, cultural loss and cultural diversity are balanced in a way that maximizes cultural complexity. Our results suggest that population structure needs to be taken into account when investigating the relationship between demography and cumulative culture.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440528 TI - Cultural complexity and evolution in fluctuating environments. AB - The effect of environmental change on the rate of innovation and level of cultural complexity in a population is a theoretically understudied piece of an important puzzle at the heart of cultural evolution. Many mathematical models of cultural complexity have focused on the role of demographic factors such as population size or density. However, statistical studies often point to environmental variability as an important factor determining complexity in many cases. The aim of this study is to explore the interaction between environmental fluctuations and the rate of cultural innovation within a population and to examine the relationship between rates of innovation and the probability of maintaining a complex cultural repertoire in a changing environment. Two models are presented that draw on previous models used to examine rates of genetic mutation. The models show that, as in a genetic system, the stable rate of cultural innovation in a population decreases with environmental stability and increases in unstable environments. This effect is similar but quantitatively different for different modes of cultural transmission (success bias, conformity bias and random oblique learning). The model shows that innovation can increase diversity but that this relationship depends critically on learning mode and learning parameters.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440530 TI - Bridging cultural gaps: interdisciplinary studies in human cultural evolution. PMID- 29440529 TI - Missing compared to what? Revisiting heritability, genes and culture. AB - Standard models for the determination of phenotypes from genes are grounded in simple assumptions that are inherent in the modern evolutionary synthesis (MES), which was developed in the 1930s, 1940s and 1950s. The MES was framed in the context of Mendelian genetic transmission enhanced by the Fisherian view of the way discretely inherited genes determine continuously quantitative phenotypes. The statistical models that are used to estimate and interpret genetic contributions to human phenotypes-including behavioural traits-are constructed within the framework of the MES. Variance analysis constitutes the main tool and is used under this framework to characterize genetic inheritance, and hence determination of phenotypes. In this essay, we show that cultural inheritance, when incorporated into models for the determination of phenotypes, can sharply reduce estimates of the genetic contribution to these phenotypes. Recognition of the importance of non-genetic transmission of many human traits is becoming ever more necessary to prevent regression to the debates of the 1970s and 1980s concerning policies based on genetic determination of complex human phenotypes.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. PMID- 29440531 TI - Can Serial Dependencies in Choices and Neural Activity Explain Choice Probabilities? AB - During perceptual decisions the activity of sensory neurons covaries with choice, a covariation often quantified as "choice-probability". Moreover, choices are influenced by a subject's previous choice (serial dependence) and neuronal activity often shows temporal correlations on long (seconds) timescales. Here, we test whether these findings are linked. Using generalized linear models, we analyze simultaneous measurements of behavior and V2 neural activity in macaques performing a visual discrimination task. Both, decisions and spiking activity show substantial temporal correlations and cross-correlations but seem to reflect two mostly separate processes. Indeed, removing history effects using semipartial correlation analysis leaves choice probabilities largely unchanged. The serial dependencies in choices and neural activity therefore cannot explain the observed choice probability. Rather, serial dependencies in choices and spiking activity reflect two predominantly separate but parallel processes, which are coupled on each trial by covariations between choices and activity. These findings provide important constraints for computational models of perceptual decision-making that include feedback signals.SIGNIFICANCE STATEMENT Correlations, unexplained by the sensory input, between the activity of sensory neurons and an animal's perceptual choice ("choice probabilities") have received attention from both a systems and computational neuroscience perspective. Conversely, whereas temporal correlations for both spiking activity ("non-stationarities") and for a subject's choices in perceptual tasks ("serial dependencies") have long been established, they have typically been ignored when measuring choice probabilities. Some accounts of choice probabilities incorporating feedback predict that these observations are linked. Here, we explore the extent to which this is the case. We find that, contrasting with these predictions, choice probabilities are largely independent of serial dependencies, which adds new constraints to accounts of choice probabilities that include feedback. PMID- 29440532 TI - Mind-Wandering in People with Hippocampal Damage. AB - Subjective inner experiences, such as mind-wandering, represent the fundaments of human cognition. Although the precise function of mind-wandering is still debated, it is increasingly acknowledged to have influence across cognition on processes such as future planning, creative thinking, and problem-solving and even on depressive rumination and other mental health disorders. Recently, there has been important progress in characterizing mind-wandering and identifying the associated neural networks. Two prominent features of mind-wandering are mental time travel and visuospatial imagery, which are often linked with the hippocampus. People with selective bilateral hippocampal damage cannot vividly recall events from their past, envision their future, or imagine fictitious scenes. This raises the question of whether the hippocampus plays a causal role in mind-wandering and, if so, in what way. Leveraging a unique opportunity to shadow people (all males) with bilateral hippocampal damage for several days, we examined, for the first time, what they thought about spontaneously, without direct task demands. We found that they engaged in as much mind-wandering as control participants. However, whereas controls thought about the past, present, and future, imagining vivid visual scenes, hippocampal damage resulted in thoughts primarily about the present comprising verbally mediated semantic knowledge. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and also reveal its impact beyond episodic memory, placing it at the heart of our mental life.SIGNIFICANCE STATEMENT Humans tend to mind-wander ~30-50% of their waking time. Two prominent features of this pervasive form of thought are mental time travel and visuospatial imagery, which are often associated with the hippocampus. To examine whether the hippocampus plays a causal role in mind-wandering, we examined the frequency and phenomenology of mind-wandering in patients with selective bilateral hippocampal damage. We found that they engaged in as much mind-wandering as controls. However, hippocampal damage changed the form and content of mind-wandering from flexible, episodic, and scene based to abstract, semanticized, and verbal. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and reveal its impact beyond episodic memory, placing it at the heart of our mental life. PMID- 29440533 TI - GUCY2D Cone-Rod Dystrophy-6 Is a "Phototransduction Disease" Triggered by Abnormal Calcium Feedback on Retinal Membrane Guanylyl Cyclase 1. AB - The Arg838Ser mutation in retinal membrane guanylyl cyclase 1 (RetGC1) has been linked to autosomal dominant cone-rod dystrophy type 6 (CORD6). It is believed that photoreceptor degeneration is caused by the altered sensitivity of RetGC1 to calcium regulation via guanylyl cyclase activating proteins (GCAPs). To determine the mechanism by which this mutation leads to degeneration, we investigated the structure and function of rod photoreceptors in two transgenic mouse lines, 362 and 379, expressing R838S RetGC1. In both lines, rod outer segments became shorter than in their nontransgenic siblings by 3-4 weeks of age, before the eventual photoreceptor degeneration. Despite the shortening of their outer segments, the dark current of transgenic rods was 1.5-2.2-fold higher than in nontransgenic controls. Similarly, the dim flash response amplitude in R838S+ rods was larger, time to peak was delayed, and flash sensitivity was increased, all suggesting elevated dark-adapted free cGMP in transgenic rods. In rods expressing R838S RetGC1, dark-current noise increased and the exchange current, detected after a saturating flash, became more pronounced. These results suggest disrupted Ca2+ phototransduction feedback and abnormally high free-Ca2+ concentration in the outer segments. Notably, photoreceptor degeneration, which typically occurred after 3 months of age in R838S RetGC1 transgenic mice in GCAP1,2+/+ or GCAP1,2+/- backgrounds, was prevented in GCAP1,2-/- mice lacking Ca2+ feedback to guanylyl cyclase. In summary, the dysregulation of guanylyl cyclase in RetGC1-linked CORD6 is a "phototransduction disease," which means it is associated with increased free-cGMP and Ca2+ levels in photoreceptors.SIGNIFICANCE STATEMENT In a mouse model expressing human membrane guanylyl cyclase 1 (RetGC1, GUCY2D), a mutation associated with early progressing congenital blindness, cone-rod dystrophy type 6 (CORD6), deregulates calcium sensitive feedback of phototransduction to the cyclase mediated by guanylyl cyclase activating proteins (GCAPs), which are calcium-sensor proteins. The abnormal calcium sensitivity of the cyclase increases cGMP-gated dark current in the rod outer segments, reshapes rod photoresponses, and triggers photoreceptor death. This work is the first to demonstrate a direct physiological effect of GUCY2D CORD6-linked mutation on photoreceptor physiology in vivo It also identifies the abnormal regulation of the cyclase by calcium-sensor proteins as the main trigger for the photoreceptor death. PMID- 29440534 TI - Individual Differences in Reading Skill Are Related to Trial-by-Trial Neural Activation Variability in the Reading Network. AB - Recent work has suggested that variability in levels of neural activation may be related to behavioral and cognitive performance across a number of domains and may offer information that is not captured by more traditional measures that use the average level of brain activation. We examined the relationship between reading skill in school-aged children and neural activation variability during a functional MRI reading task after taking into account average levels of activity. The reading task involved matching printed and spoken words to pictures of items. Single trial activation estimates were used to calculate the mean and standard deviation of children's responses to print and speech stimuli; multiple regression analyses evaluated the relationship between reading skill and trial-by trial activation variability. The reliability of observed findings from the discovery sample (n = 44; ages 8-11; 18 female) was then confirmed in an independent sample of children (n = 32; ages 8-11; 14 female). Across the two samples, reading skill was positively related to trial-by-trial variability in the activation response to print in the left inferior frontal gyrus pars triangularis. This relationship held even when accounting for mean levels of activation. This finding suggests that intrasubject variability in trial-by-trial fMRI activation responses to printed words accounts for individual differences in human reading ability that are not fully captured by traditional mean levels of brain activity. Furthermore, this positive relationship between trial-by-trial activation variability and reading skill may provide evidence that neural variability plays a beneficial role during early reading development.SIGNIFICANCE STATEMENT Recent work has suggested that neural activation variability, or moment to-moment changes in the engagement of brain regions, is related to individual differences in behavioral and cognitive performance across multiple domains. However, differences in neural activation variability have not yet been evaluated in relation to reading skill. In the current study, we analyzed data from two independent groups of children who performed an fMRI task involving reading and listening to words. Across both samples, reading skill was positively related to trial-by-trial variability in activation to print stimuli in the left inferior frontal gyrus pars triangularis, even when accounting for the more conventional measure of mean levels of brain activity. This finding suggests that neural variability could be beneficial in developing readers. PMID- 29440535 TI - Altered signaling in the descending pain modulatory system after short-term infusion of the MU-opioid agonist remifentanil. AB - MU-Opioid receptor agonists are widely used within the contemporary treatment of pain but abrupt opioid suspension, even after short-term infusion, can paradoxically increase the sensitivity to noxious stimuli - a phenomenon that has been for example reported after application of the fast-acting MU-opioid receptor agonist remifentanil. To investigate the mechanisms underlying the effects of discontinuation of remifentanil application on pain processing in the human CNS, we analyzed neuronal responses to thermal stimuli before and after a short-term infusion of remifentanil (30 min 0.1 MUg/kg-bodyweight/min) compared to control in the brain, brainstem and spinal cord in drug-naive male volunteers employing functional magnetic resonance imaging. Subsequent to remifentanil suspension we observed reduced heat pain thresholds and increased neuronal responses in pain encoding as well as in key regions of the descending pain modulatory system, such as the periaqueductal grey matter, the nucleus cuneiformis and the rostral ventromedial medulla. Moreover, the spinal pain-related multi-voxel activity pattern showed an opioid-specific change after drug suspension. Importantly, remifentanil suspension increased the functional coupling between the nucleus cuneiformis and the rostral anterior cingulate cortex, and the coupling strength between the rostral anterior cingulate cortex and the nucleus cuneiformis correlated negatively with the individual pain threshold after opioid suspension. These findings demonstrate that already subsequent to a short-term infusion of the MU-opioid receptor agonist remifentanil signaling in the descending pain modulatory system is fundamentally altered and that these changes are directly related to the behavioral sensitivity to pain.Significance Statement:Opioids are widely used in modern medicine but besides their known side effects it is increasingly recognized that opioids can also increase sensitivity to pain subsequent to their use. Employing the fast-acting MU-opioid receptor agonist remifentanil and fMRI in healthy male volunteers this study demonstrates how signaling changes occur along the entire descending pain modulatory pathway after opioid discontinuation and how these alterations are closely linked to increased behavioral pain sensitivity. Particularly, by revealing modified responses in pain modulatory brainstem regions that have been previously demonstrated to be causally involved in acute opioid withdrawal effects in rodents the data provide a plausible neuronal mechanism by which the increased sensitivity to pain after opioid suspension is mediated in humans. PMID- 29440537 TI - What's happening in Neurology(r). PMID- 29440538 TI - What's happening in Neurology(r)Clinical Practice. PMID- 29440539 TI - What's happening in Neurology(r)Genetics. PMID- 29440540 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29440536 TI - Diminished Cortical Thickness is Associated with Impulsive Choice in Adolescence. AB - Adolescence is characterized by both maturation of brain structure and increased risk of negative outcomes from behaviors associated with impulsive decision making. One important index of impulsive choice is delay discounting (DD), which measures the tendency to prefer smaller rewards available soon over larger rewards delivered after a delay. However, it remains largely unknown how individual differences in structural brain development may be associated with impulsive choice during adolescence. Leveraging a unique large sample of 427 human youths (208 males and 219 females) imaged as part of the Philadelphia Neurodevelopmental Cohort, we examined associations between delay discounting and cortical thickness within structural covariance networks. These structural networks were derived using non-negative matrix factorization, an advanced multivariate technique for dimensionality reduction, and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear developmental effects. We found that impulsive choice, as measured by greater discounting, was most strongly associated with diminished cortical thickness in structural brain networks that encompassed the ventromedial prefrontal cortex, orbitofrontal cortex, temporal pole, and temporoparietal junction. Furthermore, structural brain networks predicted DD above and beyond cognitive performance. Taken together, these results suggest that reduced cortical thickness in regions known to be involved in value-based decision-making is a marker of impulsive choice during the critical period of adolescence.SIGNIFICANCE: Risky behaviors during adolescence, such as initiation of substance use or reckless driving, are a major source of morbidity and mortality. In this study, we present evidence from a large sample of youths that diminished cortical thickness in specific structural brain networks is associated with impulsive choice. Notably, the strongest association between impulsive choice and brain structure was seen in regions implicated in value-based decision making; namely, the ventromedial prefrontal and orbitofrontal cortices. Moving forward, such neuroanatomical markers of impulsivity may aid in the development of personalized interventions targeted to reduce risk of negative outcomes resulting from impulsivity during adolescence. PMID- 29440541 TI - Hemorrhagic encephalitis associated with H3N2 influenza A viral pneumonia. PMID- 29440542 TI - Journal Club: Relationship between carotid arterial properties and cerebral white matter hyperintensities. PMID- 29440543 TI - Editors' note: Activity limitations and subjective well-being after stroke. PMID- 29440544 TI - Reader response: Activity limitations and subjective well-being after stroke. PMID- 29440546 TI - Editors' note: Odor identification as a biomarker of preclinical AD in older adults at risk. PMID- 29440545 TI - Author response: Activity limitations and subjective well-being after stroke. PMID- 29440547 TI - Reader response: Odor identification as a biomarker of preclinical AD in older adults at risk. PMID- 29440548 TI - Author response: Odor identification as a biomarker of preclinical AD in older adults at risk. PMID- 29440549 TI - Clinical Reasoning: Siblings with progressive weakness, hypotonia, nystagmus, and hearing loss. PMID- 29440550 TI - Teaching NeuroImages: Cerebrotendinous xanthomatosis: A rare treatable adult onset lipid storage disease. PMID- 29440551 TI - Protein Kinase C Enhances Electrical Synaptic Transmission by Acting on Junctional and Postsynaptic Ca2+ Currents. AB - By synchronizing neuronal activity, electrical transmission influences the coordination, pattern, and/or frequency of firing. In the hemaphroditic marine snail, Aplysia calfornica, the neuroendocrine bag cell neurons use electrical synapses to synchronize a 30 min afterdischarge of action potentials for the release of reproductive hormone. During the afterdischarge, protein kinase C (PKC) is activated, although its impact on bag cell neuron electrical transmission is unknown. This was investigated here by monitoring electrical synapses between paired cultured bag cell neurons using dual whole-cell recording. Voltage clamp revealed a largely voltage-independent junctional current, which was enhanced by treating with a PKC activator, PMA, before recording. We also examined the transfer of presynaptic action potential-like waveforms (generated in voltage clamp) to the postsynaptic cell (measured in current clamp). For control pairs, the presynaptic spike-like waveforms mainly evoked electrotonic potentials; however, when PKC was triggered, these stimuli consistently produced postsynaptic action potentials. To assess whether this involved changes to postsynaptic responsiveness, single bag cell neurons were injected with junctional-like current mimicking that evoked by a presynaptic action potential. Unlike control neurons, which were less likely to spike, cells in PMA always fired action potentials to the junctional-like current. Furthermore, PKC activation increased a postsynaptic voltage-gated Ca2+ current, which was recruited even by modest depolarization associated with an electrotonic potential. Whereas PKC inhibits gap junctions in most systems, bag cell neurons are rather unique, as the kinase potentiates the electrical synapse; in turn, this synergizes with augmented postsynaptic Ca2+ current to promote synchronous firing.SIGNIFICANCE STATEMENT Electrical coupling is a fundamental form of communication. For the bag cell neurons of Aplysia, electrical synapses coordinate a prolonged burst of action potentials known as the afterdischarge. We looked at how protein kinase C, which is upregulated with the afterdischarge, influences information transfer across the synapse. The kinase activation increased junctional current, a remarkable finding given that this enzyme is largely considered inhibitory for gap junctions. There was also an augmentation in the ability of a presynaptic neuron to provoke postsynaptic action potentials. This increased excitability was, in part, due to enhanced postsynaptic voltage dependent Ca2+ current. Thus, protein kinase C improves the fidelity of electrotonic transmission and promotes synchronous firing by modulating both junctional and membrane conductances. PMID- 29440552 TI - A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors. AB - Hyperekplexia, an inherited neuronal disorder characterized by exaggerated startle responses with unexpected sensory stimuli, is caused by dysfunction of glycinergic inhibitory transmission. From analysis of newly identified human hyperekplexia mutations in the glycine receptor (GlyR) alpha1 subunit, we found that an alanine-to-proline missense mutation (A384P) resulted in substantially higher desensitization level and lower agonist sensitivity of homomeric alpha1 GlyRs when expressed in HEK cells. The incorporation of the beta subunit fully reversed the reduction in agonist sensitivity and partially reversed the desensitization of alpha1A384P The heteromeric alpha1A384Pbeta GlyRs showed enhanced desensitization but unchanged agonist-induced maximum responses, surface expression, main channel conductance, and voltage dependence compared with that of the wild-type alpha1beta (alpha1WTbeta) GlyRs. Coexpression of the R392H and A384P mutant alpha1 subunits, which mimic the expression of the compound heterozygous mutation in a hyperekplexia patient, resulted in channel properties similar to those with alpha1A384P subunit expression alone. In comparison, another human hyperekplexia mutation alpha1P250T, which was previously reported to enhance desensitization, caused a strong reduction in maximum currents in addition to the altered desensitization. These results were further confirmed by overexpression of alpha1P250T or alpha1A384P subunits in cultured neurons isolated from SD rats of either sex. Moreover, the IPSC-like responses of cells expressing alpha1A384Pbeta induced by repeated glycine pulses showed a stronger frequency-dependent reduction than those expressing alpha1WTbeta. Together, our findings demonstrate that A384 is associated with the desensitization site of the alpha1 subunit and its proline mutation produced enhanced desensitization of GlyRs, which contributes to the pathogenesis of human hyperekplexia.SIGNIFICANCE STATEMENT Human startle disease is caused by impaired synaptic inhibition in the brainstem and spinal cord, which is due to either direct loss of GlyR channel function or reduced number of synaptic GlyRs. Considering that fast decay kinetics of GlyR-mediated inhibitory synaptic responses, the question was raised whether altered desensitization of GlyRs will cause dysfunction of glycine transmission and disease phenotypes. Here, we found that the alpha1 subunit mutation A384P, identified from startle disease patients, results in enhanced desensitization and leads to rapidly decreasing responses in the mutant GlyRs when they are activated repeatedly by the synaptic-like simulation. These observations suggest that the enhanced desensitization of postsynaptic GlyRs could be the primary pathogenic mechanism of human startle disease. PMID- 29440554 TI - Visual Information Present in Infragranular Layers of Mouse Auditory Cortex. AB - The cerebral cortex is a major hub for the convergence and integration of signals from across the sensory modalities; sensory cortices, including primary regions, are no exception. Here we show that visual stimuli influence neural firing in the auditory cortex of awake male and female mice, using multisite probes to sample single units across multiple cortical layers. We demonstrate that visual stimuli influence firing in both primary and secondary auditory cortex. We then determine the laminar location of recording sites through electrode track tracing with fluorescent dye and optogenetic identification using layer-specific markers. Spiking responses to visual stimulation occur deep in auditory cortex and are particularly prominent in layer 6. Visual modulation of firing rate occurs more frequently at areas with secondary-like auditory responses than those with primary-like responses. Auditory cortical responses to drifting visual gratings are not orientation-tuned, unlike visual cortex responses. The deepest cortical layers thus appear to be an important locus for cross-modal integration in auditory cortex.SIGNIFICANCE STATEMENT The deepest layers of the auditory cortex are often considered its most enigmatic, possessing a wide range of cell morphologies and atypical sensory responses. Here we show that, in mouse auditory cortex, these layers represent a locus of cross-modal convergence, containing many units responsive to visual stimuli. Our results suggest that this visual signal conveys the presence and timing of a stimulus rather than specifics about that stimulus, such as its orientation. These results shed light on both how and what types of cross-modal information is integrated at the earliest stages of sensory cortical processing. PMID- 29440553 TI - The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies As a Function of Age and Is Associated with Changes in Episodic Memory and Processing Speed. AB - The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimer's pathology. Little is known, however, about the longitudinal trajectory of this network's intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49-87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans (n = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age * time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50-66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. APOE status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults.SIGNIFICANCE STATEMENT Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity. PMID- 29440556 TI - Neural Decoding of Bistable Sounds Reveals an Effect of Intention on Perceptual Organization. AB - Auditory signals arrive at the ear as a mixture that the brain must decompose into distinct sources based to a large extent on acoustic properties of the sounds. An important question concerns whether listeners have voluntary control over how many sources they perceive. This has been studied using pure high (H) and low (L) tones presented in the repeating pattern HLH-HLH-, which can form a bistable percept heard either as an integrated whole (HLH-) or as segregated into high (H-H-) and low (-L-) sequences. Although instructing listeners to try to integrate or segregate sounds affects reports of what they hear, this could reflect a response bias rather than a perceptual effect. We had human listeners (15 males, 12 females) continuously report their perception of such sequences and recorded neural activity using MEG. During neutral listening, a classifier trained on patterns of neural activity distinguished between periods of integrated and segregated perception. In other conditions, participants tried to influence their perception by allocating attention either to the whole sequence or to a subset of the sounds. They reported hearing the desired percept for a greater proportion of time than when listening neutrally. Critically, neural activity supported these reports; stimulus-locked brain responses in auditory cortex were more likely to resemble the signature of segregation when participants tried to hear segregation than when attempting to perceive integration. These results indicate that listeners can influence how many sound sources they perceive, as reflected in neural responses that track both the input and its perceptual organization.SIGNIFICANCE STATEMENT Can we consciously influence our perception of the external world? We address this question using sound sequences that can be heard either as coming from a single source or as two distinct auditory streams. Listeners reported spontaneous changes in their perception between these two interpretations while we recorded neural activity to identify signatures of such integration and segregation. They also indicated that they could, to some extent, choose between these alternatives. This claim was supported by corresponding changes in responses in auditory cortex. By linking neural and behavioral correlates of perception, we demonstrate that the number of objects that we perceive can depend not only on the physical attributes of our environment, but also on how we intend to experience it. PMID- 29440555 TI - C8ORF37 Is Required for Photoreceptor Outer Segment Disc Morphogenesis by Maintaining Outer Segment Membrane Protein Homeostasis. AB - C8ORF37 is a causative gene for three different clinical forms of incurable retinal degeneration. However, the completely unknown function of C8ORF37 limits our understanding of the pathogenicity of C8ORF37 mutations. Here, we performed a comprehensive phenotypic characterization of a C8orf37 KO mouse line, generated using CRISPR/Cas9 technology. Both C8orf37 KO male and female mice exhibited progressive and simultaneous degeneration of rod and cone photoreceptors but no non-ocular phenotypes. The major ultrastructural feature of C8orf37 KO photoreceptors was massive disorganization of the outer segment (OS) membrane discs starting from the onset of disc morphogenesis during development. At the molecular level, the amounts of multiple OS-specific membrane proteins, including proteins involved in membrane disc organization, were reduced, although these proteins were targeted normally to the OS. Considering the distribution of C8ORF37 throughout the photoreceptor cell body, the normal structure of the KO photoreceptor connecting cilium, and the absence of defects in other ciliary organs of the KO mice, our findings do not support the previous notion that C8ORF37 was a ciliary protein. Because C8ORF37 is absent in the photoreceptor OS, C8ORF37 may participate in the secretory pathway of OS membrane proteins in the photoreceptor cell body and thus maintain the homeostasis of these proteins. This study established a valid animal model for future therapeutic studies of C8ORF37 associated retinal degeneration. This study also shed new light on the role of C8ORF37 in photoreceptors and on the pathogenic mechanism underlying retinal degeneration caused by C8ORF37 mutations.SIGNIFICANCE STATEMENT Inherited retinal degeneration is a group of incurable conditions with poorly understood underlying molecular mechanisms. We investigated C8ORF37, a causative gene for three retinal degenerative conditions: retinitis pigmentosa, cone-rod dystrophy, and Bardet Biedl syndrome. C8ORF37 encodes a protein with no known functional domains and thus its biological function is unpredictable. We knocked out the C8ORF37 ortholog in mice, which resulted in a retinal phenotype similar to that observed in patients. We further demonstrated that C8ORF37 is required for photoreceptor outer segment disc formation and alignment, a process that is critical for photoreceptor function and survival. This study advances our understanding of the pathogenesis of retinal degeneration and establishes a valuable mouse model for future therapeutic development. PMID- 29440557 TI - Multisensory Integration Enhances Temporal Coding in Ventral Cochlear Nucleus Bushy Cells. AB - Temporal coding of auditory stimuli is critical for understanding communication signals. The bushy cell, a major output neuron of the ventral cochlear nucleus, can "phase-lock" precisely to pure tones and the envelopes of complex stimuli. Bushy cells are also putative recipients of brainstem somatosensory projections and could therefore play a role in perception of communication signals because multisensory integration is required for such complex sound processing. Here, we examine the role of multisensory integration in temporal coding in bushy cells by activating the spinal trigeminal nucleus (Sp5) while recording responses from bushy cells. In normal-hearing guinea pigs of either sex, bushy cell single unit responses to amplitude-modulated (AM) broadband noise were compared with those in the presence of preceding Sp5 electrical stimulation (i.e., bimodal stimuli). Responses to the AM stimuli were also compared with those obtained 45 min after the bimodal stimulation. Bimodal auditory-Sp5 stimulation resulted in enhanced envelope coding for low modulation frequencies, which persisted for up to 45 min. AM detection thresholds were significantly improved 45 min after bimodal auditory Sp5 stimulation, but not during bimodal auditory-Sp5 stimulation. Anterograde labeling of Sp5 projections was found within the dendritic fields of bushy cells and their inhibitory interneurons, D-stellate cells. Therefore, enhanced AM responses and improved AM sensitivity of bushy cells were likely facilitated by Sp5 neurons through monosynaptic excitatory projections and indirect inhibitory projections. These somatosensory projections may be involved in the improved perception of communication stimuli with multisensory stimulation, consistent with psychophysical studies in humans.SIGNIFICANCE STATEMENT Multisensory integration is crucial for sensory coding because it improves sensitivity to unimodal stimuli and enhances responses to external stimuli. Although multisensory integration has typically been described in the cerebral cortex, the cochlear nucleus in the brainstem is also innervated by multiple sensory systems, including the somatosensory and auditory systems. Here, we showed that convergence of these two sensory systems in the cochlear nucleus results in improved temporal coding in bushy cells, principal output neurons that send projections to higher auditory structures. The improved temporal coding instilled by bimodal auditory-Sp5 stimulation may be important in priming the neurons for coding biologically relevant sounds such as communication signals. PMID- 29440559 TI - Botulinum toxin A increases allograft tolerance in an experimental transplantation model: a preliminary study. AB - Identifying novel and safe immunosuppressants is of crucial importance. Recently, there have been several studies revealing that botulinum toxin A (BoTA) significantly alleviates ischemia-reperfusion injuries. Emerging evidence shows that ischemia-reperfusion injuries contribute to innate immune activation, promoting rejection, and inhibiting tolerance. Therefore, we hypothesized that a pretreatment with BoTA might decrease allograft rejection in a rat transplantation model. Twenty-four Lewis (LEW) rats were randomly assigned into two groups consisting of 12 rats each, depending on whether skin allograft was performed after pretreatment with BoTA (BoTA group) or with normal saline (control group). The experimental group was pretreated with a subcutaneous injection of BoTA (10 IU), while the control group was pretreated with normal saline 5 days prior to surgery. The donor Brown-Norway (BN) rat dorsal skin was subsequently grafted to the recipient LEW rats. The recipient wounds, measuring 2 cm * 2 cm, were made via dorsal skin excision through the panniculus carnosus. The donor skins of the same dimensions were obtained and transplanted on to the wounds and sutured with 4-0 nylon sutures. Mean graft survival time was measured in both groups. Quantitative reverse-transcriptase PCR and Western blotting were performed to evaluate the gene/protein expression of CD4 and VEGF. The mean graft survival time in the BoTA group was significantly longer than that of the control group (P=0.004). The relative mRNA and protein expression of CD4 was significantly lower in the BoTA group (P<0.001), while the relative mRNA and protein expression of VEGF was significantly higher in the BoTA group (P<0.001). In conclusion, our results show that BoTA prolongs the survival of skin allografts in a rat transplantation model. PMID- 29440558 TI - Control of Homeostatic Synaptic Plasticity by AKAP-Anchored Kinase and Phosphatase Regulation of Ca2+-Permeable AMPA Receptors. AB - Neuronal information processing requires multiple forms of synaptic plasticity mediated by NMDARs and AMPA-type glutamate receptors (AMPARs). These plasticity mechanisms include long-term potentiation (LTP) and long-term depression (LTD), which are Hebbian, homosynaptic mechanisms locally regulating synaptic strength of specific inputs, and homeostatic synaptic scaling, which is a heterosynaptic mechanism globally regulating synaptic strength across all inputs. In many cases, LTP and homeostatic scaling regulate AMPAR subunit composition to increase synaptic strength via incorporation of Ca2+-permeable receptors (CP-AMPAR) containing GluA1, but lacking GluA2, subunits. Previous work by our group and others demonstrated that anchoring of the kinase PKA and the phosphatase calcineurin (CaN) to A-kinase anchoring protein (AKAP) 150 play opposing roles in regulation of GluA1 Ser845 phosphorylation and CP-AMPAR synaptic incorporation during hippocampal LTP and LTD. Here, using both male and female knock-in mice that are deficient in PKA or CaN anchoring, we show that AKAP150-anchored PKA and CaN also play novel roles in controlling CP-AMPAR synaptic incorporation during homeostatic plasticity in hippocampal neurons. We found that genetic disruption of AKAP-PKA anchoring prevented increases in Ser845 phosphorylation and CP-AMPAR synaptic recruitment during rapid homeostatic synaptic scaling-up induced by combined blockade of action potential firing and NMDAR activity. In contrast, genetic disruption of AKAP-CaN anchoring resulted in basal increases in Ser845 phosphorylation and CP-AMPAR synaptic activity that blocked subsequent scaling-up by preventing additional CP-AMPAR recruitment. Thus, the balanced, opposing phospho-regulation provided by AKAP-anchored PKA and CaN is essential for control of both Hebbian and homeostatic plasticity mechanisms that require CP AMPARs.SIGNIFICANCE STATEMENT Neuronal circuit function is shaped by multiple forms of activity-dependent plasticity that control excitatory synaptic strength, including LTP/LTD that adjusts strength of individual synapses and homeostatic plasticity that adjusts overall strength of all synapses. Mechanisms controlling LTP/LTD and homeostatic plasticity were originally thought to be distinct; however, recent studies suggest that CP-AMPAR phosphorylation regulation is important during both LTP/LTD and homeostatic plasticity. Here we show that CP AMPAR regulation by the kinase PKA and phosphatase CaN coanchored to the scaffold protein AKAP150, a mechanism previously implicated in LTP/LTD, is also crucial for controlling synaptic strength during homeostatic plasticity. These novel findings significantly expand our understanding of homeostatic plasticity mechanisms and further emphasize how intertwined they are with LTP and LTD. PMID- 29440560 TI - Osteogenic protein-1 attenuates apoptosis and enhances matrix synthesis of nucleus pulposus cells under high-magnitude compression though inhibiting the p38 MAPK pathway. AB - BACKGROUND: Disc degeneration is correlated with mechanical load. Osteogenic protein-1 (OP-1) is potential to regenerate degenerative disc. OBJECTIVE: To investigate whether OP-1 can protect against high magitude compression-induced nucleus pulposus (NP) cell apoptosis and NP matrix catabolism, and its potential mechanism. METHODS: Porcine discs were cultured in a bioreactor and compressed at a relatively high-magnitude mechanical compression (1.3 MPa at a frequency of 1.0 Hz for 2 hours once per day) for 7 days. OP-1 was added along with the culture medium to investigate the protective effects of OP-1. NP cell apoptosis and matrix biosynthesis were evaluated. Additionally, activity of the p38 MAPK pathway is also analyzed. RESULTS: Compared with the control group, high magnitude compression significantly promoted NP cell apoptosis and decreased NP matrix biosynthesis, reflected by the increase in the number of TUNEL-positive cells and caspase-3 activity, the up-regulated expression of Bax and caspase-3 mRNA and down-regulated expression of Bcl-2 mRNA, and the decreased alcian blue staining intensity and expression of matrix proteins (aggrecan and collagen II). However, OP-1 addition partly attenuated the effects of high magnitude compression on NP cell apoptosis and NP matrix biosynthesis. Further analysis showed that inhibition of the p38 MAPK pathway partly participated in this process. CONCLUSION: OP-1 can attenuate high magnitude compression-induced NP cell apoptosis and promoted NP matrix biosynthesis, and inhibition of the p38 MAPK pathway may participate in this regulatory process. This study provides that OP-1 may be efficacy in retarding mechanical overloading-exacerbated disc degeneration. PMID- 29440561 TI - Association of TNF-alpha promoter polymorphism and Graves' disease: an updated systematic review and meta-analysis. AB - Graves' disease (GD) is a common autoimmune disorder with a genetic predisposition. Owing to the biological effect of tumor necrosis factor-alpha (TNF-alpha) on the thyroid gland and its gene location, TNF-alpha should be able to influence an individual's susceptibility to GD. In the present study, we conduct a meta-analysis of rs1800629 and rs361525 in TNF-alpha gene from all eligible case-control studies to assess the associations amongst reported TNF alpha gene with GD. A total of ten case-control studies involving 2790 GD patients and 3472 healthy controls were included. The results showed that a significant association was characterized between the rs1800629 polymorphism and GD in the homozygous model (AA compared with GG: odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.27-3.06, P=0.002) and recessive model (AA compared with GA + GG: OR = 1.62, 95% CI = 1.04-2.50, P=0.03). GD susceptibility was significantly detected in European population in all genetic models after ethnicity stratification. In sharp contrast, no significant association could be detected in Asian population. Next, we conducted a meta-analysis for another promoter SNP rs361525. However, SNP rs361525 did not show a significant association with GD in any genetic model before and after ethnicity stratification. Together, our data support that only the promoter single nucleotide polymorphism (SNP) rs1800629 within the TNF-alpha gene is associated with increased risk for developing GD, especially in European population. Future large-scale studies are required to validate the associations between TNF-alpha gene and GD. PMID- 29440562 TI - MYB52 Negatively Regulates Pectin Demethylesterification in Seed Coat Mucilage. AB - Pectin, which is a major component of the plant primary cell walls, is synthesized and methyl-esterified in the Golgi apparatus and then demethylesterified by pectin methylesterases (PMEs) located in the cell wall. The degree of methylesterification affects the functional properties of pectin, and thereby influences plant growth, development and defense. However, little is known about the mechanisms that regulate pectin demethylesterification. Here, we show that in Arabidopsis (Arabidopsis thaliana) seed coat mucilage, the absence of the MYB52 transcription factor is correlated with an increase in PME activity and a decrease in the degree of pectin methylesterification. Decreased methylesterification in the myb52 mutant is also correlated with an increase in the calcium content of the seed mucilage. Chromatin immunoprecipitation analysis and molecular genetic studies suggest that MYB52 transcriptionally activates PECTIN METHYLESTERASE INHIBITOR6 (PMEI6), PMEI14, and SUBTILISIN-LIKE SER PROTEASE1.7 (SBT1.7) by binding to their promoters. PMEI6 and SBT1.7 have previously been shown to be involved in seed coat mucilage demethylesterification. Our characterization of two PMEI14 mutants suggests that PMEI14 has a role in seed coat mucilage demethylesterification, although its activity may be confined to the seed coat in contrast to PMEI6, which functions in the whole seed. Our demonstration that MYB52 negatively regulates pectin demethylesterification in seed coat mucilage, and the identification of components of the molecular network involved, provides new insight into the regulatory mechanism controlling pectin demethylesterification and increases our understanding of the transcriptional regulation network involved in seed coat mucilage formation. PMID- 29440564 TI - Fulminant encephalopathy with unusual brain imaging in disulfiram toxicity. PMID- 29440563 TI - In vivo 18F-AV-1451 tau PET signal in MAPT mutation carriers varies by expected tau isoforms. AB - OBJECTIVE: To evaluate 18F-AV-1451 tau PET binding among microtubule-associated protein tau (MAPT) mutation carriers. METHODS: Using a case-control study, we quantitatively and qualitatively compared tau PET scans in 10 symptomatic and 3 asymptomatic MAPT mutation carriers (n = 13, age range 42-67 years) with clinically normal (CN) participants (n = 241, age range 42-67 years) and an Alzheimer disease (AD) dementia cohort (n = 30, age range 52-67 years). Eight participants had MAPT mutations that involved exon 10 (N279K n = 5, S305N n = 2, P301L n = 1) and tend to form 4R tau pathology, and 5 had mutations outside exon 10 (V337M n = 2, R406W n = 3) and tend to form mixed 3R/4R tau pathology. RESULTS: Tau PET signal was qualitatively and quantitatively different between participants with AD, CN participants, and MAPT mutation carriers, with the greatest signal intensity in those with AD and minimal regional signal in MAPT mutation carries with mutations in exon 10. However, MAPT mutation carriers with mutations outside exon 10 had uptake levels within the AD range, which was significantly higher than both MAPT mutation carriers with mutations in exon 10 and controls. CONCLUSIONS: Tau PET shows higher magnitude of binding in MAPT mutation carriers who harbor mutations that are more likely to produce AD-like tau pathology (e.g., in our series, the non-exon 10 families tend to accumulate mixed 3R/4R aggregates). Exon 10 splicing determines the balance of 3R and 4R tau isoforms, with some mutations involving exon 10 predisposing to a greater proportion of 4R aggregates and consequently a lower level of AV-1451 binding, as seen in this case series, thus supporting the notion that this tau PET ligand has specific binding properties for AD-like tau pathology. PMID- 29440565 TI - Flortaucipir imaging of MAPT: Mutations emphasize challenges for tau-targeted trials. PMID- 29440566 TI - Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To systematically review evidence regarding ataxia treatment. METHODS: A comprehensive systematic review was performed according to American Academy of Neurology methodology. CONCLUSIONS: For patients with episodic ataxia type 2, 4 aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study). PMID- 29440567 TI - Cellular and Molecular Mechanisms of Centromere Drive. AB - The asymmetric outcome of female meiosis I, whereby an entire set of chromosomes are discarded into a polar body, presents an opportunity for selfish genetic elements to cheat the process and disproportionately segregate to the egg. Centromeres, the chromosomal loci that connect to spindle microtubules, could potentially act as selfish elements and "drive" in meiosis. We review the current understanding of the genetic and epigenetic contributions to centromere identity and describe recent progress in a powerful model system to study centromere drive in mice. The progress includes mechanistic findings regarding two main requirements for a centromere to exploit the asymmetric outcome of female meiosis. The first is an asymmetry between centromeres of homologous chromosomes, and we found this is accomplished through massive changes in the abundance of the repetitive DNA underlying centromeric chromatin. The second requirement is an asymmetry in the meiotic spindle, which is achieved through signaling from the oocyte cortex that leads to asymmetry in a posttranslational modification of tubulin, tyrosination. Together, these two asymmetries culminate in the biased segregation of expanded centromeres to the egg, and we describe a mechanistic framework to understand this process. PMID- 29440568 TI - Enterococcus faecalis Sex Pheromone cCF10 Enhances Conjugative Plasmid Transfer In Vivo. AB - Cell-cell communication mediated by peptide pheromones (cCF10 [CF]) is essential for high-frequency plasmid transfer in vitro in Enterococcus faecalis To examine the role of pheromone signaling in vivo, we established either a CF-producing (CF+) recipient or a recipient producing a biologically inactive variant of CF (CF- recipient) in a germfree mouse model 3 days before donor inoculation and determined transfer frequencies of the pheromone-inducible plasmid pCF10. Plasmid transfer was detected in the upper and middle sections of the intestinal tract 5 h after donor inoculation and was highly efficient in the absence of antibiotic selection. The transconjugant/donor ratio reached a maximum level approaching 1 on day 4 in the upper intestinal tract. Plasmid transfer was significantly lower with the CF- recipient. While rescue of the CF- mating defect by coculture with CF+ recipients is easily accomplished in vitro, no extracellular complementation occurred in vivo This suggests that most pheromone signaling in the gut occurs between recipient and donor cells in very close proximity. Plasmid-bearing cells (donors plus transconjugants) steadily increased in the population from 0.1% after donor inoculation to about 10% at the conclusion of the experiments. This suggests a selective advantage of pCF10 carriage distinct from antibiotic resistance or bacteriocin production. Our results demonstrate that pheromone signaling is required for efficient pCF10 transfer in vivo In the absence of CF+ recipients, a low level of transfer to CF- recipients occurred in the gut. This may result from low-level host-mediated induction of the donors in the gastrointestinal (GI) tract, similar to that previously observed in serum.IMPORTANCE Horizontal gene transfer is a major factor in the biology of Enterococcus faecalis, an important nosocomial pathogen. Previous studies showing efficient conjugative plasmid transfer in the gastrointestinal (GI) tracts of experimental animals did not examine how the enterococcal sex pheromone response impacts the efficiency of transfer. Our study demonstrates for the first time pheromone-enhanced, high-frequency plasmid transfer of E. faecalis plasmid pCF10 in a mouse model in the absence of antibiotic or bacteriocin selection. Pheromone production by recipients dramatically increased plasmid transfer in germfree mice colonized initially with recipients, followed by donors. The presence of a coresident community of common gut microbes did not significantly reduce in vivo plasmid transfer between enterococcal donors and recipients. In mice colonized with enterococcal recipients, we detected plasmid transfer in the intestinal tract within 5 h of addition of donors, before transconjugants could be cultured from feces. Surprisingly, pCF10 carriage provided a competitive fitness advantage unrelated to antibiotic resistance or bacteriocin production. PMID- 29440569 TI - Human Papillomaviruses Preferentially Recruit DNA Repair Factors to Viral Genomes for Rapid Repair and Amplification. AB - High-risk human papillomaviruses (HPVs) activate the ataxia telangiectasia mutated-dependent (ATM) DNA damage response as well as the ataxia telangiectasia mutated-dependent DNA-related (ATR) pathway in the absence of external DNA damaging agents for differentiation-dependent genome amplification. Through the use of comet assays and pulsed-field gel electrophoresis, our studies showed that these pathways are activated in response to DNA breaks induced by the viral proteins E6 and E7 alone and independently of viral replication. The majority of these virally induced DNA breaks are present in cellular DNAs and only minimally in HPV episomes. Treatment of HPV-positive cells with inhibitors of both ATM and ATR leads to the generation of DNA breaks and the fragmentation of viral episomes, indicating that DNA breaks are introduced into HPV genomes. These breaks, however, are rapidly repaired through the preferential recruitment of homologous recombination repair enzymes, such as RAD51 and BRCA1, to viral genomes at the expense of cellular DNAs. When HPV-positive cells are treated with hydroxyurea, this recruitment of RAD51 and BRCA1 to viral genomes is greatly enhanced with little recruitment to damaged cellular DNAs and with retention of the ability of viral genomes to amplify. Overall, our studies demonstrated that human papillomaviruses induce breaks into cellular and viral DNAs and that the preferential repair of these lesions in viral episomes leads to genome amplification.IMPORTANCE High-risk human papillomaviruses (HPVs) are the etiologic agents of cervical cancer and are linked to the development of many other anogenital and oropharyngeal cancers. Replication of high-risk HPVs requires the activation of the ataxia telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) DNA repair pathways. Our studies have shown that HPVs activate these pathways by inducing double-strand breaks primarily in cellular DNAs and minimally in viral genomes. Breaks are induced in viral genomes but are rapidly repaired through the preferential recruitment of homologous repair factors such as RAD51 and BRCA1 to HPV episomes. The preferential repair of breaks in viral genomes leads to amplification. Our study identified a novel mechanism by which human papillomaviruses manipulate DNA repair pathways to productively replicate viral genomes. The induction of genetic instability in cellular DNAs likely contributes to the generation of mutations that lead to the development of cancers. PMID- 29440570 TI - Erratum for Petruzzi et al., "Capsular Polysaccharide Interferes with Biofilm Formation by Pasteurella multocida Serogroup A". PMID- 29440571 TI - Functional Analysis of Mating Type Genes and Transcriptome Analysis during Fruiting Body Development of Botrytis cinerea. AB - Botrytis cinerea is a plant-pathogenic fungus producing apothecia as sexual fruiting bodies. To study the function of mating type (MAT) genes, single-gene deletion mutants were generated in both genes of the MAT1-1 locus and both genes of the MAT1-2 locus. Deletion mutants in two MAT genes were entirely sterile, while mutants in the other two MAT genes were able to develop stipes but never formed an apothecial disk. Little was known about the reprogramming of gene expression during apothecium development. We analyzed transcriptomes of sclerotia, three stages of apothecium development (primordia, stipes, and apothecial disks), and ascospores by RNA sequencing. Ten secondary metabolite gene clusters were upregulated at the onset of sexual development and downregulated in ascospores released from apothecia. Notably, more than 3,900 genes were differentially expressed in ascospores compared to mature apothecial disks. Among the genes that were upregulated in ascospores were numerous genes encoding virulence factors, which reveals that ascospores are transcriptionally primed for infection prior to their arrival on a host plant. Strikingly, the massive transcriptional changes at the initiation and completion of the sexual cycle often affected clusters of genes, rather than randomly dispersed genes. Thirty-five clusters of genes were jointly upregulated during the onset of sexual reproduction, while 99 clusters of genes (comprising >900 genes) were jointly downregulated in ascospores. These transcriptional changes coincided with changes in expression of genes encoding enzymes participating in chromatin organization, hinting at the occurrence of massive epigenetic regulation of gene expression during sexual reproduction.IMPORTANCE Fungal fruiting bodies are formed by sexual reproduction. We studied the development of fruiting bodies ("apothecia") of the ubiquitous plant-pathogenic ascomycete Botrytis cinerea The role of mating type genes in apothecium development was investigated by targeted mutation. Two genes are essential for the initiation of sexual development; mutants in these genes are sterile. Two other genes were not essential for development of stipes; however, they were essential for stipes to develop a disk and produce sexual ascospores. We examined gene expression profiles during apothecium development, as well as in ascospores sampled from apothecia. We provide the first study ever of the transcriptome of pure ascospores in a filamentous fungus. The expression of numerous genes involved in plant infection was induced in the ascospores, implying that ascospores are developmentally primed for infection before their release from apothecia. PMID- 29440572 TI - Evasion of Human Neutrophil-Mediated Host Defense during Toxoplasma gondii Infection. AB - Neutrophils are a major player in host immunity to infection; however, the mechanisms by which human neutrophils respond to the intracellular protozoan parasite Toxoplasma gondii are still poorly understood. In the current study, we found that, whereas primary human monocytes produced interleukin-1beta (IL-1beta) in response to T. gondii infection, human neutrophils from the same blood donors did not. Moreover, T. gondii inhibited lipopolysaccharide (LPS)-induced IL-1beta synthesis in human peripheral blood neutrophils. IL-1beta suppression required active parasite invasion, since heat-killed or mycalolide B-treated parasites did not inhibit IL-1beta release. By investigating the mechanisms involved in this process, we found that T. gondii infection of neutrophils treated with LPS resulted in reduced transcript levels of IL-1beta and NLRP3 and reduced protein levels of pro-IL-1beta, mature IL-1beta, and the inflammasome sensor NLRP3. In T. gondii-infected neutrophils stimulated with LPS, the levels of MyD88, TRAF6, IKKalpha, IKKbeta, and phosphorylated IKKalpha/beta were not affected. However, LPS-induced IkappaBalpha degradation and p65 phosphorylation were reduced in T. gondii-infected neutrophils, and degradation of IkappaBalpha was reversed by treatment with the proteasome inhibitor MG-132. Finally, we observed that T. gondii inhibited the cleavage and activity of caspase-1 in human neutrophils. These results indicate that T. gondii suppression of IL-1beta involves a two pronged strategy whereby T. gondii inhibits both NF-kappaB signaling and activation of the NLRP3 inflammasome. These findings represent a novel mechanism of T. gondii evasion of human neutrophil-mediated host defense by targeting the production of IL-1beta.IMPORTANCEToxoplasma gondii is an obligate intracellular parasite that infects approximately one-third of humans worldwide and can invade virtually any nucleated cell in the human body. Although it is well documented that neutrophils infiltrate the site of acute T. gondii infection, there is limited understanding of how human neutrophils respond to T. gondii Neutrophils control infectious pathogens by a variety of mechanisms, including the release of the cytokine IL-1beta, a major driver of inflammation during infection. This study reveals that T. gondii is able to inhibit IL-1beta production in human neutrophils by impairing the activation of the NF-kappaB signaling pathway and by inhibiting the inflammasome, the protein complex responsible for IL-1beta maturation. This two-pronged strategy of targeting the IL-1beta pathway may facilitate the survival and spread of T. gondii during acute infection. PMID- 29440574 TI - Glycan-Glycan Interaction Determines Shigella Tropism toward Human T Lymphocytes. AB - Direct interactions between bacterial and host glycans have been recently reported to be involved in the binding of pathogenic bacteria to host cells. In the case of Shigella, the Gram-negative enteroinvasive bacterium responsible for acute rectocolitis, such interactions contribute to bacterial adherence to epithelial cells. However, the role of glycans in the tropism of Shigella for immune cells whose glycosylation pattern varies depending on their activation state is unknown. We previously reported that Shigella targets activated, but not nonactivated, human CD4+ T lymphocytes. Here, we show that nonactivated CD4+ T lymphocytes can be turned into Shigella-targetable cells upon loading of their plasma membrane with sialylated glycosphingolipids (also termed gangliosides). The Shigella targeting profile of ganglioside-loaded nonactivated T cells is similar to that of activated T cells, with a predominance of injection of effectors from the type III secretion system (T3SS) not resulting in cell invasion. We demonstrate that gangliosides interact with the O-antigen polysaccharide moiety of lipopolysaccharide (LPS), the major bacterial surface antigen, thus promoting Shigella binding to CD4+ T cells. This binding step is critical for the subsequent injection of T3SS effectors, a step which we univocally demonstrate to be dependent on actin polymerization. Altogether, these findings highlight the critical role of glycan-glycan interactions in Shigella pathogenesis.IMPORTANCE Glycosylation of host cell surface varies with species and location in the body, thus contributing to species specificity and tropism of microorganisms. Cross talk by Shigella, the Gram-negative enteroinvasive bacterium responsible for bacillary dysentery, with its exclusively human host has been extensively studied. However, the molecular determinants of the step of binding to host cells are poorly defined. Taking advantage of the observation that human-activated CD4+ T lymphocytes, but not nonactivated cells, are targets of Shigella, we succeeded in rendering the refractory cells susceptible to targeting upon loading of their plasma membrane with sialylated glycosphingolipids (gangliosides) that are abundantly present on activated cells. We show that interactions between the sugar polar part of gangliosides and the polysaccharide moiety of Shigella lipopolysaccharide (LPS) promote bacterial binding, which results in the injection of effectors via the type III secretion system. Whereas LPS interaction with gangliosides was proposed long ago and recently extended to a large variety of glycans, our findings reveal that such glycan-glycan interactions are critical for Shigella pathogenesis by driving selective interactions with host cells, including immune cells. PMID- 29440573 TI - The ColM Family, Polymorphic Toxins Breaching the Bacterial Cell Wall. AB - Bacteria host an arsenal of antagonism-mediating molecules to combat for ecologic space. Bacteriocins represent a pivotal group of secreted antibacterial peptides and proteins assisting in this fight, mainly eliminating relatives. Colicin M, a model for peptidoglycan-interfering bacteriocins in Gram-negative bacteria, appears to be part of a set of polymorphic toxins equipped with such a catalytic domain (ColM) targeting lipid II. Diversifying recombination has enabled parasitism of different receptors and has also given rise to hybrid bacteriocins in which ColM is associated with another toxin module. Remarkably, ColM toxins have recruited a diverse array of immunity partners, comprising cytoplasmic membrane-associated proteins with different topologies. Together, these findings suggest that different immunity mechanisms have evolved for ColM, in contrast to bacteriocins with nuclease activities. PMID- 29440575 TI - A High-Throughput Approach for Identification of Nontuberculous Mycobacteria in Drinking Water Reveals Relationship between Water Age and Mycobacterium avium. AB - Nontuberculous mycobacteria (NTM) frequently detected in drinking water (DW) include species associated with human infections, as well as species rarely linked to disease. Methods for improved the recovery of NTM DNA and high throughput identification of NTM are needed for risk assessment of NTM infection through DW exposure. In this study, different methods of recovering bacterial DNA from DW were compared, revealing that a phenol-chloroform DNA extraction method yielded two to four times as much total DNA and eight times as much NTM DNA as two commercial DNA extraction kits. This method, combined with high-throughput, single-molecule real-time sequencing of NTM rpoB genes, allowed the identification of NTM to the species, subspecies, and (in some cases) strain levels. This approach was applied to DW samples collected from 15 households serviced by a chloraminated distribution system, with homes located in areas representing short (<24 h) and long (>24 h) distribution system residence times. Multivariate statistical analysis revealed that greater water age (i.e., combined distribution system residence time and home plumbing stagnation time) was associated with a greater relative abundance of Mycobacterium avium subsp. avium, one of the most prevalent NTM causing infections in humans. DW from homes closer to the treatment plant (with a shorter water age) contained more diverse NTM species, including Mycobacterium abscessus and Mycobacterium chelonae Overall, our approach allows NTM identification to the species and subspecies levels and can be used in future studies to assess the risk of waterborne infection by providing insight into the similarity between environmental and infection associated NTM.IMPORTANCE An extraction method for improved recovery of DNA from nontuberculous mycobacteria (NTM), combined with single-molecule real-time sequencing (PacBio) of NTM rpoB genes, was used for high-throughput characterization of NTM species and in some cases strains in drinking water (DW). The extraction procedure recovered, on average, eight times as much NTM DNA and three times as much total DNA from DW as two widely used commercial DNA extraction kits. The combined DNA extraction and sequencing approach allowed high throughput screening of DW samples to identify NTM, revealing that the relative abundance of Mycobacterium avium subsp. avium increased with water age. Furthermore, the two-step barcoding approach developed as part of the PacBio sequencing method makes this procedure highly adaptable, allowing it to be used for other target genes and species. PMID- 29440576 TI - Slowdown of Translational Elongation in Escherichia coli under Hyperosmotic Stress. AB - In nature, bacteria frequently experience many adverse conditions, including heat, oxidation, acidity, and hyperosmolarity, which all tend to slow down if not outright stop cell growth. Previous work on bacterial stress mainly focused on understanding gene regulatory responses. Much less is known about how stresses compromise protein synthesis, which is the major driver of cell growth. Here, we quantitatively characterize the translational capacity of Escherichia coli cells growing exponentially under hyperosmotic stress. We found that hyperosmotic stress affects bacterial protein synthesis through reduction of the translational elongation rate, which is largely compensated for by an increase in the cellular ribosome content compared with nutrient limitation at a similar growth rate. The slowdown of translational elongation is attributed to a reduction in the rate of binding of tRNA ternary complexes to the ribosomes.IMPORTANCE Hyperosmotic stress is a common stress condition confronted by E. coli during infection of the urinary tract. It can significantly compromise the bacterial growth rate. Protein translation capacity is a critical component of bacterial growth. In this study, we find for the first time that hyperosmotic stress causes substantial slowdown in bacterial ribosome translation elongation. The slowdown of translation elongation originates from a reduced binding rate of tRNA ternary complex to the ribosomes. PMID- 29440577 TI - The Birth and Demise of the ISApl1-mcr-1-ISApl1 Composite Transposon: the Vehicle for Transferable Colistin Resistance. AB - The origin and mobilization of the ~2,609-bp DNA segment containing the mobile colistin resistance gene mcr-1 continue to be sources of uncertainty, but recent evidence suggests that the gene originated in Moraxella species. Moreover mcr-1 can be mobilized as an ISApl1-flanked composite transposon (Tn6330), but many sequences have been identified without ISApl1 or with just a single copy (single ended). To further clarify the origins and mobilization of mcr-1, we employed the Geneious R8 software suite to comprehensively analyze the genetic environment of every complete mcr-1 structure deposited in GenBank as of this writing (September 2017) both with and without associated ISApl1 (n = 273). This revealed that the 2,609-bp mcr-1 structure was likely mobilized from a close relative of a novel species of Moraxella containing a chromosomal region sharing >96% nucleotide identity with the canonical sequence. This chromosomal region is bounded by AT and CG dinucleotides, which have been described on the inside ends (IE) of all intact Tn6330 described to date and represent the ancestral 2-bp target site duplications (TSDs) generated by ISApl1 transposition. We further demonstrate that all mcr-1 structures with just one ISApl1 copy or with no ISApl1 copies were formed by deletion of ISApl1 from the ancestral Tn6330, likely by a process related to the "copy-out-paste-in" transposition mechanism. Finally, we show that only the rare examples of single-ended structures that have retained a portion of the excised downstream ISApl1 including the entire inverted right repeat might be capable of mobilization.IMPORTANCE A comprehensive analysis of all intact mcr-1 sequences in GenBank was used to identify a region on the chromosome of a novel Moraxella species with remarkable homology to the canonical mcr-1 structure and that likely represents the origin of this important gene. These data also demonstrate that all mcr-1 structures lacking one or both flanking ISApl1 were formed from ancestral composite transposons that subsequently lost the insertion sequences by a process of abortive transposition. This observation conclusively shows that mobilization of mcr-1 occurs as part of a composite transposon and that structures lacking the downstream ISApl1 are not capable of mobilization. PMID- 29440578 TI - CRISPR-Cas-Mediated Phage Resistance Enhances Horizontal Gene Transfer by Transduction. AB - A powerful contributor to prokaryotic evolution is horizontal gene transfer (HGT) through transformation, conjugation, and transduction, which can be advantageous, neutral, or detrimental to fitness. Bacteria and archaea control HGT and phage infection through CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) adaptive immunity. Although the benefits of resisting phage infection are evident, this can come at a cost of inhibiting the acquisition of other beneficial genes through HGT. Despite the ability of CRISPR Cas to limit HGT through conjugation and transformation, its role in transduction is largely overlooked. Transduction is the phage-mediated transfer of bacterial DNA between cells and arguably has the greatest impact on HGT. We demonstrate that in Pectobacterium atrosepticum, CRISPR-Cas can inhibit the transduction of plasmids and chromosomal loci. In addition, we detected phage-mediated transfer of a large plant pathogenicity genomic island and show that CRISPR-Cas can inhibit its transduction. Despite these inhibitory effects of CRISPR-Cas on transduction, its more common role in phage resistance promotes rather than diminishes HGT via transduction by protecting bacteria from phage infection. This protective effect can also increase transduction of phage-sensitive members of mixed populations. CRISPR-Cas systems themselves display evidence of HGT, but little is known about their lateral dissemination between bacteria and whether transduction can contribute. We show that, through transduction, bacteria can acquire an entire chromosomal CRISPR-Cas system, including cas genes and phage targeting spacers. We propose that the positive effect of CRISPR-Cas phage immunity on enhancing transduction surpasses the rarer cases where gene flow by transduction is restricted.IMPORTANCE The generation of genetic diversity through acquisition of DNA is a powerful contributor to microbial evolution and occurs through transformation, conjugation, and transduction. Of these, transduction, the phage-mediated transfer of bacterial DNA, is arguably the major route for genetic exchange. CRISPR-Cas adaptive immune systems control gene transfer by conjugation and transformation, but transduction has been mostly overlooked. Our results indicate that CRISPR-Cas can impede, but typically enhances the transduction of plasmids, chromosomal genes, and pathogenicity islands. By limiting wild-type phage replication, CRISPR-Cas immunity increases transduction in both phage-resistant and -sensitive members of mixed populations. Furthermore, we demonstrate mobilization of a chromosomal CRISPR-Cas system containing phage targeting spacers by generalized transduction, which might partly account for the uneven distribution of these systems in nature. Overall, the ability of CRISPR Cas to promote transduction reveals an unexpected impact of adaptive immunity on horizontal gene transfer, with broader implications for microbial evolution. PMID- 29440579 TI - An Autocrine Proliferation Repressor Regulates Dictyostelium discoideum Proliferation and Chemorepulsion Using the G Protein-Coupled Receptor GrlH. AB - In eukaryotic microbes, little is known about signals that inhibit the proliferation of the cells that secrete the signal, and little is known about signals (chemorepellents) that cause cells to move away from the source of the signal. Autocrine proliferation repressor protein A (AprA) is a protein secreted by the eukaryotic microbe Dictyostelium discoideum AprA is a chemorepellent for and inhibits the proliferation of D. discoideum We previously found that cells sense AprA using G proteins, suggesting the existence of a G protein-coupled AprA receptor. To identify the AprA receptor, we screened mutants lacking putative G protein-coupled receptors. We found that, compared to the wild-type strain, cells lacking putative receptor GrlH (grlH- cells) show rapid proliferation, do not have large numbers of cells moving away from the edges of colonies, are insensitive to AprA-induced proliferation inhibition and chemorepulsion, and have decreased AprA binding. Expression of GrlH in grlH- cells (grlH-/grlHOE ) rescues the phenotypes described above. These data indicate that AprA signaling may be mediated by GrlH in D. discoideumIMPORTANCE Little is known about how eukaryotic cells can count themselves and thus regulate the size of a tissue or density of cells. In addition, little is known about how eukaryotic cells can sense a repellant signal and move away from the source of the repellant, for instance, to organize the movement of cells in a developing embryo or to move immune cells out of a tissue. In this study, we found that a eukaryotic microbe uses G protein coupled receptors to mediate both cell density sensing and chemorepulsion. PMID- 29440581 TI - Implications of New High Blood Pressure Guidelines for Stroke Primary and Secondary Prevention. PMID- 29440582 TI - Long-Term Survival After Intravenous Thrombolysis for Ischemic Stroke: A Propensity Score-Matched Cohort With up to 10-Year Follow-Up. AB - BACKGROUND AND PURPOSE: Intravenous thrombolysis with alteplase is one of the few approved treatments for acute ischemic stroke; nevertheless, little is known about its long-term effects on survival and recovery because clinical trials follow-up times are limited. METHODS: Patients registered between January 2005 and December 2015, to the population-based South London Stroke Register of first ever strokes. Propensity score was used to match thrombolyzed and control cases to a 1:2 ratio by demographical and clinical covariates. The primary outcome was survival up to 10 years using Kaplan-Meier estimates, Cox proportional hazards, and restricted mean survival time. Secondary outcomes included stroke recurrence and functional status (Barthel Index and Frenchay Activities Index scores) at 5 years. RESULTS: From 2052 ischemic strokes, 246 treated patients were matched to 492 controls. Median follow-up time 5.45 years (interquartile range, 4.56). Survival was higher in the treatment group (median, 5.72 years) compared with control group (4.98 years, stratified log-rank test <0.001). The number needed to treat to prevent 1 death at 5 years was 12 and 20 at 10 years. After Cox regression analysis, thrombolysis reduced risk of mortality by 37% (hazard ratio, 0.63; 95% confidence interval [CI], 0.48-0.82) at 10 years; however, after introducing a multiplicative interaction term into the model, mortality risk reduction was 42% (hazard ratio, 0.58; 95% CI, 0.40-0.82) at 10 years for those arriving within 3 hours to the hospital. On average, in a 10-year period, treated patients lived 1 year longer than controls. At 5 years, thrombolysis was associated with independence (Barthel Index>=90; odds ratio, 3.76; 95% CI, 1.22 13.34) and increased odds of a higher Frenchay Activities Index (proportional odds ratio, 2.37; 95% CI, 1.16-4.91). There was no difference in stroke recurrence. CONCLUSIONS: Thrombolysis with intravenous alteplase is associated with improved long-term survival and functional status after ischemic stroke. PMID- 29440583 TI - Letter by Dijkland et al Regarding Article, "Development and Validation of a Predictive Model for Functional Outcome After Stroke Rehabilitation: The Maugeri Model". PMID- 29440584 TI - Response by Guida and Scrutinio to Letter Regarding Article, "Development and Validation of a Predictive Model for Functional Outcome After Stroke Rehabilitation: The Maugeri Model". PMID- 29440585 TI - Characteristics of Randomized Trials Focusing on Stroke due to Intracerebral Hemorrhage: Systematic Review. AB - BACKGROUND AND PURPOSE: The absence of treatments for intracerebral hemorrhage with significant consistent benefit in randomized controlled trials (RCTs) could be because of lack of treatment efficacy or the design of RCTs. METHODS: We searched the Cochrane Stroke Group Trials Register in December 2015 for completed and published RCTs reporting clinical outcome in adults with intracerebral hemorrhage. We collected data on publication year and language, study characteristics, and effect size. We regarded RCTs to be at lower risk of bias if they performed >=2 of describing randomization, using blinding, or specifying the primary outcome. We registered this systematic review (PROSPERO, international prospective register of systematic reviews CRD42016051103). RESULTS: We found 136 eligible RCTs: 57% were phase II, 76% were single center, 98% studied acute treatments, 49% involved drug interventions, 24% were placebo-controlled, the primary outcome was death or disability in 30%, and median sample size was 77 (interquartile range, 47-160). Forty-six percent explained randomization, 24% blinded treatment allocation, and 24% specified the primary outcome such that 38 (28%) were at lower risk of bias. RCTs at lower risk of bias were more likely to use multicenter recruitment (adjusted odds ratio, 6.95; 95% confidence interval, 2.2-21.5) and be published in English (adjusted odds ratio, 12.9, 95% confidence interval, 2.7-62.5). RCTs with larger sample sizes were independently more likely to be phase III/IV (P<0.01) and use multicenter recruitment (P<0.01). RCTs at lower risk of bias had smaller pooled treatment effects on death/disability (P=0.02). CONCLUSIONS: Intracerebral hemorrhage RCTs have often been at high risk of bias, and these RCTs have been characterized by small sample sizes and larger effect sizes. PMID- 29440586 TI - National Practice Patterns of Obtaining Informed Consent for Stroke Thrombolysis. AB - BACKGROUND AND PURPOSE: No standard approach to obtaining informed consent for stroke thrombolysis with tPA (tissue-type plasminogen activator) currently exists. We aimed to assess current nationwide practice patterns of obtaining informed consent for tPA. METHODS: An online survey was developed and distributed by e-mail to clinicians involved in acute stroke care. Multivariable logistic regression analyses were performed to determine independent factors contributing to always obtaining informed consent for tPA. RESULTS: Among 268 respondents, 36.7% reported always obtaining informed consent and 51.8% reported the informed consent process caused treatment delays. Being an emergency medicine physician (odds ratio, 5.8; 95% confidence interval, 2.9-11.5) and practicing at a nonacademic medical center (odds ratio, 2.1; 95% confidence interval, 1.0-4.3) were independently associated with always requiring informed consent. The most commonly cited cause of delay was waiting for a patient's family to reach consensus about treatment. CONCLUSIONS: Most clinicians always or often require informed consent for stroke thrombolysis. Future research should focus on standardizing content and delivery of tPA information to reduce delays. PMID- 29440588 TI - Implementing lung cancer screening: baseline results from a community-based 'Lung Health Check' pilot in deprived areas of Manchester. AB - We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55-74 years, were invited to 'lung health checks' (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk >=1.51%, PLCOM2012 calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas. PMID- 29440587 TI - Association between acute respiratory disease events and the MUC5B promoter polymorphism in smokers. AB - A single-nucleotide polymorphism (rs35705950) in the mucin 5B (MUC5B) gene promoter is associated with pulmonary fibrosis and interstitial features on chest CT but may also have beneficial effects. In non-Hispanic whites in the COPDGene cohort with interstitial features (n=454), the MUC5B promoter polymorphism was associated with a 61% lower odds of a prospectively reported acute respiratory disease event (P=0.001), a longer time-to-first event (HR=0.57; P=0.006) and 40% fewer events (P=0.016). The MUC5B promoter polymorphism may have a beneficial effect on the risk of acute respiratory disease events in smokers with interstitial CT features. PMID- 29440589 TI - Intraobserver and interobserver agreement on the radiographical diagnosis of canine cranial cruciate ligament rupture. AB - Even though radiography is one of the most frequently used imaging techniques for orthopaedic disorders, it has been demonstrated that the interpretation can vary between assessors. As such, the purpose of this study was to examine the intraobserver and interobserver agreement and the influence of level of expertise on the interpretation of radiographs of the stifle in dogs with and without cranial cruciate ligament rupture (CCLR). Sixteen observers, divided in four groups according to their level of experience, evaluated 30 radiographs (15 cases with CCLR and 15 control stifles) twice. Each observer was asked to evaluate joint effusion, presence and location of degenerative joint disease, joint instability and whether CCLR was present or absent. Overall, intraobserver and interobserver agreement ranged from fair to almost perfect with a trend towards increased agreement for more experienced observers. Additionally, it was found that stifles that were classified with high agreement have either overt disease characteristics or no disease characteristics at all, in comparison to the ones that are classified with a low agreement. Overall, the agreement on radiographic interpretation of CCLR was high, which is important, as it is the basis of a correct diagnosis and treatment. PMID- 29440590 TI - PDGFR-alpha, PDGFR-beta, VEGFR-2 and CD117 expression in canine mammary tumours and evaluation of the in vitro effects of toceranib phosphate in neoplastic mammary cell lines. AB - Canine mammary tumours (CMTs) are one of the most common malignancies in bitches. Platelet-derived growth factor receptor (PDGFR) alpha and beta, vascular endothelial growth factor receptor-2 (VEGFR-2) and CD117 are tyrosine kinase receptors involved in several tumours and represent suitable targets for specific therapy with toceranib phosphate. The purpose of this study was to evaluate the expression of these receptors in the pathogenesis and progression of CMTs. PDGFRalpha, PDGFRbeta, VEGFR-2 and CD117 were expressed in 46/83 (55.4 per cent), 33/83 (39.8 per cent), 46/83 (55.4 per cent) and 32/83 (38.5 per cent) of CMTs, respectively. Immunohistochemical results showed a statistically significant loss of PDGFRalpha and PDGFRbeta expression in simple carcinomas compared with complex/mixed carcinomas. Protein expression by western blot revealed specific bands corresponding to PDGFRalpha and VEGFR-2 in 3/7 and in 1/7 cell lines. Moreover, in vitro treatment showed that toceranib phosphate weakly reduced cell proliferation in one canine mammary cell line. Before considering TKR inhibitors for possible therapeutic approaches, actually further studies are necessary to evaluate the effect of these drugs on CMTs in vivo. PMID- 29440592 TI - ELIGULUM-A Regulates Lateral Branch and Leaf Development in Barley. AB - The shoot apical and axillary meristems control shoot development, effectively influencing lateral branch and leaf formation. The barley (Hordeum vulgare) uniculm2 (cul2) mutation blocks axillary meristem development, and mutant plants lack lateral branches (tillers) that normally develop from the crown. A genetic screen for cul2 suppressors recovered two recessive alleles of ELIGULUM-A (ELI-A) that partially rescued the cul2 tillering phenotype. Mutations in ELI-A produce shorter plants with fewer tillers and disrupt the leaf blade-sheath boundary, producing liguleless leaves and reduced secondary cell wall development in stems and leaves. ELI-A is predicted to encode an unannotated protein containing an RNaseH-like domain that is conserved in land plants. ELI-A transcripts accumulate at the preligule boundary, the developing ligule, leaf margins, cells destined to develop secondary cell walls, and cells surrounding leaf vascular bundles. Recent studies have identified regulatory similarities between boundary development in leaves and lateral organs. Interestingly, we observed ELI-A transcripts at the preligule boundary, suggesting that ELI-A contributes to boundary formation between the blade and sheath. However, we did not observe ELI-A transcripts at the axillary meristem boundary in leaf axils, suggesting that ELI-A is not involved in boundary development for axillary meristem development. Our results show that ELI-A contributes to leaf and lateral branch development by acting as a boundary gene during ligule development but not during lateral branch development. PMID- 29440593 TI - The Glucose Sensor MdHXK1 Phosphorylates a Tonoplast Na+/H+ Exchanger to Improve Salt Tolerance. AB - Glc regulates many vital processes, including plant growth, development, metabolism, and responses to biotic and abiotic stress. However, the molecular mechanism by which Glc acts as a signal to regulate salinity tolerance remains unclear. In this study, we found that the apple (Malus domestica Borkh.) Glc sensor hexokinase1 (MdHXK1) contributes to Glc-mediated salinity tolerance. A combination of split ubiquitin system, pull-down, co-immunoprecipitation, and bimolecular fluorescence complementation assays demonstrated that MdHXK1 interacts with and phosphorylates the Na+/H+ exchanger MdNHX1 at its Ser-275 residue. Phosphorylation improved the stability of MdNHX1 and enhanced its Na+/H+ transport activity in MdNHX1 overexpression transgenic apple and yeast complementation cells. Furthermore, Ser-275 of MdNHX1 was found to be crucial for MdHXK1-mediated phosphorylation. Finally, a series of transgenic analyses demonstrated that salt tolerance mediated by MdHXK1 partially depended on MdNHX1. Overall, our findings provide insights into how sugar recruits and regulates MdNHX1 in response to high salinity in plants. PMID- 29440594 TI - The COMPASS-Like Complex Promotes Flowering and Panicle Branching in Rice. AB - Flowering time (heading date) and panicle branch number are important agronomic traits that determine yield in rice (Oryza sativa). The activation of flowering requires histone methylation, but the roles of trimethylation of Lys 4 of histone 3 (H3K4me3) in modulating heading date and panicle development are unclear. Here, we showed that the COMPASS-like complex promotes flowering and panicle branching. The rice (Oryza sativa) WD40 protein OsWDR5a interacts with the TRITHORAX-like protein OsTrx1/SET domain group protein 723 (SDG723) to form the core components of the COMPASS-like complex. Plants in which OsWDR5a or OsTrx1 expression was decreased by RNA interference produced fewer secondary branches and less grain and exhibited a delayed heading date under long-day and short-day conditions, whereas loss of OsWDR5a function resulted in embryo lethality. OsWDR5a binds to Early heading date 1 to regulate its H3K4me3 and expression levels. Together, our results show that the COMPASS-like complex promotes flowering and panicle development and suggest that modulation of H3K4me3 levels by the COMPASS-like complex is critical for rice development. PMID- 29440595 TI - BRASSINOSTEROID-SIGNALING KINASE1 Phosphorylates MAPKKK5 to Regulate Immunity in Arabidopsis. AB - Arabidopsis (Arabidopsis thaliana) immune receptor FLAGELLIN SENSING2 (FLS2) rapidly forms a complex to activate pathogen-associated molecular pattern triggered immunity (PTI) upon perception of the bacterial protein flagellin. The receptor-like cytoplasmic kinase BRASSINOSTEROID-SIGNALINGKINASE1 (BSK1) interacts with FLS2 and is critical for the activation of PTI. However, it is unknown how BSK1 transduces signals to activate downstream immune responses. We identified MEK Kinase5 (MAPKKK5) as a potential substrate of BSK1 by whole-genome phosphorylation analysis. In addition, we demonstrated that BSK1 interacts with and phosphorylates MAPKKK5. In the bsk1-1 mutant, the Ser-289 residue of MAPKKK5 was not phosphorylated as it was in the wild type. Similar to the bsk1 mutant, the mapkkk5 mutant displayed enhanced susceptibility to virulent and avirulent strains of the bacterial pathogen Pseudomonas syringae pv tomato DC3000, and to the fungal powdery mildew pathogen Golovinomyces cichoracearum Phosphorylation of the Ser-289 residue is not involved in MAPKKK5-triggered cell death but is critical for MAPKKK5-mediated resistance to both bacterial and fungal pathogens. Furthermore, MAPKKK5 interacts with multiple MAPK kinases, including MKK1, MKK2, MKK4, MKK5, and MKK6. Overall, these results indicate that BSK1 regulates plant immunity by phosphorylating MAPKKK5 and suggest a direct regulatory mode of signaling from the immune complex to the MAPK cascade. PMID- 29440598 TI - Government urged to rethink sentience law. PMID- 29440597 TI - Generational divide? PMID- 29440596 TI - Multi-Omics Driven Assembly and Annotation of the Sandalwood (Santalum album) Genome. AB - Indian sandalwood (Santalum album) is an important tropical evergreen tree known for its fragrant heartwood-derived essential oil and its valuable carving wood. Here, we applied an integrated genomic, transcriptomic, and proteomic approach to assemble and annotate the Indian sandalwood genome. Our genome sequencing resulted in the establishment of a draft map of the smallest genome for any woody tree species to date (221 Mb). The genome annotation predicted 38,119 protein coding genes and 27.42% repetitive DNA elements. In-depth proteome analysis revealed the identities of 72,325 unique peptides, which confirmed 10,076 of the predicted genes. The addition of transcriptomic and proteogenomic approaches resulted in the identification of 53 novel proteins and 34 gene-correction events that were missed by genomic approaches. Proteogenomic analysis also helped in reassigning 1,348 potential noncoding RNAs as bona fide protein-coding messenger RNAs. Gene expression patterns at the RNA and protein levels indicated that peptide sequencing was useful in capturing proteins encoded by nuclear and organellar genomes alike. Mass spectrometry-based proteomic evidence provided an unbiased approach toward the identification of proteins encoded by organellar genomes. Such proteins are often missed in transcriptome data sets due to the enrichment of only messenger RNAs that contain poly(A) tails. Overall, the use of integrated omic approaches enhanced the quality of the assembly and annotation of this nonmodel plant genome. The availability of genomic, transcriptomic, and proteomic data will enhance genomics-assisted breeding, germplasm characterization, and conservation of sandalwood trees. PMID- 29440599 TI - Decapod crustaceans have feelings too. PMID- 29440600 TI - Protecting equine vets from work injuries. PMID- 29440602 TI - Counting mountain hares in Scotland. AB - The mountain hare (Lepus timidus) is Britain's only native hare, but counting them is challenging. Here, Georgina Mills explains how new research is helping to finally discover the numbers of this elusive species. PMID- 29440606 TI - Gait abnormalities in brachycephalic breeds: should we be more concerned? PMID- 29440608 TI - First-opinion practice and shortage of vets. PMID- 29440609 TI - The value of good first-opinion practice. PMID- 29440610 TI - Preventing rabbit haemorrhagic disease. PMID- 29440611 TI - Responsible antibiotic use. PMID- 29440612 TI - Reducing plastic waste. PMID- 29440613 TI - Publisher's response. PMID- 29440614 TI - Adverse events to feeding practises. PMID- 29440615 TI - The big picture. PMID- 29440616 TI - William Howard Guest Rees. AB - A distinguished vet who became the UK's chief veterinary officer, dealing with issues such as salmonella in eggs and bovine spongiform encephalopathy. His passions were his family and rugby. PMID- 29440620 TI - Quantification of hepatic perfusion and hepatocyte function with dynamic gadoxetic acid-enhanced MRI in patients with chronic liver disease. AB - The purpose of the present study was to develop and perform initial validation of dynamic MRI enhanced with gadoxetic acid as hepatobiliary contrast agent to quantify hepatic perfusion and hepatocyte function in patients with chronic liver disease. Free-breathing, dynamic gadoxetic acid-enhanced MRI was performed at 3.0 T using a 3D time-resolved angiography sequence with stochastic trajectories during 38 min. A dual-input three-compartment model was developed to derive hepatic perfusion and hepatocyte function parameters. Method feasibility was assessed in 23 patients with biopsy-proven chronic liver disease. Parameter analysis could be performed in 21 patients (91%). The hepatocyte function parameters were more discriminant than the perfusion parameters to differentiate between patients with minimal fibrosis (METAVIR F0-F1), intermediate fibrosis (F2 F3) and cirrhosis (F4). The areas under the receiver operating characteristic curves (ROCs) to diagnose significant fibrosis (METAVIR F >= 2) were: 0.95 (95% CI: 0.87-1; P<0.001) for biliary efflux, 0.88 (95% CI: 0.73-1; P<0.01) for sinusoidal backflux, 0.81 (95% CI: 0.61-1; P<0.05) for hepatocyte uptake fraction and 0.75 (95% CI: 0.54-1; P<0.05) for hepatic perfusion index (HPI), respectively. These initial results in patients with chronic liver diseases show that simultaneous quantification of hepatic perfusion and hepatocyte function is feasible with free breathing dynamic gadoxetic acid-enhanced MRI. Hepatocyte function parameters may be relevant to assess liver fibrosis severity. PMID- 29440621 TI - Urinary levels of sirtuin-1 associated with disease activity in lupus nephritis. AB - Identifying new markers of disease flares in lupus nephritis (LN) that facilitate patient stratification and prognosis is important. Therefore, the aim of the present study was to analyze whether urinary SIRT1 expression was altered in LN and whether SIRT1 values in urine could be valuable biomarker of disease activity. In a cohort study, urinary pellets from 40 patients diagnosed with systemic lupus erythematosus (SLE) were analyzed. Clinical measures of lupus activity were assessed. The expression of SIRT1 was quantified by quantitative PCR (qRT-PCR) and immunoblot, then compared between patients with active lupus nephritis, in remission and healthy controls. Association with lupus activity and renal histological features was also analyzed. A significant increase in SIRT1 mRNA levels in patients with active LN was observed compared with those in remission (P=0.02) or healthy controls (P=0.009). In addition, SIRT-1 protein levels were also augmented in LN group than remission (P=0.029) and controls (P=0.001). A strong association was found between SIRT1 expression with anti dsDNA in SLE and in patients with LN. In addition, histological features in LN biopsies were related with SIRT1, increasing its expression in proliferative forms. Finally, SIRT1 expression values showed a strong discriminatory power of renal injury in SLE. Our study demonstrated an altered urinary expression of SIRT1 and a strong association with disease activity in LN patients, being a valuable marker of renal injury. These results showed the role of the SIRT1 pathway in the SLE pathogenesis. PMID- 29440622 TI - Short-term early exposure to thirdhand cigarette smoke increases lung cancer incidence in mice. AB - Exposure to thirdhand smoke (THS) is a recently described health concern that arises in many indoor environments. However, the carcinogenic potential of THS, a critical consideration in risk assessment, remains untested. Here we investigated the effects of short-term early exposure to THS on lung carcinogenesis in A/J mice. Forty weeks after THS exposure from 4 to 7 weeks of age, the mice had increased incidence of lung adenocarcinoma, tumor size and, multiplicity, compared with controls. In vitro studies using cultured human lung cancer cells showed that THS exposure induced DNA double-strand breaks and increased cell proliferation and colony formation. RNA sequencing analysis revealed that THS exposure induced endoplasmic reticulum stress and activated p53 signaling. Activation of the p53 pathway was confirmed by an increase in its targets p21 and BAX. These data indicate that early exposure to THS is associated with increased lung cancer risk. PMID- 29440623 TI - Bleeding Complications Related to Right Heart Catheterization in the Setting of Elevated INR. AB - OBJECTIVES: Right heart catheterization (RHC) provides cardiovascular hemodynamic information in a variety of clinical settings. RHC performed in the setting of coagulopathy may have the potential to increase bleeding complications; however, data currently are limited. This study was undertaken to determine bleeding complications during RHC with an elevated international normalized ratio (INR) value. METHODS: A total of 312 patients who underwent RHC were retrospectively studied. Patients were divided into two groups: INR <1.8 (257 patients; median INR, 1.2; range, 0.8-1.7) and INR >=1.8 (55 patients; median INR, 2.1; range, 1.8 4.0). There were 80 patients (31.1%) and 46 patients (83.6%) taking oral vitamin K antagonist (warfarin) in the INR <1.8 and >=1.8 groups, respectively. RESULTS: Overall bleeding complications related to the procedure were extremely low, occurring in 2 patients (0.6%). All bleeding complications occurred in the INR <1.8 group, and both patients developed a small-sized hematoma requiring prolonged manual pressure without further intervention (0.8% vs 0.0% in the INR <1.8 vs INR >=1.8 groups, respectively; P>.99). CONCLUSION: Bleeding complications associated with RHC were extremely low when performed by experienced operators in the cardiac catheterization laboratory. Furthermore, these complications were not related to an elevated INR, as bleeding occurred in patients with INR <1.8. Performing RHC in patients with an elevated INR in the therapeutic range did not increase bleeding compared to lower INR values. PMID- 29440624 TI - Aminophylline for Preventing Bradyarrhythmias During Orbital or Rotational Atherectomy of the Right Coronary Artery. AB - BACKGROUND: Coronary atherectomy, orbital or rotational, is frequently used for plaque modification in patients with heavily calcified lesions. Atherectomy can be associated with clinically significant bradyarrhythmias or transient atrioventricular block requiring temporary pacemaker insertion, mainly in lesions involving the right coronary artery or a dominant left circumflex artery. Bradyarrhythmias may be mediated by endogenous release of adenosine from red blood cell breakdown. Aminophylline, an adenosine antagonist, can prevent adenosine-mediated bradyarrhythmias. METHODS: This retrospective analysis examined 7 patients in whom aminophylline (250-300 mg intravenously over 10 min) was administered before coronary atherectomy. The study endpoint was the occurrence of any bradyarrhythmia. RESULTS: Orbital atherectomy was used in 3 cases, rotational atherectomy was used in 3 cases, and both systems were used in 1 case. Technical success was 100% and all patients had Thrombolysis in Myocardial Infarction 3 flow at the end of the procedure. Preprocedural aminophylline administration successfully prevented bradyarrhythmias or atrioventricular block in all cases. CONCLUSIONS: Intravenous aminophylline represents a simple, safe, widely available, and low-cost intervention for preventing bradyarrhythmias during atherectomy of the right coronary artery or a dominant circumflex artery. PMID- 29440625 TI - Safety and Feasibility of a Novel Active Fixation Temporary Pacing Lead AB - OBJECTIVE: This first-in-human study evaluated the safety and technical feasibility of the Tempo temporary cardiac pacing lead (BioTrace Medical), which includes a novel fixation mechanism and soft tip. BACKGROUND: Complications of temporary pacing leads include dislodgment, arrhythmias, and ventricular perforation. Temporary pacing applications have increased with transcatheter aortic valve replacement (TAVR) growth, for rapid pacing during balloon valvuloplasty (BAV) and valve deployment, and for periprocedural bradyarrhythmia support. METHODS: Eligible patients required temporary pacing for TAVR, BAV, or electrophysiology (EP) procedures. Transthoracic echocardiograms were obtained at baseline and 24 hours after lead removal. Safety was defined as freedom from pericardial effusion requiring intervention or evidence of tamponade. Technical feasibility involved successful intracardiac delivery and pace capture. Additional evaluations included pacing threshold (PCT), rapid pacing, dislodgment, or sustained ventricular arrhythmias. Follow-up was to 30 days. RESULTS: Twenty-five patients (60% female; mean age, 64 +/- 19 years) underwent 13 TAVRs (7 Sapien 3 valves [Edwards Lifesciences], 4 CoreValves [Medtronic], and 2 Lotus valves [Boston Scientific]), 11 EP procedures, and 1 BAV at two New Zealand centers from January 2016 to June 2016. Safety was met in all patients, with no device-related adverse events. Technical feasibility was achieved in 23 cases (92%); 2 patients had unsuitable anatomy. No patient had lead dislodgment or sustained ventricular arrhythmias, and the final procedural PCT was 0.7 +/- 0.5 mA. Rapid pacing was successful in all cases. Five patients had successful postprocedural use up to 5 days. CONCLUSION: This first-in-human study demonstrates the safety and technical feasibility of the Tempo lead, providing stable periprocedural temporary pacing support. PMID- 29440626 TI - Upper bound dose values for meson radiation in heavy-ion therapy. AB - Radiation treatment of cancer has evolved to include massive particle beams, instead of traditional irradiation procedures. Thus, patient doses and worker radiological protection have become issues of constant concern in the use of these new technologies, especially for proton- and heavy-ion-therapy. In the beam energies of interest of heavy-ion-therapy, secondary particle radiation comes from proton, neutron, and neutral and charged pions produced in the nuclear collisions of the beam with human tissue atoms. This work, for the first time, offers the upper bound of meson radiation dose in organic tissues due to secondary meson radiation in heavy-ion therapy. A model based on intranuclear collision has been used to follow in time the nuclear reaction and to determine the secondary radiation due to the meson yield produced in the beam interaction with nuclei in the tissue-equivalent media and water. The multiplicity, energy spectrum, and angular distribution of these pions, as well as their decay products, have been calculated in different scenarios for the nuclear reaction mechanism. The results of the produced secondary meson particles has been used to estimate the energy deposited in tissue using a cylindrical phantom by a transport Monte Carlo simulation and we have concluded that these mesons contribute at most 0.1% of the total prescribed dose. PMID- 29440627 TI - Evaluation of a new simple collection device for sampling of microparticles in exhaled breath. AB - The microparticle fraction of exhaled breath is of interest for developing clinical biomarkers. Exhaled particles may contain non-volatile components from all parts of the airway system, formed during normal breathing. This study aimed to evaluate a new, simple sampling device, based on impaction, for collecting microparticles from exhaled breath. Performance of the new device was compared with that of the existing SensAbues membrane filter device. The analytical work used liquid chromatography-tandem mass spectrometry methods. The new device collected three subsamples and these were separately analysed from eight individuals. No difference was observed between the centre position (0.91 ng/sample) and the side positions (1.01 ng/sample) using major phosphatidylcholine (PC) 16:0/16:0 as the analyte. Exhaled breath was collected from eight patients on methadone maintenance treatment. The intra-individual variability in measured methadone concentration between the three collectors was 8.7%. In another experiment using patients on methadone maintenance treatment, the sampling efficiency was compared with an established filter device. Compared to the existing device, the efficiency of the new device was 121% greater for methadone and 1450% greater for DPPC. The data from lipid analysis also indicated that a larger fraction of the collected material was from the distal parts. Finally, a study using an optical particle counter indicated that the device preferentially collects the larger particle fraction. In conclusion, this study demonstrates the usefulness of the new device for collecting non-volatile components from exhaled breath. The performance of the device was superior to the filter device in several aspects. PMID- 29440629 TI - The Genotype of Human Papillomavirus and Associated Factors Among High Risk Males in Shanghai, China: A Molecular Epidemiology Study. AB - BACKGROUND The aim of this study was to describe the infection rate of human papillomavirus (HPV), its genotype distribution, and associated factors among high-risk males in Shanghai, China. MATERIAL AND METHODS A total of 1,205 participants were enrolled in this study from October 2015 to March 2017. Each individual signed an informed consent before agreeing to take part in this study; participants completed a questionnaire about associated factors related to HPV infection. The HPV GenoArray test kit was used to perform HPV genotyping and was also used in DNA amplification and HybriBio's proprietary flow-through hybridization technique. RESULTS The overall infection rate of HPV was 58.4%. HPV 11 (177, 14%) was the most common low-risk (LR) genotype and HPV 16 (78, 6.47%) was the top prevalent high-risk (HR) genotype among all the male patients. Additionally, multiple infections (387, 32.1%) was the most common type among all the infected cases, while single infection was only 317 cases (26.3%). Sexual preference, number of sex partners, sexual activity, and frequency of condom use were significantly associated with HR and LR infection. CONCLUSIONS The infection rate of HPV infection among high-risk males in Shanghai was very high. PMID- 29440630 TI - Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote lung adenocarcinoma growth by transferring miR-410. AB - Although accumulating evidence has linked mesenchymal stem cells (MSCs) with tumor growth, the underlying mechanisms are poorly understood. Here, we demonstrated for the first time that human umbilical cord MSCs (hUCMSCs) dramatically increased the growth of lung adenocarcinoma (LUAD) cancer cells in a xenograft tumor model. Then, we observed that hUCMSC-derived extracellular vesicles (hUCMSC-EVs) contribute to the hUCMSC-promoted LUAD cell growth through a direct effect on LUAD cells. Furthermore, we showed that hUCMSC-EV-mediated LUAD growth is associated with increased proliferation and decreased apoptosis in LUAD cells, concomitant with reduced PTEN expression mediated by the hUCMSC-EV transmitted miR-410. Our findings provide novel insights into the intercellular communications between cancer cells and MSCs through MSC-EV-miRNA and suggest that modification of hUCMSC-EVs might be an attractive therapeutic option for the clinical application of hUCMSC-EVs that would reduce unwanted side effects. PMID- 29440631 TI - Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity. AB - Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEdelta interactions by binding to a hydrophobic pocket on PDEdelta, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS dependent lung cancer cell growth. Here, for the first time, we document that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEdelta and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated deltarasin-induced cell death. Collectively, these observations suggest that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking "tumor protective" autophagy, but inhibited if combined with an anti-oxidant. PMID- 29440628 TI - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome Secondary to Furosemide: Case Report and Review of Literature. AB - BACKGROUND DRESS is a rare, life threatening syndrome that occurs following exposure to certain medications, most commonly antibiotics and antiepileptics. While sulfonamide antibiotics are frequently implicated as causative agents for DRESS syndrome, furosemide, a nonantibiotic sulfonamide, has not been routinely reported as the causative agent despite its widespread use. CASE REPORT A 63 year old male who started furosemide for lower extremity edema 10 weeks prior presented with diarrhea, fever of 39.4 degrees C, dry cough and maculopapular rash involving >50% of his body. He self-discontinued furosemide due to concern for dehydration. The diarrhea spontaneously resolved, but he developed hypoxia requiring hospitalization. CT scan demonstrated mediastinal lymphadenopathy and interstitial infiltrates. Laboratory evaluation revealed leukocytosis, eosinophilia and thrombocytopenia. He was treated empirically for atypical pneumonia, and after resuming furosemide for fluid excess, he developed AKI, worsening rash, fever and eosinophilia of 2,394 cell/uL. Extensive infectious and inflammatory work up was negative. Skin biopsy was consistent with a severe drug reaction. Latency from introduction and clinical worsening following re-exposure indicated furosemide was the likely inciter of DRESS. The RegiSCAR scoring system categorized this case as "definite" with a score of 8. CONCLUSIONS We report a case of severe DRESS syndrome secondary to furosemide, only the second case report in medical literature implicating furosemide. Given its widespread use, the potentially life-threatening nature of DRESS syndrome and the commonly delayed time course in establishing the diagnosis, it is important to remember that, albeit rare, furosemide can be a cause of DRESS syndrome. PMID- 29440632 TI - Detecting RNA base methylations in single cells by in situ hybridization. AB - Methylated bases in tRNA, rRNA and mRNA control a variety of cellular processes, including protein synthesis, antimicrobial resistance and gene expression. Currently, bulk methods that report the average methylation state of ~104-107 cells are used to detect these modifications, obscuring potentially important biological information. Here, we use in situ hybridization of Molecular Beacons for single-cell detection of three methylations (m62A, m1G and m3U) that destabilize Watson-Crick base pairs. Our method-methylation-sensitive RNA fluorescence in situ hybridization-detects single methylations of rRNA, quantifies antibiotic-resistant bacteria in mixtures of cells and simultaneously detects multiple methylations using multicolor fluorescence imaging. PMID- 29440633 TI - KRAS induces lung tumorigenesis through microRNAs modulation. AB - Oncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRASG12D) and using inducible human and mouse cell lines, we analyzed KRAS-regulated microRNAs in non-small-cell lung cancer (NSCLC). We show that miR-30c and miR-21 are significantly upregulated by both KRAS isoforms and induce drug resistance and enhance cell migration/invasion via inhibiting crucial tumor suppressor genes, such as NF1, RASA1, BID, and RASSF8. MiR-30c and miR-21 levels were significantly elevated in tumors from patients that underwent surgical resection of early stages NSCLC compared to normal lung and in plasma from the same patients. Systemic delivery of LNA-anti-miR-21 in combination with cisplatin in vivo completely suppressed the development of lung tumors in a mouse model of lung cancer. Mechanistically, we demonstrated that ELK1 is responsible for miR-30c and miR-21 transcriptional activation by direct binding to the miRNA proximal promoter regions. In summary, our study defines that miR-30c and miR-21 may be valid biomarkers for early NSCLC detection and their silencing could be beneficial for therapeutic applications. PMID- 29440634 TI - Fluorogenic RNA Mango aptamers for imaging small non-coding RNAs in mammalian cells. AB - Despite having many key roles in cellular biology, directly imaging biologically important RNAs has been hindered by a lack of fluorescent tools equivalent to the fluorescent proteins available to study cellular proteins. Ideal RNA labelling systems must preserve biological function, have photophysical properties similar to existing fluorescent proteins, and be compatible with established live and fixed cell protein labelling strategies. Here, we report a microfluidics-based selection of three new high-affinity RNA Mango fluorogenic aptamers. Two of these are as bright or brighter than enhanced GFP when bound to TO1-Biotin. Furthermore, we show that the new Mangos can accurately image the subcellular localization of three small non-coding RNAs (5S, U6, and a box C/D scaRNA) in fixed and live mammalian cells. These new aptamers have many potential applications to study RNA function and dynamics both in vitro and in mammalian cells. PMID- 29440635 TI - Conductance quantization suppression in the quantum Hall regime. AB - Conductance quantization is the quintessential feature of electronic transport in non-interacting mesoscopic systems. This phenomenon is observed in quasi one dimensional conductors at zero magnetic field B, and the formation of edge states at finite magnetic fields results in wider conductance plateaus within the quantum Hall regime. Electrostatic interactions can change this picture qualitatively. At finite B, screening mechanisms in narrow, gated ballistic conductors are predicted to give rise to an increase in conductance and a suppression of quantization due to the appearance of additional conduction channels. Despite being a universal effect, this regime has proven experimentally elusive because of difficulties in realizing one-dimensional systems with sufficiently hard-walled, disorder-free confinement. Here, we experimentally demonstrate the suppression of conductance quantization within the quantum Hall regime for graphene nanoconstrictions with low edge roughness. Our findings may have profound impact on fundamental studies of quantum transport in finite-size, two-dimensional crystals with low disorder. PMID- 29440636 TI - Chronic neutrophilic leukemia: new science and new diagnostic criteria. AB - Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm defined by persistent, predominantly mature neutrophil proliferation, marrow granulocyte hyperplasia, and frequent splenomegaly. The seminal discovery of oncogenic driver mutations in CSF3R in the majority of patients with CNL in 2013 generated a new scientific framework for this disease as it deepened our understanding of its molecular pathogenesis, provided a biomarker for diagnosis, and rationalized management using novel targeted therapies. Consequently, in 2016, the World Health Organization (WHO) revised the diagnostic criteria for CNL to reflect such changes in its genomic landscape, now including the presence of disease-defining activating CSF3R mutations as a key diagnostic component of CNL. In this communication, we provide a background on the history of CNL, its clinical and hemopathologic features, and its molecular anatomy, including relevant additional genetic lesions and their significance. We also outline the recently updated WHO diagnostic criteria for CNL. Further, the natural history of the disease is reviewed as well as potential prognostic variables. Finally, we summarize and discuss current treatment options as well as prospective novel therapeutic targets in hopes that they will yield meaningful improvements in patient management and outcomes. PMID- 29440638 TI - Energy use and life cycle greenhouse gas emissions of drones for commercial package delivery. AB - The use of automated, unmanned aerial vehicles (drones) to deliver commercial packages is poised to become a new industry, significantly shifting energy use in the freight sector. Here we find the current practical range of multi-copters to be about 4 km with current battery technology, requiring a new network of urban warehouses or waystations as support. We show that, although drones consume less energy per package-km than delivery trucks, the additional warehouse energy required and the longer distances traveled by drones per package greatly increase the life-cycle impacts. Still, in most cases examined, the impacts of package delivery by small drone are lower than ground-based delivery. Results suggest that, if carefully deployed, drone-based delivery could reduce greenhouse gas emissions and energy use in the freight sector. To realize the environmental benefits of drone delivery, regulators and firms should focus on minimizing extra warehousing and limiting the size of drones. PMID- 29440637 TI - Cytosine modifications exhibit circadian oscillations that are involved in epigenetic diversity and aging. AB - Circadian rhythmicity governs a remarkable array of fundamental biological functions and is mediated by cyclical transcriptomic and proteomic activities. Epigenetic factors are also involved in this circadian machinery; however, despite extensive efforts, detection and characterization of circadian cytosine modifications at the nucleotide level have remained elusive. In this study, we report that a large proportion of epigenetically variable cytosines show a circadian pattern in their modification status in mice. Importantly, the cytosines with circadian epigenetic oscillations significantly overlap with the cytosines exhibiting age-related changes in their modification status. Our findings suggest that evolutionary advantageous processes such as circadian rhythmicity can also contribute to an organism's deterioration. PMID- 29440639 TI - The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma. AB - Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics. Here we demonstrate that RHOU is heterogeneously expressed in primary multiple myeloma cells and significantly modulated with disease progression. At the mRNA level, RHOU expression in myeloma patients correlated with the expression of STAT3 and its targets MIR21 and SOCS3. Also, IL-6 stimulation of human myeloma cell lines up-regulated RHOU through STAT3 activation. On the other hand, RhoU silencing led to a decrease in cell migration with the accumulation of actin stress fibers, together with a decrease in cyclin D2 expression and in cell cycle progression. Furthermore, we found that even though lenalidomide positively regulated RhoU expression leading to higher cell migration rates, it actually led to cell cycle arrest probably through a p21 dependent mechanism. Lenalidomide treatment in combination with RhoU silencing determined a loss of cytoskeletal organization inhibiting cell migration, and a further increase in the percentage of cells in a resting phase. These results unravel a role for RhoU not only in regulating the migratory features of malignant plasma cells, but also in controlling cell cycle progression. PMID- 29440640 TI - 21st Century drought-related fires counteract the decline of Amazon deforestation carbon emissions. AB - Tropical carbon emissions are largely derived from direct forest clearing processes. Yet, emissions from drought-induced forest fires are, usually, not included in national-level carbon emission inventories. Here we examine Brazilian Amazon drought impacts on fire incidence and associated forest fire carbon emissions over the period 2003-2015. We show that despite a 76% decline in deforestation rates over the past 13 years, fire incidence increased by 36% during the 2015 drought compared to the preceding 12 years. The 2015 drought had the largest ever ratio of active fire counts to deforestation, with active fires occurring over an area of 799,293 km2. Gross emissions from forest fires (989 +/- 504 Tg CO2 year-1) alone are more than half as great as those from old-growth forest deforestation during drought years. We conclude that carbon emission inventories intended for accounting and developing policies need to take account of substantial forest fire emissions not associated to the deforestation process. PMID- 29440641 TI - Publisher Correction: Network inference from glycoproteomics data reveals new reactions in the IgG glycosylation pathway. AB - Correction to: Nature Communications (2017) 8:1231. doi:10.1038/s41467-017-01525 0. PMID- 29440642 TI - Understanding the plume dynamics of explosive super-eruptions. AB - Explosive super-eruptions can erupt up to thousands of km3 of magma with extremely high mass flow rates (MFR). The plume dynamics of these super-eruptions are still poorly understood. To understand the processes operating in these plumes we used a fluid-dynamical model to simulate what happens at a range of MFR, from values generating intense Plinian columns, as did the 1991 Pinatubo eruption, to upper end-members resulting in co-ignimbrite plumes like Toba super eruption. Here, we show that simple extrapolations of integral models for Plinian columns to those of super-eruption plumes are not valid and their dynamics diverge from current ideas of how volcanic plumes operate. The different regimes of air entrainment lead to different shaped plumes. For the upper end-members can generate local up-lifts above the main plume (over-plumes). These over-plumes can extend up to the mesosphere. Injecting volatiles into such heights would amplify their impact on Earth climate and ecosystems. PMID- 29440643 TI - Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models. AB - Enhancers regulate gene expression and have been linked with disease pathogenesis. Little is known about enhancers that regulate human disease associated genes in primary cells relevant for pathogenesis. Here we use BAC transgenics and genome editing to dissect, in vivo and in primary immune cells, enhancers that regulate human TNFAIP3, which encodes A20 and is linked with autoimmune diseases. A20 expression is dependent on a topologically associating subdomain (sub-TAD) that harbors four enhancers, while another >20 enhancers in the A20 locus are redundant. This sub-TAD contains cell- and activation-specific enhancers, including an enhancer (termed TT>A) harboring a proposed causal SLE associated SNV. Deletion of the sub-TAD or the TT>A enhancer results in enhanced inflammatory responses, autoantibody production, and inflammatory arthritis, thus establishing functional importance in vivo and linking enhancers with a specific disease phenotype. These findings provide insights into enhancers that regulate human A20 expression to prevent inflammatory pathology and autoimmunity. PMID- 29440644 TI - Ultrasensitive optical biosensor for detection of miRNA-155 using positively charged Au nanoparticles. AB - An ultrasensitive optical biosensor for microRNA-155 (miR-155) was developed to diagnose breast cancer at early stages. At first, the probe DNA covalently bind to the negatively charged gold nanoparticles (citrate-capped AuNPs). Then, the target miR-155 electrostatically adsorb onto the positively charged gold nanoparticles (polyethylenimine-capped AuNP) surface. Finally, by mixing citrate capped AuNP/probe and polyethylenimine-capped AuNP/miR-155, hybridization occurs and the optical signal of the mixture give a measure to quantify the miR-155 content. The proposed biosensor is able to specify 3-base-pair mismatches and genomic DNA from target miR-155. The novelty of this biosensor is in its ability to trap the label-free target by its branched positively charged polyethylenimine. This method increases loading the target on the polyethylenimine-capped AuNPs' surface. So, proposed sensor enables miR-155 detection at very low concentrations with the detection limit of 100 aM and a wide linear range from 100 aM to 100 fM. PMID- 29440645 TI - Mammalian Cells Undergo Endoreduplication in Response to Lactic Acidosis. AB - Polyploidization, a common event during the evolution of different tumours, has been proposed to confer selective advantages to tumour cells by increasing the occurrence of mutations promoting cancer progression and by conferring chemotherapy resistance. While conditions leading to polyploidy in cancer cells have been described, a general mechanism explaining the incidence of this karyotypic change in tumours is still missing. In this study, we tested whether a widespread tumour microenvironmental condition, low pH, could induce polyploidization in mammalian cells. We found that an acidic microenvironment, in the range of what is commonly observed in tumours, together with the addition of lactic acid, induced polyploidization in transformed and non-transformed human cell lines in vitro. In addition, we provide evidence that polyploidization was mainly driven through the process of endoreduplication, i.e. the complete skipping of mitosis in-between two S-phases. These findings suggest that acidic environments, which characterize solid tumours, are a plausible path leading to polyploidization of cancer cells. PMID- 29440646 TI - Chronic exposure to low dose of bisphenol A impacts on the first round of spermatogenesis via SIRT1 modulation. AB - Spermatogenesis depends on endocrine, autocrine and paracrine communications along the hypothalamus-pituitary-gonad axis. Bisphenol A (BPA), an estrogen-mimic endocrine disrupting chemical, is an environmental contaminant used to manufacture polycarbonate plastics and epoxy resins with toxic effects for male reproduction. Here we investigated whether the chronic exposure to low BPA doses affects spermatogenesis through the modulation of SIRT1, a NAD+-dependent deacetylase involved in the progression of spermatogenesis, with outcomes on apoptosis, oxidative stress, metabolism and energy homeostasis. BPA exposure via placenta first, and lactation and drinking water later, affected the body weight gain in male offspring at 45 postnatal days and the first round of spermatogenesis, with impairment of blood testis barrier, reactive oxygen species production, DNA damage and decreased expression of SIRT1. The analysis of SIRT1 downstream molecular pathways revealed the increase of acetyl-p53Lys370, gammaH2AX foci, the decrease of oxidative stress defenses and the higher apoptotic rate in the testis of treated animals, with partial rescue at sex maturation. In conclusion, SIRT1 pathways disruption after BPA exposure can have serious consequences on the first round of spermatogenesis. PMID- 29440647 TI - Impact of Gamma rays and DBD plasma treatments on wastewater treatment. AB - The rapid growth in world population brings with it the need for improvement in the current technology for water purification, in order to provide adequate potable water to everyone. Although an advanced oxidation process has been used to purify wastewater, its action mechanism is still not clear. Therefore, in the present study we treat dye-polluted water with gamma rays and dielectric barrier discharge (DBD) plasma. We study the wastewater treatment efficiency of gamma rays and DBD plasma at different absorbed doses, and at different time intervals, respectively. Methyl orange and methylene blue dyes are taken as model dyes. To understand the effects of environment and humidity on the decolorization of these dyes, we use various gas mixtures in the DBD plasma reactor. In the plasma reactor, we use the ambient air and ambient air + other gas (oxygen, nitrogen, and argon) mixtures, respectively, for the treatment of dyes. Additionally, we study the humidity effect on the decolorization of dyes with air plasma. Moreover, we also perform plasma simulation in different environment conditions, to understand which major radicals are generated during the plasma treatments, and determine their probable densities. PMID- 29440648 TI - Publisher Correction: Maturation of the gut microbiome and risk of asthma in childhood. AB - The originally published version of this Article contained an incorrect version of Figure 3 that was introduced following peer review and inadvertently not corrected during the production process. Both versions contain the same set of abundance data, but the incorrect version has the children's asthma status erroneously disconnected from the abundance data, thereby producing the non representative p values and graphic presentations. These errors have now been rectified, with the correct version of Figure 3 replaced in both the PDF and HTML versions of the Article. PMID- 29440649 TI - High enthalpy storage thermoset network with giant stress and energy output in rubbery state. AB - Low output in stress and energy in rubbery state has been a bottleneck for wide spread applications of thermoset shape memory polymers (SMPs). Traditionally, stress or energy storage in thermoset network is through entropy reduction by mechanical deformation or programming. We here report another mechanism for energy storage, which stores energy primarily through enthalpy increase by stretched bonds during programming. As compared to entropy-driven counterparts, which usually have a stable recovery stress from tenths to several MPa and energy output of several tenths MJ/m3, our rubbery network achieved a recovery stress of 17.0 MPa and energy output of 2.12 MJ/m3 in bulk form. The giant stress and energy release in the rubbery state will enhance applications of thermoset SMPs in engineering structures and devices. PMID- 29440650 TI - Type 2 Innate Lymphocytes Actuate Immunity Against Tumours and Limit Cancer Metastasis. AB - Type 2 innate lymphoid cells (ILC2) potentiate immune responses, however, their role in mediating adaptive immunity in cancer has not been assessed. Here, we report that mice genetically lacking ILC2s have significantly increased tumour growth rates and conspicuously higher frequency of circulating tumour cells (CTCs) and resulting metastasis to distal organs. Our data support the model that IL-33 dependent tumour-infiltrating ILC2s are mobilized from the lungs and other tissues through chemoattraction to enter tumours, and subsequently mediate tumour immune-surveillance by cooperating with dendritic cells to promote adaptive cytolytic T cell responses. We conclude that ILC2s play a fundamental, yet hitherto undescribed role in enhancing anti-cancer immunity and controlling tumour metastasis. PMID- 29440652 TI - Softening due to Grain Boundary Cavity Formation and its Competition with Hardening in Helium Implanted Nanocrystalline Tungsten. AB - The unique ability of grain boundaries to act as effective sinks for radiation damage plays a significant role in nanocrystalline materials due to their large interfacial area per unit volume. Leveraging this mechanism in the design of tungsten as a plasma-facing material provides a potential pathway for enhancing its radiation tolerance under fusion-relevant conditions. In this study, we explore the impact of defect microstructures on the mechanical behavior of helium ion implanted nanocrystalline tungsten through nanoindentation. Softening was apparent across all implantation temperatures and attributed to bubble/cavity loaded grain boundaries suppressing the activation barrier for the onset of plasticity via grain boundary mediated dislocation nucleation. An increase in fluence placed cavity induced grain boundary softening in competition with hardening from intragranular defect loop damage, thus signaling a new transition in the mechanical behavior of helium implanted nanocrystalline tungsten. PMID- 29440651 TI - Reconstruction of the sialylation pathway in the ancestor of eukaryotes. AB - The biosynthesis of sialylated molecules of crucial relevance for eukaryotic cell life is achieved by sialyltransferases (ST) of the CAZy family GT29. These enzymes are widespread in the Deuterostoma lineages and more rarely described in Protostoma, Viridiplantae and various protist lineages raising the question of their presence in the Last eukaryotes Common Ancestor (LECA). If so, it is expected that the main enzymes associated with sialic acids metabolism are also present in protists. We conducted phylogenomic and protein sequence analyses to gain insights into the origin and ancient evolution of ST and sialic acid pathway in eukaryotes, Bacteria and Archaea. Our study uncovered the unreported occurrence of bacterial GT29 ST and evidenced the existence of 2 ST groups in the LECA, likely originating from the endosymbiotic event that generated mitochondria. Furthermore, distribution of the major actors of the sialic acid pathway in the different eukaryotic phyla indicated that these were already present in the LECA, which could also access to this essential monosaccharide either endogenously or via a sialin/sialidase uptake mechanism involving vesicles. This pathway was lost in several basal eukaryotic lineages including Archaeplastida despite the presence of two different ST groups likely assigned to other functions. PMID- 29440653 TI - Genetic and morphological support for possible sympatric origin of fish from subterranean habitats. AB - Two blind Iran cave barbs, Garra typhlops and Garra lorestanensis, exist in sympatry in a single subterranean habitat, raising the hypothesis that they may represent a case of sympatric speciation following a colonization event. Their different mental disc forms have prompted some authors to propose the alternative hypothesis of two separate colonization events. In this study, we analysed a genome-wide panel of 11,257 SNPs genotyped by means of genotyping-by-sequencing combined with mitochondrial cytochrome c oxidase sub-unit I sequence data, field observations and morphological traits to test these two hypotheses. Field data suggest some degree of ecological divergence despite some possible niche overlap such that hybridization is possible. According to both nuclear and mtDNA data, the cave barb species are monophyletic with close phylogenetic relationships with Garra gymnothorax from the Karun-Dez and Karkheh river basins. The historical demography analysis revealed that a model of Isolation-with-Migration (IM) best fitted the data, therefore better supporting a scenario of sympatric origin than that of allopatric isolation followed by secondary contact. Overall, our results offer stronger support to the hypothesis that speciation in the subterranean habitat could have occurred in sympatry following a colonization event from the Karun-Dez-Karkheh basins in the Zagros Mountains of Iran. PMID- 29440654 TI - Effects of diversity in olfactory environment on children's sense of smell. AB - Diversity in children's everyday olfactory environment may affect the development of their olfactory abilities and odor awareness. To test this, we collected data on olfactory abilities using the Sniffin' Sticks and odor awareness with Children's Olfactory Behaviors in Everyday Life Questionnaire in 153 preschool children and retested them one and a half year later. Parents completed an inventory on children's exposure to a variety of odors and on their own odor awareness using the Odor Awareness Scale. We controlled for the effects of age and verbal fluency on the children's performance. We found that the children's odor identification and discrimination scores differed as a function of parental odor awareness. Although these effects were rather small, they were commensurate in size with those of gender and age. To the best of our knowledge, this study is the first to present evidence that diversity in children's olfactory environment affects variation in their olfactory abilities and odor awareness. We suggest that future studies consider the long-term impact of perceptual learning out of the laboratory and its consequences for olfactory development. PMID- 29440655 TI - Functional Variants Identified Efficiently through an Integrated Transcriptome and Epigenome Analysis. AB - Although genome-wide association studies (GWAS) have identified numerous genetic loci associated with complex diseases, the underlying molecular mechanisms of how these loci contribute to disease pathogenesis remain largely unknown, due to the lack of an efficient strategy to identify these risk variants. Here, we proposed a new strategy termed integrated transcriptome and epigenome analysis (iTEA) to identify functional genetic variants in non-coding elements. We considered type 2 diabetes mellitus as a model and identified a well-known diabetic risk variant rs35767 using iTEA. Furthermore, we discovered a new functional SNP, rs815815, involved in glucose metabolism. Our study provides an approach to directly and quickly identify functional genetic variants in type 2 diabetes mellitus, and this approach can be extended to study other complex diseases. PMID- 29440656 TI - Gold nanoparticle-based rapid detection and isolation of cells using ligand receptor chemistry. AB - Identification and isolation of low-frequency cells of interest from a heterogeneous cell mixture is an important aspect of many diagnostic applications (including enumeration of circulating tumor cells) and is integral to various assays in (cancer) biology. Current techniques typically require expensive instrumentation and are not amenable to high throughput. Here, we demonstrate a simple and effective platform for cell detection and isolation using gold nanoparticles (Au NPs) conjugated with hyaluronic acid (HA) i.e. Au-PEG-HA NPs. The proposed platform exploits ligand-receptor chemistry to detect/isolate cells with high specificity and efficiency. When the Au-PEG-HA NPs come in contact with cells that express CD44 (the receptor for HA), a clear colorimetric change occurs (along with an accompanying SPR peak shift from 521 nm to 559 nm) in the solution due to NPs-cell interaction. This clearly discernible, colorimetric change can be leveraged by point-of-care devices employed in diagnostic applications. Finally, we show that we can successfully isolate viable cells from a heterogeneous cell population (including from human blood samples) with high specificity, which can be used in further downstream applications. The developed NPs-based platform can be a convenient and cost-efficient alternative for diagnostic applications and for cell isolation or sorting in research laboratories. PMID- 29440657 TI - Nippostrongylus brasiliensis infection leads to impaired reference memory and myeloid cell interference. AB - Hookworm infection is endemic in developing countries, leading to poor cognitive function-among other disruptions. In this study, the effects of Nippostrongylus brasiliensis infection (a murine model of Necator Americanus) on cognitive function were investigated. Though impaired cognition has been extensively reported, the exact domain of cognition affected is still unknown, hence requiring investigation. The objective of this study was to identify possible cognitive changes during Nippostrongylus brasiliensis infection in mice, using the Morris water maze. Here, we show for the first time that mice infected with Nippostrongylus brasiliensis were able to learn the Morris water maze task, but demonstrated impaired reference memory. Anxiety measured by thigmotaxis in the maze, did not play a role for the observed cognitive impairment. Of further interest, an increase in the number of hippocampal macrophages and microglia with training and/or infection suggested a significant role of these cell types during spatial learning. Together, these experimental mouse studies suggest that helminth infections do have an impact on cognition. Further experimental animal studies on cognition and infection might open new approaches for a better understanding and impact of pathogen infections. PMID- 29440658 TI - Emerging risks from marine heat waves. AB - Recent marine heat waves have caused devastating impacts on marine ecosystems. Substantial progress in understanding past and future changes in marine heat waves and their risks for marine ecosystems is needed to predict how marine systems, and the goods and services they provide, will evolve in the future. PMID- 29440660 TI - Concise N-doped Carbon Nanosheets/Vanadium Nitride Nanoparticles Materials via Intercalative Polymerization for Supercapacitors. AB - N-doped carbon nanosheets/vanadium nitride nanoparticles (N-CNS/VNNPs) are synthesized via a novel method combining surface-initiated in-situ intercalative polymerization and thermal-treatment process in NH3/N2 atmosphere. The pH value of the synthesis system plays a critical role in constructing the structure and enhancing electrochemical performance for N-CNS/VNNPs, which are characterized by SEM, TEM, XRD, and XPS, and measured by electrochemical station, respectively. The results show that N-CNS/VNNPs materials consist of 2D N-doped carbon nanosheets and 0D VN nanoparticles. With the pH value decreasing from 2 to 0, the sizes of both carbon nanosheets and VN nanoparticles decreased to smaller in nanoscale. The maximum specific capacitance of 280 F g-1 at the current density of 1 A g-1 for N-CNS/VNNPs is achieved in three-electrode configuration. The asymmetric energy device of Ni(OH)2||N-CNS/VNNPs offers a specific capacitance of 89.6 F g-1 and retention of 60% at 2.7 A g-1 after 5000 cycles. The maximum energy density of Ni(OH)2 ||N-CNS/VNNPs asymmetric energy device is as high as 29.5 Wh kg-1. PMID- 29440659 TI - The effects of death and post-mortem cold ischemia on human tissue transcriptomes. AB - Post-mortem tissues samples are a key resource for investigating patterns of gene expression. However, the processes triggered by death and the post-mortem interval (PMI) can significantly alter physiologically normal RNA levels. We investigate the impact of PMI on gene expression using data from multiple tissues of post-mortem donors obtained from the GTEx project. We find that many genes change expression over relatively short PMIs in a tissue-specific manner, but this potentially confounding effect in a biological analysis can be minimized by taking into account appropriate covariates. By comparing ante- and post-mortem blood samples, we identify the cascade of transcriptional events triggered by death of the organism. These events do not appear to simply reflect stochastic variation resulting from mRNA degradation, but active and ongoing regulation of transcription. Finally, we develop a model to predict the time since death from the analysis of the transcriptome of a few readily accessible tissues. PMID- 29440661 TI - Panton-Valentine Leukocidin Colocalizes with Retinal Ganglion and Amacrine Cells and Activates Glial Reactions and Microglial Apoptosis. AB - Experimental models have established Panton-Valentine leukocidin (PVL) as a potential critical virulence factor during Staphylococcus aureus endophthalmitis. In the present study, we aimed to identify retinal cell targets for PVL and to analyze early retinal changes during infection. After the intravitreous injection of PVL, adult rabbits were euthanized at different time points (30 min, 1, 2, 4 and 8 h). PVL location in the retina, expression of its binding receptor C5a receptor (C5aR), and changes in Muller and microglial cells were analyzed using immunohistochemistry, Western blotting and RT-qPCR. In this model of PVL eye intoxication, only retinal ganglion cells (RGCs) expressed C5aR, and PVL was identified on the surface of two kinds of retinal neural cells. PVL-linked fluorescence increased in RGCs over time, reaching 98% of all RGCs 2 h after PVL injection. However, displaced amacrine cells (DACs) transiently colocalized with PVL. Muller and microglial cells were increasingly activated after injection over time. IL-6 expression in retina increased and some microglial cells underwent apoptosis 4 h and 8 h after PVL infection, probably because of abnormal nitrotyrosine production in the retina. PMID- 29440662 TI - WDR1 is a novel EYA3 substrate and its dephosphorylation induces modifications of the cellular actin cytoskeleton. AB - Eyes absent (EYA) proteins are unusual proteins combining in a single polypeptide chain transactivation, threonine phosphatase, and tyrosine phosphatase activities. They play pivotal roles in organogenesis and are involved in a variety of physiological and pathological processes including innate immunity, DNA damage repair or cancer metastasis. The molecular targets of EYA tyrosine phosphatase activity are still elusive. Therefore, we sought to identify novel EYA substrates and also to obtain further insight into the tyrosine dephosphorylating role of EYA proteins in various cellular processes. We show here that Src kinase phosphorylates tyrosine residues in two human EYA family members, EYA1 and EYA3. Both can autodephosphorylate these residues and their nuclear and cytoskeletal localization seems to be controlled by Src phosphorylation. Next, using a microarray of phosphotyrosine-containing peptides, we identified a phosphopeptide derived from WD-repeat-containing protein 1 (WDR1) that is dephosphorylated by EYA3. We further demonstrated that several tyrosine residues on WDR1 are phosphorylated by Src kinase, and are efficiently dephosphorylated by EYA3, but not by EYA1. The lack of phosphorylation generates major changes to the cellular actin cytoskeleton. We, therefore, conclude that WDR1 is an EYA3-specific substrate, which implies that EYA3 is a key modulator of the cytoskeletal reorganization. PMID- 29440663 TI - A new method to optimize root order classification based on the diameter interval of fine root. AB - Plant roots are a highly heterogeneous and hierarchical system. Although the root order method is superior to the root diameter method for revealing differences in the morphology and physiology of fine roots, its complex partitioning limits its application. Whether root order can be determined by partitioning the main root based on its diameter remains uncertain. Four methods were employed for studying the morphological characteristics of seedling roots of two Pinus species in a natural and nitrogen-enriched environment. The intrinsic relationships among categories of roots by root order and diameter were systematically compared to explore the possibility of using the latter to describe root morphology. The normal transformation method proved superior to the other three in that the diameter intervals corresponded most closely (at least 68.3%) to the morphological characteristics. The applied methods clearly distinguished the results from the natural and nitrogen-rich environments. Considering both root diameter and order simplified the classification of fine roots, and improved the estimation of root lifespan and the data integrity of field collection, but failed to partition all roots into uniform diameter intervals. PMID- 29440664 TI - Grassland dynamics in response to climate change and human activities in Xinjiang from 2000 to 2014. AB - Climate change and human activities are two key factors that affect grassland ecosystem. Accurately estimating the effects of these two factors on grassland dynamics and understanding the driving forces of the dynamics are important in controlling grassland degradation. In this study, the potential Net Primary productivity (NPPP) and the difference between NPPP and actual NPP (NPPA) are used as indicators of climate change and human activities on grassland ecosystem in Xinjiang. An overall grassland NPPA increase than decrease (69.7% vs 30.3%) is found over the study period of 2000 to 2014. While human activities played a dominant role for such a NPPA increase, both human activities and climate change contributed almost equally to the grassland NPPA decrease. Within the three types of grasslands in Xinjiang, the desert grassland showed the greatest NPPA increasing trend that mostly attributed to human activities; the meadow showed an overall NPPA decreasing trend that was mainly caused by human activities; the steppe showed similar NPPA decreasing and increasing trend in terms of area percentage. Based on this study, our recommendations are (1) to continue the grazing prohibition policy in desert grassland and (2) to extensively implement the rest grazing policy in steppe and meadow grasslands. PMID- 29440665 TI - Hydrophilic fluorinated molecules for spectral 19F MRI. AB - Fluorine-19 (19F) Magnetic Resonance Imaging (MRI) is an emerging modality for molecular imaging and cell tracking. The hydrophobicity of current exogenous probes, perfluorocarbons (PFCs) and perfluoropolyethers (PFPEs), limits the formulation options available for in vivo applications. Hydrophilic probes permit more formulation flexibility. Further, the broad Nuclear Magnetic Resonance (NMR) chemical shift range of organofluorine species enables multiple probes with unique 19F MR signatures for simultaneous interrogation of distinct molecular targets in vivo. We report herein a flexible approach to stable liposomal formulations of hydrophilic fluorinated molecules (each bearing numerous magnetically equivalent 19F atoms), with 19F encapsulation of up to 22.7 mg/mL and a per particle load of 3.6 * 106 19F atoms. Using a combination of such probes, we demonstrate, with no chemical shift artifacts, the simultaneous imaging of multiple targets within a given target volume by spectral 19F MRI. PMID- 29440667 TI - Poleward upgliding Siberian atmospheric rivers over sea ice heat up Arctic upper air. AB - We carried out upper air measurements with radiosondes during the summer over the Arctic Ocean from an icebreaker moving poleward from an ice-free region, through the ice edge, and into a region of thick ice. Rapid warming of the Arctic is a significant environmental issue that occurs not only at the surface but also throughout the troposphere. In addition to the widely accepted mechanisms responsible for the increase of tropospheric warming during the summer over the Arctic, we showed a new potential contributing process to the increase, based on our direct observations and supporting numerical simulations and statistical analyses using a long-term reanalysis dataset. We refer to this new process as "Siberian Atmospheric Rivers (SARs)". Poleward upglides of SARs over cold air domes overlying sea ice provide the upper atmosphere with extra heat via condensation of water vapour. This heating drives increased buoyancy and further strengthens the ascent and heating of the mid-troposphere. This process requires the combination of SARs and sea ice as a land-ocean-atmosphere system, the implication being that large-scale heat and moisture transport from the lower latitudes can remotely amplify the warming of the Arctic troposphere in the summer. PMID- 29440666 TI - Folic Acid Exposure Rescues Spina Bifida Aperta Phenotypes in Human Induced Pluripotent Stem Cell Model. AB - Neural tube defects (NTDs) are severe congenital abnormalities, caused by failed closure of neural tube during early embryonic development. Periconceptional folic acid (FA) supplementation greatly reduces the risk of NTDs. However, the molecular mechanisms behind NTDs and the preventive role of FA remain unclear. Here, we use human induced pluripotent stem cells (iPSCs) derived from fetuses with spina bifida aperta (SBA) to study the pathophysiology of NTDs and explore the effects of FA exposure. We report that FA exposure in SBA model is necessary for the proper formation and maturation of neural tube structures and robust differentiation of mesodermal derivatives. Additionally, we show that the folate antagonist methotrexate dramatically affects the formation of neural tube structures and FA partially reverts this aberrant phenotype. In conclusion, we present a novel model for human NTDs and provide evidence that it is a powerful tool to investigate the molecular mechanisms underlying NTDs, test drugs for therapeutic approaches. PMID- 29440668 TI - Rhamnolipids production from sucrose by engineered Saccharomyces cerevisiae. AB - Biosurfactants are biological tensioactive agents that can be used in the cosmetic and food industries. Rhamnolipids are glycolipid biosurfactants naturally produced by Pseudomonas aeruginosa and are composed of one or two rhamnose molecules linked to beta-hydroxy fatty acid chains. These compounds are green alternatives to petrochemical surfactants, but their large-scale production is still in its infancy, hindered due to pathogenicity of natural producer, high substrate and purification costs and low yields and productivities. This study, for the first time, aimed at producing mono-rhamnolipids from sucrose by recombinant GRAS Saccharomyces cerevisiae strains. Six enzymes from P. aeruginosa involved in mono-rhamnolipid biosynthesis were functionally expressed in the yeast. Furthermore, its SUC2 invertase gene was disrupted and a sucrose phosphorylase gene from Pelomonas saccharophila was also expressed to reduce the pathway's overall energy requirement. Two strains were constructed aiming to produce mono-rhamnolipids and the pathway's intermediate dTDP-L-rhamnose. Production of both molecules was analyzed by confocal microscopy and mass spectrometry, respectively. These strains displayed, for the first time as a proof of concept, the potential of production of these molecules by a GRAS eukaryotic microorganism from an inexpensive substrate. These constructs show the potential to further improve rhamnolipids production in a yeast-based industrial bioprocess. PMID- 29440669 TI - Aldehyde Dehydrogenases Function in the Homeostasis of Pyridine Nucleotides in Arabidopsis thaliana. AB - Aldehyde dehydrogenase enzymes (ALDHs) catalyze the oxidation of aliphatic and aromatic aldehydes to their corresponding carboxylic acids using NAD+ or NADP+ as cofactors and generating NADH or NADPH. Previous studies mainly focused on the ALDH role in detoxifying toxic aldehydes but their effect on the cellular NAD(P)H contents has so far been overlooked. Here, we investigated whether the ALDHs influence the cellular redox homeostasis. We used a double T-DNA insertion mutant that is defective in representative members of Arabidopsis thaliana ALDH families 3 (ALDH3I1) and 7 (ALDH7B4), and we examined the pyridine nucleotide pools, glutathione content, and the photosynthetic capacity of the aldh mutants in comparison with the wild type. The loss of function of ALDH3I1 and ALDH7B4 led to a decrease of NAD(P)H, NAD(P)H/NAD(P) ratio, and an alteration of the glutathione pools. The aldh double mutant had higher glucose-6-phosphate dehydrogenase activity than the wild type, indicating a high demand for reduced pyridine nucleotides. Moreover, the mutant had a reduced quantum yield of photosystem II and photosynthetic capacity at relatively high light intensities compared to the wild type. Altogether, our data revealed a role of ALDHs as major contributors to the homeostasis of pyridine nucleotides in plants. PMID- 29440670 TI - Characterization of Conserved and Novel microRNAs in Lilium lancifolium Thunb. by High-Throughput Sequencing. AB - MicroRNAs (miRNAs) are among the class of noncoding small RNA molecules and play a crucial role in post-transcriptional regulation in plants. Although Lilium is one of the most popular ornamental flowers worldwide, however, there is no report on miRNAs identification. In the present study, therefore, miRNAs and their targets were identified from flower, leaf, bulblet and bulb of Lilium lancifolium Thunb. by high-throughput sequencing and bioinformatics analysis. In this study, a total of 38 conserved miRNAs belonging to 17 miRNA families and 44 novel miRNAs were identified. In total, 366 target genes for conserved miRNAs and 415 target genes for novel miRNAs were predicted. The majority of the target genes for conserved miRNAs were transcriptional factors and novel miRNAs targeted mainly protein coding genes. A total of 53 cleavage sites belonging to 6 conserved miRNAs families and 14 novel miRNAs were identified using degradome sequencing. Twenty-three miRNAs were randomly selected, then, their credibility was confirmed using northern blot or stem-loop qRT-PCR. The results from qRT-PCR analysis showed the expression pattern of 4 LL-miRNAs was opposite to their targets. Therefore, our finding provides an important basis to understand the biological functions of miRNAs in Lilium. PMID- 29440671 TI - Impaired airway mucociliary function reduces antigen-specific IgA immune response to immunization with a claudin-4-targeting nasal vaccine in mice. AB - Vaccine delivery is an essential element for the development of mucosal vaccine, but it remains to be investigated how physical barriers such as mucus and cilia affect vaccine delivery efficacy. Previously, we reported that C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) targeted claudin-4, which is expressed by the epithelium associated with nasopharynx-associated lymphoid tissue (NALT), and could be effective as a nasal vaccine delivery. Mice lacking tubulin tyrosine ligase-like family, member 1 (Ttll1-KO mice) showed mucus accumulation in nasal cavity due to the impaired motility of respiratory cilia. Ttll1-KO mice nasally immunized with C-CPE fused to pneumococcal surface protein A (PspA-C-CPE) showed reduced PspA-specific nasal IgA responses, impaired germinal center formation, and decreased germinal center B-cells and follicular helper T cells in the NALT. Although there was no change in the expression of claudin-4 in the NALT epithelium in Ttll1-KO mice, the epithelium was covered by a dense mucus that prevented the binding of PspA-C-CPE to NALT. However, administration of expectorant N-acetylcysteine removed the mucus and rescued the PspA-specific nasal IgA response. These results show that the accumulation of mucus caused by impaired respiratory cilia function is an interfering factor in the C-CPE-based claudin-4-targeting nasal vaccine. PMID- 29440672 TI - LINC01088 inhibits tumorigenesis of ovarian epithelial cells by targeting miR-24 1-5p. AB - The roles of long non-coding RNAs (lncRNAs), a class of long non-protein-coding RNAs, in the tumorigenesis of ovarian epithelial cells remain unknown. In this study, we discovered that the expression of long intergenic non-coding RNA 1088 (LINC01088) was clearly reduced in benign epithelial ovarian tumor tissues compared to matched normal ovarian tissues. This was shown by global cDNA gene chip scanning and real-time qPCR, and validated in 42 clinical specimens. Furthermore, we found that LINC01088 inhibited the growth of ovarian cancer xenografts in nude mice. Correlation analysis between LINC01088 and mircoRNAs (miRNAs) conducted using primary clinical samples and RNA co-precipitation experiments revealed that miR-24-1-5p was one of the targets of LINC01088. Overexpression of miR-24-1-5p facilitated cell proliferation both in vitro and in vivo, however, LINC01088 could partially reverse the cell proliferation induced by miR-24-1-5p. Finally, we demonstrated that p21 activated kinase 4 (PAK4) was one of the downstream key targets of miR-24-1-5p by luciferase reporter assay and Western blotting; and our results showed a remarkable decrease in cell proliferation after overexpression of PAK4. We conclude that LINC01088 might function as a tumor suppressor, inhibiting the tumorigenesis of ovarian epithelial cells through LINC01088/ miR-24-1-5p/ PAK4 axis. PMID- 29440673 TI - Spontaneous oscillation in cell adhesion and stiffness measured using atomic force microscopy. AB - Atomic force microscopy (AFM) is an attractive technique for studying biomechanical and morphological changes in live cells. Using real-time AFM monitoring of cellular mechanical properties, spontaneous oscillations in cell stiffness and cell adhesion to the extracellular matrix (ECM) have been found. However, the lack of automated analytical approaches to systematically extract oscillatory signals, and noise filtering from a large set of AFM data, is a significant obstacle when quantifying and interpreting the dynamic characteristics of live cells. Here we demonstrate a method that extends the usage of AFM to quantitatively investigate live cell dynamics. Approaches such as singular spectrum analysis (SSA), and fast Fourier transform (FFT) were introduced to analyze a real-time recording of cell stiffness and the unbinding force between the ECM protein-decorated AFM probe and vascular smooth muscle cells (VSMCs). The time series cell adhesion and stiffness data were first filtered with SSA and the principal oscillatory components were isolated from the noise floor with the computed eigenvalue from the lagged-covariance matrix. Following the SSA, the oscillatory parameters were detected by FFT from the noise reduced time series data sets and the sinusoidal oscillatory components were constructed with the parameters obtained by FFT. PMID- 29440674 TI - Engineering the conserved and noncatalytic residues of a thermostable beta-1,4 endoglucanase to improve specific activity and thermostability. AB - Endoglucanases are increasingly applied in agricultural and industrial applications as a key biocatalyst for cellulose biodegradation. However, the low performance in extreme conditions seriously challenges the enzyme's commercial utilization. To obtain endoglucanases with substantially improved activity and thermostability, structure-based rational design was carried out based on the Chaetomium thermophilum beta-1,4-endoglucanase CTendo45. In this study, five mutant enzymes were constructed by substitution of conserved and noncatalytic residues using site-directed mutagenesis. Mutants were constitutively expressed in Pichia pastoris, purified, and ultimately tested for enzymatic characteristics. Two single mutants, Y30F and Y173F, increased the enzyme's specific activity 1.35- and 1.87-fold using carboxymethylcellulose sodium (CMC Na) as a substrate, respectively. Furthermore, CTendo45 and mutants exhibited higher activity towards beta-D-glucan than that of CMC-Na, and activities of Y173F and Y30F were also increased obviously against beta-D-glucan. In addition, Y173F significantly improved the enzyme's heat resistance at 80 degrees C and 90 degrees C. More interestingly, the double mutant Y30F/Y173F obtained considerably higher stability at elevated temperatures but failed to inherit the increased catalytic efficiency of its single mutant counterparts. This work gives an initial insight into the biological function of conserved and noncatalytic residues of thermostable endoglucanases and proposes a feasible path for the improvement of enzyme redesign proposals. PMID- 29440675 TI - In vitro patient-derived 3D mesothelioma tumor organoids facilitate patient centric therapeutic screening. AB - Variability in patient response to anti-cancer drugs is currently addressed by relating genetic mutations to chemotherapy through precision medicine. However, practical benefits of precision medicine to therapy design are less clear. Even after identification of mutations, oncologists are often left with several drug options, and for some patients there is no definitive treatment solution. There is a need for model systems to help predict personalized responses to chemotherapeutics. We have microengineered 3D tumor organoids directly from fresh tumor biopsies to provide patient-specific models with which treatment optimization can be performed before initiation of therapy. We demonstrate the initial implementation of this platform using tumor biospecimens surgically removed from two mesothelioma patients. First, we show the ability to biofabricate and maintain viable 3D tumor constructs within a tumor-on-a-chip microfluidic device. Second, we demonstrate that results of on-chip chemotherapy screening mimic those observed in subjects themselves. Finally, we demonstrate mutation-specific drug testing by considering the results of precision medicine genetic screening and confirming the effectiveness of the non-standard compound 3 deazaneplanocin A for an identified mutation. This patient-derived tumor organoid strategy is adaptable to a wide variety of cancers and may provide a framework with which to improve efforts in precision medicine oncology. PMID- 29440676 TI - Counting the electrons in a multiphoton ionization by elastic scattering of microwaves. AB - Multiphoton ionization (MPI) is a fundamental first step in high-energy laser matter interaction and is important for understanding the mechanism of plasma formation. With the discovery of MPI more than 50 years ago, there were numerous attempts to determine the basic physical constants of this process in direct experiments, namely photoionization rates and cross-sections of the MPI; however, no reliable data was available until now, and the spread in the literature values often reaches 2-3 orders of magnitude. This is due to the inability to conduct absolute measurements of plasma electron numbers generated by MPI, which leads to uncertainties and, sometimes, contradictions between MPI cross-section values utilized by different researchers across the field. Here, we report the first direct measurement of absolute plasma electron numbers generated at MPI of air, and subsequently we precisely determine the ionization rate and cross-section of eight-photon ionization of oxygen molecule by 800 nm photons sigma8 = (3.3 +/- 0.3)*10-130 W-8m16s-1. The method, based on the absolute measurement of the electron number created by MPI using elastic scattering of microwaves off the plasma volume in Rayleigh regime, establishes a general approach to directly measure and tabulate basic constants of the MPI process for various gases and photon energies. PMID- 29440677 TI - Nanobody-triggered lockdown of VSRs reveals ligand reloading in the Golgi. AB - Protein degradation in lytic compartments is crucial for eukaryotic cells. At the heart of this process, vacuolar sorting receptors (VSRs) bind soluble hydrolases in the secretory pathway and release them into the vacuolar route. Sorting efficiency is suggested to result from receptor recycling. However, how and to where plant VSRs recycle remains controversial. Here we present a nanobody epitope interaction-based protein labeling and tracking approach to dissect their anterograde and retrograde transport routes in vivo. We simultaneously employ two different nanobody-epitope pairs: one for the location-specific post translational fluorescence labeling of receptors and the other pair to trigger their compartment-specific lockdown via an endocytosed dual-epitope linker protein. We demonstrate VSR recycling from the TGN/EE, thereby identifying the cis-Golgi as the recycling target and show that recycled VSRs reload ligands. This is evidence that bidirectional VSR-mediated sorting of vacuolar proteins exists and occurs between the Golgi and the TGN/EE. PMID- 29440678 TI - Development of a bacterial cellulose-based hydrogel cell carrier containing keratinocytes and fibroblasts for full-thickness wound healing. AB - Bacterial cellulose (BC)/acrylic acid (AA) hydrogel has successfully been investigated as a wound dressing for partial-thickness burn wound. It is also a promising biomaterial cell carrier because it bears some resemblance to the natural soft tissue. This study assessed its ability to deliver human epidermal keratinocytes (EK) and dermal fibroblasts (DF) for the treatment of full thickness skin lesions. In vitro studies demonstrated that BC/AA hydrogel had excellent cell attachment, maintained cell viability with limited migration, and allowed cell transfer. In vivo wound closure, histological, immunohistochemistry, and transmission electron microscopy evaluation revealed that hydrogel alone (HA) and hydrogel with cells (HC) accelerated wound healing compared to the untreated controls. Gross appearance and Masson's trichrome staining indicated that HC was better than HA. This study suggests the potential application of BC/AA hydrogel with dual functions, as a cell carrier and wound dressing, to promote full thickness wound healing. PMID- 29440681 TI - A sarcopenia screening test predicts mortality in hospitalized older adults. AB - The aim of this study is to investigate the validation of a sarcopenia screening test (Ishii's formula) for predicting long-term mortality among older adult inpatients. A prospective, observational study was conducted in acute geriatric wards at three hospitals in western China. Sarcopenia was estimated using Ishii's formula. Survival status was assessed at 12, 24, and 36 months after the baseline investigation. Cox proportional-hazard models were applied to calculate the hazard ratio for mortality associated with sarcopenia. Three hundred and eighty participants (100 women) with a mean age of 80.2 +/- 7.1 years were included. According to Ishii's formula, 264 participants (69.5%) were sarcopenic. The prevalence of sarcopenia was similar in men and women (71.1% vs. 65.0%, respectively, P = 0.258). Sixty-seven participants (17.6%) died during the 3-year follow-up period. The all-cause mortality was significantly higher in the sarcopenia group than in the non-sarcopenia group (20.1% vs. 12.1%, respectively, P < 0.05). Multivariate Cox proportional hazards analysis identified sarcopenia as a significant predictor of 3-year all-cause mortality (adjusted hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.02-4.15). In conclusion, sarcopenia, estimated by Ishii's formula, can predict 3-year all-cause mortality in a study population of hospitalized older adults. PMID- 29440679 TI - A defensin-like protein drives cadmium efflux and allocation in rice. AB - Pollution by heavy metals limits the area of land available for cultivation of food crops. A potential solution to this problem might lie in the molecular breeding of food crops for phytoremediation that accumulate toxic metals in straw while producing safe and nutritious grains. Here, we identify a rice quantitative trait locus we name cadmium (Cd) accumulation in leaf 1 (CAL1), which encodes a defensin-like protein. CAL1 is expressed preferentially in root exodermis and xylem parenchyma cells. We provide evidence that CAL1 acts by chelating Cd in the cytosol and facilitating Cd secretion to extracellular spaces, hence lowering cytosolic Cd concentration while driving long-distance Cd transport via xylem vessels. CAL1 does not appear to affect Cd accumulation in rice grains or the accumulation of other essential metals, thus providing an efficient molecular tool to breed dual-function rice varieties that produce safe grains while remediating paddy soils. PMID- 29440680 TI - An allogeneic 'off the shelf' therapeutic strategy for peripheral nerve tissue engineering using clinical grade human neural stem cells. AB - Artificial tissues constructed from therapeutic cells offer a promising approach for improving the treatment of severe peripheral nerve injuries. In this study the effectiveness of using CTX0E03, a conditionally immortalised human neural stem cell line, as a source of allogeneic cells for constructing living artificial nerve repair tissue was tested. CTX0E03 cells were differentiated then combined with collagen to form engineered neural tissue (EngNT-CTX), stable aligned sheets of cellular hydrogel. EngNT-CTX sheets were delivered within collagen tubes to repair a 12 mm sciatic nerve injury model in athymic nude rats. Autologous nerve grafts (autografts) and empty tubes were used for comparison. After 8 weeks functional repair was assessed using electrophysiology. Further, detailed histological and electron microscopic analysis of the repaired nerves was performed. Results indicated that EngNT-CTX supported growth of neurites and vasculature through the injury site and facilitated reinnervation of the target muscle. These findings indicate for the first time that a clinically validated allogeneic neural stem cell line can be used to construct EngNT. This provides a potential 'off the shelf' tissue engineering solution for the treatment of nerve injury, overcoming the limitations associated with nerve autografts or the reliance on autologous cells for populating repair constructs. PMID- 29440682 TI - Time-reversed magnetically controlled perturbation (TRMCP) optical focusing inside scattering media. AB - Manipulating and focusing light deep inside biological tissue and tissue-like complex media has been desired for long yet considered challenging. One feasible strategy is through optical wavefront engineering, where the optical scattering induced phase distortions are time reversed or pre-compensated so that photons travel along different optical paths interfere constructively at the targeted position within a scattering medium. To define the targeted position, an internal guidestar is needed to guide or provide a feedback for wavefront engineering. It could be injected or embedded probes such as fluorescence or nonlinear microspheres, ultrasonic modulation, as well as absorption perturbation. Here we propose to use a magnetically controlled optical absorbing microsphere as the internal guidestar. Using a digital optical phase conjugation system, we obtained sharp optical focusing within scattering media through time-reversing the scattered light perturbed by the magnetic microsphere. Since the object is magnetically controlled, dynamic optical focusing is allowed with a relatively large field-of-view by scanning the magnetic field externally. Moreover, the magnetic microsphere can be packaged with an organic membrane, using biological or chemical means to serve as a carrier. Therefore, the technique may find particular applications for enhanced targeted drug delivery, and imaging and photoablation of angiogenic vessels in tumours. PMID- 29440683 TI - Rpb9-deficient cells are defective in DNA damage response and require histone H3 acetylation for survival. AB - Rpb9 is a non-essential subunit of RNA polymerase II that is involved in DNA transcription and repair. In budding yeast, deletion of RPB9 causes several phenotypes such as slow growth and temperature sensitivity. We found that simultaneous mutation of multiple N-terminal lysines within histone H3 was lethal in rpb9Delta cells. Our results indicate that hypoacetylation of H3 leads to inefficient repair of DNA double-strand breaks, while activation of the DNA damage checkpoint regulators gammaH2A and Rad53 is suppressed in Rpb9-deficient cells. Combination of H3 hypoacetylation with the loss of Rpb9 leads to genomic instability, aberrant segregation of chromosomes in mitosis, and eventually to cell death. These results indicate that H3 acetylation becomes essential for efficient DNA repair and cell survival if a DNA damage checkpoint is defective. PMID- 29440684 TI - Characterization of 111In-labeled Glucose-Dependent Insulinotropic Polypeptide as a Radiotracer for Neuroendocrine Tumors. AB - Somatostatin receptor targeting is considered the standard nuclear medicine technique for visualization of neuroendocrine tumors (NET). Since not all NETs over-express somatostatin receptors, the search for novel targets, visualizing these NETs, is ongoing. Many NETs, expressing low somatostatin receptor levels, express glucose-dependent insulinotropic polypeptide (GIP) receptors (GIPR). Here, we evaluated the performance of [Lys37(DTPA)]N-acetyl-GIP1-42, a newly synthesized GIP analogue to investigate whether NET imaging via GIPR targeting is feasible. Therefore, [Lys37(DTPA)]N-acetyl-GIP1-42 was radiolabeled with 111In with specific activity up to 1.2 TBq/umol and both in vitro and in vivo receptor targeting properties were examined. In vitro, [Lys37(111In-DTPA)]N-acetyl-GIP1-42 showed receptor-mediated binding to BHK-GIPR positive cells, NES2Y cells and isolated islets. In vivo, both NES2Y and GIPR-transfected BHK tumors were visualized on SPECT/CT. Furthermore, co-administration of an excess unlabeled GIP1-42 lowered tracer uptake from 0.7 +/- 0.2%ID/g to 0.6 +/- 0.01%ID/g (p = 0.78) in NES2Y tumors and significantly lowered tracer uptake from 3.3 +/- 0.8 to 0.8 +/- 0.2%ID/g (p = 0.0001) in GIPR-transfected BHK tumors. In conclusion, [Lys37(111In-DTPA)]N-acetyl-GIP1-42 shows receptor-mediated binding in various models. Furthermore, both GIPR-transfected BHK tumors and NES2Y tumors were visible on SPECT/CT using this tracer. Therefore, [Lys37(111In-DTPA)]N-acetyl GIP1-42 SPECT seems promising for visualization of somatostatin receptor negative NETs. PMID- 29440685 TI - Next-generation sequencing from bulked segregant analysis identifies a dwarfism gene in watermelon. AB - Dwarfism is one of the most valuable traits in watermelon breeding mainly because of its contribution to yield as well as the decreased labor required to cultivate and harvest smaller plants. However, the underlying genetic mechanism is unknown. In this study, a candidate dwarfism gene was identified by applying next generation sequencing technology to analyze watermelon plants. We completed a whole-genome re-sequencing of two DNA bulks (dwarf pool and vine pool) generated from plants in an F2 population. A genome-wide analysis of single nucleotide polymorphisms resulted in the detection of a genomic region harboring the candidate dwarfism gene Cla010726. The encoded protein was predicted to be a gibberellin 20-oxidase-like protein, which is a well-known "green revolution" protein in other crops. A quantitative real-time PCR investigation revealed that the Cla010726 expression level was significantly lower in the dwarf plants than in the normal-sized plants. The SNP analysis resulted in two SNP locating in the Cla010726 gene promoter of dsh F2 individuals. The results presented herein provide preliminary evidence that Cla010726 is a possible dwarfism gene. PMID- 29440686 TI - araGWAB: Network-based boosting of genome-wide association studies in Arabidopsis thaliana. AB - Genome-wide association studies (GWAS) have been applied for the genetic dissection of complex phenotypes in Arabidopsis thaliana. However, the significantly associated single-nucleotide polymorphisms (SNPs) could not explain all the phenotypic variations. A major reason for missing true phenotype associated loci is the strict P-value threshold after adjustment for multiple hypothesis tests to reduce false positives. This statistical limitation can be partly overcome by increasing the sample size, but at a much higher cost. Alternatively, weak phenotype-association signals can be boosted by integrating other types of data. Here, we present a web application for network-based Arabidopsis genome-wide association boosting-araGWAB-which augments the likelihood of association with the given phenotype by integrating GWAS summary statistics (SNP P-values) and co-functional gene network information. The integration utilized the inherent values of SNPs with subthreshold significance, thus substantially increasing the information usage of GWAS data. We found that araGWAB could more effectively retrieve genes known to be associated with various phenotypes relevant to defense against bacterial pathogens, flowering time regulation, and organ development in A. thaliana. We also found that many of the network-boosted candidate genes for the phenotypes were supported by previous publications. The araGWAB is freely available at http://www.inetbio.org/aragwab/ . PMID- 29440687 TI - Reversible chromism of spiropyran in the cavity of a flexible coordination cage. AB - Confining molecules to volumes only slightly larger than the molecules themselves can profoundly alter their properties. Molecular switches-entities that can be toggled between two or more forms upon exposure to an external stimulus-often require conformational freedom to isomerize. Therefore, placing these switches in confined spaces can render them non-operational. To preserve the switchability of these species under confinement, we work with a water-soluble coordination cage that is flexible enough to adapt its shape to the conformation of the encapsulated guest. We show that owing to its flexibility, the cage is not only capable of accommodating-and solubilizing in water-several light-responsive spiropyran-based molecular switches, but, more importantly, it also provides an environment suitable for the efficient, reversible photoisomerization of the bound guests. Our findings pave the way towards studying various molecular switching processes in confined environments. PMID- 29440688 TI - Unbalanced inflammatory reaction could increase tissue destruction and worsen skin infectious diseases - a comparative study of leishmaniasis and sporotrichosis. AB - The clinical presentations of skin diseases produced by different pathogens, as American tegumentary leishmaniasis (ATL) and sporotrichosis can be similar and possibly influenced by the skin immune system (SIS). The aim of the study was to understand the underlying mechanisms of skin inflammation produced by different pathogens. We used immunohistochemistry to analyze 96 patients: a- localized cutaneous leishmaniasis (LCL-ATL); b- sporotrichoid cutaneous leishmaniasis (SCL ATL); c-lymphocutaneous (LC-SP); d- fixed (F-SP) sporotrichosis. LCL-ATL and SCL ATL had a significantly higher percentage of CD8, FasL and NOS2 than sporotrichosis. In contrast, LC-SP had a substantially higher percentage of CD4, BCl2 and neutrophils than ATL lesions. These results indicated some differences in the profile of the in situ immune response suggesting that SIS is a complex, adaptable system capable of different responses to intracellular or extracellular pathogens. However, regardless of the etiological agents, the inflammatory reaction and clinical manifestations can be similar. SCL-ATL and LC-SP presented similarities in both clinical presentation and in situ inflammatory profile (CD3, CD22, neutrophils, macrophages). The clinical presentation of ATL and sporotrichosis could be explained by a combination of factors both of the host SIS and the etiological agent. The unbalanced host parasite relationship could result in atypical manifestations of skin disease. PMID- 29440689 TI - BiFC-based visualisation system reveals cell fusion morphology and heterokaryon incompatibility in the filamentous fungus Aspergillus oryzae. AB - Aspergillus oryzae is an industrially important filamentous fungus used for Japanese traditional food fermentation and heterologous protein production. Although cell fusion is important for heterokaryon formation and sexual/parasexual reproduction required for cross breeding, knowledge on cell fusion and heterokaryon incompatibility in A. oryzae is limited because of low cell fusion frequency. Therefore, we aimed to develop a BiFC system to specifically visualise fused cells and facilitate the analysis of cell fusion in A. oryzae. The cell fusion ability and morphology of 15 A. oryzae strains were investigated using heterodimerising proteins LZA and LZB fused with split green fluorescence protein. Morphological investigation of fused cells revealed that cell fusion occurred mainly as conidial anastomosis during the early growth stage. Self-fusion abilities were detected in most industrial A. oryzae strains, but only a few strain pairs showed non-self fusion. Protoplast fusion assay demonstrated that almost all the pairs capable of non-self fusion were capable of heterokaryon formation and vice versa, thus providing the first evidence of heterokaryon incompatibility in A. oryzae. The BiFC system developed in this study provides an effective method in studying morphology of fused cells and heterokaryon incompatibility in the filamentous fungal species with low cell fusion efficiency. PMID- 29440691 TI - Tracing ultrahigh-pressure metamorphism at the catchment scale. AB - Finding traces of ultrahigh-pressure (UHP) metamorphism in the geological record has huge implications for unravelling Earth's geodynamic evolution, such as the onset of deep subduction. Usually, UHP rocks are identified by specific mineral inclusions like coesite and characteristic petrographic features resulting from its (partial) transformation to the lower-pressure polymorph quartz in thin sections of crystalline rocks. This approach relies on very small sample size and is thus limited to a few points within large regions. Here we present the first findings of coesite inclusions in detrital mineral grains. The intact monomineralic inclusions were detected in garnets from a modern sand sample from the Western Gneiss Region, SW Norway. They represent the first known intact monomineralic coesite inclusions in the Western Gneiss Region, and their presence is suggested to indicate the erosion of UHP rocks in the sampled catchment area. The novel approach introduced here allows for tracing UHP metamorphic rocks and their erosional products at the catchment scale instead of being limited to outcrops of crystalline rocks. It opens new avenues for the prospective exploration of UHP metamorphism in Earth's geological record. PMID- 29440690 TI - Synthetic Whole-Cell Biodevices for Targeted Degradation of Antibiotics. AB - Synthetic biology enables infinite possibilities in biotechnology via employing genetic modules. However, not many researches have explored the potentials of synthetic biology in environmental bioprocesses. In this study, we introduced a genetic module harboring the codon-optimized tetracycline degrading gene, tetX.co, into the model host, Escherichia coli, and generated a prototypal whole cell biodevice for the degradation of a target antibiotic. Our results suggested that E. coli with the tetX.co-module driven by either the PJ23119 or PBAD promoters conferred resistance up to 50 MUg/mL of tetracycline and degrades over 95% of tetracycline within 24 h. The detoxification ability of tetX was further verified in conditioned media by typical E. coli K-12 and B strains as well as Shewanella oneidensis. Our strategy demonstrated the feasibility of introducing genetic modules into model hosts to enable environmental functions, and this work will inspire more environmental innovations through synthetic biological devices. PMID- 29440692 TI - Half metal phase in the zigzag phosphorene nanoribbon. AB - Exploring half-metallic nanostructures is a crucial solution for developing high performance spintronic devices. Black phosphorene is an emerging two-dimensional material possessing strong anisotropic band structure and high mobility. Based on the first principles calculations, we investigated the electronic and magnetic properties of zigzag phosphorene nanoribbons (ZPNRs) with three different functionalization groups (OH/CN, OH/NO2, NH2/NO2) at the edges. We find that the interplay between edge functionalization and edge oxidation can induce the half metal phase in the ZPNRs, and the half metal phase can be controlled by the external transverse in-plane electric field and the proportion of the functional groups and edge oxidation. The results may pave a new way to construst nanoscale spintronic devices based on black phosphorene nanoribbons. PMID- 29440693 TI - New strategies for producing defect free SiGe strained nanolayers. AB - Strain engineering is seen as a cost-effective way to improve the properties of electronic devices. However, this technique is limited by the development of the Asarro Tiller Grinfeld growth instability and nucleation of dislocations. Two strain engineering processes have been developed, fabrication of stretchable nanomembranes by deposition of SiGe on a sacrificial compliant substrate and use of lateral stressors to strain SiGe on Silicon On Insulator. Here, we investigate the influence of substrate softness and pre-strain on growth instability and nucleation of dislocations. We show that while a soft pseudo-substrate could significantly enhance the growth rate of the instability in specific conditions, no effet is seen for SiGe heteroepitaxy, because of the normalized thickness of the layers. Such results were obtained for substrates up to 10 times softer than bulk silicon. The theoretical predictions are supported by experimental results obtained first on moderately soft Silicon On Insulator and second on highly soft porous silicon. On the contrary, the use of a tensily pre-strained substrate is far more efficient to inhibit both the development of the instability and the nucleation of misfit dislocations. Such inhibitions are nicely observed during the heteroepitaxy of SiGe on pre-strained porous silicon. PMID- 29440694 TI - Mutations in the Drosophila homolog of human PLA2G6 give rise to age-dependent loss of psychomotor activity and neurodegeneration. AB - Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disorder that typically begins within the first few years of life and leads to progressive impairment of movement and cognition. Several years ago, it was shown that >80% of patients with INAD have mutations in the phospholipase gene, PLA2G6. Interestingly, mutations in PLA2G6 are also causative in two other related neurodegenerative diseases, atypical neuroaxonal dystrophy and Dystonia parkinsonism. While all three disorders give rise to similar defects in movement and cognition, some defects are unique to a specific disorder. At present, the cellular mechanisms underlying PLA2G6-associated neuropathology are poorly understood and there is no cure or treatment that can delay disease progression. Here, we show that loss of iPLA2-VIA, the Drosophila homolog of PLA2G6, gives rise to age-dependent defects in climbing and spontaneous locomotion. Moreover, using a newly developed assay, we show that iPLA2-VIA mutants also display impairments in fine-tune motor movements, motor coordination and psychomotor learning, which are distinct features of PLA2G6-associated disease in humans. Finally, we show that iPLA2-VIA mutants exhibit increased sensitivity to oxidative stress, progressive neurodegeneration and a severely reduced lifespan. Altogether, these data demonstrate that Drosophila iPLA2-VIA mutants provide a useful model to study human PLA2G6-associated neurodegeneration. PMID- 29440695 TI - Combination of nutritional polyphenols supplementation with exercise training counteracts insulin resistance and improves endurance in high-fat diet-induced obese rats. AB - Separately, polyphenols and exercise are known to prevent insulin resistance (IR) but their combined curative effects on established obesity and IR require further investigation. Therefore, we compared the metabolic effects of a combination of exercise and grape polyphenols supplementation in obese IR rats with high-fat diet (EXOPP) to the effect of high-fat diet alone (HF) or with a nutritional supplementation of grape polyphenols (PP) or with endurance exercise (EXO) during 8 wks. We observed an improvement of systemic and skeletal muscle insulin sensitivity in EXO and EXOPP rats. EXOPP rats compared to HF rats presented a lower insulinemia and HOMA-IR with higher liver and muscle glycogen contents. Interestingly, EXOPP rats had a 68% enhanced endurance capacity compared to EXO rats with also a higher activation of AMPK compared to sedentary and EXO rats with increased lipid oxidation. Together, our results suggest that grape polyphenols supplementation combined with exercise has a synergistic effect by increasing muscle lipid oxidation and sparing glycogen utilization which thus enhances endurance capacity. Our data highlight that in cases of established obesity and IR, the combination of nutritional grape polyphenols supplementation and exercise heighten and intensify their individual metabolic effects. PMID- 29440696 TI - The Fate of a Hapten - From the Skin to Modification of Macrophage Migration Inhibitory Factor (MIF) in Lymph Nodes. AB - Skin (contact) allergy, the most prevalent form of immunotoxicity in humans, is caused by low molecular weight chemicals (haptens) that penetrate stratum corneum and modify endogenous proteins. The fate of haptens after cutaneous absorption, especially what protein(s) they react with, is largely unknown. In this study the fluorescent hapten tetramethylrhodamine isothiocyanate (TRITC) was used to identify hapten-protein conjugates in the local lymph nodes after topical application, as they play a key role in activation of the adaptive immune system. TRITC interacted with dendritic cells but also with T and B cells in the lymph nodes as shown by flow cytometry. Identification of the most abundant TRITC modified protein in lymph nodes by tandem mass spectrometry revealed TRITC modification of the N-terminal proline of macrophage migration inhibitory factor (MIF) - an evolutionary well-conserved protein involved in cell-mediated immunity and inflammation. This is the first time a hapten-modified protein has been identified in lymph nodes after topical administration of the hapten. Most haptens are electrophiles and can therefore modify the N-terminal proline of MIF, which has an unusually reactive amino group under physiological conditions; thus, modification of MIF by haptens may have an immunomodulating role in contact allergy as well as in other immunotoxicity reactions. PMID- 29440697 TI - Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila. AB - Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure. PMID- 29440698 TI - Gold Nanoparticles-enabled Efficient Dual Delivery of Anticancer Therapeutics to HeLa Cells. AB - Colloidal gold nanoparticles (AuNPs) are of interest as non-toxic carriers for drug delivery owing to their advanced properties, such as extensive surface-to volume ratio and possibilities for tailoring their charge, hydrophilicity and functionality through surface chemistries. To date, various biocompatible polymers have been used for surface decoration of AuNPs to enhance their stability, payloads capacity and cellular uptake. This study describes a facile one-step method to synthesize stable AuNPs loaded with combination of two anticancer therapeutics, -bleomycin and doxorubicin. Anticancer activities, cytotoxicity, uptake and intracellular localization of the AuNPs were demonstrated in HeLa cells. We show that the therapeutic efficacy of the nanohybrid drug was strongly enhanced by the active targeting by the nanoscale delivery system to HeLa cells with a significant decrease of the half-maximal effective drug concentration, through blockage of HeLa cancer cell cycle. These results provide rationale for further progress of AuNPs-assisted combination chemotherapy using two drugs at optimized effective concentrations which act via different mechanisms thus decreasing possibilities of development of the cancer drug resistance, reduction of systemic drug toxicity and improvement of outcomes of chemotherapy. PMID- 29440699 TI - Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling. AB - Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+. This was associated with enhanced vascular MR signaling. Norepinephrine (NE)-induced contraction was increased in arteries from db/db mice. These responses were attenuated in mice treated with canrenoate or fasudil. Db/db mice displayed hypertrophic remodeling and increased arterial stiffness, improved by MR blockade. Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Vascular hypercontractility in db/db mice was associated with increased myosin light chain phosphorylation and reduced expression of PKG 1alpha. Vascular RhoA/ROCK signaling and expression of pro-inflammatory and pro fibrotic markers were exaggerated in db/db mice, effects that were attenuated by MRA. Fasudil, but not MRA, improved vascular insulin sensitivity in db/db mice, evidenced by normalization of Irs1 phosphorylation. Our data identify novel pathways involving MR-RhoA/ROCK-PKG-1 that underlie vascular dysfunction and injury in diabetic mice. PMID- 29440700 TI - Age-related changes in the response of retinal structure, function and blood flow to pressure modification in rats. AB - Age-related changes to the balance between the pressure inside the eye (intraocular pressure, IOP) and the pressure inside the brain (intracranial pressure, ICP) can modify the risk of glaucoma. In this study, we consider whether the optic nerve in older rat eyes is more susceptible to acute IOP and ICP modification. We systematically manipulate both ICP and IOP and quantify their effects on ganglion cell function (electroretinography, ERG), optic nerve structure (optical coherence tomography, OCT) and retinal blood flow (Doppler OCT). We show that ganglion cell function in older eyes was more susceptible to a higher optic nerve pressure difference (ONPD = IOP - ICP). This age-related susceptibility could not be explained by poorer blood flow with elevated ONPD. Rather, as ONPD increased the retinal nerve fibre layer showed greater compression, and the retinal surface showed less deformation in older eyes. Our data suggest that age-related changes to connective tissues in and around the rat optic nerve make it less flexible, which may result in greater strain on ganglion cell axons. This may account for greater functional susceptibility to higher optic nerve pressure differences in older rat eyes. Further studies in a species with a well-developed lamina cribrosa are needed to determine the clinical importance of these observations. PMID- 29440701 TI - The burden, management rates and influencing factors of high blood pressure in a Chinese rural population: the Rural Diabetes, Obesity and Lifestyle (RuralDiab) study. AB - The aim of the present study was to examine the prevalence, awareness, treatment, control, and potentially influencing factors of high blood pressure (HBP) in Chinese rural adults based on a cross-sectional study. Using data from the Rural Diabetes, Obesity and Lifestyle (RuralDiab) study, a total of 30,834 participants aged 18-74 years were enrolled for the epidemiological study. The multivariate logistic regression model including all selected potentially influencing factors was carried out for the adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Overall, a total of 9872 individuals were diagnosed as HBP (32.02%) with substantial imparity between men and women (32.87% vs. 30.58%), and the corresponding age-standardized prevalence of HBP were 19.50% (20.94% in men and 18.85% in women). Among the HBP patients, 6654 were aware of the diagnosis (67.40%), 5391 were taking medication (54.61%), and 2572 had their blood pressure controlled (26.05%).The corresponding age-adjusted awareness, treatment, and control of HBP were 59.35%, 45.91%, and 23.87%, respectively, and the corresponding rates were higher in women than those in men. The age-specific prevalence and management rates of HBP displayed increased trends with aging in both sexes(P trend < 0.05). Aging, low level of education, unhealthy lifestyle, positive family history of hypertension, overweight, obesity, diabetes, and dyslipidemia were associated with the prevalence, awareness, treatment, and control of HBP. In conclusion, uncontrolled HBP was common with high prevalence in Chinese rural residents. Strengthening the primary prevention through lifestyle modifications is necessary for reducing the disease burden and improving the management rates of HBP. PMID- 29440702 TI - A fluidic device for the controlled formation and real-time monitoring of soft membranes self-assembled at liquid interfaces. AB - Membrane materials formed at the interface between two liquids have found applications in a large variety of technologies, from sensors to drug-delivery and catalysis. However, studying the formation of these membranes in real-time presents considerable challenges, owing to the difficulty of prescribing the location and instant of formation of the membrane, the difficulty of observing time-dependent membrane shape and thickness, and the poor reproducibility of results obtained using conventional mixing procedures. Here we report a fluidic device that facilitates characterisation of the time-dependent thickness, morphology and mass transport properties of materials self-assembled at fluid fluid interfaces. In the proposed device the membrane forms from the controlled coalescence of two liquid menisci in a linear open channel. The linear geometry and controlled mixing of the solutions facilitate real-time visualisation, manipulation and improve reproducibility. Because of its small dimensions, the device can be used in conjunction with standard microscopy methods and reduces the required volumes of potentially expensive reagents. As an example application to tissue engineering, we use the device to characterise interfacial membranes formed by supra-molecular self-assembly of peptide-amphiphiles with either an elastin-like-protein or hyaluronic acid. The device can be adapted to study self assembling membranes for applications that extend beyond bioengineering. PMID- 29440703 TI - The Model Structures of the Complement Component 5a Receptor (C5aR) Bound to the Native and Engineered hC5a. AB - The interaction of hC5a with C5aR, previously hypothesized to involve a "two site" binding, (i) recognition of the bulk of hC5a by the N-terminus (NT) of C5aR ("site1"), and (ii) recognition of C-terminus (CT) of hC5a by the extra cellular surface (ECS) of the C5aR ("site2"). However, the pharmacological landscapes of such recognition sites are yet to be illuminated at atomistic resolution. In the context, unique model complexes of C5aR, harboring pharmacophores of diverse functionality at the "site2" has recently been described. The current study provides a rational illustration of the "two-site" binding paradigm in C5aR, by recruiting the native agonist hC5a and engineered antagonist hC5a(A8). The hC5a C5aR and hC5a(A8)-C5aR complexes studied over 250 ns of molecular dynamics (MD) each in POPC bilayer illuminate the hallmark of activation mechanism in C5aR. The intermolecular interactions in the model complexes are well supported by the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) based binding free energy calculation, strongly correlating with the reported mutational studies. Exemplified in two unique and contrasting molecular complexes, the study provides an exceptional understanding of the pharmacological divergence observed in C5aR, which will certainly be useful for search and optimization of new generation "neutraligands" targeting the hC5a-C5aR interaction. PMID- 29440705 TI - Innovative lipid-based carriers containing cationic derivatives of polyisoprenoid alcohols augment the antihypertensive effectiveness of candesartan in spontaneously hypertensive rats. AB - Novel lipid-based carriers, composed of cationic derivatives of polyisoprenoid alcohols (amino-prenols, APrens) and 1,2-dioleoyl-sn-glycero-3 phosphatidylethanolamine (DOPE), were designed. The carriers, which were previously shown to be nontoxic to living organisms, were now tested if suitable for administration of candesartan, an antihypertensive drug. Spontaneously hypertensive rats (SHR) received injections of candesartan (0.1 mg/kg body weight per day; s.c.) in freshly prepared carriers for two weeks. The rats' arterial pressure was measured by telemetry. Urine and blood collection were performed in metabolic cages. In a separate group of SHR, the pharmacokinetics of the new formulation was evaluated after a single subcutaneous injection. The antihypertensive activity of candesartan administered in DOPE dispersions containing APrens was distinctly greater than that of candesartan dispersions composed of DOPE only or administered in the classic solvent (sodium carbonate). The pharmacokinetic parameters clearly demonstrated that candesartan in APren carriers reached the bloodstream more rapidly and in much greater concentration (almost throughout the whole observation) than the same drug administered in dispersions of DOPE only or in solvent. Serum creatinine (PCr) decreased significantly only in the group receiving candesartan in carriers with APrens (from 0.80 +/- 0.04 to 0.66 +/- 0.09 mg/dl; p < 0.05), whereas in the other groups PCr remained at the same level after treatment. Moreover, the new derivatives increased the loading capacity of the carriers, which is a valuable feature for any drug delivery system. Taken together, our findings led us to conclude that APrens are potentially valuable components of lipid-based drug carriers. PMID- 29440704 TI - Blood biomarkers of Hikikomori, a severe social withdrawal syndrome. AB - Hikikomori, a severe form of social withdrawal syndrome, is a growing social issue in Japan and internationally. The pathophysiology of hikikomori has not yet been elucidated and an effective treatment remains to be established. Recently, we revealed that avoidant personality disorder is the most common comorbidity of hikikomori. Thus, we have postulated that avoidant personality is the personality underpinning hikikomori. First, we herein show relationships between avoidant personality traits, blood biomarkers, hikikomori-related psychological features, and behavioural characteristics assessed by a trust game in non-hikikomori volunteers. Avoidant personality traits were negatively associated with high density lipoprotein cholesterol (HDL-C) and uric acid (UA) in men, and positively associated with fibrin degeneration products (FDP) and high sensitivity C reactive protein (hsCRP) in women. Next, we recruited actual individuals with hikikomori, and compared avoidant personality traits, blood biomarkers, and psychological features between individuals with hikikomori and age-matched healthy controls. Individuals with hikikomori had higher avoidant personality scores in both sexes, and showed lower serum UA levels in men and lower HDL-C levels in women compared with healthy controls. This is the first report showing possible blood biomarkers for hikikomori, and opens the door to clarify the underlying biological pathophysiology of hikikomori. PMID- 29440707 TI - Systematic assessment of the performance of whole-genome amplification for SNP/CNV detection and beta-thalassemia genotyping. AB - In this study, we aimed to assess the performance of two whole-genome amplification methods, multiple displacement amplification (MDA), and multiple annealing and looping-based amplification cycle (MALBAC), for beta-thalassemia genotyping and single-nucleotide polymorphism (SNP)/copy-number variant (CNV) detection using two DNA sequencing assays. We collected peripheral blood, cell lines, and discarded embryos, and carried out MALBAC and MDA on single-cell and five-cell samples. We detected and statistically analyzed differences in the amplification efficiency, positive predictive value, sensitivity, allele dropout (ADO) rate, SNPs, and CV values between the two methods. Through Sanger sequencing at the single-cell and five-cell levels, we showed that both the amplification rate and ADO rate of MDA were better than those using MALBAC, and the sensitivity and positive predictive value obtained from MDA were higher than those from MALBAC for beta-thalassemia genotyping. Using next-generation sequencing (NGS) at the single-cell level, we confirmed that MDA has better properties than MALBAC for SNP detection. However, MALBAC was more stable and homogeneous than MDA using low-depth NGS at the single-cell level for CNV detection. We conclude that MALBAC is the better option for CNV detection, while MDA is better suited for SNV detection. PMID- 29440706 TI - A homozygous NOP14 variant is likely to cause recurrent pregnancy loss. AB - Recurrent pregnancy loss is newly defined as more than two consecutive miscarriages. Recurrent pregnancy loss occurs in <5% of total pregnancies. The cause in approximately 40-60% of recurrent pregnancy loss cases remains elusive and must be determined. We investigated two unrelated Iranian consanguineous families with recurrent pregnancy loss. We performed exome sequencing using DNA from a miscarriage tissue and identified a homozygous NOP14 missense variant (c.[136C>G];[136C>G]) in both families. NOP14 is an evolutionally conserved protein among eukaryotes and is required for 18S rRNA processing and 40S ribosome biogenesis. Interestingly, in zebrafish, homozygous mutation of nop14 (possibly loss of function) resulting from retrovirus-mediated insertional mutagenesis led to embryonic lethality at 5 days after fertilization, mimicking early pregnancy loss in humans. Similarly, it is known that the nop14-null yeast is inviable. These data suggest that the homozygous NOP14 mutation is likely to cause recurrent pregnancy loss. Furthermore, this study shows that exome sequencing is very useful to determine the etiology of unsolved recurrent pregnancy loss. PMID- 29440708 TI - Differential role of FL-BID and t-BID during verotoxin-1-induced apoptosis in Burkitt's lymphoma cells. AB - The globotriaosylceramide Gb3 is a glycosphingolipid expressed on a subpopulation of germinal center B lymphocytes which has been recognized as the B cell differentiation antigen CD77. Among tumoral cell types, Gb3/CD77 is strongly expressed in Burkitt's lymphoma (BL) cells as well as other solid tumors including breast, testicular and ovarian carcinomas. One known ligand of Gb3/CD77 is Verotoxin-1 (VT-1), a Shiga toxin produced in specific E. coli strains. Previously, we have reported that in BL cells, VT-1 induces apoptosis via a caspase-dependent and mitochondria-dependent pathway. Yet, the respective roles of various apoptogenic factors remained to be deciphered. Here, this apoptotic pathway was found to require cleavage of the BID protein by caspase-8 as well as activation of two other apoptogenic proteins, BAK and BAX. Surprisingly however, t-BID, the truncated form of BID resulting from caspase-8 cleavage, played no role in the conformational changes of BAK and BAX. Rather, their activation occurred under the control of full length BID (FL-BID). Indeed, introducing a non cleavable form of BID (BID-D59A) into BID-deficient BL cells restored BAK and BAX activation following VT-1 treatment. Still, t-BID was involved along with FL-BID in the BAK-dependent and BAX-dependent cytosolic release of CYT C and SMAC/DIABLO from the mitochondrial intermembrane space: FL-BID was found to control the homo oligomerization of both BAK and BAX, likely contributing to the initial release of CYT C and SMAC/DIABLO, while t-BID was needed for their hetero-oligomerization and ensuing release amplification. Together, our results reveal a functional cooperation between BAK and BAX during VT-1-induced apoptosis and, unexpectedly, that activation of caspase-8 and production of t-BID were not mandatory for initiation of the cell death process. PMID- 29440709 TI - BRCA1 function in the intra-S checkpoint is activated by acetylation via a pCAF/SIRT1 axis. AB - Breast cancer associated gene 1 (BRCA1) function has been shown to be regulated by phosphorylation but the role of acetylation has not been determined. Therefore, we tested whether BRCA1 can be acetylated by the acetyltransferases P300/CBP-associated factor (pCAF), GCN5, and p300. p300 exhibited the highest level of BRCA1 acetylation; however, there was also a decrease in the total level of BRCA1. Therefore, we focused on pCAF and GCN5 because they both acetylated BRCA1 without affecting BRCA1 expression. Further analysis indicated that the acetylated form of BRCA1 is deacetylated by wild-type (WT) SIRT1, but not deacetylase mutant SIRT1, suggesting that SIRT1 is a specific deacetylase of BRCA1. We demonstrated that lysine 830 of BRCA1 is a preferential acetylation site by pCAF and tested its function in embryonic stem (ES) cells by changing lysine 830 to arginine using a transcription activator-like effector nuclease (TALEN) system. After exposure to DNA damage-inducing UV radiation, the viability of BRCA1 K830R mutant cells is greater than the WT ES cells. Further analysis using additional cell lines indicated that the BRCA1 K830R mutation impairs the intra-S checkpoint. Also, checkpoint kinase 1 (CHK1) phosphorylation was less in K830R cells as compared with WT cells after UV exposure. These data suggest that acetylation of BRCA1 on lysine 830 activates BRCA1 function at the intra-S checkpoint after DNA damage. PMID- 29440710 TI - CLINICAL POSTERS P-019 to P-123. PMID- 29440711 TI - NURSING POSTERS P-126 to P-131. PMID- 29440714 TI - POSTERS OF DISTINCTION P-001 to P-018. PMID- 29440712 TI - PEDIATRIC POSTERS P-124 to P-125. PMID- 29440715 TI - Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer. AB - Metabolism of cancer cells is characterized by aerobic glycolysis, or the Warburg effect. Aerobic glycolysis reduces pyruvate flux into mitochondria, preventing a complete oxidation of glucose and shunting glucose to anabolic pathways essential for cell proliferation. Here we tested a new strategy, mitochondrial uncoupling, for its potential of antagonizing the anabolic effect of aerobic glycolysis and for its potential anticancer activities. Mitochondrial uncoupling is a process that facilitates proton influx across the mitochondrial inner membrane without generating ATP, stimulating a futile cycle of acetyl- CoA oxidation. We tested two safe mitochondrial uncouplers, NEN (niclosamide ethanolamine) and oxyclozanide, on their metabolic effects and anti-cancer activities. We used metabolomic NMR to examine the effect of mitochondrial uncoupling on glucose metabolism in colon cancer MC38 cells. We further tested the anti-cancer effect of NEN and oxyclozanide in cultured cell models, APCmin/+ mouse model, and a metastatic colon cancer mouse model. Using a metabolomic NMR approach, we demonstrated that mitochondrial uncoupling promotes pyruvate influx to mitochondria and reduces various anabolic pathway activities. Moreover, mitochondrial uncoupling inhibits cell proliferation and reduces clonogenicity of cultured colon cancer cells. Furthermore, oral treatment with mitochondrial uncouplers reduces intestinal polyp formation in APCmin/+ mice, and diminishes hepatic metastasis of colon cancer cells transplanted intrasplenically. Our data highlight a unique approach for targeting cancer cell metabolism for cancer prevention and treatment, identified two prototype compounds, and shed light on the anti-cancer mechanism of niclosamide. PMID- 29440716 TI - Publisher Correction: The impact of endothermy on the climatic niche evolution and the distribution of vertebrate diversity. AB - In the version of this Article originally published, in Fig. 3a the first boundary was incorrectly labelled the "K/T boundary"; it should have read the "K/Pg boundary". The two equations in the main text were incorrectly omitted from the HTML. In the description of the posterior distribution of an ancestral state, the normal distribution was incorrectly described as being "assigned as prior to the node value"; it should have read "assigned as calibration to the node value". In the associated equation (the second equation in the text), the denominator of the last term was incorrectly given as "Node prior"; it should have read "Node calibration". In the same equation, the numerator of the third term on the right hand side of the equation contained incorrect superscript notation on the x and this is shown in the full equation in the notice below.In the Acknowledgements, the following two sentences were incorrectly omitted: "The authors thank the Vital-IT facilities of the Swiss Institute of Bioinformatics for the computational support" and "This work was funded by the University of Lausanne and the Swiss National Science Foundation (CRSIII3-147630) to N.S." In the Author contributions section, the first sentence was incorrectly given as "J.R. designed the study. J.R., N.S. and D. Silvestro designed the methodology and ran the analyses"; it should have read "J.R., D.S. and N.S. designed the study and the methodology". In the Supplementary Information, all three instances of the word "prior" were incorrect and should have read "calibration".These errors have now been corrected in all versions of the Article. PMID- 29440717 TI - Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina. AB - Retinal guanylate cyclase (RetGC) and guanylate cyclase activating proteins (GCAPs) play an important role during the light response in photoreceptor cells. Mutations in these proteins are linked to distinct forms of blindness. RetGC and GCAPs exert their role at the ciliary outer segment where phototransduction takes place. We investigated the mechanisms governing GCAP1 and GCAP2 distribution to rod outer segments by expressing selected GCAP1 and GCAP2 mutants as transient transgenes in the rods of GCAP1/2 double knockout mice. We show that precluding GCAP1 direct binding to RetGC (K23D/GCAP1) prevented its distribution to rod outer segments, while preventing GCAP1 activation of RetGC post-binding (W94A/GCAP1) did not. We infer that GCAP1 translocation to the outer segment strongly depends on GCAP1 binding affinity for RetGC, which points to GCAP1 requirement to bind to RetGC to be transported. We gain further insight into the distinctive regulatory steps of GCAP2 distribution, by showing that a phosphomimic at position 201 is sufficient to retain GCAP2 at proximal compartments; and that the bovine equivalent to blindness-causative mutation G157R/GCAP2 results in enhanced phosphorylation in vitro and significant retention at the inner segment in vivo, as likely contributing factors to the pathophysiology. PMID- 29440718 TI - Soil-borne fungi challenge the concept of long-term biochemical recalcitrance of pyrochar. AB - Pyrogenic organic matter (PyOM) is assumed to be biochemically recalcitrant, but recent studies indicated a quick decrease of PyOM in post-fire soils. Regardless erosion and abiotic degradation, microbial decomposition has been the explanation for this response, but no direct proof has been provided up to now. In the present study, we were able to demonstrate for the first time that the soil-borne fungus Fusarium oxysporum is not only colonizing the pore system of pyrochar (PyC) but is also involved in the degradation of its aromatic network. We showed that PyC not only stimulates microbial degradation of soil organic matter (SOM), but is also attacked and decomposed by microorganisms. Our observations are based on the chemical and morphological alterations of a sewage-sludge derived PyC produced at 600 degrees C after its amendment to a Calcic Cambisol by solid state 13C nuclear magnetic resonance spectroscopy, analytical pyrolysis, elemental analysis, field emission scanning electron microscopy and DNA-based analysis of the isolated fungi. We showed that biofilms detected in the PyC play an essential role in the degradation process. These results are indispensable for a reliable assessment of the carbon sequestration potential of PyC in soils but also for improving global C cycling models. PMID- 29440719 TI - Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis. AB - Preclinical models propose that the onset of psychosis is associated with hippocampal hyperactivity, thought to be driven by cortical GABAergic interneuron dysfunction and disinhibition of pyramidal neurons. Recent neuroimaging studies suggest that resting hippocampal perfusion is increased in subjects at ultra-high risk (UHR) for psychosis, but how this may be related to GABA concentrations is unknown. The present study used a multimodal neuroimaging approach to address this issue in UHR subjects. Proton magnetic resonance spectroscopy and pulsed continuous arterial spin labeling imaging were acquired to investigate the relationship between medial prefrontal (MPFC) GABA+ levels (including some contribution from macromolecules) and hippocampal regional cerebral blood flow (rCBF) in 36 individuals at UHR of psychosis, based on preclinical evidence that MPFC dysfunction is involved in hippocampal hyperactivity. The subjects were then clinically monitored for 2 years: during this period, 7 developed a psychotic disorder and 29 did not. At baseline, MPFC GABA+ levels were positively correlated with rCBF in the left hippocampus (region of interest analysis, p = 0.044 family-wise error corrected, FWE). This correlation in the left hippocampus was significantly different in UHR subjects who went on to develop psychosis relative to those who did not (p = 0.022 FWE), suggesting the absence of a correlation in the latter subgroup. These findings provide the first human evidence that MPFC GABA+ concentrations are related to resting hippocampal perfusion in the UHR state, and offer some support for a link between GABA levels and hippocampal function in the development of psychosis. PMID- 29440720 TI - Structure of prothrombin in the closed form reveals new details on the mechanism of activation. AB - The clotting factor prothrombin exists in equilibrium between closed and open conformations, but the physiological role of these forms remains unclear. As for other allosteric proteins, elucidation of the linkage between molecular transitions and function is facilitated by reagents stabilized in each of the alternative conformations. The open form of prothrombin has been characterized structurally, but little is known about the architecture of the closed form that predominates in solution under physiological conditions. Using X-ray crystallography and single-molecule FRET, we characterize a prothrombin construct locked in the closed conformation through an engineered disulfide bond. The construct: (i) provides structural validation of the intramolecular collapse of kringle-1 onto the protease domain reported recently; (ii) documents the critical role of the linker connecting kringle-1 to kringle-2 in stabilizing the closed form; and (iii) reveals novel mechanisms to shift the equilibrium toward the open conformation. Together with functional studies, our findings define the role of closed and open conformations in the conversion of prothrombin to thrombin and establish a molecular framework for prothrombin activation that rationalizes existing phenotypes associated with prothrombin mutations and points to new strategies for therapeutic intervention. PMID- 29440722 TI - Abnormal optical anisotropy in correlated disorder KTa1-xNbxO3:Cu with refractive index gradient. AB - In this report, an abnormal optical anisotropy in KTa1-xNbxO3:Cu (Cu:KTN) crystals with refractive index gradient is presented. Contrary to general regulation in a cross-polarization setup, the transmitted intensity of both TE (horizontally polarized) and TM (vertically polarized) lasers aligned with the basic crystallographic directions can be modulated quasiperiodically. The mechanism is supposed to be based on the polarization induced by the temperature gradient and the refractive index gradient. Meanwhile, the correlated disorder property of the crystals in the range of the freezing temperature (Tf) and the intermediate temperature (T *) also plays an important role. With the results verified both theoretically and experimentally, we believe this work is not only beneficial for the development of the theory associated with the correlated disorder structures in relaxor ferroelectrics, but also significant for the exploitation of numerous optical functional devices. PMID- 29440721 TI - Salt-bridge modulates differential calcium-mediated ligand binding to integrin alpha1- and alpha2-I domains. AB - Integrins are transmembrane cell-extracellular matrix adhesion receptors that impact many cellular functions. A subgroup of integrins contain an inserted (I) domain within the alpha-subunits (alphaI) that mediate ligand recognition where function is contingent on binding a divalent cation at the metal ion dependent adhesion site (MIDAS). Ca2+ is reported to promote alpha1I but inhibit alpha2I ligand binding. We co-crystallized individual I-domains with MIDAS-bound Ca2+ and report structures at 1.4 and 2.15 A resolution, respectively. Both structures are in the "closed" ligand binding conformation where Ca2+ induces minimal global structural changes. Comparisons with Mg2+-bound structures reveal Mg2+ and Ca2+ bind alpha1I in a manner sufficient to promote ligand binding. In contrast, Ca2+ is displaced in the alpha2I domain MIDAS by 1.4 A relative to Mg2+ and unable to directly coordinate all MIDAS residues. We identified an E152-R192 salt bridge hypothesized to limit the flexibility of the alpha2I MIDAS, thus, reducing Ca2+ binding. A alpha2I E152A construct resulted in a 10,000-fold increase in Mg2+ and Ca2+ binding affinity while increasing binding to collagen ligands 20%. These data indicate the E152-R192 salt bridge is a key distinction in the molecular mechanism of differential ion binding of these two I domains. PMID- 29440723 TI - Publisher Correction: BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome. AB - In the version of this article initially published, Wendy Bickmore and Madapura Pradeepa were incorrectly not indicated as corresponding authors. The error has been corrected in the HTML and PDF versions of the paper. PMID- 29440724 TI - Magnetic resonance temporal diffusion tensor spectroscopy of disordered anisotropic tissue. AB - Molecular diffusion measured with diffusion weighted MRI (DWI) offers a probe for tissue microstructure. However, inferring microstructural properties from conventional DWI data is a complex inverse problem and has to account for heterogeneity in sizes, shapes and orientations of the tissue compartments contained within an imaging voxel. Alternative experimental means for disentangling the signal signatures of such features could provide a stronger link between the data and its interpretation. Double diffusion encoding (DDE) offers the possibility to factor out variation in compartment shapes from orientational dispersion of anisotropic domains by measuring the correlation between diffusivity in multiple directions. Time dependence of the diffusion is another effect reflecting the dimensions and distributions of barriers. In this paper we extend on DDE with a modified version of the oscillating gradient spin echo (OGSE) experiment, giving a basic contrast mechanism closely linked to both the temporal diffusion spectrum and the compartment anisotropy. We demonstrate our new method on post mortem brain tissue and show that we retrieve the correct temporal diffusion tensor spectrum in synthetic data from Monte Carlo simulations of random walks in a range of disordered geometries of different sizes and shapes. PMID- 29440725 TI - Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids. AB - Here we describe a method for fabricating a primary human Small Intestine-on-a Chip (Intestine Chip) containing epithelial cells isolated from healthy regions of intestinal biopsies. The primary epithelial cells are expanded as 3D organoids, dissociated, and cultured on a porous membrane within a microfluidic device with human intestinal microvascular endothelium cultured in a parallel microchannel under flow and cyclic deformation. In the Intestine Chip, the epithelium forms villi-like projections lined by polarized epithelial cells that undergo multi-lineage differentiation similar to that of intestinal organoids, however, these cells expose their apical surfaces to an open lumen and interface with endothelium. Transcriptomic analysis also indicates that the Intestine Chip more closely mimics whole human duodenum in vivo when compared to the duodenal organoids used to create the chips. Because fluids flowing through the lumen of the Intestine Chip can be collected continuously, sequential analysis of fluid samples can be used to quantify nutrient digestion, mucus secretion and establishment of intestinal barrier function over a period of multiple days in vitro. The Intestine Chip therefore may be useful as a research tool for applications where normal intestinal function is crucial, including studies of metabolism, nutrition, infection, and drug pharmacokinetics, as well as personalized medicine. PMID- 29440726 TI - A chemoenzymatic process for amide bond formation by an adenylating enzyme mediated mechanism. AB - Amide bond formation serves as a fundamental reaction in chemistry, and is practically useful for the synthesis of peptides, food additives, and polymers. However, current methods for amide bond formation essentially generate wastes and suffer from poor atom economy under harsh conditions. To solve these issues, we demonstrated an alternative synthesis method for diverse tryptophyl-N-alkylamides by the combination of the first adenylation domain of tyrocidine synthetase 1 with primary or secondary amines as nucleophiles. Moreover, the physiological role of this domain is L-phenylalanine adenylation; however, we revealed that it displayed broad substrate flexibility from mono-substituted tryptophan analogues to even D-tryptophan. To the best of our knowledge, this is the first evidence for an adenylating enzyme-mediated direct amide bond formation via a sequential enzymatic activation of amino acids followed by nucleophilic substitution by general amines. These findings facilitate the design of a promising tool for biocatalytic straightforward amide bond formation with less side products. PMID- 29440727 TI - Quantitative analysis of the methane gas emissions from municipal solid waste in India. AB - Increased emissions of greenhouse gases have altered the global ambient temperature and adversely affected global climatic conditions. The municipal solid waste (MSW) generated by households is considered the third largest anthropogenic source of methane (CH4) emissions, constituting 11% of all global CH4 emissions. The current study derived total MSW CH4 emission estimates using the IPCC default method (DM), modified triangular method (MTM) and first order decay method (FOD). The estimated CH4 emission was higher for the DM than the other methods, and was comparable to estimates from other studies. This study observed that the net annual emission of CH4 from landfills in India increased from 404 Gg in 1999-2000 to 990 Gg and 1084 Gg in 2011 and 2015, respectively. We also found that CH4 emissions were highly correlated (R2 = 0.8) with the gross state domestic product (GSDP) of states and the gross domestic product (GDP) of the country, which is an indicator of human well-being. The MSW management policy of India needs to be reviewed in a current policy context, as the management and efficient utilization of MSW technologies might help increase the use of CH4 as an energy source and thereby improve its sustainable and cost-effective management. PMID- 29440728 TI - Highly variable contractile performance correlates with myocyte content in trabeculae from failing human hearts. AB - Heart failure (HF) is defined by compromised contractile function and is associated with changes in excitation-contraction (EC) coupling and cardiomyocyte organisation. Tissue level changes often include fibrosis, while changes within cardiomyocytes often affect structures critical to EC coupling, including the ryanodine receptor (RyR), the associated protein junctophilin-2 (JPH2) and the transverse tubular system architecture. Using a novel approach, we aimed to directly correlate the influence of structural alterations with force development in ventricular trabeculae from failing human hearts. Trabeculae were excised from explanted human hearts in end-stage failure and immediately subjected to force measurements. Following functional experiments, each trabecula was fixed, sectioned and immuno-stained for structural investigations. Peak stress was highly variable between trabeculae from both within and between failing hearts and was strongly correlated with the cross-sectional area occupied by myocytes (MCSA), rather than total trabecula cross-sectional area. At the cellular level, myocytes exhibited extensive microtubule densification which was linked via JPH2 to time-to-peak stress. Trabeculae fractional MCSA variability was much higher than that in adjacent free wall samples. Together, these findings identify several structural parameters implicated in functional impairment in human HF and highlight the structural variability of ventricular trabeculae which should be considered when interpreting functional data. PMID- 29440729 TI - Enhanced nonlinear characteristics with the assistance of a [Formula: see text] symmetric trimer system. AB - We study the parity-time (PT) symmetry characteristics and the applications to nonlinear optics in an optical trimer system consisting of two indirectly coupled standing-mode micro-cavities and a two-level quantum emitter (QE) placed at the intersection of two cavities. We find this trimer system can exhibit analogical phenomena as those in typical [Formula: see text]-symmetric dimer systems composed of a passive cavity directly coupled to an active cavity. This system, whose [Formula: see text] symmetry is demonstrated by our analytic results, can be transformed between the [Formula: see text]-symmetric phase and the [Formula: see text]-broken phase by adjusting relevant system parameters. Then, with this system, we observe both the linear and nonlinear parts of the transmission field become remarkably enhanced and can further reach peak values around the [Formula: see text] breaking point. In addition, we show the negative correlation between the gain degree of the linear (nonlinear) transmission part and decay rate of the QE. This trimer proposal is feasible for experiments and may provide a promising platform for [Formula: see text]-symmetric optics of low-light levels. Moreover, novel phenomena arising from the QE-cavity-coupling induced nonlinearity gain could be explored to fabricate photonic devices and controllable nonlinear optical media for quantum information process and communication of photons. PMID- 29440730 TI - Analyzing the genes related to nicotine addiction or schizophrenia via a pathway and network based approach. AB - The prevalence of tobacco use in people with schizophrenia is much higher than in general population, which indicates a close relationship between nicotine addiction and schizophrenia. However, the molecular mechanism underlying the high comorbidity of tobacco smoking and schizophrenia remains largely unclear. In this study, we conducted a pathway and network analysis on the genes potentially associated with nicotine addiction or schizophrenia to reveal the functional feature of these genes and their interactions. Of the 276 genes associated with nicotine addiction and 331 genes associated with schizophrenia, 52 genes were shared. From these genes, 12 significantly enriched pathways associated with both diseases were identified. These pathways included those related to synapse function and signaling transduction, and drug addiction. Further, we constructed a nicotine addiction-specific and schizophrenia-specific sub-network, identifying 11 novel candidate genes potentially associated with the two diseases. Finally, we built a schematic molecular network for nicotine addiction and schizophrenia based on the results of pathway and network analysis, providing a systematic view to understand the relationship between these two disorders. Our results illustrated that the biological processes underlying the comorbidity of nicotine addiction and schizophrenia was complex, and was likely induced by the dysfunction of multiple molecules and pathways. PMID- 29440731 TI - Microarray profile of circular RNAs identifies hsa_circ_0014130 as a new circular RNA biomarker in non-small cell lung cancer. AB - Accumulating evidence has revealed that aberrant Circular RNAs (circRNAs) expression plays important roles in carcinogenesis and tumor progression. However, their role in non-small cell lung cancer (NSCLC) remains unclear. In this study, we first used circRNA microarrays to screen for tumour-specific circRNA candidates in between NSCLC (n = 3) and adjacent lung (n = 3) tissue. Among the circRNA expression profile, two circRNAs (hsa_circ_0014130 and hsa_circ_0016760) were selected for validation in ten pairs of NSCLC and adjacent non-cancerous tissues by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Only hsa_circ_0014130 exhibited significantly overexpressed in NSCLC tissues (P < 0.001), which were further confirmed in another 36 matched tissue samples using qRT-PCR. Hsa_circ_0014130 expression significantly correlated with TNM stage (P = 0.001) and lymphatic metastasis (P = 0.004). The area under the receiver operating characteristic curve was 0.878 (95% confidence interval = 0.804-0.951; P < 0.001), which showed good diagnostic potential. Bioinformatics platforms predicted that hsa_circ_0014130 might interact with five miRNAs and their corresponding mRNAs. Gene oncology analysis and pathway analysis revealed that hsa_circ_0014130 could participate in NSCLC development. In summary, our findings indicated that hsa_circ_0014130 could be used as a potential NSCLC biomarker and might be closely related to the carcinogenesis of NSCLC. PMID- 29440732 TI - Matrimid-JUC-62 and Matrimid-PCN-250 mixed matrix membranes displaying light responsive gas separation and beneficial ageing characteristics for CO2/N2 separation. AB - The performance of two generation-3 light-responsive metal-organic framework (MOF), namely JUC-62 and PCN-250, was investigated in a mixed matrix membrane (MMM) form. Both of them were incorporated inside the matrimid as the polymer matrix. Using our custom-designed membrane testing cell, it was observed that the MMMs showed up to 9% difference in CO2 permeability between its pristine and UV irradiated condition. This shows that the light-responsive ability of the light responsive MOFs could still be maintained. Thus, this finding is applicable in designing a smart material. Apart from that, the MMMs also has the potential to be applied for post-combustion carbon capture. At loadings up to 15 wt%, both CO2 permeability and CO2/N2 ideal selectivity could be significantly improved and surpassed the value exhibited by most of the MOF-matrimid MMM. Lastly the long term performance of the MMM was also evaluated and it was observed that both MMM could maintain their performance up to 1 month with only a slight decrease in CO2 permeability observed for 10 wt% PCN-250-matrimid. This study then opens up the possibility to fabricate a novel anti-aging multifunctional membrane material that is applicable as a smart material and also in post combustion carbon capture applications. PMID- 29440733 TI - Significant Volume Expansion as a Precursor to Ablation and Micropattern Formation in Phase Change Material Induced by Intense Terahertz Pulses. AB - With rapid advances occurring in terahertz (THz) radiation generation techniques, the interaction between matter and intense THz fields has become an important research topic. Among different types of THz radiation sources, the free electron laser (FEL) is a promising experimental tool that is expected to pave the way for new forms of material processing, control of phase transitions, and serve as a test bench for extreme operating conditions in high-speed small-size electrical and magnetic devices through the exploitation of strong THz electrical and magnetic fields without the presence of interband electronic excitation. In the current work, we irradiated Ge2Sb2Te5 phase change memory material with intense THz pulse trains from an FEL and observed THz-induced surface changes due to damage as a precursor to ablation and the formation of fine surface undulations whose spatial period is comparable to or slightly smaller than the wavelength of the excitation THz pulses in the material. The formation of undulations as well as the fact that no significant thermal effect was observed below the volume expansion threshold suggests that THz-induced effects mainly contributed to the observed changes. To the best of our knowledge, this is the first experimental observation of THz-induced undulations (so-called "LIPSS"), which are of potential importance for laser material processing. PMID- 29440734 TI - Dynamics of starvation and recovery predict extinction risk and both Damuth's law and Cope's rule. AB - The eco-evolutionary dynamics of species are fundamentally linked to the energetic constraints of their constituent individuals. Of particular importance is the interplay between reproduction and the dynamics of starvation and recovery. To elucidate this interplay, here we introduce a nutritional state structured model that incorporates two classes of consumers: nutritionally replete, reproducing consumers, and undernourished, nonreproducing consumers. We obtain strong constraints on starvation and recovery rates by deriving allometric scaling relationships and find that population dynamics are typically driven to a steady state. Moreover, these rates fall within a "refuge" in parameter space, where the probability of population extinction is minimized. We also show that our model provides a natural framework to predict steady state population abundances known as Damuth's law, and maximum mammalian body size. By determining the relative stability of an otherwise homogeneous population to a competing population with altered percent body fat, this framework provides a principled mechanism for a selective driver of Cope's rule. PMID- 29440735 TI - Structural basis of protein arginine rhamnosylation by glycosyltransferase EarP. AB - Protein glycosylation regulates many cellular processes. Numerous glycosyltransferases with broad substrate specificities have been structurally characterized. A novel inverting glycosyltransferase, EarP, specifically transfers rhamnose from dTDP-beta-L-rhamnose to Arg32 of bacterial translation elongation factor P (EF-P) to activate its function. Here we report a crystallographic study of Neisseria meningitidis EarP. The EarP structure contains two tandem Rossmann-fold domains, which classifies EarP in glycosyltransferase superfamily B. In contrast to other structurally characterized protein glycosyltransferases, EarP binds the entire beta-sheet structure of EF-P domain I through numerous interactions that specifically recognize its conserved residues. Thus Arg32 is properly located at the active site, and causes structural change in a conserved dTDP-beta-L-rhamnose-binding loop of EarP. Rhamnosylation by EarP should occur via an SN2 reaction, with Asp20 as the general base. The Arg32 binding and accompanying structural change of EarP may induce a change in the rhamnose-ring conformation suitable for the reaction. PMID- 29440736 TI - Toward a consistent modeling framework to assess multi-sectoral climate impacts. AB - Efforts to estimate the physical and economic impacts of future climate change face substantial challenges. To enrich the currently popular approaches to impact analysis-which involve evaluation of a damage function or multi-model comparisons based on a limited number of standardized scenarios-we propose integrating a geospatially resolved physical representation of impacts into a coupled human Earth system modeling framework. Large internationally coordinated exercises cannot easily respond to new policy targets and the implementation of standard scenarios across models, institutions and research communities can yield inconsistent estimates. Here, we argue for a shift toward the use of a self consistent integrated modeling framework to assess climate impacts, and discuss ways the integrated assessment modeling community can move in this direction. We then demonstrate the capabilities of such a modeling framework by conducting a multi-sectoral assessment of climate impacts under a range of consistent and integrated economic and climate scenarios that are responsive to new policies and business expectations. PMID- 29440737 TI - BEAM vs FEAM high-dose chemotherapy: retrospective study in lymphoma patients undergoing autologous stem cell transplant. PMID- 29440738 TI - Advantages of non-cryopreserved autologous hematopoietic stem cell transplantation against a cryopreserved strategy. AB - Autologous stem cell transplantation (auto-HSCT) is an effective treatment strategy for hematological malignancies. The standard mode of handling hematopoietic progenitors for the autologous procedure (CRYO) consists on its collection and freezing with dimethyl sulfoxide (DMSO) and its subsequent thawing and re-infusion. This process is toxic and expensive. Non-cryopreserved (non CRYO) is a less expensive mode of auto-HSCT. We designed a comparative study between both strategies performed in two different centers to analyze the short term complications. In total 111 auto-HSCT were performed from January/2015 to October/2016 (42 non-CRYO and 74 CRYO). There were 74 males and 69 (62%) patients had the underlying diagnosis of multiple myeloma. No differences were seen on the characteristics of the apheresis products and their viability. Engraftment was significantly faster in the non-CRYO group (p = 0.001). Febrile neutropenia and severe mucositis were lower in the non-CRYO group (40% vs 92% p = 0.0001 and 11% vs 64%, p = 0.001, respectively). In addition, length of hospitalization was 5 days shorter in the non-CRYO group (p = 0.0001). Overall responses and transplantation outcomes were similar. Our data demonstrate a clear advantage of the non-CRYO over CRYO auto-HSCT with faster engraftment, lower incidence of febrile neutropenia and shorter hospital stay after the transplantation procedure. These data are especially relevant for centers with high transplant activity or with limited resources. PMID- 29440739 TI - Pyroptosis induced by enterovirus 71 and coxsackievirus B3 infection affects viral replication and host response. AB - Enterovirus 71 (EV71) is the primary causative pathogen of hand, foot, and mouth disease (HFMD), affecting children with severe neurological complications. Pyroptosis is a programmed cell death characterized by cell lysis and inflammatory response. Although proinflammatory response has been implicated to play important roles in EV71-caused diseases, the involvement of pyroptosis in the pathogenesis of EV71 is poorly defined. We show that EV71 infection induced caspase-1 activation. Responding to the activation of caspase-1, the expression and secretion of both IL-1beta and IL-18 were increased in EV71-infected cells. The treatment of caspase-1 inhibitor markedly improved the systemic response of the EV71-infected mice. Importantly, caspase-1 inhibitor suppressed EV71 replication in mouse brains. Similarly, pyroptosis was activated by the infection of coxsackievirus B3 (CVB3), an important member of the Enterovirus genus. Caspase-1 activation and the increased expression of IL-18 and NLRP3 were demonstrated in HeLa cells infected with CVB3. Caspase-1 inhibitor also alleviated the overall conditions of virus-infected mice with markedly decreased replication of CVB3 and reduced expression of caspase-1. These results indicate that pyroptosis is involved in the pathogenesis of both EV71 and CVB3 infections, and the treatment of caspase-1 inhibitor is beneficial to the host response during enterovirus infection. PMID- 29440740 TI - Boston keratoprosthesis type 1: outcomes of the first 38 cases performed at Moorfields Eye Hospital. AB - PURPOSE: To evaluate outcomes of Boston keratoprosthesis type 1 (K-Pro) surgery in a cohort of high-risk patients at Moorfields Eye Hospital. Our patients were referred to us at the end-point of their ocular disease. METHODS: A retrospective review of all K-Pro surgery performed between March 2011 and July 2015 with a minimum follow-up of 12 months. RESULTS: 39 eyes of 38 patients were included. Mean follow-up was 28.4 months (range: 12-56). The main indication for surgery was bullous keratopathy from multiple failed grafts (56%). 26 cases (72.2%) had known posterior segment disease pre-operatively. Mean BCVA for the entire cohort (n = 39) initially improved from HM vision to 1/60 before returning to CF vision by 6 months and was maintained for the duration of follow-up. By final follow-up (n = 39), 46% had improved vision (1 line improvement in 10%; 2 lines or more in 36%) and 31% maintained pre-operative visual acuity. Anterior segment pathology was not an independent variable in visual outcome. However, absence of posterior segment disease was significant and performed best, improving from HM to 6/15 and maintaining that vision in the longer term. There were 13 (33%) cases of progressive glaucomatous optic neuropathy, 10 (26%) retinal detachments, 8 (21%) retroprosthetic membranes, 3 (8%) infective keratitis and 2 (5%) vitritis of which 1 progressed to endophthalmitis. In all, 3 (8%) had NPL vision and 4 (10%) required removal of the K-Pro. CONCLUSIONS: Implantation of the Boston K-Pro can lead to improved vision, with the main limiting factor being posterior segment pathology. PMID- 29440742 TI - Genomics: Next regeneration sequencing for reference genomes. PMID- 29440743 TI - Using partitioned heritability methods to explore genetic architecture. PMID- 29440741 TI - Ecology and genomics of an important crop wild relative as a prelude to agricultural innovation. AB - Domesticated species are impacted in unintended ways during domestication and breeding. Changes in the nature and intensity of selection impart genetic drift, reduce diversity, and increase the frequency of deleterious alleles. Such outcomes constrain our ability to expand the cultivation of crops into environments that differ from those under which domestication occurred. We address this need in chickpea, an important pulse legume, by harnessing the diversity of wild crop relatives. We document an extreme domestication-related genetic bottleneck and decipher the genetic history of wild populations. We provide evidence of ancestral adaptations for seed coat color crypsis, estimate the impact of environment on genetic structure and trait values, and demonstrate variation between wild and cultivated accessions for agronomic properties. A resource of genotyped, association mapping progeny functionally links the wild and cultivated gene pools and is an essential resource chickpea for improvement, while our methods inform collection of other wild crop progenitor species. PMID- 29440744 TI - Heritable contributions versus genetic architecture. PMID- 29440745 TI - Rapid removal of ammonium from domestic wastewater using polymer hydrogels. AB - To date, technologies to recover ammonium from domestic wastewater from the mainstream have not found widespread application. This is largely due to the low ammonium concentrations in these wastewater streams. This paper reports on the use of polymer hydrogels for rapid sorption of ammonium from domestic wastewater coupled with efficient regeneration by mild acid washing. The sorption capacity of the hydrogel was 8.8-32.2 mg NH4-N/g, which corresponds to removal efficiencies ranging from 68% to 80% NH4-N, increasing proportionally with the initial ammonium concentration. It was, however, unaffected by changes in pH, as the sorption capacity remained constant from pH 5.0-8.0. Importantly, effective regeneration of the hydrogels under mildly acidic conditions (i.e. pH 4.0) was demonstrated with minimal loss in sorption performance following multiple sorption/desorption cycles. Overall, this study highlights the potential of low cost polymer hydrogels for achieving mainstream ammonium recovery from domestic wastewater. PMID- 29440746 TI - Zinc ions have a potential to attenuate both Ni ion uptake and Ni ion-induced inflammation. AB - Nickel ions (Ni2+) are eluted from various metallic materials, such as medical devices implanted in human tissues. Previous studies have shown that Ni2+ enters inflammatory cells inducing inflammation. However, the regulation of Ni2+ uptake in cells has not yet been reported in detail. In the present study, we investigated the effects of various divalent cations on Ni2+ uptake and Ni2+ induced interleukin (IL)-8 production in the human monocytic cell line, THP-1. We demonstrated that ZnCl2, MnCl2, and CoCl2 inhibited the Ni2+ uptake, while CuCl2, FeCl2, MgCl2, and divalent metal transporter (DMT)-1 inhibitor, Chlorazol Black, did not. Furthermore, ZnCl2 inhibited Ni2+-induced IL-8 production, correlating with the inhibition of Ni2+ uptake. These results suggested that Ni2+ uptake occurred through Zn2+, Mn2+, and Co2+-sensitive transporters and that the inhibition of Ni2+ uptake resulted in the inhibition of IL-8 production. Furthermore, using an Ni wire-implanted mouse model, we found that Ni wire induced expression of mouse macrophage inflammatory protein-2 (MIP-2) and cyclooxygenase-2 (COX-2) mRNA in the skin tissue surrounding the wire were enhanced by low Zn conditions. These results suggested that the physiological concentration of Zn2+ modulates Ni2+ uptake by inflammatory cells, and a Zn deficient state might increase sensitivity to Ni. PMID- 29440747 TI - Direct measurement of superdiffusive energy transport in disordered granular chains. AB - Energy transport properties in heterogeneous materials have attracted scientific interest for more than half of a century, and they continue to offer fundamental and rich questions. One of the outstanding challenges is to extend Anderson theory for uncorrelated and fully disordered lattices in condensed-matter systems to physical settings in which additional effects compete with disorder. Here we present the first systematic experimental study of energy transport and localization properties in simultaneously disordered and nonlinear granular crystals. In line with prior theoretical studies, we observe in our experiments that disorder and nonlinearity-which individually favor energy localization-can effectively cancel each other out, resulting in the destruction of wave localization. We also show that the combined effect of disorder and nonlinearity can enable manipulation of energy transport speed in granular crystals. Specifically, we experimentally demonstrate superdiffusive transport. Furthermore, our numerical computations suggest that subdiffusive transport should be attainable by controlling the strength of the system's external precompression force. PMID- 29440749 TI - Publisher Correction: EphA2 is an epithelial cell pattern recognition receptor for fungal beta-glucans. AB - In the version of this Article originally published, technical problems led to errors in Figs. 2d and 5b. In the western blot panel in Fig. 2d, actin bands were misaligned at the bottom of the image and did not line up with the other bands in the panel; the corrected figure is shown below. In Fig. 5b, the upper right panel had an incorrect title of 'CXCL3/KC'; it should have instead been 'CXCL1/KC'. These errors have now been corrected in all versions of the Article. PMID- 29440748 TI - Structural properties of apolipoprotein A-I mimetic peptides that promote ABCA1 dependent cholesterol efflux. AB - Peptides mimicking the major protein of highdensity lipoprotein (HDL), apolipoprotein A-I (apoA-I), are promising therapeutics for cardiovascular diseases. Similar to apoA-I, their atheroprotective property is attributed to their ability to form discoidal HDL-like particles by extracting cellular cholesterol and phospholipids from lipid microdomains created by the ABCA1 transporter in a process called cholesterol efflux. The structural features of peptides that enable cholesterol efflux are not well understood. Herein, four synthetic amphipathic peptides denoted ELK, which only contain Glu, Leu, Lys, and sometimes Ala, and which have a wide range of net charges and hydrophobicities, were examined for cholesterol efflux. Experiments show that ELKs with a net neutral charge and a hydrophobic face that subtends an angle of at least 140 degrees are optimal for cholesterol efflux. All-atom molecular dynamics simulations show that peptides that are effective in promoting cholesterol efflux stabilize HDL nanodiscs formed by these peptides by the orderly covering of the hydrophobic acyl chains on the edge of the disc. In contrast to apoA-I, which forms an anti-parallel double belt around the HDL, active peptides assemble in a mostly anti-parallel "picket fence" arrangement. These results shed light on the efflux ability of apoA-I mimetics and inform the future design of such therapeutics. PMID- 29440751 TI - Identification of inorganic compounds in composite alum-treated wooden artefacts from the Oseberg collection. AB - Alum-treated wooden artefacts from the Oseberg collection display a great deal of morphological, structural and compositional inhomogeneity. Thus, an in-depth understanding of chemical processes underlying their degradation requires consideration of a variety of local environments. In addition to alum, sources of inorganic compounds include metal parts, corrosion products of which can migrate into the surrounding wood. In order to characterise the inorganic compounds a range of local environments, samples from several locations in a selection of composite objects have been investigated by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy and scanning electron microscopy (SEM)-energy dispersive X-ray spectroscopy (EDS). We have found that corrosion of iron rods used in reconstruction has formed iron(II) sulfates, which have migrated into the alum-treated wood to form sulfates containing combinations of potassium, aluminium, iron(II) and iron(III) cations. Reactions of alum were also evident from the presence of alunite in some samples. Areas with significant abundances of zinc sulfates, zinc sulfide and elemental sulfur were also detected. These results provide a first-time window into the complex array of inorganic species that can be present in such composite alum-treated objects. PMID- 29440750 TI - Publisher Correction: Enterotypes in the landscape of gut microbial community composition. AB - In the version of this Perspective originally published, the first and last name of co-author Manimozhiyan Arumugam were switched. This has now been corrected in all versions of the Perspective. PMID- 29440752 TI - One-step noninvasive prenatal testing (NIPT) for autosomal recessive homozygous point mutations using digital PCR. AB - Previously, we introduced a noninvasive prenatal testing (NIPT) protocol for diagnosing compound heterozygous autosomal recessive point mutations via maternal plasma DNA and simulated control genomic DNA sampling based on fetal DNA fraction. In our present study, we have improved our NIPT protocol to make it possible to diagnose homozygous autosomal recessive point mutations without the need to acquire fetal DNA fraction. Moreover, chi-squared test and empirical statistical range based on the proportion of mutant allele reads among the total reads served as the gatekeeping method. If this method yielded inconclusive results, then the Bayesian method was performed; final conclusion was drawn from the results of both methods. This protocol was applied to three families co segregating congenital sensorineural hearing loss with monogenic homozygous mutations in prevalent deafness genes. This protocol successfully predicted the fetal genotypes from all families without the information about fetal DNA fraction using one-step dPCR reactions at least for these three families. Furthermore, we suspect that confirmatory diagnosis under this protocol is possible, not only by using picodroplet dPCR, but also by using the more readily available chip-based dPCR, making our NIPT protocol more useful in the diagnosis of autosomal recessive point mutations in the future. PMID- 29440754 TI - The effect of TiO2 on nucleation and crystallization of a Li2O-Al2O3-SiO2 glass investigated by XANES and STEM. AB - Glass ceramics based on Li2O/Al2O3/SiO2 are of high economic importance, as they often show very low coefficients of thermal expansion. This enables a number of challenging applications, such as cooktop panels, furnace windows or telescope mirror blanks. Usually, the crystallization of the desired LAS crystal phases within the glasses must be tailored by a careful choice of crystallization schedule and type of nucleation agents to be used. The present work describes the formation of nanocrystalline TiO2 within an LAS base composition that contains solely TiO2 as nucleating agent. Using a combination of scanning transmission electron microscopy as well as X-ray absorption spectroscopy, it is found that a mixture of four- and six-fold coordinated Ti4+ ions exists already within the glass. Heating of the glass to 740 degrees C immediately changes this ratio towards a high content of six-fold coordinated Ti, which accumulates in liquid liquid phase-separation droplets. During the course of thermal treatment, these droplets eventually evolve into nanocrystalline TiO2 precipitations, in which Ti4+ is six-fold coordinated. Thus, it is shown that the nucleation of nanocrystalline TiO2 is initiated by a gradual re-arrangement of the Ti ions in the amorphous, glassy matrix, from a four-fold towards a six-fold coordination. PMID- 29440753 TI - In vivo GluCEST MRI: Reproducibility, background contribution and source of glutamate changes in the MPTP model of Parkinson's disease. AB - Glutamate Chemical Exchange Saturation Transfer (GluCEST) MRI is a recently developed technique to image glutamate. In the present study, we evaluated the reproducibility and background contamination to the GluCEST and source of the GluCEST changes in a mouse model of Parkinson's disease. Repeated measurements in five mice demonstrated an intra-animal coefficient of variation (CV) of GluCEST signal to be 2.3 +/- 1.3% and inter-animal CV of GluCEST to be 3.3 +/- 0.3%. Mice were treated with MPTP to create a localized striatal elevation of glutamate. We found an elevation in the GluCEST contrast of the striatum following MPTP treatment (Control: 23.3 +/- 0.8%, n = 16; MPTP: 26.2 +/- 0.8%, n = 19; p <= 0.001). Additionally, the positive association between glutamate concentration measured via 1H MRS and GluCEST signal was used to estimate background contribution to the measured GluCEST. The contribution of signal from non glutamate sources was found to be ~28% of the total GluCEST. Immunohistochemical analysis of the brain showed co-localization of glutamate with GFAP in the striatum. This suggests that the elevated glutamate present in the striatum in this mouse model reflects astroglial proliferation or reactivity due to the action of MPTP. The potential of GluCEST as a biomarker for imaging inflammation mediated gliosis is discussed. PMID- 29440755 TI - Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms. AB - Missense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot-Marie-Tooth disease. We recently identified MORC2 as an effector of epigenetic silencing by the human silencing hub (HUSH). Here we report the biochemical and cellular activities of MORC2 variants, alongside crystal structures of wild-type and neuropathic forms of a human MORC2 fragment comprising the GHKL-type ATPase module and CW-type zinc finger. This fragment dimerizes upon binding ATP and contains a hinged, functionally critical coiled coil insertion absent in other GHKL ATPases. We find that dimerization and DNA binding of the MORC2 ATPase module transduce HUSH-dependent silencing. Disease mutations change the dynamics of dimerization by distinct structural mechanisms: destabilizing the ATPase-CW module, trapping the ATP lid, or perturbing the dimer interface. These defects lead to the modulation of HUSH function, thus providing a molecular basis for understanding MORC2-associated neuropathies. PMID- 29440756 TI - Expression, Purification and Characterization of the Human Cannabinoid 1 Receptor. AB - The human cannabinoid 1 receptor (hCB1) is involved in numerous physiological processes and therefore provides a wide scope of potential therapeutic opportunities to treat maladies such as obesity, cardio-metabolic disorders, substance abuse, neuropathic pain, and multiple sclerosis. Structure-based drug design using the current knowledge of the hCB1 receptor binding site is limited and requires purified active protein. Heterologous expression and purification of functional hCB1 has been the bottleneck for ligand binding structural studies using biophysical methods such as mass spectrometry, x-ray crystallography and NMR. We constructed several plasmids for in-cell or in vitro Escherichia coli (E. coli) based expression of truncated and stabilized hCB1 receptor (hDeltaCB1 and hDeltaCB1T4L) variants and evaluated their competency to bind the CP-55,940 ligand. MALDI-TOF MS analysis of in vitro expressed and purified hDeltaCB1T4Lhis6 variants, following trypsin digestion, generated ~80% of the receptor sequence coverage. Our data demonstrate the feasibility of a cell-free expression system as a promising part of the strategy for the elucidation of ligand binding sites of the hCB1 receptor using a "Ligand Assisted Protein Structure" (LAPS) approach. PMID- 29440758 TI - Limited accuracy of conduction band effective mass equations for semiconductor quantum dots. AB - Effective mass equations are the simplest models of carrier states in a semiconductor structures that reduce the complexity of a solid-state system to Schrodinger- or Pauli-like equations resempling those well known from quantum mechanics textbooks. Here we present a systematic derivation of a conduction-band effective mass equation for a self-assembled semiconductor quantum dot in a magnetic field from the 8-band k . p theory. The derivation allows us to classify various forms of the effective mass equations in terms of a hierarchy of approximations. We assess the accuracy of the approximations in calculating selected spectral and spin-related characteristics. We indicate the importance of preserving the off-diagonal terms of the valence band Hamiltonian and argue that an effective mass theory cannot reach satisfactory accuracy without self consistently including non-parabolicity corrections and renormalization of k . p parameters. Quantitative comparison with the 8-band k . p results supports the phenomenological Roth-Lax-Zwerdling formula for the g-factor in a nanostructure. PMID- 29440757 TI - The Primodos components Norethisterone acetate and Ethinyl estradiol induce developmental abnormalities in zebrafish embryos. AB - Primodos was a hormone pregnancy test used between 1958-1978 that has been implicated with causing a range of birth defects ever since. Though Primodos is no longer used, it's components, Norethisterone acetate and Ethinyl estradiol, are used in other medications today including treatments for endometriosis and contraceptives. However, whether Primodos caused birth defects or not remains controversial, and has been little investigated. Here we used the developing zebrafish embryo, a human cell-line and mouse retinal explants to investigate the actions of the components of Primodos upon embryonic and tissue development. We show that Norethisterone acetate and Ethinyl estradiol cause embryonic damage in a dose and time responsive manner. The damage occurs rapidly after drug exposure, affecting multiple organ systems. Moreover, we found that the Norethisterone acetate and Ethinyl estradiol mixture can affect nerve outgrowth and blood vessel patterning directly and accumulates in the forming embryo for at least 24 hrs. These data demonstrate that Norethisterone acetate and Ethinyl estradiol are potentially teratogenic, depending on dose and embryonic stage of development in the zebrafish. Further work in mammalian model species are now required to build on these findings and determine if placental embryos also are affected by synthetic sex hormones and their mechanisms of action. PMID- 29440759 TI - A heading date QTL, qHD7.2, from wild rice (Oryza rufipogon) delays flowering and shortens panicle length under long-day conditions. AB - Heading date (HD) and panicle length (PL) are important traits that affect rice breeding and are controlled by pleiotropic genes. Some alleles associated with HD and PL from wild relatives might differ from those in cultivated rice. In this study, a main effect HD quantitative trait locus from wild rice, qHD7.2, was identified using a chromosomal segment substitution line (CSSL) population. First, qHD7.2 was determined to be located near RM172 on chromosome 7 based on association analysis of phenotype data from six environments and 181 polymorphic molecular markers. CSSL39, which has the latest flowering of all CSSLs and carries qHD7.2, was selected for further study, and qHD7.2 was narrowed to a 101.1-kb interval using a CSSL39/9311 F2 population. An OsPRR37-homologous gene was found within this region. The wild type allele delayed flowering and shortened PL under long-day conditions. The HD7.2, which was identified as a candidate gene for qHD7.2, transcript level was substantially higher than that in 9311. Our data showed that HD7.2 is likely a novel OsPRR37 allele. Sequence analysis revealed that OsPRR37 in cultivated rice had multiple origins, and natural variation in the coding domain sequence and promoter region contribute to flowering time diversity in cultivated rice. PMID- 29440760 TI - Repercussion of Solid state vs. Liquid state synthesized p-n heterojunction RGO copper phosphate on proton reduction potential in water. AB - The same copper phosphate catalysts were synthesized by obtaining the methods involving solid state as well as liquid state reactions in this work. And then the optimised p-n hybrid junction photocatalysts have been synthesized following the same solid/liquid reaction pathways. The synthesized copper phosphate photocatalyst has unique rod, flower, caramel-treat-like morphology. The Mott Schottky behavior is in accordance with the expected behavior of n-type semiconductor and the carrier concentration was calculated using the M-S analysis for the photocatalyst. And for the p-n hybrid junction of 8RGO-Cu3(PO4)2-PA (PA abbreviated for photoassisted synthesis method), 8RGO-Cu3(PO4)2-EG(EG abbreviated for Ethylene Glycol based synthesis method), 8RGO-Cu3(PO4)2-PEG (PEG abbreviated for Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol based synthesis method)the amount of H2 synthesized was 7500, 6500 and 4500 umol/h/g, respectively. The excited electrons resulting after the irradiation of visible light on the CB of p-type reduced graphene oxide (RGO) migrate easily to n-type Cu3(PO4)2 via. the p-n junction interfaces and hence great charge carrier separation was achieved. PMID- 29440761 TI - Intimate Partner Violence Correlates With A Higher HIV Incidence Among MSM: A 12 Month Prospective Cohort Study in Shenyang, China. AB - Intimate partner violence (IPV) and HIV are highly prevalent worldwide among MSM. However, the association between IPV and HIV seroconversion is virtually unknown. This 12-month prospective cohort study was conducted among MSM in Shenyang, China to explore the causality between IPV and the incidence of HIV. Adjusted Hazard Ratios (aHRs) of HIV acquisition were derived from a multivariate time-dependent Cox model and applied to calculate population attributable fractions (PAFs). Among 476 HIV-negative MSM subjects, 89(18.7%) reported being victims of IPV in the past 3 months (P3M). IPV was significantly correlated with lower education, having more condomless anal intercourse (CAI) and being depressed (each P < 0.05). The incidence of HIV among IPV victims was 11.3/100 PY compared to 3.8/100 PY in non-IPV-victims. Furthermore, IPV victimization was independently associated with HIV seroconversion (aHR = 4.1, PAF = 37.9%). Other predictors for seroconversion included non-local residence in Liaoning province (aHR = 3.9, PAF = 45.2%), engaging in condomless receptive anal intercourse (CRAI)(aHR = 3.1, PAF = 24.2%) or CAI with casual male partners (aHR = 3.8, PAF = 26.3%) in the P3M and syphilis infection (aHR = 4.7, PAF = 33.7%) (each P < 0.05). IPV increased the HIV seroconversion risk of MSM, with a high PAF. HIV prevention programs should integrate IPV screening and intervention, and MSM affected by IPV need to be preferentially enrolled in pre-exposure prophylaxis. PMID- 29440762 TI - Reliable charge assessment on encapsulated fragment for endohedral systems. AB - A simple scheme to determine charge distribution in endohedral complexes is suggested. It is based on comparison of inner-shell atomic orbital energies of the encapsulated species to the corresponding energies in reference systems with unambiguously defined charges on X. This robust approach is applied to endohedral borospherenes X@B39, for which the conventional schemes provide in some cases quite different results. Efficiency of proposed scheme also has been proven for typical fullerene based Sc3N@C80 endohedral complex. PMID- 29440763 TI - RHYTHM: An Open Source Imaging Toolkit for Cardiac Panoramic Optical Mapping. AB - Fluorescence optical imaging techniques have revolutionized the field of cardiac electrophysiology and advanced our understanding of complex electrical activities such as arrhythmias. However, traditional monocular optical mapping systems, despite having high spatial resolution, are restricted to a two-dimensional (2D) field of view. Consequently, tracking complex three-dimensional (3D) electrical waves such as during ventricular fibrillation is challenging as the waves rapidly move in and out of the field of view. This problem has been solved by panoramic imaging which uses multiple cameras to measure the electrical activity from the entire epicardial surface. However, the diverse engineering skill set and substantial resource cost required to design and implement this solution have made it largely inaccessible to the biomedical research community at large. To address this barrier to entry, we present an open source toolkit for building panoramic optical mapping systems which includes the 3D printing of perfusion and imaging hardware, as well as software for data processing and analysis. In this paper, we describe the toolkit and demonstrate it on different mammalian hearts: mouse, rat, and rabbit. PMID- 29440764 TI - Sperm selection by thermotaxis improves ICSI outcome in mice. AB - The ejaculate is a heterogeneous pool of spermatozoa containing only a small physiologically adequate subpopulation for fertilization. As there is no method to isolate this subpopulation, its specific characteristics are unknown. This is one of the main reasons why we lack effective tools to identify male infertility and for the low efficiency of assisted reproductive technologies. The aim of this study was to improve ICSI outcome by sperm selection through thermotaxis. Here we show that a specific subpopulation of mouse and human spermatozoa can be selected in vitro by thermotaxis and that this subpopulation is the one that enters the fallopian tube in mice. Further, we confirm that these selected spermatozoa in mice and humans show a much higher DNA integrity and lower chromatin compaction than unselected sperm, and in mice, they give rise to more and better embryos through intracytoplasmic sperm injection, doubling the number of successful pregnancies. Collectively, our results indicate that a high quality sperm subpopulation is selected in vitro by thermotaxis and that this subpopulation is also selected in vivo within the fallopian tube possibly by thermotaxis. PMID- 29440765 TI - Baicalin induces cellular senescence in human colon cancer cells via upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling. AB - Baicalin is a natural flavonoid glycoside which has potent anti-tumor and antioxidant activity in cancer cells. In the present study, we found that baicalin treatment significantly induced senescence in colon cancer cells. Furthermore, baicalin upregulated the expression of decidual protein induced by progesterone (DEPP) in HCT116 colon cancer cells, which accompanied with the activation of Ras/Raf/MEK/ERK and p16INK4A/Rb signaling pathways. Meanwhile, these phenomena also appeared under the anti-oxidation effect exerted by baicalin. In addition, ectopic expression of DEPP in HCT116 cells significantly induced the activity of senescence-associated beta-galactosidase (SA-beta-Gal) in tumor cells regulated by Ras/Raf/MEK/ERK signaling pathway. Knockdown of DEPP by RNA interference efficiently counteracted the baicalin-mediated growth inhibition, senescence and cell cycle arrest in cancer cells. Importantly, in a xenograft mouse model of human colon cancer, we further confirmed that baicalin treatment dramatically inhibited tumor growth, which was due to the induction of tumor cellular senescence via the upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling in vivo. In addition to baicalin treatment, we found that the hypoxia-response protein DEPP functions as a positive regulator involving the regulations of Ras/Raf/MEK/ERK signaling pathway and inhibition of human colon cancer by other anti-oxidative drugs, such as curcumin and sulforaphane, resulting in tumor cellular senescence. These results collectively suggest that baicalin upregulates the expression of DEPP and activates its downstream Ras/Raf/MEK/ERK and p16INK4A/Rb pathways by acting as an antioxidant, leading to senescence in colon cancer cells. PMID- 29440766 TI - A CNOT gate between multiphoton qubits encoded in two cavities. AB - Entangling gates between qubits are a crucial component for performing algorithms in quantum computers. However, any quantum algorithm must ultimately operate on error-protected logical qubits encoded in high-dimensional systems. Typically, logical qubits are encoded in multiple two-level systems, but entangling gates operating on such qubits are highly complex and have not yet been demonstrated. Here we realize a controlled NOT (CNOT) gate between two multiphoton qubits in two microwave cavities. In this approach, we encode a qubit in the high dimensional space of a single cavity mode, rather than in multiple two-level systems. We couple two such encoded qubits together through a transmon, which is driven by an RF pump to apply the gate within 190 ns. This is two orders of magnitude shorter than the decoherence time of the transmon, enabling a high fidelity gate operation. These results are an important step towards universal algorithms on error-corrected logical qubits. PMID- 29440767 TI - Candidate-gene based GWAS identifies reproducible DNA markers for metabolic pyrethroid resistance from standing genetic variation in East African Anopheles gambiae. AB - Metabolic resistance to pyrethroid insecticides is widespread in Anopheles mosquitoes and is a major threat to malaria control. DNA markers would aid predictive monitoring of resistance, but few mutations have been discovered outside of insecticide-targeted genes. Isofemale family pools from a wild Ugandan Anopheles gambiae population, from an area where operational pyrethroid failure is suspected, were genotyped using a candidate-gene enriched SNP array. Resistance-associated SNPs were detected in three genes from detoxification superfamilies, in addition to the insecticide target site (the Voltage Gated Sodium Channel gene, Vgsc). The putative associations were confirmed for two of the marker SNPs, in the P450 Cyp4j5 and the esterase Coeae1d by reproducible association with pyrethroid resistance in multiple field collections from Uganda and Kenya, and together with the Vgsc-1014S (kdr) mutation these SNPs explained around 20% of variation in resistance. Moreover, the >20 Mb 2La inversion also showed evidence of association with resistance as did environmental humidity. Sequencing of Cyp4j5 and Coeae1d detected no resistance-linked loss of diversity, suggesting selection from standing variation. Our study provides novel, regionally-validated DNA assays for resistance to the most important insecticide class, and establishes both 2La karyotype variation and humidity as common factors impacting the resistance phenotype. PMID- 29440768 TI - A meta-analysis of diffusion tensor imaging of substantia nigra in patients with Parkinson's disease. AB - Parkinson's disease (PD) is a common neurodegenerative disease characterized by severe, selective loss of pigmented neurons in the substantial nigra (SN). Previous studies have indicated that such loss could be detected by diffusion tensor imaging (DTI). Here, we try to consolidate current DTI data to both quantitatively determine the imaging changes in SN, as well as explore the potential use of DTI for PD diagnosis. Fourteen research articles are included in this meta-analysis, each obtained by searching PubMed, EMBASE, or Cochrane library database dated until July 2017. The articles contain 14 trials with 298 total PD patients and 283 healthy controls (HCs). The results show not only significantly lower FA values of SN in PD compared to that of HCs (WMD = -0.02, 95% CI = [-0.03, -0.02], p < 0.00001), but also a significantly higher MD in PD compared to HCs (WMD = 0.05, 95% CI = [0.03, 0.07], P < 0.0001). This indicates that the sharp difference detected between PD patients and HCs can be detected by DTI. By further analyzing the heterogeneity, we found that FA measurement of SN could be potentially used as a surrogate, noninvasive diagnostic marker toward PD diagnosis. PMID- 29440769 TI - Epithelial-mesenchymal transition (EMT) signature is inversely associated with T cell infiltration in non-small cell lung cancer (NSCLC). AB - Epithelial-mesenchymal transition (EMT) is able to drive metastasis during progression of multiple cancer types, including non-small cell lung cancer (NSCLC). As resistance to immunotherapy has been associated with EMT and immune exclusion in melanoma, it is important to understand alterations to T-cell infiltration and the tumor microenvironment during EMT in lung adenocarcinoma and squamous cell carcinoma. We conducted an integrated analysis of the immune landscape in NSCLCs through EMT scores derived from a previously established 16 gene signature of canonical EMT markers. EMT was associated with exclusion of immune cells critical in the immune response to cancer, with significantly lower infiltration of CD4 T-cells in lung adenocarcinoma and CD4/CD8 T-cells in squamous cell carcinoma. EMT was also associated with increased expression of multiple immunosuppressive cytokines, including IL-10 and TGF-beta. Furthermore, overexpression of targetable immune checkpoints, such as CTLA-4 and TIM-3 were associated with EMT in both NSCLCs. An association may exist between immune exclusion and EMT in NSCLC. Further investigation is merited as its mechanism is not completely understood and a better understanding of this association could lead to the development of biomarkers that could accurately predict response to immunotherapy. PMID- 29440770 TI - Anti-Helicobacter pylori activities of selected N-substituted cinnamamide derivatives evaluated on reference and clinical bacterial strains. AB - In this study, thirty-five N-substituted derivatives of cinnamic acid amide (cinnamamide) were evaluated for anti-Helicobacter pylori activity using an agar disc-diffusion method. Qualitative screening was performed on a reference H. pylori strain (ATCC 43504), resulting in the identification of the three most active compounds, 8 (R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2 enamide, minimal inhibitory concentration, MIC = 7.5 ug/mL), 23 ((2E)-3-(4 chlorophenyl)-N-(2-hydroxycyclohexyl)prop-2-enamide, MIC = 10 ug/mL), and 28 ((2E)-3-(4-chlorophenyl)-N-(4-oxocyclohexyl)prop-2-enamide, MIC = 10 ug/mL). These compounds were further tested on twelve well-characterized clinical strains, yielding MIC values that ranged from 10 to 1000 ug/mL. Preliminary safety assessments of the compounds were made using the MTT viability test for cytotoxicity and Ames test for mutagenicity, which showed them to be generally safe, although compounds 8 and 28 showed mutagenic activity at some of the tested concentrations. The results of this study showed the anti-H. pylori potential of cinnamamide derivatives. PMID- 29440771 TI - Combined aptamer and transcriptome sequencing of single cells. AB - The transcriptome and proteome encode distinct information that is important for characterizing heterogeneous biological systems. We demonstrate a method to simultaneously characterize the transcriptomes and proteomes of single cells at high throughput using aptamer probes and droplet-based single cell sequencing. With our method, we differentiate distinct cell types based on aptamer surface binding and gene expression patterns. Aptamers provide advantages over antibodies for single cell protein characterization, including rapid, in vitro, and high purity generation via SELEX, and the ability to amplify and detect them with PCR and sequencing. PMID- 29440772 TI - Electro-optic spatial decoding on the spherical-wavefront Coulomb fields of plasma electron sources. AB - Detections of the pulse durations and arrival timings of relativistic electron beams are important issues in accelerator physics. Electro-optic diagnostics on the Coulomb fields of electron beams have the advantages of single shot and non destructive characteristics. We present a study of introducing the electro-optic spatial decoding technique to laser wakefield acceleration. By placing an electro optic crystal very close to a gas target, we discovered that the Coulomb field of the electron beam possessed a spherical wavefront and was inconsistent with the previously widely used model. The field structure was demonstrated by experimental measurement, analytic calculations and simulations. A temporal mapping relationship with generality was derived in a geometry where the signals had spherical wavefronts. This study could be helpful for the applications of electro-optic diagnostics in laser plasma acceleration experiments. PMID- 29440773 TI - Reverse Engineering the Intracellular Self-Assembly of a Functional Mechanopharmaceutical Device. AB - Weakly basic, poorly soluble chemical agents could be exploited as building blocks for constructing sophisticated molecular devices inside the cells of living organisms. Here, using experimental and computational approaches, we probed the relationship between the biological mechanisms mediating lysosomal ion homeostasis and the self-assembly of a weakly basic small molecule building block (clofazimine) into a functional, mechanopharmaceutical device (intracellular Crystal-Like Drug Inclusions - "CLDIs") in macrophage lysosomes. Physicochemical considerations indicate that the intralysosomal stabilization of the self assembled mechanopharmaceutical device depends on the pHmax of the weakly basic building block and its affinity for chloride, both of which are consistent with the pH and chloride content of a physiological lysosomal microenvironment. Most importantly, in vitro and in silico studies revealed that high expression levels of the vacuolar ATPase (V-ATPase), irrespective of the expression levels of chloride channels, are necessary and sufficient to explain the cell-type dependent formation, stabilization, and biocompatibility of the self-assembled mechanopharmaceutical device within macrophages. PMID- 29440774 TI - Water memory effects and their impacts on global vegetation productivity and resilience. AB - Memory effects refer to the impacts of antecedent climate conditions on current vegetation productivity. This temporal linkage has been found to be strong in arid and semi-arid regions. However, the dominant climatic factors that determine such patterns are still unclear. Here, we defined'water-memory effects' as the persistent effects of antecedent precipitation on the vegetation productivity for a given memory length (from 1 to up to 12 months). Based on satellite observations and climate data, we quantified the length of water-memory effects and evaluated the contributions of antecedent precipitation on current vegetation. Our results showed that vegetation productivity was highly dependent on antecedent precipitation in arid and semi-arid regions. The average length of water memory was approximately 5.6 months. Globally, water-memory effects could explain the geographical pattern and strength of memory effects, indicating that precipitation might be the dominant climatic factor determining memory effects because of its impact on water availability. Moreover, our results showed vegetation in regions with low mean annual precipitation or a longer water memory has lower engineering resilience (i.e. slower recovery rate) to disturbances. These findings will enable better assessment of memory effects and improve our understanding of the vulnerability of vegetation to climate change. PMID- 29440775 TI - Genetic defects in mtDNA-encoded protein translation cause pediatric, mitochondrial cardiomyopathy with early-onset brain disease. AB - This study aims to identify gene defects in pediatric cardiomyopathy and early onset brain disease with oxidative phosphorylation (OXPHOS) deficiencies. We applied whole-exome sequencing in three patients with pediatric cardiomyopathy and early-onset brain disease with OXPHOS deficiencies. The brain pathology was studied by MRI analysis. In consanguineous patient 1, we identified a homozygous intronic variant (c.850-3A > G) in the QRSL1 gene, which was predicted to cause abnormal splicing. The variant segregated with the disease and affected the protein function, which was confirmed by complementation studies, restoring OXPHOS function only with wild-type QRSL1. Patient 2 was compound heterozygous for two novel affected and disease-causing variants (c.[253G > A];[938G > A]) in the MTO1 gene. In patient 3, we detected one unknown affected and disease-causing variants (c.2872C > T) and one known disease-causing variant (c.1774C > T) in the AARS2 gene. The c.1774C > T variant was present in the paternal copy of the AARS2 gene, the c.2872C > T in the maternal copy. All genes were involved in translation of mtDNA-encoded proteins. Defects in mtDNA-encoded protein translation lead to severe pediatric cardiomyopathy and brain disease with OXPHOS abnormalities. This suggests that the heart and brain are particularly sensitive to defects in mitochondrial protein synthesis during late embryonic or early postnatal development, probably due to the massive mitochondrial biogenesis occurring at that stage. If both the heart and brain are involved, the prognosis is poor with a likely fatal outcome at young age. PMID- 29440776 TI - Improved estimation of SNP heritability using Bayesian multiple-phenotype models. AB - Linear mixed models (LMM) are widely used to estimate narrow sense heritability explained by tagged single-nucleotide polymorphisms (SNPs). However, those estimates are valid only if large sample sizes are used. We propose a Bayesian covariance component model (BCCM) that takes into account the genetic correlation among phenotypes and genetic correlation among individuals. The use of the BCCM allows us to circumvent issues related to small sample sizes, including overfitting and boundary estimates. Using expression of genes in breast cancer pathway, obtained from the Multiple Tissue Human Expression Resource (MuTHER) project, we demonstrate a significant improvement in the accuracy of SNP-based heritability estimates over univariate and likelihood-based methods. According to the BCCM, except CHURC1 (h2 = 0.27, credible interval = (0.2, 0.36)), all tested genes have trivial heritability estimates, thus explaining why recent progress in their eQTL identification has been limited. PMID- 29440777 TI - Views of rare disease participants in a UK whole-genome sequencing study towards secondary findings: a qualitative study. AB - With large-scale genome sequencing initiatives underway, vast amounts of genomic data are being generated. Results-including secondary findings (SF)-are being returned, although policies around generation and management remain inconsistent. In order to inform relevant policy, it is essential that the views of stakeholders be considered-including participants who have made decisions about SF since the wider debate began. We conducted semi-structured interviews with sixteen rare disease patients and parents enroled in genome sequencing to explore views towards SF. Informed by extensive contact with the healthcare system, interviewees demonstrated high levels of understanding of genetic testing and held pragmatic views: many are content not knowing SF. Interviewees expressed trust in the system and healthcare providers, as well as an appreciation of limited resources; acknowledging existing disease burden, many preferred to focus on their primary condition. Many demonstrated an expectation for recontact and assumed the possibility of later access to initially declined SF. In the absence of such an infrastructure, it is important that responsibilities for recontact are delineated, expectations are addressed, and the long-term impact of decisions is made clear during consent. In addition, some interviewees demonstrated fluid views towards SF, and suggestions were made that perceptions may be influenced by family history. Further research into the changing desirability of SF and behavioural impact of disclosure are needed, and the development and introduction of mechanisms to respond to changes in patient views should be considered. PMID- 29440778 TI - Autistic, Aberrant, and Food-Related Behaviors in Adolescents and Young Adults with Prader-Willi Syndrome: The Effects of Age and Genotype. AB - The effects of age and genotype were examined, with regard to the severity of aberrant, autistic, and food-related behaviors in Prader-Willi syndrome (PWS), with an emphasis on the contrast between adolescents and young adults. The Aberrant Behavior Checklist Japanese version (ABC-J), the Food Related Problem Questionnaire (FRPQ), and the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) were administered to 65 PWS patients, including 20 adolescents (ages 12 to 17) and 45 young adults (ages 18 to 29). Significant differences (Mann-Whitney U tests) were found in ABC-J (p = 0.004) and PARS (p = 0.021), with lower scores in adolescents than in young adults. While DEL subgroups showed no significant differences between the two age groups in ABC-J (p = 0.063) and PARS (p = 0.134), mUPD subgroups showed a statistically significant difference in terms of ABC-J (p = 0.007). No significant differences were found between adolescents and young adults, in terms of FRPQ (p = 0.163). These results suggest that aberrant and autistic behaviors follow a marked worsening trend from around the age of 18. On the other hand, food-related behaviors give no sign of change at this transitory stage. Young adults with mUPD were found to be significantly more severe than adolescents with mUPD, in terms of aberrant behaviors. PMID- 29440780 TI - An 8 mm pocket that wasn't 3 mm at one time...? PMID- 29440781 TI - Confronting challenges in post graduate admissions in our profession. PMID- 29440779 TI - Saquinavir Ameliorates Liver Warm Ischemia-Reperfusion-Induced Lung Injury via HMGB-1- and P38/JNK-Mediated TLR-4-Dependent Signaling Pathways. AB - Liver ischemia and reperfusion (I/R) induce local and distant tissue injuries, contributing to morbidity and mortality in a wider range of pathologies. This is especially seen under uncontrolled aseptic inflammatory conditions, leading to injury of remote organs, such as lung injury, and even failure. Saquinavir (SQV) is a kind of HIV protease inhibitor that possesses an anti-inflammatory property. In this study, we investigated whether SQV suppresses Toll-like receptor 4- (TLR4 ) dependent signaling pathways of high-mobility group box 1 (HMGB1) and P38/JNK, conferring protection against murine liver I/R-induced lung injury. To investigate our hypothesis, C57BL/6 mice and TLR4 knockout mice (TLR4-/-) were used to perform the study. SQV administration markedly attenuated remote lung tissue injury after 1-hour ischemia and 6-hour reperfusion of the liver. To our expectation, SQV attenuated I/R-induced lung edema, hyperpermeability, and pathological injury. The beneficial effects of SQV were associated with decreased levels of circulating and lung tissue inflammatory cytokines, such as IL-6, IL 1beta, TNF-alpha, and iNOS. The protective effect of SQV was also associated with decreased lung tissue expression of HMGB1, TLR-4, and p-P38/JNK, but not p-ERK in wild-type liver I/R mice. Overall, this study demonstrated a new role of SQV, facilitating negative regulation of HMGB1- and P38/JNK-mediated TLR-4-dependent signaling pathways, conferring protection against liver I/R-induced lung injury. PMID- 29440782 TI - Neutrophil priming: Implications in periodontal disease. AB - Periodontal disease is a well-regulated response to bacterial infection directed by the inflammatory cells of the host immune system. The host response to injury or insult is implicated to be a vital feature of the majority of periodontal diseases. The excessive activation of neutrophils plays a role in the pathogenesis in diseases such as acute respiratory distress syndrome, rheumatoid arthritis, and periodontitis by contributing to inflammatory tissue injury. In the recent times, there has been a shift of paradigm from a hypo- to hyper responsive/primed model of neutrophil dysfunction in periodontal etiopathogenesis. The aim of this review is to outline the mechanisms and effects of neutrophil priming, and thereafter, discuss the current controversy that exists regarding the role of primed neutrophils in periodontal etiopathogenesis. PMID- 29440783 TI - Comparative analysis of subgingival red complex bacteria in obese and normal weight subjects with and without chronic periodontitis. AB - Background: Obesity is one of the systemic conditions which influence the onset and progression of periodontal disease and it is stated that the metabolic changes associated with obesity may contribute to alteration in subgingival microbial flora. Aim: Our study was aimed to quantify and compare the red complex microorganisms in obese or overweight and normal weight participants with and without chronic periodontitis to identify obesity as a risk for the presence of red complex bacteria. Materials and Methods: The study group consisted of 120 participants of age between 20 and 45 years of both the sexes. According to periodontal status, the participants were categorized into four groups as follows: thirty overweight or obese individuals with generalized chronic periodontitis (Group I), thirty normal weight individuals with chronic periodontitis (Group II), thirty overweight or obese individuals with healthy periodontium (Group III), and thirty normal weight individuals with healthy periodontium (Group IV). After the assessment of periodontal parameters, subgingival plaque sample collection was carried out to quantify the red complex bacteria by real-time polymerase chain reaction. Results: Increase in red complex bacterial count was seen in group I compared to other groups. A positive correlation of red complex bacteria with body mass index and waist circumference was seen in Group I and III. Conclusion: In our study, obese individuals with periodontal disease harbored increased red complex bacteria. This states that the obesity could be a risk for the colonization of red complex microorganisms, which in turn may further lead to periodontal inflammation. PMID- 29440784 TI - Titanium particles in tissues from peri-implant mucositis: An exfoliative cytology-based pilot study. AB - Background: To evaluate the presence of titanium particles in the peri-implant mucosa of unloaded single implants. Materials and Methods: Forty participants with single unloaded implants were selected. They were divided equally into two groups: Group 1 with mild and Group 2 with moderate-to-severe peri-implant mucositis. Cytologic smears of peri-implant mucosa were obtained using cytobrush during second-stage surgery. Results: Study states that 60% of participants of Group 2 were positive for titanium particles in peri-implant cytology. Conclusion: This study concludes that the titanium particles might be the initiators of the inflammation around implant. PMID- 29440785 TI - Comparative histologic evaluation of titanium platelet-rich fibrin and platelet rich fibrin in hypertensive and smoker participants: A cell cytology study. AB - Introduction: In recent years, a growing interest has emerged with the use of platelet-rich products for the treatment of many clinical conditions in dentistry. Objective: The present study aimed to define the structural characteristics of titanium platelet-rich fibrin (TPRF) and PRF in hypertensive and smoker participants. Materials and Methods: Ten milliliters of blood samples was drawn using a syringe form ninety participants (healthy, hypertensive, and smokers). Five milliliters of blood was transferred to each of dry glass tube and titanium tube. The clot obtained after centrifugation from each tube was processed for light microscopy analysis. Results: The TPRF samples have demonstrated a highly organized and thicker fibrin network with continuous integrity as compared to PRF in healthy participants. The hypertensive and smokers showed less prominent fibrin border between the cellular structures in both the platelet concentrates, but sufficient fibrin mesh network was found in TPRF clot as compared to PRF clot in the test participants. Conclusion: This is the first human histologic study to define the fibrin meshwork in both TPRF and PRF clots in hypertensive and smokers. The platelet activation by titanium offered high characteristics to fibrin network. PMID- 29440786 TI - Effect of scaling and root planing on levels of 8-hydroxydeoxyguanosine in gingival crevicular fluid of chronic periodontitis patients with and without Type II diabetes mellitus. AB - Context: Chronic periodontitis (CP) and diabetes mellitus are associated with increased oxidative damage to DNA with formation of 8-hydroxydeoxyguanosine (8 OHdG). The aim of this study was to evaluate the change in gingival crevicular fluid (GCF) levels of 8-OHdG and glycosylated hemoglobin (HbA1c) by 3 months after scaling and root planing (SRP), in CP patients with and without Type II diabetes mellitus. Settings and Design: Sixteen patients with CP, 16 patients with CP and Type II diabetes mellitus (CP-D), and 16 systemically healthy individuals with clinically healthy periodontium who served as controls were included in the study. Materials and Methods: The clinical parameters (plaque index [PI], probing depth [PD], clinical attachment level [CAL], and bleeding on probing [BOP%]), HbA1c levels, and GCF 8-OHdG levels were measured at baseline. All the patients except controls were treated with SRP followed by evaluation of the above-mentioned clinical and biochemical parameters after 3 months. Statistical Analysis Used: Statistical analysis was performed using paired t test, independent t-test, and Mann-Whitney U-test. Results: After SRP, CP-D group showed a greater reduction in PI, PD, BOP%, and greater gain in CAL when compared to CP patients (P < 0.05). Levels of 8-OHdG and HbA1c in CP-D patients also showed a greater reduction, 3 months after SRP when compared to CP patients (P < 0.05). Conclusions: GCF 8-OHdG levels, HbA1c levels, and clinical parameters were reduced significantly in CP and CP-D patients, with maximum reduction achieved in CP-D patients 3 months after SRP. PMID- 29440787 TI - Submandibular fossa augmentation in implant dentistry. AB - Background: There are two limiting factors for determining the dental implant fixture length in mandibular posterior edentulous region: Inferior dental canal and submandibular fossa. Purpose: Submandibular fossa augmentation is a suggested way to overcome the problem of lingual undercut beneath the mylohyoid ridge in implant dentistry. Materials and Methods: Patients with lingual posterior bony undercut that interferes with the placement of a standard implant with a length of 10 mm were enrolled in this study. Results: This method was used for eight patients in 10 sites. Increased implant length and decreasing the chance of sublingual hematoma due to lingual cortical plate perforation are the results of this study. Conclusions: Submandibular fossa augmentation is a new technique to improve the maneuver of oral surgeons to increase dental implant length in the presence of deep lingual bony undercut. PMID- 29440788 TI - Effectiveness of erythrosine-mediated photodynamic antimicrobial chemotherapy on dental plaque aerobic microorganisms: A randomized controlled trial. AB - Background: Dental plaque is one of the predominant causes of major oral diseases. Although mechanical and chemical methods are extensively followed to control the development of plaque, plaque-related diseases still persist. Therefore, this necessitates for alternative measures of plaque control, one such alternative is photodynamic antimicrobial chemotherapy (PACT). Materials and Methods: Split mouth randomized clinical trial (CTRI/2017/03/008239) was conducted on 30 participants who reported to the hospital. Participants were asked to rinse their mouth for 1 min using 10 ml of 25 MUM erythrosine solutions. Same tooth on both quadrants of the same jaw are selected as the test and control. Intervention used was halogen-based composite curing light with wavelength of 500-590 nm. Plaque sample from the control tooth and test tooth was collected before and after exposure, respectively, and sent to microbiological laboratory for colony count. Results: Logarithmic mean and standard deviation of control group with 102 dilutions of aerobic microbial count were found to be 5.34 +/- 0.94, and for experimental group, it was 4.47 +/- 1.37. The statistical difference between mean CFU values between aerobic bacterial counts was significant (P = 0.006). Conclusions: Erythrosine-mediated PACT reduces the extent of dental plaque microbial count and has a potential preventive and therapeutic use in day-to-day life and dental clinics. PMID- 29440789 TI - A comparative evaluation of papillary reconstruction by modified Beagle's technique with the Beagle's surgical technique: A clinical and radiographic study. AB - Background: To assess and compare the effectiveness of two surgical procedures (Beagle's technique and modified Beagle's technique) for the reconstruction of the lost interproximal dental papilla. Materials and Methods: Twenty sites were selected based on the selection criteria which included patients within the age group of 20-50 years and the presence of Class I and Class II recession of the papilla in the maxillary anterior region. They were divided randomly into Group A and Group B. Group A sites were treated with modified Beagle's technique, whereas Group B sites were treated by the Beagle's technique. The patients were recalled at 1 week, 1 month, 3 months, and 6 months postsurgery. Parameters including classification of loss of papilla height (Nordland and Tarnow), change in vertical dimension, mesiodistal dimension and area of the papillary defect, and radiographic parameters (papilla height and bone crest-root apex distance) were recorded preoperatively and postoperatively. Results: At 6-month postsurgery, there was a statistically significant reduction in vertical dimension, mesiodistal dimension, and area of the papilla defect in Group A compared to Group B. At 6-month postsurgery, there was an increase in the height of the papilla in Group A, whereas there was a decrease in the height of the papilla in Group B. At 6-month postsurgery too, there was a reduction in the mean bone crest root apex distance in both groups. Conclusion: Thus, the modified Beagle's technique is an easy and effective technique when compared to the Beagle's surgical technique for papilla reconstruction. PMID- 29440790 TI - Subgingival prevalence rate of enteric rods in subjects with periodontal health and disease. AB - Background: The prevalence of enteric rods and their association with chronic periodontitis has gained prominence recently. Although the prevalence of these organisms from the subgingival plaque sample was reported in the literature, the carriage rate of these rods in our population is lacking. The present study was undertaken to know the carriage rate of enteric rods from our population in patients with periodontal health and disease. Materials and Methods: Eighty-four systemically healthy participants, inclusive of 46 males and 38 females, were selected for the study. The selected participants were subjected to a periodontal examination and were categorized into chronic periodontitis and healthy group. Subgingival plaque samples were taken from all the participants, plated onto McConkey agar plates, and incubated overnight at 37 degrees C to check for the growth of organisms. The grown organisms were then cultured according to the standard procedures. Results: Prevalence of 71% and 83% of enteric rods in subjects with periodontal health and disease, respectively, was found in our study which was not statistically significant. Conclusion: Although no significant differences exist in the prevalence of enteric rods between healthy and patients with chronic periodontitis, the prevalence rate of enteric rods in subgingival plaque samples is considerably high in our population. PMID- 29440791 TI - Obesity and oral health - Is there a link? An observational study. AB - Introduction: Periodontitis is defined as a destructive inflammatory disease involving the supporting tissues of the teeth due to specific microorganisms which results in a progressive destruction of supporting structures of the periodontium. Obesity is excessive body fat in proportion to lean body mass, to such an extent that health is impaired. Obesity, a serious public health problem, relates to a chronic low-grade systemic inflammation and is involved in the development of obesity-linked disorders including insulin resistance, type 2 diabetes, cardiovascular diseases, dyslipidemia, and metabolic syndrome. The accurate process whereby obesity can affect periodontal health is so far unclear. The aim of the present study was to evaluate the association between obesity (using body mass index [BMI] and waist circumference [WC]) and periodontal health and disease using various periodontal parameters. Materials and Methods: A total of 100 participants were randomly taken and were divided into two groups (fifty participants per group). The participants with BMI more than 30 were considered as obese and participants with BMI <30 were considered nonobese. WC was also measured. Gingival index (GI), pocket probing depth (PPD), gingival recession (REC), and clinical attachment level (CAL) were measured by a single examiner. Results: Independent t-test was performed to compare GI, probing depth, gingival recession, and clinical attachment level among obese and nonobese participants. The prevalence of periodontitis was significantly more in obese as compared to nonobese group (P < 0.05 for GI, P < 0.05 for PPD, and P < 0.031 for CAL). Conclusion: Strong correlation was found to exist between obesity and periodontitis. Obese participants could be at a greater risk of developing periodontal disease. PMID- 29440792 TI - Ancient schwannoma of gingiva - A rare case report. AB - Oral schwannomas (OSs) are rare benign tumors of oral cavity derived from peripheral nerve sheath, composed of proliferation of schwann cells in a characteristic pattern. AS are long-standing lesions which exhibit degenerative changes and atypia due to which they could be mistaken for malignancy. The mean age of occurrence of AS in oral cavity is 43 years, and no case of oral AS has been reported in a pediatric patient so far. Here, we present a rare case of AS of oral cavity in a 10-year-old male child. PMID- 29440793 TI - Use of an amniotic membrane as a novel barrier in a tooth with a questionable prognosis. AB - The chief goal of combination therapy using guided tissue regeneration along with bone grafts is to optimally and predictably regenerate the periodontal attachment apparatus. The evolution of regenerative therapy along with careful patient selection and treatment planning can have positive results even in cases which are not ideal. The present case report describes a tooth with a questionable prognosis treated successively by endodontic then periodontal therapy using an amniotic membrane along with a bone graft to treat an intrabony defect. The follow-up, 12 months later showed a resolution of the interradicular lesion and a radiographic bone fill. PMID- 29440794 TI - An innovative and less invasive management of recurrent pyogenic granuloma in the esthetic zone: A case report with 18-month follow-up. AB - Pyogenic granuloma (PG) is a nonneoplastic, tumor-like growth commonly seen in the oral mucosa or skin. Although nonpathological, its existence might lead to complications such as secondary infections or diastema formation. Hence, surgical removal of the growth seems mandatory. Histopathologic and radiographic evaluation is essential for accurate diagnosis and to rule out malignancy. A 28 year-old systemically healthy female patient reported with a swelling which involved the interdental space of maxillary left central and lateral incisors. The lesion initially developed as a "pimple-like" swelling and gradually increased in size over 2 years. It was managed in a novel method by reflecting a papilla preservation flap, excising the lesion from inside the flap till healthy tissue was visible, and then exposing to diode laser to prevent recurrence. Subsequent histopathologic examination confirmed the diagnosis of PG. This novel, less invasive esthetic procedure employed a papilla preservation flap and laser irradiation technique. This simple modification not only helped in healing by primary intention and producing a good esthetic outcome but also showed no recurrence till date. PMID- 29440795 TI - Root coverage of a wide anterior mucogingival defect with epithelial embossed connective tissue graft and its evaluation using root coverage esthetic scores. AB - New and innovative surgical techniques are necessary to help the clinician ensure the best results and satisfy patient's expectations. One such periodontal problem that has been challenging to the dental practitioners and impacts the oral health quality of life of patients has been gingival recession. When present anteriorly where esthetics is a major concern, patient centric parameters too become paramount. Root coverage esthetic score (RES) evaluation helps to keep the patient outcomes in mind. This case reports the successful treatment of a wide anterior mucogingival defect using epithelial embossed connective tissue graft which was evaluated for the first time using RES. PMID- 29440796 TI - Tobacco Pouch Keratosis in a young individual: A brief description. AB - Smokeless tobacco is used orally or nasally without burning tobacco. This is equally harmful as smokers due to the tobacco content and can cause oral cancer as well as systemic effects such as nicotinic dependence. Many other oral conditions have also been reported in association with smokeless tobacco. This paper presents features of tobacco pouch keratosis and aims to highlight the oral effects of smokeless tobacco, management, and guidelines for dentists in educating and counselling tobacco users. PMID- 29440797 TI - Reflective Practice in Palliative Care. PMID- 29440798 TI - Rural Palliative Care in North India: Rapid Evaluation of a Program Using a Realist Mixed Method Approach. AB - Context: Palliative care has not developed widely in rural North India. Since 2010, the Emmanuel Hospitals Association (EHA) has been developing a model of palliative care appropriate for this setting, based on teams undertaking home visits with the backup of outpatient and inpatient services. A project to further develop the model operated from 2012 to 2015 supported by funding from the UK. Aims: This study aims to evaluate the EHA palliative care project. Settings and Design: Rapid evaluation method using a mixed method realist approach at the five project hospital sites. Methods: An overview of the project was obtained by analyzing project documents and key informant interviews. Questionnaire data from each hospital were collected, followed by interviews with staff, patients, and relatives and observations of home visits and other activities at each site. Analysis: Descriptive analysis of quantitative and thematic analysis of qualitative data was undertaken. Each site was measured against the Indian Minimum Standards Tool for Palliative Care (IMSTPC). Results: Each team followed the EHA model, with local modifications. Services were nurse led with medical support. Eighty percent of patients had cancer. Staff demonstrated good palliative care skills and patients and families appreciated the care. Most essential IMSTPC markers were achieved but morphine licenses were available to only two teams. Remarkable synergy was emerging between palliative care and community health. Hospitals planned to fund palliative care through income from surgical services. Conclusions: Excellent palliative care appropriate for rural north India is delivered through the EHA model. It could be extended to other similar sites. PMID- 29440800 TI - Commentary. PMID- 29440799 TI - Is Every Life Worth Saving: Does Religion and Religious Beliefs Influence Paramedic's End-of-Life Decision-making? A Prospective Questionnaire-based Investigation. AB - Background: Paramedics, arriving on emergency cases first, have to make end-of life decisions almost on a daily basis. Faith shapes attitudes toward the meaning and worth of life itself and therefore influences decision-making. Objective: The objective of this study was to detect whether or not religious and spiritual beliefs influence paramedics in their workday life concerning end-of-life decisions, and whether it is legally possible for them to act according to their conscience. Methods and Design: This is a literature review of prior surveys on the topic using five key words and questionnaire-based investigation using a self administered online survey instrument. Settings/Participants: Paramedics all over Germany were given the opportunity to participate in this online questionnaire based study. Measurements: Two databases were searched for prior studies for literature review. Participants were asked about their religiosity, how it affects their work, especially in end-of-life situations, how experienced they are, and whether or not they have any legal latitude to withhold resuscitation. Results: A total of 429 paramedics answered the questionnaire. Religious paramedics would rather hospitalize a patient holding an advance directive than leave him/her at home (P = 0.036) and think death is less a part of life than the nonreligious (P = 0.001). Otherwise, the Spearman's rho correlation was statistically insignificant for all tests regarding resuscitation. Conclusions: The paramedic's religiosity is not the prime factor in his/her decision-making regarding resuscitation. PMID- 29440801 TI - A Retrospective Study of End-of-life Care Decisions in the Critically Ill in a Surgical Intensive Care Unit. AB - Aim: Progress in medical care and technology has led to patients with more advanced illnesses being admitted to the Intensive Care Unit (ICU). The practice of approaching end-of-life (EOL) care decisions and limiting care is well documented in Western literature but unknown in Singapore. We performed a retrospective cohort study to describe the practice of EOL care in patients dying in a Singapore surgical ICU (SICU). The surgical critical care population was chosen as it is unique because surgeons are frequently involved in the EOL process. Methods: All consecutive patients aged 21 and above admitted to the SICU from July 2011 to March 2012, and who passed away in the ICU or within 7 days of discharge from the ICU (to account for transferred patients out of the ICU after end-of life care decisions were made and subsequently passed away) were included in the study. Results: There were 473 SICU admissions during this period, out of which 53 were included with a mean age of 67.2 +/- 11.1 years. EOL discussions were held in 81.1% of patients with a median time from admission to first discussion at 1 day (IQR 0-2.75) and a median number of ICU discussion of 1 (IQR 1-2). As most patients lacked decision-making capacity (inability to retain and process information secondary to the underlying disease pathology or sedative use), a surrogate was involved: group decision in 27.9%, child in 25.6% and an unclear family nominated member in 20.9%. 28.3% of patients were managed as for full active with resuscitation, 39.6% nonescalation of care, and 32.1% for withdrawal. The main reasons for conservative management (nonescalation and withdrawal of care) were certain death in 52.3%, medical futility with minimal response to maximal care (27.3%), and the presence of underlying malignancy (18.2%). There was no significant difference between race or religion among patients for active or conservative management. Conclusion: 71.7% of patients who passed away in the ICU or within 7 days of discharge from the ICU were managed conservatively. More timely, EOL discussions and better advance care planning may be needed to improve our patient care for patients on conservative management. PMID- 29440802 TI - Patients with End-stage Oncologic and Nononcologic Disease in Emergency Service of an Urban Tertiary Hospital. AB - Context: In the last decades, patients with chronic terminal diseases have had more frequent visits to emergency services. Aims: This study aims to determine the proportion of terminal illness in patients readmitted to emergency room, to evaluate the use of this service and rate of death. Settings and Design: A cross sectional study in a tertiary hospital with 120 stretchers which annually reports 160 thousand attentions and 22 thousand admissions. Subjects and Methods: Included 18-year-old patients or older who were readmitted to emergency room. Patient and/or caregiver were interviewed; medical record was reviewed and made 1 year follow-up. Terminal cancer was determined by histologically confirmation in Stage IV and nononcologic terminal disease by total functional dependence (Katz index) or severe cognitive impairment (Pfeiffer questionnaire) in addition of advanced organ failure. Statistical Analysis Used: Fisher's exact and U of Mann Whitney tests for two independent samples. Results: Ninety-two (26%) of 349 were readmissions; 29 (36.7%) of 79 evaluated patients were identifying with terminal disease. Eleven (38%) of them had cancer (genitourinary in 64%). Nononcologic terminal disease was identified in 18 cases (62%) (Neurodegenerative involvement in 50%). More frequent symptoms were dyspnea 41%, mental confusion 24%, and pain 21%. Terminal patients had 6.2 (standard deviation 8.2) emergency visits at last year, being admitted 48,6% of these visits. Six-month mortality rate was 73 and 61% in oncologic and nononcolgic patients, respectively (P < 0.05). Conclusions: End-stage disease is frequent in readmitted patients to emergency, more of nononcologic kind. These patients use frequently emergency service, with high mortality (more elevated in oncologic). PMID- 29440803 TI - Comparison of Two Intervention Strategies on Prevention of Bedsores among the Bedridden Patients: A Quasi Experimental Community-based Trial. AB - Background: More than 80% of bedridden patients develop bedsores in home care settings. Training of informal caregivers can significantly affect the quality of care to these patients. Objective: The objective of this study is to compare the effectiveness of two caregiver training strategies on prevention of bedsores among bedridden patients. Methods: The study was carried out in Chandigarh. The study center was at PGIMER, Chandigarh. Seventy-eight bedridden patients being taken care in their homes were identified. These were randomly allocated into two groups. Group A received Prevention Package I, i.e., self-instruction Manual (SIM), training, and counseling. Group B received Prevention Package 2, i.e., only SIM. All these patients were followed up periodically for 1 year. During each follow-up, patients were observed for bedsore development. Braden scale was used to assess the risk factors of bedsores. Katz scale was used to evaluate the level of functional dependence of patients. Descriptive statistics was used to analyze the data. Results: The percentage reduction of number of patients at risk of bedsore development as per various domains of Braden Scale was more in Group A as compared to Group B on each successive visit. There was 100% improvement in mobility level in the patients who were totally dependent in both the groups. However, in moderately dependant patients, the improvement in mobility level was more (87%) in Group A as compared to Group B (75%). All the caregivers complied fully with instructions postintervention. Conclusion: Training of caregivers for the prevention of bedsores among the bedridden patients was effective in improving the practices of the caregivers and also in reducing the risk factors of bedsores. One-to-one training with SIM distribution yielded better results than the use of only SIM. PMID- 29440805 TI - Hypnotic Intervention for Unexplained Dizziness in Patients with Advanced Cancer: A Preliminary Retrospective Observation Study. AB - Context: Patients with advanced cancer rarely complain of unexplained dizziness after excluding identifiable causes. Some patients become anxious because they attribute the dizziness to the progression of their cancer. We hypothesize that unexplained dizziness is associated with neck muscle hypertonicity, a noncancer related secondary effect. However, most cases are associated with neck muscle hypertonicity, a noncancer-related secondary effect. Aims: We evaluated the usefulness of hypnotic intervention that made patients aware of the relation between dizziness and neck muscle hypertonicity through the experience of muscle relaxation and recognition of muscle tension. Settings and Design: Advanced cancer patients requiring palliative care with unexplained dizziness who received the intervention to induce neck muscle relaxation were retrospectively compared with patients who did not. Subjects and Methods: The severity of dizziness that was evaluated using a numeric rating scale and the intervention efficacy rate were compared between the hypnotic and nonhypnotic groups as the primary endpoints, 7 days after the start of the intervention. Secondary endpoints included the effect size based on dizziness handicap inventory (DHI) scores before and after the intervention, and changes in patients' awareness of the cause of dizziness. Results: The hypnotic intervention had a significantly greater efficacy rate (0.67, 95% confidence interval: 0.46-0.88) than the nonhypnotic intervention (0.26, 95% confidence interval: 0.08-0.44). DHI scores, especially on the emotional subscale, showed significant improvement after the intervention, and 71% of the patients were aware that neck muscle hypertonicity was the cause of dizziness. Conclusions: The rapid improvement in dizziness in the hypnotic group was considered to result from a change in patients' awareness of self-manageable neck muscle hypertonicity as the cause of dizziness. PMID- 29440804 TI - Prevalence and Severity of Sleep Disturbances among Patients with Early Breast Cancer. AB - Context: Data regarding health-related quality of life in breast cancer patients in the Middle East are limited with fatigue and sleep disturbance being the most distressing symptoms reported by patients treated for early breast cancer. Aims: The aim of this study was to examine the prevalence and incidence of insomnia among patients with early-stage breast cancer patients treated with chemotherapy. Subjects and Methods: This was a prospective cohort study. We enrolled patients with stage I-III breast cancer patients treated with chemotherapy at the American University of Beirut Medical Center. At three different time points (prior to, during, and following chemotherapy), we assessed the severity of sleep disturbances using the Pittsburgh Sleep Quality Index and the Insomnia Severity Index. The Institution Review Board approved the study. Results: Fifty-two patients were recruited. There was a significant increase in sleep disturbances during chemotherapy which improved to below baseline levels on completion of therapy. Prior to chemotherapy, 36% of patients reported poor sleep versus 58% during chemotherapy. The percentage of patients reporting clinical insomnia rose from 11% pretreatment to 36% during chemotherapy reflecting a significant symptomatic burden that is poorly documented and managed in routine clinical practice. Conclusions: Patients with nonmetastatic breast cancer experience an increase in sleep disturbances during the treatment phase. Physicians should be aware of the need to routinely screen for sleep disturbance in breast cancer patients undergoing chemotherapy. PMID- 29440806 TI - Prevalence and Intensity of Dyspnea in Advanced Cancer and its Impact on Quality of Life. AB - Context: Dyspnea is a subjective, multidimensional experience of breathing discomfort, commonly seen in patients with advanced cancer. To find the impact of dyspnea on the quality of life in this population, it is important to understand the prevalence and factors influencing dyspnea. Aims: This study aimed to determine the prevalence, intensity, and factors influencing dyspnea in advanced cancer and determine its impact on overall quality of life. Settings and Design: This was a prospective cross-sectional study. The prevalence of dyspnea and its impact on quality of life was determined in 500 patients registered with palliative medicine outpatient department. Subjects and Methods: The patients were asked to fill a set of questionnaires, which included the Cancer Dyspnea Scale (translated and validated Hindi and Marathi versions), visual analog scale for dyspnea and EORTC QLQ C 15 PAL. Details of demographics, symptomatology, and medical data were collected from the case record sheets of the patients. Statistical Analysis Used: Descriptive statistics, univariate, and multiple regression analysis were used to calculate the results. Results: About 44.37% of the patients experienced dyspnea. Dyspnea increased with worsening anxiety, depression, fatigue, appetite, well-being, pain, lung involvement by primary or metastatic cancer, performance status, and deteriorating overall quality of life and emotional wellbeing. Conclusions: The prevalence of dyspnea in advanced cancer patients is as high as 44.37% and has a negative impact on their overall quality of life. PMID- 29440807 TI - Palliative Care Policy Analysis in Iran: A Conceptual Model. AB - Background: Palliative care programs are rapidly evolving for patients with life threatening illnesses. Increased and earlier access for facilities is a subject of growing importance in health services, policy, and research. Aim: This study was conducted to explain stakeholders' perceptions of the factors affecting the design of such a palliative care system and its policy analysis. Methodology: Semi-structured in-depth interviews conducted following purposive sampling of the participants. Twenty-two participants were included in the study. The interviews were analyzed using qualitative-directed content analysis based on "policy analysis triangle" framework. Results: The findings showed the impact of four categories, namely context (political, social, and structural feasibility), content (target setting), process (attracting stakeholder participation, the standardization of care, and education management), and actors (the Ministry of Health and Medical Education, health-care providers, and volunteers) in the analysis of the palliative care policies of Iran. Conclusion: In the past 6 years, attention to palliative care has increased significantly as a result of the National Cancer Research Network with the support of the Ministry of Health. The success of health system plan requires great attention to its aspects of social, political, and executive feasibility. Careful management by policymakers of different stakeholders is vital to ensure support for any national plan, but this is challenging to achieve. PMID- 29440808 TI - Intranasal Ketamine for the Management of Incidental Pain during Wound Dressing in Cancer Patients: A Pilot Study. AB - Introduction: Cancer wounds need regular dressing; else they develop infection, foul odor, and in extreme cases, maggots. Patients resist dressing due to the severe incidental pain during dressing. Intranasal ketamine was tried as an analgesic to reduce this incidental pain. Materials and Methods: Twenty patients with wounds requiring regular dressing were selected; these patients had a basal pain score of 4/10 and incidental pain score of 7/10 during four consecutive dressings. Ketamine 0.5 mg/kg was administered transmucosally 10 min before dressing, and pain scores, hemodynamic parameters, and sedation were recorded for up to 2 h in six consecutive dressings. Results: Ketamine produced a significant reduction in incidental pain without any hemodynamic changes or sedation. Conclusion: Ketamine appears to be a safe and effective analgesic when used intranasally for incidental pain. PMID- 29440809 TI - Benefit or Harm? A Study on Impact of Collusion on the Quality of Life among Palliative Care Patients. AB - Background: In India, roughly one-half of patients undergoing cancer treatment are unaware of their diagnosis or treatment. The intention of this study is to determine the prevalence of collusion and its influence on quality of life (QOL) among patients in palliative care settings. Methodology: A cross-sectional study was conducted among 100 palliative care patients to assess the extent of knowledge about their diagnosis and prognosis. The caretakers and the treating doctors were interviewed using a semi-structured questionnaire to assess if diagnosis was revealed to a patient. QOL of the patients was assessed using the European Organisation for Research and Treatment of Cancer QOL Questionnaire-C30 questionnaire. Results: The prevalence of collusion was 37%, i.e., in more than one-third of the palliative care patients; caregivers restrained doctors from disclosing the diagnosis. The prevalence of collusion was less among patients with higher educational qualification (P = 0.027) and professionals (P = 0.025). Collusion was not associated with gender, type of family, place of residence, and socioeconomic status (SES). In multivariate regression, collusion (odds ratio = 10.53) was independently associated with poor QOL when adjusted for age, gender, place of residence, religion, educational status, family type, and SES. Conclusion: Collusion is fairly prevalent and it worsens the QOL among cancer patients. Since the main driver for collusion is the strong desire among caregivers to protect the physical and psychological well-being, the findings of the study could motivate the caregiver for a more open and honest communication. PMID- 29440810 TI - Validation of Malayalam Version of National Comprehensive Cancer Network Distress Thermometer and its Feasibility in Oncology Patients. AB - Context: This study was designed to translate and validate the National Comprehensive Cancer Network (NCCN) distress thermometer (DT) in regional language " Malayalam" and to see the feasibility of using it in our patients. Aims: (1) To translate and validate the NCCN DT. (2) To study the feasibility of using validated Malayalam translated DT in Malabar Cancer center. Settings and Design: This is a single-arm prospective observational study. The study was conducted at author's institution between December 8, 2015, and January 20, 2016 in the Department of Cancer Palliative Medicine. Materials and Methods: This was a prospective observational study carried out in two phases. In Phase 1, the linguistic validation of the NCCN DT was done. In Phase 2, the feasibility, face validity, and utility of the translated of NCCN DT in accordance with QQ-10 too was done. Statistical Analysis Used: SPSS version 16 (SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc.) was used for analysis. Results: Ten patients were enrolled in Phase 2. The median age was 51.5 years and 40% of patients were male. All patients had completed at least basic education up to the primary level. The primary site of cancer was heterogeneous. The NCCN DT completion rate was 100%. The face validity, utility, reliability, and feasibility were 100%, 100%, 100%, and 90%, respectively. Conclusion: It can be concluded that the Malayalam validated DT has high face validity, utility, and it is feasible for its use. PMID- 29440811 TI - Assessment of Psychological Distress and its Effect on Quality of Life and Social Functioning in Cancer Patients. AB - Purpose: The diagnosis of cancer and its treatment can make patients psychologically distressed. The purpose of this study is to evaluate the level of psychological distress and social functioning in cancer patients and to assess the association of these parameters with the quality of life (QOL) experienced by the patient. Patients and Methods: All cancer patients attending palliative care clinic who can understand and speak English or Tamil language were taken into the study. An interview technique with a questionnaire is used for data collection after informed consent. The questionnaire consisted of four sections, namely, demographic variables, general health questionnaire, WHO QOL-BREF, and SCARF social functioning index. All questionnaires were translated into the Tamil Language and were evaluated by the experts for content validity. Results: The median scores obtained are psychological distress = 44 (11-98), WHO QOL = 64 (36 117), and social function = 51 (29-79). Out of 251 patients, 30% had severe psychological distress, 25.6% had poor QOL, and 23.2% were with severely affected social function. Skilled laborers had better scores compared to unskilled laborers (P < 0.05). Family size (<2 children) had a positive impact on the QOL (P = 0.008). Patients from urban locales had better social functioning than rural counterpart (P = 0.047), but no difference was observed in distress level or QOL. Increased growth hormone distress score of the patients had a negative impact on both QOL (r = -0.522) and social function (r = -0.244). QOL correlated positively with social function (r = +0.247). Conclusion: Psychosocial stress associated with cancer and its treatment can impact the QOL and social functioning of the patient and needs to be addressed along with the cancer-directed therapy. Decreasing the symptom burden and distress level by palliative care intervention might improve the QOL and social function. PMID- 29440812 TI - "Personified as Paragon of Suffering...... Optimistic Being of Achieving Normalcy:" A Conceptual Model Derived from Qualitative Research. AB - Background: Conceptual models developed through qualitative research are based on the unique experiences of suffering and individuals' adoptions of each participant. A wide array of problems are faced by head-and-neck cancer (HNC) patients due to disease pathology and treatment modalities which are sufficient to influence the quality of life (QOL). Men possess greater self-acceptance and are better equipped with intrapersonal strength to cope with stress and adequacy compared to women. Methodology: A qualitative phenomenology study was conducted among seven women suffering from HNC, with the objective to understand their experiences of suffering and to describe the phenomenon. Data were collected by face-to-face, in-depth, open-ended interviews. Data were analyzed using Open Code software (OPC 4.0) by following the steps of Colaizzi process. Results: The phenomenon that emerged out of the lived experiences of HNC women was "Personified as paragon of suffering.optimistic being of achieving normalcy," with five major themes and 13 subthemes. Conclusion: The conceptual model developed with the phenomenological approach is very specific to the women suffering from HNC, which will be contributing to develop strategies to improve the QOL of women. PMID- 29440813 TI - Anxiety and Depression: A Cross-sectional Survey among Parents of Children with Cancer. AB - Context: Parents of children with cancer are experiencing high levels of psychological distress. Elevated levels of depression and anxiety following the disclosure of diagnosis affect many aspects of parents' health. Aims: The aim of this study was to assess anxiety and depression of parents of Iranian children with cancer. Settings and Design: This descriptive-correlational study was undertaken among 148 parents of children with cancer admitted to a pediatric hospital affiliated to Tabriz University of Medical Sciences, Tabriz/Iran. Subjects and Methods: Participants were selected using convenience sampling method. Hospital Anxiety and Depression Scale was used to evaluate patients' levels of anxiety and depression. Statistical Analysis Used: The data were analyzed using SPSS version 13.0. Results: The study findings showed that the mean anxiety and depression scores were 9.63 +/- 3.69 and 8.66 +/- 4.59 (range score: 0-21), respectively. Additionally, 41.2% (n = 61) and 32.4% (n = 48) of participants had clinical symptoms of anxiety and depression, respectively. Conclusions: Parents of children with cancer experienced high levels of anxiety and depression. Effective interventions are essential to improve the mental health of parents of children with cancer. These interventions may include mental health screening, psychological counseling, and training programs to cope with the problems caused by the child's disease. PMID- 29440814 TI - Effectiveness of the Certificate Course in Essentials of Palliative Care Program on the Knowledge in Palliative Care among the Participants: A Cross-sectional Interventional Study. AB - Background: Palliative medicine is an upcoming new specialty aimed at relieving suffering, improving quality of life and comfort care. There are many challenges and barriers in providing palliative care to our patients. The major challenge is lack of knowledge, attitude and skills among health-care providers. Objectives: Evaluate the effectiveness of the certificate course in essentials of palliative care (CCEPC) program on the knowledge in palliative care among the participants. Subjects and Methods: All participants (n = 29) of the CCEPC at All India Institute of Medical Sciences, Delhi, giving consent for pretest and posttest were recruited in the study. This educational lecture of 15 h was presented to all the participants following pretest and participants were given same set of questionnaire to be filled as postintervention test. Results: In pretest, 7/29 (24.1%) had good knowledge which improved to 24/29 (82.8%) after the program. In pretest, 62.1% had average knowledge and only 13.8% had poor knowledge. There was also improvement in communication skills, symptom management, breaking bad news, and pain assessment after completion of the program. Conclusion: The CCEPC is an effective program and improving the knowledge level about palliative care among the participants. The participants should implement this knowledge and the skills in their day-to-day practice to improve the quality of life of patients. PMID- 29440815 TI - Aspiring Pain Practitioners in India: Assessing Challenges and Building Opportunities. AB - Background: Pain medicine is a developing specialty, aimed at relieving pain and suffering, enhancing function, and improving the quality of life of patients. Pain is often ignored, under-reported and mismanaged by health-care providers. Aspiring pain physicians in India face many challenges and barriers in advancing their specialty. Objectives: The objective of this study is to determine the challenges in establishing a pain practice in India and to discuss the opportunities and strategies to overcome these barriers. Subjects and Methods: Face-to-face interactive sessions were held with 60 aspiring pain physicians of India who were chosen as registrants to an International Association for the Study of Pain-Indian Society for Study of Pain multidisciplinary evidence-based pain management program conducted at Delhi and Mumbai. The available opportunities, practical issues and the hurdles in becoming a pain specialist were analyzed and summarized in this commentary. Results: The major barriers identified were: (1) Inadequate knowledge and absence of structured, educational and training courses, (2) bureaucratic hurdles, and (3) concerns of opioid misuse and addiction. The opportunities for personal growth and that of the specialty that could be utilized include the creation of a pain resource team, increasing community awareness, changing attitudes of other physicians toward pain specialty, and research and evidence building of the effectiveness of pain management strategies. Conclusion: India needs a structured teaching and training program in the area of pain medicine that is affiliated by the Medical Council of India or other reputed boards of medical education and certification. There is an urgent need to include pain management in the undergraduate and postgraduate medical curriculum. Enhancing community level awareness by public health education campaigns, developing networks of pain physicians, and appropriate marketing of the specialty is needed to make pain medicine recognized and utilized as a valuable specialty. PMID- 29440816 TI - Empowering Nurses in Providing Palliative Care to Cancer Patients: Action Research Study. AB - Background: Chronic diseases such as cancer would lead to various health needs in patients and their families. To meet needs, developing new educational nursing courses is necessary. Therefore this study was conducted to empower nurses through designing and conducting short-term educational courses for training palliative care nurses. Materials and Methods: This study was a community-based action research which was conducted at Isfahan hospitals that provide services for cancer patients during 2015 at four stages (planning, acting, reflection, and evaluation). Participants (33 samples) included nurses, head nurses, managers of nursing services, nursing professors and professors of oncology department. Data were gathered through individual and group interviews and analyzed using content analysis. Results: Data analysis resulted in 3 categories of "professional development of nursing in palliative care" which included subcategories of: knowledge-based performance and positive change in attitude, "obstacles to provide palliative care" with subcategories of: insufficient professional responsibility, insufficient ability in managing some of patients' symptoms and inappropriate interaction between nurses and physicians and "strategies for improving provision of palliative care" with subcategories of: improving the interactions between physicians and nurses, continuous trainings for palliative care and the necessity of developing palliative care in the country. Conclusions: To facilitate the process of providing palliative care to cancer patients, necessary actions and measures must be conducted including improvement of interaction between the members of health team, organizing continuing educational courses on palliative care and development of providing palliative care all over the country by managers of health centers. PMID- 29440818 TI - Ultrasound-Guided Real-Time Pterygopalatine Block for Analgesia in an Oral Cancer Patient. AB - Oral cancers are one of the most common cancers in India. These patients have pain during the course of the disease. Various drugs including opioid and nonsteroidal anti-inflammatory drug have been used to manage pain. However, these are associated with side effects such as constipation and vomiting. An early interventional block may decrease the requirement for analgesics and improve the overall quality of life. We describe a case of oral carcinoma successfully managed with ultrasound-guided pterygopalatine block. PMID- 29440817 TI - Quality of Life of patients with chronic kidney disease in Iran: Systematic Review and Meta-analysis. AB - Introduction: Renal diseases are among the major health problems around the world that cause major changes in patients' lifestyle and affect their quality of lives. The aim of this study was to evaluate the quality of life of patients with chronic kidney disease (CKD) in Iran through a meta-analysis. Materials and Methods: This study was conducted using authentic Persian and English keywords in the national and international databases including IranMedex, SID, Magiran, IranDoc, Medlib, Science Direct, Pubmed, Scopus, Cochrane, Embase, Web of Science, and Medline. The data were analyzed using meta-analysis (random effects model). Heterogeneity of studies was assessed using I2 index. In this study, SF 36: 36-Item Short Form health-related quality of life (HRQOL), kidney disease quality of life-SF (KDQOL-SF), KDQOL and KDQOL-SFTM questionnaires were used. Data were analyzed using STATA Version 11 software. Results: A total of 17200 individuals participated in 45 reviewed studies, and the mean score of CKD patients' quality of life was estimated by SF-36 (60.31), HRQOL (60.51), and KDQOL-SF (50.37) questionnaires. In addition, meta-regression showed that the mean score of CKD patients' quality of life did not significantly decrease during the past years. Conclusion: The mean score of quality of life of patients with CKD was lower in different dimensions in comparison with that of normal people. Therefore, interventional measures should be taken to improve the quality of life of these patients in all dimensions. PMID- 29440819 TI - Intravenous Lignocaine Infusion for Intractable Pain in Ewing's Sarcoma. AB - A 23-year-old female presented to our palliative care center with Ewing's sarcoma of the humerus with lung metastases. Pain in her arm was unrelieved by nonsteroidal anti-inflammatory drugs, neuropathic medication as well as morphine. She could not tolerate any further increase in opioid dose but was so distraught due to the pain that she wanted to die. An intravenous lignocaine infusion in a dose of 2 mg/kg was given over an hour for three successive days. This successfully relieved her pain after which she was settled with her original medication. We feel that in palliative care settings, where intractable pain and tolerance to morphine are so common, intravenous lignocaine infusions could provide a safe and effective tool for pain relief. PMID- 29440820 TI - Beware! Reduced Functional Capacity and Quality of Life with Increased Fatigue Level among the Breast Cancer Survivors Undergoing Chemotherapy in India. PMID- 29440821 TI - Ziconotide: Indications, Adverse Effects, and Limitations in Managing Refractory Chronic Pain. PMID- 29440822 TI - Volunteers in Palliative Care: An Experience in South Australia. PMID- 29440823 TI - From the Editor's Desk: Congenital heart surgery in India - At the crossroads? PMID- 29440824 TI - Extracorporeal membrane oxygenation in pediatric cardiac surgery: A retrospective review of trends and outcomes in Scotland. AB - Introduction: Around 3.2%-8.4% of patients receive venoarterial (VA) extracorporeal membrane oxygenation (ECMO) support after pediatric cardiac surgery. The desired outcome is "bridge-to-recovery" in most cases. There is no universally agreed protocol, and given the associated costs and complications rates, the decisions as of when and when not to institute VA ECMO are largely empirical. Methods: A retrospective review of the ECMO database at the Scottish Pediatric Cardiac Services (SPCS) was undertaken. Inclusion criterion encompassed all children (<16 years of age) who were supported with VA ECMO following cardiac surgery between January 2011 and October 2016. The timing of ECMO support was divided into three distinct phases: "endofcase" or intheatre ECMO for patients unable to effectively wean from cardiopulmonary bypass (CPB), ECMO for cardiopulmonary resuscitation ("ECPR"), and Intensive Care Unit ECMO for "failing maximal medial therapy" following cardiac surgery. The patients were analyzed to identify survival rates, adverse prognostic indicators, and complication rates. Results: We identified 66 patients who met the inclusion criterion. 30day survival rate was 45% and survival rate to hospital discharge was 44% (the difference represents one patient). On followup (median: 960 days, range: 42-2010 days), all survivors to hospital discharge were alive at review date. "End-of case" ECMO showed a trend toward better survival of the three subcategories ("end of case," ECPR, and ECMO for "failing maximal medical therapy" survival rates were 47%, 41%, and 37.5%, respectively, P = 0.807). The poorest survival rates were in the younger children (<6 months, P = 0.502), patients who had prolonged CPB (P = 0.314) and aortic crossclamp times (P = 0.146), and longer duration of ECMO (>10 days, P = 0.177). Conclusions: Allcomers VA ECMO following pediatric cardiac surgery had survival to discharge rate of 44%. Elective "end-of-case" ECMO carries better survival rates and therefore ECMO instituted early maybe advantageous. Prolonged ECMO support has a direct correlation with mortality. PMID- 29440825 TI - Comparison of skin dose measurement using nanoDot(r) dosimeter and machine readings of radiation dose during cardiac catheterization in children. AB - Objectives: Direct measurement of skin dose of radiation for children using optically stimulated luminescence (OSL) technology using nanoDot(r) (Landauer, Glenwood, IL, USA). Background: Radiation dose is estimated as cumulative air kerma (AK) and dosearea product based on standards established for adult size patients. Body size of pediatric patients who undergo cardiac catheterization for congenital heart disease vary widely from newborn to adolescence. Direct, skindose measurement applying OSL technology may eliminate errors in the estimate. Materials and Methods: The nanoDot(r) (1 cm * 1 cm * flat plastic cassette) is applied to patient's skin using adhesive tape during cardiac catheterization and radiation skin doses were read within 24 hrs. nanoDot(r) values were compared to the currently available cumulative AK values estimated and displayed on fluoroscopy monitor. Results: A total of 12 children were studied, aged 4 months to 18 years (median 1.1 years) and weight range 5.3-86 kg (median 8.4 kg). nanoDot(r) readings ranged from 2.58 mGy to 424.8 mGy (median 84.1 mGy). Cumulative AK ranged from 16.2 mGy to 571.2 mGy (median 171.1 mGy). Linear correlation was noted between nanoDot(r) values and AK values (R2 = 0.88, R = 0.94). nanoDot(r) readings were approximately 65% of the estimated cumulative AK estimated using the International Electrotechnical Commission standards. Conclusions: Application of OSL technology using nanoDot(r) provides an alternative to directly measure fluoroscopic skin dose in children during cardiac catheterization. Our data show that the actual skin dose for children is approximately one-third lower than the AK estimated using international standards for adult size patients. PMID- 29440826 TI - Normal reference ranges for cardiac valve cross-sectional areas in preterm infants. AB - Objective: To establish normal reference ranges for cardiac valve crosssectional areas (CSAs) in preterm infants and their correlation with gestational age, body weight, and chronological age. Materials and Methods: In a prospective study, 268 preterm babies fulfilling the criteria for inclusion were examined. Echocardiograms were performed to measure aortic, pulmonary, mitral, and tricuspid valve CSAs on 0-6 day (s) of life and at weekly intervals until they reached 36 weeks. Gestational age was divided into three groups, 24-27, 28-31, and 32-35 weeks, and body weight was divided into five groups, <=999, 1000-1499, 1500-1999, 2000-2499, and >=2500 g. Overall group differences were compared for each period of life: 0-6 days and 1-2, 3-4, and >=5 weeks. Results: The mean gestational age was 29.8 (+/-2.38 standard deviation [SD]) weeks, ranging between 24 and 35 weeks, and the mean body weight was 1479 (+/-413 SD) g, ranging between 588 and 3380 g. All cardiac valve CSAs correlated well with body weight. A significant gradual increase was observed in all valve CSAs with body weight during each period of life. Overall, a progressive and significant increase in all valve CSAs was observed during the first 9 weeks of life. Conclusions: Cardiac valve CSAs were found to be significantly correlated with body weight. The study also provides reference data, which can be used as a normal reference tool for valve CSAs in preterm infants against gestational age, body weight, and chronological age. PMID- 29440827 TI - Evaluation of left ventricular function in obese children without hypertension by a tissue Doppler imaging study. AB - Background: The prevalence of obesity is increasing worldwide. Obese children without hypertension are becoming an important health challenge. Aims: Complications of obesity in adults are well established, but in obese children, cardiac dysfunction has not been reported clinically. Settings and Design: The present crosssectional study investigates subclinical systolic and diastolic dysfunction using echocardiographic modalities. Materials and Methods: Twentyfive youngsters with body mass index (BMI) >30 and 25 healthy children with BMI <25 were assigned into case and control group, respectively. In all participants, complete cardiovascular examination, electrocardiography, and echocardiography were fulfilled. Echocardiography surveys included standard, pulsed wave Doppler (PWD), and tissue Doppler imaging (TDI). Statistical Analysis Used: SPSS software, version 24. Results: The two groups were matched for age and sex. The resting heart rate and blood pressure were markedly higher in the obese group (P = 0.0001) though they were within the normal range in either category. Ejection fraction in the two groups was similar. Left ventricular (LV) mass (P = 0.0001), LV mass index (P = 0.029), left atrialtoaortic diameter ratio (P = 0.0001), and LV enddiastolic diameter (P = 0.008) were significantly greater in the case group, indicating cardiomegaly and subclinical systolic and diastolic dysfunction. Except for the aortic velocity, all PWD variables were considerably lower in the case group, suggesting subclinical diastolic dysfunction. All TDI parameters varied significantly between the two categories. There was a direct correlation between isovolumetric relaxation time and BMI. Conclusions: Obesity in children without hypertension is associated with subclinical systolic and diastolic cardiac dysfunction. We propose the evaluation of blood pressure as well as myocardial performance using PWD and TDI in all obese children without hypertension, regularly. PMID- 29440828 TI - Clinical presentation, management, and postnatal outcomes of fetal tachyarrhythmias: A 10-year single-center experience. AB - Background: Limited information is available regarding the prevalence and outcomes of fetal tachyarrhythmias from the developing countries. Aims: This study aims to report referral patterns, management protocols, and pregnancy outcomes of fetuses with tachyarrhythmias reporting to a single center in South India. Methods: All fetuses with documented sustained fetal tachyarrhythmia during the study period (2008-2017) were included. Arrhythmia characterization and hemodynamic evaluation were done using fetal echocardiography. Patients were grouped into supraventricular tachycardia (SVT) and atrial flutter (AF) groups. Patient characteristics, transplacental therapy (TPT), pregnancy, and postnatal outcomes were analyzed. Results: Total of 19 fetuses included; 11 had SVT and 8 AF. Mean gestational age at referral was higher for AF (32.5 +/- 3.2 vs. 29.6 +/- 3.3 weeks; P = 0.05). Hydrops fetalis was present 8 (42%) fetuses; 4 in each group. TPT was instituted in 18 fetuses; 12 (66.7%) received combination therapy; 4 (21%) received direct fetal therapy. Eighteen fetuses (91%) were born alive with one intrauterine death in a fetus with SVT and severe hydrops. Seven (87.5%) fetuses with hydrops survived. Twelve patients (66.7%) were delivered in sinus rhythm. Six babies (33.3%) had tachycardia at birth requiring anti-arrhythmic therapy. All patients survived the neonatal period. Duration of trans-placental therapy (3.8 + 3.3 vs. 7.3 + 3.4 weeks) was shorter in the AF group. Conclusions: Aggressive TPT using combination of drugs achieves excellent pregnancy and postnatal outcomes in fetuses with tachyarrhythmia. Early diagnosis and prompt referral before hemodynamic decompensation is critical for ensuring optimal outcomes. PMID- 29440829 TI - Exercise performance after univentricular palliation. AB - Background: The optimal timing, need for primary/staged procedure in patients undergoing univentricular palliation, is debatable. Aims: We performed this study to assess the exercise performance of patients undergoing various forms of univentricular palliation. Setting and Design: This was a retrospective, prospective comparative study conducted at a multispecialty tertiary referral center. Patients and Methods: Between January 2012 and June 2015, 117 patients undergoing either bidirectional Glenn (BDG) (n = 43) or Fontan (total cavopulmonary connection [TCPC]) (n = 74) underwent exercise testing. Statistical Analysis: Comparisons between subgroups for continuous data were made with Student's t-test if normally distributed and Wilcoxon rank-sum test otherwise. Tests between subgroups for qualitative data were made with Pearson's Chi-square test. Results: Patients who underwent BDG with open antegrade pulmonary blood flow (APBF) had higher saturations (oxygen saturation [SpO2]) compared to those without it (87.5 +/- 5.0% vs. 81.1 +/- 4.8%; P = 0.0001). However, we found no differences in exercise parameters of patients undergoing BDG with or without APBF. Extracardiac TCPC (n = 42) patients demonstrated better exercise capacity (15.0 +/- 7.7 vs. 11.2 +/- 6.2 min; P = 0.02) and increased SpO2 on exercise (87.0 +/- 8.0% vs. 83.4 +/- 7.6%; P <= 0.05) compared to lateral tunnel TCPC (n = 32). Fenestrated TCPC (n = 30) patients had higher exercise capacity reflected by higher metabolic equivalents (METs) consumption (6.4 +/- 2.3 vs. 5.2 +/- 2.0 METs, P = 0.02), fewer pleural effusions (7.0 +/- 3.2 vs. 9.2 +/- 6.2 days, P <= 0.05), and lower hospital stay (9.5 +/- 4.0 vs. 12.7 +/- 7.7 days, P = 0.04) compared to nonfenestrated TCPC (n = 44) patients. Conclusions: We observed no differences in exercise parameters of patients undergoing BDG with or without APBF. Extracardiac TCPC patients had better exercise capacity but longer postoperative hospital stay and pleural effusions than patients with lateral tunnel Fontan. Fenestrated TCPC patients seemed to fare better than nonfenestrated ones. Patients undergoing TCPC had better exercise capacity than patients undergoing BDG alone. PMID- 29440830 TI - Impact of intensive care unit attending physician training background on outcomes in children undergoing heart operations. AB - Background: The existing training pathways to become a pediatric cardiac intensivist are very variable with physicians coming from varied training backgrounds of pediatric critical care, pediatric cardiology, neonatology, or pediatric anesthesia. Aim: To evaluate the impact of cardiac Intensive Care Unit (ICU) attending physician training background on outcomes in children undergoing heart operations. Setting and Design: Patients in the age group from 1 day to 18 years undergoing heart operation at a Pediatric Health Information System database participating hospital were included (2010-2015). Patients and Methods: Based on the training background of majority of attending physicians in an ICU, the participating ICUs were divided into three groups: critical care medicine (CCM), cardiology, and indeterminate. Statistical Analysis: Multivariable logistic regression models were fitted to evaluate the association of ICU physician training background with study outcomes. Results: A total of 54,935 patients from 42 ICUs were included. Of these, 31,815 patients (58%) were treated in the CCM group (26 ICUs), 19,340 patients (35%) were treated in the cardiology group (12 ICUs), and 3780 patients (7%) were treated in the indeterminate group (4 ICUs). In adjusted models, no specific group based on ICU attending physician training background was associated with lower mortality (CCM vs. cardiology, odds ratio: 0.75, 95% confidence interval: 0.48-1.18), or lower incidence of cardiac arrest, or prolonged hospital length of stay, or prolonged mechanical ventilation. Conclusions: This large observational study did not demonstrate any impact of ICU attending training background on outcomes in children undergoing heart operations. PMID- 29440831 TI - Prognostic value of troponin in infants with hypoplastic left heart syndrome between Stage I and II of palliation. AB - Background: The period between stage I and II procedure for treatment of hypoplastic left heart syndrome (HLHS) bears high mortality and morbidity. Methods: We sought to analyze the prognostic value of Troponin T/I (Trop), a well recognized marker for myocardial damage and heart failure, for predicting outcome in a retrospective analysis of 70 infants with HLHS at our institution between March 2001 and October 2014. Results: Stage I procedure consisted of Norwood I operation in 35 (50%) and Hybrid-approach in 22 (31%) patients. Palliative care was chosen for 13 (19%) patients. Trop values were collected from clinical charts and were analyzed in relation to the overall outcome. Trop was significantly higher after Norwood I operation in comparison to Hybrid-approach (median 7.1 MUg/l (0.7-20.9), vs 1.2 MUg/l (0.3-17.9), P < 0.001). Overall mortality of treated patients was 39% (22 patients). Survival was 54% (19 patients) after Norwood and 73% (16 patients) after Hybrid-approach. Independently from the procedure used, maximal Trop and initial lactate values were significantly higher in non-survivors than in survivors, with median Trop of 9 MUg/l (0.6-18.8) vs. 3.4 MUg/l (0.4-20.9), P 0.007, and median lactate of 3.7 mmol/L (1.6-25) vs. 2.9 mmol/L (0.3-14.6), p 0.03. Reinterventions were required in 17 (30%) patients, 4 (11%) after Norwood and 13 (59%) after Hybrid procedure. No correlation was found between the need for reintervention and Trop levels in the interstage period. Conclusions: Patients with HLHS have significantly higher Trop levels after Norwood procedure than after Hybrid-approach. Maximal Trop values were related to mortality, but did not correlate with the need for reinterventions. PMID- 29440832 TI - Q fever endocarditis after right ventricle to pulmonary artery conduit insertion: Case series and review of the literature. AB - Q fever (QF) is rarely reported in children. Awareness of the disease and newer diagnostic modalities have resulted in increasing recognition of unusual manifestations. We present three cases of QF endocarditis after right ventricle to pulmonary artery conduit insertion in children. PMID- 29440833 TI - Hemodynamic rounds: Can we mimic a temporary pulmonary artery band in catheterization laboratory in corrected transposition of great arteries with severe tricuspid regurgitation? AB - Right ventricular (RV) geometry is altered by septal shift after pulmonary artery banding. This may reduce tricuspid regurgitation (TR) and improve ventricular function in patients with corrected transposition of great arteries and systemic right ventricle. However, banding is risky in sick patients with severe RV failure. There are no predictive models in clinical practice to test this septal shift hypothesis before a risky surgery. A transcatheter model to mimic a pulmonary artery band is presented in corrected transposition of great arteries with failing right ventricle and severe TR. PMID- 29440835 TI - Dual pathology causing severe pulmonary hypertension following surgical repair of total anomalous pulmonary venous connection: Successful outcome following serial transcatheter interventions. AB - Surgical repair of total anomalous pulmonary venous connection (TAPVC) can be complicated by the development of pulmonary venous stenosis later on. In addition, the vertical vein, if left unligated, can remain patent and lead to hemodynamically significant left to right shunting. We report an infant who required transcatheter correction of both these problems after surgical repair of TAPVC. PMID- 29440834 TI - Prevention and control of rheumatic heart disease: Overcoming core challenges in resource-poor environments. AB - Rheumatic heart disease (RHD) has long receded as a significant threat to public health in high-income countries. In low-resource settings, however, the specter of RHD remains unabated, as exemplified by recent data from the Global Burden of Diseases Study. There are many complex reasons for this ongoing global disparity, including inadequate data on disease burden, challenges in effective advocacy, ongoing poverty and inequality, and weak health systems, most of which predominantly affect developing nations. In this review, we discuss how each of these acts as a core challenge in RHD prevention and control. We then examine key lessons learnt from successful control programs in the past and highlight resources that have been developed to help create strong national RHD control programs. PMID- 29440836 TI - Saccular pseudoaneurysm of the left common carotid artery in an adolescent: Management with a covered stent. AB - An adolescent patient with a previous history of surgical repair for interrupted aortic arch type B presented with an asymptomatic, saccular pseudoaneurysm of the proximal, common left carotid artery, identified on a follow-up magnetic resonance angiography of the thoracic large vessels. The pseudoaneurysm was successfully excluded with a covered stent. Clinical and radiological follow-up after 2 years was uneventful. PMID- 29440837 TI - Transcatheter closure of postsurgical ruptured sinus of Valsalva with Amplatzer Duct Occluder II ASTM device. AB - Sinus of Valsalva (SV) rupture is a rare, cardiac complication after surgical repair of complex congenital heart disease. This paper reports a 4-year-old male child with double outlet right ventricle (RV) and pulmonary stenosis with superior-inferior arrangement of the ventricles, who was submitted to surgical repair using the "reparation a l'etage ventriculaire" procedure. A few months after an uneventful surgical repair, his clinical condition abruptly worsened because of the rupture of the right SV into the RV outflow tract resulting in large left-to-right shunt and RV functional impairment. To avoid surgical re-do, this late-onset complication was successfully treated by transcatheter implantation of an Amplatzer Duct Occluder Type II Additional SizeTM (ADO-IIAS, St. Jude Medical Inc., St. Paul, Minnesota, USA) device. PMID- 29440838 TI - Arterial duct and pulmonary arteriovenous malformations: A shunt masking a shunt. AB - A 5-month-old infant, referred to our institution for percutaneous arterial duct (AD) embolization, showed multiple huge pulmonary arteriovenous malformations (PAVMs) associated with a small AD and several tiny systemic-to-pulmonary collaterals. This anatomic arrangement was a possible cause of lack of cyanosis and disproportionately higher hemodynamic relevance of the ductal shunt. The PAVMs became pathophysiologically evident immediately after the closure of AD and systemic to pulmonary artery collaterals and presented clinically with a life threatening cyanosis. To improve the patient's clinical and hemodynamic condition, the PAVMs were closed in multiple sittings using a large number of Amplatzer Vascular Plugs (St. Jude Medical Inc., St. Paul, MN, USA). The hemodynamic burden of cardiac malformations resulting in left-to-right shunt may be magnified by the presence of PAVMs as a result of low pulmonary vascular resistance which in turn may completely mask the clinical impact of the latter. Transcatheter approach is life-saving in these complex arrangements. PMID- 29440839 TI - Discontinuity of the arch beyond the origin of the left subclavian artery in an adult: Interruption or coarctation? AB - Congenital aortic anomalies are uncommon causes of secondary hypertension and are seldom suspected in the adult age group. We present a case of aortic interruption unexpectedly diagnosed on autopsy in a 38-year-old male who presented with cardiovascular collapse. Apart from interruption, a finding unique to our case was aneurysmal dilation of the proximal descending aorta just before the obstruction with thrombosis. We also attempt to review the literature for interrupted aortic arch in adults and clarify the nomenclature of interruption versus coarctation. PMID- 29440840 TI - Congenital aneurysm of both left ventricle and left atrium. AB - This is a case of both congenital left ventricular (LV) free wall submitral aneurysm and left atrial appendage aneurysm with 6 years of clinical follow-up. Each lesion is a rare entity, and to the best of our knowledge, this is the first case in medical literature of both lesions occurring in the same patient, raising the likelihood of a common etiology. The workup was initiated in the third trimester of fetal life with irregular heart rate and abnormal fetal ultrasound and echocardiogram at that time. The patient required emergent atrial appendage plication due to blood clot formation and suffered from multiple other complications including ventricular ectopy and surgically induced pseudoaneurysm. Follow-up interval echocardiograms have revealed continued good LV function with persistent LV aneurysm. In review of the case, there were several potential in utero causes including maternal viral upper respiratory infection and bacteriuria with exposure to amoxicillin. These as well as other considerations are discussed along with a brief review of these rare lesions, usual presentation, and known associations. PMID- 29440841 TI - Acquired ventricular septal defect due to infective endocarditis. AB - Acquired intracardiac left-to-right shunts are rare occurrences. Chest trauma and myocardial infection are well-known causes of acquired ventricular septal defect (VSD). There have been several case reports describing left ventricle to right atrium shunt after infective endocarditis (IE). We present here a patient found to have an acquired VSD secondary to IE of the aortic and tricuspid valves in the setting of a known bicuspid aortic valve. This is the first case reported of acquired VSD in a pediatric patient in the setting of IE along with literature review of acquired left-to-right shunts. PMID- 29440842 TI - Coronary sinus atrial septal defect without persistent left superior vena cava: Three-dimensional imaging of a rare defect. AB - Coronary sinus defects refer to interatrial communications that lie out of the confines of the atrial septum and leads from left to right shunt through the ostium of the coronary sinus. When associated with persistent left superior vena cava (PLSVC), mild systemic desaturation may occur depending on the extent of unroofing of the coronary sinus. Isolated defects without PLSVC are rare. Three dimensional echocardiographic and surgical images are presented. PMID- 29440843 TI - Large pseudoaneurysm following right ventricle to pulmonary artery homograft placement in an infant. AB - Pseudoaneurysm (PSA) is a known but rare complication of the right ventricle to pulmonary artery (RV-PA) conduits. The patient's clinical presentation can be variable ranging from asymptomatic to potential rupture. We describe an unusual case of a massive PSA in an infant who underwent RV-PA pulmonary homograft placement after relief of right ventricular outflow tract obstruction. PMID- 29440844 TI - Cost-effectiveness analysis of devices for closure of patent ductus arteriosus. PMID- 29440846 TI - Melody valve implantation through a recanalized occluded femoral vein. PMID- 29440845 TI - A pediatric echocardiographic Z-score nomogram for a developing country: Indian pediatric echocardiography study - The Z-score. PMID- 29440847 TI - The traveller amplatzer: Surgical removal after device migration to the ventricle. PMID- 29440848 TI - Ominous comorbidities: Small ventricular septal defect and warm autoimmune hemolytic anemia. PMID- 29440849 TI - Improving outcomes in totally anomalous systemic venous connection. PMID- 29440850 TI - A Meta-analysis On Evidence Of Platelet-rich Plasma for Androgenetic Alopecia. AB - Background: Platelet-rich plasma (PRP) treatment has gained popularity among different surgical specialities for improving various conditions. Androgenetic alopecia (AGA) is a common disorder, with possible psychosocial implications. Plastic surgeons have increased the practice of PRP injections for hair restoration. A meta-analysis on this topic was performed comparing local injection of PRP versus control to investigate the efficacy of local PRP injections in AGA. Methods: We performed a systematic literature search. The increase in number of hairs was the primary outcome. Secondary outcomes were the increase of hair thickness and the percentage increase in hair number and thickness. Results: Seven studies involving 194 patients were retrieved and included in the present analysis. A significantly locally increased hair number per cm2 was observed after PRP injections versus control (mean difference [MD] 14.38, 95% confidence interval [CI] 6.38-22.38, P < 0.001). Similarly, a significantly increased hair thickness cross-section per 10-4 mm2 (MD 0.22, 95% CI 0.07-0.38, P = 0.005) favoring PRP group. The pooled results did not show a significant percentage increase in hair number (MD 18.79%, 95% CI - 8.50-46.08, P = 0.18), neither hair thickness (MD 32.63%, 95% CI - 16.23-81.48, P = 0.19) among patients treated with PRP. Conclusion: Local injection of PRP for androgenic alopecia might be associated with an increased number of hairs in the treated areas with minimal morbidity, but there is clearly a lack of scientific evidence on this treatment modality. Further studies are needed to evaluate the efficacy of PRP for AGA. PMID- 29440851 TI - Evaluation of Alopecia: A New Processing Technique Combining Vertical and Transverse Sections from a Single Scalp Biopsy Specimen. AB - Background: Histopathological study of alopecia generally requires both vertical and transverse sections (VS and TS) and this may demand the need for multiple scalp biopsy samples. Here, we suggest a new processing technique which provides both VS and TS from a single biopsy, thus making the interpretation easier. Materials and Methods: All formalin-fixed scalp biopsy specimens were processed routinely. Nine VS were taken and mounted on 3 glass slides. The block was then melted and the tissue reembedded with the subcutaneous tissue facing downward and the epidermal aspect toward the technician to obtain TSs. Serial 4 MU sections were cut until the tissue was exhausted and every 25th section was mounted on glass slides and stained with H and E. Results: 100 scalp biopsy specimens with the history of alopecia have been processed using this technique. The technique provides proper visualization of both VS and TS from a single scalp biopsy without compromising the quality. Further, evaluation of the remaining sections with application of special stains can also be possible with this technique which will maximize the information and contribute to the accurate diagnosis of various types of alopecia. Conclusions: This technique can be used to obtain diagnostically satisfactory VS and TS from a single scalp biopsy specimen by modifying the embedding procedure, thereby avoiding the need for a second biopsy. All types of alopecia can be diagnosed by this effective method. PMID- 29440852 TI - Rare Variant of Ankyloblepharon-ectodermal Defect-cleft Lip/Cleft Palate Syndrome: Curly Hair-ankyloblepharon-nail Disease Syndrome. AB - Ankyloblepharon-ectodermal defect-cleft lip/cleft palate (AEC) syndrome is one of the variants of ectodermal dysplasia. It is an autosomal dominant disorder comprising of ankyloblepharon, ectodermal dysplasia, and cleft palate or cleft lip. In 1976, it wasfirst described by Hay and Wells, therefore also known as Hay Wells syndrome. The characteristic feature of this syndrome is "ankyloblepharon filiforme adnatum", which refers to the partial thickness fusion of the eyelid margins. The "curly hair-ankyloblepharon-nail disease (CHAND) syndrome" is a clinical variant of AEC syndrome. We report a rare case of a 7-year-old girl child who presented with history of abnormal dentition, 20 nail dystrophy, and light-colored, sparse curly hairs since birth. Parents gave history that at the time of birth, her both eyelids were fused partially, which was surgically corrected by an ophthalmologist at 1 month of age. There was no history of hypohidrosis or anhidrosis, heat intolerance, cleft lip or cleft palate. Microscopy of the hair shaft found "bubbly hair" morphology. This case is unique as it is a rare presentation, and awareness should be there for this constellation of findings so that the systemic associations can be investigated. "Bubble hair" morphology on microscopy is a unique feature in this rare autosomal recessive condition. PMID- 29440853 TI - Efficacy of 800 nm Diode Laser to Treat Trichostasis Spinulosa in Asian Patients. AB - Context: Trichostasis spinulosa (TS) is a common but underdiagnosed follicular disorder involving retention of successive telogen hair in the hair follicle. Laser hair removal is a newer treatment modality for TS with promising results. Aims: This study aims to evaluate the efficacy of 800 nm diode laser to treat TS in Asian patients. Subjects and Methods: We treated 50 Indian subjects (Fitzpatrick skin phototype IV-V) with untreated trichostasis spinulosa on the nose with 800 nm diode laser at fluence ranging from 22 to 30 J/cm2 and pulse width of 30 ms. The patients were given two sittings at 8 week intervals. The evaluation was done by blinded assessment of photographs by independent dermatologists. Results: Totally 45 (90%) patients had complete clearance of the lesions at the end of treatment. Five (10%) subjects needed one-third sitting for complete clearance. 45 patients had complete resolution and no recurrence even at 2 years follow-up visit. 5 patients had partial recurrence after 8-9 months and needed an extra laser session. Conclusions: Laser hair reduction in patients with TS targets and removes the hair follicles which are responsible for the plugged appearance. Due to permanent ablation of the hair bulb and bulge, the recurrence which is often seen with other modalities of treatment for TS is not observed here. PMID- 29440854 TI - Whorled Scarring Alopecia - The Only Adult Marker of Incontinentia Pigmenti. AB - Incontinentia pigmenti (IP) is a rare X-linked dominant disease that affects the ectodermal tissues. It is associated with a whorled pattern of scarring alopecia, which is possibly underreported. This scarring alopecia could be used as a marker to identify adult women affected with IP as older patients may have minimal cutaneous manifestations. We report an unusual case of an 8-year-old girl who had recurrent inflammatory stage IP and later developed whorled scarring alopecia in the vertex of the scalp. PMID- 29440855 TI - Circle Hairs Involving the Extremities in a Young Girl. AB - Circle hairs (CHs) represent a body hair growth disorder which is characterized by asymptomatic presence of hairs in typical circular or spiraliform arrangement. It is not associated with follicular or inflammatory abnormalities. CHs are rarely reported, probably underestimated, as medical consultation for CH only is rare in practice. It needs to be differentiated from rolled hairs, which is a relatively common disorder of hair growth associated with follicular hyperkeratosis and keratin plugging. Trichoscopy is a noninvasive technique to confirm the diagnosis without biopsy. We present a 20-year-old female who presented with CHs over bilateral upper and lower limbs involving extensors. PMID- 29440856 TI - Development of Frontal Fibrosing Alopecia with a History of Alopecia Areata. AB - Frontal fibrosing alopecia (FFA), a scarring type of alopecia, developed in two patients with a history of alopecia areata (AA). Both patients had biopsies to confirm this interesting series of pathology. Etiology and pathogenesis of this AA-to-FFA sequence will be discussed. PMID- 29440857 TI - Eruptive Vellus Hair Cyst: An Uncommon and Underdiagnosed Entity. AB - Eruptive vellus hair cyst (EVHC) is a rare follicular developmental abnormality of the vellus hair follicles. They are usually seen in children, adolescents, or young adults and manifest as reddish-brown smooth papules most commonly involving the chest, limbs, and abdomen. An 18-year-old male presented with asymptomatic papules on the trunk and flexor aspect of both forearms for the past 2 years. There was no family history of similar lesions. His medical history was also not contributory. A clinical diagnosis of steatocystoma multiplex and chronic folliculitis was given, and a punch biopsy from the papule was performed and sent for histopathological examination. On microscopic examination, a final diagnosis of EVHC was rendered. The patient was advised topical treatment of retinoic acid cream (0.05%) for 6 months, and he is currently under follow-up period. Due to its rarity and resemblance to many similar entities, histopathological examination plays a major role in establishing a definite diagnosis and further proper management of the patient. We report this unusual case to generate awareness about this rarely diagnosed condition. PMID- 29440858 TI - Annular Alopecia Areata: A Morphologically Rare Variant. AB - Alopecia areata (AA) is the most common form of nonscarring alopecia involving the scalp and/or body. The most common pattern of hair loss is oval or round, but newer morphological variants are increasingly being described. We hereby report two cases of annular pattern of AA due to its unusual morphology. PMID- 29440859 TI - Nevus Comedonicus on Scalp: An Unusual Presentation. AB - Nevus comedonicus (NC) is a rare developmental anomaly of follicular infundibulum plugged with keratinous material that resembles comedo-like lesions. Frequently affected sites are face, neck, trunk, and upper arm. Few cases have been described on palms, soles, scalp, and genitalia. We hereby report a rare case of NC on scalp in a 14-year-old boy. PMID- 29440860 TI - Three Cases of Radiation-induced Temporary Alopecia with Hair Microscopic Examination: "Coudability Hair" Might Not be Specific for Alopecia Areata. AB - Endovascular interventional procedures are widely used for the treatment of intracranial vascular lesions. However, they sometimes produce reversible alopecia, known as radiation-induced temporary alopecia, depending on the radiation dose. Radiation-induced temporary alopecia manifested as rectangular alopecic patches without signs of inflammation, reflects damage to the keratinocytes in the hair matrix of anagen hair follicles, due to the sensitivity of these cells to radiation. The characteristics of radiation-induced temporary alopecia are similar to those of alopecia areata as follows: (1) clinical findings of well-defined alopecic patches and (2) dermoscopic findings of yellow dots, black dots, and short vellus hairs. The two conditions can be distinguished according to whether there is any history of endovascular interventional procedures, and by the shapes of the lesions and the inflammation status on histopathologic examination. A hair microscopic examination is a useful diagnostic tool in patients with hair loss disease, but the features of radiation induced temporary alopecia have not been well described. Here, we report three cases of radiation-induced temporary alopecia preceded by endovascular procedures, including stent insertion and coil embolization. PMID- 29440861 TI - Eyelashes Trichomegaly: An Unusual Side Effect of Gefitinib Therapy. AB - Evolution of targeted therapy has changed the spectrum of treatment in oncology since the past two decades as lots of newer agents are being added to the pharmacologic armamentarium of cancer therapy. Epidermal growth factor receptor inhibitors form one such advancing field with many newer agents being investigated and they are used in wide variety of malignancies such as head and neck cancer, lung cancer, and even gastrointestinal malignancies such as pancreatic cancer. Various troublesome side effects of these agents include diarrhea, severe fatigability, severe skin rashes, and deranged liver function tests which may require treatment interruption or dose reduction resulting in decreased response to treatment. However, some of the side effects may not require dose modification but incidentally observed and does not impact patient's quality of life. One such effect is trichomegaly which is very rarely observed with such agents. Herein, this conversation we report a 52-year-old female case of metastatic carcinoma lung who developed trichomegaly of eyelashes while on gefitinib therapy. PMID- 29440862 TI - A Rare Association of Pili Multigemini and Rolled Hairs in a Young Female, Title Requires a Change. PMID- 29440863 TI - Adverse Effects with Finasteride 5 mg/day for Patterned Hair Loss in Premenopausal Women. PMID- 29440865 TI - Efficacy of Palatal Applications on Fracture Resistance of Reattached Maxillary Central Incisors: An In Vitro Study. AB - The purpose of this study was to evaluate the effects of different palatal applications on fracture strength of the fractured anterior tooth. Sixty caries free human maxillary incisors were used. Endodontic treatments of the teeth were performed. Then, the teeth were divided randomly into five groups (n = 12). Crowns of all teeth in groups A-D were cut with diamond discs at a fixed distance of 3 mm from the incisal margin in a plane normal to the buccal surface. In all groups, coronal fragments were reattached to the remaining teeth by bonding with hybrid composite resin. After then, the teeth were restored to the following; group A, bonding and palatal laminate; group B, bonding and creation of a vertical groove; group C, bonding and creation of two slot grooves; group D, bonding only; and group E, intact tooth. It was lesser in group B than in groups C and E (p = 0.007 and p = 0.006, resp.) and lesser in group D than in groups A, C, and E (p = 0.002, p < 0.001, and p < 0.001, resp.). Within the limitations of this in vitro study, it can be concluded that methods employing palatinal laminate and small grooves are clinically feasible for the reattachment of tooth fragments to incisors. PMID- 29440864 TI - Validation of Material Algorithms for Femur Remodelling Using Medical Image Data. AB - The aim of this study is the utilization of human medical CT images to quantitatively evaluate two sorts of "error-driven" material algorithms, that is, the isotropic and orthotropic algorithms, for bone remodelling. The bone remodelling simulations were implemented by a combination of the finite element (FE) method and the material algorithms, in which the bone material properties and element axes are determined by both loading amplitudes and daily cycles with different weight factor. The simulation results showed that both algorithms produced realistic distribution in bone amount, when compared with the standard from CT data. Moreover, the simulated L-T ratios (the ratio of longitude modulus to transverse modulus) by the orthotropic algorithm were close to the reported results. This study suggests a role for "error-driven" algorithm in bone material prediction in abnormal mechanical environment and holds promise for optimizing implant design as well as developing countermeasures against bone loss due to weightlessness. Furthermore, the quantified methods used in this study can enhance bone remodelling model by optimizing model parameters to gap the discrepancy between the simulation and real data. PMID- 29440866 TI - Long-term progression of visual field defects and related factors in medically treated normal tension glaucoma. AB - Purpose: To analyze factors related to long-term progression of visual field defects (VFD) in patients with normal tension glaucoma (NTG) under medical therapy. Patients and methods: Clinical data from 622 eyes of 311 primary open angle glaucoma and NTG patients were collected from April 2006 to March 2016. Of these patients, those with normal intraocular pressure (IOP); glaucomatous VFD judged by Anderson's criteria; corrected visual acuity >=0.7; receiving more than 6 years medical therapy; having undergone >=10 visual field tests performed at 6 month intervals using a Humphrey field analyzer (Swedish Interactive Threshold Algorithms standard, C 24-2 program); and having reliability coefficients of visual field testing <33% and mean deviation (MD) more than -20 decibels in the initial visual field test were included in data analysis. The relationship between MD slope deterioration at final observation and consecutive decreases in MD value during the observation period, as well as clinical characteristics and IOP-related factors, were analyzed. Results: Of 134 eyes in 134 NTG patients meeting all eligibility criteria, significant MD slope deterioration was observed in 80 eyes (59.7%). MD slope deterioration was significantly associated with consecutive decreases in MD values (Cochran-Armitage trend test: P=0.0000; univariate logistic regression analysis: P<0.0001). While no significant relationship was observed between central corneal thickness, refractive error, or prevalence of disc hemorrhage, consecutive decreases in MD value was significantly related to MD slope deterioration (univariate logistic regression analysis: P<0.0001). A reduction of IOP during the follow-up period was significantly related to nondeterioration of the MD slope (multivariate logistic regression analysis: P=0.0020). Conclusion: In this 6-year observation of NTG patients treated with medical therapy, the occurrence of three or more consecutive decreases in MD value was significantly associated with visual field deterioration. Reduction in IOP was postulated to be contributing in the prevention of VFD progression. PMID- 29440867 TI - Long-term titrated IOP control with one, two, or three trabecular micro-bypass stents in open-angle glaucoma subjects on topical hypotensive medication: 42 month outcomes. AB - Purpose: Evaluate long-term outcomes after one, two, or three trabecular micro bypass stents implanted in a standalone procedure in eyes with open-angle glaucoma taking ocular hypotensive medication. Patients and methods: Prospective randomized ongoing study of 119 subjects (109 with 42-month follow-up) with open angle glaucoma, preoperative intraocular pressure (IOP) 18-30 mmHg on one to three glaucoma medications, and unmedicated (post-washout) IOP 22-38 mmHg. Subjects were randomized to receive one (n=38), two (n=41), or three (n=40) iStent trabecular micro-bypass stents in a standalone procedure. Postoperatively, IOP was measured with medication and annually following washout. Data included IOP, medications, gonioscopy, pachymetry, visual field, visual acuity, adverse events, and slit-lamp and fundus examinations. Results: Preoperative mean medicated IOP was 19.8+/-1.3 mmHg on 1.71 medications in one-stent eyes, 20.1+/ 1.6 mmHg on 1.76 medications in two-stent eyes, and 20.4+/-1.8 mmHg on 1.53 medications in three-stent eyes. Post-washout IOP prior to stent implantation was 25.0+/-1.2, 25.0+/-1.7, and 25.1+/-1.9 mmHg in the three groups, respectively. Postoperatively, Month 42 medicated IOP was 15.0+/-2.8, 15.7+/-1.0 and 14.8+/-1.3 mmHg in the three groups, and post-washout IOP (Months 36-37) was 17.4+/-0.9, 15.8+/-1.1 and 14.2+/-1.5 mmHg, respectively. IOP reduction >=20% without medication was achieved in 89%, 90%, and 92% of one-, two-, and three-stent eyes, respectively, at Month 12; and in 61%, 91%, and 91% of eyes, respectively, at Month 42. The need for additional medication remained consistent at Months 12 and 42 in multi-stent eyes (four two-stent eyes and three three-stent eyes at both time points), whereas it increased in single-stent eyes (four eyes at Month 12 versus 18 eyes at Month 42). Safety parameters were favorable in all groups. Conclusion: The standalone implantation of either single or multiple iStent(r) device(s) produced safe, clinically meaningful IOP and medication reductions through 42 months postoperatively, with incrementally greater and more sustained reductions in multi-stent eyes. PMID- 29440868 TI - Ocular comfort assessment of lifitegrast ophthalmic solution 5.0% in OPUS-3, a Phase III randomized controlled trial. AB - Purpose: To evaluate ocular comfort of lifitegrast ophthalmic solution 5.0% among patients with dry eye disease (DED) in the OPUS-3 trial. Methods: OPUS-3 was a multicenter, randomized, double-masked, placebo-controlled study. Adults with DED and recent artificial tear use were randomized 1:1 (lifitegrast:placebo) to ophthalmic drops twice daily for 84 days. On days 0 (baseline), 14, 42, and 84, drop comfort score (scale, 0-10; 0 = very comfortable, 10 = very uncomfortable) was measured at 0, 1, 2, and 3 minutes postinstillation. If the score was >3 at 3 minutes, assessment was repeated at 5, 10, and 15 minutes until score <=3. Ocular treatment-emergent adverse events (TEAEs) were assessed. Results: Overall, 711 participants were randomized (n=357 received lifitegrast; n=354 received placebo). Drop comfort scores for lifitegrast-treated participants improved within 3 minutes of instillation (mean scores on day 84 for both study and fellow eyes: instillation: lifitegrast, 3.4, placebo, 1.0; 3 minutes: lifitegrast, 1.5, placebo, 0.7). The majority (64%-66%) of participants had scores <3 within 3 minutes postinstillation on days 14, 42, and 84. In participants with scores >3 at 3 minutes, the mean score in the lifitegrast group was similar to or better than that in the placebo group at 5, 10, or 15 minutes postinstillation. Lifitegrast appeared to be well tolerated, with ocular TEAEs rarely leading to discontinuation. Conclusion: In OPUS-3, lifitegrast appeared to be well tolerated and drop comfort scores approached placebo levels by 3 minutes postinstillation. PMID- 29440869 TI - Exfoliation syndrome in Northern Nigeria. AB - Purpose: To estimate the frequency of exfoliation syndrome (XFS) and its association with ocular diseases in Northern Nigeria. Materials and methods: Consecutive patients who presented to the outpatient department of ECWA Eye Hospital Kano from February 2015 to May 2015 were included in the study. Each patient had a complete ophthalmic examination. The anterior segment examination included tonometry, gonioscopy, and detailed slit-lamp examination to assess for the presence or absence of exfoliation material, inflammatory cells, and other abnormal findings. Patients with exfoliation material on the anterior lens surface and/or pupillary margin in either or both eyes were considered to have XFS. Statistical analysis was performed using the Statistical Package for the Social Sciences version 16.0. Results: A total of 620 patients living in Northern Nigeria from the 6 geopolitical zones were examined. The majority of them (34.5%) were indigenous Hausas. There was a male preponderance of 56.6%, while the mean age at presentation for examination in all age groups was 55.7+/-13.7 years. There were 9 patients with XFS; the frequency was 1.5%, with most of the patients being 70-80 years old. In patients who were >=50 years, the frequency was 2.5%. Patients with XFS had a higher mean age of 68+/-4.9 years. The frequency of XFS among glaucoma patients was 4.4%, while among cataract patients it was 3.7%. No other associated ocular disease was found in the patients with XFS. Conclusion: This study shows that XFS does exist in Northern Nigeria, as was found in the South. The prevalence of XFS was, however, not reported in the Nigerian National Blindness and Visual Impairment Survey. Therefore, a population-based study is still needed to determine the true prevalence of XFS in Northern Nigeria. PMID- 29440870 TI - Surgical outcomes of membrane-tube-type glaucoma shunt device in indigenous West Africans. AB - Purpose: The aim of this study was to report the safety and efficacy of the membrane-tube (MT)-type glaucoma shunt device (Finetube MT) in the management of refractory glaucoma in indigenous West Africans. Methods: The Finetube MT was implanted into 25 eyes of 25 West African patients with refractory glaucoma. These patients had inadequate intraocular pressure (IOP) control despite maximum tolerable IOP-lowering medications with or without previous ocular surgeries. IOP, postoperative complications, interventions, visual acuities, and the number of IOP-lowering medications were analyzed preoperatively and postoperatively. Results: The mean (standard deviation [SD]) age of the patients was 49.7 (20.9) years. The mean (SD) follow-up duration was 21.0 (10.6) months. Postoperatively, the mean (SD) IOP reduced from a preoperative value of 38.1 (10.3) mmHg to 14.5 (4.6), 16.1 (7.8), and 14.7 (3.0) mmHg at 1, 2, and 3 years postoperatively, respectively, representing 61.9%, 57.7%, and 61.4% reduction from baseline (P<0.01). The mean (SD) number of IOP-lowering medications reduced from 4.1 (1.0) to 0.6 (0.9) at 1 year and 0.9 (1.1) at 2 years after the operation (P<0.01). Using an IOP level between 6 and 21 mmHg and reduced by >=20% from baseline, the cumulative survival rate (standard error) was 96.0% (3.9%) at 6 months, 89.0% (6.0%) at 18 months, and 81.3% (10.6%) at 3 years after the operation. There was no postoperative ocular hypotony, tube occlusion, or device exposure. Conclusion: The Finetube MT may effectively control IOP with minimal risk of postoperative complications in indigenous West Africans. PMID- 29440871 TI - Erratum: Micro-invasive glaucoma surgery (MIGS): a review of surgical procedures using stents [Corrigendum]. AB - [This corrects the article on p. 1583 in vol. 11, PMID: 28919702.]. PMID- 29440872 TI - Topical ocular 0.1% cyclosporine A cationic emulsion in dry eye disease patients with severe keratitis: experience through the French early-access program. AB - Purpose: The objective of this study was to report the evaluation of efficacy and safety of cyclosporine A cationic emulsion (CsA CE) 0.1% for the treatment of severe keratitis in adults with dry eye disease (DED) in a French early-access program. Methods: Patients with DED and severe keratitis (corneal fluorescein staining [CFS] score of 3-5 on the Oxford scale and/or the presence of corneal lesions [filaments or ulcers]) were enrolled in a compassionate use program (Authorization for Temporary Use [ATU]) for once-daily CsA CE, which was approved by French health authorities prior to its registration. Efficacy and safety at 1, 3, 6, and 12-month follow-up visits were evaluated. Results: The ATU cohort (n=1,212; mean age =60.5 years; 79.5% female; 98.1% with severe keratitis; 74.5% with corneal lesions) consisted of 601 CsA-naive patients and 611 patients treated previously with other CsA formulations. The primary DED etiology was Sjogren's syndrome (48.7%). Clinical benefit could be discerned among 548 evaluable patients from months 1 to 12: keratitis improvement, 44.8% at month 1 and 42.1% at month 12; keratitis stabilization, 47.2% and 45.7%, respectively; symptom improvement, 47.2% and 48.6%; and symptom stabilization, 44.8% and 45.0%. Corneal clearing (CFS score =0) increased from 4.8% (month 1) to 11.4% (month 12). No unexpected safety concerns were identified; instillation site pain (10.2%) and eye irritation (7.8%) were the most common adverse events. Conclusion: The French ATU cohort provides supportive data on the clinical benefit of CsA CE in improving/stabilizing symptoms and corneal damage in DED patients with severe keratitis in real-world clinical practice. PMID- 29440873 TI - Effect of phenylephrine/ketorolac on iris fixation ring use and surgical times in patients at risk of intraoperative miosis. AB - Purpose: To evaluate the effect of intracameral phenylephrine/ketorolac (1%/0.3%) during cataract surgery on the use of iris fixation ring and surgical time in patients with poor pupil dilation (<=5.0 mm) or intraoperative floppy iris syndrome (IFIS). Setting: Private practice outpatient surgical center. Design: This retrospective analysis was conducted from January 1, 2014 to October 7, 2015. Materials and methods: The use of iris fixation rings was evaluated in a retrospective analysis of 46 patients who underwent cataract surgery from January 1, 2014, to October 7, 2015, and who were identified before surgery to be at risk for intraoperative miosis. The qualifying factors were presurgical examination of pupil dilation <=5.0 mm after being administered topical tropicamide 1% and phenylephrine 2.5% or history of IFIS during surgery in the fellow eye. All patients received a 2-day preoperative course of topical nonsteroidal anti inflammatory drugs (NSAIDs) and day-of-surgery preoperative dilation using topical cyclopentolate 1%, tropicamide 1%, and phenylephrine 10%. Phenylephrine/ketorolac 1%/0.3% (Omidria(r)) or epinephrine 1:1,000 with sulfites was added to the ophthalmic irrigation solution and delivered intracamerally at the start of the procedure and throughout surgery. The use of iris fixation rings and surgical time for each patient were captured for each group. Results: Eighteen (50%) of the patients in the epinephrine group and no patients in the phenylephrine/ketorolac group required iris fixation ring insertion to maintain pupil dilation or to control IFIS (p=0.0034). Mean surgical time was significantly shorter in the group of patients who received phenylephrine/ketorolac (p=0.0068). Conclusion: In this retrospective cohort analysis of patients with poorly dilated pupils and/or IFIS, the use of intracameral phenylephrine/ketorolac in patients at risk for intraoperative miosis resulted in significantly less iris fixation ring use and significantly shorter surgical time when compared with intracameral epinephrine use. PMID- 29440874 TI - Clinical potential of mechlorethamine gel for the topical treatment of mycosis fungoides-type cutaneous T-cell lymphoma: a review on current efficacy and safety data. AB - Nitrogen mustard is a chemotherapeutic agent that has a well-documented safety and efficacy profile in the treatment of cutaneous T-cell lymphoma. Development of nitrogen mustard formulations and treatment regimens has been studied extensively over the last 40 years. In the last 5 years, a new gel formulation has been developed that is associated with a decrease in delayed hypersensitivity reactions. The authors in this review found that while the gel formulation may result in a decrease of allergic contact dermatitis, this advantage has been replaced by a higher number of irritant contact reactions and a decrease in complete response rate. The gel formulation has a complete response rate of 13.8%, which is a decrease in efficacy when compared to aqueous-based preparations of similar concentrations. PMID- 29440876 TI - Research of an emergency medical system for mass casualty incidents in Shanghai, China: a system dynamics model. AB - Objectives: Emergency medical system for mass casualty incidents (EMS-MCIs) is a global issue. However, China lacks such studies extremely, which cannot meet the requirement of rapid decision-support system. This study aims to realize modeling EMS-MCIs in Shanghai, to improve mass casualty incident (MCI) rescue efficiency in China, and to provide a possible method of making rapid rescue decisions during MCIs. Methods: This study established a system dynamics (SD) model of EMS MCIs using the Vensim DSS program. Intervention scenarios were designed as adjusting scales of MCIs, allocation of ambulances, allocation of emergency medical staff, and efficiency of organization and command. Results: Mortality increased with the increasing scale of MCIs, medical rescue capability of hospitals was relatively good, but the efficiency of organization and command was poor, and the prehospital time was too long. Mortality declined significantly when increasing ambulances and improving the efficiency of organization and command; triage and on-site first-aid time were shortened if increasing the availability of emergency medical staff. The effect was the most evident when 2,000 people were involved in MCIs; however, the influence was very small under the scale of 5,000 people. Conclusion: The keys to decrease the mortality of MCIs were shortening the prehospital time and improving the efficiency of organization and command. For small-scale MCIs, improving the utilization rate of health resources was important in decreasing the mortality. For large-scale MCIs, increasing the number of ambulances and emergency medical professionals was the core to decrease prehospital time and mortality. For super-large-scale MCIs, increasing health resources was the premise. PMID- 29440875 TI - Experimental and molecular modeling approach to optimize suitable polymers for fabrication of stable fluticasone nanoparticles with enhanced dissolution and antimicrobial activity. AB - Background and aim: The challenges with current antimicrobial drug therapy and resistance remain a significant global health threat. Nanodrug delivery systems are playing a crucial role in overcoming these challenges and open new avenues for effective antimicrobial therapy. While fluticasone (FLU), a poorly water soluble corticosteroid, has been reported to have potential antimicrobial activity, approaches to optimize its dissolution profile and antimicrobial activity are lacking in the literature. This study aimed to combine an experimental study with molecular modeling to design stable FLU nanopolymeric particles with enhanced dissolution rates and antimicrobial activity. Methods: Six different polymers were used to prepare FLU nanopolymeric particles: hydroxyl propyl methylcellulose (HPMC), poly (vinylpyrrolidone) (PVP), poly (vinyl alcohol) (PVA), ethyl cellulose (EC), Eudragit (EUD), and Pluronics(r). A low energy method, nanoprecipitation, was used to prepare the polymeric nanoparticles. Results and conclusion: The combination of HPMC-PVP and EUD-PVP was found most effective to produce stable FLU nanoparticles, with particle sizes of 250 nm +/-2.0 and 280 nm +/-4.2 and polydispersity indices of 0.15 nm +/-0.01 and 0.25 nm +/-0.03, respectively. The molecular modeling studies endorsed the same results, showing highest polymer drug binding free energies for HPMC-PVP-FLU (-35.22 kcal/mol +/-0.79) and EUD-PVP-FLU (-25.17 kcal/mol +/-1.12). In addition, it was observed that Ethocel(r) favored a wrapping mechanism around the drug molecules rather than a linear conformation that was witnessed for other individual polymers. The stability studies conducted for 90 days demonstrated that HPMC-PVP-FLU nanoparticles stored at 2 degrees C-8 degrees C and 25 degrees C were more stable. Crystallinity of the processed FLU nanoparticles was confirmed using differential scanning calorimetry, powder X-ray diffraction analysis and TEM. The Fourier transform infrared spectroscopy (FTIR) studies showed that there was no chemical interaction between the drug and chosen polymer system. The HPMC-PVP-FLU nanoparticles also showed enhanced dissolution rate (P<0.05) compared to the unprocessed counterpart. The in vitro antibacterial studies showed that HPMC-PVP-FLU nanoparticles displayed superior effect against gram-positive bacteria compared to the unprocessed FLU and positive control. PMID- 29440877 TI - Psychometric properties and assessment of the Osteoporosis Health Belief Scale among the general Arabic population. AB - Background: Any educational program should be implemented with a good understanding of the population's beliefs. Therefore, the aims of this study were to validate the Arabic version of the Osteoporosis Health Belief Scale (OHBS-A) and assess the osteoprotective attitude among the Iraqi population. Methods: A cross-sectional design, with a random cluster sampling method from the community, was used. The forward-backward-forward translation method was used to translate the questionnaire from English to Arabic. In addition, the Arabic version of Osteoporosis Knowledge Tool (OKT-A) and the Arabic version of Osteoporosis Self Efficacy Scale (OSES-A) were used to assess the osteoprotective behaviors. Results: The results showed good face validity and reliability. The construct validity analysis showed seven factors that explain 72.82% of the variance. In addition, the results revealed a low health belief score (149.95+/-35.936) with only 36.67% of the study population found to have a high OHBS-A level. The results showed significant differences among employment status, marital status, and osteoporosis (OP) awareness groups in relation to total OHBS-A scores. In addition, there were significant associations between age groups and OP awareness with health belief levels. Moreover, both exercise and calcium intake subscales of the Osteoporosis Knowledge Tool (OKT) positively correlated with all OHBS-A subscales. Exercise and calcium intake subscales of Osteoporosis Self-Efficacy Scale (OSES) positively correlated with the perceived susceptibility and perceived barriers toward exercise and calcium intake. The binary logistic regression analysis showed that OKT levels, OSES levels, and age were predictors of OHBS-A levels. Conclusion: Besides cultural obstacles, an educational program for both genders and all age groups is important and should be tailored according to culture needs. PMID- 29440878 TI - Functionality and Outcome in Older Patients with Severe Aortic Stenosis (FOOPAS): an interdisciplinary study concept for a prospective trial. AB - Background: Frailty is a geriatric syndrome that can influence mortality and functional recovery after treatment of severe aortic stenosis (AS). The integration of standardized geriatric assessment (GA) in clinical practice is limited by a lack of consensus on how to measure it. Objectives: This study aims to compare the incremental predictive value of different frailty scales to predict the outcomes following surgical aortic valve replacement, transcatheter aortic valve implantation, and conservative treatment of severe AS. Methods: A prospective cohort of 300 older adults with severe AS will be assembled after standard clinical examinations and a comprehensive GA, including 18 different tests and values. Primary outcome parameters are overall mortality, cardiovascular mortality, quality of life, and functionality. Secondary parameters are overall complications, cardiovascular complications, and costs. Results: Expected results will contribute to the growing body of evidence on frailty based on parameters that influence clinical and functional outcome in elderly patients independent of the method of treatment. The pre-procedural assessment is expected to be valuable in discriminating new post-procedural complications from simple exacerbations of pre-existing conditions. Therefore, a new frailty test which is simple and feasible for application in a clinical routine by most medical professionals, may help in identifying patients for whom further GA should be considered. Finally, such a frailty score could support heart teams to find the right treatment for patients suffering from AS. Conclusion: Comparison of different frailty scales has not only the goal of finding a predictive value of mortality but also to bring in a meaningful improvement for each individual patient and to avoid disability or fatal outcomes. PMID- 29440879 TI - Feasibility and safety of elective laparoscopic total extraperitoneal preperitoneal groin hernia repair in the elderly: a propensity score-matched comparison. AB - Background: Several studies of hernia registries have revealed that elderly patients have higher perioperative complication rates compared with younger patients. However, the incidence of hernia increases with the aging process. To evaluate the feasibility and safety of laparoscopic hernia repair in elderly patients (>=75 years), we conducted a prospective case-matched control study to compare perioperative outcomes between patients older and younger than 75 years. Methods: Between September 2008 and July 2015, 572 consecutive patients undergoing endoscopic hernia repair were included in this prospective study. This case-matched control study was matched based on sex, American Society of Anesthesiologists score, and body mass index between patients younger and >=75 years. The propensity-score matching of two groups was carried out on a 1:1 basis. Perioperative data were prospectively recorded for all patients including demographic data, operation time, length of hospital stay, narcotic dose, and complications. Results: In the final analysis, 54 patients who were <75 years were extracted to match the 54 patients >=75 years. These two groups had similar baseline characteristics excluding age. They also had similar perioperative outcomes in hernia recurrence, metachronous contralateral hernia occurrence, complication rate and chronic pain. The patients >=75 years of age had lower requirements for analgesics than those who were <75 years of age (p=0.047). Conclusion: This is the first comparative cohort study investigating the impact of aging in an Asian hernia population. Laparoscopic inguinal hernia repair is feasible and safe for older patients, with comparable perioperative outcomes to patients <75 years. PMID- 29440880 TI - Comparison of three tools for predicting primary osteoporosis in an elderly male population in Beijing: a cross-sectional study. AB - Purpose: In this cross-sectional study, three clinical tools, the Osteoporosis Self-Assessment Tool for Asians (OSTA), Fracture Risk Assessment Tool (FRAX) without bone mineral density (BMD), and body mass index (BMI), for predicting primary osteoporosis (OP) were compared and ideal thresholds for omission of screening BMD were proposed in a community-dwelling elderly Han Beijing male population. Patients and methods: A total of 1,349 community-dwelling elderly Han Beijing males aged >=50 years were enrolled in this study. All subjects completed a questionnaire and measured BMD by dual-energy X-ray absorptiometry (DXA). Osteoporosis was defined as a T-score of -2.5 SD or lower than that of the average young adult in different diagnostic criteria (lumbar spine [L1-L4], femoral neck, total hip, worst hip, and World Health Organization [WHO]). FRAX without BMD, OSTA, and BMI were assessed for predicting OP by receiver operating characteristic (ROC) curves. Sensitivity, specificity, and areas under the ROC curves (AUCs) were determined. Ideal thresholds for omission of screening BMD were proposed. Results: The prevalence of OP ranged from 1.8% to 12.8% according to different diagnostic criteria. This study showed that the BMI has highest discriminating ability. The AUC of FRAX without BMD ranged from 0.536 to 0.630, which suggested limiting predictive value for identifying OP in elderly Beijing male. The AUCs of BMI (0.801-0.880) were slightly better than OSTA (0.722-0.874) in predicting OP at all sites. The AUC of BMI to identify OP in worst hip was 0.824, yielding a sensitivity of 84.8% and a specificity of 64.4%. 40% of participants on BMD measurements saved only 0.1%-2.7% missed OP. Compared to OSTA and FRAX without BMD, the BMI got the best predictive value for OP. Conclusion: BMI may be a simple and effective tool for identifying OP in the elderly male population in Beijing to omit BMD screening reasonably. PMID- 29440881 TI - Immediate synergistic effect of a trunk orthosis with joints providing resistive force and an ankle-foot orthosis on hemiplegic gait. AB - Purpose: The synergistic effects of a trunk orthosis and an ankle-foot orthosis (AFO) in stroke patients with a hemiplegic gait are unclear. We previously developed a trunk orthosis with joints providing resistive force (TORF) to modify malalignment of the trunk and pelvis and confirmed its positive effects in stroke patients during level walking without an AFO. The aim of the present study was to determine if this trunk orthosis and an AFO have synergistic effects during level walking in community-dwelling patients with chronic stroke. Methods: Twenty-eight community-dwelling stroke patients performed level walking at a self-selected speed with an AFO and again while wearing a TORF (TORF group) or a corset (control group). Spatiotemporal, kinematic, and kinetic data were recorded using a three-dimensional motion analysis system. Results: When compared with the control group, the TORF group showed significant increases in walking speed, number of steps on the paretic leg per minute, and peak ankle plantar flexion moment during the single stance phase. Conclusion: The TORF increased the ankle joint plantar flexion moment at the end of the single stance phase during level walking in stroke patients, leading to an increase in their gait speed because of the modified trunk and pelvis alignment. PMID- 29440882 TI - The distribution of blood eosinophil levels in a Japanese COPD clinical trial database and in the rest of the world. AB - Background: Blood eosinophil measurements may help to guide physicians on the use of inhaled corticosteroids (ICS) for patients with chronic obstructive pulmonary disease (COPD). Emerging data suggest that COPD patients with higher blood eosinophil counts may be at higher risk of exacerbations and more likely to benefit from combined ICS/long-acting beta2-agonist (LABA) treatment than therapy with a LABA alone. This analysis describes the distribution of blood eosinophil count at baseline in Japanese COPD patients in comparison with non-Japanese COPD patients. Methods: A post hoc analysis of eosinophil distribution by percentage and absolute cell count was performed across 12 Phase II-IV COPD clinical studies (seven Japanese studies [N=848 available absolute eosinophil counts] and five global studies [N=5,397 available eosinophil counts] that included 246 Japanese patients resident in Japan with available counts). Blood eosinophil distributions were assessed at baseline, before blinded treatment assignment. Findings: Among Japanese patients, the median (interquartile range) absolute eosinophil count was 170 cells/mm3 (100-280 cells/mm3). Overall, 612/1,094 Japanese patients (56%) had an absolute eosinophil count >=150 cells/mm3 and 902/1,304 Japanese patients (69%) had a percentage eosinophil >=2%. Among non-Japanese patients, these values were 160 (100-250) cells/mm3, 2,842/5,151 patients (55%), and 2,937/5,155 patients (57%), respectively. The eosinophil distribution among Japanese patients was similar to that among non-Japanese patients. Within multi-country studies with similar inclusion criteria, the eosinophil count was numerically lower in Japanese compared with non-Japanese patients (median 120 vs 160 cells/mm3). Interpretation: The eosinophil distribution in Japanese patients seems comparable to that of non-Japanese patients; although within multi-country studies, there was a slightly lower median eosinophil count for Japanese patients compared with non-Japanese patients. These findings suggest that blood eosinophil data from global studies are of relevance in Japan. PMID- 29440884 TI - The minimal important difference for target lobe volume reduction after endoscopic valve therapy. AB - Objective: Endoscopic valve therapy aims at target lobe volume reduction (TLVR) that is associated with improved lung function, exercise tolerance and quality of life in emphysema patients. So far, a TLVR of >350 mL was considered to be indicative of a positive response to treatment. However, it is not really known what amount of TLVR is crucial following valve implantation. Patients and methods: TLVR, forced expiratory volume in 1 second (FEV1), residual volume (RV) and 6-minute walk distance (6-MWD) were assessed before and 3 months after valve implantation in 119 patients. TLVR was calculated based on computed tomography (CT) scan analysis using imaging software (Apollo; VIDA Diagnostics). Minimal important difference estimates were calculated by anchor-based and distribution based methods. Results: Patients treated with valves experienced a mean change of 0.11 L in FEV1, -0.51 L in RV, 44 m in 6-MWD and a TLVR of 945 mL. Using a linear regression and receiver operating characteristic analysis based on two of three anchors (DeltaFEV1, DeltaRV), the estimated minimal important difference for TLVR was between 890 and 1,070 mL (ie, 49%-54% of the baseline TLV). Conclusion: In future, a TLVR between 49% and 54% of the baseline TLV, should be used when interpreting the clinical relevance. PMID- 29440883 TI - Do not do in COPD: consensus statement on overuse. AB - Background: To identify practices that do not add value, cause harm, or subject patients with chronic obstructive pulmonary disease (COPD) to a level of risk that outweighs possible benefits (overuse). Methods: A qualitative approach was applied. First, a multidisciplinary group of healthcare professionals used the Metaplan technique to draft and rank a list of overused procedures as well as self-care practices in patients with stable and exacerbated COPD. Second, in successive consensus-building rounds, description files were created for each "do not do" (DND) recommendation, consisting of a definition, description, quality of supporting evidence for the recommendation, and the indicator used to measure the degree of overuse. The consensus group comprised 6 pulmonologists, 2 general practitioners, 1 nurse, and 1 physiotherapist. Results: In total, 16 DND recommendations were made for patients with COPD: 6 for stable COPD, 6 for exacerbated COPD, and 4 concerning self-care. Conclusion: Overuse poses a risk for patients and jeopardizes care quality. These 16 DND recommendations for COPD will lower care risks and improve disease management, facilitate communication between physicians and patients, and bolster patient ability to provide self care. PMID- 29440885 TI - Annexin A1 is elevated in patients with COPD and affects lung fibroblast function. AB - Purpose: Fibrosis in peripheral airways is responsible for airflow limitation in chronic obstructive pulmonary disease (COPD). Annexin A1 modulates several key biological events during inflammation. However, little is known about its role in airway fibrosis in COPD. We investigated whether levels of Annexin A1 were upregulated in patients with COPD, and whether it promoted airway fibrosis. Methods: We quantified serum Annexin A1 levels in never-smokers (n=12), smokers without COPD (n=11), and smokers with COPD (n=22). Correlations between Annexin A1 expression and clinical indicators (eg, lung function) were assessed. In vitro, human bronchial epithelial (HBE) cells were exposed to cigarette smoke extract (CSE) and Annexin A1 expression was assessed. Primary human lung fibroblasts were isolated from patients with COPD and effects of Annexin A1 on fibrotic deposition of lung fibroblasts were evaluated. Results: Serum Annexin A1 was significantly higher in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines stage III or IV than in those with GOLD stages I or II (12.8+/-0.8 ng/mL versus 9.8+/-0.7 ng/mL; p=0.016). Annexin A1 expression was negatively associated with airflow obstruction (forced expiratory volume in one second % predicted; r=-0.72, p<0.001). In vitro, Annexin A1 was significantly increased in CSE-exposed HBE cells in a time- and concentration-dependent manner. Annexin A1 promoted lung fibroblasts proliferation, migration, differentiation, and collagen deposition via the ERK1/2 and p38 mitogen-activated protein kinase pathways. Conclusion: Annexin A1 expression is upregulated in patients with COPD and affects lung fibroblast function. However, more studies are needed to clarify the role of Annexin A1 in airway fibrosis of COPD. PMID- 29440886 TI - Missed diagnosis and overtreatment of COPD among smoking primary care population in Central Greece: old problems persist. AB - Background: The diagnosis of COPD is not always consistent with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy in daily clinical practice, especially in primary care. This study aimed to estimate the overall COPD prevalence and severity, to identify differences between newly and previously diagnosed patients, and to evaluate the potential COPD overtreatment in a smoking population attending a primary care spirometry surveillance program. Methods: A study was conducted in 10 primary health care centers of Central Greece during a 7-month period. Eligible participants were aged >=40 years and were either current smokers or exsmokers. Results: A total of 186 subjects were included (68% males, mean age 62.3+/-12.6 years, mean life-time tobacco exposure 50 pack-years). COPD prevalence was 17.8%, identified to be higher in elderly males. Forty-two percent of the COPD group were newly diagnosed patients, who were of younger age, current smokers, presented with less dyspnea and better health status, and mainly appeared with mild-to-moderate disease. Interestingly, 61.4% of non-COPD and 85.7% of newly diagnosed COPD individuals had been using inhaled medication under primary care provider's prescription without ever undergoing spirometry or further evaluation by a pulmonologist; thus, the phenomena of COPD overdiagnosis and missed diagnosis came into the spotlight. Moreover, only 26.3% of known COPD patients were properly medicated according to GOLD guidelines, while half of them were inappropriately treated with triple inhaled therapy. Conclusion: We reported a significant prevalence of COPD in smoking population attending this spirometry program. A remarkable proportion of COPD patients were undiagnosed and made case finding worthwhile. Underutilization of spirometry in the diagnosis and management of COPD as well as general practitioners' nonadherence to the GOLD treatment guidelines was confirmed by our data. These findings highlight the need for a major overhaul and culture change in primary care settings of Central Greece. PMID- 29440887 TI - Long-term health-related quality-of-life and symptom response profiles with arformoterol in COPD: results from a 52-week trial. AB - Background: Symptom severity is the largest factor in determining subjective health in COPD. Symptoms (eg, chronic cough, dyspnea) are associated with decreased health-related quality of life (HRQoL). We evaluated the impact of arformoterol on HRQoL in COPD patients, measured by St George's Respiratory Questionnaire (SGRQ). Post hoc growth mixture model (GMM) analysis examined symptom response profiles. Methods: We examined data from a randomized, double blind, parallel-group, 12-month safety trial of twice-daily nebulized arformoterol 15 ug (n=420) versus placebo (n=421). COPD severity was assessed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) status. GMM analysis identified previously unknown patient subgroups and examined the heterogeneity in response to SGRQ Symptoms scores. Results: SGRQ Total score improved by 4.24 points with arformoterol and 2.02 points with placebo (P=0.006). Significantly greater improvements occurred for arformoterol versus placebo in SGRQ Symptoms (6.34 vs 4.25, P=0.031) and Impacts (3.91 vs 0.97, P=0.001) scores, but not in Activity score (3.57 vs 1.75, P=0.057). GMM identified responders and nonresponders based on the SGRQ Symptoms score. End-of-study mean difference in SGRQ Symptoms scores between these latent classes was 20.7 points (P<0.001; 95% confidence interval: 17.6-23.9). Compared with nonresponders, responders were more likely current smokers (55.52% vs 44.02%, P=0.0021) and had more severe COPD (forced expiratory volume in 1 second [FEV1]: 1.16 vs 1.23 L, P=0.0419), more exacerbations (0.96 vs 0.69, P=0.0018), and worse mean SGRQ Total (59.81 vs 40.57, P<0.0001), Clinical COPD Questionnaire (3.29 vs 2.05, P<0.0001), and Modified Medical Research Council Dyspnea Scale (3.13 vs 2.75, P<0.0001) scores. Arformoterol-receiving responders exhibited significantly greater improvements in FEV1 (0.09 vs 0.008, P=0.03) and fewer hospitalizations (0.13 vs 0.24, P=0.02) than those receiving placebo. Conclusion: In this study, arformoterol treatment significantly improved HRQoL reflected by SGRQ. For the analysis performed on these data, arformoterol may be particularly effective in improving lung function and reducing hospitalizations among patients who are unable to quit smoking or present with more severe symptoms. PMID- 29440888 TI - Incidence and risk of chronic obstructive pulmonary disease in a Korean community based cohort. AB - Purpose: COPD is a leading cause of morbidity and mortality. However, few studies have used spirometry to investigate its incidence, especially in Asia. In the present study, we analyzed the incidence and risk factors of COPD using a community cohort database in Korea. Patients and methods: The study included 6,517 subjects aged 40-69 years from the Ansung-Ansan cohort database I-III (2001 2006). We calculated the crude incidence rate and the standardized incidence rate corrected for the Korean general population and the world population with COPD. We also determined the relative risks (RRs) for incident COPD and the attributable risks. Results: In total, 329 new COPD cases were diagnosed during follow-up. The overall crude incidence rate per 100,000 person-years was 1,447. The standardized incidence rate corrected for the Korean general population was 1,550; this value was higher in men and increased with increasing age. Risk factors for incident COPD were age >=60 years (adjusted RR [aRR] =2.52 vs age <60 years), male sex (aRR =2.02 vs female), heavy smoking (>=20 pack-years; aRR =2.54 vs never smoker), and lowest income group (first quartile; aRR =2.03 vs fourth quartile). The adjusted attributable risk was highest for education level of high school or lower (44.9%), followed by smoking history (25.8%), income (22.9%), and sex (12.0%). Conclusion: In Korea, 15.5/1,000 people are diagnosed with COPD annually. The incidence rate increases with increasing age, heavier smoking, and decreasing income, with a higher rate in men than in women. PMID- 29440889 TI - A novel therapeutic strategy for cartilage diseases based on lipid nanoparticle RNAi delivery system. AB - Background: Cartilage degeneration affects millions of people but preventing its degeneration is a big challenge. Although RNA interference (RNAi) has been used in human trials via silencing specific genes, the cartilage RNAi has not been possible to date because the cartilage is an avascular and very dense tissue with very low permeability. Purpose: The objective of this study was to develop and validate a novel lipid nanoparticle (LNP)-siRNA delivery system that can prevent cartilage degeneration by knocking down specific genes. Methods: LNP transfection efficiency was evaluated in vitro and ex vivo. Indian Hedgehog (Ihh) has been correlated with cartilage degeneration. The in vivo effects of LNP-Ihh siRNA complexes on cartilage degeneration were evaluated in a rat model of surgery induced osteoarthritis (OA). Results: In vitro, 100% of chondrocytes were transfected with siRNA in the LNP-siRNA group. In accordance with the cell culture results, red positive signals could be detected even in the deep layer of cartilage tissue cultures treated by LNP-beacon. In vivo data showed that LNP is specific for cartilage, since positive signals were detected by fluorescence molecular tomography and confocal microscopy in joint cartilage injected with LNP beacon, but not on the surface of the synovium. In the rat model of OA, intraarticular injection of LNP-Ihh siRNA attenuated OA progression, and PCR results showed LNP-Ihh siRNA exerted a positive impact on anabolic metabolism and negative impact on catabolic metabolism. Conclusion: This study demonstrates that our LNP-RNAi delivery system has a significantly chondroprotective effect that attenuates cartilage degeneration and holds great promise as a powerful tool for treatment of cartilage diseases by knocking down specific genes. PMID- 29440890 TI - Biofunctional Sr- and Si-loaded titania nanotube coating of Ti surfaces by anodization-hydrothermal process. AB - Background: Two frequent problems associated with titanium (Ti) surfaces of bone/dental implants are their corrosion and lack of native tissue integration. Methods: Here, we present an anodization-hydrothermal method for coating Ti surfaces with a layer of silicon (Si)- and strontium (Sr)-loaded titania nanotubes (TNs). The Ti surfaces coated with such a layer (Si-Sr-TNs) were characterized with different techniques. Results: The results indicate that the Si4+ and Sr2+ ions were evenly incorporated into the TNs and that the Si-Sr-TN layer provides good protection against corrosive media like simulated body fluid. The excellent cytocompatibility of the coating was confirmed in vitro by the significant growth and differentiation of MC3T3-E1 osteoblastic cells. Conclusion: Being easily and economically fabricated, the Si-Sr-TN surfaces may find their niche in clinical applications, thanks to their excellent biological activity and corrosion resistance. PMID- 29440891 TI - pH-responsive charge-reversal polymer-functionalized boron nitride nanospheres for intracellular doxorubicin delivery. AB - Background: Anticancer drug-delivery systems (DDSs) capable of responding to the physiological stimuli and efficiently releasing drugs inside tumor cells are highly desirable for effective cancer therapy. Herein, pH-responsive, charge reversal poly(allylamine hydrochlorid)-citraconic anhydride (PAH-cit) functionalized boron nitride nanospheres (BNNS) were fabricated and used as a carrier for the delivery and controlled release of doxorubicin (DOX) into cancer cells. Methods: BNNS was synthesized through a chemical vapor deposition method and then functionalized with synthesized charge-reversal PAH-cit polymer. DOX@PAH cit-BNNS complexes were prepared via step-by-step electrostatic interactions and were fully characterized. The cellular uptake of DOX@PAH-cit-BNNS complexes and DOX release inside cancer cells were visualized by confocal laser scanning microscopy. The in vitro anticancer activity of DOX@ PAH-cit-BNNS was examined using CCK-8 and live/dead viability/cytotoxicity assay. Results: The PAH-cit-BNNS complexes were nontoxic to normal and cancer cells up to a concentration of 100 ug/mL. DOX was loaded on PAH-cit-BNNS complexes with high efficiency. In a neutral environment, the DOX@PAH-cit-BNNS was stable, whereas the loaded DOX was effectively released from these complexes at low pH condition due to amide hydrolysis of PAH-cit. Enhanced cellular uptake of DOX@PAH-cit-BNNS complexes and DOX release in the nucleus of cancer cells were revealed by confocal microscopy. Additionally, the effective delivery and release of DOX into the nucleus of cancer cells led to high therapeutic efficiency. Conclusion: Our findings indicated that the newly developed PAH-cit-BNNS complexes are promising as an efficient pH-responsive DDS for cancer therapy. PMID- 29440892 TI - Bioreducible nanocapsules for folic acid-assisted targeting and effective tumor specific chemotherapy. AB - Introduction: Increasing demands in precise control over delivery and functionalization of therapeutic agents for tumor-specific chemotherapy have led to a rapid development in nanocarriers. Herein, we report a nanocapsule (NC) system for tumor-oriented drug delivery and effective tumor therapy. Materials and methods: Functionalized hyaluronan is utilized to build up the NC shells, in which bioreduction cleavable sites, targeting ligand folic acid (FA), and zwitterionic tentacles are integrated. Results: The hollow NCs obtained (~50 nm in diameter) showed well-defined spherical shell structures with a shell thickness of ~8 nm. These specially designed NCs (doxorubicin [DOX]/FA-Z-NCs) with high drug encapsulation content exhibited good biocompatibility in vitro and fast intracellular drug release behavior mediated by intracellular glutathione. Conclusion: Cellular uptake tests demonstrated rapid uptake of these functionalized NCs and effective escape from endosomes. Antitumor efficacy of the DOX/FA-Z-NCs was confirmed by the significant tumor growth inhibition effect as well as greatly reduced side effects, in contrast with those of the free drug DOX hydrochloride. PMID- 29440893 TI - Nanoemulsion as a strategy for improving the oral bioavailability and anti inflammatory activity of andrographolide. AB - Background: Andrographolide (AG), a compound with low water solubility, possesses various pharmacological activities, particularly anti-inflammatory activity. However, its low oral bioavailability is a major obstacle to its potential use. This study developed and optimized an AG-loaded nanoemulsion (AG-NE) formulation to improve AG oral bioavailability and its protective effects against inflammatory bowel disease. Methods: A high-pressure homogenization technique was used to prepare the AG-NE and solubility, viscosity, and droplet size tests were conducted to develop the optimized AG-NE composed of alpha-tocopherol, ethanol, Cremophor EL, and water. The permeability was assessed using everted rat gut sac method and in vivo absorption and anti-inflammatory effect in rats was also evaluated. The plasma concentration of AG was determined using our validated high performance liquid chromatography method, which was used to generate a linear calibration curve over the concentration range of 0.1-25 MUg/mL in rat plasma (R2>0.999). Results: The optimized AG-NE had a droplet size of 122+/-11 nm confirmed using transmission electron microscopy and a viscosity of 28 centipoise (cps). It was stable at 4 and 25 degrees C for 90 days. An ex vitro intestinal permeability study indicated that the jejunum was the optimal site for AG absorption from the optimized AG-NE, which was 8.21 and 1.40 times higher than that from an AG suspension and AG ethanol solution, respectively. The pharmacokinetic results indicate that the absorption of AG from AG-NE was significantly enhanced in comparison with that from the AG suspension, with a relative bioavailability of 594.3%. Moreover, the ulcer index and histological damage score of mice with indomethacin-induced intestinal lesions were significantly reduced by AG-NE pretreatment. Conclusion: We conclude that the developed AG-NE not only enhanced the oral bioavailability of AG in this study but may also prove to be an effective formulation of AG for preventing gastrointestinal inflammatory disorders. PMID- 29440894 TI - Sustained-release of FGF-2 from a hybrid hydrogel of heparin-poloxamer and decellular matrix promotes the neuroprotective effects of proteins after spinal injury. AB - Introduction: The short lifetime of protein-based therapies has largely limited their therapeutic efficacy in injured nervous post-spinal cord injury (post-SCI). Methods: In this study, an affinity-based hydrogel delivery system provided sustained-release of proteins, thereby extending the efficacy of such therapies. The affinity-based hydrogel was constructed using a novel polymer, heparin poloxamer (HP), as a temperature-sensitive bulk matrix and decellular spinal cord extracellular matrix (dscECM) as an affinity depot of drug. By tuning the concentration of HP in formulation, the cold ternary fibroblast growth factor-2 (FGF2)-dscECM-HP solution could rapidly gelatinize into a hydrogel at body temperature. Due to the strong affinity for FGF2, hybrid FGF2-dscECM-HP hydrogel enabled sustained-release of encapsulated FGF2 over an extended period in vitro. Results: Compared to free FGF2, it was observed that both neuron functions and tissue morphology after SCI were clearly recovered in rats treated with FGF2 dscECM-HP hydrogel. Moreover, the expression of neurofilament protein and the density of axons were increased after treatment with hybrid FGF2-dscECM-HP. In addition, the neuroprotective effects of FGF2-dscECM-HP were related to inhibition of chronic endoplasmic reticulum stress-induced apoptosis. Conclusion: The results revealed that a hybrid hydrogel system may be a potential carrier to deliver macromolecular proteins to the injured site and enhance the therapeutic effects of proteins. PMID- 29440895 TI - Biosynthesized silver and gold nanoparticles are potent antimycotics against opportunistic pathogenic yeasts and dermatophytes. AB - Background: Epidemiologic observations indicate that the number of systemic fungal infections has increased significantly during the past decades, however in human mycosis, mainly cutaneous infections predominate, generating major public health concerns and providing much of the impetus for current attempts to develop novel and efficient agents against cutaneous mycosis causing species. Innovative, environmentally benign and economic nanotechnology-based approaches have recently emerged utilizing principally biological sources to produce nano-sized structures with unique antimicrobial properties. In line with this, our aim was to generate silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) by biological synthesis and to study the effect of the obtained nanoparticles on cutaneous mycosis causing fungi and on human keratinocytes. Methods: Cell-free extract of the red yeast Phaffia rhodozyma proved to be suitable for nanoparticle preparation and the generated AgNPs and AuNPs were characterized by transmission electron microscopy, dynamic light scattering and X-ray powder diffraction. Results: Antifungal studies demonstrated that the biosynthesized silver particles were able to inhibit the growth of several opportunistic Candida or Cryptococcus species and were highly potent against filamentous Microsporum and Trichophyton dermatophytes. Among the tested species only Cryptococcus neoformans was susceptible to both AgNPs and AuNPs. Neither AgNPs nor AuNPs exerted toxicity on human keratinocytes. Conclusion: Our results emphasize the therapeutic potential of such biosynthesized nanoparticles, since their biocompatibility to skin cells and their outstanding antifungal performance can be exploited for topical treatment and prophylaxis of superficial cutaneous mycosis. PMID- 29440896 TI - Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer's disease. AB - Background: Safe and effective delivery of therapeutic drugs to the brain is important for successful therapy of Alzheimer's disease (AD). Purpose: To develop Huperzine A (HupA)-loaded, mucoadhesive and targeted polylactide-co-glycoside (PLGA) nanoparticles (NPs) with surface modification by lactoferrin (Lf) conjugated N-trimethylated chitosan (TMC) (HupA Lf-TMC NPs) for efficient intranasal delivery of HupA to the brain for AD treatment. Methods: HupA Lf-TMC NPs were prepared using the emulsion-solvent evaporation method and optimized using the Box-Behnken design. The particle size, zeta potential, drug entrapment efficiency, adhesion and in vitro release behavior were investigated. The cellular uptake was investigated by fluorescence microscopy and flow cytometry. MTT assay was used to evaluate the cytotoxicity of the NPs. In vivo imaging system was used to investigate brain targeting effect of NPs after intranasal administration. The biodistribution of Hup-A NPs after intranasal administration was determined by liquid chromatography-tandem mass spectrometry. Results: Optimized HupA Lf-TMC NPs had a particle size of 153.2+/-13.7 nm, polydispersity index of 0.229+/-0.078, zeta potential of +35.6+/-5.2 mV, drug entrapment efficiency of 73.8%+/-5.7%, and sustained release in vitro over a 48 h period. Adsorption of mucin onto Lf-TMC NPs was 86.9%+/-1.8%, which was significantly higher than that onto PLGA NPs (32.1%+/-2.5%). HupA Lf-TMC NPs showed lower toxicity in the 16HBE cell line compared with HupA solution. Qualitative and quantitative cellular uptake experiments indicated that accumulation of Lf-TMC NPs was higher than nontargeted analogs in 16HBE and SH-SY5Y cells. In vivo imaging results showed that Lf-TMC NPs exhibited a higher fluorescence intensity in the brain and a longer residence time than nontargeted NPs. After intranasal administration, Lf-TMC NPs facilitated the distribution of HupA in the brain, and the values of the drug targeting index in the mouse olfactory bulb, cerebrum (with hippocampus removal), cerebellum, and hippocampus were about 2.0, 1.6, 1.9, and 1.9, respectively. Conclusion: Lf-TMC NPs have good sustained-release effect, adhesion and targeting ability, and have a broad application prospect as a nasal drug delivery carrier. PMID- 29440897 TI - Fabrication of paclitaxel hybrid nanomicelles to treat resistant breast cancer via oral administration. AB - Aim: Oral chemotherapy using anticancer drugs would improve the clinical practice and the life quality of patients. The aim of the present study was to develop paclitaxel hybrid nanomicelles for oral administration to treat resistant breast cancer. Methods: Evaluations were performed on human breast cancer MCF-7 cells, drug-resistant breast cancer MCF-7/Adr cells, and in MCF-7/Adr-xenografted BALB/c nude mice. The nanomicelles were composed of the polymer soluplus, d-alpha tocopheryl polyethyleneglycol 1000 succinate (TPGS1000), and dequalinium (DQA). The constructed paclitaxel hybrid nanomicelles were ~65 nm in size. Results: The nanomicelles improved cellular uptake and anticancer efficacy in the resistant breast cancer cells and induced mitochondria-mediated apoptosis. The mechanism of the apoptosis-inducing effect was related to the co-localization of the nanomicelles with mitochondria; the activation of pro-apoptotic protein Bax, cytochrome C, and apoptotic enzymes caspase 9 and 3; and the inhibition of anti apoptotic proteins Bcl-2 and Mcl-1. Oral administration of paclitaxel hybrid nanomicelles had the same anticancer efficacy as the intravenous injection of taxol in resistant breast cancer-bearing mice. The oral suitability of this formulation was associated with the nanostructure and the actions of TPGS1000 and DQA. Conclusion: The fabricated paclitaxel hybrid nanomicelles could provide a promising oral formulation to treat drug-resistant breast cancer. PMID- 29440899 TI - Aptamer-drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer functionalized liposomal delivery system reduces cardiotoxicity. AB - Introduction: The toxic side effects of doxorubicin (DOX) have limited its use in chemotherapy. Neither liposomal DOX nor pegylated liposomal DOX are able to completely resolve this issue. This is a proof-of-concept study testing aptamer drug conjugate (ApDC) targeted delivery systems for chemotherapeutic drugs. Methods: Aptamer library targeting human epidermal growth factor receptor 3 (HER3) was screened and affinity was determined by enzyme-linked immunosorbent assay. Specificity was tested in MCF-7HER3-high, BT474HER3-high, and 293THER3 negative cells using flow cytometry and confocal microscopy. We further developed a HER3 aptamer-functionalized liposome encapsulating DOX and the efficiency of this ApDC was detected by cellular uptake analysis and cell viability assay. In MCF-7 tumor-bearing mice, tumor targeting evaluation, efficacy, toxicity and preliminary pharmocokinetic study was performed. Results: The candidate #13 aptamer had highest affinity (Kd =98+/-9.7 nM) and specificity. ApDC effectively reduces the half maximal inhibitory concentration of DOX compared with lipsome DOX and free DOX. In vivo imaging and preliminary distribution studies showed that actively targeted nanoparticles, such as Apt-Lip-DOX molecules, could facilitate the delivery of DOX into tumors in MCF-7-bearing mice. This targeted chemotherapy caused greater tumor suppression than other groups and alleviated side effects such as weight loss, low survival rate, and organ (heart and liver) injury demonstrated by H&E staining. Conclusion: The results indicate that targeted chemotherapy using the aptamer-drug conjugate format could provide better tolerability and efficacy compared with non-targeted delivery in relatively low-dose toxic drugs. PMID- 29440900 TI - Gestational exposure to titanium dioxide nanoparticles impairs the placentation through dysregulation of vascularization, proliferation and apoptosis in mice. AB - Background: Titanium dioxide nanoparticles (TiO2 NPs) have recently found applications in a wide variety of consumer goods. TiO2 NPs exposure significantly increases fetal deformities and mortality. However, the potential toxicity of TiO2 NPs on the growth and development of placenta has been rarely studied during mice pregnancy. Purpose: The objective of this study was to investigate the effects of maternal exposure of TiO2 NPs on the placentation. Methods: Mice were administered TiO2 NPs by gavage at 0, 1 and 10 mg/kg/day from gestational day (GD) 1 to GD 13. Uteri and placentas from these mice were collected and counted the numbers of implanted and resorbed embryo and measured the placental weight on GD 13. Placental morphometry was observed by hematoxylin and eosin staining. The levels of Hand1, Esx1, Eomes, Hand2, Ascl2 and Fra1 mRNA were assessed by qRT PCR. Uterine NK (uNK) cells were detected by using DBA lectin. Laminin immunohistochemical staining was to identify fetal vessels. Western blotting and transmission electron micrograph (TEM) were used to assess the apoptosis of placenta. Results: No treatment-related difference was observed in the numbers of implanted and resorbed embryos and weight of placenta between the groups. However, 1 mg/kg/day TiO2 NPs treatment significantly reduced the ratio of placenta/body weight on GD 13. The proportion of spongiotrophoblast in the 10 mg/kg/day dose group became higher than that in the control group, yet that of labyrinth was significantly lower in 10 mg/kg/day mice. The expression levels of Hand1, Esx1, Eomes, Hand2, Ascl2 and Fra1 mRNA markedly decreased in TiO2 NP treated placentas. Furthermore, TiO2 NPs treatment impaired the formation of intricate networks of fetal vessels and reduced the number of uNK cells, and inhibited proliferation and induced apoptosis of placenta by nuclear pyknosis, the activation of caspase-3 and upregulation of Bax protein and downregulation of Bcl-2 protein on GD 13. Conclusion: Gestational exposure to TiO2 NPs significantly impairs the growth and development of placenta in mice, with a mechanism that seems to be involved in the dysregulation of vascularization, proliferation and apoptosis. Therefore, our results suggested the need for great caution while handling of the nanomaterials by workers and specially pregnant consumers. PMID- 29440901 TI - Guided osteoporotic bone regeneration with composite scaffolds of mineralized ECM/heparin membrane loaded with BMP2-related peptide. AB - Introduction: At present, the treatment of osteoporotic defects poses a great challenge to clinicians, owing to the lower regeneration capacity of the osteoporotic bone as compared with the normal bone. The guided bone regeneration (GBR) technology provides a promising strategy to cure osteoporotic defects using bioactive membranes. The decellularized matrix from the small intestinal submucosa (SIS) has gained popularity for its natural microenvironment, which induces cell response. Materials and methods: In this study, we developed heparinized mineralized SIS loaded with bone morphogenetic protein 2 (BMP2) related peptide P28 (mSIS/P28) as a novel GBR membrane for guided osteoporotic bone regeneration. These mSIS/P28 membranes were obtained through the mineralization of SIS (mSIS), followed by P28 loading onto heparinized mSIS. The heparinized mSIS membrane was designed to improve the immobilization efficacy and facilitate controlled release of P28. P28 release from mSIS-heparin-P28 and its effects on the proliferation, viability, and osteogenic differentiation of bone marrow stromal stem cells from ovariectomized rats (rBMSCs-OVX) were investigated in vitro. Furthermore, a critical-sized OVX calvarial defect model was used to assess the bone regeneration capability of mSIS-heparin-P28 in vivo. Results: In vitro results showed that P28 release from mSIS-heparin-P28 occurred in a controlled manner, with a long-term release time of 40 days. Moreover, mSIS heparin-P28 promoted cell proliferation and viability, alkaline phosphatase activity, and mRNA expression of osteogenesis-related genes in rBMSCs-OVX without the addition of extra osteogenic components. In vivo experiments revealed that mSIS-heparin-P28 dramatically stimulated osteoporotic bone regeneration. Conclusion: The heparinized mSIS loaded with P28 may serve as a potential GBR membrane for repairing osteoporotic defects. PMID- 29440902 TI - Chinese calligraphy handwriting (CCH): a case of rehabilitative awakening of a coma patient after stroke. AB - Introduction: This study investigated the efficacy of Chinese calligraphy handwriting (CCH) for the awakening of patients under a vegetative state after stroke. The theories, the instrument, and the treatment protocols were reported. A single case of a severe stroke patient who was in a coma state for 2 years is presented in this study. The objectives were to apply finger writing as a new method to awaken a stroke patient in a coma state and to test the effect of this method in improving the patient's vegetative states over time. Case presentation: A 55-year-old man suffered a severe stroke in 2004 which left him in a coma for 2 years without any systematic rehabilitation. A culture-based finger-writing method of visual-spatial intervention was then applied to improve his condition. The writing tasks involved aided viewing and finger tracing of sets of innovative characters with enriched visual-spatial and movement characteristics. Following regular treatment protocols involving diverse movement and sensory feedback, the patient was awakened after 12 months. As a consequence, the patient showed significant behavioral changes favoring enhanced focusing, alertness, visual scan, visual span, and quickened visual and motor responses. The treatment continued for another 12 months. As the treatment progressed, we gradually observed improvements in his attention span and mental concentration. His eye ball movements - the left eye in particular - were quickened and showed wider visual angularity in his focal vision. Currently, the patient can now watch television, engage in improved visual sighting, and focus on visual-spatial and cognitive-linguistic materials. Conclusion: This CCH method of training by finger tracking has shown its effectiveness in awakening the patient from his coma state and in producing long-term, clinical outcomes that were similar from those that took place 10 years ago. This finding supports the efficacy of the system for clinical improvement of the patient's conditions. PMID- 29440898 TI - Nanosilver: new ageless and versatile biomedical therapeutic scaffold. AB - Silver nanotechnology has received tremendous attention in recent years, owing to its wide range of applications in various fields and its intrinsic therapeutic properties. In this review, an attempt is made to critically evaluate the chemical, physical, and biological synthesis of silver nanoparticles (AgNPs) as well as their efficacy in the field of theranostics including microbiology and parasitology. Moreover, an outlook is also provided regarding the performance of AgNPs against different biological systems such as bacteria, fungi, viruses, and parasites (leishmanial and malarial parasites) in curing certain fatal human diseases, with a special focus on cancer. The mechanism of action of AgNPs in different biological systems still remains enigmatic. Here, due to limited available literature, we only focused on AgNPs mechanism in biological systems including human (wound healing and apoptosis), bacteria, and viruses which may open new windows for future research to ensure the versatile application of AgNPs in cosmetics, electronics, and medical fields. PMID- 29440903 TI - Association of the matrix metalloproteinase-3 polymorphisms rs679620 and rs3025058 with ischemic stroke risk: a meta-analysis. AB - Purpose: The relationship of the matrix metalloproteinase-3 (MMP-3) polymorphisms rs679620 and rs3025058 with ischemic stroke has received much attention. The aim of the present study was to perform a meta-analysis of published case-control studies to evaluate the cumulative evidence. Methods: We performed a search of ISI Web of Science, Embase, PubMed, and China National Knowledge Infrastructure databases. Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. Results: We identified seven eligible studies including 5,204 subjects. The pooled analysis showed that the MMP-3 rs679620 A allele carriers had increased risk of ischemic stroke compared with homozygotes for the G allele in Asians (AA + GA vs GG: OR =1.42, 95% CI: 1.05-1.91, P=0.022). Concerning the rs3025058 polymorphism, the results did not suggest an association between rs3025058 genotypes and ischemic stroke risk (5A5A + 6A5A vs 6A6A: OR =1.04, 95% CI: 0.73-1.47, P=0.844; 5A5A vs 6A5A + 6A6A: OR =1.14, 95% CI: 0.74 1.77, P=0.556; and 5A5A vs 6A6A: OR =1.11, 95% CI: 0.68-1.80, P=0.677). In subgroup analysis by ethnicity, no statistically significant associations were demonstrated for rs3025058 in Asians and Caucasians, respectively. There was no evidence for publication bias. Conclusion: Our findings indicate that the rs679620 A allele carriers have increased risk of ischemic stroke in Asians, but there is no association between rs3025058 and ischemic stroke risk. PMID- 29440904 TI - Discrepancy in Taiwanese psychiatrists' preferences for long-acting injectable antipsychotics across facilities: a nationwide questionnaire survey. AB - Background: Although many studies have discussed psychiatrists' attitudes toward long-acting injectable antipsychotics (LAIs), no previous study has focused on differences in preference based on the facilities in which the psychiatrists practiced. Materials and methods: A pilot survey was conducted in a medical center in northern Taiwan, and a questionnaire was then distributed at the annual conference of the Taiwanese Society of Psychiatry in 2013. The questionnaire included general demographic data and preferences for the use of LAIs in different situations. Results: A total of 142 psychiatrists were included in our study. Among them, 114 were male (80.3%), and most practiced in general hospitals (n=110, 77.5%). We found that general hospital psychiatrists were more likely to prescribe LAIs for patients in the acute stage and with positive symptoms than were psychiatric hospital psychiatrists. General hospital psychiatrists also tended to prescribe LAIs at every time point of the disease. Conclusion: General hospital psychiatrists were more likely to prescribe LAIs than those in psychiatric hospitals. Knowing the factors affecting psychiatrists' preferences may help us to develop a further study to explore "why" psychiatrists consider or do not consider LAIs in different facilities. PMID- 29440905 TI - Clinical predictive score of intracranial hemorrhage in mild traumatic brain injury. AB - Background: Mild traumatic brain injury (TBI) is a common condition at the Emergency Medicine Department. Head computer tomography (CT) scans in mild TBI patients must be properly justified in order to avoid unnecessary exposure to X rays and to reduce the hospital/transfer costs. This study aimed to evaluate which clinical factors are associated with intracranial hemorrhage in Asian population and to develop a user-friendly predictive model. Methods: The study was conducted retrospectively at the Emergency Medicine Department in Ramathibodi Hospital, a university-affiliated super tertiary care hospital in Bangkok, Thailand. The study period was between September 2013 and August 2016. The inclusion criteria were age >15 years and having received a head CT scan after presenting with mild TBI. Those patients with mild TBI and no symptoms/deterioration after 24 h of clinical observation were excluded. The predictive model and prediction score for intracranial hemorrhage was developed by multivariate logistic regression analysis. Results: During the study period, there were 708 patients who met the study criteria. Of those, 100 patients (14.12%) had positive head CT scan results. There were seven independent factors that were predictive of intracranial hemorrhage. The clinical risk scores to predict intracranial hemorrhage are developed with an accuracy of 92%. The score of >3 had the likelihood of intracranial hemorrhage by 1.47 times. Conclusion: Clinical predictive score of >3 was associated with intracranial hemorrhage in mild TBI. PMID- 29440907 TI - Methionine adenosyltransferase I/III deficiency: beyond the central nervous system manifestations. AB - Methionine adenosyltransferase (MAT) I/III deficiency (OMIM # 250850) is caused by a mutation in MAT1A, which encodes the two hepatic MAT isozymes I and III. With the implementation of newborn screening program to discover hypermethioninemia due to cystathionine beta-synthase deficiency, more cases are being discovered. While the majority of patients are asymptomatic, some might have central nervous system (CNS) and extra-CNS manifestations. Although neurologic manifestations and demyelination have been correlated to MAT deficiency in many reported cases, none of the previous reports focused on extra CNS manifestations associated with the disease. This is a retrospective chart review for a 40-month-old patient with confirmed diagnosis of MAT deficiency. He was found to have a novel homozygous disease-causing variant in MAT1A (NM_000429.2) c.1081G>T (p.Val361Phe). Interestingly, our patient had an unexplained zinc and iron deficiency in addition to mild speech delay. We reviewed the literature and summarized all the reported extra-CNS manifestations. In conclusion, MAT deficiency patients should be thoroughly investigated to check for CNS and extra-CNS manifestations associated with the disease. Keeping in consideration the challenge of assuming correlation, a scrutinized look at extra CNS manifestations and their course with time might pave the way to understanding the pathophysiology of the disease and MAT1A function. PMID- 29440906 TI - Percutaneous autologous bone marrow transplantation for the treatment of delayed union of limb bone in children. AB - Background and purpose: Percutaneous autologous bone marrow transplantation (PABMT) is a minimally invasive therapeutic strategy for the treatment of delayed bone union in adults, which has been confirmed by many studies. However, there is no report on PABMT application in pediatric orthopedic surgery. The aim of this article was to analyze the therapeutic effect of PABMT in children with delayed union of limb bone and its influence in relation to delayed bone union therapy, transplantation period, patients' sex, fracture location, and fracture fixation. Methods: In this study, 53 patients (aged 3-16 years, with an average age of 6.7 years) with delayed union of long bone (20 femurs, 12 tibiae, 10 humeri, 5 radiuses, 5 ulnas, and 1 fibula) were treated using PABMT. Clinical examination and X-ray were integrated to evaluate the therapeutic effect. Results: All 53 patients were followed up for 2-6 years (average time, 3.5 years). Of the 53 patients, 47 (88.7%) were healed, whereas the other 6 (11.3%) were not, and were subsequently treated by autologous bone grafting. In 30 patients who received their first PABMT treatment 6-8 months after fixation, the clinical cure rate, operation times, and healing time were 83.3%, 5.8+/-0.5 months, and 2.5+/-0.6, respectively. In the other 23 patients, whose first PABMT treatments were started within 4 to 6 months after fixation, the clinical cure rate, operation times, and healing time were 95.7% (P=0.167), 3.2+/-0.3 months (P=0.001), and 1.3+/-0.6 (P=0.001), respectively. The patients' sex, fracture location, and fracture fixation did not have statistical influence on the clinical efficacy. Conclusion: PABMT is a minimally invasive and effective strategy for the treatment of delayed union of limb bone in children. The early surgical treatment facilitates the fracture healing, reduces the number of transplantation, and shortens the course of treatment. PMID- 29440908 TI - Positive correlation of the serum angiopoietin-like protein 3 levels with the aortic augmentation index in patients with coronary artery disease. AB - Purpose: Angiopoietin-like protein 3 (ANGPTL3) plays an important role in lipid metabolism and angiogenesis and is elevated in familial hypercholesterolemia, metabolic syndrome, and insulin resistance. This study aims to evaluate the relationship between the fasting serum ANGPTL3 levels and the aortic augmentation index (AIx) in patients with coronary artery disease (CAD). Materials and methods: Fasting blood samples were obtained from 100 patients with CAD. The AIx was measured using a validated tonometry system (SphygmoCor). The serum ANGPTL3 levels were assessed using a commercial enzyme-linked immunosorbent assay kit. Results: The aortic AIx values were higher in female patients with CAD (P=0.003) than those in male patients with CAD. The univariate linear analysis of the aortic AIx values reveals that the height (r=-0.363; P<0.001) and body weight (r= 0.350; P<0.001) were negatively correlated, whereas the age (r=0.202; P=0.044) and logarithmically transformed ANGPTL3 (log-ANGPTL3, r=0.357; P<0.001) were positively correlated with the aortic AIx values in patients with CAD. The multivariate forward stepwise linear regression analysis of the factors significantly associated with the aortic AIx revealed that the height (beta= 0.269; adjusted R2 change=0.123; P=0.007) and serum log-ANGPTL3 level (beta=0.259; adjusted R2 change=0.051; P=0.010) were independent predictors of the aortic AIx values in patients with CAD. Conclusion: The fasting serum ANGPTL3 level positively correlated with the aortic AIx values among patients with CAD. PMID- 29440909 TI - Clinical characteristics, patterns of lipid-lowering medication use, and health care resource utilization and costs among patients with atherosclerotic cardiovascular disease. AB - Purpose: The aim of this study was to investigate real-world patient characteristics, medication use, and health care resource utilization (HCRU) and costs among patients with clinical atherosclerotic cardiovascular disease (ASCVD) as defined by 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, to examine burden of disease and unmet needs, such as potential undertreatment. Patients and methods: This retrospective cohort study utilized a nationally representative managed care database to identify newly diagnosed ASCVD patients between January 1, 2007, and November 30, 2012 (index = first ASCVD diagnosis date) in the USA. Patients had >=12-month pre-index (baseline) and >=12-month post-index (follow-up) health plan enrollment and no baseline lipid-lowering medication (LLM). Patient characteristics, LLM utilization patterns, HCRU, and costs were examined for all patients and by subgroups based on LLM use pattern and/or follow-up low-density lipoprotein cholesterol (LDL-C) levels. Results: A total of 128,017 ASCVD patients were identified with a mean (SD) age of 59 (13) years, 43.1% female, and 48.8% with >=36-month follow-up. Within 12-month follow-up, 10.6% had high-intensity statins and 56.9% had no LLM fills. Baseline mean (SD) all-cause costs were $8,852 ($25,608). At 12-month follow-up, mean (SD) all-cause and ASCVD-related costs were $31,443 ($54,040) and $20,289 ($45,159), respectively. The 36-month analyses showed similar distributions. Multivariable analyses showed that age, gender, region, health insurance type, baseline comorbidities, baseline use of specific medications, baseline lipid profiles, and index ASCVD type were significantly associated with all-cause and ASCVD-related health care costs. Conclusion: Patients have nonoptimal treatment for ASCVD and substantial HCRU and costs associated with residual risk. Unmet needs and cost burdens of ASCVD patients merit additional investigation. PMID- 29440910 TI - Exploration of the contexts surrounding the implementation of an intervention supporting return-to-work after breast cancer in a primary care setting: starting point for an intervention development. AB - Background: Many recommendations have been made regarding survivorship care provided by teams of primary care professionals. However, the nature of that follow-up, including support for return-to-work (RTW) after cancer, remains largely undefined. As implementation problems are frequently context-related, a pilot study was conducted to describe the contexts, according to Grol and Wensing, in which a new intervention is to be implemented. This pilot study is the first of three steps in intervention development planning. Method: In-depth semi-structured interviews (n=6) were carried out with stakeholders selected for their knowledgeable perspective of various settings, such as hospitals, primary care, employers, and community-based organizations. Interviews focused on participants' perceptions of key contextual facilitators and barriers to consider for the deployment of an RTW intervention in a primary care setting. Data from interviews were transcribed and analyzed. A content analysis was performed based on an iterative process. Results: An intervention supporting the process of RTW in primary care makes sense for participants. Results suggest that important levers are present in organizational, professional, and social settings. However, many barriers, mainly related to organizational settings, have been identified, eg, distribution of tasks for survivor follow-up, continuity of information, and coordination of care between specialized oncology care and general primary care. Conclusion: To develop and deploy the intervention, recommendations that emerged from this pilot study for overcoming barriers were identified, eg, training (professionals, survivors, and employers), the use of communication tools, and adopting a practice guide for survivor care. The results were also helpful in focusing on the relevance of an intervention supporting the RTW process as a component of primary care for survivors. PMID- 29440911 TI - Should frail older adults be in long-term care facilities? AB - Aim: Home-based nursing care is relatively easy to access in Norway compared to the rest of Europe, and the threshold for applying for assistance is relatively low. The aim of the present study was to analyze factors that enable frail older adults to live in their own homes, with a low level of care burden stress. Methodology: In 2015 and 2016, eight municipalities from different parts of Norway participated in a cross-sectional study. The quantitative part of the project consisted of assessing care of 71 older adults, aged >=80 years, using a geriatric comprehensive assessment. The qualitative part consisted of semistructured telephone interviews with 14 leaders of nursing homes and home based nursing care and interviews with 26 close relatives. Results: In this sample, 60% of the older adults were living alone, and 79% were at risk of permanent nursing home admission; 31% stated that they would be better-off at a higher caring level, mainly due to living alone. The relatives, their resources, and motivation to provide care seemed to be crucial for how long older adults with heavy care burden could stay at home. The municipalities offered a combination of comprehensive home care, day centers, and revolving short-term stays to enable them to live at home. Conclusion: The results reveal that the need for home care services is steadily increasing. The relatives are coping with the physical care, far better than the uncertainties and worries about what could happen when the older adults stay alone. The number of beds in institutional care in each municipality depends on various factors, such as the inhabitants' life expectancy, social aspects, geography, well-functioning eldercare pathways, competence of the health professionals, and a well-planned housing policy. PMID- 29440912 TI - The application of a three-dimensional visualized seed planning and navigation system in 125I seed implantation for pancreatic cancer. AB - Objectives: To evaluate the effectiveness of iodine-125 (125I) seed implantation for pancreatic cancer (PC), and preliminarily evaluate the clinical value of a self-developed three-dimensional (3D) visualized seed planning and navigation system in 125I seed implantation for treatment of PC. Patients and methods: Our team retrospectively reviewed 25 PC patients who underwent 125I seed implantation between December 2010 and November 2016. The patients were divided into two groups: 3D visualization preoperative planning group (12 patients, 13 lesions) and two-dimensional (2D) regular group (13 patients, 14 lesions). We compared and analyzed the parameters of the two groups, such as number of needle insertions, one-time treatment success rate, proportion of added seeds, local control rate, rate of complications, rate of pain relief, and the survival rate and risk factors of the two groups. There was no significant difference in clinical data of the two groups. Results: 125I seed implantation was performed successfully in all PC patients, with no occurrence of serious complications during and after the procedure. The one-time treatment success rate of 3D group (80%) was higher than that of 2D group (45.5%) (P<0.05), and the proportion of added seed number of 3D group was lower than that of 2D group (P<0.05). The local control rate of 3D group (76.9%) was higher than that of 2D group (35.7%) (P<0.05). The survival rate of 3D group was significantly higher than that of 2D group (P=0.026), and the median survival of 2D group vs 3D group was 5.00 vs 10.80 months. The median survival of all 25 patients was 7.10 months (95% confidence interval: 4.43-9.77). The rate of pain relief was 77.8% (7/9) in 2D group and 88.9% (8/9) in 3D group. Conclusion: Ultrasound-guided, 3D visualized seed planning and navigation system assisted 125I seed implantation is a safe and effective method for the treatment of PC, with a prolonged survival of patients and better local control of tumor. PMID- 29440913 TI - Role of MLH1 methylation in esophageal cancer carcinogenesis and its clinical significance. AB - The mutL homolog-1 (MLH1) is a DNA mismatch repair gene and has been reported to be frequently methylated in numerous cancers. However, the association between MLH1 methylation and esophageal cancer (EC), as well as its clinical significance, remains unclear. Hence, we conducted a systematic meta-analysis based on 19 articles (including 1384 ECs, 345 premalignant lesions, and 1244 healthy controls). Our analysis revealed that the frequency of MLH1 methylation was significantly elevated during EC carcinogenesis. In addition, we observed that MLH1 promoter methylation was associated with age (odds ratio [OR]=1.79; 95% CI =1.20-2.66), advanced tumor grade (OR=3.7; 95% CI =2.37-5.77), lymph node metastasis (OR=2.65; 95% CI =1.81-3.88), distant metastasis (OR=7.60; 95% CI =1.23-47.19), advanced clinical stage (OR=4.46; 95% CI =2.88-6.91), and poor prognosis in EC patients (hazard ratio =1.64, 95% CI =1.00-2.69). The pooled sensitivity, specificity, and area under the curve of MLH1 methylation in EC patients versus healthy individuals were 0.15, 0.99, and 0.77, respectively. Our findings indicate that MLH1 methylation is involved in the carcinogenesis, progression, and metastasis of EC. Moreover, methylated MLH1 could be a potential diagnostic and prognostic biomarker for EC. PMID- 29440914 TI - Associations between ABCG2 gene polymorphisms and gefitinib toxicity in non-small cell lung cancer: a meta-analysis. AB - Background: Gefitinib is frequently used to treat patients with non-small cell lung cancer (NSCLC) and is excreted out from cells via the ATP-binding cassette transporter ABCG2. ABCG2 gene polymorphisms have been suggested to be associated with ABCG2 protein expression and function and may influence the risk of gefitinib toxicity in NSCLC patients. Previous studies on the associations between ABCG2 gene polymorphisms and the toxicity of gefitinib in NSCLC patients have produced conflicting results. The aim of this meta-analysis was to determine whether ABCG2 gene polymorphisms are associated with the risk of gefitinib induced toxicity in NSCLC patients. Methods: The PubMed and EMBASE databases were searched systematically for all eligible studies. A relative risk with corresponding 95% CI was calculated to evaluate the associations between ABCG2 gene polymorphisms and gefitinib-induced toxicity. Results: Data were finally extracted from seven studies and 515 patients were found to meet the inclusion criteria of the meta-analysis. A dominant model showed that there was no significant association between the ABCG2 C421A polymorphism and the risk of gefitinib-induced toxicity, while the ABCG2 G34A polymorphism might be associated with an increased risk of skin toxicity in gefitinib therapy (relative risk =1.54, 95% CI 1.08-2.21, P=0.02). However, more reliable data are required to confirm the associations between the ABCG2 C421A and ABCG2 G34A polymorphisms and the toxicity of gefitinib in NSCLC patients. Conclusion: While the ABCG2 C421A polymorphism might not be a reliable marker of gefitinib-related toxicity, the ABCG2 G34A genotype may be predictive of the skin toxicity of gefitinib in NSCLC patients. These conclusions need to be verified in further large-scale studies. PMID- 29440915 TI - Effects of core needle biopsy and subsequent neoadjuvant chemotherapy on molecular alterations and outcome in breast cancer. AB - Objectives: The aim of our study is to evaluate the effect of core needle biopsy (CNB) and subsequent neoadjuvant chemotherapy (NAC) on the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth hormone receptor 2 (HER2) and Ki67 in breast cancer, and the associated influencing factors. Materials and methods: In this retrospective cohort study, 143 patients with primary operable breast cancer who received NAC were included. ER, PR, HER2 and Ki67 statuses were compared between pretreatment and posttreatment residual samples. A control group of paired core and excision tumors from 123 patients who did not receive NAC within the same study period was also assessed. Data on patients' clinicopathologic features were collected to identify associated influencing factors. Results: Ki67 value significantly increased in excision tumors compared with paired core samples in controls without presurgery treatment (P<0.01), which was associated with the pathologic lymph node status and the interaction of PR and HER2 status (P=0.008 and 0.028, respectively). In 143 patients who underwent NAC, a significant decrease was observed in the expression of PR and Ki67 after NAC (P=0.003 and P<0.01, respectively). Further subgroup analysis showed that PR decrease was more obvious in premenopausal patients and Luminal A patients (P=0.006 and 0.002, respectively). Conclusion: Core samples could provide more reliable information on determination of molecular subtype than surgical excisions. Decreases in PR and Ki67 expression following NAC could be used as positive prognostic factors. We recommend repeat testing of these biologic markers following NAC for the sake of better disease management. To the best of our knowledge, this is the most comprehensive study to analyze the effect of neoadjuvant chemotherapy on molecular alteration and its associated influencing factors after reporting a CNB-associated Ki67 increase in the same study. PMID- 29440916 TI - Overexpression of Zwint predicts poor prognosis and promotes the proliferation of hepatocellular carcinoma by regulating cell-cycle-related proteins. AB - Introduction: Zwint, a centromere-complex component required for the mitotic spindle checkpoint, has been reported to be overexpressed in different human cancers, but it has not been studied in human hepatocellular carcinoma (HCC). Materials and methods: The role of Zwint in hepatocellular carcinoma cell proliferation capacities was evaluated by using cell counting kit-8 (CCK8), flow cytometry, clone formation and tumor formation assay in nude mice. Western blot analysis and qPCR assay were performed to assess Zwint interacting with cell cycle-related proteins. Results: We report that ZWINT mRNA and protein expression were upregulated in HCC samples and cell lines. An independent set of 106 HCC tissue pairs and corresponding noncancerous tissues was evaluated for Zwint expression using immunohistochemistry, and elevated Zwint expression in HCC tissues was significantly correlated with clinicopathological features, such as tumor size and number. Kaplan-Meier survival and Cox regression analysis revealed that high expression of Zwint was correlated with poor overall survival and a greater tendency for tumor recurrence. Ectopic expression of Zwint promoted HCC cell proliferation, and Zwint expression affected the expression of several cell cycle proteins, including PCNA, cyclin B1, Cdc25C and CDK1. Conclusion: Our findings suggest that upregulation of Zwint may contribute to the progression of HCC and may be a prognostic biomarker and potential therapeutic target for treating HCC. PMID- 29440917 TI - Association between IL-17A G197A polymorphism and gastric cancer risk: an updated meta-analysis based on 6,624 cases and 7,631 controls. AB - Purpose: Previous studies investigating the association between interleukin-17A (IL-17A) G197A polymorphism and gastric cancer risk have provided inconsistent results. We, therefore, conducted this meta-analysis to clarify the association between IL-17A G197A polymorphism and gastric cancer risk. Methods: We searched PubMed, Excerpta Medica Database, and CNKI databases to identify relevant studies up to June 10, 2017. A total of 16 case-control studies including 6,624 cases and 7,631 controls were identified. Results: Overall, significant associations between IL-17A G197A polymorphism and gastric cancer risk were observed (A vs G: OR =1.24, 95% CI =1.14-1.36; AA vs GG: OR =1.63, 95% CI =1.35-1.96; GA vs GG: OR =1.12, 95% CI =1.01-1.25; AA+GA vs GG: OR =1.23, 95% CI =1.11-1.35; AA vs GA+GG: OR =1.54, 95% CI =1.27-1.87). Similar associations were also observed in Asian population (A vs G: OR =1.25, 95% CI =1.15-1.37; AA vs GG: OR =1.62, 95% CI =1.33 1.97; GA vs GG: OR =1.16, 95% CI =1.07-1.25; AA+GA vs GG: OR =1.24, 95% CI =1.15 1.33; AA vs GA+GG: OR =1.51, 95% CI =1.23-1.85), in Caucasian population (AA vs GA+GG: OR =2.19, 95% CI =1.40-3.44), and in the hospital-based controls' subgroup (A vs G: OR =1.30, 95% CI =1.17-1.45; AA vs GG: OR =1.81, 95% CI =1.46-2.25; AA+GA vs GG: OR =1.27, 95% CI =1.12-1.43; AA vs GA+GG: OR =1.71, 95% CI =1.34 2.18). Conclusions: The current meta-analysis suggests that IL-17A G197A polymorphism might enhance gastric cancer risk. PMID- 29440918 TI - Use of phosphodiesterase type 5 inhibitors and risk of melanoma: a meta-analysis of observational studies. AB - Background: Phosphodiesterase type 5 inhibitor (PE5i) administration may stimulate the proliferation and survival of melanocytes. However, discrepancies remain regarding the association between PDE5i use and melanoma risk in observational studies in humans. Aim: To evaluate the association between PDE5i use and melanoma in a meta-analysis. Materials and methods: Studies were identified by searching the PubMed and Embase databases. A random-effects model was applied to synthesize the data. A stratified study was performed to evaluate the influence of study characteristics on outcomes. Results: Four prospective cohort studies and three case-control studies with 1,534,615 male participants and 16,053 melanoma cases were incorporated. Patients who received a PDE5i had a significantly increased risk for melanoma (adjusted risk ratio [RR] =1.12, 95% CI =1.03-1.33, P=0.008) with moderate heterogeneity (I2=54%). Cohort studies (adjusted RR =1.22, 95% CI =1.02-1.46, P=0.03) largely contributed to this result rather than case-control studies. Subsequent stratified analyses revealed that sildenafil was associated with an increased risk of melanoma (adjusted RR =1.26, 95% CI =1.07-1.50, P=0.007), but tadalafil and vardenafil were not. Also, PDE5i use was associated with a significantly increased risk of in situ melanoma (adjusted RR =1.31, 95% CI =1.01-1.69, P=0.04), but not of localized or nonlocalized melanoma. Conclusion: PDE5i use may be associated with a significantly increased risk for melanoma in men. However, further research is needed to determine whether the association is causative. PMID- 29440919 TI - Efficacy and safety of COX-2 inhibitors for advanced non-small-cell lung cancer with chemotherapy: a meta-analysis. AB - Background: The study of cyclooxygenase-2 (COX-2) inhibitors is now mired in controversy. We performed a meta-analysis to assess the efficacy and safety profile of COX-2 inhibitors in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: A literature search of PubMed, EMBASE, the Cochrane Central databases, and ClinicalTrials.gov, up until March 26, 2017, identified relevant randomized controlled trials. Data analysis was performed using Stata 12.0. Results: Six eligible trials (1,794 patients) were selected from the 407 studies that were identified initially. A significant difference, favoring COX-2 inhibitors plus chemotherapy over chemotherapy alone, was observed in the overall response rate (relative risk [RR] =1.25, 95% confidence interval [CI]: 1.06-1.48). Further, we conducted two subgroup analyses according to the type of COX-2 inhibitors (celecoxib, rofecoxib, or apricoxib) and treatment line (first or second chemotherapy). The first-line treatment includes: NP (changchun red bean + cisplatin or carboplatin), GP (double fluorine cytidine + cisplatin or carboplatin), or TP (paclitaxel + cisplatin or carboplatin, docetaxel + cisplatin or carboplatin). The second-line treatment includes two internationally recognized compounds, one is docetaxel and the other is the pemetrexed, both of which are individually selected. In subgroup analysis, significantly increased overall response rate (ORR) results were found for rofecoxib plus chemotherapy (RR =1.56, 95% CI: 1.08-2.25) and COX-2 inhibitor given with first-line chemotherapy (RR =1.27, 95% CI: 1.07-1.50). However, there was no difference between COX-2 inhibitors plus chemotherapy and chemotherapy alone in overall survival (hazard ratio [HR] =1.04, 95% CI: 0.91-1.18), progression-free survival (HR =0.97, 95% CI: 0.86-1.10), and 1-year survival rate (RR =1.03, 95% CI: 0.89 1.20). Toxicity did not differ significantly between COX-2 inhibitors plus chemotherapy and chemotherapy alone with the exception of leukopenia (RR =1.21, 95% CI: 1.03-1.42), thrombocytopenia (RR =1.32, 95% CI: 1.04-1.67), and cardiovascular events (RR =2.39, 95% CI: 1.06-5.42). The results of the Egger's test indicated no significant difference in primary outcomes. Conclusion: COX-2 inhibitors improved ORR of advanced NSCLC with chemotherapy, but had no effect on survival indices. Moreover, COX-2 inhibitors may lead to higher rates of hematologic toxicities and cardiovascular events. PMID- 29440920 TI - Oral versus intravenous iron therapy in patients with inflammatory bowel disease and iron deficiency with and without anemia in Germany - a real-world evidence analysis. AB - Background: Iron-deficiency anemia and iron deficiency are common comorbidities associated with inflammatory bowel disease (IBD) resulting in impaired quality of life and high health care costs. Intravenous iron has shown clinical benefit compared to oral iron therapy. Aim: This study aimed to compare health care outcomes and costs after oral vs intravenous iron treatment for IBD patients with iron deficiency or iron deficiency anemia (ID/A) in Germany. Methods: IBD patients with ID/A were identified by ICD-10-GM codes and newly commenced iron treatment via ATC codes in 2013 within the InGef (formerly Health Risk Institute) research claims database. Propensity score matching was performed to balance both treatment groups. Non-observable covariates were adjusted by applying the difference-in-differences (DID) approach. Results: In 2013, 589 IBD patients with ID/A began oral and 442 intravenous iron treatment. After matching, 380 patients in each treatment group were analyzed. The intravenous group had fewer all-cause hospitalizations (37% vs 48%) and ID/A-related hospitalizations (5% vs 14%) than the oral iron group. The 1-year preobservation period comparison revealed significant health care cost differences between both groups. After adjusting for cost differences by DID method, total health care cost savings in the intravenous iron group were calculated to be ?367. While higher expenditure for medication (?1,876) was observed in the intravenous iron group, the inpatient setting achieved most cost savings (?1,887). Conclusion: IBD patients receiving intravenous iron were less frequently hospitalized and incurred lower total health care costs compared to patients receiving oral iron. Higher expenditures for pharmaceuticals were compensated by cost savings in other domains. PMID- 29440921 TI - Adult-onset acne: prevalence, impact, and management challenges. AB - Acne is a multifactorial and inflammatory disease of pilosebaceous follicles, which affects most adolescents. Recent epidemiological data revealed a difference in adults affected by this disease. Women have a high prevalence and incidence when compared with men, especially after 25 years of age. In contrast to what was initially thought, most of these patients do not present endocrinopathy capable of leading to the development of the lesions. When present, polycystic ovarian syndrome is the main cause. However, in these cases, acne is rarely the only dermatological manifestation; hirsutism and acanthosis nigricans are often present. The majority of the normoandrogenic acne patients present a history since adolescence, but in many cases the lesion distribution and intensity change with time. There is often a typical localization of the lesions in the lower third of the face and lateral region of the neck. Another interesting feature is related to the impact on quality of life (QoL), which is always intense. Often there are signs of depression, even when the lesions are mild. As most adult patients are women, in addition to the conventional options, there is also hormone treatment. Combined oral contraceptives and spironolactone are good options. Knowing more about the particularities in etiopathogenesis, impact on QoL, and specific treatment options is important to all dermatologists who face the challenge of treating acne in adults. PMID- 29440922 TI - Is the light at the end of the tunnel nigh? A review of ADPKD focusing on the burden of disease and tolvaptan as a new treatment. AB - Autosomal dominant polycystic kidney disease (ADPKD) causes pathological cystic changes to the kidney and is characterized by numerous renal and systemic manifestations. ADPKD is the fourth most common renal disease requiring renal replacement therapy. In this report, we present a detailed review of ADPKD, with a particular focus on its major economic, psychological, and social burden in affected patients. Treatment of this disease has been based on prophylactic and supportive measures. However, in recent years, new drugs have emerged as promising agents that may retard the progression of ADPKD, such as tolvaptan. In this report, we provide an in-depth discussion of tolvaptan, which has shown an effect in decreasing annual total kidney volume growth and renal function decline, thus slowing disease progression. The mechanism of action, side effects, and available data on cost-effectiveness are discussed together with the results of the first clinical trials and the most recent trials with regard to its efficacy and safety. Tolvaptan has recently received approval and been granted marketing authorization in Japan, Canada, Korea, Switzerland, and Europe. A demand for widely accepted guidelines for its use has emerged since its approval. The currently available series of recommendations and guidelines as to when to start treatment with tolvaptan, as well as which patients should be treated, are also reviewed in this report. We lastly offer some considerations for future trials, and raise unanswered questions. PMID- 29440923 TI - Managing hyperparathyroidism in hemodialysis: role of etelcalcetide. AB - Secondary hyperparathyroidism (SHPT) is common in patients receiving maintenance hemodialysis and is associated with adverse outcomes. Currently, SHPT is managed by reducing circulating levels of phosphate with oral binders and parathyroid hormone (PTH) with vitamin D analogs and/or the calcimimetic cinacalcet. Etelcalcetide, a novel calcimimetic administered intravenously (IV) at the end of a hemodialysis treatment session, effectively reduces PTH in clinical trials when given thrice weekly. Additional clinical effects include reductions in circulating levels of phosphate and FGF-23 and an improved profile of markers of bone turnover. However, despite being administered IV, etelcalcetide appears to be associated with rates of nausea and vomiting comparable to those of cinacalcet. Additionally, etelcalcetide, relative to placebo, causes hypocalcemia and prolonged electrocardiographic QT intervals, effects that must be considered when contemplating its use. Etelcalcetide likely has a role in treating hemodialysis patients with uncontrolled SHPT or with hypercalcemia or hyperphosphatemia receiving activated vitamin D compounds. However, its use should be at least partially constrained by consideration of the risk of hypocalcemia and resultant prolonged QT intervals in vulnerable patients. Because of its effectiveness as a PTH-reducing agent administered in the dialysis unit, etelcalcetide represents a potentially promising new therapeutic approach to the often vexing problem of SHPT in hemodialysis patients. However, whether its use is associated with changes in surrogate clinical end points, such as effects on rates of parathyroidectomy, fracture, vascular calcification, or mortality or on quality of life, remains to be studied. PMID- 29440925 TI - Chronic back pain cured by low-dose levodopa: is it a variant of restless legs syndrome? AB - Chronic back pain is one of the most common reasons for missed work and visits to the doctor. This report presents 2 interesting cases of chronic back pain that were effectively relieved by low-dose levodopa. These 2 patients showed no sign of anatomical problem of the spine or relative structures, but the discomforts on the back manifested some characteristics resembling those in restless legs syndrome (RLS), and one of them actually developed RLS after many years of back problem. We believe that this type of chronic back pain might be a variant of RLS, which we would like to call "restless back", and it can be effectively treated by dopaminergic drugs. PMID- 29440924 TI - Alterations in oral microbial flora induced by waterpipe tobacco smoking. AB - Background: Waterpipe smoking is a global health problem and a serious public concern. Little is known about the effects of waterpipe smoking on oral health. In the current study, we examined the alterations of oral microbial flora by waterpipe smoking. Methods: One hundred adult healthy subjects (59 waterpipe smokers and 41 non-smokers) were recruited into the study. Swabs were taken from the oral cavity and subgingival regions. Standard culturing techniques were used to identify types, frequency, and mean number of microorganisms in cultures obtained from the subjects. Results: It was notable that waterpipe smokers were significantly associated with a history of oral infections. In subgingiva, Acinetobacter and Moraxella species were present only in waterpipe smokers. In addition, the frequency of Candida albicans was higher in the subgingiva of waterpipe smokers (p = 0.023) while the frequency of Fusobacterium nucleatum was significantly lower in the subgingiva of waterpipe smokers (p = 0.036). However, no change was observed in other tested bacteria, such as Campylobacter species; Viridans group streptococci, Enterobacteriaceae, and Staphylococcus aureus. In oral cavity and when colony-forming units were considered, the only bacterial species that showed significant difference were the black-pigmented bacteria (p < 0.001). Conclusion: This study provides evidence indicating that some of the oral microflora is significantly altered by waterpipe smoking. PMID- 29440926 TI - Local anesthetics for brain tumor resection: current perspectives. AB - This review summarizes the added value of local anesthetics in patients undergoing craniotomy for brain tumor resection, which is a procedure that is carried out frequently in neurosurgical practice. The procedure can be carried out under general anesthesia, sedation with local anesthesia or under local anesthesia only. Literature shows a large variation in the postoperative pain intensity ranging from no postoperative analgesia requirement in two-thirds of the patients up to a rate of 96% of the patients suffering from severe postoperative pain. The only identified causative factor predicting higher postoperative pain scores is infratentorial surgery. Postoperative analgesia can be achieved with multimodal pain management where local anesthesia is associated with lower postoperative pain intensity, reduction in opioid requirement and prevention of development of chronic pain. In awake craniotomy patients, sufficient local anesthesia is a cornerstone of the procedure. An awake craniotomy and brain tumor resection can be carried out completely under local anesthesia only. However, the use of sedative drugs is common to improve patient comfort during craniotomy and closure. Local anesthesia for craniotomy can be performed by directly blocking the six different nerves that provide the sensory innervation of the scalp, or by local infiltration of the surgical site and the placement of the pins of the Mayfield clamp. Direct nerve block has potential complications and pitfalls and is technically more challenging, but mostly requires lower total doses of the local anesthetics than the doses required in surgical-site infiltration. Due to a lack of comparative studies, there is no evidence showing superiority of one technique versus the other. Besides the use of other local anesthetics for analgesia, intravenous lidocaine administration has proven to be a safe and effective method in the prevention of coughing during emergence from general anesthesia and extubation, which is especially appreciated after brain tumor resection. PMID- 29440927 TI - Adrenal myelolipoma with hyperandrogenemia and schizophrenia. AB - Adrenal myelolipoma with hyperandrogenemia is extremely rare. We report a case of a 26-year-old Chinese female with schizophrenia, who presented with a hormonally active tumor causing hyperandrogenemia. The mass was found by computerized tomography when she had her gynecologic examination for secondary amenorrhea, and it was confirmed to be an adrenal myelolipoma after a histopathological study. She was referred for a left adrenal laparoscopic excision, and the size of adrenal myelolipoma was found to be more than 10 cm. We report this case because large adrenal myelolipomas with hyperandrogenemia and schizophrenia are rare, and adrenal myelolipoma associated with hyperandrogenemia might be determined by the enzymes involved in the production of hormones. PMID- 29440928 TI - Early diagnostic potential of APC hypermethylation in esophageal cancer. AB - Background: The hypermethylation of APC gene is observed in various cancers, including esophageal cancer (EC). However, the association between APC methylation and the initiation and progression of EC is poorly understood. Purpose and methods: The current study systematically reviewed studies on abnormal methylation of APC in EC and quantitatively synthesized 18 studies by meta-analysis involving 1008 ECs, 570 Barrett's esophagus (BE), and 782 controls. Results: Our results showed higher methylation of APC in EC (OR = 23.33, P < 0.001) and BE (OR = 9.34, P < 0.001) than in normal controls. Whereas APC methylation in EC was similar to that in BE (P = 0.052), it was not associated with tumor stage (P = 0.204). Additionally, APC methylation was not significantly associated with overall survival (OS) and relapse-free survival (RFS) in patients with EC. The performance of APC methylation for the detection of EC and BE achieved areas under the receiver operating characteristic curves of 0.94 and 0.88, respectively. Conclusion: Our results imply that APC methylation detection is a potential diagnostic biomarker for EC and BE. PMID- 29440929 TI - Role of intestinal flora in colorectal cancer from the metabolite perspective: a systematic review. AB - Colorectal cancer is one of the most common human malignant tumors. Recent research has shown that colorectal cancer is a dysbacteriosis-induced disease; however, the role of intestinal bacteria in colorectal cancer is unclear. This review explores the role of intestinal flora in colorectal cancer. In total, 57 articles were included after identification and screening. The pertinent literature on floral metabolites in colorectal cancer from three metabolic perspectives - including carbohydrate, lipid, and amino acid metabolism - was analyzed. An association network regarding the role of intestinal flora from a metabolic perspective was constructed by analyzing the previous literature to provide direction and insight for further research on intestinal flora in colorectal cancer. PMID- 29440931 TI - Influential factors on radiotherapy efficacy and prognosis in patients with secondary lymph node metastasis after esophagectomy of thoracic esophageal squamous cell carcinoma. AB - Background: The purpose of this study was to clarify whether pretreatment tumor burden-related index, including the gross tumor volume (GTV) of metastatic lymph nodes (VLN) and maximum diameter of metastatic lymph nodes (DLN), and inflammatory markers, consisting of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), are useful for assessing the therapeutic effects and prognosis with secondary lymph node metastasis (LNM) receiving chemoradiotherapy (CRT) or radiotherapy (RT) alone after resection of esophageal squamous cell carcinoma (ESCC). Patients and methods: A total of 119 patients with secondary LNM after resection of ESCC were recruited and received curative RT only or CRT. The enrolled patients were grouped according to the median values of NLR, PLR, VLN, and DLN. The relationship between the responsiveness to treatment and these markers was analyzed by logistic analysis. The Kaplan-Meier method and log-rank test were adopted to calculate and compare the overall survival (OS) rates with these markers. The Cox models were used to carry out multivariate analyses. Results: Univariate logistic regression analysis showed that the responses to treatment were highly associated with treatment method (P=0.011), NLR (P=0.000), PLR (P=0.003), VLN (P=0.000), and DLN (P=0.000). Next, multivariate logistic regression analysis showed that therapeutic method (hazard ratio [HR]=1.225, P=0.032), NLR (HR=2.697, P=0.019), and VLN (HR=4.607, P=0.034) were independent risk factors for tumor response. Additionally, Kaplan-Meier survival analysis of this cohort revealed that NLR (chi2 =27.298, P=0.000), PLR (chi2=16.719, P=0.000), VLN (chi2=48.823, P=0.000), DLN (chi2=40.724, P=0.000), and treatment methods (chi2=18.454, P=0.018) were significantly associated with OS. Furthermore, multivariate analysis was performed, and the results showed that therapeutic method (HR=1.223, P=0.048), NLR (HR=2.000, P=0.018), VLN (HR=2.379, P=0.020), and DLN (HR=2.901, P=0.002) were considered independent prognostic factors for OS. Conclusion: This study found that NLR and VLN were promising as predictive markers for therapeutic effects, and NLR combined with VLN and with DLN might be useful biomarkers in predicting outcomes in patients with secondary LNM receiving CRT or single RT after esophagectomy. PMID- 29440930 TI - Advances in the treatment of soft tissue sarcoma: focus on eribulin. AB - Eribulin mesylate is a synthetic derivative of halichondrin B isolated from a marine sponge. Its mechanism of action is through microtubule inhibition, which is different from that of taxanes. Eribulin has been approved for the treatment of metastatic breast cancer and more recently for non-operable or metastatic liposarcoma in patients who have received prior anthracycline chemotherapy. The major side effects of eribulin are bone marrow suppression including neutropenia, leukopenia, anemia, and fatigue/weakness, which can be well managed. In this article, we reviewed evidence from the latest published data on eribulin and its use in the treatment of soft tissue sarcomas. We explored the drug's mechanism of action, pharmacodynamics, pharmacokinetics, and metabolism. Lastly, we reviewed all preclinical studies as well as clinical trials that investigated eribulin. PMID- 29440932 TI - Comparison of prognostic prediction between nomogram based on lymph node ratio and AJCC 8th staging system for patients with resected pancreatic head carcinoma: a SEER analysis. AB - Background: The prognosis of pancreatic carcinoma (PC) remains poor and the American Joint Committee on Cancer (AJCC) 8th staging system for survival prediction in PC patients after curative resection is still limited. Thus, the aim of this study is to refine a valuable prognostic model and novel staging system for PC with curative resection. Methods: The data of 3,458 patients used in this study were retrieved from the Surveillance, Epidemiology, and End Results database registry of National Cancer Institute. The prognostic value of lymph node ratio (LNR) was analyzed in the primary cohort and prognostic nomogram based on the LNR was established to create a novel staging system. Then, analyses were conducted to evaluate the application of the formulated nomogram staging system and the AJCC 8th staging system. The predictive performance of model was further validated in the internal validation cohort. Results: Significant positive correlations were found between LNR and all factors except for surgical procedures. The results of univariate and multivariate analyses showed that LNR was identified as an independent prognostic indicator for overall survival (OS) in both primary and validation cohorts (all P < 0.001). A prognostic nomogram based on the LNR was formulated to obtain superior discriminatory abilities. Compared with the AJCC 8th staging system, the formulated nomogram staging system showed higher hazard ratios of stage II, III, and IV disease (reference to stage I disease) that were 1.637, 2.300, and 3.521, respectively, by univariate analyses in the primary cohort and the distinction between stage I, II, and III disease at the beginning or end of the survival curves was more apparent. All these results were further verified in the validation cohort. Conclusion: LNR can be considered as a useful independent prognostic indicator for PC patients after curative resection regardless of the surgical procedures. Compared with the AJCC 8th staging system, the formulated nomogram showed superior predictive accuracy for OS and its novel staging system revealed better risk stratification. PMID- 29440933 TI - Population-based cohort study on comparative effectiveness and safety of biologics in inflammatory bowel disease. AB - Background: The comparison of effectiveness and safety of anti-tumor necrosis factor-alpha agents for the treatment of inflammatory bowel disease (IBD) is relevant for clinical practice and stakeholders. Objective: The objective of this study was to compare the risk of abdominal surgery, steroid utilization, and hospitalization for infection in Crohn's disease (CD) or ulcerative colitis (UC) patients newly treated with infliximab (IFX) or adalimumab (ADA). Methods: A retrospective population-based cohort study was performed using health information systems data from Lazio region, Italy. Patients with CD or UC diagnosis were enrolled at first prescription of IFX or ADA during 2008-2014 (index date). Only new drug users were followed for 2 years from the index date. IFX versus ADA adjusted hazard ratios were calculated applying "intention-to treat" approach, controlling for several characteristics and stratifying the analysis on steroid use according to previous drug utilization. Sensitivity analyses were performed according to "as-treated" approach, adjusting for propensity score, censoring at switching or discontinuation, and evaluating different lengths of follow-up periods. Results: We enrolled 1,432 IBD patients (42% and 83% exposed to IFX for CD and UC, respectively). In both diseases, treatment effects did not differ in any outcome considered, and sensitivity analyses confirmed the results from the main analysis. Conclusion: In our population-based cohort study, effectiveness and safety data in new users of ADA or IFX with CD or UC were comparable for the outcomes we tested. PMID- 29440934 TI - Prevalence and risk factors for maternal mortality in referral hospitals in Nigeria: a multicenter study. AB - Introduction: While reports from individual hospitals have helped to provide insights into the causes of maternal mortality in low-income countries, they are often limited for policymaking at national and subnational levels. This multisite study was designed to determine maternal mortality ratios (MMRs) and identify the risk factors for maternal deaths in referral health facilities in Nigeria. Methods: A pretested study protocol was used over a 6-month period (January 1 June 30, 2014) to obtain clinical data on pregnancies, births, and maternal deaths in eight referral hospitals across eight states and four geopolitical zones of Nigeria. Data were analyzed centrally using univariate, bivariate, and multivariate statistics. Results: The results show an MMR of 2,085 per 100,000 live births in the hospitals (range: 877-4,210 per 100,000 births). Several covariates were identified as increasing the odds for maternal mortality; however, after adjustment for confounding, five factors remained significant in the logistic regression model. These include delivery in a secondary health facility as opposed to delivery in a tertiary hospital, non-booking for antenatal and delivery care, referral as obstetric emergency from nonhospital sources of care, previous experience by women of early pregnancy complications, and grandmultiparity. Conclusion: MMR remains high in referral health facilities in Nigeria due to institutional and patient-related factors. Efforts to reduce MMR in these health facilities should include the improvement of emergency obstetric care, public health education so that women can seek appropriate and immediate evidence-based pregnancy care, the socioeconomic empowerment of women, and the strengthening of the health care system. PMID- 29440935 TI - Disruption in the diabetic device care market. AB - As diabetes mellitus (DM) has approached pandemic proportions, the pressure for effective glycemic management is mounting. The starting point for managing and living well with DM involves early diagnosis and monitoring blood glucose levels. Therefore, self-monitoring of blood glucose (SMBG) can help patients maintain their blood glucose levels within the appropriate range. The general principle behind the current SMBG method involves a finger prick test to obtain a blood drop, which is applied onto a reagent strip and read by an automated device. Novel techniques are currently under evaluation to create the next generation of painless and accurate glucose monitoring for DM. We began by outlining how the emerging technology of the noninvasive glucose monitoring devices (NIGMDs) provides both economic and clinical benefits for health systems and patients. We further explored the engineering and techniques behind these upcoming devices. Finally, we evaluated how the NIGMDs disrupt the diabetic device care market and drive health care consumerism. We postulated that the NIGMDs play a pivotal role in the implementation of next generation of diabetes prevention strategies. PMID- 29440936 TI - Contraceptive use and preferences of young married women in Kerala, India. AB - Background: As in other states of India, female sterilization is the most widely used contraceptive method in Kerala where women have higher levels of education compared to most other states in India. This paper describes the use and preferences of contraceptive methods among young married women in Trivandrum district, Kerala, India. Subjects and methods: A community-based cross-sectional survey was carried out among 203 young married women (18-28 years) during January March 2015 using multistage cluster sampling method. Statistical analysis was mainly descriptive, and chi-squared test was used to test the statistical significance of the relationship between sociodemographic factors and contraceptive use. Results: The average age at marriage for women was 21.3 years, and 23% of women had more than one child. Current use of any contraceptive methods was 58%. Female sterilization was preferred by 13% and it was significantly higher among women aged 25-28 years than in those aged 18-24 years (20% vs 2.6%, p<0.001). Female sterilization was significantly lower among women with higher levels of education than in women with an education level of plus two or below (5.8% vs 19%, p=0.006). Women were mostly in favor of female sterilization (91%), and a significantly lower proportion of highly educated women preferred female sterilization than women with an education of 12 years or below (85% vs 95.7%, p=0.008). Conclusion: A considerable number of females in the age group 25-28-years opting for sterilization and the unique preference for female sterilization when the family size is complete show the predominant reliance on female sterilization among young women. Higher education delays sterilization in young women due to delayed marriage and childbirth. Women empowerment, proper information and assuring availability and accessibility to different methods can gradually change the dominant preference for female oriented permanent method of contraception. PMID- 29440937 TI - A pilot study on the functional performance and acceptability of an innovative female condom (Wondaleaf(r)) in Malaysia. AB - Background: Female condom (FC) has been available for over 30 years, but it still lacks wide acceptability. To overcome misdirection and invagination occurring in FC and to provide a wider area of protection, Wondaleaf(r) (WL), a new-generation adhesive FC, was recently invented. This pioneering study sought to assess the acceptability and functional performance of WL among Malaysian women. Methods: A mixed method survey was conducted in three cities of Malaysia, recruiting sexually active heterosexual women, aged 18-50, by snowball sampling method. Participants were provided with WL and initially surveyed to rate its performance in five coital usages over 2 months. After that, the participants underwent a second survey to rate their satisfaction and acceptability toward WL. Descriptive statistics on clinical failure rates were tabulated with correlational analysis performed to identify major variables contributing to WL's functional performance and acceptability. Results: Out of the 51 enrolled participants, 31 women completed the required surveys. WL's total clinical failure rate was 2.60% (out of 155 condom uses) with above-average ratings of functional performance. The ease of use significantly correlated with ratings of no slippage and no misdirection. The confidence in WL's safety features significantly correlated with a sense of empowerment and protection. Conclusion: WL has a relatively low risk of clinical failures and an overall favorable acceptability among Malaysian women. However, this study also showed that its future usage largely depends on partner acceptability. It may have the potential of complementing the existing barrier toward contraceptive use. Further studies are needed to understand the global acceptability of WL. PMID- 29440938 TI - Domestic violence: a hidden barrier to contraceptive use among women in Nigeria. AB - Background: The nonuse of family planning methods remains a major public health concern in the low-and-middle-income countries, especially due to its impact on unwanted pregnancy, high rate of abortion, and transmission of sexually transmitted diseases. Various demographic and socioeconomic factors have been reported to be associated with the nonuse of family planning methods. In the present study, we aimed at assessing the influence of domestic violence (DV) on contraceptive use among ever married women in Nigeria. Methods: Data on 22,275 women aged between 15 and 49 years were collected from the most recent Nigeria Demographic and Health Survey conducted in 2013. The outcome variable was contraceptive utilization status, and the main exposure variable was DV, which was assessed by the self-reported experience of physical and psychological abuse. Complex survey method was employed to account for the multistage design of the survey. Data analyses were performed by using bivariate and multivariable techniques. Results: The mean age of the participants was 31.33+/-8.26. More than four fifths (84%) of the participants reported that they were not using any contraceptive methods at all. Lifetime prevalence of psychological and physical abuse was, respectively, 19.0% (95% CI =18.0-20.1) and 14.1% (95% CI =13.3-14.9). Women who reported physical abuse were 28% (adjusted odds ratio [AOR] =1.275; 95% CI =1.030-1.578), and those reported both physical and psychological abuse had 52% (AOR =1.520; 95% CI =1.132-2.042) higher odds of not using any contraception. Conclusion: The rate of contraception nonuse was considerably high and was found to be significantly associated with DV. Thus, the high prevalence of DV may compromise the effectiveness of the family planning programs in the long run. Evidence-based intervention strategies should be developed to protect the health and reproductive rights of the vulnerable women and to reduce DV by giving the issue a wider recognition in public policy making. PMID- 29440939 TI - Pacing in a 94-year-old runner during a 6-hour run. AB - It is well known that elderly people up to 90 years of age are able to finish a marathon. We have no knowledge, however, how runners at the age of 90 years or older pace during a long run. In this case report, we describe the pacing of a 94 year-old man competing in a 6-hour run in order to prepare for a marathon at the age of 95 years in category M95. In the "6-Stunden-Lauf " held in Brugg, Switzerland, participants have to run as many laps of 0.934 km as possible on a completely flat circuit within 6 hours to achieve as many kilometers as possible. Before and after the competition we measured body weight, percentage of body fat, fat-free mass and percentage of body water using a bioelectrical impedance scale. On the day before the start, 24 hours after the finish and then every 24 hours for the following 4 days, capillary blood samples at a fingertip were drawn to determine hemoglobin, hematocrit, leukocytes, platelets, C-reactive protein, creatine kinase, creatinine and potassium and sodium. The runner achieved 26 laps during the 6 hours, equal to 24.304 km. Lap times increased continuously and running speed decreased nearly linearly. A large main effect of time point (hours) of the race on running speed was observed (p=0.015, eta2=0.48) with running speed being slower in the last hour than that in the first hour (3.5+/ 1.4 km/h versus 5.3+/-0.4 km/h). Body mass decreased by 0.6%, percent body fat by 1.4% and fat-free mass by 0.7%. During recovery, hemoglobin, hematocrit and the number of thrombocytes increased, whereas the number of leukocytes remained unchanged. C-reactive protein was highest on day 1 after the race and decreased by day 4 nearly to zero. Creatine kinase was slightly elevated pre-race, highest the day after the race and remained slightly elevated until day 4. Creatinine and potassium were increased pre-race but returned to normal values during recovery. Sodium remained within normal values on all days. Based on the linear decrease in running speed, we extrapolated for the marathon distance to run a marathon in age group M95 (i.e., male marathoners aged 95-99 years). In the worst-case scenario (i.e., the athlete develops maximal fatigue), he would stop the race before 40 km, in the best scenario (i.e., the athlete develops minimal fatigue), he would achieve an overall race time of ~8.3 hours and in the most probable scenario (i.e., the athlete can continue in the same manner), the final race time will be longer than 11 hours. PMID- 29440940 TI - The therapeutic effectiveness of using visual art modalities with the bereaved: a systematic review. AB - Bereaved individuals are increasingly considered at risk for negative psychological and physiological outcomes. Visual art modalities are often incorporated into grief therapy interventions, and clinical application of art therapy techniques with the bereaved has been widely documented. Although clinicians and recipients of these interventions advocate for their helpfulness in adapting to bereavement, research investigating the efficacy of visual art modalities has produced equivocal results and has not yet been synthesized to establish empirical support across settings. Accordingly, this review critically evaluates the existent literature on the effectiveness of visual art modalities with the bereaved and offers suggestions for future avenues of research. A total of 27 studies were included in the current review. Meta-analysis was not possible because of clinical heterogeneity and insufficient comparable data on outcome measures across studies. A narrative synthesis reports that therapeutic application of visual art modalities was associated with positive changes such as continuing bonds with the deceased and meaning making. Modest and conflicting preliminary evidence was found to support treatment effectiveness in alleviating negative grief symptoms such as general distress, functional impairment, and symptoms of depression and anxiety. PMID- 29440942 TI - Mandibular positioning techniques to improve sleep quality in patients with obstructive sleep apnea: current perspectives. AB - The purpose of this article is to review 1) mandibular advancement device (MAD) - indication, treatment success, and side effects; 2) maxillomandibular advancement (MMA) surgery of the jaws - indication, treatment success, and side effects; and 3) current perspectives. Both MAD and MMA are administered to increase the upper airway volume and reduce the collapsibility of the upper airway. MAD is noninvasive and is indicated as a first-stage treatment in adult patients with mild-to-moderate obstructive sleep apnea (OSA) and in patients with severe OSA unable to adhere to continuous positive airway pressure (CPAP). MAD remains inferior to CPAP in reducing the apnea-hypopnea index (AHI) with a treatment success ranging between 24% and 72%. However, patient compliance to MAD is greater, and with regard to subjective sleepiness and health outcomes, MAD and CPAP have been found to be similarly effective. Short-term side effects of MAD are minor and often transient. Long-term side effects primarily appear as changes in the dental occlusion related to decreases in overjet and overbite. MMA is efficacious but highly invasive and indicated as a second-stage treatment in patients with moderate-to-severe OSA, with prior failure to other treatment modalities or with craniofacial abnormalities. The surgical success and cure rates are found to be 86.0% and 43.2%, respectively. Side effects may appear as postsurgical complications such as temporary facial paresthesia and compromised facial esthetics. However, most patients report satisfaction with their postsurgical appearance. Both treatment modalities require experienced clinicians and multidisciplinary approaches in order to efficaciously treat OSA patients. Some researchers do propose possible predictors of treatment success, but clear patient selection criteria and clinical predictive values for treatment success are still needed in both treatment modalities. PMID- 29440944 TI - Ten years after. PMID- 29440943 TI - State of the art of robotic surgery related to vision: brain and eye applications of newly available devices. AB - Background: Robot-assisted surgery has revolutionized many surgical subspecialties, mainly where procedures have to be performed in confined, difficult to visualize spaces. Despite advances in general surgery and neurosurgery, in vivo application of robotics to ocular surgery is still in its infancy, owing to the particular complexities of microsurgery. The use of robotic assistance and feedback guidance on surgical maneuvers could improve the technical performance of expert surgeons during the initial phase of the learning curve. Evidence acquisition: We analyzed the advantages and disadvantages of surgical robots, as well as the present applications and future outlook of robotics in neurosurgery in brain areas related to vision and ophthalmology. Discussion: Limitations to robotic assistance remain, that need to be overcome before it can be more widely applied in ocular surgery. Conclusion: There is heightened interest in studies documenting computerized systems that filter out hand tremor and optimize speed of movement, control of force, and direction and range of movement. Further research is still needed to validate robot-assisted procedures. PMID- 29440941 TI - Sleep disturbances in women with polycystic ovary syndrome: prevalence, pathophysiology, impact and management strategies. AB - Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting the reproductive, metabolic and psychological health of women. Clinic-based studies indicate that sleep disturbances and disorders including obstructive sleep apnea and excessive daytime sleepiness occur more frequently among women with PCOS compared to comparison groups without the syndrome. Evidence from the few available population-based studies is supportive. Women with PCOS tend to be overweight/obese, but this only partly accounts for their sleep problems as associations are generally upheld after adjustment for body mass index; sleep problems also occur in women with PCOS of normal weight. There are several, possibly bidirectional, pathways through which PCOS is associated with sleep disturbances. The pathophysiology of PCOS involves hyperandrogenemia, a form of insulin resistance unique to affected women, and possible changes in cortisol and melatonin secretion, arguably reflecting altered hypothalamic-pituitary-adrenal function. Psychological and behavioral pathways are also likely to play a role, as anxiety and depression, smoking, alcohol use and lack of physical activity are also common among women with PCOS, partly in response to the distressing symptoms they experience. The specific impact of sleep disturbances on the health of women with PCOS is not yet clear; however, both PCOS and sleep disturbances are associated with deterioration in cardiometabolic health in the longer term and increased risk of type 2 diabetes. Both immediate quality of life and longer-term health of women with PCOS are likely to benefit from diagnosis and management of sleep disorders as part of interdisciplinary health care. PMID- 29440945 TI - Molecular epidemiology of the community-associated methicillin-resistant staphylococcus aureus clones: a synthetic review. AB - The article presents a synthetic molecular characterization of the methicillin resistant Staphylococcus aureus and describes the most important community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) clones that circulate nowadays in the world: the main molecular and epidemiological characteristics, as well as notions related to the clinic of infections produced by these clones and their antibiotic resistance spectrum. The predominant clone of CA-MRSA in North America is USA300 - ST8-IV in North America, in Australia - Queensland (Qld) MRSA (ST93-IV), in Europe - ST80-IV, in Asia there is a high heterogeneity of clones population, in Africa the distribution of CA-MRSA clones is unclear, and in South America - USA 1100 and USA300-Latin American variant are predominant. The molecular diagnosis is performed by highly specialized institutions. The knowledge of clones allows the study of antibiotic resistance spectrum for each one, a fact of great importance for medical practice. Molecular epidemiology of the CA-MRSA shows that lowly restricted sales of antibiotics in shops and pharmacies, as well as medical prescribing practices without a laboratory investigation, especially in Eastern Europe and Asia, contribute to the development of new MRSA clones with increased resistance to antibiotics. PMID- 29440946 TI - Optimizing the use of anti VEGF targeted therapies in patients with metastatic colorectal cancer: review of literature. AB - Colorectal cancer is one of the most frequent forms of cancer both in men and women, and patients with metastatic disease are now being exposed to an increasing number of therapeutic agents to improve the survival outcomes. Vascular endothelial growth factor (VEGF) has o key role in the tumor growth and spreading. The approval of 4 agents that target angiogenic pathways in combination with standard chemotherapy improve overall and progression free survival and offer many opportunities to sequencing the treatment in patients with metastatic colorectal cancer (mCRC). However, the most effective strategy for the use of these agents remains unclear. This article presents an overview of the actual evidence for the use of agents that target angiogenesis in the treatment of mCRC. PMID- 29440947 TI - Psychological stress and breast cancer incidence: a systematic review. AB - Objective: Breast cancer is the world's leading cause of cancer mortality in women. Stress is an imminent risk factor with a documented negative impact on neuro-endocrine and immune system. Numerous epidemiological studies have investigated the link between stress and cancer, reporting contradictory results from no association to a close causal link. The impact of the topic and the lack of conclusion compelled this systematic review. Methods: A systematic review was carried out, including all literature studies from 1966 to 2016, investigating the relationship between stress and the occurrence of breast cancer. Of the 1813 articles identified in the PubMed/Medline database, 52 were eligible and included in the analysis. Results: A number of 17 retrospective, 20 limited prospective and 15 prospective studies were analyzed. The number of patients exceeded 29,000, for a total number of more than 700.000 women recruited from hospital, screening cohorts or population registers. We identified 26 positive articles linking personal traits, stressful events and breast cancer, 18 negative articles that did not confirm their hypothesis and 8 articles that could not be classified. Facing heterogeneity, all possible misguiding factors such as: study design, information gathering, stress type, moment of exposure, individual susceptibility and personality, were discussed independently. Conclusions: Qualitative analysis of articles has revealed a possible association between stress and cancer, especially regarding stressful life events. In the absence of a meta-analysis and taking into account the methodological heterogeneity of the studies, the results are difficult to interpret and the role of chance is difficult to exclude. PMID- 29440948 TI - Orofacial manifestations of adverse drug reactions: a review study. AB - Background: Adverse reaction to medication is common and may have a variety of clinical manifestations in the oral cavity. The present review paper aimed to describe adverse drug reactions (ADRs) which might be encountered by dental practitioners in every discipline. Methods: In this narrative review article, the specialized databases such as PubMed, PubMed Central, MEDLINE, EBSCO, Science Direct, Scopus, and reference books from the years 2000-2016 were used to find relevant documents by using MeSH terms: Adverse Drug Reaction, Drug induced, Medication Related, Mouth, Oral Manifestation, Tooth, Hard Tissue, Soft Tissue. Results: The data were categorized in 4 groups as follows: saliva and salivary glands involvement, soft tissue (mucosal) involvement, hard tissue involvement, and non specific conditions (taste disorders, halitosis, neuropathies, movement disturbances, and infection). Most articles were about the adverse effect of drugs on the function of salivary glands, which often cause a decrease in saliva secretion. Other reactions were less common; meanwhile, the side effect of bisphosphonate was increasing in the alveolar bone, because of its unlimited prescription. Conclusion: Oral health care providers should be familiar with such events, as they will be confronted with them in their practice. PMID- 29440949 TI - The prevalence of long-term oral anticoagulation therapy in a cardiology center in Bucharest, Romania. AB - Background and aims: Few studies discuss the prevalence of oral anticoagulation therapy (OAT) in clinical practice, despite their increasing use worldwide. In America, studies established that 20% to 80% of the patients with indication benefit from OAT. In Romania, there is no data regarding the utilization of oral anticoagulants. Thus, this study aims to determine the trends of OAT. Methods: We designed a cross-sectional study of the patients admitted to the Cardiology Department of the "Bagdasar-Arseni" Clinical Emergency Hospital, Bucharest, from the 1st of November 2016 until the 31st of January 2017. We considered OAT indications to be: atrial fibrillation/flutter (AF), pulmonary embolisms (PE), deep vein thrombosis (DVT), intramural or intracavitary thrombi and left ventricle aneurysms. Statistical analysis was performed with EpiInfo. Results: There were 783 patients admitted, 253 of these having an OAT indication (mean age 73.25 years, 53.75% female). Only 162 patients (64.03%) received it, either Vitamin K Antagonists (VKA) (78 patients, 48.14%), or Novel Oral Anticoagulants (NOAC) (84 patients, 51.85%). Reasons for not indicating such therapy included the hemorrhage risk (43.27%), the lack of adherence to the treatment (18.56%), the impossibility of INR monitoring (21.84%), the economic status (10.21%) and others (6.12%). 221 patients had AF (87.35%), 141 (63.8%) receiving OAT, VKA (67 patients, 47.51%), or NOAC (74 patients, 52.48%). 17 patients (6.71%) had a PE and/or DVT. 15 (88.23%) received OAT, AVK (11 patients, 73.33%), or NOAC (4 patients, 26.67%). 15 patients (5.92%) had other OAT indications (excepting AF or PE/DVT), 11 receiving OAT (73.33%), AVK (8 patients, 72.72%), or NOAC (3 patients, 27.27%). Conclusions: Our study determined that 64.03% of those with indication received OAT. Similar data is reported in the USA, suggesting an underuse of anticoagulants. The risk of hemorrhage, lack of adherence, the impossibility of INR monitoring or the economic status were some of the reasons for not recommending OAT. PMID- 29440950 TI - Relationship between etanercept and thyroid function in patients with psoriasis vulgaris. AB - Background and aim: Psoriasis vulgaris, a chronic inflammatory skin disease, requires a long term medication, in order to avoid relapsing episodes. TNF-alpha, one of the targeted molecule in psoriasis therapy, seems to be also involved in thyroid disorders etiopathogenesis. The aim of this study was to evaluate the relationship between anti TNF-alpha therapy and thyroid parameters: serum level of triiodothyronine (T3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and antithyroidperoxidase antibody (AbTPO) in psoriasis treated population. Methods: The study was performed on 44 patients with psoriasis vulgaris (20 patients under antiTNF-alpha treatment (etanercept), 24 patients with no previous systemic therapy). Serum concentrations of hormones, AbAntiTPO and TNF-alpha were measured and a thyroid ultrasonographic evaluation was performed for each patient. Results: The mean serum level of FT4 was significantly higher in patients with no systemic treatment (p<0.05). The patients treated with etanercept had a significantly higher level of TNF-alpha (p<0.05). No significant difference was observed for the other evaluated parameters. Also, we found a significant negative correlation between TNF-alpha and TSH levels (r=-0.366, p=0.015). Conclusions: We only found that the mean level of FT4 was significantly higher in patients with no systemic treatment. Also, a negative strong correlation was seen between serum level of TSH and TNF-alpha. Based on our data, comparison with other anti TNF-alpha therapies might be of interest in future studies. PMID- 29440951 TI - Double whip stitch for free graft femoral fixation in ACL reconstruction: experimental study on porcine model. AB - Background and aims: Using free quadriceps tendon graft for anterior cruciate ligament (ACL) reconstruction has become more popular in the last years due to the low morbidity at the harvest site and biomechanical and structural properties similar to other types of graft (hamstring and patellar tendons). As long as the tibial tunnel fixation with interference screws is considered the standard fixation, femoral fixation is still an open subject. Even though the most common type of femoral tunnel fixation are the cortical suspension devices, the type of suture used for tying the graft to the loop is still evaluated and discussed. We aimed to evaluate the resistance and elongation of a double whip stitch used for tying a tendon to the loop of a cortical suspension device. Method: We used 10 porcine flexor digitorum profundus as free graft for a graft-suture-cortical suspension device construct using the double whip stitch. The total length of the construct and tendon length were recorded before and after the test was performed. Tensioning curves, total construct elongation and maximum tension at breaking point were electronically recorded on the testing device's software. The mean values and coefficient of variance were assessed. Results: We noted the breaking of the suture wire where the wires passed through the loop of the cortical suspension device as final point for all tests. The mean of maximum load was 505.68N (Max=639.38 N; min=358.93 N; SD=82.88078 N) and the mean of total construct elongation was 39.54784mm (Max= 48.60466 mm; min=31.74853 mm; SD=4.85371 mm). Conclusion: With some minor improvement in technique and graft preconditioning and pretensioning, the double whip stitch can be used in connecting a free tendon to a cortical suspension device. PMID- 29440952 TI - Antibiotic treatment in childhood community-acquired pneumonia - clinical practice versus guidelines: results from two university hospitals. AB - Background and aims: Community-acquired pneumonia (CAP) is a both common and serious childhood infection. Antibiotic treatment guidelines help to reduce inadequate antibiotics prescriptions. Methods: We conducted a retrospective study at the Clinical Emergency Hospital for Children, 3rd Pediatric Clinic, Cluj Napoca and Dr. Gavril Curteanu Clinical City Hospital, in Oradea. All patients discharged with a diagnosis of CAP between December 1, 2014 and February 28, 2015, were included in the study. Results: There were 146 cases discharged with pneumonia in Cluj-Napoca center (mean age 4 years; range: 1 month - 16 years), and 212 cases in Oradea center (mean age 0.9 years; range: 2 weeks - 8 years). All cases were analyzed. The analysis made in Clinical Emergency Hospital for Children, 3rd Pediatric Clinic, Cluj-Napoca, showed that the antibiotics used in children hospitalized with community-acquired CAP are cefuroxime (43%), ceftriaxone (23%), macrolides (16%), ampicillin in association with an aminoglycoside (6%) and other antibiotics. The same antibiotics were used in Dr. Gavril Curteanu Clinical City Hospital of Oradea, where ampicillin in association with aminoglycoside was utilized in younger children (mean age 1.3 years), while ceftriaxone in older children (5.7 years) and children with high inflammation markers (ESR, CRP). From 11 pleurisy cases, 9 received cefuroxime or ceftriaxone. Conclusions: There was a wide variability in CAP antibiotic treatment across university hospitals, regarding antibiotic choice and dosing. Antibiotic selection was not always related to the clinical and laboratory characteristics of the patient. The national guideline was not followed, especially in children aged one to three months. PMID- 29440954 TI - Where are Romanian biomedical journals now and what does the future hold for them? A scientometric analysis. AB - Background and aim: There is a competition between scientific journals in order to achieve leadership in their scientific field. There are several Romanian biomedical journals which are published in English and a smaller number in Romanian. We need a periodical analysis of their visibility and ranking according to scientometric measures. Methods: We searched all biomedical journals indexed on international data bases: Web of Science, PubMed, Scopus, Embase, Google Scholar. We analyzed their evaluation factors. Results: Several journals from Romania in the biomedical field are indexed in international databases. Their scientometric indexes are not high. The best journal was acquired by an international publisher and is no longer listed for Romania. Conclusions: There are several Romanian biomedical journals indexed in international databases that deserve periodical analysis. There is a need to improve their ranking. PMID- 29440953 TI - Are negative symptoms in schizophrenia a distinct therapeutic target? AB - Background and aims: The relationship between negative symptoms and cognition in schizophrenia is not clear, inconsistent findings have been reported by multiple authors and meta analyses. The aim of this study was to investigate the relationship between cognition and primary negative symptoms. Methods: 67 outpatients diagnosed with schizophrenia were evaluated using PANSS and the NSA 16 scale. Correlation and regression analyses were used in the present study to investigate the relationship between the primary negative symptoms and cognition. Results: No relationship was found between the PANSS Cognitive factor and Negative factor, but when investigating the relationship of the Cognitive PANSS factor with the negative symptoms evaluated with the NSA-16 scale, it was shown that there is a significant association between cognition and motor retardation. Conclusions: Our study reveals the relative independence of cognitive factor from the global negative domain of the psychopathology, even though the association with motor retardation was clear. These findings also support the need of using appropriate assessment tools in order to gain a more refined understanding of the phenomenology of schizophrenia. PMID- 29440955 TI - Intraperitoneal administration of rosuvastatin prevents postoperative peritoneal adhesions by decreasing the release of tumor necrosis factor. AB - Objectives: The purpose of this experimental study was to demonstrate the reduction of peritoneal adhesions formation in rats after intraperitoneal administration of rosuvastatin, due to its anti-inflammatory effect. Method: Peritoneal adhesions were induced in 120 Wistar-Bratislava rats divided into 4 groups (n=30), using a parietal and visceral (cecal) abrasion model. Group I was designated as control group; in group II, a saline solution was administered intraperitoneally; in groups III and IV, a single dose of rosuvastatin solution, 10 mg/kg and 5 mg/kg respectively, was injected intraperitoneally. The serum values of tumor necrosis factor (TNF-alpha) and interleukin-1 (IL-1alpha) were determined on day 1 and day 7 postoperatively (ELISA). Macroscopic assessment of the peritoneal adhesions was conducted on day 14. Results: Rosuvastatin therapy induced a significant decrease of tumor necrosis factor serum levels in groups III and IV, on day 1 and day 7 (p<0.01). Intraperitoneal administration of rosuvastatin correlated with a decrease of mean interleukin-1alpha levels on postoperative day 1 in groups III (p=0.0013) and IV (p=0.00011), but not on day 7, where the differences were no longer statistically significant (p=0.8) The reduction of postoperative peritoneal adhesions in the experimental rat model is supported by the anti-inflammatory effect of rosuvastatin, mediated mainly by the tumor necrosis factor. Conclusions: Rosuvastatin prevents the formation of postoperative peritoneal adhesions in rats. This effect may be linked to the inhibition of proinflammatory cytokines release in the early stages of adhesions formation. The present study suggests that rosuvastatin may be an efficient pharmacological agent in the prevention of postoperative peritoneal adhesions development, and requires further studies as it has a promising application value. PMID- 29440956 TI - Retroperitoneal laparoscopic pyelolithotomy in renal pelvic stone versus open surgery - a comparative study. AB - Background: The introduction of endourological procedures such as percutaneous nephrolithotomy and ureterorenoscopy have led to a revolution in the the management of urinary stone disease. The indications for open stone surgery have been narrowed significantly, making it a second- or third-line treatment option. Aims and Objectives: To study the safety and efficacy of retroperitoneal laparoscopic pyelolithotomy in retroperitoneal renal stone. We compared the results of laparoscopic and open surgery in terms of easy accessibility, operative period, renal injuries, and early recovery. Methods: This prospective study was conducted on renal pelvic stone cases from January 2009 to February 2016 in Suchkhand Hospital, Agra, India. The study included a total of 1700 cases with the diagnosis of solitary renal pelvic stones. In group A - 850 cases - retroperitoneal laparoscopic pyelolithotomy was performed, while group B - 850 cases - underwent open pyelolithotomy. Results: The mean operative time was less in group B than group A (74.83 min vs. 94.43 min) which was significant (p<0.001). The blood loss was less in the laparoscopic group than in the open group (63 mL vs. 103mL). There were statistically significant differences in the post-operative pain scores, and postoperative complications compared to group B (p<0.001). The mean hospital stay was less in group A (p<0.03), which was significant. Conclusion: Laparoscopic surgery reduces analgesic requirements, hospital stay, and blood loss. The disadvantages include the reduced working space, the cost of equipment and the availability of a trained surgeon. PMID- 29440957 TI - Outcomes of robotic-assisted radical prostatectomy for patients in two extreme age-groups (< 50 years vs > 65 years). AB - Background and aims: To assess the outcomes of robotic radical prostatectomy in two different age subgroups of pre-operatively potent patients: younger than 50 years and older than 65 years. Methods: We included in the present study a number of 202 patients with prostate cancer divided into two groups: 99 patients older than 65 years (group 1) and 103 patients younger than 50 years (group 2). Results: More than half of the younger patients were low-risk vs 57% of the older patients who were high-risk. Overall positive surgical margins rate was 21.2% in group 1 vs 12.1% in group 2. The early biochemical recurrence at 6 months after radical prostatectomy was 4% in group 1 vs 11.6% in group 2. The continence rate at 6 months was similar between the two groups and was not correlated with the patients' age (p=0.72), nerve-sparing (p=0.3 for group 1, p=0.92 for group 2) or pathological staging (overall p=0.81, p=0.89 in group 1 and p=0.63 in group 2). We observed a significantly higher rate of potency for patients in group 2 (91.5% vs 47.2%, p<0.0001). The most important factor associated with the regain of potency at 6 months after the procedure was the age of the patient (p<0.0001), independently of the type of nerve-sparing performed. Conclusions: Age seems to be the most important predictor of the regain of potency after robotic radical prostatectomy. Patients should be counseled accordingly in order to have realistic expectations about the functional results after robotic-assisted surgery. PMID- 29440958 TI - Dentists' perspectives on the choice of treatment of teeth with apical periodontitis. AB - Background and aim: Therapeutic decision in dentistry is a complex cognitive process for the practitioners because it involves taking into consideration several factors, including patients' preferences. The hypothesis of this study was that apicoectomy might be indicated more often than necessary and in order to confirm or invalidate it a survey was designed. We also aimed to explore whether the preferences were associated or not with dentist-related or practice-related characteristics. Methods: The survey included questions about treatment options in case of four scenarios, each one concerning an anterior and a posterior tooth with apical periodontitis, with or without previous endodontic treatment and also general questions, such as medical specialties, age and years of experience. The distribution of the questionnaires was done by email and direct distribution in the dental offices, in Cluj County, Romania. Results: After descriptive statistical analysis was performed, preferences rates were subjected to Chi square test (including McNemar test for significance). Statistically significant differences were considered when p<=0.05. Conclusions: The results indicate that dentists prefer nonsurgical endodontic treatment in case of a tooth with apical periodontitis. Apicoectomy was the second option treatment preferred by general dentists, oral and maxillo-facial surgeons, prosthodontists and endodontists. PMID- 29440959 TI - Assessment of orthodontic treatment need among tribal children of Indore division, Central India. AB - Introduction: India is home to many tribes which have an interesting and varied history of origins, customs and social practices. Oral health care in tribal areas is limited due to shortage of dental manpower, financial constraints and the lack of perceived need for dental care among tribal masses. Objective: To assess orthodontic treatment need among tribal children of Indore division, Central India. Methods: A cross-sectional house to house survey was carried out among 800 tribal children aged 5 to 15 years old in two major tribal districts of Indore division. Permissions and consent were obtained from local administrative authorities, ethical committee and parents respectively. A structured proforma was used to record demographic data. Examination for dentofacial anomalies was conducted according to WHO 1997 survey methods. Descriptive tables and analytical tests like ANOVA, post-hoc and chi-square test were employed. Results: The mean age was 9.75(+/-2.43) years. The mean DAI score among 12 to 15 years old children was 23.19+/-5.22. Female exhibited higher (24.51+/-5.34) mean DAI score compared to males (22.12+/-4.87) (p<0.05). The Patelia tribes (24.38+/-5.13) reported higher mean DAI score than Bhilala (23.02+/-5.69) and Bhil tribe (22.73+/-4.79) (p<0.005). Conclusion: The tribal children had minor malocclusion with no or slight treatment need. Categorization of orthodontic treatment need according to malocclusion severity is particularly important for the planning of corresponding public policies. The isolation of the villages, lack of transportation options imposes limitations on the availability of health professionals to provide dental services. PMID- 29440960 TI - Acral-acroma malignant melanoma. A clinical case report and review of literature. AB - Objective: The main objective of this paper is to emphasize the importance of the early diagnosis of certainty in the cases of acral-acroma malignant melanoma in order to increase the survival rate. Method: The paper is a review of specialty literature and presents a clinical case of acral-acroma malignant melanoma. Clinical case: acral-acroma malignant melanoma with confirmed lymph node metastases and possibly secondary remote dissemination to the skin in a male patient aged 16 years. We conducted histo-pathological and immunohistochemical examinations of the collected tissue-fragments. Results: The results obtained from the histochemical and immunohisto-chemical examinations are presented, as well as the problems of differential diagnosis. Conclusion: The early diagnosis of certainty significantly increases the survival rate. Knowledge and awareness of the population on the use of preventive measures regarding the occurence of the acral-acroma malignant melanoma is therefore required. PMID- 29440961 TI - Acute pancreatitis during GLP-1 receptor agonist treatment. A case report. AB - Glucagon-like peptide 1 receptor agonists (GLP-1RA) are the newest treatment for diabetes mellitus (DM). These drugs can down-regulate fasting glucose more than oral drugs and lead to more constant glucose levels compared to regular insulin. Acute pancreatitis is a serious condition that may have a fatal outcome. It has been shown that long term and high doses of GLP-1RA can cause pancreatic changes in animals, but no connection has been proven in humans. We present the case of a 67 years old man with DM treated with oral drugs for 10 years until 3 months before, when GLP-1RA was added. He presented progressive abdominal pain, vomiting, and increased level of serum lipase and amylase were found. Ultrasonography and computed tomography found pancreatic and peripancreatic fatty tissue inflammation (inflammation score 2, necrosis score 0). All the etiologies of acute pancreatitis (lithiasis, alcohol, autoimmune, or trauma) were excluded. After GLP-1RA cessation and supportive treatment the evolution was self-limited with full recovery within 5 days. We concluded that acute pancreatitis can be considered a side effect of the GLP-1 treatment. PMID- 29440962 TI - Focal achalasia - case report and review of the literature. AB - Esophageal achalasia is a primary smooth muscle motility disorder specified by aperistalsis of the tubular esophagus in combination with a poorly relaxing and occasionally hypertensive lower esophageal sphincter (LES). These changes occur secondary to the destruction of the neural network coordinating esophageal peristalsis and LES relaxation (plexus myentericus). There are limited data on segmental involvement of the esophagus in adults. We report on the case of a 54 year-old man who presented initially with complete aperistalsis limited to the distal esophagus. After a primary good response to BoTox-infiltration of the distal esophagus the patient relapsed two years later. The manometric recordings documented now a progression of the disease with a poorly relaxing hypertensive lower esophageal sphincter and complete aperistalsis of the tubular esophagus (type III achalasia according to the Chicago 3.0 classification system). This paper also reviews diagnostic findings (including high resolution manometry, CT scan, barium esophagram, upper endoscopy and upper endoscopic ultrasound data) in patients with achalasia and summarizes the therapeutic options (including pneumatic balloon dilatation, botulinum toxin injection, surgical or endoscopic myotomy). PMID- 29440963 TI - Heritage of Stanislaw Ostrowski - the only one medical doctor who became state Polish President - Patriae Semper Fidelis. AB - Aim: Our purpose was to write a biography of Stanislaw Ostrowski that would address in the first place the medical aspect of his professional life, with a comprehensive approach of others fields of his activity. Methods: We essentially grounded the paper on primary resources that were papers authored by Ostrowski including his scientific publications, memories, speeches as well as contemporaneous official documents that referred to Ostrowski. Second resources were also used to double check some data from primary resources and to place the biography of Stanislaw Ostrowski in a proper background with special care to social, professional and political context. In this study, second resources comprised papers, that were prepared after the death of Stanislaw Ostrowski. Results: Stanislaw Ostrowski, MD was a meticulous military medical doctor with an academic engagement at the King John Casimir University of Lvov. In addition, he was an excellent organizer, who soon got involved in politics to serve the local community with essential projects in public health particularly anti-tuberculosis campaigns in Lvov district. His quiet and proficient nature made him an ideal statesman with incredible skills to reconcile social, national and political enemies. Ostrowski was elected a member of parliament three times. He also held the position of President of the city of Lvov until World War Two. During the war, he was imprisoned and deported to Siberia, Soviet Union, in years 1939-1941. Subsequently he fought against Nazi Germans in the Polish II Corps. Ostrowski survived the war providing medical service in the various military units. Afterwards, he ran his medical practice in the UK. Stanislaw Ostrowski was the only dermatologist who became a state president. He held an office of state president of the Polish Republic on exile in London. Discussion and conclusion: His life is not a simple story, but a great lesson that provides clear guidelines how to find a stable ground for lifetime being a medical doctor in the turbulent times of the 20th century even during wartime. PMID- 29440964 TI - Taxonomy, palynology and distribution notes of seven species of Passiflora L. (Passifloraceae s.s.) newly recorded from Brazil. AB - Passiflora subgenus Astrophea is one of the five recognised subgenera of Passiflora. Brazil presents ca. 26 species of this subgenus with the majority distributed in the Amazon Basin. During the ongoing taxonomic revision of the Brazilian species of subg. Astrophea, seven species previously unknown for the country were recorded: Passiflora amoena, P. fuchsiiflora, P. jussieui, P. ovata, P. plumosa, P. quelchii, and P. tessmannii. The new records expand the species distribution ranges, especially for P. plumosa, which was exclusively known from its type locality and P. quelchii, which was known only for southeastern Guyana. The authors provide taxonomic and palynological descriptions, distribution maps and illustrations for these species, in the hope that the knowledge and understanding of Brazilian Passifloraceae s.s. will be improved. PMID- 29440965 TI - Lithocarpus vuquangensis (Fagaceae), a new species from Vu Quang National Park, Vietnam. AB - Lithocarpus vuquangensis Ngoc & Hung is described from Vu Quang National Park, North Central Vietnam. The morphological comparison and phylogenetic analysis based on rbcL, matK and ITS provided evidence that the new species was not assignable to any of the previously known taxa in Vietnam and its surrounding countries. The description, photographs, preliminary conservation status and DNA barcode sequences are also provided for the new species. PMID- 29440966 TI - Lobelia hongiana (Campanulaceae), a new species from Guangxi, China. AB - Lobelia hongiana, a new species of Campanulaceae from Guangxi, South China, is described and illustrated here. This new species is most similar to L. chinensis and L. loochooensis, but differs by its elliptic-obovate or oblanceolate leaf, 2.5-3 mm long greenish-carmine hypanthium, 5 or 6 calyx lobes, purplish-white corolla, with yellowish-green blotches at the base of lower lobes, glabrous filaments, 7-8 mm long broadly obconic capsule. Molecular phylogenetic analysis has been conducted based on ITS and two chloroplast sequences (atpB and rbcL) and 14 taxa in Lobelia are included. L. hongiana is well supported as a new species by the evidence from both morphology and molecular phylogeny. PMID- 29440968 TI - Comparison of anesthetic and surgical outcomes of dacryocystorhinostomy using loco-regional versus general anesthesia. AB - Objective: The aim of this study was to compare anesthetic and surgical outcomes of external dacryocystorhinostomy (DCR) under loco-regional anesthesia (LA) versus general anesthesia (GA). Methods: Retrospective chart review of all patients that underwent DCR by one surgeon (IH) over the course of a ten-year period (April 1994 to March 2003). Results: A total of 221 DCR were performed on 209 patients during the study period: 71 were done under LA (72.0 +/- 13.3 years) and 150 under GA (64.2 +/- 13.0 years; P<0.001). LA patients had a shorter length of surgery (56.2 +/- 15.3 vs. 64.0 +/- 18.1 minutes; P=0.001) and required less antiemetic drugs during the first four hours after surgery (P=0.03). Pain was well controlled and patients were comfortable per- and post-operatively. Excluding ecchymosis (38.0% LA vs. 21.6% GA; P=0.01), the rate of minor complications did not differ between the two groups: infection, inflammation or edema (14.1 vs. 18.2%; P=0.13), hematoma (1.4 vs. 2.7%; P=0.52) and epistaxis (22.5 vs. 14.2%; P=0.44). Rates of recurrent symptoms and/or re-intervention (11.3 vs. 13.1%; P=0.91) were comparable for LA and GA. Conclusion: This study suggests that external DCR performed under LA and monitored anesthesia care may be advantageous. The length of surgery is reduced, post-operative side effects are diminished, and excluding ecchymosis, the rate of minor complications is not increased. These benefits are desirable in a predominantly elderly population where avoidance of GA risks is at times necessary. PMID- 29440967 TI - miR-29b enhances prostate cancer cell invasion independently of MMP-2 expression. AB - Background: The ability to metastasize is one of the most important characteristics of neoplastic cells. An imbalance between the action of some matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs drives the invasion process. Some studies have suggested that MMP-2 is involved in metastasis, while other studies have reported that collagen production by cancer cells might also contribute to motility. However, decreased expression of microRNA-29b (miR-29b), which may control MMP-2 and collagen gene expression, has been shown in prostate cancer (PCa). The objectives of the present study were to clarify whether MMP-2 as well as collagens I and III (encoded by COL1A1 and COL3A1, respectively) are controlled by miR-29b and to determine whether metastasis is altered by this relationship. Methods: PCa DU145 and PC-3 cells were transfected with 100 MUL of OPTI-MEM I containing 100 nmol of miR-29b (or its inhibitor) along with 1.5 MUL of lipofectamine. Positive and negative controls were prepared using the same protocol. MMP-2, COL1A1 and COL3A1 messenger RNA (mRNA) levels were evaluated via real-time polymerase chain reaction (qRT-PCR). For qRT-PCR, 6 * 104 cells were used. Invasion studies were conducted with Matrigel assays, which simulate invasion of the extracellular matrix by neoplastic cells. After transfection of 3 * 104 cells, invasion was allowed to proceed for 48 h. Invasive cells were counted under an optical microscope. Each experiment was performed in triplicate. Results: MMP-2 mRNA was not expressed in DU145 cells after transfection with miR-29b. After transfection of cells with the miR-29b inhibitor, COL1A1 (p = 0.02) and COL3A1 (p = 0.06) mRNA expression was increased in DU145 cells, and a large number of transfected DU145 and PC3 cells invaded the Matrigel membrane. Conclusions: In vitro studies showed that reducing the amount of miR-29b may lead to higher PCa cell invasion via a process that is independent of MMP-2. Collagen expression, controlled by miR-29b, may facilitate this motility process. Thus, the present study suggests that collagen production plays an active role in metastasis control and restoration of miR-29b levels may decrease metastasis. Altogether, these findings support further exploration of drug therapy targeting this aspect of the metastasis circuit. PMID- 29440969 TI - A 39-year-old man with painful proptosis after dental extraction. PMID- 29440970 TI - A 37-year-old woman with spontaneous lens dislocation after vitrectomy for retinal reattachment. PMID- 29440971 TI - A 19-month-old girl with nystagmus, paradoxical pupillary response and low vision. PMID- 29440972 TI - A 38-year-old man with bilateral foveal hemorrhages. PMID- 29440973 TI - A 51-year-old man with photopsias. PMID- 29440974 TI - A 36-year-old man with a red eye. PMID- 29440975 TI - A 65-year-old man with decreased vision OD. PMID- 29440976 TI - A 67-year-old woman with shaking of the world. PMID- 29440977 TI - A 26-year-old man with renal failure and vision loss. PMID- 29440978 TI - A 34-year-old man with visual complaints and a tapetal-like reflex. PMID- 29440979 TI - A 23-year-old man with a cystic iris lesion. PMID- 29440980 TI - Prevalence and risk factors of diabetic retinopathy among Jordanian patients with type 2 diabetes. AB - Objective: To estimate the prevalence of diabetic retinopathy among patients with type 2 diabetes mellitus (DM) who attended the National Center of Diabetes, Endocrinology and Genetics (NCDEG) in Jordan, and to determine the relationship between duration of DM, hyperglycemia, smoking, hypertension, age, gender, body mass index (BMI) and diabetic retinopathy. Methods: This is a cross-sectional study that investigates a sample of 1000 diabetic patients suffering from type 2 DM who attended the NCDEG between September 2006 and January 2007. Eye examination by an ophthalmologist under adequate dilatation was performed in all patients. Socio-demographic, clinical and laboratory data were obtained. Diabetic Retinopathy was defined according to the International Clinical Diabetic Retinopathy Severity Scale adopted by American Academy of Ophthalmology (AAO) and the International Council of Ophthalmology (ICO). Statistical analysis was carried out using the Statistical Package for Social Sciences (SPSS, version 11.5). Results: Out of 1000 patients; 51 percent were male, 49 percent were female. The mean age and duration of diabetes were 57.8 and 9.6 years, respectively. The prevalence of diabetic retinopathy in patients was 34.1 percent. Non-proliferative diabetic retinopathy was documented in 24.5 percent, while 9.6 percent had proliferative diabetic retinopathy. Duration of DM and hyperglycemia, as measured by HbA1C, were statistically significantly associated with diabetic retinopathy. Conclusion: Diabetic retinopathy is highly prevalent among Jordanian patients with type 2 DM. Serious national efforts should be directed towards increasing primary prevention through regular ophthalmic examinations and strict glycemic control in patients with type 2 DM. PMID- 29440981 TI - A 24-year-old woman with blurred vision and eye pain. PMID- 29440982 TI - A 29-year-old man with a 3-month history of blurred vision and micropsia in the left eye. PMID- 29440983 TI - Combined pars plana lensectomy/vitrectomy for idiopathic macular hole repair without postoperative prone positioning. AB - Purpose: The aim of this study is to determine the anatomic and visual outcomes following combined pars plana lensectomy/vitrectomy (CPPLV) as a primary procedure for idiopathic macular hole (MH) without post-operative prone positioning (PPP). Materials and Methods: A retrospective chart review of 42 patients (47 eyes) with MH who underwent CPPLV was performed. No PPP was performed; however, patients were instructed to avoid the supine position during the first postoperative week. The main outcome measures included MH closure rate, best corrected post-operative Snellen visual acuity (BCVA), and procedure complications. Results: Anatomical closure was achieved in 44 eyes (93.6%). The average BCVA in these eyes improved from 20/203 at baseline to 20/91 post operatively, with 28 (63.6%) having 20/40 or better. Twenty-eight (59.6%) of the 47 eyes had a BCVA of 20/40 or better post-operatively and 35 (74.5%) eyes improved by at least 2 Snellen lines. Post-operative retinal detachment (RD) was observed in 4 eyes (8.5%) and late reopening of the hole in 4 (9.1%). Discussion: The anatomical and visual outcomes and the RD rate of CPPLV with sulcus intraocular lens implantation without PPP are comparable to those of traditional MH surgery techniques. The main advantages include sparing the patient the inconvenience of PPP and eliminating the need for additional post-vitrectomy cataract extraction procedure. PMID- 29440984 TI - The Optimal Timing for Pancreatic Islet Transplantation into Subcutaneous Scaffolds Assessed by Multimodal Imaging. AB - Subcutaneously implanted polymeric scaffolds represent an alternative transplantation site for pancreatic islets (PIs) with the option of vascularisation enhancement by mesenchymal stem cells (MSC). Nevertheless, a proper timing of the transplantation steps is crucial. In this study, scaffolds supplemented with plastic rods were implanted into diabetic rats and two timing schemes for subsequent transplantation of bioluminescent PIs (4 or 7 days after rod removal) were examined by multimodal imaging. The cavities were left to heal spontaneously or with 10 million injected MSCs. Morphological and vascularisation changes were examined by MRI, while the localisation and viability of transplanted islets were monitored by bioluminescence imaging. The results show that PIs transplanted 4 days after rod removal showed the higher optical signal and vascularisation compared to transplantation after 7 days. MSCs slightly improved vascularisation of the graft but hindered therapeutic efficiency of PIs. Long-term glycaemia normalisation (4 months) was attained in 80% of animals. In summary, multimodal imaging confirmed the long-term survival and function of transplanted PIs in the devices. The best outcome was reached with PIs transplanted on day 4 after rod removal and therefore the suggested protocol holds a potential for further applications. PMID- 29440985 TI - The Orientation of Visual Space from the Perspective of Hummingbirds. AB - Vision is a key component of hummingbird behavior. Hummingbirds hover in front of flowers, guide their bills into them for foraging, and maneuver backwards to undock from them. Capturing insects is also an important foraging strategy for most hummingbirds. However, little is known about the visual sensory specializations hummingbirds use to guide these two foraging strategies. We characterized the hummingbird visual field configuration, degree of eye movement, and orientation of the centers of acute vision. Hummingbirds had a relatively narrow binocular field (~30 degrees ) that extended above and behind their heads. Their blind area was also relatively narrow (~23 degrees ), which increased their visual coverage (about 98% of their celestial hemisphere). Additionally, eye movement amplitude was relatively low (~9 degrees ), so their ability to converge or diverge their eyes was limited. We confirmed that hummingbirds have two centers of acute vision: a fovea centralis, projecting laterally, and an area temporalis, projecting more frontally. This retinal configuration is similar to other predatory species, which may allow hummingbirds to enhance their success at preying on insects. However, there is no evidence that their temporal area could visualize the bill tip or that eye movements could compensate for this constraint. Therefore, guidance of precise bill position during the process of docking occurs via indirect cues or directly with low visual acuity despite having a temporal center of acute vision. The large visual coverage may favor the detection of predators and competitors even while docking into a flower. Overall, hummingbird visual configuration does not seem specialized for flower docking. PMID- 29440987 TI - Metabolomics Based Identification of SIRT5 and Protein Kinase C Epsilon Regulated Pathways in Brain. AB - The role of Sirtuins in brain function is emerging, yet little is known about SIRT5 in this domain. Our previous work demonstrates that protein kinase C epsilon (PKCepsilon)-induced protection from focal ischemia is lost in SIRT5-/- mice. Thus, metabolic regulation by SIRT5 contributes significantly to ischemic tolerance. The aim of this study was to identify the SIRT5-regulated metabolic pathways in the brain and determine which of those pathways are linked to PKCepsilon. Our results show SIRT5 is primarily expressed in neurons and endothelial cells in the brain, with mitochondrial and extra-mitochondrial localization. Pathway and enrichment analysis of non-targeted primary metabolite profiles from Sirt5-/- cortex revealed alterations in several pathways including purine metabolism (urea, adenosine, adenine, xanthine), nitrogen metabolism (glutamic acid, glycine), and malate-aspartate shuttle (malic acid, glutamic acid). Additionally, perturbations in beta-oxidation and carnitine transferase (pentadecanoic acid, heptadecanoic acid) and glutamate transport and glutamine synthetase (urea, xylitol, adenine, adenosine, glycine, glutamic acid) were predicted. Metabolite changes in SIRT5-/- coincided with alterations in expression of amino acid (SLC7A5, SLC7A7) and glutamate (EAAT2) transport proteins as well as key enzymes in purine (PRPS1, PPAT), fatty acid (ACADS, HADHB), glutamine-glutamate (GAD1, GLUD1), and malate-aspartate shuttle (MDH1) metabolic pathways. Moreover, PKCepsilon activation induced alternations in purine metabolites (urea, glutamine) that overlapped with putative SIRT5 pathways in WT but not in SIRT5-/- mice. Finally, we found that purine metabolism is a common metabolic pathway regulated by SIRT5, PKCepsilon and ischemic preconditioning. These results implicate Sirt5 in the regulation of pathways central to brain metabolism, with links to ischemic tolerance. PMID- 29440986 TI - Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease. AB - The so-called amyloid hypothesis, that the accumulation and deposition of oligomeric or fibrillar amyloid beta (Abeta) peptide is the primary cause of Alzheimer's disease (AD), has been the mainstream concept underlying AD research for over 20 years. However, all attempts to develop Abeta-targeting drugs to treat AD have ended in failure. Here, we review recent findings indicating that the main factor underlying the development and progression of AD is tau, not Abeta, and we describe the deficiencies of the amyloid hypothesis that have supported the emergence of this idea. PMID- 29440988 TI - Inverse Modulation of Neuronal Kv12.1 and Kv11.1 Channels by 4-Aminopyridine and NS1643. AB - The three members of the ether-a-go-go-gene-like (Elk; Kv12.1-Kv12.3) family of voltage-gated K+ channels are predominantly expressed in neurons, but only little information is available on their physiological relevance. It was shown that Kv12.2 channels modulate excitability of hippocampal neurons, but no native current could be attributed to Kv12.1 and Kv12.3 subunits yet. This may appear somewhat surprising, given high expression of their mRNA transcripts in several brain areas. Native Kv12 currents may have been overlooked so far due to limited knowledge on their biophysical properties and lack of specific pharmacology. Except for Kv12.2, appropriate genetically modified mouse models have not been described; therefore, identification of Kv12-mediated currents in native cell types must rely on characterization of unique properties of the channels. We focused on recombinant human Kv12.1 to identify distinct properties of these channels. We found that Kv12.1 channels exhibited significant mode shift of activation, i.e., stabilization of the voltage sensor domain in a "relaxed" open state after prolonged channel activation. This mode shift manifested by a slowing of deactivation and, most prominently, a significant shift of voltage dependence to hyperpolarized potentials. In contrast to related Kv11.1, mode shift was not sensitive to extracellular Na+, which allowed for discrimination between these isoforms. Sensitivity of Kv12.1 and Kv11.1 to the broad-spectrum K+ antagonist 4 aminopyridine was similar. However, 4-AP strongly activated Kv12.1 channels, but it was an inhibitor of Kv11 channels. Interestingly, the agonist of Kv11 channels NS1643 also differentially modulated the activity of these channels, i.e., NS1643 activated Kv11.1, but strongly inhibited Kv12.1 channels. Thus, these closely related channels are distinguished by inverse pharmacological profiles. In summary, we identified unique biophysical and pharmacological properties of Kv12.1 channels and established straightforward experimental protocols to characterize Kv12.1-mediated currents. Identification of currents in native cell types with mode shift that are activated through 4-AP and inhibited by NS1643 can provide strong evidence for contribution of Kv12.1 to whole cell currents. PMID- 29440989 TI - Akt Protein Kinase, miR-200/miR-182 Expression and Epithelial-Mesenchymal Transition Proteins in Hibernating Ground Squirrels. AB - Hibernating 13-lined ground squirrels (Ictidomys tridecemlineatus; TLGS) rank among the most brain hypoperfusion-tolerant mammals known. Herein we provide some evidence of cycling between an epithelial phenotype and a hybrid epithelial/mesenchymal (E/M) phenotype (partial EMT) within the brains of TLGS during each bout of hibernation torpor. During hibernation torpor, expression of the epithelial marker E-cadherin (E-CDH) was reduced, while expression of the well-known mesenchymal markers vimentin and Sox2 were increased. P-cadherin (P CDH), which has recently been proposed as a marker of intermediate/partial EMT, also increased during torpor, suggesting that a partial EMT may be taking place during hibernation torpor. Members of the miR-200 family and miR-182 cluster and Akt isoforms (Akt1, Akt2), well-known EMT regulators, were also differentially regulated in the TLGS brain during hibernation bouts. Using SHSY5Y cells, we also demonstrate that the Akt1/Akt2 ratio determined the expression levels of miR 200/miR-182 miRNA family members, and that these miRNAs controlled the expression of EMT-related proteins. Accordingly, we propose that such cell state transitions (EMT/MET) may be one of the mechanisms underlying the extraordinary ischemic tolerance of the TLGS brain during hibernation bouts; hibernator brain cells appear to enter reversible states that confer the stress survival characteristics of cancer cells without the risk of neoplastic transformation. PMID- 29440991 TI - Subcellular Localization and Activity of TRPM4 in Medial Prefrontal Cortex Layer 2/3. AB - TRPM4 is a Ca2+-activated non-selective cationic channel that conducts monovalent cations. TRPM4 has been proposed to contribute to burst firing and sustained activity in several brain regions, however, the cellular and subcellular pattern of TRPM4 expression in medial prefrontal cortex (mPFC) during postnatal development has not been elucidated. Here, we use multiplex immunofluorescence labeling of brain sections to characterize the postnatal developmental expression of TRPM4 in the mouse mPFC. We also performed electrophysiological recordings to correlate the expression of TRPM4 immunoreactivity with the presence of TRPM4 like currents. We found that TRPM4 is expressed from the first postnatal day, with expression increasing up to postnatal day 35. Additionally, in perforated patch clamp experiments, we found that TRPM4-like currents were active at resting membrane potentials at all postnatal ages studied. Moreover, TRPM4 is expressed in both pyramidal neurons and interneurons. TRPM4 expression is localized in the soma and proximal dendrites, but not in the axon initial segment of pyramidal neurons. This subcellular localization is consistent with a reduction in the basal current only when we locally perfused 9-Phenanthrol in the soma, but not upon perfusion in the medial or distal dendrites. Our results show a specific localization of TRPM4 expression in neurons in the mPFC and that a 9-Phenanthrol sensitive current is active at resting membrane potential, suggesting specific functional roles in mPFC neurons during postnatal development and in adulthood. PMID- 29440990 TI - Internal State Dependent Odor Processing and Perception-The Role of Neuromodulation in the Fly Olfactory System. AB - Animals rely heavily on their sense of olfaction to perform various vital interactions with an ever-in-flux environment. The turbulent and combinatorial nature of air-borne odorant cues demands the employment of various coding strategies, which allow the animal to attune to its internal needs and past or present experiences. Furthermore, these internal needs can be dependent on internal states such as hunger, reproductive state and sickness. Neuromodulation is a key component providing flexibility under such conditions. Understanding the contributions of neuromodulation, such as sensory neuron sensitization and choice bias requires manipulation of neuronal activity on a local and global scale. With Drosophila's genetic toolset, these manipulations are feasible and even allow a detailed look on the functional role of classical neuromodulators such as dopamine, octopamine and neuropeptides. The past years unraveled various mechanisms adapting chemosensory processing and perception to internal states such as hunger and reproductive state. However, future research should also investigate the mechanisms underlying other internal states including the modulatory influence of endogenous microbiota on Drosophila behavior. Furthermore, sickness induced by pathogenic infection could lead to novel insights as to the neuromodulators of circuits that integrate such a negative postingestive signal within the circuits governing olfactory behavior and learning. The enriched emporium of tools Drosophila provides will help to build a concrete picture of the influence of neuromodulation on olfaction and metabolism, adaptive behavior and our overall understanding of how a brain works. PMID- 29440992 TI - The Bcl-2 Homology-3 Domain (BH3)-Only Proteins, Bid, DP5/Hrk, and BNip3L, Are Upregulated in Reactive Astrocytes of End-Stage Mutant SOD1 Mouse Spinal Cord. AB - The molecular mechanisms leading to motor neuron death in amyotrophic lateral sclerosis (ALS) are unknown; however, several studies have provided evidence of a central role for intrinsic apoptosis. Bcl-2 homology-3 domain (BH3)-only proteins are pro-apoptotic members of the Bcl-2 family whose enhanced expression acts as a trigger for the intrinsic apoptotic cascade. Here, we compared the relative expression of BH3-only proteins in the spinal cord of end-stage G93A mutant SOD1 mice to age-matched wild-type (WT) mice. Large alpha motor neurons in lumbar spinal cord sections of both WT and end-stage mutant SOD1 mice stained positively for a number of BH3-only proteins; however, no discernible differences were observed in either the relative intensity of staining or number of BH3 immunoreactive motor neurons between WT and mutant SOD1 mice. On the other hand, we observed significantly enhanced staining for Bid, DP5/Hrk, and BNip3L in GFAP positive astrocytes only in end-stage G93A mutant SOD1 spinal cord. Staining of additional end-stage G93A mutant SOD1 tissues showed specific upregulation of DP5/Hrk in lumbar spinal cord sections, but not in cerebellum or cortex. Finally, examination of protein expression using western blotting also revealed marked increases in DP5/Hrk and BNip3L in G93A mutant SOD1 lumbar spinal cord lysates compared to WT controls. The upregulation of a specific subset of BH3-only proteins, including Bid, DP5/Hrk, and BNip3L, in reactive astrocytes suggests that these proteins may execute a novel non-apoptotic function within astrocytes to promote ALS disease progression, thus providing a new potential target for therapeutic intervention. PMID- 29440993 TI - Increasing Agrin Function Antagonizes Muscle Atrophy and Motor Impairment in Spinal Muscular Atrophy. AB - Spinal muscular atrophy (SMA) is a pediatric genetic disease, characterized by motor neuron (MN) death, leading to progressive muscle weakness, respiratory failure, and, in the most severe cases, to death. Abnormalities at the neuromuscular junction (NMJ) have been reported in SMA, including neurofilament (NF) accumulation at presynaptic terminals, immature and smaller than normal endplates, reduced transmitter release, and, finally, muscle denervation. Here we have studied the role of agrin in SMADelta7 mice, the experimental model of SMAII. We observed a 50% reduction in agrin expression levels in quadriceps of P10 SMA mice compared to age-matched WT controls. To counteract such condition, we treated SMA mice from birth onwards with therapeutic agrin biological NT-1654, an active splice variant of agrin retaining synaptogenic properties, which is also resistant to proteolytic cleavage by neurotrypsin. Mice were analyzed for behavior, muscle and NMJ histology, and survival. Motor behavior was significantly improved and survival was extended by treatment of SMA mice with NT 1654. At P10, H/E-stained sections of the quadriceps, a proximal muscle early involved in SMA, showed that NT-1654 treatment strongly prevented the size decrease of muscle fibers. Studies of NMJ morphology on whole-mount diaphragm preparations revealed that NT-1654-treated SMA mice had more mature NMJs and reduced NF accumulation, compared to vehicle-treated SMA mice. We conclude that increasing agrin function in SMA has beneficial outcomes on muscle fibers and NMJs as the agrin biological NT-1654 restores the crosstalk between muscle and MNs, delaying muscular atrophy, improving motor performance and extending survival. PMID- 29440994 TI - Developmental Changes in HCN Channel Modulation of Neocortical Layer 1 Interneurons. AB - Layer 1 (L1) interneurons (INs) play a key role in modulating the integration of inputs to pyramidal neurons (PNs) and controlling cortical network activity. Hyperpolarization-activated, cyclic nucleotide-gated, non-specific cation (HCN) channels are known to alter the intrinsic and synaptic excitability of principal components (PCs) as well as select populations of GABAergic INs. However, the developmental profile and functional role of HCN channels in diverse L1 IN populations is not completely understood. In the present study, we used electrophysiological characterization, in conjunction with unbiased hierarchical cluster analysis, to examine developmental modulation of L1 INs by HCN channels in the rat medial agranular cortex (AGm). We identified three physiologically discrete IN populations which were classified as regular spiking (RS), burst accommodating (BA) and non-accommodating (NA). A distinct developmental pattern of excitability modulation by HCN channels was observed for each group. RS and NA cells displayed distinct morphologies with modulation of EPSPs increasing in RS cells and decreasing in NA cells across development. The results indicate a possible role of HCN channels in the formation and maintenance of cortical circuits through alteration of the excitability of distinct AGm L1 INs. PMID- 29440995 TI - Reduced Synapse and Axon Numbers in the Prefrontal Cortex of Rats Subjected to a Chronic Stress Model for Depression. AB - Stressful experiences can induce structural changes in neurons of the limbic system. These cellular changes contribute to the development of stress-induced psychopathologies like depressive disorders. In the prefrontal cortex of chronically stressed animals, reduced dendritic length and spine loss have been reported. This loss of dendritic material should consequently result in synapse loss as well, because of the reduced dendritic surface. But so far, no one studied synapse numbers in the prefrontal cortex of chronically stressed animals. Here, we examined synaptic contacts in rats subjected to an animal model for depression, where animals are exposed to a chronic stress protocol. Our hypothesis was that long term stress should reduce the number of axo-spinous synapses in the medial prefrontal cortex. Adult male rats were exposed to daily stress for 9 weeks and afterward we did a post mortem quantitative electron microscopic analysis to quantify the number and morphology of synapses in the infralimbic cortex. We analyzed asymmetric (Type I) and symmetric (Type II) synapses in all cortical layers in control and stressed rats. We also quantified axon numbers and measured the volume of the infralimbic cortex. In our systematic unbiased analysis, we examined 21,000 axon terminals in total. We found the following numbers in the infralimbic cortex of control rats: 1.15 * 109 asymmetric synapses, 1.06 * 108 symmetric synapses and 1.00 * 108 myelinated axons. The density of asymmetric synapses was 5.5/MUm3 and the density of symmetric synapses was 0.5/MUm3. Average synapse membrane length was 207 nm and the average axon terminal membrane length was 489 nm. Stress reduced the number of synapses and myelinated axons in the deeper cortical layers, while synapse membrane lengths were increased. These stress-induced ultrastructural changes indicate that neurons of the infralimbic cortex have reduced cortical network connectivity. Such reduced network connectivity is likely to form the anatomical basis for the impaired functioning of this brain area. Indeed, impaired functioning of the prefrontal cortex, such as cognitive deficits are common in stressed individuals as well as in depressed patients. PMID- 29440996 TI - Is There a Canonical Cortical Circuit for the Cholinergic System? Anatomical Differences Across Common Model Systems. AB - Acetylcholine (ACh) is believed to act as a neuromodulator in cortical circuits that support cognition, specifically in processes including learning, memory consolidation, vigilance, arousal and attention. The cholinergic modulation of cortical processes is studied in many model systems including rodents, cats and primates. Further, these studies are performed in cortical areas ranging from the primary visual cortex to the prefrontal cortex and using diverse methodologies. The results of these studies have been combined into singular models of function a practice based on an implicit assumption that the various model systems are equivalent and interchangeable. However, comparative anatomy both within and across species reveals important differences in the structure of the cholinergic system. Here, we will review anatomical data including innervation patterns, receptor expression, synthesis and release compared across species and cortical area with a focus on rodents and primates. We argue that these data suggest no canonical cortical model system exists for the cholinergic system. Further, we will argue that as a result, care must be taken both in combining data from studies across cortical areas and species, and in choosing the best model systems to improve our understanding and support of human health. PMID- 29440998 TI - Social Validation Influences Individuals' Judgments about Ownership. AB - In all domains, from informal to formal, there are conflicts about property and ownership which resolution demands consideration of alleged claims from more than one party. In this work we asked adults (N = 359) to judge cases in which a character held a property claim over an item, but is challenged by a second character who holds a different, subsequent claim over it. The specific goal of this work is to investigate how the resolution of such conflicts depends on the social endorsement of ownership claims. To achieve this aim, we designed variations of conflictive situations over property in which we manipulated details regarding the knowledge of the second agent of other third-parties about the first agent's actions. In essence, our questions were: if an agent claims ownership of something which has a previous property claim on (1) does it matter whether said agent knew of the first's agent actions or not? And (2) does it matter whether third parties were aware or notified of the first one's claim? The results confirm that adults resolve the settling of property rights based not only on the nature of ownership claims but also on the social acknowledgment of such claims, in accordance with what is stipulated in legal systems worldwide. Participants considered the second character in the stories to hold a lesser right over the object under dispute when she knew of the first character's claim. Participants also considered that the first character's claim was reinforced when there were witnesses for her actions, but not when third parties were merely communicated of such actions. This is the first study to our knowledge that studies how social validation of ownership claims drives adults' judgments on property claims. PMID- 29440999 TI - Neuronal Correlates of Auditory Streaming in Monkey Auditory Cortex for Tone Sequences without Spectral Differences. AB - This study finds a neuronal correlate of auditory perceptual streaming in the primary auditory cortex for sequences of tone complexes that have the same amplitude spectrum but a different phase spectrum. Our finding is based on microelectrode recordings of multiunit activity from 270 cortical sites in three awake macaque monkeys. The monkeys were presented with repeated sequences of a tone triplet that consisted of an A tone, a B tone, another A tone and then a pause. The A and B tones were composed of unresolved harmonics formed by adding the harmonics in cosine phase, in alternating phase, or in random phase. A previous psychophysical study on humans revealed that when the A and B tones are similar, humans integrate them into a single auditory stream; when the A and B tones are dissimilar, humans segregate them into separate auditory streams. We found that the similarity of neuronal rate responses to the triplets was highest when all A and B tones had cosine phase. Similarity was intermediate when the A tones had cosine phase and the B tones had alternating phase. Similarity was lowest when the A tones had cosine phase and the B tones had random phase. The present study corroborates and extends previous reports, showing similar correspondences between neuronal activity in the primary auditory cortex and auditory streaming of sound sequences. It also is consistent with Fishman's population separation model of auditory streaming. PMID- 29440997 TI - Layer- and Cell Type-Specific Modulation of Excitatory Neuronal Activity in the Neocortex. AB - From an anatomical point of view the neocortex is subdivided into up to six layers depending on the cortical area. This subdivision has been described already by Meynert and Brodmann in the late 19/early 20. century and is mainly based on cytoarchitectonic features such as the size and location of the pyramidal cell bodies. Hence, cortical lamination is originally an anatomical concept based on the distribution of excitatory neuron. However, it has become apparent in recent years that apart from the layer-specific differences in morphological features, many functional properties of neurons are also dependent on cortical layer or cell type. Such functional differences include changes in neuronal excitability and synaptic activity by neuromodulatory transmitters. Many of these neuromodulators are released from axonal afferents from subcortical brain regions while others are released intrinsically. In this review we aim to describe layer- and cell-type specific differences in the effects of neuromodulator receptors in excitatory neurons in layers 2-6 of different cortical areas. We will focus on the neuromodulator systems using adenosine, acetylcholine, dopamine, and orexin/hypocretin as examples because these neuromodulator systems show important differences in receptor type and distribution, mode of release and functional mechanisms and effects. We try to summarize how layer- and cell type-specific neuromodulation may affect synaptic signaling in cortical microcircuits. PMID- 29441000 TI - Self-confidence, Overconfidence and Prenatal Testosterone Exposure: Evidence from the Lab. AB - This paper examines whether foetal testosterone exposure predicts the extent of confidence and over-confidence in own absolute ability in adulthood. To study this question, we elicited incentive-compatible measures of confidence and over confidence in the lab and correlate them with measures of right hand 2D:4D, used as as a marker for the strength of prenatal testosterone exposure. We provide evidence that men with higher prenatal testosterone exposure (i.e., low 2D:4D ratio) are less likely to set unrealistically high expectations about their own performance. This in turn helps them to gain higher monetary rewards. Men exposed to low prenatal testosterone levels, instead, set unrealistically high expectations which results in self-defeating behavior. PMID- 29441001 TI - Early Life Stress-Related Elevations in Reaction Time Variability Are Associated with Brain Volume Reductions in HIV+ Adults. AB - There is burgeoning evidence that, among HIV+ adults, exposure to high levels of early life stress (ELS) is associated with increased cognitive impairment as well as brain volume abnormalities and elevated neuropsychiatric symptoms. Currently, we have a limited understanding of the degree to which cognitive difficulties observed in HIV+ High-ELS samples reflect underlying neural abnormalities rather than increases in neuropsychiatric symptoms. Here, we utilized a behavioral marker of cognitive function, reaction time intra-individual variability (RT IIV), which is sensitive to both brain volume reductions and neuropsychiatric symptoms, to elucidate the unique contributions of brain volume abnormalities and neuropsychiatric symptoms to cognitive difficulties in HIV+ High-ELS adults. We assessed the relation of RT-IIV to neuropsychiatric symptom levels and total gray and white matter volumes in 44 HIV+ adults (26 with high ELS). RT-IIV was examined during a working memory task. Self-report measures assessed current neuropsychiatric symptoms (depression, stress, post-traumatic stress disorder). Magnetic resonance imaging was used to quantify total gray and white matter volumes. Compared to Low-ELS participants, High-ELS participants exhibited elevated RT-IIV, elevated neuropsychiatric symptoms, and reduced gray and white matter volumes. Across the entire sample, RT-IIV was significantly associated with gray and white matter volumes, whereas significant associations with neuropsychiatric symptoms were not observed. In the High-ELS group, despite the presence of elevated neuropsychiatric symptom levels, brain volume reductions explained more than 13% of the variance in RT-IIV, whereas neuropsychiatric symptoms explained less than 1%. Collectively, these data provide evidence that, in HIV+ High-ELS adults, ELS-related cognitive difficulties (as indexed by RT IIV) exhibit strong associations with global brain volumes, whereas ELS-related elevations in neuropsychiatric symptoms appear to contribute minimally to these cognitive difficulties. Such findings support a growing body of evidence indicating that high ELS exposure is a significant risk factor for neurocognitive dysfunction in HIV+ adults. Further, these data highlight the need to better understand how ELS-related pathophysiological mechanisms contribute to volumetric and other neural abnormalities in HIV+ individuals. PMID- 29441002 TI - Aggression Profiles in the Spanish Child Population: Differences in Perfectionism, School Refusal and Affect. AB - The aim of this study was to identify the existence of combinations of aggression components (Anger, Hostility, Physical Aggression and Verbal Aggression) that result in different profiles of aggressive behavior in children, as well as to test the differences between these profiles in scores of perfectionism, school refusal and affect. It is interesting to analyze these variables given: (a) their clinical relevance due to their close relationship with the overall psychopathology; and (b) the need for further evidence regarding how they are associated with aggressive behavior. The sample consisted of 1202 Spanish primary education students between the ages of 8 and 12. Three aggressive behavior profiles for children were identified using Latent Class Analysis (LCA): High Aggression (Z scores between 0.69 and 0.7), Moderate Aggression (Z scores between -0.39 and -0.47) and Low Aggression (Z scores between -1.36 and -1.58). These profiles were found for 49.08%, 38.46% and 12.48% of the sample, respectively. High Aggression scored significantly higher than Moderate Aggression and Low Aggression on Socially Prescribed Perfectionism (SPP), Self-Oriented Perfectionism (SOP), the first three factors of school refusal (i.e., FI. Negative Affective, FII. Social Aversion and/or Evaluation, FIII. To Pursue Attention), and Negative Affect (NA). In addition, Moderate Aggression also reported significantly higher scores than Low Aggression for the three first factors of school refusal and NA. Conversely, Low Aggression had significantly higher mean scores than High Aggression and Moderate Aggression on Positive Affect (PA). Results demonstrate that High Aggression was the most maladaptive profile having a high risk of psychological vulnerability. Aggression prevention programs should be sure to include strategies to overcome psychological problems that characterize children manifesting high levels of aggressive behavior. PMID- 29441003 TI - The Post-mating Switch in the Pheromone Response of Nasonia Females Is Mediated by Dopamine and Can Be Reversed by Appetitive Learning. AB - The olfactory sense is of crucial importance for animals, but their response to chemical stimuli is plastic and depends on their physiological state and prior experience. In many insect species, mating status influences the response to sex pheromones, but the underlying neuromodulatory mechanisms are poorly understood. After mating, females of the parasitic wasp Nasonia vitripennis are no longer attracted to the male sex pheromone. Here we show that this post-mating behavioral switch is mediated by dopamine (DA). Females fed a DA-receptor antagonist prior to mating maintained their attraction to the male pheromone after mating while virgin females injected with DA became unresponsive. However, the switch is reversible as mated females regained their pheromone preference after appetitive learning. Feeding mated N. vitripennis females with antagonists of either octopamine- (OA) or DA-receptors prevented relearning of the pheromone preference suggesting that both receptors are involved in appetitive learning. Moreover, DA injection into mated females was sufficient to mimic the oviposition reward during odor conditioning with the male pheromone. Our data indicate that DA plays a key role in the plastic pheromone response of N. vitripennis females and reveal some striking parallels between insects and mammals in the neuromodulatory mechanisms underlying olfactory plasticity. PMID- 29441004 TI - Reverse Engineering Tone-Deafness: Disrupting Pitch-Matching by Creating Temporary Dysfunctions in the Auditory-Motor Network. AB - Perceiving and producing vocal sounds are important functions of the auditory motor system and are fundamental to communication. Prior studies have identified a network of brain regions involved in pitch production, specifically pitch matching. Here we reverse engineer the function of the auditory perception production network by targeting specific cortical regions (e.g., right and left posterior superior temporal (pSTG) and posterior inferior frontal gyri (pIFG)) with cathodal transcranial direct current stimulation (tDCS)-commonly found to decrease excitability in the underlying cortical region-allowing us to causally test the role of particular nodes in this network. Performance on a pitch matching task was determined before and after 20 min of cathodal stimulation. Acoustic analyses of pitch productions showed impaired accuracy after cathodal stimulation to the left pIFG and the right pSTG in comparison to sham stimulation. Both regions share particular roles in the feedback and feedforward motor control of pitched vocal production with a differential hemispheric dominance. PMID- 29441005 TI - Atypical Within-Session Motor Procedural Learning after Traumatic Brain Injury but Well-Preserved Between-Session Procedural Memory Consolidation. AB - Using the finger-to-thumb opposition sequence (FOS) learning task, we characterized motor skill learning in sub-acute patients hospitalized for rehabilitation following traumatic brain injury (TBI). Ten patients (Trained TBI) and 11 healthy participants (Trained Healthy) were trained using a multi-session protocol: a single session was afforded in the first week of the study, and four daily sessions were afforded during the second week. Intensity of practice was adapted to patients. Performance speed and accuracy were tested before and after each session. Retention was tested 1 month later. Ten patients (Control TBI) had no FOS training and were tested only at the beginning and the end of the 6 week period. Although baseline performance on the FOS was very slow, all three phases of skill learning found in healthy adults (acquisition, between-session consolidation gains, and long-term retention) could be identified in patients with TBI. However, their time-course of learning was atypical. The Trained TBI group improved in speed about double the spontaneous improvements observed in the Control TBI group, with no speed-accuracy tradeoff. Normalized to their initial performance on the FOS, the gains accrued by the Trained TBI group after a first training were comparable to those accrued by healthy adults. Only during the second week with daily training, the rate of improvement of the Trained TBI group lagged behind that of the Trained Healthy group, due to increasing within sessions losses in performance speed; no such losses were found in healthy participants. The Functional Independence Measure scores at the start of the study correlated with the total gains attained at the end of the study; no correlations were found with severity of injury or explicit memory impairments. Despite within-sessions losses in performance, which we propose reflect cognitive fatigue, training resulted in robust overall learning and long-term retention in patients with moderate-severe TBI. Given that the gains in performance evolved mainly between sessions, as delayed, offline, gains, our results suggest that memory consolidation processes can be effectively engaged in patients with TBI. However, practice protocols and schedules may need to be optimized to better engage the potential for long-term plasticity in these patients. PMID- 29441006 TI - Temporal Contiguity Training Influences Behavioral and Neural Measures of Viewpoint Tolerance. AB - Humans can often recognize faces across viewpoints despite the large changes in low-level image properties a shift in viewpoint introduces. We present a behavioral and an fMRI adaptation experiment to investigate whether this viewpoint tolerance is reflected in the neural visual system and whether it can be manipulated through training. Participants saw training sequences of face images creating the appearance of a rotating head. Half of the sequences showed faces undergoing veridical changes in appearance across the rotation (non-morph condition). The other half were non-veridical: during rotation, the face simultaneously morphed into another face. This procedure should successfully associate frontal face views with side views of the same or a different identity, and, according to the temporal contiguity hypothesis, thus enhance viewpoint tolerance in the non-morph condition and/or break tolerance in the morph condition. Performance on the same/different task in the behavioral experiment (N = 20) was affected by training. There was a significant interaction between training (associated/not associated) and identity (same/different), mostly reflecting a higher confusion of different identities when they were associated during training. In the fMRI study (N = 20), fMRI adaptation effects were found for same-viewpoint images of untrained faces, but no adaptation for untrained faces was present across viewpoints. Only trained faces which were not morphed during training elicited a slight adaptation across viewpoints in face-selective regions. However, both in the behavioral and in the neural data the effects were small and weak from a statistical point of view. Overall, we conclude that the findings are not inconsistent with the proposal that temporal contiguity can influence viewpoint tolerance, with more evidence for tolerance when faces are not morphed during training. PMID- 29441007 TI - Commentary: Broca Pars Triangularis Constitutes a "Hub" of the Language-Control Network during Simultaneous Language Translation. PMID- 29441008 TI - Diagnosis and Treatment of Cerebral Venous Thrombosis: A Review. AB - Cerebral venous thrombosis (CVT), also called cerebral venous sinus thrombosis (CVST), is a cerebrovascular disease with diverse clinical manifestations that often affects young adults, women of childbearing age, and children. It's most common clinical manifestations are headache, seizures, altered consciousness, and neurological focal signs on physical examination. CVT can manifest as a single symptom, or it can present as a syndrome consisting of multiple symptoms. This non-specific clinical picture makes diagnosing CVT difficult. Although the mortality rate of CVT has been significantly reduced by improvements in treatment and diagnostic techniques, the mortality rate of severe CVT remains as high as 34.2%. Survivors of this type of CVT have varying degrees of residual symptoms and are not able to return to their previous work. Hence, we performed a comprehensive literature search in the PubMed, EMBASE, and Medline databases to review the diagnosis and treatment of CVT. PMID- 29441010 TI - An Aged Canid with Behavioral Deficits Exhibits Blood and Cerebrospinal Fluid Amyloid Beta Oligomers. AB - Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Abeta in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic Abeta peptides. We report that soluble oligomers were specifically detected in the dog's blood and cerebrospinal fluid (CSF) via anti-oligomer- and anti-Abeta specific binders. Importantly, our results reveal the potent neurotoxic effects of the dog's CSF on cell viability and the seeding efficiency of the CSF-borne soluble oligomers on the thermodynamic activity and the aggregation kinetics of synthetic human Abeta. The value of further characterizing the naturally occurring Alzheimer-like neuropathology in dogs using genetic and molecular tools is discussed. PMID- 29441011 TI - Hyposalivation and Poor Dental Health Status Are Potential Correlates of Age Related Cognitive Decline in Late Midlife in Danish Men. AB - Introduction: Peripheral correlates of age-associated cognitive decline are important tools in the screening for potentially abnormal courses of cognitive aging. Since salivary gland function is controlled by the autonomic and central nervous system, associations between cognitive changes and salivary gland hypofunction were tested in two groups of middle-aged men in late midlife, who differed substantially with respect to their midlife performance in verbal intelligence when compared with their performance in young adulthood. Materials and Methods: Participants (n = 193) were recruited from the Danish Metropolit Cohort of men born in 1953. Based on their individual change in performance in two previously administered intelligence tests, they were allocated to one group of positive and one group of negative outliers in midlife cognition scores, indicating no decline versus decline in test performance. All participants underwent a clinical oral examination including assessments of their dental, periodontal, and mucosal conditions. Whole and parotid saliva flow rates were measured, and the number of systemic diseases and medication intake as well as daytime and nocturnal xerostomia were registered. Results: Participants with decline in cognitive test performance in midlife had significantly lower unstimulated whole saliva flow rates, higher prevalence of hyposalivation and daytime xerostomia and a higher caries experience than participants with no decline in midlife performance. Daytime and nocturnal xerostomia were associated with daily intake of medication and alcohol. Discussion: Overall, hyposalivation, xerostomia and poor dental status distinguished a group of men displaying relative decline in cognitive performance from a group of men without evidence of cognitive decline. Thus, hyposalivation and poor dental health status may represent potential correlates of age-related cognitive decline in late midlife, provided that other causes can be excluded. PMID- 29441012 TI - A Modified Reading the Mind in the Eyes Test Predicts Behavioral Variant Frontotemporal Dementia Better Than Executive Function Tests. AB - Behavioral variant frontotemporal dementia (bvFTD) is characterized by deep alterations in behavior and personality. Although revised diagnostic criteria agree for executive dysfunction as most characteristic, impairments in social cognition are also suggested. The study aimed at identifying those neuropsychological and behavioral parameters best discriminating between bvFTD and healthy controls. Eighty six patients were diagnosed with possible or probable bvFTD according to Rascovsky et al. (2011) and compared with 43 healthy age-matched controls. Neuropsychological performance was assessed with a modified Reading the Mind in the Eyes Test (RMET), Stroop task, Trail Making Test (TMT), Hamasch-Five-Point Test (H5PT), and semantic and phonemic verbal fluency tasks. Behavior was assessed with the Apathy Evaluation Scale, Frontal Systems Behavioral Scale, and Bayer Activities of Daily Living Scale. Each test's discriminatory power was investigated by Receiver Operating Characteristic curves calculating the area under the curve (AUC). bvFTD patients performed significantly worse than healthy controls in all neuropsychological tests. Discriminatory power (AUC) was highest in behavioral questionnaires, high in verbal fluency tasks and the RMET, and lower in executive function tests such as the Stroop task, TMT and H5PT. As fluency tasks depend on several cognitive functions, not only executive functions, results suggest that the RMET discriminated better between bvFTD and control subjects than other executive tests. Social cognition should be incorporated into diagnostic criteria for bvFTD in the future, such as in the International Classification of Diseases (ICD)-11, as already suggested in the Diagnostic and Statistical Manual for Mental Disorders (DSM)-5. PMID- 29441009 TI - Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications. AB - Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid beta (Abeta), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Abeta is dysregulated, which leads to the accumulation and aggregation of Abeta. Metabolism of Abeta and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD. PMID- 29441013 TI - alpha-Synuclein Aggregated with Tau and beta-Amyloid in Human Platelets from Healthy Subjects: Correlation with Physical Exercise. AB - The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of beta-amyloid (Abeta), tau, and alpha-synuclein (alpha-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids. In this respect, we have demonstrated that alpha-syn forms detectable hetero-aggregates with Abeta or tau in red blood cells (RBCs) of healthy subjects. In particular, alpha-syn levels and its heteromeric interactions are modulated by plasma antioxidant capability (AOC), which increases in turn with physical activity. In order to understand if a specific distribution of misfolded proteins can occur in other blood cells, a cohort of human subjects was enrolled to establish a correlation among AOC, the level of physical exercise and the concentrations of aging-related proteins in platelets. The healthy subjects were divided depending on their level of physical exercise (i.e., athletes and sedentary subjects) and their age (young and older subjects). Herein, aging-related proteins (i.e., alpha-syn, tau and Abeta) were confirmed to be present in human platelets. Among such proteins, platelet tau concentration was demonstrated to decrease in athletes, while alpha-syn and Abeta did not correlate with physical exercise. For the first time, alpha-syn was shown to directly interact with Abeta and tau in platelets, forming detectable hetero complexes. Interestingly, alpha-syn interaction with tau was inversely related to plasma AOC and to the level of physical activity. These results suggested that alpha-syn heterocomplexes, particularly with tau, could represent novel indicators to monitor aging-related proteins in platelets. PMID- 29441014 TI - Subtle Alterations in Spatial Memory Induced by Amyloid Peptides Infusion in Rats. AB - The cause of Alzheimer's disease (AD) remains uncertain. The accumulation of amyloid peptides (Abeta) is the main pathophysiological hallmark of the disease. Spatial deficit is an important initial sign of AD, while other types of memory impairments that appear in later stages. The Barnes maze allows the detection of subtle alterations in spatial search by the analysis of use of different strategies. Previous findings showed a general performance deficit in this task following long-term (35 days) infusion of Abeta, which corresponds to the moderate or severe impairments of the disease. In the present study, we evaluated the effects of a low-dose 15-day long treatment with Abeta peptides on spatial and non-spatial strategies of rats tested in the Barnes maze. Abeta peptides (0.5 MUL/site/day; 30 pmoL solution of Abeta1-40:Abeta1-42 10:1) or saline were bilaterally infused into the CA1 (on the first treatment day) and intraventricularly (on the following 15 days) in 6-month-old Wistar male rats. Abeta infusion induced a deficit in the performance (increased latency and distance traveled to reach the target compared to saline group). In addition, a significant association between treatment and search strategy in the retrieval trial was found: Abeta group preferred the non-spatial search strategy, while saline group preferred the spatial search. In conclusion, the protocol of Abeta infusion used here induced a subtle cognitive deficit that was specific to spatial aspects. Indeed, animals under Abeta treatment still showed retrieval, but using non-spatial strategies. We suggest that this approach is potentially useful to the study of the initial memory deficits in early AD. PMID- 29441015 TI - A Matrine Derivative M54 Suppresses Osteoclastogenesis and Prevents Ovariectomy Induced Bone Loss by Targeting Ribosomal Protein S5. AB - Post-menopausal osteoporosis (PMOP) is a metabolic bone disorder characterized by low bone mass and micro-architectural deterioration of bone tissue. The over activated osteoclastogenesis, which plays an important role in osteoporosis, has become an important therapeutic target. M54 was a bioactive derivative of the Chinese traditional herb matrine. We found that M54 could suppress RANKL-induced osteoclastogenesis in bone marrow mononuclear cells and RAW264.7 cells through suppressing NF-kappaB, PI3K/AKT, and MAPKs pathways activity in vitro, and prevent ovariectomy-induced bone loss in vivo. Our previous study has proved that ribosomal protein S5 (RPS5) was a direct target of M19, based on which M54 was synthesized. Thus we deduced that M54 also targeted RPS5. During osteoclastogenesis, the RPS5 level in RAW264.7 cells was significantly down regulated while M54 could maintain its level. After RPS5 was silenced, the inhibitory effects of M54 on osteoclastogenesis were partially compromised, indicating that M54 took effects through targeting RPS5. In summary, M54 was a potential clinical medicine for post-menopause osteoporosis treatment, and RPS5 is a possible key protein in PMOP. PMID- 29441016 TI - Tannins Enriched Fraction of Emblica officinalis Fruits Alleviates High-Salt and Cholesterol Diet-Induced Cognitive Impairment in Rats via Nrf2-ARE Pathway. AB - Modern diets containing high quantities of salt and cholesterol have exhibited to cause a considerable effect on our health. Such diets, when consumed in the long term, have also shown to be a precursor to several disorders such as the metabolic disorder and consequently, various other diseases, including cognitive deficits. In the present study, we used a high salt and cholesterol diet (HSCD) to induce cognitive impairment in rats and also investigated the pharmacological action of tannins enriched fractions of Emblica officinalis (EOT) - a fruit that has been traditionally used for the treatment of numerous disorders for centuries. Significant alterations in MDA, GSH, TBARS, GPx, mitochondrial ATP, and mitochondrial membrane potential levels were observed in rats fed HSCD, which indicated presence of oxidative stress. Moreover, classic signs of cognitive impairment and deficits in spatial learning and memory were observed in the neurobehavioral tests. E. officinalis tannins exhibited good affinity to Nrf2 receptors in in silico studies, significantly reversed the changes in the aforementioned biomarkers of oxidative stress which were altered in the model group, as well as improved the performance of rats in Morris water maze task. Our results also reflected that EOT supplementation significantly increased the expression of Nrf2 in the CA1 region of hippocampus and cortex. Additionally, TUNEL assay indicated that EOT supplementation led to reversal of DNA fragmentation and apoptosis caused by HSCD. Immunohistochemical analysis and western blot further revealed a surge in the nuclear location of Nrf2. Through our study, we have demonstrated that cognitive impairment can be caused in rats via HSCD as a result of the oxidative stress induced by the same. Additionally, we have investigated a novel mechanism of action for EOT (which strongly suggests to be via the Nrf2-ARE pathway) and demonstrated that it has the potential to be used in the treatment of cognitive impairment. PMID- 29441017 TI - 15, 16-Dihydrotanshinone I Inhibits Hemangiomas through Inducing Pro-apoptotic and Anti-angiogenic Mechanisms in Vitro and in Vivo. AB - Infantile hemangioma (IH) is a common and benign vascular neoplasms, which has a high incidence in children. Although IH is benign, some patients experience complications such as pain, functional impairment, and permanent disfigurement. Treatment options for IH include corticosteroids, surgery, vincristine, interferon or cyclophosphamide. However, none of these modalities are ideal due to restrictions or potential serious side effects. There is thus a great need to explore novel treatments for IH with less side effects. Angiogenesis, vasculogenesis and tumorigenesis are the main features of IH. Tanshen is mostly used in Chinese traditional medicine to treat hematological abnormalities. Therefore, the aim of our study was to evaluate anti-proliferation and anti angiogenesis effects on hemangiomas cells by extracted Tanshen compounds compared with propranolol, the first-line treatment for IH currently, both in vitro and in vivo. Cell viability, apoptosis, protein expression and anti-angiogenesis were analyzed by CCK8, Annexin V staining, Western blot and tube formation, respectively. The anti-tumor activity in vivo was evaluated using a mouse xenograft model. Fourteen major compounds extracting from Tanshen were screened for their ability to inhibit hemangiomas cells. Of the 14 compounds investigated, 15,16-Dihydrotanshinone I (DHTS) was the most potent modulator of EOMA cell biology. DHTS could significantly decrease EOMA cells proliferation by inducing cell apoptosis, which is much more efficient than propranolol in vitro. DHTS increased the expression of several apoptosis-related proteins, including caspase9, caspase3, PARP, AIF, BAX, cytochrome c, caspase8 and FADD and significantly inhibited angiogenesis, as indicated by reduced tube formation and diminished expression of vascular endothelial cell growth factor receptor 2 and matrix metalloproteinase 9. In nude mice xenograft experiment, DHTS (10 mg/kg) could significantly inhibit the tumor growth of EOMA cells as well as propranolol (40 mg/kg). Our study showed that DHTS was much more effective than propranolol in inhibiting hemangiomas proliferation and angiogenesis in vitro and in vivo, which could have potential therapeutic applications for treatment of IH. PMID- 29441018 TI - Asiaticoside Attenuates Cell Growth Inhibition and Apoptosis Induced by Abeta1-42 via Inhibiting the TLR4/NF-kappaB Signaling Pathway in Human Brain Microvascular Endothelial Cells. AB - Alzheimer's disease (AD) is a very common progressive neurodegenerative disorder with the highest incidence in the world. Dysfunction of the blood-brain barrier (BBB) may be responsible for the pathogenesis and pathology of AD for abnormally transporting amyloid-beta (Abeta, the main component of the senile plaques) from the sera into the central nervous system. Abeta peptides induce apoptosis in human brain microvascular endothelial cells (hBMECs), the main component of BBB. Apoptosis in neuronal cells plays a critical role in the pathogenesis of AD. Asiaticoside, a natural glycoside extracted from Centella asiatica (L.) Urban, has an anti-apoptotic effect on hBMECs but the molecule mechanism remains unclear. Therefore, we investigate the protective effect of asiaticoside on Abeta1-42-induced cytotoxicity and apoptosis as well as associated mechanism in hBMECs with commonly used in vitro methods for clinical development of asiaticoside as a novel anti-AD agent. In the present study, we investigated the effects of asiaticoside on cytotoxicity by Cell Counting Kit-8 assay, mitochondrial membrane potential by JC-1 fluorescence analysis, anti-apoptosis by Hoechst 33258 staining and Annexin V-FITC (fluorescein isothiocyanate) and propidium iodide (PI) analyses, the expressions of TNF-alpha and IL-6 by enzyme linked immunosorbent assay (ELISA) and TLR4, MyD88, TRAF6, p-NF-kappaB p65, and total NF-kappaB p65 by Western blotting, and nuclear translocation of NF-kappaB p65 by immunofluorescence analysis in hBMECs. The results showed that pretreatment of asiaticoside (25, 50, and 100 MUM) for 12 h significantly attenuated cell growth inhibition and apoptosis, and restored declined mitochondrial membrane potential induced by Abeta1-42 (50 MUM) in hBMECs. Asiaticoside also significantly downregulated the elevated expressions of TNF alpha, IL-6, TLR4, MyD88, TRAF6, and p-NF-kappaB p65, as well as inhibited NF kappaB p65 translocation from cytoplasm to nucleus induced by Abeta1-42 in hBMECs in a concentration-dependent manner. The possible underlying molecular mechanism of asiaticoside may be through inhibiting the TLR4/NF-kappaB signaling pathway. Therefore, asiaticoside may be developed as a novel agent for the prevention and/or treatment of AD clinically. PMID- 29441020 TI - Eriodictyol Attenuates Myocardial Ischemia-Reperfusion Injury through the Activation of JAK2. AB - Myocardial ischemia-reperfusion (I/R) injury remains the leading risk factor of disability and mortality worldwide. In this study, the myocardial protective effect of eriodictyol (EDT) and the underlying mechanism in an ex vivo model of global myocardial I/R was investigated. After treatment with different concentrations of EDT, the decreased hemodynamic parameters induced by myocardial I/R injury were significantly attenuated by EDT. The elevated levels of IL-6, CRP, IL-8, and TNF-alpha were effectively reduced by EDT treatment. EDT also remarkably suppressed the levels of Bax and cleaved Caspase-3, and up-regulated the level of Bcl-2 in cardiac tissues from EDT-treated groups. Further studies showed that EDT could increase the levels of p-JAK2 and p-STAT3 in cardiac tissues. Meanwhile, treatment of AG490, a specific inhibitor of JAK2, abolished the protective effect of EDT on hemodynamic parameters, myocardial inflammation and myocardial cell apoptosis induced by I/R injury. These results demonstrated that EDT could protect against myocardial I/R injury through the activation of JAK2, providing a potential treatment with EDT during myocardial I/R injury. PMID- 29441019 TI - Natural Medicines Used in the Traditional Tibetan Medical System for the Treatment of Liver Diseases. AB - Liver disease is one of the most risk factors threatening human health. It is of great significance to find drugs that can treat liver diseases, especially for acute and chronic hepatitis, non-alcoholic fatty liver disease, and liver cancer. The search for drugs with good efficacy from traditional natural medicines has attracted more and more attention. Tibetan medicine, one of the China's traditional medical systems, has been widely used by the Tibetan people for the prevention and treatment of liver diseases for hundreds of years. The present paper summarized the natural Tibetan medicines that have been used in Tibetan traditional system of medicine to treat liver diseases by bibliographic investigation of 22 Tibetan medicine monographs and drug standards. One hundred and ninety three species including 181 plants, 7 animals, and 5 minerals were found to treat liver diseases in traditional Tibetan medicine system. The most frequently used species are Carthamus tinctorius, Brag-zhun, Swertia chirayita, Swertia mussotii, Halenia elliptica, Herpetospermum pedunculosum, and Phyllanthus emblica. Their names, families, medicinal parts, traditional uses, phytochemicals information, and pharmacological activities were described in detail. These natural medicines might be a valuable gift from the old Tibetan medicine to the world, and would be potential drug candidates for the treatment of liver diseases. Further studies are needed to prove their medicinal values in liver diseases treatment, identify bioactive compounds, elucidate the underlying mechanism of action, and clarify their side effects or toxicity with the help of modern phytochemical, pharmacological, metabonomics, and/or clinical trial methods. PMID- 29441022 TI - Heat Shock Cognate 70 Inhibitor, VER-155008, Reduces Memory Deficits and Axonal Degeneration in a Mouse Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in structural brain changes and memory impairment. We hypothesized that reconstructing neural networks is essential for memory recovery in AD. Heat shock cognate 70 (HSC70), a member of the heat shock protein family of molecular chaperones, is upregulated in AD patient brains, and recent studies have demonstrated that HSC70 facilitates axonal degeneration and pathological progression in AD. However, the direct effects of HSC70 inhibition on axonal development and memory function have never been investigated. In this study, we examined the effects of a small-molecule HSC70 inhibitor, VER-155008, on axonal morphology and memory function in a mouse model of AD (5XFAD mice). We found that VER-155008 significantly promoted axonal regrowth in amyloid beta-treated neurons in vitro and improved object recognition, location, and episodic-like memory in 5XFAD mice. Furthermore, VER-155008 penetrated into the brain after intraperitoneal administration, suggesting that VER-155008 acts in the brain in situ. Immunohistochemistry revealed that VER-155008 reduced bulb-like axonal swelling in the amyloid plaques in the perirhinal cortex and CA1 in 5XFAD mice, indicating that VER-155008 also reverses axonal degeneration in vivo. Moreover, the two main pathological features of AD, amyloid plaques and paired helical filament tau accumulation, were reduced by VER-155008 administration in 5XFAD mice. This is the first report to show that the inhibition of HSC70 function may be critical for axonal regeneration and AD-like symptom reversal. Our study provides evidence that HSC70 can be used as a new therapeutic target for AD treatment. PMID- 29441021 TI - Biology of Platelet Purinergic Receptors and Implications for Platelet Heterogeneity. AB - Platelets are small anucleated cells present only in mammals. Platelets mediate intravascular hemostatic balance, prevent interstitial bleeding, and have a major role in thrombosis. Activation of platelet purinergic receptors is instrumental in initiation of hemostasis and formation of the hemostatic plug, although this activation process becomes problematic in pathological settings of thrombosis. This review briefly outlines the roles and function of currently known platelet purinergic receptors (P1 and P2) in the setting of hemostasis and thrombosis. Additionally, we discuss recent novel studies on purinergic receptor distribution according to heterogeneous platelet size, and the possible implication of this distribution on hemostatic function. PMID- 29441023 TI - Comparison of Fatty Acid and Gene Profiles in Skeletal Muscle in Normal and Obese C57BL/6J Mice before and after Blunt Muscle Injury. AB - Injury and obesity are two major health burdens affecting millions of people worldwide. Obesity is recognized as a state of chronic inflammation accompanied by various co-morbidities like T2D or cardiovascular diseases. There is increasing evidence that obesity impairs muscle regeneration, which is mainly due to chronic inflammation and to excessive accumulation of lipids in adipose and non-adipose tissue. To compare fatty acid profiles and changes in gene expression at different time points after muscle injury, we used an established drop tower based model with a defined force input to damage the extensor iliotibialis anticus on the left hind limb of female C57BL/6J mice of normal weight and obese mice. Although most changes in fatty acid content in muscle tissue are diet related, levels of eicosaenoic (normal weight) and DHG-linolenic acid (obese) in the phospholipid and docosahexaenoic acid (normal weight) in the triglyceride fraction are altered after injury. Furthermore, changes in gene transcription were detected in 3829 genes in muscles of normal weight mice, whereas only 287 genes were altered in muscles of obese mice after trauma. Alterations were found within several pathways, among them notch-signaling, insulin-signaling, sonic hedgehog-signaling, apoptosis related pathways, fat metabolism related cholesterol homeostasis, fatty acid biosynthetic process, fatty acid elongation, and acyl-CoA metabolic process. We could show that genes involved in fat metabolism are affected 3 days after trauma induction mostly in normal weight but not in obese mice. The strongest effects were observed in normal weight mice for Alox5ap, the activating protein for leukotriene synthesis, and Apobec1, an enzyme substantial for LDL synthesis. In summary, we show that obesity changes the fat content of skeletal muscle and generally shows a negative impact upon blunt muscle injury on various cellular processes, among them fatty acid related metabolism, notch-, insulin-, sonic hedgehog-signaling, and apoptosis. PMID- 29441025 TI - The Effect of Lower-Body Positive Pressure on the Cardiorespiratory Response at Rest and during Submaximal Running Exercise. AB - Anti-gravity treadmills facilitate locomotion by lower-body positive pressure (LBPP). Effects on cardiorespiratory regulation are unknown. Healthy men (30 +/- 8 y, 178.3 +/- 5.7 cm, 70.3 +/- 8.0 kg; mean +/- SD) stood upright (n = 10) or ran (n = 9) at 9, 11, 13, and 15 km.h-1 (5 min stages) with LBPP (0, 15, 40 mmHg). Cardiac output (CO), stroke volume (SV), heart rate (HR), blood pressure (BP), peripheral resistance (PR), and oxygen uptake (VO2) were monitored continuously. During standing, LBPP increased SV [by +29 +/- 13 (+41%) and +42 +/ 15 (+60%) ml, at 15 and 40 mmHg, respectively (p < 0.05)] and decreased HR [by 15 +/- 6 (-20%) and -22 +/- 9 (-29%) bpm (p < 0.05)] resulting in a transitory increase in CO [by +1.6 +/- 1.0 (+32%) and +2.0 +/- 1.0 (+39%) l.min-1 (p < 0.05)] within the first seconds of LBPP. This was accompanied by a transitory decrease in end-tidal PO2 [by -5 +/- 3 (-5%) and -10 +/- 4 (-10%) mmHg (p < 0.05)] and increase in VO2 [by +66 +/- 53 (+26%) and +116 +/- 64 (+46%) ml.min-1 (p < 0.05)], suggesting increased venous return and pulmonary blood flow. The application of LBPP increased baroreflex sensitivity (BRS) [by +1.8 +/- 1.6 (+18%) and +4.6 +/- 3.7 (+47%) at 15 and 40 mmHg LBPP, respectively P < 0.05]. After reaching steady-state exercise CO vs. VO2 relationships remained linear with similar slope and intercept for each participant (mean R2 = 0.84 +/- 0.13) while MAP remained unchanged. It follows that (1) LBPP affects cardiorespiratory integration at the onset of exercise; (2) at a given LBPP, once reaching steady state exercise, the cardiorespiratory load is reduced proportionally to the lower metabolic demand resulting from the body weight support; (3) the balance between cardiovascular response, oxygen delivery to the exercising muscles and blood pressure regulation is maintained at exercise steady-state; and (4) changes in baroreflex sensitivity may be involved in the regulation of cardiovascular parameters during LBPP. PMID- 29441026 TI - Hemodynamic Functionality of Transfused Red Blood Cells in the Microcirculation of Blood Recipients. AB - The primary goal of red blood cell (RBC) transfusion is to supply oxygen to tissues and organs. However, due to a growing number of studies that have reported negative transfusion outcomes, including reduced blood perfusion, there is rising concern about the risks in blood transfusion. RBC are characterized by unique flow-affecting properties, specifically adherence to blood vessel wall endothelium, cell deformability, and self-aggregability, which define their hemodynamic functionality (HF), namely their potential to affect blood circulation. The role of the HF of RBC in blood circulation, particularly the microcirculation, has been documented in numerous studies with animal models. These studies indicate that the HF of transfused RBC (TRBC) plays an important role in the transfusion outcome. However, studies with animal models must be interpreted with reservations, as animal physiology may not reflect human physiology. To test this concept in humans, we have directly examined the effect of the HF of TRBC, as expressed by their deformability and adherence to vascular endothelium, on the transfusion-induced effect on the skin blood flow and hemoglobin increment in beta-thalassemia major patients. The results demonstrated, for the first time in humans, that the TRBC HF is a potent effector of the transfusion outcome, expressed by the transfusion-induced increase in the recipients' hemoglobin level, and the change in the skin blood flow, indicating a link between the microcirculation and the survival of TRBC in the recipients' vascular system. The implication of these findings for blood transfusion practice and to vascular function in blood recipients is discussed. PMID- 29441027 TI - Pragmatically Framed Cross-Situational Noun Learning Using Computational Reinforcement Models. AB - Cross-situational learning and social pragmatic theories are prominent mechanisms for learning word meanings (i.e., word-object pairs). In this paper, the role of reinforcement is investigated for early word-learning by an artificial agent. When exposed to a group of speakers, the agent comes to understand an initial set of vocabulary items belonging to the language used by the group. Both cross situational learning and social pragmatic theory are taken into account. As social cues, joint attention and prosodic cues in caregiver's speech are considered. During agent-caregiver interaction, the agent selects a word from the caregiver's utterance and learns the relations between that word and the objects in its visual environment. The "novel words to novel objects" language-specific constraint is assumed for computing rewards. The models are learned by maximizing the expected reward using reinforcement learning algorithms [i.e., table-based algorithms: Q-learning, SARSA, SARSA-lambda, and neural network-based algorithms: Q-learning for neural network (Q-NN), neural-fitted Q-network (NFQ), and deep Q network (DQN)]. Neural network-based reinforcement learning models are chosen over table-based models for better generalization and quicker convergence. Simulations are carried out using mother-infant interaction CHILDES dataset for learning word-object pairings. Reinforcement is modeled in two cross-situational learning cases: (1) with joint attention (Attentional models), and (2) with joint attention and prosodic cues (Attentional-prosodic models). Attentional-prosodic models manifest superior performance to Attentional ones for the task of word learning. The Attentional-prosodic DQN outperforms existing word-learning models for the same task. PMID- 29441028 TI - Indirect Observation in Everyday Contexts: Concepts and Methodological Guidelines within a Mixed Methods Framework. AB - Indirect observation is a recent concept in systematic observation. It largely involves analyzing textual material generated either indirectly from transcriptions of audio recordings of verbal behavior in natural settings (e.g., conversation, group discussions) or directly from narratives (e.g., letters of complaint, tweets, forum posts). It may also feature seemingly unobtrusive objects that can provide relevant insights into daily routines. All these materials constitute an extremely rich source of information for studying everyday life, and they are continuously growing with the burgeoning of new technologies for data recording, dissemination, and storage. Narratives are an excellent vehicle for studying everyday life, and quantitization is proposed as a means of integrating qualitative and quantitative elements. However, this analysis requires a structured system that enables researchers to analyze varying forms and sources of information objectively. In this paper, we present a methodological framework detailing the steps and decisions required to quantitatively analyze a set of data that was originally qualitative. We provide guidelines on study dimensions, text segmentation criteria, ad hoc observation instruments, data quality controls, and coding and preparation of text for quantitative analysis. The quality control stage is essential to ensure that the code matrices generated from the qualitative data are reliable. We provide examples of how an indirect observation study can produce data for quantitative analysis and also describe the different software tools available for the various stages of the process. The proposed method is framed within a specific mixed methods approach that involves collecting qualitative data and subsequently transforming these into matrices of codes (not frequencies) for quantitative analysis to detect underlying structures and behavioral patterns. The data collection and quality control procedures fully meet the requirement of flexibility and provide new perspectives on data integration in the study of biopsychosocial aspects in everyday contexts. PMID- 29441024 TI - Skin Temperature Measurement Using Contact Thermometry: A Systematic Review of Setup Variables and Their Effects on Measured Values. AB - Background: Skin temperature (Tskin) is commonly measured using Tskin sensors affixed directly to the skin surface, although the influence of setup variables on the measured outcome requires clarification. Objectives: The two distinct objectives of this systematic review were (1) to examine measurements from contact Tskin sensors considering equilibrium temperature and temperature disturbance, sensor attachments, pressure, environmental temperature, and sensor type, and (2) to characterise the contact Tskin sensors used, conditions of use, and subsequent reporting in studies investigating sports, exercise, and other physical activity. Data sources and study selection: For the measurement comparison objective, Ovid Medline and Scopus were used (1960 to July 2016) and studies comparing contact Tskin sensor measurements in vivo or using appropriate physical models were included. For the survey of use, Ovid Medline was used (2011 to July 2016) and studies using contact temperature sensors for the measurement of human Tskinin vivo during sport, exercise, and other physical activity were included. Study appraisal and synthesis methods: For measurement comparisons, assessments of risk of bias were made according to an adapted version of the Cochrane Collaboration's risk of bias tool. Comparisons of temperature measurements were expressed, where possible, as mean difference and 95% limits of agreement (LoA). Meta-analyses were not performed due to the lack of a common reference condition. For the survey of use, extracted information was summarised in text and tabular form. Results: For measurement comparisons, 21 studies were included. Results from these studies indicated minor (<0.5 degrees C) to practically meaningful (>0.5 degrees C) measurement bias within the subgroups of attachment type, applied pressure, environmental conditions, and sensor type. The 95% LoA were often within 1.0 degrees C for in vivo studies and 0.5 degrees C for physical models. For the survey of use, 172 studies were included. Details about Tskin sensor setup were often poorly reported and, from those reporting setup information, it was evident that setups widely varied in terms of type of sensors, attachments, and locations used. Conclusions: Setup variables and conditions of use can influence the measured temperature from contact Tskin sensors and thus key setup variables need to be appropriately considered and consistently reported. PMID- 29441029 TI - The Bi-directional Relationship between Source Characteristics and Message Content. AB - Much of what we believe we know, we know through the testimony of others (Coady, 1992). While there has been long-standing evidence that people are sensitive to the characteristics of the sources of testimony, for example in the context of persuasion, researchers have only recently begun to explore the wider implications of source reliability considerations for the nature of our beliefs. Likewise, much remains to be established concerning what factors influence source reliability. In this paper, we examine, both theoretically and empirically, the implications of using message content as a cue to source reliability. We present a set of experiments examining the relationship between source information and message content in people's responses to simple communications. The results show that people spontaneously revise their beliefs in the reliability of the source on the basis of the expectedness of a source's claim and, conversely, adjust message impact by perceived reliability; hence source reliability and message content have a bi-directional relationship. The implications are discussed for a variety of psychological, philosophical and political issues such as belief polarization and dual-route models of persuasion. PMID- 29441030 TI - Multisensory Technology for Flavor Augmentation: A Mini Review. AB - There is growing interest in the development of new technologies that capitalize on our emerging understanding of the multisensory influences on flavor perception in order to enhance human-food interaction design. This review focuses on the role of (extrinsic) visual, auditory, and haptic/tactile elements in modulating flavor perception and more generally, our food and drink experiences. We review some of the most exciting examples of recent multisensory technologies for augmenting such experiences. Here, we discuss applications for these technologies, for example, in the field of food experience design, in the support of healthy eating, and in the rapidly growing world of sensory marketing. However, as the review makes clear, while there are many opportunities for novel human-food interaction design, there are also a number of challenges that will need to be tackled before new technologies can be meaningfully integrated into our everyday food and drink experiences. PMID- 29441031 TI - The Impact of Individual Differences, Types of Model and Social Settings on Block Building Performance among Chinese Preschoolers. AB - Children's block building performances are used as indicators of other abilities in multiple domains. In the current study, we examined individual differences, types of model and social settings as influences on children's block building performance. Chinese preschoolers (N = 180) participated in a block building activity in a natural setting, and performance was assessed with multiple measures in order to identify a range of specific skills. Using scores generated across these measures, three dependent variables were analyzed: block building skills, structural balance and structural features. An overall MANOVA showed that there were significant main effects of gender and grade level across most measures. Types of model showed no significant effect in children's block building. There was a significant main effect of social settings on structural features, with the best performance in the 5-member group, followed by individual and then the 10-member block building. These findings suggest that boys performed better than girls in block building activity. Block building performance increased significantly from 1st to 2nd year of preschool, but not from second to third. The preschoolers created more representational constructions when presented with a model made of wooden rather than with a picture. There was partial evidence that children performed better when working with peers in a small group than when working alone or working in a large group. It is suggested that future study should examine other modalities rather than the visual one, diversify the samples and adopt a longitudinal investigation. PMID- 29441032 TI - Dissociating Long and Short-term Memory in Three-Month-Old Infants Using the Mismatch Response to Voice Stimuli. AB - Auditory event-related potentials (ERPs) have been successfully used in adults as well as in newborns to discriminate recall of longer-term and shorter-term memories. Specifically the Mismatch Response (MMR) to deviant stimuli of an oddball paradigm is larger if the deviant stimuli are highly familiar (i.e., retrieved from long-term memory) than if they are unfamiliar, representing an immediate change to the standard stimuli kept in short-term memory. Here, we aimed to extend previous findings indicating a differential MMR to familiar and unfamiliar deviants in newborns (Beauchemin et al., 2011), to 3-month-old infants who are starting to interact more with their social surroundings supposedly based on forming more (social) long-term representations. Using a voice discrimination paradigm, each infant was repeatedly presented with the word "baby" (400 ms, interstimulus interval: 600 ms, 10 min overall duration) pronounced by three different female speakers. One voice that was unfamiliar to the infants served as the frequently presented "standard" stimulus, whereas another unfamiliar voice served as the "unfamiliar deviant" stimulus, and the voice of the infant's mother served as the "familiar deviant." Data collection was successful for 31 infants (mean age = 100 days). The MMR was determined by the difference between the ERP to standard stimuli and the ERP to the unfamiliar and familiar deviant, respectively. The MMR to the familiar deviant (mother's voice) was larger, i.e., more positive, than that to the unfamiliar deviant between 100 and 400 ms post stimulus over the frontal and central cortex. However, a genuine MMR differentiating, as a positive deflection, between ERPs to familiar deviants and standard stimuli was only found in the 300-400 ms interval. On the other hand, a genuine MMR differentiating, as a negative deflection, between ERPs to unfamiliar deviants from ERPs to standard stimuli was revealed for the 200-300 ms post stimulus interval. Overall results confirm a differential MMR response to unfamiliar and familiar deviants in 3-month-olds, with the earlier negative MMR to unfamiliar deviants likely reflecting change detection based on comparison processes in short-term memory, and the later positive MMR to familiar deviants reflecting subsequent long-term memory-based processing of stimulus relevance. PMID- 29441033 TI - The Relationship between Types of Attention and Auditory Processing Skills: Reconsidering Auditory Processing Disorder Diagnosis. AB - Measures of attention have been found to correlate with specific auditory processing tests in samples of children suspected of Auditory Processing Disorder (APD), but these relationships have not been adequately investigated. Despite evidence linking auditory attention and deficits/symptoms of APD, measures of attention are not routinely used in APD diagnostic protocols. The aim of the study was to examine the relationship between auditory and visual attention tests and auditory processing tests in children with APD and to assess whether a proposed diagnostic protocol for APD, including measures of attention, could provide useful information for APD management. A pilot study including 27 children, aged 7-11 years, referred for APD assessment was conducted. The validated test of everyday attention for children, with visual and auditory attention tasks, the listening in spatialized noise sentences test, the children's communication checklist questionnaire and tests from a standard APD diagnostic test battery were administered. Pearson's partial correlation analysis examining the relationship between these tests and Cochrane's Q test analysis comparing proportions of diagnosis under each proposed battery were conducted. Divided auditory and divided auditory-visual attention strongly correlated with the dichotic digits test, r = 0.68, p < 0.05, and r = 0.76, p = 0.01, respectively, in a sample of 20 children with APD diagnosis. The standard APD battery identified a larger proportion of participants as having APD, than an attention battery identified as having Attention Deficits (ADs). The proposed APD battery excluding AD cases did not have a significantly different diagnosis proportion than the standard APD battery. Finally, the newly proposed diagnostic battery, identifying an inattentive subtype of APD, identified five children who would have otherwise been considered not having ADs. The findings show that a subgroup of children with APD demonstrates underlying sustained and divided attention deficits. Attention deficits in children with APD appear to be centred around the auditory modality but further examination of types of attention in both modalities is required. Revising diagnostic criteria to incorporate attention tests and the inattentive type of APD in the test battery, provides additional useful data to clinicians to ensure careful interpretation of APD assessments. PMID- 29441034 TI - Reduced Mu Power in Response to Unusual Actions Is Context-Dependent in 1-Year Olds. AB - During social interactions infants predict and evaluate other people's actions. Previous behavioral research found that infants' imitation of others' actions depends on these evaluations and is context-dependent: 1-year-olds predominantly imitated an unusual action (turning on a lamp with one's forehead) when the model's hands were free compared to when the model's hands were occupied or restrained. In the present study, we adapted this behavioral paradigm to a neurophysiological study measuring infants' brain activity while observing usual and unusual actions via electroencephalography. In particular, we measured differences in mu power (6 - 8 Hz) associated with motor activation. In a between subjects design, 12- to 14-month-old infants watched videos of adult models demonstrating that their hands were either free or restrained. Subsequent test frames showed the models turning on a lamp or a soundbox by using their head or their hand. Results in the hands-free condition revealed that 12- to 14-month olds displayed a reduction of mu power in frontal regions in response to unusual and thus unexpected actions (head touch) compared to usual and expected actions (hand touch). This may be explained by increased motor activation required for updating prior action predictions in response to unusual actions though alternative explanations in terms of general attention or cognitive control processes may also be considered. In the hands-restrained condition, responses in mu frequency band did not differ between action outcomes. This implies that unusual head-touch actions compared to hand-touch actions do not necessarily evoke a reduction of mu power. Thus, we conclude that reduction of mu frequency power is context-dependent during infants' action perception. Our results are interpreted in terms of motor system activity measured via changes in mu frequency band as being one important neural mechanism involved in action prediction and evaluation from early on. PMID- 29441036 TI - Does Blue Uniform Color Enhance Winning Probability in Judo Contests? AB - The color of an athlete's uniform may have an effect on psychological functioning and consequently bias the chances of winning contests in sport competition. Several studies reported a winning bias for judo athletes wearing a blue outfit relative to those wearing a white outfit. However, we argue there is no winning bias and that previous studies were confounded and based on small and specific data sets. We tested whether blue biases winning in judo using a very extensive judo data set (45,874 contests from all international judo tournaments between 2008 and 2014). In judo, the first called athlete for the fight used to wear the blue judogi but this was changed to the white judogi in 2011. This switch enabled us to compare the win bias before and after this change to isolate the effect of the color of the judogi. We found a significant win bias for the first called athlete, but this effect was not significantly related to the color of the judogi. The lack of a significant win effect of judogi color suggests that blue does not bias winning in judo, and that the blue-white pairing ensures an equal level of play. Our study shows the importance of thoroughly considering alternative explanations and using extensive datasets in color research in sports and psychology. PMID- 29441035 TI - Decision Making Strategy and the Simultaneous Processing of Syntactic Dependencies in Language and Music. AB - Despite differences in their function and domain-specific elements, syntactic processing in music and language is believed to share cognitive resources. This study aims to investigate whether the simultaneous processing of language and music share the use of a common syntactic processor or more general attentional resources. To investigate this matter we tested musicians and non-musicians using visually presented sentences and aurally presented melodies containing syntactic local and long-distance dependencies. Accuracy rates and reaction times of participants' responses were collected. In both sentences and melodies, unexpected syntactic anomalies were introduced. This is the first study to address the processing of local and long-distance dependencies in language and music combined while reducing the effect of sensory memory. Participants were instructed to focus on language (language session), music (music session), or both (dual session). In the language session, musicians and non-musicians performed comparably in terms of accuracy rates and reaction times. As expected, groups' differences appeared in the music session, with musicians being more accurate in their responses than non-musicians and only the latter showing an interaction between the accuracy rates for music and language syntax. In the dual session musicians were overall more accurate than non-musicians. However, both groups showed comparable behavior, by displaying an interaction between the accuracy rates for language and music syntax responses. In our study, accuracy rates seem to better capture the interaction between language and music syntax; and this interaction seems to indicate the use of distinct, however, interacting mechanisms as part of decision making strategy. This interaction seems to be subject of an increase of attentional load and domain proficiency. Our study contributes to the long-lasting debate about the commonalities between language and music by providing evidence for their interaction at a more domain-general level. PMID- 29441037 TI - The Integration of Realistic Episodic Memories Relies on Different Working Memory Processes: Evidence from Virtual Navigation. AB - Memory is one of the most important cognitive functions in a person's life as it is essential for recalling personal memories and performing many everyday tasks. Although a huge number of studies have been conducted in the field, only a few of them investigated memory in realistic situations, due to methodological issues. The various tools that have been developed using virtual environments (VEs) have gained popularity in cognitive psychology and neuropsychology because they enable to create naturalistic and controlled situations, and are thus particularly adapted to the study of episodic memory (EM), for which an ecological evaluation is of prime importance. EM is the conscious recollection of personal events combined with their phenomenological and spatiotemporal encoding contexts. Using an original paradigm in a VE, the objective of the present study was to characterize the construction of episodic memories. While the concept of working memory has become central in the understanding of a wide range of cognitive functions, its role in the integration of episodic memories has seldom been assessed in an ecological context. This experiment aimed at filling this gap by studying how EM is affected by concurrent tasks requiring working memory resources in a realistic situation. Participants navigated in a virtual town and had to memorize as many elements in their spatiotemporal context as they could. During learning, participants had either to perform a concurrent task meant to prevent maintenance through the phonological loop, or a task aimed at preventing maintenance through the visuospatial sketchpad, or no concurrent task. EM was assessed in a recall test performed after learning through various scores measuring the what, where and when of the memories. Results showed that, compared to the control condition with no concurrent task, the prevention of maintenance through the phonological loop had a deleterious impact only on the encoding of central elements. By contrast, the prevention of visuo-spatial maintenance interfered both with the encoding of the temporal context and with the binding. These results suggest that the integration of realistic episodic memories relies on different working memory processes that depend on the nature of the traces. PMID- 29441038 TI - When Did Coloring Books Become Mindful? Exploring the Effectiveness of a Novel Method of Mindfulness-Guided Instructions for Coloring Books to Increase Mindfulness and Decrease Anxiety. AB - Mindfulness has been associated with the use of coloring books for adults; however, the question of whether they do increase mindfulness has not been addressed. In two studies, we attempted to identify whether mindfulness is increased, and whether there is a need for ongoing guidance while coloring, similar to mindfulness meditation. In the first randomized controlled experiment, university students (n = 88) were assigned to an unguided mandala coloring group (i.e., described in mainstream literature as a mindfulness practice) or to a free drawing group. Measurements of state mindfulness and state anxiety were taken pre and post- experiment. Results indicated no change in mindfulness or anxiety. In the second randomized controlled experiment, university students (n = 72) were assigned to an unguided mandala coloring group (i.e., same as Experiment 1), or, to a mindfulness-guided coloring group (i.e., same as the unguided coloring group with a mindfulness practitioner guiding participants as in mindfulness breathing meditation, with instructions modified and applied to coloring). Results indicated that the mindfulness-guided mandala coloring group performed better in decreasing anxiety, but no change was observed in mindfulness. Exit interviews revealed that some participants did not like the voice guiding them while coloring, which suggested further differing and significant findings. While mindfulness-guided coloring appears promising, guidance or instructions on how to color mindfully may require further development and adjustment to enhance health and wellbeing. PMID- 29441039 TI - Metastatic "Burned Out" Seminoma Causing Neurological Paraneoplastic Syndrome-Not Quite "Burned Out". AB - A 44-year-old man presented with cerebellar ataxia and limbic encephalitis and was ultimately diagnosed with metastatic germ cell neoplasm resulting from a "burned out" primary testicular tumor. The patient had progressive ataxia, leading to a thorough investigation for infectious, autoimmune, metabolic, and malignant causes of acquired cerebellar ataxia that revealed no significant findings. Testicular sonography demonstrated a possible right testicular lesion that was not confirmed on radical inguinal orchiectomy. F18-FDG positron emission tomography/computerized tomography scan revealed a solitary retroperitoneal lesion, concerning for metastatic disease but not amenable to percutaneous biopsy. A robotic retroperitoneal lymph node dissection was performed and pathology revealed a CD117-positive metastatic seminoma leading to appropriate germ cell tumor-directed chemotherapy. After completing chemotherapy and during 1 year of follow-up, there has been a gradual improvement of the patient's neurological manifestations. PMID- 29441040 TI - Intraoperative Photodynamic Diagnosis Using Talaporfin Sodium Simultaneously Applied for Photodynamic Therapy against Malignant Glioma: A Prospective Clinical Study. AB - Objective: The goal of this study was to demonstrate the feasibility of intraoperative photodynamic diagnosis (PDD) of malignant glioma using the fluorescence from talaporfin sodium (TS), which is used simultaneously for photodynamic therapy (PDT). Methods: Patients with suspected primary malignant glioma who were eligible for surgical removal of the tumor and PDT with TS were enrolled in this prospective study. Tissue samples were obtained from the contrast-enhanced (CE) region and from the surrounding non-contrast-enhanced (NCE) marginal tissue at the boundary between the tumor and normal tissue. The excised samples were set into a fluorescence measurement system, which consisted of a semiconductor laser with a 400-nm wavelength for excitation, and a compact spectrometer for detection, which were applied and received through a custom-made probe consisting of coaxial optical fibers. The fluorescence spectrum was obtained, and peak intensity was calculated. Tumor cellularity was histopathologically analyzed and semi-quantitatively classified into four (0-3) categories. Results: 86 samples from 17 surgical cases were available for fluorescence measurement and analysis. The fluorescence from TS had a single peak at 664 nm that was easily distinguished from the 400-nm excitation light. Samples from the CE regions showed higher fluorescence intensity than those from the NCE regions (P < 0.001). DAPI staining and fluorescence microscopy confirmed that cells in the CE regions showed red fluorescence in their cytoplasm. The fluorescence was notably strong along vascular endothelium. CE samples from newly diagnosed versus recurrent cases showed no difference in fluorescence intensity (P = 0.26). Among all samples (CE and NCE combined), the fluorescence intensity was very high in those of histopathological class 3, and a trend of increased fluorescence according to histopathological class (P < 0.001) was shown. Differences between class 0 and 3 (P < 0.001), class 1 and 3 (P < 0.001), and class 2 and 3 (P = 0.018) were significant. Conclusion: Intraoperative simultaneous PDD and PDT with TS can be performed for patients with malignant glioma. The blue excitation light that is used for 5-aminolevulinic acid PDD can be used for our technique (TS-PDD). The strong fluorescence from pathologically malignant tissues may be due at least in part to the involvement of microvascular structures. PMID- 29441041 TI - Altered Brain Functional Connectome in Migraine with and without Restless Legs Syndrome: A Resting-State Functional MRI Study. AB - Background: Migraine is frequently comorbid with restless legs syndrome (RLS), both displaying functional connectivity (FC) alterations in multiple brain networks, although the neurological basis of this association is unknown. Methods: We performed resting-state functional magnetic resonance imaging and network-wise analysis of FC in migraine patients with and without RLS and healthy controls (CRL). Network-based statistics (NBS) and composite FC matrix analyses were performed to identify the patterns of FC changes. Correlation analyses were performed to identify associations between alterations in FC and clinical profiles. Results: NBS results revealed that both migraine patients with and without RLS exhibited lower FC than CRL in the dorsal attention, salience, default mode, cingulo-opercular, visual, frontoparietal, auditory, and sensory/somatomotor networks. Further composite FC matrix analyses revealed differences in FC of the salience, default mode to subcortical and frontoparietal, auditory to salience, and memory retrieval networks between migraine patients with and without RLS. There was a trend toward a negative association between RLS severity and cross-network abnormalities in the default mode to subcortical network. Discussion: Migraine patients with and without RLS exhibit disruptions of brain FC. Such findings suggest that these disorders are associated with differential neuropathological mechanisms and may aid in the future development of neuroimaging-driven biomarkers for these conditions. PMID- 29441042 TI - Intrinsic and Extrinsic Thymic Adrenergic Networks: Sex Steroid-Dependent Plasticity. AB - The thymus is sexually differentiated organ providing microenvironment for T-cell precursor differentiation/maturation in the major histocompatibility complex restricted self-tolerant T cells. With increasing age, the thymus undergoes involution leading to the decline in efficacy of thymopoiesis. Noradrenaline from thymic nerve fibers and "(nor)adrenergic" cells is involved in the regulation of thymopoiesis. In rodents, noradrenaline concentration in thymus and adrenoceptor (AR) expression on thymic cells depend on sex and age. These differences are suggested to be implicated in the development of sexual diergism and the age related decline in thymopoiesis. The programming of both thymic sexual differentiation and its involution occurs during the critical early perinatal period and may be reprogrammed during peripubertal development. The thymic (re)programming is critically dependent on circulating levels of gonadal steroids. Although the underlying molecular mechanisms have not yet been elucidated fully, it is assumed that the gonadal steroid action during the critical perinatal/peripubertal developmental periods leads to long-lasting changes in the efficacy of thymopoiesis partly through (re)programming of "(nor)adrenergic" cell networks and AR expression on thymic cells. PMID- 29441043 TI - Synergistic Interactions in Microbial Biofilms Facilitate the Establishment of Opportunistic Pathogenic Fungi in Household Dishwashers. AB - Biofilms formed on rubber seals in dishwashers harbor diverse microbiota. In this study, we focussed on the microbial composition of bacteria and fungi, isolated from a defined area of one square centimeter of rubber from four domestic dishwashers and assessed their abilities to in vitro multispecies biofilm formation. A total of 80 isolates (64 bacterial and 16 fungal) were analyzed. Multiple combinations of bacterial isolates from each dishwasher were screened for synergistic interactions. 32 out of 140 tested (23%) four-species bacterial combinations displayed consistent synergism leading to an overall increase in biomass, in all experimental trails. Bacterial isolates from two of the four dishwashers generated a high number of synergistically interacting four-species consortia. Network based correlation analyses also showed higher co-occurrence patterns observed between bacterial members in the same two dishwasher samples, indicating cooperative effects. Furthermore, two synergistic four-species bacterial consortia were tested for their abilities to incorporate an opportunistic fungal pathogen, Exophiala dermatitidis and their establishment as biofilms on sterile ethylene propylene diene monomer M-class (EPDM) rubber and polypropylene (PP) surfaces. When the bacterial consortia included E. dermatitidis, the overall cell numbers of both bacteria and fungi increased and a substantial increase in biofilm biomass was observed. These results indicate a novel phenomenon of cross kingdom synergy in biofilm formation and these observations could have potential implications for human health. PMID- 29441044 TI - Alanine Enhances Aminoglycosides-Induced ROS Production as Revealed by Proteomic Analysis. AB - Metabolite-enabled killing of antibiotic-resistant pathogens by antibiotics is an attractive strategy to manage antibiotic resistance. Our previous study demonstrated that alanine or/and glucose increased the killing efficacy of kanamycin on antibiotic-resistant bacteria, whose action is through up-regulating TCA cycle, increasing proton motive force and enhancing antibiotic uptake. Despite the fact that alanine altered several metabolic pathways, other mechanisms could be potentially involved in alanine-mediated kanamycin killing of bacteria which remains to be explored. In the present study, we adopted proteomic approach to analyze the proteome changes induced by exogenous alanine. Our results revealed that the expression of three outer membrane proteins was altered and the deletion of nagE and fadL decreased the intracellular kanamycin concentration, implying their possible roles in mediating kanamycin transport. More importantly, the integrated analysis of proteomic and metabolomic data pointed out that alanine metabolism could connect to riboflavin metabolism that provides the source for reactive oxygen species (ROS) production. Functional studies confirmed that alanine treatment together with kanamycin could promote ROS production that in turn potentiates the killing of antibiotic-resistant bacteria. Further investigation showed that alanine repressed the transcription of antioxidant-encoding genes, and alanine metabolism to riboflavin metabolism connected with riboflavin metabolism through TCA cycle, glucogenesis pathway and pentose phosphate pathway. Our results suggest a novel mechanism by which alanine facilitates kanamycin killing of antibiotic-resistant bacteria via promoting ROS production. PMID- 29441045 TI - Network Analyses in Plant Pathogens. AB - Even in the age of big data in Biology, studying the connections between the biological processes and the molecular mechanisms behind them is a challenging task. Systems biology arose as a transversal discipline between biology, chemistry, computer science, mathematics, and physics to facilitate the elucidation of such connections. A scenario, where the application of systems biology constitutes a very powerful tool, is the study of interactions between hosts and pathogens using network approaches. Interactions between pathogenic bacteria and their hosts, both in agricultural and human health contexts are of great interest to researchers worldwide. Large amounts of data have been generated in the last few years within this area of research. However, studies have been relatively limited to simple interactions. This has left great amounts of data that remain to be utilized. Here, we review the main techniques in network analysis and their complementary experimental assays used to investigate bacterial-plant interactions. Other host-pathogen interactions are presented in those cases where few or no examples of plant pathogens exist. Furthermore, we present key results that have been obtained with these techniques and how these can help in the design of new strategies to control bacterial pathogens. The review comprises metabolic simulation, protein-protein interactions, regulatory control of gene expression, host-pathogen modeling, and genome evolution in bacteria. The aim of this review is to offer scientists working on plant-pathogen interactions basic concepts around network biology, as well as an array of techniques that will be useful for a better and more complete interpretation of their data. PMID- 29441046 TI - Searching for Glycosylated Natural Products in Actinomycetes and Identification of Novel Macrolactams and Angucyclines. AB - Many bioactive natural products are glycosylated compounds in which the sugar components usually participate in interaction and molecular recognition of the cellular target. Therefore, the presence of sugar moieties is important, in some cases essential, for bioactivity. Searching for novel glycosylated bioactive compounds is an important aim in the field of the research for natural products from actinomycetes. A great majority of these sugar moieties belong to the 6 deoxyhexoses and share two common biosynthetic steps catalyzed by a NDP-D-glucose synthase (GS) and a NDP-D-glucose 4,6-dehydratase (DH). Based on this fact, seventy one Streptomyces strains isolated from the integument of ants of the Tribe Attini were screened for the presence of biosynthetic gene clusters (BGCs) for glycosylated compounds. Total DNAs were analyzed by PCR amplification using oligo primers for GSs and DHs and also for a NDP-D-glucose-2,3-dehydratases. Amplicons were used in gene disruption experiments to generate non-producing mutants in the corresponding clusters. Eleven mutants were obtained and comparative dereplication analyses between the wild type strains and the corresponding mutants allowed in some cases the identification of the compound coded by the corresponding cluster (lobophorins, vicenistatin, chromomycins and benzanthrins) and that of two novel macrolactams (sipanmycin A and B). Several strains did not show UPLC differential peaks between the wild type strain and mutant profiles. However, after genome sequencing of these strains, the activation of the expression of two clusters was achieved by using nutritional and genetic approaches leading to the identification of compounds of the cervimycins family and two novel members of the warkmycins family. Our work defines a useful strategy for the identification new glycosylated compounds by a combination of genome mining, gene inactivation experiments and the activation of silent biosynthetic clusters in Streptomyces strains. PMID- 29441047 TI - Probiotic Lactobacillus johnsonii BS15 Improves Blood Parameters Related to Immunity in Broilers Experimentally Infected with Subclinical Necrotic Enteritis. AB - The probiotic strain Lactobacillus johnsonii BS15 could exert beneficial effects on growth performance, lipid metabolism, and intestinal microflora in healthy broilers and those afflicted with subclinical necrotic enteritis (SNE). In particular, BS15 prevents SNE by enhancing intestinal immunity. To further understand the immune regulatory mechanism of BS15, we evaluated its effects on the overall immunity of broilers by determining blood parameters in healthy and SNE broilers. In this study, two experiments were conducted. Experiment 1 involved a 42-day experimental period and used 450 1-day-old male chicks. The chicks were randomly divided into three groups and fed with a basal diet with or without 1 * 105 or 106 colony-forming units (cfu) BS15/g as feed. Experiment 2 involved a 28-day experimental period and used 180 1-day-old male chicks. The chicks were randomly allotted into three groups and given with or without 1 * 106 cfu BS15/g BS15 as feed. SNE infection was treated in all broilers, except in those in the normal diet group. Antioxidant abilities, immunoglobulins, and cytokines in the serum were assessed. T-lymphocyte subsets in peripheral blood were also determined. The first experiment demonstrated that BS15 enhanced the antioxidant abilities; the serum levels of immunoglobulins, interleukin-2, and interferon-gamma; and CD3+CD4+ T-lymphocyte percentage in peripheral blood on day 21. However, limited significant changes were observed on day 42. The second experiment revealed that BS15 supplementation positively influenced the antioxidant abilities and increased the serum levels of immunoglobulins and cytokines that were affected by SNE. BS15 also positively affected T-lymphocyte subsets in peripheral blood during SNE infection. These findings suggest that BS15 supplementation may prevent SNE in broilers by improving blood parameters related to immunity and enhancing intestinal immunity. Furthermore, BS15 supplementation can improve blood parameters in healthy broilers, especially at the starter phase. PMID- 29441048 TI - Oral Biofilms from Symbiotic to Pathogenic Interactions and Associated Disease Connection of Periodontitis and Rheumatic Arthritis by Peptidylarginine Deiminase. AB - A wide range of bacterial species are harbored in the oral cavity, with the resulting complex network of interactions between the microbiome and host contributing to physiological as well as pathological conditions at both local and systemic levels. Bacterial communities inhabit the oral cavity as primary niches in a symbiotic manner and form dental biofilm in a stepwise process. However, excessive formation of biofilm in combination with a corresponding deregulated immune response leads to intra-oral diseases, such as dental caries, gingivitis, and periodontitis. Moreover, oral commensal bacteria, which are classified as so-called "pathobionts" according to a now widely accepted terminology, were recently shown to be present in extra-oral lesions with distinct bacterial species found to be involved in the onset of various pathophysiological conditions, including cancer, atherosclerosis, chronic infective endocarditis, and rheumatoid arthritis. The present review focuses on oral pathobionts as commensal and healthy members of oral biofilms that can turn into initiators of disease. We will shed light on the processes involved in dental biofilm formation and also provide an overview of the interactions of P. gingivalis, as one of the most prominent oral pathobionts, with host cells, including epithelial cells, phagocytes, and dental stem cells present in dental tissues. Notably, a previously unknown interaction of P. gingivalis bacteria with human stem cells that has impact on human immune response is discussed. In addition to this very specific interaction, the present review summarizes current knowledge regarding the immunomodulatory effect of P. gingivalis and other oral pathobionts, members of the oral microbiome, that pave the way for systemic and chronic diseases, thereby showing a link between periodontitis and rheumatoid arthritis. PMID- 29441049 TI - Intestinal Microbiome Shifts, Dysbiosis, Inflammation, and Non-alcoholic Fatty Liver Disease. AB - Adverse fluctuations in the distribution of the intestinal microbiome cohort has been associated with the onset of intra- and extra-intestinal inflammatory conditions, like the metabolic syndrome (MetS) and it's hepatic manifestation, non-alcoholic fatty liver disease (NAFLD). The intestinal microbial community of obese compared to lean subjects has been shown to undergo configurational shifts in various genera, including but not limited to increased abundances of Prevotella, Escherichia, Peptoniphilus, and Parabacteroides and decreased levels of Bifidobacteria, Roseburia, and Eubacteria genera. At the phylum level, decreased Bacteroidetes and increased Firmicutes have been reported. The intestinal microbiota therefore presents an important target for designing novel therapeutic modalities that target extra-intestinal inflammatory disorders, such as NAFLD. This review hypothesizes that disruption of the intestinal-mucosal macrophage interface is a key factor in intestinal-liver axis disturbances. Intestinal immune responses implicated in the manifestation, maintenance and progression of NAFLD provide insights into the dialogue between the intestinal microbiome, the epithelia and mucosal immunity. The pro-inflammatory activity and immune imbalances implicated in NAFLD pathophysiology are reported to stem from dysbiosis of the intestinal epithelia which can serve as a source of hepatoxic effects. We posit that the hepatotoxic consequences of intestinal dysbiosis are compounded through intestinal microbiota-mediated inflammation of the local mucosa that encourages mucosal immune dysfunction, thus contributing important plausible insight in NAFLD pathogenesis. The administration of probiotics and prebiotics as a cure-all remedy for all chronic diseases is not advocated, instead, the incorporation of evidence based probiotic/prebiotic formulations as adjunctive modalities may enhance lifestyle modification management strategies for the amelioration of NAFLD. PMID- 29441051 TI - Predominant Non-additive Effects of Multiple Stressors on Autotroph C:N:P Ratios Propagate in Freshwater and Marine Food Webs. AB - A continuing challenge for scientists is to understand how multiple interactive stressor factors affect biological interactions, and subsequently, ecosystems-in ways not easily predicted by single factor studies. In this review, we have compiled and analyzed available research on how multiple stressor pairs composed of temperature (T), light (L), ultraviolet radiation (UVR), nutrients (Nut), carbon dioxide (CO2), dissolved organic carbon (DOC), and salinity (S) impact the stoichiometry of autotrophs which in turn shapes the nature of their ecological interactions within lower trophic levels in streams, lakes and oceans. Our analysis from 66 studies with 320 observations of 11 stressor pairs, demonstrated that non-additive responses predominate across aquatic ecosystems and their net interactive effect depends on the stressor pair at play. Across systems, there was a prevalence of antagonism in freshwater (60-67% vs. 47% in marine systems) compared to marine systems where synergism was more common (49% vs. 33-40% in freshwaters). While the lack of data impeded comparisons among all of the paired stressors, we found pronounced system differences for the L * Nut interactions. For this interaction, our data for C:P and N:P is consistent with the initial hypothesis that the interaction was primarily synergistic in the oceans, but not for C:N. Our study found a wide range of variability in the net effects of the interactions in freshwater systems, with some observations supporting antagonism, and others synergism. Our results suggest that the nature of the stressor pairs interactions on C:N:P ratios regulates the "continuum" commensalistic-competitive predatory relationship between algae and bacteria and the food chain efficiency at the algae-herbivore interface. Overall, the scarce number of studies with even more fewer replications in each study that are available for freshwater systems have prevented a more detailed, insightful analysis. Our findings highlighting the preponderance of antagonistic and synergistic effects of stressor interactions in aquatic ecosystems-effects that play key roles in the functioning of feedback loops in the biosphere-also stress the need for further studies evaluating the interactive effects of multiple stressors in a rapidly changing world facing a confluence of tipping points. PMID- 29441050 TI - Comparative Genomics of Completely Sequenced Lactobacillus helveticus Genomes Provides Insights into Strain-Specific Genes and Resolves Metagenomics Data Down to the Strain Level. AB - Although complete genome sequences hold particular value for an accurate description of core genomes, the identification of strain-specific genes, and as the optimal basis for functional genomics studies, they are still largely underrepresented in public repositories. Based on an assessment of the genome assembly complexity for all lactobacilli, we used Pacific Biosciences' long read technology to sequence and de novo assemble the genomes of three Lactobacillus helveticus starter strains, raising the number of completely sequenced strains to 12. The first comparative genomics study for L. helveticus-to our knowledge identified a core genome of 988 genes and sets of unique, strain-specific genes ranging from about 30 to more than 200 genes. Importantly, the comparison of MiSeq- and PacBio-based assemblies uncovered that not only accessory but also core genes can be missed in incomplete genome assemblies based on short reads. Analysis of the three genomes revealed that a large number of pseudogenes were enriched for functional Gene Ontology categories such as amino acid transmembrane transport and carbohydrate metabolism, which is in line with a reductive genome evolution in the rich natural habitat of L. helveticus. Notably, the functional Clusters of Orthologous Groups of proteins categories "cell wall/membrane biogenesis" and "defense mechanisms" were found to be enriched among the strain specific genes. A genome mining effort uncovered examples where an experimentally observed phenotype could be linked to the underlying genotype, such as for cell envelope proteinase PrtH3 of strain FAM8627. Another possible link identified for peptidoglycan hydrolases will require further experiments. Of note, strain FAM22155 did not harbor a CRISPR/Cas system; its loss was also observed in other L. helveticus strains and lactobacillus species, thus questioning the value of the CRISPR/Cas system for diagnostic purposes. Importantly, the complete genome sequences proved to be very useful for the analysis of natural whey starter cultures with metagenomics, as a larger percentage of the sequenced reads of these complex mixtures could be unambiguously assigned down to the strain level. PMID- 29441052 TI - Harnessing the mTOR Pathway for Tuberculosis Treatment. AB - Tuberculosis (TB) remains as one of the leading killer infectious diseases of humans. At present, the standard therapeutic regimen to treat TB comprised of multiple antibiotics administered for a minimum of six months. Although these drugs are useful in controlling TB burden globally, they have not eliminated the disease. In addition, the lengthy duration of treatment with multiple drugs contributes to patient non-compliance that can result in the development of drug resistant strains (MDR and XDR) of Mycobacterium tuberculosis (Mtb), the causative agent of TB. Therefore, new and improved therapeutic strategies are urgently needed for effective control of TB worldwide. The intracellular survival of Mtb is regarded as a cumulative effect of the host immune response and the bacterial ability to resist or subvert this response. When the host innate defensive system is manipulated by Mtb for its survival and dissemination, the host develops disease conditions that are hard to overcome. The host intrinsic factors also contributes to the poor efficacy of anti-mycobacterial drugs and to the emergence of drug resistance. Hence, strengthening the immune repertoire involved in combating Mtb through host-directed therapeutics (HDT) can be one of the approaches for effective bacterial killing and clearance of infection/disease. Recently, more scientific research has been focused toward HDT strategies that empowers host cells for effective killing of Mtb, reduce the duration of treatment and/or alleviates the development of MDR/XDR, since Mtb cannot develop resistance against a drug that targets the host cell function. Autophagy is a conserved cellular process critical for maintaining cellular integrity and function. Autophagy is regulated by multiple pathways that are either dependent or independent of mTOR (mechanistic target of rapamycin; a.k.a. mammalian target of rapamycin), a master regulatory molecules that impacts several cellular functions. In this review, we summarize the role of autophagy in Mtb pathogenesis, the mTOR pathway and, modulating the mTOR pathway with inhibitors as potential adjunctive HDT, in combination with standard anti-TB antibiotics, to improve the outcome of current TB treatment. PMID- 29441053 TI - New Insights into Clostridium difficile (CD) Infection in Latin America: Novel Description of Toxigenic Profiles of Diarrhea-Associated to CD in Bogota, Colombia. AB - Clostridium difficile (CD) produces antibiotic associated diarrhea and leads to a broad range of diseases. The source of CD infection (CDI) acquisition and toxigenic profile are factors determining the impact of CD. This study aimed at detecting healthcare facility onset- (HCFO) and community-onset (CO) CDI and describing their toxigenic profiles in Bogota, Colombia. A total of 217 fecal samples from patients suffering diarrhea were simultaneously submitted to two CDI detection strategies: (i) in vitro culture using selective chromogenic medium (SCM; chromID, bioMerieux), followed verification by colony screening (VCS), and (ii) molecular detection targeting constitutive genes, using two conventional PCR tests (conv.PCR) (conv.16S y conv.gdh) and a quantitative test (qPCR.16s). The CD toxigenic profile identified by any molecular test was described using 6 tests independently for describing PaLoc and CdtLoc organization. High overall CDI frequencies were found by both SCM (52.1%) and conv.PCR (45.6% for conv.16S and 42.4% for conv.gdh), compared to reductions of up to half the frequency by VCS (27.2%) or qPCR.16S (22.6%). Infection frequencies were higher for SCM and conv.16S regarding HCFO but greater for CO concerning conv.gdh, such differences being statistically significant. Heterogeneous toxigenic profiles were found, including amplification with lok1/3 primers simultaneously with other PaLoc markers (tcdA, tcdB or tcdC). These findings correspond the first report regarding the differential detection of CDI using in vitro culture and molecular detection tests in Colombia, the circulation of CD having heterogeneous toxigenic profiles and molecular arrays which could affect the impact of CDI epidemiology. PMID- 29441054 TI - Fungal Genetics and Functional Diversity of Microbial Communities in the Soil under Long-Term Monoculture of Maize Using Different Cultivation Techniques. AB - Fungal diversity in the soil may be limited under natural conditions by inappropriate environmental factors such as: nutrient resources, biotic and abiotic factors, tillage system and microbial interactions that prevent the occurrence or survival of the species in the environment. The aim of this paper was to determine fungal genetic diversity and community level physiological profiling of microbial communities in the soil under long-term maize monoculture. The experimental scheme involved four cultivation techniques: direct sowing (DS), reduced tillage (RT), full tillage (FT), and crop rotation (CR). Soil samples were taken in two stages: before sowing of maize (DSBS-direct sowing, RTBS reduced tillage, FTBS-full tillage, CRBS-crop rotation) and the flowering stage of maize growth (DSF-direct sowing, RTF-reduced tillage, FTF-full tillage, CRF crop rotation). The following plants were used in the crop rotation: spring barley, winter wheat and maize. The study included fungal genetic diversity assessment by ITS-1 next generation sequencing (NGS) analyses as well as the characterization of the catabolic potential of microbial communities (Biolog EcoPlates) in the soil under long-term monoculture of maize using different cultivation techniques. The results obtained from the ITS-1 NGS technique enabled to classify and correlate the fungi species or genus to the soil metabolome. The research methods used in this paper have contributed to a better understanding of genetic diversity and composition of the population of fungi in the soil under the influence of the changes that have occurred in the soil under long-term maize cultivation. In all cultivation techniques, the season had a great influence on the fungal genetic structure in the soil. Significant differences were found on the family level (P = 0.032, F = 3.895), genus level (P = 0.026, F = 3.313) and on the species level (P = 0.033, F = 2.718). This study has shown that: (1) fungal diversity was changed under the influence different cultivation techniques; (2) techniques of maize cultivation and season were an important factors that can influence the biochemical activity of soil. Maize cultivated in direct sowing did not cause negative changes in the fungal structure, even making it more stable during seasonal changes; (3) full tillage and crop rotation may change fungal community and soil function. PMID- 29441055 TI - Bacteriome from Pinus arizonica and P. durangensis: Diversity, Comparison of Assemblages, and Overlapping Degree with the Gut Bacterial Community of a Bark Beetle That Kills Pines. AB - Symbioses between plants and microorganims have been fundamental in the evolution of both groups. The endophytic bacteria associated with conifers have been poorly studied in terms of diversity, ecology, and function. Coniferous trees of the genera Larix, Pseudotsugae, Picea and mainly Pinus, are hosts of many insects, including bark beetles and especially the Dendroctonus species. These insects colonize and kill these trees during their life cycle. Several bacteria detected in the gut and cuticle of these insects have been identified as endophytes in conifers. In this study, we characterized and compared the endophytic bacterial diversity in roots, phloem and bark of non-attacked saplings of Pinus arizonica and P. durangensis using 16S rRNA gene pyrosequencing. In addition, we evaluated the degree of taxonomic relatedness, and the association of metabolic function profiles of communities of endophytic bacteria and previously reported gut bacterial communities of D. rhizophagus; a specialized bark beetle that colonizes and kills saplings of these pine species. Our results showed that both pine species share a similar endophytic community. A total of seven bacterial phyla, 14 classes, 26 orders, 43 families, and 51 genera were identified. Enterobacteriaceae was the most abundant family across all samples, followed by Acetobacteraceae and Acidobacteriaceae, which agree with previous studies performed in other pines and conifers. Endophytic communities and that of the insect gut were significantly different, however, the taxonomic relatedness of certain bacterial genera of pines and insect assemblages suggested that some bacteria from pine tissues might be the same as those in the insect gut. Lastly, the metabolic profile using PICRUSt showed there to be a positive association between communities of both pines and insect gut. This study represents the baseline into the knowledge of the endophytic bacterial communities of two of the major hosts affected by D. rhizophagus. PMID- 29441056 TI - New Insight into Biofilm Formation Ability, the Presence of Virulence Genes and Probiotic Potential of Enterococcus sp. Dairy Isolates. AB - Enterococci have controversial status due to their emerging role in nosocomial infections and transmission of antibiotic resistance genes, while some enterococci strains are used as probiotics for humans and animals and starter cultures in dairy industry. In order to improve our understanding of factors involved in the safe use of enterococci as potential probiotics, the antibiotic susceptibility, virulence and probiotic traits of 75 dairy enterococci isolates belonging to Enterococcus durans (50), En. faecium (15), En. faecalis (6), En. italicus (3), and En. hirae (1) were evaluated. The results revealed that ciprofloxacin resistance and biofilm formation are correlated with isolates originated from Golija mountain (Serbia), while gelatinase activity was more common in isolates from Prigorje region (Croatia), pointing to uncontrolled use of antibiotics and anthropogenic impact on dairy products' microbiota in these regions. The virulence genes were sporadically present in 13 selected dairy enterococci isolates. Interestingly, biofilm formation was correlated with higher ability of strains to reduce the adhesion of E. coli and Salmonella Enteritidis to HT29-MTX cells. To our knowledge this is the first study reporting the presence of the esp gene (previously correlated with pathogenesis) in dairy enterococci isolates, mostly associated with the genes involved in adhesion property. Hence, the results of this study revealed that the virulence genes are sporadically present in dairy isolates and more correlated to adhesion properties and biofilm formation, implicating their role in gut colonization rather than to the virulence traits. PMID- 29441057 TI - Stability of the HTLV-1 Antisense-Derived Protein, HBZ, Is Regulated by the E3 Ubiquitin-Protein Ligase, UBR5. AB - Human T-cell leukemia virus type 1 (HTLV-1) encodes a protein derived from the antisense strand of the proviral genome designated HBZ (HTLV-1 basic leucine zipper factor). HBZ is the only viral gene consistently expressed in infected patients and adult T-cell leukemia/lymphoma (ATL) tumor cell lines. It functions to antagonize many activities of the Tax viral transcriptional activator, suppresses apoptosis, and supports proliferation of ATL cells. Factors that regulate the stability of HBZ are thus important to the pathophysiology of ATL development. Using affinity-tagged protein and shotgun proteomics, we identified UBR5 as a novel HBZ-binding partner. UBR5 is an E3 ubiquitin-protein ligase that functions as a key regulator of the ubiquitin proteasome system in both cancer and developmental biology. Herein, we investigated the role of UBR5 in HTLV-1 mediated T-cell transformation and leukemia/lymphoma development. The UBR5/HBZ interaction was verified in vivo using over-expression constructs, as well as endogenously in T-cells. shRNA-mediated knockdown of UBR5 enhanced HBZ steady state levels by stabilizing the HBZ protein. Interestingly, the related HTLV-2 antisense-derived protein, APH-2, also interacted with UBR5 in vivo. However, knockdown of UBR5 did not affect APH-2 protein stability. Co-immunoprecipitation assays identified ubiquitination of HBZ and knockdown of UBR5 resulted in a decrease in HBZ ubiquitination. MS/MS analysis identified seven ubiquitinated lysines in HBZ. Interestingly, UBR5 expression was upregulated in established T lymphocytic leukemia/lymphoma cell lines and the later stage of T-cell transformation in vitro. Finally, we demonstrated loss of UBR5 decreased cellular proliferation in transformed T-cell lines. Overall, our study provides evidence for UBR5 as a host cell E3 ubiquitin-protein ligase responsible for regulating HBZ protein stability. Additionally, our data suggests UBR5 plays an important role in maintaining the proliferative phenotype of transformed T-cell lines. PMID- 29441059 TI - Self-Recognition Sensitizes Mouse and Human Regulatory T Cells to Low-Dose CD28 Superagonist Stimulation. AB - In rodents, low doses of CD28-specific superagonistic monoclonal antibodies (CD28 superagonists, CD28SA) selectively activate regulatory T cells (Treg). This observation has recently been extended to humans, suggesting an option for the treatment of autoimmune and inflammatory diseases. However, a mechanistic explanation for this phenomenon is still lacking. Given that CD28SA amplify T cell receptor (TCR) signals, we tested the hypothesis that the weak tonic TCR signals received by conventional CD4+ T cells (Tconv) in the absence of cognate antigen require more CD28 signaling input for full activation than the stronger TCR signals received by self-reactive Treg. We report that in vitro, the response of mouse Treg and Tconv to CD28SA strongly depends on MHC class II expression by antigen-presenting cells. To separate the effect of tonic TCR signals from self peptide recognition, we compared the response of wild-type Treg and Tconv to low and high CD28SA doses upon transfer into wild-type or H-2M knockout mice, which lack a self-peptide repertoire. We found that the superior response of Treg to low CD28SA doses was lost in the absence of self-peptide presentation. We also tested if potentially pathogenic autoreactive Tconv would benefit from self recognition-induced sensitivity to CD28SA stimulation by transferring TCR transgenic OVA-specific Tconv into OVA-expressing mice and found that low-dose CD28SA application inhibited, rather than supported, their expansion, presumably due to the massive concomitant activation of Treg. Finally, we report that also in the in vitro response of human peripheral blood mononuclear cells to CD28SA, HLA II blockade interferes with the expansion of Treg by low-dose CD28SA stimulation. These results provide a rational basis for the further development of low-dose CD28SA therapy for the improvement of Treg activity. PMID- 29441058 TI - Regulation of the Stress-Activated Degradation of Mitochondrial Respiratory Complexes in Yeast. AB - Repair and removal of damaged mitochondria is a key process for eukaryotic cell homeostasis. Here we investigate in the yeast model how different protein complexes of the mitochondrial electron transport chain are subject to specific degradation upon high respiration load and organelle damage. We find that the turnover of subunits of the electron transport complex I equivalent and complex III is preferentially stimulated upon high respiration rates. Particular mitochondrial proteases, but not mitophagy, are involved in this activated degradation. Further mitochondrial damage by valinomycin treatment of yeast cells triggers the mitophagic removal of the same respiratory complexes. This selective protein degradation depends on the mitochondrial fusion and fission apparatus and the autophagy adaptor protein Atg11, but not on the mitochondrial mitophagy receptor Atg32. Loss of autophagosomal protein function leads to valinomycin sensitivity and an overproduction of reactive oxygen species upon mitochondrial damage. A specific event in this selective turnover of electron transport chain complexes seems to be the association of Atg11 with the mitochondrial network, which can be achieved by overexpression of the Atg11 protein even in the absence of Atg32. Furthermore, the interaction of various Atg11 molecules via the C terminal coil domain is specifically and rapidly stimulated upon mitochondrial damage and could therefore be an early trigger of selective mitophagy in response to the organelles dysfunction. Our work indicates that autophagic quality control upon mitochondrial damage operates in a selective manner. PMID- 29441060 TI - Liposomal Elongation Factor-1alpha Triggers Effector CD4 and CD8 T Cells for Induction of Long-Lasting Protective Immunity against Visceral Leishmaniasis. AB - Despite advances, identification and formulation of safe and effective vaccine for long-lasting protection against leishmaniasis is still inadequate. In this study, we have identified a novel antigen, leishmanial elongation factor-1alpha (EF1-alpha), as an immunodominant component of solubilized leishmanial membrane antigens that reacts with visceral leishmaniasis (VL) sera and induces cellular proliferative and cytokine response in PBMCs of cured VL subjects. Leishmanial EF1-alpha is a 50 kDa antigen that plays a crucial role in pathogen survival by regulating oxidative burst in the host phagocytes. Previously, immunodominant truncated forms of EF1-alpha from different species of Leishmania have been reported. Formulation of the L. donovani 36 kDa truncated as well as the cloned recombinant EF1-alpha in cationic liposomes induce strong resistance to parasitic burden in liver and spleen of BALB/c mice through induction of DTH and a IL-10 and TGF-beta suppressed mixed Th1/Th2 cytokine responses. Multiparametric analysis of splenocytes for generation of antigen-specific IFN-gamma, IL2, and TNF-alpha producing lymphocytes indicate that cationic liposome facilitates expansion of both CD4+ as well as CD8+ memory and effector T cells. Liposomal EF1 alpha is a novel and potent vaccine formulation against VL that imparts long-term protective responses. Moreover, the flexibility of this formulation opens up the scope to combine additional adjuvants and epitope selected antigens for use in other disease forms also. PMID- 29441061 TI - Profiling of Human Molecular Pathways Affected by Retrotransposons at the Level of Regulation by Transcription Factor Proteins. AB - Endogenous retroviruses and retrotransposons also termed retroelements (REs) are mobile genetic elements that were active until recently in human genome evolution. REs regulate gene expression by actively reshaping chromatin structure or by directly providing transcription factor binding sites (TFBSs). We aimed to identify molecular processes most deeply impacted by the REs in human cells at the level of TFBS regulation. By using ENCODE data, we identified ~2 million TFBS overlapping with putatively regulation-competent human REs located in 5-kb gene promoter neighborhood (~17% of all TFBS in promoter neighborhoods; ~9% of all RE linked TFBS). Most of REs hosting TFBS were highly diverged repeats, and for the evolutionary young (0-8% diverged) elements we identified only ~7% of all RE linked TFBS. The gene-specific distributions of RE-linked TFBS generally correlated with the distributions for all TFBS. However, several groups of molecular processes were highly enriched in the RE-linked TFBS regulation. They were strongly connected with the immunity and response to pathogens, with the negative regulation of gene transcription, ubiquitination, and protein degradation, extracellular matrix organization, regulation of STAT signaling, fatty acids metabolism, regulation of GTPase activity, protein targeting to Golgi, regulation of cell division and differentiation, development and functioning of perception organs and reproductive system. By contrast, the processes most weakly affected by the REs were linked with the conservative aspects of embryo development. We also identified differences in the regulation features by the younger and older fractions of the REs. The regulation by the older fraction of the REs was linked mainly with the immunity, cell adhesion, cAMP, IGF1R, Notch, Wnt, and integrin signaling, neuronal development, chondroitin sulfate and heparin metabolism, and endocytosis. The younger REs regulate other aspects of immunity, cell cycle progression and apoptosis, PDGF, TGF beta, EGFR, and p38 signaling, transcriptional repression, structure of nuclear lumen, catabolism of phospholipids, and heterocyclic molecules, insulin and AMPK signaling, retrograde Golgi-ER transport, and estrogen signaling. The immunity-linked pathways were highly represented in both categories, but their functional roles were different and did not overlap. Our results point to the most quickly evolving molecular pathways in the recent and ancient evolution of human genome. PMID- 29441062 TI - TGF-beta-Induced CD8+CD103+ Regulatory T Cells Show Potent Therapeutic Effect on Chronic Graft-versus-Host Disease Lupus by Suppressing B Cells. AB - Lupus nephritis is one of most severe complications of systemic erythematosus lupus and current approaches are not curative for lupus nephritis. Although CD4+Foxp3+ regulatory T cells (Treg) are crucial for prevention of autoimmunity, the therapeutic effect of these cells on lupus nephritis is not satisfactory. We previously reported that CD8+CD103+ Treg induced ex vivo with TGF-beta1 and IL-2 (CD8+CD103+ iTreg), regardless of Foxp3 expression, displayed potent immunosuppressive effect on Th cell response and had therapeutic effect on Th cell-mediated colitis. Here, we tested whether CD8+CD103+ iTreg can ameliorate lupus nephritis and determined potential molecular mechanisms. Adoptive transfer of CD8+CD103+ iTreg but not control cells to chronic graft-versus-host disease with a typical lupus syndrome showed decreased levels of autoantibodies and proteinuria, reduced renal pathological lesions, lowered renal deposition of IgG/C3, and improved survival. CD8+CD103+ iTreg cells suppressed not only T helper cells but also B cell responses directly that may involve in both TGF-beta and IL-10 signals. Using RNA-seq, we demonstrated CD8+CD103+ iTreg have its own unique expression profiles of transcription factors. Thus, current study has identified and extended the target cells of CD8+CD103+ iTreg and provided a possible application of this new iTreg subset on lupus nephritis and other autoimmune diseases. PMID- 29441063 TI - Toll-like Receptors and Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is one relapsing and lifelong disease that affects millions of patients worldwide. Increasing evidence has recently highlighted immune-system dysfunction, especially toll-like receptors (TLRs) mediated innate immune dysfunction, as central players in the pathogenesis of IBD. TLRs and TLR-activated signaling pathways are involved not only in the pathogenesis but also in the efficacy of treatment of IBD. By understanding these molecular mechanisms, we might develop a strategy for relieving the experience of long-lasting suffering of those patients and improving their quality of life. The purpose of this review article is to summarize the potential mechanisms of TLR signaling pathways in IBD and the novel potential therapeutic strategies against IBD. PMID- 29441064 TI - Impact of Cigarette Smoking on the Gastrointestinal Tract Inflammation: Opposing Effects in Crohn's Disease and Ulcerative Colitis. AB - Cigarette smoking is a major risk factor for gastrointestinal disorders, such as peptic ulcer, Crohn's disease (CD), and several cancers. The mechanisms proposed to explain the role of smoking in these disorders include mucosal damage, changes in gut irrigation, and impaired mucosal immune response. Paradoxically, cigarette smoking is a protective factor for the development and progression of ulcerative colitis (UC). UC and CD represent the two most important conditions of inflammatory bowel diseases, and share several clinical features. The opposite effects of smoking on these two conditions have been a topic of great interest in the last 30 years, and has not yet been clarified. In this review, we summarize the most important and well-understood effects of smoking in the gastrointestinal tract; and particularly, in intestinal inflammation, discussing available studies that have addressed the causes that would explain the opposite effects of smoking in CD and UC. PMID- 29441065 TI - Adipocyte Fatty Acid-Binding Protein Promotes Palmitate-Induced Mitochondrial Dysfunction and Apoptosis in Macrophages. AB - A high level of circulating free fatty acids (FFAs) is known to be an important trigger for macrophage apoptosis during the development of atherosclerosis. However, the underlying mechanism by which FFAs result in macrophage apoptosis is not well understood. In cultured human macrophage Thp-1 cells, we showed that palmitate (PA), the most abundant FFA in circulation, induced excessive reactive oxidative substance production, increased malondialdehyde concentration, and decreased adenosine triphosphate levels. Furthermore, PA treatment also led to mitochondrial dysfunction, including the decrease of mitochondrial number, the impairment of respiratory complex IV and succinate dehydrogenase activity, and the reduction of mitochondrial membrane potential. Mitochondrial apoptosis was also detected after PA treatment, indicated by a decrease in cytochrome c release, downregulation of Bcl-2, upregulation of Bax, and increased caspase-3 activity. PA treatment upregulated the expression of adipocyte fatty acid-binding protein (A-FABP), a critical regulator of fatty acid trafficking and lipid metabolism. Inhibition of A-FABP with BMS309403, a small-molecule A-FABP inhibitor, almost reversed all of these indexes. Thus, this study suggested that PA-mediated macrophage apoptosis through A-FABP upregulation, which subsequently resulted in mitochondrial dysfunction and reactive oxidative stress. Inhibition of A-FABP may be a potential therapeutic target for macrophage apoptosis and to delay the progress of atherosclerosis. PMID- 29441066 TI - TANK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Type I Interferon Induction by Inhibiting TBK1-IRF3 Interaction and IRF3 Phosphorylation. AB - TANK-binding kinase 1 (TBK1) is an important serine/threonine-protein kinase that mediates phosphorylation and nuclear translocation of IRF3, which contributes to induction of type I interferons (IFNs) in the innate antiviral response. In mammals, TBK1 spliced isoform negatively regulates the virus-triggered IFN-beta signaling pathway by disrupting the interaction between retinoic acid-inducible gene I (RIG-I) and mitochondria antiviral-signaling protein (MAVS). However, it is still unclear whether alternative splicing patterns and the function of TBK1 isoform(s) exist in teleost fish. In this study, we identify two alternatively spliced isoforms of TBK1 from zebrafish, termed TBK1_tv1 and TBK1_tv2. Both TBK1_tv1 and TBK1_tv2 contain an incomplete STKc_TBK1 domain. Moreover, the UBL_TBK1_like domain is also missing for TBK1_tv2. TBK1_tv1 and TBK1_tv2 are expressed in zebrafish larvae. Overexpression of TBK1_tv1 and TBK1_tv2 inhibits RIG-I-, MAVS-, TBK1-, and IRF3-mediated activation of IFN promoters in response to spring viremia of carp virus infection. Also, TBK1_tv1 and TBK1_tv2 inhibit expression of IFNs and IFN-stimulated genes induced by MAVS and TBK1. Mechanistically, TBK1_tv1 and TBK1_tv2 competitively associate with TBK1 and IRF3 to disrupt the formation of a functional TBK1-IRF3 complex, impeding the phosphorylation of IRF3 mediated by TBK1. Collectively, these results demonstrate that TBK1 spliced isoforms are dominant negative regulators in the RIG I/MAVS/TBK1/IRF3 antiviral pathway by targeting the functional TBK1-IRF3 complex formation. Identification and functional characterization of piscine TBK1 spliced isoforms may contribute to understanding the role of TBK1 expression in innate antiviral response. PMID- 29441067 TI - Proteomics of Mycobacterium Infection: Moving towards a Better Understanding of Pathogen-Driven Immunomodulation. AB - Intracellular bacteria are responsible for many infectious diseases in humans and have developed diverse mechanisms to interfere with host defense pathways. In particular, intracellular vacuoles are an essential niche used by pathogens to alter cellular and organelle functions, which facilitate replication and survival. Mycobacterium tuberculosis (Mtb), the pathogen causing tuberculosis in humans, is not only able to modulate its intraphagosomal fate by blocking phagosome maturation but has also evolved strategies to successfully prevent clearance by immune cells and to establish long-term survival in the host. Mass spectrometry (MS)-based proteomics allows the identification and quantitative analysis of complex protein mixtures and is increasingly employed to investigate host-pathogen interactions. Major challenges are limited availability and purity of pathogen-containing compartments as well as the asymmetric ratio in protein abundance when comparing bacterial and host proteins during the infection. Recent advances in purification techniques and MS technology helped to overcome previous difficulties and enable the detailed proteomic characterization of infected host cells and their pathogen-containing vacuoles. Here, we summarize current findings of the proteomic analysis of Mycobacterium-infected host cells and highlight progress that has been made to study the protein composition of mycobacterial vacuoles. Current investigations focus on the pathogenicity during Mtb infection, which will allow to better understand pathogen-induced changes and immunomodulation of infected host cells. Consequently, future research in this field will have important implications on host response, pathogen survival, and persistence, induced adaptive immunity and metabolic changes of immune cells promoting the development of novel host-directed therapies in tuberculosis. PMID- 29441068 TI - Control of Intestinal Inflammation, Colitis-Associated Tumorigenesis, and Macrophage Polarization by Fibrinogen-Like Protein 2. AB - Fibrinogen-like protein 2 (Fgl2) is critical for immune regulation in the inflammatory state. Elevated Fgl2 levels are observed in patients with inflammatory bowel disease (IBD), but little is known about its functional significance. In this study, we sought to investigate the role of Fgl2 in the development of intestinal inflammation and colitis-associated colorectal cancer (CAC). Here, we report that Fgl2 deficiency increased susceptibility to dextran sodium sulfate-induced colitis and CAC in a mouse model. During colitis development, the expression of the membrane-bound and secreted forms of Fgl2 (mFgl2 and sFgl2, respectively) in the colon were increased and predominantly expressed by colonic macrophages. In addition, using bone marrow chimeric mice, we determined that Fgl2 function in colitis is strictly related to its expression in the hematopoietic cells. Loss of Fgl2 induced the polarization of M1, but suppressed that of M2 both in vivo and in vitro, independent of intestinal inflammation. Thus, Fgl2 suppresses intestinal inflammation and CAC development through its role in macrophage polarization and may serve as a therapeutic target in inflammatory diseases, including IBD. PMID- 29441069 TI - Interleukin-6 and Interferon-alpha Signaling via JAK1-STAT Differentially Regulate Oncolytic versus Cytoprotective Antiviral States. AB - Malignancy-induced alterations to cytokine signaling in tumor cells differentially regulate their interactions with the immune system and oncolytic viruses. The abundance of inflammatory cytokines in the tumor microenvironment suggests that such signaling plays key roles in tumor development and therapy efficacy. The JAK-STAT axis transduces signals of interleukin-6 (IL-6) and interferons (IFNs), mediates antiviral responses, and is frequently altered in prostate cancer (PCa) cells. However, how activation of JAK-STAT signaling with different cytokines regulates interactions between oncolytic viruses and PCa cells is not known. Here, we employ LNCaP PCa cells, expressing (or not) JAK1, activated (or not) with IFNs (alpha or gamma) or IL-6, and infected with RNA viruses of different oncolytic potential (EHDV-TAU, hMPV-GFP, or HIV-GFP) to address this matter. We show that in JAK1-expressing cells, IL-6 sensitized PCa cells to viral cell death in the presence or absence of productive infection, with dependence on virus employed. Contrastingly, IFNalpha induced a cytoprotective antiviral state. Biochemical and genetic (knockout) analyses revealed dependency of antiviral state or cytoprotection on STAT1 or STAT2 activation, respectively. In IL-6-treated cells, STAT3 expression was required for anti-proliferative signaling. Quantitative proteomics (SILAC) revealed a core repertoire of antiviral IFN-stimulated genes, induced by IL-6 or IFNs. Oncolysis in the absence of productive infection, induced by IL-6, correlated with reduction in regulators of cell cycle and metabolism. These results call for matching the viral features of the oncolytic agent, the malignancy-induced genetic-epigenetic alterations to JAK/STAT signaling and the cytokine composition of the tumor microenvironment for efficient oncolytic virotherapy. PMID- 29441070 TI - A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations. AB - The identification of recurrent human leukocyte antigen (HLA) neoepitopes driving T cell responses against tumors poses a significant bottleneck in the development of approaches for precision cancer therapeutics. Here, we employ a bioinformatics method, Prediction of T Cell Epitopes for Cancer Therapy, to analyze sequencing data from neuroblastoma patients and identify a recurrent anaplastic lymphoma kinase mutation (ALK R1275Q) that leads to two high affinity neoepitopes when expressed in complex with common HLA alleles. Analysis of the X-ray structures of the two peptides bound to HLA-B*15:01 reveals drastically different conformations with measurable changes in the stability of the protein complexes, while the self epitope is excluded from binding due to steric hindrance in the MHC groove. To evaluate the range of HLA alleles that could display the ALK neoepitopes, we used structure-based Rosetta comparative modeling calculations, which accurately predict several additional high affinity interactions and compare our results with commonly used prediction tools. Subsequent determination of the X-ray structure of an HLA-A*01:01 bound neoepitope validates atomic features seen in our Rosetta models with respect to key residues relevant for MHC stability and T cell receptor recognition. Finally, MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes are recognized by CD8+ T cells. This work provides a rational approach toward high throughput identification and further optimization of putative neoantigen/HLA targets with desired recognition features for cancer immunotherapy. PMID- 29441071 TI - Regulation of CD8+ T Cells and Antitumor Immunity by Notch Signaling. AB - Cancer immunosurveillance is critical for the elimination of neoplastic cells. In addition, recent advances in immunological checkpoint blockade drugs have revealed the importance of the immune system in cancer treatment. As a component of the immune system, CD8+ T cells have important roles in suppressing tumors. CD8+ T cells can kill tumor cells with cytotoxic molecules, such as granzymes and perforin. IFNgamma, which is produced by CD8+ T cells, can increase the expression of MHC class I antigens by tumor cells, thereby rendering them better targets for CD8+ T cells. IFNgamma also has crucial functions in enhancing the antitumor abilities of other immune cells. Therefore, it has been hypothesized that antitumor immunity could be improved by modulating the activity of CD8+ T cells. The Notch pathway regulates CD8+ T cells in multiple ways. It directly upregulates mRNA expression of granzyme B and perforin, enhances differentiation toward short-lived effector cells, and maintains memory T cells. Intriguingly, CD8+ T cell-specific Notch2 deletion impairs antitumor immunity, whereas the stimulation of the Notch pathway can increase tumor suppression. In this review, we will summarize the roles of the Notch pathway in CD8+ T cells and discuss issues and implications for its use in antitumor immunity. PMID- 29441072 TI - Fatal Necrotizing Encephalopathy after Treatment with Nivolumab for Squamous Non Small Cell Lung Cancer: Case Report and Review of the Literature. AB - Immune checkpoint inhibitors are antibodies, which enhance cellular and humoral immune responses and are approved for the treatment of various tumors. Immune related adverse events (irAE) involving different organs and systems are, however, among the side-effects. Recent reports of severe persistent neurological deficits and even fatal cases underpin the need for better understanding of the exact pathomechanisms of central nervous system (CNS) toxicity. To our knowledge, we report the first biopsy-proven case of fatal necrotizing encephalopathy after treatment with nivolumab. Nivolumab targets the immune-check point inhibitor programmed cell death-1 and was used for squamous non-small cell lung cancer. Partly reversible neurologic and psychiatric symptoms and unremarkable brain magnetic resonance imaging (MRI) were observed after the first course. Neurological symptoms progressed and recurrent seizures developed after the second course. Brain MRI disclosed multiple edematous and confluent supra- and infratentorial lesions, partly with contrast-enhancement. We excluded autoimmune and paraneoplastic causes and performed ancillary investigations to rule out common and opportunistic infections. Eventually, postmortem histopathological analysis of the brain revealed a necrotizing process, which contrasts previous cases reporting parenchymal immune cell infiltration or demyelination. Appropriate diagnostic pathways and treatment algorithms need to be implemented for the work-up of CNS toxicity and irAEs related to immune checkpoint inhibitor treatment. PMID- 29441073 TI - Macrophage Clearance of Apoptotic Cells: A Critical Assessment. AB - As the body continues to grow and age, it becomes essential to maintain a balance between living and dying cells. Macrophages and dendritic cells play a central role in discriminating among viable, apoptotic, and necrotic cells, as selective and efficient phagocytes, without inducing inappropriate inflammation or immune responses. A great deal has been learnt concerning clearance receptors for modified and non-self-ligands on potential targets, mediating their eventual uptake, disposal, and replacement. In this essay, we assess current understanding of the phagocytic recognition of apoptotic cells within their tissue environment; we conclude that efferocytosis constitutes a more complex process than simply removal of corpses, with regulatory interactions between the target and effector cells, which determine the outcome of this homeostatic process. PMID- 29441074 TI - Quantitative Analysis of Cotton Canopy Size in Field Conditions Using a Consumer Grade RGB-D Camera. AB - Plant canopy structure can strongly affect crop functions such as yield and stress tolerance, and canopy size is an important aspect of canopy structure. Manual assessment of canopy size is laborious and imprecise, and cannot measure multi-dimensional traits such as projected leaf area and canopy volume. Field based high throughput phenotyping systems with imaging capabilities can rapidly acquire data about plants in field conditions, making it possible to quantify and monitor plant canopy development. The goal of this study was to develop a 3D imaging approach to quantitatively analyze cotton canopy development in field conditions. A cotton field was planted with 128 plots, including four genotypes of 32 plots each. The field was scanned by GPhenoVision (a customized field-based high throughput phenotyping system) to acquire color and depth images with GPS information in 2016 covering two growth stages: canopy development, and flowering and boll development. A data processing pipeline was developed, consisting of three steps: plot point cloud reconstruction, plant canopy segmentation, and trait extraction. Plot point clouds were reconstructed using color and depth images with GPS information. In colorized point clouds, vegetation was segmented from the background using an excess-green (ExG) color filter, and cotton canopies were further separated from weeds based on height, size, and position information. Static morphological traits were extracted on each day, including univariate traits (maximum and mean canopy height and width, projected canopy area, and concave and convex volumes) and a multivariate trait (cumulative height profile). Growth rates were calculated for univariate static traits, quantifying canopy growth and development. Linear regressions were performed between the traits and fiber yield to identify the best traits and measurement time for yield prediction. The results showed that fiber yield was correlated with static traits after the canopy development stage (R2 = 0.35-0.71) and growth rates in early canopy development stages (R2 = 0.29-0.52). Multi-dimensional traits (e.g., projected canopy area and volume) outperformed one-dimensional traits, and the multivariate trait (cumulative height profile) outperformed univariate traits. The proposed approach would be useful for identification of quantitative trait loci (QTLs) controlling canopy size in genetics/genomics studies or for fiber yield prediction in breeding programs and production environments. PMID- 29441075 TI - Corrigendum: Light Deprivation-Induced Inhibition of Chloroplast Biogenesis Does Not Arrest Embryo Morphogenesis but Strongly Reduces the Accumulation of Storage Reserves during Embryo Maturation in Arabidopsis. AB - [This corrects the article on p. 1287 in vol. 8, PMID: 28775734.]. PMID- 29441076 TI - Parental Expression Variation of Small RNAs Is Negatively Correlated with Grain Yield Heterosis in a Maize Breeding Population. AB - Heterosis refers to a quantitative phenomenon in which F1 hybrid trait values exceed the mean of the parental values in a positive direction. Generally, it is dependent on a high degree of heterozygosity, which is maintained in hybrid breeding by developing parental lines in separate, genetically distinct heterotic groups. The mobility of small RNAs (sRNAs) that mediate epigenetic regulation of gene expression renders them promising candidates for modulating the action of combined diverse genomes in trans-and evidence already indicates their contribution to transgressive phenotypes. By sequencing small RNA libraries of a panel of 21 maize parental inbred lines we found a low overlap of 35% between the sRNA populations from both distinct heterotic groups. Surprisingly, in contrast to genetic or gene expression variation, parental sRNA expression variation is negatively correlated with grain yield (GY) heterosis. Among 0.595 million expressed sRNAs, we identified 9,767, predominantly 22- and 24-nt long sRNAs, which showed an association of their differential expression between parental lines and GY heterosis of the respective hybrids. Of these sRNAs, 3,485 or 6,282 showed an association with high or low GY heterosis, respectively, thus the low heterosis associated group prevailing at 64%. The heterosis associated sRNAs map more frequently to genes that show differential expression between parental lines than reference sets. Together these findings suggest that trans-chromosomal actions of sRNAs in hybrids might add up to a negative contribution in heterosis formation, mediated by unfavorable gene expression regulation. We further revealed an exclusive accumulation of 22-nt sRNAs that are associated with low GY heterosis in pericentromeric genomic regions. That recombinational suppression led to this enrichment is indicated by its close correlation with low recombination rates. The existence of this enrichment, which we hypothesize resulted from the separated breeding of inbred lines within heterotic groups, may have implications for hybrid breeding strategies addressing the recombinational constraints characteristic of complex crop genomes. PMID- 29441077 TI - Beyond Chemical Triggers: Evidence for Sound-Evoked Physiological Reactions in Plants. AB - Sound is ubiquitous in nature. Recent evidence supports the notion that naturally occurring and artificially generated sound waves contribute to plant robustness. New information is emerging about the responses of plants to sound and the associated downstream signaling pathways. Here, beyond chemical triggers which can improve plant health by enhancing plant growth and resistance, we provide an overview of the latest findings, limitations, and potential applications of sound wave treatment as a physical trigger to modulate physiological traits and to confer an adaptive advantage in plants. We believe that sound wave treatment is a new trigger to help protect plants against unfavorable conditions and to maintain plant fitness. PMID- 29441078 TI - Epigenetic Variance, Performing Cooperative Structure with Genetics, Is Associated with Leaf Shape Traits in Widely Distributed Populations of Ornamental Tree Prunus mume. AB - Increasing evidence shows that epigenetics plays an important role in phenotypic variance. However, little is known about epigenetic variation in the important ornamental tree Prunus mume. We used amplified fragment length polymorphism (AFLP) and methylation-sensitive amplified polymorphism (MSAP) techniques, and association analysis and sequencing to investigate epigenetic variation and its relationships with genetic variance, environment factors, and traits. By performing leaf sampling, the relative total methylation level (29.80%) was detected in 96 accessions of P. mume. And the relative hemi-methylation level (15.77%) was higher than the relative full methylation level (14.03%). The epigenetic diversity (I* = 0.575, h* = 0.393) was higher than the genetic diversity (I = 0.484, h = 0.319). The cultivated population displayed greater epigenetic diversity than the wild populations in both southwest and southeast China. We found that epigenetic variance and genetic variance, and environmental factors performed cooperative structures, respectively. In particular, leaf length, width and area were positively correlated with relative full methylation level and total methylation level, indicating that the DNA methylation level played a role in trait variation. In total, 203 AFLP and 423 MSAP associated markers were detected and 68 of them were sequenced. Homologous analysis and functional prediction suggested that the candidate marker-linked genes were essential for leaf morphology development and metabolism, implying that these markers play critical roles in the establishment of leaf length, width, area, and ratio of length to width. PMID- 29441079 TI - Fine Mapping and Identification of a Novel Phytophthora Root Rot Resistance Locus RpsZS18 on Chromosome 2 in Soybean. AB - Phytophthora root rot (PRR) caused by Phytophthora sojae is a major soybean disease that causes severe economic losses worldwide. Using soybean cultivars carrying a Rps resistance gene is the most effective strategy for controlling this disease. We previously detected a novel Phytophthora resistance gene, RpsZS18, on chromosome 2 of the soybean cultivar Zaoshu18. The aim of the present study was to identify and finely map RpsZS18. We used 232 F2:3 families generated from a cross between Zaoshu18 (resistant) and Williams (susceptible) as the mapping population. Simple sequence repeat (SSR) markers distributed on chromosome 2 were used to map RpsZS18. First, 12 SSR markers linked with RpsZS18 were identified by linkage analyses, including two newly developed SSR markers, ZCSSR33 and ZCSSR46, that flanked the gene at distances of 0.9 and 0.5 cM, respectively. Second, PCR-based InDel markers were developed based on sequence differences between the two parents and used to further narrow down the mapping region of RpsZS18 to 71.3 kb. Third, haplotype analyses were carried out in the RpsZS18 region using 14 soybean genotypes with whole-genome resequencing. We detected six genes with unique haplotype sequences in Zaoshu18. Finally, quantitative real-time PCR assays of the six genes revealed an EF-hand calcium binding domain containing protein encoding gene (Glyma.02g245700), a pfkB carbohydrate kinase encoding gene (Glyma.02g245800), and a gene with no functional annotation (Glyma.02g246300), are putative candidate PRR resistance genes. This study provides useful information for breeding P. sojae-resistant soybean cultivars. PMID- 29441080 TI - Asymmetric Evolution and Expansion of the NAC Transcription Factor in Polyploidized Cotton. AB - Polyploidy in Gossypium hirsutum conferred different properties from its diploid ancestors under the regulation of transcription factors. The NAC transcription factor is a plant-specific family that can be related to plant growth and development. So far, little is known about the NAC family in cotton. This study identified 495 NAC genes in three cotton species and investigated the evolution and expansion of different genome-derived NAC genes in cotton. We revealed 15 distinct NAC subfamilies in cotton. Different subfamilies had different gene proportions, expansion rate, gene loss rate, and orthologous exchange rate. Paleohexaploidization (35%) and cotton-specific decaploidy (32%) might have primarily led to the expansion of the NAC family in cotton. Half of duplication events in G. hirsutum were inherited from its diploid ancestor, and others might have occurred after interspecific hybridization. In addition, NAC genes in the At and Dt subgenomes displayed asymmetric molecular evolution, as evidenced by their different gene loss rates, orthologous exchange, evolutionary rates, and expression levels. The dominant duplication event was different during the cotton evolutionary history. Different genome-derived NACs might have interacted with each other, which ultimately resulted in morphogenetic evolution. This study delineated the expansion and evolutionary history of the NAC family in cotton and illustrated the different fates of NAC genes during polyploidization. PMID- 29441082 TI - Nitrogen (N) Application Gradually Enhances Boll Development and Decreases Boll Shell Insecticidal Protein Content in N-Deficient Cotton. AB - Expression of insecticidal protein in transgenic Bacillus thuringiensis (Bt) is lower in cotton reproduction organs, especially during boll development period. The current study investigated the effects of nitrogen fertilization under nitrogen deficit on boll development and Bt toxin content in boll shell, which is the first target of boll worm harm. The protein synthesis and degradation in this process was also studied to uncover the underlying mechanism. Five nitrogen levels (under nitrogen deficiency) were imposed on two cultivars, Sikang3 (hybrid) and Sikang1 (conventional), at the Yangzhou University Farm, Yangzhou, China during 2015 to 2016 cotton growth seasons. Under nitrogen deficiency, enhanced nitrogen dose increased the boll number per plant, boll volume, boll weight, boll shell amino acid content, protease, and peptidase activities, but reduced boll shell Bt protein content, soluble protein content, glutamic pyruvic transaminase (GPT) and glutamate oxaloacetate transaminase (GOT) activities. There was a significant negative correlation between boll growth and boll shell insecticidal protein content under nitrogen deficiency, which was a result of uneven distribution of nitrogen in cotton bolls. Under increased nitrogen application, most nitrogen was transported and assimilated in boll seed instead of boll shell in developing cotton bolls, which resulted in decreased protein synthesis and increased protein degradation, and thus declined Bt protein content in boll shell. PMID- 29441081 TI - Non-parent of Origin Expression of Numerous Effector Genes Indicates a Role of Gene Regulation in Host Adaption of the Hybrid Triticale Powdery Mildew Pathogen. AB - Powdery mildew is an important disease of cereals. It is caused by one species, Blumeria graminis, which is divided into formae speciales each of which is highly specialized to one host. Recently, a new form capable of growing on triticale (B.g. triticale) has emerged through hybridization between wheat and rye mildews (B.g. tritici and B.g. secalis, respectively). In this work, we used RNA sequencing to study the molecular basis of host adaptation in B.g. triticale. We analyzed gene expression in three B.g. tritici isolates, two B.g. secalis isolates and two B.g. triticale isolates and identified a core set of putative effector genes that are highly expressed in all formae speciales. We also found that the genes differentially expressed between isolates of the same form as well as between different formae speciales were enriched in putative effectors. Their coding genes belong to several families including some which contain known members of mildew avirulence (Avr) and suppressor (Svr) genes. Based on these findings we propose that effectors play an important role in host adaptation that is mechanistically based on Avr-Resistance gene-Svr interactions. We also found that gene expression in the B.g. triticale hybrid is mostly conserved with the parent-of-origin, but some genes inherited from B.g. tritici showed a B.g. secalis-like expression. Finally, we identified 11 unambiguous cases of putative effector genes with hybrid-specific, non-parent of origin gene expression, and we propose that they are possible determinants of host specialization in triticale mildew. These data suggest that altered expression of multiple effector genes, in particular Avr and Svr related factors, might play a role in mildew host adaptation based on hybridization. PMID- 29441083 TI - A Genome-Wide Association Study of Field and Seedling Response to Individual Stem Rust Pathogen Races Reveals Combinations of Race-Specific Genes in North American Spring Wheat. AB - Stem rust of wheat caused by the fungal pathogen Puccinia graminis f. sp. tritici historically caused major yield losses of wheat worldwide. To understand the genetic basis of stem rust resistance in contemporary North American spring wheat, genome-wide association analysis (GWAS) was conducted on an association mapping panel comprised of 250 elite lines. The lines were evaluated in separate nurseries each inoculated with a different P. graminis f. sp. tritici race for 3 years (2013, 2015, and 2016) at Rosemount, Minnesota allowing the evaluation of race-specificity separate from the effect of environment. The lines were also challenged with the same four races at the seedling stage in a greenhouse facility at the USDA-ARS Cereal Disease Laboratory. A total of 22,310 high quality SNPs obtained from the Infinium 90,000 SNPs chip were used to perform association analysis. We observed often negative and sometimes weak correlations between responses to different races that highlighted the abundance of race specific resistance and the inability to predict the response of the lines across races. Markers strongly associated with resistance to the four races at seedling and field environments were identified. At the seedling stage, the most significant marker-trait associations were detected in the regions of known major genes (Sr6, Sr7a, and Sr9b) except for race QFCSC where a strong association was detected on chromosome arm 1AL. We postulated the presence of Sr2, Sr6, Sr7a, Sr8a, Sr9b, Sr11, Sr12, Sr24, Sr25, Sr31, and Sr57 (Lr34) in this germplasm based on phenotypic and marker data. We found over half of the panel possessed three or more Sr genes, and most commonly included various combinations of Sr6, Sr7a, Sr8a, Sr9b, Sr11, Sr12, and Sr57. Most of these genes confer resistance to specific P. graminis f. sp. tritici races accounting for the prevalent stem rust resistance in North American spring wheat. PMID- 29441084 TI - Auxin-to-Gibberellin Ratio as a Signal for Light Intensity and Quality in Regulating Soybean Growth and Matter Partitioning. AB - The intensity and quality (red to far-red (R/Fr) ratio) of light directly affect growth of plant under shading. Gibberellins (GAs) and auxin [indole-3-acetic acid (IAA)] play important roles in mediating the shading adaptive responses of plants. Thus, the intensity and quality of the uncoupling light from shading were assessed to identify the influence of each component on the morphology and matter distribution of the leaf, stem, and petiole. This assessment was based on the changes in endogenous Gibberellin 1 (GA1) and IAA levels. Soybean plants were grown in a growth chamber with four treatments [normal (N), N+Fr, low (L), and L+Fr light]. Results revealed that the reductions in photosynthetically active radiation (PAR) and R/Fr ratio equally increased height and stem mass fractions (SMFs) of the soybean seedling. The light intensity significantly influenced the dry mass per unit area and mass fraction of soybean leaves, whereas the light quality regulated the petiole elongation and mass fraction. Low R/Fr ratio (high Fr light) increased the soybean biomass by improving the photosynthetic assimilation rate and quantum yield of photosystem II. In addition, the IAA and GA1 levels in the leaf, stem, and petiole did not reflect the growth response trends of each tissue toward light intensity and quality; however, trends of the IAA-to-GA1 content ratios were similar to those of the growth and matter allocation of each soybean tissue under different light environments. Therefore, the response of growth and matter allocation of soybean to light intensity and quality may be regulated by the IAA-to-GA1 content ratio in the tissues of the soybean plant. PMID- 29441086 TI - Development and Validation of a New Methodology to Assess the Vineyard Water Status by On-the-Go Near Infrared Spectroscopy. AB - Assessing water status and optimizing irrigation is of utmost importance in most winegrowing countries, as the grapevine vegetative growth, yield, and grape quality can be impaired under certain water stress situations. Conventional plant based methods for water status monitoring are either destructive or time and labor demanding, therefore unsuited to detect the spatial variation of moisten content within a vineyard plot. In this context, this work aims at the development and comprehensive validation of a novel, non-destructive methodology to assess the vineyard water status distribution using on-the-go, contactless, near infrared (NIR) spectroscopy. Likewise, plant water status prediction models were built and intensely validated using the stem water potential (psis) as gold standard. Predictive models were developed making use of a vast number of measurements, acquired on 15 dates with diverse environmental conditions, at two different spatial scales, on both sides of vertical shoot positioned canopies, over two consecutive seasons. Different cross-validation strategies were also tested and compared. Predictive models built from east-acquired spectra yielded the best performance indicators in both seasons, with determination coefficient of prediction ([Formula: see text]) ranging from 0.68 to 0.85, and sensitivity (expressed as prediction root mean square error) between 0.131 and 0.190 MPa, regardless the spatial scale. These predictive models were implemented to map the spatial variability of the vineyard water status at two different dates, and provided useful, practical information to help delineating specific irrigation schedules. The performance and the large amount of data that this on-the-go spectral solution provides, facilitates the exploitation of this non-destructive technology to monitor and map the vineyard water status variability with high spatial and temporal resolution, in the context of precision and sustainable viticulture. PMID- 29441085 TI - Three-Dimensional Architecture and Biogenesis of Membrane Structures Associated with Plant Virus Replication. AB - Positive-sense (+) RNA viruses represent the most abundant group of viruses and are dependent on the host cell machinery to replicate. One remarkable feature that occurs after (+) RNA virus entry into cells is the remodeling of host endomembranes, leading to the formation of viral replication factories. Recently, rapid progress in three-dimensional (3D) imaging technologies, such as electron tomography (ET) and focused ion beam-scanning electron microscopy (FIB-SEM), has enabled researchers to visualize the novel membrane structures induced by viruses at high resolution. These 3D imaging technologies provide new mechanistic insights into the viral infection cycle. In this review, we summarize the latest reports on the cellular remodeling that occurs during plant virus infection; in particular, we focus on studies that provide 3D architectural information on viral replication factories. We also outline the mechanisms underlying the formation of these membranous structures and discuss possible future research directions. PMID- 29441087 TI - Prolonged Expression of a Putative Invertase Inhibitor in Micropylar Endosperm Suppressed Embryo Growth in Arabidopsis. AB - Proper seed development requires coordinated growth among the three genetically distinct components, the embryo, the endosperm, and the seed coat. In Arabidopsis, embryo growth rate accelerates after endosperm cellularization, which requires a chromatin-remodeling complex, the FIS2-Polycomb Repressive Complex 2 (PRC2). After cellularization, the endosperm ceases to grow and is eventually absorbed by the embryo. This sequential growth pattern displayed by the endosperm and the embryo suggests a possibility that the supply of sugar might be shifted from the endosperm to the embryo upon endosperm cellularization. Since invertases and invertase inhibitors play an important role in sugar partition, we investigated their expression pattern during early stages of seed development in Arabidopsis. Two putative invertase inhibitors (InvINH1 and InvINH2) were identified as being preferentially expressed in the micropylar endosperm that surrounds the embryo. After endosperm cellularization, InvINH1 and InvINH2 were down-regulated in a FIS2-dependent manner. We hypothesized that FIS2 PRC2 complex either directly or indirectly represses InvINH1 and InvINH2 to increase invertase activity around the embryo, making more hexose available to support the accelerated embryo growth after endosperm cellularization. In support of our hypothesis, embryo growth was delayed in transgenic lines that ectopically expressed InvINH1 in the cellularized endosperm. Our data suggested a novel mechanism for the FIS2-PRC2 complex to control embryo growth rate via the regulation of invertase activity in the endosperm. PMID- 29441088 TI - Hydroponic Treatment of Nicotiana benthamiana with Kifunensine Modifies the N glycans of Recombinant Glycoprotein Antigens to Predominantly Man9 High-Mannose Type upon Transient Overexpression. AB - Nicotiana benthamiana transient overexpression systems offer unique advantages for rapid and scalable biopharmaceuticals production, including high scalability and eukaryotic post-translational modifications such as N-glycosylation. High mannose-type glycans (HMGs) of glycoprotein antigens have been implicated in the effectiveness of some subunit vaccines. In particular, Man9GlcNAc2 (Man9) has high binding affinity to mannose-specific C-type lectin receptors such as the mannose receptor and dendritic cell-specific intracellular adhesion molecule 3 grabbing non-integrin (DC-SIGN). Here, we investigated the effect of kifunensine, an alpha-mannosidase I inhibitor, supplemented in a hydroponic culture of N. benthamiana for the production of Man9-rich HMG glycoproteins, using N glycosylated cholera toxin B subunit (gCTB) and human immunodeficiency virus gp120 that are tagged with a H/KDEL endoplasmic reticulum retention signal as model vaccine antigens. Biochemical analysis using anti-fucose and anti-xylose antibodies as well as Endo H and PNGase F digestion showed that kifunensine treatment effectively reduced plant-specific glycoforms while increasing HMGs in the N-glycan compositions of gCTB. Detailed glycan profiling revealed that plant produced gp120 had a glycan profile bearing mostly HMGs regardless of kifunensine treatment. However, the gp120 produced under kifunensine-treatment conditions showed Man9 being the most prominent glycoform (64.5%), while the protein produced without kifunensine had a substantially lower Man9 composition (20.3%). Our results open up possibilities for efficient production of highly mannosylated recombinant vaccine antigens in plants. PMID- 29441090 TI - Acute Pesticide Poisoning in Children: Hospital Review in Selected Hospitals of Tanzania. AB - Background: Acute pesticide poisoning (APP) is a serious problem worldwide. Because the burden of childhood APP is unknown in Tanzania, this study describes the distribution, circumstances, and patterns of APP involving children under 18 years in Tanzania. Methodology: A 12-month prospective study was conducted in 10 Tanzanian healthcare facilities in 2006 using a data collection tool for surveillance. Results: Of 53 childhood poisoning cases identified, 56.6% were female. The most common poisoning circumstances were accidents (49.1%) and suicide (30.2%). The most vulnerable children were 16-17 years old (30.2%). Suicide was significantly more common in females (PRR females/males = 1.66; 95% CI = 1.03-2.68) and accidental cases were more common in children aged 10 years or younger. Suicide was concentrated in children over 10 years, comprising 53% of cases in this age group. Organophosphates (OPs), zinc phosphide, and endosulfan were common amongst reported poisoning agents. The annual APP incidence rate was 1.61/100,000. Conclusion: APP is common among children in this region of Tanzania. Prevention of suicide in older children should address mental health issues and control access to toxic pesticides. Prevention of accidents in younger children requires safer storage and hygiene measures. Diverse interventions are needed to reduce pesticide poisoning among children in Tanzania. PMID- 29441092 TI - Is an Interventional Oncology Center an advantage in the service of cancer patients or in the education? The Gemelli Hospital and INTERACTS experience. PMID- 29441091 TI - Magnetic Targeted Delivery of Induced Pluripotent Stem Cells Promotes Articular Cartilage Repair. AB - Cartilage regeneration treatments using stem cells are associated with problems due to the cell source and the difficulty of delivering the cells to the cartilage defect. We consider labeled induced pluripotent stem (iPS) cells to be an ideal source of cells for tissue regeneration, and if iPS cells could be delivered only into cartilage defects, it would be possible to repair articular cartilage. Consequently, we investigated the effect of magnetically labeled iPS (m-iPS) cells delivered into an osteochondral defect by magnetic field on the repair of articular cartilage. iPS cells were labeled magnetically and assessed for maintenance of pluripotency by their ability to form embryoid bodies in vitro and to form teratomas when injected subcutaneously into nude rats. These cells were delivered specifically into cartilage defects in nude rats using a magnetic field. The samples were graded according to the histologic grading score for cartilage regeneration. m-iPS cells differentiated into three embryonic germ layers and formed teratomas in the subcutaneous tissue. The histologic grading score was significantly better in the treatment group compared to the control group. m-iPS cells maintained pluripotency, and the magnetic delivery system proved useful and safe for cartilage repair using iPS cells. PMID- 29441089 TI - Identification and Expression Analysis of Wheat TaGF14 Genes. AB - The 14-3-3 gene family members play key roles in various cellular processes. However, little is known about the numbers and roles of 14-3-3 genes in wheat. The aims of this study were to identify TaGF14 numbers in wheat by searching its whole genome through blast, to study the phylogenetic relationships with other plant species and to discuss the functions of TaGF14s. The results showed that common wheat harbored 20 TaGF14 genes, located on wheat chromosome groups 2, 3, 4, and 7. Out of them, eighteen TaGF14s are non-epsilon proteins, and two wheat TaGF14 genes, TaGF14i and TaGF14f, are epsilon proteins. Phylogenetic analysis indicated that these genes were divided into six clusters: cluster 1 (TaGF14d, TaGF14g, TaGF14j, TaGF14h, TaGF14c, and TaGF14n); cluster 2 (TaGF14k); cluster 3 (TaGF14b, TaGF14l, TaGF14m, and TaGF14s); cluster 4 (TaGF14a, TaGF14e, and TaGF14r); cluster 5 (TaGF14i and TaGF14f); and cluster 6 (TaGF14o, TaGF14p, TaGF14q, and TaGF14t). Tissue-specific gene expressions suggested that all TaGF14s were likely constitutively expressed, except two genes, i.e., TaGF14p and TaGF14f. And the highest amount of TaGF14 transcripts were observed in developing grains at 20 days post anthesis (DPA), especially for TaGF14j and TaGF14l. After drought stress, five genes, i.e., TaGF14c, TaGF14d, TaGF14g, TaGF14h, and TaGF14j, were up-regulated expression under drought stress for both 1 and 6 h, suggesting these genes played vital role in combating against drought stress. However, all the TaGF14s were down-regulated expression under heat stress for both 1 and 6 h, indicating TaGF14s may be negatively associated with heat stress by reducing the expression to combat heat stress or through other pathways. These results suggested that cluster 1, e.g., TaGF14j, may participate in the whole wheat developing stages, e.g., grain-filling (starch biosynthesis) and may also participate in combating against drought stress. Subsequently, a homolog of TaGF14j, TaGF14-JM22, were cloned by RACE and used to validate its function. Immunoblotting results showed that TaGF14-JM22 protein, closely related to TaGF14d, TaGF14g, and TaGF14j, can interact with AGP-L, SSI, SSII, SBEIIa, and SBEIIb in developing grains, suggesting that TaGF14s located on group 4 may be involved in starch biosynthesis. Therefore, it is possible to develop starch-rich wheat cultivars by modifying TaGF14s. PMID- 29441094 TI - Artificial neural network based gynaecological image-guided adaptive brachytherapy treatment planning correction of intra-fractional organs at risk dose variation. AB - Purpose: Intra-fractional organs at risk (OARs) deformations can lead to dose variation during image-guided adaptive brachytherapy (IGABT). The aim of this study was to modify the final accepted brachytherapy treatment plan to dosimetrically compensate for these intra-fractional organs-applicators position variations and, at the same time, fulfilling the dosimetric criteria. Material and methods: Thirty patients with locally advanced cervical cancer, after external beam radiotherapy (EBRT) of 45-50 Gy over five to six weeks with concomitant weekly chemotherapy, and qualified for intracavitary high-dose-rate (HDR) brachytherapy with tandem-ovoid applicators were selected for this study. Second computed tomography scan was done for each patient after finishing brachytherapy treatment with applicators in situ. Artificial neural networks (ANNs) based models were used to predict intra-fractional OARs dose-volume histogram parameters variations and propose a new final plan. Results: A model was developed to estimate the intra-fractional organs dose variations during gynaecological intracavitary brachytherapy. Also, ANNs were used to modify the final brachytherapy treatment plan to compensate dosimetrically for changes in 'organs-applicators', while maintaining target dose at the original level. Conclusions: There are semi-automatic and fast responding models that can be used in the routine clinical workflow to reduce individually IGABT uncertainties. These models can be more validated by more patients' plans to be able to serve as a clinical tool. PMID- 29441093 TI - Correlations of post-implant regional dosimetric parameters at 24 hours and one month, with clinical results of low-dose-rate brachytherapy for localized prostate cancer. AB - Purpose: To evaluate the correlations of post-implant regional dosimetrics at 24 hours (24 h) and 1 month after implant procedures, with clinical outcomes of low dose-rate (LDR) brachytherapy for localized prostate cancer. Material and methods: Between January 2008 and December 2014, 130 consecutive patients treated for localized prostate cancer, receiving definitive iodine-125 (125I) brachytherapy treatment were retrospectively analyzed. All patients underwent post-implant CT imaging for dosimetric analysis at 24 h and 1 month after implantation procedure. Prostate contours were divided into quadrants: anterior superior (ASQ), posterior-superior (PSQ), anterior-inferior (AIQ), and posterior inferior (PIQ). Predictive factors and cut-off values of biochemical failure-free survival (BFFS) and toxicities of LDR brachytherapy were analyzed. Results: The median follow-up time was 69.5 months. Seven patients (5.4%) had biochemical failure. The 3-year and 5-year BFFS rates were 96.7% and 93.1%, respectively. On multivariate analysis, prostate-specific antigen and Gleason score were significant prognostic factors for biochemical failure. D90 (the minimal dose received by 90% of the volume) of PSQ and PIQ at 24 h, and D90 of PSQ at 1 month were also significant factors. The cut-off values of PSQ D90 were 145 Gy at 24 h and 160 Gy at 1 month. D90 of the whole prostate was not significant at 24 h and at 1 month. D90 of PSQ at 1 month was a significant factor for rectal hemorrhage. Conclusions: Post-implant D90 of PSQ is significantly associated with BFFS for localized prostate cancer not only at 1 month, but also at 24 hours. D90 of PSQ at 1 month is also a significant factor for rectal hemorrhage. PMID- 29441095 TI - Off-line magnetic resonance imaging navigation of cervix cancer brachytherapy in patients with risk factors for uterine perforation. AB - Purpose: There are no reports on pre-insertion identification of cervix cancer patients at risk for uterine perforation during brachytherapy (BT). Our aim was to assess the incidence of risk factors in our patient cohort, and assess feasibility of a novel technique of magnetic resonance imaging (MRI)-guided navigation for applicator insertion (NAI) in high-risk cases. Material and methods: All patients with locally advanced cervical cancer, treated with image guided adaptive BT at our department between October 2013 and June 2017 were considered for analysis. Tumor characteristics on initial MRI (MRIinitial), pre BT MRI (MRIpre-BT), and BT MRI (MRIBT) were assessed. Frequency of risk factors (age above 60 years, retroverted/retroflected uterus, tumor necrosis, non-visible cervical orifice, distorted cervical canal) was recorded. Patients with two or more factors underwent MRI guided NAI. Time needed for NAI was estimated and procedure feasibility score assigned using a three-tiered scoring system. Results: Twenty-seven patients (98 insertions) were included. Mean tumor volume was 70.2 (+/- 47.9), 17.8 (+/- 18.9), and 10.3 (+/- 9.1) cm3 on MRIinitial, MRIpre-BT, and MRIBT1, respectively (p < 0.05). In 16 (59%) cases, >= 1 perforation risk factor was found on MRIpre-BT: distorted canal in 12 (44%), necrosis in 9 (33%), retroverted/retroflected uterus in 8 (30%) cases. Nine (33%) patients had >= 2 risk factors and underwent MRI guided NAI. Additional time to perform NAI was estimated at 105 minutes, and feasibility score was 1 in all cases. There were no cases of uterine perforation. Conclusions: Using pre insertion MRI, we found >= 2 risk factors for uterine perforation in 1/3 of patients. Off-line MRI navigation was feasible and enabled non-complicated insertion in all cases. Further studies with larger sample size are warranted to assess its clinical efficacy. PMID- 29441097 TI - The feasibility of using ultrasound during follow-up for superficial non-melanoma skin cancers after electronic brachytherapy. AB - Purpose: Non-melanoma skin cancers (NMSCs) can be treated with a number of modalities including surgery, topical chemotherapy, or radiotherapy. Amongst the radiotherapeutic options, electronic brachytherapy (eBT) is an appealing treatment as it is usually given in a few fractions, it leads to good outcomes, and is increasingly being used. However, currently no follow-up imaging is routinely used or recommended to evaluate treatment response of NMSC. We aimed to use ultrasound (US) in follow-up after eBT for superficial NMSC to assess its feasibility in detecting possible tumor response. Material and methods: Fourteen patients were treated between 2013-2015 for a NMSC using eBT. US guidance was used for treatment planning prior to eBT initiation. After completion of eBT, patients were seen in follow-up for both clinical exam and a repeat US at 1 month to evaluate if tumor response was detectable. Results: Of the 14 patients, 6 were male and 8 were female. The mean age was 71 years. With a median follow-up of 20.5 months, all patients had a complete response based on physical exam. Eleven patients appeared to have a complete response based on US obtained > 1 month after completing eBT. To date, there have been no local recurrences or progression, and all patients are alive. Conclusions: US is an objective imaging modality that may be able to assess NMSC response after eBT. Based on follow-up imaging, further treatment or observation may be recommended. Although this study is hypothesis generating, larger studies with pathologic confirmation of recurrences would be needed to validate US use for follow-up, avoiding possible painful and scarring biopsies in case of low suspicion of recurrence. PMID- 29441096 TI - Implantation of computed tomography-guided Iodine-125 seeds in combination with chemotherapy for the treatment of stage III non-small cell lung cancer. AB - Purpose: We investigated the role of computed tomography (CT)-guided Iodine-125 (125I) seed implantation in combination with chemotherapy for the treatment of stage III non-small cell lung carcinoma (NSCLC). Material and methods: The data from 182 patients with stage III NSCLC who were treated with radioactive 125I seed implantation between June 2002 and June 2009, and who received sequential platinum-based combination chemotherapy using the most common combination of platinum and gemcitabine, were retrospectively reviewed. The 182 patients received a prescribed dose of 110.0 Gy, with a median radioactivity of 0.70 mCi (range, 0.64-0.78 mCi, 2.37-3.26 * 107 Bq). The median number of 125I seeds was 38 pellets (range, 6-105 pellets). The median post-operation dose covering 100% of the target volume (D100) was 94.5 Gy (range, 54.6-125.5 Gy). The median D90 was 143.0 Gy (range, 121.6-184.0). Results: The 1-, 3-, and 5-year overall survival rates were 83.35%, 25.57%, and 11.34%, respectively; the median survival time was 24.76 months. At 1, 3, and 5 years, the local control rates were 92.01%, 86.51%, and 76.45%, respectively; the median local control time was 25.28 months. For patients with stage IIIA and IIIB NSCLC, the median survival times were 26.67 and 24.59 months, respectively (p = 0.2). Pre-treatment hemoglobin level, tumor volume, and postoperative D100 were significantly associated with survival. A total of 24 patients experienced pneumothorax (incidence rate, 13.20%), and 17 patients experienced hemothorax (incidence rate, 5.0%). Conclusions: CT-guided 125I seed implantation combined with chemotherapy is an effective, minimally invasive method for the treatment of stage III NSCLC. Furthermore, hemoglobin levels before treatment, D100, and the maximum diameter of the tumor may be prognostic factors in patients with NSCLC treated sequentially with radiotherapy and chemotherapy. PMID- 29441098 TI - Nomogram for predicting radiation maculopathy in patients treated with Ruthenium 106 plaque brachytherapy for uveal melanoma. AB - Purpose: To develop a predictive model and nomogram for maculopathy occurrence at 3 years after 106Ru/106Rh plaque brachytherapy in uveal melanoma. Material and methods: Clinical records of patients affected by choroidal melanoma and treated with 106Ru/106Rh plaque from December 2006 to December 2014 were retrospectively reviewed. Inclusion criteria were: dome-shaped melanoma, distance to the fovea > 1.5 mm, tumor thickness > 2 mm, and follow-up > 4 months. The delivered dose to the tumor apex was 100 Gy. Primary endpoint of this investigation was the occurrence of radiation maculopathy at 3 years. Analyzed factors were as follows: gender, age, diabetes, tumor size (volume, area, largest basal diameter and apical height), type of plaque, distance to the fovea, presence of exudative detachment, drusen, orange pigment, radiation dose to the fovea and sclera. Univariate and multivariate Cox proportional hazards analyses were used to define the impact of baseline patient factors on the occurrence of maculopathy. Kaplan Meier curves were used to estimate freedom from the occurrence of the maculopathy. The model performance was evaluated through internal validation using area under the ROC curve (AUC), and calibration with Gronnesby and Borgan tests. Results: One hundred ninety-seven patients were considered for the final analysis. Radiation-related maculopathy at 3 years was observed in 41 patients. The proposed nomogram can predict maculopathy at 3 years with an AUC of 0.75. Distance to fovea appeared to be the main prognostic factor of the predictive model (hazard ratio of 0.83 [0.76-0.90], p < 0.01). Diabetes (hazard radio of 2.92 [1.38-6.20], p < 0.01), and tumor volume (hazard radio of 21.6 [1.66 281.14], p = 0.02) were significantly predictive for maculopathy occurrence. The calibration showed no statistical difference between actual and predicted maculopathy (p = 1). Conclusions: Our predictive model, together with its nomogram, could be a useful tool to predict the occurrence of radiation maculopathy at 3 years after the treatment. PMID- 29441099 TI - Ruthenium brachytherapy for uveal melanoma - single institution experience. AB - Purpose: The aim of this study was to report on results of uveal melanoma treatment with ruthenium-106 (106Ru) brachytherapy with long-term follow-up, in terms of local tumor control, eye retention rate, radiation retinopathy, and patients' survival. Material and methods: Medical records of patients treated with ruthenium plaque due to uveal melanoma at the Department of Ophthalmology, Poznan University of Medical Sciences, Poland, between 1994 and 2014 were retrospectively reviewed. Results: We identified 126 patients: 53 men, 73 women, mean age 60.04 years (range, 21-89). The largest basal diameter ranged from 4.04 mm to 18.9 mm (median, 10.67 mm), tumor height was 1.9 mm to 7.42 mm (median, 4.8 mm). Median scleral radiation dose was 570 Gy (range, 235-1,500 Gy), median apical dose 100 Gy (range, 60-129 Gy). Median follow-up was 66.5 months (range, 2 261 months). We noted a total of 19 (15%) recurrences. The actuarial rate of recurrence was 9.5% at 3 years, and 13.5% at 5 years postoperatively. Nine (7%) eye globes were lost, median time to enucleation was 5 years. The eye retention rate at 5 years was 92.7% and 81% at 10 years. Forty-three (34%) patients died before the end of the study, 24 (19%) of them due to metastatic disease. Metastatic death was related to: tumor size and TNM stage at presentation (p = 0.002 vs. p = 0.0006, respectively) but not to age, gender, and plaque dosimetry. Conclusions: 106Ru brachytherapy is an effective, globe sparing treatment that provides good tumor control and a high rate of survival. However, some ocular complications tend to appear late post-treatment, and therefore long-term follow up is advised. PMID- 29441100 TI - Dose-volume analysis of target volume and critical structures in computed tomography image-based multicatheter high-dose-rate interstitial brachytherapy for head and neck cancer. AB - Purpose: To evaluate dose-volume relationships of target volume and critical structures in computed tomography (CT) image-based brachytherapy for head and neck cancer. Material and methods: Thirty-seven patients with mobile tongue, floor of mouth, and base of tongue cancer treated with brachytherapy (post operative alone and as a boost after external beam radiotherapy [EBRT], or definitive alone or as a boost after EBRT) were selected. Treatment plans were made using post-implant CT images. The fractionation schedule was 7-15 * 3-5 Gy for post-operative (with or without EBRT), 14-15 * 3 Gy for definitive alone, and 5-10 * 3 Gy for boost treatments. For the target volume, V100, D90, and dose non uniformity ratio (DNR) were calculated. For the mandible, spinal cord and salivary glands doses to specified volumes were reported. Results: The median values of V100 and D90 were 89.9% and 99.9%, respectively; the median values of DNR was 0.46. The median D2cm3 of the mandible and spinal cord were 48.3% and 5.8%, respectively. The ipsilateral median D2cm3 of parotid and submandibular glands were 6.4% and 12.5%, whereas on the contralateral side, the corresponding values were 5.3% and 7.0%, respectively. Conclusions: Using conformal treatment planning, it was desirable to keep the dose to the mandible, spinal cord, and salivary glands at an acceptable level. The quantitative plan evaluation may help us find correlations between dosimetric parameters and clinical outcome, which may lead to improve the quality of the treatment, but it requires longer follow up and results from other studies. PMID- 29441101 TI - High-dose-rate brachytherapy in the treatment of skin Kaposi sarcoma. AB - Purpose: The aim of the study is to review our experience in treatment of Kaposi sarcoma (KS) lesions with high-dose-rate (HDR) brachytherapy. Material and methods: We present five new KS lesions (three patients) that were treated in our hospital from May 2016 to February 2017 with HDR brachytherapy using Valencia applicators. The treatment was delivered in 5 Gy fractions over five sessions, on alternate days. Total dose of 25 Gy (EQD2 31.25 Gy) was delivered. All patients were male, Caucasian, without a history of HIV, organ transplantation, or current immunosuppressive therapy. The median age was 76 years. Results: All lesions (100%) were located in lower limbs (60% in the ankle, 20% in the leg, and 20% in the foot), and their development was progressive. No lesion was greater than 2 cm (range, 0.5-1.5 cm). With a median follow-up of 15 months, all patients had a complete response to the treatment, with no evidence of local recurrence or tumor progression. Most of the patients (80%) had no acute toxicity; only one patient developed erythema grade 2. Conclusions: HDR brachytherapy could be a good option of treatment for these types of lesions, especially in elderly patients, or when cosmetic results are not good after surgery. Brachytherapy with the Valencia applicator, using hypofractionated regimen provides excellent results in terms of cosmetic and local control, and furthermore, facilitates treatment compliance, which is very relevant in elderly patients. HDR brachytherapy offers a simple, safe, quick, and attractive non-surgical treatment option. PMID- 29441102 TI - Dosimetric analysis of rib interference of the CTV during interstitial brachytherapy of lung tumors. AB - Purpose: In interstitial brachytherapy for lung tumors, the placement and alignment of the source needles are influenced by the ribs, which can affect the dose distribution. This study evaluated the change in dose to the target by comparing the dose between the actual interstitial brachytherapy plan (AIBP, what is deliverable due to anatomic constraints), and the virtual interstitial brachytherapy plan (VIBP, pretreatment-modified dose distribution). Material and methods: AIBPs and VIBPs were designed for 20 lung tumors. The VIBP was designed with uniform spacing between needles, regardless of the presence of ribs. The prescription dose was 30 Gy. The percentage of normal ipsilateral lung volume that received a dose >= 5 Gy (V5), conformity index (COIN), incremental dose percentage (IDP) to the target, and the dose covering 95% (D95) of the clinical target volume (CTV) were calculated. Results: The V5 of the VIBPs was significantly smaller than that of the AIBPs (p < 0.01). The mean COIN value was 0.41 +/- 0.12 for the AIBPs, which was significantly smaller than the value 0.54 +/- 0.12 for the VIBPs (p < 0.01). The D95 of CTV in VIBP-adjusted was greater than that in AIBPs (p < 0.01). The mean IDP was 44% +/- 40%. The Dmax of the ribs was 20.16 Gy +/- 15.76 Gy in AIBPs, and 18.57 Gy +/- 15.14 Gy in VIBPs, which was not significantly different (p > 0.05). Conclusions: The regular geometric alignment of needles is important for increasing the target dose and limiting the normal lung dose in interstitial brachytherapy for thoracic tumors. Thus, we recommend that radiation oncologists attempt to achieve the regular alignment of needles during implantation. PMID- 29441103 TI - Complete response in a patient with gynecological hidradenocarcinoma treated with exclusive external beam radiotherapy and brachytherapy: a case report. AB - Hidradenocarcinoma (HC) is a very rare disease. This case report illustrates a successful treatment of a 60-year-old woman with vulvo-vaginal localization of hidradenocarcinoma treated with external beam radiotherapy delivered by helical tomotherapy with a simultaneous integrated boost (SIB), followed by brachytherapy. External beam radiotherapy dose prescription was 50.4 Gy in 28 fractions, five fractions per week to whole pelvis (planning target volume 1 - PTV1), 60.2 Gy in 28 fractions to SIB1 (fundus of uterus and right inguinal node), and 58.8 Gy in 28 fractions to SIB2 (lower/middle third of vagina, paraurethral region and right inguinal lymph nodes). Brachytherapy dose prescription was 28 Gy in 4 fractions for cervix, fundus of uterus and upper third of vagina (HR-CTV1), and 22 Gy in 4 fractions to middle third of vagina and paraurethral region (HR-CTV2). D90 for whole treatment was 91.9 Gy and 86.0 Gy for HR-CTV1 and HR-CTV2, respectively. Patient remained 12-months disease-free without treatment related side effects. PMID- 29441105 TI - Quality improvement in pediatric care. AB - We often overlook the importance of several safety issues such as identification of patients, timeout procedure, hand hygiene, handoff communication, and many others. This ignorance, along with many other issues, leads to medical error being ranked as a third leading cause of death in the U.S. Consequently, quality improvement (QI) has become one of the major subjects in healthcare despite a relatively short history. Improving quality is about making healthcare safe, effective, patient-centered, timely, efficient, and equitable. Understanding the need and methodology of QI as well as participation is now essential for physicians. Although basic QI methodology has not changed, one of the most fascinating changes in recent QI is conducting large-scale QI projects through multicenter networks. Prospective multicenter QI projects utilizing the Korean Neonatal Network are a substantial initiation of pediatric QI in Korea. The Korean Pediatric Society should set ambitious goals for QI activities for every primary care pediatrician and pediatric subspecialist. PMID- 29441104 TI - Current status of brachytherapy in cancer treatment - short overview. AB - Cancer incidence and mortality depend on a number of factors, including age, socio-economic status and geographical location, and its prevalence is growing around the world. Most of cancer treatments include external beam radiotherapy or brachytherapy. Brachytherapy, a type of radiotherapy with energy from radionuclides inserted directly into the tumor, is increasingly used in cancer treatment. For cervical and skin cancers, it has become a standard therapy for more than 100 years as well as an important part of the treatment guidelines for other malignancies, including head and neck, skin, breast, and prostate cancers. Compared to external beam radiotherapy, brachytherapy has the potential to deliver an ablative radiation dose over a short period of time directly to the altered tissue area with the advantage of a rapid fall-off in dose, and consequently, sparing of adjacent organs. As a result, the patient is able to complete the treatment earlier, and the risks of occurrence of another cancer are lower than in conventional radiotherapy treatment. Brachytherapy has increased its use as a radical or palliative treatment, and become more advanced with the spread of pulsed-dose-rate and high-dose-rate afterloading machines; the use of new 3D/4D planning systems has additionally improved the quality of the treatment. The aim of the present study was to present short summaries of current studies on brachytherapy for the most frequently diagnosed tumors. Data presented in this manuscript should help especially young physicians or physicists to explore and introduce brachytherapy in cancer treatments. PMID- 29441106 TI - Mid-upper-arm circumference as a screening measure for identifying children with elevated body mass index: a study for Pakistan. AB - Purpose: Mid-upper-arm circumference (MUAC) is considered an alternative screening method for obesity. The aims of this investigation were to examine the ability of MUAC to correctly identify children with elevated body mass index (BMI) and to determine the best MUAC cutoff point for identification of children with high BMI. Methods: Anthropometric measurements (height, weight, and MUAC) from a cross-sectional sample of 7,921 Pakistani children aged 5-14 years were analyzed. Pearson correlation coefficients between MUAC and other anthropometric measurements were calculated. Receiver operating characteristic curve analysis was used to determine the optimal MUAC cutoff point for identifying children with high BMI. Results: Among 7,921 children, the mean (+/-standard deviation) age, BMI, and MUAC were 10.00 (+/-2.86 years), 16.16 (+/-2.66 kg/m2), and 17.73 (+/ 2.59 cm), respectively. The MUAC had a strong positive correlation with BMI. The optimal MUAC cutoff points indicating elevated BMI in boys ranged from 16.76 to 22.73, while the corresponding values in girls ranged from 16.38 to 20.57. Conclusion: MUAC may be used as a simple indicator of overweight/obesity in children, with reasonable accuracy in clinical settings. PMID- 29441107 TI - C-reactive protein and N-terminal pro-brain natriuretic peptide discrepancy: a differentiation of adenoviral pharyngoconjunctival fever from Kawasaki disease. AB - Purpose: To differentiate adenoviral pharyngoconjunctival fever (PCF) from acute Kawasaki disease (KD) using laboratory tests before results of virus-real time polymerase chain reaction and ophthalmologic examination are obtained. Methods: Baseline patient characteristics and laboratory measurements were compared between 40 patients with adenovirus infection and 123 patients with KD. Results: The patients with adenovirus infection were generally older than those with KD (median: 3.9 years vs. 2 years, P=0.000). White blood cell and, platelet count, and aspartate aminotransferase, alanine aminotransferase, and N-terminal pro brain natriuretic peptide (NT-proBNP) levels showed significant differences between the 2 groups, but the C-reactive protein (CRP) levels did not (6.8+/-3.0 mg/dL vs. 8.3+/-5.8 mg/dL, P=0.126). In the adenovirus infection group, the CRP levels were <1, <3, <10, and >=10 mg/dL in 2 (5%), 3 (7.5%), 30 (75%), and 5 patients (12.5%), respectively. The cutoff NT-proBNP level was 265 pg/mL. Discrepancy was defined as CRP and NT-proBNP levels of >=3 or <3 mg/dL, and <265 or >=265 pg/mL, respectively. Among the 35 patients with adenovirus infection whose CRP levels were >=3 mg/dL, 29 (82.9%) showed a discrepancy. Conversely, of the 103 patients with KD whose CRP levels were >=3 mg/dL, 83 (80.6%) showed no discrepancy. Between the groups, a significant difference in discrepancy rate was observed (P=0.000). None of the patients with adenovirus infection had CRP and NT proBNP levels of <3 mg/dL and >=265 pg/mL, respectively. Conclusion: With a sensitivity of 82.9% and a specificity of 80.6%, CRP and NT-proBNP levels may differentiate between adenoviral PCF and acute KD. PMID- 29441108 TI - Is vaginal reflux associated with urinary tract infection in female children under the age of 36 months? AB - Purpose: To determine the relationship between vaginal reflux (VR) and urinary tract infection (UTI) in female children aged <36 months. Methods: A single center retrospective study was performed for 191 girls aged <36 months, with a diagnosis of febrile UTI, who underwent a voiding cystourethrography (VCUG) for assessment of vesicoureteral reflux (VUR) at Sanggye Paik Hospital. Fifty-one girls, who underwent VCUG for assessment of congenital hydronephrosis or renal pelvis dilatation, without a UTI, formed the control group. The correlation between the presence and grade of VR and UTI was evaluated. Results: The prevalence rate of VR was higher in the UTI (42.9%) than control (13.7%) group (P<0.05), with a higher VR severity grade in the UTI (mean, 0.64) than control (mean, 0.18) group (P<0.05). On subanalysis with age-matching (UTI group: n=126, age, 5.28+/-2.13 months; control group: n=22, age, 4.79+/-2.40 months; P=0.33), both VR prevalence (43.65% vs. 18.18%, P<0.05) and grade (0.65 vs. 0.22, P<0.05) remained higher in the UTI than control group. Presence and higher grade of VR were associated with UTI recurrence (P<0.05). VR was correlated to urosepsis (P<0.05). The renal defect rate of patients with VR (VR [+]/VUR [+]) was not different from that of patients without VR (74% vs. 52%, P=0.143) in the VUR group; however, it was higher than that of VR (+)/VUR (-) patients (74% vs. 32%, P=0.001). If a child with VR (+)/VUR (+) is exposed to a UTI, the risk of renal defect increases. Conclusion: Occurrence of VR is associated with UTI recurrence and urosepsis in pediatric female patients. PMID- 29441109 TI - Diagnostic accuracy of urinary biomarkers in infants younger than 3 months with urinary tract infection. AB - Purpose: The aim of this study was to evaluate the diagnostic accuracy of urinary biomarkers, such as neutrophil gelatinase-associated lipocalin (uNGAL) and beta-2 microglobulin (uB2MG), in early detection of urinary tract infection (UTI) in infants aged <3 months with fever. Methods: A total of 422 infants aged <3 months (male:female=267:155; mean age, 56.4 days), who were admitted for fever, were retrospectively included in this study. We compared uNGAL and uB2MG between the UTI and non-UTI groups at the time of admission. The sensitivity, specificity, accuracy, and area under the curve (AUC) of uNGAL and uB2MG for use in diagnosing UTI were assessed. Results: Among 422 patients, 102 (24.2%) were diagnosed with UTI. Levels of uNGAL were higher in the UTI group than in the non-UTI group (366.6 ng/mL vs. 26.9 ng/mL, P<0.001). Levels of uB2MG were not different between the 2 groups. Multivariate analysis revealed that uNGAL was an independent predictive factor for UTI (P=0.033). The sensitivity, specificity, and accuracy were 90.2%, 92.5%, and 91.9% for uNGAL, and 48.0%, 43.8%, and 44.8% for uB2MG, respectively. AUC of uNGAL was 0.942 and that of uB2MG was 0.407. Conclusion: Accuracy of uNGAL in the diagnosis of UTI is high in febrile infants aged <3 months. uNGAL can help in the early diagnosis and treatment of UTI in infants. PMID- 29441110 TI - Case of mucinous adenocarcinoma of the lung associated with congenital pulmonary airway malformation in a neonate. AB - Congenital pulmonary airway malformation (CPAM), previously known as congenital cystic adenomatoid malformation, is a rare developmental lung abnormality associated with rhabdomyosarcoma, pleuropulmonary blastoma, and mucinous adenocarcinoma of the lung. We report an unusual case of a 10-day-old male newborn with a left lower lobe pulmonary cyst who underwent lobectomy, which revealed type II CPAM complicated by multifocal mucinous adenocarcinoma. KRAS sequencing revealed a somatic mutation in Codon12 (GGT -> GAT), suggesting the development of a mucinous adenocarcinoma in the background of mucinous metaplasia. Mucinous adenocarcinoma is the most common lung tumor associated with CPAM, but it generally occurs in older children and adults. Further, all cases in the literature are of type I CPAM. This case in a neonate indicates that malignant transformation can occur very early in type II CPAM. PMID- 29441111 TI - Commentary on "Megalencephaly-capillary malformation-polymicrogyria syndrome: the first case report in Korea". PMID- 29441112 TI - Qingxuan Jiangya Decoction Mitigates Renal Interstitial Fibrosis in Spontaneously Hypertensive Rats by Regulating Transforming Growth Factor-beta1/Smad Signaling Pathway. AB - Qingxuan Jiangya Decoction (QXJYD) is a traditional Chinese medicine commonly used in the clinical treatment of hypertension. Earlier studies had shown that QXJYD could inhibit the elevation of blood pressure in spontaneously hypertensive rats (SHRs) and prevent remodeling of arterial vessels. This study examines the therapeutic efficacy of QXJYD against elevated blood pressure using the SHR model, as well as the mechanisms behind its antihypertensive activity and protection against renal fibrosis. The results showed that QXJYD significantly attenuated the increase in blood pressure in SHRs and mitigated the development of renal interstitial fibrosis. In addition, QXJYD also robustly decreased the excess accumulation of extracellular matrix and attenuated the elevated expression of MMPs. The antihypertensive effects and renal protection of QXJYD were determined to be strongly associated with inhibition of TGF-beta1/Smad signaling pathway. PMID- 29441113 TI - In Vivo and In Vitro Evaluation of Pharmacological Potentials of Secondary Bioactive Metabolites of Dalbergia candenatensis Leaves. AB - Background. Dalbergia species has wide range of secondary metabolites and is traditionally used in treatment of painful micturition, swelling, and leprosy and as blood tonic. The study evaluates membrane stabilizing, anticoagulant, analgesic, cytotoxic, subacute anti-inflammatory, and depression potentials of D. candenatensis leaves metabolites. Methods. Membrane stabilizing activity was evaluated by hypotonic induced hemolysis assay, whereas anticoagulant activity is done through extrinsic pathway by measuring prothrombin time. Analgesic action, cytotoxic effect, and subacute anti-inflammatory activity were determined by acetic acid induced writhing model, brine shrimp lethality bioassay, and formaldehyde induced model, respectively. Depression activity was measured by the Open Field, Hole Cross, Hole Board, and thiopentone induced sleeping time measuring methods. Results. D. candenatensis contains phenolic, flavonoid, and tannin, quantified as 416.25 mg, 330.00 mg, and 432.22 mg Gallic Acid Equivalent/100 g of dry extract, respectively. Extract showed maximum inhibition of writhe, hemolysis, and edema, approximate to 57.14%, 36.62%, and 34.1%, respectively. LC50 value for nauplii was 151.499 MUg/ml. Mean prothrombin time was approximate to 31.0 +/- 2.31 seconds at 1.0 mg/ml. Extract showed depression activity, and maximum sleeping time was noted to be about 141 minutes. Conclusion. D. candenatensis leaves show dose dependent membrane stabilizing, anticoagulant, depression, analgesic, moderate cytotoxic, and subacute anti inflammatory activities. PMID- 29441114 TI - Chuna (or Tuina) Manual Therapy for Musculoskeletal Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Objective: To review the literature and systematically evaluate the effectiveness of Chuna (or Tuina) manual therapy (C[T]MT) on pain and function for musculoskeletal disorders. Methods: We searched 15 English, Chinese, Japanese, and Korean databases using relevant keywords. All randomized controlled trials (RCTs) of C(T)MT for musculoskeletal disorders were considered, and we limited analyses to studies with a low-risk bias for randomization and/or allocation concealment. Results: Sixty-six RCTs with 6,170 participants were included. One sham-controlled RCT showed that C(T)MT relieved pain more effectively than a sham control (SMD -3.09 [-3.59, -2.59]). For active-controlled RCTs, pooled meta analysis showed that C(T)MT had statistically significant effects on pain reduction, especially compared to traction (P < 0.00001), drugs (P = 0.04), and physical therapies (P < 0.0001). For functional improvement, combined effects of C(T)MT with drugs (P = 0.04) and traction (P = 0.05) also showed similar positive effects. Conclusions: This systematic review suggests that C(T)MT is safe and effective for pain reduction and functional improvement for musculoskeletal diseases; however, the evidence for functional improvement was not as strong as for pain reduction. For future studies, high-quality RCTs such as sham-controlled studies with standardized interventions are needed to provide sufficient evidence on the effects of C(T)MT for musculoskeletal diseases. Protocol registration number is CRD42016038307 04/07/2016. PMID- 29441116 TI - Efficacy and Safety of Sipjeondaebo-Tang for Anorexia in Patients with Cancer: A Pilot, Randomized, Double-Blind, Placebo-Controlled Trial. AB - Background: Anorexia occurs in about half of cancer patients and is associated with high mortality rate. However, safe and long-term use of anorexia treatment is still an unmet need. Objective: The purpose of the present study was to examine the feasibility of Sipjeondaebo-tang (Juzen-taiho-to, Shi-Quan-Da-Bu Tang) for cancer-related anorexia. Methods: A total of 32 participants with cancer anorexia were randomized to either Sipjeondaebo-tang group or placebo group. Participants were given 3 g of Sipjeondaebo-tang or placebo 3 times a day for 4 weeks. The primary outcome was a change in the Anorexia/Cachexia Subscale of Functional Assessment of Anorexia/Cachexia Therapy (FAACT). The secondary outcomes included Visual Analogue Scale (VAS) of anorexia, FAACT scale, and laboratory tests. Results: Anorexia and quality of life measured by FAACT and VAS were improved after 4 weeks of Sipjeondaebo-tang treatment. However, there was no significant difference between changes of Sipjeondaebo-tang group and placebo group. Conclusions: Sipjeondaebo-tang appears to have potential benefit for anorexia management in patients with cancer. Further large-scale studies are needed to ensure the efficacy. Trial Registration: This trial is registered with ClinicalTrials.gov NCT02468141. PMID- 29441115 TI - A Herbal Formula HT051, a Combination of Pueraria lobata and Rehmannia glutinosa, Prevents Postmenopausal Obesity in Ovariectomized Rats. AB - Menopause is strongly associated with an increased risk of metabolic dysfunctions due to the decline in estrogen. Here, we hypothesized that dietary HT051, containing the roots of Pueraria lobata and Rehmannia glutinosa, has beneficial effects on ovariectomized (OVX) rats by regulating lipid metabolism. Forty-eight female Sprague-Dawley rats were randomly divided into 4 groups: sham-operated (Sham), OVX, OVX with low-dose HT051 supplementation, and OVX with high-dose HT051 supplementation. The rats were fed with a modified AIN-93G diet or an HT051 containing modified AIN-93G diet for 8 weeks. Body weight, fat mass, and serum levels of total cholesterol, triglyceride, glucose, alanine transaminase, and aspartate transaminase decreased in HT051-fed OVX rats. Dietary HT051 supplementation significantly decreased the mRNA expression of lipogenesis related genes, including sterol regulatory element-binding protein 1c and fatty acid synthase, and increased the mRNA expression of beta-oxidation-related genes, including peroxisome proliferator-activated receptor and carnitine palmitoyl transferase 1 in the liver of OVX rats. Moreover, the expression of genes involved in adipogenesis and inflammation was significantly lower in the adipose tissue of OVX rats fed with HT051 than in the OVX group. These findings suggest that HT051 may be a potential natural alternative for the management of postmenopausal metabolic dysfunctions. PMID- 29441117 TI - Contextual factors in maternal and newborn health evaluation: a protocol applied in Nigeria, India and Ethiopia. AB - Background: Understanding the context of a health programme is important in interpreting evaluation findings and in considering the external validity for other settings. Public health researchers can be imprecise and inconsistent in their usage of the word "context" and its application to their work. This paper presents an approach to defining context, to capturing relevant contextual information and to using such information to help interpret findings from the perspective of a research group evaluating the effect of diverse innovations on coverage of evidence-based, life-saving interventions for maternal and newborn health in Ethiopia, Nigeria, and India. Methods: We define "context" as the background environment or setting of any program, and "contextual factors" as those elements of context that could affect implementation of a programme. Through a structured, consultative process, contextual factors were identified while trying to strike a balance between comprehensiveness and feasibility. Thematic areas included demographics and socio-economics, epidemiological profile, health systems and service uptake, infrastructure, education, environment, politics, policy and governance. We outline an approach for capturing and using contextual factors while maximizing use of existing data. Methods include desk reviews, secondary data extraction and key informant interviews. Outputs include databases of contextual factors and summaries of existing maternal and newborn health policies and their implementation. Use of contextual data will be qualitative in nature and may assist in interpreting findings in both quantitative and qualitative aspects of programme evaluation. Discussion: Applying this approach was more resource intensive than expected, in part because routinely available information was not consistently available across settings and more primary data collection was required than anticipated. Data was used only minimally, partly due to a lack of evaluation results that needed further explanation, but also because contextual data was not available for the precise units of analysis or time periods of interest. We would advise others to consider integrating contextual factors within other data collection activities, and to conduct regular reviews of maternal and newborn health policies. This approach and the learnings from its application could help inform the development of guidelines for the collection and use of contextual factors in public health evaluation. PMID- 29441118 TI - Effect of correcting for gestational age at birth on population prevalence of early childhood undernutrition. AB - Background: Postmenstrual and/or gestational age-corrected age (CA) is required to apply child growth standards to children born preterm (< 37 weeks gestational age). Yet, CA is rarely used in epidemiologic studies in low- and middle-income countries (LMICs), which may bias population estimates of childhood undernutrition. To evaluate the effect of accounting for GA in the application of growth standards, we used GA-specific standards at birth (INTERGROWTH-21st newborn size standards) in conjunction with CA for preterm-born children in the application of World Health Organization Child Growth Standards postnatally (referred to as 'CA' strategy) versus postnatal age for all children, to estimate mean length-for-age (LAZ) and weight-for-age (WAZ) z scores at 0, 3, 12, 24, and 48-months of age in the 2004 Pelotas (Brazil) Birth Cohort. Results: At birth (n = 4066), mean LAZ was higher and the prevalence of stunting (LAZ < -2) was lower using CA versus postnatal age (mean +/- SD): - 0.36 +/- 1.19 versus - 0.67 +/- 1.32; and 8.3 versus 11.6%, respectively. Odds ratio (OR) and population attributable risk (PAR) of stunting due to preterm birth were attenuated and changed inferences using CA versus postnatal age at birth [OR, 95% confidence interval (CI): 1.32 (95% CI 0.95, 1.82) vs 14.7 (95% CI 11.7, 18.4); PAR 3.1 vs 42.9%]; differences in inferences persisted at 3-months. At 12, 24, and 48 months, preterm birth was associated with stunting, but ORs/PARs remained attenuated using CA compared to postnatal age. Findings were similar for weight for-age z scores. Conclusions: Population-based epidemiologic studies in LMICs in which GA is unused or unavailable may overestimate the prevalence of early childhood undernutrition and inflate the fraction of undernutrition attributable to preterm birth. PMID- 29441119 TI - Diagnosis, monitoring and prevention of exposure-related non-communicable diseases in the living and working environment: DiMoPEx-project is designed to determine the impacts of environmental exposure on human health. AB - The WHO has ranked environmental hazardous exposures in the living and working environment among the top risk factors for chronic disease mortality. Worldwide, about 40 million people die each year from noncommunicable diseases (NCDs) including cancer, diabetes, and chronic cardiovascular, neurological and lung diseases. The exposure to ambient pollution in the living and working environment is exacerbated by individual susceptibilities and lifestyle-driven factors to produce complex and complicated NCD etiologies. Research addressing the links between environmental exposure and disease prevalence is key for prevention of the pandemic increase in NCD morbidity and mortality. However, the long latency, the chronic course of some diseases and the necessity to address cumulative exposures over very long periods does mean that it is often difficult to identify causal environmental exposures. EU-funded COST Action DiMoPEx is developing new concepts for a better understanding of health-environment (including gene environment) interactions in the etiology of NCDs. The overarching idea is to teach and train scientists and physicians to learn how to include efficient and valid exposure assessments in their research and in their clinical practice in current and future cooperative projects. DiMoPEx partners have identified some of the emerging research needs, which include the lack of evidence-based exposure data and the need for human-equivalent animal models mirroring human lifespan and low-dose cumulative exposures. Utilizing an interdisciplinary approach incorporating seven working groups, DiMoPEx will focus on aspects of air pollution with particulate matter including dust and fibers and on exposure to low doses of solvents and sensitizing agents. Biomarkers of early exposure and their associated effects as indicators of disease-derived information will be tested and standardized within individual projects. Risks arising from some NCDs, like pneumoconioses, cancers and allergies, are predictable and preventable. Consequently, preventative action could lead to decreasing disease morbidity and mortality for many of the NCDs that are of major public concern. DiMoPEx plans to catalyze and stimulate interaction of scientists with policy-makers in attacking these exposure-related diseases. PMID- 29441121 TI - Simulation of Atrial Fibrosis Using Coupled Myocyte-Fibroblast Cellular and Human Atrial Models. AB - Atrial fibrosis is characterized by expansion of extracellular matrix and increase in the number of fibroblasts which has been associated with the development and maintenance of atrial arrhythmias. However, the mechanisms how the fibrosis contributes to atrial arrhythmia remain incompletely understood. In this study, we used a proposed fibroblast model coupled with the human atrial myocyte to investigate the effects of fibrosis on atrial excitability and repolarization at both cellular and macroscopic levels. The 12-lead electrocardiogram (ECG) was also simulated to explore the index of clinical diagnosis for fibrosis. The simulation results showed that the fibrosis can modify action potential morphology of human atrial myocyte, slow down wave propagation, and have rate adaptation, thus causing the atrial electrical heterogeneity. The fibrosis alone was sufficient to cause arrhythmia, induce reentry wave, and result in low amplitude and wide P waves at normal heart rate and significant prolonged and inverse P waves at high heart rate. All these symptoms aggravated when the level of fibrosis increased. Our simulations demonstrated that fibrosis is the substrate of atrial arrhythmia and thereby may be a potential target in the treatment of atrial arrhythmias. PMID- 29441120 TI - Computational Insight into Protein Tyrosine Phosphatase 1B Inhibition: A Case Study of the Combined Ligand- and Structure-Based Approach. AB - Protein tyrosine phosphatase 1B (PTP1B) is an attractive target for treating cancer, obesity, and type 2 diabetes. In our work, the way of combined ligand- and structure-based approach was applied to analyze the characteristics of PTP1B enzyme and its interaction with competitive inhibitors. Firstly, the pharmacophore model of PTP1B inhibitors was built based on the common feature of sixteen compounds. It was found that the pharmacophore model consisted of five chemical features: one aromatic ring (R) region, two hydrophobic (H) groups, and two hydrogen bond acceptors (A). To further elucidate the binding modes of these inhibitors with PTP1B active sites, four docking programs (AutoDock 4.0, AutoDock Vina 1.0, standard precision (SP) Glide 9.7, and extra precision (XP) Glide 9.7) were used. The characteristics of the active sites were then described by the conformations of the docking results. In conclusion, a combination of various pharmacophore features and the integration information of structure activity relationship (SAR) can be used to design novel potent PTP1B inhibitors. PMID- 29441122 TI - Time-consistent reconciliation maps and forbidden time travel. AB - Background: In the absence of horizontal gene transfer it is possible to reconstruct the history of gene families from empirically determined orthology relations, which are equivalent to event-labeled gene trees. Knowledge of the event labels considerably simplifies the problem of reconciling a gene tree T with a species trees S, relative to the reconciliation problem without prior knowledge of the event types. It is well-known that optimal reconciliations in the unlabeled case may violate time-consistency and thus are not biologically feasible. Here we investigate the mathematical structure of the event labeled reconciliation problem with horizontal transfer. Results: We investigate the issue of time-consistency for the event-labeled version of the reconciliation problem, provide a convenient axiomatic framework, and derive a complete characterization of time-consistent reconciliations. This characterization depends on certain weak conditions on the event-labeled gene trees that reflect conditions under which evolutionary events are observable at least in principle. We give an [Formula: see text]-time algorithm to decide whether a time-consistent reconciliation map exists. It does not require the construction of explicit timing maps, but relies entirely on the comparably easy task of checking whether a small auxiliary graph is acyclic. The algorithms are implemented in C++ using the boost graph library and are freely available at https://github.com/Nojgaard/tc-recon. Significance: The combinatorial characterization of time consistency and thus biologically feasible reconciliation is an important step towards the inference of gene family histories with horizontal transfer from orthology data, i.e., without presupposed gene and species trees. The fast algorithm to decide time consistency is useful in a broader context because it constitutes an attractive component for all tools that address tree reconciliation problems. PMID- 29441123 TI - Circulation first - the time has come to question the sequencing of care in the ABCs of trauma; an American Association for the Surgery of Trauma multicenter trial. AB - Background: The traditional sequence of trauma care: Airway, Breathing, Circulation (ABC) has been practiced for many years. It became the standard of care despite the lack of scientific evidence. We hypothesized that patients in hypovolemic shock would have comparable outcomes with initiation of bleeding treatment (transfusion) prior to intubation (CAB), compared to those patients treated with the traditional ABC sequence. Methods: This study was sponsored by the American Association for the Surgery of Trauma multicenter trials committee. We performed a retrospective analysis of all patients that presented to trauma centers with presumptive hypovolemic shock indicated by pre-hospital or emergency department hypotension and need for intubation from January 1, 2014 to July 1, 2016. Data collected included demographics, timing of intubation, vital signs before and after intubation, timing of the blood transfusion initiation related to intubation, and outcomes. Results: From 440 patients that met inclusion criteria, 245 (55.7%) received intravenous blood product resuscitation first (CAB), and 195 (44.3%) were intubated before any resuscitation was started (ABC). There was no difference in ISS, mechanism, or comorbidities. Those intubated prior to receiving transfusion had a lower GCS than those with transfusion initiation prior to intubation (ABC: 4, CAB:9, p = 0.005). Although mortality was high in both groups, there was no statistically significant difference (CAB 47% and ABC 50%). In multivariate analysis, initial SBP and initial GCS were the only independent predictors of death. Conclusion: The current study highlights that many trauma centers are already initiating circulation first prior to intubation when treating hypovolemic shock (CAB), even in patients with a low GCS. This practice was not associated with an increased mortality. Further prospective investigation is warranted. Trial registration: IRB approval number: HM20006627. Retrospective trial not registered. PMID- 29441124 TI - Re-direction of carbon flux to key precursor malonyl-CoA via artificial small RNAs in photosynthetic Synechocystis sp. PCC 6803. AB - Background: Photosynthetic cyanobacteria have attracted a significant attention as promising chassis to produce renewable fuels and chemicals due to their capability to utilizing solar energy and CO2. Notably, the enhancing supply of key precursors like malonyl-CoA would benefit the production of many bio compounds. Nevertheless, the lacking of genetic tools in cyanobacteria, especially the knockdown strategies for essential pathways, has seriously restricted the attempts to re-direct carbon flux from the central carbohydrate metabolism to the synthesis of bioproducts. Results: Aiming at developing new genetic tools, two small RNA regulatory tools are reported for the model cyanobacterium Synechocystis sp. PCC6803, based on paired termini RNAs as well as the exogenous Hfq chaperone and MicC scaffold (Hfq-MicC) previously developed in Escherichia coli. Both regulatory tools functioned well in regulating exogenous reporter gene lacZ and endogenous glgC gene in Synechocystis sp. PCC6803, achieving a downregulation of gene expression up to 90% compared with wildtype. In addition, the Hfq-MicC tool was developed to simultaneously regulate multiple genes related to essential fatty acids biosynthesis, which led to decreased fatty acids content by 11%. Furthermore, aiming to re-direct the carbon flux, the Hfq MicC tool was utilized to interfere the competing pathway of malonyl-CoA, achieving an increased intracellular malonyl-CoA abundance up to 41% (~ 698.3 pg/mL/OD730 nm) compared to the wildtype. Finally, the Hfq-MicC system was further modified into an inducible system based on the theophylline-inducible riboswitch. Conclusions: In this study, two small RNA regulatory tools for manipulating essential metabolic pathways and re-directing carbon flux are reported for Synechocystis sp. PCC6803. The work introduces efficient and valuable metabolic regulatory strategies for photosynthetic cyanobacteria. PMID- 29441125 TI - SACCHARIS: an automated pipeline to streamline discovery of carbohydrate active enzyme activities within polyspecific families and de novo sequence datasets. AB - Background: Deposition of new genetic sequences in online databases is expanding at an unprecedented rate. As a result, sequence identification continues to outpace functional characterization of carbohydrate active enzymes (CAZymes). In this paradigm, the discovery of enzymes with novel functions is often hindered by high volumes of uncharacterized sequences particularly when the enzyme sequence belongs to a family that exhibits diverse functional specificities (i.e., polyspecificity). Therefore, to direct sequence-based discovery and characterization of new enzyme activities we have developed an automated in silico pipeline entitled: Sequence Analysis and Clustering of CarboHydrate Active enzymes for Rapid Informed prediction of Specificity (SACCHARIS). This pipeline streamlines the selection of uncharacterized sequences for discovery of new CAZyme or CBM specificity from families currently maintained on the CAZy website or within user-defined datasets. Results: SACCHARIS was used to generate a phylogenetic tree of a GH43, a CAZyme family with defined subfamily designations. This analysis confirmed that large datasets can be organized into sequence clusters of manageable sizes that possess related functions. Seeding this tree with a GH43 sequence from Bacteroides dorei DSM 17855 (BdGH43b, revealed it partitioned as a single sequence within the tree. This pattern was consistent with it possessing a unique enzyme activity for GH43 as BdGH43b is the first described alpha-glucanase described for this family. The capacity of SACCHARIS to extract and cluster characterized carbohydrate binding module sequences was demonstrated using family 6 CBMs (i.e., CBM6s). This CBM family displays a polyspecific ligand binding profile and contains many structurally determined members. Using SACCHARIS to identify a cluster of divergent sequences, a CBM6 sequence from a unique clade was demonstrated to bind yeast mannan, which represents the first description of an alpha-mannan binding CBM. Additionally, we have performed a CAZome analysis of an in-house sequenced bacterial genome and a comparative analysis of B. thetaiotaomicron VPI-5482 and B. thetaiotaomicron 7330, to demonstrate that SACCHARIS can generate "CAZome fingerprints", which differentiate between the saccharolytic potential of two related strains in silico. Conclusions: Establishing sequence-function and sequence-structure relationships in polyspecific CAZyme families are promising approaches for streamlining enzyme discovery. SACCHARIS facilitates this process by embedding CAZyme and CBM family trees generated from biochemically to structurally characterized sequences, with protein sequences that have unknown functions. In addition, these trees can be integrated with user-defined datasets (e.g., genomics, metagenomics, and transcriptomics) to inform experimental characterization of new CAZymes or CBMs not currently curated, and for researchers to compare differential sequence patterns between entire CAZomes. In this light, SACCHARIS provides an in silico tool that can be tailored for enzyme bioprospecting in datasets of increasing complexity and for diverse applications in glycobiotechnology. PMID- 29441127 TI - Time-series lipidomic analysis of the oleaginous green microalga species Ettlia oleoabundans under nutrient stress. AB - Background: Microalgae are uniquely advantageous organisms cultured and harvested for several value-added biochemicals. A majority of these compounds are lipid based, such as triacylglycerols (TAGs), which can be used for biofuel production, and their accumulation is most affected under nutrient stress conditions. As such, the balance between cellular homeostasis and lipid metabolism becomes more intricate to achieve efficiency in bioproduct synthesis. Lipidomics studies in microalgae are of great importance as biochemical diversity also plays a major role in lipid regulation among oleaginous species. Methods: The aim of this study was to analyze time-series changes in lipid families produced by microalga under different nutrient conditions and growth phases to gain comprehensive information at the cellular level. For this purpose, we worked with a highly adaptable, oleaginous, non-model green microalga species, Ettlia oleoabundans (a.k.a. Neochloris oleoabundans). Using a mass spectrometry-based untargeted and targeted metabolomics' approach, we analyzed the changes in major lipid families under both replete and deplete nitrogen and phosphorus conditions at four different time points covering exponential and stationary growth phases. Results: Comprehensive analysis of the lipid metabolism highlighted the accumulation of TAGs, which can be utilized for the production of biodiesel via transesterification, and depletion of chlorophylls and certain structural lipids required for photosynthesis, under nutrient deprived conditions. We also found a correlation between the depletion of digalactosyldiacylglycerols (DGDGs) and sulfoquinovosyldiacylglycerols (SQDGs) under nutrient deprivation. Conclusions: High accumulation of TAGs under nutrient limitation as well as a depletion of other lipids of interest such as phosphatidylglycerols (PGs), DGDGs, SQDGs, and chlorophylls seem to be interconnected and related to the microalgal photosynthetic efficiency. Overall, our results provided key biochemical information on the lipid regulation and physiology of a non-model green microalga, along with optimization potential for biodiesel and other value-added product synthesis. PMID- 29441126 TI - Association of improved oxidative stress tolerance and alleviation of glucose repression with superior xylose-utilization capability by a natural isolate of Saccharomyces cerevisiae. AB - Background: Saccharomyces cerevisiae wild strains generally have poor xylose utilization capability, which is a major barrier for efficient bioconversion of lignocellulosic biomass. Laboratory adaption is commonly used to enhance xylose utilization of recombinant S. cerevisiae. Apparently, yeast cells could remodel the metabolic network for xylose metabolism. However, it still remains unclear why natural isolates of S. cerevisiae poorly utilize xylose. Here, we analyzed a unique S. cerevisiae natural isolate YB-2625 which has superior xylose metabolism capability in the presence of mixed-sugar. Comparative transcriptomic analysis was performed using S. cerevisiae YB-2625 grown in a mixture of glucose and xylose, and the model yeast strain S288C served as a control. Global gene transcription was compared at both the early mixed-sugar utilization stage and the latter xylose-utilization stage. Results: Genes involved in endogenous xylose assimilation (XYL2 and XKS1), gluconeogenesis, and TCA cycle showed higher transcription levels in S. cerevisiae YB-2625 at the xylose-utilization stage, when compared to the reference strain. On the other hand, transcription factor encoding genes involved in regulation of glucose repression (MIG1, MIG2, and MIG3) as well as HXK2 displayed decreased transcriptional levels in YB-2625, suggesting the alleviation of glucose repression of S. cerevisiae YB-2625. Notably, genes encoding antioxidant enzymes (CTT1, CTA1, SOD2, and PRX1) showed higher transcription levels in S. cerevisiae YB-2625 in the xylose-utilization stage than that of the reference strain. Consistently, catalase activity of YB 2625 was 1.9-fold higher than that of S. cerevisiae S288C during the xylose utilization stage. As a result, intracellular reactive oxygen species levels of S. cerevisiae YB-2625 were 43.3 and 58.6% lower than that of S288C at both sugar utilization stages. Overexpression of CTT1 and PRX1 in the recombinant strain S. cerevisiae YRH396 deriving from S. cerevisiae YB-2625 increased cell growth when xylose was used as the sole carbon source, leading to 13.5 and 18.1%, respectively, more xylose consumption. Conclusions: Enhanced oxidative stress tolerance and relief of glucose repression are proposed to be two major mechanisms for superior xylose utilization by S. cerevisiae YB-2625. The present study provides insights into the innate regulatory mechanisms underlying xylose utilization in wild-type S. cerevisiae, which benefits the rapid development of robust yeast strains for lignocellulosic biorefineries. PMID- 29441128 TI - Chromosomal microarray analysis in the genetic evaluation of 279 patients with syndromic obesity. AB - Background: Syndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study. The aim of this study was to characterize the CNVs detected by CMA in 279 patients with a syndromic obesity phenotype. Results: Pathogenic CNVs were detected in 61 patients (22%) and, among them, 35 had overlapping/recurrent CNVs. Genomic imbalance disorders known to cause syndromic obesity were found in 8.2% of cases, most commonly deletions of 1p36, 2q37 and 17p11.2 (5.4%), and we also detected deletions at 1p21.3, 2p25.3, 6q16, 9q34, 16p11.2 distal and proximal, as well as an unbalanced translocation resulting in duplication of the GNB3 gene responsible for a syndromic for of childhood obesity. Deletions of 9p terminal and 22q11.2 proximal/distal were found in 1% and 3% of cases, respectively. They thus emerge as being new putative obesity-susceptibility loci. We found additional CNVs in our study that overlapped with CNVs previously reported in cases of syndromic obesity, including a new case of 13q34 deletion (CHAMP1), bringing to 7 the number of patients in whom such defects have been described in association with obesity. Our findings implicate many genes previously associated with obesity (e.g. PTBP2, TMEM18, MYT1L, POU3F2, SIM1, SH2B1), and also identified other potentially relevant candidates including TAS1R3, ALOX5AP, and GAS6. Conclusion: Understanding the genetics of obesity has proven difficult, and considerable insight has been obtained from the study of genomic disorders with obesity associated as part of the phenotype. In our study, CNVs known to be causal for syndromic obesity were detected in 8.2% of patients, but we provide evidence for a genetic basis of obesity in as many as 14% of cases. Overall, our results underscore the genetic heterogeneity in syndromic forms of obesity, which imposes a substantial challenge for diagnosis. PMID- 29441130 TI - Cytogenetics and stripe rust resistance of wheat-Thinopyrum elongatum hybrid derivatives. AB - Background: Amphidiploids generated by distant hybridization are commonly used as genetic bridge to transfer desirable genes from wild wheat species into cultivated wheat. This method is typically used to enhance the resistance of wheat to biotic or abiotic stresses, and to increase crop yield and quality. Tetraploid Thinopyrum elongatum exhibits strong adaptability, resistance to stripe rust and Fusarium head blight, and tolerance to salt, drought, and cold. Results: In the present study, we produced hybrid derivatives by crossing and backcrossing the Triticum durum-Th. elongatum partial amphidiploid (Trititrigia 8801, 2n = 6* = 42, AABBEE) with wheat cultivars common to the Sichuan Basin. By means of cytogenetic and disease resistance analyses, we identified progeny harboring alien chromosomes and measured their resistance to stripe rust. Hybrid progenies possessed chromosome numbers ranging from 40 to 47 (mean = 42.72), with 40.0% possessing 42 chromosomes. Genomic in situ hybridization revealed that the number of alien chromosomes ranged from 1 to 11. Out of the 50 of analyzed lines, five represented chromosome addition (2n = 44 = 42 W + 2E) and other five were chromosome substitution lines (2n = 42 = 40 W + 2E). Importantly, a single chromosome derived from wheat-Th. elongatum intergenomic Robertsonian translocations chromosome was occurred in 12 lines. Compared with the wheat parental cultivars ('CN16' and 'SM482'), the majority (70%) of the derivative lines were highly resistant to strains of stripe rust pathogen known to be prevalent in China. Conclusion: The findings suggest that these hybrid-derivative lines with stripe rust resistance could potentially be used as germplasm sources for further wheat improvement. PMID- 29441129 TI - Rare partial octosomy and hexasomy of 15q11-q13 associated with intellectual impairment and development delay: report of two cases and review of literature. AB - Background: Small supernumerary marker chromosomes (sSMCs) are common structurally abnormal chromosomes that occur in 0.288% of cases of mental retardation. Isodicentric 15 (idic(15)) is common in sSMCs and usually leads to a rare chromosome disorder with distinctive clinical phenotypes, including early central hypotonia, developmental delay, epilepsy, and autistic behavior. It was previously shown that the partial tetrasomy 15q and partial hexasomy 15q syndromes are usually caused by one and two extra idic(15), respectively. Karyotypes containing a mosaic partial octosomy 15q resulting from three extra idic(15) have rarely been reported. Case presentation: Two patients with profound intellectual impairment, development delay and hyperpigmentation were recruited for this study. The phenotype was relatively more severe in patient 1 than in patient 2. Conventional cytogenetic analysis of peripheral blood obtained from patients 1 and 2 revealed rare mosaic karyotypes containing sSMCs, i.e., mos 49,XX,+mar * 3[83]/48,XX,+mar * 2[7]/46,XX[10] and mos 48,XX,+mar * 2[72]/47,XX,+mar[28], respectively. The results of analyses of copy number variation (CNV) and fluorescence in situ hybridization (FISH) analyses, showed that the sSMCs were found to be idic(15) involving the Prader-Willi/Angelman Syndrome Critical Region (PWACR) genes and the P gene, with duplication sizes of 6.3 Mb and 9.7 Mb, respectively. DNA fingerprinting analysis of patient 1 showed a maternal origin for the idic(15). Both patients had mosaic idic(15) karyotypes: patient 1 had cells with a 15q partial octosomy (83%), and patient 2 had cells with a 15q partial hexasomy (72%). Conclusions: We detected two rare mosaic idic(15) karyotypes that were associated with congenital abnormalities, including a rare mosaic octosomy of 15q11-q13. Our cases further validate the notion that the phenotypic severity is correlated with the level of mosaicism and the dosage effect of related genes in the proximal 15q. PMID- 29441131 TI - Centre of pressure characteristics in normal, planus and cavus feet. AB - Background: The aim of this study was to compare centre of pressure (COP) characteristics between healthy adults with normal, planus or cavus feet who were allocated to groups based on reliable foot posture measurement techniques. Methods: Ninety-two healthy adult participants (aged 18 to 45) were recruited and classified as either normal (n = 35), pes planus (n = 31) or pes cavus (n = 26) based on Foot Posture Index, Arch Index and normalised navicular height truncated measurements. Barefoot walking trials were conducted using an emed(r)-x 400 plantar pressure system (Novel GmbH, Munich, Germany). Average, maximum, minimum and range (difference between maximum and minimum) values were calculated for COP velocity and lateral-medial force index during loading response, midstance, terminal stance and pre-swing phases of stance. The COP excursion index was also calculated. One-way analyses of variance were used to compare the three foot posture groups. Results: The cavus foot exhibited the slowest average and minimum COP velocity during terminal stance, but this pattern was reversed during pre swing, when the cavus foot exhibited the fastest maximum COP velocity. The planus foot exhibited the smallest lateral medial force index range during terminal stance. There were no differences between the groups for COP excursion index. Conclusion: These findings indicate that there are differences in COP characteristics between foot postures, which may represent different mechanisms for generating force to facilitate forward progression of the body during the propulsive phases of gait. PMID- 29441133 TI - Polarization spectroscopy methods in the determination of interactions of small molecules with nucleic acids - tutorial. AB - The structural characterization of non-covalent complexes between nucleic acids and small molecules (ligands) is of a paramount significance to bioorganic research. Highly informative methods about nucleic acid/ligand complexes such as single crystal X-ray diffraction or NMR spectroscopy cannot be performed under biologically compatible conditions and are extensively time consuming. Therefore, in search for faster methods which can be applied to conditions that are at least similar to the naturally occurring ones, a set of polarization spectroscopy methods has shown highly promising results. Electronic circular dichroism (ECD) is the most commonly used method for the characterization of the helical structure of DNA and RNA and their complexes with ligands. Less common but complementary to ECD, is flow-oriented linear dichroism (LD). Other methods such as vibrational CD (VCD) and emission-based methods (FDCD, CPL), can also be used for suitable samples. Despite the popularity of polarization spectroscopy in biophysics, aside several highly focused reviews on the application of these methods to DNA/RNA research, there is no systematic tutorial covering all mentioned methods as a tool for the characterization of adducts between nucleic acids and small ligands. This tutorial aims to help researchers entering the research field to organize experiments accurately and to interpret the obtained data reliably. PMID- 29441134 TI - Stereochemical outcomes of C-F activation reactions of benzyl fluoride. AB - In recent years, the highly polar C-F bond has been utilised in activation chemistry despite its low reactivity to traditional nucleophiles, when compared to other C-X halogen bonds. Paquin's group has reported extensive studies on the C-F activation of benzylic fluorides for nucleophilic substitutions and Friedel Crafts reactions, using a range of hydrogen bond donors such as water, triols or hexafluoroisopropanol (HFIP) as the activators. This study examines the stereointegrity of the C-F activation reaction through the use of an enantiopure isotopomer of benzyl fluoride to identify whether the reaction conditions favour a dissociative (SN1) or associative (SN2) pathway. [2H]-Isotopomer ratios in the reactions were assayed using the Courtieu 2H NMR method in a chiral liquid crystal (poly-gamma-benzyl-L-glutamate) matrix and demonstrated that both associative and dissociative pathways operate to varying degrees, according to the nature of the nucleophile and the hydrogen bond donor. PMID- 29441132 TI - Association of zygotic piRNAs derived from paternal P elements with hybrid dysgenesis in Drosophila melanogaster. AB - Background: P-element transposition in the genome causes P-M hybrid dysgenesis in Drosophila melanogaster. Maternally deposited piRNAs suppress P-element transposition in the progeny, linking them to P-M phenotypes; however, the role of zygotic piRNAs derived from paternal P elements is poorly understood. Results: To elucidate the molecular basis of P-element suppression by zygotic factors, we investigated the genomic constitution and P-element piRNA production derived from fathers. As a result, we characterized males of naturally derived Q, M' and P strains, which show different capacities for the P-element mobilizations introduced after hybridizations with M-strain females. The amounts of piRNAs produced in ovaries of F1 hybrids varied among the strains and were influenced by the characteristics of the piRNA clusters that harbored the P elements. Importantly, while both the Q- and M'-strain fathers restrict the P-element mobilization in ovaries of their daughters, the Q-strain fathers supported the production of the highest piRNA expression in the ovaries of their daughters, and the M' strain carries KP elements in transcriptionally active regions directing the highest expression of KP elements in their daughters. Interestingly, the zygotic P-element piRNAs, but not the KP element mRNA, contributed to the variations in P transposition immunity in the granddaughters. Conclusions: The piRNA-cluster-embedded P elements and the transcriptionally active KP elements from the paternal genome are both important suppressors of P element activities that are co-inherited by the progeny. Expression levels of the P-element piRNA and KP-element mRNA vary among F1 progeny due to the constitution of the paternal genome, and are involved in phenotypic variation in the subsequent generation. PMID- 29441136 TI - Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines - a novel total synthesis of the alkaloid 7-hydroxy-6 methoxy-1-methylisoquinoline. AB - Highly-substituted isoquinolines are important scaffolds in syntheses of natural products and in drug development and hence, effective synthetic approaches are required. Here we present a novel method for the introduction of a methyl group at C1 of isoquinolines. This is exemplified by a new total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline. Direct metalation of 7 benzyloxy-6-methoxyisoquinoline with Knochel-Hauser base, followed by cuprate mediated methylation gives the target alkaloid directly, but separation from the educt is cumbersome. Quenching the metalated intermediate with Eschenmoser's reagent gives an easy to clean tertiary benzylamine, which, after quaternization with iodomethane, is easily converted into the desired 1-methylisoquinoline by hydrogenolysis of both the benzylamine and benzyl ether groups. PMID- 29441135 TI - Fluorescent nucleobase analogues for base-base FRET in nucleic acids: synthesis, photophysics and applications. AB - Forster resonance energy transfer (FRET) between a donor nucleobase analogue and an acceptor nucleobase analogue, base-base FRET, works as a spectroscopic ruler and protractor. With their firm stacking and ability to replace the natural nucleic acid bases inside the base-stack, base analogue donor and acceptor molecules complement external fluorophores like the Cy-, Alexa- and ATTO-dyes and enable detailed investigations of structure and dynamics of nucleic acid containing systems. The first base-base FRET pair, tCO-tCnitro, has recently been complemented with among others the adenine analogue FRET pair, qAN1-qAnitro, increasing the flexibility of the methodology. Here we present the design, synthesis, photophysical characterization and use of such base analogues. They enable a higher control of the FRET orientation factor, kappa2, have a different distance window of opportunity than external fluorophores, and, thus, have the potential to facilitate better structure resolution. Netropsin DNA binding and the B-to-Z-DNA transition are examples of structure investigations that recently have been performed using base-base FRET and that are described here. Base-base FRET has been around for less than a decade, only in 2017 expanded beyond one FRET pair, and represents a highly promising structure and dynamics methodology for the field of nucleic acids. Here we bring up its advantages as well as disadvantages and touch upon potential future applications. PMID- 29441137 TI - Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales). AB - The volatiles from the fungus Daldinia clavata were collected by use of a closed loop stripping apparatus and analysed by GC-MS. A few compounds were readily identified by comparison of measured to library mass spectra and of retention indices to published data, while for other compounds a synthesis of references was required. For one of the main compounds, 5-hydroxy-4,6-dimethyloctan-3-one, the relative and absolute configuration was determined by synthesis of all eight stereoisomers and gas chromatographic analysis using a homochiral stationary phase. Another identified new natural product is 6-nonyl-2H-pyran-2-one. The antimicrobial and cytotoxic effects of the synthetic volatiles are also reported. PMID- 29441138 TI - Gram-scale preparation of negative-type liquid crystals with a CF2CF2-carbocycle unit via an improved short-step synthetic protocol. AB - Herein, we demonstrate an improved short-step protocol for the synthesis of multicyclic molecules having a CF2CF2-containing cyclohexadiene or cyclohexane framework in a mesogenic structure. These molecules are promising candidates for vertical alignment (VA)-mode liquid crystal (LC) display devices owing to their large negative dielectric constant. The tetrafluorinated multicyclic molecules were successfully obtained in only five or six reaction steps without the need for special handling techniques, as is generally required for thermally unstable organometallic species, representing a reduction of three reaction steps. The improved short-step synthetic protocol was also amenable to the multigram preparation of these promising molecules, which may contribute significantly to the development of novel negative-type LC molecules containing CF2CF2 carbocycles. PMID- 29441139 TI - Progress in copper-catalyzed trifluoromethylation. AB - The introduction of trifluoromethyl groups into organic molecules has attracted great attention in the past five years. In this review, we describe the recent efforts in the development of trifluoromethylation via copper catalysis using nucleophilic, electrophilic or radical trifluoromethylation reagents. PMID- 29441140 TI - Nucleophilic fluoroalkylation/cyclization route to fluorinated phthalides. AB - Discribed in this article is a versatile and practical method for the synthesis of C3-perfluoroalkyl-substituted phthalides in a one-pot manner. Upon treatment of KF or triethylamine, 2-cyanobenzaldehyde reacted with (perfluoroalkyl)trimethylsilanes via nucleophilic addition and subsequent intramolecular cyclization to give perfluoroalkylphthalides in good yields. PMID- 29441141 TI - Synthesis and spectroscopic properties of beta-meso directly linked porphyrin corrole hybrid compounds. AB - The preparation of beta-meso directly linked porphyrin-corrole hybrids was realized for the first time via an InCl3-catalyzed condensation reaction of 2 formyl-5,10,15,20-tetraphenylporphyrins with meso-substituted dipyrromethanes. Hybrid compounds have been characterized by 1H NMR, 13C NMR, 2D NMR, UV-vis absorption and fluorescence spectroscopy. PMID- 29441142 TI - Transition-metal-free [3 + 3] annulation of indol-2-ylmethyl carbanions to nitroarenes. A novel synthesis of indolo[3,2-b]quinolines (quindolines). AB - Indol-2-ylmethyl carbanions stabilized by alkoxycarbonyl, cyano or benzenesulfonyl groups react with nitroarenes to form sigmaH-adducts, which in the presence of base (triethylamine or DBU) and trimethylchlorosilane transform into indolo[3,2-b]quinoline derivatives in moderate to good yields. PMID- 29441143 TI - 5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines. AB - The condensation of 5-aminopyrazole with various bielectrophilic moieties results in the formation of pyrazoloazines, an interesting array of fused heterocyclic systems. The development of new synthetic routes towards pyrazoloazines for their biological and medicinal exploration is an attractive area for researchers throughout the world. The present review focuses on various synthetic methods developed in the last decade for the synthesis of differently substituted pyrazoloazines by a broad range of organic reactions by means of 5-aminopyrazole as a precursor. PMID- 29441144 TI - One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates. AB - Herein, we describe a novel approach for the practical synthesis of tetrasubstituted thiophenes 8. The developed method was particularly used for the facile preparation of thienyl heterocycles 8. The mechanism for this reaction is based on the formation of a sulfur ylide-like intermediate. It was clearly suggested by (i) the intramolecular cyclization of ketene N,S-acetals 7 to the corresponding thiophenes 8, (ii) 1H NMR studies of Meldrum's acid-substituted aminothioacetals 9, and (iii) substitution studies of the methoxy group on Meldrum's acid containing N,S-acetals 9b. Notably, in terms of structural effects on the reactivity and stability of sulfur ylide-like intermediates, 2-pyridyl substituted compound 7a exhibited superior properties over those of others. PMID- 29441147 TI - Food protein-induced enterocolitis syndrome: a review of the new guidelines. AB - Food protein-induced enterocolitis syndrome (FPIES) is a non IgE-mediated gastrointestinal food allergy that presents with delayed vomiting after ingestion primarily in infants. While the pathophysiology of FPIES is poorly understood, the clinical presentation of acute FPEIS reactions has been well characterized. The first International Consensus Guidelines for the Diagnosis and Management of Food Protein-induced Enterocolitis Syndrome were published in 2017 and reviewed epidemiology, clinical presentation, and prognosis of acute and chronic FPIES. The workgroup outlined clinical phenotypes, proposed diagnostic criteria, and made recommendations on management. This article summarizes the guidelines and adds recent updates. FPIES is gaining recognition, however there continues to be delays in diagnosis and misdiagnosis due to overlap of symptoms with over conditions, lack of a diagnostic test, and because some of the common trigger foods are not thought of as allergenic. More research into disease mechanisms and factors influencing differences between populations is needed. PMID- 29441146 TI - Vespa crabro immunotherapy versus Vespula-venom immunotherapy in Vespa crabro allergy: a comparison study in field re-stings. AB - Background: In ascertained allergic sensitization to Vespa crabro (VC) venom, the European guidelines still consider venom immunotherapy (VIT) with Vespula (VE) venom sufficient to achieve an adequate protection against VC. However, antigen 5 immunoblotting studies showed that a genuine sensitization to VC venom may exist. In such cases, a specific VC venom would be preferable for VIT treatment. Since in the last few years, VC venom extracts became available for diagnosis and desensitization, we assessed the efficacy and safety of VIT with a VC-VIT, compared to VE extract. Methods: Patients stung by VC, and carefully diagnosed for specific sensitization and indication to VIT underwent a 5-year course of immunotherapy with either VE or VC extracts. The severity of reactions at the first sting (pre-VIT) and after field re-stings (during VIT) were compared. Results: Eighty-three patients, treated with VE extract and 130 patients treated with VC extract completed the 5-year course of VIT. Only a fraction of those patients (43,8%) were field-re-stung by VC: 64 patients on VC VIT and 69 on VE VIT. In the VC VIT group, reactions at re-sting were: 50 negative, 12 large local reactions, 4 systemic reactions (Muller grade I). In this group the VC VIT efficacy was 93,8%. In the VE VIT treated group the reactions at VC re-sting were: 51 negative, 10 large local reactions and 9 systemic reactions (5 Muller I, 3 Mueller III, 1 Muller IV). In this group the overall efficacy of VIT was 87,0%. The difference in efficacy between the two groups was not statistically significant, as previously reported in literature. Nonetheless, field sting systemic reactions Muller III and IV were recorded only in those patients receiving VE VIT. Conclusion: This observation suggests that in patients with ascertained VC-induced allergic reactions a specific VC VIT, where available, would be more adequate, at least concerning the safety profile. PMID- 29441145 TI - Epigenetic regulation of HIV-1 latency: focus on polycomb group (PcG) proteins. AB - HIV-1 latency allows the virus to persist until reactivation, in a transcriptionally silent form in its cellular reservoirs despite the presence of effective cART. Such viral persistence represents a major barrier to HIV eradication since treatment interruption leads to rebound plasma viremia. Polycomb group (PcG) proteins have recently got a considerable attention in regulating HIV-1 post-integration latency as they are involved in the repression of proviral gene expression through the methylation of histones. This epigenetic regulation plays an important role in the establishment and maintenance of HIV-1 latency. In fact, PcG proteins act in complexes and modulate the epigenetic signatures of integrated HIV-1 promoter. Key role played by PcG proteins in the molecular control of HIV-1 latency has led to hypothesize that PcG proteins may represent a valuable target for future HIV-1 therapy in purging HIV-1 reservoirs. In this regard, various small molecules have been synthesized or explored to specifically block the epigenetic activity of PcG. In this review, we will highlight the possible therapeutic approaches to achieve either a functional or sterilizing cure of HIV-1 infection with special focus on histone methylation by PcG proteins together with current and novel pharmacological approaches to reactivate HIV-1 from latency that could ultimately lead towards a better clearance of viral latent reservoirs. PMID- 29441148 TI - Experimental and Clinical Applications of Chamaecyparis obtusa Extracts in Dry Eye Disease. AB - Purpose: To investigate the effects of Chamaecyparis obtusa (CO) on human corneal epithelial (HCE) cells, a murine experimental dry eye (EDE) model, and the efficacy of antioxidant eye mask in dry eye disease (DED) patients. Methods: 0.001%, 0.01%, and 0.1% CO extracts were used to treat HCE cells, cell viability, and production of antioxidative enzymes, and reactive oxygen species (ROS) were assessed. Afterwards, CO extracts or balanced salt solution (BSS) was applied in EDE. Clinical and experimental parameters were measured at 7 days after treatment. In addition, DED patients were randomly assigned to wear either an eye mask containing CO extracts or a placebo. Clinical parameters were evaluated. Results: The viability of HCE cells and antioxidative enzyme expression significantly improved after treatment with 0.1% CO extracts. Mice treated with 0.1% CO extracts showed significant improvement in clinical parameters. During the trial, the clinical parameters significantly improved in the treatment group at 4 weeks after application. Conclusions: 0.1% CO extracts could promote the expression of antioxidative proteins and ROS production. In addition, an eye mask containing CO extracts could improve DED clinical parameters. These suggest that CO extracts may be useful as an adjunctive option for the DED treatment. PMID- 29441150 TI - Punica granatum (Pomegranate) activity in health promotion and cancer prevention. AB - Cancer has become one of the most fatal diseases in most countries. In spite of the medical care developing, cancer still remains a significant problem. The majority of the cancers are resistant to treatment. Thus, the research for novel, more efficient and less side effect treatment methods continues. Pomegranate contains strong antioxidant activity, with potential health interests. Research concern in pomegranate is increasing because of their anticancer potential due to possess rich in polyphenols. We highlight the pomegranate potential health benefits and mechanism of cancer progression inhibition. Pomegranate has indicated antiproliferative, anti-metastatic and anti-invasive effects on different cancer cell line in vitro, in vivo and clinical trial. The aim of this review is to evaluate functional properties and the medical benifits of pomegranate against various cancer diseases. In addition, pomegranate properties in in vitro and in vivo experimental human and animal clinical trials and its future use are explored. The available data suggest that Punica granatum (pomegranate) might be used in the control and potential therapeutic for some disease conditions and benefits human health status. This review summarizes in vitro, in vivo and clinical trial studies highlighting the pomegranate role in prevent and treatment of breast, prostate, lung, colon, skin and hepatocellular cell cancers. PMID- 29441149 TI - Supplementation of Micronutrient Selenium in Metabolic Diseases: Its Role as an Antioxidant. AB - Selenium is an essential mineral naturally found in soil, water, and some of the food. As an antioxidant, it is one of the necessary trace elements in human body and has been suggested as a dietary supplement for health benefit. Although the human body only needs a trace amount of selenium every day, plenty of recent studies have revealed that selenium is indispensable for maintaining normal functions of metabolism. In this study, we reviewed the antioxidant role of nutritional supplementation of selenium in the management of major chronic metabolic disorders, including hyperlipidaemia, hyperglycaemia, and hyperphenylalaninemia. Clinical significance of selenium deficiency in chronic metabolic diseases was elaborated, while clinical and experimental observations of dietary supplementation of selenium in treating chronic metabolic diseases, such as diabetes, arteriosclerosis, and phenylketonuria, were summarized. Toxicity and recommended dose of selenium were discussed. The mechanism of action was also proposed via inspecting the interaction of molecular networks and predicting target protein such as xanthine dehydrogenase in various diseases. Future direction in studying the role of selenium in metabolic disorders was also highlighted. In conclusion, highlighting the beneficial role of selenium in this review would advance our knowledge of the dietary management of chronic metabolic diseases. PMID- 29441151 TI - Development and testing of TraumaGameplay: an iterative experimental approach using the trauma film paradigm. AB - Background: Vivid trauma-related intrusions are a hallmark symptom of posttraumatic stress disorder (PTSD), and may be involved in its onset. Effective interventions to reduce intrusions and to potentially prevent the onset of subsequent PTSD are scarce. Studies suggest that playing the videogame Tetris, shortly after watching aversive film clips, reduces subsequent intrusions. Other studies have shown that taxing working memory (WM) while retrieving an emotional memory reduces the memory's vividness and emotionality. Objective: We developed TraumaGameplay (TGP), a gaming app designed to reduce intrusions. This paper describes two successive experiments to determine whether playing TGP without memory retrieval (regular TGP) or TGP with memory retrieval (dual-task TGP) reduces intrusion frequency at one week compared to a no-game control. Method: For both experiments, healthy university students were recruited. Experiment 1: 92 participants were exposed to a trauma film and randomized to (1) regular TGP1 (n = 31), (2) dual-task TGP1 (n = 31) or (3) control (n = 30). In experiment 2, 120 healthy students were exposed to a trauma film and randomized to (1) regular TGP2 (n = 30), (2) dual-task TGP2 (n = 29), (3) recall only (n = 31) or (4) control (n = 30). Results: We found no significant difference between conditions on the number of intrusions for either playing regular TGP or dual-task TGP in both experiment 1 and experiment 2. Conclusion: Our results could not replicate earlier promising findings from preceding experimental research. Several reasons may underpin this difference ranging from the visuospatial videogame used in our experiments to the method of the experiment to the difficulties of replicability in general. PMID- 29441152 TI - A five-day inpatient EMDR treatment programme for PTSD: pilot study. AB - Background: Trauma-focused psychotherapies for posttraumatic stress disorder (PTSD) have been demonstrated to be efficacious, but also have considerable non response and dropout rates. Intensive treatment may lead to faster symptom reduction, which may contribute to treatment motivation and thereby to reduction of dropout. Objective: The aim of the current study was to investigate the feasibility and preliminary effectiveness of an intensive five-day inpatient treatment with Eye Movement Desensitization and Reprocessing (EMDR) and trauma informed yoga for patients with PTSD. Method: A non-controlled pilot study with 12 adult patients with PTSD was conducted. At baseline the PTSD diagnosis was assessed with the Clinician-Administered PTSD Scale (CAPS-5) and comorbid disorders with the Mini International Neuropsychiatric Interview (MINI). Primary outcome was self-reported PTSD symptom severity (PTSD Check List for DSM-5; PCL 5) measured at the beginning of day 1 (T1), at the end of day 5 (T2) and at follow-up on day 21 (T3). Reliable change indexes (RCI) and clinically significant changes were calculated. Results: From T1 to T3, PTSD symptoms significantly improved with a large effect size (Cohen's d = 0.91). Nine of the 11 patients who completed treatment showed reliable changes in terms of self reported PTSD. At T3, two of the patients no longer met criteria for PTSD as measured with the PCL-5. One patient dropped out after the first day. No serious adverse events occurred. Conclusions: The majority of patients in our pilot study experienced symptom reduction consistent with reliable changes in this five-day inpatient treatment with EMDR and yoga. Randomized controlled trials - with longer follow up periods - are needed to properly determine efficacy and efficiency of intensive clinical treatments for PTSD compared to regular treatment. This is one of the first studies to show that intensive EMDR treatment is feasible and is indicative of reliable improvement in PTSD symptoms in a very short time frame. PMID- 29441153 TI - The impact of childhood sexual abuse on the outcome of intensive trauma-focused treatment for PTSD. AB - Background: It is assumed that PTSD patients with a history of childhood sexual abuse benefit less from trauma-focused treatment than those without such a history. Objective: To test whether the presence of a history of childhood sexual abuse has a negative effect on the outcome of intensive trauma-focused PTSD treatment. Method: PTSD patients, 83% of whom suffered from severe PTSD, took part in a therapy programme consisting of 2 * 4 consecutive days of Prolonged Exposure (PE) and EMDR therapy (eight of each). In between sessions, patients participated in sport activities and psycho-education sessions. No prior stabilization phase was implemented. PTSD symptom scores of clinician administered and self-administered measures were analysed using the data of 165 consecutive patients. Pre-post differences were compared between four trauma groups; patients with a history of childhood sexual abuse before age 12 (CSA), adolescent sexual abuse (ASA; i.e. sexual abuse between 12 and 18 years of age), sexual abuse (SA) at age 18 and over, or no history of sexual abuse (NSA). Results: Large effect sizes were achieved for PTSD symptom reduction for all trauma groups (Cohen's d = 1.52-2.09). For the Clinical Administered PTSD Scale (CAPS) and the Impact of Event Scale (IES), no differences in treatment outcome were found between the trauma (age) groups. For the PTSD Symptom Scale Self Report (PSS-SR), there were no differences except for one small effect between CSA and NSA. Conclusions: The results do not support the hypothesis that the presence of a history of childhood sexual abuse has a detrimental impact on the outcome of first-line (intensive) trauma-focused treatments for PTSD. PMID- 29441155 TI - Involving children in disaster risk reduction: the importance of participation. AB - Background: Millions of children are affected by disasters every year. Children need not be passive victims, however, but instead may contribute to disaster risk reduction activities. Objective: This paper provides a theoretical foundation for children's involvement in disaster risk reduction activities. Method: The paper reviews and analyses the literature on children's participation, on their developmental capacity to participate, and on disaster risk reduction activities involving children. Results: Participation yields numerous potential benefits for children, including enhanced personal development and skills, self-efficacy, and interpersonal relationships, and for communities through improved social connections and networks and disaster preparedness. Conclusions: Children are resources to be cultivated and mobilized for disaster preparedness, response, recovery, and resilience. Attention is needed to identify approaches to appropriately enlist, engage, and involve children in disaster risk reduction activities; to promote these efforts; and to evaluate these approaches. PMID- 29441154 TI - e-PTSD: an overview on how new technologies can improve prediction and assessment of Posttraumatic Stress Disorder (PTSD). AB - Background: New technologies may profoundly change our way of understanding psychiatric disorders including posttraumatic stress disorder (PTSD). Imaging and biomarkers, along with technological and medical informatics developments, might provide an answer regarding at-risk patient's identification. Recent advances in the concept of 'digital phenotype', which refers to the capture of characteristics of a psychiatric disorder by computerized measurement tools, is one paradigmatic example. Objective: The impact of the new technologies on health professionals practice in PTSD care remains to be determined. The recent evolutions could disrupt the clinical practices and practitioners in their beliefs, ethics and representations, going as far as questioning their professional culture. In the present paper, we conducted an extensive search to highlight the articles which reflect the potential of these new technologies. Method: We conducted an overview by querying PubMed database with the terms [PTSD] [Posttraumatic stress disorder] AND [Computer] OR [Computerized] OR [Mobile] OR [Automatic] OR [Automated] OR [Machine learning] OR [Sensor] OR [Heart rate variability] OR [HRV] OR [actigraphy] OR [actimetry] OR [digital] OR [motion] OR [temperature] OR [virtual reality]. Results: We summarized the synthesized literature in two categories: prediction and assessment (including diagnostic, screening and monitoring). Two independent reviewers screened, extracted data and quality appraised the sources. Results were synthesized narratively. Conclusions: This overview shows that many studies are underway allowing researchers to start building a PTSD digital phenotype using passive data obtained by biometric sensors. Active data obtained from Ecological Momentary Assessment (EMA) could allow clinicians to assess PTSD patients. The place of connected objects, Artificial Intelligence and remote monitoring of patients with psychiatric pathology remains to be defined. These tools must be explained and adapted to the different profiles of physicians and patients. The involvement of patients, caregivers and health professionals is essential to the design and evaluation of these new tools. PMID- 29441156 TI - Communicating with children and adolescents about the risk of natural disasters. AB - A vast number of people annually are affected by natural disasters. Children are at risk of losing their lives and suffer mentally or physically after such events. The fostering of resilience and preparedness ahead of disasters can reduce untoward effects of disastrous events. Risk communication and disaster education are considered important aspects of disaster preparedness, but little is known about whether such strategies influence children's behaviour when natural disasters occur or how they cope in the aftermath. This paper presents and discusses various strategies that promote preparedness activities to save lives. To a minor extent, it also includes strategies that can promote coping in the aftermath. Strategies such as informational campaigns, educational activities, psychoeducation and parental guidance are addressed. The literature to date indicates that schools are a suitable arena for risk communication, and that adolescents themselves should be involved and engaged in the communication strategies. However, the relationship between knowledge of preparedness strategies and the resulting preparedness actions is largely unknown. It is unknown whether changes in awareness and attitudes have resulted in actual behaviour change. It is advocated that preparedness activities and parental involvement should supplement information-based strategies. PMID- 29441157 TI - Oiling the gate: a mobile application to improve the admissions process from the emergency department to an academic community hospital inpatient medicine service. AB - The process of admitting patients from the emergency department (ED) to an academic internal medicine (AIM) service in a community teaching hospital is one fraught with variability and disorder. This results in an inconsistent volume of patients admitted to academic versus private hospitalist services and results in frustration of both ED and AIM clinicians. We postulated that implementation of a mobile application (app) would improve provider satisfaction and increase admissions to the academic service. The app was designed and implemented to be easily accessible to ED physicians, regularly updated by academic residents on call, and a real-time source of the number of open AIM admission spots. We found a significant improvement in ED and AIM provider satisfaction with the admission process. There was also a significant increase in admissions to the AIM service after implementation of the app. We submit that the implementation of a mobile app is a viable, cost-efficient, and effective method to streamline the admission process from the ED to AIM services at community-based hospitals. PMID- 29441158 TI - Computed tomography pulmonary angiography is overused to diagnose pulmonary embolism in the emergency department of academic community hospital. AB - Background: Pulmonary embolism (PE) is a common disease in the USA responsible for up to 10% of hospital mortality. Modified wells score (MWS) and D-dimer assay are used to categorize patients into high or low probability of PE. Patient with high probability need Computed tomography pulmonary angiography (CTPA), while patients with low probability and low D-dimer can safely forgo the CTPA. Objectives: The aim of this study was to investigate the rate of inappropriate CTPA use in the emergency department of a community teaching hospital. Methods: A retrospective chart review of adult patients who underwent CTPA for suspected PE in the emergency department for 2015 was done. CTPA use was considered inappropriate if MWS was less than or equal to 4 and D-dimer was either not ordered or its value was less than 500 MUg/L. Bivariate analysis with Fisher's exact tests and Student's t-tests as well as multivariate logistic regression analysis were done to examine relationship between study explanatory variables and study outcome. Results: 295 patients were included in the study. The mean age was 51.2(+/-14.5) years, 68.8% were females. The prevalence of PE was 5.4% and 41% of the CTPAs -were inappropriately ordered. Males were twice (OR 2.1; 95% CI 1.2, 3.6) as likely as females to have an inappropriately ordered CTPA after controlling for a high MWS, age, and tobacco history. Conclusion: CTPA is overused to diagnose PE in the emergency department. Quality improvement projects are needed to encourage physicians to adhere to the current guidelines. PMID- 29441160 TI - Era of hospitalists. AB - Hospitalists, known as physicians, are an emerging group in the medical field that is focused on the general medical care of hospitalized patients. Specializing in hospital medicine, they often attract a mix of appreciation and criticism. In the present manuscript, we review the pros and cons of a hospitalist in the health-care system. Although experts agree that hospitalists add value to the health-care system by reducing costs, streamlining administrative processes, and contributing to improved health-care outcomes, there is a large degree of disagreement regarding the extent of hospitalist contribution to overall improvements on health-care outcomes. In this paper, new strategies to overcome reported shortcomings and to further improve the quality of health care are discussed. Abbreviations: SHM: Society of Hospital Medicine; BOOST: Better Outcomes by Optimizing Safe Transitions; RED: Re-Engineered Discharge; CHF: chronic heart failure; MI: myocardial infarction; ICU: intensive care unit; PACT: post-acute care transitions; MRSA: methicillin-resistant Staphylococcus aureus; CINAHL: The Cumulative Index to Nursing and Allied Health Literature; PCP: primary care physician. PMID- 29441159 TI - Prevalence of subclinical hypothyroidism in adults visiting primary health-care setting in Riyadh. AB - Background and objectives: Subclinical hypothyroidism is an asymptomatic condition with normal thyroxin and raised thyroid stimulating hormone (TSH) level. The objective of the study was to determine the prevalence of subclinical hypothyroidism in primary health care (PHC) settings in Riyadh and explore the relationship of TSH level with age, gender, family history, body mass index, and co-morbid conditions. Subjects and methods: A cross-sectional study of adult visitors to nine satellites PHC clinics in military housing in Riyadh was carried out. TSH concentration and free T4 levels were measured. Data were collected by nurses and physicians during routine clinical practice in primary care. Descriptive analysis was performed on all variables in study, and relationships were explored using chi-square, t-test, analysis of variance, and linear regression. Results: A total of 340 out of 394 participants in the study gave blood samples. Subclinical hyperthyroidism was identified in 2.1% (p = .001) and subclinical hypothyroidism in 10.3% (p = .001) of the PHC visitors. TSH levels were found to be significantly higher (p = .047) in elderly population of >=60 years and those with family history of thyroid disease. Non-significant upward trends were noted in TSH levels with hyperlipidemia and increasing blood pressure. No overt hyperthyroidism or hypothyroidism was found in our study sample. Conclusion: Subclinical hypothyroidism has a prevalence of 10% of adults visiting PHC's. TSH levels are higher in the elderly, which warrants screening of those aged 60 years and above. PMID- 29441162 TI - A multimodal high-value curriculum affects drivers of utilization and performance on the high-value care component of the internal medicine in-training exam. AB - Background: Teaching the practice of high-value care (HVC) is an increasingly important function of graduate medical education but best practices and long-term outcomes remain unknown. Objective: Whether a multimodal curriculum designed to address specific drivers of low-value care would affect resident attitudes, skills, and performance of HVC as tested by the Internal Medicine In-Training Exam (ITE). Methods: In 2012, we performed a baseline needs assessment among internal medicine residents at a community program regarding drivers of healthcare utilization. We then created a multimodal curriculum with online interactive worksheets, lectures, and faculty buy-in to target specific skills, knowledge, and culture deficiencies. Perceived drivers of care and performance on the Internal Medicine ITE were assessed yearly through 2016. Results: Fourteen of 27 (52%) residents completed the initial needs assessment while the curriculum was eventually seen by at least 24 of 27 (89%). The ITE was taken by every resident every year. Long-term, 3-year follow-up demonstrated persistent improvement in many drivers of utilization (patient requests, reliance on subspecialists, defensive medicine, and academic curiosity) and improvement with sustained high performance on the high-value component of the ITE. Conclusion: A multimodal curriculum targeting specific drivers of low-value care can change culture and lead to sustained improvement in the practice of HVC. PMID- 29441161 TI - Canakinumab and cardiovascular outcomes: results of the CANTOS trial. AB - IL-1 cytokines are mainly responsible for controlling a series of pro inflammatory reactions induced in response to pathogen mediated tissue injury. Among the IL-1 cytokine family, IL-1 beta results in upregulation of genes responsible for boosting immune system reactivity and inflammatory response. With growing pathophysiological relevance of IL-1beta in a myriad of disease pathogenesis, new biological drugs have been developed in recent years. One such drug, Canakinumab, targeting IL-1beta has been recently approved for clinical use. The recent results from the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial are encouraging in this aspect. The results suggest that anti-inflammatory therapy using canakinumab at a dose of 150 mg every 3 months led to significantly lower recurrent cardiovascular events than the placebo drug. These results were independent of lipid-lowering effects of these drugs. If the results are widely applicable, the CANTOS trial would reaffirm the hypothesis of atherothrombosis due to inflammation, hence supporting the need for a cytokine based therapy for the secondary prevention of cardiovascular diseases. Moreover, the potential benefits of the phenomenal reduction in the inflammatory cascade induced by canakinumab should be carefully balanced against its long-term safety profile which is yet unknown. However, the inflammatory hypothesis of atherothrombosis supports a cytokine-based therapy for the secondary prevention of cardiovascular disease. Furthermore, the potential benefits from the reduction in inflammatory markers induced by canakinumab should be carefully balanced against its unknown long-term safety profile. PMID- 29441163 TI - In with acute bronchitis; out with duodenal perforation: the potentially harmful cascade of over-testing. A case report. AB - Overutilization of diagnostic imaging can lead to unnecessary interventions and subsequently can jeopardize patient safety. When ordered, the results of these images should always be interpreted in the appropriate clinical context taking into consideration the patient clinical presentation and the natural history of the diseases which are being investigated. We presented a case that demonstrates for the practicing physicians how violating these two notions can lead ultimately to patient harm. PMID- 29441164 TI - Rare case of Mycobacterium nebraskense presenting as asymptomatic cavitary lung lesion. AB - Introduction: Mycobacterium Nebraskense is a rare nontuberculous mycobacterial infection. The first isolate of the species was from human sputum at University of Nebraska Medical Center. There are only a few cases have been reported and the exact behavior of the disease is not clearly described. Here, we present a case from New York City incidentally found to have a cavitary lung lesion due to M. nebraskense.Case report: An 82-year-old female with a history of diabetes mellitus, hypertension, and dementia presented with constipation and urinary retention for 1 day. She had no fever, cough, shortness of breath, nausea, vomiting, appetite change, or weight loss. Computed tomography (CT) scan of abdomen and pelvis revealed retained fecal material in the colon, non-obstructing left renal calculus, and bilateral small pleural effusion with right-sided lung infiltrates. Subsequent CT scan of the chest showed 4.5 cm pleural-based opacity in right lung base with a small cavity. Sputum smear for Acid-fast bacilli was positive. Mycobacterial culture reported positive growth of M. nebraskense, while polymerase chain reaction returned negative for Mycobacterium gordonae, Mycobacterium kansasii, Mycobacterium avium complex and Mycobacterium tuberculosis. With the patient asymptomatic and her constipation improved, she was discharged with plans for close follow-up as outpatient. Conclusion: M. nebraskense is a very rare nontuberculous mycobacterial infection. From only a few cases reported in the USA, the exact presentation of infection, disease progression, and treatment have not been described well. Asymptomatic cavitary lung disease caused by M. nebraskense has not been reported before. PMID- 29441165 TI - Propylthiouracil-induced ANCA-negative cutaneous small vessel vasculitis. AB - Propylthiouracil (PTU) is a commonly used medication for the treatment of hyperthyroidism. PTU is known to cause different adverse reactions including autoimmune syndromes. PTU-induced autoimmune syndromes can be classified into drug-induced lupus or drug-induced vasculitis. Differential diagnoses could be very challenging. PTU-induced vasculitis is more common than PTU-induced lupus, and has a higher risk of morbidity and mortality. Usually it is limited to the skin in a form of cutaneous leukocytoclastic vasculitis, but may also affect organs including kidneys and lungs. Discontinuation of PTU should be a first step in the treatment and could lead to complete resolution of symptoms. Typically, lesions resolve spontaneously within 2-4 weeks, but chronic or recurrent disease may occur in up to 10% of patients. In cases without improvement after drug discontinuation, cases refractory to glucocorticosteroids, with necrotizing skin lesions or extracutaneous organ involvement referral to rheumatologist for more aggressive immunosuppressive treatment is indicated. Optimal duration of immunosuppressive therapy is unknown, but it is reasonable to gradually taper mediations and monitor clinical response. Frequent monitoring for side effects is mandatory for patients on PTU therapy. Treatment should be stopped immediately, if patient develops any of autoimmune syndromes. An accurate and prompt diagnosis is essential, because it determines further management. We report a rare case of antineutrophil cytoplasm antibody-negative cutaneous small vessel vasculitis as a result of longstanding exposure to PTU. PMID- 29441166 TI - A case of madness resulting in a fortunate outcome; case report of a psychotic break as a result of cortisol secreting thymic neuroendocrine thymic tumor. AB - Representing a mere 2-5% of the total thymic malignancies and 0.4% of total carcinoid tumors, primary thymic neuroendocrine tumors (NETs) are the zebras of the thymic neoplasms. They were initially characterized as 'epithelial thymomas'; later, the term carcinoid tumors was coined by Rosai and Higa. These tumors are highly unpredictable in their presentation and prognosis. Coupled with variable clinical presentation, rare pathologic diagnosis and absence of diagnostic and prognostic parameters, it is a challenge for both patients and clinicians. Treatment entails local definitive therapy, symptom control and systemic chemoradiation given either pre or post operatively based on staging and resectability. We hereby report a peculiar case of psychosis that likely resulted from one such rare tumor. PMID- 29441167 TI - Is this a worrisome red eye? Episcleritis in the primary care setting. AB - Episcleritis is the inflammation of the thin, loose, highly vascular connective tissue layer that lies between the conjunctiva and sclera. Incidence is less than 1/1000. It is more common in women and those between 40 and 50 years of age. Most cases are idiopathic. It is classified into simple and nodular. Most attacks resolve within 1-3 months. The nodular type tends to be more recurrent and painful. It presents with acute onset of redness, lacrimation, and photophobia. The diagnosis of is essentially clinical, and eye pain or tenderness should raise the concern for scleritis. Ophthalmological referral is recommended to rule out scleritis. Bloodwork to diagnose associated systemic rheumatological disease may be helpful. Cold compresses and artificial tears provide symptomatic relief. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids are used for persistent symptoms. Rarely, systemic steroids may be necessary. Immunosuppressive treatment to control an underlying autoimmune disorder is the last resort for resistant cases. PMID- 29441168 TI - Avoiding pressure ulcers: beyond proper positioning. PMID- 29441169 TI - Perioperative stroke: pathophysiology and management. AB - Although perioperative stroke is uncommon during low-risk non-vascular surgery, if it occurs, it can negatively impact recovery from the surgery and functional outcome. Based on the Society for Neuroscience in Anesthesiology and Critical Care Consensus Statement, perioperative stroke includes intraoperative stroke, as well as postoperative stroke developing within 30 days after surgery. Factors related to perioperative stroke include age, sex, a history of stroke or transient ischemic attack, cardiac surgery (aortic surgery, mitral valve surgery, or coronary artery bypass graft surgery), and neurosurgery (external carotid internal carotid bypass surgery, carotid endarterectomy, or aneurysm clipping). Concomitant carotid and cardiac surgery may further increase the risk of perioperative stroke. Preventive strategies should be individualized based on patient factors, including cerebrovascular reserve capacity and the time interval since the previous stroke. PMID- 29441170 TI - Management of traumatic brain injury patients. AB - Traumatic brain injury (TBI) has been called the 'silent epidemic' of modern times, and is the leading cause of mortality and morbidity in children and young adults in both developed and developing nations worldwide. In recent years, the treatment of TBI has undergone a paradigm shift. The management of severe TBI is ideally based on protocol-based guidelines provided by the Brain Trauma Foundation. The aims and objectives of its management are prophylaxis and prompt management of intracranial hypertension and secondary brain injury, maintenance of cerebral perfusion pressure, and ensuring adequate oxygen delivery to injured brain tissue. In this review, the authors discuss protocol-based approaches to the management of severe TBI as per recent guidelines. PMID- 29441171 TI - Optimal propofol dosage for i-gel(r) insertion in healthy paralyzed patients. AB - Background: Propofol is used for supraglottic airway device insertion, often with the i-gel. However, the propofol requirement for i-gel insertion has not been explored in paralyzed patients. This study was performed to explore hemodynamic changes and sedation level with different propofol doses in healthy paralyzed patients when the i-gel was inserted. Methods: A total of 141 patients undergoing a urologic operation were randomly allocated to three groups depending on the propofol dose (1.5, 2, and 2.5 mg/kg; Groups P1.5, P2, and P2.5, respectively). After patients had been administered each propofol dose and rocuronium, the i-gel was inserted and changes in hemodynamic parameters and bispectral index were evaluated. Results: Group P2 showed a lower incidence of complications (17%) such as hemodynamic instability and inadequate sedation than Group P1.5 (55.3%, P < 0.001) or Group P2.5 (40.4%, P = 0.012). The incidence and dose of additional propofol increased in Group P1.5 (51%, median [range]; 20 [0-50]) compared with those in the other groups (0%, 0 [0-0] in Group P2 and 8.5%, 0 [0-50] in Group P2.5, all P < 0.001), and the incidence and dose of additional ephedrine were significantly higher in Group P2.5 (31.9%; 0 [0-20]) than in Group P1.5 (10.6%, P = 0.012; 0 [0-5], P = 0.007, respectively). Conclusions: For the stable maintenance of hemodynamic parameters and proper sedation level during i-gel insertion, 2 mg/kg propofol has an advantage over 1.5 mg/kg or 2.5 mg/kg propofol in healthy paralyzed patients. PMID- 29441172 TI - Association of direct bilirubin level with postoperative outcome in critically ill postoperative patients. AB - Background: Hyperbilirubinemia is a common postoperative complication. Elevated direct bilirubin (D-Bil) and indirect bilirubin (I-Bil) levels are related to different pathophysiologies; therefore, their associations with outcomes also differ. However, there have been few comparative studies of such associations in postoperative patients. Methods: This retrospective study compared the associations of postoperative D-Bil and I-Bil with outcomes. We included adult patients requiring postoperative intensive care for more than 48 hours between 2008 and 2013, except those undergoing liver operations. The number of patients was determined using a power calculation. D-Bil and I-Bil measurements were obtained on postoperative days (POD) 1 and 2. The primary outcome was defined as hospital mortality, with the number of ICU-free survival days (IFSD) at POD 28 as the secondary outcome. Results: The study population consisted of 1,903 patients with a mortality rate of 2.2%. D-Bil at POD 1 was significantly higher in non survivors than survivors (P = 0.001), but I-Bil at POD 1 showed no such relation (P = 0.209). Multivariate logistic analysis indicated that higher postoperative D Bil was independently associated with increased postoperative mortality (POD 1: adjusted odds ratio [OR] = 2.32, P < 0.001; POD 2: adjusted OR = 1.95, P < 0.001), but I-Bil showed no such relation (POD 1: P = 0.913; POD 2: P = 0.209). Increased D-Bil was independently associated with decreased IFSD at POD 28 (POD 1: adjusted coefficient = -1.54, P < 0.001; POD 2: -1.84, P < 0.001). In contrast, increased I-Bil at POD 1 was independently associated with increased IFSD at POD 28 (POD 1: adjusted coefficient = +0.39, P = 0.021; POD 2: +0.33, P = 0.080). Conclusions: D-Bil indices have a higher capability than I-Bil for predicting poorer outcomes in critically ill postoperative patients. PMID- 29441173 TI - A comparison of i-gelTM and Laryngeal Mask Airway SupremeTM during general anesthesia in infants. AB - Background: The i-gelTM (i-gel) and Laryngeal Mask Airway SupremeTM (LMA Supreme) have been safely used in children. We compared the airway performance of the i gel and LMA Supreme in infants undergoing general anesthesia. Methods: Sixty infants with American Society of Anesthesiologists physical status I or II were randomly assigned to place either the i-gel or the LMA Supreme. The size 1 or 1.5 of each airway was selected by the weight of infants. The primary outcome variable was oropharyngeal leak pressure (OLP). We also assessed insertion success rate, insertion time, fiberoptic view of the larynx, airway quality, airway manipulations, and perioperative complications. Results: Demographic data did not differ between the two groups. Insertion success rate was similar in both groups. OLP for the i-gel (26.0 +/- 3.8 cmH2O) was higher than for the LMA Supreme (23.7 +/- 3.2 cmH2O) (P = 0.016). Insertion time for the i-gel (16.4 +/- 2.8 s) was shorter than for the LMA Supreme (18.5 +/- 2.7 s) (P = 0.002). There were no differences in fiberoptic view of the larynx, airway quality, airway manipulations, and complications between the two groups. Conclusions: This study demonstrated that the i-gel and LMA Supreme provided a similar performance of airway in infants. Compared with the LMA Supreme, the i-gel provided shorter insertion time and higher OLP in infants. PMID- 29441174 TI - Comparison of propofol alone and in combination with ketamine or fentanyl for sedation in endoscopic ultrasonography. AB - Background: We evaluated whether the addition of a small dose of ketamine or fentanyl would lead to a reduction in the total dose of propofol consumed without compromising the safety and recovery of patients having endoscopic ultrasonography (EUS). Methods: A total of 210 adult patients undergoing elective EUS under sedation were included in the study. Patients were randomized into three groups. Patients were premedicated intravenously with normal saline in group 1, 50 ug fentanyl in group 2, and 0.5 mg/kg ketamine in group 3. All patients received intravenous propofol for sedation. Propofol consumption in mg/kg/h was noted. The incidence of hypotension, bradycardia, desaturation, and coughing was noted. The time to achieve a Post Anesthesia Discharge Score (PADS) of 10 was also noted. Results: There were 68 patients in group 1, 70 in group 2, and 72 in group 3. The amount of propofol consumed was significantly higher in group 1 (9.25 [7.3-13.2]) than in group 2 (8.8 [6.8-12.2]) and group 3 (7.6 [5.7 9.8]). Patient hemodynamics and oxygenation were well maintained and comparable in all groups. The time to achieve a PADS of 10 was significantly higher in group 3 compared to the other two groups. Conclusions: The use of 50 ug fentanyl or 0.5 mg/kg ketamine in a single dose during EUS reduces the dose of propofol required for sedation. However, unlike the addition of fentanyl, the addition of ketamine increased the time to recovery. Thus, 50 ug fentanyl is a good additive to propofol infusion for sedation during EUS to reduce the requirement for propofol without affecting the time to recovery. PMID- 29441175 TI - Perioperative factors associated with pressure ulcer development after major surgery. AB - Background: Postoperative pressure ulcers are important indicators of perioperative care quality, and are serious and expensive complications during critical care. This study aimed to identify perioperative risk factors for postoperative pressure ulcers. Methods: This retrospective case-control study evaluated 2,498 patients who underwent major surgery. Forty-three patients developed postoperative pressure ulcers and were matched to 86 control patients based on age, sex, surgery, and comorbidities. Results: The pressure ulcer group had lower baseline hemoglobin and albumin levels, compared to the control group. The pressure ulcer group also had higher values for lactate levels, blood loss, and number of packed red blood cell (pRBC) units. Univariate analysis revealed that pressure ulcer development was associated with preoperative hemoglobin levels, albumin levels, lactate levels, intraoperative blood loss, number of pRBC units, Acute Physiologic and Chronic Health Evaluation II score, Braden scale score, postoperative ventilator care, and patient restraint. In the multiple logistic regression analysis, only preoperative low albumin levels (odds ratio [OR]: 0.21, 95% CI: 0.05-0.82; P < 0.05) and high lactate levels (OR: 1.70, 95% CI: 1.07-2.71; P < 0.05) were independently associated with pressure ulcer development. A receiver operating characteristic curve was used to assess the predictive power of the logistic regression model, and the area under the curve was 0.88 (95% CI: 0.79-0.97; P < 0.001). Conclusions: The present study revealed that preoperative low albumin levels and high lactate levels were significantly associated with pressure ulcer development after surgery. PMID- 29441176 TI - Intravenous lidocaine infusions for 48 hours in open colorectal surgery: a prospective, randomized, double-blinded, placebo-controlled trial. AB - Background: Although intravenous (i.v.) lidocaine is used as a perioperative analgesic in abdominal surgery, evidence of efficacy is limited. The infusion dose and duration remain unclear. This study aimed to investigate the effect of a longer low-dose 48-hour infusion regimen on these outcomes. Methods: Fifty-eight adults undergoing elective open colorectal surgery were randomized into the lidocaine group (1.5 mg/kg bolus followed by 1 mg/kg/h infusion for 48 hours) and control group. After surgery, patients were given a fentanyl patient-controlled analgesia machine and time to first bowel movement (primary outcome) and flatus were recorded. Postoperative pain scores and fentanyl consumption were assessed for 72 hours. Results: There was no significant difference in time to first bowel movement (80.1 +/- 42.2 vs. 82.5 +/- 40.4 hours; P = 0.830), time to first flatus (64.7 +/- 38.5 vs. 70.0 +/- 31.2 hours; P = 0.568), length of hospital stay (9 [8 13] vs. 11 [9-14) days; P = 0.531], nor postoperative pain scores in the lidocaine vs. control groups. Cumulative opioid consumption was significantly lower in the lidocaine vs. the control group from 24 hours onwards. At 72 hours, cumulative opioid consumption (ug fentanyl) in the lidocaine group (1,570 [825 3,587]) was over 40% lower than in the placebo group (2,730 [1,778-5,327]; P = 0.039). Conclusions: A 48-hour low-dose i.v. lidocaine infusion does not significantly speed the return of bowel function in patients undergoing elective open colorectal surgery. It was associated with reduced postoperative opioid consumption, but not with earlier hospital discharge, or lower pain scores. PMID- 29441177 TI - Anesthetic management of the first forearm transplantation in Korea. AB - Vascularized composite allotransplantation for the forearm is a complex surgical procedure, requiring multidisciplinary collaboration. It is important to provide optimal blood flow to the grafts, effective immunosuppression, and early rehabilitation for graft survival and good functional outcomes. As ischemia reperfusion injury and substantial but unquantifiable blood loss are inevitable in this type of surgery, anesthetic management should focus on providing adequate hemodynamic management with proper monitoring, and anesthetic and analgesic strategies to prevent vasoconstriction in the graft. In this paper, we describe the anesthetic management of the first forearm transplantation performed in Korea. PMID- 29441178 TI - Negative pressure pulmonary edema. PMID- 29441179 TI - Bilateral transnasal sphenopalatine block for treating postdural puncture headache. PMID- 29441180 TI - Corrigendum: A high-flow nasal cannula system set at relatively low flow effectively washes out CO2 from the anatomical dead space of a respiratory-system model. AB - [This corrects the article on p. 105 in vol. 70, PMID: 28184277.]. PMID- 29441181 TI - Public Health Aspects of Global Population Health and Well-being in the 21st Century Regarding Determinants of Health. AB - Why did I recall the details about public health aspects of global population and well-being in the 21st century regarding the determinants of health? Most of all because today, at the end of 2017, we are talking about the same principles from the "Declaration on Primary Health Care" from 1978, and the same goals as those in "Health for all" which are still current or perhaps even more current than when they were published for the first time in scientific and professional literature. This is a notorious fact, even though we are talking about "Global Health" and its determinants, in all countries of the world, regardless of their social wealth, and all existing resources, especially those, intended to organize health care. In the field of practice, public health has advanced in knowledge and methodology. Biomedical scientists have identified many causes of infectious diseases and developed methods to put them under control. Epidemiologists have identified risk factors that favor many chronic illnesses and information that can be used to reduce the risk of disease. Efforts to cleanse the environment have resulted in air and water that are far safer than half a century ago. Intensive educational efforts have convinced the health-care organizers to improve their health behavior that is to quit tobacco use, and a combination of drinking and driving. The ability to assess the populations' health behaviors and assess the share of health interventions has also significantly improved the availability of health-care databases and computer software capable of analyzing them. However, much of the targets from the World Health Organization declarations are not improved or in some countries provided by official institutions responsible for public health activities. PMID- 29441182 TI - Pediatric Cardiac Anamnesis: Prevention of Additional Diagnostic Tests. AB - Pediatrics is defined as the science of a healthy and sick child from birth to end of adolescence. Diseases of the cardiovascular system are the leading causes of mortality in adults, with frequent onset in childhood. The cardiologic examination starts with anamnesis in a pleasant atmosphere, refined space, enough time and patience, detailed measurements, and preferably a noncrying child. Anamnesis, regardless of the development of diagnostic procedures, still constitutes the basis of every clinical examination. The basic characteristics of pediatric cardiac anamnesis are comprehensiveness, that is, details, clarity, concurrency, and chronology. Proper and conscientiously taken anamnesis with a thorough clinical examination of a sick child is a solid protection against dehumanizing the relationship between a physician and patient. Pediatric cardiac anamnesis can be variable, completely negative, but very rich. Anamnesis should, first of all, clarify whether only a child is sick or it is perceived like that be his or her environment. Preschool and school-age children are normally attending anamnesis. High-quality, comprehensive medical history can keep the patient at one level of health care, with a strict focus primarily on the diagnostic processes, reduce crowds in specialist and subspecialist institutions, and make economic savings. A large number of patients in specialist and subspecialist clinics can be reduced by proper screening and by developing primary health-care system (from the local health-care center). Taking patient's medical history with thoroughness has a strong educative character for young doctors at the beginning of their careers. PMID- 29441183 TI - Association of Lifestyle Risk Factors with Metabolic Syndrome Components: A Cross sectional Study in Eastern India. AB - Background: Approximately 20%-25% of the world adult population and nearly 30% of Indians have metabolic syndrome disorder. Our objective was designed to find out the association between important nutrients and potential lifestyle risk factors such as diet, physical inactivity, and smoking and alcohol consumption with the number of metabolic syndrome components. Methods: This was a cross-sectional study. A total of 205 patients of metabolic syndrome were enrolled for this study. Diagnosis of metabolic syndrome was done on the basis of National Cholesterol Education Program Adult Treatment Panel III criteria (NCEP ATP III 2004). Dietary data were collected with the validated food frequency questionnaire and 24 h dietary recall method, and the nutrient intake was calculated with the specially designed software. Results: Unhealthy dietary habits were seen more among the participants who had more than 3 risk factors. Results showed the odds of taking >5 times junk foods was 3 times higher (odds ratio [OR]: 2.97; 95% confidence interval [CI]: 1.61-5.47), and sweet dishes was 2.3 times higher (OR: 2.33; 95% CI: 1.28-4.24) among the participants who had 4-5 risk factors. However, milk and dairy products > 4 servings/day (OR: 0.54; 95% CI: 0.175-1.67) and pulses and legumes more than 2 servings/day (OR: 0.57; 95% CI: 0.25-1.29) was protective against hypertension. Mean carbohydrate, saturated fat, and sodium intake was significantly higher in the participants who had 4-5 metabolic risk factors compared to 3 risk factors (P < 0.0001). Conclusions: It was concluded that low intake of fruits, vegetables, and higher intake of flesh food and inadequate physical activity significantly associated with the metabolic syndrome risk factors. PMID- 29441184 TI - Revised Risk Priority Number in Failure Mode and Effects Analysis Model from the Perspective of Healthcare System. AB - Background: Methodology of Failure Mode and Effects Analysis (FMEA) is known as an important risk assessment tool and accreditation requirement by many organizations. For prioritizing failures, the index of "risk priority number (RPN)" is used, especially for its ease and subjective evaluations of occurrence, the severity and the detectability of each failure. In this study, we have tried to apply FMEA model more compatible with health-care systems by redefining RPN index to be closer to reality. Methods: We used a quantitative and qualitative approach in this research. In the qualitative domain, focused groups discussion was used to collect data. A quantitative approach was used to calculate RPN score. Results: We have studied patient's journey in surgery ward from holding area to the operating room. The highest priority failures determined based on (1) defining inclusion criteria as severity of incident (clinical effect, claim consequence, waste of time and financial loss), occurrence of incident (time - unit occurrence and degree of exposure to risk) and preventability (degree of preventability and defensive barriers) then, (2) risks priority criteria quantified by using RPN index (361 for the highest rate failure). The ability of improved RPN scores reassessed by root cause analysis showed some variations. Conclusions: We concluded that standard criteria should be developed inconsistent with clinical linguistic and special scientific fields. Therefore, cooperation and partnership of technical and clinical groups are necessary to modify these models. PMID- 29441185 TI - The Effects of Thymoquinone Against Morphine-induced Damages on Male Mice Liver. AB - Background: Morphine is a pain medication. It is mostly processed in liver and reasons disturbing effects. It can increase the production of free radicals. Thymoquinone is a phytochemical compound found in the plant Nigella sativa. It has diverse pharmacological properties such as antioxidant and anticancer. This study was intended to assess the effects of thymoquinone against morphine damages on the liver of mice. Methods: In this study, various doses of thymoquinone (4.5, 9, and 18 mg/kg) and thymoquinone plus morphine was administered (once a day) intraperitoneally to 48 male mice for 20 consequent days. These mice were randomly assigned to eight groups (n = 6). Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum nitric oxide (NO) levels, liver weight, and histology have been studied. Results: The results indicated that morphine administration significantly increased the mean diameter of central hepatic vein and hepatocyte, blood serum NO level, liver enzymes level, and decreased liver weight compared to saline group (P < 0.05). However, thymoquinone and thymoquinone plus morphine administration significantly enhanced liver weight and reduced the mean diameter of hepatocyte, central hepatic vein, liver enzymes, and NO levels in all groups compared to morphine group (P < 0.05). Conclusions: It seems that antioxidant effect of thymoquinone could protect damage of liver parameters against morphine toxicity. PMID- 29441186 TI - Effects of Different Modes of Exercise Training on Body Composition and Risk Factors for Cardiovascular Disease in Middle-aged Men. AB - Background: Previous studies have indicated that exercise training improves body composition and cardiovascular disease risk factors. The aim of the present study was to investigate the effect of 12 weeks of aerobic, strength and combined training on body composition, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and C-reactive protein (CRP) in sedentary middle-aged men. Methods: Forty-seven male aged 40-60 years voluntarily participated in this study and were divided in four groups: aerobic (n = 12), strength (n = 12), combined (n = 11), and control (n = 12) groups randomly. Body composition, ICAM-1, VCAM-1, and CRP were measured before and after 12 weeks. Data were analyzed using paired t-test and analysis of variance statistical methods. Results: There were significant differences in body weight between aerobic and strength training (P = 0.004) and aerobic and control groups (P = 0.018), body mass index between combined and strength training (P = 0.004) and combined and control groups (P = 0.001), fat percentage between aerobic training and control group (P = 0.017) and combined training and control groups (P = 0.004), and finally, fat-free mass between aerobic and strength training (P = 0.024), aerobic and combined training (P = 0.0001), strength and control groups (P = 0.035), and combined and control groups (P = 0.0001). Conclusions: The results indicated that 12-week workout, 20-60 min/session, 3 days a week of moderate intensity exercise improved body composition, ICAM-1, VCAM-1, and CRP compared to those who did not participate in any training. However, all three types of exercises had small benefits on body composition, ICAM-1, VCAM-1, and CRP in sedentary middle-aged men, and the importance of combined training required further investigations. PMID- 29441187 TI - Promoting Physical Activity of Adolescent and Young Iranian Girls. AB - Background: Women play a central role in the health of the whole family, but they are faced with more barriers while taking part in physical activities. Methods: This study was composed of two main phases. In the first phase, the status of physical activity among young and adolescent in Iran and global evidence of effective interventions were searched. In the second phase, Focused Group Discussion (FGD) sessions were held with the key stakeholders in Tehran to investigate the results obtained from the first phase. Results: Physical activity among young and adolescent in Iran is inadequate. Based on the results obtained from the evidence and analysis of the FGDs, solutions defined as supporting policies, supporting environment, and supporting programs for physical activities. Conclusions: Multilevel cooperation among schools, families, and society is necessary to develop and implement policies and supporting programs, with an emphasis on combined interventions. PMID- 29441188 TI - Novel complication of an emerging disease: Invasive Klebsiella pneumoniae liver abscess syndrome as a cause of acute respiratory distress syndrome. AB - Klebsiella pneumoniae is an increasingly recognized cause of a unique invasive syndrome manifesting as pyogenic liver abscess and hematogenous extrahepatic dissemination to a variety of sites, including the lung. Originally described only in Asia, this entity has now been reported across continents and ethnicities. Intrathoracic complications of invasive Klebsiella pneumoniae liver abscess syndrome (IKPLAS) have been characterized sporadically but have not been the subject of an all-encompassing investigation. Review of the English-language literature yields no reports of the acute respiratory distress syndrome as a consequence of IKPLAS. Herein we report what, to our knowledge, is the first such description. PMID- 29441189 TI - Neuroleptic malignant syndrome: a case responding to electroconvulsive therapy plus bupropion. AB - Neuroleptic malignant syndrome (NMS) is a severe motor syndrome occurring as a consequence of neuroleptic treatment. We present a case of a 67-year-old Caucasian woman with a history of a major depressive disorder with psychotic features. During her third hospital admission, symptoms of autonomic instability, hyperpyrexia, severe extrapyramidal side effects, and delirium appeared, suggesting NMS due to concomitant treatment with risperidone and quetiapine, among other drugs. Despite several consecutive pharmacological treatments (lorazepam, bromocriptine and amantadine) and prompt initiation of electroconvulsive therapy (ECT), clinical improvement was observed only after combining bupropion with ECT. The symptoms that had motivated the admission gradually remitted and the patient was discharged home. Bupropion increases dopaminergic activity in both the nucleus accumbens and the prefrontal cortex. Therefore, from a physiopathological standpoint, bupropion has a potential role in treating NMS. However, there is scarce evidence supporting this approach and therefore future cases should be carefully considered. PMID- 29441190 TI - Nephrotic syndrome in very elderly: Should we treat aggressively? AB - Chronic kidney disease and acute kidney injury are being increasingly recognized in very elderly patients, aged 80 or more. In cases of suspected glomerulonephritis with or without nephrotic syndrome, the clinical decision making of whether to obtain a renal biopsy and treat with immunosuppressive therapy should not be based on advanced age alone but take into consideration the patient's functional status and overall prognosis. Herein, we report a case of an elderly patient with minimal change disease who benefitted from a timely renal biopsy and aggressive immunosuppressive therapy. PMID- 29441191 TI - Studying the effects of primary arthroplasty on post-treatment results among elderly patients with pertrochanteric fracture. AB - Various therapeutic methods are available to treat patients with intertrochantric fracture, which is usually caused by falling down. This complication is usually observed among the elderly, particularly old women. The choice of the proper therapeutic method depends on many factors including patient's condition, type of fracture, and the amount of movement. Hip arthroplasty is one of these therapeutic methods, which have certain advantages and disadvantages. Immediate resumption of walking with the ability of weight toleration and absence of complications such as aseptic necrosis are some advantages of this method. Sixtyeight elderly patients with pertrochanteric fracture who had resorted to Iranian Army's hospitals and had undergone arthroplasty. These cases were examined with due comparison with historical and external controls. Variables such a type of operation, age, post-operation pain, the pace of resuming walking ability, embolism, surgical site infection, bedsore and DVT were studied and compared against standard operation. The results achieved through assessment of variables showed a significant difference with standard operation in terms of variables such as post-operative movement ability, pain scale in various times, surgical complications, embolism, surgical site infection, bedsore, and DVT. Post operative pain within the first 3 months following it are some complications with not much attention is paid to them, but they are important complications which can cause many negative and influential effects on patients. Arthroplasty is more expensive than standard operation and the patient may initially feel more pain. PMID- 29441192 TI - Knockdown of LncRNA MAPT-AS1 inhibites proliferation and migration and sensitizes cancer cells to paclitaxel by regulating MAPT expression in ER-negative breast cancers. AB - Background: MAPT-AS1, a long non-coding RNA, has not been reported in any previous research about its function in cancers. In this study, we investigated the role of MAPT-AS1 in the progression and paclitaxel resistance in breast cancer, and the regulation between MAPT-AS1 and its natural comparable sense transcripts MAPT. Methods: We analysed the breast cancer patients' clinical information and explored the function of MAPT-AS1 by gain- and loss-of function assays in vitro and in vivo. The regulation between MAPT-AS1 and MAPT was confirmed by gene expression analysis and rescue assays. To verify the hypothesis that MAPT-AS1 and MAPT might form a duplex structure, we performed RT-PCR assays on RNA after alpha-amanitin treatment. Results: By analysing the breast cancer patients' clinical information from the TCGA database, we found that ER-negative patients with younger age (< 60), larger tumors (>= 2 cm), metastatic lymph nodes and stages (III-IV) had higher expression of MAPT-AS1. MAPT-AS1 is correlated with the cell growth, invasiveness and paclitaxel resistance by regulating its natural comparable sense transcripts MAPT in ER-negative breast cancer cells. The result revealed that MAPT-AS1 overexpression could partially protect the MAPT mRNA from degradation, while MAPT-AS1 knockdown decreased the stability of MAPT mRNA. Meanwhile, MAPT knockdown decreased the expression of MAPT-AS1 mRNA. MAPT AS1 expressed coordinately with MAPT in breast tumor tissues. Conclusion: Our study is the first to report a novel lncRNA MAPT-AS1 in human cancer. ER-negative patients with younger age (< 60), larger tumors (>= 2 cm), metastatic lymph nodes and stages (III-IV) had higher expression of MAPT-AS1. MAPT-AS1 is correlated with the cell growth, invasiveness and paclitaxel resistance in ER-negative breast cancer cells through antisense pairing with MAPT. MAPT-AS1 may serve as a potential therapeutic target in ER-negative breast cancers. PMID- 29441194 TI - Leadership and capacity building in international chiropractic research: introducing the chiropractic academy for research leadership (CARL). AB - In an evidence-based health care environment, healthcare professions require a sustainable research culture to remain relevant. At present however, there is not a mature research culture across the chiropractic profession largely due to deficiencies in research capacity and leadership, which may be caused by a lack of chiropractic teaching programs in major universities. As a response to this challenge the Chiropractic Academy for Research Leadership, CARL, was created with the aim of develop a global network of successful early-career chiropractic researchers under the mentorship of three successful senior academics from Australia, Canada, and Denmark. The program centres upon an annual week-long program residential that rotates continental locations over the first three-year cycle and between residentials the CARL fellows work on self-initiated research and leadership initiatives. Through a competivite application process, the first cohort was selected and consists of 13 early career researchers from five professions in seven countries who represent diverse areas of interests of high relevance for chiropractic. The first residential was held in Odense, Denmark, with the second being planned in April 2018 in Edmonton, Canada, and the final residential to be held in Sydney, Australia in 2019. PMID- 29441193 TI - Insights into the roles of lncRNAs in skeletal and dental diseases. AB - Long noncoding RNAs (lncRNAs) are a class of non-protein-coding transcripts with the length longer than 200 nucleotides. Growing evidence suggests that lncRNAs, which were initially thought to be merely transcriptional "noise", participate in a wide repertoire of biological processes. It has been well established that lncRNAs not only play important roles in genomic regulation, transcription, posttranscriptional processes but are also implicated in the pathogenesis of human diseases including cardiovascular diseases, diabetes, neurodegenerative disorders, and cancer. However, the pathological role of lncRNAs in skeletal and dental diseases is just beginning to be uncovered. In the present review, we outline the current understanding of the established functions and underlying mechanisms of lncRNAs in various cellular processes. Furthermore, we discuss new findings on the role of lncRNAs in osteoblastogenesis and osteoclastogenesis as well as their involvement in skeletal and dental diseases. This review intends to provide a general framework for the actions of lncRNAs and highlight the emerging evidence for the functions of lncRNAs in skeletal and dental diseases. PMID- 29333228 TI - Quantification of polysaccharides fixed to Gram stained slides using lactophenol cotton blue and digital image processing. AB - Dark blue rings and circles emerged when the non-specific polysaccharide stain lactophenol cotton blue was added to Gram stained slides. The dark blue staining is attributable to the presence of capsular polysaccharides and bacterial slime associated with clumps of Gram-negative bacteria. Since all bacterial cells are glycosylated and concentrate polysaccharides from the media, the majority of cells stain light blue. The contrast between dark and light staining is sufficient to enable a digital image processing thresholding technique to be quantitative with little background noise. Prior to the addition of lactophenol cotton blue, the Gram-stained slides appeared unremarkable, lacking ubiquitous clumps or stained polysaccharides. Adding lactophenol cotton blue to Gram stained slides is a quick and inexpensive way to screen cell cultures for bacterial slime, clumps and biofilms that are invisible using the Gram stain alone. The presence of cell clumping provides a possible explanation of the presence of persisters and paradoxical points observed in Virtual Colony Count antimicrobial assays, and suggests a phenotypic resistance mechanism to antimicrobial peptides involving capsular polysaccharides. PMID- 29441195 TI - Identification, differentiation and antibiotic susceptibility of Gallibacterium isolates from diseased poultry. AB - Background: Gallibacterium anatis is an opportunistic pathogen of intensively reared poultry causing oophoritis, salpingitis, peritonitis and enteritis. Gallibacterium anatis infection often remains undiagnosed. Recently multi-drug resistant isolates have been described. Methods: A newly developed PCR restriction fragment length polymorphism assay targeting the 16S rRNA gene was used to identify and differentiate Gallibacterium isolates from chicken, turkey and partridge samples originating from 18 different geographical locations in Thuringia, Germany. Antimicrobial susceptibility to 19 compounds of different classes was assessed. Results: Nineteen Gallibacterium isolates were investigated. In 9 birds (47.4%) Gallibacterium species were isolated exclusively while in 10 birds (52.6%) other bacterial or viral agents could be detected in addition. In one chicken a mixed infection of Gallibacterium anatis and Gallibacterium genomospecies was identified. All isolates were susceptible to apramycin, florfenicol and neomycin and resistant to clindamycin, sulfathiazole and penicillin. Resistance to sulfamethoxim, spectinomycin, tylosin and oxytetracycline was observed in 93.3%, 93.3%, 86.7% and 80.0% of the field strains, respectively. Conclusions: The PCR-RFLP assay allows specific detection and differentiation of Gallibacterium spp. from poultry. Antimicrobial resistance of Gallibacterium spp. is highly significant in Thuringian field isolates. PMID- 29333228 TI - Quantification of polysaccharides fixed to Gram stained slides using lactophenol cotton blue and digital image processing. AB - Dark blue rings and circles emerged when the non-specific polysaccharide stain lactophenol cotton blue was added to Gram stained slides. The dark blue staining is attributable to the presence of capsular polysaccharides and bacterial slime associated with clumps of Gram-negative bacteria. Since all bacterial cells are glycosylated and concentrate polysaccharides from the media, the majority of cells stain light blue. The contrast between dark and light staining is sufficient to enable a digital image processing thresholding technique to be quantitative with little background noise. Prior to the addition of lactophenol cotton blue, the Gram-stained slides appeared unremarkable, lacking ubiquitous clumps or stained polysaccharides. Adding lactophenol cotton blue to Gram stained slides is a quick and inexpensive way to screen cell cultures for bacterial slime, clumps and biofilms that are invisible using the Gram stain alone. The presence of cell clumping provides a possible explanation of the presence of persisters and paradoxical points observed in Virtual Colony Count antimicrobial assays, and suggests a phenotypic resistance mechanism to antimicrobial peptides involving capsular polysaccharides. PMID- 29333228 TI - Quantification of polysaccharides fixed to Gram stained slides using lactophenol cotton blue and digital image processing. AB - Dark blue rings and circles emerged when the non-specific polysaccharide stain lactophenol cotton blue was added to Gram stained slides. The dark blue staining is attributable to the presence of capsular polysaccharides and bacterial slime associated with clumps of Gram-negative bacteria. Since all bacterial cells are glycosylated and concentrate polysaccharides from the media, the majority of cells stain light blue. The contrast between dark and light staining is sufficient to enable a digital image processing thresholding technique to be quantitative with little background noise. Prior to the addition of lactophenol cotton blue, the Gram-stained slides appeared unremarkable, lacking ubiquitous clumps or stained polysaccharides. Adding lactophenol cotton blue to Gram stained slides is a quick and inexpensive way to screen cell cultures for bacterial slime, clumps and biofilms that are invisible using the Gram stain alone. PMID- 29375810 TI - Optimal cutoff for the evaluation of insulin resistance through triglyceride glucose index: A cross-sectional study in a Venezuelan population. AB - Background: Insulin resistance (IR) evaluation is a fundamental goal in clinical and epidemiological research. However, the most widely used methods are difficult to apply to populations with low incomes. The triglyceride-glucose index (TGI) emerges as an alternative to use in daily clinical practice. Therefore the objective of this study was to determine an optimal cutoff point for the TGI in an adult population from Maracaibo, Venezuela. Methods: This is a sub-study of Maracaibo City Metabolic Syndrome Prevalence Study, a descriptive, cross sectional study with random and multi-stage sampling. For this analysis, 2004 individuals of both genders >=18 years old with basal insulin determination and triglycerides < 500 mg/dl were evaluated.. A reference population was selected according to clinical and metabolic criteria to plot ROC Curves specific for gender and age groups to determine the optimal cutoff point according to sensitivity and specificity.The TGI was calculated according to the equation: ln [Fasting triglyceride (mg / dl) x Fasting glucose (mg / dl)] / 2. Results: The TGI in the general population was 4.6+/-0.3 (male: 4.66+/-0.34 vs. female: 4.56+/ 0.33, p=8.93x10 -10). The optimal cutoff point was 4.49, with a sensitivity of 82.6% and specificity of 82.1% (AUC=0.889, 95% CI: 0.854-0.924). There were no significant differences in the predictive capacity of the index when evaluated according to gender and age groups. Those individuals with TGI>=4.5 had higher HOMA2-IR averages than those with TGI <4.5 (2.48 vs 1.74, respectively, p<0.001). Conclusions: The TGI is a measure of interest to identify IR in the general population. We propose a single cutoff point of 4.5 to classify individuals with IR. Future studies should evaluate the predictive capacity of this index to determine atypical metabolic phenotypes, type 2 diabetes mellitus and even cardiovascular risk in our population. PMID- 29259763 TI - Blinding in trials of interventional procedures is possible and worthwhile. AB - In this paper, we use evidence from our earlier review of surgical randomised controlled trials with a placebo arm to show that blinding in trials of interventional procedures is feasible. We give examples of ingenious strategies that have been used to simulate the active procedure and to make the placebo control indistinguishable from the active treatment. We discuss why it is important to blind of patients, assessors, and caregivers and what types of bias that may occur in interventional trials. Finally, we describe the benefits of blinding, from the obvious ones such as avoiding bias, as well as less evident benefits such as avoiding patient drop out in the control arm. PMID- 29441201 TI - Leech management before application on patient: a nationwide survey of practices in French university hospitals. AB - Background: Leech therapy in plastic/reconstructive microsurgery significantly improves a successful outcome of flap salvage but the drawback is a risk of severe infection that results in a drop of the salvage rates from 70-80% to below 30%. We report the results of a national survey conducted in all the French university hospitals to assess the current extent of use of leech for medical practices in the hospital and to investigate maintenance, delivery practices and prevention of the risk of infection. Methods: Data concerning conditions of storage, leech external decontamination, microbiological controls, mode of delivery and antibiotic prophylaxis were collected from all the French university hospitals in practicing leech therapy, on the basis of a standardized questionnaire. Results: Twenty-eight of the 32 centers contacted filled the questionnaire, among which 23 practiced leech therapy, mostly with a centralized storage in the pharmacy; 39.1% of the centers declared to perform leech external decontamination and only 2 centers recurrent microbiological controls of the water storage. Leech delivery was mostly nominally performed (56.5%), but traceability of the leech batch number was achieved in only 39.1% of the cases. Only 5 centers declared that a protocol of antibiotic prophylaxis was systematically administered during leech therapy: either quinolone (2), sulfamethoxazole/trimethoprim (2) or amoxicillin/clavulanic acid (1). Conclusions: Measures to prevent infectious complications before application to patient have to be better applied and guidelines of good practices are necessary. PMID- 29441203 TI - Correction of self-reported BMI based on objective measurements: a Belgian experience. AB - Background: Based on successive Health Interview Surveys (HIS), it has been demonstrated that also in Belgium obesity, measured by means of a self-reported body mass index (BMI in kg/m2), is a growing public health problem that needs to be monitored as accurately as possible. Studies have shown that a self-reported BMI can be biased. Consequently, if the aim is to rely on a self-reported BMI, adjustment is recommended. Data on measured and self-reported BMI, derived from the Belgian Food Consumption Survey (FCS) 2014 offers the opportunity to do so. Methods: The HIS and FCS are cross-sectional surveys based on representative population samples. This study focused on adults aged 18-64 years (sample HIS = 6545 and FCS = 1213). Measured and self-reported BMI collected in FCS were used to assess possible misreporting. Using FCS data, correction factors (measured BMI/self-reported BMI) were calculated in function of a combination of background variables (region, gender, educational level and age group). Individual self reported BMI of the HIS 2013 were then multiplied with the corresponding correction factors to produce a corrected BMI-classification. Results: When compared with the measured BMI, the self-reported BMI in the FCS was underestimated (mean 0.97 kg/m2). 28% of the obese people underestimated their BMI. After applying the correction factors, the prevalence of obesity based on HIS data significantly increased (from 13% based on the original HIS data to 17% based on the corrected HIS data) and approximated the measured one derived from the FCS data. Conclusions: Since self-reported calculations of BMI are underestimated, it is recommended to adjust them to obtain accurate estimates which are important for decision making. PMID- 29441202 TI - Pulse wave Doppler ultrasound of testicular arteries and their relationship with semen characteristics in healthy bulls. AB - Background: Semen evaluation is used to estimate the testicular function. In bulls, the spermatozoa present in the ejaculate are the result of a process that begun more than 2 mo earlier, bequeathing a delayed depiction of the actual function of the testis. Since testis vascularization might be critical for the gonad function, selected pulse wave Doppler ultrasound parameters were assessed in this study, for instance the peak systolic velocity, the end diastolic velocity and the resistive index of the testicular artery along the spermatic cord, the marginal portion of the testicular artery and the intratesticular branches of the testicular artery both in healthy adult and young bulls. Correlations between these parameters and characteristics of semen that was collected numerous times, before and after the Doppler ultrasound examination. Results: The peak systolic velocity and the end diastolic velocity measured in the testicular artery along the spermatic cord (supratesticular artery - SA) were variable among the bulls and within individual bulls, likely due to the convoluted course of the vessel. The resistive index was found highly repeatable in the same bull. A reduction in the resistive index was found between the supratesticular artery and the marginal portion of the testicular artery (P < 0.01), and between the marginal portion of the testicular artery and the intratesticular branches of the testicular artery (P < 0.05). No differences were recorded for the pulse wave Doppler ultrasound parameters in young bulls compared with adults. A significant correlation was found between the resistive index of the marginal portion of the testicular artery and total sperm in the ejaculate (r = 0.516, P < 0.05), the immature sperm (r = 0.462, P < 0.05), the teratoid sperm (r = 0.375, P < 0.05), and the "Dag defect" sperm (r = 0.389, P < 0.05). Similarly, the resistive index of the intratesticular branches of the testicular artery were found correlated with the total sperm number in the ejaculate (r = 0.568, P < 0.05), the immature sperm (r = 0.523, P < 0.05), the teratoid sperm (r = 0.418, P < 0.05), and the "Dag defect" sperm (r = 0.341, P < 0.05). Conclusions: The data presented in this study suggest that the resistive index, measured at the marginal portion of the testicular artery, could be an easy-to perform parameter to evaluate the spermatogenesis quality in young bulls and normal adults. PMID- 29441204 TI - Relationships between compulsive exercise, quality of life, psychological distress and motivation to change in adults with anorexia nervosa. AB - Background: For people with anorexia nervosa (AN), compulsive exercise is characterized by extreme concerns about the perceived negative consequences of stopping/reducing exercise, dysregulation of affect, and inflexible exercise routines. It is associated with increased eating disorder psychopathology and poor clinical outcome. However, its relationships with two important clinical issues, quality of life (QoL) and motivation to change, are currently unknown. This study aimed to assess the cross-sectional relationships between compulsive exercise, QoL, psychological distress (anxiety and depressive symptoms, and obsessive-compulsive traits) and motivation to change in patients with AN. Method: A total of 78 adults with AN participated in this study, which was nested within a randomized controlled trial of psychological treatments for AN. At baseline (pre-treatment), participants completed questionnaires assessing compulsive exercise, eating disorder (ED) psychopathology, QoL, psychological distress and motivation to change. Results: Baseline correlational analyses demonstrated a moderate positive relationship between compulsive exercise and ED psychopathology, and a weak positive relationship between compulsive exercise and psychological distress. There was a moderate negative relationship between compulsive exercise and eating disorder QoL. Conclusions: These results indicate compulsive exercise is moderately associated with poorer QoL and weakly associated with higher distress. Targeting compulsive exercise in the treatment of anorexia nervosa may help reduce the burden of illness and improve patients' engagement in treatment. Trial registration: ACTRN12610000585022. Taking a LEAP forward in the treatment of anorexia nervosa: a randomized controlled trial. NHMRC grant: 634922. PMID- 29441206 TI - Endobronchial valves for emphysema: an individual patient-level reanalysis of randomised controlled trials. AB - Introduction: Endobronchial valve placement has potential as a treatment for patients with chronic obstructive pulmonary disease (COPD). However, a robust evidence base will be needed to convince commissioners of healthcare that it is a high-value treatment. We sought to develop the evidence base by performing an individual patient-level analysis of randomised controlled trials in people with heterogeneous emphysema and an absence of collateral ventilation. Methods: A literature search (PROSPERO register CRD42016048127) identified two trials meeting these criteria, the BelieVeR-HIFi and STELVIO studies. Anonymised individual patient data were obtained from investigators and analysed. The primary outcome measure was a comparison of change in forced expiratory volume in 1 s (FEV1) from baseline between the treatment and control groups. Secondary end points were change from baseline in 6 min walk distance (6MWD), Medical Research Council dyspnoea score and St George's Respiratory Questionnaire (SGRQ). Results: 114 individuals were treated with 3-month to 6-month follow-up data available for 101 individuals. FEV1 improved by 23.1 (+/-28.3)% in patients treated with valves with a mean (95% CI) difference in response between groups of 17.8 (26.5, 9.2)% (p<0.0001). Relative to controls valve placement was associated with a fall in residual volume of 0.64 (0.43, 0.86) L (p<0.0001), a 9.5 (3.5, 15.6) unit fall in SGRQ (p=0.0022) and a 64.2 (94.0, 34.5) m increase in 6MWD. There were three deaths in the treatment arm and the pneumothorax rate was 15%. Conclusions: These data strengthen the evidence that endobronchial valve treatment can produce clinically meaningful improvements in appropriately selected COPD patients. PMID- 29441205 TI - Sphingosine kinase 2 supports the development of BCR/ABL-independent acute lymphoblastic leukemia in mice. AB - Background: Sphingosine kinase (SphK) 2 has been implicated in the development of a range of cancers and inhibitors of this enzyme are currently in clinical trial. We have previously demonstrated a role for SphK2 in the development of acute lymphoblastic leukemia (ALL). Methods: In this and our previous study we use mouse models: in the previous study the disease was driven by the proto-oncogene BCR/ABL1, while in this study cancer risk was elevated by deletion of the tumor suppressor ARF. Results: Mice lacking ARF and SphK2 had a significantly reduced incidence of ALL compared mice with wild type SphK2. Conclusions: These results show that the role of SphK2 in ALL development is not limited to BCR/ABL1 driven disease extending the potential use of inhibitors of this enzyme to ALL patients whose disease have driver mutations other than BCR/ABL1. PMID- 29441207 TI - Synthesis, Antimicrobial, and Computational Evaluation of Novel Isobutylchalcones as Antimicrobial Agents. AB - A series of 25 new chalcones were synthesized by Claisen-Schmidt condensation, well characterized by spectroscopic data, and evaluated for their antibacterial and antifungal activities by serial tube dilution method. Among the compounds tested, A3 and A6 containing 2,4-dichlorophenyl and 2,4-difluorophenyl moiety, respectively, were found to be the most potent in the series against both bacterial and fungal strains with a MIC value of 16 ug/mL in each case. Further computational evaluation for antimicrobial activity was performed by atom based 3D-QSAR using PHASETM software in order to have a correlation between the observed activities and predicted activities. The computational studies were in agreement with the in vitro antimicrobial results and had identified the most promising chalcones as antimicrobial agents and the responsible structural features for the proposed activity. PMID- 29441209 TI - Retrospective Identification of Herpes Simplex 2 Virus-Associated Acute Liver Failure in an Immunocompetent Patient Detected Using Whole Transcriptome Shotgun Sequencing. AB - Acute liver failure (ALF) is a severe condition in which liver function rapidly deteriorates in individuals without prior history of liver disease. While most cases result from acetaminophen overdose or viral hepatitis, in up to a third of patients, no clear cause can be identified. Liver transplantation has greatly reduced mortality among these patients, but 40% of patients recover without liver transplantation. Therefore, there is an urgent need for rapid determination of the etiology of acute liver failure. In this case report, we present a case of herpes simplex 2 virus- (HSV-) associated ALF in an immunocompetent patient. The patient recovered without LT, but the presence of HSV was not suspected at the time, precluding more effective treatment with acyclovir. To determine the etiology, stored blood samples were analyzed using whole transcriptome shotgun sequencing followed by mapping to a panel of viral reference sequences. The presence of HSV-DNA in blood samples at the time of admission was confirmed using real-time polymerase chain reaction, and, at the time of discharge, HSV-DNA levels had decreased by a factor of 106. Conclusions. In ALF cases of undetermined etiology, uncommon causes should be considered, especially those for which an effective treatment is available. PMID- 29441208 TI - Microvessel Density in Patients with Cutaneous Melanoma: An Up-to-Date Systematic Review and Meta-Analysis. AB - Background: We conducted a meta-analysis, in order to appraise the effect of microvessel density (MVD) on the survival of patients with cutaneous melanoma. Methods: This study was conducted according to the PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. A systematic literature search in electronic databases (MEDLINE, Web of Science, and Cochrane Central Register of Controlled Clinical Trials) was performed. Fixed Effects or Random Effects model was used, based on the Cochran Q test. Results: In total 9 studies (903 patients) were included. Pooled HR for overall survival (OS) and disease-free survival (DFS) were 2.62 (95% CI: 0.71-9.60, p = 0.15) and 2.64 (95% CI: 0.82-8.47, p = 0.10), respectively. Odds ratios of overall survival between high and low MVD groups, at 12 (1.45, 95% CI: 0.16-13.24), 36 (2.93, 95% CI: 0.63 13.59), and 60 (4.09, 95% CI: 0.85-19.77) months did not reach statistical significance. Significant superiority of low MVD group, in terms of DFS, at all time intervals (OR: 4.69, p < 0.0001; OR: 2.18, p = 0.004; OR: 7.46, p = 0.01, resp.) was documented. Discussion: MVD does not affect the HR of OS and DFS. A strong correlation with DFS rates at 12, 36, and 60 months was recorded. PMID- 29441210 TI - Acute, Nontraumatic Spontaneous Spinal Subdural Hematoma: A Case Report and Systematic Review of the Literature. AB - Spontaneous spinal subdural hematoma (sSDH) is a rare condition outright. Moreover, cases that occur spontaneously in the absence of an identifiable etiology are considerably less common and remain poorly understood. Here, we present the case of a 43-year-old man with spontaneous sSDH presenting with acute onset low back pain and paraplegia. Urgent magnetic resonance imaging identified a dorsal SDH from T8 to T11 with compression of the spinal cord. Emergent T8-T10 laminectomies with intradural exploration and hematoma evacuation were performed. However, despite prompt identification and appropriate action, the patient's recovery was modest and significant disability remained at discharge. This unique and unusual case demonstrates that spontaneous sSDH requires prompt surgical treatment to minimize associated morbidity and supports the association between the presence of severe neurological deficits upon initial presentation with less favorable outcomes. We performed a comprehensive systematic review of spontaneous sSDH of unknown etiology, which demonstrates that emergent surgical intervention is indicated for patients presenting with severe neurological deficits and the presence of these deficits is predictive of poor neurological outcome. Furthermore, conservative management should be considered in patients presenting with mild neurological deficits as spontaneous resolution followed by favorable neurological outcomes is often observed in these patients. PMID- 29441211 TI - A Rare Case of Craniopharyngioma in the Temporal Lobe. AB - Herein, we report on a rare case of craniopharyngioma arising in the left temporal lobe with no prior history of head trauma or surgery. There was a solid cystic mass in the left temporal lobe on MR images. To the best of our knowledge, this is the second case of a craniopharyngioma occurring in the temporal lobe. PMID- 29441212 TI - Misplacement of a Port Catheter: A Differentiated View. AB - Clinical radiological controls after the insertion of central venous catheters (CVC) are of high importance. Misplacement of the CVC, outside of large vessels, as described in our first case, occurs in more than 7% of cases and may be associated with life-threatening events. A persistent left-sided superior vena cava (PLSSVC) occurs in 0.3-0.5% of the standard population. In one of the cases a CT scan of the chest showed the catheter in a PLSSVC. Neoadjuvant radiochemotherapy was indicated in a patient with an adenocarcinoma of the oesophagus. Under hospitalised monitoring, full-dose chemotherapy was given. Consequences for the patients arise when the findings are known for future interventions. If a PLSSVC is expected and a CVC is to be inserted, the venous return to the heart should be evaluated first, to preclude a possible backflow to the left atrium. With this constellation, a right-to-left shunt can be expected in in 10% of cases. Affected patients face a high risk of developing cardioembolic events. PMID- 29441213 TI - Newly Developed Nano-Calcium Carbonate and Nano-Calcium Propanoate for the Deacidification of Library and Archival Materials. AB - Paper-based cultural heritage objects are subject to natural deterioration due to internal and external factors, that is, the presence of heavy metals, incorrect conservation, humidity, exposure of the artifacts to pollutants, light, and high temperatures. To contrast the decay of the original objects, it is necessary to study and apply innovative specific techniques, set up novel preservation methodologies, and implement or synthesize new products. As the nanomaterial science field developed over the last decades, the usage of nanomaterials in cultural heritage gained a prominent role. Such an excitement for the novel materials opened the path for an uncontrolled transfer of nanoparticles developed for different applications to paper restoration, neglecting all their possible interactions with the support or the graphic media. The aim of this work was to synthesize new nanomaterials expressly conceived for the treatment of library materials. To evaluate their possible insertion in the official conservation treatments that are subjected to validation by Istituto Centrale Restauro e Conservazione Patrimonio Archivistico e Librario, the new nanomaterials were tested both on laboratory paper samples and on original documents. This work presents the results of these studies (some of which still preliminary) stressing the positive and extremely promising outcomes of this research. PMID- 29441215 TI - Pycnodysostosis: Novel Variants in CTSK and Occurrence of Giant Cell Tumor. AB - Pycnodysostosis is an autosomal recessive skeletal dysplasia caused by pathogenic variants in the cathepsin K ( CTSK ) gene. We report seven patients from four unrelated families with this condition in whom we have identified three novel pathogenic variants, c.120 + 1G > T in intron 2, c.399 + 1G > A in intron 4, and c.148T > G (p.W50G) in exon 2, and a known variant, c.568C > T (p.Q190*) in exon 5 of CTSK . We present the clinical, radiographic, and molecular findings of all individuals with molecularly proven pycnodysostosis from the present cohort. We also report the occurrence of giant cell tumor in the skull of a patient with this condition. PMID- 29441214 TI - Syndromic Hearing Loss: A Brief Review of Common Presentations and Genetics. AB - Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400 different syndromes involving hearing loss have been described, it is important to be familiar with a wide range of syndromes involving hearing loss so an early diagnosis can be made and early intervention can be pursued to maximize functional hearing and speech-language development in the setting of verbal communication. This review aims to describe the presentation and genetics for some of the most frequently occurring syndromes involving hearing loss, including neurofibromatosis type 2, branchio-oto-renal syndrome, Treacher Collins syndrome, Stickler syndrome, Waardenburg syndrome, Pendred syndrome, Jervell and Lange Nielsen syndrome, Usher syndromes, Refsum disease, Alport syndrome, MELAS, and MERRF. PMID- 29441216 TI - Cathepsin D Polymorphism C224T in Childhood-Onset Neurodegenerative Disorders: No Impact for Childhood Dementia. AB - Compromised lysosomal functioning has been identified as a major risk factor for neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Furthermore, the association between a defined cathepsin D ( CTSD ) polymorphism and a higher risk of sporadic Alzheimer's disease has been established for particular populations. Here, we analyzed 189 children with rare neurodegenerative disease for carrying the T-allele by polymerase chain reaction restriction fragment length polymorphism. We found no statistical differences in genotype and allele frequencies between the neurodegenerative group and European descent participants of genetic studies using the Cochran-Armitage's trend test. In contrast to adult-onset neurodegenerative diseases, analysis of clinical datasets of children carrying the T-allele did not demonstrate differences to the general disease group. PMID- 29441217 TI - No Association of Genetic Markers with Carotid Intimal Medial Thickness in beta Thalassemia Major Patients. AB - Regular transfusion leads to cardiac siderosis resulting in cardiac complications that account for more than 71% of the total mortality in thalassemia patients. We aimed to study the variants of matrix metalloproteinase-9 (MMP9), matrix Gla protein (MGP), and estrogen receptor alpha(ERalpha), which might be contributing to atherosclerosis, leading to heart failure in thalassemia major. One hundred and five thalassemia patients on regular transfusion and iron chelation therapy were enrolled for the study. Carotid artery intimal medial thickness (CIMT) measurement was done to check for atherosclerosis. MMP 9 (C1562T), MGP (T138C), and ER alpha gene ( Pvu II (rs2234693T > C) and Xba I (rs9340799A > G) polymorphism were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. CIMT values were within the normal range (<0.90 mm) in all patients. There was no difference in mean CIMT values between males and females (0.56 +/- 0.11 versus 0.56 +/- 0.12, p = 0.928). There was no correlation of CIMT with age, body surface area, and body mass index as well as with serum ferritin levels. No statistically significant difference in frequency of MMP9, MGP, and ERalpha genotypes was seen in two dichotomized groups of CIMT (CIMT < 0.56 and CIMT >= 0.56). Variants of MMP9 , MGP , and ERalpha have a reserved influence on cardiac disease pathogenesis, and the disease phenotype in thalassemia patients may be more strongly impacted by other factors. PMID- 29441218 TI - A Rare Combination of Functional Disomy Xp, Deletion Xq13.2-q28 Spanning the XIST Gene, and Duplication 3q25.33-q29 in a Female with der(X)t(X;3)(q13.2;q25.33). AB - We report a 19-year-old female patient with a history of short stature, primary ovarian insufficiency, sensorineural hearing loss, sacral teratoma, neurogenic bladder, and intellectual disability with underlying mosaicism for der(X)t(X;3)(q13.2;q25.33), a ring X chromosome, and monosomy X. Derivative X chromosomes from unbalanced X-autosomal translocations are preferentially silenced by the XIST gene (Xq13.2) located within the X-inactivation center. The unbalanced X-autosomal translocation in our case resulted in loss of the XIST gene thus precluding the inactivation of the derivative X chromosome. As a result, clinical features of functional disomy Xp, Turner's syndrome, and duplication 3q syndrome were observed. Importantly, indications of the derivative X chromosome were revealed by microarray analysis following an initial diagnosis of Turner's syndrome made by conventional cytogenetic studies approximately 18 months earlier. This case demonstrates the importance of utilizing microarray analysis as a first-line test in patients with clinical features beyond the scope of a well-defined genetic syndrome. PMID- 29441219 TI - A New Patient with Potocki-Lupski Syndrome: A Literature Review. AB - Speech delay, intellectual disability, and behavioral disturbances are the main clinical manifestations of Potocki-Lupski syndrome. Other features include infantile hypotonia, the absence of major dysmorphism, sleep disorders, and congenital anomalies, particularly of the cardiovascular system. A male patient with Potocki-Lupski syndrome is reported herein. He showed speech and borderline cognitive delay, behavioral troubles with no signs suggestive of autism, in the absence of major dysmorphism. A de novo 17p12-p11.2 duplication spanning 3.6 Mb was detected, with boundaries from 15,284,052 to 18,647,233 (hg19 assembly). At the age of 5 years, the child showed a noticeable improvement of speech skills and a moderate scholastic performance was reached. Upon analysis of the clinical manifestations of the present patient and those reported in existing literature, we found that the syndrome may present in various degrees of clinical expressivity. Affected patients may manifest symptoms ranging from mild behavioral disturbances to severe degrees of autism. PMID- 29441220 TI - Inheritance of a Balanced t(12;20)(q24.33;p12.2) and Unbalanced der(13)t(7;13)(p21.3;q33.2) from a Maternally Derived Double Balanced Translocation Carrier. AB - We report a 4-month-old male proband with a history of prominent forehead, hypertelorism, ear abnormalities, micrognathia, hypospadias, and multiple cardiac abnormalities. Initial microarray analysis detected a concurrent 7p21.3-p22.3 duplication and 13q33.2-q34 deletion indicating an unbalanced rearrangement. However, subsequent conventional cytogenetic studies only revealed what appeared to be a balanced t(12;20)(q24.33;p12.2). Fluorescence in situ hybridization (FISH) using chromosome-specific subtelomere probes confirmed the presence of an unbalanced der(13)t(7;13)(p21.3;q33.2) and balanced t(12;20)(q24.33;p12.2), both of maternal origin. In addition to our unique clinical findings, this case highlights the benefits and limitations of both conventional cytogenetic studies and microarray analysis and how FISH complements each methodology. PMID- 29441221 TI - NFU1 -Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy. AB - Genetic leukoencephalopathies represent an expanding group of inherited disorders associated with involvement of brain white matter. Cystic degeneration has been previously described with some acquired or inherited leukoencephalopathies. We describe a 6-month-old Brazilian boy with a 2-month history of severe and rapidly progressive developmental and psychomotor regression and seizures. Neurological examination showed spastic tetraparesis and lethargy. Neuroimaging showed diffuse and symmetric cavitating cystic leukoencephalopathy. Whole-exome sequencing revealed compound heterozygous mutations in the NFU1 gene, providing definite genetic diagnosis of multiple mitochondrial dysfunction syndrome type 1. We report a rare presentation of early-onset cystic leukoencephalopathy in the context of multiple mitochondrial dysfunction syndrome type 1. PMID- 29441222 TI - Disability-Related Problems of Children and Adolescents with Moebius Sequence and their Mothers' Coping. PMID- 29441223 TI - Sensorineural Hearing Loss and Congenital Cytomegalovirus Infection. PMID- 29441224 TI - 22q11 Deletion Syndrome with Vascular Anomalies. AB - DiGeorge syndrome, also termed 22q11.2 deletion syndrome, represents a spectrum of disorders that include thymic aplasia/hypoplasia, parathyroid aplasia/hypoplasia, conotruncal vascular anomalies, and velocardiofacial (Shprintzen) syndrome. This case report describes a novel constellation of cardiovascular anomalies in a 31-year-old patient with 22q11.2 deletion confirmed by fluorescence in situ hybridization at the age of 24. CT angiogram of the thorax revealed a right aortic arch with mirror image branching and unilateral absence of the left pulmonary artery with collateral flow through left intercostal arteries and hypertrophied left bronchial artery. This particular cluster of vascular findings has not been previously described in the imaging literature in a patient with known 22q11.2 deletion. PMID- 29441226 TI - Plexiform Neurofibroma in the Axilla with Intraosseous Neurofibroma in the Humerus in Neurofibromatosis 5. AB - Segmental neurofibromatosis type 5 (NF5) is a rare form of NF, in which the cutaneous and/or neural changes are confined to one region of the body. It is often underdiagnosed or undetected due to the absence of symptoms. Inheritance of NF is different from other types of NF. Intraosseous neurofibromas are rare tumors which develop from nerves supplying the periosteum or nerves following the intraosseous course. Plexiform neurofibroma with associated intraosseous neurofibroma is extremely rare. We report a case of plexiform neurofibroma in the left axilla of a 17-year-old female with associated intraosseous neurofibroma in adjoining left humerus. PMID- 29441225 TI - Assessment of the Agreement between Cerebral Hemodynamic Indices Quantified Using Dynamic Susceptibility Contrast and Dynamic Contrast-enhanced Perfusion Magnetic Resonance Imagings. AB - Background: Brain tumor is one of the most common tumors. A successful treatment might be achieved with an early identification. Pathological investigation as the gold standard method for tumor identification has some limitations. Noninvasive assessment of tumor specifications may be possible using perfusion-weighted magnetic resonance imaging (MRI). Cerebral blood volume (CBV) and cerebral blood flow (CBF) could be calculated based on dynamic contrast-enhanced MRI (DCE-MRI) in addition to dynamic susceptibility contrast MRI (DSC-MRI) modality. Each category of the cerebral hemodynamic and permeability indices revealed the specific tumor characteristics and their collection could help for better identification of the tumor. Some mathematical methods were developed to determine both cerebral hemodynamic and permeability indices based on a single dose DCE perfusion MRI. There are only a few studies available on the comparison of DSC- and DCE-derived cerebral hemodynamic indices such as CBF and CBV. Aim: The objective of the study was to validate first-pass perfusion parameters derived from T1-based DCE method in comparison to the routine T2*-based DSC protocol. Materials and Methods: Twenty-nine patients with brain tumor underwent DCE- and DSC-MRIs to evaluate the agreement between DSC- and DCE-derived cerebral hemodynamic parameters. Agreement between DSC- and DCE-derived cerebral hemodynamic indices was determined using the statistical method described by Bland and Altman. The reliability between DSC- and DCE-derived cerebral hemodynamic indices was measured using the intraclass correlation analysis. Results: The achieved magnitudes for DCE-derived CBV (gray matter [GM]: 5.01 +/- 1.40 mL/100 g vs. white matter [WM]: 1.84 +/- 0.74 mL/100 g) and DCE-derived CBF (GM: 60.53 +/- 12.70 mL/100 g/min vs. WM: 32.00 +/- 6.00 mL/100 g/min) were in good agreement with other studies. The intraclass correlation coefficients showed that the cerebral hemodynamic indices could accurately be estimated based on the DCE-MRI using a single-compartment model (>0.87), and DCE-derived cerebral hemodynamic indices are significantly similar to the magnitudes achieved based on the DSC-MRI (P < 0.001). Furthermore, an acceptable agreement was observed between DSC- and DCE-derived cerebral hemodynamic indices. Conclusion: Based on the measurement of the cerebral hemodynamic and blood-brain barrier permeability using DCE-MRI, a more comprehensive collection of the physiological parameters cloud be achieved for tumor evaluations. PMID- 29441227 TI - Pancreaticoportal Fistula Formation as a Consequence of Recurrent Acute Pancreatitis: Clinical and Imaging Considerations. AB - A pancreatic-portal vein fistula (PPVF) is an extremely rare complication of pancreatitis. In this report, we present a patient with a PPVF in the setting of recurrent pancreatitis and portal vein thrombosis diagnosed by cross-sectional imaging and endoscopic retrograde cholangio-pancreatography, who responded to medical management and anticoagulation. A critical review of this disease process is explored to highlight pathology, imaging characteristics, and essential alternative diagnostic considerations. We also discuss potential complications and current treatment strategies. PPVFs pose a unique diagnostic challenge and awareness of its clinical presentation can further improve patient outcomes. PMID- 29441228 TI - A gene expression-based risk model reveals prognosis of gastric cancer. AB - Background: The prognosis of gastric cancer is difficult to determine, although clinical indicators provide valuable evidence. Methods: In this study, using screened biomarkers of gastric cancer in combination with random forest variable hunting and multivariable Cox regression, a risk score model was developed to predict the survival of gastric cancer. Survival difference between high/low-risk groups were compared. The relationship between risk score and other clinicopathological indicators was evaluated. Gene set enrichment analysis (GSEA) was used to identify pathways associated with risk scores. Results: The patients with high risk scores (median overall survival: 20.2 months, 95% CI [16.9-26.0] months) tend to exhibit early events compared with those with low risk scores (median survival: 70.0 months, 95% CI [46.9-101] months, p = 1.80e-5). Further validation was implemented in another three independent datasets (GSE15459, GSE26253, GSE62254). Correlation analyses between clinical observations and risk scores were performed, and the results indicated that the risk score was not significantly associated with gender, age and primary tumor size but was significantly associated with grade and tumor stage. In addition, the risk score was also not influenced by radiation therapy. Cox multivariate regression and three-year survival nomogram suggest that the risk score is an important indicator of gastric cancer prognosis. GSEA was used to identified KEGG pathways significantly associated with risk score, and signaling pathways involved in focal adhesion and the TGF-beta signaling pathway were identified. Conclusion: The risk score model successfully predicted the survival of 1,294 gastric cancer samples from four independent datasets and is among the most important indicators in clinical clinicopathological information for the prognosis of gastric cancer. To our knowledge, it is the first report to predict the survival of gastric cancer using optimized expression panel. PMID- 29441229 TI - Isolation, identification, and pathological effects of beach sand bacterial extract on human skin keratinocytes in vitro. AB - Background: Beaches are recreational spots for people. However, beach sand contains harmful microbes that affect human health, and there are no established methods for either sampling and identifying beach-borne pathogens or managing the quality of beach sand. Method: This study was conducted with the aim of improving human safety at beaches and augmenting the quality of the beach experience. Beach sand was used as a resource to isolate bacteria due to its distinctive features and the biodiversity of the beach sand biota. A selected bacterial isolate termed FSRS was identified as Pseudomonas stutzeri using 16S rRNA sequencing and phylogenetic analysis, and the sequence was deposited in the NCBI GenBank database under the accession number MF599548. The isolated P. stutzeri bacterium was cultured in Luria-Bertani growth medium, and a crude extract was prepared using ethyl acetate to examine the potential pathogenic effect of P. stutzeri on human skin. A human skin keratinocyte cell line (HaCaT) was used to assess cell adhesion, cell viability, and cell proliferation using a morphological analysis and a WST-1 assay. Result: The crude P. stutzeri extract inhibited cell adhesion and decreased cell viability in HaCaT cells. We concluded that the crude extract of P. stutzeri FSRS had a strong pathological effect on human skin cells. Discussion: Beach visitors frequently get skin infections, but the exact cause of the infections is yet to be determined. The beach sand bacterium P. stutzeri may, therefore, be responsible for some of the dermatological problems experienced by people visiting the beach. PMID- 29441230 TI - Forecasting biodiversity in breeding birds using best practices. AB - Biodiversity forecasts are important for conservation, management, and evaluating how well current models characterize natural systems. While the number of forecasts for biodiversity is increasing, there is little information available on how well these forecasts work. Most biodiversity forecasts are not evaluated to determine how well they predict future diversity, fail to account for uncertainty, and do not use time-series data that captures the actual dynamics being studied. We addressed these limitations by using best practices to explore our ability to forecast the species richness of breeding birds in North America. We used hindcasting to evaluate six different modeling approaches for predicting richness. Hindcasts for each method were evaluated annually for a decade at 1,237 sites distributed throughout the continental United States. All models explained more than 50% of the variance in richness, but none of them consistently outperformed a baseline model that predicted constant richness at each site. The best practices implemented in this study directly influenced the forecasts and evaluations. Stacked species distribution models and "naive" forecasts produced poor estimates of uncertainty and accounting for this resulted in these models dropping in the relative performance compared to other models. Accounting for observer effects improved model performance overall, but also changed the rank ordering of models because it did not improve the accuracy of the "naive" model. Considering the forecast horizon revealed that the prediction accuracy decreased across all models as the time horizon of the forecast increased. To facilitate the rapid improvement of biodiversity forecasts, we emphasize the value of specific best practices in making forecasts and evaluating forecasting methods. PMID- 29441231 TI - CCR6+ Th cell distribution differentiates systemic lupus erythematosus patients based on anti-dsDNA antibody status. AB - Background: Systemic lupus erythematosus (SLE) disease has been shown to be associated with the generation of multiple auto-antibodies. Among these, anti dsDNA antibodies (anti-DNAs) are specific and play a pathogenic role in SLE. Indeed, anti-DNA+ SLE patients display a worse disease course. The generation of these pathogenic anti-DNAs has been attributed to the interaction between aberrant T helper (Th) cells and autoimmune B cells. Thus, in this study we have investigated whether CCR6+Th cells have the ability to differentiate SLE patients based on anti-DNA status, and if their distribution has any correlation with disease activity. Methods: We recruited 25 anti-DNA+ and 25 anti-DNA- treatment naive onset SLE patients, matched for various clinical characteristics in our nested matched case-control study. CCR6+ Th cells and their additional subsets were analyzed in each patient by flow cytometry. Results: Anti-DNA+ SLE patients specifically had a higher percentage of Th cells expressing CCR6 and CXCR3. Further analysis of CCR6+ Th cell subsets showed that anti-DNA+ SLE patients had elevated proportions of Th9, Th17, Th17.1 and CCR4/CXCR3 double-negative (DN) cells. However, the proportions of CCR6- Th subsets, including Th1 and Th2 cells, did not show any association with anti-DNA status. Finally, we identified a correlation between CCR6+ Th subsets and clinical indicators, specifically in anti-DNA+ SLE patients. Conclusions: Our data indicated that CCR6+ Th cells and their subsets were elevated and correlated with disease activity in anti-DNA+ SLE patients. We speculated that CCR6+ Th cells may contribute to distinct disease severity in anti-DNA+ SLE patients. PMID- 29441232 TI - Detection of stable community structures within gut microbiota co-occurrence networks from different human populations. AB - Microbes in the gut microbiome form sub-communities based on shared niche specialisations and specific interactions between individual taxa. The inter microbial relationships that define these communities can be inferred from the co occurrence of taxa across multiple samples. Here, we present an approach to identify comparable communities within different gut microbiota co-occurrence networks, and demonstrate its use by comparing the gut microbiota community structures of three geographically diverse populations. We combine gut microbiota profiles from 2,764 British, 1,023 Dutch, and 639 Israeli individuals, derive co occurrence networks between their operational taxonomic units, and detect comparable communities within them. Comparing populations we find that community structure is significantly more similar between datasets than expected by chance. Mapping communities across the datasets, we also show that communities can have similar associations to host phenotypes in different populations. This study shows that the community structure within the gut microbiota is stable across populations, and describes a novel approach that facilitates comparative community-centric microbiome analyses. PMID- 29441233 TI - A new species of Amazonian snouted treefrog (Hylidae: Scinax) with description of a novel species-habitat association for an aquatic breeding frog. AB - The genus Scinax is one of the most specious genera of treefrogs of the family Hylidae. Despite the high number of potential new species of Scinax revealed in recent studies, the rate of species descriptions for Amazonia has been low in the last decade. A potential cause of this low rate may be the existence of morphologically cryptic species. Describing new species may not only impact the taxonomy and systematics of a group of organisms but also benefit other fields of biology. Ecological studies conducted in megadiverse regions, such as Amazonia, often meet challenging questions concerning insufficient knowledge of organismal alpha taxonomy. Due to that, detecting species-habitat associations is dependent on our ability to properly identify species. In this study, we first provide a description of a new species (including its tadpoles) of the genus Scinax distributed along heterogeneous landscapes in southern Amazonia; and secondly assess the influence of environmental heterogeneity on the new species' abundance and distribution. Scinax ruberoculatus sp. nov. differs from all nominal congeners by its small size (SVL 22.6-25.9 mm in males and 25.4-27.5 mm in females), by having a dark brown spot on the head and scapular region shaped mainly like the moth Copiopteryx semiramis (or a human molar in lateral view, or a triangle), bicolored reddish and grey iris, snout truncate in dorsal view, bilobate vocal sac in males, by its advertisement call consisting of a single pulsed note with duration of 0.134-0.331 s, 10-23 pulses per note, and dominant frequency 1,809-1,895 Hz. Both occurrence and abundance of the new species are significantly influenced by silt content in the soil. This finding brings the first evidence that edaphic factors influence species-habitat association in Amazonian aquatic breeding frogs. PMID- 29441235 TI - An Indo-Pacific damselfish (Neopomacentrus cyanomos) in the Gulf of Mexico: origin and mode of introduction. AB - The Indo-West Pacific (IWP) coral-reef damselfish Neopomacentrus cyanomos is well established across the south-west Gulf of Mexico (SwGoMx). Comparisons of mtDNA sequences of the SwGoMx population with those from conspecifics from 16 sites scattered across its native geographic range show that the SwGoMx population is derived from two of four native lineages: one from the north-west Pacific Ocean, the other from the northern Indian Ocean. Three hypotheses address how this species was introduced to the SwGoMX: (1) aquarium release; (2) borne by cargo ship; and (3) carried by offshore petroleum platform (petro-platform). The first is unlikely because this species rarely features in the aquarium trade, and "N. cyanomos" traded to the USA from the sole IWP source we are aware of are a misidentified congener, N. taeniurus. The second hypothesis is unlikely because shipping has not been associated with the introduction of alien damselfishes, there is little international shipping between the IWP and the SwGoMx, and voyages between those areas would be lengthy and along environmentally unfavorable routes. Various lines of evidence support the third hypothesis: (i) bio-fouled petro-platforms represent artificial reefs that can sustain large and diverse populations of tropical reef-fishes, including N. cyanomos in the SwGoMx; (ii) relocation of such platforms has been implicated in trans-oceanic introductions leading to establishment of non-native populations of such fishes; and (iii) genetic characteristics of the SwGoMx population indicate that it was established by a large and diverse group of founders drawn from the IWP regions where many petro-platforms currently in the SwGoMx and other Atlantic offshore oilfields originated. PMID- 29441234 TI - Inter-domain microbial diversity within the coral holobiont Siderastrea siderea from two depth habitats. AB - Corals host diverse microbial communities that are involved in acclimatization, pathogen defense, and nutrient cycling. Surveys of coral-associated microbes have been particularly directed toward Symbiodinium and bacteria. However, a holistic understanding of the total microbiome has been hindered by a lack of analyses bridging taxonomically disparate groups. Using high-throughput amplicon sequencing, we simultaneously characterized the Symbiodinium, bacterial, and fungal communities associated with the Caribbean coral Siderastrea siderea collected from two depths (17 and 27 m) on Conch reef in the Florida Keys. S. siderea hosted an exceptionally diverse Symbiodinium community, structured differently between sampled depth habitats. While dominated at 27 m by a Symbiodinium belonging to clade C, at 17 m S. siderea primarily hosted a mixture of clade B types. Most fungal operational taxonomic units were distantly related to available reference sequences, indicating the presence of a high degree of fungal novelty within the S. siderea holobiont and a lack of knowledge on the diversity of fungi on coral reefs. Network analysis showed that co-occurrence patterns in the S. siderea holobiont were prevalent among bacteria, however, also detected between fungi and bacteria. Overall, our data show a drastic shift in the associated Symbiodinium community between depths on Conch Reef, which might indicate that alteration in this community is an important mechanism facilitating local physiological adaptation of the S. siderea holobiont. In contrast, bacterial and fungal communities were not structured differently between depth habitats. PMID- 29441237 TI - Comparison of complex networks and tree-based methods of phylogenetic analysis and proposal of a bootstrap method. AB - Complex networks have been successfully applied to the characterization and modeling of complex systems in several distinct areas of Biological Sciences. Nevertheless, their utilization in phylogenetic analysis still needs to be widely tested, using different molecular data sets and taxonomic groups, and, also, by comparing complex networks approach to current methods in phylogenetic analysis. In this work, we compare all the four main methods of phylogenetic analysis (distance, maximum parsimony, maximum likelihood, and Bayesian) with a complex networks method that has been used to provide a phylogenetic classification based on a large number of protein sequences as those related to the chitin metabolic pathway and ATP-synthase subunits. In order to perform a close comparison to these methods, we selected Basidiomycota fungi as the taxonomic group and used a high-quality, manually curated and characterized database of chitin synthase sequences. This enzymatic protein plays a key role in the synthesis of one of the exclusive features of the fungal cell wall: the presence of chitin. The communities (modules) detected by the complex network method corresponded exactly to the groups retrieved by the phylogenetic inference methods. Additionally, we propose a bootstrap method for the complex network approach. The statistical results we have obtained with this method were also close to those obtained using traditional bootstrap methods. PMID- 29441236 TI - Differential gene expression during early development in recently evolved and sympatric Arctic charr morphs. AB - Phenotypic differences between closely related taxa or populations can arise through genetic variation or be environmentally induced, leading to altered transcription of genes during development. Comparative developmental studies of closely related species or variable populations within species can help to elucidate the molecular mechanisms related to evolutionary divergence and speciation. Studies of Arctic charr (Salvelinus alpinus) and related salmonids have revealed considerable phenotypic variation among populations and in Arctic charr many cases of extensive variation within lakes (resource polymorphism) have been recorded. One example is the four Arctic charr morphs in the ~10,000 year old Lake Thingvallavatn, which differ in numerous morphological and life history traits. We set out to investigate the molecular and developmental roots of this polymorphism by studying gene expression in embryos of three of the morphs reared in a common garden set-up. We performed RNA-sequencing, de-novo transcriptome assembly and compared gene expression among morphs during an important timeframe in early development, i.e., preceding the formation of key trophic structures. Expectedly, developmental time was the predominant explanatory variable. As the data were affected by some form of RNA-degradation even though all samples passed quality control testing, an estimate of 3'-bias was the second most common explanatory variable. Importantly, morph, both as an independent variable and as interaction with developmental time, affected the expression of numerous transcripts. Transcripts with morph effect, separated the three morphs at the expression level, with the two benthic morphs being more similar. However, Gene Ontology analyses did not reveal clear functional enrichment of transcripts between groups. Verification via qPCR confirmed differential expression of several genes between the morphs, including regulatory genes such as AT-Rich Interaction Domain 4A (arid4a) and translin (tsn). The data are consistent with a scenario where genetic divergence has contributed to differential expression of multiple genes and systems during early development of these sympatric Arctic charr morphs. PMID- 29441238 TI - Bioreactor virome metagenomics sequencing using DNA spike-ins. AB - With the emergence of Next Generation Sequencing, major advances were made with regard to identifying viruses in natural environments. However, bioinformatical research on viruses is still limited because of the low amounts of viral DNA that can be obtained for analysis. To overcome this limitation, DNA is often amplified with multiple displacement amplification (MDA), which may cause an unavoidable bias. Here, we describe a case study in which the virome of a bioreactor is sequenced using Ion Torrent technology. DNA-spiking of samples is compared with MDA-amplified samples. DNA for spiking was obtained by amplifying a bacterial 16S rRNA gene. After sequencing, the 16S rRNA gene reads were removed by mapping to the Silva database. Three samples were tested, a whole genome from Enterobacteria P1 Phage and two viral metagenomes from an infected bioreactor. For one sample, the new DNA-spiking protocol was compared with the MDA technique. When MDA was applied, the overall GC content of the reads showed a bias towards lower GC%, indicating a change in composition of the DNA sample. Assemblies using all available reads from both MDA and the DNA-spiked samples resulted in six viral genomes. All six genomes could be almost completely retrieved (97.9%-100%) when mapping the reads from the DNA-spiked sample to those six genomes. In contrast, 6.3%-77.7% of three viral genomes was covered by reads obtained using the MDA amplification method and only three were nearly fully covered (97.4%-100%). This case study shows that DNA-spiking could be a simple and inexpensive alternative with very low bias for sequencing of metagenomes for which low amounts of DNA are available. PMID- 29441239 TI - A simple molecular technique for distinguishing species reveals frequent misidentification of Hawaiian corals in the genus Pocillopora. AB - Species within the scleractinian genus Pocillopora Lamarck 1816 exhibit extreme phenotypic plasticity, making identification based on morphology difficult. However, the mitochondrial open reading frame (mtORF) marker provides a useful genetic tool for identification of most species in this genus, with a notable exception of P. eydouxi and P. meandrina. Based on recent genomic work, we present a quick and simple, gel-based restriction fragment length polymorphism (RFLP) method for the identification of all six Pocillopora species occurring in Hawai'i by amplifying either the mtORF region, a newly discovered histone region, or both, and then using the restriction enzymes targeting diagnostic sequences we unambiguously identify each species. Using this approach, we documented frequent misidentification of Pocillopora species based on colony morphology. We found that P. acuta colonies are frequently mistakenly identified as P. damicornis in Kane'ohe Bay, O'ahu. We also found that P. meandrina likely has a northern range limit in the Northwest Hawaiian Islands, above which P. ligulata was regularly mistaken for P. meandrina. PMID- 29441240 TI - Evolution of the scholarly mega-journal, 2006-2017. AB - Mega-journals are a new kind of scholarly journal made possible by electronic publishing. They are open access (OA) and funded by charges, which authors pay for the publishing services. What distinguishes mega-journals from other OA journals is, in particular, a peer review focusing only on scientific trustworthiness. The journals can easily publish thousands of articles per year and there is no need to filter articles due to restricted slots in the publishing schedule. This study updates some earlier longitudinal studies of the evolution of mega-journals and their publication volumes. After very rapid growth in 2010 2013, the increase in overall article volumes has slowed down. Mega-journals are also increasingly dependent for sustained growth on Chinese authors, who now contribute 25% of all articles in such journals. There has also been an internal shift in market shares. PLOS ONE, which totally dominated mega-journal publishing in the early years, currently publishes around one-third of all articles. Scientific Reports has grown rapidly since 2014 and is now the biggest journal. PMID- 29441241 TI - Antitumor activity of Chlorella sorokiniana and Scenedesmus sp. microalgae native of Nuevo Leon State, Mexico. AB - Cancer cases result in 13% of all deaths worldwide. Unwanted side effects in patients under conventional treatments have led to the search for beneficial alternative therapies. Microalgae synthesize compounds with known in vitro and in vivo biological activity against different tumor cell lines. Therefore, native microalgae from the State of Nuevo Leon, Mexico may become a potential source of antitumor agents. The aim of the present study was to evaluate the in vitro cytotoxic effect of Nuevo Leon regional Chlorella sorokiniana (Chlorellales: Chlorellaceae) and Scenedesmus sp. (Chlorococcales: Scenedesmaceae). Native microalgae crude organic extracts cytotoxicity against murine L5178Y-R lymphoma cell line and normal lymphocyte proliferation were evaluated using the MTT reduction colorimetric assay. Cell death pathway was analyzed by acridine orange and ethidium bromide staining, DNA degradation in 2% agarose gel electrophoresis and caspases activity. Results indicated significant (p < 0.05) 61.89% +/- 3.26% and 74.77% +/- 1.84% tumor cytotoxicity by C. sorokiniana and Scenedesmus sp. methanol extracts, respectively, at 500 ug/mL, by the mechanism of apoptosis. This study contributes to Mexican microalgae biodiversity knowledge and their potential as antitumor agent sources. PMID- 29441242 TI - Use and misuse of temperature normalisation in meta-analyses of thermal responses of biological traits. AB - There is currently unprecedented interest in quantifying variation in thermal physiology among organisms, especially in order to understand and predict the biological impacts of climate change. A key parameter in this quantification of thermal physiology is the performance or value of a rate, across individuals or species, at a common temperature (temperature normalisation). An increasingly popular model for fitting thermal performance curves to data-the Sharpe Schoolfield equation-can yield strongly inflated estimates of temperature normalised rate values. These deviations occur whenever a key thermodynamic assumption of the model is violated, i.e., when the enzyme governing the performance of the rate is not fully functional at the chosen reference temperature. Using data on 1,758 thermal performance curves across a wide range of species, we identify the conditions that exacerbate this inflation. We then demonstrate that these biases can compromise tests to detect metabolic cold adaptation, which requires comparison of fitness or rate performance of different species or genotypes at some fixed low temperature. Finally, we suggest alternative methods for obtaining unbiased estimates of temperature-normalised rate values for meta-analyses of thermal performance across species in climate change impact studies. PMID- 29441243 TI - Calpain activation and disturbance of autophagy are induced in cortical neurons in vitro by exposure to HA/beta-Ga2O3:Cr3+ nanoparticles. AB - The toxicity of engineered nanoparticles remains a concern. The knowledge of biohazards associated with particular nanoparticles is crucial to make this cutting-edge technology more beneficial and safe. Here, we evaluated the toxicity of Ga2O3 nanoparticles (NPs), which are frequently used to enhance the performance of metal catalysts in a variety of catalytic reactions. The potential inflammatory signaling associated with the toxicity of HA/beta-Ga2O3:Cr3+ NPs in primary cortical neurons was examined. We observed a dose-dependent decrease in cell viability and an increase in apoptosis in neurons following various concentrations (0, 1, 5, 25, 50, 100 ug/ml) of HA/beta-Ga2O3:Cr3+ NPs treatment. Consistently, constitutively active forms of calcineurin (48 kDa) were significantly elevated in cultured primary cortical neurons, which was consistent with calpain activation indicated by the breakdown products of spectrin. Moreover, HA/beta-Ga2O3:Cr3+ NPs result in the elevation of LC3-II formation, SQSTM/p62, and Cathepsin B, whereas phosphorylation of CaMKII (Thr286) and Synapsin I (Ser603) were downregulated in the same context. Taken together, these results demonstrate for the first time that calpain activation and a disturbance of autophagy signaling are evoked by exposure to HA/beta-Ga2O3:Cr3+ NPs, which may contribute to neuronal injury in vitro. PMID- 29441245 TI - Case of Enteric Fever with Bicytopenia. AB - Infectious diseases are one of the major causes of morbidity and mortality in developing countries. Typhoid has its own contribution to the disease burden, especially in Pakistan and other tropical countries. Herein, we present a case of enteric fever with a rare presentation. Our patient is a 20-year-old man who gradually developed high-grade fever lasting seven days associated with rigors and chills. No additional accompanying systemic signs helped to localize the infection. After extensive laboratory testing, his typhoid serology was positive along with leukocytopenia and thrombocytopenia. Typhoid fever is typically associated with either diarrhea or constipation and sphygmothermic dissociation (Faget's sign); our patient did not have these symptoms or signs. As leukocytopenia and thrombocytopenia contribute to mortality and complications, it was necessary to monitor the patient accordingly. PMID- 29441244 TI - Smartphone-based reminder system to promote pelvic floor muscle training for the management of postnatal urinary incontinence: historical control study with propensity score-matched analysis. AB - Background: The purpose of this study was to evaluate the efficacy of a smartphone-based reminder system in promoting pelvic floor muscle training (PFMT) to help postpartum women manage urinary incontinence (UI). Methods: Forty-nine and 212 postpartum women in the intervention and control groups, respectively, received PFMT guidance using a leaflet and verbal instruction as the standard care at an obstetrics clinic in Japan. Women in the intervention group also received PFMT support using the smartphone-based reminder system between January and August 2014. For analysis, they were compared with historical controls between February 2011 and January 2012, who did not receive such support and were chosen by propensity score matching. The outcomes examined were PFMT adherence and UI prevalence. The former consisted of implementation rate (i.e., the percentage of women who reported performing PFMT during the intervention period), training intensity (i.e., the number of pelvic floor muscle contractions (PFMCs) per day), and training frequency (i.e., the number of days PFMT was performed per week); the latter consisted of self-reported UI prevalence at baseline and at the end of the eight-week intervention period. Result: Propensity score matching resulted in 58 postpartum women (n = 29 per group). The intervention group exhibited better PFMT adherence than the control group, in terms of PFMT implementation rate (69 vs. 31%, p = 0.008), median training intensity (15 vs. 1 PFMC reps/day, p = 0.006), and training frequency (7 vs. 3 days/week, p < 0.001). UI prevalence was not different between the groups at baseline, but was significantly reduced in the intervention group at eight weeks (0 vs. 24%, p = 0.004). Conclusion: Our smartphone-based reminder system appears promising in enhancing PFMT adherence and managing postpartum UI in postpartum women. By enhancing PFMT adherence and improving women's ability to manage the condition, the reminder system could improve the health-related quality of life of postpartum women with UI. PMID- 29441246 TI - Spinal Cord Infarction Mimicking Acute Transverse Myelitis. AB - Spinal cord infarction (SCI) is a rare type of stroke. The initial magnetic resonance imaging (MRI) is usually normal and can mimic the presentation of the acute transverse myelitis (ATM), acute inflammatory demyelinating polyneuropathy, and compressive myelopathies from neoplasm, epidural or subdural hematoma, or abscess. The aim of this report is to describe and discuss the case of a patient with SCI presenting as a diagnostic confusion with acute transverse myelitis. A 64-year-old male with a medical history of hypertension presented with an acute onset of urinary retention with lower limb weakness. Based on the initial MRI and evaluation, a diagnosis of acute transverse myelitis was made. Despite thorough evaluation, the etiology of transverse myelitis was undetermined. Hence, the MRI of the thoracic spine was repeated which showed patchier enhancements of the vertebral body with features suggestive of the spinal cord and vertebral body infarction. Thus, a repeat MRI is required to make an accurate diagnosis. The vertebral body is always involved and can be of diagnostic significance as it reflects the pathology of underlying blood supply. PMID- 29441247 TI - Using the Association of American Medical Colleges Standardized Video Interview in a Holistic Residency Application Review. AB - Each year, residency programs work diligently to identify the best applicants for their respective programs, given the increasing volume of applications. Interview offers are often based on a mix of subjective and objective measures, with different programs relying more or less on each. A holistic application review involves a flexible and individualized way of assessing an applicant's capabilities through a balanced consideration of experiences, attributes, and academic metrics. When considered collectively, these attributes may define how an individual may perform as a physician. One particular tool developed by the American Association of Medical Colleges (AAMC), the Standardized Video Interview (SVI), provides an objective measure of an applicant's professional behavior and interpersonal communication skills. The SVI may provide applicants with a chance to showcase the intangibles about themselves that are neither entered on their application nor reflected by their standardized examination scores. PMID- 29441248 TI - Addressing Hazards from Unscheduled Novel Psychoactive Substances as Research Chemicals: The Case of U-50488. AB - Increased experimentation with easily accessible synthetic opioids is posing a hazard to the public. We discuss one such synthetic opioid, U-50488. Much is unknown about U-50488; however, due to its structural similarity to U-47700, there is possible risk associated with its use. Curtailing the use of synthetic opioids such as U-50488 will require a concerted effort targeting multiple problems. PMID- 29441249 TI - Surgical Access to a Complex Composite Odontoma via Sagittal Split Osteotomy of the Mandible. AB - This case report presents the removal of complex composite odontoma in a young patient in the right body of mandible via the unilateral sagittal splitting of the mandible. This article shows that sagittal split osteotomy of the mandible can be very useful to access various pathologies in the body, angle, and ramus of the mandible and to navigate lesions that are in proximity to the inferior alveolar nerve. This technique also helps in avoiding postoperative morbidity when compared to other conventional surgical approaches. It can be used to remove large cysts, benign non-infiltrative tumours of the mandible, odontogenic myxoma, large odontoma, and deeply impacted lower third molars. PMID- 29441250 TI - An Unusual Case of Acute Chondrocalcinosis in Wrist Joint Presenting as Cellulitis. AB - Chondrocalcinosis is a common arthritic disorder among elderly patients. We present a case of a 71-year-old woman presenting with an acute episode of the left forearm with hand swelling. A provisional diagnosis of cellulitis was made and the patient was started on intravenous antibiotics. The patient's condition did not improve. Joint aspiration of the wrist joint was done and showed positive birefringent rhomboid-shaped crystals. A final diagnosis of acute chondrocalcinosis was made. PMID- 29441251 TI - Self-Shielding Analysis of the Zap-X System. AB - The Zap-X is a self-contained and first-of-its-kind self-shielded therapeutic radiation device dedicated to brain as well as head and neck stereotactic radiosurgery (SRS). By utilizing an S-band linear accelerator (linac) with a 2.7 megavolt (MV) accelerating potential and incorporating radiation-shielded mechanical structures, the Zap-X does not typically require a radiation bunker, thereby saving SRS facilities considerable cost. At the same time, the self shielded features of the Zap-X are designed for more consistency of radiation protection, reducing the risk to radiation workers and others potentially exposed from a poorly designed or constructed radiotherapy vault. The hypothesis of the present study is that a radiosurgical system can be self-shielded such that it produces radiation exposure levels deemed safe to the public while operating under a full clinical workload. This study summarizes the Zap-X system shielding and found that the overall system radiation leakage values are reduced by a factor of 50 compared to the occupational radiation limit stipulated by the Nuclear Regulatory Commission (NRC) or agreement states. The goal of self shielding is achieved under all but the most exceptional conditions for which additional room shielding or a larger restricted area in the vicinity of the Zap X system would be required. PMID- 29441252 TI - Growth model and structure evolution of Ag layers deposited on Ge films. AB - We investigated the crystallinity and optical parameters of silver layers of 10 35 nm thickness as a function 2-10 nm thick Ge wetting films deposited on SiO2 substrates. X-ray reflectometry (XRR) and X-ray diffraction (XRD) measurements proved that segregation of germanium into the surface of the silver film is a result of the gradient growth of silver crystals. The free energy of Ge atoms is reduced by their migration from boundaries of larger grains at the Ag/SiO2 interface to boundaries of smaller grains near the Ag surface. Annealing at different temperatures and various durations allowed for a controlled distribution of crystal dimensions, thus influencing the segregation rate. Furthermore, using ellipsometric and optical transmission measurements we determined the time-dependent evolution of the film structure. If stored under ambient conditions for the first week after deposition, the changes in the transmission spectra are smaller than the measurement accuracy. Over the course of the following three weeks, the segregation-induced effects result in considerably modified transmission spectra. Two months after deposition, the slope of the silver layer density profile derived from the XRR spectra was found to be inverted due to the completed segregation process, and the optical transmission spectra increased uniformly due to the roughened surfaces, corrosion of silver and ongoing recrystallization. The Raman spectra of the Ge wetted Ag films were measured immediately after deposition and ten days later and demonstrated that the Ge atoms at the Ag grain boundaries form clusters of a few atoms where the Ge-Ge bonds are still present. PMID- 29441253 TI - Electron-driven and thermal chemistry during water-assisted purification of platinum nanomaterials generated by electron beam induced deposition. AB - Focused electron beam induced deposition (FEBID) is a versatile tool for the direct-write fabrication of nanostructures on surfaces. However, FEBID nanostructures are usually highly contaminated by carbon originating from the precursor used in the process. Recently, it was shown that platinum nanostructures produced by FEBID can be efficiently purified by electron irradiation in the presence of water. If such processes can be transferred to FEBID deposits produced from other carbon-containing precursors, a new general approach to the generation of pure metallic nanostructures could be implemented. Therefore this study aims to understand the chemical reactions that are fundamental to the water-assisted purification of platinum FEBID deposits generated from trimethyl(methylcyclopentadienyl)platinum(IV) (MeCpPtMe3). The experiments performed under ultrahigh vacuum conditions apply a combination of different desorption experiments coupled with mass spectrometry to analyse reaction products. Electron-stimulated desorption monitors species that leave the surface during electron exposure while post-irradiation thermal desorption spectrometry reveals products that evolve during subsequent thermal treatment. In addition, desorption of volatile products was also observed when a deposit produced by electron exposure was subsequently brought into contact with water. The results distinguish between contributions of thermal chemistry, direct chemistry between water and the deposit, and electron-induced reactions that all contribute to the purification process. We discuss reaction kinetics for the main volatile products CO and CH4 to obtain mechanistic information. The results provide novel insights into the chemistry that occurs during purification of FEBID nanostructures with implications also for the stability of the carbonaceous matrix of nanogranular FEBID materials under humid conditions. PMID- 29441254 TI - Comparative study of post-growth annealing of Cu(hfac)2, Co2(CO)8 and Me2Au(acac) metal precursors deposited by FEBID. AB - Non-noble metals, such as Cu and Co, as well as noble metals, such as Au, can be used in a number modern technological applications, which include advanced scanning-probe systems, magnetic memory and storage, ferroelectric tunnel junction memristors, metal interconnects for high performance integrated circuits in microelectronics and nano-optics applications, especially in the areas of plasmonics and metamaterials. Focused-electron-beam-induced deposition (FEBID) is a maskless direct-write tool capable of defining 3-dimensional metal deposits at nanometre scale for above applications. However, codeposition of organic ligands when using organometallic precursors is a typical problem that limits FEBID of pure metal nanostructures. In this work, we present a comparative study using a post-growth annealing protocol at 100, 200, and 300 degrees C under high vacuum on deposits obtained from Co2(CO)8, Cu(II)(hfac)2, and Me2Au(acac) to study improvements on composition and electrical conductivity. Although the as deposited material was similar for all precursors, metal grains embedded in a carbonaceous matrix, the post-growth annealing results differed. Cu-containing deposits showed the formation of pure Cu nanocrystals at the outer surface of the initial deposit for temperatures above 100 degrees C, due to the migration of Cu atoms from the carbonaceous matrix containing carbon, oxygen, and fluorine atoms. The average size of the Cu crystals doubles between 100 and 300 degrees C of annealing temperature, while the composition remains constant. In contrast, for Co-containing deposits oxygen release was observed upon annealing, while the carbon content remained approximately constant; the cobalt atoms coalesced to form a metallic film. The as-deposited Au-containing material shows subnanometric grains that coalesce at 100 degrees C, maintaining the same average size at annealing temperatures up to 300 degrees C. Raman analysis suggests that the amorphous carbonaceous matrix of the as-written Co, Cu and Au deposits turned into nanocrystalline graphite with comparable crystal sizes of 12-14 nm at 300 degrees C annealing temperature. However, we observed a more effective formation of graphite clusters in Co- than in Cu- and Au-containing deposits. The graphitisation has a minor influence on the electrical conductivity improvements of Co-C deposits, which is attributed to the high as-deposited Co content and the related metal grain percolation. On the contrary, electrical conductivity improvements by factors of 30 and 12 for, respectively, Cu-C and Au-C deposits with low metal content are mainly attributed to the graphitisation. This relatively simple vacuum-based post-growth annealing protocol may be useful for other precursors as it proved to be efficient in reliably tuning the electrical properties of as-deposited FEBID materials. Finally, a H2-assisted gold purification protocol is demonstrated at temperatures around 300 degrees C by fully removing the carbon matrix and drastically reducing the electrical resistance of the deposit. PMID- 29441255 TI - Design of photonic microcavities in hexagonal boron nitride. AB - We propose and design photonic crystal cavities (PCCs) in hexagonal boron nitride (hBN) for diverse photonic and quantum applications. Two dimensional (2D) hBN flakes contain quantum emitters which are ultra-bright and photostable at room temperature. To achieve optimal coupling of these emitters to optical resonators, fabrication of cavities from hBN is therefore required to maximize the overlap between cavity optical modes and the emitters. Here, we design 2D and 1D PCCs using anisotropic indices of hBN. The influence of underlying substrates and material absorption are investigated, and spontaneous emission rate enhancements are calculated. Our results are promising for future quantum photonic experiments with hBN. PMID- 29441256 TI - Nematic topological defects positionally controlled by geometry and external fields. AB - Using a Landau-de Gennes approach, we study the impact of confinement topology, geometry and external fields on the spatial positioning of nematic topological defects (TDs). In quasi two-dimensional systems we demonstrate that a confinement enforced total topological charge of m > 1/2 decays into elementary TDs bearing a charge of m = 1/2. These assemble close to the bounding substrate to enable essentially bulk-like uniform nematic ordering in the central part of a system. This effect is reminiscent of the Faraday cavity phenomenon in electrostatics. We observe that in certain confinement geometries, varying the correlation length size of the order parameter could trigger a global rotation of an assembly of TDs. Finally, we show that an external electric field could be used to drag the boojum fingertip towards the interior of the confinement cell. Assemblies of TDs could be exploited as traps for appropriate nanoparticles, opening several opportunities for the development of functional nanodevices. PMID- 29441257 TI - Atomic layer deposition and properties of ZrO2/Fe2O3 thin films. AB - Thin solid films consisting of ZrO2 and Fe2O3 were grown by atomic layer deposition (ALD) at 400 degrees C. Metastable phases of ZrO2 were stabilized by Fe2O3 doping. The number of alternating ZrO2 and Fe2O3 deposition cycles were varied in order to achieve films with different cation ratios. The influence of annealing on the composition and structure of the thin films was investigated. Additionally, the influence of composition and structure on electrical and magnetic properties was studied. Several samples exhibited a measurable saturation magnetization and most of the samples exhibited a charge polarization. Both phenomena were observed in the sample with a Zr/Fe atomic ratio of 2.0. PMID- 29441258 TI - Combined scanning probe electronic and thermal characterization of an indium arsenide nanowire. AB - As electronic devices are downsized, physical processes at the interface to electrodes may dominate and limit device performance. A crucial step towards device optimization is being able to separate such contact effects from intrinsic device properties. Likewise, an increased local temperature due to Joule heating at contacts and the formation of hot spots may put limits on device integration. Therefore, being able to observe profiles of both electronic and thermal device properties at the nanoscale is important. Here, we show measurements by scanning thermal and Kelvin probe force microscopy of the same 60 nm diameter indium arsenide nanowire in operation. The observed temperature along the wire is substantially elevated near the contacts and deviates from the bell-shaped temperature profile one would expect from homogeneous heating. Voltage profiles acquired by Kelvin probe force microscopy not only allow us to determine the electrical nanowire conductivity, but also to identify and quantify sizable and non-linear contact resistances at the buried nanowire-electrode interfaces. Complementing these data with thermal measurements, we obtain a device model further permitting separate extraction of the local thermal nanowire and interface conductivities. PMID- 29441259 TI - Co-reductive fabrication of carbon nanodots with high quantum yield for bioimaging of bacteria. AB - A simple and straightforward synthetic approach for carbon nanodots (C-dots) is proposed. The strategy is based on a one-step hydrothermal chemical reduction with thiourea and urea, leading to high quantum yield C-dots. The obtained C-dots are well-dispersed with a uniform size and a graphite-like structure. A synergistic reduction mechanism was investigated using Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The findings show that using both thiourea and urea during the one-pot synthesis enhances the luminescence of the generated C-dots. Moreover, the prepared C-dots have a high distribution of functional groups on their surface. In this work, C-dots proved to be a suitable nanomaterial for imaging of bacteria and exhibit potential for application in bioimaging thanks to their low cytotoxicity. PMID- 29441260 TI - Dopant-stimulated growth of GaN nanotube-like nanostructures on Si(111) by molecular beam epitaxy. AB - In this paper we study growth of quasi-one-dimensional GaN nanowires (NWs) and nanotube (NT)-like nanostructures on Si(111) substrates covered with a thin AlN layer grown by means of plasma-assisted molecular beam epitaxy. In the first part of our study we investigate the influence of the growth parameters on the geometrical properties of the GaN NW arrays. First, we find that the annealing procedure carried out prior to deposition of the AlN buffer affects the elongation rate and the surface density of the wires. It has been experimentally demonstrated that the NW elongation rate and the surface density drastically depend on the substrate growth temperature, where 800 degrees C corresponds to the maximum elongation rate of the NWs. In the second part of the study, we introduce a new dopant-stimulated method for GaN nanotube-like nanostructure synthesis using a high-intensity Si flux. Transmission electron microscopy was used to investigate the morphological features of the GaN nanostructures. The synthesized structures have a hexagonal cross-section and possess high crystal quality. We propose a theoretical model of the novel nanostructure formation which includes the role of the dopant Si. Some of the Si-doped samples were studied with the photoluminescence (PL) technique. The analysis of the PL spectra shows that the highest value of donor concentration in the nanostructures exceeds 5?1019 cm-3. PMID- 29441261 TI - Electrical properties of a liquid crystal dispersed in an electrospun cellulose acetate network. AB - Electro-optical devices that work in a similar fashion as PDLCs (polymer dispersed liquid crystals), produced from cellulose acetate (CA) electrospun fibers deposited onto indium tin oxide coated glass and a nematic liquid crystal (E7), were studied. CA and the CA/liquid crystal composite were characterized by multiple investigation techniques, such as polarized optical microscopy, dielectric spectroscopy and impedance measurements. Dielectric constant and electric energy loss were studied as a function of frequency and temperature. The activation energy was evaluated and the relaxation time was obtained by fitting the spectra of the dielectric loss with the Havriliak-Negami functions. To determine the electrical characteristics of the studied samples, impedance measurements results were treated using the Cole-Cole diagram and the three element equivalent model. PMID- 29441262 TI - Dielectric properties of a bisimidazolium salt with dodecyl sulfate anion doped with carbon nanotubes. AB - A new bisimidazolium salt with dodecyl sulfate as counterion has been designed and prepared. This salt shows a SmA phase that is stable at room temperature. The new ionic liquid crystal (ILC) was characterized by 1H NMR, 13C NMR and IR spectroscopy. Its liquid crystalline properties were analyzed by polarizing optical microscopy (POM), differential scanning calorimetry (DSC) and powder X ray diffraction (XRD) studies. The dielectric spectra of the ILC doped with different concentrations of carbon nanotubes (CNT) were recorded over a wide frequency and temperature range of 10-1 to 107 Hz and 293-338 K, respectively. The values of the activation energy were found in the range of 0.46-0.61 eV; the characteristic time was obtained by fitting the spectra of the dielectric loss with the Havriliak-Negami functions. As a result of doping the ILC with CNT, the electric conductivity increases significantly. Ionic conductivity is dominant and it was indirectly observed through the electrode polarization (EP) effect. The very high dielectric permittivity values and the decrease of the electric conductivity at low frequencies confirm the presence of EP. PMID- 29441263 TI - Humidity-dependent wound sealing in succulent leaves of Delosperma cooperi - An adaptation to seasonal drought stress. AB - During evolution, plants evolved various reactions to wounding. Fast wound sealing and subsequent healing represent a selective advantage of particular importance for plants growing in arid habitats. An effective self-sealing function by internal deformation has been found in the succulent leaves of Delosperma cooperi. After a transversal incision, the entire leaf bends until the wound is closed. Our results indicate that the underlying sealing principle is a combination of hydraulic shrinking and swelling as the main driving forces and growth-induced mechanical pre-stresses in the tissues. Hydraulic effects were measured in terms of the relative bending angle over 55 minutes under various humidity conditions. The higher the relative air humidity, the lower the bending angle. Negative bending angles were found when a droplet of liquid water was applied to the wound. The statistical analysis revealed highly significant differences of the single main effects such as "humidity conditions in the wound region" and "time after wounding" and their interaction effect. The centripetal arrangement of five tissue layers with various thicknesses and significantly different mechanical properties might play an additional role with regard to mechanically driven effects. Injury disturbs the mechanical equilibrium, with pre stresses leading to internal deformation until a new equilibrium is reached. In the context of self-sealing by internal deformation, the highly flexible wide band tracheids, which form a net of vascular bundles, are regarded as paedomorphic tracheids, which are specialised to prevent cell collapse under drought stress and allow for building growth-induced mechanical pre-stresses. PMID- 29441264 TI - Bombyx mori silk/titania/gold hybrid materials for photocatalytic water splitting: combining renewable raw materials with clean fuels. AB - The synthesis, structure, and photocatalytic water splitting performance of two new titania (TiO2)/gold(Au)/Bombyx mori silk hybrid materials are reported. All materials are monoliths with diameters of up to ca. 4.5 cm. The materials are macroscopically homogeneous and porous with surface areas between 170 and 210 m2/g. The diameter of the TiO2 nanoparticles (NPs) - mainly anatase with a minor fraction of brookite - and the Au NPs are on the order of 5 and 7-18 nm, respectively. Addition of poly(ethylene oxide) to the reaction mixture enables pore size tuning, thus providing access to different materials with different photocatalytic activities. Water splitting experiments using a sunlight simulator and a Xe lamp show that the new hybrid materials are effective water splitting catalysts and produce up to 30 mmol of hydrogen per 24 h. Overall the article demonstrates that the combination of a renewable and robust scaffold such as B. mori silk with a photoactive material provides a promising approach to new monolithic photocatalysts that can easily be recycled and show great potential for application in lightweight devices for green fuel production. PMID- 29441265 TI - Liquid-crystalline nanoarchitectures for tissue engineering. AB - Hierarchical orders are found throughout all levels of biosystems, from simple biopolymers, subcellular organelles, single cells, and macroscopic tissues to bulky organs. Especially, biological tissues and cells have long been known to exhibit liquid crystal (LC) orders or their structural analogues. Inspired by those native architectures, there has recently been increased interest in research for engineering nanobiomaterials by incorporating LC templates and scaffolds. In this review, we introduce and correlate diverse LC nanoarchitectures with their biological functionalities, in the context of tissue engineering applications. In particular, the tissue-mimicking LC materials with different LC phases and the regenerative potential of hard and soft tissues are summarized. In addition, the multifaceted aspects of LC architectures for developing tissue-engineered products are envisaged. Lastly, a perspective on the opportunities and challenges for applying LC nanoarchitectures in tissue engineering fields is discussed. PMID- 29441266 TI - Al2O3/TiO2 inverse opals from electrosprayed self-assembled templates. AB - The fabrication of high optical quality inverse opals is challenging, requiring large size, three-dimensional ordered layers of high dielectric constant ratio. In this article, alumina/TiO2-air inverse opals with a 98.2% reflectivity peak at 798 nm having an area of 2 cm2 and a thickness of 17 um are achieved using a sacrificial self-assembled structure of large thickness, which was produced with minimum fabrication errors by means of an electrospray technique. Using alumina as the first supporting layer enables the deposition of TiO2 at a higher temperature, therefore providing better optical quality. PMID- 29441267 TI - Gas-assisted silver deposition with a focused electron beam. AB - Focused electron beam induced deposition (FEBID) is a flexible direct-write method to obtain defined structures with a high lateral resolution. In order to use this technique in application fields such as plasmonics, suitable precursors which allow the deposition of desired materials have to be identified. Well known for its plasmonic properties, silver represents an interesting candidate for FEBID. For this purpose the carboxylate complex silver(I) pentafluoropropionate (AgO2CC2F5) was used for the first time in FEBID and resulted in deposits with high silver content of up to 76 atom %. As verified by TEM investigations, the deposited material is composed of pure silver crystallites in a carbon matrix. It showed good electrical properties and a strong Raman signal enhancement. Interestingly, silver crystal growth presents a strong dependency on electron dose and precursor refreshment. PMID- 29441268 TI - Dynamic behavior of a nematic liquid crystal with added carbon nanotubes in an electric field. AB - The dynamic behavior of a nematic liquid crystal with added carbon nanotubes (CNTs) in an electric field was analyzed. A theoretical model based on elastic continuum theory was developed and the relaxation times of nematic liquid crystals with CNTs were evaluated. Experiments made with single-walled carbon nanotubes dispersed in nematic 4-cyano-4'-pentylbiphenyl (5CB) indicated a significant difference of the relaxation time when compared to pure liquid crystal. We also noticed that the relaxation time when the field is switched off depends on how long the field was applied. It is shorter when the field is switched off immediately after application and longer when the field was applied for at least one hour. PMID- 29441269 TI - Anchoring of a dye precursor on NiO(001) studied by non-contact atomic force microscopy. AB - The properties of metal oxides, such as charge-transport mechanisms or optoelectronic characteristics, can be modified by functionalization with organic molecules. This kind of organic/inorganic surface is nowadays highly regarded, in particular, for the design of hybrid devices such as dye-sensitized solar cells. However, a key parameter for optimized interfaces is not only the choice of the compounds but also the properties of adsorption. Here, we investigated the deposition of an organic dye precursor molecule on a NiO(001) single crystal surface by means of non-contact atomic force microscopy at room temperature. Depending on the coverage, single molecules, groups of adsorbates with random or recognizable shapes, or islands of closely packed molecules were identified. Single molecules and self assemblies are resolved with submolecular resolution showing that they are lying flat on the surface in a trans-conformation. Within the limits of our Kelvin probe microscopy setup a charge transfer from NiO to the molecular layer of 0.3 electrons per molecules was observed only in the areas where the molecules are closed packed. PMID- 29441270 TI - BN/Ag hybrid nanomaterials with petal-like surfaces as catalysts and antibacterial agents. AB - BN/Ag hybrid nanomaterials (HNMs) and their possible applications as novel active catalysts and antibacterial agents are investigated. BN/Ag nanoparticle (NP) hybrids were fabricated using two methods: (i) chemical vapour deposition (CVD) of BN NPs in the presence of Ag vapours, and (ii) ultraviolet (UV) decomposition of AgNO3 in a suspension of BN NPs. The hybrid microstructures were studied by high-resolution transmission electron microscopy (HRTEM), high-angular dark field scanning TEM imaging paired with energy dispersion X-ray (EDX) mapping, X-ray photoelectron spectroscopy (XPS), and infrared spectroscopy (FTIR). They were also characterized in terms of thermal stability, Ag+ ion release, catalytic and antibacterial activities. The materials synthesized via UV decomposition of AgNO3 demonstrated a much better catalytic activity in comparison to those prepared using the CVD method. The best catalytic characteristics (100% methanol conversion at 350 degrees C) were achieved using the UV BN/Ag HNMs without preliminary annealing at 600 degrees C in an oxidizing atmosphere. Both types of the BN/Ag HNMs possess a profound antibacterial effect against Escherichia coli K 261 bacteria. PMID- 29441271 TI - Synthesis and characterization of electrospun molybdenum dioxide-carbon nanofibers as sulfur matrix additives for rechargeable lithium-sulfur battery applications. AB - One-dimensional molybdenum dioxide-carbon nanofibers (MoO2-CNFs) were prepared using an electrospinning technique followed by calcination, using sol-gel precursors and polyacrylonitrile (PAN) as a processing aid. The resulting samples were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, Brunauer-Emmet-Teller (BET) surface area measurements, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). MoO2-CNFs with an average diameter of 425-575 nm obtained after heat treatment were used as a matrix to prepare sulfur/MoO2-CNF cathodes for lithium-sulfur (Li-S) batteries. The polysulfide adsorption and electrochemical performance tests demonstrated that MoO2-CNFs did not only act as polysulfide reservoirs to alleviate the shuttle effect, but also improve the electrochemical reaction kinetics during the charge-discharge processes. The effect of MoO2-CNF heat treatment on the cycle performance of sulfur/MoO2-CNFs electrodes was examined, and the data showed that MoO2-CNFs calcined at 850 degrees C delivered optimal performance with an initial capacity of 1095 mAh g-1 and 860 mAh g-1 after 50 cycles. The results demonstrated that sulfur/MoO2-CNF composites display a remarkably high lithium-ion diffusion coefficient, low interfacial resistance and much better electrochemical performance than pristine sulfur cathodes. PMID- 29441272 TI - Review: Electrostatically actuated nanobeam-based nanoelectromechanical switches materials solutions and operational conditions. AB - This review summarizes relevant research in the field of electrostatically actuated nanobeam-based nanoelectromechanical (NEM) switches. The main switch architectures and structural elements are briefly described and compared. Investigation methods that allow for exploring coupled electromechanical interactions as well as studies of mechanically or electrically induced effects are covered. An examination of the complex nanocontact behaviour during various stages of the switching cycle is provided. The choice of the switching element and the electrode is addressed from the materials perspective, detailing the benefits and drawbacks for each. An overview of experimentally demonstrated NEM switching devices is provided, and together with their operational parameters, the reliability issues and impact of the operating environment are discussed. Finally, the most common NEM switch failure modes and the physical mechanisms behind them are reviewed and solutions proposed. PMID- 29441273 TI - The nanofluidic confinement apparatus: studying confinement-dependent nanoparticle behavior and diffusion. AB - The behavior of nanoparticles under nanofluidic confinement depends strongly on their distance to the confining walls; however, a measurement in which the gap distance is varied is challenging. Here, we present a versatile setup for investigating the behavior of nanoparticles as a function of the gap distance, which is controlled to the nanometer. The setup is designed as an open system that operates with a small amount of dispersion of ~20 MUL, permits the use of coated and patterned samples and allows high-numerical-aperture microscopy access. Using the tool, we measure the vertical position (termed height) and the lateral diffusion of 60 nm, charged, Au nanospheres as a function of confinement between a glass surface and a polymer surface. Interferometric scattering detection provides an effective particle illumination time of less than 30 MUs, which results in lateral and vertical position detection accuracy ~10 nm for diffusing particles. We found the height of the particles to be consistently above that of the gap center, corresponding to a higher charge on the polymer substrate. In terms of diffusion, we found a strong monotonic decay of the diffusion constant with decreasing gap distance. This result cannot be explained by hydrodynamic effects, including the asymmetric vertical position of the particles in the gap. Instead we attribute it to an electroviscous effect. For strong confinement of less than 120 nm gap distance, we detect the onset of subdiffusion, which can be correlated to the motion of the particles along high gap-distance paths. PMID- 29441274 TI - Wafer-scale bioactive substrate patterning by chemical lift-off lithography. AB - The creation of bioactive substrates requires an appropriate interface molecular environment control and adequate biological species recognition with minimum nonspecific attachment. Herein, a straightforward approach utilizing chemical lift-off lithography to create a diluted self-assembled monolayer matrix for anchoring diverse biological probes is introduced. The strategy encompasses convenient operation, well-tunable pattern feature and size, large-area fabrication, high resolution and fidelity control, and the ability to functionalize versatile bioarrays. With the interface-contact-induced reaction, a preformed alkanethiol self-assembled monolayer on a Au surface is ruptured and a unique defect-rich diluted matrix is created. This post lift-off region is found to be suitable for insertion of a variety of biological probes, which allows for the creation of different types of bioactive substrates. Depending on the modifications to the experimental conditions, the processes of direct probe insertion, molecular structure change-required recognition, and bulky biological species binding are all accomplished with minimum nonspecific adhesion. Furthermore, multiplexed arrays via the integration of microfluidics are also achieved, which enables diverse applications of as-prepared substrates. By embracing the properties of well-tunable pattern feature dimension and geometry, great local molecular environment control, and wafer-scale fabrication characteristics, this chemical lift-off process has advanced conventional bioactive substrate fabrication into a more convenient route. PMID- 29441275 TI - Improving the cardiac cath-lab interventional imaging eco-system. PMID- 29441276 TI - The paradox of choice in the surgical management of congenitally corrected transposition: what should we do with all of these options supported by little evidence? PMID- 29441277 TI - Is one-and-a-half better than two? PMID- 29441278 TI - Re: American Gastroenterological Association Institute Guideline on therapeutic drug monitoring in inflammatory bowel disease. PMID- 29441279 TI - Externally applied compression therapy for Fontan patients. AB - Background: Limited therapeutic options are available for Fontan patients with dysfunctional or failing single ventricle physiology. This study describes the evaluation of an alternative, non-invasive, at-home therapeutic compression treatment for Fontan patients. Our hypothesis is that routinely administered, externally applied compression treatments to the lower extremities will augment systemic venous return, improve ventricular preload, and thus enhance cardiac output in Fontan patients. Methods: To initially evaluate this hypothesis, we employed the NormaTec pneumatic compression device (PCD) in a pilot clinical study (n=2). This device is composed of inflatable trouser compartments that facilitate circumferentially and uniformly applied pressure to a patient's lower extremities. Following an initial health screening, test subjects were pre evaluated with a modified-Bruce treadmill exercise stress test, and baseline data on cardiorespiratory health was collected. After training, test subjects conducted 6 days of external compression therapy at-home. Subjects were then re evaluated with a final treadmill stress test and data acquisition of new cardiorespiratory parameters. Results: Both subjects demonstrated improvement in exercise duration time, peak oxygen volume, and ventilator threshold, as compared to the baseline evaluation. Conclusions: These findings are promising and provide the foundation for future studies that will focus on increasing study participation (sample size) to better assess the clinical benefit of compression therapy for Fontan patients. PMID- 29441280 TI - Pharmacological treatment of anxiety disorders in children and adolescents: a review for practitioners. AB - Anxiety disorders are common in children and adolescents with reported prevalence rates between 10% and 30%. A combined approach to treatment has been found to be the most effective for optimal outcomes and is typically comprised of psychotherapy (especially exposure-based cognitive behavior therapy), family and patient education, and use of medication if indicated. In children and adolescents who might benefit from use of medications, selective serotonin reuptake inhibitors (SSRIs) are the drugs of choice. The safety and efficacy of medications other than SSRIs in the treatment of children and adolescents with anxiety disorders are not fully established. Most children and adolescents respond well to treatment with long lasting resolution of symptoms, although, recurrence of the same, or development of a different type of anxiety disorder, is not uncommon. In most children and adolescents, anxiety disorders tend to persist into adulthood requiring long-term treatment planning. This paper reviews the pharmacological agents used in the treatment of anxiety disorders in children and adolescents. PMID- 29441281 TI - Pharmacologic management of attention deficit hyperactivity disorder in children and adolescents: a review for practitioners. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children and adolescents. ADHD affects multiple aspects of an individual's life and functioning in family, social, and academic realms. Effective management of ADHD is necessary for children and adolescents and may include non-pharmacologic treatments, pharmacologic therapy including use of stimulant and non-stimulant medications, or a combination of the different treatment modalities. In general, medications used to treat ADHD are safe and effective. Medical practitioners can follow a step-wise approach in the selection and adjustment of pharmacologic agents to treat ADHD, while working closely with families, caregivers, and other medical and educational professionals to form appropriate treatment plans. This article reviews practical aspects of pharmacological treatment of ADHD in children and adolescents. PMID- 29441282 TI - Specific learning disability in mathematics: a comprehensive review. AB - Math skills are necessary for success in the childhood educational and future adult work environment. This article reviews the changing terminology for specific learning disabilities (SLD) in math and describes the emerging genetics and neuroimaging studies that relate to individuals with math disability (MD). It is important to maintain a developmental perspective on MD, as presentation changes with age, instruction, and the different models (educational and medical) of identification. Intervention requires a systematic approach to screening and remediation that has evolved with more evidence-based literature. Newer directions in behavioral, educational and novel interventions are described. PMID- 29441283 TI - Caspofungin resistant disseminated candidiasis in a 7-year-old girl with T cell lymphoma: a case report. AB - Immunocompromised patients are at increased risk of disseminated candidiasis. Guidelines for the treatment of invasive candidiasis were last published in 2009, but resistance to the recommended treatment has recently been described in the literature. Here we present the case of an immunocompromised child with T-cell lymphoma who died secondary to disseminated candidiasis despite prolonged antifungal therapy. Awareness of the increasing resistance patterns of Candida when caring for immunocompromised patients, especially pediatric patients, may improve treatment and create better patient outcomes. PMID- 29441284 TI - Infected renal hematoma in a healthy adolescent with no renal structural anomaly. AB - Renal abscesses are uncommon in otherwise healthy children and adolescents who have no underlying renal structural anomalies. A previously healthy, immunocompetent, 14-year-old male without a history of abdominal trauma or urinary tract infection (UTI) was found to have a renal hematoma that became infected and developed into a renal abscess. He presented with a 2-day history of nausea, vomiting, fever and 1-day history of abdominal pain that radiated to the right flank. Clinical examination, blood work, and initial imaging indicated likely infection; however, findings were normal on urinalysis and urine culture had no growth. Complete blood count (CBC) showed a leukocytosis with a left shift. Renal ultrasound showed a 4-cm mass-like area of liquefaction in the upper pole of the right kidney, confirmed by abdominal computed tomography (CT) scan with and without contrast. Intravenous ceftriaxone was started and the patient continued to improve. He was discharged on hospital day 6 after remaining afebrile for over 20 hours and inflammatory markers continued to decrease. Intravenous ceftriaxone was continued, and oral clindamycin was added. Both antibiotics were discontinued on day 24 since onset of illness. PMID- 29441285 TI - Ascending aortic slide for interrupted aortic arch repair. PMID- 29441286 TI - Burying the appendiceal stump during appendicectomy: state of art. PMID- 29441287 TI - Dr. Patrick Chung: you can't simply treat a child as a smaller adult! PMID- 29441288 TI - Prof. John C. Carey: learning to look at facial features before diagnosis. PMID- 29441290 TI - Indian Dermatology Online Journal (IDOJ) Going the Print Way! PMID- 29441289 TI - High-Density in Spinal Cord stimulation: Virtual Expert Registry (DISCOVER): Study Protocol for a Prospective Observational Trial. AB - Background: Spinal cord stimulation (SCS) is a proven and effective treatment for neuropathic pain conditions such as failed back surgery syndrome (FBSS). The hypothesis that different settings for SCS parameters activate unique, pain relieving mechanisms has boosted the development of various SCS paradigms. High density spinal cord stimulation (HD-SCS) is one of those promising, novel stimulation forms characterized by subthreshold stimulation, delivering more pulses per second and a higher pulse density to the spinal cord than conventional SCS. Objectives: The aim of DISCOVER is to gather evidence about the effectiveness, feasibility, and (possible) side effects of HD stimulation. Methods: The prospective, non-interventional, multi-center, clinical study, DISCOVER, is currently restricted to Belgium where 19 neuromodulation centers were selected. Patient recruitment started in October 2016 and is expected to end in October 2017. Subjects included are (1) patients with insufficient pain relief from conventional SCS or (2) neurostimulation-naive patients suited for SCS. Patients will be assessed 1 month, 3 months, and 12 months after conversion to HD SCS settings. Each patient's visit will include: a numerical rating scale (NRS), Oswestry disability index (ODI), Pittsburgh sleep quality index (PSQI), EQ-5D, a pain map, registration of SCS settings, and a list of used pain medication. Conclusions: Although promising results have been reported, adequate registration of its effectiveness and (possible) side-effects remains an unmet need. Main results are expected in 2019. PMID- 29441291 TI - Nail Biopsy: A User's Manual. AB - Nail biopsy is a procedure not routinely resorted to; but when indicated, it is often the only clue left for diagnosis. At such times, it pays to be conversant with it. It is an investigation that not only provides etiologic, diagnostic, and prognostic information but also aids in understanding the pathogenesis of nail diseases. It can be of therapeutic value, especially with respect to nail tumors. This article compiles the procedural techniques for nail biopsy of various types and attempts to summarize the evidence available in the literature. The objective of nail biopsy is to clinch a precise diagnosis of nail pathology with a simple and safe surgical procedure, avoiding pain or permanent nail damage. Patient selection is of utmost importance, wherein, the patient does not have typical skin lesions, yields inadequate information on routine nail investigations, and has no peripheral vascular compromise. The patient needs to be explained about the risks associated, the expected functional handicap, the time required for regrowth, a possibility of permanent nail dystrophy, and a possibility of not achieving a diagnosis even after the biopsy. Techniques and types of various nail biopsies are being discussed in this article. The specimen could be collected as an excision biopsy, punch biopsy, shave biopsy, or longitudinal biopsy. The trick lies in choosing the appropriate area for biopsy. Various biopsy types discussed in this article include nail plate biopsy (easiest and least scarring); nail bed biopsy (elliptical excision or punch); nail matrix biopsy (elliptical excision, punch excision (<=3 mm) or tangential/shave excision); and nail fold biopsy. Complications reported along with means to minimize them are also discussed. PMID- 29441292 TI - Dermoscopic Features of Distal Lateral Subungual Onychomycosis. AB - Background: Onychomycosis is a very common disease and accounts for upto 50% of the diseases affecting the nail apparatus. Diagnosis of onychomycosis is usually confirmed with the help of a potassium hydroxide (KOH) mount and fungal culture. Onychoscopy can be a handy and additional tool for the diagnosis. Aims and Objectives: To determine the dermoscopic findings in distal lateral subungual onychomycosis (DLSO). Materials and Methods: A prospective study of 60 nails with a clinical and mycological diagnosis (KOH with Chicago sky blue positive) of DLSO. Dermoscopic examination was performed using a Heine delta 20 plus dermatoscope and the features were recorded. Results: Longitudinal striae and jagged proximal edges seen in all 60 (100%) patients. Intermittent spiked pattern was seen in 47 nails (78.3%). Chromonychia and distal irregular termination were noticed in 23 (38.3%) and 7 (11.7%) nails, respectively. Conclusions: Onychoscopy can be used as an important diagnostic tool while evaluating nail disease, especially in DLSO. Limitations: Small study sample and lack of comparison with other nail diseases that manifests with distal onycholysis. PMID- 29441293 TI - Mucocutaneous Manifestations in Patients with Chronic Kidney Disease: A Cross sectional Study. AB - Background: Chronic kidney disease (CKD)-associated mucocutaneous manifestations significantly impair the quality of life but often remain understudied. They may also vary across regions, socioeconomic and nutritional status, and racial differences. Objectives: To study the patterns of mucocutaneous disorders and their prevalence in CKD patients irrespective of clinical stage or dialysis status. Materials and Methods: 122 (M:F = 77:45) patients aged 21-85 (Mean +/- SD = 57.5 +/- 14.0) years having CKD for 3 month to 5 years were studied for mucocutaneous manifestations. Fifty (41%) patients were on hemodialysis for 1-42 months. Detailed medical history, clinical and mucocutaneous examination, and lab investigations were performed. KOH mounts, skin biopsy, Gram's and Giemsa staining, bacterial or fungal cultures were performed as required. Results: Xerosis in 93 (76.2%), skin pallor in 61 (50%), pruritus in 57 (46.7%), pigmentation in 47 (38.5%), and purpura in 18 (14.8%) patients were the major dermatoses. Bullous lesions and perforating folliculitis occurred in 3 (2.5%) patients each. Major nail abnormalities were pallor (in 35.2%), absent lunula (in 23.8%), nail discoloration (in 18%), and "half-and-half nails" in 16.4% patients, respectively. Hair abnormalities included sparse scalp and body hairs (in 35.2% and 13.1%, respectively) and lusterless hair in 12.3% patients. Coated tongue (in 14.8%), xerostomia (in 12.3%), and macroglossia with teeth indention (in 7.4%) patients were the mucosal manifestations. Conclusions: Xerosis, pruritus, skin pallor/pigmentary changes, nail pallor, absent lunula, nail discoloration, sparse hairs, coated tongue, xerostomia, macroglossia, and infections were the most common mucocutaneous manifestations in the studied patients irrespective of hemodialysis status. Cold and dry climates might be additional aggravators for xerosis/pruritus. Lifelong follow-up may be needed to reduce the morbidity associated with CKD/hemodialysis specific dermatoses appearing over a period. PMID- 29441294 TI - Effect of an Educational and Psychological Intervention on Knowledge and Quality of Life among Patients with Psoriasis. AB - Background: Psoriasis is one of the most common skin disorders with a prevalence rate of 0.1%-3%. Chronic nature, frequent relapses, absence of permanent cure, and the cosmetic disfigurement of psoriasis have a negative impact on quality of life (QoL) by causing psychological stress. Patients with psoriasis often have unambiguous ideas about the causes, controllability, consequences, and expected time-course of their disease. Aim: The aim of this study is to assess the effectiveness of a video-assisted teaching program regarding psoriasis on the level of knowledge and relaxation therapy on QoL among patients with psoriasis. Materials and Methods: Experimental design was adapted. One hundred and four participants diagnosed with psoriasis were randomly allocated either to an experimental or to a control group. Fifty-two participants were included in each group by simple random sampling. A video-assisted teaching program on psoriasis and relaxation exercises was taught to the participants over a period of 3 months. The tools used were: Psoriasis Knowledge Assessment Questionnaire, modified psoriasis disability index, and modified psoriasis life stress inventory. Results: In the experimental group, the knowledge score was increased significantly from 9 +/- 2.2 at baseline to 23.6 +/- 1.5 after the intervention. The disability score was decreased from 15.6 to 9.9 and the stress score related to the illness was decreased from 22.8 to 16.9 after the intervention. Conclusion: Educational intervention about disease process and relaxation exercises was effective in improving the knowledge and QoL of patients with psoriasis. PMID- 29441295 TI - A 19-Year Retrospective Study of Adverse Drug Reactions to Multidrug Therapy in Leprosy Requiring a Change in Regime. AB - Background and Aims: Multidrug therapy (MDT) in leprosy has brought the prevalence of leprosy to elimination levels. However, these drugs are not without toxicity. The primary aim of this study was to find the prevalence of adverse drug reactions (ADR) to MDT and the secondary aim to study the clinical features of these drug reactions. Materials and Methods: This is a19-year retrospective descriptive study of all new leprosy cases with ADR to MDT, requiring a change in regime. Results: There were 901 new leprosy cases in the study period. There were 28 cases of documented ADR to MDT necessitating a change in regime, thus accounting for a prevalence of 3.11%. There were 24 males (85.71%) and 4 females (14.29%) with a male/female ratio 6:1. Mean age was 39.58 years. Borderline tuberculoid was the commonest type of leprosy in which ADR were seen (46.43%). Dapsone was the commonest drug to cause ADR seen in 17 cases (60.71%). Hepatic involvement in the form of drug-induced hepatitis was the commonest presentation of ADR in this study accounting for 13 cases (46.43%), followed by skin rash, 9 cases (32.14%). There were no ADR reported to clofazimine. No ADR was reported to the alternative regimes given. Conclusions: The prevalence of ADRs was low in this study, with dapsone being the commonest drug. There were no adverse reactions to clofazimine. No adverse reactions were reported with the alternative regimes of ofloxacin and minocycline. PMID- 29441296 TI - Tuberous Sclerosis Complex and Diffuse Lipomatosis: Case Report of a Rare Association. AB - Lipomatosis is characterized by diffuse infiltration of adipocytes in a tissue. A young male patient presented for evaluation of unilateral limb swelling. On evaluation, he was found to have tuberous sclerosis complex with diffuse lipomatosis of the right leg. To the best of the authors' literature search, only two previous reports of association of tuberous sclerosis complex with diffuse lipomatosis were found. The molecular mechanisms behind the co-occurrence of these two entities have not been studied in detail. Abnormalities in lipolysis and lipogenesis pathway may underlie the co-occurrence of tuberous sclerosis complex and diffuse lipomatosis. PMID- 29441298 TI - Acquired Cutis Laxa Associated with Light and Heavy Chain Deposition Disease. AB - Acquired cutis laxa (ACL) is a rare connective tissue disorder characterized by pendulous and coarsely wrinkled skin. There have been few cases of its association to monoclonal immunoglobulin deposition disease (MIDD), which constitutes the light chain (LCDD), heavy chain (HCDD), and light and heavy chain (LHCDD) deposition disease. MIDD predominantly involves the kidney. Skin is the next common organ to be affected by HCDD, which presents as ACL. We report the case of a 40-year-old male who presented with ACL associated with LHCDD. The clinical features of ACL in the present case appeared prior to the development of clinical features related to LHCDD. PMID- 29441297 TI - Branch Duct-type Intraductal Papillary Mucinous Neoplasm Presenting as Paraneoplastic Small Plaque Para-psoriasis. AB - To present and discuss a novel association between branch duct-type intraductal papillary mucinous neoplasm and paraneoplastic parapsoriasis. We present the case of a middle-aged male presenting with skin lesions that were suggestive of parapsoriasis, resistant to treatment, and in whom a diagnosis of branch-type intraductal papillary mucinous neoplasm of the pancreas was eventually made. A curative Whipple's surgery led to complete resolution of the skin lesions within 3 weeks. Paraneoplastic parapsoriasis in association with intraductal papillary mucinous pancreatic neoplasm has never been reported before. PMID- 29441299 TI - Livedo Racemosa, Reticulated Ulcerations, Panniculitis and Violaceous Plaques in a 46-year-old Woman. AB - Clinically amyopathic dermatomyositis (CADM) is a subset of dermatomyositis (DM) that has conventional cutaneous manifestations of DM, but paradoxically, little or no muscle involvement. In 2005, a novel antibody was described in association with CADM - anti-melanoma differentiation-associated gene 5 (anti-MDA5). Patients with this serologic marker have a characteristic mucocutaneous phenotype consisting of skin ulceration among other signs. We describe the case of a 46 year-old woman with CADM, elevated anti-MDA5 autoantibodies, and unusual clinical features (livedo racemosa, florid acral edema) among the classical phenotype of MDA5 DM (arthralgias, ulcerations, panniculitis) and classical DM lesions (Gottron papules, heliotrope rash). The patients did not develop interstitial lung disease or internal malignancies and experienced a rapid response to prednisolone and intravenous immunoglobulins. After 2 years, she has no relapse of her cutaneous disease and continues 5 mg prednisolone and 2 g/kg kilogram of intravenous immunoglobulin every 3 months for maintenance. Our case highlights the clinical heterogeneity of CADM and underscores the importance of a comprehensive approach to DM patients. It was previously postulated that anti MDA5 antibody could target vascular cells and compromise vascular function, the presence of livedo racemosa lesions, and MDA5 antibodies in a patient with negative thrombophilia workup, reinforce this idea. This is the first case, to our knowledge, of CADM with acral panniculitis and livedo racemosa. PMID- 29441300 TI - Trauma-induced Focal Nodular Mucinoses: A Rare Entity. AB - Cutaneous mucinoses refer to disorders with abnormal accumulation of mucin in the skin. Mucin is an amorphous material that is a part of the extracellular matrix in dermis. Cutaneous mucinoses could be primary or secondary. The latter is associated with systemic disorders such as autoimmune diseases, diabetes mellitus, paraproteinemia, or altered thyroid function. Here, we report an adult female patient with trauma-induced cutaneous focal nodular mucinoses on left sided scapular region. Histology showed replacement of collagen bundles by mucinous deposits in superficial and mid-dermis. Mucinous substance was present in peri-eccrine location on Alcian blue staining. PMID- 29441301 TI - Serum Levels of Hypersensitive-C-Reactive Protein in Vitiligo. PMID- 29441302 TI - Fixed Drug Eruption to Cetirizine: An Unusual Villain. PMID- 29441303 TI - Bilateral Periorbital Involvement Localized to Eyelids in Lichen Planus Pigmentosus. PMID- 29441304 TI - Relationship between Disease Activity and Helicobacter pylori Infection in Patients with Vitiligo. PMID- 29441305 TI - Familial Case of Darier Disease with Guttate Leukoderma: A Case Series from India. PMID- 29441306 TI - Idiopathic Eruptive Macular Pigmentation in an Indian Male. PMID- 29441307 TI - Hypotrichosis in a Child with Olmsted Syndrome. PMID- 29441308 TI - Granulomatous Periorificial Dermatitis Effectively Managed with Oral Isotretinoin. PMID- 29441310 TI - SkIndia Quiz 43: Firm Asymptomatic Nodular Skin Lesion on the Nose. PMID- 29441309 TI - Plica Polonica Following Use of Homeopathic Antidandruff Shampoo Containing Canthalin. PMID- 29441311 TI - Solitary Plaque on the Chin. PMID- 29441312 TI - Extensive Post-Kala-Azar Dermal Leishmaniasis. PMID- 29441313 TI - Dermoscopy of Post Kala-Azar Dermal Leishmaniasis. PMID- 29441314 TI - Dermoscopy of Sarcoidosis: A Useful Clue to Diagnosis. PMID- 29441316 TI - Pharmaceutical "quality by design" approach. PMID- 29441315 TI - Targeting IL-23 in psoriasis: current perspectives. AB - The recent advances in the understanding of psoriasis pathogenesis have clarified the pivotal role of interleukin (IL)-23. It is a heterodimeric cytokine consisting of two subunits, the unique p19 and the p40, which are shared with IL 12. The basic role of IL-23 in psoriasis is the activation and maintenance of the T-helper 17 pathway. New research findings indicate that IL-23 is more important than IL-12 in the pathogenesis of psoriasis. Based on that background, the selective targeting of the IL-23p19 subunit emerged as an attractive therapeutic option and led to the development of a new category of biologic agents. Three monoclonal antibodies that selectively inhibit the IL-23p19 subunit, guselkumab, tildrakizumab, and risankizumab, are in the pipeline for the treatment of moderate-to-severe psoriasis. In this article, we review the most recent efficacy and safety data regarding these IL-23p19 inhibitors. PMID- 29441317 TI - Polymeric micelles as cutaneous drug delivery system in normal skin and dermatological disorders. AB - The easy accessibility of skin made dermal application, one of the approaches for local drug therapy. Effectiveness of topical drug application is depended on different parameters such as skin barrier properties, physicochemical properties of drug and vehicle, and interaction between drug and its vehicle with the skin layers. In this review, an overview of skin structure and feature of polymeric micelles as topical nanocarriers is provided. We also summarized the research studies dealing with the application of polymeric micelles for cutaneous delivery. In the past decades, numerous types of nanocarriers have been widely investigated as a novel delivery approach to improve skin penetration and localization of drugs in normal skin and dermatological diseases. Polymeric micelles are one of them, with their specific ability to encapsulate hydrophilic drugs. These carriers can enhance the therapeutic efficacy and minimize the systemic side effects of the drugs. Polymeric micelles could enhance the deposition of drugs in targeted sites of the skin in the normal and dermatological diseases such as psoriasis and acne. Nevertheless, still there is a need to investigate the mechanism of action of these carriers and the fate of polymeric micelles in skin. PMID- 29441318 TI - The off-label use of drugs for parenteral nutrition as a solvent of substances slightly soluble in water in pharmacological research. AB - Because of the problem to evaluate biological activity in water-soluble substances in all phases of preclinical and clinical studies, the research work enabled to develop the original solvent for poorly soluble compounds based on substances for parenteral nutrition. The main aim is to examine the impact of the original solvent based on substances for parenteral nutrition on biological systems exemplified by the hemostatic system, characterized by sensitivity and variability of the effects in response to any impact, and its comparison with the solvents that are conventional in pharmacological research. Experimental work is performed according to the "guidance on preclinical research of new pharmacological substances" in vitro. The findings show that traditional solvents at low dosages affect all the researched indicators of the hemostasis system. The smallest effect in respect of the hemostatic system was characterized by ethanol, and the most apparent antiaggregational effect was registered with dioxane. 10% concentration of original blend of lipids made no effect on hemostasis system. Thus, according to their own findings and experience in application of lipid emulsions as substances of parenteral nutrition, they can be considered to be an adequate solvent in all phases of preclinical and clinical studies of new drugs. PMID- 29441320 TI - Zika virus disease knowledge among the future health-care providers of the United Arab Emirates. AB - Zika virus (ZIKV) disease has become a major public health concern. Although there are no reported cases of ZIKV disease in the United Arab Emirates (UAE), there is a potential risk of transmission due to large expatriate population and high influx of international travelers. This cross-sectional study was conducted to assess the knowledge of ZIKV disease among the students of a medical and health sciences university in the UAE. Their knowledge of ZIKV disease was assessed using a specially designed, pretested, and validated questionnaire. Of the 500 respondents included in the final analysis, 314 (62.8%) respondents presented with poor knowledge of ZIKV disease. The mean knowledge score of the study population was 10.48 +/- 2.48 out of a maximum of 17. Gender, college and year of study, nationality and attendance in lecture/conference/workshop on Zika were significantly associated with the level of knowledge. The males possessed significantly (P = 0.046) better knowledge as compared to the females. Students of medical college had significantly (P = 0.005) better knowledge as compared to students of other colleges. The level of knowledge improved significantly (P = 0.026) as the year of study progressed. There is a need for medical and paramedical students to update their knowledge of ZIKV disease as they are the future health-care providers who will be responsible for creating awareness about such outbreaks and their preventive measures. PMID- 29441319 TI - The effect of Calendula officinalis versus metronidazole on bacterial vaginosis in women: A double-blind randomized controlled trial. AB - Bacterial vaginosis (BV) is a common disorder among women of reproductive age. This study aimed to compare the effect of a Calendula officinalis extract-based cream and metronidazole on BV among women of reproductive age. In this study, 80 women of reproductive age with BV were randomly assigned to the C. officinalis (n = 40) or metronidazole (n = 40). Diagnosis of BV was confirmed when at least 3 of the 4 Amsel criteria were met (pH >4.5, whitish grey or thin homogeneous discharge, release of a fishy odor on adding 10% KOH, and detection of clue cells on microscopic examination). For each group, either a methanol extract of C. officinalis or metronidazole vaginal cream (5 g) was used for 1 week intravaginally, and all signs and symptoms were assessed 1 week after treatment completion. Before the intervention, the two groups did not differ significantly with regard to vaginal burning, odor, dysuria, and dyspareunia, but itching was significantly more common in the C. officinalis group than in the metronidazole group (22.5% vs. 2.5%, P = 0.01). One week after the intervention, all women in both groups were free of symptoms, including vaginal itching and burning sensation, odor, dysuria, and dyspareunia. None of the women in either group suffered any side effects from C. officinalis or metronidazole. C. officinalis was effective for the treatment of BV in women of reproductive age, without any side effects. This herb could be recommended for women of reproductive age who uncomfortable with the potential side effects of synthetic drugs. PMID- 29441321 TI - Quality evaluation of Kaempferia parviflora rhizome with reference to 5,7 dimethoxyflavone. AB - Kaempferia parviflora Wall. ex Baker is a medicinal plant found in the upper Northeastern regions of Thailand, which belongs to Zingiberaceae family. The present study aims to investigate the standardization parameters, to analyze chemical constituents of volatile oil by gas chromatography-mass spectrometry, and to determine the content of 5,7-dimethoxyflavone in K. parviflora rhizomes by thin-layer chromatography (TLC)-densitometry compared to TLC image analysis. K. parviflora rhizomes from 15 different sources throughout Thailand were investigated for morphological and pharmacognostic parameters. 5,7 Dimethoxyflavone contents were determined by TLC-densitometry with winCATS software and TLC image analysis with ImageJ software. The mobile phase for TLC development consisted of toluene: chloroform: Acetone: formic acid (5: 4: 1: 0.2). For the Results, the pharmacognostic parameters of K. parviflora rhizome were demonstrated. The loss on drying, total ash, acid-insoluble ash, water content, volatile oil content, ethanol, and water-soluble extractive values were found to be 8.979 +/- 0.041, 5.127 +/- 0.060, 2.174 +/- 0.092, 9.291 +/- 0.458, 0.028 +/- 0.003, 5.138 +/- 0.092, and 8.254 +/- 0.191 g/100 g of dry weight, respectively. K. parviflora volatile oil showed the major components of alpha copaene, dauca-5, 8-diene, camphene, beta-pinene, borneol, and linalool. The 5,7 dimethoxyflavone content of K. parviflora rhizomes determined by TLC-densitometry and TLC image analysis were found to be 2.15 +/- 0.64 and 1.96 +/- 0.51 g/100 g of dry rhizomes, respectively. The 5,7-dimethoxyflavone contents of both methods were not significantly different (P > 0.05) using paired t-test. PMID- 29441322 TI - Effect of Vitamin E and omega 3 fatty acids in type 2 diabetes mellitus patients. AB - Diabetes mellitus (DM) and its complications have been implicated in hyperglycemia-induced oxidative stress. Antioxidants can improve glycemic control, lipid profile, and cognitive functions. We assessed the effect of Vitamin E and omega 3 fatty acids (OFA) on the above parameters. One hundred patients with type 2 DM receiving metformin 500 mg and glimepiride 1 mg were randomized to receive add-on therapy of Vitamin E 400 mg or OFA once daily for 12 weeks and the third group served as control. Fasting blood sugar (FBS), postprandial blood sugar (PPBS), glycated hemoglobin (HbA1c), body mass index (BMI), waist-hip ratio (WHR), lipid profile, and mini-mental state examination were done at baseline and 12 weeks. Eighty-seven patients completed the study. A significant reduction in FBS, PPBS, and HbA1c was observed in all the three groups at 12 weeks. There was significant reduction in total cholesterol and triglycerides (TG) in patients receiving either of the antioxidants and also significant reduction in low-density lipoprotein in patients receiving OFA at 12 weeks compared to baseline. BMI and WHR were significantly increased in control group. Intergroup analysis showed that in patients receiving Vitamin E and OFA, the reduction of FBS, PPBS, and HbA1c were similar. The patients receiving OFA had significant reduction in TG compared to control. There was no significant effect on cognitive function. Vitamin E and OFA had beneficial effects on lipid profile and anthropometric measurements; however, the glycemic control was similar to the patients in control group. PMID- 29441323 TI - The ethanolic extract of ashitaba stem (Angelica keskei [Miq.] Koidz) as future antituberculosis. AB - Considering the easy contagion of tuberculosis (TB) disease spread and the emergence of multidrug-resistant TB, which directly impacts the failure of therapeutic goals and mortality rates increasing, TB disease control remains to be the main concern of continuous health development effort. Therefore, the discovery of new TB drug is needed. This research assessed the new natural anti TB drug from the ethanolic extract of Angelica keiskei stem obtained from Lombok, Indonesia. The objectives of this study were to evaluate the sensitivity of Mycobacterium tuberculosis (Mtb) H37Rv strain to A. keiskei stem extract and to determine its minimum inhibitory concentration (MIC). The extraction methods of A. keiskei stem were done using a maceration method. In addition to phytochemical screening and water content analysis using standard method, the phytochemical parameters were analyzed by thin-layer chromatography. Ethanolic extract of A. keiskei stem was assayed for their Mtb inhibitory activity using the proportion method. The phytochemical analysis result showed that the secondary metabolites contain in the extract were flavonoid, polyphenol, tannin, monoterpenoid and sesquiterpen, quinon, and saponin. The anti-TB test result showed the active activity of ethanolic extract of A. keiskei against Mtb H37Rv strain with MIC ranging from 6% to 8% w/v. In conclusion, ethanolic extract of A. keiskei is a prospective natural anti-TB for the future. PMID- 29441325 TI - Editorial: The Role of Microenvironment in the Homing, Maintenance, and Release of Glioma Stem-Like Cells. PMID- 29441324 TI - MicroRNA, an Antisense RNA, in Sensing Myeloid Malignancies. AB - Myeloid malignancies, including myelodysplastic syndromes and acute myeloid leukemia, are clonal diseases arising in hematopoietic stem or progenitor cells. In recent years, microRNA (miRNA) expression profiling studies have revealed close associations of miRNAs with cytogenetic and molecular subtypes of myeloid malignancies, as well as outcome and prognosis of patients. However, the roles of miRNA deregulation in the pathogenesis of myeloid malignancies and how they cooperate with protein-coding gene variants in pathological mechanisms leading to the diseases have not yet been fully understood. In this review, we focus on recent insights into the role of miRNAs in the development and progression of myeloid malignant diseases and discuss the prospect that miRNAs may serve as a potential therapeutic target for leukemia. PMID- 29441326 TI - A Rare Case of Primary Intrapulmonary Neurilemmoma Diagnosed in a 43-Year-Old Asymptomatic Man with a Well-defined Intrapulmonary Mass. AB - Neurilemmoma (NL), also termed schwannoma, presents as a well-circumscribed and encapsulated mass in the human body and is almost always solitary. CT scan of a patient with NL shows a round, ovoid, or lobulated well-demarcated solid mass of soft tissue density. Primary intrathoracic neurogenic tumors location varies. However, the development of such tumors is by far more common in the costovertebral angle of the posterior mediastinum. Here, we report a rare case of a 43-year-old patient, never smoker and previously healthy, who presented with a mass adjacent to the right pulmonary hilum. This was an incidental finding on a chest X-ray after annual checkup at his workplace. The diagnosis was primary intrapulmonary NL. Primary intrapulmonary NL is an extremely rare tumor. However, based on the above, chest CT findings of a well-defined solid mass in an asymptomatic patient should raise the suspicion of NL, irrespective of the tumor localization. PMID- 29441327 TI - Inorganic Polyphosphate Is Essential for Salmonella Typhimurium Virulence and Survival in Dictyostelium discoideum. AB - Inorganic polyphosphate (polyP) deficiency in enteric bacterial pathogens reduces their ability to invade and establish systemic infections in different hosts. For instance, inactivation of the polyP kinase gene (ppk) encoding the enzyme responsible for polyP biosynthesis reduces invasiveness and intracellular survival of Salmonella enterica serovar Typhimurium (S. Typhimurium) in epithelial cells and macrophages in vitro. In addition, the virulence in vivo of a S. Typhimurium Deltappk mutant is significantly reduced in a murine infection model. In spite of these observations, the role played by polyP during the Salmonella-host interaction is not well understood. The social amoeba Dictyostelium discoideum has proven to be a useful model for studying relevant aspects of the host-pathogen interaction. In fact, many intracellular pathogens can survive within D. discoideum cells using molecular mechanisms also required to survive within macrophages. Recently, we established that S. Typhimurium is able to survive intracellularly in D. discoideum and identified relevant genes linked to virulence that are crucial for this process. The aim of this study was to determine the effect of a polyP deficiency in S. Typhimurium during its interaction with D. discoideum. To do this, we evaluated the intracellular survival of wild-type and Deltappk strains of S. Typhimurium in D. discoideum and the ability of these strains to delay the social development of the amoeba. In contrast to the wild-type strain, the Deltappk mutant was unable to survive intracellularly in D. discoideum and enabled the social development of the amoeba. Both phenotypes were complemented using a plasmid carrying a copy of the ppk gene. Next, we simultaneously evaluated the proteomic response of both S. Typhimurium and D. discoideum during host-pathogen interaction via global proteomic profiling. The analysis of our results allowed the identification of novel molecular signatures that give insight into Salmonella-Dictyostelium interaction. Altogether, our results indicate that inorganic polyP is essential for S. Typhimurium virulence and survival in D. discoideum. In addition, we have validated the use of global proteomic analyses to simultaneously evaluate the host-pathogen interaction of S. Typhimurium and D. discoideum. Furthermore, our infection assays using these organisms can be exploited to screen for novel anti virulence molecules targeting inorganic polyP biosynthesis. PMID- 29441330 TI - Measurement of health system performance at district level: A study protocol. AB - Background: Limited efforts have been observed in low and middle income countries to undertake health system performance assessment at district level. Absence of a comprehensive data collection tool and lack of a standardised single summary measure defining overall performance are some of the main problems. Present study has been undertaken to develop a summary composite health system performance index at district level. Methods: A broad range of indicators covering all six domains as per building block framework were finalized by an expert panel. The domains were classified into twenty sub-domains, with 70 input and process indicators to measure performance. Seven sub-domains for assessing health system outputs and outcomes were identified, with a total of 28 indicators. Districts in Haryana state from north India were selected for the study. Primary and secondary data will be collected from 378 health facilities, district and state health directorate headquarters. Indicators will be normalized, aggregated to generate composite performance index at district level. Domain specific scores will present the quality of individual building block domains in the public health system. Robustness of the results will be checked using sensitivity analysis. Expected impact for public health: The study presents a methodology for comprehensive assessment of all health system domains on basis of input, process, output and outcome indicators which has never been reported from India. Generation of this index will help identify policy and implementation areas of concern and point towards potential solutions. Results may also help understand relationships between individual building blocks and their sub-components. : PMID- 29441329 TI - Social marketing for a farmer's market in an underserved community: A needs assessment. AB - The aim of the present paper is to assess local residents' awareness of utilizing Supplemental Nutrition Assistance Program (SNAP) benefits to purchase fresh produce at local farmers' markets, and to determine internet use and media preferences of study participants prior to implementation of a social marketing campaign. A needs assessment was conducted to collect baseline data in an underserved neighbourhood in New Orleans (La, USA). The study was carried out August 2014-May 2015. The assessment revealed that 73% of the respondents were unaware that the SNAP benefits could be used to purchase food in farmers' markets; 63% of low-income participants never attended a farmers' market compared to 27% of mid/high-income. Over 50% of the low-income respondents have access to the internet at least once per day. The results show the potential of raising awareness among a wide range of members in the community. This needs assessment will serve as the foundation for a social marketing intervention, which will be disseminated city-wide. PMID- 29441328 TI - Cellular Tight Junctions Prevent Effective Campylobacter jejuni Invasion and Inflammatory Barrier Disruption Promoting Bacterial Invasion from Lateral Membrane in Polarized Intestinal Epithelial Cells. AB - Campylobacter jejuni invasion is closely related to C. jejuni pathogenicity. The intestinal epithelium contains polarized epithelial cells that form tight junctions (TJs) to provide a physical barrier against bacterial invasion. Previous studies indicated that C. jejuni invasion of non-polarized cells involves several cellular features, including lipid rafts. However, the dynamics of C. jejuni invasion of polarized epithelial cells are not fully understood. Here we investigated the interaction between C. jejuni invasion and TJ formation to characterize the mechanism of C. jejuni invasion in polarized epithelial cells. In contrast to non-polarized epithelial cells, C. jejuni invasion was not affected by depletion of lipid rafts in polarized epithelial cells. However, depletion of lipid rafts significantly decreased C. jejuni invasion in TJ disrupted cells or basolateral infection and repair of cellular TJs suppressed lipid raft-mediated C. jejuni invasion in polarized epithelial cells. In addition, pro-inflammatory cytokine, TNF-alpha treatment that induce TJ disruption promote C. jejuni invasion and lipid rafts depletion significantly reduced C. jejuni invasion in TNF-alpha treated cells. These data demonstrated that TJs prevent C. jejuni invasion from the lateral side of epithelial cells, where they play a main part in bacterial invasion and suggest that C. jejuni invasion could be increased in inflammatory condition. Therefore, maintenance of TJs integrity should be considered important in the development of novel therapies for C. jejuni infection. PMID- 29441331 TI - Fear of crime and its relationship to self-reported health and stress among men. AB - Background: Fear of crime is a growing social and public health problem globally, including in developed countries such as Sweden. This study investigated the impact of fear of crime on self-reported health and stress among men living in Gavleborg County. Design and Methods: The study used data collected from 2993 men through a cross sectional survey in the 2014 Health in Equal Terms survey. Descriptive and logistic regression analyses were carried out to study the relationship between fear of crime and self-reported health and stress. Results: There was a statistically significant association between fear of crime and self reported poor health and stress among men residing in Gavleborg County. In the bivariate analysis, men who reported fear of crime had odds of 1.98 (CI 1.47 2.66) and 2.23 (CI 1.45-3.41) respectively. Adjusting for demographic, social and economic variables in the multivariate analysis only reduced the odds ratio for self-reported poor health to 1.52 (CI 1.05-2.21) but not for self-reported stress with odds of 2.22 (1.27-3.86). Conclusions: Fear of crime among men was statistically significantly associated with self-reported poor health and stress in Gavleborg County. However, the statistically significant relationship remained even after accounting for demographic, social and economic factors, which warrants further research to better understand the role played by other variables. : PMID- 29441332 TI - Are the Ethical Committees for pharmacological research bureaucratic bodies? PMID- 29441333 TI - The effect of mesenchymal stem cell use on intra-abdominal adhesions in a rat model. AB - Purpose: Intra-abdominal adhesions (IAA) are among the most frequently seen pathologies in general surgery practice with an increased morbidity and mortality. In the present study, we investigated the effect of locally applied mesenchymal stem cells (MSCs) on IAA. Methods: Twenty-four Wistar Albino rats were used in the study. The rats were divided into three groups including: Sham, control, and MSCs group. On day 0, cecum was reached under anesthesia in all groups, except the Sham group. Scraping with a sponge was performed until petechial bleeding occurred. The control group received no treatment. In the stem cell group, MSCs were applied topically immediately after surgery on adhesions. The rats were sacrificed on day 10 and colon tissues and blood samples were collected for macroscopic, histopathological, and biochemical analysis. Results: In our study, E-selectin, P-selectin, TNF-alpha and IL-1 levels were statistically significantly lower in the MSC group than the control group, while the sham group has the lowest levels. In both the macroscopic and histopathological analyses (Zuhlke's scale), the least amount of adhesion was observed in the Sham group. In addition, although there was less adhesion in the MSC group than the control group, the difference did not reach statistical significance. Conclusion: Topical MSC application immediately after surgery suppresses the inflammatory process. However it was found to be ineffective in histopathological and macroscopic examinations performed on the 10th day. PMID- 29441334 TI - The usefulness of fluorodeoxyglucose-PET/CT for preoperative evaluation of ductal carcinoma in situ. AB - Purpose: PET/CT is useful in preoperative evaluation of invasive breast cancer (IBC) to predict axillary metastasis and staging workup. The usefulness is unclear in cases of ductal carcinoma in situ (DCIS) diagnosed at biopsy before surgery, which sometimes is upgraded to IBC after definitive surgery. The aim of this study is to find out the usefulness of PET/CT on DCIS as a preoperative evaluation tool. Methods: We investigated 102 patients preoperatively diagnosed with DCIS who subsequently underwent definitive surgery between 2010 and 2015. The uptake of 18F-fluorodeoxyglucose was graded by visual and semiquantitative methods. We analyzed the maximum standardized uptake value (SUVmax) of each patient with clinicopathologic variables. We determined optimal cutoff values for SUVmax by receiver operating characteristic curve analysis. Results: Fifteen cases out of 102 cases (14.7%) were upgraded to IBC after surgery. The SUVmax was higher in patients upgraded to IBC (mean: 2.56 vs. 1.36) (P = 0.007). The SUVmax was significantly higher in patients who had symptoms, palpable masses, lesions over 2 cm in size and BI-RAD category 5. Both visual and semiquantitative analysis were significant predictors of IBC underestimation. SUVmax of 2.65 was the theoretical cutoff value in ROC curve analysis in predicting the underestimation of IBC. The underestimation rate was significantly higher in patients with SUVmax >2.65 (P < 0.001), over the moderate enhanced uptake on visual analysis (P < 0.001). Conclusion: PET/CT can be used as a complementary evaluation tool to predict the underestimation of DCIS combined with the lesion size, palpable mass, symptomatic lesion, and BI-RAD category. PMID- 29441335 TI - Clinical usefulness of intraoperative parathyroid hormone monitoring for primary hyperparathyroidism. AB - Purpose: The availability of intraoperative parathyroid hormone (IOPTH) monitoring allows successful focused parathyroidectomy for primary hyperparathyroidism (pHPT). The objective of this study was to report our initial experience in IOPTH monitoring during parathyroid surgery for primary hyperparathyroidsim. Methods: Between May 2011 and February 2013, 37 patients underwent focused parathyroidectomy due to pHPT. IOPTH monitoring based on Miami criteria was used to confirm complete excision of hyperfunctioning parathyroid gland during surgery. Medical records of patients were reviewed retrospectively. Results: Preoperative mean maximal calcium level was 11.7 +/- 0.9 mg/dL. Preoperative technetium (99mTc) sestamibi scan and ultrasonography identified 32 of 37 (86.5%) and 29 of 37 (78.4%) of abnormal parathyroid glands, retrospectively. Results of the 2 imaging modalities were discordant for 8 cases (21.6%). The mean pre-excision PTH level was 147.2 +/- 201.5 pg/mL. At 5- and 10 minute post tumor resection, PTH levels were 65.3 +/- 25.4 pg/mL and 47.5 +/- 24.3 pg/mL, respectively. In all cases, IOPTH levels fell by at least 50% after removing all suspected abnormal glands. All patients had a successful return to normocalcemia after surgery (mean follow-up period: 60.2 +/- 15.4 months). Conclusion: Surgeon could confirm complete excision of abnormal hyperfunctioning parathyroid glands by IOPTH monitoring during surgery for pHPT. IOPTH monitoring can maximize performance of successful focused para thyroidectomy for pHPT, especially when preoperative imaging results are discordant. PMID- 29441336 TI - A prospective randomized study comparing radiofrequency ablation and hepatic resection for hepatocellular carcinoma. AB - Purpose: Although there are several prospective clinical studies comparing radiofrequency ablation (RFA) and hepatic resection (HR) for the treatment of hepatocellular carcinoma, there are few trials that have been performed in strictly homogeneous patients. Methods: Patients who were newly diagnosed with a solitary hepatocellular carcinoma were randomized to the HR or RFA group. Inclusion criteria were as follows: age >= 20 years but <= 70 years, Child-Pugh class A, maximal diameter of the tumor >= 2 cm but <= 4 cm, no previous treatment history, and platelet count > 80,000/mm3. Results: Although the study was early terminated, 29 and 34 patients were enrolled in the HR and RFA groups, respectively, and prospectively followed on an intention-to-treat basis. The 5 year overall survival rates were 83.4% and 86.2% in the HR and RFA groups, respectively, which were not significantly different (P = 0.812 by log-rank, P = 0.990 by Breslow). The 3- and 5-year disease-free survival rates in the HR group were significantly superior to those in the RFA group (66.7%, 44.4% vs. 44.1%, 31.2%, P = 0.071 by log-rank, P = 0.023 by Breslow). Intrahepatic local recurrence tended to develop more frequently in the RFA group (P = 0.042), while the frequency of intrahepatic distant and extrahepatic recurrence was similar bet ween the 2 groups. There were no significant differences in the frequency and severity of complications between the 2 groups. Conclusion: HR was significantly superior to RFA in terms of disease-free survival; however, the overall survival was excellent in both groups. PMID- 29441337 TI - A novel robotic right colectomy for colon cancer via the suprapubic approach using the da Vinci Xi system: initial clinical experience. AB - Purpose: We developed a technique of totally-robotic right colectomy with D3 lymphadenectomy and intracorporeal anastomosis via a suprapubic transverse linear port. This article aimed to introduce our novel robotic surgical technique and assess the short-term outcomes in a series of five patients. Methods: All colectomies were performed using the da Vinci Xi system. Four robot trocars were placed transversely in the supra pubic area. Totally-robotic right colectomy was performed, including colonic mobilization, D3 lymphadenectomy, and intra corporeal stapled functional anastomosis. The 2 middle suprapubic trocar incisions were then extended to retrieve the specimen. Results: Five robotic right colectomies via the suprapubic approach were performed between August 2015 and February 2016. The mean operation time was 183 +/- 29.37 minutes, and the mean estimated blood loss was 27 +/- 9.75 mL. The time to clear liquid intake was 3 days in all patients, and the mean length of stay after surgery was 6.2 +/- 0.55 days. No patient required conversion to conventional laparoscopic surgery. There were no perioperative complications. According to the pathology report, the mean number of harvested lymph nodes was 36.6 +/- 4.45. Four patients were stage III, and 1 patient was stage II according to the 7th edition of the American Joint Committee on Cancer system. Conclusion: Totally-robotic right colectomy via the suprapubic approach can be performed successfully in selected patients. Further comparative studies are required to verify the clinical advantages of our technique over conventional robotic surgery. PMID- 29441338 TI - Evaluation of intradermal absorbable and mattress sutures to close pilonidal sinus wounds with Limberg flap: a prospective randomized comparative study. AB - Purpose: We aimed to compare skin closure techniques, standard (intermittent mattress) and continuous subcuticular sutures, following Limberg flap procedure. Methods: From July 2013 to July 2015, 92 patients with sacrococcygeal pilonidal disease were prospectively randomized into 2 groups consisting of 46 patients for both. Patients underwent sinus excision and closure with Limberg flap; continuous subcuticular suture was used in subcuticular group (SG) and intermittent mattress sutures were used in mattress group (MG) for skin closure. Characteristics of patients, features of pilonidal disease, macerations, infections, wound dehiscence, flap necrosis, operation time, time of drain removal, wound complications, early recurrences, and time till return to work were compared between the 2 groups. Results: There was no statistical difference between groups per sex, age, body mass index, smoking, number of sinuses, depth of intergluteal sulcus, distance of incision to anus, volume of extracted tissue, number of hair follicles per cm2, recurrence, operation, and mean follow-up time. Two patients showed signs of wound complications (4.4%) in SG, whereas 8 cases (17.4%) showed signs in MG (P < 0.05). One patient in SG had surgical site infection and required antibiotics (2.2%), where as there were 6 cases treated in MG (13.0%) (P < 0.05). Removal of drain tube, and time till return to work rates are lower for SG than MG (P < 0.05). Conclusion: In conclusion, surgical procedures which include Limberg flap method and subcuticular closure may reduce infection and maceration rates. Future studies are needed to achieve greater detailed evaluation. PMID- 29441339 TI - Early postoperative small bowel obstruction after laparotomy for trauma: incidence and risk factors. AB - Purpose: This study aimed to investigate the incidence and risk factors of early postoperative small bowel obstruction (EPSBO) after laparotomy for trauma patients. Methods: From 2009 to 2016, consecutive patients who had undergone laparotomy for trauma were retrospectively evaluated. EPSBO was defined as the presence of signs and symptoms of obstruction between postoperative days 7 and 30, or obstruction occurring anytime within 30 days and lasting more 7 days. Results: Among 297 patients who met the inclusion criteria, 72 (24.2%) developed EPSBO. The length of hospital stay was significantly longer in patients with EPSBO than in those without EPSBO (median [interquartile range], 34 [21-48] days 24 [14-38] days, P < 0.001). Multivariate logistic analysis identified male sex (adjusted odds ratio [AOR], 3.026; P = 0.008), intraoperative crystalloid (AOR, 1.130; P = 0.031), and Abbreviated Injury Scale (AIS) score for mesenteric injury (AOR, 1.397; P < 0.001) as independent risk factors for EPSBO. The incidence of adhesive small bowel adhesion after 30 days postoperatively did not significantly differ between the 2 groups (with EPSBO, 5.6% without EPSBO, 5.3%; P = 0.571). Most of the patients with EPSBO were recovered by conservative treatment (95.8%). Conclusion: After laparotomy for trauma patients, the incidence of EPSBO was 24.2% in our study. EPSBO was associated with a longer hospital stay. Male sex, use of intraoperative crystalloid, and AIS score for mesenteric injury were significant independent risk factors for EPSBO. Patients with these risk factors should be followed-up more carefully. PMID- 29441340 TI - Small bowel obstruction from distant metastasis of primary breast cancer: a case report. AB - Gastrointestinal (GI) tract metastasis of primary breast cancer is very rare. We present a patient with small bowel obstruction from distant metastasis of primary breast cancer. Each characteristic features of concern of GI tract distant metastasis from many pervious studies has been reported differently. We should remember that GI tract metastasis may coexist when patients with breast cancer have intermittent or recurrent abdominal pain with or without obstructive symptoms. PMID- 29441341 TI - Single incision laparoscopic cholecystectomy for patients with Mirizzi syndrome. AB - Since multiport laparoscopic cholecystectomy has become a standard treatment for gallbladder (GB) disease, a single incision laparoscopic surgical technique has been tried to decrease the surgical site pain and achieve a better cosmetic out come in selected patients. The development of devices dedicated for single incision laparoscopic cholecystectomy (SILC) is expanding the indication of this single incision laparoscopic technique to more complicated GB diseases. Mirizzi syndrome (MS) is one of the complex uncommon gallstone diseases in patients undergoing cholecystectomy. Because the laparoscopic procedure has become a routine treatment for cholecystectomy, several studies have reported their experience with the laparoscopic technique for the treatment of MS with a comparable outcome in Csendes type I or II. Because the indication for SILC cholecystectomy is expanded to more complicated GB conditions, and the desire of patients for a less painful, better cosmetic surgical outcome has increased, our medical center used this single incision laparoscopic surgical technique for MS Csendes types I and II patients. Here, we report 2 successful cases of SILC for patients with MS types I and II without significant morbidity. PMID- 29441343 TI - Construct Validity of the Movement Assessment Battery for Children-Second Edition Test in Preschool Children with Respect to Age and Gender. AB - Background: The Movement Assessment Battery for Children-second edition (MABC-2) Age Band 1 is widely used to identify preschoolers with motor difficulties. Despite unsatisfactory construct validity of the original three-factor model, MABC-2 (manual dexterity, aiming and catching, and balance), previous research has not considered possible age and gender differences throughout the entire preschool period. Aim: The aim of this study was to verify the construct validity of the MABC-2 Age Band 1 in a population of Czech preschoolers with respect to age and gender. Methods: Using data from 510 Czech preschoolers (3-6 years; 4.9 +/- 1.1 years), confirmatory factor analyses (CFA) were used for each age category and gender. Results: The goodness-of-fit indices of CFA supported the original three-factor model of the MABC-2 only in 3- and 4-year-old children, and in boys (3-6 years). Low factor loadings and ceiling effects of several test items (Drawing Trail, Walking Heels Raised, and Jumping on Mats) seem to be a probable cause of weak fit indices in 5- and 6-year-old children and in girls (3 6 years). Conclusion: These results suggest that the MABC-2 can be a valid tool for assessing motor development and identifying motor difficulties among 3- to 4 year olds, and generally fits better for preschool boys in the Czech Republic. However, in 5- to 6-year olds, ceiling effects and a low power of discrimination was found for the Drawing Trail, Walking Heels Raised, and Jumping on Mats tests. Therefore, the three-factor model is not appropriate for all preschoolers, and separate norms should be established for each age and gender. PMID- 29441344 TI - Implementation of a Sustainable Training System for Emergency in Vietnam. AB - Purpose: This study analyzed the project outcomes to share lessons regarding the development of an emergency medicine education system in Vietnam. Methods: Retrospective evaluation was implemented using project outcome indicators. Results: A total of 13 training courses were administered, with the collaboration of international experts in Korea and Vietnam. A total of 23 kinds of emergency medicine education equipment were purchased, and a basic life support (BLS) and two advanced cardiac life support labs were remodeled to provide appropriate simulation training. Throughout the 2 years of the project, nine Vietnamese BLS instructors were approved by the Korea Association of Cardiopulmonary Resuscitation under American Heart Association. Results of evaluation by Korean international development experts were based on five criteria, provided by the Development Assistance Committee of the Organization for Economic Co-operation and Development, were excellent. Success factors were identified as partnership, ownership, commitment, government support, and global networking. Conclusion: Project indicators were all accomplished and received an excellent evaluation by external experts. For sustainable success, healthcare policy and legal regulation to promote high quality and safe service to the Vietnamese people are recommended. PMID- 29441342 TI - Outcomes following Serial Intragastric Balloon Therapy for Obesity and Nonalcoholic Fatty Liver Disease in a Single Centre. AB - Background: The incidence of nonalcoholic fatty liver disease (NAFLD) continues to parallel the rise in obesity rates. Endobariatric devices such as the intragastric balloon (IGB) may provide an alternative treatment option. Methods: Outcomes following IGB treatment in 135 patients with obesity and NAFLD (mean baseline weight 117.9 kg; BMI 41.7 kg/m2; HOMA-IR 3.6) were retrospectively examined. Clinical, anthropometric, and biochemical changes were analysed at six months and after consecutive treatment with two and three serial IGBs. Results: After six months, significant changes were seen with weight and BMI (mean reductions of 11.3 kg and 4.1 kg/m2, resp., p < 0.01 for both). Significant improvements were also seen with ALT, GGT, and HOMA-IR, with all changes corresponding with weight loss. Forty-eight patients received two IGBs, and 20 were treated with three serial IGBs. The greatest amount of total weight loss was observed after the first 6 months (mean weight lost 7.4 kg, versus 3.6 kg and 1.9 kg with two and three IGBs, resp.). Conclusions: IGB therapy is an effective, alternative nonsurgical means for weight loss in the management of obesity and NAFLD over the short term, with greatest outcomes observed after six months. Improvements in insulin resistance and hepatic transaminases correlated with weight change. PMID- 29441345 TI - Luminescence Properties of Self-Aggregating TbIII-DOTA-Functionalized Calix[4]arenes. AB - Self-aggregating calix[4]arenes carrying four DOTA ligands on the upper rim for stable complexation of paramagnetic GdIII-ions have already been proposed as MRI probes. In this work, we investigate the luminescence properties of TbIII-DOTA calix[4]arene-4OPr containing four propyl-groups and compare them with those of the analog substituted with a phthalimide chromophore (TbIII-DOTA-calix[4]arene 3OPr-OPhth). We show that, given its four aromatic rings, the calix[4]arene core acts as an effective sensitizer of Tb-centered luminescence. Substituents on the lower rim can modulate the aggregation behavior, which in turn determines the luminescence properties of the compounds. In solid state, the quantum yield of the phthalimide derivative is almost three times as high as that of the propyl functionalized analog demonstrating a beneficial role of the chromophore on Tb luminescence. In solution, however, the effect of the phthalimide group vanishes, which we attribute to the large distance between the chromophore and the lanthanide, situated on the opposite rims of the calix[4]arene. Both quantum yields and luminescence lifetimes show clear concentration dependence in solution, related to the strong impact of aggregation on the luminescence behavior. We also evidence the variability in the values of the critical micelle concentration depending on the experimental technique. Such luminescent calix[4]arene platforms accommodating stable lanthanide complexes can be considered valuable building blocks for the design of dual MR/optical imaging probes. PMID- 29441346 TI - Structural Insights into the Osteopontin-Aptamer Complex by Molecular Dynamics Simulations. AB - Osteopontin is an intrinsically disordered protein involved in tissue remodeling. As a biomarker for pathological hypertrophy and fibrosis, the protein is targeted by an RNA aptamer. In this work, we model the interactions between osteopontin and its aptamer, including mono- (Na+) and divalent (Mg2+) cations. The molecular dynamics simulations suggest that the presence of divalent cations forces the N terminus of osteopontin to bind the shell of divalent cations adsorbed over the surface of its RNA aptamer, the latter exposing a high negative charge density. The osteopontin plasticity as a function of the local concentration of Mg is discussed in the frame of the proposed strategies for osteopontin targeting as biomarker and in theranostic. PMID- 29441347 TI - Pyridine 2,4-Dicarboxylic Acid Suppresses Tomato Seedling Growth. AB - Pyridine 2,4-dicarboxylic acid is a structural analog of 2-oxoglutarate and is known to inhibit 2-oxoglutare-dependent dioxygenases. The effect of this inhibitor in tomato seedlings grown in MS media supplied with various concentrations of PDCA was investigated, resulting in shorter roots and hypocotyls in a dose-dependent manner. The partial inhibition of growth in roots was more drastic compared to hypocotyls and was attributed to a decrease in the elongation of root and hypocotyl cells. Concentrations of 100 and 250 MUM of PDCA decreased hydroxyproline content in roots while only the 250 MUM treatment reduced the hydroxyproline content in shoots. Seedlings treated with 100 MUM PDCA exhibited enhanced growth of hypocotyl and cotyledon cells and higher hydroxyproline content resulting in cotyledons with greater surface area. However, no alterations in hypocotyl length were observed. Prolyl 4 hydroxylases (P4Hs) are involved in the O-glycosylation of AGPs and were also highly expressed during seedling growth. Moreover PDCA induced a decrease in the accumulation of HRGPs and particularly in AGPs-bound epitopes in a dose dependent-manner while more drastic reduction were observed in roots compared to shoots. In addition, bulged root epidermal cells were observed at the high concentration of 250 MUM which is characteristic of root tissues with glycosylation defects. These results indicate that PDCA induced pleiotropic effects during seedling growth while further studies are required to better investigate the physiological significance of this 2-oxoglutarate analog. This pharmacological approach might be used as a tool to better understand the physiological significance of HRGPs and probably P4Hs in various growth and developmental programs in plants. PMID- 29441348 TI - Modeling Neurovascular Disorders and Therapeutic Outcomes with Human-Induced Pluripotent Stem Cells. AB - The neurovascular unit (NVU) is composed of neurons, astrocytes, pericytes, and endothelial cells that form the blood-brain barrier (BBB). The NVU regulates material exchange between the bloodstream and the brain parenchyma, and its dysfunction is a primary or secondary cause of many cerebrovascular and neurodegenerative disorders. As such, there are substantial research thrusts in academia and industry toward building NVU models that mimic endogenous organization and function, which could be used to better understand disease mechanisms and assess drug efficacy. Human pluripotent stem cells, which can self renew indefinitely and differentiate to almost any cell type in the body, are attractive for these models because they can provide a limitless source of individual cells from the NVU. In addition, human-induced pluripotent stem cells (iPSCs) offer the opportunity to build NVU models with an explicit genetic background and in the context of disease susceptibility. Herein, we review how iPSCs are being used to model neurovascular and neurodegenerative diseases, with particular focus on contributions of the BBB, and discuss existing technologies and emerging opportunities to merge these iPSC progenies with biomaterials platforms to create complex NVU systems that recreate the in vivo microenvironment. PMID- 29441350 TI - Perioperative Goal-Directed Therapy Using Invasive Uncalibrated Pulse Contour Analysis. AB - "Perioperative goal-directed therapy" (PGDT) aims at an optimization of basic and advanced global hemodynamic variables to maintain adequate oxygen delivery to the end-organs. PGDT protocols help to titrate fluids, vasopressors, or inotropes to hemodynamic target values. There is considerable evidence that PGDT can improve patient outcome in high-risk patients if both fluids and inotropes are administered to target hemodynamic variables reflecting blood flow. Despite this evidence, PGDT strategies aiming at an optimization of blood flow seem to be not well implemented in routine clinical care. The analysis of the arterial blood pressure waveform using invasive uncalibrated pulse contour analysis can be used to assess hemodynamic variables used in PGDT protocols. Pulse contour analysis allows the assessment of stroke volume (SV)/cardiac output (CO) and pulse pressure variation (PPV)/stroke volume variation (SVV) and thus helps to titrate fluids and vasoactive agents based on principles of "functional hemodynamic monitoring." Pulse contour analysis-based PGDT treatment algorithms can be classified according to the hemodynamic variables they use as targets: PPV/SVV, SV/CO, or a combination of these variables. From a physiologic point of view, algorithms using both dynamic cardiac preload and blood flow variables as hemodynamic targets might be most effective in improving patient outcome. Future research should focus on the improvement of hemodynamic treatment algorithms and on the identification of patient subgroups in which PGDT based on uncalibrated pulse contour analysis can improve patient outcome. PMID- 29441351 TI - Effect of Weight-Bearing in Conservative and Operative Management of Fractures of the Base of the Fifth Metatarsal Bone. AB - Background: There is no established principle regarding weight-bearing in conservative and operative management of fifth metatarsal base fractures. Methods: We reviewed 86 patients with acute fifth metatarsal base fractures. Conservatively treated late or early weight-bearing patients were assigned to Group A or C, respectively. Operatively treated late or early weight-bearing patients were assigned to Group B or D, respectively. Results were evaluated by clinical union, bone resorption, and the American Orthopaedic Foot and Ankle Society (AOFAS) and Visual Analogue Scale (VAS) scores. Results: All 4 groups had bone union at a mean of 6.9 weeks (range, 5.1-15.0). There were no differences between the groups in the AOFAS and VAS scores. In the early weight-bearing groups, there were fewer cases of bone resorption, and the bone unions periods were earlier. Conclusions: Early weight-bearing may help this patient population. Moreover, conservative treatment could be an option in patients with underlying diseases. PMID- 29441349 TI - Liquid Biopsy in Clinical Management of Breast, Lung, and Colorectal Cancer. AB - Examination of tumor molecular characteristics by liquid biopsy is likely to greatly influence personalized cancer patient management. Analysis of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and tumor-derived exosomes, all collectively referred to as "liquid biopsies," are not only a modality to monitor treatment efficacy, disease progression, and emerging therapy resistance mechanisms, but they also assess tumor heterogeneity and evolution in real time. We review the literature concerning the examination of ctDNA and CTC in a diagnostic setting, evaluating their prognostic, predictive, and monitoring capabilities. We discuss the advantages and limitations of various leading ctDNA/CTC analysis technologies. Finally, guided by the results of clinical trials, we discuss the readiness of cell-free DNA and CTC as routine biomarkers in the context of various common types of neoplastic disease. At this moment, one cannot conclude whether or not liquid biopsy will become a mainstay in oncology practice. PMID- 29441352 TI - Modeling and Multiresponse Optimization for Anaerobic Codigestion of Oil Refinery Wastewater and Chicken Manure by Using Artificial Neural Network and the Taguchi Method. AB - To study the optimum process conditions for pretreatments and anaerobic codigestion of oil refinery wastewater (ORWW) with chicken manure, L9 (34) Taguchi's orthogonal array was applied. The biogas production (BGP), biomethane content (BMP), and chemical oxygen demand solubilization (CODS) in stabilization rate were evaluated as the process outputs. The optimum conditions were obtained by using Design Expert software (Version 7.0.0). The results indicated that the optimum conditions could be achieved with 44% ORWW, 36 degrees C temperature, 30 min sonication, and 6% TS in the digester. The optimum BGP, BMP, and CODS removal rates by using the optimum conditions were 294.76 mL/gVS, 151.95 mL/gVS, and 70.22%, respectively, as concluded by the experimental results. In addition, the artificial neural network (ANN) technique was implemented to develop an ANN model for predicting BGP yield and BMP content. The Levenberg-Marquardt algorithm was utilized to train ANN, and the architecture of 9-19-2 for the ANN model was obtained. PMID- 29441353 TI - Influences of Anlotinib on Cytochrome P450 Enzymes in Rats Using a Cocktail Method. AB - The present study aimed to investigate the effect of anlotinib (AL3818) on pharmacokinetics of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C6, CYP2D1, CYP2D2, and CYP3A1/2) by using five cocktail probe drugs in vivo. After pretreatment for 7 days with anlotinib (treatment group) or saline (control group) by oral administration, probe drugs phenacetin, tolbutamide, omeprazole, metoprolol, and midazolam were administered to rats by oral administration. Blood samples were obtained at a series of time-points and the concentrations of five probe drugs in plasma were determined by a UHPLC-MS/MS method. The results showed that treatment with anlotinib had no significant effect on rat CYP1A2, CYP2D2, and CYP2C6. However, anlotinib had a significant inductive effect on CYP2D1 and CYP3A1/2. Therefore, caution is needed during the concomitant use of anlotinib with other drugs metabolized by CYP2D1 and CYP3A1/2 because of potential drug anlotinib interactions. PMID- 29441354 TI - Anticancer Effect of a Novel Octahydropyrazino[2,1-a:5,4-a']diisoquinoline Derivative and Its Synergistic Action with Nigella sativa in Human Gastric Cancer Cells. AB - Many studies have shown that naturally occurring compounds may support prevention and treatment of various diseases, including cancer. Pharmacological investigations revealed a wide spectrum of Nigella sativa biological activities. Combining natural compounds together with synthetic drugs may increase the anticancer activity and limit severe side effects of such a treatment and may be an alternative to monotherapy. The aim of the study was to evaluate the cytotoxic and proapoptotic effects of a novel octahydropyrazino[2,1-a:5,4-a']diisoquinoline derivative and its effect in combination with Nigella sativa seed oil or extract in human gastric cancer cells (AGS). Etoposide was used as a reference. Our studies proved that combination strategy based on novel octahydropyrazino[2,1 a:5,4-a']diisoquinoline derivative (OM-90) with Nigella sativa seed oil or extract represents the strongest efficacy in AGS cancer cells as compared to monotherapy and combined treatment with Nigella sativa seed oil or extract together with etoposide. Such a combination also leads to the activation of mitochondrial pathway, which plays a significant role in molecular mechanism of induction of apoptosis by these compounds. PMID- 29441355 TI - Eponychial lesions following bilateral upper extremity vascular composite allotransplantation: a case report. AB - Vascularized composite allotransplantation represents a useful addition to reconstructive options available to the plastic surgeon. Though the procedure provides beneficial functional outcomes, there remain complications, often associated with the immunosuppression necessary to maintain an allograft. We report a case of eponychial fold lesions following successful bilateral upper extremity allotransplantation. PMID- 29441356 TI - Persistent producer-scrounger relationships in bats. AB - Social foraging theory suggests that group-living animals gain from persistent social bonds, which lead to increased tolerance in competitive foraging and information sharing. Bats are among the most social mammals, often living in colonies of tens to thousands of individuals for dozens of years, yet little is known about their social foraging dynamics. We observed three captive bat colonies for over a year, quantifying >13,000 social foraging interactions. We found that individuals consistently used one of two foraging strategies, either producing (collecting) food themselves or scrounging it directly from the mouth of other individuals. Individual foraging types were consistent over at least 16 months except during the lactation period when females shifted toward producing. Scroungers intentionally selected whom to interact with when socially foraging, thus generating persistent nonrandom social relationships with two to three specific producers. These persistent producer-scrounger relationships seem to reduce aggression over time. Finally, scrounging was highly correlated with vigilance, and we hypothesize that vigilant-prone individuals turn to scrounging in the wild to mitigate the risk of landing on a potentially unsafe fruit tree. We find the bat colony to be a rich and dynamic social system, which can serve as a model to study the role that social foraging plays in the evolution of mammalian sociality. Our results highlight the importance of considering individual tendencies when exploring social behavior patterns of group-living animals. These tendencies further emphasize the necessity of studying social networks over time. PMID- 29441357 TI - UV-B-induced forest sterility: Implications of ozone shield failure in Earth's largest extinction. AB - Although Siberian Trap volcanism is considered a primary driver of the largest extinction in Earth history, the end-Permian crisis, the relationship between these events remains unclear. However, malformations in fossilized gymnosperm pollen from the extinction interval suggest biological stress coinciding with pulsed forest decline. These grains are hypothesized to have been caused by enhanced ultraviolet-B (UV-B) irradiation from volcanism-induced ozone shield deterioration. We tested this proposed mechanism by observing the effects of inferred end-Permian UV-B regimes on pollen development and reproductive success in living conifers. We find that pollen malformation frequencies increase fivefold under high UV-B intensities. Surprisingly, all trees survived but were sterilized under enhanced UV-B. These results support the hypothesis that heightened UV-B stress could have contributed not only to pollen malformation production but also to deforestation during Permian-Triassic crisis intervals. By reducing the fertility of several widespread gymnosperm lineages, pulsed ozone shield weakening could have induced repeated terrestrial biosphere destabilization and food web collapse without exerting a direct "kill" mechanism on land plants or animals. These findings challenge the paradigm that mass extinctions require kill mechanisms and suggest that modern conifer forests may be considerably more vulnerable to anthropogenic ozone layer depletion than expected. PMID- 29441359 TI - CO2 leakage alters biogeochemical and ecological functions of submarine sands. AB - Subseabed CO2 storage is considered a future climate change mitigation technology. We investigated the ecological consequences of CO2 leakage for a marine benthic ecosystem. For the first time with a multidisciplinary integrated study, we tested hypotheses derived from a meta-analysis of previous experimental and in situ high-CO2 impact studies. For this, we compared ecological functions of naturally CO2-vented seafloor off the Mediterranean island Panarea (Tyrrhenian Sea, Italy) to those of nonvented sands, with a focus on biogeochemical processes and microbial and faunal community composition. High CO2 fluxes (up to 4 to 7 mol CO2 m-2 hour-1) dissolved all sedimentary carbonate, and comigration of silicate and iron led to local increases of microphytobenthos productivity (+450%) and standing stocks (+300%). Despite the higher food availability, faunal biomass ( 80%) and trophic diversity were substantially lower compared to those at the reference site. Bacterial communities were also structurally and functionally affected, most notably in the composition of heterotrophs and microbial sulfate reduction rates (-90%). The observed ecological effects of CO2 leakage on submarine sands were reproduced with medium-term transplant experiments. This study assesses indicators of environmental impact by CO2 leakage and finds that community compositions and important ecological functions are permanently altered under high CO2. PMID- 29441358 TI - Growing old, yet staying young: The role of telomeres in bats' exceptional longevity. AB - Understanding aging is a grand challenge in biology. Exceptionally long-lived animals have mechanisms that underpin extreme longevity. Telomeres are protective nucleotide repeats on chromosome tips that shorten with cell division, potentially limiting life span. Bats are the longest-lived mammals for their size, but it is unknown whether their telomeres shorten. Using >60 years of cumulative mark-recapture field data, we show that telomeres shorten with age in Rhinolophus ferrumequinum and Miniopterus schreibersii, but not in the bat genus with greatest longevity, Myotis. As in humans, telomerase is not expressed in Myotis myotis blood or fibroblasts. Selection tests on telomere maintenance genes show that ATM and SETX, which repair and prevent DNA damage, potentially mediate telomere dynamics in Myotis bats. Twenty-one telomere maintenance genes are differentially expressed in Myotis, of which 14 are enriched for DNA repair, and 5 for alternative telomere-lengthening mechanisms. We demonstrate how telomeres, telomerase, and DNA repair genes have contributed to the evolution of exceptional longevity in Myotis bats, advancing our understanding of healthy aging. PMID- 29441360 TI - Anomalous K-Pg-aged seafloor attributed to impact-induced mid-ocean ridge magmatism. AB - Eruptive phenomena at all scales, from hydrothermal geysers to flood basalts, can potentially be initiated or modulated by external mechanical perturbations. We present evidence for the triggering of magmatism on a global scale by the Chicxulub meteorite impact at the Cretaceous-Paleogene (K-Pg) boundary, recorded by transiently increased crustal production at mid-ocean ridges. Concentrated positive free-air gravity and coincident seafloor topographic anomalies, associated with seafloor created at fast-spreading rates, suggest volumes of excess magmatism in the range of ~105 to 106 km3. Widespread mobilization of existing mantle melt by post-impact seismic radiation can explain the volume and distribution of the anomalous crust. This massive but short-lived pulse of marine magmatism should be considered alongside the Chicxulub impact and Deccan Traps as a contributor to geochemical anomalies and environmental changes at K-Pg time. PMID- 29441361 TI - Increased proteomic complexity in Drosophila hybrids during development. AB - Cellular proteomes are thought to be optimized for function, leaving no room for proteome plasticity and, thus, evolution. However, hybrid animals that result from a viable cross of two different species harbor hybrid proteomes of unknown complexity. We charted the hybrid proteome of a viable cross between Drosophila melanogaster females and Drosophila simulans males with bottom-up proteomics. Developing hybrids harbored 20% novel proteins in addition to proteins that were also present in either parental species. In contrast, adult hybrids and developmentally failing embryos of the reciprocal cross showed less additional proteins (5 and 6%, respectively). High levels of heat shock proteins, proteasome associated proteins, and proteasomal subunits indicated that proteostasis sustains the expanded complexity of the proteome in developing hybrids. We conclude that increased proteostasis gives way to proteomic plasticity and thus opens up additional space for rapid phenotypic variation during embryonic development. PMID- 29441362 TI - The coupling between auditory and motor cortices is rate-restricted: Evidence for an intrinsic speech-motor rhythm. AB - The relation between perception and action remains a fundamental question for neuroscience. In the context of speech, existing data suggest an interaction between auditory and speech-motor cortices, but the underlying mechanisms remain incompletely characterized. We fill a basic gap in our understanding of the sensorimotor processing of speech by examining the synchronization between auditory and speech-motor regions over different speech rates, a fundamental parameter delimiting successful perception. First, using magnetoencephalography, we measure synchronization between auditory and speech-motor regions while participants listen to syllables at various rates. We show, surprisingly, that auditory-motor synchrony is significant only over a restricted range and is enhanced at ~4.5 Hz, a value compatible with the mean syllable rate across languages. Second, neural modeling reveals that this modulated coupling plausibly emerges as a consequence of the underlying neural architecture. The findings suggest that the temporal patterns of speech emerge as a consequence of the intrinsic rhythms of cortical areas. PMID- 29441363 TI - Structure-function covariation with nonfeeding ecological variables influences evolution of feeding specialization in Carnivora. AB - Skull shape convergence is pervasive among vertebrates. Although this is frequently inferred to indicate similar functional underpinnings, neither the specific structure-function linkages nor the selective environments in which the supposed functional adaptations arose are commonly identified and tested. We demonstrate that nonfeeding factors relating to sexual maturity and precipitation related arboreality also can generate structure-function relationships in the skulls of carnivorans (dogs, cats, seals, and relatives) through covariation with masticatory performance. We estimated measures of masticatory performance related to ecological variables that covary with cranial shape in the mammalian order Carnivora, integrating geometric morphometrics and finite element analyses. Even after accounting for phylogenetic autocorrelation, cranial shapes are significantly correlated to both feeding and nonfeeding ecological variables, and covariation with both variable types generated significant masticatory performance gradients. This suggests that mechanisms of obligate shape covariation with nonfeeding variables can produce performance changes resembling those arising from feeding adaptations in Carnivora. PMID- 29441365 TI - Erratum: Mutation of TBCK causes a rare recessive developmental disorder. AB - [This corrects the article on p. e76 in vol. 2, PMID: 27275012.]. PMID- 29441364 TI - Impaired cohesion and homologous recombination during replicative aging in budding yeast. AB - The causal relationship between genomic instability and replicative aging is unclear. We reveal here that genomic instability at the budding yeast ribosomal DNA (rDNA) locus increases during aging, potentially due to the reduced cohesion that we uncovered during aging caused by the reduced abundance of multiple cohesin subunits, promoting increased global chromosomal instability. In agreement, cohesion is lost during aging at other chromosomal locations in addition to the rDNA, including centromeres. The genomic instability in old cells is exacerbated by a defect in DNA double-strand break (DSB) repair that we uncovered in old yeast. This was due to limiting levels of key homologous recombination proteins because overexpression of Rad51 or Mre11 reduced the accumulation of DSBs and largely restored DSB repair in old cells. We propose that increased rDNA instability and the reduced DSB repair capacity of old cells contribute to the progressive accumulation of global chromosomal DNA breaks, where exceeding a threshold of genomic DNA damage ends the replicative life span. PMID- 29441366 TI - Gastric cancer lymph node resection-the more the merrier? PMID- 29441368 TI - Neoadjuvant therapy for gastrointestinal stromal tumor. AB - Molecular-targeting therapy using tyrosine kinase inhibitor imatinib mesylate is effective for metastasis/recurrent gastrointestinal stromal tumors (GISTs). Likewise, imatinib would be effective in the neoadjuvant therapy for high-risk GIST. Neoadjuvant therapy may have the potential to increase the complete resection rate and to avoid the surgical rupture by decreasing the tumor size. Thereby, it is expected that improvement of recurrence rate and survival rate can be obtained by neoadjuvant therapy. Neoadjuvant therapy is also expected to be favored from the viewpoint of organ/function preservation by tumor shrinkage. The existing results of clinical trials established the feasibility of neoadjuvant imatinib therapy. However, proof of the survival effectiveness of neoadjuvant imatinib therapy has not been sufficiently demonstrated. The aim of this article is to introduce previous evidence and strategies regarding neoadjuvant therapy for GIST. PMID- 29441369 TI - Limited activity of metronomic cyclophosphamide and pembrolizumab for soft tissue sarcomas. PMID- 29441367 TI - Molecular characterization and pathogenesis of gastrointestinal stromal tumor. AB - Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. The sites of the tyrosine kinase gene mutations are associated with the biological behavior of GISTs, including risk category, clinical outcome and drug response. Mutations in RAS signaling pathway genes, including KRAS and BRAF, have also been reported in KIT/PDGFRA wild-type GISTs, though they are rare. Neurofibromin 1 (NF1) is a tumor suppressor gene mutated in neurofibromatosis type 1. Patients with NF1 mutations are at high risk of developing GISTs. Recent findings suggest that altered expression or mutation of members of succinate dehydrogenase (SDH) heterotetramer are causally associated with GIST development through induction of aberrant DNA methylation. At present, GISTs with no alterations in KIT, PDGFRA, RAS signaling genes or SDH family genes are referred to as true wild-type GISTs. KIT and PDGFRA mutations are thought as the earliest events in GIST development, and subsequent accumulation of chromosomal aberrations and other molecular alterations are required for malignant progression. In addition, recent studies have shown that epigenetic alterations and noncoding RNAs also play key roles in the pathogenesis of GISTs. PMID- 29441370 TI - Adenoma detection rate: is it the master key for the colonoscopy quality indicator? PMID- 29441372 TI - Quality standards and performance measures: steps to high quality diagnostic endoscopy. PMID- 29441371 TI - Gastrointestinal stromal tumor of the esophagus: current issues of diagnosis, surgery and drug therapy. AB - Gastrointestinal stromal tumors (GISTs) often arise in the stomach and small intestine, while esophageal GISTs are rare. Due to their rarity, clinicopathological data on esophageal GISTs are extremely limited, and this results in a lack of clear recommendations concerning optimal surgical management for esophageal GISTs. It is difficult to distinguish esophageal GIST from leiomyoma, the most frequent esophageal mesenchymal tumor, prior to resection, because the two types of tumors appear similar on computed tomography (CT), endoscopic ultrasound (EUS), and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Fine-needle aspiration biopsy (FNAB) under EUS enables definitive diagnosis, but it is often avoided because scarring could make enucleation more difficult and increase the risk of tumor dissemination by capsule destruction. Esophageal segmental and wedge resections are not usually performed due to the anatomical peculiarity of the esophagus, and the surgical options are limited to the highly invasive esophagectomy or the much less invasive surgical tumor enucleation. The decision as to which surgical procedure should be performed for esophageal GISTs is still under debate. Tumor enucleation may be permitted for smaller tumors, and esophagectomy may be recommended for larger GISTs or high-risk tumors with a high mitotic rate. The purpose of neoadjuvant imatinib administration is downsizing of the GIST to reduce the extent of resection and to reduce the risk of intraoperative complications, including tumor rupture. The efficacy of neoadjuvant/adjuvant imatinib therapy for esophageal GISTs is poorly understood, because the reports are limited to case reports or case series with small numbers. More clinicopathological data and clinical trials for esophageal GIST are expected. PMID- 29441373 TI - Metathesis cleavage of an N[double bond, length as m-dash]N bond in benzo[c]cinnolines and azobenzenes by triply-bonded ditungsten complexes. AB - A metathesis reaction of a W[triple bond, length as m-dash]W bond and an N[double bond, length as m-dash]N bond was observed by reacting a W-W triply-bonded W(iii)2 complex, (tBuO)3W[triple bond, length as m-dash]W(OtBu)3 (1), with benzo[c]cinnoline derivatives to form biphenyl-linked dinuclear (imido)tungsten complexes 2-4. When azobenzene was used as the substrate, a trans to cis isomerization induced by blue-LED light was essential prior to the metathesis cleavage of the N[double bond, length as m-dash]N bond by the W[triple bond, length as m-dash]W bond of (Me2N)2(TfO)W[triple bond, length as m dash]W(OTf)(NMe2)2 (6), affording the corresponding imido-bridged dinuclear tungsten complexes 7-9. PMID- 29441374 TI - Combining single source chemical vapour deposition precursors to explore the phase space of titanium oxynitride thin films. AB - In this paper we report on a novel chemical vapour deposition approach to the formation and control of composition of mixed anion materials, as applied to titanium oxynitride thin films. The method used is the aerosol assisted chemical vapour deposition (AACVD) of a mixture of single source precursors. To explore the titanium-oxygen-nitrogen system the single source precursors selected were tetrakis(dimethylamido) titanium and titanium tetraisopropoxide which individually are precursors to thin films of titanium nitride and titanium dioxide respectively. However, by combining these precursors in specific ratios in a series of AACVD reactions at 400 degrees C, we are able to deposit thin films of titanium oxynitride with three different structure types and a wide range of compositions. Using this precursor system we can observe films of nitrogen doped anatase, with 25% anion doping of nitrogen; a new composition of pseudobrookite titanium oxynitride with a composition of Ti3O3.5N1.5, identified as being a UV photocatalyst; and rock-salt titanium oxynitride in the range TiO0.41N0.59 to TiO0.05N0.95. The films were characterised using GIXRD, WDX and UV-vis spectroscopy, and in the case of the pseudobrookite films, assessed for photocatalytic activity. This work shows that a so-called dual single-source CVD approach is an effective method for the deposition of ternary mixed anion ceramic films through simple control of the ratio of the precursors, while keeping all other experimental parameters constant. PMID- 29441376 TI - Self-assemblies of TTF derivatives programmed by alkyl chains and functional groups. AB - Tetrathiafulvalenes (TTFs) are a class of important functional materials whose intermolecular interaction, which will contribute to constructing a supramolecular structure, still needs further understanding. In this study, the self-assembly behavior and structure of a series of TTFs bearing different alkyl chains and substituents were investigated by scanning tunneling microscopy (STM) in combination with density functional theory (DFT) calculations. Contrary to previous reports, herein, a series of benzoic acid-functionalized TTFs (CnTTFCOOH) and pyridine-functionalized TTFs (CnTTFN) with different lengths of alkyl chains have been substituted on the sulfur atom, where n is equal to 8, 10, 14, or 16. Due to the weak intra- and intermolecular interactions, CnTTFN (n = 8 and 10) molecules cannot be observed during STM scanning. For other cases, various self-assembled monolayers with different nanostructures were observed depending on different substituents. The results reveal that the alkyl chains and functional groups on the TTF skeleton synergistically affect the molecular self assembly process, which results from the synergism of van der Waals, hydrogen bonding, and SS interactions. These results not only help to explain the relationship between structures and properties, but also help to design better molecular structures for various fields. PMID- 29441377 TI - Molecular characterization of PAHs based on land use analysis and multivariate source apportionment in multiple phases of the Yangtze estuary, China. AB - Spatial-temporal distributions, source identification, and possible effects of land use patterns on PAHs were studied in overlying water and surface sediments in Yangtze estuarine and nearby coastal areas. The concentrations of PAHs ranged from 172.6 +/- 9.3 to 5603.7 +/- 548.7 ng L-1, 841.0 +/- 36.6 to 31 190.5 +/- 3711.5 ng g-1 and 312.3 +/- 7.6 to 9081.1 +/- 862.3 ng g-1, with mean contents of 1042.9 ng L-1, 8922.9 ng g-1 and 2400.2 ng g-1 in water, suspended particulate matter (SPM) and sediments. PAH concentrations in three phases were higher in dry seasons (January and April) than in rainy seasons (July and October), and showed a distribution pattern as freshwater area > transition area > seawater area. Water and urban (especially for industrial) land uses contributed significantly to the PAH content in water and sediments. Urban and agricultural land uses were identified as important factors for regulating PAH concentrations in the SPM. TOC and BC were crucial controlling factors for the sorption and distribution of PAHs. The stable carbon isotope signatures of TOC and BC indicated the terrestrial origin of PAHs. Multivariate statistical and toxicity assessments revealed that LHK and SDK were contamination hotspots. Traffic emissions contributed 63% of PAH loadings in the three phases, yet biomass/coal combustion contributed over 85% of the toxicity caused by PAHs. Potential ecological and health risks of PAHs were low. We thus conclude that PAH pollution in the study area was primarily of terrestrial origin. BC and TOC were important predictors for PAH fate in the estuary. Urban and agricultural land use and river systems along the estuary were the major input pathways for the PAH loadings. PMID- 29441378 TI - Iron-montmorillonite clays as active sorbents for the decontamination of hazardous chemical warfare agents. AB - A class of heterogeneous catalysts based on commercial bentonite from natural origin, containing at least 80 wt% of montmorillonite clay, was designed to transform selectively and under mild conditions toxic organosulfur and organophosphorus chemical warfare agents into non-noxious products with a reduced impact on health and environment. The bentonite from the natural origin was modified by introducing iron species and acid sites in the interlayer space, aiming to obtain a sorbent with strong catalytic oxidising and hydrolytic properties. The catalytic performance of these materials was evaluated in the oxidative abatement of (2-chloroethyl)ethyl sulfide (CEES), a simulant of sulfur mustard, in the presence of aqueous hydrogen peroxide as an oxidant. A new decontamination formulation was, moreover, proposed and obtained by mixing sodium perborate, as a solid oxidant, to iron-bentonite catalysts. Solid-phase decontamination tests, performed on a cotton textile support contaminated with organosulfide and organophosphonate simulant agents revealed the good activity of the solid formulation, especially in the in situ detoxification of blistering agents. Tests carried out on the real blistering warfare agent, sulfur mustard (HD agent), showed that, thanks to the co-presence of the iron-based clay together with the solid oxidant component, a good decontamination of the test surface from the real warfare agent could be achieved (80% contaminant degradation, under ambient conditions, in 24 h). PMID- 29441379 TI - Novel two-dimensional ferromagnetic semiconductors: Ga-based transition-metal trichalcogenide monolayers. AB - Ga-based two-dimensional transition-metal trichalcogenides with tunable ferromagnetic semiconducting properties are explored by first-principles calculations. It is found that the CrGaTe3 monolayer is an intrinsic ferromagnetic semiconductor with an indirect bandgap of 0.3 eV and exhibits strong dynamical, thermal and mechanical stabilities in the free-standing form. Its Curie temperature of 71 K estimated by Monte Carlo simulations can be significantly enhanced up to near room-temperature (263 K) by 5% biaxial tensile strain at which its structure still remains dynamically stable, while compressive strain can turn the monolayer from a ferromagnetic semiconductor to an antiferromagnetic semiconductor and finally to a ferromagnetic metal with a Curie temperature of 473 K at -5% strain. It is revealed that the pronounced strain tunability originates from the competition between a variety of magnetic exchange interactions. The CrGaSe3 monolayer is found to exhibit similar intrinsic ferromagnetic semiconducting properties and strain tunability. The exceptional properties render Ga-based transition-metal trichalcogenides promising candidates for spintronic applications. PMID- 29441375 TI - Parallel lives of symbionts and hosts: chemical mutualism in marine animals. AB - Covering: up to 2018 Symbiotic microbes interact with animals, often by producing natural products (specialized metabolites; secondary metabolites) that exert a biological role. A major goal is to determine which microbes produce biologically important compounds, a deceptively challenging task that often rests on correlative results, rather than hypothesis testing. Here, we examine the challenges and successes from the perspective of marine animal-bacterial mutualisms. These animals have historically provided a useful model because of their technical accessibility. By comparing biological systems, we suggest a common framework for establishing chemical interactions between animals and microbes. PMID- 29441385 TI - Asymmetric triphenylamine-phenothiazine based small molecules with varying terminal acceptors for solution processed bulk-heterojunction organic solar cells. AB - Three compounds consisting of the electron-donating triphenylamine-phenothiazine conjugate backbone and each of the electron-withdrawing groups 3-ethylrhodanine, malononitrile and 1,3-indandione have been synthesized and used as donors in blends with [6,6]-phenyl-C70-butyric acid methyl ester (PC71BM) for organic solar cell devices. After improvements of the active layer structure by a selected donor-to-acceptor weight ratio and a two-step solvent and thermal annealing, the organic solar cells showed power conversion efficiency (PCE) values in the range of 4.79-7.25%. The highest PCE was obtained for the bulk heterojunction device with the indandione compound, which can be attributed to its better absorption profile, higher crystallinity, more balanced electron and hole transport, higher charge collection efficiency and reduced recombination, in comparison with the photovoltaic cells from the other two compounds. DFT-calculated characteristics, absorption spectra and cyclic voltammetry of the compounds, along with X-ray diffraction patterns of the blend films, are used to validate the photovoltaic results. PMID- 29441390 TI - Observing different dynamic behaviors of weakly and strongly adsorbed polystyrene chains at interfaces. AB - Understanding the dynamic behavior of polymer chains adsorbed onto a solid surface is of great importance for elucidating polymer-surface interactions. Here by using sum frequency generation (SFG) vibrational spectroscopy, we probed the conformational changes of weakly adsorbed and strongly adsorbed polystyrene (PS) chains on sapphire surfaces perturbed by a nonsolvent (deuterated water, D2O) and a good solvent (carbon tetrachloride, CCl4). The SFG results indicated that the PS chains in the weakly adsorbed state were flexible and the chain conformation could easily be altered. Differently, the PS chains in the strongly adsorbed state were rigid and the chain conformation could not be changed. The local structural variations of the weakly and strongly adsorbed PS chains at the interfaces were also discussed in detail with respect to the SFG spectral characteristics. These intriguing experimental results shed light on our understanding of molecular behaviors of polymer chains adsorbed onto a solid surface. PMID- 29441392 TI - A 2D rhomboidal system of manganese(ii) [Mn(3-MeC6H4COO)2(H2O)2]n with spin canting: rationalization of the magnetic exchange. AB - The crystal structure of Mn(ii) carboxylate with 3-methylbenzoate as a bridging ligand [Mn(3-MeC6H4COO)2(H2O)2]n shows a rhomboidal layer, where each pair of neighbor Mn(ii) ions are bridged through only one carboxylate group with a syn anti conformation. The magnetic exchange between neighbor ions is weakly antiferromagnetic (J = -0.52 cm-1, g = 2.04), and at low temperature the system shows spin canting with TB = 3.8 K. Computational studies, based on periodic calculations of the energies of the significant spin states on the magnetic cell and some higher supercells, corroborate the weak AF interaction between the adjacent Mn(ii) ions and preclude the negligible effect of frustration caused by very weak interactions between the non-adjacent ions in the magnetic response of the system. The results provide compelling evidence that the observed spin canting is due to the local coordination geometry of the manganese ions leading to two antiferromagnetically coupled subnets with different axial vectors. PMID- 29441393 TI - Neutral ligand TIPA-based two 2D metal-organic frameworks: ultrahigh selectivity of C2H2/CH4 and efficient sensing and sorption of Cr(vi ). AB - One neutral tripodal semi-rigidity ligand tri(4-imidazolylphenyl)amine (TIPA) with excellent hole-transfer nature, was selected as a linker to construct MOFs. Two two-dimensional (2D) microporous metal-organic frameworks (MOFs) were synthesized solvothermally: [Ni(TIPA)(COO-)2(H2O)].2(DMF)2(H2O) (1) and [Cd(TIPA)2(ClO4-)2].(DMF)3(H2O) (2). Compound 1 incorporated carboxylic groups into the channel and exhibited the high capacity of light hydrocarbons as well as the remarkable selectivity of C2H2/CH4. The value is in excess of 100 at room temperature, which is the highest value reported to date. Compound 2, as a cationic framework with high water stability, was not only applied as a sensor, displaying the ultrahigh sensitivity against Cr2O72- with a detection limit as low as 8 ppb, but also possessed excellent Cr(vi) sorption with good repeatability in aqueous solution. This study provides an efficient strategy to design cationic MOFs for the selective separation of light hydrocarbons and the sensing and trapping of toxic chromate for the purification of water. PMID- 29441395 TI - Systematic dimensional reduction of the layered beta-FeSe structure by solvothermal synthesis. AB - Dimensional reduction of superconducting anti PbO-type iron selenide has been achieved by terminating the tetragonal square layers of FeSe4/4 tetrahedra by ethylenediamine (en) ligands. We obtained three new structures in the Fe-Se-en system. Fe3Se4(en)3 contains FeSe2 single chains bridged via Fe(en)3 complexes. Fe10Se12(en)7 has Fe2Se3 double strands separated by Fe(en)3 complexes and free en molecules. Fe0.85Se(en)0.3 conserves the tetragonal layers of bulk FeSe which are now widely separated by en molecules. Through systematic dilution of the solvent we were able to introduce an additional parameter in solvothermal synthesis and thus have control over the connectivity of the tetrahedra. Additionally, a phase diagram of the Fe-Se-en system is generated by variation of the reaction temperature. The magnetic properties of the FeSe derivatives range from superconductivity and antiferromagnetism to paramagnetism. PMID- 29441396 TI - Expanding the allyl analogy: accessing eta3-P,B,P diphosphinoborane complexes of group 10. AB - Using the diphosphinoborane, (PPh2)2BMes (Mes = 2,4,6-Me3C6H3), we report the first examples of eta3-P,B,P-ligated complexes using Ni(0) and Pt(ii). Reaction of (PPh2)2BMes with Ni(COD)2 or Pt(COD)Me2 (COD = 1,5-cyclooctadiene) results in gradual COD displacement to give [eta3-P,B,P-(PPh2)2BMes]Ni(COD) (3) or [eta3 P,B,P-(PPh2)2BMes]Pt(CH3)2 (6). Complex 3 serves as a versatile Ni-containing synthon for the preparation of square planar or tetrahedral Ni(0) complexes. Notably, the M-B interaction in these systems is non-negligible - with coordination resulting in an upfield shift of ca. 80 ppm in the 11B NMR spectrum. We also show that treatment of the PtIV halide precursor, [PtMe3I]4 with this ligand framework results in migration of X-type ligands (CH3- and I-) to boron and reductive elimination of ethane (C2H6) to give a distorted square planar zwitterionic PtII complex, Pt[kappa2-P,P-(PPh2)2B(Mes)(CH3)][kappa2-P,P (PPh2)2B(Mes)(I)] (10). This reactivity suggests the feasibility of (PPh2)2BMes ligand-induced labilization of M-X ligands. PMID- 29441397 TI - Kinetic stabilization of a Ni(ii) bis(dithiobenzoate)-type complex achieved using three-dimensional insulation by a [1]rotaxane structure. AB - We describe herein the synthesis of a Ni(ii) bis(dithiobenzoate)-type complex three-dimensionally insulated by a [1]rotaxane structure to reveal the importance of the insulation. Under cyclic voltammetry conditions, the complex showed a stable and reversible redox behavior in contrast to a non-insulated reference complex, clearly demonstrating the effectiveness of the rotaxane-type insulation as a new method of kinetic metal complex stabilization. PMID- 29441398 TI - A protic ionic liquid as an atom economical solution for palladium catalyzed asymmetric allylic alkylation. AB - The asymmetric allylic alkylation of rac-1,3-diphenyl-3-acetoxyprop-1-ene (I) catalysed by palladium and diverse phosphorus containing ligands [(S)-BINAP, (R,R)-Chiraphite and (R,R)-Et-Duphos] in an ionic liquid [HDBU][OAc] was successfully performed, achieving full conversions and up to 96% ee of the (S) product when (R,R)-Et-Duphos was used as a ligand. The reaction could be performed using an equimolar amount of substrate, malonate and base DBU, in which case the total products sum to the desired alkylated product and the ionic pair [HDBU][OAc]; this system thus produces its own IL solvent as the only co-product. These catalytic systems were active in recycling experiments for up to four cycles, albeit with a loss of activity due to the poor retention of palladium in the ionic liquid. The catalytic performance of each Pd/ligand system was optimized by varying the ratio of the substrate and malonate. Systems based on [HDBU][OAc] were found to be the best. PMID- 29441401 TI - Exercise-induced fatigue in young people: advances and future perspectives. AB - PURPOSE: In recent decades, the interest for exercise-induced fatigue in youth has substantially increased, and the effects of growth on the peripheral (muscular) and central (neural) mechanisms underpinning differences in neuromuscular fatigue between healthy children and adults have been described more extensively. The purpose of this review is to retrieve, report, and analyse the findings of studies comparing neuromuscular fatigue between children and adults. Objective measures of the evaluation of the physiological mechanisms are discussed. METHOD: Major databases (PubMed, Ovid, Scopus and Web of Science) were systematically searched and limited to English language from inception to September 2017. RESULT: Collectively, the analyzed studies indicate that children experience less muscular and potentially more neural fatigue than adults. However, there are still many unknown aspects of fatigue regarding neural (supraspinal and spinal) and peripheral mechanisms that should be more thoroughly examined in children. CONCLUSION: Suitable methods, such as transcranial magnetic stimulation, transcranial electrical stimulation, functional magnetic resonance imaging, near-infrared spectroscopy, tendon vibration, H-reflex, and ultrasound are recommended in the research field of fatigue in youth. By designing studies that test the fatigue effects in movements that replicate daily activities, new knowledge will be acquired. The linkage and interaction between physiological, cognitive, and psychological aspects of human performance remain to be resolved in young people. This can only be successful if research is based on a foundation of basic research focused on the mechanisms of fatigue while measuring all three above aspects. PMID- 29441402 TI - "Left to my own devices, I don't know": using theory and patient-reported barriers to move from physical activity recommendations to practice. AB - : Knowledge exchange with community-dwelling individuals across Ontario revealed barriers to implementation of physical activity recommendations that reflected capability, opportunity, and motivation; barriers unique to individuals with osteoporosis include fear of fracturing, trust in providers, and knowledge of exercise terminology. Using the Behaviour Change Wheel, we identified interventions (training, education, modeling) and policy categories (communication/marketing, guidelines, service provision). INTRODUCTION: Physical activity recommendations exist for individuals with osteoporosis; however, to change behavior, we must address barriers and facilitators to their implementation. The purposes of this project are (1) to identify barriers to and facilitators of uptake of disease-specific physical activity recommendations (2) to use the findings to identify behavior change strategies using the Behaviour Change Wheel (BCW). METHODS: Focus groups and semi-structured interviews were conducted with community-dwelling individuals attending osteoporosis-related programs or education sessions in Ontario. They were stratified by geographic area, urban/rural, and gender, and transcribed verbatim. Two researchers coded data and identified emerging themes. Using the Behaviour Change Wheel framework, themes were categorized into capability, opportunity, and motivation, and interventions were identified. RESULTS: Two hundred forty community-dwelling individuals across Ontario participated (mean +/- SD age = 72 +/- 8.28). Barriers were as follows: capability: disease-related symptoms hinder exercise and physical activity participation, lack of exercise-related knowledge, low exercise self-efficacy; opportunity: access to exercise programs that meet needs and preferences, limited resources and time, physical activity norms and preferences; motivation: incentives to exercise, fear of fracturing, trust in exercise providers. Interventions selected were training, education, and modeling. Policy categories selected were communication/marketing, guidelines, and service provision. CONCLUSIONS: Barriers unique to individuals with osteoporosis included the following: lack of knowledge on key exercise concepts, fear of fracturing, and trust in providers. Behavior change techniques may need tailoring to gender, age, or presence of comorbid conditions. PMID- 29441403 TI - Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension. AB - It is widely known that the incidence of pulmonary arterial hypertension (PAH) is higher in female, whereas prognosis is poorer in male patients. However, sex differences in hemodynamic response to and long-term prognosis with PAH-targeted treatment in the modern era remain to be fully elucidated. We examined the long term prognosis of 129 consecutive PAH patients (34 males and 95 females) diagnosed in our hospital from April 1999 to October 2014, and assessed hemodynamic changes in response to PAH-targeted therapy. Female patients had better 5-year survival compared with male patients (74.0 vs. 53.4%, P = 0.003); however, higher age quartiles in females were associated with poor outcome. Follow-up examination after medical treatment showed significant decreases in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and pulmonary arterial capacitance (PAC) in both sexes (both P < 0.05), whereas only females had a significant improvement in right ventricular end-diastolic pressure (RVEDP), right atrial pressure (RAP), cardiac index, and mixed venous oxygen saturation (SvO2) (all P < 0.05). Baseline age significantly correlated with the hemodynamic changes only in female patients; particularly, there were significant sex interactions in RVEDP and RAP (both P < 0.10). The multivariable analysis showed that SvO2 at baseline and mPAP and SvO2 at follow-up were significant prognostic factors in males, whereas the changes in mPAP, PVR, and PAC and use of endothelin-receptor antagonist in females. These results indicate that female PAH patients have better long-term prognosis than males, for which better improvements of right ventricular functions and hemodynamics may be involved. PMID- 29441404 TI - PDGF-induced migration of synthetic vascular smooth muscle cells through c-Src activated L-type Ca2+ channels with full-length CaV1.2 C-terminus. AB - In atherosclerosis, vascular smooth muscle cells (VSMC) migrate from the media toward the intima of the arteries in response to cytokines, such as platelet derived growth factor (PDGF). However, molecular mechanism underlying the PDGF induced migration of VSMCs remains unclear. The migration of rat aorta-derived synthetic VSMCs, A7r5, in response to PDGF was potently inhibited by a CaV1.2 channel inhibitor, nifedipine, and a Src family tyrosine kinase (SFK)/Abl inhibitor, bosutinib, in a less-than-additive manner. PDGF significantly increased CaV1.2 channel currents without altering CaV1.2 protein expression levels in A7r5 cells. This reaction was inhibited by C-terminal Src kinase, a selective inhibitor of SFKs. In contractile VSMCs, the C-terminus of CaV1.2 is proteolytically cleaved into proximal and distal C-termini (PCT and DCT, respectively). Clipped DCT is noncovalently reassociated with PCT to autoinhibit the channel activity. Conversely, in synthetic A7r5 cells, full-length CaV1.2 (CaV1.2FL) is expressed much more abundantly than truncated CaV1.2. In a heterologous expression system, c-Src activated CaV1.2 channels composed of CaV1.2FL but not truncated CaV1.2 (CaV1.2Delta1763) or CaV1.2Delta1763 plus clipped DCT. Further, c-Src enhanced the coupling efficiency between the voltage sensing domain and activation gate of CaV1.2FL channels by phosphorylating Tyr1709 and Tyr1758 in PCT. Compared with CaV1.2Delta1763, c-Src could more efficiently bind to and phosphorylate CaV1.2FL irrespective of the presence or absence of clipped DCT. Therefore, in atherosclerotic lesions, phenotypic switching of VSMCs may facilitate pro-migratory effects of PDGF on VSMCs by suppressing posttranslational CaV1.2 modifications. PMID- 29441406 TI - The additional value of gravity stress radiographs in predicting deep deltoid ligament integrity in supination external rotation ankle fractures. AB - OBJECTIVES: Goal of this study was to investigate whether a gravity stress radiograph is beneficial in determining instability in Supination-External rotation (SER)-type ankle fractures without a medial fracture. METHODS: 39 Patients with a SER-type ankle fracture without a medial or posterior fracture and medial clear space (MCS) < 6 mm at regular mortise view were included. A gravity stress radiograph and Magnetic Resonance imaging (MRI)-scan were made. The MCS measurements of the regular and gravity stress radiographs were compared with the MRI findings (set as reference standard) to determine the sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values as indication for a complete deltoid ligament rupture. RESULTS: Mean MCS at regular mortise views was 3.11 (range 1.73-5.93) mm, compared to 4.54 (range 2.33-10.40) mm at gravity stress radiographs. With MCS >= 4 mm as threshold for predicting a complete rupture at regular ankle mortise views the sensitivity was 66.7, specificity 91.7, PPV 40.0 and NPV 97.0. Gravity stress radiographs with MCS >= 6 mm as threshold led to a sensitivity of 100, specificity 91.7, PPV 50.0 and NPV 100. CONCLUSION: Gravity stress radiographs have more discriminative ability for diagnosing SER-type fractures with or without a complete deltoid ligament tear than regular ankle mortise views. PMID- 29441405 TI - Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking. AB - Abstinence from unregulated methamphetamine self-administration increases hippocampal dependent, context-driven reinstatement of methamphetamine seeking. The current study tested the hypothesis that alterations in the functional properties of granule cell neurons (GCNs) in the dentate gyrus (DG) of the hippocampus in concert with altered expression of synaptic plasticity-related proteins and ultrastructural changes in the DG are associated with enhanced context-driven methamphetamine-seeking behavior. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naive (controls) and methamphetamine experienced animals (during acute withdrawal, during abstinence, after extinction and after reinstatement). Spontaneous excitatory postsynaptic currents (sEPSCs) and intrinsic excitability were recorded from GCNs. Reinstatement of methamphetamine seeking increased sEPSC frequency and produced larger amplitude responses in GCNs compared to controls and all other groups. Reinstatement of methamphetamine seeking reduced spiking capability in GCNs compared to controls, and all other groups, as indicated by reduced intrinsic spiking elicited by increasing current injections, membrane resistance and fast after hyperpolarization. In rats that reinstated methamphetamine seeking, these altered electrophysiological properties of GCNs were associated with enhanced expression of Fos, GluN2A subunits and PSD95 and reduced expression of GABAA subunits in the DG and enhanced expression of synaptic PSD in the molecular layer. The alterations in functional properties of GCNs and plasticity related proteins in the DG paralleled with no changes in structure of microglial cells in the DG. Taken together, our results demonstrate that enhanced reinstatement of methamphetamine seeking results in alterations in intrinsic spiking and spontaneous glutamatergic synaptic transmission in the GCNs and concomitant increases in neuronal activation of GCNs, and expression of GluNs and decreases in GABAA subunits that may contribute to the altered synaptic connectivity-neuronal circuitry-and activity in the hippocampus, and enhance propensity for relapse. PMID- 29441407 TI - Disability Weights for Pediatric Surgical Procedures: A Systematic Review and Analysis. AB - BACKGROUND: Metrics to measure the burden of surgical conditions, such as disability weights (DWs), are poorly defined, particularly for pediatric conditions. To summarize the literature on DWs of children's surgical conditions, we performed a systematic review of disability weights of pediatric surgical conditions in low- and middle-income countries (LMICs). METHOD: For this systematic review, we searched MEDLINE for pediatric surgery cost-effectiveness studies in LMICs, published between January 1, 1996, and April 1, 2017. We also included DWs found in the Global Burden of Disease studies, bibliographies of studies identified in PubMed, or through expert opinion of authors (ES and HR). RESULTS: Out of 1427 publications, 199 were selected for full-text analysis, and 30 met all eligibility criteria. We identified 194 discrete DWs published for 66 different pediatric surgical conditions. The DWs were primarily derived from the Global Burden of Disease studies (72%). Of the 194 conditions with reported DWs, only 12 reflected pre-surgical severity, and 12 included postsurgical severity. The methodological quality of included studies and DWs for specific conditions varied greatly. INTERPRETATION: It is essential to accurately measure the burden, cost-effectiveness, and impact of pediatric surgical disease in order to make informed policy decisions. Our results indicate that the existing DWs are inadequate to accurately quantify the burden of pediatric surgical conditions. A wider set of DWs for pediatric surgical conditions needs to be developed, taking into account factors specific to the range and severity of surgical conditions. PMID- 29441408 TI - Macronutrient composition and food groups associated with gestational weight gain: the GUSTO study. AB - PURPOSE: To examine the associations of energy, macronutrient and food intakes with GWG on 960 pregnant women from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) mother-offspring cohort. METHODS: Dietary intake was assessed at 26-28 weeks' gestation with a 24-hour recall and 3-day food diary. GWG z-scores were calculated from first (4-13 weeks' gestation) and last (30-40 weeks gestation) measured weights; inadequate and excessive GWG were defined using the Institute of Medicine recommendations based on weights between 15 and 35 weeks' gestation. Associations were examined using substitution models for macronutrient composition, with linear or multinomial logistic regressions. RESULTS: Mean +/- SD daily energy intake was 1868 +/- 598 kcal, and percentage energy intakes were 51.8 +/- 8.9% from carbohydrate, 15.7 +/- 3.9% from protein and 32.6 +/- 7.7% from fat. Higher energy intake (per 500 kcal increment) was associated with 0.18 SD higher GWG. In isocaloric diets, higher-carbohydrate and lower-fat intakes (at 5% energy substitution) were associated with 0.07 SD higher GWG, and 14% higher likelihood of excessive GWG. Concordantly, the highest tertile of carbohydrate rich foods intake was associated with 0.20 SD higher GWG, but the highest tertile of fruit and vegetable intake was independently associated with 60% lower likelihood of inadequate GWG. Additionally, the highest tertile of dairy intake was associated with 0.18 SD lower GWG; and the highest tertile of plant-based protein foods intake was associated with 60% and 34% lower likelihood of inadequate and excessive GWG. CONCLUSIONS: Balancing the proportions of carbohydrates and fat, and a higher intake of plant-based protein foods may be beneficial for achieving optimal GWG. PMID- 29441409 TI - Listening in the bog: I. Acoustic interactions and spacing between males of Sphagniana sphagnorum. AB - Males of the katydid Sphagniana sphagnorum form calling aggregations in boreal sphagnum bogs to attract mates. They broadcast frequency-modulated (FM) songs in steady series, each song comprised of two wing-stroking modes that alternate audio and ultrasonic spectra. NN analysis of three populations found mean distances between 5.1 and 8.4 m, but failed to find spacing regularity: in one males spaced randomly, in another they were clumped, but within the clumps spaced at random. We tested a mechanism for maintaining inter-male distances by playback of conspecific song to resident males and analysing song interactions between neighbouring males in the field. The results indicate that the song rate is an important cue for males. Information coded in song rates is confounded by variation in bog temperatures and by the linear correlation of song rates with temperature. The ultrasonic and audio spectral modes suffer different excess attenuation: the ultrasonic mode is favoured at shorter distances (< 6 m), the audio mode at longer distances (> 6 m), supporting a hypothesized function in distance estimation. Another katydid, Conocephalus fasciatus, shares habitat with S. sphagnorum and could mask its ultrasonic mode; however, mapping of both species indicate the spacing of S. sphagnorum is unaffected by the sympatric species. PMID- 29441410 TI - [Hyperkeratotic papules with a reticular pattern on the decollete]. PMID- 29441411 TI - Interrater variability in ASA physical status assignment: an analysis in the pediatric cancer setting. AB - BACKGROUND: The American Society of Anesthesiologists (ASA) physical status is a universal classification system that helps clinicians to categorize their patients preoperatively. However, there is a lack of both inter-rater and intra rater reliability among clinicians for the ASA physical status classification. Our study focuses on testing these reliabilities within pediatric anesthesia providers in the cancer setting. METHODS: In our retrospective observational study, a total of 1177 anesthesia records were reviewed. The cohort included all pediatric patients (<= 18 years old) diagnosed with either retinoblastoma or neuroblastoma who had two or more anesthesia procedure within a 14-day time period. RESULTS: Overall, the ASA physical status score among two different anesthesia providers for the same patient treated at different times had very little inter-rater reliability, kappa = - 0.042 (95% CI - 0.17; 0.09). Of the 1177-patient anesthesia records, only 25% had two or more ASA physical status score assigned by the same anesthesiologist within a 14-day time period. There was moderate intra-rater reliability kappa = 0.48 (95% CI 0.29; 0.68) for patients who were assigned an ASA physical status score by the identical anesthesia provider at different times points within a 14 day period. CONCLUSION: In contrast to observations in earlier studies, findings indicate poor agreement in inter-rater reliability. Although there was moderate agreement in intra-rater reliability, one would expect to find stronger, even perfect, intra-rater reliability. These findings suggest the need to develop a specific physical status classification system directed toward patients with a systemic illness such as cancer in both young and adult patients. PMID- 29441412 TI - Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. AB - Multiple sclerosis (MS) is a highly heterogeneous disease with large inter individual differences in disease course. MS lesion pathology shows considerable heterogeneity in localization, cellular content and degree of demyelination between patients. In this study, we investigated pathological correlates of disease course in MS using the autopsy cohort of the Netherlands Brain Bank (NBB), containing 182 MS brain donors. Using a standardized autopsy procedure including systematic dissection from standard locations, 3188 tissue blocks containing 7562 MS lesions were dissected. Unbiased measurements of lesion load were made using the tissue from standard locations. Lesion demyelinating and innate inflammatory activity were visualized by immunohistochemistry for proteolipid protein and human leukocyte antigen. Lesions were classified into active, mixed active/inactive (also known as chronic active), inactive or remyelinated, while microglia/macrophage morphology was classified as ramified, amoeboid or foamy. The severity score was calculated from the time from first symptoms to EDSS-6. Lesion type prevalence and microglia/macrophage morphology were analyzed in relation to clinical course, disease severity, lesion load and sex, and in relation to each other. This analysis shows for the first time that (1) in progressive MS, with a mean disease duration of 28.6 +/- 13.3 years (mean +/- SD), there is substantial inflammatory lesion activity at time to death. 57% of all lesions were either active or mixed active/inactive and 78% of all patients had a mixed active/inactive lesion present; (2) patients that had a more severe disease course show a higher proportion of mixed active/inactive lesions (p = 6e-06) and a higher lesion load (p = 2e-04) at the time of death, (3) patients with a progressive disease course show a higher lesion load (p = 0.001), and a lower proportion of remyelinated lesions (p = 0.03) compared to patients with a relapsing disease course, (4) males have a higher incidence of cortical grey matter lesions (p = 0.027) and a higher proportion of mixed active/inactive lesions compared to females across the whole cohort (p = 0.007). We confirm that there is a higher proportion of mixed active/inactive lesions (p = 0.006) in progressive MS compared to relapsing disease. Identification of mixed active/inactive lesions on MRI is necessary to determine whether they can be used as a prognostic tool in living MS patients. PMID- 29441413 TI - Distribution and health risk assessment of natural fluoride of drinking groundwater resources of Isfahan, Iran, using GIS. AB - Fluoride (F) contamination in groundwater can be problematic to human health. This study evaluated the concentration of fluoride in groundwater resources of Isfahan Province, the central plateau of Iran, and its related health issues to the inhabitant populations. For this purpose, 573 drinking groundwater samples were analyzed in 2016 by using the spectrophotometric method. Non-carcinogenic health risks due to F exposure through consumption of drinking water were assessed using the US EPA method. In addition, the associated zoning maps of the obtained results were presented using geographic information system (GIS). The results indicated that F content in drinking water ranged from 0.02 to 2.8 mg/L. The F contents were less than 0.50 mg/L in 63% of the drinking groundwater samples, 0.51-1.5 mg/L in 33.15%, and higher than 1.5 mg/L in 3.85% (Iran and World Health Organization guidelines) of the drinking groundwater samples. The F levels in the west and the south groundwater resources of the study areas were lower than 0.5 mg/L, which is within the recommended values for controlling dental caries (0.50-1.0 mg/L). Therefore, these places require more attention and more research is needed to increase F intake for health benefit. The HQ index for children, teens and male and female adults had health hazards (HQ > 1) in 51, 17, 28, and 18 of samples, respectively. Groundwater resources having a risk of more than one were located in the counties of Nayin, Natanz, and Ardestan. So, in these areas, there are potential risks of dental fluorosis. The most vulnerable groups were children. The F levels must be reduced in this region to decrease endemic fluorosis. PMID- 29441414 TI - Association between IgH enhancer hs1.2 and type 1 diabetes. AB - AIM: To investigate the association of alleles of the 3' immunoglobulin heavy chain regulatory region 1 (3'RR-1) enhancer hs1.2 in patients with type 1 diabetes (T1D). METHODS: Eighty-one patients with T1D [among which 12 had concomitant coeliac disease (CD) and 25 an autoimmune thyroid disease (AITD)] were compared to 248 healthy individuals. All subjects were recruited from the same geographical area. Blood samples were collected from all patients and a nested PCR was performed to amplify the core of the 3'RR-1 and detect the alleles of the hs1.2 enhancer. RESULTS: Allele distribution in healthy individuals was significantly different when compared to that of patients with T1D (p < 0.01). Even greater differences were detected comparing allele distribution of patients with T1D alone versus those with concomitant CD, but not versus those with concomitant AITD. The frequency of *2 allele is increased by 23% in patients with T1D and CD. CONCLUSIONS: The present study establishes that the multiallelic hs1.2 enhancer of the 3'RR-1 is associated with T1D, with higher frequency when there is co-occurrence of CD. This evidence has been previously observed in other immune diseases. PMID- 29441416 TI - High pressure and high temperature investigation of metallic perovskite SnTaO3. AB - High pressure electronic, elastic, mechanical, and thermodynamic properties of cubic perovskite SnTaO3 have been explored with density function theory (DFT), and the quasi-harmonic Debye model has been applied for the incorporation of high temperature. The experimental lattice constant has been used for the optimization of structure. The optimization results present the paramagnetic (PM) nature of the compound. The spin dependent electronic band structures at ambient conditions and under high pressure present the metallic nature with complete uniformity for the majority and minority spin states. The mechanical properties, such as Young's modulus and bulk modulus, have been calculated and suggest an increase in stiffness and hardness of the material under the application of pressure. The thermodynamic properties, such as specific heat and Gruneisen parameter, have been predicted in the temperature range of 0 to 1000 K and pressure range of 0 to 60 Gpa. PMID- 29441415 TI - Novel approach to study gastropod-mediated innate immune reactions against metastrongyloid parasites. AB - The anthropozoonotic metastrongyloid nematodes Angiostrongylus cantonensis and Angiostrongylus costaricensis, as well as Angiostrongylus vasorum, Crenosoma vulpis, Aelurostrongylus abstrusus and Troglostrongylus brevior are currently considered as emerging gastropod-borne parasites and have gained growing scientific attention in the last years. However, the knowledge on invertebrate immune responses and on how metastrongyloid larvae are attacked by gastropod immune cells is still limited. This work aims to describe an in vitro system to investigate haemocyte-derived innate immune responses of terrestrial gastropods induced by vital axenic metastrongyloid larvae. We also provide protocols on slug/snail management and breeding under standardized climate conditions (circadian cycle, temperature and humidity) for the generation of parasite-free F0 stages which are essential for immune-related investigations. Adult slug species (Arion lusitanicus, Limax maximus) and giant snails (Achatina fulica) were maintained in fully automated climate chambers until mating and production of fertilized eggs. Newly hatched F0 juvenile specimens were kept under parasite free conditions before experimental use. An improved protocol for gastropod haemolymph collection and haemocyte isolation was established. Giemsa-stained haemolymph preparations showed adequate haemocyte isolation in all three gastropod species. Additionally, a protocol for the production of axenic first and third stage larvae (L1, L3) was established. Haemocyte functionality was tested in haemocyte-nematode-co-cultures. Scanning electron microscopy (SEM) and light microscopy analyses revealed that gastropod-derived haemocytes formed clusters as well as DNA-rich extracellular aggregates catching larvae and decreasing their motility. These data confirm the usefulness of the presented methods to study haemocyte-mediated gastropod immune responses to better understand the complex biology of gastropod-borne diseases. PMID- 29441417 TI - The adolescent idiopathic scoliotic IVD displays advanced aggrecanolysis and a glycosaminoglycan composition similar to that of aged human and ovine IVDs. AB - PURPOSE: The present study was designed to ascertain how altered biomechanics in adolescent idiopathic scoliotic (AIS) intervertebral discs (IVDs) affected tissue compositions and aggrecan processing compared to age matched and aged human IVDs. Newborn, 2- and 10-year-old ovine IVDs were also examined. METHODS: Aggrecan populations were separated by Sepharose CL2B chromatography, composite agarose polyacrylamide gel electrophoresis (CAPAGE) and identified by immunoblotting. The KS and CS content of IVD tissue extracts from AIS IVDs were compared with age matched normal adolescent IVDs and with old human IVDs. Extracts from newborn, 2- and 10-year-old ovine IVDs were also examined in a similar manner. RESULTS: Adolescent idiopathic scoliotic IVD Aggrecan populations shared similar levels of polydispersity and aggregatability with hyaluronan as old IVD proteoglycans. CAPAGE demonstrated three aggrecan populations in AIS, aged human and ovine IVDs increased polydispersity and mobility in CAPAGE. AIS IVDs had GAG compositions similar to aged human and ovine IVDs. Sulphated KS (5-D-4) and chondroitin-6 sulphate, 3-B-3(+) were markers of tissue maturation, and chondroitin-4-sulphate, 2-B-6(+) was prominent in immature IVDs but its levels were lower in mature IVDs. DISCUSSION: Sulphated KS and 3-B-3(+) CS were prominently associated with IVD maturation and AIS IVDs, while the 2-B-6(+) CS isomer was associated with immature IVD tissues. The polydispersity of aggrecan in AIS IVDs, which was similar to in old human and ovine IVDs, reflected altered processing in the AIS IVDs in response to the biomechanical microenvironments the disc cells were exposed to in AIS IVDs. These slides can be retrieved under Electronic Supplementary Material. PMID- 29441418 TI - Editorial. PMID- 29441419 TI - Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients. AB - PURPOSE: To report outcomes of a population of anal cancer patients treated with modern intensity-modulated radiotherapy and daily image-guided radiotherapy techniques. METHODS: We analyzed data of 155 patients consecutively treated with intensity-modulated radiotherapy +/- chemotherapy in three radiotherapy departments. One hundred twenty-two patients presented a stage II-IIIA disease. Chemotherapy was administered in 138 patients, mainly using mitomycin C and 5 fluorouracil (n = 81). All patients received 36 Gy (1.8 Gy/fraction) on the pelvic and inguinal nodes, on the rectum, on the mesorectum and on the anal canal, and a sequential boost up to a total dose of 59.4 Gy (1.8 Gy/fraction) on the anal canal and on the nodal gross tumor volumes. RESULTS: Median follow-up was 38 months (interquartile range 12-51). Toxicity data were available for 143 patients: 22% of them presented a G3+ acute toxicity, mainly as moist desquamation (n = 25 patients) or diarrhea (n = 10). Three patients presented a late grade 3 gastrointestinal toxicity (anal incontinence). No grade 4 acute or late toxicity was recorded. Patients treated with fixed-gantry IMRT delivered with a sliding window technique presented a significantly higher risk of acute grade 3 (or more) toxicity compared to those treated with VMAT or helical tomotherapy (38.5 vs 15.3%, p = 0.049). Actuarial 4-year local control rate was 82% (95% CI 76-91%). CONCLUSIONS: Modern intensity-modulated radiotherapy with daily image-guided radiotherapy is effective and safe in treating anal cancer patients and should be considered the standard of care in this clinical setting. PMID- 29441422 TI - Mapping brain functional alterations in betel-quid chewers using resting-state fMRI and network analysis. AB - RATIONALE: The World Health Organization regards betel quid (BQ) as a human carcinogen, and DSM-IV and ICD-10 dependence symptoms may develop with its heavy use. BQ's possible effects of an enhanced reward system and disrupted inhibitory control may increase the likelihood of habitual substance use. OBJECTIVES: The current study aimed to employ resting-state fMRI to examine the hypothesized enhanced reward system (e.g., the basal forebrain system) and disrupted inhibitory control (e.g., the prefrontal system) in BQ chewers. METHODS: The current study recruited three groups of 48 male participants: 16 BQ chewers, 15 tobacco- and alcohol-user controls, and 17 healthy controls. We used functional connectivity (FC), mean fractional amplitude of low-frequency fluctuations (mfALFF), and mean regional homogeneity (mReHo) to evaluate functional alternations in BQ chewers. Graph theoretical analysis (GTA) and network-based statistical (NBS) analysis were also performed to identify the functional network differences among the three groups. RESULTS: Our hypothesis was partially supported: the enhanced reward system for the BQ chewers (e.g., habitual drug seeking behavior) was supported; however, their inhibitory control was relatively preserved. In addition, we reported that the BQ chewers may have enhanced visuospatial processing and decreased local segregation. CONCLUSIONS: The current results (showing an enhanced reward system in the chewers) provided the clinicians with important insight for the future development of an effective abstinence treatment. PMID- 29441421 TI - Diagnostic Error in Stroke-Reasons and Proposed Solutions. AB - PURPOSE OF REVIEW: We discuss the frequency of stroke misdiagnosis and identify subgroups of stroke at high risk for specific diagnostic errors. In addition, we review common reasons for misdiagnosis and propose solutions to decrease error. RECENT FINDINGS: According to a recent report by the National Academy of Medicine, most people in the USA are likely to experience a diagnostic error during their lifetimes. Nearly half of such errors result in serious disability and death. Stroke misdiagnosis is a major health care concern, with initial misdiagnosis estimated to occur in 9% of all stroke patients in the emergency setting. Under- or missed diagnosis (false negative) of stroke can result in adverse patient outcomes due to the preclusion of acute treatments and failure to initiate secondary prevention strategies. On the other hand, the overdiagnosis of stroke can result in inappropriate treatment, delayed identification of actual underlying disease, and increased health care costs. Young patients, women, minorities, and patients presenting with non-specific, transient, or posterior circulation stroke symptoms are at increased risk of misdiagnosis. Strategies to decrease diagnostic error in stroke have largely focused on early stroke detection via bedside examination strategies and a clinical decision rules. Targeted interventions to improve the diagnostic accuracy of stroke diagnosis among high-risk groups as well as symptom-specific clinical decision supports are needed. There are a number of open questions in the study of stroke misdiagnosis. To improve patient outcomes, existing strategies to improve stroke diagnostic accuracy should be more broadly adopted and novel interventions devised and tested to reduce diagnostic errors. PMID- 29441423 TI - How Do MRI-Detected Subchondral Bone Marrow Lesions (BMLs) on Two Different MRI Sequences Correlate with Clinically Important Outcomes? AB - The aim of this study is to describe the association of bone marrow lesions (BMLs) present on two different MRI sequences with clinical outcomes, cartilage defect progression, cartilage volume loss over 2.7 years, and total knee replacement (TKR) over 13.3 years. 394 participants (50-80 years) were assessed at baseline and 2.7 years. BML presence at baseline was scored on T1-weighted fat suppressed 3D gradient-recalled acquisition (T1) and T2-weighted fat-suppressed 2D fast spin-echo (T2) sequences. Knee pain, function, and stiffness were assessed using WOMAC. Cartilage volume and defects were assessed using validated methods. Incident TKR was determined by data linkage. BMLs were mostly present on both MRI sequences (86%). BMLs present on T2, T1, and both sequences were associated with greater knee pain and functional limitation (odds ratio = 1.49 to 1.70; all p < 0.05). Longitudinally, BMLs present on T2, T1, and both sequences were associated with worsening knee pain (beta = 1.12 to 1.37, respectively; p < 0.05) and worsening stiffness (beta = 0.45 to 0.52, respectively; all p < 0.05) but not worsening functional limitation or total WOMAC. BMLs present on T2, T1, and both sequences predicted site-specific cartilage defect progression (relative risk = 1.22 to 4.63; all p < 0.05) except at the medial tibial and inferior patellar sites. Lateral tibial and superior patellar BMLs present on T2, T1, and both sequences predicted site-specific cartilage volume loss (beta = - 174.77 to 140.67; p < 0.05). BMLs present on T2, T1, and both sequences were strongly associated with incident TKR. BMLs can be assessed on either T2- or T1-weighted sequences with no clinical predictive advantage of either sequence. PMID- 29441420 TI - Multilayered signaling pathways for pollen tube growth and guidance. AB - Sexual reproductive success is essential for the survival of all higher organisms. As the most prosperous and diverse group of land plants on earth, flowering plants evolved highly sophisticated fertilization mechanisms. To adapt to the terrestrial environment, a tubular structure pollen tube has been evolved to deliver the immobile sperm cells to the egg and central cell enclosed within the ovule. The pollen tube is generated from the vegetative cell of the pollen (male gametophyte), where two sperm cells are hosted. Pollen tube elongation in the maternal tissue and navigation to the ovule require intimate cell-cell interactions between the tube and female tissues. Questions on how the single celled pollen tube accomplishes such task and how the female tissues accommodate the tube have attracted many plant biologists. Here, we review recent progresses and concepts in understanding the molecular mechanisms governing pollen tube growth and its interactions with the female tissues. We will also discuss the future perspective in this field. PMID- 29441424 TI - Selective Serotonin Reuptake Inhibitors (SSRIs) and Markers of Bone Turnover in Men. AB - Selective serotonin reuptake inhibitors (SSRIs) have been shown to have a clinically significant impact on bone metabolism. To explore this further, we aimed to determine whether these agents are associated with serum markers of bone turnover utilising a population-based sample of men (n = 1138; 20-96 year) participating in the Geelong Osteoporosis Study. Blood samples were obtained and the bone resorption marker, C-telopeptide (CTx) and formation marker, type 1 procollagen amino-terminal-propeptide (PINP) were measured. Anthropometry and socio-economic status (SES) were determined and information on medication use and lifestyle was obtained via questionnaire. Lifetime mood disorders were assessed using semi-structured clinical interviews. Thirty-seven (3.3%) men reported using SSRIs. Age was an effect modifier in the association between SSRIs and markers of bone turnover. Among younger men (20-60 year; n = 557), adjusted mean CTx and PINP values were 12.4% [16.7 (95% CI 14.6-18.8) vs 19.1 (95% CI 18.7-19.4) pg/ml, p = 0.03] and 13.6% [5.6 (95% CI 4.9-6.3) vs 6.4 (95% CI 6.3-6.6) pg/ml, p = 0.02] lower among SSRI users compared to non-users, respectively. No differences in SSRI use and markers of bone turnover were detected among older men (61-94 year; all p > 0.05). These patterns persisted after further adjustment for activity, alcohol, smoking, SES, depression, bone active medications and other antidepressants. Our data suggest that SSRI use is associated with alterations in bone turnover markers among younger men. The observed decreases in both CTx and PINP are likely to contribute to a low bone turnover state and increased skeletal fragility with this potential imbalance between formation and resorption resulting in subsequent bone loss. PMID- 29441427 TI - Isolated focal cartilage and labral defects in patients with femoroacetabular impingement syndrome may represent new, unique injury patterns. AB - PURPOSE: Develop a framework to quantify the size, location and severity of femoral and acetabular-sided cartilage and labral damage observed in patients undergoing hip arthroscopy, and generate a database of individual defect parameters to facilitate future research and treatment efforts. METHODS: The size, location, and severity of cartilage and labral damage were prospectively collected using a custom, standardized post-operative template for 100 consecutive patients with femoroacetabular impingement syndrome. Chondrolabral junction damage, isolated intrasubstance labral damage, isolated acetabular cartilage damage and femoral cartilage damage were quantified and recorded using a combination of Beck and ICRS criteria. Radiographic measurements including alpha angle, head-neck offset, lateral centre edge angle and acetabular index were calculated and compared to the aforementioned chondral data using a multivariable logistic regression model and adjusted odd's ratio. Reliability among measurements were assessed using the kappa statistic and intraclass coefficients were used to evaluate continuous variables. RESULTS: Damage to the acetabular cartilage originating at the chondrolabral junction was the most common finding in 97 hips (97%) and was usually accompanied by labral damage in 65 hips (65%). The width (p = 0.003) and clock-face length (p = 0.016) of the damaged region both increased alpha angle on anteroposterior films. 10% of hips had femoral cartilage damage while only 2 (2%) of hips had isolated defects to either the acetabular cartilage or labrum. The adjusted odds of severe cartilage (p = 0.022) and labral damage (p = 0.046) increased with radiographic cam deformity but was not related to radiographic measures of acetabular coverage. CONCLUSIONS: Damage at the chondrolabral junction was very common in this hip arthroscopy cohort, while isolated defects to the acetabular cartilage or labrum were rare. These data demonstrate that the severity of cam morphology, quantified through radiographic measurements, is a primary predictor of location and severity of chondral and labral damage and focal chondral defects may represent a unique subset of patients that deserve further study. LEVEL OF EVIDENCE: IV. PMID- 29441426 TI - Conformational change of the extracellular parts of the CFTR protein during channel gating. AB - Cystic fibrosis can be treated by potentiators, drugs that interact directly with the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel to increase its open probability. These substances likely target key conformational changes occurring during channel opening and closing, however, the molecular bases of these conformational changes, and their susceptibility to manipulation are poorly understood. We have used patch clamp recording to identify changes in the three-dimensional organization of the extracellularly accessible parts of the CFTR protein during channel opening and closing. State-dependent formation of both disulfide bonds and Cd2+ bridges occurred for pairs of cysteine side-chains introduced into the extreme extracellular ends of transmembrane helices (TMs) 1, 6, and 12. Between each of these three TMs, we found that both disulfide bonds and metal bridges formed preferentially or exclusively in the closed state and that these inter-TM cross-links stabilized the closed state. These results indicate that the extracellular ends of these TMs are close together when the channel is closed and that they separate from each other when the channel opens. These findings identify for the first time key conformational changes in the extracellular parts of the CFTR protein that can potentially be manipulated to control channel activity. PMID- 29441428 TI - The complexity of patellofemoral instability. PMID- 29441425 TI - Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins. AB - The isolation of extracellular vesicles (EVs) from blood is of great importance to understand the biological role of circulating EVs and to develop EVs as biomarkers of disease. Due to the concurrent presence of lipoprotein particles, however, blood is one of the most difficult body fluids to isolate EVs from. The aim of this study was to develop a robust method to isolate and characterise EVs from blood with minimal contamination by plasma proteins and lipoprotein particles. Plasma and serum were collected from healthy subjects, and EVs were isolated by size-exclusion chromatography (SEC), with most particles being present in fractions 8-12, while the bulk of the plasma proteins was present in fractions 11-28. Vesicle markers peaked in fractions 7-11; however, the same fractions also contained lipoprotein particles. The purity of EVs was improved by combining a density cushion with SEC to further separate lipoprotein particles from the vesicles, which reduced the contamination of lipoprotein particles by 100-fold. Using this novel isolation procedure, a total of 1187 proteins were identified in plasma EVs by mass spectrometry, of which several proteins are known as EV-associated proteins but have hitherto not been identified in the previous proteomic studies of plasma EVs. This study shows that SEC alone is unable to completely separate plasma EVs from lipoprotein particles. However, combining SEC with a density cushion significantly improved the separation of EVs from lipoproteins and allowed for a detailed analysis of the proteome of plasma EVs, thus making blood a viable source for EV biomarker discovery. PMID- 29441429 TI - Three-dimensional printing improves osteochondral allograft placement in complex cases. AB - The use of three-dimensional (3D) printing has seen a vast expansion over recent years, with an increased application for its use in orthopaedics. This report details the use of 3D printing technology to aid in the treatment of a medial femoral condyle osteochondral defect in a 26-year-old female who had previously undergone a failed autograft procedure. A preoperative computed tomography scan of the knee and chondral defect was used to generate a 3D printed, one-to-one scale replica of the distal femur. This replica was then used to size a patient specific allograft plug for the osteochondral transplantation procedure. The patient recovered well, and 1 year postoperatively the allograft was well incorporated into the medial femoral condyle and healed. This report illustrates the advantages of using a 3D printed model to allow for tactile feedback and improved visualization that will allow for improved understanding of complex surgical procedures.Level of evidence V. PMID- 29441430 TI - Prenatal diagnosis of Apert syndrome using ultrasound, magnetic resonance imaging, and three-dimensional virtual/physical models: three case series and literature review. AB - OBJECTIVE: This aimed to describe the prenatal diagnosis of three cases of Apert syndrome using two-dimensional (2D) and three-dimensional (3D) ultrasound, magnetic resonance imaging (MRI), and 3D virtual/physical models. METHODS: We retrospectively analyzed three cases of Apert syndrome at our service. The prenatal diagnostic methods used were 2D ultrasound, 3D ultrasound in conventional and HDlive rendering modes, T2-weighted MRI sequences, and 3D virtual/physical models from MRI or 3D ultrasound scan data. All imaging methods were performed by one observer. All prenatal diagnoses were confirmed by autopsy in cases of termination of pregnancy or genetic assessment during the postnatal period. RESULTS: Mean +/- standard deviation of maternal and gestational age at the time of diagnosis was 36.5 +/- 3.5 years and 32 +/- 4.2 weeks, respectively. Main 2D/3D ultrasound and MRI findings were craniosynostosis, hypertelorism, low ear implantation, increased kidneys dimensions, and syndactyly of hands and feet. 3D virtual/physical models allowed 3D view of fetal head and extremity abnormalities. Termination of pregnancy occurred in two cases. CONCLUSION: Prenatal 3D ultrasound and MRI enabled the identification of all Apert syndrome phenotypes. 3D virtual/physical models provided both the parents and the medical team a better understanding of fetal abnormalities. PMID- 29441431 TI - An assessment of deep venous thrombosis in Irish older adults in an acute medical assessment unit. PMID- 29441432 TI - Pediatric Intracranial Hypertension: a Current Literature Review. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update on pediatric intracranial hypertension. RECENT FINDINGS: The annual pediatric incidence is estimated at 0.63 per 100,000 in the USA and 0.71 per 100,000 in Britain. The Idiopathic Intracranial Hypertension Treatment Trial found improvement in visual fields, optical coherence tomography, Frisen grade, and quality of life with acetazolamide compared to placebo in adult patients, and these findings have been translated to the pediatric population. Pediatric intracranial hypertension is a disorder that if left untreated can lead to poor quality of life and morbidity. There are no current treatment studies in pediatrics, but adult data suggests acetazolamide remains an acceptable first line medication. PMID- 29441434 TI - A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram. AB - PURPOSE: Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates. PROCEDURES: Positron emission tomography (PET) measurements with (R) [11C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 MUg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (VT) and VT/fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy. RESULTS: The brain uptake of (R)-[11C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose- and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 MUg/kg of roflumilast, regardless of outcome measures, VT or VT/fp. CONCLUSIONS: This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates. Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects. PMID- 29441435 TI - Impacts of hydrous manganese oxide on the retention and lability of dissolved organic matter. AB - Minerals constitute a primary ecosystem control on organic C decomposition in soils, and therefore on greenhouse gas fluxes to the atmosphere. Secondary minerals, in particular, Fe and Al (oxyhydr)oxides-collectively referred to as "oxides" hereafter-are prominent protectors of organic C against microbial decomposition through sorption and complexation reactions. However, the impacts of Mn oxides on organic C retention and lability in soils are poorly understood. Here we show that hydrous Mn oxide (HMO), a poorly crystalline delta-MnO2, has a greater maximum sorption capacity for dissolved organic matter (DOM) derived from a deciduous forest composite Oi, Oe, and Oa horizon leachate ("O horizon leachate" hereafter) than does goethite under acidic (pH 5) conditions. Nonetheless, goethite has a stronger sorption capacity for DOM at low initial C:(Mn or Fe) molar ratios compared to HMO, probably due to ligand exchange with carboxylate groups as revealed by attenuated total reflectance-Fourier transform infrared spectroscopy. X-ray photoelectron spectroscopy and scanning transmission X-ray microscopy-near-edge X-ray absorption fine structure spectroscopy coupled with Mn mass balance calculations reveal that DOM sorption onto HMO induces partial Mn reductive dissolution and Mn reduction of the residual HMO. X-ray photoelectron spectroscopy further shows increasing Mn(II) concentrations are correlated with increasing oxidized C (C=O) content (r = 0.78, P < 0.0006) on the DOM-HMO complexes. We posit that DOM is the more probable reductant of HMO, as Mn(II)-induced HMO dissolution does not alter the Mn speciation of the residual HMO at pH 5. At a lower C loading (2 * 102 MUg C m-2), DOM desorption-assessed by 0.1 M NaH2PO4 extraction-is lower for HMO than for goethite, whereas the extent of desorption is the same at a higher C loading (4 * 102 MUg C m-2). No significant differences are observed in the impacts of HMO and goethite on the biodegradability of the DOM remaining in solution after DOM sorption reaches steady state. Overall, HMO shows a relatively strong capacity to sorb DOM and resist phosphate-induced desorption, but DOM-HMO complexes may be more vulnerable to reductive dissolution than DOM-goethite complexes. PMID- 29441433 TI - Early ecotoxic effects of ZnO nanoparticle chronic exposure in Mytilus galloprovincialis revealed by transcription of apoptosis and antioxidant-related genes. AB - Recently, China became one of the largest nanomaterial markets in the world. The wide use of ZnO nanoparticles in a number of products implies an increasing release in marine environment and consequently the evaluation of the potential effects upon marine organisms largely cultured in China for commercial purposes, such as invertebrate bivalves is a current need. To this aim, survival, bioaccumulation, and transcription pattern of key genes, p53, PDRP, SOD, CAT, and GST, involved in DNA damage/repair and antioxidation, in Mytilus galloprovincialis digestive gland, exposed to ZnO NPs (<100 nm) and ZnO bulk (150 200 nm) for 4 weeks, were evaluated. ZnSO4 was also assessed to appraise the role of zinc ions. Starting from 72 h, increasing mortality values along the exposure time were observed for all ZnO compounds. The highest difference was evident after 28 d when NPs resulted three times more toxic than bulk, (LC50) = 0.78 mg Zn/L (confidence limits: 0.64, 1.00) and 2.62 mg Zn/L (confidence limits: 1.00, 4.00), respectively. For ZnSO4 the (LC50) was always the lowest reaching the minimum value at 28 d 0.25 mg Zn/L (confidence limits: 0.10-0.40). Digestive gland showed higher uptake rate of ionic Zn respect to ZnO NPs and bulk during the first three days of exposure. In particular at the end of the exposure time (28 d) at 1 mg Zn/L the rank of Zn uptake rate was Zinc ion > ZnO NPs > ZnO bulk. The relative expression of investigated genes evidenced that distinct actions of apoptosis and antioxidation occurred in M. galloprovincialis exposed to ZnO NPs with a peculiar pattern dependent on exposure time and concentration. Application of the qRT-PCR technique revealed evidence of sensitivity to the nanomaterial since the first time of exposure. PMID- 29441436 TI - Sexual (Dis)satisfaction and Its Contributors Among People Living with HIV Infection in Sweden. AB - Earlier research reports lower sexual satisfaction among people living with HIV (PLHIV) compared to HIV-negative persons. A number of psychosocial factors directly associated with sexual dissatisfaction have been identified. Little is known about sexual satisfaction and their contributors among PLHIV in Sweden. The aim of this study was to examine direct and indirect effects of variables within sociodemographic, clinical HIV-related, psychological, and sexual domains on sexual (dis)satisfaction among PLHIV in Sweden. Data for this study were derived from a nationally representative, anonymous survey among PLHIV conducted in 2014 (n = 1096). Statistical analysis included four steps: descriptive analyses, identification of variables associated with sexual (dis)satisfaction, identification of variables associated with those contributors of sexual (dis)satisfaction, and a path model integrating all these analyses. A total of 49% of participants reported being sexually dissatisfied, and no significant differences were observed when non-heterosexual men, heterosexual men, and women were compared. Among women, a negative change in sex life after HIV diagnosis and distress with orgasmic difficulties was directly associated with sexual dissatisfaction. For men, hopelessness, high HIV stigma, sexual inactivity in the last 6 months, and a negative change in sex life after HIV diagnosis were directly associated with sexual dissatisfaction. Path analyses showed in both men and women significant indirect associations between not being involved in an intimate relationship, lower self-reported CD4 cell counts, and perceiving obligation to disclose HIV status to sexual partners as a barrier to look for a long-term partner and sexual dissatisfaction. Our results show that despite good treatment outcomes, the HIV diagnosis has a negative bearing on sexual satisfaction. The need for gender-tailored interventions and clinical implications of these findings are discussed. PMID- 29441438 TI - Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines. AB - BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton's tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment. OBJECTIVE: To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors. METHODS: We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects. RESULTS: The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib. CONCLUSIONS: The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro-survival pathways (by ibrutinib) might offer a promising new therapeutic strategy for MCL patients. PMID- 29441439 TI - Pediatric Dose Selection and Utility of PBPK in Determining Dose. AB - Interest in determining safe and efficacious doses for drug administration in pediatric patients has increased dramatically in recent years. However, published pediatric clinical studies have failed to increase proportionally with adult clinical study publications. In order to assess the current state of pediatric dose determination and the supporting role of physiologically based pharmacokinetic modeling and simulation in determining pediatric dose, the pediatric clinical literature (2006-2016) and case examples of pediatric PBPK modeling efforts were reviewed. The objective of this assessment was to investigate the contribution of PBPK to our understanding of the differences between children and adults, which lead to differences in drug dose. Pediatric and adult dose data were available for 31 small molecule drugs. In general, pediatric dose was well-correlated with adult data, with an apparent tendency for higher body weight- or body surface area-normalized pediatric dose. Overall performance of pediatric PBPK modeling approaches was considered to adequately predict observed data. However, model performance was dependent upon age group simulated, with approximately half of neonatal predictions falling outside of 1.5 fold of observed. In conclusion, there is a clear need for further refinement of starting dose in pediatric phase 1 studies, and utilization of PBPK could lead to reduced numbers of patients required to establish safe and efficacious doses in the pediatric population. PMID- 29441437 TI - Immune Checkpoint Blockade: The New Frontier in Cancer Treatment. AB - Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise. PMID- 29441440 TI - gammadelta T cells in liver diseases. AB - gammadelta T cells display unique developmental, distributional, and functional patterns and can rapidly respond to various insults and contribute to diverse diseases. Different subtypes of gammadelta T cells are produced in the thymus prior to their migration to peripheral tissues. gammadelta T cells are enriched in the liver and exhibit liver-specific features. Accumulating evidence reveals that gammadelta T cells play important roles in liver infection, non-alcoholic fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis, and liver cancer and regeneration. In this study, we review the properties of hepatic gammadelta T cells and summarize the roles of gammadelta T cells in liver diseases. We believe that determining the properties and functions of gammadelta T cells in liver diseases enhances our understanding of the pathogenesis of liver diseases and is useful for the design of novel gammadelta T cell-based therapeutic regimens for liver diseases. PMID- 29441441 TI - Comparison of Practice Guidelines, BRCAPRO, and Genetic Counselor Estimates to Identify Germline BRCA1 and BRCA2 Mutations in Pancreatic Cancer. AB - Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC. PMID- 29441442 TI - Internal patterned injuries in trauma. AB - Patterned bruising of the internal organs is unusual. In these cases a cutaneous pattern of bruising is not observed but the underlying tissue may show unusual injuries that may even be recognizable as a tramline pattern. We report the suicide of a 23-year-old man by jumping off a bridge. At autopsy, an unusual finding was "tramline" bruising of the right liver lobe. The "blunt objects" that inflicted the bruising were determined to be the right ribs which were pushed against the liver capsule as a consequence of the extensive thoracic and vertebral trauma after a fall from a height with intermediate impact. PMID- 29441443 TI - Double-chambered left ventricle - a "heart within a heart". AB - A 20-year-old previously well man drowned after performing a back-flip off a bridge into a river. At autopsy no significant injuries or organic illness were identified. An unusual incidental finding was a double chambered left ventricle, or so-called "heart within a heart", with the left ventricle subdivided into two separate chambers by a muscular septum. Awareness of this entity in forensic casework is important as this anomaly, despite its dramatic appearance, is not associated with anomalous conduction tracts or arrhythmogenic conditions, and so is usually a completely incidental finding at autopsy. PMID- 29441444 TI - Listening to the Patient Perspective: Psychiatric Inpatients' Attitudes Towards Physical Restraint. AB - When other options fail, physical restraint is used in inpatient psychiatric units as a means to control violent behavior of agitated inpatients and to prevent them from harm. The professional and social discourse regarding the use of restrictive measures and the absence of the inpatients' attitudes towards these measures is notable. Our research therefore tries to fill this gap by interviewing inpatients about these issues. To assess the subjective experience and attitudes of inpatients who have undergone physical restraint. Forty inpatients diagnosed with psychiatric disorders were interviewed by way of a structured questionnaire. Descriptive statistics were conducted via use of SPSS statistical software. 1.Inpatients reported that physical restraint evoked an experience of loneliness (77.5%) and loss of autonomy (82.5%). 2.Staff visits during times of physical restraint were reported as beneficial according to 73.6% of the inpatients interviewed. 3.Two thirds of the inpatients viewed the use of physical restraints as justified when an inpatient was dangerous. 4.Two thirds of the inpatients regarded physical restraint as the most aversive experience of their hospitalization. Our pilot study explored the subjective experience and attitudes of psychiatric inpatients towards the use of physical restraint. Inpatients viewed physical restraint as a practice that was sometimes justified but at the same time evoked negative subjective feelings. We conclude that listening to inpatients' perspectives can help caregivers to evaluate these measures. PMID- 29441445 TI - Promoting Ethics and Integrity in Management Academic Research: Retraction Initiative. AB - In the management academic research, academic advancement, job security, and the securing of research funds at one's university are judged mainly by one's output of publications in high impact journals. With bogus resumes filled with published journal articles, universities and other allied institutions are keen to recruit or sustain the appointment of such academics. This often places undue pressure on aspiring academics and on those already recruited to engage in research misconduct which often leads to research integrity. This structured review focuses on the ethics and integrity of management research through an analysis of retracted articles published from 2005 to 2016. The study employs a structured literature review methodology whereby retracted articles published between 2005 and 2016 in the field of management science were found using Crossref and Google Scholar. The searched articles were then streamlined by selecting articles based on their relevance and content in accordance with the inclusion criteria. Based on the analysed retracted articles, the study shows evidence of ethical misconduct among researchers of management science. Such misconduct includes data falsification, the duplication of submitted articles, plagiarism, data irregularity and incomplete citation practices. Interestingly, the analysed results indicate that the field of knowledge management includes the highest number of retracted articles, with plagiarism constituting the most significant ethical issue. Furthermore, the findings of this study show that ethical misconduct is not restricted to a particular geographic location; it occurs in numerous countries. In turn, avenues of further study on research misconduct in management research are proposed. PMID- 29441446 TI - Relationship Between Declarations of Conflict of Interests and Reporting Positive Outcomes in Iranian Dental Journals. AB - Conflict of interests is a situation when someone is in need of other people's trust on one the hand and has personal or general interests on the other hand, resulting in conflict with the given responsibility. In this research work, an attempt was made to find the relation between declarations of conflict of interests and reporting positive outcomes in the dental journals in Iran (2000 2016). In this analytical/cross-sectional study, first Health and Biomedical Information was searched and all the Persian and English dental journals published in Iran were collected. Then, all the papers published in the journals from December 2000 to December 2016 were collected and categorized in terms of the year of publication, author or authors' affiliations, Persian and English journal, type of the substance or the drug used (including the manufacturing company), declarations of conflict of interests and the positive or negative conclusion of the report. Data were analyzed with the Fisher's exact test and Chi squared test, using the program SPSS 18. In numerical analysis, the significance was set at P < 0.05. Seventeen dental journals in Persian and English were analyzed: 10 in English and 7 in Persian. Reviewing these studies showed that of 1021 articles in Persian, in 128 cases there was no mention of a declaration of conflict of interests and in 11 cases, the COI had been stated. In addition, from 1220 articles in English, in 825 cases there was no mention of declarations of conflict of interests and in 45 cases, the declarations of COI had been mentioned. There was no significant relation between the COI and 'no' COI and the reporting of positive outcomes in papers in Iranian dental journals in terms of the journal type, year of publication and the journals' guarantee form (P = 0.25, P = 0.41 and P = 0.09). A total of 83% of studies with declarations of COI had one positive outcome, with a significant relationship in this field; however, in 73% of studies with no COI, there was one positive outcome, too. In general, the society expects that doctors would not consider any incentives except the health of the patients in the efforts made by them. The severity of the consequences of COI is of higher value when the patients' health is endangered due to it. In addition, COI might change the attitude and approach of other doctors and peers. PMID- 29441447 TI - Transcriptional Mechanisms of Secondary Fracture Healing. AB - PURPOSE OF REVIEW: Growing evidence supports the critical role of transcriptional mechanisms in promoting the spatial and temporal progression of bone healing. In this review, we evaluate and discuss new transcriptional and post-transcriptional regulatory mechanisms of secondary bone repair, along with emerging evidence for epigenetic regulation of fracture healing. RECENT FINDINGS: Using the candidate gene approach has identified new roles for several transcription factors in mediating the reactive, reparative, and remodeling phases of fracture repair. Further characterization of the different epigenetic controls of fracture healing and fracture-driven transcriptome changes between young and aged fracture has identified key biological pathways that may yield therapeutic targets. Furthermore, exogenously delivered microRNA to post-transcriptionally control gene expression is quickly becoming an area with great therapeutic potential. Activation of specific transcriptional networks can promote the proper progression of secondary bone healing. Targeting these key factors using small molecules or through microRNA may yield effective therapies to enhance and possibly accelerate fracture healing. PMID- 29441448 TI - Accumulation Patterns of Sub-chronic Aluminum Toxicity Model After Gastrointestinal Administration in Rats. AB - Although aluminum chronic neurotoxicity is well documented, there are no well established experimental protocols of Al exposure. In the current study, toxic effects of sub-chronic Al exposure have been evaluated in outbreed male rats (gastrointestinal administration). Forty animals were used: 10 were administered with AlCl3 water solution (2 mg/kg Al per day) for 1 month, 10 received the same concentration of AlCl3 for 3 month, and 20 (10 per observation period) saline as control. After 30 and 90 days, the animals underwent behavioral tests: open field, passive avoidance, extrapolation escape task, and grip strength. At the end of the study, the blood, liver, kidney, and brain were excised for analytical and morphological studies. The Al content was measured by inductively coupled plasma mass-spectrometry. Essential trace elements-Co, Cr, Cu, Fe, Mg, Mn, Mo, Se, and Zn-were measured in whole blood samples. Although no morphological changes were observed in the brain, liver, or kidney for both exposure terms, dose-dependent Al accumulation and behavioral differences (increased locomotor activity after 30 days) between treatment and control groups were indicated. Moreover, for 30 days exposure, strong positive correlation between Al content in the brain and blood for individual animals was established, which surprisingly disappeared by the third month. This may indicate neural barrier adaptation to the Al exposure or the saturation of Al transport into the brain. Notably, we could not see a clear neurodegeneration process after rather prolonged sub chronic Al exposure, so probably longer exposure periods are required. PMID- 29441450 TI - Photobiomodulation improves motor response in patients with spinal cord injury submitted to electromyographic evaluation: randomized clinical trial. AB - : Photobiomodulation is a treatment that has been widely used in neurotrauma and neurodegenerative diseases. In the present study, low-level laser therapy was administered to patients with spinal cord injury. Twenty-five individuals were divided into two groups: placebo photobiomodulation plus physiotherapy and active photobiomodulation plus physiotherapy. Electromyographic evaluations were performed before and after 12 sessions of phototherapy as well as 30 days after the end of treatment. In the active phototherapy group, median frequency values of the brachial biceps and femoral quadriceps muscles were higher at rest and during isotonic contraction 30 days after photobiomodulation (p = 0.0258). No significant results were found regarding the rest and isotonic conditions in the pre-photobiomodulation period (p = 0.950) or immediately following photobiomodulation (p = 0.262). The data provide evidence that phototherapy improves motor responses in individuals with spinal cord injury, as demonstrated by differences in the EMG signal before and after treatment. TRIAL REGISTRATION: NCT 03031223. PMID- 29441451 TI - Trauma, Psychosocial Factors, and Help-Seeking in Three Immigrant Groups in Finland. AB - Multiple psychosocial factors influence help-seeking behavior among immigrants, but studies have focused on separate issues in single cultural groups. This study tested a model of help-seeking behavior among three ethnically different immigrant groups. Participants were 1356 Somali, Russian, and Kurdish immigrants (18-64 years). They reported past traumatic events, social network, acculturation indices, trust in services, and mental health as well as usage of mental and somatic health services. Structural equation modeling (SEM) with multigroup procedure was applied. First, past traumatic events were associated with seeking more mental health services, indirectly mediated through increased risk for mental health problems in all three ethnic groups. Second, acculturation played a significant role in the use of mental and somatic health services only in Kurds and social networks in Kurds and Russians. The unique culturally influenced dynamics in help-seeking behavior should be considered in the development of health services. PMID- 29441452 TI - Long-term follow-up of the effects of fecal microbiota transplantation in combination with soluble dietary fiber as a therapeutic regimen in slow transit constipation. AB - As some studies have reported that strategies targeting the gut microbiota such as fecal microbiota transplantation (FMT) with or without other microecological therapy might have efficacy in treating slow transit constipation (STC), we conducted a single-center, open-label trial to study the long-term effect of FMT combined with soluble dietary fiber (pectin) on STC. Thirty-one adult patients with STC were enrolled into the trial. Patients received 6-day FMT procedures repeatedly for the first 3 months and soluble dietary fiber (pectin) daily during the follow-up. The rate of clinical remission and improvement, stool consistency, the Wexner constipation scale, and assessment of constipation-related symptoms were evaluated at week 4 and 1 year later. The clinical remission and improvement rates at week 4 were 69.0% (20/29) and 75.9% (22/29), respectively. At the end of the study, 48.3% (14/29) of patients continued to have at least three complete spontaneous bowel movements per week and 58.6% (17/29) of patients showed clinical improvements. Stool consistency, the Wexner constipation scale, and constipation symptoms improved both at short-term and long-term follow-up. The results indicated that FMT in combination with soluble dietary fiber (pectin) had both short-term and long-term efficacy in treating STC. PMID- 29441453 TI - Prognostic significance of combining high mobility group Box-1 and OV-6 expression in hepatocellular carcinoma. AB - The inflammatory environment and existence of cancer stem cells are critical for progression and intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resections. Here, we investigated the prognostic significance of combining high mobility group box 1 (HMGB1) expression and hepatic progenitor marker OV6 in hepatocellular carcinoma. Expression of HMGB1 and OV6 was evaluated using immunohistochemistry profiling in tissue microarrays containing samples from 208 HCC patients. Invasive clinical or pathological factors were found in patients with high expression of HMGB1 or OV6. Higher HMGB1 was associated with poorer clinical outcomes, and independently related to elevated 5-year recurrence incidence (85.5% vs. 62.4%, P<0.001). We also found that more OV6 positive staining was correlated with poor prognosis of HCC patients (P<0.001). Notably, expression of HMGB1 was positively correlated with OV6 in density (R2=0.032, P<0.001) and reversely related to HCC outcomes. Abnormal expression of HMGB1 in combination with positive staining of OV6 displayed poorer prognostic performance than single biomarker alone (area under curve (AUC) survival=0.696). Therefore, HMGB1 and OV6 positive staining are promising prognostic parameters for HCC, and we propose that HMGB1 and OV6 may cooperate with each other and predict poor prognosis of HCC. PMID- 29441455 TI - Author Correction to: L-Acetyl-carnitine in Patients with Carpal Tunnel Syndrome: Effects on Nerve Protection, Hand Function and Pain. AB - In the original publication the name of third author was incorrectly published. PMID- 29441454 TI - Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: a systematic review. AB - Head and neck cancer (HNC) is a fatal malignancy with an overall long-term survival of about 50% for all stages. The diagnosis is not rarely delayed, and the majority of patients present with loco-regionally advanced disease. The rate of second primary tumors after a diagnosis of HNC is about 3-7% per year, the highest rate among solid tumors. Currently, a single-modality or a combination of surgery, radiotherapy and chemotherapy (CHT), is the standard treatment for stage III-IV HNC. For the recurrent/metastatic setting, in the last 40 years great efforts have been made in order to develop a more effective CHT regimen, from the use of methotrexate alone, to the combination of cisplatin (CDDP) and 5 fluorouracile (5FU) or paclitaxel. Recently, the introduction of cetuximab, an anti-EGFR monoclonal antibody, to the CDDP-5FU doublet (EXTREME regimen) has improved the overall response rate, the progression-free survival and the overall survival (OS) compared to CHT alone. Nowadays, the EXTREME regimen is the standard of care for the first-line treatment of recurrent/metastatic head and neck carcinoma (RMHNC). In the last years, new promising therapies for RMHNC such as immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials, gained special interest. Nivolumab and pembrolizumab are the first two ICIs able to prolong OS in the second-, later line and platinum-refractory setting, with tolerable toxicities. This review summarizes the current state of the art in RMHNC treatment options. PMID- 29441457 TI - Effect of VSL#3 Probiotic in a Patient with Glycogen Storage Disease Type Ia and Irritable Bowel Disease-like Disease. AB - Gut Inflammatory bowel disease (IBD) is a group of chronic gastrointestinal disorders characterised by relapsing and remitting inflammation of the gastrointestinal tract. The two most common types of IBDs are ulcerative colitis and Crohn's disease. Patients with glycogen storage disease (GSD) type Ia present with gastrointestinal symptoms such as recurrent abdominal pain, bloating and changes in stool form or frequency, which is clinically difficult to distinguish from IBD. We report the case of a 36-year-old man with GSD type Ia and IBD-like disease. A commercial probiotic (VSL#3(r)) was chosen as a nutritional supplement treatment because of its high content of microbial species and strains. Three different tests were performed: normal-dose, no-dose and half-dose tests. The study periods for the normal-dose, no-dose and half-dose tests were 4 weeks from the treatment initiation, 72 h from the end of the previous period and 4 weeks to 6 months after the end of the 72-h period, respectively. When the probiotic treatment was stopped, he experienced several symptoms similar to those before the start of the treatment. The intestinal symptoms were less severe with the half-dose nutritional supplement treatment than with no treatment. Probiotics may reduce the number of irritable gut episodes and improve the patient's well-being and overall quality of life. More studies are needed to determine whether the improvement in more severe cases of GSD is due mainly to changes in the composition of the gut microbiota, as in this patient. PMID- 29441456 TI - Knowledge, Attitude and Practice (KAP) Study of Pediatricians on Infantile Spasms. AB - OBJECTIVE: To investigate the knowledge, attitude, and practice of Infantile Spasms among pediatricians. METHODS: A survey was carried out among pediatricians serving in Punjab, Haryana, Chandigarh, Himachal Pradesh and Delhi. The survey was done by Survey Monkey Software through emails by using a structured questionnaire between July 2016 and December 2017. RESULTS: A total of 236 pediatricians responded to the survey. Most of the respondents (95.5%) correctly considered Infantile Spasms as a seizure type. The most preferred investigation was Electroencephalogram by 91.8% pediatricians; however, only 57.7% considered it to decide the treatment. Perinatal asphyxia was the most recognized etiology (60.7% pediatricians). For treatment of Infantile Spasms, 66.8% follow Nelson textbook of Pediatrics. Adrenocorticotropic hormone was the most preferred first choice drug by 40% pediatricians. Alternate anti-epileptic drug was considered by 60.9% pediatricians when there is no clinical response. Only 24% pediatricians considered treatment response as a complete cessation of spasms. Majority (90%) of pediatricians felt that there is a necessity for increased awareness and 62% pediatricians felt that available information was insufficient. CONCLUSIONS: A substantial number of pediatricians lack precise knowledge on evidence-based practice of Infantile Spasms. In developing countries, where pediatricians provide the initial management of Infantile Spasms, there is need to empower them and develop simplified national guidelines/consensus statement for management of Infantile Spasms. PMID- 29441458 TI - Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis. AB - Among a variety of phytocannabinoids, Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most promising therapeutic compounds. Besides the well known palliative effects in cancer patients, cannabinoids have been shown to inhibit in vitro growth of tumor cells. Likewise, the major endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), induce tumor cell death. The purpose of the present study was to characterize cannabinoid elements and evaluate the effect of cannabinoids in endometrial cancer cell viability. The presence of cannabinoid receptors, transient receptor potential vanilloid 1 (TRPV1), and endocannabinoid-metabolizing enzymes were determined by qRT-PCR and Western blot. We also examined the effects and the underlying mechanisms induced by eCBs and phytocannabinoids in endometrial cancer cell viability. Besides TRPV1, both EC cell lines express all the constituents of the endocannabinoid system. We observed that at concentrations higher than 5 MUM, eCBs and CBD induced a significant reduction in cell viability in both Ishikawa and Hec50co cells, whereas THC did not cause any effect. In Ishikawa cells, contrary to Hec50co, treatment with AEA and CBD resulted in an increase in the levels of activated caspase -3/-7, in cleaved PARP, and in reactive oxygen species generation, confirming that the reduction in cell viability observed in the MTT assay was caused by the activation of the apoptotic pathway. Finally, these effects were dependent on TRPV1 activation and intracellular calcium levels. These data indicate that cannabinoids modulate endometrial cancer cell death. Selective targeting of TPRV1 by AEA, CBD, or other stable analogues may be an attractive research area for the treatment of estrogen-dependent endometrial carcinoma. Our data further support the evaluation of CBD and CBD-rich extracts for the potential treatment of endometrial cancer, particularly, that has become non-responsive to common therapies. PMID- 29441459 TI - Thyroid Hormone in the Clinic and Breast Cancer. AB - There is preclinical and recent epidemiological evidence that thyroid hormone supports breast cancer. These observations raise the issue of whether management of breast cancer in certain settings should include consideration of reducing the possible contribution of thyroid hormone to the advancement of the disease. In a preliminary experience, elimination of the clinical action of endogenous L thyroxine (T4) in patients with advanced solid tumors, including breast cancer, has favorably affected the course of the cancer, particularly when coupled with administration of exogenous 3,5,3'-triiodo-L-thyronine (T3) (euthyroid hypothyroxinemia). We discuss in the current brief review the possible clinical settings in which to consider whether endogenous thyroid hormone-or exogenous thyroid hormone in the patient with hypothyroidism and coincident breast cancer is significantly contributing to breast cancer outcome. PMID- 29441460 TI - Bayesian inference for psychology, part IV: parameter estimation and Bayes factors. AB - In the psychological literature, there are two seemingly different approaches to inference: that from estimation of posterior intervals and that from Bayes factors. We provide an overview of each method and show that a salient difference is the choice of models. The two approaches as commonly practiced can be unified with a certain model specification, now popular in the statistics literature, called spike-and-slab priors. A spike-and-slab prior is a mixture of a null model, the spike, with an effect model, the slab. The estimate of the effect size here is a function of the Bayes factor, showing that estimation and model comparison can be unified. The salient difference is that common Bayes factor approaches provide for privileged consideration of theoretically useful parameter values, such as the value corresponding to the null hypothesis, while estimation approaches do not. Both approaches, either privileging the null or not, are useful depending on the goals of the analyst. PMID- 29441461 TI - Superficially Spreading Signet-Ring Cell Carcinoma Perpendicularly Colliding with Gastric Adenoma: a Rare Case Report. PMID- 29441462 TI - Up-regulation of miR-340-5p promotes progression of thyroid cancer by inhibiting BMP4. AB - PURPOSE: The incidence of thyroid cancer is increasing and the proliferation of thyroid cancer cells is incompletely understood. microRNAs may play key roles in thyroid cancer progression. METHODS: We analyzed miR-340-5p in thyroid cancer tissue and normal tissue, and using informatics to predict its target. Cell lines and a mouse model were used to study the role of miR-340-5p in cancer proliferation. RESULTS: Overexpression of miR-340-5p was found in thyroid cancer specimens. Tumors with higher pathological grade had higher levels of miR-340-5p. Overexpression of miR-340-5p significantly enhanced cell viability and colony formation. Treatment of anti-miR-340-5p, however, showed opposite alterations. We predicted that bone morphogenetic protein 4 (BMP4) is a possible target, and found a negative correlation between miR-340-5p and BMP4 levels in thyroid cancer tissue. miR-340-5p reduced BMP4 expression. BMP4 overexpression attenuated the effects of miR-340-5p in cell viability and colony formation. In addition, using a xenograft mouse model we proved that anti-miR-340-5p was able to inhibit tumor growth. CONCLUSIONS: miR-340-5p promotes thyroid cancer proliferation by inhibiting BMP4. Anti-miR-340-5p can be a promising strategy to control thyroid cancer. PMID- 29441463 TI - Cumulative Risk and Impact Modeling on Environmental Chemical and Social Stressors. AB - PURPOSE OF REVIEW: The goal of this review is to identify cumulative modeling methods used to evaluate combined effects of exposures to environmental chemicals and social stressors. The specific review question is: What are the existing quantitative methods used to examine the cumulative impacts of exposures to environmental chemical and social stressors on health? RECENT FINDINGS: There has been an increase in literature that evaluates combined effects of exposures to environmental chemicals and social stressors on health using regression models; very few studies applied other data mining and machine learning techniques to this problem. The majority of studies we identified used regression models to evaluate combined effects of multiple environmental and social stressors. With proper study design and appropriate modeling assumptions, additional data mining methods may be useful to examine combined effects of environmental and social stressors. PMID- 29441465 TI - Xylanilyticolides A-C, Three New Compounds from Cultures of the Actinomycete Promicromonospora xylanilytica YIM 61515. AB - Three new lactones, xylanilyticolides A-C (1-3), were isolated from cultures of the actinomycete Promicromonospora xylanilytica YIM 61515. Their structures were elucidated by 1D and 2D NMR spectroscopic data in conjunction with HRESIMS analysis. Compound 1 exhibited potent cytotoxicities against five human cancer cell lines HL-60, A-549, SMMC-7721, MCF-7 and SW480 with the IC50 values of 3.9, 15.2, 11.2, 5.9, and 4.7 MUM, respectively. PMID- 29441464 TI - The Toxicology of Engineered Nanomaterials in Asthma. AB - PURPOSE OF REVIEW: The explosive growth of the nanotechnology industry has necessitated the examination of engineered nanomaterials (ENMs) for their toxicity. The unique properties that make ENMs useful also make them a health risk, and individuals with pre-existing diseases such as asthma are likely more susceptible. This review summarizes the current literature on the ability of ENMs to both exacerbate and directly cause asthma. RECENT FINDINGS: Recent studies highlight the ability of metal nanoparticles (NPs) and carbon nanotubes (CNTs) to not only exacerbate pre-existing asthma in animal models but also initiate allergic airway disease directly. CNTs alone are shown to cause airway mucus production, elevated serum IgE levels, and increased TH2 cytokine levels, all key indicators of asthma. The ability of ENMs to modulate the immune response in asthma varies depending on their physicochemical properties and exposure timing. CNTs consistently exacerbate asthma, as do Ni and TiO2 NPs, whereas some NPs like Au attenuate asthma. Evidence is strong that ENMs can contribute to allergic airway disease; however, more work is required to determine their mechanisms, and more epidemiological studies are needed to validate results from animal models. PMID- 29441466 TI - Hyaluronic acid-grafted PLGA nanoparticles for the sustained delivery of berberine chloride for an efficient suppression of Ehrlich ascites tumors. AB - To promote the specific targeting and elimination of CD44-positive cancer cells, berberine chloride (BRB)-encapsulated hyaluronic acid-grafted poly(lactic-co glycolic acid) copolymer (BRB-d(HA)-g-PLGA) nanoparticles (NPs) were prepared. The targeted action of these NPs was compared to non-targeted BRB-loaded PLGA NPs and bulk BRB. The in vitro studies demonstrated faster release of BRB and increased cytotoxicity of BRB-d(HA)-g-PLGA NPs in Hela and MCF-7 cells in comparison to BRB-PLGA NPs and bulk BRB. The uptake of BRB-d(HA)-g-PLGA NPs was increased in case of MCF-7 cells as compared to HeLa cells owing to the higher expression of CD44 receptors on MCF-7 cells. The CD44 receptor-mediated uptake of these NPs was confirmed through competitive inhibition experiments. The in vitro results were further validated in vivo in Ehrlich Ascites Carcinoma (EAC)-bearing mice. EAC-bearing mice were injected intravenously with these NPs and the results obtained were compared with that of BRB-PLGA NPs and bulk BRB. BRB-d(HA)-g-PLGA NPs were found to significantly enhance apoptosis, sub-G1 content, life span, mean survival time, and ROS levels in EAC cells with subsequent decrease in mitochondrial membrane potential and tumor burden ion tumor-bearing mice. Taking into account the findings of in vitro and in vivo studies, the enhanced and targeted anti-tumor activity of HA-grafted PLGA copolymer-encapsulated NPs of BRB cannot be negated. Therefore, HA-grafted nanoparticle-based delivery of BRB may offer a promising and improved alternative for anti-tumor therapy. PMID- 29441467 TI - Implementation of an online thermal imaging to study the effect of process parameters of roller compactor. AB - During roller compaction, not only the properties of the primary powder affect the product quality but also the process parameters. Any change in the process parameters during roller compaction will result in changing the properties of the ribbon. In this study, the temperature of the ribbon during production was monitored online using a thermal camera. The information from the thermal camera was used to explain the differences in ribbon properties at varying process parameters. Lactose powder was used as a primary powder, and ribbons were produced at different process parameters. The surface temperature of the ribbon during production was found to increase with increasing both the gap between the two rollers and the roller speed. This was attributed to the screw feeder speed, which increased to feed additional powder as required to adjust to the change in process parameters. Increasing the roller gap resulted in wider ribbons and decreased the percentage of fines in the product, which was a signature of better powder distribution across the roller width. The results were also supported by the uniform temperature distribution recorded across the ribbon width. It was found that increasing the roller speed during roller compaction decreased the width of the ribbon while increasing the percentage of fines in the product. The feeder screw speed was found to have a similar effect as the roller gap. PMID- 29441468 TI - A Novel Approach for Dry Powder Coating of Pellets with Ethylcellulose. Part II: Evaluation of Caffeine Release. AB - The objective of this study was to assess the efficacy and the capability of a novel ethylcellulose-based dry-coating system to obtain prolonged and stable release profiles of caffeine-loaded pellets. Lauric and oleic acids at a suitable proportion were used to plasticize ethylcellulose. The effect of coating level, percentage of drug loading, inert core particle size, and composition of the coating formulation including the anti-sticking agent on the drug release profile were fully investigated. A coating level of 15% w/w was the maximum layered amount which could modify the drug release. The best controlled drug release was obtained by atomizing talc (2.5% w/w) together with the solid plasticizer during the dry powder-coating process. SEM pictures revealed a substantial drug re crystallization on the pellet surface, and the release studies evidenced that caffeine diffused through the plasticized polymer acting as pore former. Therefore, the phenomenon of caffeine migration across the coating layer had a strong influence on the permeability of the coating membrane. Comparing dry powder-coated pellets to aqueous film-coated ones, drug migration happened during storage, though more sustained release profiles were obtained. The developed dry powder-coating process enabled the production of stable caffeine sustained release pellets. Surprisingly, the release properties of the dry-coated pellets were mainly influenced by the way of addition of talc into the dry powder-coating blend and by the drug nature and affinity to the coating components. It would be interesting to study the efficacy of novel coating system using a different API. PMID- 29441469 TI - Gaze anchoring guides real but not pantomime reach-to-grasp: support for the action-perception theory. AB - Reach-to-grasp movements feature the integration of a reach directed by the extrinsic (location) features of a target and a grasp directed by the intrinsic (size, shape) features of a target. The action-perception theory suggests that integration and scaling of a reach-to-grasp movement, including its trajectory and the concurrent digit shaping, are features that depend upon online action pathways of the dorsal visuomotor stream. Scaling is much less accurate for a pantomime reach-to-grasp movement, a pretend reach with the target object absent. Thus, the action-perception theory proposes that pantomime movement is mediated by perceptual pathways of the ventral visuomotor stream. A distinguishing visual feature of a real reach-to-grasp movement is gaze anchoring, in which a participant visually fixates the target throughout the reach and disengages, often by blinking or looking away/averting the head, at about the time that the target is grasped. The present study examined whether gaze anchoring is associated with pantomime reaching. The eye and hand movements of participants were recorded as they reached for a ball of one of three sizes, located on a pedestal at arms' length, or pantomimed the same reach with the ball and pedestal absent. The kinematic measures for real reach-to-grasp movements were coupled to the location and size of the target, whereas the kinematic measures for pantomime reach-to-grasp, although grossly reflecting target features, were significantly altered. Gaze anchoring was also tightly coupled to the target for real reach-to grasp movements, but there was no systematic focus for gaze, either in relation with the virtual target, the previous location of the target, or the participant's reaching hand, for pantomime reach-to-grasp. The presence of gaze anchoring during real vs. its absence in pantomime reach-to-grasp supports the action-perception theory that real, but not pantomime, reaches are online visuomotor actions and is discussed in relation with the neural control of real and pantomime reach-to-grasp movements. PMID- 29441470 TI - Early manifestation of arm-leg coordination during stepping on a surface in human neonates. AB - The accomplishment of mature locomotor movements relies upon the integrated coordination of the lower and upper limbs and the trunk. Human adults normally swing their arms and a quadrupedal limb coordination persists during bipedal walking despite a strong corticospinal control of the upper extremities that allows to uncouple this connection during voluntary activities. Here we investigated arm-leg coordination during stepping responses on a surface in human neonates. In eight neonates, we found the overt presence of alternating arm-leg oscillations, the arms moving up and down in alternation with ipsilateral lower limb movements. These neonates moved the diagonal limbs together, and the peak of the arm-to-trunk angle (i.e., maximum vertical excursion of the arm) occurred around the end of the ipsilateral stance phase, as it occurs during typical adult walking. Although episodes of arm-leg coordination were sporadic in our sample of neonates, their presence provides significant evidence for a neural coupling between the upper and lower limbs during early ontogenesis of locomotion in humans. PMID- 29441472 TI - Phylogeography of the Asian lesser white-toothed shrew, Crocidura shantungensis, in East Asia: role of the Korean Peninsula as refugium for small mammals. AB - Many peninsulas in the temperate zone played an important role as refugia of various flora and fauna, and the southern Korean Peninsula also served as a refugium for many small mammals in East Asia during the Pleistocene. The Asian lesser white-toothed shrew, Crocidura shantungensis, is a widely distributed species in East Asia, and is an appropriate model organism for exploring the role of the Korean Peninsula as a refugium of small mammals. Here, we investigated phylogenetic relationships and genetic diversity based on the entire sequence of the mitochondrial cytochrome b gene (1140 bp). A Bayesian tree for 98 haplotypes detected in 228 C. shantungensis specimens from East Asia revealed the presence of three major groups with at least 5 subgroups. Most haplotypes were distributed according to their geographic proximity. Pairwise FST's and analysis of molecular variance (AMOVA) revealed a high degree of genetic differentiation and variance among regions as well as among populations within region, implying little gene flow among local populations. Genetic evidence from South Korean islands, Jeju-do Island of South Korea, and Taiwan leads us to reject the hypothesis of recent population expansion. We observed unique island-type genetic characteristics consistent with geographic isolation and resultant genetic drift. Phylogeographic inference, together with estimates of genetic differentiation and diversity, suggest that the southern most part the Korean Peninsula, including offshore islands, played an important role as a refugium for C. shantungensis during the Pleistocene. However, the presence of several refugia on the mainland of northeast Asia is also proposed. PMID- 29441471 TI - Transcranial direct current stimulation generates a transient increase of small world in brain connectivity: an EEG graph theoretical analysis. AB - Transcranial direct current stimulation (tDCS) is a non-invasive technique able to modulate cortical excitability in a polarity-dependent way. At present, only few studies investigated the effects of tDCS on the modulation of functional connectivity between remote cortical areas. The aim of this study was to investigate-through graph theory analysis-how bipolar tDCS modulate cortical networks high-density EEG recordings were acquired before and after bipolar cathodal, anodal and sham tDCS involving the primary motor and pre-motor cortices of the dominant hemispherein 14 healthy subjects. Results showed that, after bipolar anodal tDCS stimulation, brain networks presented a less evident "small world" organization with a global tendency to be more random in its functional connections with respect to prestimulus condition in both hemispheres. Results suggest that tDCS globally modulates the cortical connectivity of the brain, modifying the underlying functional organization of the stimulated networks, which might be related to changes in synaptic efficiency of the motor network and related brain areas. This study demonstrated that graph analysis approach to EEG recordings is able to intercept changes in cortical functions mediated by bipolar anodal tDCS mainly involving the dominant M1 and related motor areas. Concluding, tDCS could be an useful technique to help understanding brain rhythms and their topographic functional organization and specificity. PMID- 29441474 TI - Optimality, Future and Terminal Costs: Comment on "Adjuvant Trastuzumab Therapy for Early HER2-Positive Breast Cancer in Iran". PMID- 29441473 TI - Cost and Cost Effectiveness of Treatments for Psoriatic Arthritis: A Systematic Literature Review. AB - BACKGROUND: Psoriatic arthritis is a long-term inflammatory arthropathy occurring in a subgroup of patients with psoriasis. In addition to irreversible bone erosions, joint destruction, and skin manifestations, psoriatic arthritis is associated with numerous comorbid conditions. Over the last 5 years, new treatments emerged; the analysis and comparisons of their additional costs and the added benefits have become increasingly important to optimize the limited resources available. METHODS: A systematic literature review covering PubMed, EMBASE, and the Cochrane Library was performed from May 2012 to October 2017 focusing on the most recent evidence of costs, benefits, and burden of psoriatic arthritis and its treatments. All economic evaluations assessing the burden of patients with psoriatic arthritis and written in English were eligible for inclusion. We also performed an assessment of the quality of the studies. RESULTS: Of the 1652 references found in the literature search, nine cost effectiveness analyses and 12 cost-of-illness studies were included in the current review. Patients with psoriatic arthritis incur substantially higher direct and indirect costs, as compared with patients with psoriasis without arthritis or patients with other inflammatory diseases. The cost of treatment with biologic therapies is the major predictor of the total cost. However, individuals with psoriatic arthritis are also affected by substantial productivity losses and indirect costs. Biologic therapies are generally cost effective vs. conventional therapies (e.g., synthetic drugs) for treating psoriatic arthritis. CONCLUSIONS: Psoriatic arthritis is associated with a significant economic burden and biologic therapies contribute significantly to these costs. Biologic therapies are more effective than disease-modifying anti rheumatic drugs for the symptoms and signs of psoriatic arthritis and for improving quality of life and inhibiting structural radiological damage. Therefore, biologic therapies are cost effective compared with conventional therapies: the increased direct cost associated with biologic drugs is offset by the significant improvement in the efficacy of treatments and in patient management of psoriatic arthritis. PMID- 29441475 TI - Robot-assisted distal gastrectomy with lymph node dissection for gastric cancer in a patient with situs inversus partialis: a case report with video file. AB - BACKGROUND: Situs inversus is a rare congenital condition that is currently classified into two types: complete situs inversus (situs inversus totalis, SIT) and partial situs inversus (situs inversus partialis, SIP). In SIP patients, some organs are inverted and others are in their expected position, and individual patient variation in organ position increases surgical difficulty. Several surgeons have performed laparoscopic or robotic surgeries in situs inversus patients, but almost all were SIT patients. We report the first case, to our knowledge, of an SIP patient with gastric cancer who was successfully treated by robot-assisted distal gastrectomy (RADG) with lymph node dissection. CASE PRESENTATION: A 64-year-old woman diagnosed with early gastric cancer on the posterior midbody of the stomach was referred to our hospital for treatment. Computed tomography showed levocardia and inverted abdominal organs without enlarged lymph nodes or distant metastases. Polysplenia syndrome, intestinal malrotation, and left-sided gallbladder were also detected. RADG with D1+ lymph node dissection and Billroth I reconstruction (delta-shaped anastomosis) were performed using robotics. Hepatopathy caused by a liver retractor and pancreatic fistula were identified during the postoperative course, and the latter was classified as grade II based on Clavien-Dindo classification. The patient was discharged 18 days after the operation. CONCLUSIONS: Preoperative three dimensional imaging is beneficial, and anatomical organ identification should be routinely performed, especially in SIP patients. We consider RADG a therapeutic option in SIP patients. PMID- 29441476 TI - Augmented Renal Clearance in Critically Ill Patients: A Systematic Review. AB - BACKGROUND: Traditionally, renal function in critically ill patients has been assessed to identify renal dysfunction, and dose adjustment is generally accepted in such a context. Nevertheless, augmented renal clearance (ARC) is a less well studied phenomenon that could lead to faster elimination of drugs, resulting in subtherapeutic concentrations and poorer clinical outcomes when standard dosage guidelines are followed. OBJECTIVE: The aim of this systematic review was to gather and summarise all the available evidence on ARC in critically ill patients, including its definition, underlying mechanisms, epidemiology, diagnosis and impact on both drug pharmacokinetics and clinical outcomes. METHOD: A systematic review was conducted to include all the original studies that provided information on ARC in critically ill patients, and is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Augmented renal clearance, defined as a creatinine clearance (CrCl) > 130 mL/min/1.73 m2, preferably measured in urine, is present in 20-65% of critically ill patients. Younger age, polytrauma and lower severity illness have been identified as risk factors. An influence of ARC on antimicrobial pharmacokinetics has been observed, with ARC consistently being associated with subtherapeutic antibiotic plasma concentrations. CONCLUSION: ARC is a prevalent condition in critically ill patients, especially in young people, with urinary CrCl being the best diagnostic method because mathematical estimates tend to underestimate CrCl. ARC increases renal drug elimination and has a clear influence on certain antimicrobial plasma levels, but is yet to define its impact on clinical outcomes and on pharmacokinetics of other types of drugs. Research on the need to stage ARC and establish specific dosing guidelines is warranted. PMID- 29441477 TI - Betel nut chewing and the risk of chronic kidney disease: evidence from a meta analysis. AB - PURPOSE: To investigate and quantify the potential association between betel nut chewing and the risk of chronic kidney disease (CKD). METHODS: We searched five online databases including PubMed, EMBASE, ISI Web of Science, Wanfang and CNKI to identify observational studies that published prior to May, 1, 2017. The primary outcome was the association between betel nut chewing and CKD expressed as odds ratio (OR) and the corresponding 95% confidence interval (95%CI) after adjustment for other covariates. Meta-analysis was performed using RevMan 5.3 software; the leave-one-out sensitivity analysis was used to confirm the stability of drawn conclusion. RESULTS: Five studies comprising a total of 10,562 CKD patients and 34,038 subjects without CKD that analyzed the relationship between betel nut chewing and CKD were included in our study; all the included studies were performed in Taiwan. After the adjustment for covariates, the combined adjusted ORs showed that betel nut used had 1.44 times higher risk to develop CKD compared with non-chewers (OR 1.44, 95%CI 1.08-1.92). CONCLUSIONS: Betel nut chewing could significantly increase the risk of CKD, indicating that betel nut chewing may exist as an independent risk factor for CKD. Further investigation should be warranted. PMID- 29441478 TI - Re: Letter to the editor. PMID- 29441479 TI - Re: Lebentrau S, Gilfrich C, Vetterlein MW, Schumacher H, Spachmann PJ, Brookman May SD, Fritsche HM, Schostak M, Wagenlehner F, Burger M, May M, MR2 study group (2017) Impact of the medical specialty on knowledge regarding multidrug-resistant organisms and strategies toward antimicrobial stewardship. Int Urol Nephrol 49:1311-1318. PMID- 29441480 TI - Prognostic value of cardiovascular calcifications in hemodialysis patients: a longitudinal study. AB - PURPOSE: Cardiovascular calcifications (CVC) are present in up to 70% of non diabetic dialysis patients. Sparse data are available on predictors of very long term outcomes of such patients. The Belgrade Aachen Study on Calcification in Hemodialysis patients (BASCH study) aimed to study this using a comprehensive CVC assessment. METHODS: We prospectively analyzed 220 hemodialysis patients followed for a mean of 76 months (median 73 months, range 6-160 months). We compared patients deceased from cardiovascular diseases (CVD) and survivors. Analyses included composite calcification scores (determined by combining ultrasound and X ray analyses), demographic, clinical and laboratory data and pulse wave velocity (PWV). For survival analysis, patients were divided into group according to quartiles (Q). RESULTS: Compared to survivors, deceased patients from CVD were significantly older, more frequently hypertensive, had shorter dialysis times per week and lower Kt/V values, and they exhibited lower serum fetuin A, osteoprotegerin and hemoglobin as well as higher CRP levels. Composite calcification and Adragao scores were significantly higher in deceased patients from CVD as was PWV. Mean survival was 101 +/- 47 months (Q1), 87 +/- 51 month (Q2), 66 +/- 48 (Q3) and 54 +/- 45 months (Q4), p = 0.000. Cox multivariate regression analysis showed that independent predictors for cardiovascular mortality were composite calcification score in the range of third and fourth quartiles. CONCLUSION: Composite calcification score emerged as significant predictors of long-term survival in our group of largely non-diabetic dialysis patient population, finding that should be confirmed by intervention studies. PMID- 29441482 TI - Spontaneous intracranial hypotension with chronic brain sagging causing foramen magnum CSF circulation disorder reversible after lumbar epidural blood patch. PMID- 29441481 TI - Whole-exome sequencing reveals a rare interferon gamma receptor 1 mutation associated with myasthenia gravis. AB - Our study is aimed to explore the underlying genetic basis of myasthenia gravis. We collected a Chinese pedigree with myasthenia gravis, and whole-exome sequencing was performed on the two affected siblings and their parents. The candidate pathogenic gene was identified by bioinformatics filtering, which was further verified by Sanger sequencing. The homozygous mutation c.G40A (p.V14M) in interferon gamma receptor 1was identified. Moreover, the mutation was also detected in 3 cases of 44 sporadic myasthenia gravis patients. The p.V14M substitution in interferon gamma receptor 1 may affect the signal peptide function and the translocation on cell membrane, which could disrupt the binding of the ligand of interferon gamma and antibody production, contributing to myasthenia gravis susceptibility. We discovered that a rare variant c.G40A in interferon gamma receptor 1 potentially contributes to the myasthenia gravis pathogenesis. Further functional studies are needed to confirm the effect of the interferon gamma receptor 1 on the myasthenia gravis phenotype. PMID- 29441483 TI - Natalizumab reduces serum pro-angiogenic activity in MS patients. AB - Angiogenesis has been implicated in the pathobiology of multiple sclerosis (MS). Osteopontin exerts a pro-angiogenetic effect and is increased in body fluid of MS patients. To evaluate the effect of 1 year natalizumab treatment on serum pro angiogenic activity and on plasma osteopontin levels in relapsing (RR) MS patients. Ten RRMS patients scheduled for natalizumab treatment were enrolled and evaluated at baseline and after 1-year natalizumab treatment. Pro-angiogenic activity was assessed by a chick embryo chorioallantoic membrane assay (CAM), osteopontin levels were evaluated by an enzyme-linked immunosorbent assay. Plasma and serum samples of 10 treatment-naive RRMS and 10 healthy controls (HCs) were used as controls of baseline evaluations. Both treatment-naive and natalizumab scheduled RRMS patients had higher baseline vessel density (22.0 +/- 3.9 and 22.5 +/- 2.6, p < 0.0001) and higher osteopontin levels (65.7 +/- 24.3 ng/ml and 65.9 +/- 16.6 ng/ml, p = 0.019 and p = 0.029, respectively) than HCs (9.0 +/- 2.2; 48.5 +/- 7.8 ng/ml, respectively). Baseline osteopontin levels and vessel density were significantly correlated (rs = 0.373, p = 0.043). After 1 year of treatment, the number of vessels and the osteopontin levels, were significantly reduced (11.9 +/- 2.1, p < 0.005; 49.3 +/- 20.0 ng/ml, p = 0.028). Our results suggest that natalizumab could exert its anti-inflammatory properties also by inhibiting the angiogenetic mechanisms in RRMS patients. PMID- 29441485 TI - Clinical spectrum of C9orf72 expansion in a cohort of Huntington's disease phenocopies. AB - The expansion in the C9orf72 gene has been recently reported as a genetic cause of Huntington's disease (HD) phenocopies. We aim to assess the frequency of the C9orf72 gene expansion in a Portuguese HD phenocopies cohort. Twenty HD phenotype like patients without diagnosis were identified in our institutional database. C9orf72 gene expansion was detected using repeat-primed PCR. Clinical files were reviewed to characterize the phenotype of expansion-positive cases. One patient (5%) was positive for the C9orf72 expansion. A second patient presented 27 repeats-within the intermediate size interval. Both had familial neuropsychiatric disease characterized by diverse movement disorders, dementia, and psychiatric dysfunction that was distinct in severity and clinical expression. C9orf72 disease is clinically heterogeneous and without evident imaging markers. The definition of the role of intermediate alleles and of the pathological threshold for C9orf72 repeat expansions may have diagnostic implications. PMID- 29441484 TI - Real life evaluation of safinamide effectiveness in Parkinson's disease. AB - In this retrospective study, we evaluated both efficacy and effectiveness of safinamide 50 and 100 mg in the treatment of motor fluctuations and disabling dyskinesias in a cohort of patients with idiopathic Parkinson's disease (PD). Ninety-one PD patients were evaluated during the first year of commercialization of the drug, both prior to starting safinamide and at the last available follow up. Evaluations were based on the Unified Parkinson's Disease Scale part III (UPDRS III), Hoehn & Yahr (HY), Unified Dyskinesia Rating Scale (UDysRS) walking and balance item 9 score, daily time spent in OFF and in ON with disabling dyskinesias (1 week diary), mean daily dose of levodopa (LD), dopamine-agonists (DA), catechol-O-methyl transferase inhibitor (COMT-I), monoamine oxidase B inhibitor (MAOB-I), and their LD equivalent dose (LEDD). Eight patients withdrew safinamide within the first month for minor side effects. At the follow-up evaluation, after a mean time with safinamide of 7.5 months +/- 3.4, all patients showed a significant improvement of all the scale scores, except for HY, and of the daily dosages of the drugs and the LEDD. The same results were shown by PD patients treated with safinamide 50 mg and patients who started safinamide without switching from a previous MAOBI. PD patients with safinamide 100 mg and patients who started safinamide switching from a previous MAOBI significantly improved in time spent in OFF and LEDD. In conclusion, safinamide is safe and effective in improving motor complications in patients with idiopathic PD and can be considered a useful levodopa sparing strategy. PMID- 29441486 TI - Dopamine transport system imaging is pathologic in Niemann-Pick type C-case report. PMID- 29441487 TI - Prior antiplatelet therapy is not associated with larger hematoma volume or hematoma growth in intracerebral hemorrhage. AB - Hematoma volume (HV) and hematoma growth (HG) predict mortality and poor outcome in intracerebral hemorrhage (ICH). While the influence of oral anticoagulation on HV, HG and outcome is well established, the effect of prior antiplatelet therapy (APT) remains uncertain. We retrospectively examined data from all patients with acute, primary ICH, and baseline head CT admitted to our department between January 2005 and February 2014. HV were calculated by ABC/2 method. HG was defined as present if HV increased between baseline and follow-up CT >= 30% or >= 6 mL. We analyzed the influence of APT on HV, HG, and in-hospital mortality using univariate and multivariate analyses. In addition, we used propensity score matching to assess differences in in-hospital mortality rates. From 668 screened patients, 343 had primary ICH and fulfilled all inclusion criteria. APT was present in 99 patients (29%). Baseline median HV was 16 mL (IQR 6-46). HG occurred in 44 of 160 patients with follow-up CT (28%). In-hospital mortality was 10% (n = 36). APT was associated with older age, a mRS score before admission (pre-mRS) of > 2, and presence of cardiovascular comorbidities. We did not find an association between APT and larger baseline HV (p = 0.32), or HG (OR 0.8, 95% CI 0.4-1.9). After propensity score matching for age, pre-mRS, gender, and cardiovascular comorbidities, APT was not associated with higher in-hospital mortality (OR 1.90, 95% CI 0.85-4.24, p = 0.117). This study did not show a higher risk for larger HV, HG, or in-hospital mortality in primary ICH patients with APT. PMID- 29441488 TI - Visualization of Rostral Migratory Stream in the Developing Rat Brain by In Vivo Electroporation. AB - Interneurons in the olfactory bulb (OB) are generated from neuronal precursor cells migrating from anterior subventricular zone (SVZa) not only in the developing embryo but also throughout the postnatal life of mammals. In the present study, we established an in vivo electroporation assay to label SVZa cells of rat both at embryonic and postnatal ages, and traced SVZa progenitors and followed their migration pathway and differentiation. We found that labeled cells displayed high motility. Interestingly, the postnatal cells migrated faster than the embryonic cells after applying this assay at different ages of brain development. Furthermore, based on brain slice culture and time-lapse imaging, we analyzed the detail migratory properties of these labeled precursor neurons. Finally, tissue transplantation experiments revealed that cells already migrated in subependymal zone of OB were transplanted back into rostral migratory stream (RMS), and these cells could still migrate out tangentially along RMS to OB. Taken together, these findings provide an in vivo labeling assay to follow and trace migrating cells in the RMS, their maturation and integration into OB neuron network, and unrecognized phenomena that postnatal SVZa progenitor cells with higher motility than embryonic cells, and their migration was affected by extrinsic environments. PMID- 29441489 TI - Pirh2 mediates the sensitivity of myeloma cells to bortezomib via canonical NF kappaB signaling pathway. AB - Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma (MM). While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 (Pirh2) in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor-kappaB (NF-kappaB) p65, pp65, pIKBa, and IKKa were higher in bortezomib resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of pIKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-kappaB p65, pIKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF-kappaB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells. PMID- 29441490 TI - Zika virus outbreak: a review of neurological complications, diagnosis, and treatment options. AB - Zika virus (ZIKV) is an arbovirus transmitted mainly by mosquitos of Aedes species. The virus has emerged in recent years and spread throughout North and South Americas. The recent outbreak of ZIKV started in Brazil (2015) has resulted in infections surpassing a million mark. Contrary to the previous beliefs that Zika causes mildly symptomatic infections fever, headache, rash, arthralgia, and conjunctivitis, the recent outbreak associated ZIKV to serious neurological complications such as microcephaly, Guillain-Barre syndrome, and eye infections. The recent outbreak has resulted in an astonishing number of microcephaly cases in fetus and infants. Consequently, numerous studies were conducted using in vitro cell and in vivo animal models. These studies showed clear links between ZIKV infections and neurological abnormalities. Diagnosis methods based on nucleic acid and serological detection facilitated rapid and accurate identification of ZIKV infections. New transmission modalities such as sexual and transplacental transmission were uncovered. Given the seriousness of ZIKV infections, WHO declared the development of safe and effective vaccines and new antiviral drugs as an urgent global health priority. Rapid work in this direction has led to the identification of several vaccine and antiviral drug candidates. Here, we review the remarkable progress made in understanding the molecular links between ZIKV infections and neurological irregularities, new diagnosis methods, potential targets for antiviral drugs, and the current state of vaccine development. PMID- 29441492 TI - Health System Efficiency: A Fragmented Picture Based on OECD Data. AB - BACKGROUND: Globally, health expenditure as a percentage of GDP has increased in recent years, so evaluating the health care systems used in different countries is an important tool for identifying best practices and improving inefficient health care systems. OBJECTIVE: We investigate health system efficiency at the country level based on OECD health data. We focus on several aspects of health care systems to identify specific inefficiencies within them. This information hints at potential policy interventions that could improve specific parts of a country's health care system. METHODS: A discussion is provided of ideal-typical evaluations of health systems, ignoring data restrictions, which provide the theoretical basis for an analysis performed under factual data restrictions. This investigation includes health care systems in 34 countries and is based on OECD health data. Health care system efficiency scores are obtained using data envelopment analysis (DEA). Relative productivity measures are calculated based on average DEA prices. Given the severe data limitations involved, instead of performing an all-encompassing analysis of each health care system, we focus on several aspects of each system, performing five partial analyses. RESULTS: For each country, the efficiencies yielded by the five partial analyses varied considerably, resulting in an ambiguous picture of the efficiencies of the various health care systems considered. A synopsis providing comprehensive rankings of the analyzed countries is provided. CONCLUSION: Analysis of several aspects of the health care systems considered here highlights potential improvements in specific areas of these systems, thereby providing information for policymakers on where to focus when aiming to improve a country's health care system. PMID- 29441491 TI - In Silico Preliminary Association of Ammonia Metabolism Genes GLS, CPS1, and GLUL with Risk of Alzheimer's Disease, Major Depressive Disorder, and Type 2 Diabetes. AB - Ammonia is a toxic by-product of protein catabolism and is involved in changes in glutamate metabolism. Therefore, ammonia metabolism genes may link a range of diseases involving glutamate signaling such as Alzheimer's disease (AD), major depressive disorder (MDD), and type 2 diabetes (T2D). We analyzed data from a National Institute on Aging study with a family-based design to determine if 45 single nucleotide polymorphisms (SNPs) in glutaminase (GLS), carbamoyl phosphate synthetase 1 (CPS1), or glutamate-ammonia ligase (GLUL) genes were associated with AD, MDD, or T2D using PLINK software. HAPLOVIEW software was used to calculate linkage disequilibrium measures for the SNPs. Next, we analyzed the associated variations for potential effects on transcriptional control sites to identify possible functional effects of the SNPs. Of the SNPs that passed the quality control tests, four SNPs in the GLS gene were significantly associated with AD, two SNPs in the GLS gene were associated with T2D, and one SNP in the GLUL gene and three SNPs in the CPS1 gene were associated with MDD before Bonferroni correction. The in silico bioinformatic analysis suggested probable functional roles for six associated SNPs. Glutamate signaling pathways have been implicated in all these diseases, and other studies have detected similar brain pathologies such as cortical thinning in AD, MDD, and T2D. Taken together, these data potentially link GLS with AD, GLS with T2D, and CPS1 and GLUL with MDD and stimulate the generation of testable hypotheses that may help explain the molecular basis of pathologies shared by these disorders. PMID- 29441494 TI - Cost-Minimisation Analysis of Erythropoiesis-Stimulating Agents in the Treatment of Anaemia in Dialysed Patients: A Pilot Study. AB - OBJECTIVE: This study aimed to assess the cost impact of administering erythropoiesis-stimulating agents once every 4 weeks instead of one to three times a week to treat anaemia in patients undergoing dialysis. METHODS: This was a monocentric retrospective study involving 27 patients who underwent haemodialysis between 2009 and 2013 in a university hospital in Angers, France. The study was a cost-minimisation analysis from the hospital perspective. Only direct medical costs were considered. RESULTS: This study demonstrated that therapeutic management of anaemia with methoxy polyethylene glycol-epoetin beta would save medical and nurse time (7 days and 15 days per year, respectively) and reduce costs by ?59,960 a year for an active file of 40 patients undergoing haemodialysis, assuming a 100% occupancy rate in the above-mentioned hospital. CONCLUSION: This study indicated that treating anaemia by administering erythropoiesis-stimulating agents once every 4 weeks instead of one to three times a week in patients undergoing haemodialysis would be beneficial for the hospital. PMID- 29441495 TI - Evaluating the Treatment Costs for Uncomplicated Malaria at a Public Healthcare Facility in Nigeria and the Implications. AB - BACKGROUND: Accurate information on the facility costs of treatment is essential to enhance decision making and funding for malaria control. OBJECTIVE: The objective of this study was to estimate the costs of providing treatment for uncomplicated malaria through a public health facility in Nigeria. METHODS: Hospital costs were estimated from a provider perspective, applying a standard costing procedure. Capital and recurrent expenditures were estimated using an ingredient approach combined with step-down methodology. Costs attributable to malaria treatment were calculated based on the proportion of malaria cases to total outpatient visits. The costs were calculated in local currency [Naira (N)] and converted to US dollars at the 2013 exchange rate. RESULTS: Total annual costs of N28.723 million (US$182,953.65) were spent by the facility on the treatment of uncomplicated malaria, at a rate of US$31.49 per case, representing approximately 25% of the hospital's total expenditure in the study year. Personnel accounted for over 82.5% of total expenditure, followed by antimalarial medicines at 6.6%. More than 45% of outpatients visits were for uncomplicated malaria. Changes in personnel costs, drug prices and malaria prevalence significantly impacted on the study results, indicating the need for improved efficiency in the use of hospital resources. CONCLUSION: Malaria treatment currently consumes a considerable amount of resources in the facility, driven mainly by personnel cost and a high proportion of malaria cases. There is scope for enhanced efficiency to prevent waste and reduce costs to the provider and ultimately the consumer. PMID- 29441496 TI - Differences in Incremental Cost-Effectiveness Ratios for Common Versus Rare Conditions: A Case from Oncology. AB - BACKGROUND: Incremental cost-effectiveness ratios (ICERs) are used to assess the value for money of new drugs. Many believe that ICERs for drugs that treat rare diseases are much higher than those of common drugs. Our objective was to compare the proportion of ICERs that are cost effective for rare and common cancers. METHODS: We used the Tufts Medical Center Cost-Effectiveness Analysis (CEA) Registry to identify cost-effectiveness studies of pharmaceutical interventions for cancers. Studies that assessed FDA-approved 'orphan drugs' were categorized as assessing rare cancers. The proportion of common and rare cancer drugs that were cost effective at various ICER thresholds were compared along with study characteristics. Logistic regressions were conducted to assess important predictors of cost effectiveness. RESULTS: We identified 303 studies that reported 701 ICERs. Seventy nine percent (n = 240) of studies evaluated drugs for common cancers. At a threshold of US$50,000/QALY, 58% (n = 321) of ICERs for drugs treating common cancers and 64% (n = 94) of ICERs for drugs treating rare cancers were cost effective (p = 0.23). At US$100,000/QALY, 74% (n = 409) of ICERs for common cancers and 78% (n = 115) of ICERs for rare cancers were cost effective (p = 0.35). Results from the logistic regressions demonstrated that rarity was not a statistically significant predictor of cost effectiveness at both thresholds with publication year, study sponsorship, and cancer type as covariates. CONCLUSIONS: The proportion of ICERs that were cost effective at both thresholds does not appear to be significantly different between the two groups. Rarity is not statistically significantly associated with cost effectiveness, even when adjusted for important covariates. PMID- 29441493 TI - Model-Based Economic Evaluation of Treatments for Depression: A Systematic Literature Review. AB - BACKGROUND: An increasing number of model-based studies that evaluate the cost effectiveness of treatments for depression are being published. These studies have different characteristics and use different simulation methods. OBJECTIVE: We aimed to systematically review model-based studies evaluating the cost effectiveness of treatments for depression and examine which modelling technique is most appropriate for simulating the natural course of depression. METHODS: The literature search was conducted in the databases PubMed, EMBASE and PsycInfo between 1 January 2002 and 1 October 2016. Studies were eligible if they used a health economic model with quality-adjusted life-years or disability-adjusted life-years as an outcome measure. Data related to various methodological characteristics were extracted from the included studies. The available modelling techniques were evaluated based on 11 predefined criteria. RESULTS: This methodological review included 41 model-based studies, of which 21 used decision trees (DTs), 15 used cohort-based state-transition Markov models (CMMs), two used individual-based state-transition models (ISMs), and three used discrete-event simulation (DES) models. Just over half of the studies (54%) evaluated antidepressants compared with a control condition. The data sources, time horizons, cycle lengths, perspectives adopted and number of health states/events all varied widely between the included studies. DTs scored positively in four of the 11 criteria, CMMs in five, ISMs in six, and DES models in seven. CONCLUSION: There were substantial methodological differences between the studies. Since the individual history of each patient is important for the prognosis of depression, DES and ISM simulation methods may be more appropriate than the others for a pragmatic representation of the course of depression. However, direct comparisons between the available modelling techniques are necessary to yield firm conclusions. PMID- 29441497 TI - Cost-Effectiveness of Haemorrhoidal Artery Ligation versus Rubber Band Ligation for the Treatment of Grade II-III Haemorrhoids: Analysis Using Evidence from the HubBLe Trial. AB - AIM: Haemorrhoids are a common condition, with nearly 30,000 procedures carried out in England in 2014/15, and result in a significant quality-of-life burden to patients and a financial burden to the healthcare system. This study examined the cost effectiveness of haemorrhoidal artery ligation (HAL) compared with rubber band ligation (RBL) in the treatment of grade II-III haemorrhoids. METHOD: This analyses used data from the HubBLe study, a multicentre, open-label, parallel group, randomised controlled trial conducted in 17 acute UK hospitals between September 2012 and August 2015. A full economic evaluation, including long-term cost effectiveness, was conducted from the UK National Health Service (NHS) perspective. Main outcomes included healthcare costs, quality-adjusted life-years (QALYs) and recurrence. Cost-effectiveness results were presented in terms of incremental cost per QALY gained and cost per recurrence avoided. Extrapolation analysis for 3 years beyond the trial follow-up, two subgroup analyses (by grade of haemorrhoids and recurrence following RBL at baseline), and various sensitivity analyses were undertaken. RESULTS: In the primary base-case within trial analysis, the incremental total mean cost per patient for HAL compared with RBL was L1027 (95% confidence interval [CI] L782-L1272, p < 0.001). The incremental QALYs were 0.01 QALYs (95% CI -0.02 to 0.04, p = 0.49). This generated an incremental cost-effectiveness ratio (ICER) of L104,427 per QALY. In the extrapolation analysis, the estimated probabilistic ICER was L21,798 per QALY. Results from all subgroup and sensitivity analyses did not materially change the base-case result. CONCLUSIONS: Under all assessed scenarios, the HAL procedure was not cost effective compared with RBL for the treatment of grade II III haemorrhoids at a cost-effectiveness threshold of L20,000 per QALY; therefore, economically, its use in the NHS should be questioned. PMID- 29441498 TI - Cost of Illness of Japanese Patients with Chronic Lymphocytic Leukemia (CLL), and Budget Impact of the Market Introduction of Ibrutinib. AB - BACKGROUND: Ibrutinib was introduced in Japan in 2016 as a new oral treatment option for patients with relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). There is increasing interest from the Japanese government to assess economic aspects of new medical interventions, especially in the area of oncology. OBJECTIVE: We describe the treatment patterns of Japanese patients with CLL, estimate the cost of the disease from a health insurance perspective, and predict the budget impact of the introduction of ibrutinib. METHODS: A budget impact model was set up and populated with data that were collected from a survey of Japanese hematologists (n = 202) and official statistics. Uncertainty was addressed by one-way sensitivity analysis of several model parameters. RESULTS: Among the 2000 Japanese CLL patients, 42.2% have not yet commenced medical treatment, 29.1% were on a treatment break, and 26.8% received medical treatment, mainly rituximab in combination with either fludarabine or bendamustine. Among the patients under medical treatment, 65.7% were receiving first-line treatment and 34.3% were receiving second-line or later treatment. In Japan, the estimated burden of illness for 2015 was Y1563 million for RR CLL and Y5471 million for overall CLL. The expected average budget impact of introducing ibrutinib is Y3077 million per year for the next 5 years. CONCLUSION: Due to low disease prevalence, the burden of illness in Japan is low compared with Western countries. PMID- 29441499 TI - Can Price Transparency Contribute to More Affordable Patient Access to Medicines? PMID- 29441500 TI - The Epidemiology of Clostridium difficile Infection in Japan: A Systematic Review. AB - : To increase understanding of the epidemiology, risks, consequences and resource utilization of Clostridium difficile infection (CDI) in Japan, a systematic literature review was undertaken of relevant publications from January 2006 to November 2017. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and methods, 55 articles met the criteria for full review. The majority (58%) of studies were from a single site, with the most recent data from 2015. The incidence, reported prevalence and recurrence rate of CDI in Japan were 0.8-4.71/10,000 patient-days, 0.3-5.5/1000 patients and 3.3 27.3%, respectively, and varied according to setting, population, CDI definition and detection method. Most C. difficile isolates associated with CDI in Japan were toxin A+B+, with a low level of C. difficile binary toxin-positive (CDT+) strains (0-6.8% reported across studies). The most common C. difficile PCR ribotypes associated with infection in Japan were smz/018, 002, 052 and 369. Data regarding the impact of CDI on length of hospital stay were limited. Reported all cause mortality in patients with CDI ranged from 3.4 to 15.1% between 2007 and 2013. Two studies assessed risk factors for CDI recurrence, identifying malignant disease, intensive care unit hospitalization and use of proton pump inhibitors as factors increasing the risk of initial and/or recurrent CDI. No study analyzed initial CDI treatment in relation to recurrence. More comprehensive surveillance and coordinated studies are needed to map trends, understand risk factors, and recognize the extent and impact of CDI in Japanese patients. FUNDING: Astellas Pharma, Inc. Plain language summary available for this article. PMID- 29441501 TI - Choosing Between Unicompartmental and Total Knee Replacement: What Can Economic Evaluations Tell Us? A Systematic Review. AB - BACKGROUND AND OBJECTIVE: Patients with anteromedial arthritis who require a knee replacement could receive either a unicompartmental knee replacement (UKR) or a total knee replacement (TKR). This review has been undertaken to identify economic evaluations comparing UKR and TKR, evaluate the approaches that were taken in the studies, assess the quality of reporting of these evaluations, and consider what they can tell us about the relative value for money of the procedures. METHODS: A search of MEDLINE, EMBASE and the Centre for Reviews and Dissemination National Health Service Economic Evaluation Database was undertaken in January 2016 to identify relevant studies. Study characteristics were described, the quality of reporting and methods assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist, and study findings summarised. RESULTS: Twelve studies satisfied the inclusion criteria. Five were within-study analyses, while another was based on a literature review. The remaining six studies were model-based analyses. All studies were informed by observational data. While methodological approaches varied, studies generally had either limited follow-up, did not fully account for baseline differences in patient characteristics or relied on previous research that did not. The quality of reporting was generally adequate across studies, except for considerations of the settings to which evaluations applied and the generalisability of the results to other decision-making contexts. In the short-term, UKR was generally associated with better health outcomes and lower costs than TKR. Initial cost savings associated with UKR seem to persist over patients' lifetimes even after accounting for higher rates of revision. For older patients, initial health improvements also appear to be maintained, making UKR the dominant treatment choice. However, for younger patients findings for health outcomes and overall cost effectiveness are mixed, with the difference in health outcomes depending on the lifetime risk of revision and patient outcomes following revision. CONCLUSIONS: UKR appears to be less costly than TKR. For older patients, UKR is also expected to lead to better health outcomes, making it the dominant choice; however, for younger patients health outcomes are more uncertain. Future research should better account for baseline differences in patient characteristics and consider how the relative value of UKR and TKR varies depending on patient and surgical factors. PMID- 29441502 TI - Methodological Issues in Economic Evaluations Submitted to the Pan-Canadian Oncology Drug Review (pCODR). AB - BACKGROUND: Public drug plans are faced with increasingly difficult funding decisions. In Canada, the pan-Canadian Oncology Drug Review (pCODR) makes funding recommendations to the provincial and territorial drug plans responsible for cancer drugs. Assessments of the economic models submitted by pharmaceutical manufacturers are publicly reported. OBJECTIVES: The main objective of this research was to identify recurring methodological issues in economic models submitted to pCODR for funding reviews. The secondary objective was to explore whether there exists any observed relationships between reported methodological issues and funding recommendations made by pCODR's expert review committee. METHODS: Publicly available Economic Guidance Reports from July 2011 (inception) until June 2014 for drug reviews with a final funding recommendation (N = 34) were independently examined by two authors. Major methodological issues from each review were abstracted and grouped into nine main categories. Each issue was also categorized based on perception of the reviewer's actions to manage it. RESULTS: The most commonly reported issues involved costing (59% of reviews), time horizon (56%), and model structure (36%). Several types of issues were identified that usually could not be resolved, such as quality of clinical data or uncertainty with indirect comparisons. Issues with costing or choice of utility estimates could usually be addressed or explored by reviewers. No statistically significant relationship was found between any methodological issue and funding recommendations from the expert review committee. CONCLUSIONS: The findings provide insights that can be used by parties who submit or review economic evidence for continuous improvement and consistency in economic modeling, reporting, and decision making. PMID- 29441503 TI - Utilization of Intergovernmental Funds to Implement Maternal and Child Health Plans of a Multi-Strategy Community Intervention in Haryana, North India: A Retrospective Assessment. AB - INTRODUCTION: A multi-strategy community intervention known as the National Rural Health Mission (NRHM) was implemented in India from 2005 to 2012 in an attempt to reduce maternal and child mortality. OBJECTIVE: This study examined the extent to which the NRHM's maternal and child health (MCH) sector plans were implemented. We observed trends in how intergovernmental (use of central government funds by state governments) budgets were allocated and used to implement MCH plans in Haryana, India. METHODS: We conducted a retrospective assessment of programme implementation plans, MCH budget allocation and expenditure and financial monitoring reports during the NRHM implementation period. The yearly budget utilization rate was calculated for each MCH strategy implemented. On the basis of this budget utilization rate, we classed the extent of MCH strategy implementation as fully, partially or not implemented. The status of MCH indicators before, during and after the NRHM period was obtained from national demographic surveys. The budget utilization rate was correlated with MCH outcomes. RESULTS: The overall budget allocated for MCH plans increased from $US6.6 million during the 2005-2006 period to $US66.7 million in the 2012-2013 period. The rate of budget utilization increased from 20.6% in 2007-2008 to 89% in 2012-2013. Expenditure exceeded the initially allocated budget for patient referral services (111.5%), human resources (110.1%), drugs and logistics (170%), accredited social health activists (133.3%) and immunization (106.4%). Additional budget was obtained from the state health budget. Plans for referral services, human resources, drug provision, accredited social health activists and immunization were fully implemented, few schemes (<1%) were not implemented, and all other schemes were only partially implemented. MCH indicators improved significantly (p < 0.05). The rate of institutional childbirth was highly and positively correlated with rates of budget utilization for implementing accredited social health activists (r = 0.96) and financial incentives for hospital delivery schemes (r = 0.5). CONCLUSIONS: The trend for increasing use of the allocated budget for MCH strategies, improvement in MCH indicators and their positive correlation indicate better and more effective implementation of NRHM MCH strategies than in the past in Haryana, India. However, overall, the NRHM was only partially implemented. PMID- 29441504 TI - Statistical Alchemy: Conceptual Validity and Mapping to Generate Health State Utility Values. AB - Mapping between non-preference- and preference-based health-related quality-of life instruments has become a common technique for estimating health state utility values for use in economic evaluations. Despite the increased use of mapped health state utility estimates in health technology assessment and economic evaluation, the methods for deriving them have not been fully justified. Recent guidelines aim to standardise reporting of the methods used to map between instruments but do not address fundamental concerns in the underlying conceptual model. Current mapping methods ignore the important conceptual issues that arise when extrapolating results from potentially unrelated measures. At the crux of the mapping problem is a question of validity; because one instrument can be used to predict the scores on another, does this mean that the same preference for health is being measured in actual and estimated health state utility values? We refer to this as conceptual validity. This paper aims to (1) explain the idea of conceptual validity in mapping and its implications; (2) consider the consequences of poor conceptual validity when mapping for decision making in the context of healthcare resource allocation; and (3) offer some preliminary suggestions for improving conceptual validity in mapping. PMID- 29441505 TI - Eliciting the Monetary Value of a Quality-Adjusted Life Year in a Greek Outpatient Department in Times of Economic Austerity. AB - BACKGROUND AND OBJECTIVE: Contingent valuation is widely used to determine individuals' willingness to pay (WTP) for a health gain. Our study aimed to elicit an empirical estimate of the monetary value of a quality-adjusted life year (QALY) in a Greek outpatient setting in times of economic austerity and assess the impact of patients' characteristics on their valuations. METHODS: We used a questionnaire as a survey tool to determine the maximum WTP for a health gain of a hypothetical therapy and to evaluate patients' health-related quality of life (EuroQoL-5D-3L) and demographic and socioeconomic characteristics. EuroQoL tariffs were used to estimate health utilities. Mean WTP values were computed and ordinary least squares regressions performed on transformed Box-Cox and logarithmic dependent WTP per QALY variables to remedy observed skewness problems. RESULTS: Analyses were performed for 167 patients with utility values less than unity. Mean WTP per QALY reported was similar for both payment vehicles examined: payments made out-of-pocket (?2629) and payments made through new tax imposition (?2407). Regression results showed that higher net monthly family income was associated with higher WTP per QALY for both payment vehicles. Moreover, the presence of a chronic condition and higher level of education were associated with higher out-of-pocket WTP per QALY and WTP per QALY through taxes, respectively. CONCLUSION: The very low WTP per QALY estimates could be explained by the recent severe economic depression and austerity in Greece. In fact, family income was found to be a significant predictor of WTP per QALY. Since these estimates deviate significantly from the cost-effectiveness thresholds still employed in economic evaluations in this country, research should be undertaken promptly to further examine this important issue using a nationwide representative sample of the general population along with WTP and other methodologies. PMID- 29441507 TI - Economic Evaluation of Fulvestrant 500 mg Compared to Generic Aromatase Inhibitors in Patients with Advanced Breast Cancer in Sweden. AB - OBJECTIVES: In Sweden, breast cancer (BC) represents 30% of newly diagnosed cancers and is the most common cancer in women. For hormone-dependent BC, endocrine therapies varying in efficacy and price are available. The aim of this study is to assess the cost effectiveness of fulvestrant 500 mg as a second-line hormonal therapy for postmenopausal women with estrogen receptor-positive metastatic or locally advanced BC versus letrozole, anastrozole, and exemestane in Sweden. METHODS: A three-state (pre-progression, post-progression, and death) partitioned-survival model was used to estimate progression-free (PFS) and overall survival (OS) by extrapolating trial results beyond the trial period to capture costs and benefits over a lifetime perspective. The comparative effectiveness was sourced from a network meta-analysis. The evaluation was conducted from a Swedish national payer perspective; costs, resource use, and quality of life were based on published sources and expert opinion. RESULTS: Compared to anastrozole, letrozole, and exemestane the incremental cost effectiveness ratios (ICERs) were ?33,808, ?33,883, and ?49,225 per QALY with incremental costs of ?13,283, ?14,986, and ?13,862, and incremental QALYs of 0.393, 0.442, and 0.282, respectively. Incremental cost per life-year (LY) gained ?21,312 (incremental LY of 0.623), ?20,338 (incremental LY of 0.737), and ?27,854 (incremental LY of 0.498) for respective comparators. Applying the upper and lower credible intervals for PFS/OS from the meta-analysis had the greatest effect on the ICER in the sensitivity analysis. The results were relatively stable when varying other parameters. CONCLUSIONS: Our results indicate that fulvestrant 500 mg may be a cost-effective alternative to aromatase inhibitors at a threshold of ?100,000/QALY. PMID- 29441506 TI - Development of a Procedure for the Government Provision of Bone-Anchored Prosthesis Using Osseointegration in Australia. AB - BACKGROUND: Governmental organizations are facing challenges in adjusting procedures providing equitable assistance to consumers with amputation choosing newly available osseointegrated fixations for bone-anchored prostheses (BAPs) over socket-suspended prostheses. OBJECTIVES: The aims of this study were to (1) present a procedure focusing on tasks, documents and costs of prosthetic care, and (2) share observed obstacles and facilitators to implementation. METHODS: This research aimed at developing a governmental procedure for the provision of BAPs was designed as an action research study. A total of 18 individuals with transfemoral amputation solely funded by a Queensland State organization were considered. RESULTS: The procedure, developed between January 2011 and June 2015, included seven processes involving fixed expenses during treatment and five processes regulating ongoing prosthetic care expenses. Prosthetic care required 22 h of labor, corresponding to AUD$3300 per patient, during rehabilitation. Prosthetists spend 64 and 36% of their time focusing on prosthetic care and other activities, respectively. The procedure required adjustments related to the scope of practice of prosthetists, funding of prosthetic limbs during rehabilitation, and allocation of microprocessor-controlled prosthetic knees. Approximately 41% (7) and 59% (10) of obstacles were within (e.g. streamlining systematic processes, sustaining evaluation of this complex procedure) or outside (e.g. early and consistent consultations of stakeholders, lack of a definitive rehabilitation program) governmental control, respectively, and approximately 89% (17) of the facilitators were within governmental control (e.g. adapting existing processes). CONCLUSION: This study provides a working plan to stakeholders developing and implementing policies around the care of individuals choosing osseointegration for BAPs. PMID- 29441510 TI - Translating the combination of gene therapy and tissue engineering for treating recessive dystrophic epidermolysis bullosa. AB - The combination of gene therapy and tissue engineering is one of the most promising strategies for the treatment of recessive dystrophic epidermolysis bullosa (RDEB). RDEB is a rare genetic disease characterised by mutations in the COL7A1 gene, encoding type VII collagen (COLVII), which forms anchoring fibrils at the dermal-epidermal junction of the skin. This disease causes severe blistering and only palliative treatments are offered. In this study, the base of a strategy combining gene therapy and a tissue-engineered skin substitute (TES), which would be suitable for the permanent closure of skin wounds, was set-up. As a high transduction efficiency into fibroblasts and/or keratinocytes seems to be a prerequisite for a robust and sustained correction of RDEB, different envelope pseudotyped retroviral vectors and the transduction enhancer EF-C were tested. When green fluorescent protein (GFP) was used as a reporter gene to evaluate the retroviral-mediated gene transfer, the fibroblast infection efficiency was 30 % higher with the Ampho pseudotyped vector as compared with the other pseudotypes. At least a 3.1-fold and a 1.3-fold increased transduction were obtained in fibroblasts and keratinocytes, respectively, with EF-C as compared with polybrene. A continuous and intense deposit of haemagglutinin (HA)-COLVII was observed at the dermal-epidermal junction of self-assembled TESs made of cells transduced with a HA-tagged COL7A1 vector. Furthermore, HA-tagged basal epidermal cells expressing keratin 19 were observed in TESs, suggesting stem cell transduction. This approach could be a valuable therapeutic option to further develop, in order to improve the long-term life quality of RDEB patients. PMID- 29441509 TI - NRF2, DJ1 and SNRX1 and their prognostic impact in astrocytic gliomas. AB - Nuclear factor erythroid 2-related factor 2 (NRF2), DJ1 and sulfiredoxin 1 (SRXN1) are transcription factors which protect cells from the oxidative damage caused by reactive oxygen species and, on the other hand, are associated with resistance to cancer treatments. The immunohistochemical expression of NRF2, DJ1 and SRNX1 was assessed in human grade II-IV astrocytic gliomas. Their association to clinicopathologic and essential molecular factors was evaluated. The RNA expression levels and genetic alterations were analyzed from publicly available datasets. All studied molecules were commonly expressed. The cytoplasmic NRF2 expression was higher in tumors with a higher malignancy grade, whereas the nuclear and cytoplasmic DJ1 expression was associated with a lower grade. The presence of the isocitrate dehyrdogenase 1 mutation (IDH1) was associated with an increasing cytoplasmic and nuclear expression of NRF2 and a nuclear DJ1 expression. When primary grade IV astrocytomas were compared to secondary glioblastomas, nuclear DJ1 was associated with secondary tumors. In grade II-IV tumors, the cytoplasmic NRF2 expression was associated with a poor prognosis, whereas nuclear NRF2 and both cytoplasmic and nuclear DJ1 were associated with a better patient prognosis. Recurrent homozygous deletions of DJ1 were observed, especially in the IDH wild-type samples. When only the glioblastomas were evaluated, nuclear NRF2 and SRNX1 predicted better survival. As a conclusion, NRF2, DJ1 and SNXR1 can be used as prognosticators in gliomas. PMID- 29441511 TI - [Cardiology telemedicine solutions - opinion of the experts of the Committee of Informatics and Telemedicine of Polish Society of Cardiology, Section of Non invasive Electrocardiology and Telemedicine of Polish Society of Cardiology and Clinical Sciences C]. AB - For several years, we have observed the dynamic development of technologies that allow patients to access medical care from the comfort of their homes, without direct contact with the doctor. Innovative solutions based on telemedicine improve care coordination and communication among clinicians, patients, and their families, as well as increases patients' security and gives them greater independence, thus eliminating health care inequalities. The rapidly growth of telemedicine and the adoption of new technologies in clinical practice is also observed in Poland. Crucial moment for the telemedicine facilitation process in our country was Baltic Declaration approved by Minister of Health in 2015, as well as the Medical Profession Amendment Act and remote medical care admission. Since then, as part of the work of the Information Technology and Telemedicine Committee of the Polish Cardiac Society and the Telemedical Working Group, important steps have been taken to implement a telemedicine solutions in the Polish healthcare system, resulting in improved quality and efficiency of this system. The presented document reflects the above actions and encompasses following issues: available telemedicine solutions in the world, analysis of their effectiveness based on clinical trials, funding opportunities, legal status and development prospects telecardiology in Poland. PMID- 29441512 TI - [Left atrial appendage occlusion: consensus document of Association of Cardiovascular Interventions and Heart Rhythm Section of Polish Cardiac Society]. AB - Left atrial appendage (LAA) occlusion devices have the potential to influence the clinical approach to stroke prevention in patients with atrial fibrillation. A number of percutaneous techniques have been proposed, including various intracardiac plugs and also external ligation. Several devices have been already used in Poland. One of them has been evaluated in randomised controlled trials compared with the current standard of care. Others are less well studied but quite commonly used in Eu-rope. It is anticipated that the use of LAA occlusion technologies in clinical practice will expand. This Consensus Document prepared jointly by Association of Cardiovascular Interventions (AISN) and Heart Rhythm Section (HRS) of Polish Cardiac Society seeks to highlight the critical issues surrounding LAA occlusion therapies and to facilitate the alignment of multiple interests, including those of primary care physicians, general cardiologists and procedural specialists (electrophysiologists and interventional cardiologists) but also other medical professionals. The article summarises current evidence and provides spe-cific recommendations on organisation and conduct of LAA therapy in patients with atrial fibrillation in Poland and defines also operator and institutional requirements fundamental to the establishment of successful LAA occlusion programmme. PMID- 29441513 TI - Evaluation of indications for reduced-dose non-vitamin K antagonist oral anticoagulants in hospitalised patients with atrial fibrillation. AB - BACKGROUND: Prevention of thromboembolic complications is a priority in patients with atrial fibrillation (AF). The use of non-vitamin K antagonist oral anticoagulants (NOACs) is more common and some patients have indications for a reduced dose. AIM: We sought to evaluate the frequency of NOACs being prescribed to AF patients and to compare the groups of AF patients receiving standard and reduced doses. METHODS: The study included 1327 patients diagnosed with AF and hospitalised at an institution of the highest referral level in cardiology in the years 2015-2016. Final analysis encompassed 713 patients with nonvalvular AF, who were prescribed NOACs upon discharge. RESULTS: In the group of patients receiving NOACs, standard doses were used in 383 (53.7%) patients, while 330 (46.3%) patients received reduced doses. Among patients treated with reduced doses, dabigatran was prescribed to 186 (56.4%) patients, rivaroxaban to 124 (37.5%) patients, and apixaban to 20 (6.1%) patients. Absence of indications for dose reduction was identified in 54 out of 330 (16.4%) patients receiving reduced-dose NOACs, including six out of 20 patients receiving reduced-dose apixaban (30%), 21 out of 186 patients receiving reduced-dose dabigatran (11.3%), and 24 out of 124 pa-tients receiving reduced-dose rivaroxaban (19.3%). Among patients treated with reduced dose of dabigatran (n = 186), one indication for dose reduction was observed in 75 patients, and at least two indications were observed in 90 patients. One indication was observed in 71 patients, and at least two indications were observed in 30 patients treated with a reduced dose of rivaroxaban (n = 124). CONCLUSIONS: Standard doses of NOACs were prescribed to most hospitalised AF patients. Apixaban was prescribed more frequently in the reduced-dose regimen, while the frequencies of standard and reduced doses prescribed were similar for dabigatran and rivaroxaban. Absence of indications for dose reduction as defined in relevant guidelines and Summaries of Product Characteristics was identified in 15.5% of patients receiving reduced doses of NOACs. More than one indication for dose reduction was identified in most patients receiving reduced-dose dabigatran, while one indication was identified in most patients receiving reduced-dose rivaroxaban. PMID- 29441514 TI - Treating postoperative pain in the patient who is in recovery or remission from opioid abuse: Focus on Tapentadol. PMID- 29441515 TI - Can 28-day prescription prevent unintentional medication surplus with 30-day prescription? PMID- 29441516 TI - Detection of naltrexone and naltrexol in patients prescribed Embeda(r). PMID- 29441517 TI - Association Between Knee Pain, Impaired Function, and Development of Depressive Symptoms. AB - OBJECTIVES: To examine the association between knee pain and function and depressive symptoms in older Japanese adults. DESIGN: Community-based prospective cohort study. SETTING: Kurabuchi Town, Gumma Prefecture, Japan. PARTICIPANTS: Individuals aged 65 and older (N = 573; n = 260 men, n = 313 women) without depressive symptoms participated in baseline examinations in 2005 and 2006; 95.6% participated in follow-up interviews (2007-08). MEASUREMENTS: Degree of knee pain and functional impairment was assessed at baseline using a self-administered questionnaire in Japanese based on an English version of the Western Ontario and McMaster Universities Osteoarthritis Index. The Geriatric Depression Scale was used to identify depressive symptoms in face-to-face home-visit interviews conducted 2 years later, and the association between knee pain and functional impairment and depressive symptoms was assessed using logistic regression. RESULTS: During the 2-year follow-up, 11.9% of participants developed depressive symptoms, and pain and functional impairment were found to be associated with development of these symptoms. Pain at night while in bed (adjusted odds ratio (aOR) = 2.6, 95% confidence interval (CI) = 1.4-4.9) and difficulty putting on socks (aOR = 3.7, 95% CI: 1.8-7.5), getting into and out of a car (aOR = 3.4, 95% CI = 1.8-6.5), and taking off socks (aOR = 3.1, 95% CI = 1.5-6.5) were found to be most strongly associated with development of depressive symptoms. CONCLUSION: Examining elderly people's responses to questions about pain at night and difficulties performing daily activities may be an efficient way of identifying those at high risk of developing depressive symptoms. PMID- 29441518 TI - Haloperidol for delirium in critically ill patients - protocol for a systematic review. AB - BACKGROUND: In the intensive care unit, the prevalence of delirium is high. Delirium has been associated with morbidity and mortality including more ventilator days, longer intensive care unit stay, increased long-term mortality, and cognitive impairment. Thus, the burden of delirium for patients, relatives, and societies is considerable. The objective of this systematic review was to critically access the evidence of randomised clinical trials on the effects of haloperidol vs. placebo or any other agents for delirium in critically ill patients. METHODS: We will search for randomised clinical trials in the following databases: Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cumulative Index to Nursing and Allied Health Literature, Latin American and Caribbean Health Sciences Literature, and Allied and Complementary Medicine Database. Two authors will independently screen and select references for inclusion using Covidence, extract data and assess the methodological quality of the included randomised clinical trials using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will analyse the extracted data using Review Manager, STATA 15, and Trial Sequential. ANALYSIS: The aim of this study was to assess the quality of the evidence, we will create a 'Summary of Findings' table containing our primary and secondary outcomes using the GRADE assessment. DISCUSSION: Our ambition with this systematic review is to provide reliable and powered evidence to better inform decision makers on the use of or future trials with haloperidol for the management of delirium in critically ill patients. PMID- 29441519 TI - Trajectory analysis of anxiolytic dispensing over 10 years among new users aged 50 and older. AB - OBJECTIVE: To identify temporal trajectories of anxiolytic benzodiazepine (A-BZD) use over 10 years among new A-BZD users aged 50 and older and describe treatment patterns and demographic and clinical characteristics associated with each trajectory. METHOD: A representative cohort of the French national health insurance fund users was tracked from 2006 through 2015. We used latent class mixed models to identify the trajectories. RESULTS: We observed four trajectories among new users (no A-BZD dispensing in 2005) plus one non-use trajectory. The proportion of occasional use among users was 60%; early increasing use, 10%; late increasing use, 17%; and increasing/decreasing use, 13%. Prevalence of occasional use decreased with age in women, but not men. Duration of treatment episodes and doses differed between trajectories. Multiple regression analyses with occasional use as the reference showed that the other three trajectories shared characteristics (age, coprescriptions of other psychotropic drugs, and more general practitioner consultations) but differed by the presence at inclusion or occurrence during follow-up of psychiatric, neurodegenerative, and somatic conditions. CONCLUSION: We found four different long-term temporal trajectories in new A-BZD users (occasional, early increasing, late increasing, and increasing/decreasing use). Difficulties quitting or reducing consumption may be very different for each trajectory, requiring tailored care approaches. PMID- 29441520 TI - Methods for multivariate recurrent event data with measurement error and informative censoring. AB - In multivariate recurrent event data regression, observation of recurrent events is usually terminated by other events that are associated with the recurrent event processes, resulting in informative censoring. Additionally, some covariates could be measured with errors. In some applications, an instrumental variable is observed in a subsample, namely a calibration sample, which can be applied for bias correction. In this article, we develop two non-parametric correction approaches to simultaneously correct for the informative censoring and measurement errors in the analysis of multivariate recurrent event data. A shared frailty model is adopted to characterize the informative censoring and dependence among different types of recurrent events. To adjust for measurement errors, a non-parametric correction method using the calibration sample only is proposed. In the second approach, the information from the whole cohort is incorporated by the generalized method of moments. The proposed methods do not require the Poisson-type assumption for the multivariate recurrent event process and the distributional assumption for the frailty. Moreover, we do not need to impose any distributional assumption on the underlying covariates and measurement error. Both methods perform well, but the second approach improves efficiency. The proposed methods are applied to the Nutritional Prevention of Cancer trial to assess the effect of selenium treatment on the recurrences of basal cell carcinoma and squamous cell carcinoma. PMID- 29441521 TI - An alternative robust estimator of average treatment effect in causal inference. AB - The problem of estimating the average treatment effects is important when evaluating the effectiveness of medical treatments or social intervention policies. Most of the existing methods for estimating the average treatment effect rely on some parametric assumptions about the propensity score model or the outcome regression model one way or the other. In reality, both models are prone to misspecification, which can have undue influence on the estimated average treatment effect. We propose an alternative robust approach to estimating the average treatment effect based on observational data in the challenging situation when neither a plausible parametric outcome model nor a reliable parametric propensity score model is available. Our estimator can be considered as a robust extension of the popular class of propensity score weighted estimators. This approach has the advantage of being robust, flexible, data adaptive, and it can handle many covariates simultaneously. Adopting a dimension reduction approach, we estimate the propensity score weights semiparametrically by using a non-parametric link function to relate the treatment assignment indicator to a low-dimensional structure of the covariates which are formed typically by several linear combinations of the covariates. We develop a class of consistent estimators for the average treatment effect and study their theoretical properties. We demonstrate the robust performance of the estimators on simulated data and a real data example of investigating the effect of maternal smoking on babies' birth weight. PMID- 29441523 TI - Dynamic Changes in Peer Victimization and Adjustment Across Middle School: Does Friends' Victimization Alleviate Distress? AB - Although some adolescents are chronically bullied throughout middle school, others may only experience peer victimization temporarily. This study examined the effects of time-invariant (average level) and time-varying (year-to-year) victimization experiences across middle school on adolescents' depressive symptoms, somatic complaints, and self-blame. A key question was whether friends' victimization buffered students from their victimization-related distress. The diverse sample (n = 5,991) was surveyed four times between sixth and eighth grade (Mage at sixth grade = 11.54 years). Three-level multilevel models revealed both time-invariant and time-varying effects of victimization on adjustment, but these maladaptive associations were attenuated when adolescents' friends experienced more victimization across middle school. The results suggest that even temporarily victimized youth may have unmet mental health needs, and sharing social plight with friends can protect victims. PMID- 29441524 TI - The economy of smiles: affect, labour and the contemporary deserving poor. AB - This paper examines the affective dimensions of new forms of informal entrepreneurial work carried out in spaces of unemployment. Situating the analysis within contemporary scholarship on deservingness and on affect and labour, I shed light on the forms of entrepreneurial labour that rely upon affect driven economies of exchange underpinned by moral judgements of deservingness, value and worth. In particular, this paper draws on a multi-city (Melbourne, London, San Francisco) study of homeless street press sellers (The Big Issue and Street Sheet) to explore the ways in which contemporary practices of charity and care are carried out through individualized market-place exchanges. Sellers' accounts of their work reveal how smiling and being (or looking) happy is a performative expectation that must be managed in the face of poverty and precarity. PMID- 29441522 TI - Cell-fate determination in Myxococcus xanthus development: Network dynamics and novel predictions. AB - Myxococcus xanthus is a myxobacterium that exhibits aggregation and cellular differentiation during the formation of fruiting bodies. Therefore, it has become a valuable model system to study the transition to multicellularity via cell aggregation. Although there is a vast set of experimental information for the development on M. xanthus, the dynamics behind cell-fate determination in this organism's development remain unclear. We integrate the currently available evidence in a mathematical network model that allows to test the set of molecular elements and regulatory interactions that are sufficient to account for the specification of the cell types that are observed in fruiting body formation. Besides providing a dynamic mechanism for cell-fate determination in the transition to multicellular aggregates of M. xanthus, this model enables the postulation of specific mechanisms behind some experimental observations for which no explanations have been provided, as well as new regulatory interactions that can be experimentally tested. Finally, this model constitutes a formal basis on which the continuously emerging data for this system can be integrated and interpreted. PMID- 29441525 TI - Core outcome sets in dermatology: report from the second meeting of the International Cochrane Skin Group Core Outcome Set Initiative. AB - Results of clinical trials are the most important information source for generating external clinical evidence. The use of different outcomes across trials, which investigate similar interventions for similar patient groups, significantly limits the interpretation, comparability and clinical application of trial results. Core outcome sets (COSs) aim to overcome this limitation. A COS is an agreed standardized collection of outcomes that should be measured and reported in all clinical trials for a specific clinical condition. The Core Outcome Set Initiative within the Cochrane Skin Group (CSG-COUSIN) supports the development of core outcomes in dermatology. In the second CSG-COUSIN meeting held in 2017, 11 COS development groups working on skin diseases presented their current work. The presentations and discussions identified the following overarching methodological challenges for COS development in dermatology: it is not always easy to define the disease focus of a COS; the optimal method for outcome domain identification and level of detail needed to specify such domains is challenging to many; decision rules within Delphi surveys need to be improved; appropriate ways of patient involvement are not always clear. In addition, there appear to be outcome domains that may be relevant as potential core outcome domains for the majority of skin diseases. The close collaboration between methodologists in the Core Outcome Set Initiative and the international Cochrane Skin Group has major advantages for trialists, systematic reviewers and COS developers. PMID- 29441526 TI - Effects of parental care on resource allocation into immune defense and buccal microbiota in mouthbrooding cichlid fishes. AB - Sexual dimorphism is founded upon a resource allocation trade-off between investments in reproduction versus other life-history traits including the immune system. In species with conventional parental care roles, theory predicts that males maximize their lifetime reproductive success by allocating resources toward sexual selection, while females achieve this through prolonging their lifespan. Here, we examine the interrelation between sexual dimorphism and parental care strategies in closely related maternal and biparental mouthbrooding cichlid fishes from East African Lake Tanganyika. We measured cellular immune parameters, examined the relative expression of 28 immune system and life history-related candidate genes and analyzed the microbiota composition in the buccal cavity. According to our predictions, maternal mouthbrooders are more sexually dimorphic in immune parameters than biparental mouthbrooders, which has possibly arisen through a differential resource allocation into parental care versus secondary sexual traits. Biparental mouthbrooders, on the other hand, which share the costs of parental care, feature an upregulated adaptive immune response and stronger antiviral properties, while their inflammation response is reduced. Overall, our results suggest a differential resource allocation trade-off between the two modes of parental investment. PMID- 29441527 TI - Global macroevolution and macroecology of passerine song. AB - Studying the macroevolution of the songs of Passeriformes (perching birds) has proved challenging. The complexity of the task stems not just from the macroevolutionary and macroecological challenge of modeling so many species, but also from the difficulty in collecting and quantifying birdsong itself. Using machine learning techniques, we extracted songs from a large citizen science dataset, and then analyzed the evolution, and biotic and abiotic predictors of variation in birdsong across 578 passerine species. Contrary to expectations, we found few links between life-history traits (monogamy and sexual dimorphism) and the evolution of song pitch (peak frequency) or song complexity (standard deviation of frequency). However, we found significant support for morphological constraints on birdsong, as reflected in a negative correlation between bird size and song pitch. We also found that broad-scale biogeographical and climate factors such as net primary productivity, temperature, and regional species richness were significantly associated with both the evolution and present-day distribution of bird song features. Our analysis integrates comparative and spatial modeling with newly developed data cleaning and curation tools, and suggests that evolutionary history, morphology, and present-day ecological processes shape the distribution of song diversity in these charismatic and important birds. PMID- 29441528 TI - Type 2 diabetes and colorectal cancer survival: The multiethnic cohort. AB - This analysis examined type 2 diabetes (T2D) as a predictor of colorectal cancer (CRC) survival within the Multiethnic Cohort Study. Registry linkages in Hawaii and California identified 5,284 incident CRC cases. After exclusion of cases with pre-existing cancer diagnosis within 1 year and systemic disease, the analytic dataset had 3,913 cases with 1,800 all-cause and 678 CRC-specific deaths after a mean follow-up of 9.3 +/- 5.2 years. Among CRC cases, 707 were diagnosed with T2D 8.9 +/- 5.3 years before CRC. Cox regression with age as time metric was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for T2D status as predictor of CRC-specific and all-cause survival while adjusting for known confounders. Overall, CRC-specific survival was not associated with pre-existing T2D (HR = 0.84; 95% CI = 0.67-1.07). However, a significant interaction was seen for comorbidity (pinteraction = 0.03) with better survival among those without pre-existing conditions (HR = 0.49; 95% CI = 0.25-0.96) while no association was seen in patients with comorbid conditions. All-cause mortality was also not related to pre-existing T2D (HR = 1.11; 95% CI = 0.98-1.27), but significantly elevated for individuals with T2D reporting comorbid conditions (HR = 1.36; 95% CI = 1.19-1.56). Stratification by T2D duration suggested higher CRC-specific and all-cause mortality among participants with a T2D history of >=10 than <10 years. The findings were consistent across sex and ethnic subgroups. In contrast to previous reports, pre-existing T2D had no influence on disease-specific and all cause survival among CRC patients. Only participants with additional comorbidity and possibly those with long T2D duration experienced higher mortality related to T2D. PMID- 29441531 TI - The time healthcare workers wear disposable gloves daily is associated with hand eczema in a dose-dependent fashion. PMID- 29441529 TI - Toward a diagnostic toolkit for linear models with Gaussian-process distributed random effects. AB - Gaussian processes (GPs) are widely used as distributions of random effects in linear mixed models, which are fit using the restricted likelihood or the closely related Bayesian analysis. This article addresses two problems. First, we propose tools for understanding how data determine estimates in these models, using a spectral basis approximation to the GP under which the restricted likelihood is formally identical to the likelihood for a gamma-errors GLM with identity link. Second, to examine the data's support for a covariate and to understand how adding that covariate moves variation in the outcome y out of the GP and error parts of the fit, we apply a linear-model diagnostic, the added variable plot (AVP), both to the original observations and to projections of the data onto the spectral basis functions. The spectral- and observation-domain AVPs estimate the same coefficient for a covariate but emphasize low- and high-frequency data features respectively and thus highlight the covariate's effect on the GP and error parts of the fit, respectively. The spectral approximation applies to data observed on a regular grid; for data observed at irregular locations, we propose smoothing the data to a grid before applying our methods. The methods are illustrated using the forest-biomass data of Finley et al. (2008). PMID- 29441532 TI - Novel interactions among ultraviolet B, skin and adipose tissue. PMID- 29441533 TI - Concurrent hidradenitis suppurativa and Dowling-Degos disease taken down a 'Notch'. PMID- 29441534 TI - Beyond country-specific incidence and mortality: the global burden of melanoma. PMID- 29441535 TI - BJD research letters: concise, thought provoking and of general interest. PMID- 29441537 TI - Image Gallery: Rapidly spontaneous onset of erythroderma in a neonate. PMID- 29441538 TI - The BJD is embracing core outcome set development - why this is good news. PMID- 29441539 TI - Wet work and healthcare workers: use of hand disinfectants not associated with self-reported eczema. PMID- 29441540 TI - What can we learn from 'dropouts' in clinical trials? PMID- 29441541 TI - Survival of the fittest. PMID- 29441542 TI - Image Gallery: Sir William Osler. PMID- 29441543 TI - Image Gallery: Dermoscopic, confocal and histopathological characteristics of a naevus with white globules. PMID- 29441544 TI - Treating actinic keratosis: assessment of effectiveness, discomfort, costs and follow-up. PMID- 29441545 TI - Standardized classification tools in dermatology: time to focus on cutaneous warts. PMID- 29441547 TI - Alopecia: the questions we need to answer. PMID- 29441546 TI - Systematic reviews of case reports and case series: from anecdote to evidence. PMID- 29441548 TI - Orf - a potential trigger for self-limiting epidermolysis bullosa acquisita-like blistering. PMID- 29441549 TI - Ulcerative colitis: yet another paradoxical effect of tumour necrosis factor blockers? PMID- 29441550 TI - Image Gallery: Periumbilical purpura: a dermatological clue for disseminated strongyloidiasis. PMID- 29441552 TI - JAK inhibitors appear to have a bright future in the treatment of atopic dermatitis. PMID- 29441551 TI - Image Gallery: Acquired zinc deficiency of prematurity. PMID- 29441553 TI - BJD support for dermatology journal clubs: nurturing Sir William Osler's legacy. PMID- 29441555 TI - Is occupational sun exposure important for squamous cell carcinoma risk? PMID- 29441554 TI - Image Gallery: Paraneoplastic pemphigus and follicular dendritic cell sarcoma. PMID- 29441557 TI - Impact of dupilumab on health-related quality of life in patients with atopic dermatitis. PMID- 29441558 TI - Safety gains don't translate into reduced costs or increased QALYs for doxycycline compared with prednisolone for patients with bullous pemphigoid. PMID- 29441559 TI - Prognostic features for acral lentiginous melanoma. PMID- 29441560 TI - Automated diagnosis: shedding the light on skin cancer. PMID- 29441561 TI - Image Gallery: Pigmented mammary Paget disease: a rare clinicopathological variant mimicking melanoma. PMID- 29441562 TI - Neoadjuvant treatments for locally advanced, resectable esophageal cancer: A network meta-analysis. AB - The relative survival benefits and postoperative mortality among the different types of neoadjuvant treatments (such as chemotherapy only, radiotherapy only or chemoradiotherapy) for esophageal cancer patients are not well established. To evaluate the relative efficacy and safety of neoadjuvant therapies in resectable esophageal cancer, a Bayesian network meta-analysis was performed. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for publications up to May 2016. ASCO and ASTRO annual meeting abstracts were also searched up to the 2015 conferences. Randomized controlled trials that compared at least two of the following treatments for resectable esophageal cancer were included: surgery alone, surgery preceded by neoadjuvant chemotherapy, neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy. The primary outcome assessed from the trials was overall survival. Thirty-one randomized controlled trials involving 5496 patients were included in the quantitative analysis. The network meta-analysis showed that neoadjuvant chemoradiotherapy improved overall survival when compared to all other treatments including surgery alone (HR 0.75, 95% CR 0.67-0.85), neoadjuvant chemotherapy (HR 0.83. 95% CR 0.70-0.96) and neoadjuvant radiotherapy (HR 0.82, 95% CR 0.67-0.99). However, the risk of postoperative mortality increased when comparing neoadjuvant chemoradiotherapy to either surgery alone (RR 1.46, 95% CR 1.00-2.14) or to neoadjuvant chemotherapy (RR 1.58, 95% CR 1.00-2.49). In conclusion, neoadjuvant chemoradiotherapy improves overall survival but may also increase the risk of postoperative mortality in patients locally advanced resectable esophageal carcinoma. PMID- 29441563 TI - Acute myeloid/T-lymphoblastic leukaemia (AMTL): a distinct category of acute leukaemias with common pathogenesis in need of improved therapy. AB - Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T-cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T-ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T-ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T-lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches. PMID- 29441564 TI - A hyperpigmented rash on face and chest. PMID- 29441565 TI - Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer. AB - Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies. PMID- 29441567 TI - Water fluoridation and the quality of information available online. AB - BACKGROUND: The Internet has transformed the way in which people approach their health care, with online resources becoming a primary source of health information. Little work has assessed the quality of online information regarding community water fluoridation. This study sought to assess the information available to individuals searching online for information, with emphasis on the credibility and quality of websites. METHODS: We identified the top 10 web pages returned from different search engines, using common fluoridation search terms (identified in Google Trends). Web pages were scored using a credibility, quality and health literacy tool based on Global Advisory Committee on Vaccine Safety (GAVCS) and Center for Disease Control and Prevention (CDC) criteria. Scores were compared according to their fluoridation stance and domain type, then ranked by quality. The functionality of the scoring tool was analysed via a Bland-Altman plot of inter-rater reliability. RESULTS: Five-hundred web pages were returned, of which 55 were scored following removal of duplicates and irrelevant pages. Of these, 28 (51%) were pro-fluoridation, 16 (29%) were neutral and 11 (20%) were anti-fluoridation. Pro, neutral and anti-fluoridation pages scored well against health literacy standards (0.91, 0.90 and 0.81/1 respectively). Neutral and pro fluoridation web pages showed strong credibility, with mean scores of 0.80 and 0.85 respectively, while anti-fluoridation scored 0.62/1. Most pages scored poorly for content quality, providing a moderate amount of superficial information. CONCLUSION: Those seeking online information regarding water fluoridation are faced with comprehensible, yet poorly referenced, superficial information. Sites were credible and user friendly; however, our results suggest that online resources need to focus on providing more transparent information with appropriate figures to consolidate the information. PMID- 29441566 TI - Aneustat (OMN54) has aerobic glycolysis-inhibitory activity and also immunomodulatory activity as indicated by a first-generation PDX prostate cancer model. AB - Aneustat (OMN54) is a multivalent, botanical anticancer candidate therapeutic. A recent Phase-I clinical trial has indicated that it is well tolerated by patients and has immunomodulatory activity. In our study, using in vitro and in vivo prostate cancer models, we investigated Aneustat with regard to effects on (i) cancer-generated immunosuppression based on aerobic glycolysis leading to acidification of the tumor microenvironment, and (ii) immune-related processes such as macrophage differentiation and shifts in the intratumoral levels of host immune cells. Aneustat markedly reduced glucose consumption, lactic acid secretion, glycolysis-related gene expressions and proliferation of human LNCaP prostate cancer cells. In addition, Aneustat induced differentiation of RAW264.7 macrophages to the M1 anticancer phenotype. Treatment of LNCaP xenografts and first-generation patient-derived prostate cancer tissue xenografts with Aneustat in both cases led to a marked shift in intratumoral host (mouse/patient) immune cell levels: a higher ratio of cytotoxic CD8+ T/Treg cells, higher numbers of NK cells, lower numbers of Treg cells and MDSCs, i.e. changes favoring the host anticancer immune response. Taken together, the data indicate that Aneustat has immunomodulatory activity based on inhibition of aerobic glycolysis which in patients may lead to reduction of cancer-induced immunosuppression. Furthermore, first-generation patient-derived cancer tissue xenograft models may be used for screening compounds for immunomodulatory activity. PMID- 29441568 TI - Evaluation of the benefits, harms and cost-effectiveness of potential alternatives to iFOBT testing for colorectal cancer screening in Australia. AB - The Australian National Bowel Cancer Screening Program (NBCSP) will fully roll out 2-yearly screening using the immunochemical Faecal Occult Blood Testing (iFOBT) in people aged 50 to 74 years by 2020. In this study, we aimed to estimate the comparative health benefits, harms, and cost-effectiveness of screening with iFOBT, versus other potential alternative or adjunctive technologies. A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate a total of 13 screening approaches involving use of iFOBT, colonoscopy, sigmoidoscopy, computed tomographic colonography (CTC), faecal DNA (fDNA) and plasma DNA (pDNA), in people aged 50 to 74 years. All strategies were evaluated in three scenarios: (i) perfect adherence, (ii) high (but imperfect) adherence, and (iii) low adherence. When assuming perfect adherence, the most effective strategies involved using iFOBT (annually, or biennially with/without adjunct sigmoidoscopy either at 50, or at 54, 64 and 74 years for individuals with negative iFOBT), or colonoscopy (10-yearly, or once-off at 50 years combined with biennial iFOBT). Colorectal cancer incidence (mortality) reductions for these strategies were 51-67(74-80)% in comparison with no screening; 2-yearly iFOBT screening (i.e. the NBCSP) would be associated with reductions of 51(74)%. Only 2-yearly iFOBT screening was found to be cost-effective in all scenarios in context of an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS); this strategy was associated with an incremental cost-effectiveness ratio of A$2,984/LYS-A$5,981/LYS (depending on adherence). The fully rolled-out NBCSP is highly cost-effective, and is also one of the most effective approaches for bowel cancer screening in Australia. PMID- 29441569 TI - Epidemiologic associations of HPV-positive oropharyngeal cancer and (pre)cancerous cervical lesions. AB - Human papillomavirus (HPV)-induced oropharyngeal squamous cell carcinoma (OPSCC) remains increasing worldwide. We aimed to investigate if the HPV-prevalence of OPSCC in the Netherlands is rising as well, also in female patients. In addition, we evaluated the association between HPV-positive OPSCC and suspicious Pap results of the cervix in these female patients. Patients with OPSCC treated in the period 2000-2015 at the VU University Medical Center Amsterdam, were included (n = 926). The presence of an oncogenic HPV infection was determined by p16 immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-immunopositive cases. A review of pathology reports in all female patients (n = 305) was undertaken to identify cytological signs of HPV-related (pre)cancer of the cervix. In total 281 of 926 (30.3%) OPSCCs were HPV-positive. Moreover, a significant increase in the prevalence of HPV-positive OPSCCs was observed from 14.0% in 2000 to 48.1% in 2015 (p < 0.001). Among the female patients with an HPV positive OPSSC (n = 70), the results of cervical smears were available in 56 of 70 patients (80.0%). Of the female patients with HPV-positive OPSCC, 9 of 56 (16.1%) patients had a vaginal cuff Papanicolaou (Pap) test >=3b in their medical history compared to 7 of 168 (4.2%) in the HPV-negative group (p = 0.003). In conclusion, a continuous increase in the HPV-attributable fraction of OPSCC was demonstrated in the period 2000-2015 in the Amsterdam region. HPV-positive OPSCC has a significant association with a history of suspicious Pap results of the cervix in female patients. PMID- 29441571 TI - Arterial and microvascular supply of cerebral hemispheres in the nude mouse revealed using corrosion casting and scanning electron microscopy. AB - Morphological analyses of cerebral vascularization are not only important for the characterization of the anatomical and physiological relationships between vascular and nervous tissue, but also required to understand structural modifications that occur in many pathological conditions affecting the brain. The aim of this study was to generate a three-dimensional vascular map of the cerebral hemispheres in the nude mouse brain, a widely used animal model for studying tumour biology. We used the corrosion casting (CC) technique to isolate blood vessels from 30 nude mouse brains. All casts were analysed using scanning electron microscopy (SEM), which generated quantitative data regarding vessel length and diameter as well as inter-vascular and inter-branching distances. We identified three different topographical regions: (i) the cortical region, characterized by a superficial wide sheet of vessels giving rise to terminal perforant vessels that penetrate the grey matter; (ii) the inner part of the grey matter, in which dense capillary nets form many flake-like structures extending towards the grey-white matter boundary, where perforant vessels finally change direction and form a well-defined vascular sheet; and (iii) the white matter layer, characterized by a more disorganized vascular architecture. In this study, we demonstrate the accuracy of the CC-SEM method in revealing the 3D topographical organization of the vascular network of the normal nude mouse brain. These baseline data will serve as a reference for future anatomical investigations of pathological alterations, such as tumour infiltrations, using the nude mouse model. PMID- 29441570 TI - Inhibition of Nox4-dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal-mediated protumorigenic interactions. AB - Carcinoma-associated fibroblasts (CAFs) play a key onco-supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)-producing enzyme NADPH oxidase 4 (Nox4) is essential for TGFbeta1-mediated activation of primary prostate human fibroblasts to a CAF-like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine-mediated PCa-relevant processes. RNA in situ hybridization revealed significantly elevated Nox4 mRNA levels predominantly in the peri-tumoral stroma of clinical PCa with intense stromal Nox4 staining adjacent to tumor foci expressing abundant TGFbeta protein levels. At pharmacologically relevant concentrations, the Nox1/Nox4 inhibitor GKT137831 attenuated ROS production, CAF-associated marker expression and migration of TGFbeta1-activated but not nonactivated primary human prostate fibroblasts. Similar effects were obtained upon shRNA-mediated silencing of Nox4 but not Nox1 indicating that GKT137831 primarily abrogates TGFbeta1-driven fibroblast activation via Nox4 inhibition. Moreover, inhibiting stromal Nox4 abrogated the enhanced proliferation and migration of PCa cell lines induced by TGFbeta1 activated prostate fibroblast conditioned media. These effects were not restricted to recombinant TGFbeta1 as conditioned media from PCa cell lines endogenously secreting high TGFbeta1 levels induced fibroblast activation in a stromal Nox4- and TGFbeta receptor-dependent manner. Importantly, GKT137831 also attenuated PCa cell-driven fibroblast activation. Collectively, these findings suggest the TGFbeta-Nox4 signaling axis is a key interface to dysregulated reciprocal stromal-epithelial interactions in PCa pathophysiology and provide a strong rationale for further investigating the applicability of Nox4 inhibition as a stromal-targeted approach to complement current PCa treatment modalities. PMID- 29441573 TI - Widening control of fin inter-rays in zebrafish and inferences about actinopterygian fins. AB - The amputation of a teleost fin rapidly triggers an intricate maze of hierarchically regulated signalling processes which ultimately reconstruct the diverse tissues of the appendage. Whereas the generation of the fin pattern along the proximodistal axis brings with it several well-known developmental regulators, the mechanisms by which the fin widens along its dorsoventral axis remain poorly understood. Utilizing the zebrafish as an experimental model of fin regeneration and studying more than 1000 actinopterygian species, we hypothesized a connection between specific inter-ray regulatory mechanisms and the morphological variability of inter-ray membranes found in nature. To tackle these issues, both cellular and molecular approaches have been adopted and our results suggest the existence of two distinguishable inter-ray areas in the zebrafish caudal fin, a marginal and a central region. The present work associates the activity of the cell membrane potassium channel kcnk5b, the fibroblast growth factor receptor 1 and the sonic hedgehog pathway to the control of several cell functions involved in inter-ray wound healing or dorsoventral regeneration of the zebrafish caudal fin. This ray-dependent regulation controls cell migration, cell type patterning and gene expression. The possibility that modifications of these mechanisms are responsible for phenotypic variations found in euteleostean species, is discussed. PMID- 29441572 TI - Systematic review of shorter versus longer duration of bladder catheterization after surgical repair of urinary obstetric fistula. AB - BACKGROUND: Bladder catheterization duration after urinary obstetric fistula surgery varies widely. OBJECTIVE: To assess the effect of bladder catheterization duration after urinary obstetric fistula surgery. SEARCH STRATEGY: Medline, EMBASE, CINAHL, GIM, and POPLINE databases were searched, without language restrictions, using "obstetric urinary fistula" and "catheterization" from inception to September 30, 2017. SELECTION CRITERIA: Randomized controlled trials comparing shorter versus longer (>10 days) bladder catheterization after urinary obstetric fistula repair were included. DATA COLLECTION AND ANALYSIS: Data were extracted and meta-analyses were conducted. The GRADE system was used to assess evidence quality. MAIN RESULTS: Two unblinded non-inferiority trials (684 patients combined) were included. There were no differences between shorter and longer bladder catheterization in the risk of fistula repair breakdown either before (relative risk [RR] 1.14; 95% confidence interval [CI] 0.49-2.64) or after (RR 1.64; 95% CI 0.81-3.31) hospital discharge. Similarly, urinary infection (RR 5.18; 95% CI 0.25-107.44); urinary incontinence before (RR 1.15; 95% CI 0.54 2.43) or after (RR 1.16; 95% CI 0.62-2.18) discharge; urinary retention (RR 1.34; 95% CI 0.79-2.27); or extended hospital stay (RR 9.33; 95% CI 0.51-172.41) were not associated with duration of catheterization. Evidence quality was low or moderate. CONCLUSIONS: Shorter, compared to longer, bladder catheterization duration after urinary obstetric fistula surgery was not associated with significant outcome differences. PMID- 29441574 TI - Intrathecal pramoxine causes long-lasting spinal sensory and motor block in rats. AB - OBJECTIVES: The objective of this experiment was to investigate spinal anaesthetic effects of pramoxine and its comparison with bupivacaine, a long lasting local anaesthetic. METHODS: After intrathecal injection, three neurobehavioural assessments, which consisted of nociceptive, proprioceptive and motor block, were constructed in rats. The effects of bupivacaine and pramoxine (four doses of each drug) in a dose-related manner were conducted to obtain the ED50 (50% effective dose). Pramoxine potency and duration at provoking spinal nociceptive, proprioceptive and motor block were compared with those of bupivacaine. KEY FINDINGS: We manifested that pramoxine provoked dose-relatedly spinal blockades of nociception, proprioception and motor function. Based on the ED50 , the rank potency at producing spinal nociceptive, proprioceptive and motor block was bupivacaine (0.90 (0.82-1.02), 1.00 (0.92-1.08) and 1.16 (1.02-1.34) MUmol/kg) greater (P < 0.01 for the differences) than pramoxine (15.47 (14.04 17.05), 16.46 (15.06-17.99), and 17.77 (16.48-19.15) MUmol/kg). The spinal block duration created by bupivacaine was not predominantly different (P > 0.05 for the differences) from that created by pramoxine at the equipotent doses (ED75 , ED50 and ED25 ). CONCLUSIONS: Our preclinical experiment indicated that pramoxine elicited a dose-related spinal block, was less potent than bupivacaine and had a similar duration of spinal block compared with bupivacaine. PMID- 29441576 TI - Barleria cristata: perspective towards phytopharmacological aspects. AB - OBJECTIVES: Barleria cristata (Family: Acanthaceae), commonly known as Philippine violet, is used in different ethnomedical systems for the treatment of a wide range of ailments. This review aimed to provide a scientific overview of B. cristata with reference to its ethnobotanical aspects, geographical distribution, medicinal uses, phytochemistry and pharmacological activity, and critical analyses research gaps and future research opportunities for investigations on this plant. KEY FINDINGS: Ethnomedical uses of the plant have been observed in lungs disorders, inflammatory conditions, toothache, anaemia, snake bite, diabetes and tuberculosis. The exhaustive bibliographic research carried out on this plant revealed that the plant parts are rich in various phytochemical constituents including triterpenes, phenolic compounds, glycosides and flavonoids type phenolic compounds. Furthermore, the plant was also investigated in terms of its anti-inflammatory, antibacterial, antidiabetic, antifungal, hepatoprotective and antioxidant activity. CONCLUSIONS: This review confirms that B. cristata is a potential herb for the treatment of a wide range of diseases especially lung disorders and inflammatory conditions. Modern pharmacological studies have also validated many ethnobotanical uses of B. cristata, though data regarding many aspects of this plant such as mechanism of action, adverse effects of extracts and active compounds are still limited which call for additional studies. PMID- 29441575 TI - The dermal arteries in the cutaneous angiosome of the descending genicular artery. AB - Studies examining thick skin of the thumb pad have challenged the existence of an arterial plexus in the papillary dermis. Instead of a plexus, discrete arterial units, interconnected by arterio-arterial anastomoses, were identified. We hypothesise that the dermal arteries of thin skin are arranged likewise and that there are fewer arterio-arterial anastomoses in the centre of an angiosome than in zones where neighbouring angiosomes overlap. To test these hypotheses, we examined the dermal arteries in the centre of the cutaneous angiosome of the descending genicular artery (DGA) and its zone of overlap with neighbouring angiosomes. Using traditional perfusion techniques, the cutaneous angiosomes of the DGA and the popliteal artery were identified in 11 fresh frozen human lower limbs. Biopsies were harvested from the centre of the cutaneous DGA angiosome and from the zone where neighbouring vascular territories overlapped. Employing high resolution episcopic microscopy (HREM), digital volume data were generated and the dermal arteries were three-dimensionally reconstructed and examined. In all examined skin areas, the dermal arteries showed tree-like ramifications. The branches of the dermal arteries were connected on average by 1.73 +/- 1.01 arterio-arterial anastomoses in the centre of the DGA angiosome and by 3.27 +/- 1.27 in the zone where angiosomes overlapped. We demonstrate that discrete but overlapping dermal arterial units with a mean dimension of 1.62 +/- 1.34 and 1.80 +/- 1.56 mm2 , respectively, supply oxygen and nutrients to the superficial dermis and epidermis of the thin skin of the medial femur. This forms the basis for diagnosing and researching skin pathologies. PMID- 29441577 TI - Can a Gender Equity and Family Planning Intervention for Men Change Their Gender Ideology? Results from the CHARM Intervention in Rural India. AB - We assess the effect of CHARM, a gender equity and family planning counseling intervention for husbands in rural India, on men's gender ideology. We used a two armed cluster randomized control trial design and collected survey data from husbands (n=1081) at baseline, 9 months, and 18 months. We used a continuous measure of support for gender equity and a dichotomous measure of equitable attitudes toward women's role in household decision-making. To assess differences on these outcomes, we used generalized linear mixed models. After controlling for socio-demographic factors, men who received the CHARM intervention were significantly more likely than men in the control group to have equitable attitudes toward household decision-making at 9-months follow-up; there was a non significant difference between the groups for the measure of support for gender equity. For household decision-making, differences were not sustained at 18 months follow-up. Given the role of husbands' gender ideology in women's contraceptive use, the CHARM intervention represents a promising approach for challenging root causes of women's unmet need for contraception. PMID- 29441579 TI - Brain anatomy of the 4-day-old European rabbit. AB - The European rabbit (Oryctolagus cuniculus) is a widely used model in fundamental, medical and veterinary neurosciences. Besides investigations in adults, rabbit pups are relevant to study perinatal neurodevelopment and early behaviour. To date, the rabbit is also the only species in which a pheromone - the mammary pheromone (MP) - emitted by lactating females and active on neonatal adaptation has been described. The MP is crucial since it contributes directly to nipple localisation and oral seizing in neonates, i.e. to their sucking success. It may also be one of the non-photic cues arising from the mother, which stimulates synchronisation of the circadian system during pre-visual developmental stages. Finally, the MP promotes neonatal odour associative and appetitive conditioning in a remarkably rapid and efficient way. For these different reasons, the rabbit offers a currently unique opportunity to determine pheromonal-induced brain processing supporting adaptation early in life. Therefore, it is of interest to create a reference work of the newborn rabbit pup brain, which may constitute a tool for future multi-disciplinary and multi approach research in this model, and allow comparisons related to the neuroethological basis of social and feeding behaviour among newborns of various species. Here, in line with existing experimental studies, and based on original observations, we propose a functional anatomical description of brain sections in 4-day-old rabbits with a particular focus on seven brain regions which appear important for neonatal perception of sensory signals emitted by the mother, circadian adaptation to the short and single daily nursing of the mother in the nest, and expression of specific motor actions involved in nipple localisation and milk intake. These brain regions involve olfactory circuits, limbic-related areas important in reward, motivation, learning and memory formation, homeostatic areas engaged in food anticipation, and regions implicated in circadian rhythm and arousal, as well as in motricity. PMID- 29441580 TI - 1,25-Dihydroxy vitamin D prevents tumorigenesis by inhibiting oxidative stress and inducing tumor cellular senescence in mice. AB - Human epidemiological studies suggest that 1,25(OH)2 D3 deficiency might increase cancer incidence, but no spontaneous tumors have been reported in mice lacking 1,25(OH)2 D3 or deficient in its receptor. In our study, we detected, for the first time, diverse types of spontaneous tumors in l,25(OH)2 D3 deficient mice more than 1 year of age. This was associated with increased oxidative stress, cellular senescence and senescence-associated secretory phenotype molecules, such as hepatocyte growth factor, mediated via its receptor c-Met. Furthermore, 1,25(OH)2 D3 prevented spontaneous tumor development. We also demonstrated that l,25(OH)2 D3 deficiency accelerates allograft tumor initiation and growth by increasing oxidative stress and DNA damage, activating oncogenes, inactivating tumor suppressor genes, stimulating malignant cell proliferation and inhibiting their senescence; in contrast, supplementation with exogenous l,25(OH)2 D3 or antioxidant, or knock-down of the Bmi1 or c-Met oncogene, largely rescued the phenotypes of allograft tumors. Results from our study suggest that 1,25(OH)2 D3 deficiency enhances tumorigenesis by increasing malignant cell oxidative stress and DNA damage, stimulating microenvironmental cell senescence and a senescence associated secretory phenotype, and activating oncogenes and inactivating tumor suppressor genes, thus increasing malignant cell proliferation. Our study provides direct evidence supporting the role of vitamin D deficiency in increasing cancer incidence. Conversely, 1,25(OH)2 D3 prevented spontaneous tumor development, suggesting that this inhibitory effect prevents the initiation and progression of tumorigenesis, thus provides a mechanistic basis for 1,25(OH)2 D3 to prevent tumorigenesis in an aging organism. PMID- 29441578 TI - Cell type specific tracing of the subcortical input to primary visual cortex from the basal forebrain. AB - The basal forebrain provides cholinergic inputs to primary visual cortex (V1) that play a key modulatory role on visual function. While basal forebrain afferents terminate in the infragranular layers of V1, acetylcholine is delivered to more superficial layers through volume transmission. Nevertheless, direct synaptic contact in deep layers 5 and 6 may provide a more immediate effect on V1 modulation. Using helper viruses with cell type specific promoters to target retrograde infection of pseudotyped and genetically modified rabies virus evidence was found for direct synaptic input onto V1 inhibitory neurons. These inputs were similar in number to geniculocortical inputs and, therefore, considered robust. In contrast, while clear evidence for dorsal lateral geniculate nucleus input to V1 excitatory neurons was found, there was no evidence of direct synaptic input from the basal forebrain. These results suggest a direct and more immediate influence of the basal forebrain on local V1 inhibition. PMID- 29441581 TI - Genetic polymorphisms of HTR2C, LEP and LEPR on metabolic syndromes in patients treated with atypical antipsychotic drugs. AB - OBJECTIVE: Single nucleotide polymorphisms in serotonin 2C receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR) genes are reportedly associated with the presence of metabolic syndrome (MS). We investigated whether HTR2C:rs518147 ( 697G/C), rs12836771 (A/G), LEP: rs7799039 (-2548G/A) and LEPR:rs1137101 (668A/G) are related to MS in psychotic disorder patients treated with atypical antipsychotics. METHODS: A cross-sectional study including 200 patients was conducted; genetic polymorphisms in HTR2C (rs518147 and rs12836771), LEP (rs7799039) and LEPR (rs1137101) were genotyped. The presence of MS was evaluated according to the 2005 International Diabetes Federation (IDF) Asia criteria. The associations of genetic factors with the presence of MS are analysed. KEY FINDINGS: Two SNPs in the HTR2C gene but not LEP and LEPR were associated with the presence of MS after adjustment for the combination of atypical antipsychotics. With respect to the effect of gender after treatment with risperidone and clozapine was statistically significant. Moreover, genotype combinations had no effect on MS. CONCLUSIONS: Therefore, HTR2C genetic variants may be involved in the susceptibility to MS in patients treated with atypical antipsychotics. Additionally, there was a gender effect in the presence of MS. No effect of LEP or LEPR polymorphisms or the combination of HTR2C-LEP and HTR2C LEPR was observed for the presence of MS. PMID- 29441582 TI - c.49T>C mutation on the alpha-(1,2)-fucosyltransferase gene responsible for an individual with para-Bombay phenotype. PMID- 29441583 TI - Photoenzymes and Related Topics: An Update. AB - Photoenzymes are enzymes that catalyze photochemical reactions. For a long time, it was believed that only two types of photoenzymes exist: light-dependent NADPH:protochlorophyllide oxidoreductase and photolyase. However, other photoenzymes have now been discovered, most recently fatty acid photodecarboxylase. PMID- 29441585 TI - Validating dispersal distances inferred from autoregressive occupancy models with genetic parentage assignments. AB - Dispersal distances are commonly inferred from occupancy data but have rarely been validated. Estimating dispersal from occupancy data is further complicated by imperfect detection and the presence of unsurveyed patches. We compared dispersal distances inferred from seven years of occupancy data for 212 wetlands in a metapopulation of the secretive and threatened California black rail (Laterallus jamaicensis coturniculus) to distances between parent-offspring dyads identified with 16 microsatellites. We used a novel autoregressive multi-season occupancy model that accounted for both unsurveyed patches and imperfect detection to quantify patch isolation using buffer radius (BRM) and incidence function (IFM) connectivity measures at 15 scales (1-10, 15, 20, 25, and 30 km). Connectivity measures were then fit as colonization covariates in occupancy models to estimate a model-averaged dispersal distance. As predicted, colonization was more strongly related to connectivity at small spatial scales (<10 km). AIC weights were greatest at 7 km for BRM and at 4 km for IFM. Model averaged dispersal distances (BRM = 7.46 km; IFM = 5.48 km) showed good agreement with the mean M(+/-SE) dispersal distance from 23 parent-offspring dyads (5.58 +/ 1.92 km), indicating reasonably accurate mean dispersal distances can be inferred from occupancy data when isolation strongly affects colonization. PMID- 29441584 TI - Comparative analysis of Lacistema pubescens and dexamethasone on topical treatment of skin inflammation in a chronic disease model and side effects. AB - OBJECTIVES: This study aimed to evaluate the chronic topical anti-inflammatory activity of the pharmaceutical formulation ProHLP containing the hexane fraction of Lacistema pubescens (HLP). It was also investigated the possible cutaneous and systemic adverse effects of HLP and ProHLP in mice when compared to dexamethasone. METHODS: The chronic topical anti-inflammatory activity was determined by croton oil multiple application-induced mouse ear oedema model. Histopathological analyses of ear tissue samples sensitized with croton oil were performed. Cutaneous atrophy induced by HLP and topical glucocorticoid treatments and excision skin wounds model to evidenced possible adverse reactions were also determined. KEY FINDINGS: ProHLP significantly reduced the mice ear oedema and considerably accelerated the wound-healing process. Also, HLP did not lead cutaneous atrophy and preserved the clinical aspect of the thymus, adrenal and spleen, unlike dexamethasone. CONCLUSIONS: The results suggested that ProHLP is an efficient and safer pharmaceutical formulation to treat chronic inflammatory diseases. PMID- 29441586 TI - Biphasic voltage-dependent inactivation of human NaV 1.3, 1.6 and 1.7 Na+ channels expressed in rodent insulin-secreting cells. AB - KEY POINTS: Na+ current inactivation is biphasic in insulin-secreting cells, proceeding with two voltage dependences that are half-maximal at ~-100 mV and -60 mV. Inactivation of voltage-gated Na+ (NaV ) channels occurs at ~30 mV more negative voltages in insulin-secreting Ins1 and primary beta-cells than in HEK, CHO or glucagon-secreting alphaTC1-6 cells. The difference in inactivation between Ins1 and non-beta-cells persists in the inside-out patch configuration, discounting an involvement of a diffusible factor. In Ins1 cells and primary beta cells, but not in HEK cells, inactivation of a single NaV subtype is biphasic and follows two voltage dependences separated by 30-40 mV. We propose that NaV channels adopt different inactivation behaviours depending on the local membrane environment. ABSTRACT: Pancreatic beta-cells are equipped with voltage-gated Na+ channels that undergo biphasic voltage-dependent steady-state inactivation. A small Na+ current component (10-15%) inactivates over physiological membrane potentials and contributes to action potential firing. However, the major Na+ channel component is completely inactivated at -90 to -80 mV and is therefore inactive in the beta-cell. It has been proposed that the biphasic inactivation reflects the contribution of different NaV alpha-subunits. We tested this possibility by expression of TTX-resistant variants of the NaV subunits found in beta-cells (NaV 1.3, NaV 1.6 and NaV 1.7) in insulin-secreting Ins1 cells and in non-beta-cells (including HEK and CHO cells). We found that all NaV subunits inactivated at 20-30 mV more negative membrane potentials in Ins1 cells than in HEK or CHO cells. The more negative inactivation in Ins1 cells does not involve a diffusible intracellular factor because the difference between Ins1 and CHO persisted after excision of the membrane. NaV 1.7 inactivated at 15--20 mV more negative membrane potentials than NaV 1.3 and NaV 1.6 in Ins1 cells but this small difference is insufficient to solely explain the biphasic inactivation in Ins1 cells. In Ins1 cells, but never in the other cell types, widely different components of NaV inactivation (separated by 30 mV) were also observed following expression of a single type of NaV alpha-subunit. The more positive component exhibited a voltage dependence of inactivation similar to that found in HEK and CHO cells. We propose that biphasic NaV inactivation in insulin-secreting cells reflects insertion of channels in membrane domains that differ with regard to lipid and/or membrane protein composition. PMID- 29441587 TI - Transfusion-transmitted hepatitis B virus (HBV) infection from an individual donation nucleic acid (ID-NAT) non-reactive donor. AB - Lookback was initiated upon notification of an acute HBV infection in a repeat Irish donor, 108 days post-donation. The donation screened non-reactive by individual-donation nucleic acid testing (ID-NAT) using the Procleix Ultrio Elite multiplex assay and again when the archived sample was retested, but the discriminatory assay for HBV was reactive. The immunocompromised recipient of the implicated red cell component was tested 110 days post-transfusion, revealing a HBV DNA viral load of 470 IU/ml. Genotype C2 sequences identical across two regions of the HBV genome were found in samples from the donor and recipient. PMID- 29441588 TI - The role of STIM proteins in neutrophil functions. AB - Stromal interaction molecule (STIM) proteins regulate store-operated Ca2+ entry (SOCE) in innate and adaptive immune cells and participate in the Ca2+ signals that control the functions of neutrophils, the first line of host defence against bacterial and fungal infections. Loss-of-function experiments in animal and cellular models indicate that both STIM1 and STIM2 regulate neutrophil functions, but the complexity of the SOCE machinery and the versatility of neutrophils complicate the evaluation of the results. This review aims to summarize the latest progress in the field, with special attention to the details of the experimental designs. Future study design should aim to improve the standardization of experimental procedures and to provide a more holistic understanding of the role of STIM proteins in neutrophils function. PMID- 29441589 TI - Dissecting the decline of hepatitis C in first-time donors in England and Wales. AB - BACKGROUND AND OBJECTIVES: The rate of confirmed hepatitis C virus (HCV) cases, in first-time donors, is much lower in 2015 than 20 years ago. We investigate reasons for the decline. MATERIALS AND METHODS: HCV rates were analysed by gender and birth cohort for 1996 to 2015 and ethnic group for 2006 to 2015. Variables for confirmed positive cases were compared for two ten-year periods (1996 to 2005 and 2006 to 2015) including genotyping data for 2006 to 2015. RESULTS: There were 2007 confirmed HCV cases identified between 1996 and 2015. The rate per 100 000 donations fell from 78.6 in 1996 to 26.9 by 2015. By birth cohort, HCV rates were highest in donors born in the 1950s and 1960s who contributed a decreasing proportion of first-time donors. Between 2006 and 2015, there was no significant decline in HCV rate. The HCV-positive donor profile has changed in the last 10 years with increased proportions of younger donors, donors born abroad and decreased reported injecting drug use. Genotype 1a remains predominate, but genotype 1b has increased associated with this change in birth cohort and ethnicity. CONCLUSION: The decline in number and rate of confirmed HCV-positive first-time donors is mainly due to a decrease in first-time donors born before 1970, with the highest rate of HCV. However, the decline has slowed and the profile of HCV-positive first-time donors is changing. A better understanding of behaviour and sources of HCV in younger and ethnic minority donors are needed. PMID- 29441590 TI - The prevalence, immunogenicity, and evanescence of alloantibodies to MUT and Mur antigens of GP.Mur red blood cells in a Southeast Asian patient cohort. AB - BACKGROUND: Antibodies to Mia , MUT, and Mur are among the most frequently identified alloantibodies in Southeast Asia. Understanding the characteristics of these antibodies in terms of induction and evanescence would aid in optimizing methods for their detection. STUDY DESIGN AND METHODS: Antibody testing results between the years 2013 and 2015 with relevant patient demographic data and red blood cell (RBC) transfusion history were retrieved. Cumulative alloimmunization incidence and evanescence to MUT and Mur were estimated by Kaplan-Meier analysis in relation to the number of RBC units transfused and time. RESULTS: Of 70,543 selected patients, 6186 nonalloimmunized subjects with available antibody testing results posttransfusion were identified. Cumulative alloimmunization incidence for MUT increased from 0.12% (95% confidence interval [CI], 0.03-0.21) to 0.63% (95% CI, 0.25-1.01), while for Mur it increased from 0.04% (95% CI, 0-0.09) to 0.42% (95% CI, 0.05-0.79) when a patient was transfused 2 RBC units as compared to 12. Both antibodies had high evanescence rates and at 1 year, anti-MUT and Mur will be detected in only 45% (95% CI, 35%-57%) and 27% (95% CI, 17%-43%), respectively, of previously positive patients. MUT and Mur immunogenicity was estimated to be 1.7 and 1.2 times higher than E when their rate of evanescence was taken into account. CONCLUSION: Antibodies to MUT and Mur develop following multiple RBC exposures. Immunogenicity of MUT/Mur and evanescence rates of the corresponding antibodies is higher compared to anti-E. Appropriate selection of antibody screening cells is needed in view of the high prevalence, immunogenicity, and evanescence of the antibodies. PMID- 29441591 TI - Beyond the binaries: reshaping pain communication through arts workshops. AB - Pain is difficult to communicate and translate into language, yet most social research on pain experience uses questionnaires and semi-structured interviews that rely on words. In addition to the mind/body dualism prevalent in pain medicine in these studies pain communication is characterised by further value laden binaries such as real/unreal, visible/invisible, and psychological/physical. Starting from the position that research methods play a role in constituting their object, this article examines the potential of participatory arts workshops for developing different versions of pain communication. Twenty-two participants were involved in workshops using drawing, digital photography, sound and physical theatre to explore pain communication. The use of arts materials made pain tangible. By manipulating pain-related objects, participants could consider alternative relationships to their pain. Pain's sociality was also explored, with relations with clinicians and others emerging as potentially cooperative rather than adversarial. Discussions considered whether pain felt internal or external, and whether it was possible to conceive of a self without pain. We argue that the socio-material context of participatory arts workshops enabled these alternative versions of pain. Such methods are a useful addition to medical sociology's heavy reliance on qualitative interviewing. PMID- 29441592 TI - Identification of reference genes and miRNAs for RT-qPCR in testosterone propionate-induced benign prostatic hyperplasia in rats. AB - Testosterone propionate-induced benign prostatic hyperplasia in rats is a common model that is widely used in studies of the effects and molecular mechanisms of drugs designed to treat benign prostatic hyperplasia. RT-qPCR is a widely used technique in gene expression studies. Proper normalisation is critical for accurate expression analysis. Currently, no validated reference genes are available for RT-qPCR in rat benign prostatic hyperplasia. Given that microRNAs regulate mRNA expression at the post-transcriptional level, they are usually studied together. Here, the expression stability of 21 putative reference genes including 8 mRNAs and 13 miRNAs was evaluated in benign prostatic hyperplasia in rats. Relative expression levels of each gene were detected in rats from a model group and a normal group using SYBR RT-qPCR. Expression stability was evaluated by geNorm and NormFinder. The commonly used reference genes, such as ACTB, B2M and mir-16, were less stable, and let-7a was eliminated due to a large Ct value, most likely indicating a relatively low expression level. Therefore, to obtain reliable results, mir-26a was recommended as a suitable reference for miRNA expression analysis and EF-1a as a suitable reference for mRNA analysis in testosterone propionate-induced benign prostatic hyperplasia in rats. PMID- 29441593 TI - What is the real "price" of more prenatal screening and fewer diagnostic procedures? Costs and trade-offs in the genomic era. AB - Any screening approach, including with cell-free DNA, will have an inferior detection rate compared with 100% diagnostic testing with chromosomal microarrays. Cell-free DNA-based screening, however, should not be seen as a threat to informed choice or maximising the benefits of diagnostic testing. Screening methods have become so much better that more women are now comfortable relying on such screening and do not need the certainty of a diagnostic test. This has not lead to a decline in detection of fetal chromosome abnormalities-in fact, we are now seeing historically high yields from prenatal screening. There are both economic and ethical consequences of offering universal diagnostic testing and abandoning the presumption of a normal infant in otherwise uncomplicated pregnancies. However, for some women, comprehensive information and diagnostic accuracy are important. Offering these women all options, with a careful and comprehensive explanation of the risks and benefits of each, results in outcomes that are best aligned with woman's preferences while at the same time requiring fewer diagnostic tests and lowering costs. It is one of the primary challenges of the modern era of prenatal testing to ensure that women receive sufficient information on which to make informed decisions. PMID- 29441594 TI - Influence of extended incubation time on Human sperm chromatin condensation, sperm DNA strand breaks and their effect on fertilisation rate. AB - The purpose of this study was to determine influence of extended incubation time on sperm chromatin condensation and DNA strand breaks and their effect on fertilisation rate. Forty couples undergoing ICSI therapy were included. Semen was prepared by PureSperm gradient centrifugation and divided into two parts. The first part (G1) was used immediately for ICSI, whereas the second part (G2) was kept in the incubator at 37 degrees C, 5% and 90% Humidity for 5 hr, and thereafter, the capacitated spermatozoa were used for ICSI. The TUNEL test and chromomycin CMA3 were used to evaluate the DNA strand breaks and chromatin condensation respectively. The percentage of condensed chromatin was 73.92 +/- 12.70 in the group 1 and 81.13 +/- 10.31% in group 2 (p = .001). However, the double-strand breaks were 11.15 +/- 8.67% in G.1 and 16.30 +/- 11.12% in G.2. (p = .001). Fertilisation rate in the (Group 1) was 62.45% and 69.17% in (Group 2). There was a positive correlation between condensed chromatin and fertilisation rate (r = 0.846, p = .001) and a negative correlation with DNA double-strand breaks (r = -0.802; p = .001). In conclusion, the prolonged sperm incubation (5 hr) leads to a higher chromatin condensation and to a significantly increased number of DNA strands double breaks with no influence on fertilisation rates. PMID- 29441595 TI - Analysing barriers to service improvement using a multi-level theory of innovation: the case of glaucoma outpatient clinics. AB - The development and implementation of innovation by healthcare providers is understood as a multi-determinant and multi-level process. Theories at different analytical levels (i.e. micro and organisational) are needed to capture the processes that influence innovation by providers. This article combines a micro theory of innovation, actor-network theory, with organisational level processes using the 'resource based view of the firm'. It examines the influence of, and interplay between, innovation-seeking teams (micro) and underlying organisational capabilities (meso) during innovation processes. We used ethnographic methods to study service innovations in relation to ophthalmology services run by a specialist English NHS Trust at multiple locations. Operational research techniques were used to support the ethnographic methods by mapping the care process in the existing and redesigned clinics. Deficiencies in organisational capabilities for supporting innovation were identified, including manager clinician relations and organisation-wide resources. The article concludes that actor-network theory can be combined with the resource-based view to highlight the influence of organisational capabilities on the management of innovation. Equally, actor-network theory helps to address the lack of theory in the resource based view on the micro practices of implementing change. PMID- 29441596 TI - Responding to intimate partner violence: Healthcare providers' current practices and views on integrating a safety decision aid into primary care settings. AB - Supportive care for survivors of intimate partner violence (IPV) remains limited in primary care settings. Low-income and Spanish-speaking survivors of IPV are even more disadvantaged, given the dearth of linguistically and culturally appropriate interventions for IPV. We conducted semi-structured individual interviews with 17 healthcare workers, including physicians, nurses, and social workers, to describe how healthcare workers serving primarily low-income, Latina populations are currently screening and responding to IPV disclosure, and to explore the acceptability of integrating an interactive, personalized safety decision aid application-myPlan app-into the clinic setting. Despite recognition of IPV as a problem, none of the clinical sites had a protocol to guide screening and response to IPV disclosure. Screening practices varied across the sites, sometimes conducted by medical assistants prior to the provider visit and other times by the physician or nurse provider. When IPV was disclosed, it was often during assessment for a presenting problem such as poor sleep or anxiety. Most healthcare workers felt that clinical and community resources were limited for their patients experiencing IPV. The "warm hand-off" to a social worker was the most common response strategy when possible; otherwise, women were given information about available resources such as hotlines and safe houses. We discuss structural, family, and individual barriers to accessing safety resources for underserved women and review how an easily accessible safety decision app, such as myPlan, could be a resource for women to safely tailor an action plan for her situation. PMID- 29441597 TI - Toxic stress and protective factors in multi-ethnic school age children: A research protocol. AB - Exposure to stressful environments in early childhood can cause a toxic stress response and lead to poor health outcomes, including obesity, cardiac disease, diabetes, and mental illness. In animals and maltreated children, the presence of a nurturing caregiver can buffer against the physiological disruptions associated with a toxic stress response; however, the specific caregiver and parenting characteristics that best promote a protective relationship in humans remain largely unexplored, particularly in families living in high-risk environments. In this study, framed in an ecobiodevelopmental (EBD) model, a cross-sectional design is being used to study 54 multi-ethnic, urban maternal-child dyads with children at early school age (4-9 years). Mothers' past experiences, mental health, and caregiving patterns and children's hair cortisol, C-reactive protein, pro-inflammatory cytokines, blood pressure, BMI, behavior, and school performance are being analyzed to identify maternal characteristics that may protect against children's toxic stress response in families at high risk for exposure to stressors such as poverty, trauma, or exposure to violence. PMID- 29441598 TI - Genome-wide association analysis reveals the common genetic locus for both the typical and atypical polycerate phenotype in Tibetan sheep. PMID- 29441599 TI - Derivation of a no-significant-risk-level for tetrabromobisphenol A based on a threshold non-mutagenic cancer mode of action. AB - A no-significant-risk-level of 20 mg day-1 was derived for tetrabromobisphenol A (TBBPA). Uterine tumors (adenomas, adenocarcinomas, and malignant mixed Mullerian) observed in female Wistar Han rats from a National Toxicology Program 2-year cancer bioassay were identified as the critical effect. Studies suggest that TBBPA is acting through a non-mutagenic mode of action. Thus, the most appropriate approach to derivation of a cancer risk value based on US Environmental Protection Agency guidelines is a threshold approach, akin to a cancer safe dose (RfDcancer ). Using the National Toxicology Program data, we utilized Benchmark dose software to derive a benchmark dose lower limit (BMDL10 ) as the point of departure (POD) of 103 mg kg-1 day-1 . The POD was adjusted to a human equivalent dose of 25.6 mg kg-1 day-1 using allometric scaling. We applied a composite adjustment factor of 100 to the POD to derive an RfDcancer of 0.26 mg kg-1 day-1 . Based on a human body weight of 70 kg, the RfDcancer was adjusted to a no-significant-risk-level of 20 mg day-1 . This was compared to other available non-cancer and cancer risk values, and aligns well with our understanding of the underlying biology based on the toxicology data. Overall, the weight of evidence from animal studies indicates that TBBPA has low toxicity and suggests that high doses over long exposure durations are needed to induce uterine tumor formation. Future research needs include a thorough and detailed vetting of the proposed adverse outcome pathway, including further support for key events leading to uterine tumor formation and a quantitative weight of evidence analysis. PMID- 29441600 TI - Berberine inhibits experimental varicocele-induced cell cycle arrest via regulating cyclin D1, cdk4 and p21 proteins expression in rat testicles. AB - The aim of this study was to uncover the protective effect of berberine (BBR), an antioxidant chemical, on experimental varicocele (VCL)-induced adverse effects on cell cycle machinery during early germ cells mitosis. To follow-up this study, 30 mature male Wistar rats were divided into control-sham, nontreated VCL, 50 mg kg 1 and 100 mg kg-1 BBR-treated VCL groups. Following 60 days, histological alterations were analysed by haematoxylin and eosin (H and E) staining, and expressions of cyclin-D1, cyclin-dependent kinase-4 (cdk4) and p21 were investigated by immunohistochemical (IHC) staining technique. Finally, DNA ladder test was carried out to examine the testicular DNA fragmentation. Administration of BBR remarkably diminished the percentage of seminiferous tubules with deformed shape, depleted germ cells and germ cells dissociation compared to VCL-sole group. The IHC observations showed that BBR significantly (p < .05) reduced VCL induced p21 expression increase and up-regulated cyclin-D1 and cdk4 expressions. Moreover, BBR decreased VCL-induced DNA fragmentation. In conclusion, BBR can promote cell cycle through cellular DNA content protection, p21 expression down regulation and maintaining cyclin-D1 and cdk4 expressions. Thus, BBR could be considered as a novel protective biochemical agent against experimental VCL induced derangements. However, more studies are needed to uncover BBR-induced effects on cells cycle process and germ cells development. PMID- 29441601 TI - Refrigeration, cryopreservation and pathogen inactivation: an updated perspective on platelet storage conditions. AB - Conventional storage of platelet concentrates limits their shelf life to between 5 and 7 days due to the risk of bacterial proliferation and the development of the platelet storage lesion. Cold storage and cryopreservation of platelets may facilitate extension of the shelf life to weeks and years, and may also provide the benefit of being more haemostatically effective than conventionally stored platelets. Further, treatment of platelet concentrates with pathogen inactivation systems reduces bacterial contamination and provides a safeguard against the risk of emerging and re-emerging pathogens. While each of these alternative storage techniques is gaining traction individually, little work has been done to examine the effect of combining treatments in an effort to further improve product safety and minimize wastage. This review aims to discuss the benefits of alternative storage techniques and how they may be combined to alleviate the problems associated with conventional platelet storage. PMID- 29441602 TI - ERK1/2 and Akt phosphorylation were essential for MGF E peptide regulating cell morphology and mobility but not proangiogenic capacity of BMSCs under severe hypoxia. AB - : Severe hypoxia inhibits the adhesion and mobility of bone marrow-derived mesenchymal stem cells (BMSCs) and limits their application in bone tissue engineering. In this study, CoCl2 was used to simulate severe hypoxia and the effects of mechano-growth factor (MGF) E peptide on the morphology, adhesion, migration, and proangiogenic capacity of BMSCs under hypoxia were measured. It was demonstrated that severe hypoxia (500-MUM CoCl2 ) significantly caused cell contraction and reduced cell area, roundness, adhesion, and migration of BMSCs. RhoA and ROCK1 expression levels were upregulated by severe hypoxia, but p-RhoA and mobility-relevant protein (integrin beta1, p-FAK and fibronectin) expression levels in BMSCs were inhibited. Fortunately, MGF E peptide could restore all abovementioned indexes except RhoA expression. MEK-ERK1/2 pathway was involved in MGF E peptide regulating cell morphological changes, mobility, and relevant proteins (except p-FAK). PI3K-Akt pathway was involved in MGF E peptide regulating cell area, mobility, and relevant proteins. Besides, severe hypoxia upregulated vascular endothelial growth factor alpha expression but was harmful for proangiogenic capacity of BMSCs. Our study suggested that MGF E peptide might be helpful for the clinical application of tissue engineering strategy in bone defect repair. SIGNIFICANCE OF THE STUDY: Sever hypoxia impairs bone defect repair with bone marrow-derived mesenchymal stem cells (BMSCs). This study proved that mechano-growth factor E (MGF E) peptide could improve the severe hypoxia induced cell contraction and decline of cell adhesion and migration of BMSCs. Besides, MGF E peptide weakened the effects of severe hypoxia on the cytoskeleton arrangement- and mobility-relevant protein expression levels in BMSCs. The underlying molecular mechanism was also verified. Finally, it was confirmed that MGF E peptide showed an adverse effect on the expression level of vascular endothelial growth factor alpha in BMSCs under severe hypoxia but could make up for this deficiency through accelerating cell proliferation. PMID- 29441603 TI - Molecular analysis of CAG repeat length of the androgen receptor gene and Y chromosome microdeletions among Jordanian azoospermic infertile males. AB - Assisted reproductive technology is a common procedure which helps millions of couples who suffer fertility problems worldwide every year. Screening for genetic abnormalities prior to such procedure is very important to prevent the transmission of harmful genetic mutations to future generations. Microdeletions within the azoospermia factor (AZF) region of the Y chromosome and the expansion of the CAG trinucleotides in the androgen receptor (AR) gene are among the susceptible causes of male infertility in different ethnic groups. Such association has never been studied in Jordan. In this study, we compared CAG repeat length between azoospermic infertile and normospermic fertile Jordanian males and we also screened the frequency of Y chromosome microdeletions in the same cohort. The study included 142 nonobstructive azoospermic cases and 145 normospermic controls. Results have shown that the median CAG repeat length in the azoospermic group is 19 +/- 2 compared to 19 +/- 1.5 (p = .6262) in the control group. Deletions within the Y chromosome AZF region were detected in 7 of 142 cases (4.93%) and no deletions were seen in the control group. The results of this study confirm the importance of the AZF region in normal spermatogenesis, whereas it shows no link between the length of CAG repeats in the AR gene and male azoospermia in Jordanian group examined. PMID- 29441604 TI - National survey of patch testing in the United Kingdom and Republic of Ireland: what proportion of the population is and should be tested? AB - BACKGROUND: An initial study of patch testing practices across Wales, United Kingdom, showed wide variation in practice against a standardized set of guidelines and best practice recommendations. OBJECTIVES: To evaluate (i) current patch testing practice on a national level in the United Kingdom and Republic of Ireland (ROI), (ii) compliance with the current published guidelines, and (iii) the proportion of the catchment population tested by patch testing centres. METHODS: In consultation with the British Association of Dermatologists and British Society for Cutaneous Allergy, proformas addressing clinical guidelines and best practice recommendations were sent to all dermatology units in the United Kingdom and ROI. RESULTS: Ninety one of 325 centres (28%) performed patch testing. The optimum proportion of annual tests was not being achieved in the United Kingdom and ROI. The range tested varied between 1:1200 and 1:1600. CONCLUSIONS: Most centres achieved a high level of best practice outcomes. Shortcomings were found in the recording of minimum data, benchmarking, and attendance at meetings. We suggest that the findings of this study should be used as evidence to help improve services locally. PMID- 29441605 TI - Circulating 25-hydroxy vitamin D correlates with serum level of anti-Mullerian hormone in male patients with chronic kidney disease. AB - This study was designed to assess the relationship between serum levels of anti Mullerian hormone and 25-hydroxy vitamin D in chronic kidney disease male patients. For that, serum 25-hydroxy vitamin D and anti-Mullerian hormone along with follicle-stimulating hormone, luteinising hormone, prolactin, total testosterone and estradiol were assayed in 59 patients with different stages of chronic kidney disease and 21 healthy participants. Compared to controls, serum levels of anti-Mullerian hormone and 25-hydroxy vitamin D were significantly decreased in patients with chronic kidney disease. The decreased anti-Mullerian hormone level correlated positively with estimated glomerular filtration rate and serum levels of testosterone and 25-hydroxy vitamin D. Meanwhile, it was negatively correlated with age and serum levels of urea, creatinine, follicle stimulating hormone, luteinising hormone and prolactin. 25-Hydroxy vitamin D and luteinising hormone explained the 65.9% variability of anti-Mullerian hormone in a multiple linear regression model. However, anti-Mullerian hormone in crude correlation was more strongly associated with serum 25-hydroxy vitamin D than luteinising hormone. In conclusion, serum level of 25-hydroxy vitamin D might be a determinant factor of anti-Mullerian hormone level, and their relationship might explain in part the dysfunction of Sertoli cells and the impaired testicular functions in chronic kidney disease male patients. PMID- 29441606 TI - Differential research of inflammatory and related mediators in BPH, histological prostatitis and PCa. AB - Prostate cancer (PCa) is one of the most common male malignancies in the world. It was aimed to investigate differential expression of inflammatory and related factors in benign prostatic hyperplasia (BPH), prostate cancer (PCa), histological prostatitis (HP) and explore the role of Inducible nitric oxide synthase (iNOS), (VEGF) Vascular endothelial growth factor, androgen receptor (AR) and IL-2, IL-8 and TNF-alpha in the occurrence and development of prostate cancer. RT-PCR was used to detect the mRNA expression level of iNOS, VEGF, AR and IL-2, IL-8 and TNF-alpha in BPH, PCa and BPH+HP. Western blotting and immunohistochemical staining were used to detect the protein levels of various proteins in three diseases. The results showed the mRNA and protein levels of iNOS, VEGF and IL-2, IL-8 and TNF-alpha were significantly increased in PCa and BPH+HP groups compared with BPH group (p < .05), while the AR was significantly lower than those in PCa and BPH+HP groups (p < .05). There was no significant difference in the mRNA and protein levels of iNOS, VEGF, AR and IL-2, IL-8 and TNF-alpha between PCa and BPH+HP groups (p > .05). iNOS, VEGF, AR and IL-2, IL-8 and TNF-alpha are involved in the malignant transformation of prostate tissue and play an important role in the development and progression of Prostate cancer (PCa). PMID- 29441607 TI - An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for the assessment of sexual health of women with pelvic floor dysfunction. AB - AIMS: The terminology in current use for sexual function and dysfunction in women with pelvic floor disorders lacks uniformity, which leads to uncertainty, confusion, and unintended ambiguity. The terminology for the sexual health of women with pelvic floor dysfunction needs to be collated in a clinically-based consensus report. METHODS: This report combines the input of members of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA), and the International Continence Society (ICS), assisted at intervals by many external referees. Internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Importantly, this report is not meant to replace, but rather complement current terminology used in other fields for female sexual health and to clarify terms specific to women with pelvic floor dysfunction. RESULTS: A clinically based terminology report for sexual health in women with pelvic floor dysfunction encompassing over 100 separate definitions, has been developed. Key aims have been to make the terminology interpretable by practitioners, trainees, and researchers in female pelvic floor dysfunction. Interval review (5-10 years) is anticipated to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus based terminology report for female sexual health in women with pelvic floor dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research. PMID- 29441608 TI - Hyperpolarized Laplace NMR. AB - Laplace nuclear magnetic resonance (NMR), dealing with NMR relaxation and diffusion experiments, reveals details of molecular motion and provides chemical resolution complementary to NMR spectra. Laplace NMR has witnessed a great progress in past decades due to the development of methodology and signal processing, and it has lots of extremely interesting applications in various fields, including chemistry, biochemistry, geology, archaeology, and medicine. The aim of this minireview is to give a pedagogically oriented overview of Laplace NMR. It does not provide a full literature review of the field, but, instead, it elucidate the benefits and features of Laplace NMR methods through few selected examples. The minireview describes also recent progress in multidimensional Laplace NMR and Laplace inversion methods. Furthermore, the potential of modern hyperpolarization methods as well as ultrafast approach to increase the sensitivity and time-efficiency of the Laplace NMR experiments is highlighted. PMID- 29441609 TI - Histopathological characteristics of ketamine-associated uropathy and their clinical association. AB - AIM: To investigate the histopathological findings in ketamine-associated uropathy (KU) and their clinical association. METHODS: Thirty-eight KU patients had received history investigation and video urodynamic study. Twelve of them were clinically mild KU who were admitted for cystoscopic hydrodistention. The other 26 patients were severe KU who were admitted for enterocystoplasty with or without ureter reimplantation. Bladder and ureter specimens were harvested during operation, and a single pathologist reviewed all specimens under hematoxylin and eosin stain. The severity of histopathological findings was graded with a 4-point scale (0: none, 1: mild, 2: moderate, and 3: severe) RESULTS: Inflammatory cells infiltrations and nerve hyperplasia were found in the mucosa, muscle, and subserosal layers of KU bladders and ureter. In the mild KU bladder mucosa, the predominant component of the infiltrating inflammatory cells was lymphocytes. In contrast, neutrophils, eosinophils, lymphocytes, and plasma cells infiltration were noted in the mucosa of almost all severe KU bladders. Clinical severe KU was significantly correlated with severe to moderate lymphocytes, plasma cells, neutrophils, eosinophils infiltration, and nerve hyperplasia in bladder mucosa. KU patients with moderate or severe neutrophils or lymphocytes infiltration in bladder mucosa had significantly more severe bladder pain and smaller bladder capacity. CONCLUSION: The histological findings of KU showed whole-layer inflammation and nerve hyperplasia in bladder mucosa. The severity of inflammatory cell infiltration in the bladder mucosa is associated with clinical symptoms. A histopathological examination might be a useful tool to discriminate the KU severity in patients. PMID- 29441610 TI - A cross sectional single institution study of quality of life in adult patients with spina bifida. AB - OBJECTIVE: To describe and compare differences in perception of independence, urinary continence, and quality of life in an adult spina bifida (SB) population. METHODS: We collected data on adult neurogenic bladder patients which included demographics, relevant procedures, and quality of life (QoL) questionnaires. QoL and functional outcomes were assessed using spinal cord independence measure (SCIM) and SF-8 health questionnaire. International consultation of incontinence questionnaire (ICIQ) was used to assess incontinence. Comparisons were drawn between patients who underwent surgical reconstruction and those who did not. Student t-tests were used for comparisons and a P-value <0.05 was considered statistically significant. RESULTS: Fifty-four patients with SB were included. A total of 43% underwent bladder augmentation (BA) and 30% underwent antegrade continence enema (ACE). Patients with BA scored 49 +/- 25 on the SCIM survey while those without had higher scores of 68 +/- 19 with a P-value of 0.016. This difference remained evident when patients with ACE were excluded. When comparing ICIQ and SF-8, no statistically significant differences were found between those who underwent surgical procedures and those who did not. CONCLUSIONS: Assessing QoL in congenital NGB patients is a complex task. In our cohort, patients who underwent BA and ACE were shown to have decreased SCIM scores. SCIM scores for BA patients were significantly higher in patients who did not receive a BA independent of ACE status. SF-8 and ICIQ scores did not show any statistically significant difference in quality of life survey scores in those who underwent procedures versus those who did not. PMID- 29441611 TI - Asymptomatic facial nodules. PMID- 29441612 TI - Corrigendum. PMID- 29441613 TI - Rational Design of Multifunctional Fe@gamma-Fe2 O3 @H-TiO2 Nanocomposites with Enhanced Magnetic and Photoconversion Effects for Wide Applications: From Photocatalysis to Imaging-Guided Photothermal Cancer Therapy. AB - Titanium dioxide (TiO2 ) has been widely investigated and used in many areas due to its high refractive index and ultraviolet light absorption, but the lack of absorption in the visible-near infrared (Vis-NIR) region limits its application. Herein, multifunctional Fe@gamma-Fe2 O3 @H-TiO2 nanocomposites (NCs) with multilayer-structure are synthesized by one-step hydrogen reduction, which show remarkably improved magnetic and photoconversion effects as a promising generalists for photocatalysis, bioimaging, and photothermal therapy (PTT). Hydrogenation is used to turn white TiO2 in to hydrogenated TiO2 (H-TiO2 ), thus improving the absorption in the Vis-NIR region. Based on the excellent solar driven photocatalytic activities of the H-TiO2 shell, the Fe@gamma-Fe2 O3 magnetic core is introduced to make it convenient for separating and recovering the catalytic agents. More importantly, Fe@gamma-Fe2 O3 @H-TiO2 NCs show enhanced photothermal conversion efficiency due to more circuit loops for electron transitions between H-TiO2 and gamma-Fe2 O3 , and the electronic structures of Fe@gamma-Fe2 O3 @H-TiO2 NCs are calculated using the Vienna ab initio simulation package based on the density functional theory to account for the results. The reported core-shell NCs can serve as an NIR-responsive photothermal agent for magnetic-targeted photothermal therapy and as a multimodal imaging probe for cancer including infrared photothermal imaging, magnetic resonance imaging, and photoacoustic imaging. PMID- 29441614 TI - Characterization of oily mature skin by biophysical and skin imaging techniques. AB - BACKGROUND: The skin is a complex biological system and may suffer change according to the environmental factors, as higher temperatures can increase sebum excretion, presenting oiliness and acne. These alterations can persist during the aging and provoke more changes in aged skin. In this study we evaluated the mature oily skin characteristics using biophysical and skin imaging techniques. MATERIAL AND METHODS: Sixty healthy female subjects, aged between 39 and 55 years old were recruited and separated into 2 groups according to their skin type: normal/dry and oily skin. The skin was evaluated in terms of stratum corneum water content, transepidermal water loss (TEWL) sebum content, dermis thickness and echogenicity, skin microrelief, and pores content. RESULTS: The mature oily skin presented no significant differences when compared to the normal/dry skin on the stratum corneum water content and TEWL parameters. The sebum content was significantly higher on the oily skin group. The microrelief analysis showed an increase of skin roughness values in the oily skin and increase of scaliness in the normal/dry skin. The oily skin showed lower dermis echogenicity mainly in the frontal region and higher dermis thickness when compared to normal/dry skin. CONCLUSION: The mature oily skin showed different characteristics from normal/dry skin in terms of sebum content, microrelief parameters, and dermis thickness. This way, the characterization of mature oily skin in an objective way is very important to development of dermocosmetic products for more effective treatments focused specially on this type of skin. PMID- 29441615 TI - Amide-Catalyzed Phase-Selective Crystallization Reduces Defect Density in Wide Bandgap Perovskites. AB - Wide-bandgap (WBG) formamidinium-cesium (FA-Cs) lead iodide-bromide mixed perovskites are promising materials for front cells well-matched with crystalline silicon to form tandem solar cells. They offer avenues to augment the performance of widely deployed commercial solar cells. However, phase instability, high open circuit voltage (Voc ) deficit, and large hysteresis limit this otherwise promising technology. Here, by controlling the crystallization of FA-Cs WBG perovskite with the aid of a formamide cosolvent, light-induced phase segregation and hysteresis in perovskite solar cells are suppressed. The highly polar solvent additive formamide induces direct formation of the black perovskite phase, bypassing the yellow phases, thereby reducing the density of defects in films. As a result, the optimized WBG perovskite solar cells (PSCs) (Eg ~ 1.75 eV) exhibit a high Voc of 1.23 V, reduced hysteresis, and a power conversion efficiency (PCE) of 17.8%. A PCE of 15.2% on 1.1 cm2 solar cells, the highest among the reported efficiencies for large-area PSCs having this bandgap is also demonstrated. These perovskites show excellent phase stability and thermal stability, as well as long term air stability. They maintain ~95% of their initial PCE after 1300 h of storage in dry air without encapsulation. PMID- 29441616 TI - Augmenting Photoinduced Charge Transport in a Single-Component Gel System: Controlled In Situ Gel-Crystal Transformation at Room Temperature. AB - Smart single-component materials with versatile functions require pre-programming of a higher order molecular assembly. An electroactive supergelator (c=0.07 wt %) triphenylamine core-appended poly(aryl ether) dendron (TPAPAE) is described, where substantial dendritic effects improve the order and crystallinity by switching the local minima from self-assembled molecular wires to thermodynamically favorable global minima of ordered crystals, ripened within the fibers. Controlled in situ phase change at room temperature ultimately stabilized the mixed valence states in the single-component supramolecular assembly with photoluminescence and photoinduced charge transport amplified by two orders of magnitude. PMID- 29441617 TI - Flourishing Bioinspired Antifogging Materials with Superwettability: Progresses and Challenges. AB - Antifogging (AF) structure materials found in nature have great potential for enabling novel and emerging products and technologies to facilitate the daily life of human societies, attracting enormous research interests owing to their potential applications in display devices, traffics, agricultural greenhouse, food packaging, solar products, and other fields. The outstanding performance of biological AF surfaces encourages the rapid development and wide application of new AF materials. In fact, AF properties are inextricably associated with their surface superwettability. Generally, the superwettability of AF materials depends on a combination of their surface geometrical structures and surface chemical compositions. To explore their general design principles, recent progresses in the investigation of bioinspired AF materials are summarized herein. Recent developments of the mechanism, fabrication, and applications of bioinspired AF materials with superwettability are also a focus. This includes information on constructing superwetting AF materials based on designing the topographical structure and regulating the surface chemical composition. Finally, the remaining challenges and promising breakthroughs in this field are also briefly discussed. PMID- 29441618 TI - Enhanced Drug Photosafety by Interchromophoric Interaction Owing to Intramolecular Charge Separation. AB - Imatinib is a synthetic tyrosinase inhibitor that is employed for the treatment of some kinds of human cancer. This drug has a low phototoxicity towards DNA, but its pyridylpyrimidine (1) fragment by itself exhibits significant phototoxicitiy. The intrinsic mechanism that leads to the enhanced photosafety of Imatinib is not yet known. Here, the properties of the excited state and interchromophoric interactions of Imatinib have been explored by using ultrafast laser flash photolysis and agarose electrophoresis studies. An intramolecular charge separation was directly observed for the irradiated Imatinib, which accounts for the relaxation of its excited state. An anionic form of pyridylpyrimidine (1) was deduced from the results of time-resolved resonance Raman spectra and by quenching experimental studies on compound 1 and diaminotoluene. In contrast, compound 1 efficiently transformed into triplet excited states with a long lifetime, which explained the phototoxicity associated with this fragment. This work provides insight into how to design drugs with lower phototoxicitiy or improved photostability by using interchromophoric interactions. PMID- 29441620 TI - Heterogeneous Single-Atom Catalyst for Visible-Light-Driven High-Turnover CO2 Reduction: The Role of Electron Transfer. AB - Visible-light-driven conversion of CO2 into chemical fuels is an intriguing approach to address the energy and environmental challenges. In principle, light harvesting and catalytic reactions can be both optimized by combining the merits of homogeneous and heterogeneous photocatalysts; however, the efficiency of charge transfer between light absorbers and catalytic sites is often too low to limit the overall photocatalytic performance. In this communication, it is reported that the single-atom Co sites coordinated on the partially oxidized graphene nanosheets can serve as a highly active and durable heterogeneous catalyst for CO2 conversion, wherein the graphene bridges homogeneous light absorbers with single-atom catalytic sites for the efficient transfer of photoexcited electrons. As a result, the turnover number for CO production reaches a high value of 678 with an unprecedented turnover frequency of 3.77 min 1 , superior to those obtained with the state-of-the-art heterogeneous photocatalysts. This work provides fresh insights into the design of catalytic sites toward photocatalytic CO2 conversion from the angle of single-atom catalysis and highlights the role of charge kinetics in bridging the gap between heterogeneous and homogeneous photocatalysts. PMID- 29441621 TI - Novel interstitial deletion in Xp22.3 in a typical X-linked recessive family with Kallmann syndrome. AB - Kallmann syndrome (KS) is a clinically and genetically heterogeneous condition characterised by hypogonadotropic hypogonadism with anosmia or hyposmia. More than nineteen genes causing KS have been reported to date. KAL1, first identified to causing the X-linked form of KS, accounts for 10%-20% of KS patients. In this study, we designed a panel including 17 known genes causing KS for genetic diagnosis and research and report a typical and rare family of which three generations had been affected by KS. A novel CNV in Xp22.3 was identified through targeted next-sequencing technology and high-resolution microarray. The breakpoint (chrX:8536480 and chrX:8730416) was defined, and the size of deletion is about 0.24 Mb. The CNV including KAL1 and FAM9A had a negative effect on the expression of KAL1, resulting in decreased level of KAL1 mRNA in whole blood. In addition, the proband had significant improvement in testicular volumes and secondary sex characters except spermatogenesis after regular treatment, which indicates the CNV may have a negative effect on spermatogenesis. Our study expands the genotypic spectrum of KAL1 mutations associated with KS and provides a practical pipeline for genetic diagnosis or research. PMID- 29441622 TI - Self-Assembly of a Guanosine Derivative To Form Nanostructures and Transmembrane Channels. AB - We herein report the self-assembly of a lipophilic bromoguanosine derivative (G1) in homogeneous solution, in the solid state and in planar bilayer membranes. The self-assembly of G1, driven by H-bonding and pi-pi stacking interactions can form different nano-structures depending on incubation time. The G1 nanostructure is able to bind a bioactive dye like Rose Bengal. In crystal state, it shows ribbon type H-bonding pattern and exhibits birefringence in polarized light. And further, the self-assembled nanostructure of G1 can form discrete transmembrane ion channels in lipid bilayer membranes, enabling passage of potassium ions. PMID- 29441623 TI - 12-Vertex Zwitterionic Bis-phosphonium-nido-carborates through Ring-Opening Reactions of 1,2-Diphosphetanes. AB - Carborane-substituted 1,2-diphosphetanes (Ia,b) react with elemental lithium in THF with cleavage of the P-P bond to give a deep red solution from which, in the case of Ia, red crystals of a lithiated intermediate, [{1-Li(THF)PtBu-6-PtBu 4,1,6-closo-Li(THF)C2 B10 H10 }{Li(THF)3 }]2 ?2 THF (2 a), are obtained. The compound is dimeric, C2 -symmetric and contains six lithium and four phosphorus atoms. Two lithium atoms cap the six-membered C2 B4 faces, resulting in two 13 vertex closo-clusters (according to Wade's rules) with docosahedral geometry. The addition of methyl iodide resulted in the formation of zwitterionic bis phosphonium-nido-carborates 7,10-bis(tert-butyldimethylphosphonium)dodecahydro 7,10-dicarba-nido-dodecaborate(2-) (1 a) and 7,10-bis(N,N diisopropylaminodimethylphosphonium)dodecahydro-7,10-dicarba-nido-dodecaborate(2 ) (1 b) in moderate to good yields. Compounds 1 a and 1 b exhibit short Ccluster P bonds and large Ccluster ???Ccluster distances in the solid state. Further insight into the ring opening and reduction potential of the alkyl halide was obtained from methylation reactions of different 1,2-bis-phosphinocarboranes. The reaction of rac-/meso-1,2-bis(tert-butylmethylphosphino)-1,2-dicarba-closo dodecaborane(12) (3 a) with two equivalents of methyl iodide also resulted in the formation of 1 a (as shown by NMR spectroscopy), whereas the reaction of 1,2 bis(diphenylphosphino)-1,2-dicarba-closo-dodecaborane(12) with methyl triflate afforded the phosphonium salt 1-methyl-diphenylphosphonium-2-diphenylphosphino 1,2-dicarba-closo-dodecaborane(12) triflate (4) without reduction of the cluster. PMID- 29441624 TI - Optimization of Synthetically Versatile Pyridylidene Amide Ligands for Efficient Iridium-Catalyzed Water Oxidation. AB - The synthetic versatility of pyridylidene amide (PYA) ligands has been exploited to prepare and evaluate a diverging series of iridium complexes containing C,N bidentate chelating aryl-PYA ligands for water oxidation catalysis. The phenyl PYA lead structure 1 was modified (i) electronically through introduction of one, two, or three electron-donating methoxy substituents on the aryl ring, (ii) by incorporating long aliphatic chains to the pyridyl fragment of the PYA unit, and (iii) by altering the PYA positions from para-PYA to its ortho- and meta-isomers. Electrochemistry indicated no substantial electronic effect of the aliphatic chains, and only minor changes of the electron density at iridium when modifying the aryl ligand site, yet substantial alteration if the PYA ligand is the ortho- (E1/2 =+0.72 V), para- (E1/2 =+0.64 V), or meta-isomer (E1/2 =+0.56 V vs. saturated calomel electrode; SCE). In water oxidation catalysis, the long alkyl chains did not induce any rate enhancement compared with the phenyl-PYA lead compound, whereas MeO groups incorporated in the aryl group enhanced the catalytic activity from a turnover frequency (TOFmax )=1600 h-1 in the original Ph-PYA system gradually as more MeO groups were introduced up to a TOFmax =3300 h 1 for a tris(MeO)-substituted aryl-PYA system. The variation of the PYA substitution had only a minor impact on catalytic activity and revealed only a weak trend in the sequence ortho>meta>para. The high activity of the tris(MeO) system and the ortho-PYA isomer were attributed to efficient hydrogen bonding, which assists O-H bond activation and proton transfer. Remarkably, merging of the two optimized motifs, that is, an aryl unit with three MeO substituents and the PYA as the ortho isomer, into a single new aryl-PYA ligand system failed to improve the catalytic activity. Computational analysis suggests too much congestion at the active site, which hinders catalytic turnover. These results illustrate the complexity of ligand design and the subtle effects at play in water oxidation catalysis. PMID- 29441625 TI - Biodegradable Spheres Protect Traumatically Injured Spinal Cord by Alleviating the Glutamate-Induced Excitotoxicity. AB - New treatment strategies for spinal cord injury with good therapeutic efficacy are actively pursued. Here, acetalated dextran (AcDX), a biodegradable polymer obtained by modifying vicinal diols of dextran, is demonstrated to protect the traumatically injured spinal cord. To facilitate its administration, AcDX is formulated into microspheres (~7.2 um in diameter) by the droplet microfluidic technique. Intrathecally injected AcDX microspheres effectively reduce the traumatic lesion volume and inflammatory response in the injured spinal cord, protect the spinal cord neurons from apoptosis, and ultimately, recover the locomotor function of injured rats. The neuroprotective feature of AcDX microspheres is achieved by sequestering glutamate and calcium ions in cerebrospinal fluid. The scavenging of glutamate and calcium ion reduces the influx of calcium ions into neurons and inhibits the formation of reactive oxygen species. Consequently, AcDX microspheres attenuate the expression of proapoptotic proteins, Calpain, and Bax, and enhance the expression of antiapoptotic protein Bcl-2. Overall, AcDX microspheres protect traumatically injured spinal cord by alleviating the glutamate-induced excitotoxicity. This study opens an exciting perspective toward the application of neuroprotective AcDX for the treatment of severe neurological diseases. PMID- 29441626 TI - Identification of metabolites of anticancer candidate salinomycin using liquid chromatography coupled with quadrupole time-of-flight and hybrid triple quadrupole linear ion trap mass spectrometry. AB - RATIONALE: Salinomycin is an ionophore antibiotic with potential anticancer activity. The history of its use in veterinary medicine shows large differences in species susceptibility to its toxicity. At the same time, the results of research to date suggest a correlation between the extent and pathways of ionophore biotransformation and its toxicity. The biotransformation pattern of salinomycin has not been studied so far. METHODS: Extracts from culture media of human hepatoma cells (HepG2) exposed to salinomycin were analysed with two mass spectrometry techniques. For the first one, micro-liquid chromatography coupled with a quadrupole time-of-flight (Q-TOF) mass spectrometer was used. In the second approach, high-performance liquid chromatography was coupled with a hybrid triple quadrupole linear ion trap. Both experiments were operated in positive electrospray ionization mode. To identify unknown salinomycin metabolites, information-dependent acquisition was applied. RESULTS: Metabolites identified with tandem mass spectrometry included hydroxylated, demethylated and hydroxylated-demethylated derivatives, in total 14 compounds. Using high resolution, only eight isomers of hydroxysalinomycin were detected. The efficiency of biotransformation was low, and so was the abundance of the signals; only for two metabolites did the signal exceed 1% of the salinomycin signal. The analysis of fragmentation patterns narrowed the structure combinations but the actual modification site could not be specified. CONCLUSIONS: Tandem mass spectrometry was more sensitive in the identification of salinomycin metabolites in comparison to the Q-TOF approach. Because of low efficiency of biotransformation of the applied model, the obtained fragmentation data are not sufficient to fully characterize the detected compounds. A study with more metabolically active primary hepatocytes is needed. PMID- 29441628 TI - A serine protease homologue Bombyx mori scarface induces a short and fat body shape in silkworm. AB - Body shape is one of the most prominent and basic characteristics of any organism. In insects, abundant variations in body shape can be observed both within and amongst species. However, the molecular mechanism underlying body shape fine-tuning is very complex and has been largely unknown until now. In the silkworm Bombyx mori, the tubby (tub) mutant has an abnormal short fat body shape and the abdomen of tub larvae expands to form a fusiform body shape. Morphological investigation revealed that the body length was shorter and the body width was wider than that of the Dazao strain. Thus, this mutant is a good model for studying the molecular mechanisms of body shape fine-tuning. Using positional cloning, we identified a gene encoding the serine protease homologue, B. mori scarface (Bmscarface), which is associated with the tub phenotype. Sequence analysis revealed a specific 312-bp deletion from an exon of Bmscarface in the tub strain. In addition, recombination was not observed between the tub and Bmscarface loci. Moreover, RNA interference of Bmscarface resulted in the tub like phenotype. These results indicate that Bmscarface is responsible for the tub mutant phenotype. This is the first study to report that mutation of a serine protease homologue can induce an abnormal body shape in insects. PMID- 29441627 TI - A targeted genotyping approach enhances identification of variants in taste receptor and appetite/reward genes of potential functional importance for obesity related porcine traits. AB - Taste receptors (TASRs) and appetite and reward (AR) mechanisms influence eating behaviour, which in turn affects food intake and risk of obesity. In a previous study, we used next generation sequencing to identify potentially functional mutations in TASR and AR genes and found indications for genetic associations between identified variants and growth and fat deposition in a subgroup of animals (n = 38) from the UNIK resource pig population. This population was created for studying obesity and obesity-related diseases. In the present study we validated results from our previous study by investigating genetic associations between 24 selected single nucleotide variants in TASR and AR gene variants and 35 phenotypes describing obesity and metabolism in the entire UNIK population (n = 564). Fifteen variants showed significant association with specific obesity-related phenotypes after Bonferroni correction. Six of the 15 genes, namely SIM1, FOS, TAS2R4, TAS2R9, MCHR2 and LEPR, showed good correlation between known biological function and associated phenotype. We verified a genetic association between potentially functional variants in TASR/AR genes and growth/obesity and conclude that the combination of identification of potentially functional variants by next generation sequencing followed by targeted genotyping and association studies is a powerful and cost-effective approach for increasing the power of genetic association studies. PMID- 29441629 TI - The acceptability and feasibility of lay-health led interventions for the prevention and early detection of cancer. AB - BACKGROUND: US-based evidence suggests that lay-health worker (LHW) interventions can increase awareness around cancer risk-related lifestyles, symptom recognition, and screening programme uptake. The suitability of LHW interventions in the UK and the potential barriers and facilitators for implementation is currently unknown. This study explored the acceptability and feasibility of developing LHW interventions for cancer prevention, screening, and early diagnosis. METHODS: Purposive sampling recruited 5 separate lay groups: (1) completed cancer treatment; (2) friends/family of cancer patients; (3) cancer hospital volunteers; (4) cancer charity volunteers; and (5) members of the public. Audio-recorded focus groups and semi-structured interviews were transcribed for thematic analysis using framework matrices. RESULTS: Forty-one people (66% female, aged 23-84 years) participated. Three main themes are reported: (1) scope of LHW roles, with a clear remit embedded within communities or primary care practices; (2) defining LHW tasks, with a focus on supporting people overcome barriers including lack of cancer symptom knowledge and non attendance at screening; and (3) clear boundaries, with LHW training and on-going support from healthcare staff seen as key for intervention success. All groups were uncomfortable about having lifestyle-related risk conversations and potentially inflicting guilt. The post-treatment group expressed less concern about the possible emotional impact of discussing cancer symptoms, compared with the other groups. CONCLUSIONS: LHW interventions to promote early diagnosis or screening were generally considered acceptable in a UK context. LHW interventions focussing on reducing cancer risk may be less feasible. PMID- 29441630 TI - A case for clean conferences in gambling research. AB - INTRODUCTION AND AIMS: Gambling research is characterised by widespread gambling industry involvement. It is likely (as with alcohol and tobacco industry influence) that this will delay or divert effective harm prevention or minimisation measures. Gambling harms are known to be significant and widespread. Effective action to reduce these harms requires concomitant efforts to eliminate industry influence. DESIGN AND METHODS: Gambling industry influence and activity in three research forums is described. The influence of tobacco and alcohol industry involvement in research directions and outcomes is discussed. Aspects of the discursive elements of industry funded and/or directed research outputs are analysed in the context of industry-friendly discourse and its effects. Industry activity and participation at representative research forums is outlined. RESULTS: The examples and background provided demonstrate that specific material and discursive effects of gambling industry involvement can be discerned in the gambling literature. The consequences of this for the gambling evidence base around harm prevention and minimisation are presented. DISCUSSION AND CONCLUSIONS: Industry influence operates at multiple levels within the gambling research field. There is increasing awareness of this, and of the effects it may have on the development and deployment of effective harm prevention and minimisation efforts. Key reforms are proposed: (i) the elimination of industry participation and sponsorship of gambling research associations and forums; and (ii) the establishment where necessary of new research forums and international scholarly associations. PMID- 29441631 TI - Respirable powder formulation of a shortened vasoactive intestinal peptide analog for treatment of airway inflammatory diseases. AB - The aim of present study was to develop a respirable powder (RP) of a shortened vasoactive intestinal peptide (VIP) analog for inhalation. VIP and C-terminally truncated VIP analogs were synthesized with a solid-phase method. A structure activity relationship (SAR) study was carried out in terms with binding and relaxant activities of the peptides. Prepared RP formulation of a shortened VIP analog was physicochemically characterized by morphological, in vitro aerodynamic, and pharmacological assessments. The SAR study demonstrated that the N-terminal 23 amino acid residues were required for biological activity of VIP. Upon chemical modification of VIP(1-23), [R15, 20, 21 , L17 ]-VIP(1-23) was newly developed, which had higher binding activity in rat lung and smooth muscle relaxant effect in mouse stomach than VIP(1-23). The [R15, 20, 21 , L17 ]-VIP(1 23)-based RP, [R15, 20, 21 , L17 ]-VIP(1-23)/RP, exhibited fine in vitro inhalation performance. Airway inflammation evoked by sensitization of antigen in rats was attenuated by pre-treatment with the [R15, 20, 21 , L17 ]-VIP(1-23)/RP at a dose of 50 MUg-[R15, 20, 21 , L17 ]-VIP(1-23)/rat as evidenced by a 70% reduction of recruited inflammatory cells in bronchoalveolar lavage fluid. On the basis of these results, [R15, 20, 21 , L17 ]-VIP(1-23)/RP might be a promising agent for treatment of airway inflammatory diseases. PMID- 29441632 TI - Cross-country comparison of proportion of alcohol consumed in harmful drinking occasions using the International Alcohol Control Study. AB - INTRODUCTION AND AIMS: This study examines the proportion of alcohol markets consumed in harmful drinking occasions in a range of high-, middle-income countries and assesses the implications of these findings for conflict of interest between alcohol producers and public health and the appropriate role of the alcohol industry in alcohol policy space. DESIGN AND METHODS: Cross-sectional surveys were conducted in 10 countries as part of the International Alcohol Control study. Alcohol consumption was measured using location- and beverage specific measures. A level of consumption defined as harmful use of alcohol was chosen and the proportion of the total market consumed in these drinking occasions was calculated for both commercial and informal alcohol. RESULTS: In all countries, sizeable proportions of the alcohol market were consumed during harmful drinking occasions. In general, a higher proportion of alcohol was consumed in harmful drinking occasions by respondents in the middle-income countries than respondents in the high-income countries. The proportion of informal alcohol consumed in harmful drinking occasions was lower than commercial alcohol. DISCUSSION AND CONCLUSIONS: Informal alcohol is less likely to be consumed in harmful drinking occasions compared with commercial alcohol. The proportion of commercial alcohol consumed in harmful drinking occasions in a range of alcohol markets shows the reliance of the transnational alcohol corporations on harmful alcohol use. This reliance underpins industry lobbying against effective policy and support for ineffective approaches. The conflict of interest between the alcohol industry and public health requires their exclusion from the alcohol policy space. PMID- 29441634 TI - Corrigendum. PMID- 29441633 TI - Balance or tension? Walking the tightrope between training and patient care. PMID- 29441636 TI - In search of meaningful feedback conversations. PMID- 29441637 TI - From intelligence analysis to medical education: using structured tools to manage bias. PMID- 29441638 TI - Where is student support most needed? PMID- 29441639 TI - Efficiency in health care professional education. PMID- 29441640 TI - Erratum. PMID- 29441641 TI - The need for formal peer support programmes for international medical graduates. PMID- 29441642 TI - Lycra splinting garments for adults with intellectual disabilities who fall due to gait or balance issues: a feasibility study. AB - BACKGROUND: Adults with intellectual disabilities (IDs) experience high rates of falls and have high rates of gait or balance issues which contribute to falls. Lycra splinting garments (LSGs) have potential to improve gait or balance, but they have never before been tested with adults with IDs who fall due to gait or balance issues. The aim of this study was to test in adults with IDs, the feasibility of using LSGs to improve movement and function and reduce falls, whilst also exploring usability and likely compliance. METHOD: A convenience sample of nine adults with IDs wore tailored LSGs over a 6-week assessment period. Laboratory-based foot clearance, balance, and gait measures were collected pre- and post-LSG-wear. Falls charts and questionnaires on usability and likely compliance were also completed. RESULTS: Seven participants experienced a reduction in falls during their six weeks of LSG wear; most notably in the group of five participants who wore lycra splinting socks, compared with only two in the group of four who wore lycra splinting shorts or leggings only. CONCLUSION: Lycra splinting socks are likely to bring about positive outcomes for adults with IDs who fall due to gait/balance issues on an individual case by case basis over time, but further research is required to test this hypothesis under randomised controlled trial conditions. Potential benefits of more intrusive LSGs are outweighed by reported problems with usability and compliance. PMID- 29441643 TI - Methyl group transfer upon gas phase decomposition of protonated methyl benzoate and similar compounds. AB - Gas phase decompositions of protonated methyl benzoate and its conjugates have been studied by using electrospray ionization-collision induced dissociation tandem mass spectrometry. Loss of CO2 molecule, thus transfer of methyl group, has been observed. In order to better understand this process, the theoretical calculations have been performed. For methyl benzoate conjugates, it has been found that position of substituent affects the loss of CO2 molecule, not the electron donor/withdrawing properties of the substituent. Therefore, electrospray ionization-mass spectrometry in positive ion mode may be useful for differentiation of isomers of methyl benzoate conjugates. PMID- 29441644 TI - Brief school-based interventions to assist adolescents' sleep-onset latency: Comparing mindfulness and constructive worry versus controls. AB - Difficulties falling asleep are common among adolescents, especially during times of stress. Adolescents may thus benefit from brief techniques (15 min) that decrease pre-sleep cognitive-emotional arousal and sleep-onset latency. The present study used a 3 (intervention: mindfulness bodyscan mp3, constructive worry, control) by 3 (time: baseline, week 1, week 2) mixed-model design on a school-based sample of adolescents (N = 232; Mage = 15.9 +/- 0.8 years, range = 14-18 years; 19% male), and a sub-sample of adolescents with prolonged sleep onset latency (i.e. >=30 min; N = 119; Mage = 16.9 +/- 0.9 years; 21% male). It was expected that the 15-min pre-recorded breath-based mindfulness bodyscan, and constructive worry, would decrease sleep-onset latency and pre-sleep arousal similarly over time, relative to the control condition. A significant interaction was observed among adolescents with prolonged sleep-onset latency, who completed >=3 days for at least 1 week (p = .001), where mindfulness decreased sleep-onset latency relative to constructive worry and the control. Neither technique changed pre-sleep worry or cognitive-emotional arousal, or associated daytime functioning (both the whole sample and sub-sample). A pre-recorded mp3 breath-based mindfulness bodyscan technique is a promising means by which adolescents with prolonged sleep-onset latency can decrease sleep-onset latency. This simple tool has potential for scalable dissemination by stakeholders (e.g. teachers), unqualified to treat adolescent sleep difficulties. Future studies are needed to determine whether benefits may extend to academic performance and mental health, if performed for a longer time period with increased compliance. PMID- 29441646 TI - bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM)-the active metabolite of the laxatives bisacodyl and sodium picosulfate-enhances contractility and secretion in human intestine in vitro. AB - BACKGROUND: Stimulant laxatives are widely used to treat constipation. We investigated in human small and large intestinal preparations the effects of bis (p-hydroxyphenyl)-pyridyl-2-methane (BHPM), the active metabolite of the laxatives bisacodyl and sodium picosulfate on smooth muscle tone and epithelial secretion. METHODS: Circular and longitudinal muscle tone of small or large intestinal preparations were recorded with isometric force transducers. Epithelial ion flux (ISC ) and tissue resistance was measured with Ussing chamber technique after apical and basolateral BHPM application to large intestinal mucosa/submucosa preparations. Studies were performed in macroscopically normal specimens from 79 patients. KEY RESULTS: BHPM concentration-dependently (0.5-5 MUM) increased the tone of circular and longitudinal muscle from small to large intestine. The effect was strongest in large intestinal longitudinal muscle and smallest in small intestinal circular muscle. Increase in muscle tone was prevented by the L-type Ca++ channel blocker nifedipine but insensitive to the nerve blocker tetrodotoxin. Apical or basolateral BHPM concentration-dependently decreased or increased ISC, respectively. The KCa 1.1 (BK) channel blocker iberiotoxin reversed apical ISC decrease whereas tetrodotoxin reversed basolateral ISC increase. BHPM had no effect on tissue resistance or nerve mediated secretory or muscle response with one exception: at the highest concentration basolateral BHPM reduced nerve-mediated secretion. CONCLUSIONS AND INTERFERENCES: BHPM enhanced mucosal secretion and muscle contractility. Results suggested that the laxative effect of BHPM was a consequence of the increase in muscle tone as well as an increased K+ secretion when acting luminally and a nerve-driven Cl- and HCO3- secretion once acting basolaterally after absorption. PMID- 29441645 TI - Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate. AB - Aging severely limits myocardial repair and regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesized that short telomeres activate p53 and induce autophagy to elicit the age-associated change in CPC fate. We isolated CPCs and compared mouse strains with different telomere lengths for phenotypic characteristics of aging. Wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres exhibits early cardiac aging with cardiac dysfunction, hypertrophy, fibrosis, and senescence, as compared with common lab strains FVB and C57 bearing longer telomeres. CAST CPCs with short telomeres demonstrate altered cell fate as characterized by cell cycle arrest, senescence, basal commitment, and loss of quiescence. Elongation of telomeres using a modified mRNA for telomerase restores youthful properties to CAST CPCs. Short telomeres induce autophagy in CPCs, a catabolic protein degradation process, as evidenced by reduced p62 and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation reverses the cell fate to a more youthful phenotype. Mechanistically, cell fate changes induced by short telomeres are partially p53 dependent, as p53 inhibition rescues senescence and commitment observed in CAST CPCs, coincident with attenuation of autophagy. In conclusion, short telomeres activate p53 and autophagy to tip the equilibrium away from quiescence and proliferation toward differentiation and senescence, leading to exhaustion of CPCs. This study provides the mechanistic basis underlying age-associated cell fate changes that will enable identification of molecular strategies to prevent senescence of CPCs. Stem Cells 2018;36:868-880. PMID- 29441647 TI - Methods for addressing "innocent bystanders" when evaluating safety of concomitant vaccines. AB - PURPOSE: The need to develop methods for studying the safety of childhood immunization schedules has been recognized by the Institute of Medicine and Department of Health and Human Services. The recommended childhood immunization schedule includes multiple vaccines in a visit. A key concern is safety of concomitant (same day) versus separate day vaccination. This paper addresses a methodological challenge for observational studies using a self-controlled design to investigate the safety of concomitant vaccination. METHODS: We propose a process for distinguishing which of several concomitantly administered vaccines is responsible for increased risk of an adverse event while adjusting for confounding due to relationships between effect modifying risk factors and concomitant vaccine combinations. We illustrate the approach by re-examining the known increase in risk of seizure 7 to 10 days after measles-mumps-rubella (MMR) vaccination and evaluating potential independent or modifying effects of other vaccines. RESULTS: Initial analyses suggested that DTaP had both an independent and potentiating effect on seizure. After accounting for the relationship between age at vaccination and vaccine combination, there was little evidence for increased risk of seizure with same day administration of DTaP and MMR; incidence rate ratio, 95% confidence interval 1.2 (0.9-1.6), P value = theta.226. CONCLUSION: We have shown that when using a self-controlled design to investigate safety of concomitant vaccination, it can be critically important to adjust for time-invariant effect modifying risk factors, such as age at time of vaccination, which are structurally related to vaccination patterns due to recommended immunization schedules. PMID- 29441648 TI - Aggregatibacter actinomycetemcomitans infection causes DNA double-strand breaks in host cells. AB - Periodontal disease, an inflammatory disease, is caused by infection with periodontal pathogens. Long-term periodontal disease increases the risk of oral carcinogenesis. Similar to other peptic cancers, oral carcinogenesis also requires multiple genome instabilities; however, the risk factors related to the accumulation of genome instabilities are poorly understood. Here, we suggested that specific periodontal pathogens may increase the risk of genome instability. Accordingly, we screened several periodontal pathogens based on the ability to induce DNA double-strand breaks (DSBs) in host cells. We found that Aggregatibacter actinomycetemcomitans Y4 infection induced DSB formation in host cells. To assess whether DSB formation induced by infection with A. actinomycetemcomitans occurred through apoptotic chromosome fragmentation, cells were treated with a caspase inhibitor, Z-VAD-FMK. DSB accumulation induced by infection with A. actinomycetemcomitans was observed, even in the presence of Z VAD-FMK, suggesting that this breakage occurred independently of apoptosis. These results suggested that some periodontal pathogens can increase the risk of genome instabilities in host cells and subsequently increase the risk of carcinogenesis. PMID- 29441649 TI - Concise Review: Assessing the Genome Integrity of Human Induced Pluripotent Stem Cells: What Quality Control Metrics? AB - Human induced pluripotent stem cells (hiPSCs) have the potential to differentiate virtually into any cell type in unlimited quantities. Therefore, they are ideal for in vitro tissue modeling or to produce cells for clinical use. Importantly, and differently from immortalized and cancer cell lines, the hiPSC genome scrupulously reproduces that of the cell from which they were derived. However, hiPSCs can develop genetic abnormalities during reprogramming or prolonged cell culture, such as aneuploidies or oncogenic mutations (e.g., in TP53). Therefore, hiPSC genome integrity must be routinely monitored because serious genome alterations would greatly compromise their usefulness or safety of use. Here, we reviewed hiPSC genome quality control monitoring methods and laboratory practice. Indeed, due to their frequency and functional consequences, recurrent genetic defects found in cultured hiPSCs are inacceptable and their appearance should be monitored by routine screening. Hence, for research purposes, we propose that the genome of hiPSC lines should be systematically screened at derivation, at least by karyotyping, and then regularly (every 12 weeks) during experiments, for instance with polymerase chain reaction-based techniques. For some specific applications, such as research on aging, cell cycle, apoptosis or cancer, other tests (e.g., TP53 mutation detection) should also be included. For clinical use, in addition to karyotyping, we advise exome sequencing. Stem Cells 2018;36:814 821. PMID- 29441650 TI - Incidence, prevalence and clinical correlates of antidepressant-emergent mania in bipolar depression: a systematic review and meta-analysis. AB - BACKGROUND: Treatment-emergent mania (TEM) represents a common phenomenon inconsistently reported across primary studies, warranting further assessment. METHODS: A systematic review and meta-analysis following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were conducted. Major electronic databases were searched from inception to May 2017 to assess the incidence and prevalence rates and clinical features associated with manic switch among bipolar depressed patients receiving antidepressants, using meta-regression and subgroup analysis. RESULTS: Overall, 10 098 depressed patients with bipolar disorder (BD) across 51 studies/arms were included in the quantitative analysis. The cumulative incidence of cases (TEM+ ) among 4767 patients with BD over 15 retrospective studies was 30.9% (95% confidence interval [CI] 19.6-45.0%, I2 = 97.9%). The cumulative incidence of TEM+ among 1929 patients with BD over 12 prospective open studies was 14.4% (95% CI 7.4-26.1%, I2 = 93.7%). The cumulative incidence of TEM+ among 1316 patients with BD over 20 randomized controlled trials (RCTs) was 11.8% (95% CI 8.4-16.34%, I2 = 73.46%). The pooled prevalence of TEM+ among 2086 patients with BD over four cross-sectional studies was 30.9% (95% CI 18.1-47.4%, I2 = 95.6%). Overall, concurrent lithium therapy predicted the lowest TEM rates. Inconsistent operational definitions of TEM were recorded, and the lack of information about age, sex, co-occurring anxiety, and other clinically relevant moderators precluded further stratification of the results. CONCLUSIONS: Rates of TEM vary primarily depending on study setting, which is concordant with the high degree of heterogeneity of the included records. Forthcoming RCT studies should adopt consistent operational definitions of TEM and broaden the number of moderators, in order to contribute most effectively to the identification of clear-cut sub-phenotypes of BD and patient tailored pharmacotherapy. PMID- 29441652 TI - Bladder pain syndrome/interstitial cystitis is associated with asthma: A case control study. AB - OBJECTIVE: Although asthma and bladder pain syndrome/interstitial cystitis (BPS/IC) are considered to share similar pathophysiological pathways, the relationship between asthma and BPS/IC is uncertain. This case-control study aimed to investigate the relationship between prior asthma and BPS/IC using a large database in Taiwan. MATERIALS AND METHODS: This study used data from the Taiwan Longitudinal Health Insurance Database 2005. We identified 500 female patients with BPS/IC as cases and 500 propensity score-matched females without BPS/IC as controls. We conducted logistic regressions to estimate the odds ratio (OR) and 95% confidence interval (CI) for prior asthma between cases and controls. RESULTS: Results indicated that 143 (14.30%) of the total sampled patients had received a prior diagnosis of asthma. Moreover, prior asthma was found in 86 (17.20%) cases and 57 (11.40%) controls. The OR of prior asthma for cases was 1.61 (95%CI: 1.13-2.32) compared to propensity score-matched controls. Additionally, the ORs of prior asthma for females with BPS/IC aged 18-59 and >=60 years were 1.72 (95%CI: 1.11-2.69) and 1.40 (95%CI: 0.74-2.62), respectively, compared to controls. CONCLUSIONS: We concluded that prior asthma was significantly associated with BPS/IC in a female Taiwanese population. PMID- 29441651 TI - Invasive pneumococcal infections in pediatric liver-small bowel-pancreas transplant recipients. AB - Children undergoing LSBPTx are at increased risk of IPI due to splenectomy. We aimed to describe the clinical features and outcomes of IPI in pediatric LSBPTx recipients. Between 2008 and 2016, 122 LSBPTx children at our center were retrospectively reviewed. Nine patients had 12 episodes of IPI; the median age at first infection was 3.5 years (range: 1.5-7.1 years). The median time from transplant to first infection was 3 years (range: 0.8-5.8 years). Clinical presentation included as follows: pneumonia (n = 1), bacteremia/sepsis (n = 7), pneumonia with sepsis (n = 1), meningitis with sepsis (n = 2), pneumonia and meningitis with sepsis (n = 1). The overall risk for IPI was 7.4% or 0.9% per year. The mortality rate was 22%. Seven (78%) children had received at least one dose of PCV13, four (44%) patients had received 23-valent pneumococcal polysaccharide vaccine prior to IPI. All patients were on oral penicillin prophylaxis. In conclusion, despite partial or complete pneumococcal immunization and reported antimicrobial prophylaxis, IPI in LSBPTx children can have a fatal outcome. Routine monitoring of pneumococcal serotype antibodies to determine the timing for revaccination might be warranted to ensure protective immunity in these transplant recipients. PMID- 29441653 TI - Cognitive control under stressful conditions in transitional age youth with bipolar disorder: Diagnostic and sleep-related differences in fronto-limbic activation patterns. AB - OBJECTIVES: Adults with bipolar disorder (BD) display aberrant activation in fronto-limbic neural circuitry during cognitive control. However, fronto-limbic response to cognitive control, and factors destabilizing this circuitry, remain under-studied during the transition from adolescence to young adulthood in BD. Sleep patterns are disturbed in BD, undergo change in adolescence, and support brain function. Among transitional age youth, BD diagnosis and sleep (duration and variability) were tested as predictors of fronto-limbic response to a stressful cognitive control task. METHODS: Two groups of youth (13-22 years old) participated: 15 with BD type I, II or not otherwise specified (NOS) [BD; age 18.1 +/- 2.7 years (mean +/- standard deviation, SD); 17 female] and 25 healthy controls [CTL; age 19.4 +/- 2.7 years (mean +/- SD); 17 female]. Sleep was monitored with actigraphy for at least 1 week prior to an adaptive multi-source interference functional magnetic resonance imaging (fMRI) paradigm (a Stroop-like cognitive interference task). Group status and sleep duration (average and intra individual variability) were examined as predictors of activation in response to incongruent>congruent trials within the bilateral amygdala, anterior cingulate (ACC), ventrolateral prefrontal and dorsolateral prefrontal cortical regions of interest. RESULTS: The BD group displayed greater right amygdala activation than the CTL group. Average sleep duration and rostroventral ACC (rvACC) activity were negatively associated in the CTL group, but exhibited a quadratic relationship in the BD group such that short and long sleep were related to greater rvACC activation. Sleep duration variability and dorsal ACC activity were negatively associated in the BD group, and unrelated in the CTL group. Findings remained significant after controlling for age, sex, and mood symptoms. CONCLUSIONS: Subjects with BD displayed a hyper-limbic response during cognitive control, and sleep was a source of variability in ACC engagement. Stabilizing sleep may be one avenue for improving cognitive control in BD. PMID- 29441654 TI - Effect of rivastigmine on plasma butyrylcholine esterase activity and plasma ghrelin levels in patients with dementia in Alzheimer's disease. AB - AIM: Alzheimer's disease causes loss of appetite, resulting in bodyweight reduction. This, in turn, causes progression of cognitive dysfunction and physical complications that hasten death. Earlier care for loss of appetite is essential in Alzheimer's disease management. Rivastigmine is a therapeutic agent for Alzheimer's disease that has dual inhibition effects on acetylcholine esterase and butyrylcholine esterase. Butyrylcholine esterase is known to degrade the gastric hormone, ghrelin, which regulates appetite; therefore, we considered that rivastigmine might have an effect on appetite. The present study aimed to evaluate the hypothesis that rivastigmine improves appetite in Alzheimer's disease patients. METHODS: Rivastigmine was given to mild-to-moderate Alzheimer's disease patients for 16 weeks. We evaluated the effects of rivastigmine on food intake, bodyweight, motivation (estimated by the vitality index), cognition function (estimated by the Hasegawa Dementia Scale-Revised), plasma butyrylcholine esterase activity, active ghrelin and inactive ghrelin. RESULTS: Plasma butyrylcholine esterase activity significantly decreased over time (percent change: -18.9 +/- 27.0%, P < 0.05 at week 8; percent change: -33.4 +/- 45.4%, P < 0.05 at week 16). Negative correlations were detected between percent changes in butyrylcholine esterase activity and active ghrelin (rs = -0.62, P = 0.033) or active/inactive ghrelin ratio (rs = -0.73, P = 0.007). Furthermore, motivation (including appetite) improved significantly (percent change: 17.9 +/- 18.6%, P < 0.05 at week 16). CONCLUSIONS: The present study suggests that rivastigmine might improve appetite in mild-to-moderate Alzheimer's disease patients by suppressing degradation of plasma active ghrelin through the inhibition of plasma butyrylcholine esterase. Geriatr Gerontol Int 2018; 18: 886 891. PMID- 29441655 TI - The importance of cardiovascular disease in pediatric transplantation and its link to the kidneys. AB - Cardiovascular disease is a frequent cause of morbidity and mortality in pediatric patients following solid organ transplant. CKD is also common in pediatric patients after a solid organ transplant, and the link between CKD and cardiovascular morbidity is strong. In this review, we examine potential etiologies to explain the risk of cardiovascular morbidity and mortality in pediatric solid organ recipients and identify targets for improving outcomes. PMID- 29441656 TI - Patterns of wounding in hamadryas baboons (Papio hamadryas) in North American zoos. AB - In North American zoos, hamadryas baboons (Papio hamadryas) have traditionally been housed as single one-male units (single male groups). In recent years, efforts have been made to house hamadryas in groups composed of multiple one-male units (multi-male groups) to more closely mirror their natural social structure, in addition to all-male or bachelor groups to manage surplus males. Given that the majority of social conflict in hamadryas occurs between males during the acquisition and defense of females, it was thought that managing hamadryas in these multi-male groups would result in increased rates of wounding. To assess this, incidences of wounding were recorded over one year across seven zoos (10 social groups, 59 individuals). Overall, we found no difference in wounding rates between group types, or by sex, and group type. These data provide evidence that managing hamadryas in multi-male and bachelor groups is an effective husbandry practice that does not negatively impact the welfare of the individuals, in addition to providing a more species-appropriate social setting for hamadryas in zoos. As the management of hamadryas in multi-male and bachelor groups continues and expands, additional research will be needed to understand what factors contribute to optimal cohesion, and welfare of groups and if wounding rates change as group size continues to increase. PMID- 29441657 TI - Towards Sequence-Controlled Antimicrobial Polymers: Effect of Polymer Block Order on Antimicrobial Activity. AB - Synthetic polymers have shown promise in combating multidrug-resistant bacteria. However, the biological effects of sequence control in synthetic antimicrobial polymers are currently not well understood. As such, we investigate the antimicrobial effects of monomer distribution within linear high-order quasi block copolymers consisting of aminoethyl, phenylethyl, and hydroxyethyl acrylamides made in a one-pot synthesis approach via photoinduced electron transfer-reversible addition-fragmentation chain transfer polymerisation (PET RAFT). Through different combinations of monomer/polymer block order, antimicrobial and haemolytic activities are tuneable in a manner comparable to antimicrobial peptides. PMID- 29441658 TI - Host genetic variation strongly influences the microbiome structure and function in fungal fruiting-bodies. AB - Despite increasing knowledge on host-associated microbiomes, little is known about mechanisms underlying fungus-microbiome interactions. This study aimed to examine the relative importance of host genetic, geographic and environmental variations in structuring fungus-associated microbiomes. We analyzed the taxonomic composition and function of microbiomes inhabiting fungal fruiting bodies in relation to host genetic variation, soil pH and geographic distance between samples. For this, we sequenced the metagenomes of 40 fruiting-bodies collected from six fairy rings (i.e., genets) of a saprotrophic fungus Marasmius oreades. Our analyses revealed that fine genetic variations between host fungi could strongly affect their associated microbiome, explaining, respectively, 25% and 37% of the variation in microbiome structure and function, whereas geographic distance and soil pH remained of secondary importance. These results, together with the smaller genome size of fungi compared to other eukaryotes, suggest that fruiting-bodies are suitable for further genome-centric studies on host microbiome interactions. PMID- 29441660 TI - A Sulfur-Limonene-Based Electrode for Lithium-Sulfur Batteries: High-Performance by Self-Protection. AB - The lithium-sulfur battery is considered as one of the most promising energy storage systems and has received enormous attentions due to its high energy density and low cost. However, polysulfide dissolution and the resulting shuttle effects hinder its practical application unless very costly solutions are considered. Herein, a sulfur-rich polymer termed sulfur-limonene polysulfide is proposed as powerful electroactive material that uniquely combines decisive advantages and leads out of this dilemma. It is amenable to a large-scale synthesis by the abundant, inexpensive, and environmentally benign raw materials sulfur and limonene (from orange and lemon peels). Moreover, owing to self protection and confinement of lithium sulfide and sulfur, detrimental dissolution and shuttle effects are successfully avoided. The sulfur-limonene-based electrodes (without elaborate synthesis or surface modification) exhibit excellent electrochemical performances characterized by high discharge capacities (~1000 mA h g-1 at C/2) and remarkable cycle stability (average fading rate as low as 0.008% per cycle during 300 cycles). PMID- 29441659 TI - Genetic polymorphisms associated with circadian rhythm dysregulation provide new perspectives on bipolar disorder. AB - OBJECTIVES: The objective of this study was to present a broad view of how genetic polymorphisms in genes that control the rhythmicity and function of circadian rhythm may influence the etiology, pathophysiology and treatment of bipolar disorder (BD). METHODS: A bibliographic search was performed to identify and select papers reporting studies on variations in circadian genes and BD. A search of Medline, Google Scholar, Scopus, and Web of Science was carried out to review the literature. RESULTS: Several studies provide evidence of contributions of variations in circadian genes to disease etiology, pathophysiological variations and lithium drug response. Dysfunction of the sleep-wake cycle, an important brain function regulator, is indicated as the primary means by which circadian gene variations act in mood disorders. CONCLUSIONS: Investigations of the effects of circadian genes have suggested that the chronotype offers hope for guiding and improving management of patients with BD. However, BD is a disease of a complex nature and presents multiple endophenotypes determined by different associations between genetics and the environment. Thus, new genomic studies to delimit variations that may help improve the clinical condition of these patients are extremely important. PMID- 29441661 TI - Pyrodiversity interacts with rainfall to increase bird and mammal richness in African savannas. AB - Fire is a fundamental process in savannas and is widely used for management. Pyrodiversity, variation in local fire characteristics, has been proposed as a driver of biodiversity although empirical evidence is equivocal. Using a new measure of pyrodiversity (Hempson et al.), we undertook the first continent-wide assessment of how pyrodiversity affects biodiversity in protected areas across African savannas. The influence of pyrodiversity on bird and mammal species richness varied with rainfall: strongest support for a positive effect occurred in wet savannas (> 650 mm/year), where species richness increased by 27% for mammals and 40% for birds in the most pyrodiverse regions. Range-restricted birds were most increased by pyrodiversity, suggesting the diversity of fire regimes increases the availability of rare niches. Our findings are significant because they explain the conflicting results found in previous studies of savannas. We argue that managing savanna landscapes to increase pyrodiversity is especially important in wet savannas. PMID- 29441662 TI - Differential vocational rehabilitation service patterns and outcomes for transition-age youth with autism. AB - BACKGROUND: It is important to investigate receipt of vocational rehabilitation (VR) services, service patterns and outcomes for youth with autism, so that limited public resources can be used more efficiently. METHOD: This study used chi-squared automatic interaction detector, and multivariate logistic regression analysis to investigate relationships between demographic variables, receipt of VR services and employment outcomes for transition-age youth (TAY) with Autism. RESULTS: The results indicate that gender, education level and cash benefits are significant predictors of employment outcomes. After controlling for the effect of demographic variables, several VR services (i.e., job placement, on-the-job support, on-the-job training, maintenance, other services, information referral, and diagnostic and treatment services) were significantly associated with competitive employment. CONCLUSIONS: Overall, the results indicate that job related services were significantly related to employment outcomes for TAY with Autism; therefore, it is important these youths are provided with more targeted job placements and supported employment services (Wehman et al., ). PMID- 29441663 TI - Preceptors' perspectives of an integrated clinical learning model in a mental health environment. AB - Supervised clinical practice is an essential component of undergraduate nursing students' learning and development. In the mental health setting, nursing students traditionally undertake four-week block placements. An integrated clinical learning model, where preceptors mentor students on an individual basis, has been used successfully in the clinical learning environment. This flexible model provides the opportunity for students to work across morning, afternoon, night and weekend shifts. There is a need to improve the evidence base for a flexible model for students undertaking a mental health placement. The aim of this study was to understand preceptors' experience of, and satisfaction with, a mental health integrated clinical learning model. Focus groups were used to elicit the views of preceptors from a mental health service. Findings highlight the advantages and disadvantages of an integrated clinical learning model in the mental health setting. Participants suggested that students may benefit from flexible work arrangements, a variety of experiences and a more realistic experience of working in a mental health service. However, they found it challenging to mentor and evaluate students under this model. Most also agreed that the model impeded students' ability to engage with consumers and develop rapport with staff. The findings indicate the need to develop a placement model that meets the unique needs of the mental health setting. PMID- 29441664 TI - A comparative hierarchical analysis of bacterioplankton and biofilm metacommunity structure in an interconnected pond system. AB - It is unknown whether bacterioplankton and biofilm communities are structured by the same ecological processes, and whether they influence each other through continuous dispersal (known as mass effects). Using a hierarchical sampling approach we compared the relative importance of ecological processes structuring the dominant fraction (relative abundance >=0.1%) of bacterioplankton and biofilm communities from three microhabitats (open water, Nuphar and Phragmites sites) at within- and among-pond scale in a set of 14 interconnected shallow ponds. Our results demonstrate that while bacterioplankton and biofilm communities are highly distinct, a similar hierarchy of ecological processes is acting on them. For both community types, most variation in community composition was determined by pond identity and environmental variables, with no effect of space. The highest beta-diversity within each community type was observed among ponds, while microhabitat type (Nuphar, Phragmites, open water) significantly influenced biofilm communities but not bacterioplankton. Mass effects among bacterioplankton and biofilm communities were not detected, as suggested by the absence of within site covariation of biofilm and bacterioplankton communities. Both biofilm and plankton communities were thus highly structured by environmental factors (i.e., species sorting), with among-lake variation being more important than within-lake variation, whereas dispersal limitation and mass effects were not observed. PMID- 29441666 TI - The particles around us. PMID- 29441667 TI - Corrigendum. PMID- 29441665 TI - Cortical thickness abnormalities in bipolar disorder patients with a lifetime history of auditory hallucinations. AB - OBJECTIVES: We aimed to investigate morphometric correlates of auditory hallucinations in bipolar disorder (BD) by comparing cortical thickness and cortical surface area in bipolar disorder patients with (BD+) and without (BD-) a lifetime history of auditory hallucinations. Based on previous findings in schizophrenia patients, we hypothesized that the cortex would be thinner in the auditory cortex in BD+ compared to BD-. METHODS: Bipolar disorder spectrum (n = 157) patients and healthy controls (n = 279) underwent 1.5T magnetic resonance imaging (MRI) scanning. Hypothesis-driven analyses of cortical thickness and surface area in regions of the auditory cortex (Heschl's gyrus [HG], planum temporale and superior temporal gyrus) were conducted comparing BD+ (n = 49) and BD- (n = 108) using linear regression models, covaried for age and sex. Furthermore, we explored vertex-wise group differences in thickness and surface area across the whole cerebral cortex. RESULTS: Hypothesis-driven analyses:BD+ had significantly thicker cortex in the left HG compared to BD- (B = 0.128, P = .0046). The finding was not explained by duration of illness, global functioning, bipolar subtype, IQ or use of antipsychotic, antidepressant or antiepileptic medication, or by lithium. Exploratory analyses: A small region of thicker cortex in BD+ compared to BD- was seen in the left superior parietal lobule (false discovery rate <0.05). There were no significant group differences in cortical surface area. CONCLUSION: A lifetime history of auditory hallucinations in BD was associated with cortical thickness alterations in both the left HG and the superior parietal lobule. Contrary to our hypothesis, BD+ showed thicker, rather than thinner cortex compared to BD-. Replications in independent samples are needed. PMID- 29441668 TI - Increased socially mediated plasticity in gene expression accompanies rapid adaptive evolution. AB - Recent theory predicts that increased phenotypic plasticity can facilitate adaptation as traits respond to selection. When genetic adaptation alters the social environment, socially mediated plasticity could cause co-evolutionary feedback dynamics that increase adaptive potential. We tested this by asking whether neural gene expression in a recently arisen, adaptive morph of the field cricket Teleogryllus oceanicus is more responsive to the social environment than the ancestral morph. Silent males (flatwings) rapidly spread in a Hawaiian population subject to acoustically orienting parasitoids, changing the population's acoustic environment. Experimental altering crickets' acoustic environments during rearing revealed broad, plastic changes in gene expression. However, flatwing genotypes showed increased socially mediated plasticity, whereas normal-wing genotypes exhibited negligible expression plasticity. Increased plasticity in flatwing crickets suggests a coevolutionary process coupling socially flexible gene expression with the abrupt spread of flatwing. Our results support predictions that phenotypic plasticity should rapidly evolve to be more pronounced during early phases of adaptation. PMID- 29441669 TI - HIV: ageing, cognition and neuroimaging at 4-year follow-up. AB - OBJECTIVES: The aim of the study was to investigate the hypothesis of accelerated cognitive ageing in HIV-positive individuals using longitudinal assessment of cognitive performance and quantitative magnetic resonance imaging (MRI). METHODS: We assessed a broad cognitive battery and quantitative MRI metrics [voxel-based morphometry (VBM) and diffusion tensor imaging (DTI)] in asymptomatic HIV positive men who have sex with men (15 aged 20-40 years and 15 aged >= 50 years), and HIV-seronegative matched controls (nine aged 20-40 years and 16 aged >= 50 years). RESULTS: Being HIV positive was associated with greater decreases in executive function and global cognition. Additionally, using DTI, we found that the HIV-positive group had a greater increase in mean diffusivity, but we did not find group differences in volume change using VBM. With respect to the HIV status by age group interaction, this was statistically significant for change in global cognition, with older HIV-positive individuals showing greater global cognitive decline, but there were no significant interaction effects on other measures. Lastly, change in cognitive performance was correlated with change in the DTI measures, and this effect was stronger for the HIV-positive participants. CONCLUSIONS: In the present study, we found some evidence for accelerated ageing in HIV-positive individuals, with a statistically significant HIV status by age group interaction in global cognition, although this interaction could not be explained by the imaging findings. Moreover, we also found that change in cognitive performance was correlated with change in the DTI measures, and this effect was stronger for the HIV-positive participants. This will need replication in larger studies using a similarly lengthy follow-up period. PMID- 29441670 TI - Energy drives the dynamic localization of cyanobacterial nitrogen regulators during diurnal cycles. AB - Cyanobacteria, phototrophic organisms performing oxygenic photosynthesis, must adapt their metabolic processes to the challenges imposed by the succession of days and nights. Two conserved cyanobacterial proteins, PII and PipX, function as hubs of the nitrogen interaction network, forming complexes with a variety of diverse targets. While PII proteins are found in all three domains of life as integrators of signals of the nitrogen and carbon balance, PipX proteins are unique to cyanobacteria, where they provide a mechanistic link between PII signalling and the control of gene expression by the global nitrogen regulator NtcA. Here we demonstrate that PII and PipX display distinct localization patterns during diurnal cycles, co-localizing into the same foci at the periphery and poles of the cells during dark periods, a circadian-independent process requiring a low ATP/ADP ratio. Genetic, cellular biology and biochemical approaches used here provide new insights into the nitrogen regulatory network, calling attention to the roles of PII as energy sensors and its interactions with PipX in the context of essential signalling pathways. This study expands the contribution of the nitrogen regulators PII and PipX to integrate and transduce key environmental signals that allow cyanobacteria to thrive in our planet. PMID- 29441671 TI - Enzymatic stimuli-responsive methotrexate-conjugated magnetic nanoparticles for target delivery to breast cancer cells and release study in lysosomal condition. AB - In this study, magnetic nanoparticles (MNPs) coated with glycine (F-Gly NPs) and conjugated with methotrexate (MTX) (F-Gly-MTX NPs) were synthesized through a coprecipitation method followed by amidation reaction between the carboxylic acid end groups on MTX and the amine groups on the MNPs surface and studied its cytotoxic effect in vitro. The successful conjugating of MTX onto the nanoparticles (NPs) was confirmed by X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy, vibrating sample magnetometer, and transmission electron microscopy techniques. The results showed that the average size was 46.82 +/- 5.03 nm. This target drug delivery system is dependent on the release of the MTX within the lysosomal compartment. Hemolysis assay and cytotoxicity study results on HFF-2 and HEK-293 cell lines show that as prepared MNPs are biocompatible. The cytotoxicity of void of the MTX and F-Gly-MTX NPs were compared to each other by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay of the treated MCF-7 cell line. Enzymatic release studies exhibited the release of the MTX via peptide bond cleavage in the presence of proteinase K. These studies specify that the F-Gly-MTX NPs have a very remarkable anticancer effect, for breast cancer cell line. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1646 1654, 2018. PMID- 29441672 TI - Role of solid lipid nanoparticles as photoprotective agents in cosmetics. AB - BACKGROUND: Novel drug delivery systems have gained popularity since last two decades because of its advantages over conventional dosage forms. Effect of UV radiation on skin can cause either acute or chronic damage to our skin. Solid lipid nanoparticles (SLNs) were developed as novel carrier over the conventional carrier systems like liposomes and emulsions. The SLNs were selected as a carrier for the formulation because of its ability to protect the labile drug particles, the ability to make the drug release in a controlled manner, and occlusive property of the SLNs. OBJECTIVE: The current review is an attempt to focus on the characteristics of solid lipid nanoparticles, methods for the preparations, and their cosmetic applications along with some future perspectives of the nanodrug delivery systems. METHODS: A review of the current literature of solid lipid nanoparticles (SLNs) as novel carrier showed better photoprotection in sunscreens. RESULTS AND CONCLUSIONS: The disadvantages of conventional sunscreens can be overcome by incorporation of solid lipid nanoparticles. On comparing the lipid nanobased systems with traditional cosmetic products, the occlusion can be achieved without the use of paraffin and other greasy oils. The film formed by lipid nanoparticles will be smooth as compared to the inflexible films formed by the paraffin. Newer approaches may lead to even better results. They also possess excellent UV-blocking activity and showed better photoprotection. PMID- 29441673 TI - Plasma-Assisted Synthesis and Surface Modification of Electrode Materials for Renewable Energy. AB - Renewable energy technology has been considered as a "MUST" option to lower the use of fossil fuels for industry and daily life. Designing critical and sophisticated materials is of great importance in order to realize high performance energy technology. Typically, efficient synthesis and soft surface modification of nanomaterials are important for energy technology. Therefore, there are increasing demands on the rational design of efficient electrocatalysts or electrode materials, which are the key for scalable and practical electrochemical energy devices. Nevertheless, the development of versatile and cheap strategies is one of the main challenges to achieve the aforementioned goals. Accordingly, plasma technology has recently appeared as an extremely promising alternative for the synthesis and surface modification of nanomaterials for electrochemical devices. Here, the recent progress on the development of nonthermal plasma technology is highlighted for the synthesis and surface modification of advanced electrode materials for renewable energy technology including electrocatalysts for fuel cells, water splitting, metal-air batteries, and electrode materials for batteries and supercapacitors, etc. PMID- 29441675 TI - Uterine adenosarcoma in Japan: Clinicopathologic features, diagnosis and management. AB - AIM: Uterine adenosarcoma is a rare malignancy with limited cohort data in Asian countries. This study evaluated the clinicopathologic features of Japanese patients with uterine adenosarcoma and their potential treatment challenges. METHODS: A retrospective chart review was performed at the National Cancer Center Hospital, Japan from 2000 to 2016. A literature search for Japanese cases of uterine adenosarcoma was conducted using PubMed, Japanese Central Review of Medicine, and the Annual of Pathological Autopsy Cases in Japan. Only histologically confirmed cases of uterine adenosarcoma were included. All collected data were analyzed. RESULTS: A total of 110 cases was identified (6 from our hospital and 104 from the literature review). Most baseline characteristics were similar to those reported in western countries. Death due to the disease was observed in 34% (29/86) of patients, whereas patients with stage IA disease showed a 13% (4/30) recurrence rate and a 3.3% (1/30) mortality rate. Preoperative radiological and pathological examinations occasionally failed to help reach the correct diagnosis. In cases of sarcomatous overgrowth, the recurrence and mortality rates were 45% (9/20) and 35% (7/20), respectively. Distant recurrence occurred in 44% (12/27) of cases, 75% of which included lung metastasis. CONCLUSIONS: This study showed the clinicopathologic features of Japanese patients with uterine adenosarcoma and suggested potential solutions for improving prognosis including early treatment based on a timely diagnosis, the development of effective adjuvant therapy for patients at high risk of recurrence, and optimal follow-up focusing on late recurrence and lung metastasis. PMID- 29441676 TI - Fate of human mesenchymal stem cells (MSCs) in humans and rodents-Is the current paradigm obtained on rodents applicable to humans? PMID- 29441677 TI - A novel susceptibility locus in MST1 and gene-gene interaction network for Crohn's disease in the Chinese population. AB - The incidence of Crohn's disease is increasing in many Asian countries, but considerable differences in genetic susceptibility have been reported between Western and Asian populations. This study aimed to fine-map 23 previously reported Crohn's disease genes and identify their interactions in the Chinese population by Illumina-based targeted capture sequencing. Our results showed that the genetic polymorphism A>G at rs144982232 in MST1 showed the most significant association (P = 1.78 * 10-5 ; odds ratio = 4.87). JAK2 rs1159782 (T>C) was also strongly associated with Crohn's disease (P = 2.34 * 10-4 ; odds ratio = 3.72). Gene-gene interaction analysis revealed significant interactions between MST1 and other susceptibility genes, including NOD2, MUC19 and ATG16L1 in contributing to Crohn's disease risk. Main genetic associations and gene-gene interactions were verified using ImmunoChip data set. In conclusion, a novel susceptibility locus in MST1 was identified. Our analysis suggests that MST1 might interact with key susceptibility genes involved in autophagy and bacterial recognition. These findings provide insight into the genetic architecture of Crohn's disease in Chinese and may partially explain the disparity of genetic signals in Crohn's disease susceptibility across different ethnic populations by highlighting the contribution of gene-gene interactions. PMID- 29441678 TI - Strategic Advances in Formation of Cell-in-Shell Structures: From Syntheses to Applications. AB - Single-cell nanoencapsulation, forming cell-in-shell structures, provides chemical tools for endowing living cells, in a programmed fashion, with exogenous properties that are neither innate nor naturally achievable, such as cascade organic-catalysis, UV filtration, immunogenic shielding, and enhanced tolerance in vitro against lethal factors in real-life settings. Recent advances in the field make it possible to further fine-tune the physicochemical properties of the artificial shells encasing individual living cells, including on-demand degradability and reconfigurability. Many different materials, other than polyelectrolytes, have been utilized as a cell-coating material with proper choice of synthetic strategies to broaden the potential applications of cell-in shell structures to whole-cell catalysis and sensors, cell therapy, tissue engineering, probiotics packaging, and others. In addition to the conventional "one-time-only" chemical formation of cytoprotective, durable shells, an approach of autonomous, dynamic shellation has also recently been attempted to mimic the naturally occurring sporulation process and to make the artificial shell actively responsive and dynamic. Here, the recent development of synthetic strategies for formation of cell-in-shell structures along with the advanced shell properties acquired is reviewed. Demonstrated applications, such as whole-cell biocatalysis and cell therapy, are discussed, followed by perspectives on the field of single cell nanoencapsulation. PMID- 29441679 TI - ABO and Rh blood group genotypes in a cohort of Saudi stem cell donors. AB - The ABO and rhesus (Rh) blood group antigens are the most frequently studied genetic markers in a large group of people. Blood type frequencies vary in different racial/ethnic groups. Our objective was to investigate the distribution of the ABO and rhesus (Rh) blood groups by molecular typing method in a population of Saudi stem cell donors. Our data indicate that the most common blood group in our population is group O followed by group A then group B, and finally, the least common is group AB. PMID- 29441680 TI - When 2D Materials Meet Molecules: Opportunities and Challenges of Hybrid Organic/Inorganic van der Waals Heterostructures. AB - van der Waals heterostructures, composed of vertically stacked inorganic 2D materials, represent an ideal platform to demonstrate novel device architectures and to fabricate on-demand materials. The incorporation of organic molecules within these systems holds an immense potential, since, while nature offers a finite number of 2D materials, an almost unlimited variety of molecules can be designed and synthesized with predictable functionalities. The possibilities offered by systems in which continuous molecular layers are interfaced with inorganic 2D materials to form hybrid organic/inorganic van der Waals heterostructures are emphasized. Similar to their inorganic counterpart, the hybrid structures have been exploited to put forward novel device architectures, such as antiambipolar transistors and barristors. Moreover, specific molecular groups can be employed to modify intrinsic properties and confer new capabilities to 2D materials. In particular, it is highlighted how molecular self-assembly at the surface of 2D materials can be mastered to achieve precise control over position and density of (molecular) functional groups, paving the way for a new class of hybrid functional materials whose final properties can be selected by careful molecular design. PMID- 29441681 TI - SV40 intron, a potent strong intron element that effectively increases transgene expression in transfected Chinese hamster ovary cells. AB - Chinese hamster ovary (CHO) cells have become the most widely utilized mammalian cell line for the production of recombinant proteins. However, the product yield and transgene instability need to be further increased and solved. In this study, we investigated the effect of five different introns on transgene expression in CHO cells. hCMV intron A, adenovirus tripartite leader sequence intron, SV40 intron, Chinese hamster EF-1alpha gene intron 1 and intervening sequence intron were cloned downstream of the eGFP expression cassette in a eukaryotic vector, which was then transfected into CHO cells. qRT-PCR and flow cytometry were used to explore eGFP expression levels. And gene copy number was also detected by qPCR, respectively. Furthermore, the erythropoietin (EPO) protein was used to test the selected more strong intron. The results showed that SV40 intron exhibited the highest transgene expression level among the five compared intron elements under transient and stable transfections. In addition, the SV40 intron element can increase the ratio of positive colonies and decrease the coefficient of variation in transgene expression level. Moreover, the transgene expression level was not related to the gene copy number in stable transfected CHO cells. Also, the SV40 intron induced higher level of EPO expression than IVS intron in transfected CHO cell. In conclusion, SV40 intron is a potent strong intron element that increases transgene expression, which can readily be used to more efficient transgenic protein production in CHO cells. PMID- 29441682 TI - Genome-wide analysis of odorant-binding proteins and chemosensory proteins in the sweet potato whitefly, Bemisia tabaci. AB - Odorant-binding proteins (OBPs) and chemosensory proteins (CSPs) of insects are thought to play roles in olfactory recognition affecting host choice, copulation, reproduction and other behaviors. Previous descriptions of OBPs and CSPs in the whitefly Bemisia tabaci often provided no or incomplete genetic information. In this study, we present a genome-wide and transcriptome-wide investigation of the OBPs and CSPs in B. tabaci MEAM1 (Middle East-Asia Minor1 species). Eight OBP and 19 CSP genes were identified that covered all previous sequences. Phylogenetic analyses showed that the CSP genes had a lineage-specific expansion (BtabBCSP1, BtabBCSP3, BtabBCSP13, BtabBCSP17, BtabBCSP18 and BtabBCSP19). Expression profiling of OBPs and CSPs by transcriptome sequencing and quantitative real-time polymerase chain reaction (qPCR) revealed that expression patterns differed among developmental stages of B. tabaci MEAM1. Five OBP genes and 11 CSP genes significantly differed between males and females; four of the 19 CSP genes were highly expressed in adults, while two were highly expressed in nymphs. The expression profiles of the OBP and CSP genes in different tissues of B. tabaci MEAM1 adults were analyzed by qPCR. Four OBP genes found in B. tabaci MEAM1 were highly expressed in the head. Conversely, only two CSPs were enriched in the head, while the other six CSPs were specifically expressed in other tissues. Our results provide a foundation for future research on OBPs and CSPs in B. tabaci. PMID- 29441683 TI - Cardiovascular safety of prokinetic agents: A focus on drug-induced arrhythmias. AB - BACKGROUND: Gastrointestinal sensorimotor dysfunction underlies a wide range of esophageal, gastric, and intestinal motility and functional disorders that collectively constitute nearly half of all referrals to gastroenterologists. As a result, substantial effort has been dedicated toward the development of prokinetic agents intended to augment or restore normal gastrointestinal motility. However, the use of several clinically efficacious gastroprokinetic agents, such as cisapride, domperidone, erythromycin, and tegaserod, is associated with unfavorable cardiovascular safety profiles, leading to restrictions in their use. PURPOSE: The purpose of this review is to detail the cellular and molecular mechanisms that lead commonly to drug-induced cardiac arrhythmias, specifically drug-induced long QT syndrome, torsades de pointes, and ventricular fibrillation, to examine the cardiovascular safety profiles of several classes of prokinetic agents currently in clinical use, and to explore potential strategies by which the risk of drug-induced cardiac arrhythmia associated with prokinetic agents and other QT interval prolonging medications can be mitigated successfully. PMID- 29441684 TI - Development of drug discovery screening system by molecular interaction kinetics mass spectrometry. AB - RATIONALE: Drug discovery studies invariably require qualitative and quantitative analyses of target compounds at every stage of drug discovery. We have developed a system combining molecular interaction analysis and mass spectrometry (LC-MS) using the principle of nanopore optical interferometry (nPOI) called molecular interaction kinetics-mass spectrometry (MIK-MS). Since nPOI has high binding capacity, the bond-dissociated compound can be directly detected using LC-MS. In this study, we use carbonic anhydrase II (CAII) as a ligand and apply six small compounds as analytes and report the affinity analysis using MIK-MS. METHODS: CAII was immobilized onto a COOH sensor chip using standard amine coupling. A reference surface was prepared by activating and subsequently blocking the surface under identical conditions. An amount of 50 MUL of mix solution was injected over the reference channel and sample channel for CAII immobilization. The solutions eluting from the sensor chip were collected from the waste-line of the SKi Pro system every 30 s. Reconstructed elution samples were then injected into the LC-MS/MS system. RESULTS: A mixture containing furosemide, acetazolamide, 4-sulfamoylbenzoic acid, 5-(dimethylamino)-1-naphthalene sulfonamide (DNSA), sulfanilamide and sulpiride (15 MUM each) was injected into the CAII-immobilized sensor chip, and the fractions eluted from the SKi Pro system were collected and subjected to selected reaction monitoring LC-MS characterization. Specific results were obtained for acetazolamide, DNSA, furosemide and sulpiride. The results suggest that the association-dissociation curve of a mixed sample can be obtained by one-time MIK-MS analysis. CONCLUSIONS: Six small-molecule binders of CAII were analyzed quantitatively using nPOI and MIK-MS, and the results were compared to published surface plasmon resonance (SPR) results. The nPOI and SPR results show good agreement, confirming the reliability of the analysis. Time-dependent binding results may be obtained by our MS sensorgram approach. Drugs that meet medical needs in a short period are required; this nPOI-LC-MS system is considered an important tool for rapid drug discovery. PMID- 29441686 TI - Miniaturizing EM Sample Preparation: Opportunities, Challenges, and "Visual Proteomics". AB - This review compares and discusses conventional versus miniaturized specimen preparation methods for transmission electron microscopy (TEM). The progress brought by direct electron detector cameras, software developments and automation have transformed transmission cryo-electron microscopy (cryo-EM) and made it an invaluable high-resolution structural analysis tool. In contrast, EM specimen preparation has seen very little progress in the last decades and is now one of the main bottlenecks in cryo-EM. Here, we discuss the challenges faced by specimen preparation for single particle EM, highlight current developments, and show the opportunities resulting from the advanced miniaturized and microfluidic sample grid preparation methods described, such as visual proteomics and time resolved cryo-EM studies. PMID- 29441688 TI - 99m Tc-HYNIC-(Ser)3 -J18 peptide: A radiotracer for non-small-cell lung cancer targeting. AB - Radiolabeled peptide could be a useful tool for the diagnosis of non-small-cell lung cancer (NSCLC). In this study, HYNIC-(Ser)3 -J18 peptide was labeled with 99m Tc using EDDA/tricine as coligands. The in vitro and in vivo studies of this radiolabeled peptide were performed for cellular-specific binding and tumor targeting in A-549 cells and tumor-bearing mice, respectively. The high radiochemical purity was obtained and this radiolabeled peptide exhibited high stability in buffer and serum. The radiolabeled peptide showed high affinity for the A-549 cells with a dissociation constant value (KD ) of 4.4 +/- 0.8 nm. The tumor-muscles ratios were 2.7 and 4.4 at 1 and 2 hr after injection of 99m Tc (EDDA/tricine)-HYNIC-(Ser)3 -J18 in tumor-bearing mice. The tumor uptake was decreased after preinjection with non-labeled peptide for this radiolabeled peptide in blocking experiment. The results of this study showed the 99m Tc (EDDA/tricine)-(Ser)3 -HYNIC-J18 peptide might be a promising radiolabeled peptide for NSCLC targeting. PMID- 29441689 TI - Inducible nitric oxide synthase inhibition by 1400W limits pain hypersensitivity in a neuropathic pain rat model. AB - NEW FINDINGS: What is the central question of this study? Can modulation of inducible NO synthase reduce pain behaviour and pro-inflammatory cytokine signalling in a rat model of neuropathic pain? What is the main finding and its importance? Nitric oxide synthase-based therapies could be effective for the treatment of peripheral neuropathic pain. ABSTRACT: Peripheral neuropathic pain (PNP), resulting from injury to or dysfunction of a peripheral nerve, is a major health problem that affects 7-8% of the population. It is inadequately controlled by current drugs and is characterized by pain hypersensitivity, which is believed to be attributable to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: (i) whether reducing levels of nitric oxide (NO) with 1400W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent or attenuate pain hypersensitivity; and (ii) the effects of 1400W on plasma concentrations of several cytokines that are secreted after iNOS upregulation during chronic pain states. The L5 spinal nerve axotomy (SNA) model of PNP was used, and 1400W (20 mg kg-1 ) was administered i.p. at 8 h intervals for 3 days starting at 18 h post-SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400W were examined using multiplex enzyme-linked immunosorbent assay. The SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400W significantly: (i) limited development of mechanical hypersensitivity at 66 h post-SNA and of heat hypersensitivity at 42 h and at several time points tested thereafter; and (ii) increased the plasma concentrations of interleukin (IL)-1alpha, IL-1beta and IL-10 in the SNA rats. The findings suggest that 1400W might exert its analgesic effects by reducing iNOS and altering the balance between the pro-inflammatory (IL-1beta and IL 1alpha) and anti-inflammatory (IL-10) cytokines and that therapies targeting NO or its enzymes might be effective for the treatment of PNP. PMID- 29441687 TI - Aldehyde dehydrogenase 2 Glu504Lys variant predicts a worse prognosis of acute coronary syndrome patients. AB - Aldehyde dehydrogenase 2 (ALDH2) Glu504Lys variant was an independent risk factor for acute coronary syndrome (ACS). However, there are lacking researches about the relationship between the variant and prognosis of ACS. In the prospective study, 377 ACS patients were grouped into the wild-type (*1/*1) and the mutation (*2/*2 + *1/*2) groups according to genotype detection. Compared with the wild type group, incidences of major adverse cardiac events (MACE) and cardiac death were both higher in the mutation group (9.2% vs 21.0%, P = .002; 5.2% vs 12.2%, P = .026); the MACE-free and the cardiac-death-free cumulative survival rates were obviously lower in the mutation group. Moreover, the mutant genotypes were associated with significantly increased risk of MACE and cardiac death (HR 2.443, 95%CI: 1.390-4.296, P = .002; HR 2.727, 95%CI: 1.303-5.708, P = .008). These results suggested that ALDH2 Glu504Lys variant could predict a worse prognosis of ACS patients. PMID- 29441690 TI - Hepatitis E virus infection of slaughtered healthy pigs in Brazil. AB - Hepatitis E virus (HEV) is an emerging pathogen that can be transmitted through contaminated raw or undercooked meat derived from domestic pigs. HEV infections have been documented among pig herds, pig products and environmental samples raising concern about the spread of the virus. HEV genotypes 3 and 4 are considered zoonotic and have been linked to human cases. HEV was detected in 51 of 335 bile samples (15.2%) from healthy pigs in Minas Gerais, Brazil. Phylogenetic analysis of partial sequences from ORF1 and ORF2 regions yielded discordant results, assigning isolates to subtypes 3c and 3i, respectively, suggesting intragenotypic HEV recombination. PMID- 29441691 TI - Probing the Most Aromatic and Antiaromatic Pyrrolium Rings by Maximizing Hyperconjugation and Push-Pull Effect. AB - Hyperconjugation, a weak interaction in organic chemistry, can have a strong effect on aromaticity, leading to the concept of hyperconjugative aromaticity, which was first proposed by Mulliken in 1939. However, most studies are limited to main group chemistry. Here we report the most aromatic and antiaromatic pyrrolium ring by maximizing the hyperconjugation caused by transition metal fragments and the push-pull effect. Our calculations reveal that the origin of the outperformance of transition metal substituents over main group ones on hyperconjugative aromaticity could be attributed to their higher highest occupied molecular orbitals (HOMOs). Among the group 11 transition metals, a silver substituent results in the best performance. All these findings highlight the magic of the transition metal (silver) and could be particularly helpful for the design of other aromatic and antiaromatic counterparts based on a nonaromatic parent species. PMID- 29441692 TI - A conservation planning tool for Greater Sage-grouse using indices of species distribution, resilience, and resistance. AB - Managers require quantitative yet tractable tools that identify areas for restoration yielding effective benefits for targeted wildlife species and the ecosystems they inhabit. As a contemporary example of high national significance for conservation, the persistence of Greater Sage-grouse (Centrocercus urophasianus) in the Great Basin is compromised by strongly interacting stressors of conifer expansion, annual grass invasion, and more frequent wildfires occurring in sagebrush ecosystems. Associated restoration treatments to a sagebrush-dominated state are often costly and may yield relatively little ecological benefit to sage-grouse if implemented without estimating how Sage grouse may respond to treatments, or do not consider underlying processes influencing sagebrush ecosystem resilience to disturbance and resistance to invasive species. Here, we describe example applications of a spatially explicit conservation planning tool (CPT) to inform prioritization of: (1) removal of conifers (i.e., pinyon-juniper); and (2) wildfire restoration aimed at improving habitat conditions for the Bi-State Distinct Population Segment of Sage-grouse along the California-Nevada state line. The CPT measures ecological benefits to sage-grouse for a given management action through a composite index comprised of resource selection functions and estimates of abundance and space use. For pinyon juniper removal, we simulated changes in land-cover composition following the removal of sparse trees with intact understories, and ranked treatments on the basis of changes in ecological benefits per dollar-unit of cost. For wildfire restoration, we formulated a conditional model to simulate scenarios for land cover changes (e.g., sagebrush to annual grass) given estimated fire severity and underlying ecosystem processes influencing resilience to disturbance and resistance to invasion by annual grasses. For both applications, we compared CPT rankings to land cover changes along with sagebrush resistance and resilience metrics. Model results demonstrated how the CPT can be an important step in identifying management projects that yield the highest quantifiable benefit to Sage-grouse while avoiding costly misallocation of resources, and highlight the importance of considering changes in sage-grouse ecological response and factors influencing sagebrush ecosystem resilience to disturbance and resistance to invasion. This unique framework can be adopted to help inform other management questions aimed at improving habitat for other species across sagebrush and other ecosystems. PMID- 29441693 TI - Epidemiology of fractures: The role of kick injuries in equine fractures. AB - BACKGROUND: Fractures occur commonly in equids and often are associated with complications and a poor outcome. There are no reports on the epidemiology of fractures in a heterogeneous equine population. OBJECTIVES: To study the epidemiology of fractures in a heterogeneous equine population, focusing on differences between fractures resulting from a kick and fractures, resulting from other causes and investigating predictors for recovery. STUDY DESIGN: Retrospective case series. METHODS: Data of all equids presented to the Equine Department, Vetsuisse Faculty, University of Zurich between 1990 and 2014 and diagnosed with a fracture were reviewed and those with a known cause were included in this study. Mann-Whitney and chi-squared tests were used to compare recovery rates of fractures resulting from a kick and fractures resulting from other causes, and a logistic regression was carried out for multivariate analysis of the most important factors affecting recovery. RESULTS: Here, 1144 cases fulfilled the inclusion criteria. Of all fractures (with a known cause), 43.6% were the result of a kick from another equid. Kicks often produced open fractures (44.7%) that involved bones of the limbs (85.6%). Overall recovery was 70.1%. Logistic regression showed that high-grade lameness accompanying the fracture and severe comminution negatively affected recovery. MAIN LIMITATIONS: The equids in this study were drawn from a referred population, which likely precluded the inclusion of both minor fractures and catastrophic fractures that necessitated immediate euthanasia. Moreover, many cases were excluded because the cause of the fracture could not be determined from the patient record. CONCLUSIONS: Kicks are the most common cause of fractures in a heterogeneous equine population and measures to reduce the incidence of kicks are necessary in group-housing systems. PMID- 29441694 TI - Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in RPH3A. AB - BACKGROUND: Monogenic defects of synaptic vesicle (SV) homeostasis have been implicated in many neurologic diseases, including autism, epilepsy, and movement disorders. In addition, abnormal vesicle exocytosis has been associated with several endocrine dysfunctions. METHODS: We report an 11 year old girl with learning disabilities, tremors, ataxia, transient hyperglycemia, and muscle fatigability responsive to albuterol sulfate. Failure of neuromuscular transmission was confirmed by single fiber electromyography. Electron microscopy of motor nerve terminals revealed marked reduction in SV density, double-membrane bound sacs containing SVs, abundant endosomes, and degenerative lamellar bodies. The patient underwent whole exome sequencing (WES) and relevant sequence variants were expressed and studied in a mammalian cell line. RESULTS: Chromosomal microarray studies and next generation sequencing (NGS) of mitochondrial DNA were unrevealing; however, NGS of genomic DNA showed two rare sequence variants in the gene encoding rabphilin 3a (RPH3A). The paternally inherited variant c.806 G>A (p.Arg269Gln) involves a substitution of a conserved residue in the linker region, while the maternally inherited variant c.1390 G>T (p.Val464Leu) involves a conserved amino acid substitution in the highly conserved C2A region. Expression studies revealed that p.Arg269Gln strongly impairs the binding of rabphilin 3a to 14-3-3, which is a proposed regulator of synaptic transmission and plasticity. In contrast, the binding of rabphilin 3a to 14-3-3 is only marginally impaired by p.Val464Leu; thus, the pathogenic role of p.Val464Leu remains unclear. CONCLUSION: In summary, we report a patient with a multisystem neurologic disorder and altered SV regulation attributed to defects in RPH3A, which grants further studies of this gene in human disorders of synaptic transmission. PMID- 29441695 TI - Protein phosphatase 2A (PP2A) inhibitor CIP2A indicates resistance to radiotherapy in rectal cancer. AB - Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low-CIP2A-expressing tumors had more frequently moderate or excellent response to long-course (C)RT than patients with high-CIP2A-expressing tumors. They also had higher 36-month disease-specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long-course (C)RT in rectal cancer patients. PMID- 29441696 TI - Relationships between family resilience and posttraumatic growth in breast cancer survivors and caregiver burden. AB - OBJECTIVE: To examine the relationships between family resilience and posttraumatic growth (PTG) of breast cancer survivors and caregiver burden among principal caregivers in China. METHODS: Participants in this cross-sectional study comprised 108 women aged 26 to 74 years (M = 49, SD = 9) with early-stage breast cancer and 108 principal caregivers. Participants were recruited from a comprehensive cancer center of a public hospital in Shandong Province, China. The principal caregivers completed the Shortened Chinese Version of the Family Resilience Assessment Scale and the Chinese Version of the Zarit Caregiver Burden Interview; patients completed the Short Form of the Posttraumatic Growth Inventory and questions designed to obtain sociodemographic information. Hierarchical regression analysis was conducted to assess the adjusted association between family resilience and PTG and caregiver burden, while controlling for sociodemographics. RESULTS: Families showed a slightly elevated level of family resilience since the cancer experience, and patients showed a moderate degree of PTG. Principal caregivers reported moderate burden. The Shortened Chinese Version of the Family Resilience Assessment Scale total score was positively related to the Short Form of the Posttraumatic Growth Inventory total score (beta = .28, P < .01) and was negatively related to Zarit Caregiver Burden Interview total score (beta = -.28, P < .01). CONCLUSIONS: Family resilience impacts PTG of breast cancer survivors and caregiver burden. Our findings indicated the necessity of interventions to facilitate family resilience, promote PTG among breast cancer survivors, and decrease family members' caregiver burden. PMID- 29441697 TI - Long-term outcomes of proton therapy for prostate cancer in Japan: a multi institutional survey of the Japanese Radiation Oncology Study Group. AB - This is the first multi-institutional retrospective survey of the long-term outcomes of proton therapy (PT) for prostate cancer in Japan. This retrospective analysis comprised prostate cancer patients treated with PT at seven centers between January 2008 and December 2011 and was approved by each Institutional Review Board. The NCCN classification was used. Biochemical relapse was based on the Phoenix definition (nadir + 2.0 ng/mL). Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. There were 215, 520, and 556 patients in the low-risk, intermediate-risk, and high-risk groups, respectively. The median follow-up period of surviving patients was 69 months (range: 7-107). Among all patients, 98.8% were treated using a conventional fractionation schedule and 1.2% with a hypofractionation schedule; 58.5% and 21.5% received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The 5-year biochemical relapse-free survival (bRFS) and overall survival rates in the low-risk, intermediate-risk, and high-risk groups were 97.0%, 91.1%, and 83.1%, and 98.4%, 96.8%, and 95.2%, respectively. In the multivariate analysis, the NCCN classification was a significant prognostic factor for bRFS, but not overall survival. The incidence rates of grade 2 or more severe late gastrointestinal and genitourinary toxicities were 4.1% and 4.0%, retrospectively. This retrospective analysis of a multi-institutional survey suggested that PT is effective and well-tolerated for prostate cancer. Based on this result, a multi-institutional prospective clinical trial (UMIN000025453) on PT for prostate cancer has just been initiated in order to define its role in Japan. PMID- 29441698 TI - Familial aortic disease and a large duplication in chromosome 16p13.1. AB - BACKGROUND AND PURPOSE: A recurrent duplication of chromosome 16p13.1 was associated with aortic dissection as well as with cervical artery dissection. We explore the segregation of this duplication in a family with familial aortic disease. METHODS: Whole exome sequencing (WES) analysis was performed in a patient with a family history of aortic diseases and ischemic stroke due to an aortic dissection extending into both carotid arteries. RESULTS: The index patient, his affected father, and an affected sister of his father carried a large duplication of region 16p13.1, which was also verified by quantitative PCR. The duplication was also found in clinically asymptomatic sister of the index patient. WES did not detect pathogenic variants in a predefined panel of 11 genes associated with aortic disease, but identified rare deleterious variants in 14 genes that cosegregated with the aortic phenotype. CONCLUSIONS: The cosegregation of duplication 16p13.1 with the aortic phenotype in this family suggested a causal relationship between the duplication and aortic disease. Variants in known candidate genes were excluded as disease-causing in this family, but cosegregating variants in other genes might modify the contribution of duplication 16p13.1 on aortic disease. PMID- 29441699 TI - Psychosocial functioning and risk factors among siblings of children with cancer: An updated systematic review. AB - OBJECTIVES: Siblings' psychosocial adjustment to childhood cancer is poorly understood. This systematic review summarizes findings and limitations of the sibling literature since 2008, provides clinical recommendations, and offers future research directions. METHOD: MEDLINE/Pubmed, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO were searched for articles related to siblings, psychosocial functioning, and pediatric cancer. After systematic screening, studies meeting inclusion criteria were rated for scientific merit, and findings were extracted and synthesized. In total, 102 studies were included (63 quantitative, 35 qualitative, 4 mixed-methods). RESULTS: Methodological limitations are common. Mean levels of anxiety, depression, and general adjustment are similar across siblings and comparisons, but symptoms of cancer related posttraumatic stress are prevalent. School-aged siblings display poorer academic functioning and more absenteeism but similar peer relationships as peers. Quality of life findings are mixed. Adult siblings engage in higher levels of risky health behaviors and may have poorer health outcomes than comparisons. Risk factors for poor sibling adjustment include lower social support, poorer family functioning, lower income, non-White race, and shorter time since diagnosis, but findings are inconsistent. Qualitative themes include siblings' maturity, compassion, and autonomy, but also strong negative emotions, uncertainty, family disruptions, limited parental support, school problems, altered friendships, and unmet needs. CONCLUSION: Despite methodological limitations, research indicates a strong need for sibling support. Clinical recommendations include identifying at-risk siblings and developing interventions to facilitate family communication and increase siblings' social support, cancer related knowledge, and treatment involvement. Future longitudinal studies focusing on mechanisms and moderators of siblings' adjustment would inform timing and targets of psychosocial care. PMID- 29441700 TI - Knowledge about cervical cancer and barriers toward cervical cancer screening among HIV-positive women attending public health centers in Addis Ababa city, Ethiopia. AB - Screening rate for cervical cancer among HIV-infected women and among women overall is low in Ethiopia despite the high burden of the disease and HIV infection, which increases cervical cancer risk. In this paper, we assessed knowledge about cervical cancer symptoms, prevention, early detection, and treatment and barriers to screening among HIV-positive women attending community health centers for HIV-infection management in Addis Ababa. A cross-sectional survey of 581 HIV-positive women aged 21-64 years old attending 14 randomly selected community health centers without cervical cancer screening service in Addis Ababa. We used univariate analysis to calculate summary statistics for each variable considered in the analysis, binary logistic regression analysis to measure the degree of association between dependent and independent variables, and multiple regressions for covariate adjusted associations. Statistical significance for all tests was set at P < 0.05. We used thematic analysis to describe the qualitative data. Of the 581 women enrolled in the study with mean age 34.9 +/- 7.7 years, 57.8% of participants had heard of cervical cancer and 23.4% were knowledgeable about the symptoms, prevention, early detection, and treatment of the disease. In multivariate analysis, higher educational attainment and employment were significantly associated with good knowledge about cervical cancer. In addition, only 10.8% of the participants ever had screening and 17% ever received recommendation for it. However, 86.2% of them were willing to be screened if free of cost. Knowledge about cervical cancer is poor and cervical cancer screening rate and provider recommendation are low among HIV-positive women attending community health centers for management and follow-up of their disease in Addis Ababa. These findings underscore the need to scale up health education about cervical cancer prevention and early detection among HIV-positive women as well as among primary healthcare providers in the city. PMID- 29441701 TI - Metabolomics-based chemotaxonomy of root endophytic fungi for natural products discovery. AB - Fungi are prolific producers of natural products routinely screened for biotechnological applications, and those living endophytically within plants attract particular attention because of their purported chemical diversity. However, the harnessing of their biosynthetic potential is hampered by a large and often cryptic phylogenetic and ecological diversity, coupled with a lack of large-scale natural products' dereplication studies. To guide efforts to discover new chemistries among root-endophytic fungi, we analyzed the natural products produced by 822 strains using an untargeted UPLC-ESI-MS/MS-based approach and linked the patterns of chemical features to fungal lineages. We detected 17 809 compounds of which 7951 were classified in 1992 molecular families, whereas the remaining were considered unique chemistries. Our approach allowed to annotate 1191 compounds with different degrees of accuracy, many of which had known fungal origins. Approximately 61% of the compounds were specific of a fungal order, and differences were observed across lineages in the diversity and characteristics of their chemistries. Chemical profiles also showed variable chemosystematic values across lineages, ranging from relative homogeneity to high heterogeneity among related fungi. Our results provide an extensive resource to dereplicate fungal natural products and may assist future discovery programs by providing a guide for the selection of target fungi. PMID- 29441703 TI - Effect of Cation-pi Interaction on Macroionic Self-Assembly. AB - A series of rod-shaped polyoxometalates (POMs) [Bu4 N]7 [Mo6 O18 NC(CH2 O)3 MnMo6 O18 (OCH2 )3 CNMo6 O18 ] and [Bu4 N]7 [ArNMo6 O17 NC(CH2 O)3 MnMo6 O18 (OCH2 )3 CNMo6 O17 NAr] (Ar=2,6-dimethylphenyl, naphthyl and 1-methylnaphthyl) were chosen to study the effects of cation-pi interaction on macroionic self-assembly. Diffusion ordered spectroscopy (DOSY) and isothermal titration calorimetry (ITC) techniques show that the binding affinity between the POMs and Zn2+ ions is enhanced significantly after grafting aromatic groups onto the clusters, leading to the effective replacement of tetrabutylammonium counterions (TBAs) upon the addition of ZnCl2 . The incorporation of aromatic groups results in the significant contribution of cation-pi interaction to the self-assembly, as confirmed by the opposite trend of assembly size vs. ionic strength when compared with those without aromatic groups. The small difference between two aromatic groups toward the Zn2+ ions is amplified after combining with the clusters, which consequently triggers the self-recognition behavior between two highly similar macroanions. PMID- 29441702 TI - Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs. AB - Hydrogels are under active development for controlled drug delivery, but their clinical translation is limited by low drug loading capacity, deficiencies in mechanical toughness and storage stability, and poor control over the drug release that often results in burst release and short release duration. This work reports a design of composite clay hydrogels, which simultaneously achieve a spectrum of mechanical, storage, and drug loading/releasing properties to address the critical needs from translational perspectives. The clay nanoparticles provide large surface areas to adsorb biological drugs, and assemble into microparticles that are physically trapped within and toughen hydrogel networks. The composite hydrogels demonstrate feasibility of storage, and extended release of large quantities of an insulin-like growth factor-1 mimetic protein (8 mg mL-1 ) over four weeks. The release rate is primarily governed by ionic exchange and can be upregulated by low pH, which is typical for injured tissues. A rodent model of Achilles tendon injury is used to demonstrate that the composite hydrogels allow for highly extended and localized release of biological drugs in vivo, while demonstrating biodegradation and biocompatibility. These attributes make the composite hydrogel a promising system for drug delivery and regenerative medicine. PMID- 29441704 TI - Chemoselective Synthesis of Z-Olefins through Rh-Catalyzed Formate-Mediated 1,6 Reduction. AB - Z-olefins are important functional units in synthetic chemistry; their preparation has thus received considerable attention. Many prevailing methods for cis-olefination are complicated by the presence of multiple unsaturated units or electrophilic functional groups. In this study, Z-olefins are delivered through selective reduction of activated dienes using formic acid. The reaction proceeds with high regio- and stereoselectivity (typically >90:10 and >95:5, respectively) and preserves other alkenyl, alkynyl, protic, and electrophilic groups. PMID- 29441705 TI - Injectable, Tough Alginate Cryogels as Cancer Vaccines. AB - A covalently crosslinked methacrylated (MA)-alginate cryogel vaccine has been previously shown to generate a potent response against murine melanoma, but is not mechanically robust and requires a large 16G needle for delivery. Here, covalent and ionic crosslinking of cryogels are combined with the hypothesis that this will result in a tough MA-alginate cryogel with improved injectability. All tough cryogels can be injected through a smaller, 18G needle without sustaining any damage, while covalently crosslinked-only cryogels break after injection. Cytosine-phosphodiester-guanine (CpG)-delivering tough cryogels effectively activate dendritic cells (DCs). Granulocyte macrophage colony-stimulating factor releasing tough cryogels recruit four times more DCs than blank gels by day 7 in vivo. The tough cryogel vaccine induces strong antigen-specific cytotoxic T lymphocyte and humoral responses. These vaccines prevent tumor formation in 80% of mice inoculated with HER2/neu-overexpressing DD breast cancer cells. The MA alginate tough cryogels provide a promising minimally invasive delivery platform for cancer vaccinations. PMID- 29441706 TI - New Strategies in the Design of Nanomedicines to Oppose Uptake by the Mononuclear Phagocyte System and Enhance Cancer Therapeutic Efficacy. AB - The application of nanotechnology in the treatment of tumors has boomed owing to the vigorous development in cancer nanomedicine. Despite the great success achieved in this field, nanomedicine has not realized its full potential owing to a delivery barrier, the mononuclear phagocytic system (MPS), which cuts off more than 95 % of the administrated nanoparticles. This results in an extremely low drug-delivery efficacy to the tumor and leads to poor therapeutic outcomes. Moreover, the injection of excess nanoparticles also raises toxicity concerns induced by the accumulation of nanomaterials in organs, such as the liver and spleen. Therefore, a reduction in the uptake of nanomedicines by the MPS is vital to enhance the cancer therapeutic effect and decrease side effects. In this critical review, we will summarize the new strategies to reduce nanoparticle uptake by the MPS based on current knowledge of the bio-nano interaction. Further directions will also be highlighted for the development of cancer nanomedicine with a lower off-target rate and better therapeutic outcomes. PMID- 29441707 TI - The influence of diet on masticatory motor patterns in musteloid carnivorans: An analysis of jaw adductor activity in ferrets (Mustela putorius furo) and kinkajous (Potos flavus). AB - Broad similarities in the timing of jaw adductor activity driving jaw movements across distantly related and morphologically disparate species have led to the hypothesis that mammalian masticatory motor patterns are conserved. However, some quantitative analyses also suggest that masticatory motor patterns have evolved in concert with dietary and/or morphological specialization. Here, we assess this relationship in two closely related carnivoran species with divergent diets and morphology: carnivorous ferrets and frugivorous kinkajous. Using electromyography to characterize jaw adductor activity during rhythmic mastication, we test the hypotheses that (1) carnivoran masticatory motor patterns differ from those of non-carnivorans based on previously published data, and (2) differences between ferret and kinkajou motor patterns are associated with dietary and morphological differences. We find that both species exhibit highly synchronous jaw adductor activity that is likely typical of most carnivorans. Kinkajous differ from ferrets, however, in having a balancing-side zygomaticomandibularis that is active later than all other adductors. The significance of these different masticatory motor patterns may relate to morphological differences in the dentition of ferrets and kinkajous. Whereas ferret cheek teeth have vertical occlusal surfaces that limit jaw closing to a primarily dorsally directed movement, kinkajous have relatively flat occlusal surfaces that allow more transverse movement, which may be essential for processing fruits. Our results suggest that some aspects of masticatory motor patterns are highly conserved yet some components are modified in concert with functional and morphological evolution of the masticatory apparatus. PMID- 29441708 TI - Loneliness in people with intellectual and developmental disorders across the lifespan: A systematic review of prevalence and interventions. AB - BACKGROUND: The aim of the study was to conduct the first systematic review investigating the prevalence of loneliness in people with intellectual developmental disabilities (IDD) and the interventions targeting loneliness. METHOD: A search across five databases was conducted (May 2016-June 2016). One reviewer (A. P.) selected the articles for inclusion and assessed their risk of bias using a standardized tool. The second reviewer (A. H.) examined the list of included/excluded articles and the ratings of the studies. RESULTS: Five prevalence studies met the inclusion criteria and provided an average loneliness prevalence of 44.74%. Only one intervention study was included, and it demonstrated that there was not any significant group difference for loneliness outcomes (p = .21). The majority of the studies had a weak quality rating. CONCLUSION: The systematic review evidenced that loneliness is a common experience in people with IDD and there is a need to extend current research. PMID- 29441709 TI - Multifunctional Cell Instructive Silk-Bioactive Glass Composite Reinforced Scaffolds Toward Osteoinductive, Proangiogenic, and Resorbable Bone Grafts. AB - The successful regeneration of large volume bone defects necessitates the use of proangiogenic and resorbable scaffolding matrix. Impaired and slow ingrowth of host vasculature within implanted grafts greatly compromises its effective osseointegration. By addressing this, it is demonstrated that the use of copper doped bioactive glass functionalizes silk microfiber reinforcements to improve the physicochemical and osteoinductive properties of two silk scaffolding matrices (mulberry Bombyx mori and non-mulberry Antheraea assama) employed in the study. The reinforced composite matrices increase the surface area and present an open porous biomimetic micromillieu favoring stem cell and endothelial cell migration within the matrix. Biochemical results indicate the stabilization of hypoxia-inducible factor-1alpha and expression of C-X-C chemokine receptor type-4 in adipose derived human mesenchymal stem cells, which regulate the downstream proangiogenic signaling and endothelial cell homing, respectively. Osteoinduction, matrix turnover, and resorption effectiveness are favored better in the non-mulberry silk matrices. The composite matrices significantly promote neo-osseous tissue formation in volumetric femur defect in rabbits with periosteal restoration seen in the non-mulberry silk composite matrices. Evidences of total resorption, enhanced vascular-fibrous tissue ingrowth within the scaffold, vouch for the potential clinical translation of these developed composite silk matrices. PMID- 29441710 TI - Olfactory processing in bipolar disorder, major depression, and anxiety. AB - OBJECTIVES: Although olfactory abnormalities are well established in schizophrenia, considerably less work has examined olfactory performance in other neuropsychiatric conditions. In the current study, we examined odor identification, odor discrimination, detection threshold, and odor hedonic processing performance in individuals with bipolar I disorder (n = 43; n = 13 with psychotic features), bipolar II disorder (n = 48), major depressive disorder (MDD) (n = 134), anxiety (n = 48), and no mental disorder (n = 72) who participated in a community-based family study. METHODS: Best estimate DSM-IV diagnoses were based on in-depth personal interviews as well as interviews with family members. Olfactory tests were administered during an in-person clinical visit and were compared using robust linear regression adjusting for age, sex, and psychiatric medication use, as well as nicotine use when necessary. RESULTS: Compared to controls, odor identification performance was lower among individuals with MDD (b = -1.37, 95% confidence interval [CI]: -2.50, -0.24) and bipolar I disorder (b = -1.79, 95% CI: -3.51, -0.67). Among the latter group, performance was only reduced among those with psychotic features (b = -3.49, 95% CI: -6.33, 0.65), particularly for pleasant odors (b = -1.46, 95% CI: -2.51, -0.42). Those with MDD showed lower identification accuracy for neutral odors (b = -0.63, 95% CI: -1.20, -0.06). Performances on measures of odor discrimination and detection threshold did not differ by diagnostic group. CONCLUSIONS: Collectively, these findings indicate that odor identification difficulties may exist in mood disorders, especially when psychotic features are present. In contrast, the global olfactory dysfunction observed in schizophrenia may not be a feature of other neuropsychiatric conditions. PMID- 29441711 TI - Effects of residential summer camp on body mass index and body composition in type 1 diabetes. AB - BACKGROUND: Body mass index (BMI) and fat mass may be higher in children with diabetes compared to healthy peers. It is not certain how diabetic children respond to exercise and diet interventions. OBJECTIVE: To investigate the effect of summer camp on BMI and body composition in children with type 1 diabetes. METHODS: Five hundred eighty-six children (5-19 years, 518 with type 1 diabetes, 68 without diabetes) were followed while attending camp. BMI z-scores (BMIz) and body composition (bioelectrical impedance analysis) were measured at the beginning and end of each 19-day session. Diet and activity were directly supervised, blood glucose closely monitored. A nested diabetic/non-diabetic sib pair analysis was also conducted. Changes in BMIz and percent fat mass (%FM) were the primary outcomes. Findings were confirmed by analysis of data from 612 campers (549 with diabetes) the following summer. RESULTS: At entry, campers with diabetes had higher BMIz and %FM. They tended to gain BMIz (0.04 +/- 0.01) whereas non-diabetic campers lost (-0.16 +/- 0.11, P < .0001). BMIz increases were positively correlated with precamp hemoglobin A1c values. The differences in initial values and changes in BMIz remained when campers with diabetes were compared to their siblings. All experienced a similar reduction in %FM. Similar results were obtained the following summer. CONCLUSIONS: Children with diabetes may, therefore, accrue more lean body tissue with increased exercise and a healthy diet than those without diabetes. This effect is greatest in those with initially poor metabolic control. PMID- 29441712 TI - Effectiveness of maintenance therapy of lithium vs other mood stabilizers in monotherapy and in combinations: a systematic review of evidence from observational studies. AB - OBJECTIVES: For the first time to present a systematic review of observational studies on the efficiency of lithium monotherapy in comparison with other maintenance mood stabilizers in monotherapy and in combination. METHODS: As part of the International Society for Bipolar Disorders (ISBD) Task Force on Lithium Treatment, we undertook a systematic literature search of non-randomized controlled observational studies on (i) lithium monotherapy vs treatment with another maintenance mood stabilizer in monotherapy and (ii) lithium in combination with other mood stabilizers vs monotherapy. RESULTS: In eight out of nine identified studies including a total of < 14 000 patients, maintenance lithium monotherapy was associated with improved outcome compared with another mood stabilizer in monotherapy, including valproate, lamotrigine, olanzapine, quetiapine, unspecified anticonvulsants, carbamazepine/lamotrigine, unspecified atypical antipsychotics and unspecified antipsychotics. Among the four identified studies including a total of > 4000 patients comparing maintenance combination therapy with maintenance monotherapy, a few combination therapies were found to be superior to monotherapy in some analyses, but many were not. CONCLUSIONS: The results show the superiority in real life of lithium monotherapy compared with monotherapy with other maintenance mood stabilizers. The four largest register based studies largely addressed confounding, but, as ever, residual confounding cannot be excluded. Nevertheless, the observational findings substantially add to the findings from randomized controlled trials, whose designs often limit the validity of comparison between medicines. PMID- 29441714 TI - Time-dependent regional brain distribution of methadone and naltrexone in the treatment of opioid addiction. AB - Opioid addiction is a serious public health concern with severe health and social implications; therefore, extensive therapeutic efforts are required to keep users drug free. The two main pharmacological interventions, in the treatment of addiction, involve management with methadone an mu (MU)-opioid agonist and treatment with naltrexone, MU-opioid, kappa (kappa)-opioid and delta (delta) opioid antagonist. MET and NAL are believed to help individuals to derive maximum benefit from treatment and undergo a full recovery. The aim of this study was to determine the localization and distribution of MET and NAL, over a 24-hour period in rodent brain, in order to investigate the differences in their respective regional brain distributions. This would provide a better understanding of the role of each individual drug in the treatment of addiction, especially NAL, whose efficacy is controversial. Tissue distribution was determined by using mass spectrometric imaging (MSI), in combination with quantification via liquid chromatography tandem mass spectrometry. MSI image analysis showed that MET was highly localized in the striatal and hippocampal regions, including the nucleus caudate, putamen and the upper cortex. NAL was distributed with high intensities in the mesocorticolimbic system including areas of the cortex, caudate putamen and ventral pallidum regions. Our results demonstrate that MET and NAL are highly localized in the brain regions with a high density of MU-receptors, the primary sites of heroin binding. These areas are strongly implicated in the development of addiction and are the major pathways that mediate brain stimulation during reward. PMID- 29441715 TI - Transcriptome analysis reveals TMPRSS6 isoforms with distinct functionalities. AB - TMPRSS6 (matriptase-2) is a type II transmembrane serine protease involved in iron homoeostasis. At the cell surface of hepatocytes, TMPRSS6 cleaves haemojuvelin (HJV) and regulates the BMP/SMAD signalling pathway leading to production of hepcidin, a key regulator of iron absorption. Although four TMPRSS6 human isoforms and three mice Tmprss6 isoforms are annotated in databases (Ensembl and RefSeq), their relative expression or activity has not been studied. Analyses of RNA-seq data and RT-PCR from human tissues reveal that TMPRSS6 isoform 1 (TMPRSS6-1) and 3 are mostly expressed in human testis while TMPRSS6-2 and TMPRSS6-4 are the main transcripts expressed in human liver, testis and pituitary. Furthermore, we confirm the existence and analyse the relative expression of three annotated mice Tmprss6 isoforms. Using heterologous expression in HEK293 and Hep3B cells, we show that all human TMPRSS6 isoforms reach the cell surface but only TMPRSS6-1 undergoes internalization. Moreover, truncated TMPRSS6-3 or catalytically altered TMPRSS6-4 interact with HJV and prevent its cleavage by TMPRSS6-2, suggesting their potential role as dominant negative isoforms. Taken together, our results highlight the importance of understanding the precise function of each TMPRSS6 isoforms both in human and in mouse. PMID- 29441716 TI - Behavioural mating displays depend on mitochondrial function: a potential mechanism for linking behaviour to individual condition. AB - Males of many animal species court females using complex behavioural displays that are challenging to produce, and some of these displays have been shown to be associated with aspects of male quality. However, the mechanisms by which behavioural displays are linked to individual condition remain uncertain. Herein, we illustrate fundamental mechanistic connections between mitochondrial function and neurogenesis, energy production, and a variety of pathways that underlie the ability of an individual to perform complex behaviours. We consider the biomedical evidence for how mitochondrial activity shapes neurogenesis during development and neural function in adulthood, and how both genetics and environmental conditions can cause variation in mitochondrial function in wild animals. An individual's mitochondrial phenotype determines not just metabolism and available energy, but also appears to serve as an important driver of capacity to perform cognitively complex and other challenging display behaviours. We apply this concept to the example of birdsong, a well-studied display behaviour with known links to neural pathways, and we describe how mitochondrial involvement in a variety of important internal processes creates links between display quality and key traits like immunocompetence. By synthesizing the intimate involvement of mitochondria in neural processes with the physiological bases of display behaviour, we aim to provide new mechanistic explanations for information that females may gain by assessing complex male displays. PMID- 29441713 TI - Human expression patterns: qualitative and quantitative analysis of thrombospondin-1 under physiological and pathological conditions. AB - Thrombospondin-1 (TSP-1), a matricellular protein and one of the first endogenous anti-angiogenic molecules identified, has long been considered a potent modulator of human diseases. While the therapeutic effect of TSP-1 to suppress cancer was investigated in both research and clinical settings, the mechanisms of how TSP-1 is regulated in cancer remain elusive, and the scientific answers to the question of whether TSP-1 expressions can be utilized as diagnostic or prognostic marker for patients with cancer are largely inconsistent. Moreover, TSP-1 plays crucial functions in angiogenesis, inflammation and tissue remodelling, which are essential biological processes in the progression of many cardiovascular diseases, and therefore, its dysregulated expressions in such conditions may have therapeutic significance. Herein, we critically analysed the literature pertaining to TSP-1 expression in circulating blood and pathological tissues in various types of cancer as well as cardiovascular and inflammation-related diseases in humans. We compare the secretion rates of TSP-1 by different cancer and non-cancer cells and discuss the potential connection between the expression changes of TSP-1 and vascular endothelial growth factor (VEGF) observed in patients with cancer. Moreover, the pattern and emerging significance of TSP-1 profiles in cardiovascular disease, such as peripheral arterial disease, diabetes and other related non-cancer disorders, are highlighted. The analysis of published TSP-1 data presented in this review may have implications for the future exploration of novel TSP-1-based treatment strategies for cancer and cardiovascular-related diseases. PMID- 29441717 TI - S100A9 gene silencing inhibits the release of pro-inflammatory cytokines by blocking the IL-17 signalling pathway in mice with acute pancreatitis. AB - The study aimed to investigate whether S100A9 gene silencing mediating the IL-17 pathway affected the release of pro-inflammatory cytokines in acute pancreatitis (AP). Kunming mice were assigned to the normal, AP, AP + negative control (NC), AP + shRNA, AP + IgG and AP + anti IL-17 groups. ELISA was applied to measure expressions of AMY, LDH, CRP, TNF-alpha, IL-6 and IL-8. The cells were distributed into the control, blank, NC, shRNA1 and shRNA2 groups. MTT assay, flow cytometry, RT-qPCR and Western blotting were used to evaluate cell proliferation, cell cycle and apoptosis, and expressions of S100A9, TLR4, RAGE, IL-17, HMGB1 and S100A12 in tissues and cells. Compared with the normal group, the AP group displayed increased expressions of AMY, LDH, CRP, TNFalpha, IL-6, IL 8, S100A9, TLR4, RAGE, IL-17, HMGB1 and S100A12. The AP + shRNA and AP + anti IL 17 groups exhibited an opposite trend. The in vivo results: Compare with the control group, the blank, NC, shRNA1 and shRNA2 groups demonstrated increased expressions of S100A9, TLR4, RAGE, IL-17, HMGB1 and S100A12, as well as cell apoptosis and cells at the G1 phase, with reduced proliferation. Compared with the blank and NC groups, the shRNA1 and shRNA2 groups had declined expressions of S100A9, TLR4, RAGE, IL-17, HMGB1 and S100A12, as well as cell apoptosis and cells at the G1 phase, with elevated proliferation. The results indicated that S100A9 gene silencing suppressed the release of pro-inflammatory cytokines through blocking of the IL-17 pathway in AP. PMID- 29441718 TI - The checkpoint kinase TOR (target of rapamycin) regulates expression of a nuclear encoded chloroplast RelA-SpoT homolog (RSH) and modulates chloroplast ribosomal RNA synthesis in a unicellular red alga. AB - Chloroplasts are plant organelles that carry out oxygenic photosynthesis. Chloroplast biogenesis depends upon chloroplast ribosomes and their translational activity. However, regulation of chloroplast ribosome biogenesis remains an important unanswered question. In this study, we found that inhibition of target of rapamycin (TOR), a general eukaryotic checkpoint kinase, results in a decline in chloroplast ribosomal RNA (rRNA) transcription in the unicellular red alga, Cyanidioschyzon merolae. Upon TOR inhibition, transcriptomics and other analyses revealed increased expression of a nuclear-encoded chloroplast RelA-SpoT homolog (RSH) gene (CmRSH4b), which encodes a homolog of the guanosine 3'-diphosphate 5' diphosphate (ppGpp) synthetases that modulate rRNA synthesis in bacteria. Using an Escherichia coli mutant lacking ppGpp, CmRSH4b was demonstrated to have ppGpp synthetase activity. Expression analysis of a green fluorescent protein-fused protein indicated that CmRSH4b localizes to the chloroplast, and overexpression of the CmRSH4b gene resulted in a decrease of chloroplast rRNA synthesis concomitant with growth inhibition and reduction of chloroplast size. Biochemical analyses using C. merolae cell lysates or purified recombinant proteins revealed that ppGpp inhibits bacteria-type RNA polymerase-dependent chloroplast rRNA synthesis as well as a chloroplast guanylate kinase. These results suggest that CmRSH4b-dependent ppGpp synthesis in chloroplasts is an important regulator of chloroplast rRNA transcription. Nuclear and mitochondrial rRNA transcription were both reduced by TOR inhibition, suggesting that the biogeneses of the three independent ribosome systems are interconnected by TOR in plant cells. PMID- 29441719 TI - AZD1208, a pan-Pim kinase inhibitor, inhibits adipogenesis and induces lipolysis in 3T3-L1 adipocytes. AB - The proviral integration moloney murine leukaemia virus (Pim) kinases, consisting of Pim-1, Pim-2 and Pim-3, are involved in the control of cell growth, metabolism and differentiation. Pim kinases are emerging as important mediators of adipocyte differentiation. AZD1208 is a pan-Pim kinase inhibitor and is known for its anti cancer activity. In this study, we investigated the effect of AZD1208 on adipogenesis and lipolysis in 3T3-L1 cells, a murine preadipocyte cell line. AZD1208 markedly suppressed lipid accumulation and reduced triglyceride contents in differentiating 3T3-L1 cells, suggesting the drug's anti-adipogenic effect. On mechanistic levels, AZD1208 reduced not only the expressions of CCAAT/enhancer binding protein-alpha (C/EBP-alpha), peroxisome proliferator-activated receptor gamma (PPAR-gamma), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC) and perilipin A but also the phosphorylation of signal transducer and activator of transcription-3 (STAT-3) in differentiating 3T3-L1 cells. Remarkably, AZD1208 increased cAMP-activated protein kinase (AMPK) and LKB-1 phosphorylation while decreased intracellular ATP contents in differentiating 3T3-L1 cells. Furthermore, in differentiated 3T3-L1 adipocytes, AZD1208 also partially promoted lipolysis and enhanced the phosphorylation of hormone-sensitive lipase (HSL), a key lipolytic enzyme, indicating the drug's HSL-dependent lipolysis. In summary, the findings show that AZD1208 has anti-adipogenic and lipolytic effects on 3T3 L1 adipocytes. These effects are mediated by the expression and/or phosphorylation levels of C/EBP-alpha, PPAR-gamma, FAS, ACC, perilipin A, STAT-3, AMPK and HSL. PMID- 29441720 TI - Identification and characterization of homeobox (Hox) genes and conservation of the single Hox cluster (324.6 kb) in the water flea Daphnia magna. AB - We report the complete sequence analysis of the entire complement of eight typical homeobox (Hox) genes (Lab, Pb, Dfd, Scr, Antp, Ubx, Abd-A, and Abd-B) and two other genes (Hox3 and Ftz) in a 324.6-kb region in the water flea Daphnia magna. In the cluster of D. magna Hox genes, we found one long interspersed nuclear element (LINE)/R2-NeSL between Ubx and Abd-A that was not present in Daphnia pulex Hox genes. In basal expression of Hox genes at different developmental stages, biothorax complex genes (Ubx, Abd-A, and Abd-B) and some antennapedia complex genes (Lab, Scr, Antp) were moderately expressed, but the Hox3 gene was barely expressed. Three homeobox genes (Antp, Ubx, Abd-A) were highly expressed at 6-7 days after release from the brood chamber and/or in the adult stage. The structural array and transcribed orientation of Dm-Hox genes were identical to those of the sister species D. pulex (~340 kb), indicating that the Hox gene structure in daphnids is highly conserved. However, Dm- and Dp-Hox3, -deformed (Dfd), and -fushi tarazu (Ftz) genes varied from orthologous genes in pancrustacean species. PMID- 29441721 TI - Application of Mono- and Disaccharides in Drug Targeting and Efficacy. AB - Carbohydrates and their conjugates play important roles in many biological processes including fertilization, differentiation, development, immune response, and infection. Their activities are largely dependent on the properties of terminal mono- or disaccharides. Galactose, mannose, fucose, glucose, sialic acid, etc., are commonly used as powerful scaffolds installed on drug molecules for targeting specific tissues including brain, liver, and cancers, and as epitopes for enhancing the targeting of various vaccines. This review focuses on the influence of their structural variations, including changes in sugar type, substituent groups and their positions, as well as length of linker portion, on the targeting of drugs or their efficacy. Particular attention is paid to the targeting properties of mono- and disaccharides applied in drug design and discovery. PMID- 29441722 TI - The growing importance of lesion volume as a prognostic factor in patients with multiple brain metastases treated with stereotactic radiosurgery. AB - Stereotactic Radiosurgery (SRS) is considered standard of care for patients with 1-3 brain metastases (BM). Recent observational studies have shown equivalent OS in patients with 5+ BM compared to those with 2-4, suggesting SRS alone may be appropriate in these patients. We aim to review outcomes of patients treated with SRS with 2-4 versus 5+ BM. This analysis included consecutive patients from 1994 to 2015 treated with SRS. Of 1017 patients, we excluded patients with a single BM and patients without adequate survival data, resulting in 391 patients. All risk factors were entered into univariate analysis using Cox proportional hazards model, and significant factors were entered into multivariate analysis (MVA). We additionally analyzed outcomes after excluding patients with prior surgery or whole-brain radiotherapy (WBRT). Median follow-up was 7.1 months. Median KPS was 90, mean age was 59, and most common histologies were melanoma and lung. Median tumor volume was 3.41 cc. Patients with 2-4 BM had a median OS of 8.1 months compared to 6.2 months for those with 5+ BM (P = 0.0136). On MVA, tumor volume, KPS, and histology remained significant for OS, whereas lesion number did not. Similar results were found when excluding patients with prior surgery or WBRT. Rather than lesion number, the strongest prognostic factors for patients undergoing SRS were tumor volume >10 cc, KPS, and histology. BM number may therefore not be the most important criterion for candidacy for SRS. Patients with 5 or more BM should be considered for SRS. PMID- 29441723 TI - Mortality risk after cancer diagnosis in kidney transplant recipients: the limitations of analyzing hospital administration data alone. AB - Administrative data are frequently used for epidemiological studies but its usefulness to analyze cancer epidemiology after kidney transplantation is unclear. In this retrospective population-based cohort study, we identified every adult kidney-alone transplant performed in England (2003-2014) using administrative data from Hospital Episode Statistics. Results were compared to the hospitalized adult general population in England to calculate standardized incidence and mortality ratios. Data were analyzed for 19,883 kidney allograft recipients, with median follow-up 6.0 years' post-transplantation. Cancer incidence was more common after kidney transplantation compared to the general population in line with published literature (standardized incidence ratio 2.47, 95% CI: 2.34-2.61). In a Cox proportional hazards model, cancer development was associated with increasing age, recipients of deceased kidneys, frequent readmissions within 12 months post-transplant and first kidney recipients. All cause mortality risk for kidney allograft recipients with new-onset cancer was significantly higher compared to those remaining cancer-free (42.0% vs. 10.3%, respectively). However, when comparing mortality risk for kidney allograft recipients to the general population after development of cancer, risk was lower for both cancer-related (standardized mortality ratio 0.75, 95% CI: 0.71-0.79) and noncancer-related mortality (standardized mortality ratio 0.90, 95% CI: 0.85 0.95), which contradicts reported literature. Although some plausible explanations are conceivable, our analysis likely reflects the limitations of administrative data for analyzing cancer data. Future studies require record linkage with dedicated cancer registries to acquire more robust and accurate data relating to cancer epidemiology after transplantation. PMID- 29441724 TI - PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma. AB - Increasing evidence suggests that PRMT5, a protein arginine methyltransferase, has roles in cell growth regulation and cancer development. However, the role of PRMT5 in hepatocellular carcinoma (HCC) progression remains unclear. Here, we showed that PRMT5 expression was frequently upregulated in HCC tissues, and its expression was inversely correlated with overall survival in HCC patients. PRMT5 knockdown markedly inhibited in vitro HCC proliferation and in vivo tumorigenesis. We revealed that the mechanism of PRMT5-induced proliferation was partially mediated by BTG downregulation, leading to cell cycle arrest during the G1 phase in HCC cells. Ectopic BTG2 overexpression decreased HCC growth, caused cell cycle arrest at the G1 phase, and downregulated Cyclin D1 and Cyclin E1 protein expression. Furthermore, we found that PRMT5-induced ERK phosphorylation regulated BTG2 expression in HCC cells, whereas pretreatment with a selective ERK1/2 inhibitor (PD184352) significantly reversed the effect of PRMT5 on BTG2 expression. Our results indicated that PRMT5 promotes HCC proliferation by downregulating BTG2 expression via the ERK pathway. PMID- 29441725 TI - High expression of DJ-1 promotes growth and invasion via the PTEN-AKT pathway and predicts a poor prognosis in colorectal cancer. AB - Cancer cell invasion and unlimited proliferation are key factors in patients with colorectal cancer (CRC). Increased protein deglycase DJ-1 in cancer cells is known to promote tumor growth; however, its role in CRC progression is not well defined. In this study, we investigated 100 CRC patients with disease stages I-IV to determine whether DJ-1 could serve as a prognostic biomarker in CRC. These results showed that DJ-1 expression in CRC tissues was higher than that in normal colon tissues and was associated with the (Tumor Node Metastasis) TNM stage. CRC patients with low DJ-1 expression had a longer overall survival than those with high expression, and multivariate and univariate analyses indicated that DJ-1 expression was an independent prognostic factor for overall survival in CRC. Furthermore, DJ-1 overexpression in two colon cancer cell lines, HCT116 and SW480, activated protein kinase AKT and downregulated tumor suppressor PTEN, whereas DJ-1 knockdown upregulated PTEN expression and effectively suppressed CRC cell invasion and proliferation both in vitro and in vivo, revealing a mechanism underlying DJ-1 pro-oncogenic activity in CRC. Treatment of MK2206, the specific AKT inhibitor, significantly decreased DJ-1-mediated cell proliferation and mobility in vitro. Taken together, these results suggest that DJ-1 may be a novel prognostic biomarker and potential therapeutic target in human CRC. PMID- 29441726 TI - Commentary on 'Sleep variability as a symptom and as a treatment target: Let's not sleep on it' by Soehner et al. PMID- 29441727 TI - CORRIGENDUM. PMID- 29441728 TI - CORRIGENDUM. PMID- 29441731 TI - Environmental Microbiology Reports is 10! PMID- 29441732 TI - Milestones in environmental microbiology: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 29441730 TI - Potency of Delta9 -tetrahydrocannabinol and other cannabinoids in cannabis in England in 2016: Implications for public health and pharmacology. AB - In 2005 and 2008, studies reported that cannabis in England had become dominated by the sinsemilla (unseeded female) form. The average potency (Delta9 tetrahydrocannabinol [THC] content) of this material had doubled over the previous decade. Cannabis resin then circulating contained approximately equal ratios of THC and cannabidiol (CBD), whereas sinsemilla was almost devoid of CBD. Despite raised health concerns regarding sinsemilla use and the development of psychotic disorders, no update on street cannabis potency has been published since 2008. A total of 995 seized cannabis samples were acquired from the same 5 constabulary areas included in the 2005 study. The differing forms were segregated, and a representative 460 samples analyzed to assess their cannabinoid content using gas chromatography. The resultant median sinsemilla potency of 14.2% THC was similar to that observed in 2005 (13.9%). In each case, sinsemilla contained minimal CBD. Compared with 2005, resin had significantly higher mean THC (6.3%) and lower CBD (2.3%) contents (p < 0.0001). Although the average THC concentration in sinsemilla samples across the 5 constabularies has remained stable since 2005, the availability of this potent form of cannabis has further increased. Moreover, the now rarer resin samples show significantly decreased CBD contents and CBD:THC ratios, leaving the United Kingdom's cannabis street market populated by high-potency varieties of cannabis, which may have concerning implications for public health. PMID- 29441734 TI - Cross-sectional serum metabolomic study of multiple forms of muscular dystrophy. AB - Muscular dystrophies are characterized by a progressive loss of muscle tissue and/or muscle function. While metabolic alterations have been described in patients'-derived muscle biopsies, non-invasive readouts able to describe these alterations are needed in order to objectively monitor muscle condition and response to treatment targeting metabolic abnormalities. We used a metabolomic approach to study metabolites concentration in serum of patients affected by multiple forms of muscular dystrophy such as Duchenne and Becker muscular dystrophies, limb-girdle muscular dystrophies type 2A and 2B, myotonic dystrophy type 1 and facioscapulohumeral muscular dystrophy. We show that 15 metabolites involved in energy production, amino acid metabolism, testosterone metabolism and response to treatment with glucocorticoids were differentially expressed between healthy controls and Duchenne patients. Five metabolites were also able to discriminate other forms of muscular dystrophy. In particular, creatinine and the creatine/creatinine ratio were significantly associated with Duchenne patients performance as assessed by the 6-minute walk test and north star ambulatory assessment. The obtained results provide evidence that metabolomics analysis of serum samples can provide useful information regarding muscle condition and response to treatment, such as to glucocorticoids treatment. PMID- 29441735 TI - The role of mmu-miR-155-5p-NF-kappaB signaling in the education of bone marrow derived mesenchymal stem cells by gastric cancer cells. AB - Bone marrow-derived mesenchymal stem cells (BM-MSCs) are important precursors of tumor stromal cells. Previously, we have demonstrated that miR-155-5p inhibition directly induced transition of BM-MSCs into gastric cancer-associated MSCs. Whether miR-155-5p is involved in the education of BM-MSCs by gastric cancer cells has not been established. Murine BM-MSCs (mMSCs) were isolated and grown in conditioned medium derived from gastric cancer cell line MFC (MFC-CM). The tumor promoting phenotype and function of mMSCs were detected by immunofluorescence staining, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), cell colony formation assay, transwell migration, and invasion assays. Luciferase reporter assays and western blot analyses were conducted to reveal the relationship between nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) p65 and mmu-miR-155-5p. miRNA mimics, inhibitor, and the NF kappaB inhibitor pyrrolidine dithiocarbamic acid (PDTC) were used to evaluate the role of miR-155-5p-NF-kappaB signaling in the education of mMSCs by MFC-CM. We successfully established the education model of mMSCs by MFC-CM and found that mmu-miR-155-5p expression levels were reduced in mMSCs. Mimicking this deregulation by transfecting miRNA inhibitor into mMSCs produced a similar effect as that of MFC-CM on mMSCs. NF-kappaB p65 was validated as a target of mmu-miR 155-5p, which also negatively regulated NF-kappaB activation. Inhibition of NF kappaB activation by PDTC abolished the effect of the miRNA inhibitor on mMSCs. mmu-miR-155-5p overexpression partially blocked the effect of MFC-CM in educating mMSCs, while PDTC treatment completely eliminated MFC-CM activity. These results indicate that miR-155-5p is not the sole miRNA mediating the education of BM-MSCs by gastric cancer cells, but downstream NF-kappaB signaling is indispensable for this process. PMID- 29441736 TI - The Legal Doctrine on the Liability of Physicians in Medical Malpractice Lawsuits Involving Complex Regional Pain Syndrome. AB - BACKGROUND: Complex regional pain syndrome (CRPS) involves severe pain and it is difficult to identify the exact cause or pathogenesis. Therefore, there are controversies regarding legal issues related to the establishment of damage in medical malpractice lawsuits involving CRPS. This study aimed to analyze malpractice lawsuits involving CRPS, which occurred after the disputed medical treatment, to provide information on the courts' opinion and characteristics of the cases. METHODS: This study analyzed 23 lawsuit judgments involving CRPS that were sentenced from 2005 to 2015. RESULTS: A total of 12 of the 23 cases were partially ruled in favor of the plaintiff. The average amount (KRW) claimed was 470,638,385 +/- 860,634,092 (21,000,000 to 4,020,000,000), and that awarded was 72,906,843 +/- 53,389,367 (15,000,000 to 181,080,803). Sixteen of the 23 cases had CRPS type I. In 11 of 23 cases, the site of the pain was located in the lower limb and in 14 cases there was no presence of trauma or event prior to medical treatment. CONCLUSION: Nerve injury was the most frequent reason for taking responsibility in compensating damage in malpractice cases involving CRPS. Physicians should consider various possibilities of such complications in medical practices. It is important to identify and improve areas which need to be improved for patient safety through analyzing the lawsuit judgment cases. PMID- 29441737 TI - Cesium-137 Contaminated Roads and Health Problems in Residents: an Epidemiological Investigation in Seoul, 2011. AB - BACKGROUND: In 2011, two roads in a residential area in Seoul were found to be contaminated with the radionuclide cesium-137 (137Cs). In response to public concerns, an epidemiological study was conducted. METHODS: The standardized cancer incidence ratios in the affected and neighboring regions were calculated based on the central cancer registry. Households in the region were sampled using the random stratified sampling technique, and questionnaires were administered to family members, via home visit and via students in elementary to high schools. Information on duration of residency and frequency of use of the roads was applied to calculate cumulative radiation exposure dose from the roads, alongside with the reported 137Cs contamination amounts. Information on past medical history, perceived risk, anxiety and psychological stress was also obtained. Of the 31,053 residents, 8,875 were analyzed. To examine possible associations between radiation exposure and health problems, logistic regression adjusted for covariates were performed with consideration of the sampling design, population weight and stratification. RESULTS: No significant association was found between self-informed diseases, including cancers, and estimated radiation exposure dose. According to an increase of radiation level, a significant increase in anxiety in all and a decline in the psychosocial wellbeing of the adults was noted. The risk perception level was higher in the elderly, females, the less educated, and the highest exposed individuals. CONCLUSION: This study provides a basis for risk communication with residents and community environmental health policy. PMID- 29441738 TI - The First Reported Case of Fibrous Hamartoma of Infancy with Hyperhidrosis and Hypertrichosis in Korea. AB - Fibrous hamartoma of infancy (FHI) is a rare entity with a benign nature. The typical clinical features are a single, slowly growing, painless mass on the trunk that appears within the first 2 years of life. We report a 13-month-old boy who presented with a plaque on the lower back since 4 months of age. The plaque had gradually become larger and firm, and hyperhidrosis and hypertrichosis were noticed. No visible connection between the spinal cord and the lesion was found in radiologic studies, indicating a disease other than spinal dysraphism. Histopathological findings showed well-defined fibrous trabeculae, mature adipose tissue, and primitive mesenchymal cells, all consistent with FHI. This is the first case of FHI presenting with hyperhidrosis and hypertrichosis reported in Korea. PMID- 29441739 TI - A Survey of Radiation Therapy Utilization in Korea from 2010 to 2016: Focusing on Use of Intensity-Modulated Radiation Therapy. AB - BACKGROUND: This study aimed to assess the recent changes of radiation therapy (RT) modalities in Korea. In particular, we focused on intensity-modulated radiation therapy (IMRT) utilization as the main index, presenting the application status of advanced RT. METHODS: We collected information from the Korean Health and Insurance Review and Assessment Service data based on the National Health Insurance Service claims and reimbursements records by using treatment codes from 2010 to 2016. We classified locating region of each institution as capital vs. non-capital areas and metropolitan vs. non metropolitan areas to assess the regional difference in IMRT utilization in Korea. RESULTS: IMRT use has been steadily increased in Korea, with an annual increase estimate (AIE) of 37.9% from 2011 to 2016 (P < 0.001) resulting in IMRT being the second most common RT modality following three-dimensional conformal radiotherapy. In general, an increasing trend of IMRT utilization was observed, regardless of the region. The rate of AIE in the capital areas or metropolitan areas was higher than that in non-capital areas or non-metropolitan areas (40.7% vs. 31.9%; P < 0.001 and 39.7% vs. 29.4%; P < 0.001, respectively). DISCUSSION: The result of our survey showed that IMRT has become one of the most common RT modalities. IMRT is becoming popular in both metropolitan and non-metropolitan areas, while metropolitan area has faster AIE possibly due to concentration of medical resources and movement of advanced patients. PMID- 29441740 TI - Changes of Epidemiological Characteristics of Japanese Encephalitis Viral Infection and Birds as a Potential Viral Transmitter in Korea. AB - Japanese encephalitis (JE) cases have been increasingly reported recently especially in Seoul and its vicinity. Pigs are known as amplifying host of JE virus (JEV), but do not play an important role in these recent events because pig breeding is not common in Seoul. The distribution and the density of migratory birds are correlated with JE cases in cities and they might be highly potential hosts contributing to transmit JEV in metropolitan areas. JE genotype and sero prevalence in birds should be determined for the verification of the transmission route of JEV in the recent sporadic occurrence of JE cases in Seoul. PMID- 29441741 TI - The Concept of Door-to-Surgery Time in Distal Digital Replantation. AB - BACKGROUND: Digital replantation has become a well-established technique that has revolutionized hand surgery. One of the most important factors to a successful replantation is less than 12 hours of warm and 24 hours of cold ischemia time. The purpose of this article was to present a concept of door-to-surgery time and test the hypothesis that success in distal digital replantation is associated with this time. METHODS: Forty-five patients with 49 distal amputations were included in the study. Data regarding patient demographics, amputation characteristics, ischemia time, and surgical outcome were collected. Factors related to a successful replantation were analyzed. Fisher's exact test was used for statistical analysis. RESULTS: Type I, II, and III Yamano classification were noted in 11 (22.4%), 11 (22.4%), and 27 (55.1%) amputations. All the digits had arterial anastomoses while 19 (38.8%) digits were replanted without venous anastomosis. The mean door-to-surgery time was 229 minutes. The overall success rate was 77.6%. There were no differences in the survival rates between replantations with or without venous anastomosis. Patients with less than 180 minutes of door-to-surgery time had a significantly better survival rate compared to patients with greater time. CONCLUSION: The overall success rate was 77.6%. Patients with less than 180 minutes of door-to-surgery time had a significantly greater success rate (95.0%) compared to patients with longer door-to-surgery time (65.5%). Further effort must be made to achieve this goal in digital replantation. PMID- 29441743 TI - Moving Forward to Improve Safety and Quality of Neonatal Intensive Care in Korea. PMID- 29441744 TI - Cryoballoon Ablation for Atrial Fibrillation: a Comprehensive Review and Practice Guide. AB - The cryoballoon was invented to achieve circumferential pulmonary vein isolation more efficiently to compliment the shortcomings of point-by-point ablation by radiofrequency ablation (RFA). Its efficacy and safety were shown to be comparable to those of RFA, and the clinical outcomes have improved with the second-generation cryoballoon. The basic biophysics, implemental techniques, procedural recommendations, clinical outcomes, and complications of the cryoballoon are presented in this practical and systematic review. PMID- 29441742 TI - The Effect of Mycophenolate Mofetil versus Cyclosporine as Combination Therapy with Low Dose Corticosteroids in High-risk Patients with Idiopathic Membranous Nephropathy: a Multicenter Randomized Trial. AB - BACKGROUND: Appropriate immunosuppressive therapy for patients with idiopathic membranous nephropathy (MN) remains controversial. The effect of mycophenolate mofetil (MMF) versus cyclosporine (CsA) combined with low-dose corticosteroids was evaluated in patients with idiopathic MN in a multi-center randomized trial (www.ClinicalTrials.gov NCT01282073). METHODS: A total of 39 biopsy-proven idiopathic MN patients with severe proteinuria were randomly assigned to receive MMF combined with low-dose corticosteroids (MMF group) versus CsA combined with low-dose corticosteroids (CsA group), respectively, and followed up for 48 weeks. Complete or partial remission rate of proteinuria and estimated glomerular filtration rate (eGFR) at 48 weeks were compared. RESULTS: The level of proteinuria at baseline and at 48 weeks was 8.9 +/- 5.9 and 2.1 +/- 3.1 g/day, respectively, in the MMF group compared to 8.4 +/- 3.5 and 3.2 +/- 5.7 g/day, respectively, in the CsA group. In total, 76.1% of the MMF group and 66.7% of the CsA group achieved remission at 48 weeks (95% confidence interval, -0.18 to 0.38). There was no difference in eGFR between the two groups. Anti-phospholipase A2 receptor Ab levels at baseline decreased at 48 weeks in the complete or partial remission group (P = 0.001), but were unchanged in the no-response group. There were no significant differences between the two groups in changes in the Gastrointestinal Symptom Rating Scale and Gastrointestinal Quality of Life Index scores from baseline to 48 weeks. CONCLUSION: In combination with low-dose corticosteroids, the effect of MMF may not be inferior to that of CsA in patients with idiopathic MN, with similar adverse effects including gastrointestinal symptoms. Trial registry at ClinicalTrials.gov (NCT01282073). PMID- 29441745 TI - Evaluation of Atherosclerotic Plaque in Non-invasive Coronary Imaging. AB - Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Over the last decade coronary computed tomography angiography (CCTA) has gained wide acceptance as a reliable, cost-effective and non-invasive modality for diagnosis and prognostication of CAD. Use of CCTA is now expanding to characterization of plaque morphology and identification of vulnerable plaque. Additionally, CCTA is developing as a non-invasive modality to monitor plaque progression, which holds future potential in individualizing treatment. In this review, we discuss the role of CCTA in diagnosis and management of CAD. Additionally, we discuss the recent advancements and the potential clinical applications of CCTA in management of CAD. PMID- 29441746 TI - Long-term Prognosis and Clinical Characteristics of Patients with Newly Diagnosed Diabetes Mellitus Detected after First Acute Myocardial Infarction: from KAMIR NIH Registry. AB - BACKGROUND AND OBJECTIVES: After the first acute myocardial infarction (AMI), a considerable proportion of patients are newly diagnosed with diabetes mellitus (DM). However, in AMI, controversy remains regarding the disparity in prognosis between previously diagnosed DM (known-DM) and newly diagnosed DM (new-DM). METHODS: The study included 10,455 patients with AMI (non-DM, 6,236; new-DM, 659; known-DM, 3,560) admitted to one of 15 participating centers in Korea between November 2011 and January 2016 (average follow-up, 523 days). We compared the characteristics and clinical course of patients with known-DM and those with new- or non-DM. RESULTS: Compared to patients with known-DM, those with new-DM or non DM were younger, more likely to be male, and less likely to have hypertension, dyslipidemia, prior stroke, angina, or myocardial infarction. Compared to patients with new-DM or non-DM (reference), those with known-DM had higher risks of major adverse cardiac events (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.06-1.35; p=0.004), cardiac death (HR, 1.26; 95% CI, 1.01-1.57; p=0.042), and congestive heart failure (HR, 1.58; 95% CI, 1.20-2.08). Unlike known-DM, new DM did not increase the risk of cardiac events (including death). CONCLUSIONS: Known-DM was associated with a significantly higher risk of cardiovascular events after AMI, while new-DM had a similar risk of cardiac events as that noted for non-DM. There were different cardiovascular outcomes according to diabetes status in patients with AMI. PMID- 29441747 TI - The Complexity of Pediatric Multifocal Atrial Tachycardia and Its Prognostic Factors. AB - BACKGROUND AND OBJECTIVES: Multifocal atrial tachycardia (MAT), in general, has a favorable outcome. However, there are insufficient data regarding MAT in a pediatric population. This study sought to determine the clinical course of MAT and identify potential prognostic factors. METHODS: The medical records of MAT patients from 1997-2015 were reviewed. The arrhythmia control rate and factors for unfavorable outcomes were assessed and compared to those in the literature. RESULTS: Of the 33 included patients (19 boys and 14 girls), 27 were infants less than 1 year of age. The median age at diagnosis was 1.7 months (range, 0 day to 14 years). Fourteen (42%) patients had structural heart disease. Eight (24%) patients had lung disease and 6 (18%) had a syndromic diagnosis belonging to RASopathy. Two patients developed polymorphic ventricular tachycardia, in whom genetic analysis confirmed the presence of the RyR2 mutation several years later. MAT was controlled in 26 patients (84%) within 3.9 months (median; range, 16 days 18.4 years) using an average of 2.4 medications. There were 3 cases of cardiopulmonary mortality. The arrhythmia control rate was higher in the infant group (85%) than in the non-infant group (67%), although this trend was not statistically significant. There was a significantly lower rate of unfavorable outcomes in the idiopathic infant group (n=11) than in the other groups (p=0.008). Considering the findings of previous studies, the mortality rate was significantly higher in patients with structural heart disease than in patients without (21% vs. 5%, p=0.01). CONCLUSIONS: MAT usually affects infants and has a favorable prognosis, particularly in the idiopathic infant group. However, in the presence of other comorbidities, MAT may have a variable clinical course. PMID- 29441748 TI - Association between Serum Parathyroid Hormone Levels and the Prevalence of Atrial Fibrillation: the Dong-gu Study. AB - BACKGROUND AND OBJECTIVES: We aimed to investigate the association between serum parathyroid hormone (PTH) levels and the prevalence of atrial fibrillation (AF) in a population based study. METHODS: This study included a total of 9,007 community-dwelling Koreans aged 50 years and over who were enrolled in the Dong gu study from 2007 to 2010. Electrocardiograms were recorded from the subjects using the HP-PageWriter 200 M1771A. All potential cases of AF were determined by 2 cardiologists. PTH concentration was measured by a chemiluminescent microparticle immunoassay. Multiple logistic regression analysis was used to evaluate the relationship between the quartiles of PTH and AF, adjusting for potential confounders. RESULTS: The prevalence of AF was 2.41% in males and 0.9% in females and increased with advanced age in both genders. The median and interquartile range (IQR) of serum PTH was 39.5 pg/mL (IQR, 30.6-50.8), which was significantly higher in patients with AF than in patients without AF (p<0.001). The prevalence of AF increased with increasing PTH quartile (0.8%, 0.9%, 1.6%, and 2.8% in the lowest, second, third, and highest PTH quartiles, respectively; p<0.001). Multivariable logistic analysis adjusted for cardiovascular risk factors showed the highest quartile of serum PTH levels was associated with a higher prevalence of AF than the lowest quartile (odds ratio, 3.34; 95% confidence interval, 1.93-5.78). CONCLUSIONS: Higher levels of serum PTH were associated with higher prevalence of AF. Further studies are needed to determine whether this association is present in other populations and in a prospective study setting. PMID- 29441749 TI - Clinical Significance of Newly Diagnosed Diabetes Mellitus in the Era of DES for Acute Myocardial Infarction. PMID- 29441750 TI - Current Understanding on Mechanisms Leading to Atrial Fibrillation. PMID- 29441751 TI - Clinical Implication of Multifocal Atrial Tachycardia in Children for Pediatric Cardiologist. PMID- 29441753 TI - Diabetes, Frequency of Exercise, and Mortality Over 12 Years: Analysis of the National Health Insurance Service-Health Screening (NHIS-HEALS) Database. AB - BACKGROUND: The goal of this study was to analyze the relationship between exercise frequency and all-cause mortality for individuals diagnosed with and without diabetes mellitus (DM). METHODS: We analyzed data for 505,677 participants (53.9% men) in the National Health Insurance Service-National Health Screening (NHIS-HEALS) cohort. The study endpoint variable was all-cause mortality. RESULTS: Frequency of exercise and covariates including age, sex, smoking status, household income, blood pressure, fasting glucose, body mass index, total cholesterol, and Charlson comorbidity index were determined at baseline. Cox proportional hazard regression models were developed to assess the effects of exercise frequency (0, 1-2, 3-4, 5-6, and 7 days per week) on mortality, separately in individuals with and without DM. We found a U-shaped association between exercise frequency and mortality in individuals with and without DM. However, the frequency of exercise associated with the lowest risk of all-cause mortality was 3-4 times per week (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.65-0.73) in individuals without DM, and 5-6 times per week in those with DM (HR, 0.93; 95% CI, 0.78-1.10). CONCLUSION: A moderate frequency of exercise may reduce mortality regardless of the presence or absence of DM; however, when compared to those without the condition, people with DM may need to exercise more often. PMID- 29441752 TI - Bilateral Obstructive Uropathy Caused by Congenital Bladder Diverticulum Presenting as Hypertensive Retinopathy. AB - A congenital bladder diverticulum (CBD) is caused by inherent muscular weakness instead of obstruction of the bladder outlet. The major clinical conditions are recurrent urinary tract infection (UTI) and voiding dysfunction. This report describes a 15-year-old male adolescent who developed sudden visual disturbance resulting from hypertensive retinopathy. The cause of hypertension was bilateral obstructive uropathy caused by enlarged paraureteral bladder diverticula. After the non-functioning right kidney and ureter and the bilateral diverticula were removed, the left ureter was reimplanted in the bladder. Pathologic findings showed chronic pyelonephritis and partial loss of the bladder musculature in the diverticular wall. This observation indicates that dilated CBD can cause latent UTI, ureteral obstruction, hydronephrosis, and secondary hypertension. PMID- 29441754 TI - Extraspinal Percutaneous Osteoplasty for the Treatment of Painful Bony Metastasis. AB - BACKGROUND: Extraspinal percutaneous osteoplasties (POPs) are novel techniques for the treatment of painful bony metastasis, which is often the cause of both persistent and incidental breakthrough pain. This retrospective study explored the efficacy and complications of extraspinal POPs. METHODS: The origin of the cancer metastasis, performed POP sites, necessity of adjacent joint injections, pain and Karnofsky Performance Scale (KPS) scores, complications related to the POPs, and life expectancy were evaluated from the medical records from 2009 to 2016. RESULTS: A total of 47 (M/F = 28/19) patients had received 54 POPs, including costoplasty, scapuloplasty, ilioplasty, humeroplasty, ischioplasty, femoroplasty, sternoplasty, and puboplasty, in order of frequency. The most common sites for the origin of the cancer, in order of frequency, were the lung, liver, breast, colon, and kidney. All patients receiving POPs including scapuloplasty, ilioplasty, humeroplasty, and femoroplasty needed adjacent joint injections before or after the POPs. Pain due to metastatic lesions was reduced significantly immediately after the POPs and the reduction was sustained until the end of their lives. The median KPS was increased from 35.4% to 67.7% immediately after the POPs. There were no complications related to the procedures. The mean life expectancy after performing the POPs, for 35 patients which died afterwards, was 99.3 days, ranging from 1 to 767 days. CONCLUSION: Even though pain in the isolated POP sites may be difficult to measure due to overlapping systemic pain, the POPs provided immediate local pain relief, and the patients showed better physical performance without procedure-related complications. PMID- 29441756 TI - Three Software Tools for Viewing Sectional Planes, Volume Models, and Surface Models of a Cadaver Hand. AB - BACKGROUND: The hand anatomy, including the complicated hand muscles, can be grasped by using computer-assisted learning tools with high quality two dimensional images and three-dimensional models. The purpose of this study was to present up-to-date software tools that promote learning of stereoscopic morphology of the hand. METHODS: On the basis of horizontal sectioned images and outlined images of a male cadaver, vertical planes, volume models, and surface models were elaborated. Software to browse pairs of the sectioned and outlined images in orthogonal planes and software to peel and rotate the volume models, as well as a portable document format (PDF) file to select and rotate the surface models, were produced. RESULTS: All of the software tools were downloadable free of charge and usable off-line. The three types of tools for viewing multiple aspects of the hand could be adequately employed according to individual needs. CONCLUSION: These new tools involving the realistic images of a cadaver and the diverse functions are expected to improve comprehensive knowledge of the hand shape. PMID- 29441755 TI - A Multicenter Study of the Antiviral Efficacy of Entecavir Monotherapy Compared to Lamivudine Monotherapy in Children with Nucleos(t)ide-naive Chronic Hepatitis B. AB - BACKGROUND: The aim of this study was to compare the long-term efficacy of entecavir (ETV) and lamivudine (LAM) therapy in children with chronic hepatitis B (CHB) who had not received nucleoside analogue treatment. METHODS: In this multicenter, retrospective study, we included pediatric CHB patients younger than 20 years who received ETV or LAM treatment for at least 12 months and had no concomitant diseases. All of the patients were followed up every 1 to 3 months. At each visit, the patients underwent clinical evaluation and biochemical testing. RESULTS: Eight (53.3%), 14 (93.3%), and 2 (15.4%) of the ETV-treated patients achieved virologic suppression, alanine aminotransferase (ALT) normalization and hepatitis B e antigen (HBeAg) seroconversion, respectively, at 1 year. In the ETV group, the cumulative rate of virologic suppression at 3 years was 91.7%, which was significantly higher than that in the LAM group (P < 0.001). The mean duration of treatment before virologic suppression was shorter in the ETV group than in the LAM group (P = 0.040). The cumulative rate of seroconversion in the ETV group at 3 years was 39.4%, which was not significantly different from that in the LAM group (P = 0.439). The ETV group showed lower cumulate rates of virologic breakthrough (33.3% at 6 years) and genotypic mutation than the LAM group (P = 0.033 and P = 0.011, respectively). CONCLUSION: ETV is superior to LAM in pediatric CHB treatment because of its higher virologic suppression rate and lower cumulative rates of virologic breakthrough and genotypic mutation. PMID- 29441758 TI - What Are the Main Differences in the Treatment of Chronic Hepatitis B between Korean Children and Adults? PMID- 29441757 TI - Changing Epidemiology of Nontuberculous Mycobacterial Lung Diseases in a Tertiary Referral Hospital in Korea between 2001 and 2015. AB - This study investigated the changes in the major etiologic organisms and clinical phenotypes of nontuberculous mycobacterial lung disease (NTM-LD) over a recent 15 year period in Korea. The increase of number of patients with NTM-LD was primarily due to an increase of Mycobacterium avium complex (MAC) lung disease (LD). Among MAC cases, the proportion of M. avium increased compared with M. intracellulare, whereas the incidence of M. abscessus complex and M. kansasii LD remained relatively stable. The proportion of cases of the nodular bronchiectatic form increased compared with the fibrocavitary form of NTM-LD. PMID- 29441759 TI - Determinants Used to Justify the Strength of Recommendations among Korean Clinical Practice Guidelines. AB - BACKGROUND: A standardized systematic approach to grade evidence and the strength of recommendations is important for guideline users to minimize bias and help interpret the most suitable decisions at the point of care. The study aims to identify and classify determinants used to make judgement for the strength of recommendations among 56 Korean clinical practice guidelines (CPGs), and explore strong recommendations based on low quality of evidence. METHODS: Determinants used in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach among 34 CPGs which have reported both strength of recommendations and level of evidence were reviewed. RESULTS: Five of 34 CPGs (14.7%) considered quality of evidence, benefits and harms, patients' values and preferences, and costs. And 24 of 34 CPGs (70.6%) considered both magnitude of effect and feasibility as additional determinants. Judgement table was not widely provided for use to translate evidence into recommendations. Eighty-two of 121 recommendations (67.8%, ranged 20.0% to 100.0%) among 11 CPGs using the same judgement scheme showed 'strong' strength of recommendations based on low or very low quality of evidence. Among 5 paradigmatic situations that justify strong recommendations based on low or very low evidence, situation classified as 'potential equivalence, one option clearly less risky or costly' was 87.8% for 82 strong recommendations. Situation classified as 'uncertain benefit, certain harm' was 4.9%. CONCLUSION: There is a need to introduce and systematize an evidence based grading system. Using judgement table to justify the strength of recommendations and applying the 5 paradigmatic situations mentioned above is also recommended in the near future. PMID- 29441760 TI - Healthcare-associated Infection Control on the Edge of a 'Carrot-and-Stick' and a 'Crime-and-Punishment' Frame. PMID- 29441761 TI - [Reconstruction of Vehicle-human Crash Accident and Injury Analysis Based on 3D Laser Scanning, Multi-rigid-body Reconstruction and Optimized Genetic Algorithm]. AB - OBJECTIVES: To reconstruct a vehicle-bicycle-cyclist crash accident and analyse the injuries using 3D laser scanning technology, multi-rigid-body dynamics and optimized genetic algorithm, and to provide biomechanical basis for the forensic identification of death cause. METHODS: The vehicle was measured by 3D laser scanning technology. The multi-rigid-body models of cyclist, bicycle and vehicle were developed based on the measurements. The value range of optimal variables was set. A multi-objective genetic algorithm and the nondominated sorting genetic algorithm were used to find the optimal solutions, which were compared to the record of the surveillance video around the accident scene. RESULTS: The reconstruction result of laser scanning on vehicle was satisfactory. In the optimal solutions found by optimization method of genetic algorithm, the dynamical behaviours of dummy, bicycle and vehicle corresponded to that recorded by the surveillance video. The injury parameters of dummy were consistent with the situation and position of the real injuries on the cyclist in accident. CONCLUSIONS: The motion status before accident, damage process by crash and mechanical analysis on the injury of the victim can be reconstructed using 3D laser scanning technology, multi-rigid-body dynamics and optimized genetic algorithm, which have application value in the identification of injury manner and analysis of death cause in traffic accidents. PMID- 29441763 TI - [Expression of Brain Natriuretic Peptide in Myocardial Tissue of Sudden Cardiac Death and Non-sudden Cardiac Death]. AB - OBJECTIVES: To study the expression pattern of brain natriuretic peptide (BNP) in myocardial tissue from forensic routine cases and to explore its application value in the forensic determination of sudden cardiac death (SCD). METHODS: The data of 96 autopsy cases accepted by the center of Medico-legal Investigation of China Medical University between December 2008 to May 2014 were collected. There were 62 cases in SCD group cardiac and 34 cases in non-SCD group. The myocardial tissues were taken from left and right ventricular wall, respectively. The expressions of BNP protein and BNP mRNA in myocardial tissue were detected by HE staining, immunohistochemical staining, Western blotting and quantitative real time reverse transcription-polymerase chain reaction (RT-qPCR), etc. RESULTS: The immunohistochemical staining of myocardial tissue showed diffusely positive staining in SCD group, and patchily or diffusely positive staining in non-SCD group with lighter degree. The result of Western blotting showed that the expression of BNP protein elevated in left ventricular wall of SCD group. The result of RT-qPCR showed a positive correlation between the BNP mRNA expressions in bilateral ventricular walls and the heart weight, bilateral lung weight, and N terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration. There were large differences between the BNP mRNA concentrations in SCD group and non SCD group, and the former was statistically higher (P<0.05). CONCLUSIONS: The expressions of BNP protein and BNP mRNA in myocardial tissue are related to the causes of death. Combined with pathological changes, the expressions of BNP protein and BNP mRNA in myocardial tissue have certainly practical significance for the determination of SCD and the analysis of the death mechanism in the cases related to forensic pathology. PMID- 29441762 TI - [Time-dependent Protein Expressions of MMP-2 and MMP-9 in Liver Contusion Rats after Impact]. AB - OBJECTIVES: To observe the protein expression patterns of matrix metalloproteinase (MMP)-2 and MMP-9 in the liver tissue of liver contusion rats at different time after impact. METHODS: Fifty healthy adult male SD rats were randomly and evenly divided into control group and experimental groups (1 h, 3 h, 6 h, 12 h, 18 h, 24 h, 3 d, 5 d, 7 d after liver contusion). A rat liver contusion model was established by a free-falling device. The rats were killed at corresponding time, and the contused hepatic lobes were extracted. The protein expressions of MMP-2 and MMP-9 in contused liver tissue of the rats in each group were observed by immunohistochemical staining (SP method) and Western blotting. RESULTS: After the liver contusion, the expression of positive cell and the protein semiquantitative result showed that the protein expression of MMP-2 enhanced at 6 h and peaked at 24 h, then decreased gradually at 3-5 d, and returned to normal levels at 7 d. The difference of expression between group and its previous adjacent group after 6 h (except 18 h) had statistical significance (P<0.05). The protein expression of MMP-9 rose obviously at 1 h after liver contusion and peaked at 18 h, then decreased gradually at 3-7 d which still higher than control group. The expression difference between group and its previous adjacent group (except 12 h and 24 h) had statistical significance (P<0.05). CONCLUSIONS: The protein expressions of MMP-2 and MMP-9 in contused liver tissue after impact show good time-dependent patterns, which may provide important reference indicators for the time estimation of liver contusion. PMID- 29441765 TI - [Range of Hip Joint Motion and Weight of Lower Limb Function under 3D Dynamic Marker]. AB - OBJECTIVES: To explore the range of reasonable weight coefficient of hip joint in lower limb function. METHODS: When the hip joints of healthy volunteers under normal conditions or fixed at three different positions including functional, flexed and extension positions, the movements of lower limbs were recorded by LUKOtronic motion capture and analysis system. The degree of lower limb function loss was calculated using Fugl-Meyer lower limb function assessment form when the hip joints were fixed at the aforementioned positions. One-way analysis of variance and Tamhane's T2 method were used to proceed statistics analysis and calculate the range of reasonable weight coefficient of hip joint. RESULTS: There were significant differences between the degree of lower limb function loss when the hip joints fixed at flexed and extension positions and at functional position. While the differences between the degree of lower limb function loss when the hip joints fixed at flexed position and extension position had no statistical significance. In 95% confidence interval, the reasonable weight coefficient of hip joint in lower limb function was between 61.05% and 73.34%. CONCLUSIONS: Expect confirming the reasonable weight coefficient, the effects of functional and non-functional positions on the degree of lower limb function loss should also be considered for the assessment of hip joint function loss. PMID- 29441764 TI - [Relationship between Myofibril Fragmentation Index and Postmortem Interval]. AB - OBJECTIVES: To study the relationship between myofibril fragmentation index (MFI) of human skeletal muscle and postmortem interval (PMI). METHODS: The protein concentrations of human right biceps brachii muscle and right quadriceps femoris muscle were obtained at different PMI, and detected at room temperature by biuret method. The MFI of skeletal muscle at 540 nm was measured by ultraviolet spectrophotometer. Regression analysis was performed with time of death as independent variable (x) and MFI as dependent variable (y). RESULTS: In early PMI, the MFI of human skeletal muscle increased obviously according to the prolongation of PMI, and peaking by 12 h and then tended to steady. Within 12 h after death, the regression equations of right biceps brachii muscle and right quadriceps femoris muscle were y=32.660+3.227 x(r=0.987 9) and y=32.380+3.495 x(r=0.983 9), respectively. CONCLUSIONS: There's high correlation between MFI and PMI. Combining with forensic practice, MFI can be used for the estimation of early PMI (especially in 12 h). PMID- 29441766 TI - [Identification of Methamphetamine Abuse and Selegiline Use: Chiral Analysis of Methamphetamine and Amphetamine in Urine]. AB - OBJECTIVES: To study the content variation of selegiline and its metabolites in urine, and based on actual cases, to explore the feasibility for the identification of methamphetamine abuse and selegiline use by chiral analysis. METHODS: The urine samples were tested by chiral separation and LC-MS/MS method using CHIROBIOTICTM V2 chiral liquid chromatography column. The chiral analysis of methamphetamine and amphetamine were performed on the urine samples from volunteers of selegiline use and drug addicts whom suspected taking selegiline. RESULTS: After 5 mg oral administration, the positive test time of selegiline in urine was less than 7 h. The mass concentrations of R(-)-methamphetamine and R(-) amphetamine in urine peaked at 7 h which were 0.86 MUg/mL and 0.18 MUg/mL and couldn't be detected after 80 h and 168 h, respectively. The sources of methamphetamine and amphetamine in the urine from the drug addicts whom suspected taking selegiline were analysed successfully by present method. CONCLUSIONS: The chiral analysis of methamphetamine and amphetamine, and the determination of selegiline's metabolites can be used to distinguish methamphetamine abuse from selegiline use. PMID- 29441767 TI - [Forensic Analysis of 498 Road Traffic Accident Deaths in Haikou City]. AB - OBJECTIVES: To analyse the characteristics of road traffic accident deaths in Haikou city, and to provide reference for the identification of causes of death and the preventive measures. METHODS: Totally 498 road traffic accident deaths accepted by the Traffic Police Branch of Haikou City Public Security Bureau in 2014-2016 were collected, and the related parameters such as sex, age, time of the accidents, travel mode of the victims, the types of vehicle and the cause of death were analysed. RESULTS: Most victims aged 21-40 years old with the sex ratio of 3:1, and the accidents mainly happened in March, April, May and October and peaked at 6:01-8:00 and 20:01-22:00 per day. Riding motorbike and electric bicycle, as travel modes, had the highest accident incidence (30.9%). The vast majority of involved vehicles were motorbike and electric bicycle (57.4%). The most common cause of death was craniocerebral injury, followed by chest and abdominal injury. CONCLUSIONS: The autopsy of road traffic accident deaths plays an important role in identification of death manner and responsibility confirmation. PMID- 29441768 TI - [Application of SNP-STR Composed by D18S51 and Three SNPs of Its Flanking Region in Paternity Testing]. AB - OBJECTIVES: To develop a SNP-STR haplotype by consisting of the SNP and STR genetic markers, both of which locate in a haplotype block. To investigate its distribution in Han population from Chengdu, and explore its application in some special cases of paternity testing. METHODS: D18S51, one of the high mutation rate STR markers in combined DNA index system (CODIS), and three SNP loci rs8089331, rs8094489 and rs7236090 in its flanking region, were chosen to establish SNP-STR. Its haplotype was obtained by nested allele-specific polymerase chain reaction, and the relevant distribution of 75 unrelated individuals were investigated in Han population from Chengdu. The SNP-STR haplotype was tentatively applied in duo paternity testing cases with D18S51 incompatibility. RESULTS: The SNP-STR typing method was established and a total of 43 haplotypes were obtained successfully in Han population from Chengdu. Its polymorphism was 0.948 6, and duo paternity testing cases were resolved by this method. CONCLUSIONS: SNP-STR shows high diversity and can be applied in the identifications of some special paternity testing cases. PMID- 29441769 TI - [Genetic Polymorphism of 30 InDel Loci in Han Population from Jiangsu Province]. AB - OBJECTIVES: To investigate the genetic information of 30 insertion/deletion (InDel) loci in Han population from Jiangsu Province, and to explore the application values of Investigator(r) DIPplex kit for guiding the forensic analysis in Han population from Jiangsu Province. METHODS: The autosomal InDel loci of 305 unrelated healthy Han individuals from Jiangsu Province were genotyped and analysed by Investigator(r) DIPplex kit, and the allelic frequencies and forensic parameters of 30 InDel loci were statistically analysed. RESULTS: The distribution of 30 InDel loci in Han population from Jiangsu Province conformed to Hardy-Weinberg equilibrium. The minor allele frequencies of 21 InDel loci were above 0.3. The polymorphism information content ranged from 0.089 to 0.375, while the discrimination power distributed from 0.093 to 0.500. The paternity exclusion in duo cases and trio cases were 0.047-0.250 and 0.046 0.219, respectively. The linkage disequilibrium analysis of 30 InDel loci showed that all loci were independent from each other. The combined discrimination power was 1-7.369*10-8, whereas the combined mean exclusion chance in duo cases was 0.998 933 978, in trio cases was 0.997 806 392. The Fst values were all less than 0.06 except HLD118 and other four loci, which showed small differences between groups. CONCLUSIONS: The InDel loci of Investigator(r) DIPplex kit can be used as complementary genetic markers for the cases associated with forensic genetics. PMID- 29441770 TI - [Determination of Hair Shafts by InnoTyper(r) 21 Kit]. AB - OBJECTIVES: To explore the application value of InnoTyper(r) 21 kit in forensic practice. METHODS: Samples of hair shafts and saliva were collected from 8 unrelated individuals. Template DNA was extracted by AutoMate ExpressTM forensic DNA automatic extraction system. DNA was amplified by InnoTyper(r) 21 kit and AmpFlSTRTM IdentifilerTM Plus kit, respectively, and then the results were compared. RESULTS: After the amplification by InnoTyper(r) 21 kit, complete specific genotyping could be detected from the saliva samples, and the peak value of genotyping profiles of hair shafts without sheath cells was 57-1 219 RFU. Allelic gene deletion could be found sometimes. When amplified by AmpFlSTRTM IdentifilerTM Plus kit, complete specific genotyping could be detected from the saliva samples, and the specific fragment was not detected in hair shafts without sheath cells. CONCLUSIONS: The InnoTyper(r) 21 kit has certain application value in the cases of hair shafts without sheath cells. PMID- 29441771 TI - [Determination of 1-methylhydantoin Concentration in Blood by GC-MS Method and Its Application in Forensic Medicine]. AB - OBJECTIVES: To establish a gas chromatographic-mass spectrometric (GC-MS) analysis method for quantifying 1-methylhydantoin concentration in whole blood. To provide technical support to forensic identification related cases of 1 methylhydantoin. METHODS: As an internal standard, 500 ng SKF525A was added to 0.5 mL blood sample, and then 2 mL 0.01 mol/L dilute hydrochloric acid and 0.5 g ammonium carbonate were added in order to buffer the pH value to 9, and following 2 mL ethyl acetate. The organic solvent layer was obtained after centrifuge and then analysed by GC-MS after drying. RESULTS: Good linear relationship of 1 methylhydantoin in blood was obtained in the range of 0.5-50 ng/mL. The equation of linear regression was y=0.015 51 x+0.007 26(R2=0.999 7) with 0.1 ng/mL detection limit, and the recovery was 93.02%-108.12%. The intra-day and inter-day precision were less than 6.07% and 13.37%, respectively. CONCLUSIONS: The results gotten by this method is accurate and reproducible, which can be used for the determination of 1-methylhydantoin concentration in blood samples. PMID- 29441772 TI - [Current Status of Forensic Identification for Blunt Injuries of Internal Carotid Arterial System]. AB - Internal carotid arterial system is the main source of blood supply in brain. In forensic identification practice, blunt injures of internal carotid arterial system usually cause complications such as thrombus, aneurysm and arteriovenous fistula, etc. The deaths following delayed cerebral infarction or intracranial haemorrhage are not rare. At present, literature of deaths caused by blunt injuries of internal carotid arterial system mainly consist of case reports in China. This paper reviews related literature and case reports at home and abroad, and summarizes forensic medical features and identification method of the deaths caused by such injuries. The results show that blunt injures of internal carotid arterial system are related to the direct or indirect force on head and neck, which can result in exceed physiological range traction of head and neck, incision following basicranial fracture, etc. Such injuries are common in the cases as mechanical asphyxia, cervical manipulation, traffic accident and fall, etc. The artery should be examined carefully, and the relationship among injury, disease and death should be analysed correctly when no cause of infarction and hemorrhage was found in routine examination of such cases in forensic pratice. Because of the difficulty for exposing the artery completely in autopsy, angiography can be used to infer the location when necessary for improving the scientificity and reliability of the appraisal conclusion. PMID- 29441773 TI - [Advantages and Application Prospects of Deep Learning in Image Recognition and Bone Age Assessment]. AB - Deep learning and neural network models have been new research directions and hot issues in the fields of machine learning and artificial intelligence in recent years. Deep learning has made a breakthrough in the applications of image and speech recognitions, and also has been extensively used in the fields of face recognition and information retrieval because of its special superiority. Bone X ray images express different variations in black-white-gray gradations, which have image features of black and white contrasts and level differences. Based on these advantages of deep learning in image recognition, we combine it with the research of bone age assessment to provide basic datum for constructing a forensic automatic system of bone age assessment. This paper reviews the basic concept and network architectures of deep learning, and describes its recent research progress on image recognition in different research fields at home and abroad, and explores its advantages and application prospects in bone age assessment. PMID- 29441774 TI - [Progress on Determination and Analysis of Zopiclone in Biological Samples]. AB - As a new hypnotic, zopiclone is widely used in clinical treatment. There are many methods for determination of zopiclone, including spectrophotometry, chromatography and chromatography mass spectrum, etc. Present paper reviews different kinds of biological samples associated with zopiclone, extraction and purification methods, and determination and analysis methods, which aims to provide references for the relevant research and practice. PMID- 29441775 TI - [Hydrating cleansing: efficacy and tolerability of new formulations with hyaluronic acid 0.2% for intimate hygiene in the woman in fertile age and menopause]. AB - Dehydration of genital areas, known as vaginal dryness, frequently affects woman's life, from fertile to postmenopausal period, and must be treated with specific products, including proper intimate cleansing. Based on that, two new cleanser formulations, characterized by Hyaluronic Acid 0.2% as main ingredient, have been developed (Hyalo Gyn(r) Intimo Active and Hyalo Gyn(r) Intimo Advance), with the aim to provide an effective hydration of the vaginal, vulvar, perianal and anal areas beyond guaranteeing daily intimate hygiene. The two intimate cleansing mousses have been formulated in mousse and differentiated, in terms of ingredients, accordingly to the different physiological conditions and female needs of fertile age and menopause respectively. Clinical trials conducted on women of childbearing age and menopause showed that daily cleansing with these intimate washes promotes hydration of vaginal tissues thanks to the presence of hyaluronic acid. In particular, the cleansing mousse for fertile women gives also a soothing effect, offers antimicrobial protection and a long lasting feeling of freshness. The cleansing mousse for menopausal women provides a freshness sensation, improves elasticity and tonicity and exerts an anti-smell and anti oxidative effect. PMID- 29441776 TI - Nanocavity-in-Multiple Nanogap Plasmonic Coupling Effects from Vertical Sandwich Like Au@Al2O3@Au Arrays for Surface-Enhanced Raman Scattering. AB - The development of ideal three-dimensional (3D) tailorable surface-enhanced Raman scattering (SERS) substrates with the properties of timesaving, large area, high throughput, single or few molecules detection, reproducibility, reusable ability, and high density of "hot spots" has been the mainstream challenge and the robust task. Here, we construct perpendicular sandwich-like Au@Al2O3@Au hybrid nanosheets (PSHNs) on the Al foil as a 3D flexible substrate for SERS. The design of 3D PSHNs incorporates several advantageous aspects for SERS to enhance the performance of plasmonic diamers via bifunctions of vertical Al2O3 nanosheets (NSs) including the nanoscaffold and nanobaffle plate effects. As a nanoscaffold, it increases the space utilization of Au-Au diamers, whereas as a nanobaffle, it forms densely homogeneous Au@Al2O3@Au nanojunctions by sub-4 nm thickness of Al2O3 NSs as the dielectric isolated layer for the double-sided exposure of slitlike surface plasmon resonance. The optimized PSHN substrate exhibits a fascinating SERS sensitivity with an experimental enhancement factor of 1012 and is able to detect rhodamine B at an extremely low concentration up to the limit of single or few molecules (10-18 M), as well as can be recycled without the loss of SERS enhancement via the simple impregnation process. These advantages will greatly facilitate the wider use of SERS in many fields. PMID- 29441777 TI - Highly Stretchable DNA/Clay Hydrogels with Self-Healing Ability. AB - We present mechanically strong and self-healable clay hydrogels containing 2-8 w/v % ds-DNA together with a synthetic biocompatible polymer, poly( N, N dimethylacrylamide). Clay nanoparticles in the hydrogels act like a chemical cross-linker and promote their elastic behavior, whereas DNA contributes to their viscoelastic energy dissipation. The extent of mechanical hysteresis during cyclic tensile tests reveals that the strength of intermolecular bonds in DNA/clay hydrogels is in the range of the strength of hydrogen bonds. The hydrogels exhibit a high stretchability (up to 1500%) and a tensile strength between 20 and 150 kPa. They have the ability to self-heal, which is induced by heating the damaged gel samples above the melting temperature of ds-DNA. When comparing the mechanical properties of the hydrogels before and after healing, the healing efficiency is greater than 100%. We also demonstrate that ds-DNA molecules entrapped in the gel network undergoes thermal denaturation/renaturation cycles, leading to a further improvement in the mechanical properties of the hydrogels. PMID- 29441778 TI - Nickel-Catalyzed Phosphine Free Direct N-Alkylation of Amides with Alcohols. AB - Herein, we developed an operational simple, practical, and selective Ni-catalyzed synthesis of secondary amides. Application of renewable alcohols, earth-abundant and nonprecious nickel catalyst facilitates the transformations, releasing water as byproduct. The catalytic system is tolerant to a variety of functional groups including nitrile, allylic ether, and alkene and could be extended to the synthesis of bis-amide, antiemetic drug Tigan, and dopamine D2 receptor antagonist Itopride. Preliminary mechanistic studies revealed the participation of a benzylic C-H bond in the rate-determining step. PMID- 29441779 TI - Molecularly Imprinted Nanocavities Capable of Ligand-Binding Domain and Size/Shape Recognition for Selective Discrimination of Vascular Endothelial Growth Factor Isoforms. AB - Vascular endothelial growth factor 165 (VEGF165) is known to be predominantly expressed in the first stage of vascularization; therefore, the detection of VEGF165 is important in the stage diagnosis of cancers. Molecularly imprinted nanocavities, capable of the selective discrimination of VEGF165 from other VEGF isoforms, were prepared by surface-initiated atom transfer radical polymerization. VEGF165 was immobilized on a gold-coated glass substrate by anchored heparin moieties, where the immobilized heparin was able to capture VEGF165 by binding with the heparin-binding domain (HBD) on VEGF165. Molecular imprinting was conducted on the immobilized VEGF165 by using methacrylic acid (MAA) as a functional monomer to interact with basic amino acids outside of the HBD of VEGF165 by electrostatic interaction. After the removal of VEGF165 from the obtained polymer thin layer (ca. 7 nm), VEGF165-imprinted nanocavities remained, in which the heparin moiety and MAA residues were located in suitable positions for VEGF165 recognition. The molecularly imprinted polymer (MIP) thin layer showed a binding affinity for VEGF165 (dissociation constant: 3.4 nM) that was ten times higher than that of the substrate before polymerization (heparin immobilized substrate). A much lower binding affinity for VEGF121, which contains no heparin-binding domain, was observed. Moreover, the MIP thin layer distinguished VEGF165 from VEGF189, which possesses a larger molecular size than VEGF165, an amino acid sequence homology of 87%, and contains HBDs, whereas the heparin-immobilized substrate showed almost no selectivity. These results suggested that the heparin moiety within the nanocavity provided HBD selectivity and the polymer matrix composed of the molecularly imprinted nanocavity provided size/shape selectivity, which resulted in the highly selective discrimination of VEGF isoforms. PMID- 29441780 TI - Extending Circulating Tumor DNA Analysis to Ultralow Abundance Mutations: Techniques and Challenges. AB - Liquid biopsies that analyze circulating tumor DNA (ctDNA) hold great promise in the guidance of clinical treatment for various cancers. However, the innate characteristics of ctDNA make it a difficult target: ctDNA is highly fragmented, and found at very low concentrations, both in absolute terms and relative to wildtype species. Clinically relevant target sequences often differ from the wildtype species by a single DNA base pair. These characteristics make analyzing mutant ctDNA a uniquely difficult process. Despite this, techniques have recently emerged for analyzing ctDNA, and have been used in pilot studies that showed promising results. These techniques each have various drawbacks, either in their analytical capabilities or in practical considerations, which restrict their application to many clinical situations. Many of the most promising potential applications of ctDNA require assay characteristics that are not currently available, and new techniques with these properties could have benefits in companion diagnostics, monitoring response to treatment and early detection. Here we review the current state of the art in ctDNA detection, with critical comparison of the analytical techniques themselves. We also examine the improvements required to expand ctDNA diagnostics to more advanced applications and discuss the most likely pathways for these improvements. PMID- 29441781 TI - Flexible and Micropatternable Triplet-Triplet Annihilation Upconversion Thin Films for Photonic Device Integration and Anticounterfeiting Applications. AB - Triplet-triplet annihilation upconversion (TTA-UC) has recently drawn widespread interest for its capacity to harvest low-energy photons and to broaden the absorption spectra of photonic devices, such as solar cells. Although conceptually promising, effective integration of TTA-UC materials into practical devices has been difficult due to the diffusive and anoxic conditions required in TTA-UC host media. Of the solid-state host materials investigated, rubbery polymers facilitate the highest TTA-UC efficiency. To date, however, their need for long-term oxygen protection has limited rubbery polymers to rigid film architectures that forfeit their intrinsic flexibility. This study introduces a new multilayer thin-film architecture, in which scalable solution processing techniques are employed to fabricate flexible, photostable, and efficient TTA-UC thin films containing layers of oxygen barrier and host polymers. This breakthrough material design marks a crucial advance toward TTA-UC integration within rigid and flexible devices alike. Moreover, it introduces new opportunities in unexplored applications such as anticounterfeiting. Soft lithography is incorporated into the film fabrication process to pattern TTA-UC host layers with a broad range of high-resolution microscale designs, and superimposing host layers with customized absorption, emission, and patterning ultimately produces proof-of-concept anticounterfeiting labels with advanced excitation-dependent photoluminescent security features. PMID- 29441782 TI - Soliseptide A, A Cyclic Hexapeptide Possessing Piperazic Acid Groups from Streptomyces solisilvae HNM30702. AB - Soliseptide A (1), a cyclic hexapeptide possessing piperazic acid groups, together with two known azalomycin derivatives (2 and 3) were isolated from Streptomyces solisilvae HNM30702. Their structures were determined through spectroscopic methods and single crystal X-ray diffraction analysis. Soliseptide A (1) possessed a cyclic hexapeptide core featured with two piperazic acid units rarely discovered in nature, and exhibited weak antibacterial and antiviral activities. Besides, compounds 2 and 3 displayed significant fungicidal effects. PMID- 29441783 TI - Synthesis of a Next-Generation Taxoid by Rapid Methylation Amenable for 11C Labeling. AB - Next-generation taxoids, such as SB-T-1214, are highly potent cytotoxic agents that exhibit remarkable efficacy against drug-resistant tumors in vivo, including those that overexpress the P-glycoprotein (Pgp) efflux pump. As SB-T-1214 is not a substrate for Pgp-mediated efflux, it may exhibit a markedly different biodistribution and tumor-accumulation profile than paclitaxel or docetaxel, which are both Pgp substrates. To investigate the biodistribution and tumor accumulation levels of SB-T-1214 using positron emission tomography (PET), a new synthetic route has been developed to allow the incorporation of 11C, a commonly employed positron-emitting radionucleide, via methyl iodide at the last step of chemical synthesis. This synthetic route features a highly stereoselective chiral ester enolate-imine cyclocondensation, regioselective hydrostannation of the resulting beta-lactam, and the Stille coupling of the novel vinylstannyl taxoid intermediate with methyl iodide. Conditions have been established to allow the rapid methylation and HPLC purification of the target compound in a time frame amenable to 11C-labeling for applications to PET studies. PMID- 29441784 TI - Yellow-Emissive Carbon Dot-Based Optical Sensing Platforms: Cell Imaging and Analytical Applications for Biocatalytic Reactions. AB - Carbon dots (CDs) have attracted increasing interest in bioimaging and sensing recently. Herein, we present a simple synthetic strategy to prepare yellow emissive CDs (lambdaem = 535 nm) by one-pot hydrothermal treatment of p phenylenediamine and aspartic acid. The as-prepared CDs possess outstanding optical features, excellent biocompatibility, and low cytotoxicity, especially for fluorescence (FL) cellular imaging. Interestingly, by combining the quenching and recognition ability of silver nanoparticles (AgNPs) with the optical capacity of CDs, a label-free strategy for specifically monitoring H2O2-generated biocatalytic processes was proposed, such as glucose oxidase-induced conversion of glucose, cholesterol oxidase-catalyzed oxidization of cholesterol, and bienzyme of acetylcholinesterase and choline oxidase-mediated reaction of acetylcholine. In this process, AgNPs act as a "nanoquencher" to decrease the FL intensity of CDs via surface plasmon-enhanced energy-transfer mechanism. The enzymatic oxidation product (H2O2) subsequently etches the AgNPs to silver ions, thus recovering the FL of CDs, which enabled this proposed nanosensor to sensitively detect H2O2-generated biocatalytic processes. The above results pave the way to implement CDs as FL labels for biosensors and biological imaging. PMID- 29441785 TI - Tunable Resistive Pulse Sensing: Better Size and Charge Measurements for Submicrometer Colloids. AB - Tunable resistive pulse sensing (TRPS) uses the Coulter principle to detect, measure, and analyze particles at length scales ranging from tens of nanometers through to micrometers. The technology and its associated methods have advanced so that TRPS is regularly used as a characterization technique in peer-reviewed studies. This Perspective is concerned with opportunities to further develop TRPS, with a specific focus on improved measurement of size and charge for submicrometer particles. There is currently broad demand for increased rigor in such measurements. Particular points of interest include consistent use of statistics, development of accurate physical models, and realistic assessment of uncertainties associated with the usual measurement protocols. Highlights from recent studies involving TRPS are also reviewed. The technique is particularly popular in the burgeoning research field relating to extracellular vesicles, and the range of biologically relevant applications also includes liposomes, viruses, and on-bead assays. PMID- 29441786 TI - Transparent Conductive Adhesives for Tandem Solar Cells Using Polymer-Particle Composites. AB - Transparent conductive adhesives (TCAs) can enable conductivity between two substrates, which is useful for a wide range of electronic devices. Here, we have developed a TCA composed of a polymer-particle blend with ethylene-vinyl acetate as the transparent adhesive and metal-coated flexible poly(methyl methacrylate) microspheres as the conductive particles that can provide conductivity and adhesion regardless of the surface texture. This TCA layer was designed to be nearly transparent, conductive in only the out-of-plane direction, and of practical adhesive strength to hold the substrates together. The series resistance was measured at 0.3 and 0.8 Omega cm2 for 8 and 0.2% particle coverage, respectively, while remaining over 92% was transparent in both cases. For applications in photovoltaic devices, such as mechanically stacked multijunction III-V/Si cells, a TCA with 1% particle coverage will have less than 0.5% power loss due to the resistance and less than 1% shading loss to the bottom cell. PMID- 29441787 TI - Robust Operation of Mesoporous Antireflective Coatings under Variable Ambient Conditions. AB - Generating mesoporous films with adequate film thickness and refractive index is a common method to achieve amplitude and phase matching in low-cost interference based antireflective coatings (ARCs). For high-surface-energy materials, pores on the 2-50 nm (i.e., on the subwavelength scale) are subject to capillary condensation by surrounding gas phase water molecules, which hampers their functioning. In this work, we examine the effect of relative humidity on mesoporous ARCs and present a simple method for the preparation of ARCs with robust operation under variable conditions. The materials route is based on the generation of well-defined porous aluminosilicate networks by block copolymer co assembly with poly(isobutylene)- block-poly(ethylene oxide) and postsynthesis grafting of trichloro(octyl)silane molecules to the pore walls. The functionalized films exhibited a maximum transmittance value of 99.8%, with an average transmittance of 99.1% in the visible wavelength range from 400 to 700 nm. Crucially, the antireflection performance was maintained at high humidity values, with an average transmittance decrease of only 0.2% and maximum values maintained at 99.7%. This compared to maximum and average losses of 3.6 and 2.7%, respectively, for nonfunctionalized reference samples. The ARCs were shown to retain their optical properties within 50 humidity cycles, indicating long-term stability against fluctuating environmental conditions. PMID- 29441789 TI - Excellent Resistive Switching Performance of Cu-Se-Based Atomic Switch Using Lanthanide Metal Nanolayer at the Cu-Se/Al2O3 Interface. AB - The next-generation electronic society is dependent on the performance of nonvolatile memory devices, which has been continuously improving. In the last few years, many memory devices have been introduced. However, atomic switches are considered to be a simple and reliable basis for next-generation nonvolatile devices. In general, atomic switch-based resistive switching is controlled by electrochemical metallization. However, excess ion injection from the entire area of the active electrode into the switching layer causes device nonuniformity and degradation of reliability. Here, we propose the fabrication of a high performance atomic switch based on Cu x-Se1- x by inserting lanthanide (Ln) metal buffer layers such as neodymium (Nd), samarium (Sm), dysprosium (Dy), or lutetium (Lu) between the active metal layer and the electrolyte. Current-atomic force microscopy results confirm that Cu ions penetrate through the Ln-buffer layer and form thin conductive filaments inside the switching layer. Compared with the Pt/Cu x-Se1- x/Al2O3/Pt device, the optimized Pt/Cu x-Se1- x/Ln/Al2O3/Pt devices show improvement in the on/off resistance ratio (102-107), retention (10 years/85 degrees C), endurance (~10 000 cycles), and uniform resistance state distribution. PMID- 29441790 TI - Inexpensive Radical Methylation and Related Alkylations of Heteroarenes. AB - A simple method for the introduction of a methyl and higher aliphatic group to various heteroarenes using very inexpensive reagents is described. It is based on the radical addition of a carboxylic xanthate followed by decarboxylation. Depending on the heteroarene structure, the decarboxylation can be spontaneous or induced by heating in N,N-dimethylacetamide or N-methyl pyrrolidone in a microwave oven. PMID- 29441788 TI - Expression, Purification, and Biochemical Characterization of Human Afamin. AB - Afamin is an 87 kDa glycoprotein with five predicted N-glycosylation sites. Afamin's glycan abundance contributes to conformational and chemical inhomogeneity presenting great challenges for molecular structure determination. For the purpose of studying the structure of afamin, various forms of recombinantly expressed human afamin (rhAFM) with different glycosylation patterns were thus created. Wild-type rhAFM and various hypoglycosylated forms were expressed in CHO, CHO-Lec1, and HEK293T cells. Fully nonglycosylated rhAFM was obtained by transfection of point-mutated cDNA to delete all N-glycosylation sites of afamin. Wild-type and hypo/nonglycosylated rhAFM were purified from cell culture supernatants by immobilized metal ion affinity and size exclusion chromatography. Glycan analysis of purified proteins demonstrated differences in micro- and macro-heterogeneity of glycosylation enabling the comparison between hypoglycosylated, wild-type rhAFM, and native plasma afamin. Because antibody fragments can work as artificial chaperones by stabilizing the structure of proteins and consequently enhance the chance for successful crystallization, we incubated a Fab fragment of the monoclonal anti-afamin antibody N14 with human afamin and obtained a stoichiometric complex. Subsequent results showed sufficient expression of various partially or nonglycosylated forms of rhAFM in HEK293T and CHO cells and revealed that glycosylation is not necessary for expression and secretion. PMID- 29441791 TI - Pyrrole- and Naphthobipyrrole-Strapped Calix[4]pyrroles as Azide Anion Receptors. AB - The binding interactions between the azide anion (N3-) and the strapped calix[4]pyrroles 2 and 3 bearing auxiliary hydrogen bonding donors on the bridging moieties, as well as of normal calix[4]pyrrole 1, were investigated via 1H NMR spectroscopic and isothermal titration calorimetry analyses. The resulting data revealed that receptors 2 and 3 have significantly higher affinities for the azide anion in organic media as compared with the unfunctionalized calix[4]pyrrole 1 and other azide receptors reported to date. Single crystal X ray diffraction analyses and calculations using density functional theory revealed that receptor 2 binds CsN3 in two distinct structural forms. As judged from the metric parameters, in the resulting complexes one limiting azide anion resonance contributor is favored over the other, with the specifics depending on the binding mode. In contrast to what is seen for 2, receptor 3 forms a CsN3 complex in 20% CD3OD in CDCl3, wherein the azide anion is bound only vertically to the NH protons of the calix[4]pyrrole and the cesium cation is complexed within the cone shaped-calix[4]pyrrole bowl. The bound cesium cation is also in close proximity to a naphthobipyrrole subunit present in a different molecule, forming an apparent cation-pi complex. PMID- 29441793 TI - What Is Bad From the Gander Is Bad From the Goose: Development and Validation of the Women's Objectification of Women Scale. AB - Existing measures of experiences of sexualization and objectification of women focus on behaviors that men do toward women. However, women may also contribute to the objectification of other women. The aim of the present study was to develop the Women's Objectification of Women Scale (WOWS). Through a series of four studies using samples of college women and samples obtained through MTurk, we (a) established that existing measures of objectification focus on behaviors that men perform, (b) gathered qualitative data on women's experiences of objectification by women, (c) developed models of the WOWS using classical test theory methods and item response theory, and (d) subjected the WOWS to confirmatory factor analysis and validity testing. The WOWS is a psychometrically sound, brief assessment of women's experiences of objectification by other women and may help further research on women's interpersonal experiences as they pertain to body image concerns, mental health, and well-being. PMID- 29441792 TI - High-Performance Visible-Blind Ultraviolet Photodetector Based on IGZO TFT Coupled with p-n Heterojunction. AB - A visible-blind ultraviolet (UV) photodetector was designed based on a three terminal electronic device of thin-film transistor (TFT) coupled with two terminal p-n junction optoelectronic device, in hope of combining the beauties of both of the devices together. Upon the uncovered back-channel surface of amorphous indium-gallium-zinc-oxide (IGZO) TFT, we fabricated PEDOT:PSS/SnO x/IGZO heterojunction structure, through which the formation of a p-n junction and directional carrier transfer of photogenerated carriers were experimentally validated. As expected, the photoresponse characteristics of the newly designed photodetector, with a photoresponsivity of 984 A/W at a wavelength of 320 nm, a UV-visible rejection ratio up to 3.5 * 107, and a specific detectivity up to 3.3 * 1014 Jones, are not only competitive compared to the previous reports but also better than those of the pristine IGZO phototransistor. The hybrid photodetector could be operated in the off-current region with low supply voltages (<0.1 V) and ultralow power dissipation (<10 nW under illumination and ~0.2 pW in the dark). Moreover, by applying a short positive gate pulse onto the gate, the annoying persistent photoconductivity presented in the wide band gap oxide-based devices could be suppressed conveniently, in hope of improving the response rate. With the terrific photoresponsivity along with the advantages of photodetecting pixel integration, the proposed phototransistor could be potentially used in high performance visible-blind UV photodetector pixel arrays. PMID- 29441794 TI - Biophysical properties of extracellular vesicles in diagnostics. AB - Extracellular vesicles (EVs) are cell-derived nanoparticles, involved in cell-to cell communication, in both normal and pathological processes. Originating by the outward budding of the plasma membrane or released by exocytosis, they are natural cargoes for lipids, carbohydrates, proteins and nucleic acids. EV-based diagnostics promises unique advantages compared with conventional strategies involving whole body fluid analysis, including the reduction of biofluids complexity and more specific and sensitive detection of low abundance biomacromolecules. Besides EV cargoes, new breakthrough technologies are addressing EV 'colloidal properties' - including particle content, size and membrane mechanical properties - directly experienced by researchers to be critical factors in biomarkers discovery. This article focuses on the progresses in EV biophysical properties characterization as diagnostic tools for different pathological conditions. PMID- 29441796 TI - Heart Failure Symptoms Profile Associated With Depressive Symptoms. AB - Heart failure (HF) symptoms are known to influence depressive symptoms, yet a symptom profile has not been identified. HF symptoms relative to symptom experience (frequency, severity, interference with physical activity and enjoyment of life) associated with depressive symptoms were examined. Data from three HF studies ( N = 308) which used the Heart Failure Symptom Survey were included in this cross-sectional secondary analysis. Supervised classification for and identification of symptoms most associated with depressive symptoms were accomplished using random forest algorithms via conditional inference trees. The HF symptom profile associated with depressive symptoms across all four symptom experience domains included fatigue, dizziness, and forgetfulness/difficulty concentrating. Abdominal bloating, worsening cough, and difficulty sleeping were also important, but did not consistently rank in the top 5 for symptom importance relative to all symptom experience domains. Symptom profiling may enhance early identification of patients at risk for depressive symptoms and inform symptom management interventions. PMID- 29441797 TI - Animal-Assisted Intervention and Dementia: A Systematic Review. AB - This review discusses the relationship between animal-assisted interventions (AAI) and behavioral and psychological symptoms of dementia (BPSD). A systematic search was conducted within CINAHL, Web of Science CAB Abstracts, PubMed, Abstracts in Social Gerontology, Google Scholar, and PsycINFO for primary research articles. A total of 32 studies were included in the final review. Variation was noted in study designs and in study setting. Twenty-seven of 32 studies used dogs as the intervention. Agitation/aggression showed a significant decrease in nine of 15 studies. Eleven of 12 studies demonstrated increased social interaction with AAI. Mood had mixed results in nine studies. Quality of life was increased in three of four studies. Resident activity and nutritional intake were each increased in two studies. Animal assisted activities/interventions showed a strong positive effect on social behaviors, physical activity, and dietary intake in dementia patients and a positive effect on agitation/aggression and quality of life. PMID- 29441798 TI - Investigating miRNA-661 and ATG4-B mRNA expression as potential biomarkers for hepatocellular carcinoma. AB - AIM: We aimed to examine the statistical association between serum expression of miRNA 661 (miR-661) and ATG-4B mRNA and hepatocellular carcinoma (HCC) based on in silico data analysis followed by clinical validation. PATIENTS & METHODS: Quantitative reverse-transcriptase real-time PCR was used to examine the expression of miR-661 and ATG-4B mRNA in the sera of HCC patients versus control. RESULTS: The expression of miR-661 and ATG-4B mRNA was positive in 97.14 and 77.14%, respectively, in HCC patients. The survival analysis showed that ATG-4B mRNA was an independent prognostic factor. CONCLUSION: Our data are the first report of its kind regarding the considerable clinical significance of miR-661 and ATG-4B mRNA in HCC patients. PMID- 29441799 TI - Formative Evaluation of a Pilot Afterschool Physical Activity-Based Positive Youth Development Program. AB - 4-H PALS is an afterschool positive youth development program for pre- and early adolescents delivered within the 4-H platform and designed to use physical activity to promote character development. The conceptual framework for this program, informed by the theory of triadic influence, prioritizes the social environment created during physical activities to promote adaptive outcomes. Given the novelty of the 4-H PALS curriculum, it is important to outline program components and identify both strengths and challenges to be addressed. Thus, this study aimed to document, describe, and conduct a formative evaluation of 4-H PALS. Major themes were identified across leader and participant interviews, program observations, lesson planning notes, attendance records, and intervention team feedback using inductive analysis methods. Three key areas of evaluation were identified: curriculum implementation fidelity, participant engagement with the curriculum and context, and the social environment. The program was successful in creating an affirmative, engaging environment fostering positive self-perceptions and social outcomes for participants. Challenges with logistical and conceptual implementation of the curriculum's character development concepts were identified. This evaluation will inform program refinements, with the goal of preparing the program for an efficacy study examining outcomes among participating youth. PMID- 29441800 TI - Erratum. PMID- 29441801 TI - Characterizing the meningococcal glycointeractome: what is new? PMID- 29441802 TI - Phage-derived lysins as therapeutic agents against multidrug-resistant Enterococcus faecalis. PMID- 29441803 TI - Trauma-Related Disclosure in Sexual Assault Survivors' Intimate Relationships: Associations With PTSD, Shame, and Partners' Responses. AB - Relative to survivors of other traumatic events, survivors of sexual assault have an increased likelihood of meeting criteria for posttraumatic stress disorder (PTSD). They are also comparatively more likely to exhibit higher levels of PTSD symptom severity. Recent research has highlighted the importance of trauma related disclosure within the context of intimate relationships for posttrauma functioning and recovery, but this phenomenon has yet to be examined specifically in sexual assault survivor samples. Accordingly, this study examines the association of PTSD symptom severity with disclosure about one's experience of sexual assault to one's intimate partner, as well as the association of such disclosure with trauma-related shame and perception of partners' negative and positive responses to trauma-related disclosure. A sample of 104 female participants who had disclosed their experience of sexual assault to their current romantic partner provided survey data. On average, these participants reported a moderate amount of trauma-related disclosure. Counter to hypotheses, level of engagement in trauma-related disclosure was not significantly correlated with PTSD symptom severity, shame, or perceived negative responses to disclosure. Only perceived positive responses to disclosure demonstrated a significant, bivariate association with overall level of engagement in trauma-related disclosure. Similarly, when trauma-related shame, negative responses, and positive responses were accounted for simultaneously, only positive responses were related to level of disclosure. Overall, results suggest that intimate relationships may serve as a unique context for disclosure about one's history of sexual assault, with perceived positive responses demonstrating particularly strong associations with level of engagement in trauma-related disclosure. PMID- 29441804 TI - Using Social Media to Explore the Consequences of Domestic Violence on Mental Health. AB - A great deal of research has focused on the negative consequences of domestic violence (DV) on mental health. However, current studies cannot provide direct and reliable evidence on the impacts of DV on mental health in a short term as it is not feasible to measure mental health shortly before and after an unpredictable event like DV. This study aims to explore the short-term outcomes of DV on individuals' mental health. We collected a sample of 232 victims (77% female) and 232 nonvictims (gender and location matched with 232 victims) on Sina Weibo. In both the victim and nonvictim groups, we measured their mental health status during the 4 weeks before the first DV incident and during the 4 weeks after the DV incident. We used our proposed Online Ecological Recognition (OER) system, which is based on several predictive models to identify individuals' mental health statuses. Mental health statuses were measured based on individuals' Weibo profiles and messages, which included "Depression," "Suicide Probability," and "Satisfaction With Life." The results showed that mental health in the victim group was impacted by DV while individuals in the nonvictim group were not. Furthermore, the victim group demonstrated an increase in depression symptoms, higher suicide risks, and decreased life satisfaction after their DV experience. In addition, the effect of DV on individuals' mental health could appear in the conditions of child abuse, intimate partner violence, and exposure to DV. These findings inform that DV significantly impacts individuals' mental health over the short term, as in 4 weeks. Our proposed new data collection and analyses approach, OER, has implications for employing "big data" from social networks to identify individuals' mental health. PMID- 29441805 TI - Imaging after radiofrequency ablation of renal tumors. AB - The number of percutaneous radiofrequency ablation procedures performed for renal tumors is progressively increasing worldwide. Periodic imaging follow-up has the double role to guarantee the treatment efficacy over time and to early detect any possible complication. Tumor size reductions, as well as the appearance of the characteristic 'halo sign', are normal findings that represent good ablative outcomes. However the most reliable factor of ablation efficacy remains the total absence of contrast enhancing zones within the ablated area. The aim of this article is to illustrate the typical aspect of an effective radiofrequency ablation treatment, which are the imaging findings that may suggest the presence of residual tumoral tissue and which are the main early and late procedural complications. PMID- 29441806 TI - Improving decision making on DPYD and UGT1A1*28 patients' profiling with an innovative reimbursement strategy. PMID- 29441807 TI - Alterations of IGF-1, complement C3 and superoxide dismutase in patients with moderate-to-severe obstructive sleep apnea hypopnea syndrome. AB - AIM: To evaluate various biomarkers of metabolism, immunity and inflammation in obstructive sleep apnea hypopnea syndrome (OSAHS). MATERIALS & METHODS: After overnight polysomnography, blood was collected from 292 OSAHS patients or healthy volunteers. Serum content of inflammatory, immune, metabolic biomarkers were investigated. In addition, the effects of 1-month continuous positive airway pressure (CPAP) were studied in moderate/severe OSAHS. RESULTS: C3, serum total complement activity, superoxide dismutase, uric acid were significantly higher in moderate/severe OSAHS than that in no/mild OSAHS. In contrast, IGF-1 in moderate/severe OSAHS was lower than it in no/mild OSAHS, which was negative correlated with apnea-hypopnea index. Moreover, CPAP significantly decreased C3, meanwhile elevated IGF-1. CONCLUSION: C3, serum total complement activity and superoxide dismutase were higher in moderate/severe OSAHS, while IGF-1 decreased. Elevated C3 and reduced IGF-1 in moderate/severe OSAHS may be reversed by CPAP. PMID- 29441808 TI - Individualized ablation strategy guided by live simultaneous global mapping to treat persistent atrial fibrillation. AB - Atrial fibrillation (AF) is the most common clinical arrhythmia encountered. Catheter ablation has become the first-line therapy for symptomatic drug refractory paroxysmal and persistent AF. Although pulmonary vein electrical isolation is still the cornerstone of the ablation strategy, the clinical outcome particularly in treating persistent AF is suboptimal. Significant efforts have been applied with live global chamber mapping of AF aimed to identify patient specific drivers and/or maintainers located outside of the pulmonary veins to further improve the outcome of catheter ablation. Within this review, we present an overview of contemporary global chamber AF mapping technologies and characteristics, with a particular focus on global, noncontact, dipole density mapping illustrated with a clinical case of persistent AF ablation using this novel methodology. PMID- 29441809 TI - Essential oils in niosomes for enhanced transdermal delivery of felodipine. AB - The fluidity of vesicular membrane affects vesicular transdermal drug delivery. Essential oils can be located in vesicular membrane imparting flexibility and influencing transdermal delivery. Accordingly, the objective was to investigate the effect of incorporation of essential oils in niosomes on felodipine transdermal delivery. Rigid niosomes comprising Span 60 with cholesterol (2:1, w/w) were used with clove, eucalyptus or lemon oils being incorporated in the vesicles at increasing concentrations. The vesicle size and shape was monitored using scanning electron microscopy. Thermal analysis was used to monitor the thermal behavior. Drug entrapment efficiency, release and skin permeation were monitored. Niosomes were spherical with size ranging from 279 to 345 nm. The drug entrapment ranged from 97.9 to 98.8%. Thermal analysis confirmed the existence of oils within vesicular membrane and highlighted the membrane fluidizing effect. Drug release depended on the oil with clove oil or eucalyptus oil showing a trend of increased drug release compared with plain niosomes. In contrast, lemon oil reduced drug release rate. Skin permeation study reflected the superiority of oil containing niosomes. The results correlated with the fluidizing and penetration enhancing effects of oils. The study introduced essential oils as potential niosomes fluidizing agents for enhanced transdermal drug delivery. PMID- 29441810 TI - PON2 and PPARG polymorphisms as biomarkers of risk for coronary heart disease. AB - AIM: Investigate the correlation between paraoxonase 2 (PON2) Ser311Cys polymorphism as well as the peroxisome proliferator-activated receptor gamma (PPARG) His477His polymorphism and the susceptibility to development of coronary heart diseases (CHD) through a meta-analysis. METHODS: Odds ratio and the corresponding 95% CI were used to assess the results. We included 7476 CHD patients and 8504 healthy controls. All the statistical analyses were performed by Comprehensive Meta-Analysis software (CMA, version 2.0). RESULTS: The Ser311Cys polymorphism decreased susceptibility in the overall population and Asian population to CHD. The His477His polymorphism has a protective role in the overall population; however, the subgroup analysis by ethnicity suggested that in Asian population, His477His might increase the risk of CHD. CONCLUSION: These polymorphisms constitute important predictive indicators of CHD susceptibility. PMID- 29441811 TI - Abstracts of the 7th Asian Pain Symposium. AB - The Asian Pain Symposium (APS) is a main pain research meeting in Asia. Since established in 2000 in Kyoto, five other APSs have been held in different Asian regions including Seoul of Korea in 2004, Fukuoka of Japan in 2008, Shanghai of China in 2011, Okazaki of Japan in 2013, and Suzhou of China in 2015. The 7th Asian Pain Symposium (APS 2017) was held in Taipei of Taiwan during October 26th to October 29th, 2017. The APS 2017 was sponsored by The Ministry of Science and Technology of Taiwan and Institute of Biomedical Science and Neuroscience Program of Academia Sinica and Taiwan Pain Society. The president of the APS 2017 was Dr. Bai Chuang Shyu, Institute of Biomedical Sciences, Academia Sinica, Taiwan. Local organizing committee also include Dr. Jen-Chuen Hsieh, Institute of Brain Science, National Yang-Ming University and Veteran General Hospital, Taiwan, Dr. Wei-Zen Sun, Department of Anesthesiology, National Taiwan University Hospital, Taiwan, and Dr. Chih-Cheng Chen, Institute of Biomedical Sciences, Academia Sinica, Taiwan. Main topics of the APS 2017 included the latest progress of pain research and novel strategies of pain treatments. Symposium attendees presented their interesting and exciting research findings in the areas of 1) basic sensory and nociceptive functions, 2) ion channels and their functions in somatosensory physiology and pain, 3) brain functions and regulations in pain, 4) spinal cord mechanisms of nociception and pain, 5) analgesia and pain regulations, 6) chronic pain mechanisms and treatment, and 7) brain circuits underlying the physiological and pathological pain. There were a total of 29 oral presentations and 23 poster presentations at the 7th APS. A council meeting was held during the 7th APS, and at this council meeting Dr. Seog Bae OH (Seoul National University) was elected as the president of 8th Asian Pain Symposium to organize the next symposium in Seoul, Korea in 2019. In order to keep a permanent record and to help promote pain research in Asia, we have collected abstracts of oral presentations and posted them below in the order when the presentations were given at the 7th Asian Pain Symposium. PMID- 29441812 TI - Associations Between Functional Biological Age and Cognition Among Older Adults in Rural Bangladesh: Comparisons With Chronological Age. AB - OBJECTIVES: We constructed a functional biological age (fBioAge) indicator by using four functional variables: grip strength, forced expiratory lung volume, visual acuity, and hearing. Our aim was to compare how chronological age (ChronAge) and fBioAge are related to cognitive abilities in older adults. METHOD: We used data from the Poverty and Health in Aging project, Bangladesh. Participants ( N = 400) were 60+ years of age and diagnosed as nondemented. Examined cognitive abilities were four episodic memory measures (including recall and recognition), two verbal fluency indicators, two semantic knowledge, and two processing speed tasks. RESULTS: fBioAge accounted for cognitive variance beyond that explained by ChronAge also after controlling for medical diagnoses and blood markers. DISCUSSION: Compared with ChronAge, fBioAge was a stronger predictor of cognition during a broad part of the old adult span. fBioAge seems, in that respect, to have the potential to become a useful age indicator in future aging studies. PMID- 29441813 TI - Understanding the nuances of microwave ablation for more accurate post-treatment assessment. AB - Microwave ablation (MWA) is a relatively new thermal modality for minimally invasive procedures compared with radiofrequency ablation. Although MWA and radiofrequency ablation are thermal modalities, their underlying physics and principles greatly differ. Consequently, it is imperative that clinicians be aware of how these differences impact realized ablation volumes to consistently ensure technical success and better patient outcomes. This paper will review the nuances specific to MWA technology (i.e., tissue properties, perfusion/heat sink effect, ablation assessment, imaging accuracy and tissue contraction) that are often overlooked based on familiarity with conventional thermal modalities to guide more accurate assessment of post-treatment MWA volumes. PMID- 29441814 TI - Analysis of gastric myoelectrical activity from the electrogastrogram signals based on wavelet transform and line length feature. AB - Electrogastrogram is used for the abdominal surface measurement of the gastric electrical activity of the human stomach. The electrogastrogram technique has significant value as a clinical tool because careful electrogastrogram signal recordings and analyses play a major role in determining the propagation and coordination of gastric myoelectric abnormalities. The aim of this article is to evaluate electrogastrogram features calculated by line length features based on the discrete wavelet transform method to differentiate healthy control subjects from patients with functional dyspepsia and diabetic gastroparesis. For this analysis, the discrete wavelet transform method was used to extract electrogastrogram signal characteristics. Next, line length features were calculated for each sub-signal, which reflect the waveform dimensionality variations and represent a measure of sensitivity to differences in signal amplitude and frequency. The analysis was carried out using a statistical analysis of variance test. The results obtained from the line length analysis of the electrogastrogram signal prove that there are significant differences among the functional dyspepsia, diabetic gastroparesis, and control groups. The electrogastrogram signals of the control subjects had a significantly higher line length than those of the functional dyspepsia and diabetic gastroparesis patients. In conclusion, this article provides new methods with increased accuracy obtained from electrogastrogram signal analysis. The electrogastrography is an effective and non-stationary method to differentiate diabetic gastroparesis and functional dyspepsia patients from the control group. The proposed method can be considered a key test and an essential computer-aided diagnostic tool for detecting gastric myoelectric abnormalities in diabetic gastroparesis and functional dyspepsia patients. PMID- 29441815 TI - The Secret Drama at the Patient's Bedside-Refusal of Treatment Because of the Practitioner's Ethnic Identity: The Medical Staff 's Point of View. AB - Patients' refusal of treatment based on the practitioner's ethnic identity reveals a clash of values: neutrality in medicine versus patient-centered care. Taking the Israeli-Palestinian conflict into account, this article aims at examining Israeli health care professionals' points of view concerning patients' refusal of treatment because of a practitioner's ethnic identity. Fifty in-depth interviews were conducted with 10 managers and 40 health care professionals, Jewish and Arab, employed at 11 public hospitals. Most refusal incidents recorded are unidirectional: Jewish patients refusing to be treated by Arab practitioners. Refusals are usually directed toward nurses and junior medical staff members, especially if recognizable as religious Muslims. Refusals are often initiated by the patients' relatives and occur more frequently during periods of escalation in the conflict. The structural competency approach can be applied to increase awareness of the role of social determinants in shaping patients' ethnic-based treatment refusals and to improve the handling of such incidents. PMID- 29441816 TI - "It Was Not Me That Was Sick, It Was the Building": Rhetorical Identity Management Strategies in the Context of Observed or Suspected Indoor Air Problems in Workplaces. AB - Suffering from a contested illness poses a serious threat to one's identity. We analyzed the rhetorical identity management strategies respondents used when depicting their health problems and lives in the context of observed or suspected indoor air (IA) problems in the workplace. The data consisted of essays collected by the Finnish Literature Society. We used discourse-oriented methods to interpret a variety of language uses in the construction of identity strategies. Six strategies were identified: respondents described themselves as normal and good citizens with strong characters, and as IA sufferers who received acknowledge from others, offered positive meanings to their in-group, and demanded recognition. These identity strategies located on two continua: (a) individual- and collective-level strategies and (b) dissolved and emphasized (sub)category boundaries. The practical conclusion is that professionals should be aware of these complex coping strategies when aiming to interact effectively with people suffering from contested illnesses. PMID- 29441817 TI - Return to surfing using an adapted prosthesis: A case report. AB - BACKGROUND: Surfing with transfemoral knee prosthesis requires flexion of the hip, knee, and ankle and balance between flexibility and stiffness of the prosthetic limb. We report on Mr D, a transfemoral amputee, who wanted to surf again. Case Description and Methods: Technical specifications were based on Mr D's complaint. The prosthesis is salt water resistant and combines a shock absorber associated with elastic tendons to permit the knee to bend easily and to facilitate eccentric braking. Surfing was observed using videos of movements and subjective analysis of compensations. Findings and Outcomes: Mr D uses this prosthesis for surfing with good results and got back to his former level using compensations. During the takeoff, he cannot shorten his left leg. He makes a circumduction movement to put his leg in front of the board. CONCLUSION: This prosthesis is adapted for surfing and allows precise adjustments to surfing conditions. Clinical relevance Appropriate prosthesis design can enable return to surfing for a transfemoral amputee. PMID- 29441818 TI - Comparative Effectiveness and Harms of Intraoperative Transesophageal Echocardiography in Noncardiac Surgery: A Systematic Review. AB - Intraoperative use of transesophageal echocardiography (TEE) has become commonplace in high-risk noncardiac surgeries but the balance of benefits and harms remains unclear. This systematic review investigated the comparative effectiveness and harms of intraoperative TEE in noncardiac surgery. We searched Ovid MEDLINE, PubMed, EMBASE, and the Cochrane Library from 1946 to March 2017. Two reviewers independently screened the literature for eligibility. Studies were assessed for the risk of selection bias, confounding, measurement bias, and reporting bias. Three comparative and 13 noncomparative studies were included. Intraoperative TEE was employed in a total of 1912 of 3837 patients. Studies had important design limitations. Data were not amenable to quantitative synthesis due to clinical and methodological diversity. Reported incidence of TEE complications ranged from 0% to 1.7% in patients undergoing various procedures (5 studies, 540 patients). No serious adverse events were observed for mixed surgeries (2 studies, 197 patients). Changes in surgical or medical management attributable to the use of TEE were noted in 17% to 81% of patients (7 studies, 558 patients). The only randomized trial of intraoperative TEE was grossly underpowered to detect meaningful differences in 30-day postoperative outcomes. There is lack of high-quality evidence of effectiveness and harms of intraoperative TEE in the management of non-cardiac surgeries. Evidence, however, indicates timely evaluation of cardiac function and structure, and hemodynamics. Future studies should be comparative evaluating confounder-adjusted impact on both intraoperative and 30-day postoperative clinical outcomes. PMID- 29441819 TI - Hoisted by their own petard: do microbial enzymes hold the solution to treating and preventing biofilm infections? PMID- 29441820 TI - Concentration of metabolites from Phoma sp. using microfiltration membrane for increasing bioherbicidal activity. AB - This study is focused on the concentration of fermented broth from Phoma sp. to increase its herbicidal activity. For this purpose, biomolecules produced by submerged fermentation using Phoma sp. were concentrated by hollow fiber microfiltration membranes. The membrane feed was separated into two streams (retentate and permeate) and the crude broth was concentrated to 10, 30, 50, 70 and 90% (relative to the initial volume). The retentate samples were submitted to bioassays (triplicate) for evaluating their phytotoxic effects on five young leaves of species of Cucumis sativus and also on pre-emergence of weeds as Bidens pilosa and Amaranthus retroflexus. The highest herbicidal activity was 80.7% obtained for a concentration of 30% in the retentate fraction. At this condition, the bioherbicide presented severe damage symptoms on the detached leaves of Cucumis sativus if compared to the crude fermented broth. In the pre-emergence of B. pilosa and A. retroflexus, 100% control was obtained for assays performed in a germination chamber. For greenhouse assays using the substrate, the control rate of A. retroflexus was dependent of concentration of bioherbicide. The promising results achieved in the research with membrane separation process allow us to propose and develop further studies for evaluating this technology in the concentration of other metabolites produced by fermentation which also have bioherbicidal activity. PMID- 29441821 TI - To Be Immortal, Do Good or Evil. AB - Many people believe in immortality, but who is perceived to live on and how exactly do they live on? Seven studies reveal that good- and evil-doers are perceived to possess more immortality-albeit different kinds. Good-doers have "transcendent" immortality, with their souls persisting beyond space and time; evil-doers have "trapped" immortality, with their souls persisting on Earth, bound to a physical location. Studies 1 to 4 reveal bidirectional links between perceptions of morality and type of immortality. Studies 5 to 7 reveal how these links explain paranormal perceptions. People generally tie paranormal events to evil spirits (Study 5), but this depends upon location: Evil spirits are perceived to haunt houses and dense forests, whereas good spirits are perceived in expansive locations such as mountaintops (Study 6). However, even good spirits may be seen as trapped on Earth given extenuating circumstances (Study 7). Materials include a scale for measuring trapped and transcendent immorality. PMID- 29441823 TI - Electron donation characteristics and interplays of major volatile fatty acids from anaerobically fermented organic matters in bioelectrochemical systems. AB - Anaerobic fermentation liquid of waste organic matters (WOMs) is rich in volatile fatty acids (VFAs), which can be treated with bioelectrochemical systems for both electrical energy recovery and organics removal. In this work, four major VFAs in the fermented WOMs supernatant were selected to examine their electron donation characteristics for power output and their complicated interplays in microbial fuel cells (MFCs). Results indicated a priority sequence of acetate, propionate, n-butyrate and i-valerate when served as the sole electron donor for electricity generation. The MFC solely fed with acetate showed the highest coulombic efficiency and power density, and the longest period for electricity production. When two of the VFAs were added with equal proportion, both acids contributed positively to electricity generation, while the selective or competitive use of substrates by diverse microorganisms behaved as an antagonism effect to prolong the degradation time of each VFA. When acetate and propionate, the preferable substrates for electricity generation, were mixed in various proportions, their large concentration difference led to improved electrical performance but decreased organic removal rate. PMID- 29441822 TI - Role and regulation of the orphan AphA protein of quorum sensing in pathogenic Vibrios. AB - Quorum sensing (QS), a cell-to-cell communication process, is widely distributed in the bacterial kingdom. Bacteria use QS to control gene expression in response to cell density by detecting the signal molecules called autoinducers. AphA protein is the master QS regulator of vibrios operating at low cell density. It regulates the expression of a variety of genes, especially those encoding virulence factors, flagella/motility and biofilm formation. The role and regulation of AphA in vibrios, especially in human pathogenic vibrios, are summarized in this review. Clarification of the roles of AphA will help us to understand the pathogenesis of vibrios. PMID- 29441825 TI - Paraquat-induced inflammatory response of microglia through HSP60/TLR4 signaling. AB - Previous studies showed that paraquat (PQ) caused the apoptosis of dopaminergic neurons by inducing the generation of oxygen radical. The purpose of this study is to explore PQ-induced microglial inflammatory response and its underlying molecular mechanisms. The murine microglia BV2 cell line was used. After stimulation with PQ and lipopolysaccharides (positive control), the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL 1beta), and interleukin 6 (IL-6) in the culture supernatant and mRNA expression of TNF-alpha and IL-1beta were determined by ELISA and quantitative real-time Polymerase Chain Reaction (PCR), respectively. The protein expression of heat shock protein 60 (HSP60) and toll-like receptor 4 (TLR4), along with the mRNA expression of transcription factors of nuclear factor kappaB-p65 (NF-kappaB-p65) and activated protein 1 (AP1, c-fos, and c-jun dimer) were evaluated with western blot and quantitative real-time PCR, respectively. The results showed that PQ activated microglia, which was characterized by increasing the generation and upregulated mRNA expression of pro-inflammatory cytokines, TNF-alpha, IL-1beta, and IL-6. In addition, PQ significantly enhanced the expressions of HSP60 and TLR4 proteins in BV2 cells, as well as NF-kappaB-p65, c-fos, and c-jun mRNA. These findings suggest that PQ can activate microglia and enhance the expression and secretion of pro-inflammatory cytokines in a HSP60/TLR4 signaling, leading to the inflammatory response. PMID- 29441826 TI - Protective effect of an L-type calcium channel blocker, amlodipine, on paracetamol-induced hepatotoxicity in rats. AB - Paracetamol (P), one of the most popular and commonly used analgesic and antipyretic agents, causes hepatotoxicity in overdoses. Amlodipine (AML), an L type calcium channel blocker, has been shown to have anti-inflammatory activity by reversing the effect of calcium in the inflammation pathogenesis. In this study, the hepatoprotective activity of AML on P-induced hepatotoxicity was evaluated. Thirty male albino Wistar rats were divided into five groups: (1) control, (2) 2 g/kg of P, (3) 2 g/kg of P + 5 mg/kg of AML, (4) 2 g/kg of P + 10 mg/kg of AML, and (5) 10 mg/kg of AML. Some liver enzymes, oxidative parameters, cytokine mRNA expressions, histopathology, and immunohistochemical studies were performed in liver and blood samples. The serum levels of alanine aminotransferase and aspartate aminotransferase and the mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta in the liver tissues were significantly increased in the group treated with P. The superoxide dismutase and glutathione parameters decreased and malondialdehyde levels increased in the livers of the rats treated with P. All these parameters were increased with both doses of the AML similar to the control group. A histopathological examination of the liver showed that AML administration ameliorated the P-induced inflammatory liver damage. In immunohistochemical staining, the expression of TNF-alpha in the cytoplasm of the hepatocytes was increased in the P group but not in other treatment groups when compared to the control. In conclusion, AML treatment showed significant protective effects against P-induced hepatotoxicity by increasing the activity of antioxidants and reducing inflammatory cytokines. PMID- 29441824 TI - Green synthesis of silver nanoparticles combined to calcium glycerophosphate: antimicrobial and antibiofilm activities. AB - AIM: To synthesize, characterize and evaluate the antimicrobial and antibiofilm activities of novel nanocomposites containing silver nanoparticles (AgNPs) associated or not to beta-calcium glycerophosphate. MATERIALS & METHODS: These nanocomposites were produced through a 'green' route using extracts of different parts of pomegranate. Antimicrobial and antibiofilm properties against Candida albicans and Streptococcus mutans were determined by the minimum bactericidal/fungicidal concentration and biofilm density after treatments. RESULTS: All extracts used were successful in producing AgNPs. Composites made with peel extracts showed the highest antimicrobial and antibiofilm activity against both microorganisms tested and performed similarly or even better than chlorhexidine. CONCLUSION: AgNPs associated or not to calcium glycerophosphate produced by a 'green' process may be a promising novel antimicrobial agent against oral microorganisms. PMID- 29441827 TI - Urinary bisphenol A concentrations in relation to asthma in a sample of Egyptian children. AB - BACKGROUND: Bronchial asthma is one of the top disabling diseases in pediatrics. Limited research has been studied the association of the widely used plastic monomer bisphenol A (BPA) with childhood asthma. OBJECTIVE: To compare the levels of urinary BPA in asthmatic and control children and to investigate the implication of BPA among other risk factors for the development of asthma. SUBJECTS AND METHODS: This case-control study included 97 children (45 asthmatic and 52 healthy controls) aged 3-8 years. Asthmatic children were diagnosed according to Global initiative for asthma (GINA) guidelines. Sociodemographic factors were assessed and urinary levels of BPA were determined in spot urine samples using high-performance liquid chromatography. The contribution of BPA among predictors for developing asthma was studied in asthmatic children. RESULTS: Median total urinary BPA levels were significantly higher in asthmatic children than in control group (1.56 ng/mL in asthmatic children compared to 0.790 ng/mL in control group, p = 0.001). Children who had total urinary BPA levels >1.3 ng/mL were more likely to be asthmatic (odds ratio: 2.84, 95% confidence interval 1.22-6.59, p = 0.015). Multiple logistic regression analysis for predictors of asthma showed the importance of higher levels of BPA (>1.3 ng/mL) as a more significant predictor than passive smoking ( p = 0.006 for BPA categories vs. p = 0.049 for passive smoking). CONCLUSION: Association of higher levels of urinary BPA with the diagnosis of asthma in children may indicate the potential risk of BPA exposure in the precipitation of bronchial asthma. Further clinical and biochemical research are needed to clarify the proper mechanism explaining this association. PMID- 29441829 TI - Role of peroxisome proliferator-activated receptor-gamma activation on visfatin, advanced glycation end products, and renal oxidative stress in obesity-induced type 2 diabetes mellitus. AB - The present study focused on the role of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation on renal oxidative damages, serum visfatin, and advanced glycation end products (AGEs) in high-fat diet (HFD) induced type 2 diabetes mellitus. Following the institutional animal ethics committee guidelines, Wistar rats were categorized into five groups: group 1: fed on a normal rat diet; group 2: HFD-induced obese rats (HFD for 8 weeks); group 3: HFD-fed rats treated with rosiglitazone (RSG; 3 mg/kg orally for 7 days); group 4: T2DM rats induced by HFD and low dose of streptozotocin (i.p. 35 mg/kg); group 5: T2DM rats treated with RSG (3 mg/kg orally for 7 days). Serum levels of AGEs and visfatin, renal damage, and oxidative stress were analyzed. Results showed that HFD-induced obesity and T2DM caused an elevated blood glucose, serum AGEs, visfatin, insulin, urea, creatinine, and tissue malondialdehyde, whereas a decreased catalase and superoxide dismutase activity were observed. The PPAR gamma activation via agonist restored these changes. Our findings suggest that AGEs and visfatin possess an important role in the progression of renal oxidative stress, which can be reduced by the PPAR-gamma agonist that impede deleterious effects of HFD and HFD-induced T2DM on renal damage. PMID- 29441828 TI - Fluoride-associated ultrastructural changes and apoptosis in human renal tubule: a pilot study. AB - The susceptibility of the kidneys to fluoride toxicity can largely be attributed to its anatomy and function. As the filtrate moves along the complex tubular structure of each nephron, it is concentrated in the proximal and distal tubules and collecting duct. It has been frequently observed that the children suffering from renal impairments also have some symptoms of dental and skeletal fluorosis. The findings suggest that fluoride somehow interferes with renal anatomy and physiology, which may lead to renal pathogenesis. The aim of this study was to evaluate the fluoride-associated nephrotoxicity. A total of 156 patients with childhood nephrotic syndrome were screened and it was observed that 32 of them had significantly high levels ( p <= 0.05) of fluoride in urine (4.01 +/- 1.83 ppm) and serum (0.1 +/- 0.013 ppm). On the basis of urinary fluoride concentration, patients were divided into two groups, namely group 1 (G-1) ( n = 32) containing normal urine fluoride (0.61 +/- 0.17 ppm) and group 2 (G-2) ( n = 32) having high urine fluoride concentration (4.01 +/- 1.83 ppm). Age-matched healthy subjects ( n = 33) having normal levels of urinary fluoride (0.56 +/- 0.15 ppm) were included in the study as control (group 0 (G-0)). Kidney biopsies were taken from G-1 and G-2 only, who were subjected to ultrastructural (transmission electron microscopy) and apoptotic (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling) analysis. Various subcellular ultrastructural changes including nuclear disintegration, chromosome condensation, cytoplasmic ground substance lysis, and endoplasmic reticulum blebbing were observed. Increased levels of apoptosis were observed in high fluoride group (G-2) compared to normal fluoride group (G-1). Various degrees of fluoride-associated damages to the architecture of tubular epithelia, such as cell swelling and lysis, cytoplasmic vacuolation, nuclear condensation, apoptosis, and necrosis, were observed. PMID- 29441830 TI - Corrigendum. PMID- 29441831 TI - Lead inhalation and hepatic damage: Morphological and functional evaluation in mice. AB - Lead (Pb) is a heavy metal that plays an unknown biological role and is very toxic even at low concentrations. The main sources of Pb are Pb-contaminated areas in industrial areas or landfills. Inhalation is one of the most common routes of exposure to this metal, but there is little information on its effect on the liver. Thirty male mice were exposed to 0.1 M Pb acetate by inhalation for 8 weeks, twice a week for 1h. A recovery group was free of exposure for 4 weeks. Histological evaluation showed an increase in the inflammatory infiltrate and in the percentage of meganuclei in the liver. This was observed since the first week and throughout the whole exposure time. A significant increase in the aspartate aminotransferase concentration was observed in the liver function tests; yet, the alanine aminotransferase concentration did not show significant changes. The 4 hydroxynonenal (4-HNE) and nitrotyrosine levels in Pb-exposed mice, identified by immunohistochemistry, showed a significant increment compared to the controls. This effect was observed throughout Pb exposure. After a 4-week period of suspended exposure, recovery time, the concentration of 4-HNE and nitrotyrosine decreased to similar levels of those previously observed in controls, this suggests a decrease in the generation of oxidative stress by Pb inhalation. Although our results suggest that the lungs are the first contact organs and filters during Pb inhalation, this metal eventually reaches the liver and might cause damage by oxidative stress. This damage can decrease in time if exposure is discontinued. PMID- 29441833 TI - Role of number of sentinel nodes in predicting non-sentinel node metastasis in breast cancer. AB - Objective The aim of the present study was to determine how many sentinel lymph nodes (SLNs) are appropriate for predicting non-SLN metastasis in breast cancer. Methods The association between clinicopathological features and non-SLN metastasis was retrospectively analyzed in 472 patients who underwent axillary lymph node dissection (ALND) following SLN biopsy. Another 251 patients who underwent only SLN biopsy without ALND were analyzed and followed up for 2 years. Results A large tumor size, positive SLN, and HER-2 positivity were independent predictors of non-SLN metastasis. There were significant differences in non-SLN metastasis between patients with one negative SLN and patients with an absence of negative SLNs. There was no significant difference in non-SLN metastasis between patients with one negative SLN and two or more negative SLNs. The recurrence-free survival rate for patients who did not undergo ALND was 99.6% (245/246). Conclusion Surgeons should ensure that the number of SLNs obtained is appropriate. The presence of one negative SLN is enough in SLN biopsy. Considering the invasiveness of the surgery, two or more negative SLNs may be unnecessary. PMID- 29441834 TI - Speech Processing to Improve the Perception of Speech in Background Noise for Children With Auditory Processing Disorder and Typically Developing Peers. AB - Auditory processing disorder (APD) may be diagnosed when a child has listening difficulties but has normal audiometric thresholds. For adults with normal hearing and with mild-to-moderate hearing impairment, an algorithm called spectral shaping with dynamic range compression (SSDRC) has been shown to increase the intelligibility of speech when background noise is added after the processing. Here, we assessed the effect of such processing using 8 children with APD and 10 age-matched control children. The loudness of the processed and unprocessed sentences was matched using a loudness model. The task was to repeat back sentences produced by a female speaker when presented with either speech shaped noise (SSN) or a male competing speaker (CS) at two signal-to-background ratios (SBRs). Speech identification was significantly better with SSDRC processing than without, for both groups. The benefit of SSDRC processing was greater for the SSN than for the CS background. For the SSN, scores were similar for the two groups at both SBRs. For the CS, the APD group performed significantly more poorly than the control group. The overall improvement produced by SSDRC processing could be useful for enhancing communication in a classroom where the teacher's voice is broadcast using a wireless system. PMID- 29441836 TI - Temporal changes in arthropod activity in tropical anthropogenic forests. AB - Arthropod communities in the tropics are increasingly impacted by rapid changes in land use. Because species showing distinct seasonal patterns of activity are thought to be at higher risk of climate-related extirpation, global warming is generally considered a lower threat to arthropod biodiversity in the tropics than in temperate regions. To examine changes associated with land use and weather variables in tropical arthropod communities, we deployed Malaise traps at three major anthropogenic forests (secondary reserve forest, oil palm forest, and urban ornamental forest (UOF)) in Peninsular Malaysia and collected arthropods continuously for 12 months. We used metabarcoding protocols to characterize the diversity within weekly samples. We found that changes in the composition of arthropod communities were significantly associated with maximum temperature in all the three forests, but shifts were reversed in the UOF compared with the other forests. This suggests arthropods in forests in Peninsular Malaysia face a double threat: community shifts and biodiversity loss due to exploitation and disturbance of forests which consequently put species at further risk related to global warming. We highlight the positive feedback mechanism of land use and temperature, which pose threats to the arthropod communities and further implicates ecosystem functioning and human well-being. Consequently, conservation and mitigation plans are urgently needed. PMID- 29441835 TI - Current Profile of Adults Presenting for Preoperative Cochlear Implant Evaluation. AB - Considerable advancements in cochlear implant technology (e.g., electric acoustic stimulation) and assessment materials have yielded expanded criteria. Despite this, it is unclear whether individuals with better audiometric thresholds and speech understanding are being referred for cochlear implant workup and pursuing cochlear implantation. The purpose of this study was to characterize the mean auditory and demographic profile of adults presenting for preoperative cochlear implant workup. Data were collected prospectively for all adult preoperative workups at Vanderbilt from 2013 to 2015. Subjects included 287 adults (253 postlingually deafened) with a mean age of 62.3 years. Each individual was assessed using the minimum speech test battery, spectral modulation detection, subjective questionnaires, and cognitive screening. Mean consonant-nucleus consonant word scores, AzBio sentence scores, and pure-tone averages for postlingually deafened adults were 10%, 13%, and 89 dB HL, respectively, for the ear to be implanted. Seventy-three individuals (25.4%) met labeled indications for Hybrid-L and 207 individuals (72.1%) had aidable hearing in the better hearing ear to be used in a bimodal hearing configuration. These results suggest that mean speech understanding evaluated at cochlear implant workup remains very low despite recent advancements. Greater awareness and insurance accessibility may be needed to make cochlear implant technology available to those who qualify for electric acoustic stimulation devices as well as individuals meeting conventional cochlear implant criteria. PMID- 29441837 TI - Nurses as change agents for a better future in health care: the politics of drift and dilution. AB - This paper takes the 70th Anniversary of the National Health Service (NHS) in the United Kingdom as an opportunity to reflect upon the strategic direction of nursing policy and the extent to which nurses can realise their potential as change agents in building a better future for health care. It argues that the policy trajectory set for nursing at the outset of the NHS continues to influence its strategic direction, and that the trajectory needs to be reset with the voices of nurses being more engaged in the design, as much as the delivery of health policy. There is a growing evidence base about the benefits for patients and nurses of deploying well-educated nurses at the top of their skill set, to provide needed care for patients in adequately staffed and resourced units, as well as the value that nurses contribute to decision-making in clinical care. Yet much of this evidence is not being implemented. On the contrary, some of it is being ignored. Policy remains fragmented, driven by short-term financial constraints and underinvestment in high quality care. Nurses need to make their voices heard, and use the evidence base to change the dialogue with the public, policy makers and politicians, in order to build a better future for health care. PMID- 29441838 TI - In your face. AB - Research suggests that people can accurately predict the political affiliations of others using only information extracted from the face. It is less clear from this research, however, what particular facial physiological processes or features communicate such information. Using a model of emotion developed in psychology that treats emotional expressivity as an individual-level trait, this article provides a theoretical account of why emotional expressivity may provide reliable signals of political orientation, and it tests the theory in four empirical studies. We find statistically significant liberal/conservative differences in self-reported emotional expressivity, in facial emotional expressivity measured physiologically, in the perceived emotional expressivity and ideology of political elites, and in an experiment that finds that more emotionally expressive faces are perceived as more liberal. PMID- 29441839 TI - The impact of parasites during range expansion of an invasive gecko. AB - Host-parasite dynamics can play a fundamental role in both the establishment success of invasive species and their impact on native wildlife. The net impact of parasites depends on their capacity to switch effectively between native and invasive hosts. Here we explore host-switching, spatial patterns and simple fitness measures in a slow-expanding invasion: the invasion of Asian house geckos (Hemidactylus frenatus) from urban areas into bushland in Northeast Australia. In bushland close to urban edges, H. frenatus co-occurs with, and at many sites now greatly out-numbers, native geckos. We measured prevalence and intensity of Geckobia mites (introduced with H. frenatus), and Waddycephalus (a native pentastome). We recorded a new invasive mite species, and several new host associations for native mites and geckos, but we found no evidence of mite transmission between native and invasive geckos. In contrast, native Waddycephalus nymphs were commonly present in H. frenatus, demonstrating this parasite's capacity to utilize H. frenatus as a novel host. Prevalence of mites on H. frenatus decreased with distance from the urban edge, suggesting parasite release towards the invasion front; however, we found no evidence that mites affect H. frenatus body condition or lifespan. Waddycephalus was present at low prevalence in bushland sites and, although its presence did not affect host body condition, our data suggest that it may reduce host survival. The high relative density of H. frenatus at our sites, and their capacity to harbour Waddycephalus, suggests that there may be impacts on native geckos and snakes through parasite spillback. PMID- 29441840 TI - The Ethics of Real-Time EMS Direction: Suggested Curricular Content. AB - Ethical dilemmas can create moral distress in even the most experienced emergency physicians (EPs). Following reasonable and justified approaches can help alleviate such distress. The purpose of this article is to guide EPs providing Emergency Medical Services (EMS) direction to navigate through common ethical issues confronted in the prehospital delivery of care, including protecting privacy and confidentiality, decision-making capacity and refusal of treatment, withholding of treatment, and termination of resuscitation (TOR). This requires a strong foundation in the principles and theories underlying sound ethical decisions that EPs and prehospital providers make every day in good faith, but will now also make with more awareness and conscientiousness. Brenner JM , Aswegan AL , Vearrier LE , Basford JB , Iserson KV . The ethics of real-time EMS direction: suggested curricular content. Prehosp Disaster Med. 2018;33(2):201 212. PMID- 29441841 TI - Efficacy of platelet transfusion for acute intracerebral hemorrhage among patients on antiplatelet therapy. AB - Clinical questionIn patients taking antiplatelet therapy, does a platelet transfusion after acute spontaneous primary intracerebral hemorrhage reduce the risk of death or dependence?Article chosenBaharoglu MI, Cordonnier C, Al-Shahi Salman R, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral hemorrhage associated with antiplatelet therapy (PATCH): a randomized, open-label, phase 3 trial. Lancet 2016;387(10038):2605-13.Study objectiveThe primary objective of this study was to investigate whether a platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral hemorrhage associated with antiplatelet therapy use. PMID- 29441842 TI - Crowding in the first intermediate host does not affect infection probability in the second host in two helminths. AB - When many worms co-infect the same host, their average size is often reduced. This negative density-dependent growth is called the crowding effect. Crowding has been reported many times for worms in their intermediate hosts, but rarely have the fitness consequences of crowding been examined. This study tested whether larval crowding reduces establishment success in the next host for two parasites with complex life cycles, the nematode Camallanus lacustris and the cestode Schistocephalus solidus. Infected copepods, the first host, were fed to sticklebacks, the second host. Fish received a constant dose, but the infection intensity in copepods was varied (e.g. giving two singly infected copepods or one doubly infected copepod). Worms from higher-intensity infections did not have significantly reduced infection success in fish. However, crowded treatments had a disproportionate number of low and high infection rates, and although this trend was not significant, it hints at the possibility that multiple worms within a copepod are more likely to either all infect or all die when transmitted to the next host. These results indicate that a smaller larval size due to crowding need not reduce the establishment probability of a worm in the next host. PMID- 29441843 TI - Inhaled antibiotics in non-cystic fibrosis bronchiectasis: A meta-analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of inhaled antibiotics for the treatment of non-cystic fibrosis bronchiectasis (NCFB). METHODS: Pubmed, Cochrane library, Embase, Elsevier, OVID, Springerlink, Web of knowledge and NEJM were searched for randomized controlled trials (RCTs) on inhaled antibiotics in treatment of NCFB from inception until April 2015. Meta-analysis was conducted to assess the efficacy and safety of inhaled antibiotics in the treatment of NCFB. RESULTS: Twelve RCTs involving 1154 participants were included. They showed that inhaled antibiotics were more effective in reduction of sputum bacterial density, eradication of P. aeruginosa, prolonged time to exacerbation and reduction of new pathogens emergence with no significant difference in adverse events compared with control groups. However, we did not find significant benefits of inhaled antibiotics in reducing the risk of acute exacerbation, improving health-related quality of life and reduction of P. aeruginosa resistance. Moreover, inhaled antibiotics exerted a statistically significant reduction in FEV1%. CONCLUSIONS: Inhaled antibiotics may be an alternative pathway to inhibit airway inflammation with no more adverse events in patients with NCFB. PMID- 29441844 TI - Adjunctive therapy with V-5 Immunitor (V5) for the treatment of tuberculosis patients: a meta-analysis. AB - OBJECTIVE: To evaluate the effectiveness and safety of V-5 immunitor (V5) added to chemotherapy of tuberculosis (TB) patients. METHODS: The databases Medline, Embase, Biosis, Cochrane Central Register of Controlled Trials, SCI, CBM, VIP and CNKI were searched. Randomized controlled trials (RCT) and controlled clinical trials (CCT) of V5 immunitor with or without a placebo-control as adjuvant therapy in the chemotherapy of TB patients were included. Two reviewers independently performed data extraction and quality assessment. Data were analyzed using RevMan 5.3 software by The Cochrane Collaboration. RESULTS: Four studies were included. At the end of the follow-up period, pooled RR (Risk Ratio) and its 95% CI of sputum smear conversion rate were 4.91 (3.32, 7.28) in drug sensitive, drug-resistant TB patients or HIV-TB co-infection patients. When analyzing inflammation biomarkers including ESR and leukocyte accounts, pooled mean difference and its 95% CI of ESR and leukocyte accounts were -7.62 (-9.55, 5.68) and -2.13 (-2.58, -1.68), respectively. As to body weight, pooled mean difference and its 95% CI were 0.96 (-1.13, 3.05) in TB patients. Two clinical trials were included for analyzing temperature after using V5 immunitor, pooled mean difference and its 95% CI were -0.34 (-0.46, -0.22) in TB patients. These results suggested that V5 immunitor holds important promise in improving sputum conversion to AFB- and inhibiting inflammatory reaction in TB patients, but showed no significant promotion to the increase in body weight based on this meta analysis. Compared with the control group, V5 immunitor may have some potential in decreasing the temperature of TB patients. No systemic adverse events were reported. CONCLUSION: Added to chemotherapy, V5 immunitor seems to be helpful in the treatment of TB patients in terms of improving sputum conversion and reducing inflammatory reactions. PMID- 29441845 TI - A randomized, controlled, double-blind, multi-center trial to evaluate the efficacy and safety of a liquid containing ivy leaves dry extract (EA 575(r)) vs. placebo in the treatment of adults with acute cough. AB - This randomized, placebo-controlled, double-blind trial was conducted to assess the efficacy and safety of ivy leaves cough liquid in the treatment of acute cough. A total of 181 adult patients with acute cough were treated with either ivy leaves cough liquid containing EA 575(r) or with placebo three times a day for one week. The primary efficacy outcome was cough severity (CS) assessed by Visual Analogue Scale (VAS) over the whole treatment period (area-under-the-curve (AUC0-168 h) over 7 days (visit (V)1, V2, V3, V4, and V5). The secondary endpoints were defined as the CS assessed by VAS over the whole observation period (V1 - V6) and by Bronchitis Severity Score (BSS) and Verbal Category Descriptive (VCD) score. The evaluation of the VAS, BSS and VCD score revealed that subjects treated with ivy leaves cough liquid showed statistically significant and clinically relevant reductions in CS, severity of symptoms associated with cough and bronchitis compared to the placebo group. Furthermore, a remarkable early onset of efficacy was observed as significant reductions of cough severity were detected within 48 hours after the first drug intake. At all following visits and even 7 days after the end of treatment (V6) this significant treatment advantage was detected in comparison to placebo. All adverse events (AEs) in this clinical trial were non-serious, mild or of moderate severity and not drug-related. This clinical trial proved consistent superiority of the ivy leaves cough liquid treatment versus placebo and confirmed the EA 575(r) preparation to be a safe and efficacious option for the treatment of acute cough. PMID- 29441846 TI - The association between the increase in pulse pressure and renal function in chronic kidney disease patients with dyslipidemia. AB - In recent years, an association between chronic kidney disease (CKD) and arteriosclerosis has been identified. Pulse pressure (PP) is used as an index of arteriosclerosis. However, there have been few studies of the relationship between PP and renal dysfunction in patients with CKD. Therefore, we examined the association of increased PP on renal function in patients with CKD and dyslipidemia. This study included 104 patients with CKD who were diagnosed with dyslipidemia and commenced on drug treatment. In the present study, patients with PP >=65 mmHg were included in the High PP group, and patients with PP <65 mmHg were included in the Low PP group. We compared the High PP group with the Low PP group about background patient characteristics, laboratory data and antihypertensive medications and type. Mutiple logistic regression analysis identified estimated glomerular filtration rate (eGFR) as a significant predictor of PP >=65 mmHg. In addition, values of BUN, Ccr, and eGFR baseline and 12 months later were compared. In the High PP group, compared with baseline, BUN increased significantly and Ccr and eGFR decreased significantly after 12 months later. We consider that PP may be an auxiliary indicator of generalized arterial sclerosis and renal function. PMID- 29441847 TI - Resveratrol protects against triptolide-induced cardiotoxicity through SIRT3 signaling pathway in vivo and in vitro. AB - Clinical application of triptolide (TP), a main active ingredient of the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF), is limited by a series of severe toxicities, including cardiotoxicity. In previous studies, we found the activation of sirtuin 3 (SIRT3) attenuated TP-induced toxicity in cardiomyocytes. Resveratrol (RSV), a polyphenol from the skins of grapes and red wine, is an activator of SIRT3. The current study aimed to investigate the protective effect of RSV against TP-induced cardiotoxicity and the underlying mechanisms. Mice were treated with a single dose of TP (2.5 mg/kg) via the intragastric (i.g.) route. After 24 h, TP induced abnormal changes of serum biochemistry, activity decrease of antioxidant enzymes and damage of heart tissue such as myocardial fiber rupture, cell swelling and interstitial congestion. In contrast, administration with RSV (50 mg/kg i.g. 12 h before and 2 h after the administration of TP) attenuated the detrimental effects induced by TP in BALB/c mice. Moreover, the cardiomyocyte protective effects of RSV on TP-induced heart injury were associated with the activation of SIRT3 and its downstream targets. In vitro study also indicated that RSV counteracted TP-induced cardiotoxicity through SIRT3-FOXO3 signaling pathway in H9c2 cells. Collectively, these findings suggest the potential of RSV as a promising agent in protecting heart from TP induced damage. PMID- 29441848 TI - Combination therapy with local radiofrequency ablation and YC-1 inhibits the proliferation and metastasis of hepatocellular carcinoma through activating beta catenin signaling. AB - AIM: This study was aimed to investigate the possible role of combination therapy of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) and radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The two kinds of HCC HCCLM3 and HepG2 cells were intervened by the RFA and YC-1 respectively to construct the model cell. Then cell proliferation, apoptosis, migration and invasion were analyzed using the MTT, flow cytometry and transwell assay respectively. Moreover, the cell signal-related protein expression was also analyzed using western blotting. RESULTS: Our results showed that the combination therapy of RFA and YC-1 significantly inhibited the proliferation and induced the apoptosis of the two kinds of cells (P < 0.05). Besides, cell migration and invasion were inhibited by the combination of RFA and YC-1, followed with the EMT symbols of E-cadherin, N-cadherin and vimentin expression in cells (P < 0.05). Moreover, the beta-catenin signal was activated by the combination treatment. CONCLUSION: Taken together, the data presented in this study reveals that the novel method about combination of RFA and YC-1 may opposite an improve effect on the treatment of HCC than the RFA single treatment. Also, the combination therapy of RFA and YC-1 may well inhibit the development and metastasis of HCC via preventing the EMT through activating the beta-catenin signal. PMID- 29441849 TI - Taurine as a protective agent for 5-fluorouracil-induced hepatic damage related to oxidative stress. AB - 5-Fluorouracil (5-FU) is a pyrimidine analog widely used for the treatment of various cancers, but often causes hepatic damage in clinical practice. In this study, we examined the influence of taurine on 5-FU-induced hepatotoxicity in mice with respect to changes in oxidative stress. Elevations in the aspartate aminotransferase and alanine aminotransferase serum levels after 5-FU administration were significantly suppressed in a dosedependent manner by concurrent treatment with taurine. The activity of superoxide dismutase and reduced glutathione content in the liver were significantly decreased following treatment with 5-FU alone, but these changes were markedly inhibited by the administration of taurine. Our findings suggest that taurine protects against 5 FU-induced hepatotoxicity by suppressing oxidative stress. PMID- 29441850 TI - MiR-150 promotes the cell invasion of prostate cancer cells by directly regulating the expression of p53. AB - Therapeutic targeting of p53 has been implicated as a promising strategy for cancer treatment. MiRNAs are emerging as important modulators of invasion, regulation of p53. Resent reports have shown that miR-150 is involved in the growth, invasion and metastasis in numerous tumor types. However, the role of miR 150 in prostate cancer pathology is unclear. In this study, we firstly determined the miR-150 expression levels of prostate cancer cell lines by quantitative real time PCR (qRT-PCR). The effects of miR-150 on prostate cancer cell proliferation and invasion were evaluated using MTT, colony and transwell assays. The target of miR-150 was identified and confirmed using a luciferase activity assay. The results revealed that miR-150 was significantly upregulated in prostate cancer cells compared with RWPE-1 normal prostate epithelial cells. The ectopic expression of miR-150 significantly promoted prostate cancer cell proliferation, colony formation and invasion. In addition, p53 was confirmed as a downstream target of miR-150 in the prostate cancer cells by western blot and qRT-PCR analysis as well as luciferase activity assays. Together, these findings show that miR-150 promotes prostate cancer cell proliferation and invasion by targeting p53, suggesting that targeting miR-150 may be a potential therapeutic strategy in prostate cancer patients. PMID- 29441851 TI - A myrsinol diterpene isolated from Euphorbia prolifera reverses multidrug resistance in breast cancer cells. AB - P-glycoprotein (P-gp), a member of ATP-Binding Cassette transporter superfamily, can expel a variety of anti-cancer drugs so that it impairs the effect of cancer chemotherapy and results in multidrug resistance (MDR). The P-gp inhibitors are important to circumvent MDR and improve efficacy of cancer chemotherapy. The dried root of Euphorbia prolifera Buch.-Ham. has been used to treat cancer and inflammation in Chinese folk medicine for several hundred years. A myrsinol diterpene derived from Euphorbia prolifera Buch.-Ham. (J196-9-4) could modulate multidrug resistance. Cytotoxicity assays were performed to measure the reversal efficiency of J196-9-4. Efflux assay and ATPase assay were used to elucidate the mechanism of the chemical. J196-9-4 potentiated cytotoxicity of anti-cancer drugs in the P-gp over-expressing resistant breast cancer cell line MCF-7/Adr as compared to MCF-7 cells. Concentrations of 5 and 10 MUM J196-9-4 could reverse the resistance to daunorubicin, vincristine, and topotecan significantly. Since J196-9-4 inhibited P-gp mediated efflux and stimulated ATP hydrolysis, J196-9-4 was a substrate of P-gp. Thus J196-9-4 is a competitive inhibitor of P-gp and reverses multidrug resistance induced by the transporter. PMID- 29441852 TI - Methyl jasmonate inhibits lipopolysaccharide-induced inflammatory cytokine production via mitogen-activated protein kinase and nuclear factor-kappaB pathways in RAW 264.7 cells. AB - Methyl jasmonate is an important signaling molecule involved in plant defense as well as in the regulation of plant growth and development. Despite its various functions in plants, its effects on animal cells have not been widely studied and no report has been issued on the molecular aspects of its anti-inflammatory effect. In the present study, we investigated the in vitro anti-inflammatory properties of methyl jasmonate in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Methyl jasmonate treatment effectively inhibited LPS-induced production of pro-inflammatory mediators (nitric oxide and prostaglandin E2) and cytokines (tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6) in a concentration-dependent manner. Furthermore, it attenuated the LPS-induced activation of nuclear factor-kappaB (NF-kappaB) by suppressing the degradation of the inhibitor of kappaB-alpha (IkappaB-alpha). Additionally, methyl jasmonate dose-dependently blocked the phosphorylation of mitogen-activated protein kinases (MAPKs), i.e., p38 kinase, extracellular signal-regulated kinase (ERK) 1/2, and c Jun N-terminal kinase (JNK), in these cells. These results suggest that methyl jasmonate attenuated the LPS-induced release of pro-inflammatory mediators and cytokines by suppressing the activation of MAPK (JNK, ERK and p38) and NF-kappaB signaling. This study not only demonstrated that methyl jasmonate exerts anti inflammatory activities in macrophages but also revealed its potential as a candidate for the treatment of various inflammation-associated diseases. PMID- 29441853 TI - Grandisin, 2-methoxy 6,7,2',6'-tetrahydroxy flavanone 6-O-glucoside, from Cassia grandis leaves - antioxidant and cytotoxic activities. AB - Chemical investigation of Cassia grandis leaves resulted in the isolation of the new 2-methoxy 6,7,2',6'-tetrahydroxy flavanone 6-O-beta-glucoside together with the known flavonol glycosides, kaempferol-3-O-alpha-rhamnoside, and quercetin 3-O alpha-rhamnoside. The structure assign ments were based on conventional analytical methods and confirmed by HRFTESIMS, 1H and 13C NMR, COSY, HSQC and HMBC data. The total phenolic content of the extract was estimated by Folin Ciocalteu's method. The antioxidant capacity was investigated using DPPH radical scavenging assay. The ethyl acetate and the n-butanol fractions showed poor cytotoxic activity only at high concentrations against the three different cancer cell lines, hepatocellular (HepG-2), breast (MCF-7), and prostate (PC3) by the neutral red uptake assay. PMID- 29441854 TI - Drug-related problems identified by pharmacist-led medication review in Slovak hospitalised patients. AB - Medication review is an effective tool for identification of drug-related problems (DRPs). It has become an integral part of healthcare systems worldwide, however, it is still rare in Slovakia. Therefore, the aim of the present study was to assess the implementation of a medication review in hospitalised patients and to describe prevalence and nature of DRPs. A prospective 3-month study was conducted at Cardiology Department of Teaching Hospital in Nitra. All patients admitted during this period were included and their medications were reviewed regularly during the whole hospitalisation. Information on patient status and medication was obtained from admission reports, medication charts, laboratory results, ward rounds and consultations with attending physicians. Identified DRPs were classified using APS-Doc classification. A total of 261 medication records were analysed (52.1% women; average age 71.4+/-12.7 years). Geriatric patients (>= 65 years) accounted for 72.8%. The patients had on average 7.7+/-4.0 drugs in medication history. Polypharmacy (>= 5 drugs) was found in 75.1 % of them. At least one DRP was identified in 78.2 % of all records. Totally, 514 DRPs were recorded. The most frequent DRPs were clinically significant drug-drug interactions (n = 121; 23.5%), incomplete or missing drug history (n = 73; 14.2 %) and inappropriate time of administration (n = 67; 13.0 %). All identified potential and manifested DRPs were consulted with attending physicians. This study describes early outcomes of implementation of regular medication review in hospitalised patients in one Slovak hospital. Our results highlight the need for a wide implementation of medication review in hospitalised patients. PMID- 29441855 TI - Comparative study between UHPLC-UV and UPLC-MS/MS methods for determination of alogliptin and metformin in their pharmaceutical combination. AB - A new UPLC-MS/MS method (method A), for simultaneous determination of alogliptin (ALN) and metformin (MET) in their recently approved pharmaceutical combination Kazano(r) tablets, was developed and compared to a new UHPLC-UV method (method B). Concerning method A, separation was achieved on Hypersil gold 50 mm * 2.1 mm (1.9 MUm) column, using acetonitrile and 0.2 % formic acid aqueous solution as the mobile phase with a gradient elution. Electrospray ionization (ESI) source was operated in positive ion mode. Selected reaction monitoring (SRM) mode on a triple quadropole mass spectrometer was used to quantify the drugs utilizing the transitions of 340.33 -> 116.32 (m/z) and 130.12 -> 71.32 (m/z) for ALN and MET, respectively. Concerning chromatographic separation using UV detection in method B, it was achieved on a Symmetry(r) C18 column 100 mm * 2.1 mm (2.2 MUm) applying an isocratic elution based on methanol - water (10:90, v/v) at pH 3 as a mobile phase. The photodiode array detector was operated at 210 nm. Method A showed good linearity over the concentration ranges of 5-400 ng mL-1 and 25-2000 ng mL-1 for ALN and MET, respectively, while method B showed satisfactory results using ranges of 0.25-8 MUg mL-1 and 5-50 MUg mL-1 for ALN and MET, respectively. The optimized validated methods are suitable for QC labs but the UPLC-MS/MS method offered the advantage of shorter analytical times and higher sensitivity and selectivity. PMID- 29441857 TI - Effect of hyaluronic acid initial concentration on cross-linking efficiency of hyaluronic acid - based hydrogels used in biomedical and cosmetic applications. AB - This work was aimed to explore the potential effect of hyaluronic acid (HA) initial concentration (7.0 - 14.0 % w/v) on cross-linking efficiency of HA hydrogels cross-linked with 1,4-butanediol diglycidyl ether (BDDE). The results revealed that the hydrogel prepared at 10.0 % HA concentration exhibited a slower degradation rate, a lower swelling ability and more regular porosity than those prepared at either lower or higher HA concentration. After four days incubating with hyaluronidase, the content of NAG (N-acetyl glucosamine) remaining in the 10.0 HA hydrogel was 25.1+/-1.9 % with respect to the total NAG content found in the original mass. In contrast, the hydrogels prepared at 7.0 % and 14.0 % HA concentration showed a less remaining content of NAG equaled to approximately 15.9+/-5.4 % and 19.5+/-2.6 % respectively. On the other hand, the swelling ability of tested hydrogels was steadily decreased with the increase of HA initial concentration until the 10.0 % HA hydrogel and then showed an opposite trend. Based on this finding, the 10.0 % HA hydrogel exhibited the lowest swelling ratio which was observed at 129+/-3.2 g/g in distilled water and at 116+/-2.4 g/g in phosphate buffer saline (PBS). The SEM images showed various morphologies within the entire range of tested hydrogels. However, the hydrogel prepared at 10.0 % HA concentration was more homogenous and appeared with narrower pore-size distribution ranged in diameter from less than 50 MUm to approximately 300 MUm. Finally, the effect of HA initial concentration was investigated by FTIR which confirmed that the 10.0 % HA hydrogel was subject to a greater loss of (- OH) at 3343 cm-1 than other hydrogels except the 11.0 % HA hydrogel. This phenomenon was probably attributed to the formation of pendants that allowed the 11.0 % HA hydrogel to appear with a lower peak intensity than the 10.0 % HA hydrogel in the FTIR spectra. In conclusion, the HA initial concentration plays a crucial role in determining the cross-linking efficiency of HA hydrogels cross-linked with BDDE. PMID- 29441856 TI - Characterization of degradation products of midazolam maleate by UHPLC-HR-IT-MSn and NMR. AB - Forced degradation studies on midazolam maleate were carried out according to ICH guidelines. Midazolam maleate was subjected to acidic and basic hydrolysis, oxidation, photolysis, high humidity and thermal stress conditions, and the resulting degradation products were investigated by HPLC. Significant degradation of the drug was observed under acidic/basic hydrolysis and thermal stress conditions. The thermal degradation product (Impurity I) was isolated using column chromatography and its structure was elucidated by UHPLC-HRIT-MSn and extensive NMR studies, which was not reported in previous literatures. The acidic/basic hydrolytic degradation product (Impurity II) was characterized by UHPLC-HR-IT-MSn technique and previous literature. The fragmentation pathways of these two degradation products are also described in the paper. PMID- 29441858 TI - Inhibitory effects of 2-methoxyestradiol on cell growth and invasion in human bladder cancer T-24 cells. AB - Recently, 2-methoxyestradiol (2-ME) has been considered to be a potential anticancer agent but has not been investigated in bladder cancer. This study was conducted to clarify the role of 2-ME in bladder cancer cells. The bladder cancer cell line T-24 was treated with 2 MUm 2-ME for 2 d. The T-24 cell viability, colony formation, invasion and apoptosis were observed in 2-ME-treated and control cells. The expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) was detected using reverse transcription-polymerase chain reaction (RT-PCR). Then western blotting assay was applied to assess expressions of HIF-1alpha and apoptosis factors caspase-3 and Bcl-x proteins. The mRNA and protein expressions of HIF-1alpha in 2-ME-treated T-24 cells were remarkably lower than that of the control cells (P < 0.05). Treatment of 2-ME could significantly inhibit T-24 the cell viability, colony formation, invasion, and promote apoptosis (all P < 0.05). In addition, the protein expression of Caspase-3 was higher and that of Bcl-x protein was lower after administration of 2-ME compared to control (both P < 0.05). Collectively, we characterized the efficacy of 2-ME on bladder cancer T-24 cells as being mediated by inhibition of cell viability, colony fomation, invasion and promoting cell apoptosis, which may be achieved by suppressing HIF 1alpha levels. This study suggests 2-ME as a potential drug for bladder cancer therapy. PMID- 29441859 TI - A combination of irsogladine maleate and azithromycin exhibits addictive protective effects in LPS-induced human gingival epithelial cells. AB - OBJECTIVE: This study aimed to investigate the potential effects of the combination therapy of irsogladine maleate (IM) and azithromycin (AZM) on the inflammation in lipopolysaccharide (LPS)-induced gingival epithelial cells. METHODS: Human gingival epithelial cell OBA-9 was stimulated by LPS to construct the periodontitis model, followed by the treatment of irsogladine maleate (IM) or azithromycin (AZM) with different concentration. Transepithelial electrical resistance (TER) of cells in each group was analyzed, and qRT-PCR and western blotting were used to detect the expressions of inflammatory cytokines. Immunofluorescence staining was performed to detect the protein expression. RESULTS: The TER for cells was significantly decreased while the inflammatory cytokines expressions including IL-6, IL-8, IL-1beta and TNF-alpha were all significantly increased by LPS compared to the control (P<0.05). However, TER was increased significantly, whereas the cytokine levels were decreased by IM or AZM, but these effects was more apparent in cells treated with IM and AZM combination (P<0.01). Moreover, E-cadherin and vimentin expressions were more positive in the IM and AZM group than in the other groups. The application of ERK and P38 MAPK inhibitors reversed the effects of LPS on cell inflammatory cytokine production and cell TER. CONCLUSION: This study revealed that the combination therapy of IM and AZM performed excellent effects on preventing the inflammatory progression of periodontitis. PMID- 29441860 TI - Suppression of infliximab antibody levels by azathioprine in patients with rheumatoid arthritis. AB - In rheumatoid arthritis (RA) treatment, the concomitant use of methotrexate has been shown to reduce the incidence of antibodies to infliximab (ATI), on the other hand, it is unclear whether azathioprine can reduce ATI production. We enrolled a total of 10 Japanese adult patients with RA who were treated with infliximab concomitantly with methotrexate or azathioprine. Serum concentrations of infliximab and ATI of these patients were measured. The mean serum infliximab concentrations was 1.6+/-1.3 MUg/ml in patients with methotrexate and 1.0+/-0.5 MUg/ml in patients with azathioprine. Serum ATI concentrations were below the limit of quantitation in 4 of 5 patients in each group. The results from the present study suggest that azathioprine suppresses ATI production. PMID- 29441861 TI - Upstream stimulating factor1 (USF1) enhances the proliferation of glioblastoma stem cells mainly by activating the transcription of mucin13 (MUC13). AB - Glioblastoma is one of the most aggressive and deadly tumors among the adults. MUC13 is a membrane bound mucin and abnormal expression of MUC13 has been identified in various tumors. However, its specific role in glioblastoma has never been explored. Firstly, the expression of MUC13 was explored in glioblastoma stem cells (GSCs) and we found that MUC13 was significantly enhanced in GSCs. Overexpression of MUC13 significantly enhanced GSCs invasion and migration capacities. Further study showed that overexpression of MUC13 significantly increased the phosphorylation levels of AKT and P38. Dual luciferase reporter and ChIP assay demonstrated that USF1 could bind the promoter region of MUC13, thereby enhancing the activation of MUC13. More importantly, when MUC13 was silenced, the phosphorylation levels of AKT and P38 were suppressed even in cells transfected with ad-USF1. These data showed that USF1 prompted glioblastoma progression mainly by activating MUC13. In summary, our study first demonstrated that USF1 could activate the transcription of MUC13, thereby enhancing the proliferation and self-renewal of GSCs. PMID- 29441862 TI - Association of endothelin-1 gene single-nucleotide polymorphisms and haplotypes with risk of hormone refractory prostate cancer. AB - Androgen deprivation is often the treatment of choice for patients with a new diagnosis of metastatic or locally advanced prostate cancer (CaP). However, most CaP patients showing a first response to androgen deprivation will progress to a hormone refractory phase of the disease (HRPC) with a much poorer prognosis. Accumulating evidence suggests that endothelin-1 (ET-1) plays an important role in CaP progression. Singlenucleotide polymorphisms (SNPs) of the ET-1 gene reportedly have been associated with cancer progression and chemoresistance. In the present study, we explored the association of SNPs and haplotypes of the ET-1 gene with the risk of HRPC. We genotyped three SNPs (rs1800541, rs2070699 and rs5370) in the ET-1 gene in a case-control study; 234 CaP patients who developed HRPC within six years after androgen deprivation therapy was used as HRPC cases, and 234 age- and primary therapy-matched CaP patients who had not developed HRPC within six years after androgen deprivation therapy were used as non-HRPC controls. Our results revealed that the G allele at rs1800541 and the G allele at rs2070699 were respectively associated with reduced and increased risk of HRPC at borderline statistical significance (p=0.047 and p=0.058, respectively). With adjustment for potential confounders including body mass index, initial Gleason score at diagnosis of CaP, and post-treatment nadir serum PSA level, we found that rs1800541-rs2070699 TG haplotype was significantly associated with increased risk of HRPC (p=0.033; adjusted OR, 2.10; 95% CI, 1.37-5.04). In conclusion, this study provides the first evidence that a 2-SNP haplotype of the ET-1 gene is associated with increased risk of HRPC, which adds new insights into early identification of CaP patients who are likely to develop HRPC in a later stage of the disease. PMID- 29441863 TI - Serum miR-129 functions as a biomarker for colorectal cancer by targeting estrogen receptor (ER) beta. AB - Aberrantly expressed miRNAs widely participate in the signaling cascades of colorectal carcinogenesis. The present study aimed to identify a potential miRNA that serves as effective biomarker for colorectal cancer (CRC). The expression of estrogen receptorbeta (ERbeta) was explored using immunohistochemistry. The possible miRNAs targeting ERbeta were predicted by TargetScan, and their expression patterns were validated using real time PCR. Dual luciferase reporter assays were performed to determine the potential binding of miR-129 in the 3' untranslated region (3'UTR) of ERbeta. In vitro scratch assays and flow cytometry assays were conducted to determine the role of miR-129 on colon cancer cell migration and apoptosis. Proteins related to cell proliferation were determined using western blots. Compared with adjacent non-cancer tissues, the protein level of ERbeta was significantly decreased in CRC tissues, and compared with NC the level of miR-129 was significantly increased in blood and tissue samples. Dual luciferase reporter assays demonstrated that ERbeta was a direct target gene of miR-129. Further study showed that inhibition of miR-129 decreases HCT116 cell migration and enhances cell apoptosis. More importantly, we found that the silencing of ERbeta significantly decreased the activation of caspase3 but increased the protein expression of PCNA. Interestingly, miR-129 inhibitor induced protein expression pattern changes could be reversed by the siRNA targeting ERbeta. The high expression level of circulating miR-129 in the tissue and blood samples of CRC patients contributes to aberrant colon cancer cell proliferation and migration mainly by targeting ERbeta. PMID- 29441864 TI - Long non-coding RNA HOTAIR promotes expression of ADAMTS-5 in human osteoarthritic articular chondrocytes. AB - Accumulating evidence indicated that inhibiting the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 ameliorate cartilage degradation, suggesting ADAMTS-5 as an effective target for treating osteoarthritis (OA). A recent study has identified long noncoding RNA (lncRNA) HOTAIR and ADAMTS-5 as the most up-regulated lncRNA and the most upregulated gene, respectively, in human OA cartilage compared with normal cartilage. In the present study, we explored the regulatory effect of HOTAIR on the expression of ADAMTS-5 as well as the underlying mechanisms in human normal and OA articular chondrocytes. We found that human OA articular chondrocytes had significantly higher basal expression levels of HOTAIR and ADAMTS-5 than normal articular chondrocytes. Tumor necrosis factor (TNF)-alpha significantly enhanced the basal expression of HOTAIR and ADAMTS-5 in OA but not in normal articular chondrocytes. Lentiviral overexpression and knockdown of HOTAIR markedly increased and decreased the expression of ADAMTS-5, respectively, in OA but not in normal articular chondrocytes in the presence or absence of TNF-alpha. Neither overexpression/ knockdown of HOTAIR nor TNF-alpha showed a significant effect on the ADAMTS-5 gene promoter in OA articular chondrocytes. Although HOTAIR showed no significant effect on the stability of ADAMTS-5 mRNA in normal articular chondrocytes, HOTAIR overexpression and knockdown respectively increased and decreased the ADAMTS-5 mRNA stability in OA articular chondrocytes. TNF-alpha enhanced the protective effect of HOTAIR on the ADAMTS-5 mRNA stability. In conclusion, this study provides the first evidence supporting that HOTAIR strongly promotes the expression of ADAMTS-5 by increasing its mRNA stability in human OA articular chondrocytes; this effect is enhanced by TNF-alpha. It adds new insights into the pathogenesis of OA and suggests that HOTAIR could be a new therapeutic target for ADAMTS-5 inhibition in human OA cartilage. PMID- 29441865 TI - Efficacy of sucroferric oxyhydroxide treatment in Japanese hemodialysis patients and its effect on gastrointestinal symptoms. AB - Sucroferric oxyhydroxide (SFOH) is a non-calcium, iron-based phosphate binder indicated for the treatment of hyperphosphatemia in adult dialysis patients. Studies in Japan about the side effects of SFOH treatment indicate that the incidence of diarrhea (25%) is greater while that of constipation (2.9%) is lesser in comparison to that observed upon treatment with an existing phosphate binder. In the present study, the effect of treatment with a combination of the existing phosphate binders and SFOH on the serum phosphorus level and digestive symptoms was observed in hemodialysis patients with hyperphosphatemia, which is untreatable using only the existing phosphate binders. We evaluated the serum phosphorus levels and gastrointestinal symptoms (using the gastrointestinal symptom rating scale) of 6 patients (2 men, 4 women) before and 2, 4, 6, and 8 weeks after continuous administration. The serum phosphorus levels before and 2, 4, 6, and 8 weeks after combination treatment were 7.4+/-1.0 mg/dL, 5.9+/-1.3 mg/dL, 5.8+/-1.5 mg/dL, 5.8+/-1.4 mg/dL, and 5.8+/-1.3 mg/dL, respectively, with significant reduction in the levels being observed 2 weeks after administration (p<0.05) and persisting even 8 weeks after continuous administration. The constipation scores before and 2, 4, and 8 weeks after drug administration were 2.39+/-0.85, 2.34+/-1.93, 2.56+/-1.44, and 3.28+/-2.19, respectively, with no changes observed during the investigation period. The diarrhea scores before and 2, 4, and 8 weeks after drug administration were 2.22+/-0.91, 2.06+/-1.16, 1.28+/ 0.39, and 1.06+/-0.13 respectively. The scores improved significantly, 4 weeks after drug administration (p<0.05), and the improvement persisted, even 8 weeks after continuous administration. Thus, by using a combination of the existing phosphate binders and SFOH, we were able to reduce the serum phosphorus level in patients with hyperphosphatemia, which is untreatable using the existing phosphate binder alone, with no sign of exacerbation of the gastrointestinal symptoms despite a few contradictory case reports. PMID- 29441866 TI - Effect of Curcuma comosa extracts on the functions of peptide transporter and P glycoprotein in intestinal epithelial cells. AB - Curcuma comosa has been widely used as a herbal medicine in Thailand; however, it remains unclear whether C. comosa influences the absorption of drugs that are substrates for the transporters in the small intestine. In this study, we investigated the effect of C. comosa extracts on the functioning of peptide transporter 1 (PEPT1), an influx transporter, and P-glycoprotein (P-gp), an efflux transporter, in Caco-2 cells and rat intestine. In Caco-2 cells, the ethanolic extract of C. comosa (CCE) lowered the uptake of glycylsarcosine (Gly Sar), a PEPT1 substrate, while it enhanced the uptake of rhodamine 123 (Rho123), a P-gp substrate, in a concentrationdependent manner. In addition, CCE inhibited apical-to-basal transport of Gly-Sar and basal-to-apical transport of Rho123. Furthermore, the absorption of cephalexin, another PEPT1 substrate, and the exsorption of Rho123 across the rat intestine were inhibited by CCE. Conversely, CCW, the hot water extract of C. comosa, suppresses the function of PEPT1 but not of P-gp in Caco-2 cells. These results suggest that C. comosa used as a herbal medicine in Thailand may affect the intestinal absorption of certain drugs. PMID- 29441867 TI - Investigation of transferrin interaction with medicinally important noble metal ions using affinity capillary electrophoresis. AB - Transferrins (TFs) consist of a large group of glycoproteins, whose function is to transport iron across the cell membrane. Apart from iron, serum transferrin can also bind several other metal ions and hence can offer a potential route for the delivery of these metal ions into the cellular fluids. In the present study the interaction behavior of nine noble metal ions, Ag+, Au+, Au3+, Os3+, Pd2+, Pt4+, Rh3+, Ru3+ and Ir3+ with transferrin was investigated by affinity capillary electrophoresis (ACE) using the dynamic mobility shift mode. A proper rinsing procedure was applied to regenerate the capillary tube. The influence of these metal ions on transferrin was studied through comparison of the mobility ratios of free protein and protein-metal ion complex. The interaction results were expressed by the normalized difference of the mobility ratios (DeltaR/Rf) and its confidence intervals. Most of the tested metal ions showed significant interaction with transferrin with small confidence intervals, except Ag+, Au+ and Rh3+ that exhibited very weak interactions. Maximum interaction was observed between transferrin and Ir3+, followed by Pd2+ that also showed strong affinity towards the test protein. The screening results were compared with Bovine Serum Albumin (BSA)- and Human Serum Albumin (HSA)-noble metal ions interactions. An excellent precision (% RSD of mobility ratios were less than 1%, except for transferrin-Pd2+ interaction ~ 4%) was recorded for repeated runs of transferrin metal ions interactions. This study contributes to the understanding of the affinity of transferrin to the tested metal ions and will provide preliminary information for the investigation of other protein-ligands interactions. PMID- 29441868 TI - An injectable in situ hexagonal mesophase system for local delivery of minocycline hydrochloride: Preparation and pharmacodynamics in rats. AB - In this study, an optimized in situ reversed hexagonal mesophase loaded with minocycline hydrochloride (MH) was developed for the chronic periodontitis treatment. The in situ hexagonal liquid crystals (ISH2) comprised phytantriol (PT), propylene glycol (PG), water and vitamin E acetate (VitEA). The physicochemical properties, in vitro drug release and the therapeutic effects on chronic periodontitis of the formed samples were tested. The injectable liquid crystal-forming systems were characterized by crossed-polarized light microscopy, small angle X-ray scattering, and rheological measurements. The optimal ISH2 (PT/PG/water/VitEA, 56:27:10:7, w/w/w/w) loaded with 20 mg.g-1 MH was proved to be injectable with suitable pH, and was able to sustain the drug release for 10 days. The pharmacodynamic studies of the optimal formula were performed on male SPF rats, the Periocline(r) ointment was used as a control. The investigated ISH2 loaded with MH was demonstrated to be effective for periodontal treatment with significantly improved gingival index, pocket depth and alveolar bone loss. The developed ISH2 may be a promising application for local delivery system of MH in treating periodontal diseases. PMID- 29441869 TI - Monosodium glutamate-induced obesity changed the expression and activity of glutathione S-transferases in mouse heart and kidney. AB - Obesity may affect activity and/or expression of enzymes participating in xenobiotics' detoxification and antioxidant defense. This study sought to investigate the activities and expression of cardiac and renal glutathione S transferase (GST) isoforms in order to reveal possible differences between obese and control mice. For this purpose, mice with monosodium glutamate (MSG)-induced obesity were used as an experimental model. Obesity was induced in newborn male mice by repeated s.c. administration of MSG. At 8 months of age, mice were sacrificed and specific activity, protein and mRNA expressions levels of GSTs were analyzed in their heart and kidney. In hearts of obese mice, specific activity of GST was decreased by 51% compared to control. This reduction was accompanied by a decline in GSTP-class protein and Gstp1/2 mRNA expression levels. In contrast, specific activity of GST was elevated by 31% in kidney of obese mice and this increase was accompanied by upregulation of GSTA-class protein and Gsta1/2 mRNA expressions. Increased capacity of renal GSTs together with GSTA upregulation may serve as compensatory mechanism against elevated oxidative stress, which accompanies obesity. On the other hand, decreased cardiac GST activity in obese mice and GSTP downregulation may worsen the defense against oxidative stress and harmful xenobiotics. PMID- 29441870 TI - P54/nrb prompts rheumatoid arthritis progression mainly by transcriptionally activating NF-kappaB signaling. AB - In various tumors, aberrant expression of P54/nrb has been identified. However, the expression pattern and specific role of P54/nrb in rheumatoid arthritis (RA) has never been explored. Here, we first demonstrated that the expression of P54/nrb was markedly enhanced in the synovial tissues of RA patients. Functional study showed that P54/nrb could enhance the levels of inflammatory factors, including IL-1, IL-2, IL-6, IL-8 and TNFalpha. More importantly, we first found that overexpression of P54/nrb can induce the protein levels of P65, an important subunit of NF-kappaB. In contrast, knockdown of P54/nrb by RNAi significantly decreased the expression of NF-kappaB. Luciferase reporter assay and CHIP assay showed that P54/nrb could transcriptionally activate the expression of NF-kappaB, thereby enhancing pro-inflammatory responses. In summary, the expression of p54 was markedly increased in the synovial tissues of RA patients. Further study demonstrated that p54 could transcriptionally activate the expression of p65, an important NF-kappaB subunit, thereby enhancing the pro-inflammatory response. PMID- 29441871 TI - Enhanced inflammatory damage by microRNA-136 targeting Klotho expression in HK-2 cells by modulating JAK/STAT pathway. AB - MiR-136 acts as a tumor suppressor by promoting cell apoptosis and downregulating Bcl-2 in glioma cells. Hence, an attempt has been made to evaluate the role of miR-136 in regulation of inflammatory damage in HK-2 cells. HK-2 cells were cultured and assessed for viability. The cells were then transfected with miR-136 mimic, si- miR-136, si-Klotho, and NC. Dual luciferase test was performed to confirm the target of miR-136 which was assumed to be Klotho. Cell viability, apoptosis, expressions of inflammatory cytokines like TNF-alpha, IL-1beta, IL-6 and IL-8 were assessed in HK-2 cells with overexpressing miR-136 or with knocked down miR-136 activities, following exposure to LPS. LPS induced inflammatory damage decreased cell viability, induced cell apoptosis, and increased the expression of different inflammatory cytokines. It was found that LPS decreased the expression of miR-136. Over-expression of miR-136 inhibited cell viability, enhanced apoptosis, and increased expression of inflammatory cytokines while knockdown of miR-136 showed opposite results with p-values < 0.05. MiR-136 negatively regulated the expression of Klotho with p-value < 0.05. Over expression of miR-136 inhibited the expression of Klotho and activated JAK/STAT and mTOR signaling pathways and vice versa. Hence, it can be concluded that miR 136 enhances inflammatory damage probably by targeting klotho as has been observed in luciferase assay by inactivation of JAK/STAT and mTOR signaling pathways. PMID- 29441872 TI - MicroRNA-489-3p inhibits neurite growth by regulating PI3K/AKT pathway in spinal cord injury. AB - Spinal cord injury (SCI) is caused by mechanical disruption of the spinal cord. This primary injury is followed by a devastating secondary SCI. It has been shown that various microRNAs (miRNAs) are involved in secondary SCI. The present study explored the role of miR-489-3p on secondary SCI, and its underlying mechanisms. First, we determined the expression of miR-489-3p in blood samples of SCI patients and healthy controls. Further experiments were performed on human neural cell lines, treated with bupivacaine to induce neuron damage. The cultured neural cells were transfected with miR-489-3p mimic, ASO-miR-489-3p or negative control. We then measured cell proliferation and apoptosis in cultured neurons, followed by measurement of neurite outgrowth. After confirming NAA10 as a target gene for miR-489-3p, we measured expression of NAA10 in neurons transfected with miR-489 3p. Finally, we evaluated the effects of miR-489-3p on the PI3K/AKT signal pathway. miR-489-3p was highly expressed in SCI patients and in bupivacaine treated injured neurons. In cell model, miR-489-3p inhibited proliferation of neurons and promoted apoptosis. miR-489-3p and bupivacaine synergistically inhibited neurite growth. NAA10 gene was negatively regulated by miR-489-3p. Overexpression of NAA10 reversed the effects of miR-489-3p on neurons. Lastly, we found that the inhibitory effects of miR-489-3p on neurons are mediated via activation of the PI3K/AKT pathway. Inhibition of PI3K/AKT pathway using miR-489 3p inhibitor reversed the effects of miR-489-3p on neurons. PMID- 29441873 TI - MicroRNA-190b inhibits tumor cell proliferation and induces apoptosis by regulating Bcl-2 in U2OS osteosarcoma cells. AB - Osteosarcoma (OS) is one of the most prevalent malignancies in bone with no established therapy so far. This study was aimed to clarify the role of miR-190b in tumor cell growth of OS. The miR-190b mimic, inhibitor and miR-control were transfected into human OS U2OS cells. Then U2OS cell proliferation was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and bromodeoxyuridine (BrdU) incorporation assay. The apoptotic U2OS cells were detected by flow cytometry. Additionally, cell-cycle regulators p27, p21 and apoptosis factors B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), caspase-3 were examined by western blotting. Overexpressing miR-190b observably reduced cell viability, BrdU-positive cells (both P < 0.05) and caused strong accumulation of cell-cycle inhibitor p27 in U2OS cells compared with the miR control, whereas the miR-190b inhibitor exerted opposite effects. Further, a marked increase of 18% rate of apoptotic cells by the overexpressing miR-190b (P < 0.01) and 4% decrease by miR-190b inhibitor (P < 0.05) were detected. The protein expressions of Bcl-2 were downregulated, Bax, pro-caspase-3 and active caspase-3 were upregulated by overexpressing miR-190b in U2OS cell line, while miR-190b inhibitor achieved opposite effects. The present study demonstrates that miR-190b inhibits tumor cell proliferation and induces apoptosis by regulating Bcl-2 in U2OS cells, which points to miR-190b as a novel oncosuppressor for OS. The identified tumor suppressive capacity of miR-190b provides novel avenues for achieving better OS therapy. PMID- 29441874 TI - Serum IL-6, IL-23 profile and Treg/Th17 peripheral cell populations in pediatric patients with inflammatory bowel disease. AB - IL-6 and IL-23 are both pleiotropic cytokines involved in the regulation of the immune response, inflammation, and hematopoeisis. They also could mediate effector cells and tolerance mediated by cells with regulatory function. Inflammatory bowel disease (IBD) is associated with a reduced ratio of Treg cells ato Th17 effector cells in peripheral blood and is characterised by a pro inflammatory cytokine microenvironment which supports the continued generation of Th17 cells. It is well described in adults but little is known in a pediatric population. This study was aimed to investigate the role of IL-6, IL-23 and its association with Treg and Th17 subsets in pediatric IBD patients. Peripheral blood mononuclear cells from patients and controls were stimulated with PMA, ionomycin, and brefeldin A. The frequencies of CD4+Foxp3+ cells, and CD4+IL17a+ cells were analyzed by flow cytometry. The serum level of IL-6 and IL-23 was determined by Elisa kit. The mRNA expression of Foxp3, IL-17a, IL-6 and IL-23 was detected by real-time quantitative PCR. The ratio of Treg/Th17 decreased in pediatric IBD patients, and it strongly correlated with IL-6 and IL-23. The present study provides a quantitative analysis regarding the Th17/Treg cell balance in peripheral blood of children with IBD and its association with serum IL-6 and IL-23 level. PMID- 29441875 TI - Influence of SLCO1B1 polymorphisms on atorvastatin efficacy and safety in Macedonian subjects. AB - Atorvastatin, as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is a widely prescribed medication for the treatment of dyslipidemia. However, despite its clinical efficacy in reducing major cardiovascular events, a wide inter-individual variability in its response exists. Several studies in this area point to the effect of polymorphisms in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene encoding the multiple organic anion-transporting polypeptide 1B1 (OATP1B1) involved in hepatic uptake of atorvastatin. Hence, the aim of this study was to analyze the association between the SLCO1B1 c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G polymorphisms and lipid-lowering effect and safety of atorvastatin. A hundred and fifty six patients with hyperlipidemia IIa and IIb, all of Macedonian origin, were included in the study receiving atorvastatin 20 - 80 mg/day for 3 months. SLCO1B1 single nucleotide polymorphisms (SNPs) were genotyped using the TaqMan allelic discrimination assay. As parameters of atorvastatin response, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein A (ApoAI), apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), creatine phosphokinase (CPK), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, using standard laboratory methods, at baseline and after 3 months of treatment. No statistically significant association between the different SLCO1B1 SNPs and atorvastatin response was observed. However, the carriers of c.521CC manifested a lower decrease in plasma levels of TG, TC, LDL-C and Lp(a), with percentage difference being 16%, 7%, 29% and 149%, respectively, compared to the carriers of c.521TT variant. Lower increase in HDL-C (271%) and ApoAI (293%) and higher increase in CPK (69%) in c.521CC carriers were also observed, confirming the lower OATP1B1 activity in carriers of the variant c.521 C allele. Similar results were obtained when a comparison between the percentage of biochemical parameter change was made between *15/*16/*17 heterozygotes and *15/*16/*17 non-carriers. The lack of a statistically significant association between the SLCO1B1 polymorphism and atorvastatin response can be explained dominantly by the low number of individuals homozygous for the rare c.521C variant allele. Despite this limitation, the study offers valuable information on the influence of the genetic determinant SLCO1B1 on atorvastatin response in the Macedonian population. PMID- 29441876 TI - Evaluation of antimicrobial stewardship (AS) for appropriate use of antimicrobial agents. AB - We implemented an antimicrobial stewardship (AS) program whereby pharmacists sought appropriate use of antimicrobial agents in January 2012. At that time, we targeted anti-methicillin-resistant Staphylococcus aureus (MRSA) agents and carbapenems; however, in January 2014, we added tazobactam/piperacillin (TAZ/PIPC). We evaluated outcomes using multilateral analyses. The average one day dosage of carbapenems increased; however, the duration of administration and number of recipient patients decreased significantly (P < 0.01). Moreover, the percentage of patients receiving meropenem (MEPM), for whom the time above minimal inhibitory concentration (MIC) was 40% or higher increased (P < 0.01). In contrast, patient utilization of TAZ/PIPC increased significantly after targeting of carbapenems as specific antibacterial agents. However, after TAZ/PIPC was targeted as a specific antibacterial agent, the number of TAZ/PIPC administrations decreased significantly (P < 0.01). The duration of hospitalization and mortality rate in patients receiving specific antibacterial agents significantly decreased after implementation of the AS program (P < 0.01). In conclusion, pharmacist's interventions to provide AS and patient follow-up reduced improper use and promoted proper administration of antibacterial agents. Furthermore, AS was effective in improving patient prognoses and suppressing drug resistant strains, as well as promoting effective treatment. PMID- 29441877 TI - Activities of Latvian pharmacists in the Latvian Red Cross organization in exile in Germany (1945-1976). AB - The Latvian Red Cross has performed its assistance mission outside the territory of Latvia for several decades. In the 40-s of the 20th century, the state of Latvia and its people went through one of the most tragic pages of their history. Due to the re-occupation made by the Soviet Union in 1944, many people of Latvia fled to exile and under exile conditions the Latvian societies, parishes and public organizations came into being, including the Latvian Red Cross. It started its activities in the second part of the 40-s of the 20th century in Germany and then representative offices emerged in the U.S.A., Sweden, France, Italy, Denmark, Belgium, Australia, New Zealand. Special attention should be paid to the fact that the activity under exile conditions was of a large scale, well organized and long-lasting. Substantial work at that time has been done by a number of pharmacists. Among them, the pharmacist and doctor Hugo Skudins (1903 1976) should be emphasized, who organized the purveyance of medication and sending them to Latvians in the occupied Latvia and to the penal camps in Siberia. PMID- 29441878 TI - An ultra-high performance liquid chromatography method to determine the skin penetration of an octyl methoxycinnamate-loaded liquid crystalline system. AB - Cutaneous penetration is a critical factor in the use of sunscreen, as the compounds should not reach systemic circulation in order to avoid the induction of toxicity. The evaluation of the skin penetration and permeation of the UVB filter octyl methoxycinnamate (OMC) is essential for the development of a successful sunscreen formulation. Liquid-crystalline systems are innovative and potential carriers of OMC, which possess several advantages, including controlled release and protection of the filter from degradation. In this study, a new and effective method was developed using ultra-high performance liquid chromatography (UPLC) with ultraviolet detection (UV) for the quantitative analysis of penetration of OMC-loaded liquid crystalline systems into the skin. The following parameters were assessed in the method: selectivity, linearity, precision, accuracy, robustness, limit of detection (LOD), and limit of quantification (LOQ). The analytical curve was linear in the range from 0.25 to 250 MUg.m-1, precise, with a standard deviation of 0.05-1.24%, with an accuracy in the range from 96.72 to 105.52%, and robust, with adequate values for the LOD and LOQ of 0.1 and 0.25 MUg.mL -1, respectively. The method was successfully used to determine the in vitro skin permeation of OMC-loaded liquid crystalline systems. The results of the in vitro tests on Franz cells showed low cutaneous permeation and high retention of the OMC, particularly in the stratum corneum, owing to its high lipophilicity, which is desirable for a sunscreen formulation. PMID- 29441879 TI - Development and validation of a LC-FL method for the simultaneous determination of doxorubicin and celecoxib in nanoparticulate fixed dose combination (NanoFDC). AB - An isocratic reversed phase HPLC method for the simultaneous determination of doxorubicine (DOX) and celecoxib (CXB) out of a nanoparticulate fixed dose combination (NanoFDC) was developed and validated. Linearity of the results was demonstrated from 1-11 MUg/mL for both components. Lower limits of detection were determined as 7 ng/mL for DOX and 13 ng/mL for CXB. Total run time was approximately 15 min. PMID- 29441880 TI - Crystal form conversion of nevirapine solvates subjected to elevated temperature and humidity: a qualitative study. AB - Some known nevirapine solvates have been reported to undergo solvent exchange in aqueous media to form a stable hemihydrate. This study aimed to determine the effects of atmospheric moisture on said nevirapine solvates and to gain insight into which factors determine the end product of transformation. Solvates were prepared by solvent recrystallisation and stored, together with the anhydrous and hemihydrate forms, in a climate chamber at 40 degrees C and 75% RH for a period of 28 days. Samples were analyzed using DSC, TGA, FT-IR, PXRD and Karl Fischer titration. Some solvates were observed to undergo desolvation to the anhydrous form of nevirapine (Form I), whilst others converted to the hemihydrate. It was found that water miscibility of the guest solvent determined the stable form of nevirapine, anhydrous or hemihydrate, to which each solvate eventually transformed. Transformation to the hemihydrate only occurred if the guest solvent was sufficiently water soluble to allow water molecules to enter solvent channels and displace the original guest. Solvates with hydrophobic guests desolvated to the anhydrous form. We concluded that, in the absence of a guest, solvent channels are lost during transformation to the monoclinic crystal system and space group P21/c (Form I) so that water cannot enter after desolvation. PMID- 29441881 TI - Cyclodextrin complexes of a globular protein and a lipophilic oligopeptide: the effect of structure and physicochemical properties. AB - Cyclosporine A (CyA) is a lipophilic oligopeptide that has a very limited solubility in water of only 0.008 mg/ml at ambient temperature. It has the ability to form inclusion complexes with cyclodextrin (CD) whose complexes can self-assemble to form aggregates. We have previously developed eye drops with CyA/CD aggregates. Our aim was to study cyclodextrin complexes of lysozyme, a small polar globular protein, and to compare the results with those obtained for CyA. We also wanted to test the stabilizing effect of CDs on lysozyme. Phase solubility studies of various CDs were performed with CyA and lysozyme. Complexation and particle size measurements were made with dynamic light scattering (DLS) and UV. Solid drug fractions were determined. Thermal and chemical stability studies were performed on lysozyme in the presence of various CDs. Recovery of lysozyme activity in the presence of various CDs after a heat shock was determined. Both CyA and lysozyme are able to form non-inclusion complexes with CD and those complexes can self-assemble and form micro sized aggregates. In case of lysozyme the forces involved are relativity weak and the lysozyme/CD complexes dissociate upon centrifuging, however for CyA the aggregates are stronger and do not dissociate upon centrifuging. CyA is therefore suitable for eye drop preparations containing CDs for sustained drug release whereas lysozyme is not. This is mainly due to the fact that CyA forms inclusion complexes with CDs, whereas lysozyme is not able to do so due to its polar surface. The lysozyme/CD non-inclusion complexes can offer some protection against lysozymes chemical and thermal denaturation. CD can, however, form complexes with unfolded lysozyme and hamper refolding of the protein after heat shock. PMID- 29441882 TI - Dissolution/permeation: The importance of the experimental setup for the prediction of formulation effects on fenofibrate in vivo performance. AB - The evaluation of formulation strategies in early drug development requires in vitro methods that correctly predict oral drug absorption. The present study aimed to define key parameters for the predictability of dissolution/permeation experiments. Dissolution/permeation experiments were performed in various setups. The IDAS1 chamber, Ussing chamber, and transwells were used as Caco-2 cell based dissolution/permeation models to study the impact of chamber volumes and vertical or horizontal membrane orientation. Dissolution/permeation experiments in Ussing chambers with excised rat intestine were performed to depict the impact of the permeation membrane. Fenofibrate served as model compound in formulations of different particle size. Caco-2 cell based dissolution/permeation experiments with a vertical membrane orientation correctly depicted the formulation effect seen in vivo. The chamber volumes did not affect the outcome. A horizontal membrane orientation achieved no distinction. Experiments using excised rat intestinal sheets did not distinguish between the formulations, and the permeation was much lower than across Caco-2 cells. Mucus might present an artificially enhanced barrier for fenofibrate. Factors that greatly affected the predictivity of the dissolution/permeation experiments were thus the type and orientation of the permeation membrane, whereas chamber volumes only had a minor influence. Vertically mounted Caco-2 cells resulted in the best formulation distinction. PMID- 29441883 TI - MiR-204 enhances the progression of osteoarthritis by suppressing the production of IL-1beta. AB - Recent studies suggest that cytokines and microRNAs play a key role in the destruction of cartilage matrix in osteoarthritis (OA) tissues. In the current study, we focused on miR-204, which has never been explored in OA. We found that the level of miR-204 was markedly reduced in the OA cartilage tissues compared with that of normal control. Real time PCR analysis demonstrated that the level of miR-204 was markedly decreased after IL-1beta treatment for 3, 6, 12 h in the normal chondrocytes and OA chondrocytes, respectively. Furthermore, overexpression of miR-204 markedly suppressed the protein levels of IL-1beta, COX 2 and IL6 in human OA chondrocytes and chondrogenic SW1353 cells. Dual luciferase reporter assay demonstrated that miR-204 significantly suppressed the relative luciferase activity of pmirGLO-IL-1beta-3'UTR, indicating that IL-1beta was a target gene of miR-204. More importantly, treatment with IL-1beta significantly enhanced the protein levels of IL-1beta, COX-2 and IL6. However, overexpression of miR-204 could partially abolish such effects. In conclusion, our data demonstrate that reduced miR-204 expression enhances the destruction of the cartilage tissues among OA patients mainly through targeting IL-1beta. PMID- 29441884 TI - MiR-204/14-3-3zeta axis regulates osteosarcoma cell proliferation through SATA3 pathway. AB - Hyperproliferation of cells is a major problem is osteosarcoma (OS). So, further elucidation of the molecular mechanisms underlying hyperproliferation of OS is needed. Western blots results showed that 14-3-3zeta protein was upregulated in OS cell lines; 14-3-3zeta knockdown significantly suppressed OS cell proliferation, as well as the protein levels of p-STAT3, c-Myc and Cyclin D1. MicroRNA-204 (miR-204) has been regarded as an essential regulator in cancer carcinogenesis, including OS. Here, we revealed that miR-204 directly targets the 3'UTR of 14-3-3zeta to inhibit its expression, thus to suppress 14-3-3zeta induced OS cell hyperproliferation. Further, we demonstrated that the STAT3 pathway was involved in miR-204/14-3-3zeta regulation of OS cell proliferation. Our findings provide information about the underlying mechanisms of miR-204/14-3 3zeta in OS cell proliferation through the STAT3 pathway, and suggest miR-204 and 14-3-3zeta as potential therapeutic targets in OS. PMID- 29441885 TI - Reduced lncRNA Aim enhances the malignant invasion of triple-negative breast cancer cells mainly by activating Wnt/beta-catenin/mTOR/PI3K signaling. AB - Increasing evidence has suggested the important role of lncRNAs in the progression of triple-negative breast cancer (TNBC). In the current study, we first demonstrated that the expression of Airn was reduced in TNBC tissues and cells. Our data showed that the level of Airn was reduced in TNBC tissues and cell lines compared with that of normal control. Furthermore, silencing of Airn markedly enhanced MDA-MB-231 cell migration. Meanwhile, knockdown of Airn significantly increased MDA-MB-231 cell invasion. Western blot analysis showed that knockdown of Airn markedly enhanced the activation of Wnt/beta catenin/mTOR/PI3K in both MDA-MB-231 cells. Moreover, real time PCR analysis showed that the mRNA level of IGF2R was significantly enhanced when Airn was silenced in MDA-MB-231 cells. In addition, overexpression of IGF2R significantly increased MDA-MB-231 cell migration and invasion. To further explore whether Airn activated Wnt/beta-catenin/mTOR/PI3K signaling independent of IGF-2R, a specific siRNA targeting IGF2R was selected. Western blot analysis showed that Wnt/beta catenin/mTOR/PI3K signaling could be largely activated in MDA-MB-231 cells transfected with siRNA targeting Airn, even when the protein level of IGF2R was silenced. In summary, decreased expression of lncRNA Aim enhanced the malignant invasion of triple-negative breast cancer cells mainly by activating Wnt/beta catenin/mTOR/PI3K signaling independent of Igf2R. PMID- 29441886 TI - Effects and mechanisms of ambroxol inhalation (Mucosolvan(r)) in the treatment of neonatal pneumonia. AB - Neonatal pneumonia is the leading cause of mortality in children aged <5 years. Ambroxol (Mucosolvan(r)) is a mucolytic and secretolytic drug and belongs to the group of expectorants with anti-oxidative and anti-inflammatory effects. The purpose of the present study was to observe the effects and mechanisms of Mucosolvan (r) inhalation on neonatal pneumonia. Between January 2014 and October 2015, a total of 80 newborns with pneumonia were randomly divided into control and observation groups. While the patients in the control group were treated with conventional treatment only, those patients in the observation group were treated with Mucosolvan(r) in addition to the conventional treatment. The lung function index and serum inflammatory mediators were measured before and after treatment on days 1, 3 and 7. In the observation group, there was a significant increase in the lung function index as compared to the control group. Also, there was a significant decrease observed in the expression of inflammatory factors which in turn activated NF-kappaB pathway and cell apoptosis. The above findings had shown that Mucosolvan(r) improved lung function and exhibited good inflammatory response. In addition, we found that Mucosolvan(r) inhibited cell apoptosis and NF-kappaB pathway activation and effectively improved pulmonary functions. PMID- 29441887 TI - Effect of NPM1 type B mutation on the proliferation, invasion and chemosensitivity of THP-1 leukemia cells. AB - Acute myeloid leukemia (AML) is the most malignant myeloid disorder in adults. AML with mutated nucleophosmin (NPM1) is regarded as an independent leukemia subtype. According to previous studies, the role of NPM1 gene A mutation in AML has been well established; however, another major type, NPM1 gene B type mutation (NPM1 MutB) has been rarely reported. In the present study, we found that overexpression of NPM1 MutB enhanced the proliferation and invasion of THP-1 AML cells through the regulation of TIMP-2, MMP-2, Ang-1, c-myc and CCND1; led to no significant change of apoptosis rate with the absence of chemotherapy agents, while enhanced the chemosensitivity of THP-1 AML cells to chemotherapy agents DNR and Ara-C through the regulation of Bax, Bcl-2 and caspase-3. Further, we revealed that NPM1 MutB overexpression reduced the NF-kappaB activity of THP-1 cells upon drug treatment. Taken together, we demonstrated the detailed functions of NPM1MutB in THP-1 proliferation, invasion, apoptosis and chemo-sensitivity. We provided a novel understanding of prognosis of patients carrying the NPM1 B mutation. PMID- 29441888 TI - Anti-fibrotic potential of a Matthiola arabica isothiocyanates rich fraction: impact on oxidative stress, inflammatory and fibrosis markers. AB - The present study is the first one to investigate the glucosinolates (GLS) profile and anti-fibrotic effect of isothiocyanates (ITCs) rich fraction of Matthiola arabica (Brassicaceae) using an experimental model of liver fibrosis in rats. Five GLS (ethyl glucosinolate, gluconapin, glucodehydroerucin, glucoerucin and glucoraphanin) were identified by gas liquid chromatography-mass spectrometric (GLC-MS) analysis of their hydrolysis products, produced by the natural autolysis and exogenous myrosinase hydrolysis using one and two units of the enzyme. Spectrophotometric determination of the total intact GLS revealed that content in the fresh sample was 1.8 times higher than in the dry one. ITCs rich fraction was prepared by natural autolysis of the fresh aerial part. Male albino rats were given carbon tetrachloride (CCl4) (0.5 ml/kg, twice a week) and/or ITCs -rich fraction (30 mg/ kg, three times a week) for six weeks. Liver function, different oxidative stress, inflammatory and fibrosis markers were investigated. Treatment of animals with ITCs rich fraction significantly counteracted the changes in liver function induced by CCl4. Histopathological examination under both light and electron microscope showed the anti-fibrotic effect of ITCs rich fraction. This finding was confirmed with the markedly improved liver fibrosis markers with ITCs rich fraction co-treatment. In elucidation of anti-fibrotic mechanisms of ITCs rich fraction, the significant glutathione depletion and lipid peroxidation caused by CCl4 intoxication was restored by ITCs rich fraction co-treatment. Besides, ITCs rich fraction showed an anti-inflammatory effect through its ability to counteract the significant increase in nuclear factor kappa B (NF-kappaB), cyclooxygenase-2 (COX-2) expression, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) levels in liver tissue that caused by CCl4 intoxication. These findings indicate that ITCs-rich fraction of M. arabica possesses a promising anti-fibrotic effect which can be attributed to its antioxidant and anti-inflammatory properties. PMID- 29441889 TI - Investigations on the constituents of SagaPro tablets, a food supplement manufactured from Angelica archangelica leaf. AB - Saga Pro is a food supplement product manufactured in Iceland and marketed internationally. It is claimed to have anti-nocturia effect and the flavonoid isoquercitrin has been suggested to play a role in this assumed activity. The purpose of this study was to identify and quantify the main flavonoids and furanocoumarins in the SagaPro tablets and to evaluate the importance of their presence. Isoquercitrin was identified as a constituent in an amount of 158 MUg/tablet. This is a p.o. dosage highly unlikely to have an effect on nocturia or any other pharmacologically significant effect in humans. The main furanocoumarins, xanthotoxin and imperatorin, were also identified and quantified to 280 and 2 MUg/tablet, respectively. PMID- 29441890 TI - Increased serum miR-300 level serves as a potential biomarker of lipopolysaccharide-induced lung injury by targeting IkappaBalpha. AB - MicroRNAs (miRs) are reported to play key roles in various disease models. In this study, the functional role of miR-300 in the regulation of lung injury was explored to assess the feasibility of serum miR-300 as a potential biomarker for lung injury. Firstly, the expression of miR-300 was studied in the serum of 50 lung injury patients and 50 healthy controls. And the expression of miR-300 was also explored in the serum and lung tissues of mouse models. To further explore the possible mechanism in which miR-300 may contribute to lung injury, the target genes of miR-300 were predicted by TargetScan and validated using dual luciferase reporter assay. Moreover, the expression of inflammation factors was studied after transfection of miR-300 mimics and inhibitors into A549 cells. Here, we first identified that the level of miR-300 was significantly upregulated in the blood samples of acute lung injury patients compared with healthy control. Meanwhile, miR-300 was also found to be enhanced in the blood samples and lung tissues of LPS-induced mouse models. Further study showed that miR-300 significantly suppressed the expression of IkappaBalpha and luciferase reporter assay showed that IkappaBalpha was a target gene of miR-300. More importantly, the levels of inflammatory factors, such as TNFalpha, COX-2, iNOS, IL-6 and IL8, were significantly upregulated accompanied by overexpression of miR-300 in A549 cells. In summary, enhanced miR-300 expression in the peripheral blood contributed to the lung injury mainly by inhibiting the expression of IkappaBalpha. PMID- 29441891 TI - Hepatotoxicity, nephrotoxicity, and drug/chemical interaction toxicity of platinum nanoparticles in mice. AB - Nanomaterials are frequently used in microelectronics, cosmetics, and sunscreens. Platinum reagents are commonly used in disease diagnosis, cosmetics, and the food industry. Although research into the development of nanomaterialbased drug delivery systems has yielded promising results, the toxicity of these materials is not fully understood. We investigated the toxicity and drug interactions of 1- and 8-nm diameter platinum nanoparticles (nPt1 and nPt8, respectively) in mice. Acute hepato-renal toxicity of intravenously administered platinum nanoparticles was evaluated biochemically and histologically. Dose-dependent increases in serum markers of hepato-renal function (serum aminotransferases and blood urea nitrogen) were observed following administration of nPt1, whereas nPt8 had no effect, even at 20 mg/kg. Moreover, nPt1 induced interleukin (IL)-6 and IL-1beta production 3 and 6 hours after administration. The effect of nPts on drug-induced toxicity was evaluated in mice injected intraperitoneally with carbon tetrachloride or cisplatin, with or without intravenous administration of platinum nanoparticles. All treatments in the absence of nanoparticles were non lethal and resulted in moderate toxicity. However, exacerbated toxicity was observed in mice injected with carbon tetrachloride or cisplatin together with nPt1, but not in mice co-injected with nPt8. We found that nPt1 cause hepato renal damage, and the effect is enhanced by chemical inducers of hepatotoxicity and nephrotoxicity. This is the first report demonstrating that nPt1 not only are hepatotoxic and nephrotoxic but also exacerbate drug toxicity. These findings will be useful for future nanotechnology and nanoscience research. PMID- 29441892 TI - Association of AGTR1 and ACE2 gene polymorphisms with structural atrial fibrillation in a Chinese Han population. AB - The renin-angiotensin system (RAS) is thought to play an important role in atrial fibrillation (AF). The RAS contains the ACE/AngII/AGTR1 axis and the ACE2/Ang(1 7)/MAS axis, which restrict each other via mutual antagonism and regulate myocardial hypertrophy, fibrosis and remodelling. The aim of our study was to investigate the association between single nucleotide polymorphisms (SNPs) in angiotensin-II type-1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) and structural AF in a Chinese Han population. The SNPs (rs1492100, rs1492099, rs1492097, rs3772616) in AGTR1 and the SNP rs6632677 in ACE2 were compared in 300 structural AF patients (67.61+/-12.56 years) and 300 controls (66.08+/-12.47 years). The genotype frequencies of SNP rs1492099 in AGTR1 in the structural AF cohort vs controls were as follows: GG, 72.7 vs 83.0%; AG 26.0 vs 16.3%; AA 1.3 vs 0.7% (P=0.009). The frequency of the minor allele of SNP rs1492099 in AGTR1 was 14.2% in the structural AF group compared with 8.8% in the controls (t=0.004; odds ratio [OR], 1.727; 95% confidence interval [CI]: 1.154-2.487). In addition, the genotype frequencies of SNP rs6632677 in ACE2 in the structural AF male patients vs male controls were as follows: GG, 70.5 vs 83.1%; CG 26.3 vs 15.6%; and CC 3.2 vs 1.3% (P=0.029). The frequency of the minor allele of SNP rs6632677 in ACE2 was 16.3% in structural AF male patients compared with 9.1% in male controls (P=0.008; OR, 1.954; 95%CI: 1.196-3.192). Furthermore, we found an interaction between the SNP rs6632677 in ACE2 and the SNPs (rs1492100/rs1492099/rs3772616) in AGTR1 in structural AF patients by the multifactor dimensionality reduction (MDR) method. The results indicate that polymorphism rs1492099 in the AGTR1 gene is associated with structural AF in a Chinese Han population. It was hypothesized that the ACE2 gene, which maps to the X chromosome, may be correlated with the risk of structural AF in a Chinese Han male population. Furthermore, we found an interaction between ACE2 and AGTR1 in structural AF patients in a Chinese Han population. PMID- 29441893 TI - Effect of genetic polymorphisms of azathioprine-metabolizing enzymes on response to rheumatoid arthritis treatment. AB - Azathioprine (AZA) is increasingly being prescribed to rheumatoid arthritis (RA) patients. Following oral administration, AZA is converted into its active form. Inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) patients with low thiopurine (S)-methyltransferase (TPMT) activity tend to respond well to AZA therapy. In a previous study of Japanese SLE patients under low-dose AZA therapy, the group with the 94C>A mutation in inosine triphosphatase (ITPA) showed greater improvement in their disease activity index. However, it is not yet clear how genotypes relate to responsiveness to RA treatment. The genotypes ITPA 94C>A, TPMT*3C, NUDT15 595C>T, GST-M1, GST-T1 and MRP4/ABCC4 2269G>A of Japanese patients with RA were determined. The relationship between these genotypes and response to AZA therapy was evaluated using the Disease Activity Score 28 (DAS28) and various medical data. Of the 22 patients 15 had the ITPA 94C/C genotype, 7 had the ITPA 94C/A genotype, none had the TPMT*3C mutation, 4 had the NUDT15 595C>T mutation, 8 had the GST-M1 and T1 null genotypes and 9 had the MRP4/ABCC4 2269G>A mutation. Changes in DAS28 at 6 months after baseline were similar in both ITPA genotype groups. However, the maintenance dose of AZA was significantly lower in the C/A group than in the C/C group (0.85+/-0.30 mg/kg/day vs. 1.2+/-0.46 mg/kg/day, respectively; p = 0.043). The ITPA 94C/A group showed the same response to RA treatment as the C/C group, but at a lower dose. This demonstrates that RA patients with the ITPA 94C>A mutation are more responsive to AZA. PMID- 29441894 TI - Pharmacokinetics of talinolol is modified by barnidipine: implication of P glycoprotein modulation. AB - Concomitant administration of P-glycoprotein substrates and inhibitors may cause pharmacokinetic drug interactions leading to increased concentrations associated with serious side effects and toxicities. Barnidipine is a longacting calcium channel blocker and potent inhibitor of P-glycoprotein in vitro, and talinolol is a beta-blocker and probe substrate of P-glycoprotein. This study was designed to investigate the effects of single and repeated oral doses of barnidipine on talinolol pharmacokinetics in rats. In the single-dose study, talinolol (20 mg/kg) alone and with barnidipine at low (1 mg/kg) and high doses (10 mg/kg) were orally administered to rats. In the repeated-dose study, rats were treated with barnidipine (1 mg/kg/day) or vehicle only for four days, then with talinolol (20 mg/kg, on day 5). Blood samples were collected at 0.5, 1, 2, 4, 6 h following last dose and plasma talinolol levels were determined by HPLC. Compared to the control, Cmax of talinolol elevated 10% (p=0.79) and 110% (p<0.05); plasma AUC0 6h increased 33% (p=0.41) and 46% (p<0.05) following low and high single doses of barnidipine co-administration, respectively. In the repeated-dose study, Cmax and AUC0-6h of talinolol increased 131% (p<0.05) and 130% (p<0.05) respectively, following co-administration of a low barnidipine dose. Double-peaks were observed when single or repeated low doses of barnidipine were co-administered. There may be coupling between occurrence of double-peak phenomenon and P-glycoprotein inhibition. Increment of talinolol bioavailability upon low and high doses of barnidipine co-administration may be due to P-glycoprotein inhibition. The higher increase of talinolol plasma AUC0-6h due to the repeated doses of barnidipine may be explained by downregulation of P-glycoprotein. PMID- 29441895 TI - Daidzein promotes proliferation and differentiation in osteoblastic OCT1 cells via activation of the BMP-2/Smads pathway. AB - Daidzein, the most widely studied soy phytoestrogen, is not only a potential antiosteoporosis agent owing to its possible osteogenic activity, but also shows anticancer activity. However, the mechanisms through which daidzein affects osteoblast function have not been well understood. Here, we show that daidzein stimulated cell proliferation and differentiation of osteoblasts, demonstrated by upregulation of XTT activity, enhancement of alkaline phosphatase (ALP) activity, and upregulation of osteoblast-specific marker genes, including Runt-related transcription factor 2 (Runx2) and Smad1, as well as up-regulation of Runx2 and Smad1 protein expression. To determine the mechanisms underlying daidzein's effects on osteoblast differentiation, we first tested the role of daidzein in bone morphogenetic protein (BMP)-2 gene expression in OCT1 cells, and found that it significantly upregulated the expression of BMP-2. Furthermore, it significantly enhanced the phosphorylated protein level of Smad1/5/8and protein expression of Osterix (Osx, a direct target gene of BMP signaling) and increased the activity of BMP signaling reporter (12xSBE-OC-Luc). Finally, we demonstrated that daidzein stimulated Col I, Runx2, and ALP expression, while these effects were significantly blocked by the BMP signaling inhibitor noggin. Thus, our data indicate that daidzein acts through stimulating the activation of BMP-2/Smads pathway to promote osteoblast proliferation and differentiation. PMID- 29441896 TI - Apocynum leaf extract inhibits the progress of atherosclerosis in rats via the AMPK/mTOR pathway. AB - Apocynum leaf extract is an extract of the dried leaves of Apocynum venetum (a member of the Apocynaceae family) that has many effects on the cardiovascular system. The aim of the present study was to evaluate the protective effects of apocynum leaf extract on the atherosclerosis in rats induced by high-fat diet combined with vitamin D3 intraperitoneal injection. The atherosclerosis in rats were induced with a high-fat diet and an intraperitoneal injection of VD3 once daily for three contiguous days at a total injection dose of 70 U/kg. At the end of the 18th week, serum total cholesterol (TC) and triglyceride (TG) contents were measured. Hydroxyproline content in the aorta were measured by the alkali hydrolysis method. The hematoxylin-eosin (HE) and immunohistochemical staining were applied to evaluate the morphological changes and the collagen I and alpha smooth muscle actin expression. The protein expression and the mRNA level of AMPK and mTOR were detected by western blot analysis and reverse transcript PCR. After treatment with apocynum leaf extract, the serum total cholesterol and triglyceride concentration of the atherosclerotic rats were significantly decreased, both the Collagen I expression and the hydroxyproline content in the aorta were significantly reduced, and the alpha-SMA, a smooth muscle-specific marker, expression were also lower than the untreated atherosclerotic rats. Western blot analyses showed that the apocynum can marked increase the p-AMPK but decrease the mTOR protein expression. The apocynum leaf extract also exhibited higher AMPK and lower mTOR mRNA expression of the aorta in the atherosclerotic rats. We believe that the apocynum leaf extract can effectively reduce blood lipid levels in rats with atherosclerosis, delay atherosclerotic progression by inhibiting excessive collagen synthesis and inhibiting smooth muscle cell over proliferation. The underlying mechanism may be related to the AMPK/mTOR signaling pathway activity. Our results contribute towards validation of the traditional use of apocynum leaf extract in the treatment of atherosclerosis. PMID- 29441897 TI - Severe neutropenia: a prognosticator in patients with advanced/recurrent colorectal cancer under oral trifluridine-tipiracil (TAS-102) chemotherapy. AB - BACKGROUND/AIM: The effect of oral trifluridine-tipiracil (TAS-102)-induced neutropenia on survival of patients with advanced/recurrent colorectal cancer was investigated. PATIENTS AND METHODS: Between August 2014 and May 2016, 41 patients underwent TAS-102 monotherapy at Ogaki Municipal Hospital. Risk factors for survival were examined by univariate and multivariate analyses. RESULTS: In 41 patients, mild neutropenia (grade 1-2) occurred in 10 patients (24.4%), severe neutropenia (grade 3-4) occurred in 13 (31.7%), and 18 (43.9%) did not experience neutropenia. The median overall survival times in the absent, mild, and severe groups were 120 days (95% confidence interval [CI], 67-179), 184 days (95% CI, 94 274), and 299 days (95% CI, 192-404), respectively (p = 0.045). In patients with severe neutropenia, the death hazard ratio was 0.442 (95% CI, 0.201-0.974; p = 0.042). CONCLUSION: In patients with advanced/recurrent colorectal cancer, TAS 102-induced severe neutropenia was associated with superior survival. PMID- 29441898 TI - A simplified chart for determining the initial loading dose of teicoplanin in critically ill patients. AB - AIM OF THE STUDY: A simplified chart to determine the initial loading dose of teicoplanin (TEIC chart) for achieving the target trough concentration was developed. The aim of the present study was to evaluate the usefulness of this chart in critically ill patients. PATIENTS AND METHODS: The initial loading dose and maintenance dose to achieve a target trough concentration >=10 MUg/mL on day 4 was determined using the teicoplanin TDM software and presented in a TEIC chart. The dosage of teicoplanin, including the loading dose for the first 2 days and the maintenance dose thereafter, was selected from the chart (chart method, N = 41) or calculated using TDM software (software method, N = 39). RESULTS: The performance rate of initial loading of teicoplanin increased from 83.0% to 100% after the TEIC chart was introduced (P = 0.016). The TEIC chart significantly reduced the time required for determining the initial loading dose compared with the use of software (1.9+/-0.6 min vs. 29.7+/-13.8 min, P < 0.001). No significant differences were observed in the rates of achieving a target level >=10 MUg/mL (P = 0.766). CONCLUSION: The TEIC chart enables a simple, rapid, and reliable determination of teicoplanin dosage. PMID- 29441899 TI - Ethnopharmacology in the work of the British botanist Arthur Francis George Kerr (1877 - 1942). AB - Reports on traditional use of medicinal plants may be used as starting points for phytochemical and pharmacological research. As has recently been shown, publications, letters, diaries and reports of exploring botanists are a valuable source of historical ethnopharmacological information. In this study, the heritage of the British botanist Arthur Francis George Kerr (1877-1942), mainly working in Thailand, was screened for information about traditionally used medicinal plants. Information given was compared to state-of-the-art scientific knowledge about these species. Many historical uses could be confirmed, some did not, while a number of species reported to be traditionally used have not been sufficiently investigated so far. These, strongly suggested for further research, include Kurrimia robusta, Alpinia siamensis, Amomum krervanh (A. testaceum), Trichosanthes integrifolia (= Gymnopetalum scabrum), Croton cumingii (= C. cascarilloides), Lobelia radicans (= L. chinensis), Willughbeia sp., Nyctanthes arbor-tristis, Pluchea indica, Heliotropum indicum, as well as some fungi and woods. PMID- 29441900 TI - Role of the endocannabinoid system in the formation and development of depression. AB - Two types of cannabinoid (CB) receptors have been described in the human body: CB1 and CB2 receptors. CB1 receptor distribution may be related to the cannabinoid functions of memory and cognition regulation as well as motor control. In addition, the endocannabinoid system (ECS) related to CB1 receptors may be involved in human emotion regulation, especially depression occurrence. Indeed, CB1 receptors are all distributed in depression associated neuroanatomical structures and neural circuits. Both animal experiments and clinical studies have demonstrated that impairment of the ECS pathway is present in depression models and patients, and application of both CB1 receptor agonists and anandamide (cannabinoid-like substance) degradation inhibitors produce similar biochemical and behavioral effects as antidepressants. These findings provide a solid basis for understanding the ECS role in the formation and development of depression. Therefore, it can be inferred that the ECS may have an important function in both depression treatment and the effects of antidepressants. PMID- 29441901 TI - Retarder action of isosorbide in a microemulsion for a targeted delivery of ceramide NP into the stratum corneum. AB - Ceramide [NP] is an integral component of the stratum corneum (SC) lipid matrix and is capable of forming tough and stable lamellar structures. It was proven, that in skin diseases as psoriasis or atopic dermatitis different ceramide (CER) classes, including [NP], are degraded. It is obvious that topically application of CER on impaired skin is useful for repairing the skin barrier but a tendency for low penetration due to its poor solubility in conventional dosage forms was observed. Therefore, a stable and physiologic compatible colloidal carrier system, a microemulsion (ME), was developed and characterized. The increasing knowledge of the new colloidal systems in this last decade shows their benefits in dermal application. Isosorbide (Polysorb P) was incorporated into the ME developed. It was expected that Polysorb P has a retarder potential in order to accumulate the CER in the SC, the outermost layer of the skin. Thereby the CER [NP] would be able to interact with the affected skin layers to strengthen the skin barrier. The release and penetration behavior of the CER [NP] from the ME was assessed ex vivo in a Franz diffusion cell. The results of the study showed that CER [NP] penetrate largely in the upper layers of the skin (from SC to stratum basale), which was the desired region. A recovery in the acceptor could not be detected that underlines an accumulation in upper layers. Furthermore, significantly increased values for the SC for the ME with retarder were not received. No differences in the concentrations of CER [NP] were observed. However, the toxicity of MEs was investigated using hens egg test chorioallantoic membrane (HET-CAM). For the isosorbide-containing ME no difference was obtained in comparison to the non-containing. The results showed that both MEs are safe to be used on the skin for the controlled penetration of CER [NP] into the skin. The isosorbide had no effect on the irritating effect as well as on the penetration of the used CER. PMID- 29441902 TI - Solution-mediated crystallization of amorphous azithromycin. AB - Water and water vapor are the bane of amorphous drug stability, both in storage and after administration. As is to be expected, crystallization of amorphous azithromycin did occur when exposed to water as dissolution medium. However, experimental results showed that, although solution-mediated phase transformation had occurred, it was not a rapid process for this drug. It is considered to be an advantageous characteristic of amorphous azithromycin and likely due to the high molecular mass (748.984 g/mol) and complex structure necessitating more energy for transformations to occur. A high apparent solubility is maintained for a considerable period of time, potentially rendering a higher percentage of this BCS Class II drug available for absorption when administered orally. PMID- 29441903 TI - IVIVC approach based on carbamazepine bioequivalence studies combination. AB - The aim of the present study was to explore the feasibility of obtaining an IVIVC by combination of data from two bioequivalence (BE) studies of carbamazepine (CBZ) in order to assess if the previously published dissolution media and conditions could be applicable to any other oral immediate release (IR) CBZ products with conventional excipients. Twenty-four healthy male subjects from two BE study received one IR dose of the test (test 1 or 2) or the reference formulation (Tegretol, 400 mg). Dissolution studies of the IR CBZ tablets were performed in two different laboratories. In order to develop IVIVC, individual or average data analysis were considered. A level C, level B and level A correlation have been successfully developed by combining data from different BE studies of CBZ immediate release drug products. A level A IVIVC was developed with all four datasets with a good R2 for all the combinations of in vivo and in vitro data. A dissolution medium containing 1% SLS has demonstrated its suitability as the universal biopredictive dissolution medium, even if different batches and in vivo/in vitro studies were combined. PMID- 29441904 TI - MicroRNA-33a deficiency inhibits proliferation and fibrosis through inactivation of TGF-beta/Smad pathway in human cardiac fibroblasts. AB - Cardiac fibroblasts (CFBs) play pivotal roles in myocardial fibrosis, which is the leading cause of arrhythmia. This study was aimed to investigate the modulation of microRNA (miR)-33a on proliferation, apoptosis and fibrosis of human CFBs. CFBs were respectively transfected with miR-control, miR-33a mimic or miR-33a inhibitor, followed by induction of transforming growth factor-beta (TGF beta). Non-treated CFBs acted as control. Cell viability, apoptosis, and fibrosis which reflected by expressions of Col-I, Col-III and alpha-smooth muscle actin (alpha-SMA) were evaluated by CCK-8 assay, flow cytometry, qRT-PCR and Western blot analysis. Finally, key kinases involved in the TGF-beta/Smad pathway were evaluated by Western blot analysis. TGF-beta enhanced CFB viability, and expression levels of Col-I, Col-III and alpha-SMA in CFBs (P < 0.01 or P < 0.001). The increased CFB proliferation, and upregulation of Col-I, Col-III and alpha-SMA were all further enhanced by miR-33a mimic (P < 0.05 or P < 0.001), whereas reversed by miR-33a inhibitor (P < 0.05, P < 0.01 or P < 0.001). The CFB apoptosis was remarkably promoted by miR-33a inhibitor (P < 0.001). Results of signaling pathway showed that phosphorylated levels of Smad-2 and Smad-3 were both upregulated by TGF-beta (P < 0.001). The upregulated phosphorylations were further improved by miR-33 mimic (P < 0.05) while reversed by miR-33a inhibitor (P < 0.05 or P < 0.001). miR-33a deficiency inhibits proliferation and fibrosis of CFBs while promotes CFB apoptosis by inactivation of TGF-beta/Smad pathway. PMID- 29441905 TI - MiR-99a inhibits keratinocyte proliferation by targeting Frizzled-5 (FZD5) / FZD8 through beta-catenin signaling in psoriasis. AB - Psoriasis, a common chronic skin disorder, is characterized by hyperproliferation and aberrant differentiation of keratinocytes and infiltration of inflammatory cells into the dermis and epidermis. MicroRNAs (miRNAs) are a large family of highly conserved small non-coding RNA which regulates diverse biological process, including cell proliferation, by modulating gene expression at the posttranscriptional level. In the present study, we indicated that miR-99a was specifically downregulated in psoriatic dermatic lesions, and could inhibit HaCaT cells' proliferation; by direct targeting, miR-99a could also regulate the expression of Frizzled-5 (FZD5)/Frizzled-8 (FZD8). In addition, we found that the downstream factor of FZD5/FZD8 signaling, beta-catenin, and the downstream target gene of beta-catenin, cyclinD1, could be suppressed by miR-99a; the suppressive effect of miR-99a on beta-catenin and cyclinD1 could be partially abolished by forced FZD5/FZD8 expression. Taken together, we assume that miR-99a inhibits HaCaT cells' proliferation by targeting FZD5/FZD8 through downstream factors beta catenin and cyclinD1, and provide diagnostic markers and a novel target for psoriasis treatment. PMID- 29441906 TI - MiR-130a protects against lipopolysaccharide-induced glomerular cell injury by upregulation of Klotho. AB - AIMS: Lupus nephritis is a frequent and serious complication of systemic lupus erythematosus (SLE). Therefore, better understanding regarding the underlying mechanism of renal tubular injury induced by SLE, is beneficial to develop different therapeutic strategies for lupus nephritis. The study aimed to investigate the role of miR-130a against lipopolysaccharide-induced glomerular cell injury. METHODS: HK-2 cells (human renal proximal tubule cells) were used for detecting miR-130a levels. Cells were divided into scramble, miR-130 mimic, siNC, si-miR-130a and si-Klotho groups apoptosis and CCK-8 assays were performed to investigate the cell apoptosis and proliferation rates. qRT-PCR, ELISA, and western blotting were performed to detect the proteins and their expressions. RESULTS: LPS induced inflammatory injury in HK-2 cells by inducing cell apoptosis (P < 0.01) and by expressing the inflammatory factors such as IL-1beta, IL-6, IL 8 and TNF-alpha in HK-2 cells. LPS increased the expression of miR-130a compared to control group of cells (P < 0.01). miR-130a was highly expressed in HK-2 cells (P < 0.001). Overexpression of miR-130a reversed LPS-induced apoptosis (P < 0.05), increased expression of inflammatory mediators and decreased cell viability (P < 0.05), and miR-130a knockdown in HK-2 cells revealed to just the opposite effects upon treatment with LPS. Western blotting results showed that overexpression of miR-130a promoted the expression of Klotho and activated the PI3K/AKT pathway but inhibited Wnt and NF-kappaB pathways. CONCLUSIONS: These findings demonstrated that miR-130a promoted PI3K/AKT pathway but inhibited Wnt and NF-kappaB pathways through upregulation of Klotho. Furthermore, miR-130a protects against lipopolysaccharide-induced glomerular cell injury by upregulating Klotho expression. PMID- 29441907 TI - microRNA-335 inhibits colorectal cancer HCT116 cells growth and epithelial mesenchymal transition (EMT) process by targeting Twist1. AB - Colorectal cancer is one of the most commonly diagnosed cancers. Recently, several microRNAs (miRNAs) have been characterized as oncogenes or tumor suppressors in colorectal cancer. This study was aimed to explore the tumor suppressive effects and its underling mechanism of miR-335 on colorectal cancer cells. Human colorectal cancer HCT116 cells were employed and the expression of miR-335 in cells was altered by transfection with miR-335 mimic and miR-335 inhibitor. Thereafter, CCK-8 assay, flow cytometry, Transwell assay and Western blotting were used to detect cell viability, apoptosis, migration, invasion, and the expression of epithelial-mesenchymal transition (EMT)-related proteins. Dual luciferase activity assay was performed to test whether Twist1 was a direct target of miR-335. Moreover, cells were co-transfected with miR-335 inhibitor and Twist1 siRNA, and then cell growth and metastasis were re-evaluated. miR-335 overexpression inhibited cell viability, migration and invasion, and promoted apoptotic cells rate. miR-335 overexpression up-regulated E-Cadherin, while down regulated N-Cadherin, Vimentin and Snail. Twist1 was a direct target of miR-335, and Twist1 silence promoted apoptosis, and abolished miR-335 suppression induced increases in cell viability, migration, invasion, and abnormal expressions of EMT related proteins. Besides, Twist1 silence abolished miR-335 suppression induced activations of p65 and IkappaBalpha, and miR-335 suppression induced up regulations of Wnt3a, Wnt5a and beta-Catenin. miR-335 inhibited HCT116 cells growth, migration, invasion, and ETM process. miR-335 exhibited tumor suppressive effects possibly by inhibition of Twsit1 and thus inactivating NF-kappaB and Wnt/beta-catenin pathways. PMID- 29441908 TI - microRNA-340 induces apoptosis by downregulation of BAG3 in ovarian cancer SKOV3 cells. AB - Aberrant expression of miR-340 has been found in several kinds of cancers including ovarian cancer. Pro-apoptotic and anti-metastasis roles of miR-340 in ovarian cancer have also been reported; however, the underling molecular mechanisms by which miR-340 suppresses ovarian cancer are still unclear. This study focused on the role and molecular mechanism of miR-340 in ovarian cancer. Human ovarian carcinoma SKOV3 cells were used and transfected with miR-340 mimic, miR-340 inhibitor and their correspondingly negative controls (mimic control and inhibitor control). Thereafter, cell viability, apoptosis, and the expressions of apoptosis-associated factors and BAG3 were respectively assessed by MTT assay, flow cytometry, qRT-PCR and Western blotting. SKOV3 cells were then co transfected with miR-340 inhibitor and BAG3 targeted siRNA, then cell viability, apoptosis and the expression of apoptosis-associated factors were retested. Besides, the expressions of main factors in PI3K/AKT pathway were detected. Overexpression of miR-340 suppressed BAG3 cells viability (P < 0.05), but improved apoptosis (P < 0.001). BAG3 was negatively regulated by miR-340 (P < 0.05 or P < 0.01). BAG3 silence significantly induced cell apoptosis (P < 0.001), and abolished miR-340 suppression-induced increase in cell viability (P < 0.001). Besides, BAG3 silence abolished miR-340 suppression-induced activation of PI3K and AKT. This study revealed the tumor suppressive role of miR-340 in SKOV3 cells by negative regulation of BAG3. PI3K/AKT pathway might be involved in the regulation of miR-340 and BAG3. PMID- 29441909 TI - The effect of continuous perfusion of esmolol on cardiovascular risk in elderly patients undergoing noncardiac surgery. AB - We evaluated the effect of continuous perfusion of esmolol on cardiovascular risk during curative laparoscopic surgery for gastrointestinal cancer in elderly patients. Sixty patients with gastrointestinal cancer, aged from 60 to 80 years, were divided into an esmolol group (ES, n = 30) and a control group (NS, n = 30). ES patients were treated with esmolol at a dose of 0.3 mg/kg 3 min before tracheal intubation, and received continuous perfusion of esmolol at a dose of 50 MUg/kg/min during operation. In NS, esmolol was replaced by saline. SBP/DBP, MAP, HR, SPO2, PETCO2, the depth of anesthesia and the value of RPP were recorded before anesthesia (T0), during intubation (T1), 10 min before pneumoperitoneum (T2), during pneumoperitoneum (T3), 30 min after incision (T4), at the end of surgery (T5), during extubation (T6) and 30 min after extubation (T7). The serum levels of cTnI, CK, CK-MB and LDH were measured before anesthesia, 6 and 30 h after surgery. HR, MAP, RPP at T1, T3, T6 in ES were obviously decreased compared with NS (P < 0.05). There were no significant differences between both groups at different time points with respects to the serum levels of cTnI, CK, CK-MB and LDH. No major adverse cardiocerebral event was observed in both groups in three postoperative months. The present study indicated that the application of esmolol during curative laparoscopic surgery for gastrointestinal cancer can effectively reduce the cardiovascular responses in intubation, operation and extubation, sustain hemodynamic stable, reduce myocardial oxygen consumption, and prevent perioperative adverse cardiovascular events, but had no significant myocardial protective effect. PMID- 29441910 TI - SOD activity and extremophilicity: a screening of various plant species. AB - All aerobes are dependent on enzymatic and non-enzymatic antioxidants to withstand the presence of reactive oxygen species (ROS). Superoxide dismutase (SOD) is a part of the enzymatic antioxidant system. It is one of the most important antioxidant enzymes, enabling organisms to survive in an oxygen containing atmosphere. A disorder in the oxidative and antioxidative balance can be associated with the occurrence of diseases in human organisms. Little data exist on the relevance of SOD in plants. Moreover, it is not known whether there is any association between a plant's origin and its SOD activity. Our screening of 27 different plant species was intended to expose whether there is a connection. The highest SOD activities were found for extremophile plants. Especially the Crassulaceae Aeonium haworthii Salm-Dyck Ex Webb & Berthel. and Crassula multiflora Schonland & Baker F. were highly active. Nevertheless, we did not find unambiguous evidence for a correlation between extremophilicity and SOD activity. PMID- 29441911 TI - Evaluation of the pharmacokinetic parameters of standard oral antibiotics in a bioequivalence study of generic products. AB - Pharmacokinetic parameters were summarized in clinical bioequivalence studies in Japan to confirm the validity for the use of parameters obtained from the clinical studies. Pharmacokinetic parameters, including maximum plasma/serum concentrations (Cmax), area under the plasma/serum drug concentration-time curve (AUC), time to achieve Cmax (Tmax), and half life (t1/2), of the standard products (original drugs) after oral administration of antimicrobials, including respiratory quinolones, cephalosporins, macrolides, and penicillin-based antibiotics were investigated by use of interview forms and/or package inserts from the generic products and the relationship among the pharmacokinetic parameters such as Cmax, AUC, Tmax, and t1/2 were estimated. In all the studies, the standard and generic products were administrated orally to healthy fasting subjects. Although there was more than a 1.5-fold difference in the Cmax and AUC0 24 h, but not in the Tmax and t1/2 values for levofloxacin tablets and cefacrol tablets, these parameters for other antibiotics were similar in various studies. The obtained results suggested that the parameters obtained from recent bioequivalence studies would be useful in identifying pharmacokinetic behavior of the original drugs, especially early time release; however, the pharmacokinetic results obtained from the recently conducted bioequivalence studies may be superior to those obtained from studies conducted in the past. PMID- 29441912 TI - Determination of gamithromycin in an injection by ultra-performance liquid chromatography-tandem quadrupole-time-of-flight mass spectrometry. AB - In this study, a sensitive and precise method was developed for the determination of gamithromycin in an injection using ultra-performance liquid chromatography tandem quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS) and the results were compared with a similar analysis for the ion fragments of gamithromycin in MS/ MS. The sample was dissolved in methanol then filtered and separated on a C18 column using acetonitrile-0.1% formic acid (containing 2 mmol/L ammonium acetate) as the mobile phase. The flow rate was 0.4 mL/min and the column temperature was 40 degrees C. The mass spectrometry conditions were electrospray ionization (ESI) operated in positive ion full scan mode and quantified using external calibration. Subsequently, ion fragments of the MS/MS were compared and analyzed. The linear range was 10 ~ 200 MUg/L with a correlation coefficient of 0.9992. The limit of detection (LOD) was 0.77 MUg/L and the limit of quantitation (LOQ) was 2.55 MUg/L. The average recoveries of the intra-assay were 98.8%-105.6% with a relative standard deviation ranging from 1.79% to 2.38% and the inter-assay were 89.3%-110.7% with a relative standard deviation ranging from 4.93% to 6.27%. After the comparative analysis of the fragments with a Molecular Structure Correlator, the score of the total matching degree reached 83.19 and the scores of each ion fragment matching degree were all greater than 90, which supplied the basis for the confirmation of gamithromycin. The results indicated that the method was simple, sensitive and precise and could be applied in the determination of gamithromycin in real samples. PMID- 29441913 TI - Stimulation of bone regeneration with pigment epithelium-derived factor microparticles: evidence in silico, in vitro and in vivo. AB - The occurrence of bone defects can be due to a variety of factors not limited to bone fractures and tumours. Most diseased bone is removed and the patient fitted with prosthetics, prior to use of certain factors such as bone morphogenetic proteins (BMPs) to aid healing. Recently, the protein pigment epithelium-derived factor (PEDF) and the polysaccharide chitosan have been found to have promising effects on the regeneration of bone, with the major advantage of these agents being their safety to date. A study was performed to determine whether the combination of both chitosan and PEDF would enhance greater bone regeneration effects. Post-formulation, in silico tests (particle sizing and surface charge determination) were followed by several cell-based assays (microparticle cellular uptake, cytotoxicity, mitochondrial abundance, bone mineral formation, colony formation in matrigel, and colony formation in collagen I matrix), and finally in vivo testing where microparticles were injected periosteally in the hindlimb. Collectively, these findings support the idea that PEDF microencapsulated within chitosan promotes bone regeneration, and has potential for bone trauma management. Future studies will examine the ability of this promising bone regeneration microparticle to heal bone in disease states such as fracture and tumour-mediated osteolysis. PMID- 29441914 TI - Effects of taurochenodeoxycholic acid on Ca2+/CaM signalling mediated by the TGR5 signalling pathway. AB - Taurochenodeoxycholic acid (TCDCA), a natural bioactive substance in animal bile, has anti-inflammatory and immunoregulatory effects. This study evaluates the effects of TCDCA on calcium/calmodulin (Ca2+/CaM) signalling mediated by G Protein Coupled Bile Acid Receptor 1 (TGR5) to provide preliminary information on the mechanism of TCDCA in immune regulation and also to benefit future research. After treatment of NR8383 and high TGR5 expression cell (TGR5-NR8383) with TCDCA (10-6 mol/L, 10-5 mol/L, and 10-4 mol/L) for 1 h, we measured TGR5 and CaM gene and protein levels by quantitative reverse transcription-polymerase chain reaction (qPCR) and western blotting, respectively. The inositol triphosphate (IP3) concentration was measured by Enzyme-linked Immunosorbent Assay (ELISA), and the Ca2+ concentration was measured by calcium fluorescent probe (Fluo-3 AM). The present study showed that the expression levels of IP3, Ca2+, and CaM in NR8383 cells were increased by TCDCA at concentrations ranging from 10-6 mol/L to 10-4 mol/L. TCDCA (10-4 mol/L) increased both the gene and protein expression of IP3and CaM through TGR5. TCDCA (10-4 mol/L or 10-5 mol/L) also increased the Ca2+ concentration via the TGR5 receptor. Our data suggest TCDCA activates Ca2+/CaM signalling via the TGR5 signalling pathway. PMID- 29441915 TI - Isoliquiritigenin protects against triptolide-induced hepatotoxicity in mice through Nrf2 activation. AB - Isoliquiritigenin, a flavonoid found in licorice, has been considered as an antioxidive and hepato-protective agent. Recent studies have shown that a possible mechanism for triptolide-induced hepatotoxicity is related to oxidative damage induced by reactive oxygen species. This study was done to investigate the protection effect of isoliquiritigenin against triptolide-induced hepatotoxicity and the mechanism involved. An acute liver injury model was established by intraperitoneal injection of triptolide (1.0 mg . kg-1) in mice. Different doses of isoliquiritigenin (12.5, 25 and 50 mg . kg-1) were employed as protection. The activities of AST, ALT, ALP and LDH in serum and levels of GSH, GPx, SOD, CAT and MDA in liver tissue were detected. The histopathological changes of liver tissues were observed after HE staining. The protein expression of Nrf2 was detected by western blot. Pretreatment with isoliquiritigenin significantly prevented the triptolide-induced hepatotoxicity indicated by reduced activities of AST, ALT, ALP and LDH. Moreover, isoliquiritigenin pretreatment also prevented from triptolide-induced hepatotoxicity by inhibiting MDA and restoring the levels of GSH, GPx, SOD and CAT. In addition, isoliquiritigenin could attenuate histopathological changes induced by triptolide. Furthermore, the results indicated that isoliquiritigenin pretreatment caused an increase in the protein expression of Nrf2. These results indicated that isoliquiritigenin could protect against triptolide-induced hepatotoxicity via activation of the Nrf2 pathway. PMID- 29441916 TI - Oleanolic acid derivatives inhibit the Wnt/beta-catenin signaling pathway by promoting the phosphorylation of beta-catenin in human SMMC-7721 cells. AB - Oleanolic acid, isolated from privet, has shown antitumor effects in several cancers. However, the underlying molecular mechanism associated with these effects is largely unknown. In this study, we explored the effect of oleanolic acid derivatives on the Wnt/beta-catenin signaling pathway in human hepatocellular carcinoma SMMC-7721 cells. The mRNA and protein levels of related genes were determined by real-time quantitative PCR and Western blot, respectively. Treatment of SMMC-7721 cells with oleanolic acid derivatives led to the downregulation of the mRNA and protein levels of beta-catenin, c-myc, and cyclin D1. Treatment with oleanolic acid derivatives decreased the levels of beta catenin in both the cytoplasm and the nucleus. Moreover, oleanolic acid derivatives promoted the phosphorylation of beta-catenin (Ser33/37/Thr41) in the cytoplasm. Our results suggest that oleanolic acid derivatives inhibit the Wnt/beta-catenin signaling pathway by stimulating the phosphorylation of beta catenin (Ser33/37/Thr41) in human SMMC-7721 cells. PMID- 29441917 TI - Analysis of the necessity of serum electrolyte monitoring for up to eight weeks after the completion of anti-epidermal growth factor receptor antibody administration. AB - Electrolyte disturbances are a known side effect of cetuximab (cmab) and panitumumab (pmab) administration and monitoring is recommended during and for at least 8 weeks after pmab administration. However, the recommended duration of electrolyte monitoring is not stated on the cmab package insert in the EU or Japan and no previous studies have investigated the appropriate monitoring period for cmab and pmab. We retrospectively investigated electrolyte levels in 16 cmab treated patients and 7 pmab-treated patients between 1 June 2009 and 31 December 2014. The mean minimum levels of serum magnesium, potassium, and calcium were analyzed in these patients before administration (baseline) and in period A (during administration), period B (time of the last administration), period C (from the completion of administration to 4 weeks after), and period D (from 4-8 weeks after administration). Hypokalemia persisted until period D in 1 cmab treated patient. Hypomagnesemia persisted until period D in two pmab-treated patients and hypokalemia persisted until period D in 1 pmab-treated patient. In addition, the serum magnesium levels in periods A, B, and C in the cmab-treated patients were significantly lower than the baseline level (P < 0.05). In pmabtreated patients, the serum magnesium levels in periods A, C, and D, and the serum calcium levels in periods A, B, and C were lower than the baseline levels (P < 0.05). These findings indicate that it is necessary to monitor electrolyte levels for at least 8 weeks after the completion of administration of cmab or pmab. PMID- 29441918 TI - Ligustrazine attenuates neuropathic pain by inhibition of JAK/STAT3 pathway in a rat model of chronic constriction injury. AB - AIM: Neuropathic pain is a common clinical complication of nerve injury, and the effective treatment of neuropathic pain is still challenging. Ligustrazine is mainly used for the treatment of cardiovascular disease and its role in neuropathic pain is less investigated. The purpose of our study was to explore the effects of ligustrazine on neuropathic pain, as well as the underlying molecular mechanism. METHODS: Neuropathic pain was induced by chronic constriction injury (CCI) of the right sciatic nerve in Sprague-Dawley (SD) rats. After CCI, rats received ligustrazine, IL-6, or both. Mechanical withdrawal threshold (MWT) and paw withdrawal thermal latency (PWTL) were assessed on days 1, 3, 7, and 14 after surgery. Expression levels of tumor necrosis factor (TNF) alpha, interleukin (IL)-beta, IL-2, and phosphorylation of Signal Transducer and Activator of Transcription (STAT) 3 were analyzed. RESULTS: Our results showed that both MWT and PWTL were significantly decreased by CCI on days 1, 3, 7 and 14 compared to sham group, however, ligustrazine reversed this effects. Additionally, the elevated levels of TNF-alpha, IL-1beta, and IL-2 in CCI spinal cord were inhibited by ligustrazine. Quantitative real-time (qRT-PCR) and Western blotting analysis showed that the test substance reduced the elevated expression of pSTAT3 in the spinal cord induced by CCI, and while IL-6 administration reversed the levels as well as the behavior responses. CONCLUSION: Our results suggest that ligustrazine could effectively attenuate neuropathic pain by inhibition of Janus Kinase (JAK)/STAT3 pathway in CCI rats. PMID- 29441919 TI - Contribution of ginsenoside Re to cellular redox homeostasis via upregulating glutathione and superoxide dismutase in HaCaT keratinocytes under normal conditions. AB - Ginsenoside Re (Re) is one of the main ginsenosides which are known to be responsible for diverse pharmacological properties of ginseng, widely used as a dietary supplement and a general tonic. The present work was undertaken to evaluate the antioxidative property of Re by analyzing reactive oxygen species (ROS), nitric oxide (NO), pro-matrix metalloproteinase-2 (proMMP-2) and -9 (proMMP-9), total glutathione (GSH) and superoxide dismutase (SOD) in normal, unstressed HaCaT keratinocytes. When HaCaT cells were subjected to Re, Re suppressed the ROS and NO levels in a concentration-dependent manner. Re at concentrations used exhibited no cytotoxicity on the cellular viabilities of HaCaT cells. It was also able to attenuate proMMP-2 and -9 at both activity and protein levels. On the contrary, Re was capable of enhancing the total GSH and SOD activity levels. The findings suggest that Re has an antioxidative property through the upregulation of some antioxidant components, including total GSH and SOD, in HaCaT keratinocytes, which then can play its underlying role in maintaining the cellular redox homeostasis. PMID- 29441920 TI - Pancreatic lipase and alpha-amylase inhibitory activities of plants used in Traditional Chinese Medicine (TCM). AB - To find new, plant based drugs for the treatment of obesity and/or diabetes mellitus type 2 through the inhibition of essential digestive enzymes, in vitro tests were carried out on selected plants or fungi with weight-reducing, blood glucose-reducing or related potential, used in Traditional Chinese Medicine (TCM). Aqueous and methanolic extracts of 32 Chinese herbal medicines were assayed for their in vitro inhibitory activity against pancreatic lipase (PL) and alpha-amylase (PA). PL activity was measured by using an enzymatic in vitro assay based on the hydrolysis kinetics of an oleate ester of 4-methylumbelliferone. For the determination of alpha-amylase activity an enzyme assay based on the hydrolytic cleavage of a modified starch derivative was used. Our findings have shown that the methanolic extract of Lycopus lucidus Turcz. var. hirtus Regel (Lamiaceae) was a very effective PL inhibitor (IC50: 88.3+/-4.1 MUg/mL). A high anti-amylase activity showed the methanolic extract of Trichosanthes kirilowii Maxim. (Curcurbitaceae, IC50: 248.8+/-67.3 MUg/mL). This work provides a priority list of interesting plants for further study with respect to the treatment of obesity and associated metabolic diseases. PMID- 29441921 TI - Gpnmb/osteoactivin: an indicator and therapeutic target in tumor and nontumorous lesions. AB - Non-metastatic melanoma glycoprotein B (Gpnmb), a type I transmembrane glycoprotein, was first cloned and described in low-metastatic human melanoma and xenografts in 1995. Up to now a growing number of studies have confirmed that Gpnmb is expressed not only in numerous normal tissues but also at pathological sites and malignant tissues and often connected with the invasive and metastatic phenotypes, including breast cancer. Nowadays, immunotherapeutic approaches for cancer therapy, by which monoclonal antibodies (Mabs) target tumor specific antigens, have shown great potential. Glembatumumabvedotin, also called CR011 vcMMAE, is a Mab-drug conjugate which was developed for the treatment of Gpnmb expressing cancers. Several phase I/II studies have confirmed the safety and activity of glembatumumabvedotin in patients with advanced/metastatic breast cancer and unresectable cutaneous melanoma. Moreover, increasing numbers of studies have supported the potential roles of targeting Gpnmb with glembatumumabvedotin in patients with recurrent osteosarcoma, uveal melanoma, ALS, Gaucher disease, pancreatic ductal adenocarcinoma etc. This review will summarize the latest understanding of Gpnmb in the aspects of diagnosis, progression and prognosis of pathological disorders and neoplasms, emphasizing the clinical advances in targeting Gpnmb-expressing malignancies. PMID- 29441922 TI - The impact of CYP3A5 on the metabolism of cyclosporine A and tacrolimus in the evaluation of efficiency and safety of immunosuppressive treatment in patients after kidney transplantation. AB - The aim of the study was to determine the impact of CYP3A5 mutation on the serum levels of immunosuppressive drugs (tacrolimus and cyclosporine A), and on the occurrence of acute rejection episodes among patients after kidney transplantation. A limited number of such research in Polish patients was also an important factor encouraging to perform the study. Fifty-two persons were recruited. The tested patients underwent kidney transplantation and were treated either with cyclosporine A (17 persons) or with tacrolimus (35 persons). The group included 21 women and 31 men. DNA was isolated from whole blood and a modified Van Schaik et al. (2002) PCR-RFLP method was used for genotyping. The serum levels were controlled at the 7th, 14th, 30th, 90th, 180th and 360th day after transplantation. The CYP3A5 genotype had no impact on the concentrations of cyclosporine A and tacrolimus at any investigated time point. No correlation between the rate of acute rejection episodes and different genotypes of the CYP3A5 isoenzyme could be proven. PMID- 29441923 TI - Randomised, double blind, cross-over, placebo and active controlled human pharmacodynamic study on the influence of silver fir wood extract (Belinal) on post-prandial glycemic response. AB - The aim of this study was to test the extract from silver fir wood (Belinal) on the reduction of the blood glucose concentrations after consumption of a standard meal. 31 healthy participants consumed 100 g of white bread 4 times (with 1 week washout period, consequently) concomitantly with a capsule of Belinal, capsule of chestnut wood extract, placebo or acarbose (active control). Glucose and insulin in the blood were measured before and after the meal. The area under the curve of glucose concentration in blood after the meal was 35 % lower when Belinal was added compared with the placebo group (p = 0.019). Acarbose lowered the area for 43 % (p = 0.002). By this, we proved that the effect of Belinal might be beneficial for prevention of diabetes. This is the first study that provides a scientific rationale for use of silver fir wood extract as food supplement for reduction of health risks connected to type 2 diabetes mellitus. PMID- 29441924 TI - Sildenafil improves the function of endothelial cells in patients suffering from congenital heart disease with pulmonary hypertension. AB - Aim of this study was to investigate the potential effects of sildenafil on the function of endothelial cells from patients with congenital heart disease with pulmonary hypertension (CHDPH). Patients who are diagnosed as CHD with PH (n=30) or without PH (n=30), and 30 healthy persons (control) were enrolled in this study. The 30 CHDPH cases were separated into two groups, one was given aspirin while the other received aspirin and sildenafil. An ELISA assay was used to detect the biological indexes for endothelial cells. Furthermore, 24 male New Zealand white rabbits were used to construct the CHDPH model. The signal pathway related protein expression was analyzed using RT-PCR and western blotting. Compared to that in healthy people, levels for flowmediated dilatation (FDM), NO, and adiponectin (APN) were significantly decreased while endothelin (ET-1) was significantly increased in CHD patients, while their levels were drastically changed in CHDPH patients (P<0.01). Besides, no significant differences for expression levels including FDM, APN, NO, and ET-1 was observed in CHDPH patients receiving aspirin. But the levels for FDM, APN, NO, and ET-1 were significantly changed in CHDPH patients after treatment with sildenafil for 3 months (P<0.01). The mRNA and protein levels for JNK1/2, MAPK, and NF-kappaB were significantly increased in CHDPH rabbits compared to the control (P<0.01), but their levels were significantly suppressed by the sildenafil application compared to the CHDPH group (P<0.01). Taken together, our study suggested that sildenafil may play a protective role on endothelial function via suppressing the JNK and NF-kappaB signal pathways in CHDPH patients. PMID- 29441925 TI - Anti-neuroinflammation activity of acetylpuerarin mediated by a PKC-delta dependent caspase signaling pathway: in vivo and in vitro studies. AB - OBJECTIVE: This study was performed to evaluate the regulating effects of acetylpuerarin on inflammation in an Alzheimer's disease (AD) rat model and an inflammatory cell model. METHODS: Healthy female Wistar rats and mouse BV2 microglia cells were selected. AD rat models were established with the method of bilateral intrahippocampal amyloid-beta(Abeta)1-42 injections and the inflammatory cell models were established using Abeta25-35-induced mouse BV2 microglia cells. The cytotoxicity of acetylpuerarin on BV2 microglial cells was detected by MTT assay and the morphological changes of BV2 microglia cells were observed under inverted phase contrast microscope. As inflammatory parameters, the expressions of IL-1beta, iNOS, IL-6 and TNF-alpha were examined by Elisa, Immunohistochemistry, Quantitative real-time PCR (qRT-PCR), Western blot and Immunofluorescence analyses. We also examined the acetylpuerarin's effect on the activity of PKC-delta, IKKbeta and caspase-8/caspase-3 pathway. RESULTS: Acetylpuerarin exerted no significant cytotoxicity on BV2 microglia cells and was applied in all subsequent experiments. Acetylpuerarin treatment mitigated Abeta25 35-induced morphological changes associated with microglia activation. Moreover, the expressions of caspase-8, cleaved caspase-3, PKC-delta, IKKbeta, iNOS, IL 1beta and TNF-alpha in Abeta25-35-stimulated BV2 microglia cells were significantly suppressed by acetylpuerarin and in a dose-dependent manner. Additionally, the expression of IL-1beta in hippocampus and the level of IL-6 in serum of Abeta1-42 treated rat were reduced by acetylpuerarin and in a concentration-dependent manner. CONCLUSION: Our results suggest that acetylpuerarin's anti-inflammation mechanism on AD may be mediated through the PKC-delta-dependent caspase signalling pathway. PMID- 29441927 TI - Ginkgolide A inhibits lipopolysaccharide-induced inflammatory response in human coronary artery endothelial cells via downregulation of TLR4-NF-kappaB signaling through PI3K/Akt pathway. AB - Ginkgolide A (GA) is a one of the active components of Ginkgo biloba. We aimed to detect the effects GA on the lipopolysaccharide (LPS)-induced inflammatory response in human coronary artery endothelial cells (HCAECs) and whether the effects are associated with the inhibition of toll-like receptor 4 (TLR4)-NF kappaB signaling through PI3K/Akt pathway. HCAECs were stimulated with LPS and treated with GA or TLR4 inhibitor CLI-095. A PI3K/Akt inhibitor LY294002 was used to block the PI3K/Akt pathway. The toxic effects of GA, LPS and LY294002 on HCAEC were evaluated using MTT assay. Levels inflammatory mediators, TLR4 mRNA, NF kappaB signaling activity were valuated. We found LPS stimulation significantly increased the release of IL-6, IL-8, MCP-1 and TNF-alpha from HCAECs, elevated the TLR4 mRNA expression and activated the NF-kappaB signaling. GA and CLI-095 abolished the LPS-induced inflammatory mediator release and NF-kappaB signaling activation, and GA reduced the TLR4 mRNA expression without affecting cell viability. However, PI3K/Akt blocking abolished the effects of GA on HCAECs. We conclude that GA could attenuate the LPS-induced inflammatory response in HCAECs and the anti-inflammatory activity might be associated with the inhibition of TLR4-NF-kappaB signaling through PI3K/AKT pathway. These findings suggest a therapeutic potential of GA in endothelial inflammation. PMID- 29441926 TI - TAK-242 suppresses lipopolysaccharide-induced inflammation in human coronary artery endothelial cells. AB - TAK-242 (resatorvid), a novel small-molecule cyclohexene derivative, inhibits TLR4 signaling selectively. TAK-242 blocked the Toll-like receptor (TLR) 4 triggered inflammatory signaling by binding directly to a specific amino acid Cys747 in the intracellular domain of TLR4. The present study was designed to examine the effects of TAK-242 on vascular inflammatory responses in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS, a TLR4 ligand). The results show that TAK-242 attenuated the LPS-induced expression of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein 1 both at the transcription and translation levels in HCAECs. LPS-induced endothelial cell adhesion molecules, intercellular adhesion molecular-1 and vascular cell adhesion molecule-1 expressions were also reduced by treatment with TAK-242. In addition, coincubation with TAK-242 did not effect the expression of TLR4 in LPS-activated HCAECs. Furthermore, TAK-242 efficiently suppressed LPS induced phosphorylation of nuclear factor kappaB (NF-kappaB) and IL-1 associated kinase-1 (IRAK-1) in HCAECs. These findings show that TAK-242 can suppress endothelial cell inflammation, suggesting that TAK-242 might be suitable for development as a therapeutic agent for inflammatory cardiovascular disease. PMID- 29441928 TI - Interleukin 6 induces expression of NADPH oxidase 2 in human aortic endothelial cells via long noncoding RNA MALAT1. AB - Human abdominal aortic aneurysm (AAA) is characterized by the induction of intracellular and extracellular inflammatory cytokines and the production of reactive oxygen species (ROS) associated with localized inflammatory responses in the vascular wall. Recent studies have shown that greater circulating levels of the proinflammatory cytokine interleukin-6 (IL-6) are closely associated with AAA presence, suggesting that IL-6 plays an important role in the development of AAA. Previous in vivo studies have indicated that excess activities of NADPH oxidase (NOX), a major oxidase system for ROS production, promote AAA development. Furthermore, long noncoding RNAs (lncRNAs) are involved in the development of AAA. LncRNA MALAT1 has been found closely involved in endothelial cell functions and dysfunctions. In the present study, we explored the effects and the underlying mechanisms of IL-6 and MALAT1 on the expression/activity of NOXs in human aortic endothelial cells (HAOECs). Primary HAOECs with or without overexpression or knockdown of MALTA1 were cultured in the presence of IL-6. We found that IL-6 concentration- and time-dependently elevated the NOX activity as well as the MALAT1 level in HAOECs. Among different NOXs, only NOX2 was induced by IL-6. Overexpression and knockdown of MALAT1 respectively augmented and abolished IL6-induced expression of NOX2, NOX activity/cellular ROS production, and activation of the human NOX2 gene promoter, whereas MALAT1 alone in the absence of IL-6 treatment showed no significant effect. Knockdown of extracellular signal-regulated kinase (ERK) abolished IL6-induced expression of MALAT1. In conclusion, this study provides the first evidence that IL-6 induces expression/activity of NOX2 in HAOECs via inducing MALAT1 by an ERK-dependent mechanism. It adds new insights into the molecular mechanisms underlying AAA development. PMID- 29441929 TI - Knockdown of long noncoding RNA urothelial cancer-associated 1 enhances cisplatin chemosensitivity in tongue squamous cell carcinoma cells. AB - Cisplatin-based chemotherapy has been found to improve the prognosis of patients with tongue squamous cell carcinoma (TSCC), the most common oral cancer with a poor prognosis. Chemoresistance to cisplatin appears to be an important clinical problem for cisplatin-based TSCC chemotherapy. Long noncoding RNAs (lncRNAs) play important roles in regulating tumor cells' sensitivity to chemotherapeutic agents. A recent study has shown that the expression of lncRNA UCA1 is significantly enhanced in TSCCs, suggesting that UCA1 may play a role in TSCC progression. In the present study, we explored the effects and the underlying mechanisms of UCA1 on cisplatin chemosensitivity/chemoresistance and apoptosis in TSCC cells. Transient transfection of siRNA was used to knock down UCA1 in human TSCC cell lines CAL 27 and SCC-9, where UCA1 was highly overexpressed compared to normal human tongue tissues. Knockdown of UCA1 markedly increased cisplatin induced caspase 3 activity and apoptosis in CAL 27 and SCC-9 cells. On the other hand, it decreased cisplatin-induced phosphatidylinositol 3-kinase (PI3K) activity and activation phosphorylation of Akt. UCA1 knockdown resulted in one magnitude decrease in the half maximal inhibitory concentration (IC50) of cisplatin in CAL 27 and SCC-9 cells, from 8.9 mM and 20.7 mM down to 0.6 mM and 1.7 mM, respectively. In conclusion, this study has shown that UCA1 knockdown markedly increased cisplatin-induced apoptosis and chemosensitivity in TSCC cells, likely through inhibiting cisplatin-activated PI3K/Akt signaling. It provides new insights into the functional role of UCA1 in cancer cells and suggests that UCA1 knockdown could be a new strategy to increase cisplatin chemosensitivity and thereby improve the therapeutic outcomes of cisplatin-based chemotherapy for TSCC. PMID- 29441930 TI - MiR-873-5P controls gastric cancer progression by targeting hedgehog-GLI signaling. AB - Gastric cancer is one of the most common human malignancies. Thus, it is important to explore the specific mechanism in which gastric cancer is induced. The level of miR-873-5p was determined using real time PCR. The expression of Gli1 was determined using western blot and immunohistochemistry. A specific siRNA targeting Gli1 was selected. The role of Gli1 and miR-873-5p on gastric cancer cell viability, apoptosis and cell cycle was determined using MTT assay and flow cytometry, respectively. The 3'untranslated region (3'UTR) of Gli1 was cloned into the pmirGLO plasmid. Dual luciferase reporter assay was applied to determine the target gene of miR-873-5p. The expression of miR-873-5p was decreased in gastric cancer, while the expression of Gli1 was significantly enhanced. Overexpression of miR-873-5P decreased cell viability, increased cell apoptosis and cell cycle arrest. Meanwhile, knockdown of Gli1 obviously induced SGC-7901 cell apoptosis and cell cycle arrest. Dual luciferase reporter assay showed that Gli1 was the target gene of miR-873-5p. More importantly, inhibition of miR-873 5p obviously decreased the protein expression of CyclinB1 and Bcl2 even in cells transfected with si-Gli1. To conclude, MiR-873-5p functions as a tumor suppressor in gastric cancer mainly by targeting Gli1. PMID- 29441931 TI - Calycosin attenuates osteoporosis and regulates the expression of OPG/RANKL in ovariectomized rats via MAPK signaling. AB - We aimed at exploring the effect of calycosin (CA) on osteoporosis in ovariectomized (OVX) rats. Sprague-Dawley (SD) rats were divided into five groups: Sham group, OVX group, OVX group treated with estradiol valerate (EV), CAL group treated with 15 mg/kg/d of CA and CAH group treated with 30 mg/kg/d of CA for 12 weeks. Bone mineral density (BMD), histopathology, body weight, parameters in serum and urine were observed. Gene expression and protein level of OPG/RANKL were also studied by real-time PCR and western blot, respectively. We further identified the effect of CA on mitogen-activated protein kinase (MAPK) signaling. In comparison with OVX rats, CAL and CAH significantly increased the BMD by 8.3% and 19.0%. Treatment with CA notably inhibited the excretion of Ca, P and Cr. CAH also significantly increased the level of alkaline phosphatase (ALP) and decreased the level of tartrate-resistant acid phosphatase (TRAP) in serum of OVX rats. CA could improve the trabecular bone area, and increased the trabecular number and the trabecular connection after 12-week. CA also increased the expression of osteoprotegerin (OPG) and decreased the Receptor Activator for Nuclear Factor-kappaB Ligand (RANKL) mRNA expression compared with the OVX rats. In addition, CA could effectively decrease the phosphorylation of MAPKs induced by ovariectomy. In conclusion, CA had remarkable antiosteoporotic activity and therefore can be a promising candidate for the treatment of postmenopausal osteoporosis. PMID- 29441932 TI - Translation and psychometric evaluation of the Turkish version of the pharmacy students' perceptions of preparedness to provide pharmaceutical care scale. AB - The aim of the study is to conduct the psychometric evaluation of the Turkish version of the Pharmacy Students' Perceptions of Preparedness to Provide Pharmaceutical Care (PREP) scale. The present study was conducted at three faculties of pharmacy among fifth-year students during a three-month period in 2015. After the translation process, the Turkish version was developed. Psychometric evaluation consisted of the calculation of inter-rater and test retest reliability and factor analysis. The mean age of 184 students (71.2% of female) was 23.74+/-1.07. The mean score of the Pharmacy Students' PREP scale was 4.54+/-1.00 and the Cronbach's alpha was 0.971. Inter-rater and test-retest reliability and factor analysis were also in concordance with the literature. In the present study, the Turkish version of Pharmacy Students' Perceptions of Preparedness to Provide Pharmaceutical Care Scale has been determined to be a reliable and validated tool to assess students' perceptions of preparedness to provide pharmaceutical care. PMID- 29441933 TI - Synthesis, chemical behavior, structure elucidation and iNOS inhibitory activity of 1-substituted 3-methylsulfanyl-5,6,7,8-tetrahydro-1H-[1,2,4]triazolo[1,2 a]pyridazines. AB - Novel slim and shapely sp3-rich nitrogen containing heterocyclic ring systems are sought-after platforms for the expansion of molecular diversity in lead discovery. The present work describes the synthesis and characterization of a series of derivatives of hitherto unknown 3-methylsulfanyl-5,6,7,8-tetrahydro-1H [1,2,4]triazolo[1,2-a]pyridazines 2. This approach was guided by a computational study, aiming at an optimization of previously reported [1,2,4]triazolo[1,2 a]pyridazine-1-thiones 1 known to inhibit the inducible nitric oxide synthase (iNOS). The title compounds are accessible by methylation of compounds 1 under mild conditions. The products were biologically evaluated by the same cell-based assay as applied for previous products of type 1 using RINm5F cells, which were stimulated to produce NO on the influence of proinflammatory cytokines IL-1beta and IFN-gamma. Compounds 2 did not display the anticipated improved iNOS inhibitory activity in the selected assay but contribute to SAR in the field. In addition, an unprecedented formation of side-products 3 via oxidation has been investigated. The novel scaffolds represent attractive starting points for the construction of diverse molecules which differ considerably from known compounds based on flat and lipophilic aromatic scaffolds. PMID- 29441934 TI - Implants composed of digoxin and poly(epsilon-caprolactone): development, characterization, anti-proliferative and anti-angiogenic activities. AB - Drug delivery systems could be applied to locally treat cervical cancer, thus preventing the drawbacks of conventional therapy. In this study, anti proliferative and anti-angiogenic effects of digoxin incorporated into poly(epsilon-caprolactone) implants were evaluated, aiming at the local treatment of cervical cancer. Implants were characterized, and the in vitro release profile of digoxin was demonstrated. Anti-proliferative and anti-angiogenic activities of digoxin were investigated by using chorioallantoic membrane and human cervix carcinoma (HeLa) cells, respectively. The chemical structure of digoxin and the semi-crystalline nature of poly(epsilon-caprolactone) were preserved after designing implants. The hydrophobicity of drug and polymer as well as the semi crystalline structure provided a controlled diffusion of digoxin from implants. Digoxin released from implantable devices exhibited anti-proliferative activity against HeLa cells. The anti-angiogenic effect was also shown. Finally, implants composed of digoxin and poly(epsilon-caprolactone) could be applied as a therapeutic alternative to treat the early stage of cervical cancer, once they were able to locally control the release of this anti-angiogenic and anti proliferative drug, minimizing its systemic side effects and toxicity. PMID- 29441935 TI - Preparation and evaluation of furosemide containing orally disintegrating tablets by direct compression. AB - The purpose of this research was to develop and prepare orally disintegrating tablets (ODTs) containing furosemide by direct compression method. Furosemide, microcrystalline cellulose (MCC), low-substituted hydroxypropylcellulose LH-11 (L HPC), aspartame, sodium stearyl fumarate were used for ODT formulation. MCC and L HPC were used in ratios of 1:9 (ODT1) and 1:4 (ODT2). The results of the quality control parameters obtained for bulk powders (angle of repose, compressibility index, Hausner ratio, bulk density and volume, apparent density and volume, swelling of superdisintegrants and powder moisture) were taken as an indication of good compressibility of tablets. Both ODT1 and ODT2 disintegrated within 15 s and fulfilled the required disintegration time given by the European Pharmacopoeia (3 min). The average weight variation was less than 5% for both tablets. The friability of the tablets was less than 1%. Wetting time of both tablets was in the range of 12-21.7 s. Water absorption ratio was 1.41+/-0.03 for ODT1 and 1.96+/-0.10 for ODT2. Dissolution studies revealed that more than 85% of furosemide was dissolved in 15 min from both ODTs. Based on cell culture studies, permeability of furosemide was low (Papp=1x10-5 cm/s) but increased when prepared in the ODT form (ODT1: Papp=2x10-5 cm/s; ODT2: Papp=3.6x10-5 cm/s). Collectively, all these results showed that ODT formulations of furosemide were developed successfully. To improve patient compliance, ODT approach can be suggested for development and manufacturing of furosemide ODTs. PMID- 29441936 TI - Long non-coding RNA SNHG1 promotes cell proliferation and tumorigenesis in colorectal cancer via Wnt/beta-catenin signaling. AB - Nucleolar RNA Host Gene 1 (SNHG1) is responsible for initiation, progression, and metastasis of various cancers. However, the role and molecular mechanism of SNHG1 is poorly understood in colorectal cancer. Here we discovered that SNHG1 is high expressed in colorectal cancer cells. We find that SNHG1 knockdown inhibits cell proliferation and induces apoptosis in colorectal cancer. Moreover, SNHG1 can promote the expression of target genes, and SNHG1 expression is positively correlated with WNT expression. Thus, SNHG1 regulates colorectal cancer by Wnt/beta-catenin signaling pathway. Our study provides strong evidence that SNHG1 may significantly be associated with the development and progression of colorectal cancer. PMID- 29441937 TI - Antisense lncRNA As-SLC7A11 suppresses epithelial ovarian cancer progression mainly by targeting SLC7A11. AB - Antisense lncRNAs play a key role in the progression of multiple cancers. Thus, it is important to elucidate the function and mechanism of antisense lncRNAs, which may play a role in the treatment of epithelial ovarian cancer (EOC). In the current study, for the first time, we showed that the level of As-SLC7A11 was markedly reduced in EOC cancer tissues and cell lines compared with those of normal control. Further study showed that silencing of As-SLC7A11 could enhance ovarian cancer cell migration. In comparison, overexpression of As-SLC7A11 markedly induced ovarian cancer cell apoptosis. These data demonstrate the tumor suppressor role of As-SLC7A11 in ovarian cancer malignancies. We also demonstrated that overexpression of As-SLC7A11 could significantly suppress the expression of SLC7A11, indicating a negative correlation between As-SLC7A11 and SLC7A11 in ovarian cancer cells. In summary, we first showed that reduction of As SLC7A11 level prompted ovarian cancer cell migration mainly by suppressing the expression of SLC7A11. PMID- 29441938 TI - UBR5 promotes cell proliferation and inhibits apoptosis in colon cancer by destablizing P21. AB - UBR5 is recently recognized as a key player in a large number of prevalent cancers. In this study, we sought to explore the connection of UBR5 expression with cell proliferation, apoptosis, as well as the regulation mechanism in colon cancer cell line. SiUBR5 or oeUBR5 were separately applied to interfere the expression of UBR5. Western blot, DNA gel electrophoresis and qPCR were performed to detect the expression of UBR5 at mRNA and protein level. Then MTT and flow cytometry were used to explore the proliferation and apoptosis in a colon cancer cell line in vitro. Finally, we explored the interaction and correlation of UBR5 and P21 in the colon cancer regulation. We found that UBR5 was highly expressed in colon cancer not only at mRNA level but also at protein level. Moreover, UBR5 can promote the growth of colon cancer cells, and inhibit apoptosis. The mechanism exploration proved that UBR5 can degrade P21 via ubiquitination. All these findings suggest that UBR5 may be involved in progression of colon cancer and could be a new therapeutic target for this disease. PMID- 29441939 TI - p63 protects chondrosarcoma malignancies mainly by enhancing the expression of PTEN. AB - Abnormal expression of p63 has been well identified in multiple malignancies. However, little study has been done on the association between p63 and chondro sarcoma. In the current study, we mainly explored the expression of p63 in different grades of chondrosarcoma. Our data showed that p63 was significantly decreased in grade II and III chondrosarcoma compared with that of grade I chondrosarcoma and normal control. As the characteristic of grade II and III chondrosarcoma is metastasis, we then searched the function of p63 chondrosarcoma. In vitro study showed that overexpression of p63 significantly suppressed chondrosarcoma cell viability, migration and invasion. Meanwhile, upregualtion of p63 induced chondrosarcoma cell apoptosis. Furthermore, we showed that overexpression of p63 could significantly increase the protein expression of PTEN. In contrast, silencing of PTEN markedly reduced the protein levels of Bax, and enhanced the expression of PCNA and p27, even in cells transfected with p p63. These data showed that p63 was a tumor suppressor mainly through regulating PTEN in chondrosarcoma cells. In summary, reduction of p63 in grade II and III chondrosarcoma enhances the malignant phenotype mainly through modulating the expression of PTEN. PMID- 29441940 TI - IL-1beta-mediated NF-kappaB signaling augments the osteosarcoma cell growth through modulating miR-376c/TGFA axis. AB - Overexpression of IL-1beta, one of the most well-known pro-inflammatory cytokines, is related to a plenty of diseases including cancer. Diversion of microRNAs exposed to pro-inflammatory cytokines have been noted in cancer cells, however, their functions in inflammation stress are still to be further studied. In our previous study, we reported that miR-376c inhibited the growth of osteosarcoma (OS) cells by targeting TGFA. Here, we revealed that miR-376c was downregulated in OS tissues and cells while IL-1beta, NF-kappaB and TGFA were upregulated in OS tissues and cells. IL-1beta or NF-kappaB could promote the OS cells growth through inducing miR-376c expression and decreasing TGFA protein levels. Furthermore, forced expression of miR-376c restored the suppression of IL 1beta on the OS cells. A decrease in miR-376c and an increase in TGFA depended on IL-1beta-induced NF-kappaB protein level, which attenuates miR-376c expression upon IL-1beta reduction. Taken together, our findings indicated that IL-1beta augmented miR-376c-reduction to promote OS cell growth via upregulating NF-kappaB levels. Knock-down NF-kappaB suppressed the expression of TGFA. Enhanced TGFA upon IL-1beta induction was attenuated by NF-kappaB inhibition. Hence, the regulation of IL-1beta/NF-kappaB/miR-376c/TGFA signaling in OS might present a promising strategy for the treatment of OS. PMID- 29441941 TI - ATP binding cassette subfamily A member 7 rs3764650 polymorphism and the risk of Alzheimer's disease. AB - We did a meta-analysis to assess the association between ABCA7 rs3764650 polymorphism and the risk of Alzheimer's Disease (AD). A total of 10 eligible studies with 20511 patients and 40503 controls met the inclusion criteria. ABCA7 rs3764650 polymorphism was significantly associated with AD risk (OR=1.21, 95% CI 1.16-1.26, P<0.00001; I2=5%). In the subgroup analysis by race, statistically significant associations were found in Asians (OR=1.09, 95% CI 1.01-1.18, P =0.03; I2=0%) and in Caucasians (OR=1.25, 95% CI 1.19-1.31, P<0.00001; I2=0%). In conclusion, this meta-analysis suggested that ABCA7 rs3764650 polymorphism is significantly associated with AD risk. PMID- 29441942 TI - Risk factors for the failure of treatment of Pseudomonas aeruginosa bacteremia in critically ill patients. AB - Pseudomonas aeruginosa bacteremia is associated with high morbidity and mortality in critically ill patients. In this study, we assessed risk factors for clinical failure of first definitive therapy for P. aeruginosa bacteremia in critically ill patients. All patients with P. aeruginosa bacteremia who entered the intensive care unit in Gifu University Hospital from January 2006 to December 2015 were retrospectively identified from electronic records. Risk factors associated with clinical failure of the first definitive therapy for P. aeruginosa bacteremia were analyzed by logistic regression analysis. A total of 28 patients were enrolled in the analysis. On multivariate analysis, severe burns (odds ratio [OR] = 70.9, 95% CI 2.9-1720.3; p = 0.009) and SOFA score >= 10 (OR = 28.5, 95% CI 1.1-754.3; p = 0.045) were significant factors in the clinical failure of first definitive therapy for P. aeruginosa bacteremia. The clinical success rate of first definitive therapy was significantly reduced in patients with these risk factors compared with those without them (p < 0.001). Severe burns and a SOFA score (>= 10) were significant risk factors associated with the clinical failure of first definitive therapy for P. aeruginosa bacteremia in critically ill patients. We therefore recommend the use of therapeutic drug monitoring to optimize antibiotic dosing in these critically ill patients. PMID- 29441943 TI - Effect of surface charge, particle size, and modification by polyethylene glycol of liposomes on their association with Caco-2 cells across an unstirred water layer. AB - For the development of orally available liposomes, understanding the interaction of liposomes with the intestinal mucosa is important. An unstirred water layer (UWL) on the intestinal epithelium surface is a considerable permeability barrier for lipophilic drugs. Therefore, the effects of an UWL on liposome transport across intestinal epithelial cells must be elucidated. We evaluated the effects of the surface charge, particle size, and polyethylene glycol (PEG) modification of liposomes on their association with Caco-2 cells across an UWL. When the association of cationic liposomes with Caco-2 cells was evaluated under a reduction in UWL thickness by shaking, the uptake and/or amount of surface-bound cationic liposomes in cells was increased significantly in a shaking rate dependent manner. The uptake and/or amount of surface-bound neutral liposomes were increased only at the highest shaking rate. No significant differences in the cellular association of anionic liposomes and PEG-modified liposomes were observed with or without shaking. The association of large liposomes with Caco-2 cells was affected considerably by an UWL compared with that of small liposomes. These results suggest that an UWL affects the surface binding and subsequent uptake of liposomes in Caco-2 cells according to their particle size, surface charge, and PEG modification. PMID- 29441945 TI - Biocompatibility investigation of different pharmaceutical excipients used in liquid dosage forms. AB - Aqueous pharmaceutical solutions provide prosperous living conditions for microbiological agents. In order to eliminate these microbes, we use preservatives which can harm human cells as well. Their cytotoxicity is concentration-dependent and the aim of our study was to find how other pharmaceutical excipients modify the cytotoxic attributes of preservatives. We tested the following compounds: methylparaben, benzalkonium chloride, polysorbate 20, Labrasol(r) and hydroxyethyl cellulose. The MTT tests indicated that surfactants increase the cytotoxicity while polymers may decrease it in some cases. PMID- 29441944 TI - Nonionic microemulsions for oral and transdermal delivery of gentamicin. AB - Gentamicin sulfate (GS) is used usually as intravenous or intramuscular solution because of its poor oral bioavailability. However, the intravenous administration is associated with pain and needs some skills. In this study, five nonionic microemulsions (MEs) for oral and transdermal application were developed using nonionic surfactants. The MEs were characterized for their droplets sizes and rheological properties. Moreover, GS encapsulation in the MEs was studied using Fourier Transform Infrared Spectroscopy (FTIR). The transdermal release was evaluated through rat's skin using Franz diffusion cell. Furthermore, one of these formulations was chosen for oral bioavailability studies in rats in comparison to an aqueous solution of GS. These MEs complied with the colloidal properties. Also, FTIR was used successfully to prove the encapsulation of GS and alignment of the surrounding surfactants in the MEs. The best transdermal flux of MEs was 1.892 mg/cm2*h. The same ME showed a relative bioavailability of 239.7 % in comparison to the oral solution. PMID- 29441946 TI - Perphenazine and prochlorperazine induce concentration-dependent loss in human glioblastoma cells viability. AB - Phenothiazine derivatives possess biological properties very useful for cancer therapy, such as antiemetic and sedative activity as well as good blood-brain barrier permeability. Our goal was to determine if perphenazine and prochlorperazine are possessing cytotoxic activity towards U87-MG cells. It has been shown that the analyzed drugs induce concentration-dependent loss in cell viability, what correlates with their chemical structure. The calculated EC50 values for perphenazine (0.98 MUM) and prochlorperazine (0.97 MUM) are related to their toxic concentrations in human plasma. The obtained results suggest that perphenazine and prochlorperazine may have a potential for the development of new and effective anticancer therapies. PMID- 29441947 TI - Effect of brefelamide on proliferation of 1321N1 human astrocytoma cells induced by glial cell line-derived neurotrophic factor. AB - Malignant gliomas are highly resistant to chemotherapy and radiation and more effective options for treatment are urgently needed. We reported previously that the aromatic amide brefelamide, which is isolated from methanolic extracts of the cellular slime molds Dictyostelium giganteum and D. brefeldianum, hinders cellular proliferation in a glioma model utilizing 1321N1 human astrocytoma cells. Herein, we examined the mechanisms underlying the inhibition of 1321N1 cell proliferation by brefelamide. Glial cell line-derived neurotrophic factor (GDNF) was found to enhance the rate of proliferation of serum-free cultured 1321N1 cells, but did not affect proliferation in PC12 cells. Brefelamide pretreatment inhibited GDNF-induced cell proliferation and expression of rearranged during transfection (RET). GDNF enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and c-jun-N-terminal kinase (JNK); however, brefelamide pretreatment inhibited these effects. Brefelamide also reduced the expression of GDNF mRNA and GDNF secretion. Together, the findings from this study indicate that brefelamide inhibits the proliferation of 1321N1 cell via several mechanisms including reduced GDNF receptor expression and GDNF secretion, and reduced phosphorylation of ERK, AKT, and JNK. PMID- 29441948 TI - Regulation and mechanism of miR-146 on renal ischemia reperfusion injury. AB - AIM: MicroRNAs (miRs) are endogenous substances that act as important diagnostic and treatment targets in renal diseases. miR-146 plays an important role in the development of endotoxin tolerance through NF-kappaB pathway, but the underlying mechanism is not clearly understood. The aim of this study was to determine the molecular regulation and function of miR-146 and also the expression of miR-146 in an experimental model of renal ischemia reperfusion injury (IRI). METHODS: IRI was induced in mouse by bilateral IRI for 45 min followed by reperfusion. The male mice were randomized as: sham, I/R, I/R+miR-146, and I/R+antago-miR-146 groups. Renal function, histological damage, and cell apoptosis were evaluated at 24 h after reperfusion. RESULTS: Overexpression of miR-146 protected renal function. Renal cells with upregulated miR-146 had lower plasma levels of blood urea nitrogen (BUN) and creatinine, decreased apoptosis and active caspase-3 protein expressions. miR-146 was shown to have a role in renal IR injury. miR-146 has a protective effect on renal function and plays a significant role in apoptosis. IGSF1 acts as a target of miR-146. IGSF1 rescued the effects of miR 146 on renal IRI. miR-146 protected renal function by activation of PI3K/AKT. CONCLUSION: These findings suggest that miR-146 might regulate apoptosis and can cause injury in I/R via targeting IGSF1 and also exert renal protection property. PMID- 29441949 TI - Effect of serotonin transporter genotype on self-reported efficacy and activity changes of brain prefrontal area in response to placebo. AB - Patients benefit from drug therapy not only through pharmacological mechanisms, but also through non-pharmacological action (placebo effect), which may be mediated in part by the prefrontal area of the brain. We consider that the difference between responders and non-responders to placebo might be related to polymorphisms in the serotonin transporter-linked polymorphic region (5-HTTLPR). To study this idea, we performed a randomized double-blind clinical trial using caffeine and lactose (placebo). Activity in the prefrontal area of the brain was measured in terms of blood flow by means of near-infrared spectroscopy (NIRS) as an objective indicator. Self-reported feelings of drowsiness on established scales were used as subjective indicators. Twenty-one subjects in block A took caffeine on the first day and placebo on the third day, and 21 in block B took placebo on the first day and placebo on the third day. After placebo administration, improvement of sleepiness was significantly enhanced, a similar extent to that after caffeine medication. Among the 42 subjects, 22 showed S/S type polymorphism in the serotonin transporter (52.4 %), 17 showed S/L type (40.5 %) and 3 showed L/L type (7.10 %). Statistical analysis of the results indicate that subjects with L/L genotype showed a significantly greater placebo response in terms of both self-reported feeling of drowsiness and blood flow in the prefrontal area of the brain associated with working memory (46 area). Our results indicate that the L/L genotype of 5-HTTLPR, which is rare in Japanese (3.2 %) but common in Americans (32.2 %), may be associated with a greater placebo effect. PMID- 29441950 TI - Long noncoding RNA CCAL promotes gastric cancer cell proliferation and migration in a Myc dependent way. AB - AIMS: Long non-coding RNAs (lncRNAs) play key roles in cancers, yet their potential molecular mechanisms are not well understood. The objective of this study is to examine the expression, biological functions and mechanism of lncRNA CCAL in gastric cancer (GC). METHODS: MTT and Colony formation assay were used to detect cell proliferation and the colony formation ability of gastric cancer cells. Wound healing, Migration, and invasion assay were respectively used to explore the migration, and invasion in gastric cancer cell lines. Real-time polymerase chain reaction (RT-PCR) was performed to determine the expression level of CCAL. Western Blot was used to determine the expression of related proteins. RESULTS: In the present study, we found that CCAL was upregulated in gastric cancer cell lines. Patients whose tumors had high CCAL expression had a shorter overall survival than patients whose tumors had low CCAL expression. Overexpression CCAL promoted the proliferation, migration and invasion of GC by regulating the expression of myc. CONCLUSION: The present study reveals that CCAL is an oncogenic lncRNA that promotes the tumorigenesis and progression of GC. PMID- 29441951 TI - LncRNA HULC promotes epithelial and smooth-muscle-like differentiation of adipose derived stem cells by upregulation of BMP9. AB - AIMS: Adipose-derived stem cells (ADSCs), a source of mesenchymal stem cells, are able to differentiate into numerous cell lineages, including epithelial and smooth muscle cells. The use of ADSCs in tissue engineering technology has become the most promising therapeutic approach for urethral reconstruction. This study aimed to explore the effect of lncRNA highly upregulated in liver cancer (HULC) on the induction of ADSCs to differentiate into epithelial and smooth-muscle-like cells. METHODS: ADSCs were isolated from a male dog, and the expression of HULC in ADSCs was overexpressed by transfection with HULC expressing vector lentivirus. The transfected ADSCs were then incubated with 5 MUM ATRA or 2.5 ng/ml TGF-beta1 and 5 ng/ml PDGF-BB for 21 days. The expression of epithelial differentiation and smooth-muscle-like differentiation markers were monitored. Besides, cross-regulation between HULC and BMP9 was detected in the differentiated epithelial cells and smooth-muscle-like cells. RESULTS: HULC increased cell viability of ADSCs, but has no impact on ADSCs apoptosis. HULC promotes ADSCs to differentiate into epithelial and smooth-muscle-like cells, as evidenced by the increases in the expression of Uroplakin-II, AE1/AE3, alpha-SMA, SM-MHC, Calponin, and SM-22alpha. In addition, HULC could positively regulate BMP9, and BMP9 silence abolished HULC-promoted ADSC's differentiation. Furthermore, HULC activated Wnt/beta-catenin pathway while deactivated Notch pathway. CONCLUSION: HULC was demonstrated to be a promoter during the epithelial and smooth-muscle-like differentiation of ADSCs via the BMP9/Wnt/beta catenin/Notch network. This study provides the first in vitro evidence that HULC based therapy could be a valuable approach to promote urethral reconstruction. PMID- 29441952 TI - Efficacy of a polyphenolic extract from silver fir (Abies alba) bark on psoriasis: a randomised, double-blind, placebo-controlled trial. AB - Silver fir (Abies alba) bark extract contains a mixture of bioactive polyphenols. We tested their effectiveness in the treatment of psoriasis in order to further investigate the potential topical anti-inflammatory activity of polyphenols by means of a randomized, double-blind, placebo-controlled add-on clinical trial, after having examined their ability to downregulate the expression of IL-1beta cytokine in monocyte/macrophage primary cell culture. 61 patients with mild psoriasis met the inclusion criteria and were willing to comply with protocol requirements, were enrolled in the study. The severity of the disease was measured by psoriasis area severity index (PASI). Treatment efficacy was evaluated by assessing erythema (E, 0 to 4-point scale), desquamation (D, 0 to 4 point scale) and induration (I, 0 to 4-point scale) of lesions before and after the treatment. All patients enrolled in the study had symmetrical psoriasis plaques on the skin. All patients received O/V ointment with 2% of silver fir bark extract and/or placebo, respectively. We compared medications by right/left intra-patient comparison, so that the control group was always contralateral of the tested one. Location of the tested or control site was randomised, using a computer-generated randomisation schedule. Silver fir extract was well-tolerated. A superiority of active treatment above placebo, based on the clinical investigational PASI score system was observed by 15 % in all volunteers and in 40% regarding the improvement of psoriasis on elbows. However, statistical analysis showed no significant differences between placebo and active treatment with the extract from silver fir bark (p < 0.05). PMID- 29441954 TI - Synthesis and biological evaluation of novel 4,5-bisindolyl-1,2,4-triazol-3-ones as glycogen synthase kinase-3beta inhibitors and neuroprotective agents. AB - A series of novel 4,5-bisindolyl-1,2,4-triazol-3-ones were designed, prepared and evaluated for their glycogen synthase kinase (GSK)-3beta inhibitory activities. Compounds exhibited favorable inhibitory potency towards GSK-3beta kinase at the molecular level and in cells indicated by significantly reducing GSK-3beta substrate Tau phosphorylation at Ser396 in primary neurons showing the inhibition of cellular GSK-3beta. In an in vitro model of neuronal injury, compounds 6b, 6d and 6f prevented glutamate-induced neuronal death which was closely associated with cerebral ischemic stroke. Preliminary structure-activity relationship was examined and showed that different substituents on the indole ring had significant influences on the GSK-3beta inhibitory potency. These findings may provide new insights into the development of novel GSK-3beta inhibitors as neuroprotective agents. PMID- 29441953 TI - A cytotoxic flavonol glycoside from Melaleuca leucadendra leaves extract with immunostimulant activity. AB - Leaves of Melaleuca leucadendra contain the novel flavonol glycoside, myricetin 3 O-beta-4C1-galactopyranuronoid. In addition, known fifteen phenolics were identified. All isolates are characterized for the first time from this plant. Structures were established by conventional methods and confirmed by spectral methods of analysis, including one and two-dimensional nuclear magnetic resonance spectroscopy (1D and 2D-NMR) and high resolution electro-spray ionization mass spectrometry (HRESIMS), as well. Assessment of some immunological and biological efficacy, of the extract in combination with a parallel cytotoxicity evaluation, using the method of cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) technique was carried out. Besides, evaluation of the antioxidant effectiveness, using the free radical 2,2-diphenyl-1 picrylhydrazyl (DPPH) and the oxygen radical absorption capacity (ORAC) methods was performed. In addition, the cytotoxicity against liver (Huh-7), breast (MCF 7) and prostate (PC-3) cancers using the neutral red assay (NRU) technique for the extract and the new flavonol glycoside also, was assessed. PMID- 29441955 TI - PEGylation of coenzyme Q10 and in vitro release studies. AB - Methoxy polyethylene glycol conjugated with coenzyme Q10 (mPEG)-CoQ10 and analog adducts with amino acids as spacers were synthesized as a new drug delivery systems for CoQ10. Alanine and branched chain amino acids (valine, leucine and isoleucine) were conjugated to mPEG by an amide linkage and to CoQ10 by an ester bond. Recently, branched chain amino acids (BCAAs), which are released along with CoQ10, have received increasing attention as 'anti-fatigue' elements. FT-IR and 1H NMR spectroscopic analysis were useful to characterize the synthesized conjugates. Studies in vitro, in buffer solutions at different pH and in the presence of esterase were conducted. The hydrolysis studies showed a specific cleavage dependent on the pH of the medium and by the presence of proteolytic enzymes. The results showed the improvement of the pharmacokinetic properties of CoQ10. The antioxidant activity of the synthesized conjugates was also evaluated by DPPH assay. PMID- 29441956 TI - Curcumin-loaded cationic solid lipid nanoparticles as a potential platform for the treatment of skin disorders. AB - Curcumin (CUM) possesses therapeutic activity against diverse skin disorders (SD); however, its clinical use faces many challenges related to physicochemical and bioavailability characteristics, that can be solve designing a new drug delivery system for CUM to treat SD. Cationic solid lipid nanoparticles (CSLN) were developed and physicochemically analyzed. The ingredients and methods adopted in this study promoted the successful preparation of CSLN with a monodispersed particle size of 218.4-238.6 nm and a polydispersity index of 0.156 0.350. A differential scanning calorimetric assay demonstrated that CUM was incorporated. The atomic force microscopy images showed uniform spherical particles, and light scattering technique confirmed the size of the particles. The zeta potential of the CSLN was +23.1 to +30.1 mV, which is important in targeting the drug to the diseased tissue that presents unregulated apoptosis. All formulations behaved as controlled drug delivery systems of CUM, as demonstrated by an in vitro drug release study, which delayed the start of drug release from formulations. At the end of the experiment, the formulations had released 14.74-21.23% of the incorporated CUM. In conclusion, the results suggest the potential of this CSLN as a controlled CUM delivery system for the treatment of SD. PMID- 29441957 TI - smartLipids(r) as third solid lipid nanoparticle generation - stabilization of retinol for dermal application. AB - smartLipids(r) as the 3rd lipid nanoparticle generation are made from a complex lipid mixture. The chaotic particle matrix structure provides higher loading with actives and a firmer inclusion inside the particle matrix being more protective for chemically labile molecules. Thus, these particles were used to develop an optimized retinol formulation. As a new approach, the old concept of the core shell SLN particles was combined with the novel smartLipids(r) technology as new stabilization model. Particles were produced by hot high pressure homogenization, loaded with increasing amounts of retinol (5%, 15%, 20%), and both the physical (size, crystallinity) and chemical stability were monitored. According to the core-shell model, the retinol precipitates first, forming a core. Then, in the final solidification stage of the particles the retinol core gets surrounded by a shell of lipid-retinol eutectic mixture. With increasing retinol content, more retinol precipitates in the core and is chemically protected. The model was confirmed by the stability data obtained, e.g. with 5%, 15% and 20% retinol loading, after 60 days of storage 37%, 59% and 75% of retinol remained in the particle suspensions. Thus, chemical stability increased with loading. Size remained unchanged at about 200 nm. Crystallinity showed absence of polymorphic transitions, which can cause expulsion of active from the particle matrix, leading to degradation. After incorporation of the particles into a gel as dermal formulation, similar stability was observed. The developed concept can be transferred to other chemically labile dermal actives, in cosmetics and pharma. PMID- 29441958 TI - Preparation and in-vivo evaluation of cytochrome-C-containing liposomes. AB - This study investigates the development of a method for obtaining cytochrome C containing liposomes (LS-Cyt), and evaluates their stability and specific activity. LS-Cyt were intended for the therapy of ophthalmic diseases. LS-Cyt were prepared by high pressure homogenization technique and lyophilized to obtain freeze-dried LS-Cyt. It was proposed to use anionic phospholipid- dipalmitoylphosphatidylglycerol (DPPG-Na) and phosphatidylcholine (PC) in a nanoparticulate composition. Were investigated various concentrations of lactose and trehalose as cryoprotectants. Samples with a lactose concentration of 6% showed the best results in terms of the emulsion formation time, encapsulation and preservation of nanosize. The main technological parameters for the obtained freeze-dried LS-Cyt were encapsulation of no less than 95% of cytochrome C (Cyt C), particle size of 140-170 nm, pH of 6.85+/-0.1, osmolarity of 330+/-3 mOsmol/kg, a lysophosphatidylcholine content (LPC) of 0.65+/-0.05 % of the total of lipids. Stability of the freeze-dried LS-Cyt during storage was established. The freeze-dried LS-Cyt was kept for 1 year in a light protected place at the temperature of -15 degrees C. No changes in the composition of LS-Cyt samples were detected over the observation period. Preclinical in-vivo research was conducted, namely the evaluation of specific activity on the model of the penetrating corneal injury. It was established that use of LS-Cyt contributes to a more rapid process of tissue regeneration and reduction of the inflammatory response in comparison with a non-liposomal dosage form. PMID- 29441960 TI - Carbamazepine 10,11-epoxidation in human liver microsomes: influence of the CYP3A5*3 polymorphism. AB - Carbamazepine (CBZ) is a commonly prescribed antiepileptic drug, and is mainly metabolized to 10,11-CBZ epoxide in humans. Its biotransformation is catalyzed by cytochrome P450 (CYP) enzymes, with the predominant isoforms being CYP3A4 and CYP3A5. In the present study, the effects of the CYP3A5*3 (rs776746) polymorphism on CBZ 10,11-epoxidation in human liver microsomes genotyped as CYP3A5*3 were examined using a kinetic analysis. The kinetics for CBZ 10,11-epoxidation fit the Hill model with n of approximately 1.9-2.1 in all liver microsomes of the wild type (CYP3A5*1/*1) and heterozygous (CYP3A5*1/*3) and homozygous (CYP3A5*3/*3) variants. The S50, Vmax, and CLmax values of wild-type liver microsomes were 263 327 MUM, 793-1590 pmol/min/mg protein, and 1.51-2.95 MUL/min/mg protein, respectively. The Vmax and CLmax values of liver microsomes of the heterozygous variant were approximately 15-40% those of wild-type liver microsomes. On the other hand, the Vmax and CLmax values of liver microsomes of the homozygous variant were more similar to those of the wild-type than the heterozygous variant. These results suggest that the CYP3A5*3 polymorphism has a negligible effect on CBZ 10,11-epoxidation in an in vitro system using human liver microsomes. PMID- 29441959 TI - Stability studies of five anti-infectious eye drops under exhaustive storage conditions. AB - Several ocular infections require anti-infectious eye drops prepared by hospital pharmacy. Stability of these preparations is described in the literature, but studies do not always adequately consider physico-chemical parameters or storage conditions. We describe herein a complete study conducted on five anti-infectious eye drops containing vancomycin, gentamicin, ceftazidime, amphotericin B and voriconazole. We looked for significant changes in active pharmaceutical ingredient content, pH, osmolality and subvisible particles. Our study was designed to monitor stability at ambient temperature, at 2-8 degrees C, and also at 2-8 degrees C after various freezing periods. Under ambient storage conditions, eye drops were stable for 15 days, except for ceftazidime, which was stable for less than 1 day only. Under refrigeration conditions (2-8 degrees C), amphotericin B and voriconazole were stable for 60 days, vancomycin and gentamicin were stable for 30 days while ceftazidime was only stable for 15 days. After 90 days freezing and thawing, voriconazole remained stable at 2-8 degrees C for 60 days, vancomycin and amphotericin B for 30 days and gentamicin only for 21 days. Ceftazidime eye drops were stable for only 7 days at 2-8 degrees C after 60 days freezing. Our results are compared to the most relevant publications. Results of this study allow the compounding of large batches of harmonized anti-infectious eye drops. PMID- 29441962 TI - MiR-139 prompts the development of osteosarcomas mainly through targeting ROCK1. AB - Abnormal expression of miR-139 was found to be aberrantly expressed in various tumors. However, whether it is involved in osteosarcomas (OS) has never been explored. In the current study, we found that the level of ROCK1 was markedly increased in OS cancer tissues compared to that of noncancerous tissues. Meanwhile, the expression of miR-139 was markedly reduced in OS cancer tissues and cell lines. Enhanced miR-139 expression markedly suppressed colony-formation and cell invasion capacity of OS cancer cells. Dual luciferase reporter assay demonstrated that ROCK1 was a target gene of miR-139. Moreover, overexpression of ROCK1 also led to increased invasion capacity in OS cancer cells even when miR 139 was inhibited, suggesting the anti-invasion effects of miR-139 were mediated through ROCK1. In summary, our present findings indicate that miR-139 functions as a tumor suppressor in OS cancer cells mainly by targeting ROCK1. PMID- 29441961 TI - Clinically relevant interactions of anti-apoptotic Bcl-2 protein inhibitors with ABC transporters. AB - : In this work we studied clinically relevant interactions between the BH3 mimetics and the ABCB1 and ABCG2 transporters. We observed that the intracellular levels of ABT-263 and ABT-199, but not ABT-737, might be reduced by ABCB1 or ABCG2. Importantly, this effect was proportional to the transporter expression level. High transporter expression levels decreased the intracellular levels of ABT-263 and ABT-199 substantially. Low transporter expression levels, which are clinically relevant, affected the intracellular level of ABT-263 slightly but significantly, however, they failed to decrease the intracellular level of ABT 199 below the control level in parental cells. Our results further revealed that ABT-263 did not inhibit the ABCB1 mediated transport, however, it partially inhibited the ABCG2 mediated transport at clinically relevant concentrations. In contrast, ABT-199 inhibited partially the ABCB1 mediated transport and it fully inhibited the ABCG2 mediated transport at clinically relevant concentrations. Importantly, cells expressing higher drug transporters levels required higher concentrations of ABT-263 or ABT-199 to achieve certain inhibition of substrate efflux. CONCLUSIONS: Antiproliferative effects of ABT-263 and ABT-199 might be reduced by ABCB1 or ABCG2, however, this effect depends on transporter expression levels. Since the expression levels of ABCB1 and ABCG2 are rarely high in clinical samples, their contribution to the overall resistance to ABT-263 or ABT 199 is probably low. Inhibition study revealed that ABT-199, but not ABT-263, fully inhibited low expression level of ABCG2. Our data suggest that ABT-199 should be evaluated beyond its original application as an inhibitor of the ABCG2 transporter in clinical settings. PMID- 29441963 TI - Do patients with diabetes type 2 or chronic heart failure understand a medication plan? AB - A standardized medication plan (MP) was recently enacted into German law (S 31a SGB V). The purpose of our study was to assess if patients with chronic diseases requiring polymedication understand the standardized MP and can transfer the given information into practice. 100 patients who took at least five medicines regularly were prospectively included in a cross-sectional study: 50 patients with the primary diagnosis chronic heart failure (CHF), and 50 with diabetes mellitus type 2 (DMT2). We performed a structured test-scenario studying the handling of a provided MP then evaluated the execution of the information on the MP by filling pill boxes and requested patients' opinion. An established weighted scoring system, the "Evaluation Tool to test the handling of the Medication Plan" (ET-MP) was applied to quantitate the ability of the patients to handle the MP. In addition, signs of depression, cognitive function and self-care behavior in chronic heart failure were characterized using the PHQ-9, Mini-Cog, and G9-EHFScB 9 questionnaires, respectively. The understanding of the MP was poor and irrespective of the underlying primary diagnosis. Only 32% of all patients were able to handle the MP without difficulties (ET-MP score >90%), the median ET-MP score was 83 [(IQR) 50-98]. Comprehension of the MP was better in patients aged <70 years compared to >=70 years (p<0.01). Patients >=10 years of education achieved higher ET-MP results than patients with <10 years of education (p<0.01). Patients with signs of cognitive impairment exhibited significantly lower ET-MP scores than patients without cognitive impairment (p<0.001). There were no significant correlations of the ET-MP score with number of daily medications, living situation, sex, the Charlson Comorbidity Index, the PHQ-9 score, and use of a dosing aid or possession of a medication list. PMID- 29441964 TI - Dextran sodium sulfate alters cytokine production in macrophages in vitro. AB - Macrophages have been assumed to have a crucial role in the development of inflammatory bowel disease (IBD). However, involvement of intestinal macrophages in IBD onset and functional alterations of macrophages during IBD development has not been clarified. We investigated the effect of exposure of compounds used in the induction of colitis in mice on the immune responses of peritoneal macrophages in mice. 2,4,6- trinitrobenzenesulfonic acid and oxazolone did not affect the production of interleukin (IL)-10 and IL-12 from lipopolysaccharide (LPS)-stimulated peritoneal macrophages from BALB/c mice. A significant increase in IL-10 secretion and decrease in IL-12 production from LPS-stimulated macrophages were observed upon exposure to dextran sodium sulfate (DSS). TNF alpha production was enhanced significantly by exposure to DSS and LPS. The level of nitric-oxide production from macrophages was increased slightly by exposure to DSS and LPS. Expression of sphingosine kinase-1 and LIGHT (both of which are specific biomarkers of M2b macrophages) was observed in macrophages upon DSS exposure. Alteration of cytokine production in macrophages was observed upon DSS exposure in the absence of LPS stimulation. Peritoneal macrophages from C57BL/6 mice showed similar responses to peritoneal macrophages from BALB/c mice against DSS. These results suggest that DSS directs the immune response of macrophages towards the M2b phenotype. PMID- 29441965 TI - MiR-455 enhances adipogenic differentiation of 3T3-L1 cells through targeting uncoupling protein-1. AB - Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating the pathways in adipose tissue that control processes such as adipogenesis, insulin resistance, and inflammation. Adipogenic differentiation of preadipocytes is a complex process regulated by various factors including miRNAs and cytokines. MiR-455 is a well-known miRNA that enhances adipogenesis. Uncoupling protein-1 (UCP-1), a heparinbinding growth factor, plays a negative role in adipogenesis. In this investigation, we demonstrate that UCP-1 is a target gene of miR-455 during adipogenic differentiation in 3T3-L1 preadipocytes. MiR-455 downregulates UCP-1 expression through interaction with a target site of miR-455 in the coding region of mouse UCP-1. The rare codons upstream of the target site regulate miR-455-induced translational knockdown of UCP-1, which provides more insight into the mechanism of adipogenic differentiation. Thus, these results suggest that the acceerative adipogenic effect of miR-455 in 3T3-L1 cells is due, at least in part, to suppression of UCP-1. PMID- 29441966 TI - The protective effects of CHIR99021 against oxidative injury in LO2 cells. AB - Hepatic ischemia-reperfusion injury is one of the most important factors for the prognosis of liver transplantation and hepatic surgery. It was reported that glycogen synthase kinase-3 (GSK-3) regulated injury response during ischemia reperfusion. In this study, we investigated the protective effects of the GSK-3 inhibitor CHIR99021 against hepatic ischemia-reperfusion injury. A H2O2-induced oxidative injury model using LO2 cells was established. LO2 cells were divided into four groups, including blank control group, CHIR99021 control group treated with CHIR99021 alone, H2O2-injury group treated with H2O2 and protection group treated with H2O2 plus CHIR99021. Cell viability, cell apoptosis or necrosis was determined. Meanwhile, mitochondrial membrane potential, lipid peroxidation, cellular ROS levels, SOD activity, and serum contents of ALS and AST were measured. Protein and mRNA expressions were also detected. The results showed that a cell oxidative injury model was established by treating LO2 cells with 200 MUmol/L H2O2 for 6 h. Cells exposed to H2O2 resulted in a significant decrease of cell viability and increase of cell apoptosis, which was accompanied by increasing ROS levels, disruption of mitochondrial membrane potential, excessive lipid peroxidation, reduction of SOD activity, and increased levels of ALT and AST. Treatment with CHIR99021 significantly protected LO2 cells against H2O2 induce oxidative injury by inhibiting the changes of above oxidative injury related indicators. Moreover, CHIR99021 treatment significantly reversed H2O2 induced decrease in p-GSK-3betaSer9 , Bcl-2, Bcl-xl, survivin and beta-catenin expression, whereas it significantly attenuated H2O2-induced increase in caspase 3, cleaved caspase-3 and p-JNK protein expression. In conclusion, CHIR99021 protected LO2 cells against H2O2-induced oxidative injury through reducing GSK 3beta activity and apoptosis, with underlying mechanisms involved in stabilizing mitochondrial membrane potential, attenuating cellular ROS generation, suppressing mitochondria-mediated apoptotic pathway, and activation of GSK 3beta/beta-catenin signaling pathway. PMID- 29441967 TI - Interleukin 6 receptor inhibitor tocilizumab suppresses cytokine expression, inflammasome activation and phagocytosis in a cell model of sepsis. AB - OBJECTIVE: Sepsis is a life-threatening condition, usually accompanied by excessive inflammation. Tocilizumab (TCZ) is a humanized monoclonal antibody against the interleukin (IL) 6 receptor and has been studied in various inflammatory diseases, but little is known about its effects in sepsis. This study aims to reveal the role of TCZ in inflammation during sepsis. METHODS: Human monocyte cell line THP-1 was stimulated by lipopolysaccharide (LPS) as a cell model for sepsis. After TCZ treatment, the expression of cytokines tumor necrosis factor (TNF) and IL10, the production of chemokine (C-C motif) ligand 2 (CCL2) and IL1B, and the expression of inflammasome factors NLR family pyrin domain containing 3 (NLRP3) and caspase 1 (CASP1), were detected by qRT-PCR and ELISA. Phagocytosis assay was also performed to assess the phagocytosis activity of TCZ-treated cells. RESULTS: LPS stimulation significantly upregulated TNF and IL10 mRNA levels (P < 0.01) and CCL2 and IL1B production (P < 0.001), promoted NLRP3 and CASP1 levels (P < 0.01) and elevated phagocytosis activity of THP-1 cells (P < 0.001). TCZ treatment had the opposite effects of decreasing TNF and IL10 mRNA levels (P < 0.05), CCL2 and IL1B production (P < 0.001), inhibiting NLRP3 and CASP1 (P < 0.01), and suppressing phagocytosis activity (P < 0.001) compared to the LPS group. CONCLUSION: These results indicate the suppressive role of TCZ in cytokine production, inflammation activation and phagocytosis in sepsis cell model, implying its effects on controlling "cytokine storm" during sepsis. Thus TCZ provides a promising strategy for treating sepsis. PMID- 29441969 TI - Effects of leonurine on intracerebral haemorrhage by attenuation of perihematomal edema and neuroinflammation via the JNK pathway. AB - Perihematomal edema plays a critical role in secondary brain injury in intracerebral hemorrhage (ICH), which is associated with inflammation, hematoma toxicity and oxidative stress. In this work, we investigated the protective effects of leonurine, an alkaloid of Herbal Leonuri, and possible mechanisms to provide a basis for a new therapeutic approach for ICH treatment. In in vivo studies, we demonstrated for the first time that leonurine treatment substantially decreased perihematomal edema, ameliorated neurobehavioral function deficits, reduced apoptosis and protected injured cerebral tissue after ICH. These benefits appear to be ascribed to leonurine effectively attenuating bloodbrain barrier (BBB) breakdown in vivo, by inhibiting degradation of hemoglobin and alleviating inflammatory mediator release. In this study, BV-2 cells were exposed in vitro to oxyhemoglobin (OxyHb) at a concentration of 10 MUM to mimic neuroinflammation after ICH. Consistent with the results of the in vivo study, leonurine significantly inhibited OxyHbinduced inflammatory proteins expression in BV-2 cells, mainly through inhibiting the c-Jun N-terminal kinase (JNK) signaling pathway. This is the first time that leonurine is proved to be capable to protect the injured cerebral tissue after ICH, based on alleviating neuroinflammation and attenuating BBB breakdown to ameliorate perihematomal edema. PMID- 29441968 TI - miR-149 reverses cisplatin resistance of gastric cancer SGC7901/DDP cells by targeting FoxM1. AB - Drug resistance remains a major unresolved obstacle for gastric cancer (GC) treatment. Recently, increasing studies have showen that microRNAs (miRNAs) are involved in cancer chemotherapeutic resistance and can potentially be applied to reverse drug resistance in cancers. The relationship between miRNA-149 expression and cisplatin (DDP) resistance in GC cells is still unknown. Here, we detected miR-149 expression by using RT-PCR and found that expression of miR-149 was downregulated in SGC7901/DDP cells compared with SGC7901cells, indicating a role of miR-149 in determining cisplatin-resistance of GC cells. Then, SGC7901/DDP cells were tansfected with miR-149 mimics, MTT assay was performed to determine SGC7901/DDP cell viability, and showed that overexpression of miR-149 inhibited the cell viability after cisplatin treatment, suggesting that up-regulation of miR-149 enhanced SGC7901/DDP cell sensitivity to cisplatin. Furthermore, we confirmed that Forkhead box M1 (FoxM1) is a direct target of miR-149 in SGC7901/DDP cells by using luciferase reporter assay. Besides, we also demonstrated that miR-149 enhances SGC7901/DDP cell sensitivity to cisplatin by downregulating FoxM1 expression. In summary, our data provide new insights that miR-149 plays an important role in determining sensitivity of cisplatin-resistant GC cells by targeting FoxM1 and suggest that miR-149 could be a potential target for reversing drug resistance in GC. PMID- 29441970 TI - Anti-platelet effects of chalcones from Angelica keiskei Koidzumi (Ashitaba) in vivo. AB - Angelica keiskei Koidzumi (Ashitaba) is a traditional folk medicine that is also regarded in Japan as a health food with potential antithrombotic properties. The ability of the major chalcones, xanthoangelol (XA) and 4-hydroxyderricin (4-HD) extracted from Ashitaba roots to inhibit platelet aggregation activity in vitro was recently determined. However, the anti-platelet activities of Ashitaba chalcones in vivo have remained unclear. The present study examines the anti platelet effects of Ashitaba exudate and its constituent chalcones using mouse tail-bleeding models that reflect platelet aggregation in vivo. Ashitaba exudate and the major chalcone subtype XA, suppressed the lipopolysaccharide (LPS) induced shortening of mouse tail bleeding. However, trace amounts of other Ashitaba chalcone subtypes including xanthoangelols B (XB), D (XD), E (XE) and F (XF) did not affect tail bleeding. These results suggest that the major chalcone subtype in Ashitaba, XA, has anti-platelet-activities in vivo. PMID- 29441971 TI - The anxiolytic activity of n-3 PUFAs enriched egg yolk phospholipids in rat behavioral studies. AB - Phospholipids play an important role in the biochemical and physiological processes of cells. An association between disturbed phospholipids metabolism in neuronal tissue and anxiety it was shown. The aim of this study was to examine the anxiolytic properties of phospholipids obtained from a new generation of eggs enriched in n-3 PUFA and its effect on locomotor activity in rat behavioral studies N-3 PUFA-enriched egg yolk phospholipids ("super lecithin") were added to the standard feed. Rats were fed by chow without (control group) or with (experimental group) addition of phospholipids. After six weeks of supplementation, the effect of phospholipids on locomotor activity in the open field test and anxiolytic properties in elevated plus maze and Vogel conflict test were examined. In the open field test the total distance traveled in the experimental group was similar to the control group. In the elevated plus maze test a six weeks phospholipids' administration significantly prolonged the time spent on the open arms by rats from experimental group compared to control group. The number of entries into the open arms was also increased but the difference was not statistically significant. The number of punished drinking water in the Vogel conflict test increased significantly in experimental versus control group. The obtained results suggest that the phospholipids isolated from n-3 PUFA enriched egg yolk have a specific anxiolytic effect, without general sedative influence. PMID- 29441972 TI - An investigation of visual hallucinations associated with voriconazole administration to patients with hematological malignancies. AB - Voriconazole (VRCZ) is commonly administered to treat fungal infections in patients with hematological malignancies. Some of these patients experience VRCZ associated visual hallucinations. We conducted a retrospective survey to investigate the characteristic features of this side effect. Patients with hematological malignancies who were treated with VRCZ for a fungal infection after hospitalization at Ichinomiya municipal hospital between 1 October 2005 and 31 December 2015 were included in this study (n = 103). Fifteen of these (14.6%) reported visual hallucinations that started on day 1-7. Seven of these 15 patients developed this symptom rapidly (day 1 or 2). Three patients had transient symptoms (lasting 2-12 days), 6 patients experienced hallucinations throughout the treatment, and the duration was unknown in 6 patients. Eleven patients experienced visual hallucinations when their eyes were closed (73 %) and these disappeared when they opened their eyes. One patient had visual hallucinations with open eyes, while the state of the eyes was unknown in 3 patients. The patients saw a range of images including people, animals, landscapes, and foods; several reported seeing images like those found in movies. In addition, 9 of 15 patients (60%) with visual hallucinations had visual disturbances. This was a higher proportion than that observed in patients who did not develop hallucinations (17 of 88; 19.3 %; P < 0.05). However, we found no significant difference between the blood VCRZ concentrations of patients who developed or did not develop visual hallucinations. This study indicated that most of these patients had visual hallucinations that manifested on eye closure, and they did not progress to serious mental illness. Our findings emphasized the importance of fully explaining the features of this symptom to each patient prior to starting VRCZ administration in order to reduce anxiety. In addition, since VRCZ discontinuation will compromise patient management, therapeutic drug monitoring should be used to increase the likelihood of successful therapy. PMID- 29441973 TI - Clinical effects of Angelica dahurica dressing on patients with I-II phase pressure sores. AB - OBJECTIVE: Angelica dahurica is a well-known traditional Chinese Medicine (TCM), while little information is available about its effects on pressure sores. We aimed to investigate the clinical effect of Angelica dahurica on patients with I II phase pressure sores, as well as the underlying mechanism. METHODS: Patients (n = 98) with phase I and phase II pressure sores were enrolled and randomly assigned to control and treated groups. In addition to holistic nursing, patients in the control group received compound clotrimazole cream, while patients in the treated group received continuous 4 weeks of external application of Angelica dahurica dressing. Therapeutic effect was recorded, along with the levels of interleukin-8 (IL-8), epidermal growth factor (EGF), transforming growth factor (TGF)-beta, and vascular endothelial growth factor (VEGF). Besides, HaCaT cells were cultured with different concentrations of Angelica dahurica, and then cell viability, clone formation numbers, cell cycle, and levels of cyclin D1 and cyclin-dependent kinase (CDK) 2 were determined. RESULTS: The total effective rate in the treated group was significantly higher than in the control group. Levels of IL-8, EGF, TGF-beta, and VEGF were statistically increased by Angelica dahurica. In addition, the cell viability and clone formation numbers were significantly upregulated by Angelica dahurica in a dose-dependent manner. Also, the percentage of cells in G0/G1 phase, and levels of cyclin D1 and CDK2 were significantly elevated. CONCLUSION: Our results suggest that Angelica dahurica may provide an effective clinical treatment for I-II phase pressure sores. PMID- 29441974 TI - The medical treatment of Maria, Dowager Empress of the Russian Empire: an analysis of her prescription book from 1807 and 1808. AB - This study analyzes the medicines that were used to treat the Dowager Russian Empress Maria, widow of Tsar Paul I, and describes the doctors who cared for her health in 1807 and 1808. The source for this research was the imperial court pharmacy prescription book 1807-1811. Hypotheses about the diseases and medical problems of the Empress and how treatment for her differed according to circumstances, particularly after the loss of her granddaughter Princess Elizabeth, have been made based on the prescriptions recorded in the book. The content of the prescriptions suggests that the Empress suffered from gastrointestinal tract disorders, skin and eye diseases, neuralgic pains and insomnia. Foreign physicians educated in European universities worked at the imperial court and implemented European medical traditions. They took high positions in the administration and the medical education system, and gradually spread their experience and modern knowledge to Tsarist Russian society. PMID- 29441976 TI - Calreticulin: a potential anti-cancer therapeutic target. AB - Calreticulin (CRT) is an endoplasmic reticulum luminal calcium-binding protein with multiple cellular functions, including intracellular Ca2+ homeostasis, oxidative stress responses, and lectin binding. CRT can also modulate cell adhesion, cell-cell interactions, migration, phagocytosis, integrin-dependent Ca2+ signaling, and immune responses, and plays an important role in cellular proliferation, differentiation, and apoptosis. Given these roles, it is not surprising that CRT function has important implications in health and disease. Considerable evidence in recent years suggests that CRT dysfunction is associated with cancer and that CRT could be a diagnostic marker and a target for cancer therapy. These topics are discussed in depth in this review. PMID- 29441975 TI - Novel insights into the pharmacological effects of resveratrol on the management of depression: a short review. AB - Recently, it was suggested that resveratrol (RES), a natural polyphenol, possesses beneficial therapeutic roles in depression. The aim of this review is to discuss the novel potential pharmacological effects of RES on depression. We first consider the pathophysiology of depression and then review the potential antidepressant effects of RES. Apart from the alternation of the monoaminergic system and the molecular markers related to depression, RES might exert an antidepressant-like effect through modulating the HPA axis, BDNF and synaptic vesicle proteins, inflammatory cytokines and oxidative stress, and thyroid hormones. Consumption of RES may represent an alternative strategy to delay the onset and progression of depression, and depressive-like symptoms through multiple pharmacological activities. PMID- 29441977 TI - Production and in vitro evaluation of a lamotrigine extended release tablet based on a controlled-porosity osmotic pump system. AB - Osmotic pump delivery systems have made significant advances in the past decades for controlled drug release over a long period of time. Usually, osmotic pump products require sophisticated and expensive laser drill technology resulting in increase in production cost and decrease in production efficiency. In this study, a lamotrigine extended release tablet based on a controlled-porosity osmotic pump (CPOP) system was developed to circumvent laser drill technology in reference, Lamictal XR(r). The tablet core was coated by a polymer blend of Acryl-EZE(r) and HPMC E5. Lactose and HPMC were added in the CPOP core to adjust the release profile. An orthogonal design was employed to optimize the formulation from factors, i.e., core composition, coating materials ratio and coating levels. Comparisons of in vitro drug release profiles were also conducted. The optimized formulation showed a satisfactory zero-order release profile (R2 = 0.9912). Similarity factor, f2 of 77 was obtained in larger scale. The lamotrigine extended release tablets based on the CPOP system showed ideal reproducibility and stability. The developed system has the ability to be an alternative production method for Lamictal XR(r), which could circumvent the laser drill technology and promote the osmotic pump generalization. PMID- 29441978 TI - The use of experimental design for the development of a capillary zone electrophoresis method for the quantitation of captopril. AB - A capillary zone electrophoresis (CZE) method for the quantitation of captopril (CPT) using UV detection was developed. Influence of electrolyte concentration and system variables on electrophoretic separation was evaluated and a central composite design (CCD) was used to optimize the method. Variables investigated were pH, molarity, applied voltage and capillary length. The influence of sodium metabisulphite on the stability of test solutions was also investigated. The use of sodium metabisulphite prevented degradation of CPT over 24 hours. A fused uncoated silica capillary of 67.5cm total and 57.5 cm effective length was used for analysis. The applied voltage and capillary length affected the migration time of CPT significantly. A 20 mM phosphate buffer adjusted to pH 7.0 was used as running buffer and an applied voltage of 23.90 kV was suitable to effect a separation. The optimized electrophoretic conditions produced sharp, well resolved peaks for CPT and sodium metabisulphite. Linear regression analysis of the response for CPT standards revealed the method was linear (R2 = 0.9995) over the range 5-70 MUg/mL. The limits of quantitation and detection were 5 and 1.5 MUg/mL. A simple, rapid and reliable CZE method has been developed and successfully applied to the analysis of commercially available CPT products. PMID- 29441979 TI - Using PVA and TPGS as combined emulsifier in nanoprecipitation method improves characteristics and anticancer activity of ibuprofen loaded PLGA nanoparticles. AB - In the preparation of nanoparticles (NPs) by the nanoprecipitation method, emulsifiers play a key role for NPs' characteristics. The present study aimed to investigate the combined emulsifier effect on ibuprofen loaded poly(lactic-co glycolic acid) (PLGA) NPs' characteristics and anticancer activity. Ibuprofen loaded PLGA NPs were prepared by nanoprecipitation using different concentrations of PVA (poly(vinyl alcohol)) or PVA-TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) combination as emulsifier. It was found that encapsulation efficiencies of NPs varied between 17.9 and 41.9 % and the highest encapsulation efficiency was obtained with 0.5% PVA + 0.1% TPGS (coded as PLGA PVA/TPGS NPs). PLGA PVA/TPGS NPs were characterized and compared with PLGA PVA NPs, which was obtained by 0.5% PVA alone. Polydispersity index of PLGA PVA/TPGS and PLGA PVA NPs were found to be 0.08 and 0.15, respectively. Incorporation of TPGS with PVA slightly decreased the initial ibuprofen release. Transmission electron microscopy analyses demonstrated a nearly uniform particle size distribution and spherical particle shape of the PLGA PVA/TPGS NPs. Additionally, PLGA PVA/TPGS NPs were significantly more cytotoxic than PLGA PVA NPs on the MCF-7 (human breast adenocarcinoma cells) and Caco-2 (human epithelial colorectal adenocarcinoma) cells (p<0.05). Also PLGA PVA/TPGS NPs were not cytotoxic on normal cells (L929, mouse healthy fibroblast cells) (p>0.05). In conclusion, these results indicated that using a combination of TPGS and PVA as an emulsifier in nanoprecipitation could be a promising approach for preparing ibuprofen loaded PLGA NPs because of their improved characteristics and anticancer activity. PMID- 29441980 TI - Computational prediction of new CYP17 inhibitors based on pharmacophore modeling, virtual screening and docking approach. AB - 17alpha-Hydroxylase/C17-20-lyase (P450 17, CYP 17) is an important enzyme in the androgen biosynthesis and inhibitors of this enzyme can be used for the treatment of prostate cancer. With the aim of developing new inhibitors for the target enzyme, we generated a structure-based pharmacophore model to further explain the binding requirements for human CYP17 inhibitors. Seven common features of steroidal CYP17 inhibitors were determined using MOE software. This pharmacophore model was then used to search the Cambridge Structural Database (CSD) with the aim of developing more potent and selective CYP17 inhibitors by identifying new hits. We were able to identify 36 structures as possible active CYP17 inhibitors. Docking studies for the selected compounds from the database were also performed and the best three compounds were chosen as possible hits. PMID- 29441981 TI - Long non-coding RNA Sox4 promotes proliferation and migration by activating Wnt/beta-catenin signaling pathway in osteosarcoma. AB - Osteosarcoma is a bone tumor without effective treatment in the world. Recently, long non-coding RNAs (lncRNAs) are considered as essential regulators in cancer progression. LncSox4 plays crucial roles in liver tumor-initiating cells self renewal and tumor initiation. However, the effect of lncSox4 in osteosarcoma remains largely unclear. Quantitative real-time PCR (qRT-PCR) and Northern blot were performed to detect lncSox4 expressions in osteosarcoma. The functions of lncSox4 in osteosarcoma were determined using cell viability and migration assays. In addition, the proteins associated with lncSox4 were further evaluated by western blot. We found that lncSox4 was expressed highly in U-20S and Mg63 cells and osteosarcoma tumor tissues (all P < 0.001). LncSox4 silencing attenuated but lncSox4 overexpression promoted cell viability (all P < 0.001) and migration (P < 0.01) in the Mg63 cells. Next, we found lncSox4 regulation of osteosarcoma is involved in beta-catenin, and overexpression of lncSox4 could stable beta-catenin expression. Further, Wnt agonist CID11210285 completely abolished the decrease of Mg63 cells viability induced by lncSox4 silencing when cells cultured for 3 and 4 days (both P < 0.01), while Wnt inhibitor IWP-3 abolished the increase of Mg63 cells viability induced by overexpression of lncSox4 after treatment for 2 (P < 0.01), 3 (P < 0.001) and 4 (P < 0.01) days. Our study offers evidence for the first time that lncSox4 plays a positive role in osteosarcoma development and progression, and could act as a potential prognostic and therapy biomarker. PMID- 29441983 TI - MicroRNA-137 promotes hepatitis B virus gene expression and replication via targeting the protein inhibitor of activated STAT 2. AB - Hepatitis B virus (HBV) infection is one of the most important infectious diseases in China. In this study, we investigated the functional role of miR-137 in HBV infection to further elucidate the mechanism underlying the associated pathology. Viral replication was determined after transfection of HEK293 cells with the replication-competent vector pHBV1.3 and miR137 mimics or inhibitors. Expression of HBV genes was determined by quantitative real-time PCR (qRT-PCR). Expression of miR-137 and protein inhibitor of activated STAT 2 (PIAS2) was determined by qRT-PCR and Western blotting. Activity of the PIAS2 3'-UTR was determined by dual-luciferase reporter assays. Transfection of HEK293 cells with pHBV1.3 increased the expression of miR-137. Co-transfection with miR-137 mimic upregulated HBV gene expression and viral replication. MiR-137 targeted the PIAS2 3'-UTR, and suppressed PIAS2 mRNA and protein expressions. SiRNA-mediated PIAS2 knockdown suppressed HBV gene expression and viral replication. PIAS2 expression rescued the promotion effect of miR-137 on HBV expression and viral replication. MiR-137 expression was significantly upregulated following HBV infection. Furthermore, miR-137 promoted the expression of HBV genes and viral replication by targeting the expression of PIAS2. Our findings might provide a new insight into the diagnosis and treatment of HBV infection. PMID- 29441982 TI - MicroRNA-17-3p promotes keratinocyte cells growth and metastasis via targeting MYOT and regulating Notch1/NF-kappaB pathways. AB - Wound healing is a fundamental biological process to restore skin integrity. The role of microRNAs (miRNAs) during this process remains elusive. Thus, our study aimed to investigate the biological functions and its molecular mechanisms of miR 17-3p in cutaneous wound healing. Human keratinocyte cell line HaCaT was transfected with miR-17-3p mimic, antisense oligonucleotides (ASO)-miR-17-3p and corresponding controls respectively. After transfection, MTT, flow cytometry, qRT PCR and western blot were performed to analyze cell viability, colony-formation and cell cycle. Next, scratch wound, Transwell and western blot were used to examine cell migration ability. Besides, prediction of miR-17-3p target was performed by TargetScan and microRNA database, dual-luciferase reporter assay, qRT-PCR and western blot. Moreover, the functions of the MYOT on cell proliferation and metastasis were detected by transfection with its expression vector. Signal pathways of Notch1 and NF-kappaB were performed by qRT-PCR and western blot. Results showed that miR-17-3p overexpression distinctly promoted cell viability, colony formation, arrested cells at G2/M phase, and upregulated cyclin D1, cyclin B1 and CDK2. Simultaneously, miR-17-3p overexpression increased cell migration and downregulated E-cadherin but upregulated vimentin and alpha SMA expression. Moreover, MYOT was verified as a target of miR-17-3p, and it remarkably inhibited HaCaT cells proliferation and metastasis. Protein expression levels of cyclin D1, cyclin B1, CDK2, vimentin and alpha-SMA were downregulated while E-cadherin was upregulated by MYOT. Furthermore, miR-17-3p signally activated Notch1/NF-kappaB pathways. These data demonstrated that miR-17-3p promoted keratinocyte cells proliferation and metastasis via targeting MYOT and activating Notch1/NF-kappaB signal pathways in cutaneous wound healing. PMID- 29441984 TI - Direct oral anticoagulants in real clinical practice: analysis of patient characteristics and prescribing patterns in a large teaching hospital. AB - Direct oral anticoagulants (DOACs) became rapidly accepted as an alternative to warfarin in the prevention of stroke in atrial fibrillation and prophylaxis of thromboembolic events. Their safety and efficacy have been well documented in several studies, however, as with any new drug, use in real-world population often reveals risk factors that may affect treatment outcomes. The aim of the study was to determine the prescribing patterns and analyse patient characteristics to identify incidence of selected factors (age, weight, comorbidities and interacting medication) that may affect DOAC safety and efficacy. We conducted a 12-months retrospective study of 504 patients who were initiated DOAC in a large university hospital. Basic demographics, indication for DOAC prescribing, renal functions, co-medication, comorbidities and prescribing service were collected from the hospital's electronic records. Rivaroxaban accounted for the majority of DOAC prescriptions (58.9%), and prophylaxis of deep venous thromboembolism was the main reason for initiation of DOACs (58.7%). We found significant variability in terms of age (16 - 96 years) and weight (34.5 - 184 kg). Chronic renal failure was present in 5.6% of patients. We identified 101 clinically relevant drug interactions of DOACs, mostly with selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors (31.7%) and nonsteroidal anti-inflammatory drugs (28.7%). Only three drug interactions were rated as contraindicated. Hypertension (48.6%), dyslipidaemia (33.1%), musculoskeletal disorders (21.0%) and diabetes mellitus (16.1%) were the most frequent comorbidities. Clinicians should be careful when prescribing DOACs to patients with comorbidities or co-medication that have the potential to increase risk of bleeding or decrease anticoagulant activity of DOACs. PMID- 29441985 TI - Total phenolic and tannins determination: a modification of Ph. Eur. 2.8.14 for higher throughput. AB - A principle mostly being used to quantify phenols and tannins is the Folin Ciocalteu's reagent method described in the European Pharmacopeia's method 2.8.14. Aim of the present study was to simplify this procedure in order to handle larger sample numbers. By changing the wavelength, the amounts of reagents, miniaturizing the setting to microtiter scale and changing the incubation time before measurement, the Ph. Eur. method 2.8.14 was optimized for a larger number of experiments. Calibration curves and time kinetics with different phenolic compounds (catechol, procyanidin B1, gallic acid, (+) catechin, tannic acid, salicylic acid, ferulic acid) were determined. In addition, the absorbance of a 1 M solution was calculated by extrapolation of each calibration curve, to examine correlations due to the reaction's stoichiometry. Furthermore, the repeatability concerning herbal samples was investigated using Quercus cortex. The method was validated concerning its repeatability, robustness, linearity and reproducibility. Using this method, at least 120 samples can be handled per day by one person to quantify the total phenolic and tannin content. PMID- 29441986 TI - Caspofungin infusion solutions (50 mg/100 mL): chemical stability and antifungal activity against Candida spp. AB - BACKGROUND: Ready to use caspofungin infusion bags are centrally prepared in the Hospital Pharmacy, University Hospital of Heidelberg, for economic reasons and possibly occurring problems with drug shortages. The aim of this study was a quality control of the in-house preparation of caspofungin infusion bags and the preparation process. Caspofungin concentration with regard to chemical stability and antifungal activity of caspofungin preparations were defined as quality parameters. METHODS: Three caspofungin infusion bags (50 mg in 100 mL 0.9% sodium chloride) were examined every seven days for a total of four weeks. Chemical stability of caspofungin solutions was analyzed using a validated high performance liquid chromatography (HPLC) method. Antifungal activity was assessed by microdilution tests according to the EUCAST protocol. Additionally, concentration and sterility were determined in returned caspofungin infusion bags. RESULTS: The amount of caspofungin in the infusion solutions still exceeded 90% after four weeks (2-8 degrees C). Antifungal activity was consistent over 28 days with a MIC <=2 mg/L for different Candida spp. In returned infusion bags, caspofungin concentration was found to be >=90% in 12 out of 13 bags and sterility was given in all preparations. CONCLUSION: These results show that chemical stability of caspofungin infusion solutions (50 mg/100 mL) can be guaranteed for four weeks at 2-8 degrees C and are confirmed by corresponding results regarding sterility and antifungal activity. PMID- 29441987 TI - Enhancement of trans-resveratrol photostability by encapsulation in lipid microparticles: in vitro and in vivo studies. AB - Lipid microparticles (LMs) loaded with the antioxidant polyphenol, trans resveratrol were developed in order to enhance its photostability in topical formulations. The LMs were prepared by the melt emulsification technique, using tristearin as the lipidic material and hydrogenated phosphatidylcholine as the surfactant. The obtained microparticles were characterized by optical microscopy and release studies. The trans-resveratrol loading was 10.8% (w/w). Free or microencapsulated trans-resveratrol was introduced in model topical formulations (cream and hydrogel) and irradiated with a solar simulator. The light-induced degradation of trans-resveratrol was significantly reduced by incorporation into the LMs both in the cream (the trans-resveratrol loss decreased from 34.3% to 19.9%) and in the hydrogel (the trans-resveratrol decomposition decreased from 15.4% to 9.4%) vehicles. Moreover, the in vitro (i.e., antioxidant action) and in vivo (i.e., anti-inflammatory action) biological activities of trans-resveratrol in the cream preparation were not altered by the encapsulation process. PMID- 29441988 TI - Co-administration of tLyp-1 with polymeric paclitaxel conjugates: Enhanced intratumoral accumulation and anti-tumor efficacy. AB - BACKGROUND: It has been previously demonstrated that conjugation of paclitaxel to a linear poly(l-gamma-glutamylglutamine) backbone can enhance water solubility of paclitaxel. However, intratumoral penetration of the nanoscale poly(l-gamma glutamylglutamine)-paclitaxel conjugate (PGG-PTX) was still limited due to dysfunctional tumor blood vessels as well as high interstitial pressure in the tumor microenvironment. PURPOSE: The objective of the present research was to investigate the feasibility of co-administration of a tumor penetration enhancing peptide tLyp-1 for improving intratumoral accumulation and consequent anti-tumor efficacy of PGG-PTX. METHODS: The influence of co-administration of tLyP-1 with PGG-PTX on intratumoral accumulation (via HPLC-MS/MS) and anti-tumor efficacy (by monitoring the change in the tumor volume) was investigated using a breast cancer (4T1) tumor-bearing mouse model. In addition, the systemic toxicity of co administration of tLyP-1 with PGG-PTX was assessed by monitoring the change in the animal body weight. RESULTS: It was observed that co-administration of tLyP-1 with PGG-PTX dramatically improved PGG-PTX accumulation in the tumors, resulting in improved inhibition efficiency against tumor growth. Moreover, co administration of tLyP-1 with PGG-PTX did not change the systemic toxicity profile of PGG-PTX. CONCLUSION: Co-administration of tLyp-1 may be a promising strategy for improving the passive tumortargeting performance of polymeric drug conjugates. PMID- 29441990 TI - The autophagy inhibitor 3-methyladenine restores sevoflurane anesthesiainduced cognitive dysfunction and neurons apoptosis. AB - This study was designed to explore the effect of 3-methyladenine (3-MA) on sevoflurane anesthesia-induced cognitive dysfunction. A total of 60 C57BL/6 (5-8 months old) mice were randomly arranged into 3 groups: Control, sevoflurane (Sev) and Sev+3-MA group with 3-MA administration was performed during Sev administration. Morris water maze and Y-maze test were performed to examine the behavioral disorders. Moreover, hippocampal neuronal cell apoptosis and expression of autophagy related genes were detected. Sevoflurane induced cognitive dysfunction in mice showing significant longer escape latency, lower number of correct response, higher apoptotic neurons, and higher expression of autophagy related genes. However, additional 3-MA administration inhibited the effect of sevoflurane on cognitive dysfunction by shorting escape latency, reducing correct response number, inhibiting neurons apoptosis and autophagy genes expression. 3-MA additional administration inhibited sevoflurane anesthesia induced cognitive dysfunction on mice. 3-MA might be usefull as an inhibitor for sevoflurane anesthesia-induced cognitive dysfunction in clinical trials. PMID- 29441989 TI - Modulated function of multidrug resistance-associated proteins in cisplatin induced acute renal failure rats. AB - The effect of cisplatin-induced acute renal failure (ARF) on the function and expression of multidrug resistanceassociated proteins (MRPs) was evaluated in rats. Rats received an intraperitoneal injection of cisplatin (9 mg/kg), and the induction of ARF state with high plasma concentrations of indoxyl sulfate and creatinine was observed 72 h after cisplatin treatment. The function of MRPs in the liver, kidney and brain was evaluated by measuring the tissue accumulation and biliary excretion of 2,4-dintrophenyl-S-glutathione (DNP-SG), a substrate for MRPs, after administration of 1-chloro-2,4-dintrobenzene (CDNB), a precursor of DNP-SG, in rats. The levels of MRP1-4 expression were evaluated by Western blot analysis. Effect of ARF plasma components on MRP function was also examined by using calcein acetoxymethyl ester (calcein-AM) in HepG2 cells. In ARF rats (72 h after cisplatin treatment), the accumulation of DNP-SG in the liver, kidney and brain was significantly higher than those in control and cisplatin-treated rats (1 h after treatment). In ARF rats, intrinsic biliary excretion clearance of DNP SG, estimated by dividing the biliary excretion rate of DNP-SG with the liver concentration, was also significantly reduced, though the expression levels of MRP1-4 in the liver remained unchanged. ARF rat plasma (5%) significantly increased the accumulation of calcein, a MRP substrate, in HepG2 cells after application of calcein-AM. In conclusion, MRP function was found to be suppressed not only in the kidney but also in the liver and brain in cisplatin-induced ARF rats, possibly due to the accumulation of some MRP substrates/inhibitors in plasma. PMID- 29441991 TI - Efficacy and mechanism of action of etanercept in bone cancer pain. AB - Bone cancer pain treatment remains a major clinical challenge, and the mechanism underlying bone cancer pain remains insufficiently understood. The purpose of the current study was to evaluate the efficacy of etanercept, a TNF- inhibitor, against bone cancer pain in an established bone cancer pain model. The mechanical pain threshold value was tested, and the expression of inflammatory factors, NOS, MrgC and NR2B were assessed. The results showed that etanercept decreases the mechanical pain threshold value and inhibits expression of inflammatory factors, NOS, MrgC and NR2B. Etanercept may moderate bone cancer pain via the MrgC-NR2B signaling pathway. PMID- 29441992 TI - MicroRNA-320a protects against osteoarthritis cartilage degeneration by regulating the expressions of BMI-1 and RUNX2 in chondrocytes. AB - Osteoarthritis (OA) is one of the most common chronic degenerative diseases characterized by deterioration of articular cartilage. Many studies have demonstrated the role of microRNAs (miRNAs) in OA, but the role of miR-320a in OA remains elusive. The aim of this study was to identify the protective role of miR 320a in OA cartilage degeneration by regulating the expression of BMI-1 and RUNX 2 proteins in chondrocytes. Normal and OA chondrocytes obtained from patients were cultured in vitro. The chondrocytes (both normal and OA) were transfected with miR-320a inhibitor to investigate the effects of miR-320a on chondrocyte proliferation, and to identify the miR-320a target proteins. The results indicated that miR-320a expression was significantly higher (P<0.05) in OA chondrocytes than in normal chondrocytes. Inhibition of miR-320a effectively enhanced chondrocyte cell viability in vitro in a time-dependent manner. Inhibition of miR-320a showed a significant decrease (P<0.05) in the secretion of matrix metalloproteinase-13 (MMP-13). Furthermore, miR-320a could regulate the expression levels of BMI-1 and RUNX-2 proteins in OA chondrocytes (P<0.05). The data suggested that miR-320a protected against OA cartilage degeneration and regulated the expression levels of BMI-1 and RUNX2 proteins in chondrocytes. Our study might provide a new insight in the clinical treatment of OA. PMID- 29441994 TI - Decreased miR-144 expression as a non-invasive biomarker for acute myeloid leukemia patients. AB - MicroRNAs are found to be stable in blood and they demonstrated tissue specific expression patterns. Thus, they may be used as potential non-invasive biomarkers of specific cancers. In the current study, we mainly focused on miR-144, which has never been studied in acute myeloid leukemia (AML). The expression of miR-144 was explored in the bone marrow and peripheral blood of AML patients and healthy control. The correlation between peripheral blood miR-144 level and key clinical parameters, including overall survival and prognostic value, was further explored. We showed that miR-144 was markedly reduced in both the peripheral blood and bone marrow of AML patients compared with healthy controls. Further study revealed that there is a significant correlation between peripheral blood miR-144 level and FAB classification (p=0.0023) and cytogenetics (p=0.001). More importantly, a lower expression of peripheral blood miR-144 level was found to be positively correlated with poorer overall survival rate. In summary, peripheral blood miR-144 may be utilized as a potential novel non-invasive biomarker for AML screening. PMID- 29441993 TI - Klotho protects against LPS-induced inflammation injury by inhibiting Wnt and NF kappaB pathways in HK-2 cells. AB - AIM: This study aimed to investigate the effect and mechanism of Klotho in lipopolysaccharide (LPS)-induced inflammation injury in HK-2 cells. METHODS: We established LPS-induced inflammation injury model in HK-2 cells. The LPS-induced HK-2 cells were transfected with pc-Klotho, pcDNA3.1, siKlotho or siNC. Cell viability, apoptosis and reactive oxygen species (ROS) level were detected by MTT assay, Annexin V-FITC/PI Apoptosis Detection kit and 2,7-dichlorofluorescein diacetate, respectively. The levels of inflammatory factors and the expressions of proteins related to Wnt and nuclear factor-kappaB (NF-kappaB) signaling pathway were detected by RT-qPCR and western blotting, respectively. RESULTS: Compared with cells transfected with pcDNA 3.1, cell viability was remarkably increased and cell apoptosis rate was decreased in LPS-induced cells with pc Klotho (p < 0.05). Conversely, LPS-induced cells with siKlotho showed lower cell viability and higher cell apoptosis rate than cells with siNC (p < 0.05). The levels of ROS, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) was significantly reduced in LPS-induced cells with pc-Klotho compared with cells with pcDNA3.1 (p < 0.05). Consistently, LPS-induced cells with siKlotho showed increased levels of ROS, TNF-alpha and IL-6 compared with cells with siNC (p < 0.05). Wnt signaling pathway related protein Wnt3a and NF-kappaB signaling pathway related to proteins p-IkappaBalpha were significantly down-regulated in LPS-induced cells with pc-Klotho compared with cells with pcDNA3.1, while up regulated in LPS-induced cells with pc-Klotho compared with cells with pcDNA3.1 (p < 0.05). CONCLUSIONS: Klotho may play an inhibiting role in LPS-induced inflammation injury by inhibiting NF-kappaB and Wnt signaling pathways in HK-2 cells. PMID- 29441995 TI - Short-term curative effect of S-1 plus oxaliplatin as perioperative chemotherapy for locally advanced gastric cancer: a prospective comparison study. AB - This research aimed to investigate the efficacy of S-1 plus oxaliplatin (SOX) as perioperative chemotherapy for locally advanced gastric cancer. We enrolled 102 patients with preoperative clinical stage T3-4N*M0 gastric cancer who were then randomly assigned to receive SOX as either perioperative chemotherapy (group A, 50 patients) or postoperative adjuvant chemotherapy (group B, 52 patients). Short term curative efficacy and adverse effects of perioperative chemotherapy were analyzed. The rates of R0 resection, surgical complications, combined multiple organ resection, overall survival (OS), and disease-free survival (DFS) were compared between the groups. Results showed an overall response rate in group A of 42%, with a disease control rate of 94% and a tumor down-staging rate of 50%. An R0 resection rate of 90% was achieved in group A, which was significantly higher than that in group B (75%). No surgical mortality was observed, and the differences in surgical complications and combined multiple organ resection rates between the groups were not significant. The postoperative pathological examination of 4 patients in group A did not show any cancer cells in the tumor bed, resulting in a histological complete remission rate of 8%. The average OS and DFS for group A patients were 17.928 and 16.134 months, respectively, which were both longer than that of group B patients. However, the differences were not significant. In all, our results shows that in locally advanced gastric carcinoma, SOX perioperative chemotherapy is effective and results in a significantly improved R0 resection rate compared to postoperative SOX administration. Perioperative SOX does not cause additional surgical complications and has low adverse reaction rates; moreover, it appears to prolong survival. PMID- 29441996 TI - A guide for using experimental design in chromatographic method development: applied to the analysis of selected anti-diabetic pharmaceutical combinations. AB - A guide experimental design in chromatographic method development was described and applied successfully to the analysis of different recently approved anti diabetic pharmaceutical combinations. Enhancement of UHPLC analysis of alogliptin benzoate either with pioglitazone hydrochloride or with metformin hydrochloride was achieved. The optimal chromatographic conditions were not attained by trial and error that requires a large number of experiments. Alternatively, a computer program was used as a systematic optimization strategy for the design of the experiment which accurately predicts the combined effect of different factors simultaneously. Resolution between peaks was studied by the proposed fractional factorial design approach performed by the Minitab(r) Program using screening and optimization steps. Application of the central composite design was implemented. A Pareto chart was used to exclude the insignificant variables. Linearity ranges were found to be 0.5-40 MUg ml-1, 1-20 MUg ml-1 and 1-32 MUg ml-1 for alogliptin benzoate, pioglitazone hydrochloride and metformin hydrochloride, respectively. The proposed method is applicable for the analysis of six pharmaceutical dosage forms namely, Nesina(r), Actos(r), Glucophage(r), Oseni(r), Kazano(r) and Actoplus MET(r) tablets. PMID- 29441997 TI - Curcumin diethyl disuccinate encapsulated in chitosan/alginate nanoparticles for improvement of its in vitro cytotoxicity against MDA-MB-231 human breast cancer cells. AB - Curcumin diethyl disuccinate (CDD) is a succinate prodrug of curcuminoids that has better stability in human plasma and improved in vitro cytotoxicity compared to curcumin. Therefore, CDD has the potential for further development as an anticancer agent. In this study, we focused on optimization of the formulation of CDD-loaded chitosan/alginate nanoparticles using Box-Behnken statistical design to enhance the therapeutic efficacy of CDD. Oil-in-water emulsification followed by ionotropic gelification was used to prepare the CDD-loaded chitosan/ alginate nanoparticles. A formulation with a 0.05:1 chitosan/alginate mass ratio, 0.65% (w/v) Pluronic F127 and 1.5 mg/ml CDD was found to be optimal. FTIR, TGA and XRD confirmed the encapsulation of CDD molecules in the nanoparticles. In vitro cytotoxicity and cellular uptake studies showed that CDD-loaded chitosan/alginate nanoparticles had significantly higher cytotoxicity and cellular uptake in human breast adenocarcinoma MDA-MB-231 cells, compared to free CDD. Physical and chemical stability studies indicated that the optimally formulated CDD-loaded chitosan/alginate nanoparticles were stable at 4 degrees C for 3 months. PMID- 29441998 TI - Alternative approaches in formulating floating hollow tablets via sublimation technique; a platform tailored drug release profile. AB - The aim of this study was to formulate floating hollow tablets of salbutamol sulphate with a platform tailored drug release profile to attain a controllable drug release. Eight formulations (F1-F8) were prepared using sublimation technique. L-menthol was directly compressed as sublimable core followed by compression coating of hydroxypropylmethyl cellulose (HPMC-K15M) or polyethylene oxide (PEO-WSR301) as release retarding polymer coat. Tablets were then subjected to heat to allow sublimation of the core. The effect of polymer type and that of different drug coat/core distribution on swelling and drug release profile was studied. FTIR and DSC revealed the absence of any drug-excipients interaction. Tablets showed a hollow morphology, resulting in low density tablets that floated for over 24 hours without lag time. Moreover, different drug coat/core distribution resulted in controllable release profiles. Based on these results, an optimum drug release behavior was recorded for HPMC-based hollow tablets consisting of 2:1 drug coat/core distribution ratio (F4), revealing a zero order drug release for over 14 hours. Furthermore, F4 showed no changes in drug content, floating properties and drug release profile upon exposure to accelerated stability conditions. PMID- 29441999 TI - High-density lipoprotein-biomimetic nanocarriers for glioblastoma-targeting delivery: the effect of shape. AB - Rational design of the physicochemical properties of nanocarriers can optimize their pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. In particular, particle shape is one of the crucial parameters that can impact the circulation time, tumor accumulation and tumor cell internalization of nanocarrier. Biomimetic reconstituted high-density lipoprotein (rHDL), by mimicking the endogenous shape and structure of high-density lipoprotein, has been indicated as a promising tumor-targeting nanoparticulate drug delivery system whereas the effect of shape on tumor-targeting efficiency has not been fully evaluated. Herein, we constructed apolipoprotein E-based biomimetic rHDL in both discoidal form (d-rHDL) and spherical form (s-rHDL), and compared their efficiency in glioblastoma multiforme (GBM)-targeting delivery. s rHDL showed higher cellular association in GBM cells especially at a high exposure dosage or after a long incubation time. Moreover, it exhibited deeper penetration in 3D GBM spheroids in vitro and higher accumulation at the GBM site in vivo with the GBM-targeting accumulation of s-rHDL increased by 73% when compared with that of d-rHDL at 24 h post-injection. The findings collectively indicated that s-rHDL might serve as a more efficient nanocarrier for glioblastoma-targeting drug delivery. PMID- 29442000 TI - MicroRNA-132 sensitizes nasopharyngeal carcinoma cells to cisplatin through regulation of forkhead box A1 protein. AB - Chemoresistance in cancer is one of the major hindrances in cisplatin (DPP) treatment for nasopharyngeal carcinoma (NPC). The mechanism of such resistance remains unknown. Therefore, the present study aimed to clarify the mechanism of DDP resistance and attempted to reduce chemoresistance. Here, we found that miR 132, as a tumor suppressor, was poorly expressed in a cisplatin resistant CNE2 cell line (CNE2/DPP) accompanied with a decreased expression of miR-132 and an increased expression of FOXA1 compared with the parental cells CNE2. Exogenous overexpression of miR-132 in CNE2/DPP could sensitize their reaction to the treatment of cisplatin. In addition, FOXA1 knockdown in CNE2/DPP cells increased the chemosensitivity to DPP, suggesting the dependence of FOXA1 regulation in miR 132 activity. Moreover, miR-132 can restore cisplatin treatment response in cisplatin-resistant xenografts in vivo, while FOXA1 protein levels were decreased. In summary, our results provide novel mechanistic insights into the role of miR-132/FOXA1 signaling in the cisplatin resistance of NPC cells. Targeting of miR-132 is a potential therapeutic approach for NPC. PMID- 29442001 TI - Decreased miR-208 induced ischemia myocardial and reperfusion injury by targeting p21. AB - Aberrant expression of miR-208 was previously reported in cardiomyocytes after cardiac ischemia reperfusion (CIR) injury. However, the underlying mechanism has never been elucidated. In the current study, the relative level of miR-208 was determined in the hearts of CIR injury mice models using real time PCR. The effect of miR-208 on cardiomyocytes apoptosis was determined by Hoechst staining and annexin V-PI staining. Meanwhile, caspase3 activity was explored using an assay kit. To identify left ventricular fraction and relative wall thickness, the two-dimensional echocardiography was applied. Dual luciferase assay was applied to determine the target gene of miR-208. Compared with normal control, the level of miR-208 was significantly reduced in the hearts of CIR injury mouse models. Further studies revealed that reduction of miR-208 contributed to reactive oxygen species (ROS) production in the cardiomyocytes. We also found that inhibition of miR-208 prompted cardiomyocyte apoptosis. More importantly, the phosphorylation level of Akt and p38 was enhanced in primary cardiomyocytes transfected with miR 208 inhibitor, indicating a potential stress-response after CIR injury in primary cardiomyocytes. Dual luciferase assay and western blot analysis showed that transfection with miR-208 markedly suppressed the protein expression of p21, suggesting p21 was a target gene of miR-208. To conclude, we showed that reduced miR-208 level enhanced cardiomyocyte apoptosis mainly by targeting p21. PMID- 29442002 TI - Comparative analysis of synthetic and nutraceutical antioxidants as possible neuroprotective agents. AB - Damage caused by oxidative stress in cases of neurodegenerative diseases such as Alzheimer's or Parkinson's has been proven to be irreversible. However, diet supplementation of antioxidants can be beneficial to the total antioxidant status of the human body. Given that oxidative stress is a principal cause of neurodegenerative disease, effective natural antioxidants could provide therapeutic options for these disorders. Therefore we investigated the antioxidant properties of two natural extracts and five synthetic compounds in lipid rich environment of liposomes with oxidation induced by Fenton's reagent. Antioxidant activity has been quantified using the Klein peroxidation index and oxygen uptake. Both natural extracts from Acai berry and Ginseng as well as all synthetic compounds - N-acetyl-L-cysteine, tocopherol, huperzines, caffeic acid and lipoic acid displayed good antioxidants properties, which confirm their suitability as neuroprotective agents. PMID- 29442003 TI - Evaluating the relationship between cell viability and volatile organic compound production following DMSO treatment of cultured human cells. AB - Methylsulfinylmethane (dimethyl sulfoxide; DMSO) is widely used in clinical treatment and bioresearch. Moreover, there is bioconversion between methylsulfanylmethane (dimethyl sulfide; DMS), DMSO, and methylsulfonylmethane (DMSO2) in mammalian metabolism. Due to the real-time detection limits for volatile compounds, most research has focused on DMSO2 as a stable byproduct of DMSO. Therefore, details about the production of DMS as a byproduct of DMSO metabolism remain to be elucidated. Here, we report the characterization of trace level volatile organic compounds (VOCs) produced following DMSO treatment of cultured human cells using an ultrasensitive vacuum ultraviolet photoionization mass spectrometer (VUV-PIMS). Using this approach, 24 h after DMSO treatment we detected 16.9 and 21 parts per billion by volume (ppbv) DMS in the atmosphere above the cells (headspace) within HeLa and 293T tissue culture flasks, respectively. When simultaneously exposed to 50 nM paclitaxel (PTX), 17.6 and 22.3 ppbv DMS were detected in the headspace of HeLa and 293T culture flasks, respectively. Nevertheless, at doses of PTX more or less than 50 nM, the detectable levels of DMS were reduced to as low as 8.4 ppbv. Our experimental results demonstrate that by co-administering 5 to 10 nM PTX with DMSO, it is possible to moderate the production of DMS considerably. However, at higher doses of PTX, increased apoptosis was observed that likely contributed to higher DMS production by cells. PMID- 29442005 TI - Neuropathic organophosphates: from Scrugham, Heim and Lorot to Jake leg paralysis. AB - Henry Scrugham (1811-1898), the father of triphenyl-phosphate, was a student of Alexander Williamson (1824-1904), Professor of analytical and practical chemistry at the University College London. Williamson using the approach perfected by Scurgham reacted phosphorus pentachloride with cresol (a mixture of ortho, para and meta isomers) thus obtaining tricresyl phosphate (TCP). The triesters of phenol, cresol and naphtol were prepared with a higher yield by Rudolf Heim (1861 1919) by their respective reaction with phosphorus oxychloride (POCl3). Heim is also the first one to obtain pure tri-o-cresyl phosphate (TOCP). In the meantime French pharmacist Jules Brissonnet (1859-1915) synthesized creosote phosphate (containing i.a. TOCP) and popularized its use in the treatment of pulmonary phthisis (tuberculosis). Camille Lorot (1872-1951) and others in France and Germany recognized the ability of creosote phosphate to induce polyneuropathies but this knowledge did not prevent the Ginger Jake epidemic (Jake leg) of the 1930s in the US. The Jake induced neuropathy was first recognized and described in Oklahoma City by a General Practitioner, Ephraim Goldfain (1894-1983). Soon thereafter Maurice Isadore Smith (1887-1951), a pharmacologist, and chemist Elias Elvove (1883-1962) identified TOCP in Jamaican ginger extract as the causative agent. We attempt to shed some light on the life and family of the less known chemists, pharmacists and physicians associated with the synthesis of neuropathic organophosphates and with the recognition of their toxicity. PMID- 29442004 TI - Rapamycin attenuates palmitate-induced lipid aggregation by up-regulating sirt-1 signaling in AML12 hepatocytes. AB - Rapamycin (Rap), a specific inhibitor of the mTOR signaling, has been shown to affect lipid metabolism in vitro and in vivo. Sirt-1, an NAD+ dependent deacetylase, regulates a variety of cellular processes, including aging, lifespan extension and glucose and lipid metabolism. Herein, we applied a cellular steatosis model to investigate whether rapamycin's role in lipid metabolism is sirt 1-associated. Cells were exposed to palmitate stimulation for 48 h with or without rapamycin treatment. Lipid droplets in AML12 cells were observed by oil red O staining, and the intracellular lipid content was measured. We found that rapamycin treatment, at a relatively low concentration, significantly attenuated lipid aggregation, whereas knockdown of sirt-1 by siRNA abrogated rapamycin's effect on ameliorating lipid accumulation. Moreover, rapamycin exposure increased the expression levels of sirt-1 and AMPK, and enhanced sirt-1 deacetylase activity in steatotic AML12 hepatocytes. This is the first report demonstrating that rapamycin ameliorates lipid accumulation through upregulating sirt-1 signaling supporting the hypothesis that rapamycin may positively influence sirt 1 signaling in maintaining metabolic homeostasis. PMID- 29442006 TI - A time-scaled convolution approach to construct IVIVC for enteric-coated acetylsalicylic acid tablets. AB - A scaled convolution-based in vitro-in vivo (IVIVC) model was constructed for two enteric-coated acetylsalicylic acid tablet formulations. The in vitro data used were the results of dissolution testing performed using three different dissolution methods: the United States Pharmacopoeia (USP) method, a method employing blank Fasted State Simulated Fluid (FaSSIF), and a new method developed in house. The in vivo data were obtained from a pharmacokinetic study on human subjects in the fasted state. When the new dissolution method results were used, an average prediction error less than 10% and a maximum prediction error less than 15% were obtained for the peak plasma concentration (Cmax) and area under the curve (AUC) parameters, thus meeting the internal validation criteria of the IVIVC guidance of the US Food and Drug Administration (FDA). PMID- 29442008 TI - Altered drug release from Orfiril(r) long following ethanol consumption - extent and consequences. AB - Orfiril(r) long is a widely used antiepileptic drug preparation despite being characterized by features associated with susceptibility to ethanol induced changes to drug release. In vitro dissolution studies revealed that 30 % ethanol was required in order to cause dose dumping of valproic acid within two hours at pH 1. However, after exposure to only 5 % of ethanol for 45 minutes at pH 1, the subsequent release of sodium valproate increased by ~ 10 % for the first two hours in ethanol-free media of pH 6.8. The drug solubility increases with pH, likely to also increase the vulnerability to ethanol. This indicates that Orfiril(r) long is affected by exposure to low concentrations of ethanol as well, only that this effect was exclusively displayed at an elevated pH value not part of the standard regulatory recommendations. Even so, simplified pharmacokinetic simulations revealed no risk of a lower therapeutic effect. Postponing the drug intake in case of moderate drinking, likely to increase the risk of omission altogether, is therefore not necessary. However, for slim patients with a small volume of distribution and low tolerability, a longer duration of mild side effects such as drowsiness and nausea might be experienced. PMID- 29442007 TI - Development and analytical characterization of a new antiparasitic fenbendazole compound tablet and pharmacokinetic investigations after its oral administration to dogs. AB - The objective of this study was to prepare a new compound fenbendazole tablet containing 29.7 % fenbendazole, 1.50 % praziquantel and 0.059 % ivermectin for oral administration. The tablets were successfully prepared using mannitol as filler agent, polyvinyl polypyrrolidone as disintegrant, 5 % povidone (PVAK30) as a binder agent and magnesium stearate as lubricant. The appearance, hardness, fragility, time limit of disintegration and fenbendazole dissolution at 45 min all met the technical standards of the Ministry of Agriculture for the People's Republic of China. We used high performance liquid chromatography and electrospray-mass spectrometry for drug detection. Oral administration of 100 mg/kg fenbendazole, 5 mg/kg praziquantel and 0.2 mg/kg ivermectin using a non compartmental model defined peak plasma concentrations (Cmax) of 495, 826, 73 ng/mL, and 218 ng/mL for the metabolite oxfendazole, respectively. The area under the curve (AUClast) values for these drugs were 4653, 1045, 1971 and 5525 h*ng/mL, respectively. This study enriches the pharmacokinetic data of compound fenbendazole tablets using dogs as a model system. The new tablet formulation was assimilated quickly and systemically and this study will be beneficial for the clinical application of parasite treatments in dogs. PMID- 29442009 TI - Anti-ganglioside GD2 monoclonal antibody synergizes with cisplatin to induce endoplasmic reticulum-associated apoptosis in osteosarcoma cells. AB - Cisplatin is an effective chemotherapeutic agent for osteosarcoma (OS) and has been shown to induce endoplasmic reticulum (ER) stress-associated apoptosis in human cancer cells. Ganglioside GD2-specific antibodies can inhibit tumor cell viability without involvement of the immune system. A recent study has shown that antiGD2 monoclonal antibody (mAb) 14G2a effectively inhibits the viability and invasiveness of human OS cells. In this study, we explored the effect of anti-GD2 mAb and cisplatin alone and in combination on ER stress-associated apoptosis in osteosarcoma cells. MG-63 and Saos-2 human OS cells were treated with cisplatin and/or an-GD2 mAb 14G2a for 48 hours. Cisplatin and 14G2a dose-dependently induced apoptosis in MG-63 and Saos-2 cells. They in combination induced 70%-77% of apoptosis in MG-63 cells and 79%-85% of apoptosis in Saos-2 cells, exhibiting a synergistic effect stronger than addition of their individual effects over the control level. Showing no significant effect on the expression of protein kinase RNA-like ER kinase (PERK), cisplatin and 14G2a exhibited a marked synergistic effect on inducing phosphorylation/activation of PERK, phosphorylation/inactivation of eukaryotic translation initiation factor 2alpha (eIF2alpha), expression of CHOP, in parallel to inducing the caspase-3 activity and apoptosis in MG-63 and Saos-2 cells. The effects were abolished by lentivirus mediated knockdown of PERK. Particularly, PERK knockdown abolished 63% and 65% of the combined apoptotic effect of cisplatin and 14G2a on MG-63 and Saos-2 cells, respectively. In conclusion, this study provides the first evidence supporting that cisplatin and 14G2a synergize to induce ER stress-associated apoptosis in human OS cells through activating the PERK ER stress pathway by synergistically inducing phosphorylation/activation of PERK. Our findings add new insights into the pharmacologic effects of anti-GD2 mAb in anticancer treatment and suggest that cisplatin plus anti-GD2 mAb could be a new effective therapeutic strategy for OS. PMID- 29442010 TI - Ganoderic acid A potentiates the antioxidant effect and protection of mitochondrial membranes and reduces the apoptosis rate in primary hippocampal neurons in magnesium free medium. AB - Ganoderma lucidum extracts have shown antiepileptic effects in in vivo and in vitro studies. In this work, primary hippocampal neurons cultured in magnesium free medium were used to study the neuroprotective effects of ganoderic acid A and B (GA-A and GA-B) on superoxide dismutase (SOD) activity and mitochondrial membrane potential, to improve our understanding of their antiepileptic effect. The activity of SOD was determined by the xanthine oxidase assay, the variations of mitochondrial membrane potential and cell apoptosis were measured by JC-1 fluorescent staining and flow cytometry. It was found that the SOD activity and mitochondrial membrane potential (118.84 U/mg protein and 244.08 Deltapsim) of the epileptic hippocampal neurons were significantly lower than control values (135.95 U/mg protein and 409.81 Deltapsim), associated with an increase of cell apoptosis (31.88% vs. 8.84%). These circumstances can be improved by treatment of GA-A/GA-B (for SOD, 127.15+/-3.82 / 120.52+/-4.30 U/mg protein; for membrane potential (Deltapsim), 372.35 / 347.28; and for cell apoptosis (%), 14.93 / 20.52). Results indicated that GA-A significantly improved SOD activity, while both GA-A/GA-B tranquillized the mitochondrial membrane potential of hippocampal neurons, and thereby protected these neurons by inhibiting apoptosis. PMID- 29442011 TI - Acetylpuerarin protects against OGD-induced cell injury in BV2 microglia by inhibiting HMGB1 release. AB - High mobility group box 1 (HMGB1), a non-histone DNA-binding protein, is massively released into the extracellular space from neuronal cells after ischemic injury, initiates inflammatory response and aggravates brain tissue damage. Acetylpuerarin (AP), an acetylated derivative of puerarin, was reported to protect against cerebrovascular ischemia-reperfusion injury in rats through anti-inflammation. In the present study, we aim to investigate whether AP inhibited HMGB1 release in oxygen-glucose deprivation (OGD)-treated BV2 microglia. BV2 microglia viability after OGD with or without AP was measured by CCK-8 assay, apoptosis of BV2 microglia was determined by Hoechst 33258 staining and FITC-Annexin V/7-AAD staining. HMGB1 protein level and release was detected by western blotting and immunofluorescent FITC-staining. The results demonstrated that AP significantly rescued OGD-induced cell death and apoptosis in a dose dependent manner. AP inhibited OGD-induced HMGB1secretion at the level of nuclear to cytoplasmic translocation, decreased cytoplasmic HMGB1 at protein level, and the effects showed dose-dependent. The findings suggest that AP can protect against OGD-induced cellular injury in BV2 microglia by inhibition of HMGB1 release. PMID- 29442012 TI - Effects of the oligostilbenes from Iris lactea Pall. var. chinensis (Fisch.) Koidz on the adipocytes differentiation of 3T3-L1 cells. AB - The dried seeds of Iris lactea Pall. var. chinensis (Fisch.) Koidz, an important traditional Chinese medicine, are regarded to have effects of clearing heat, eliminating dampness and pharyngitis and so on. It has been used in the treatment of jaundice, diarrhea, leucorrhea and carbuncles. Previous phytochemical studies of Iris species showed the presence of flavones, isoflavones, triterpenes and stilbenes. In our previous research, we isolated five known oligostilbenes, vitisin A, vitisin B, vitisin C, vitisin D, and cis-vitisin A were successfully isolated from Iris lactea for the first time. The aim of this study was to assess the effects of these oligostilbenes on the differentiation and adipogenes in 3T3 L1 cells. Our results showed that vitisin A, vitisin B, cis-vitisin A significantly inhibited adipocytes differentiation and reduced lipid accumulation in 3T3-L1 cells. In addition, vitisin A, vitisin B, cis-vitisin A strongly suppressed the expression levels of adipocyte-specific genes including peroxisome proliferator activated receptor-gamma (PPARgamma), CCAAT/enhancer binding protein alpha (C/EBPalpha) and adipocyte fatty acid binding protein 4 (FABP4). In contrast, vitisin C and vitisin D significantly promoted adipogenesis and increased intracellular lipid accumulation, while the two oligostilbenes markedly increased the expression of adipocyte marker genes. In the present study, we found that vitisin A, vitisin B and cis-vitisin A inhibit the adipogenesis and adipocytes differentiation by their influence on the expression of PPARgamma, which leads to subsequenet downregulation of PPARgamma mediated adipocyte specific gene during adipogenesis. PMID- 29442013 TI - P-gp modulating effect of Azadirachta indica extract in multidrug-resistant cancer cell lines. AB - The extract of Azadirachta indica, commonly known as neem, has found extensive use in traditional medicine for treating various human diseases. In this study, the effect of the 50% ethanol extract of A. indica (AI01) on P-glycoprotein (P gp)-mediated multidrug resistance (MDR) was examined using MDR cell lines, specifically paclitaxel-resistant HepG2 (PR-HepG2) and doxorubicin (DOX) resistant (DR) colon-26 cells. 96-h treatment of the two cell lines with AI01 (30 MUg/mL) showed no effect on the expression of P-gp mRNA (human MDR1 and mouse mdr1b) and protein, while AI01 increased the accumulation of rhodamine 123, a P gp substrate, in both PR-HepG2 and DR-colon-26 cells. The cytotoxic effects of 48 h treatment with AI01 on the viability of PR-HepG2 and DR-colon-26 cells were not observed. Therefore, 30 MUg/mL AI01 may have no cytotoxic and P-gp-inducing effects. Finally, AI01 potentiated the sensitivity of PR-HepG2 and DR-colon-26 cell lines to DOX by 8.6- and 15.3-fold, respectively. These findings suggest that A. indica may be a promising source for a new class of P-gp modulators without cytotoxic/P-gp induction effects. PMID- 29442014 TI - Improvement of treatment outcomes after implementation of comprehensive pharmaceutical care in breast cancer patients receiving everolimus and exemestane. AB - Combination therapy with everolimus and an aromatase inhibitor such as exemestane is an effective treatment option for advanced or recurrent breast cancer. However, the therapy is often limited because of the occurrence of severe adverse events (AEs), including oral mucositis, interstitial lung disease, diarrhea, and rash. Therefore, early management of AEs is extremely important to obtain maximum treatment outcome. We investigated here the effects of comprehensive pharmaceutical care for prevention of severe AEs on patient's quality-of-life (QOL) and continuation of therapy. QOL was assessed every month based on the five level version of EuroQol-5-Dimension (EQ-5D-5L). AEs were graded according to the Common Terminology Criteria for Adverse Events (ver 4.0). Implementation of comprehensive pharmaceutical care remarkably reduced the incidence of severe oral mucositis as compared with those without such interventions. EQ-5D-5L health states were almost constant during 6 months after intervention, ranging from 0.850 to 0.889. Median time to treatment failure (TTF) was significantly longer after intervention than before [224.0 days, 95% confidence interval (CI): 117-331 days versus 34 days, 21-47 days, hazard ratio (HR): 0.027, 95% CI: 0.005 - 0.154, p<0.001]. These findings suggest that our comprehensive pharmaceutical care is highly effective for enhancing treatment outcome by maintaining patient's QOL. PMID- 29442015 TI - Prognostic factors in patients with advanced and recurrent colorectal cancer receiving last-line chemotherapy. AB - For patients with advanced/recurrent colorectal cancer, the trifluridine/tipiracil combination tablet (TAS 102) and regorafenib are last-line treatments. This study aimed to clarify prognostic factors in patients receiving last-line chemotherapy. Between April 2014 and December 2016, 47 patients received last-line chemotherapy at Ogaki Municipal Hospital, Japan. The primary outcome was overall survival. To determine factors associated with survival, those considered significant in the univariate analysis (p <0.10), were entered into a multivariate Cox proportional hazards model. KRAS type and the use of opioid formulations were independently and significantly associated with survival in the multivariate analysis. For patients with KRAS-wild relative to KRAS mutation cancers, the hazard ratio for death was 0.478 (95% CI, 0.249-0.919; p = 0.03). For patients taking opioid formulations, relative to those not, the hazard ratio for death was 3.557 (95% CI, 1.032-12.257; p = 0.04). The median overall survival duration for patients with KRAS-wild (n = 24) and KRAS-mutation (n = 23) cancers were 223.5 days (range: 115-703) and 154 days (range: 51-503), respectively (p = 0.05). This finding provides a useful index to make an early decision on discontinuation of treatment and to guide decisions around agents to use in last-line chemotherapy. PMID- 29442017 TI - Determination of coumarin in seasonal bakery products using QuEChERS and GC-MS. AB - Cinnamon is a traditional herbal drug, but more importantly, it is used as a flavor compound in the production of foodstuff. Due to the content of significant concentrations of coumarin in Cassia cinnamon, effective control of the coumarin content in seasonal bakery products like ginger bread and cinnamon biscuits is urgently needed. Here we present a novel, fast and fully validated protocol for the determination of coumarin in marketed bakery products using the QuEChERS sample preparation technique in combination with GC-MS analysis. Ten grams of homogenized sample was mixed with 20 mL acetonitrile/water (1:1) and 5 g magnesium sulfate/sodium chloride mixture (4:1). The organic phase was cleaned by dSPE with 25 mg magnesium sulfate/PSA (5:1). The LOD was 0.15 MUg/mL and the LOQ 0.50 MUg/mL. We detected a mean coumarin content of 19.5 MUg/kg in 9 out of 14 seasonal food products (ranging from 1.45 to 39.4 mg/kg). No coumarin was detected in five cinnamon containing products. With this investigation we demonstrate that the QuEChERS sample preparation, previously applied mainly to the analysis of pesticides in vegetables, is also suitable for other complex matrices. PMID- 29442016 TI - Properties and role of the quorum sensing molecule farnesol in relation to the yeast Candida albicans. AB - Farnesol is a quorum sensing (QS) molecule synthesized by Candida albicans acting as a negative regulator of morphogenesis; it blocks the yeast-to-hyphae transformation. This molecule is currently studied in particular from the viewpoint of possible use as a substance with anticancer properties and with an antimicrobial, and anti-biofilm effect in yeasts resistant or tolerant to conventional therapeutic agents, for example fluconazole. Besides the aforementioned effect on morphological transformation through cyclic AMP (cAMP)/protein kinase A (cAMP-PKA) pathway, it also affects other biochemical pathways of yeasts, for example those ones for sterol biosynthesis or triggering of apoptosis via accumulation of ROS (reactive oxygen species) that damage essential cellular compartments. ROS activate intracellular caspases that are indicators of apoptotic response in C. albicans. However, an influence of farnesol on C. albicans yeasts is dependent on used concentrations; while higher concentrations (200 - 300 MUM) are stressful for yeasts, lower concentrations (about 40 MUM) protect them from stress. This QS molecule is also able to modulate efflux pumps in resistant yeasts. This review provides an overview of the current knowledge about production, role, and mode of action of farnesol in the clinically most important yeast C. albicans. PMID- 29442019 TI - Gastroresistant gelatin films prepared by addition of cellulose acetate phthalate. AB - Gastroresistant capsules are obtained mostly by using modified-release fill in hard capsules, or by coating the gelatin shell with acid-resistant polymers. Modification of the material used at the stage when the capsule shell is produced would reduce the complexity and cost of introducing new products to the market. Gastroresistant gelatin films were obtained by using commercial cellulose acetate phthalate (aqueous dispersion Aquacoat(r) CPD). Only films casted from non alkalized mixtures showed no visible disintegration at pH from 1.2 (simulated gastric fluid) to 4.5 (phosphate buffer). Elasticity of the dry films was comparable with the one determined for non-modified gelatin films, however tear resistance was 2-fold smaller, but still acceptable for practical application. PMID- 29442018 TI - A new model to determine lipophilicity of 1,2-ethanediamine-N,N'-di-2-(3 cyclohexyl)propanoic acid and 1,3-propanediamine-N,N'-di-2-(3 cyclohexyl)propanoic acid derivatives with antiproliferative activity by combining shake flask procedure and UHPLC-MS method. AB - Fourteen compounds representing ester derivatives of (S,S)-1,2-ethanediamine-N,N' di-2-(3-cyclohexyl) propanoic and (S,S)-1,3-propanediamine-N,N'-di-2-(3 cyclohexyl)propanoic acids, expressing antiproliferative activity in vitro were examined. The objective of this study was to determinate their lipophilicity data, and also to ensure a mathematical model for prediction lipophilicity data of potential in vivo metabolites and new derivatives of (S,S)-1,2-ethanediamine N,N'-di-2-(3-cyclohexyl)propanoic acid, based on chromatographic parameters. Experimentally, lipophilicity data were obtained by a traditional shake flask procedure and an ultra-high performance liquid chromatographic tandem mass spectrometry (UHPLC-MS) method. A correlation between the partition coefficient n octanol/water (logD7,4) and chromatographic data (CHI, ?0), and also, between logD7,4 and retention time was investigated. A very good correlation (r2=0.8969) was found between lipophilicity parameters ?0 and logD7,4 obtained using UHPLC-MS and shake flask methods: logD7,4 = (0.11+/-0.01)*?0 + (1.25+/-0.20)*Nc - (9.19+/ 1.18); statistical parameter F=47.84; significance of F = 3.74*10-6, Nc=number of C atoms between two amino groups (Nc=2 for 1,2-ethanediamine derivatives and Nc=3 for 1,3-propanediamine derivatives). The model predictivity power was determined by cross validation leave one out (LOO) technique, and expressed by the term Q2, was 0.89. The developed model has good predictivity power for prediction lipophilicity data of potential in vivo metabolites of the investigated compounds, such as novel 1,2-ethanediamine and 1,3-propanediamine N,N'-di-2-(3 cyclohexyl)propanoic acid derivatives. Also, the lipophilicity data obtained in the present study correlated with the antiproliferative activity of the investigated substances shown previously in in vitro studies. PMID- 29442020 TI - TNF-alpha was involved in calcium hydroxide-promoted osteogenic differentiation of human DPSCs through NF-kappaB/p38MAPK/Wnt pathway. AB - It has been reported that calcium hydroxide can induce proliferation, migration, and mineralization in dental pulp stem cells (DPSCs), but the underlying molecular mechanisms are still unclear. In this study, we sought to explore the role of calcium hydroxide in the cell proliferation and directional differentiation of DPSCs and to study the regulatory effect of NF-kappaB, p38MAPK, and Wnt signaling on differentiation of DPSCs. CCK8 cell assay, Wound Healing Assay, and Alkaline Phosphatase Staining Assay were respectively used to determine the proliferation rate, migration and ALP expression of DPSCs. Alizarin Red Staining Assay was used to observe the mineralization of DPSCs. RT-PCR analysis and Western Blot Analysis displayed the expression of related fators at mRNA and protein level, respectively. In the present study, we found that NF kappaB, p38MAPK, and Wnt signaling could abolish calcium hydroxide-induced proliferation of DPSCs. The inhibition of NF-kappaB, p38MAPK, and Wnt signaling suppressed the migration, ALP expression, and mineralization of DPSCs. NF-kappaB, p38MAPK, and Wnt signaling involved in directional differentiation of DPSCs. Moverover, calcium hydroxide could activate NF-kappaB, p38MAPK, and Wnt pathway by regulating TNF-alpha. Our study showed that NF-kappaB, p38MAPK, and Wnt signaling pathway were involved in calcium hydroxide-induced proliferation, migration, mineralization, and osteogenic differentiation in DPSCs. Calcium hydroxide affected NF-kappaB, p38MAPK, and Wnt pathway by regulating TNF-alpha. PMID- 29442021 TI - Hsp70 protects human trabecular meshwork cells injury induced by UVB through Smad pathway. AB - AIM: Glaucoma is a universal eye disease which is commonly associated with increased intraocular pressure caused by impaired aqueous humor (AH) drainage. This study aimed to investigate the effects of Hsp70 on trabecular meshwork (TM) injury induced by UVB. METHODS: Real-time quantitative PCR (qRT-PCR) was used to examine the mRNA levels of Hsp70. siRNA was used to downregulate Hsp70 expression in the TM cells to inspect changes in cell proliferation and apoptosis. Cell proliferation was assessed by a Cell Counting Kit-8 (CCK-8) assay and the number of apoptotic cells was assessed using annexin V-FITC/PI apoptosis detection kit. The Smad signaling pathway was investigated using western blotting analyses. RESULTS: The overexpression of Hsp70 promoted cell proliferation and suppressed apoptosis. What's more, the overexpression of Hsp70 suppressed the expression of Smad-2, Smad-3 and Smad-7. CONCLUSION: Hsp70 might improve cell viability and inhibit TM apoptosis by inhibition of the Smad pathway. Hsp70 is a potential therapeutic target for the treatment of glaucoma. PMID- 29442023 TI - miR-122-5p inhibits tumor cell proliferation and induces apoptosis by targeting MYC in gastric cancer cells. AB - MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including Gastric cancer (GC). In this study, we investigated the correlation of miR-122-5p expression with cell proliferation, and apoptosis in a GC cell line. GC cells SCG 7901 were transfected with control, miR-122-5p or miR 122-5p inhibitor and MTT assay, western blot, and BrdU staining were respectively used to investigate the effect of miR-122-5p on GC cell cycle. The overexpression of miR-122-5p could reduce cell proliferation in SCG7901 cells, and BrdU staining finally verified miR-122-5p induced cell growth arrest by upregulation p27 expression in SCG7901cells. On the other hand, cells apoptosis research showed that miR-122-5p induced apoptosis by targeting MYC in SCG7901 cells. Finally, in this study, miR-122-5p was confirmed inhibiting tumor GC cells proliferation and inducing cells apoptosis by targeting MYC. All these findings suggest that miR 122-5p may be involved in progression of GC and could be a new therapeutic target for this disease. PMID- 29442022 TI - miR-152-5p inhibits proliferation and induces apoptosis of liver cancer cells by up-regulating FOXO expression. AB - Currently, a lot of microRNAs (miRNAs) have been confirmed to be closely related with liver cancer occurrence and development. This study was aimed to explore the role of miR-152-5p in liver cancer. HepG2 and MHCC97 cells were transfected with miR-152-5p mimic, inhibitor or corresponding scramble controls, respectively. The expression level of miR-152-5p in transfected cells was detected by qPCR. Cell viability, apoptosis, migration and invasion of miR-transfected cells were measured to determine the effect of miR-152-5p on the activity of hepatoma cells. The protein expressions of fork head transcription factor O (FOXO) and apoptosis related factors in miR-transfected cells were detected by western blot assay. In addition, western blot was used to detect the relationship of FOXO expression and mainly factors of the JNK signaling pathway after concurrent treatment with miR 152-5p mimic and JNK inhibitor. The results showed that the miR-152-5p was effectively overexpressed or repressed in both HepG2 and MHCC97 cells. Overexpression of miR-152-5p inhibited cell viability, promoted apoptosis, and reduced migration and invasion. In these cells, miR-152-5p overexpression activated the expression of apoptosis-related factors and upregulated the expression of FOXO by activating the phosphorylation of mainly factors in the JNK pathway. miR-152-5p might be a potential anti-tumor factor for liver cancer treatment. PMID- 29442024 TI - Anti-cancer activity of Bacillus amyloliquefaciens AK-0 through cyclin D1 proteasomal degradation via GSK3beta-dependent phosphorylation of threonine-286. AB - Microorganisms have been regarded as important sources of novel bioactive natural products. In this study, we evaluated the anti-cancer activity and the potential mechanism of Bacillus amyloliquefaciens AK-0 newly isolated from the rhizosphere soil of Korean ginseng. The ethyl acetate fraction from the culture medium of B. amyloliquefaciens AK-0 (EA-AK0) inhibited markedly the proliferation of human colorectal cancer cells such as HCT116, SW480, LoVo and HT-29. EA-AK0 effectively decreased cyclin D1 protein level in human colorectal cancer cells, while cyclin D1 mRNA level was not changed by EA-AK0 treatment. Inhibition of proteasomal degradation by MG132 blocked EA-AK0-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with MRB. In addition, EA-AK0 increased threonine-286 (T286) phosphorylation of cyclin D1, and a point mutation of T286 to alanine attenuated cyclin D1 degradation by EA-AK0. Inhibition of GSK3beta by LiCl suppressed cyclin D1 phosphorylation and downregulation by EA-AKO. From these results, EA-AK0 may suppress the proliferation of human colorectal cancer cells by inducing cyclin D1 proteasomal degradation through GSK3beta-dependent T286 phosphorylation. These results indicate that EA-AK0 could be used for treating colorectal cancer and serve as a potential candidate for anticancer drug development. In addition, these findings will be helpful for expanding the knowledge on the molecular anti-cancer mechanisms of EA-AK0. PMID- 29442025 TI - Sinomenine inhibits the inflammatory responses of human fibroblast-like synoviocytes via the TLR4/MyD88/NF-kappaB signaling pathway in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disorder mainly characterized by inflammation of the synovial tissue that can lead to destruction of bone and cartilage. Sinomenine is an alkaloid extracted from the stem of the Chinese medicinal plant Sinomenium acutum. It has been reported that sinomenine has immunosuppressive and anti-inflammatory properties. However, the molecular mechanism underlying the effect of sinominine on IL-1beta-induced human RA fibroblast-like synoviocytes (RAFLS) is poorly understood. Therefore, in this study, we investigated the effect of sinomenine on the expression of inflammatory cytokines in IL-1beta-treated human RAFLS in vitro and the underlying mechanism. RAFLS viability was evaluated using the MTS assay after sinomenine treatment. The levels of inflammatory cytokines were measured with ELISA, RT-PCR and western blot, respectively. The levels of TLR4 and its downstream signaling targets were determined by western blot analysis. We found that sinomenine suppressed not only NO and PGE2 production but also iNOS and COX-2 expression in IL-1beta-induced RAFLS. It also inhibited the expression of TNF-alpha and IL-6 in IL-1beta stimulated RAFLS. Furthermore, sinomenine prevented IL-1beta-induced TLR4, MyD88 and p-NF-kappaB p65 expression. Taken together, these results demonstrated that sinomenine prevented IL-1beta-induced inflammation in human RAFLS at least in part by inhibiting the TLR4/MyD88/NF-kappaB signaling pathway, suggesting that sinomenine could be a potential agent in the treatment of RA. PMID- 29442026 TI - Upregulation of P63 inhibits chondrocyte autophagy thereby enhancing the malignant progression of osteoarthritis. AB - Loss of autophagy is suggested to play a key role in the progression of osteoarthritis (OA). P63 is a member of the P53 family, which is widely dysregulated in various tumors. However, the specific role of P63 in chondrocyte autophagy has never been fully understood. Here, the expression level of P63 in the articular cartilages of OA patients and chondrocytes treated with 3-MA was explored using western blot. Autophagy was determined using transmission electron microscopy and mRFP-GFP-LC3 assay. Fewer autophagic vesicles were identified in the articular cartilages of OA patients compared with that of normal control. Both the mRNA and protein levels of P63 was markedly increased in the articular cartilages of OA patients compared with that of normal control. MTT assay demonstrated that P63 overexpression markedly reduced chondrocyte viability at 24, 36 and 48 h, while inhibition of P63 inhibited cell viability at 24, 36 and 48 h, respectively. Furthermore, autophagic flux assay showed that transfection of ad-P63 markedly decreased the yellow dots in chondrocytes, while inhibition of P63 induced chondrycyte autophagy. In summary, we first demonstrated that upregulation of P63 in the cartilage tissues of OA patients inhibited chondrocyte autophagy thereby contributing to the malignant progression of OA. PMID- 29442027 TI - The effect of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and 2 hydroxyatorvastatin in healthy Chinese people. AB - The pharmacokinetics of statins show substantial inter-subject variability. Increasing systemic exposure of statins may lead to adverse drug reactions such as myopathy. The variation in statin pharmacokinetics is partly explained by genetic factors. OATP1B1, coded by SLCO1B1 transports a large number of therapeutic drugs, such as atorvastatin. Here we investigated the effect of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and its metabolites. Two pharmacokinetic studies were conducted in Chinese Han volunteers and 132 volunteers were enrolled in our study as 72 in trial 1 and 60 in trial 2. A LC MS/MS method was developed for the identification and quantification of atorvastatin acid and its metabolites. S LCO1B1 c.521T>C (rs4149056) was identified by the MALDI-TOF MS and Sequenom MassARRAY system. The distribution frequencies of SLCO1B1 c.521T>C were in agreement with Hardy-Weinberg equilibrium both in trial 1 and trial 2. In subjects with 521C allele the mean Cmax, AUC0-24h and AUC0-infinity of atorvastatin acid and 2-hydroxyatorvastatin acid were significantly higher than subjects with 521TT genotype, while the mean CL was lower. In conclusion, our results suggested that SLCO1B1 c.521T>C had an effect on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in Chinese Han population. Subjects with 521C allele have an increased risk of toxic effects caused by atorvastatin. PMID- 29442028 TI - Treatment of bone disorders with parathyroid hormone: success and pitfalls. AB - Bone diseases such as osteoporosis, osteoarthritis, bone tumours and bone fractures are rather common and not just in the elderly. Parathyroid hormone (PTH) is responsible for maintaining calcium homeostasis, increasing bone mineral density (BMD), increasing cortical and trabecular bone thickness and thus increasing bone strength. Teriparatide (PTH 1-34) has the same effects as endogenous PTH and is pharmacologically used to treat bone diseases such as osteoporosis, osteoarthritis, bone fractures and bone tumours. This review discusses how PTH 1-34 plays a role in managing bone diseases. Clinical studies have shown that short or intermittent dosing of PTH 1-34 has minimal adverse effects, while long-term dosing (over two years) has been linked to de novo osteoarthritis and bone deformation. Currently PTH therapy is only approved in the treatment of post-menopausal osteoporosis, however it is also proven to have effects in treating osteoarthritis, bone tumours and bone fractures. If the patient undergoing therapy is closely monitored, the major pitfalls are very unlikely to take place, thus it is highly recommended that patients be closely monitored by a medical practitioner. PMID- 29442029 TI - Expression, regulation and function of MicroRNAs in endometriosis. AB - Endometriosis (EMS), characterized by the presence and growth of functional en do met rial-like tissues outside the uterine cavity, is a common and benign gyneco logical disorder with a poorly understood and somewhat enigmatic etiopathogenesis and pathophysiology. MicroRNAs (miRNAs) are single-stranded 19-25 nucleotide-long RNAs and have an important role in post-transcriptional gene silencing by base pairing with target mRNAs. Recent research has shown that miRNAs and their target mRNAs are differentially expressed in endometriosis and other disorders of the female reproductive system. In this paper, we review the recent progress in understanding the roles of miRNAs in endometriosis, and specific miRNAs as biomarkers and therapeutic targets for endometriosis. PMID- 29442030 TI - PLGA Implants containing vancomycin and dexamethasone: development, characterization and bactericidal effects. AB - Post-operative endophthalmitis is an infection and an inflammation of the eye following a surgical procedure. Its treatment is based on drug injections into the eye. However, this treatment can lead to ocular complications. Intraocular implants could substitute the conventional therapy. Poly(lactic-co-glycolic acid) (PLGA) implants comprising on vancomycin and dexamethasone were evaluated as drug delivery system to treat endophthalmitis after cataract surgery. Implants were characterized by drug content uniformity, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Wide Angle X-ray Scattering (WAXS), Scanning Electron Microscopy (SEM) and in vitro drug release. The bactericidal effect of vancomycin, eluted from the implants, was demonstrated against Staphylococcus aureus and Staphylococcus epidermidis. The drugs were uniformly distributed in the polymer. The analytical techniques revealed the chemical integrity of the drugs incorporated into the polymer and the modification of dexamethasone semi-crystalline nature. Drugs were controlled released from implants; and the eluted vancomycin showed bactericidal effects. In conclusion, PLGA implants containing vancomycin and dexamethasone may represent a therapeutic alternative to treat post-operative endophthalmitis. PMID- 29442031 TI - Analysis of ABCG2 methylation in stool samples of Chinese healthy males by pyrosequencing. AB - ABCG2, an efflux pump protein-BCRP coding gene, is involved in the acquisition of chemotherapeutic drug resistance. In recent years, the epigenetic regulation of ABCG2, such as DNA methylation, has become a research hotspot and been attracting widespread attention. Methylation Special PCR (MSP) has been the mainly used method for gene methylation detection for a long time. With the development of pyrosequencing (PSQ) instrument and the convenience, simpleness, and economical benefit it brings, it will become the mainstream method for gene methylation detection in the near future. This study aims to establish a pyrosequencing method for detecting the methylation sites on ABCG2 gene promoter up-stream region, the promoter region and the first exon region, and to detect the methylation level of each site in stool samples, respectively. Thus, it cannot only lay the methodological foundation for the study of BCRP-mediated multi-drug resistance mechanisms in tumor cells, but also can give knowledge of ABCG2 methylation distribution in the intestine of Chinese healthy males by detecting the ABCG2 methylation levels in stool samples as the exfoliated intestinal epithelial cells constantly shed into the stool. PMID- 29442032 TI - Ampelopsin sodium induces mitochondrial-mediated apoptosis in human lung adenocarcinoma SPC-A-1 cell line. AB - Ampelopsin is a well-known flavonoid which has variety of biological and pharmacological actions including anticancer effects and induction of apoptosis on the several cancer cell lines. The present study aimed to evaluate the role of ampelopsin sodium (Amp-Na) in the mitochondrial-mediated apoptosis of human lung adenocarcionma SPC-A-1 cells. The analysis of cell proliferation and ultrastructure were performed. Furthermore, to clarify its action mechanism by determining the mitochondrial membrane potential (Deltapsim), intracellular calcium (Ca2+) concentration, mitochondrial nitric oxide (NO) level and total ATPase activity. The results showed that Amp-Na markedly inhibited the SPC-A-1 cell proliferation and caused ultrastructural apoptosis feature in SPC-A-1 cells in a dose-dependent manner. Amp-Na led to a rapid and sustained Ca2+ elevation and Deltapsim reduction, and induced the mitochondrial NO production and decreased the total ATPase activity in SPC-A-1 cells. The results enhance the potential of Amp-Na as a therapeutic drug for treating lung cancer, and provide new information for mechanism of Amp-Na which induces mitochondrial-mediated apoptosis in tumor cells. PMID- 29442033 TI - MiR-224 promotes proliferation and migration of gastric cancer cells through targeting PAK4. AB - Although recent studies have shown the important role and overexpression of miR 224 in several tumors, its function in gastric cancer has not yet been defined. In the present study, we tried to confirm the result of microRNAs microarray and further investigated the functions of miR-224 in gastric cancer, and tried to find new downstream targets of miR-224. In this study, the level of miR-224 was measured in gastric cancer cells with the normal human gastric epithelial cell. The effects of miR-224 of on proliferation, migration, and target protein expression were evaluated by CCK8 assay, colony assay, transwell migration assay, western blotting. In addition, luciferase reporter plasmid was constructed to demonstrate the direct target of miR-224. Overexpression of miR-224 was detected in the gastric cancer cells, especially in SCG-7901. Exogenous miR-224 expression promoted the proliferation and migration of gastric cells and abrogating expression of miR-224 suppressed proliferation, and migration of SCG-7901 cells in vitro. Luciferase assays revealed that miR-224 directly targeted the 3'UTR of p21-activated kinase 4 (PAK4). The present study provides an experimental foundation for miR-224 as a potential tumor suppressor that may decrease PAK4 expression to inhibit gastric cancer cells and that in the future, targeting of this miRNA may provide a novel strategy for the diagnosis and treatment of patients with this lethal disease. PMID- 29442034 TI - Crosstalk between 6-OHDA-induced autophagy and apoptosis in PC12 cells is mediated by phosphorylation of Raf-1/ERK1/2. AB - Parkinson's disease (PD) is a degenerative brain disorder characterized by motor symptoms and loss of dopaminergic (DA) neurons in the substantia nigra. The mechanisms for DA cell death in PD have been extensively investigated using PC12 cells treated with a dopamine neurotoxin 6-hydroxydopamine (6-OHDA). 6-OHDA may induce both autophagy and apoptosis in PC12 cells. However, it remains unclear whether crosstalk occurs between autophagy and apoptosis in PC12 cells treated with 6-OHDA and whether Raf-1/ERK1/2 and their phosphorylation status play a role in autophagy. In this study, we used MDC staining assay and flow cytometry and found that 6-OHDA induced autophagy in PC12 cells. This induction was inhibited by the autophagy inhibitor 3-MA. Our electron microscopy observations also supported 6-OHDA induced autophagy in PC12 cells. Apoptosis of PC12 cells was increased with inhibition of autophagy by 3-MA. In addition, Inhibition of Raf-1 resulted in a decreased 6-OHDA-induced autophagy rate among PC12 cells. Phosphorylation levels of Raf-1 and ERK1/2 were increased in PC12 cells treated with 6-OHDA and inhibited by co-treatment with 6-OHDA and 3-MA. These data suggest that crosstalk between 6-OHDA-induced apoptosis and autophagy in PC12 cells may be regulated via the Raf-1/ERK1/2 signaling pathway. Our data suggest a mechanism for 6-OHDA toxicity in PC12 cells, contributing to our understanding of the pathogenesis of PD. PMID- 29442035 TI - Assessment of the potential drug-drug interaction between carvedilol and clopidogrel mediated through intestinal P-glycoprotein. AB - The most widely prescribed oral antiplatelet agent, clopidogrel, shows high interindividual variability resulting in an increased risk of cardiovascular events in the patients with reduced platelet inhibition. The purpose of this study was to investigate the role of the P-glycoprotein (P-gp) efflux pump in limiting the intestinal permeability of clopidogrel and the effect of a beta blocker, namely, carvedilol, on its intestinal transport. Effective permeabilities (Peff) of clopidogrel and carvedilol were investigated in the proximal jejunum and distal ileum of rats using an in situ intestinal perfusion model. Peff values of clopidogrel and carvedilol were found to be concentration dependent with decreased Peff values at the low perfusate concentrations. Coperfusion with the P-gp inhibitors verapamil (100 MUM) and carvedilol (10 MUM) significantly increased the Peff of clopidogrel in the jejunum (8.31+/-0.20 x 10 5 and 6.98+/-0.75 x 10-5 vs. 3.60+/-0.51 x 10-5, respectively) and ileum (9.08+/ 2.19 x 10-5 and 8.35+/-1.58 x 10-5 vs. 3.85+/-0.15 x 10-5, respectively). However, at the highest concentration tested (30 MUM), clopidogrel exhibited 3 and 1.4 times higher Peff than those of metoprolol, an FDA high permeability reference standard, in the jejunum and ileum, respectively. Overall, this study indicates that the efflux function appears not to have a significant impact on the in vivo intestinal absorption of clopidogrel due to the saturation of P-gp, suggesting no clinically relevant interaction between carvedilol and clopidogrel mediated through P-gp at intestinal level. PMID- 29442036 TI - In vitro study of 2,3-dehydrosilybin and its galloyl esters as potential inhibitors of angiogenesis. AB - 2,3-Dehydrosilybin exhibits substantial anticancer and antiangiogenic effects, which can be potentially improved by semi-synthetic modification such as esterification with gallic acid. The aim of this study was to examine the potential antiangiogenic effect of 2,3-dehydrosilybin and its galloyl esters (3-O galloyl-2,3-dehydrosilybin; 7-O-galloyl-2,3-dehydrosilybin; 20-O-galloyl-2,3 dehydrosilybin and 23-O-galloyl-2,3-dehydrosilybin) and to determine which molecular mechanism could be responsible for their activity. The effect on cell proliferation, tube formation, signal transduction pathways (PI3K/Akt and ERK) and the cell cycle was studied in human microvascular endothelial cells (HMEC). The results showed that all compounds decreased the growth of HMEC, but the strongest effect was observed for 20-O-galloyl-2,3-dehydrosilybin at 5 MUmol/l. In addition, at 5 and 10 MUmol/l, this was the only compound that significantly inhibited HMEC tube formation. Based on an assessment of Akt and ERK1/2 expression, we suggest that 20-O-galloyl-2,3-dehydrosilybin influences the angiogenic process through the Akt pathway. PMID- 29442037 TI - A comparative analysis of micafungin and caspofungin for empirical antifungal therapy in antibiotic-unresponsive febrile patients with hematologic malignancies. AB - This study was retrospectively carried out to compare the efficacy of echinocandins such as micafungin (MCFG) and caspofungin (CPFG) in the treatment of antibiotic-unresponsive febrile patients with hematologic malignancies. A total of 163 patients received either MCFG or CPFG. We evaluated the efficacy of echinocandin against fever decline in all patients. Fever decline, defined as a body temperature of less than 37.5 degrees C sustained for more than 48 h without scheduled antipyretic medication. Efficacy assessments showed that the incidence of fever decline was not significantly different between the MCFG and CPFG groups (P=0.599). The median number of days from the start of echinocandin administration to fever decline was 5 in both the MCFG and CPFG groups. Multivariate analysis showed that the use of anti-MRSA drugs (HR, 0.64; 95%CI, 0.45-0.90; P=0.011) and a change from echinocandins to voriconazole or liposomal amphotericin B (HR, 0.50; 95%CI, 0.30-0.74; P<0.001) are significant risk factors for sustained fever. A significant difference (P=0.002) in incidence of fever decline was however associated with differences in the timing of anti-MRSA drug administration. The median number of days from the start of echinocandin administration to fever decline was 5 when administration of the anti-MRSA drug occurred "simultaneously or prior to echinocandin start" and 11 in the "next day or later of echinocandin start" group. In other words, starting anti-MRSA drug treatment after echinocandin treatment is a risk factor. In conclusion, MCFG and CPFG have similar efficacy as empirical antifungal agents in the treatment of antibioticunresponsive febrile patients with hematopoietic malignancies. PMID- 29442038 TI - Non-viral gene delivery systems: hurdles for bench-to-bedside transformation. AB - Biologist and Nobel Prize winner James Watson's quote, "We used to think that our fate was in our stars, but now we know that, in large measure, our fate is in our genes", represents the initial food for thought that revolutionized the way medications and active pharmaceutical ingredients are defined (Rocholl 1996). This fate engraved in the genetic material, as mentioned in Watson's quote, fueled a tremendous revolution wave in gene therapy. Gene therapy is a promising technology for treating genetic and acquired diseases by modulating the expression of a specific gene in the pathological cells. This is achieved by introducing a DNA sequence or other nucleic acid material or oligonucleotides to the target cell (Kay, 2011). Moreover, gene therapy contributes to correction of genetic defects, expression of therapeutic proteins, and inhibition of the synthesis of malignant proteins. In this review article, different non-viral gene delivery systems and their applications are discussed in detail. We reviewed and tabulated over 90 papers and 50 patents from 2006 to date discussing non-viral gene delivery technologies, innovation, and bench-to-bedside transformation. Furthermore, we are going to shed light on the lack of standardization in the design and characterization of non-viral gene delivery systems worldwide, which is a major concern in this research's field. This review would aid in getting an eagle eye view through non-viral gene delivery technologies during the past 20 years. Such a view, capturing the advances, the hurdles, and experimental details, would aid expert researchers in tuning their experimentation strategies and help newcomers better initially design their studies to generate solid and comprehensive results that can be reliable and reproducible. PMID- 29442039 TI - Design and production of methyl jasmonate nanoemulsions using experimental design technique and evaluation of its anti-cancer efficacy. AB - Methyl jasmonate (MJ), a plant-derived stress hormone, has been shown to be a promising anti-cancer agent with high selectivity toward cancerous cells. The aim of the present study was to design a MJ loaded nanoemulsion (NE) to overcome the low MJ water solubility and also improve its anti-cancer efficiency. Box-Behnken design (BBD) was employed to optimize the composition effect of three independent manufacturing variables on two responses including average droplet size and poly dispersity index (PDI). ANOVA analysis indicated that both of the studied responses were well fitted by resultant quadratic models with the coefficient of determinations (R2) 0.994 and 0.975, respectively. The actual average droplet size 75.06 nm and PDI 0.017 obtained for the optimum MJNE was in good agreement with those values predicted with numerical optimization. Physicochemical characterization indicated that the optimum MJNE was transparent, isotropic, spherical and sterically stabilized. MTT assay indicated that MJNE was more efficacious in killing cancer cells than MJ solution. Cell cycle analysis revealed that MJNE induced a stronger sub-G1 arrest than MJ solution. A considerable absence of toxicity was achieved for MJNE and blank NE in HUVEC normal cells. These results may provide strong support to develop a NE delivery system as a promising carrier for improving the safety and anti-cancer efficacy of MJ. PMID- 29442040 TI - Lidocaine sensitizes the cytotoxicity of 5-fluorouacil in melanoma cells via upregulation of microRNA-493. AB - Lidocaine is a well-documented local anesthetic that has been reported to sensitize the cytotoxicity of cisplatin in cancer cells. However, little information is available concerning whether lidocaine sensitizes the cytotoxicity of 5-fluorouracil (5-FU) in melanoma cells. The study was aimed to explore the effects and mechanisms of lidocaine on the sensitivity to 5-FU in the melanoma cell line SK-MEL-2. Cell viability and apoptosis were analyzed after administration of different concentrations of lidocaine, 5-FU, or the combinations. Expression of microRNA (miR)-493 was assessed following lidocaine administration. The target genes of miR-493 were verified by luciferase reporter assay, PCR, and Western blot. The effects of abnormal expression of miR-493 and/or SRY-Box 4 (SOX4) on cell viability, apoptosis, and key proteins in phosphatidylinositol-3-kinase (PI3K)/AKT and the Smad pathways were detected. The effects of (0-100 uM) lidocaine on cell viability and apoptosis was not obvious; however, lidocaine could significantly increase the cell viability and inhibit apoptosis in 5-FU-treated cells. In addition, lidocaine induced upregulation of miR-493 in a dose-dependent manner, and we confirmed that the effects of miR-493 on the sensitivity were by upregulating miR-493. Moreover, we verified that Sox4 was a target of miR-493, and Sox4 overexpression decreased the sensitivity to 5 FU. Besides, Sox4 overexpression increased the levels of p-PI3K, p-AKT, p-Smad2 and p-Smad3, and Sox4 suppression showed contrary results. Our results suggest that lidocaine sensitizes the cytotoxicity of 5-FU in melanoma cells via upregulation of miR-493, which might be involved in SOX4-mediated PI3K/AKT and Smad pathways. PMID- 29442041 TI - The interaction between ATRIP and MCM complex is essential for ATRIP chromatin loading and its phosphorylation in mantle cell lymphoma cells. AB - AIM: The ATR-interacting protein (ATRIP) is responsible for the recognition of DNA damage-induced structure and regulation of cellular responses to DNA damage and replication stress. The purpose of our study was to identify the underlying mechanism with respect to chromatin loading and phosphorylation of ATRIP in mantle cell lymphoma (MCL). METHODS: JeKo cells were used in our study. Differently tagged ATRIP (Myc-, hemaglutinin (HA) or Flag) and minichromosome maintenance (MCM) complex (MCM2, MCM3, MCM5, and MCM6) were transfected into 293T cells. After 48 h, ATRIP-interacting protein was identified by mass spectrometry (MS). Cell fractionation was done to localize proteins inside the cells. Immunoprecipitation (IP) and immunoblot (IB) analysis were used to identify immunoreactive species, and Glutathione S-transferase (GST) pull-down assays were performed to detect protein-protein interaction between ATRIP and MCM complex. After silencing the expression of MCM2 and MCM6 by short hairpin RNA (shRNA), chromatin fraction were analyzed. The expression of ATRIP phosphorylation (pS224 ATRIP) was determined after application of different doses of MCM2 shRNA (0.5 MUg, 1 MUg, and 2.5 MUg). RESULTS: ATRIP directly interacts with MCM2, MCM3, MCM6, and MCM7 in JeKo cells. Downregulation of MCM2 and MCM6 significantly reduced ATRIP chromatin fraction. Downregulation of MCM2 statistically decreased the expression of ATRIP phosphorylation. The expression levels of pS224-ATRIP were regulated by MCM2 shRNA in a dose-dependent manner. CONCLUSION: Our results suggest that interaction between ATRIP and MCM complex is required for ATRIP chromatin loading and ATRIP phosphorylation. PMID- 29442042 TI - TRIM59 promotes cell proliferation, migration and invasion in human hepatocellular carcinoma cells. AB - The human tripartite motif (TRIM) 59 has been implicated in tumorigenesis of many types of cancer. However, the biological function and molecular mechanism of TRIM59 in hepatocellular carcinoma (HCC) remains unknown. In our study, the purpose was to investigate the impact of TRIM59 on the biologic behavior of HCC cells. We observed that TRIM59 was highly expressed in HCC cells compared with a normal human hepatocyte cell line. Lentivirus-mediated knocking down of TRIM59 significantly suppressed the proliferation, migration and invasion of HCC cells, whereas overexpression of TRIM59 enhanced cell growth and metastasis. Furthermore, our study showed that silencing of TRIM59 decreased the expression of E-cadherin and increased N-cadherin and vimentin expression, whereas TRIM59 overexpression had the opposite effects on the above proteins. Finally, we found that p53 protein expression level was regulated by TRIM59, so we proposed that TRIM59 may enhance HCC cell proliferation and metastasis through p53 signaling pathway. In summary, these data indicated that TRIM59 may be a potential biomarker and therapeutic target for the treatment of hepatocellular carcinoma. PMID- 29442043 TI - Satb1 promotes osteoclastogenesis by recruiting CBP to upregulate miR-223 expression in chronic kidney disease-mineral and bone disorder. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a complex disease which is associated with alterations of bone and mineral metabolism. miR-223 is implicated in both vascular calcification and osteoporosis. In the present study, we investigated the influence of Stab1 gene on miRNA-223 expression in osteoclastogenesis. Differentiation of monocyte/macrophage precursors was assessed by using RAW264.7 cells and peripheral blood mononuclear cells (PBMC). TRAP activity and bone resorption were used to measure osteoclast activity. Overexpression of Satb1 induced a marked increase in osteoclastogenesis in RAW cells (P<0.01) and a decrease in miR-223 expression (P<0.01). In contrast, upregulation of miR-223 increased osteoclastogenesis, as measured by osteoclast number (P<0.01) and TRAP activity (P<0.001). We showed that miR-223 affected the expression of its target genes NFIA and RhoB (P<0.01). Silencing of Satb1 promoted the expression of the osteoclast marker gene OPG and inhibited the expression of NF-kappaB (P<0.01) and TNF-alpha (P<0.001). These results were confirmed by measuring bone resorption activity of human PBMC differentiated into osteoclasts where Satb1 suppression inhibited the differentiation of PBMC cells. We have shown that Stab1 modulates osteoclatogenensis by regulating the expression of miR-223. Thus, upregulation of this miRNA to selectively increase osteoclast-like activity in calcified vessels of CKD-MBD could alleviate vascular calcification without altering bone structure. PMID- 29442044 TI - MicroRNA-3188 targets ETS-domain protein 4 and participates in RhoA/ROCK pathway to regulate the development of atherosclerosis. AB - We aimed to elucidate the roles and regulatory mechanism of miR-3188 in oxidized low-density lipoprotein (ox-LDL)-induced cell injury in THP-1 derived macrophages, thus providing a new insight for the treatment of atherosclerosis (AS). A total of 85 AS patients and 45 healthy controls were enrolled. The levels of miR-3188 and lipoprotein-associated phospholipase A2 (Lp-PLA2) in AS patients and healthy controls were detected. Then ox-LDL was used to treat human THP-1 derived macrophages. The effects of overexpression and suppression of miR-3188 on regulating ox-LDL-induced cell injury in THP-1 derived macrophages were investigated. Additionally, the potential target of miR-3188 was identified, which was verified by luciferase reporter assay. Besides, the relationship between miR-3188 and RhoA/ROCK pathway was explored. miR-3188 was downregulated in AS patients, while the levels of Lp-PLA2 in AS patients were increased. Ox-LDL significantly induced cell injury by decreasing cell viability, inducing cell apoptosis and increasing the production of inflammatory cytokines, including IL 1beta, IL-6, MCP-1 and TNF-alpha. In addition, miR-3188 was significantly downregulated after ox-LDL treatment. Overexpression of miR-3188 alleviated ox LDL-induced cell injury, while inhibition of miR-3188 had opposite effects. ETS domain protein 4 (ELK4) was a target of miR-3188. The effects of miR-3188 inhibition on ox-LDL-induced cell injury were markedly reversed by knockdown of ELK4. Besides, inhibition of miR-3188 enhanced ox-LDL-activated RhoA/ROCK pathway, while knockdown of ELK4 suppressed this pathway. Downregulation of miR 3188 may contribute to AS development via negatively regulating Lp-PLA2, targeting ELK4 and activating RhoA/ROCK pathway. miR-3188 may serve as a target for AS treatment. PMID- 29442045 TI - MiR-200a promotes epithelial-mesenchymal transition of endometrial cancer cells by negatively regulating FOXA2 expression. AB - Endometrial cancer is the most common gynecological cancer. Epithelial mesenchymal transition (EMT) plays a critical role in tumor invasion and metastasis, which limits the success of treatment. Here, we investigated the roles of forkhead box A2 (FOXA2) and microRNA-200a (miR-200a) in regulating the EMT of endometrial cancer cells RL95-2. Empty vector or FOXA2 was stably transfected into RL95-2 cells. MTT assay measured cell proliferation, apoptosis assay measured apoptosis, Transwell invasion assay measured cell invasion, and Western blot measured the protein expression of FOXA2, E-cadherin, and vimentin. ChIP assay determined the binding of FOXA2 to E-cadherin promoter. For miR-200a analysis, the cells with stable FOXA2 expression were transfected with miR negative control or miR-200a. Forced expression of FOXA2 decreased the proliferation and invasion, and increased the apoptosis of RL95-2 cells. FOXA2 also affected the EMT-associated proteins: FOXA2 increased the protein expression of E-cadherin and decreased the expression of vimentin. Moreover, FOXA2 positively regulated the promoter of E-cadherin in RL95-2 cells. Luciferase reporter assay identified FOXA2 as a target of miR-200a, which negatively regulated FOXA2. Western blot results showed that overexpression of miR-200a decreased the expression of E-cadherin but increased the expression of vimentin in the endometrial cancer cells by downregulating FOXA2 expression. FOXA2 may act as a tumor suppressor and inhibit EMT of endometrial cancer cells. FOXA2 expression is controlled by miR-200a, which promotes EMT of the endometrial cancer cells. PMID- 29442046 TI - MicroRNA-146 regulates the inflammatory cytokines expression in vascular endothelial cells during sepsis. AB - AIMS: The purpose of this study was to investigate the functional role of microRNA (miR)-146 in sepsis, as well as the underlying mechanism. METHODS: Human vascular endothelial cell line EA. hy926 cells were treated with lipopolysaccharide (LPS) and/or transfected with miR-146 mimics, inhibitor, and their corresponding controls. Expression of miR-146 was then analyzed after treatment and/or transfection, as well as the expression of inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, intercellular adhesion molecule (ICAM)-1, and E-selectin, and nuclear factor kappa B (NF-kappaB) binding activity. RESULTS: The results showed that the expression of miR-146 was significantly downregulated by LPS stimulation compared to the control group (P < 0.05). Also, the expression of miR-146 was remarkably increased by miR-146 mimics but decreased by miR-146 inhibitor following stimulation with LPS (P < 0.05). In addition, the expression levels of TNF-alpha, IL-6, ICAM-1, and E-selectin were shown to increase following induction by LPS, and further markedly elevated by miR-146 inhibitor (all P < 0.05). However, the expression levels of these inflammatory cytokines were outstandingly decreased by miR-146 mimics (all P < 0.05). Moreover, we observed that the relative NF-kappaB activity was statistically upregulated by miR-146 inhibitor but downregulated by miR-146 mimics. CONCLUSIONS: MiR-146 may play an important role in the pathogenesis and development of sepsis by suppressing the expression of inflammatory cytokines. PMID- 29442047 TI - Comprehensive phytochemical characterization of St. John's wort (Hypericum perforatum L.) oil macerates obtained by different extraction protocols via analytical tools applicable in routine control. AB - The aim of the present study was to investigate the impact of crucial process parameters, i.e. of light and temperature conditions, during the preparation of St. John's wort (SJW, Hypericum perforatum L.) Arachis oil macerates. Extracts were prepared according to a standardized protocol over a period of 28 days. For this purpose, flowering tops of H. perforatum were macerated with Arachis oil (drug extract ratio, DERnative 1:4) under different light and temperature conditions. Spectrophotometric measurements were carried out to quantitate naphthodianthrones and to characterize extract color in the CIE L*C*h degrees system. Moreover, individual plant secondary metabolites were screened by UHPLC DAD-MSn measurements following liquid-liquid extraction of the oil macerates with methanol. For quantitation purposes, the chromatographic method was validated using reference standards. This methodology allowed the separation of up to 25 constituents in oily and methanolic SJW extracts, covering hydroxycinnamic acids, flavanols, proanthocyanidins, flavonol glycosides, flavonol aglyca, biflavones, bisanthraquinone glycosides, naphthodianthrones and phloroglucinols. Lowest naphthodianthrone contents were determined in oil macerates recovered at 5 degrees C, whereas highest amounts were detected upon extraction at 50 degrees C (both under the exclusion of light). Color shades of the oil macerates differed markedly, revealing e. g. a*-values ranging from -4.6+/-0.3 to 42.5+/-0.3. The flavonoids quercetin, kaempferol and I3, II8-biapigenin as well as the phloroglucinols hyperforin and adhyperforin could be simultaneously detected and quantitated in all oil macerates. Contents of these constituents varied noticeably between macerates prepared under different conditions (quercetin 14.7+/-1.2 to 21.8+/-0.6 MUg/g, kaempferol 3.0+/-0.1 to 5.4+/-0.4 MUg/g, I3, II8 biapigenin 4.4+/-0.2 to 7.4+/-0.4 MUg/g, hyperforin 52.6+/-46.0 to 451.4+/-24.9 MUg/g, adhyperforin 6.9+/-5.7 to 74.5+/-7.1 MUg/g). These results confirm that the quality of the resulting plant extracts is largely determined by the respective process parameters, i.e. especially temperature and light conditions, and thus must be thoroughly chosen and monitored to obtain tailor-made preparations. PMID- 29442048 TI - Storage stability of serum formulations containing ofloxacin for autologous serum eardrop therapy. AB - OBJECTIVE: The storage stability of serum formulations containing ofloxacin for autologous serum eardrop therapy was evaluated for microbiological quality and component stability. METHODS: Sterile serum formulations were prepared by mixing human serum and ofloxacin otic solution (1:1, v/v). To simulate eardrop contamination with external ear surface substances, prepared serum formulations were contaminated with a cotton swab that was rubbed sufficiently on the human external ear. Formulations were stored at 4 degrees C or room temperature in the dark. Colony forming units (CFUs), ofloxacin, and basic fibroblast growth factor (bFGF) concentrations in the stored serum formulations were determined. RESULTS: The growth of microorganisms derived from the external ear was not detected in serum formulations after storage for 14 days, regardless of temperature. However, microbial growth was detected in serum formulations stored without ofloxacin, indicating that this is necessary for storage. In addition, concentrations of ofloxacin and bFGF did not decrease over 14 days, indicating that ofloxacin and bFGF in serum formulations are stable for this time period. CONCLUSION: The present study indicates that the efficacy and safety of serum formulations used as a therapy for perforated eardrums are stable and safe for at least 14 days. PMID- 29442049 TI - Solidification of cinnarizine self-nanoemulsifying drug delivery systems by fluid bed coating: optimization of the process and formulation variables. AB - Self-nanoemulsifying drug delivery systems (SNEDDS) offer an efficient choice to improve the poor dissolution and erratic bioavailability of poorly-water soluble drugs. However, liquid SNEDDS experience some manufacturing and stability limitations. To overcome these limitations, the current study aims to investigate and optimize the solidification of cinnarizine (CN) liquid SNEDDS onto pellets by fluid bed coating. The study involved optimization of process and formulation variables. The coated self-nanoemulsifying pellets (SNEP) were characterized, their droplet size and dissolution profiles were compared to the corresponding liquid SNEDDS. Higher spray/microclimate air pressure led to minimal agglomeration and minimal spray drying. However, slight increase in inlet air volume above 35 m3/h led to extensive spray drying. The optimized coating formula included oleic acid/Imwitor308/Cremophor El (25/25/50) as liquid SNEDDS, HPMC E3 as coating polymer and PlasacrylTMT20 as anti-tacking agent. The optimum concentration of coating solution was 15% and optimum SNEDDS proportion in the coating layer was 40%. The droplet size of reconstituted SNEP was significantly (p < 0.05) higher than liquid SNEDDS, yet the SNEP aqueous dispersion was still within the nano-metric scale. Pure CN showed sharp precipitation upon shifting the media from pH 1.2 to 6.8. In contrast, Both SNEP and liquid SNEDDS maintained >85% CN in solution, even at pH 6.8. Therefore, CN-SNEP seems to be an excellent dosage form that maintains the solubilization benefits of liquid SNEDDS, overcomes their limitations along with the additional benefits of solid dosage form. PMID- 29442050 TI - Inhibiting the proliferation, migration and invasion of triple negative breast cancer cells through anti-tumor human serum albumin nanoparticles loading aziditaxel as a novel taxane derivative. AB - Triple negative breast cancer (TNBC) is a severe breast cancer subtype with the high mortality rate, and still is lack of effective therapeutic means so far. Aziditaxel, a water-insoluble compound, is a novel taxane derivative with strong anti-tumor activity. In this study, we constructed an aziditaxel-loaded nano drug delivery system using human serum albumin as a carrier, and further investigated its anti-tumor effect on TNBC in vitro. An emulsion solvent evaporation method was employed to prepare aziditaxel-loaded human serum albumin nanoparticles (AT NPs). Their physicochemical properties were characterized according to morphology, particle size, zeta potential, reconstitution stability and in vitro drug release. The in vitro anti-tumor effects of AT-NPs on TNBC were evaluated using a 4T1 murine triple negative mammary cancer cell lines as the TNBC model. The results showed that AT-NPs could be effectively taken up by 4T1 cells in a time-dependent manner. Cell Counting Kit-8 assay showed that the IC50 of AT-NPs was 0.17 MUg/ml. Meanwhile, compared with AT, AT-NPs had a better ability to promote apoptosis and induce G2/M cycle arrest. On the other hand, AT-NPs had significantly inhibitory effects on the 4T1 cell adhesion, migration and invasion with the respective average inhibition ratios of 32.53%, 83.26% and 75.78%. Thus, our study revealed that AT-NPs had favorable antitumor activity in vitro and exhibited a good prospect for application in the field of TNBC therapy. PMID- 29442051 TI - 3',4',7,8-Tetrahydroxyflavone inhibits RANKL-induced osteoclast formation and bone resorption. AB - Osteoclasts, which are specialized bone multinuclear cells, are responsible for bone lytic diseases such as osteoporosis. 3',4',7,8-tetrahydroxyflavone is a flavonoid from Acacia confusa. In the present study, we found that 3',4',7,8 tetrahydroxyflavone markedly inhibited receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastic differentiation from mouse bone marrow derived macrophages (BMMs). 3',4',7,8-tetrahydroxyflavone also reduced the mRNA expression levels of osteoclastic marker genes including the calcitonin receptor (CTR) and cathepsin K. In addition, 3',4',7,8-tetrahydroxyflavone decreased the bone resorption activity of osteoclasts on dentin slices. We found that 3',4',7,8 tetrahydroxyflavone inhibited RANKL-induced expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), a key transcription factor of osteoclast differentiation. Furthermore, ectopic overexpression of a constitutively active form of NFATc1 completely rescued the anti-osteoclastogenic effect of 3',4',7,8 tetrahydroxyflavone, suggesting that the anti-osteoclastogenic effect was mainly attributed to the reduction in NFATc1 expression. Taken together, our data suggest that 3',4',7,8-tetrahydroxyflavone inhibits osteoclast differentiation and bone loss and may therefore be considered a promising drug candidate for treating or preventing bone-lytic diseases. PMID- 29442052 TI - Liver, blood microdialysate and plasma pharmacokinetics of matrine following transdermal or intravenous administration. AB - Matrine is contained in several herbs used in traditional Chinese medicine, named Sophora alopecuroides, Sophora flavescens or Sophora subprostrata. In vitro and in vivo studies have focused on the treatment of chronic hepatitis or liver fibrosis using matrine. However, little is known about its liver pharmacokinetic profile. In this study pharmacokinetics of matrine in rat organs and tissues, such as liver, blood and skin were studied after intravenous (40 mg/kg) or transdermal administration (6 mg/cm2, 5 cm2). Samples were collected at timed intervals for measurement of matrine by a HPLC-UV method. The pharmacokinetic parameters were calculated by non-compartmental analysis using DAS 2.0. The AUC(0 t) values in the liver, blood microdialysates and plasma after intravenous administration were 395.91+/-74.48, 848.86+/-146.35 and 1304.07+/-305.92 min.mg/l, respectively. Following transdermal administration, the AUC(0-t) value in the liver, blood, plasma and skin microdialysates were 695.30+/-233.79, 1096.07+/-390.71, 2767.57+/-518.48 and 42735.77+/-27938.33 min.mg/l, respectively. Here, we show a promising delivery system for matrine that could replace traditional administration, and a better understanding of the transdermal pharmacokinetics of matrine, which may be helpful for further clinical and laboratory studies. PMID- 29442053 TI - Prochlorperazine interaction with melanin and melanocytes. AB - Prochlorperazine is a phenothiazine-class antipsychotic drug usually used to treat nausea, vomiting and schizophrenia. Phenothiazine derivatives have been known to cause serious side effects, like extrapyramidal symptoms, but also skin disorders which mechanism has not been fully established. The aim of this study was to examine the interaction between prochlorperazine and melanin as well as to estimate the effect of prochlorperazine on cell viability, melanogenesis and antioxidant defense system in normal human melanocytes. We have demonstrated that prochlorperazine forms stable complexes with melanin, characterized by two classes of independent binding sites with the association constants K1~106 M-1 and K2~102 M-1. It has been shown that prochlorperazine induces concentration dependent loss in cell viability. The value of EC50 was calculated to be 18.49 MUM. Prochlorperazine in a concentration of 0.001 MUM stimulated melanogenesis, while in concentrations 1.0 and 10.0 MUM melanization process was inhibited. Furthermore, the drug in concentrations of 0.1, 1.0 and 10.0 MUM caused changes in cellular antioxidant defense system, what indicated the induction of oxidative stress. The observed changes in cell viability, melanization and antioxidant defense system in normal human melanocytes after prochlorperazine treatment may explain a potential role of melanin, oxidative stress and melanocytes in mechanisms of undesirable side effects after accumulation of this drug in pigmented tissues. PMID- 29442054 TI - mRNA expression profiling of histone modifying enzymes in pediatric acute monoblastic leukemia. AB - Histone modification is dysregulated in various types of cancers, including hematological malignancies. However, the expression profile of histone-modifying enzymes in pediatric acute monoblastic leukemia (AML FAB M5) has not been investigated. In this study, we evaluated the mRNA expression profile of 85 genes that encode enzymes involved in histone-modification in 27 pediatric AML FAB M5 samples by using a novel real-time PCR array. We obtained a gene cluster consisting of a total of 28 genes (15 up-regulated genes and 13 down-regulated genes). This gene signature revealed up-regulated expression of putative oncogenes GCN5L2, SETD8, KDM5C, AURKA and AURKB, and downregulated putative tumor suppressor genes (TSGs) EP300, PRMT3, PRMT8 and NOTCH2. We investigated possible biological interactions between differentially expressed genes using ingenuity pathway analysis (IPA) and found 12 significant networks. Among these, gene expression, cancer, and embryonic development showed the highest number of networks with 39 focus molecules and had an associated significance score of 68. Further, Rb, CDKN2C, and E2F1 were found to be upstream regulators of histone modifying enzymes. This study provides additional insights into the molecular pathogenesis of pediatric AML FAB M5. These genes represent interesting targets with potential for diagnostic, prognostic and therapeutic application in pediatric AML patients. PMID- 29442055 TI - Incidence of statin-drug interactions in Croatian community pharmacy. AB - Statins are among the most frequently issued drugs that patients usually need to take for a lifetime. They are often an integral part of a polytherapeutic approach in preventing and treating cardiovascular diseases. As such, they might often interact with drugs prescribed for treating acute and chronic conditions. A pharmacist is the final professional control before a drug reaches the patient and his role in preventing drug-drug interactions is crucial. The objective of this research was to analyse the incidence and relevance of potential drug interactions with statins in community pharmacy. We retrospectively analysed the prescribed pharmacotherapy of 153 patients who were taking statins. Lexicomp(r) Lexi-InteractTM Online (Lexi-Comp, Inc., Hudson, USA) was used to identify interactions. The mean age of study patients was 65.5 (52.3% women). The most frequently used statin was atorvastatin and the least used was fluvastatin. The average number of coprescribed drugs was 4. The highest number of interactions which required enhanced patient surveillance were registered with atorvastatin, while interactions which might need specific therapy modification were mostly seen with simvastatin. Systematic and regular control of potential clinically significant drug-drug interactions in the prescribed pharmacotherapy is important for therapy outcomes and appropriate pharmaceutical surveillance in issuing pharmacotherapy. PMID- 29442056 TI - The open abdomen - still a challenge for the surgeons. Which is the best technique for temporary abdominal closure? A focus on negative pressure wound therapy. PMID- 29442058 TI - Multiparametric evaluation of risk factors associated to seroma formation in abdominal wall surgery. AB - INTRODUCTION: Incisional hernia is one of the main topics in the general surgery since there is not a unanimous consensus concerning to the best surgical methodology to adopt. It seems that prosthetic surgery is the best technique, even if responsible for the development of periprosthetic seroma. The aim of this study is to assess whether the preoperative abnormalities of the bio-humoral parameters may be considered as risk factors for seroma. PATIENTS AND METHODS: From July 2016 to July 2017 at the "Policlinico Paolo Giaccone", Palermo, Department of Emergency Surgery, 56 patients included in this study, underwent laparotomic mesh repair. The inclusion criteria were: age > 18 years, incisional hernia W2R0 according to the Chevrel classification and a monoperator technique. The main variables were: sex, age, BMI, smoke, ASA score, and co-morbidities. Among the main serum-blood variables: natraemia, kalaemia, chloraemia, calcaemia, PCR, level of glucose, creatinine, albumin and proteins in the blood. The data were analyzed using SPSS software. RESULTS: Univariate analysis highlighted hypo- and hyper-natraemia, hyper-kalaemia, hypo-chloraemia, high levels of PCR, hyper glycemia, low level of serum-blood albumin and proteins, as statistically significant variables. Multivariate analysis revealed a p<0.05 for PCR, hypo albuminemia and total serum-blood-protein level. CONCLUSIONS: Alterations of pre operative bio-humoral parameters could be associated to a greater risk of seroma development. A better understanding of such alterations may lead to more efficient risk stratification methods. This could be essential to better address the medical resources, reducing the post-operative complications and the outpatient controls as well as the risk associated to seroma. PMID- 29442057 TI - Inguinal hernia repair in day surgery: the role of MAC (Monitored Anesthesia Care) with remifentanil. AB - BACKGROUND: The extension of indications for procedures in a Day Surgery (DS) setting has led to changes in the anesthetic and surgical treatment of Inguinal Hernias (IH). According to the recommendations of the European Hernia Society, the treatment of IH in DS units should be performed under Monitored Anesthesia Care (MAC). PATIENTS AND METHODS: 960 patients underwent IH repairs over a period of 24 months. The patients were randomly divided into two groups: R (remifentanil) and F (fentanyl); the group F was considered as a control group. The exclusion criteria in both group were: morbid obesity (BMI>40 or BMI>35 in association with high blood pressure or diabetes); coagulopathy; OSAS (obstructive sleep apnea syndrome) with AHI >10; cardiovascular, respiratory, renal, hepatic or metabolic disease; history of substances abuse; GERD-related esophagitis (gastro-esophageal reflux disease); chronic analgesic use; allergy to local anesthetic and ASA>III. Patients reported their level of pain on a verbal numeric scale (VNS), with scores ranging from 0 to 10. For each patient systolic and diastolic blood pressure (SBP and DBP), mean arterial pressure (MAP), heart rate (HR) and peripheral oxygen saturation (SpO2) were recorded. The results are presented as the mean value +/- standard deviations; statistical analysis was performed using Student's t-test. RESULTS: Amongst the 960 procedures, complications or side effects related to the anesthetic techniques didn't occur; no procedure-related complications requiring mechanical ventilation support were reported. Our research focused on evaluating remifentanil effectiveness in pain control and its impact on hemodynamic stability and respiratory function. There was a significant difference between the two groups with regard to the VNS. CONCLUSIONS: Remifentanil, is an excellent drug for pain control during intra operative procedures, that allows an optimal hemodynamic stability for IH repairs in a DS setting, due to its pharmacokinetic and pharmacodynamic properties and few adverse effects. PMID- 29442059 TI - Modified transverse coloplasty pouch: new reconstruction techniques after total mesorectal excision. Our experience. AB - AIM: The incidence of rectal cancer continues to rise. The functional results after complete Total Mesorectal Excision (TME) depend on the segment of colon used for reconstruction of colonic continuity and the form, the volume and the functional proprieties of the "neorectum". The aim of our study is evaluate the efficacy of our Modified Transverse Coloplasty Pouch (MTCP) after the treatment of low rectal cancer in terms of functional outcomes and quality of life. PATIENTS AND METHODS: The study included 136 patients, underwent TME from January 2007 to December 2016 with diagnosis of extraperitoneal carcinoma of the rectum. The average distance of the tumor from the dentate line was 5.6 cm. Our follow-up protocol included functional outcome evaluation at 7th post-operative day (POD), 2nd month, and 6th month after the surgery. RESULTS: All patients (M/F 84/52) underwent anterior rectal resection (TME) with MTCP. Frequency of bowel movements per 24 hours in the studied patients compared at 7th POD, 2 months, and 6 months. Since the first post-operative weeks there is an encouraging reduction of the frequency of bowel movements. CONCLUSION: Modified Transverse Coloplasty Pouch (MTCP) had better functional results and quality of life compared to patients with a Colonic J Pouch (CJP) and traditional Transverse Coloplasty Pouch (TCP). PMID- 29442060 TI - Thyroid hemiagenesis associated with multinodular goiter and Hashimoto's thyroiditis. AB - Thyroid hemiagenesis is a rare congenital abnormality in which one of the thyroid lobes is not developed. It can be associated with various thyroid diseases, such as Grave's disease, nodular goiter and thyroid neoplasm, rarely with hyperparathyroidism. We report a case of a 50-year old woman with left thyroid lobe agenesis diagnosed by ultrasonography and scintigraphy. Right thyroidectomy was performed and the histopathological examination showed diffuse hyperplasia, multinodular goiter and Hashimoto's thyroiditis. To our knowledge, this is the first description of multinodular goiter and Hashimoto's thyroiditis in a patient with thyroid hemiagenesis. PMID- 29442061 TI - Unusual presentation of retroperitoneal Schwannoma: case report. AB - Schwannoma is a rare tumor that develops from the Schwann cells in the nerve sheath. A 42 years old woman was found incidentally to have a bulky mass in epigastric region. Abdominal ultrasonography CT and MRI have been of aid to know the position and size of the tumor. A massive capsulated retroperitoneal lesion was identified. It moved forward the hepatoduodenal ligament, inferior vena cava laterally and aorta medially. The mass is exte-riorized and detached from adhesions. There were no complications after the operation and the patient was discharged on the fourth post-operative day. The microscopically examina-tion showed features suggestive of Cellular Schwannoma. After 8 months during follow up, the patient did not report any neurological deficit and control CT did not suggest the presence of recurrent disease. PMID- 29442062 TI - Gallstone ileus in a ninety-two years old colecistectomized patient after endoscopic biliary sphincterotomy: a case report. AB - INTRODUCTION: Gallstone ileus is an uncommon condition of mechanical bowel obstruction caused by the passage of a gallstone into the bowel. It occurs more frequently in female patients older than 65 years and often for a biliary-enteric fistula. The pathognomonic features of gallstone ileus - the Rigler's triad - are pneumobilia, ectopic gallstone and bowel obstruction. Less commonly, a gallstone may enter the intestinal lumen through the common bile duct, after endoscopic retrograde cholangiopancreatography, and very rarely in colecistectomized patient. CASE REPORT: A 92-year old colecistectomized male patient was admitted to our unit for the clinical suspicion of bowel obstruction. He was also submitted to ERCP seven months before. Physical examination revealed tenderness in the lower abdomen and CT showed intrahepatic and extrahepatic biliary dilatation and small bowel obstruction with a hyperdense formation in right iliac fossa as gallstone ileus. It was performed an emergency laparotomy with enterotomy and a 5x3 cm gallstone removal. There were no post-operative complications and the patient was discharged 8 days after surgery. DISCUSSION: Cholecysto-duodenal fistulas are most frequently described in worldwide-reports. There are only few cases in literature of gallstone which enter the gastrointestinal tract following endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy through papilla of Vater, without a biliary-enteric fistula, causing gallstone ileus. If the patient is cholecistectomized, gallstone removal alone is required. CONCLUSION: The differential diagnosis in case of small bowel obstruction should always include gallstone ileus, even if the patient previously underwent a cholecystectomy. PMID- 29442063 TI - Bowel perforation in Crohn's Disease: correlation between CDAI and Clavien-Dindo scores. AB - BACKGROUND: Many studies have elaborated different kind of activity indices for Crohn's Disesase (CD) with the endpoint of univocally measure and evaluate the gravity of its lesions and symptoms. AIM: Purpose of this work is to study and define the correlation that runs between the preoperative score obtained at the Crohn's Disease Activity Index, the occurrence of postoperative complications that will require re-intervention and the severity of the postoperative lesions evaluated using the Clavien-Dindo score. PATIENTS AND METHODS: We have collected and analyzed data from 23 patients (12 males, 11 females) that in a period that spans from 2010 to 2016 had been recovered in our Operative Unit and then undergone surgical treatment for the perforative complications of the CD. RESULTS: The CDAI scores obtained for each patient and the data concerning their postoperative period have been analyzed using the ANOVA system. Results demonstrate the existence of a statistically signifying correlation (p = 0.0016) between the mean category's CDAI score and the Clavien-Dindo classification. CONCLUSIONS: Despite the small number of patients that had been recruited and analyzed in our study, it clearly shows a statistically signifying correlation between CDAI scores higher than 150 points and the risk of occurrence of severe postoperative complications in patients that had been subjected to surgical procedures for perforative or abscessual complications in Crohn's Disease. PMID- 29442064 TI - Pilonidal disease mimicking anterior anal fistula and associated with posterior anal fistula: a two-step surgery. Case report. AB - AIM: Anal fistula is a common disease originated from abscess according the cryptoglandular theory. A rare etiology is the pilonidal disease. In our case we observed a pilonidal disease mimicking an anterior perianal fistula, associated with another posterior anal fistula. CASE PRESENTATION: A 36-year old man was referred to our department with an anal fistula with an anterior opening. Despite the clinical examination and the endoanal ultrasound, only during the surgery we discovered the origin of the anterior fistula from a misdiagnosed pilonidal sinus. There was also a posterior anal fistula in communication with the same abscess of the anterior one. We performed a two-step surgery with a first fistulectomy of the anterior tract, a drainage of abscess and the positioning of a seton for the posterior fistula. After about one month and the fall of the seton we evaluate the good healing of posterior anal fistula and excised the residual pilonidal sinus. CONCLUSION: This misdiagnosed pilonidal disease created in our clinical report a true challenge. Our goal was to eliminate as much disease as possible, but also to avoid major complications or recurrences. We refused an aggressive approach and chose a two-step surgery, with in the first approach not only a demolitive time but also a reconstruction to facilitate healing, and in the second time the complete eradication of the pathology. PMID- 29442065 TI - [Steven D. WEXNER, James W. FLESHMAN CHIRURGIA DEL COLON E DEL RETTO: OPERAZIONI ADDOMINALI Piccin, Padova, 2015 Steven D. WEXNER, James W. FLESHMAN CHIRURGIA DEL COLON E DEL RETTO: OPERAZIONI ANORETTALI Piccin, Padova, 2015]. PMID- 29442066 TI - [28 degrees CONGRESSO CHIRURGIA DELL'APPARATO DIGERENTE 14 degrees CORSO PER INFERMIERI DI SALA OPERATORIA Presidente: Prof. Giorgio Palazzini Roma, 23-24 novembre 2017]. PMID- 29442067 TI - Retreatment with sofosbuvir/velpatasvir in cirrhotic patients with genotype 4 who failed a previous interferon-free regimen: a case series. AB - BACKGROUND: The novel available interferon (IFN)-free regimens significantly improved the sustained virological response (SVR) in patients with chronic hepatitis C (CHC), without important side-effects and with shorter duration of treatment. In a subset of patients, however, the treatment failure (TF) was due to the presence of resistance-associated substitutions (RAS) that lead to virological breakthrough (BT) or relapse. We analyzed in this case-series the role of RAS on the TF in cirrhotic patients with GT4, treated with a previous IFN free regimen, and retreated with the combination of sofosbuvir (SOF)/velpatasvir (VEL) for 12 or 24 weeks, without ribavirin (RBV). METHODS: We included in this analysis all patients with GT4 who failed a previous IFN-free treatment, with the presence of RAS at BT or relapse. All patients were retreated with a fixed combination of SOF/VEL for 12/24 weeks, without RBV. We evaluated the SVR and the MELD score change after the treatment. RESULTS: Seven patients were described. All were cirrhotic, Child-Pug A (n=5), B (n=2); baseline RAS were detected in 4/7 subjects; at post-treatment detection, NS5 RAS were: F28S (n=1), Q30K (n=2), S30G (n=1), NS3 were: S122R (n=1), S122G (n=2), D168V (n=3). All retreated patients gained the SVR. MELD score improved in all subjects with a median change of 3 points. No significant side-effects or adverse events were reported. CONCLUSIONS: The combination SOF/VEL could be considered for the retreatment of cirrhotic GT4 patients who failed a previous IFN-free treatment with the presence of RAS in NS3 or NS5 regions. PMID- 29442068 TI - Tunable dielectric properties of mesoporous carbon hollow microspheres via textural properties. AB - In this study, mesoporous carbon hollow microspheres (PCHMs) with tunable textural properties have been prepared through a facile hard template etching method. The PCHMs were characterized by scanning electron microscopy, transmission electron microscopy, x-ray diffraction, Raman spectra, and nitrogen adsorption and desorption systems. Uniform PCHMs with shell thickness ranging from 23 nm to 55 nm are realized. PCHMs with different textural properties can regulate dielectric and electromagnetic (EM) wave absorption effectively. The composite of paraffin wax mixed with 10 wt% PCHMs (the shell thickness of PCHMs is 35 nm) exhibits a minimum coefficient value of -53.8 dB at 8.8 GHz, with a thickness of 3.4 mm. Besides, it is remarkable that the effective absorption bandwidth covers all the X band with as low as a 10 wt% filler ratio, compared with other spherical EM wave absorbers. The excellent EM wave absorption capability of PCHMs can be ascribed to the better impendence matching and strong EM wave attenuation constant based on tunable textural properties. Our results provide a facile strategy to tune dielectric properties of spherical carbon absorbers based on textural properties, and can be extended to other spherical absorbers. PMID- 29442069 TI - Human Rett-derived neuronal progenitor cells in 3D graphene scaffold as an in vitro platform to study the effect of electrical stimulation on neuronal differentiation. AB - Studies of electrical stimulation therapies for the treatment of neurological disorders, such as deep brain stimulation, have almost exclusively been performed using animal-models. However, because animal-models can only approximate human brain disorders, these studies should be supplemented with an in vitro human cell culture based model to substantiate the results of animal-based studies and further investigate therapeutic benefit in humans. This study presents a novel approach to analyze the effect of electrical stimulation on the neurogenesis of patient-induced pluripotent stem cell (iPSC) derived neural progenitor cell (NPC) lines, in vitro using a 3D graphene scaffold system. The iPSC-derived hNPCs used to demonstrate the system were collected from patients with Rett syndrome, a debilitating neurodevelopmental disorder. The graphene scaffold readily supported both the wild-type and Rett NPCs. Electrical stimulation parameters were optimized to accommodate both wild-type and Rett cells. Increased cell maturation and improvements in cell morphology of the Rett cells was observed after electrical stimulation. The results of the pilot study of electrical stimulation to enhance Rett NPCs neurogenesis were promising and support further investigation of the therapy. Overall, this system provides a valuable tool to study electrical stimulation as a potential therapy for neurological disorders using patient-specific cells. PMID- 29442070 TI - Superconductivity in tantalum self-intercalated 4Ha-Ta1.03Se2. AB - TaSe2 has several different polytypes and abundant physical properties, such as superconductivity and charge density waves (CDW), which have been investigated in the past few decades. However, there has been no report on the physical properties of the 4Ha polytype up to now. Here we report the crystal growth and discovery of superconductivity in the tantalum self-intercalated 4Ha-Ta1.03Se2 single crystal with a superconducting transition onset temperature of [Formula: see text] K, which is the first observation of superconductivity in the 4Ha polytype of TaSe2. A slightly suppressed CDW transition is found around 106 K. A large [Formula: see text] value of about 4.48 is found when a magnetic field is applied in the ab-plane, which probably results from the enhanced spin-orbit coupling. Special stacking faults are observed, which further enhance the anisotropy. Although the density of states at the Fermi level is lower than that of other polytypes, T c remains the same, indicating that the stack mode of the 4Ha polytype may be beneficial to superconductivity in TaSe2. PMID- 29442071 TI - Differentiation of osteoclast precursors on gellan gum-based spongy-like hydrogels for bone tissue engineering. AB - Bone tissue engineering with cell-scaffold constructs has been attracting a lot of attention, in particular as a tool for the efficient guiding of new tissue formation. However, the majority of the current strategies used to evaluate novel biomaterials focus on osteoblasts and bone formation, while osteoclasts are often overlooked. Consequently, there is limited knowledge on the interaction between osteoclasts and biomaterials. In this study, the ability of spongy-like gellan gum and hydroxyapatite-reinforced gellan gum hydrogels to support osteoclastogenesis was investigated in vitro. First, the spongy-like gellan gum and hydroxyapatite-reinforced gellan gum hydrogels were characterized in terms of microstructure, water uptake and mechanical properties. Then, bone marrow cells isolated from the long bones of mice and cultured in spongy-like hydrogels were treated with 1,25-dihydroxyvitamin D3 to promote osteoclastogenesis. It was shown that the addition of HAp to spongy-like gellan gum hydrogels enables the formation of larger pores and thicker walls, promoting an increase in stiffness. Hydroxyapatite-reinforced spongy-like gellan gum hydrogels support the formation of the aggregates of tartrate-resistant acid phosphatase-stained cells and the expression of genes encoding DC-STAMP and Cathepsin K, suggesting the differentiation of bone marrow cells into pre-osteoclasts. The hydroxyapatite reinforced spongy-like gellan gum hydrogels developed in this work show promise for future use in bone tissue scaffolding applications. PMID- 29442072 TI - Cortical excitability correlates with the event-related desynchronization during brain-computer interface control. AB - OBJECTIVE: Brain-computer interfaces (BCIs) based on motor control have been suggested as tools for stroke rehabilitation. Some initial successes have been achieved with this approach, however the mechanism by which they work is not yet fully understood. One possible part of this mechanism is a, previously suggested, relationship between the strength of the event-related desynchronization (ERD), a neural correlate of motor imagination and execution, and corticospinal excitability. Additionally, a key component of BCIs used in neurorehabilitation is the provision of visual feedback to positively reinforce attempts at motor control. However, the ability of visual feedback of the ERD to modulate the activity in the motor system has not been fully explored. APPROACH: We investigate these relationships via transcranial magnetic stimulation delivered at different moments in the ongoing ERD related to hand contraction and relaxation during BCI control of a visual feedback bar. MAIN RESULTS: We identify a significant relationship between ERD strength and corticospinal excitability, and find that our visual feedback does not affect corticospinal excitability. SIGNIFICANCE: Our results imply that efforts to promote functional recovery in stroke by targeting increases in corticospinal excitability may be aided by accounting for the time course of the ERD. PMID- 29442073 TI - Flow induced crystallisation of penetrable particles. AB - For a system of Brownian particles interacting via a soft exponential potential we investigate the interaction between equilibrium crystallisation and spatially varying shear flow. For thermodynamic state points within the liquid part of the phase diagram, but close to the crystallisation phase boundary, we observe that imposing a Poiseuille flow can induce nonequilibrium crystalline ordering in regions of low shear gradient. The physical mechanism responsible for this phenomenon is shear-induced particle migration, which causes particles to drift preferentially towards the center of the flow channel, thus increasing the local density in the channel center. The method employed is classical dynamical density functional theory. PMID- 29442074 TI - Inconsistencies and omissions in the implementation of IRR17 to medical, dental and veterinary practices. PMID- 29442076 TI - Erectile dysfunction is associated with subclinical carotid vascular disease in young men lacking widely-known risk factors. AB - This study aimed to gain insight into the underlying pathogenesis of erectile dysfunction in young men under the age of 40 years without widely-known risk factors. Compared with normal controls, patients with erectile dysfunction had increased carotid intima-media thickness, fasting levels of blood glucose and insulin, and homeostatic model assessment index, as well as lower flow-mediated vasodilation and testosterone levels (P < 0.05), though all of these values were within their respective normal range. Multivariate logistic regression analysis identified carotid intima-media thickness, flow-mediated vasodilation, insulin level, and homeostatic model assessment index as significant predictors of erectile dysfunction. Young men with flow-mediated vasodilation <10.65% were 11.645 times more likely to have erectile dysfunction, young men with carotid intima-media thickness >0.623 mm had a 4.16-fold, and young men with homeostatic model assessment index >1.614 had a 5.993-fold greater risk of having erectile dysfunction. In conclusions, in young men with normal results from general clinical screening, an increased carotid intima-media thickness and homeostatic model assessment index and reduced flow-mediated vasodilation were associated with a higher incidence of erectile dysfunction. Erectile dysfunction may appear before the detection of traditional cardiovascular risk factors and may be the earliest clinical sign of subclinical cardiovascular disease. PMID- 29442077 TI - Newer accomplishment in research. PMID- 29442078 TI - Dental caries: Research perspective. PMID- 29442075 TI - Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system. AB - Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure (CHF), shortening of the Q T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality. Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance. Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO2maxand vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms. Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength. Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels. Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition. Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis. PMID- 29442079 TI - Effect of orthodontic pain on quality of life of patients undergoing orthodontic treatment. AB - Introduction: Pain is an important aspect of oral health-related quality of life (OHRQOL). Understanding how patients' pain experiences during their treatment affect their quality of life (QOL) is important and the absence of pain/discomfort is important for achieving a high QOL. Aim and Objective: The objective of this study was to assess the relationship between pain and OHRQOL among patients wearing fixed orthodontic appliances and to evaluate whether patient motivation and counseling had an effect on the pain and discomfort. Materials and Methods: The McGill-Short-Form with visual analog scale and present pain intensity and Oral Health Impact Profile-14 indices were used to determine the intensity and severity of pain and to evaluate the QOL of 200 adolescents undergoing fixed orthodontic treatment during different phases of treatment. Results: There was a significant correlation found between pain and the QOL of patients undergoing orthodontic treatment. Overall score of OHRQOL increased significantly (mean 43.5 +/- 10.9) in the initial phase of treatment where the incidence of severe to moderate pain was reported in 80% patients. Ninety-five percent patients felt pain or discomfort. After 1 day of appliance placement, more than 85% of patients experienced severe to mild pain whereas 9% of patients suffered very severe pain. Pain reduced over a week, and at the end of a month, 10.5% patients had moderate pain whereas majority, i.e., 58% of patients complained of only mild pain (P < 0.05). Conclusion: Pain is important sequelae of orthodontic treatment and has a significant effect on the QOL of orthodontic patients, especially during the initial phases of treatment. Patient motivation and counseling by the orthodontist have a profounding effect in reducing the pain and discomfort, improving the QOL, and an overall improvement in the patient compliance affecting the successful outcome of the treatment. PMID- 29442080 TI - Dental anxiety and influencing factors: A cross-sectional questionnaire-based survey. AB - Background: Dental treatment still remains as one of the most anxious visits despite awareness between dentists and patients in building trusting relationships. The fear of dental treatment determines the frequency of treatment availed with long-term implications in oral health maintenance. Aim: This study aims to estimate prevalence, extent, and factors influencing dental anxiety in a sample of the adult population visiting a private dental hospital in Chennai, India. Materials and Methods: The study sample included 300 consecutive outpatients visiting a private dental hospital in Chennai. Any patient aged 18 and above was considered for the study. A structured custom-made questionnaire composed of ten questions was designed to assess the anxiety levels of dental patients. The level of the patient's anxiety was assessed taking into account various factors that could influence their mental state. This included their age, gender, educational qualification, number/frequency of their dental visits, reason for their visit, past dental experiences, and nature of the dental procedure planned. Enquiries about the related time of anxiety manifestations as well as their preferred anxiety reducing protocols were done as part of the study. Statistics: The data analysis was performed using SPSS Version 11.5. Analysis initially was performed with Chi-square test for frequency and reason of visit, with the independent samples t-test used for assessing mean score differences along with Pearson's correlation coefficient. Results: The study revealed that dental anxiety has a wide prevalence rate encompassing both genders. Distinctive predominance among females (65.2%) and professionals (66.9%) exhibiting a greater degree of anxiety was identified. Pain and extraction have been cited as duress and anxiety inciting procedures (72.6%). Conclusion: This survey has revealed that age, gender, level of education, and procedure along with visit frequency has a direct effect on the patient's state of mind and anxiety. PMID- 29442081 TI - Qualitative and quantitative salivary changes and subjective oral dryness among patients with thyroid dysfunction. AB - Context: There is a paucity of literature regarding the effects of thyroid disorders on the oral cavity by influencing the salivary gland function. Aims: This study aims to understand the qualitative and quantitative changes that thyroid disorder can cause in the salivary function. Settings and Design: : After obtaining ethical clearance, 46 consecutive newly diagnosed thyroid dysfunction patients were enrolled in this cross-sectional study, along with 45 age-and sex matched controls. Subjects and Methods: : Unstimulated and stimulated salivary flow rates, pH, and buffering capacity of the whole saliva were studied in addition to subjective oral dryness in the study participants. Statistical Analysis Used: : The independent t-test was employed to compare the means between the two groups and Pearson's Chi-square test was used to assess the goodness of fit. Results: The findings showed that females are more affected with thyroid disorders and that hypothyroidism is more commonly reported than hyperthyroidism. A significant reduction in the salivary flow rates and buffering capacity was observed among the affected group compared to the controls, whereas the salivary pH did not show significant differences between genders and also between the case and control groups. A feeling of subjective oral dryness was perceived by many affected patients. Conclusions: The study was able to establish an association between thyroid dysfunction and salivary gland function. We hope that this study leads to more high-impact research in this field as salivary diagnostics is gaining more popularity with every passing day. PMID- 29442082 TI - Comparative analysis of salivary sialic acid levels in patients with chronic obstructive pulmonary disease and chronic periodontitis patients: A biochemical study. AB - Aim: Sialic acid plays a central role in the functioning of biological systems, in stabilizing the glycoproteins and cellular membranes, assisting in cell-cell recognition and interaction. The aim of this study is to evaluate and compare the periodontal health status and salivary Sialic acid levels in patients suffering from chronic obstructive pulmonary diseases (COPD) and chronic periodontitis patients. Materials and Methods: Ninety subjects were included in the study, which were divided into the following groups, 30 in each group. Group 1: patients suffering from COPD and chronic periodontitis, Group 2: periodontitis patients without any systemic diseases Group 3: healthy subjects. Unstimulated whole saliva samples were collected around 9-10 AM; 2 h after the subjects had breakfast. The sialic acid content was determined by a combined modification of the thiobarbituric acid method of Skoza and Mohos. Results: The mean salivary sialic acid levels were least in the healthy group followed by the periodontitis group, and it was highest in the COPD group. Conclusions: We can thus conclude that promotion of dental care knowledge is very much essential in the prevention and treatment of COPD. Thus, estimation of levels of salivary sialic acid can be used as an adjunct to diagnose the current periodontal disease status and to assess the treatment outcomes in subjects with COPD and chronic periodontitis. PMID- 29442083 TI - Cleft rhinoplasty columellar lengthening: Comparison of techniques. AB - Background: Nasal deformity in bilateral cleft lip and palate (BCLP) correction is highly challenging. Several solution has been proposed. The aim of the present study is to assess qualitatively and quantitatively the results of Cronin's flap, Fork flap, and Abbe's flap for BCLP rhinoplasty at a follow-up period. Materials and Methods: : Records of all BCLP rhinoplasty performed between 2010 and 2016, fulfilling inclusion and exclusion criteria were collected. From records, qualitative improvement and previously described methods of quantification of columella length were performed. These collected data were analyzed with descriptive statistics, Chi-square tests, and one-way analysis of variance tests. P <= 0.05 was taken as statistically significant. Results: Forty-eight cases fulfilled the criteria of which 31 patients had Abbe's flap, 9 Cronin, and 8 forked flaps. The mean age of the study population was 20.33 +/- 4.94 years in 21 females and 27 males with a mean follow-up of 15.3 +/- 2.3 months. The success of the lengthening of columella at immediate postoperative period as compared to the preoperative columella length was not statistically different (P = 0.176) between the three flaps, while the same was statistically different at 1-year period (P = 0.031). The extent of change was very minimal for the Abbe flap with a high degree of statistical significance (P = 0.000). At 1-year postoperative period, 83.9% (n = 26) of Abbe flap patients felt their nose to be good after surgery while the same was 55.6% (n = 5) in Cronin flap design and 37.5% (n = 3) in forked flap design (P = 0.007). Discussion and Conclusion: Abbe flap gave the best results under most of the common BCLP rhinoplasty, and a flap choice algorithm for choice of flap was arrived based on this experience. PMID- 29442084 TI - Comparative evaluation of antiplaque and antigingivitis effects of an herbal and chlorine dioxide mouthwashes: A clinicomicrobiological study. AB - Aim: The aim of the present study was to compare the efficacy of herbal mouthwash and chlorine dioxide mouthwash in reduction of plaque and gingivitis. Settings and Design: In a randomized clinical trial, forty patients were randomly selected and divided equally into two groups. Materials and Methods: After professional oral prophylaxis, the clinical parameters plaque index, gingival index, and modified sulcular bleeding index were recorded at baseline, 7th day, 14th day, and 21st day. The plaque samples were collected from gingival sulcus with an absorbent sterile paper point and were stored in a thioglycollate broth, then sent for microbiological examination. The microbial colony-forming units were assessed at baseline, 7th day, 14th day, and 21st day for Streptococcus mutans, Tannerella forsythia, and Fusobacterium nucleatum. Results: There was a statistical significant reduction in both clinical and microbiological parameters were observed with use of both the mouthwashes. However, herbal mouthwash was more effective in reducing the plaque and gingivitis than chlorine dioxide mouthwash. Conclusion: Herbal mouthwash was statistically efficacious in controlling plaque and gingivitis with potent antimicrobial activity. PMID- 29442085 TI - An insight into diagnosis of a hidden entity: Impacted food material. AB - Introduction: Foreign bodies and tissue reactions to foreign materials are commonly encountered in the oral cavity. Exogenous materials causing foreign body reactions may be metallic (amalgam) or nonmetallic (suture materials, vegetable matter). Implantation of food particles in the oral tissues has been known to cause reactive lesions such as oral pulse granuloma. Implantation could be through extraction sockets, deep periodontal pockets, associated with tumor growth, interdental areas of teeth, unfilled root canals, and grossly decayed teeth. These get rapidly digested and altered by host responses. Cellulose persists as hyaline material and invokes chronic granulomatous response. This change may mimic other pathologies. Materials and Methods: Representative specimens from commonly consumed food groups were selected, fixed in 10% neutral buffered formalin, processed, sectioned, stained with hematoxylin and eosin stain and observed under light microscope. Results: Each specimen revealed unique, distinct histology of each food type. The plant materials had a characteristic appearance of rigid double cell wall while rigid regular partitions containing nutrient material were revealed in seeds and beans. Starch-contained lentils exhibited clear spaces. Following is a brief description of some of the significant histological findings of each of the specimens processed and stained. Conclusion: Thus, the study of histological structure of vegetables and legumes will enable their easy recognition in oral biopsy samples and help in distinguishing them from other pathologies and artifact. PMID- 29442086 TI - Effect of preoperative ibuprofen in controlling postendodontic pain with and without low-level laser therapy in single visit endodontics: A randomized clinical study. AB - Aim: The aim of this study is to evaluate the effect of low-level laser irradiation and ibuprofen in reducing the onset and severity of postoperative pain following single visit endodontics. Materials and Methods: One hundred and twenty patients were recruited for this study. Group A (n = 30) patients were administered 400 mg of ibuprofen orally 1 h before the institution of an endodontic procedure. Group B (n = 30) patients were given irradiation of a low level laser at 50 Hz for 3 min after the standard endodontic procedure at the periapical region on both buccal and lingual aspect. Group C (n = 30) patients were given preoperative ibuprofen followed with a low-level laser at 50 Hz for 3 min after endodontic treatment. Group D (n = 30) patients were administered no preoperative ibuprofen nor low-level laser irradiation after the endodontic procedure. The patient immediately recorded his/her pain perception on the Heft Parker pain survey after completion of the appointment and at 4, 8, 12, 24, and 48 h postoperatively. Inter group analysis was carried out using the analysis of variances with "least significant difference" post hoc test. For intra group analysis, Student's t-test was used. Chi-square test was applied for nonparametric data. Results: Pain was significantly reduced in all the treatment groups postoperatively. Ibuprofen showed significant pain reduction at 4 h and 8 h period. The combination of low-level laser and ibuprofen showed the best results in terms of postoperative pain reduction. Conclusion: This study proved that low-level laser therapy can be an effective alternative for conventional use of nonsteroidal anti-inflammatory drugs in controlling postendodontic pain thereby eliminating the adverse effects of such drugs on the patients. PMID- 29442088 TI - Morphological and morphometric analysis of accessory mental foramen in dry human mandibles of south indian population. AB - Background: Mental foramen (MF) is an important landmark for administration of local anesthesia in surgical procedures involving the mandible. Additional mental foramina, called accessory mental foramina (AMF) transmitting branches of mental nerve, have been reported. Detection of AMFs in presurgical imaging may reduce postoperative pain in dental surgical procedures. Aim: The aim of the study was to study the incidence and morphometric analysis of accessory MF in the dry human mandibles of South Indian population. Materials and Methods: Two hundred and sixty dry human mandibles were studied for the presence, location, shape of AMF, and its relation to MF. The horizontal diameter of AMF, and its distance from symphysis menti, the posterior border of mandible and from the base of mandible were measured and statistically analyzed. Results and Conclusions: In our study, AMF were present in 8.85% mandibles (unilateral - 7.6% [4.6% - left, 2.69% - right] and bilateral 1.6%). The most common position was below the second premolar (48.1%). AMF were round in shape (74%) and was often located either superomedial or inferolateral to MF. Their transverse diameter ranged from 0.5 to 1 mm. The AMF were situated at a mean distance of 2.96 mm from MF, 23.47 mm from symphysis menti, 11.24 mm from the lower border of the body of the mandible, and 57.35 mm from the posterior border of ramus of mandible. The knowledge of the presence of AMF and its dimensions would enable the clinicians to do mandibular procedures carefully and avoid injury to the branches of mental nerve that may be passing through it. PMID- 29442087 TI - The effect of three desensitizing agents on dentin hypersensitivity: A randomized, split-mouth clinical trial. AB - Objectives: This randomized clinical trial tested the effect of three different desensitizing agents on reduction of pain due to hypersensitive cervical dentin lesions. Materials and Methods: Twenty-eight individuals with 84 teeth diagnosed with cervical dentin hypersensitivity (DH) in at least one tooth in any three of the four quadrants were selected. Patients exhibiting pain scores of two or more on the visual analog scale (VAS) were included in the study. Each quadrant in an individual was randomly assigned to one of the three treatment groups based on computer-generated random number. The desensitizing agents used were Profluorid Varnish (Voco: Cuxhaven Germany), Admira Protect (Voco: Cuxhaven Germany), and PRG-Barrier Coat (Shofu: japan). One operator recorded the baseline sensitivity scores after evaporative and tactile stimuli by visual analog score system. The second operator who was not aware of the baseline values applied the desensitizing agents and recorded the sensitivity scores. VAS scores for both the stimuli were noted immediately after application, 1 week, and after 1 month. The data were analyzed using repeated measure ANOVA and post hoc Tukey's multiple comparison tests (P < 0.05 was considered statistically significant). Results: There was a significant reduction in VAS scores from baseline in all the three groups at all the time intervals (P < 0.001). Admira Protect showed significant reduction of hypersensitivity scores at 1 month compared to other groups (P < 0.001). Conclusion: Admira Protect was proved to be better in reducing pain due to DH than PRG-Barrier Coat and Profluorid Varnish after 1 month of application. PMID- 29442089 TI - Reactive hyperplastic lesions of the oral cavity: A retrospective survey study and literature review. AB - Context: The reactive lesions are relatively common in the oral cavity because of the frequency with which the tissues are injured. They often result from a known stimulus or injury such as dental plaque, calculus, or foreign material. Aims: : The aim of this study was to review the clinicopathologic features of reactive hyperplastic lesions (RHLs) of the oral cavity at MIDSR, Dental College and Hospital, Latur, Maharashtra, and to compare these data with those of previously reported studies. Settings and Design: The patient case files from the Department of Oral and Maxillofacial Pathology from June 2010 to May 2016 were reviewed for cases of RHLs of the oral cavity. Subjects and Methods: Both clinical and histopathological diagnosis of reactive lesions was selected for the study. Data including the type of the lesion, age, gender, and the site involved were collected. Statistical Analysis Used: Descriptive statistics was applied to the data and differences in frequencies among groups were evaluated using SPSS (IBM Corporation) software. Results: : A total of 155 histologically diagnosed cases of RHLs were obtained with a prevalence of 11.7%. The data consist of 56 (36.1%) males and 99 (63.9%) females. The most common lesion clinically was traumatic fibroma (36.5%) and histologically fibrous hyperplasia (37.4%). The reactive lesions clinically presented as either sessile (51%) or pedunculated (49%) lesions. Conclusions: The clinical features of reactive hyperplasia among our patients were similar to those reported previously with divergence in some analyzed data. The novelty in our study was the correlation between histopathology and clinical features which were not reported in literature till date. PMID- 29442091 TI - Influence of light transmission through fiber posts: Quantitative analysis, microhardness, and on bond strength of a resin cement. AB - Context: Light transmission (LT) into deeper areas of the dentin root is limited. Aim: The aim of this study is to perform a quantitative investigation of the radial transmission of light (LT) through different fiber posts and its influence on the Knoop hardness number (KHN) and bond strength (BS) of a dual-cure self adhesive resin cement at 3 different depths. Materials and Methods: Four types of fiber posts (2 translucent and 2 conventional) were used. LT and KHN analyses were performed in a specially designed matrix, which allowed measurements at 3 different depths. LT was measured using a volt-ampere meter while KHN tests were performed in a microhardness tester. For BS analysis, endodontically treated bovine roots were divided into 4 groups, each group receiving one type of post. After cementation, cross sections of the root were tested for resistance to displacement using a universal testing machine. Statistical Analysis Used: : Statistical analysis was performed by using this ANOVA and Tukey's test. Results: For LT, translucent posts showed significantly higher values at all depths compared to the conventional ones. For all posts, LT decreased at the deeper depths. The KHN results showed no statistical differences among the different posts, regardless of depth. For BS, a translucent post showed the highest values, and comparative analyses between the different depths of posts also showed statistically significant differences while comparisons among the different depths of the same post showed no differences. Conclusions: LT depended on the type of post and on depth. The type of post did not significantly influence the cement KHN. A translucent post showed higher BS in pooled data. PMID- 29442090 TI - Effect of chemical disinfectants and accelerated aging on maxillofacial silicone elastomers: An In vitro Study. AB - Context: Maxillofacial prostheses need frequent refabrication due to degradation of color and deterioration of physical properties of the elastomer. Aims: This study attempted to evaluate the change in color stability, Shore A hardness, and surface roughness of two maxillofacial silicones, A-2186 and Cosmesil M511, when submitted to chemical disinfection and accelerated aging. Settings and Design: This was a comparative in vitro study. Subjects and Methods: The materials included two silicone elastomers - A-2186 and Cosmesil M511 (Factor II Incorporated) - functional intrinsic red pigment and three disinfectants - Fittydent tablet, chlorhexidine gluconate 4%, and neutral soap. The specimens in each group of elastomer were evaluated initially for color, hardness, and surface roughness, which were further divided into subgroups and subjected to disinfection and accelerated aging. The evaluation of color was performed with the help of an ultraviolet reflectance spectrophotometer. Shore A hardness was evaluated using a durometer and surface roughness, with a digital roughness tester followed by scanning electron microscopy analysis. Statistical Analysis Used: : Analysis of variance and Tukey's multiple comparison test were used for statistical analysis. Results: Accelerated aging caused a significant decrease in color, increase in Shore A hardness, and variation in surface roughness in both silicone elastomer groups. Chemical disinfection presented significant changes in color and surface roughness whereas no significant effect on Shore hardness, irrespective of the disinfectant used. Conclusions: The maxillofacial silicone elastomers presented deterioration in color, hardening, and significant variations in surface roughness when subjected to chemical disinfection and accelerated aging, which provides a valid baseline for future research. PMID- 29442092 TI - Various bio-mechanical factors affecting heat generation during osteotomy preparation: A systematic review. AB - Background: As implant site preparation and bone are critical precursors to primary healing, thermal and mechanical damage to the bone must be minimized during the preparation of the implant site. Moreover, excessively traumatic surgery can adversely affect the maturation of bone tissue at the bone/implant interface and consequently diminish the predictability of osseointegration. So, this study was carried out to evaluate the various biological and mechanical factors responsible for heat generation during osteotomy site preparation to reduce the same for successful osseointegration of dental implants. Study Design: A broad search of the dental literature in PubMed added by manual search was performed for articles published between 1992 and December 2015. Various bio mechanical factors related to dental implant osteotomy preparation such as dental implant drill designs/material/wear, drilling methods, type of irrigation, and bone quality were reviewed. Titles and abstracts were screened and articles which fulfilled the inclusion criteria were selected for a full-text reading. Results: The initial database search yielded 123 titles, of which 59 titles were discarded after reading the titles and abstracts, 30 articles were again excluded based on inclusion and exclusion criteria, and finally 34 articles were selected for data extraction. Many biological and mechanical factors responsible for heat generation were found. Conclusion: Literatures of this review study have indicated that there are various bio-mechanical reasons, which affect the temperature rise during osteotomy and suggest that the amount of heat generation is a multifactorial in nature and it should be minimized for better primary healing of the implant site. PMID- 29442093 TI - A review of research on cytological approach in salivary gland masses. AB - To evaluate the diagnostic accuracy of fine-needle aspirations (FNAs) in salivary gland pathologies. A comprehensive literature search was conducted in the PubMed database using related Medical Subject Heading terms "sensitivity and specificity of FNA in salivary gland" and "diagnostic accuracy of FNA in salivary gland" for the period 1980-2016, and we found that 414 research studies had been published. PRISMA technology was utilized to prepare flow chart for displaying data search strategy. A total of 385 articles were excluded based on the established inclusion and exclusion criteria of the study. Twenty-nine research studies were included. Those twenty-nine studies on the sensitivity and specificity of FNAs in salivary gland pathology consisted of 5274 cases of benign, malignant and inflammatory salivary gland lesions. The present study identified a range of 87% 100% sensitivity and 90%-100% specificity for the usefulness of FNAs in distinguishing benign and malignant salivary gland lesions. Although a considerable number of studies have been identified that reported on sensitivity and specificity of FNAs in salivary gland pathologies, each study had a different approach in reporting the sensitivity and specificity. We emphasize that standardized reporting protocols of sensitivity and specificity report supported with checklists would help future researchers to interpret this cytological method and make more accurate clinical utility and usefulness reports on salivary gland pathologies. PMID- 29442094 TI - A potential side effect of oral topical steroids: Central serous chorioretinopathy. AB - Topical corticosteroids are some of the most common drugs used in oral medicine for treating atrophic and erosive lesions that affect the mucosa. Adverse effects of these drugs include oral candidiasis with associated burning mouth and hypogeusia, hypersensitive reactions to the drug, and inhibition of the hypothalamic-pituitary-adrenal axis and secondary adrenal insufficiency. The ocular side effects of oral topical steroids are less documented. This short communication describes a case of central serous retinopathy that developed following administration of oral topical steroid. PMID- 29442095 TI - Assessment of malocclusion status, dentition status, and treatment needs among 15 year-old school children of Mangalore. AB - Background and Objectives: Dental caries and malocclusion are common dental public health problems. Surveys provide us with an insight into the oral health status and treatment needs and also help in proper treatment planning. Hence, the objective of this study was to assess the malocclusion status, dentition status, and treatment needs of 15-year-old school children of Mangalore. Methodology: A cross-sectional study of 1001 school children aged 15-year-old was conducted in Mangalore. Their malocclusion status, dentition status, and treatment needs were recorded using the WHO oral health assessment pro forma. Statistical analysis was done using Statistical Package for Social Sciences version 17. Descriptive statistics was obtained and Chi-square test was used. The level of significance was set at 0.05. Results: Decayed teeth were prevalent in 45.5% of the study subjects. Malocclusion was present in 30% of the study subjects. Teeth missing due to caries and those requiring extraction and prosthetic rehabilitation were significantly higher in government schools (P < 0.05). Malocclusion and treatment need was significantly higher in government schools (P < 0.05). Conclusion: From the present study, we can conclude that the school children aged 15 years of Mangalore had varied malocclusion status, dentition status, and treatment needs with significantly higher treatment needs and malocclusion among children of government school. PMID- 29442096 TI - Oral and masticatory rehabilitation using osseointegrated dental implants after resective treatment of multicystic ameloblastoma in the lower jaw with a fibula graft. AB - Ameloblastoma is an aggressive odontogenic tumor which typically occurs between third and fourth decade of life that often needs resective approach. Immediate reconstruction may show better results. The treatment of multicystic ameloblastoma in the mandible being a rare case that occurred in the late second decade of life, which was surgically removed along with the affected teeth with safety margins, and the region was immediately reconstructed using a vascularized graft, removed from the fibula. Its integration, in combination with osseointegrated dental implants and fixed implant-supported prostheses, restored chewing function and esthetics. After 6 years from fibular graft and 24 months of dental implants, an excellent outcome was observed, with oral health and normal functions properly restored, and the immediate reconstruction of the mandible in resective cases, associated with oral rehabilitation with dental implants, may be considered a suitable treatment option. PMID- 29442097 TI - A cast partial obturator with hollow occlusal shim and semi-precision attachment. AB - A maxillofacial patient's quality of life is distorted and social integration becomes difficult. An obturator is a maxillofacial prosthesis used to close a congenital or acquired tissue defect, primarily of the hard palate and/or contiguous alveolar/soft-tissue structures. Subsequently, it restores the esthetics, speech, and function. The present clinical report aimed for the prosthetic rehabilitation of a maxillectomy defect by the incorporation of a semi precision attachment as PRECI-SAGIX - male part of 2.2 mm on fixed partial denture (#22 and #23 teeth) and matrix - plastic female part of size 2.2 mm and height 4.2 mm of yellow on cast partial in polymer base. It aids in the retention of a hollow lightweight obturator. The technique also described the method to make a bulbless obturator with a hollow self-cured acrylic resin occlusal shim. A patient is quite satisfied with bulb less, lightweight cast partial and hollow shim palatal obturator. PMID- 29442098 TI - The prevalence of malocclusion and orthodontic treatment needs in schoolgoing children of Nalagarh, Himachal Pradesh, India. PMID- 29442099 TI - Prescribing or deprescribing in older persons: what are the real-life concerns in geriatric practice? AB - INTRODUCTION Multimorbidity in older adults leads to polypharmacy with all its hazardous outcomes and drug-related problems. OBJECTIVES We aimed to assess the difference in the number of drugs between admission to and discharge from a geriatric ward and identified the patient-related factors associated with changes in the drug regimen. PATIENTS AND METHODS This retrospective cross-sectional study included 301 geriatric patients who underwent drug optimization in line with the Beers and STOPP/START criteria. The numbers of drugs per individual at hospital admission and discharge were compared using the Wilcoxon signed-rank test. A multiple linear regression model was used to identify patient characteristics that influenced the observed difference in the number of drugs following geriatric hospitalization. RESULTS A significant reduction of 1.29 in the number of drugs per patient, on average, was observed. The Spearman's correlation coefficient between the number of prescribed medications and the number of coexisting conditions per individual changed from 0.28 to 0.51. The patient-related characteristics that jointly and independently explained (P <0.001) the difference in the number of drugs in the multiple regression model (R2 = 0.73) were the number of drugs on admission, number of coexisting conditions, age, fact of living alone, and the incidence of adverse drug reactions. CONCLUSIONS Geriatric hospitalization results in deprescribing rather than prescribing medications, especially in individuals who were overtreated, older, undernourished, at risk of an adverse drug reaction, and living alone. Appropriate deprescribing may potentially lead to fewer drug related problems in the senior population as well as reduce health care costs. PMID- 29442100 TI - Predictors of Deterioration in Sagittal Balance Following Long Fusion Arthrodesis to L5 in Patients with Adult Scoliosis. AB - BACKGROUND The aim of this study was to identify the predictors of deterioration in sagittal balance in patients with adult scoliosis following long fusion arthrodesis to L5. MATERIAL AND METHODS A retrospective clinical study included 63 patients with adult scoliosis who underwent long fusion arthrodesis to L5, between February 2005 and May 2015. Radiological imaging values included the angle of lumbar lordosis (LL), and the angle of pelvic incidence (PI). The patients were divided into two cohorts, according to the threshold of average loss of sagittal vertical axis (SVA): a cohort with stable sagittal balance (SSB) and a cohort with deteriorated sagittal balance (DSB). Multivariate logistic regression analysis and the receiver operating characteristic (ROC) curve were used to identify the predictors of clinical outcome. RESULTS There were significant differences between the SSB and DSB cohorts in age (p<0.001), preoperative SVA (p<0.001), last follow-up SVA (p<0.001), preoperative LL (p=0.001), last follow-up LL (p<0.001), subsequent L5-S1 disc degeneration (p<0.001) and PI (p=0.028). Patient age >61.5 years (OR=1.251, 95% CI, 1.055 1.484) (P=0.010), preoperative SVA >3.54 cm (OR=1.844, 95% CI, 1.249-2.732) (P=0.002) and preoperative LL <19.0 degrees (OR=0.922, 95% CI, 0.869-0.979) (P=0.008) were identified as predictors of deterioration in sagittal balance. CONCLUSIONS Deterioration in sagittal balance following long fusion arthrodesis to L5 in patients with adult scoliosis was associated with subsequent L5-S1 disc degeneration and loss of LL, age >61.5 years, preoperative SVA >3.54 cm, and preoperative LL <19.0 degrees. PMID- 29442101 TI - A molecular dynamics study of the complete binding process of meropenem to New Delhi metallo-beta-lactamase 1. AB - The mechanism of substrate hydrolysis of New Delhi metallo-beta-lactamase 1 (NDM 1) has been reported, but the process in which NDM-1 captures and transports the substrate into its active center remains unknown. In this study, we investigated the process of the substrate entry into the NDM-1 activity center through long unguided molecular dynamics simulations using meropenem as the substrate. A total of 550 individual simulations were performed, each of which for 200 ns, and 110 of them showed enzyme-substrate binding events. The results reveal three categories of relatively persistent and noteworthy enzyme-substrate binding configurations, which we call configurations A, B, and C. We performed binding free energy calculations of the enzyme-substrate complexes of different configurations using the molecular mechanics Poisson-Boltzmann surface area method. The role of each residue of the active site in binding the substrate was investigated using energy decomposition analysis. The simulated trajectories provide a continuous atomic-level view of the entire binding process, revealing potentially valuable regions where the enzyme and the substrate interact persistently and five possible pathways of the substrate entering into the active center, which were validated using well-tempered metadynamics. These findings provide important insights into the binding mechanism of meropenem to NDM-1, which may provide new prospects for the design of novel metallo-beta-lactamase inhibitors and enzyme-resistant antibiotics. PMID- 29442102 TI - Emergent property of high hardness for C-rich ruthenium carbides: partial covalent Ru-Ru bonds. AB - Hard materials are being investigated all the time by combining transition metals with light elements. Combining a structure search with first-principles functional calculations, we first discovered three stable stoichiometric C-rich ruthenium carbides in view of three synthesis routes, namely, the ambient phases of Ru2C3 and RuC, and two high pressure phases of RuC4. There is a phase transition of RuC4 from the P3[combining macron]m1 structure to the R3[combining macron]m structure above 98 GPa. The calculations of elastic constants and phonon dispersions show their mechanical and dynamical stability. The large elastic modulus, high Debye temperature and the estimated hardness values suggest that these hard ruthenium carbides have good mechanical properties. The analyses of electronic structure and chemical bonding indicate that chemical bonding, not carbon content, is the key factor for the hardness in these metallic C-rich ruthenium carbides. The partial covalent Ru-C bonds and strong covalent C-C bonds are responsible for the high hardness. Moreover, the emergence of partial covalent Ru-Ru bonds can enhance the hardness of RuC, while the ionic Ru-Ru bonds can weaken the hardness of Ru2C3. PMID- 29442103 TI - NO prodrug-conjugated, self-assembled, pH-responsive and galactose receptor targeted nanoparticles for co-delivery of nitric oxide and doxorubicin. AB - Targeted delivery and controlled release of nitric oxide (NO) locoregionally are in high demand and challenging in cancer treatment. Herein, we report an example of galactose receptor targeted, pH-responsive and self-assembled nanoparticle based delivery of the NO prodrug O2-(2,4-dinitrophenyl) 1-[4 (propargyloxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (alkynyl-JSK), which was chemically conjugated to an amphiphilic block copolymer through a click reaction for the first time. The assembled NO prodrug nanoparticles show high NO capacity (the content of the NO prodrug in the copolymer, ~23.4% (w/w)), good stability and a sustained NO release pattern with unique glutathione/glutathione S-transferase (GSH/GST) activated NO-releasing kinetics. Such NO-loaded nanoparticles exhibit superior cytotoxicity to HepG2 cells. More importantly, in combination with doxorubicin (DOX) chemotherapy a significant synergistic therapeutic effect was achieved, due to its excellent galactose receptor targeting capability, rapid acid-triggered DOX release and sustained NO release. Our findings indicate that these multifunctional nanoparticles can serve as an efficient NO and chemotherapeutic agent delivery platform, holding great promise in cancer combinatorial treatment. PMID- 29442104 TI - Early stage structural development of prototypical zeolitic imidazolate framework (ZIF) in solution. AB - Given the wide-ranging potential applications of metal organic frameworks (MOFs), an emerging imperative is to understand their formation with atomic scale precision. This will aid in designing syntheses for next-generation MOFs with enhanced properties and functionalities. Major challenges are to characterize the early-stage seeds, and the pathways to framework growth, which require synthesis coupled with in situ structural characterization sensitive to nanoscale structures in solution. Here we report measurements of an in situ synthesis of a prototypical MOF, ZIF-8, utilizing synchrotron X-ray atomic pair distribution function (PDF) analysis optimized for sensitivity to dilute species, complemented by mass spectrometry, electron microscopy, and density functional theory calculations. We observe that despite rapid formation of the crystalline product, a high concentration of Zn(2-MeIm)4 (2-MeIm = 2-methylimidazolate) initially forms and persists as stable clusters over long times. A secondary, amorphous phase also pervades during the synthesis, which has a structural similarity to the final ZIF-8 and may act as an intermediate to the final product. PMID- 29442105 TI - Co-VN encapsulated in bamboo-like N-doped carbon nanotubes for ultrahigh stability of oxygen reduction reaction. AB - The electrocatalytic activity of carbon-based non-precious metal composites towards oxygen reduction reaction (ORR) is far from that of the recognized Pt/C catalyst. Thus, it is necessary to exploit novel catalysts based on multicomponent carbon-based composites with both high activity and high stability. Herein, a bottom-up strategy was used for constructing bamboo-like N doped graphitic CNTs with a few encapsulated Co and VN nanoparticles (namely, NGT CoV) by adopting melamine as both a nitrogen source and a carbon source. During the synthesis, melamine initially coordinated with cobalt and vanadium ions and then decomposed into carbon nitride nanosheet structures. Simultaneously, cobalt ions/clusters were converted into metal nanocatalysts by the reduced gases that were generated, which further rearranged the carbon nitride nanostructures to form N-doped CNTs. The presence of vanadium species strengthened the electronic structure and increased the contents of Co and N species by enhancing the interactions among Co and N species. The optimized NGT-Co35V65-45-900 exhibited an Eonset of 0.92 V (vs. RHE), an E1/2 of 0.81 V (vs. RHE), and a Tafel slope of 66.1 mV dec-1 in the ORR. It also displayed much higher durability (a negative shift in E1/2 of only 11 mV after 10 000 cycles) and methanol tolerance than a commercial Pt/C catalyst. The excellent performance should be attributed to the high exposure level of active sites that originated from Co-N, VN and N-doped bamboo-like graphitic CNTs. Moreover, the skeleton composed of hollow graphitic ultra-long CNTs could not only provide smooth mass transport pathways but also facilitate fast electron transfer. PMID- 29442106 TI - Monolayer and bilayer polyaniline C3N: two-dimensional semiconductors with high thermal conductivity. AB - Polyaniline (PANI) has been extensively studied in the past few decades owing to its broad applications in electronic devices. However, two dimensional PANI was not realized until very recently. In this work, the thermal transport properties of one of the newly synthesized 2D PANI structures, C3N, are systematically investigated using classical molecular dynamics simulations. The in-plane thermal conductivity (kappa) of monolayer and bilayer C3N structures is computed, and the kappa values for infinite-length systems are found to be as high as 820 and 805 W m-1 K-1, respectively. Both the values are markedly higher than those of many prevailing 2D semiconducting materials such as phosphorene, hexagonal boron nitride, MoS2 and MoSe2. The effects of different modulators, such as system dimension, temperature, interlayer coupling strength and tensile strain, on the calculated thermal conductivity are evaluated. Monotonic decreasing trends of thermal conductivity with temperature and tensile strain are found, while a positive correlation between the thermal conductivity and system dimension is revealed. Interlayer coupling strength is found to have negligible effects on the in-plane thermal conductivity of bilayer C3N. The cross-plane interfacial thermal resistance (R) between two adjacent C3N layers is evaluated in the temperature range from 100 to 500 K and at different coupling strengths. The predicted R at temperature 300 K equals 3.4 * 10-8 K m-2 W-1. The maximum reductions of R can amount to 59% and 68% with respect to temperature and coupling strength, respectively. Our results provide theoretical guidance to future applications of C3N-based low-dimensional materials in electronic devices. PMID- 29442107 TI - Calorimetric study of water's two glass transitions in the presence of LiCl. AB - A DSC study of dilute glassy LiCl aqueous solutions in the water-dominated regime provides direct evidence of a glass-to-liquid transition in expanded high density amorphous (eHDA)-type solutions. Similarly, low density amorphous ice (LDA) exhibits a glass transition prior to crystallization to ice Ic. Both glass transition temperatures are independent of the salt concentration, whereas the magnitude of the heat capacity increase differs. By contrast to pure water, the glass transition endpoint for LDA can be accessed in LiCl aqueous solutions above 0.01 mole fraction. Furthermore, we also reveal the endpoint for HDA's glass transition, solving the question on the width of both glass transitions. This suggests that both equilibrated HDL and LDL can be accessed in dilute LiCl solutions, supporting the liquid-liquid transition scenario to understand water's anomalies. PMID- 29442108 TI - Evaporation dynamics of a sessile droplet on glass surfaces with fluoropolymer coatings: focusing on the final stage of thin droplet evaporation. AB - The evaporation dynamics of a water droplet with an initial volume of 2 MUl from glass surfaces with fluoropolymer coatings are investigated using the shadow technique and an optical microscope. The droplet profile for a contact angle of less than 5 degrees is constructed using an image-analyzing interference technique, and evaporation dynamics are investigated at the final stage. We coated the glass slides with a thin film of a fluoropolymer by the hot-wire chemical vapor deposition method at different deposition modes depending on the deposition pressure and the temperature of the activating wire. The resulting surfaces have different structures affecting the wetting properties. Droplet evaporation from a constant contact radius mode in the early stage of evaporation was found followed by the mode where both contact angle and contact radius simultaneously vary in time (final stage) regardless of wettability of the coated surfaces. We found that depinning occurs at small contact angles of 2.2-4.7 degrees for all samples, which are smaller than the measured receding contact angles. This is explained by imbibition of the liquid into the developed surface of the "soft" coating that leads to formation of thin droplets completely wetting the surface. The final stage, which is little discussed in the literature, is also recorded. We have singled out a substage where the contact line velocity is abruptly increasing for all coated and uncoated surfaces. The critical droplet height corresponding to the transition to this substage is about 2 MUm with R/h = 107. The duration of this substage is the same for all coated and uncoated surfaces. Droplets observed at this substage for all the tested surfaces are axisymmetric. The specific evaporation rate clearly demonstrates an abrupt increase at the final substage of the droplet evaporation. The classical R2 law is justified for the complete wetting situation where the droplet is disappearing in an axisymmetric manner. PMID- 29442109 TI - Flexibility of components alters the self-assembly pathway of Pd2L4 coordination cages. AB - The self-assembly process of a Pd2L4 cage consisting of flexible ditopic ligands and Pd(ii) ions was revealed by QASAP (quantitative analysis of self-assembly process), which enables one to obtain information about the intermediates transiently produced during the self-assembly as the average composition of all the intermediates. It was found that the dominant pathway to the cage is the formation of a submicrometre-sized sheet structure, which was characterized by dynamic light scattering (DLS) and scanning transmission electron microscopy (STEM), followed by the addition of free ditopic ligands to the Pd(ii) centres of the sheet structure to trigger the cage formation. This assembly process is completely different from that of a Pd2L4 cage composed of rigid ditopic ligands, indicating that the flexibility of the components strongly affects the self assembly process. PMID- 29442110 TI - Zero- and two-dimensional hybrid carbon phosphors for high colorimetric purity white light-emission. AB - Carbon nanomaterials are promising phosphors for white light emission. A facile single-step synthesis method has been developed to prepare zero- and two dimensional hybrid carbon phosphors for the first time. Zero-dimensional carbon dots (C-dots) emit bright blue luminescence under 365 nm UV light and two dimensional nanoplates improve the dispersity and film forming ability of C-dots. As a proof-of-concept application, the as-prepared hybrid carbon phosphors emit bright white luminescence in the solid state, and the phosphor-coated blue LEDs exhibit high colorimetric purity white light-emission with a color coordinate of (0.3308, 0.3312), potentially enabling the successful application of white emitting phosphors in the LED field. PMID- 29442111 TI - Reactivity of fluorographene is triggered by point defects: beyond the perfect 2D world. AB - Preparation of graphene derivatives using fluorographene (FG) as a precursor has become a key strategy for the large-scale synthesis of new 2-D materials (e.g. graphene acid, cyanographene, allyl-graphene) with tailored physicochemical properties. However, to gain full control over the derivatization process, it is essential to understand the reaction mechanisms and accompanying processes that affect the composition and structure of the final products. Despite the strength of C-F bonds and high chemical stability of perfluorinated hydrocarbons, FG is surprisingly susceptible to reactions under ambient conditions. There is clear evidence that nucleophilic substitution on FG is accompanied by spontaneous defluorination, and solvent-induced defluorination can occur even in the absence of any nucleophilic agent. Here, we show that distributed radical centers (fluorine vacancies) on the FG surface need to be taken into account in order to rationalize the defluorination mechanism. Depending on the environment, these radical centers can react as electron acceptors, electrophilic sites and/or cause homolytic bond cleavages. We also propose a new radical mechanism of FG defluorination in the presence of N,N'-dimethylformamide (DMF) solvent. Spin-trap experiments as well as 19F NMR measurements unambiguously confirmed formation of N,N'-dimethylformyl radicals and also showed that N,N'-dimethylcarbamoyl fluoride plays a key role in the proposed mechanism. These findings imply that point defects in 2D materials should be considered as key factor determining their chemical properties and reactivity. PMID- 29442113 TI - Thermoresponsive plasmonic core-satellite nanostructures with reversible, temperature sensitive optical properties. AB - Herein is described a facile method for the assembly of plasmonic gold nanoparticles into smart plasmonic core-satellite nanostructures that allow for the dynamic and reversible tuning of the localised surface plasmon resonance using temperature. This smart system takes advantage of the thermoresponsive polymer linker that modulates the gap distance between the core and satellites in response to the temperature, resulting in the tuning of the surface plasmon coupling and resultant optical shift. It permits optical shifts over a wide wavelength range and reversible control of the optical properties by altering the temperature, which may allow these systems to become candidates for temperature sensitive nanosensors. PMID- 29442118 TI - Effects of polymer-nanoparticle interactions on the viscosity of unentangled polymers under extreme nanoconfinement during capillary rise infiltration. AB - We explore the effect of confinement and polymer-nanoparticle interactions on the viscosity of unentangled polymers undergoing capillary rise infiltration (CaRI) in dense packings of nanoparticles. In CaRI, a polymer is thermally induced to wick into the dense packings of nanoparticles, leading to the formation of polymer-infiltrated nanoparticle films, a new class of thin film nanocomposites with extremely high concentrations of nanoparticles. To understand the effect of this extreme nanoconfinement, as well as polymer-nanoparticle interactions on the polymer viscosity in CaRI films, we use two polymers that are known to have very different interactions with SiO2 nanoparticles. Using in situ spectroscopic ellipsometry, we monitor the polymer infiltration process, from which we infer the polymer viscosity based on the Lucas-Washburn model. Our results suggest that physical confinement increases the viscosity by approximately two orders of magnitude. Furthermore, confinement also increases the glass transition temperature of both polymers. Thus, under extreme nanoconfinement, the physical confinement has a more significant impact than the polymer-nanoparticle interactions on the viscosity of unentangled polymers, measured through infiltration dynamics, as well as the glass transition temperature. These findings will provide fundamental frameworks for designing processes to enable the fabrication of CaRI nanocomposite films with a wide range of nanoparticles and polymers. PMID- 29442119 TI - Chiral lyotropic chromonic liquid crystals composed of disodium cromoglycate doped with water-soluble chiral additives. AB - We investigated the pitches of cholesteric liquid crystals prepared by mixing disodium cromoglycate (DSCG) in water with 5 different water-soluble chiral additives. The measurements are based on the Grandjean-Cano wedge cell method. Overall, the twisting effect is weak, and the shortest pitch of 2.9 +/- 0.2 MUm is obtained using trans-4-hydroxy-l-proline, by which the cholesteric sample is iridescent at certain viewing angles. Freeze-fracture transmission electron microscopy (FFTEM) was also performed for the first time on both the nematic and cholesteric phases, revealing that stacked chromonic aggregates are very long, up to a few hundred nm, which explains why cholesteric chromonic liquid crystals hardly have pitches in the visible wavelength region. PMID- 29442124 TI - Scalable and continuous fabrication of bio-inspired dry adhesives with a thermosetting polymer. AB - Many research groups have developed unique micro/nano-structured dry adhesives by mimicking the foot of the gecko with the use of molding methods. Through these previous works, polydimethylsiloxane (PDMS) has been developed and become the most commonly used material for making artificial dry adhesives. The material properties of PDMS are well suited for making dry adhesives, such as conformal contacts with almost zero preload, low elastic moduli for stickiness, and easy cleaning with low surface energy. From a performance point of view, dry adhesives made with PDMS can be highly advantageous but are limited by its low productivity, as production takes an average of approximately two hours. Given the low productivity of PDMS, some research groups have developed dry adhesives using UV-curable materials, which are capable of continuous roll-to-roll production processes. However, UV-curable materials were too rigid to produce good adhesion. Thus, we established a PDMS continuous-production system to achieve good productivity and adhesion performance. We designed a thermal roll imprinting lithography (TRL) system for the continuous production of PDMS microstructures by shortening the curing time by controlling the curing temperature (the production speed is up to 150 mm min-1). Dry adhesives composed of PDMS were fabricated continuously via the TRL system. PMID- 29442125 TI - The supramolecular polymer complexes with oppositely charged calixresorcinarene: hydrophobic domain formation and synergistic binding modes. AB - The association of branched polyethyleneimine (PEI) with a series of octacarboxy calixresorcinarenes bearing different low-rim substituents leads to the formation of nanosized supramolecular complexes. The PEI-macrocycle complexes have fine tunable sizes regulated by variations in the self-association capacity of the calixresorcinarenes. In the supramolecular complexes, hydrophobic fragments of the polymer and calixresorcinarenes form cooperative hydrophobic domains which provide synergistic enhancement of guest molecule binding. The formation of the supramolecular complexes was investigated by NMR FT-PGSE, NMR 2D NOESY, DLS and TEM methods. In addition, fluorimetry and UV-vis methods were used with the help of optical probes, namely water-soluble Crystal Violet and water-insoluble Orange OT. The investigation demonstrates the first example of the formation of cooperative hydrophobic domains in supramolecular polyelectrolyte-macrocycle complexes which enhance the binding of both water-soluble and water-insoluble organic compounds. The presented supramolecular systems have potential as sensory and drug delivery systems. PMID- 29442126 TI - Synthesis of layered double hydroxide/poly(N-isopropylacrylamide) nanocomposite hydrogels with excellent mechanical and thermoresponsive performances. AB - Nanocomposite (NC) hydrogels of positively charged layered double hydroxide (LDH) single-layer nanosheet (SLNS) cross-linked poly(N-isopropylacrylamide) (PNIPAM) were synthesized. Especially, the LDH SLNSs used here were pre-synthesized via an aqueous synthetic route without using organic solvents and modifiers. The obtained LDH/PNIPAM NC hydrogels were characterized using XRD, SEM, TEM, and DSC. The mechanical and thermoresponsive properties were determined using tensile, compression, and swelling/deswelling tests. Interestingly, different network structures are observed for the NC hydrogels along the horizontal and vertical directions; those along the horizontal direction exhibit a fine and uniform sponge-like network structure while those along the vertical direction exhibit a hierarchical layered architecture. Compared with the conventional N,N'-methylene bisacrylamide cross-linked PNIPAM hydrogel, the NC hydrogels exhibit extraordinary deformability and stretchability and obviously improved thermoresponsive swelling/deswelling characteristics. Furthermore, the fracture elongation observed here is obviously higher than those reported for negatively charged clay/PNIPAM NC hydrogels. With the increase in the LDH content from 0.8 to 2.0 wt%, the fracture strength and the compressive strength at an 85% strain increase from 23.5 to 37.2 kPa and from 0.15 to 0.57 MPa, respectively, while the fracture elongation decreases from 2689 to 2202%. The mechanism for the improved mechanical performances of the NC hydrogels is discussed. To the best of our knowledge, this is the first report on LDH/PNIPAM hydrogels. This work provides a green synthesis route for LDH-containing NC hydrogels. The new NC hydrogels may have great potential applications such as in tissue engineering, drug vehicles, and sorbents. PMID- 29442127 TI - Situation analysis of rehabilitation service to support the national disability and rehabilitation plan in the Democratic People's Republic of Korea. AB - OBJECTIVE: In 2013, the Democratic People's Republic of Korea (DPRK) signed the United Nations Convention on the Rights of Persons with Disabilities (UN-CRPD). Since the concept of rehabilitation services in the DPRK did not meet international standards, the government, through the Korean Federation for Protection of the Disabled (KFPD) and Munsu Rehabilitation Hospital (MRH), set up a technical consultation with external experts. METHODS: Two rounds of consultations were performed, in August 2016 and March 2017, with available methodology, as used in previous consultation processes, but excluding site visits. The consultations started by collecting available data and holding workshops with representatives from the KFPD and the MRH. The results are listed as recommendations for the improvement of health-related rehabilitation services in the DPRK. The results were further developed by KFPD into a draft National Strategy and Action Plan on Comprehensive Rehabilitation (NSAPCR) 2017-2020. The draft was discussed with external experts for further improvement prior to discussion with the government. RESULTS AND DISCUSSION: Overall, the consultation processes was successful, despite the limitation of not making site visits. Recent developments in the DPRK include ratification of the UN-CRPD in December 2016. The authors hope that the NSAPCR can be implemented successfully, leading to improved quality of life for people with disabilities in the DPRK. PMID- 29442128 TI - Semantic imaging features predict disease progression and survival in glioblastoma multiforme patients. AB - BACKGROUND: For glioblastoma (GBM), multiple prognostic factors have been identified. Semantic imaging features were shown to be predictive for survival prediction. No similar data have been generated for the prediction of progression. The aim of this study was to assess the predictive value of the semantic visually accessable REMBRANDT [repository for molecular brain neoplasia data] images (VASARI) imaging feature set for progression and survival, and the creation of joint prognostic models in combination with clinical and pathological information. METHODS: 189 patients were retrospectively analyzed. Age, Karnofsky performance status, gender, and MGMT promoter methylation and IDH mutation status were assessed. VASARI features were determined on pre- and postoperative MRIs. Predictive potential was assessed with univariate analyses and Kaplan-Meier survival curves. Following variable selection and resampling, multivariate Cox regression models were created. Predictive performance was tested on patient test sets and compared between groups. The frequency of selection for single variables and variable pairs was determined. RESULTS: For progression free survival (PFS) and overall survival (OS), univariate significant associations were shown for 9 and 10 VASARI features, respectively. Multivariate models yielded concordance indices significantly different from random for the clinical, imaging, combined, and combined + MGMT models of 0.657, 0.636, 0.694, and 0.716 for OS, and 0.602, 0.604, 0.633, and 0.643 for PFS. "Multilocality," "deep white-matter invasion," "satellites," and "ependymal invasion" were over proportionally selected for multivariate model generation, underlining their importance. CONCLUSIONS: We demonstrated a predictive value of several qualitative imaging features for progression and survival. The performance of prognostic models was increased by combining clinical, pathological, and imaging features. PMID- 29442129 TI - Aquincola amnicola sp. nov., isolated from a freshwater river. AB - Strain TTM-94T, isolated from a water sample taken from the Caohu River in Taiwan, was characterized using a polyphasic taxonomic approach. Cells of strain TTM-94T were Gram-staining-negative, aerobic, poly-beta-hydroxybutyrate accumulating, motile by a single polar flagellum, short rod-shaped and surrounded by a thick capsule and it formed cream colored colonies. Growth occurred at 20-30 degrees C (optimum, 30 degrees C), at pH 6.0-8.0 (optimum, pH 6.0), and in the presence of 0-2% NaCl (optimum 0.5%). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain TTM-94T belonged to the genus Aquincola in the Rubrivivax-Roseateles-Leptothrix-Ideonella-Aquabacterium branch of the class Betaproteobacteria and its most closely related neighbour was Aquincola tertiaricarbonis L10T with sequence similarity of 97.0%. Strain TTM-94T contained summed feature 3 (comprising C16:1omega7c and/or C16:1omega6c), C16:0 and C18:1omega7c as the predominant fatty acids. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and several uncharacterized lipids. The major respiratory quinone was Q-8. Genomic DNA G + C content of strain TTM-94T was 70.7 mol%. Strain TTM-94T exhibited less than 30% DNA-DNA relatedness with A. tertiaricarbonis L10T. Differential phenotypic properties, together with the phylogenetic inference, demonstrate that strain TTM-94T should be classified as a novel species of the genus Aquincola, for which the name Aquincola amnicola sp. nov. is presented. The type strain is TTM-94T (= BCRC 80890T = LMG 28709T). PMID- 29442130 TI - Distribution, Seasonal Variations and Ecological Risk Assessment of Polycyclic Aromatic Hydrocarbons in Foliar Dust of Nanjing, China. AB - Polycyclic aromatic hydrocarbons (PAHs) are of concern for both ecosystem and human health due to their potential teratogenic, carcinogenic, and mutagenic properties. The concentration of ?16PAHs in foliar dust ranged from 49.4 to 19,018.1 ug kg-1, with a mean value of 7074.5 ug kg-1. There were significant seasonal variations in the concentration of ?16PAHs, with the concentration in winter being almost twice as high as in summer. Similarly, the differences between PAH profiles in different seasons indicated that they had common sources, which were attributed to the combined effect of regional transport and local emissions. The diagnostic ratios of indicator compounds indicated that PAHs detected in foliar dust originated from a mixture of gasoline vehicle emissions, biomass, and coal combustion in Nanjing. According to the ecological risk classification of ?16PAHs, the ecological risk caused by PAHs was high since the value of RQ?16PAHs(MPCs) was >= 1 and RQ?16PAHs(NCs) were >= 800. The mean values for RQ?16PAHs(MPCs) and RQ?16PAHs(NCs) were 14.8 and 2368.9, which indicated a relatively high ecological risks of PAHs in foliar dust in Nanjing. PMID- 29442131 TI - Effects of Dracontomelon duperreanum Leaf Litter on the Growth and Photosynthesis of Microcystis aeruginosa. AB - This study investigated the use of Dracontomelon duperreanum leaf litter extract (DDLLE) in inhibiting the growth and photosynthesis of the algae Microcystis aeruginosa. The goal of the study was to evaluate a potential solution for cyanobacterial bloom prevention. M. aeruginosa was exposed to extract concentrations from 0.4 to 2.0 g L-1. Chlorophyll-a (Chl-a) content and photosynthesis levels were assessed using pulse amplitude modulated fluorimetry phytoplankton analyzer. Results suggested that the extract could efficiently suppress M. aeruginosa growth. The content of Chl-a was only 19.0 ug L-1 and achieved 96.0% inhibition rate when exposed to 2.0 g L-1 on day 15. Growth rate in response to different extract concentrations were consistent with changes in the photosynthesis efficiency (alpha), maximal relative electron transport rate and maximal photochemical efficiency of photosystem II (F v /F m ). Furthermore, several kinds of volatile chemicals and their concentrations in DDLLE had been identified by GC-MS, which of them play major role to suppress the growth of M. aeruginosa should be further studied. PMID- 29442132 TI - Correction to: Baseline and annual repeat rounds of screening: implications for optimal regimens of screening. AB - The original version of this article unfortunately contained a mistake. The conflict of interest was incorrect. PMID- 29442134 TI - Torgny Greitz, MD, PhD, FACR, Professor of Neuroradiology, Emeritus. PMID- 29442136 TI - Spontaneous regression of a large calcified thoracic disk extrusion. AB - Although spontaneous regression of herniated disk material has been reported in the lumbar and cervical spine, reports of complete spontaneous regression of calcified thoracic disk herniations are exceedingly rare. In symptomatic patients, surgery is typically the treatment of choice; however, conservative therapy with surveillance may allow time for spontaneous resolution and potentially avoid high-risk surgery. We report a 40-year-old woman with complete spontaneous resolution of a large calcified thoracic disk extrusion with conservative management over an 8-month period. PMID- 29442133 TI - Follicle-stimulating hormone enhances hepatic gluconeogenesis by GRK2-mediated AMPK hyperphosphorylation at Ser485 in mice. AB - AIMS/HYPOTHESIS: Increased serum follicle-stimulating hormone (FSH) is correlated with fasting hyperglycaemia. However, the underlying mechanism remains unclear. Because excessive hepatic gluconeogenesis is a major cause of fasting hyperglycaemia the present study investigated whether FSH increases hepatic gluconeogenesis in mice. METHODS: Ovariectomised mice supplemented with oestradiol (E2) to maintain normal levels of serum E2 (OVX+E2 mice) were injected with low or high doses of FSH. We knocked out Crtc2, a crucial factor in gluconeogenesis, and Fshr to discern their involvement in FSH signalling. To evaluate the role of the G-protein-coupled receptor (GPCR) kinase 2 (GRK2), which could affect glucose metabolism and interact directly with non-GPCR components, a specific GRK2 inhibitor was used. The pyruvate tolerance test (PTT), quantification of PEPCK and glucose-6-phosphatase (G6Pase), key enzymes of gluconeogenesis, GRK2 and phosphorylation of AMP-activated protein kinase (AMPK) were examined to evaluate the level of gluconeogenesis in the liver. A nonphosphorylatable mutant of AMPK Ser485 (AMPK S485A) was transfected into HepG2 cells to evaluate the role of AMPK Ser485 phosphorylation. RESULTS: FSH increased fasting glucose (OVX+E2+high-dose FSH 8.18 +/- 0.60 mmol/l vs OVX+E2 6.23 +/- 1.33 mmol/l), the PTT results, and the transcription of Pepck (also known as Pck1; 2.0-fold increase) and G6pase (also known as G6pc; 2.5-fold increase) in OVX+E2 mice. FSH also enhanced the promoter luciferase activities of the two enzymes in HepG2 cells. FSH promoted the membrane translocation of GRK2, which is associated with increased AMPK Ser485 and decreased AMPK Thr172 phosphorylation, and enhanced the nuclear translocation of cyclic AMP-regulated transcriptional coactivator 2 (CRTC2). GRK2 could bind with AMPK and induce Ser485 hyperphosphorylation. Furthermore, either the GRK2 inhibitor or AMPK S485A blocked FSH-regulated AMPK Thr172 dephosphorylation and gluconeogenesis. Additionally, the deletion of Crtc2 or Fshr abolished the function of FSH in OVX+E2 mice. CONCLUSIONS/INTERPRETATION: The results indicate that FSH enhances CRTC2-mediated gluconeogenesis dependent on AMPK Ser485 phosphorylation via GRK2 in the liver, suggesting an essential role of FSH in the pathogenesis of fasting hyperglycaemia. PMID- 29442137 TI - Treatment preferences and treatment satisfaction among psoriasis patients: a systematic review. AB - A critical gap exists in determining treatment preferences and treatment satisfaction from patient perspectives, which is paramount to achieving therapeutic success. The objective of this systematic review is to determine factors influencing treatment preferences and treatment satisfaction among psoriasis patients. PubMed, EMBASE, and Web of Science databases were searched between November 1, 2010, and December 1, 2017. Observational and interventional research studies published in the English language that discussed patient preferences and patient satisfaction in the treatment of psoriasis were reviewed and synthesized. We utilized data on treatment preferences and treatment satisfaction from 35,388 psoriasis patients based on 60 articles from the years 2010 to 2017. Treatment preferences were heterogeneous and changed over time among psoriasis patients. Across all treatment modalities, the most important treatment attributes were treatment location, probability of improvement, and delivery method. For biologics specifically, the most important attributes were risk of adverse events and probability of treatment benefit. Factors that influenced patients' preferences for certain treatments included age, sex, comorbidities, disease duration, and prior treatments. Notably, some psoriasis patients placed higher importance on a treatment's process attributes (e.g., access and delivery) over its outcome attributes (e.g., efficacy). Overall, patient satisfaction with existing therapies remains modest; however, those treated with biologic agents exhibited highest treatment satisfaction over oral therapy, phototherapy, and topical therapy. PMID- 29442138 TI - Effect of Dickkopf1 on the senescence of melanocytes: in vitro study. AB - Fibroblasts secrete several growth factors which are important for the regulation of skin pigmentation. Dickkopf1 (DKK1) is also secreted by fibroblasts which inhibit the growth and function of melanocytes. Therefore, the study was designed to check the role of DKK1 in vitiligo pathogenesis. This study confirmed the higher expression of DKK1 in lesional skin of vitiligo patients. In vitro effect of DKK1 on cultured melanocytes revealed decrease in the melanocytes proliferation and pigmentation. In vitro effect of DKK1 was then checked on the melanocytes senescence and found that DKK1 induced senescence in the treated melanocytes. Expression of senescence markers was significantly higher in DKK1 treated melanocytes. This study suggests that higher expression of DKK1 in the dermis induced senescence in melanocytes that may lead to hypopigmentation and play role in vitiligo pathogenesis. PMID- 29442140 TI - Discrepancy between colposcopy, punch biopsy and final histology of cone specimen: a prospective study. AB - PURPOSE: Tauo estimate the discrepancy rate between colposcopy, punch biopsy histology and surgical specimen histology as well as the positive (PPV) and negative predictive value (NPV) of colposcopic diagnosis for high-grade squamous intraepithelial lesions (HGSIL). METHODS: A prospective study was conducted during the period of 2012-2016. Alphall cases in which surgical treatment had been applied and histopathological diagnosis of those surgical specimens was available were included. Cases in which ablation was performed and cases with incomplete data or conservative approach were excluded. Primary outcome was the agreement rate between histologic diagnosis of surgical specimen, histologic diagnosis of punch biopsy and colposcopic diagnosis according to REID Colposcopic Index. PPV and NPV of colposcopy and biopsy to diagnose HGSIL were also assessed. RESULTS: Tauhere were 120 cases meeting our inclusion criteria, while biopsy was obtained in 104 cases. Mean age of women was 32.7 +/- 9.0. Colposcopic diagnosis was CIN2 in 65 cases, CIN3 in 11 cases, CIN1 or less in 44 cases. Tauhe level of agreement was fair between colposcopy-surgical specimen histology (kappa value 0.443), fair between colposcopy-punch biopsy (kappa value 0.34) and moderate between punch biopsy-cone specimen histology (kappa value 0.443). PPV of colposcopy to detect HGSIL was 72.3%, while NPV was only 47.7%. CONCLUSION: Punch biopsy and surgical specimen histology present the highest agreement between the different diagnostic procedures. Colposcopy presented satisfying PPV for HGSIL cases, but its NPV was poor. In contrary, punch biopsy was characterized by both satisfying PPV and NPV for HGSIL cases. PMID- 29442139 TI - Safety profile of nivolumab administered as 30-min infusion: analysis of data from CheckMate 153. AB - PURPOSE: Nivolumab has been administered using a 60-min infusion time. Reducing this time to 30 min would benefit both patients and infusion facilities. This analysis compared the safety of 30- and 60-min infusions of nivolumab in patients with previously treated advanced non-small cell lung cancer. METHODS: CheckMate 153 is an open-label, phase 3b/4, predominantly community-based study ongoing in the United States and Canada. Patients with stage IIIB/IV disease with progression/recurrence after at least one prior systemic therapy received nivolumab 3 mg/kg every 2 weeks over 30 or 60 min for 1 year or until disease progression. The primary outcome overall was to estimate the incidence of grade 3 5 treatment-related select adverse events; a retrospective objective was to estimate the incidence of hypersensitivity/infusion-related reactions (IRRs) with the 30-min infusion. Exploratory pharmacokinetic analyses were performed using a population pharmacokinetics model. RESULTS: Of 1420 patients enrolled, 369 received only 30-min infusions and 368 received only 60-min infusions. Similar frequencies of hypersensitivity/IRRs were noted in patients receiving 30-min [2% (n = 8)] and 60-min [2% (n = 7)] infusions. Grade 3-4 treatment-related hypersensitivity/IRRs led to treatment discontinuation in < 1% of patients in each group; < 1% of patients in each group received systemic corticosteroids. Hypersensitivity/IRRs were managed by dosing interruptions, with minimal impact on total dose received. Nivolumab pharmacokinetics were predicted to be similar in the two groups. CONCLUSIONS: Nivolumab infused over 30 min had a comparable safety profile to the 60-min infusion, including a low incidence of IRRs. PMID- 29442141 TI - Impact of Soil and Water Conservation Interventions on Watershed Runoff Response in a Tropical Humid Highland of Ethiopia. AB - Various soil and water conservation measures (SWC) have been widely implemented to reduce surface runoff in degraded and drought-prone watersheds. But little quantitative study has been done on to what extent such measures can reduce watershed-scale runoff, particularly from typical humid tropical highlands of Ethiopia. The overall goal of this study is to analyze the impact of SWC interventions on the runoff response by integrating field measurement with a hydrological CN model which gives a quantitative analysis future thought. Firstly, a paired-watershed approach was employed to quantify the relative difference in runoff response for the Kasiry (treated) and Akusty (untreated) watersheds. Secondly, a calibrated curve number hydrological modeling was applied to investigate the effect of various SWC management scenarios for the Kasiry watershed alone. The paired-watershed approach showed a distinct runoff response between the two watersheds however the effect of SWC measures was not clearly discerned being masked by other factors. On the other hand, the model predicts that, under the current SWC coverage at Kasiry, the seasonal runoff yield is being reduced by 5.2%. However, runoff yields from Kasiry watershed could be decreased by as much as 34% if soil bunds were installed on cultivated land and trenches were installed on grazing and plantation lands. In contrast, implementation of SWC measures on bush land and natural forest would have little effect on reducing runoff. The results on the magnitude of runoff reduction under optimal combinations of SWC measures and land use will support decision-makers in selection and promotion of valid management practices that are suited to particular biophysical niches in the tropical humid highlands of Ethiopia. PMID- 29442142 TI - Classic papers on pelvic floor physiotherapy: the most frequently cited articles in three decades (1983-2013). AB - INTRODUCTION AND HYPOTHESIS: Pelvic floor physiotherapy has been utilized extensively over the past decades for the treatment of pelvic floor dysfunctions. The aim of this study was to identify and characterize the most frequently cited articles on pelvic floor physiotherapy published in the last 30 years. METHODS: A PubMed search of all articles published between 1983 and 2013 was performed. Articles with more than 100 citations were identified as "classic," and were further analyzed based on author names, year of publication, journal of publication, subject, study design, country of research, and number of citations. In 2017, a new search for papers on pelvic floor physiotherapy was conducted using the same methods to compare them with the 2013 data. RESULTS: Of 1,285 articles published between 1983 and 2013, only 20 articles were cited more than 100 times. Among them, we found 12 randomized clinical trials (RCTs) and only 4 reviews. The most common topics among the classic articles were behavior therapy, pelvic floor muscle training (PFMT), biofeedback-assisted PFMT, and neuromuscular electrical stimulation. In 2017, we found 1,745 papers containing the term "pelvic floor physiotherapy," indicating an increase of around 35% in 4 years. CONCLUSIONS: Although there is a fast-growing number of publications, we still have few classic papers on pelvic floor physiotherapy, concentrated in a few research centers. However, the large number of RCTs shows that these papers have a high scientific level, confirming that they can be classified as classic papers. PMID- 29442143 TI - Randomized Controlled Study Comparing Disposable Negative-Pressure Wound Therapy with Standard Care in Bilateral Breast Reduction Mammoplasty Evaluating Surgical Site Complications and Scar Quality. AB - BACKGROUND: Negative pressure wound therapy (NPWT) for postsurgical incision treatment has demonstrated benefits. A prospective randomized study was developed including 32 patients who underwent bilateral breast reduction mammoplasty. Patients served as their own control and received NPWT to one breast and fixation strips to the other breast. METHODS: The primary outcome was the number of wound healing complications within 21 days when comparing NPWT treatment with fixation strips. The secondary outcome was aesthetic appearance and quality of scarring using questionnaires [visual analogue scale (VAS) and Patient and Observer Scar Assessment Scale (POSAS)] scored at day 42-, 90-, 180- and 365-day follow-up using additional scar measurement modalities, such as viscoelasticity. RESULTS: For the 32 included patients, the number of wound complications was significantly lower (p < 0.004) for the NPWT treated sites compared to fixation strips. POSAS and VAS scores at 42 and 90 days revealed a significantly better quality of scarring in the NPWT treatment breasts than in fixation strips. At 180-day follow up, there was a significant improvement in VAS scores, as well as a comparable improvement in POSAS scores. No consistent significant improvement in scar quality was demonstrated with the assays that were used. CONCLUSIONS: Our study showed less complications and a significant improvement in quality of scarring in favor of the NPWT-treated sites. The results indicate NPWT to be an attractive option for these patients. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29442144 TI - Quantitative structure -retention relationship modeling of selected antipsychotics and their impurities in green liquid chromatography using cyclodextrin mobile phases. AB - Applying green chromatography methods is currently one of the challenges in liquid chromatography. Among different strategies, using cyclodextrin (CD) mobile phase modifiers was applied in this paper. CDs can form inclusion complexes with a wide variety of hydrophobic organic compounds and, consequently, affect their retention behavior. CD-containing mobile phases possess complicated complexation and adsorption equilibria so retention is dependent not only on chromatographic parameters and properties of the compound but also on properties of compound-CD complex. Docking study was used to calculate association constants of the selected antipsychotics (risperidone, olanzapine, and their impurities) and beta CD complexes and predict which part of the molecule structure will most likely incorporate into the beta-CD cavity. Quantitative structure-retention relationship model (QSRR) for selected model substances was built employing artificial neural network (ANN) technique. Reliable QSRR model was obtained using molecular descriptors, complex association constants, and chromatographic factors. The multilayer perceptron network with 11-8-1 topology, trained with back propagation algorithm, showed the best performance. Root mean square error for training, validation, and test was 0.2954, 0.3633, and 0.4864, respectively. The correlation coefficient (R2) between experimentally obtained retention factor values [k(exp)] and values computed or predicted by ANN [k(ANN)] was 0.9962 for training, 0.9927 for validation, and 0.9829 for test, indicating good predictive ability of the model. The optimized network was used for development of green chromatography method for separation of risperidone and its related impurities, as well as olanzapine and its related impurities in a relatively short run time and with low consumption of organic modifier. The developed methods were validated in accordance with ICH Q2 (R1) quideline and all parameters fulfilled the defined criteria. The greenness of the proposed methods has also been demonstrated. Graphical Abstract Complex association constants as inputs of QSRR model in beta-cyclodextrin modified HPLC system and development of green chromatography methods. PMID- 29442145 TI - Correction to: Analysis of bronopol (2-bromo-2-nitropropan-1,3-diol) residues in rice (Oryza sativa L.) by SPE using Bond Elut Plexa and liquid chromatography tandem mass spectrometry. AB - The authors would like to call the reader's attention to the fact that unfortunately during a recent cross-check of the experimental record, they found that the positions of intercept and slope were reversed in Table 1 in the original manuscript. The authors apologize for the mistake. PMID- 29442146 TI - [The new tremor classification of the International Parkinson and Movement Disorder Society : Update on frequent tremors]. AB - Tremor is one of the most frequent movement disorders. The recently published new classification of the Movement Disorder Society separates the clinical description of tremor syndromes as so-called axis 1 symptom constellations from the etiologies of tremor (axis 2). The same tremor syndromes can therefore be combined with different causes and vice versa. The terminology used in this classification is precisely defined and thereby also the necessary language for medical communication. Frequent tremor syndromes, such as enhanced physiologic tremor, dystonic and parkinsonian tremor as well as focal tremors and task and position-specific tremors are discussed with respect to the phenomenology, and current therapy. PMID- 29442147 TI - [Urosepsis]. AB - Urosepsis is defined as a severe disease due to organ failure caused by a urinary tract infection. An empirical antibiotic therapy should be instigated within the first hour after diagnosis. Urine cultures and blood cultures should be performed before antibiotic treatment. Further diagnostics should be carried out at an early stage to enable an interventional focus control in the case of urinary tract obstruction or abscess formation, if necessary. Gram-negative pathogens are most frequently isolated. Extended spectrum beta-lactamase (ESBL) forming bacteria as a cause of urosepsis are increasing. Carbapenemase-forming Enterobacteriaceae, on the other hand, are still rare. The empirical treatment consists of a broad spectrum beta-lactam antibiotic. While piperacillin/tazobactam, carbapenems and the new cephalosporin/beta-lactamase inhibitor (BLI) combinations are given as monotherapy, cephalosporins should be combined with aminoglycosides (preferred) or fluoroquinolones. If a combination therapy is given, it should be de-escalated to a monotherapy after 48-72 h. PMID- 29442148 TI - Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects. AB - BACKGROUND: Ticagrelor, the first reversible P2Y12 receptor antagonist, exhibits faster onset and offset of antiplatelet effects and more consistent platelet inhibition than clopidogrel in both healthy subjects and patients with stable coronary artery disease. OBJECTIVE: The objectives of this study were to establish a population pharmacokinetics (PK) and pharmacodynamics (PD) model of ticagrelor and to provide a theoretical basis for the optimization of ticagrelor treatment in clinic. METHODS: A single oral dose of 180 mg ticagrelor was administered to 14 healthy male subjects in a randomized study. Common single nucleotide polymorphisms (SNPs) in biotransformation enzymes CYP3A4 and CYP3A5 (CYP3A4*1G and CYP3A5*3) were genotyped by PCR-direct sequencing. Blood samples were collected to measure plasma concentrations of ticagrelor and its active metabolite AR-C124910XX and maximal platelet inhibition. Various models were evaluated to characterize the pharmacokinetics of ticagrelor and AR-C124910XX as well as their PK-PD relationship. Covariates that may potentially affect PK or PD of ticagrelor and AR-C124910XX were included and assessed. Simulation for dosage regimen was performed based on the final PK-PD model. RESULTS: Ticagrelor and AR C124910XX PK were best described by a two-compartment model with first-order transit absorption model. CYP3A4*1G increased clearance for AR-C124910XX, but had no significant effect on ticagrelor clearance. The relationship between concentration and platelet response of ticagrelor was best described by a turnover model. Simulation results indicated that a lower dosage regimen of 30 mg maintenance dose (MD) could produce an anticipated anti-platelet response in comparison to the routine clinical dosage regimen (180 mg loading dose (LD), 90 mg MD). CONCLUSION: Our study developed a population PK-PD model for ticagrelor and further simulation for dosage regimen was performed based on the final model. Compared to the current recommended dosage regimen (180 mg LD, 90 mg MD), our simulation result of a relatively lower dose (30 mg MD) could also obtain an acceptable anti-platelet response, which may provide a reference for further dosage regimen design in Chinese population. PMID- 29442149 TI - Influence of Different Sugars and Initial pH on beta-Glucan Formation by Lactobacillus brevis TMW 1.2112. AB - We wanted to identify key factors influencing the extent of beta-glucan production by Lactobacillus brevis TMW 1.2112, which has been isolated from viscous, spoiled beer and which could contribute to viscosity increases of spoiled beverages via exopolysaccharide (EPS) production. In this way, we analyzed the influence of different initial pH values and carbohydrate sources on growth of and slime/beta-glucan formation by this strain. In a screening of 48 carbohydrates, 14 fermentable sugars which enabled growth were identified. These sugars were further investigated regarding their EPS formation-promoting properties. The hexose-based mono- and di-saccharides enabled slime formation, while all pentoses failed to cause any thickening effect. The strongest slime formation was observed upon growth on D-maltose, the weakest on D-fructose. A lower initial pH (4.3) caused significant higher viscosities than an initially higher one (pH 6.2). This effect was independent from the carbohydrate supplied. Although the thickening of nutrient media by L. brevis TMW 1.2112 strongly depended on the initial pH and the available carbon source, all isolated polysaccharides were exclusively composed of glucose moieties and exhibited highly similar elution profiles after separation via asymmetric flow field-flow fractionation independently of the provided carbon source. Our results suggest that the extent of beta-glucan/slime formation by special L. brevis strains isolated from the brewery environment is strongly influenced by the initial pH and the availability of certain EPS formation-promoting sugars with maltose being the most favored carbohydrate for the regulated and directive biosynthesis of capsular beta-glucan. PMID- 29442151 TI - Relevance of Right Ventricular Outflow Tract Velocity Time Integral (RVOT VTI) and Tricuspid Regurgitation Velocity/RVOT VTI Ratio Determination in Children Following Heart Transplantation. PMID- 29442152 TI - Pediatric contrast-enhanced ultrasound in the United States: a survey by the Contrast-Enhanced Ultrasound Task Force of the Society for Pediatric Radiology. AB - BACKGROUND: The United States Food and Drug Administration (FDA) recently approved an ultrasound (US) contrast agent for intravenous and intravesical administration in children. OBJECTIVE: Survey the usage, interest in and barriers for contrast-enhanced US among pediatric radiologists. MATERIALS AND METHODS: The Contrast-Enhanced Ultrasound Task Force of the Society for Pediatric Radiology (SPR) surveyed the membership of the SPR in January 2017 regarding their current use and opinions about contrast-enhanced US in pediatrics. RESULTS: The majority (51.1%, 166) of the 325 respondents (26.7% of 1,218) practice in either a university- or academic affiliated group. The most widely used US contrast agent was Lumason(r) 52.3% (23/44). While lack of expertise and training were reported barriers, all respondents who are not currently using US contrast agents are considering future use. CONCLUSION: Interest in pediatric contrast US is very high. Education and training are needed to support members who plan to adopt contrast US into practice. PMID- 29442150 TI - Ultrasound scans and dual energy CT identify tendons as preferred anatomical location of MSU crystal depositions in gouty joints. AB - OBJECTIVE: The present study was performed to localize the articular deposition of monosodium urate (MSU) crystal in joints. We compare the detection efficiencies of dual-energy CT (DECT) and ultrasound scans. METHODS: Analyses by DECT and ultrasound were performed with 184 bilateral joints of the lower limbs of 54 consecutive gout patients. All joints were categorized into (1) knee, (2) ankle, (3) MTP1, and (4) MTP2, and sorted into those with and those without detectable MSU deposition. The comparison of the positive rate between DECT and ultrasound and the agreement was performed using the McNemar test and the Cohen's kappa coefficient, respectively. Next, we listed the MSU crystal deposition as assessed by ultrasound between the DECT-positive and -negative joints according to their interior structure. We included tendons, synovia, cartilage, subcutaneous tissue, etc. RESULTS: Among all joints, the percentages with MSU crystal deposition detected by DECT (99/184, 53.8%) and ultrasound (106/184, 57.6%) were comparable (P = 0.530 > 0.05). For MTP1 (21/34, 61.8%; 12/34, 35.3%; P < 0.05) and MTP2-5 (17/34, 50.0%; 10/34, 29.4%, P < 0.05), ultrasound and DECT were more efficient, respectively. The data concordance in 46 of 50 joints (92.00%; kappa = 0.769, P < 0.05) for knee; and 27 of 34 joints (79.41%; kappa = 0.588, P < 0.05) for MTP2-5 and suggested that tendons were the most frequent anatomical location of MSU crystal deposition. CONCLUSIONS: The tendons are the most frequent anatomical location of MSU crystal depositions. The concordance rate of knee joints and MTP2-5 joints shows good agreement between DECT and ultrasound depending on the location. PMID- 29442153 TI - Quantification of scatter radiation from radiographic procedures in a neonatal intensive care unit. AB - BACKGROUND: In a neonatal intensive care unit (NICU), preterm infants are often exposed to a large number of radiographic examinations, which could cause adjacent neonates, family caregivers and staff members to be exposed to a dose amount due to scatter radiation. OBJECTIVE: To provide information on scatter radiation exposure levels in a NICU, to compare these values with the effective dose limits established by the European Union and to evaluate the effectiveness of radiation protection devices in this setting. MATERIALS AND METHODS: Radiation exposure levels due to scatter radiation were estimated by passive detectors (thermoluminescent dosimeters) and direct dosimetric measurements (with a dose rate meter); in the latter case, an angular map of the scatter dose distribution was achieved. RESULTS: The dose due to scatter radiation to staff in our setting is approximately 160 MUSv/year, which is markedly lower than the effective dose limit for workers established by the European Union (20 mSv/year). The doses range between 0.012 and 0.095 MUSv/radiograph. Considering a mean hospitalization period of 3 months and our NICU workload, the corresponding scatter radiation dose to an adjacent patient and/or his/her caregiver is at most 40 MUSv. CONCLUSION: For distances greater than 1 m from the irradiation field, both scatter dose absorbed by a staff member during a year and that by an adjacent patient and/or his/her caregiver during hospitalization is less than 1 mSv, which is the exposure limit for public members in a year. PMID- 29442154 TI - Modified York Mason technique for repair of iatrogenic recto-urinary fistula: 20 years of the Montsouris experience. AB - PURPOSE: Iatrogenic recto-urinary fistulas are a disastrous complication of therapeutic interventions on the prostate. Many surgical approaches have been described to repair recto-urinary fistulas and no consensus has been reached regarding the better approach. The objective of this study is to present the results of our updated 20-year experience in the surgical management of recto urinary fistula using a modified York Mason procedure. METHODS: We proceed to a retrospective single-institution review of surgically treated patients for iatrogenic recto-urinary fistulas between 1998 and 2017 by the modified York Mason technique. Descriptive analysis of our population was performed. Continuous and categorical variables were compared using Mann-Whitney and Fischer tests, respectively. All tests were two-sided with a significance level set at p value < 0.05. RESULTS: We included 30 consecutive patients treated for iatrogenic recto urinary fistula. The median follow-up was 76 months (2-195). The median size of the fistula was 5 mm (2-20). Successful healing of the recto-urinary fistula was observed in 80, 97, and 100% of patients after 1, 2, or 3 York Mason procedure. During the study period, no one single case of acquired urinary incontinence or durable fecal incontinence has been observed. CONCLUSIONS: Our modified York Mason technique is a reliable and effective procedure with a 100% success rate for the repair of small iatrogenic recto-urinary fistulas in non-irradiated patients. It has a very low morbidity rate, and no case of postoperative urine or fecal incontinence has been observed. PMID- 29442156 TI - Ventral rectopexy with biological mesh: short-term functional results. AB - PURPOSE: Ventral mesh rectopexy (VMR) is an established, minimally invasive, nerve-sparing procedure for the treatment of various symptomatic morphological changes in the posterior pelvic compartment. We present the short-term functional outcome and patient satisfaction after laparoscopic and robotic VMR with biological mesh. METHODS: We analyzed data from 123 patients who underwent laparoscopic ventral mesh rectopexy (LVMR) or robotic ventral mesh rectopexy (RVMR) from August 2012 to January 2017. Included in these data were patient demographics, intra- and postoperative findings, Cleveland Clinic Constipation Score (CCCS), Obstructed Defecation Score Longo (ODS), Cleveland Clinic Incontinence Score (CCIS), and patient satisfaction as measured by visual analog scale (0-10). RESULTS: Improvements in CCCS, CCIS, and ODS were statistically significant at 6 and 12 months (p < 0.001). Patient satisfaction was excellent at 6 and 12 months (8.2/10 and 8.3/10, respectively). The overall complication rate was 14%, with a major complication rate of 2%. No mesh-related complications were observed. The need for surgical re-intervention because of relapse, symptom persistence or recurrence, or new symptoms was 3%. Outcome appears to be similar between LVMR and RVMR. CONCLUSIONS: Both LVMR and RVMR with biological mesh are safe and effective in reducing symptoms, as measured by CCCS, CCIS, and ODS, and patient satisfaction is high. PMID- 29442155 TI - Outcomes and prognostic factors of selective lateral pelvic lymph node dissection with preoperative chemoradiotherapy for locally advanced rectal cancer. AB - PURPOSE: The clinical significance of preoperative chemoradiotherapy (CRT) and lateral lymph node dissection (LLND) for locally advanced rectal cancer remains unclear. We have employed total mesorectal excision and selective LLND following preoperative CRT for patients with locally advanced rectal cancer. The validity of our strategy was evaluated. METHODS: A total of 45 patients with locally advanced rectal cancer who underwent curative surgery after CRT from November 2005 to September 2016 were retrospectively analyzed. LLND was performed only for the patients with lateral lymph nodes suspected to have metastasis based on the pretreatment images. RESULTS: Rates of 5-year overall survival (OS) and 5-year relapse-free survival (RFS) were 85.7 and 61.8%, respectively. Univariate and multivariate analyses detected only histological response (grades 2 and 3 vs. grade 1) as a significant prognostic factor for OS and local recurrence. ypN and ypStage were significant factors for RFS by univariate analysis, while no significant factor was detected by multivariate analysis. There was no significant factor for distant recurrence. In good responders (grades 2 and 3), the local recurrence rate was 0% (P = 0.006, vs. grade 1), while distant recurrence developed in 4 of 20 cases (20%, P = 0.615, vs. grade 1). There was no local recurrence in LLND (-) group regardless the histological response. CONCLUSIONS: Although selective LLND with preoperative CRT seems effective and valid for good responders, new treatment strategy is necessary for poor responders. Therefore, development of reliable biomarkers for histological response to CRT is an urgent need. PMID- 29442157 TI - Distribution Patterns of Microbial Community Structure Along a 7000-Mile Latitudinal Transect from the Mediterranean Sea Across the Atlantic Ocean to the Brazilian Coastal Sea. AB - A central goal in marine microecology is to understand the ecological factors shaping spatiotemporal microbial patterns and the underlying processes. We hypothesized that abiotic and/or biotic interactions are probably more important for explaining the distribution patterns of marine bacterioplankton than environmental filtering. In this study, surface seawater samples were collected about 7000 miles from the Mediterranean Sea, transecting the North Atlantic Ocean, to the Brazilian marginal sea. In bacterial biosphere, SAR11, SAR86, Rhodobacteraceae, and Rhodospiriaceae were predominant in the Mediterranean Sea; Prochlorococcus was more frequent in Atlantic Ocean; whereas in the Brazilian coastal sea, the main bacterial members were Synechococcus and SAR11. With respect to archaea, Euryarchaeota were predominant in the Atlantic Ocean and Thaumarchaeota in the Mediterranean Sea. With respect to the eukaryotes, Syndiniales, Spumellaria, Cryomonadida, and Chlorodendrales were predominant in the open ocean, while diatoms and microzooplankton were dominant in the coastal sea. Distinct clusters of prokaryotes and eukaryotes displayed clear spatial heterogeneity. Among the environmental parameters measured, temperature and salinity were key factors controlling bacterial and archaeal community structure, respectively, whereas N/P/Si contributed to eukaryotic variation. The relative contribution of environmental parameters to the microbial distribution pattern was 45.2%. Interaction analysis showed that Gammaproteobacteria, Alphaproteobacteria, and Flavobacteriia were the keystone taxa within the positive-correlation network, while Thermoplasmata was the main contributor in the negative-correlation network. Our study demonstrated that microbial communities are co-governed by environmental filtering and biotic interactions, which are the main deterministic driving factors modulating the spatiotemporal patterns of marine plankton synergistically at the regional or global levels. PMID- 29442158 TI - Effects of human parathyroid hormone 1-34 on bone loss and lumbar intervertebral disc degeneration in ovariectomized rats. AB - PURPOSE: Lumbar intervertebral disc degeneration is a common cause of lower back pain that affects the physical and mental health of patients and increases social burden. Parathyroid hormone has been reported to be effective at inhibiting disc degeneration; however, these effects have not been fully established in vivo in ovariectomized (OVX) rats. Thus, in this study, we aimed to address this issue and examine the effects of parathyroid hormone treatment in OVX rats. METHODS: Thirty female Sprague-Dawley rats, three months-old, were subjected to sham or ovariectomy surgery. Twelve weeks postsurgery, OVX rats were treated with either human parathyroid hormone [hPTH(1-34), 30 MUg/kg/day] or vehicle (normal saline (NS)) treatment. The L3-6 spinal segments were harvested after 12 weeks treatment. Bone mineral density (BMD), micro-architectural parameters, and biomechanical assessment were measured at the lumbar vertebral bodies. Histology and immunohistochemistry were performed to analyze the characteristics of the lumbar intervertebral discs. RESULTS: OVX + PTH rats had significantly higher BMD, percentage bone volume density, trabecular thickness, and biomechanical strength compared with those in Sham and OVX + NS rats. Histology and immunostaining revealed that disc degeneration was not significantly different between the OVX + NS rats and the OVX + PTH rats, compared with the Sham group; the structure of nucleus pulposus was disordered, the expression of collagen I was increased, and collagen II and aggrecan were decreased. CONCLUSIONS: These findings confirmed that hPTH(1-34) treatment has substantial anabolic effects on bone mass and trabecular micro-architecture, while the excessively enhanced bone mass and strength were coupled with a non-significant effect on the disc degeneration in ovariectomized rats. PMID- 29442159 TI - Open reduction and fixation with a locking plate without bone grafting is a reasonable and safe option for treating proximal humerus nonunion. AB - AIM OF THE STUDY: The aim of this study was to evaluate union rate and clinical outcome in patients with proximal humeral nonunions treated by open reduction and locking plate fixation without bone grafting. METHODS: From 2011 to 2016, nine patients were treated using open reduction and locking plate stabilization without bone grafting. They were examined both clinically and radiologically, with a mean follow-up period of 31 months. Outcome was evaluated using pain and range of motion (ROM) parameters. In addition, self-assessment by patients was registered on the Disability of the Arm, Shoulder and Hand score, Constant-Murley Score, Oxford Shoulder Score, and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form. A CT scan of the shoulder was performed to analyze union. RESULTS: At checkup, all patients showed union in the CT scans, where the mean ROM in abduction was 139 degrees (SD 50 degrees ), in adduction 39 degrees (SD 8 degrees ), in forward flexion 136 degrees (SD 40 degrees ), in extension 44 degrees (SD 11 degrees ), in internal rotation 62 degrees (SD 15 degrees ), and external rotation 54 degrees (SD 31 degrees ). ROM improved significantly in all planes of motion, except for adduction, post-surgery (p < 0.05). Plate removal was necessary in three patients. No complications were reported. CONCLUSION: Open reduction and locking plate fixation without bone grafting is a reasonable and safe option for treating proximal humerus nonunion. It leads to a high union rate, significant improvement in ROM, and in the majority of the cases to an "excellent" and "good" functional outcome without an increased risk of complications. PMID- 29442160 TI - Peri-articular injection of an analgesic mixture in primary total hip arthroplasty: an effective strategy for pain control during the first post operative day. AB - BACKGROUND: Previous studies of soft tissue infiltration in hip arthroplasty present variable results. The purpose of this study is to identify whether injection of an analgesic mixture improves pain management during the immediate post-operative period. MATERIALS AND METHODS: This cohort study compared 129 patients that received peri-articular soft tissue injection with 20 ml of 0.25% bupivacaine and 2 ml of ketorolac (30 mg/1 ml) in 28 ml of saline solution, with 71 patients who did not received injections. Pain intensity in the Verbal Analog Scale (VAS), opioid titration, and consumption (mg morphine equivalents) in the post-anaesthetic care unit (PACU) and during the first post-operative day were assessed for both groups. All patients received the same analgesia protocol. RESULTS: Median VAS score in the PACU was 4 (IQR 2-7) in the injection group and 7 (IQR 4-8) in the non-injection group (p = 0.001). Median opioid titration was 0 mg for the injection group and 2.6 mg for the non-injection group (p = 0.011). In the first post-operative day, the difference in VAS scores between groups was statistically significant (p = 0.009), but there was no difference in opioid consumption. CONCLUSION: Soft tissue injection with local anesthetics and non steroidal anti-inflammatory drugs allows adequate pain control in the immediate post-operative period and reduces the requirement for opioid consumption. We recommend the implementation of this safe and effective strategy in post operative pain management after primary hip arthroplasty. LEVEL OF EVIDENCE: Level II, cohort study. PMID- 29442161 TI - Allogeneic hematopoietic stem cell transplantation in Primary Cutaneous T Cell Lymphoma. AB - In our retrospective study, 16 patients affected by advanced cutaneous T cell lymphoma (CTCL) underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two patients (12.5%) were in complete remission (CR), nine (56.3%) in partial remission (PR), and five (31.2%) with active disease. The patients were transplanted from an HLA-identical (n = 7) from a mismatched (n = 1) or haploidentical (n = 1) sibling, from matched unrelated donor (n = 5), or from a single cord blood unit (n = 2). Conditioning regimen was standard myeloablative in 6 patients and at reduced intensity in 10. Seven patients died from non relapse mortality (NRM) and four patients relapsed or progressed, three of them achieved a second CR after donor lymphocyte infusion (DLI) or chemotherapy plus DLI. To date, with a median follow-up of 76 months (range 6-130), nine patients are alive, eight in CR, and one with active disease. Overall survival (OS) and disease-free survival (DFS) at 1 and 10 years are 61% (95% CI 40-91%) and 54% (95% CI 33-86%), 40% (95% CI 22-74%), and 34% (95% CI 16-68%), respectively. The time from diagnosis to transplant seems to influence negatively both OS (log-rank p < 0.04) and DFS (log-rank p < 0.05). Our results confirm on a long follow-up that CTCL appears particularly susceptible to the graft versus lymphoma (GVL) effect, so that allogeneic HSCT represents a possibility of cure for advanced CTCL. The timing of HSCT in the clinical course of disease remains an open issue. PMID- 29442163 TI - Accuracy and feasibility of a dedicated image guidance solution for endoscopic lateral skull base surgery. AB - OBJECTIVE: We aimed to design, build and validate a surgical navigation system which fulfills the accuracy requirements for surgical procedures on the ear and the lateral skull base, and which integrates with the endoscopic workflow and operating room setup. MATERIALS AND METHODS: The navigation system consists of portable tablet computer (iPad Pro, Apple Computer, USA) and an optical tracking system (Cambar B1, Axios3D, Germany), both connected via a wireless Bluetooth link and attached directly to the OR table. Active optical tracking references are rigidly fixed to both the patient and surgical tools. Software to support image import, registration and 2D/3D visualization has been developed. Two models were used for targeting accuracy assessment: a technical phantom model and an ex vivo temporal bone model. Additionally, workflow integration and usability of the navigation system during endoscopic lateral skull base procedures was investigated in ex vivo experiments on 12 sides of cadaver head specimens. RESULTS: The accuracy experiments revealed a target registration error in the technical phantom model of 0.20 +/- 0.10 mm (n = 36) and during the ex vivo assessment of 0.28 +/- 0.10 mm (n = 21). Navigation was successfully carried out in n = 36 procedures (infracochlear, suprageniculate and transpromontorial approach), with navigated instruments usable without interference with the endoscope. The system aided in the successful and accurate identification of vital anatomical structures. CONCLUSIONS: Useful surgical navigation is, to a large extent, a result of sufficiently accurate tracking technology. We have demonstrated sufficient accuracy and a potentially suitable integration for surgical application within endoscopic lateral skull base procedures. PMID- 29442162 TI - Prognostic meaning of neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ration (LMR) in newly diagnosed Hodgkin lymphoma patients treated upfront with a PET-2 based strategy. AB - Recent reports identify NLR (the ratio between absolute neutrophils counts, ANC, and absolute lymphocyte count, ALC), as predictor of progression-free survival (PFS) and overall survival (OS) in cancer patients. We retrospectively tested NLR and LMR (the ratio between absolute lymphocyte and monocyte counts) in newly diagnosed Hodgkin lymphoma (HL) patients treated upfront with a PET-2 risk adapted strategy. NLR and LMR were calculated using records obtained from the complete blood count (CBC) from 180 newly diagnosed HL patients. PFS was evaluated accordingly to Kaplan-Meier method. Higher NLR was associated to advanced stage, increased absolute counts of neutrophils and reduced count of lymphocytes, and markers of systemic inflammation. After a median follow-up of 68 months, PFS at 60 months was 86.6% versus 70.1%, respectively, in patients with NLR >= 6 or NLR < 6. Predictors of PFS at 60 months were PET-2 scan (p < 0.0001), NLR >= 6.0 (p = 0.02), LMR < 2 (p = 0.048), and ANC (p = 0.0059) in univariate analysis, but only PET-2 was an independent predictor of PFS in multivariate analysis. Advanced-stage patients (N = 119) were treated according to a PET-2 risk-adapted protocol, with an early switch to BEACOPP regimen in case of PET-2 positivity. Despite this strategy, patients with positive PET-2 still had an inferior outcome, with PFS at 60 months of 84.7% versus 40.1% (negative and positive PET-2 patients, respectively, p < 0.0001). Independent predictors of PFS by multivariate analysis were PET-2 status and to a lesser extend NLR in advanced stage, while LMR maintained its significance in early stage. By focusing on PET-2 negative patients, we found that patients with NLR >= 6.0 or LMR < 2 had an inferior outcome compared to patients with both ratios above the cutoff (78.7 versus 91.9 months, p = 0.01). We confirm NLR as predictor of PFS in HL patients independently from stage at diagnosis. Integration of PET-2 scan, NLR and LMR can result in a meaningful prognostic system that needs to be further validated in prospective series including patients treated upfront with PET-2 adapted-risk therapy. PMID- 29442164 TI - Diagnostic flexible pharyngo-laryngoscopy: development of a procedure specific assessment tool using a Delphi methodology. AB - PURPOSE: Proper training and assessment of skill in flexible pharyngo laryngoscopy are central in the education of otorhinolaryngologists. To facilitate an evidence-based approach to curriculum development in this field, a structured analysis of what constitutes flexible pharyngo-laryngoscopy is necessary. Our aim was to develop an assessment tool based on this analysis. METHODS: We conducted an international Delphi study involving experts from twelve countries in five continents. Utilizing reiterative assessment, the panel defined the procedure and reached consensus (defined as 80% agreement) on the phrasing of an assessment tool. RESULTS: FIFTY PANELISTS COMPLETED THE DELPHI PROCESS. THE MEDIAN AGE OF THE PANELISTS WAS 44 YEARS (RANGE 33-64 YEARS). MEDIAN EXPERIENCE IN OTORHINOLARYNGOLOGY WAS 15 YEARS (RANGE 6-35 YEARS). TWENTY-FIVE WERE SPECIALIZED IN LARYNGOLOGY, 16 WERE HEAD AND NECK SURGEONS, AND NINE WERE GENERAL OTORHINOLARYNGOLOGISTS. AN ASSESSMENT TOOL WAS CREATED CONSISTING OF TWELVE DISTINCT ITEMS.: Conclusion The gathering of validity evidence for assessment of core procedural skills within Otorhinolaryngology is central to the development of a competence-based education. The use of an international Delphi panel allows for the creation of an assessment tool which is widely applicable and valid. This work allows for an informed approach to technical skills training for flexible pharyngo-laryngoscopy and as further validity evidence is gathered allows for a valid assessment of clinical performance within this important skillset. PMID- 29442166 TI - Prognostic value of age, subglottic, and anterior commissure involvement for early glottic carcinoma treated with CO2 laser transoral microsurgery: a retrospective, single-center cohort study of 261 patients. AB - PURPOSE: CO2 laser transoral microsurgery for glottic carcinoma, when indicated, has the well-established advantages of low morbidity and positive oncological outcomes. The present study aims to determine how patient age, and tumor site could negatively impact prognosis; other variables such as the status of the margins of resection, tobacco and alcohol intake, and the grade of differentiation of the tumors have been evaluated. METHODS: This was a retrospective analysis on 261 patients with a glottic carcinoma who underwent CO2 laser transoral microsurgery. The impact of different variables was calculated using univariate and multivariate analyses. RESULTS: The study included 248 males and 13 females. The median follow-up period was 4.3 years. Five-year disease specific survival, recurrence-free survival, local control with laser alone, overall laryngeal preservation, and overall survival rates were 99.4, 92.2, 93.8, 97.6, and 85.5%, respectively. Equivalent results were observed in young and elderly patients. Patients with positive margins after CO2 laser transoral microsurgery showed a reduced local control with laser alone. T2 patients with true subglottic spreading and patients with anterior commissure involvement of grade 3 (Rucci's classification) experienced worse local control rates, despite free surgical margins confirmed by histology. CONCLUSIONS: CO2 laser transoral microsurgery is an effective and reproducible single-stage modality therapy for young and elderly patients with glottic carcinoma. Superficial close margins can be managed by a careful wait-and-see policy, while positive margins should undergo surgical enlargement. In our experience, undifferentiated tumors, true subglottic extension, and anterior commissure involvement of grade 3 were associated with worse outcomes. PMID- 29442167 TI - Real-time monitoring of hyaluronic acid fermentation by in situ transflectance spectroscopy. AB - Hyaluronic acid (HA) is a high-value polysaccharide with many biomedical applications. Microbial production of HA is now replacing the traditional extraction method from rooster combs. Production of medical-grade HA with defined characteristics requires controlled process conditions because there are many fermentation process parameters that affect the microbial synthesis of HA. This necessitates the development of online tools for monitoring multiple analytes during microbial fermentation. Here, we describe the application of in situ transflectance spectroscopy for online quantification of seven major fermentation analytes, viz. biomass, glucose, lactate, formate, ethanol, acetate and HA in metabolically engineered Lactococcus lactis fermentations. The near-infrared spectral information acquired from synthetic mixtures and untransformed L. lactis fermentations were used to develop chemometric models. Based on principal component analysis and partial least squares regression methods, analyte-specific models were developed for quantification. These models were then independently validated for fermentation analytes from four different recombinant L. lactis strains. The chemometric model developed for HA based on recombinant L. lactis fermentation data and pure HA standards could accurately predict HA concentrations under homolactic conditions. The online estimation of HA was found to be poor under heterolactic conditions due to the overlapping absorbance of acetate produced in these cultures. Alternatively, an independent model based on yield correlation was successfully developed for indirect real-time quantification of HA. PMID- 29442165 TI - A comparison of Dysphonia Severity Index and Acoustic Voice Quality Index measures in differentiating normal and dysphonic voices. AB - PURPOSE: The aim of the study was to investigate and compare the feasibility and robustness of the Acoustic Voice Quality Index (AVQI) and the Dysphonia Severity Index (DSI) in diagnostic accuracy, differentiating normal and dysphonic voices. METHODS: A group of 264 subjects with normal voices (n = 105) and with various voice disorders (n = 159) were asked to read aloud a text and to sustain the vowel /a/. Both speech tasks were concatenated, and perceptually rated for dysphonia severity by five voice clinicians. They rated the Grade (G) and the overall dysphonia severity with a visual analog scale (VAS). All concatenated voice samples were acoustically analyzed to receive an AVQI score. For DSI analysis, the required voice parameters were obtained from the sustained phonation of the vowel /a/. RESULTS: The results achieved significant and marked concurrent validity between both auditory-perceptual judgment procedures and both acoustic voice measures. The DSI threshold (i.e., DSI = 3.30) pertaining to Gmean obtained reasonable sensitivity of 85.8% and specificity of 83.4%. For VASmean, the DSI threshold of 3.30 was determined also with reasonable sensitivity of 70.3% and excellent specificity of 93.9%. Also, the AVQI threshold (i.e., AVQI = 3.31) pertaining to Gmean demonstrated reasonable sensitivity of 78.1% and excellent specificity of 92.0%. For VASmean, an AVQI threshold of 3.33 was determined with excellent sensitivity of 97.0% and reasonable specificity of 81.8%. CONLUSION: The outcomes of the present study indicate comparable results between DSI and AVQI with a high level of validity to discriminate between normal and dysphonic voices. However, a higher level of accuracy was yielded for AVQI as a correlate of auditory perceptual judgment suggesting a reliable voice screening potential of AVQI. PMID- 29442168 TI - Biofuel production with a stress-resistant and growth phase-independent promoter: mechanism revealed by in vitro transcription assays. AB - The carbon and energy needed for bioconversion processes face trade-offs between cell reproduction and chemical synthesis. In most processes, microbial cells containing overexpressed pathway enzymes were accumulated in exponential phase before the productions of value-added chemicals dominate the carbon and energy fluxes in stationary phase. The pathway enzymes need to be continuously supplied to compensate their degradation, but the promoters driving their overexpressions are downregulated under stationary phase or stressed conditions. In this study, the gadA promoter enabled stress-resistant and growth phase-independent isobutanol production up to 10-28 g l-1. To investigate the activation mechanism of gadA promoter and its potential in metabolic engineering, an in vitro transcription system was established. Results showed that gadA promoter could be transcribed efficiently under environments that inhibit the transcription of ribosomal promoters, while under moderate to rapid growth conditions, the large majority of new cellular transcripts are ribosomal. This differential transcription relies on the accumulation of environmental glutamate and/or the loss of supercoiling. These results implied that the gadA promoter could be functional or even dominate the cellular transcription under an exceedingly wide range of physiological conditions. Therefore, the gadA promoter is a novel candidate for driving pathway enzyme overexpressions under not only exponential phase but also stationary phase and stressed conditions, which is important for achieving efficient biofuel production. PMID- 29442171 TI - The role of Saccharomyces cerevisiae in stabilizing emulsions of hexadecane in aqueous media. AB - During downstream operations involved in the purification of hydrophobic biofuels produced by microorganisms, undesired stable emulsions may be formed. Understanding the mechanisms behind this stability is a pre-requisite for designing cost-effective strategies to break these emulsions. In this work, we aimed at increasing our knowledge on the mechanisms responsible for stabilizing yeast-containing oil-in-water emulsions. For this purpose, emulsions containing hexadecane and different yeast-based aqueous phases were prepared and analyzed for phase separation, surface charge density, particle size, and rheology. First, we observed that compounds present in fresh tablet baker's yeast contribute to emulsion stability. In order to eliminate this effect, we generated stocks with this yeast in the laboratory, and compared its performance with an industrial fuel ethanol strain, namely Saccharomyces cerevisiae PE-2. We confirmed that the presence of yeast cells enhances emulsion stability. The cultivation medium (complex or defined) in which cells are grown, as well as the physiological state of the cells (pre- or post-diauxic), prior to emulsion preparation, influenced emulsion stability. The smaller cell size of tablet yeast probably also contributes to more stable emulsions, when compared to those prepared with yeast cells grown in the laboratory. Baker's and fuel ethanol yeast cells in post diauxic phase promote the formation of more stable emulsions than those with cells in the pre-diauxic physiological state. Finally, we propose a mechanism to explain the enhanced emulsion stability due to the presence of yeast cells, with electrostatic repulsion between emulsion droplets having the prevailing effect. PMID- 29442169 TI - Applications of bacteriophages versus phage enzymes to combat and cure bacterial infections: an ambitious and also a realistic application? AB - Bacteriophages (phages) are viruses that infect bacteria. The "predator-prey" interactions are recognized as a potentially effective way to treat infections. Phages, as well as phage-derived proteins, especially enzymes, are intensively studied to become future alternative or supportive antibacterials used alone or in combination with standard antibiotic regimens treatment. There are many publications presenting phage therapy aspects, and some papers focused separately on the application of phage-derived enzymes. In this review, we discuss advantages and limitations of both agents concerning their specificity, mode of action, structural issues, resistance development, pharmacokinetics, product preparation, and interactions with the immune system. Finally, we describe the current regulations for phage-based product application. PMID- 29442170 TI - Surface proteins involved in the adhesion of Streptococcus salivarius to human intestinal epithelial cells. AB - The adhesion properties of 14 Streptococcus salivarius strains to mucus (HT29 MTX) and non-mucus secreting (Caco-2/TC7) human intestinal epithelial cells were investigated. Ability to adhere to these two eukaryotic cell lines greatly differs between strains. The presence of mucus played a major factor in adhesion, likely due to high adhesiveness to mucins present in the native human mucus layer covering the whole cell surface. Only one S. salivarius strain (F6-1), isolated from the feces of a healthy baby, was found to strongly adhere to HT-29 MTX cells at a level comparable to that of Lactobacillus rhamnosus GG, a probiotic strain considered to be highly adherent. By sequencing the genome of F6-1, we were able to identify 36 genes encoding putative surface proteins. Deletion mutants were constructed for six of them and their adhesion abilities on HT-29 MTX cells were checked. Our study confirmed that four of these genes encode adhesins involved in the adhesion of S. salivarius to host cells. Such adhesins were also identified in other S. salivarius strains. PMID- 29442172 TI - Structure Shift of GaN Among Nanowall Network, Nanocolumn, and Compact Film Grown on Si (111) by MBE. AB - Structure shift of GaN nanowall network, nanocolumn, and compact film were successfully obtained on Si (111) by plasma-assisted molecular beam epitaxy (MBE). As is expected, growth of the GaN nanocolumns was observed in N-rich condition on bare Si, and the growth shifted to compact film when the Ga flux was improved. Interestingly, if an aluminum (Al) pre-deposition for 40 s was carried out prior to the GaN growth, GaN grows in the form of the nanowall network. Results show that the pre-deposited Al exits in the form of droplets with typical diameter and height of ~ 80 and ~ 6.7 nm, respectively. A growth model for the nanowall network is proposed and the growth mechanism is discussed. GaN grows in the area without Al droplets while the growth above Al droplets is hindered, resulting in the formation of continuous GaN nanowall network that removes the obstacles of nano-device fabrication. PMID- 29442174 TI - Correction to: Tandem affinity purification of AtTERT reveals putative interaction partners of plant telomerase in vivo. AB - In the published online version, the affiliations were mixed up. Corrected affiliation section is shown below. Also, the update has also been reflected in the author group section above. PMID- 29442173 TI - Hypofractionated postmastectomy radiotherapy with helical tomotherapy in patients with immediate breast reconstruction: dosimetric results and acute/intermediate toxicity evaluation. AB - The aim of this study was to evaluate the dosimetry and toxicity of hypofractionation in postmastectomy radiotherapy (PMRT) with intensity-modulated radiotherapy (IMRT) in breast cancer (BC) patients. Stage II-III BC patients with implant-based immediate breast reconstruction received PMRT to the chest wall (CW) and to the infra/supraclavicular nodal region (NR) using a 15-fraction schedule (2.67 Gy/fraction) and helical IMRT (Tomotherapy(r) System, Accuray Incorporated, Sunnyvale, CA). A score was assigned to each treatment plan in terms of planning target volume (PTV) coverage of CW and NR and the sparing of the organs at risk (OARs). The total score for each plan was calculated. Toxicity was prospectively assessed according to validated scales. Data from 120 consecutive patients treated in the period 2012-2015 were analysed with a median follow-up from the end of radiotherapy of 13.2 months (range 0.0-35 months). 70.8% (85/120) of the plans had high total scores as a result of an optimal coverage of both CW and RN and optimal sparing of all OARs. The maximum acute toxicity was of grade 2 in 36.7% of the cases. Early late toxicity was mild in the majority of cases. In the study population, helical tomotherapy-based IMRT produced optimal treatment plans in most cases. Acute and late toxicity was mild/moderate. Hypofractionated helical IMRT appears to be safe and feasible in the moderate term for PMRT. PMID- 29442175 TI - Common Models Used for Inpatient Diabetes Management. AB - PURPOSE OF REVIEW: Diabetes affects about a third of all hospitalized patients and up to 50% of inpatients go on to experience hyperglycemia. Despite strong evidence supporting the importance of adequate glycemic control, as well detailed guidelines from major national organizations, many patients continue to have hypo and hyperglycemia during their hospital stay. While this may be partially related to provider and patient-specific factors, system-based barriers continue to pose a major obstacle. Therefore, there is a need to go beyond merely discussing specific insulin protocols and provide guidance for effective models of care in the acute glycemic management of hospitalized patients. RECENT FINDINGS: To date, there is limited data evaluating the various models of care for inpatient diabetes management in terms of efficacy or cost, and there is no summary on this topic guiding physicians and hospital administrators. In this paper, four common models of inpatient diabetes care will be presented including those models led by the following: an endocrinologist(s), mid-level provider(s), pharmacist(s), and a virtual glucose management team. The authors will outline the intrinsic benefits as well as limitations of each model of care as well as cite supporting evidence, when available. Discussion pertaining to how a given model of care shapes and formulates a particular organization's structured glucose management program (GMP) will be examined. Furthermore, the authors describe how the model of care chosen by an institution serves as the foundation for the creation of a GMP. Finally, the authors examine the critical factors needed for GMP success within an institution and outline the nature of hospital administrative support and accompanying reporting structure, the function of a multidisciplinary diabetes steering committee, and the role of the medical director. PMID- 29442176 TI - The cortical blood-brain barrier in multiple sclerosis: a gateway to progression? PMID- 29442177 TI - Effectiveness of Rotigotine plus intensive and goal-based rehabilitation versus Rotigotine alone in "de-novo" Parkinsonian subjects: a randomized controlled trial with 18-month follow-up. AB - BACKGROUND: Dopamine Replacement Therapy (DRT) represents the most effective treatment for Parkinson's disease (PD). Nevertheless, several symptoms are unresponsive to treatment and its long-term use leads to serious side effects. To optimize the pharmacological management of PD, dopamine-agonists are often prescribed to "de-novo" patients. Moreover, several studies have shown the effectiveness and the synergic effect of rehabilitation in treating PD. OBJECTIVE: To evaluate the synergism between DRT and rehabilitation in treating PD, by investigating the short and the long-term effectiveness of a multidisciplinary, intensive and goal-based rehabilitation treatment (MIRT) in a group of patients treated with Rotigotine. MATERIALS AND METHODS: In this multicenter, single blinded, parallel-group, 1:1 allocation ratio, randomized, non-inferiority trial, 36 "de-novo" PD patients were evaluated along 18 months: 17 were treated with Rotigotine plus MIRT; 19 were treated with Rotigotine alone (R). The primary outcome measure was the total score of Unified Parkinson's Disease Rating Scale (UPDRS). The secondary outcomes included the UPDRS sub sections II and III (UPDRS II-III), the 6-Minute Walk Test (6MWT), the Timed Up and Go Test (TUG) and the amount of Rotigotine. Patients were evaluated at baseline (T0), 6 months (T1), 1 year (T2), and at 18 months (T3). RESULTS: No differences in UPDRS scores in the two groups (total score, III part and II part, p = 0.48, p = 0.90 and p = 0.40, respectively) were found in the time course. Conversely, a greater improvement in Rotigotine + MIRT group was observed for 6MWT (p < 0.0001) and TUG (p = 0.03). Along time, the dosage of Rotigotine was higher in patients who did not undergo MIRT, at all observation times following T0. CONCLUSIONS: Over the course of 18 months, the effectiveness of the combined treatment (Rotigotine + MIRT) on the patients' global clinical status, evaluated with total UPDRS, was not inferior to that of the pharmacological treatment with Rotigotine alone. Importantly, rehabilitation allowed patients to gain better motor performances with lower DRT dosage. PMID- 29442178 TI - The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews. AB - PURPOSE OF REVIEW: Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects. RECENT FINDINGS: We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms. Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non cannabinoid comparators; this is an important gap in the evidence. PMID- 29442179 TI - Efficacy and safety of nilotinib therapy in patients with newly diagnosed chronic myeloid leukemia in the chronic phase. AB - ABL1-tyrosine kinase inhibitors (TKIs) have led to dramatic changes in treatment strategies for chronic myeloid leukemia in the chronic phase (CML-CP). However, clinical studies have highlighted increasing numbers of adverse events (AE) with TKIs. Although TKI modification plays a key role in AE management, this process is poorly understood, particularly in terms of the TKI nilotinib. In the present study, we retrospectively analyzed the records of 70 patients with newly diagnosed (ND)-CML-CP who were treated with nilotinib to investigate the drug potency of nilotinib and treatment management. During a median observation period of 3.4 years, 76% of patients continued nilotinib as a first-line treatment. The 1-year and overall major molecular response (MMR) rates and the overall molecular response (MR) 4.5 rate for all patients receiving first-line nilotinib therapy were 70, 84.2, and 50%, respectively. No case progressed to the accelerated or blast phase during the study. To avoid AEs during the early phase, nilotinib doses were reduced to < 600 mg/day in a third of patients (Reduced group); these patients experienced better therapeutic efficacy and a lower rate of AEs relative to those in Standard group (300 mg twice daily). Ten patients who received < 600 mg/day of nilotinib throughout the study had a 1-year MMR rate and overall MR4.5 rate of 90 and 60%, respectively. In summary, our findings indicate that careful management, including dose reduction, can yield better outcomes in patients with ND-CML-CP. PMID- 29442180 TI - Effect of crosslinking concentration on properties of 3-(trimethoxysilyl) propyl methacrylate/N-vinyl pyrrolidone gels. AB - BACKGROUND: The incorporation of two different monomers, having different properties, in the same polymer molecule leads to the formation of new materials with great scientific and commercial importance. The basic requirements for polymeric materials in some areas of biomedical applications are that they are hydrophilic, having good mechanical and thermal properties, soft, and oxygen permeable. RESULTS: A series of 3-(trimethoxysilyl) propyl methacrylate/N-vinyl pyrrolidone (TMSPM/NVP) xerogels containing different concentration of ethylene glycol dimethacrylate (EGDMA) as crosslinking agent were prepared by bulk polymerization to high conversion using BPO as initiator. The copolymers were characterized by FTIR. The corresponding hydrogels were obtained by swelling the xerogels in deionized water to equilibrium. Addition of EGDMA increases the transparency of xerogels and hydrogels. The minimum amount of EGDMA required to produce a transparent xerogel is 1%. All the Swelling parameters, including water content (EWC), volume fraction of polymer (phi2) and weight loss during swelling decrease with increasing EGDMA. Young's and shear modulus (E and G) increase as EGDMA increases. The hydrogels were characterized in terms of modulus cross linking density (v e and v t ) and polymer-solvent interaction parameters (chi). Thermal properties include TGA and glass transition temperature (Tg) enhance by adding EGDMA whereas the oxygen permeability (P) of hydrogels decreases as water content decrease. CONCLUSIONS: This study prepared and studied the properties for new copolymer (TMSPM-co-NVP) contains different amounts of (EGDMA). These copolymers possess new properties with potential use in different biomedical applications. The properties of the prepared hydrogels are fit with the standard properties of materials which should be used for contact lenses. PMID- 29442181 TI - Do functional outcomes and cuff integrity correlate after single- versus double row rotator cuff repair? A systematic review and meta-analysis study. AB - PURPOSE: The purpose of this study is to perform a systematic review and meta analysis of all available level I prospective randomized controlled trials comparing arthroscopic single-row (SR) with double-row (DR) rotator cuff repairs by both clinical outcomes and radiological re-tear rates. METHODS: PubMed, EMBASE, Google Scholar, and Cochrane databases search was done for level I RCTs comparing clinical and radiological outcomes after SR versus DR rotator cuff repair. Clinical outcomes included UCLA, ASES, Constant, WORC, and SANE scores; structural outcomes included MRI, MRA, or US. RESULTS: Seven level I studies were included (5 mid-term and 2 short-term). Postoperative ASES, Constant, WORC, and SANE scores showed nonsignificant slightly better function of DR groups. Only, UCLA score showed significantly better scores with DR repair (p = 0.007). Full thickness re-tear incidence was reported in 15/174 (8.6%) in DR group and 20/175 (11.4%) in SR group (p = 0.44). Partial-thickness re-tear rate was reported in 18/174 patients (10.3%) in DR group and 41/175 patients (23.4%) in SR group (p = 0.009). CONCLUSION: Within the domain of level I mid-term and short-term studies, DR repair showed significant better UCLA score only. (ASES, Constant, WORC, and SANE scores showed no significance.) This may correlate weakly with the significant lower partial-thickness re-tear rates of DR repairs. In contrary, long-term level III studies showed a direct correlation of both functional outcomes and cuff structural integrity, with significant superiority of DR over SR repair techniques. LEVEL OF EVIDENCE: Level 1, systematic review and meta analysis. PMID- 29442182 TI - Structure and dynamics of the peptide strand KRFK from the thrombospondin TSP-1 in water. AB - Theoretical investigations of a solute in liquid water at normal temperature and pressure can be performed at different levels of theory. Static quantum calculations as well as classical and ab initio molecular dynamics are used to completely explore the conformational space for large solvated molecular systems. In the classical approach, it is essential to describe all of the interactions of the solute and the solvent in detail. Water molecules are very often described as rigid bodies when the most commonly used interaction potentials, such as the SPCE and the TIP4P models, are employed. Recently, a physical model based upon a cluster of rigid water molecules with a tetrahedral architecture (AB4) was proposed that describes liquid water as a mixture of both TIP4P and SPCE molecular species that occur in the proportions implied by the tetrahedral architecture (one central molecule versus four outer molecules; i.e., 20% TIP4P versus 80% SPCE molecules). In this work, theoretical spectroscopic data for a peptide strand were correlated with the structural properties of the peptide strand solvated in water, based on data calculated using different theoretical approaches and physical models. We focused on a particular peptide strand, KRFK (lysine-arginine-phenylalanine-lysine), found in the thrombospondin TSP-1, due to its interesting properties. As the activity and electronic structure of this system is strongly linked to its structure, we correlated its structure with charge-density maps obtained using different semi-empirical charge Qeq equations. The structural and thermodynamic properties obtained from classical simulations were correlated with ab initio molecular dynamics (AIMD) data. Structural changes in the peptide strand were rationalized in terms of the motions of atoms and groups of atoms. To achieve this, conformational changes were investigated using calculated infrared spectra for the peptide in the gas phase and in water solvent. The calculated AIMD infrared spectrum for the peptide was correlated with static quantum calculations of the molecular system based on a harmonic approach as well as the VDOS (vibrational density of states) spectra obtained using various classical solvent models (SPCE, TIP4P, and AB4) and charge maps. PMID- 29442183 TI - Monitoring the convection coefficient in fermentative processes using numerical methods. AB - This work is based on the importance of monitoring the thermodynamic variables of sugarcane juice fermentation by Saccharomyces cerevisiae, using a numerical technique, and providing artifices that lead to the best performance of this bioprocess. Different combinations of yeast quantity were added to diverse dilutions of cane juice, allowing the evaluation of the fermentation performance. This was conducted by observing the temperature signal obtained from thermal probes inserted in the experimental set up. The best performances are utilized in the mathematical model evaluation. Thus, the signal reconstructed by the appropriate inverse problem and subsequently, regularized by the simplified method of least squares (the method used for adjusting the defined parameters) allows a common method to process the convection coefficient that can be monitored and controlled within an actuation range. This leads to an increased level of refinement in the technique. Results show that it is possible to determine the best parameters for this technique and observe the occurrence of fermentation by monitoring the temperature signal, thereby ensuring the realization of a high-quality and high-performance bioprocess. PMID- 29442184 TI - Preparation of porous hollow Fe3O4/P(GMA-DVB-St) microspheres and application for lipase immobilization. AB - Functional porous hollow microspheres with superparamagnetism, Fe3O4/P(GMA-DVB St) microspheres, were prepared via a dispersion polymerization based on hollow Fe3O4 microspheres. The resulting hollow microspheres were characterized by means of Fourier-transform infrared spectrophotometer (FT-IR), X-ray diffraction (XRD), transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET) gas sorptometry, and vibrating sample magnetometer (VSM). It is verified that the resulting hollow microspheres are porous and have high saturation magnetization. For further application, candida rugosa lipase (CRL) was immobilized onto the hollow microshperes, the loading amount of lipase was 143.88 mg CRL/g support and the activity recovery of the obtained immobilized lipase reached 73.25%. Besides, the resulting immobilized CRL (ICRL) were found to have better pH endurance and temperature endurance than the free ones, which showed the optimal catalytic activity with pH of 9.0 and temperature of 60 degrees C. The ICRL displayed excellent reusability as well. PMID- 29442185 TI - Colorado Water Watch: real-time groundwater monitoring for possible contamination from oil and gas activities. AB - Currently, only a few states in the USA (e.g., Colorado and Ohio) require mandatory baseline groundwater sampling from nearby groundwater wells prior to drilling a new oil or gas well. Colorado is the first state to regulate groundwater testing before and after drilling, which requires one pre-drilling sample and two additional post-drilling samples within 6-12 months and 5-6 years of drilling. However, the monitoring method is limited to the state's regulatory agency and to ex situ sampling, which offers only a snapshot in time. To overcome the limitations and increase monitoring performance, a new groundwater monitoring system, Colorado Water Watch (CWW), was introduced as a decision-making tool to support the state's regulatory agency and also to provide real-time groundwater quality data to both the industry and the public. The CWW uses simple in situ water quality sensors based on the surrogate sensing technology that employs an event detection system to screen the incoming data in near real-time. PMID- 29442186 TI - Structural and functional characterization of the Vindoline biosynthesis pathway enzymes of Catharanthus roseus. AB - Vinblastine and its related compound vincristine are important mono terpenoid indole alkaloids accumulated in the leaves of Catharanthus roseus (Madagascar periwinkle). They serve as major anticancer drugs. Vinblastine is formed by the condensation of vindoline and catharanthine. The vindoline moiety is derived from tabersonine via vindoline biosynthesis pathway. The reaction sequence from tabersonine to vindoline is now well established and the enzymes involved in this pathway are identified. However, to date, the structures of the enzymes involved in the vindoline biosynthesis pathway are not known, leading to limited mechanistic understanding of the substrate binding and catalysis. The purpose of this work is to provide structural insight regarding all the steps of the vindoline pathway via rigorous homology modeling, molecular docking, and molecular dynamics analyses. Substrate and cofactors required for each step were docked onto the computationally built and validated three-dimensional (3D) model of the corresponding enzyme, and the catalytic reaction was analyzed from the structural point of view. Possible binding modes of the substrates and cofactors were generated and corresponding binding residues were identified. Enzyme substrate models were verified based on structure evaluation methods and molecular dynamics based approaches. Findings of our analysis would be useful in rational designing of these important enzymes aimed toward bio-production of vindoline. PMID- 29442187 TI - Effect of multiple autoclave cycles on the surface roughness of HyFlex CM and HyFlex EDM files: an atomic force microscopy study. AB - AIM: To compare the effect of autoclave cycles on the surface topography and roughness of HyFlex CM and HyFlex EDM instruments using atomic force microscopy (AFM) analysis. METHODOLOGY: Eight new files of each brand were subdivided into four subgroups (n = 2/each subgroup). One group was allocated as the control group and not subjected to autoclave sterilization. The other three groups were subjected to different numbers (1, 5, and 10) of autoclave sterilization cycles. After the cycle instruments were subjected to AFM analysis. Roughness average (Ra) and the root mean square (RMS) values were chosen to investigate the surface features of endodontic files. The data was analyzed using one-way ANOVA and post hoc Tamhane tests at 5% significant level. RESULTS: The lowest Ra and RMS values were observed in the HyFlex EDM files that served as the control and in those subjected to a single cycle of autoclave sterilization (P < 0.05). The highest Ra and RMS values were observed in the HyFlex CM and HyFlex EDM files that were subjected to 10 cycles of autoclave sterilization (P < 0.05). The surface roughness values of the HyFlex CM group showed a significant increase after ten autoclave cycles, whereas those of the HyFlex EDM group exhibited a significant change after five autoclave cycles (P < 0.05). CONCLUSIONS: Although the initial surface roughness values of the HyFlex EDM files were lower than those of the HyFlex CM files, the surface roughness values of the EDM files showed a statistically significant increase after 5 cycles of autoclave sterilization. In contrast, the surface roughness values of the HyFlex CM files did not increase until 10 cycles of autoclave sterilization. CLINICAL RELEVANCE: Present study indicated that autoclave sterilization negatively affected the surface roughness of the tested NiTi files. PMID- 29442189 TI - Chemical Valorization of Cashew Nut Shell Waste. AB - Cashew nut shells are agro-wastes produced from cashew nut processing factories and contain about 30-35 wt% oil called cashew nut shell liquid (CNSL). This liquid is a mixture of four potential compounds, namely anacardic acid, cardanol, cardol and 2-methyl cardol. Various reactions have been developed to convert the components of cashew nut shell liquid into industrially important chemicals, and these materials are herein described. Such reactions employed in the transformation include transfer hydrogenation reactions, isomerization reactions, metathesis reactions, carbonylation reactions, polymerization reactions, isomerizing metathesis reaction, and isomerizing carbonylation reactions. Through these descriptions, one realizes that cashew nut shells are not a waste, but they are rather a good source of a potential liquid, CNSL, which is a promising renewable resource for synthesizing various industrial chemicals. PMID- 29442188 TI - Damage-regulated autophagy modulator 1 in oral inflammation and infection. AB - OBJECTIVES: Damage-regulated autophagy modulator (DRAM) 1 is a p53 target gene with possible involvement in oral inflammation and infection. This study sought to examine the presence and regulation of DRAM1 in periodontal diseases. MATERIAL AND METHODS: In vitro, human periodontal ligament fibroblasts were exposed to interleukin (IL)-1beta and Fusobacterium nucleatum for up to 2 days. The DRAM1 synthesis and its regulation were analyzed by real-time PCR, immunocytochemistry, and ELISA. Expressions of other autophagy-associated genes were also studied by real-time PCR. In vivo, synthesis of DRAM1 in gingival biopsies from rats and patients with and without periodontal disease was examined by real-time PCR and immunohistochemistry. For statistics, ANOVA and post-hoc tests were applied (p < 0.05). RESULTS: In vitro, DRAM1 was significantly upregulated by IL-1beta and F. nucleatum over 2 days and a wide range of concentrations. Additionally, increased DRAM1 protein levels in response to both stimulants were observed. Autophagy associated genes ATG3, BAK1, HDAC6, and IRGM were also upregulated under inflammatory or infectious conditions. In vivo, the DRAM1 gene expression was significantly enhanced in rat gingival biopsies with induced periodontitis as compared to control. Significantly increased DRAM1 levels were also detected in human gingival biopsies from sites of periodontitis as compared to healthy sites. CONCLUSION: Our data provide novel evidence that DRAM1 is increased under inflammatory and infectious conditions in periodontal cells and tissues, suggesting a pivotal role of DRAM1 in oral inflammation and infection. CLINICAL RELEVANCE: DRAM1 might be a promising target in future diagnostic and treatment strategies for periodontitis. PMID- 29442190 TI - Effects of open dumping of MSW on metal contamination of soil, plants, and earthworms in Ranchi, Jharkhand, India. AB - Influence of open dumping of municipal solid wastes (MSW) on metal contamination of soil, plants, and earthworms in Ranchi, Jharkhand, India, was studied over 6 month period. Dumpsite in the study area exists in two sections, old section where waste dumping has stopped and new section where wastes are currently disposed. Soil around dumpsite had high concentration of Co, Cr, Cu, Pb, and Zn than that at control site. Geoaccumulation index indicated uncontaminated to moderate level of soil contamination at old dumpsite and soil at new dumpsite was found to be uncontaminated. Parthenium hysterophorus, Lantana camara, and Calotropis procera were the main plants found in patchy distribution around dumpsite. Plants exhibited almost similar levels of metal concentration in roots and shoots. P. hysterophorus and L. camara showed high bioaccumulation capacity and low translocation capacity. C. procera showed moderate bioaccumulation capacity and high translocation capacity as the concentration of metals was higher in the shoot. P. hysterophorus and L. camara due to higher bioaccumulation capacity and lower translocation capacity appear to be suitable for phytostabilization of metal-contaminated soil. Earthworms present at the dumpsite showed high concentration of Cr, Cu, Pb, and Zn with bioconcentration factor > 1. Results highlights that soil contamination due to metals is occurring at the dumpsite which is also leading to transfer of metals to plants and earthworms which can pose serious risk to environment and human health. The plants identified can be used for decontamination of metals from the dumpsite. PMID- 29442192 TI - Confining annealed branched polymers inside spherical capsids. AB - The Lifshitz equation for the confinement of a linear polymer in a spherical cavity of radius R has the form of the Schrodinger equation for a quantum particle trapped in a potential well with flat bottom and infinite walls at radius R. We show that the Lifshitz equation of a confined annealed branched polymer has the form of the Schrodinger equation for a quantum harmonic oscillator. The resulting confinement energy has a 1/R4 dependence on the confinement radius R, in contrast to the case of confined linear polymers, which have a 1/R2 dependence. We discuss the application of this result to the problem of the confinement of single-stranded RNA molecules inside spherical capsids. PMID- 29442191 TI - Measurement and implications of the distance between the sphenopalatine ganglion and nasal mucosa: a neuroimaging study. AB - BACKGROUND: Historical reports describe the sphenopalatine ganglion (SPG) as positioned directly under the nasal mucosa. This is the basis for the topical intranasal administration of local anaesthetic (LA) towards the sphenopalatine foramen (SPF) which is hypothesized to diffuse a distance as short as 1 mm. Nonetheless, the SPG is located in the sphenopalatine fossa, encapsulated in connective tissue, surrounded by fat tissue and separated from the nasal cavity by a bony wall. The sphenopalatine fossa communicates with the nasal cavity through the SPF, which contains neurovascular structures packed with connective tissue and is covered by mucosa in the nasal cavity. Endoscopically the SPF does not appear open. It has hitherto not been demonstrated that LA reaches the SPG using this approach. METHODS: Our group has previously identified the SPG on 3 T MRI images merged with CT. This enabled us to measure the distance from the SPG to the nasal mucosa covering the SPF in 20 Caucasian subjects on both sides (n = 40 ganglia). This distance was measured by two physicians. Interobserver variability was evaluated using the intraclass correlation coefficient (ICC). RESULTS: The mean distance from the SPG to the closest point of the nasal cavity directly over the mucosa covering the SPF was 6.77 mm (SD 1.75; range, 4.00 11.60). The interobserver variability was excellent (ICC 0.978; 95% CI: 0.939 0.990, p < 0.001). CONCLUSIONS: The distance between the SPG and nasal mucosa over the SPF is longer than previously assumed. These results challenge the assumption that the intranasal topical application of LA close to the SPF can passively diffuse to the SPG. PMID- 29442194 TI - "I don't have to do this all by myself": Systems Navigation to Ensure Continuity of HIV Care for Persons Leaving Prison. AB - Ensuring continuity of and retention in care after release from prison is critical for optimizing health outcomes among people living with HIV. As part of a large federal initiative, we conducted qualitative interviews (n = 24) with individuals living with HIV and recently released from prison in four states to understand their experiences in different navigation interventions to improve access to HIV care post-release. Interventions were delivered only in prison, only in the community, or in both settings. While the interventions varied by design, overall, participants appreciated the breadth of support received from interventionists, including health system navigation, case management and social support. Even when individuals leaving prison were returning to clinics that they were familiar with, systems navigation supported continuity of care. Our findings elucidate why navigational support was instrumental, and underscore the value of a variety of types of navigation programs in facilitating continuity of care and reintegration post-prison. PMID- 29442195 TI - The changing epidemiology of VanB Enterococcus faecium in Poland. AB - Increasing prevalence of VanB Enterococcus faecium in Polish hospitals reported to National Reference Centre for Susceptibility Testing (NRCST) prompted us to investigate the basis of this phenomenon. Two-hundred seventy-eight E. faecium isolates of VanB phenotype from the period 1999 to 2010 obtained by NRCST were investigated by multilocus sequence typing (MLST) and multilocus VNTR analysis (MLVA). Localization, transferability, and partial structure of the vanB-carrying Tn1549 transposon were studied by hybridization, PCR mapping, sequencing, and conjugation. VanB isolates almost exclusively represented hospital-associated E. faecium, with a significant shift from representatives of 17/18 lineage to 78 lineage after 2005. The vanB determinant, initially located mostly on transferable plasmids of the pRUM-, pLG1-, and pRE25-replicon types, later on was found almost exclusively on the host chromosome. Fifteen different plasmid and chromosomal insertion sites were identified, typically associated with single transposon coupling sequences, mostly not observed before. Our study demonstrates the significant change in the epidemiology of VanB-E. faecium in Poland, associated with the introduction and spread of the lineage 78 of the hospital adapted E. faecium. These data point to the importance of the lineage 78 for the spread of vancomycin-resistance, determined by the vanB gene cluster, resulting in an increasing VRE prevalence in hospitals. This study also supports the scenario, in which representatives of the hospital-associated E. faecium independently acquire the vanB determinant de novo and spread within and among hospitals, concomitantly undergoing differentiation. PMID- 29442196 TI - QSAR study on the removal efficiency of organic pollutants in supercritical water based on degradation temperature. AB - This paper aims to study temperature-dependent quantitative structure activity relationship (QSAR) models of supercritical water oxidation (SCWO) process which were developed based on Arrhenius equation between oxidation reaction rate and temperature. Through exploring SCWO process, each kinetic rate constant was studied for 21 organic substances, including azo dyes, heterocyclic compounds and ionic compounds. We propose the concept of TR95, which is defined as the temperature at removal ratio of 95%, it is a key indicator to evaluate compounds' complete oxidation. By using Gaussian 09 and Material Studio 7.0, quantum chemical parameters were conducted for each organic compound. The optimum model is TR95 = 654.775 + 1761.910f(+)n - 177.211qH with squared regression coefficient R2 = 0.620 and standard error SE = 35.1. Nearly all the compounds could obtain accurate predictions of their degradation rate. Effective QSAR model exactly reveals three determinant factors, which are directly related to degradation rules. Specifically, the lowest f(+) value of main-chain atoms (f(+)n) indicates the degree of affinity for nucleophilic attack. qH shows the ease or complexity of valence-bond breakage of organic molecules. BOx refers to the stability of a bond. Coincidentally, the degradation mechanism could reasonably be illustrated from each perspective, providing a deeper insight of universal and propagable oxidation rules. Besides, the satisfactory results of internal and external validations suggest the stability, reliability and predictive ability of optimum model. PMID- 29442197 TI - A Lack of Aquatic Rescue Competency: A Drowning Risk Factor for Young Adults Involved in Aquatic Emergencies. AB - Drowning is an important public health issue with major impacts on young adults aged 15-24 years, yet little is known about the causal factors for drowning for this group. As young adults recreate with peers in unpatrolled aquatic environments, the capacity to perform effective and efficient rescues seems pivotal. This study examined perceived ability of young adults to perform a rescue; determined the level of aquatic rescue knowledge; and measured the effect of an aquatic rescue intervention. In total, 135 participants completed pre- and post-intervention surveys and rescue practical testing. Wilcoxon matched pairs signed rank tests were used to assess significant differences pre- and post intervention and Mann-Whitney tests used to compare groups. Pre-intervention, participants had a low level of rescue knowledge (Mdn = 50) and the relationship between perceived rescue ability and practical rescue testing was weak (rs = 0.33, p <= 0.001). Post-intervention, ability to perform a contact tow demonstrated significant improvement (z = - 9.09, p < 0.001, r = - 0.79) and rescue knowledge also improved significantly (Mdn = 100, z = - 9.42, p < 0.001, r = - 0.81). Many young adults lacked both the physical capacity and knowledge required to safely perform a rescue, a factor that may place them at increased drowning risk if they attempt an aquatic rescue. As a rescue based intervention can significantly improve competency of young adults regardless of previous experience and/or qualifications, research needs to consider how best these competencies can be promoted and/or developed with this high risk group. PMID- 29442198 TI - HGF Reduces Disease Severity and Inflammation by Attenuating the NF-kappaB Signaling in a Rat Model of Pulmonary Artery Hypertension. AB - The purpose of the present study was to investigate the anti-inflammatory effect of hepatocyte growth factor (HGF) on pulmonary artery hypertension (PAH) in a rat model and underlying mechanisms. Wistar rats were treated with monocrotaline intravenously to induce PAH and then treated with vehicle or HGF for 2 weeks, respectively. The mean pulmonary artery pressure (mPAP), the index of right heart ventricular hypertrophy (RHVI), pathological changes, and inflammation in the lungs of individual rats were measured. The levels of serum inflammatory interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), and high mobility group protein B1 (HMGB1) and the relative levels of IkappaBalpha and NF-kappaB p65 expression in the lungs of individual rats were determined by methods of enzyme-linked immunosorbent assay (ELISA) and Western blot. The levels of mPAP and RVHI in the HGF group were significantly lower than that in the PAH group (P < 0.05), but remained significantly higher than that of the control group (P < 0.05). Similar patterns of inflammatory scores and the levels of serum IL-6, TNF-alpha, ICAM-1, and HMGB1 were detected among the different groups of rats. Furthermore, the relative levels of IkappaBalpha expression in the lungs of the HGF group of rats were significantly higher than that in the control group, which were significantly higher than that in the PAH group. In contrast, the relative levels of NF-kB p65 expression in the HGF group were significantly lower than that in the PAH group (P < 0.05). HGF treatment significantly mitigated the severity of PAH and inhibited inflammation by attenuating the NF-kB signaling in the lungs of PAH rats. PMID- 29442199 TI - Multisite cardiac resynchronization therapy for traditional and non-traditional indications. AB - PURPOSE: Multisite cardiac resynchronization therapy (MSCRT) with dual-vein left ventricular (LV) pacing has theoretical advantages over conventional CRT in faster and more physiological LV activation. We aimed to define indications, feasibility, safety, acute, and long-term results of MSCRT. METHODS: All patients implanted with MSCRT during 2008-2014 in a single center were reviewed and analyzed. RESULTS: Thirty-nine patients (90% CRT-defibrillators, 64 +/- 9 years, 85% male, 74% ischemic etiology) were included. Four groups of indications were recognized: (1) significant tricuspid regurgitation (TR) in patients planned for device implantation without right ventricular lead (n = 3). Follow-up (f/u) of 4 +/- 3 years showed major symptomatic improvement in all, with stable LV size and function and deferral of valve surgery; (2) severe heart failure with reduced ejection fraction (HFrEF) and refractory ventricular tachycardia (VT) (n = 4). Except for 1 early death for acute renal failure, all others showed no VT episodes and HF improvement (f/u 4.5 +/- 0.5 years); (3) severe HFrEF and wide QRS (>= 150 ms) or failure of biventricular pacing to narrow QRS during implantation (n = 5). One patient had periprocedural mortality. The others had major clinical improvement; (4) severe HF and narrow QRS/RBBB (n = 27). 23/24 patients with available f/u of 3 +/- 1.7 years improved clinically and 57% had EF improvement. In 3 patients, LV1 was disabled and one had LV2 dislodgement. CONCLUSIONS: MSCRT is feasible, safe, and valuable in selected patients with a need to avoid RV lead during device implantation, refractory VT with no other solution, severe HFrEF with wide QRS or CRT non-responsiveness, and severe HF without LBBB. Randomized controlled studies are required. PMID- 29442201 TI - No Evidence Against Sketch Reinstatement of Context, Verbal Labels or the Use of Registered Intermediaries for Children with Autism Spectrum Disorder: Response to Henry et al. (2017). AB - Recently, Henry et al. (J Autism Dev Disord 8:2348-2362, 2017) found no evidence for the use of Verbal Labels, Sketch Reinstatement of Context and Registered Intermediaries by forensic practitioners when interviewing children with a diagnosis of autism spectrum disorder. We consider their claims, noting the limited ecological validity of the experimental paradigm, the impacts of repeated interviewing where retrieval support is not provided at first retrieval, question the interviewer/intermediary training and their population relevant experience, and comment on the suppression of population variances. We submit that rejecting these techniques on the basis of this study is completely unwarranted and potentially damaging, particularly if used in legal proceedings to undermine the value of testimony from children with ASD, who continually struggle to gain access to justice. PMID- 29442200 TI - Seasonal occurrence, source evaluation and ecological risk assessment of polycyclic aromatic hydrocarbons in industrial and agricultural effluents discharged in Wadi El Bey (Tunisia). AB - Polycyclic aromatic hydrocarbons are of great concern due to their persistence, bioaccumulation and toxic properties. The occurrence, source and ecological risk assessment of 26 polycyclic aromatic hydrocarbons in industrial and agricultural effluents affecting the Wadi El Bey watershed were investigated by means of gas chromatographic/mass spectrometric analysis (GC/MS). Total PAHs (? 26 PAH) ranged from 1.21 to 91.7 ug/L. The 4- and 5-ring compounds were the principal PAHs detected in most of 5 sites examined. Diagnostic concentration ratios and molecular indices were performed to identify the PAH sources. Results show that PAHs could originate from petrogenic, pyrolytic and mixed sources. According to the ecotoxicological assessment, the potential risk associated with PAHs affecting agricultural and industrial effluents ranged from moderate to high for both aquatic ecosystem and human health. The toxic equivalency factor (TEF) approach indicated that benzo[a]pyrene and benz[a]anthracene were the principal responsible for carcinogenic power of samples. PMID- 29442202 TI - Anti-inflammatory effect of oligostilbenoids from Vitis heyneana in LPS stimulated RAW 264.7 macrophages via suppressing the NF-kappaB activation. AB - BACKGROUND: Vitis heyneana is widely distributed in the north of Vietnam, it has been used in Vietnamese traditional medicine as an agent for treatment of arthritis, bronchitis, carbuncles and inflammatory conditions, and menstrual irregularities. However, this plant has not been investigated in phytochemical constituents and biological effects, especially in the anti-inflammatory property. RESULTS: Bioassay-guided fractionation of the EtOAc soluble fraction from the aerial part of Vitis heyneana resulted in the isolation of a series of oligostilbenoids as piceid (1), 2-r-viniferin (2), betulifol A (3), vitisinol C (4), (-)-trans-epsilon-viniferin (5), alpha-viniferin (6), shoreaketon (7), amurensin B (8), vitisinol B (9), and cis-vitisin B (10). Compound 5 showed the most potent inhibitory activities by suppressing LPS-induced COX-2 expression and PGE2 production. This compound exhibited significantly reduced LPS-induced nitric oxide (NO) release in a dose-dependent manner. These effects are accompanied with the inhibition of transcription factor NF-kappaB activation. CONCLUSION: The results suggested that trans-epsilon-viniferin exerts anti-inflammatory effects via suppression the NF-kappaB activation in RAW 264.7 cells. PMID- 29442203 TI - Cyclic vomiting syndrome: epidemiology, diagnosis, and treatment. AB - Cyclic-vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder characterized by recurrent episodes of nausea and vomiting. Although once thought to be a pediatric disorder, there has been a considerable increase in recognition of CVS in adults. The exact pathogenesis is unknown and several theories have been proposed. Migraine and CVS share a similar pathophysiology as suggested by several studies. Since there are no specific biomarkers available for this disorder, physicians should rely on Rome criteria for the diagnosis. Due to the lack of randomized control trials, the treatment of CVS is primarily empirical. PMID- 29442205 TI - Antibacterial and immunomodulatory activities of bovine lactoferrin against Escherichia coli O157:H7 infections in cattle. AB - Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a zoonotic pathogen that causes food-borne disease in humans ranging from watery diarrhea to bloody diarrhea and severe hemorrhagic colitis, renal failure and hemolytic uremic syndrome. Cattle, the most important source of E. coli O157:H7 transmission to humans, harbor the bacteria in their gastrointestinal tract without showing clinical symptoms. Prevention of E. coli O157:H7 infections in ruminants could diminish the public health risk. However, there is no specific treatment available nor a vaccine or a therapeutic agent which completely prevents E. coli O157:H7 infections in cattle. This paper provides an overview of latest research data on eradicating enterohemorrhagic E. coli O157:H7 in ruminants by use of bovine lactoferrin administration. The article provides insights into the anti microbial and immunomodulatory activities of bovine lactoferrin against E. coli O157:H7 infections in cattle. PMID- 29442204 TI - Relationship between retinal artery trajectory and axial length in Japanese school students. AB - PURPOSE: The trajectories of the supratemporal and infratemporal retinal arteries are associated with the position of the nerve fiber layer defects of glaucomatous eyes. However, no reports have thus far been published on changes in the retinal artery trajectory (RA trajectory) along with growth. Thus, the purpose of this study was to investigate the differences in the RA trajectories of elementary and junior high school students and the associations with axial length (AL). STUDY DESIGN: Prospective cross-sectional observational study. METHODS: In total, 122 right eyes of healthy elementary school students (61 boys, 61 girls) and 170 right eyes of healthy junior high school students (83 boys, 87 girls) were studied. The AL was measured and color fundus photographs were taken, and used for the analysis. The RA trajectory was plotted in the color fundus photographs and fitted to a second-degree polynomial equation, [Formula: see text], using ImageJ. The coefficient "a" represented the steepness of the trajectories. The differences in the RA trajectories and ALs of elementary and junior high school students were determined using the Mann-Whitney test. The association between the RA trajectory and AL was determined using the Spearman rank correlation. RESULTS: The AL and the RA trajectory of the junior high school students were significantly greater than those of the elementary school students (P < 0.001). The RA trajectory was significantly associated with the AL in both elementary (r = 0.26, P = 0.005) and junior high (r = 0.32, P < 0.001) school students. CONCLUSIONS: Junior high school students have a longer AL and narrower RA trajectory than do elementary school students. A longer AL is associated with a narrower RA trajectory in both elementary and junior high school students. PMID- 29442206 TI - Thrown into the world of independent practice: from unexpected uncertainty to new identities. AB - One of the most exciting yet stressful times in a physician's life is transitioning from supervised training into independent practice. The majority of literature devoted to this topic has focused upon a perceived gap between clinical and non-clinical skills and interventions taken to address it. Building upon recent streams of scholarship in identity formation and adaptation to new contexts, this work uses a Heideggerian perspective to frame an autoethnographical exploration of the author's transition into independent paediatric practice. An archive of reflective journal entries and personal communications was assembled from the author's first 3 years of practice in four different contexts and analyzed using Heidegger's linked existentials of understanding, attunement and discourse. Insights from his journey suggest this period is a time of anxiety and vulnerability when one questions one's competence and very identity as a medical professional. At the same time, it illustrates the inseparable link between practitioners and the network of relationships in which they are bound, how these relationships contextually vary and how recognizing and tuning to these differences may allow for a more seamless transition. While this work is the experience of one person, its insights support the ideas that change is a constant in professional practice and competence is contextual. As a result, developing educational content that inculcates contextual flexibility and an increased comfort level with uncertainty may prepare our trainees not just to navigate the unavoidable novelty of transition, but lay the groundwork for professional identities attuned to engage more broadly with change itself. PMID- 29442207 TI - I'm shocked: informed consent in ECT and the phenomenological-self. AB - This paper argues that phenomenological insights regarding selfhood are relevant to the informed consent process in the treatment of depression using electro convulsive therapy (ECT). One of the most significant side-effects associated with ECT is retrograde amnesia. Unfortunately, the current informed consent model does not adequately appreciate the full extent in which memory loss disturbs lived-experience. Through the philosophy of Merleau-Ponty, it is possible to appreciate the way in which memory loss affects a person's self-experience, with emphasis given to one's pre-reflective and embodied, relationship with things in the world. This paper aims to demonstrate that proper informed consent should acknowledge the extent to which repeated ECT treatments affect a patient's sense self. PMID- 29442208 TI - The role of acyl-CoA thioesterase ACOT8I in mediating intracellular lipid metabolism in oleaginous fungus Mortierella alpina. AB - Thioesterases (TEs) play an essential role in the metabolism of fatty acids (FAs). To explore the role of TEs in mediating intracellular lipid metabolism in the oleaginous fungus Mortierella alpina, the acyl-CoA thioesterase ACOT8I was overexpressed. The contents of total fatty acids (TFAs) were the same in the recombinant strains as in the wild-type M. alpina, whilst the production of free fatty acids (FFAs) was enhanced from about 0.9% (wild-type) to 2.8% (recombinant), a roughly threefold increase. Linoleic acid content in FFA form constituted about 9% of the TFAs in the FFA fraction in the recombinant strains but only about 1.3% in the wild-type M. alpina. The gamma-linolenic acid and arachidonic acid contents in FFA form accounted for about 4 and 25%, respectively, of the TFAs in the FFA fraction in the recombinant strains, whilst neither of them in FFA form were detected in the wild-type M. alpina. Overexpression of the TE ACOT8I in the oleaginous fungus M. alpina reinforced the flux from acyl-CoAs to FFAs, improved the production of FFAs and tailored the FA profiles of the lipid species. PMID- 29442209 TI - Capillary rarefaction and altered renal development: the imbalance between pro- and anti-angiogenic factors in response to angiotensin II inhibition in the developing rat kidney. AB - Proper and timely assembly of the kidney vasculature with their respective nephrons is crucial during normal kidney development. In this study, we investigated the effects of enalapril (angiotensin-converting enzyme inhibitor) on angiogenesis-related gene expression and microvascular endothelium related to glomeular and tubular changes in the neonatal rat kidney. Enalapril-treated rats had higher tubular injury scores and lower glomerular maturity grades than those of untreated rats. In the enalapril-treated group, intrarenal angiopoietin-2, Tie 2, and thrombospondin-1 protein expression increased, whereas intrarenal angiopoietin-1 protein expression decreased. JG12-positive glomerular and peritubular capillary staining was reduced in the enalapril-treated rat kidney. The number of JG12-positive capillary endothelial cells was directly correlated with glomerular maturation grade and was inversely related with the tubular injury. Our findings suggest the imbalance between pro- and anti-angiogenic factors may be implicated in the loss of capillaries in associated with impaired nephrogenesis after angiotensin II blockade in the developing rat kidney. PMID- 29442210 TI - Proteasome inhibition and mechanism of resistance to a synthetic, library-based hexapeptide. AB - Background The hexapeptide 4A6 (Ac-Thr(tBu)-His(Bzl)-Thr(Bzl)-Nle-Glu(OtBu)-Gly Bza) was isolated from a peptide library constructed to identify peptide-based transport inhibitors of multidrug resistance (MDR) efflux pumps including P glycoprotein and Multidrug Resistance-associated Protein 1. 4A6 proved to be a substrate but not an inhibitor of these MDR efflux transporters. In fact, 4A6 and related peptides displayed potent cytotoxic activity via an unknown mechanism. Objective To decipher the mode of cytotoxic activity of 4A6. Methods Screening of 4A6 activity was performed against the NCI60 panel of cancer cell lines. Possible interactions of 4A6 with the 26S proteasome were assessed via proteasome activity and affinity labeling, and cell growth inhibition studies with leukemic cells resistant to the proteasome inhibitor bortezomib (BTZ). Results The NCI60 panel COMPARE analysis revealed that 4A6 had an activity profile overlapping with BTZ. Consistently, 4A6 proved to be a selective and reversible inhibitor of beta5 subunit (PSMB5)-associated chymotrypsin-like activity of the 26S proteasome. This conclusion is supported by several lines of evidence: (i) inhibition of chymotrypsin-like proteasome activity by 4A6 and related peptides correlated with their cell growth inhibition potencies; (ii) 4A6 reversibly inhibited functional beta5 active site labeling with the affinity probe BodipyFL-Ahx3L3VS; and (iii) human myeloid THP1 cells with acquired BTZ resistance due to mutated PSMB5 were highly (up to 287-fold) cross-resistant to 4A6 and its related peptides. Conclusion 4A6 is a novel specific inhibitor of the beta5 subunit-associated chymotrypsin-like proteasome activity. Further exploration of 4A6 as a lead compound for development as a novel proteasome-targeted drug is warranted. PMID- 29442211 TI - Circulating Tumor Cells Predict Occult Metastatic Disease and Prognosis in Pancreatic Cancer. AB - BACKGROUND: Occult metastatic tumors, below imaging thresholds, are a limitation of staging systems that rely on cross-sectional imaging alone and are a cause of the routine understaging of pancreatic ductal adenocarcinomas (PDACs). We investigated circulating tumor cells (CTCs) as a preoperative predictor of occult metastatic disease and as a prognostic biomarker for PDAC patients. EXPERIMENTAL DESIGN: A total of 126 patients (100 with cancer, 26 with benign disease) were enrolled in our study and CTCs were identified and enumerated from 4 mL of venous blood using the microfluidic NanoVelcro assay. CTC enumeration was correlated with clinicopathologic variables and outcomes following both surgical and systemic therapies. RESULTS: CTCs were identified in 78% of PDAC patients and CTC counts correlated with increasing stage (rho = 0.42, p < 0.001). Of the 53 patients taken for potentially curative surgery, 13 (24.5%) had occult metastatic disease intraoperatively. Patients with occult disease had significantly more CTCs than patients with local disease only (median 7 vs. 1 CTC, p < 0.0001). At a cut-off of three or more CTCs/4 mL, CTCs correctly identified patients with occult metastatic disease preoperatively (area under the receiver operating characteristic curve 0.82, 95% confidence interval (CI) 0.76-0.98, p < 0.0001). CTCs were a univariate predictor of recurrence-free survival following surgery [hazard ratio (HR) 2.36, 95% CI 1.17-4.78, p = 0.017], as well as an independent predictor of overall survival on multivariate analysis (HR 1.38, 95% CI 1.01 1.88, p = 0.040). CONCLUSIONS: CTCs show promise as a prognostic biomarker for PDAC patients at all stages of disease being treated both medically and surgically. Furthermore, CTCs demonstrate potential as a preoperative biomarker for identifying patients at high risk of occult metastatic disease. PMID- 29442212 TI - Spatial clustering of childhood cancers in Switzerland: a nationwide study. AB - PURPOSE: Childhood cancers are rare and little is known about their etiology. Potential risk factors include environmental exposures that might implicate spatial variation of cancer risk. Previous studies of spatial clustering have mainly focused on childhood leukemia. We investigated spatial clustering of different childhood cancers in Switzerland using exact geocodes of place of residence. METHODS: We included 6,034 cancer cases diagnosed at age 0-15 years during 1985-2015 from the Swiss Childhood Cancer Registry. Age and sex-matched controls (10 per case) were randomly sampled from the national censuses (1990, 2000, 2010). Geocodes of place of residence were available at birth and diagnosis for both cases and controls. We used the difference in k-functions and Cuzick Edwards test to assess global clustering and Kulldorff's circular scan to detect individual clusters. We also carefully adjusted for multiple testing. RESULTS: After adjusting for multiple testing, we found no evidence of spatial clustering of childhood cancers neither at birth (p = 0.43) nor diagnosis (p = 0.13). Disregarding multiple testing, results of individual tests indicated spatial clustering of all childhood cancers combined (p < 0.01), childhood lymphoma (p = 0.01), due to Hodgkin lymphoma (HL) (p = 0.02) at diagnosis, and embryonal tumors of the central nervous system (CNS) at birth and diagnosis, respectively (p = 0.05 and p = 0.02). CONCLUSIONS: This study provides weak evidence of spatial clustering of childhood cancers. Evidence was strongest for HL and embryonal CNS tumors, adding to the current literature that these cancers cluster in space. PMID- 29442213 TI - Elbow Injuries in the Adolescent Thrower. AB - PURPOSE OF REVIEW: With an increasing rate of adolescent elbow injuries, especially in throwing athletes, the purpose of this review is to investigate the current literature regarding the diagnosis, treatment, and non-operative and operative outcomes of medial epicondyle fractures, ulnar collateral ligament repair, osteochondritis dissecans of the elbow, and olecranon stress fractures. RECENT FINDINGS: Acceptable outcomes with both non-operative and operative treatments of medial epicondyle fractures have been reported, with surgical indications continuing to evolve. Unstable osteochondritis dissecans lesions, especially in patients with closed growth plates, require operative fixation, and emerging open and arthroscopic techniques including lesion debridement, marrow stimulation, autograft transfer, and allograft transplantation are described with good outcomes. Ulnar collateral repair has emerged as an exciting treatment option for an avulsion of either end of the ligament in young throwing athletes, with faster rehabilitation times than traditional ulnar collateral ligament reconstruction. Olecranon stress fractures are increasing in prevalence, and when a non-operative treatment course is unsuccessful, athletes have a high return-to play rate after percutaneous cannulated screw placement. With proper indications, non-operative and operative treatment modalities are reported with a high return to-play and acceptable clinical outcomes for common elbow injuries, including medial epicondyle fractures, ulnar collateral ligament repair, osteochondritis dissecans of the elbow, and olecranon stress fractures, in adolescent throwing athletes. Further research is needed to better define treatment algorithms, surgical indications, and outcomes. PMID- 29442214 TI - En masse lentiviral gene delivery to mouse fertilized eggs via laser perforation of zona pellucida. AB - Lentiviruses are highly efficient vehicles for delivering genes into cells. They readily transduce primary and immortalized cells in vivo and in vitro. Genes delivered by lentiviruses are incorporated and replicated as part of their host genome and therefore offer a powerful tool for creation of stable cell lines and transgenic animals. However, the zona pellucida surrounding the fertilized eggs acts as a barrier and hinders lentiviral transduction of embryos. Here, we utilize a laser, typically used to perforate the zona pellucida for in vitro fertilization, to permeabilize the zona for lentiviral gene delivery. A single hole in the zona is sufficient for the lentivirus to gain access to fertilized eggs without the need for microinjection for en masse gene delivery. Embryos generated by this method elicit no damage and can develop to term for creation of transgenic animals. PMID- 29442215 TI - Meta-analysis for psychological impact of breast reconstruction in patients with breast cancer. AB - AIMS: This meta-analysis aimed to evaluate the impact of breast reconstruction on the psychological aspects in patients with breast cancer. METHODS: A literature search on PubMed, Embase, ScienceDirect and Google scholar databases was conducted up to September 2017. The pooled risk radio (RR) or standard mean difference (SMD) and the corresponding 95% confidence intervals (CIs) were calculated using the RevMan 5.3 software. RESULTS: A total of 5 studies were included in this meta-analysis. There were 551 breast cancer patients receiving mastectomy plus breast reconstruction and 574 breast cancer patients receiving mastectomy alone. The results showed that breast reconstruction can significantly decrease the incidence of anxiety (RR = 0.62, 95% CI 0.47-0.82, P = 0.0006)/depression (RR = 0.54, 95% CI 0.32-0.93, P = 0.02) and scale score for evaluating anxiety (SMD = - 0.20, 95% CI - 0.37 to - 0.03, P = 0.02)/depression (SMD = - 0.22, 95% CI - 0.39 to - 0.66, P = 0.007) compared with mastectomy alone. CONCLUSIONS: Breast reconstruction after mastectomy was benefit for improving the psychological damages in patients with breast cancer. PMID- 29442216 TI - Psychiatric comorbidities among patients undergoing liver transplantation in South Korea: a nationwide population-based study. AB - OBJECTIVES: The aim of this study was to analyze the prevalence of mental disorders in patients undergoing liver transplantation (LT) based on claims data from the Health Insurance Review and Assessment Service (HIRA) in South Korea. METHODS: We confirmed mental disorders in a nationwide cohort of 3758 patients receiving LT between January 2010 and December 2014. We categorized the prevalence of mental disorders based on patient age at the time of LT. RESULTS: A total of 288 patients for LT were diagnosed with a mental disorder 1 year before their cancer diagnosis. Of those patients, depression was present in 90 (31.25%) and anxiety in 92 (31.9%) patients at the first diagnosis. The overall frequency of mental disorders peaked just before LT, and substance abuse was the most prevalent mental disorder before LT. The risk of mental disorders after LT was significantly lower in those with hepatocellular carcinoma (HCC) than in those without HCC (hazard ratio = 1.70, p < 0.001). CONCLUSIONS: Mental disorders in patients receiving LT showed different patterns of prevalence depending on age at the time of surgery and the nature of underlying diseases. Personalized intervention based on patient characteristics could improve the quality of life. PMID- 29442218 TI - Revisiting The Depleted Self. AB - This article revisits Donald Capps's book The Depleted Self (The depleted self: sin in a narcissistic age. Fortress Press, Minneapolis, 1993), which grew out of his 1990 Schaff Lectures at Pittsburgh Theological Seminary. In these lectures Capps proposed that the theology of guilt had dominated much of post-Reformation discourse. But with the growing prevalence of the narcissistic personality in the late twentieth century, the theology of guilt no longer adequately expressed humanity's sense of "wrongness" before God. Late twentieth-century persons sense this disjunction between God and self through shame dynamics. Narcissists are not "full" of themselves, as popular perspectives might indicate. Instead, they are empty, depleted selves. Psychologists suggest this stems from lack of emotional stimulation and the absence of mirroring in the early stages of life. The narcissist's search for attention and affirmation takes craving, paranoid, manipulative, or phallic forms and is essentially a desperate attempt to fill the internal emptiness. Capps suggests that two narratives from the Gospels are helpful here: the story of the woman with the alabaster jar and the story of Jesus's dialogue with Mary and John at Calvary. These stories provide us with clues as to how depleted selves experienced mirroring and the potential for internal peace in community with Jesus. PMID- 29442217 TI - Large-scale total synthesis of 13C3-labeled citrinin and its metabolite dihydrocitrinone. AB - The analysis of the nephrotoxic mycotoxin citrinin in food, feed, and physiological samples is still challenging. Nowadays, liquid chromatography coupled with mass spectrometry is the method of choice for achieving low limits of detection. But matrix effects can present impairments for this method. Stable isotope dilution analysis can prevent some of these problems. Therefore, a stable isotopically labeled standard of citrinin for use in stable isotope dilution analysis was synthesized on large scale. The improved diastereoselective total synthetic strategy offered the possibility to introduce three 13C-labels in two steps by ortho-toluate anion chemistry. This led to a mass difference of 3 Da, sufficient for preventing spectral overlap. Additionally, a stable isotopically labeled form of dihydrocitrinone, the main urinary metabolite of citrinin, was synthesized with the same mass difference. This was achieved by a sequence of cyclisation, oxidation, deprotection, and carboxylation reactions starting from a protected intermediate of the labeled citrinin synthesis. Thus, this method also offers a complete way to synthesize dihydrocitrinone from citrinin on large scale. PMID- 29442219 TI - A case of mixed adenoneuroendocrine carcinoma of the pancreas mimicking intraductal papillary mucinous carcinoma. AB - A previously healthy 52-year-old man was referred to our hospital for further evaluation of main pancreatic duct dilatation. The preoperative work-up was consistent with intraductal papillary mucinous carcinoma (IPMC) derived from a mixed type intraductal papillary mucinous neoplasm (IPMN), because multilocular cysts with enhancing thickened pancreatic head walls and dilated pancreatic ducts lined with dysplastic mucinous epithelium, with papillary proliferation from the pancreatic body to the tail, were observed; in addition, the pancreatic juice cytology was class V, which is suggestive of adenocarcinoma. Total pancreatectomy was performed because a definite mass was not found before surgical resection and the tumors could have spread to the tail. The pathological diagnosis was mixed adenoneuroendocrine carcinoma of the pancreatic head. IPMN with high- or low grade dysplasia was not observed anywhere in the pancreatic duct. The pancreatic ductal adenocarcinoma consisted of large caliber malignant glands with intraluminal flat or papillary structures; therefore, we were unable to recognize a definite pancreatic mass before surgical resection, and suspected an IPMC derived from a mixed type IPMN. PMID- 29442220 TI - Methylquercetins stimulate melanin biosynthesis in a three-dimensional skin model. AB - In a previous study, we found that both synthetic 3-O-methylquercetin (3MQ) and 3,4',7-O-trimethylquercetin (34'7TMQ) increased extracellular melanin content. 34'7TMQ increased the activity of melanogenic enzymes by stimulating the p38 pathway and the expression of microphthalmia-associated transcription factor (MITF). In contrast, 3MQ increased the activity of melanogenic enzymes without the involvement of MITF, which suggests that 3MQ inhibits the degradation of melanogenic enzymes. In the present study, we investigated the effects of 3MQ and 34'7TMQ on melanogenesis in normal human melanocytes and using a commercial three dimensional (3D) skin model system. Both 3MQ and 34'7TMQ elongated the dendrites of normal human melanocytes from a Caucasian donor, but did not stimulate melanogenesis in the melanocytes. In the 3D skin model, which included melanocytes from an Asian donor, 3MQ and 34'7TMQ increased and elongated the melanocytes and showed a tendency to stimulate melanogenesis. These results suggest that 3MQ and 34'7TMQ could be put to practical use in skin care products and agents aimed at preventing hair graying. PMID- 29442221 TI - Dual-Stained Cervical Cytology and Histology with Claudin-1 and Ki67. AB - Several biomarkers are in use to improve the sensitivity and specificity of cervical cancer screening. Previously, increased expression of tight junction protein claudin-1 (CLDN1) was detected in premalignant and malignant cervical lesions and applied for cytology screening. To improve the specificity, a double immunoreaction with CLDN1/Ki67 was developed in the recent study. Parallel p16/Ki67 (CINtec(r) PLUS) and CLDN1/Ki67 dual-stained cytology and histology were performed and compared. p16/Ki67 immunoreaction showed positivity in 317 out of 1596 smears with negativity in 1072 and unacceptable reactions in 207 samples. CLDN1/Ki67 dual staining was positive in 200 of 1358 samples, negative in 962, whereas 196 smears could not be evaluated due to technical reasons. Considering the high-grade squamous intraepithelial lesion cytology as gold standard, sensitivity of CLDN1/Ki67 reaction was 76%, specificity was 85.67%, while for p16/Ki67 sensitivity was 74% and specificity was 81.38%. Comparison of CLDN1/Ki67 and p16/Ki67 dual stainings showed the results of the two tests not to be significantly different. Analysing histological slides from 63 cases, the results of the two tests agreed perfectly. As conclusion the sensitivity and specificity proved to be similar using p16/Ki67 and CLDN1/Ki67 double immunoreactions both on LBC samples and on histological slides. PMID- 29442222 TI - Novel Methods for Environmental Assessment of Pedestrian Injury: Creation and Validation of the Inventory for Pedestrian Safety Infrastructure. AB - Nationally, 80% of pedestrian fatalities occur in urban environments, yet the distribution of injuries across urban areas is not uniform. Identifying street level risk factors for pedestrian injury is essential for urban planning and improvement projects, as well as targeted injury prevention efforts. However, creating and maintaining a comprehensive database of a city's traffic safety infrastructure can be cumbersome and costly. The purpose of this study was to create and validate a neighborhood environmental observational assessment tool to capture evidence-based pedestrian safety infrastructure using Google Street View (GSV)-The Inventory for Pedestrian Safety Infrastructure (IPSI). We collected measures in-person at 172 liquor stores in Baltimore City from June to August 2015 to assess the tool's reliability; we then collected IPSI measures at the same 172 locations using GSV from February to March 2016 to assess IPSI reliability using GSV. The majority of items had good or excellent levels of inter-rater reliability (ICC >= 0.8), with intersection features showing the highest agreement across raters. Two scales were also developed using exploratory factor analysis, and both showed strong internal consistency (Cronbach's alpha >= 0.6). The IPSI provides a valid, economically efficient tool for assessing pedestrian safety infrastructure that can be employed for a variety of research and urban planning needs. It can also be used for in-person or GSV observation. Reliable and valid measurement of pedestrian safety infrastructure is essential to effectively prevent future pedestrian injuries. PMID- 29442223 TI - Beneficial Role of Low-Intensity Laser Irradiation on Neural beta-tubulin III Protein Expression in Human Bone Marrow Multipotent Mesenchymal Stromal Cells. AB - The purpose of the present study was to evaluate the neural protein expression pattern of human multipotent mesenchymal stromal cells (hMSCs) treated with forskolin (free-form/FF). The study investigated forskolin's capacity to enhance intracellular levels of cyclic adenosine monophosphate (cAMP) by activating adenylate cyclase and probably by inducing neuron-like cells in vitro. In addition, because nanotechnology is a growing field of tissue engineering, we also assessed the action of a new system called the nanostructured-forskolin (NF) to examine the improvement of drug delivery. Afterwards, the cells were submitted to low-level laser irradiation to evaluate possible photobiostimulatory effects. Investigations using the immunofluorescence by confocal microscopy and Western blot methods revealed the expression of the neuronal marker beta-tubulin III. Fluorescence intensity quantification analysis using INCell Analyzer System for beta-tubulin III was used to examine significant differences. The results showed that after low-level laser irradiation exposure, there was a tendency to increase the beta-tubulin III expression in all groups, as expected in the photobiostimulation process. Notably, this process induced for irradiation was more pronounced in irradiated nanoforskolin cells (INF) compared to non irradiated free-forskolin control cells (NFFC). However, there was also an increase in beta-tubulin III protein expression in the groups: irradiated nanocontrol cells (INC) compared to non-irradiated free-forskolin control cells (NFF) and after treatment with non-irradiated free-forskolin (NFF) and non irradiated nanoforskolin (NNFC). We concluded that the methods using low-level laser irradiation and/or nanoparticles showed an up-regulation of neural-protein expression in hMSCs that could be used to facilitate cellular therapy protocols in the near future. PMID- 29442224 TI - Vitamin C and sodium bicarbonate enhance the antioxidant ability of H9C2 cells and induce HSPs to relieve heat stress. AB - Heat stress is exacerbated by global warming and affects human and animal health, leading to heart damage caused by imbalances in reactive oxygen species (ROS) and the antioxidant system, acid-base chemistry, electrolytes and respiratory alkalosis. Vitamin C scavenges excess ROS, and sodium bicarbonate maintains acid base and electrolyte balance, and alleviates respiratory alkalosis. Herein, we explored the ability of vitamin C alone and in combination with equimolar sodium bicarbonate (Vitamin C-Na) to stimulate endogenous antioxidants and heat shock proteins (HSPs) to relieve heat stress in H9C2 cells. Control, vitamin C (20 MUg/ml vitamin C for 16 h) and vitamin C-Na (20 MUg/ml vitamin C-Na for 16 h) groups were heat-stressed for 1, 3 or 5 h. Granular and vacuolar degeneration, karyopyknosis and damage to nuclei and mitochondria were clearly reduced in treatment groups, as were apoptosis, lactate dehydrogenase activity and ROS and malondialdehyde levels, while superoxide dismutase activity was increased. Additionally, CRYAB, Hsp27, Hsp60 and Hsp70 mRNA levels were upregulated at 3 h (p < 0.01), and protein levels were increased for CRYAB at 0 h (p < 0.05) and 1 h (p < 0.01), and for Hsp70 at 3 and 5 h (p < 0.01). Thus, pre-treatment with vitamin C or vitamin C-Na might protect H9C2 cells against heat damage by enhancing the antioxidant ability and upregulating CRYAB and Hsp70. PMID- 29442225 TI - Feeder-cell-independent culture of the pig embryonic stem cell-derived exocrine pancreatic cell line, PICM-31. AB - The adaptation to feeder-independent growth of a pig embryonic stem cell-derived pancreatic cell line is described. The parental PICM-31 cell line, previously characterized as an exocrine pancreas cell line, was colony-cloned two times in succession resulting in the derivative cell line, PICM-31A1. PICM-31A1 cells were adapted to growth on a polymerized collagen matrix using feeder cell-conditioned medium and were designated PICM-31FF. Like the parental cells, the PICM-31FF cells were small and grew relatively slowly in closely knit colonies that eventually coalesced into a continuous monolayer. The PICM-31FF cells were extensively cultured: 40 passages at 1:2, 1:3, and finally 1:5 split ratios over a 1-yr period. Ultrastructure analysis showed the cells' epithelial morphology and revealed that they retained their secretory granules typical of pancreas acinar cells. The cells maintained their expression of digestive enzymes, including carboxypeptidase A1 (CPA1), amylase 2A (AMY2A), and phospholipase A2 (PLA2G1B). Alpha-fetoprotein (AFP), a fetal cell marker, continued to be expressed by the cells as was the pancreas alpha cell-associated gene, transthyretin. Several pancreas-associated developmental genes were also expressed by the cells, including pancreatic and duodenal homeobox 1 (PDX1) and pancreas-specific transcription factor, 1a (PTF1A). Proteomic analysis of cellular proteins confirmed the cells' production of digestive enzymes and showed that the cells expressed cytokeratin-8 and cytokeratin-18. The PICM-31FF cell line provides an in vitro model of fetal pig pancreatic exocrine cells without the complicating presence of feeder cells. PMID- 29442227 TI - Complete coding sequence of a novel picorna-like virus in a blackbird infected with Usutu virus. AB - Using random high-throughput RNA sequencing, the complete coding sequence of a novel picorna-like virus (a 9,228-nt contig containing 212,202 reads) was determined from a blackbird (Turdus merula) infected with Usutu virus. This sequence shares only 36% amino acid sequence identity with its closest homolog, arivirus 1, (an unclassified member of the order Picornavirales), and shares its dicistronic genome arrangement. The new virus was therefore tentatively named "blackbird arilivirus" (ari-like virus). The nearly complete genome sequence consists of at least 9,228 nt and contains two open reading frames (ORFs) encoding the nonstructural polyprotein (2235 amino acids) and structural polyprotein (769 amino acids). Two TaqMan RT-qPCR assays specific for ORF1 confirmed the presence of high levels of this novel virus in the original sample. Nucleotide composition analysis suggests that blackbird arilivirus is of dietary (plant) origin. PMID- 29442226 TI - Molecular evolution and phylodynamics of hepatitis B virus infection circulating in Iran. AB - Previous local and national Iranian publications indicate that all Iranian hepatitis B virus (HBV) strains belong to HBV genotype D. The aim of this study was to analyze the evolutionary history of HBV infection in Iran for the first time, based on an intensive phylodynamic study. The evolutionary parameters, time to most recent common ancestor (tMRCA), and the population dynamics of infections were investigated using the Bayesian Monte Carlo Markov chain (BMCMC). The effective sample size (ESS) and sampling convergence were then monitored. After sampling from the posterior distribution of the nucleotide substitution rate and other evolutionary parameters, the point estimations (median) of these parameters were obtained. All Iranian HBV isolates were of genotype D, sub-type ayw2. The origin of HBV is regarded as having evolved first on the eastern border, before moving westward, where Isfahan province then hosted the virus. Afterwards, the virus moved to the south and west of the country. The tMRCA of HBV in Iran was estimated to be around 1894, with a 95% credible interval between the years 1701 and 1957. The effective number of infections increased exponentially from around 1925 to 1960. Conversely, from around 1992 onwards, the effective number of HBV infections has decreased at a very high rate. Phylodynamic inference clearly demonstrates a unique homogenous pattern of HBV genotype D compatible with a steady configuration of the decreased effective number of infections in the population in recent years, possibly due to the implementation of blood donation screening and vaccination programs. Adequate molecular epidemiology databases for HBV are crucial for infection prevention and treatment programs. PMID- 29442230 TI - Challenges and opportunities in refugee mental health: clinical, service, and research considerations. PMID- 29442229 TI - Long-term safety and efficacy of guanfacine extended release in children and adolescents with ADHD. AB - Data are reported from SPD503-318, a phase 3, open-label, safety study of guanfacine extended release (GXR) in European children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants received dose optimized GXR (1-7 mg/day) for up to 2 years. Of 215 enrolled participants, 214 were included in the safety population and 133 completed the study. Participants' mean age was 11.7 years and 73.8% were male. Overall, 177 participants (82.7%) experienced a treatment-emergent adverse event (TEAE). TEAEs reported in at least 10% of participants were somnolence (36.0%), headache (28.5%), fatigue (20.1%), and nasopharyngitis (11.7%). Serious TEAEs were reported in 4.7% of participants and TEAEs leading to discontinuation were reported in 3.3% of participants. There were no deaths. Mean z-scores for BMI were stable throughout the study. The incidence of sedative TEAEs (somnolence, sedation, and hypersomnia) peaked during week 3 and decreased thereafter. Small changes from baseline to the final assessment in mean supine pulse [- 5.5 bpm (standard deviation, 12.98)] and blood pressure [systolic, 0.6 mmHg (9.32); diastolic, 0.2 mmHg (9.17)] were reported. ADHD symptoms initially decreased and remained significantly lower than baseline at study endpoint. At the final assessment, the mean change in ADHD-RS-IV total score from baseline was - 19.8 (standard error of mean, 0.84; nominal p < 0.0001). In conclusion, GXR was well tolerated and more than 60% of participants completed the 2-year study. PMID- 29442228 TI - Effect of an 88-amino-acid deletion in nsp2 of porcine reproductive and respiratory syndrome virus on virus replication and cytokine responses in vitro. AB - Previously, a spontaneous 88-amino-acid (aa) deletion in nsp2 was associated with cell-adaptation of porcine reproductive and respiratory syndrome virus (PRRSV) strain JXM100, which arose during passaging of the highly pathogenic PRRSV (HP PRRSV) strain JX143 in MARC-145 cells. Here, to elucidate the biological role of this deletion, we specifically deleted the region of a cDNA clone of HP-PRRSV strain JX143 (pJX143) corresponding to these 88 amino acids. The effect of the deletion on virus replication in cultured cells and transcriptional activation of inflammatory cytokines and chemokines in pulmonary alveolar macrophages (PAMs) was examined. Mutant virus with the 88-aa deletion in nsp2 (rJX143-D88) had faster growth kinetics and produced larger plaques in MARC-145 cells than the parental virus (rJX143), suggesting that the deletion enhanced virus replication in MARC-145 cells. In contrast, the overall yield of rJX143 was almost 1 log higher than that of rJX143-D88, suggesting that the 88-aa deletion in nsp2 decreased the production of infectious viruses in PAMs. Infection with the mutant virus with the 88-aa deletion resulted in increased mRNA expression of type I interferon (IFN-alpha and IFN-beta) and chemokines genes. In addition, the mRNA expression of antiviral genes (ISG15, ISG54 and PKR) regulated by the IFN response was upregulated in PAMs infected with the mutant virus rJX143-D88. Our results demonstrate that virus-specific host immunity can be enhanced by modifying certain nsp2 epitope regions. These findings provide important insights for understanding virus pathogenesis and development of future vaccines. PMID- 29442231 TI - A cost-effectiveness analysis of school-based suicide prevention programmes. AB - Suicide is one of the leading causes of death among young people globally. In light of emerging evidence supporting the effectiveness of school-based suicide prevention programmes, an analysis of cost-effectiveness is required. We aimed to conduct a full cost-effectiveness analysis (CEA) of the large pan-European school based RCT, Saving and Empowering Young Lives in Europe (SEYLE). The health outcomes of interest were suicide attempt and severe suicidal ideation with suicide plans. Adopting a payer's perspective, three suicide prevention interventions were modelled with a Control over a 12-month time period. Incremental cost-effectiveness ratios (ICERs) indicate that the Youth Aware of Mental Health (YAM) programme has the lowest incremental cost per 1% point reduction in incident for both outcomes and per quality adjusted life year (QALY) gained versus the Control. The ICERs reported for YAM were ?34.83 and ?45.42 per 1% point reduction in incident suicide attempt and incident severe suicidal ideation, respectively, and a cost per QALY gained of ?47,017 for suicide attempt and ?48,216 for severe suicidal ideation. Cost-effectiveness acceptability curves were used to examine uncertainty in the QALY analysis, where cost-effectiveness probabilities were calculated using net monetary benefit analysis incorporating a two-stage bootstrapping technique. For suicide attempt, the probability that YAM was cost-effective at a willingness to pay of ?47,000 was 39%. For severe suicidal ideation, the probability that YAM was cost-effective at a willingness to pay of ?48,000 was 43%. This CEA supports YAM as the most cost-effective of the SEYLE interventions in preventing both a suicide attempt and severe suicidal ideation.Trial registration number DRKS00000214. PMID- 29442232 TI - Neuroimaging of first seizure in the adult emergency patients. AB - The aim is to establish the role of head computed tomography (CT) and magnetic resonance imaging (MRI) in adults presenting to the emergency department (ED) with first-time seizure (FS) and to analyze the potential predictor variables for the adverse imaging outcome. We retrospectively reviewed the medical records of all adults who underwent cranial CT or MRI between January 1, 2011, and December 1, 2016, to an academic ED for FS. Patients were excluded if were under 18 years of age, had known recent intracranial pathology, known brain tumor or having a history of trauma. Important predictive variables to indicate pathology in either CT or MR scan in patients with FS were evaluated with logistic regression analysis. A total of 546 FS (293 men and 253 women; range, 18-81 years; mean, 47 years) were identified in patients receiving either cranial CT or MR scan. Of them, abnormal findings were observed in 22/451 (4.8%) patients on CT and 18/95 (18.9%) patients on MRI. Predictor variables of age greater than 50 years, focal neurologic deficit, hypoglycemia, and history of malignancy were identified on CT, whereas a history of malignancy, age greater than 50 years and focal neurological deficit were determined on MRI. Limiting neuroimaging to this population would potentially reduce head CT scans by 67% and would potentially reduce head MRI scans by 47%. Clinical suspicion should be heightened and the neuroimaging should be considered for advanced age, history of malignancy, hypoglycemia or focal neurological deficits in patients with FS. PMID- 29442233 TI - A novel CACNA1A mutation associated with episodic ataxia 2 presenting with periodic paralysis. PMID- 29442234 TI - Microstructural changes in patients with Parkinson disease and REM sleep behavior disorder: depressive symptoms versus non-depressed. AB - Search for Parkinson's disease (PD) progression biomarkers has led to the identification of both motor and non-motor symptoms relevant of prodromal PD that could be eye-opening to the spreading underlying Lewy body pathogenesis. One most robust predictor of PD is the REM sleep behavior disorder (RBD), and one most common early non-motor symptom of PD is depression. With RBD, frequently coexisting with clinical depression and both predicting dopamine transmission dysfunction, we aimed to survey structural associates of depressive symptoms in early PD patients with comorbid RBD. Through diffusion MRI connectometry, we tracked fiber differences comparing DWI images obtained from 14 patients with depressive symptoms and 18 without depression from a group with comorbid RBD and PD. DWI images and patients were recruited from the Parkinson's Progression Markers Initiative database. PD-RBD patients with depressive symptoms showed pathways with significantly reduced connectivity in the right cingulum, left and right fornix, left inferior longitudinal fasciculus, right corticospinal tract, left middle cerebellar peduncle and genu of corpus callosum (FDR = 0.0228). Diffusivity alteration of the mentioned fibers in depressed, early PD patients with RBD might reflect underlying PD pathology and serve as common structural DWI signatures for early PD diagnosis. PMID- 29442235 TI - Medico-legal aspects of deaths related to neglect and abandonment in the elderly. AB - As life expectancy increases, the phenomenon of the neglect of elderly persons is becoming increasingly relevant in the fields of both medicine and social care. This work analyses the cases of two subjects whose deaths initially seemed to have been attributable to natural causes. The autopsy findings and the analysis of clinical data, however, were able to establish that neglect had played a determining role in their deaths. These cases highlight the need for healthcare workers to be more alert to the clinical signs of neglect. Finally, in cases of death, the forensic pathologist must conduct a meticulous post-mortem examination to detect the physical signs of neglect and to establish if abuse has been responsible for the death. PMID- 29442236 TI - Racial/Ethnic Contrasts in the Relationships between Physical Disability, Perceived Discrimination, and Depressive Symptoms. AB - INTRODUCTION: The systematic deprivation of equal access to valued opportunities has greatly harmed the disadvantaged. Discrimination, whether it is based on gender, race, sexual orientation, or physical health exacts a high toll. This is especially true with respect to the role of race and equality in the USA today. This paper attempts to evaluate the significance of perceived discrimination among a multiethnic sample of physically disabled and non-disabled study participants. METHODS: We employ survey data from a community-based multiethnic sample of study participants to assess whether physical disability increases perceptions of discrimination across racial/ethnic groups. Additionally, we assess whether physical disability impacts the relationship between discrimination and depressive symptoms and whether this relationship is consistent across race/ethnicity. RESULTS: Descriptive and multivariate analyses indicate that disabled whites and Hispanics report higher levels of discrimination than their non-disabled counterparts. However, this pattern was not observed among black respondents who report high levels of discrimination regardless of their disability status. OLS models indicate that among Hispanics, physical disability moderates the relationship between discrimination and depressive symptoms. Among black and white study participants, physical disability does not moderate this relationship. CONCLUSION: Taken together, the results demonstrate the continuing significance of race as a source of discrimination and a health risk. PMID- 29442237 TI - Fellowship training in critical care ultrasound. PMID- 29442238 TI - Two-point measurement of amylase in drainage fluid predicts severe postoperative pancreatic fistula after gastric cancer surgery. AB - BACKGROUND: Early identification of patients at risk of postoperative pancreatic fistula (POPF) allows appropriate management after gastrectomy. Although some reports have suggested a correlation between POPF and the concentration of amylase in drained abdominal fluid (D-AMY), this has not been proven to impact sufficiently on clinical decision-making. A sustained high level of D-AMY is often assumed to be due to unsatisfactory drainage or excessive pancreatic leakage. We assessed the clinical utility of measuring D-AMY on postoperative day (POD) 1 and POD3 for prediction of POPF. METHODS: Starting in April 2014, 801 patients who underwent radical gastrectomy with prophylactic drain placement were consecutively enrolled. We routinely measured D-AMY on POD1 and POD3, and compared the incidence of problematic POPF and clinical factors including D-AMY. We also attempted to clarify whether such two-point D-AMY measurement was clinically useful for patient management after gastrectomy. RESULTS: Fifty-one of the patients (6.4%) developed Clavien-Dindo grade III or worse POPF. Using D-AMY cutoffs of 2218 IU/L on POD1 and 555 IU/L on POD3, the patients were successfully classified. The highest risk group, in which D-AMY was higher than the cut-off value on both POD1 and POD3, showed a significantly high rate of occurrence (33/105, 31.4%) and high positive likelihood ratio (6.74). Multivariate analysis showed that classification into this highest risk group was an independent risk factor for development of severe POPF (odds ratio 15.2, 95% CI 7.92-29.0). CONCLUSION: Two-point measurement of D-AMY may be an efficient tool for achieving individualized management of POPF following radical gastrectomy. PMID- 29442239 TI - Randomized double-blind clinical trial of combined treatment with megestrol acetate plus celecoxib versus megestrol acetate alone in cachexia-anorexia syndrome induced by GI cancers. AB - PURPOSE: Previous studies reported promising efficacy for celecoxib in the treatment of cancer cachexia. We designed this study to test the hypothesis that combination therapy with megestrol acetate (MA) plus celecoxib is superior to MA alone. METHODS: Ninety eligible gastrointestinal cancer patients randomly received either MA 320 mg/day plus placebo (arm1) or MA 320 mg/day plus celecoxib 200 mg/day (arm2). Patients were evaluated at baseline, then 1 and 2 months after starting interventions. The primary outcome was body weight. Secondary outcomes were quality of life, grip strength, appetite score, performance status, plasma albumin, CRP, IL-6, and Glasgow Prognostic Score. RESULTS: Patients were comparable at baseline. Sixty patients were assessable for the first month and 33 patients for the second month. After 2 months, patients in arm1 (MA + placebo) and arm2 (MA + celecoxib) experienced 4.0 +/- 3.4 and 2.2 +/- 3.6Kg of weight gain respectively (P = 0.163). Changes relative to baseline were statistically significant in both arms of the study (P = 0.001). Regarding secondary outcomes, comparisons between groups did not show any statistically significant difference, but within-group changes were significant in both arms of the study. CONCLUSION: Since both MA alone and MA plus celecoxib are associated with improvement of cachexia in GI cancer patients, this study failed to show that adding celecoxib (200 mg/day) to megestrol (320 mg/day) could enhance anti-cachexic effects of megestrol. PMID- 29442240 TI - Review of emerging surgical robotic technology. AB - BACKGROUND: The use of laparoscopic and robotic procedures has increased in general surgery. Minimally invasive robotic surgery has made tremendous progress in a relatively short period of time, realizing improvements for both the patient and surgeon. This has led to an increase in the use and development of robotic devices and platforms for general surgery. The purpose of this review is to explore current and emerging surgical robotic technologies in a growing and dynamic environment of research and development. METHODS: This review explores medical and surgical robotic endoscopic surgery and peripheral technologies currently available or in development. The devices discussed here are specific to general surgery, including laparoscopy, colonoscopy, esophagogastroduodenoscopy, and thoracoscopy. Benefits and limitations of each technology were identified and applicable future directions were described. RESULTS: A number of FDA-approved devices and platforms for robotic surgery were reviewed, including the da Vinci Surgical System, Sensei X Robotic Catheter System, FreeHand 1.2, invendoscopy E200 system, Flex(r) Robotic System, Senhance, ARES, the Single-Port Instrument Delivery Extended Research (SPIDER), and the NeoGuide Colonoscope. Additionally, platforms were reviewed which have not yet obtained FDA approval including MiroSurge, ViaCath System, SPORTTM Surgical System, SurgiBot, Versius Robotic System, Master and Slave Transluminal Endoscopic Robot, Verb Surgical, Miniature In Vivo Robot, and the Einstein Surgical Robot. CONCLUSIONS: The use and demand for robotic medical and surgical platforms is increasing and new technologies are continually being developed. New technologies are increasingly implemented to improve on the capabilities of previously established systems. Future studies are needed to further evaluate the strengths and weaknesses of each robotic surgical device and platform in the operating suite. PMID- 29442241 TI - Does the number of operating specialists influence the conversion rate and outcomes after laparoscopic colorectal cancer surgery? AB - BACKGROUND: Laparoscopic techniques in colorectal surgery have been widely utilised due to short-term patient benefits but conversion to open surgery is associated with adverse short- and long-term patient outcomes. The aim of this study was to investigate the influence of dual specialist operating on the conversion rate and patient outcomes following laparoscopic colorectal surgery. METHODS: A prospectively populated colorectal cancer surgery database was reviewed. Cases were grouped into single or dual consultant procedures. Cluster analysis and odds ratio (OR) were used to identify risk factors for conversion. Primary outcome measures were conversion to open and five year overall survival (OS) calculated using the Kaplan-Meier log-rank method. RESULTS: 750 patients underwent laparoscopic colorectal cancer resection between 2002 and 2015 (median age 73, 319 (42.5%) female, 282 (37.6%) rectal malignancies, 135 patients (18%) had two consultants). The single surgeon conversion rate was 20.4% compared to 5.5% for dual operating (OR 4.4, 95% CI 1.87-10.2, p < 0.001). There were no demographic or tumour differences between the laparoscopic/converted and number of surgeon groups. Two-step cluster analysis identified cluster I (lower risk) 406 patients, 8% converted and cluster II (higher risk) 261 patients, conversion rate 30%. Median follow-up was 48 months (range 0-168). Five-year OS was significantly inferior for both converted and single surgeon cases (63% vs. 77%, p < 0.001 and 61% vs. 70%, p = 0.033, respectively). CONCLUSION: In selected colorectal cancer patients operated by fully trained laparoscopic surgeons, we observed a reduction in conversion with associated long-term survival benefit from dual operating specialists. PMID- 29442242 TI - FUSE certification enhances performance on a virtual computer based simulator for dispersive electrode placement. AB - BACKGROUND: The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) has developed the fundamental use of surgical energy (FUSE) didactic curriculum in order to further understanding of the safe use of surgical energy. The virtual electrosurgical skill trainer (VEST) is being developed as a complementary simulation-based curriculum, with several modules already existing. Subsequently, a new VEST module has been developed about dispersive electrode placement. The purpose of this study is to assess knowledge about dispersive electrode placement in surgeons and surgical trainees in addition to describing a new VEST module. METHODS: Forty-six subjects (n = 46) were recruited for participation at the 2016 SAGES conference Learning Center. Subjects were asked to complete demographic surveys, a five-question pre-test, and a five-question post-test after completing the VEST dispersive electrode module. Subjects were then asked to rate different aspects of the module using a five-point Likert scale questionnaire. RESULTS: Mean pre-simulator and post-simulator assessment scores were 1.5 and 3.4, respectively, with Wilcoxon signed rank analysis showing a significant difference in the means (p < 0.05). Subjects were grouped by the presence (n = 12) or absence (n = 31) of prior FUSE experience and by training level. Mann-Whitney U testing showed no significant difference in pre-simulator assessment scores between attending surgeons and trainees (p > 0.05). In those with and without FUSE exposure, a significant difference (p < 0.05) was seen in pre-simulator assessment scores, and no significant difference in Likert scale assessment scores was seen. CONCLUSIONS: This study demonstrated a new VEST educational module. Consistently high Likert assessment scores showed that users felt that the VEST module helped their understanding of dispersive electrode placement. Additionally, the study reflected a potential knowledge deficit in the safe use of dispersive electrodes in the surgical community, also demonstrating that even some exposure to the FUSE curriculum developed by SAGES provides increased awareness about dispersive electrode use. PMID- 29442243 TI - Treatment of benign perforations and leaks of the esophagus: factors associated with success after stent placement. AB - BACKGROUND: Self-expanding metal stent (SEMS) is effective and safe for the treatment of benign esophageal perforations or leaks. The purpose of this study was to identify factors associated with clinical success after SEMS placement. METHODS: Patients who received SEMS placement for treatment of benign esophageal perforations or leaks were retrospectively identified. These patients were analyzed for factors associated with clinical success and complications. RESULTS: A total of 31 patients underwent stent insertion for benign esophageal perforations (n = 11) or anastomotic leaks (n = 20). Clinical success was achieved in twenty-three patients (74.2%) after initial stent insertion. In multivariate analysis, early stent insertion within 1 day was identified as a significant independent predictor of successful sealing (Odds ratio = 3.14, 95% CI 1.36-7.24; p = 0.013). The anastomotic leak group needed a longer stent dwelling time (>= 4 weeks) compared to the perforation group (75.0% vs. 27.3%, p = 0.022). CONCLUSIONS: Clinical success was significantly associated with early stent insertion. The dwelling time of stent was shorter for benign perforations compared to anastomotic leaks. PMID- 29442244 TI - Postural assessment in class III patients before and after orthognathic surgery. AB - PURPOSE: This study aimed to assess body posture before and after bimaxillary orthognathic surgery by photogrammetry in skeletal class III patients. METHODS: Thirty-one patients with skeletal class III dentofacial deformities (14 men, 17 women) who underwent orthodontic preparation for surgery were included in this non-randomized controlled trial. Of these, 15 who did not undergo orthognathic surgery during the period of this study served as controls. Postural assessment was performed by photogrammetry using SAPO(r) (Postural Assessment Software) based on anterior-, posterior-, and lateral-view images taken 1 month before and 4 months after bimaxillary orthognathic surgery with internal rigid fixation (or 4 months after the initial assessment, for the control group). The study was approved by PUCRS Research Ethics Committee, and written informed consent was obtained from all individual participants prior to their inclusion in the study. RESULTS: There was no significant difference between groups for age, gender, and GAP. In the intervention group, the right leg/hindfoot angle, which initially indicated a valgus deformity, normalized after intervention (P < 0.048). Posterior displacement of the head (P < 0.005) and trunk (P < 0.004) were observed after intervention. CONCLUSIONS: These results suggest that correction of class III dentofacial deformities by bimaxillary orthognathic surgery can produce systemic postural adjustments, especially posterior displacement of the head and trunk and knee and ankle valgus. PMID- 29442245 TI - Retrobulbar and intraocular blood flow in anterior ischaemic optic neuropathy are linked to the functional impairment. AB - PURPOSE: Evaluation of ocular haemodynamics in patients with acute non-arteritic anterior ischaemic optic neuropathy (NAION) by colour Doppler imaging and fluorescein angiography and correlation of blood flow parameters to visual field loss and visual acuity. METHODS: Blood flow velocities (peak systolic velocity (PSV), end-diastolic velocity (EDV)) of the ophthalmic artery (OA), central retinal artery (CRA) and nasal and temporal posterior ciliary arteries (PCAs) were measured via colour Doppler imaging. Resistive index (RI) of all vessels was calculated (PSV-EDV/PSV). Retinal arteriovenous passage times (AVP) were evaluated using fluorescein angiography (scanning laser ophthalmoscope) and digital image analysis. The visual field global index mean deviation (MD, 30-2 programme, Humphrey Field Analyzer) and visual acuity (logMar) was used for analysis of functional impairment after NAION. RESULTS: Twenty patients (age: 64.62 +/- 11.63 years) with acute NAION were included. Mean duration of symptoms was 7.6 +/- 6.9 days. Mean defect was 15.4 +/- 8.9 dB, AVP was determined with 1.66 +/- 0.37 s. EDV of the CRA was significantly correlated to visual field MD (r = 0.52, p = 0.017) and AVP (r = - 0.49, p = 0.025). The RI of the OA was significantly correlated to visual acuity (r = 0.493, p < 0.037). No significant correlations were recorded for the PCAs. A significant correlation was found between AVP and the EDV of the CRA (r = - 0.49, p = 0.025). CONCLUSION: Decreased EDV in the CRA and increased RI in the OA seem to be linked to the functional damage in NAION. An improvement of the retrobulbar circulation might be beneficial in the treatment of NAION. PMID- 29442246 TI - Cataract surgery in patients with glaucoma drainage implants: the hooked tube technique. AB - PURPOSE: Cataract surgery has been reported to adversely affect the IOP control in eyes with the glaucoma drainage implant (GDI). One reason might be the flow of lens debris/viscoelastic material through the GDI tube into the bleb. This pilot study was conducted to determine the clinical results of a novel technique for temporary occlusion of the GDI tube with an iris retractor hook during phacoemulsification. METHODS: Retrospective analysis of 15 patients (control group) who underwent phacoemulsification between January 2005 and December 2010 and 17 patients (treatment group) who underwent phacoemulsification with the hooked tube technique between January 2011 and April 2016 with a minimum 1-year follow-up. RESULTS: The IOP remained within 4 mmHg of the preoperative level in all eyes of the treatment group. Three eyes exhibited IOP spikes (>= 10 mmHg) among controls. The mean postoperative IOP at 1 month was statistically significantly increased in the control group compared with the treatment group (P = 0.040). The number of antiglaucoma medications at 3 and 6 months was significantly increased in the control group (1.4 +/- 1.1 vs. 1.7 +/- 1.1; P = 0.041, 1.4 +/- 1.1 vs. 2.3 +/- 1.2; P = 0.017, respectively). After phacoemulsification, there was a significant increase in the mean number of antiglaucoma medications used at 6 months in the control group compared with the treatment group (P = 0.049). In both groups, one eye developed corneal decompensation. CONCLUSIONS: The hooked tube technique seems to provide an effective way to reduce the risk of the IOP spikes after cataract surgery in eyes with GDI. PMID- 29442247 TI - Thermostable marine microbial proteases for industrial applications: scopes and risks. AB - Thermostable proteases are important in biotechnological and industrial sectors, due to their stability against denaturing agents and chemicals. The feature that gives them such unique applicability is their reaction at high temperatures, which affords a high concentration of substrate, and less risk of microbial contamination. Nearly 65% of industrial proteases are isolated from marine microbial source, and they can significantly resist a wide range of organic solvents at high temperatures. The most important trait of marine organisms is their adaptability, which allows them to grow optimally in harsh environments such as high salt, temperatures, and pressure-the characteristics of deep-sea hot springs and geothermal sediments. However, proteases are immunogenic, and they can trigger inflammatory conditions in human; so their safety assessment prior to industrial usage is of paramount importance. This review focusses on marine origin thermophilic proteases, their thermal resistance, scopes of their industrial applications, and risks. PMID- 29442248 TI - The genes and enzymes of sucrose metabolism in moderately thermophilic methanotroph Methylocaldum szegediense O12. AB - Four enzymes involved in sucrose metabolism: sucrose phosphate synthase (Sps), sucrose phosphate phosphatase (Spp), sucrose synthase (Sus) and fructokinase (FruK), were obtained as his-tagged proteins from the moderately thermophilic methanotroph Methylocaldum szegediense O12. Sps, Spp, FruK and Sus demonstrated biochemical properties similar to those of other bacterial counterparts, but the translated amino acid sequences of Sps and Spp displayed high divergence from the respective microbial enzymes. The Sus of M. szegediense O12 catalyzed the reversible reaction of sucrose cleavage in the presence of ADP or UDP and preferred ADP as a substrate, thus implying a connection between sucrose and glycogen metabolism. Sus-like genes were found only in a few methanotrophs, whereas amylosucrase was generally used in sucrose cleavage in this group of bacteria. Like other microbial fructokinases, FruK of M. szegediense O12 showed a high specificity to fructose. PMID- 29442249 TI - The vertical distribution of prokaryotes in the surface sediment of Jiaolong cold seep at the northern South China Sea. AB - In deep-sea cold seeps, microbial communities are shaped by geochemical components in seepage solutions. In the present study, we report the composition of microbial communities and potential metabolic activities in the surface sediment of Jiaolong cold seep at the northern South China Sea. Pyrosequencing of 16S rRNA gene amplicons revealed that a majority of the microbial inhabitants of the surface layers (0-6 cm) were sulfur oxidizer bacteria Sulfurimonas and archaeal methane consumer ANME-1, while sulfate reducer bacteria SEEP-SRB1, ANME 1 and ANME-2 dominated the bottom layers (8-14 cm). The potential ecological roles of the microorganisms were further supported by the presence of functional genes for methane oxidation, sulfur oxidation, sulfur reduction and nitrate reduction in the metagenomes. Metagenomic analysis revealed a significant correlation between coverage of 16S rRNA gene of sulfur oxidizer bacteria, functional genes involved in sulfur oxidation and nitrate reduction in different layers, indicating that sulfur oxidizing may be coupled to nitrate reducing at the surface layers of Jiaolong seeping site. This is probably related to the sulfur oxidizers of Sulfurimonas and Sulfurovum, which may be the capacity of nitrate reduction or associated with unidentified syntrophic nitrate-reducing microbes in the surface of the cold seep. PMID- 29442250 TI - Can dogs use vocal intonation as a social referencing cue in an object choice task? AB - Evidence from the literature indicates that dogs' choices can be influenced by human-delivered social cues, such as pointing, and pointing combined with facial expression, intonation (i.e., rising and falling voice pitch), and/or words. The present study used an object choice task to investigate whether intonation conveys unique information in the absence of other salient cues. We removed facial expression cues and speech information by delivering cues with the experimenter's back to the dog and by using nonword vocalizations. During each trial, the dog was presented with pairs of the following three vocal cues: Positive (happy-sounding), Negative (sad-sounding), and Breath (neutral control). In Experiment 1, where dogs received only these vocal cue pairings, dogs preferred the Positive intonation, and there was no difference in choice behavior between Negative or Breath. In Experiment 2, we included a point cue with one of the two vocal cues in each pairing. Here, dogs preferred containers receiving pointing cues as well as Negative intonation, and preference was greatest when both of these cues were presented together. Taken together, these findings indicate that dogs can indeed extract information from vocal intonation alone, and may use intonation as a social referencing cue. However, the effect of intonation on behavior appears to be strongly influenced by the presence of pointing, which is known to be a highly salient visual cue for dogs. It is possible that in the presence of a point cue, intonation may shift from informative to instructive. PMID- 29442251 TI - Adaptive learning and forgetting in an unconventional experimental routine. AB - Forgetting is often thought of as the inability to remember, but remembering and forgetting allow behavior to adapt to a changing environment in distinct and separable ways. Learning and forgetting were assessed concurrently in two pigeon experiments that involved the same unconventional routine where the schedule of reinforcement changed every session. Sessions were run back-to-back with a 23-h mid-session break such that in a single visit to the testing chamber, a pigeon completed the second half of one session and the first half of the next. The beginning of a new session was either signaled or unsignaled. Experiment 1 involved concurrent variable-interval variable-interval schedules with four possible reinforcer ratios. Response allocation was sensitive to the richer schedule and was retained through the mid-session break. Experiment 2 involved peak interval schedules of varying durations. Temporal discrimination was rapidly acquired before and after the mid-session break, but not retained. Signaling the session change decreased control by past contingencies in both experiments, demonstrating that learning and forgetting can be investigated separately. These results suggest that the temporal structure of training, such as multiple short daily sessions instead of one long session, can meaningfully impact measurement of animals' capacity to forget and remember. PMID- 29442252 TI - Survey of Staphylococcus aureus in a general pediatric population and focus on isolates with three clinically relevant toxin-encoding genes. AB - BACKGROUND: In children, surveys on Staphylococcus aureus have focused on specific infections, situations or strains but no study has so far given an overview on S. aureus isolation without any selection. Here, we describe the overall bacteriological and clinical characteristics of S. aureus isolation in children, with a special focus on isolates harbouring tst, sea, and/or luk-PV genes, respectively, encoding the three clinically relevant toxins: toxic shock syndrome toxin-1, enterotoxin A and Panton-Valentine leukocidin. METHODS: Data associated with S. aureus isolation were reviewed: isolation site, infection status, tst, sea and luk-PV genes, antimicrobial susceptibility pattern, agr typing. RESULTS: Three hundred and seventy-seven isolates retrieved from 328 children during S. aureus infection (55.2%) or colonisation (44.8%) were included. tst, sea and luk-PV genes were amplified in 14.3, 9.5 and 5.8% of the isolates, respectively. These isolates were significantly more frequently retrieved during infection (69.1%) than colonisation but differences were observed according to isolation site. Methicillin-resistance was found in 7.2% of the isolates, 78% of which harboured >= 1 of the targeted toxin-encoding genes. CONCLUSIONS: This first comprehensive study of S. aureus in children showed S. aureus to be mainly retrieved during infection and a high rate of colonisation, not limited to the nasopharynx. Predominant infections were skin and soft tissue infections where tst was most frequently detected. luk-PV was most commonly detected during bone and joint infections. Isolates harbouring targeted toxin encoding genes were significantly associated with infections but a quarter of children were asymptomatic carriers representing a reservoir for dissemination of isolates with virulence potency. PMID- 29442253 TI - Socioeconomic inequality in screen time frequency in children and adolescents: the weight disorders survey of the CASPIAN IV study. AB - BACKGROUND: This study aimed to assess the socioeconomic inequality and determinants of screen time (ST) frequency in Iranian children and adolescents. METHODS: This nationwide study was conducted as part of a national school-based surveillance program among 36,486 students consisting of 50.79% boys and 74.23% urban inhabitants, aged 6-18 years, living in urban and rural areas of 30 provinces of Iran. Socioeconomic inequality in ST, including the time spent for ST, watching TV and leisure-time working with computer, was assessed across quintiles of SES using concentration index (C) and slope index of inequality (SII). RESULTS: Overall, 36,486 students completed the study (response rate 91.25%). Their mean (SD) age was 12.14 (3.36) years. The national estimation of frequency of ST was 31.66% (95% CI 31.16-32.17) with ascending change from 20.80% (95% CI 19.81-21.82) to 36.66% (95% CI 35.47-37.87) from the first to the last quintal of SES. Estimated C value at national level was positive (0.08), which indicate inequality was in favor of low SES groups. Considering the SII values, at national level [- 0.16 (- 0.39, 0.06)], the absolute difference in ST frequency between the bottom and top of the socioeconomic groups had descending trends. In multivariate logistic regression model, family history of obesity, generalized obesity and age were the main significant determinants of prolonged ST, watching TV, and computer working (P < 0.001). CONCLUSIONS: Socioeconomic inequality in ST frequency was in favor of low SES groups. These findings are useful for health policies, better programming and future complementary analyses. PMID- 29442255 TI - Impact of seasonal thermal stress on physiological and blood biochemical parameters in pigs under different dietary energy levels. AB - The present study was formulated to find out the status of important season related thermal stress biomarkers of pure-bred (Hampshire) and crossbred (50% Hampshire * 50% local) pigs under the agro-climatic condition of Assam State, India. The experiment was also aimed to study the role of different level of energy ration (110, 100, and 90% energy of NRC feeding standard for pig) in variation of physiological and biochemical parameters in two genetic groups of pigs in different seasons. The metabolizable energy value were 3260, 2936.5, and 3585.8 kcal/kg in grower ration and 3260.2, 2936.6, and 3587 kcal/kg in finisher ration for normal energy (NE), low energy (LE) and high energy (HE), respectively. Both the genetic group of animals were housed separately under intensive system of management. Each pen was measuring 10' * 12' along with an outer enclosure. Six weaned piglets (almost similar body weight of average 10.55 kg) of each group were kept in a separate pen. However, after attainment of 35 kg body weight, the animals of a group were divided in two pens of three animals each. The present experiment indicated that average ambient temperature during summer months (27.33-29.51 degrees C) was above the comfort zone for pigs (22 degrees C). The significantly (P < 0.01) higher relative humidity (RH) (%) was recorded in outdoor environment (87.26-91.10%) and in the morning time (86.60 91.10%). The temperature humidity index (THI) during the study period was found to be indicative of thermal stress to the experimental animals during summer (79.55-82.56). Physiological parameters viz., respiration rate (RR) and rectal temperature (RT) were significantly (P < 0.01) higher in summer season (43.75 72.12 breaths/min. and 102.29-103.23 degrees F) and non-significantly higher values were recorded in Hampshire pigs. It was also found that the significantly (P < 0.01) lower RR as well as RT was recorded in the pigs fed with high energy (HE) ration during summer season. Serum triiodothyronine (T3) and thyroxine (T4) concentrations were significantly (P < 0.01) lower during summer, while both the genetic groups showed significantly (P < 0.01) higher concentration of serum cortisol during summer season. It was also observed that thyroid hormone and cortisol concentrations were maintained in groups of pig fed vegetable oil incorporated HE diet during summer. From the present study, it is found that the increasing the energy level of the ration might be helpful to minimize the effects of thermal stress during summer. PMID- 29442254 TI - Heat stress and effect of shade materials on hormonal and behavior response of dairy cattle: a review. AB - In tropical countries, at high temperatures, several physiological rearrangements occur in cows as they attempt to facilitate heat dissipation and/or reduce metabolic heat production. Following exposure to heat, cattle appear to acclimatize within 2-7 weeks. The failure of homeostasis at high temperatures may lead to reduced productivity or even death. The situation is even worse when humidity adds to high temperature. Livestock with elevated body temperature exhibit lower DMI and growth with less efficiency, reducing profitability for dairy farms in hot and humid climates. Shading of feed and water also offers production advantages. Although several elaborate methods for reducing heat stress in cows have been reported, simple shade materials appear to be the most cost-effective methods that are currently applicable to tropical developing countries. Different materials are being used to provide shade during warm weather. The shade material determines the microclimate-it should be light, strong, durable, weatherproof, good looking and a bad conductor of heat, and free from tendency to condense moisture inside. This review discusses various shade materials and their advantages and disadvantages in different situations. PMID- 29442256 TI - Plasma microRNAs levels are different between pulmonary and extrapulmonary ARDS patients: a clinical observational study. AB - BACKGROUND: Mesenchymal stem cells (MSC) obviously alleviate the damage of the structure and function of pulmonary vascular endothelial cells (VEC). The therapeutic effects of MSC are significantly different between pulmonary ARDS (ARDSp) and extrapulmonary ARDS (ARDSexp). MicroRNAs (miRNAs), as important media of MSC regulating VEC, are not studied between ARDSp and ARDSexp. We aimed to explore the plasma levels difference of miRNAs that regulate VEC function and are associated with MSC (MSC-VEC-miRNAs) between ARDSp and ARDSexp patients. METHODS: MSC-VEC-miRNAs were obtained through reviewing relevant literatures screened in PubMed database. We enrolled 57 ARDS patients within 24 h of admission to the ICU and then collected blood samples, extracted plasma supernatant. Patients' clinical data were collected. Then, plasma expression of MSC-VEC-miRNAs was measured by real-time fluorescence quantitative PCR. Simultaneously, plasma endothelial injury markers VCAM-1, vWF and inflammatory factors TNF-alpha, IL-10 were detected by ELISA method. RESULTS: Fourteen miRNAs were picked out after screening. A total of 57 ARDS patients were included in this study, among which 43 cases pertained to ARDSp group and 14 cases pertained to ARDSexp group. Plasma miR-221 and miR-27b levels in ARDSexp group exhibited significantly lower than that in ARDSp group (miR-221, 0.22 [0.12-0.49] vs. 0.57 [0.22-1.57], P = 0.008, miR-27b, 0.34 [0.10-0.46] vs. 0.60 [0.20-1.46], P = 0.025). Plasma vWF concentration in ARDSexp group exhibited significantly lower than that in ARDSp group (0.77 [0.29-1.54] vs. 1.80 [0.95-3.51], P = 0.048). Significant positive correlation was found between miR-221 and vWF in plasma levels (r = 0.688, P = 0.022). Plasma miR-26a and miR-27a levels in non-survival group exhibited significantly lower than that in survival group (miR-26a, 0.17 [0.08-0.20] vs. 0.69 [0.24-2.33] P = 0.018, miR-27a, 0.23 [0.16-0.58] vs. 1.45 [0.38-3.63], P = 0.021) in ARDSp patients. CONCLUSION: Plasma miR-221, miR-27b and vWF levels in ARDSexp group are significantly lower than that in ARDSp group. Plasma miR-26a and miR-27a levels in non-survival group are significantly lower than that in survival group in ARDSp patients. PMID- 29442257 TI - Effect of long-term fertilization strategies on bacterial community composition in a 35-year field experiment of Chinese Mollisols. AB - Bacteria play vital roles in soil biological fertility; however, it remains poorly understood about their response to long-term fertilization in Chinese Mollisols, especially when organic manure is substituted for inorganic nitrogen (N) fertilizer. To broaden our knowledge, high-throughput pyrosequencing and quantitative PCR were used to explore the impacts of inorganic fertilizer and manure on bacterial community composition in a 35-year field experiment of Chinese Mollisols. Soils were collected from four treatments: no fertilizer (CK), inorganic phosphorus (P) and potassium (K) fertilizer (PK), inorganic P, K, and N fertilizer (NPK), and inorganic P and K fertilizer plus manure (MPK). All fertilization differently changed soil properties. Compared with CK, the PK and NPK treatments acidified soil by significantly decreasing soil pH from 6.48 to 5.53 and 6.16, respectively, while MPK application showed no significant differences of soil pH, indicating alleviation of soil acidification. Moreover, all fertilization significantly increased soil organic matter (OM) and soybean yields, with the highest observed under MPK regime. In addition, the community composition at each taxonomic level varied considerably among the fertilization strategies. Bacterial taxa, associated with plant growth promotion, OM accumulation, disease suppression, and increased soil enzyme activity, were overrepresented in the MPK regime, while they were present at low abundant levels under NPK treatment, i.e. phyla Proteobacteria and Bacteroidetes, class Alphaproteobacteria, and genera Variovorax, Chthoniobacter, Massilia, Lysobacter, Catelliglobosispora and Steroidobacter. The application of MPK shifted soil bacterial community composition towards a better status, and such shifts were primarily derived from changes in soil pH and OM. PMID- 29442258 TI - Evaluation of the effects of miRNAs in familial Mediterranean fever. AB - Familial Mediterranean fever (FMF) is an inherited autoinflammatory disorder that can result in attacks with accompanying recurrent episodes of fever, serositis, and skin rash. MiRNAs are demonstrated to be associated with a number of other diseases; however, no comprehensive study has revealed its association with FMF disease. The aim is to investigate the role of microRNAs in FMF. We included 51 patients with genetically diagnosed FMF who had clinical symptoms and 49 healthy volunteers. Fifteen miRNAs that were found to be associated with autoinflammatory diseases and have a part in immune response were evaluated. The expression levels of 11 miRNAs (miR-125a, miR-132, miR-146a, miR-155, miR-15a, miR-16, miR-181a, miR-21, miR-223, miR-26a, and miR-34a) in the patient group were significantly low, compared with the control group (p < 0.05). The patient group was analyzed and compared within itself, and the expression levels of 5 miRNAs (miR-132, miR 15a, miR-181a, miR-23b, miR-26a) in the patients who took colchicine seemed to have increased and levels of 5 miRNAs (miR-146a, miR-15a, miR-16, miR-26a, miR 34a) in the patients who took colchicine were significantly lower (p < 0.05). Furthermore, the attack patients were compared with the control group, and their expression levels of 4 miRNAs (miR-132, miR-15a, miR-21, miR-34a) were significantly lower (p < 0.05). Levels of 9 miRNAs (miR-132, miR-146a, miR-15a, miR-16, miR-181a, miR-21, miR-223, miR-26a, miR-34a) in non-attack patients decreased significantly (p < 0.05). Our study demonstrates that miRNAs could be effective in the pathogenesis of FMF. PMID- 29442259 TI - LC-MS-based serum metabolomics reveals a distinctive signature in patients with rheumatoid arthritis. AB - Metabolomics has been applied to explore altered metabolite profiles in disease and identify unique metabolic signatures in recent years. We aim to characterize the metabolic profile of rheumatoid arthritis patients and explore its underlying pathological processes using metabolomics approach. Serum samples from 30 rheumatoid arthritis (RA) patients, 30 primary Sjogren's syndrome (pSS) patients, and 32 healthy controls (HC) were collected. The sample was analyzed by ultra high-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS). Potential biomarkers were screened from orthogonal projection to latent structure discriminate analysis (OPLS-DA) and further evaluated by receiver operating characteristic analysis (ROC). Compared with HC and pSS patients, the RA patients had increased serum levels of 4 methoxyphenylacetic acid, glutamic acid, L-leucine, L-phenylalanine, L tryptophan, L-proline, glyceraldehyde, fumaric acid, and cholesterol as well as decreased capric acid, argininosuccinic acid, and billirubin. A total of eight potential biomarkers were screened and tentatively identified for RA. A panel of three metabolites (4-methoxyphenylacetic acid, L-phenylalanine, and L-leucine) was identified as specific biomarkers of RA. ROC analysis showed that the panel had a sensitivity of 93.30% with a specificity of 95.20% in discrimination RA from other groups. UPLC-HRMS-based quantification of circulating metabolites was a useful tool for identifying RA patients from pSS patients and healthy controls. The potential biomarkers indicated that the RA metabolic disturbance might be associated with inflammation injury, amino acid metabolism, oxidative stress, and phospholipid metabolism. PMID- 29442260 TI - Esophageal high-resolution impedance manometry alterations in asymptomatic patients with systemic sclerosis: prevalence, associations with disease features, and prognostic value. AB - This study aims to investigate pre-clinical esophageal involvement in systemic sclerosis (SSc) by high-resolution impedance manometry (HRiM), its associations with disease features including lung involvement, and its predictivity of esophageal symptoms overtime. Charts of 45 asymptomatic (no heartburn/regurgitation/dysphagia) SSc patients (96% females; mean age 46 years) with at least one follow-up (FU) visit and complete clinical, serological, functional, and radiological assessment, including high-resolution computed tomography (HRCT) of the chest and lung function tests, that had undergone esophageal HRiM were retrospectively evaluated. Esophagogastric junction contractile integral (EGJ-CI) and esophageal body motility, as evaluated by mean distal contractile integral (DCI), were assessed. SSc patients had a normal esophageal motility in 7/45 cases, a defective EGJ-CI in 28, an ineffective esophageal motility (IEM) in 17, and aperistalsis in 12. Defective EGJ-CI was associated with IEM/aperistalsis in 20 cases, while 9 patients had isolated IEM. Defective EGJ-CI and/or IEM/aperistalsis were associated with a diffusing lung capacity for CO < 80% of predicted value (all p < 0.05), while defective EGJ-CI was also associated with interstitial lung disease on HRCT (p = 0.03). Prevalence of any HRiM abnormality was higher in anti-centromere antibody negative patients (all p < 0.05). IEM/aperistalsis independently increased the risk of esophageal symptoms by 2.3-fold (95% CI 1.1-5.7) and was associated with their higher cumulative incidence with respect to patients with other HRiM patterns at FU (chi2 = 4.63; p = 0.03). SSc patients asymptomatic for esophageal involvement can have HRiM abnormalities in up to 84% of cases. A baseline-impaired motility is a risk factor for symptomatic esophageal disease. PMID- 29442262 TI - Nutrients, Antioxidant Capacity and Safety of Hot Water Extract from Sugar Maple (Acer saccharum M.) and Red Maple (Acer rubrum L.) Bark. AB - Sugar maple (Acer saccharum M.) and red maple (Acer rubrum L.) barks were treated with hot water to extract nutrients in order to explore, for the first time, its potential as safe dietary antioxidants. The organic and inorganic nutrients of these extracts, as well as their safety on human PLB-985 cells differentiated into neutrophils-like cells, were determined. Proximate analysis showed that both bark extracts were low in moisture and fat. Sugar maple bark extract (SM-BX) showed crude protein and ash content higher than those found in red maple bark extract (RM-BX). In addition, SM-BX had total sugars higher than those evaluated in RM-BX, while complex sugars (oligo- and/or poly-saccharides) were similarly abundant in both bark extracts. Furthermore, SM-BX demonstrated a wide array of vital minerals (K, Ca, Mg, P, Na, Fe and Cu) in quantity larger than that evaluated in RM-BX, whereas RM-BX have Zn and Mn levels higher than those found in SM-BX. Phytochemical analyses showed that RM-BX exhibited total phenolic and flavonoid contents higher than those measured in SM-BX. Consequently, RM-BX presented an antioxidant activity higher than that of SM-BX: 2.85-fold ABTS radical cation scavenging capacity and 1.9-fold oxygen radical absorbance capacity. Finally, RM-BX and SM-BX were greatly safe since, at concentration up to 100 MUg/ml, they did not modify the viability of neutrophils as determined by flow-cytometry assay using Annexin V-FITC/Propidum Iodide as markers. In conclusion, our in vitro studies indicate that both red and sugar maple bark extracts have a real potential as food additives. PMID- 29442263 TI - Effect of Drying on the Phenolic Content and Antioxidant Activity of Red Grape Pomace. AB - Winemaking by-products are considered to be a rich source of bioactive compounds. Grape pomace is susceptible to microbial degradation due to the degree of residual moisture, so the drying of this pomace for conservation is considered to be an essential first step. Previous studies concerning the way in which drying affects winery by-products have produced contradictory results. In this study, a new methodology for drying grape pomace in a climatic chamber has been evaluated. Five red grape pomace varieties were dried in a climatic chamber at 40 degrees C and 10% relative humidity and the phenolic content and antioxidant activity of the dried and wet pomace samples were compared. The results indicate that this drying process is both feasible and beneficial because significant increases in the extractability of phenolic compounds and antioxidant activity were achieved. PMID- 29442264 TI - Evaluation of [89Zr]trastuzumab-PET/CT in differentiating HER2-positive from HER2 negative breast cancer. AB - PURPOSE: To evaluate whether tumor uptake of [89Zr]trastuzumab can distinguish HER2-positive from HER2-negative breast cancer. METHODS: Women with HER2-positive (n = 34) and HER2-negative (n = 16) breast cancer underwent PET/CT 5 +/- 2 days following [89Zr]trastuzumab administration. HER2 status was determined based on immunohistochemistry and/or fluorescence in situ hybridization of primary or metastatic/recurrent tumor. Tumor [89Zr]trastuzumab uptake was assessed qualitatively and semiquantitatively as maximum standardized uptake value (SUVmax), and correlated with HER2 status. Additionally, intrapatient heterogeneity of [89Zr]trastuzumab uptake was evaluated. RESULTS: On a per patient basis, [89Zr]trastuzumab-PET/CT was positive in 30/34 (88.2%) HER2 positive and negative in 15/16 (93.7%) HER2-negative patients. Considering all lesions, the SUVmax was not significantly different in patients with HER2 positive versus HER2-negative disease (p = 0.06). The same was true of when only hepatic lesions were evaluated (p = 0.42). However, after excluding hepatic lesions, tumor SUVmax was significantly higher in HER2-positive compared to HER2 negative patients (p = 0.003). A cutoff SUVmax of 3.2, determined by ROC analysis, demonstrated positive-predictive value of 83.3% (95% CI 65.3%, 94.4%), sensitivity of 75.8% (57.7%, 88.9%), negative-predictive value of 50% (24.7%, 75.3%), and specificity of 61.5% (95% 31.6%, 86.1%) for differentiating HER2 positive from HER2-negative lesions. There was intrapatient heterogeneity of [89Zr]trastuzumab uptake in 20% of patients with multiple lesions. CONCLUSIONS: [89Zr]trastuzumab has the potential to characterize the HER2 status of the complete tumor burden in patients with breast cancer, thus obviating repeat or multiple tissue sampling to assess intrapatient heterogeneity of HER2 status. PMID- 29442265 TI - Integrated mRNA and miRNA profiling revealed deregulation of cellular stress response in bone marrow mesenchymal stem cells derived from patients with immune thrombocytopenia. AB - Our understanding of the pathogenesis of immune thrombocytopenia (ITP) remains limited due to the complexity and heterogeneity of the disease. Recently, we observed that bone marrow mesenchymal stem cells (MSCs) derived from ITP patients exhibited growth defects and functional abnormalities that might be involved in the breakdown of self-tolerance. However, the underlying mechanism remains unclear. In this study, we profiled the expression of both mRNAs and miRNAs by utilizing the microarray technique and deciphered the mechanism underlying the impairment of MSCs derived from ITP patients (MSC-ITP). In total, we identified 740 genes and 32 miRNAs that were differentially expressed between ITP patients and controls. A compromised unfolded protein response (UPR) and decreased DNA transcription were shown to be significantly related to MSC-ITP. The interaction of miRNA with mRNA suggested that the cellular stress response, the UPR, and DNA transcription may be involved in the defects observed in MSC-ITP. Key differentially expressed genes were further validated by RT-PCR. Our results highlight that defects in the cellular stress response, as shown by a compromised UPR and differential DNA transcription, play key roles in causing the abnormalities observed in MSC-ITP. These data might contribute to a better understanding of the abnormal bone marrow niche and provide new insights into the pathogenesis of ITP. PMID- 29442266 TI - Promoting epithelial-to-mesenchymal transition by D-kynurenine via activating aryl hydrocarbon receptor. AB - Epithelial-to-mesenchymal transition (EMT) is believed to play key roles in the process of cancer metastasis. The molecular changes during EMT are characterized by the down-regulation of epithelial proteins, such as E-cadherin, and the up regulation of mesenchymal proteins, such as vimentin (VIM). It has been demonstrated that L-kynurenine (L-Kyn), a physiological ligand of Aryl hydrocarbon receptor (Ahr), promotes cancer cells to metastasize. However, the effects of D-enantiomer of kynurenine, D-kynurenine (D-Kyn), on metastasis are still unclear. In the present paper, we firstly confirmed that D-Kyn (10, 40, 60, and 100 uM) positively regulated the metastasis of 95D cells, a lung cancer cell line, which was reduced upon siRNAAhr treatment. Moreover, significant enhancement VIM expression was detected in the presence of D-Kyn (10 and 40 uM). In contrast, 10 uM D-Kyn markedly attenuated E-cadherin level. Additionally, 10 uM D-Kyn-mediated changes of VIM and E-cadherin were substantially attenuated on siRNAAhr treatment as well. Most importantly, the evidences-10/40 uM D-Kyn induced up-regulation of CYP1A1, 10 uM D-Kyn-induced increase of nuclear transfer of Ahr, and 10/40/60/100 uM D-Kyn-induced enhancement of DER-luciferase activity indicated that D-Kyn was capable of activating Ahr in fact. These results suggest that D-Kyn increases lung cancer cells to metastasize by activating Ahr. PMID- 29442267 TI - Tumor necrosis factor alpha stimulates endogenous apolipoprotein A-I expression and secretion by human monocytes and macrophages: role of MAP-kinases, NF-kappaB, and nuclear receptors PPARalpha and LXRs. AB - Apolipoprotein A-I (ApoA-I) is the main structural and functional protein component of high-density lipoprotein. ApoA-I has been shown to regulate lipid metabolism and inflammation in macrophages. Recently, we found the moderate expression of endogenous apoA-I in human monocytes and macrophages and showed that pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) increases apoA-I mRNA and stimulates ApoA-I protein secretion by human monocytes and macrophages. Here, we present data about molecular mechanisms responsible for the TNFalpha-mediated activation of apoA-I gene in human monocytes and macrophages. This activation depends on JNK and MEK1/2 signaling pathways in human monocytes, whereas inhibition of NFkappaB, JNK, or p38 blocks an increase of apoA-I gene expression in the macrophages treated with TNFalpha. Nuclear receptor PPARalpha is a ligand-dependent regulator of apoA-I gene, whereas LXRs stimulate apoA-I mRNA transcription and ApoA-I protein synthesis and secretion by macrophages. Treatment of human macrophages with PPARalpha or LXR synthetic ligands as well as knock-down of LXRalpha, and LXRbeta by siRNAs interfered with the TNFalpha mediated activation of apoA-I gene in human monocytes and macrophages. At the same time, TNFalpha differently regulated the levels of PPARalpha, LXRalpha, and LXRbeta binding to the apoA-I gene promoter in THP-1 cells. Obtained results suggest a novel tissue-specific mechanism of the TNFalpha-mediated regulation of apoA-I gene in monocytes and macrophages and show that endogenous ApoA-I might be positively regulated in macrophage during inflammation. PMID- 29442268 TI - Cytoplasmic localization of programmed cell death 4 contributes to its anti apoptotic function. AB - We have demonstrated that the loss of programmed cell death 4 (Pdcd4), a translation inhibitor, induces apoptosis; however, when, where, and how Pdcd4 decreases in response to apoptotic stimuli and, conversely, exerts the anti apoptotic function within normal cells are incompletely understood. Endogenous Pdcd4 was present in both the cytoplasm and nucleus of cells that survived. In cells that had committed to die by apoptotic stimuli, cytoplasmic Pdcd4 was lost more slowly than was nuclear Pdcd4; eventually, Pdcd4 remaining in the cytoplasm was lost and then apoptotic events were induced. Treatment with leptomycin B led to blocked nuclear export of Pdcd4 in cells exposed to apoptotic stimuli, assuming its translocation from the nucleus to the cytoplasm in the early phase of apoptotic processes. In cells overexpressing Pdcd4, the protein localized exclusively cytoplasmic. Overexpression of Pdcd4 resulted in reduced incidence of apoptosis in cells exposed to apoptotic stimuli compared to control cells. In addition, the expression of Procaspase-3, which is translated from the mRNA targeted by Pdcd4, was suppressed in cells overexpressing Pdcd4. Thus, the localization of Pdcd4 to the cytoplasm may be responsible for the suppression of the target mRNA translation and apoptosis. PMID- 29442270 TI - Spatial distribution bias in subject-specific abnormalities analyses. AB - The neuroimaging community has seen a renewed interest in algorithms that provide a location-independent summary of subject-specific abnormalities (SSA) to assess individual lesion load. More recently, these methods have been extended to assess whether multiple individuals within the same cohort exhibit extrema in the same spatial location (e.g., voxel or region of interest). However, the statistical validity of this approach has not been rigorously established. The current study evaluated the potential for a spatial bias in the distribution of SSA using several common z-transformation algorithms (leave-one-out [LOO]; independent sample [IDS]; Enhanced Z-Score Microstructural Assessment of Pathology [EZ-MAP]; distribution-corrected z-scores [DisCo-Z]) using both simulated data and DTI data from 50 healthy controls. Results indicated that methods which z-transformed data based on statistical moments from a reference group (LOO, DisCo-Z) led to bias in the spatial location of extrema for the comparison group. In contrast, methods that z-transformed data using an independent third group (EZ-MAP, IDS) resulted in no spatial bias. Importantly, none of the methods exhibited bias when results were summed across all individual elements. The spatial bias is primarily driven by sampling error, in which differences in the mean and standard deviation of the untransformed data have a higher probability of producing extrema in the same spatial location for the comparison but not reference group. In conclusion, evaluating SSA overlap within cohorts should be either be avoided in deference to established group-wise comparisons or performed only when data is available from an independent third group. PMID- 29442271 TI - Exploring variability in basal ganglia connectivity with functional MRI in healthy aging. AB - Changes in functional connectivity (FC) measured using resting state fMRI within the basal ganglia network (BGN) have been observed in pathologies with altered neurotransmitter systems and conditions involving motor control and dopaminergic processes. However, less is known about non-disease factors affecting FC in the BGN. The aim of this study was to examine associations of FC within the BGN with dopaminergic processes in healthy older adults. We explored the relationship between FC in the BGN and variables related to demographics, impulsive behavior, self-paced tasks, mood, and motor correlates in 486 participants in the Whitehall II imaging sub-study using both region-of-interest- and voxel-based approaches. Age was the only correlate of FC in the BGN that was consistently significant with both analyses. The observed adverse effect of aging on FC may relate to alterations of the dopaminergic system, but no unique dopamine-related function seemed to have a link with FC beyond those detectable in and linearly correlated with healthy aging. PMID- 29442272 TI - The way to "left" Piazza del Popolo: damage to white matter tracts in representational neglect for places. AB - The ability of seeing with the mind's eye, the visual mental imagery, is peculiarly compromised in patients with representational neglect. Representational neglect affects the processing of the left side of a mental image and may selectively concern the ability to imagine places and/or objects. Right-brain damaged patients with representational neglect for places (RN+) lose the ability to imagine themselves within a familiar place and fail in transforming an egocentric representation of the environment into an allocentric one and vice-versa. A peak region located at the posterior junction between the parietal and temporal lobes has emerged as pivotal in determining representational neglect for places. Here we aimed at verifying whether white matter disconnections affecting parietal lobe, by preventing the integration of egocentric information with the allocentric one, play a role in representational neglect for places. A track-wise statistical analysis on 58 right brain damaged patients, with and without extrapersonal perceptual neglect and/or representational neglect for places, suggests that the disconnection of the superior longitudinal fasciculus and that of the posterior arcuate segment, together with the disconnection of a fronto-parietal u-shaped tract, may be crucial in determining the representational neglect for places. These results suggest that representational neglect for places emerges from a complex pattern of lesion location and disconnection that involves parietal, temporal and frontal lobes. PMID- 29442269 TI - Effects of carvacrol on human fibroblast (WS-1) and gastric adenocarcinoma (AGS) cells in vitro and on Wistar rats in vivo. AB - Carvacrol is a natural phenolic compound found in essential oils of Lamiaceae species. In the present study, an attempt has been made to elucidate the mechanism behind the anti-cancer potential of carvacrol on human gastric adenocarcinomas (AGS) by comparing its effects on cancer cells AGS to those on normal human fibroblast (WS-1) cells, in vitro. Cytotoxicity, reactive oxygen species (ROS) generation, glutathione (GSH) levels, genotoxicity, and apoptotic effects of carvacrol (0-600 uM) were studied in both cell lines. Additionally, the effect of high dose carvacrol (100 mg/kg BW) on the oxidative status was investigated in vivo. For this purpose, carvacrol was administered orally to male Wistar rats over a period of 60 days. Rats were weighed regularly. At the end of the experiment, rats were euthanized. Blood and stomach tissues were collected for biochemical and pathological examinations. The in vitro results showed significant differences in cell viability of AGS compared to WS-1 cells exposed to carvacrol. Also the extent of ROS generation, GSH reduction and DNA damage differed significantly between the cell lines studied (P <= 0.001). The differences observed were statistically significant at all concentrations applied (P <= 0.001). The results found in AGS cells were mirrored in the pathohistological findings obtained from animals of the in vivo experimental group. Changes in body weight, and oxidative stress index for plasma and stomach tissues of animals in this group were found to differ statistically significant from those found in the control group of Wistar rats (P <= 0.001). The data obtained from our present study uncovered that carvacrol has the potential to cause toxic effects in both, AGS and WS-1 cells but more effectively in cancer cells than in normal cells. The carvacrol-mediated responses observed in the in vitro and in vivo experiments presented suggest a double-edged pro-oxidative effect. Via this mechanism carvacrol induced cytotoxicity, apoptosis, and DNA damage in a dose-dependent manner in both cancer and normal cells and these activities were higher in cancer cells than those of normal cells. PMID- 29442273 TI - A comparative study of segmentation techniques for the quantification of brain subcortical volume. AB - Manual tracing of magnetic resonance imaging (MRI) represents the gold standard for segmentation in clinical neuropsychiatric research studies, however automated approaches are increasingly used due to its time limitations. The accuracy of segmentation techniques for subcortical structures has not been systematically investigated in large samples. We compared the accuracy of fully automated [(i) model-based: FSL-FIRST; (ii) patch-based: volBrain], semi-automated (FreeSurfer) and stereological (Measure(r)) segmentation techniques with manual tracing (ITK SNAP) for delineating volumes of the caudate (easy-to-segment) and the hippocampus (difficult-to-segment). High resolution 1.5 T T1-weighted MR images were obtained from 177 patients with major psychiatric disorders and 104 healthy participants. The relative consistency (partial correlation), absolute agreement (intraclass correlation coefficient, ICC) and potential technique bias (Bland Altman plots) of each technique was compared with manual segmentation. Each technique yielded high correlations (0.77-0.87, p < 0.0001) and moderate ICC's (0.28-0.49) relative to manual segmentation for the caudate. For the hippocampus, stereology yielded good consistency (0.52-0.55, p < 0.0001) and ICC (0.47-0.49), whereas automated and semi-automated techniques yielded poor ICC (0.07-0.10) and moderate consistency (0.35-0.62, p < 0.0001). Bias was least using stereology for segmentation of the hippocampus and using FreeSurfer for segmentation of the caudate. In a typical neuropsychiatric MRI dataset, automated segmentation techniques provide good accuracy for an easy-to-segment structure such as the caudate, whereas for the hippocampus, a reasonable correlation with volume but poor absolute agreement was demonstrated. This indicates manual or stereological volume estimation should be considered for studies that require high levels of precision such as those with small sample size. PMID- 29442274 TI - Congenital olfactory impairment is linked to cortical changes in prefrontal and limbic brain regions. AB - The human sense of smell is closely associated with morphological differences of the fronto-limbic system, specifically the piriform cortex and medial orbitofrontal cortex (mOFC). Still it is unclear whether cortical volume in the core olfactory areas and connected brain regions are shaped differently in individuals who suffer from lifelong olfactory deprivation relative to healthy normosmic individuals. To address this question, we examined if regional variations in gray matter volume were associated with smell ability in seventeen individuals with isolated congenital olfactory impairment (COI) matched with sixteen normosmic controls. All subjects underwent whole-brain magnetic resonance imaging, and voxel-based morphometry was used to estimate regional variations in grey matter volume. The analyses showed that relative to controls, COI subjects had significantly larger grey matter volumes in left middle frontal gyrus and right superior frontal sulcus (SFS). COI subjects with severe olfactory impairment (anosmia) had reduced grey matter volume in the left mOFC and increased volume in right piriform cortex and SFS. Within the COI group olfactory ability, measured with the "Sniffin' Sticks" test, was positively associated with larger grey matter volume in right posterior cingulate and parahippocampal cortices whereas the opposite relationship was observed in controls. Across COI subjects and controls, better olfactory detection threshold was associated with smaller volume in right piriform cortex, while olfactory identification was negatively associated with right SFS volume. Our findings suggest that lifelong olfactory deprivation trigger changes in the cortical volume of prefrontal and limbic brain regions previously linked to olfactory memory. PMID- 29442275 TI - Five Novel Oncogenic Signatures Could Be Utilized as AFP-Related Diagnostic Biomarkers for Hepatocellular Carcinoma Based on Next-Generation Sequencing. AB - BACKGROUND: Alpha-fetal protein (AFP) is an important conventional clinical diagnostic indicator of hepatocellular carcinoma (HCC). However, the utilization of AFP alone might yield deceptive results due to its limited sensitivity and accuracy. AIMS: Our study was designed to investigate latent diagnostic biomarkers that could function as auxiliary clinical indicators of HCC and enhance the accuracy of joint diagnosis with AFP. METHODS: We analyzed gene expression profiles and clinical data from HCC patients in The Cancer Genome Atlas database. Differentially expressed genes were identified, and a gene set enrichment analysis was conducted to uncover their biological functions and molecular processes. A weighted correlation network analysis and a protein protein interaction analysis were performed to detect AFP-related biomarkers. The diagnostic performance of these biomarkers was verified using datasets from the GEO database. A diagnostic nomogram was established using the expression levels of potential biomarkers. Quantitative real-time PCR was performed using tissues from 16 HCC patients to validate the results. RESULTS: Five AFP-related diagnostic biomarkers, CDT1, MCM7, NUDT1, CENPM, and HDAC11, were discovered. The diagnostic performance of these biomarkers and the nomogram were demonstrated to be excellent according to receiver operating characteristic curves. CDT1, MCM7, and NUDT1 were shown to be up-regulated in HCC tissues through quantitative real time PCR. CONCLUSIONS: We discovered five diagnostic biomarkers and established a nomogram as a complement to AFP in the diagnosis of HCC. Our results provide a more accurate diagnostic plan for HCC patients based on next-generation sequencing compared with AFP alone. PMID- 29442276 TI - Novel Albumin-Bilirubin Grade-Based Risk Prediction Model for Patients with Hepatocellular Carcinoma Undergoing Chemoembolization. AB - BACKGROUND: Recently, albumin-bilirubin (ALBI) grade has been suggested as a better surrogate for hepatic functional reserve for patients with hepatocellular carcinoma (HCC). AIMS: We developed and validated a novel prediction model to predict outcome for HCC patients who underwent transcatheter arterial chemoembolization (TACE) as a first-line therapy. METHODS: From a multivariate Cox regression model for overall survival, five objective variables (ALBI grade), the Barcelona clinic liver cancer (BCLC) stage, response after the first TACE session, Alpha-fetoprotein level, and sex were chosen and the ABRAS score was developed from the derivation cohort (n = 476) and scored to generate an 8-point risk prediction model. The model's prognostic performance was assessed in the randomly assigned internal validation set (n = 475) and external validation set (n = 243). RESULTS: The ALBI grade was able to stratify patient survival within the same Child-Pugh class. The time-dependent area under receiver operating characteristics curves (AUROCs) for overall survival at 1 and 3 years were 0.78 and 0.73 in the training set, 0.78 and 0.71 in the internal validation set, and 0.70 and 0.65 in the external validation set, respectively. When stratified by BCLC stage, ABRAS score at a cutoff point of more than 3, 4, and 5 for BCLC stage 0/A, B, and C could identify subset of patients with dismal prognosis. CONCLUSION: ABRAS score was useful in estimating prognosis for patients who underwent TACE as a first-line therapy. This score can be useful in planning and guiding treatment strategies with TACE, which warrants prospective validation. PMID- 29442277 TI - Exploring Lactation Consultant Views on Infant Safe Sleep. AB - Objectives The purpose of this qualitative study was to explore the infant safe sleep beliefs and occupational practices of lactation consultants and to determine if lactation consultants give advice to clients that is consistent with the American Academy of Pediatrics' recommendations on this topic. Methods Focus groups were conducted with certified lactation consultants in two cities in Ohio. Participants discussed the role of lactation consultants, the infant sleep advice they provide to women, their views on the American Academy of Pediatrics' infant safe sleep recommendations and related policies, and perceived benefits and barriers associated with providing infant safe sleep education as part of their work. A member-checking session was held to ensure the credibility of the findings. Results Four focus groups were conducted with 22 certified lactation consultants between September and November 2015. Major themes that emerged included: lactation consultants' beliefs regarding the importance of bedsharing for supporting breastfeeding success; their disagreement with the infant safe sleep recommendations of the American Academy of Pediatrics; their frustration with policies that restrict consultants' ability to discuss bedsharing; and the impact of infant safe sleep policies on their work and the advice they provide. Conclusions for Practice Lactation consultants interact with mothers of newborns at a critical time for infant safe sleep decision-making and may influence a woman's choices related to this topic. Women may not be receiving messages from lactation consultants that are consistent with the infant safe sleep recommendations of the American Academy of Pediatrics. PMID- 29442278 TI - Racial/Ethnic Inequities in Low Birth Weight and Preterm Birth: The Role of Multiple Forms of Stress. AB - Introduction Racial/ethnic inequities in low birth weight (LBW) and preterm birth (PTB) persist in the United States. Research has identified numerous risk factors for adverse birth outcomes; however, they do not fully explain the occurrence of, or inequalities in PTB/LBW. Stress has been proposed as one explanation for differences in LBW and PTB by race/ethnicity. Methods Using the Pregnancy Risk Assessment Monitoring System (PRAMS) data from 2012 to 2013 for 21 states and one city (n = 15,915) we used Poisson regression to estimate the association between acute, financial and relationship stressors and LBW and PTB, and to examine the contribution of these stressors individually and simultaneously to racial/ethnic differences in LBW and PTB. Results Adjusting for age and race/ethnicity, acute (p < 0.001), financial (p < 0.001) and relationship (p < 0.05) stressors were associated with increased risk of LBW, but only acute (p < 0.05) and financial (p < 0.01) stress increased risk of PTB. Across all models, non-Hispanic blacks had higher risk of LBW and PTB relative to non-Hispanic whites (IRR 1.87, 95% CI 1.55, 2.27 and IRR 1.46, 95% CI 1.18, 1.79). Accounting for the effects of stressors attenuated the risk of LBW and PTB by 17 and 22% respectively, but did not fully explain the increased likelihood of LBW and PTB among non-Hispanic blacks. Discussion Results of this study demonstrate that stress may increase the risk of LBW and PTB. While stressors may contribute to racial/ethnic differences in LBW and PTB, they do not fully explain them. Mitigating stress during pregnancy may help promote healthier birth outcomes and reduce racial/ethnic inequities in LBW and PTB. PMID- 29442279 TI - Robust estimation in accelerated failure time models. AB - The accelerated failure time model is widely used for analyzing censored survival times often observed in clinical studies. It is well-known that the ordinary maximum likelihood estimators of the parameters in the accelerated failure time model are generally sensitive to potential outliers or small deviations from the underlying distributional assumptions. In this paper, we propose and explore a robust method for fitting the accelerated failure time model to survival data by bounding the influence of outliers in both the outcome variable and associated covariates. We also develop a sandwich-type variance-covariance function for approximating the variances of the proposed robust estimators. The finite-sample properties of the estimators are investigated based on empirical results from an extensive simulation study. An application is provided using actual data from a clinical study of primary breast cancer patients. PMID- 29442280 TI - Patient satisfaction with a chronic kidney disease risk assessment service in community pharmacies. AB - BACKGROUND: Patient satisfaction is an important determinant of the feasibility and sustainability of community pharmacy screening services. However, few studies have evaluated this, with no such study performed for a chronic kidney disease risk assessment service. OBJECTIVE: The aim was to determine patient satisfaction with a chronic kidney disease risk assessment service performed in community pharmacies. SETTING: Community pharmacies in the state of Tasmania, Australia. METHOD: An anonymous nine-item satisfaction survey, with Likert-type scales, was developed following a literature review of existing surveys. Reliability of the nine-item scale was determined using Cronbach's alpha. Patients were asked an additional question on willingness to pay, with choices of amount from $5 to $25. The satisfaction survey was mailed to 389 patients who participated in the chronic kidney disease risk assessment study. MAIN OUTCOME MEASURE: Patient level of satisfaction with and willingness to pay for the chronic kidney disease service. RESULTS: Responses from 143 participants were included in the final analysis. Cronbach's alpha for the nine-item satisfaction scale was 0.87. The majority of participants agreed that the time required to undergo the risk assessment process was justified (90.2%); overall, they were satisfied with the chronic kidney disease risk assessment service (90.0%) and they felt comfortable with the pharmacist referring their results to their doctor (88.9%). Of 136 participants who answered the question on willingness to pay, 62.9% indicated that they would pay for the chronic kidney disease service. Of these, 29.2, 25.8 and 19.1% were willing to pay $20, $10 and $5, respectively. CONCLUSION: Patient satisfaction with the community pharmacy-based chronic kidney disease risk assessment was high. These findings provide support for the implementation of the service within community pharmacy practice. PMID- 29442281 TI - Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab. AB - BACKGROUND: There is an unmet need to identify markers that predict the response to nivolumab in patients with non-small-cell lung cancer (NSCLC). The neutrophil to-lymphocyte ratio (NLR) was recently recognized as an indicator of a poor prognosis in patients with various cancers. In the present study, we quantified the predictive impact of NLR in patients with NSCLC treated with nivolumab. METHODS: We retrospectively analyzed 101 patients with advanced NSCLC treated with nivolumab at Kansai Medical University Hospital from December 2015 to December 2016. Patients were administered nivolumab at a dose of 3 mg/kg every 2 weeks. The predictive value of NLR for disease progression before treatment and 2 and 4 weeks after nivolumab treatment was assessed. RESULTS: The median progression-free survival (PFS) of patients with an NLR of < 3 before treatment was 3.4 months, whereas that of patients with an NLR of >= 3 was 2.9 months (p = 0.484). The median PFS of patients with an NLR of < 3 at 2 weeks after treatment was 5.3 months, whereas that of patients with an NLR of >= 3 was 2.1 months (p = 0.00528). The median PFS of patients with an NLR of < 3 at 4 weeks after treatment was 5.3 months, whereas that of patients with an NLR of >= 3 was 2.0 months (p = 0.00515). CONCLUSION: The NLR at 2 and 4 weeks after treatment might be a useful marker for the prediction of the treatment response or disease progression in patients with advanced NSCLC receiving nivolumab. PMID- 29442282 TI - Complications within 90 days after radical cystectomy for bladder cancer: results of a multicenter prospective study in Japan. AB - PURPOSE: We prospectively evaluated the 90-day postoperative mortality and morbidity of open radical cystectomy by using a standardized reporting methodology. Additionally, we assessed the preoperative characteristics to determine risk factors for major complications. METHODS: This multicenter prospective study included 185 consecutive patients undergoing open radical cystectomy from October 2010 through March 2014. Postoperative complications within 90 days were recorded and graded according to the modified Clavien-Dindo classification. RESULTS: Totally, 328 postoperative complications were observed in 149 patients (80.5%). Of these events, 73 (22.2%) were high grade (>= Grade III), and developed in 46 patients (24.9%). Three patients (1.6%) died postoperatively. Urinary tract infection, wound complications, and paralytic ileus were common complications that occurred in 55 (29.7%), 42 (22.7%) and 41 (22.2%) patients, respectively. Ureteroenteric stricture was diagnosed in 13 of the 151 patients (8.6%) undergoing intestinal urinary diversion. Emergency room visits were required for 13 patients (7.0%) and readmission after discharge was needed for 36 (19.5%). A body mass index >= 25 kg/m2, smoking history and Charlson Comorbidity Index >= 2 were independent risk factors for high-grade complications, and their odds ratios (95% confidence intervals) were 2.357 (1.123 4.948), 2.843 (1.225-6.596) and 3.025 (1.390-6.596), respectively. CONCLUSIONS: Open radical cystectomy is associated with a high incidence of postoperative complications. Most, however, are of low grade. Our results suggest that obesity, a smoking history, and increasing comorbidity are risk factors for major complications. PMID- 29442283 TI - Eplerenone Versus Observation in the Treatment of Acute Central Serous Chorioretinopathy: A Retrospective Controlled Study. AB - INTRODUCTION: To investigate the effects of eplerenone compared to observation in the treatment of acute central serous chorioretinopathy (CSC). METHODS: Charts of consecutive patients with a diagnosis of acute CSC (visual symptoms < 12 weeks) were reviewed. Included patients were divided into a treatment group (treated with eplerenone) and a control group (observation). Main outcome measures included changes in best-corrected visual acuity (BCVA), central macular thickness (CMT), height of subretinal fluid (SRF) and subfoveal choroidal thickness (CT) at 1 and 3 months in the two groups. RESULTS: Fifteen eyes of 15 patients (2 female, 13 male) and 12 eyes of 12 patients (1 female, 11 male [p = 1.000]) were included in the treatment and control groups, respectively. The mean age was 44 +/- 9 (30-65) and 47 +/- 11 years (28-66 years, p = 0.493), respectively. In the treatment group, BCVA improved significantly at 1 month (p = 0.018) and 3 months of follow-up (p = 0.011), while a non-significant improvement was seen in the control group. At 3 months, 12 of 15 eyes (80%) in the treatment group demonstrated complete SRF resolution, versus 3 of 12 eyes (25%) in the control group (p = 0.007). In the treatment group, SRF and CMT were significantly reduced at the 1-month follow-up (p = 0.014, p = 0.028, respectively) and the 3 month follow-up (p < 0.001 for both analyses), while in the control group the changes were not statistically significant. Eplerenone was well tolerated in all patients. CONCLUSION: Patients affected by acute CSC treated with eplerenone achieved greater and faster resolution of the disease compared to the observation group. Eplerenone may represent an attractive new first-line treatment option for acute CSC. PMID- 29442284 TI - Sex differences in the neural underpinnings of social and monetary incentive processing during adolescence. AB - The brain's reward system undergoes major changes during adolescence, and an increased reactivity to social and nonsocial incentives has been described as a typical feature during this transitional period. Little is known whether there are sex differences in the brain's responsiveness to social or monetary incentives during adolescence. The aim of this event-related potential (ERP) study was to compare the neurophysiological underpinnings of monetary and social incentive processing in adolescent boys versus girls. During ERP recording, 38 adolescents (21 females, 17 males; 13-18 years) completed an incentive delay task comprising (a) a reward versus punishment condition and (b) social versus monetary incentives. The stimulus-preceding negativity (SPN) was recorded during anticipation of reward and punishment, and the feedback P3 (fP3) along with the feedback-related negativity (FRN) after reward/punishment delivery. During anticipation of social punishment, adolescent boys compared with girls exhibited a reduced SPN. After delivery, male adolescents exhibited higher fP3 amplitudes to monetary compared with social incentives, whereas fP3 amplitudes in girls were comparable across incentive types. Moreover, whereas in boys fP3 responses were higher in rewards than in punishment trials, no such difference was evident in girls. The results indicate that adolescent boys show a reduced neural responsivity in the prospect of social punishment. Moreover, the findings imply that, once the incentive is obtained, adolescent boys attribute a relatively enhanced motivational significance to monetary incentives and show a relative hyposensitivity to punishment. The findings might contribute to our understanding of sex-specific vulnerabilities to problem behaviors related to incentive processing during adolescence. PMID- 29442285 TI - Diverse effect of BMP-2 homodimer on mesenchymal progenitors of different origin. AB - Bone morphogenetic protein-2 (BMP-2), is a potential factor to enhance osseointegration of dental implants. However, the appropriate cellular system to investigate the osteogenic effect of BMP-2 in vitro in a standardized manner still needs to be defined. The aim of this study was to examine the effect of BMP 2 on the cell proliferation and osteogenic differentiation of human osteogenic progenitors of various origins: dental pulp stem cells (DPSC), human osteosarcoma cell line (Saos-2) and human embryonic palatal mesenchymal cell line (HEPM). For induction of osteogenic differentiation, cell culture medium was supplemented with BMP-2 homodimer alone or in combination with conventionally used differentiation inducing agents. Differentiation was monitored for 6-18 days. To assess differentiation, proliferation rate, alkaline phosphatase activity, calcium deposition and the expression level of osteogenic differentiation marker genes (Runx2, BMP-2) were measured. BMP-2 inhibited cell proliferation in a concentration and time-dependent manner. In a concentration which caused maximal cell proliferation, BMP-2 did not induce osteogenic differentiation in any of the tested systems. However, it had a synergistic effect with the osteoinductive medium in both DPSC and Saos-2, but not in HEPM cells. We also found that the differentiation process was faster in Saos-2 than in DPSCs. Osteogenic differentiation could not be induced in the osteoblast progenitor HEPM cells. Our data suggest that in a concentration that inhibits proliferation the differentiation inducing effect of BMP-2 is evident only in the presence of permissive osteoinductive components. beta-glycerophosphate, was identified interacting with BMP-2 in a synergistic manner. PMID- 29442287 TI - Recent Developments in Adolescent and Young Adult (AYA) Acute Lymphoblastic Leukemia. AB - PURPOSE OF REVIEW: Adolescent and Young Adult (AYA) Oncology is a relatively new field encompassing research in the unique pathophysiology, clinical care, and psychosocial issues facing patients between the ages of 15 and 40 with cancer. About 100,000 of the approximately 1.5 million people diagnosed annually with cancer in the USA are in this age range. This chapter will review notable new developments in the care of adolescents and young adults with acute lymphoblastic leukemia (ALL) within the last 3 years. RECENT FINDINGS: The preponderance of data favors the treatment of AYA ALL patients with pediatric-inspired treatment regimens due to better relapse-free and overall survival. Minimal residual disease (MRD) measurement is emerging as an important prognostic factor and can serve as a new measure of efficacy of the addition of novel therapies to the treatment of patients with new diagnoses. There have been several treatment advances ranging from new cytotoxic agents for ALL to new antibody-based therapy to novel immune therapies such as CAR-T cells. The care of AYA ALL patients is improving as the unique issues for this patient population are addressed. PMID- 29442286 TI - Targeted Orexin and Hypothalamic Neuropeptides for Migraine. AB - The hypothalamus is involved in the regulation of homeostatic mechanisms and migraine-related trigeminal nociception and as such has been hypothesized to play a central role in the migraine syndrome from the earliest stages of the attack. The hypothalamus hosts many key neuropeptide systems that have been postulated to play a role in this pathophysiology. Such neuropeptides include but are not exclusive too orexins, oxytocin, neuropeptide Y, and pituitary adenylate cyclase activating protein, which will be the focus of this review. Each of these peptides has its own unique physiological role and as such many preclinical studies have been conducted targeting these peptide systems with evidence supporting their role in migraine pathophysiology. Preclinical studies have also begun to explore potential therapeutic compounds targeting these systems with some success in all cases. Clinical efficacy of dual orexin receptor antagonists and intranasal oxytocin have been tested; however, both have yet to demonstrate clinical effect. Despite this, there were limitations in these cases and strong arguments can be made for the further development of intranasal oxytocin for migraine prophylaxis. Regarding neuropeptide Y, work has yet to begun in a clinical setting, and clinical trials for pituitary adenylate cyclase activating protein are just beginning to be established with much optimism. Regardless, it is becoming increasingly clear the prominent role that the hypothalamus and its peptide systems have in migraine pathophysiology. Much work is required to better understand this system and the early stages of the attack to develop more targeted and effective therapies aimed at reducing attack susceptibility with the potential to prevent the attack all together. PMID- 29442289 TI - Correction to: Obstructive sleep apnea does not impair cardiorespiratory responses to progressive exercise performed until exhaustion in hypertensive elderly. AB - The original version of this article was published online containing two items that require correction, namely the abstract (Results section) and Table 3. PMID- 29442288 TI - Updates of Peripheral T Cell Lymphomas Based on the 2017 WHO Classification. AB - PURPOSE OF REVIEW: This review will describe and update the readers on the recent changes of the 2017 WHO classification in regard to peripheral T cell lymphomas. RECENT FINDINGS: Significant advances in molecular studies have resulted in revisions of the classification as well as introduction of provisional entities (such as breast implant-associated ALCL, nodal PTCL with TFH phenotype). Major advances in molecular and gene expression profiling have expanded our knowledge of T cell lymphomas, including updates in the diagnostic criteria and sub classification which will facilitate in improving patient care and research. PMID- 29442290 TI - The Optimisation of the Expression of Recombinant Surface Immunogenic Protein of Group B Streptococcus in Escherichia coli by Response Surface Methodology Improves Humoral Immunity. AB - Group B Streptococcus (GBS) is the leading cause of neonatal meningitis and a common pathogen in livestock and aquaculture industries around the world. Conjugate polysaccharide and protein-based vaccines are under development. The surface immunogenic protein (SIP) is a conserved protein in all GBS serotypes and has been shown to be a good target for vaccine development. The expression of recombinant proteins in Escherichia coli cells has been shown to be useful in the development of vaccines, and the protein purification is a factor affecting their immunogenicity. The response surface methodology (RSM) and Box-Behnken design can optimise the performance in the expression of recombinant proteins. However, the biological effect in mice immunised with an immunogenic protein that is optimised by RSM and purified by low-affinity chromatography is unknown. In this study, we used RSM for the optimisation of the expression of the rSIP, and we evaluated the SIP-specific humoral response and the property to decrease the GBS colonisation in the vaginal tract in female mice. It was observed by NI-NTA chromatography that the RSM increases the yield in the expression of rSIP, generating a better purification process. This improvement in rSIP purification suggests a better induction of IgG anti-SIP immune response and a positive effect in the decreased GBS intravaginal colonisation. The RSM applied to optimise the expression of recombinant proteins with immunogenic capacity is an interesting alternative in the evaluation of vaccines in preclinical phase, which could improve their immune response. PMID- 29442291 TI - Health-Related Information-Seeking Behaviors and Preferences Among Mexican Patients with Cancer. AB - Understanding the preferred sources of health-related information among patients with cancer is essential for designing successful cancer education and prevention strategies. However, little is known about health-related information-seeking practices among patients living in low- and middle-income countries. We studied the preferred sources of health-related information among Mexican patients with cancer and explored which factors influence these choices. The health-related information-seeking practices among patients with cancer treated at a public hospital in Mexico City were evaluated using questions from the Spanish Version of the Health Information National Trends Survey. The characteristics of patients who sought health-related information, and of those who chose the internet as their preferred source of information, were analyzed. Fisher's exact test and logistic regression were used for statistical analyses. One hundred forty-eight patients answered the survey (median age 60 years, 70% female), of which 88 (59%) had sought for health-related information. On multivariate analysis, the only characteristic associated with lower odds of seeking health-related information was increasing age (OR 0.93, 95% CI 0.90-0.97). Sixty-one respondents (69%) listed the internet as their preferred source of health-related information. On multivariate analysis, only being of the female gender (OR 4.9, 95% CI 1.3-18.3) was related with higher odds of preferring other sources of information over the internet. Among Mexican patients with cancer, the Internet is the most widely used information source. Older age was the characteristic most strongly associated with not seeking health-related information, while being female was strongly associated with preferring other sources of information over the Internet. PMID- 29442292 TI - Topical Immunotherapy of Alopecia Areata: A Large Retrospective Study. AB - INTRODUCTION: Topical immunotherapy is frequently used in the treatment of alopecia areata (AA) although few studies report long-term follow-up. Our goals were to determine the efficacy and the prognostic factors of topical immunotherapy in a large cohort of patients with AA treated in the departments of Dermatology and Venereology of Bergamo, Como and Pavia, from 1978 to January 2016. METHODS: A total of 252 patients with AA were evaluated retrospectively. RESULTS: All our patients developed an allergic reaction to a 2% solution of dinitrochlorobenzene (DNCB) or squaric acid dibutylester (SADBE) or diphenylcyclopropenone (DPCP). No patients discontinued therapy because of side effects. In total 112 patients (44.05%, p < 0.001) had a good response. Statistical analysis revealed that the main prognostic factors influencing the clinical results were the severity of hair loss at the beginning of therapy, the duration of AA, a history of atopy (particularly eczema), and the early development of sensitization to the three sensitizers. CONCLUSION: Topical immunotherapy in patients with AA is quite effective, mostly well tolerated, and provides prolonged therapeutic benefits. PMID- 29442293 TI - Recombinant Human PH20: Baseline Analysis of the Reactive Antibody Prevalence in the General Population Using Healthy Subjects. AB - BACKGROUND: Recombinant human PH20 (rHuPH20) is used to depolymerize hyaluronan in the subcutaneous space, increasing the dispersion and absorption of co administered drugs. While ~ 5 to 10% of rHuPH20 treatment-naive healthy volunteers have demonstrated rHuPH20-reactive antibodies, associations with age, sex, fertility, and immune disorders remain unknown. OBJECTIVES: Using demographically diverse healthy volunteers, we assessed the prevalence of rHuPH20 reactive antibodies in the general population and potential associations with fertility and autoimmunity diseases. METHODS: In total, 896 subjects aged >= 12 years (767 adults; 129 children) without prior exposure to rHuPH20 were enrolled. A demographic and limited medical history review was performed, and K3-EDTA anticoagulated plasma was analyzed for rHuPH20-reactive antibodies using a bridging immunoassay. RESULTS: Adult and pediatric positivity rates for rHuPH20 reactive antibodies were 5.2% (40/767) and 1.6% (2/129), respectively. Titers ranged from 5 to 2560 (median 30). In five antibody-positive subjects from whom repeated samples were available, antibody titers remained unchanged or decreased fourfold over periods up to 590 days. The prevalence of rHuPH20-reactive antibodies significantly increased with age (p = 0.0006) and was significantly higher in males than in females (p = 0.0010). Men who had fathered children had a significantly increased prevalence of rHuPH20-reactive antibodies than men who had not (p = 0.0036), whereas the rate of childbearing was not significantly different between rHuPH20 antibody-positive and -negative women. The prevalence between racial/ethnic groups was not significantly different, nor was the presence/absence of an autoimmune disorder. CONCLUSIONS: Approximately 1/20 of the adult population had rHuPH20-reactive antibodies. The reason remains unknown; however, no evidence for a negative effect on fertility or association with autoimmune disease was demonstrated. PMID- 29442294 TI - Plasma Pharmacokinetics of Valanafusp Alpha, a Human Insulin Receptor Antibody Iduronidase Fusion Protein, in Patients with Mucopolysaccharidosis Type I. AB - BACKGROUND: Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the alpha-L-iduronidase (IDUA) lysosomal enzyme and the majority of MPSI patients have severe central nervous system (CNS) involvement. Enzyme replacement therapy (ERT) with recombinant IDUA does not treat the CNS, due to the lack of transport of the enzyme across the blood-brain barrier (BBB). Human IDUA has been re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb domain binds the endogenous insulin receptor on the human BBB to trigger receptor-mediated transport across the BBB, and acts as a molecular Trojan horse to ferry the fused IDUA into the brain of patients with MPSI. METHODS: The present investigation describes the initial dosing, plasma pharmacokinetics, and plasma glucose response to the intravenous infusion of doses of valanafusp alpha ranging from 0.3 to 3 mg/kg in five adults and from 1 to 6 mg/kg in 13 pediatric subjects with MPSI. RESULTS: Valanafusp alpha plasma clearance is increased four-fold in children, and shows a linear pharmacokinetic response over the dose range of 0.3-3 mg/kg with a stable plasma elimination half life (t1/2). The plasma pharmacokinetic parameters for valanafusp alpha overlapped with the same parameters previously reported for recombinant human IDUA (laronidase). The majority of the tested subjects had been receiving laronidase ERT for years, and some showed high levels of anti-drug antibodies (ADAs). However, the presence of these ADAs did not generally alter the rate of plasma clearance of valanafusp alpha in MPSI. The infusion of 0.3-6 mg/kg doses of valanafusp alpha had no effect on plasma glucose for up to 24 h after the drug infusion. CONCLUSION: The plasma clearance of valanafusp alpha is increased four fold in children with MPSI compared with adult subjects at a dose of 1-3 mg/kg. The plasma pharmacokinetic profile of valanafusp alpha, at a dose of 1-3 mg/kg, is comparable to that of laronidase in children with MPSI. PMID- 29442295 TI - Sustainable technologies for recycling and reuse: an overview. PMID- 29442296 TI - First Report of the Presence of Hepatitis E Virus in Scottish-Harvested Shellfish Purchased at Retail Level. AB - Shellfish samples (n = 310) purchased from local supermarkets were analysed for the presence of hepatitis E virus (HEV) by nested RT-PCR and real-time qRT-PCR. Overall, 2.9% of samples tested positive for the presence of HEV. Phylogenetic analysis of HEV sequences revealed all as being genotype 3 HEV. This is the first report of the detection of HEV in commercially sold shellfish in Scotland. These findings may encourage further research that will help address the gaps in the knowledge in respect to foodborne transmission of HEV in Scotland and the rest of the United Kingdom. PMID- 29442297 TI - A Single-Center Cost Analysis of Treating Primary and Metastatic Brain Cancers with Either Brain Laser Interstitial Thermal Therapy (LITT) or Craniotomy. AB - BACKGROUND: Brain laser interstitial thermal therapy (LITT) under magnetic resonance imaging (MRI) guidance has recently gained US clinical approval for the ablation of soft, neurological tissue. LITT is a minimally invasive alternative to craniotomy. OBJECTIVE: While safety and efficacy are the focus of most current LITT studies, it is unclear how acute care costs (inpatient care +/- aftercare) of LITT compare to craniotomy in an academic medical center. Therefore, the purpose of this analysis is to examine these costs of using brain LITT under MRI guidance compared to craniotomy in complex anatomies. METHODS: Consecutive patients treated at a single US center from 1 January 2010 to 21 October 2014 were retrospectively evaluated. Patients were included if they had a primary procedure for LITT or craniotomy (International Classification of Diseases, 9th revision, Clinical Modification [ICD-9-CM] procedure code 17.61 or ICD-9-CM procedure code 01.59, respectively) and were subgrouped according to their diagnosis of primary brain or metastatic brain cancer (ICD-9-CM 191.0-191.9 or ICD-9-CM 198.3, respectively). Patients were excluded if they had co-morbid conditions such as brain edema (ICD-9-CM 348.5). Patients were matched (LITT vs. craniotomy) based on diagnosis. Appropriate statistical analyses were undertaken to examine the year 2015 costs for care in all settings (acute hospital and post hospital care, i.e., skilled nursing facility, rehabilitation, and home care) were examined. RESULTS: In patients treated for a primary brain cancer, there was no statistical difference in the acute and post-care costs of LITT and craniotomy (inverse variance, mean difference [MD], random effects model): MD = -US$1669; 95% confidence interval (CI) -$8192 to $4854; P = 0.62. When examining difficult to access primary malignancies, no difference was found: MD = -US$4719; 95% CI $12,183 to $2745; P = 0.22. In metastatic brain cancer, LITT was found to be significantly less costly than craniotomy: MD = -US$6522; 95% CI -$11,911 to $1133; P = 0.02. CONCLUSIONS: In patients with metastatic brain cancer, LITT is less costly than craniotomy. Patients receiving LITT had a significantly shorter length of hospital stay, were significantly older, and were more likely to be discharged home. The use of LITT may be a reasonable option in bundled episodes of care for brain cancer and may fit into the Bundled Payment for Care Improvement (BPCI) program being evaluated by Medicare and providers. PMID- 29442298 TI - Communal Sharing and the Provision of Low-Volume High-Cost Health Services: Results of a Survey. AB - INTRODUCTION: This paper suggests and tests a reason why the public might support the funding of services for rare diseases (SRDs) when the services are effective but not cost effective, i.e. when more health could be produced by allocating funds to other services. It is postulated that the fairness of funding a service is influenced by a comparison of the average patient benefit with the average cost to those who share the cost. METHODS: Survey respondents were asked to allocate a budget between cost-effective services that had a small effect upon a large number of relatively well patients and SRDs that benefited a small number of severely ill patients but were not cost effective because of their high cost. RESULTS: Part of the budget was always allocated to the SRDs. The budget share rose with the number sharing the cost. DISCUSSION: Sharing per se appears to characterise preferences. This has been obscured in studies that focus upon cost per patient rather than cost per person sharing the cost. PMID- 29442299 TI - Forecasting Pharmaceutical Prices for Economic Evaluations When There Is No Market: A Review. AB - BACKGROUND: Economic evaluation helps policy makers and healthcare payers make decisions on drug listing, coverage, and reimbursement. When economic evaluations are conducted before a product launch, the prices of the pharmaceuticals have to be forecast. OBJECTIVE: The aim of this study was to examine the methods of establishing proxy prices and their accuracies compared with actual market prices after the product launch. METHODS: We searched the literature for evaluations for drugs that were licensed in the US between 2010 and 2015. We reviewed the studies for the forecasting strategies used, and then estimated the difference between actual 2016 post-launch prices and what the proxy prices would be if the forecast was carried out in the US in 2016. RESULTS: We identified six such studies, with seven drugs. Four studies used substitute drugs as proxies for the study drug, and three used other methods. The range of the values of actual minus proxy price varied considerably, and no trend was observed. CONCLUSION: Forecasting drug prices is as precarious as forecasting in other areas of the economy. We urge caution in reviewing and accepting a cost-effectiveness ratio that is based on forecast prices. PMID- 29442301 TI - Authors' Reply to Holko: "Forecasting Pharmaceutical Prices for Economic Evaluations When There Is No Market: A Review". PMID- 29442300 TI - Population Screening for Hereditary Haemochromatosis in Australia: Construction and Validation of a State-Transition Cost-Effectiveness Model. AB - INTRODUCTION: HFE-associated haemochromatosis, the most common monogenic disorder amongst populations of northern European ancestry, is characterised by iron overload. Excess iron is stored in parenchymal tissues, leading to morbidity and mortality. Population screening programmes are likely to improve early diagnosis, thereby decreasing associated disease. Our aim was to develop and validate a health economics model of screening using utilities and costs from a haemochromatosis cohort. METHODS: A state-transition model was developed with Markov states based on disease severity. Australian males (aged 30 years) and females (aged 45 years) of northern European ancestry were the target populations. The screening strategy was the status quo approach in Australia; the model was run over a lifetime horizon. Costs were estimated from the government perspective and reported in 2015 Australian dollars ($A); costs and quality adjusted life-years (QALYs) were discounted at 5% annually. Model validity was assessed using goodness-of-fit analyses. Second-order Monte-Carlo simulation was used to account for uncertainty in multiple parameters. RESULTS: For validity, the model reproduced mortality, life expectancy (LE) and prevalence rates in line with published data. LE for C282Y homozygote males and females were 49.9 and 40.2 years, respectively, slightly lower than population rates. Mean (95% confidence interval) QALYS were 15.7 (7.7-23.7) for males and 14.4 (6.7-22.1) for females. Mean discounted lifetime costs for C282Y homozygotes were $A22,737 (3670-85,793) for males and $A13,840 (1335-67,377) for females. Sensitivity analyses revealed discount rates and prevalence had the greatest impacts on outcomes. CONCLUSION: We have developed a transparent, validated health economics model of C282Y homozygote haemochromatosis. The model will be useful to decision makers to identify cost-effective screening strategies. PMID- 29442302 TI - Comment on: "Forecasting Pharmaceutical Prices for Economic Evaluations When There is No Market: A Review". PMID- 29442303 TI - Economic Impact of Mirabegron Versus Antimuscarinics for the Treatment of Overactive Bladder in the UK. AB - PURPOSE: Our objective was to estimate the economic outcomes of using mirabegron versus antimuscarinics in the treatment of patients with overactive bladder (OAB) from a societal perspective in the UK. MATERIALS AND METHODS: A Markov model was developed using Microsoft Excel(r). The time horizon and cycle length are 12 and 1 months, respectively; and the hypothetical cohort size 100 patients. Antimuscarinic comparators are fesoterodine, oxybutynin extended release (ER) and immediate release (IR), solifenacin, tolterodine ER/IR, trospium ER/IR, darifenacin and flavoxate. Model inputs included real-world treatment patterns data, healthcare resource use (e.g. clinic visits) and direct and indirect costs (e.g. drug acquisition and productivity loss). Model outputs included patient disposition, healthcare resource use, drug acquisition costs and other treatment related costs over a 1-year time horizon. A one-way sensitivity analysis was performed to determine the key drivers of the model. RESULTS: In a hypothetical cohort of 100 patients, total annual costs per patient were lower with mirabegron than with all antimuscarinics (L1270.84 vs. 1321.71-1607.48). Healthcare resource use was lower with mirabegron than with all antimuscarinics (115 vs. 119-123 general practitioner visits; 173 vs. 178-185 specialist visits and 0.0042 vs. 0.0050-0.0060 surgical operations) and fewer work hours were lost (4017 vs. 5114 6990 [all per 100 patients]). Sensitivity analysis showed the model was sensitive to persistence and switching rates, although the impact on the overall results was minimal. CONCLUSIONS: In the UK, using mirabegron to treat OAB may improve persistence and lead to reductions in switching treatment, healthcare resource utilization, productivity costs, and overall treatment costs versus antimuscarinics. PMID- 29442304 TI - Effect of calcination temperature on the properties of Ti/SnO2-Sb anode and its performance in Ni-EDTA electrochemical degradation. AB - Pd-doped Ti/SnO2-Sb anode was prepared at different calcination temperatures by a wet-impregnation method and employed in simultaneous electrochemical catalytic degradation of Ni-EDTA and recovery of nickel. The results showed that Ti/SnO2-Sb Pd-500 could achieve the highest electrochemical activity (87.5% of Ni-EDTA removal efficiency), superior durability (50.7 h of accelerated lifetime), and higher Ni recovery (19.8%) on cathode. Cyclic voltammetry (CV) and linear sweep voltammetry (LSV) analysis suggested that Ni-EDTA degradation on anode was mainly indirect oxidation-controlled reaction, attributing to the high oxide state of MOX + 1 and MOX(.OH), rather than direct oxidation. Scanning electron microscope (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) analyses indicated that calcination temperature could modify the morphology of electrode surface and affect the incorporation and valence state transformation of metal species (Sb and Pd) in SnO2 lattice. Ti/SnO2-Sb-Pd-500 achieved the highest electrochemical capacity with the highest levels of adsorbed oxygen Oads/ET (27.11%) and lattice oxygen Olat/ET (29.69%). Moreover, the operation conditions for Ni-EDTA electrochemical degradation were optimized. These findings were valuable for developing a high-performance electrode for Ni-EDTA electrochemical degradation. PMID- 29442305 TI - Antioxidant capacity of omega-3-fatty acids and vitamin E against imidacloprid induced hepatotoxicity in Japanese quails. AB - Imidacloprid (IM) is a neonicotinoid insecticide, used in a wide range of agricultural activities worldwide. However, it results in ecosystem disturbances and signs of toxicity in human and animals. The current study was designed to elucidate the protective effects of omega-3-fatty acids (OFAs) and vitamin E (Vit E) against IM hepatotoxicity in Japanese quails. Seventy male quails (30 days old) were divided into seven groups (n = 10); G1 -ve control; G2 received IM (+ve control); G3 received OFA; G4 received Vit E; and G5, G6, and G7 received OFA and/or Vit E with IM for 30 days, respectively. Blood and liver tissue samples were collected. Imidacloprid significantly (p < 0.05) increased serum levels of alanine transferase (ALT), aspartate transferase (AST), triglycerides (TGC), and low-density lipoprotein cholesterol (LDL-C), as well as liver tissue malondialdehyde (MDA) concentration. Moreover, IM caused a significant (p < 0.05) decrease in the levels of serum high-density lipoprotein cholesterol (HDL-C), as well as liver superoxide dismutase (SOD) enzyme activity and reduced-glutathione (GSH) concentration in comparison to the -ve control group. Histopathological changes in hepatocytes, including thick cell trabeculae with marked hydropic vacuolar degeneration of cytoplasm, were found in IM-treated group. Treatment with OFA and/or Vit E resulted in significant improvements in general body condition, serum HDL-C level, and liver tissue SOD enzyme activity and GSH concentration, as well as significant decreases in the levels of serum AST, ALT, TGC, LDL-C, and hepatic tissue MDA. In conclusion, OFA and Vit E have a protective effect against IM toxicity, especially in their combination. PMID- 29442306 TI - Protective effect of Uncaria tomentosa extract against oxidative stress and genotoxicity induced by glyphosate-Roundup(r) using zebrafish (Danio rerio) as a model. AB - Oxidative stress and DNA damage are involved in the glyphosate-based herbicide toxicity. Uncaria tomentosa (UT; Rubiaceae) is a plant species from South America containing bioactive compounds with known beneficial properties. The objective of this work was to evaluate the antioxidant and antigenotoxic potential of UT extract in a model of acute exposure to glyphosate-Roundup(r) (GR) in zebrafish (Danio rerio). We showed that UT (1.0 mg/mL) prevented the decrease of brain total thiols, the increase of lipid peroxidation in both brain and liver, and the decrease of liver GPx activity caused after 96 h of GR (5.0 mg/L) exposure. In addition, UT partially protected against the increase of micronucleus frequency induced by GR exposure in fish brain. Overall, our results indicate that UT protects against damage induced by a glyphosate-based herbicide by providing antioxidant and antigenotoxic effects, which may be related to the phenolic compounds identified in the extract. PMID- 29442307 TI - Hypertension prevalence and living conditions related to air pollution: results of a national epidemiological study in Lebanon. AB - Hypertension is a risk factor of several diseases, linked to high mortality and morbidity, particularly in developing countries. Some studies have linked indoor and outdoor pollution exposure items to hypertension, but results were inconsistent. Our objective was to assess the association of living conditions related to air pollution to hypertension in Lebanon, a Middle Eastern country. A national cross-sectional study was conducted all over Lebanon. Blood pressure and its related medications were assessed to be able to classify participants as hypertensive or not. Moreover, in addition to living conditions related to air pollution exposure, we assessed potential predictors of hypertension, including sociodemographic characteristics, self-reported health information and biological measurements. Furthermore, we assessed dose-effect relationship of air pollution items in relation with hypertension. Living conditions related to indoor and outdoor air pollution exposures were associated with hypertension, with or without taking biological values into account. Moreover, we found a dose-effect relationship of exposure with risk of disease (15% increase in risk of disease for every additional pollution exposure item), after adjustment for sociodemographics and biological characteristics (Ora = 1.15 [1.03-1.28]). Although additional studies would be necessary to confirm these findings, interventions should start to sensitize the population about the effect of air pollution on chronic diseases. The work on reducing pollution and improving air quality should be implemented to decrease the disease burden on the population and health system. PMID- 29442308 TI - Nanofibers of resorcinol-formaldehyde for effective adsorption of As (III) ions from mimicked effluents. AB - In the present study, the core-shell structured RF/PVA nanofibers have been developed and used for the adsorption of As3+ ions from the mimicked liquid effluents. Efficient-facile fabrication of the structured nanofibers (300-417 nm diameter) was accomplished using facile electrospinning technique. Chi parameter (chi = 25.56) and free energy of mixing (Emix = 17.19 kcal/mol) calculated via molecular dynamics simulations depicted compatibility of the polymeric system resulting supermolecular core-shell nanofibers, whose adsorption results were also supported by the FE-SEM, FT-IR, and UV-VIS spectroscopy analysis. The adsorption analysis was performed using both linear and non-linear regression methods, for kinetic models and adsorption isotherms. The developed nanofibers demonstrated an adsorption capacity of 11.09 mg/g at a pH of 7, and an adsorption efficiency of 97.46% on protracted exposure, which is even adaptable at high temperatures with 93.1% reclamation. FE-SEM analysis and FT-IR spectra confirm the adsorption of As (III) ions on RF/PVA nanofibers and the presence of embedded hydrophilic oxygen sites for metal ion adsorption. The developed RF/PVA nanofibers demonstrate scalability in fabrication, low-cost, recycling, and less solid waste generation, depicting the large-scale applicability in removing arsenic ions from effluent waste. Graphical Abstract ?. PMID- 29442309 TI - Lead-induced changes of cytoskeletal protein is involved in the pathological basis in mice brain. AB - Lead poisoning is a geochemical disease. On the other hand, lead is highly carcinogenic and exhibits liver and kidney toxicity. This element can also cross the blood-brain barrier, reduce learning and memory ability and damage the structure of the cerebral cortex and hippocampus. To further investigate the mechanism of lead neurotoxicity, 4-week-old Kunming mice were used to explore the effects of different concentrations of Pb2+ (0, 2.4, 4.8 and 9.6 mM) for 9 days. In this study, pathological and ultrastructural changes in brain cells of the treated group were related to damages to mitochondria, chromatin and the nucleus. Lead content in blood was tested by atomic absorption spectroscopy, which showed high lead concentrations in the blood with increasing doses of lead. Distribution of lead in nerve cells was analysed by transmission electron microscopy with energy dispersive spectroscopy. Data showed the presence of lead in nucleopores, chromatin and nuclear membrane of nerve cells in the treatment groups, whereas lead content increased with increasing doses of lead acetate. Finally, microtubule-associated protein 2 (MAP2) mRNA and protein expression levels were detected by real-time PCR and Western blotting, which showed a reduction in MAP2 expression with increasing lead doses in the mouse brain. These findings suggest that acute lead poisoning can cause significant dose-dependent toxic effects on mouse brain function and can contribute to better understanding of lead-induced toxicity. PMID- 29442310 TI - Synthesis and characterization of Ag/Bi2WO6/GO composite for the fast degradation of tylosin under visible light. AB - Ag/Bi2WO6/graphene oxide composite with excellent photocatalytic properties was successfully prepared by hydrothermal-photoreduction synergistic method and is applied in antibiotics degradation. The structure and properties of as-prepared photocatalysts were characterized by Fourier infrared spectrum (FTIR), X-ray photoelectron spectroscopy (XPS), specific surface area analyzer (BET), scanning electron microscopy (SEM), X-ray diffraction (XRD), and atomic force microscope (AFM). The results indicated that Ag and Bi2WO6 were uniformly loaded on the surface of graphene oxide. In addition, graphene oxide with conjugated carbon network structures has been applied as a photocatalyst supporter for the high electronic conductivity and the large reactive sites. Compared with the pure graphene oxide, the as-prepared Ag/Bi2WO6/graphene oxide catalyst exhibited excellent degradation efficiency and stability for degrading tylosin under Xe lamp irradiation. Under simulated sunlight irradiation, the photodegradation efficiency of tylosin by Ag/Bi2WO6/graphene oxide achieved at 98% within 2 h, compared to 50% by pure graphene oxide. The excellent photodegradation ability is caused by the synergetic effect of Ag, Bi2WO6, and graphene oxide nanoparticles. PMID- 29442311 TI - Effect of H2O on the NO emission characteristics of pulverized coal during oxy fuel combustion. AB - The NO emission characteristics of Datong bituminous coal and Yangquan anthracite in O2/H2O/CO2 atmospheres were investigated by using a fixed-bed reactor system, and the emission characteristics were compared with the experimental results from O2/N2 and O2/CO2 atmospheres, especially at low O2 concentrations and high temperatures. The results showed that NO emissions of pulverized coal in O2/CO2 environments were less than those in the O2/N2 environments, regardless of the O2 concentration and the furnace temperature. Adding H2O decreased the possibility of reactions between the reductive groups (NH) and the oxygen radical during devolatilization, which led to a decrease in NO emissions at 1000 degrees C. However, as the furnace temperature increased, "additional" nitrogen precursors (HCN and NH3) generated by enhanced char-H2O gasification were quickly oxidized to generate a large amount of NO during char oxidation that exceeded the amount of NO reduced by NH during devolatilization. Thus, the NO emissions in O2/CO2/H2O atmosphere were higher than those in O2/CO2 atmosphere at a low O2 concentration. However, as the O2 concentration increased, the NO emissions in O2/CO2/H2O atmosphere became lower than those in O2/CO2 atmosphere because the effect of H2O gasification became weaker. The NO emissions of Yangquan anthracite (YQ) were higher than those of DT, but the changing trend of YQ was similar to that of DT. PMID- 29442312 TI - Halimeda jolyana (Bryopsidales, Chlorophyta) presents higher vulnerability to metal pollution at its lower temperature limits of distribution. AB - Seaweeds living at their temperature limits of distribution are naturally exposed to physiological stressors, facing additional stress when exposed to coastal pollution. The physiological responses of seaweeds to environmental conditions combining natural and anthropogenic stressors provide important information on their vulnerability. We assessed the physiological effects and ultrastructural alterations of trace metals enrichment at concentrations observed in polluted regions within the temperature ranges of distribution of the endemic seaweed Halimeda jolyana, an important component of tropical southwestern Atlantic reefs. Biomass yield and photosynthetic performance declined substantially in samples exposed to metal, although photosynthesis recovered partially at the highest temperature when metal enrichment was ceased. Metal enrichment caused substantial ultrastructural alterations to chloroplasts regardless of temperatures. The lack of photosynthetic recovery at the lower temperatures indicates a higher vulnerability of the species at its temperature limits of distribution in the southwestern Atlantic. PMID- 29442313 TI - Impact of oxytetracycline and bacterial bioaugmentation on the efficiency and microbial community structure of a pesticide-degrading biomixture. AB - An experimental study evaluating the effect of bioaugmentation and antibiotic (oxytetracycline) application on pesticide degradation and microbial community structure of a biomixture used in a biopurification system (BPR) was conducted. The bioaugmentation employed a carbofuran-degrading bacterial consortium. The non bioaugmented biomixture showed excellent performance for removal of atrazine (t1/2: 9.9 days), carbendazim (t1/2: 3.0 days), carbofuran (t1/2: 2.8 days), and metalaxyl (t1/2: 2.7 days). Neither the addition of oxytetracycline nor bioaugmentation affected the efficiency of pesticide removal or microbial community (bacterial and fungal) structure, as determined by DGGE analysis. Instead, biomixture aging was mainly responsible for microbial population shifts. Even though the bioaugmentation did not enhance the biomixtures' performance, this matrix showed a high capability to sustain initial stresses related to antibiotic addition; therefore, simultaneous elimination of this particular mixture of pesticides together with oxytetracycline residues is not discouraged. PMID- 29442314 TI - Comparative Genomics of the Zic Family Genes. AB - Zic family genes encode five C2H2-type zinc finger domain-containing proteins that have many roles in animal development and maintenance. Recent phylogenetic analyses showed that Zic family genes are distributed in metazoans (multicellular animals), except Porifera (sponges) and Ctenophora (comb jellies). The sequence comparisons revealed that the zinc finger domains were absolutely conserved among the Zic family genes. Zic zinc finger domains are similar to, but distinct from those of the Gli, Glis, and Nkl gene family, and these zinc finger protein families are proposed to have been derived from a common ancestor gene. The Gli Glis-Nkl-Zic superfamily and some other eukaryotic zinc finger proteins share a tandem CWCH2 (tCWCH2) motif, a hallmark for inter-zinc finger interaction between two adjacent C2H2 zinc fingers. In Zic family proteins, there exist additional evolutionally conserved domains known as ZOC and ZFNC, both of which may have appeared before cnidarian-bilaterian divergence. Comparison of the exon-intron boundaries in the Zic zinc finger domains revealed an intron (A-intron) that was absolutely conserved in bilaterians (metazoans with bilateral symmetry) and a placozoan (a simple nonparasitic metazoan). In vertebrates, there are five to seven Zic paralogs among which Zic1, Zic2, and Zic3 are generated through a tandem gene duplication and carboxy-terminal truncation in a vertebrate common ancestor, sharing a conserved carboxy-terminal sequence. Several hypotheses have been proposed to explain the Zic family phylogeny, including their origin, unique features in the first and second zinc finger motif, evolution of the nuclear localization signal, significance of the animal taxa-selective degeneration, gene multiplication in the vertebrate lineage, and involvement in the evolutionary alteration of the animal body plan. PMID- 29442315 TI - Cnidarian Zic Genes. AB - To understand the ancestral and evolved roles of zic homologs, it is important to reconstruct the putative roles of ancient zic homologs in the animal phylogeny. Most studies of zic genes have been conducted in model systems that are members of the bilaterian phylum. However, two additional phyla have zic homologs encoded in their genomes. The three animal phyla that contain zic homologs all share a common ancestor and collectively are termed the parahoxozoans (cnidarians (corals, sea anemones, and jellyfish), placozoans (Trichoplax adhaerens), and bilaterians (chordates, insects, nematodes, annelids, echinoderms, etc.). In this chapter we briefly discuss our understanding of zic genes in the parahoxozoans with a particular focus on how expression of cnidarian zic homologs in the medusozoan Hydra vulgaris and the anthozoan Nematostella vectensis informs our understanding of the putative ancestral roles zic homologs played in the cnidarian-bilaterian common ancestor. PMID- 29442316 TI - Odd-Paired: The Drosophila Zic Gene. AB - Zinc finger in the cerebellum (Zic) proteins are a family of transcription factors with multiple roles during development, particularly in neural tissues. The founding member of the Zic family is the Drosophila odd-paired (opa) gene. The Opa protein has a DNA binding domain containing five Cys2His2-type zinc fingers and has been shown to act as a sequence-specific DNA binding protein. Opa has significant homology to mammalian Zic1, Zic2, and Zic3 within the zinc finger domain and in two other conserved regions outside that domain. opa was initially identified as a pair-rule gene, part of the hierarchy of genes that establish the segmental body plan of the early Drosophila embryo. However, its wide expression pattern during embryogenesis indicates it plays additional roles. Embryos deficient in opa die before hatching with aberrant segmentation but also with defects in larval midgut formation. Post-embryonically, opa plays important roles in adult head development and circadian rhythm. Based on extensive neural expression, opa is predicted to be involved in many aspects of neural development and behavior, like other proteins of the Zic family. Consensus DNA binding sites have been identified for Opa and have been shown to activate transcription in vivo. However, there is evidence Opa may serve as a transcriptional regulator in the absence of direct DNA binding, as has been seen for other Zic proteins. PMID- 29442317 TI - Zic Genes in Nematodes: A Role in Nervous System Development and Wnt Signaling. AB - Transcription factors of the Zic family play important roles during animal development, and their misregulation has been implicated in several human diseases. Zic proteins are present in nematodes, and their function has been mostly studied in the model organism C. elegans. C. elegans possesses only one Zic family member, REF-2. Functional studies have shown that this factor plays a key role during the development of the nervous system, epidermis, and excretory system. In addition, they have revealed that the C. elegans Zic protein acts as an atypical mediator of the Wnt/beta-catenin pathway. In other animals including vertebrates, Zic factors are also regulators of nervous system development and modulators of Wnt signaling, suggesting that these are evolutionary ancient functions of Zic proteins. PMID- 29442318 TI - Lophotrochozoan Zic Genes. AB - Lophotrochozoa is a sister taxon of Ecdysozoa in the Protostomia that includes mollusks, annelids, brachiopods, and platyhelminths. Recent studies have clarified the structure, expression, and roles of lophotrochozoan Zic family genes. Zic genes in oligochaete annelid Tubifex tubifex (freshwater sludge worm) and polychaete annelid Capitella teleta (bristle worm) are commonly expressed in a subset of developing brain and mesoderm derivatives. The latter includes the naive mesoderm and the associated chaetal sacs in each body segment, although the segmentation processes differ between the two species. Furthermore, in brachiopod Terebratalia transversa (lamp shell), Zic is expressed in the anterior ectodermal domains and mesodermal derivatives, including those associated with the chaetal sacs. This result suggests the common involvement of Zic genes in the development of chaetae, a lophotrochozoan novelty acquired in the course of evolution. In addition, the highly simplified lophotrochozoan Dicyema acuticephalum (dicyemid mesozoan, a cephalopod endoparasite), which lost its gut, nervous system, and muscles during evolution, expresses its Zic genes in hermaphroditic gonads, highlighting the role of Zic genes in germ cell development. The role of Zic in head regeneration was revealed in studies on platyhelminth Schmidtea mediterranea (freshwater planarian). Planarian Zic expression was induced in a subpopulation of neoblasts that includes adult pluripotent stem cells. It is needed for head regeneration and production of an anterior signaling center. Suppression of Wnt beta-catenin signaling underlies Zic-mediated head regeneration, reminiscent of Wnt-beta-catenin suppression by vertebrate Zic genes. Taken together, studies on the lophotrochozoan Zic genes are essential to understanding not only the roles of these genes in body plan evolution but also the molecular mechanism underlying adult stem cell regulation. PMID- 29442319 TI - Ascidian Zic Genes. AB - Ascidians are tunicates, which constitute the sister group of vertebrates. The ascidian genome contains two Zic genes, called Zic-r.a (also called Macho-1) and Zic-r.b (ZicL). The latter is a multi-copy gene, and the precise copy number has not yet been determined. Zic-r.a is maternally expressed, and soon after fertilization Zic-r.a mRNA is localized in the posterior pole of the zygote. Zic r.a protein is translated there and is involved in specification of posterior fate; in particular it is important for specification of muscle fate. Zic-r.a is also expressed zygotically in neural cells of the tailbud stage. On the other hand, Zic-r.b is first expressed in marginal cells of the vegetal hemisphere of 32-cell embryos and then in neural cells that contribute to the central nervous system during gastrulation. Zic-r.b is required first for specification of mesodermal tissues and then for specification of the central nervous system. Their upstream and downstream genetic pathways have been studied extensively by functional assays, which include gene knockdown and chromatin immunoprecipitation assays. Thus, ascidian Zic genes play central roles in specification of mesodermal and neural fates. PMID- 29442320 TI - Amphibian Zic Genes. AB - Studies in Xenopus laevis have greatly contributed to understanding the roles that the Zic family of zinc finger transcription factors play as essential drivers of early development. Explant systems that are not readily available in other organisms give Xenopus embryos a unique place in these studies, facilitated by the recent sequencing of the Xenopus laevis genome. A number of upstream regulators of zic gene expression have been identified, such as inhibition of BMP signaling, as well as calcium, FGF, and canonical Wnt signaling. Screens using induced ectodermal explants have identified genes that are direct targets of Zic proteins during early neural development and neural crest specification. These direct targets include Xfeb (also called glipr2; hindbrain development), aqp3b (dorsal marginal zone in gastrula embryos and neural folds), snail family members (premigratory neural crest), genes that play roles in retinoic acid signaling, noncanonical Wnt signaling, and mesoderm development, in addition to a variety of genes some with and many without known roles during neural or neural crest development. Functional experiments in Xenopus embryos demonstrated the involvement of Zic family members in left-right determination, early neural patterning, formation of the midbrain-hindbrain boundary, and neural crest specification. The role of zic genes in cell proliferation vs. differentiation remains unclear, and the activities of Zic factors as inhibitors or activators of canonical Wnt signaling may be dependent on developmental context. Overall, Xenopus has contributed much to our understanding of how Zic transcriptional activities shape the development of the embryo and contribute to disease. PMID- 29442321 TI - Zic Genes in Teleosts: Their Roles in Dorsoventral Patterning in the Somite. AB - The medaka contains seven zic genes, two of which, zic1 and zic4, have been studied extensively. The analyses are mainly based on the double anal fin (Da) mutant, which was isolated from the wild. Da is an enhancer mutant of zic1/zic4, and the expression of zic1/zic4 is specifically lost in the dorsal half of the somites, which leads to a mirror-image duplication of the ventral half across the lateral midline from larva to adult. The studies of medaka Da give us important insights into the function of zic1/zic4 in mesodermal tissues and also the mechanism of dorsoventral patterning in the vertebrate trunk region occurring during late development, which is a long-standing mystery in developmental biology. In this chapter, we introduce genomic organization of medaka zic genes and discuss their function, mainly focusing on zic1 and zic4 in dorsoventral patterning of the trunk region and possible connections to human congenital disorders. PMID- 29442322 TI - Zebrafish Zic Genes Mediate Developmental Signaling. AB - The introduction of genomics into the field of developmental biology led to a vast expansion of knowledge about developmental genes and signaling mechanisms they are involved in. Unlike mammals, the zebrafish features seven Zic genes. This provides an interesting insight into Zic gene evolution. In addition, an unprecedented bioimaging capability of semitransparent zebrafish embryos turns to be a crucial factor in medium- to large-scale analysis of the activity of potential regulatory elements. The Zic family of zinc finger proteins plays an important, relatively well-established, role in the regulation of stem cells and neural development and, in particular, during neural fate commitment and determination. At the same time, some Zic genes are expressed in mesodermal lineages, and their deficiency causes a number of developmental defects in axis formation, establishing body symmetry and cardiac morphogenesis. In stem cells, Zic genes are required to maintain pluripotency by binding to the proximal promoters of pluripotency genes (Oct4, Nanog, Sox2, etc.). During embryogenesis, the dynamic nature of Zic transcriptional regulation is manifested by the interaction of these factors with distal enhancers and other regulatory elements associated with the control of gene transcription and, in particular, with the Nodal and Wnt signaling pathways that play a role in establishing basic organization of the vertebrate body. Zic transcription factors may regulate development through acting alone as well as in combination with other transcription factors. This is achieved due to Zic binding to sites adjacent to the binding sites of other transcription factors, including Gli. This probably leads to the formation of multi-transcription factor complexes associated with enhancers. PMID- 29442323 TI - Overview of Rodent Zic Genes. AB - The five murine Zic genes encode multifunctional transcriptional regulator proteins important for a large number of processes during embryonic development. The genes and proteins are highly conserved with respect to the orthologous human genes, an attribute evidently mirrored by functional conservation, since the murine and human genes mutate to give the same phenotypes. Each ZIC protein contains a zinc finger domain that participates in both protein-DNA and protein protein interactions. The ZIC proteins are capable of interacting with the key transcriptional mediators of the SHH, WNT and NODAL signalling pathways as well as with components of the transcriptional machinery and chromatin-modifying complexes. It is possible that this diverse range of protein partners underlies characteristics uncovered by mutagenesis and phenotyping of the murine Zic genes. These features include redundant and unique roles for ZIC proteins, regulatory interdependencies amongst family members and pleiotropic Zic gene function. Future investigations into the complex nature of the Zic gene family activity should be facilitated by recent advances in genome engineering and functional genomics. PMID- 29442324 TI - Rodent Zic Genes in Neural Network Wiring. AB - The formation of the nervous system is a multistep process that yields a mature brain. Failure in any of the steps of this process may cause brain malfunction. In the early stages of embryonic development, neural progenitors quickly proliferate and then, at a specific moment, differentiate into neurons or glia. Once they become postmitotic neurons, they migrate to their final destinations and begin to extend their axons to connect with other neurons, sometimes located in quite distant regions, to establish different neural circuits. During the last decade, it has become evident that Zic genes, in addition to playing important roles in early development (e.g., gastrulation and neural tube closure), are involved in different processes of late brain development, such as neuronal migration, axon guidance, and refinement of axon terminals. ZIC proteins are therefore essential for the proper wiring and connectivity of the brain. In this chapter, we review our current knowledge of the role of Zic genes in the late stages of neural circuit formation. PMID- 29442325 TI - Zic Family Proteins in Emerging Biomedical Studies. AB - Zic family proteins have been investigated in various biomedical studies. Here we summarize the contact points between Zic proteins and recent medical research. The topics cover a wide range, reflecting the pleiotropic roles of these proteins in early embryogenesis and organogenesis. Zic1, Zic2, and Zic3 proteins play important roles in the development of axial and limb bones, and of muscles, among the derivatives of the notochord and somites. Zic1 is involved in bone's response to mechanical stress, and it also serves as a marker specific for brown adipocytes. Zic1, Zic2, Zic3, and Zic5 proteins are required for the development of neural crest derivatives, including the meningeal membrane and facial bones, and deficiency of these proteins causes cortical lamination defects resembling those in type II lissencephaly. In vascular systems, Zic3 is associated not only with normal cardiovascular development, failure of which causes congenital heart anomalies, but also controls maturation of the blood-brain barrier. Zic1 is also expressed in the brain pericytes possessing stem cell properties that control the blood-brain barrier activity and capillary hemodynamic responses. The possible involvement of Zic proteins in neuropsychiatric disorders has been indicated by the analyses of mutant mice behaviors. Zic1 and Zic3 mutant mice show hypotonia and decreased locomotor activities. Zic2 hypomorphic mutant mice exhibit schizophrenia-related behavioral abnormalities such as cognitive dysfunction and impaired sensorimotor gating and social behaviors, and ZIC2 mutations found in schizophrenia patients included a severely functionally defective one. Based on these facts, the application of Zic protein activities in translational medicine might be considered. PMID- 29442326 TI - ZIC1 Function in Normal Cerebellar Development and Human Developmental Pathology. AB - Zic genes are strongly expressed in the cerebellum. This feature leads to their initial identification and their name "zic," as the abbreviation of "zinc finger protein of the cerebellum." Zic gene function in cerebellar development has been investigated mainly in mice. However, association of heterozygous loss of ZIC1 and ZIC4 with Dandy-Walker malformation, a structural birth defect of the human cerebellum, highlights the clinical relevance of these studies. Two proposed mechanisms for Zic-mediated cerebellar developmental control have been documented: regulation of neuronal progenitor proliferation-differentiation and the patterning of the cerebellar primordium. Clinical studies have also revealed that ZIC1 gain of function mutations contribute to coronal craniosynostosis, a rare skull malformation. The molecular pathways contributing to these phenotypes are not fully explored; however, embryonic interactions with sonic hedgehog signaling, retinoic acid signaling, and TGFbeta signaling have been described during mouse cerebellar development. Further, Zic1/2 target a multitude of genes associated with cerebellar granule cell maturation during postnatal mouse cerebellar development. PMID- 29442327 TI - ZIC2 in Holoprosencephaly. AB - The ZIC2 transcription factor is one of the most commonly mutated genes in Holoprosencephaly (HPE) probands. HPE is a severe congenital defect of forebrain development which occurs when the cerebral hemispheres fail to separate during the early stages of organogenesis and is typically associated with mispatterning of the embryonic midline. Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that ZIC2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non forebrain phenotypes. Furthermore, the studies confirm the extent of ZIC2 allelic heterogeneity and that pathogenic variants of ZIC2 are associated with both classic and middle interhemispheric variant (MIHV) HPE which arise from defective ventral and dorsal forebrain patterning, respectively. An allelic series of mouse mutants has helped to delineate the cellular and molecular mechanisms by which one gene leads to defects in these related but distinct embryological processes. PMID- 29442328 TI - ZIC3 in Heterotaxy. AB - Mutation of ZIC3 causes X-linked heterotaxy, a syndrome in which the laterality of internal organs is disrupted. Analysis of model organisms and gene expression during early development suggests ZIC3-related heterotaxy occurs due to defects at the earliest stage of left-right axis formation. Although there are data to support abnormalities of the node and cilia as underlying causes, it is unclear at the molecular level why loss of ZIC3 function causes such these defects. ZIC3 has putative roles in a number of developmental signalling pathways that have distinct roles in establishing the left-right axis. This complicates the understanding of the mechanistic basis of Zic3 in early development and left right patterning. Here we summarise our current understanding of ZIC3 function and describe the potential role ZIC3 plays in important signalling pathways and their links to heterotaxy. PMID- 29442329 TI - Deregulation of ZIC Family Members in Oncogenesis. AB - In the last decade, the amount of investigations on the involvement of ZIC genes in the cancer field have exponentially expanded. In most cancer types, promoter methylation leads to silenced ZIC family members, but specific subsets of patients clearly show increased expression of one or head-to-head located ZIC genes in the respective tumor tissue. It is unclear at this stage how these transcription factors contribute to tumorigenesis, but the potential implications in pathways that are most frequently mutated in cancer such as the canonical Wnt, TGF-beta, and STAT-3 pathway are evident. By exploring well-established developmental models, researchers were able to position ZIC genes not only as classical transcription factors but also as cofactors of chromatin remodeling complexes that are crucial for maintenance of the cell but also during differentiation and maturation of ZIC-expressing tissues in vivo. The translation of this obtained evidence to the cancer field will be challenging but will indisputably lead to a better understanding how the factors can contribute to the tumor development in the given subsets of patients. PMID- 29442330 TI - Roles of ZIC2 in Regulation of Pluripotent Stem Cells. AB - Pioneered by the classical mouse embryonic stem cells (ESCs), various stem cell lines representing the peri- and postimplantation stages of embryogenesis have been established. To gain insight into the gene regulatory network operating in these cells, we first investigated epiblast stem cells (EpiSCs), performing ChIP seq analysis for five major transcription factors (TFs) involved in epiblast regulation. The analysis indicated that SOX2-POU5F1 TF pairs highlighted in mouse ESCs are not the major players in other stem cells. The major acting transcription factors shift from SOX2/POU5F1 in mouse ESCs to ZIC2/OTX2 in EpiSCs, and this shift is primed in ESCs by binding of ZIC2 at relevant genomic positions that later function as enhancers. PMID- 29442331 TI - Role of Zic Family Proteins in Transcriptional Regulation and Chromatin Remodeling. AB - Proper functions of Zic proteins are essential for animals in health and disease. Here, we summarize our current understanding of the molecular properties and functions of the Zic family across animal species and paralog subtypes. Zics are basic proteins with some posttranslational modifications and can move to the cell nucleus via importin- and CRM1-based nucleocytoplasmic shuttling mechanisms. Degradation is mediated by the ubiquitin proteasome system. Many Zic proteins are capable of binding to two types of target DNA sequences (CTGCTG-core-type and GC stretch-type). Recent chromatin immunoprecipitation assays showed that CTGCTG core-type target sequences are enriched in enhancers. Nonetheless, the DNA binding is not always required for transcriptional regulation by Zic proteins. On the other hand, Zic proteins bind many proteins including transcription factors (Gli1-3, Tcf1 or Tcf4, Smad2 or Smad3, Oct4, Pax3, Cdx, and SRF), chromatin remodeling factors (NuRD and NURF), and other nuclear enzymes (DNA-PK, PARP1, and RNA helicase A). Zic family-mediated gene expression control involves both their actions near the transcription start site and those affecting the global gene expression via binding to enhancers. Although Zic proteins perform essential functions in transcriptional regulation of Oct4 and Nanog expression via their promoters, recent genome-wide analyses of the Zic-binding sites and their downstream targets indicate that Zic proteins are associated with distant regulatory elements and are the critical enhancer-priming nuclear regulators in organismal development. Chromatin-remodeling complexes such as NuRD and NURF that interact with Zic proteins have been shown to participate in Zic-mediated enhancer regulation. PMID- 29442332 TI - Issues Related to the Frequency of Exploratory Analyses by Evidence Review Groups in the NICE Single Technology Appraisal Process. AB - BACKGROUND: Evidence Review Groups (ERGs) critically appraise company submissions as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) process. As part of their critique of the evidence submitted by companies, the ERGs undertake exploratory analyses to explore uncertainties in the company's model. The aim of this study was to explore pre defined factors that might influence or predict the extent of ERG exploratory analyses. OBJECTIVE: The aim of this study was to explore predefined factors that might influence or predict the extent of ERG exploratory analyses. METHODS: We undertook content analysis of over 400 documents, including ERG reports and related documentation for the 100 most recent STAs (2009-2014) for which guidance has been published. Relevant data were extracted from the documents and narrative synthesis was used to summarise the extracted data. All data were extracted and checked by two researchers. RESULTS: Forty different companies submitted documents as part of the NICE STA process. The most common disease area covered by the STAs was cancer (44%), and most ERG reports (n = 93) contained at least one exploratory analysis. The incidence and frequency of ERG exploratory analyses does not appear to be related to any developments in the appraisal process, the disease area covered by the STA, or the company's base-case incremental cost effectiveness ratio (ICER). However, there does appear to be a pattern in the mean number of analyses conducted by particular ERGs, but the reasons for this are unclear and potentially complex. CONCLUSIONS: No clear patterns were identified regarding the presence or frequency of exploratory analyses, apart from the mean number conducted by individual ERGs. More research is needed to understand this relationship. PMID- 29442333 TI - Cost-Benefit Analysis of Telemedicine Systems/Units in Greek Remote Areas. AB - BACKGROUND: Telemedicine units and information technology systems provide special healthcare services to remote populations using telecommunication technology, in order to reduce or even remove the usual and typical face-to-face contact between doctor and patient. This innovative approach to medical care delivery has been expanding for several years and currently covers various medical specialties. OBJECTIVE: To facilitate installation of telemedicine systems/units in Greek remote areas, this article presents results of a cost-benefit analysis for two Greek islands, Patmos and Leros, using specific economic criteria. METHODS: Net present value (NPV), internal rate of return (IRR), and payback period were calculated, in order to monetize the economic benefits and the costs savings, estimate the depreciation of each project, and highlight the social benefits. RESULTS: Costs were reduced (through saved air medical transportations) by ?19,005 for Patmos and ?78,225 for Leros each year. NPV and IRR were positive; NPV was ?29,608 for Patmos and ?293,245 for Leros, and IRR was 21.5% for Patmos and 140.5% for Leros. Each project depreciated faster than the 5-year life-cycle period, and specifically in 3.13 years for Patmos and in 0.70 years for Leros. CONCLUSION: The establishment of telemedicine systems/units in Patmos and Leros was evaluated and assessed positively, with large savings, economical and social, gained by reducing or even removing the face-to-face contact between doctor and patient. Telemedicine systems/units seem to be a promising solution, especially in Greece, where the problem of primary healthcare services in remote/inaccessible areas is of great concern. PMID- 29442334 TI - Utilization, Spending, and Price Trends for Quinolones in the US Medicaid Programs: 25 Years' Experience 1991-2015. AB - BACKGROUND: Given that the quinolones is one of the antibacterial classes most frequently used to treat patients with bacterial infections in the United States, any change in prescribing patterns of quinolones will impact Medicaid medical expenditures. OBJECTIVES: This study was undertaken to examine trends in utilization, reimbursement, and prices of quinolone antibacterials for the US Medicaid population. METHODS: The publicly available Medicaid State Drug Utilization outpatient pharmacy files were used for this study. Quarterly and annual prescription counts and reimbursement amounts were calculated for each of the quinolones reimbursed by Medicaid from quarter 1, 1991 through quarter 2, 2015. Average per-prescription reimbursement, as a proxy for drug price, was calculated as the drug reimbursement divided by the number of prescriptions. RESULTS: The total annual number of quinolone prescriptions increased 402%, from 247,395 in the first quarter of 1991 to 1.2 million in the second quarter of 2015, peaking at 1.3 million in the first quarter of 2005. Similarly, the total reimbursement for quinolone agents increased by 245.5% over the same period. More than 80% of quinolone prescriptions reimbursed by Medicaid were for the second generation agent, ciprofloxacin, and the third-generation agent, levofloxacin. The average payment per prescription for quinolones increased from US$43.8 in the first quarter of 1991 to US$87.6 in the second quarter of 2015. CONCLUSIONS: A substantial rise in Medicaid expenditures on quinolones was observed during the 25-year study period, which was mainly because of rising utilization. Therefore, there is a need for additional research that has access to clinically relevant data with which to measure the rate of inappropriate quinolone use among the Medicaid population and associated clinical outcomes and healthcare costs. PMID- 29442335 TI - Early Assessment of the Likely Cost Effectiveness of Single-Use Flexible Video Bronchoscopes. AB - BACKGROUND: Bronchoscopic procedures are common in the clinical setting, with estimates indicating 500,000 are undertaken per year in the USA alone. These procedures are generally regarded as safe. Unfortunately, a risk of cross contamination between patients, with possible subsequent infection, is associated with the re-usable technology typically used in these procedures. OBJECTIVE: Our objective was to conduct an early cost-effectiveness analysis (CEA) of single-use flexible video bronchoscope technology compared with the current reusable technology in a US hospital intensive care setting. METHODS: We conducted a CEA to determine an incremental cost-effectiveness ratio (ICER), and constructed a decision analytic model based on the best available evidence from a literature search and a Delphi panel. We also conducted several one- and two-way sensitivity analyses and a probabilistic sensitivity analysis to illuminate the uncertainty associated with the estimates. RESULTS: The literature search showed ample evidence of risk, albeit little of it was quantifiable. Estimates from the Delphi method found approximately a 3% risk of cross-contamination and approximately a 21% risk of subsequent infection. Pneumonia was estimated as the most likely manifestation of infection. The CEA showed a saving of $US118 per procedure and elimination of 0.7% of the risk of infection with the single-use technology. Relevant sensitivity analyses generally validated this result. CONCLUSION: This study suggests that implementation of the single-use technology in the intensive care unit is cost effective in most scenarios. However, this result should be interpreted with caution because of the lack of certain knowledge on this particular topic. PMID- 29442337 TI - Model Registration: A Call to Action. PMID- 29442338 TI - Erratum to: Handling Missing Data in Within-Trial Cost-Effectiveness Analysis: A Review with Future Recommendations. PMID- 29442339 TI - Erratum to: Urinary Protein Markers for the Detection and Prognostication of Urothelial Carcinoma. PMID- 29442336 TI - Handling Missing Data in Within-Trial Cost-Effectiveness Analysis: A Review with Future Recommendations. AB - Cost-effectiveness analyses (CEAs) alongside randomised controlled trials (RCTs) are increasingly designed to collect resource use and preference-based health status data for the purpose of healthcare technology assessment. However, because of the way these measures are collected, they are prone to missing data, which can ultimately affect the decision of whether an intervention is good value for money. We examine how missing cost and effect outcome data are handled in RCT based CEAs, complementing a previous review (covering 2003-2009, 88 articles) with a new systematic review (2009-2015, 81 articles) focussing on two different perspectives. First, we provide guidelines on how the information about missingness and related methods should be presented to improve the reporting and handling of missing data. We propose to address this issue by means of a quality evaluation scheme, providing a structured approach that can be used to guide the collection of information, elicitation of the assumptions, choice of methods and considerations of possible limitations of the given missingness problem. Second, we review the description of the missing data, the statistical methods used to deal with them and the quality of the judgement underpinning the choice of these methods. Our review shows that missing data in within-RCT CEAs are still often inadequately handled and the overall level of information provided to support the chosen methods is rarely satisfactory. PMID- 29442340 TI - Aortic valve replacement using autologous pericardium: single centre experience with the Ozaki technique. AB - OBJECTIVE: To assess the clinical implementation and report preliminary results of a novel technique called the Ozaki procedure for stentless aortic valve replacement through reconstruction of the valve leaflets from autologous pericardium. METHOD: Between September 2015 and May 2017 30 patients (20 males, mean +/- standard deviation age 66.83 +/- 10.55 years) suffering from aortic stenosis (AS, n = 7), aortic regurgitation (AR, n = 12), or a combination of both (AS/AR, n = 11) were assigned for an Ozaki procedure. The glutaraldehyde-treated autologous pericardium was intraoperatively customised and tailored according to individual sinus measurements and appropriate Ozaki templates (CE marked). RESULTS: Mean and peak preoperative transvalvular pressure gradients in patients with AS were 46.34 +/- 14.71 and 78.00 +/- 22.54 mm Hg, respectively and effective orifice area was 0.93 +/- 0.26 cm2. Ejection fraction was preserved at 57.37 +/- 10.33%. Twenty-four valves were tricuspid and 6 bicuspid; 13 patients had concomitant cardiac surgery (coronary artery bypass graft, mitral valve repair, replacement of ascending aorta). Mean +/- SD cross-clamp time for replacement only was 85.18 +/- 18.10 minutes and perfusion time 104.76 +/- 38.52 minutes. Cusp sizes were 27.76 +/- 3.52 mm for the left coronary cusp (CC), 28.20 +/- 3.51 mm for the right CC and 29.20 +/- 3.34 mm for non-CC. Mean and peak postoperative gradients decreased to 8 +/- 3.55 and 14.8 +/- 6.21 mm Hg, respectively. Mean length of stay on the intensive care unit was 2.19 +/- 2.34 days and in-hospital stay was 8.81 +/- 2.04 days after isolated Ozaki procedures. No pacemaker had to be implanted after an isolated Ozaki procedure. Thirty-day mortality was 3.33% (n = 1). After 3 months, no patient presented with aortic stenosis, and regurgitation of the substituted valves was graded nil/trace in 85.71%, mild in 10.71%, and moderate in 3.57% of the patients. Ejection fraction remained unchanged at 58.89 +/- 11.29%. No reoperation was required within the first 3 months. CONCLUSION: This aortic valve replacement technique has become available only recently. In our experience, it can be mastered after a relatively short training period, and has become part of our routine clinical toolbox. The use of autologous pericardium in combination with excellent haemodynamics may have the potential to overcome the structural disadvantages of biological aortic valves, to be beneficial in infective endocarditis, and to represent an alternative for patients with small annuli. PMID- 29442341 TI - The influence of hospitalisation on the initiation, continuation and discontinuation of benzodiazepines and Z-drugs - an observational study. AB - BACKGROUND AND OBJECTIVES: Hospitalisation influences drug therapy in ambulatory care and this influence is generally negatively perceived. The few studies that have explored changes in benzodiazepine or sleep medication use as a function of hospitalisation failed to precisely determine the hospital's role in initiating, continuing and discontinuing these drugs on a valid basis. The aim of the study was to ascertain the overall influence of hospitalisation on the prescription of benzodiazepines and Z-drugs in outpatient care with a special focus on the role of different hospital departments and drug classes. METHODS: In a secondary data analysis, we used prescription data for 181 037 patients who visited 127 hospitals and compared the numbers of patients with prescriptions of benzodiazepines and Z-drugs 50 days before and 50 or 100 days after hospitalisation. RESULTS: The proportion of patients who received benzodiazepines or Z-drugs increased from 3.1% before admission to 3.6% at 50 days after discharge and fell to the former level after an additional 50 days. A multivariable logistic regression showed that gender and department had an additional impact on these results. Of those patients without a prescription for a benzodiazepine or Z-drug before admission, 0.6% received a prescription in both time-windows after discharge. Of those patients who were prescribed a benzodiazepine, 38.0% received short-acting substances and 40.3% received long acting substances before hospitalisation. After hospitalisation, these rates changed to favour short-acting substances (44.4% and 34.4%, respectively). CONCLUSIONS: The hospital effect on initiating and increasing hypnotic or sedative drug use seems to be only moderate and temporary. A change in favour of short-acting substances is even welcome. In less than 1% of patients, the hospital initiated the continuous use of benzodiazepines and Z-drugs, which may put pressure on primary care physicians. However, the widespread use of these drugs in hospitals does not seem to be continued on a large scale in primary care. PMID- 29442342 TI - A ten-year follow-up study of treatment outcome of craniopharyngiomas. AB - PURPOSE: Craniopharyngioma-related hypothalamic obesity is a devastating complication with limited data on whether long-term follow-up should focus on problems other than endocrine deficiencies and weight gain. The primary endpoint was the assessment of predictors of hypothalamic obesity development; the secondary endpoint was the assessment of functional outcome (endocrine deficiencies, visual acuity) at long-term follow-up. METHODS: This retrospective case-note study examined craniopharyngioma patients with at least 2 years of follow-up. Clinical, radiological and biochemical characteristics were assessed at diagnosis, postoperatively, and at last follow-up. RESULTS: Thirty-two patients met the inclusion criteria. Median follow-up period was 9.8 years (range 2.2-33 years). Longitudinal changes in body mass index (BMI) were substantial (median DeltaBMI/year was +0.48 kg/m2/year, interquartile range 0.28-1.33). The prevalence of patients with hypothalamic obesity had significantly increased at last follow-up (45 vs 4%; p = 0.003). Long-term pituitary deficiencies remained high. Diabetes insipidus was common (66% vs 34%, p<0.001), with postoperative diabetes insipidus but not hypothalamic involvement, being an independent predictor for hypothalamic obesity (odds ratio 15.2, 95% confidence interval 1.3 174.8, p = 0.03). Osteodensitometry in two thirds of patients at last follow-up revealed a pathological bone density in 53% of those tested. CONCLUSIONS: Rates of hypothalamic obesity and long-term pituitary deficiencies are substantial, with postoperative diabetes insipidus being a potential marker for hypothalamic obesity development. Besides long-term monitoring of endocrine deficiencies with consideration of osteodensitometry, early weight control programmes and continuing multidisciplinary care are mandatory in craniopharyngioma patients. PMID- 29442343 TI - Diet, medication use and drug intake during pregnancy: data from the Swiss Health Surveys 2007 and 2012. PMID- 29442345 TI - Craniopharyngioma - a chronic disease. PMID- 29442344 TI - Comparison of ESSDAI and ClinESSDAI in potential optimisation of trial outcomes in primary Sjogren's syndrome: examination of data from the UK Primary Sjogren's Syndrome Registry. AB - OBJECTIVES: To assess the use of the Clinical EULAR Sjogren's Syndrome Disease Activity Index (ClinESSDAI), a version of the ESSDAI without the biological domain, for assessing potential eligibility and outcomes for clinical trials in patients with primary Sjogren's syndrome (pSS), according to the new ACR-EULAR classification criteria, from the UK Primary Sjogren's Syndrome Registry (UKPSSR). METHODS: A total of 665 patients from the UKPSSR cohort were analysed at their time of inclusion in the registry. ESSDAI and ClinESSDAI were calculated for each patient. RESULTS: For different disease activity index cut-off values, more potentially eligible participants were found when ClinESSDAI was used than with ESSDAI. The distribution of patients according to defined disease activity levels did not differ statistically (chi2 p = 0.57) between ESSDAI and ClinESSDAI for moderate disease activity (score >=5 and <14; ESSDAI 36.4%; ClinESSDA 36.5%) or high disease activity (score >=14; ESSDAI 5.4%; ClinESSDAI 6.8%). We did not find significant differences between the indexes in terms of activity levels for individual domains, with the exception of the articular domain. We found a good level of agreement between both indexes, and a positive correlation between lymphadenopathy and glandular domains with the use of either index and with different cut-off values. With the use of ClinESSDAI, the minimal clinically important improvement value was more often achievable with a one grade improvement of a single domain than with ESSDAI. We observed similar results when using the new ACR-EULAR classification criteria or the previously used American European Consensus Group (AECG) classification criteria for pSS. CONCLUSIONS: In the UKPSSR population, the use of ClinESSDAI instead of ESSDAI did not lead to significant changes in score distribution, potential eligibility or outcome measurement in trials, or in routine care when immunological tests are not available. These results need to be confirmed in other cohorts and with longitudinal data. PMID- 29442346 TI - Modification of a two blood sample method used for measurement of GFR with 99mTc DTPA. AB - BACKGROUND: Measurements of GFR may be performed with a slope/intercept method (S/I), using only two blood samples taken in strictly defined time points. The aim of the study was to modify this method in order to extend time intervals suitable for blood sampling. Modification was based on a variation of a Russel et al. model parameter, selection of time intervals suitable for blood sampling and assessment of uncertainty of calculated results. MATERIAL AND METHODS: Archived values of GFR measurements of 169 patients with different renal function, from 5.5 to 179 mL/min, calculated with a multiple blood sample method were used. Concentrations of a radiopharmaceutical in consecutive minutes, from 60th to 190th after injection, were calculated theoretically, using archived parameters of biexponential functions describing a decrease in 99mTc-DTPA concentration in blood plasma with time. These values, together with injected activities, were treated as measurements and used for S/I clearance calculations. Next, values of S/I clearance were compared with the multiple blood sample method in order to calculate suitable values of exponent present in a Russel's model, for every combination of two blood sampling time points. A model was considered accurately fitted to measured values when SEE <= 3.6 mL/min. Assessments of uncertainty of obtained results were based on law of error superposition, taking into account mean square prediction error and also errors introduced by pipetting, time measurement and stochastic radioactive decay. RESULTS: The accepted criteria resulted in extension of time intervals suitable for blood sampling to: between 60 and 90 minutes after injection for the first sample and between 150 and 180 minutes for the second sample. Uncertainty of results was assessed as between 4 mL/min for GFR = 5-10 mL/min and 8 mL/min for GFR = 180 mL/min. CONCLUSIONS: Time intervals accepted for blood sampling fully satisfy nuclear medicine staff and ensure proper determination of GFR. Uncertainty of results is entirely acceptable and for high GFR values even comparable with uncertainty of multi-sample measurements. PMID- 29442347 TI - F-18 FDG PET/CT in pulmonary artery sarcoma: clinical vignette. AB - Pulmonary artery sarcomas (PAS's) are extremely rare malignant tumors that arise from the endothelial lining of the pulmonary arteries. On CT scans PAS's appear as intraluminal filling defects in the pulmonary arteries, mimicking pulmonary embolism (PE). Due to the similarities in radiographic features as well as in clinical presentation, PAS's are usually misdiagnosed as pulmonary embolism. Since PASs are F-18 FDG avid, F-18 FDG PET/CT scan is a useful imaging tool for differentiating between these two conditions, as shown in this case report. We report a case of a 60-year-old woman presented with a 6-month history of chest pain, dyspnea on exertion, non-productive cough and weight loss. The initial CT pulmonary artery angiography showed extensive intraluminal mass in the pulmonary trunk and left pulmonary artery, diagnosed as massive pulmonary embolism. Since there was no clinical improvement after anticoagulant therapy, CT pulmonary angiography was repeated, and with no change observed in the intraluminal filling defect in pulmonary trunk, the possibility of tumor was raised. For further evaluation of a possible malignancy, F-18 FDG PET/CT was performed. It showed increased FDG uptake, suspicious for an aggressive tumor, in the intraluminal lesion of the pulmonary trunk and along the wall of the left pulmonary artery. There was no extrathoracic abnormality seen on PET/CT scan. Histopathological finding after complete pulmonary artery resection showed high grade undifferentiated pleomorphic sarcoma. F-18 FDG PET/CT is a useful tool for differentiating between pulmonary embolism and malignant intraluminal mass, and at the same time it enables the proper staging of the malignancy. < p > < /p >. PMID- 29442348 TI - Quantitation in Dextrocardia on myocardial perfusion imaging: how to perform quantitative analysis using Cedars-Sinai software. AB - Dextrocardia, although a rare cardiac abnormality, carries the same risk for cardiac events as other people. SPECT Myocardial perfusion imaging is a potentially helpful diagnostic tool in patients with dextrocardia. Because of swapping of lateral and septal walls on SPECT slices, although visual analysis is possible, quantitation is substantially limited. Here, we introduce a simple practical method to make quantitative analysis feasible and accurate. PMID- 29442349 TI - 18F-FDG avid Sclerosing Angiomatoid Nodular Transformation (SANT) of spleen on PET-CT - a rare mimicker of metastasis. AB - Sclerosing Angiomatoid Nodular Transformation (SANT) is a rare benign vascular tumor of spleen. It consists of multiple angiomatoid nodules surrounded by dense fibrous tissue that often coalesces centrally to form a scar, which is considered to be a characteristic feature. These are usually asymptomatic and incidentally detected on imaging for other underlying pathology. SANTs can be 18F Fluorodeoxyglucose (18F-FDG) avid on positron emission tomography-computed tomography (PET-CT) and thus can lead to false positive finding in oncological patients. PMID- 29442350 TI - Occult phosphaturic mesenchymal tumour of femur cortex causing oncogenic osteomalacia - diagnostic challenges and clinical outcomes. AB - BACKGROUND: Tumor induced osteomalacia (TIO) are extremely rare paraneoplastic syndrome with less than 300 reported cases. This report highlights the pitfalls and challenges in diagnosing and localizing TIO in patients with refractory and resistant osteomalacia. PATIENT AND METHODS: 41- year gentleman with 4-year history of musculoskeletal weakness and pathologic fractures presented in wheelchair bound incapacitated state of 1-year duration. Investigations were significant for severe hypophosphatemia, severe phosphaturia, normal serum calcium, reduced 1,25-dihydroxy vitamin-D, elevated ALP, elevated intact parathyroid hormone (iPTH), and pseudo-fractures involving pelvis and bilateral femur. Whole body MRI and 99mTc methylene diphosphonate bone-scan were also normal. Whole body FDG-PET scan involving all 4 limbs revealed a small FDG avid lesion at lateral border of lower end of left femur (SUV max 3.9), which was well characterized on 3-dimensional CT reconstruction. Plasma C-terminal fibroblast growth factor (FGF)-23 was 698 RU/ mL (normal < 150 RU/ml). Wide surgical excision of the tumor was done. Histopathology confirmed mesenchymal tumor of mixed connective tissue variant. Serum phosphorous normalized post-surgery day-1. High dose oral calcium and vitamin-D was continued. FGF-23 normalized post surgery (73RU/ml). Physical strength improved significantly and now he is able to walk independently. CONCLUSION: TIO is frequently confused with normocalcemic hyperparathyroidism and vitamin-D resistant rickets/osteomalacia, which increases patient morbidity. Imaging for tumor localization should involve whole body from head to tip of digits, cause these tumors are notoriously small and frequently involve digits of hands and legs. Complete surgical removal of the localized tumor is key to good clinical outcomes. PMID- 29442351 TI - Milk-alkali syndrome (MAS) as a complication of the treatment of hypoparathyroidism - a case study. AB - Milk-alkali syndrome (MAS), characterized by renal failure, metabolic alkalosis and hypercalcemia, is a severe and life-threatening complication of the treatment of hypoparathyroidism. The clinical course is often sudden and is not preceded by any prodromal symptoms. Occurrence does not depend on the duration of hypoparathyroidism treatment, although it is closely related to the applied therapy, especially the dose of calcium carbonate and active vitamin D preparations. Drugs influencing the glomerular filtration rate (angiotensin receptor blockers, sartans, aldosterone receptor antagonists, thiazide diuretics), lack of adequate routine control, changing the calcium carbonate supplementation, dehydration, a diet rich in pH-basic foods (i.e. vegetarian diet), pregnancy and other associated conditions are listed among the factors triggering MAS. A higher calcium carbonate dose is directly associated with an increased risk of milk-alkali syndrome. In case of a high calcium demand it is necessary to control renal function and monitor the level of calcium in the serum more frequently, aiming for the lower end of the reference range. If MAS has been confirmed or if there are alarming neurological symptoms suggestive of hypercalcemia, the patient must be sent to the hospital immediately. Treatment of MAS involves: discontinuation of calcium and vitamin D supplementation, and intravenous infusion of normal saline solution to eliminate volume deficiencies and to achieve forced diuresis while maintaining proper fluid balance. As soon as there is improvement in the patient's clinical condition, it is necessary to begin the treatment of comorbidities increasing the risk of renal failure or alkalosis (i.e. vomiting, diarrhea). PMID- 29442352 TI - Guidelines of Polish National Societies Diagnostics and Treatment of Thyroid Carcinoma. 2018 Update. AB - Significant advances have been made in thyroid can-cer research in recent years, therefore relevant clinical guidelines need to be updated. The current Polish guidelines "Diagnostics and Treatment of Thyroid Carcinoma" have been formulated at the "Thyroid Cancer and Other Malignancies of Endocrine Glands" conference held in Wisla in November 2015 [1]. PMID- 29442356 TI - Editorial. PMID- 29442353 TI - The effect of vitamin D supplementation on sexual functioning and depressive symptoms in young women with low vitamin D status. AB - BACKGROUND: Hypovitaminosis D is associated with abnormal female sexual functioning. The aim of our study was to assess whether vitamin D supplementation affects sexual functioning and depressive symptoms in young women with low vitamin D status. METHODS: The study included 47 women with vitamin D deficiency or insufficiency. All women with vitamin D deficiency were treated with oral vitamin D, while women with vitamin D insufficiency were either treated with vitamin D or left untreated. At the beginning of the study and six months later, all patients completed questionnaires evaluating female sexual function (FSFI) and depressive symptoms (BDI-II). RESULTS: The total FSFI score and scores in three domains (sexual desire, orgasm and satisfaction) were lower while the overall BDI-II score was higher in women with vitamin D deficiency than in women with vitamin D insufficiency. Vitamin D improved sexual desire in women with both vitamin D deficiency and vitamin D insufficiency, increased the total FSFI score and scores for orgasm and sexual satisfaction, as well as decreased the total BDI II score in women with vitamin D deficiency. CONCLUSIONS: The obtained results indicate that vitamin D supplementation improves female sexual functioning and mood in women with low vitamin D status. < p > < /p >. PMID- 29442357 TI - Virtual reality training for children with unilateral cerebral palsy. PMID- 29442359 TI - Visible Light Degradation of Naproxen by Enhanced Photocatalytic Activity of NiO and NiS, Scavenger Study and Focus on Catalyst Support and Magnetization. AB - This research was aimed to prepare a magnetically photocatalyst enabling to degrade pharmaceutical wastewater and detoxification of pollutant such as naproxen, by visible light irradiation. The nano-sized NiS and NiO photocatalysts exhibit higher reactivity than their microsized counterparts, but separation of the used photocatalyst from the degradation solution is hard and imperfect. To remove this difficulty, magnetic polypyrrole core-shell (Fe3 O4 @PPY) was synthesized and employed as catalyst support. The magnetization property of the synthesized photocatalysts measured by VSM technique indicated that the photocatalysts were sufficiently magnetized to be readily separated from degradation solution by use of external magnetic field. The DRS study showed that the band gap of the photocatalysts shifted to lower energy after immobilization on the support materials leading to higher degradation efficiency. The optimal efficiency was obtained with the catalysts loaded with 50% of NiO and 50% of NiS. The augmenting effect of H2 O2 and the inhibition influence of some organic and inorganic compounds on the degradation process were studied. Regeneration of the used photocatalyst was performed by heat treatment, and the catalyst treated at 400 degrees C retained most of its initial capacity. The degradation capacity was kinetically fast, and the equilibrium was attained within 30 min. PMID- 29442358 TI - Maternal care-related differences in males and females rats' sensitivity to ethanol and the associations between the GABAergic system and steroids in males. AB - This study investigated the effect of maternal care on adolescent ethanol consumption, sensitivity to ethanol-induced hypnosis, as well as gonadal hormones and gamma-aminobutyric acid type-A (GABAA ) systems. Long Evans rat dams were categorized by maternal licking/grooming (LG) frequency into High- and Low-LG mothers. Both female and male offspring from Low-LG rats demonstrated a greater sensitivity to ethanol-induced hypnosis in the loss-of-righting-reflex test at ethanol doses of 3.0 and 3.5 g/kg during late-adolescence (postnatal Day 50) but not at mid-adolescence (postnatal Day 42). However, we found no effect of maternal care on consumption of a 5% ethanol solution in a two-bottle choice test. We further investigated the association between the observed variations in sensitivity to ethanol-induced hypnosis and baseline hormonal levels in males. In male offspring from Low-LG mothers compared to High-LG mothers, baseline plasma corticosterone and progesterone levels were higher. GABAA alpha1 and delta subunit expressions were also higher in the cerebral cortex of Low-LG males but lower in the cerebellar synaptosomal fraction. Early environmental influences on adolescent sensitivity to ethanol-induced hypnosis, consumption, and preference may be mediated by gonadal hormones and possibly through GABAergic functions. PMID- 29442360 TI - Lexical Predictability During Natural Reading: Effects of Surprisal and Entropy Reduction. AB - What are the effects of word-by-word predictability on sentence processing times during the natural reading of a text? Although information complexity metrics such as surprisal and entropy reduction have been useful in addressing this question, these metrics tend to be estimated using computational language models, which require some degree of commitment to a particular theory of language processing. Taking a different approach, this study implemented a large-scale cumulative cloze task to collect word-by-word predictability data for 40 passages and compute surprisal and entropy reduction values in a theory-neutral manner. A separate group of participants read the same texts while their eye movements were recorded. Results showed that increases in surprisal and entropy reduction were both associated with increases in reading times. Furthermore, these effects did not depend on the global difficulty of the text. The findings suggest that surprisal and entropy reduction independently contribute to variation in reading times, as these metrics seem to capture different aspects of lexical predictability. PMID- 29442361 TI - Comparison of lipid peroxidation and catalase response in invasive dreissenid mussels exposed to single and multiple stressors. AB - Dreissenid mussels Dreissena bugensis (quagga mussel) and Dreissena polymorpha (zebra mussel) are prolific invasive species to the freshwaters of the United States and Western Europe. In the Great Lakes, D. polymorpha has initially dominated the system since its invasion in the mid-1980s; however, recently D. bugensis has displaced D. polymorpha as the dominant species. Dreissena bugensis has several competitive advantages over D. polymorpha, including greater tolerances to deeper and colder waters and lower respiration rates. Nevertheless, physiological differences between the species remain largely unknown. The oxidative stress response is a mechanism used by all organisms to mitigate environmental stress by reducing oxygen radicals in the body, and comparing this mechanism between similar species can be useful for understanding how different species compete in aquatic environments. We compared oxidative stress biomarkers (lipid peroxidation [LPO] and catalase [CAT] activity) in mussels after exposure to 4 stressors (i.e., high densities, temperature, hypoxia, and polychlorinated biphenyls [PCBs]) independently and in combinations of 2 stressors. Overall, D. bugensis had lower LPO and CAT activity than D. polymorpha when exposed to single stressors; however, in multiple stressor treatments D. bugensis had increased LPO, especially with high temperatures and PCBs. The lower lipid damage in D. bugensis compared with D. polymorpha under single stressor conditions may come at the cost of the ability to respond to multiple stressors. Environ Toxicol Chem 2018;37:1643-1654. (c) 2018 SETAC. PMID- 29442363 TI - Increased neuronal synchrony prepares mesial temporal networks for seizures of neocortical origin. AB - OBJECTIVE: To gain understanding of the neuronal mechanisms underlying regional seizure spread, the impact of regional synchrony between seizure focus and downstream networks on neuronal activity during the transition to seizure in those downstream networks was assessed. METHODS: Seven patients undergoing diagnostic intracranial electroencephalographic studies for surgical resection of epileptogenic regions were implanted with subdural clinical electrodes into the cortex (site of seizure initiation) and mesial temporal lobe (MTL) structures (downstream) as well as microwires into MTL. Neural activity was recorded (24/7) in parallel with the clinical intracranial electroencephalogram recordings for the duration of the patient's diagnostic stay. Changes in (1) regional synchrony (ie, coherence) between the presumptive neocortical seizure focus and MTL, (2) local synchrony between MTL neurons and their local field potential, and (3) neuronal firing rates within MTL in the time leading up to seizure were examined to study the mechanisms underlying seizure spread. RESULTS: In seizures of neocortical origin, an increase in regional synchrony preceded the spread of seizures into MTL (predominantly hippocampal). Within frequencies similar to those of regional synchrony, MTL networks showed an increase in unit-field coherence and a decrease in neuronal firing rate, specifically for inhibitory interneuron populations but not pyramidal cell populations. SIGNIFICANCE: These results suggest a mechanism of spreading seizures whereby the seizure focus first synchronizes local field potentials in downstream networks to the seizure activity. This change in local field coherence modifies the activity of interneuron populations in these downstream networks, which leads to the attenuation of interneuronal firing rate, effectively shutting down local interneuron populations prior to the spread of seizure. Therefore, regional synchrony may influence the failure of downstream interneurons to prevent the spread of the seizures during generalization. PMID- 29442362 TI - A descriptive systematic review of salivary therapeutic drug monitoring in neonates and infants. AB - AIMS: Saliva, as a matrix, offers many benefits over blood in therapeutic drug monitoring (TDM), in particular for infantile TDM. However, the accuracy of salivary TDM in infants remains an area of debate. This review explored the accuracy, applicability and advantages of using saliva TDM in infants and neonates. METHODS: Databases were searched up to and including September 2016. Studies were included based on PICO as follows: P: infants and neonates being treated with any medication, I: salivary TDM vs. C: traditional methods and O: accuracy, advantages/disadvantages and applicability to practice. Compounds were assessed by their physicochemical and pharmacokinetic properties, as well as published quantitative saliva monitoring data. RESULTS: Twenty-four studies and their respective 13 compounds were investigated. Four neutral and two acidic compounds, oxcarbazepine, primidone, fluconazole, busulfan, theophylline and phenytoin displayed excellent/very good correlation between blood plasma and saliva. Lamotrigine was the only basic compound to show excellent correlation with morphine exhibiting no correlation between saliva and blood plasma. Any compound with an acid dissociation constant (pKa) within physiological range (pH 6-8) gave a more varied response. CONCLUSION: There is significant potential for infantile saliva testing and in particular for neutral and weakly acidic compounds. Of the properties investigated, pKa was the most influential with both logP and protein binding having little effect on this correlation. To conclude, any compound with a pKa within physiological range (pH 6-8) should be considered with extra care, with the extraction and analysis method examined and optimized on a case-by-case basis. PMID- 29442364 TI - An Exception to Mental Simulation: No Evidence for Embodied Odor Language. AB - Do we mentally simulate olfactory information? We investigated mental simulation of odors and sounds in two experiments. Participants retained a word while they smelled an odor or heard a sound, then rated odor/sound intensity and recalled the word. Later odor/sound recognition was also tested, and pleasantness and familiarity judgments were collected. Word recall was slower when the sound and sound-word mismatched (e.g., bee sound with the word typhoon). Sound recognition was higher when sounds were paired with a match or near-match word (e.g., bee sound with bee or buzzer). This indicates sound-words are mentally simulated. However, using the same paradigm no memory effects were observed for odor. Instead it appears odor-words only affect lexical-semantic representations, demonstrated by higher ratings of odor intensity and pleasantness when an odor was paired with a match or near-match word (e.g., peach odor with peach or mango). These results suggest fundamental differences in how odor and sound-words are represented. PMID- 29442366 TI - Effects of partial selfing on the equilibrium genetic variance, mutation load, and inbreeding depression under stabilizing selection. AB - The mating system of a species is expected to have important effects on its genetic diversity. In this article, we explore the effects of partial selfing on the equilibrium genetic variance Vg , mutation load L, and inbreeding depression delta under stabilizing selection acting on a arbitrary number n of quantitative traits coded by biallelic loci with additive effects. When the U/n ratio is low (where U is the total haploid mutation rate on selected traits) and effective recombination rates are sufficiently high, genetic associations between loci are negligible and the genetic variance, mutation load, and inbreeding depression are well predicted by approximations based on single-locus models. For higher values of U/n and/or lower effective recombination, moderate genetic associations generated by epistasis tend to increase Vg , L, and delta, this regime being well predicted by approximations including the effects of pairwise associations between loci. For yet higher values of U/n and/or lower effective recombination, a different regime is reached under which the maintenance of coadapted gene complexes reduces Vg , L, and delta. Simulations indicate that the values of Vg , L, and delta are little affected by assumptions regarding the number of possible alleles per locus. PMID- 29442365 TI - Vein of Galen malformation: optimizing the management of postneonatal presentations. PMID- 29442367 TI - No strict requirement for eosinophils for bone marrow plasma cell survival. AB - Lasting antibody responses are maintained by long-lived plasma cells, which are thought to lodge in the BM in specialized survival niches. Eosinophils have been reported to function as a critical component of the BM survival niche where they are thought to provide pro-survival signals to nearby plasma cells. Recent study shows that many BM plasma cells are recently generated and chiefly short-lived cells, raising the possibility that rare plasma cell-eosinophil interactions are a rate-limiting step needed to establish lasting humoral immunity. To address these issues, we examined the impact of eosinophil depletion on short- and long lived BM plasma cells in the context of antibody responses induced by both T-cell dependent and T-cell independent antigens. Surprisingly, our results failed to support a role for eosinophils in either plasma cell generation or survival. These studies included examination of plasma cell frequencies in mice lacking eosinophils either after antibody-mediated depletion, or due to mutation of the GATA1 locus. PMID- 29442368 TI - Effects of copper on olfactory, behavioral, and other sublethal responses of saltwater organisms: Are estimated chronic limits using the biotic ligand model protective? AB - There is concern over whether regulatory criteria for copper (Cu) are protective against chemosensory and behavioral impairment in aquatic organisms. We compiled Cu toxicity data for these and other sublethal endpoints in 35 tests with saltwater organisms and compared the Cu toxicity thresholds with biotic ligand model (BLM)-based estimated chronic limits (ECL values, which are 20% effect concentrations [EC20s] for the embryo-larval life stage of the blue mussel [Mytilus edulis], a saltwater species sensitive to Cu that has historically been used to derive saltwater Cu criteria). Only 8 of the 35 tests had sufficient toxicity and chemistry data to support unequivocal conclusions (i.e., a Cu EC20 or no-observed-effect concentration could be derived, and Cu and dissolved organic carbon [DOC] concentrations were measured [or DOC concentrations could be inferred from the test-water source]). The BLM-based ECL values would have been protective (i.e., the ECL was lower than the toxicity threshold) in 7 of those 8 tests. In the remaining 27 tests, this meta-analysis was limited by several factors, including 1) the Cu toxicity threshold was a "less than" value in 19 tests because only a lowest-observed-effect concentration could be calculated and 2) Cu and/or DOC concentrations often were not measured. In 2 of those 27 tests, the ECL would not have been protective if based only on a conservatively high upper-bound DOC estimate. To facilitate future evaluations of the protectiveness of aquatic life criteria for metals, we urge researchers to measure and report exposure-water chemistry and test-metal concentrations that bracket regulatory criteria. Environ Toxicol Chem 2018;37:1515-1522. (c) 2018 SETAC. PMID- 29442369 TI - Spinal Cord Stimulation Therapy for Gait Dysfunction in Advanced Parkinson's Disease Patients. AB - BACKGROUND: Benefits of dopaminergic therapy and deep brain stimulation are limited and unpredictable for axial symptoms in Parkinson's disease. Dorsal spinal cord stimulation may be a new therapeutic approach. The objective of this study was to investigate the therapeutic effect of spinal cord stimulation on gait including freezing of gait in advanced PD patients. METHODS: Five male PD participants with significant gait disturbances and freezing of gait underwent midthoracic spinal cord stimulation. Spinal cord stimulation combinations (200 500 MUs/30-130 Hz) at suprathreshold intensity were tested over a 1- to 4-month period, and the effects of spinal cord stimulation were studied 6 months after spinal cord stimulation surgery. Protokinetics Walkway measured gait parameters. Z scores per gait variable established each participant's best spinal cord stimulation setting. Timed sit-to-stand and automated freezing-of-gait detection using foot pressures were analyzed. Freezing of Gait Questionnaire (FOG-Q), UPDRS motor items, and activities-specific balance confidence scale were completed at each study visit. RESULTS: Spinal cord stimulation setting combinations of 300 400 MUs/30-130 Hz provided gait improvements. Although on-medication/on stimulation at 6 months, mean step length, stride velocity, and sit-to-stand improved by 38.8%, 42.3%, and 50.3%, respectively, mean UPDRS, Freezing of Gait Questionnaire, and activities-specific balance confidence scale scores improved by 33.5%, 26.8%, and 71.4%, respectively. The mean number of freezing-of-gait episodes reduced significantly from 16 presurgery to 0 at 6 months while patients were on levodopa and off stimulation. CONCLUSIONS: By using objective measures to detect dynamic gait characteristics, the therapeutic potential of spinal cord stimulation was optimized to each participant's characteristics. This pilot study demonstrated the safety and significant therapeutic outcome of spinal cord stimulation in advanced PD patients, and thus a larger and longer clinical study will be conducted to replicate these results. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29442370 TI - Responsiveness of rat fetuses to sibling motor activity: Communication in utero? AB - Previous research has revealed that fetuses detect and respond to extrauterine stimuli such as maternal movement and speech, but little attention has been cast on how fetuses may directly influence and respond to each other in the womb. This study investigated whether motor activity of E20 rat fetuses influenced the behavior of siblings in utero. Three experiments showed that; (a) contiguous siblings expressed a higher frequency of synchronized movement than noncontiguous siblings; (b) fetuses that lay between two siblings immobilized with curare showed less movement relative to fetuses between saline or uninjected controls; and (c) fetuses between two siblings behaviorally activated by the opioid agonist U50,488 also showed less activity and specific behavioral changes compared to controls. Our findings suggest that rat fetuses are directly impacted by sibling motor activity, and thus that a rudimentary form of communication between siblings may influence the development of fetuses in utero. PMID- 29442371 TI - Good Daphnia parents do not control the offspring microbiome. AB - In Focus: Mushegian, A. A., Walser, J. -C., Sullam, K. E., & Ebert, D. (2018). The microbiota of diapause: How host-microbe associations are formed after dormancy in an aquatic crustacean. Journal of Animal Ecology, 87, 400-413. https://doi.org/10.1111/1365-2656.12709. All animals are colonized by micro organisms, most of which are benign or beneficial. Where do these micro-organisms come from? Theory predicts that micro-organisms which are transmitted vertically from parent to offspring are especially likely to be beneficial to the host, while horizontally acquired micro-organisms are opportunistic and more variable in their impact on host performance. In this issue, Mushegian et al. () investigate the source of bacteria that are required for the growth and development of Daphnia water fleas to reproductive adults. They find that, although vertically transmitted bacteria can occur in the capsule enclosing the Daphnia eggs, the micro-organisms that promote Daphnia performance are associated with the external surface of the capsule and are of likely environmental origin. This mode of transmission may be adaptive for Daphnia because, linked to the longevity and capacity for long-distance dispersal of these eggs, the environmental circumstances encountered by parent and offspring may be different; with the implication, the parental micro-organisms may not be optimal for the offspring. This study demonstrates that, although some animals require symbioses with specific coevolved, vertically transmitted microbial symbionts, other animals have evolved dependence on taxonomically variable micro-organisms of environmental origin. PMID- 29442372 TI - Animal host-microbe interactions. PMID- 29442373 TI - Corrigendum. PMID- 29442374 TI - Eosinophils are not essential for maintenance of murine plasma cells in the bone marrow. AB - Eosinophils were reported to serve as an essential component of the plasma cell niche within the bone marrow. As the potential contribution of eosinophils to humoral immunity has remained incompletely understood, we aimed to further characterize their role during antibody responses and to additionally investigate their role in autoimmune disease. Contrary to our expectations and the currently prevailing paradigm, we found that eosinophils are fully dispensable for the survival of murine bone marrow plasma cells and accordingly do not contribute to antibody production and autoantibody-mediated disease. Littermate wild type and eosinophil-deficient DeltadblGATA-1 animals showed similar numbers and frequencies of plasma cells and did not differ in steady state levels of immunoglobulins or their ability to raise antigen-specific antibody responses. Eosinophils were likewise dispensable for autoantibody production or autoantibody induced disease in a mouse model of systemic lupus erythematosus. Our findings thus argue against a role of eosinophils during the maintenance of the plasma cell pool and challenge the hitherto postulated concept of an eosinophil sustained bone marrow niche. PMID- 29442375 TI - Characterization of neuropeptide K processing in rat spinal cord S9 fractions using high-resolution quadrupole-Orbitrap mass spectrometry. AB - Tachykinins are a family of pronociceptive neuropeptides with a specific role in pain and inflammation. Several mechanisms regulate endogenous tachykinins levels, including the differential expression of protachykinin mRNA and the controlled secretion of tachykinin peptides from neurons. We suspect that proteolysis regulates extracellular neuropeptide K (NPK) and neurokinin A (NKA) concentrations and NPK is a precursor of NKA. Here, we provide evidence that proteolysis controls NPK and NKA levels in the spinal cord, leading to the formation of active C-terminal peptide fragments. Using high-resolution mass spectrometry, specific tachykinin fragments were identified and characterized. The metabolic stability in rat spinal cord fractions of NPK and NKA was very short, resulting in half-lives of 1.9 and 2.2 min respectively. Following the degradation of NPK, several C-terminal fragments were identified, including NPK1 26 , NKA, NKA2-10 , NKA3-10 , NKA5-10 and NKA6-10 , which conserve affinity for the neurokinin 2 receptor but also for the neurokinin 1 receptor. Interestingly, the same fragments were identified following the degradation of NKA. A specific proprotein convertases inhibitor was used and showed a significant reduction in the rate of formation of NKA, providing strong evidence that proprotein convertase is involved in C-terminal processing of NPK in the spinal cord, leading to the formation of NKA. PMID- 29442378 TI - 'Shine bright like a diamond!': is research on high-functioning ADHD at last entering the mainstream? AB - The paper by Greven and colleagues (this issue) is intensifying discussion how research on attention-deficit/hyperactivity disorder (ADHD) can be moved away from the deficit-focused view to a concept, which is oriented towards resources a patient might be able to recruit to function at a high-level despite impairments. To promote understanding of high-functioning (HF)-ADHD, more longitudinal studies are required employing neuropsychologic, neuroimaging and neurobiologic approaches, with focus on compensatory mechanisms during fronto-striatal-amygdala maturation and adult plasticity as well as epigenetic modification marker screening strategies to identify homoeostatic processes of resilience in endophenotypic traits related to coping styles of target groups. PMID- 29442376 TI - Multiple system atrophy and apolipoprotein E. AB - BACKGROUND: Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA. OBJECTIVE: This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and alpha-synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect alpha-synuclein uptake in a oligodendrocyte cell. METHODS: One hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with alpha-synuclein and recombinant human apolipoprotein E, with internalized alpha-synuclein imaged by confocal microscopy and cells analyzed by flow cytometry. RESULTS: No significant association with risk of MSA or was observed for either Apolipoprotein E E2 or E4. alpha-Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E E4 significantly reduced alpha-synuclein uptake in the oligodendrocytic cell line. CONCLUSIONS: Despite differential effects of apolipoprotein E isoforms on alpha-synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or alpha-synuclein pathology. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29442377 TI - A cold and organic solvent tolerant lipase produced by Antarctic strain Rhodotorula sp. Y-23. AB - Psychrotolerant yeast Rhodotorula sp. Y-23 was isolated from the sediment core sub-samples of Nella Lake, East Antarctica. Isolate was screened for lipase production using plate assay method followed by submerged fermentation. Production optimization revealed the maximum lipase production by using palmolein oil (5% v/v), pH 8.0 and inoculum size of 2.5% v/v at 15 degrees C. The potential inducers for lipase were 1% w/v of galactose and KNO3 , and MnCl2 (0.1% w/v). Final productions with optimized conditions gave 5.47-fold increase in lipase production. Dialyzed product gave a purification fold of 5.63 with specific activity of 26.83 U mg-1 and 15.67% yields. This lipase was more stable at pH 5.0 and -20 degrees C whereas more activity was found at pH 8.0 and 35 degrees C. Stability was more in 50 mM Fe3+ , EDTA-Na (20 mM), sodium deoxycholate (20 mM), H2 O2 (1% v/v), and almost all organic solvents (50% v/v). Tolerance capacity at wider range of pH and temperature with having lower Km value i.e., 0.08 mg ml-1 and higher Vmax 385.68 U mg-1 at 15 degrees C make the studied lipase useful for industrial applications. Besides this, the lipase was compatible with commercially available detergents, and its addition to them increases lipid degradation performances making it a potential candidate in detergent formulation. PMID- 29442379 TI - Editorial Perspective: Integrating exploratory and competitive-confirmatory approaches to testing person * environment interactions. AB - Students of child development and of psychopathology have long been interested in how person characteristics (e.g. genotype, temperament) might moderate the effect of environmental exposures (e.g. harsh parenting, negative life events) on development. Historically, most such research on person * environment interaction has been guided by diathesis-stress thinking, which stipulates that some individuals, due to their personal characteristics, are more susceptible to the adverse effects of contextual risk than are others (but do not function differently under supportive or even benign conditions). PMID- 29442380 TI - Marketing medicines: charting the rise of modern therapeutics through a systematic review of adverts in UK medical journals (1950-1980). AB - AIMS: To examine how pharmaceutical products that were first marketed between 1950 and 1980 were promoted to physicians through advertisements and briefly review advertising regulations and accuracy of the advertisements in the light of modern knowledge. METHODS: We systematically reviewed advertisements promoting drugs for specific therapeutic areas, namely central nervous system disorders (anxiety and sleep disorders, depression, psychoses, and Parkinson's disease), respiratory disorders, cardiovascular disorders, and gastrointestinal disorders. We examined about 800 issues of the British Medical Journal (1950-1980) and about 150 issues of World Medicine (1965-1984). RESULTS: Advertising material was minimally regulated until the mid-1970s. Many drugs were marketed with little preclinical or clinical knowledge and some with the expectation that prescribers would obtain further data. The peak of advertising occurred in parallel with the surge in the release of novel drugs during the 1960s, but declined markedly after the mid-1970s. Advertisements generally contained little useful prescribing information. The period we investigated saw the release of many novel pharmaceuticals in the therapeutic areas we examined, and many (or their class successors) still play important therapeutic roles, including benzodiazepines, tricyclic antidepressants, phenothiazines, levodopa, selective and non-selective beta-adrenoceptor antagonists, thiazide diuretics, beta-adrenoceptor agonists, and histamine H2 receptor antagonists. CONCLUSIONS: Advertising pharmaceuticals in the BMJ and World Medicine in 1950-1980 was poorly regulated and often lacked rigour. However, advertisements were gradually modified in the light of increasing clinical pharmacological knowledge, and they reflect an exciting period for the introduction of many drugs that continue to be of benefit today. PMID- 29442381 TI - Fostering caring relationships: Suggestions to rethink liberal perspectives on the ethics of newborn screening. AB - Newborn screening (NBS) involves the collection of blood from the heel of a newborn baby and testing it for a list of rare and inheritable disorders. New biochemical screening technologies led to expansions of NBS programs in the first decade of the 21st century. It is expected that they will in time be replaced by genetic sequencing technologies. These developments have raised a lot of ethical debate. We reviewed the ethical literature on NBS, analyzed the issues and values that emerged, and paid particular interest to the type of impacts authors think NBS should have on the lives of children and their families. Our review shows that most authors keep their ethical reflection confined to policy decisions, about for instance (a) the purpose of the program, and (b) its voluntary or mandatory nature. While some authors show appreciation of how NBS information empowers parents to care for their (diseased) children, most authors consider these aspects to be 'private' and leave their evaluation up to parents themselves. While this division of moral labor fits with the liberal conviction to leave individuals free to decide how they want to live their private lives, it also silences the ethical debate about these issues. Given the present and future capacity of NBS to offer an abundance of health-related information, we argue that there is good reason to develop a more substantive perspective to whether and how NBS can contribute to parents' good care for children. PMID- 29442382 TI - Reproductive cloning revisited. PMID- 29442383 TI - Atrial overdrive pacing during LBBB tachycardia: What is the mechanism? PMID- 29442384 TI - Single Heterozygous ATP13A2 Mutations Cause Cellular Dysfunction Associated with Parkinson's Disease. PMID- 29442385 TI - Is yoghurt an acceptable alternative to raw milk for reducing eczema and allergy in infancy? PMID- 29442386 TI - Best available science still supports an ancient common origin of Devils Hole and Devils Hole pupfish. AB - The age of DHP and how pupfish colonized Devils Hole have always been a topic of interest. Recently, two different publications (Martin, Crawford, Turner, & Simons, & Saglam et al., ) tackled this issue using genomic data sets and demographic models but came to widely different conclusions. In their comment, Martin and Hohne () argue that our results (Saglam et al., ) were misleading because we used inappropriate calibration information and biased a priori assumptions. They then re-analysed our data using a "biologically informed" mutation rate prior and concluded that our data support a much younger age of DHP (12.6 kya) as opposed to 60 kya reported in our study. Below we will summarize why their arguments do not hold up and explore some of the inconsistencies between their claims and what was actually presented in our study. Furthermore, we will demonstrate their re-analyses provide no new information compared to what was presented in our original manuscript and reinforce our estimate of a 60 kya divergence of DHP as outweighing competing hypotheses. PMID- 29442387 TI - Scabies is strongly associated with acute rheumatic fever in a cohort study of Auckland children. AB - AIM: This study sought to determine whether scabies infection is associated with acute rheumatic fever (ARF) or chronic rheumatic heart disease (CRHD). METHODS: A cohort study was undertaken using health records of children aged 3-12 years attending an oral health service for the first time. Subjects were then linked to hospital diagnoses of scabies and ARF or CRHD. RESULTS: A total of 213 957 children free of rheumatic heart disease at baseline were available for analysis. During a mean follow-up time of 5.1 years, 440 children were diagnosed with ARF or CRHD in hospital records. Children diagnosed with scabies during follow-up were 23 times more likely to develop ARF or CRHD, compared with children who had no scabies diagnosis. After adjustment for confounders in a Cox model, the association reduced but remained strong (adjusted hazard ratio: 8.98; 95% confidence interval: 6.33-20.2). In an analysis restricted to children hospitalised at least once during follow-up, the adjusted hazard ratio for the same comparison was 3.43 (95% confidence interval: 1.85-6.37). CONCLUSIONS: A recent diagnosis of scabies from hospital records is strongly associated with a subsequent diagnosis of ARF. Further investigation of the role that scabies infestation may play in the aetiology of ARF is warranted. PMID- 29442389 TI - Children detained in French police cells. AB - AIM: Police custody is detention in response to a suspicion of crime. In France, until the age of 13, pre-trial detention and police custody are not allowed. We aimed to evaluate the practical implementation of police detention of children aged between 10 and 12 years and describe the medical characteristics and history, perceived health status and opinion on custody of the potentially affected children. METHODS: A descriptive study was conducted in a French reference regional department of forensic medicine at the time of medical examination in police cells among arrestees younger than 13 years old examined over a 5-year period (1 January 2011-31 December 2015). RESULTS: Children aged 10 12 years (n = 60; males, 48, 80%), accounting for 60 of 57 687 examined arrestees (0.1%), were examined over the study period. Six individuals (10%) were arrested twice or more times during the study period (for a total of 76 detentions analysed). The most common suspected crimes were theft or robbery (42/76, 55%) and physical assault (22/76, 29%). Arrestees had a favourable opinion of custody in 33 of 76 cases (43%). Children reported physical assault by the police in 6 of 76 cases (8%), and the physicians observed recent traumatic injuries in 7 of 76 cases (9%). Daily tobacco consumption was reported by 4 of 60 children (7%). No child was considered unfit for detention by the physician. CONCLUSIONS: Children aged 10-12 years suspected of serious crimes accounted for 0.1% of detained individuals in police cells. Although infrequent, such situations are a matter of concern. PMID- 29442388 TI - Maximizing sensitivity for fast GABA edited spectroscopy in the visual cortex at 7 T. AB - The combination of functional MRI (fMRI) and MRS is a promising approach to relate BOLD imaging to neuronal metabolism, especially at high field strength. However, typical scan times for GABA edited spectroscopy are of the order of 6-30 min, which is long compared with functional changes observed with fMRI. The aim of this study is to reduce scan time and increase GABA sensitivity for edited spectroscopy in the human visual cortex, by enlarging the volume of activated tissue in the primary visual cortex. A dedicated setup at 7 T for combined fMRI and GABA MRS is developed. This setup consists of a half volume multi-transmit coil with a large screen for visual cortex activation, two high density receive arrays and an optimized single-voxel MEGA-sLASER sequence with macromolecular suppression for signal acquisition. The coil setup performance as well as the GABA measurement speed, SNR, and stability were evaluated. A 2.2-fold gain of the average SNR for GABA detection was obtained, as compared with a conventional 7 T setup. This was achieved by increasing the viewing angle of the participant with respect to the visual stimulus, thereby activating almost the entire primary visual cortex, allowing larger spectroscopy measurement volumes and resulting in an improved GABA SNR. Fewer than 16 signal averages, lasting 1 min 23 s in total, were needed for the GABA fit method to become stable, as demonstrated in three participants. The stability of the measurement setup was sufficient to detect GABA with an accuracy of 5%, as determined with a GABA phantom. In vivo, larger variations in GABA concentration are found: 14-25%. Overall, the results bring functional GABA detections at a temporal resolution closer to the physiological time scale of BOLD cortex activation. PMID- 29442390 TI - Deciphering the biochemical and molecular mechanism underlying the in vitro and in vivo chemotherapeutic efficacy of ruthenium quercetin complex in colon cancer. AB - Flavonoids are the most investigated phytochemicals due to their pharmacological and therapeutic activities. Their ability to chelate with metal ions has resulted in the emergence of a new category of molecules with a broader spectrum of pharmacological activities. In this study, the ruthenium quercetin complex has been synthesized and anticancer activity has been evaluated on a well-defined model of DMH followed by DSS induced rat colon cancer and on human colon cancer cell line HT-29. The characterizations accomplished through UV-visible, NMR, IR, Mass spectra and XRD techniques, and antioxidant activity was assessed by DPPH, FRAP, and ABTS methods. In vitro study confirmed that the complex increased p53 expression, reduced VEGF and mTOR expression, apoptosis induction, and DNA fragmentation in the HT-29 cells. Acute and subacute toxicity study was also assessed and results from in vivo study revealed that complex was efficient to suppress ACF multiplicity and hyperplastic lesions and elevated the CAT, SOD, and glutathione levels. Furthermore, the complex was found to decrease cell proliferation and increased apoptotic events in tumor cells correlates upregulation of p53 and Bax and downregulation of Bcl2 expression. Our findings from the in vitro and in vivo study support the continued investigation of ruthenium quercetin complex possesses a potential chemotherapeutic activity against colon cancer and was efficient in reducing ACF multiplicity, hyperplastic lesions in the colon tissues of rats by inducing apoptosis. PMID- 29442391 TI - Cation-Triggered Stannate(II)/Stannylenoid/Stannylene Conversion. AB - The reaction of dipotassio-tetrasilan-1,4-diide (4) with anhydrous SnCl2 at low temperature results in the formation of a five-membered cyclic potassio chlorostannate(II) ([(18-C-6)K](1)). By careful cation exchange reactions, it was transformed into the sodium chlorostannylenoid 2 (by using Na2 [B12 Cl12 ]) or into the non-stabilized cyclic bissilylstannylene 3 (through applying Li[Al(OC(CF3 )3 )4 ]). The increasing Lewis basicity of the bissilylstannylene 3 was analyzed by combined methods of DFT calculations and NMR spectroscopy and substantiated by the synthesis of the corresponding iron carbonyl complexes 7 and 8 from the chlorostannate 1 and the stannylene 3, respectively. PMID- 29442392 TI - Selection of Normative Group Affects Rates of Mild Cognitive Impairment in Parkinson's Disease. AB - OBJECTIVE: The objective of this study was to examine the impact of different methods of standardizing cognitive data in the Parkinson's Progression Marker Initiative. METHODS: Cognitive data from 423 participants with Parkinson's disease were included (age = 61.7 [9.7], education = 15.6 [3.0]). Internal norms were calculated using the group mean and standard deviation of the healthy control group. Published norms were compared to the overall group mean of and to age-stratified norms from healthy controls for each neuropsychological test over 4 visits. Rates of mild cognitive impairment were calculated using established criteria. RESULTS: The use of internal norms resulted in lower standardized scores than published norms on all tests with the exception of memory and processing speed (P <= .001). Individuals were 1.5 to 2.1 times more likely to be diagnosed with mild cognitive impairment using internal norms than published norms. CONCLUSIONS: Standardization approaches with cognitive data are not interchangeable. Selection of a normative comparison group impacts research and clinical interpretations of cognitive data. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29442393 TI - Mineral trioxide aggregate enriched with iron disulfide nanostructures: an evaluation of their physical and biological properties. AB - The purpose of this study was to characterize mineral trioxide aggregates (MTA) enriched with iron disulfide (FeS2 ) nanostructures at different concentrations, and to investigate their storage modulus, radiopacity, setting time, pH, cytotoxicity, and antimicrobial activity. Iron disulfide nanostructures [with particle size of 0.357 +/- 0.156 MUm (mean +/- SD)] at weight ratios of 0.2, 0.4, 0.6, 0.8, and 1.0 wt% were added to white MTA (wMTA). The radiopacity, rheological properties, setting time, and pH, as well as the cytotoxicity (assessed using the MTT assay) and antibacterial activity (assessed using the broth microdilution test) were determined for MTA/FeS2 nanostructures. The nanostructures did not modify the radiopacity values of wMTA (~6 mm of aluminium); however, they reduced the setting time from 18.2 +/- 3.20 min to 13.7 +/- 1.8 min, and the storage modulus was indicative of a good stiffness. Whereas the wMTA/FeS2 nanostructures did not induce cytotoxicity when in contact with human pulp cells (HPCs) and human gingival fibroblasts (HGFs), they showed bacteriostatic activity against Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis. Adding FeS2 nanostructures to MTA might be an option for improving the root canal sealing and antibacterial effects of wMTA in endodontic treatments. PMID- 29442394 TI - Surveying social adversity in pregnancy: The antenatal risk burden experienced by Australian women. AB - AIM: Many, varied, antenatal risk factors can adversely impact children's health, behaviour and cognition. Understanding the antenatal risk factors experienced by women can help identify which families are most likely to benefit from additional early supports; however, there is a dearth of published Australian antenatal risk data. This study aimed to determine the prevalence and co-occurrence of a broad range of risk factors in a community-based sample of pregnant Australian women. METHODS: A brief risk factor survey (10 items, including age, social support, health, smoking, stress or anxious mood, education, household income, employment) completed by pregnant women attending the antenatal clinic waiting rooms of 10 public maternity hospitals, which were selected for their provision of care to areas with fewer socio-economic resources in the states of Victoria and Tasmania, between May 2013 and August 2014. RESULTS: A total of 5586 women participated, with an average age of 29.0 years and gestation of 26.9 weeks. The most prevalent antenatal risk factors were poorer global health (38.9%), not finishing high school (33.5%) and smoking (14.9%), all proportions higher than the general population. Most women reported at least one risk factor (68.6%), with 21.5% reporting >=3. There was a high degree of co-occurrence between risk factors, especially the three most prevalent. CONCLUSIONS: This study reveals the considerable and varied risk burden experienced by Australian women during pregnancy. By understanding where need is greatest and tailoring support accordingly, risk factor assessment provides an opportunity to address equity through health care, ultimately optimising the future developmental outcomes of all children. PMID- 29442395 TI - Paediatric thoracic empyema in the tropical North Queensland region of Australia: Epidemiological trends over a decade. AB - AIM: The Townsville Hospital and Health Service is the regional referral centre for children in the north of Queensland. Aboriginal and Torres Strait Islander (ATSI) people make up 7-10% of the population. Increasing numbers of children with paediatric thoracic empyema (pTE) are being referred to Townsville Hospital and Health Service for management. This study aims to describe the incidence rates, epidemiology, microbiology and trends of this disease in North Queensland over a 10-year period. METHODS: A retrospective chart review of all children (1 month to 16 years), admitted in the years 2007-2016, with community-acquired pTE was conducted. International Classification of Diseases codes were used to identify the patients. Epidemiological and microbiological data were extracted from records. RESULTS: Of the 123 cases identified, incidence rates per 100 000 were 8.5 (95% confidence interval (CI) 8.4-8.6) in all children and much higher at 19.8 (95% CI: 19.5-21.9) in ATSI children. The under 5 years age group had the highest rate (24.5; 95% CI: 24.4-24.6). There was a progressive rise in incidence during the 10-year period, with the highest incidence of 15.2 (95% CI: 15.1-15.2) occurring in 2016. A pathogen was isolated in 76% of cases. Non-multi-resistant methicillin-resistant Staphylococcus aureus was the most common pathogen isolated in 22 of 64 ATSI children (34%), while Streptococcus pneumoniae was the most common pathogen isolated in 27 of 59 non-ATSI children (46%). CONCLUSIONS: A high and increasing incidence of pTE in North Queensland is being observed. ATSI children have higher incidence rates and are more likely to have non-multi resistant methicillin-resistant Staphylococcus aureus as a causative agent. PMID- 29442396 TI - Effect of hyaluronic acid-enriched transfer medium on frozen-thawed embryo transfer outcomes. AB - AIM: To determine if hyaluronic acid-enriched transfer medium (HETM) affects the implantation rate (IR) and clinical pregnancy rate (PR) in women undergoing frozen-thawed embryo transfer (FET). METHODS: The records of women who underwent FET from May 2014 to October 2014 were retrospectively reviewed. Outcome measures were IR and PR. RESULTS: In all 1721 cycles of 1632 patients were included in this study. HETM was used for 347 cycles of 342 patients, and standard medium for 1374 cycles of 1290 patients. Overall, FET outcomes were similar between the groups. For patients undergoing their first FET attempt, the IR (24.3% vs 31.6%, P = 0.042) and clinical PR (34.3% vs 50.1%, P = 0.004) were lower in the HETM group. For patients undergoing their second FET attempt, pregnancy outcomes were similar between the groups. For patients undergoing their third or more FET attempt, HETM was associated with a higher IR (33.3% vs 16.4%, P < 0.001) and higher PR (52.2% vs 27.4%, P < 0.001). CONCLUSIONS: HETM can improve the embryo IR and clinical PR in patients with repeated implantation failure in the third or more FET attempt. However, the use of HETM for first and second FET should be done with caution. PMID- 29442397 TI - Tuberculin skin test versus interferon-gamma release assay in refugee children: A retrospective cohort study. AB - AIM: The aim of this study was to assist clinicians evaluating refugee children for latent tuberculosis infection (LTBI) by comparing paired tuberculin skin test (TST) and Quantiferon Gold In-Tube (QGIT) test results with clinical management decisions and follow-up data in a large cohort of newly arrived refugee children. METHODS: This was a retrospective analysis of all refugee children (<15 years of age) evaluated for LTBI with both TST and interferon-gamma release assay between 2007 and 2010 in the Illawarra-Shoalhaven region of New South Wales, Australia. Demographics, country of origin, bacille Calmette-Guerin (BCG) vaccination status, chest X-ray results, TST and QGIT test results, clinical management and outcome on long-term follow-up were assessed. RESULTS: Of 272 children evaluated, complete results were available for 212 (78%). The vast majority (207; 98%) were from Africa or Southeast Asia. Overall, 33 (16%) children were treated for LTBI; 13 (39%) had concordant TST and QGIT results and 20 (61%) discordant results. Of 63 (30%) TST-positive (>=10 mm) children, 46 (73%) were QGIT assay-negative, 44 (70%) had a BCG scar, 3 (5%) were younger than 2 years and 6 (10%) were treated for LTBI. Of 32 QGIT assay-positive children, 15 (47%) were TST negative, 31 (97%) had a BCG scar, all were older than 2 years and 14 (44%) were treated for LTBI. CONCLUSIONS: Discordant TST and QGIT results were found in a high percentage of refugee children. QGIT is convenient and more specific than TST to diagnose LTBI in BCG-vaccinated children, although a careful tuberculosis exposure history and clinical assessment to rule out active disease remain important. PMID- 29442398 TI - Restricting tobacco sales to only pharmacies as an endgame strategy: are pharmacies likely to opt in? PMID- 29442399 TI - Clinicopathologic characteristics of double primary endometrial and colorectal cancers in a single institution. AB - AIM: To investigate the clinicopathologic and genetic correlations between double primary endometrial and colorectal cancer related to Lynch syndrome and to analyze germline mutations in mismatch repair genes in endometrial cancer patients in Korea. METHODS: Thirteen patients diagnosed with pathologically endometrial and colorectal cancer between January 2005 and November 2016 in a single institution were enrolled in the study. The medical records were retrospectively analyzed. The genetic mutational information of endometrial cancer in Korea was retrieved from the literature review. RESULTS: Endometrial cancer was diagnosed first in eight (62%) patients, and one patient was diagnosed with colorectal cancer first. Endometrioid adenocarcinoma was reported in 10 of 13 (77%) endometrial cancer patients. Endometrial cancer was found at the low uterine segment in three patients. Three of four patients had high microsatellite instability. The loss of mismatch repair proteins was confirmed in 7 of 11 cases using immunohistochemistry. Four patients fulfilled clinical criteria based on a family history of cancer. Overall, the incidence of suspected Lynch syndrome was 77% (10/13). Four of them underwent genetic testing and three were found to have a pathogenic germline mutation. A possible founder mutation, c.1757_1758insC in MLH1, was observed in 21 germline mutation information from literature review. CONCLUSION: The present study describes the clinicopathologic data of double primary endometrial and colorectal cancer patients and supports that these patients should undergo closed approach for Lynch syndrome. Moreover, a possible founder mutation in Korean endometrial cancer patients was identified. PMID- 29442400 TI - What information can change the attitude of teachers toward the human papillomavirus vaccine? AB - AIM: We conducted a self-administered survey on the perception of teachers toward human papillomavirus (HPV) vaccine to determine the ways to increase their willingness to encourage its use. METHODS: Answers were obtained both prior to and after having the teachers read five brief information articles: (i) cervical cancer knowledge, (ii) vaccine knowledge, (iii) result of a survey in Nagoya, (iv) news report of the World Health Organization statement and (v) articles written by Dr Muranaka, a journalist. RESULTS: Most of the respondents (180/247) did not know about the natural history of cervical cancer. Only 36% knew that HPV is the cause of cervical cancer, although 63% knew that HPV vaccine would prevent cervical cancer. Few respondents had knowledge regarding adverse events following immunization and the survey results from Nagoya. Among those who were initially negative for the HPV vaccine, only 43% revealed that they fully understood its safety and only 29% reversed their opinion to recommend vaccination to their daughters and/or students, even after reading our informational material. The most useful information for changing their attitudes was to increase their understanding of vaccines and informing them about Nagoya city survey results. They mostly wanted a proof of the preventive effects of the vaccine on cervical cancer in Japan. CONCLUSION: Gynecologists and pediatricians must proactively communicate accurate scientific information to the government and the media to spread awareness among people in Japan. Also, we must try to demonstrate the capabilities of this vaccine to prevent cervical cancer and/or its precancerous lesions. PMID- 29442401 TI - Single arm phase II study of oral vitamin B12 for the treatment of musculoskeletal symptoms associated with aromatase inhibitors in women with early stage breast cancer. AB - Breast cancer patients receiving endocrine therapy with aromatase Inhibitors (AIs) often experience musculoskeletal and joint-related side effects. The purpose of this study was to evaluate the effect of Vitamin B12 supplements on musculoskeletal symptoms such as pain and arthralgias induced by AIs and to correlate response with serum and inflammatory biomarkers. Upon receiving approval by the Institutional Review Board (IRB), the majority of the patients consented into the study were treated at the Texas Tech Breast Care Center. Included were patients who had a diagnosis of invasive breast cancer (Stages I III), and were experiencing significant musculoskeletal symptoms associated to AIs. Only patients with an average pain score >= 4, as assessed by the Brief Pain Inventory-Short Form (BPI-SF) questionnaire, were included in the study. Participants received 2500 mcg of sublingual vitamin B12 daily for 90 days. Assessments at baseline and at 3 months included: BPI-SF pain scores, the impact on quality of life determined by Functional Assessment of Cancer Therapy Endocrine Symptoms (FACT-ES), and correlative serum markers relative to baseline (a pre-post study). A total of forty-one patients were enrolled. Average pain scores were improved by 34% (P < .0001) at 3 months compared to baseline. In addition, a 23% improvement in worst pain was noted (P = .0003). Analysis of the results for the FACT-ES scoring showed improvement on all scales. No significant adverse events were observed. Decrease in pain score was correlated with increased serum B12 levels. This study suggests that Vitamin B12 reduces pain and improves quality of life for patients taking AIs who experienced AI-related musculoskeletal symptoms. If confirmed in large randomized prospective trials, Vitamin B12 would be a safe and cost-effective option for the treatment of AI related musculoskeletal symptoms. PMID- 29442402 TI - Ectopic pregnancy in women with recurrent miscarriage. AB - AIM: The aim of this study was to investigate the possible association between recurrent miscarriage (RM) and ectopic pregnancy (EP). METHODS: In this case control retrospective study, the clinical cards of women followed as outpatients in the RM and low-risk pregnancy offices of the Obstetrics and Gynecology Unit at the Policlinico Tor Vergata University Hospital were carefully reviewed for the occurrence of EP. RESULTS: Overall, 598 women with RM and 2043 normal women without RM (controls) were included in the study. Among these women, 4974 pregnancies were analyzed, in which 2028 miscarriages occurred. The EP rate (3.51%) was significantly higher in RM than in control women (1.51%) [odds ratio = 2.31 (95% confidence interval: 2.3-2.4)]; it was particularly high in women with primary RM (5.11%). However, when EP rates were calculated not by women but by overall pregnancies, no differences could be found between RM and control women. In control women, the absence of a miscarriage in the reproductive history was associated with a lower rate of EP. CONCLUSIONS: Women with RM, particularly primary RM, are at increased risk of EP. This increased risk seems to be dependent on the high number of pregnancies occurring in women with RM rather than to specific characteristics of these women. PMID- 29442403 TI - Increasing injuries as trampoline parks expand within Australia: a call for mandatory standards. AB - OBJECTIVE: To quantify an apparent increase in indoor trampoline park related injuries in children and young people across Australia, and to understand the implications for current regulatory standards. METHODS: Retrospective analyses of three state-based Injury Surveillance databases, identifying children and adolescents presenting to emergency departments between the years 2005 and 2017, who had sustained injuries during trampolining activity at an indoor trampoline park. RESULTS: Across the three datasets, 487 cases were identified. No cases were recorded prior to 2012, the year the first indoor trampoline park opened. At least half occurred among those aged 10-14 years. In Victoria, 58% were male, with 52% in Queensland and 60% in Western Australia being male, respectively. Hospital admission rates in these states were 15%, 11.7% and 14.5%, respectively. The most frequent injury types were dislocations, sprains and strains, followed by fractures, with some head and spinal injuries. CONCLUSIONS: Across several states in Australia, the incidence of indoor trampoline park related injuries is concerning, as these venues are increasing in number. Some injuries can be serious and result in lifelong disability for children or adolescents. Implications for public health: National safety standards that apply to indoor trampoline park operators are not currently mandatory; injury prevention efforts would be assisted if such standards were mandatory. PMID- 29442404 TI - Cesarean section and diabetes during pregnancy: An NSW population study using the Robson classification. AB - AIM: The aim of this study was to identify the main contributors to cesarean section (CS) among women with and without diabetes during pregnancy using the Robson classification and to compare CS rates within Robson groups. METHODS: A population-based cohort study was conducted of all women who gave birth in New South Wales, Australia, between 2002 and 2012. Women with pregestational diabetes (types 1 and 2) and gestational diabetes mellitus (GDM) were grouped using the Robson classification. Adjusted odd ratios (AOR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression. RESULTS: The total CS rate was 53.6% for women with pregestational diabetes, 36.8% for women with GDM and 28.5% for women without diabetes. Previous CS contributed the most to the total number of CS in all populations. For preterm birth, the contribution to the total was 20.5% for women with pregestational diabetes and 5.7% for women without diabetes. Compared to women without diabetes, for nulliparous with pregestational diabetes, the odds of CS was 1.4 (95% CI, 1.1-1.8) for spontaneous labor and 2.0 (95% CI, 1.7-2.3) for induction of labor. CONCLUSION: A history of CS was the main contributor to the total CS. Reducing primary CS is the first step to lowering the high rate of CS among women with diabetes. Nulliparous women were more likely to have CS if they had pregestational diabetes. This increase was also evident in all multiparous women giving birth. The high rate of preterm births and CS reflects the clinical issues for women with diabetes during pregnancy. PMID- 29442405 TI - Long-term outcomes for children with neurodevelopmental disorders: Are they core business for paediatricians? PMID- 29442406 TI - Supporting youth wellbeing with a focus on eating well and being active: views from an Aboriginal community deliberative forum. AB - OBJECTIVE: Including and prioritising community voice in policy development means policy is more likely to reflect community values and priorities. This project trialled and evaluated a storyboard approach in a deliberative community forum to engage Australian Aboriginal people in health policy priority setting. METHODS: The forum was co-constructed with two Aboriginal community-controlled organisations. A circle storyboard was used to centre Aboriginal community knowledge and values and encourage the group to engage with broader perspectives and evidence. The forum asked a diverse (descriptively representative) group of Aboriginal people in a rural town what governments should do to support the wellbeing of children and youth, particularly to encourage them to eat well and be active. RESULTS: The storyboard provided a tactile device to allow shared stories and identification of community issues. The group identified policies they believed governments should prioritise, including strategies to combat racism and provide local supports and outlets for young people. CONCLUSIONS: An informed deliberative storyboard approach offers a novel way of engaging with Aboriginal communities in a culturally appropriate and inclusive manner. Implications for public health: The identification of racism as a major issue of concern in preventing children from living healthy lifestyles highlights the need for policy responses in this area. PMID- 29442407 TI - Prediction and prevention of pre-eclampsia in Asian subpopulation. AB - The benefit of the early administration of aspirin to reduce preterm pre eclampsia among screened positive European women from multivariate algorithmic approach (ASPRE trial) has opened an intense debate on the feasibility of universal screening. This review aims to assess the new perspectives in the combined screening of pre-eclampsia in the first trimester of pregnancy and the chances for prevention using low-dose aspirin with special emphasis on the particularities of the Asian population. PubMed, CENTRAL and Embase databases were searched from inception until 15 November 2017 using combinations of the search terms: preeclampsia, Asian, prenatal screening, early prediction, ultrasonography, pregnancy, biomarker, mean arterial pressure, soluble fms-like tyrosine kinase-1, placental growth factor, pregnancy-associated plasma protein-A and pulsatility index. This is not a systematic review or meta-analysis, so the risk of bias of the selected published articles and heterogeneity among the studies need to be considered. The prevalence of pre-eclampsia and serum levels of biochemical markers in Asian are different from Caucasian women; hence, Asian ethnicity needs to be corrected for in the algorithmic assessment of multiple variables to improve the screening performance. Aspirin prophylaxis may still be viable in Asian women, but resource implication needs to be considered. Asian ethnicity should be taken into account before implementing pre-eclampsia screening strategies in the region. The variables included can be mixed and matched to achieve an optimal performance that is appropriate for economical restriction in individual countries. PMID- 29442408 TI - The long history of health inequality in New Zealand: occupational class and lifespan in the late 1800s and early 1900s. AB - OBJECTIVE: As relatively little is known about how socioeconomic position might have affected health prior to the Second World War, we aimed to study lifespan by occupational class in two cohorts in New Zealand. METHODS: The first study included men on the electoral rolls in Dunedin in the period 1893 to 1902. The second study used an established cohort of male military personnel who were recruited for the First World War. Linear regression was used to estimate lifespan by occupational class. RESULTS: The first study of 259 men on the electoral rolls found no substantive lifespan differences between the high and low occupational class groups. But the second study of 2,406 military personnel found that men in the three highest occupational classes lived 3.5 years longer (95%CI: 0.3-6.8 years) than the three lowest classes (in the multivariable analysis adjusting for age in 1918 and rurality of occupation). CONCLUSIONS: We found no significant lifespan differences in one cohort, but a second cohort is the earliest demonstration to our knowledge of substantial differences in mortality by socioeconomic position in this country prior to the 1960s. Implications for public health: This study provides historical context to the long-term efforts to address health inequalities in society. PMID- 29442410 TI - Letter to 'Late pubertal growth spurt in a girl with growth hormone deficiency: Is Kaufmann therapy effective in a girl with short stature who responds poorly to growth hormone therapy and estrogen replacement therapy?' PMID- 29442409 TI - Socioeconomic status and multimorbidity: a systematic review and meta-analysis. AB - OBJECTIVES: We performed a systematic review to identify, critically appraise and synthesise the existing literature on the association between SEP and multimorbidity occurrence. METHODS: We searched Medline and Embase from inception to December 2014. Where possible we performed meta-analysis to obtain summary odds ratios (ORs), exploring heterogeneity between studies through sub-group analysis. RESULTS: We identified 24 cross-sectional studies that largely reported on education, deprivation or income in relation to multimorbidity occurrence. Differences in analysis methods allowed pooling of results for education only. Low versus high education level was associated with a 64% increased odds of multimorbidity (summary OR: 1.64, 95% CI 1.41 to 1.91), with substantial heterogeneity between studies partly explained by method of multimorbidity ascertainment. Increasing deprivation was consistently associated with increasing risk of multimorbidity, whereas the evidence on income was mixed. Few studies reported on interaction with age or sex. CONCLUSIONS: More methodologically robust studies that address these gaps and investigate alternate measures of social circumstances and environment may advance our understanding of how SEP affects multimorbidity risk. Implications for public health: A deeper understanding of the socioeconomic and demographic patterning of multimorbidity will help identify sub-populations at greatest risk of becoming multimorbid. PMID- 29442411 TI - A multiprofessional approach to teaching child neurology in Africa - a powerful project for local needs and the avoidance of brain drain. PMID- 29442412 TI - Effect of chewing gum on gastrointestinal function after gynecological surgery: A systematic literature review and meta-analysis. AB - AIM: Recently, several randomized controlled trials (RCT) reported the effect of chewing gum on gastrointestinal function after gynecological surgery; however, these results are inconsistent. The aim of this study was to systematically analyze the effect of chewing gum on postoperative gastrointestinal function and complications in women undergoing gynecological surgery. METHODS: Pumbed, Embase, Cochrane Library, Web of Science, Chinese Wanfang databases, China National Knowledge Infrastructure and http://clinicaltrials.gov were searched from inceptions to April 30, 2017. Studies including chewing gum's impact on postoperative gastrointestinal function or complications were evaluated. Two authors individually performed data extraction from 10 RCT. Weighted mean difference (WMD) and odds ratio (OR) were used. RESULTS: Contrasting the group of standard postoperative care, the gum chewing group had a lower duration from the end of operation to first aerofluxus (WMD -7.55, 95%CI: -10.99 to -4.12); first intestinal sounds (WMD -6.20, 95%CI: -8.14 to -4.27); first defecation (WMD 12.24, 95%CI: -18.47 to -6.01); hospitalization duration (WMD -0.72. 95%CI -1.19 to -0.25); and lower incidence of nausea (OR 0.45, 95%CI: 0.29 to 0.69), vomiting (OR 0.38, 95%CI: 0.22 to 0.68) and postoperative ileus (OR 0.25, 95%CI: 0.14 to 0.44). CONCLUSION: Chewing gum is an effective measure to ameliorate gastrointestinal function and decrease complications after gynecological surgery. PMID- 29442413 TI - Ongoing changes in migration phenology and winter residency at Bracken Bat Cave. AB - Bats play an important role in agroecology and are effective bioindicators of environmental conditions, but little is known about their fundamental migration ecology, much less how these systems are responding to global change. Some of the world's largest bat populations occur during the summer in the south-central United States, when millions of pregnant females migrate from lower latitudes to give birth in communal maternity colonies. Despite a relatively large volume of research into these colonies, many fundamental questions regarding their abundance-including their intra- and interseasonal variability-remain unanswered, and even estimating the size of individual populations has been a long-running challenge. Overall, monitoring these bat populations at high temporal resolution (e.g., nightly) and across long time spans (e.g., decades) has been impossible. Here, we show 22 continuous years of nightly population counts at Bracken Cave, a large bat colony in south-central Texas, enabling the first climate-scale phenological analysis. Using quantitative radar monitoring, we found that spring migration and the summer reproductive cycle have advanced by approximately 2 weeks over the study period. Furthermore, we quantify the ongoing growth of a newly-established overwintering population that indicates a system-wide response to changing environmental conditions. Our observations reveal behavioral plasticity in bats' ability to adapt to changing resource availability, and provide the first long-term quantification of their response to a changing climate. As aerial insectivores, these changes in bat phenology and propensity for overwintering indicate probable shifts in prey availability, with clear implications for pest management across wider regional agrisystems. PMID- 29442414 TI - Frequent lunch purchases from NSW school canteens: a potential marker for children's eating habits? PMID- 29442415 TI - Thrombin-reduced miR-27b attenuates platelet angiogenic activities in vitro via enhancing platelet synthesis of anti-angiogenic thrombospondin-1. AB - : Essentials It is unclear if platelet micro-RNAs can regulate de novo protein synthesis of platelets. Platelet de novo protein synthesis of thrombospondin-1 (TSP-1) was induced by thrombin. Thrombin stimulation in vitro altered platelet microRNA profiles, including decreased miR-27b. Decreased miR-27b hampers platelet angiogenic activities via enhancing de novo TSP-1 synthesis. SUMMARY: Background Platelets can synthesize proteins upon activation. Platelets contain a number of microRNAs (miRNA) and a fully functional miRNA effector machinery. It is, however, unclear if platelet miRNAs can regulate protein synthesis of platelets, and whether the regulation may produce a physiological impact. Objectives To investigate if and how platelet miRNAs regulate de novo syntheses of angiogenic regulators and subsequently modulate platelet angiogenic activities. Methods and Results Microarray-based miRNA profiling showed that thrombin stimulation in vitro down- or up-regulated a number of platelet miRNAs, both in the total platelet miRNAs and in Ago2-associated miRNAs. Among those altered miRNAs, miR-27b was down-regulated in both the total and Ago2 immunoprecipitated miRNA profiles of platelets, which was confirmed by reverse transcription-quantitative PCR (RT-qPCR). Using western blotting assays, we showed that thrombin induced platelet de novo synthesis of thrombospondin-1, and that the level of thrombospondin-1 synthesis could reach a level of 3-5-fold higher than that before thrombin stimulation. With either the platelet precursor megakaryocyte cell line MEG-01 cells or mature platelets, we demonstrated that transfection of miR-27b mimic, but not the negative control of miRNA mimic, markedly reduced thrombospondin-1 protein levels. The latter subsequently enhanced platelet-dependent endothelial tube formation on matrigel. Conclusions Thrombin stimulation in vitro reduces platelet miR-27b levels that may markedly enhance thrombin-evoked platelet de novo synthesis of thrombospondin-1. Elevation of platelet miR-27b by transfection inhibits thrombospondin-1 synthesis, and subsequently enhances platelet pro-angiogenic activities. Hence, platelet activation-dependent reduction of miR-27b levels may represent a novel negative regulatory mechanism of platelet angiogenic activities. PMID- 29442416 TI - T1- or T2-weighted magnetic resonance imaging: what is the best choice to evaluate atrophy of the hippocampus? AB - BACKGROUND AND PURPOSE: Magnetic resonance imaging is part of the diagnostic criteria for Alzheimer's disease (AD) through the evaluation of hippocampal atrophy. The objective of this study was to evaluate which sequence of T1 weighted (T1WI) and T2-weighted (T2WI) imaging allowed the best visual evaluation of hippocampal atrophy. METHODS: Visual qualitative ratings of the hippocampus of 100 patients with mild cognitive impairment (MCI) and 50 patients with AD were made independently by four operators according to the medial temporal lobe atrophy score based either on T1WI or T2WI. These two evaluations were compared in terms of interobserver reproducibility, concordance with a quantitative volumetric measure, discrimination power between AD and MCI groups, and correlation with several neuropsychological tests. RESULTS: The medial temporal lobe atrophy score evaluated on either T1WI or T2WI exhibited similar interobserver variability and accordance with quantitative volumetric evaluation. However, the visual evaluation on T2WI seemed to provide better discrimination power between AD and MCI groups for both left (T1WI, P = 0.0001; T2WI, P = 7.072 * 10-5 ) and right (T1WI, P = 0.008; T2WI, P = 0.001) hippocampus, and a higher overall correlation with neuropsychological tests. CONCLUSIONS: The present study suggests that T2WI provides a more adequate visual rating of hippocampal atrophy. PMID- 29442417 TI - Comparison of ICare tonometry to Goldmann tonometry for the measurement of intraocular pressure changes following intravitreal anti-vascular endothelial growth factor injection. PMID- 29442418 TI - Electrolyte Additives for Lithium Metal Anodes and Rechargeable Lithium Metal Batteries: Progress and Perspectives. AB - Lithium metal (Li0 ) rechargeable batteries (LMBs), such as systems with a Li0 anode and intercalation and/or conversion type cathode, lithium-sulfur (Li-S), and lithium-oxygen (O2 )/air (Li-O2 /air) batteries, are becoming increasingly important for electrifying the modern transportation system, with the aim of sustainable mobility. Although some rechargeable LMBs (e.g. Li0 /LiFePO4 batteries from Bollore Bluecar, Li-S batteries from OXIS Energy and Sion Power) are already commercially viable in niche applications, their large-scale deployment is hampered by a number of formidable challenges, including growth of lithium dendrites, electrolyte instability towards high voltage intercalation type cathodes, the poor electronic and ionic conductivities of sulfur (S8 ) and O2 , as well as their corresponding reduction products (e.g. Li2 S and Li2 O), dissolution, and shuttling of polysulfide (PS) intermediates. This leads to a short lifecycle, low coulombic/energy efficiency, poor safety, and a high self discharge rate. The use of electrolyte additives is considered one of the most economical and effective approaches for circumventing these problems. This Review gives an overview of the various functional additives that are being applied and aims to stimulate new avenues for the practical realization of these appealing devices. PMID- 29442420 TI - A liver for a kidney: Ethics of trans-organ paired exchange. AB - Living donation provides important access to organ transplantation, which is the optimal therapy for patients with end-stage liver or kidney failure. Paired exchanges have facilitated thousands of kidney transplants and enable transplantation when the donor and recipient are incompatible. However, frequently willing and otherwise healthy donors have contraindications to the donation of the organ that their recipient needs. Trans-organ paired exchanges would enable a donor associated with a kidney recipient to donate a lobe of liver and a donor associated with a liver recipient to donate a kidney. This article explores some of the ethical concerns that trans-organ exchange might encounter including unbalanced donor risks, the validity of informed consent, and effects on deceased organ donation. PMID- 29442419 TI - Synthesis of Sub-2 nm Iron-Doped NiSe2 Nanowires and Their Surface-Confined Oxidation for Oxygen Evolution Catalysis. AB - Ultrathin nanostructures are attractive for diverse applications owing to their unique properties compared to their bulk materials. Transition-metal chalcogenides are promising electrocatalysts, yet it remains difficult to make ultrathin structures (sub-2 nm), and the realization of their chemical doping is even more challenging. Herein we describe a soft-template mediated colloidal synthesis of Fe-doped NiSe2 ultrathin nanowires (UNWs) with diameter down to 1.7 nm. The synergistic interplay between oleylamine and 1-dodecanethiol is crucial to yield these UNWs. The in situ formed amorphous hydroxide layers that is confined to the surface of the ultrathin scaffolds enable efficient oxygen evolution electrocatalysis. The UNWs exhibit a very low overpotential of 268 mV at 10 mA cm-2 in 0.1 m KOH, as well as remarkable long-term stability, representing one of the most efficient noble-metal-free catalysts. PMID- 29442421 TI - What the neighbors say. PMID- 29442422 TI - A Benzene-1,3,5-Triaminyl Radical Fused with ZnII -Porphyrins: Remarkable Stability and a High-Spin Quartet Ground State. AB - A benzene-1,3,5-triaminyl radical fused with three ZnII -porphyrins was synthesized through a three-fold oxidative fusion reaction of 1,3,5-tris(ZnII porphyrinylamino)benzene followed by oxidation with PbO2 as key steps. This triaminyl radical has been shown to possess a quartet ground state with a doublet quartet energy gap of 3.1 kJ mol-1 by superconducting quantum interference device (SQUID) studies. Despite its high-spin nature, this triradical is remarkably stable, which allows its separation and recrystallization under ambient conditions. Moreover, this triradical can be stored as a solid for more than one year without serious deterioration. The high stability of the triradical is attributed to effective spin delocalization over the porphyrin segments and steric protection at the nitrogen centers and the porphyrin meso positions. PMID- 29442423 TI - Impact of type 1 diabetes mellitus and sitagliptin treatment on the neuropeptide Y system of rat retina. AB - BACKGROUND: Neuropeptide Y (NPY) is a neuromodulator that is expressed in the retina. Increasing evidence suggests that NPY has pronounced anti-inflammatory effects, which might depend on the inhibition of dipeptidyl-peptidase-IV (DPP IV). The aim of this study was to investigate the impact of type 1 diabetes mellitus (DM) and sitagliptin, a DPP-IV inhibitor, on the NPY system in the retina using an animal model. METHODS: Type 1 DM was induced in male Wistar rats by an intraperitoneal injection of streptozotocin. Starting 2 weeks after DM onset, animals were treated orally with sitagliptin (5 mg/kg.day) for 2 weeks. The expression of NPY and NPY receptors (Y1 , Y2 and Y5 receptors) was measured by quantitative polymerase chain reaction, Western blot and/or enzyme-linked immunosorbent assay. The immunoreactivity of NPY and NPY receptors was evaluated by immunohistochemistry, and the [35 S]GTPgammaS binding assay was used to assess the functional binding of NPY receptors. RESULTS: DM decreased the mRNA levels of NPY in the retina, as well as the protein levels of NPY and Y5 receptor. No changes were detected in the localization of NPY and NPY receptors in the retina and in the functional binding of NPY to all receptors. Sitagliptin alone reduced retinal NPY mRNA levels. The effects of DM on the NPY system were not affected by sitagliptin. CONCLUSION: DM modestly affects the NPY system in the retina and these effects are not prevented by sitagliptin treatment. These observations suggest that DPP-IV enzyme is not underlying the NPY changes detected in the retina induced by type 1 DM. PMID- 29442425 TI - Effect of co-culture human endothelial progenitor cells with porcine oocytes during maturation and subsequent embryo development of parthenotes in vitro. AB - Human endothelial progenitor cells (EPCs) have been applied to regenerative medicine for their roles in angiogenesis as well as neovascularization, and these angiogenetic functions have beneficial effects on maturation of ovarian follicles. However, little information is available on whether EPCs on culture systems affect oocyte maturation and subsequent embryo development. Therefore, the objective of this study was to investigate the effect of EPC co-culture on porcine oocytes during in vitro maturation (IVM) and subsequent embryo development, and to examine gene expression in cumulus cells, oocytes and blastocysts. The effect of co-culture using EPC on porcine oocyte IVM was investigated. Oocytes were activated using electrical stimulation and embryo developmental competence was estimated. The expression of the genes related to cumulus expansion, oocyte maturation, embryo development, and apoptosis were analyzed. In result, there was a significantly increased maturation rate in EPC group compared with control (p < 0.05). Also, oocytes co-cultured with EPCs exhibited significantly improved blastocyst formation rates (p < 0.05). The expression of mRNAs associated with cumulus expansion and apoptosis in cumulus cells was significantly up-regulated in EPC group. Also, markedly increased levels of GDF9, BMP15, and BCL2 were observed in oocytes from the EPC group. Blastocysts in the co-culture group showed significantly higher SOX2, OCT4, and NANOG levels. In conclusion, co-culturing porcine oocytes with EPCs improves their maturation by regulating genes involved in cumulus cell expansion, oocyte maturation, and apoptosis. Moreover, EPC co-culture during IVM enhanced embryo development as shown by increased blastocyst formation rate and pluripotency related gene expression. PMID- 29442424 TI - Incidence, characterization, and impact of newly detected donor-specific anti-HLA antibody in the first year after pediatric heart transplantation: A report from the CTOTC-04 study. AB - Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population. In the absence of preexisting DSAs, patients with ndDSAs had significantly more acute cellular rejection but not antibody-mediated rejection, and there was no impact on graft and patient survival in the first year posttransplantation. Risk factors for ndDSAs included common sensitizing events. Given the early detection of the antibody response, memory responses may be more important in the first year after pediatric heart transplantation and patients with a history of a sensitizing event may be at risk even with a negative pretransplantation antibody screen. The impact on late graft and patient outcomes of first-year ndDSAs is being assessed in an extended cohort of patients. PMID- 29442426 TI - Shape-Tunable Colloids from Structured Liquid Droplet Templates. AB - Shaping colloidal building units is of paramount importance for their self assembly into complex objects. Continuous tuning of colloidal shapes is highly desired for understanding self-assembly, but it still remains a challenge. Herein, we report a new template strategy for the shape-tunable synthesis of anisotropic colloids with shapes that can be continuously tuned from discs (oblate spheroids) to spheres to theta shapes to dumbbells. This was realized by creating structured shape-tunable droplets from patchy colloidal discs and using these droplets as templates. In particular, we found that a controlled dumbbell to-eyeball droplet transformation can be used for the synthesis of eyeball-shaped colloids. We also demonstrated the droplet transformation pathways and applied the method to the synthesis of colloidal molecules. These colloids provide possibilities for exploring their ordered packing structures, and the method based on the use of structured droplets can be adapted for the synthesis of other functional colloidal particles. PMID- 29442427 TI - Retraction gonioscopy: a novel method in the diagnosis of cyclodialysis clefts. PMID- 29442428 TI - Optogenetic Control by Pulsed Illumination. AB - Sensory photoreceptors evoke numerous adaptive responses in nature and serve as light-gated actuators in optogenetics to enable the spatiotemporally precise, reversible, and noninvasive control of cellular events. The output of optogenetic circuits can often be dialed in by varying illumination quality, quantity, and duration. A programmable matrix of light-emitting diodes has been devised to efficiently probe the response of optogenetic systems to intermittently applied light of varying intensity and pulse frequency. Circuits for light-regulated gene expression markedly differed in their responses to pulsed illumination of a single color which sufficed for their sequential triggering. In addition to quantity and quality, the pulse frequency of intermittent light hence provides a further input variable for output control in optogenetics and photobiology. Pulsed illumination schemes allow the reduction of overall light dose and facilitate the multiplexing of several lightdependent actuators and reporters. PMID- 29442429 TI - Towards K-Ion and Na-Ion Batteries as "Beyond Li-Ion". AB - Li-ion battery commercialized by Sony in 1991 has the highest energy-density among practical rechargeable batteries and is widely used in electronic devices, electric vehicles, and stationary energy storage system in the world. Moreover, the battery market is rapidly growing in the world and further fast-growing is expected. With expansion of the demand and applications, price of lithium and cobalt resources is increasing. We are, therefore, motivated to study Na- and K ion batteries for stationary energy storage system because of much abundant Na and K resources and the wide distribution in the world. In this account, we review developments of Na- and K-ion batteries with mainly introducing our previous and present researches in comparison to that of Li-ion battery. PMID- 29442430 TI - Cocrystals Strategy towards Materials for Near-Infrared Photothermal Conversion and Imaging. AB - A cocrystal strategy with a simple preparation process is developed to prepare novel materials for near-infrared photothermal (PT) conversion and imaging. DBTTF and TCNB are selected as electron donor (D) and electron acceptor (A) to self assemble into new cocrystals through non-covalent interactions. The strong D-A interaction leads to a narrow band gap with NIR absorption and that both the ground state and lowest-lying excited state are charge transfer states. Under the NIR laser illumination, the temperature of the cocrystal sharply increases in a short time with high PT conversion efficiency (eta=18.8 %), which is due to the active non-radiative pathways and inhibition of radiative transition process, as revealed by femtosecond transient absorption spectroscopy. This is the first PT conversion cocrystal, which not only provides insights for the development of novel PT materials, but also paves the way of designing functional materials with appealing applications. PMID- 29442431 TI - Elution-extrusion countercurrent chromatography separation of six pairs of isomeric iridoids from Cornus officinalis Sieb. et Zucc. guided by ion current extraction in mass spectrometry. AB - A mass spectrometry-guided elution-extrusion countercurrent chromatography protocol was developed to separate chemical components from Cornus officinalis Sieb. et Zucc. In this study, ion current extraction, a mass spectrometry-based data postacquisition method, was utilized to boost the separation power and scope of countercurrent chromatography technique. As a peak repicking and denoising tool, ion current extraction was carried out to process the liquid chromatography with mass spectrometry and the countercurrent chromatography with mass spectrometry data. So the target components were reacquired in the created extracted ion current patterns with enhanced responses and diminished background noise, which facilitated the distribution constant determination (by liquid chromatography with extracted ion current) and the targets fractionation (by countercurrent chromatography with extracted ion current). Under the guidance of the extracted ion currents of the target components and with the support of elution-extrusion mode in the countercurrent chromatography separation, six pairs of minor iridoid isomers were obtained in shortened experimental duration. Besides, a reciprocal shifted symmetry plot was established to represent the elution-extrusion countercurrent chromatography chromatogram. The results demonstrated the capability of the ion current extraction-guided elution extrusion countercurrent chromatography protocol in discovery, analysis, and fractionation of low-concentration and structurally similar chemicals from a complicated sample. PMID- 29442432 TI - Investigation of corneal endothelial changes post selective laser trabeculoplasty. AB - IMPORTANCE: Transient corneal endothelial changes are routinely noted on slit lamp examination immediately following selective laser trabeculoplasty (SLT). BACKGROUND: To determine the mechanism of transient corneal endothelial changes observed following SLT. DESIGN: University laboratory-based observational study. SAMPLES: Ten corneas from six human cadaveric donors. METHODS: Corneas were treated with SLT, direct laser or peroxide, or used as controls. Haematoxylin and eosin staining and immunolabelling for zonula occludens-1 (ZO-1) and beta-catenin were performed. MAIN OUTCOME MEASURES: Histological appearance; ZO-1 and beta catenin immunostaining. RESULTS: There were no differences in histological features between SLT-treated and control corneas. Corneas treated with SLT or peroxide showed reduced and less regular ZO-1 immunofluorescence along cell membranes compared with ZO-1 expression in controls. These changes were generalized across the endothelium. There was no effect on the ZO-1 immunostaining after direct laser. There was no difference in beta-catenin immunostaining patterns between control, SLT and peroxide-treated corneas. CONCLUSIONS AND RELEVANCE: Altered ZO-1 immunostaining may represent disassembly of tight junctions between corneal endothelial cells. The similarity of our findings between SLT-treated and peroxide-treated corneas suggests that both conditions trigger changes at the level of endothelial tight junctions, perhaps triggered by liberation of free radicals as previously proposed. PMID- 29442433 TI - Acute crocodile tear syndrome without antecedent facial nerve palsy. PMID- 29442434 TI - Me3 Si-SiMe2 [oCON(iPr)2 -C6 H4 ]: An Unsymmetrical Disilane Reagent for Regio- and Stereoselective Bis-Silylation of Alkynes. AB - The air-stable unsymmetrical disilane Me3 Si-SiMe2 [oCON(iPr)2 C6 H4 ] has been developed for bis-silylation of alkynes. This reagent tolerates a range of functional groups, providing Z-vinyl disilanes in high yields. It is proposed that the phenyl-ring-tethered amide group directs oxidative addition of Pd0 into the Si-Si bond, which might facilitate formation of a six-membered Pd cycle, generating products with good to excellent regioselectivity. PMID- 29442435 TI - An unsettling explanation for the failure of skatole-baited ovitraps to capture Culex mosquitoes. AB - Culex mosquitoes are primarily found in temperate and tropical regions worldwide where they play a crucial role as main vectors of filarial worms and arboviruses. In Recife, a northeast city in Brazil, high densities of Culex quinquefasciatus are often found in association with human populated areas. In marked contrast to another part of the city, field tests conducted in the neighborhood of Sitio dos Pintos showed that trapping of mosquitoes in skatole-baited ovitraps did not differ significantly from captures in control (water) traps. Thus, classical and molecular taxonomic approaches were used to analyze the Culex species circulating in Sitio dos Pintos. Results obtained from both approaches agreed on the cocirculation of Culex quinquefasciatus and Culex nigripalpus in three different areas of this neighborhood. What was initially considered as an unexpected failure of this lure turned out to be a more unsettling problem, that is, the first report in Recife of Culex nigripalpus, a vector of Venezuelan equine encephalitis virus and West Nile virus. Unplanned urbanization processes close to remnants of the Atlantic forest, such as observed in Sitio dos Pintos, may have contributed to the introduction of Cx. nigripalpus in urban areas. PMID- 29442436 TI - Prediction of Protein-compound Binding Energies from Known Activity Data: Docking score-based Method and its Applications. AB - We used protein-compound docking simulations to develop a structure-based quantitative structure-activity relationship (QSAR) model. The prediction model used docking scores as descriptors. The binding free energy was approximated by a weighted average of docking scores for multiple proteins. This approximation was based on a pharmacophore model of receptor pockets and compounds. The weights of the docking scores were restricted to small values to avoid unrealistic weights by a regularization term. Additional outlier elimination improved the results. We applied this method to two groups of targets. The first target was the kinase family. The cross-validation results of 107 kinase proteins showed that the RMSE of predicted binding free energies was 1.1 kcal/mol. The second target was the matrix metalloproteinase (MMP) family, which has been difficult for docking programs. MMPs require metal-binding groups in their inhibitor structures in many cases. A quantum effect contributes to the metal-ligand interaction. Despite this difficulty, the present method worked well for the MMPs. This method showed that the RMSE of predicted binding free energies was 1.1 kcal/mol. In comparison, with the original docking method the RMSE was 1.7 kcal/mol. The results suggest that the present QSAR model should be applied to general target proteins. PMID- 29442438 TI - Synthesis, Characterization, and Biodistribution of a Dinuclear Gadolinium Complex with Improved Properties as a Blood Pool MRI Agent. AB - A dinuclear gadolinium(III) chelate containing two moieties of diethylenetriaminepentaacetic acid (DTPA), covalently conjugated to an analogue of deoxycholic acid, was synthesized and thoroughly characterized. A full relaxometric analysis was carried out, consisting of 1) the acquisition of nuclear magnetic resonance dispersion (NMRD) profiles in various media; 2) the study of binding affinity to serum albumin; 3) the measurement of 17 O transverse relaxation rate versus temperature, and 4) a transmetallation assay. In vivo biodistribution MRI studies at 1 T and blood pharmacokinetics assays were carried out in comparison with Gd-DTPA (Magnevist) and gadocoletic acid trisodium salt (B22956/1), two well-known Gd complexes that share the same chelating cage and the same deoxycholic acid residue of the Gd complex investigated herein ((GdDTPA)2 -Chol). High affinity for plasma protein and, in particular, the availability of more than one binding site, allows the complex to reach a fairly high relaxivity value in plasma (~20 mm-1 s-1 , 20 MHz, 310 K) as well as to show unexpectedly enhanced properties of blood pooling, with an elimination half life in rats approximately seven times longer than that of B22956/1. PMID- 29442437 TI - Prospective Studies Exploring the Possible Impact of an ID3 Polymorphism on Changes in Obesity Measures. AB - OBJECTIVE: Changes in fat mass depend on adipogenesis and angiogenesis, mechanisms regulated by the inhibitor of differentiation-3 (ID3). Id3 knockout mice showed attenuated increases in BMI and visceral fat mass. We hypothesized that the ID3 missense variant (rs11574-A) would lead to an attenuated increase over time in fat mass, BMI, waist circumference (WC), and waist-hip ratio (WHR) in humans. METHODS: The genotyped study populations included the Obesity Research Group - Genetics (ORGGEN) cohort, a cohort of men with obesity (N = 716) and of randomly selected men (N = 826) from the Danish draft register who were examined at mean ages of 20 and 46 years, and the Inter99 (N = 6,116) and Health2006 (N = 2,761) cohorts, two population-based samples of middle-aged people, followed up after 5 years. RESULTS: In meta-analyses of all data, no association was found between rs11574-A and changes in BMI, WC, WHR, or fat mass. We found an association between rs11574-A and cross-sectional BMI (N = 10,359, beta: -0.16 kg/m2 per allele, 95% CI: -0.30 to -0.01, P = 0.033) and fat mass (N = 4,188, beta: -0.52 kg/m2 per allele, 95% CI: -1.03 to -0.01, P = 0.046). CONCLUSIONS: No consistent impact of the genetic variant on changes in fat mass, BMI, or fat distribution was found in three Danish cohorts. PMID- 29442439 TI - Wet Imprinting of Channel-Type Superstructures in Nanostructured Titania Thin Films at Low Temperatures for Hybrid Solar Cells. AB - Hierarchically structured titania films, exhibiting interconnected foam-like nanostructures and large-scale channel-type superstructures, were achieved in an energy-saving way at low temperatures by a polymer template-assisted sol-gel synthesis in combination with a wet-imprinting process. The surface morphology was probed with scanning electron microscopy and atomic force microscopy, whereas the inner morphology was characterized with grazing incidence small-angle X-ray scattering measurements. Compared to the initial hybrid films, the titania films showed reduced structure sizes caused by removal of the polymer template. UV/Vis measurements showed an additional light-scattering effect at various angles of light incidence in the hierarchically structured titania films, which resulted in higher light absorption in the wet-imprinted active layer. To give proof of viability, the titania films were evaluated as photoanodes for dye-free hybrid solar cells. The dye-free layout allowed for low-cost fabrication, avoided problems related to dye bleaching, and was a more environmentally friendly alternative to using dyes. Under different angles of light incidence, the enhancement in the short-circuit current density was in good agreement with the improvement in light absorption in the superstructured active layer, demonstrating a positive impact of the superstructures on the photovoltaic performance of hybrid solar cells. PMID- 29442440 TI - Time to Peak Weight Loss During Extended Behavioral Treatment. AB - OBJECTIVE: This study was designed to examine the variability in timing of peak weight loss in behavioral treatment (BT), that is, when treatment participants reach their greatest amount of cumulative weight loss. METHODS: Secondary data analyses were conducted, drawing upon data from two clinical trials that provided 12 months of group-based BT, with sessions meeting less frequently in the second half of the treatment year. Weight was measured at the beginning of each treatment session. RESULTS: Cumulative proportions of participants reaching peak weight loss were as follows: 25.0% of study 1 and 20.0% of study 2 participants by month 4; 43.2% of study 1 and 52.2% of study 2 participants by month 6; 54.5% of study 1 and 77.8% of study 2 participants by month 8. Among participants who peaked after 4 months, the mean amount of additional weight loss achieved between 4 months and the peak session was 4.74 kg in study 1 and 4.07 kg in study 2. CONCLUSIONS: Substantial variability in the timing of peak weight loss was observed, with larger than expected proportions of participants reaching their greatest amount of cumulative weight loss in the final months of treatment. This variability may create methodological and clinical challenges. PMID- 29442442 TI - Scope. PMID- 29442443 TI - Teratology Society Strategic Plan 2017-2022. PMID- 29442444 TI - Erratum: Generative Recurrent Networks for De Novo Drug Design. PMID- 29442445 TI - Cheminformatics and the Mean. PMID- 29442446 TI - Generative Models for Artificially-intelligent Molecular Design. PMID- 29442447 TI - Corrigendum. PMID- 29442441 TI - A comprehensive review of the genetic and biological evidence supports a role for MicroRNA-137 in the etiology of schizophrenia. AB - Since it was first associated with schizophrenia (SCZ) in a 2011 genome-wide association study (GWAS), there have been over 100 publications focused on MIR137, the gene encoding microRNA-137. These studies have examined everything from its fundamental role in the development of mice, flies, and fish to the intriguing enrichment of its target gene network in SCZ. Indeed, much of the excitement surrounding MIR137 is due to the distinct possibility that it could regulate a gene network involved in SCZ etiology, a disease which we now recognize is highly polygenic. Here we comprehensively review, to the best of our ability, all published genetic and biological evidence that could support or refute a role for MIR137 in the etiology of SCZ. Through a careful consideration of the literature, we conclude that the data gathered to date continues to strongly support the involvement of MIR137 and its target gene network in neuropsychiatric traits, including SCZ risk. There remain, however, more unanswered than answered questions regarding the mechanisms linking MIR137 genetic variation with behavior. These questions need answers before we can determine whether there are opportunities for diagnostic or therapeutic interventions based on MIR137. We conclude with a number of suggestions for future research on MIR137 that could help to provide answers and hope for a greater understanding of this devastating disorder. PMID- 29442448 TI - Horizontal gene transfer (HGT) in biodegradation: An annotated selection of world wide web sites relevant to the topics in environmental microbiology. PMID- 29442449 TI - Microbial biocatalysis databases: An annotated selection of World Wide Web sites relevant to the topics in microbial biotechnology. PMID- 29442450 TI - Corrigendum. PMID- 29442451 TI - Application of an anionic polymer in the formulation of floating tablets containing an alkaline model drug. AB - BACKGROUND: Gastric residence time is the key factor affecting the bioavailability of active pharmaceutical ingredients absorbed mainly through the gastric mucous membrane and influencing the local activity of some drugs. OBJECTIVES: The aim of this study was the development of a new composition of non effervescent floating tablets and the evaluation of the effect of an anionic polymer and compressive force on the floating properties and release characteristics of tablets containing a model alkaline drug, chlorhexidine (CHX). MATERIAL AND METHODS: Direct compression was applied to a polyacrylic acid derivative and sorbitol to fabricate the tablets. Drug release was analyzed using several kinetic models. The formulations floated on the surface of the fluid for 24 h. The values of the rate constants, statistical parameters, and half-release time (t0.5) were calculated. RESULTS: The diffusion coefficient n falls between 0.54 +/-0.02 and 0.81 +/-0.03 for most formulations. The floating time (FT) and floating lag time (FLT) were found to depend on the amount of polymer incorporated in the formulations. A high compressive force sustained the release of the drug but reduced the FT and FLT. Based on the FT and t0.5, it was determined that the C1 composition is the optimal formulation with FT >24 h and t0.5 between 113 +/-2 and 144 +/-13 min, depending on the drug release model. CONCLUSIONS: The application of an anionic polymer results in a prolonged release of the drug from the tablets and allows them to float on fluid surfaces. PMID- 29442452 TI - The neuroprotective effect of N-acetylcysteine in spinal cord-injured rats. AB - BACKGROUND: Spinal cord injury (SCI) is an important cause of impairment of sensory and motor nerve function. It has been shown that free-radical species play an important role in the pathogenesis of acute tissue trauma after SCI. There are no proven pharmacological therapies that provide neuroprotection and stimulate axonal growth after trauma. OBJECTIVES: The aim of this study was to investigate the neuroprotective effect of N-acetylcysteine (NAC) on the regeneration of spinal cord injuries in rats. MATERIAL AND METHODS: A total of 20 male Wistar C rats were subjected to SCI and divided into control and experimental groups. In the control group (n = 10) trepanation and SCI by means of a pressure impactor was performed without any therapy. In the study group (n = 10), 1 dose of NAC was applied intraperitoneally (150 mg/kg b.w.) immediately after SCI, and another one after 24 h. The functional outcome on the Basso Beattie-Bresnahan (BBB) scale and sciatic functional index (SFI) and morphological features of regeneration were analyzed during a 12-week follow-up. The spinal cords and brains were collected 12 weeks after SCI for histopathological and immunohistochemical analyses. RESULTS: The rats treated with NAC presented some improvement in locomotor activity and spinal cord morphology when compared to the control group. Namely, the hind paw angle of rotation was significantly lower in the NAC group than in the control group. No differences were observed between the control and study groups in terms of interlimb coordination. The area of the main lesion was only slightly decreased in the NAC group as compared to the control group. The length of lesions in the injured spinal cord in the NAC group was diminished in comparison to the control group. The number of FG-positive cells was higher in the NAC group than in the control group. CONCLUSIONS: The study showed that the neuroprotective activity of NAC had limited positive influence on the regeneration of the isolated SCI in rats. PMID- 29442453 TI - Transcriptomic analysis of the PI3K/Akt signaling pathway reveals the dual role of the c-Jun oncogene in cytotoxicity and the development of resistance in HL-60 leukemia cells in response to arsenic trioxide. AB - BACKGROUND: Arsenic trioxide (ATO) is a well-recognized antileukemic drug used for the treatment of newly diagnosed and relapsed acute promyelocytic leukemia (APL). A major drawback of therapy with ATO is the development of APL cell resistance, the mechanisms of which are still not clear. OBJECTIVES: The aim of this study was to investigate the role of the PI3K/Akt signaling pathway in ATOtreated human acute myeloid leukemia (HL-60) cells and in ATO-resistant clones. MATERIAL AND METHODS: The cytotoxicity of ATO was assessed using Trypan blue staining or a WST-1 reduction assay. The Akt phosphorylation level was measured by immunofluorescent staining and flow cytometry. Gene expression analysis was performed using real-time polymerase chain reaction (PCR). RESULTS: The clones derived by culturing for 8-12 weeks in the presence of 1.75, 2.5, and 5 MUM ATO were characterized by high viability but a slower growth rate compared to the parental HL-60 cells. The flow cytometry analysis showed that in the parental cells the levels of p-Akt were undetectable or very low, and that ATO had no effect on the level of p-Akt in either the ATO-treated parental cells or the clones. The gene expression analysis revealed that some of the genes involved in the Akt pathway may play a key role in the induction of resistance to ATO, e.g., genes encoding cyclin D1 (CCND1), fork head box O1 (FOXO1), Jun oncogene (JUN), protein kinase C isoform B1 (PRKCB1), because their expression profiles were predominantly changed in the clones and/or the ATO-treated parental HL-60 cells. CONCLUSIONS: The overall results indicate that CCND1, FOXO1, and JUN may contribute to the induction of resistance to ATO, and that the C-Jun N-terminal kinase (JNK) signaling pathway may have greater significance than the phosphoinositide 3-kinase (PI3K)/Akt pathway in mediating the cytotoxic effects of ATO and the development of resistance to ATO in the HL-60 cell line. PMID- 29442454 TI - Higher concentrations of osteoprotegerin in type 1 diabetic patients are related to retinopathy: Results from the Poznan Prospective Study. AB - BACKGROUND: Osteoprotegerin (OPG) is an arterial calcification marker which has been associated with vascular damage. Elevated OPG concentrations associated with low-grade inflammatory processes are found in diabetic subjects. OBJECTIVES: The aim of the study was to assess concentrations of OPG in relation to the presence of diabetic complications in patients with diabetes type 1 (DM 1) participating in the Poznan Prospective Study (PoProStu). MATERIAL AND METHODS: The study included 74 patients with DM1 (48 men) with a median age of 39 years (interquartile range [IQR]: 34-43) and a median 15-year history (IQR: 14-16) of diabetes, who were participants in the PoProStu. Serum OPG concentration was measured using the ELISA method, and serum concentration of C-reactive protein was measured with a high sensitivity test (hsCRP). The visceral adipose index (VAI) was used to determine indirect markers of insulin resistance (IR). The prevalence of microangiopathic diabetes complications was assessed. RESULTS: Retinopathy was diagnosed in 28 patients (38%), diabetic kidney disease (DKD) in 28 (38%) patients, and neuropathy in 17 (23%) patients. The median OPG level was 43.8 (28.0-74.0) pg/mL. Patients with retinopathy had higher levels of OPG than those without retinopathy: 47.5 (35.0-88.0) vs 35.4 (24.7-69.4) pg/mL (p = 0.04). Positive correlations were observed between OPG concentration and hsCRP (Rs = 0.53; p < 0.001), HbA1c level (Rs = 0.36; p = 0.002), VAI (Rs = 0.23; p = 0.04) and waist circumference (Rs = 0.24; p = 0.04). CONCLUSIONS: Higher concentrations of osteoprotegerin in DM1 patients are related to the presence of retinopathy. The study results indicate that OPG might play a role in the pathogenesis of vascular complications in association with hyperglycemia and low-grade inflammatory processes. PMID- 29442456 TI - An inverse relationship between plasma glutathione concentration and fasting glycemia in patients with coronary artery disease and concomitant type 2 diabetes: A pilot study. AB - BACKGROUND: There have been occasional reports indicating that plasma concentrations of reduced glutathione (GSH) may be associated in some way with blood glucose. This relationship, however, has not hitherto been explored in the blood plasma of patients with coronary artery disease (CAD). OBJECTIVES: The aim of this study was to evaluate potential associations of fasting glycemia and peripheral blood plasma GSH concentrations in CAD-free and CAD-affected subjects. MATERIAL AND METHODS: In blood samples obtained from patients with CAD, defined by coronary angiography and/or echocardiography, and from an age-matched control group of patients with a confirmation of no coronary artery occlusion and with no history of cardiovascular events, plasma concentrations of glucose and reduced glutathione were analyzed by routine laboratory diagnostic methods and high performance liquid chromatography (HPLC), respectively. RESULTS: The results showed that in the CAD patients, but not in the non-CAD controls, fasting glycemia is negatively associated with plasma levels of GSH (r = -0.328; p = 0.011). Moreover, in the CAD-affected subjects (but not in the controls) the presence of type 2 diabetes mellitus significantly discriminated plasma levels of GSH (rP = -0.125; p = 0.350, between GSH and glucose adjusted for the occurrence of diabetes). CONCLUSIONS: The study suggests that GSH may be an important factor contributing to glucose metabolism in CAD patients. Hence, it may be considered a significant therapeutic target in strategies aimed at improving glycemic control in CAD-affected subjects. PMID- 29442455 TI - Oral mucositis and saliva IgA, IgG and IgM concentration during anti-tumor treatment in children suffering from acute lymphoblastic leukemia. AB - BACKGROUND: Oral mucositis is a problem occurring within the oral cavity, which is the most difficult to deal with during anti-tumor treatment. The first symptom reported by the patient is discomfort. Salivary immunoglobulins play an important role in pathological processes occurring in the oral cavity. OBJECTIVES: The study objective was to assess the occurrence of oral mucositis and to assess changes in the saliva IgA, IgG, and IgM concentration in children with acute lymphoblastic leukemia during antitumor treatment. MATERIAL AND METHODS: The study included 78 children with acute lymphoblastic leukemia (ALL) and a control group of healthy children. All the participants underwent 3 examinations. RESULTS: Mucosal opacity followed by redness usually occurred within 2-4 days after the methotrexate infusion. The most severe lesions of the oral mucosa were observed after the 1st month of chemotherapy. Correlations were found between hard-to-heal wounds and ulcers and blood morphology parameters. The mean saliva IgA concentration in children with ALL during chemotherapy was significantly lower than in children in the control group. A comparison of the mean saliva IgG in a given patient in subsequent examinations revealed a significant saliva IgG decrease occurring between the 1st and 3rd examinations. CONCLUSIONS: Wounds and ulcers that were difficult to heal were related to blood morphology parameters. A low salivary IgA concentration in children with ALL may result in the development and potentiation of oral lesions typical of mucositis during anti-tumor treatment. A significant decrease in salivary IgG and IgM concentrations in children with ALL during chemotherapy may cause potentiation of pathological lesions in the oral mucosa. PMID- 29442457 TI - Dietary patterns and breast or lung cancer risk: A pooled analysis of 2 case control studies in north-eastern Poland. AB - BACKGROUND: Breast cancer in women and lung cancer in men are the most prevalent cancers in Poland and worldwide. Evidence of the impact of food groups and nutrients on the risk of breast and lung cancer is limited and lacking conclusions. Studies on food consumption and breast or lung cancer are limited. OBJECTIVES: Assessment of the association between dietary patterns and the prevalence of breast and lung cancers in adult Poles. MATERIAL AND METHODS: The study involved a pooled analysis of 2 case-control studies on 320 subjects aged 50-70 years from north-eastern Poland (160 women, 160 men). Breast cancer cases in 80 women and lung cancer cases in 80 men were diagnosed. The food consumption frequency for 21 selected foods was collected using the Questionnaire of Eating Behaviors (QEB). Principal component analysis and multiple logistic regression analysis were used. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated. RESULTS: Three dietary patterns (DPs) were identified: 'Prudent', 'Processed & fast food', and 'Traditional Polish'. In the pooled analysis for both cancers, the ORs were from 0.35 (95% CI: 0.20-0.61; p < 0.05 with adjustment for age) to 0.48 (95% CI: 0.26-0.88; p < 0.05 with adjustment for age, socioeconomic status index, physical activity, smoking, and abuse of alcohol) in the upper tertile of the 'Prudent' DP in comparison to the absence of cancers (OR = 1.00). The ORs of both cancers were 1.83 (95% CI: 1.06-3.16; p < 0.05 with adjustment for age) in the upper tertile of the 'Processed & fast food' DP. The ORs of both cancers for the 'Traditional Polish' DP were insignificant. CONCLUSIONS: In the pooled analysis, a strong inverse relation was found between the 'Prudent' dietary pattern, characterized by higher frequency of dairy, fruit, vegetables, wholemeal bread, fish and juices consumption, and breast or lung cancer prevalence, irrespective of age, socioeconomic status, physical activity, smoking, alcohol abuse, and type of cancer in Polish adults from north-eastern Poland. PMID- 29442458 TI - The influence of vitamin D deficiency on eradication rates of Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori eradication therapy improves the healing of various gastro-duodenal diseases such as chronic gastritis and peptic ulcer, and also reduces gastric cancer incidence. Several studies have reported on risk factors other than antibiotic resistance related to Helicobacter pylori eradication failure. OBJECTIVES: In this study, we aimed to investigate whether or not the serum levels of 25-hydroxy-vitamin D (25(OH)D) influence eradication rates of H.pylori. MATERIAL AND METHODS: 220 patients diagnosed with H.pylori gastritis using endoscopic biopsy had their 25-OH vitamin D levels measured via the electrochemiluminescence method before beginning eradication therapy of H.pylori. Gastric biopsies obtained at endoscopy were examined for H.pylori strains and histopathologic findings. All patients were treated with bismuth containing quadruple therapy for 14 days. H.pylori eradication was determined via the 14C-urea breath test performed 4 weeks after the end of therapy. Based on the 25-OH vitamin D levels, the patients were divided into 2 groups: group 1 (deficient) had a vitamin D level of <10 ng/mL, while group 2 (sufficient) had a vitamin D level of >=10 ng/ mL. RESULTS: Eradication was successful in 170 (77.2%) patients and failed in 50 (22.7%) patients. The prevalence of 25(OH)D deficiency was 30.5%. Mean 25(OH)D levels were significantly lower in the eradication failure group compared to the successful treatment group (9.13 +/-4.7 vs 19.03 +/-8.13; p = 0.001). There were significantly more patients with deficient 25(OH)D levels in the failed treatment group compared to the successful treatment group (p = 0.001). CONCLUSIONS: Our findings suggest that 25-OH vitamin D deficiency may be considered a risk factor related to eradication failure of H.pylori, which may lead to a need for supplementation of vitamin D before eradication of H.pylori. PMID- 29442460 TI - Do medical students adhere to advice regarding a healthy lifestyle? A pilot study of BMI and some aspects of lifestyle in medical students in Poland. AB - BACKGROUND: The components of lifestyle of medical students, with comprehensive reporting of their physical activity and drinking and eating behavior, are rarely evaluated. Being overweight (increased body mass index - BMI) is associated with health problems, an unhealthy lifestyle (inadequate sleep, diet and exercise) being implicated. OBJECTIVES: The aim was to determine if there were discrepancies between assessments of actual lifestyle and advice regarding the principles of a healthy lifestyle. MATERIAL AND METHODS: The relationship between lifestyle and BMI was investigated in 270 medical students (158 females, 112 males) who answered a questionnaire about aspects of their lifestyle. RESULTS: The mean +/-SD BMI in males (23.41 +/-0.25kg/m2) was significantly higher than in females (20.52 +/-0.16kg/m2). Many aspects of lifestyle differed significantly with gender, including sleep habits, number of meals eaten, types of food eaten (fast food, amounts of fresh fruit and vegetables, sweets, etc.) and alcohol consumption, males generally having less healthy lifestyles. After correcting the associations between BMI and lifestyle factors for gender, one main finding was a positive association between BMI and alcohol intake, BMI rising by 0.014 kg/m2/g alcohol intake per week. CONCLUSIONS: These results show clear differences between actual and advised lifestyle with regard to many aspects of sleep, food and fluid intake, and exercise. Most students, particularly males, had not adopted a healthy lifestyle. Possible future problems associated with this require more emphasis. PMID- 29442459 TI - The usefulness of routinely used malnutrition screening tools in predicting anemia in lung cancer patients. AB - BACKGROUND: Anemia and malnutrition are frequently observed during lung cancer development, and the associations between them have been researched. However, no study concerning the utility of routinely used nutritional screening tools in predicting anemia in lung cancer has been performed. OBJECTIVES: The aim of this study was to assess the usefulness of routinely used malnutrition screening tools in predicting anemia in lung cancer patients. MATERIAL AND METHODS: Eighty-five male patients were recruited to this study. Blood counts, serum iron concentration, total iron binding capacity (TIBC) and serum transferrin saturation (STS), measurements of selected anthropometric parameters, Mini Nutritional Assessment (MNA) and Glasgow Prognostic Score (GPS) were performed for the subjects. To evaluate the differences in the distribution of hematological and iron status parameters according to nutritional status, a t test (Mann-Whitney U test for non-parametric data) and an analysis of variance (ANOVA) were performed. Tukey's post hoc test was performed for intergroup comparison of parametric data. The sensitivity, specificity, positive and negative predictive values of MNA and GPS were compared to blood counts and biochemical parameters of iron status. RESULTS: Using the MNA test, we observed that ca. 60% of subjects had deteriorated nutritional status. About half of the patients had inflammation cumulated with malnutrition. A similar part of the subjects had anemia. The MNA test showed a significant difference in the distribution of Hb and Htc, while GPS showed the distribution of Fe and TIBC among lung cancer patients. We did not observe any influence of fat-free mass index (FFMI) on hematological and iron status parameters. The MNA test had very high specificity and positive predictive values (PPV) for all the hematological parameters evaluated as well as GPS for serum Fe concentration and TIBC. CONCLUSIONS: Our data demonstrates that an evaluation of nutritional status with the MNA test can provide additional predictive information regarding anemia, while GPS may do the same with type of anemia in lung cancer patients. PMID- 29442461 TI - Central aortic pressure, arterial stiffness and echocardiographic parameters of children with overweight/obesity and arterial hypertension. AB - BACKGROUND: A non-invasive estimation of central aortic pressure and echocardiographic parameters, and appropriate interpretation thereof make it possible to determine the status of the vascular wall and myocardium. These parameters are early markers of unfavorable remodeling of the cardiovascular system. OBJECTIVES: The aim of this study was to analyze the central aortic pressure and echocardiographic parameters of overweight/obese children (with or without concomitant arterial hypertension). MATERIAL AND METHODS: The study included 84 children (mean age: 15 years) - 45 with primary arterial hypertension, 39 normotensive, and 38 controls. Central aortic systolic (cSys) and diastolic (cDia) pressures, pulse wave augmentation index (Aix@75), peripheral resistance, pulse wave reflection and pulse wave velocity (PWV) were determined by means of brachial oscillometry. A number of echocardiographic parameters were recorded. RESULTS: Obese children with arterial hypertension showed the highest values of cSys, cDia and PWV, as well as interventricular septal end-diastolic thickness (IVS), left atrial diameter (LAD), left ventricular mass index (LVMI), elongation index and cardiac output (CO). Patient age, cSYS, cDIA and LAD were identified as significant predictors of PWV. The groups did not differ in terms of Aix@75, peripheral resistance and pulse wave reflection values. CONCLUSIONS: Children with overweight/obesity present with elevated values of cSys, PWV, LVMI, LAD and CO. The risk of these abnormalities is further increased due to concomitant arterial hypertension. PMID- 29442462 TI - Biologically active form of vitamin B1 in human peritoneal effluent. AB - BACKGROUND: Supplementation with vitamin B1 protects the peritoneal membrane from inflammatory and oxidative insults and preserves residual kidney function in rat models of peritoneal dialysis (PD). It is assumed that an active form of vitamin B1, thiamin diphosphate (ThDP), is responsible for this protective effect. However, it has never been shown whether ThDP, a compound known not to cross cellular membranes, is actually detectable in human peritoneal effluent. OBJECTIVES: This study was designed to investigate the concentration, appearance rate, and daily loss of ThDP in the peritoneal effluent of patients treated with PD. MATERIAL AND METHODS: We performed 24-hour effluent collection as well as the peritoneal equilibration test (PET) and analyzed the relation between the transport characteristics of the peritoneal membrane and appearance rate of ThDP in a cohort of 26 PD patients. RESULTS: ThDP was detectable in peritoneal effluent in humans. ThDP appearance rate was independent of the transport characteristic of peritoneal membrane, and was not associated with peritoneal transport of other small solutes. CONCLUSIONS: We conclude that ThDP can be found in detectable concentrations in the peritoneal effluent in humans and is transported through the peritoneal membrane in a pattern independent of other small solutes. Our finding opens novel opportunities in further research on the protection of peritoneal membrane in humans. PMID- 29442463 TI - Knowledge and selected variables as determinants of the quality of life and general health of patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is an incurable disease resulting in progressive disability, which is associated with the loss of productivity and the inability to earn money, which might lead to a financial burden on the patient's family. Undoubtedly, the clinical picture of the disease and its consequences lead to the reduction of the quality of life. OBJECTIVES: The aim of this study is to evaluate the influence of selected factors on the subjective assessment of the quality of life and general health of patients with RA. MATERIAL AND METHODS: The study was conducted among 270 patients with RA treated at the Department of Rheumatology and Internal Medicine. The quality of life and general health were assessed with the use of the SF-36 and the GHQ-30 questionnaires. RESULTS: In the study group, a statistically significant correlation between the results of the SF-36 and the GHQ-30 questionnaires was observed. It has been shown that the level of role limitations due to physical health problems (RP) is mostly affected by interpersonal relationships based on GHQ-30 questionnaire (p = 0.002), general health (GHQ-30) (p = 0.001) and subjective health condition (SF-36) (p < 0.001). In contrast, general health (GHQ-30) is positively affected by education (p = 0.003) and professional activity (p = 0.001), and negatively affected by a positive family history of RA (p = 0.002), frequent hospitalization (p = 0.008) and poor subjective health condition (p < 0.001). CONCLUSIONS: People with poor subjective health condition are characterized by more limited activity due to physical health and lower general health condition. General health (GHQ-30) in patients with rheumatoid arthritis is influenced by education, place of residence, professional work, family history of RA and subjective health status. PMID- 29442464 TI - Effects of vector ultrasonic system debridement and conventional instrumentation on the levels of TNF-alpha in gingival crevicular fluid of patients with chronic periodontitis. AB - BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is an inflammatory mediator whose levels are increased in the gingival crevicular fluid and blood serum in the case of chronic periodontitis. OBJECTIVES: The aim of this study was to determine the effect of vector ultrasonic system (VUS) on the levels of TNF-alpha in gingival crevicular fluid (GCF) and the clinical parameters in patients with chronic periodontitis. MATERIAL AND METHODS: The study protocol was conducted using split-mouth design in 30 patients with chronic periodontitis. VUS and scaling and root planing (S/RP) were applied separately to 2 quadrants, including the upper and the lower jaws. At baseline and after 6 months, clinical parameters including plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment level (CAL) were recorded, and concentrations of TNF-alpha in GCF were determined by enzyme-linked immunosorbent assay (ELISA). Intergroup comparisons were evaluated by the independent Students' t-test, and the Pearson correlation was used to determine the relationship between parameters. The level of significance was set at 5%. RESULTS: Both treatment modalities provided statistically significant improvements in clinical periodontal parameters and TNF alpha levels after 6 months (p < 0.05). Also, there were no significant correlations between the TNF-alpha levels in GCF and the clinical parameters in both treatment group at baseline and at the end of 6 months period (p > 0.05). CONCLUSIONS: The use of the vector ultrasonic system in the non-surgical treatment of chronic periodontitis presents beneficial improvements for the clinical attachment level and the probing pocket depth as well as TNF-alpha levels in GCF. PMID- 29442465 TI - Polymorphism of Gly39Glu (c.116G>A) hMSH6 is associated with sporadic colorectal cancer development in the Polish population: Preliminary results. AB - BACKGROUND: Colorectal cancer (CRC) remains a major source of cancer-related mortality, accounting for 10% of all cancer-related deaths. DNA mismatch repair mechanism (MMR) responsible for correcting errors generated during DNA replication and its deficiency is associated with both hereditary and sporadic CRC. Single-nucleotide polymorphisms (SNPs) are the most common forms of genetic variation, and it has been shown that the SNPs in MMR genes may modify CRC risk. OBJECTIVES: The aim of the study was to determine the relationship between gene polymorphism Glu39Gly (c.116G>A) of the hMSH6 gene and the modulation of the risk of sporadic colorectal cancer in the Polish population. MATERIAL AND METHODS: A total of 128 patients with resectable colorectal carcinoma as well as 189 sex-, age-, and ethnicity-matched control subjects without cancer history were enrolled in this study. Patients with a family history of CRC or inflammatory bowel diseases were excluded from this study. The DNA was isolated from peripheral blood lymphocytes of enrolled patients, and gene polymorphisms were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). RESULTS: We observed that the genotype G/A variant of Glu39Gly (c.116G>A) genotype is associated with an increased risk of colorectal cancer (OR 1.65; 95% CI: 1.01-2.69; p = 0.44). The presence of A allele was also significantly higher in patients with CRC (OR 1.57; 95% CI: 1.04-2.38; p = 0.032). When comparing the prevalence of genotypes with clinical staging, genotype G/A and A allele were significantly less frequent in stage III-IV than in I (OR 0.3409; 95% CI: 0.124 0.939; p = 0.0375, and OR 0.4462; 95% CI: 0.201-0.991; p = 0.044, respectively). CONCLUSIONS: These findings suggest that hMSH6 Glu39Gly polymorphism is associated with the risk of developing colorectal cancer in the Polish population, probably due to a defective mismatch repair system. The presence of G/A genotype and A allele is, however, associated with less advanced disease. PMID- 29442466 TI - Relationship between resistin and IL-23 levels in follicular fluid in infertile patients with endometriosis undergoing IVF-ET. AB - BACKGROUND: Endometriosis (EM) interferes with the reproductive process and affects the success rate of in vitro fertilization (IVF). Inflammatory cytokines are suggested to play a role in infertility in patients with EM. OBJECTIVES: In this study, we aimed to investigate the relationship between resistin and interleukin 23 (IL-23) levels in follicular fluid (FF) and serum together with the severity of endometriosis and in vitro fertilization/ embryo transfer (IVF ET) outcome. MATERIAL AND METHODS: Samples from 116 infertile women were studied using enzyme-linked immunosorbent assay (ELISA). The study group consisted of 76 infertile patients diagnosed with EM (40 with stages I-II and 36 with stages III IV) undergoing IVF-ET. The control group included 40 women with tubal factor infertility. FF and serum samples were collected on the day of follicle aspiration and hCG administration, respectively. RESULTS: The serum and FF resistin levels were significantly higher in the EM group than in the control group (p-value <0.05). The FF resistin and IL-23 levels were significantly higher in EM stages III-IV than in stages I-II (p-value <0.05), and the serum resistin and IL-23 levels were also significantly (p-value <0.01) higher in stages III-IV than in stages I-II. The E2 level on the day of hCG administration and the implantation rate were both significantly lower in the EM group than in the control group. However, there were no differences in the Gn duration and dose, and the cleavage, implantation and clinical pregnancy rates between the 2 groups. CONCLUSIONS: Our results suggest that patients with EM exhibit increased resistin level in FF and serum. Advanced EM may contribute to infertility via decreased embryo implantation rates because of inflammation and immune rejection. No influence was observed on pregnancy outcomes after IVF-ET. PMID- 29442467 TI - Intestinal epithelial barrier: The target for pathogenic Escherichia coli. AB - Diarrheagenic Escherichia coli strains are included in 9 pathotypes (pathovars) that present different virulence factors responsible for the patomechanism of infections they cause. As all other intestinal pathogens, E. coli exerts a significant effect on intestinal epithelium. To initiate the infection, these microorganisms have evolved countless strategies to subvert the epithelial barrier and efficiently colonize the intestinal epithelium. The barrier function of the intestinal epithelium is achieved by the presence of a tight junction protein network surrounding individual cells around their circumference that links neighboring cells and seals the intracellular space. Pathogenic E. coli strains may impair intestinal epithelial barrier in 3 different pathways: (i) through a direct effect of their virulence factors on tight junctions proteins, (ii) by disrupting host cell actin cytoskeleton that indirectly damages epithelial barrier, and (iii) via stimulation of the secretion of proinflammatory cytokines that directly disrupt epithelial tight junctions or trigger neutrophils migration through intestinal epithelium, thus disrupting the intestinal barrier. Most pathogenic E. coli generates all these 3 pathways concomitantly upon interaction with intestinal epithelium. PMID- 29442468 TI - The role of pancreatic polypeptide in pancreatic diseases. AB - The aim of this study was to review the diagnostic significance of pancreatic polypeptide (PP) in pancreatic diseases. PP may play a significant role in monitoring the development of the disease and the patient's healing process, particularly after the removal of a portion of the pancreas. Determining PP in acute pancreatitis is quite controversial. At the 1st stage of severe pancreatic damage, there is excessive PP release followed by its fall. In patients with chronic pancreatitis, a significant decrease in PP secretion was found in the presence of a food stimulant. In this case, PP could be a good marker for determining the stage of pancreatitis. Pancreatic polypeptide also functions as a hepatic glucose regulator. PP increases hepatic insulin sensitivity, resulting in reduced hepatic glucose production. Therefore, impaired hepatic insulin sensitivity in chronic pancreatitis is abrogated after the PP administration. Endocrine pancreatic tumors initially grow without specific symptoms. In contrast, they are almost always correlated with elevated serum pancreatic polypeptide. Therefore, the level of PP may be a good diagnostic parameter confirming the presence of pancreatic cancer. Depending on the type of disease, the polypeptide concentration can be increased or decreased, evidencing the disease progress or regression. PMID- 29442469 TI - Brain death-associated pathological events and therapeutic options. AB - BACKGROUND: At present, organ transplantation is the most efficient treatment of end-stage failure of various organs, including the heart, lungs, pancreas, intestines, kidney, and liver. Despite the efforts to use organs from living donors or from donors after circulatory death, most of the organs are recovered from brain dead (BD) donors. METHODS: The Medline and Web of Science databases were searched without time limit on November 2015 using the terms "brain dead donor" and "deceased donor" in conjunction with "transplantation", "graft", "organ", "hemodynamic", "hormonal", or "management". The search was limited to the English, Polish and Spanish literature. Articles that did not address the topics were excluded and the full text of the remaining articles was reviewed. RESULTS: It is well established that brain death is associated with a cascade of hemodynamic, inflammatory, and immunologic events that affect the outcome of transplanted organs. Proper management of the potential organ donor may help increase the supply of organs for transplantation. However, because there is a lack of good quality evidence, it is difficult to establish specific BD donor management guidelines. CONCLUSION: In this paper we present a review of studies and literature concerning the detrimental impact of donor brain death on graft function. We present pathologic changes that take place after brain death, their influence on graft quality and therapeutic solutions to enhance transplanted organ function. PMID- 29442470 TI - Overview of the incidence, early identification and management of sepsis. AB - Sepsis is a potentially life-threatening condition that is triggered by an infection. Sepsis is an urgent public health issue globally, and is one of the leading causes of death in emergency departments and hospitals. However, consensus definitions of sepsis are imprecise and the incidence and costs of the condition are thought to be underestimated. This article discusses the incidence of sepsis globally and nationally, and the effects of the condition. It emphasises the early identification and effective management of sepsis, which remain crucial to improving patient outcomes such as morbidity and mortality. It also outlines the nurse's role in providing sepsis care. PMID- 29442471 TI - Use of combined inhalers for stable chronic obstructive pulmonary disease. AB - The mission of the Cochrane Nursing Care Field (CNCF) is to improve health outcomes through increasing the use of the Cochrane Library and supporting Cochrane's role by providing an evidence base for nurses and healthcare professionals who deliver, lead or research nursing care. The CNCF produces Cochrane Corner columns, summaries of recent nursing-care-relevant Cochrane Reviews that are regularly published in collaborating nursing-related journals. Information on the processes CNCF has developed can be accessed at: cncf.cochrane.org/evidence-transfer-program-review-summaries . This is a Cochrane review summary of: Horita N, Goto A, Shibata Y et al (2017) Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD). Cochrane Database of Systematic Reviews. Issue 2. CD012066. doi: 10.1002/14651858. CD012066.pub2. PMID- 29442472 TI - Safe transfusion of blood components. AB - Administering the wrong blood component to the wrong patient can have serious clinical consequences, including death. Patients have a right to safe clinical practice in line with nurses' professional standards and code of conduct, and other healthcare regulatory frameworks. Transfusion of blood components is no exception to this; therefore, it is important for healthcare organisations to have policies in place to support healthcare practitioners in ensuring patient safety throughout the transfusion process. This article outlines the clinical practice and administration required to undertake blood component transfusions safely and effectively. It also explains the rationale for checking processes, with reference to clinical guidelines. PMID- 29442473 TI - Parent and Child Perceptions of the Benefits of Research Participation. AB - The primary objective of this study was to describe parents' and children's perceptions of the health benefits of research participation. We assessed 180 children ages 8 to 17 years who recently enrolled in medical research and their parents. Of the 136 parents with children on observational protocols, 41% indicated that there would be a health benefit to the child. Their descriptions of benefits revealed that many envisioned a future health benefit to the child arising from improvements in treatment due to the research. There was no difference in ratings of likelihood or importance of benefit between parents of children enrolled in observational protocols versus interventional protocols. Children enrolled in observational protocols were more likely to respond "don't know" to the question about potential health benefit compared to children on interventional protocols. For both observational and interventional protocols, the informed consent process may be enhanced when research personnel explicitly differentiate between different types of potential benefits, including heretofore unrecognized future direct health benefits. PMID- 29442474 TI - A Tool Kit to Enhance the Informed Consent Process for Community-Engaged Pediatric Research. PMID- 29442475 TI - Association of heterogeneity of the thyroid gland with matrix metalloproteinase-3 in rheumatoid arthritis patients with Hashimoto's thyroiditis. AB - BACKGROUND: Hashimoto's thyroiditis (HT) is highly prevalent in patients with rheumatoid arthritis (RA). The aim is to determine their relation, focusing on matrix metalloproteinase-3 (MMP-3), a marker predicting joint destruction and RA activity. METHODS: Fifty-three consecutive RA patients were prospectively separated into two groups based on the presence or absence of HT; those with and without TPO-Ab or Tg-Ab (34.0% and 66.0%, respectively). To estimate the extent of inflammation and destruction of the thyroid gland, Heterogeneity Index (HI) was determined ultrasonographically. RESULTS: While the male/female ratio, TSH and HI were significantly higher in those with HT than in those without (5/13 vs. 7/28, P=0.047, mean+/-SE; 7.25+/-0.69 vs.2.52+/-0.30 mIU/L, P<0.001; 3.8+/-0.2 vs.3.2+/-0.2%, P=0.042, respectively), no differences existed in MMP-3. In those with HT, MMP-3 correlated negatively with FT3 (rho=-0.545, P=0.048) and positively with TPO-Ab and HI (rho=0.735, P=0.02; rho=0.769, P=0.01, respectively). Among them, HI was a significant factor associated positively with MMP-3 (r=0.883, F=31.91). CONCLUSIONS: The present study demonstrated significant increases of HI and an association between HI and MMP-3 in RA patients with HT. These findings suggest that the inflammation and destruction of the thyroid gland might be closely related to the current activity and terminal joint destruction of RA. PMID- 29442477 TI - Role of thyroid ultrasound combined with thyroglobulin in the diagnosis of postoperative recurrence of thyroid cancer. AB - BACKGROUND: To study the application value of thyroid ultrasound combined with thyroglobulin (Tg) in the diagnosis of postoperative recurrence of thyroid cancer, so as to provide a reference for clinical practice. METHODS: 80 patients with thyroid cancer who underwent operative treatment for more than 2 times in our hospital from January 2014 to December 2016 were selected as the objects of study. After operation, residual thyroid tissues were removed via131 iodine (131 I)treatment, the serum Tg and thyroid globulin antibody (TgAb) were detected, and the cervical ultrasound was performed. At 1 week after 131 I treatment, the systemic single photon emission computed tomography (SPECT) was performed. Finally, the application values of serum Tg, TgAb and ultrasound in the diagnosis of postoperative recurrence of thyroid cancer were analyzed. RESULTS: The sensitivity, specificity and accuracy of Tg level in detecting of recurrence and metastasis of differentiated thyroid cancer were 78.5%, 73.3% and 77.5%, respectively, and it was difficult to show whether the postoperative recurrence and metastasis of thyroid cancer occurred through the expression level of serum TgAb. Moreover, TgAb in different concentrations had an effect on the diagnosis of metastasis of differentiated thyroid cancer via Tg. When the TgAb level >=100 IU/mL, the sensitivity, specificity and accuracy of Tg diagnosis were 51.9%, 50.0% and 51.7%, respectively. When the TgAb level <100 IU/mL, the sensitivity, specificity and accuracy of Tg diagnosis were 94.6%, 71.4% and 88.2%, respectively. Besides, the sensitivity, specificity and accuracy of ultrasonic diagnosis of lymphatic metastasis after the treatment of differentiated thyroid cancer were 78.5%, 60.0% and 75.0%, respectively. The sensitivity, specificity and accuracy of ultrasound combined with Tg in the diagnosis of thyroid cancer were 97.4%, 75.0% and 93.6%, respectively. The difference in the metastasis rate of thyroid cancer was not statistically significant between patients with papillary carcinoma and patients with follicular carcinoma after treatment (P>0.05). CONCLUSIONS: Thyroid ultrasound combined with Tg is of high clinical value in the diagnosis of postoperative recurrence of thyroid cancer, which can significantly improve the sensitivity, specificity and accuracy of clinical diagnosis. The TgAb level can be detected when Tg is used to monitor the postoperative recurrence and metastasis of thyroid cancer, providing a reference for the clinical prevention and treatment. PMID- 29442476 TI - Analysis of the correlation of gestational diabetes mellitus and peripheral ferritin with iron levels in early pregnancy. AB - BACKGROUND: To investigate the relationship of serum iron and ferritin concentrations in early pregnancy with gestational diabetes mellitus (GDM) complicated in pregnant metaphase through detecting the serum iron and ferritin concentrations in early pregnancy of normal pregnant women, so as to provide new ideas for the early detection and prevention of GDM. METHODS: Spontaneously pregnant women with single fetus receiving prenatal routine examination in our hospital from December 2014 to October 2016 were selected. They were in good health before with normal fasting blood-glucose in early pregnancy without anemia during pregnancy and any medication history. The serum iron and ferritin concentrations were measured at 12 gestational weeks, the fasting blood-glucose was detected at 12 weeks of pregnancy, and 75g oral glucose tolerance test was performed at 24-26 weeks. According to the results of oral glucose tolerance test, the pregnant women were divided into GDM group (n=52) and normal control group (n=310). The detection results of pregnant women in the two groups were statistically analyzed. RESULTS: The serum ferritin and iron levels at 12 gestational weeks in GDM group were higher than those in normal pregnancy group (p<0.05). The cut-off values of serum ferritin and iron at 12 gestational weeks in the prediction of GDM were 67.8 MUg/L and 52.9 mmol/L. CONCLUSIONS: The high concentrations of serum iron and ferritin in early pregnancy have a certain correlation with the incidence of GDM, and the early detection of serum iron and ferritin levels can improve the detection rate of GDM in pregnant metaphase. PMID- 29442478 TI - A clinical Audit: diagnostic and epidemiological evaluation of the Adrenal Incidentaloma (AI). AB - Audit is a clinical instrument of government characterized by a whole process of evaluation inter pares to improve medical behaviors in the clinical practice. Different endocrinopathies are underestimated in the clinical and diagnostics practice but they can be a real problem in patients admitted in the departments of Internal Medicine. The Adrenal Incidentaloma (AI) is an accidental discovery with an incidence equal to 4% in radiologic studies but it's rarely considereted in the internal disorders. In the departments of Internal Medicine are hospitalized each year approximately 1.450.000 patients and 58.000 about them show a surrenalic lesion identified with CT or MRI as Adrenal Incidentaloma. Through a search in the radiological archives, were reviewed all abdominal CT performed in the year 2012 in 8 departments of Internal Medicine of 8 Italian public hospitals. They also examined all medical records of these patients to value clinical management of the adrenal masses and the real incidence of the Adrenal Incidentaloma. Distribution of patological results show an important incidence about Adrenal Incidentaloma in Italian patients although this pathology is represented as a rare disease and its clinical and economic burden are significant. Many questions remain unanswered as the association between duration and severity of the disease, morbidity and how the dimensions affecting it. These results need to be supported by important studies with long follow-up to realize an easy diagnosis. The results of this Audit confirm the real incidence of this pathology in the internistic patients and the final target is to implement changes about therapeutic diagnostic patway of the hospital patients in the Internal Medicine Departments. PMID- 29442479 TI - Adrenocortical carcinoma: where we stand. PMID- 29442480 TI - Cushing's disease: major difficulties in diagnosis and management during pregnancy. AB - Pregnancy in women with a diagnosis of Cushing' syndrome (CS) is an extremely rare event and its diagnosis and treatment are a real medical challenge. During pregnancy, the hypothalamus-pituitary-adrenal axis undergoes major changes leading to a significant increase in plasma cortisol levels throughout gestation. The difficulties in diagnosis are related to the resemblance of symptoms of CS and those of pregnancy, and to the complex interpretation of the screening tests. Moreover, the diagnostic work up in the postnatal period may be difficult in the first weeks postpartum. Importantly, the etiology of CS in pregnancy differs from non-pregnant status. In pregnancy, the adrenal origin is the most frequent in up to 60% of the cases, in contrast to ACTH-secreting corticotroph adenomas of the pituitary gland, which account for 70% of the cases outside pregnancy. Nevertheless, maternal and fetal outcomes are severely affected in the context of CS whichever the etiology is, with high rates of maternal and fetal morbimortality, and with a rate of overall fetal loss of about 25% of the pregnancies. There is no consensus as to the most effective treatment in these circumstances in terms of improving maternal and fetal outcomes, as there are no studies comparing the different modalities of treatment for CS in pregnancy. However, evidence suggests that patients receiving treatment during pregnancy achieve better fetal outcomes than those who do not receive treatment. We aim to summarize in this review the major diagnostic and management difficulties during pregnancy. PMID- 29442481 TI - Quality of life in women with advanced pelvic organ prolapse treated with Gellhorn pessary. PMID- 29442482 TI - The relationship between plasma selenium concentration and erythrocyte deformability in rat models of coronary heart disease. PMID- 29442483 TI - Quantification of ultrasound imaging in the staging of hepatic fibrosis. AB - BACKGROUND: The need for a staging of hepatic fibrosis has become particularly urgent in the last few years in order to start new therapeutic treatments. The objective of this study is to identify ultrasound descriptors and achieve a staging of hepatic fibrosis with non-invasive, rapid and inexpensive methods, both as an alternative and a support to the ultrasound elastography examination. METHODS: This study evaluated 196 patients under treatment at the Alcohological Regional Center. An image regarding a scanning of the epigastrium with a high frequency linear probe (7.5-12 MHz) has been selected for quantification. The hyperechogenic line corresponding to the Glisson capsule on the hepatic segment III has been evaluated with the Genoa Line Quantification (GLQ) software. These data have been compared with the shearwave ultrasound elastography. RESULTS: The best discrimination between patients with medium-advanced fibrosis (F3-F4) and healthy patients or patients with no fibrosis or mild fibrosis (F0-F1) has been achieved using the three parameters of variance and mean of gradient and line continuity. In particular, a sensitivity of 74%, a specificity of 82%, positive predictive value 80.4%, negative predictive value 75.9% and an accuracy of 78% has been obtained. CONCLUSIONS: GQL has allowed a classification, which is well concordant with the ultrasound elastography data. The use of the GQL may also be developed within centers, which are not provided with ultrasound elastography techniques, when an ultrasound elastography examination cannot be performed due to technical problems and as a support to elastography, if the outcome of this examination is not sufficiently clear. PMID- 29442484 TI - Role of genetics and metabolism in non-alcoholic fatty liver disease. PMID- 29442485 TI - A Psychobiographical and Psycho-Political Comparison of Clinton and Trump. AB - A comparison of the family backgrounds, childhoods, personal lives, personalities, and political views of the Republican and Democratic nominees in the 2016 presidential election. The author is a presidential psychobiographer who has been presenting and publishing on candidates and presidents since 1976. He uses his training in child development and psychoanalysis to demonstrate some of the influences of early development on the candidates' subsequent lives and careers. The strengths and weaknesses of Hillary Clinton and Donald Trump are discussed. Included in the analysis are family background, childhood, character, coping mechanisms, temperament, role models, foreign policy, health, interpersonal relations, marriage, parenting, and religious views, as well as the appeal and obstacles to election faced by each candidate. PMID- 29442487 TI - Successful endoscopic closure of tracheoesophageal fistula using a Padlock ClipTM. PMID- 29442486 TI - The Psychohistory of Climate Change: A Clear and Present Danger. AB - The inability of contemporary society to transition from fossil fuels to green energy was engineered by the oil industry, which has worked for decades to stifle the emergence of ecological awareness. Climate change presents a clear and present danger to our society. The present dilemma is the result of the psychopathic corporate system, that pillages the earth for profit (extractivism), evades the real costs of production (externalizing costs), and pursues only self interest (the best interests of the corporation). The well-being of the environment is thereby sacrificed for profit and our collective future is jeopardized. The corporate practice of creative destruction has gained such Thanatos-like momentum that it threatens the earth in its obsession with profit. Conservatives, under the sway of the unreality principle, dismiss climate change and block efforts to solve climate issues. For them, science is wish fulfillment based on denial. Their willingness to endanger the world results from their authoritarian upbringing. The corporal punishment they endured as children left a residue of rage-the impulse to destroy life-that underlies corporate rationality's assault on the environment. Fearing death, they inflict death in a perverse ritual to feel alive. Compensating for the narcissistic wounds of childhood through the formation of a grandiose self, they are identified with the omnipotent parent, and alternate between suicidal impulse and escape via godlike technology. Conservative attacks on women highlight the residual wounds of relatedness to their dragon mothers, just as their relatedness to the environment involves a restaging of their encounters with their breast and toilet mothers. Solving environmental problems, however, will require more than overcoming conservative intransigence. The concept of ecological debt accentuates the importance of consumer choice for the environment. The United Nations Human Development Report 2015 regarding CO2 emissions demonstrates the massive environmental debt of Northern Hemisphere societies and suggests the magnitude of the transformation necessary to resolve the problem of climate change. PMID- 29442488 TI - Biological properties and pathogenicity factors of Helicobacter pylori. AB - The unexpected discovery of Helicobacter pylori (H. pylori) has revolutionised the history of microbiology as well as of gastroenterology in the last 30 years, with an invaluable benefit for millions of persons worldwide. The confirmation that this Gram-negative spiral bacterium could live in the stomach has rendered out-of-date the concept of inhospitality of micro-organisms in the gastric environment, after a long history of unheard reports on the presence of spiral bacteria in the stomach. The pathogenicity of H. pylori depends on its ability to colonize as well as the capability to survive in the harsh gastric environment. This is possible by a coevolution between the pathogen itself and the host. Any perturbation of this equilibrium disrupts the host-pathogen interaction, promoting the pathological effects. H. pylori has a wide range of pathogenicity factors, in particular cytotoxins, enzymes of aggression, and factors providing protection against human defense systems. The most well-characterized cytotoxins contributing to epithelial cell damage are the vacuolating cytotoxin A (VacA) and the cytotoxin-associated gene A (CagA). Only detailed knowledge of the microbiology and genomics of H. pylori infection will allow a vaccine to be produced. Today, we know that H. pylori induces strong humoral and cellular immune responses, but these are incapable of eliminating the bacterium, raising doubts about the possibility of developing an effective vaccine easily. This review highlights microbiological findings concerning H. pylori infection, focusing on colonization, survival and pathogenicity. PMID- 29442489 TI - Helicobacter pylori: what are the challenges of today and in the years to come? PMID- 29442490 TI - "Sailing in Paper Boats" Sexual Trauma, Psychosis, and a Critical Examination of the Freudian Metaphor in Antonia White's Autobiographical Fiction. AB - This paper is part of a larger project on Catholic writer Antonia White's series of autobiographical novels, Frost in May, The Lost Traveller, and The Sugar House, in which readers are presented with a Freudian Oedipal drama that reaches a dramatic climax in the last autobiographical novel in the series, Beyond the Glass, where the main protagonist spirals into psychosis. A central question addressed is whether or not White's autobiographical fiction is an unconscious projection of sexual trauma from her own history. Psychoanalytically speaking, the answer depends upon whether one subscribes to Freudian or Ferenczian perspectives.The paper also addresses the question of whether White's accounts of psychosis in her autobiographical fiction are real and meaningful descriptions of lived traumatic experiences. Jacques Lacan asserts that it is impossible to authenticate narratives of psychosis and for readers to draw any meaningful value from them because they lack a coherent transfer of metaphorical language from the unconscious to the conscious in the pursuit of truth of a lived experience. He uses Judge Daniel Paul Schreber's Memoirs of My Nervous Illness to support his case, a text in which Schreber confesses to only being able to communicate his experiences in similes and metaphors; therefore, he claims his experiences cannot be understood. I argue that Lacan does not give due credit to Schreber's attempts to grapple with spiritual and sexual preservation in the throes of delusion through the agency of his alter egos. These alter egos are the other "self," a deluded self that offers, paradoxically, truth to emotional experience of a man's ego in crisis. Schreber shares these pursuits with White's alter egos in her autobiographical fiction, "The House of Clouds" and Beyond the Glass. In an analysis of White's texts as recollections of her personal history, I highlight how White's experiences shape her testimony in its raw portrayal of an identity in crisis. PMID- 29442491 TI - Interface Design of Nanochannels for Energy Utilization. AB - Nanochannels offer a variety of significant advantages for innovative applications, such as biosensing, filtering, and energy utilization. In this Perspective, we highlight the interface design and applications of nanochannels for energy utilization and discuss further challenges in the development of nanochannels for energy conversion, energy conservation, and energy recovery. PMID- 29442492 TI - Homogeneous Coating with an Anion-Exchange Ionomer Improves the Cycling Stability of Secondary Batteries with Zinc Anodes. AB - Limited cycling stability of secondary cells with zinc anodes arises mainly from the high solubility of oxidized zinc species in the alkaline electrolyte resulting in electrode shape change and loss of active material during repeated discharge and charge. We propose and successfully employ a homogeneous coating with an anion-exchange ionomer (AEI) on model electrodes with electron-conductive host structures to confine the oxidized zinc species. Ideally, the confinement of oxidized zinc species reduces the shape change of the electrode and keeps the active material as close as possible at its place of origin. In this work, the confinement concept for the oxidized zinc species is elucidated by means of electrochemical studies and X-ray photoelectron spectroscopy: as intended, an interlayer of zinc oxide forms between the AEI and the surface of the zinc electrode. This interlayer implies that the hydroxide ions are able to pass and react as intended, whereas the migration of oxidized zinc species into the bulk electrolyte is hindered. The coating with an AEI yields a higher amount of restored zinc during electrodeposition in comparison to an uncoated zinc electrode-applying an AEI coating increases the achievable cycle number by up to six times. We investigate the morphology of the cycled electrodes and derive thereby the needs for further material classes that might be employed in the confinement concept. This approach demonstrates the benefit of ion-selective coatings, allowing for the permeation of hydroxide ions but not of oxidized zinc species, a concept which improves rechargeable batteries with zinc anodes, such as zinc-oxygen batteries. PMID- 29442493 TI - SnO2 Model Electrode Cycled in Li-Ion Battery Reveals the Formation of Li2SnO3 and Li8SnO6 Phases through Conversion Reactions. AB - SnO2 is an attractive negative electrode for Li-ion battery owing to its high specific charge compared to commercial graphite. However, the various intermediate conversion and alloy reactions taking place during lithiation/delithiation, as well as the electrolyte stability, have not been fully elucidated, and many ambiguities remain. An amorphous SnO2 thin film was investigated for use as a model electrode by a combination of postmortem X-ray photoelectron spectroscopy supported by density functional theory calculations and scanning electron microscopy to shed light on these different processes. The early stages of lithiation reveal the presence of multiple overlapping reactions leading to the formation of Li2SnO3 and Sn0 phases between 2 and 0.8 V vs Li+/Li. Between 0.45 V and 5 mV vs Li+/Li Li8SnO6, Li2O and Li xSn phases are formed. Electrolyte reduction occurs simultaneously in two steps, at 1.4 and 1 V vs Li+/Li, corresponding to the decomposition of the LiPF6 salt and ethylene carbonate/dimethyl carbonate solvents, respectively. Most of the reactions during delithiation are reversible up to 1.5 V vs Li+/Li, with the reappearance of Sn0 accompanied by the decomposition of Li2O. Above 1.5 V vs Li+/Li, Sn0 is partially reoxidized to SnO x. This process tends to limit the conversion reactions in favor of the alloy reaction, as also confirmed by the long-term cycling samples. PMID- 29442494 TI - Thickness-Dependent Double-Epitaxial Growth in Strained SrTi0.7Co0.3O3-delta Films. AB - Perovskite-structured SrTi0.7Co0.3O3-delta (STCo) films of varying thicknesses were grown on SrTiO3(001) substrates using pulsed laser deposition. Thin films grow with a cube-on-cube epitaxy, but for films exceeding a critical thickness of about 120 nm, a double-epitaxial microstructure was observed, in which (110) oriented crystals nucleated within the (001)-oriented STCo matrix, both orientations being epitaxial with the substrate. The crystal structure, strain state, and magnetic properties are described as a function of film thickness. Both the magnetic moment and the coercivity show maxima at the critical thickness. The formation of a double-epitaxial microstructure provides a mechanism for strain relief in epitaxially mismatched films. PMID- 29442496 TI - Novel Photoalignment Method Based on Low-Molecular-Weight Azobenzene Dyes and Its Application for High-Dichroic-Ratio Polarizers. AB - Photoalignment is a simple technique for the manipulation of molecular orientations, which has been widely used in liquid crystal displays. Here, we propose a novel photoalignment method, in which an azobenzene dye thin film is deposited by thermal evaporation and in situ exposed to linearly polarized light simultaneously. We obtain polarizers with a dichroic ratio of up to 62, which is the highest value ever realized by a photoalignment method. Moreover, the polarizing thin film has a thickness of just 200 nm, compatible with flexible substrates, making it perfect for use as a dichroic polarizer in ultrathin and flexible displays. PMID- 29442495 TI - Flexible, Disposable Cellulose-Paper-Based MoS2/Cu2S Hybrid for Wireless Environmental Monitoring and Multifunctional Sensing of Chemical Stimuli. AB - Multifunctional sensors responding to different chemical stimuli fabricated using functional nanomaterials still remain a challenge because of the usage of the same sensor multiple times for different sensing applications and unreliable front-end processing of the sensing data. This challenge is intensified by the lack of suitable techniques for fabricating disposable sensors, which can be integrated into smartphones with a dedicated application developed for each sensing application. A novel MoS2/Cu2S hybrid grown on disposable cellulose paper by the hydrothermal method is reported for its utilization in sensing humidity, temperature, breath, and ethanol adulteration, wherein the data can be wirelessly transmitted to a smartphone with the dedicated application module for each sensing application. The sensor can be utilized for a particular sensing application and then can be disposed, avoiding the need for utilizing the same sensor for different sensing applications, thereby increasing the accuracy of the sensing data. The sensing mechanism of the fabricated sensor is explained for each stimulus in terms of change in the transport properties of the MoS2/Cu2S hybrid. The development of such unique hybrid materials for wireless disposable multifunctional sensors is a great step ahead in flexible and wearable electronics having potential applications in medical, security, Internet of things, etc. PMID- 29442497 TI - Electrospun Poly(lactic acid)-Based Fibrous Nanocomposite Reinforced by Cellulose Nanocrystals: Impact of Fiber Uniaxial Alignment on Microstructure and Mechanical Properties. AB - Uniform poly(lactic acid)/cellulose nanocrystal (PLA/CNC) fibrous mats composed of either random or aligned fibers reinforced with up to 20 wt % CNCs were successfully produced by two different electrospinning processes. Various concentrations of CNCs could be stably dispersed in PLA solution prior to fiber manufacture. The microstructure of produced fibrous mats, regardless of random or aligned orientation, was transformed from smooth to nanoporous surface by changing CNC loading levels. Aligning process through secondary stretching during high-speed collection can also affect the porous structure of fibers. With the same CNC loading, fibrous mats produced with aligned fibers had higher degree of crystallinity than that of fibers with random structure. The thermal properties and mechanical performances of PLA/CNC fibrous mats can be enhanced, showing better enhancement effect of aligned fibrous structure. This results from a synergistic effect of the increased crystallinity of fibers, the efficient stress transfer from PLA to CNCs, and the ordered arrangement of electrospun fibers in the mats. This research paves a way for developing an electrospinning system that can manufacture high-performance CNC-enhanced PLA fibrous nanocomposites. PMID- 29442498 TI - Proteostasis and the Regulation of Intra- and Extracellular Protein Aggregation by ATP-Independent Molecular Chaperones: Lens alpha-Crystallins and Milk Caseins. AB - Molecular chaperone proteins perform a diversity of roles inside and outside the cell. One of the most important is the stabilization of misfolding proteins to prevent their aggregation, a process that is potentially detrimental to cell viability. Diseases such as Alzheimer's, Parkinson's, and cataract are characterized by the accumulation of protein aggregates. In vivo, many proteins are metastable and therefore under mild destabilizing conditions have an inherent tendency to misfold, aggregate, and hence lose functionality. As a result, protein levels are tightly regulated inside and outside the cell. Protein homeostasis, or proteostasis, describes the network of biological pathways that ensures the proteome remains folded and functional. Proteostasis is a major factor in maintaining cell, tissue, and organismal viability. We have extensively investigated the structure and function of intra- and extracellular molecular chaperones that operate in an ATP-independent manner to stabilize proteins and prevent their misfolding and subsequent aggregation into amorphous particles or highly ordered amyloid fibrils. These types of chaperones are therefore crucial in maintaining proteostasis under normal and stress (e.g., elevated temperature) conditions. Despite their lack of sequence similarity, they exhibit many common features, i.e., extensive structural disorder, dynamism, malleability, heterogeneity, oligomerization, and similar mechanisms of chaperone action. In this Account, we concentrate on the chaperone roles of alpha-crystallins and caseins, the predominant proteins in the eye lens and milk, respectively. Intracellularly, the principal ATP-independent chaperones are the small heat shock proteins (sHsps). In vivo, sHsps are the first line of defense in preventing intracellular protein aggregation. The lens proteins alphaA- and alphaB-crystallin are sHsps. They play a crucial role in maintaining solubility of the crystallins (including themselves) with age and hence in lens proteostasis and, ultimately, lens transparency. As there is little metabolic activity and no protein turnover in the lens, crystallins are very long lived proteins. Lens proteostasis is therefore very different to that in normal, metabolically active cells. Crystallins undergo extensive post-translational modification (PTM), including deamidation, racemization, phosphorylation, and truncation, which can alter their stability. Despite this, the lens remains transparent for tens of years, implying that lens proteostasis is intimately integrated with crystallin PTMs. Many PTMs do not significantly alter crystallin stability, solubility, and functionality, which thereby facilitates lens transparency. In the long term, however, extensive accumulation of crystallin PTMs leads to large-scale crystallin aggregation, lens opacification, and cataract formation. Extracellularly, various ATP-independent molecular chaperones exist that exhibit sHsp-like structural and functional features. For example, caseins, the major milk proteins, exhibit chaperone ability by inhibiting the amorphous and amyloid fibrillar aggregation of a diversity of destabilized proteins. Caseins maintain proteostasis within milk by preventing deleterious casein amyloid fibril formation via incorporation of thousands of individual caseins into an amorphous structure known as the casein micelle. Hundreds of nanoclusters of calcium phosphate are sequestered within each casein micelle through interactions with short, highly phosphorylated casein sequences. This results in a stable biofluid that contains a high concentration of potentially amyloidogenic caseins and concentrations of calcium and phosphate that can be far in excess of the solubility of calcium phosphate. Casein micelle formation therefore performs vital roles in neonatal nutrition and calcium homeostasis in the mammary gland. PMID- 29442499 TI - Forty Years after "Heterodiene Syntheses with alpha,beta-Unsaturated Carbonyl Compounds": Enantioselective Syntheses of 3,4-Dihydropyran Derivatives. AB - This review is focused on the enantioselective synthesis of 3,4-dihydropyran derivatives, whose importance as chiral building blocks in the synthesis of bioactive molecules and natural products is well established. The review analyzes the different synthetic strategies by grouping them as a function of the atom numbers of the reagents involved. Starting from the classical [4 + 2] and [2 + 4] approaches, the [3 + 3], [5 + 1], and [6] strategies have been sequentially analyzed, and for each of them, the asymmetry induced by both chiral metal complexes and different kinds of organocatalysts has been examined. More than 400 papers have been reviewed, whose results have been described in the highest synthetic manner, in the attempt to emphasize the mechanism of the chirality transfer from the chiral messengers to the reaction products. This analysis allows the great flexibility of the diverse catalytic systems, the complementary of the results obtained from the different reaction pathways, and the very high level of control of the achievable molecular complexity to be evidenced. PMID- 29442500 TI - A Series of Banana-Shaped 3d-4f Heterometallic Cluster Substituted Polyoxometalates: Syntheses, Crystal Structures, and Magnetic Properties. AB - Four seven-nuclearity 3d-4f heterometallic cluster {Fe6LnO28} substituted polyoxometalates (HPz)11K4Fe6Ln(MU3-O)2(B-alpha-GeW9O34)2(GeW6O26). xH2O (1-Ln, Pz = piperazine, Ln = Tb, Dy, Ho, Er for x = 27, 25, 25, 24, respectively) have been hydrothermally prepared and structurally characterized by single-crystal X ray diffraction, powder X-ray diffraction, infrared spectrometry, thermogravimetric analyses, elemental analyses, and electrospray ionization mass spectrometry. Single-crystal X-ray diffraction analyses revealed that 1-Ln contain an unprecedented banana-shaped polyanion constructed from an iron lanthanide heterometallic {Fe6LnO28} cluster, two trilacunary {B-alpha-GeW9O34} units, and one hexalacunary {GeW6O26} fragment. The magnetic susceptibility surveying proved the presence of antiferromagnetic coupling in 1-Ln. PMID- 29442501 TI - Exploiting the S4-S5 Specificity of Human Neutrophil Proteinase 3 to Improve the Potency of Peptidyl Di(chlorophenyl)-phosphonate Ester Inhibitors: A Kinetic and Molecular Modeling Analysis. AB - The neutrophilic serine protease proteinase 3 (PR3) is involved in inflammation and immune response and thus appears as a therapeutic target for a variety of infectious and inflammatory diseases. Here we combined kinetic and molecular docking studies to increase the potency of peptidyl-diphenyl phosphonate PR3 inhibitors. Occupancy of the S1 subsite of PR3 by a nVal residue and of the S4-S5 subsites by a biotinylated Val residue as obtained in biotin-VYDnVP(O-C6H4-4-Cl)2 enhanced the second-order inhibition constant kobs/[I] toward PR3 by more than 10 times ( kobs/[I] = 73000 +/- 5000 M-1 s-1) as compared to the best phosphonate PR3 inhibitor previously reported. This inhibitor shows no significant inhibitory activity toward human neutrophil elastase and resists proteolytic degradation in sputa from cystic fibrosis patients. It also inhibits macaque PR3 but not the PR3 from rodents and can thus be used for in vivo assays in a primate model of inflammation. PMID- 29442502 TI - Carbohydrate/DBU Cocatalyzed Alkene Diboration: Mechanistic Insight Provides Enhanced Catalytic Efficiency and Substrate Scope. AB - A mechanistic investigation of the carbohydrate/DBU cocatalyzed enantioselective diboration of alkenes is presented. These studies provide an understanding of the origin of stereoselectivity and also reveal a strategy for enhancing reactivity and broadening the substrate scope. PMID- 29442503 TI - Improved Access to 1,8-Diformyl-carbazoles Leads to Metal-Free Carbazole-Based [2 + 2] Schiff Base Macrocycles with Strong Turn-On Fluorescence Sensing of Zinc(II) Ions. AB - Development of a new and high yielding synthetic route to 1,8-diformyl-carbazoles 3 (3a 3,6-di- tert-butyl substituted; 3b 3,6-unsubstituted) is reported. Use of a Heck coupling reaction, followed by ozonolysis, has greatly facilitated the preparation of these interesting head units in useful quantities. An initial foray into the new generations of Schiff base macrocycles that ready access to these head units (3) opens up, has led to the direct (i.e., metal-free) synthesis of two [2 + 2] macrocycles from 3a or 3b with 1,2-diaminoethane, H2LtBu (4a) and H2LH (4b), respectively, obtained as yellow powders in high yields (87-88%). The dizinc complex [Zn2LH(OAc)2] (5b) was isolated as a bright yellow solid in 83% yield, by 1:2:2 reaction of H2LH with zinc(II) acetate and triethylamine. Aldehydes 3a and 3b, macrocycle H2LH, and complex [Zn2LH(OAc)2] (5b) have been structurally characterized. The carbazole NH makes bifurcated hydrogen bonds with the pair of flanking 1,8-diformyl-moieties in 3, or 1,8-diimine-moieties in H2LH, leading to a flat, all- cis conformation. The stepped conformation of the metal free macrocycle H2LH is retained in [Zn2LH(OAc)2], despite deprotonation and binding of two zinc(II) centers within the two tridentate pockets. The N3O2 coordination of the zinc ions is completed by one MU1,1- and one MU1,3- bridging acetate anion. Excitation of nanomolar [Zn2LH(OAc)2] in DMF at 335 nm results in clearly visible blue fluorescence (lambdamax = 460 nm). Further studies on the H2LH macrocycle revealed turn-on fluorescence, with selectivity (over Ca2+, Mg2+ and a range of 3d dications) and nanomolar sensitivity for zinc(II) ions, highlighting one of the many potential applications for these new carbazole-based Schiff base macrocycles. PMID- 29442504 TI - Ligand-Controlled Electron Structure of Catalytically Active Ni Complexes. AB - We have performed a systematic study of the electron structure of a series of Ni(I) and Ni(II) iodo and methyl complexes with a variety of di- and tridentate nitrogen ligands to study the influence of these ligands in the structure of catalytically active complexes in cross-coupling reactions. Ni(II) compounds show the expected square-planar configuration typical of complexes of d8 metals, regardless of the kind of coordinating nitrogen atom (sp2 or sp3) found in ligands derived from either trialkylamines or pyridines. In contrast, Ni(I) complexes show different structures. Thus, the absence of orbitals capable of delocalizing the unpaired electron (such as in TMEDA and PMDTA derivatives) leads to nonplanar iodo or methyl tetracoordinate complexes. In contrast, the presence of ligands derived from pyridine allows delocalization of the unpaired electron on the ligand. This delocalization is especially effective for terpyridine species. PMID- 29442505 TI - Concise Total Synthesis of (+/-)-Deguelin and (+/-)-Tephrosin Using a Vinyl Iodide as a Key Building Block. AB - A concise and protecting-group-free total synthesis of the antiproliferative natural product (+/-)-deguelin (2) was accomplished in four steps and 62% overall yield from commercially available precursors. The key transformation employed a vinyl iodide as the pivotal building block to construct the 4-acylchromene substructure present in deguelin. Subsequent Cu2O-mediated alpha-hydroxylation of deguelin (2) afforded tephrosin (3) in 90% yield. PMID- 29442506 TI - Rollover Cyclometalated Bipyridine Platinum Complexes as Potent Anticancer Agents: Impact of the Ancillary Ligands on the Mode of Action. AB - Platinum-based anticancer coordination compounds are widely used in the treatment of many tumor types, where they are very effective but also cause severe side effects. Organoplatinum compounds are significantly less investigated than the analogous coordination compounds. We report here rollover cyclometalated Pt compounds based on 2,2'-bipyridine which are demonstrated to be potent antitumor agents both in vitro and in vivo. Variation of the co-ligands on the Pt(2,2' bipyridine) backbone resulted in the establishment of structure-activity relationships. They showed that the biological activity was in general inversely correlated with the reaction kinetics to biomolecules as shown for amino acids, proteins, and DNA. The less stable compounds caused higher reactivity with biomolecules and were shown to induce p53-dependent DNA damage. In contrast, the presence of bulky PTA and PPh3 ligands was demonstrated to cause lower reactivity and increased antineoplastic activity. Such compounds were devoid of DNA-damaging activity and induced ATF4, a component of the endoplasmic reticulum (ER) stress pathway. The lead complex inhibited tumor growth similar to oxaliplatin while showing no signs of toxicity in test mice. Therefore, we demonstrated that it is possible to fine-tune rollover-cyclometalated Pt(II) compounds to target different cancer pathways and be a means to overcome the side effects associated with cisplatin and analogous compounds in cancer chemotherapy. PMID- 29442507 TI - Functional Insights Revealed by the Kinetic Mechanism of CRISPR/Cas9. AB - The discovery of prokaryotic adaptive immunity prompted widespread use of the RNA guided clustered regularly interspaced short palindromic repeat (CRISPR) associated (Cas) endonuclease Cas9 for genetic engineering. However, its kinetic mechanism remains undefined, and details of DNA cleavage are poorly characterized. Here, we establish a kinetic mechanism of Streptococcus pyogenes Cas9 from guide-RNA binding through DNA cleavage and product release. Association of DNA to the binary complex of Cas9 and guide-RNA is rate-limiting during the first catalytic turnover, while DNA cleavage from a pre-formed ternary complex of Cas9, guide-RNA, and DNA is rapid. Moreover, an extremely slow release of DNA products essentially restricts Cas9 to be a single-turnover enzyme. By simultaneously measuring the contributions of the HNH and RuvC nuclease activities of Cas9 to DNA cleavage, we also uncovered the kinetic basis by which HNH conformationally regulates the RuvC cleavage activity. Together, our results provide crucial kinetic and functional details regarding Cas9 which will inform gene-editing experiments, guide future research to understand off-target DNA cleavage by Cas9, and aid in the continued development of Cas9 as a biotechnological tool. PMID- 29442508 TI - Chloroxyanion Residue on Seeds and Sprouts after Chlorine Dioxide Sanitation of Alfalfa Seed. AB - The effects of a 6-h chlorine dioxide sanitation of alfalfa seed (0, 50, 100, and 200 mg/kg seed) on total coliform bacteria, seed germination, and the presence of chlorate and perchlorate residues in seed rinse, seed soak, and alfalfa sprouts was determined. Chlorate residues in 20,000 mg/L calcium hypochlorite, commonly used to disinfect seed, were quantified. Chlorine dioxide treatment reduced (P < 0.05) total coliforms on seeds with no effect (P > 0.05) on germination. Dose dependent sodium chlorate residues were present in seed rinse (4.1 to 31.2 MUg/g seed) and soak (0.7 to 8.3 MUg/g seed) waters, whereas chlorate residues were absent (LOQ 5 ng/g) in sprouts, except for 2 of 5 replicates from the high chlorine dioxide treatment. Copious chlorate residues were present (168 to 1260 mg/L) in freshly prepared 20,000 mg/L calcium hypochlorite solution, and storage at room temperature increased chlorate residues significantly (P < 0.01). PMID- 29442509 TI - A Series of Organic-Inorganic Hybrid Zinc Phosphites Containing Extra-Large Channels. AB - A series of organic-inorganic hybrid zinc phosphites with extra-large channels were synthesized and characterized by single-crystal X-ray diffraction. This is an unusual example of introducing 1,4-benzenedicarboxylate and/or biphenyl-4,4' dicarboxylate ligands into the organically templated metal phosphite system to build extra-large-channel zeolite-related materials via hydro(solvo)thermal reactions. Those frameworks are composed of carboxylate linkers and inorganic tubes of zinc phosphites, translating their channel windows from a square shape (NTOU-1) to rhombus forms (NTOU-2 and NTOU-3) via the replacement of organic amines or ligands under synthesis conditions otherwise identical with those used to prepare NTOU-1. The synthesis, structural diversity, photoluminescence, and adsorption properties for dye molecules and lanthanide ions are also reported. PMID- 29442510 TI - Accessing the Nitromethane (CH3NO2) Potential Energy Surface in Methanol (CH3OH) Nitrogen Monoxide (NO) Ices Exposed to Ionizing Radiation: An FTIR and PI-ReTOF MS Investigation. AB - (D3-)Methanol-nitrogen monoxide (CH3OH/CD3OH-NO) ices were exposed to ionizing radiation to facilitate the eventual determination of the CH3NO2 potential energy surface (PES) in the condensed phase. Reaction intermediates and products were monitored via infrared spectroscopy (FTIR) and photoionization reflectron time-of flight mass spectrometry (PI-ReTOF-MS) during the irradiation and temperature controlled desorption (TPD) phase, respectively. Distinct photoionization energies were utilized to discriminate the isomer(s) formed in these processes. The primary methanol radiolysis products were the methoxy (CH3O) and hydroxymethyl (CH2OH) radicals along with atomic hydrogen. The former was found to react barrierlessly with nitrogen monoxide resulting in the formation of cis- and trans-methyl nitrite (CH3ONO), which is the most abundant product that can be observed in the irradiated samples. On the other hand, the self-recombination of hydroxymethyl radicals yielding ethylene glycol (HO(CH2)2OH) and glycerol (HOCH2CH2(OH)CH2OH) is preferred over the recombination with nitrogen monoxide to nitrosomethanol (HOCH2NO). PMID- 29442511 TI - Lanthanide Coordination Polymers of Mixed Phthalate/Adipate for Ratiometric Temperature Sensing in the Upper-Intermediate Temperature Range. AB - Based on the mixed phthalate (phth2-) and adipate (ad2-), [Nd2(ad)(phth)2(H2O)4] (I) and [Ln(ad)0.5(phth)(H2O)2] (Ln = EuIII (II), GdIII (III), TbIII (IV), DyIII (V), ErIII (VI), TmIII (VII), 1EuIII:10TbIII (VIII), 3EuIII:10TbIII (IX), and 5EuIII:10TbIII (X)) were synthesized and characterized. Complexes VIII-X show excellent ratiometric temperature sensing behavior in physiological and higher temperature ranges (303-423 K) rendered by the TbIII-to-EuIII energy transfer process. The efficiency of the process as illustrated through the lifetime measurements depends on both the EuIII:TbIII mole ratio and the temperature. The performance of X in terms of relative sensitivity ( Sr), temperature resolution, and measurement repeatability were determined, revealing the maximum Sr ( Sm) of 1.21%.K-1 at 303 K with reliable temperature resolution and excellent repeatability. PMID- 29442512 TI - Discovery of Hydrocarbon-Stapled Short alpha-Helical Peptides as Promising Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Fusion Inhibitors. AB - The hexameric alpha-helical coiled-coil formed between the C-terminal and N terminal heptad repeat (CHR and NHR) regions of class I viral fusion proteins plays an important role in mediating the fusion of the viral and cellular membranes and provides a clear starting point for molecular mimicry that drives viral fusion inhibitor design. Unfortunately, such peptide mimicry of the short alpha-helical region in the CHR of Middle East respiratory syndrome coronavirus (MERS-CoV) spike protein has been thwarted by the loss of the peptide's native alpha-helical conformation when taken out of the parent protein structure. Here, we describe that appropriate all-hydrocarbon stapling of the short helical portion-based peptide to reinforce its bioactive secondary structure remarkably improves antiviral potency. The resultant stapled peptide P21S10 could effectively inhibit infection by MERS-CoV pseudovirus and its spike protein mediated cell-cell fusion; additionally, P21S10 exhibits improved pharmacokinetic properties than HR2P-M2, suggesting strong potential for development as an anti MERS-CoV therapeutic. PMID- 29442513 TI - Chemiluminescent Determination of Oxamyl in Drinking Water and Tomato Using Online Postcolumn UV Irradiation in a Chromatographic System. AB - High-performance liquid chromatography (HPLC) was used to separate oxamyl from other pesticides in drinking water and tomato paste. The eluate emerging from the column tail was mixed with an alkaline solution of Co2+ in EDTA and irradiated with UV light to induce photolysis of the carbamate in order to obtain free radicals and other reactive species that oxidize luminol and produce chemiluminescence (CL) as a result. The intensity of the CL signal was monitored in the form of chromatographic peaks. Under the optimum operating conditions for the HPLC-UV-CL system, the analyte concentration was linearly related to peak area. The limit of detection as determined in accordance with the IUPAC criterion was 0.17 mg L-1. Oxamyl was successfully extracted with recoveries of 88.7-103.1% from spiked tomato paste by using a simple QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) sample preparation approach. Similar recoveries were obtained from drinking water samples spiked with oxamyl concentrations above the LOD. The proposed method is a simple, fast, accurate choice for quantifying this pesticide. PMID- 29442514 TI - A Dual-Functional Luminescent MOF Sensor for Phenylmethanol Molecule and Tb3+ Cation. AB - A highly luminescent porous metal-organic framework Cd3(L)2.5(4-PTZ)(DMF)3, labeled as NBU-9, has been designedly synthesized based on Cd(NO3)2.4H2O and mixed ligands of 4-(1 H-tetrazol-5-yl)pyridine (4-HPTZ) with N-coordinated sites and thiophene-2,5-dicarboxylic acid (H2L) with heteroatomic (S) ring and carboxylate groups in N, N-dimethylformamide (DMF) at 100 degrees C for 3 days. The interesting result is that this compound NBU-9 can be also obtained via the mixed raw materials of Cd(NO3)2.4H2O, 4-cyanopyridine, NaN3, and H2L under solvothermal condition at a higher temperature of 140 degrees C for 3 days, involving in situ ligand synthesis of 4-HPTZ. Its structure was indentified by single-crystal X-ray study, powder X-ray diffraction, element analysis, and TGA results. Structural analysis shows that the three-dimensional framework of NBU-9 contains cubic channels of 9.59 * 10.26 A2 covered by a large number of open S- and O-coordinated sites and can be simplified into a 8-connected uninodal eca net with high potential solvent accessible volumes of 34.1%. Its luminescent properties demonstrate that NBU-9 as a multifunctional sensory material realizes the selective detection for the phenylmethanol molecule on the basis of fluorescence quenching mechanism and effectively sensitizing the visible emitting of the Tb3+ cation based on luminescence enhancement. PMID- 29442515 TI - Isobaric Vapor-Liquid Phase Diagrams for Multicomponent Systems with Nanoscale Radii of Curvature. AB - At any given temperature, pressure, and composition, a compound or a mixture of compounds will exist either in a single phase, whether solid, liquid, or vapor, or in a combination of these phases coexisting in equilibrium. For multiphase systems, it is known that the geometry of the interface impacts the equilibrium state; this effect has been well-studied in single component systems with spherical interfaces. However, multicomponent phase diagrams are usually calculated assuming a planar interface between phases. Recent experimental and theoretical work has started to investigate the effect of curved interfaces on multicomponent phase equilibrium, but these analyses have been limited to isothermal conditions or to a portion of the isobaric phase diagram. Herein, we consider complete vapor-liquid phase diagrams (both bubble and dew lines) under isobaric conditions. We use Gibbsian composite-system thermodynamics to derive the equations governing vapor-liquid equilibrium for systems with a spherical interface separating the phases. We validate our approach by comparing the predicted nitrogen/argon dew points with reported literature data. We then predict complete isobaric phase diagrams as a function of radius of curvature for an ideal methanol/ethanol system and for a nonideal ethanol/water system. We also determine how the azeotropic composition of ethanol/water changes. The effect of curvature on isobaric phase diagrams is similar to that seen on isothermal phase diagrams. This work extends the study of curved-interface multicomponent phase equilibrium to isobaric systems, expanding the conditions under which nanoscale systems, such as nanofluidic systems, shale gas reservoirs, and cloud condensation nuclei, can be understood. PMID- 29442516 TI - Engineering Nitroxide Functional Surfaces Using Bioinspired Adhesion. AB - We pioneer a versatile surface modification strategy based on mussel-inspired oxidative catecholamine polymerization for the design of nitroxide-containing thin polymer films. A 3,4-dihydroxy-l-phenylalanine (l-DOPA) monomer equipped with a 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-derived oxidation-labile hydroxylamine functional group is employed as a universal coating agent to generate polymer scaffolds with persistent radical character. Various types of materials including silicon, titanium, ceramic alumina, and inert poly(tetrafluoroethylene) (PTFE) were successfully coated with poly(DOPA-TEMPO) thin films in a one-step dip-coating procedure under aerobic, slightly alkaline (pH 8.5) conditions. Steadily growing polymer films (~1.1 nm h-1) were monitored by ellipsometry, and their thicknesses were critically compared with those obtained from atomic force microscopic cross-sectional profiles. The heterogeneous composition of surface-adherent nitroxide scaffolds examined by X ray photoelectron spectroscopy was correlated to that examined by in-solution polymer analysis via high-resolution electrospray ionization mass spectrometry, revealing oligomeric structures with up to six repeating units, mainly composed of covalently linked dihydroxyindole along the polymer backbone. Critically, the reversible redox-active character of the nitroxide-containing polymer scaffolds was investigated by cyclic voltammetric measurements, revealing a convenient and facile access route to electrochemically active nitroxide polymer coatings with potential application in electronic devices such as organic radical batteries. PMID- 29442517 TI - Preparation of High-Density Polymer Brushes with a Multihelical Structure. AB - It is well-known that a mixture of isotactic and syndiotactic polymethyl methacrylate (PMMA) forms a stereocomplex consisting of a multihelical structure in which an isotactic chain is surrounded by a syndiotactic chain. Here, we report the basic structure of the stereocomplex formed when the syndiotactic PMMA chains are tethered to a silicon substrate and form a high-density polymer brush. The influence of geometric confinement was investigated by preparing the high density polymer brushes on a flat and spherical substrate. In both cases, mixing the untethered isotactic PMMA with the grafted syndiotactic PMMA led to the formation of a stereocomplex with a multihelical structure. Static contact angle measurements showed a hindered surface mobility at the outermost surface of the polymer brush, indicating that the stereocomplex forms a crystalline structure. A syndiotactic polymer brush with substituted fluoroalkyl groups was prepared to increase the contrast for grazing incidence wide-angle X-ray diffraction (GIWAXD) measurements. The GIWAXD results verified that the stereocomplex forms a crystalline structure oriented perpendicular to the substrate with a relatively low degree of orientation. PMID- 29442518 TI - Large-Area High-Performance Flexible Pressure Sensor with Carbon Nanotube Active Matrix for Electronic Skin. AB - Artificial "electronic skin" is of great interest for mimicking the functionality of human skin, such as tactile pressure sensing. Several important performance metrics include mechanical flexibility, operation voltage, sensitivity, and accuracy, as well as response speed. In this Letter, we demonstrate a large-area high-performance flexible pressure sensor built on an active matrix of 16 * 16 carbon nanotube thin-film transistors (CNT TFTs). Made from highly purified solution tubes, the active matrix exhibits superior flexible TFT performance with high mobility and large current density, along with a high device yield of nearly 99% over 4 inch sample area. The fully integrated flexible pressure sensor operates within a small voltage range of 3 V and shows superb performance featuring high spatial resolution of 4 mm, faster response than human skin (<30 ms), and excellent accuracy in sensing complex objects on both flat and curved surfaces. This work may pave the road for future integration of high-performance electronic skin in smart robotics and prosthetic solutions. PMID- 29442519 TI - Snapshots of Light Induced Accumulation of Two Charges on Methylviologen using a Sequential Nanosecond Pump-Pump Photoexcitation. AB - Methylviologen (MV2+) is perhaps the most used component as a reversible electron acceptor in photophysical studies. While MV2+ is most commonly implicated as a reversible one-electron mediator, its electrochemical properties clearly evidence two successive one-electron reduction processes. In this report, we have investigated on the light driven two-charge accumulation on MV2+ using a multicomponent system composed of the prototypical molecular photosensitizer [Ru(bpy)3]2+ and MV2+ in the presence of ascorbate as reversible electron donor. The sequential addition of two electrons on the methylviologen was tracked upon sequential excitation of the [Ru(bpy)3]2+ at optimized concentration of the electron acceptor. The charge accumulated state carries an energy of 0.9 eV above the ground state and has a lifetime of ca. 50 MUs. We have reached a fairly good global yield of approximately 9% for the two-charge accumulation. This result clearly demonstrates the potential of this simple approach for applications in artificial photosynthesis. PMID- 29442520 TI - Photofluorination of Aliphatic C-H Bonds Promoted by the Phthalimide Group. AB - Aliphatic C-H fluorination of phthalimide derivatives with Selectfluor was investigated under photoirradiation conditions. The reaction did not require any additive or catalyst and afforded C-H fluorinated products in moderate to good yields. It is likely that the reaction site depends on the C-H bond energy, and this may be the reason for the good to high regioselectivity. PMID- 29442521 TI - Changes in Reactivity as Chemistry Becomes Confined to an Interface. The Case of Free Radical Oxidation of C30H62 Alkane by OH. AB - We examine in a simple organic aerosol the transition between heterogeneous chemistry under well-mixed conditions to chemistry under interfacial confinement. A single reaction mechanism, shown to reproduce observed OH oxidation chemistry for liquid and semisolid C30H62, is used in reaction-diffusion simulations to explore reactivity over a broad viscosity range. The results show that when internal mixing of the aerosol is fast and the particle interface is enriched in C-H groups, ketone and alcohol products, formed via peroxy radical disproportionation, predominate. As viscosity increases the reactions become confined to a shell at the gas-aerosol interface. The confinement is accompanied by emergence of acyloxy reaction pathways that are particularly active when the shell is 1 nm or less. We quantify this trend using a reaction-diffusion index, allowing the parts of the mechanism that control reactivity as viscosity increases to be identified. PMID- 29442522 TI - The impact of PTSD clusters on cannabis use in a racially diverse trauma-exposed sample: An analysis from ecological momentary assessment. AB - BACKGROUND: Accumulating evidence indicates a link between post-traumatic stress disorder (PTSD) and cannabis use and suggests that this link may vary as a function of the PTSD symptom cluster type. Consistent with negative reinforcement models of substance use, individuals with elevated Cluster D (Hyperarousal) symptoms may be more likely to use cannabis in response to elevated state anxiety and experience decreases in state anxiety after using cannabis. OBJECTIVES: We aimed to test hypotheses that the interaction of Cluster D and state anxiety would be related to subsequent cannabis use and that those with elevated Cluster D symptoms who used cannabis would report the greatest decreases in state anxiety. To test the specificity, we tested whether Clusters B (re-experiencing) and C (avoidance) showed similar relationships. METHODS: The present study used ecological momentary assessment to examine cannabis use among 87 cannabis-using individuals with PTSD symptoms (64.4% male, 56.3% non-Hispanic Caucasian). State anxiety and cannabis use were assessed over the two-week period via signal contingent (six random prompts per day), interval contingent (each bedtime), and event contingent (cannabis use episodes) assessments. RESULTS: Consistent with negative reinforcement models, participants with clinically significant Cluster D symptoms with elevated state anxiety had a greater likelihood of subsequent cannabis use and cannabis use resulted in less subsequent anxiety. The negative reinforcement hypothesis was only partially supported for those with Cluster B and C symptoms. CONCLUSIONS: The results suggest that negative reinforcement models may be especially relevant to understanding cannabis use among those with clinically elevated Cluster D symptoms. PMID- 29442523 TI - Patterns of heart failure symptoms are associated with self-care behaviors over 6 months. AB - BACKGROUND: Both heart failure symptoms and self-care are associated with patient outcomes. Although it is thought that symptoms drive self-care, there is limited evidence to support this assumption over time. AIMS: To determine whether patterns of physical symptoms are significantly associated with heart failure self-care over time. METHOD: Latent mixture analysis was used to identify subgroups based on physical symptoms of dyspnea, sleepiness and edema (using the heart failure somatic perception and Epworth sleepiness scales). Growth modeling was used to determine if symptom subgroups were associated with self-care behaviors (using the self-care in heart failure index) over 6 months. Sociodemographic and clinical variables predicting the likelihood of subgroup membership were identified using logistic regression. RESULTS: The sample ( n=146) was on average 57 years old, 70% were men and 59% had class III/IV heart failure. Two symptom subgroups were identified (entropy 0.91): a high symptom group ( n=24; 16%) with no significant change in symptoms over time (high sustained), and a low symptom group ( n=122; 84%) with no significant change in symptoms over time (low sustained). The high sustained group was associated significantly with better self-care behaviors at baseline and over 6 months. Women (odds ratio (OR) 3.67, P=0.023) and patients with more depressive symptoms (OR 1.16, P=0.015) were more likely to be in the high sustained symptom group. Those treated with a renin-angiotensin-aldosterone system agent were less likely to be in the high symptom group (OR 0.17, P=0.015). CONCLUSION: Patients bothered more by symptoms are consistently more engaged in self-care behaviors over time. The results of this study support symptoms as an important driver of self-care behaviors. PMID- 29442525 TI - Comparative Analysis of Mesenchymal Stem Cells from Bone Marrow, Adipose Tissue, and Dental Pulp as Sources of Cell Therapy for Zone of Stasis Burns. AB - INTRODUCTION: The implantation of mesenchymal stem cells (MSCs) has been shown to exert benefits for the survival of the zone-of-stasis. However, the clinical experience indicates the importance of selecting the right source and type of stem cells. Therefore, we planned the current study to perform a quantitative comparison of MSCs isolated from three different sources to provide information useful in selection of the optimal source and to see whether critical mechanisms are conserved between different populations. METHODS: The protective effects of MSCs derived from bone marrow, adipose tissue and dental pulp were compared in a rat model of thermal trauma. The stasis zones were evaluated 72 h after the burn using histochemistry, immunohistochemistry and biochemistry. RESULTS: Gross evaluation of burn wounds revealed that the differences between the mean percentages of the calculated necrotic areas weren't statistically significant. Semi-quantitative grading of the histopathological findings revealed that there were no significant differences between damage scores. Immunohistochemical assessment of apoptotic and necrotic cell deaths revealed that the differences between the mean numbers of apoptotic and necrotic cells weren't statistically significant. Myeloperoxidase activity was found to be significantly lower in the adipose tissue group. Biochemical and immunohistochemical assessment of tissue malondialdehyde revealed that the differences between the groups weren't statistically significant. Finally, the number of neo-vessels in the dental pulp group was found to be significantly higher. CONCLUSION: Our findings suggest that bone marrow, adipose tissue and dental pulp may serve as a universal donor MSC source for the prevention of burn wound progression. PMID- 29442524 TI - Exacerbations of Chronic Obstructive Pulmonary Disease and Cardiac Events. A Post Hoc Cohort Analysis from the SUMMIT Randomized Clinical Trial. AB - RATIONALE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common, associated with acute inflammation, and may increase subsequent cardiovascular disease (CVD) risk. OBJECTIVES: Determine whether AECOPD events are associated with increased risk of subsequent CVD. METHODS: We performed a secondary cohort analysis of the SUMMIT (Study to Understand Mortality and Morbidity) trial, a convenience sample of current/former smokers with moderate COPD from 1,368 centers in 43 countries. All had CVD or increased CVD risk. AECOPD was defined as an increase in respiratory symptoms requiring treatment with antibiotics, systemic corticosteroids, and/or hospitalization. CVD events were a composite outcome of cardiovascular death, myocardial infarction, stroke, unstable angina, and transient ischemic attack. All CVD events were adjudicated. Cox proportional hazards models compared the hazard for a CVD event before AECOPD versus after AECOPD. MEASUREMENTS AND MAIN RESULTS: Among 16,485 participants in SUMMIT, 4,704 participants had at least one AECOPD and 688 had at least one CVD event. The hazard ratio (HR) for CVD events after AECOPD was increased, particularly in the first 30 days after AECOPD (HR, 3.8; 95% confidence interval, 2.7-5.5) and was elevated up to 1 year after AECOPD. The 30-day HR after hospitalized AECOPD was more than twofold greater (HR, 9.9; 95% confidence interval, 6.6-14.9). CONCLUSIONS: In patients with COPD with CVD or risk factors for CVD, exacerbations confer an increased risk of subsequent CVD events, especially in hospitalized patients and within the first 30 days after exacerbation. Patients and clinicians should have heightened vigilance for early CVD events after AECOPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01313676). PMID- 29442526 TI - Cost-efficacy analysis of 3% diclofenac sodium, ingenol mebutate, and 3.75% imiquimod in the treatment of actinic keratosis. AB - Actinic keratosis (AK) is a clinical condition characterized by keratinocytic dysplastic lesions of the epidermis, affecting individuals chronically exposed to sunlight. Topical therapies allow the treatment of a whole area of affected skin and currently include diclofenac sodium gel, 5-fluorouracil cream, 5-fluorouracil and acetylsalicylic acid solution, imiquimod cream, and ingenol mebutate gel. Due to the comparable efficacy of 3% diclofenac, ingenol mebutate, and 3.75% imiquimod in treating AK multiple lesions, a pharmacoeconomic evaluation of cost effectiveness of the three treatments was needed. A cost-efficacy analysis comparing 3% diclofenac sodium with ingenol mebutate and 3.75% imiquimod was performed. In this analysis, efficacy data were combined with quality-of-life measurement derived from previous studies as well as the costs associated with the management of these lesions in Italy. Patients' demographics and clinical characteristics were assumed to reflect those from the clinical studies considered. PMID- 29442527 TI - Decreased generation of C-terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease. AB - Increasing evidence indicates that altered reelin signaling could contribute to synaptic dysfunction in Alzheimer's disease (AD). We found that reelin protein and mRNA levels were increased in the AD brain (particularly at advanced Braak stages in apolipoprotein E4 noncarriers), compared with that of control subjects. The beta-amyloid (Abeta) protein impairs reelin activity and increases reelin expression through a mechanism that is not yet understood. To explore that mechanism, we examined the effect of Abeta aa 1-42 (Abeta42) on DNA methylation of the RELN promoter and the processing of reelin receptor apolipoprotein E receptor 2 (ApoER2) in differentiated SH-SY5Y cells because ApoER2 C-terminal fragments (CTFs), generated after reelin binding, regulate reelin expression. We found that Abeta42 decreased nuclear levels of DNA-methyltransferase 1. However, RELN promoter methylation did not change in Abeta42-treated cells or in AD brain extracts. Instead, the levels of ApoER2-CTF appeared significantly lower in Abeta42-treated cells and in AD extracts from advanced Braak stages of apolipoprotein E4 noncarriers. Our data show that ApoER2-CTF levels are decreased, whereas reelin expression is increased in AD brain at advanced Braak stages and after Abeta treatment, supporting the view that ApoER2-CTF exerts a modulatory role on reelin expression.-Mata-Balaguer, T., Cuchillo-Ibanez, I., Calero, M., Ferrer, I., Saez-Valero, J. Decreased generation of C-terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease. PMID- 29442528 TI - Structure and function of the open canalicular system - the platelet's specialized internal membrane network. AB - The open canalicular system (OCS) is an internal membrane structure found in platelets. First identified 50 years ago, the OCS comprises a tunneling network of surface-connected channels that appear to play an important role in platelet function. Yet, our understanding of how the OCS forms, how it functions, and what might regulate its structure and behavior remains fairly rudimentary. Structural abnormalities of the OCS are observed in some human platelet disorders. Yet, because platelets from these patients display multiple defects, the specific contribution of any OCS dysregulation to the impaired platelet function is unclear. However, recent studies have begun to shed light on mechanisms that regulate the OCS structure and to understand what influence the OCS has on overall platelet function. Advances in cellular imaging techniques have allowed whole-cell visualization of the OCS, providing the opportunity for a more detailed structural examination. Furthermore, recent work indicates that the modulation of the OCS structure may be sufficient to impact in vivo platelet function, opening up the intriguing possibility of manipulating the OCS structure as an anti-thrombotic approach. On the 50th anniversary of its discovery, we review here what is known about OCS structure and function, and outline some of the key microscopy tools for studying this intriguing internal membrane system. PMID- 29442529 TI - Signaling mediators modulated by cardioprotective interventions in healthy and diabetic myocardium with ischaemia-reperfusion injury. AB - Ischaemic heart diseases are one of the major causes of death in the world. In most patients, ischaemic heart disease is coincident with other risk factors such as diabetes. Patients with diabetes are more prone to cardiac ischaemic dysfunctions including ischaemia-reperfusion injury. Ischaemic preconditioning, postconditioning and remote conditionings are reliable interventions to protect the myocardium against ischaemia-reperfusion injuries through activating various signaling pathways and intracellular mediators. Diabetes can disrupt the intracellular signaling cascades involved in these myocardial protections, and studies have revealed that cardioprotective effects of the conditioning interventions are diminished in the diabetic condition. The complex pathophysiology and poor prognosis of ischaemic heart disease among people with diabetes necessitate the investigation of the interaction of diabetes with ischaemia-reperfusion injury and cardioprotective mechanisms. Reducing the outcomes of ischaemia-reperfusion injury using targeted strategies would be particularly helpful in this population. In this study, we review the protective interventional signaling pathways and mediators which are activated by ischaemic conditioning strategies in healthy and diabetic myocardium with ischaemia reperfusion injury. PMID- 29442530 TI - Obesity and acute cardiovascular events. PMID- 29442531 TI - The impact of pneumatic tube transport on whole blood coagulation and platelet function assays. AB - Pneumatic tube is an attractive way to transport blood samples from the emergency department to the central laboratory facility. We aimed to investigate the impact of pneumatic tube transportation on blood samples for analysis of whole blood coagulation and platelet function. We included 21 healthy adult individuals and measured global coagulation assays by rotational thromboelastometry (ROTEM) and platelet aggregation induced by arachidonic acid (AA) and adenosine diphosphate (ADP) using impedance aggregometry (ROTEM Platelet), on samples transported manually or by pneumatic tube transport. Statistical testing was performed with paired tests with post-hoc Bonferroni correction for multiple testing. Our data revealed no difference in the far majority of ROTEM parameters (P > 0.003), while significantly decreased values were observed for INTEM clotting time (CT) (P = 0.002) and maximum clot firmness (MCF) including the amplitude after 10 min (A10) (P < 0.0001). No statistically significant difference was observed on impedance aggregometry results when manual transport was compared to pneumatic tube transport (P > 0.003). This study indicates that only minor and unsystematic differences between manual transport and pneumatic tube transport may be observed in ROTEM analyses, and that there is no influence from pneumatic tube transport on impedance aggregometry analyses using AA and ADP. PMID- 29442532 TI - Varying Opinions on Who Deserves Collectively Financed Health Care Services: A Discrete Choice Experiment on Allocation Preferences of the General Public. AB - In Europe, health insurance arrangements are under reform. These arrangements redistribute collectively financed resources to ensure access to health care for all. Allocation of health services is historically based on medical needs, but use of other criteria, such as lifestyle, is debated upon. Does the general public also have preferences for conditional allocation? This depends on their opinions regarding deservingness. The aim of this study was to gain insight in those opinions, specifically by examining the perceived weight of different criteria in allocation decisions. Based on literature and expert interviews, we included 5 criteria in a discrete choice experiment: need, financial capacity, lifestyle, cooperation with treatment, and package/premium choice. A representative sample of the Dutch population was invited to participate (n = 10 760). A total of 774 people accessed the questionnaire (7.2%), of whom 375 completed it (48.4%). Medical need was overall the most important criterion in determining deservingness (range beta = 1.60). Perceived deservingness decreased if claimants had higher financial capacity (1.26) and unhealthier lifestyle (1.04), if their cooperation was less optimal (1.05), or if they had opted for less insurance coverage (0.56). However, preferences vary among respondents, in relation to demographic and ideological factors. PMID- 29442533 TI - Variation of Care Time Between Nursing Units in Classification-Based Nurse-to Resident Ratios: A Multilevel Analysis. AB - A validity test was conducted to determine how care level-based nurse-to-resident ratios compare with actual daily care times per resident in Germany. Stability across different long-term care facilities was tested. Care level-based nurse-to resident ratios were compared with the standard minimum nurse-to-resident ratios. Levels of care are determined by classification authorities in long-term care insurance programs and are used to distribute resources. Care levels are a powerful tool for classifying authorities in long-term care insurance. We used observer-based measurement of assignable direct and indirect care time in 68 nursing units for 2028 residents across 2 working days. Organizational data were collected at the end of the quarter in which the observation was made. Data were collected from January to March, 2012. We used a null multilevel model with random intercepts and multilevel models with fixed and random slopes to analyze data at both the organization and resident levels. A total of 14% of the variance in total care time per day was explained by membership in nursing units. The impact of care levels on care time differed significantly between nursing units. Forty percent of residents at the lowest care level received less than the standard minimum registered nursing time per day. For facilities that have been significantly disadvantaged in the current staffing system, a higher minimum standard will function more effectively than a complex classification system without scientific controls. PMID- 29442534 TI - Efficacy and safety of combination therapy with prednisolone and oral tacrolimus for progressive interstitial pneumonia with systemic sclerosis: A retrospective study. AB - OBJECTIVES: We retrospectively investigated efficacy and safety of combination therapy with prednisolone (PSL) and tacrolimus (TAC) for progressive interstitial pneumonitis with systemic sclerosis (SSc-PIP). METHODS: We studied 11 patients with SSc-PIP who received combination therapy with PSL (0.5 mg/kg/d) and TAC (3 mg/d). RESULTS: Baseline Hugh-Jones grades were I, II, III, and IV in 2, 6, 2, and 1 patients, respectively. Krebs von den Lungen-6 (KL-6) values were elevated to 914 (range 300-2614) U/mL. % Diffusing capacity of carbon monoxide (%DLco) remarkably decreased to 47.4 (range 9.7-64.4) %. All patients were alive at 1 year after therapy. In response to treatment, interstitial pneumonia (IP) improved in three patients, stable in seven patients, and deteriorated in one patient. Total ground-glass opacity (GGO) score improved (p = .005). No significant changes occurred in values of KL-6, % forced vital capacity (%FVC), and %DLco. Presently, all seven patients who could be followed up were alive. IP improved in three patients and stable in four patients. Total GGO score improved (p = .016). KL-6, %FVC, and %DLco did not change. Mild cytomegalovirus or herpes zoster infection occurred in two patients. Grade I renal injuries were observed in three and one patient at 1 year and present, respectively. CONCLUSION: Combination therapy with PSL and TAC appeared to be well tolerated and effective in suppressing the disease activity of SSc-PIP. PMID- 29442535 TI - Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors. AB - The purpose of antithrombotic therapy is the prevention of thrombus formation and/or its extension with a minimum risk of bleeding. The inhibition of a variety of proteolytic processes, particularly those of the coagulation cascade, has been reported as a property of plant protease inhibitors. The role of trypsin inhibitors (TIs) from Delonix regia (Dr) and Acacia schweinfurthii (As), members of the Kunitz family of protease inhibitors, was investigated on blood coagulation, platelet aggregation, and thrombus formation. Different from Acacia schweinfurthii trypsin inhibitor (AsTI), Delonix regia trypsin inhibitor (DrTI) is a potent inhibitor of FXIa with a Kiapp of 1.3 * 10-9 M. In vitro, both inhibitors at 100 ug corresponding to the concentrations of 21 MUM and 15.4 MUM of DrTI and AsTI, respectively, increased approximately 2.0 times the activated partial thromboplastin time (aPTT) in human plasma compared to the control, likely due to the inhibition of human plasma kallikrein (huPK) or activated factor XI (FXIa), in the case of DrTI. Investigating in vivo models of arterial thrombus formation and bleeding time, DrTI and AsTI, 1.3 uM and 0.96 uM, respectively, prolonged approximately 50% the time for total carotid artery occlusion in mice compared to the control. In contrast to heparin, the bleeding time in mice treated with the two inhibitors did not differ from that of the control group. DrTI and AsTI inhibited 49.3% and 63.8%, respectively, ex vivo murine platelet aggregation induced by adenosine diphosphate (ADP), indicating that these protein inhibitors prevent arterial thrombus formation possibly by interfering with the plasma kallikrein (PK) proteolytic action on the intrinsic coagulation pathway and its ability to enhance the platelet aggregation activity on the intravascular compartment leading to the improvement of a thrombus. PMID- 29442536 TI - A new surgical technique for excision of orbital cavernous hemangioma: a 15-year experience. AB - PURPOSE: To present a new surgical technique for excision of orbital cavernous hemangiomas (CHs). METHODS: This retrospective case series study included patients with orbital CH who were operated from 2001 to 2016 at our referral center. Epidemiologic data, symptoms, signs, and images were reviewed from patients' files with at least one year of follow-up. Surgical results and complications were documented. We used the "index finger dissection" technique without grasping the tumor for release of adhesions and its removal. RESULTS: We included 60 patients with orbital CH consisting of 36 (60%) female and 24 (40%) male patients with mean age of 40 +/- 12.1 (range 9-66) years. The main complaint was proptosis with average size of 5.3 +/- 2 millimeters. The surgical approach was lateral orbitotomy in 49 (81.7%) patients, medial transcutaneous in seven (11.7%) patients, inferior transconjunctival in three (5%) patients, and simultaneous lateral and medial orbitotomy in one (1.6%) patient. All tumors were removed intact; complications included ptosis in one subject, lower lid retraction in one case, and diplopia in two patients, all of which improved before 2 months. No optic nerve damage occurred. CONCLUSION: The "index finger dissection" technique without grasping the tumor for excision of orbital CH, via any external approach to the tumor, is a safe technique with minimal complications. PMID- 29442537 TI - Once- versus twice-daily aspirin treatment in patients with essential thrombocytosis. AB - Insufficient platelet inhibition has been reported in up to 40% of aspirin treated patients, including patients with essential thrombocytosis. To maintain sufficient platelet inhibition, a shorter dosing interval with aspirin has been suggested. We aimed to investigate the antiplatelet effect of low-dose aspirin given twice-daily compared to standard once-daily dosing in patients with essential thrombocytosis. We included 22 patients, who were treated for 7 days with standard once-daily aspirin (75 mg once-daily) followed by 7 days treatment of twice-daily aspirin (37.5 mg twice-daily). The two regimens were separated by 14 days aspirin washout. Blood samples were obtained 1h and 24h/12h after the last pill intake in each regimen. The effect of aspirin was evaluated by: (1) platelet aggregation measured by whole blood impedance aggregometry (Multiplate(r) Analyser) using arachidonic acid (ASPItest 0.5 mM) as agonist and (2) serum thromboxane B2 levels determined using an enzyme-linked immunosorbent assay. The difference in platelet aggregation from 1h to the end of the dosing interval (24h/12h) was used to compare the two regimens. We demonstrated a significantly smaller difference in platelet aggregation in the twice-daily regimen compared to the once-daily: mean of difference = 228 AU*min (95% confidence interval (CI): 92-363, p < 0.01). In addition, a significantly smaller difference in thromboxane B2 was demonstrated in the twice-daily regimen compared to the once-daily regimen: mean of difference = 16.3 ng/mL (95% CI: 9.9-22.7, p < 0.01). In conclusion, twice-daily dosing with low-dose aspirin provides a more consistent platelet inhibition compared with standard once-daily dosing in patients with essential thrombocytosis. PMID- 29442538 TI - Serum cystatin C level is associated with locomotive syndrome risk and can be an early predictor in community-living people: The Yakumo study. AB - OBJECTIVES: The locomotive syndrome (LS) risk has been recently proposed as a criterion for evaluating physical ability. Serum cystatin C level is an early renal function marker and a cardiovascular disease predictor. This study aimed to evaluate the relationship between serum cystatin C level and LS risk. METHODS: We enrolled 54 participants and conducted the two-step test, stand-up test, 25 question geriatric locomotive function scale, LS risk test, Timed Up and Go test, back muscle strength, grip strength, blood test and serum cystatin C level measurement. A comparative study was conducted in participants with and without LS risk and in subgroups aged <60 and >=60 years. RESULTS: No significant difference was found in the serum cystatin C level in subgroups aged <60 years and without LS risk. However, it was significantly higher in subjects with LS risk and aged >=60 years. The area under the curve of the serum cystatin C level for LS risk was 0.824. CONCLUSION: The serum cystatin C level is significantly related to LS risk and can be an early predictor. In middle-aged and elderly people with high serum cystatin C levels, it is strongly recommended to enforce LS risk test and intervention. PMID- 29442539 TI - Platelets in wound healing and regenerative medicine. AB - Although platelets are widely recognized as having a critical role in primary hemostasis and thrombosis, increasing experimental and clinical evidence identifies these enucleated cells as relevant modulators of other physiopathological processes including inflammation and tissue regeneration. These phenomena are mediated through the release of growth factors, cytokines, and extracellular matrix modulators that sequentially promote (i) revascularization of damaged tissue through the induction of migration, proliferation, differentiation, and stabilization of endothelial cells in new blood vessels; (ii) restoration of damaged connective tissue through migration, proliferation, and activation of fibroblasts; and (iii) proliferation and differentiation of mesenchymal stem cells into tissue-specific cell types. For these reasons, platelet-rich plasma (PRP) derivatives are used in regenerative medicine for the treatment of several clinical conditions including ulcers, burns, muscle repair, bone diseases, and tissue recovery following surgery. The benefits of PRP administration are associated with an economical advantage, taking into consideration that PRP administration does not require complex equipment or training for its execution. Moreover, due to their primary autologous origin, concerns of disease transmission or immunogenic reactions can be disregarded. Thus, platelet-enriched materials have become highly relevant in the last decade and constitute a growing focus of experimental and clinical study in the context of wound healing and tissue regeneration. However, despite the diverse applications, the efficacy of regenerative treatments using PRP is being called into question due to the lack of large controlled clinical trials and the lack of consensus regarding the PRP preparation techniques. This review describes the biological mechanisms underlying PRP's regenerative effects, the different methods of preparation and application of these biomaterials, and the controversies and future prospects related to the use of PRP in regenerative medicine. PMID- 29442540 TI - Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. AB - Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki . PMID- 29442541 TI - The Ophthalmology Surgical Competency Assessment Rubric (OSCAR) for anterior approach ptosis surgery. AB - PURPOSE: The International Council of Ophthalmology (ICO) is currently developing a series of standardized, internationally validated, teaching tools for key ophthalmic surgical procedures called the Ophthalmology Surgical Competency Assessment Rubrics (OSCARs). This study aims to develop an OSCAR for anterior approach ptosis surgery. METHODS: An international panel of content experts, representing Australia, India, Iran, Italy, Turkey, UK, and the USA was established and worked to develop the rubric using a range of online collaboration tools. The team used the standardised OSCAR template as a baseline, developing explicit behavioural descriptors (the behaviour and performance expected for each step) that were reviewed and modified with successive models. Learners were scored a modified 4-point Dreyfus scale of skill acquisition (novice, beginner, advanced beginner, competent) with the removal of the expert domain. RESULTS: The final OSCAR ptosis tool was developed in alignment with the ICO-OSCAR standard. Seventeen agreed and weighted stems were produced. Domains such as communication and postoperative complications were removed from this rubric as they are evaluated in other spheres of residency training. Specific comments with regard to the parameters and wording were incorporated to formulate the final rubric, which was internationally agreed and demonstrated face and content validity. CONCLUSIONS: The OSCAR for anterior approach ptosis is skill and behaviour-based, has ICO agreed standards for assessment and provides learners with specific targets for improvement. Although the OSCAR ptosis tool has face and content validity, further development could better elucidate its precise role. PMID- 29442542 TI - Comparison of the Nephrotoxicity of Vancomycin in Combination With Cefepime, Meropenem, or Piperacillin/Tazobactam: A Prospective, Multicenter Study. AB - BACKGROUND: Patients often receive broad-spectrum antibiotics for nosocomial infections commonly with activity against Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus. Previous retrospective and/or single-center studies have suggested that the combination of vancomycin and piperacillin/tazobactam might be associated with an increased risk of acute kidney injury. OBJECTIVES: To compare the incidence of nephrotoxicity in patients receiving intravenous vancomycin in combination with cefepime, meropenem, or piperacillin/tazobactam. METHODS: This was a prospective, multicenter observational study of patients receiving vancomycin in combination with piperacillin/tazobactam versus cefepime or meropenem. Adult patients 18 years of age or older who were hospitalized and received 72 or more hours of intravenous vancomycin and 72 hours or more of cefepime, meropenem, or piperacillin/tazobactam were eligible. Patient and medication characteristics were examined for the 242 patients included. RESULTS: The incidence of acute kidney injury for patients treated with vancomycin and piperacillin/tazobactam was significantly higher than for those treated with vancomycin and cefepime or meropenem, 29.8% versus 8.8%, respectively, P < 0.001. Binary logistic regression demonstrated that patients receiving vancomycin and piperacillin/tazobactam were 6.7 times more likely to develop acute kidney injury compared with the other cohort. CONCLUSIONS: The combination of vancomycin with piperacillin/tazobactam significantly increases the risk of acute kidney injury compared with other broad spectrum antibiotic combinations. Clinicians should be vigilant when employing this regimen. PMID- 29442543 TI - Dolutegravir Dual Therapy as Maintenance Treatment in HIV-Infected Patients: A Review. AB - OBJECTIVE: To review available evidence for dolutegravir-based dual therapy as maintenance treatment in HIV-1 infected patients. DATA SOURCES: A literature search was conducted using PubMed, MEDLINE, and Google Scholar to the end of January 2018. Conference abstracts and article bibliographies were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language, randomized, and observational studies were included. DATA SYNTHESIS: In all, 12 studies were identified: 10 were observational, and 2 were randomized trials. Rilpivirine or lamivudine were the most common second agent used in combination with dolutegravir. Virological suppression seen in observational studies appear promising; however, the most compelling evidence to date is the 48-week results from 2 large open-label randomized trials (SWORD 1 and 2). These studies found that dual therapy with rilpivirine and dolutegravir was noninferior to 3- or 4 drug combination antiretroviral therapy (cART). The long-term efficacy, safety, and tolerability of dual therapy, as compared with usual cART, are less clear and require further data. CONCLUSIONS: Regimen switching in virally suppressed HIV-1 infected patients may be considered to reduce pill burden or dosing frequency, decrease short- or long-term toxicity, prevent or manage drug-drug interactions, and/or decrease cost. Based on available evidence, a switch to dual therapy with dolutegravir and rilpivirine appears viable for virologically suppressed patients without prior resistance mutations to these agents. Randomized studies of other dual-therapy regimens that include dolutegravir and longer-term follow-up as well as cost-effectiveness analyses are needed to provide confirmation that this strategy offers advantages to traditional cART regimens. PMID- 29442544 TI - Pyridoxine Add-On Treatment for the Control of Behavioral Adverse Effects Induced by Levetiracetam in Children: A Case-Control Prospective Study. AB - BACKGROUND: Few studies on adult and pediatric patients have shown pyridoxine efficacy as additional therapy for those receiving levetiracetam (LEV) to prevent and mitigate behavioral adverse effects (BAEs). OBJECTIVE: The aim of our study was to analyze the safety and efficacy of pyridoxine supplementation in the prevention of LEV adverse effects, including suicidal ideation. METHODS: This randomized, case-control trial included patients receiving LEV as monotherapy treatment. Patients were subdivided into 2 groups, according to whether they were treated with LEV only (group 1) or LEV with supplemental pyridoxine (group 2). RESULTS: In both cohorts, the most frequent BAEs were irritability/aggression followed by depression and confusion. Those patients (92%) who initiated pyridoxine after 1 month of LEV treatment did not need to change or suspend LEV ( P < 0.001), and BAE improved after 9.06 +/- 3.05 days of pyridoxine supplementation. None of the patients complained of symptoms of pyridoxine toxicity, and no new adverse effects of LEV off-label were reported. CONCLUSIONS: In our study, we found pyridoxine to be safe and effective in controlling LEV induced BAEs in children. PMID- 29442545 TI - Novel compound heterozygous CLCNKB gene mutations (c.1755A>G/c.848_850delTCT) cause classic Bartter syndrome. AB - Inactivated variants in CLCNKB gene encoding the basolateral chloride channel ClC Kb cause classic Bartter syndrome characterized by hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism. Here, we identified two cBS siblings presenting hypokalemia in a Chinese family due to novel compound heterozygous CLCNKB mutations (c.848_850delTCT/c.1755A>G). Compound heterozygosity was confirmed by amplifying and sequencing the patient's genomic DNA. The synonymous mutation c.1755A>G (Thr585Thr) was located at +2 bp from the 5' splice donor site in exon 15. Further transcript analysis demonstrated that this single nucleotide mutation causes exclusion of exon 15 in the cDNA from the proband and his mother. Furthermore, we investigated the expression and protein trafficking change of c.848_850delTCT (DeltaTCT) and exon 15 deletion (DeltaE15) mutation in vitro. The DeltaE15 mutation markedly decreased the expression of ClC Kb and resulted in a low-molecular-weight band (~55 kDa) trapping in the endoplasmic reticulum, while the DeltaTCT mutant only decreased the total and plasma membrane ClC-Kb protein expression but did not affect the subcellular localization. Finally, we studied the physiological functions of mutations by using whole cell patch-clamp and found that the DeltaE15 or DeltaTCT mutation decreased the current of the ClC-Kb/barttin channel. These results suggested that the compound defective mutations of the CLCNKB gene are the molecular mechanism of the two cBS siblings. PMID- 29442546 TI - VEGF therapy for the kidney: emerging strategies. AB - Renovascular disease (RVD), which is prevalent in the elderly, significantly increases cardiovascular risk and can progressively deteriorate renal function. The loss of renal function in patients with RVD is associated with a progressive dysfunction, damage, and loss of renal microvessels, which can be combined with decreased renal bioavailability of vascular endothelial growth factor (VEGF) and a defective vascular repair and proliferation. This association has been the impetus for recent efforts that have focused on developing methods to stop the progression of renal injury by protecting the renal microvasculature. This mini review focuses on recent studies supporting potential applications of VEGF therapy for the kidney and discusses underlying mechanisms of renoprotection. PMID- 29442547 TI - Role of the serotonergic system in urethral continence reflexes during sneezing in rats. AB - To clarify the role of serotonin (5-HT) in the prevention of stress urinary incontinence (SUI) during sneezing, we investigated the effect of intraperitoneal application of p-chlorophenylalanine (PCPA; a serotonin synthesis inhibitor) and intravenous application of CP-809101 (a 5-HT2C agonist) or LP44 (a 5-HT7 agonist) using female rats, in which the neurally evoked continence reflex during sneezing was examined. Amplitudes of urethral pressure response during sneezing (A-URS), urethral baseline pressure (UBP) at the middle urethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats with or without drug administration. PCPA decreased A-URS by 35.1 cmH2O and UBP by 13.3 cmH2O compared with normal rats. In PCPA-administrated rats, CP-809101 increased A-URS by 24.1 cmH2O and UBP by 15.1 cmH2O, and LP44 also increased A-URS by 20.6 cmH2O and UBP by 11.4 cmH2O compared with rats treated with PCPA alone. SUI was observed with S-LPP of 40.1 cmH2O in PCPA-administrated rats, in which CP-809101 and LP44 increased S-LPP by 28.0 and 15.2 cmH2O, respectively, compared with rats treated with PCPA alone. The effects of CP-809101 and LP44 were antagonized by SB 242084 (a selective 5-HT2C antagonist) and SB-269970 (a selective 5-HT7 antagonist), respectively. These results indicate that activation of 5-HT receptors enhances the active urethral closure reflex during sneezing, at least in part via 5-HT2C and 5-HT7 receptors. PMID- 29442550 TI - Framing Suicide - Investigating the News Media and Public's Use of the Problematic Suicide Referents Freitod and Selbstmord in German-Speaking Countries. AB - BACKGROUND: In German-speaking countries, suicide experts recommend not using the suicide referents Freitod and Selbstmord, as their associative meanings relate to problematic concepts such as free will and crime. AIMS: To investigate which terms - the neutral and recommended Suizid or Freitod and Selbstmord - have dominated news coverage and to reveal what terms the public actually used. METHOD: A retrospective database study was undertaken on data from the period 2004-2016. First, we investigated how frequently the terms were used in news coverage via an automated content analysis. Second, we investigated how often individuals used the terms for information-seeking via Google's search engine, since it can be used as an indicator of the popularity of a given term within a given period. RESULTS: Analyses revealed that Selbstmord was the most frequently used term in the news and by the public. Importantly, the use of Suizid increased in both datasets, nearly approaching the Selbstmord level in the later years. Although on a low level, the highly problematic term Freitod has also been in regular use. CONCLUSION: Media interventions should continue trying to increase journalists' awareness so that they use appropriate terms when reporting on suicide. PMID- 29442549 TI - Age at Exposure to Parental Suicide and the Subsequent Risk of Suicide in Young People. AB - BACKGROUND: We investigated the age at exposure to parental suicide and the risk of subsequent suicide completion in young people. The impact of parental and offspring sex was also examined. METHOD: Using a cohort study design, we linked Taiwan's Birth Registry (1978-1997) with Taiwan's Death Registry (1985-2009) and identified 40,249 children who had experienced maternal suicide (n = 14,431), paternal suicide (n = 26,887), or the suicide of both parents (n = 281). Each exposed child was matched to 10 children of the same sex and birth year whose parents were still alive. This yielded a total of 398,081 children for our non exposed cohort. A Cox proportional hazards model was used to compare the suicide risk of the exposed and non-exposed groups. RESULTS: Compared with the non exposed group, offspring who were exposed to parental suicide were 3.91 times (95% confidence interval [CI] = 3.10-4.92 more likely to die by suicide after adjusting for baseline characteristics. The risk of suicide seemed to be lower in older male offspring (HR = 3.94, 95% CI = 2.57-6.06), but higher in older female offspring (HR = 5.30, 95% CI = 3.05-9.22). Stratified analyses based on parental sex revealed similar patterns as the combined analysis. LIMITATIONS: As only register--based data were used, we were not able to explore the impact of variables not contained in the data set, such as the role of mental illness. CONCLUSION: Our findings suggest a prominent elevation in the risk of suicide among offspring who lost their parents to suicide. The risk elevation differed according to the sex of the afflicted offspring as well as to their age at exposure. PMID- 29442551 TI - Passing the Baton. PMID- 29442548 TI - Mechanisms of altered renal sodium handling in age-related hypertension. AB - The prevalence of hypertension rises with age to approximately two out of three adults over the age of 60 in the United States. Although the mechanisms underlying age-related hypertension are incompletely understood, sodium homeostasis is critical to the long-term regulation of blood pressure and there is strong evidence that aging is associated with alterations in renal sodium handling. This minireview focuses on recent advancements in our understanding of the vascular, neurohumoral, and renal mechanisms that influence sodium homeostasis and promote age-related hypertension. PMID- 29442554 TI - Neurogenesis: remembering all or forgetting some. AB - Research over the last 20 years has begun to elucidate the importance of adult neurogenesis in cognition. Three studies recently asked what might be happening to memories formed before neurogenesis in the hippocampus (Akers KG, Martinez Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang HL, Wheeler AL, Guskjolen A, Niibori Y, Shoji H, Ohira K, Richards BA, Miyakawa T, Josselyn SA, Frankland PW. Science 344: 598-602, 2014; Epp JR, Silva Mera R, Kohler S, Josselyn SA, Frankland PW. Nat Commun 7: 10838, 2016; Kodali M, Megahed T, Mishra V, Shuai B, Hattiangady B, Shetty AK. J Neurosci 36: 8112-8122, 2016). These studies found conflicting results: running (which increases neurogenesis) induced forgetting in two studies, but there was no difference in memory retrieval after exercise in another. To reconcile these studies, one must understand the processes behind memory maintenance and recall and consider context, species, and other factors. PMID- 29442553 TI - Phase reorganization leads to transient beta-LFP spatial wave patterns in motor cortex during steady-state movement preparation. AB - Previous studies on the origin and properties of spatial patterns in motor cortex beta-local field potential (beta-LFP) oscillations have focused on planar traveling waves. However, it is unclear 1) whether beta-LFP waves are limited to plane waves, or even 2) whether they are propagating waves of excito-excitatory activity, i.e., primarily traveling waves in excitable media; they could reflect, instead, reorganization in the relative phases of transient oscillations at different spatial sites. We addressed these two problems in beta-LFPs recorded via microelectrode arrays implanted in three adjacent motor cortex areas of nonhuman primates during steady-state movement preparation. Our findings are fourfold: 1) beta-LFP wave patterns emerged as transient events, despite stable firing rates of single neurons concurrently recorded during the same periods. 2) beta-LFP waves showed a richer variety of spatial dynamics, including rotating and complex waves. 3) beta-LFP wave patterns showed no characteristic wavelength, presenting instead a range of scales with global zero-lag phase synchrony as a limiting case, features surprising for purely excito-excitatory waves but consistent with waves in coupled oscillator systems. 4) Furthermore, excito excitatory traveling waves induced by optogenetic stimulation in motor cortex showed, in contrast, a characteristic wavelength and reduced phase synchrony. Overall, beta-LFP wave statistics differed from those of induced traveling waves in excitable media recorded under the same microelectrode array setup. Our findings suggest phase reorganization in neural coupled oscillators contribute significantly to the origin of transient beta-LFP spatial dynamics during preparatory steady states and outline important constraints for spatially extended models of beta-LFP dynamics in motor cortex. NEW & NOTEWORTHY We show that a rich variety of transient beta-local field potential (beta-LFP) wave patterns emerge in motor cortex during preparatory steady states, despite stable neuronal firing rates. Furthermore, unlike optogenetically induced traveling waves, beta-LFP waves showed no characteristic wavelength, presenting instead a range of scales with global phase synchrony as a limiting case. Overall, our statistical analyses suggest that transient phase reorganization in neural coupled oscillators, beyond purely excito-excitatory traveling waves, contribute significantly to the origin of motor cortex beta-LFP wave patterns. PMID- 29442556 TI - Neural correlates of economic value and valuation context: an event-related potential study. AB - The value of environmental cues and internal states is continuously evaluated by the human brain, and it is this subjective value that largely guides decision making. The present study aimed to investigate the initial value attribution process, specifically the spatiotemporal activation patterns associated with values and valuation context, using electroencephalographic event-related potentials (ERPs). Participants completed a stimulus rating task in which everyday household items marketed up to a price of L4 were evaluated with respect to their desirability or material properties. The subjective values of items were evaluated as willingness to pay (WTP) in a Becker-DeGroot-Marschak auction. On the basis of the individual's subjective WTP values, the stimuli were divided into high- and low-value items. Source dipole modeling was applied to estimate the cortical sources underlying ERP components modulated by subjective values (high vs. low WTP) and the evaluation condition (value-relevant vs. value irrelevant judgments). Low-WTP items and value-relevant judgments both led to a more pronounced N2 visual evoked potential at right frontal scalp electrodes. Source activity in right anterior insula and left orbitofrontal cortex was larger for low vs. high WTP at ~200 ms. At a similar latency, source activity in right anterior insula and right parahippocampal gyrus was larger for value-relevant vs. value-irrelevant judgments. A stronger response for low- than high-value items in anterior insula and orbitofrontal cortex appears to reflect aversion to low valued item acquisition, which in an auction experiment would be perceived as a relative loss. This initial low-value bias occurs automatically irrespective of the valuation context. NEW & NOTEWORTHY We demonstrate the spatiotemporal characteristics of the brain valuation process using event-related potentials and willingness to pay as a measure of subjective value. The N2 component resolves values of objects with a bias toward low-value items. The value-related changes of the N2 component are part of an automatic valuation process. PMID- 29442555 TI - Direct intertectal inputs are an integral component of the bilateral sensorimotor circuit for behavior in Xenopus tadpoles. AB - The circuit controlling visually guided behavior in nonmammalian vertebrates, such as Xenopus tadpoles, includes retinal projections to the contralateral optic tectum, where visual information is processed, and tectal motor outputs projecting ipsilaterally to hindbrain and spinal cord. Tadpoles have an intertectal commissure whose function is unknown, but it might transfer information between the tectal lobes. Differences in visual experience between the two eyes have profound effects on the development and function of visual circuits in animals with binocular vision, but the effects on animals with fully crossed retinal projections are not clear. We tested the effect of monocular visual experience on the visuomotor circuit in Xenopus tadpoles. We show that cutting the intertectal commissure or providing visual experience to one eye (monocular visual experience) is sufficient to disrupt tectally mediated visual avoidance behavior. Monocular visual experience induces asymmetry in tectal circuit activity across the midline. Repeated exposure to monocular visual experience drives maturation of the stimulated retinotectal synapses, seen as increased AMPA-to-NMDA ratios, induces synaptic plasticity in intertectal synaptic connections, and induces bilaterally asymmetric changes in the tectal excitation-to-inhibition ratio (E/I). We show that unilateral expression of peptides that interfere with AMPA or GABAA receptor trafficking alters E/I in the transfected tectum and is sufficient to degrade visuomotor behavior. Our study demonstrates that monocular visual experience in animals with fully crossed visual systems produces asymmetric circuit function across the midline and degrades visuomotor behavior. The data further suggest that intertectal inputs are an integral component of a bilateral visuomotor circuit critical for behavior. NEW & NOTEWORTHY The developing optic tectum of Xenopus tadpoles represents a unique circuit in which laterally positioned eyes provide sensory input to a circuit that is transiently monocular, but which will be binocular in the animal's adulthood. We challenge the idea that the two lobes of tadpole optic tectum function independently by testing the requirement of interhemispheric communication and demonstrate that unbalanced sensory input can induce structural and functional plasticity in the tectum sufficient to disrupt function. PMID- 29442557 TI - Reference frames in the decisions of hand choice. AB - For the brain to decide on a reaching movement, it needs to select which hand to use. A number of body-centered factors affect this decision, such as the anticipated movement costs of each arm, recent choice success, handedness, and task demands. While the position of each hand relative to the target is also known to be an important spatial factor, it is unclear which reference frames coordinate the spatial aspects in the decisions of hand choice. Here we tested the role of gaze- and head-centered reference frames in a hand selection task. With their head and gaze oriented in different directions, we measured hand choice of 19 right-handed subjects instructed to make unimanual reaching movements to targets at various directions relative to their body. Using an adaptive procedure, we determined the target angle that led to equiprobable right/left hand choices. When gaze remained fixed relative to the body this balanced target angle shifted systematically with head orientation, and when head orientation remained fixed this choice measure shifted with gaze. These results suggest that a mixture of head- and gaze-centered reference frames is involved in the spatially guided decisions of hand choice, perhaps to flexibly bind this process to the mechanisms of target selection. NEW & NOTEWORTHY Decisions of target and hand choice are fundamental aspects of human reaching movements. While the reference frames involved in target choice have been identified, it is unclear which reference frames are involved in hand selection. We tested the role of gaze- and head-centered reference frames in a hand selection task. Findings emphasize the role of both spatial reference frames in the decisions of hand choice, in addition to known body-centered computations such anticipated movement costs and handedness. PMID- 29442558 TI - Progression of convulsive and nonconvulsive seizures during epileptogenesis after pilocarpine-induced status epilepticus. AB - Although convulsive seizures occurring during pilocarpine-induced epileptogenesis have received considerable attention, nonconvulsive seizures have not been closely examined, even though they may reflect the earliest signs of epileptogenesis and potentially guide research on antiepileptogenic interventions. The definition of nonconvulsive seizures based on brain electrical activity alone has been controversial. Here we define and quantify electrographic properties of convulsive and nonconvulsive seizures in the context of the acquired epileptogenesis that occurs after pilocarpine-induced status epilepticus (SE). Lithium-pilocarpine was used to induce the prolonged repetitive seizures characteristic of SE; when SE was terminated with paraldehyde, seizures returned during the 2-day period after pilocarpine treatment. A distinct latent period ranging from several days to >2 wk was then measured with continuous, long-term video-EEG. Nonconvulsive seizures dominated the onset of epileptogenesis and consistently preceded the first convulsive seizures but were still present later. Convulsive and nonconvulsive seizures had similar durations. Postictal depression (background suppression of the EEG) lasted for >100 s after both convulsive and nonconvulsive seizures. Principal component analysis was used to quantify the spectral evolution of electrical activity that characterized both types of spontaneous recurrent seizures. These studies demonstrate that spontaneous nonconvulsive seizures have electrographic properties similar to convulsive seizures and confirm that nonconvulsive seizures link the latent period and the onset of convulsive seizures during post-SE epileptogenesis in an animal model. Nonconvulsive seizures may also reflect the earliest signs of epileptogenesis in human acquired epilepsy, when intervention could be most effective. NEW & NOTEWORTHY Nonconvulsive seizures usually represent the first bona fide seizure following a latent period, dominate the early stages of epileptogenesis, and change in severity in a manner consistent with the progressive nature of epileptogenesis. This analysis demonstrates that nonconvulsive and convulsive seizures have different behavioral outcomes but similar electrographic signatures. Alternatively, epileptiform spike-wave discharges fail to recapitulate several key seizure features and represent a category of electrical activity separate from nonconvulsive seizures in this model. PMID- 29442560 TI - Optical study of interactions among propagation waves of neural excitation in the rat somatosensory cortex evoked by forelimb and hindlimb stimuli. AB - Multisite optical recording has revealed that the neural excitation wave induced by a sensory stimulation begins at a focus and propagates in the cortex. This wave is considered to be important for computation in the sensory cortex, particularly the integration of sensory information; however, the nature of this wave remains largely unknown. In the present study, we examined the interaction between two waves in the rat sensory cortex induced by hindlimb and forelimb stimuli with different interstimulus intervals. We classified the resultant patterns as follows: 1) the collision of two waves, 2) the hindlimb response being evoked while the forelimb-induced wave is passing the hindlimb focus, and 3) the hindlimb response being evoked after the forelimb-induced wave has passed the hindlimb focus. In pattern 1, the two waves fused into a single wave, but the propagation pattern differed from that predicted by the superimposition of two singly induced propagation courses. In pattern 2, the state of the interaction between the two waves varied depending on the phase of optical signals constituting the forelimb-induced wave around the hindlimb focus. Although no hindlimb-induced wave was observed in the rising phase, the propagating velocity of the forelimb-induced wave increased. At the peak, neither the hindlimb-induced response nor a modulatory effect on the forelimb-induced wave was detected. In pattern 3, the hindlimb-induced wave showed a reduced amplitude and spatial extent. These results indicate that the state of the interaction between waves was strongly influenced by the relative timing of sensory inputs. NEW & NOTEWORTHY Sensory stimulation-induced cortical excitation propagates as a wave and spreads over a wide area of the sensory cortex. To elucidate the characteristics of this relatively unknown phenomenon, we examined the interaction between two individually induced waves in the somatosensory cortex. Either the waves collided or the preceding wave affected the emergence of the following one. Our results indicate that the state of the interaction was strongly influenced by the relative timing of sensory inputs. PMID- 29442561 TI - New 2006 Current Procedural Terminology Codes for Drug Administration. PMID- 29442562 TI - The ASCO Foundation and the Hurricane Relief Fund: A Critical Collaboration. PMID- 29442563 TI - Clinical Co-Management: Hospitals and Oncologists Working Together. PMID- 29442564 TI - Tools You Can Use: Helping Your Patients Quit Smoking. PMID- 29442565 TI - Health Subcommittee Chairman Takes Lead on Cancer Care: Interview With Rep. Nathan Deal. PMID- 29442567 TI - Clinical Trials Participation Awards Presented to Practices in Canada, New York, and North Carolina. PMID- 29442566 TI - Erratum. PMID- 29442569 TI - CMS Announces 2006 Medicare Oncology Demonstration Project. PMID- 29442559 TI - Neural mechanisms of navigation involving interactions of cortical and subcortical structures. AB - Animals must perform spatial navigation for a range of different behaviors, including selection of trajectories toward goal locations and foraging for food sources. To serve this function, a number of different brain regions play a role in coding different dimensions of sensory input important for spatial behavior, including the entorhinal cortex, the retrosplenial cortex, the hippocampus, and the medial septum. This article will review data concerning the coding of the spatial aspects of animal behavior, including location of the animal within an environment, the speed of movement, the trajectory of movement, the direction of the head in the environment, and the position of barriers and objects both relative to the animal's head direction (egocentric) and relative to the layout of the environment (allocentric). The mechanisms for coding these important spatial representations are not yet fully understood but could involve mechanisms including integration of self-motion information or coding of location based on the angle of sensory features in the environment. We will review available data and theories about the mechanisms for coding of spatial representations. The computation of different aspects of spatial representation from available sensory input requires complex cortical processing mechanisms for transformation from egocentric to allocentric coordinates that will only be understood through a combination of neurophysiological studies and computational modeling. PMID- 29442568 TI - Copayment Assistance Programs: The Landscape Today and After Part D. PMID- 29442570 TI - New Content on PLWC to Share With Your Patients. PMID- 29442571 TI - JCO's 2006 Special Series: Translational Oncology Series Debuts, Editors Announce Review Series Topics. PMID- 29442573 TI - The R.A. Bloch Cancer Foundation. PMID- 29442572 TI - Enhancing Oncology's Business Case: How the Hospital Can Help. PMID- 29442574 TI - ASCO Clinical Practice Guidelines: Frequently Asked Questions. PMID- 29442575 TI - The Gender-Equality Paradox in Science, Technology, Engineering, and Mathematics Education. AB - The underrepresentation of girls and women in science, technology, engineering, and mathematics (STEM) fields is a continual concern for social scientists and policymakers. Using an international database on adolescent achievement in science, mathematics, and reading ( N = 472,242), we showed that girls performed similarly to or better than boys in science in two of every three countries, and in nearly all countries, more girls appeared capable of college-level STEM study than had enrolled. Paradoxically, the sex differences in the magnitude of relative academic strengths and pursuit of STEM degrees rose with increases in national gender equality. The gap between boys' science achievement and girls' reading achievement relative to their mean academic performance was near universal. These sex differences in academic strengths and attitudes toward science correlated with the STEM graduation gap. A mediation analysis suggested that life-quality pressures in less gender-equal countries promote girls' and women's engagement with STEM subjects. PMID- 29442576 TI - Cabozantinib and Vandetanib in medullary thyroid carcinoma: mitochondrial function and its potential as a therapeutic target towards novel strategies to design anti-CSCs drugs. PMID- 29442578 TI - Distinct Trophic Specializations Affect How Phytophthora ramorum and Clade 6 Phytophthora spp. Colonize and Persist on Umbellularia californica Leaves in Streams. AB - Phytophthora spp. are regularly recovered from streams but their ecology in aquatic environments is not well understood. Phytophthora ramorum, invasive in California forests, persists in streams at times when sporulation in the canopy is absent, suggesting that it reproduces in the water. Streams are also inhabited by resident, clade 6 Phytophthora spp., believed to be primarily saprotrophic. We conducted experiments to determine whether differences of trophic specialization exist between these two taxa, and investigated how this may affect their survival and competition on stream leaf litter. P. ramorum effectively colonized fresh (live) rhododendron leaves but not those killed by freezing or drying, whereas clade 6 species colonized all leaf types. However, both taxa were recovered from naturally occurring California bay leaf litter in streams. In stream experiments, P. ramorum colonized bay leaves rapidly at the onset; however, colonization was quickly succeeded by clade 6 species. Nevertheless, both taxa persisted in leaves over 16 weeks. Our results confirm that clade 6 Phytophthora spp. are competent saprotrophs and, though P. ramorum could not colonize dead tissue, early colonization of suitable litter allowed it to survive at a low level in decomposing leaves. PMID- 29442580 TI - The Association of Community Cancer Centers: Providing Advocacy and Education for the Multidisciplinary Cancer Care Team. PMID- 29442577 TI - High Rate of Return to Yoga for Athletes After Hip Arthroscopy for Femoroacetabular Impingement Syndrome. AB - BACKGROUND: Femoroacetabular impingement syndrome (FAIS) is most commonly diagnosed in patients who perform activities that require repetitive hip flexion and rotational loading. Yoga is an activity growing in popularity that involves these motions. The purpose of this study was to evaluate patients' ability to return to yoga after hip arthroscopy for FAIS. HYPOTHESIS: There would be a high rate of return to yoga after hip arthroscopy. STUDY DESIGN: Retrospective analysis. LEVEL OF EVIDENCE: Level 4. METHODS: Consecutive patients with FAIS who had identified themselves as participating in yoga and had undergone hip arthroscopy for the treatment of FAIS between 2012 and 2015 were reviewed. Demographic data were collected and assessed for all patients, as well as preoperative physical examination, imaging, and patient-reported outcome (PRO) scores, including the modified Harris Hip Score (mHHS), Hip Outcome Score Activities of Daily Living (HOS-ADL) and Sports-Specific (HOS-SS) subscales, and visual analog scale (VAS) for pain. Postoperatively, examination and PRO data were collected at a minimum 1 year after surgery, including a yoga-specific questionnaire. RESULTS: A total of 42 patients (90% female; mean age, 35 +/- 9 years; mean body mass index, 23.1 +/- 3.2 kg/m2) were included. Thirty patients (71%) had to discontinue their yoga routine preoperatively because of hip-related symptoms at a mean 9.5 +/- 8.2 months before surgery. After surgery, 39 patients (93%) were able to return to yoga at a mean 5.3 +/- 2.2 months after surgery. Two of the 3 patients who did not return to yoga noted loss of interest as their reason for stopping, while 1 patient was unable to return because of persistent hip pain. Nineteen patients (45%) returned to a higher level of yoga practice, 17 patients (40%) returned to the same level, and 3 patients (7%) returned to a lower level. There was no difference in the number of hours spent practicing yoga per week pre- and postoperatively (2.7 +/- 1.9 vs 2.5 +/- 1.3 hours; P = 0.44). All patients demonstrated significant improvement in all PROs as well as pain scores after surgery (HOS-ADL, 67.4 +/- 18.3 to 93.1 +/- 6.9 [ P < 0.001]; HOS SS, 45.6 +/- 24.7 to 81.5 +/- 18.8 [ P < 0.001]; mHHS, 62.3 +/- 11.3 to 86.8 +/- 12.3 [ P < 0.0001]; VAS pain, 6.3 +/- 2.2 to 0.90 +/- 1.1 [ P < 0.001]). CONCLUSION: Patients participating in yoga return to yoga 93% of the time and at a mean 5.3 +/- 2.2 months after hip arthroscopy for FAIS. CLINICAL RELEVANCE: Information regarding surgical outcomes is critical in counseling patients, particularly female athletes, on their expectations with respect to returning to yoga after hip arthroscopy for FAIS. PMID- 29442581 TI - Colon Cancer Surveillance. PMID- 29442579 TI - Changes in Cryphonectria parasitica Populations Affect Natural Biological Control of Chestnut Blight. AB - Invasive species, especially plant pathogens, have a potential to completely eradicate native plant species and remodel landscapes. Tripartite interactions among sweet chestnut (Castanea sativa), chestnut blight-causing invasive fungus Cryphonectria parasitica, and hyperparasitic virus Cryphonectria hypovirus 1 (CHV1) were studied in two populations. The number of different vegetative compatibility (vc) types of C. parasitica more than doubled over the 10 years, while the hypovirulence incidence dropped in one population and slightly increased in the other one. Over the course of our 3-year monitoring experiment, the prevalence of hypovirulent isolates obtained from monitored cankers increased slowly (i.e., more hypovirulent isolates were being obtained from the same cankers over time). Within studied cankers, considerable changes in vc type and CHV1 presence were observed, indicating a highly dynamic system in which virulent and hypovirulent mycelia, sometimes of discordant vc types, often appeared together. The increase in hypovirulence prevalence did not have any observable curative effect on the cankers and, occasionally, reactivation of healed cankers by new, virulent C. parasitica isolates was observed. Both short- and long-term observations and revalidation of the infected plant populations are necessary to accurately estimate disease progress and formulate an adequate disease management strategy. PMID- 29442582 TI - The 2005 ASCO Clinical Trials Participation Awards. PMID- 29442583 TI - ASCO Guideline Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: Guideline Summary. PMID- 29442584 TI - 2005 Update of ASCO Practice Guideline Recommendations for Colorectal Cancer Surveillance: Guideline Summary. PMID- 29442585 TI - Carrier Advisory Committee Network Meeting 2005 Focuses on Key Issues in Medicare Coverage. PMID- 29442586 TI - ASCO's Legislative Conference: NCI, FDA, and CMS Outline Projects to Enhance the Quality of Cancer Care. PMID- 29442587 TI - Katrina and ASCO: Lessons to be Learned. PMID- 29442588 TI - Alliance for Childhood Cancer: Addressing the Needs of Children With Cancer. PMID- 29442589 TI - Staff Training: How to Meet OSHA Requirements. PMID- 29442590 TI - Proposed Restructuring of NCI Clinical Trials System Calls for Increased Role of Community Oncologists: An Interview With James H. Doroshow, MD. PMID- 29442591 TI - Can Hospitals Share Cost Savings With Their Oncologists? PMID- 29442592 TI - Is Source Information Automatically Available in Working Memory? AB - We often remember information without its source (e.g., word or picture format). This phenomenon has been studied extensively in long-term memory but rarely in the context of short-term working memory (WM), which leaves open the question of whether source amnesia can result from a lack of memory encoding rather than forgetting. This study provided a series of striking and novel demonstrations showing participants' inability to report the source of a color representation immediately after that color was used in a task and stored in memory. These counterintuitive findings occurred when participants repeatedly judged the congruency between two color representations from one single object (i.e., color and identity of a color word) or two distinct objects (i.e., color of a square and identity of a color word) and then were unexpectedly asked to report the source of one color representation. These discoveries suggest that source information is often not stored in WM. PMID- 29442593 TI - Reward motivation in humans and its relationship to dopamine D2/3 receptor availability: A pilot study with dual [11C]-raclopride and [11C]-(+)-PHNO imaging. AB - Rodent studies suggest that dopamine signaling at D2/3 receptors in the ventral striatum is critical for reward motivation. Whether this is also true in humans is unclear. Positron emission tomography studies in healthy humans have generally not observed a relationship between D2/3 receptor availability in the ventral striatum and motivation. We developed the "mounting-effort for reward task" to assess high motivational demand for (a) gaining money (CS+), (b) losing money or avoiding electric shock (CS-), and (c) non-reward (Neutral). Receipt was contingent on participants making sufficient button responses relative to a "reward-threshold" determined by prior motor performance. This reward-threshold was dynamically increased if surpassed, making the task increasingly more difficult on every trial. The mounting-effort for reward task was preliminarily validated in 29 healthy volunteers (mean age: 25.83+/-3.58; 15 female). In this sample, %CS+ and %CS- significantly correlated with different dimensions of self reported apathy. In a sub-sample of eight healthy volunteers (mean age: 25.75+/ 1.91; four female), the mounting-effort for reward task demonstrated good test retest reliability (%variance: 0.20-2.61%). Seven healthy male volunteers (mean age: 31.14+/-5.43) completed the mounting-effort for reward task and provided both [11C]-raclopride and [11C]-(+)-PHNO PET scans to assess D2/3 receptor availability. %CS+ and %CS- were positively correlated with [11C]-raclopride binding in the dorsal striatum. %CS+, %Cs-, and %Neutral were positively correlated with [11C]-(+)-PHNO binding in the globus pallidus. Thus, increased expression of D2 receptors in the dorsal striatum, and D3 receptors in the globus pallidus, may be related to motivation for rewards. Larger positron emission tomography studies are required to formally validate the mounting-effort for reward task and replicate our pilot findings. PMID- 29442596 TI - Oncology Education for Nurse Practitioners and Physician Assistants. PMID- 29442597 TI - Us TOO Network: Helping Patients and Caregivers Cope With Prostate Cancer. PMID- 29442598 TI - Patient-Friendly ASCO Cancer Prevention Curriculum on PLWC.org. PMID- 29442599 TI - ERRATUM. PMID- 29442601 TI - ERRATUM. PMID- 29442600 TI - Using an Electronic Health Record for Research. PMID- 29442602 TI - In Memoriam: Christopher E. Desch, MD. PMID- 29442603 TI - Who Will Take Care of Us When We Get Sick? PMID- 29442604 TI - State Affiliate Grant Program. PMID- 29442595 TI - Dietary Modulation of the Epigenome. AB - Epigenetics is the study of heritable mechanisms that can modify gene activity and phenotype without modifying the genetic code. The basis for the concept of epigenetics originated more than 2,000 yr ago as a theory to explain organismal development. However, the definition of epigenetics continues to evolve as we identify more of the components that make up the epigenome and dissect the complex manner by which they regulate and are regulated by cellular functions. A substantial and growing body of research shows that nutrition plays a significant role in regulating the epigenome. Here, we critically assess this diverse body of evidence elucidating the role of nutrition in modulating the epigenome and summarize the impact such changes have on molecular and physiological outcomes with regards to human health. PMID- 29442605 TI - Malpractice Insurance: What You Need to Know. PMID- 29442606 TI - CMS's Recovery Audit Contractor Initiative. PMID- 29442594 TI - Pharmacoperones as Novel Therapeutics for Diverse Protein Conformational Diseases. AB - After synthesis, proteins are folded into their native conformations aided by molecular chaperones. Dysfunction in folding caused by genetic mutations in numerous genes causes protein conformational diseases. Membrane proteins are more prone to misfolding due to their more intricate folding than soluble proteins. Misfolded proteins are detected by the cellular quality control systems, especially in the endoplasmic reticulum, and proteins may be retained there for eventual degradation by the ubiquitin-proteasome system or through autophagy. Some misfolded proteins aggregate, leading to pathologies in numerous neurological diseases. In vitro, modulating mutant protein folding by altering molecular chaperone expression can ameliorate some misfolding. Some small molecules known as chemical chaperones also correct mutant protein misfolding in vitro and in vivo. However, due to their lack of specificity, their potential as therapeutics is limited. Another class of compounds, known as pharmacological chaperones (pharmacoperones), binds with high specificity to misfolded proteins, either as enzyme substrates or receptor ligands, leading to decreased folding energy barriers and correction of the misfolding. Because many of the misfolded proteins are misrouted but do not have defects in function per se, pharmacoperones have promising potential in advancing to the clinic as therapeutics, since correcting routing may ameliorate the underlying mechanism of disease. This review will comprehensively summarize this exciting area of research, surveying the literature from in vitro studies in cell lines to transgenic animal models and clinical trials in several protein misfolding diseases. PMID- 29442607 TI - Use of Clinical Practice Guidelines in Medical Malpractice Litigation. PMID- 29442608 TI - Local Versus National Medicare Coverage. PMID- 29442610 TI - Balancing statistical and ethical considerations in planning clinical trials: recommendations for response-adaptive randomization urn designs. AB - During a clinical trial, balancing statistical and ethical considerations are important. Response-adaptive randomization methods use the information from past patients to increase the probability of the next patient receiving the better treatment while avoiding the statistical concern of selection bias. We compared three response-adaptive randomization urn designs, Randomized Play-the-Winner, Modified Play-the-Winner, and Birth-and-Death Urn with Immigration, to the traditional equal allocation design with respect to power and allocation of patients to the better treatment. Because these designs have been described separately, our motivation was to systematically compare them and provide recommendations. With simulations, we varied sample size and combinations of treatment and control success probabilities. We also compared the response adaptive randomization designs using exact distribution algorithms and applied them to past clinical trial data that used an equal allocation design. We conclude that Modified Play-the-Winner tends to be unpredictable and can result in allocation of all of the patients to the better treatment. Randomized Play-the Winner allocates more patients to the better treatment than Birth-and-Death Urn with Immigration, but Birth-and-Death Urn with Immigration is more consistent in its allocations. Randomized Play-the-Winner and Birth-and-Death Urn with Immigration produce allocations that have comparable powers to equal allocation design. PMID- 29442609 TI - Caveat emptor: Folate in unipolar depressive illness, a systematic review and meta-analysis. AB - BACKGROUND: International guideline recommendations for the use of folate and its derivatives in the treatment of unipolar depressive disorders are confused and contradictory, perhaps reflecting wide variations in the underpinning evidence base. INTRODUCTION: We discuss differing methods of evidence synthesis in the formulation of international guideline recommendations. As an example we evaluated the efficacy of folate and its derivatives in unipolar depression via systematic review and meta-analysis. METHODS: We searched Medline, EMBASE, PsychInfo and CENTRAL from database inception until 1 May 2017 for randomised controlled trials. We included trials that evaluated folate or its derivatives as monotherapy or to augment antidepressant therapy compared with placebo in patients with unipolar depressive illness. Standardised mean differences were used and studies were introduced as subgroups to explain the heterogeneity. Quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation. RESULTS: No trials report on folate or methylfolate versus placebo as a monotherapeutic option. Only when the evidence was restricted to folate at a dose of <5 mg/day or methylfolate at a dose of 15 mg once daily as an adjunct to selective serotonin reuptake inhibitor therapy was there a significant benefit compared with placebo. All evidence was graded as low or very low quality for each outcome. DISCUSSION: Whilst previous guidelines on the treatment of unipolar depression have either avoided this topic entirely, or made recommendations on the basis of cherry-picked evidence, this review is the first to attempt to provide clinically useful recommendations based on comprehensive, current randomised placebo-controlled data. We invite discussion of the review and its recommendations, which are based on the limited evidence regarding folate formulation delivered and appropriate dosage. PMID- 29442611 TI - Relative toxicity of benzodiazepines and hypnotics commonly used for self poisoning: An epidemiological study of fatal toxicity and case fatality. AB - The relative toxicity of anxiolytic and hypnotic drugs commonly used for self poisoning was assessed using data on suicides, prescriptions and non-fatal self poisonings in England, 2005-2012. Data on suicide by self-poisoning were obtained from the Office for National Statistics, information on intentional non-fatal self-poisoning was derived from the Multicentre Study of Self-harm in England and data on prescriptions in general practice from the Clinical Practice Research Datalink. We used two indices of relative toxicity: fatal toxicity (the number of fatal self-poisonings relative to the number of individuals prescribed each drug) and case fatality (the number of fatal relative to non-fatal self-poisonings). Diazepam was the reference drug in all analyses. Temazepam was 10 times (95% confidence interval 5.48-18.99) and zopiclone/zolpidem nine times (95% confidence interval 5.01-16.65) more toxic in overdose than diazepam (fatal-toxicity index). Temazepam and zopiclone/zolpidem were 13 (95% confidence interval 6.97-24.41) and 12 (95% confidence interval 6.62-22.17) times more toxic than diazepam, respectively (case-fatality index). Differences in alcohol involvement between the drugs were unlikely to account for the findings. Overdoses of temazepam and zopiclone/zolpidem are considerably more likely to result in death than overdoses of diazepam. Practitioners need to exercise caution when prescribing these drugs, especially for individuals who may be at risk of self-harm, and also consider non pharmacological options. PMID- 29442612 TI - A Review of a Decade of Rugby Union Injury Epidemiology: 2007-2017. AB - CONTEXT: Rugby union is the most widely played team collision sport globally. As with other contact sports, there is substantial risk of injury. To date, the majority of studies on injury epidemiology have focused on elite male cohorts, which inherently prevents extrapolation of research findings to other groups within the player continuum. This review aims to describe emerging injury trends across the spectrum of various rugby union subpopulations and to highlight gaps that may influence future injury prevention tactics. EVIDENCE ACQUISITION: Relevant articles published from 2007 to 2017 were obtained by searching MEDLINE, PubMed, and SPORT Discus. Studies on 15-a-side rugby union, implemented according to the 2007 consensus statement on injury definitions and data collection procedures for injuries in rugby union, were used. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: Match injuries occur more frequently than training injuries. Injury rates increase consistently according to age and level of play. Severity of injury often is greater among lower levels of the game, and sex-specific differences relating to injury patterns and incidence rates exist. CONCLUSION: To date, a paucity of injury surveillance data exists for women and players of both sexes at all levels of community rugby union. Furthermore, the incidence of injuries and illnesses are poorly reported in epidemiological studies. Despite methodological differences, injury trends remain consistent throughout all levels of play. PMID- 29442613 TI - Beyond the 30-Million-Word Gap: Children's Conversational Exposure Is Associated With Language-Related Brain Function. AB - Children's early language exposure impacts their later linguistic skills, cognitive abilities, and academic achievement, and large disparities in language exposure are associated with family socioeconomic status (SES). However, there is little evidence about the neural mechanisms underlying the relation between language experience and linguistic and cognitive development. Here, language experience was measured from home audio recordings of 36 SES-diverse 4- to 6-year old children. During a story-listening functional MRI task, children who had experienced more conversational turns with adults-independently of SES, IQ, and adult-child utterances alone-exhibited greater left inferior frontal (Broca's area) activation, which significantly explained the relation between children's language exposure and verbal skill. This is the first evidence directly relating children's language environments with neural language processing, specifying both an environmental and a neural mechanism underlying SES disparities in children's language skills. Furthermore, results suggest that conversational experience impacts neural language processing over and above SES or the sheer quantity of words heard. PMID- 29442615 TI - Endovenous varicose vein treatment in patients with right heart failure and tricuspid valve regurgitation - A relative contraindication? PMID- 29442617 TI - Assembly of highly repetitive genomes using short reads: the genome of discrete typing unit III Trypanosoma cruzi strain 231. AB - Next-generation sequencing (NGS) methods are low-cost high-throughput technologies that produce thousands to millions of sequence reads. Despite the high number of raw sequence reads, their short length, relative to Sanger, PacBio or Nanopore reads, complicates the assembly of genomic repeats. Many genome tools are available, but the assembly of highly repetitive genome sequences using only NGS short reads remains challenging. Genome assembly of organisms responsible for important neglected diseases such as Trypanosoma cruzi, the aetiological agent of Chagas disease, is known to be challenging because of their repetitive nature. Only three of six recognized discrete typing units (DTUs) of the parasite have their draft genomes published and therefore genome evolution analyses in the taxon are limited. In this study, we developed a computational workflow to assemble highly repetitive genomes via a combination of de novo and reference based assembly strategies to better overcome the intrinsic limitations of each, based on Illumina reads. The highly repetitive genome of the human-infecting parasite T. cruzi 231 strain was used as a test subject. The combined-assembly approach shown in this study benefits from the reference-based assembly ability to resolve highly repetitive sequences and from the de novo capacity to assemble genome-specific regions, improving the quality of the assembly. The acceptable confidence obtained by analyzing our results showed that our combined approach is an attractive option to assemble highly repetitive genomes with NGS short reads. Phylogenomic analysis including the 231 strain, the first representative of DTU III whose genome was sequenced, was also performed and provides new insights into T. cruzi genome evolution. PMID- 29442618 TI - Core/Shell Structured Fe3O4@TiO2-DNM Nanospheres as Multifunctional Anticancer Platform: Chemotherapy and Photodynamic Therapy Research. AB - The dose-dependent toxicity and low specificity against cancerous cells have restricted the clinical use of daunomycin (DNM). Titanium dioxide (TiO2) has been wildly used as an inorganic photodynamic therapy (PDT) agent and drug carrier. To facilitate the targeted drug delivery and combined therapy, in the present study, TiO2-coated Fe3O4 nanoparticles (Fe3O4@TiO2 NPs) were employed to load DNM and the drug-loaded Fe3O4@TiO2-DNM Nps exhibited smart pH-controlled releasing and satisfactory cytotoxicity as well as photocytotocity. The combination of prussian blue staining and fluorescence methods evidenced the effortless cell internalization of the fabricated Fe3O4@TiO2-DNM Nps for the cancer cells. The cell cycle status experiments indicated that the as-prepared nanospheres arrested the S and G2/M periods of the cancer cell proliferation in the dark, and further induced the apoptosis under the irradiation of ultraviolet light. The cell apoptotic results revealed that the apoptosis induced by the Fe3O4@TiO2-DNM Nps was in the early stage. The constructed Fe3O4@TiO2-DNM NPs have been endowed with multifunctions that allow them to selectively deliver combinatorial therapeutic payload and exhibit integrated therapeutic effectiveness to tumors. PMID- 29442619 TI - One-Step Hydrothermal Approach to Synthesis Carbon Dots from D-Sorbitol for Detection of Iron(III) and Cell Imaging. AB - A facile and economic approach to synthesis highly fluorescence carbon dots (CDs) via one-step hydrothermal treatment of D-sorbitol was presented. The as synthesized CDs were characterized by good water solubility, well monodispersion, and excellent biocompatibility. Spherical CDs had a particle size about 5 nm and exhibited a quantum yield of 8.85% at excitation wavelength of 360 nm. In addition, the CDs can serve as fluorescent probe for sensitive and selective detection of Fe3+ ions with the detection limit of 1.16 MUM. Moreover, the potential of the as-prepared carbon dots for biological application was confirmed by employing it for fluorescence imaging in MCF-7 cells. PMID- 29442620 TI - A Dual pH/Magnetic Responsive Nanocarrier Based on PEGylated Fe3O4 Nanoparticles for Doxorubicin Delivery. AB - Cancer chemotherapy has limitations such as nonselective distribution of drugs, detrimental side effects on normal tissues; here we reported a smart pH and magnetic sensitive drug delivery system (DDS) based on PEGylated Fe3O4 superparamagnetic nanoparticles. The citric-coated Fe3O4 (CIO) nanoparticles were firstly synthesized and further functionalized by biocompatible poly(ethylene glycol) bis(carboxymethyl ether) (COOH-PEG-COOH), thus PEGylated CIO (GCIO) nanoparticles were obtained. Doxorubicin (DOX) was conjugated as a model drug to the nanoparticles via hydrazone bond. The roughly sphere GCIO nanoparticles were comparatively strong magnetism with high drug loading capability (~89%) in relatively uniform size. Drug release study revealed that the GCIO-DOX performed pH-responsive drug-release properties. MTT assay demonstrated that GCIO nanoparticles possessed low cytotoxicity and good physiological stability. Further, cell viability results indicated that the GCIO-DOX showed effective cytotoxicity only a bit lower than free DOX. All obtained data indicated that the combined pH-responsive and magnetic multifunction drug delivery system can has excellent potential applications in cancer therapy. PMID- 29442621 TI - Construction of Fluorescein Isothiocyanate-Labeled MSNs/PEG/Lycorine/Antibody as Drug Carrier for Targeting Prostate Cancer Cells. AB - Lycorine possesses various pharmacological effects, including anti-tumor, antiviral, anti-malarial and anti-inflammatory properties, as well as a potential therapeutic against prostate cancer cells. Therefore, a drug carrier of lycorine with good biocompatibility, high drug loading capacity and good release ability is required to develop to gain maximum benefit from lycorine to target cancer cells. In this study, MSNs labeled with FITC and PEG were synthesized. These FITC labeled MSNs/PEG/Lycorine/Antibody were loaded with lycorine and anti-EpCAM antibody, and analyzed for endocytosis, biocompatibility, drug loading and release ability. Furthermore, the effects of FITC-labeled MSNs/PEG/Lycorine/Antibody on PC-3M cell line were also investigated. The results revealed that the FITC-labeled MSNs/PEG/Lycorine/Antibody contained excellent biocompatibility, as well as efficiently penetrated into cancer cells. Moreover, the FITC-labeled MSNs/PEG/Lycorine/Antibody nano-composites exhibited excellent drug release ability and induced PC-3M cell death more quickly, as compared to the free lycorine, even at relatively lower concentrations. In conclusion, the FITC-labeled MSNs/PEG/Lycorine/Antibody developed in this study could be used as promising candidates of drug carriers of lycorine for cancer chemotherapy with maximization of anticancer efficacy and reduction of the undesirable side effects to normal cells. PMID- 29442622 TI - Chitosan Stabilized Gold-Folate-Poly(lactide-co-glycolide) Nanoplexes Facilitate Efficient Gene Delivery in Hepatic and Breast Cancer Cells. AB - The biodegradable polymer, poly(lactide-co-glycolide) is a popular polymer of choice in many nanotherapeutic studies. Herein, we report on the synthesis and evaluation of four chitosan stabilized poly(lactide-co-glycolide) nanoparticles with and without coating with gold, and the targeting ligand, folic acid, as potential non-viral gene delivery vectors. The poly(lactide-co-glycolide) nanoparticles were synthesized via nanoprecipitation/solvent evaporation method in conjunction with the surface functionalizing folic acid and chitosan. The physiochemical properties (morphology, particle size, zeta potential, folic acid/chitosan presence, DNA binding), and biological properties (nuclease protection, in vitro cytotoxicity and transfection potential in human kidney, hepatocellular carcinoma and breast adenocarcinoma cells), of all four gene bound nanoparticles were evaluated. Gel retardation assays confirmed that all the nanoparticles were able to successfully bind the reporter plasmid, pCMV-luc DNA at varying weight ratios. The gold-folate-poly(lactide-co-glycolide) nanoplexes with the highest binding efficiency (w/w ratio 4:1), best protected the plasmid DNA as evidenced from the nuclease protection assays. Furthermore, these nanoplexes presented as spherical particles with an average particle size of 199.4 nm and zeta potential of 35.7 mV. Folic acid and chitosan functionalization of the nanoparticles was confirmed by attenuated total reflection-Fourier transform infrared spectroscopy. All nanoplexes maintained over 90% cell viability in all cell lines investigated. Interestingly, the gold-folate poly(lactide-co-glycolide) nanoplexes showed a greater transgene activity in the hepatic and breast cancer cells compared to the other nanocomplexes in the same cell lines. The favorable size, colloidal stability, low cytotoxicity, significant transgene expression, and nuclease protection ability in vitro, all provide support for the use of gold-folate-poly(lactide-co-glycolide) nanoplexes in future gene therapy applications. PMID- 29442623 TI - Structural Characterization and Analysis of Human Immunodeficiency Virus Encapsulating Quantum Dots. AB - Virus internal labeling by inorganic nanoparticle is a suitable technique for single virus imaging. However, it is unknown that the effect of the internal inorganic nanoparticle on morphology and structure of viral core in mature enveloped Human immunodeficiency virus 1 (HIV-1). Also, the analysis of intact HIV-1 particles and virus-inorganic nanoparticle hybrids is almost impossible with conventional negative staining because HIV-1 is inherently fragile and unstable. Herein, we carried out morphological and structural analysis of a newly constructed quantum dot (QD)-encapsulated infectious HIV-1 particle by using an optimized procedure for the electron microscopic analysis of negatively stained HIV-1 particles. The virus fixation and staining conditions were optimized to ensure the integrity of HIV-1, allowing the ready access to structural information on the viral envelope and core. Morphological and structural analysis by optimized TEM provide key information about viruses, viral core and nanoparticles, which indicates that the encapsulation of quantum dots had no effect on the morphology or mean size of the viral particle, or on the shape, length, width, or angle of the HIV-1 core. PMID- 29442624 TI - Additive-Free Gold Nanoparticles Induced by Gamma Ray Irradiation for Voltammetric Detection of Dopamine. AB - In this paper, gold nanoparticles were obtained by gamma-ray irradiation in aqueous solution containing HAuCl4 as the precursor. The reaction generated particles that contained no foreign stabilizer. The additive-free gold nanoparticles were employed to modify glassy carbon electrode for the detection of dopamine in phosphate buffer solution. Electrochemical properties of the modified electrode were examined by cyclic voltammertry and electrochemical impedance spectroscopy. Linear analytical curves were obtained in the range from 2 to 120 MUM for dopamine by differential pulse voltammetry, with the detection limit of 0.13 MUM (signal-to-noise ratio of 3). The relatively simple synthetic method of the gold nanoparticles and excellent electrochemical performance with high reproducibility and stability of the detection were promising for further applications. PMID- 29442625 TI - Label-Free Silver Nanoparticles for the Determination of Gentamicin. AB - A new spectrophotometric method for the determination of gentamicin has been developed. The method is based on the aggregation of label-free silver nanoparticles leading to change in absorption spectra and color of the solution. Influence of different factors on the aggregation and analytical performance of the method were investigated. Results showed that the absorption ratio in 510 nm and 394 nm of silver nanoparticles was liner with gentamicin concentration in human urine samples in the range of 0.2-4.5 MUg/mL and the detection limit was calculated to be 0.16 MUg/mL. The proposed method is a promising mean for the detection of gentamicin in human urine, with the recovery between 97% and 103%. Compared with the reported methods for the determination of gentamicin, the method established in this paper is simple, rapid, cost-effective, intuitive and sensitive. PMID- 29442626 TI - Synthesis of Copper Nanowires and Their Antimicrobial Activity on Strains Isolated Persistent Endodontic Infections. AB - Copper nanowires, Cu-NWs may have a good antimicrobial effect in endodontic treatment. The objective of this work was to synthesize, characterize and evaluate the antibacterial activity of Cu-NWs on strains obtained from human root canal. A wide distribution of Cu-NWs diameters from 30 to 90 nm was obtained with lengths ranging from 5 to 40 MUm. Structural analysis of Cu-NWs showed crystalline planes, which corresponded to Cu, with preferential growth in the direction [110]. The geometric mean MICs was of 289.30 MUg/mL, with a MIC50 of 256 MUg/mL and a MIC90 of 512 MUg/mL for Cu-NWs. Cellular viability of 28 a biofilm tends to decrease the longer it is exposed to Cu-NWs. Synthesized and characterized Cu-NWs have a good antimicrobial effect against clinical strains used in the present study and has a potential to be used for disinfection of the root canal system. PMID- 29442627 TI - Studies on Mechanical, Biocompatibility and Antibacterial Activity of Plasma Sprayed Nano/Micron Ceramic Bilayered Coatings on Ti-6Al-4V Alloy for Biomedical Application. AB - Ceramic oxides such as alumina and zirconia are used to fabricate dental and orthopedic implants. However, their usage is limited as they fail due to low fracture toughness. To overcome this issue, ceramic coatings on metallic implants is attempted to have a combined effect of ceramics and metallic materials. This paper reports on the microstructure, phase analysis, mechanical properties, osseointegration and antibacterial activity of three different wear-resistant coatings developed on Ti-6Al-4V alloy which is used widely as orthopedic and dental implants. The powders of following compositions, i. Nanostructured Al2O3 + 13 wt% TiO2/MU-TiO2 BL coating (S1), ii. MU-Al2O3 + 13 wt% nanostructured TiO2/MU TiO2 BL coating (S2), iii. Nanostructured Al2O3 + 13 wt% TiO2/MU-YSZ BL coating (S3), were sprayed using atmospheric plasma spray process onto Ti-6Al-4V alloy. The coatings were characterized using X-ray diffraction (XRD), Scanning electron microscope (SEM), Profilometer and gonieometer to determine their phases, microstructure, surface roughness and contact angle. In addition, micro indentation hardness and scratch resistance were also evaluated. Amongst the three coatings, S2 exhibited higher hardness value with higher scratch resistance. The antibacterial activity was studied using colony formation on all three coatings. The antibacterial efficiency of S1 as well as S3 coatings was higher as seen from less number of bacterial colonies on the surface. The results of in-vitro studies on the biocompatibility of nano/micron alumina and zirconia ceramic coatings which were analyzed with hMSC's, reveals that S1 is cytotoxic with less number of cell attachment when compared to S2 and S3. PMID- 29442628 TI - Antibacterial Properties Enhancement of Layer-by-Layer Self-Assembled Nanofiltration Membranes. AB - Membrane technology is now being widely used in the field of water treatment for its unique advantages. Layer-by-layer (LbL) self-assembly technique is a convenient and versatile method of modified nanofiltration (NF) membranes fabrication, which can be used to control the thickness and the surface properties of membranes by chemical deposition of polyelectrolytes. Herein, a new kind of composite NF membrane with enhanced antibacterial properties was successfully fabricated through LbL self-assembly method, having polyether sulfone (PES) ultrafiltration (UF) membrane as support layer, N-[(2-hydroxy-3 trimethylammonium)propyl] chloride chitosan (HTCC) and polyacrylic acid (PAA) as active layer, and epichlorohydrin (ECH) as crosslinking reagent. Subsequently, nanosilver was finally loaded on the membrane surface by photoreduction technique. Our results revealed that the positively charged four semi-assembled membranes prepared using 5 g/L HTCC aqueous solution, 1 g/L PAA solution (pH = 6 8), and 0.5 g/L NaCl as supporting salt exhibited optimum performance. Atomic force microscopy and contact angle tests showed that the prepared membranes improved the surface roughness and hydrophilicity as compared to those of the polyether sulfone (PES) membranes. The retention test indicated that the (HTCC/PAA)4HTCC membranes exhibited highly-efficient removal of pharmaceuticals and personal care products in the order of Amlodipine > Atenolol > Carbamazepine > Ibuprofen. The X-ray Diffraction results confirmed the presence of nano-silver on the membrane surface. In addition, the prepared membranes exhibited excellent antibacterial activity, especially against gram-negative bacteria. PMID- 29442629 TI - Phase Competition Induced Bio-Electrochemical Resistance and Bio-Compatibility Effect in Nanocrystalline Zrx-Cu100-x Thin Films. AB - Nano-crystalline Zrx-Cu100-x (x = 20-100 at.%) thin films with thickness ranging from 50 to 185 nm were deposited by magnetron co-sputtering with individual Zr and Cu targets. The as-sputtered thin films were characterized by Field Emission Scanning Electron Microscope (FE-SEM), Atomic Force Microscopy (AFM) and Glancing Incidence X-ray Diffraction (GIXRD) for structural and morphological properties. The crystallite size was found to decrease from 57 nm to 37 nm upon increasing the Zr content from 20 to 30 at.% with slight increase in the lattice strain from 0.17 to 0.33%. Further, increase in Zr content to 40 at.% leads to increase in the crystallite size to 57 nm due to stabilization of C10Zr7 phase along with the presence of nanocrystalline Cu-Zr phase. A bimodal distribution of grain size was observed from FE-SEM micrograph was attributed to the highest surface roughness in Zr30Cu70 thin films comprised of Cu10Zr7, Cu9Zr2, Cu-Zr intermetallic phases. In-vitro electrochemical behaviors of nano-crystalline Zrx-Cu100-x thin films in simulated body fluid (SBF) were investigated using potentiodynamic polarization studies. Electrochemical impedance spectroscopy (EIS) data fitting by equivalent electrical circuit fit model suggests that inner bulk layer contributes to high bio-corrosion resistance in Zrx-Cu100-x thin films with increase in Zr content. The results of cyto-compatibility assay suggested that Zr-Cu thin film did not introduce cytotoxicity to osteoblast cells, indicating its suitability as a bio coating for minimally invasive medical devices. PMID- 29442630 TI - Direct Electrodeposition of Gold Nanoparticles on Glassy Carbon Electrode for Selective Determination Catechol in the Presence of Hydroquinone. AB - A simple and reliable voltammetric sensor for simultaneous determination of Catechol (CT) and Hydroquinone (HQ) was developed by electrodepositing the gold nanoparticles on the surface of the Glassy Carbon Electrode (GCE). The cyclic voltammograms in a mixed solution of CT and HQ have shown that the oxidation peaks become well resolved and were separated by 110 mV, although the bare GCE gave a single broad oxidation peak. Moreover, the oxidation peak currents of both CT and HQ were remarkably increased three times in comparison with the bare GCE. This makes gold nanoparticles deposited GCE a suitable candidate for the determination of these isomers. In the presence of 1 mM HQ isomer, the oxidation peak currents of differential pulse voltammograms are proportional to the concentration of CT in the range of 21 MUM to 323 MUM with limit of detection 3.0 MUM (S/N = 3). The proposed sensor has some important advantages such as low cost, ease of preparation, good stability and high reproducibility. PMID- 29442631 TI - Poly-L-Arginine-Modified Boron-Doped Diamond and Glassy Carbon Electrodes for Terbutaline Sulfate Detection. AB - This work describes the electro polymerization of a poly-L-arginine film onto boron-doped diamond (BDD) electrode and glassy carbon electrode (GCE) surfaces. The morphological and electrochemical properties of the modified electrodes were studied by atomic force microscopy and electrochemical methods, and their potential for terbutaline sulfate (TBS) detection was determined by voltammetry and chronoamperometry techniques. Our results demonstrate that the electrochemical surface area of both uncoated-bare electrodes (GCE e BDD) did not have significant differences in performance. However, higher current observed for TBS at poly-arginine/GCE is probably due to the higher surface coverage poly arginine at GCE than BDD. It was concluded that for the systems under study, the poly-L-arginine/GCE was more suitable for TBS detection than that by the poly-L arginine/BDD electrode, due to the more continuous and thicker poly-L-arginine film formed on the GCE, as revealed by the microscopy images. The TBS sensitivity and detection limit of the poly-L-arginine/GCE were determined to be 0.9 +/-0.1 MUA MUmol-1L cm-2 and 0.10 MUmol L-1, respectively, by chronoamperometry. Furthermore, the abilities of the electrodes to detect other beta-agonists, namely clenbuterol and salbutamol, were studied by performing electrochemical experiments in the presence of these analytes. The results suggest that this film is a promising material for TBS detection due to high-surface-area electrochemical electrodes, and for the electrostatically-controlled thin film interference filter. PMID- 29442632 TI - A Facile Way to Increase the Cellular Uptake Efficiency of Hybrid Nanoparticles. AB - Lipid-polymer hybrid nanoparticles composed of polymer cores and lipid shells have been intensively studied as cancer drug delivery systems. The aim of the present study was to investigate the effect of phosphatidylcholine (PC) on physicochemical properties, stability and cellular uptake of lipid-poly(lactic-co glycolic acid) (PLGA) hybrid nanoparticles. Coumarin-6 (cou-6) loaded hybrid nanoparticles (NPs) were prepared using PC with different alkyl chain lengths from C12 to C18, and were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), and encapsulation efficiency (EE). The quality and quantity of cellular uptake of NPs were carefully assessed. The NPs were 140-180 nm in size, negatively charged of 7-12 mV and with EE values higher than 80%. NPs remained stable in storage at 4 degrees C for 28 d. Cell viability rates of NPs were above 90%, and the as-prepared nanoparticles showed excellent biocompatibility by MTT assay. Interestingly, the uptake order was as follows: C12 < C14 < C16-C18. As the alkyl chain length of PC increased, the cellular uptake efficiency of hybrid nanoparticles was enhanced. C16 to C18 saturated PC exhibited the highest cellular uptake efficiency and did not significantly differ. PC had little or no effect on physicochemical properties and stability but did affect cellular uptake of hybrid nanoparticles. The obtained findings could provide a fundamental basis for rational design of hybrid nanoparticles and a facile way to improve the cellular uptake of hybrid nanoparticles. PMID- 29442633 TI - Comparative Study of Various Types of Metal-Free N and S Co-Doped Porous Graphene for High Performance Oxygen Reduction Reaction in Alkaline Solution. AB - Heteroatom doping into carbon structures is an effective approach to enhance the electrochemical performance of carbon materials. In the work presented here, the electrocatalysts including: nitrogen and co-doped nitrogen and sulfur on porous graphene (PG) were synthesized by different precursors. The physico-chemical properties of the prepared samples were determined using X-ray Diffraction (XRD), Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), N2 sorption desorption, Transmission electron microscopy (TEM), Field Emission Scanning Electron Microscopy (FESEM) and X-ray photoelectron spectroscopy (XPS). The prepared samples were further applied for oxygen reduction reaction (ORR) and the effects of pyrolysis temperature, precursor type and dose, on the prepared samples structure and their electrochemical performances were investigated. The results revealed that synergistic effect of nitrogen and sulfur co-doped on the graphene structure leads to improvement in catalytic activity and current. Furthermore, S and N co-doped graphene prepared using sulfur trioxide pyridine complex exhibited excellent methanol tolerance and long-term stability. PMID- 29442634 TI - Performance Analysis of GaN Capping Layer Thickness on GaN/AlGaN/GaN High Electron Mobility Transistors. AB - In this paper, we present an investigation of the impact of GaN capping layer and AlGaN layer thickness on the two-dimensional (2D)-electron mobility and the carrier concentration which was formed close to the AlGaN/GaN buffer layer for Al0.25Ga0.75N/GaN and GaN/Al0.25Ga0.75N/GaN heterostructures deposited on sapphire substrates. The results of our analysis clearly indicate that expanding the GaN capping layer thickness from 1 nm to 100 nm prompts an increment in the electron concentration at hetero interface. As consequence of which drain current was additionally increments with GaN cap layer thicknesses, and eventually saturates at approximately 1.85 A/mm for capping layer thickness greater than 40 nm. Interestingly, for the same structure, the 2D-electron mobility, decrease monotonically with GaN capping layer thickness, and saturate at approximately 830 cm2/Vs for capping layer thickness greater than 50 nm. A device with a GaN cap layer didn't exhibit gate leakage current. Furthermore, it was observed that the carrier concentration was first decrease 1.03 * 1019/cm3 to 6.65 * 1018/cm3 with AlGaN Layer thickness from 5 to 10 nm and after that it increases with the AlGaN layer thickness from 10 to 30 nm. The same trend was followed for electric field distributions. Electron mobility decreases monotonically with AlGaN layer thickness. Highest electron mobility 1354 cm2/Vs were recorded for the AlGaN layer thickness of 5 nm. Results obtained are in good agreement with published experimental data. PMID- 29442635 TI - Solvent Free Transesterification of Glycerol Into Glycerol Carbonate Over Nanostructured CaAl Hydrotalcite Catalyst. AB - Drastic increase in green house gases due to fossil fuels usage urges the mankind to look for alternative fuel resources. Biodiesel is one of the alternative fuels which attracted the attention of many researchers. In recent years, bio-diesel drags much attention as an alternative clean fuel. Glycerol is an unavoidable byproduct in the transesterification process of vegetable oils into bio diesel and therefore market is flooded with glycerol. So it is high time to find ways of utilizing the abundant glycerol into value added products. Herein we report the catalytic transesterification of glycerol using dimethyl carbonate over MgAl hydrotalcite (MgAl-HT), CaAl-hydrotalcite (CaAl-HT) and nano structured CaAl-HT catalysts. All the catalysts were characterized by XRD, FT-IR, TPD-CO2, BET, SEM and HR-TEM techniques. Among them Ca4Al-HT was found to be best in terms of conversion of glycerol (82.4%) and selectivity (95.9%) towards glycerol carbonate. The effect of CTAB template concentration in the nano synthesis of Ca4Al-HT on conversion and selectivity was studied and Ca4Al-HT synthesized with 0.4 moles of CTAB showed the best conversion of glycerol (98.7%) and the highest selectivity towards glycerol carbonate (97.9%). The recyclability test performed with the best catalyst showed that the catalyst was recyclable even after 5 cycles. Valorization of glycerol yields glycerol carbonate (GC) which is a very good polar solvent with high boiling point, building block in several organic syntheses and used in the production of surfactants, poly urethanes etc. PMID- 29442636 TI - A Method for Estimating the Filling Rate of the Mold Cavity in Nanoimprint Lithography. AB - When the dimensions of a microelectronic structure decrease, high manufacturing costs are inevitable. A low cost and high throughput manufacturing technique for nanostructures is desired. Nanoimprint lithography involves patterning the resist through physical deformation by using a mold at nanoscale and has the potential to meet these expectations. Therefore, nanoimprint lithography has been extensively studied in recent years. Many real time measurements have been proposed for enhancing the yield of nanoimprint lithography. Among these measurements, the application of surface plasmon resonance has the advantage of quick, highly accurate analysis. In surface plasmon resonance application, the mold contains a gold film for exciting surface plasmon resonance and an adhesion layer is applied to both sides of the gold film to increase the lifespan of the mold. However, the effect of the geometric characteristics of the adhesive layer on the surface plasmon resonance spectrum and the mechanical strength of the mold has not been extensively studied. To improve the detection accuracy and reliability of the measurement, this study investigated the aforementioned effect. Analytical and experimental investigations confirmed that the shape of the spectrum is influenced by the surface roughness and thickness of the titanium adhesion layer. To maintain the sharpness of the resonance dip, we suggest reducing the thickness of the titanium adhesion layer to below 6 nm and maintaining the surface roughness below 3 nm. Moreover, the proposed mold structure conforms to these requirements and is applied to estimate the filling rate. The measurement results demonstrate that the surface plasmon resonance spectrum is clearly affected by the mold filling. Specifically, the change in the surface plasmon resonance spectrum curve and resonance angle can indicate the quality of the imprinted pattern. This study demonstrates the effectiveness and high sensitivity of the proposed technique for estimating the filling rate of the mold cavity in nanoimprint lithography. PMID- 29442637 TI - Gold Nanoparticles Prepared by beta-CD and Dispersion Behavior in Oil/Water Mixed System. AB - In this paper, we report a green and controllable synthetic method of gold nanoparticles (AuNPs) by directly beta-CD reduction under mild conditions. Analysis of UV-vis spectra, along with TEM was applied to study the effects of experimental parameters on morphologies of the gold nanoparticles. The corresponding formation mechanism of the nanoparticles was evaluated by redox potential. In particular, compared with the traditional method of sodium citrate or ascorbic reduction, this method can facilely realize multi-dimensional regulation. On this basis, we further studied the dispersion behavior of the as prepared gold nanoparticles in oil/water mixed system that would provide a possible strategy for optical sensor. PMID- 29442638 TI - Nickel Nanocatalyst Ex-Solution from Ceria-Nickel Oxide Solid Solution for Low Temperature CO Oxidation. AB - In this work, in situ growth of Ni nanocatalysts to attach onto the ceria (CeO2) surface through direct Ni ex-solution from the NiO-CeO2 solid solution in a reducing atmosphere at high temperatures with an aim to improve the catalytic activity, and stability for low temperature carbon monoxide (CO) oxidation reaction have been reported. The NiO-CeO2 solid solutions were prepared by solution combustion method, and the results of XRD and RAMAN showed that doping of Ni increases the oxygen vacancies due to charge compensation. Ni is clearly visible in XRD and TEM of Ni ex-solved sample (R-UCe5Ni10) after reduction of NiO CeO2 (UCe5Ni10) sample by 5% H2/Ar reduction at 1000 degrees C. TEM analysis revealed a size of 9.2 nm of Ni nanoparticle that is ex-solved on the surface CeO2. This ex-solved sample showed very high catalytic activity (T50 ~ 110 degrees C), and stability (100 h) for CO oxidation reaction as compared to prepared solid solution samples. This is due to the highly active metallic nano phase which is ex-solved on the surface of CeO2 and strongly adherent to the support. The apparent activation energy Ni ex-solved sample is found out to be 48.4 kJ mol-1. Thus, the above Ni ex-solved sample shows a practical applicability for the CO reaction. PMID- 29442639 TI - Effect of Plasma, Gamma and Chemically Surface Modified MWNTs on the Rheological and Electrical Properties of Ethylene Methyl Acrylate (EMA) Nanocomposites. AB - Surface modifications of the MWNTs have been carried out by treating the as received MWNTs with plasma (N2 and O2), piranha (H2SO4/H2O2) and gamma-ray irradiation under well specified conditions. Surface modifications introduce polar functional groups onto MWNTs surfaces. A variety of characterization techniques including FTIR, Raman spectroscopy, and XPS were employed to characterize the functional group introduced onto MWNTs after the modification. A series of poly(ethylene-comethyl acrylate) (EMA) based nanocomposites containing modified MWNTs has been prepared. Mechanical, morphological, thermal, rheological and electrical properties of these nanocomposites have been investigated. Morphological analyses revealed that MWNTs are more uniformly dispersed in EMA especially for plasma modified MWNTs. Rheological and electrical properties of the nanocomposites are also studied. The nanocomposites register a slightly higher viscosity than that of neat EMA depending on the type of treatment. Storage modulus (in dynamic shear) increases especially at higher frequency levels due to increased polymer-filler interactions. The EMA/MWNT nanocomposites were tested to evaluate their electromagnetic interference (EMI) shielding effectiveness. The enhancements of mechanical properties along with the improvements in electrical and electromagnetic properties by the addition of modified MWNTs have been observed. The MWNTs treated by O2 plasma provides EMA nanocomposites with a higher conductivity than those produced by N2 plasma or by chemical oxidation or by gamma-ray irradiation. Overall, the improvements of technical properties of the matrix have been found to be highest with the plasma modified MWNTs in comparison with other modified MWNTs. PMID- 29442640 TI - Fluorescent Biomolecules Capped ZnSe Quantum Dots and Their Photocatalytic Activities. AB - The preparation of semiconductor Quantum Dots (QDs) with controllable size, shape and doping remains a biggest challenge, especially the size below 10 nm. To date, only scarce attempts have been made on the synthesis of ZnSe QDs using biomolecule-assisted hydrothermal approach. Hence the current research work examines the influence of some amino acids namely L-cysteine, methionine and tyrosine as stabilizing agents in the synthesis of ZnSe nanocrystals. The ZnSe QDs exhibited strong absorption and photoluminescence properties in the region from 200-600 nm. Spectroscopic and structural properties of the as-synthesized biomolecule-capped ZnSe QDs were characterized by UV-vis absorption spectrophotometer, FT-IR, fluorescence spectrophotometer, X-ray diffractometer, Scanning Electron Microscope and EDX analysis. The stabilizing agents have played a crucial role in preparing ZnSe QDs and in determining the photoluminescence properties. The luminescence intensity was enhanced significantly when amino-acid capped ZnSe QDs were illuminated by UV light compared to visible light. The as synthesised ZnSe QDs were capable of effectively degrading an organic azo dye Azophlexin, under direct sunlight irradiation and exhibited good stability during photocatalytic experiments which can be attributed to the small size of amino acid capped ZnSe. The degradation mechanism is discussed. The absorbance and FT IR measurements confirmed the biocompatibility and water-solubility of the pure ZnSe and capped ZnSe QDs. PMID- 29442641 TI - Highly Enhanced Visible Light Photocatalytic Performance of BiOCl/X (X = Br, I) Nanocomposites with Controllable-Exposed {001} Facets. AB - A series of BiOClyX1-y (X = Br, I.) with controllable-exposed {001} facets have been prepared by a facile liquid preparation method, using NaBiO3, HX (X = Br, I) and hydroxylamine hydrochloride (HONH2 . HCl) as the raw materials. The fundamental properties of the as-synthesized samples were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), FT-IR spectrophotometer and UV-Vis absorption spectrometry. The photocatalytic activities of these as-prepared photocatalysts were investigated by photodegradation of Rhodamine B (RB) under visible light irradiation. BiOCl0.5Br0.5 and BiOCl0.75I0.25 nanocomposites show the best photocatalytic performance for removal of RB in individual system, respectively. A possible photocatalytic mechanism has been discussed on the basis of the results of photocatalytic experiments. PMID- 29442642 TI - Low Cost and Reliable Electrochemical Sensor for Rutin Detection Based on Au Nanoparticles-Loaded ZnS Nanocomposites. AB - Facile preparation of electrode modified materials with low-cost nanocomposites is an important step to develop highly active electrochemical sensors for mass market applications. Here we fabricated Au nanoparticles (AuNPs)-loaded ZnS nanocomposites for the sensitive determination of rutin due to the cooperative amplification of the conductivity and catalytic activity of AuNPs on ZnS spheres resulting from the high loading ratio of AuNPs on ZnS spheres. Under the optimal conditions, the developed sensor based on AuNPs-loaded ZnS nanocomposites exhibited excellent electrocatalytic activity towards rutin in a linear range from 1 * 10-7 mol/L to 2 * 10-5 mol/L with a limit of detection of 15.3 nM at a signal-to-noise ratio of 3. Furthermore, the proposed method gave satisfactory results for rutin determination in pharmaceutical tablets, which offer promising potential for rutin electrochemical analysis in serum monitoring or Chinese medical analysis owing to its simplicity, low cost, high sensitivity and good stability. PMID- 29442643 TI - Structural, Optical and Magnetic Properties of NiO Nanopowders. AB - Nickel oxide (NiO) nanopowders were synthesized without using surfactant by chemical reduction technique. NaBH4 influence on structural, optical and magnetic properties of NiO product was investigated. XRD results revealed the formation of dominant single phase, cubic face centered nickel oxide. Raman peaks depicts the characteristic first-order transverse optical (TO) phonon, two phonon excitation (TO + LO), excitation (2LO) Raman mode vibrations of face centered cubic NiO. PL studies revealed the presence of strong emission band which is in good agreement with the intrinsic NiO product. FTIR studies explored metal oxygen vibrations of the obtained product. TEM results revealed the nanoscale product with spherical shape structures. VSM studies explored weak ferromagnetic behavior of the obtained product. High concentration of NaBH4 increases magnetization value and exhibits the typical weak ferromagnetic curve. Reducing agent played a vital role in the structural, optical and magnetic properties of the obtained NiO product. PMID- 29442644 TI - Carbonization of Fe-Based Metal Organic Frameworks with Mesoporous Structure as Electrocatalyst for Catalysis of Oxygen to Hydrogen Peroxide. AB - H2O2 production from electron reduction of oxygen (O2) is considered to be a potential alternative to the current anthraquinone process. Herein, we reported a mesoporous catalyst with iron-carboxylate metal-organic framework (MOF) as precursors to catalyze O2 to hydrogen peroxide (H2O2). Iron-carboxylate MOF (Fe MOF) was synthesized by the novel cetyltrimethylammonium bromide (CTAB)-citric acid (CA) double-template method. The SEM and SAXD results revealed octahedral structure of the nanoparticles, as well as the presence of mesopores in the Fe MOF, while the molar ratio 2.03 of CTAB to CA that resulted in the largest value (0.914 cm3g-1) of the mesopores in the Fe-MOFs. The pyrolysis of Fe-MOF with the largest amount of mesopores resulted in its carbonization and produced gamma Fe2O3@carbon material, significantly reduced the BET surface area from 3036 m2 g 1 to 387 m2 g-1, but increased the average pore diameter up to 5.78 nm and disintegrated their octahedral structures to an irregular morphology of Fe-MOF (550), and modified the carbon matrix with trace oxygen and metal oxides. The gamma-Fe2O3@carbon material possessed mesoporous structure, with predominant graphitic carbon in the matrix (graphite to amorphous carbon ratio 0.79), which contributed to increased potential for electron reduction of O2 through a 2e- electron transfer pathway. PMID- 29442645 TI - Synthesis of Fe3O4/C with Cauliflower-Like BiVO4 for Improved Separation Efficiency of Charge Carriers and Photocatalytic Activity. AB - Fe3O4/C/BiVO4 composite photocatalyst was fabricated successfully by a simple approach using yeast as a carbon source. Fe3O4/C/BiVO4 sample exhibited higher efficiency for photocatalytic degradation of tetracycline (TC) as compared to pure BiVO4 under visible light. In addition, after five recycles of photodegradation of TC, Fe3O4/C/BiVO4 showed a slight loss in photocatalytic activity, which confirmed its stability and long-time reusability. The photocatalytic mechanism was studied by active species trapping experiments, which revealed that the holes (h+) and superoxide radical (O-2) played a key role in TC degradation. Moreover, photocatalyst could be easily recycled by an external magnetic field and reused without any loss in photocatalytic activity. This work provides a simple, eco-friendly and exemplary strategy for improving photodegradation activity of BiVO4-based photocatalyst. PMID- 29442646 TI - 2-Dimensional Clay/Reduced Graphene Oxide Ordered Heterostructures Dispersible in Water via a One-Step Hydrothermal Route. AB - A facile and green method for trapping the hydrophobic reduced graphene oxide between the hydrophilic Kunipia F layers in order to attain stable aqueous dispersions of reduced graphene oxide is described. Initially stable aqueous dispersions of hydrophilic clay intercalated with hydrophilic graphene oxide sheets were formed providing well-organized heterostructures, as it was revealed by scanning electron microscopy images. These structures were preserved in the product obtained after hydrothermal treatment where the hydrophilic graphene oxide was converted to hydrophobic reduced graphene oxide. Ultraviolet measurements revealed the aforementioned conversion which was accompanied by a characteristic change in color from yellow-brown to black in the corresponding aqueous dispersions of these hybrids before and after hydrothermal treatment. The stability of these homogeneous dispersions was confirmed by Zeta Potential measurements implying interactions both in cases of graphene oxide and reduced graphene oxide with clay sheets that made feasible the effective interstratification of graphene-clay layered materials. In these stable dispersions chemistry in aqueous environment could be fully utilized making possible their incorporation e.g., as fillers to hydrophilic polymeric matrices extending thus the limits of application. PMID- 29442648 TI - The Preparation and Optical Properties of Ni(II) and Mn(II) Doped in ZnTe Nanobelt/Nanorod by Using Chemical Vapor Deposition. AB - The doping techniques are often used to modify the properties of semiconductors. Transition metal ion doping in semiconductor can lead to dilute magnetic semiconductors (DMSs), which may initiate some novel properties related to spins. In contrast to the wide band semiconductor ZnO, ZnSe and CdS crystal the transition metal (TM) ion aggregate can be the origin of the ferromagnetic behaviors, which influence their optical properties mainly through the exciton spin interactions due to their high exciton binding energy. For narrow band semiconductor, the carrier-spin coupling is the main cause of magnetism as observed in ZnTe. The ZnTe nanobelt for DMS with the TM ions such as Ni(II) and Mn(II) doping mainly induce the excess carrier effect in the lattice after photo excitation, whose optical properties are also strongly depended on the fabrication method structure and morphology. Photo-excited carriers and electron phonon interaction (but less excitons) are responsible for their large redshifts in ZnTe nanostructures. The strong interaction between the doped magnetic ion spins and holes, electron-phonon coupling, p-d hybridization as well as local electron correlation in TM ions determined their optical properties. TM ions incorporation in ZnTe lattice has suppressed the broad defect emission band far from the bandedge and broadened the electron correlations and electron hole plasma band near bandedge when excited by the rising excitation powers. We also identified that the polarized PL of Ni(II) and Mn(II) doped samples to calculate the strain dependence of band splitting near valance band. PMID- 29442647 TI - Removal of Cu(II) Ions from Aqueous Solution Using Fe/La-CTAB-Graphene Oxide Nanocomposite as Efficient Adsorbent. AB - We report an approach for synthesis of Fe/La-CTAB-graphene oxide (GO) nanocomposite with coprecipitation method prepared from natural graphite. The nanocomposite was characterized by XRD, FT-IR, SEM and TEM, and was applied to remove copper ions in aqueous system. Also, the effect of various factors such as contact time, temperature, initial concentration of Cu(II) ions, and solution pH on Cu(II) ions adsorption over Fe/La-CTAB-GO nanocomposite was investigated. The results reveal that removal percentage of Cu(II) ions is over 91% (pH = 6.0) within 90 min, along with the initial concentration of Cu(II) ions of 10 mg/L and the dose of 15 mg. The adsorption of Cu(II) ions over Fe/La-CTAB-GO nanocomposite fitted well to Langmuir isotherm model (R2 = 0.99855) and followed the pseudo second-order kinetic (R2 = 0.99974). Thermodynamic parameters declare that the adsorption process is endothermic and spontaneous. Results of this work suggest that Fe/La-CTAB-GO nanocomposite can be a promising adsorbent for the removal of copper ions in aqueous solutions. PMID- 29442649 TI - In-Situ Synthesis of Amorphous Co Nanoparticles Supported onto TiO2 Nanofibers as a Catalyst for Hydrogen Generation from the Hydrolysis of Ammonia Borane. AB - Co0 nanoparticles supported on TiO2 nanofibers (nanocomposite) were prepared using a simple electrospinning technique and In-Situ chemical reduction. The synthesized nanocomposite was used to generate hydrogen from ammonia borane (AB). Standard characterization techniques revealed dense distribution of Co0 nanoparticles (Co NPs) onto the TiO2 nanofibers (TiO2 NFs) in the prepared nanocomposite. The introduced nanocomposite has been showed a good catalytic activity as compared to those unsupported Co NPs. As, the hydrogen evolutions for the nanocomposite and Co NPs were 3 mol in 23 min and 47 min, respectively. Furthermore, both the nanocomposite concentration and the temperature have a significant catalytic activity in the AB dehydrogenation. The nanocomposite also showed low effective activation energy of ~26.03 KJ . mol-1. PMID- 29442651 TI - Prepared Reticulated Nickel Hydroxide for Sensing Urea by Differential Pulse Voltammetry. AB - A urea sensor base on reticulated nickel hydroxide is prepared by hydrothermal way and operated by differential pulse voltammetry method. The reticulated nickel hydroxide has been successfully synthesized by a hydrothermal method and has been characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). The Ni(OH)2 sensor exhibits a higher sensor response (S) of 7.1 than NiO and Au sensing materials to 0.05 M urea concentration at 0.62 V. Various concentration of urea from 0.1 mM to 50 mM are performed on Ni(OH)2, and the sensor response are increased from 1.1 to 7.1 by differential pulse voltammetry (DPV) method. The urea detection limit is measured as 0.1 MUM in this system. In addition, the Ni(OH)2 sensor exhibited good reproducibility and short term stability, and the response exhibits no obvious changes after 20 days tests. A possible sensing mechanism of Ni(OH)2 urea sensor is presented. PMID- 29442650 TI - Electrospun LiFePO4/C Composite Fiber Membrane as a Binder-Free, Self-Standing Cathode for Power Lithium-Ion Battery. AB - A LiFePO4/C composite fiber membrane was fabricated by the electrospinning method and subsequent thermal treatment. The thermal decomposition process was analyzed by TG/DSC, the morphology, microstructure and composition were studied using SEM, TEM, XRD, Raman, respectively. The results indicated that the prepared LiFePO4/C composite fibers were composed of nanosized LiFePO4 crystals and amorphous carbon coatings, which formed a three dimensional (3D) long-range networks, greatly enhanced the electronic conductivity of LiFePO4 electrode up to 3.59* 10-2 S . cm 2. The 3D LiFePO4/C fiber membrane could be directly used as a binder-free, self standing cathode for lithium-ion battery, and exhibited an improved capacity and rate performance. The LiFePO4/C composite electrode delivered a discharge capacity of 116 mAh.g-1, 109 mAh.g-1, 103 mAh.g-1, 91 mAh.g-1, 80 mAh.g-1 at 0.1 C, 0.5 C, 1 C, 3 C, 5 C, respectively. And a stable cycling performance was also achieved that the specific capacity could retain 75 mA.g-1 after 500 cycles at 5 C. Therefore, this LiFePO4/C composite fiber membrane was promising to be used as a cathode for power lithium ion battery. PMID- 29442652 TI - Catalytic Conversion of Glycerol to Lactic Acid Over Hydroxyapatite-Supported Metallic Ni0 Nanoparticles. AB - Catalytic conversion of low-priced biomass glycerol to value-added lactic acid is an alternative route to the conventional fermentation process using sugar as the starting material. Nanosized hydroxyapatite-supported metallic Ni0 nanoparticles (Nix/HAP) prepared by the wetness chemical reduction method effectively catalyzed the conversion of high-concentrated glycerol (1.5-3 mol L-1) to lactic acid in a NaOH aqueous solution. The Nix/HAP catalysts exhibited higher catalytic activity for glycerol conversion to lactic acid than the sole metallic Ni0 nanoparticles. When the reaction was carried out over the Ni0.2/HAP catalyst with the initial glycerol and NaOH concentrations of 2.0 and 2.2 mol L-1 at 200 degrees C for 2 h, the selectivity of lactic acid reached 94.7% at the glycerol conversion of 92.1%. PMID- 29442653 TI - Effect of Titania Concentration in Bioglass/TiO2 Nanostructures and Its In Vitro Biological Property Assessment. AB - Bioglass 45S5 (45% SiO2-24.5% NaO-24.5% CaO-6% P2O5) is a unique bioactive material, which is being used for bone and dental substitution. This system has been highly preferred for its osteoconductive and osteoinductive performance. Despite its attractive bioactivity, there are limitations in using this material for orthopedic and dental applications due to its poor processability and mechanical strength. To improve the load-sharing and stress distribution, TiO2 nanoparticles have been introduced into the nanoBioglass (nBG) by sol-gel method. The structural analyses of the samples were confirmed using X-ray diffraction, Raman-spectroscopy and FTIR. The morphologies of the samples were characterized by FESEM. The apatite formation of the nBG/TiO2 composites was investigated by immersing the samples in simulated body Fluid (SBF) solution for 1 and 3 days, which reveals the acceptable compatibility for different concentrations of all the composition. Hemolysis studies of the nanobiomaterials were carried out to understand the interactions of biomaterials with blood which shows 0.2%-2% of lysis which is acceptable as per ASTM standard. Cell culture and cell proliferation studies of bioglass, nBG/TiO2 nanocomposite on MG-63 pre-osteoblast cell line for 24 h, 48 h and 72 h showed 80% to 95% of cell viability. Also, it was found that the nBG/TiO2 bio-nanocomposites containing low content of titania had good bioactivity properties that is comparable to cortical bone. Hence, nBG/TiO2 bio-nanocomposites are greatly promising for medical applications such as bone substitutes especially in load-bearing sites. PMID- 29442654 TI - Highly Efficient Visible-Light-Driven Graphene-CdS Nanocomposite Photocatalysts. AB - Graphene-CdS nanocomposites with different CdS contents were synthesized via a solvothermal route. Compared with pure CdS, graphene-CdS composites exhibited higher efficiency in photodegradation of methylene blue (MB) under visible light irradiation. TEM observations demonstrated that a homogeneous distribution of CdS nanoparticles on the graphene nanosheets was formed, while the CdS nanoparticles on graphene-CdS composite (1 g/7.5 mmol) distributed best among graphene-CdS composites. The results show that the graphene-CdS composite (1 g/7.5 mmol) has the highest efficiency and well stability. It demonstrated the mechanism of photodegration was that OH radical generated by graphene-CdS composite plays a vital role by adding dimethyl sulfoxide (DMSO). PMID- 29442655 TI - Preparation of Multiwall Carbon Nanotubes with Zinc Phthalocyanine Hybrid Materials and Their Nonlinear Optical (NLO) Properties. AB - Hybrid material of multi walled carbon nanotubes (MWCNT)-zinc phthalocyanine (ZnPcs) (MWCNT-ZnPc) composites were synthesized and compared with ZnPc. Nonlinear optical properties of MWCNT-ZnPc and ZnPc were studied. The synthesized MWCNT-ZnPc characterized by UV-visible absorption spectroscopy, photoluminescence and TEM. Their nonlinear optical properties were measured through Z-scan technique with 800 nm, 110 fs, 1 kHz Ti:Sapphire laser and 532 nm, 30 ps and 10 Hz Nd:YAG laser. The results showed that phthalocyanines were anchored onto the surface of the multi walled carbon nanotubes by using TEM. Photoluminescence spectra had shown quenching in emission of MWCNT-ZnPcs hybrid material due to the energy transfer. Reverse saturable absorption in MWCNT-ZnPcs hybrid material was compared with pure phthalocyanine, which had shown an increase in nonlinear absorption coefficient with 532 nm and reduction with 800 nm. The results concluded that MWCNT and MWCNT-ZnPc can be used as effective optical limiters. PMID- 29442656 TI - Convenient Synthesis and Enhanced Photocatalytic Activity of BiOI/BiOBr Nanostructures with Different Morphologies. AB - A facile solvothermal method for the synthesis of BiOI with different morphologies was proposed. The results indicated that the ethylene glycol and isopropyl alcohol system could control the consecutive dimension and size changes of BiOI from zero-dimension to three-dimension kinetically and thermodynamically. On this basis, BiOI/BiOBr composite photocatalysts were prepared, and the correlation between the catalytic performance and structure of the photocatalyst was also investigated. The enhanced photocatalytic activity of BiOI/BiOBr composite photocatalysts can be attributed to the intact three-dimensional hierarchical micro-nanostructures, appropriate phase composition and the efficient separation of photogenerated charge carriers. PMID- 29442657 TI - Preparation of Poly(D,L-lactic-co-glycolic acid) Nanoparticles Through Solvent Displacement and Structural Evaluation Using Time-Domain Nuclear Magnetic Resonance. AB - The present study obtained coated poly(lactic-co-glycolic acid) nanoparticles using the solvent displacement method aiming to evaluate the effect of the polymer concentration in the pharmaceutical formulations' and polymer properties. Nanosuspensions were evaluated by fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), zeta potential (ZP), thermogravimetric analysis (TGA), X-ray diffraction (XRD) and time-domain nuclear magnetic resonance (TD NMR). Uniform nanoparticles could be obtained using this method and higher polymer concentrations led to an increase in particle size and negatively charged surfaces were observed. However typical PLGA halo was observed in XRD, diffractograms revealed the Pluronic chains behavior when PLGA concentration changed. Additionally, samples' spin-lattice relaxation times, dipolar interaction and correlation times were evaluated using time-domain nuclear magnetic resonance (TD-NMR), which revealed the interference of PLGA chain packing when Pluronic was incorporated as well as Pluronic chains organization and its behavior around the particle. PMID- 29442658 TI - WO3@Bi2WO6/NiWO4 Nanocomposites with Outstanding Visible-Light-Driven Photocatalysis for the Degradation of Organic Dyes. AB - By hydrothermal reaction, the WO3@Bi2WO6/NiWO4 nanocomposite was prepared by the coprecipitation reaction between Bi3+/Ni2+ and WO2-4 in the presence of urea and PVP. It resulted in the formation of uniform and well-dispersed nanocomposite structures with ultrathin Bi2WO6/NiWO4 nanosheets attached with ultrafine WO3 nanoparticles. The nanocomposites exhibited a wide light absorbance up to 680 nm with low indirect band gaps of 2.54 eV, leading to outstanding photocatalytic efficiency for the degradation of both Rhodamine B (Rh B) and Xylenol Orange (XO) under visible light. With irradiation for only 15 minutes, Rh B was nearly completely degraded. XO, which is difficult to degrade usually, and the strong absorption peak nearly vanishes in about 60 min. The ultrathin Bi2WO6/NiWO4 nanosheets and ultrafine WO3 nanoparticles mean high specific areas and high active sites. A lot of hydroxy groups in WO3@Bi2WO6/NiWO4-III due to the presence of Ni and Bi helps for the formation of OH. According to the ladder theory, the photogenerated e- and h+ by the irradiation light of high wavelength according with band gap can be activated again by that of lower wavelength step by step. The lower wavelength means the higher energy. The broader adsorption means the higher efficiency for energy adsorption and more e- and h+ with higher energy were activated to photocatalytically degrade dyes. This provides new potential to explore nanocomposites for efficient photo-driven degradation of organic dyes under visible light irradiation. PMID- 29442659 TI - Effect of Solution Concentration on Magnetic Ni0.5Zn0.5Fe2O4 Nanoparticles and Their Adsorption Behavior of Neutral Red. AB - Magnetic Ni0.5Zn0.5Fe2O4 nanoparticles were prepared via the methanol combustion process, the morphology, chemical composition, microstructure and magnetic properties of them were investigated by SEM, EDX, TEM, XRD, VSM, and BET. The experimental data revealed that the solution concentration was a key factor to the Ni0.5Zn0.5Fe2O4 nanoparticles, with the solution concentration of ferric nitrate decreasing from 3.37 to 1.12 mol/L, the saturation magnetization decreased from 69.3 Am2/kg to 37.2 Am2/kg, and the average crystalline size of Ni0.5Zn0.5Fe2O4 nanoparticles decreased from 32 to 25 nm. While, with the solution concentration of ferric nitrate decreasing from 1.12 to 0.56 mol/L, the saturation magnetization increased from 37.2 Am2/kg to 104.6 Am2/kg, and the average crystalline size increased from 25 to 44 nm. The adsorption behavior of neutral red (NR) onto magnetic Ni0.5Zn0.5Fe2O4 nanoparticles was investigated by UV spectroscopy at room temperature; the adsorption kinetics data related to the adsorption of NR from aqueous solutions were in good agreement with the pseudo second-order kinetic model in a range of initial concentration of 50-300 mg/L. By comparison of the Langmuir and Freundlich models for adsorption isotherm of NR, the Langmuir model (correlation coefficient R2 = 0.9918) could be used to evaluate the adsorption isotherm of NR onto magnetic Ni0.5Zn0.5Fe2O4 nanoparticles at room temperature, which suggested that the adsorption of NR onto magnetic Ni0.5Zn0.5Fe2O4 nanoparticles was monolayer, and the adsorption energy was constant. PMID- 29442660 TI - Direct Electrochemistry of Methanobactin Functionalized Gold Nanoparticles on Au Electrode. AB - Mathanobatins (Mb, Mbtins) were immobilized successfully on nanometer-sized gold colloid particles associated with beta-mercaptoethylamine. The structures of Mb functionalized gold nanoparticles were characterized and confirmed by UV-vis spectroscopy (UV-vis), FTIR spectra and electrochemical analyses. Direct electron transfer between Mb or copper-loading Mbtins and the modified electrode was investigated without the aid of any electron mediator. The copper-loading Mbtins act as a better electrocatalyst for the reduction of H2O2 than Mb. The copper loading Mb, with which gold nanoparticles were functionalized, as a model enzyme, was immobilized on gold electrode to construct a novel H2O2 biosensor. In pH 6.4 phosphate buffer solution, the reduction and oxidation peak potentials of Mb functionalized gold nanoparticles modified Au electrode (copper-loading Mbtins) were 0.115 and 0.222 V. On the surface, capacitance per unite area (Cd) of Mb functionalized gold nanoparticles modified electrode were 38 MUF cm-2. The immobilized Mb displayed the features of a peroxidase and gave an excellent electrocatalytic response to the reduction of H2O2. The detection limit of Mb functionalized gold nanoparticles (copper-loading) were 09 * 10-5 mA/M (S/N = 3). The Michaelis-Menten constant (Km) was 0.787 mM. Good stability and sensitivity were assessed for the biosensor. PMID- 29442661 TI - Effect of O2 Concentration on the Electrochromic Properties of NiOx Films. AB - Nickel oxide (NiOx) films were deposited onto ITO-coated glass at room temperature by DC magnetron sputtering in Ar/O2 mixing gas. The effect of O2 concentration on structure, morphology, electrochemical and electrochromic properties of NiOx films was systematically investigated. X-ray diffraction results showed NiOx films had the polycrystalline structure. NiOx films deposited at low O2 concentration had the preferred (200) peak. On the other hand, the films exhibited the strong (111) peak at high O2 concentration. Small roughness and grain size of NiOx film deposited at 15% O2 concentration were observed by atomic force microscope and scanning electron microscope results, and small crystallite size was obtained from the XRD data which leads to the good cyclic durability. The large transmittance modulation, high color efficiency and fast coloring/bleaching response time make NiOx films suitable to be applied as an anodic coloring material complemented with WO3 electrochromic window. PMID- 29442662 TI - Photocatalytic Performance of 3D Ni/Graphene/ZnO Composites Fabricated by Hydrothermal Processing. AB - ZnO nanorods are fabricated by the hydrothermal processing on the 3 dimensional (3D) Ni/Chemical Vapor Deposition (CVD) grown multilayer graphene and 3D Ni foams, respectively, and their photocatalytic performance are investigated. It is found that the composites with the graphene sandwiched between the 3D Ni and ZnO nanorods with 4 hours hydrothermal growth exhibits superior photocatalytic performance toward methyl orange (MO) under simulated sunlight, whose apparent degradation rate constant is about 1.3 times larger compared to that without graphene incorporated. Meanwhile, the underlying substrates show tremendous influence on the morphology and structures of ZnO nanorods, which imposes vital influence on the composites photocatalytic performance. The sparsely distributed and well crystalized ZnO flower-like nanorods with the enhanced content ratio of (002) plane on the 3D Ni/graphene foam reveal optimal performance, which can be attributed to the hybrid effect of the effective separation of the photo generated electron-hole pairs due to the easy transferring of charges at graphene/ZnO interface through secure graphene/ZnO contacts, and the enhanced photocatalytic reduction of well crystallized and (002) enriched ZnO nanorods. The mechanism responsible for the enhancement of the photocatalytic degradation and the formation of the distinguished morphology and structure of ZnO nanorods are discussed in details. PMID- 29442663 TI - Cuttlefish Ink Tagged Photonic Crystal Particles and Their Ion-Responsive Construction. AB - Colloidal crystal materials have potential values in coding, sensing, displaying and so on. Attempts to promote these values tend to focus on the development of functional colloidal crystal materials with high color saturations and bright structural colors for practical applications. Thus, this work presented novel cuttlefish ink nanoparticles doped colloidal crystal particle material, which had distinguishable and high saturation colors, and could response to the electric field and pH obviously. It was also found that the doping could result in a short range order and long-range disorder structure of the colloidal crystals, which endowed them with wide viewing angles. More importantly, by using electric field and ions dual-responsive hydrogel to replicate the composite colloidal crystals particles, the resultant cuttlefish ink nanoparticles doped inverse opal particles were imparted with the same high saturation vivid structural colors, as well as obviously structural color tunability. These features make the cuttlefish ink nanoparticles doped colloidal crystal particles ideal for many practical applications where structural color materials is needed. PMID- 29442664 TI - Synthesis of Au-Ag Alloy Nanoparticles in Deionized Water by Pulsed Laser Ablation Technique. AB - Au-Ag alloy nanoparticles are physically synthesized using rapid, simple and efficient Q-switched Nd:YAG pulsed laser ablation in liquid technique (PLAL). Au and Ag colloidal solutions are separately prepared by 1064 nm laser ablation of metallic target (gold and silver) which is immersed in deionized water. Au-Ag alloy nanoparticles are prepared by irradiating the mixture of Au and Ag colloidal solutions with 532 nm of second harmonic wavelength of Nd:YAG laser at three different ratio, 3:1, 1:1 and 1:3 within different exposure times. The three of plasmon absorption bands of Au-Ag nanoparticles are shifted linearly to the lower wavelength [499.67 nm (3:1), 481.25 nm (1:1), 467.91 nm (1:3)], as compared to plasmon absorption spectra of pure Au (520 nm) and Ag (400 nm). Moreover, the change in colors are also observed from red (Au) and yellow (Ag) to orange, brown and green color due to the Au-Ag alloy formations, respectively. Transmission electron microscopy shows the Ag shell around the inner core of Au spherical metal with broad size distribution due to the three different volume ratio, respectively (1.7 nm, 0.7 nm, 1.4 nm). Energy-dispersive X-ray spectroscopy analysis confirms the presence of Au and Ag elements in Au-Ag alloy nanoparticles without any contaminations. Attenuated total reflectance fourier transform infrared spectroscopy analysis also confirms the homogenous Au-Ag alloys chemical bonding. PMID- 29442665 TI - Preparation of Expoxy-Functionalized Magnetic Nanoparticles for Immobilization of Glycerol Dehydrogenase. AB - Immobilization of glycerol dehydrogenase (GDH) from Serratia marcescens H30 onto epoxy functional magnetic nanoparticles by covalent attachment was carried out. The optimal immobilization conditions were obtained as follows: enzyme/support 6.08 mg/g, temperature 25 degrees C, pH 7.0 and time 8 h. Under these conditions, a high immobilization yield above 90% was obtained. The characterization of the immobilized GDH indicated that enhanced pH and thermal stability were achieved. Kinetic parameters Km of free and immobilized GDH were determined as 10.35 mM and 15.76 mM, respectively. The immobilized GDH retained about 85% initial activity after ten cycles. These results suggested that GDH immobilized onto magnetic nanoparticles is a simple and efficient way for preparation of stable enzyme. And the immobilized GDH has potential applications in the production of DHA. PMID- 29442666 TI - Electrocatalysis and Detection of Nitrite on a Pd/Fe2O3 Nanocomposite Modified Glassy Carbon Electrode. AB - An electrochemical palladium/ferric oxide (Pd/Fe2O3) nanocomposite modified glassy carbon electrode (GCE) was fabricated by hydrothermal method of Fe2O3 and electrochemical deposition of palladium nanoparticles, respectively. As-prepared Pd/Fe2O3 composite modified electrode exhibits enhanced electrocatalytic activity towards the catalytic oxidation of nitrite compared to Fe2O3, PdNPs modified electrodes and bare electrode. The parameters such as the influence of amount of Pd nanoparticles deposition onto the Pd/Fe2O3 modified electrode (ME) and effect of solution pH were investigated and discussed in detail. Under the optimal conditions, the Pd/Fe2O3 modified GCE can be used to detect nitrite concentration in a wide linear range of 10 and 1000 MUM with the detection limit of 0.1 MUM. The presence of Cu2+, Na+, Cl-, PO3-4 SO2-4, Mg2+ K+, NO-3, and NH+4 showed a trivial effect on the response of nitrite determination, revealing that developed modified electrode has an excellent anti-interference ability to common ions. It also shows good stability and reproducibility. PMID- 29442667 TI - Electrodeposition of Ni and CeO2/Ni Nanotubes for Hydrogen Evolution Reaction Electrode. AB - Ni NTs and CeO2-Ni nanotubes (NTs) have been prepared by galvanostatic electrodeposition in anodic aluminum oxide (AAO) Templates. Scanning electron microscope (SEM), high resolution transmission electron microscopy (HRTEM), energy dispersive X-ray spectroscopic (EDS) and X-ray Diffraction (XRD) are used to characterize the prepared NTs. The results showed that the preparation process of CeO2-Ni NTs was accompanied by the formation of many new phases CeNix (x = 1, 2, 3.5 or 5) and preferential orientation crystal face of Ni in CeO2-Ni NTs is <111>, which is different from that Ni <200> in Ni NTs. Then linear scan voltammetry (LSV) is applied to test the electrocatalytic activity for hydrogen revolution reaction (HER) of the two electrodes in 1 M NaCl aqueous solution and find that both of the two materials exhibited good performance. Finally, the kinetics analyses from the HER process showed that Tafel slope b was mainly dependent on phase composition and electric conductivity of the electrode, while j0 was mainly dependent on its real specific surface area. PMID- 29442668 TI - Cellulose Whiskers Influence the Morphology and Antibacterial Properties of Silver Nanoparticles Composites. AB - Cellulose, the main component of plant cell walls, is a biopolymer widely used for industrial applications, including, food, paper and textile fabrication. More recently, hybrid materials composed of cellulose nanostructures and metal nanoparticles have been applied in diverse areas such as medical and pharmaceutical applications. In this work, cellulose-silver nanoparticles (AgNPs) hybrid material was synthesized and the influence of cellulose, employed as a stabilizer agent, was investigated. Specifically, cellulose whiskers (CCW) were extracted from commercial cotton fibers by acid hydrolysis route, while the AgNPs were synthesized by reducing silver salt using sodium citrate and/or sodium borohydride in the presence of CCW. The synthesized AgNPs/CCW nanocomposites were characterized in terms of morphology, chemical composition, surface charge and antibacterial properties. The varied synthetic routes generated AgNPs with different morphological characteristics in terms of size, shape and coalescence. The particularity of each sample resulted in distinct behaviors for the tested bacteria. Syntheses employing CCW resulted in AgNPs/CCW nanocomposites with controlled morphology and improved antibacterial effects against E. coli (Gram negative) and S. aureus (Gram-positive), indicating CCW as a promising compound to be used in the syntheses of silver and other metal nanoparticles with controlled morphology and antibacterial properties. PMID- 29442669 TI - Fabrication of Porous ZnO/Co3O4 Composites for Improving Cycling Stability of Supercapacitors. AB - To tackle the issue of poor cycling stability for metal oxide nanoparticles as supercapacitor electrode, porous ZnO/Co3O4 composites were fabricated via solid state thermolysis of [CoZn(BTC)(NO3)](2H2O)(0.5DMF) under air atmosphere. The results demonstrate that the products are mesoporous polyhedron structure with the diameter of about 10 MUm, which are constructed by many interconnected nanocrystals with the sizes of around 20 nm. ZnO/Co3O4 composites as supercapacitor electrode exhibited excellent cyclic stability capacity, showing a maximum specific capacitance of 106.7 F g-1 and a capacity retention of 102.7 F . g-1 after 1000 cycles at 0.5 A . g-1. The superior electrochemical performance was contributed to ZnO/Co3O4 composites with porous structures and small size, which shortened the route of electronic transmission as well as ions insertion and desertion processes. Additionally, the synergetic effect of bimetallic oxides improved the electrochemical stability. PMID- 29442670 TI - Redox State Detection of Fruits and Vegetables by a Simple Surface-Enhanced Raman Scattering Method. AB - In order to detect the redox states of fruits and vegetables simply, a SERS (surface-enhanced Raman scattering) method was developed based on a redox sensitive probe and a pH-sensitive probe. The two probes were dropped onto the flesh of the fresh incision of fruits and vegetables, respectively. The SERS spectra of redox-sensitive probes were used to indicate their redox states, and the SERS spectra of pH-sensitive probes were used to indicate their pH values to discount the influence of pH on the redox states. The order of redox states (redox potential) of the detected fruits and vegetables is as follows: carrot < Green delicious apple < Xinjiang kuerle fragrant pear < Chinese royal pear < Fuji apple < crystal pear < Golden marshall apple < potato. Compared with traditional methods based on the detection of extracts, the developed method is simple without any pretreatments and consumption of additional chemicals, which would become a popular evaluation methodology of the redox states of fruits and vegetables during their growth and storage stages. PMID- 29442671 TI - Improved UV Photodetection by Indium Doped TiO2 Thin Film Based Photodetector. AB - Indium (In) was doped into TiO2 thin film (TF) using the electron beam evaporation technique followed by an annealing process. The high resolution X-ray diffraction (HRXRD) analysis revealed lower angle diffraction peak (2?) shifting of Rutile (002) phases of TiO2 from 61.9 to 61.56 for an increased In doped samples. Calculated average grain size from FESEM (field emission scanning electron microscope) gradually decreased from 21.12 nm to 17.03 mm with an increase in In content ranging from 1.45~17.30 at%. HRXRD data revealed that crystallite sizes also reduced from 21.79 nm to 16.93 nm with an increased In doping concentration. Doping of In leads to the formation of inhomogeneous InxTiy O2 alloy that enhances the transition between 3.3-3.42 eV energy levels with variation in doping concentration. The photo-efficiencies for increased doping concentration of In with 3.47 at% and 17.30 at% were enhanced by 2.56 and 2.76 times, respectively, compared to the undoped TiO2 TF detector and both were larger than low doped In with 1.45 at% sample. The ratio of main band detection intensity to oxygen defect level was also increased from 0.22 to 2.22 with the gradual increase in In content. PMID- 29442672 TI - Ag/MnO2 Nanorod as Electrode Material for High-Performance Electrochemical Supercapacitors. AB - A one-dimensional hierarchical Ag nanoparticle (AgNP)/MnO2 nanorod (MND) nanocomposite was synthesized by combining a simple solvothermal method and a facile reduction approach in situ. Owing to its high electrical conductivity, the resulting AgNP/MND nanocomposite displayed a high specific capacitance of 314 F g 1 at a current density of 2 A g-1, which was much higher than that of pure MNDs (178 F g-1). Resistances of the electrolyte (Rs) and charge transportation (Rct) of the nanocomposite were much lower than that of pure MNDs. Moreover, the nanocomposite exhibited outstanding long-term cycling ability (9% loss of initial capacity after 1000 cycles). These results indicated that the nanocomposite could serve as a promising and useful electrode material for future energy-storage applications. PMID- 29442673 TI - Polypyrrole Nanotube-Derived Carbon Aerogels as Efficient and Recyclable Oil Absorbents. AB - Polypyrrole nanotube-derived carbon aerogels with three-dimensional networks have been prepared via freeze-drying and pyrolysis method using polypyrrole nanotubes as precursors. The resulting carbon nanotube aerogels display ultra-low density, fairly high mechanical properties, water repellency, superoleophilicity, high absorption capacity and fast absorption rate of oil and organic solvents. Its absorption capacity can reach in the range from 140 to 600 times of its own weight for the utilized common oil and organic solvents. Furthermore, the carbon nanotube aerogels demonstrate outstanding recyclability by distill or direct combustion in air because of their excellent hydrophobicity and fire-resistant properties. Significantly, the carbon nanotube aerogels maintain 82.2% absorption capacity after 100 absorption/combustion cycles. Our results suggest that the polypyrrole nanotube-derived carbon aerogels are suitable absorbents for a wide range of applications in water environment protection. PMID- 29442674 TI - Development of Biomimetic Hybrid Porous Scaffold of Chitosan/Polyvinyl Alcohol/Carboxymethyl Cellulose by Freeze-Dried and Salt Leached Technique. AB - Freeze drying and salt leaching methods were applied to fabricate Chitosan/Poly(vinyl alcohol)/Carboxymethyl cellulose (CPCMC) biomimetic porous scaffolds for soft tissue engineering. The properties of these scaffolds were investigated and compared to those by freeze drying and salt leaching methods respectively. The salt-leached CS/PVA/CMC scaffolds were easily formed into desired shapes with a uniformly distributed and interconnected pore structure with an average pore size. The mechanical strength of the scaffolds increased with the porosity, and were easily modulated by the addition of carboxymethyl cellulose. The morphology of the porous scaffolds observed using a SEM exhibited good porosity and interconnectivity of pores. MTT assay using L929 fibroblast cells demonstrated that the cell viability of the porous scaffold was good. Scaffolds prepared by salt leached method show larger swelling capacity, and mechanical strength, potent antibacterial activity and more cell viability than freeze dried method. It is found that salt leaching method has distinguished characteristics of simple, efficient, feasible and less economic than freeze dried scaffolds. PMID- 29442675 TI - Multifunctional Property of Graphene Oxide Nanostructures on Silica-Coated Cotton Fabrics. AB - In this article, the hydrophobic nature of colloidal silica sol prepared using the sol-gel method was studied. Uncoated cotton fabrics were impregnated with the prepared nanosols followed by pad-dry-cure method. The internal structure of nanosol was obtained through transmission electron microscopy. Graphene oxide nanostructures were deposited on the silica-coated fabrics by direct current (DC) magnetron sputtering techniques. The structural and morphological analyses of the coated and uncoated fabrics were performed using the X-ray diffraction and scanning electron microscopy techniques, respectively. The elemental analysis using energy-dispersive spectroscopy confirmed the presence of nanoparticles adhered to the cellulose present on the surface of the fabric. The thermal stability and wettability properties of the coated and uncoated fabrics were studied. The graphene oxide-coated cotton fabrics showed better UV properties and antibacterial activity against Staphylococcus aureus and Escherichia coli. The biocompatibility and UV protection of the coated fabrics were in the order of GOSiCF > silica-coated cotton fabrics > uncoated cotton fabrics. PMID- 29442676 TI - Bandgap-Engineered Zinc-Tin-Oxide Thin Films for Ultraviolet Sensors. AB - Zinc-tin-oxide thin-film transistors were prepared by radio frequency magnetron co-sputtering, while an identical zinc-tin-oxide thin film was deposited simultaneously on a clear glass substrate to facilitate measurements of the optical properties. When we adjusted the deposition power of ZnO and SnO2, the bandgap of the amorphous thin film was dominated by the deposition power of SnO2. Since the thin-film transistor has obvious absorption in the ultraviolet region owing to the wide bandgap, the drain current increases with the generation of electron-hole pairs. As part of these investigations, a zinc-tin-oxide thin-film transistor has been fabricated that appears to be very promising for ultraviolet applications. PMID- 29442677 TI - Preparation and Characterization of Nanosized Bi-Doped SnO2/Reduced Graphene Oxide 3D Hybrids for Visible-Light-Driven Photocatalysis. AB - The nanosized Bi-doped SnO2/reduced graphene oxide 3D hybrids have been synthesized via one-step hydrothermal method. The structures, morphologies, photocatalytic activities of the as-prepared samples were discussed, respectively. The formation mechanism of the as-prepared hybrids was also proposed. Experimental results indicated that the usage amount of Bi2Sn2O7 obviously affected the photocatalytic performance of the as-prepared products. When it was 450 mg, the as-prepared sample possessed the band gap energy of 1.9 eV and the photocatalytic efficiency of 90% in 210 min for degradation of rhodamine B solution. In addition, triethylene tetramine and the as-prepared carbon hydrogel could act as reductant to synergistically reduce Bi2Sn2O7 into Bi doped SnO2 particles during the formation of the hybrids. PMID- 29442678 TI - Surface Modification of Short Carbon Fibers with Carbon Nanotubes to Reinforce Epoxy Matrix Composites. AB - The homogeneous carbon nanotubes (CNTs) directly grown on short cut carbon fibers (CFs) surface by chemical vapor deposition (CVD) using iron nanoparticles as catalyst. The iron nanoparticles were obtained by the reduction of magnetite particles using mixed nitrogen and hydrogen gas flow at 415 degrees C. Magnetite particles were prepared through a solvothermal reaction, where iron(III) acetylacetone as catalyst source and polylol as solvent. CNTs grown on CFs were used as reinforcement in epoxy (EP). The effects of density of CNTs grown on CFs (CNTs-CFs) and different mass fractions of CNTs-CFs in EP on the composites flexural strength were investigated. Results indicate that the reaction of iron(III) acetylacetone can synthesize magnetite particles of ca. 10 nm coated on CFs only in triethylene glycol (TREG) or polyethylene glycol 200 (PEG200). When CNTs grown on CFs surfaces at catalyst source concentration of 1.5 mmol/L, the flexural strength of CNTs-CF/EP composites with the addition of 0.8 wt% CNTs-CFs was improved by 28.1% to 102.5 MPa compared to that of pure EP. The homogeneous CNTs grown on CFs enhanced interfacial bonding are responsible for the improvement of composites flexural strength. PMID- 29442679 TI - Synthesis, Structural, Optical and Dielectric Properties of Nanostructured 0-3 PZT/PVDF Composite Films. AB - Nanostructured PbZr0.52Ti0.48O3 (PZT) powder was synthesized at 500 degrees C 800 degrees C using sol-gel route. X-ray diffraction and Rietveld analysis confirmed the formation of perovskite structure. The sample heat treated at 800 degrees C alone showed the formation of morphotropic phase boundary with coexistence of tetragonal and rhombohedral phase. The PZT powder and PVDF were used in 0-3 connectivity to form the PZT/PVDF composite film using solvent casting method. The composite films containing 10%, 50%, 70% and 80% volume fraction of PZT in PVDF were fabricated. The XRD spectra validated that the PZT structure remains unaltered in the composites and was not affected by the presence of PVDF. The scanning electron microscopy images show good degree of dispersion of PZT in PVDF matrix and the formation of pores at higher PZT loading. The quantitative analysis of elements and their composition were confirmed from energy dispersive X-ray analysis. The optical band gap of the PVDF film is 3.3 eV and the band gap decreased with increase in volume fraction of PZT fillers. The FTIR spectra showed the bands corresponding to different phases of PVDF (alpha, beta, gamma) and perovskite phase of PZT. The thermogravimetric analysis showed that PZT/PVDF composite films showed better thermal stability than the pure PVDF film and hydrophobicity. The dielectric constant was measured at frequency ranging from 1 Hz to 6 MHz and for temperature ranging from room temperature to 150 degrees C. The composite with 50% PZT filler loading shows the maximum dielectric constant at the studied frequency and temperature range with flexibility. PMID- 29442680 TI - Tensile, Thermal, Dielectric and Morphological Properties of Polyoxymethylene/Silica Nanocomposites. AB - This paper presents the tensile, thermal, dielectric and morphological properties of composites based on polyoxymethylene (POM) and nanosilica (NS) prepared by melt mixing method at 190 degrees C. Based on the torque readings, the processing of POM/NS composites were found to be easier in comparison to only POM. The FT-IR spectra analysis of the POM/NS nanocomposites showed the presence of peak at approximately 910 cm-1, attributed to the Si-O and C-O groups in NS and POM on the POM/NS nanocomposite. The absorption at these peaks increased on gradually increasing the content of NS. Tensile property testing (tensile strength, elongation at break, and Young's modulus) indicated that the tensile strength of POM/NS nanocomposites increases as the NS content increases from 0.5 wt.% to 1.5 wt.%, and sharply dropped when the NS content was more than 2 wt.%. A similar trend was observed for Young's modulus and elongation at break of the nanocomposites. The DSC analysis of the nanocomposites showed that the melting temperature (Tm) of POM/NC composites increased in the presence of low weight % of NS which can be attributed to the interaction between POM and NS leading to the rising crystallinity of all nanocomposites. POM/NS have a slightly higher temperature resistance as confirmed from the TGA analysis and POM/NS 1.5 wt.% had the maximum degradation temperature (Tmax) value and consequently the lowest weight loss. The dielectric constant of the nanocomposites increased from 3.26 to 3.56, while the dielectric loss tangent and volume resistivity were dropped, corresponding to the NS content from 0.5 to 2 wt.%. The SEM images of POM/NS nanocomposites demonstrated that the NS particles were dispersed relatively regularly into POM with a size in the range of 100 to 500 nm. They were dispersed more regularly into the polymer matrix at 1.5 wt.% NS. Based on the obtained results, the suitable NS content for the preparation of the POM/NS nanocomposites was found to be 1.5 wt.%. PMID- 29442681 TI - Corrosion Protection Properties of Nano NH2-Reduced Graphene Oxide/Epoxy Composite Coatings Formed by Self-Curing on Magnesium Alloy. AB - Nano NH2-reduced graphene oxide (NGO) and NGO/epoxy resin coatings were prepared, respectively. NGO/epoxy coating was successfully coated on magnesium alloy substrates. X-ray diffraction patterns, Fourier transform infrared spectroscopy, Scanning electron microscopy techniques were used to characterize the composition and morphology of NGO and composite coatings. The effect of the content of NGO on the corrosion protection performance of coatings was evaluated with electrochemical measurements in 3.5 wt.% NaCl solutions. Tafel and electrochemical impedance spectroscopy analysis revealed that an optimal addition amount of 0.3 wt.% NGO provided the superior corrosion protection properties. The composite coatings exhibited outstanding barrier properties against aggressive species compared to pure epoxy coating. The self-curing reaction of amine and epoxy radicals could produce the compact cross-linking reticular structure. This self-curing reaction was a nucleophilic addition, and amine radical preferred to bond the (b) site of graphene sheets due to the lowest Gibbs free energy. The cross-linking structure and some polar groups could act as a good reservoir for corrosive medium via absorption and fixation. PMID- 29442682 TI - Improved Photocatalytic Hydrogen Production Performance Over NaTaO3/Reduced Graphene Oxide Composite Photocatalyst. AB - NaTaO3/reduced graphene oxide (RGO) composite were prepared via a two-step hydrothermal method. The as-prepared NaTaO3/RGO composite were characterized by X ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), UV-Vis diffuse reflectance spectra (DRS), photoluminescence spectra (PL) and X-ray photoelectron spectroscopy (XPS). The results indicated the reduction of graphene oxide and the chemical bonding between RGO and NaTaO3 are achieved simultaneously. As a result, NaTaO3/RGO composite possessed efficient charge separation properties. Hence, in the photocatalytic measurement toward the H2 production from an aqueous Na2S/Na2SO3 solution under UV illumination, a significant improvement in the H2 production rate was observed over NaTaO3/RGO composite, compared to the pure NaTaO3 and mechanically mixed NaTaO3-RGO composite with the same RGO content. In particular, the photocatalytic H2 production rate over NaTaO3/2%RGO with RGO content of 2 wt% was 3.82 times higher than that of pure NaTaO3. Moreover, the photocatalytic hydrogen production performance of NaTaO3/2%RGO was rather stable. A plausible electron transfer mechanism was proposed to discuss the improved photocatalytic H2 production performance. PMID- 29442683 TI - Time-Dependent Density Functional Theory Analysis of Triphenylamine Functionalized Graphene Doped with Transition Metals for Photocatalytic Hydrogen Production. AB - The electronic structures and optical properties of triphenylamine-functionalized graphene (G-TPA) doped with transition metals, using water as a solvent, were theoretically investigated to verify the efficiency of photocatalytic hydrogen production with the use of transition metals. This study was performed by Density Functional Theory and Time-dependent Density Functional Theory through Gaussian 09W software, adopting the B3LYP functional for all structures. The 6-31g(d) basis set was used for H, C and N atoms, and the LANL2DZ basis set for transition metals using the Effective Core Potentials method. Two approaches were adopted: (1) using single metallic dopants (Ni, Pd, Fe, Os and Pt) and (2) using combinations of Ni with the other dopants (NiPd, NiPt, NiFe and NiOs). The DOS spectra reveal an increase of accessible states in the valence shell, in addition to a gap decrease for all dopants. This doping also increases the absorption in the visible region of solar radiation where sunlight is most intense (400 nm to 700 nm), with additional absorption peaks. The results lead us to propose the G TPA structures doped with Ni, Pd, Pt, NiPt or NiPd to be novel catalysts for the conversion of solar energy for photocatalytic hydrogen production, since they improve the absorption of solar energy in the range of interest for solar radiation; and act as reaction centers, reducing the required overpotential for hydrogen production from water. PMID- 29442684 TI - Corrosion Protection Properties and Mechanism of Epoxy/Acetic Acid-Doped Polyaniline Coating on Magnesium Alloy. AB - Poly(amidoamine)(PAMAM)/epoxy/acetic acid-doped polyaniline (PAni) coatings were successfully prepared and coated on magnesium alloy substrates. X-ray diffraction pattern, Fourier transform infrared spectroscopy, scanning electron microscopy technique were used to characterize the composition and morphology of acetic acid doped PAni and composite coatings. The effect of the usage amount of doped PAni on the corrosion protection performance was evaluated with electrochemical measurement in 3.5 wt.% NaCl solutions. Tafel and electrochemical impedance spectroscopy analysis revealed that the addition of 1.0 wt.% doped PAni provided the superior corrosion protection properties. The corrosion protection mechanism was investigated by using electron probe microanalysis test and theoretical physical model. The doped PAni could obviously shrink the pits and made epoxy resin matrix denser by cross-linking and hydrogen bonding. The composite coatings exhibited better corrosion protection properties compared to pure epoxy coating. The in situ generated corrosion products provided anodic corrosion inhibition due to the easier penetration of acetate ions, and better physical barrier mechanism was promoted by the addition of doped PAni. PMID- 29442685 TI - Adsorption Performance of DNA onto Magnetic Core-Shell Structure (1 x)Ni0.5Zn0.5Fe2O4/xSiO2 Nanopowders Prepared via Methanol Combustion Process. AB - Magnetic core-shell structure (1-x)Ni0.5Zn0.5Fe2O4/xSiO2 (x = 0-0.2) nanopowders were successfully prepared via the methanol combustion process, the as-prepared magnetic core-shell structure nanopowders were characterized by XRD, SEM, TEM, HRTEM, BET, and VSM techniques, and the adsorption performance of DNA onto them was investigated. The results showed that the magnetic core-shell structure 0.9Ni0.5Zn0.5Fe2O4/0.1SiO2 nanopowders exhibited a good adsorption capacity of DNA, and the adsorbance of DNA for magnetic core-shell structure 0.9Ni0.5Zn0.5Fe2O4/0.1SiO2 nanopowders was enhanced to 2.8 times for Ni0.5Zn0.5Fe2O4 nanoparticles. The adsorption kinetics of DNA in aqueous solution onto the magnetic core-shell structure 0.9Ni0.5Zn0.5Fe2O4/0.1SiO2 nanopowders at room temperature were investigated, and the kinetics data were in good agreement with the pseudo-first-order kinetic model in the initial DNA concentration of 50 MUg/mL. PMID- 29442686 TI - Effects of the Trifluoromethyl Group on the Emission Efficiency of Red Phosphorescent Iridium(III) Complexes. AB - In this work, three novel phosphorescent iridium(III) complexes, namely (PT TFP)2Ir(tmd), (PT-P)2Ir(tmd), and (MN-TFP)2Ir(tmd), were synthesized. All three complexes were phosphorescent red-emitting diode materials. The main ligands were synthesized by the Suzuki coupling reaction, and comprised an electron donor and an electron acceptor group. Subsequently, the iridium(III) complexes were synthesized by the Nonoyama reaction and their photochemical luminescence properties were investigated by ultraviolet-visible and photoluminescence spectroscopy. The manufactured devices were characterized by current density voltage-luminance, power efficiency, external quantum efficiency, as well as their electroluminescence spectra. Finally, the effects of the trifluoromethyl group on the emission efficiency of the organic light-emitting diodes were investigated by comparing the energy levels and luminescence efficiency of the three iridium complexes. PMID- 29442687 TI - Analysis of Laser Injection Condition and Electrical Properties in Local BSF for Laser Fired Contact c-Si Solar Cell Applications. AB - A crystalline silicon (c-Si) local-back-contact (LBC) solar cell for which a laser-condition-optimized surface-recombination velocity (SRV), a contact resistance (Rc), and local back surface fields (LBSFs) were utilized is reported. The effect of the laser condition on the rear-side electrical properties of the laser-fired LBC solar cell was studied. The Nd:YAG-laser (1064-nm wavelength) power and frequency were varied to obtain LBSF values with a lower contact resistance. A 10-kHz laser power of 44 mW resulted in an Rc of 0.125 ohms with an LBSF thickness of 2.09 MUm and a higher open-circuit voltage (VOC) of 642 mV. PMID- 29442688 TI - Biosynthesis of SnO2 Nanoparticles Based on Response Surface Methodology and the Study of Their Dye Removal. AB - Litsea cubeba is an evergreen tree from the Lauraceae family, with the common name of mountain pepper in Taiwan. The extracts from different parts such as the bark, leaf, root and fruit have various medicinal properties and have been extensively used in traditional Chinese medicine. SnO2 nanoparticles (NPs) were synthesized using an extract of Litsea cubeba fruit based on response surface methodology (RSM). The phytochemicals present in the extract of Litsea cubeba fruit played a crucial role in the NP formation, which could be confirmed by Fourier-Transform Infrared Spectrometer (FTIR). Analysis of variance (ANOVA) was used to evaluate the validation of the RSM models and indicated that the quadratic model was highly significant and suitable to represent the response of the NP formation yield. The optimum parameters were determined using the Design Expert Program and were as follows: extract volume ratio 30.0%, pH 6.3 and reaction temperature 44.4 degrees C. Using the optimal reaction conditions from the central composite design (CCD) of RSM, the SnO2 NPs were prepared and characterized by field-emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM) and X ray diffraction (XRD). The FE-SEM results showed that the SnO2 NPs were spherical, and XRD results showed that the NPs had a tetragonal crystal structure. Furthermore, the photodegradation kinetics of malachite green by the SnO2 NPs was represented well with a pseudo first-order model. PMID- 29442689 TI - Synthesis and Characterization of Silicon/Reduced Graphene Oxide Composites as Anodes for Lithium Secondary Batteries. AB - Silicon (Si) is one of the most attractive anode materials for lithium secondary batteries because of its large theoretical capacity, high safety, low cost and environmental benignity. However, Si-based anode material needs to overcome the structural change of the solid-electrolyte interphase due to the large volume change during cycling. To resolve these problems of composites by exploiting the superior conductivity, large specific surface area and flexibility of graphene, we have synthesized reduced graphene oxide (rGO)/Si composite electrode via a simple dip-coating method. Nickel foam is used as a current collector and template for the electrode fabrication. At 0.03 wt%, Si concentration, the rGO/Si composite anode presented the excellent cycle performance with large reversible capacity (778 mAh g-1 after 100 cycles). The characteristics of the rGO/Si composites were analyzed by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), Raman and X-ray photoelectron spectroscopy (XPS). The improved anode performance of the rGO/Si composite anode is ascribed to the rGO serving as a buffer layer, thereby preventing the volume expansion of Si nanoparticles, and provide facile electron pathways. PMID- 29442690 TI - Physical Properties of Photo-Aged Graphene/Polypropylene Nanocomposites. AB - In the present research, graphene nanoplatelets/polypropylene (GNP/PP) nanocomposites were prepared by melt mixing and were subjected to accelerated ageing. The effect of graphene on the morphology and physical properties of aged GNP/PP nanocomposites was investigated. The incorporation of graphene to non-aged PP matrix led to changes in its crystal conformation, decreased the ultraviolet visible (UV-Vis) transmittance and tensile strain and increased the elastic modulus. The ageing of non-reinforced PP increased the beta-phase of PP and caused the formation of cracks on its surface, while voids were observed in its cross-section. The aged PP was also characterized by significantly lower UV-Vis transmittance, thermal stability and tensile strain, but increased elastic modulus compared to non-aged PP. Graphene retarded the ageing of PP matrix, according to Fourier Transform Infrared spectroscopy (FTIR) and X-ray Photoelectron Spectroscopy (XPS) results. In the aged GNP/PP nanocomposite, the morphology did not present any changes and the examined properties were maintained to similar values with that of non-aged GNP/PP nanocomposite. PMID- 29442691 TI - Insulator-to-Semiconductor-to-Conductor Phase-Like Transition of DNA Chains. AB - Using a tight-binding model, we study the transport of charge carriers through DNA molecular wires. In double-stranded DNA chains, according to Chargaff's rules, only Adenine-Thymine (AT) and Cytosine-Guanine (CG) pairs are allowed. In our model, a decimation procedure allows us to represent each pair of bases by a single site with one localized electronic state. We consider chains of different lengths with only AT (CG) sites, and ordered and disordered chains with both types of sites. Disordered chains may include short range correlation. Additionally, hydration is considered in the form of a change of the site energy. We find a conductor-to-semiconductor-to-insulator transition as a function of the three effects taken into account: chain size, intrinsic disorder of CG and AT pairs, and hydration. This model predicts that an appropriate choice of chain size and concentration of AT pairs can be used to tailor the electrical behavior of DNA strands. PMID- 29442692 TI - Observation of High-Frequency Raman Modes in FeCl3- and Zn-Intercalated MoS2 Flakes. AB - In place of the widely studied graphene, monolayer or few-layer MoS2 flakes are promising materials for next-generation optoelectronic devices. MoS2 has attracted increasing attention in physics and its applications because of its capacity to undergo indirect-to-direct band gap transition. Raman spectroscopy is a useful and versatile tool to probe the physical properties of pristine and intercalated MoS2. This study investigates for the first time the multiphoton modes of FeCl3- and Zn-intercalated few-layer MoS2 at high frequencies of 1513 and 1732 cm-1 for FeCl3-MoS2 and 1341 and 1604 cm-1 for Zn-MoS2. The substrates interact with MoS2 during intercalation. The Raman peak intensities of the intercalated samples vary with intercalation time while keeping the peak position nearly constant. This finding is interesting and suitable for studying other 2D layered materials. PMID- 29442693 TI - A Study of Preparation and Characterization of Poly(vinyl alcohol) Coated Copper Nanoparticles in Aqueous Solution. AB - We have developed a new solution-phase chemical reduction method for the synthesis of poly(vinyl alcohol) coated copper nanoparticles in aqueous solution. Copper nitrate is used as the precursor, sodium hypophosphite as the reducing agent, and poly(vinyl alcohol) as the coating agent. The synthesis of copper nanoparticles could be completed within several hours and the copper nanoparticles in powder form could be stored within one week in ambient condition. In Ar atmosphere, the complete thermal decomposition temperature of coated layer was lower than 450 degrees C. The antioxidative properties of poly(vinyl alcohol) coated copper nanoparticles were evaluated compared to that of polyvinylpyrrolidone coated copper nanoparticles. PMID- 29442694 TI - Effect of Ag Doping on the Glancing Angle Deposition Synthesized TiO2 Nanowire for Enlarged Photodetection. AB - Glancing Angle Deposition (GLAD) technique was employed to synthesize Ag doped TiO2 nanowire on n-type Si-substrate. FEG-SEM confirms the perpendicular growth of Ag doped TiO2 nanowire with an average height and diameter of ~554 nm and ~40 nm respectively. The composition analysis by EDAX indicates the presence of Ti, O, Si and Ag elements. The increase in PL intensity has been observed with the increase in temperature. Following the growth of Ag doped TiO2 nanowire, Au contacts were deposited to form the Ag doped TiO2 NW based Schottky detector. The enhancement in the photoresponse of the device was observed at -4 V. The device also shows low leakage current of -0.049 MUA at -1 V which makes it suitable for enlarged photodetector application. PMID- 29442695 TI - Enhancing Upconversion from NaYF4:Yb,Er@NaYF4 Core-Shell Nanoparticles Assembled on Metallic Nanostructures. AB - We report a simple method for the fabrication of a three-layered plasmonic structure of silicon substrate-Au nanospheres-upconversion particles (UCNPs) that displays up to 101-fold fluorescence enhancement. Monodispersed pure hexagonal phase NaYF4:Yb,Er core and NaYF4:Yb,Er@NaYF4 core@shell nanocrystals were prepared by a solvothermal method. Two dimensional (2D) assembled Au spheres were prepared on a Si substrate, and then, 2D arrays of UCNPs were deposited on the grown 2D monolayered Au spheres by a self-organizing process. The distance between plasmonic Au NPs and rare-earth (RE) core was finely adjusted by changing the undoped NaYF4 shell thickness. The UC emission enhancement shows a pronounced shell thickness dependence. For the non-plasmonic structured samples, a single peak in upconversion luminescence (UCL) enhancement was observed as the undoped NaYF4 shell thickness increases from 0 nm to 23.0 nm. In contrast, for the plasmonic structured samples, multi-oscillations in UCL enhancement were observed in the undoped NaYF4 shell thickness range of 0-23.0 nm, where the UCL enhancement factors of three bands (521 nm, 540 nm and 654 nm) are high up to 65, 101 and 61, respectively, at 19.6 nm-thick NaYF4 shell. The multi-oscillations in UCL enhancement in the plasmonic samples can be associated with plasmonic coupling between arrays of core-shell UCNPs with various sizes and the underlying 2D Au spheres. The related mechanisms of the UCL enhancements are discussed. PMID- 29442696 TI - Effect of Selenization Processes on CIGS Solar Cell Performance. AB - Cu(In, Ga)Se2 (CIGS) films were fabricated by a two-step process method using sputtering from Cu0.7Ga0.3 and In targets. The metallic precursor structures of In/CuGa/In were prepared, and CuGa film was adjusted to the thicknesses of 150, 200, 250 and 300 nm, in order to optimize the CIGS film. After selenization, three independent CIGS (112), CIGS (220/204) and CIGS (312/116) began to crystallize at ~280 degrees C and phase peaks continued growing until 560 degrees C. Experimental results showed that with a single stage selenization method, the excessive stoichiometry of the CIGS films was obtained. Using three sequential stages for the selenization process, with a annealing time of 20 min, the stoichiometry of the CIGS absorbers with the Cu/(In + Ga) and Ga/(In + Ga) showed atomic ratios of 0.94 and 0.34, respectively. The intensity of the (112) XRD diffraction peak became stronger, indicating an improvement in the crystallinity. Raman spectra of CIGS absorbers showed a main peak (174 cm-1) and two weak signals (212 and 231 cm-1). TEM image for electron diffraction pattern showed that the grains were randomly oriented. CIGS solar cell device prepared with a proper selenization, a maximum efficiency of 12.45% was obtained. PMID- 29442697 TI - A Facile Way to Fabricate Transparent Superhydrophobic Surfaces. AB - A fast, easy, and low-cost way to fabricate transparent superhydrophobic (SHP) surfaces is developed. By simply mixing silica nanoparticles (SiNPs), polydimethylsiloxane (PDMS) and heptane to form a suspension, dip- or drop coating the suspension onto different surfaces, transparent SHP surfaces can be obtained. By tuning the ratio of the three components above, transparency of the coating can reach more than 90% transmittance in the visible region, while static water contact angle of the coating can reach as high as 162 degrees . Dynamic contact angle study shows the advancing contact angle and receding contact angle of water can be as high as 168 degrees and 161 degrees , and the resulting contact angle hysteresis can be as low as 7 degrees . The reported facile way of fabricating transparent superhydrophobic (SHP) surfaces is potential for applications which need both optical transparency and self-cleaning capability, such as solar cells, optical equipment, and visible microfluidic chips. PMID- 29442698 TI - Surface Reconstruction for Preparation of Plasmonic Au/TiO2 Nanoparticle with Perfect Hetero Interface and Improved Photocatalytic Capacity. AB - The photocatalytic activity of plasmonic Au/TiO2 nanoparticles (NPs) is dependent on distances between Au and TiO2. The preparation of plasmonic NPs is still a challenge because of an inherent lattice mismatch on heterogeneous interfaces. The combination between Au and TiO2 NPs often exhibits physical adsorption, which affect block the electron transferring process by photo-induction from TiO2 to Au NPs and weaken the photocatalytic activity. In this work an approach for preparing plasmonic Au/TiO2 NPs with perfect hetero-interface was proposed based on reconstruction of anatase TiO2 with (101) surface and in-situ reduction of Au NPs. Under UV-irradiation, anatase TiO2 NPs with a high percentage of (001) facets in formaldehyde solution undergo photochemical reactions to reconstruct the (101) surface of TiO2 and simultaneously allow polyformaldehyde to absorb on the same surface. Thus, Au(OH)-4 ions could be adsorbed on the (101) surfaces of TiO2 through electrostatic adsorption and reduced to form nano-Au in situ after recrystallization at 180 degrees C. The high-resolution transmission electron microscopy (HRTEM) images showed clear nanoscale lattice transition on heterogeneous interfaces of Au/TiO2 NPs. The surface structure of TiO2 NPs and the growth mechanism of Au/TiO2 NPs were evaluated with HRTEM, X-ray photoelectron spectra (XPS) and Fourier transform infrared spectroscopy (FTIR). It was demonstrated that the as-prepared plasmonic Au/TiO2 NPs had higher photocatalytic activity and corrosion resistance in comparison with primary TiO2 NPs by photo-electrochemical measurements. The reinforcing mechanism could be interpreted with Mott-Schottky analysis in terms of quantum mechanics. Our study implied that the reconstruction based synthesis may open up more opportunities to obtain lattice-mismatch nanomaterials for photocatalysis. PMID- 29442699 TI - Br-Doping CH3NH3PbI3-xBrx Thin Films for Efficient TiO2 Nanorod Array Perovskite Solar Cells. AB - CH3NH3PbI3-xBrx thin films with different Br contents were successfully prepared on TiO2 nanorod array using 1.7 M PbI2 . DMSO complex solution and 0.465 M CH3NH3x(x = Br, I) precursors with different CH3NH3Br contents (molar ratios) by sequential deposition method. The influence of CH3NH3Br contents on the chemical composition, crystallinity, optical absorption and surface morphology of the CH3NH3PbI3-xBrx thin films was systematically investigated, and the photovoltaic performance of the corresponding TiO2 nanorod array perovskite solar cells was evaluated. The results revealed that the CH3NH3PbI3-xBrx solar cells using CH3NH3x precursors with 5% CH3NH3Br exhibited the best photoelectric conversion efficiency (PCE) of 16.47%, along with an open-circuit voltage (Voc) of 1.02 V, short-circuit photocurrent density (Jsc) of 20.99 mA . cm-2 and fill factor (FF) of 0.77, and the average PCE of 16.06 +/- 0.52%, along with Voc of 1.02 +/- 0.01 V, Jsc of 20.41 +/- 0.58 mA . cm-2 and FF of 0.77 +/- 0.01 under illumination of simulated AM 1.5 sunlight (100 mA cm-2). PMID- 29442700 TI - Synthesis of Cu Nanoparticles Using Copper Carbonate as Cu Source Toward Versatile Applications. AB - Cu nanoparticles (NPs) coated with polyvinylpyrrolidone (PVP) were fabricated by polyol method using copper carbonate as a raw material. To increase the reaction temperature, glycol multimers such as diethylene glycol, triethylene glycol, or tetraethylene glycol were examined as a solvent. With increasing degree of multimerization, average diameter of Cu NPs decreased. The synthesis of Cu NPs was further investigated by changing reaction temperature, the amount and molecular weight of PVP in triethylene glycol as a solvent. Average diameter and standard deviation of Cu NPs were found to be highly dependent on those factors. As a result, fine Cu NPs ranging from 28 to 67 nm in average size with narrow size distribution (standard deviation: 16-28%) were obtained. The obtained Cu NPs were applied to a nanofluid, which showed higher thermal conductivity than the theoretical value. The antibacterial activity of Cu NPs was also demonstrated, and found to have strong antibacterial activity. PMID- 29442701 TI - Graphene Oxide Nanocoating Prevents Flame Spread on Polyurethane Sponge. AB - Many current flame retardant technologies for polymeric materials contain environmentally harmful compounds, negatively impact processing and mechanical properties. In an effort to tackle these issues, graphene oxide (GO) nanocoating was deposited on the surface of polyurethane sponge (PUS) to reduce its flammability via layer-by-layer (LbL) assembly method. The results indicated that GO was evenly distributed on the surface of PUS to form GO coating PUS (PUS@GO) composites. This coating system completely eliminated melt dripping of sponge upon exposure to the direct flame from a butane torch. According to the result of cone calorimeter test, PUS@GO composites exhibited excellent flame retardancy. In particular, PUS@GO composites submerging into 5 mg . mL-1 GO suspension, had significant reduction in the PHRR value (53.3%), THR value (35.9%), SPR value (61.8%), TSR value (81.9%), and peak CO production value (65.8%). Such significant improvement in flame retardancy suggested that GO nanosheets were good candidate as a flame-retardant LbL coating to reduce the flammability of PUS. PMID- 29442702 TI - Template-Assisted Hydrothermal Growth of One-Dimensional Zinc Oxide Nanowires for Photocatalytic Application. AB - One-dimensional (1D) semiconductor ZnO nanowires have been successfully synthesized by a novel soft-chemical hydrothermal method with allylpolyethoxy amino carboxylate (AA-APEA) at low temperature. Their structure and properties have been characterized by a series of techniques, including X-ray diffraction (XRD), energy dispersive X-ray analysis (EDX) and transmission electron microscopy (TEM). It was found that ZnO nanowires with diameters around 50 nm and lengths up to about several micrometers are well-distributed. The photocatalytic activity toward degradation of methylene blue (MB) aqueous solution under ultraviolet (UV) was investigated and the results showed that the ZnO nanowires exhibit a markedly higher photoactivity compared to the ZnO nanoparticles which were obtained without AA-APEA polymer assistant, and it can be ascribed to the special 1D morphology of the ZnO nanowires. In particular, the rate of degradation of the ZnO nanowires was 11 times faster than that of ZnO nanoparticles. In addition, the ZnO nanowires could be easily recycled in UV photocatalytic activity. These observations could promote new applications of photocatalyst for wastewater treatment utilizing oxide semiconductor nanostructures. PMID- 29442703 TI - Microstructure, In-Plane Magnetic Properties, and Surface Energy of Co60Fe20V20 Thin Films. AB - Co60Fe20V20 thin films with thicknesses ranging from 3 to 13 nm were sputtered onto a Si(100) substrate at room temperature (RT). Captured selected-area diffraction patterns (SADs) and high-resolution cross-sectional transmission electron microscopy (HR X-TEM) images revealed that the microstructures of the Co60Fe20V20 thin films were amorphous. The hysteresis loop of the thinner Co60Fe20V20 thin films displayed the in-plane magnetic anisotropy, possibly as a result of atmo-spheric exposure. A comparison of saturation magnetization (Ms) and thicknesses indicated a concave-down phenomenon due to magnetic coupling. In addition, the coercivity (Hc) also suggested a concave-down trend because the thinner Co60Fe20V20 thin films had a greater pining sites effect and rendered the domain wall difficult to move, resulting in higher Hc and lower Ms. The contact angles were smaller than 90 degrees , indicating that the films were hydrophilic. The surface energy, which had a close positive correlation with adhesion ranged from 22.3 to 33.3 mJ/mm2 and displayed a concave-up trend. The critical thickness was 5 nm. Based on the magnetic and surface energy results, the optimal thickness of Co60Fe20V20 films is 7 nm due to high Ms, low Hc, and strong adhesion. They are suitable for use as a free layer of the magnetic tunneling junction and can be applied in magnetic recording media. PMID- 29442704 TI - Ziegler-Natta Catalyst Based on MgCl2/Clay/ID/TiCl4 for the Synthesis of Spherical Particles of Polypropylene Nanocomposites. AB - In the present work, we have designed MgCl2/clay/internal donor (ID)/TiCl4 based bisupported Ziegler-Natta catalysts containing varying amounts of organoclay (montmorillonite) in order to synthesize spherical particles of polypropylene/clay nanocomposites (PCN). The organoclay was introduced into the catalyst support formulation and PCN was obtained using the in situ polymerization technique. Decreasing the reaction time, it was possible to obtain nanocomposites with high concentrations of clay (masterbatches). Micrographs of SEM confirmed the spherical morphology of the catalysts. In addition, XRD patterns show that the active sites for polymerization were inserted in the clay galleries. The catalytic performance was evaluated in slurry propylene polymerization using triethylaluminium as cocatalyst and silane as external electron donor at 70 degrees C, 4 bar, and different reaction times. The PCNs obtained containing different clay amounts were characterized by X-ray diffraction, thermal analyses, transmission electronic microscopy, and extractables in heptane. The results revealed that the synthesized PP/clay particles were also spherical showing that the morphological control is possible even using catalysts containing high amounts of clay. The PCN presented high degradation temperature (459 degrees C). The XRD peak related to the clay interlamellar distance has shifted to lower angles, and TEM images confirmed the formation of exfoliated/intercalated clay on the PP matrix and absence of microparticles of clay. PMID- 29442705 TI - Synthesis of Nanocomposites of Polypropylene with Graphite Nanosheets by In Situ Polymerization Using a Fourth Generation Ziegler-Natta Catalyst. AB - Polypropylene nanocomposites with expanded graphite nanosheets (xGN) were synthesized by In Situ polymerization employing a Ziegler-Natta catalyst supported on particles of MgCl2 containing xGN (mass ratio 1:1) and internal electron donor to control isotacticity, and their properties were compared with those of neat polypropylene obtained using a prepared standard Ziegler-Natta catalyst. SEM micrographs showed an alteration in the morphology of the catalyst with nanoparticles when compared with the standard one. It was noted that the catalyst containing xGN was more reactive for propylene polymerization than the standard one. By thermogravimetric analyses, it was detected that the PP/xGN nanocomposites showed higher thermal stability than PP. Differential scanning calorimetry (DSC) showed that the nanocomposites presented higher crystallinity degree, indicating that the nanofillers acted as nucleating agent. Scanning (SEM) and transmission (TEM) electron microscopies showed that the nanofillers were well dispersed into the PP matrix. By dynamic-mechanical analyses (DMA) it was observed an increase in glass transition temperature and the nanocomposites moduli. PMID- 29442706 TI - Human Adipose Derived Stem Cells and Osteoblasts Interaction with Fe-Cr-Nb-B Magnetic Nanoparticles. AB - The use of materials at nanoscale is currently of increasing interest for life sciences and medicine. Magnetic nanoparticles (MNPs) are under scrutiny for a large array of applications in nanomedicine as diagnostic and therapeutic tools. Proprietary Fe-Cr-Nb-B MNPs display heating properties that recommends them as potent agents for delivery of local hyperthermia for the treatment of solid tumours. Stem cell mediated delivery represents a safe and accurate modality to target remote or metastatic tumour sites. In this study we investigated the interaction of Fe-Cr-Nb-B nanoparticles with human adipose derived mesenchymal stem cells and human primary osteoblasts. We found that: (a) bare and chitosan coated Fe-Cr-Nb-B are internalized by both cell types, (b) they can be detected up to 28 days inside the cells without signs of membrane disruption and (c) they do not display in vitro toxicity. MNPs are uploaded by cells in a time dependent manner with maximum uptake after 7-8 days cell-particle incubation. Particle internalization do not interfere with proliferative and differentiation potential (osteogenesis and adipogenesis) demonstrating an unaltered cellular phenotype. Further investigation of the potential effect of MNPs internalization on cytoskeleton dynamics and in inducing oxidative stress will be required as it is of interest for predicting cell migration and survival after transplantation. Present results are encouraging for designing a stemcell mediated delivery of Fe Cr-Nb-B magnetic nanoparticles to solid tumour sites for hyperthermia applications. PMID- 29442707 TI - Applications of Metal Nanoparticles as Catalysts in Cleaning Dyes Containing Industrial Effluents: A Review. AB - From the last few decades, water pollution due to the dye containing effluents, which are released from various dyeing industries, has become one of the major environmental problems. Continuous efforts are going on to effectively deal with industrial wastewater containing aromatic pollutants. Varieties of physical, biological and chemical methods have been developed for this purpose. Among these methods, recently the catalytic reduction of water soluble dyes over heterogeneous catalysts has gained immense attention for treatment of dye containing wastewater because it offers high efficiency. In this review article, the use of metal nanoparticles based catalysts for the catalytic reduction of water soluble dyes has been discussed. Various synthetic methods to prepare these nanocatalysts with typical examples, their advantages, as well as limitations, have also been discussed in details. PMID- 29442708 TI - Aptamer-Targeted Magnetic Resonance Imaging Contrast Agents and Their Applications. AB - Magnetic resonance imaging is a powerful diagnostic technology with high spatial resolution and non-invasion. The contrast agents have significant effect on the resolution of the MR imaging. However, the commercial contrast agents (CAs) usually consist of individual Gd3+ chelated with a low molecular weight acyclic or cyclic ligand, and these small-molecule CAs are usually subjected to nonspecificity, thus leading to rapid renal clearance and modest contrast enhancement for tumor imaging. In recent years, the nanostructured materials conjugated with aptamers were widely used and opened a new door in biomedical imaging due to excellent specificity, non-immunogenicity, easily synthesis and chemical modification of aptamers. This review summarizes all kinds of aptamertargeted MRI CAs and their applications. PMID- 29442709 TI - Radiosensitization by Liposome-Encapsulated Fullerenes to Mitochondria/DNA Damages on Human Melanoma Cells. AB - The polyhydroxy small-gap fullerenes [C120O30(OH)30 . 30H2O . 25Na+: SGFs] were encapsulated in multilamellar liposomes (Lpsm) composed of 1,2-dioleoyl-sn glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phospho-l-serine (DOPS), which are designated as LpsmSGFs (DOPC/DOPS/SGFs = 35 mM:15 mM:246-445 MUM, diameter = 141.2 nm, zeta-potential = -35.65 mV). Radiosensitization by LpsmSGFs under X-ray irradiation was evaluated on human melanoma HMV-II cells. On 7th day after X-ray irradiation, cell proliferation degree assessed by WST-8 decreased more markedly on cells pretreated with LpsmSGFs than Lpsm or free-SGFs. Fluorescent imaging of cells with Rhodamine123, dihydroethidium or anti-8 hydroxydeoxyguanosine antibody was monitored as an indicator for mitochondrial membrane potentials, intracellular superoxide anion radicals (O-2) or oxidative DNA-damages, respectively. After X-ray irradiation, LpsmSGFs obviously exhibited more augmented mitochondrial membrane potentials on perinuclear region of cells than Lpsm or free-SGFs. Without X-ray irradiation, superoxide anion radicals were found principally in the cytoplasm, but, when exposed to X-ray, they were found in cell nuclei associated with oxidative DNA-damages on cells pretreated with LpsmSGFs. Meanwhile, the oxidation-reduction potentials of SGFs aqueous solution increased by X-ray irradiation. These results suggest that LpsmSGFs-mediated generation of reactive oxygen species results in damages to cellular components such as mitochondria and DNA on cells, and thereby cell proliferation decreased. The LpsmSGFs has a potential as a pro-oxidative type radiosensitizer. PMID- 29442710 TI - PEG-dBSA-RuS1.7 Nanoclusters as a NIR Light and pH Responsive Drug Delivery Nanoplatform for Chemo-Photothermal Synergistic Therapy. AB - A combination of chemotherapy and photothermal therapy has emerged as a promising method of cancer treatment since it can enhance therapeutic efficacies and reduce side effects. Herein, we fabricated doxorubicin (DOX) loaded PEG-dBSA-RuS1.7 which could be used as a synergistic therapeutic nanoplatform. The PEG-dBSA RuS1.7/DOX nanoparticles exhibit good monodispersity, physiological stability and biocompatibility. Moreover, the prepared PEG-dBSA-RuS1.7/DOX nanoparticles can intelligently release DOX by pH- and NIR-triggered therapy. In comparison with chemotherapy or photothermal treatment alone, the combined therapy shows a better therapeutic effect. We believe that the PEG-dBSA-RuS1.7/DOX can act as an efficient multifunctional nanoplatform for chemophotothermal synergistic cancer therapy. PMID- 29442711 TI - Synthesis of Nitrogen- and Chlorine-Doped Graphene Quantum Dots for Cancer Cell Imaging. AB - In this study, we synthesized high quantum yield nitrogen and chlorine-doped graphene quantum dots (Cl-GQDs-N) for cancer cell imaging using simple and high production yield hydrothermal method from low-cost fructose. Prepared Cl-GQDs-N are about 30 nm in diameter and these Cl-GQDs-N display powerful blue color photoluminescence under the 365 nm UV lamp. We have further investigated their optical performances under various conditions. In vitro study shows no toxicity effect in normal and cancer cells treated with Cl-GQDs-N. Finally, we believe that our synthesized Cl-GQDs-N will bring more application opportunities in the field of bioimaging, optoelectronics and beyond. PMID- 29442712 TI - Development of a Colloidal Gold-Based Immunochromatographic Assay for the Rapid Detection of Edwardsiella Ictaluri. AB - Edwardsiella Ictaluri is known as the etiological agent of enteric septicaemia of channel catfish, causing heavy economic losses in the aquaculture industry. In this study, a colloidal gold-based immunochromatography assay (GICA) was developed for rapid detection of E. ictaluri. Briefly, monoclonal antibody (MAbs) and polyclonal antibody (PAbs) against E. ictaluri were prepared. Sensitivity of MAbs and PAbs to E. ictaluri was analyzed by Dot ELISA. Mouse MAb5D11 against E. ictaluri was conjugated with the 20 nm colloidal gold particles as the detector. Rabbit PAbs of E. ictaluri and goat anti-mouse IgG antibody was sprayed on nitrocellulose membranes as test line (T) and control line (C) respectively. The minimum detectable amount of this method to E. ictaluri was 5 * 106 CFU/mL. Cross reactions wouldn't occur when detecting E. tarda, Aeromonas hydrophila, V. parahaemolyticus and other several common standard strains. The result could be got in only 5 to 10 minutes. It didn't need professional technologies and testing experience. So this assay was very suitable for basic departments of aquatic product companies. PMID- 29442713 TI - Antibacterial Activities of Bacteriagenic Silver Nanoparticles Against Nosocomial Acinetobacter baumannii. AB - Acinetobacter baumannii has emerged as one of the major nosocomial pathogens implicated in variety of severe infections and mortality. It is rapidly developing multi-drug resistance and also possesses surface colonization ability, which make it most difficult to treat through traditional antibiotics. This is an extensive study to describe the antibacterial activity of bacteriagenic silver nanoparticles (AgNPs) against A. baumannii AIIMS 7 in planktonic and biofilm mode. Minimum inhibitory concentration of antibiotics were in the range of 1 to 4096 MUg/ml whereas AgNPs inhibited planktonic bacteria at concentration of 16 MUg/ml. Fractional inhibitory concentration index revealed the synergistic interaction of AgNPs with doxycycline, tetracycline and erythromycin. Nanoparticles exhibited significant biofilm disruption activity with minimum biofilm eradication concentration of 2 mg/ml. Eradication of mature biofilm was enhanced on exposure to combination of AgNPs and antibiotics. These nanoparticles affected bacterial growth and distorted cellular morphology. Intracellular oxidative stress, induced in presence of AgNPs, also rendered bacteria susceptible to killing by nanoparticles. Besides this, AgNPs were found to interact with thiol-groups, which indicate their potential to interact with cellular proteins to exhibit antimicrobial activity. PMID- 29442714 TI - Silver Nanoparticles Modified with Sodium Triphosphate: Antibacterial Activity, Hemocompatibility and Cytotoxicity. AB - In this study, we report silver nanoparticles (Ag NPs) modified with sodium triphosphate (STTP) (Ag-STPP NPs) prepared by a simple surface modification and chemical reduction method. It was confirmed by 31P NMR spectroscopy that STPP was successfully introduced to the surface of Ag NPs. It was revealed by conductivity change measurements, bacterial growth kinetics and antibacterial efficiency tests that Ag-STPP NPs still retained the strong antibacterial ability. It was demonstrated by hemolysis assays, red blood cell morphology measurements, plasma recalcification time and in vitro clotting times that Ag-STPP NPs had improved hemocompatibility. It was also implied by cell viability measurements that Ag STPP NPs possessed low cytotoxicity and high cytocompatibility. These findings, combined with the low-cost and ease of synthesis, make Ag-STPP NPs a promising candidate for biomedical applications. PMID- 29442715 TI - Surface-Enhanced Raman Spectroscopy for Staphylococcus aureus DNA Detection by Using Surface-Enhanced Raman Scattering Tag on Au Film Over Nanosphere Substrate. AB - We developed a high-performance surface-enhanced Raman scattering (SERS) sensing platform that can be used for specific and sensitive DNA detection. The SERS platform combines the advantages of Au film over nanosphere (AuFON) substrate and Ag@PATP@SiO2 SERS tag. SERS tag-on-AuFON is a sensing system that operates by the self-assembly of SERS tag onto an AuFON substrate in the presence of target DNAs. The SERS signals can be dramatically enhanced by the formation of "hot spots" in the interstices between the assembled nanostructures, as confirmed by finite difference time-domain (FDTD) simulation. As a new sensing platform, SERS tag-on AuFON was utilized to detect Staphylococcus aureus (S. aureus) DNA with a limit of detection at 1 nM. A linear relationship was also observed between the SERS intensity at Raman peak 1439 cm-1 and the logarithm of target DNA concentrations ranging from 1 MUM to 1 nM. Besides, the sensing platform showed good homogeneity, with a relative standard deviation of about 1%. The sensitive SERS platform created in this study is a promising tool for detecting trace biochemical molecules because of its relatively simple and effective fabrication procedure, high sensitivity, and high reproducibility of the SERS effect. PMID- 29442717 TI - Fabrication of a Novel Beta Tricalcium Phosphate/Sodium Alginate/Poly(D,L-lactic acid) Composite Microsphere and Its Drug Releasing Property. AB - Bone repair microspheres have been widely studied due to their convenience during clinical operations. In this study, beta tricalcium phosphate/sodium alginate/poly(D,L-lactic acid) (beta-TCP/SA/PDLLA) composite microspheres were successfully prepared using the liquid droplet method. Then, beta-TCP/SA/PDLLA composite microspheres were soaked in simulated body fluids (SBF) for 7 days, and tested in an X-ray diffractometer (XRD). The results indicated that sodium alginate (SA) and poly(D,L-lactic acid) (PDLLA) are not limiting factors for the transformation of beta-TCP to HA. Since sodium ions and bicarbonate ions were abundant, the final products were not pure HA but (Na, CO3)-substituted HA. When soaked in SBF, the structure of beta-TCP/SA/PDLLA composite microspheres remained stable for at least 14 days suggesting that their anti-washout ability was suitable. Furthermore, the absence of calcination during the preparation of beta TCP/SA/PDLLA composite microspheres enabled the easy incorporation of vancomycin into the microspheres in situ at a final embedding ratio of 26.18%. Furthermore, the beta-TCP/SA/PDLLA composite microspheres possessed excellent sustained drug release capability, and the release of vancomycin (92.8 wt.%) lasted for almost 168 h. Our results suggest that the beta-TCP/SA/PDLLA composite microspheres could be used as a promising graft material particularly for bone repair. PMID- 29442716 TI - Development of a Promising Antitumor Compound Based on Rhodium(II) Succinate Associated with Iron Oxide Nanoparticles Coated with Lauric Acid/Albumin Hybrid: Synthesis, Colloidal Stability and Cytotoxic Effect in Breast Carcinoma Cells. AB - In this study, we report the synthesis and characterization of a new rhodium(II) succinate complex (Rh2(suc)4) and its immobilization on lauric acid bilayer coated maghemite nanoparticles (MGH-2L/Rh2(suc)4) and subsequent adsorption with bovine serum albumin (MGH-2L/Rh2(suc)4/BSA). Rh2(suc)4 has been characterized by elemental analysis, potentiometric titration, TGA, MS, FTIR and UV-Vis analysis. The maghemite phase was confirmed by XRD, and a diameter of 10 nm was obtained by Sherrer equation. The VSM experiment showed superparamagnetic properties. TEM showed nanoparticles with a spherical shape and a mean diameter of 8.5+/-0.4 and 9.1 +/- 0.4 nm for MGH-2L/Rh2(suc)4 and MGH-2L/Rh2(suc)4/BSA, respectively. FTIR and TGA confirmed the immobilization of Rh2(suc)4 and bovine serum albumin adsorption on superparamagnetic iron oxide. Hydrodynamic size (DH) and zeta potential (zeta) measurements were made in aqueous, NaCl and DMEM media. DH for dispersions was lower in aqueous medium, but increased in saline and DMEM media. In aqueous and saline media, zeta was not altered for MGH-2L and MGH 2L/Rh2(suc)4, but was significantly lower for MGH-2L/Rh2(suc)4/BSA. Therefore, MGH-2L/Rh2(suc)4/BSA was the most stable dispersion, meaning that BSA coating prevents aggregation more than lauric acid bilayer coating. MGH-2L/Rh2(suc)4 and MGH-2L/Rh2(suc)4/BSA dispersions induced cytotoxicity in breast carcinoma (MCF-7) and fibroblast cells in culture, and this effect was higher than that exerted by free Rh2(suc)4 and more specific to breast carcinoma cells than to fibroblasts. Therefore, we suggest that these dispersions have an important potential for future clinical applications and, thus, they should be considered a platform to enhance Rh2(suc)4 cytotoxicity, specifically in breast carcinoma. PMID- 29442718 TI - Deacetyl Mycoepoxydience Nanocrystals Dispersible Tablets Formulation and In Vitro Study. AB - A novel nanocrystal dispersible tablets was developed by apply quality by design (QbD) approach in this study. Following Deacetyl Mycoepoxydience (DM) nanosuspensions was prepared by antisolvent precipitation approach; the DM nanocrystal was solidified by freeze-drying method. Following the screening of cryoprotectants for solidification of the nanosuspensions, the physicochemical properties including re-dispersability, mean particle size (MPS), morphology and dissolution behavior of the DM nanocrystal was investigated. Experiment was designed with focus on the types and quantities of disintegrating agent during the DM nanocrystal dispersible tablets preparation. The DM nanocrystal-loaded dispersible tablets were produced using direct powder compression. Judging form the tablet disintegration time, central composite design (CCD) and response surface methodology was adopted to optimize disintegrating agent. In conclusion, the nanocrystal dispersible tablets approach was a reliable method for improving the dissolution and thereby the oral bioavailability of the DM in formulation development. PMID- 29442719 TI - Nanoliposomal Resveratrol as a Novel Approach to Treatment of Diabetes Mellitus. AB - Diabetes mellitus (DM) is a chronic metabolic disease and the subgroup of DM is called type II which is the most common form. The incidence of type II is increasing worldwide and it focuses on several new approaches to efficiently treatment of diabetes. Resveratrol (RSV) is known to be strong antioxidant and has an insulin-like effect in streptozotocin (STZ)-induced diabetic cells. It plays an active role at treatment of diabetes with reducing the oxidative stress, lowering glucose levels and protection of beta cells which are responsible for insulin secretion. In our study, we prepared two different RSV-loaded nanoliposomes (LPs), characterized in vitro and evaluated efficiencies of LPs on diabetes and related oxidative stress. Release and transport studies of RSV through dialyse membrane and pancreatic beta TC (beta TC) cells were investigated from its solution and LPs. Stability studies were performed at two different conditions (4 degrees C and 25 degrees C +/- 60% relative humidity) for 3 months. Particle size (PS), zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency (EE) and type of the formulations were determined. beta TC cell line was used in cell culture studies and cell viability was measured with using 3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) cytotoxicity test. The antidiabetic effects of RSV LPs were investigated on beta TC cell induced with glucose and STZ and we evaluated relationship between glucose and insulin concentration before and after incubation with LPs containing RSV. Antioxidant and preventive effects of RSV-loaded LPs against diabetes associated oxidative stress were determined with superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzyme assay. When all results were evaluated together, these new developed liposomal formulations significantly decreased high glucose levels in diabetic cell groups synchronous with increasing insulin levels and they showed prolonged antioxidant activity against oxidative stress for 24 hours compared to RSV solution. PMID- 29442720 TI - Ceria Oxide Nanoparticles an Ideal Carrier Given Little Stress to Cells and Rats. AB - Nanoparticles were used as ideal carrier for its passive and active targeting property. Unfortunately, many of them were failed for its biotoxicology. Thus, find a safe and targeted drug delivery was the new goal of pharmaceutical industries. Here, A549 and H1299 cells were exposed to ceria oxide nanoparticles, silicon oxide nanoparticles and zinc oxide nanoparticles for 12 h to induce autophagy and late apoptosis. Rats were exposed to ceria oxide nanoparticles (20 mg/kg . bw) for 1, 7, 14 or 28 days to induce lung injury and cytokines change. Luckily, compare with silicon oxide nanoparticles and zinc oxide nanoparticles, autophagy and late apoptosis were failed to fund in ceria oxide nanoparticles groups in 100 MUg/ml in cell lines for 12 h. At the same time, the autophagy related genes LC3, atg5, beclin1 and bcl2 were not change in protein level at 0 to 200 MUg/ml. What's more, histopathology change of the lung was recovered at the day of 28, only four of twenty-seven cytokines (IL12P70, RANTES, IL-X and MIP 1alpha) were changed at the day of 28 after exposed to ceria oxide nanoparticles (20 mg/kg . bw). Therefore, we indicated that ceria oxide nanoparticles can't give a stress both in vivo and vitro, and ceria oxide nanoparticles will be an ideal carrier for targeted drug delivery. PMID- 29442721 TI - Crosstalk Between Co-Cultured 3T3-L1 and C2C12 Cells After the Exposure of Nano Titanium Dioxide. AB - Nanotechnology is a promptly growing field in this century, and it have been extensively used in several solicitations. Reactive oxygen species (ROS) generation is one of the important mechanism of action of nanoparticles. The excess ROS generation can induce oxidative stress, so the cells are unable to sustain the normal biological redox-regulated tasks. The high oxidative stress and ROS formation condition, damage the biological macromolecules, cell signaling pathways and finally leads to cell death or cancer initiation. The objective of the present study is to reveal the effects of TiO2 nanoparticle on co-culture system. The cell viability, oxidative stress and apoptosis were evaluated in monolayer and co-culture 3T3-L1 cells after the exposure of TiO2. Our results indicated that TiO2 significantly induces the reactive oxygen species (ROS), lipid peroxidation and decrease in the level of glutathione. Additionally, real time PCR data analysis shown an increased in the expression of p53, Bax, caspase 9, caspase-3 and decreased the level of Bcl-2, by this means specifying that apoptosis induced by TiO2 NPs occurs via the caspase-dependent pathway. This study analytically shows that oxidative stress is the fundamental mechanism by which TiO2 causes apoptosis in a co-culture system even at very low concentrations. In the future, the use of such nanoparticles should be cautiously scrutinized. PMID- 29442722 TI - Anisotropic Snowman-Like Silver Nanoparticles Synthesized by Caesalpinia sappan Extract and In Vitro Antibacterial Activity. AB - Anisotropic snowman-like silver nanoparticles (AgNPs) were synthesized using the extract of Caesalpinia sappan heartwood as a reducing agent in the presence of cetyltrimethylammonium bromide. Two surface plasmon resonance bands of the orange solution were observed at 446 nm and 539 nm in UV-visible spectra. High resolution X-ray diffraction analysis confirmed the face-centered cubic structure of the AgNPs. High-resolution transmission electron microscopy images clearly revealed snowman-like AgNPs with an average size of 34.36 +/- 11.44 nm. The C-O functional group was most likely involved in the synthesis of the AgNPs, which was demonstrated by Fourier transform infrared spectra. Most interestingly, the snowman-like AgNPs exhibited higher antibacterial activity than the spherical AgNPs and the extract alone. Among the tested strains, the snowman-like AgNPs showed the highest activity against Staphylococcus aureus, with minimum inhibitory concentrations of 4.69 MUg/mL for the extract and 0.443 MUg/mL for the silver. The antibacterial activity of the snowman-like AgNPs increased 24-fold against S. aureus. These results strongly suggested that the snowman-like AgNPs synthesized from C. sappan extract have potential for treating infected disease caused by S. aureus when the antibacterial activity was combined from plant extract and AgNPs. To our knowledge, the present report is the first in which the snowman-like AgNPs synthesized using a plant extract as a reducing agent showed excellent In Vitro antibacterial activity. PMID- 29442723 TI - Preparation of NH2-Functionalized Graphene Oxide Nanosheets for Immobilization of NADH Oxidase. AB - Graphene oxide nanosheets was prepared, modification with 3 aminopropyltriethoxysilane and used as the carrier for immobilization of NADH oxidase (NOX) from Streptococcus mutans. The prepared nanosheets were characterized with FTIR. A high immobilization yield of 92% and activity recovery of 91% were achieved at pH 7.0 and 25 degrees C. The thermostability of the immobilized NOX was improved about 60% compared with the free enzyme. And the immobilized NOX preserved about 92% of its initial activity after 500 h storage at 4 degrees C, while free NOX was totally denatured after 200 h at the same conditions. These results indicate that NH2-functionalized graphene oxide nanosheets has a good potential as carrier for immobilization of proteins, especially enzymes. PMID- 29442724 TI - Bio-Inspired Growth of Silver Nanoparticles on 2D Material's Scaffolds as Heterostructures with Their Enhanced Antibacterial Property. AB - We developed a facile and green bio-inspired strategy to fabricate silver nano particles growth in-situ on different scaffolds materials, building novel heterostructures for promoting their antibacterial activities and durability. Firstly, fluorinated graphene oxide (FGO) nanosheets, layered molybdenum disulfide (MoS2), and layered tungsten disulfide (WS2) were exfoliated by chemical liquid with intense sonication. And silicon dioxide (SiO2) nano-spheres were prepared via wet chemical method. Then, silver nanoparticles were grown onto those surfaces of layered nanosheets and nano-spheres, hybridizing three dimensional hetero-architectures. The obtained silver-hybridized nanoarchitechtures were further analyzed by TEM and EDS. Additionally, three bacteria were applied to evaluate their antibacterial property, illustrating distinctive antibacterial effects, expecting to explore more applications in water disinfection and food packing fields. PMID- 29442725 TI - Effect of Bulk MoS2 on the Metabolic Profile of Yeast. AB - MoS2, a kind of two-dimensional material with unique performances, has been widely used in many fields. However, an in-depth understanding of its toxicity is still needed, let alone its effects on the environmental microorganism. Herein, we used different methods, including metabolomics technology, to investigate the influence of bulk MoS2 (BMS) on yeast cells. The results indicated that high concentrations (1 mg/L and more) of BMS could destroy cell membrane and induce ROS accumulation. When exposed to a low concentration of BMS (0.1 mg/L), the intracellular concentrations of many metabolites (e.g., fumaric acid, lysine) increased. However, most of their concentrations descended significantly as the yeast cells were treated with BMS of high concentrations (1 mg/L and more). Metabolomics analysis further revealed that exposure to high concentrations of BMS could significantly affect some metabolic pathways such as amino acid and citrate cycle related metabolism. These findings will be beneficial for MoS2 toxicity assessment and further applications. PMID- 29442726 TI - Poly(allylamine hydrochloride) (PAH) and Bovine Serum Albumin (BSA) Protein Nanostructured as Layer-by-Layer Thin Films. AB - In this work it was studied the production of nanostructured thin films containing alternating layers of poly(allylamine hydrochloride) (PAH) and bovine serum albumin protein (BSA). It was studied the adsorption processes of these materials onto solid surfaces, which included adsorption kinetics and film growth studies by using UV-Vis spectroscopy. The film morphology, thickness and roughness were studied by using atomic force microscopy (AFM). The AFM results showed that the film presented a globular-like surface morphology and a thickness within the nanoscale, which could be controlled by the number of deposited layers. The roughness and thickness of the film depend on the number of deposited bilayers, where the film roughness increased for films with a number of bilayers up to five, after which the film roughness remained almost constant. This is an indicative that the adsorption and growth processes might occur under two different mechanisms, first under the influence of the substrate (films containing up to five bilayers of PAH/BSA), and second under the influence of the film previously deposited (films containing more than five bilayers of PAH/BSA), respectively. PMID- 29442727 TI - TiO2/Ag-TiO2 Nanohybrid Films are Cytocompatible with Primary Epithelial Cells of Human Origin: An In Vitro Study. AB - Failure of dental implants is caused mainly by peri-implant infections resulting in loss of supporting bone. Since there is no ideal therapy of peri-implantitis, the focus of research has been shifted toward better prevention and the development of antibacterial surfaces. In our study we examined the attachment and proliferation of primary epithelial and MG-63 osteosarcoma cells on Ti dental implants coated with photocatalytic nanohybrid films. Two polyacrylate resin based layers were investigated on commercially pure (CP4) Ti discs: 60 wt% TiO2/40 wt% copolymer and 60 wt% Ag-TiO2/40 wt% copolymer ([Ag] = 0,001 wt%). Surface properties were examined by scanning electron microscopy (SEM) and profilometry. Cell responses were investigated via dimethylthiazol-diphenyl tetrazolium bromide (MTT) and visualized with fluorescence microscopy. Profilometry revealed significant changes in surface roughness of TiO2 (Ra = 1.79 MUm) and Ag-TiO2 layers (Ra = 5.76 MUm) compared to the polished (Ra(P) = 0.13 MUm) and sandblasted, acid-etched control surfaces (Ra(SA) = 1.26 MUm). MTT results demonstrated that the attachment (24 h) of epithelial cells was significantly higher on the Ag-TiO2 coated samples (OD540 = 0.079) than on the polished control surfaces (OD540 = 0.046), whereas MG-63 cells did not show any difference in attachment between the groups. After one week, epithelial cells showed slightly increased survival as compared to MG-63 cells. The results suggest that the tested coatings are cytocompatible with epithelial cells, which means that they are not only antibacterial, but they also appear to be promising candidates for implantological use. PMID- 29442728 TI - Inhibition of p53 Relieves Insulin Resistance in Fetal Growth Restriction Mice with Catch-Up Growth via Activating IGFBP3/IGF-1/IRS-1/Akt Signaling Pathway. AB - To investigate insulin resistance of the fetal growth restriction (FGR) mice with catch-up growth (CUG) and the underlying mechanism, in this study, low protein diet was used during pregnancy to establish the FGR mice model, and high fat diet was applied to establish the CUG model of FGR mice. The insulin and Pifithrin alpha stimulation was performed via intraperitoneal injection. The physical characters, biochemical parameters, expression of related molecules in each group were detected via ELISA, RT-PCR, WB, etc. The results showed FBG, FINS and HOAM IR in CUG-FGR group were higher than those in high fat feeding control group (NC+HF), but the content of IGF-1 in blood was lower than that in NC + HF group. Meanwhile, RT-PCR and WB showed that the expression of IGF was negatively correlated with the expression of P53/IGFBP3. Moreover, the expression of P-IRS/p PI3K/p-Akt decreased with the increasing of HOAM-IR in IGF signaling pathway. When the mice were injected with Pifithrin-alpha, the phosphorylation level of IGF signaling pathway and insulin resistance index in the CUG-FGR group were increased and decreased, respectively. In conclusion, insulin resistance in CUG FGR mice is correlated with the IGFBP3/IGF-1/IRS-1/Akt signaling pathway and inhibited p53 could activate this signaling pathway and relieve insulin resistance. PMID- 29442729 TI - Genomic and Proteomic Evidences for Exopolysaccharide Biosynthesis in Sphingobium chungbukense DJ77. AB - Sphingobium chungbukense DJ77 is a Gram-negative bacterium has metabolic capability of producing exopolysaccharide (EPS) as a potential reducing and stabilizing agent for metallic nanoparticle synthesis. In this study, we investigated the genomic and proteomic analysis to verify metabolic pathway and involved genes and enzymes related to EPS biosynthesis in S. chungbukense DJ77. End-sequencing results of randomly selected fosmid library, which were prepared from high molecular weight DNA of S. chungbukense DJ77, showed identity to sequences from genes related the EPS biosynthesis pathways in several bacteria. We also observed that proteomic responses in S. chungbukense DJ77 by heterogeneously expressing gelA and gelN involved in gellan biosynthesis in Sphingomonas elodea. Comparative two-dimensional gel electrophoresis revealed that both GelA and GelN altered internal expression levels of proteins involved in EPS biosynthesis in S. chungbukense DJ77. The results might provide the genomic and proteomic evidences for presence of EPS biosynthesis pathways in S. chungbukense DJ77. PMID- 29442730 TI - Assimilation of NH4Br in Polyvinyl Alcohol/Poly(N-vinyl pyrrolidone) Polymer Blend-Based Electrolyte and Its Effect on Ionic Conductivity. AB - Biodegradable polymer blend electrolyte based on ammonium based salt in variation composition consisting of PVA:PVP were prepared by using solution casting technique. The obtained films have been analyzed by various technical methods like as XRD, FT-IR, TG-DSC, SEM analysis and impedance spectroscopy. The XRD and FT-IR analysis exposed the amorphous nature and structural properties of the complex formation between PVA/PVP/NH4Br. Impedance spectroscopy analysis revealed the ionic conductivity and the dielectric properties of PVA/PVP/NH4Br polymer blend electrolyte films. The maximum ionic conductivity was determined to be 6.14 * 10-5 Scm-1 for the composition of 50%PVA: 50%PVP: 10% NH4Br with low activation energy 0.3457 eV at room temperature. Solid state battery is fabricated using highest ionic conducting polymer blend as electrolyte with the configuration Zn/ZnSO4 . 7H2O (anode) ? 50%PVA: 50%PVP: 10% NH4Br ? Mn2O3 (cathode). The observed open circuit voltage is 1.2 V and its performance has been studied. PMID- 29442731 TI - New Route for Synthesis of Fluorescent SnO2 Nanoparticles for Selective Sensing of Fe(III) in Aqueous Media. AB - A simple new route for synthesis of fluorescent SnO2 and its application as an efficient sensing material for Fe3+ in aqueous media is reported. The fluorescent SnO2 nanoparticles were obtained by oxidation of SnCl2, which when used as reducing agent for the reduction of organic nitro compounds to corresponding amino compounds in ethanol. The SnO2 nanoparticles have been characterized on the basis of powder-XRD, IR, UV-Vis, TEM, FESEM and EDX analysis and found that this material is highly fluorescent in aqueous media. Detail study revealed that this material functions as a selective probe for Fe3+ out of a large number of metal ions used. The oxygen vacancies (defects) generated on the surface of the SnO2 during synthesis, are the source of emission due to recombination of electrons with the photo-excited hole in the valance bond. The quenching of emission intensity in presence of Fe3+ is due to the nonradiative recombination of electrons and holes at the surface. This material is used for estimation of Fe3+ in real samples such as drinking water, tap water and soil. PMID- 29442732 TI - Facile One-Pot Synthesis of Flower Like Cobalt Oxide Nanostructures on Nickel Plate and Its Supercapacitance Properties. AB - A flower like cobalt oxide nanostructured thin film (Co2O3) on Nickel (Ni) plate as have been successfully developed via alcoholic Seed Layer assisted chemical bath Deposition (SLD) process. Through the controlled alkaline electrolytes, the flower and paddles like Co2O3 nanoarchitectures were formed. The prepared thin film was characterized by X-ray diffraction (XRD), scanning electron microscope with energy dispersive X-ray (SEM and EDX), Atomic Force Microscope (AFM), Raman spectroscopy techniques. Electron micrograph reveals the flower and paddles like nanostructured Co2O3 thin film deposited on Ni plates. The electrochemical characteristics were investigated using cyclic voltammetry (CV), charge-discharge and AC impedance spectroscopy in different aqueous electrolytes such as NaOH, KOH, and LiOH. The maximum specific capacitance of 856 Fg-1 was attained with 2 M KOH electrolyte with 2 mVs-1 of the Co2O3 thin film coated Ni plate at 80 degrees C using SLD method. The capacitance values obtained with various electrolytes are in the order of KOH > NaOH > LiOH. The results indicate that the present method is economical and the material is ecofriendly with enhanced capacitance property. PMID- 29442733 TI - Thermal Stability and X-ray Attenuation Studies on alpha-Bi2O3, beta-Bi2O3 and Bi Based Nanocomposites for Radiopaque Fabrics. AB - Nanocomposites containing alpha-Bi2O3, beta-Bi2O3 and Bi nanoparticles as nanofillers in vulcanized silicone resin as a matrix are prepared and their diagnostic X-ray attenuation property is studied. The nanocomposites are prepared using a simple solution casting technique, with nanofiller concentration varying from 2-50 wt%. Thermogravimetric analysis and differential scanning calorimetry are performed to study the thermal stability of the nanocomposites. The attenuation property is studied by exposing the nanocomposites containing alpha Bi2O3, beta-Bi2O3 and Bi nanoparticles to X-rays of energy 30-60 keV. Nanocomposites containing beta-Bi2O3 nanoparticles are found to exhibit the highest attenuation than nanocomposites of alpha-Bi2O3 and Bi nanoparticles of similar concentration. Nanocomposites containing 50 wt% of beta-Bi2O3 nanoparticles exhibit an X-ray attenuation of 93, 86, 71, 45 and 10% at an X-ray photon energy of 40, 45, 50, 55 and 59 keV, respectively. Further increase in photon energy is found to saturate the flat panel detector owing to the lower thickness of the nanocomposites. Analysis of high resolution X-ray radiographs of the nanocomposites confirms the uniform distribution of nanofillers in the matrix. Thermal analysis confirms the structural integrity and thermal stability of the nanocomposites. Heat flow curves also confirm the interaction of nanofillers with the matrix, corroborated by a change in the peak position and its endothermic/exothermic nature, corresponding to the phase transition of the nanofillers. It is also interpreted from thermal analysis of nanocomposites that the nanofillers interact with the matrix either by intercalating in the bridging polymer chain of silicone resin network structure or by occupying the interchain space. Thermal analysis of X-ray exposed nanocomposites shows no significant change in heat flow rates, thus, confirming the stability of the nanocomposites. Our study shows that nanocomposites containing beta-Bi2O3 nanofiller are potential candidates for radiopaque fabrics which can find application in diagnostic X-ray shielding in mammography, dental scan, etc. PMID- 29442734 TI - MnO2/MWCNTs Nanocomposites as Highly Efficient Catalyst for Indoor Formaldehyde Removal. AB - Formaldehyde (HCHO) is a main indoor pollutant that is capable of harming the health of residents. Here, we fabricated a novel MnO2/MWCNTs nanocomposite film for non-photocatalytic, room temperature removal of indoor HCHO. MnO2/MWCNTs nanocomposites with various amounts of a-MWCNTs, which were fabricated by a co precipitation method, were assembled into composite films using vacuum filtration and solvent evaporation. Structural analysis confirms that MnO2 nanoparticles are homogeneously distributed on a-MWCNTs. The acetyl acetone method was used to characterize the catalytic activity of MnO2/MWCNTs nanocomposites. The results show that MnO2/MWCNTs composites with 30 wt% a-MWCNTs present the highest catalytic activity due to a highly active surface. The catalytic activity of MnO2/MWCNTs composite film was characterized in a glovebox at room temperature and showed good removal of HCHO. This study suggests that supporting catalysts on MWCNTs and then assembling them into fibers (1D), films (2D) or aerogels (3D) is a worthwhile approach to promote catalytic activity and prevent dust pollution. PMID- 29442735 TI - Solid-State Synthesis of POPD@AgNPs Nanocomposites for Electrochemical Sensors. AB - In the present work, Poly(o-phenylenediamine) (POPD) stabilized silver nanoparticles (POPD@AgNPs) nanocomposites was synthesized by solid state oxidative polymerization method using o-phenylenediamine dihydrochloride (oPD HCl) as monomer and silver nitrate (AgNO3) used as metal precursor as well as oxidizing agent no other external oxidizing agent was used. POPD@AgNPs nanocomposites were characterized by various instrumental techniques to confirm their size, shape and its composition. The electrocatalytic activity of POPD and POPD@AgNPs modified electrode was investigated over the oxidation of hydrazine (N2H4) and reduction of hydrogen peroxide (H2O2) using Cyclic Voltammetry (CV), Differential Pulse Voltammetry (DPV) and Chronoamperometry techniques. POPD and POPD@AgNPs were characterized using HR-TEM, FE-SEM, XRD, UV-Visible, FT-IR, Micro Raman spectroscopy and those results were confirmed their chemical purity, particle size, shape and its elemental compositions. Moreover, the DPV and chronoamperometry reveals that POPD@AgNPs is a good sensor for the electrochemical gas detection of N2H4 and H2O2 because it has good stability, easy-operation, excellent reproducibility, high sensitivity and good limit of detection when compared to with pure POPD. This system shows good stability, excellent sensitivity, response and the detection limit was obtained for the detection of N2H4 and H2O2 in trace level gases, which was lower than some of the modified electrodes. PMID- 29442736 TI - Preparation of Lanthanide Ions-Doped BiPO4 Nanoparticles and Fe3+ Ions Assay. AB - A facile method for the synthesis of a Ln3+ (Eu, Tb) doped BiPO4 (BPO) nanocrystals were developed using an environment-friendly low temperature hydrothermal method assisting with phenol formaldehyde resin (PFr). Structure and surface functional groups of BPO samples were characterized by XRD and IR patterns. Morphology was studied by SEM technology also. Furthermore, doped BPO display strong red and green emissions from Eu3+ and Tb3+ ions respectively, and the BPO suspension is selectively quenched upon addition Fe3+ ions, and there is barely any interference by other metal ions, thus making the nanocrystals as a potential Fe3+ ions Fluorescent Probe, and the detection limit is below micromole level. PMID- 29442737 TI - Adsorption of Chromate from Aqueous Solution by Polyethylenimine Modified Multi Walled Carbon Nanotubes. AB - In this paper, multiwall carbon nanotubes (MWCNTs) were modified by Polyethylenimine of different molecular weight of 1800 (MWCNTs-18) and 7000 (MWCNTs-70). The structure and morphology of the functionalized MWCNTs were characterized by thermogravimetric analysis (TGA), X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). The curve of TGA showed that the mass loss of MWCNTs-18 and MWCNTs-70 were 46.5% and 51.9% respectively, which was remarkably different with pristine MWCNTs. The XRD demonstrated that the structure of the pristine MWCNTs and functionalized MWCNTs were similar. In addition, the experiment of the removal of chromate from water solution using functionalized MWCNTs was also conducted. The experimental conditions such as concentration of chromate, temperature, pH were studied. The maximum uptake capacities for chromate anions were obtained at the concentration of 0.4 mmol.L 1. The solution pH showed a significant effect on chromate removal over a pH range from 4.0 to 9.0. Besides, the uptake capacities for chromate anions on MWCNTs-18 and MWCNTs-70 increased as the temperature increase within the range from 30 to 60 degrees C. Under the experimental conditions, the maximum uptake capacities of MWCNTs-18 and MWCNTs-70 for chromate anions were 0.27 and 0.33 mmol.g-1 respectively. The thermodynamic parameters of the uptake process were calculated, and the results showed that the process of uptake chromate was spontaneous. PMID- 29442738 TI - Optimization of Graphene Conductive Ink with 73 wt% Graphene Contents. AB - With the pace of development accelerating in printed electronics, the fabrication and application of conductive ink have been brought into sharp focus in recent years. The discovery of graphene also unfolded a vigorous research campaign. In this paper, we prepared graphene conductive ink and explored the feasibility of applying the ink to flexible paper-based circuit. Since experimental study concentrating upon ink formulation was insufficient, orthogonal test design was used in the optimization of preparation formula of conductive ink for the first time. The purpose of this study was to determine the effect of constituent dosage on conductivity of graphene conductive ink, so as to obtain the optimized formula and prepare graphene conductive ink with good conductivity. Characterization of optimized graphene conductive ink we fabricated showed good adhesion to substrate and good resistance to acid and water. The graphene concentration of the optimized ink reached 73.17 wt% solid content. Particle size distribution of graphene conductive ink was uniform, which was about 1940 nm. Static surface tension was 28.9 mN/m and equilibrium contact angle was 23 degrees , demonstrating that conductive ink had good wettability. Scanning Electron Microscope (SEM) analysis was also investigated, moreover, the feasibility of lightening a light-emitting diode (LED) light was verified. The graphene conductive ink with optimized formula can be stored for almost eight months, which had potential applications in flexible paper-based circuit in the future. PMID- 29442739 TI - One-Pot Strategy to Bi2S3/BiOCl Heterojunction with Enhanced Photocatalytic Activity. AB - Bi2S3/BiOCl (denoted as BS-BC) heterojunction photocatalyst has been reported to be able to increase light absorption, promote charge separation and consequently enhance photocatalytic efficiency in comparison with single BiOCl. However, the heterojunction was usually prepared by a two-step method, i.e., BiOCl was firstly prepared and then to BS-BC heterojunction through an ion exchange strategy. In this work, BS-BC was prepared by a one-pot room temperature route, where Bi(NO3)3 dissolved in aqueous urea solution could homogeneously react with a mixture solution of NaCl and thiacetamide (TAA) to form BS-BC heterojunction. The urea could prohibit the hydrolysis of Bi(NO3)3 and accelerate the decomposition of TAA to release S2-, and as a consequence, the heterojunction photocatalyst with small size and large interfacial area could be prepared in several hours. The resulted heterojunction exhibited better visible-light photocatalytic activity for RhB degradation than individual BiOCl or that prepared by a two-step route due to close contact between Bi2S3 and BiOCl, modified band structures and effective interfacial charge transfer. PMID- 29442740 TI - Effects of Oxidizing Media on the Composition, Morphology and Optical Properties of Colloidal Zirconium Oxide Nanoparticles Synthesized via Pulsed Laser Ablation in Liquid Technique. AB - In this work, pulsed laser ablation in liquid (PLAL) technique was applied to synthesize colloidal nanoparticles of zirconium oxide (ZrO2) in three different aqueous media (de-ionized water, ethanol and acetone). The structure, morphology, composition and optical properties of the synthesized nanoparticles were characterized by XRD, SEM, TEM, XPS, UV-Vis spectrophotometer and FT-IR analysis respectively. The structural analysis by XRD reveals the formation of mixture of monoclinic and tetragonal phases of nanocrystalline zirconia. The average crystallite sizes of ZrO2 by using Scherrer's formula were estimated to be 41.8, 42.6 and 40.3 nm in water, ethanol and acetone respectively for monoclinic phase while 20.1, 24.8 and 18.9 nm were for tetragonal phase of ZrO2 in water, ethanol and acetone respectively. Microstructure of our starting materials was confirmed from SEM analysis and morphology of the synthesized nanostructured ZrO2 was studied by TEM. TEM images show that the average particle size is less than 10 nm with spherical shapes. The XPS analysis reveals the elemental compositions of ZrO2 nanoparticles and their stoichiometric ratios. Optical properties of the synthesized ZrO2 nanoparticles were studied by UV-Vis absorption spectroscopy and Fourier transform infrared spectroscopy (FT-IR). Uv-Vis absorption spectroscopy revealed that the nanoparticle produced in water has higher absorption due to higher NPs concentrations suspended in water. The band gap of the synthesized ZrO2 nanoparticles in water, ethanol and acetone were estimated from Tauc's plot to be 5.19, 5.22 and 4.94 eV respectively. FT-IR analysis also ascertained the functional groups of ZrO2 nanoparticles in the three liquid media. PMID- 29442741 TI - Fabrication and Characterization of Carbon Nanotubes/Fluorhydroxyapatite Composites. AB - Hydroxyapatite (HA) ceramics have important biomedical applications as hard tissue replacements. However, the mechanical properties and chemical stability of HA ceramics in physiological environments need to be tailored for specific applications. To improve the mechanical properties of HA ceramics, carbon nanotubes (CNTs) are introduced into HA matrix materials by an in-situ chemical synthesis method. Meanwhile, fluorine is also incorporated into the HA structure to form fluorinesubstituted hydroxyapatite (FHA). A uniform distribution of CNTs and good interfacial bonding help to improve the hardness by 76.2% and fracture toughness by 74.5% compared to pure HA. Both the dissolution behavior and antibacterial activities of CNTs/FHA composites show close relativity with the fluorine content. Increasing the fluorine contents of CNTs/FHA composites increases their chemical stability and ability to inhibit Streptococcus mutans. PMID- 29442742 TI - Synthesis of Anisotropic Tin Monosulphide Nanoparticles Using Sn-Thiourea as a Single Molecular Precursor. AB - We report the synthesis of high quality tin sulphide nanoparticles from tetrathiourea tin(II) chloride complex as a single molecular precursor. Thiourea ligand was used in the preparation of the complex due to its low toxicity and thermal stability. The reaction conditions were changed (reaction time, reaction temperature and nature of surfactant) to obtain high quality SnS nanoparticles that varied in morphology and size. The metal to sulphur ratio (Sn:S::1:1) and purity were confirmed using energy dispersive X-ray analysis (EDX). Spherical and rod shapes were obtained with an average particle size of 92.79 nm, estimated from transmission electron microscopy (TEM) images. Highresolution electron microscopy and X-ray diffraction (XRD) analysis show that the as-synthesized SnS nanoparticles had a pure orthorhombic crystal phase, with lattice spacing of 3.27 and 0.32 nm, which were assigned to the (111) and (021) reflection planes. A strong quantum effect was evident from the far blue shifted optical direct and indirect band gaps of 1.77 and 1.52 eV, respectively. PMID- 29442743 TI - Ethylene-co-Vinyl Acetate/MWCNTs/Hectorite Elastomeric Nanocomposites: Characterization and Electrical Properties. AB - MWCNTs/hectorite 3D hybrid filler was prepared from the 1:1 combination by weight of constituent MWCNTs (1D) and hectorite (2D) through simple dry grinding method. The resulting hybrid filler was subsequently utilized for the preparation of Ethylene-co-vinyl acetate (EVA)/MWCNTs/hectorite nanocomposites by solution intercalation method. Transmission electron microscopy and X-ray diffraction studies of the nanocomposites confirm homogeneous dispersion of the fillers in the polymer matrix. Mechanical, thermal and dielectric properties of neat EVA are significantly enhanced with increase in filler content. The improvement in tensile properties observed at 4 wt.% filler content are: 243% in tensile strength (1.78 MPa to 6.11 MPa), 105% in elongation at break (366% to 750%) and 426% in toughness (3.36 MPa to 17.67 MPa) without significant change (1.12 MPa to 1.31 MPa) in Young's modulus. Differential scanning calorimetry confirms significant increase in crystallinity, crystallisation temperature (Tc) and crystallite melting temperature (Tm) of the nanocomposites vis-a-vis neat EVA. Observed shift in Tc by more than 10 degrees C (~87 to ~98 degrees C) and Tm by more than 30 degrees C (~118 to ~151 degrees C) are really significant confirming the improved thermal stability of the nanocomposites. Maximum improvements in dielectric constant and AC conductivity observed at 5 wt.% hybrid filler content are ~25% and ~50% respectively. Superior mechanical properties of the nanocomposites combined with enhanced thermal stability and dielectric properties make it a prospective material for flexible dielectric applications. Properties attained can be attributed to improved polymer-filler interaction on account of homogeneous dispersion. PMID- 29442744 TI - A Novel Heterojunction AgI/WO3 Nanocomposite with the Highly Enhanced Photocatalytic Activity. AB - Herein, a novel visible-light-driven heterojunction AgI/WO3 nanocomposite was successfully prepared using a facile two-step hydrothermal-precipitation process and applied for photodegradation of organic pollutants. The information of phase structures, morphology, optical properties of the asprepared samples was analysed in detail by XRD, TEM, EDS, STEM, DRS measurement and so on. Formation of the heterostructure and intimate interactions between AgI and WO3 can promote highly effective photogenerated electron-hole pairs separation, which enable the heterojuctions to perform excellent photocatalytic activity as greatly enhanced photocatalysts compared to that of pristine AgI and WO3 for decomposing Rhodamine B (RhB) dye under visible light irradiation. In addition, the AgI/WO3 (1:1) nanocomposites exhibit optimal photocatalytic activity. Moreover, the as-prepared samples exhibit good stability, which is favorable for its potential application. Additionally, we have an analysis on a possible photocatalytic mechanism based on trapping experiments together with other experimental results. PMID- 29442746 TI - Fast Microfluidic Chip Fabrication Technique by Laser Erosion and Sticky Tape Assist Bonding Technique. AB - Disposable microfluidic chips are becoming increasingly important for biological and chemical researches. Future advances in their commercial applications depends on the mass fabrication of low cost microfluidic chip. In this study we are presenting a simple, low cost and fast way of fabricating PMMA microfluidic chips based on laser erosion. The influence of the width and depth of PMMA microchannels on erosion current and erosion times was analyzed. To bond the open PMMA microchannels at low pressure and temperature, sticky tape assist bonding method was proposed. By this method, the microfluidic chip can be fully sealed without using any equipment. The leakage test indicated that the bonded microfluidic chip can endure an pressure up to 0.82 MPa. PMID- 29442745 TI - Okra (Abelmoschus esculentus) Plant Extract-Assisted Combustion Synthesis and Characterization Studies of Spinel ZnAl2O4 Nano-Catalysts. AB - Spinel ZnAl2O4 nano-catalysts were synthesized by a simple, economical and eco friendly microwave irradiation (MIM) and conventional heating methods (CHM), using metal nitrates and Okra (Abelmoschus esculentus) plant extract, which play a dual role of both oxidizing and reducing nature. Powder X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, energy dispersive X-ray (EDX) and selected area electron diffraction (SAED) pattern results were confirmed that the samples have a single-phase cubic spinel structure with high crystalline nature of ZnAl2O4. Surface morphology of the samples was revealed by high resolution scanning electron microscopy (HR-SEM) and high resolution transmission electron microscopy (HR-TEM) techniques and they are confirmed particle-like structure with grain size below 50 nm. The optical band gap (Eg) was measured using Kubelka-Munk model by UV-Vis diffuse reflectance spectroscopy (DRS) and photoluminescence (PL) and the Eg value is higher for MIM product than CHM, due to the smaller particle size of ZnAl2O4-MIM. The magnetic property of the samples was determined by vibrating sample magnetometer (VSM) and showed a superparamagnetic behavior. Spinel ZnAl2O4 nano-catalysts are magnetically recyclable and could be reused with no significant loss in catalytic activity. Both the samples were successfully tested as catalysts for the conversion of alcohols into respective carbonyl compounds using H2O2 (as oxidant) and acetonitrile (as a solvent) system. It was found that the ZnAl2O4-MIM nanocatalysts show best performance of conversion of alcohols into a carbonyl compounds than that of ZnAl2O4-CHM, due to the smaller particle size and higher surface area of ZnAl2O4-MIM samples. PMID- 29442747 TI - Triangular Silver Nanoplate-Coated ZnO Nanoflowers Photocatalysis of Norfloxacin Under Visible Light. AB - T-Ag/ZnO nanoflowers were successfully fabricated via two steps methods on zinc foil. The chemical composition of norfloxacin was investigated by FTIR spectroscopy. The morphology, composition, and structural and optical properties of the as-synthesized materials were characterized. The results show that triangular silver nanoplates exhibit unique surface plasmon resonance (SPR) absorption spectra, and the absorption spectrum range of ZnO nanoflowers are effectively expanded by coating triangular silver nanoplates. The photocatalytic degradation of norfloxacin activity can be obviously improved because of a synergetic effect and unique SPR of triangular silver nanoplates in the T-Ag/ZnO nanoflowers under visible light. In addition, the possible mechanism for T-Ag/ZnO nanoflowers for the photodegradation of norfloxacin are discussed. The stability of T-Ag/ZnO nanoflowers are also studied. PMID- 29442748 TI - Hexamine Role on Pseudocapacitive Behaviour of Cobalt Oxide (Co3O4) Nanopowders. AB - Influence of hexamine surfactant concentration on crystallite size, structure, morphology, vibrational and optical properties of cobalt oxide nanopowders were explored. The cobalt oxide nanopowders were synthesized by employing a simple chemical reduction method using cobalt (II) nitrate hexahydrate (Co(NO3)2 .6H2O) as precursor and sodium borohydride (NaBH4) as reducing agent along with hexamine as surfactant. XRD studies revealed the formation of face-centered cubic (Fd3m) crystalline structure of Co3O4 with an average crystallite size of 8-18 nm. The observed prominent characteristic Raman active modes of A1g, Eg, and F2g revealed the formation of Co3O4 nanopowders. The optical properties of Co3O4 nanopowders are examined by photoluminescence spectra. The obtained IR results confirmed the formation of Co3O4 nanopowders. The band observed 569 cm-1 is the characteristic of the Co3+ ions in the octahedral hole vibration and the 665 cm-1 band is attributable to the Co2+ ions in the tetrahedral hole vibration in the cubic lattice. The estimated specific capacitance of the obtained Co3O4 nanopowders was 291 F/g at 10 mV/s which could be a potential candidate for pseudo capacitive nature of the active materials. PMID- 29442749 TI - Macroporous Graphene Thin Films as Electrochemical Electrodes: Enhancing the Sensitivity for Detection of Metal Ions. AB - A macroporous graphene thin films coated on ITO substrates (MGTFs@ITO) have been developed as electrodes for the electrochemical detection of heavy metal ions. The MGTF@ITO electrodes were characterized by scanning electron microscopy, Raman spectroscopy and contact angle measurements. The results demonstrated that the MGTF@ITO has a high specific area with robust macroporous framework and a hydrophilic surface. The cyclic voltammetry and electrochemical impedance spectroscopy using MGTFs@ITO as electrochemical electrodes indicated enhanced currents at the redox peaks, enlarged electrochemical surface area and a decreased charge transfer resistance. Based on these outstanding properties, the MGTF@ITO electrodes exhibited excellent stripping performace for the analysis of Ag(I) with a detection limit of 0.005 MUg L-1. The high sensitivity of the MGTF@ITO electrodes can be ascribed to the well defined macroporous framework, high electrical conductivity, high specific area and good wettability. The MGTF@ITO electrodes were further demonstrated applicable to the simultaneous determination of Zn(II), Cd(II), Pb(II), Cu(II) and Ag(I) ions with outstanding sensing performance. PMID- 29442750 TI - Cooked Food Waste-An Efficient and Less Expensive Precursor for the Generation of Activated Carbon. AB - Activated carbon was synthesized from cooked food waste, especially dehydrated rice kernels, by chemical activation method using NaOH and KOH as activating agents. It was then characterized by ultimate and proximate analysis, BET surface analysis, XRD, FTIR, Raman and SEM. The XRD patterns and Raman spectra confirmed the amorphous nature of the prepared activated carbons. Ultimate analysis showed an increase in the carbon content after activation of the raw carbon samples. Upon activation with NaOH and KOH, the surface area of the carbon sample was found to have increased from 0.3424 to 539.78 and 306.83 m2g-1 respectively. The SEM images revealed the formation of heterogeneous pores on the surface of the activated samples. The samples were then tested for their adsorption activity using acetic acid and methylene blue. Based on the regression coefficients, the adsorption kinetics of methylene blue dye were fitted with pseudo-second order model for both samples. Similarly, the Freundlich isotherm was found to be a better fit than Langmuir isotherm for both samples. The activity of thus prepared activated carbons was found to be comparable with the commercial carbon. PMID- 29442751 TI - Enhanced Electromagnetic Interference Shielding Performance of Sisal Fiber/Polypropylene Composites with RGO-Fe3O4 Nanohybrids Treatment. AB - RGO (reduced graphene oxide)-Fe3O4 nanohybrids were successfully synthesized by a solvothermal reduction method. Fe3O4 nanoparticles, RGO and the nanohybrids were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy and vibrating sample magnetometer (VSM). The electromagnetic interference (EMI) shielding effectiveness (SE) of RGO-Fe3O4/SF/PP composite was much higher than that of Fe3O4/SF/PP composite at 8-12 GHz, which was attributed to synergistic effect between RGO and Fe3O4 nanoparticles. The EMI SE (%) improved with the increase of RGO-Fe3O4 content and the maximum value of 80.44% was obtained for the RGO Fe3O4/SF/PP composite. Furthermore, the dominant shielding mechanism of RGO Fe3O4/SF/PP was absorption. PMID- 29442752 TI - Effect of Particle Size and Impact Velocity on Collision Behaviors Between Nano Scale TiN Particles: MD Simulation. AB - Inter-particle bonding formation which determines qualities of nano-scale ceramic coatings is influenced by particle collision behaviors during high velocity collision processes. In this study, collision behaviors between nano-scale TiN particles with different diameters were illuminated by using Molecular Dynamics simulation through controlling impact velocities. Results show that nano-scale TiN particles exhibit three states depending on particle sizes and impact velocities, i.e., bonding, bonding with localized fracturing, and rebounding. These TiN particles states are summarized into a parameter selection map providing an overview of the conditions in terms of particle sizes and velocities. Microstructure results show that localized atoms displacement and partial fracture around the impact region are main reasons for bonding formation of nano-scale ceramic particles, which shows differences from conventional particles refining and amorphization. A relationship between the adhesion energy and the rebound energy is established to understand bonding formation mechanism for nano-scale TiN particle collision. Results show that the energy relationship is depended on the particle sizes and impact velocities, and nano-scale ceramic particles can be bonded together as the adhesion energy being higher than the rebound energy. PMID- 29442753 TI - General Approach to Prepare 0.33Li2MnO3 . 0.67LiNi1/3Co1/3Mn1/3O2 Hollow Microspheres for High Performance Lithium Ion Batteries. AB - Li-excess manganese-based oxide layered structures, have drawn increasing interests as the promising cathodes to succeed the conventional LiCoO2 in lithium ion batteries (LIBs). It could deliver a higher energy density and output potential, as well as the nature of environment benign and low cost. Pristine Li excess manganese-based oxides however suffer from poor rate capacity and voltage fading after cycling, and their inherent capacity limits of bulk size in performance. Micro-/Nanostructured electrode materials are considered to hold the key to overcome these thresholds. This paper reports a general approach to prepare 0.33Li2MnO3 . 0.67LiNi1/3Co1/3Mn1/3O2 microspheres with pores and void space, which benefits improving both the capacity and cyclability. The electrode made of hollow 0.33Li2MnO3 . 0.67LiNi1/3Co1/3Mn1/3O2 microspheres exhibits a 224 mAh g-1 discharge capacity over 200 cycles at 0.25 C rate, and 195 mAh g-1 at 5.0 C rate. These results indicated good perspective of hollow microspheres for practical battery applications. PMID- 29442754 TI - Low Temperature Electrical Spin Injection from Highly Spin Polarized Co2CrAl Heusler Alloy into p-Si. AB - The low temperature spin accumulation in p-Si using Co2CrAl/SiO2 tunnel junction has been investigated in detail. The heterojunction has been fabricated using electron beam evaporation (EBE) technique. The 3-terminal contacts in Hanle geometry has been made for spin transport measurements. The electrical transport properties have been investigated at different isothermal conditions in the temperature range of 10-300 K. The current-voltage characteristics of the junction shows excellent rectifying magnetic diode like behaviour in lower temperature range (below 200 K). At higher temperature, the junction shows nonlinear behaviour without rectifying characteristics. We have observed spin accumulation signal in p-Si semiconductor using SiO2/Co2CrAl tunnel junction in the low temperature regime (30-100 K). Hence the highly spin polarized Full Heusler alloys compounds, like Co2CrAl etc., are very attractive and can act as efficient tunnel device for spin injection in the area of spintronics devices in near future. The estimated spin life time is tau = 54 pS and spin diffusion length inside p-Si is LSD = 289 nm at 30 K for this heterostructure. PMID- 29442755 TI - Comparative Study of Pure g-C3N4 and Sulfur-Doped g-C3N4 Catalyst Performance in Photo-Degradation of Persistent Pollutant Under Visible Light. AB - Graphitic carbon nitride (g-C3N4) and sulfur-doped g-C3N4 were prepared by pyrolysis of melamine and thiourea respectively. Their comparative performance was investigated for photo-degradation of a Rhodamine B (RhB) an organic toxic pollutant. The crystal structure, morphology, microscopic components and properties of the synthesized samples were characterized by XRD, TEM, FT-IR, photoluminescence (PL) emission spectroscopy and zeta potential. TG-DTA is a record of the process for pyrolysis of thiourea. Two simplified kinetic models, pseudo-first-order and pseudo-second-order were applied to predict the adsorption rate constants. Thermodynamic parameters, such as the change in free energy, enthalpy and entropy were also calculated to analyze the process of adsorption. Adsorption isotherms and equilibrium adsorption capacities were established by three well-known isotherm models including Langmuir, Freundlich and Dubinin Radushkevich (D-R). Both samples were investigated for underlining the reaction mechanism during the photodegradation RhB process and then can be assigned to the overall reaction. The photosensitive hole is regarded as main oxidation species for the degradation by sulfur-doped g-C3N4, but not the exclusive way for g-C3N4. It is worth mentioning that the optimum operating condition can be obtained by orthogonal experiments. PMID- 29442756 TI - Extraction of Dysprosium Ions with DTPA Functionalized Superparamagnetic Nanoparticles Probed by Energy Dispersive X-ray Fluorescence and TEM/High-Angle Annular Dark Field Imaging. AB - The extraction of dysprosium (Dy3+) ions from aqueous solution was carried out successfully, using magnetite (Fe3O4) nanoparticles functionalized with diethylenetriaminepentaacetic acid (MagNP@DTPA). The process was monitored by energy dispersive X-ray fluorescence spectroscopy, as a function of concentration, proceeding according to a Langmuir isotherm with an equilibrium constant of 2.57 * 10-3 g(MagNP) L-1 and a saturation limit of 63.2 mgDy/gMagNP. The presence of paramagnetic Dy3+ ions attached to the superparamagnetic nanoparticles led to an overall decrease of magnetization. By imaging the nanoparticles surface using scanning transmission electron microscopy equipped with high resolution elemental analysis, it was possible to probe the binding of the Dy3+ ions to DTPA, and to show their distribution in a region of negative magnetic field gradients. This finding is coherent with the observed decrease of magnetization, associated with the antiferromagnetic coupling between the lanthanide ions and the Fe3O4 core. PMID- 29442757 TI - Optical and Electrical Characterization of Stable p-Type ZnO Thin Films Obtained by Bismuth Doping. AB - We report the growth of stable p-type ZnO thin films obtained by doping bismuth (Bi) in ZnO and deposited over ITO coated glass substrate. The Bi doped ZnO thin films have been deposited by a sol-gel spin coating method using zinc acetate and bismuth nitrate as main precursors. The structural, optical and electrical properties of annealed Bi doped thin films have been studied in detail using X ray diffraction (XRD), Atomic force microscopy (AFM), ellipsometry, hot probe system and Hall measurement. The presence of strong diffraction peak along (101) obtained from the XRD spectra shows that the high-quality Bi doped ZnO nanostructures grow along (101) orientation. A number of important micro structural parameters for the thin films such as grain size, lattice parameters, stress and texture coefficient have been calculated, in order to show the effect of Bi incorporation in ZnO thin film. Further, transmittance has been calculated over the range of 350- 800 nm wavelength regions. The optical band gap of Bi doped ZnO films have also been calculated for different concentrations of Bi using the data taken by an ellipsometer. Hot probe characterization method has been used to ascertain the type of semiconductor thin film and it was observed that films doped with the concentration of 10 mol% Bi show p-type nature that was found to be stable over the period of eight months. Further, in order to calculate the resistivity, hole concentration, and mobility of p-type Bi doped ZnO thin film Hall measurement have been performed. PMID- 29442758 TI - Cellulose Nanofibrils Aerogel Cross-Linked by Poly(vinyl alcohol) and Acrylic Acid for Efficient and Recycled Adsorption with Heavy Metal Ions. AB - Cellulose nanofibrils (CNFs), disintegrated from natural fibers, are promising alternatives in wastewater purification for the porous structure and numerous hydroxyls. The pristine CNFs aerogel has limited mechanical strength and are vulnerable to collapse when exposed to water. In this work, eco-friendly and recycled CNFs aerogel adsorbents were successfully prepared using cellulose nanofibrils (CNFs), which cross-linked by poly(vinyl alcohol) (PVA) and acrylic acid (AA). The combination of PVA and AA endowed CNFs aerogel strong three dimensional porous structure and desirable adsorption properties. The heavy metal ions were adsorbed on the CNFs-PVA-AA (CPA) adsorbents efficiently and the maximum adsorption capacities for Cu2+ and Pb2+ approached 30.0 mg/g and 131.5 mg/g, respectively. The CPA adsorbent also showed excellent reusability and their adsorption capacities maintained 89% and 88% for Cu2+ and Pb2+ after 5 repeated uses. The adsorption of these heavy metal ions were confirmed to follow pseudo second-order kinetic and Langmuir isotherm model. The functions of C ? O and -OH were the major adsorption sites. Chemical adsorption combined with the porous physical adsorption made the CPA to be excellent adsorbent for the removal of heavy metal ions in wastewater. PMID- 29442759 TI - Preparation and Extraordinary Room-Temperature CO Sensing Capabilities of Pd-SnO2 Composite Nanoceramics. AB - Pd-SnO2 composite nanoceramics have been prepared from SnO2 and Pd nanoparticles through traditional pressing and sintering. Their responses to CO at room temperature are found to depend greatly on the content of Pd. For those samples with 1.0 and 5.0 mol% Pd, their resistance increases dramatically upon being exposed to CO in air; while for samples of 0.2 mol% Pd, their resistance decreases greatly upon being exposed to CO in air, and extraordinary room temperature CO sensing capabilities, including high sensitivities around 15, short response time of 20 s and recovery time of 60 s for 100 ppm CO in air, a high selectivity against H2, have been observed for them. X-ray photoelectron spectroscopy analyses showed that Pd2+ was formed in samples of 1 mol% Pd, while both Pd2+ and Pd4+ were formed in samples of 0.2 mol% Pd. It is proposed that for Pd-SnO2 composite nanoceramics, Pd2+ is responsible for CO-induced increase while Pd4+ is responsible for CO-induced decrease in resistance. PMID- 29442760 TI - Hybrid ZnO Nanorod Grafted Carbon Fiber Reinforced Polymer Composites; Randomly versus Radially Aligned Long ZnO Nanorods Growth. AB - Integrating nano-sized reinforcing materials into carbon fiber polymer composites (CFRPs) could enhance several aspects of their mechanical performance; e.g., interfacial strength, delamination resistance and vibrations attenuation. In this study, ZnO nanorods were grown on the surface of carbon fibers to create hybrid reinforcements. The hydrothermal synthesis of ZnO nanorods was tuned such that relatively long (>2.0 MUm) nanorods can be grown. This synthesis technique requires pre-deposition of a thin seeding layer of ZnO particulates on the carbon fibers to initiate the ZnO nanorods growth. Depending on the method by which the seeding layer is deposited, the grown ZnO nanorods could display different morphologies. In this study, two different techniques were utilized to pre deposit the ZnO seeding layer on the carbon fibers; ZnO nanoparticles/solution mixture airbrush spraying, and magnetron sputtering. The carbon fibers pre-coated with the airbrush spraying method yielded forests of randomly oriented ZnO nanorods, while the fibers pre-coated via the sputtering technique exhibited radially aligned ZnO nanorods forests. Hybrid CFRPs were fabricated based on the aforementioned carbon fiber fabrics and tested via 3-point bending dynamic mechanical analysis (DMA) and quasi-static tension tests. The loss tangent of the CFRPs, which delineates the damping capability, increased by 28% and 19% via radially and randomly grown ZnO nanorods, respectively. The in-plane tensile strength of the hybrid CFRPs were improved by 18% for the composites based on randomly oriented ZnO nanorods over the carbon fibers. The fractographs of the tension samples were also captured to reveal the role of the long ZnO nanorods in the in-plane performance of the hybrid CFRPs. PMID- 29442761 TI - Synthesis of Silica/Polypyrrole Nanocomposites and Application in Corrosion Protection of Carbon Steel. AB - Silica/polypyrrole nanocomposites without dopant (SiO2/PPy) and with oxalate dopant (SiO2/PPyOx) were synthesized using polymerization of pyrrole in the presence of nano SiO2. Synthesized SiO2/PPy and SiO2/PPyOx were characterized by FTIR, SEM, TEM and EDX and their electrical conductivities were determined by CV method through the two-point-electrode without electrolyte. The corrosion protection performance of polyvinylbutyral (PVB) coatings containing SiO2/PPyOx was evaluated and compared with that of pure PVB coatings and of PVB coatings containing SiO2/PPy by electrochemical impedance spectroscopy and adhesion measurement. The results show that electrical conductivities of SiO2/PPy and SiO2/PPyOx were 0.181 and 0.109 S/cm, respectively. The ratio of PPy on SiO2 in SiO2/PPy and SiO2/PPyOx composites was 0.77/1 and the ratio of oxalate on PPy in SiO2/PPyOx composite was 1.24/1. SiO2/PPy and SiO2/PPyOx improved corrosion resistance and adhesion of PVB coatings. The presence of oxalate in SiO2/PPyOx significantly enhanced the effect of SiO2/PPy on the protection performance of PVB coatings. PMID- 29442762 TI - High Quality Nitrogen and Silicon Co-Doped Carbon Dots (N/Si-CDs) for Fe3+ Sensing. AB - Nitrogen and silicon co-doped carbon nanodots (N/Si-CDs) were synthesized by one step hydrothermal carbonization of folic acid and 3-aminopropyl trimethoxy silane with the assistance of glycerol. The resultant N/Si-CDs present intense excitation-independent photoluminescence (PL) emission owing to their monodisperse sizes and specific surface states. In comparison to nitrogen single doped CDs (N-CDs), the co-doped N/Si-CDs possess better PL properties following different emission manner due to the synergistic effects of the nitrogen and silicon dopants. Besides, the functionalized surfaces of N/Si-CDs endow them with superior solubility and stability. The as-synthesized N/Si-CDs demonstrate selective and sensitive fluorescence response to Fe3+, which could be explained by the PL quenching effects of Fe3+ on N/Si-CDs. Based on this finding, the quantitative analysis of aqueous Fe3+ by N/Si-CDs was established, showing good linearity in a range of 10 nM~45 MUM and good sensitivity with a detection limit of 3.8 nM, so did for the detection of Fe3+ in fetal bovine serum (FBS) spiked samples. Therefore, the N/Si-CDs as a novel fluorescence probe hold promising for monitoring environmental and clinical Fe3+. PMID- 29442763 TI - Deposition Time Dependent Properties of Copper Tin Telluride (Cu2SnTe3) Nanoparticles for Solar Absorber Applications. AB - We report the growth of copper tin telluride nanoparticles as an absorber layer using a chemical bath deposition (CBD) process for solar selective applications. The XRD results showed the phase of Cu2SnTe3 with a cubical structure. The larger sized nanoparticles resulted with increased absorption properties and the optical band gap ranging from 1.93, 1.90, 1.58 and 1.56 eV for deposition times of 20-120 min, respectively. Then, the electrical properties of Cu2SnTe3 nanoparticles were also provided a higher current (~6-8 mA) with bias potential of zero. PMID- 29442764 TI - A Facile Solution Combustion and Calcination Process for the Preparation of Magnetic NiFe2O4/SiO2 Nanocomposites. AB - A facile solution combustion and calcination process for the preparation of magnetic NiFe2O4/SiO2 nanocomposites was introduced, the as-prepared NiFe2O4/SiO2 nanocomposites were characterized by XRD, VSM, BET, FTIR, SEM, and TEM techniques. The results showed that the single ferrite phase of NiFe2O4 could be formed at 400 degrees C; the calcination temperature, the content of silica in nanocomposites, and the volume of absolute alcohol were three key factors to the properties of the magnetic NiFe2O4/SiO2 nanocomposites: with the volume of absolute alcohol increasing from 10 mL to 100 mL, the average grain size of NiFe2O4/SiO2 nanocomposites calcined at 400 degrees C for 2 h with the heating rate of 3 degrees C/min decreased from about 16.6 nm to 8.4 nm, while the saturation magnetization decreased from about 6.1 Am2/kg to 1.5 Am2/kg; with the calcination temperature increasing from 400 degrees C to 800 degrees C, the average grain size of NiFe2O4/SiO2 nanocomposites calcined for 2 h with the heating rate of 3 degrees C/min and absolute alcohol of 30 mL increased from about 11.0 nm to 14.1 nm, and the saturation magnetization increased from about 3.4 Am2/kg to 24.0 Am2/kg; at the same time, with the content of silica in nanocomposites increasing from 0 to 10 wt.%, the average grain size of NiFe2O4/SiO2 nanocomposites calcined at 400 degrees C for 2 h with the heating rate of 3 degrees C/min decreased from about 18.4 nm to 11.0 nm, while the saturation magnetization decreased from about 18.2 Am2/kg to 3.4 Am2/kg. PMID- 29442765 TI - The Impact of the Shallow-Trench Isolation Effect on Flicker Noise of Source Follower MOSFETs in a CMOS Image Sensor. AB - The flicker noise of source follower transistors is the dominant noise source in image sensors. This paper reports a systematic study of the shallow trench isolation effect in transistors with different sizes under high temperature conditions that correspond to the quantity of empty defect sites. The effects of shallow trench isolation sidewall defects on flicker noise characteristics are investigated. In addition, the low-frequency noise and subthreshold swing degrade simultaneously in accordance to the device gate width scaling. Both serious subthreshold leakage and considerable noise can be attributed to the high trap density near the STI edge. Consequently, we propose a coincidental relationship between the noise level and the subthreshold characteristic; its trend is identical to the experiments and simulation results. PMID- 29442766 TI - Electrochromic Properties of NiOx Films Deposited by DC Magnetron Sputtering. AB - Nickel oxide (NiOx) films were deposited onto ITO-coated glass at room temperature by DC magnetron sputtering and the electrochromic properties were investigated. The effects of film thickness on structure, morphology, electrochemical and electrochromic properties of NiOx films were systematically studied. X-ray diffraction and scanning electron microscopy results indicate NiOx films have the polycrystalline structure and the crystallinity improves with the increase of thickness. In atomic force microscopy analysis, the surface roughness of NiOx films increases as the thickness increases and large roughness is obtained in the films of more than 300 nm. The electrochemical properties were measured by using conventional three-electrode configuration in 1 M LiClO4-PC electrolyte and all the samples show good cyclic stability. A transmittance modulation of 62% between colored and bleached state at 550 nm wavelength is obtained for 500 nm thick film and the high color efficiencies of more than 62 cm2C-1 are obtained in NiOx films. However, coloring and bleaching response times increase with the increase of thickness because of the larger depth of charge insertion/extraction. The results confirm that magnetron sputtering technology provides a feasibility for electrochromic devices with excellent electrochromic performance. PMID- 29442767 TI - Characterization of Phase Evolution, Microstructure and Electrical Properties of Sol-Gel Auto-Combustion Derived BCZT Ceramics. AB - This work aims to study the effect of sintering temperature on properties of barium calcium zirconate titanate (BCZT) ceramics. The BCZT is a Pb-free material that shows excellent piezoelectric properties. In this study, BCZT ceramics were prepared from BCZT powders synthesized from barium nitrate, calcium nitrate, zirconium (IV) oxynitrate hydrate, titanium (IV) butoxide and citric acid precursors by the sol-gel auto-combustion method. The BCZT powder was calcined at the temperature ranging from 700 to 1000 degrees C. Green bodies were sintered at various temperatures (1200-1450 degrees C). The X-ray diffraction patterns showed only non-crystalline phase of as-burnt powder. For the calcined powders, XRD patterns showed that the amount of crystalline, perovskite phase increased with increasing calcination temperature. The crystalline particles have a spherical shape and the size in the range of 25-35 nm. For the BCZT ceramics sintered at 1200-1300 degrees C, the density tended to increase with increasing sintering temperature. Very high bulk densities of 5.62-5.63 g/cm3 (which were higher than those of the ceramics synthesized by the wet-chemical method) were achieved at the sintering temperature of 1400-1450 degrees C. Ceramics produced at these temperatures possessed fully-developed microstructures, very good dielectric properties as well as high response of polarization and strain to applied electric field. PMID- 29442768 TI - Fabrication and Emission Performance of Nanostructured Re-W Matrix Impregnated Cathodes. AB - In this study, rhenium-tungsten mixed particles with different content of rhenium have been prepared by spray-drying method followed by hydrogen reduction. Using such particles, the cathodes have been prepared by powder metallurgy followed by impregnating BaO, CaO, and Al2O3 with 4:1:1 molar ratio. After proper activation, electron emission test is performed in standard parallel-plate diode configuration. The emission results reveal that the Re-W matrix cathode containing 75% rhenium has the highest direct current emission density of 11.67 A/cm2 at 1000 degrees C. The work function of Re-W matrices has been investigated by density functional theory method in the frame of the generalized gradient approximation (GGA). The theoretical calculation results indicate that the work function of the matrix has limited contribution to the emission current density of Re-W matrix dispenser cathode. The in situ AES, SEM, and XRD were applied and the results reveal that the superior emission property of the 75Re cathode is owing to a plenty of nanoparticles and higher free barium concentration on the cathode surface, which is attributed to the Re3W single phase in 75Re matrix. PMID- 29442769 TI - Photodetector Based on Multilayer SnSe2 Field Effect Transistor. AB - We demonstrate a high-performance photodetector with multilayer tin diselenide (SnSe2) exfoliated from a high-quality crystal which was synthesized by the temperature gradient growth method. This SnSe2 photodetector exhibits high photoresponsivity of 5.11 * 105 A W-1 and high specific detectivity of 2.79 * 1013 Jones under laser irradiation (lambda = 450 nm). We also observed a reproducible and stable time-resolved photoresponse to the incident laser beam from this SnSe2 photodetector, which can be used as a promising material for future optoelectronic applications. PMID- 29442771 TI - Structures and Properties of Polyacrylonitrile/Graphene Composite Nanofiber Yarns Prepared by Multi-Needle Electrospinning Device with an Auxiliary Electrode. AB - In this paper, polyacrylonitrile/graphene composite nanofiber filaments were manufactured continuously by a homemade eight-needle electrospinning device with an auxiliary electrode. The polyacrylonitrile/graphene composite nanofiber yarns were obtained continuously by plying and twisting the composite nanofiber filaments. The structures and properties of the composite nanofiber filaments with different GP mass fractions and yarns were investigated. The results demonstrated that the maximum alignment degree of the composite nanofibers along the filament axis could reach 74.3% with 1%, and the alignment degree decreased with increasing graphene mass fraction. The diameters of the composite nanofibers were considerably smaller than those of the pure polyacrylonitrile nanofiber, and the minimum diameter was 156 nm for 1%. The conductivity of the composite nanofiber filaments was significantly enhanced by seven orders of magnitude compared with that of the pure polyacrylonitrile nanofiber filament, and the maximum value was 3.73*10-7 S/cm for 1.5%. Due to graphene agglomeration, the conductivity decreased when the mass fraction was more than 1.5%. The different number of filaments and twists were examined in detail to improve the poor mechanical properties of the nanofiber filaments. With an increase in twists, the breaking stress and strain increased initially and later decreased, and the maximum breaking stress and strain were 16.54 MPa and 26.42%, respectively. This study demonstrates the possibility of continuously and stably manufacturing polyacrylonitrile/graphene composite nanofiber yarns. PMID- 29442770 TI - Analysis of Colchicine-Induced Effects on Hepatoma and Hepatocyte Cells by Atomic Force Microscopy. AB - Biomechanical properties of cells are altered by many diseases. Cancer cell metastasis is related to the properties such as the cell stiffness that influences cell proliferation, differentiation and migration. In this paper, we used an atomic force microscope to analyze the colchicine-induced effects on the mechanical properties of hepatocyte (HL-7702 cells) and hepatoma cells (SMCC-7721 cells) in culture at the nanoscale. The cells were exposed to a solution with a normal dose of colchicine for two, four and six hours. Surface topographic images showed that colchicine decreased the stability of the cytoskeleton. After the same six-hour treatment in a solution with a normal dose of colchicine, the biomechanical properties of HL-7702 cells were almost unchanged. However, the stiffness and the adhesion force of the SMCC-7721 cells were clearly increased (more than twofold of the normal values), especially after four hours. The deformability of SMCC-7721 cancer cells was significantly decreased within the six-hour treatment in the solution with a normal dose of colchicine. Analysis of the biomechanical properties of post-treatment hepatoma cells provided a complementary explanation for the mechanism of action of colchicine on cells at the nanoscale. This method is expected to allow the monitoring of potential metastatic cancer cell changes, thus preventing the emergence and the transmission of disease, and improving the diagnosis of cancer. PMID- 29442772 TI - Mechanical and Electrical Properties of Direct Spun Carbon Nanotube Fibers Exposed to Ultrahigh Temperatures in Vacuum. AB - Carbon nanotube (CNT) fibers are promising reinforcements in ceramic matrix composites where the service environments involve extremely high temperatures that are generally beyond 1000 degrees C. This work focuses on the thermal stability of a direct spun CNT fiber in vacuum and in a wide temperature (25-2000 degrees C). The microstructure, mechanical and electrical properties of the fibers as a function of the heat-treatment temperature were investigated. The results show that high temperature exposure could increase the defect density and loosen the packing state of the fiber, but enhance the graphitization degree of the CNTs. Accordingly, there was a ductile-to-brittle transition in the uniaxial tensile response as the heat-treatment temperature increased, and this was mainly a consequence of the failure mode transitions from localized shear to defect dominant fracture. The tensile modulus was enhanced, but the tensile strength was decreased after the heat-treatment. The former can be explained by the enhanced graphitization degree of CNT and the latter should be a result of the increased defect density. Finally, the electrical property of the fiber was degraded, due to the increased contact resistance of mutual CNTs. PMID- 29442773 TI - Boehmite-An Efficient and Recyclable Acid-Base Bifunctional Catalyst for Aldol Condensation Reaction. AB - In this work boehmite was used as an acid-base bifunctional catalyst for aldol condensation reactions of aromatic aldehydes and ketones. The catalyst was prepared by simple sol-gel method using Al(NO3)3.9H2O and NH4OH as precursors. The catalyst has been characterized by X-ray diffraction (XRD), Fourier Transform Infrared (FTIR), Scanning Electron Microscopy (SEM), UV-visible spectroscopy (DRS), BET surface area analyses. Boehmite is successfully applied as catalyst for the condensation reaction between 4-nitrobenzaldehyde and acetone as a model substrate giving alpha, beta-unsaturated ketones without any side product. The scope of the reaction is extended for various substituted aldehydes. A probable mechanism has been suggested to explain the cooperative behavior of the acidic and basic sites. The catalyst is environmentally friendly and easily recovered from the reaction mixture. Also the catalyst is reusable up to 3 catalytic cycles. PMID- 29442774 TI - The Use of Magnetic Orientation as a Pinning Modality for Investigation of Photon Magnon Interactions in Magnetic Nanoparticle Systems. AB - In this work, an experimental setup to study the dependence of a visible-light transmission through a magnetic granular film on the magnetic field direction was presented. The results measured the transmission (T) of the visible light, with the wavelengths lambda were in the range from 560 to 695 nm, by the magnetic nanogranular films Cox-(Al2O3)100-x system, with Co compositions are x = 10 / 45 at.%, as a function of the magnetic field direction were reported. These investigations were carried out under an external magnetic field of H = 400 Oe, which directs to the normal of the sample surface by an angle varied in the range of phi = 0 degrees / 45 degrees , to magnetize the magnetization direction of all the Co particles following this direction. Consequently, the angle phi between the magnetization direction with the incident-light direction, which sets as the optical axis of the system and always keeps fixedly to the normal of the sample surface, is established. The experimental results showed the different dependencies of T on the angle phi, the magnetic field H, the Co composition x, and the wavelength lambda. These dependencies attributed to a behavior that relates to so-called photon-magnon interaction. PMID- 29442775 TI - Surface Modified Nano Fly Ash as an Activator in the Reduction of Ketones. AB - Surface modified nano fly ash has been used as an activator, in the reduction of a few cyclic and acyclic ketones with NaBH4 as reducing agent. Exclusive formation of trans-4--butyl cyclohexanol was observed in such case. Reduction of 3-methylcyclohexanone yielded only cis-3-methylcyclohexanol (equatorial -OH). In case of reduction of other substituted cyclohexanones, propensity to form more of equatorial alcohol was observed. The chemical yields of various alcohols were high (~95-99%). The rates of reductions of the ketones were also appreciably high. It appears that the silanol groups present in the surface modified fly ash cause nucleophilic activation of the carbonyl groups leading to faster reaction rate. Exclusive formation of the epimer with equatorially disposed -OH group is most likely due to the same reason. Finally, the advantage of the activator lies in its low cost. PMID- 29442776 TI - Photo-Fenton Degradation of Organic Dyes Based on a Fe3O4 Nanospheres/Biomass Composite Loaded Column. AB - In order to deal with pollution of organic dyes, magnetic Fe3O4 nanospheres (NPs) with an average diameter of 202 +/- 0.5 nm were synthesized by a solvothermal method at 200 degrees C, and they can efficiently degrade organic dyes (methylene blue (MB), rhodamine B (RhB) and xylenol orange (XO)) aqueous solutions (20 mg/L) within 1 min. Based on this Fenton reagent, Fe3O4 NPs/biomass composite degradation column was made using sawdust as substrate, and it can efficiently degrade organic dyes continually. More importantly, the composite can be regenerated just by an ultrasonic treatment, and its degradation performance almost remains the same. PMID- 29442777 TI - Cu-Doped alpha-Fe2O3 Microspheres as Anode Materials for Lithium-Ion Batteries. AB - alpha-Fe2O3 and Cu-doped alpha-Fe2O3 microspheres were similarly synthesized by solvothermal method. These microspheres were characterized by X-ray diffraction (XRD), and scanning electron microscope (SEM) technique. As anode materials for lithium-ion batteries (LIBs), Cu-doped alpha-Fe2O3 electrodes exhibit better electrochemical performance (higher specific capacities of 600 mAhg-1 and better cycling performance), compared with pure alpha-Fe2O3 electrode. Additionally, the effects of different Cu2+-doping contents and reaction times on the morphology and the electrochemical properties were also discussed. Cu-doped alpha-Fe2O3 proves to be a potential anode material for LIB applications. PMID- 29442778 TI - Preparation of Wrinkled Graphene Oxide Using Solution Method. AB - Wrinkled graphene oxide (WGO) is formed using the solution method. The sub-MUm sized wrinkles are generated on the GO surface, with more wrinkles forming as the GaCl3 in the solution increases. The wrinkles are observed using scanning electron microscopy (SEM) and atomic force microscopy (AFM) methods. The OH bonds connected to the GO surface are believed to cause the WGO, and these additional chemical bonds are detected via the Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy. As with the wrinkled graphene, the wrinkled GO provides a much larger surface area and can expedite the production of advanced sensor and energy charging devices. PMID- 29442779 TI - Fabrication of Ag2O-Bi2Sn2O7 Heterostructured Nanoparticles for Enhanced Photocatalytic Activity. AB - Ag2O-Bi2Sn2O7 composites were prepared by a chemical co-precipitation method. The microstructural, morphological and optical properties of the as-prepared composites were characterized and studied. Effects of Ag2O contents on photocatalytic activity of the Ag2O-Bi2Sn2O7 composites were also investigated in detail. Compared with pure Bi2Sn2O7, the 0.03Ag2O-Bi2Sn2O7 composite exhibits the highest photocatalytic activity for the degradation of Rhodamine B aqueous solution under visible light irradiation. The enhanced photocatalytic activity of the Ag2O-Bi2Sn2O7 composite can be attributed to the existence of the Ag2O Bi2Sn2O7 heterojunction, which is propitious to an effective separation of the photogenerated electron-hole pairs. PMID- 29442780 TI - Crystalline, Mechanical and Dielectric Properties of Polyarylene Ether Nitrile with Multi-Walled Carbon Nanotube Filled with Polyarylene Ether Nitrile. AB - Multi-walled carbon nanotube (MWCNT) filled with poly(arylene ether nitrile) (PEN) (PEN-in-MWCNT) is used as additive to improve the physical performances of PEN matrix. The influences of PEN-in-MWCNT on the crystallization, mechanical, dielectric and thermal properties of PEN are investigated by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier Transform Infrared Spectoscopy (FT-IR), dielectric testing, mechanical testing and scanning electron microscope (SEM) observation. The filling of the PEN into the MWCNT is confirmed by transmission electron microscopy (TEM) and scanning transmission electron microscopy (STEM) observation, FT-IR spectra, TGA and DSC curves. TGA results indicate that the mass fraction of PEN filled in the MWCNT is 61.56 wt% and the thermal property of PEN-in-MWCNT is significantly enhanced after the filling of PEN. Comparing with MWCNT, the oxidation temperature of PEN-in-MWCNT increases more than 180 degrees C. DSC results demonstrate that PEN-in-MWCNT is a better nucleating agent for PEN than MWCNT, as it can promote the crystallinity of PEN at relative lower concentration. When the concentration of MWCNT is 0.5 wt%, the melting enthalpy of the composite PEN-in-MWCNT/PEN5 is 41.13 J/g. The tensile strength of the obtained composite PEN-in-MWCNT/PEN10 enhances by 34% after 1.0 wt% of MWCNT is incorporated. Improved dielectric properties are also observed when PEN-in-MWCNT is incorporated into the PEN matrix. The PEN-in-MWCNT appears to be an excellent additive candidate for PEN. PMID- 29442782 TI - High Difference-Frequency Generation in SiO2/MnF2/Ag Sandwich Structures. AB - In this work, a simple antiferromagnetic (AF) sandwich structure is proposed to increase the difference-frequency (DF) outputs, where a noble metal, Ag layer, is put under an AF film. Numerical calculations are based on the SiO2/MnF2/Ag sandwich structure, where MnF2 is a typical AF material. We found that the DF outputs on the above surface are increased at least two orders which compared with those of MnF2 film. The continuous DF windows show that the outputs decrease with the increasing incident angles. The effect of the external magnetic field on DF outputs is also discussed. PMID- 29442781 TI - Aqueous Synthesis of Mn3O4 Nanoparticle@MnOOH Nanobelt Heterostructures. AB - A combined heterostructures with Mn3O4 nanoparticles attached to MnOOH nanobelts were prepared via an aqueous oxidation method at 90 degrees C with H2O2 as oxidant. The crystalline structures and morphologies of the as-prepared samples were detected by X-ray powder diffraction (XRD), field emission scanning electron microscope (FESEM) and high resolution transmission electron microscope (HRTEM) analysis, and the forming mechanism of Mn3O4@MnOOH nanomaterials was discussed. Crystalline composition and morphologies of samples changed with reaction time and crystallinity of Mn(OH)2 precursor. beta-MnOOH nanoplates can be obtained in the initial reaction, then it transformed to gamma-MnOOH nanobelts and/or Mn3O4 nanoparticles as reaction time increasing. The ratio of Mn3O4 in Mn3O4@MnOOH nanomaterials increased with the better crystallinity of Mn(OH)2 precursor. The as-prepared Mn3O4@MnOOH nanomaterials with varied compositions were used for degradation of Rhodamine B (RhB) in acid condition. The degradation reactions carried out in acid condition without stimulated light sources. The results showed that the manganese heterostructures had good activity based on synergy of Mn3O4 and MnOOH nanocrystals. PMID- 29442784 TI - Hot-Roll-Pressing Mediated Transfer of Chemical Vapor Deposition Graphene for Transparent and Flexible Touch Screen with Low Sheet-Resistance. AB - Obstacles associated with graphene as transparent conductive films mainly consist of the difficulties in high-quality graphene synthesis, efficient transfer and doping of samples with lateral size of tens of centimeters for practical applications. Herein we demonstrate a hot-roll-pressing transfer technique followed by wet-chemical doping of large area graphene film grown on copper foil by chemical vapor deposition (CVD). This method enabled cost-effective and ultraclean transfer of single-layer graphene with an arbitrary size onto transparent ethylene vinyl acetate/polyethylene terephthalate (EVA/PET) substrate without any polymer residues. The sheet resistance of the single-layer graphene covered EVA/PET (graphene/EVA/PET) reached 200 Omega/sq with optical transparency of 87.3%. The graphene/EVA/PET film can be bent over 10000 cycles at a radius of 2 mm with ~0.02% increase in sheet resistance, showing excellent mechanical flexibility for bendable electronics which was demonstrated by a capacitive-type touch screen based on the graphene/EVA/PET transparent conducting film. PMID- 29442783 TI - Electronic Structures and Nanofilm Growth of 2,7-Dioctyl[1]Benzothieno[3,2 b]Benzothiophene on Black Phosphorus. AB - The interfacial electronic structure and morphology of nanofilm of 2,7 dioctyl[1]benzothieno[3,2-b]benzothiophene (C8-BTBT) on black phosphorus (BP) was investigated with photoemission spectroscopy (PES) and atomic force microscopy (AFM). The heterojunction of C8-BTBT/BP is a straddling one with a hole injection barrier of 1.41 eV and electron injection barrier of 2.43 eV from BP to C8-BTBT. There is a 0.18 eV interface dipole pointing from BP to C8-BTBT, which means a relative weak interaction of substrate BP and the C8-BTBT molecules. Volmer-Weber growth mode of C8-BTBT nanofilm on BP was confirmed and the C8-BTBT molecules adopt standing up configuration. PMID- 29442785 TI - Manganese2+-Doped Copper Tin Telluride Absorber Layer-Sensitized Solar Cells. AB - Manganese2+-doped copper tin telluride nanoparticles (Mn2+:Cu2SnTe3 NPs), as an absorber layer, were grown using a chemical bath deposition (CBD) technique and demonstrated for solar cell applications. The cubical structure was formed on the WO3 surface with the band gap (Eg) of Cu2SnTe3 NPs decreased from 1.80 to 1.67 eV after Mn2+ doping. The photovoltaic property at 1 sun shows the efficiency (eta) of 0.276%. The eta was increased with reducing sunlight intensity due to the lower carrier recombination process at an electrode and electrolyte interface, which leads to the increasing eta. The highest eta of 1.120% was yielded at 0.1 sun with a Jsc = 2.81 mA/cm2, a Voc = 0.148 V, a FF = 26.8%. It can be noted that this kind of material and a synthesis procedure can be feasibly further improved for a higher efficiency and more stability on an absorber layer. PMID- 29442786 TI - Preparation of Polyurethane/Graphite Composite Films with Stable Mechanical Property and Wear Resistance Underwater. AB - The wear resistance and stable mechanical properties affect the service life of the underwater functional materials to a certain extent. Unfortunately, the current study of underwater functional materials is rarely related to these aspects. Herein, we successfully designed and prepared polyurethane/graphite nanosheet (PU/GN) composite materials, which exhibited excellent wear resistance and stable mechanical properties underwater. The PU/GN composite films were prepared by evaporating a mixed solution of PU and GN on concave hexagonal honeycomb silicon templates. The mechanical properties of the composite films were determined by tensile test, and the wear resistance was evaluated by comparing the surface morphology before and after grind. By adjusting the content of graphite in the composite films, we found that the composite films containing 23 wt% GN had higher tensile strength and superior wear resistance. Moreover, this composite film showed an outstanding stability when expose to water. The impressive results along with simple preparation process made PU/GN composite films had potential applications in robust underwater functional materials. PMID- 29442787 TI - Influence of the Quantum Well Structure and Growth Temperature on a Five-Layer InGaMnAs Quantum Well with an InGaAs Buffer Layer. AB - The influence of quantum well structure and growth temperature on a synthesized multilayer system composed of a five-layer InMnGaAs quantum well with an InGaAs buffer layer grown on semi-insulating (100)-oriented substrates prepared by low temperature molecular beam epitaxy was studied. The magnetization measurements using a superconducting quantum interference device indicated the existence of ferromagnetism with a Curie temperature above room temperature in the five-layer InGaMnAs quantum well structure with an InGaAs buffer layer in a GaAs matrix. X ray diffraction and secondary ion mass spectroscopy measurements confirmed the second phase formation of ferromagnetic GaMn clusters. The ferromagnetism that exists in the five-layer of the InMnGaAs quantum well with the InGaAs buffer layer results from a superposition of the ferromagnetism of the low temperature region from the substitutional Mn ions into Ga sites or interstitial Mn ions as well as the presence of manganese ions dopant clusters such as GaMn clusters. PMID- 29442788 TI - Hydroxyapatite Nanoparticle-Coated 3D-Printed Porous Ti6Al4V and CoCrMo Alloy Scaffolds and Their Biocompatibility to Human Osteoblasts. AB - Hydroxyapatite nanoparticles were prepared by hydrothermal method using calcium nitrate and phosphoric acid as precursors and ammonia aqueous solution as a pH value adjustor. The 3D-printed porous Ti6Al4V and CoCrMo alloy scaffolds were effectively coated with hydroxyapatite nanoparticles in the hydrothermal synthesis process by deposition method. Coating hydroxyapatite nanoparticles on the implant surfaces increased their biocompatibility and bioactivity. HAP deposited Ti6Al4V or HAP-deposited CoCrMo scaffold induced no statistical increase in terms of apoptosis in hFOB1.19 cells compared with bare Ti6Al4V or bare CoCrMo. Interestingly, HAP coating groups presented CCK-8 values compared with bare groups suggesting that HAP could enhance cell proliferation. PMID- 29442789 TI - Ultrasonic Remove of Particle Aggregation in Carbon Based Counter Electrodes for Dye-Sensitized Solar Cells. AB - Low-cost carbon materials (carbon black and graphite power) were applied as substitution of platinum (Pt) in counter electrodes (CEs) for dye-sensitized solar cells (DSSCs). Three fabrication methods, such as ball-milled, pulp refined, and ultrasonic-crushed, were applied to remove the particle aggregation in the carbon pastes. Then the carbon based pastes were printed on fluorine-doped transparent conducting oxide (FTO) glasses, used as the CEs for DSSCs. Under illumination of 100 mW/cm2, DSSCs with ultrasonic-crushed CEs (U-CEs) show an energy conversion efficiency of 3.57%, which reach to 65.38% of that with conventional sputtered platinum CEs (5.46%). In addition, U-CEs exhibit a higher catalytic activity and a faster charge transfer rate toward the reduction of I-3 to I-. PMID- 29442791 TI - Fabrication of Highly Sensitive Nonenzymatic Electrochemical H2O2 Sensor Based on Pt Nanoparticles Anchored Reduced Graphene Oxide. AB - A highly sensitive nonenzymatic hydrogen peroxide (H2O2) sensor was fabricated using platinum nanoparticles decorated reduced graphene oxide (Pt/rGO) nanocomposite. The Pt/rGO nanocomposite was prepared by single-step chemical reduction method. Nanocomposite was characterized by various analytical techniques including Raman spectroscopy, X-ray diffraction, field emission scanning electron microscope and high-resolution transmission electron microscopy. Screen printed electrodes (SPEs) were fabricated and the nanocomposite was cast on the working area of the SPE. Cyclic voltammetry and amperometry demonstrated that the Pt/rGO/SPE displayed much higher electrocatalytic activity towards the reduction of H2O2 than the other modified electrodes. The sensor exhibited wide linear detection range (from 10 MUM to 8 mM), very high sensitivity of 1848 MUA mM-1 cm-2 and a lower limit of detection of 0.06 MUM. The excellent performance of Pt/rGO/SPE sensor were attributed to the reduced graphene oxide being used as an effective matrix to load a number of Pt nanoparticles and the synergistic amplification effect of the two kinds of nanomaterials. Moreover, the sensor showed remarkable features such as good reproducibility, repeatability, long-term stability, and selectivity. PMID- 29442790 TI - Fabrication of Electrochemical Biosensor with ZnO-PVA Nanocomposite Interface for the Detection of Hydrogen Peroxide. AB - Hydrogen peroxide (H2O2) is considered to be highly toxic and its increased concentration in human body may lead to diseases like alzheimer's, parkinson's, cardiovascular, tumor and cancer. Hence, there is an increasing demand for the detection of H2O2 in human blood serum. In this context, an electrochemical sensor was developed using zinc oxide-polyvinyl alcohol (ZnO-PVA) nanocomposite as a nano-interface. The fabricated Au/ZnO-PVA/CAT/Chitosan bio-electrode exhibited a well-defined redox peak with anodic and cathodic peak potential of 0.408 V and 0.259 V for Fe(III):Fe(II) and H2O2:1/2 O2 redox couples respectively. The developed biosensor exhibited a linear range of 1 MUM-17 MUM with a sensitivity of 210.49 MUA MUM-1 cm-2, response time of less than 1 s, limit of detection of 9.13 nM and a limit of quantification of 30.13 nM. The developed bio-electrode showed a Michaelis-Menten constant (KM) of 0.39 MUM and dry stability of 93% up to 20 days. The obtained biosensor was successfully utilized to determine the H2O2 concentration in human blood serum sample. PMID- 29442792 TI - Hydrogen and Carbon Nanotubes Production by Catalytic of Ethanol Over the Co-Mo Catalysts. AB - A series of Cobalt-Carbon, Cobalt-Molybdenum-Carbon catalysts were prepared by impregnation. The molar ratios of Co:Mo were 9:1, 8:2 and 7:3 and the total metal weights of them in the supported catalysts were 5 wt%. Moreover, the effects of reaction temperature and the Co:Mo molar ratios on the produce hydrogen and carbon nanotubes were investigated systematically. Of all the catalysts, Co-Mo (5 wt%, Co:Mo = 9:1)/C was the most effective one on the basis of hydrogen yield (84%), ethanol conversion (95%) and the quality of carbon nanotubes at 600 degrees C. A small amount of Mo added into the Co/C catalysts resulted in increasing in the yield of hydrogen and improving on quality of carbon nanotubes from ethanol decomposition over the Co-Mo catalysts. PMID- 29442793 TI - Phthalocyanine-Sensitized Generation of Silver Nanoparticles in Aqueous Buffer Solution Triggered by Red LED-Light. AB - Silver nanoparticles have been generated in aqueous buffer solution using a water soluble silicon phthalocyanine sensitizer. Red light illumination (660 nm LED) was performed under aerobic conditions at ambient temperature in the presence of TEOA as a reductant. Structural characterization of the Ag nanoparticles formed was carried out by transmission electron microscopy (TEM). The resulting silver particles, depending on irradiation time and choice of procedure, were found to have a spheric shape and a narrow size distribution of 5-10 nm. PMID- 29442794 TI - Well-Aligned Au/TiO2 Nanorods by Magnetron Sputtering with Enhanced Photocatalytic Properties. AB - In this work, we demonstrate the feasibility of preparing Au/TiO2 nanorods via a dc magnetron sputtering at room temperature and heat-treatment at 500 degrees C in air for 2 h. The heat treatment leads to the migration of Au atoms into TiO2 nanofilm to form Au/TiO2 nanorods with Au nanoparticles embedded in the TiO2 nanorods of anatase phase. The Au nanoparticles in the TiO2 nanorods suppress the charge recombination. These Au/TiO2 nanorods showed high absorption and intensive response to the visible light and had improved photocatalytic properties in comparison with pure TiO2 nanoparticles formed by using similar method. PMID- 29442795 TI - Preparation and Characterization of Zn1-xNixO Nanoparticles: Application as a SERS Substrate. AB - In this paper, the study of the Zn1-xNixO (x = 0, 0.01, 0.03, 0.05) nanoparticles as SERS active substrate has been reported. The structural, morphological and optical studies are carried out by XRD, XPS, SEM, UV-vis and Raman spectroscopy. The XRD spectra indicate that the four Zn1-xNixO nanoparticles (x = 0, 0.01, 0.03, 0.05) are all single wurtzite structure. XPS study further demonstrates that Ni atoms are successfully doped into ZnO lattice. We have observed strong SERS signals when the 4-mercaptobenzoic acid used as the probe molecules. An interesting phenomenon is that an appropriate amount of the Ni atoms doping can enhance the SERS spectrum, and the maximum SERS intensity appeared when the Zn1 xNixO (x = 0.03) as the SERS active substrate, and we ascribe the SERS mechanism to the charge-transfer mechanism. The energy levels caused by the surface defects of ZnO NPs by Ni doping have influence on the charge-transfer process and have benefit for the SERS performance. PMID- 29442796 TI - Effect of Temperature, Precursor Type and Dripping Time on the Crystallite Size of Nano ZnO Obtained by One-Pot Synthesis: 2k Full Factorial Design Analysis. AB - The aim of this work was to determine the effect of temperature, precursor and dripping time on the crystallite size of ZnO nanoparticles synthesized by controlled precipitation according a 2k full factorial design. ZnCl2, Zn(NO3)2 and NaOH were used as precursors. After synthesis, the nano crystalline powder was characterized by XRD (Cu Kalpha), UV-Vis, and HR-TEM. The nano ZnO particles presented a crystallite size between 210 and 260 A (HR-TEM and XRD). The results show that the crystallite size depends on the type of precursor and temperature of synthesis, but not on the dripping time. PMID- 29442797 TI - Preparation of Paraffin@Poly(styrene-co-acrylic acid) Phase Change Nanocapsules via Combined Miniemulsion/Emulsion Polymerization. AB - The fast development of solid-liquid phase change materials calls for nanomaterials with large specific surface area for rapid heat transfer and encapsulation of phase change materials to prevent potential leakage. Here we report a combined miniemulsion/emulsion polymerization method to prepare poly(styrene-co-acrylic acid)-encapsulated paraffin (paraffin@P(St-co-AA)) nanocapsules. The method could suppress the shortcomings of common miniemulsion polymerization (such as evaporation of monomer and decomposition of initiator during ultrasonication). The paraffin@P(St-co-AA) nanocapsules are uniform in size and the polymer shell can be controlled by the weight ratio of St to paraffin. The phase change behavior of the nanocapsules is similar to that of pure paraffin. We believe our method can also be utilized to synthesize other core-shell phase change materials. PMID- 29442798 TI - Direct Synthesis of Graphene Layer Covered Micro Channel on Diamond Surface Using Ni Wire. AB - In order to propose a new simple method for the fabrication of a microchannel covered with a graphene layer on a diamond substrate, the application of a phase transition via a solid solution phenomenon, that is, the dissolution of a thermodynamic-metastable phase and the deposition of a thermodynamic-stable phase, was performed in this study. A CVD diamond film in contact with a Ni wire (100 micrometers in diameter) was heated under flowing H2. The experimental results in this study proved that a micro-channel (ca. 5 micrometers deep) covered with a graphene layer, the stacking number of which was more than 6, can be successfully patterned on a diamond substrate. The etching rate was estimated to be ca. 1.3-1.4 MUm h-1. It was proved based on the experimental data from this study that this method can be used to fabricate a microreactor on a diamond substrate although the technique may be refined. PMID- 29442799 TI - Biomimetic Nanohydroxyapatite Synthesized With/Without Tris-Buffered Simulated Body Fluid: A Comparative Analysis. AB - Nano hydroxyapatite (nHAp) mimics the inorganic phase of hard tissue such as bone and teeth and, thus, has a wide range of clinical applications. The present study reports on the biomimetic synthesis of nHAp with and without Tris-buffered simulated body fluid (SBF) and investigated the role of buffering conditions on nHAp formation. The hypothesis of this study was that the nucleation and growth rate of nHAp may depend on buffering conditions during the precipitation process. The results of this study suggest that both of the above methods effectively synthesized carbonated "bone-like" nHAp. However, an increased incubation period of 8 hrs was necessary for nHAp synthesized using non Tris-buffered SBF as compared to Tris-buffered SBF which synthesized nHAp in just 3 hrs. Interestingly, there was no change in the chemical functionality for both samples. XRD and TGA analysis confirmed that Tris-buffered SBF facilitated more carbonate ion substitution than the non-Tris-buffered SBF approach. Therefore, this study concluded for the first time that the addition of Tris in SBF accelerates nHAp formation with more carbonate ion substitution. Nevertheless, carbonate ion substituted nHAp could also be synthesized using non Tris-buffered SBF, but would require longer incubation periods. This analysis highlights the importance of pH stability in the SBF for biomimetic nHAp synthesis which is useful for the synthesis of nHAp for a wide range of biomedical applications. PMID- 29442800 TI - Characterization of Articaine-Loaded Poly(epsilon-caprolactone) Nanocapsules and Solid Lipid Nanoparticles in Hydrogels for Topical Formulations. AB - This work describes the development of poly-epsilon-caprolactone nanocapsules (PCL-NC) and solid lipid nanoparticles (SLN) aiming delivery for articaine (ATC), in order to improve its chemical stability in semi-solid preparations looking forward their use for skin delivery. The nanoparticles were characterized by size, polydispersity index, and pH. Cellular viability was evaluated using the MTT test and the in vitro release kinetics was determined using a two-compartment model. The hydrogels with nanoparticle suspensions were characterized considering their rheological aspects and in vitro permeation across artificial membranes. Colloidal stability was satisfactory, since the formulations did not present major alterations during 120 days. High ATC encapsulation was achieved (78% for PCL-NC and 65% for SLN). The release profile of PCL-NC-ATC was slower, compared to the free molecule and SLN-ATC. MTT experiments showed the nanosystems were capable to increase cellular viability compared with free ATC. The hydrogels showed good consistency, homogeneity, and stability and presented pseudoplastic behavior with thixotropy, improving drug efficacy in clinical applications. The gel based on PCL-NC showed faster onset of activity and flux of 35.68 +/- 1.98 MUg/cm2/h, which then continued for up to 8 h. This study opens up prospects for employment of nanoparticulate systems for modified release of ATC. PMID- 29442801 TI - Cytocompatibility and Osteogenesis of Adipose Tissue-Derived Stem Cells on POSS PEG Coated Collagen. AB - Nanostructured POSS-PEG nanoparticles (NPs, 42.4 nm ~) synthesized by formation of the urethane linkage between the monoisocyanate group (O?C?N-) of Polyhedral oligosilsesquioxane (POSS) macromers and the diol end groups (-OH) of polyethylene glycol (PEG) homopolymers as catalyzed by dibutyl tin dilaurate are of great interest for biomedical applications. However, NP materials based on nonorganic compounds can be cytotoxic. In this study, the preparation of PEG-POSS NPs followed the coating collagen assembly, which alleviates this problem. They also showed controlled surface properties in such a manner that hydrophobicity and biocompatibility were both reachable to give rise to improved cell viability. It indicates that the PEG-POSS coated collagen was appropriate for the proliferation of adipose tissue-derived stem cells to osteogenesis. PMID- 29442802 TI - Metal- and Carbon-Based Materials as Heterogeneous Electrocatalysts for CO2 Reduction. AB - Climate change caused by continuous rising level of CO2 and the depletion of fossil fuels reserves has made it highly desirable to electrochemically convert CO2 into fuels and commodity chemicals. Implementing this approach will close the carbon cycle by recycling CO2 providing a sustainable way to store energy in the chemical bonds of portable molecular fuels. In order to make the process commercially viable, the challenge of slow kinetics of CO2 electroreduction and low energy efficiency of the process need to be addressed. To this end, this review summarizes the progress made in the past few years in the development of heterogeneous electrocatalysts with a focus on nanostructured material for CO2 reduction to CO, HCOOH/HCOO-, CH2O, CH4, H2C2O4/HC2O-4, C2H4, CH3OH, CH3CH2OH, etc. The electrocatalysts presented here are classified into metals, metal alloys, metal oxides, metal chalcogenides and carbon based materials on the basis of their elemental composition, whose performance is discussed in light of catalyst activity, product selectivity, Faradaic efficiency (FE), catalytic durability and in selected cases mechanism of CO2 electroreduction. The effect of particle size, morphology and solution-electrolyte type and composition on the catalyst property/activity is also discussed and finally some strategies are proposed for the development of CO2 electroreduction catalysts. The aim of this article is to review the recent advances in the field of CO2 electroreduction in order to further facilitate research and development in this area. PMID- 29442803 TI - N2-BET is a Proxy for Primary Particle Size and May Not Be Representative of Available Specific Surface Area for Aggregated Nanoparticle Aerosols. AB - The knowledge of the specific surface area of aerosolized engineered nanoparticles could be important for mechanistically understanding their toxic potential or functional characteristics. The most widely method to perform this measurement, N2-BET, however, may not accurately represent the available surface area for hetero-aggregated nanoparticles in the context of large biological molecules. This study conducted an analysis of published characterization measurements including primary particle size, aggregation state, and specific surface area made for dry aerosolized nanoparticles. Results indicate that primary particle size explains 65% of the variance in specific surface area, while aggregation (as measured by mass median aerodynamic diameter) only explains 20% of the variance. Curiously, increasing aggregation (larger MMAD) is associated with increasing SSA as measured by N2-BET, likely an artifact of the measurement method, which suggests that this technique may not be appropriate for studies investigating biological interactions with nanoparticles. PMID- 29442804 TI - Synthesis of Mesoporous Yolk-Shell Magnetic Prussian Blue Particles for Multi Functional Nanomedicine. AB - Mesoporous magnetic Prussian Blue (PB) particles are good condidates for theragnostic nanomedicine. However, there are lack of efficient methods for fabrication of such materials. Here, we reported the synthesis of the mesoporous yolk-shell Fe3O4@PB particles by one-pot coordination replication and etching. Time-dependent transmission electron microscopy illustrated that the PB crystals nucleated and grew on the surface of Fe3O4 spheres by coordination replication with the help of protons. The extra protons in the reaction medium further disassociated the Fe3O4 and PB, leading to mesoporous particles. The mesoporous yolk-shell Fe3O4@PB particles showed enhanced efficacy for loading cisplatin. The release of the drug molecules could be facilitated by increasing temperature. Both photo irradiation and alternating magnetic fields could trigger the release of heat from the composite. The obtained materials could delivery cisplatin to kill cancer cell intracellularly. PMID- 29442805 TI - Hollow Fe3O4/Graphene Oxide Nanocomposites as Novel Rapamycin Carrier: Formulation Optimization and In Vitro Characterization. AB - In the present research an attempt was made to develop and optimize rapamycin (Rapa) loaded hollow magnetic Fe3O4/graphene oxide (Fe3O4/GO) nanocomposites using solvent evaporation technique and response surface methodology (RSM). A Box Behnken design (BBD) with a three-level, three-factor was used to determine preparation parameters that would achieve the highest encapsulation efficiency (EE) and drug loading capacity (DLC). At optimum conditions such as mass ratio of Rapa to Fe3O4/GO (Rapa: Fe3O4/GO) 0.45, oscillation rate 144.0, and volume ratio of water to solvent (W/S) 4.2, the EE and DLC of experimentally prepared particles reached 84.92 +/- 5.50% and 28.68 +/- 2.54% respectively. The morphological assessment results showed that hollow Fe3O4 nano-aggregates were evenly and tightly dispersed on the layer of GO membrane. After the addition of GO and encapsulation of Rapa, the Fe3O4/GO nanocomposites and Rapa loaded magnetic Fe3O4/GO (Fe3O4/GO-Rapa) nanocomposites showed saturation magnetization of 57.77 and 40.71 emu/g respectively. The drug releasing experiment indicated a slightly acidic atmosphere, which was suitable for Rapa releasing from the obtained Fe3O4/GO nanocomposites. The cell counting Kit-8 (CCK-8) assays demonstrated the hollow Fe3O4/GO nanocomposites could effectively improve the efficacy of Rapa in killing HepG2 cells, which displayed a concentration dependent manner. All these results suggested the prepared Fe3O4/GO nanocomposites have a potential application in drug delivery system. PMID- 29442806 TI - Hetero-Functionalized Gold Nanoparticles to Silence AU-Rich Element Containing mRNAs in RAGE-Expressing Inflammatory Cells: Preparation, Characterization, and In-Vitro Evaluation. AB - Diabetes, a chronic metabolic disorder associated with significantly accelerated rates of inflammation. Gold nanoparticle plays a crucial role in biomedical applications. We described the development of hetero-functionalized gold nanoparticles (hfAuNPs) for targeted selective gene silencing by RNAi interference. This hfAuNPs was developed by parallelly conjugating biotinylated ARE-siRNA (siRNA to Adenosine Uridine-rich elements) and biotinylated RAGE interacting-peptide (RIP) to streptavidin coated gold nanoparticles (aAuNPs) thus forms a complex that provides biocompatibility and functionality in a physiological environment. RIP can function as targeting agent and ARE-siRNA involve in silencing ARE containing proinflammatory cytokine/chemokine and related molecules mRNAs. Characterization of nanoparticle was performed by UV-Vis spectrophotometry, fourier transform infrared spectroscopy (FTIR), dynamic light scattering, zeta potential, field emission-scanning electron microscope with energy dispersive spectrometer (FE-SEM with EDS) and atomic force microscope analysis (AFM). Plasmonic emission spectra of hfAuNPs and aAuNPs showed spectra at 275 nm and 235 nm respectively. Interestingly spectra shift from 235 nm to 275 nm proved presence of functionalized molecules in hfAuNPs. FTIR showed the hfAuNPs peak at 3338 cm-1 conveying combined O-H and N-H vibrations of streptavidin and biotin in the infrared spectra. The spherical morphology and Au presence were analyzed by FE-SEM with EDS. A complex formation was confirmed by a decrease in size and a change in zeta potential of hfAuNPs. AFM showed an increased surface roughness of hfAuNPs. The comparison of our initial in-vitro studies suggested the significant increased cellular uptake of hfAuNPs in RAGE overexpressing HeLa cells. Thus hfAuNPs could serve as novel therapeutic candidates to alleviate inflammatory disease like diabetes. PMID- 29442807 TI - Inhibition of Lysozyme Fibrillation by Gold Nanorods and Nanoparticles. AB - Amyloid fibrillation has been implicated in many neurodegenerations, dialysis related amyloidosis, type II diabetes and more than 30 other amyloid-related diseases. Nanomaterials as potential inhibitors of amyloid fibrillation have attracted increasing interests. In the present study, the effects of gold nanorods (AuNRs) and nanoparticles (AuNPs) on amyloid fibrillation were investigated using hen egg white lysozyme (HEWL) as a model system. Our results indicated that AuNRs and AuNPs, especially AuNRs, present significant inhibitory effects on HEWL amyloid fibril formation during all the kinetic processes, from nucleation to elongation and equilibration stages. The stronger adsorption capacity of HEWL on AuNRs surface is the key mechanism of inhibition of HEWL amyloid fibrillation. Furthermore, AuNRs lead to more stable alpha-helix conformation and hydrophobic microenvironment of aromatic side groups in HEWL molecules, which facilitate the system to form small amorphous aggregates rather than oligomer, profibril or mature fibril. PMID- 29442808 TI - Aptamer-Immobilized Surface Plasmon Resonance Biosensor for Rapid and Sensitive Determination of Virulence Determinant. AB - Shigella sonnei isolate invasion plasmid antigen protein, IpaH, was successfully expressed in recombinant overexpression bacterial system. The soluble expression IpaH was enhanced with molecular chaperon co-expressed environment. Specific aptamer IpaH17 was isolated through the SELEX process and showed fM binding affinity. IpaH17-SPR biosensor platform was involved to verify the binding sensitivity and specificity. The IpaH concentration dependent IpaH17-SPR sensor response was highly linear with a linear regression constant of 99.4% in the range between 0 and 100 ng/mL. In addition, S. sonnei revealed the specific RU value and detected in a real-time manner within 1 hour. Our study indicated that IpaH17-SPR sensor can allow for rapid, sensitive and specific determination of Shigella sonnei virulent factor. PMID- 29442809 TI - Reduction-Responsive Release of Solid Lipid Nanoparticle Composed of Stearic Acid and Cystamine. AB - A reduction-responsive solid lipid nanoparticles (SLNs) were prepared by an emulsification evaporation and solidification method using stearic acid (SA) and cystamine as constituting materials. The mean hydrodynamic diameter of the SLN decreased from 510.6 nm to 117.0 nm, as the molar ratio of SA to cystamine increased from 1:0 to 1:1. On the TEM photo, negatively stained SLNs were found as black circles and the diameter was tens to hundreds of nanometer. According to the EDS analysis, the sulfur content of SLN was found to be 1.19% (w/w) to 3.62% (w/w), depending on the molar ratio of SA to cystamine (1:0.125 to 1:1) employed in the preparation. According to the differential scanning calorimetric analysis, the melting point decreased gradually from about 52 degrees C to 50 degrees C as the molar ratio of SA to cystamine increased from 1:0 to 1:1. Even if cystamine (a disulfide compound) was contained in SLN, the release degree at 25 degrees C was not significantly affected by dithiothreitol (DTT, a reducing agent). Whereas, the release degree at 37 degrees C and 52 degrees C was significantly suppressed by DTT when cystamine was contained in SLN, possibly because cystamine would be more readily reduced to aminoethanethiols in the SLN matrix at the higher temperatures. PMID- 29442810 TI - One-Pot Facile Synthesis of Pt Nanoparticles Using Cultural Filtrate of Microgravity Simulated Grown P. chrysogenum and Their Activity on Bacteria and Cancer Cells. AB - Platinum nanoparticles (Pt NPs) was synthesized via a facile and cost competitive ont-pot green mediated synthesis using cell free cultural filtrate (microgravity simulated grown Penicillium chrysogenum) as a reducing agent. The toxicity effect of synthesized Pt NPs toward myoblast C2C12 carcinoma cells was then investigated. The particle size analyzer (DLS) and transmission electron microscopy (TEM) results demonstrates that both NG-Pt NPs and MG-Pt NPS are spherical in shape with an average diameter of 15 nm and 8.5 nm, respectively. The results from UV-visible (UV-vis) spectroscopy and X-ray diffraction (XRD) analysis show a characteristic strong resonance centered at 265 nm and a single crystalline nature, respectively. The results derived from in vitro cytotoxicity showed a significant concentration-dependent decrement in cell viability when C2C12 cells were exposed to Pt NPs. Such decrement in cell viability is because of increased reactive oxygen species (ROS) generation. Cell apoptosis was proved by acridine orange-ethidium bromide (AO/EtBr) dual staining, annexin V-FITC/PI staining and immunocytochemistry. Moreover, the protein expression of both (i) apoptosis related proteins such as cas-3 and cas-9, (ii) inflammatory response proteins such as TNF-alpha, TGF-beta and NF-kappaB were significantly upregulated in MG-Pt NPs treated cells than NG-Pt NPs treated cells. Uptake and intracellular localization of MG-Pt NPs caused by accumulation of autophagosomes in C2C12 cells and bacterial cells, indicate that synthesized MG-Pt NPs enable for the swift cell apoptosis than NG-Pt NPs. Interestingly, At the concentration of 40 and 80 MUg/ml MG-Pt NPs showed more potent cytotoxicity toward cancer cells while, under identical concentration, NG-Pt NPs exhibited rather lower cytotoxicity. Overall, our results demonstrated that MG-Pt NPs could be selectively inhibit the growth of cancer cells via ROS-mediated nucleus NF-kappaB and caspases activation when compared to NG-Pt NPs. PMID- 29442811 TI - Immobilization of N-Halamine Based Polycation on Nanodiamonds for High Dispersity and Enhanced Biocidal Activity. AB - Novel bactericidal materials, polycation-based N-halamine functionalized nanodiamonds (PCN-NDs), were fabricated by coating of nanodiamonds (NDs) with quaternarized N-halamine polymers via a facile approach. Chemical modification of the particles was confirmed by FTIR, XPS and TGA. The particle diameters and dispersity of the functionalized NDs were investigated by TEM and DLS measurements. It was found that ND tight core aggregates could be broken into tiny nanoparticles with 40-50 nm through functionalization procedure, which resulted in stable colloidal dispersion solution over one month. The antibacterial tests showed that the PCN-NDs exhibited enhanced antibacterial activity against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) compared with their bulk counterparts. The minimum inhibitory concentration values of the as-prepared PCN-NDs are 62.5 MUg/mL for both E. coli and S. aureus, even PCN-NDs eliminated nearly 100% of E. coil and S. aureus (107-108 CFU/mg nanoparticles) within 15 min. Furthermore, the as-prepared antimicrobial PCN-NDs exhibited good storage stability and regenerability. PMID- 29442812 TI - Tea Polyphenol-Reduced Graphene Oxide Deposition on Titanium Surface Enhances Osteoblast Bioactivity. AB - Graphene, a novel carbon-based material, has been widely used as osteogenic agent for the potential effect on the promotion of osteoblast proliferation. Tea polyphenol-reduced graphene oxide (TPG) is a simple and environmental-friendly raw material to obtain graphene. In this study, TPG was deposited on the Ti substrate to promote the bone regeneration. We prepared a honeycomb-like structure by acid and alkali pretreatment and immobilized the TPG layer (Ti-TPG) on the surface via electrochemical deposition. Scanning electron microscopy (SEM), atomic force microscopy (AFM) and X-ray diffraction (XRD) were used to identify the immobilization of TPG on the titanium (Ti) successfully. Furthermore, the biological response of the Ti-TPG surface to rat osteoblast was evaluated. We also studied the cell adhesion, proliferation and expression of ossification genes on the sample. The results revealed that Ti-TPG had an advantage over Ti alloys in modulating cellular activity and Ti-TPG may be a promising coating for biological materials. PMID- 29442813 TI - Prostate Cancer Cell-Specific Cytotoxicity of Sub-Micron Potassium Niobate Powder. AB - Oxide nanoparticles have numerous potential applications in medicine such as carriers for therapeutic drugs, contrast agents for bio-imaging and targeting agents for tumors. Oxide nanoparticles may also have an inherent cytotoxicity towards cancer cells, as recently found for cerium oxide. KNbO3 nanoparticles have a combination of low toxicity and nonlinear optical properties which make them attractive for use as a bio-imaging material. However, little is known yet about the cytotoxicity of KNbO3 particles towards cancerous cells. In the present work, the cytotoxicity of KNbO3 particles to normal and prostate cancer cell lines is studied. The mixed oxide method is used to prepare KNbO3 powder. Using dynamic light scattering the mean particle diameter of the KNbO3 powder is found to be ~500 nm. X-ray diffraction, Fourier transform infra-red spectroscopy and Raman scattering spectroscopy are used to examine the structure of the KNbO3 powder. Powder morphology is examined using scanning electron microscopy. MTT assays of EA.hy926, PC-3 and DU-145 cell lines are carried out to study cell specific cytotoxicity. KNbO3 sub-micron particles are found to have low toxicity to PC-3 cells, moderate toxicity to EA.hy926 cells and high toxicity to DU-145 cells. A new avenue towards the treatment of prostate cancer may be opened by the cell-specific cytotoxicity of KNbO3. PMID- 29442815 TI - Non-Metal Doped Titania Photocatalysts for the Degradation of Neonicotinoid Insecticides Under Visible Light Irradiation. AB - Recombination of e-/h+ pair, the major issue of any titania based photocatalytic material, is addressed here by doping non-metals such as C, N, B, F into the lattice of nano TiO2. The as-synthesised catalysts were characterized by using various instrumental techniques such as X-ray diffraction (XRD), UV-Diffuse reflectance spectroscopy (UV-DRS), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). Nanosize of titania was confirmed by both XRD and TEM studies. Visible light inactivity of TiO2 is overcome by C, N, B, F doped titania catalysts in the degradation of neonicotinoid type insecticides namely imidacloprid (IMI) and thiamethoxam (TMX). The degradation efficiencies of the catalysts under different irradiations namely UV, visible and solar were compared. Among the catalysts, CNBF/TiO2 degraded IMI completely at 150, 240 and 330 min whereas TMX has been degraded completely at 210, 270 and 420 min under UV, solar and visible irradiations respectively. The recyclability test of CNBF/TiO2 confirmed its stability towards photocatalytic reaction. PMID- 29442814 TI - Evaluation of Functional SiO2 Nanoparticles Toxicity by a 3D Culture Model. AB - CONTEXT: as a kind of non-metal oxide SiO2 NPs have been extensively used in biomedicine, pharmaceuticals and other industrial manufacturing fields, such as DNA delivery, cancer therapy... Our group had developed a method based on microemulsion process to prepare SiO2 NPs incorporating photonic or magnetic nanocrystals and luminescent nanosized inorganic metal atom clusters. However, the toxicity of nanoparticles is known to be closely related to their physico chemical characteristics and chemical composition. OBJECT: it is therefore of interest to investigate the toxicity of these novel SiO2 NPs to the cells that may come in contact. MATERIALS AND METHODS: the potential toxic effect of the functional @SiO2 NPs containing Mo6 clusters with or without gold nanoparticles was investigated, at concentrations 1 MUg/mL, 10 MUg/mL and 100 MUg/mL each, on three different cell lines. Cell viability was measured by the MTT test in monolayer's culture whereas the cytotoxicity in spheroid model was examined by the APH assay. In a second time, oxidative-stress-induced cytotoxicity was investigated through glutathione levels dosages. RESULTS: the results indicated that both A549 and L929 cell lines did not exhibit susceptibility to functional @SiO2 NPs-induced oxidative stress unlike KB cells. DISCUSSION: SiO2 NPs containing CMB may become toxic to cultured cells but only at a very high dosage level. Therefore, this toxicity depends on cell lines and more, on the model of cell cultures. The selection of appropriate cell line remains a critical component in nanotoxicology. CONCLUSION: these results are relevant to future applications of SiO2 gold-cluster NPs in controlled release applications. PMID- 29442816 TI - Liquid Exfoliation and Electrochemical Properties of WS2 Nanosheets. AB - Commercial WS2 powders were exfoliated in sodium dodecyl sulfate solution with a combination of ball-milling and sonication. WS2 nanosheets can be uniformly dispersed in the solution. The layers and thicknesses of WS2 nanosheets could be tailored via changing the ball-milling speed. The effects of the ball-milling speed on crystallinity and morphology of the samples were analyzed. The results show that the layer structure of WS2 nanosheets is destroyed and the crystallinity is decreased with increase of the ball-milling rate. The monolayer WS2 nanosheets at 200 rpm are obtained, which are mesoporous with the specific surface area as 5.419 m2 g-1. The specific capacitance and charge/discharge efficiency of WS2 nanosheets at 200 rpm are better than those of other samples. Its specific capacitance under the scanning rate of 20 mV s-1 and the current density of 0.5 A g-1 are 13.46 F g-1 and 22.50 F g-1, respectively. The charge/discharge curve of WS2 nanosheets at 200 rpm is a symmetrical triangle, which shows rapid charge and slow discharge. It means that WS2 nanosheets at 200 rpm has good electrochemical reversibility. The load transfer resistance and the internal series resistance of this sample are 84.60 Omega and 4.18 Omega, respectively. PMID- 29442817 TI - Room Temperature Formation of Carbon Onions via Ultrasonic Agitation of MoS2 in Isopropanol. AB - Ultrasonic agitation is a proven method for breaking down layered materials such as MoS2 into single or few layer nanoparticles. In this experiment, MoS2 powder is sonicated in isopropanol for an extended period of time in an attempt to create particles of the smallest possible size. As expected, the process yielded a significant quantity of nanoscale MoS2 in the form of finite layer sheets with lateral dimensions as small as a few tens of nanometers. Although no evidence was found to indicate a larger the longer sonication times resulted in a significant increase in yield of single layer MoS2, the increased sonication did result in the formation of several types of carbon allotropes in addition to the sheets of MoS2. These carbon structures appear to originate from the breakdown of the isopropanol and consist of finite layer graphite platelets as well as a large number of multi-walled fullerenes, also known as carbon onions. Both the finite layer graphite and MoS2 nanoplatelets were both found to be heavily decorated with carbon onions. However, isolated clusters of carbon onions could also be found. Our results show that liquid exfoliation of MoS2 is not only useful for forming finite layer MoS2, but also creating carbon onions at room temperature as well. PMID- 29442818 TI - One-Step Electrospinning Method to Prepare Gold Decorated on TiO2 Nanofibers with Enhanced Photocatalytic Activity. AB - A gold doped titanium dioxide (TiO2) nanofiber was prepared by one-step electrospinning technique to control the DC high voltage and the following calcination. The crystal structures and morphology of Au-TiO2 nanofibers were characterized in detail by X-ray diffraction (XRD), energy dispersive photoelectron spectroscopy (EDS), scanning electron microscope (SEM) and transmission electron microscope (TEM). These results indicate that Au is successfully incorporated into TiO2 nanofibers without gold loss, while Au and TiO2 form a heterogeneous structure. It implied that the Schottky barrier existed by X-ray photoelectron spectroscopy (XPS) of 0.075% Au-TiO2. For 0.075% Au-TiO2 nanofibers, the rate of photocatalytic degradation of methylene (MB) was significantly higher than that of pure TiO2 nanofibers. PMID- 29442819 TI - One-Step Hydrothermal Synthesis of Small TiO2 Porous Nanoparticles for Efficient Degradation of Organic Dyes. AB - In the work, small TiO2 porous nanoparticles with an average size of 60 nm have been prepared by a simple, eco-friendly, and one-step hydrothermal method. The TiO2 products are achieved by only using tetrabutyl titanate (TBOT), tetrapropylammonium hydroxide (TPAOH), and water as the starting materials. Various techniques such as SEM, TEM, HRTEM, XRD, Raman, and BET are used to characterize the surface morphology and structural features of products. The growth parameters including reaction time, titanium source and temperature of thermal treatment are systematically investigated. In the synthesis, TPAOH plays a decisive role as structure-directing agent for the formation of desirable TiO2 nanostructure. The photocatalytic tests manifest that the TiO2 nanoparticles annealed at 450 degrees C shows an outstanding photocatalytic activity for degradation of methyl orange (MO) and rhodamine B (RhB), which is comparable to Degussa P25. The superior performance may mainly come from the contributions of their small particle size and unique nanostructure. PMID- 29442820 TI - Synthesis, Optical, Electrochemical and Theoretical Studies of New Multicyclic Substituted Phthalocyanines. AB - Here novel phenanthrenoxy and pyrenoxy substituted phthalocyanines were synthesized and fully characterized by general spectroscopic methods such as elemental analysis, 1H NMR, MALDI-TOF, FT-IR, UV-Visible absorption. The aggregation property of these phthalocyanines was investigated in CHCl3 and Triton X. Furthermore, electrochemical and DFT calculations were performed for these molecules. PMID- 29442821 TI - Supramolecular Arrangement of Iron Phthalocyanine in Langmuir-Schaefer and Electrodeposited Thin Films. AB - The supramolecular arrangement in thin film technology has been explored through different deposition techniques aiming to control the film properties at the molecular level. We report on the formation of iron phthalocyanine (FePc) films using both Langmuir-Schaefer (LS) and electrodeposition methods. The multilayer formation was monitored with ultraviolet-visible absorption spectroscopy (UV-vis) and electrochemical measurements. According to Raman spectroscopy, atomic force microscopy (AFM), and scanning electron microscopy (SEM), the surface morphology of electrodeposited films is more homogeneous than LS films at micro and nanometer scales. From FTIR spectroscopy, the FePc molecules in the electrodeposited films are oriented preferentially with the macrocycle parallel to the substrate surface (flat-on), while a slight tilt is suggested in LS films, being both films crystalline. Therefore, the use of different deposition techniques allowed the fabrication of thin films from FePc with distinct supramolecular arrangements, leading to distinct electrochemical properties. For instance, the electrodeposited films show higher surface coverage, suggesting a more compact structure, which favors the charge transfer and smaller energy gap. The possibility of tuning some properties according to deposition technique for the same material can help the development of technological applications such as electronic or sensing devices. PMID- 29442822 TI - Surfactant Coated Silica Nanoparticles as Smart Scavengers for Adsorptive Removal of Naphthalene. AB - This manuscript represents the synthesis of silica nanoparticles modified with four different types of cationic surfactants. The surfactant capped nanoparticles have better control over the size of silica nanoparticles. The as formed as model nanomaterials were used for the removal of naphthalene, a simple white crystalline polycyclic aromatic hydrocarbon (PAH) from aqueous media. The obtained materials were characterized by various microscopic and spectroscopic techniques. The average particle size of nanoparticles was approximately between 50 and 75 nm. The removal kinetic and adsorption studies were also conducted on silica nanoparticles with different contact time, initial concentrations of silica and naphthalene to achieve the optimum adsorption conditions. CPB functionalized nanoparticles have displayed higher removal efficiency of more than 85% as compared to 75 to 80% in case of CTAB, CTAC and CPC functionalized silica nanoparticles. The effects of various parameters like pH, adsorbent doses, naphthalene concentration and addition of salt have also been investigated for better understanding of the removal efficacy of prepared nanoparticles. PMID- 29442823 TI - Rational Synthesis of Hollow Prussian Blue Analogue Through Coordination Replication and Controlled-Etching for Cs-Ion Removal. AB - Radioactive cesium pollution have received considerable attention due to the increasing risks in development of the nuclear power plants in the world. Although various functional porous materials are utilized to adsorb Cs+ ions in water, Prussian blue analogues (PBAs) are an impressive class of candidates because of their super affinity of Cs+ ions. The adsorption ability of the PBAs strongly relate to the mesostructure and interstitial sites. To design a hollow PBA with large number of interstitial sites, the traditional hollowing methods are not suitable owing to the difficulty in processing the specific PBAs with large number of interstitial sites. In this work, we empolyed a rational strategy which was to form a "metal oxide"@"PBA" core-shell structure via coordination replication at first, then utilized a mild etching to remove the metal oxide core, led to hollow PBA finally. The obtained hollow PBAs were of high crystallinity and large number of interstitial sites, showing a super adsorption performance for Cs+ ions (221.6 mg/g) within a short period (10 min). PMID- 29442824 TI - Nanocrystalline Cellulose-Functionalized Reduced Graphene Oxide Nanosheets and Their Composite Papers. AB - Aqueous-dispersed nanocrystalline cellulose functionalized-reduced graphene oxide (NCC-RGO) nanosheets (the precursor of the composite papers) were prepared via the reaction of graphene oxide (GO) nanosheets, NCC, and ascorbic acid. In this reaction, stiff rod-like NCC was attached to the surface of GO nanosheets via hydrogen bond interactions, which prevented the agglomeration of the nanosheets as the surface oxygen-containing functional groups were removed by ascorbic acid The NCC-RGO composite papers were fabricated using a flow-induced self-assembly strategy with vacuum filtration. NCC-RGO nanosheets underwent layer-by-layer self assembly on the filter membrane as water permeated the membrane. The structures as well as the electrical and mechanical properties of the NCC-RGO nanosheets and the NCC-RGO composite papers were investigated. The results revealed that the aqueous dispersions of the NCC-RGO nanosheets exhibited long-term stability, consequently producing well-aligned, robust, electrically conductive NCC-RGO composite papers. PMID- 29442825 TI - Palm Fatty Acid Functionalized Fe3O4 Nanoparticles as Highly Selective Oil Adsorption Material. AB - The present work highlights the facile synthesis of hydrophobic palm fatty acid functionalized Fe3O4 nanoparticles (MNP-FA) for the efficient removal of oils from the surface of water. An intense hydrophobic layer was introduced on the surface of Fe3O4 nanoparticles functionalized by the palm fatty acid obtained from the hydrolysis of palm olein. Scanning electron microscopy (SEM), vibrating sample magnetometer (VSM), Energy dispersive X-ray spectroscopy (EDX) and water contact angle analysis (WCA) measurements were used to characterize the newly fabricated palm fatty acid adorned magnetic Fe3O4 nanoparticles (MNP-FA). The obtained results confirmed the successful synthesis of palm fatty acid functionalized magnetic nanoparticles. Oil removal tests performed with MNP-FA revealed that this newly prepared material could selectively adsorb lubricating oil up to 3.5 times of the particles' weight while completely repelling water. The main parameters affecting the adsorption of oil i.e., sorption time, mass of sorbent and pH of water were optimized. PMID- 29442826 TI - Superior Photocatalytic Performance of CeO2 Nanoparticles and Reduced Graphene Oxide Nanocomposite Prepared by Low Cost Co-Precipitation Method. AB - In this article, cerium oxide nanoparticles (CeO2 NPs) and reduced graphene oxide nanocomposite have been fabricated through simple, easy and cost effective co precipitation method. The structural, optical and morphological characterization provides the evidence of successful synthesis of CeO2 NPs and nanocomposite. X ray photoelectron spectroscopic characterization provides useful information about the concentrations and proportions of Ce3+ and Ce4+ ions in nanoparticles as well as in nanocomposite. These studies provide an insight to understand enhanced photocatalytic activity of nanocomposite. The nanocomposite produces 81% photocatalytic degradation of methyl orange compared to only 45% degradation by CeO2 NPs alone. PMID- 29442827 TI - Synthesis and Self-Assembly of Block Copolymers Containing Temperature Sensitive and Degradable Chain Segments. AB - In this work, polylactide-b-poly(N-isopropylacrylamide) were synthesized by the combination of controlled ring-opening polymerization and reversible addition fragmentation chain transfer polymerization. These block copolymers with molecular weight range from 7,900 to 12,000 g/mol and narrow polydispersity (<=1.19) can self-assemble into micelles (polylactide core, poly(N isopropylacrylamide) shell) in water at certain temperature range, which have been evidenced by laser particle size analyzer proton nuclear magnetic resonance and transmission electron microscopy. Such micelles exhibit obvious thermo responsive properties: (1) Poly(N-isopropylacrylamide) blocks collapse on the polylactide core as system temperature increase, leading to reduce of micelle size. (2) Micelles with short poly(N-isopropylacrylamide) blocks tend to aggregate together when temperature increased, which is resulted from the reduction of the system hydrophilicity and the decreased repulsive force between micelles. PMID- 29442828 TI - Preparation of Nanofibrous Silver/Poly(vinylidene fluoride) Composite Membrane with Enhanced Infrared Extinction and Controllable Wetting Property. AB - Nanofibrous silver (Ag)/poly(vinylidene fluoride) (PVDF) composite membranes were obtained from a two-step preparation method. In the first step, the electrospun silver nitrate (AgNO3)/PVDF membranes were prepared and the influence of the AgNO3 content on the electrospinning process was studied. According to scanning electron microscopy (SEM) results, when the electrospinning solution contained AgNO3 in the range between 3 to 7 wt.%, the nanofiber morphologies can be obtained. In the second step, the electrospun AgNO3/PVDF membranes were reduced by sodium borohydride to form the nanofibrous Ag/PVDF composite membranes. The resultant composite membranes were characterized by SEM, X-ray diffraction (XRD), energy-dispersive spectroscopy (EDS), differential scanning calorimetry, X-ray photoelectron spectroscopy (XPS), and Fourier-transform infrared. The XRD, XPS, and EDS characterizations proved the existence of Ag in the nanofibrous Ag/PVDF composite membranes. The crystallinity degree of PVDF for composite membranes declined with the increase in Ag content. More importantly, the nanofibrous Ag/PVDF composite membranes had obviously higher Rosseland extinction coefficients and lower thermal radiative conductivities in comparison with electrospun PVDF membrane, which demonstrates that such composite membranes with high porosity, low density, and good water vapor permeability are promising thermal insulating materials to block the heat transfer resulting from thermal radiation. In addition, three different methods for surface modification have been used to successfully improve the hydrophobicity of nanofibrous Ag/PVDF composite membranes. PMID- 29442829 TI - Remarkably Improved Dispersion Stability and Thermal Conductivity of WO3-H2O Suspension by SiO2 Coating. AB - The long term dispersion stability for an improved thermal conductivity is a challenging issue that needs to be solved for heat transfer applications. Hence, this research investigated that a thin layer of SiO2 coating (2-5 nm) over WO3 nanostructures (SiO2@WO3) of different shapes exhibit superior dispersion (0.01%) stability for longer duration (~3 days) as evident by steady zeta potential (-30 <-> -60.70 mV), no significant change in particle-size (139 <-> 147 nm) distribution, density (1.001 <-> 0.988 g/cm3) and refractive index (1.335 <-> 1.332) etc., are indicator for colloidal stability relative to bare WO3 nanoparticles and bulk SiO2 aqueous suspension which quickly settles down within 1-2 hours after 30 min sonication at 23 degrees C. Thin Si-OH layer over WO3 surface imparts superior hydrophilicity, larger surface area for effective solute solvent (SiO2@WO3-H2O) interaction for improved colloidal stability showing no sedimentation and color change of SiO2@WO3 dispersion (0.01%) even after 3 days due to repulsive interaction between negatively charged Si-O- particles. Thereby, thermal conductivity is found to be quite stable (0.631 <-> 0.618 W/m K) up to 3 days, whereas aqueous suspension of bare WO3 and SiO2 particles quickly settle down and thermal conductivity rapidly decreased to a value of 0.584 W/m K for de ionized water further indicates the significance of SiO2 coating. Depending on the thickness of SiO2 layer and volume fraction of SiO2@WO3, a maximum of 8-10% increment of thermal conductivity was achieved where anisotropic WO3 displayed always more (~5%) thermal conductivity than typical spherical nanoparticles. PMID- 29442830 TI - Enhanced Thermal Conductivity of Polyimide Composites Filled with Modified h-BN and Nanodiamond Hybrid Filler. AB - A new thermally conductive and electrically insulative polyimide were prepared by filling different amounts of hexagonal boron nitride (h-BN) particles, and the thermal conductivity of Polyimide (PI) composites were improved with the increasing h-BN content. Based on this, two methods were applied to improve thermal conductivity furtherly at limited filler loading in this paper. One is modifying the h-BN to improve interface interaction, another is fabricating a nano-micro hybrid filler with 2-D h-BN and 0-D nano-scale nanodiamond (ND) to build more effective conductive network. Both surface modification and hybrid system have a positive effect on thermal conductivity. The composites introducing 40 wt% hybrid filler (the weight ratio of ND/modified BN was 1/10) showed the highest thermal conductivity, being up to 0.98 W/(m K) (5.2 times that of PI). In addition, the composites exhibits excellent electrical insulation, thermal stability properties etc. PMID- 29442831 TI - Thermally Reversible Fluorans: Synthesis, Thermochromic Properties and Real Time Application. AB - In the present study, two fluoran molecules (TH1 and TH2) have been synthesized, and their reversible thermochromic properties have been investigated. This work demonstrates the thermochromic reversibility of the fluoran. Furthermore, the three-component mixtures that comprising fluorans (TH1/TH2), bisphenol-A (color developer), and methyl stearate a low melting solvent were used to examine the thermochromic behavior with sturdy heating and cooling rates and the thermochromic properties of the fluorans were detailed using UV-Vis, reflectance and FT-IR spectroscopic techniques. Finally, test strip similar to pH paper and acrylic fiber a versatile material used as thermal indicators also been successfully made from these two fluoran derivatives. PMID- 29442832 TI - Synthesis of TiO2/Fly Ash Cenospheres by Sol-Gel Method and Their Photacatalytic Activities Under Visible Light. AB - Fly ash is a solid waste discharged from thermal power plant. Specific surface area of floating fly ash cenospheres (FACs) would increase after it was modified. The photocatalytic composite of TiO2/FACs was successfully synthesized by sol-gel method using the carrier of modified FACs and tetrabutyl titanate as starting materials. The different influence factors on the photocatalytic performance of TiO2/FACs composites were characterized through SEM, EDS, XRD, UV-vis DRS and BET surface measurements. The UV-vis DRS spectra revealed that the absorption edge of TiO2 is 387 nm while that of TiO2/FACs photocatalysts red-shifts to 500 nm. Photocatalytic activity of TiO2/FACs was evaluated by the photocatalytic depigmentation of methyl orange solution (MO, 20 mg L-1, pH = 6.3) under visible light irradiation. It was found that the specific surface area, surface roughness and activity of FACs were increased by NaOH solution activation. The degradation rate of MO reaches 52% in 180 min under the visible light illumination. But too much FACs could decrease its photocatalytic activity and degradation rate. And the recovery test indicated that TiO2/FACs photocatalyst was rather stable, easy to recover from the treated wastewater. PMID- 29442833 TI - Hexamethyldisilazane Removal with Mesoporous Materials Prepared from Calcium Fluoride Sludge. AB - A large amount of calcium fluoride sludge is generated by the semiconductor industry every year. It also requires a high amount of fuel consumption using rotor concentrators and thermal oxidizers to treat VOCs. The mesoporous adsorbent prepared by calcium fluoride sludge was used for VOCs treatment. The semiconductor industry employs HMDS to promote the adhesion of photo-resistant material to oxide(s) due to the formation of silicon dioxide, which blocks porous adsorbents. The adsorption of HMDS (Hexamethyldisiloxane) was tested with mesoporous silica materials synthesized from calcium fluoride (CF-MCM). The resulting samples were characterized by XRD, XRF, FTIR, N2-adsorption-desorption techniques. The prepared samples possessed high specific surface area, large pore volume and large pore diameter. The crystal patterns of CF-MCM were similar with Mobil composite matter (MCM-41) from TEM image. The adsorption capacity of HMDS with CF-MCM was 40 and 80 mg g-1, respectively, under 100 and 500 ppm HMDS. The effects of operation parameters, such as contact time and mixture concentration, on the performance of CF-MCM were also discussed in this study. PMID- 29442834 TI - Enhanced Photocatalytic Properties of Nanostructured WO3 Semiconductor Photocatalyst Prepared via Hydrothermal Method. AB - Ground and distilled water-mediated tungsten trioxide (WO3) nanostructures are prepared via hydrothermal approach. The physical and surface chemical properties of catalyst are analyzed using XRD, SEM-EDAX, HR-TEM, FT-IR, UV-DRS, Zeta potential and photoluminescence spectroscopy. It is confirmed that ground water has high impacts on the materials properties such as crystallinity and morphology. HR-TEM results proved the transformation of single crystalline to polycrystalline for sample W1 and W3 respectively. The photocatalytic efficiency of the various catalyst was analyzed by the degradation of methylene blue as a probe dye-molecule which was monitored by UV-vis spectroscopy. The decolorization efficiency was observed as 1.14 times maximized in distilled water prepared catalyst when compared with ground water prepared catalyst. Moreover, the persulfate activation was found as 2.3 fold amplified in distilled water prepared catalyst when compared with other catalyst. On the development of various water assisted WO3 semiconductor photocatalysis, this work can provide new insights into the design of novel photocatalyst for potential applications in the energy and environmental remediation sectors. PMID- 29442835 TI - Biomass Fly Ash as an Alternative Approach for Synthesis of Amorphous Silica Nanoparticles with High Surface Area. AB - In this study, the monodisperse amorphous silica nanoparticles (SiO2 NPs) with uniform size distribution and high surface area were successfully synthesized from fly ash as a silica source by chemical sol-gel method. The influence of reaction conditions such as surfactant concentration, aging temperature (Ta), and aging time (Ta) on formation of SiO2 NPs was investigated. Through SEM characterization, it was founded that the uniform and small spherical SiO2 NPs with diameter of 20-30 nm could be synthesized at the appropriate CTAB content of 3 wt%, Ta of 60 degrees C, and Ta of 8 h. In addition, XRD and nitrogen adsorption-desorption measurements indicated that the SiO2 NPs were obtained under amorphous structure, which possesses a high specific surface area of 408 m2 g-1. The obtained results imply that the successful synthesis of SiO2 NPs from fly ash not only displays an effectively alternative approach to provide high quality SiO2 NPs for various necessary applications but also help solving environmental issues due to large amount of fly ash waste each year. PMID- 29442836 TI - Facile Hydrothermal Synthesis and Enhanced Methane Sensing Properties of Pt Decorated ZnO Nanosheets. AB - Pure and Pt-decorated ZnO nanosheets were synthesized via a facile and environment-friendly hydrothermal process, and characterized by X-ray powder diffraction (XRD), field-emission scanning electron microscopy (FESEM) and energy dispersive X-ray spectroscopy (EDS), respectively. Side-heated chemical gas sensors were fabricated with the synthesized ZnO based powders and their sensing properties to methane CH4, an important characteristic hydrocarbon contaminant extracted from power transformer oil with overheating or discharging fault, were systemically investigated. Interestingly, Pt decoration not only obviously increased the gas response of sensor fabricated with the synthesized ZnO nanosheets to CH4, but also effectively reduced its optimum operating temperature. Its highest response to 50 ppm of CH4 was about 63.45 at 240 degrees C, which was about two times larger when compared with the pure one. Meanwhile, the Pt-decorated ZnO nanosheets sensor exhibited shorter response recovery characteristic, good linearity in low concentration range and excellent stability towards CH4. Those superior sensing features indicate the synthesized Pt-decorated ZnO nanosheets is a promising candidate for fabricating high performance CH4 sensor. PMID- 29442837 TI - Polyethylene Glycol Based Graphene Aerogel Confined Phase Change Materials with High Thermal Stability. AB - Polyethylene glycol (PEG) based graphene aerogel (GA) confined shaped-stabilized phase change materials (PCMs) are simply prepared by a one-step hydrothermal method. Three-dimensional GA inserted by PEG molecule chains, as a supporting material, obtained by reducing graphene oxide sheets, is used to keep their stabilized shape during a phase change process. The volume of GA is obviously expended after adding PEG, and only 9.8 wt% of GA make the composite achieve high energy efficiency without leakage during their phase change because of hydrogen bonding widely existing in the GA/PEG composites (GA-PCMs). The heat storage energy of GA-PCMs is 164.9 J/g, which is 90.2% of the phase change enthalpy of pure PEG. In addition, this composite inherits the natural thermal properties of graphene and thus shows enhanced thermal conductivity compared with pure PEG. This novel study provides an efficient way to fabricate shape-stabilized PCMs with a high content of PEG for thermal energy storage. PMID- 29442838 TI - Manganese-Doped CeO2 Nanocubes for Catalytic Combustion of Chlorobenzene: An Experimental and Density Functional Theory Study. AB - Manganese oxide (MnOx) supported on CeO2 nanocubes (MnOx/CeO2) were synthesized and tested for the catalytic combustion of chlorobenzene (CB), which was taken as a model compound of chlorinated volatile organic compounds (CVOCs). The catalytic activity tests demonstrated that MnOx/CeO2 nanocube catalysts exhibited a catalytic activity significantly better than that of bare CeO2 nanocubes, indicating MnOx plays a significant role for CB oxidation. To illustrate the effect of MnOx on the CeO2 nanocubes, experimental and theoretical methods such as density functional theory (DFT) calculations were carried out. Experimental characterization testified that the introduction of MnOx to CeO2 nanocubes brought the facile reduction of cerium species, larger amount of Oalpha species and oxygen vacancies, which lead to the enhanced catalytic performance of MnOx/CeO2 nanocube. Furthermore, DFT calculations clearly validated that MnOx/CeO2 (100) models could form the oxygen vacancies more easily, and CB molecules were preferentially adsorbed on the MnOx/CeO2 (100) models than on the CeO2 (100) models, which facilitated the easier formation of C-O* bond; this facile bond formation enabled faster CB decomposition into COx, thereby a higher CB conversion on the MnOx/CeO2 (100) could be found. Therefore, the vital role of MnOx can be successfully elucidated by both experimental and theoretical methods. Hence, this finding can be utilized for enhanced catalytic performance of CeO2 nanocube catalysts for the CVOCs elimination. PMID- 29442839 TI - Simultaneous Surface Modification and Chemical Reduction of Graphene Oxide Using Glucose. AB - In this paper, we develop a simple and facile approach to prepare graphene nanosheets through chemical reduction with glucose as reducing agent and modification agent. The reduced and modified graphene by glucose (denoted as g rGO) was characterized with techniques of Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), Raman spectra, scanning electron microscopy (SEM) and transmission electron microscopy (TEM), etc. It is found that, besides the desired reduction capability to graphene oxide (denoted as GO), glucose plays an important role as a modifying reagent in stabilizing the as prepared graphene nanosheets simultaneously and the g-rGO exhibits good dispersibility and stability in water and waterborne polyurethane matrix (denoted as WPU). Moreover, the g-rGO can improve evidently the mechanical properties, weather ability and water resistance of WPU. PMID- 29442840 TI - Selective Oxidation of 1,2-Propanediol to Carboxylic Acids Catalyzed by Copper Nanoparticles. AB - Copper nanoparticles with different particle sizes were prepared by a wet chemical reduction method in the presence of organic modifiers, such as citric acid (CA), hexadecyl trimethyl ammonium bromide, Tween-80 (Tween), and polyethylene glycol 6000. Selective oxidation of sustainable 1,2-propanediol with O2 to high-valued lactic, formic, and acetic acids catalyzed by the copper nanoparticles in an alkaline medium was investigated. The small-sized CuCA nanoparticles with the average particle size of 15.2 nm favored the formation of acetic and formic acids while the CuTween nanoparticles with the average particle size of 26.9 nm were beneficial to the formation of lactic acid. The size effect of copper nanoparticles on the catalytic oxidation of 1,2-propanediol to the carboxylic acids was obvious. PMID- 29442841 TI - Synthesis of the Hollow Silica Nanospheres and P, Al and Yb Co-Doped Silica for Optical Fiber Preform. AB - The hollow silica nanospheres were synthesized by the template method and sol-gel method with ammonium hydroxide as base catalysts. Phase compositions, microstructures and specific surface area of the products were characterized by X ray powder diffraction (XRD), scanning electron microscope (SEM), field emission transmission electron microscopy (TEM), energy-dispersive spectrometry (EDS) and Brunauere-Emmette-Teller (BET). The results show that the hollow silica nanospheres synthesized with 10 ml polystyrene-methylacrylic acid latex, 116.13 ml absolute ethanol, 11.16 ml tetraethyl orthosilicate and 2 ml NH3 . H2O as raw materials were even spherical particles and around 150 nm, and the specific surface area is 160.699 m2 . g-1. The P, Al and Yb co-doped silica was prepared by vacuum inhaling and nitrate coating method with the hollow silica nanospheres and solid silica nanospheres as raw materials. The results show that the P, Al and Yb co-doped silica prepared using the hollow silica nanospheres had higher the molar ratio of phosphorus to silicon than using the solid silica nanospheres, and the phosphorus had rather uniform distribution on the silica surface, it shows that this method can improve the phosphorus retention ratio of materials. This study would provide a way to preparing the P, Al and Yb co-doped silica by sol-gel method with ammonium hydroxide as base catalysts. PMID- 29442843 TI - Piezoresistive Composite Silicon Dioxide Nanocantilever Surface Stress Sensor: Design and Optimization. AB - In this paper, we present the design and optimization of a rectangular piezoresistive composite silicon dioxide nanocantilever sensor. Unlike the conventional design approach, we perform the sensor optimization by not only considering its electro-mechanical response but also incorporating the impact of self-heating induced thermal drift in its terminal characteristics. Through extensive simulations first we comprehend and quantify the inaccuracies due to self-heating effect induced by the geometrical and intrinsic parameters of the piezoresistor. Then, by optimizing the ratio of electrical sensitivity to thermal sensitivity defined as the sensitivity ratio (upsilon) we improve the sensor performance and measurement reliability. Results show that to ensure upsilon >= 1, shorter and wider piezoresistors are better. In addition, it is observed that unlike the general belief that high doping concentration of piezoresistor reduces thermal sensitivity in piezoresistive sensors, to ensure upsilon >= 1 doping concentration (p) should be in the range: 1E18 cm-3 <= p <= 1E19 cm-3. Finally, we provide a set of design guidelines that will help NEMS engineers to optimize the performance of such sensors for chemical and biological sensing applications. PMID- 29442842 TI - Preparation and Characterization of Highly Efficient CuFe Mixed Oxides for Total Oxidation of Toluene. AB - In this study, Cu/Fe type mixed oxides catalysts with different ratios of metal irons are successfully synthesized via fixed hydrothermal treatment. The prepared samples were then characterized by a combination of several techniques, such as XRD, BET, SEM, H2-TPR and FT-IR. The catalytic activity enhanced with the increasing amount of Cu in the HT-precursors, but it decreases when the ratio of Cu/Fe is above 4. The influence of calcination temperature was also studied in the search of highly dispersed active catalysts. The catalytic test indicated that the Cu/Fe mixed oxides possessed outstanding highly activity towards toluene oxidation. The highest catalytic activity was exhibited by Cu4Fe-400 of which the T50 and T90 reaches at about 258 degrees C and 294 degrees C respectively. PMID- 29442844 TI - Structural Effect of One-Dimensional Samarium Oxide Catalysts on Oxidative Coupling of Methane. AB - We report an interesting structural effect of one-dimensional Sm2O3 catalysts such as nanorods, nanobelts and nanotubes synthesized by a simple solvothermal method on oxidative coupling of methane. The Sm2O3 nanobelts showed the 28% CH4 conversion and 42% C2 selectivity at 500 degrees C. The different spatial structures and surface structures of these Sm2O3 catalysts indeed brought about the distinct exposed facets, surface active oxygen species and surface active sites, which could account for their diverse activity and products selectivity in OCM reaction. Otherwise, the Sm2O3 nanobelts doped with Sr increased the C2 selectivity to 48% at 500 degrees C, which enhanced the C2 yield sharply. PMID- 29442845 TI - Pt-CeO2 Catalysts Synthesized by Glucose Assisted Hydrothermal Method: Impact of Calcination Parameters on the Structural Properties and Catalytic Performance in PROX-CO. AB - We synthesized Pt supported catalysts by the glucose assisted hydrothermal method, in which a carbon template was used to form a porous CeO2 structure upon calcination. Special emphasis was given to evaluate the influence of calcination parameters in the structural and textural properties of the catalysts and the final impact in the catalytic activity of CO oxidation reaction under hydrogen rich atmosphere (PROX-CO). We show that at 350 degrees C the carbon matrix was already mostly burnt and that higher temperatures and holding times mostly increase the CeO2 crystallite sizes. The sample prepared at 350 degrees C presented the highest surface area, 106 m2 .g-1, in comparison to 60-70 m2 .g-1 obtained for all other conditions. Transmission electron microscopy images of the catalyst calcined at 600 degrees C for 6 h showed 200 nm spheres formed by aggregation of ceria crystallites with crystalline domains of about 20 nm. All samples showed similar catalytic activity in PROX-CO indicating that the creation of the catalytic sites were mostly determined during the synthesis conditions and the catalytic performance were not deeply affected by the differences on CeOx matrix. PMID- 29442846 TI - Thermo-Electric Properties of Cu and Ni Nanoparticles Packed Beds. AB - The hot-wire method and the four-probe resistivity method are applied to probe the thermal conductivity (k) and the electric conductivity (sigma) of Cu and Ni nanoparticle packed beds (NPBs). A fitting method based on classical physical theory is devised to separate ke (electronic thermal conductivity) and kp (phonon thermal conductivity) from k at room temperature. Results turn out that kp only accounts for a small proportion of k (4-20%); the proportion decreases with increasing porosity or temperature. Most importantly, this fitting method provides a simple way to separate ke and kp from k at room temperature. The Wiedemann-Franz law is checked and is found to be unsuitable for NPBs. The Lorenz number (L) is calculated from measurements of ke, k, and sigma. Results turn out that L is found to be 50-60 times that of the bulk. With a Seebeck coefficient (S) measured, the thermoelectric property of NPBs is also calculated. We find that the NPB possess an advantage in thermoelectric property than bulk, the thermoelectric figure of merit (ZT) of Ni (Cu) NPBs can be 20.17 (1.87) times that of bulk Ni (Cu). The effect of porosity on ZT is also discussed, and results show that a NPB with a small porosity is more preferable as a thermoelectric material. With a small porosity, ZT can be even 1.73 times that of a large porosity. Although metals are not good thermoelectric material, the method in this paper supplies a way to improve the thermoelectric property of other thermoelectric materials. PMID- 29442847 TI - L-Cysteine Capped CdSe Quantum Dots Synthesized by Photochemical Route. AB - L-cysteine capped CdSe quantum dots were synthesized via photochemical route in aqueous solution under UV photo-irradiation. The as grown CdSe quantum dots exhibit broad fluorescence at room temperature. The CdSe quantum dots were found to be formed only through the reactions of the precursors, i.e., Cd(NH3)2+4 and SeSO2-3 with the photochemically generated 1-hydroxy-2-propyl radicals, (CH3)2COH radicals, which are formed through the process of H atom abstraction by the photoexcited acetone from 2-propanol. L-Cysteine was found to act as a suitable capping agent for the CdSe quantum dots and increases their biocompatability. Cytotoxicty effects of these quantum dots were evaluated in Chinese Hamster Ovary (CHO) epithelial cells, indicated a significant lower level for the L-cysteine capped CdSe quantum dots as compare to the bare ones. PMID- 29442848 TI - Frictional Reduction with Partially Exfoliated Multi-Walled Carbon Nanotubes as Water-Based Lubricant Additives. AB - In this work, partially exfoliated multi-walled carbon nanotubes (Px-CNTs) were prepared by oxidizing multi-walled carbon nanotubes (MWCNTs) and applied into water-based lubricant as a kind of new additives, resulting in an outstanding anti-friction effect. The Px-CNTs have the structures of both MWCNTs and graphene oxide nanoribbons (GONRs). The special structure could prevent aggregation in water-based lubricant and reduce friction effectively. At the same time, Px-CNTs generate both sliding and rolling friction like MWCNTs and GONRs simultaneously. The friction force of Px-CNTs tended to go up after declining with increasing its loading, suggesting the existence of optimum additive amount of additions. Compared with water, water with 0.5 wt% Px-CNTs further reduced the friction force up to 66.4%. Compared with CNTs-COOH and GONRs dispersed in water via a similar method, Px-CNTs in water displays remarkable friction characteristic, suggesting that the friction force of water with 0.5 wt% Px-CNTs is decreased by 19.82% and 13.82% compared with water with 0.3 wt% MWCNTs and GONRs. PMID- 29442849 TI - Synthesis and Electrochemical Properties of Yb3+-Doped Li1.20Mn0.54Ni0.13Co0.13O2 Cathode Materials Obtained by Sol-Gel Method. AB - The Li1.20[Mn0.54Ni0.13Co0.13]0.80-xYbxO2 (x = 0, 0.01, 0.02, 0.03) cathode materials have been synthesized by using sol-gel method and characterized by means of XRD, SEM, ICP-OES analysis. The galvanostatic charge-discharge tests results showed the improved electrochemical properties were obtained through the Yb3+ doping modification. With the increase of Yb3+ doping content, the capacity retentions enhanced from 85.6% to 88.9% and then decrease to 86.5% after 100 cycles with x = 0.01, 0.02 and 0.03, respectively, while the un-doped sample delivered the capacity retention of 83.0%. Besides, the discharge capacity of Li1.20 [Mn0.54Ni0.13Co0.13]0.78Yb0.02O2 was about 23.1 mAh g-1 larger than that of un-doped sample at 5C high rate. The electrochemical impedance spectroscopy (EIS) and cyclic voltammetric results indicated that the Yb3+ doping modification could suppress the layered-spinel phase transformation during cycling and maintain a lower value of charge transfer impedance. PMID- 29442850 TI - Single-Stroke Synthesis of Tin Sulphide/Oxide Nanocomposites Within Engineering Thermoplastic and Their Humidity Response. AB - SnS nanostructured materials have attracted enormous interest due to their important properties and potential application in low cost solar energy conversion systems and optical devices. From the perspective of SnS based device fabrication, we offer single-stroke in-situ technique for the generation of Sn based sulphide and oxide nanostructures inside the polymer network via polymer inorganic solid state reaction route. In this method, polyphenylene sulphide (PPS)-an engineering thermoplastic-acts as chalcogen source as well as stabilizing matrix for the resultant nano products. Typical solid state reaction was accomplished by simply heating the physical admixtures of the tin salts (viz. tin acetate/tin chloride) with PPS at the crystalline melting temperature (285 degrees C) of PPS in inert atmosphere. The synthesized products were characterized by using various physicochemical characterization techniques. The prima facie observations suggest the concurrent formation of nanocrystalline SnS with extraneous oxide phase. The TEM analysis revealed formation of nanosized particles of assorted morphological features with polydispersity confined to 5 to 50 nm. However, agglomerated particles of nano to submicron size were also observed. The humidity sensing characterization of these nanocomposites was also performed. The resistivity response with the level of humidity (20 to 85% RH) was compared for these nanocomposites. The linear response was obtained for both the products. Nevertheless, the nanocomposite product obtained from acetate precursor showed higher sensitivity towards the humidity than that of one prepared from chloride precursor. PMID- 29442851 TI - Improvement Photocatalytic Activity of P25 by Modification with a Rare Earth-Free Upconversion Nanocrystal. AB - It has been reported that coupling TiO2 with rare earth upconversion nanocrystals (UCNCs) is an efficient strategy to significantly improve photocatalytic activity of TiO2. However, the rare earth materials are scarcity and cost, and the synthesis process of UCNCs using the rare earth materials is complicated. In the present study, we have designed a new approach using a rare earth-free upconversion nanocrystal (REF-UCNCs) as upconversion luminescent material to replace the rare earth UCNCs. A novel nanocomposite photocatalyst of REF UCNCs@P25: Mo/GN was developed for the first time. Based on the designed structure, the REF-UCNCs, Mo-doping, and GN (graphene) have a synergistic effect that can improve catalytic activity of P25 significantly. The results of photocatalytic experiments using RhB as a model pollutant under simulated solar light irradiation show that the photocatalytic efficiency of the as-prepared catalyst is 3-folds higher than that of benchmark substance P25. This work provides a new strategy for efficiently improving catalytic activity of semiconductor photocatalysts by coupling with REF-UCNCs. This approach is facile and low-cost which can be widely applied for modification of semiconductor photocatalysts and facilitates their applications in environmental protection issues using solar light. PMID- 29442852 TI - Synthesis, Characterization and Humidity Sensing Properties of Nanocrystalline Composites of Sr1-xCoxMoO4 (x = 0, 0.3, 0.5, 0.7, 1). AB - The nanocrystalline strontium cobalt molybdate composites of Sr1-xCoxMoO4 (x = 0, 0.3, 0.5, 0.7, 1) were prepared by mixing various mole ratios (SrM-1, SrCM-2, SrCM-3, SrCM-4 and CoM-5) and investigated for their humidity sensing properties. The composites were characterized by thermal analysis (TG/DTA), X-ray powder diffraction (XRD), Fourier Transform-Infrared spectroscopy (FT-IR), Fourier Transform Raman (FT-Raman) spectroscopy, Scanning Electron Microscopy (SEM/EDAX), Transmission Electron Microscopy (TEM) and UV-Visible absorption spectroscopy. The composites were subjected to dc electrical conductivity based humidity sensing studies at room temperature. The resistance measurements as a function of relative humidity (RH) in the range of 5-98% were carried out and the sensitivity factor (Sf) were calculated. The SrM-1 is found to possess with the highest Sf of 33014 +/- 660 and CoM-5 is found to possess a low Sf of 868 +/- 43. The SrCM-2, SrCM-3 and SrCM-4 possessed the sensitivity factors (Sf) of 915 +/- 45, 3713 +/- 185 and 3390 +/- 102 respectively. PMID- 29442853 TI - Effect of Annealing Temperature on Morphological and Optical Transition of Silver Nanoparticles on c-Plane Sapphire. AB - As a promising candidate for the improved performance, silver nanoparticles (Ag NPs) have been successfully adapted in various applications such as photovoltaics, light emitting diodes (LEDs), sensors and catalysis by taking the advantage of their controllable plasmonic properties. In this paper, the control on the morphologies and optical properties of Ag NPs on c-plane sapphire (0001) is demonstrated by the systematic control of annealing temperature (between 200 and 950 degrees C) with 20 and 6 nm thick Ag films through the solid state dewetting. With the relatively thicker film of 20 nm, various configuration and size of Ag NPs are fabricated such as irregular, round dome-shaped and tiny Ag NPs depending on the annealing temperature. In a shrill contrast, the 6 nm Ag set exhibits a sharp distinction with the formation of densely packed small NPs and ultra-highly dense tiny Ag NPs due to the higher dewetting rate. While, the surface diffusion assumes the main driving force in the evolution process of Ag NP morphologies up to 550 degrees C, the sublimation of Ag atoms has played a significant role on top on the surface diffusion between 600 and 950 degrees C. The reflectance spectra of Ag NPs exhibit the quadrupolar resonance and dipolar resonance peaks, and the evolution of peaks, shift and average reflectance were discussed based on the Ag NPs size and surface coverage. In particular, the dipolar resonance peak in the reflectance spectra red shifts from ~475 to ~570 nm due to the size increment of Ag NPs (38.31 to 74.68 nm). The wide surface coverage of Ag NPs exhibits the highest average reflectance (~27%) and the lowest Raman intensity. PMID- 29442854 TI - Barium Hexaferrite (BaFe12O19) Nanoparticles as Highly Active and Magnetically Recoverable Catalyst for Selective Epoxidation of Styrene to Styrene Oxide. AB - Herein, we are reporting the use of pure single phase barium hexaferrite (BaFe12O19) nanoparticles as an efficient catalyst for epoxidation of styrene. BaFe12O19 nanocatalysts exhibit high conversion of styrene with excellent selectivity of styrene oxide formation. Easy method of preparation, capability of catalyzing the epoxide reaction of styrene to styrene oxide with excellent styrene conversion (~91%) and high styrene oxide selectivity (~86.5%), easy magnetic separation and very good reusability make the synthesized BaFe12O19 nanocatalyst an excellent catalyst for this reaction. To the best of our knowledge, this is the first time the use of BaFe12O19 as catalyst for this reaction has been reported. PMID- 29442855 TI - Adsorption Kinetics, Isotherms, and Thermodynamics of Cr(III), Pb(II), and Cu(II) on Porous Hydroxyapatite Nanoparticles. AB - Porous hydroxyapatite (HAP) nanoparticles with the specific surface area of 76.1 m2 g-1 were facilely prepared using calcium nitrate and phosphoric acid as the starting materials and ammonia aqueous solution as the pH regulator by a hybrid precipitation and hydrothermal method at lower reaction temperatures of 35 and 110 degrees C. The adsorption of Cr(III), Pb(II), and Cu(II) ions on HAP nanoparticles was well simulated by the pseudo-second-order adsorption kinetics and Langmuir adsorption isotherm. The maximum adsorption capacities of HAP nanoparticles for Cr(III), Pb(II), and Cu(II) ions were 96.9, 440.5, and 69.9 mg g-1, respectively, at 20 degrees C based on the Langmuir adsorption isotherms. The thermodynamic analysis revealed that the adsorption processes of Cr(III), Pb(II), and Cu(II) ions on HAP nanoparticles were spontaneous and endothermic. PMID- 29442856 TI - Electrodeposition of Gold Nanostructures Having Controlled Morphology. AB - Gold (Au) nanostructures exhibit unique electronic, optoelectronic and plasmonic properties. This makes them potential candidates for applications in areas including biosensing, catalysis, optics, and electronics. These unique properties are governed by the precise control over their morphologies and size. The present work investigates the electrodeposition process of Au nanostructures. Additionally, the influence of applied potential, electrolyte pH and presence of L-cysteine on the morphology, size, distribution and density of Au nanostructured was studied. The observations elucidated the relationship between the process parameters and the formation mechanism of the Au nanostructures. The morphology and composition of these Au nanostructures were characterized by scanning electron microscopy and X-ray diffraction respectively. PMID- 29442857 TI - High Aspect Ratio Perforated Co3O4 Nanowires Derived from Cobalt-Carbonate Hydroxide Nanowires with Enhanced Sensing Performance. AB - Herein, we report the facile synthesis of high-aspect ratio perforated Co3O4 nanowires derived from cobalt-carbonate-hydroxide (Co(CO3)0.5(OH) 0.11H2O) nanowires. The Co(CO3)0.5(OH) 0.11H2O nanowires were synthesized by simple hydrothermal process at 120 degrees C while annealing of such nanowires at 400 degrees C leads the formation of perforated Co3O4 nanowires. The prepared nanowires were characterized by several techniques which confirmed the high aspect ratio and well-crystallinity for the synthesized nanowires. For application point of view, the prepared perforated Co3O4 nanowires were used as efficient electrode material to fabricate highly sensitive and selective hydrazine chemical sensor. The electrochemical impedance spectroscopy (EIS) technique was employed to confirm the successful modification of the electrode. The key parameters of chemical sensor, such as detection limit, sensitivity, and linear range, have been systematically explored. The fabricated hydrazine sensor displayed a rather low detection limit of 4.52 MUM (S/N = 3), a good sensitivity of 25.70 MUA . mM-1, and a wide linear range of 16.97-358.34 MUM. PMID- 29442858 TI - Green Synthesis of Silver Nanoparticles Decorated by Fe3O4/GO with Enhanced Catalytic Activity. AB - We report a simple and green approach to synthesize stable water-dispersible silver nanoparticles decorated by magnetic Fe3O4 and graphene oxide (GO). These results of UV-Vis spectra, along with TEM and SEM indicated that the water dispersible silver nanoparticles had cluster flat structure and retained the optical properties of the original silver particle. Combining the advantages of Fe3O4 and GO, the composite nanoparticles showed enhanced catalytic activity with good recycling utilization rate by magnetic separation. PMID- 29442859 TI - Structural, Optical, Morphological and Microbial Studies on SnO2 Nanoparticles Prepared by Co-Precipitation Method. AB - Nanoparticles of tin oxide (SnO2) powders were prepared by co-precipitation method at 500 degrees C, 700 degrees C and 900 degrees C temperature. The sintered SnO2 nanoparticles, structural, optical, magnetic, morphological properties and microbial activity have been studied. XRD studies reveals that sintered powder which exhibits tetragonal crystal structure and both crystallinity as well as crystal size increase with increase in temperature. The morphological studies reveal randomly arranged grains with compact nature grain size increases with sintering temperature. The compositional analyses of SnO2 nanoparticles have been studied using X-ray photoelectron spectroscopy analysis. The optical band gap values of SnO2 nanoparticles were calculated to be about 4.3 eV in the temperature 500 degrees C, comparing with that of the bulk SnO2 3.78 eV, by optical absorption measurement. Room temperature M-H curve for pure SnO2 nanoparticles exhibits ferromagnetic behaviour. The tin oxide nanoparticles are acted as potential candidate material for bacterial and fungal activity. PMID- 29442860 TI - Fabrication of Zinc Oxide-Based Thin-Film Transistors by Radio Frequency Sputtering for Ultraviolet Sensing Applications. AB - In this study, zinc indium tin oxide thin-film transistors (ZITO TFTs) were fabricated by the radio frequency (RF) sputtering deposition method. Adding indium cations to ZnO by co-sputtering allows the development of ZITO TFTs with improved performance. Material characterization revealed that ZITO TFTs have a threshold voltage of 0.9 V, a subthreshold swing of 0.294 V/decade, a field effect mobility of 5.32 cm2/Vs, and an on-off ratio of 4.7 * 105. Furthermore, an investigation of the photosensitivity of the fabricated devices was conducted by an illumination test. The responsivity of ZITO TFTs was 26 mA/W, with 330-nm illumination and a gate bias of -1 V. The UV-to-visible rejection ratio for ZITO TFTs was 2706. ZITO TFTs were observed to have greater UV light sensitivity than that of ZnO TFTs. We believe that these results suggest a significant step toward achieving high photosensitivity. In addition, the ZITO semiconductor system could be a promising candidate for use in high performance transparent TFTs, as well as further sensing applications. PMID- 29442861 TI - Comparative Study of Structural, Morphological, Magneto-Optical and Photo Catalytic Properties of Magnetically Reusable Spinel MnFe2O4 Nano-Catalysts. AB - Spinel MnFe2O4 nanostructures were synthesized by simple, economical and eco friendly microwave combustion (MCM) and conventional combustion (CCM) methods using metal nitrates and glycine used as the fuel, instead of toxic inorganic/organic catalyst, template and surfactant. Powder XRD and FT-IR, EDX and SAED results were confirmed the products have a cubic phase spinel structure. EDX and SAED results confirmed purity and high crystallinity without any other secondary phase impurities. HR-SEM and HR-TEM analysis indicate that the MCM and CCM products consist of nano- and microstructures, respectively. The optical band gap (Eg) was measured using Kubelka-Munk model and it shows higher value (2.37 eV) for MnFe2O4-MCM than MnFe2O4-CCM (2.15 eV), due to the smaller particle size of MnFe2O4-MCM. VSM results showed a superparamagnetic behavior and the magnetization (Ms) value of MnFe2O4-MCM is higher i.e., 39.68 emu/g than MnFe2O4 CCM (33.59 emu/g). It was found that the sample MnFe2O4-MCM have higher surface area than MnFe2O4-CCM, which in turn leads to the improved performance towards the photocatalytic degradation (PCD) of methylene blue (MB) and it was found that the sample MnFe2O4-MCM show higher PCD efficiency (96.48%) than MnFe2O4-CCM (84.95%). Also, MnFe2O4 show higher activity with good reusability, and eco friendly materials for industrial and technological applications. PMID- 29442862 TI - Synthesis and Characterization of ZnO-CeO2 Nanocomposite with Enhanced UV-Light Driven Photocatalytic Dye Degradation of Rhodamine-B. AB - ZnO-CeO2 nanocomposite was synthesized by co-precipitation and reverse micelle methods, which show rod-shaped morphologies. In co-precipitation method, the nanocomposite has uniform rodshaped structure, whereas in reverse micelle method rods like structures are made up of spherical shaped nanoparticles. The photocatalytic dye degradation of rhodamine-B (RhB) has been examined using ZnO CeO2 nanocomposite at room temperature. The photodegradation rates of catalysts in co-precipitation and reverse micelle methods were observed as 0.026 min-1 and 0.042 min-1, respectively. PMID- 29442863 TI - One-Step Pyrolytic Synthesis of Multiwalled Carbon Nanotubes: The Role of Resupply of Carbon Species on the Quality Control. AB - An investigation on varying experimental parameters such as solution quantity (2.5, 5 and 7.5 mL) and reaction time (15, 30, 45 and 60 min) was carried out for the production of high-quality multiwalled carbon nanotubes (MWCNTs) in one step pyrolysis. Structural analysis revealed the uniform diameter distribution and the length of nanotubes in the range of 60-80 nm and 0.4-2 MUm, respectively. Raman and X-ray diffraction analysis showed a remarkable reduction in defect density with increase in graphitization degree, upon increasing the solution volume and reaction time. MWCNTs prepared at higher solution quantity (7.5 mL) with higher reaction time (60 min) showed higher crystallinity (70% graphitization) and lower defect density (ID/IG: 0.56). The attainment in equilibrium of evaporation cum precipitation in formation of high quality nanotubes structure is evaluated. An effective resupplying of condensed precursors by re-evaporation leads for the achievement of low defect density nanotubes with higher product yield is achieved. PMID- 29442864 TI - Immobilization of Papain onto Graphene Oxide Nanosheets. AB - Graphene oxide nanosheets was prepared, functionlized with 3 aminopropyltriethoxysilane and used as the carrier for immobilization of papain. A high immobilization yield and efficiency higher than 80% were achieved at pH 8.0 and 35 degrees C. The thermal stability of the immobilized papain was improved compared with the free enzyme. And the immobilized papain retained about 63% of its initial activity after 30 days storage at 4 degrees C, while free enzyme was only 41% at the same conditions. The immobilized enzyme displayed higher binding affinity to substrate because of the unique properties of GO. These results indicate that modified graphene oxide nanosheets has a good potential as carrier for immobilization of proteins, especially enzymes. PMID- 29442865 TI - Complementary Characterization of Cu(In,Ga)Se2 Thin-Film Photovoltaic Cells Using Secondary Ion Mass Spectrometry, Auger Electron Spectroscopy, and Atom Probe Tomography. AB - To enhance the conversion performance of solar cells, a quantitative and depth resolved elemental analysis of photovoltaic thin films is required. In this study, we determined the average concentration of the major elements (Cu, In, Ga, and Se) in fabricated Cu(In,Ga)Se2 (CIGS) thin films, using inductively coupled plasma atomic emission spectroscopy, X-ray fluorescence, and wavelengthdispersive electron probe microanalysis. Depth profiling results for CIGS thin films with different cell efficiencies were obtained using secondary ion mass spectrometry and Auger electron spectroscopy to compare the atomic concentrations. Atom probe tomography, a characterization technique with sub-nanometer resolution, was used to obtain three-dimensional elemental mapping and the compositional distribution at the grain boundaries (GBs). GBs are identified by Na increment accompanied by Cu depletion and In enrichment. Segregation of Na atoms along the GB had a beneficial effect on cell performance. Comparative analyses of different CIGS absorber layers using various analytical techniques provide us with understanding of the compositional distributions and structures of high efficiency CIGS thin films in solar cells. PMID- 29442866 TI - Ag-Doped ZnO Nanoparticles for Enhanced Ethanol Gas Sensing Application. AB - Herein, we report the synthesis, characterization and ethanol gas sensing application of Ag-doped ZnO nanoparticles. The nanoparticles were synthesized through a facile hydrothermal process and characterized through various characterization techniques. The detailed characterizations confirmed that the synthesized Ag-doped ZnO nanoparticles are grown in high density with an average diameter of ~20 +/- 5 nm, possessing well-crystalline wurtzite hexagonal crystal structure and exhibiting good optical properties. The as-synthesized Ag-doped ZnO nanoparticles were further used as functional material to fabricate efficient ethanol gas sensor which exhibited excellent gas response. The detailed gas sensing experiments revealed that at an optimized temperature, i.e., 320 degrees C, the recorded gas response was 32.815 for 200 ppm concentration of ethanol gas. Finally, a plausible gas sensing mechanism was also presented in this paper. PMID- 29442867 TI - Effects of Different Sacrificial Agents and Hydrogen Production from Wastewater by Pt-Graphene/TiO2. AB - The Pt and graphene (GN) were used to modify TiO2 nanoparticles. GN/TiO2, Pt TiO2, Pt-GN/TiO2 were successfully synthesized by modified Hummers' method, alcohol thermal and photodeposition method, respectively. The characterizations of the synthesized catalysts by different characterization techniques, including N2 adsorption-desorption isotherm, fourier transform infrared spectroscopy (FTIR), inductively coupled plasma (ICP) technique and element analyzer (EA), respectively. In addition, different sacrificial agents (methanol, ethanol, n propanol, i-propanol, n-butanol, ethylene glycol, 1,2-propanediol, 1,3 propanediol and glycerol) have been investigated. There is clearly a linear relationship between hydrogen production rate and the polarity of monohydric alcohols. According to the Langmuir-Hinshelwood results, the surface pseudo-first order rate constant k = 15.06 mmol h-1 g-1 and the adsorption coefficient k = 0.50 mol L-1 were obtained. The feasibility of hydrogen production from wastewater obtained from terephthalic acid industry was studied. After reusing the catalyst under the same experimental conditions, the hydrogen production rate has only slightly decreased for 3 more cycles, which indicated the stability of the synthesized catalysts. PMID- 29442868 TI - Wet Chemically Synthesized Bismuth Oxyiodide (BiOI) Quantum Dots for Photocatalytic Degradation of Malachite Green. AB - Using the chelating effect of ethylene glycol, bismuth oxyiodide (BiOI) quantum dots were prepared by a liquid phase reaction at room temperature. A variety of techniques including scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray powder diffraction (XRD), and ultraviolet-visible absorption spectra were used to characterize the morphology, size distribution, crystal phase and photocatalytic degradation performance of BiOI quantum dots. Results show that the prepared BiOI quantum dots have higher photocatalytic activity, and the k value is 20 times higher than that of BiOI nanoflakes. PMID- 29442869 TI - Electrochemical Sensor Based on Rh(III) Ion-Imprinted Polymer as a New Modifying Agent for Rhodium Determination. AB - A rhodium (III) ion carbon paste electrode (CPE) based on an ion imprinted polymer (IIP) as a new modifying agent has been prepared and studied. Rh(III) ion imprinted polymer was synthesized by copolymerization of acrylamide-Rh(III) complex and ethylene glycol dimethacrylate according to the precipitation polymerization. Acrylamide acted as both functional monomer and complexing agent to create selective coordination sites in a cross-linked polymer. The ion imprinted carbon paste electrode (IIP-CPE) was prepared by mixing rhodium IIP nanoparticles and graphite powder in n-eicosane as an adhesive and then embedding them in a Teflon tube. Amperometric i-t curve method was applied as the determination technique. Several parameters, including the functional monomer, molar ratio of template, monomer and cross-linking agent, the amounts of IIP, the applied potential, the buffer solution and pH have been studied. According to the results, IIP-CPE showed a considerably higher response in comparison with the electrode embedded with non-imprinted polymer (NIP), indicating the formation of suitable recognition sites in the IIP structure during the polymerization stage. The introduced electrode showed a linear range of 1.00*10-8~3.0*10-5 mol.L-1 and detection limit of 6.0 nmol L-1 (S/N = 3). The IIP-CPE was successfully applied for the trace rhodium determination in catalyst and plant samples with RSD of less than 3.3% (n = 5) and recoveries in the range of 95.5~102.5%. PMID- 29442870 TI - An Innovative Electrochemical Sensor Ground on NiO Nanoparticles and Multi-Walled Carbon Nanotubes for Quantitative Determination of Nitrite. AB - An electrochemical sensor ground on nickel oxide (NiO) nanoparticles and multi walled carbon nanotubes (MWCNTs) was exploited for the detection of nitrite. Scanning electron microscopy (SEM) ensure the morphology of the nanocomposite consisted of NiO nanoparticle and MWCNTs. High Resolution Transmission electron microscopy (HR-TEM) reveals that the structure of NiO nanoparticles and MWCNTs. Scanning transmission electron microscopy (STEM) persuasively verified presence of the C, Ni and O element. The electrochemical character of the nanocomposite were researched by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), and the behavior of electrochemical oxidation to nitrite on NiO/MWCNTs/CP was explored by chronoamperometry. In tests, the NiO/MWCNTs/CP shown a sensitive current response toward nitrite, the oxidation peak current are linearly related to nitrite concentration in the range from 10-6 M to 10-4 M (R = 0.997) with a sensitivity of 3.53 MUA MUM-1 and a detection limit of 0.25 MUM (S/N = 3). The validity of utilizing the proposed electrode to determine nitrite in tap water was also demonstrated. PMID- 29442871 TI - Rheological Properties of Graphene Oxide/Konjac Glucomannan Sol. AB - We have demonstrated there is a significant intermolecular interaction between GO and KGM that results from hydrogen bonding and physical cross-linking by studying the rheological properties of a graphene oxide/konjac glucomannan (GO/KGM) solution. When the addition of GO was 5%, the storage modulus (G') and loss modulus (G") were only improved by 0.25%. However, G' and G" were improved by approximately 90% and 73.4%, respectively, when the GO content was increased to 7.5%. The moduli also displayed a relationship between the power function and concentration. Furthermore, the formation mechanism of GO/KGM was investigated by Raman, FT-IR, XPS and SEM. The results suggested that hydrogen bonding and physical crosslinking are generated from the abundant carboxy and hydroxyl groups of graphene oxide and the hydroxyl groups of konjac glucomannan. PMID- 29442872 TI - Lithium Storage Performance of Zinc Ferrite Nanoparticle Synthesized with the Assistance of Triblock Copolymer P123. AB - The ZnFe2O4 samples with the triblock copolymer P123 (P123) additive quantity of 0 wt.%, 2 wt.%, 5 wt.%, 8 wt.% and 10 wt.% were prepared by a very facile homogeneous precipitation method followed by high temperature sintering. The microstructures of the prepared samples were analyzed by X-ray diffraction (XRD) and Field emission scanning electron microscopy (FESEM). The results revealed that the five prepared samples are all normal spinel zinc ferrite (ZnFe2O4); the sample with the P123 additive quantity of 8 wt.% has the smallest particle size among the five samples. The lithium storage performances of the prepared samples are characterized by cyclic voltammograms (CV), electrochemical impedance spectroscopy (EIS), and charge-discharge tests. The results demonstrated that adding proper amount of P123 can obviously improve the lithium storage performances of zinc ferrite spinel powder. But excessive P123 can induce the particle agglomerates so that the lithium storage performance of sample decays significantly. The ZnFe2O4 sample with the P123 additive quantity of 8 wt.% exhibited the highest electrochemical activity, the best rate performance, and superior cycling stability. For example, after 50 charge/discharge cycles under a current density of 120 mA g-1, the ZnFe2O4 sample with the P123 additive quantity of 8 wt.% can retain a specific discharge capacity of 468 mAh g-1, much higher than that of for the ZnFe2O4 sample with the P123 additive quantity of 0 wt.% (224 mAh g-1). PMID- 29442873 TI - Magnetic Properties of Nano-Maghemites with Different Crystal Shapes. AB - The differences between the macroscopic and microscopic magnetic properties of granular, rod, and tubular nano-maghemites were studied. The macroscopic magnetic properties of the different nano-maghemites were all ferrimagnetic by using a superconducting quantum interference device (SQUID). However, the coercive magnetic field and magnetization per unit volume were both in the orders of grain > tube > rod, which indicated that the crystal shape influenced macroscopic magnetic properties. A magnetic force microscope (MFM) was used to observe the microscopic magnetic structures; the samples were all magnetic in multiple domains, but the form and distribution of these domains were different. However, the domain information of nano-maghemites calculated from SQUID results suggested that all specimens were pseudo-single domains. The MFM results suggested that the crystal morphology had a significant effect on magnetic properties of these nano maghemites owing to their different magnetic domain structures. Therefore, MFM can be used to detect minute magnetic-properties that are imperceptible to macroscopic measurements. Thus, it is a tool with potential development in earth science. PMID- 29442874 TI - Optimization of Growth Temperature of beta-Ga2O3 Thin Films for Solar-Blind Photodetectors. AB - Monoclinic gallium oxide thin films were deposited on c-plane sapphire substrates at various substrate temperatures ranging from 450 degrees C to 700 degrees C by radio frequency magnetron sputtering technology. X-ray diffraction results showed that the deposited beta-Ga2O3 films were oriented at ( 2 - 01) direction. As the substrate temperature increased, the intensity of beta-Ga2O3 peaks increased and bandgap decreased accordingly. Metal/semiconductor/metal structured solar-blind photodetectors based on beta Ga2O3 thin films growing at various substrate temperatures had been fabricated. The growth temperatures of thin films had no obvious influence on dark current and response to 365 nm light illuminations. The photoelectric properties such as responsivity and response speed of the thin films to 254 nm light illuminations were growth temperature dependent. At an applied bias of 50 V, the photodetectors prepared with 450 degrees C grown film had the highest responsivity of 2.18 A/W, and the photodetectors prepared with 700 degrees C grown film had the shortest rising time of 0.95 s under 254 nm light illuminations. PMID- 29442875 TI - Adsorption of Cu2+ Ions from Aqueous Solutions on Nano-Titanate Engelhard Titanosilicate-2 (ETS-2). AB - Adsorption of Cu2+ ions from aqueous solutions is an increasingly important problem. Nano-titanate ETS-2 (Engelhard Titanosilicate-2) was studied for Cu2+ removal from aqueous solutions through the batch technique at room temperature. Structural and chemical properties of both ETS-2 sorbent and aqueous solution were studied by different characterization tests such as Thermogravimetric Analysis, Energy Dispersive X-ray spectroscopy, X-ray Photoelectron Spectroscopy and Inductively Coupled Plasma measuremen. Copper adsorption capacity was found to increase upon raising the contact time or the pH of the solution. The maximum uptake of Cu2+ (99.9%) by ETS-2 occurred at pH of 6.7 and 30 min of contact time. The Cu2+ removal capacity of ETS-2 was found to be 53.58 mg/g at pH = 5.16, which improved to 54.02 mg/g, when rising the contact time to 90 min. Chemical properties of ETS-2 indicated that ETS-2 surface possessed sodium exchange sites making it a favourable sorbent for metal exchange. PMID- 29442876 TI - Characteristics and Morphology of Nanosilica Modified with Isopropyl Tri(dioctyl Phosphate) Titanate Coupling Agent. AB - In order to improve dispersiveness of nanosilica in polymer matrix, surface organo-modification of nanosilica is necessary. This work reveals silica nanoparticles modified by titanate coupling agent isopropyltri (dioctylphosphate) titanate (KR12) in toluene solvent. Effect of reaction temperature, reaction time and reactant ratio on grafting efficiency have been studied by Thermogravimetric Analysis (TGA). The obtained results exhibit the grafted percentage of titanate coupling agent KR-12 on the surface of nanosilica increased quickly from 4.97 to 13.11 wt.% as increasing the content of KR-12 from 5 to 15 wt.% and raise slower from 13.21 to 13.43 wt.% as content of KR-12 in the range of 30 to 45 wt.%, respectively. The KR-12 content and grafting reaction time affect significantly on the grafting efficiency while temperature of grafting reaction is negative to the grafting efficiency. The results of analysis related to Infrared Spectroscopy and Energy-Dispersive X-ray spectroscopy (EDS) displayed titanate coupling agent KR-12 have been covalently bonded to surface of the nanosilica. The Transmission Electron Microscopy (TEM) images and size distribution indicated that after organic modification, nanosilica particles had average size about 86 nm and the agglomeration of nanoparticles decreased significantly. The obtained results showed that surface treatment of nanosilica with titanate coupling agent KR-12 was successful. PMID- 29442877 TI - Effect of Nanophase Li3PO4 and Li4P2O7 on the Electrochemical Performance of LiFePO4 Cathode Materials. AB - The Li3PO4 modified LiFePO4/C and Li4P2O7 modified LiFePO4/C cathode materials were synthesized by in-situ synthesis method, respectively. Phase compositions and microstructures of the products were characterized by X-ray powder diffraction (XRD), scanning electronic microscope (SEM). Results indicate that Li3PO4 and Li4P2O7 can sufficiently coat on the LiFePO4 surface and does not alter LiFePO4 crystal structure. The electrochemical behavior of cathode materials was analyzed using galvanostatic measurement and cyclic voltammetry (CV). Compared with Li3PO4, the existence of Li4P2O7 can better improve the electrochemical performance of LiFePO4 cathode materials in specific capability and lithium ion diffusion of cathode materials. The charge-discharge specific capacity and apparent lithium ion diffusion coefficient increase with Li4P2O7 content and maximizes around the Li4P2O7 content is 5 wt%. The results indicated that the Li4P2O7 adding enhances the lithium ion diffusion rate of LiFePO4. However, because of the interface fracture between Li4P2O7 and LiFePO4 particles during charging and discharging process, the cycling performance of Li4P2O7 modified LiFePO4/C cathode materials is very poor. PMID- 29442878 TI - Nanoparticle Structures with (Un-)Hydrogenated Castor Oil as Hydrophobic Paper Coating. AB - The encapsulation of vegetable oils within an aqueous dispersion of polymer nanoparticles provides an alternative route to create functional paper coatings from renewable resources, by combining the presentation of hydrophobic moieties together with variations in roughness at the paper surface. The effects of two selected vegetable oil types, i.e., castor oil and hydrogenated castor oil (wax), are compared in terms of nanoparticle synthesis, coating hydrophobicity and surface gloss. The nanoparticles were synthesized by adding 50 wt.-% oil during imidization of poly(styrene-co-maleic anhydride) with ammonium hydroxide. From evaluation of the thermal properties, the nanoparticles have a high glass transition temperature that is suppressed in presence of oil. The nanoparticles with hydrogenated castor oil have higher imide content and better thermal stability compared to castor oil, in parallel with lower chemical reactivity of the hydrogenated oil and less interference with the imidization reaction. After deposition as a coating on paper, the physical coating properties are discussed in parallel with the coating chemistry and morphology or roughness at different scale lengths. The nanoparticle coatings with hydrogenated oil provides a multi scale roughness with an open, porous nanoparticles structures and presentation of some amount free oil augmenting hydrophobicity towards a water contact angle of 128 degrees (static contact angle) or 138 degrees (advancing contact angle). The differences in surface coverage of coated papers in terms of imide and oil contents are confirmed by chemical Raman mapping. The differences in surface roughness are confirmed by non-contact profilometry, laser interferometry and atomic force microscopy. PMID- 29442880 TI - Improving the Thermal Stability and Flame Retardancy of PP/IFR Composites by NiAl Layered Double Hydroxide. AB - Nickel and aluminum layered double hydroxide (NiAl-LDH) was synthesized via co precipitation and modified by sodium dodecyl sulfate (SDS), which was marked as NiAl-OLDH. The structure of NiAl-LDH was characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). In order to investigate the role of LDH on polymer/intumescent flame retardant (IFR) systems, polypropylene (PP)/IFR/NiAl OLDH nanocomposites were prepared by melt intercalation. Thermal and flame retardant properties of PP/IFR/NiAl-OLDH nanocomposites were studied. The results indicated that incorporation of NiAl-OLDH in PP/IFR composites significantly improved the thermal stability, flame retardancy and smoke suppression properties. With the addition of 5 wt% NiAl-OLDH, PP/IFR/NiAl-OLDH nanocomposites obtained UL-94 V0 level and the LOI value reached 27.5%. Compared with those of PP/IFR, the peak heat release rate (PHRR), total heat release (THR) and peak smoke production rate (PSPR) values reduced 49%, 10%, and 63%, respectively, which were attributed to the barrier effect and excellent charring performance of NiAl-OLDH. PMID- 29442879 TI - Optimization of Synthesis and Modification of ZnSe/ZnS Quantum Dots for Fluorescence Detection of Escherichia coil. AB - This study prepared an innovative 3-mercaptopropionic acid modified ZnSe/ZnS core/shell quantum dots (MPA-ZnSe/ZnS QDs), and established a rapid fluorescence method to detect the E. coli cells count by using MPA-ZnSe/ZnS QDs as fluorescence probe. The formulation variables and process were optimized using the response surface methodology (RSM). Fluorescence microscopy was used to obtain fluorescence microscope images of MPA-ZnSe/ZnS QDs that bind to bacteria. The fluorescence peak intensity increases with increasing cells count in the range of 101-108 CFU/mL. Compared with the traditional based on fluorescent detection methods, this method is more convenient and useful in the bacterial count determination. PMID- 29442881 TI - Facile Fabrication of Ordered Anodized Aluminum Oxide Membranes with Controlled Pore Size by Improved Hard Anodization. AB - We have fabricated highly ordered anodized aluminum oxide (AAO) membranes with different diameter through improved hard anodization (HA) at high temperature. This process can generate thick AAO membranes (30 MUm) in a short anodizing time with high growth rate 20-60 MUm h-1 which is much faster than that in traditional mild two-step anodization. We enlarged the AAO pore diameter by adjusting the voltage rise rate at the same time, which has a great influence on current density and temperature. The AAO pore diameter varies from 60-110 nm to 160-190 nm. The pore diameter (Dp) of the AAO prepared by this improved process is much larger than that prepared by HA (40-60 nm) when H2C2O4 as electrolyte. It can expand potential use of the AAO membranes such as for the template-based synthesis of nanowires or nanotubes with modulated diameters and also for practical separation technology. We also has used the AAO with different diameters prepared by this improved HA to fabricate Co nanowires and gamma-Fe2O3 superparamagnetic nanorods. PMID- 29442882 TI - Biogenic Synthesis, Characterization and Evaluation of Silver Nanoparticles from Aspergillus niger JX556221 Against Human Colon Cancer Cell Line HT-29. AB - Nanobiotechnology has emerged as a promising technology to develop new therapeutically active nanomaterials. The present study was aimed to biosynthesize AgNPs extracellularly using Aspergillus niger JX556221 fungal extract and to evaluate their anticancer potential against colon cancer cell line, HT-29. UV-visible spectral characterization of the synthesized AgNPs showed higher absorption peak at 440 nm wavelength. Transmission Electron Microscopy (TEM) analysis revealed the monodispersed nature of synthesized AgNPs occurring in spherical shape with a size in the range of 20-25 nm. Further, characterization using Energy Dispersive Spectroscopy (EDX) confirmed the face centred cubic crystalline structure of metallic AgNPs. FTIR data revealed the occurrence of various phytochemicals in the cell free fungal extract which substantiated the fungal extract mediated AgNPs synthesis. The cytotoxic effect of AgNPs was studied by using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The results evidenced the cytotoxic effect of AgNPs on HT-29 cell lines in a dose dependent manner. The highest activity was found at 100 MUg/ml concentration after 24 h of incubation. Use of propidium iodide staining examination method confirmed the cytotoxic effect of AgNPs through inducing cell apoptosis. AgNPs cytotoxicity was found to be through elevating reactive oxygen species (ROS), and caspase-3 activation resulting in induced apoptosis. Therefore, this research finding provides an insight towards the development of novel anticancer agents using biological sources. PMID- 29442883 TI - Hydrothermal Synthesis of Rock Candy-Shaped Mn3O4 Nanoparticles with High Stability Electrochemical Performances. AB - A type of rock candy-shaped Mn3O4 nanoparticles was synthesized by a facile hydrothermal approach with Pluronic P123 and polyethylene glycol (PEG200), which were chosen as template and reducing agent, respectively. The co-surfactant system played a crucial role in the growth of nanoparticles. In addition, Transmission Electron Microscopy (TEM) and X-ray Diffraction (XRD) were employed to confirm the morphology and structure. These results demonstrated that the length-width ratios of the as-prepared Mn3O4 nanoparticles were about 1.0-1.4 and the average size was about 200 nm. Furthermore, the product presented high stability electrochemical performances both in the 1.0 M Na2SO4 and in 1.0 M KOH electrolytes, which had the potential as an electrode material for energy conversion and storage devices. PMID- 29442884 TI - Hydrothermal Growth of ZnO Nanowires on UV-Nanoimprinted Polymer Structures. AB - Integration of zinc oxide (ZnO) nanowires on miniaturized polymer structures can broaden its application in multi-functional polymer devices by taking advantages of unique physical properties of ZnO nanowires and recent development of polymer microstructures in analytical systems. In this paper, we demonstrate the hydrothermal growth of ZnO nanowires on polymer microstructures fabricated by UV nanoimprinting lithography (NIL) using a polyurethane acrylate (PUA). Since PUA is a siloxane-urethane-acrylate compound containing the alpha-hydroxyl ketone, UV cured PUA include carboxyl groups, which inhibit and suppress the nucleation and growth of ZnO nanowires on polymer structures. The presence of carboxyl groups in UV-cured PUA was substantiated by Fourier transform infrared spectroscopy (FTIR), and a Ag thin film was deposited on the nanoimprinted polymer structures to limit their inhibitive influence on the growth of ZnO nanowires. Furthermore, the naturally oxidized Ag layer (Ag2O) reduced crystalline lattice mismatches at the interface between ZnO-Ag during the seed annealing process. The ZnO nanowires grown on the Ag-deposited PUA microstructures were found to have comparable morphological characteristics with ZnO nanowires grown on a Si wafer. PMID- 29442885 TI - Enhanced Efficiency of Dye-Sensitized Solar Cells Benefited from Graphene Modified by Ag Nanoparticles. AB - In this paper, graphene modified by Ag nanoparticles was successfully applied into dye sensitized solar cells. The morphologies and compositions of graphene and graphene-Ag nanoparticles were characterized by scanning electron microscope and energy dispersive X-ray spectroscopy. The optical and electrical properties were evaluated by UV-vis-NIR absorption spectroscopy, electrochemical impedance spectroscopy and current-voltage curve. The results indicated that the incorporation of graphene or graphene-Ag nanoparticles can improve the light absorption and decrease the charge recombination. The solar cells with graphene Ag nanoparticles exhibited short-circuit current density of 14.34 mA cm-2, open circuit voltage of 709 mV and conversion efficiency of 6.01%, which were higher than those of DSSCs with graphene or pure TiO2. PMID- 29442886 TI - Fabrication and Characterization of Dye-Sensitized Solar Cells Based on Flower Shaped ZnO Nanostructures. AB - Herein, we report a facile synthesis, characterization and dye sensitized solar cell (DSSC) application of flower-shaped ZnO nanostructures. The flower-shaped ZnO nanostructures were synthesized by low-temperature hydrothermal process and characterized in detail by several techniques. The detailed morphological studies confirmed that the flower-shaped structures are formed by the accumulation of several nanoneedles which are axially arranged through their bases in a special fashion that they made flower-like morphologies. The compositional, structural and optical characterizations revealed that the synthesized flowers possess high purity, well-crystallinity with the wurtzite hexagonal phase and good optical properties. The synthesized flower-shaped ZnO nanostructures were used as photoanode to fabricate DSSC which attained a reasonable solar to electrical conversion efficiency of ~1.1%, open-circuit current (VOC) of 0.611 V, short circuit current (JSC) of 3.53 mA/cm2 and fill factor (FF) of 0.51. PMID- 29442887 TI - Extraction of Cellulose Micro-Whiskers from Rice Husk: A Greener Approach. AB - Herein, we report a greener, total chlorine free, ultrasonic physicochemical process of extraction and purification of cellulose micro-whiskers from rice husk. The initial step involves the treatment of the rice husk with a concentrated aqueous alkali solution for the duration of 6 h at 80 degrees C in round bottom flask in order to completely dissolve lignin and silica. After alkali pretreatment, the product obtained was thoroughly washed with distilled water, filtered and dried. The dried product was subjected to mechanical treatment followed by a bleaching process. A sonolytic technique was applied for the bleaching of rice husk using Na2O2/H2O2 as a chlorine-free bleaching agent. The detailed mechanism for the ultrasonic physicochemical bleaching of extracted cellulose from rice husk was also proposed. Extracted and bleached cellulose was characterized for morphological, compositional and thermal properties through different characterization techniques. PMID- 29442888 TI - Synthesis and Characteristics of Large-Area and High-Filling CdS Nanowire Arrays in AAO Template. AB - CdS nanowires arrays were successfully synthesized by a simple solvothermal process using AAO as templates. The phase structures, morphologies, and optical properties of the products were investigated by X-ray diffraction, scanning electron microscopy, high-resolution transmission electron microscopy, Raman spectroscopy, and photoluminescence spectroscopy. It was found that the nanowires were composed of hexagonal structure CdS nanoparticles and the average diameters is about 60-70 nm. A strong green emission with a maximum around 505 nm was observed from the synthesized CdS nanowires at room temperature, which was attributed to near-band-edge emission. A 3D self-seed nucleation coalescent process was proposed for the formation of CdS nanowires structures. The present synthetic route is expected to be applied to the synthesis of other II-VI groups or other group's 1D semiconducting materials. PMID- 29442889 TI - Influence of Thermal Modification and Morphology of TiO2 Nanotubes on Their Electrochemical Properties for Biosensors Applications. AB - The morphology of self-assembled TiO2 nanotubes layer plays a key role in electrical conductivity and biocompatibility properties in terms of cell proliferation, adhesion and mineralization. Many research studies have been reported in using a TiO2 nanotubes for different medical applications, there is a lack of unified correlation between TNT morphology and its electrochemical properties. The aim of this study was to examine the effects of diameter and annealing conditions on TiO2 nanotubes with identical height and their behaviour as biosensor platform. TiO2 nanotubes layer, 1000 nm thick with nanotubes of diameters in range: 25 / 100 nm, was prepared by anodizing of the titanium foil in ethylene glycol solution. To change the crystal structure and improve the electrical conductivity of the semiconductive TiO2 nanotubes layer the thermal treatment by annealing in argon, nitrogen or air was used. Basing on the electrochemical tests, the XPS and scanning microscopy examinations, as well as the contact angle measurements and the amperometric detection of potassium ferricyanide, it was concluded that the 1000 nm thick TiO2 nanotubes layer with nanotubes of 50 nm diameter, annealed in argon, showed the best physicochemical properties, which helps investigate the adsorption immobilization mechanism. The possibility of using TNT as a biosensor platform was confirmed in hydrogen detection. PMID- 29442890 TI - Photocatalytic and Cytotoxic Effects of Nitrogen-Doped TiO2 Nanoparticles on Melanoma Cells. AB - Titanium dioxide (TiO2) has attracted attention as a photosensitizer in the field of photodynamic therapy (PDT) due to its low toxicity and high photostability. In the present work, nitrogen-doped TiO2 (N-TiO2) nanoparticles had their photokilling efficiency evaluated on a murine melanoma cell line (B16-F10) and fibroblasts (NIH 3T3). The N-TiO2 nanoparticles were prepared by a modified hydrogen peroxide sol-gel process using triethylamine as nitrogen precursor. XRD measurements showed that all TiO2 and N-TiO2 samples consisted of an anatase crystalline phase and no trace of rutile was detected. N-TiO2 nanoparticles showed higher absorbance in the visible region than pure TiO2. Nanoparticle dosage increase from 0.1 mg/ml to 0.5 mg/ml played a role in cell viability, causing high cytotoxicity in melanoma and fibroblast cells. The cytotoxic potential of N-TiO2 on cells was analyzed using visible light, UV-A irradiation and dark conditions. All samples were cytotoxic in a PDT test, and N-TiO2 caused 93% death in melanoma cells under UV irradiation treatment at 0.5 mg/ml. Gene expression analysis of this sample showed, under ultraviolet photoexcitation, an increase of pro-apoptotic BAX gene expression, suggesting cell death by apoptosis. PMID- 29442891 TI - Shot Noise in Superconducting Wires Applied with a Periodic Electric Field. AB - We have investigated the differential conductance and shot noise for the system of superconducting nanowires irradiated with a periodic electric field by nonequilibrium Green's functions. The numerical results show that the coupling between the Majorana bound states (MBSs) can be tuned by the periodic electric field. The width of barriers has huge influence on the coupling of MBSs, however, the separation between barriers affect the coupling faintly. The coupling increases with the width of barriers, the number of barriers and the strength of barriers. In addition, super-Poissonian shot noise emerges as the coupling increases. PMID- 29442892 TI - Facile Synthesis of Near-Infrared Emissive CdS Quantum Dots for Live Cells Imaging. AB - CdS quantum dots (QDs) have attracted extensive attention owing to their great potential in optoelectronic nanodevices and biosensors. But their poor water solubility and high cytotoxicity restrict their practical application in live cell imaging. In addition, CdS QDs usually emit blue or green fluorescence, which also have some limitations for cell imaging due to the "water window" effect. In this study, we report a novel strategy to directly synthesize water-soluble and low-cytotoxic CdS QDs with near infrared (NIR) fluorescence through confinement into BSA templates with the mediation of L-cysteine (Cys). The obtained CdS QDs emit NIR fluorescence at 730 nm when exited by 468 nm excitation light, and show good water solubility and low cell cytotoxicity, which can be directly used for live RAW cell imaging. In addition, the effects of the type of amino acids for mediations, and the ratio of both Cys/Cd and Cd/BSA on the fluorescence properties of CdS QDs have also been investigated comprehensively. The mediation of L-cysteine plays a critical role on the formation of CdS QDs emitting NIR fluorescence. PMID- 29442893 TI - Polyethylene Glycol-Functionalized Magnetic Fe3O4/P(MMA-AA) Composite Nanoparticles Enhancing Efficient Capture of Circulating Tumor Cells. AB - Circulating tumor cells (CTCs) played a significant role in early diagnosis and prognosis of carcinomas, and efficient capture of CTCs was highly desired to provide important and reliable evidence for clinical diagnosis. In present work, we successfully synthesized functional magnetic Fe3O4/P(MMA-AA) composite nanoparticles (FCNPs) inspired by a counterbalance concept for recognition and capture of CTCs. This counterbalance, composed of polyethylene glycol (PEG) suppressing cell adhesion and anti-epithelial-cell-adhesion-molecule (anti-EpCAM) antibody targeting tumor cells, could both enhance the specific capture of tumor cells and reduce unspecific adhesion of normal cells. The study showed that the PEG density on the surface of the FCNPs affected the specificity of the materials, and a density of ca. 15% was efficient for reducing the unspecific adhesion. After incubation with the mixture of HepG2 cells and Jurkat T cells, the FCNPs reached a capture efficiency as high as about 86.5% of the cancer cells, suggesting great potential on detection of CTCs in the diagnoses and prognoses of cancer metastasis. PMID- 29442894 TI - Graphene Oxide Incorporated PLGA Nanofibrous Scaffold for Solid Phase Gene Delivery into Mesenchymal Stem Cells. AB - Delivery of functional genes into stem cells shows great application prospect in DNA-based tissue engineering. However, comparing with epithelial cells and cancer cells, stem cells usually exhibit low gene transfection efficiency. To enhance the transfection efficiency, non-viral gene delivery in combination with biomaterial scaffolds, has raised increasing interests from researchers in tissue engineering. Nanofibers fabricated by electrospinning technique mimicking extracellular matrix (ECM) are widely used in tissue engineering applications. In addition, graphene oxide (GO) with ultrahigh specific surface area and ultra strong adsorption capability, is an ideal candidate for gene delivery. In this work, polyethylenimine (PEI)/plasmid DNA-GO/poly(D,L-lactic-co-glycolic acid) (PLGA) scaffold was developed as a substrate for solid phase gene delivery and a tissue engineering substrate for stem cells growth and differentiation. In order to improve the transfection efficiency of stem cells, PEI/pDNA complexes were immobilized at the surface of electropun GO incorporated PLGA nanofibrous mat. Human embryonic kidney 293 cells and human umbilical cord derived mesenchymal stem cells cultured on PEI/pDNA-GO/PLGA scaffold showed significantly higher green fluorescent protein (GFP) expression than PEI/pGFP in the medium. These findings demonstrated that solid phase gene delivery using PEI/pDNA-GO/PLGA significantly enhanced the gene transfection efficiency, and may find potential application of gene therapy and regeneration medicine. PMID- 29442895 TI - Polylactic Acid/Chitosan Nanoparticles Loading Nifedipine: Characterization Findings and In Vivo Investigation in Animal. AB - This paper presents the results of zeta potential, water contact angle, atomic force microscopy image, in vitro solubility, and content of heavy metals in polylactic acid (PLA)/chitosan (CS) nanoparticles loading nifedipine. In addition, the In Vivo test of the PLA/CS nanoparticles loading nifedipine in the mice is also one of highlights of this work. The Zeta potential result shows that the charged surface of the PLA/CS nanoparticles loading nifedipine is neutral, negative or complex depending on nifedipine content. Nifedipine plays a role in increase of hydrophobic property, swelling degree and regular surface as well as decrease of surface rough of the nanoparticles. The PLA/CS/nifedipine nanoparticles are dissolved in the solutions with pH 6.8, pH 4.5 and pH 1.2. The In Vivo test of PLA/CS nanoparticles loading nifedipine on mice was evaluated by the change in diastolic pressure, systolic pressure, arterial pressure and heart rate. The obtained results confirm that the PLA/CS nanoparticles loading nifedipine is suitable to apply in the treatment of hypertension patients lately. PMID- 29442896 TI - Fabrication of Silver Decorated Graphene Oxide Composite for Photocatalytic Inactivation of Escherichia coli. AB - In this study, silver decorated graphene oxide (Ag/GO) composite was fabricated through a reduction process in the presence of potassium borohydride solution. Subsequently, physicochemical properties of the resulting Ag/GO composite were studied by scanning electron microscope, X-ray diffraction, Raman spectra, Fourier transformation infrared spectroscopy and UV-visible diffuse reflectance spectrum. Results indicated that Ag species existed in the form of Ag0, which greatly facilitated the visible light absorbance ability. Furthermore, the performance of Ag/GO was evaluated by PC inactiviation of Escherichia coli under Xenon lamp illumination. It was found that Ag/GO sample could kill the Escherichia coli within 60 min illumination by the non-selective attack of ?OH radicals. This study provides a novel and facile strategy to fabricate high efficient catalyst to kill the bacteria in drinking water treatment. PMID- 29442897 TI - Development of Targeted Nanoscale Drug Delivery System for Osteoarthritic Cartilage Tissue. AB - Osteoarthritis is a severe and debilitating joint disease, which is characterized as results from damage and degeneration of the articular cartilage of the joint surfaces. The incidence of osteoarthritis is growing increasingly high while current treatment methods remain suboptimal. The major issue for current osteoarthritic medications is that patients frequently experience adverse, nonspecific side effects that are not a direct result of the specific pharmacological action of the drug. The treatment processes could be made more effective, safe, and comfortable if it were possible to deliver the drugs specifically to cartilage tissue. Therefore, developing site-specific and controlled drug release delivery systems is needed for overcoming the aforementioned issues. We have developed a poly(lactic-co-glycolic acid) (PLGA) based nanoscale drug delivery system based on a short cartilage-targeting peptide sequence: WYRGRL. Nanoparticles (NPs) made of methoxy-poly(ethylene glycol) (PEG) PLGA and maleimide-PEG-PLGA were prepared using a water-in-oil-in-water double emulsion and solvent evaporation method. Fluorescein isothiocyanate (FITC)-tagged WYRGRL peptide was then linked to the surface of the nanoparticles through the alkylation reaction between the sulfhydryl groups at the N-terminal of the peptide and the C?C double bond of maleimide at one end of the polymer chain to form thioether bonds. The conjugation of FITC-tagged WYRGRL peptide to PLGA NPs was confirmed by NMR technique. We further demonstrated that the novel delivery system binds very specifically to cartilage tissue in vitro and ex vivo. Given that biodegradable PLGA-based NPs have shown promise for drug delivery, they could be used for a positive advancement for treatments of osteoarthritic patients by creating a more effective treatment process that achieves healing results faster and with fewer deleterious side effects. Taken together, these promising results indicated that this nanoscale targeting drug delivery system was able to bind to cartilage tissue and might have a great potential for treating osteoarthritis. PMID- 29442898 TI - Development of Egg Shell Derived Carbonated Apatite Nanocarrier System for Drug Delivery. AB - Carbonated apatite has a chemical composition quite similar to biological apatite found in native bone. The incorporation of carbonate (CO2-3) ions groups into the apatitic crystal structure can tailor its crystallinity, solubility and biological activity that benefit the bone repair and regeneration. In this study, we report a simple and elegant method of synthesizing carbonated calcium deficient hydroxyapatite (ECCDHA) nanoparticles from egg shell wastes and its efficacy has been compared with synthetic calcium deficient hydroxyapatite (SCDHA) nanoparticles. Egg shell contains about 94% of calcium carbonate. Fourier transform infrared (FT-IR) spectroscopy results confirmed the carbonate substitution in the apatite as B-type and CHNS/O elemental analysis showed 6 wt.% of carbonate content in ECCDHA. Energy dispersive spectroscopy (EDS) analysis confirmed the presence of biologically relevant elements such as magnesium, strontium, fluoride, potassium etc., in ECCDHA inherited from the egg shell. In vitro cell culture studies confirmed that the ECCDHA is cellular compatible and it has enhanced cell adhesion and proliferation of L6 myoblast cells as compared to SCDHA. The potential of ECCDHA suitable for bone drug applications was tested with an antibiotic drug, doxycycline. The results showed higher drug loading and releasing for ECCDHA as compared to SCDHA during the period of study. Based on these results, the ECCDHA may be considered as a potential bone substitute and drug carrier system. PMID- 29442899 TI - Highly Efficient Glioma Targeting of Tat Peptide-TTA1 Aptamer-Polyephylene Glycol Modified Gelatin-Siloxane Nanoparticles. AB - Gliomas are the most common type of intracranial malignant tumor; however, current treatment approaches are often ineffective due to limited penetration of genes or drugs through the blood-brain barrier (BBB). Here we describe the synthesis of gelatin-siloxane nanoparticles (GS NPs) as candidate gene carriers through a two-step sol-gel process. To increase the efficiency of glioma targeting, human immunodeficiency virus-derived Tat, tumor-targeting aptamer (TTA)1, and polyethylene glycol (PEG) were conjugated to the GS NPs to generate Tat-TTA1-PEG-GS NPs. In vivo imaging revealed that these modified NPs not only evaded capture by the reticulo-endothelial system, but were able to cross the BBB to reach gliomas. Our results suggest that Tat-TTA1-PEG-GS NPs are a new type of non-viral vector that can deliver therapeutic DNA or drugs for highly efficient glioma treatment. PMID- 29442900 TI - Doxorubicin Loaded Silica Nanoparticles with Dual Modification as a Tumor Targeted Drug Delivery System for Colon Cancer Therapy. AB - In the following study, we describe the preparation and characterization of poly(ethylene glycol) (PEG) and biotin modified, doxorubicin (DOX) loaded silica nanoparticles (Dox/SLN-PEG-Biotin), which was employed as a drug delivery system for colon cancer therapy. The DOX/SLN-PEG-Biotin exhibited small particle size and low cytotoxicity in vitro. Moreover, the Dox releases from DOX/SLN-PEG-Biotin followed a redox-sensitive behavior. Biotin functionalized Dox/SLN-PEG-Biotin demonstrated tumor-targeted delivery of their payload, resulting in enhanced cellular uptake in HCT116 tumor cells and potentiated tumor accumulation in HCT116 tumor-bearing mice. In particular, in vivo anti-cancer assay confirmed that DOX/SLN-PEG-Biotin as a tumor-targeted delivery system exerted strong anti cancer efficacy. Altogether, DOX chemotherapy using DOX/SLN-PEG-Biotin might be an effective strategy for improved treatment in colon cancer. PMID- 29442901 TI - Tumor-Targeting Nanoparticles of Small-Molecule Diketopyrrolopyrrole Derivative for Photothermal Therapy. AB - Herein, an small-molecule organic nanoparticles, BNTP NPs, has been synthesized. Due to its strong and broad absorption spectra and tumor targeting, BNTP NPs is used as a photothermal agent with photothermal conversion efficiency of 23.2%. BNTP NPs can target tumors, realize tumor diagnosis and suppress the growth of tumor effectively both in vitro and in vivo. Xenon lamp instead of laser is used as light source of BNTP NPs to make PTT safer. No obvious toxicity reaction is observed from histologic analysis and body weight of mice. The results confirm that BNTP NPs have potential for clinical application of PTT. PMID- 29442902 TI - Synthesis of Starch-Based Amphiphilic Fluorescent Nanoparticles and Their Application in Biological Imaging. AB - Due to the extensive source, good biocompatibility and biodegradability, the starch of carbohydrates has been extensively investigated for application in biological field. Recently, the development of fluorescent organic nanoparticles (FONs) on the basis of aggregation induced emission (AIE) dyes has attracted great research interest. In this article, novel starch-based S-TPEV polymers with AIE property were successfully fabricated by atom transfer radical polymerization (ATRP) of TPEV dye into water-soluble starch for the first time, subsequently, their structure and properties were detailedly investigated by 1H NMR, TEM, UV vis, FL and FTIR. The characterization results confirmed the successful synthesis of S-TPEV polymers, and the molar fraction of TPEV and C6H10O5 ring in the starch polymers could be respectively calculated as approximate 5.8% and 94.2%. In aqueous solution, the as-prepared S-TPEV polymers will tend to self-assemble into FONs with 100-200 nm diameters, and their fluorescence intensity increased with the increase of the concentration of water in the mixed solution of water and DMSO, indicative of the obvious AIE property. More importantly, owing to their high water dispersity, good fluorescence and excellent biocompatibility, the S TPEV FONs can be uptaken by HepG2 cells and show promising application in biological imaging field. PMID- 29442903 TI - Ultrasonic-Assisted Dispersion of ZnO Nanoparticles and Its Inhibition Activity to Trichoderma viride. AB - The activity inhibition of fungi by ZnO nanoparticles (NPs) has shown huge potential applications in the area of hygienic coatings. However, the inhibition efficiency was limited due to the agglomeration of NPs. To obtain well-dispersed and highly stabilized ZnO nanofluids, ZnO NPs were capped with four kinds of surfactants under ultrasonication. The capping procedure was optimized by varying the dosage of surfactants, the ultrasonic duration, ultrasonic power and temperature. Capped ZnO nanofluids were then used for the inhibition of Trichoderma viride. The influence on the activity of the capping conditions, illumination, ZnO NPs content, humidity and temperature were investigated in details. Results suggest that well-dispersed ZnO NPs were obtained through ultrasonic-assisted functionalization using sodium polyacrylate as a dispersant. Moreover, capped ZnO nanofluids revealed long-term stability at pH above 6. The optimal capping procedure was obtained for a sonication power of 250 W, treatment duration of 40 min, dosage of 0.4% and temperature of 60 degrees C. Antifungal tests indicated that capped ZnO NPs showed an inhibition ability versus T. viride even in the dark. The antifungal ability of ZnO NPs increased with the increasing ZnO content, and humidity and temperature only affected the growth of fungi. Capped ZnO NPs showed an excellent antifungal performance even in the circumstance that was beneficial for the fungi growth (temperature of 30 degrees C, humidity of 95%), demonstrating the antimicrobial capability in practical applications. PMID- 29442904 TI - Self-Assembled Tea Tannin Graft Copolymer as Nanocarriers for Antimicrobial Drug Delivery and Wound Healing Activity. AB - Green chemistry polymers from renewable resources have recently received much more attention from pharmaceutical researchers. However, the appropriate application of a polymer depends on its chemical nature, biocompatibility and microstructure. Here, tannin polyphenols from the common beverage, tea, are used to develop a novel self-assembled porous capsule as a microstructure of hydrogel for versatile biological applications, such as drug delivery, antioxidant and wound healing activity. Hydrogel has been successfully used for the delivery of both anticancer and antimicrobial drugs. The developed material shows excellent biocompatibility and antioxidant activity in vitro. The scratch assay for in vitro wound healing activity reveals their higher potential to repair the damaged cells in comparison to control. PMID- 29442905 TI - A Miniature Cell Pattern Formation of Ovarian Cancer Cell Lines on Self Assembling Peptide Nanofiber-Coated Coverslip and In Vitro Chemosensitivity Assay. AB - BACKGROUND: Despite of intensive efforts, the tumor progression of ovarian cancer has not yet been fully understood. Various studies suggest that an effective experimental model system In Vitro to mimic microenvironment in vivo and the fabrication of cell pattern formation In Vitro are of great importance for the ovarian cancer research. METHODS: This study cultivates SKOV3, A2780 and A2780/DDP ovarian cancer cell lines in RADA16-I peptide hydrogel to obtain 3D precultured cancer cells and fabricate a type of miniature cell pattern formation In Vitro on RADA16-I peptide nanofibercoated coverslip by in situ AFM analysis and chemosensitivity assay in vitro. RESULTS: SKOV3, A2780 and A2780/DDP cells were regularly cultivated in RADA16-I peptide hydrogel, respectively, and present defined cellular characteristics, such as small cell colonies, cell clusters and cell aggregates, etc. On coverslip coated with RADA16-I peptide nanofiber, three 3D-precultured cell lines were flat and spread on coverslips and the regular topographic images by AFM were obtained. The chemosensitivity assay of three ovarian cancer cell lines were significantly different in RADA16-I peptide-coated coverslips compared with 2D dish plates. CONCLUSIONS: By 3D cell culture of ovarian cancer cell lines in RADA16-I peptide hydrogel In Vitro, the cell culture model systems was fabricated. The miniature cell pattern formation In Vitro on peptide nanofiber-coated coverslip was particularly useful experiemental model systems to be served as a valuable methodology for studying ovarian cancer biology. PMID- 29442906 TI - Amine-Functionalized Silica Nanoparticles with Drug and Gene Co-Delivery for Anti Angiogenesis Therapy of Breast Cancer. AB - In our study, we report on the design and characterization of a combined angiogenesis therapy for breast cancer based on well-formed amine-functionalized silica nanoparticles (SLNs). The aminefunctionalized SLNs was employed to simultaneously deliver angiostatin (ANG) plasmid and candesartan (CD) to the same cancer cell. The well-formed ANG/CD/SLNs exhibited small particle size, reasonable positive charges, excellent loading of drug and gene in vitro. Moreover, aminefunctionalized SLNs were almost no cytotoxicity. ANG/CD/SLNs resulted in enhanced gene transfection compared to naked plasmid. More importantly, ANG/CD/SLNs as a co-delivery system achieved a stronger inhibitory effect on angiogenesis in vitro, possibly resulting from significant downregulation of vascular endothelial growth factor (VEGF) expression via different pathways. In particular, in vivo investigation on nude mice bearing MCF 7 xenografts confirmed that ANG/CD/SLNs codelivery system exerted strong anti tumor efficacy by synergistic antiangiogenic mechanism. PMID- 29442907 TI - Impact of Titanium Dioxide and Fullerenol Nanoparticles on Caco-2 Gut Epithelial Cells. AB - The application of nano-products in the food industry increases the risk of people exposed to nanoparticles. Titanium dioxide nanoparticles (T-NPs) are typically and widely used in food field, while fullerenol nanoparticles (F-NPs) have great promise to be used as food additives. Therefore, it is necessary and important to understand the safety of T-NPs and F-NPs in foods. In the present study, Caco-2 gut epithelial cell line was selected as a model to investigate the impact of T-NPs and F-NPs. The viability and proliferation of Caco-2 gut epithelial cells incubated with different concentrations of T-NPs and F-NPs were observed. The results showed that the two kinds of nanoparticles did not induce cell death even lasting for 48 h. The results of apoptosis and DNA damages in the cells indicated that both T-NPs with 50 and 100 MUg/mL caused Caco-2 gut epithelial cell apoptosis, but didn't cause significantly DNA damages. F-NPs with 200 and 500 MUg/mL concentrations also can induce cell apoptosis but no DNA damage. PMID- 29442908 TI - Systemic Toxicity and Teratogenicity of Copper Oxide Nanoparticles and Copper Sulfate. AB - Acceleration in development of metallic nanoparticles for their utility in medical and technological applications due to their unique physicochemical properties has concurrently raised a matter of concern due to their potential toxicity. Of the enormous metallic nanostructures, copper oxide nanoparticles (CuONPs) having optical and electrochemical properties are scrutinized for theranostic applications. Therefore, their safety profile is of a major concern in optimizing a safe dose for its clinical utility. Considering the potency of CuONPs in epitomizing toxicity, we report a dose and time dependent acute, systemic and transgenerational toxicity profile of CuONPs in comparison to the bulk copper as copper sulfate (CuSO4). Acute toxic dose (LD50(14)) of CuONPs (400 mg/kg . b . wt) was found to be three fold higher that of CuSO4(100 mg/kg . b . wt). Comparative steady state evaluation showed that CuONPs (>=5 mg/kg . b . wt.) induce greater dose and time dependent oxidative stress by increase in protein carbonylation and decreased glutathione levels in comparison to the bulk CuSO4. Furthermore, CuONPs were found to disrupt blood brain barrier (BBB) and sneak in to the brain which was quantified by atomic absorption spectroscopy (AAS) and also coax toxicity in liver, kidney and spleen, ascertained by histopathological findings (at >=5 mg/kg . b . wt.). Considering transgenerational toxicity, CuONPs in comparison to CuSO4 severely affected sperm count and morphology in male animals, though not much teratological effects were observed, except certain extent of embryo resorption. The present study highlights a complete toxicity profile of CuONPs, giving forethought for considering them for clinical applications. PMID- 29442909 TI - Synthetic Polysaccharides as Drug Carriers: Synthesis of Polyglucose-Amphotericin B Conjugates and In Vitro Evaluation of Their Anti-Fungal and Anti-Leishmanial Activities. AB - While many naturally occurring polysaccharides have been widely used as drug carriers, there are two main drawbacks in their use: the first is their physical properties such as molecular weight, branching, type of glycosidic linkages and solubility depend on their source and the method of isolation and purification, the second is many of them are contaminated with proteins and protein removal is essential for preventing immune reactions. Synthetic polysaccharides on the other hand can be tailor made from their respective monomers with consistent physical properties and are, free from protein contamination, both being significant advantages in their use. Although, the synthesis of polysaccharides such as polyglucose, polymannose, polygalactose etc., by the polycondensation of their respective monomers have been reported more than half a century ago, their use as drug carriers have not received any attention so far. In this report, we show that polyglucose (PG) having a weight average molar mass of 37,000 g/mol can be synthesized in a single step by the melt polycondensation of glucose in over 70% yield. Oxidation using sodium periodate generated aldehyde functions on the polymer. Amphotericin B, (AmB) a water-insoluble polyene antibiotic was chosen as a model drug to couple onto periodate oxidized PG via imine linkage at ~20 wt% concentration. The drug loading capacity of the conjugates was above 90%. Further reduction using sodium borohydride gave the more stable amine conjugates with any residual aldehyde on the polymer backbone getting reduced to hydroxyl groups. The conjugates were highly soluble in water and stable on storage. At ten times the concentration of AmB, the conjugates produced negligible hemolysis to human blood. The AmB conjugates were then evaluated for their anti-fungal activity against C. albicans and A. fumigatus and anti-leishmanial activity against different strains of L. donovani in culture. The conjugates showed potent anti fungal and anti-leishmanial activity. The use of synthetic polysaccharides in drug delivery and in other biomedical applications will have many potential advantages. PMID- 29442910 TI - Antibacterial Performance of PCL-Chitosan Core-Shell Scaffolds. AB - In this study, antibacterial performance of the coaxially electrospun Poly epsilon-caprolactone (PCL)-chitosan core-shell scaffolds developed, optimized and identified physically and chemically in our previous study, were evaluated for the suitability in wound healing applications. The aim of utilizing a core-shell fibrous scaffold with PCL as core and chitosan as shell was to combine natural biocompatibility, biodegradability and antibacterial properties of chitosan with mechanical properties and resistance to enzymatic degradation of PCL. The scaffolds were prepared with the optimized parameters, obtained from our previous study. Thickness and contact angle measurements as well as Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) analyses confirmed repeated fabrication of PCL-chitosan core-shell scaffolds. In this study, assays specific to wound dressing materials, such as water vapor transmission rate (WVTR), in vitro degradability and antibacterial tests were carried out. WVTR value of PCL-chitosan core-shell scaffolds was higher (2315 +/- 3.4 g/m2 . day) compared to single PCL scaffolds (1654 +/- 3.2 g/m2 . day) due to the higher inter-fiber pore size. Additionally, in vitro degradability assays showed that the susceptibility of chitosan to enzymatic degradation can be significantly improved by hybridization with more resistant PCL while still keeping the scaffold to be considered as biodegradable. Finally, inhibition ratio and inhibition zone measurements showed that the PCL-chitosan core-shell polymeric scaffolds had significant antibacterial performance (52.860 +/- 2.298% and 49.333 +/- 0.719% inhibition ratios; 13.975 +/- 0.124 mm and 12.117 +/- 0.133 mm clear inhibition zones, against E. coli and S. aureus, respectively), close to the native chitosan. Therefore, the developed scaffolds can be considered as suitable candidates for biodegradable wound dressing applications. PMID- 29442911 TI - Carbonyl Functionalized Single-Walled Carbon Nanotube-Hb Crosslinked Network: A Novel Platform for Studying Bio-Electrochemistry and Electrocatalysis of Hemoglobin. AB - In this work, the direct electrochemistry of hemoglobin (Hb), which was immobilized on carbonyl functionalized single walled carbon nanotube (SWCNT) and deposited onto a gold (Au) electrode has been described. The synthesis of the network of crosslinked SWCNT/Hb was done with the help of crosslinking agent EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide). The UV-Vis and FTIR spectroscopy of SWCNT/Hb networks showed that Hb maintained its natural structure and kept good stability. In addition with this, scanning electron microscopy (SEM) illustrated that SWCNT/Hb networks had a featured layered structure and Hb being strongly liked with SWCNT surface. Cyclic voltammetry (CV) was used to study and to optimize the performance of the resulting modified electrode. The cyclic voltammetric (CV) responses of SWCNT/Hb networks in pH 7.0 exhibit prominent redox couple for the FeIII/II redox process with a midpoint potential of -0.46 V and -0.34, cathodic and anodic respectively. Furthermore, SWCNT/Hb networks are utilized for the detection of hydrogen peroxide (H2O2). Electrochemical measurements reveal that the resulting SWCNT/Hb electrodes display high electrocatalytic activity to H2O2 with high sensitivity, wide linear range, and low detection limit. Overall, the electrochemical results are due to excellent biocompatibility and excellent electron transport efficiency of CNT as well as high Hb loading and synergistic catalytic effect of the modified electrode toward H2O2. PMID- 29442912 TI - Effect of Eu3+ Ion Concentration on Phase Transition, Site Symmetry and Quantum Efficiency of ZrO2 Nanocrystal Rods. AB - This work report the influence of Eu3+ ion concentration on the photophysical properties of zirconia nanocrystal rods including its intrinsic quantum efficiency (IQE). A simple chemical route was employed in the synthesis procedure. X-ray diffraction results show mixed phases of monoclinic and tetragonal structures. Phase transition occurred at low (1 mol%) and high (7 and 8 mol%) Eu3+ concentrations. There are three forms of excitations for this phosphor; band edge excitation at 216 nm, charge transfer state transition at 247 and 263 nm, and direct excitation at 362, 395 and 535 nm. Photoluminescence emission for all the doped samples at room temperature appeared to be entirely from intraconfigurational Eu3+ emissions and depends both on the site symmetry as well as the Eu3+ concentration. Low temperature measurements indicate the presence of defect bands associated with oxygen vacancies. Defects were also shown to be temperature dependent. The Eu3+ ions were distributed in both phases especially at high ion concentrations (7 and 8 mol% Eu3+). Two multipolar processes where found to be responsible for the luminescence quenching process in the mixed-structure; the dipole-dipole and the dipole-quadrupole transitions. The intensity parameters (Omega2, Omega4), asymmetry ratio, R0 and the average decay lifetime of the nanocrystals show dependence on concentration and excitation wavelength. High IQE values were obtained at 1, 7 and 8 mol% Eu3+ where the monoclinic phase is dominant. The CIE coordinates values are comparable to existing red phosphors and in combination with high average IQE of 55% makes this phosphor a good candidate for red emitting phosphor application. PMID- 29442913 TI - Highly Sensitive Fluorescent Sensor for Cartap Based on Fluorescence Resonance Energy Transfer Between Gold Nanoparticles and Rhodamine B. AB - Cartap residue poses a great threat to human health and its derivatives would remain in soils, natural waters and other environmental domains for a long time. Herein, a simple, rapid and ultrasensitive analytical method for the determination of cartap based on fluorescence resonance energy transfer (FRET) between Au nanoparticles (AuNPs) and rhodamine B (RB) is first described. With the presence of citrate-stabilized AuNPs, the fluorescence of RB was remarkably quenched by AuNPs via FRET. The fluorescence of the AuNPs-RB system was recovered upon addition of cartap, cartap can be adsorbed on the surface of AuNPs due to its amino group that has good affinity with gold, which could induce the aggregation of AuNPs accompanying color change from red to blue. Thus, the FRET between AuNPs and RB was weakened and the PL intensity of RB was recovered accordingly. A good linear correlation for detection of RB was exhibited from 1 nM to 180 nM, and the detection limit reached 0.88 nM, which was much lower than the safety limit required by USA, UK and China. To the best of our knowledge, it has been the lowest detection ever without the aid of costly instrumentation. This method was successfully carried out for the assessment of cartap in real samples with satisfactory results, which revealed many advantages such as high sensitivity, low cost and non-time-consuming compared with traditional methods. PMID- 29442914 TI - Structural, Spectroscopic Investigation and Computational Study on Nitrate and Hydrogen Oxalate Salts of 2-Aminopyrimidine. AB - The proton transfer salts of 2-aminopyrimidine with nitric acid (2APNO) and oxalic acid (2APOX) were synthesized and crystallized successfully by solvent evaporation solution growth technique. The crystal packing is stabilized through intricate three dimensional hydrogen bonded network. Both, the molecular structures were optimized with Density Functional Theory (DFT) using B3LYP function and Hartree-Fock method with a 6-311++G(d,p) basis set. Optimized molecular parameters between the methods were compared for the cation showing appreciable agreement. The computed vibrational spectra are compared with experimental result which clearly demonstrates the strong N-H... O vibrational behaviour. Thermal stability of the crystals were analyzed with TGA/DTA and the melting points of the salts, viz. 2APNO and 2APOX, were identified at 189.5 and 210.9 degrees C, respectively. The chemical hardness, electronegativity, chemical potential and electrophilicity index of the two crystals were determined by HOMO-LUMO plot. The lower band gap value obtained from the Frontier Molecular Orbital (FMO) analysis favours the possible pharmaceutical/biological activity of the salts. PMID- 29442915 TI - Vapour Phase Dehydration of Glycerol to Acrolein Over Wells-Dawson Type H6P2W18O62 Supported on Mesoporous Silica Catalysts Prepared by Supercritical Impregnation. AB - The H6P2W18O62/MCM-41-SUP was first synthesized using supercritical impregnation as highly efficient catalyst during glycerol conversion reaction. For comparison, the H6P2W18O62/MCM-41 prepared by conventional wet impregnation was also studied. The catalysts were studied using XRD, BET, FTIR, SEM, TEM, pyridine-FTIR, NH3 TPD, TG, ICP and elemental analysis. The characterization results showed that the preparation condition of supercritical carbon dioxide contributed to improve the dispersion of H6P2W18O62 on MCM-41, strengthen the interaction between H6P2W18O62 and MCM-41, increase the thermostability of H6P2W18O62 and enhance the amount of medium and Bronsted acid sites on the catalyst. Therefore, the formation of coke was retarded, and the lifetime of catalyst was prolonged. After 15 h reaction, the glycerol conversion rapidly reduced from 92% to 64% on H6P2W18O62/MCM-41-IMG (15.4 wt% coke), while the glycerol conversion slightly decreased from 94% to 82% on H6P2W18O62/MCM-41-SUP (9.8 wt% coke). PMID- 29442916 TI - Facile Synthesis and High Activity of Novel Composite C/Fe-BiVO4 Photocatalyst for Degradation of Cipfloxacin. AB - A novel C/Fe-BiVO4 nanosheet composite photocatalyst combining the properties of both semiconductor and Fenton like catalyst was prepared via a two-step method involving Resin carbonization and hydrothermal process. The samples were characterized by X-ray diffraction (XRD), scanning electronic microscopy (SEM) and energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM), UV-vis diffuse reflectance spectra (DRS), X-ray photoelectron spectroscopy (XPS), Fourier transformed infrared spectroscopy (FT-IR) and nitrogen adsorption desorption measurements and fluorescence spectrum technique. Structure analyses indicated that C/Fe-BiVO4 presented a nanosheet and macro-meso dual porosity structure. Photocatalytic degradation of cipfloxacin (CIP) (10 mg/L) was studied using C/Fe-BiVO4 under simulated solar light (SSL) irradiation in a cylindrical reactor. Three experimental parameters were chosen as independent variables: pH, C/Fe-BiVO4 concentration, and H2O2 concentration. The catalyst shows high catalytic activity in cipfloxacin photodegradation reaction with the cipfloxacin conversion efficiency higher than 95.61% at experimental conditions (catalyst dose, 0.75 g . L-1; H2O2 dose, 200 mg . L-1; solution pH, 5.0). The process obeyed the pseudo first-order kinetics by assuming a constant concentration of OH*. The as-prepared composite exhibited high efficiency in the photocatalytic decomposition of Cipfloxacin (CIP) by the assistance of H2O2. This method is promising due to its inexpensive starting materials and good photocatalyst for degradation of emerging micropollutants. PMID- 29442917 TI - Synthesis of Various Ferrite (MFe2O4) Nanoparticles and Their Application as Efficient and Magnetically Separable Catalyst for Biginelli Reaction. AB - Herein, we reports the application of various spinel ferrite nanoparticles, MFe2O4 (M = Co, Ni, Cu, Zn), as efficient catalyst for Biginelli reaction. All ferrite nanoparticles were synthesized using a novel aqueous solution based method. It was observed that, the catalytic activity of the ferrite nanoparticles followed the decreasing order of CoFe2O4 > CuFe2O4 > NiFe2O4 > ZnFe2O4. The most important feature of these ferrite nanocatalysts is that, these nanoparticles can directly be used as catalyst and no surface modification or functionalization is required. These ferrite nanoparticles are easily separable from reaction mixture after reaction by using a magnet externally. Easy synthesis methodology, high catalytic activity, easy magnetic separation and good reusability make these ferrite nanoparticles attractive catalysts for Biginelli reaction. PMID- 29442918 TI - Doping Nitrogen in InGaZnO Thin Film Transistor with Double Layer Channel Structure. AB - This paper presents the electrical characteristics of doping nitrogen in an amorphous InGaZnO thin film transistor. The IGZO:N film, which acted as a channel layer, was deposited using RF sputtering with a nitrogen and argon gas mixture at room temperature. The optimized parameters of the IGZO:N/IGZO TFT are as follows: threshold voltage is 0.5 V, field effect mobility is 14.34 cm2V-1S-1. The on/off current ratio is 106 and subthreshold swing is 1.48 V/decade. The positive gate bias stress stability of InGaZnO doping with nitrogen shows improvement compared to doping with oxygen. PMID- 29442919 TI - Synthesis of Bimetal Fe and Cu Altered TUD-1: A Mesoporous Catalyst for Phenol Hydroxylation Reaction. AB - Fe and Cu ions incorporated (Si/Cu = 50, Si/Fe = 50 and Si/Cu + Fe = 50) amorphous, wormhole structured mesoporous catalysts (CuTUD-1, FeTUD-1 and FeCuTUD 1) (TUD-1-Technische Universiteit Delft) have been synthesized hydrothermally using low cost, non-surfactant template triethanolamine (TEA). Physicochemical properties of the catalysts were made using X-ray diffraction (XRD), Nitrogen sorption, FT-IR, DRS UV Visible, FT Raman, SEM, TEM and TG-DTG techniques. The results showed that the materials possess mesoporous, foam type morphology, surface area 485-634 m2/g, pore size 4.8-6.8 nm, pore volume 0.67-0.83 cm3/g and metal ions (Cu2+ and Fe3+) coordinative environment. The highly dispersed Cu2+ and Fe3+ active sites are observed in FeCuTUD-1 catalyst. Also, the synthesized catalysts are tested in the oxidation of phenol with hydrogen peroxide (H2O2) oxidant. Further, reaction parameters such as time, temperature, and catalyst were also investigated. PMID- 29442920 TI - Investigation of Disorder in Mixed Phase, sp2-sp3 Bonded Graphene-Like Nanocarbon. AB - Disorder in a mixed phase, sp2-sp3 bonded graphene-like nanocarbon (GNC) lattice has been extensively studied for its electronic and field emission properties. Morphological investigations are performed using scanning electron microscopy (SEM) which depicts microstructures comprising of atomically flat terraces (c planes) with an abundance of edges (ab planes which are orthogonal to c-planes). Scanning tunneling microscopy (STM) is used to observe the atomic structure of basal planes whereas field emission microscopy (FEM) is found to be suitable for resolving nanotopography of edges. STM images revealed the hexagonal and non hexagonal atomic arrangements in addition to a variety of defect structures. Scanning tunneling spectroscopy is carried out to study the effect of this short range disorder on the local density of states. Current versus voltage (I-V) characteristics have been recorded at different defect sites and are compared with respect to the extent of the defect. As sharp edges of GNC are expected to be excellent field emitters, because of low work function and high electric field, enhancement in current is observed particularly when applied electric field is along basal planes. Therefore, it is worthwhile to investigate field emission from these samples. The FEM images show a cluster of bright spots at low voltages which later transformed into an array resembling ledges of ab-planes with increasing voltage. Reproducible I-V curves yield linear Fowler-Nordheim plots supporting field emission as the dominant mechanism of electron emission. Turn on field for 10 MUA current is estimated to be ~3 V/MUm. PMID- 29442921 TI - Effect of Graphene Oxide Mixed Epoxy on Mechanical Properties of Carbon Fiber/Acrylonitrile-Butadiene-Styrene Composites. AB - In this study, the watersoluble epoxy resin was prepared via the ring-opening reaction between diethanolamine and epoxy resin. The modified resin mixed with graphene oxide (GO) as a sizing agent was coated onto carbon fiber (CF) and then the GO-CF reinforced acrylonitrile-butadienestyrene (ABS) composites were prepared. The influences of the different contents of GO on CF and CF/ABS composite were explored. The combination among epoxy, GO sheets and maleic anhydride grafted ABS (ABSMA) showed a synergistic effect on improving the properties of GO-CF and GO-CF/ABS composite. The GO-CF had higher single tensile strength than the commercial CF. The maximum ILSS of GO-CF/ABS composite obtained 19.2% improvement as compared with that of the commercial CF/ABS composite. Such multiscale enhancement method and the synergistic reinforced GO-CF/ABS composite show good prospective applications in many industry areas. PMID- 29442922 TI - Use of Sulfobetaine-Based Block Copolymer as Stabilizer in Silver Nanoparticle Production and Catalytic Activity Studies. AB - A zwitterionic sulfobetaine-based diblock copolymer was successfully synthesized and used in the preparation and stabilization of Ag nanoparticles (AgNPs). For the related block copolymer, a precursor AB type diblock copolymer was synthesized via atom transfer radical polymerization by using a MPEG-based ATRP macroinitiator and 2-(N-dimethylamino)ethyl methacrylate (DMA) comonomer. Tertiary amine residues of PDMA blocks in poly(ethylene glycol) methyl ether-b poly[2-(N-diethylamino)ethyl methacrylate] (MPEG-b-PDMA) precursor was then converted to polybetaine structures by reacting with 1,3-propanesultone to obtain poly(ethylene glycol) methyl ether-b-poly[3-dimethyl(methacryloyloxyethyl) ammonium propane sulfonate] (MPEG-b-PbetaDMA) derivative. The resulting block copolymer was successfully used as stabilizer in the chemical and sonochemical synthesis of spherical AgNPs with a diameter in the range of 7.9-9.3 nm. The average diameter of AgNPs synthesized by sonochemical method was smaller than those synthesized by chemical method. The MPEG-b-PbetaDMA diblock copolymer was determined to be a good stabilizer for AgNPs. The AgNPs dispersion was stable for more than 5 months without any flocculation at room temperature. The catalytic activity of polymer-AgNP dispersion was also investigated in the reduction of p nitrophenol to p-aminophenol and was found to be quite effective. PMID- 29442923 TI - Polycarbonate Nanofluidic Chip Fabrication Technique by Hot Embossing and Thermal Bonding. AB - Nanofluidic devices are becoming increasingly critical for medical, chemical and biological applications. In this paper, a 2D Polycarbonate (PC) nanofluidic chip was fabricated by hot embossing and thermal bonding method. In this paper, the effect of the hot embossing parameters on the replication precision of 2D PC nanochannels was investigated by finite element method. To increase the bonding rate of the chip, the parameters of the thermal bonding process were optimized. Under the optimized parameters the 2D PC nanofluidic chip was successfully fabricated. The results show that the replication precision of the nanochannels can be as high as 97% and the bonding rate of the chip can be 96%. The fluorescent images demonstrate that there is no block and leakage through the whole microchannels and nanochannels. It is expected that this fabrication method has great potential to fabricate 2D nanofluidic chip with low cost and high precision. PMID- 29442924 TI - Green Synthesis and Catalytic Activity of Gold Nanoparticles/Graphene Oxide Nanocomposites Prepared By Tannic Acid. AB - Tannic acid is a phenolic compound that is abundant in plants. Five different concentrations of tannic acid were used as a reducing agent to synthesize gold nanoparticles (AuNPs). Three kinds of AuNPs were prepared to evaluate their catalytic activity for the 4-nitrophenol reduction reaction in the presence of sodium borohydride: (i) Colloidal solutions of AuNPs synthesized using tannic acid as a reducing agent (TA-AuNPs), (ii) Nanoparticles made by centrifuging the colloidal solution of TA-AuNPs followed by re-dispersion with deionized water (cf TA-AuNPs), and (iii) Nanoparticles made by the in situ crystallization of TA AuNPs on graphene oxide (TA-AuNPs-GO). TA-AuNPs, cf-TA-AuNPs and TA-AuNPs-GO exhibited a characteristic surface plasmon resonance band at 527~564 nm. High resolution transmission electron microscopy images revealed spherical-shaped nanoparticles. The rate constants of 4-nitrophenol reduction reaction increased for all three types of AuNPs with decreasing tannic acid concentration used during the synthetic process. The rate constants of cf-TA-AuNPs and TA-AuNPs-GO increased 1.45~1.64-fold and 2.25~4.49-fold, respectively, compared with the rate constants of TA-AuNPs. The conversion yields from 4-nitrophenol to 4-aminophenol in the presence of the cf-TA-AuNPs catalysts were measured using reverse phase high performance liquid chromatography. The conversion yield was excellent in a range of 97.57~99.43%. PMID- 29442925 TI - Effect of Protective Agents on Silver Nanoparticle Preparation by Vacuum Evaporation on Running Hydrocarbon Solution. AB - In order to simply compare the performance of protective agents in the preparation of metal nanoparticles, a systematic investigation based on the same synthetic conditions is necessary. We successfully achieved this objective using improved vacuum evaporation on running oil substrate (VEROS) method. The efficient synthesis of nanoparticles with the improved VEROS method enabled us to characterize them by various analytical methods. In this study, five types of protective agents with different functional groups were employed to clarify their effect on the preparation of silver nanoparticles. They are sorbitan monooleate, oleylamine, oleic acid, oleyl alcohol, and methyl oleate. Particles synthesized by the improved VEROS method were evaluated by transmission electron microscope (TEM) and UV-vis spectrophotometer. These results indicate that sorbitan monooleate and oleic acid effectively protect the aggregation between particles. It is also evident from the evaluation of powdered nanoparticles isolated from the trap solution by thermogravimetric analysis (TGA) that these protective agents adsorb on the surface of the particles. On the other hand, the aggregates of silver nanoparticles were formed in the cases using oleic alcohol and methyl oleate. Silver nanoparticles were obtained in the case of oleylamine but the material efficiency of silver was extremely low. As a result, our systematic investigation using the improved VEROS method disclosed suitable protective agents in the preparation of silver nanoparticles with the physical method. PMID- 29442926 TI - Controlled Synthesis and Photocatalytic Performance of Au@ZnO Nanospheres with Core-Shell and Yolk-Shell Structures Assisted by Carbonaceous Layers as Intermediate. AB - Au@ZnO nanospheres with controlled core-shell and yolk-shell features were successfully fabricated through a facile template-based solvothermal method using carbonaceous layers as intermediate. The active carbonaceous layers containing numerous surface functional groups such as OH and C?O play key roles in fabrication of the Au@ZnO nanospheres. The structures of Au@ZnO can easily controlled by adjusting the concentration of Zn ions aqueous solution and/or the size of Au@C microspheres. The synthesis strategy proposed in this paper is also verified to be suitable for fabricating some other Au@metallic oxides nanospheres such as Au@SnO2 and Au@Fe2O3 with controlled structures. Furthermore, due to the synergic effect of the surface plasma resonance effect of Au cores and the large surface area of 122.67 m2 g-1, the Au@ZnO nanospheres with yolk-shell feature exhibite good photocatalytic activity and stability under visible-light irradiation. PMID- 29442927 TI - Metal-Crown Ether-Porphyrin Decorated Gold Nanoparticles as High Sensitive Raman Ion Probe. AB - A kind of gold nanoparticles modified with metal crown ether porphyrin (GNPs-CP) was synthesized and characterized. The surface of the resulting gold particles was partially covered by metal crown ether porphyrin molecules through strong covalent Au-S bond. Based on the coupling effect of metal porphyrin and crown ether, the resulting composite gold nanoparticles can serve as a kind of ion probe. Raman and UV-Vis spectra were utilized to evaluate the ion recognition of the system, both of which changed dramatically when meeting metal ion corresponding to ligand of crown ether. Compared with UV-Vis spectra, Raman spectra of the composites are more sensitive and the limit of detection (LOD) can reach 1 * 10-8 g/mL. The study provides a candidate with higher sensitivity to replace current UV-Vis spectrum based evaluation tool for ion recognition. PMID- 29442928 TI - Deposition of Tin Oxide Thin Films by Successive Ionic Layer Adsorption Reaction Method and Its Characterization. AB - Tin oxide thin films were uniformly deposited by successive ionic layer adsorption reaction (SILAR) method on glass substrates using ethylene diamine as a complexing agent. The proper annealing treatment in air converts as-deposited amorphous films into crystalline and removes defects, reducing strain in the crystal lattice. The films were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), Atomic Force Microscopy (AFM), Fourier Transform Infrared (FTIR) spectroscopy. The film shows good optical transparency in the range of 200-1000 nm wavelength and electrical resistivity decreases upon annealing. PMID- 29442929 TI - Characteristics of Molybdenum Disulfide Nanoparticles for Heterojunction Polymer Solar Cells. AB - We have used different molybdenum disulfide (MoS2) nanoparticle concentrations (0~10 wt%) for doping the hybrid active P3HT:PCBM layer. The root mean square (rms) roughness of the layer increased as the MoS2 nanoparticle concentration increased. The hybrid film with MoS2 has higher absorption intensity than the pristine film. The maximum power conversion efficiency (PCE) was 2.73% with 5 wt% MoS2 concentration, higher than that (2.08%) obtained without MoS2. PMID- 29442930 TI - Fluorescence Stability of Mercaptopropionic Acid Capped Cadmium Telluride Quantum Dots in Various Biochemical Buffers. AB - Quantum dots are the semiconductor nanocrystals having unique optical and electronic properties. Quantum dots are category of fluorescent labels utilized for biological tagging, biosensing, bioassays, bioimaging and in vivo imaging as they exhibit very small size, signal brightness, photostability, tuning of light emission range, longer photoluminescence decay time as compared to organic dyes. In this work, we have synthesized and characterized mercaptopropionic acid capped cadmium telluride quantum dots (MPA-CdTe QDs) using hydrothermal method. The study further reports fluorescence intensity stability of quantum dots suspended in different buffers of varying concentration (1-100 mM), stored at various photophysical conditions. Fluorescence intensity values were reduced with increase in buffer concentration. When the samples were stored at room temperature in ambient light condition the quantum dots suspended in different buffers lost the fluorescence intensity after day 15 (except TRIS II). Fluorescence intensity values were found stable for more than 30 days when the samples were stored in dark condition. Samples stored in refrigerator displayed modest fluorescence intensity even after 300 days of storage. Thus, storage of MPA-CdTe QDs in refrigerator may be the suitable choice to maintain its fluorescence stability for longer time for further application. PMID- 29442931 TI - Anti-Oxidative and Antibacterial Self-Healing Edible Polyelectrolyte Multilayer Film in Fresh-Cut Fruits. AB - The consumption of fresh-cut fruits is limited because of the oxidation browning and pathogenic bacteria's growth on the fruit surface. Besides, crack of the fresh-keeping film may shorten the preservation time of fruit. In this work, polyelectrolyte multilayer (PEM) film was fabricated by layer-by-layer (LBL) electrostatic deposition method. The film was made by carboxy methylcellulose sodium (CMC) and chitosan (CS). The as-prepared PEM film had good anti-oxidative and antibacterial capability. It inhibited the growth of Gram-negative bacteria and the antibacterial rate was more than 95%. The stratified structure and linear increase of the absorbance in the film verified a linear increase of film thickness. The slight scratched film could self-heal rapidly after the stimulation of water whatever the layer number was. Moreover, the film could heal cracks whose width was far bigger than the thickness. The application of PEM film on fresh-cut apples showed that PEM film had good browning, weight loss and metabolic activity inhibition ability. These results showed that the PEM film is a good candidate as edible film in fresh-cut fruits applications. PMID- 29442932 TI - Preparation of Graphene Oxide/Poly(1-vinylimidazole) Composites for Resistive Switching Memory. AB - In this study, a photochemical polymerization using graphene oxide (GO) as an initiator generated a new composite film with poly(1-vinylimidazole) (PVI) covered the GO sheets. Atomic force microscopy and infrared spectroscopy revealed the uniform layering of the PVI on the sheets. An ITO/GO-PVI/Cu device was fabricated from this synthesized film, and it exhibited a write-once-read-many times (WORM) memory functionality with resistance switching under an applied voltage of -3.2 V. The ON/OFF current ratio of the device reached 106. An analysis of the current-voltage characteristics of the device indicated that the ON-state charge transport followed Ohmic conduction with metallic behavior, while the OFF-state charge transport was dominated by a trap-limited space charge limited conduction. PMID- 29442933 TI - Flower-Shaped Mg3Al1-xFex-CO3 Layered Double Hydroxides Derived Adsorbents with Tunable Memory Effect for Environmental Remediation. AB - Herein, flower-shaped ternary layered double hydroxides (LDHs) Mg3Al1-xFex-CO3 with tunable memory effect as promising adsorbents was developed for the removal of acid red 88 anionic dye. All the samples were prepared using a co precipitation method and were thoroughly characterized using several analytical techniques. The influence of Fe/(Al + Fe) ratio on the memory effect and dye adsorption capacity of Mg3Al1-xFex-CO3 LDHs was evaluated. Among all samples, Mg3Fe0.1Al0.9CO3 LDH resulted in the best adsorption capacity of 2709 mg/g in the first cycle. Comparing to Mg3Al1-CO3 and Mg3Fe1-CO3 LDHs, it also showed much better cycling performance during 4 cycles at 30 degrees C and atmospheric pressure. The influence of regeneration temperature was also investigated and found that 400 degrees C exhibit best performance. The detailed studies demonstrated that the adsorption capacity of Mg3Al1-CO3 can be improved by partially replacing Al by Fe. PMID- 29442934 TI - A Facile Strategy to Prepare Zr4+-Modified Bi2WO6 with Enhanced Visible-Light Photocatalytic Activities. AB - A series of Zr4+-modified Bi2WO6 photocatalysts were synthesized using a hydrothermal method employing Bi(NO3)3.5H2O, Na2WO4.2H2O and Zr(NO3)4 as precursors. The samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), UV-vis absorption spectroscopy (UV-vis) and photoluminescence spectroscopy (PL). The investigations indicated that the flower-like Bi2WO6 3D structures were constructed from a large number of 2D layers of interconnected nanoplates. The energy gaps of Zr4+-modified Bi2WO6 decreased compared with that of pure Bi2WO6. In addition, fluorescence quenching was observed because the recombination of charge carriers was effectively suppressed by Zr4+. The photocatalytic properties of samples were evaluated by the degradation of Rhodamine B (RhB) solution under visible-light irradiation. The results indicate that the 1.0 mol% Zr4+-modified Bi2WO6 possesses obviously enhanced photocatalytic activity, showing the great potential for wastewater purification. In addition, a tentative photocatalytic mechanism is proposed to understand the experimental results over the Zr4+ modified Bi2WO6 photocatalysts. PMID- 29442935 TI - Controlled Hydrothermal Synthesis, Optical and Magnetic Properties of Monodisperse Leaf-Like CeO2 Nanosheets. AB - The monodisperse leaf-like CeO2 nanosheets of about 40 nm in thickness have been successfully synthesized by a simple hydrothermal route. SEM, XRD, FT-IR, TG-DSC, XPS, Raman scattering, Photoluminescence (PL) spectra and M-H curves were employed to characterize the samples. The results showed that all the CeO2 samples had a cubic fluorite structure and there are Ce3+ ions and oxygen vacancies in the surface of samples. Based on the SEM patterns, a clear morphology transformation from leaf-like to heart-shaped, and then to triangular prism-like structure was observed. The magnetic and photoluminescence measurements displayed that all the samples have excellent ferromagnetism and optical properties at room temperature and the ferromagnetism and optical properties increase along with the rise of NH4HCO3 concentration, which can be reasonably explained for the affects of the morphology of samples, the concentration of oxygen vacancies and Ce3+ ions. PMID- 29442936 TI - Facile Synthesis and Lithium Storage Properties of Zn1-xCoxCO3 Microspheres. AB - Zn1-xCoxCO3 (ZCCO) microspheres were synthesized by a modified solvothermal method (ball milling-solvothermal combination method) using ZnCl2, CoCl2, and NH4HCO3 as raw materials. All samples were characterized by X-ray diffractometer (XRD), Fourier transform infrared spectra (FT-IR), and Scanning electron microscopy (SEM) technique. The results showed the introduction of Co and molar ratio of Zn and Co play crucial roles in the morphology and electrochemical performance of the ZCCO. As anode materials for lithium ion battery (LIB), all ZCCO electrodes possess high specific capacities and good cycle performance. The as-obtained Zn0.5Co0.5CO3 electrode exhibits higher discharge capacity (1526 mAh/g) and better rate properties with the reversible capacity of 976 mAh/g after 100 cycles when the molar ratio of Zn/Co is 1:1. Moreover, the present work provides a new and simple approach to the fabrication of novel anode materials (transition metal carbonates) for LIB applications. PMID- 29442937 TI - Effect of Fenton Oxidation Performance and Kinetics with Different Morphologies of alpha-Fe2O3 Nanocrystals. AB - Different morphologies hematite (alpha-Fe2O3) nanocrystals were synthesized by hydrothermal process and subsequent calcination treatment. The crystal structure and shape of the products were confirmed by X-ray diffraction (XRD) and transmission electron microscopy (TEM). Fenton oxidation degradation of Congo red (CR) was carried out with alpha-Fe2O3 nanocrystals with different morphologies to compare their catalytic performance. The result shows that CR can be degraded above 90% after 2 h by using alpha-Fe2O3 nanorods. In addition, degradation efficiencies of alpha-Fe2O3 nanocrystals with different morphologies towards CR were also investigated. It reveals that alpha-Fe2O3 nanorods with exposed {210} and {001} planes exhibited superior Fenton oxidation performance to that of nanoparticles. It is traceable to the higher density of Fe3+ exposed on the {210} and {001} planes of nanorods than that of other morphologies crystals. The mechanism of Fenton oxidation and kinetics analysis were extensively studied. PMID- 29442938 TI - Preparation of Octadecylamine-Graphene/MgCl2-Supported Ziegler-Natta Catalyst and Its Application in Ethylene Polymerization. AB - A facile coagglomeration method for preparing a long alkyl chain modified graphene oxide (MGO)/MgCl2-supported Ti-based Ziegler-Natta catalyst was reported. The effects of MGO on the catalyst morphology and activity for ethylene polymerization were examined. The resultant polyethylene (PE)/MGO nanocomposites exhibited a layered morphology, with the MGO fillers being well dispersed and exhibiting strong interfacial adhesion to the PE matrix. The thermal stability and mechanical properties of the PE were significantly enhanced with the introduction of a small amount of the MGO filler. Thus, this work provides a facile approach to the production of high-performance PE. PMID- 29442939 TI - Photo-Induced Multiple-State Memory Behaviour in Non-Volatile Bipolar Resistive Switching Devices. AB - The recent discovery of non-volatile resistive-switching memory is a promising phenomenon for the semiconductor industry and electronic device technology. In our work, CaWO4 nanoparticles were synthesised through a one-step hydrothermal reaction. A resistive-switching memory device with Ag/CaWO4/fluorine-doped tin oxide structure was prepared. This device presents photo-induced multiple-state memory behaviour at room temperature. This study is valuable for exploring multi functional materials and their applications in photo-controlled multiple-state non-volatile memories. PMID- 29442940 TI - MD Simulation on Collision Behavior Between Nano-Scale TiO2 Particles During Vacuum Cold Spraying. AB - Particle collision behavior influences significantly inter-nano particle bonding formation during the nano-ceramic coating deposition by vacuum cold spraying (or aerosol deposition method). In order to illuminate the collision behavior between nano-scale ceramic particles, molecular dynamic simulation was applied to explore impact process between nano-scale TiO2 particles through controlling impact velocities. Results show that the recoil efficiency of the nano-scale TiO2 particle is decreased with the increase of the impact velocity. Nano-scale TiO2 particle exhibits localized plastic deformation during collision at low velocities, while it is intensively deformed by collision at high velocities. This intensive deformation promotes the nano-particle adhesion rather than rebounding off. A relationship between the adhesion energy and the rebound energy is established for the bonding formation of the nano-scale TiO2 particle. The adhesion energy required to the bonding formation between nano-scale ceramic particles can be produced by high velocity collision. PMID- 29442941 TI - Adsorption Kinetics and Adsorption Isotherm of Methylene Blue on Magnetic 0.9NiFe2O4/0.1SiO2 Nanocomposites Prepared via a Rapid Combustion Process. AB - Magnetic 0.9NiFe2O4/0.1SiO2 nanocomposites were successfully prepared via a rapid combustion process, and the morphology and magnetic properties of them were investigated by TEM, XRD, VSM, and BET techniques. The magnetic 0.9NiFe2O4/0.1SiO2 nanocomposites calcined at 400 degrees C for 2 h with absolute alcohol of 20 mL were characterized with the average particle size of about 28 nm and the specific magnetization of 192.0 Am2/kg. The magnetic 0.9NiFe2O4/0.1SiO2 nanocomposites were employed to remove methylene blue (MB) from aqueous solutions, the adsorption kinetics and adsorption isotherm of MB onto 0.9NiFe2O4/0.1SiO2 nanocomposites at room temperature were investigated, and the regression equations were found in good agreement with the pseudo-second order model in the initial MB concentrations of 100-600 mg/L; the adsorption equilibrium data of MB onto 0.9NiFe2O4/0.1SiO2 nanocomposites at room temperature were analyzed with Langmuir, Freundlich and Redlich-Peterson models, and the adsorption isotherm was most effectively described by the Redlich-Peterson model based on the value of the correlation coefficient (0.9810). PMID- 29442942 TI - Tailoring Catalytic Properties of Pd/Co3O4 Catalysts via Structure Engineering for Methane Oxidation. AB - The catalytic behavior of Co3O4 catalysts loaded by Pd for methane oxidation can be tailored by distinct spatial architectures and surface structures of such catalysts. Pd nanoparticles nested in Co3O4 with hexagonal-like microflakes exhibited superior catalytic activity, that is, T10 = 250 degrees C and T90 = 325 degrees C are correlated to 10% and 90% conversion of methane. Further Pd/Co3O4 microflakes catalyst can almost restore to its initial value in the absence of water when water vapor was cut off. This excellent catalysis should be attributed to its exposed more open surface, more active oxygen species and stronger redox properties. PMID- 29442943 TI - Ultrasensitive Detection of Protein Based on Graphene Quantum Dots with Resonance Light Scattering Technique. AB - In this paper, a simple, label-free and ultrasensitive resonance light scattering (RLS) method for ultratrace protein detection was investigated using graphene quantum dots (GQDs) as probes. Due to the electrostatic interaction between GQDs and protein, the RLS intensity was gradually enhanced as the protein was added into the GQDs solution. Through a series of optimization experiments, the optimal detection conditions of the GQDs solution were as follows: pH = 7.4, 2 M ion concentration and 60 MUM GQDs. Under the optimized conditions, the linear correlation between the GQDs and the concentration of protein was observed from 10 MUM to 60 MUM with the correlation coefficient (R2) of 0.9978, and the limit of detection (LOD) was 2.4 MUM. Time-resolved fluorescence spectrum showed that the electron transition channel was not affected by the protein self-assembled on the surface of GQDs, which indicated that the interaction between GQDs and protein was mainly the electrostatic interaction. The proposed method revealed that the RLS enhancement effect from the self-assembled GQDs-protein hybrid nano system provided a green and simple method to establish ultrasensitive biosensors. PMID- 29442944 TI - Photoluminescence Quenching Based Visual and Spectroscopic Method for Mercury Sensing by Surface-Modified Cadmium Sulphide Quantum Dots. AB - Here we present a simple yet efficient analytical method for sensing ultratrace levels of Hg2+ ions by highly water soluble CdS quantum dots functionalized with thiourea as a probe. The bluish photoluminescence emission of the probe responded to a systematic linear photoluminescence quenching in the presence of increasing concentration of Hg2+ ions. The photoluminescence quenching by Hg2+ ions was attributed to agglomeration of the quantum dots, which has been confirmed by zeta potential measurements. The sensitivity (31.38 L/mg) and LoD (0.11 MUg/L) of Hg2+ ion detection by our method are two folds improved with respect to the existing data of CdS as sensor. The improved detection is attributable to synthesis of less than 3 nm diameter CdS quantum dots which rendered very high water solubility and hence facilitated better interaction with Hg2+ ions. The detection of Hg2+ ion was free from most interfering cations and anions, except for minor interference from Cu2+ and Pb2+ corresponding their concentrations expected in ground water. Further, the scope for visual detection of Hg2+ was explored, which revealed naked eye recognizable photoluminescence quenching of the probe treated 0.3 mg/L of Hg2+ ion when excited by a light source of 365 nm. The suitability of our probe to analyze Hg2+ in real samples has been demonstrated by Hg2+ spike analysis in groundwater and river water samples. PMID- 29442945 TI - Synthesis and Characterization of Controlled Size CdSe Quantum Dots by Colloidal Method. AB - Monodispersed and highly luminescence cadmium selenide (CdSe) quantum dots (QDs) have been prepared in a single pot by colloidal reaction method. The QDs were characterized using X-ray diffraction (XRD), Raman Spectroscopy, transmission electron microscope (TEM), energy dispersive spectroscopy (EDS), UV-visible absorption spectroscopy and photoluminescence (PL) spectroscopy to study the structural, morphological, compositional and optical properties. The growth temperature played an important role to control the particle size. The optical wavelength was found to be shifted systematically from 460 nm to 575 nm upon increasing the reaction temperature from 110 degrees C to 260 degrees C. The size of CdSe QDs, ~2-4 nm was estimated from absorption data. The emission tail exhibited at higher wavelength in PL measurement for the QDs synthesized for lower reaction temperature revealed the presence of surface trap-states. A cubic crystal structure of CdSe QDs was revealed by XRD analysis. The spherical QDs of size 2 to 4.5 nm were observed from TEM analysis for the samples prepared at 140 degrees C, 200 degrees C and 260 degrees C. The sizes of QDs obtained by TEM are in good agreement with the results obtained from optical and XRD data. High resolution transmission electron microscopy (HRTEM) confirmed the cubic crystal structure of CdSe QDs. The Selected area diffraction (SAD) pattern exhibited diffused ring corresponds to (111), (220) and (311) reflections of cubic structure of CdSe. The compositional analysis studied by EDS revealed the growth of nearly stoichiometric CdSe QDs. The LO1 vibrational mode observed about 202 205 cm-1 decreases the broadening systematically upon increasing the reaction temperature. PMID- 29442946 TI - Organic Photovoltaic Devices Based on Oriented n-Type Molecular Films Deposited on Oriented Polythiophene Films. AB - The molecular orientation of pi-conjugated molecules has been reported to significantly affect the performance of organic photovoltaic devices (OPVs) based on molecular films. Hence, the control of molecular orientation is a key issue toward the improvement of OPV performance. In this research, oriented thin films of an n-type molecule, 3,4,9,10-Perylenetetracarboxylic Bisbenzimida-zole (PTCBI), were formed by deposition on in-plane oriented polythiophene (PT) films. Orientation of the PTCBI films was evaluated by polarized UV-vis spectroscopy and 2D-Grazing incidence X-ray diffraction. Results indicated that PTCBI molecules on PT film exhibit nearly edge-on and in-plane orientation (with molecular long axis along the substrate), whereas PTCBI molecules without PT film exhibit neither. OPVs composed of PTCBI molecular film with and without PT were fabricated and evaluated for correlation of orientation with performance. The OPVs composed of PTCBI film with PT showed higher power conversion efficiency (PCE) than that of film without PT. The experiment indicated that in-plane orientation of PTCBI molecules absorbs incident light more efficiently, leading to increase in PCE. PMID- 29442947 TI - Control of Microstructure and Magnetic Properties of FePt Thin Films with TiN-MgO Intermediate Layer. AB - The effects of TiN-MgO intermediate layer on the microstructure and magnetic properties of FePt-SiNx-C films were investigated. With doping MgO into TiN, three components were formed, including titanium dioxide, titanium nitride and titanium oxynitride. This caused the decrease of the surface energy and the increase of the interface energy, and further induced the promotion of island growth of FePt, thus the improvement of the isolation and the decrease of FePt grains. On the other hand, the decrease of surface energy and the forming of some titanium dioxide with doping MgO would accompany the deterioration of epitaxial growth and thus the deterioration of the perpendicular magnetic anisotropy of FePt films in a certain degree. By optimizing the concentration of TiN and MgO, the FePt-SiNx-C films with small grain size of 5.86+/-1.03 nm and good perpendicular anisotropy would be obtained. PMID- 29442948 TI - Investigation on Low Firing Copper for Front Electrode of Si-Based Solar Cell Applications. AB - Solar cell is one of the most popular alternative energies. The aim of this study is to construct an ohmic contact between front electrode and Si-based solar cell by a Newly-invented low-cost paste and low temperature sintering process. The core-shell of CucoreAgshell powders were prepared for making high solid content paste, then screen printing the fine line on laser-opening H-pattern silicon substrate and applying firing process. Because the silver coverage is more than 95% and silver nanoparticles start to melt at 200 degrees C. The shell of nanoparticles of silver not only is used to prevent copper from oxidized, but also connected core Cu particles for enhancing the conductivity of CucoreAgshell. TEM, EDS, SEM were used to examine the microstructure of CucoreAgshell. Fourpoint probe and transmission line model were employed to analyze the sheet resistance and the specific contact resistance. The lowest specific contact resistivity is 0.005 Omegacm2, sheet resistance is 0.0138 Omega/ and the lowest resistivity of front electrode measured is 2.65 * 10-5 Omegacm when CucoreAgshell paste with 94 wt% solid content was fired at 550 degrees C. PMID- 29442949 TI - Cu Nanoparticles Improved Thermal Property of Form-Stable Phase Change Materials Made with Carbon Nanofibers and LA-MA-SA Eutectic Mixture. AB - A novel form-stable phase change materials (FSPCMs) was fabricated by incorporating fatty acid eutectics with electrospun carbon nanofibers (CNFs) surface-attached with copper (Cu) nanoparticles. Three different Cu/CNFs mats were made through combining the technique and principle of electrospinning, pre oxidation/carbonization and in-situ reduction, while lauric-myristic-stearic acid (LA-MA-SA) ternary eutectic mixture was prepared as the model PCM. The morphology and crystal structure of Cu/CNFs were characterized by Fourier transfer infrared (FT-IR) spectra, Scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray energy dispersive spectroscopy (EDS), respectively. The results showed that Cu nanoparticles dispersed uniformly on the surface of CNFs mats without agglomeration, and Cu/CNFs mats could provide the mechanical support for FSPCMs and effectively prevent the flow/leakage of molten fatty acid. Morphological structures, as well as the properties of thermal energy storage and thermal energy storage/retrieval rates, of the resulting FSPCMs were investigated by SEM, Differential scanning calorimetry (DSC), and measurement of melting/freezing times, respectively. The results indicated that the fabricated FSPCMs exhibited desired structural morphology, and LA-MA-SA well dispersed in three-dimensional porous structure of Cu/CNFs mats. The melting and crystallization enthalpies of the fabricated FSPCMs were in the range of 117.1-140.7 kJ/kg and 117.2-142.4 kJ/kg, respectively. In comparison with melting/freezing times of LA-MA-SA ternary eutectic mixture, the melting/freezing times of fabricated FSPCMs were respectively decreased ~27.0-49.2% and ~44.1-63.0%. The fabricated FSPCMs possessed good thermal energy storage/retrieval property, and might have great potential for renewable energy storage applications. PMID- 29442950 TI - Flexible and Compressible Temperature Sensors Based on Hierarchically Buckled Carbon Nanotube/Rubber Bi-Sheath-Core Fibers. AB - Flexible and compressible temperature sensors are highly desired for artificial skin and epidermal electronics. Here we demonstrated a flexible and compressible resistive temperature sensor using hierarchically buckled carbon nanotube/rubber bi-sheath-core structure (a buckled carbon nanotube outer sheath and a buckled rubber inner sheath wrapped around a rubber fiber core). When heated, lateral contacts of the adjacent buckles increase, resulting in electrical resistance decrease and serving as highly sensitive temperature sensors. This bi-sheath-core fiber temperature sensor showed high linearity, good repeatability, large negative temperature coefficient of resistance (NTC = -54.7/ degrees C), and insensitivity to compressive deformations (up to -20% strain). The NTC and temperature dependence of percent resistance change can be easily tuned by modulating the buckling bi-sheath-core structures such as varying the number of nanotube layers and the rubber sheath stiffness. PMID- 29442951 TI - Fabrication and Photocatalytic Activity of Tunable Triangular- and Circular-Like Ag/AgCl Nanoplates. AB - Triangular- and circular-like Ag/AgCl nanoplates with various edge length and thickness have been successfully synthesized by a facile in situ oxidation process. Uniform Ag triangular nanoplates with tunable sizes and thicknesses obtained by adjusting the adding amounts of trisodium citrate and polyvinylpyrrolidone (PVP) were employed as Ag precursors to form triangular- and circular-like Ag/AgCl heterostructures by changing the adding amounts of FeCl3 in the reaction process. The morphological evolution mechanism of Ag nanoplates and Ag/AgCl heterostructures was discussed. It is clear that the morphologies of Ag/AgCl products can be gradually converted from the large and thick triangular like nanoplates into the small and thin circular-like ones as the AgCl ratio increasing from 5 to 100%, which can be mainly assigned to the synergistic effect of the oxidation of Fe3+ and the etching action of Cl-. The photocatalytic results indicate that Ag/AgCl nanoplates with different ratios of AgCl can exhibit good photocatalytic activity for degradation of methyl orange (MO) pollutant under ultraviolet-light-driven (UVD) and visible-light-driven (VLD) irradiation, respectively. The Ag/AgCl nanoplates with an AgCl ratio of 30% have the superior photocatalytic activity with the photocatalytic efficiency calculated to be 83.5% within 160 min under UVD irradiation and 53.6% within 240 min under VLD irradiation, respectively, owing to the combination of the favorable crystallinity, excellent photoabsorption, and the efficient separation of the photo-induced carriers between Ag and AgCl. PMID- 29442952 TI - Dipolar Interaction and Magneto-Viscoelasticity in Nanomagnetic Fluid. AB - We investigate the effect of dilution on dipolar interaction with linear and non linear rheological properties of kerosene based magnetic fluid. The steady-state behavior demonstrate a shear thinning behavior and corroborated with a power law, (eta = c gamma n + etainfinity) exponent, n <= 1. The shear-induced-breakup (separation) of nanoparticles and the yielding behavior has been explained by Bingham model. Moreover, the magnetoviscous effect showed an initial increase at low shear rate and decrease at higher shear rate. Further, specific viscosity (etaF)-versus-Mason number (Mn) shows a perfect scaling at lower Mn (<=10-4) confirming negligible thermal and colloidal forces. Whereas, at higher Mn (>=10-3) deviation from collapse indicates the dominance of Brownian forces acting on nanofluids. The magnetic field dependent elastic (G') and viscous (G") modulus reveal a crossover from viscoelastic-to-viscous behavior of nanofluid at critical concentration. Finally, we compare viscoelastic results with De Gans diagonal scaling theory to correlate the functional dependence of storage and loss modules with different particle volume concentration. PMID- 29442953 TI - Fabrication and Evaluation of Aluminum Laminated Film for a Pouch-Type Secondary Battery. AB - In this study, we intend to find the laminate condition for improvement of the chemical resistance of the aluminum pouch film widely used as the coating material of the secondary battery. Here, we investigated the properties including the initial adhesive strength and electrolyte resistance between the metal film layer aluminum and the sealant layer cast polypropylene (CPP) film. As for the laminating condition, we changed the temperature and line speed and maintained the identical pressure conditions. A roll-to-roll dry laminate coating system was used in surface treatment agent coating, adhesive coating, and film laminate. As for the laminate condition of the surface treated aluminum and CPP film, the initial adhesive strength of the laminated pouch film manufactured with 110 degrees C temperature and 30 m/min line speed was 1300 gf/15 mm. The adhesive strength of the 85 degrees C electrolyte resistance measured after being immersed for 7 days was found to be 800 gf/15 mm. The initial adhesive strength of CPP film laminated to aluminum without surface treatment showed 900 gf/15 mm and decreased sharply to 150 gf/15 mm in the electrolyte at 85 degrees C after an hour. The initial adhesive strength and electrolyte resistance of the aluminum and CPP were measured by using the universal testing machine. PMID- 29442954 TI - NiFe2O4 Nanofibers: Morphology, Lithium Storage and Photocatalytic Properties. AB - One dimensional (1D) NiFe2O4 nanofibers have been successfully fabricated using single-nozzle electrospinning technique and subsequent calcination process through adjusting heat-treatment parameters. The calcination procedure plays a key role for the formation of nanofibers with different morphologies. The lithium storage properties of NiFe2O4 nanofibers were evaluated by galvanostatic cycling studies in half-cell configuration. Furthermore, their photocatalytic property under vis-light irradiation with H2O2 addition is investigated at room temperature. As-synthesized nanofibers with regular 1D nanostructure with large surface area and high crystallinity calcined at 600 degrees C exhibited fine lithium storage with excellent cycling and rate performance, as well as excellent photocatalytic performance with 97% degradation proportion of methylene blue after 30 min. This is ascribed to NiFe2O4 absorbed the photon energy and generated electron-hole pairs under vis-light irradiation. PMID- 29442955 TI - Generation of Elliptically Polarized Terahertz Waves from Antiferromagnetic Sandwiched Structure. AB - The generation of elliptically polarized electromagnetic wave of an antiferromagnetic (AF)/dielectric sandwiched structure in the terahertz range is studied. The frequency and external magnetic field can change the AF optical response, resulting in the generation of elliptical polarization. An especially useful geometry with high levels of the generation of elliptical polarization is found in the case where an incident electromagnetic wave perpendicularly illuminates the sandwiched structure, the AF anisotropy axis is vertical to the wave-vector and the external magnetic field is pointed along the wave-vector. In numerical calculations, the AF layer is FeF2 and the dielectric layers are ZnF2. Although the effect originates from the AF layer, it can be also influenced by the sandwiched structure. We found that the ZnF2/FeF2/ZnF2 structure possesses optimal rotation of the principal axis and ellipticity, which can reach up to about thrice that of a single FeF2 layer. PMID- 29442956 TI - Facile Synthesis of Mesoporous MnCO3 for Supercapacitor Applications. AB - We report a rapid and facile synthesis of MnCO3 with uniform mesopores for supercapacitor applications. Mesoporous MnCO3 was synthesised by a co precipitation method using MnSO4 and (NH4)HCO3 as manganese and carbonate source, respectively. Powder X-ray diffraction study confirmed the formation of rhodochrosite phase of MnCO3. X-ray photoelectron spectroscopic study ascertained the oxidation state of Mn as 2+ in MnCO3. Scanning and Transmission electron microscopic studies revealed that nanograins of size less than 10 nm agglomerated into submicron sized spherical particles of MnCO3. N2 sorption studies displayed a typical type-IV isotherm with H2 hysteresis, demonstrating mesoporosity of as prepared MnCO3. Furthermore, the mesoporous MnCO3 particles were evaluated for their capacitance properties by cyclic voltammetry and galvanostatic charge discharge cycling in aqueous 0.1 M Mg(ClO4)2 electrolyte. The fabricated mesoporous MnCO3 electrodes delivered a specific capacitance of 144 F g-1 at a current density of 0.34 A g-1. It also exhibited good rate capability, high reversibility and cyclic stability over 1000 cycles. PMID- 29442957 TI - Pt-TiO2 Nanocomposites as Catalysts for Proton Exchange Membrane Fuel Cell: Prominent Effects of Synthesis Medium pH. AB - Pt-TiO2 nanocomposite catalysts in different Pt:Ti atomic ratios (1:1, 2:1 and 3:1) were synthesized in acidic (pH < 3) and basic (pH >10) medium for oxygen reduction reaction of proton exchange membrane fuel cells. The pH of synthesis medium significantly affected both physicochemical and catalytic properties of Pt TiO2. Pt-TiO2 prepared in acidic medium exhibited smaller crystallite size, higher specific surface area and more non-stoichiometric titania with higher electrical conductivity as compared to that prepared in basic medium. The oxygen reduction reaction performance from fuel cell polarization curves showed that, Pt TiO2 catalysts synthesized in acidic medium performed better than those prepared in basic medium. Among the catalysts with varying Pt:Ti atomic ratios, performance decreased in the order 3:1 > 2:1 > 1:1. Among all, Pt:Ti 3:1-A was found to exhibit better fuel cell performance as ORR catalyst (power density-530 mWcm-2; mass activity-123 mAmg-1Pt) compared to commercial Pt/C catalyst (power density-440 mWcm-2; mass activity-87 mAmg-1Pt), under identical conditions. The favourable conditions of synthesis of Pt-TiO2 catalyst achieved in acidic medium contribute to its enhanced properties. PMID- 29442958 TI - Chemical Preparation of Bimetallic Fe/Ag Core/Shell Composite Nanoparticles. AB - Bimetallic iron/silver (Fe/Ag) core/shell nanoparticles were prepared by chemical reduction from ferrous sulfate in the presence of sodium borohydride as a reducing agent in water, followed then by redox transmetalation with addition of silver nitrate (AgNO3) solution. When the reduction temperature was increased from room temperature to 85 degrees C, Fe nanoparticles with a reduced crystallite size ranging from 5.5 to 2.0 nm resulted. The particles changed from spherical to plate-like morphology as the temperature reached 85 degrees C. Addition of trisodium citrate was able to protect the precipitated Fe nanoparticles from oxidation; nonetheless, the citrate would facilitate chelation of the Fe clusters so that dense Fe aggregates with a mean diameter greater than 100 nm were found as the concentration of trisodium citrate exceeded 3.33 mM. A continuous Ag film was formed on the Fe surface by the redox transmetalation. This Ag film became a raspberry structure involving preferential deposition of particulate Ag on the Fe particles when the AgNO3 concentration exceeded 76.9 mM. Magnetic saturation was found to reduce with the increasing Ag concentration in the bimetallic composite nanoparticles. PMID- 29442959 TI - Relation Between Crystal Structure and Electrochemical Performance of LiNi1/3ZnxCo1/3-xMn1/3O2 (0.000 <= x <= 0.133). AB - LiNi1/3ZnxCo1/3-xMn1/3O2 (0.000 <= x <= 0.133) hollow microspheres are synthesized using MnO2 hollow microspheres both as a self-template and Mn source. These hollow microspheres, ~4 MUm in diameter, are composed of approximately 300 nm basic nanoparticles. The XRD patterns of LiNi1/3ZnxCo1/3-xMn1/3O2 were analyzed by the RIETAN-FP program, and the obtained samples have a layered alpha NaFeO2 structure. Electrochemical performances of the samples were carried out between 2.5 V and 4.5 V. The behavior of the lattice parameters is consistent with Cycling performance and rate performance change with increase of x. Compared with the others, the sample of x = 0.133 exhibits a relatively superior electrochemical performance. The specific capacity of x = 0.133 was increased by 10.7% than no-doped. In addition, the cyclic voltammograms curves of the second cycle show no significant alteration compared with the first cycle and the electrochemical impedance of zinc doping sample showed smaller transfer resistance than the no-doping sample. PMID- 29442960 TI - Morphological and Near-Field Properties of Silver Columnar Thin Film for Surface Enhanced Raman Scattering. AB - Noble metal sculptured thin films have attracted great research interest last decade as competitive surface-enhanced Raman scattering (SERS) substrates. However, the influences of the deposition conditions and the morphology on the plasmonic properties and SERS performance of the metal sculptured thin films have not been well understood due to the complexities of the morphology. In this work, the influences of the deposition angle and the height are investigated in both experiment and numerical simulation. A more accurate geometrical model based on the binarized scanning electron microscope images has been utilized to study the near-field plasmonic properties of Ag column thin films by taking account of the geometry irregularities, size distributions and random arrangement of the columns. It's found that the cross-sectional electric field enhancement is mainly dominated by the column density. When the deposition angle increases from 68 degrees to 82 degrees the SERS enhancement factors increases monotonously due to the increase of the self-shadow effect. While with the increase of height the SERS enhancement factors firstly increase to the largest value of 3.05 * 108 at the thickness of 694 nm then decrease because of competitive growth mechanism during the deposition. The detection limit of the optimized sample is found to be lower than 10-12 M. Our work could be helpful in understanding the SERS mechanism and useful to the optimization of metal sculptured thin films as SERS substrates. PMID- 29442961 TI - New Green Hydrogels Based on Lignin. AB - The development of various green materials from lignin, which is most often considered as waste, is of prime interest from environmental and economic points of view. In the last years, only few studies regarding the use of lignin as a backbone component in the hydrogels have been made. The potential efficacy of lignin in hydrogels with particular emphasis on synthesis and characterization was investigated. By using steam explosion lignin from aspen wood or the corresponding epoxy-resin mixed with poly(vinyl alcohol), a series of new green hydrogels were prepared by covalent crosslinking in the presence of the epichlorohydrin. The unmodified and modified lignins were characterized by determination of functional groups content (OHT, OHph, OCH3 and epoxy groups), average particle size and zeta potential. The intermolecular interactions between lignin and poly(vinyl alcohol) was evaluated by Fourier transform infrared spectroscopy (FTIR), when the achievement of the cross-linking reaction was proved. The structural features of lignin-based hydrogels were revealed by X-ray diffraction (XRD) analysis. The scanning electron microscopy (SEM) images showed the porous nature of the hydrogels and that the pore size increase with increasing the lignin content. The yield in hydrogel showed a dependence on the structure of the lignins. In addition, it has been established that the lignin nature significantly influences the swelling process of hydrogels. PMID- 29442962 TI - Effect of (Ti, Al)N Nanostructured Arc-Coatings on Wear and Corrosion Properties of 4340 Alloy Steel. AB - This study utilized cathodic arc deposition technology to coat Ti-Al-N hard films on AISI 4340 alloy steel. Composition, morphology, and structure of the coatings were analyzed using EPMA, FESEM, XRD, and TEM. Both wear tests and polarization tests were conducted to determine the abrasion and corrosion properties of the steel before and after coating. The results showed that a specific (Ti, Al)N nanostructured multilayer was synthesized smoothly. The multilayer consisted of 10 nm-TiN and 15 nm-TiAlN interaction layers. The coating not only greatly reduced the friction coefficient of AISI 4340 alloy steel from 0.81 to 0.45, but also provided an effective improvement in corrosion resistance. PMID- 29442963 TI - Improvement of Mechanical and Dielectric Properties of Epoxy Resin Using CNTs/ZnO Nanocomposite. AB - In this study, carbon nanotubes (CNTs)/ZnO composites had been prepared using the sol-gel method and then incorporated into an epoxy resin for reinforcement of mechanical and electrical properties. Fourier Transform Infrared (FTIR), X-ray diffraction (XRD) Field Emission Scanning Electron Microscope (FE-SEM) analyses show that the ZnO nanoparticles deposited on CNTs were crystallized in a hexagonal wurtzite structure. Average particle size of ZnO deposited on the CNT was about 8 nm. The mechanical and dielectric properties of epoxy containing CNTs/ZnO were investigated in comparison to epoxy resin and epoxy resin containing only CNT or ZnO nanoparticles. The results indicated that tensile strength and elongation at break of the nanocomposite were substantially improved with the presence of CNTs/ZnO at the equal volume. The DSC analysis associate with the dielectric results shows that the behavior of epoxy/CNTs/ZnO is identical to epoxy/ZnO composite, and the CNTs is essential to the distributed arrangement of ZnO in the epoxy resin. PMID- 29442964 TI - Optimization of Citrate-Gel Preparation Process for Magnetic Ni-Zn Ferrite Nanoparticles. AB - Magnetic Ni-Zn ferrite nanoparticles were prepared via the citrate-gel process, their microstructure and the properties were characterized by XRD, VSM, SEM, and TEM techniques. For smaller grain size and larger specific saturation magnetization, the preparation technology for magnetic Ni-Zn ferrite nanoparticles was optimized, and the optimization conditions followed as: the molar ratio of Ni, Zn and Fe was 1:1:4, citric acid was applied according to the mole ratio of 1:1 for citric acid and metal, the solvent of 100 mL was the mixed liquor of alcohol and water with volume ratio of 1:1, pH value was 1, reaction time was 24 h, the calcination temperature was 400 degrees C, and the heating rate was 3 degrees C/min. The average crystallite size of the as-prepared Ni0.5Zn0.5Fe2O4 nanoparticles calcined under the optimization conditions was around 14 nm, and the specific saturation magnetization was about 46 emu/g. PMID- 29442965 TI - Facile Passivation of Silicon Nanowires Array as Stable Photoanode in Aqueous Electrolytes. AB - We herein report a facile approach to passivate Si(100) nanowires (SiNWs) array by methylation and poly(3,4-ethylenedioxythiophene) (PEDOT) coating as stable photoanode in aqueous electrolytes. The photoanode was stable in both acid and base electrolytes. This facile approach deals with both the dangling bond and the anti-corrosion protection of SiNWs array. A combination of microstructural characterization, photoelectrochemical (PEC) measurements and electrochemical impedance spectroscopy (EIS) analysis were employed to confirm the methyl terminated SiNWs/PEDOT (CH3-SiNWs/PEDOT) array structure and the role of methylation in enhancing the photocurrent of SiNWs array photoanode. It was found that the methylation increased the donor concentration and significantly decreased the charge transfer impedance (Rct), which means that the methylation facilitates majority transport and collection, and thus may account for the PEC enhancement. PMID- 29442966 TI - Facile Synthesis and Down-Conversion Emission of RE3+-Doped Lutetium Oxide Nanoparticles. AB - Lu2O3:RE3+ (RE3+ = Eu3+, Tb3+, Ho3+) nanoparticles have been successfully synthesized by a facile homogeneous precipitation method with subsequent sintering process. The crystal structure, morphology and luminescence properties of the as-prepared samples have been characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA), photoluminescence (PL) and cathodoluminescence (CL) spectra. Upon ultraviolet (UV) and low-voltage electron beam excitation, Lu2O3:RE3+ (RE3+ = Eu3+, Tb3+, Ho3+) nanoparticles show strong red (Eu3+,5D0 -> 7F2), green (Tb3+,5D4 -> 7F5), and green (Ho3+,5S2 -> 5I8) emissions. They exhibit a good advantage of multicolor emissions in the visible region, and endow these kinds of materials with potential application in many fields, such as light display systems, optoelectronic devices and biological imaging. PMID- 29442967 TI - 2D Effective Electron Mass at the Fermi Level in Accumulation and Inversion Layers of MOSFET Nano Devices. AB - In this paper an attempt is made to study the 2D Fermi Level Mass (FLM) in accumulation and inversion layers of nano MOSFET devices made of nonlinear optical, III-V, ternary, Quaternary, II-VI, IV-VI, Ge and stressed materials by formulating 2D carrier dispersion laws on the basis of k -> ? p -> ? formalism and considering the energy band constants of a particular material. It is observed taking accumulation and inversion layers of Cd3As2, CdGeAs2, InSb, Hg1-xCdxTe and In1-xGaxAsyP1-y lattice matched to InP, CdS, GaSb and Ge as examples that the FLM depends on sub band index for nano MOSFET devices made of Cd3As2 and CdGeAs2 materials which is the characteristic features such 2D systems. Besides, the FLM depends on the scattering potential in all the cases and the same mass changes with increasing surface electric field. The FLM exists in the band gap which is impossible without heavy doping. PMID- 29442968 TI - Adsorption Kinetics of Bovine Serum Albumin onto Ni0.5Zn0.5Fe2O4/SiO2 Nanocomposites Prepared via the Solution Combustion Process. AB - Magnetic Ni0.5Zn0.5Fe2O4/SiO2 nanocomposites were prepared via the solution combustion process, their structure and magnetic properties were investigated by XRD, SEM, TEM and VSM. The asprepared magnetic Ni0.5Zn0.5Fe2O4/SiO2 nanocomposites were characterized with the average grain size of about 20 nm, the specific magnetization of 31.6 Am2/kg, and the specific surface area of 117.0 m2/g. The adsorption kinetics of bovine serum albumin (BSA) from aqueous solution onto the magnetic Ni0.5Zn0.5Fe2O4/SiO2 nanocomposites at room temperature was investigated. The kinetics data related to the adsorption of BSA from aqueous solutions were in good agreement with the pseudo-second-order kinetics model in the initial concentrations of 0.2-0.8 mg/mL. PMID- 29442969 TI - Development of Antibacterial Composite Electrospun Chitosan-Coated Polypropylene Materials. AB - In this study, a natural antibacterial substance chitosan was coated with/without potassium sorbate (KS) (0.8% (w/w) of KS, 8% (w/v) chitosan) onto the polypropylene (PP) film by using electrospinning technique to obtain novel antibacterial composite materials for various applications such as wound dressing, tissue engineering, drug delivery and food packaging. Atmospheric pressure plasma surface treatment was applied onto polypropylene films in order to increase its wettability thus enhancing the adhesion capacity of the films and the optimum CA value was determined as 42.75 +/- 0.80 degrees . Scanning Electron Microscope (SEM) and X-ray Photoelectron Spectroscopy (XPS) analyses were realized to observe the morphological changes and chemical properties of the samples, respectively. Contact angle measurements, tensile testing, oxygen and water vapor transmission rate analyses were performed to obtain wettability values, mechanical properties and WVTRs, respectively. The WVTR was increased by plasma treatment and addition of KS (from 14.264 +/- 0.214% to 21.020 +/- 0.659%). The desired antibacterial performance of the samples was assessed with Staphylococcus aureus and Escherichia coli by inhibition ratio calculation and disc diffusion assay. The highest inhibition ratios were found as 64% for S. aureus and 92% for E. coli for plasma-treated CS-KS-PP films. PMID- 29442970 TI - Fabrication and Characterizations of Ethanol Sensor Based on CuO Nanoparticles. AB - In this paper, we report the synthesis, characterization and ethanol sensing applications of CuO nanoparticles. The CuO nanoparticles were prepared by a facile, low-temperature hydrothermal method and characterized in detail in terms of their structural, morphological, compositional and crystalline properties, through different characterization techniques including X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) attached with energy dispersive spectroscopy (EDS), and Fourier transform infrared (FTIR) spectroscopy. The detailed studies revealed that the synthesized CuO nanoparticles were well-crystalline and possessed monoclinic crystal structure. The synthesized CuO nanoparticles were utilized for the fabrication of highly sensitive ethanol gas sensor. At an optimized temperature of 320 degrees C, high sensitivity (Ra/Rg) of 39.29 was observed for 200 ppm of ethanol gas. Additionally, very low response (taures = 14 s) and recovery (taurec = 30 s) times were observed for 100 ppm of ethanol. PMID- 29442971 TI - Cobalt Salt as Efficient Dopant for Spiro-MeOTAD in Cesium-Containing Planar Perovskite Solar Cells. AB - The chemical doping is an effective strategy to improve the charge transport property of hole transport material (HTM). Herein, tris(2-(1H-pyrazol-1 yl)pyridine]cobalt(III) (FK102) doped 2,2,7,7-tetrakis(N, N-di-p methoxyphenylamine)-9,9-spirobifluorene (spiro-MeOTAD) as HTM for semi transparent cesium-containing planar perovskite solar cell (Cs0.1MA0.9PbI3) is demonstrated. Incorporating FK102 realizes efficient doping, which improves the mobility of HTM from 3.948 * 10-3 m2V-1s-1 to 2.22 * 10-2 m2V-1s-1, which is 5.6 times enhancement. As a result, the power conversion efficiency (PCE) is largely improved from 7.58% to 10.09% due to the improved hole transport and extraction. PMID- 29442972 TI - Effects of Grain Size and Twin Layer Thickness on Crack Initiation at Twin Boundaries. AB - A theoretical model to explore the effect on crack initiation of nanotwinned materials was proposed based on the accumulation of dislocations at twin boundaries. First, a critical cracking initiation condition was established considering the number of dislocations pill-up at TBs, grain size and twin layer thickness, and a semi-quantitative relationship between the crystallographic orientation and the stacking fault energy was built. In addition, the number of dislocations pill-up was described by introducing the theory of strain gradient. Based on this model, the effects of grain size and twin lamellae thickness on dislocation density and crack initiation at twin boundaries were also discussed. The simulation results demonstrated that the crack initiation resistance can be improved by decreasing the grain size and increasing the twin lamellae, which keeps in agreement with recent experimental findings reported in the literature. PMID- 29442973 TI - Junctionless Thin-Film Transistors Gated by an H3PO4-Incorporated Chitosan Proton Conductor. AB - We fabricated an H3PO4-incorporated chitosan proton conductor film that exhibited the electric double layer effect and showed a high specific capacitance of 4.42 MUF/cm2. Transparent indium tin oxide thin-film transistors gated by H3PO4 incorporated chitosan films were fabricated by sputtering through a shadow mask. The operating voltage was as low as 1.2 V because of the high specific capacitance of the H3PO4-incorporated chitosan dielectrics. The junctionless transparent indium tin oxide thin film transistors exhibited good performance, including an estimated current on/off ratio and field-effect mobility of 1.2 * 106 and 6.63 cm2V-1s-1, respectively. These low-voltage thin-film electric-double layer transistors gated by H3PO4-incorporated chitosan are promising for next generation battery-powered "see-through" portable sensors. PMID- 29442974 TI - Vinyl Functionalized Porous Silica Nanospheres Prepared by Poly(1-vinyl-2 pyrrolidone) Grafted Surface-Protected Selective Etching Strategy. AB - A new effective surface poly(1-vinyl-2-pyrrolidone) (PVP) grafted layer protected selective etching strategy has been used for preparing vinyl functionalized porous silica nanospheres (V-PSNSs). The main reaction mechanism was relied on the vinyl groups distributed on the surface of outer vinyl silica nanospheres (V SiO2) which can be polymerized with another vinyl monomer, such as 1-vinyl-2 pyrrolidone (VP), in the presence of initiator. It was observed from the research results that only grafting PVP on the surface of outer vinyl silica nanospheres (V-SiO2) can V-PSNSs be obtained, because grafting PVP was able to protect outer V-SiO2 from being etched prior to inner pure silica (sSiO2). In addition, effect of the amounts of sSiO2@V-SiO2 as another monomer substrate on the formation of PVP grafted sSiO2@V-SiO2 (sSiO2@V-SiO2/PVP) was discussed. The results showed that the less of the sSiO2@V-SiO2 amounts, the thinner of the PVP grafted layer on the surface of sSiO2@V-SiO2, the poorer protection ability of the surface. In the present study, V-PSNSs with 29 m2g-1 of BET surface areas and 0.1 cm3g-1 pore volumes were successfully synthesized by grafting 0.3 g of VP on the surface of 0.3 g of sSiO2@V-SiO2 and subsequent etching. PMID- 29442975 TI - Photocatalytic Degradation of Textile Reactive Dyes-A Comparative Study Using Nano Silver Decorated Titania-Silica Composite Photocatalysts. AB - Photocatalytic degradation of commercial textile azo dyes such as Reactive Red 120 (RR 120), Acid Orange 20 (AO 20), Reactive Orange 16 (RO 16) and Congo Red (CR) was studied under UV light and visible light irradiations of wave length 365 nm and 420 nm respectively over bare and modified titania catalysts such as TiO2, 1% Ag/TiO2, 30% TiO2/SiO2 and 1% Ag/30% TiO2/SiO2. On comparison of the catalytic activity of all the synthesized catalysts under UV and Visible irradiations, it was found that the composite catalysts showed higher photocatalytic activity than bare TiO2. Among the catalysts 1% Ag/30% TiO2/SiO2 composite catalyst was the best catalyst for the decolourization of the chosen dyes. Results obtained showed that the time taken for the complete decolourization of dyes was found to be significantly different for different dyes under both UV and visible light irradiations. Among the four dyes, AO 20 decolourised completely (100%) in 2 hrs, whereas Congo Red (CR) decolourised to the least extent (35%) over 1% Ag/30% TiO2/SiO2 under UV light irradiation. Experiments carried out under dark condition in the presence of catalyst revealed very high adsorption of CR (~60%) over titania catalysts and hence this could be reason for suppressed catalytic activity of 1% Ag/30% TiO2/SiO2. Various optimization studies such as effects of substrate concentration, weight of catalyst and substrate pH were carried out. TOC analysis revealed a very high mineralization of all the dyes. PMID- 29442977 TI - Low Temperature Synthesis of Cobalt-Chromium Carbide Nanoparticles-Doped Carbon Nanofibers. AB - Electrospinning has been used to synthesize cobalt-chromium carbide nanoparticles (NPs)-doped carbon nanofibers (CNFs) (Composite). Electrospun mat comprising of cobalt acetate, chromium acetate and poly(vinyl alcohol) (PVA) has been carbonized at low temperature (850 degrees C) for 3 h under argon atmosphere to produce the introduced composite. The process was achieved at low temperature due to the presence of cobalt as an activator. Field emission scanning electron microscope (FE-SEM), X-ray diffractometry (XRD), and transmission electron microscopy (TEM) equipped with EDX techniques were used to determine the products characteristics. The results indicated the formation of pure cobalt (Co), Cr7C3 NPs and crystalline CNFs. The Co and Cr7C3 NPs were covered with CNFs. Overall, the proposed NFs open new avenue to prepare different metals-metal carbides carbon NFs at low temperature and short reaction time. PMID- 29442976 TI - Crosslinked Dextran Gel Microspheres with Computed Tomography Angiography and Drug Release Function. AB - For computed tomography (CT) angiography and drug release application, a kind of novel dextran hydrogel microspheres were prepared. beta-cyclodextrin (beta-CD) grafted poly(methyl vinyl ether-altmaleic acid) (PMVE-alt-MA-g-beta-CD) and succinic acid modified dextran (Dex-SA) were first prepared, and then PMVE-alt-MA g-beta-CD was further used as the cross-linking agent to cross link Dex-SA for the formation of dextran hydrogel microspheres by using an inverse suspension polymerization method for the potential interventional embolization. The average diameter of the dextran hydrogel microspheres was 35 MUm with 90% ranging from 20 MUm to 50 MUm. The obtained microspheres showed a rather high swelling rate and loading capacity of drug doxorubicin hydrochloride with content of 9.2 wt%. The results of in vitro experiments showed that about 35.5% of the total amount of the encapsulated doxorubicin hydrochloride can be released after 4 h at 37 degrees C. The microspheres had a good mechanical stiffness with Young's modulus of about 20.0 kPa. Iodine molecules (I2) can be incorporated within the cavity of grafted cyclodextrin only through simply soaking in I2 aqueous solution, and these I2-loaded microspheres can preliminarily realize the function of CT angiography. This kind of dextran hydrogel microspheres with good biocompatibility would be a promising embolization material. PMID- 29442978 TI - Interactions of Fluorescein Dye with Spherical and Star Shaped Gold Nanoparticles. AB - UV-vis absorption, FT-IR, steady state fluorescence and fluorescence lifetime measurements were made on Fluorescein dye (Fl dye) molecules in presence of gold nanoparticles of different morphologies: spherical gold nanoparticles (GNP) and star shaped gold nanoparticles (GNS). The experimental observations demonstrate that Fl dye molecules form dimers when adsorbed on nanosurface of spherical gold particles. On the other hand possibly due to lack of adsorption on the surface of GNS the dye molecules were unable to form dimers. The projected tips on the surface of GNS may possibly hinder the dyes to adsorb on the surface of this nanoparticle. From the spectral analysis and measurements of thermodynamic parameters it is inferred that two different types of ground state interactions occur between Fl-dye-GNP and Fl dye-GNS systems. Both the observed negative values of the thermodynamic parameters DeltaH and DeltaS in the case of the former system predict the possibility of occurrences of hydrogen bonding interactions between two neighboring Fl dye molecules when adsorbed on the nanosurface of GNP. On the other hand in Fl dye-GNS system electrostatic interactions appear to occur, as evidenced from negative DeltaH and positive value of DeltaS, between the positive charges residing on the tips of the nanoparticles and anionic form of Fl dye. It has been concluded that as the adsorption of organic dyes on solid surfaces is prerequisite for the degradation of dye pollutants, the present experimental observations demonstrate that GNP could be used as a better candidate than GNS in degradation mechanism of the xanthenes dyes. PMID- 29442979 TI - Development of Silver-Based Bactericidal Composite Nanofibers by Airbrushing. AB - In this article, we report a simple, cost-effective and eco-friendly method of airbrushing for the fabrication of antibacterial composite nanofibers using Nylon 6 and silver chloride (AgCl). The Nylon-6 is a widely used polymer for various biomedical applications because of its excellent biocompatibility and mechanical properties. Similarly, silver has also been known for their antibacterial, antifungal, antiviral, and anti-inflammatory properties. In order to enhance the antibacterial functionality of the Nylon-6, composite nanofibers in combination with AgCl have been fabricated using airbrush method. The chemical functional groups and morphological studies of the airbrushed Nylon-6/AgCl composite nanofibers were carried out by FTIR and SEM, respectively. The antibacterial activity of airbrushed Nylon-6/AgCl composite nanofibers was evaluated using Gram +ve (Staphylococcus aureus) and Gram -ve (Escherichia coli) bacterial strains. The results showed that the airbrushed Nylon-6/AgCl composite nanofibers have better antibacterial activity against the tested bacterial strains than the airbrushed Nylon-6 nanofibers. Therefore, the airbrushed Nylon-6/AgCl composite nanofibers could be used as a potential antibacterial scaffolding system for tissue engineering and regenerative medicine. PMID- 29442980 TI - The Influence of the Charge Compensating Anions of Layered Double Hydroxides (LDHs) in LDH-NS/Graphene Oxide Nanohybrid for CO2 Capture. AB - In this paper, the influence of charge compensating anions of Layered double hydroxides (LDHs) in the LDH-NS/GO nanohybrid for carbon dioxide capture was systematically investigated. The four kinds of different charge compensating anion intercalated LDH were exfoliated and the LDH and Graphene oxide (GO) nanohybrids were synthesized by "exfoliation-self-assembly" method. In this contribution, the CO2 capture capacity of LDH was improved by introducing of GO. And the calcination and adsorption conditions were tested, which proved that the LDH-NS/GO nanohybrids can be used in a wide temperature range for carbon dioxide capture, and the appropriate calcination temperature is 400 degrees C. Furthermore, the LDH-NS/GO nanohybrids also have a good multiple adsorption/desorption stability, which is vital for practical application. PMID- 29442981 TI - Polymer Foam-Supported Chemically Reduced Graphene Oxide Conductive Networks for Gas Sensing. AB - In this work, gas sensors based on chemically reduced graphene oxide (rGO) foams were reported for NH3 detection. Polymer foams were used as scaffolds to support rGO, and the resultant soft sensing devices exhibited a high sensitivity, high selectivity, and rapid recovery for NH3 detection at room temperature. The sensor showed more than 0.90% and 3.67% resistance changes respectively, when it's exposed to 1 ppm and 50 ppm NH3. The graphene foam gas sensors (FGS) also showed excellent repeatability. Furthermore, the response of rGO foam gas sensor to NH3 was more than two times higher than that to methanol vapors diluted to 1% of the saturated vapor concentration. Above all, the unique features, such as simple preparation, low cost and energy consumption, as well as excellent sensing performance, endow the sensor a great potential for NH3 detection. PMID- 29442982 TI - Comparative Studies on Enzyme Activity of Immobilized Horseradish Peroxidase in Silica Nanomaterials with Three Different Shapes and Methoxychlor Degradation of Vesicle-Like Mesoporous SiO2 as Carrier. AB - In the present work, three differently shaped mesoporous silica nanoparticles, spherical nano-SiO2, tubular mesoporous SiO2 and vesicle-like mesoporous SiO2 (VSL), were prepared and used to immobilize Horse radish peroxidase (HRP), and their enzyme's activity was also evaluated. It was found that the VSL immobilized HRP displayed higher specific activity than free enzyme and other two differently shaped silica immobilized HRP. After immobilization, the thermal stability, pH tolerance resistance and storage stability on vesicle-like SiO2 were studied as well. In addition, the kinetic constants Km and Vmax for HRP were significantly altered by immobilization. The affinity for HRP towards its substrate increased (with decreasing Km), leading to enhanced catalytic efficiency (with increased Vmax). Moreover, the reusability for degradation of methoxychlor (MXC) by VSL immobilized enzyme was studied and its degradation products were detected by GC MS and NMR analysis. PMID- 29442983 TI - Formaldehyde Treatment Using Overexpressed Aldehyde Dehydrogenase 6 from Recombinant Saccharomyces cerevisiae. AB - Formaldehyde is a toxic compound due to its ability to react with proteins, nucleic acids and lipids and is the primary cause of nasopharyngeal cancer and sick building syndrome (SBS). Aldehyde dehydrogenases (ALDHs) are able to oxidize aldehyde substrates and maintain cellular homeostasis by metabolic reactions in prokaryotic and eukaryotic cells. ALDHs catalyze the conversions of various aldehydes to carboxylic acids using NAD or NADP as a cofactor. In this study, we designed a method for using aldehyde dehydrogenase 6 (ALD6) from recombinant Saccharomyces cerevisiae to reduce formaldehyde. The ALD6 gene was cloned under the GAL1 promoter in pYES2 and attached to green fluorescent protein (GFP). To reduce the activity of ALD6, a dominant mutant was constructed with deleted catalytic residues. These strains were successfully transformed in Saccharomyces cerevisiae as confirmed by fluorescence microscopy. The produced enzymes isolated from each strain were used to treat formaldehyde. Formaldehyde reduction was determined via measured luminescence in Vibrio fischeri. Formaldehyde levels were lowest in enzymes from cells overexpressing ALD6. Furthermore, when the strains were exposed to formaldehyde stress, NADH levels increased for strains overexpressing ALD6 and decreased for dominant negative strains. Therefore, our results suggest that ALD6 plays a key role in formaldehyde treatment. We expect that ALD6 could be used in applications related to the removal of formaldehyde. PMID- 29442984 TI - Cyclohexylation of Resorcinol with Cyclohexanol Catalyzed by Tungstophosphoric Acid Supported Zirconia Catalysts. AB - We demonstrate a highly active and reusable heterogeneous catalyst system, tungstophosphoric acid (TPA) supported on zirconia (ZrO2), for the cyclohexylation of resorcinol by cyclohexanol to produce value added chemicals such as 2-cyclohexyl resorcinol, 4-cyclohexyl resorcinol and 3-Hydroxy cyclohexyl phenyl ether under liquid phase reaction condition. TPA/ZrO2 catalysts prepared with different TPA loadings (5-30 wt.%) by wet impregnation method and calcined in the temperature range of 650-850 degrees C were characterized by Nitrogen sorption analysis, XRD, FTIR, DTG and DTA, and 31P MAS NMR spectroscopy. Among the catalysts studied, 15 wt.%TPA/ZrO2 catalyst calcined at 750 degrees C gave the highest conversion of resorcinol (51.2%) with the selectivities for 3-Hydroxy cyclohexyl phenyl ether (53.9%) and 2-cyclohexyl resorcinol and 4-cyclohexyl resorcinol together (46.1%) under optimum reaction conditions. However, the selectivity of the products were controlled by varying the reaction conditions. At higher conversion of resorcinol (78.9%), only C-alkylated products were formed at 200 degrees C with 15 wt.%TPA/ZrO2 catalyst calcined at 750 degrees C. The combination of TPA and ZrO2 coupled with calcination temperature offered an excellent platform for the conversion of resorcinol into O- or C-alkylated products. PMID- 29442985 TI - Enhanced Room-Temperature Phosphorescence of Mn-Doped ZnS Quantum Dots Composited with PDDA for Detection of Adriamycin. AB - In this work, a simple room-temperature phosphorescence (RTP) method was first proposed to detect adriamycin, by using a functional material of Mn doped ZnS quantum dots (Mn-ZnS QDs) composited with poly(diallyldimethylammonium chloride) (PDDA). After PDDA was associated to the Mn-ZnS QDs, the RTP intensity was significantly enhanced. As a result, Mn-ZnS QDs/PDDA nanoassemblies greatly improve the adriamycin detection ability of QDs and provide an important method for developing more effective and sensitive adriamycin detection sensor. The method based upon RTP has a linear range from 0.5 to 64.0 MUM with a detection limit (3sigma/s) for adriamycin of 0.45 MUM. The developed method was further successfully applied to detect adriamycin in human serum samples (diluted 50 times) with satisfactory results, and the recovery ranged from 98.3 to 101.3. PMID- 29442986 TI - Insights into Pore Size Control in Cellulose Nanopapers Through Modeling and Experiments. AB - An easy way of controlling pore sizes during the preparation of cellulose nanopapers using nanofibrillated cellulose and different solvents, such as water, ethanol and acetone, was applied in this study. A possible mathematical model is also presented, that describes the occuring processes, which model is based on simple probability theory computations taking the number of possible hydrogen bonds into consideration. This model allows the better understanding of the solvent dependence of pore formation on a molecular level. For the comparison of the effects of solvents two different series of cellulose nanopapers were prepared. In the cases of both series, an aqueous nanofibrillated cellulose suspension was used for the fabrication of nanopapers, and different solvents were used for their modification. Based on scanning electron microscopy images and mercury intrusion porosimetry data it has been concluded, that using different solvents was a crucial point in controlling pore sizes. A theory about the swelling effects, as well as the formation and decomposition of nanofibrillated cellulose aggregates based on the hydrogen bonding abilities of the solvents, was proposed and proven in this paper. As-prepared nanocellulose papers can be excellent candidates for further applications as support materials (e.g., virus filtration). PMID- 29442987 TI - Cresyl Violet Adsorption on Sonicated Graphite Oxide. AB - We present a study of adsorption of Cresyl Violet (CV) in aqueous solution on sonicated Graphite Oxide (sGO). For comparison, we also show adsorption results of Methylene Blue (MB) and Acridine Orange (AO) performed in the same conditions. The adsorbent was synthesized by the Tour's method followed by washing in water and ethanol and sonication, without any reduction, and studied by Raman, IR, UV Vis, SEM and TEM techniques. Our results show that adsorption fits the pseudosecond order model for the three dyes, and that the adsorption quantity for CV is 125.0 mg g-1, while for MB and AO is 123.3 and 94.6 mg g-1 respectively. PMID- 29442988 TI - Preparation of Silver Nanowires with High Aspect Ratio and Influence of Reaction Conditions on the Morphology Size. AB - Silver nanowires with high yield, uniform size and high aspect ratio were successfully synthesized by a simple and effective polyol method under low temperature and quiescent conditions, adopting CuCl2.2H2O as the nucleation control agent for the first time. The synthesized silver nanowires were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and UV-Vis diffuse reflectance spectroscopy (DRS). The results indicate that the silver nanowires were composed of face-centered cubic structure of pure metallic silver with high crystallinity. And the silver nanowires have an average length of 80~100 MUm and an average diameter of 40~80 nm. Thus, the aspect ratio of the nanowires was greater than 1000. In addition, the influence on the morphology and structure of the silver nanowires were investigated for reaction temperature, mole ratio of PVP:AgNO3, molecular weight of PVP and mole ratio of control agent CuCl2 . 2H2O:AgNO3. Finally, the optimum reaction condition were obtained for the preparation of the silver nanowires with high aspect ratio. PMID- 29442989 TI - Hyperthermia Temperature of Magnetic Fluid with Superparamagnetic Nanoparticles Subjected to an Alternating Magnetic Field. AB - This paper conducts the thermal analysis of magnetic fluid with superparamagnetic nanoparticles subjected to an alternating magnetic field. Magnetic fluid hyperthermia (MFH) provides a potential method for cancer treatment, which has fewer side effects than chemotherapy and radiotherapy. Superparamagnetic nanoparticles dispersed in water are suitable for safe application of MFH. A well defined hyperthermia should only kill the cancer cells without injuring neighbouring normal tissue. A key factor for hyperthermia is to correctly control the alternating magnetic field-induced temperature of the magnetic fluid in the tumour. Therefore, this study develops a thermal transport model combined with a linear response theory of magnetic nanoparticle (MNP) heat dissipation to analyze the effects of parameters on temperatures in the magnetic fluid with superparamagnetic nanoparticles subjected to an alternating magnetic field. The results predicted by this model are compared with the available experimental data and show that the rise rates of temperature with time and temperatures along the radial direction are enhanced by the increase of MNP concentrations in magnetic fluid, the amplitude of magnetic field strength, frequency, and magnetization. PMID- 29442991 TI - Variation in Residential Care Community Resident Characteristics, by Size of Community: United States, 2016. AB - Residents of residential care communities are persons who cannot liveindependently but generally do not require the skilled care provided by nursinghomes. On any given day in 2016, an estimated 811,500 residents were inresidential care communities (1,2). As the population ages, the numbers inresidential care communities will likely increase, creating a sizeable groupwithin the long-term care population. This report presents national estimatesof selected characteristics of residential care community residents in 2016 andcompares them by community size. State-level estimates are available from: PMID- 29442990 TI - Alteration of MicroRNA Expression Profiles by Surface-Modified Gold Nanoparticles in Human Lung Adenocarcinoma Cells. AB - MicroRNAs that bind to mRNA are important post-transcriptional regulators that control gene expression by degradation or suppressing translation of target mRNAs. Several studies indicate that nanoparticles (NPs) induce alterations in microRNA expression relating to cell processes including cell development and progressive diseases. However, the alteration of microRNA expression by surface modified gold nanoparticles (AuNPs) in A549 cells has not been reported. In order to investigate the patterns of microRNA expression, we analyzed data from microRNA arrays using cells treated with citrate- or chitosan-AuNPs. The results demonstrate that the expression of microRNA (hsa-miR-198) in cells treated with citrate-AuNPs significantly differed from non-treated cells, and the expression of 16 microRNAs in cells treated with chitosan-AuNPs significantly differed from non-treated cells. Furthermore, the predicted target genes of microRNAs were related to proliferation, apoptosis, migration, and cell differentiation, including the mitogen-activated protein kinase, ErbB, and Wnt signaling pathway. Thus, the alteration of microRNA expression profiles by citrate- and chitosan AuNPs would mediate the regulation of the cell processes including cell survival, migration, and differentiation. PMID- 29442992 TI - Emergency Department Visits by Patients Aged 45 and Over With Diabetes: United States, 2015. AB - An estimated 30 million Americans have diabetes, of whom 26 millionare aged 45 and over (1). Healthy eating and exercise can prevent diabetesprogression (1,2). Around 12 million emergency department (ED) visits in2015 were by patients aged 45 and over with diabetes, representing 24% of EDvisits by patients aged 45 and over and 80% of diabetes ED visits by patientsof all ages (3). This report presents data on ED visits by patients aged 45 andover with diabetes, defined as visits for which diabetes is mentioned as either adiagnosis or as one of a set of conditions that the patient is reported to have. PMID- 29442993 TI - Parental Report of Significant Head Injuries in Children Aged 3-17 Years: United States, 2016. AB - In recent years, there has been increased awareness and prevention effortstoward reducing concussion incidence. Previous research has most oftenestimated the prevalence of concussions among youth using medical claimsdata (1-4). In the 2016 National Health Interview Survey (NHIS), parents orguardians answered questions about whether their children have ever had asignificant head injury or concussion. This report presents estimates ofparent-reported lifetime significant head injuries among children aged 3-17years, providing information about head injuries beyond those that weremedically attended. PMID- 29442994 TI - Prevalence of Herpes Simplex Virus Type 1 and Type 2 in Persons Aged 14-49: United States, 2015-2016. AB - Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are common, lifelonginfections, which often have no symptoms (1). People with symptoms mayhave painful blisters or sores at the site of infection (2,3). The viruses aretransmitted through contact with an infected person's lesion, mucosal surface,or genital or oral secretions. This report provides recent national estimates ofHSV-1 and HSV-2 antibody prevalence from the 2015-2016 National Healthand Nutrition Examination Survey (NHANES) among persons aged 14-49 byage, sex, and race and Hispanic origin, and examines trends in prevalence byrace and Hispanic origin from 1999-2000 to 2015-2016. PMID- 29442995 TI - Maternal Characteristics of Prenatal WIC Receipt in the United States, 2016. AB - The Special Supplemental Nutrition Program for Women, Infants, andChildren (WIC) seeks to improve fetal development and reduce the incidenceof low birth weight, preterm birth, and maternal anemia through interventionduring pregnancy (1). Prenatal WIC receipt is associated with lower infantmortality and stronger cognitive development among toddlers and children(2,3). All states and the District of Columbia reported information on maternalreceipt of WIC food during pregnancy on the birth certificate for the firsttime in 2016 based on the question, "Did you receive WIC food for yourselfbecause you were pregnant with this child?" This report describes prenatalWIC receipt in the United States in 2016 by state and by maternal age, raceand Hispanic origin, and education. PMID- 29442996 TI - Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies. AB - Eliciting antibodies that are cross reactive with surface proteins of diverse strains of highly mutable pathogens (e.g., HIV, influenza) could be key for developing effective universal vaccines. Mutations in the framework regions of such broadly neutralizing antibodies (bnAbs) have been reported to play a role in determining their properties. We used molecular dynamics simulations and models of affinity maturation to study specific bnAbs against HIV. Our results suggest that there are different classes of evolutionary lineages for the bnAbs. If germline B cells that initiate affinity maturation have high affinity for the conserved residues of the targeted epitope, framework mutations increase antibody rigidity as affinity maturation progresses to evolve bnAbs. If the germline B cells exhibit weak/moderate affinity for conserved residues, an initial increase in flexibility via framework mutations may be required for the evolution of bnAbs. Subsequent mutations that increase rigidity result in highly potent bnAbs. Implications of our results for immunogen design are discussed. PMID- 29442998 TI - Acute kidney injury following percutaneous edge-to-edge vs. minimally invasive surgical mitral valve repair: incidence, predictors and prognostic value. AB - AIMS: This study sought to determine the incidence and identify predictors of acute kidney injury (AKI) following percutaneous edge-to-edge mitral valve repair (PMVR) and compare the risk of AKI between PMVR and surgical mitral valve repair (SMVR). METHODS AND RESULTS: We performed a single-centre analysis of 378 patients receiving treatment for mitral regurgitation (196 consecutive patients undergoing PMVR and 182 patients undergoing SMVR). The incidence of AKI (any stage according to KDIGO) following PMVR was 17.9%. Intervention duration (OR 1.01, 95% CI: 1.00-1.02) and peripheral vascular disease (OR 7.69, 95% CI: 3.25 18.17) predicted AKI after PMVR. Patients suffering from AKI after PMVR demonstrated poorer survival (median followup 428 days). SMVR patients were significantly younger, had fewer comorbidities and better renal function at baseline. Nevertheless, AKI occurred numerically more often after SMVR than PMVR (25.8% vs. 17.9%, p=0.060), and a multivariable regression model adjusting for differences between both groups confirmed a significantly lower risk for AKI following PMVR (OR 0.22, 95% CI: 0.11-0.44, p<0.001). CONCLUSIONS: These data show a significant incidence of AKI after PMVR that must be taken into account in periprocedural care. Nevertheless, our data suggest that SMVR carries an even higher risk of AKI, which should be considered when a decision has to be made between the two therapies. PMID- 29442997 TI - Spatial structure of disordered proteins dictates conductance and selectivity in nuclear pore complex mimics. AB - Nuclear pore complexes (NPCs) lined with intrinsically disordered FG-domains act as selective gatekeepers for molecular transport between the nucleus and the cytoplasm in eukaryotic cells. The underlying physical mechanism of the intriguing selectivity is still under debate. Here, we probe the transport of ions and transport receptors through biomimetic NPCs consisting of Nsp1 domains attached to the inner surface of solid-state nanopores. We examine both wildtype FG-domains and hydrophilic SG-mutants. FG-nanopores showed a clear selectivity as transport receptors can translocate across the pore whereas other proteins cannot. SG mutant pores lack such selectivity. To unravel this striking difference, we present coarse-grained molecular dynamics simulations that reveal that FG-pores exhibit a high-density, nonuniform protein distribution, in contrast to a uniform and significantly less-dense protein distribution in the SG mutant. We conclude that the sequence-dependent density distribution of disordered proteins inside the NPC plays a key role for its conductivity and selective permeability. PMID- 29442999 TI - Ultraclean individual suspended single-walled carbon nanotube field effect transistor. AB - In this work, we report an effective technique of fabricating ultraclean individual suspended single-walled carbon nanotube (SWNT) transistors. The surface tension of molten silver is utilized to suspend an individual SWNT between a pair of Pd electrodes during annealing treatment. This approach avoids the usage and the residues of organic resist attached to SWNTs, resulting ultraclean SWNT devices. And the resistance per micrometer of suspended SWNTs is found to be smaller than that of non-suspended SWNTs, indicating the effect of the substrate on the electrical properties of SWNTs. The ON-state resistance (~50 kOmega), mobility of 8600 cm2 V-1 s-1 and large on/off ratio (~105) of semiconducting suspended SWNT devices indicate its advantages and potential applications. PMID- 29443000 TI - Novel elastic, lattice dynamics and thermodynamic properties of metallic single layer transition metal phosphides: 2H-M 2P (Mo2P, W2P, Nb2P and Ta2P). AB - Recently, there has been a surge of interest in the research of two-dimensional (2D) phosphides due to their unique physical properties and wide applications. Transition metal phosphides 2H-M 2Ps (Mo2P, W2P, Nb2P and Ta2P) show considerable catalytic activity and energy storage potential. However, the electronic structure and mechanical properties of 2D 2H-M 2Ps are still unrevealed. Here, first-principles calculations are employed to investigate the lattice dynamics, elasticity and thermodynamic properties of 2H-M 2Ps. Results show that M 2Ps with lower stiffness exhibit remarkable lateral deformation under unidirectional loads. Due to the largest average Gruneisen parameter, single-layer Nb2P has the strongest anharmonic vibrations, resulting in the highest thermal expansion coefficient. The lattice thermal conductivities of Ta2P, W2P and Nb2P contradict classical theory, which would predict a smaller thermal conductivity due to the much heavier atom mass. Moreover, the calculations also demonstrate that the thermal conductivity of Ta2P is the highest as well as the lowest thermal expansion, owing to its weak anharmonic phonon scattering and the lowest average Gruneisen parameter. The insight provided by this study may be useful for future experimental and theoretical studies concerning 2D transition metal phosphide materials. PMID- 29443001 TI - Short and medium range structures of 80GeSe2-20Ga2Se3 chalcogenide glasses. AB - The short and medium range structures of 80GeSe2-20Ga2Se3 (or Ge23.5Ga11.8Se64.7) chalcogenide glasses have been studied by combining ab initio molecular dynamics (AIMD) simulations and experimental neutron diffraction studies. The structure factor and total correlation function were calculated from glass structures generated from AIMD simulations and compared with neutron diffraction experiments showing reasonable agreement. The atomic structures of ternary chalcogenide glasses were analyzed in detail, and it was found that gallium atoms are four fold coordinated by selenium (Se) and form [GaSe4] tetrahedra. Germanium atoms on average also have four-fold coordination, among which Se is 3.5 with the remaining being Ge-Ge homo-nuclear bonds. Ga and Ge tetrahedra link together mainly through corner-sharing and some edge-sharing of Se. No homo-nuclear bonds were observed among Ga atoms or between Ge and Ga. In addition, Se-Se homo nuclear bonds and Se chains with various lengths were observed. A small fraction of Se atom triclusters that bond to three cations of Ge and Ga were also observed, confirming earlier proposals from 77Se solid state nuclear magnetic resonance studies. Furthermore, the electronic structures of ternary chalcogenide glasses were studied in terms of atomic charge and electronic density of states in order to gain insights into the chemical bonding and electronic properties, as well as to provide an explanation of the observed atomic structures in these ternary chalcogenide glasses. PMID- 29443002 TI - Photonic crystal micro-pixelation and additive color mixing in weevil scales. AB - The origin of the brilliant near angle-independent coloration of the weevil Eupholus chevrolati was investigated by a combination of optical and electron microscopy tools, photonic band structure calculations, and color mixing analysis. Optical microscopy and scanning micro-spectroscopy revealed the presence of micrometer-sized red, yellow, green, and blue reflective pixels covering the entire exoskeleton of the weevil. Scanning electron microscopy in combination with focused ion beam milling showed that each micro-pixel consisted of a diamond-based photonic crystal structure and the different reflective colors were the result of different orientations of the photonic crystal. Color mixing analysis was used to study the collective behavior of the reflective micro pixels. A pointillist, additive color-mixing scheme of the reflective photonic crystal micro-pixels was determined as the origin of the weevil's bright and near angle-independent yellow-green coloration. PMID- 29443003 TI - Towards understanding of magnetization reversal in Nd-Fe-B nanocomposites: analysis by high-throughput micromagnetic simulations. AB - We demonstrate how micromagnetic simulations can be employed in order to characterize and analyze the magnetic microstructure of nanocomposites. For the example of nanocrystalline Nd-Fe-B, which is a potential material for future permanent-magnet applications, we have compared three different models for the micromagnetic analysis of this material class: (i) a description of the nanocomposite microstructure in terms of Stoner-Wohlfarth particles with and without the magnetodipolar interaction; (ii) a model based on the core-shell representation of the nanograins; (iii) the latter model including a contribution of superparamagnetic clusters. The relevant parameter spaces have been systematically scanned with the aim to establish which micromagnetic approach can most adequately describe experimental data for this material. According to our results, only the last, most sophisticated model is able to provide an excellent agreement with the measured hysteresis loop. The presented methodology is generally applicable to multiphase magnetic nanocomposites and it highligths the complex interrelationship between the microstructure, magnetic interactions, and the macroscopic magnetic properties. PMID- 29443004 TI - Magnetic order of Nd5Pb3 single crystals. AB - We report millimeter-sized Nd5Pb3 single crystals grown out of a Nd-Co flux. We experimentally study the magnetic order of Nd5Pb3 single crystals by measuring the anisotropic magnetic properties, electrical resistivity under high pressure up to 8 GPa, specific heat, and neutron single crystal diffraction. Two successive magnetic orders are observed at T N1 = 44 K and T N2 = 8 K. The magnetic cells can be described with a propagation vector [Formula: see text]. Cooling below T N1, Nd1 and Nd3 order forming ferromagnetic stripes along the b axis, and the ferromagnetic stripes are coupled antiferromagnetically along the a axis for the [Formula: see text] magnetic domain. Cooling below T N2, Nd2 orders antiferromagnetically to nearby Nd3 ions. All ordered moments align along the crystallographic c-axis. The magnetic order at T N1 is accompanied by a quick drop of electrical resistivity upon cooling and a lambda-type anomaly in the temperature dependence of specific heat. At T N2, no anomaly was observed in electrical resistivity but there is a weak feature in specific heat. The resistivity measurements under hydrostatic pressures up to 8 GPa suggest a possible phase transition around 6 GPa. Our first-principles band structure calculations show that Nd5Pb3 has the same electronic structure as does Y5Si3 which has been reported to be a one-dimensional electride with anionic electrons that do not belong to any atom. Our study suggests that R 5Pb3 (R = rare earth) can be a materials playground for the study of magnetic electrides. This deserves further study after experimental confirmation of the presence of anionic electrons. PMID- 29443005 TI - Entanglement entropy and entanglement spectrum of Bi1-xSbx (111) bilayers. AB - We study topological properties of Bi$_{1-x}$Sb$_{x}$ bilayers in the (111) plane using entanglement measures. Electronic structures are investigated within multi orbital tight-binding model and structural stability is confirmed through first principles calculations. Topologically non-trivial nature of bismuth bilayer is proved by the presence of spectral flow in the entanglement spectrum. We consider topological phase transitions driven by a composition change x, an applied external electric field in Bi bilayer and strain in Sb bilayer. Composition- and strain-induced phase transitions reveal a finite discontinuity in the entanglement entropy. This quantity remains a continuous function of the electric field strength, but shows a finite discontinuity in the first derivative. We relate the difference in behavior of the entanglement entropy to the breaking of inversion symmetry in the last case. PMID- 29443006 TI - Simple and green synthesis of piperazine-grafted reduced graphene oxide and its application for the detection of Hg(II). AB - In this paper, piperazine-grafted reduced graphene oxide (NH-rGO) was synthesized via a simple and green two-step procedure: (i) opening of the resulting epoxides of graphene oxide (GO) with piperazine (NH) through nucleophilic substitution; (ii) reduction of GO with ascorbic acid. Its structure and morphology were characterized by scanning electron microscopy and x-ray photoelectron spectroscopy. The NH-rGO modified glassy carbon electrode was explored as an electrochemical sensor for the determination of Hg(II) using a differential pulse anodic stripping voltammetry technique. Hg(II) can be efficiently accumulated and deposited on the surface of a modified electrode by strong coordination chemical bonds formed between Hg(II) and NH. And then the anodic stripping current can be significantly enhanced by rGO with the merits of large specific surface area and high conductivity, which served as a signal amplifier, finally realizing the highly sensitive determination of Hg(II). The experimental parameters including the pH value of the acetate buffer, deposition potential and deposition time were optimized. Under optimal conditions, the developed sensor exhibited a wide linear range from 0.4-12 000 nM with a low limit of detection of 0.2 nM, which is well below the guideline value in drinking water set by the WHO. Moreover, the practical application of this method was confirmed by an assay of Hg(II) in tap water samples with acceptable results. PMID- 29443007 TI - Direct synthesis of bimetallic PtCo mesoporous nanospheres as efficient bifunctional electrocatalysts for both oxygen reduction reaction and methanol oxidation reaction. AB - The engineering of electrocatalysts with high performance for cathodic and/or anodic catalytic reactions is of great urgency for the development of direct methanol fuel cells. Pt-based bimetallic alloys have recently received considerable attention in the field of fuel cells because of their superior catalytic performance towards both fuel molecule electro-oxidation and oxygen reduction. In this work, bimetallic PtCo mesoporous nanospheres (PtCo MNs) with uniform size and morphology have been prepared by a one-step method with a high yield. The as-made PtCo MNs show superior catalytic activities for both oxygen reduction reaction and methanol oxidation reaction relative to Pt MNs and commercial Pt/C catalyst, attributed to their mesoporous structure and bimetallic composition. PMID- 29443008 TI - Defect induced structural inhomogeneity, ultraviolet light emission and near-band edge photoluminescence broadening in degenerate In2O3 nanowires. AB - We demonstrate here defect induced changes on the morphology and surface properties of indium oxide (In2O3) nanowires and further study their effects on the near-band-edge (NBE) emission, thereby showing the significant influence of surface states on In2O3 nanostructure based device characteristics for potential optoelectronic applications. In2O3 nanowires with cubic crystal structure (c In2O3) were synthesized via carbothermal reduction technique using a gold catalyst-assisted vapor-liquid-solid method. Onset of strong optical absorption could be observed at energies greater than 3.5 eV consistent with highly n-type characteristics due to unintentional doping from oxygen vacancy [Formula: see text] defects as confirmed using Raman spectroscopy. A combination of high resolution transmission electron microscopy, x-ray photoelectron spectroscopy and valence band analysis on the nanowire morphology and stoichiometry reveals presence of high-density of [Formula: see text] defects on the surface of the nanowires. As a result, chemisorbed oxygen species can be observed leading to upward band bending at the surface which corresponds to a smaller valence band offset of 2.15 eV. Temperature dependent photoluminescence (PL) spectroscopy was used to study the nature of the defect states and the influence of the surface states on the electronic band structure and NBE emission has been discussed. Our data reveals significant broadening of the NBE PL peak consistent with impurity band broadening leading to band-tailing effect from heavy doping. PMID- 29443009 TI - Radon in Brazilian underground mines. AB - Radon is a chemically inert noble radioactive gas found in several radioactive decay chains. In underground mines, especially those that contain or have contained ores associated with uranium-bearing minerals, workers might be exposed to high levels of radon and its decay products (RDP). This work aims to investigate whether the exposure of workers to radon gas and its progeny has been evaluated in Brazilian non-uranium and non-thorium underground mines. Any such results and control measures undertaken or recommended to maintain concentrations under Brazilian occupational exposure limits (OELs) are documented. The methodology we adopted consists of three main phases. The first was an extensive bibliographical survey of the concentration levels of radon and RDP, as well as the radiation dose estimates, considering measurements made heretofore by various Brazilian researchers and exhibiting original measurement work undertaken by the one of the authors (mine O). In the second phase, the values obtained were compared with OELs. In the third phase, any control measures undertaken in mines with high exposure of workers to radon and its progeny were verified, and the adopted controls were determined. Radon concentration data obtained from 52 campaigns in 40 underground mines were analyzed. The results show that assessment of the exposure of workers to radon and its progeny was undertaken in many mines at least once, and that radon levels in 62.5% of the mines, when visited for the first time, were below the Brazilian OELs. As expected, the main control measure adopted or recommended was improvement of the ventilation system. PMID- 29443010 TI - New insight of high temperature oxidation on self-exfoliation capability of graphene oxide. AB - The preparation of graphene oxide (GO) via Hummers method is usually divided into two steps: low temperature oxidation at 35 degrees C (step I oxidation) and high temperature oxidation at 98 degrees C (step II oxidation). However, the effects of these two steps on the exfoliation capability and chemical structure of graphite oxide remain unclear. In this study, both the functional group content of graphite oxide and the entire evolution of interlayer spacing were investigated during the two steps. Step I oxidation is a slowly inhomogeneous oxidation step to remove unoxidized graphite flakes. The prepared graphite oxide can be easily self-exfoliated but contains a lot of organic sulfur. During the first 20 min of step II oxidation, the majority of organic sulfur can be efficiently removed and graphite oxide still remains a good exfoliation capability due to sharp increasing of carboxyl groups. However, with a longer oxidation time at step II oxidation, the decrease of organic sulfur content is slowed down apparently but without any carboxyl groups forming, then graphite oxide finally loses self-exfoliation capability. It is concluded that a short time of step II oxidation can produce purer and ultralarge GO sheets via self exfoliation. The pure GO is possessed with better thermal stability and liquid crystal behavior. Besides, reduced GO films prepared from step II oxidation show better mechanical and electric properties after reducing compared with that obtained only via step I oxidation. PMID- 29443011 TI - Dynamics, thermodynamics and structure of liquids and supercritical fluids: crossover at the Frenkel line. AB - We review recent work aimed at understanding dynamical and thermodynamic properties of liquids and supercritical fluids. The focus of our discussion is on solid-like transverse collective modes, whose evolution in the supercritical fluids enables one to discuss the main properties of the Frenkel line separating rigid liquid-like and non-rigid gas-like supercritical states. We subsequently present recent experimental evidence of the Frenkel line showing that structural and dynamical crossovers are seen at a pressure and temperature corresponding to the line as predicted by theory and modelling. Finally, we link dynamical and thermodynamic properties of liquids and supercritical fluids by the new calculation of liquid energy governed by the evolution of solid-like transverse modes. The disappearance of those modes at high temperature results in the observed decrease of heat capacity. PMID- 29443012 TI - Domain-wall motion at an ultrahigh speed driven by spin-orbit torque in synthetic antiferromagnets. AB - In this article, we present our numerical investigation about the spin-orbit torque induced domain-wall (DW) motion in a synthetic antiferromagnetic multilayer nanotrack. This nanotrack was composed by two ferromagnetic (FM) layers with a RKKY inter-layer antiferromagnetic (AFM) exchange coupling. The velocity of DW was well manipulated by varying parameters including inter-layer exchange constant, the Dzyaloshinskii-Moriya interaction (DMI) strength, the current density and the magnetic anisotropy. The DW velocity was found to be strictly related to the orientation of the moments in the two FM layers. When the interlayer exchange constant or the DMI constant were larger than a critical value, there was a large angle between the moments in one FM layer and that in the other one under the current, and the DW was driven to move at an ultrahigh speed (around 10 000 m s-1). However, when the DMI or the AFM exchange coupling was weaker than the critical value, the moments in one FM layer were parallel to that in the other one under the current, and the velocity was significantly reduced. PMID- 29443013 TI - Stability enhancement of Cu2S against Cu vacancy formation by Ag alloying. AB - As a potential solar absorber material, Cu2S has proved its importance in the field of renewable energy. However, almost all the known minerals of Cu2S suffer from spontaneous Cu vacancy formation in the structure. The Cu vacancy formation causes the structure to possess very high p-type doping that leads the material to behave as a degenerate semiconductor. This vacancy formation tendency is a major obstacle for this material in this regard. A relatively new predicted phase of Cu2S which has an acanthite-like structure was found to be preferable than the well-known low chalcocite Cu2S. However, the Cu-vacancy formation tendency in this phase remained similar. We have found that alloying silver with this structure can help to reduce Cu vacancy formation tendency without altering its electronic property. The band gap of silver alloyed structure is higher than pristine acanthite Cu2S. In addition, Cu diffusion in the structure can be reduced with Ag doped in Cu sites. In this study, a systematic approach is presented within the density functional theory framework to study Cu vacancy formation tendency and diffusion in silver alloyed acanthite Cu2S, and proposed a possible route to stabilize Cu2S against Cu vacancy formations by alloying it with Ag. PMID- 29443014 TI - Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland. AB - Intraductal carcinoma (IC) is the World Health Organization designation for lesions previously called low-grade cribriform cystadenocarcinoma. The relationship of IC to salivary duct carcinoma (SDC) is controversial, but currently these are considered distinct entities. It is hypothesized that IC and SDC should have different genomic signatures that may be identifiable by next generation sequencing. A total of 23 ICs were identified: 14 pure IC and 9 invasive carcinomas with an intraductal component. Five invasive carcinomas were subjected to next-generation paired-end RNA sequencing. Data analysis was performed using FusionSeq and Mutation detection algorithms (MuTect and VarScan) for variant callers. Gene fusion candidates were validated by fluorescence in situ hybridization and reverse transcription polymerase chain reaction, and mutations by Sanger sequencing. Among the 9 invasive carcinomas, all except 1 were apocrine SDCs with an intraductal component. The remaining case showed typical intercalated duct type IC with invasive adenocarcinoma. The 14 pure ICs had typical intercalated duct features (2 showed hybrid intercalated/apocrine features). RNA sequencing predicted a NCOA4-RET fusion, confirmed by reverse transcription polymerase chain reaction, in the intercalated duct type IC invasive component. Six additional cases of pure IC showed RET rearrangement by fluorescence in situ hybridization (7/15=47%). No apocrine carcinomas showed RET rearrangement. RNA sequencing and Sanger sequencing identified PIK3CA (p.E545K/p.H1047R) and/or HRAS (p.Q61R) hotspot mutations in 6 of 8 (75%) apocrine carcinomas. In conclusion, 2 distinctive types of intraductal lesions are emerging based on molecular analysis. Classic intercalated type ICs commonly harbor fusions involving RET and rarely show widespread invasion. Apocrine intraductal lesions are typically associated with widespread invasion with no pure examples and show similar PIK3CA and HRAS mutations to SDC. PMID- 29443016 TI - Resurrection of Dormant Daphnia magna: Protocol and Applications. AB - Long-term studies enable the identification of eco-evolutionary processes that occur over extended time periods. In addition, they provide key empirical data that may be used in predictive modelling to forecast evolutionary responses of natural ecosystems to future environmental changes. However, excluding a few exceptional cases, long-term studies are scarce because of logistic difficulties associated with accessing temporal samples. Temporal dynamics are frequently studied in the laboratory or in controlled mesocosm experiments with exceptional studies that reconstruct the evolution of natural populations in the wild. Here, a standard operating procedure (SOP) is provided to revive or resurrect dormant Daphnia magna, a widespread zooplankton keystone species in aquatic ecosystems, to dramatically advance the state-of-the-art longitudinal data collection in natural systems. The field of Resurrection Ecology was defined in 1999 by Kerfoot and co-workers, even though the first attempts at hatching diapausing zooplankton eggs date back to the late 1980s. Since Kerfoot's seminal paper, the methodology of resurrecting zooplankton species has been increasingly frequently applied, though propagated among laboratories only via direct knowledge transfer. Here, an SOP is described that provides a step-by-step protocol on the practice of resurrecting dormant Daphnia magna eggs. Two key studies are provided in which the fitness response of resurrected Daphnia magna populations to warming is measured, capitalizing on the ability to study historical and modern populations in the same settings. Finally, the application of next generation sequencing technologies to revived or still dormant stages is discussed. These technologies provide unprecedented power in dissecting the processes and mechanisms of evolution if applied to populations that have experienced changes in selection pressure over time. PMID- 29443015 TI - Isolation and Cultivation of Neural Progenitors Followed by Chromatin Immunoprecipitation of Histone 3 Lysine 79 Dimethylation Mark. AB - Brain development is a complex process, which is controlled in a temporo-spatial manner by gradients of morphogens and different transcriptional programs. Additionally, epigenetic chromatin modifications, like histone methylation, have an important role for establishing and maintaining specific cell fates within this process. The vast majority of histone methylation occurs on the flexible histone tail, which is accessible to histone modifiers, erasers, and histone reader proteins. In contrast, H3K79 methylation is located in the globular domain of histone 3 and is implicated in different developmental functions. H3K79 methylation is evolutionarily conserved and can be found in a wide range of species from Homo sapiens to Saccharomyces cerevisiae. The modification occurs in different cell populations within organisms, including neural progenitors. The location of H3K79 methylation in the globular domain of histone 3 makes it difficult to assess. Here, we present methods to isolate and culture cortical progenitor cells (CPCs) from embryonic cortical brain tissue (E11.5-E14.5) or cerebellar granular neuron progenitors (CGNPs) from postnatal tissue (P5-P7), and to efficiently immunoprecipitate H3K79me2 for quantitative PCR (qPCR) and genome wide sequencing. PMID- 29443017 TI - Assessment of DNA Contamination in RNA Samples Based on Ribosomal DNA. AB - One method extensively used for the quantification of gene expression changes and transcript abundances is reverse-transcription quantitative real-time PCR (RT qPCR). It provides accurate, sensitive, reliable, and reproducible results. Several factors can affect the sensitivity and specificity of RT-qPCR. Residual genomic DNA (gDNA) contaminating RNA samples is one of them. In gene expression analysis, non-specific amplification due to gDNA contamination will overestimate the abundance of transcript levels and can affect the RT-qPCR results. Generally, gDNA is detected by qRT-PCR using primer pairs annealing to intergenic regions or an intron of the gene of interest. Unfortunately, intron/exon annotations are not yet known for all genes from vertebrate, bacteria, protist, fungi, plant, and invertebrate metazoan species. Here we present a protocol for detection of gDNA contamination in RNA samples by using ribosomal DNA (rDNA)-based primers. The method is based on the unique features of rDNA: their multigene nature, highly conserved sequences, and high frequency in the genome. Also as a case study, a unique set of primers were designed based on the conserved region of ribosomal DNA (rDNA) in the Poaceae family. The universality of these primer pairs was tested by melt curve analysis and agarose gel electrophoresis. Although our method explains how rDNA-based primers can be applied for the gDNA contamination assay in the Poaceae family, it could be easily used to other prokaryote and eukaryote species. PMID- 29443018 TI - Corneal Tissue Engineering: An In Vitro Model of the Stromal-nerve Interactions of the Human Cornea. AB - Tissue engineering has gained substantial recognition due to the high demand for human cornea replacements with an estimated 10 million people worldwide suffering from corneal vision loss1. To address the demand for viable human corneas, significant progress in three-dimensional (3D) tissue engineering has been made2,3,4. These cornea models range from simple monolayer systems to multilayered models, leading to 3D full-thickness corneal equivalents2. However, the use of a 3D tissue-engineered cornea in the context of in vitro disease models studied to date lacks resemblance to the multilayered 3D corneal tissue structure, function, and the networking of different cell types (i.e., nerve, epithelium, stroma, and endothelium)2,3. In addition, the demand for in vitro cornea tissue models has increased in an attempt to reduce animal testing for pharmaceutical products. Thus, more sophisticated models are required to better match systems to human physiological requirements, and the development of a model that is more relevant to the patient population is absolutely necessary. Given that multiple cell types in the cornea are affected by diseases and dystrophies, such as Keratoconus, Diabetic Keratopathy, and Fuchs, this model includes a 3D co culture model of primary human corneal fibroblasts (HCFs) from healthy donors and neurons from the SH-SY5Y cell line. This allows us for the first time to investigate the interactions between the two cell types within the human corneal tissue. We believe that this model could potentially dissect the underlying mechanisms associated with the stromal-nerve interactions of corneal diseases that exhibit nerve damages. This 3D model mirrors the basic anatomical and physiological nature of the corneal tissue in vivo and can be used in the future as a tool for investigating corneal defects as well as screening the efficacy of various agents before animal testing. PMID- 29443019 TI - A Community-based Stress Management Program: Using Wearable Devices to Assess Whole Body Physiological Responses in Non-laboratory Settings. AB - A pragmatic breath-based intervention to benefit human performance and stress management is timely and valuable to individuals seeking holistic approaches for emotional regulation and optimizing compensatory reserve mechanisms. This protocol is designed to not only teach mind-body awareness but also to provide feedback utilizing physiological data and survey results. The primary findings of this study showed that heart coherence and alpha variables were significantly correlated after four weeks of the breath-based meditation stress protocol. Meditation and rhythmic breathing produced significant increases in alpha brain activity. These brain physiological responses conformed to the Pleth Variability Index (PVI) changes, suggesting the ability of the human body to enter into a meditative state and effectively manage stress. When assessed after four weeks of daily practicing the techniques employed in the stress management protocol, based on the Five Facet Mindfulness Questionnaire, subjects improved in applying mindfulness skills. The overall mindfulness score, Pleth variability index (PVI), and perfusion index (PI) increased after the 4-week intervention period. Results from electroencephalography (brain waves) were consistent with a meditative state during the post-study follow-up session. This provides evidence that wearable devices are feasible for data collection during a breath-based stress management intervention. This protocol can be easily and efficiently implemented into any study design in which physiological data are desired in a non-laboratory-based setting. PMID- 29443021 TI - Measurement & Analysis of the Temporal Discrimination Threshold Applied to Cervical Dystonia. AB - The temporal discrimination threshold (TDT) is the shortest time interval at which an observer can discriminate two sequential stimuli as being asynchronous (typically 30-50 ms). It has been shown to be abnormal (prolonged) in neurological disorders, including cervical dystonia, a phenotype of adult onset idiopathic isolated focal dystonia. The TDT is a quantitative measure of the ability to perceive rapid changes in the environment and is considered indicative of the behavior of the visual neurons in the superior colliculus, a key node in covert attentional orienting. This article sets out methods for measuring the TDT (including two hardware options and two modes of stimuli presentation). We also explore two approaches of data analysis and TDT calculation. The application of the assessment of temporal discrimination to the understanding of the pathogenesis of cervical dystonia and adult onset idiopathic isolated focal dystonia is also discussed. PMID- 29443020 TI - Autologous Microfractured and Purified Adipose Tissue for Arthroscopic Management of Osteochondral Lesions of the Talus. AB - In recent years, regenerative techniques have been increasingly studied and used to treat osteochondral lesions of the talus. In particular, several studies have focused their attention on mesenchymal stem cells derived from adipose tissue. Adipose-derived stem cells (ADSCs) exhibit morphological characteristics and properties similar to other mesenchymal cells, and are able to differentiate into several cellular lines. Moreover, these cells are also widely available in the subcutaneous tissue, representing 10 - 30% of the normal body weight, with a concentration of 5,000 cells per gram of tissue. In the presented technique, the first step involves harvesting ADSCs from the abdomen and a process of microfracture and purification; next, the surgical procedure is performed entirely arthroscopically, with less soft tissue dissection, better joint visualization, and a faster recovery compared with standard open procedures. Arthroscopy is characterized by a first phase in which the lesion is identified, isolated, and prepared with microperforations; the second step, performed dry, involves injection of adipose tissue at the level of the lesion. Between January 2016 and September 2016, four patients underwent arthroscopic treatment of osteochondral lesion of the talus with microfractured and purified adipose tissue. All patients reported clinical improvement six months after surgery with no reported complications. Functional scores at the latest follow-up are encouraging and confirm that the technique provides reliable pain relief and improvements in patients with osteochondral lesion of the talus. PMID- 29443022 TI - Detecting Behavioral Deficits in Rats After Traumatic Brain Injury. AB - With the increasing incidence of traumatic brain injury (TBI) in both civilian and military populations, TBI is now considered a chronic disease; however, few studies have investigated the long-term effects of injury in rodent models of TBI. Shown here are behavioral measures that are well-established in TBI research for times early after injury, such as two weeks, until two months. Some of these methods have previously been used at later times after injury, up to one year, but by very few laboratories. The methods demonstrated here are a short neurological assessment to test reflexes, a Beam-Balance to test balance, a Beam Walk to test balance and motor coordination, and a working memory version of the Morris water maze that can be sensitive to deficits in reference memory. Male rats were handled and pre-trained to neurological, balance, and motor coordination tests prior to receiving parasagittal fluid percussion injury (FPI) or sham injury. Rats can be tested on the short neurological assessment (neuroscore), the beam-balance, and the Beam-Walk multiple times, while testing on the water maze can only be done once. This difference is because rats can remember the task, thus confounding the results if repeated testing is attempted in the same animal. When testing from one to three days after injury, significant differences are detected in all three non-cognitive tasks. However, differences in the Beam-Walk task were not detectable at later time points (after 3 months). Deficits were detected at 3 months in the Beam-Balance and at 6 months in the neuroscore. Deficits in working memory were detected out to 12 months after injury, and a deficit in a reference memory first appeared at 12 months. Thus, standard behavioral tests can be useful measures of persistent behavioral deficits after FPI. PMID- 29443023 TI - Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage. AB - DNA damage induces specific signaling and repair responses in the cell, which is critical for protection of genome integrity. Laser microirradiation became a valuable experimental tool to investigate the DNA damage response (DDR) in vivo. It allows real-time high-resolution single-cell analysis of macromolecular dynamics in response to laser-induced damage confined to a submicrometer region in the cell nucleus. However, various laser conditions have been used without appreciation of differences in the types of damage induced. As a result, the nature of the damage is often not well characterized or controlled, causing apparent inconsistencies in the recruitment or modification profiles. We demonstrated that different irradiation conditions (i.e., different wavelengths as well as different input powers (irradiances) of a femtosecond (fs) near infrared (NIR) laser) induced distinct DDR and repair protein assemblies. This reflects the type of DNA damage produced. This protocol describes how titration of laser input power allows induction of different amounts and complexities of DNA damage, which can easily be monitored by detection of base and crosslinking damages, differential poly (ADP-ribose) (PAR) signaling, and pathway-specific repair factor assemblies at damage sites. Once the damage conditions are determined, it is possible to investigate the effects of different damage complexity and differential damage signaling as well as depletion of upstream factor(s) on any factor of interest. PMID- 29443024 TI - Battery of Behavioral Tests Assessing General Locomotion, Muscular Strength, and Coordination in Mice. AB - Behavioral testing is used in pre-clinical trials to assess the phenotypic effects and outcomes that a particular disease or treatment has on the animal's wellbeing and health. There are numerous behavioral tests that may be applied. We selected a test for general locomotion, the open field test (OFT); a test for muscular strength, the mesh test (MT); and a test for coordination, the rotarod test (RR). Testing can be accomplished on a weekly or monthly basis. As a test for general locomotion, the OFT works by objectively monitoring movement parameters while the mouse is in an open field apparatus. The field is generally a 2' x 2' box, and the movements are recorded through laser sensing or through video capture. The mouse is placed in the center of the open field and allowed to move freely for the test. The MT uses the latency for a mouse to fall off an inverted screen as a measure of muscular strength. A mouse is placed on a screen, which is inverted over a clear box, and is timed for their latency to fall. Three trials are performed, with the best of the three trials scored for that day. A score of 60 s is the maximum time a mouse is left inverted. Mice are given a 5 min rest period between mesh test trials. Lastly, an accelerated protocol on the RR assesses motor coordination and endurance. During a trial, a mouse walks on a rotating rod as it increases in speed from 4 rpm to 40 rpm over 5 min. The trial ends when the mouse touches the magnetized pressure sensor upon falling. Each mouse undergoes three trials, and the best trial is scored for that day. This combined behavioral data allows for the global assessment of mobility, coordination, strength, and movement of the test animals. At least two out of the three behavioral testing measures must show improvement for an animal to qualify as having overall improved motor function. PMID- 29443025 TI - Dendrimer-based Uneven Nanopatterns to Locally Control Surface Adhesiveness: A Method to Direct Chondrogenic Differentiation. AB - Cellular adhesion and differentiation is conditioned by the nanoscale disposition of the extracellular matrix (ECM) components, with local concentrations having a major effect. Here we present a method to obtain large-scale uneven nanopatterns of arginine-glycine-aspartic acid (RGD)-functionalized dendrimers that permit the nanoscale control of local RGD surface density. Nanopatterns are formed by surface adsorption of dendrimers from solutions at different initial concentrations and are characterized by water contact angle (CA), X-ray photoelectron spectroscopy (XPS), and scanning probe microscopy techniques such as scanning tunneling microscopy (STM) and atomic force microscopy (AFM). The local surface density of RGD is measured using AFM images by means of probability contour maps of minimum interparticle distances and then correlated with cell adhesion response and differentiation. The nanopatterning method presented here is a simple procedure that can be scaled up in a straightforward manner to large surface areas. It is thus fully compatible with cell culture protocols and can be applied to other ligands that exert concentration-dependent effects on cells. PMID- 29443026 TI - A Paired Bead and Magnet Array for Molding Microwells with Variable Concave Geometries. AB - A spheroid culture is a useful tool for understanding cellular behavior in that it provides an in vivo-like three-dimensional environment. Various spheroid production methods such as non-adhesive surfaces, spinner flasks, hanging drops, and microwells have been used in studies of cell-to-cell interaction, immune activation, drug screening, stem cell differentiation, and organoid generation. Among these methods, microwells with a three-dimensional concave geometry have gained the attention of scientists and engineers, given their advantages of uniform-sized spheroid generation and the ease with which the responses of individual spheroids can be monitored. Even though cost-effective methods such as the use of flexible membranes and ice lithography have been proposed, these techniques incur serious drawbacks such as difficulty in controlling the pattern sizes, achievement of high aspect ratios, and production of larger areas of microwells. To overcome these problems, we propose a robust method for fabricating concave microwells without the need for complex high-cost facilities. This method utilizes a 30 x 30 through-hole array, several hundred micrometer order steel beads, and magnetic force to fabricate 900 microwells in a 3 cm x 3 cm polydimethylsiloxane (PDMS) substrate. To demonstrate the applicability of our method to cell biological applications, we cultured adipose stem cells for 3 days and successfully produced spheroids using our microwell platform. In addition, we performed a magnetostatic simulation to investigate the mechanism, whereby magnetic force was used to trap the steel beads in the through-holes. We believe that the proposed microwell fabrication method could be applied to many spheroid based cellular studies such as drug screening, tissue regeneration, stem cell differentiation, and cancer metastasis. PMID- 29443027 TI - Personalized Needles for Microinjections in the Rodent Brain. AB - Microinjections have been used for a long time for the delivery of drugs or toxins within specific brain areas and, more recently, they have been used to deliver gene or cell therapy products. Unfortunately, current microinjection techniques use steel or glass needles that are suboptimal for multiple reasons: in particular, steel needles may cause tissue damage, and glass needles may bend when lowered deeply into the brain, missing the target region. In this article, we describe a protocol to prepare and use quartz needles that combine a number of useful features. These needles do not produce detectable tissue damage and, being very rigid, ensure reliable delivery in the desired brain region even when using deep coordinates. Moreover, it is possible to personalize the design of the needle by making multiple holes of the desired diameter. Multiple holes facilitate the injection of large amounts of solution within a larger area, whereas large holes facilitate the injection of cells. In addition, these quartz needles can be cleaned and re-used, such that the procedure becomes cost effective. PMID- 29443028 TI - Microinjection of CRISPR/Cas9 Protein into Channel Catfish, Ictalurus punctatus, Embryos for Gene Editing. AB - The complete genome of the channel catfish, Ictalurus punctatus, has been sequenced, leading to greater opportunities for studying channel catfish gene function. Gene knockout has been used to study these gene functions in vivo. The clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) system is a powerful tool used to edit genomic DNA sequences to alter gene function. While the traditional approach has been to introduce CRISPR/Cas9 mRNA into the single cell embryos through microinjection, this can be a slow and inefficient process in catfish. Here, a detailed protocol for microinjection of channel catfish embryos with CRISPR/Cas9 protein is described. Briefly, eggs and sperm were collected and then artificial fertilization performed. Fertilized eggs were transferred to a Petri dish containing Holtfreter's solution. Injection volume was calibrated and then guide RNAs/Cas9 targeting the toll/interleukin 1 receptor domain-containing adapter molecule (TICAM 1) gene and rhamnose binding lectin (RBL) gene were microinjected into the yolk of one-cell embryos. The gene knockout was successful as indels were confirmed by DNA sequencing. The predicted protein sequence alterations due to these mutations included frameshift and truncated protein due to premature stop codons. PMID- 29443029 TI - In Vivo Multimodal Imaging and Analysis of Mouse Laser-Induced Choroidal Neovascularization Model. AB - Laser-induced choroidal neovascularization (CNV) is a well-established model to mimic the wet form of age-related macular degeneration (AMD). In this protocol, we aim to guide the reader not simply through the technical considerations of generating laser-induced lesions to trigger neovascular processes, but rather focus on the powerful information that can be obtained from multimodal longitudinal in vivo imaging throughout the follow-up period. The laser-induced mouse CNV model was generated by a diode laser administration. Multimodal in vivo imaging techniques were used to monitor CNV induction, progression and regression. First, spectral domain optical coherence tomography (SD-OCT) was performed immediately after the lasering to verify a break of Bruch's membrane. Subsequent in vivo imaging using fluorescein angiography (FA) confirmed successful damage of Bruch's membrane from serial images acquired at the choroidal level. Longitudinal follow-up of CNV proliferation and regression on days 5, 10, and 14 after the lasering was performed using both SD-OCT and FA. Simple and reliable grading of leaky CNV leasions from FA images is presented. Automated segmentation for measurement of total retinal thickness, combined with manual caliber application for measurement of retinal thickness at CNV sites, allow unbiased evaluation of the presence of edema. Finally, histological verification of CNV is performed using isolectin GS-IB4 staining on choroidal flatmounts. The staining is thresholded, and the isolectin-positive area is calculated with ImageJ. This protocol is especially useful in therapeutics studies requiring high-throughput-like screening of CNV pathology as it allows fast, multimodal, and reliable classification of CNV pathology and retinal edema. In addition, high resolution SD-OCT enables the recording of other pathological hallmarks, such as the accumulation of subretinal or intraretinal fluid. However, this method does not provide a possibility to automate CNV volume analysis from SD-OCT images, which has to be performed manually. PMID- 29443030 TI - Treatment of Ankle Osteoarthritis with Total Ankle Replacement Through a Lateral Transfibular Approach. AB - Total ankle replacement (TAR) is a valid option for the treatment of ankle osteoarthritis. The traditional surgical approach for TAR is the anterior approach. Recently, the lateral transfibular approach to the ankle has gained popularity since a new TAR implant was designed to be performed via this approach that results in an ideal visualization of the center of rotation of the ankle and curved resections that allow for sparing bone cuts. The aim of the present paper is to present our preoperative, operative, and postoperative protocols for the treatment of the osteoarthritis of the ankle with TAR via lateral approach. We present our preoperative clinical and radiographic protocol. In addition, we describe our surgical technique with some technical tips. Finally, we report our follow-up schedule that includes the collection of clinical, functional, and radiographic data. The results of this procedure are encouraging: TAR through a lateral transfibular approach provides reliable pain relief and improvements in functional outcomes in patients with ankle osteoarthritis. PMID- 29443031 TI - Ultrasound Cyclo Plasty in Eyes with Glaucoma. AB - Glaucoma is a chronic disease caused by the progressive degeneration of the optical nerve fibers, resulting in decreased visual field that can lead to severe visual impairment, and eventually blindness. This manuscript describes a simple, surgeon-friendly, non-incisional technique, named Ultrasound Cyclo Plasty (UCP), for reducing intraocular pressure (IOP) in glaucoma patients. The technique determines a selective coagulation necrosis of the ciliary body; in addition, the stimulation of supra-choroidal and trans-scleral portions of the uveo-scleral outflow pathway has been recently proposed. UCP shows several technical improvements in ultrasound technology compared to previous techniques, providing more precise focusing on the target zone. The procedure is performed in the operating room under peribulbar anesthesia. Briefly, the coupling cone is put in contact with the eye and the ring probe, that contains six piezoelectric transducers which produce the ultrasound beams, is inserted inside it. Their proper centering over the ocular surface represents a crucial step for the correct targeting of the ciliary body. Sterile balanced salt solution is used to fill the empty spaces to ensure ultrasound acoustic propagation. Surgical treatment consists in the sequential automatic activation of each of the six transducers, for a total duration of less than 3 min. The patient leaves the hospital 1 h after the procedure with the treated eye patched. In the present study, 10 patients with open-angle glaucoma were followed-up during at least 12 months after the procedure. IOP was reduced at each interval compared to pre operative, as well as the number of hypotensive medications. Twenty percent of patients did not respond to the treatment, and needed subsequent surgery to better control IOP. Treatment tolerability was good, with no cases of hypotony or phthisis. The UCP procedure is simpler, faster, safer, and less invasive than traditional cyclodestructive procedures with similar results in reducing IOP. PMID- 29443032 TI - Kinetic Analysis of Vasculogenesis Quantifies Dynamics of Vasculogenesis and Angiogenesis In Vitro. AB - Vasculogenesis is a complex process by which endothelial stem and progenitor cells undergo de novo vessel formation. Quantitative assessment of vasculogenesis has become a central readout of endothelial progenitor cell functionality, and therefore, several attempts have been made to improve both in vitro and in vivo vasculogenesis models. However, standard methods are limited in scope, with static measurements failing to capture many aspects of this highly dynamic process. Therefore, the goal of developing this novel protocol was to assess the kinetics of in vitro vasculogenesis in order to quantitate rates of network formation and stabilization, as well as provide insight into potential mechanisms underlying vascular dysfunction. Application of this protocol is demonstrated using fetal endothelial colony forming cells (ECFCs) exposed to maternal diabetes mellitus. Fetal ECFCs were derived from umbilical cord blood following birth, cultured, and plated in slides containing basement membrane matrix, where they underwent vasculogenesis. Images of the entire slide wells were acquired using time-lapse phase contrast microscopy over 15 hours. Images were analyzed for derivation of quantitative data using an analysis software called Kinetic Analysis of Vasculogenesis (KAV). KAV uses image segmentation followed by skeletonization to analyze network components from stacks of multi-time point phase contrast images to derive ten parameters (9 measured, 1 calculated) of network structure including: closed networks, network areas, nodes, branches, total branch length, average branch length, triple-branched nodes, quad-branched nodes, network structures, and the branch to node ratio. Application of this protocol identified altered rates of vasculogenesis in ECFCs obtained from pregnancies complicated by diabetes mellitus. However, this technique has broad implications beyond the scope reported here. Implementation of this approach will enhance mechanistic assessment and improve functional readouts of vasculogenesis and other biologically important branching processes in numerous cell types or disease states. PMID- 29443033 TI - A Method for the Measurement of Salivary Gland Function in Mice. AB - Patients with Sjogren's syndrome, an autoimmune disease affecting the exocrine glands, develop salivary gland inflammation and have reduced saliva production. Similarly, saliva production is severely compromised in patients receiving radiation treatment for head and neck cancers. Rodent models, developed to mimic these clinical conditions, facilitate an understanding of the disease pathogenesis and allow for the development of new therapeutic strategies. Therefore, the ability to accurately, reproducibly, and repeatedly measure salivary gland function in animal models is critical. Building on procedures previously described in the literature, a method was developed that meets these criteria and was used to evaluate salivary gland function in mice. An additional advantage of this new method is that it is easily mastered, and has little inter operator variation. Salivary gland function is evaluated as the amount (weight or volume) or rate (mL/min) of saliva produced in response to pilocarpine stimulation. The collected saliva is a good source for the analyses of protein content, immunoglobulin concentrations, and other biomolecules. PMID- 29443034 TI - Subretinal Transplantation of Human Embryonic Stem Cell Derived-retinal Pigment Epithelial Cells into a Large-eyed Model of Geographic Atrophy. AB - Geographic atrophy (GA), the late stage of dry age-related macular degeneration is characterized by loss of the retinal pigment epithelial (RPE) layer, which leads to subsequent degeneration of vital retinal structures (e.g., photoreceptors) causing severe vision impairment. Similarly, RPE-loss and decrease in visual acuity is seen in long-term follow up of patients with advanced wet age-related macular degeneration (AMD) receiving intravitreal anti vascular endothelial growth factor (VEGF) treatment. Therefore, on the one hand, it is fundamental to efficiently derive RPE cells from an unlimited source that could serve as replacement therapy. On the other hand, it is important to assess the behavior and integration of the derived cells in a model of the disease entailing surgical and imaging methods as close as possible to those applied in humans. Here, we provide a detailed protocol based on our previous publications that describes the generation of a preclinical model of GA using the albino rabbit eye, for evaluation of the human embryonic stem cell derived retinal pigment epithelial cells (hESC-RPE) in a clinically relevant setting. Differentiated hESC-RPE are transplanted into naive eyes or eyes with NaIO3 induced GA-like retinal degeneration using a 25 G transvitreal pars plana technique. Evaluation of degenerated and transplanted areas is performed by multimodal high-resolution non-invasive real-time imaging. PMID- 29443035 TI - Automated Protocols for Macromolecular Crystallization at the MRC Laboratory of Molecular Biology. AB - When high quality crystals are obtained that diffract X-rays, the crystal structure may be solved at near atomic resolution. The conditions to crystallize proteins, DNAs, RNAs, and their complexes can however not be predicted. Employing a broad variety of conditions is a way to increase the yield of quality diffraction crystals. Two fully automated systems have been developed at the MRC Laboratory of Molecular Biology (Cambridge, England, MRC-LMB) that facilitate crystallization screening against 1,920 initial conditions by vapor diffusion in nanoliter droplets. Semi-automated protocols have also been developed to optimize conditions by changing the concentrations of reagents, the pH, or by introducing additives that potentially enhance properties of the resulting crystals. All the corresponding protocols will be described in detail and briefly discussed. Taken together, they enable convenient and highly efficient macromolecular crystallization in a multi-user facility, while giving the users control over key parameters of their experiments. PMID- 29443036 TI - Reliable Mechanochemistry: Protocols for Reproducible Outcomes of Neat and Liquid Assisted Ball-mill Grinding Experiments. AB - The equilibrium outcomes of ball mill grinding can dramatically change as a function of even tiny variations in the experimental conditions such as the presence of very small amounts of added solvent. To reproducibly and accurately capture this sensitivity, the experimentalist needs to carefully consider every single factor that can affect the ball mill grinding reaction under investigation, from ensuring the grinding jars are clean and dry before use, to accurately adding the stoichiometry of the starting materials, to validating that the delivery of solvent volume is accurate, to ensuring that the interaction between the solvent and the powder is well understood and, if necessary, a specific soaking time is added to the procedure. Preliminary kinetic studies are essential to determine the necessary milling time to achieve equilibrium. Only then can exquisite phase composition curves be obtained as a function of the solvent concentration under ball mill liquid assisted grinding (LAG). By using strict and careful procedures analogous to the ones here presented, such milling equilibrium curves can be obtained for virtually all milling systems. The system we use to demonstrate these procedures is a disulfide exchange reaction starting from the equimolar mixture of two homodimers to obtain at equilibrium quantitative heterodimer. The latter is formed by ball mill grinding as two different polymorphs, Form A and Form B. The ratio R = [Form B] / ([Form A] + [Form B]) at milling equilibrium depends on the nature and concentration of the solvent in the milling jar. PMID- 29443038 TI - All-electronic Nanosecond-resolved Scanning Tunneling Microscopy: Facilitating the Investigation of Single Dopant Charge Dynamics. AB - The miniaturization of semiconductor devices to scales where small numbers of dopants can control device properties requires the development of new techniques capable of characterizing their dynamics. Investigating single dopants requires sub-nanometer spatial resolution, which motivates the use of scanning tunneling microscopy (STM). However, conventional STM is limited to millisecond temporal resolution. Several methods have been developed to overcome this shortcoming, including all-electronic time-resolved STM, which is used in this study to examine dopant dynamics in silicon with nanosecond resolution. The methods presented here are widely accessible and allow for local measurement of a wide variety of dynamics at the atomic scale. A novel time-resolved scanning tunneling spectroscopy technique is presented and used to efficiently search for dynamics. PMID- 29443037 TI - High Resolution 3D Imaging of the Human Pancreas Neuro-insular Network. AB - Using traditional histological methods, researchers are hampered in their ability to image whole tissues or organs in large-scale 3D. Histological sections are generally limited to <20 um as formalin fixed paraffin section on glass slides or <500 um for free-floating fixed sections. Therefore, extensive efforts are required for serial sectioning and large-scale image reconstruction methods to recreate 3D for samples >500 um using traditional methods. In addition, light scatters from macromolecules within tissues, particularly lipids, prevents imaging to a depth >150 um with most confocal microscopes. To reduce light scatter and to allow for deep tissue imaging using simple confocal microscopy, various optical clearing methods have been developed that are relevant for rodent and human tissue samples fixed by immersion. Several methods are related and use protein crosslinking with acrylamide and tissue clearing with sodium dodecyl sulfate (SDS). Other optical clearing techniques used various solvents though each modification had various advantages and disadvantages. Here, an optimized passive optical clearing method is described for studies of the human pancreas innervation and specifically for interrogation of the innervation of human islets. PMID- 29443039 TI - Quantitative Measurement of gamma-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms. AB - We have developed a pair of cell-based reporter gene assays to quantitatively measure gamma-secretase cleavage of distinct substrates. This manuscript describes procedures that may be used to monitor gamma-secretase-mediated cleavage of either APP-C99 or Notch, using a Gal4 promoter-driven firefly luciferase reporter system. These assays were established by stably co transfecting HEK293 cells with the Gal4-driven luciferase reporter gene and either the Gal4/VP16-tagged C-terminal fragment of APP (APP-C99; CG cells), or the Gal4/VP16-tagged Notch-DeltaE (NDeltaE; NG cells). Using these reporter assays in parallel, we have demonstrated that an ErbB2 inhibitor, CL-387,785, can preferentially suppress gamma-secretase cleavage of APP-C99 in CG cells, but not NDeltaE in NG cells. The differential responses exhibited by the CG and NG cells, when treated with CL-387,785, represent a preferred characteristic for gamma secretase modulators, and these responses are in stark contrast to the pan inhibition of gamma-secretase induced by DAPT. Our studies provide direct evidence that gamma-secretase activities toward different substrates can be differentiated in a cellular context. These new assays may therefore be useful tools in drug discovery for improved AD therapies. PMID- 29443040 TI - Total Internal Reflection Absorption Spectroscopy (TIRAS) for the Detection of Solvated Electrons at a Plasma-liquid Interface. AB - The total internal reflection absorption spectroscopy (TIRAS) method presented in this article uses an inexpensive diode laser to detect solvated electrons produced by a low-temperature plasma in contact with an aqueous solution. Solvated electrons are powerful reducing agents, and it has been postulated that they play an important role in the interfacial chemistry between a gaseous plasma or discharge and a conductive liquid. However, due to the high local concentrations of reactive species at the interface, they have a short average lifetime (~1 us), which makes them extremely difficult to detect. The TIRAS technique uses a unique total internal reflection geometry combined with amplitude-modulated lock-in amplification to distinguish solvated electrons' absorbance signal from other spurious noise sources. This enables the in situ detection of short-lived intermediates in the interfacial region, as opposed to the bulk measurement of stable products in the solution. This approach is especially attractive for the field of plasma electrochemistry, where much of the important chemistry is driven by short-lived free radicals. This experimental method has been used to analyze the reduction of nitrite (NO2-(aq)), nitrate (NO3 (aq)), hydrogen peroxide (H2O2(aq)), and dissolved carbon dioxide (CO2(aq)) by plasma-solvated electrons and deduce effective rate constants. Limitations of the method may arise in the presence of unintended parallel reactions, such as air contamination in the plasma, and absorbance measurements may also be hindered by the precipitation of reduced electrochemical products. Overall, the TIRAS method can be a powerful tool for studying the plasma-liquid interface, but its effectiveness depends on the particular system and reaction chemistry under study. PMID- 29443042 TI - Single-cell Microfluidic Analysis of Bacillus subtilis. AB - Microfluidic technology overcomes many of the limitations to traditional analytical methods in microbiology. Unlike bulk-culture methods, it offers single cell resolution and long observation times spanning hundreds of generations; unlike agarose pad-based microscopy, it has uniform growth conditions that can be tightly controlled. Because the continuous flow of growth medium isolates the cells in a microfluidic device from unpredictable variations in the local chemical environment caused by cell growth and metabolism, authentic changes in gene expression and cell growth in response to specific stimuli can be more confidently observed. Bacillus subtilis is used here as a model bacterial species to demonstrate a "mother machine"-type method for cellular analysis. We show how to construct and plumb a microfluidic device, load it with cells, initiate microscopic imaging, and expose cells to a stimulus by switching from one growth medium to another. A stress-responsive reporter is used as an example to reveal the type of data that may be obtained by this method. We also briefly discuss further applications of this method for other types of experiments, such as analysis of bacterial sporulation. PMID- 29443041 TI - In Vitro SUMOylation Assay to Study SUMO E3 Ligase Activity. AB - Small ubiquitin-like modifier (SUMO) modification is an important post translational modification (PTM) that mediates signal transduction primarily through modulating protein-protein interactions. Similar to ubiquitin modification, SUMOylation is directed by a sequential enzyme cascade including E1 activating enzyme (SAE1/SAE2), E2-conjugation enzyme (Ubc9), and E3-ligase (i.e., PIAS family, RanBP2, and Pc2). However, different from ubiquitination, an E3 ligase is non-essential for the reaction but does provide precision and efficacy for SUMO conjugation. Proteins modified by SUMOylation can be identified by in vivo assay via immunoprecipitation with substrate-specific antibodies and immunoblotting with SUMO-specific antibodies. However, the demonstration of protein SUMO E3 ligase activity requires in vitro reconstitution of SUMOylation assays using purified enzymes, substrate, and SUMO proteins. Since in the in vitro reactions, usually SAE1/SAE2 and Ubc9, alone are sufficient for SUMO conjugation, enhancement of SUMOylation by a putative E3 ligase is not always easy to detect. Here, we describe a modified in vitro SUMOylation protocol that consistently identifies SUMO modification using an in vitro reconstituted system. A step-by-step protocol to purify catalytically active K-bZIP, a viral SUMO-2/3 E3 ligase, is also presented. The SUMOylation activities of the purified K-bZIP are shown on p53, a well-known target of SUMO. This protocol can not only be employed for elucidating novel SUMO E3 ligases, but also for revealing their SUMO paralog specificity. PMID- 29443043 TI - A Microcontroller Operated Device for the Generation of Liquid Extracts from Conventional Cigarette Smoke and Electronic Cigarette Aerosol. AB - Electronic cigarettes are the most popular tobacco product among middle and high schoolers and are the most popular alternative tobacco product among adults. High quality, reproducible research on the consequences of electronic cigarette use is essential for understanding emerging public health concerns and crafting evidence based regulatory policy. While a growing number of papers discuss electronic cigarettes, there is little consistency in methods across groups and very little consensus on results. Here, we describe a programmable laboratory device that can be used to create extracts of conventional cigarette smoke and electronic cigarette aerosol. This protocol details instructions for the assembly and operation of said device, and demonstrates the use of the generated extract in two sample applications: an in vitro cell viability assay and gas-chromatography mass-spectrometry. This method provides a tool for making direct comparisons between conventional cigarettes and electronic cigarettes, and is an accessible entry point into electronic cigarette research. PMID- 29443044 TI - Scanning Skeletal Remains for Bone Mineral Density in Forensic Contexts. AB - The purpose of this paper is to introduce a promising, novel method to aid in the assessment of bone quality in forensically relevant skeletal remains. BMD is an important component of bone's nutritional status and in skeletal remains of both juveniles and adults, and it can provide information about bone quality. For adults remains, it can provide information on pathological conditions or when bone insufficiency may have occurred. In juveniles, it provides a useful metric to elucidate cases of fatal starvation or neglect, which are generally difficult to identify. This paper provides a protocol for the anatomical orientation and analysis of skeletal remains for scanning via dual-energy X-ray absorptiometry (DXA). Three case studies are presented to illustrate when DXA scans can be informative to the forensic practitioner. The first case study presents an individual with observed longitudinal fractures in the weight bearing bones and DXA is used to assess bone insufficiency. BMD is found to be normal suggesting another etiology for the fracture pattern present. The second case study employed DXA to investigate suspected chronic malnutrition. The BMD results are consistent with results from long bone lengths and suggest the juvenile had suffered from chronic malnutrition. The final case study provides an example where fatal starvation in a fourteen-month infant is suspected, which supports autopsy findings of fatal starvation. DXA scans showed low bone mineral density for chronological age and is substantiated by traditional assessments of infant health. However, when dealing with skeletal remains taphonomic alterations should be considered before applying this method. PMID- 29443046 TI - A Simple Planting Technique for Re-establishing Trees Where Frequent Inundation Occurs. AB - Many of the Everglades tree islands have lost elevation over the past century and most of their trees have died such that they are now covered with herbaceous plants. This protocol describes a simple, cost-effective tree planting technique needed for restoring degraded Everglade tree islands. The design is patterned after a natural Everglades process that creates floating peat islands, which allows tree survival and growth in flooded conditions and often leads to the development of tree islands. Commercially available peat bags were used as the medium for the growth and establishment of potted native tree saplings. The pop up configuration floated initially and provided additional elevation to minimize inundation, with a single native tree species sapling and a single tree fertilizer spike. During a 3 year study involving 105 pop-ups, most plants survived (80%) and many thrived. Determining whether this technique can establish trees on a degraded tree island will require longer studies and extensive field tests. PMID- 29443045 TI - Routine Screening Method for Microparticles in Platelet Transfusions. AB - Platelet inventory management based on screening microparticle content in platelet concentrates is a new quality improvement initiative for hospital blood banks. Cells fragment off microparticles (MP) when they are stressed. Blood and blood components may contain cellular fragments from a variety of cells, most notably from activated platelets. When performing their roles as innate immune cells and major players in coagulation and hemostasis, platelets change shape and generate microparticles. With dynamic light scattering (DLS)-based microparticle detection, it is possible to differentiate activated (high microparticle) from non-activated (low microparticle) platelets in transfusions, and optimize the use of this scarce blood product. Previous research suggests that providing non activated platelets for prophylactic use in hematology-oncology patients could reduce their risk of becoming refractory and improve patient care. The goal of this screening method is to routinely differentiate activated from non-activated platelets. The method described here outlines the steps to be performed for routine platelet inventory management in a hospital blood bank: obtaining a sample from a platelet transfusion, loading the sample into the capillary for DLS measurement, performing the DLS test to identify microparticles, and using the reported microparticle content to identify activated platelets. PMID- 29443047 TI - Application of Chronic Stimulation to Study Contractile Activity-induced Rat Skeletal Muscle Phenotypic Adaptations. AB - Skeletal muscle is a highly adaptable tissue, as its biochemical and physiological properties are greatly altered in response to chronic exercise. To investigate the underlying mechanisms that bring about various muscle adaptations, a number of exercise protocols such as treadmill, wheel running, and swimming exercise have been used in the animal studies. However, these exercise models require a long period of time to achieve muscle adaptations, which may be also regulated by humoral or neurological factors, thus limiting their applications in studying the muscle-specific contraction-induced adaptations. Indirect low frequency stimulation (10 Hz) to induce chronic contractile activity (CCA) has been used as an alternative model for exercise training, as it can successfully lead to muscle mitochondrial adaptations within 7 days, independent of systemic factors. This paper details the surgical techniques required to apply the treatment of CCA to the skeletal muscle of rats, for widespread application in future studies. PMID- 29443048 TI - Generation of Standardized and Reproducible Forebrain-type Cerebral Organoids from Human Induced Pluripotent Stem Cells. AB - The human cortex is highly expanded and exhibits a complex structure with specific functional areas, providing higher brain function, such as cognition. Efforts to study human cerebral cortex development have been limited by the availability of model systems. Translating results from rodent studies to the human system is restricted by species differences and studies on human primary tissues are hampered by a lack of tissue availability as well as ethical concerns. Recent development in human pluripotent stem cell (PSC) technology include the generation of three-dimensional (3D) self-organizing organotypic culture systems, which mimic to a certain extent human-specific brain development in vitro. Currently, various protocols are available for the generation of either whole brain or brain-region specific organoids. The method for the generation of homogeneous and reproducible forebrain-type organoids from induced PSC (iPSC), which we previously established and describe here, combines the intrinsic ability of PSC to self-organize with guided differentiation towards the anterior neuroectodermal lineage and matrix embedding to support the formation of a continuous neuroepithelium. More specifically, this protocol involves: (1) the generation of iPSC aggregates, including the conversion of iPSC colonies to a confluent monolayer culture; (2) the induction of anterior neuroectoderm; (3) the embedding of neuroectodermal aggregates in a matrix scaffold; (4) the generation of forebrain-type organoids from neuroectodermal aggregates; and (5) the fixation and validation of forebrain-type organoids. As such, this protocol provides an easily applicable system for the generation of standardized and reproducible iPSC derived cortical tissue structures in vitro. PMID- 29443049 TI - Handling and Treatment of Male European Eels (Anguilla anguilla) for Hormonal Maturation and Sperm Cryopreservation. AB - During the last years, several research groups have been working on the development and improvement of new protocols for the European eel handling and maturation. As of yet, weekly injections of human chorionic gonadotropin (hCG) have proved to maturate males after just 5-6 weeks of treatment, producing high volumes of high-quality sperm during several weeks. In addition, sperm cryopreservation protocols using different extenders, cryoprotectants and cooling and thawing times have been previously described for European eel. Here, we show that Tanaka's extender solution can be directly used for fertilization or for cryopreservation, making unnecessary the usage of different types of solutions and dilutions. Furthermore, the use of methanol as a cryoprotectant makes this protocol easy to use as methanol has low toxicity and does not activate the sperm. The sperm does not need to be cryopreserved immediately after the addition of the cryoprotectant, and it can be used long after being thawed. Moreover, sperm motility is still high after thawing although it is lower than that of fresh sperm. The aim of this work is to show the best available protocol for European eel handling, maturation, and sperm cryopreservation. PMID- 29443050 TI - A Co-culture Method to Investigate the Crosstalk Between X-ray Irradiated Caco-2 Cells and PBMC. AB - The protocol adopted in this work aims at unraveling how X-rays perturb the functioning of the intestinal barrier, focusing on the interplay between colorectal tumor cells and the immune system. Colorectal carcinoma is among the most common type of cancer, typically treated by surgery, chemotherapy, and radiotherapy. Advantages of radiotherapy in targeting the tumor are well known. However, even limited exposures of healthy tissues are of great concern, particularly regarding the effects on the intestinal barrier and the immune system. The adopted setup allows to study the interplay between two cell populations in a condition more similar to the physiological one, when compared to normal cell cultures. For this purpose, we resort to different techniques and we used an in vitro co-culture model, based on Caco-2 cells differentiated as a monolayer and PBMC, sharing the same culture medium. This protocol has been developed to focus on both macroscopic effects, i.e. cell viability and Trans Epithelial Electrical Resistance (TEER), and, through western blot, molecular alterations, i.e. the activation of inflammatory pathway in immune cells and the tight junction protein expression in Caco-2 cells. Initial evaluation of radiation effects on Caco-2 cell viability was assessed via the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Trypan blue assays, while TEER was measured at fixed time intervals through an ohmmeter specifically designed for co-culture systems. In this way, the effects due to radiation, the presence of Peripheral Blood Mononuclear Cells (PBMC), and eventually their synergistic effect, can be demonstrated. Through these complementary techniques, we observed a high radio-resistance of Caco-2 within the range of 2 - 10 Gy of X-rays and an increased Caco-2 monolayer permeability when PBMCs were added. In particular, PBMC presence was found to be associated with the variation in the tight junction scaffold proteins expression. PMID- 29443052 TI - Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice. AB - Tumor and tumor vessel development, as well as tumor response to therapeutics, are highly dynamic biological processes. Histology provides static information and is often not sufficient for a correct interpretation. Intravital evaluation, in which a process is followed in time, provides extra and often unexpected information. With the creation of transgenic animals expressing cell-specific markers and live cell tracers, improvements to imaging equipment, and the development of several imaging chambers, intravital microscopy has become an important tool to better understand biological processes. This paper describes an experimental design for the investigation of tumor vessel development and of therapeutic effects in a spatial and temporal manner. Using this setup, the stage of vessel development, tip cell and lumen formation, blood flow, extravasation, an established vascular bed, and vascular destruction can be visualized and followed. Furthermore, therapeutic effects, intratumoral fate, and the localization of chemotherapeutic compounds can also be followed. PMID- 29443051 TI - Detecting Anastasis In Vivo by CaspaseTracker Biosensor. AB - Anastasis (Greek for "rising to life") is a recently discovered cell recovery phenomenon whereby dying cells can reverse late-stage cell death processes that are generally assumed to be intrinsically irreversible. Promoting anastasis could in principle rescue or preserve injured cells that are difficult to replace such as cardiomyocytes or neurons, thereby facilitating tissue recovery. Conversely, suppressing anastasis in cancer cells, undergoing apoptosis after anti-cancer therapies, may ensure cancer cell death and reduce the chances of recurrence. However, these studies have been hampered by the lack of tools for tracking the fate of cells that undergo anastasis in live animals. The challenge is to identify the cells that have reversed the cell death process despite their morphologically normal appearance after recovery. To overcome this difficulty, we have developed Drosophila and mammalian CaspaseTracker biosensor systems that can identify and permanently track the anastatic cells in vitro or in vivo. Here, we present in vivo protocols for the generation and use of the CaspaseTracker dual biosensor system to detect and track anastasis in Drosophila melanogaster after transient exposure to cell death stimuli. While conventional biosensors and protocols can label cells actively undergoing apoptotic cell death, the CaspaseTracker biosensor can permanently label cells that have recovered after caspase activation - a hallmark of late-stage apoptosis, and simultaneously identify active apoptotic processes. This biosensor can also track the recovery of the cells that attempted other forms of cell death that directly or indirectly involved caspase activity. Therefore, this protocol enables us to continuously track the fate of these cells and their progeny, facilitating future studies of the biological functions, molecular mechanisms, physiological and pathological consequences, and therapeutic implications of anastasis. We also discuss the appropriate controls to distinguish cells that undergo anastasis from those that display non-apoptotic caspase activity in vivo. PMID- 29443053 TI - Neuroimaging Field Methods Using Functional Near Infrared Spectroscopy (NIRS) Neuroimaging to Study Global Child Development: Rural Sub-Saharan Africa. AB - Portable neuroimaging approaches provide new advances to the study of brain function and brain development with previously inaccessible populations and in remote locations. This paper shows the development of field functional Near Infrared Spectroscopy (fNIRS) imaging to the study of child language, reading, and cognitive development in a rural village setting of Cote d'Ivoire. Innovation in methods and the development of culturally appropriate neuroimaging protocols allow a first-time look into the brain's development and children's learning outcomes in understudied environments. This paper demonstrates protocols for transporting and setting up a mobile laboratory, discusses considerations for field versus laboratory neuroimaging, and presents a guide for developing neuroimaging consent procedures and building meaningful long-term collaborations with local government and science partners. Portable neuroimaging methods can be used to study complex child development contexts, including the impact of significant poverty and adversity on brain development. The protocol presented here has been developed for use in Cote d'Ivoire, the world's primary source of cocoa, and where reports of child labor in the cocoa sector are common. Yet, little is known about the impact of child labor on brain development and learning. Field neuroimaging methods have the potential to yield new insights into such urgent issues, and the development of children globally. PMID- 29443054 TI - The Mouse Hindbrain As a Model for Studying Embryonic Neurogenesis. AB - The mouse embryo forebrain is the most commonly employed system for studying mammalian neurogenesis during development. However, the highly folded forebrain neuroepithelium is not amenable to wholemount analysis to examine organ-wide neurogenesis patterns. Moreover, defining the mechanisms of forebrain neurogenesis is not necessarily predictive of neurogenesis in other parts of the brain; for example, due to the presence of forebrain-specific progenitor subtypes. The mouse hindbrain provides an alternative model for studying embryonic neurogenesis that is amenable to wholemount analysis, as well as tissue sections to observe the spatiotemporal distribution and behavior of neural progenitors. Moreover, it is easily dissected for other downstream applications, such as cell isolation or molecular biology analysis. As the mouse hindbrain can be readily analyzed in the vast number of cell lineage reporter and mutant mouse strains that have become available, it offers a powerful model for studying the cellular and molecular mechanisms of developmental neurogenesis in a mammalian organism. Here, we present a simple and quick method to use the mouse embryo hindbrain for analyzing mammalian neural progenitor cell (NPC) behavior in wholemount preparations and tissue sections. PMID- 29443055 TI - A Seminiferous Tubule Squash Technique for the Cytological Analysis of Spermatogenesis Using the Mouse Model. AB - Meiotic progression in males is a process that requires the concerted action of a number of highly regulated cellular events. Errors occurring during meiosis can lead to infertility, pregnancy loss or genetic defects. Commencing at the onset of puberty and continuing throughout adulthood, continuous semi-synchronous waves of spermatocytes undergo spermatogenesis and ultimately form haploid sperm. The first wave of mouse spermatocytes undergoing meiotic initiation appear at day 10 post-partum (10 dpp) and are released into the lumen of seminiferous tubules as mature sperm at 35 dpp. Therefore, it is advantageous to utilize mice within this developmental time-window in order to obtain highly enriched populations of interest. Analysis of rare cell stages is more difficult in older mice due to the contribution of successive spermatogenic waves, which increase the diversity of the cellular populations within the tubules. The method described here is an easily implemented technique for the cytological evaluation of the cells found within the seminiferous tubules of mice, including spermatogonia, spermatocytes, and spermatids. The tubule squash technique maintains the integrity of isolated male germ cells and allows examination of cellular structures that are not easily visualized with other techniques. To demonstrate the possible applications of this tubule squash technique, spindle assembly was monitored in spermatocytes progressing through the prophase to metaphase I transition (G2/MI transition). In addition, centrosome duplication, meiotic sex chromosome inactivation (MSCI), and chromosome bouquet formation were assessed as examples of the cytological structures that can be observed using this tubule squash method. This technique can be used to pinpoint specific defects during spermatogenesis that are caused by mutation or exogenous perturbation, and thus, contributes to our molecular understanding of spermatogenesis. PMID- 29443056 TI - Primordial Germ Cell Transplantation for CRISPR/Cas9-based Leapfrogging in Xenopus. AB - The creation of mutant lines by genome editing is accelerating genetic analysis in many organisms. CRISPR/Cas9 methods have been adapted for use in the African clawed frog, Xenopus, a longstanding model organism for biomedical research. Traditional breeding schemes for creating homozygous mutant lines with CRISPR/Cas9-targeted mutagenesis have several time-consuming and laborious steps. To facilitate the creation of mutant embryos, particularly to overcome the obstacles associated with knocking out genes that are essential for embryogenesis, a new method called leapfrogging was developed. This technique leverages the robustness of Xenopus embryos to "cut and paste" embryological methods. Leapfrogging utilizes the transfer of primordial germ cells (PGCs) from efficiently-mutagenized donor embryos into PGC-ablated wildtype siblings. This method allows for the efficient mutation of essential genes by creating chimeric animals with wildtype somatic cells that carry a mutant germline. When two F0 animals carrying "leapfrog transplants" (i.e., mutant germ cells) are intercrossed, they produce homozygous, or compound heterozygous, null F1 embryos, thus saving a full generation time to obtain phenotypic data. Leapfrogging also provides a new approach for analyzing maternal effect genes, which are refractory to F0 phenotypic analysis following CRISPR/Cas9 mutagenesis. This manuscript details the method of leapfrogging, with special emphasis on how to successfully perform PGC transplantation. PMID- 29443057 TI - Functional Imaging of Viral Transcription Factories Using 3D Fluorescence Microscopy. AB - It is well known that spatial and temporal regulation of genes is an integral part of governing proper gene expression. Consequently, it is invaluable to understand where and when transcription is taking place within nuclear space and to visualize the relationship between episomes infected within the same cell's nucleus. Here, both immunofluorescence (IFA) and RNA-FISH have been combinedto identify actively transcribing Kaposi's sarcoma-associated herpesvirus (KSHV) episomes. By staining KSHV latency-associated nuclear antigen (LANA), it is possible to locate where viral episomes exist within the nucleus. In addition, by designing RNA-FISH probes to target the intron region of a viral gene, which is expressed only during productive infection, nascent RNA transcripts can be located. Using this combination of molecular probes, it is possible to visualize the assembly of large viral transcription factories and analyze the spatial regulation of viral gene expression during KSHV reactivation. By including anti RNA polymerase II antibody staining, one can also visualize the association between RNA polymerase II (RNAPII) aggregation and KSHV transcription during reactivation. PMID- 29443058 TI - Two-photon Intravital Imaging of Leukocytes During the Immune Response in Lipopolysaccharide-treated Mouse Liver. AB - Sepsis is a type of severe infection that can cause organ failure and tissue damage. Although the mortality and morbidity rates associated with sepsis are extremely high, no direct treatment or organ-related mechanism has been examined in detail in real time. The liver is the key organ that manages toxins and infections in the human body. Herein, we aimed to perform intravital imaging of mouse liver after induction of endotoxemia in order to track the motility of immune cells, such as neutrophils and liver capsular macrophages (LCMs). Accordingly, we designed a novel surgical method for exposure of the liver with minimally invasive surgery. Mice were intraperitoneally injected with lipopolysaccharide (LPS), a common endotoxin. Using our novel surgical approach for exposure and intravital imaging of the mouse liver, we found that neutrophil recruitment in LPS-treated LysM-green fluorescent protein (GFP) mouse liver was increased compared with that in phosphate-buffered saline-treated liver. After LPS treatment, the number of neutrophils increased significantly with time. Additionally, using CX3Cr1-GFP mice, we successfully visualized liver resident macrophages called LCMs. Therefore, to investigate the efficacy of new reagents to control immune mobility in vivo, determining the motility and morphology of neutrophils and LCMs in the liver may allow us to identify therapeutic effect in organ failure and tissue damage caused by leukocytes activation in sepsis. PMID- 29443059 TI - In Vivo Electrophysiological Measurement of the Rat Ulnar Nerve with Axonal Excitability Testing. AB - Electrophysiology enables the objective assessment of peripheral nerve function in vivo. Traditional nerve conduction measures such as amplitude and latency detect chronic axon loss and demyelination, respectively. Axonal excitability techniques "by threshold tracking" expand upon these measures by providing information regarding the activity of ion channels, pumps and exchangers that relate to acute function and may precede degenerative events. As such, the use of axonal excitability in animal models of neurological disorders may provide a useful in vivo measure to assess novel therapeutic interventions. Here we describe an experimental setup for multiple measures of motor axonal excitability techniques in the rat ulnar nerve. The animals are anesthetized with isoflurane and carefully monitored to ensure constant and adequate depth of anesthesia. Body temperature, respiration rate, heart rate and saturation of oxygen in the blood are continuously monitored. Axonal excitability studies are performed using percutaneous stimulation of the ulnar nerve and recording from the hypothenar muscles of the forelimb paw. With correct electrode placement, a clear compound muscle action potential that increases in amplitude with increasing stimulus intensity is recorded. An automated program is then utilized to deliver a series of electrical pulses which generate 5 specific excitability measures in the following sequence: stimulus response behavior, strength duration time constant, threshold electrotonus, current-threshold relationship and the recovery cycle. Data presented here indicate that these measures are repeatable and show similarity between left and right ulnar nerves when assessed on the same day. A limitation of these techniques in this setting is the effect of dose and time under anesthesia. Careful monitoring and recording of these variables should be undertaken for consideration at the time of analysis. PMID- 29443060 TI - Avian Semen Collection by Cloacal Massage and Isolation of DNA from Sperm. AB - Collection of semen may be useful for a wide range of applications including studies involving sperm quality, sperm telomere dynamics, and epigenetics. Birds are widely used subjects in biological research and are ideal for studies involving repeated sperm samples. However, few resources are currently available for those wishing to learn how to collect and extract DNA from avian sperm. Here we describe cloacal massage, a gentle, non-invasive manual technique for collecting avian sperm. Although this technique is established in the literature, it can be difficult to learn from the available descriptions. We also provide information for extracting DNA from avian semen using a commercial extraction kit with modifications. Cloacal massage can be easily used on any small- to medium sized male bird in reproductive condition. Following collection, the semen can be used immediately for motility assays, or frozen for DNA extraction following the protocol described herein. This extraction protocol was refined for avian sperm and has been successfully used on samples collected from several passerine species (Passer domesticus, Spizella passerina, Haemorhous mexicanus, and Turdus migratorius) and one columbid (Columba livia). PMID- 29443061 TI - Detecting the Lyme Disease Spirochete, Borrelia Burgdorferi, in Ticks Using Nested PCR. AB - Lyme disease is a serious vector-borne infection that is caused by the Borrelia burgdorferi sensu lato family of spirochetes, which are transmitted to humans through the bite of infected Ixodes ticks. The primary etiological agent in North America is Borrelia burgdorferi sensu stricto. As geographic risk regions expand, it is prudent to support robust surveillance programs that can measure tick infection rates, and communicate findings to clinicians, veterinarians, and the general public. The molecular technique of nested polymerase chain reaction (nPCR) has long been used for this purpose, and it remains a central, inexpensive, and robust approach in the detection of Borrelia in both ticks and wildlife. This article demonstrates the application of nPCR to tick DNA extracts to identify infected specimens. Two independent B. burgdorferi targets, genes encoding Flagellin B (FlaB) and Outer surface protein A (OspA), have been used extensively with this technique. The protocol involves tick collection, DNA extraction, and then an initial round of PCR to detect each of the two Borrelia specific loci. Subsequent polymerase chain reaction (PCR) uses the product of the first reaction as a new template to generate smaller, internal amplification fragments. The nested approach improves upon both the specificity and sensitivity of conventional PCR. A tick is considered positive for the pathogen when inner amplicons from both Borrelia genes can be detected by agarose gel electrophoresis. PMID- 29443062 TI - Generation of Discriminative Human Monoclonal Antibodies from Rare Antigen specific B Cells Circulating in Blood. AB - Monoclonal antibodies (mAbs) are powerful tools useful for both fundamental research and in biomedicine. Their high specificity is indispensable when the antibody needs to distinguish between highly related structures (e.g., a normal protein and a mutated version thereof). The current way of generating such discriminative mAbs involves extensive screening of multiple Ab-producing B cells, which is both costly and time consuming. We propose here a rapid and cost effective method for the generation of discriminative, fully human mAbs starting from human blood circulating B lymphocytes. The originality of this strategy is due to the selection of specific antigen binding B cells combined with the counter-selection of all other cells, using readily available Peripheral Blood Mononuclear Cells (PBMC). Once specific B cells are isolated, cDNA (complementary deoxyribonucleic acid) sequences coding for the corresponding mAb are obtained using single cell Reverse Transcription-Polymerase Chain Reaction (RT-PCR) technology and subsequently expressed in human cells. Within as little as 1 month, it is possible to produce milligrams of highly discriminative human mAbs directed against virtually any desired antigen naturally detected by the B cell repertoire. PMID- 29443063 TI - In Situ Detection and Single Cell Quantification of Metal Oxide Nanoparticles Using Nuclear Microprobe Analysis. AB - Micro-analytical techniques based on chemical element imaging enable the localization and quantification of chemical composition at the cellular level. They offer new possibilities for the characterization of living systems and are particularly appropriate for detecting, localizing and quantifying the presence of metal oxide nanoparticles both in biological specimens and the environment. Indeed, these techniques all meet relevant requirements in terms of (i) sensitivity (from 1 up to 10 ug.g-1 of dry mass), (ii) micrometer range spatial resolution, and (iii) multi-element detection. Given these characteristics, microbeam chemical element imaging can powerfully complement routine imaging techniques such as optical and fluorescence microscopy. This protocol describes how to perform a nuclear microprobe analysis on cultured cells (U2OS) exposed to titanium dioxide nanoparticles. Cells must grow on and be exposed directly in a specially designed sample holder used on the optical microscope and in the nuclear microprobe analysis stages. Plunge-freeze cryogenic fixation of the samples preserves both the cellular organization and the chemical element distribution. Simultaneous nuclear microprobe analysis (scanning transmission ion microscopy, Rutherford backscattering spectrometry and particle induced X-ray emission) performed on the sample provides information about the cellular density, the local distribution of the chemical elements, as well as the cellular content of nanoparticles. There is a growing need for such analytical tools within biology, especially in the emerging context of Nanotoxicology and Nanomedicine for which our comprehension of the interactions between nanoparticles and biological samples must be deepened. In particular, as nuclear microprobe analysis does not require nanoparticles to be labelled, nanoparticle abundances are quantifiable down to the individual cell level in a cell population, independently of their surface state. PMID- 29443064 TI - Assessment of Social Transmission of Food Preferences Behaviors. AB - Olfactory recognition deficits are suggested to be able to serve as clinical marker to differentiate Alzheimer's disease (AD) subjects from healthy aging groups. For example, olfactory dysfunction in AD can present as impairment in olfactory recognition, emerging during early stages of the disease and worsening while the disease progresses. The social transmission of food preferences (STFP) task is based on a rudimentary form of communication between rodents concerning distant foods dependent on the transmission of olfactory cues. Healthy wild-type mice would prefer to eat a novel, flavored food that was previously cued by a conspecific, and this food preference would be hampered in transgenic AD mice, such as the APP/PS1 model. Indeed, a strong preference for the cued food in C57Bl6/J mice of 3 months of age was found, and this was reduced in 3 months old transgenic APP/PS1 mice. In summary, STFP task could be a powerful measure to be integrated in present subclinical detection assays of AD. PMID- 29443065 TI - Balloon-based Injury to Induce Myointimal Hyperplasia in the Mouse Abdominal Aorta. AB - The use of animal models is essential for a better understanding of MH, one major cause for arterial stenosis.In this article, we demonstrate a murine balloon denudation model, which is comparable with established vessel injury models in large animals. The aorta denudation model with balloon catheters mimics the clinical setting and leads to comparable pathobiological and physiological changes. Briefly, after performing a horizontal incision in the aorta abdominalis, a balloon catheter will be inserted into the vessel, inflated, and introduced retrogradely. Inflation of the balloon will lead to intima injury and overdistension of the vessel. After removing the catheter, the aortic incision will be closed with single stiches. The model shown in this article is reproducible, easy to perform, and can be established quickly and reliably. It is especially suitable for evaluating expensive experimental therapeutic agents, which can be applied in an economical fashion. By using different knockout-mouse strains, the impact of different genes on MH development can be assessed. PMID- 29443066 TI - Constitutive and Inducible Systems for Genetic In Vivo Modification of Mouse Hepatocytes Using Hydrodynamic Tail Vein Injection. AB - In research models of liver cancer, regeneration, inflammation, and fibrosis, flexible systems for in vivo gene expression and silencing are highly useful. Hydrodynamic tail vein injection of transposon-based constructs is an efficient method for genetic manipulation of hepatocytes in adult mice. In addition to constitutive transgene expression, this system can be used for more advanced applications, such as shRNA-mediated gene knock-down, implication of the CRISPR/Cas9 system to induce gene mutations, or inducible systems. Here, the combination of constitutive CreER expression together with inducible expression of a transgene or miR-shRNA of choice is presented as an example of this technique. We cover the multi-step procedure starting from the preparation of sleeping beauty-transposon constructs, to the injection and treatment of mice, and the preparation of liver tissue for analysis by immunostaining. The system presented is a reliable and efficient approach to achieve complex genetic manipulations in hepatocytes. It is specifically useful in combination with Cre/loxP-based mouse strains and can be applied to a variety of models in the research of liver disease. PMID- 29443067 TI - High-resolution Respirometry to Measure Mitochondrial Function of Intact Beta Cells in the Presence of Natural Compounds. AB - High-resolution respirometry allows for the measurement of oxygen consumption of isolated mitochondria, cells and tissues. Beta cells play a critical role in the body by controlling blood glucose levels through insulin secretion in response to elevated glucose concentrations. Insulin secretion is controlled by glucose metabolism and mitochondrial respiration. Therefore, measuring intact beta cell respiration is essential to be able to improve beta cell function as a treatment for diabetes. Using intact 832/13 INS-1 derived beta cells we can measure the effect of increasing glucose concentration on cellular respiration. This protocol allows us to measure beta cell respiration in the presence or absence of various compounds, allowing one to determine the effect of given compounds on intact cell respiration. Here we demonstrate the effect of two naturally occurring compounds, monomeric epicatechin and curcumin, on beta cell respiration under the presence of low (2.5 mM) or high glucose (16.7 mM) conditions. This technique can be used to determine the effect of various compounds on intact beta cell respiration in the presence of differing glucose concentrations. PMID- 29443068 TI - Design and Characterization Methodology for Efficient Wide Range Tunable MEMS Filters. AB - Here, we demonstrate the advantages of the laser Doppler vibrometer (LDV) over conventional techniques (the network analyzer), as well as the techniques to create an application-based microelectromechanical systems (MEMS) filter and how to use it efficiently (i.e., tuning the tuning-capability and avoiding both failure and stiction). LDV enables crucial measurements that are impossible with the network analyzer, such as higher mode detection (highly sensitive biosensor application) and resonance measurement for very small devices (fast prototyping). Accordingly, LDV was used to characterize the frequency tuning range and resonance frequency at different modes of the MEMS filters built for this study. This wide range frequency tuning mechanism is based simply on Joule heating from the embedded heaters and relatively high thermal stress with respect to the temperature of a fixed-fixed beam. However, we demonstrate that another limitation of this method is the resulting high thermal stress, which can burn the devices. Further improvement was achieved and shown for the first time in this study, such that the tuning capability was increased by 32% through an increase in the applied DC bias voltage (25 V to 35 V) between the two adjacent beams. This important finding eliminates the need for the extra Joule heating at the wider frequency tuning range. Another possible failure is through stiction and requirement of structure optimization: We propose a simple and easy technique of low frequency square wave signal application that can successfully separate the beams and eliminates the need for the more sophisticated and complicated methods given in the literature. The above findings necessitate a design methodology, and so we also provide an application-based design. PMID- 29443069 TI - The Use of a beta-lactamase-based Conductimetric Biosensor Assay to Detect Biomolecular Interactions. AB - Biosensors are becoming increasingly important and implemented in various fields such as pathogen detection, molecular diagnosis, environmental monitoring, and food safety control. In this context, we used beta-lactamases as efficient reporter enzymes in several protein-protein interaction studies. Furthermore, their ability to accept insertions of peptides or structured proteins/domains strongly encourages the use of these enzymes to generate chimeric proteins. In a recent study, we inserted a single-domain antibody fragment into the Bacillus licheniformis BlaP beta-lactamase. These small domains, also called nanobodies, are defined as the antigen-binding domains of single chain antibodies from camelids. Like common double chain antibodies, they show high affinities and specificities for their targets. The resulting chimeric protein exhibited a high affinity against its target while retaining the beta-lactamase activity. This suggests that the nanobody and beta-lactamase moieties remain functional. In the present work, we report a detailed protocol that combines our hybrid beta lactamase system to the biosensor technology. The specific binding of the nanobody to its target can be detected thanks to a conductimetric measurement of the protons released by the catalytic activity of the enzyme. PMID- 29443070 TI - Application of Electrophysiology Measurement to Study the Activity of Electro Neutral Transporters. AB - The transport of ions through cell membranes ensures the fine control of ion content within and outside the cell that is indispensable for cell survival. These transport mechanisms are mediated by the activities of specialized transporter proteins. Specifically,pH dynamics are finely controlled by plasma membrane proton (H+) extrusion systems, such as the Na+/H+ exchanger (NHE) protein family. Despite extensive efforts to study the mechanisms underlying NHE regulation, our current understanding of the biophysical and molecular properties of the NHE family is inadequate because of the limited availability of methods to effectively measure NHE activity. In this manuscript, we used H+-selective electrodes during whole-cell patch clamping recording to measure NHE-induced H+ flux. We proposed this approach to overcome some limitations of typically used methods to measure NHE activity, such as radioactive uptake and fluorescent membrane permeants. Measurement of NHE activity using the described method enables high sensitivity and time resolution and more efficient control of intracellular H+ concentrations. H+-selective electrodes are based on the fact that transporter activity creates an ion gradient in close proximity to the cell membrane. An H+-selective electrode moving up to and away from the cell membrane in a repetitive, oscillatory fashion records a voltage difference that is dependent on H+ flux. While H+-selective electrodes are used to detect H+ flux moving out of the cell, the patch clamp method in the whole-cell configuration is used to control the intracellular ion composition. Moreover, application of the giant patch clamp technique allows modification of the intracellular composition of not only ions but also lipids. The transporter activity of NHE isoform 3 (NHE3) was measured using this technical approach to study the molecular basis of NHE3 regulation by phosphoinositides. PMID- 29443071 TI - Thermal Scanning Conductometry (TSC) as a General Method for Studying and Controlling the Phase Behavior of Conductive Physical Gels. AB - The thermal scanning conductometry protocol is a new approach in studying ionic gels based on low molecular weight gelators. The method is designed to follow the dynamically changing state of the ionogels, and to deliver more information and details about the subtle change of conductive properties with an increase or decrease in the temperature. Moreover, the method allows the performance of long term (i.e. days, weeks) measurements at a constant temperature to investigate the stability and durability of the system and the aging effects. The main advantage of the TSC method over classical conductometry is the ability to perform measurements during the gelation process, which was impossible with the classical method due to temperature stabilization, which usually takes a long time before the individual measurement. It is a well-known fact that to obtain the physical gel phase, the cooling stage must be fast; moreover, depending on the cooling rate, different microstructures can be achieved. The TSC method can be performed with any cooling/heating rate that can be assured by the external temperature system. In our case, we can achieve linear temperature change rates between 0.1 and approximately 10 degrees C/min. The thermal scanning conductometry is designed to work in cycles, continuously changing between heating and cooling stages. Such an approach allows study of the reproducibility of the thermally reversible gel-sol phase transition. Moreover, it allows the performance of different experimental protocols on the same sample, which can be refreshed to initial state (if necessary) without removal from the measuring cell. Therefore, the measurements can be performed faster, in a more efficient way, and with much higher reproducibility and accuracy. Additionally, the TSC method can be also used as a tool to manufacture the ionogels with targeted properties, like microstructure, with an instant characterization of conductive properties. PMID- 29443072 TI - Extraction of Ramie Fiber in Alkali Hydrogen Peroxide System Supported by Controlled-release Alkali Source. AB - This protocol demonstrates a method for ramie fiber extraction by scouring raw ramie in an alkali hydrogen peroxide system supported by a controlled-release alkali source. The fiber extracted from ramie is a type of textile material of great importance. In previous studies, ramie fiber was extracted in an alkali hydrogen peroxide system supported only by sodium hydroxide.However, due to the strong alkalinity of sodium hydroxide, the oxidation reaction speed of hydrogen peroxide was difficult to control and thus resulted in great damage to the treated fiber. In this protocol, a controlled-release alkali source, which is composed of sodium hydroxide and magnesium hydroxide, is used to provide an alkali condition and buffer the pH value of the alkali hydrogen peroxidesystem. The substitution rate of magnesium hydroxide can adjust the pH value of the hydrogen peroxide system and has great influence on the fiber properties. The pH value and oxidation-reduction potential (ORP) value, which represents the oxidation ability of alkali hydrogen peroxide system, were monitored using a pH meter and ORP meter, respectively. The residual hydrogen peroxide content in the alkali hydrogen peroxide system during the extraction process and the chemical oxygen demand (COD) value of wastewater after fiber extraction are tested by KMnO4 titration method. The yield of fiber is measured using a precision electronic balance, and residual gums of fiber are tested by a chemical analysis method. The polymerization degree (PD value) of fiber is tested by an intrinsic viscosity method using the Ubbelohde viscometer. The tensile property of fiber, including tenacity, elongation, and rupture, is measured using a fiber strength instrument. Fourier transform infrared spectroscopy and X-ray diffraction are used to characterize the functional groups and crystal property of fiber. This protocol proves that the controlled-release alkali source can improve the properties of the fiber extracted in an alkali hydrogen peroxide system. PMID- 29443073 TI - Percutaneous Contrast Echocardiography-guided Intramyocardial Injection and Cell Delivery in a Large Preclinical Model. AB - Cell and gene therapy are exciting and promising strategies for the purpose of cardiac regeneration in the setting of heart failure with reduced ejection fraction (HFrEF). Before they can be considered for use, and implemented in humans, extensive preclinical studies are required in large animal models to evaluate the safety, efficacy, and fate of the injectate (e.g., stem cells) once delivered into the myocardium. Small rodent models offer advantages (e.g., cost effectiveness, amenability for genetic manipulation); however, given inherent limitations of these models, the findings in these rarely translate into the clinic. Conversely, large animal models such as rabbits, have advantages (e.g., similar cardiac electrophysiology compared to humans and other large animals), whilst retaining a good cost-effective balance. Here, we demonstrate how to perform a percutaneous contrast echocardiography-guided intramyocardial injection (IMI) technique, which is minimally invasive, safe, well tolerated, and very effective in the targeted delivery of injectates, including cells, into several locations within the myocardium of a rabbit model. For the implementation of this technique, we also have taken advantage of a widely available clinical echocardiography system. After putting in practice the protocol described here, a researcher with basic ultrasound knowledge will become competent in the performance of this versatile and minimally invasive technique for routine use in experiments, aimed at hypothesis testing of the capabilities of cardiac regenerative therapeutics in the rabbit model. Once competency is achieved, the whole procedure can be performed within 25 min after anaesthetizing the rabbit. PMID- 29443074 TI - Workflow Based on the Combination of Isotopic Tracer Experiments to Investigate Microbial Metabolism of Multiple Nutrient Sources. AB - Studies in the field of microbiology rely on the implementation of a wide range of methodologies. In particular, the development of appropriate methods substantially contributes to providing extensive knowledge of the metabolism of microorganisms growing in chemically defined media containing unique nitrogen and carbon sources. In contrast, the management through metabolism of multiple nutrient sources, despite their broad presence in natural or industrial environments, remains virtually unexplored. This situation is mainly due to the lack of suitable methodologies, which hinders investigations. We report an experimental strategy to quantitatively and comprehensively explore how metabolism operates when a nutrient is provided as a mixture of different molecules, i.e., a complex resource. Here, we describe its application for assessing the partitioning of multiple nitrogen sources through the yeast metabolic network. The workflow combines information obtained during stable isotope tracer experiments using selected 13C- or 15N-labeled substrates. It first consists of parallel and reproducible fermentations in the same medium, which includes a mixture of N-containing molecules; however,a selected nitrogen source is labeled each time. A combination of analytical procedures (HPLC, GC-MS) is implemented to assess the labeling patterns of targeted compounds and to quantify the consumption and recovery of substrates in other metabolites. An integrated analysis of the complete dataset provides an overview of the fate of consumed substrates within cells. This approach requires an accurate protocol for the collection of samples-facilitated by a robot-assisted system for online monitoring of fermentations-and the achievement of numerous time-consuming analyses. Despite these constraints, it allowed understanding, for the first time, the partitioning of multiple nitrogen sources throughout the yeast metabolic network. We elucidated the redistribution of nitrogen from more abundant sources toward other N-compounds and determined the metabolic origins of volatile molecules and proteinogenic amino acids. PMID- 29443075 TI - Human Pluripotent Stem Cell Culture on Polyvinyl Alcohol-Co-Itaconic Acid Hydrogels with Varying Stiffness Under Xeno-Free Conditions. AB - The effect of physical cues, such as the stiffness of biomaterials on the proliferation and differentiation of stem cells, has been investigated by several researchers. However, most of these investigators have used polyacrylamide hydrogels for stem cell culture in their studies. Therefore, their results are controversial because those results might originate from the specific characteristics of the polyacrylamide and not from the physical cue (stiffness) of the biomaterials. Here, we describe a protocol for preparing hydrogels, which are not based on polyacrylamide, where various stem, cells including human embryonic stem (ES) cells and human induced pluripotent stem (iPS) cells, can be cultured. Hydrogels with varying stiffness were prepared from bioinert polyvinyl alcohol-co-itaconic acid (P-IA), with stiffness controlled by crosslinking degree by changing crosslinking time. The P-IA hydrogels grafted with and without oligopeptides derived from extracellular matrix were investigated as a future platform for stem cell culture and differentiation. The culture and passage of amniotic fluid stem cells, adipose-derived stem cells, human ES cells, and human iPS cells is described in detail here. The oligopeptide P-IA hydrogels showed superior performances, which were induced by their stiffness properties. This protocol reports the synthesis of the biomaterial, their surface manipulation, along with controlling the stiffness properties and finally, their impact on stem cell fate using xeno-free culture conditions. Based on recent studies, such modified substrates can act as future platforms to support and direct the fate of various stem cells line to different linkages; and further, regenerate and restore the functions of the lost organ or tissue. PMID- 29443076 TI - Optimized Management of Endovascular Treatment for Acute Ischemic Stroke. AB - This manuscript describes a streamlined protocol for the management of patients with acute ischemic stroke, which aims at the minimization of time from hospital admission to reperfusion. Rapid restoration of cerebral blood flow is essential for the outcomes of patients with acute ischemic stroke. Endovascular treatment (EVT) has become the standard of care to accomplish this in patients with acute stroke due to large vessel occlusion (LVO). To achieve reperfusion of ischemic brain regions as fast as possible, all in-hospital time delays have to be carefully avoided. Therefore, management of patients with acute ischemic stroke was optimized with an interdisciplinary standard operating procedure (SOP). Stroke neurologists, diagnostic as well as interventional neuroradiologists, and anesthesiologists streamlined all necessary processes from patient admission and diagnosis to EVT of eligible patients. Target times for every step were established. Actually achieved times were prospectively recorded along with clinical data and imaging scores for all endovascularly treated stroke patients. These data were regularly analyzed and discussed in interdisciplinary team meetings. Potential issues were evaluated and all staff involved was trained to adhere to the SOP. This streamlined patient management approach and enhanced interdisciplinary collaboration reduced time from patient admission to reperfusion significantly and was accompanied by a beneficial effect on clinical outcomes. PMID- 29443077 TI - Contractility Measurements of Human Uterine Smooth Muscle to Aid Drug Development. AB - Discovery and characterization of novel pharmaceutical compounds or biochemical probes rely on robust and physiologically relevant assay systems. We describe methods to measure ex vivo myometrium contractility. This assay can be used to investigate factors and molecules involved in the modulation of myometrial contraction and to determine their excitatory or inhibitory actions, and hence their therapeutic potential in vivo. Biopsies are obtained from women undergoing cesarean section delivery with informed consent. Fine strips of myometrium are dissected, clipped and attached to a force transducer within 1 mL organ baths superfused with physiological saline solution at 37 degrees C. Strips develop spontaneous contractions within 2-3 h under set tension and remain stable for many hours (>6 h). Strips can also be stimulated to contract such as by the endogenous hormones, oxytocin and vasopressin, which cause concentration dependent modulation of contraction frequency, force and duration, to more closely resemble contractions in labor. Hence, the effect of known and novel drug leads can be tested on spontaneous and agonist-induced contractions. This protocol specifically details how this assay can be used to determine the potency of known and novel agents by measuring their effects on various parameters of human myometrial contraction. We use the oxytocin- and V1a receptor antagonists, atosiban and SR49059 as examples of known compounds which inhibit oxytocin- and vasopressin-induced contractions, and demonstrate how this method can be used to complement and validate pharmacological data obtained from cell-based assays to aid drug development. The effects of novel agonists in comparison to oxytocin and vasopressin can also be characterized. Whilst we use the example of the oxytocin/ vasopressin system, this method can also be used to study other receptors and ion channels that play a role in uterine contraction and relaxation to advance the understanding of human uterine physiology and pathophysiology. PMID- 29443078 TI - Chemo-enzymatic Synthesis of N-glycans for Array Development and HIV Antibody Profiling. AB - We present a highly efficient way for the rapid preparation of a wide range of N linked oligosaccharides (estimated to exceed 20,000 structures) that are commonly found on human glycoproteins. To achieve the desired structural diversity, the strategy began with the chemo-enzymatic synthesis of three kinds of oligosaccharyl fluoride modules, followed by their stepwise alpha-selective glycosylations at the 3-O and 6-O positions of the mannose residue of the common core trisaccharide having a crucial beta-mannoside linkage. We further attached the N-glycans to the surface of an aluminum oxide-coated glass (ACG) slide to create a covalent mixed array for the analysis of hetero-ligand interaction with an HIV antibody. In particular, the binding behavior of a newly isolated HIV-1 broadly neutralizing antibody (bNAb), PG9, to the mixture of closely spaced Man5GlcNAc2 (Man5) and 2,6-di-sialylated bi-antennary complex type N-glycan (SCT) on an ACG array, opens a new avenue to guide the effective immunogen design for HIV vaccine development. In addition, our ACG array embodies a powerful tool to study other HIV antibodies for hetero-ligand binding behavior. PMID- 29443079 TI - Gene Regulation and Targeted Therapy in Gastric Cancer Peritoneal Metastasis: Radiological Findings from Dual Energy CT and PET/CT. AB - Gastric cancer remains fourth in cancer incidence worldwide with a five-year survival of only 20%-30%. Peritoneal metastasis is the most frequent type of metastasis that accompanies unresectable gastric cancer and is a definitive determinant of prognosis. Preventing and controlling the development of peritoneal metastasis could play a role in helping to prolong the survival of gastric cancer patients. A non-invasive and efficient imaging technique will help us to identify the invasion and metastasis process of peritoneal metastasis and to monitor the changes in tumor nodules in response to treatments. This will enable us to obtain an accurate description of the development process and molecular mechanisms of gastric cancer. We have recently described experiment using dual energy CT (DECT) and positron emission tomography/computed tomography (PET/CT) platforms for the detection and monitoring of gastric tumor metastasis in nude mice models. We have shown that weekly continuous monitoring with DECT and PET/CT can identify dynamic changes in peritoneal metastasis. The sFRP1 overexpression in gastric cancer mice models showed positive radiological performance, a higher FDG uptake and increasing enhancement, and the SUVmax (standardized uptake value) of nodules demonstrated an obvious alteration trend in response to targeted therapy of TGF-beta1 inhibitor. In this article, we described the detailed non-invasive imaging procedures to conduct more complex research on gastric cancer peritoneal metastasis using animal models and provided representative imaging results. The use of non-invasive imaging techniques should enable us to better understand the mechanisms of tumorigenesis, monitor tumor growth, and evaluate the effect of therapeutic interventions for gastric cancer. PMID- 29443080 TI - DNA Staining Method Based on Formazan Precipitation Induced by Blue Light Exposure. AB - DNA staining methods are very important for biomedical research. We designed a simple method that allows DNA visualization to the naked eye by the formation of a colored precipitate. It works by soaking the acrylamide or agarose DNA gel in a solution of 1x (equivalent to 2.0 uM) SYBR Green I (SG I) and 0.20 mM nitro blue tetrazolium that produces a purple precipitate of formazan when exposed to sunlight or specifically blue light. Also, DNA recovery tests were performed using an ampicillin resistant plasmid in an agarose gel stained with our method. A larger number of colonies was obtained with our method than with traditional staining using SG I with ultraviolet illumination. The described method is fast, specific, and non-toxic for DNA detection, allowing visualization of biomolecules to the "naked eye" without a transilluminator, and is inexpensive and appropriate for field use. For these reasons, our new DNA staining method has potential benefits to both research and industry. PMID- 29443081 TI - Recombinant Collagen I Peptide Microcarriers for Cell Expansion and Their Potential Use As Cell Delivery System in a Bioreactor Model. AB - Tissue engineering is a promising field, focused on developing solutions for the increasing demand on tissues and organs regarding transplantation purposes. The process to generate such tissues is complex, and includes an appropriate combination of specific cell types, scaffolds, and physical or biochemical stimuli to guide cell growth and differentiation. Microcarriers represent an appealing tool to expand cells in a three-dimensional (3D) microenvironment, since they provide higher surface-to volume ratios and mimic more closely the in vivo situation compared to traditional two-dimensional methods. The vascular system, supplying oxygen and nutrients to the cells and ensuring waste removal, constitutes an important building block when generating engineered tissues. In fact, most constructs fail after being implanted due to lacking vascular support. In this study, we present a protocol for endothelial cell expansion on recombinant collagen-based microcarriers under dynamic conditions in spinner flask and bioreactors, and we explain how to determine in this setting cell viability and functionality. In addition, we propose a method for cell delivery for vascularization purposes without additional detachment steps necessary. Furthermore, we provide a strategy to evaluate the cell vascularization potential in a perfusion bioreactor on a decellularized biological matrix. We believe that the use of the presented methods could lead to the development of new cell-based therapies for a large range of tissue engineering applications in the clinical practice. PMID- 29443082 TI - Analysis of Arabidopsis thaliana Growth Behavior in Different Light Qualities. AB - Plant biologists often need to observe the growth behavior of their chosen species. To this end, the plants need constant environmental and stable light conditions, which are preferably variable in quantity and quality so that studies under different setups can be conducted. These requirements are met by climatic chambers featuring light emitting diodes (LED) lights, which can - in contrast to fluorescent lights - be set to different wavelengths. LEDs are energy conserving and emit virtually no heat even at light intensities, which often constitutes a problem with other light sources. The presented protocol provides a step-by-step guidance of how to program a climatic chamber equipped with variable LED lights as well as describing several approaches for in depth analysis of growth phenotypes. Depending on the experimental set-up various characteristics of the growing plants can be observed and analyzed. Here we describe how to determine fresh weight, leaf area, photosynthetic activity, and stomatal density. We demonstrate that in order to obtain reliable data and draw valid conclusions it is mandatory to use a sufficient number of individuals for statistical evaluation. Taking too few plants for this kind of analysis results in high statistical errors and consequently in less clear interpretations of the data. PMID- 29443083 TI - Mouse Adipose Tissue Collection and Processing for RNA Analysis. AB - Compared to other tissues, white adipose tissue has a considerably less RNA and protein content for downstream applications such as real-time PCR and Western Blot, since it mostly contains lipids. RNA isolation from adipose tissue samples is also challenging as extra steps are required to avoid these lipids. Here, we present a procedure to collect three anatomically different white adipose tissues from mice, to process these samples and perform RNA isolation. We further describe the synthesis of cDNA and gene expression experiments using real-time PCR. The hereby described protocol allows the reduction of contamination from the animal's hair and blood on fat pads as well as cross-contamination between different fat pads during tissue collection. It has also been optimized to ensure adequate quantity and quality of the RNA extracted. This protocol can be widely applied to any mouse model where adipose tissue samples are required for routine experiments such as real-time PCR but is not intended for isolation from primary adipocytes cell culture. PMID- 29443084 TI - Essential Metal Uptake in Gram-negative Bacteria: X-ray Fluorescence, Radioisotopes, and Cell Fractionation. AB - We demonstrate a scalable method for the separation of the bacterial periplasm from the cytoplasm. This method is used to purify periplasmic protein for the purpose of biophysical characterization, and measure substrate transfer between periplasmic and cytoplasmic compartments. By carefully limiting the time that the periplasm is separated from the cytoplasm, the experimenter can extract the protein of interest and assay each compartment individually for substrate without carry-over contamination between compartments. The extracted protein from fractionation can then be further analyzed for three-dimensional structure determination or substrate-binding profiles. Alternatively, this method can be performed after incubation with a radiotracer to determine total percent uptake, as well as distribution of the tracer (and hence metal transport) across different bacterial compartments. Experimentation with a radiotracer can help differentiate between a physiological substrate and artefactual substrate, such as those caused by mismetallation. X-ray fluorescence can be used to discover the presence or absence of metal incorporation in a sample, as well as measure changes that may occur in metal incorporation as a product of growth conditions, purification conditions, and/or crystallization conditions. X-ray fluorescence also provides a relative measure of abundance for each metal, which can be used to determine the best metal energy absorption peak to use for anomalous X-ray scattering data collection. Radiometal uptake can be used as a method to validate the physiological nature of a substrate detected by X-ray fluorescence, as well as support the discovery of novel substrates. PMID- 29443085 TI - Mimicking and Measuring Occlusal Erosive Tooth Wear with the "Rub&Roll" and Non contact Profilometry. AB - Chewing, drinking, and occasional tooth grinding will result in physiological tooth wear during a lifetime. Extreme challenges, such as bruxism or habitual chewing on foreign objects, may lead to excessive wear. Recently, the role of erosion in accelerating mechanical tooth wear has been recognized, but the interplay between chemical and mechanical wear processes has not been extensively studied. Our laboratory recently introduced a novel oral wear simulation device, the Rub&Roll, that enables the user to perform wear and loading studies separately or simultaneously in an erosive and/or abrasive environment. This manuscript describes an application of the device: the combined mechanical and erosive loading of extracted human (pre)molars in a simulated chewing movement, with a controlled application of force, velocity, fluid, and time, and the application of non-contact profilometry in visualizing and measuring the resulting wear pattern. The occlusal morphology that was created in the experiment with the highest loading level is very similar to the clinical presentation of erosive wear. PMID- 29443086 TI - Using Three-color Single-molecule FRET to Study the Correlation of Protein Interactions. AB - Single-molecule Forster resonance energy transfer (smFRET) has become a widely used biophysical technique to study the dynamics of biomolecules. For many molecular machines in a cell proteins have to act together with interaction partners in a functional cycle to fulfill their task. The extension of two-color to multi-color smFRET makes it possible to simultaneously probe more than one interaction or conformational change. This not only adds a new dimension to smFRET experiments but it also offers the unique possibility to directly study the sequence of events and to detect correlated interactions when using an immobilized sample and a total internal reflection fluorescence microscope (TIRFM). Therefore, multi-color smFRET is a versatile tool for studying biomolecular complexes in a quantitative manner and in a previously unachievable detail. Here, we demonstrate how to overcome the special challenges of multi color smFRET experiments on proteins. We present detailed protocols for obtaining the data and for extracting kinetic information. This includes trace selection criteria, state separation, and the recovery of state trajectories from the noisy data using a 3D ensemble Hidden Markov Model (HMM). Compared to other methods, the kinetic information is not recovered from dwell time histograms but directly from the HMM. The maximum likelihood framework allows us to critically evaluate the kinetic model and to provide meaningful uncertainties for the rates. By applying our method to the heat shock protein 90 (Hsp90), we are able to disentangle the nucleotide binding and the global conformational changes of the protein. This allows us to directly observe the cooperativity between the two nucleotide binding pockets of the Hsp90 dimer. PMID- 29443087 TI - A Quantitative Sensory Testing Paradigm to Obtain Measures of Pain Processing in Patients Undergoing Breast Cancer Surgery. AB - Chronic pain following surgery, persistent postsurgical pain, is an important highly prevalent condition contributing to significant symptom burden and lower quality of life. Persistent postsurgical pain is relatively refractory to treatment hence generating a high need for preventive strategies and treatments. Therefore, the identification of patients at risk of developing persistent pain is an area of active ongoing research. Recently it was demonstrated that peri operative disruptions in central pain processing may be able to predict persistent postsurgical pain at long term follow-up in breast cancer patients. The aim of the current report is to present a short protocol to obtain pain thresholds to different stimuli at multiple sites and a measure of endogenous analgesia in breast cancer patients. We have used this method successfully in a clinical context and detail some representative results from a clinical study. PMID- 29443088 TI - Simultaneous Video-EEG-ECG Monitoring to Identify Neurocardiac Dysfunction in Mouse Models of Epilepsy. AB - In epilepsy, seizures can evoke cardiac rhythm disturbances such as heart rate changes, conduction blocks, asystoles, and arrhythmias, which can potentially increase risk of sudden unexpected death in epilepsy (SUDEP). Electroencephalography (EEG) and electrocardiography (ECG) are widely used clinical diagnostic tools to monitor for abnormal brain and cardiac rhythms in patients. Here, a technique to simultaneously record video, EEG, and ECG in mice to measure behavior, brain, and cardiac activities, respectively, is described. The technique described herein utilizes a tethered (i.e., wired) recording configuration in which the implanted electrode on the head of the mouse is hard wired to the recording equipment. Compared to wireless telemetry recording systems, the tethered arrangement possesses several technical advantages such as a greater possible number of channels for recording EEG or other biopotentials; lower electrode costs; and greater frequency bandwidth (i.e., sampling rate) of recordings. The basics of this technique can also be easily modified to accommodate recording other biosignals, such as electromyography (EMG) or plethysmography for assessment of muscle and respiratory activity, respectively. In addition to describing how to perform the EEG-ECG recordings, we also detail methods to quantify the resulting data for seizures, EEG spectral power, cardiac function, and heart rate variability, which we demonstrate in an example experiment using a mouse with epilepsy due to Kcna1 gene deletion. Video-EEG-ECG monitoring in mouse models of epilepsy or other neurological disease provides a powerful tool to identify dysfunction at the level of the brain, heart, or brain heart interactions. PMID- 29443089 TI - A Simple Method for Isolation of Soybean Protoplasts and Application to Transient Gene Expression Analyses. AB - Soybean (Glycine max (L.) Merr.) is an important crop species and has become a legume model for the studies of genetic and biochemical pathways. Therefore, it is important to establish an efficient transient gene expression system in soybean. Here, we report a simple protocol for the preparation of soybean protoplasts and its application for transient functional analyses. We found that young unifoliate leaves from soybean seedlings resulted in large quantities of high quality protoplasts. By optimizing a PEG-calcium-mediated transformation method, we achieved high transformation efficiency using soybean unifoliate protoplasts. This system provides an efficient and versatile model for examination of complex regulatory and signaling mechanisms in live soybean cells and may help to better understand diverse cellular, developmental and physiological processes of legumes. PMID- 29443090 TI - Native Chromatin Immunoprecipitation Using Murine Brain Tumor Neurospheres. AB - Epigenetic modifications may be involved in the development and progression of glioma. Changes in methylation and acetylation of promoters and regulatory regions of oncogenes and tumor suppressors can lead to changes in gene expression and play an important role in the pathogenesis of brain tumors. Native chromatin immunoprecipitation (ChIP) is a popular technique that allows the detection of modifications or other proteins tightly bound to DNA. In contrast to cross-linked ChIP, in native ChIP, cells are not treated with formaldehyde to covalently link protein to DNA. This is advantageous because sometimes crosslinking may fix proteins that only transiently interact with DNA and do not have functional significance in gene regulation. In addition, antibodies are generally raised against unfixed peptides. Therefore, antibody specificity is increased in native ChIP. However, it is important to keep in mind that native ChIP is only applicable to study histones or other proteins that bind tightly to DNA. This protocol describes the native chromatin immunoprecipitation on murine brain tumor neurospheres. PMID- 29443091 TI - Synthesizing Sodium Tungstate and Sodium Molybdate Microcapsules via Bacterial Mineral Excretion. AB - We present a method, the bacterial mineral excretion (BME), for synthesizing two kinds of microcapsules, sodium tungstate and sodium molybdate, and the two metal oxides' corresponding nanoparticles-the former being as small as 22 nm and the latter 15 nm. We fed two strains of bacteria, Shewanella algae and Pandoraea sp., with various concentrations of tungstate or molybdate ions. The concentrations of tungstate and molybdate were adjusted to make microcapsules of different length to-diameter ratios. We found that the higher the concentration the smaller the nanoparticles were. The nanoparticles came in with three length-to-diameter ratios: 10:1, 3:1 and 1:1, which were achieved by feeding the bacteria respectively with a low concentration, a medium concentration, and a high concentration. The images of the hollow microcapsules were taken via the scanning electron microsphere (SEM). Their crystal structures were verified by X-ray diffraction (XRD)-the crystal structure of molybdate microcapsules is Na2MoO4 and that of tungstate microcapsules is Na2WO4 with Na2W2O7. These syntheses all were accomplished under a near ambient condition. PMID- 29443092 TI - Single-Cell Quantification of Protein Degradation Rates by Time-Lapse Fluorescence Microscopy in Adherent Cell Culture. AB - Proteins are in a dynamic state of synthesis and degradation and their half-lives can be adjusted under various circumstances. However, most commonly used approaches to determine protein half-life are either limited to population averages from lysed cells or require the use of protein synthesis inhibitors. This protocol describes a method to measure protein half-lives in single living adherent cells, using SNAP-tag fusion proteins in combination with fluorescence time-lapse microscopy. Any protein of interest fused to a SNAP-tag can be covalently bound by a fluorescent, cell permeable dye that is coupled to a benzylguanine derivative, and the decay of the labeled protein population can be monitored after washout of the residual dye. Subsequent cell tracking and quantification of the integrated fluorescence intensity over time results in an exponential decay curve for each tracked cell, allowing for determining protein degradation rates in single cells by curve fitting. This method provides an estimate for the heterogeneity of half-lives in a population of cultured cells, which cannot easily be assessed by other methods. The approach presented here is applicable to any type of cultured adherent cells expressing a protein of interest fused to a SNAP-tag. Here we use mouse embryonic stem (ES) cells grown on E-cadherin-coated cell culture plates to illustrate how single cell degradation rates of proteins with a broad range of half-lives can be determined. PMID- 29443093 TI - Determining if DNA Stained with a Cyanine Dye Can Be Digested with Restriction Enzymes. AB - Visualization of DNA for fluorescence microscopy utilizes a variety of dyes such as cyanine dyes. These dyes are utilized due to their high affinity and sensitivity for DNA. In order to determine if the DNA molecules are full length after the completion of the experiment, a method is required to determine if the stained molecules are full length by digesting DNA with restriction enzymes. However, stained DNA may inhibit the enzymes, so a method is needed to determine what enzymes one could use for fluorochrome stained DNA. In this method, DNA is stained with a cyanine dye overnight to allow the dye and DNA to equilibrate. Next, stained DNA is digested with a restriction enzyme, loaded into a gel and electrophoresed. The experimental DNA digest bands are compared to an in silico digest to determine the restriction enzyme activity. If there is the same number of bands as expected, then the reaction is complete. More bands than expected indicate partial digestion and less bands indicate incomplete digestion. The advantage of this method is its simplicity and it uses equipment that a scientist would need for a restriction enzyme assay and gel electrophoresis. A limitation of this method is that the enzymes available to most scientists are commercially available enzymes; however, any restriction enzymes could be used. PMID- 29443094 TI - In Vivo Imaging of Muscle-tendon Morphogenesis in Drosophila Pupae. AB - Muscles together with tendons and the skeleton enable animals including humans to move their body parts. Muscle morphogenesis is highly conserved from animals to humans. Therefore, the powerful Drosophila model system can be used to study concepts of muscle-tendon development that can also be applied to human muscle biology. Here, we describe in detail how morphogenesis of the adult muscle-tendon system can be easily imaged in living, developing Drosophila pupae. Hence, the method allows investigating proteins, cells and tissues in their physiological environment. In addition to a step-by-step protocol with helpful tips, we provide a comprehensive overview of fluorescently tagged marker proteins that are suitable for studying the muscle-tendon system. To highlight the versatile applications of the protocol, we show example movies ranging from visualization of long-term morphogenetic events - occurring on the time scale of hours and days - to visualization of short-term dynamic processes like muscle twitching occurring on time scale of seconds. Taken together, this protocol should enable the reader to design and perform live-imaging experiments for investigating muscle-tendon morphogenesis in the intact organism. PMID- 29443095 TI - Cystometric and External Urethral Sphincter Measurements in Awake Rats with Implanted Catheter and Electrodes Allowing for Repeated Measurements. AB - Lower urinary tract function is mainly assessed by means of cystometric bladder function analysis in rodents. Conventional cystometries are usually performed as terminal analysis under urethane anesthesia. It is well known that anesthetic drugs can influence bladder function. Hence, the aim of this technique is to perform cystometric measurements of the urinary bladder and external urethral sphincter in lightly restrained awake rats. For this purpose, a bladder catheter is implanted into the bladder dome. Subsequently, two electrodes are implanted bilateral to the external urethral sphincter and a ground electrode is sutured to a non-responsive skeletal muscle. The bladder catheter and the three electrodes are finally tunneled subcutaneously to the neck region and affixed to a harness. With this technique, the lower urinary tract can be measured at multiple time points in the same animal to assess lower urinary tract function. The main application of this technique is the follow-up of simultaneous urinary bladder and external urethral sphincter function in awake healthy rats and after induction of a disease or injury. Moreover, subsequent lower urinary tract monitoring can be performed during evaluation of the disease/injury and to monitor treatment efficacy. PMID- 29443096 TI - Color Spot Test As a Presumptive Tool for the Rapid Detection of Synthetic Cathinones. AB - Synthetic cathinones are a large class of new psychoactive substances (NPS) that are increasingly prevalent in drug seizures made by law enforcement and other border protection agencies globally. Color testing is a presumptive identification technique indicating the presence or absence of a particular drug class using rapid and uncomplicated chemical methods. Owing to their relatively recent emergence, a color test for the specific identification of synthetic cathinones is not currently available. In this study, we introduce a protocol for the presumptive identification of synthetic cathinones, employing three aqueous reagent solutions: copper(II) nitrate, 2,9-dimethyl-1,10-phenanthroline (neocuproine) and sodium acetate. Small pin-head sized amounts (approximately 0.1 0.2 mg) of the suspected drugs are added to the wells of a porcelain spot plate, and each reagent is then added dropwise sequentially before heating on a hotplate. A color change from very light blue to yellow-orange after 10 min indicates the likely presence of synthetic cathinones. The highly stable and specific test reagent has the potential for use in the presumptive screening of unknown samples for synthetic cathinones in a forensic laboratory. However, the nuisance of an added heating step for the color change result limits the test to laboratory application and decreases the likelihood of an easy translation to field testing. PMID- 29443097 TI - Variations on Negative Stain Electron Microscopy Methods: Tools for Tackling Challenging Systems. AB - Negative stain electron microscopy (EM) allows relatively simple and quick observation of macromolecules and macromolecular complexes through the use of contrast enhancing stain reagent. Although limited in resolution to a maximum of ~18 - 20 A, negative stain EM is useful for a variety of biological problems and also provides a rapid means of assessing samples for cryo-electron microscopy (cryo-EM). The negative stain workflow is straightforward method; the sample is adsorbed onto a substrate, then a stain is applied, blotted, and dried to produce a thin layer of electron dense stain in which the particles are embedded. Individual samples can, however, behave in markedly different ways under varying staining conditions. This has led to the development of a large variety of substrate preparation techniques, negative staining reagents, and grid washing and blotting techniques. Determining the most appropriate technique for each individual sample must be done on a case-by-case basis and a microscopist must have access to a variety of different techniques to achieve the highest-quality negative stain results. Detailed protocols for two different substrate preparation methods and three different blotting techniques are provided, and an example of a sample that shows markedly different results depending on the method used is shown. In addition, the preparation of some common negative staining reagents, and two novel Lanthanide-based stains, is described with discussion regarding the use of each. PMID- 29443098 TI - A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes. AB - Astrocytes are the major cell type in the brain and directly contact synapses and blood vessels. Although microglial cells have been considered the major immune cells and only phagocytes in the brain, recent studies have shown that astrocytes also participate in various phagocytic processes, such as developmental synapse elimination and clearance of amyloid beta plaques in Alzheimer's disease (AD). Despite these findings, the efficiency of astrocyte engulfment and degradation of their targets is unclear compared with that of microglia. This lack of information is mostly due to the lack of an assay system in which the kinetics of astrocyte- and microglia-mediated phagocytosis are easily comparable. To achieve this goal, we have developed a long-term live-imaging in vitro phagocytosis assay to evaluate the phagocytic capacity of purified astrocytes and microglia. In this assay, real-time detection of engulfment and degradation is possible using pH indicator-conjugated synaptosomes, which emit bright red fluorescence in acidic organelles, such as lysosomes. Our novel assay provides simple and effective detection of phagocytosis through live-imaging. In addition, this in vitro phagocytosis assay can be used as a screening platform to identify chemicals and compounds that can enhance or inhibit the phagocytic capacity of astrocytes. As synaptic pruning malfunction and pathogenic protein accumulation have been shown to cause mental disorders or neurodegenerative diseases, chemicals and compounds that modulate the phagocytic capacity of glial cells should be helpful in treating various neurological disorders. PMID- 29443099 TI - Detection of a CDH1 Rare Transcript Variant in Fresh-frozen Gastric Cancer Tissues by Chip-based Digital PCR. AB - CDH1a, a non-canonical transcript of the CDH1 gene, has been found to be expressed in some gastric cancer (GC) cell lines, whereas it is absent in normal gastric mucosa. Recently, we detected CDH1a transcript variant in fresh-frozen tumor tissues obtained from patients with GC. The expression of this variant in tissue samples was investigated by the chip-based digital PCR (dPCR) approach presented here. dPCR offers the potential for an accurate, robust, and highly sensitive measurement of nucleic acids and is increasingly utilized for many applications in different fields. dPCR is capable of detecting rare targets; in addition, dPCR offers the possibility for absolute and precise quantification of nucleic acids without the need for calibrators and standard curves. In fact, the reaction partitioning enriches the target from the background, which improves amplification efficiency and tolerance to inhibitors. Such characteristics make dPCR an optimal tool for the detection of the CDH1a rare transcript. PMID- 29443100 TI - Single-cell Resolution Fluorescence Live Imaging of Drosophila Circadian Clocks in Larval Brain Culture. AB - The circadian pacemaker circuit orchestrates rhythmic behavioral and physiological outputs coordinated with environmental cues, such as day/night cycles. The molecular clock within each pacemaker neuron generates circadian rhythms in gene expression, which underlie the rhythmic neuronal functions essential to the operation of the circuit. Investigation of the properties of the individual molecular oscillators in different subclasses of pacemaker neurons and their interaction with neuronal signaling yields a better understanding of the circadian pacemaker circuit. Here, we present a time-lapse fluorescent microscopy approach developed to monitor the molecular clockwork in clock neurons of cultured Drosophila larval brain. This method allows the multi-day recording of the rhythms of genetically encoded fluorescent circadian reporters at single-cell resolution. This setup can be combined with pharmacological manipulations to closely analyze real-time response of the molecular clock to various compounds. Beyond circadian rhythms, this multipurpose method in combination with powerful Drosophila genetic techniques offers the possibility to study diverse neuronal or molecular processes in live brain tissue. PMID- 29443101 TI - Methods for Analyzing the Impacts of Natural Uranium on In Vitro Osteoclastogenesis. AB - Uranium has been shown to interfere with bone physiology and it is well established that this metal accumulates in bone. However, little is known about the effect of natural uranium on the behavior of bone cells. In particular, the impact of uranium on osteoclasts, the cells responsible for the resorption of the bone matrix, is not documented. To investigate this issue, we have established a new protocol using uranyl acetate as a source of natural uranium and the murine RAW 264.7 cell line as a model of osteoclast precursors. Herein, we detailed all the assays required to test uranium cytotoxicity on osteoclast precursors and to evaluate its impact on the osteoclastogenesis and on the resorbing function of mature osteoclasts. The conditions we have developed, in particular for the preparation of uranyl-containing culture media and for the seeding of RAW 264.7 cells allow to obtain reliable and highly reproductive results. Moreover, we have optimized the use of software tools to facilitate the analysis of various parameters such as the size of osteoclasts or the percentage of resorbed matrix. PMID- 29443102 TI - Expression of Exogenous Antigens in the Mycobacterium bovis BCG Vaccine via Non genetic Surface Decoration with the Avidin-biotin System. AB - Tuberculosis (TB) is a serious infectious disease and the only available vaccine M. bovis bacillus Calmette-Guerin (BCG) is safe and effective for protection against children's severe TB meningitis and some forms of disseminated TB, but fails to protect against pulmonary TB, which is the most prevalent form of the disease. Promising strategies to improve BCG currently rely either on its transformation with genes encoding immunodominant M. tuberculosis (Mtb)-specific antigens and/or complementation with genes encoding co-factors that would stimulate antigen presenting cells. Major limitations to these approaches include low efficiency, low stability, and the uncertain level of safety of expression vectors. In this study, we present an alternative approach to vaccine improvement, which consists of BCG complementation with exogenous proteins of interest on the surface of bacteria, rather than transformation with plasmids encoding corresponding genes. First, proteins of interest are expressed in fusion with monomeric avidin in standard E. coli expression systems and then used to decorate the surface of biotinylated BCG. Animal experiments using BCG surface decorated with surrogate ovalbumin antigen demonstrate that the modified bacterium is fully immunogenic and capable of inducing specific T cell responses. Altogether, the data presented here strongly support a novel and efficient method for reshaping the current BCG vaccine that replaces the laborious conventional approach of complementation with exogenous nucleic acids. PMID- 29443103 TI - Paradigms of Lower Extremity Electrical Stimulation Training After Spinal Cord Injury. AB - Skeletal muscle atrophy, increased adiposity and reduced physical activity are key changes observed after spinal cord injury (SCI) and are associated with numerous cardiometabolic health consequences. These changes are likely to increase the risk of developing chronic secondary conditions and impact the quality of life in persons with SCI. Surface neuromuscular electrical stimulation evoked resistance training (NMES-RT) was developed as a strategy to attenuate the process of skeletal muscle atrophy, decrease ectopic adiposity, improve insulin sensitivity and enhance mitochondrial capacity. However, NMES-RT is limited to only a single muscle group. Involving multiple muscle groups of the lower extremities may maximize the health benefits of training. Functional electrical stimulation-lower extremity cycling (FES-LEC) allows for the activation of 6 muscle groups, which is likely to evoke greater metabolic and cardiovascular adaptation. Appropriate knowledge of the stimulation parameters is key to maximizing the outcomes of electrical stimulation training in persons with SCI. Adopting strategies for long-term use of NMES-RT and FES-LEC during rehabilitation may maintain the integrity of the musculoskeletal system, a pre requisite for clinical trials aiming to restore walking after injury. The current manuscript presents a combined protocol using NMES-RT prior to FES-LEC. We hypothesize that muscles conditioned for 12 weeks prior to cycling will be capable of generating greater power, cycle against higher resistance and result in greater adaptation in persons with SCI. PMID- 29443104 TI - Absorption of Nasal and Bronchial Fluids: Precision Sampling of the Human Respiratory Mucosa and Laboratory Processing of Samples. AB - The methods of nasal absorption (NA) and bronchial absorption (BA) use synthetic absorptive matrices (SAM) to absorb the mucosal lining fluid (MLF) of the human respiratory tract. NA is a non-invasive technique which absorbs fluid from the inferior turbinate, and causes minimal discomfort. NA has yielded reproducible results with the ability to frequently repeat sampling of the upper airway. By comparison, alternative methods of sampling the respiratory mucosa, such as nasopharyngeal aspiration (NPA) and conventional swabbing, are more invasive and may result in greater data variability. Other methods have limitations, for instance, biopsies and bronchial procedures are invasive, sputum contains many dead and dying cells and requires liquefaction, exhaled breath condensate (EBC) contains water and saliva, and lavage samples are dilute and variable. BA can be performed through the working channel of a bronchoscope in clinic. Sampling is well tolerated and can be conducted at multiple sites in the airway. BA results in MLF samples being less dilute than bronchoalveolar lavage (BAL) samples. This article demonstrates the techniques of NA and BA, as well as the laboratory processing of the resulting samples, which can be tailored to the desired downstream biomarker being measured. These absorption techniques are useful alternatives to the conventional sampling techniques used in clinical respiratory research. PMID- 29443105 TI - Mechanical and Controlled PRP Injections in Patients Affected by Androgenetic Alopecia. AB - 23 patients (18 male and 5 female) aged 21-70 years who displayed male pattern hair loss (MPHL) in Stage 1 to Stage 5 as determined by the Norwood-Hamilton classification scale, and female pattern hair loss (FPHL) in Stage 1 to Stage 2 as determined by the Ludwig classification scale, were treated with non-activated autologous platelet-rich plasma (A-PRP). Autologous blood (55 mL) was harvested using sodium citrate as an anticoagulant. A-PRP (23 mL) was produced for all cases using a closed system according to the transfusion service protocol. Following centrifugation (260 x g for 10 min) the A-PRP was inserted in a laser light selector device, and after the centrifugation, 9 mL of A-PRP was collected. The scalp of the patients affected by androgenetic alopecia (AGA) was divided into four areas (frontal, parietal, vertex, and occipital); local anesthesia was not performed. Interfollicular A-PRP injections (0.2 mL x cm2) were performed by controlled and mechanical injections scheduled at a depth of 5 mm using a medical injector gun. Treatment sessions were performed with a 30-day interval. For each patient, three treatment sessions were performed. PRP was injected in the androgen-related areas of scalp affected by hair loss. Placebo (normal saline solution) was loaded in another syringe (10 mL) and injected on the adjacent side in a similar fashion. PMID- 29443107 TI - Visualizing Lignification Dynamics in Plants with Click Chemistry: Dual Labeling is BLISS! AB - Lignin is one of the most prevalent biopolymers on the planet and a major component of lignocellulosic biomass. This phenolic polymer plays a vital structural and protective role in the development and life of higher plants. Although the intricate mechanisms regulating lignification processes in vivo strongly impact the industrial valorization of many plant-derived products, the scientific community still has a long way to go to decipher them. In a simple three-step workflow, the dual labeling protocol presented herein enables bioimaging studies of actively lignifying zones of plant tissues. The first step consists in the metabolic incorporation of two independent chemical reporters, surrogates of the two native monolignols that give rise to lignin H- and G-units. After incorporation into growing lignin polymers, each reporter is then specifically labeled with its own fluorescent probe via a sequential combination of bioorthogonal SPAAC/CuAAC click reactions. Combined with lignin autofluorescence, this approach leads to the generation of three-color localization maps of lignin within plant cell walls by confocal fluorescence microscopy and provides precise spatial information on the presence or absence of active lignification machinery at the scale of plant tissues, cells and different cell wall layers. PMID- 29443106 TI - Visualization of Cortical Modules in Flattened Mammalian Cortices. AB - The cortex of mammalian brains is parcellated into distinct substructures or modules. Cortical modules typically lie parallel to the cortical sheet, and can be delineated by certain histochemical and immunohistochemical methods. In this study, we highlight a method to isolate the cortex from mammalian brains and flatten them to obtain sections parallel to the cortical sheet. We further highlight selected histochemical and immunohistochemical methods to process these flattened tangential sections to visualize cortical modules. In the somatosensory cortex of various mammals, we perform cytochrome oxidase histochemistry to reveal body maps or cortical modules representing different parts of the body of the animal. In the medial entorhinal cortex, an area where grid cells are generated, we utilize immunohistochemical methods to highlight modules of genetically determined neurons which are arranged in a grid-pattern in the cortical sheet across several species. Overall, we provide a framework to isolate and prepare layer-wise flattened cortical sections, and visualize cortical modules using histochemical and immunohistochemical methods in a wide variety of mammalian brains. PMID- 29443108 TI - Preparation of Hollow Polystyrene Particles and Microcapsules by Radical Polymerization of Janus Droplets Consisting of Hydrocarbon and Fluorocarbon Oils. AB - In this article, we have demonstrated a method for producing hollow particles and microcapsules using oil droplets consisting of hydrocarbon oil (styrene) and fluorocarbon oil (perfluoro-n-octane, PFO) in aqueous surfactant (sodium dodecylsulfate, SDS) solutions. Since fluorocarbon oils are immiscible with hydrocarbon oils, the two oils are separated. Emulsions are prepared by stirring styrene/PFO/aqueous SDS solution mixtures at 80 degrees C. The type of emulsions and the morphology of droplets in the emulsions are observed by light microscope and scanning confocal fluorescence microscope. It is found that oil droplets with Janus-type morphologies consisting of mutually immiscible styrene and PFO are formed in aqueous SDS solutions. Polystyrene particles are fabricated by radical polymerization of the ternary mixtures of styrene/PFO/aqueous SDS solution at 80 degrees C. The morphologies of the polystyrene are confirmed by scanning electron microscopy and scanning transmission electron microscopy observations. These observations show the preparation of hollow polystyrene particles with a single hole on the surface. To our knowledge, this method is a novel strategy using the immiscibility of hydrocarbon and fluorocarbon oils. The hollow particles can also be applied to the preparation of microcapsules. PMID- 29443109 TI - Methods for Staging Pupal Periods and Measurement of Wing Pigmentation of Drosophila guttifera. AB - Diversified species of Drosophila (fruit fly) provide opportunities to study mechanisms of development and genetic changes responsible for evolutionary changes. In particular, the adult stage is a rich source of morphological traits for interspecific comparison, including wing pigmentation comparison. To study developmental differences among species, detailed observation and appropriate staging are required for precise comparison. Here we describe protocols for staging of pupal periods and quantification of wing pigmentation in a polka dotted fruit fly, Drosophila guttifera. First, we describe the method for detailed morphological observation and definition of pupal stages based on morphologies. This method includes a technique for removing the puparium, which is the outer chitinous case of the pupa, to enable detailed observation of pupal morphologies. Second, we describe the method for measuring the duration of defined pupal stages. Finally, we describe the method for quantification of wing pigmentation based on image analysis using digital images and ImageJ software. With these methods, we can establish a solid basis for comparing developmental processes of adult traits during pupal stages. PMID- 29443111 TI - Zika Virus Infection of Cultured Human Fetal Brain Neural Stem Cells for Immunocytochemical Analysis. AB - Human fetal brain neural stem cells are a unique non-genetically modified model system to study the impact of various stimuli on human developmental neurobiology. Rather than use an animal model or genetically modified induced pluripotent cells, human neural stem cells provide an effective in vitro system to examine the effects of treatments, screen drugs, or examine individual differences. Here, we provide the detailed protocols for methods used to expand human fetal brain neural stem cells in culture with serum-free media, to differentiate them into various neuronal subtypes and astrocytes via different priming procedures, and to freeze and recover these cells. Furthermore, we describe a procedure of using human fetal brain neural stem cells to study Zika virus infection. PMID- 29443110 TI - Imaging Approaches to Assessments of Toxicological Oxidative Stress Using Genetically-encoded Fluorogenic Sensors. AB - While oxidative stress is a commonly cited toxicological mechanism, conventional methods to study it suffer from a number of shortcomings, including destruction of the sample, introduction of potential artifacts, and a lack of specificity for the reactive species involved. Thus, there is a current need in the field of toxicology for non-destructive, sensitive, and specific methods that can be used to observe and quantify intracellular redox perturbations, more commonly referred to as oxidative stress. Here, we present a method for the use of two genetically encoded fluorogenic sensors, roGFP2 and HyPer, to be used in live-cell imaging studies to observe xenobiotic-induced oxidative responses. roGFP2 equilibrates with the glutathione redox potential (EGSH), while HyPer directly detects hydrogen peroxide (H2O2). Both sensors can be expressed into various cell types via transfection or transduction, and can be targeted to specific cellular compartments. Most importantly, live-cell microscopy using these sensors offers high spatial and temporal resolution that is not possible using conventional methods. Changes in the fluorescence intensity monitored at 510 nm serves as the readout for both genetically-encoded fluorogenic sensors when sequentially excited by 404 nm and 488 nm light. This property makes both sensors ratiometric, eliminating common microscopy artifacts and correcting for differences in sensor expression between cells. This methodology can be applied across a variety of fluorometric platforms capable of exciting and collecting emissions at the prescribed wavelengths, making it suitable for use with confocal imaging systems, conventional wide-field microscopy, and plate readers. Both genetically-encoded fluorogenic sensors have been used in a variety of cell types and toxicological studies to monitor cellular EGSH and H2O2 generation in real-time. Outlined here is a standardized method that is widely adaptable across cell types and fluorometric platforms for the application of roGFP2 and HyPer in live-cell toxicological assessments of oxidative stress. PMID- 29443112 TI - Ratiometric Calcium Imaging of Individual Neurons in Behaving Caenorhabditis Elegans. AB - It has become increasingly clear that neural circuit activity in behaving animals differs substantially from that seen in anesthetized or immobilized animals. Highly sensitive, genetically encoded fluorescent reporters of Ca2+ have revolutionized the recording of cell and synaptic activity using non-invasive optical approaches in behaving animals. When combined with genetic and optogenetic techniques, the molecular mechanisms that modulate cell and circuit activity during different behavior states can be identified. Here we describe methods for ratiometric Ca2+ imaging of single neurons in freely behaving Caenorhabditis elegans worms. We demonstrate a simple mounting technique that gently overlays worms growing on a standard Nematode Growth Media (NGM) agar block with a glass coverslip, permitting animals to be recorded at high resolution during unrestricted movement and behavior. With this technique, we use the sensitive Ca2+ reporter GCaMP5 to record changes in intracellular Ca2+ in the serotonergic Hermaphrodite Specific Neurons (HSNs) as they drive egg-laying behavior. By co-expressing mCherry, a Ca2+-insensitive fluorescent protein, we can track the position of the HSN within ~ 1 um and correct for fluctuations in fluorescence caused by changes in focus or movement. Simultaneous, infrared brightfield imaging allows for behavior recording and animal tracking using a motorized stage. By integrating these microscopic techniques and data streams, we can record Ca2+ activity in the C. elegans egg-laying circuit as it progresses between inactive and active behavior states over tens of minutes. PMID- 29443113 TI - Simple Generation of a High Yield Culture of Induced Neurons from Human Adult Skin Fibroblasts. AB - Induced neurons (iNs), the product of somatic cells directly converted to neurons, are a way to obtain patient-derived neurons from tissue that is easily accessible. Through this route, mature neurons can be obtained in a matter of a few weeks. Here, we describe a straightforward and rapid one-step protocol to obtain iNs from dermal fibroblasts obtained through biopsy samples from adult human donors. We explain each step of the process, including the maintenance of the dermal fibroblasts, the freezing procedure to build a stock of the cell line, seeding of the cells for reprogramming, as well as the culture conditions during the conversion process. In addition, we describe the preparation of glass coverslips for electrophysiological recordings, long-term coating conditions, and fluorescence activated cell sorting (FACS). We also illustrate examples of the results to be expected. The protocol described here is easy to perform and can be applied to human fibroblasts derived from human skin biopsies from patients with various different diagnoses and ages. This protocol generates a sufficient amount of iNs which can be used for a wide array of biomedical applications, including disease modeling, drug screening, and target validation. PMID- 29443114 TI - Causes and circumstances of death in a neonatal unit over 20 years. AB - BackgroundWe examined changes in the causes and circumstances of death in our neonatal intensive care unit (NICU) over 20 years.MethodsFor 551 infants who died between 1993 and 2013, the principal cause of death was recorded. Circumstances of death were assigned to one of the following four categories: death following cardiopulmonary resuscitation (CPR), death while being mechanically ventilated without CPR, death after withholding life-support interventions, and death after withdrawal of life support. Data were compared across four 5-year epochs.ResultsThe mortality rate decreased from 5.9% in the first epoch to 3.0% in the last epoch (P<0.0001). The leading cause of death in all epochs was congenital anomalies. The percentage of deaths due to all other categories decreased or remained stable. Withdrawal of life support was the most common circumstance of death in all four epochs. Only 16% of deaths followed CPR. The percentage of neonates with documented do-not-resuscitate orders was highest in the final cohort (52%).ConclusionsThe mortality rate per admission decreased between 1993 and 2013. Each cause of death was stable or decreased as a percentage of all deaths except for deaths due to congenital anomalies. Withdrawal of life-support interventions is the most common circumstance of death in neonates. PMID- 29443115 TI - Women and alcoholic liver disease - warning of a silent danger. PMID- 29443116 TI - Liver: A protective role for TREM2 in liver injury. PMID- 29443117 TI - CRISPR-Cas-related technologies in basic and translational liver research. PMID- 29443119 TI - Incidence of meningeal enhancement on brain MRI secondary to lumbar puncture. AB - Background: Concern for reactive meningeal enhancement after lumbar puncture (LP) is a common reason for performing brain MRI prior to LP. We sought to determine actual incidence of unexplained meningeal enhancement after LP. Methods: We collected results from all contrasted brain MRIs in patients admitted to adult neurology at a New York City hospital over a 3-year period. We used electronic medical records to determine whether an LP had been done within 30 days prior to brain MRI. The control group comprised those brain MRIs not preceded by an LP within 30 days prior to imaging. Number of cases of unexplained meningeal enhancement was compared between groups using a Fisher exact test. We recorded variables such as number of LP attempts, needle size, amount of fluid removed, and days from LP to brain MRI. Results: From 2011 to 2013, there were 77 cases of LP prior to brain MRI and 707 controls (n = 784). Of the cases, 3 had meningeal enhancement, 1 (1.2%) of which was unexplained. Of the 707 controls, 36 had enhancement, and none was unexplained. The p value comparing unexplained enhancement in the cases vs controls was 0.098. Conclusions: Iatrogenic meningeal enhancement from prior LP that is not attributable to traumatic LP or intracranial hypotension is rare and not more common than in cases without a prior LP. Results suggest that the practice of delaying LP until after brain MRI might not be supported in cases where LP is necessary. PMID- 29443118 TI - Neurometabolic disorders: Five new things. AB - Purpose of review: To present emerging issues in neurometabolic disorders, with an emphasis on the diagnostic workup of patients with suspected neurometabolic disorders and some future challenges in the care for these patients. Recent findings: Next-generation sequencing and next-generation metabolic screening increase the speed and yield of the diagnostic process in neurometabolic disorders. Furthermore, they deepen our insights into the underlying disease mechanisms. Care of adult patients with neurometabolic disorders is an expanding subspecialty, especially in internal medicine and neurology. Summary: We briefly discuss some novel genetic and biochemical laboratory techniques and changing insights in the molecular basis of disease, and illustrate the importance of MRI pattern recognition in the diagnostic process. Furthermore, we discuss gene therapy that is cautiously entering the field, and pay attention to the new field of (transition of) care for adult patients with inborn errors of metabolism. PMID- 29443120 TI - Differing trends in the incidence of vascular comorbidity in MS and the general population. PMID- 29443121 TI - The Duke neurology advanced practice provider residency: Its time has come. AB - The acknowledgment that specialization in neurology based on a clinician's extensive background in neuroscience contributes to expertise in patient care was a motivating factor in developing neurology residency programs. The increasing demand for more and better access to neurologic care has created a health care environment ripe for innovation. Advanced practice providers currently do not have the opportunity during primary training to gain much experience in neurologic care. We discuss the challenges and benefits of developing a 1-year neurology residency program for nurse practitioner and physician assistant graduates at our institution. We propose that providing advanced practice providers with specialty skills through neurology residency programs such as ours will be integral to meet the growing clinical need for neurologic care. PMID- 29443122 TI - First seizure management: I can see clearly now? PMID- 29443123 TI - Adding to the neurologist's toolkit. PMID- 29443124 TI - Care of persons with MS in clinical practice: Management by majority. PMID- 29443125 TI - Defending the solo and small practice neurologist. PMID- 29443126 TI - Tuberous sclerosis complex: Five new things. AB - Purpose of review: Tuberous sclerosis complex (TSC) is a variably expressed neurocutaneous genetic disorder characterized by hamartomatous growths in multiple organ systems. Neurologic involvement often confers the most severe symptoms, and can include epilepsy, increased intracranial pressure from hydrocephalus, intellectual deficits, and autism. The purpose of this review is to provide a neurologically focused update in the diagnosis and treatment of these complications in patients with TSC. Recent findings: We highlight 5 new areas of understanding in TSC: the neurobiology of TSC and its translation into clinical practice, vigabatrin in the treatment of infantile spasms, the role of tubers and epilepsy surgery, the treatment of subependymal giant cell astrocytomas, and TSC-related neuropsychiatric disorders. Summary: These recent advances in diagnosis and treatment give our patients with TSC and their families hope for the future for improved care and possible preventive cures, to the end goal of improving quality of life. PMID- 29443127 TI - Referring people with medically refractory seizures to an epilepsy center: It's not just for surgery. PMID- 29443128 TI - Nerve sonography to detect peripheral nerve involvement in vasculitis syndromes. AB - Background: We sought to determine the usefulness of sonography in the detection of nerve involvement in patients with vasculitic neuropathy. Methods: We enrolled 16 consecutive patients with vasculitic neuropathy (11 systemic vasculitis and 5 single organ peripheral nerve vasculitis), who met the diagnostic criteria of the Peripheral Nerve Society, and 16 disease controls with noninflammatory axonal polyneuropathy (10 cryptogenic, 4 metabolic, 2 hereditary). Patients underwent standardized nerve conduction studies and assessment of muscle strength (Medical Research Council scale), in addition to sonography of large arm and leg nerves, and brachial plexus. Nerves were evaluated bilaterally at predetermined sites for nerve size (cross-sectional area) and presence of hypervascularization. Results: We found enlarged nerves at common sites of nerve compression in all vasculitic and control patients. Multifocal enlargement in arm nerves, proximal to common sites of nerve compression, was sensitive (94%) and specific (88%) for vasculitic neuropathy. Sonography showed nerve enlargement in 51% of clinically or electrodiagnostically unaffected nerves. Sonography of the brachial plexus was normal. We found hypervascularization in 3 patients with systemic vasculitis. Conclusions: Sonographic enlargement of arm nerves proximal to sites of nerve compression with sparing of the brachial plexus may indicate a pattern characteristic of patients with vasculitic neuropathy. Sonography may represent a sensitive and specific technique for the detection of inflammatory neuropathy. Classification of evidence: This study provides Class III evidence that sonographic enlargement of arm nerves proximal to sites of nerve compression accurately identifies patients with vasculitic neuropathy. PMID- 29443129 TI - Swollen superficial temporal artery in dural arteriovenous fistula. PMID- 29443130 TI - Microembolism detection in giant cell arteritis. PMID- 29443131 TI - Chronic care management codes: A small step in the right direction. PMID- 29443133 TI - Practice Current: What is your diagnostic evaluation of cryptogenic stroke? PMID- 29443132 TI - CSF pleocytosis and syndrome of inappropriate antidiuretic hormone secretion in Creutzfeldt-Jakob disease. PMID- 29443135 TI - Minding the gaps in evidence, professionalism, and patient care. PMID- 29443134 TI - The association between serum calcium levels and Chvostek sign: A population based study. AB - Background: The Chvostek sign-a contraction of ipsilateral facial muscles subsequent to percussion over the facial nerve-is considered a clinical indicator of hypocalcemia. I sought to evaluate the association between Chvostek sign and serum calcium levels. Methods: I performed a cross-sectional analysis of data gathered from a nationwide probability sample of 3,434 individuals, aged 25-74 years, in the First National Health and Nutrition Examination Survey, conducted from 1971 to 1975. Results: Increasing serum calcium levels were associated with an increased odds for a positive Chvostek sign. When compared to calcium levels in the lowest quartile (5.47-9.4 mg/dL), individuals with serum calcium levels of 9.4-9.6 mg/dL, 9.6-9.9 mg/dL, and 9.9-11.9 mg/dL had a 195% (95% confidence interval [CI] 23.3%-604%), 124% (95% CI -0.8% to 407%), and 159% (95% CI 33.8% 401%) increased odds-as opposed to the expected decreased odds-for a positive Chvostek sign. When adjusting for age, sex, and race, these increased odds were 220% (95% CI 32%-679%), 125% (95% 0.00%-409%), and 172% (35%-448%), respectively. For every 1 g/dL increase in serum calcium level, the odds for a positive Chvostek sign increased by 4% (95% CI 0.00%-8%). Conclusions: A positive Chvostek sign is informative of normal to increased serum calcium levels rather than hypocalcemia. PMID- 29443137 TI - Neuro-Sweet disease: A case of recurrent encephalitis and febrile neutrophilic dermatosis. PMID- 29443136 TI - Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Payment policy perspectives. AB - This article is presented as a companion to the American Academy of Neurology guideline update on the use of botulinum neurotoxin (BoNT) for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache. Whereas the guideline update provides clarity on the efficacy of different BoNT-branded preparations for the 4 listed indications, this companion piece identifies ambiguities in the evidence for efficacy among various brand names for a given clinical indication, their dosing equivalencies, as well as different clinical indications. This article provides guidance and background information to reduce obstacles for third party payment, especially when uncertainties exist and levels of evidence are lower. PMID- 29443138 TI - Stroke due to large vessel atherosclerosis: Five new things. AB - Purpose of review: Extracranial (EC) and intracranial (IC) large vessel atherosclerosis account for about 20% of ischemic stroke cases. In recent years, new treatments have emerged for treatment of both EC and IC disease. Recent findings: The stroke rate in patients with carotid stenosis is decreasing with modern medical therapy. For patients with asymptomatic stenosis, the stroke rate is likely <1% per year. Some subsets of patients with symptomatic carotid disease benefit less from revascularization, and medical management can be considered in these patients. A second clinical trial has confirmed that aggressive medical management is the treatment of choice for IC atherosclerotic disease. Vessel wall imaging may be useful to define pathophysiology in patients with IC stenosis and could ultimately help tailor therapy, but further studies are needed. Medical therapy is preferred to stenting for patients with vertebral artery-origin stenosis. Summary: Recent data and emerging concepts regarding large vessel atherosclerosis are provided. PMID- 29443139 TI - The disappearing thrombus: An uncommon cause of ischemic stroke. PMID- 29443140 TI - Superficial greater petrosal neuropathy. PMID- 29443142 TI - Pontine infarction responsible for wall-eyed bilateral internuclear ophthalmoplegia syndrome. PMID- 29443141 TI - Innovative approaches in caring for people with Parkinson disease: Filling the gaps. PMID- 29443143 TI - Hashimoto encephalopathy with angiographic CNS vasculitis. PMID- 29443144 TI - SMART syndrome: Stroke-like migraine attack after radiation therapy. PMID- 29443145 TI - An exotic cause of encephalopathy in a patient with chronic kidney disease. PMID- 29443146 TI - Atypical presentation of venous infarct: Developmental venous anomaly thrombosis propagating from clot in dural venous sinus. PMID- 29443147 TI - Symptomatic free-floating carotid thrombus extending to the skull base. PMID- 29443148 TI - The value proposition of case reports: Novelty, pedagogy, anecdotal aggregation, humanity. PMID- 29443149 TI - Eight-and-a-half syndrome. PMID- 29443150 TI - Central neurogenic hyperventilation: A sign of CNS lymphoma. PMID- 29443151 TI - Primary Whipple disease of the CNS presenting with chorea and dystonia: A video case report. PMID- 29443153 TI - Knowledge is power? PMID- 29443152 TI - Posterior spinal cord infarctions due to neurosyphilis. PMID- 29443154 TI - Long segment spinal cord involvement as the clinical manifestation of sarcoidosis. PMID- 29443155 TI - Occasional resolution of multiple parenchymal brain calcifications in patients with neurocysticercosis. PMID- 29443156 TI - Configuring electronic health records to meet the needs of neurologists: A case study. PMID- 29443157 TI - Clinical challenges in the diagnosis and assessment of sports-related concussion. PMID- 29443158 TI - Mal de debarquement syndrome. PMID- 29443159 TI - First seizure management: I can see clearly now? PMID- 29443160 TI - Hearing loss in Wernicke encephalopathy. PMID- 29443161 TI - A cautionary tale about a global problem. PMID- 29443162 TI - Periodic alternating gaze deviation and nystagmus in posterior reversible encephalopathy syndrome. PMID- 29443163 TI - Interval progression of idiopathic hypertrophic pachymeningitis. PMID- 29443164 TI - Management of levodopa-induced jig-like gait disorder with pallidal stimulation. PMID- 29443165 TI - Defending the solo and small practice neurologist. AB - Changes in health care are having a dramatic effect on the practice of medicine. In 2005, a National Center for Health Statistics survey showed that 55%-70% of physicians are in small/solo practices. These data also demonstrated that 70% of physicians identified themselves as owners. Since passage of the Affordable Care Act (ACA) in 2010, neurologists report an 8% increase in academic practice settings, a 2% decrease in private practice settings, and a 5% decrease in solo practice settings. Surveys of family physicians showed that 60% are now employees of hospitals or larger groups. A survey by The Physicians Foundation showed that 89% of physicians believed that the traditional model of independent private practice is either "on shaky ground" or "a dinosaur soon to go extinct." With the changes expected from the ACA, solo/small practices will continue to face challenges and therefore must pay close attention to business and clinical metrics. PMID- 29443166 TI - Dystonia: Five new things. PMID- 29443167 TI - Acute peripheral vestibulopathy in a cocaine addict: Cracking the vestibular nucleus. PMID- 29443168 TI - Recognizing and reducing cognitive bias in clinical and forensic neurology. AB - In medicine, cognitive errors form the basis of bias in clinical practice. Several types of bias are common and pervasive, and may lead to inaccurate diagnosis or treatment. Forensic and clinical neurology, even when aided by current technologies, are still dependent on cognitive interpretations, and therefore prone to bias. This article discusses 4 common biases that can lead the clinician astray. They are confirmation bias (selective gathering of and neglect of contradictory evidence); base rate bias (ignoring or misusing prevailing base rate data); hindsight bias (oversimplification of past causation); and good old days bias (the tendency for patients to misremember and exaggerate their preinjury functioning). We briefly describe strategies adopted from the field of psychology that could minimize bias. While debiasing is not easy, reducing such errors requires awareness and acknowledgment of our susceptibility to these cognitive distortions. PMID- 29443169 TI - Pneumocephalus associated with epidural and spinal anesthesia for labor. AB - Headache resulting from dural puncture in epidural and spinal anesthesia is usually secondary to a CSF leak. Pneumocephalus may also occur in this setting but has not been well-characterized. Although the risk factors for a CSF leak and pneumocephalus may overlap, their rates, clinical features, and treatments may be different. Our retrospective review of 182 patients with acute headache in the antepartum, peripartum, and postpartum settings yielded a 5:1 ratio of postdural puncture headache to pneumocephalus. The 3 patients with pneumocephalus had the defining characteristic of thunderclap headache during anesthesia. Early diagnosis is helpful as treatment with supplemental oxygen may hasten recovery. Pneumocephalus should be considered as a possible etiology of thunderclap headache in the setting of epidural and spinal anesthesia. PMID- 29443170 TI - How to work with insurance companies. AB - Neurologists in all practice settings will benefit from working better with insurance companies and other payers. This article discusses who the insurance companies and others are that practices should work with, why it is important to maintain and develop ongoing relationships, and several strategies that successful practices of all types employ to achieve success. PMID- 29443171 TI - Neurologists and end-of-life decision-making: The role of "protective paternalism". PMID- 29443172 TI - Diagnosis and treatment of limb-girdle and distal dystrophies: Payment policy perspectives. AB - Limb-girdle muscular dystrophies (LGMDs) and distal dystrophies are a diverse group of genetically heterogeneous myopathies characterized by an evolving and often confusing nomenclature. Though rare as a group, they are commonly seen in neuromuscular clinics and occasionally in general neurology clinics, and are frequently a source of diagnostic dilemma. A recent evidence-based guideline by the American Academy of Neurology provides a comprehensive analysis of the clinical phenotypes, diagnostic approach, and management principles of the LGMDs and associated disorders. There remain many unanswered questions regarding the role of radiologic and genetic testing, cardiorespiratory screening, and physical therapy in managing these patients. This payment policy article suggests potential solutions to challenging coverage scenarios that result from incomplete or conflicting evidence. PMID- 29443173 TI - Is nonadmission-based care for TIA patients cost-effective?: A microcosting study. AB - We previously demonstrated the safety and effectiveness of a nonadmission-based model for TIA care (Monash TIA Triaging Treatment [M3T]). In this microcosting study, we used a pre-post cohort design with multivariable uncertainty analyses to compare actual resource utilization costs between M3T (years 2004-2007) and the previous admission-based model (2003). Average total episode costs per patient were significantly less for M3T (Australian dollars [AUD] 1,927.00, 95% confidence interval [CI] AUD 1,829.00-1,037.00) compared with the admission-based model (AUD 4,841.00, 95% CI AUD 4,178.00-5,590.00). Nonadmission care in M3T was substantially cost-saving with a median 3 (95% uncertainty interval 0.7-6.0) additional strokes averted per 100 patients treated, based on an observed 90-day stroke rate of 1.50% (95% CI 0.73%-3.05%) and 4.67% (95% CI 2.28%-9.32%) in the admission-based model. PMID- 29443174 TI - Neurotoxic snakes of the Americas. AB - Snake envenomation is a global problem and often a matter of life or death. Emergency treatment is not always readily available or effective. There are numerous neurotoxic snakes in the Americas, chiefly elapids; some crotalids have also evolved neurotoxic venom. The variability of neurotoxins found in snake venom within the same species makes development and choice of proper antivenom a major challenge that has not been completely addressed. This article reviews the epidemiology, clinical effects, and current treatment of neurotoxic snake envenomation in the Americas. PMID- 29443175 TI - Vision testing is additive to the sideline assessment of sports-related concussion. AB - We examined the King-Devick (K-D) test, a vision-based test of rapid number naming, as a complement to components of the Sport Concussion Assessment Tool, 3rd edition (SCAT3) for diagnosis of concussion. Baseline and postconcussion data for the University of Florida men's football, women's soccer, and women's lacrosse teams were collected, including the K-D test, Standardized Assessment of Concussion (SAC), and Balance Error Scoring System (BESS). Among 30 athletes with first concussion during their athletic season (n = 217 total), differences from baseline to postinjury showed worsening of K-D time scores in 79%, while SAC showed a >=2-point worsening in 52%. Combining K-D and SAC captured abnormalities in 89%; adding the BESS identified 100% of concussions. Adding a vision-based test may enhance the detection of athletes with concussion. PMID- 29443176 TI - Special requirements for electronic medical records in neurology. PMID- 29443177 TI - Aspirin and intracerebral hemorrhage: Where are we now? AB - For the past 3 decades, aspirin has been widely used for prevention of ischemic stroke and myocardial infarction. Although the evidence supporting the effectiveness of aspirin in prevention of vascular events is clear, data regarding the risk of acute and recurrent intracerebral hemorrhage related to the use of this medication have been conflicting. We review past and contemporary data on aspirin use in relation to intracerebral hemorrhage. PMID- 29443178 TI - Symptom exaggeration and symptom validity testing in persons with medically unexplained neurologic presentations. AB - Neurologists often evaluate patients whose symptoms cannot be readily explained even after thorough clinical and diagnostic testing. Such medically unexplained symptoms are common, occurring at a rate of 10%-30% among several specialties. These patients are frequently diagnosed as having somatoform, functional, factitious, or conversion disorders. Features of these disorders may include symptom exaggeration and inadequate effort. Symptom validity tests (SVTs) used by psychologists when assessing the validity of symptoms and impairments are structured, validated, and objectively scored. They could detect poor effort, underperformance, and exaggeration. In settings with appropriate prior probabilities, detection rates for symptom exaggeration have diagnostic utility. SVTs may help in moderating expensive diagnostic testing and redirecting treatment plans. This article familiarizes practicing neurologists with their merits, shortcomings, utility, and applicability in practice. PMID- 29443179 TI - How Dutch neurologists involve families of critically ill patients in end-of-life care and decision-making. AB - When critically ill neurologic patients are cognitively incapacitated, decisions about treatment options are delegated to surrogates, usually family members. We conducted qualitative interviews with 20 Dutch neurologists and residents in neurology varying in age, work experience, and workplace to investigate how they involve their patients' family members in decision-making. Their reports revealed that they ascribed 3 different, yet tightly interwoven roles to families: (1) informants about values and preferences of patients, (2) participants in care and care planning, and (3) sufferers themselves. Neurologists regarded decision making as an integral part of end-of-life care rather than an isolated process, changing the meaning of what decision-making entails. All different roles of family members were important in end-of-life care and decision-making, instead of the single one of legal surrogate. Neurologists need to support family members in these various roles. PMID- 29443180 TI - An electronic medical record just for neurologists: A daunting proposition. PMID- 29443182 TI - The science and art of neurology. PMID- 29443181 TI - The application of optical coherence tomography in neurologic diseases. AB - Optical coherence tomography (OCT) has become an increasingly popular tool in various disciplines of medicine, particularly ophthalmology and neurology. It is an imaging technology that has revolutionized the practice of ophthalmology by providing anatomic detail of pathologic changes in the retina and optic nerve. OCT is routinely used as an ancillary test that can aid in the diagnosis and monitoring of neuro-ophthalmic diseases such as papilledema, optic neuritis, and neuroretinitis. OCT measurements have also been shown to predict visual prognosis in compressive optic neuropathies. Changes in OCT measurements have been used to study the course of particular neurologic diseases such as multiple sclerosis, suggesting that the data obtained may be useful as a biomarker in diagnosing and treating neurodegenerative disease. We present an up-to-date review of the OCT findings in several diseases of neurologic interest and provide clinical examples pertinent to the general neurologist. PMID- 29443183 TI - Structured handoff checklists improve clinical measures in patients discharged from the neurointensive care unit. AB - While up to 80% of medical errors may result from poor communication at clinical transitions of care, there has been relatively little study of the effect of standardized communication tools on clinical quality measures. We prospectively examined the effect of a standardized handoff checklist on clinical outcomes for patients dismissed from the neurointensive care unit. We found that the checklist resulted in significant reductions in patients transferred with inaccurate medication reconciliation and unnecessary urinary catheters. Participating physicians were surveyed and generally viewed the handoff checklist favorably. Standardized communication tools such as checklists may play a useful role in reducing medical errors related to communication between patient care teams. PMID- 29443184 TI - Complementary and alternative medicine in multiple sclerosis: Payment policy perspectives. AB - This article identifies payment policy perspectives of the American Academy of Neurology's guideline on complementary and alternative medicine (CAM) in multiple sclerosis (MS). The guideline is a reliable repository of information for advocating or not recommending certain CAM treatments in MS. It eases the burden of searching for information on each separate CAM treatment. It frequently emphasizes the need for patient counseling. To provide such generally undervalued, but needed, cognitive services, neurologists could use advanced practice providers and patient-friendly visual aids during or between visits. They should also rely on evaluation and management codes that recognize time spent predominantly on counseling or coordination of care. The guideline's categorization of probable effectiveness of certain therapies will not influence coverage decisions because payers do not generally cover CAM therapies. PMID- 29443185 TI - Ulnar neuropathy at the elbow: Five new things. AB - Ulnar neuropathy at the elbow (UNE) is the second most frequent compression neuropathy. While other diagnostic imaging tools are emerging to assist in the diagnosis of UNE, electrodiagnosis remains the gold standard. However, the electrodiagnostic approach to UNE presents unique challenges limiting its diagnostic accuracy. We review advances in 5 areas relevant to the diagnosis of UNE: technologic advancements with modern EMG machines have allowed for reconsideration of the question of experimental error and lesion detection; how temperature effects can lead to misdiagnosis; the effect of body mass index on the electrodiagnosis of UNE; the validation of short segment studies; and the emerging role of high-resolution sonography as a diagnostic tool. PMID- 29443186 TI - Surviving in solo and small practices. PMID- 29443187 TI - Movement disorders and psychiatry: Five new things. AB - In this article we report recent interesting diagnostic and therapeutic advances in a diverse range of movement disorders with associated psychiatric comorbidity. Areas discussed include social cognition in Huntington disease, neuroimaging of functional movement disorders, treatment of psychosis in Parkinson disease, new advances in autoimmune disease, and management of Tourette syndrome. PMID- 29443188 TI - Encouraging trends toward reduced risk of Alzheimer disease: What's good for the heart is good for the brain. PMID- 29443189 TI - Temporal arteritis. AB - Temporal or giant cell arteritis is an inflammation of medium and small extracranial vessels that may result in ocular ischemia, an aortitis followed by aortic dissection and peripheral limb ischemia. It should be considered a medical emergency due to the seriousness of end organ damage, in particular visual symptoms. While the presentation may be nonspecific, the presence of a tender temporal artery mandates a temporal artery biopsy. High-dose steroids should be begun the moment the diagnosis is considered and only withdrawn once it has been excluded. A gradual tapering of the steroid dose should occur over at least 1 year, with the consideration of the use of steroid-sparing agents if iatrogenic steroid complications occur. Careful monitoring of the response both clinically as well as with serial inflammatory markers is required. PMID- 29443190 TI - Recent advances in bioelectric prostheses. AB - Worldwide prevalence of amputation has created an increasing demand for improved upper and lower extremity prostheses. Current prosthetics are often uncomfortable and difficult to control and provide limited functional restoration. Moreover, the inability to normalize anthropomorphic biomechanics with a prosthesis increases one's risk of developing long-term health risks such as arthritis, skin breakdown, and pain. Recent advances in bionic prosthetic development hold great promise for rehabilitation and improving quality of life with limb loss. This brief review discusses the current state of advanced prostheses, the integration of robotics in the care of individuals with major limb amputation, and some innovative surgical techniques that are being explored for clinical feasibility. PMID- 29443191 TI - Autonomy and the "demanding encounter" in clinical neurology. AB - We describe a case of psychogenic nonepileptic seizures as an example of what has been called the demanding encounter in clinical neurology. Patients in these encounters are more likely to see themselves as informed consumers who expect to receive requested diagnostic tests and treatments from health care providers, potentially creating a conflict over treatment goals and appropriate limit setting. Demanding encounters are associated with physician burnout and patient dissatisfaction. We survey some of the ethical frameworks introduced to navigate this type of encounter. We argue that physicians are obligated to identify the underlying beliefs that are leading to requests for unnecessary testing and treatment and that, by addressing these beliefs, providers have the best chance of establishing a respectful, meaningful therapeutic relationship with their patients. PMID- 29443192 TI - Neurology and altitude illness. AB - Problems at altitude are most often thought of in trained athletes summiting extremes of elevation. A more common group that needs consideration is the average person with obstructive sleep apnea who must travel to high altitudes for business or pleasure. While the altitudes involved are not likely to be as extreme as for those athletes climbing peaks like Mt. Everest, the increases in elevation may present difficulties for patients, especially if overnight stay is expected. The pathophysiology of altitude-related CNS, respiratory, and sleep disorders is discussed along with treatment options. PMID- 29443193 TI - Blood pressure management in stroke: Five new things. PMID- 29443195 TI - Two leaps forward, one step back? PMID- 29443194 TI - Chronic lymphocytic meningitis with low CSF sugar, pulmonary infiltrate, and hilar lymphadenopathies in an immunocompetent patient. PMID- 29443196 TI - Anterior sacral meningocele presenting with purulent rectal discharge and altered mental status. PMID- 29443197 TI - Recurrent paradoxical embolic cerebral ischemia after patent foramen ovale closure. PMID- 29443198 TI - The US Food and Drug Administration, neurologists, and drug development and regulation. AB - The US Food and Drug Administration (FDA) plays a vital role in the regulation of human drugs and therapeutic biologics. Most physicians, while aware of the broad reach of the FDA, are unaware of what the agency actually does and how it does it. Practicing neurologists should be aware of the role neurologists can play in drug development, the informational resources that the FDA provides to practitioners, and the process of submitting reports of suspected adverse drug reactions to the FDA. PMID- 29443199 TI - Managing loss of intrathecal baclofen efficacy: Review of the literature and proposed troubleshooting algorithm. AB - Spasticity is a debilitating symptom associated with numerous neurologic conditions. While intrathecal baclofen therapy (ITB) is an established treatment for spasticity, complications can lead to loss of efficacy (LOE) and baclofen withdrawal. Untreated withdrawal syndrome can be fatal. Prompt diagnosis and management of LOE is essential. Numerous methods have been described in the literature for diagnosing the cause of LOE. Many of the methods require equipment not readily available in the outpatient setting. Furthermore, there is no established consensus on the sequencing of these diagnostic tests. Herein, we review ITB literature on troubleshooting LOE for applicability to the managing clinician. Using this information and our clinical experience, we propose an algorithm with management recommendations to simplify and expedite the troubleshooting process in the outpatient setting. PMID- 29443200 TI - Neurology advanced practice providers: A position paper of the American Academy of Neurology. AB - There are many factors driving health care reform, including unsustainable costs, poor outcomes, an aging populace, and physician shortages. These issues are particularly relevant to neurology. New reimbursement models are based on value and facilitated by the use of multidisciplinary teams. Integration of advanced practice providers (APPs) into neurology practice offers many advantages with new models of care. Conversely, there are many and varied challenges financially and logistically with these practice models. The American Academy of Neurology has formed a Work Group to address the needs of both neurologists and neurologic APPs and monitor the effect of APPs on quality and cost of neurologic care. PMID- 29443202 TI - A cautionary tale about a global problem. PMID- 29443201 TI - Development of benzodiazepines for out-of-hospital management of seizure emergencies. AB - Management of seizure emergencies substantially changed after the introduction of rectal diazepam in Europe in the 1970s and in the United States in the 1990s. Although safe and effective, social objections and legal concerns have limited use of rectal diazepam products in out-of-hospital treatment of seizure emergencies. Shortly after the introduction of Diastat (diazepam rectal gel), commercial development of innovative formulations began involving several benzodiazepines and routes of administration, including buccal, IM, nasal, and subcutaneous. All benzodiazepines have the same mechanism of action; however, there are major differences in physicochemical properties and pharmacokinetic characteristics, which affect the choice of drug and route. This article highlights some of those differences and their effect on selection of therapies for treating seizure emergencies. We also present results from key clinical studies of these drugs and provide an update on current status of new products under development. PMID- 29443203 TI - Creutzfeldt-Jakob disease: The search for definitive diagnostic tests continues. PMID- 29443204 TI - An electronic medical record just for neurologists: A daunting proposition. PMID- 29443205 TI - Testicular ptosis as a sign of L2 radiculopathy. PMID- 29443206 TI - Autonomy and the "demanding encounter" in clinical neurology. PMID- 29443207 TI - Alzheimer disease prevention: New optimism. AB - Alzheimer disease (AD) poses a major threat to medicine and society, but recent epidemiologic data indicate declining incidence of the disease. This development may be due to prevention of many cases by attention to modifiable risk factors. Meanwhile, all treatment efforts using drugs targeting amyloid have failed. In contrast to the assumption of recent decades that sporadic AD is primarily a genetic disease in which neuritic plaques and neurofibrillary tangles are mainly responsible for clinical features, it is now time for a more nuanced approach that considers the role of environmental factors preceding dementia onset and the appearance of aggregated proteins. This view of AD has important implications for medical care and health policy, and for counseling individuals to adopt lifestyle strategies that can be effective for prevention. PMID- 29443209 TI - Modifiable risk factors and multidisciplinary approaches. PMID- 29443208 TI - Advanced practice providers: The solution to all that ails medicine? PMID- 29443210 TI - Freezing of gait after a hemorrhagic stroke can respond to venlafaxine and rivastigmine. PMID- 29443211 TI - Proust and madeleine: Together in the thalamus? PMID- 29443212 TI - Conjunctival biopsy to diagnose neurosarcoidosis in patients with inflammatory nervous system disease of unknown etiology. AB - Neurosarcoidosis mimics many neurologic diseases and poses a major diagnostic challenge. Blind conjunctival biopsy is often used to help diagnose neurosarcoidosis when biopsy of affected nervous system tissue is not feasible. While this test is relatively inexpensive and well-tolerated, the diagnostic yield in patients with inflammatory nervous system disease of unknown etiology remained uncertain. We evaluated 440 patients who underwent conjunctival biopsy due to concern for neurosarcoidosis. Only a small minority of patients (3%) had positive conjunctival biopsies consistent with sarcoidosis, and some patients (1%) with positive biopsies were found to have a cause for their neurologic disease other than neurosarcoidosis. Many patients (14%) had negative conjunctival biopsies but were later confirmed to have neurosarcoidosis after additional evaluations. This study demonstrates that conjunctival biopsy has a low diagnostic yield for neurosarcoidosis in patients with inflammatory nervous system disease and suggests that alternative diagnostic means should be pursued. PMID- 29443214 TI - Absence and reappearance of N20 response after thiopental withdrawal in postanoxic coma. PMID- 29443213 TI - Characteristic abnormal signals in medulla oblongata-"eye spot" sign: Four cases of elderly-onset Alexander disease. PMID- 29443215 TI - Mal de debarquement syndrome: Review and proposed diagnostic criteria. AB - Mal de debarquement syndrome (MdDS) is a rare cause of imbalance encountered in a neurology practice. However, it consists of classic features that the practicing neurologist should be able to recognize when evaluating a patient with dizziness. It is characterized by a feeling of rocking and swaying, and typically follows prolonged exposure to motion, such as being on a boat or plane. In this review article, we provide the clinical neurologist with the history of this disorder followed by illustrative cases of patients diagnosed with MdDS. Next we present proposed criteria for aiding in diagnosis. Finally, we will discuss a differential diagnosis for the syndrome, insights into the possible pathophysiology, current treatments, and future directions in management. PMID- 29443216 TI - Multiple sclerosis in US minority populations: Clinical practice insights. PMID- 29443217 TI - Cannabis to concussion. PMID- 29443218 TI - Neurology and the correctional environment. PMID- 29443219 TI - Cost-saving innovations for acute ischemic stroke and transient ischemic attack. AB - Health care costs continue to rise toward unsustainable levels that will affect our nation's ability to support other key funding priorities for education, military, and infrastructure. Changing the way we deliver health care is critical to mitigating this financial crisis. This review highlights opportunities for redesigning care of acute ischemic stroke and TIA to maintain quality while substantially lowering costs. The recent innovations described are (1) adopting teleneurology networks to improve access to thrombolysis for acute ischemic stroke; (2) improving efficiency of emergency care for acute ischemic stroke; and (3) providing alternatives to inpatient care for TIA. Applying such process innovations will enable us to achieve the goal of patients and the nation-high quality care at an affordable cost. PMID- 29443220 TI - Medical marijuana: Between a plant and a hard place. PMID- 29443221 TI - Acquired idiopathic cold-induced hyperhidrosis in a case of dementia with Lewy bodies. PMID- 29443222 TI - Sumatriptan iontophoretic transdermal system: A novel approach to migraine specific therapy. AB - The sumatriptan iontophoretic transdermal system (TDS) (Zecuity, NuPathe, Malvern, PA), a novel approach to the acute treatment of migraine, circumvents the gastrointestinal tract by using low-level electrical energy to transport sumatriptan across the skin. In clinical trials, sumatriptan TDS has provided consistent drug delivery; rapid relief of migraine headache pain and migraine related nausea; and an excellent safety profile, with a low incidence of triptan sensation adverse events. Ease of use/application of sumatriptan TDS by migraineurs during an attack is rated highly. Sumatriptan TDS will provide a convenient, acute migraine-specific therapeutic option to the significant subset of patients for whom oral formulations are suboptimal, particularly those with migraine-related nausea (MRN). PMID- 29443223 TI - Clinical and imaging clues to posterior cortical atrophy. PMID- 29443224 TI - Managing loss of intrathecal baclofen efficacy: Review of the literature and proposed troubleshooting algorithm. PMID- 29443225 TI - Care of an undocumented immigrant: Case and comment. AB - This commentary addresses the care of an undocumented immigrant with neuromyelitis optica in the context of a state law designed to deny state-funded medical services to individuals whose presence in the United States is unlawful. It considers specific circumstances in which the law would permit or require medical care for undocumented persons in state medical facilities, including a duty to "stabilize" an "emergency medical condition" and the provision of care necessary to "protect life or safety." It also addresses dilemmas clinicians may experience when faced with an apparent tension between their professional ethical obligations and legal rules aimed at enforcing immigration policies. PMID- 29443227 TI - The practice of neuroimaging within a neurology office setting. PMID- 29443226 TI - Advances in endovascular therapy for ischemic stroke: A whole new ball game. AB - Purpose of review: The burden of disability from ischemic stroke continues to intensify. Any acute therapeutic option that reduces disability after ischemic stroke should be encouraged and further studied. In particular, the need for an effective treatment in patients with large vessel occlusion has been long overdue. Recent findings: Consistent trial evidence has answered this need in an emphatic fashion, demonstrating improved functional outcomes with endovascular therapy following better patient selection, new device technology, and reduced treatment times. The article discusses the current evidence and guidelines and highlights the inherent complexities of a specialized intervention whose demand will grow exponentially. The scope for future investigation especially using advanced imaging to expand patient selection will be considered. Summary: Endovascular thrombectomy is an established and highly efficacious acute treatment for ischemic stroke that we need to apply and implement to maximize benefit to the population. PMID- 29443228 TI - Nonmydriatic retinal photography in the evaluation of acute neurologic conditions. PMID- 29443229 TI - A 69-year-old woman with a "sweet" cause of instability. PMID- 29443230 TI - The application of optical coherence tomography in neurologic diseases. PMID- 29443233 TI - Discover our content and keep your practice current. PMID- 29443232 TI - Peripheral nervous system hyperexcitability in VV2 sporadic Creutzfeldt-Jakob disease. AB - Creutzfeldt-Jakob disease (CJD) is a fatal, rapidly progressive neurodegenerative disease. Most cases are sporadic (sCJD). The pathogenesis of sCJD is associated with a conformational change in abnormal prion protein causing widespread neuronal degeneration, and clinical manifestations can be quite protean. Peripheral nerve hyperexcitability syndrome (PNHS) is rarely associated with CJD and is more commonly associated with autoimmune/paraneoplastic syndromes associated with antibodies against the voltage-gated potassium channel complex (VGKC-Abs). Reports of PNHS in CJD are rare. We report 2 patients with progressive cognitive decline in the setting of peripheral nerve hyperexcitability on electrodiagnostic testing. In both patients VGKC-Abs were negative, and autopsy confirmed that both had sCJD, VV2 subtype. While uncommon, it is important to consider sCJD in patients presenting with PNHS and rapidly progressive dementia. PMID- 29443234 TI - Practice Current: How do you treat anti-NMDA receptor encephalitis? PMID- 29443235 TI - The plantar reflex: A study of observer agreement, sensitivity, and observer bias. AB - The utility of the plantar reflex in modern neurology is controversial. We studied the Babinski, Chaddock, and Oppenheim reflexes in terms of intraobserver, interobserver, and intertest agreement; sensitivity; positive predictive value (PPV); and observer bias. Sixty-two patients and 1,984 reflexes were analyzed. Intraobserver and interobserver agreement were weak (median kappa <0.4). Intertest agreement was weak (median kappa < 0.4) for all paired reflexes, although highest for the Babinski/Chaddock (0.30) (p < 0.05). There was no evidence of observer bias. Sensitivity was 59.7% for the Babinski, 55.3% for the Chaddock, and 30.0% for the Oppenheim. PPV was 70.3% for the Babinski, 66.5% for the Chaddock, and 61.3% for the Oppenheim. Our results show consistently low observer agreement for the plantar reflex. The Babinski and the Chaddock demonstrated comparable sensitivity and PPV. PMID- 29443237 TI - Ethics, practically speaking. PMID- 29443236 TI - An elusive brain death diagnosis: You can't get there from here. PMID- 29443238 TI - Erratum: Management of unruptured intracranial aneurysms. AB - [This corrects the article on p. 99 in vol. 3, PMID: 23914319.]. PMID- 29443239 TI - Relationships between physicians and Pharma: Why physicians should not accept money from the pharmaceutical industry. PMID- 29443240 TI - Eastchester clapping sign. PMID- 29443241 TI - Neuroimaging of first-ever seizure: Contribution of MRI if CT is normal. PMID- 29443242 TI - An option for improving access to outpatient general neurology. AB - Creating a team of nurse practitioner/physician assistant providers with a supervising physician is one potential model to extend limited physician resources for those medical specialties such as neurology, whose outpatient access is suboptimal. We offered new patient appointments with the access team. Monthly lead time (time to third available appointment) revealed that overall new patient access improved from an average time-to-appointment wait of 299 days down to 10 days. Patients completed an anonymous satisfaction survey about providers before and after the launch of the new access team; the results demonstrated preserved patient satisfaction with providers in this new team-based model. PMID- 29443243 TI - Adult-onset adrenoleukodystrophy presenting after chemotherapy: No black and white matter. PMID- 29443244 TI - Evaluation and management of a patient with possible cerebral venous thrombosis. AB - Cerebral venous thrombosis (CVT) is a relatively rare form of stroke usually affecting young individuals. CVT is characterized by the diversity of its neurologic manifestations, which require a high level of clinical suspicion for diagnosis and prompt, appropriate treatment. Multiple circumstances have been associated with CVT, such as prior medical conditions, transient situations, certain medications, and some predisposing conditions. Headache, focal neurologic deficit, and seizures are the most frequent clinical manifestations at onset. MRI in combination with venography has become the imaging modality of choice, as this technique has a high sensitivity and specificity for establishing a diagnosis. CT venography is an alternative to MRI because this technique produces similar diagnostic results. Pharmacologic treatment of CVT with anticoagulants is widely accepted. Per 100 cases, the recurrence of CVT is 2.8% and the mortality of CVT is 10%. PMID- 29443245 TI - The feasibility of establishing a free clinic for uninsured patients with neurologic disorders. PMID- 29443246 TI - Current controversies: Physicians vs Pharma. PMID- 29443247 TI - Clinical stroke challenges: A practical approach. PMID- 29443248 TI - Neurology goes global: Opportunities in international health. PMID- 29443250 TI - Measuring time and money to improve patient outcomes. PMID- 29443249 TI - Isolated vestibular syndrome in posterior circulation stroke: Frequency and involved structures. AB - Dizziness/vertigo is a common symptom of posterior circulation stroke and usually accompanies other neurologic symptoms and signs. Although strokes involving the brainstem or cerebellum may produce isolated vestibular syndrome (isolated vertigo or imbalance), the overall frequency and involved structures of isolated vestibular syndrome in the posterior circulation stroke remain uncertain. Isolated vestibular syndrome occurs in approximately 25% of the patients with posterior circulation stroke, and mostly involves the cerebellum, inferior or superior cerebellar peduncles, and caudal lateral or rostral dorsolateral medulla. The occasional negative neuroimaging in patients with acute isolated vascular vertigo highlights the importance of appropriate bedside evaluation in acute vestibular syndrome. PMID- 29443251 TI - Health literacy and medication awareness in outpatient neurology. PMID- 29443252 TI - Cefepime neurotoxicity can mimic postanoxic coma with myoclonic status epilepticus. PMID- 29443253 TI - Evaluating persistent altered mental status after status epilepticus. PMID- 29443254 TI - CORRECTION: Treating patients with medically resistant epilepsy. AB - [This corrects the article on p. 14 in vol. 1, PMID: 23634355.]. PMID- 29443255 TI - Fingolimod and macular edema: Pathophysiology, diagnosis, and management. AB - Fingolimod causes macular edema (ME) by acting via the S1P3 receptor agonism, thereby reducing the tight junction between the endothelial cells of the retinal capillaries. This results in the breakdown of the inner blood retinal barrier, causing ME. Ophthalmologic evaluation including optical coherence tomography is recommended at baseline and then at 3 months, 6 months, and annually thereafter in all patients on fingolimod. The risk of ME increases in patients who are diabetic, have had uveitis, or who undergo intraocular procedures such as cataract surgery, and hence these patients need close monitoring. Cessation of the drug results in resolution of the ME. However, ME can also be treated using anti-inflammatory medication (steroids) in patients who opt to remain on fingolimod. PMID- 29443257 TI - Medicare payment transparency: Implications for neurologists. AB - In 2014, the Centers for Medicare and Medicaid Services began a now annual process of releasing payment data made to physicians and other providers from Medicare Part B. The unprecedented availability of detailed payment information has generated considerable interest among policymakers, the public, and the media, and raised concerns from a number of physician groups. In the current climate of financial transparency, publication of Medicare payment data will likely continue. In an effort to prepare neurologists for future releases of payment data, we review the background, limitations, potential benefits, and appropriate responses to Medicare payment data releases. PMID- 29443256 TI - Decompressive craniectomy in malignant middle cerebral artery infarction: To be, or not to be? PMID- 29443258 TI - Medical decisions are not just about facts: What a life-threatening virus can teach us about empathy, psychology, and the practice of neurology. PMID- 29443260 TI - Evaluating and treating neurobehavioral symptoms in professional American football players: Lessons from a case series. PMID- 29443261 TI - Practice Current: A new way of interpreting contemporary neurology. PMID- 29443259 TI - Post-IV thrombolytic headache and hemorrhagic transformation risk in acute ischemic stroke. AB - Background: Headache during or soon after administration of IV tissue plasminogen activator (tPA) in patients with acute ischemic stroke (AIS) is a concern for hemorrhagic transformation (HT). However, no data are available regarding the incidence of HT in these patients or the prognostic indication of these headaches. We examine the importance of tPA-associated headaches among AIS patients in terms of HT rates and clinical outcomes. Methods: AIS patients treated with IV tPA at a comprehensive stroke center between January 2007 and November 2012 were retrospectively reviewed for documented tPA-associated headache in the first 24 hours post-tPA. We compared the headache and nonheadache groups for differences in various clinical and radiologic outcomes. Results: Of the 193 patients, 63 (32.6%) had tPA-associated headache. Headache patients (HP) were younger than nonheadache patients (NHP) (mean +/- SD, 59.5 +/- 17.4 years vs 69.9 +/- 15.5 years, p < 0.0001), and 53% of HP were men, compared to 49.2% of NHP (p = 0.537). Comorbid conditions did not differ between the 2 groups. There were no statistical differences between HP and NHP in admission NIH Stroke Scale (NIHSS) score (11.2 +/- 5.7 vs 11.5 +/- 5.5, p = 0.646), NIHSS score at 24 hours (6.5 +/- 5.7 vs 7.4 +/- 6.9, p = 0.466), NIHSS score at discharge (6.7 +/- 10.1 vs 8.1 +/- 11.6, p = 0.448), HT (12.7% vs 18.4%, p = 0.3), cervical artery dissection (4.7% vs 5.38%, p = 0.764), length of hospitalization (6.29 +/- 5 days vs 6.35 +/- 4.7 days, p = 0.935), and disposition. Conclusion: tPA-associated headache does not predict increased risk of HT and has no other prognostic importance in patients with AIS. Prospective studies with a larger cohort may be needed to further explore this relationship. PMID- 29443262 TI - Hypoxic-ischemic encephalopathy following vaso-occlusive crisis in hemoglobin SC disease. PMID- 29443263 TI - Clinical strategies for managing the overweight neurology patient. AB - Obesity and excess body fat contribute to both the risk for and progression of several prevalent neurologic conditions. While obesity treatment is not generally considered part of the job description of the neurologist, we summarize the evidence for this important relationship, and describe ways that being mindful of diet and lifestyle factors in the neurologic patient can yield dividends for patient outcomes. PMID- 29443264 TI - Spontaneous cervical internal carotid artery vasospasm: Case report and literature review. PMID- 29443265 TI - Facial pain: After the dentist and ENT have finished. AB - A 63-year-old woman is referred for neurologic consultation because of electrical shocks of pain in a left V3 distribution. The attacks are very brief, but occur many times a day, triggered by cold, touch, and chewing. In between attacks, she is pain free. Her neurologic examination is normal. This straightforward presentation of trigeminal neuralgia leaves the consulting neurologist wondering what to do with the other 45 minutes of the visit. The current article is vignette-based and deals with patients who may not fit into such a neat category. It is meant for the general neurologist, not the headache specialist. Aside from routine scenarios, it includes discussions of atypical facial pain, temporomandibular joint disorder, burning mouth syndrome, and other vexing types of facial pain. PMID- 29443266 TI - Let live or let die after traumatic coma: Scrutinizing somatosensory evoked potentials. AB - It is now firmly established that bilateral abolition of somatosensory evoked potentials (SEPs) after a nontraumatic coma has 100% specificity for nonawakening. In traumatic coma, a bilateral absence of the N20 components of SEPs does not implicate nonawareness. Comatose brain-injured patients should be systematically explored with auditory evoked potentials to check the functional integrity of another sensory pathway and the mesencephalic tegmento-tectal region on cerebral MRI should be carefully examined. Repeated evaluations during follow up are also mandatory. PMID- 29443267 TI - Posterior circulation ischemic stroke with aberrant vertebral artery cervical entrance at the C4 vertebral level. PMID- 29443268 TI - A tardy tongue palsy: Delayed post-traumatic isolated unilateral hypoglossal neuropathy. PMID- 29443269 TI - MACRA and the future of value-based care. AB - The passage of Medicare Access and Children's Health Insurance Program Reauthorization Act of 2015 (MACRA) heralded a fundamental shift from volume based to value-based payment for health care services in the United States. Beginning in 2019, neurologists will participate in 1 of 2 Medicare pathways: the Merit-Based Incentive Payment System or Alternative Payment Models. Both options represent an important change from the current fee-for-service payment models, and neurologists will need to be prepared well in advance of the MACRA launch. This article reviews the background, structure, uncertainties, and implications of MACRA on the practice of neurology, with recommendations for preparation. PMID- 29443270 TI - Silent majority. PMID- 29443271 TI - Ipsilateral eye closure and hemifacial weakness: Useful clinical clue to diagnose pseudostroke. PMID- 29443272 TI - The breadth and burden of data collection in clinical practice. AB - The clinical practice of neurology generates an enormous amount of data. Current data entry tools and reporting requirements are inefficient and frustrating. This comprehensive review of data collection in multiple domains of clinical practice includes billing and payment requirements, electronic health record documentation requirements, quality measurements, public reporting, and the evolution of clinical decision support. Quality measurements are increasingly affecting patient care and physician reimbursement. By understanding current data collection and by using appropriate tools, neurologists can begin to reduce the burden of data collection and ensure maximum reimbursement. The American Academy of Neurology's Axon registry is the next step in the evolution of clinical data collection and will begin to empower every neurologist to succeed in the shifting landscape of health care and physician payment reform. PMID- 29443273 TI - Rapid screening for inflammatory neuropathies by standardized clinical criteria. AB - Background: Delay in recognition and treatment of inflammatory neuropathies increases morbidity and mortality. We have developed and standardized 3 clinical screening criteria that rapidly detect inflammatory neuropathies. Methods: We reviewed all patients with definite large fiber neuropathy in 2 different patient populations: 1 from a private neurology clinic and the other from a tertiary care center. Patients were divided into 2 groups: those with an inflammatory neuropathy and those with a noninflammatory neuropathy. We specifically noted the 3 key neuropathy characteristics: onset, distribution, and associated systemic features (ODS). We studied the sensitivity and specificity of ODS in differentiating between inflammatory and noninflammatory neuropathies. Results: A total of 206 patients were included: 51 from the private clinic and 155 from the tertiary care center. The sensitivity of using ODS in detecting an inflammatory neuropathy was 96% and the specificity was 85%. The positive predictive value of ODS was 0.8 and negative predictive value was 0.97. Conclusions: Rapid screening for inflammatory neuropathies by ODS clinical criteria is highly sensitive and has a high negative predictive value for noninflammatory neuropathies. ODS uses simple clinical criteria to rapidly screen for patients with a potentially treatable form of neuropathy and accelerate their diagnostic evaluation. Classification of evidence: This study provides Class IV evidence that 3 neuropathy characteristics-onset, distribution, and associated systemic features accurately identify patients with inflammatory neuropathies. PMID- 29443274 TI - CORRECTION: Neurogenetics Five new things. AB - [This corrects the article on p. 41 in vol. 1.]. PMID- 29443275 TI - Crafting a positive professional digital profile to augment your practice. AB - A digital profile is the sum content about a person on the Internet. A digital profile can be composed of personal or professional information shared on public Web sites posted personally or by others. One of the most effective ways to build a positive professional digital profile is through social media. It is increasingly important to maintain a positive digital profile as others mine the Internet to find out about a professional prior to meeting him or her. As the digital environment continues to grow, it will become increasingly difficult to neglect a professional digital profile without potential negative consequences. There are many benefits to creating a digital presence and using the tools available to learn about neurology and interact with other professionals and patients in ways that were not possible in the past. The spread of social media to a large part of the population makes it unlikely to go away. PMID- 29443276 TI - Pregnancy and delivery in anti-NMDA receptor encephalitis survivors. PMID- 29443277 TI - Chipping away at neurologist burnout, one refill request at a time. PMID- 29443279 TI - Confronting clinical challenges and professional stress. PMID- 29443278 TI - Deep brain stimulation. AB - High-frequency deep brain stimulation (DBS) is an established therapy for Parkinson disease (PD), essential tremor, and primary dystonia, and is under investigation for several neuropsychiatric diseases. DBS for PD, in the subthalamic nucleus or globus pallidus interna (GPi), improves tremor, bradykinesia, and rigidity, emotional well-being and sleep, and "on" time without dyskinesias, but may not improve axial and cognitive impairment or speech. DBS in motor thalamus may improve or resolve rest, action, and postural tremor. DBS in the GPi results in functional improvement in hyperkinetic greater than tonic aspects of primary and tardive dystonias. Perioperative risks include hemorrhage and stroke (<2%) and infection (~8%). The benefit/risk ratio may be optimized with individualized patient selection and the use of an experienced surgical team. DBS is expensive and well-placed unilateral ablation therapy has been shown to be efficacious. Bilateral ablations pose an unacceptable risk of speech impairment and disequilibrium. PMID- 29443280 TI - Payment reform and the changing landscape in medical practice: Implications for neurologists. AB - The growth in health care spending in the United States, though slowed in the last few years, remains unsustainable. Since higher health care spending does not correlate with most measures of improved patient outcome, there are new attempts to define "value" in health care as the ratio of quality to cost. This article reviews newer proposed models for provider payment and organization and their possible effects on neurologic practice. PMID- 29443281 TI - Reducing after-hours prescription refill requests. AB - Background: It is not convenient or always possible to address parent requests for prescription refills after hours. The primary objective of this quality improvement study was to decrease the number of refill requests received outside of regular business hours. A secondary objective was to reduce the negative effects of call fatigue and related exhaustion for physicians taking calls. Methods: Voluntary participation in this quality improvement project was solicited from the Child Neurology Division at a single academic, tertiary, metropolitan children's hospital. Study design was developed from a project charter, fishbone diagram, process map, driver diagram, and plan-do-study-act worksheet. A peer-reviewed letter was mailed to all clinic patient families and signs were displayed in the clinic space as notification of a policy change. A peer-reviewed script was provided to the Children's Mercy Contact Center triage personnel addressing after-hours refill requests. The number of refill requests received during each after-hours call shift was recorded from April 1, 2015, to March 31, 2016, with a primary outcome measure of the monthly number of refill requests. Results: Postintervention, the average number of refill requests after hours decreased by 39% from 21 to 11 per month (p = 0.0055). Conclusions: This simple intervention has promise to limit prescription refill requests made after hours and improve physician quality of life. Continued data collection will help establish the sustainability of the effect made by this intervention. PMID- 29443282 TI - Call for submissions! PMID- 29443284 TI - Persistent nasal speech in a patient with myasthenia gravis. PMID- 29443283 TI - Epilepsy: Five new things. AB - Purpose of review: Technological advance has revolutionized epilepsy management recently. Herein, we review some recent developments. Recent findings: Responsive neurostimulation (Food and Drug Administration [FDA]-approved 2013) works by continuous analysis of brain rhythms and direct brain stimulation on detecting patterns thought to be epileptogenic, thereby aborting seizures. Cardio responsive vagus nerve stimulation (FDA-approved 2015) is an improvement over traditional vagus nerve stimulation systems, taking advantage of the fact that 80% of seizures are associated with tachycardia. Automated tachycardia detection leads to vagus nerve stimulation to abort seizures. In MRI-guided stereotactic laser ablation (developed 2012), a directed laser emitting fiberoptic catheter is used to ablate epileptogenic lesions. The procedure can be completed in 3 to 4 hours, potentially under local anesthesia and with next-day discharge. Perampanel (FDA-approved 2012) is a promising new class of AMPA (alpha-amino-3-hydroxy-5 methyl-4-isoxazole propionic acid)-antagonist antiseizure therapy. Meanwhile, a millennia-old remedy for epilepsy, cannabis, is staging a comeback with recent legal and social permissiveness accelerating research into this use. Summary: The coming years will demonstrate how these recent advances in device and drug management will improve the care of epilepsy. PMID- 29443285 TI - Neurohospitalist: A newly popular career choice. AB - The rapid expansion of neurohospitalist programs nationally has been fueled by recent graduates as well as by practicing neurologists increasingly choosing this career direction. An inpatient-focused job is compelling from an intellectual perspective as it allows the opportunity to treat acute disorders where new treatments are constantly emerging. Challenges entail arranging coverage, defining financial models of reimbursement, expanding into rural and international settings, and assuring proper training for those entering this emerging field. A diverse set of opportunities in both practice and academics are viable career options. Those choosing to embark on the neurohospitalist path have the opportunity to lead the field through a time of tremendous growth and change for years to come. PMID- 29443286 TI - Treatment for routine, symptomatic, carotid bulb atherosclerosis: Carotid endarterectomy and stenting are comparable. PMID- 29443287 TI - The Duke neurology advanced practice provider residency: Its time has come. PMID- 29443288 TI - Multiple sclerosis therapeutic strategies: Use second-line agents as first-line agents when time is of the essence. PMID- 29443289 TI - Chronic neuropathic shoulder pain: The diagnosis is just a "black hole". PMID- 29443290 TI - Advances in neurosurgery: Five new things. AB - Surgical options for disease of the nervous system continue to expand in breadth and scope. These advances have been related in large part to progress in technology, translational application of molecular biology, and increasing understanding of the physiologic processes associated with neurologic disease. The current review will outline recent neurosurgical advances in the management of brain tumors, movement disorders, spinal degenerative disease, and neurologic injury. In addition, we include a brief discussion of exciting data from recent trials focusing on the brain-machine interface. PMID- 29443291 TI - Practice across borders. PMID- 29443292 TI - Asymptomatic swollen optic discs and CT scan. PMID- 29443293 TI - Pediatric epilepsy: Five new things. AB - Epilepsy in children can be very different from epilepsy in adults, both in seizure type and epilepsy syndrome. The goal in treating children is seizure freedom, no treatment side effects, and function that is no different from the general population. In a significant percentage of patients, this goal remains unachievable, but many aspects of epilepsy are becoming clearer. This review will highlight 5 areas where progress is being made to achieve these goals in pediatric epilepsy. Specific research animal models are being developed to reflect the unique features of different pediatric epilepsies. As genetic syndromes are better identified, for some patients this has led to improved treatment. New advances in drug therapy have led to 3 new medications approved for children. More effective drug choices can now be recommended due to comparative drug trials and better overall care of children can be provided due to awareness of the comorbidities of epilepsy. PMID- 29443294 TI - Isolated fever caused by an unruptured giant intracranial aneurysm. PMID- 29443296 TI - Broadening our vision. PMID- 29443295 TI - An analysis of AAN's evidence-based guideline for IVIg use in neurologic disorders: Provider impact and payer perspectives. AB - Health insurers look for reliable, published evidence such as evidence-based guidelines put forth by medical specialty societies to craft their coverage policies. These guidelines generate both beneficial and controversial consequences on policies. Coverage policies aim to address the most typical clinical presentations. The American Academy of Neurology guideline for IV immunoglobulin strengthens the case for coverage when it is used to treat Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. The guideline is less likely to strengthen coverage for several other diagnoses with lower levels of evidence. The responsibility to clarify specific situations when patient need falls outside of what is considered to be routine evaluation or treatment rests heavily on the physician. Advice on appealing an unfavorable coverage decision is also provided to the reader. PMID- 29443297 TI - Approach to the patient with acute monocular visual loss. AB - Acute visual loss in one eye is a common symptom brought to the attention of the practicing neurologist. In this circumstance, it is critical to identify whether visual loss is due to an optic neuropathy or an ocular disorder (especially retinal disease). This review addresses the elements of the history and examination that are useful in evaluating a patient with visual loss, with the goals of correctly localizing the lesion and constructing a likely differential diagnosis. PMID- 29443298 TI - Lipoma of trigeminal nerve in a patient with severe trigeminal neuralgia. PMID- 29443299 TI - Aneurysm of the internal carotid artery with bone arrosion and extradural compression of the optic nerve. PMID- 29443300 TI - Office assessment for abuse and management of the battered patient. AB - Domestic violence is an enormous public health problem that is frequently encountered in health care settings, but often not recognized. In addition to physical injuries directly related to maltreatment, there is a growing scientific literature demonstrating that abuse and neglect, particularly when beginning early in life, results in brain functional, structural, and even epigenetic changes that have enduring effects. This article reviews the definitions and prevalence of domestic violence, summarizes the known neurobiological effects, and describes the fundamentals of office assessment for abuse and the management of the battered patient. Ethical challenges with regards to abuse assessment and reporting, particularly in states with mandatory reporting laws, are discussed. Comprehensive resources for both patients and clinicians are included. PMID- 29443301 TI - An overview of third-generation antiseizure drugs: Clobazam, lacosamide, rufinamide, and vigabatrin. AB - Four antiseizure drugs have been approved in the United States since 2008. Clobazam, a 1,5-benzodiazepine, was approved in October 2011 as an adjunctive therapy for Lennox-Gastaut syndrome (LGS) in patients 2 years and older. Lacosamide, an amino acid that selectively enhances the slow inactivation of voltage-gated sodium channels, was approved in October 2008 as an add-on therapy for partial onset seizures in patients 17 years and older. Rufinamide, a triazole derivative, was approved in November 2008 as an adjunctive therapy for LGS in patients 4 years and older. Vigabatrin, an irreversible inhibitor of GABA transaminase, was approved in August 2009 for the treatment of infantile spasms in children ages 1 month to 2 years and intractable complex partial seizures in adults. PMID- 29443302 TI - Bell's palsy treatment strategies: Antivirals may help some patients. PMID- 29443303 TI - Ruptured dermoid cyst arising from Meckel cave. PMID- 29443304 TI - Bell's palsy treatment strategies: No obligation to use antivirals. PMID- 29443305 TI - Fornix infarction and Korsakoff dementia after coiling of a large anterior communicating artery aneurysm. PMID- 29443306 TI - Smell and taste in clinical neurology: Five new things. AB - Advancements in the field of smell and taste disorders have allowed easier and more reliable diagnosis with minimal effort and cost. Posttraumatic smell and taste disorders have shown a better prognosis than previously recognized. The recognition that many neurodegenerative disorders, such as amnestic mild cognitive impairment, Alzheimer disease, and premotor and idiopathic Parkinson disease have impaired smell loss is an important advancement in the clinical course of these disorders. Smell and taste abnormalities often lead to unexplained weight loss, decreased appetite, depression, and inability to smell smoke and recognize spoiled foods. Symptoms of dysosmia and dysgeusia have been more clinically defined and treated in the last 10 years, but treatment benefits are anecdotal. The morbidity and impaired quality of life in smell and taste disorders has been increasingly recognized and reported this last decade. Information on changes in food preparation has increased for those with impaired taste who do not enjoy eating. PMID- 29443307 TI - Fingolimod. AB - Fingolimod is the first oral disease therapy approved for relapsing-remitting multiple sclerosis (MS). Patients can be switched directly from interferon-beta or glatiramer acetate to fingolimod without a washout period. Fingolimod's potent efficacy, oral route of administration, and generally good safety and tolerability make it appealing to patients and clinicians. However, several adverse effects have already been identified, overall experience with its use is limited compared to other agents, and its novel and complex mechanism of action make predicting adverse effects challenging. Fingolimod's place in the MS treatment algorithm is evolving. We anticipate that once centers have solved the logistical issues associated with fingolimod initiation and if the experience in clinical practice parallels the efficacy, safety, and tolerability demonstrated in the phase 3 trials, fingolimod's routine use will increase. PMID- 29443308 TI - The evaluation of polyneuropathies. PMID- 29443309 TI - Critical care neurology: Five new things. AB - Critical care neurology has generated interest both because of the urgency to understand acute brain injury and because acute interventions could improve outcomes. Unifying themes include intervention without delay and early recognition of the potential for deterioration of the patient. While monitoring devices offer useful prognostic indicators, conducting a thorough clinical neurologic examination is paramount in determining the most effective course of patient management. Recent progress has been made in acute brain injury monitoring, more effective reversal of anticoagulation after cerebral hemorrhage, use of hypothermia as a therapeutic intervention, and in the management of severe Guillain-Barre syndrome. PMID- 29443311 TI - Amyotrophic lateral sclerosis: Ethical challenges. PMID- 29443310 TI - Smoking cessation for the neurologic patient. AB - Given the vast health and socioeconomic effects of tobacco use, smoking cessation is no longer a topic reserved for the primary care physician. As a modifiable risk factor that can lead to stroke, dementia, multiple sclerosis, and other neurologic diseases, cigarette smoking should be addressed by all health care providers, including neurologists. Counseling, nicotine replacement therapies, and other medications are the mainstays of treatment. However, even brief advice from a health care professional at the end of a routine office visit can increase a patient's chances of quitting. Armed with a better understanding of smoking's effect on neurologic disease and available resources, such as toll-free quit lines and Web-based interventions, neurologists can help their patients who smoke take the first step to successful cessation. PMID- 29443312 TI - Erratum: PUMA mediates the anti-cancer effect of osimertinib in colon cancer cells [Corrigendum]. AB - [This corrects the article on p. 5281 in vol. 10, PMID: 29138581.]. PMID- 29443314 TI - Breaking clinical ground. PMID- 29443313 TI - Global imperatives and challenges facing the practice of neurology. AB - The change in the practice of neurology from a diagnostic to a therapeutic specialty has empowered neurologists to make increasingly important decisions and recommendations for patients. With better understanding of disease pathogenesis and treatment has come the need to focus on disease prevention and the avoidance of treatment side effects. An increasingly automated and mechanized health care system has challenged us to integrate vast amounts of data that have a direct effect on patient risks and treatment, and to develop systems that avoid medical errors and allocate resources appropriately. It is imperative that we reaffirm the wisdom of clinical experience and judgment to inform our use of new technologies lest we lose the art of listening to and caring for the patient. PMID- 29443315 TI - Airway management in a patient with severe angioedema after thrombolysis for ischemic stroke. PMID- 29443316 TI - Intracerebral pseudotumors in a family with cerebroretinal vasculopathy. PMID- 29443317 TI - Medical decisions are not just about the facts: What a life-threatening virus can teach us about empathy, psychology, and the practice of neurology. AB - Getting the facts about risk and benefit is a critical part of medical decision making. But when doctors and patients disagree on what is reasonable risk, it takes more than a grasp of the data to establish the way forward. Our competence as physician-scientists relies on our ability to master the mechanics and information flow of our specialty. But we physicians, curious amalgams of scientists, scholars, researchers, and healers, should be aware of how we respond to the uniqueness of each of our physician-patient relationships, and be willing to explore ways in which the psychological and interpersonal dynamics influence the ethical, medically correct choices we pursue in them. PMID- 29443318 TI - Neurogenetics: Five new things. AB - Clinical neurology has benefitted greatly from recent remarkable advances in molecular genetics. In 1991, we could approximate a patient's risk for Huntington disease (HD) based only on linkage analysis. Now, 20 years later, not only can we identify the HD mutation with certainty, we can do the same with several hundred diseases. Whole genome or exome sequencing will soon allow for one-step interrogation of multiple genes for an even larger range of diseases. The recognition of these genes and their associated proteins in combination with new technology has led to creative new approaches to treatment. The challenge for the practicing neurologist is to provide clinically relevant and accurate interpretation of the genetic test results, with successfully treating once "incurable" neurogenetic diseases our ultimate goal. PMID- 29443319 TI - Early sign of hemodynamic insufficiency in the MCA watershed territories: Just the (finger)tip of the iceberg? PMID- 29443320 TI - Erratum: Cooperation of IRAK1/4 inhibitor and ABT-737 in nanoparticles for synergistic therapy of T cell acute lymphoblastic leukemia [Corrigendum]. AB - [This corrects the article on p. 8025 in vol. 12, PMID: 29184402.]. PMID- 29443321 TI - Diagnosis and treatment of somatoform disorders. AB - Many patients with somatoform disorders present to the neurology clinic, often after extensive evaluation that has left the patient and multiple other physicians frustrated. Knowledge of the typical characteristics of particular disorders enables the clinician to arrive at a positive diagnosis and facilitate referral to appropriate services. Using a series of representative cases, we review the DSM-IV-TR somatoform disorders most likely to present to the practicing neurologist, highlighting the epidemiologic features, typical presentations, and possible therapeutic approaches to each condition. PMID- 29443322 TI - Is intraoperative neuromonitoring a good idea in my practice? AB - Intraoperative neuromonitoring (IONM) is a growing field within neurology. IONM uses a variety of neurophysiologic modalities to detect signs of potential injury to neural structures while a patient is undergoing surgery. An early warning to the surgeon about signal changes may prevent permanent neurologic disability. Since all monitoring is done in real time, the work pace is fast. The operating room environment poses additional challenges for signal acquisition and interpretation. Specific training in the field is becoming increasingly available. Several practice models exist and IONM can be performed in an academic or a private practice setting. A career in intraoperative neuromonitoring can offer lots of opportunities, a high degree of job satisfaction, and flexibility to those choosing to enter the field. PMID- 29443323 TI - Can cerebral microbleeds cause an acute stroke syndrome? PMID- 29443324 TI - Cefepime neurotoxicity can mimic postanoxic coma with myoclonic status epilepticus. PMID- 29443325 TI - A survey on Integrated Management of Neonatal and Childhood Illness implementation by nurses in four districts of West Arsi zone of Ethiopia. AB - Background: In Ethiopia, one in 17 children dies before 1 year of age and one in 11 children dies before 5 years. Research that examines the factors influencing the implementation of the Integrated Management of Neonatal and Childhood Illnesses (IMNCI) strategy in Ethiopia is limited. This study aimed to identify the factors compelling the execution of IMNCI by nurses in four districts of West Arsi zone of Ethiopia. Methods: A mixed-method cross-sectional study was conducted from February to March 2016 in West Arsi zone of Oromia regional state, Ethiopia. A total of 185 Integrated Management of Childhood Illness (IMCI) trained registered nurses working at Under-Five Clinic were purposively chosen for the study among 291 registered nurses based at health centers and hospitals in the Arsi zone. The study was complemented by a qualitative method. Results: More than half (57.8%) of the nurses interviewed had been trained (51.35% of them attended in-service training). The most common issues encountered in the implementation of IMCI were: lack of trained staff (56.2%), lack of essential drugs and supplies (37.3%), and irregular supportive supervision (89.2%). The qualitative data supplemented the factors that influence IMNCI implementation, including drug unavailability, lack of human resources, and lack of effective supportive supervision and follow-up visits. Therefore, interventions aiming at training nurses, with emphasis on performing supportive consistent supervision and supporting the system of health care by enhancing admittance to indispensable drugs and supplies, are recommended to help IMCI implementation. PMID- 29443326 TI - Corrigendum: Proteome and Acetyl-Proteome Profiling of Camellia sinensis cv. 'Anji Baicha' during Periodic Albinism Reveals Alterations in Photosynthetic and Secondary Metabolite Biosynthetic Pathways. AB - [This corrects the article on p. 2104 in vol. 8, PMID: 29312376.]. PMID- 29443327 TI - The AAN's role in the development of health insurer coverage policy. AB - Scientific, evidence-based clinical practice guidelines (CPGs) differ from coverage/policy statements. The latter incorporate values and priorities and translate evidence into human benefit. They assist provider and payer decisions, and abide by extant laws and regulations. Payers have set internal processes for balancing and integrating the intent of CPGs into their coverage/payment policies. Recently, however, their efforts to reach out to respected medical specialty societies for input are increasing. In response, the American Academy of Neurology (AAN) has taken the following steps: 1) it is reacting to, and providing input to, payer requests for policy reviews; 2) it is taking a proactive approach by developing AAN guideline companion documents that describe potential provider impacts and policy implications; and 3) it is commencing an initiative to write its own template policies. This new involvement has met with initial positive outcomes. The AAN will continue to expand efforts to fulfill a growing need in this area. PMID- 29443328 TI - Prevalence and predictors of anemia among children under 5 years of age in Arusha District, Tanzania. AB - Anemia is a global health problem affecting most developing countries. We examined the prevalence of anemia and its predictors among children under 5 years of age in Arusha District, Tanzania. Random sampling technique was used to identify 436 children aged 6-59 months. Anemia status was assessed by measuring hemoglobin concentration from blood sample obtained from a finger prick and HemoCue(r) Hb 201+ photometer. Demographic information and dietary intake data were collected using a standardized questionnaire. Anemia cut-off points were defined according to World Health Organization standards for children aged 6-59 months. Logistic regression using backward procedure was used to estimate odds ratios (ORs) at 95% confidence intervals (CIs). Prevalence rate of anemia among under-fives was found to be 84.6% (n=369). Multivariable logistic regression identified the following predictors of anemia; low birth weight (adjusted OR (AOR): 2.1, 95% CI: 1.1-3.8), not consuming meat (AOR: 6.4, 95% CI: 3.2-12.9), not consuming vegetables (AOR: 2.1, 95% CI: 1.1-4.1), drinking milk (AOR: 2.5, 95% CI: 1.1-5.2), and drinking tea (AOR: 4.5, 95% CI: 1.5-13.7). It was concluded that low birth weight and dietary factors (ie, low or nonconsumption of iron-rich foods like meat, vegetables, and fruits) were predictors of anemia among under five children living in this rural setting. Community education on exclusive breastfeeding and introduction of complementary foods should be improved. Mothers and caretakers should be educated about nutrition, in general, as well as potential use of micronutrient powder to improve the nutritional quality of complementary foods. PMID- 29443329 TI - Correction to: Psychological and somatic distress in Chinese outpatients at general hospitals: a cross-sectional study. AB - [This corrects the article DOI: 10.1186/s12991-017-0158-y.]. PMID- 29443330 TI - Reply to the Letter: "Sensorineural Hearing Loss and Congenital Cytomegalovirus Infection". PMID- 29443331 TI - COPD in Primary Care: Key Considerations for Optimized Management: Dyspnea and Hyperinflation in Chronic Obstructive Pulmonary Disease: Impact on Physical Activity. AB - Physical inactivity is often considered to be a major contributor to the progression of chronic obstructive pulmonary disease, and is linked to hospitalizations and increased all-cause mortality. There is, therefore, a need to recognize symptoms early and treat them accordingly. PMID- 29443332 TI - COPD in Primary Care: Key Considerations for Optimized Management: Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management. AB - Ensuring that anxiety and depression are recognized and treated effectively in patients with chronic obstructive pulmonary disease (COPD) is essential for optimizing outcomes. Primary care practitioners are well placed to diagnose anxiety and depression, and to ensure these conditions are suitably managed alongside treatments of COPD. PMID- 29443333 TI - COPD in Primary Care: Key Considerations for Optimized Management: Considerations for Optimal Inhaler Device Selection in Chronic Obstructive Pulmonary Disease. AB - Understanding the advantages and limitations of inhaler devices for chronic obstructive pulmonary disease helps clinicians in choosing the proper device for the individual patient's clinical needs and preferences. However, with the wide range of permutations of drug combinations now possible, inhaler selection remains challenging. For all inhaler devices, adequate training for patients on how to use their device is required to achieve optimal therapeutic benefits. PMID- 29443334 TI - COPD in Primary Care: Key Considerations for Optimized Management: Treatment Options for Stable Chronic Obstructive Pulmonary Disease: Current Recommendations and Unmet Needs. AB - Primary care physicians manage the care of approximately 80% of patients with chronic obstructive pulmonary disease (COPD). This provides the opportunity to engage patients in management goal-setting that facilitates more tailored treatments, and can improve adherence to therapy, which is historically poor in patients with COPD, thereby improving outcomes. PMID- 29443336 TI - Reactions of SO2 and NH3 with epoxy groups on the surface of graphite oxide powder. AB - Graphite oxide powder was obtained using the modified Hummers' method and characterized using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The XPS results indicated that the epoxy groups were the main functional groups on the graphite oxide powder surface. The graphite oxide powder was then reacted with SO2 and NH3 gases, respectively, at 25 degrees C. The XPS and ToF-SIMS analyses of the surface of the reacted graphite oxide powder showed that the reactions mainly occurred in the epoxy groups. Bisulfate and amine groups were formed on the surface of the graphite oxide powder after the reactions between the graphite oxide powder and SO2 and NH3 gases. This work demonstrates a new method of removing SO2 and NH3 gases using graphite oxide powder. PMID- 29443335 TI - Surface functionalized nanostructures via position registered supramolecular polymer assembly. AB - Versatile control of cylindrical nanostructures formed by supramolecular assembly of end-functionalized polymer blends is demonstrated not only in their orientation over large areas but also in their surface chemical functionalities. Two binary blends consisting of supramolecular analogues of diblock copolymers with complementary end-sulfonated and aminated groups are investigated, viz., mono-end-functionalized polymers of (i) one-end-sulfonated polystyrene (SPS) and one-end-aminated poly(butadiene) (APBD) and (ii) one end-aminated polystyrene (APS) and one end-sulfonated poly(butadiene) (SPBD). The orientation of the cylinders with respect to the substrate surface depends on the solvent annealing time; either hexagonally ordered vertical cylinders or in-plane ones are readily obtained by controlling the solvent annealing time. Selective chemical etching of one of the polymers provides four different chemically modified nanostructures, viz., hexagonally ordered cylindrical holes and cylindrical posts with either sulfonate or amine surface functional groups. Additional supramolecular assembly is successfully achieved by solution coating either polymers or organic dyes that complementarily interact with the functional groups on the nanostructures. Furthermore, the supramolecularly assembled nanostructures are controlled by confining them to topographically pre-patterned Si substrates with pattern geometries of various shapes and sizes to produce globally ordered vertical or in plane cylinders with chemical functionalities on their surfaces. PMID- 29443338 TI - Recent advances in molecular rearrangements involving aryne intermediates. AB - This Feature Article is aimed at highlighting the recent developments in the transition-metal-free molecular rearrangements involving arynes. The chemistry of arynes has shown incredible developments especially in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions in the last three decades. The rapid growth in this field is mainly due to the development of mild methods for the generation of arynes. One aspect of the recent developments in the chemistry of arynes involves the molecular rearrangements proceeding via this electrophilic intermediate. The molecular rearrangements have provided direct access to a library of valuable molecules, which cannot be accessed in a single step through other synthetic routes. Herein, we present a concise account on the developments that occurred in this field over the last three decades. PMID- 29443339 TI - A new series of tetrahedral Co(ii) complexes [CoLX2] (X = NCS, Cl, Br, I) manifesting single-ion magnet features. AB - A series of tetrahedral CoII complexes [CoLX2] (X = NCS (1), Cl (2), Br (3) and I (4); L = 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene) based on a P-donor ligand has been prepared to investigate the influence of terminal ligand field strength on the anisotropy of CoII single-ion magnets. It has been observed that heavier and softer terminal ligands are able to decrease the anisotropy of the tetrahedral CoII centers. Thorough analyses of experimental and theoretical studies show that all complexes have an easy-axis type magnetic anisotropy and slow relaxation behaviors of tetrahedral CoII centers. Detailed ab initio theory studies disclose that the changes in the ligand field strength imposed by the terminal ligands result in modifying the single ion anisotropy (D) of polyhedra 1 4. Furthermore, the isostructural ZnII analogue (5) has been prepared to examine the influence of dipolar interactions between adjacent CoII centres and magnetic dilution experiments were performed. PMID- 29443340 TI - Ancistrocyclinones A and B, unprecedented pentacyclic N,C-coupled naphthylisoquinoline alkaloids, from the Chinese liana Ancistrocladus tectorius. AB - Two unique pentacyclic N,C-coupled naphthylisoquinolines, the ancistrocyclinones A (5) and B (6), were discovered in the Chinese liana Ancistrocladus tectorius. Furthermore, six known, likewise N,C-coupled alkaloids, viz., ancistrocladinium A (7a) and its mono- and bisphenolic analogs 8a and 9a were isolated, along with their atropo-diastereomers 7b, 8b, and 9b. The stereostructures of 5 and 6 were determined by HRESIMS, 1D and 2D NMR, oxidative degradation, and ECD calculations. The pentacyclic ancistrocyclinones A (5) and B (6) are structurally similar to berberine alkaloids - yet arising from a most different biosynthetic pathway: they are apparently formed by N,C-coupling of their polyketide-derived molecular halves, followed by oxidative cyclo-condensation. Biomimetic conversion of the co-occurring 4'-O-demethylancistrocladinium A (8a) to ancistrocyclinone A (5) via a quinoid intermediate supported the postulated pathway. Ancistrocyclinone A (5) was found to significantly inhibit the viability of drug sensitive human leukemia (CCRF-CEM) and multidrug-resistant tumor cells (CEM/ADR5000) with comparable efficacies. PMID- 29443341 TI - Super-resolution localization microscopy of radiation-induced histone H2AX phosphorylation in relation to H3K9-trimethylation in HeLa cells. AB - Ionizing radiation (IR)-induced damage confers functional and conformational changes to nuclear chromatin associated with DNA single and double strand breaks. This leads to the activation of complex DNA repair machineries that aim to preserve the integrity of the DNA molecule. Since hetero- and euchromatin are differentially accessible to DNA repair pathways, local chromatin re-arrangements and structural changes are among the consequences of an activated DNA damage response. Using super-resolution localization microscopy (SRLM), we investigated the X-ray-induced repositioning of gamma-H2AX and histone H3K9me3 heterochromatin marks in the nuclei of HeLa cells. Aliquots of cells exposed to different IR doses (0.5, 1 and 2 Gy) were fixed at certain repair times for SRLM imaging. The number and size of nano-scale gamma-H2AX molecule signal clusters detected increased with rising irradiation doses, with the number and size being the highest 0.5 h after irradiation. With growing repair time both the number and size of gamma-H2AX nano-clusters decreased. Eight hours after irradiation, the number of clusters reached control levels, in agreement with the disappearance of most IR-induced foci seen by conventional microscopy. SRLM investigation of heterochromatin marks in spatial relation to gamma-H2AX clusters showed that on average the heterochromatin density was high in the vicinity of gamma-H2AX, which is in agreement with the observation that DSBs seem to relocate to the surface of heterochromatin clusters for DNA repair. The data demonstrate the potential of pointillist images obtained by SRLM for quantitative investigations of chromatin conformation changes and repair-protein recruitment on the nanoscale as measures for a radiation response. PMID- 29443342 TI - Mannich reaction of trifluoroacetaldehyde hydrazones: a useful entry to trifluoromethyl substituted heterocycles. AB - NH-aryl hydrazones derived from trifluoroacetaldehyde hemiacetal may be involved in efficient Mannich type reactions with formaldehydes and aromatic aldehydes. The resulting hydrazones are useful building blocks for the preparation of trifluoromethyl substituted heterocycles as shown by a straightforward preparation of 1,2-diazine derivatives under heating with beta-ketoesters. PMID- 29443343 TI - UV absorption of Criegee intermediates: quantitative cross sections from high level ab initio theory. AB - Criegee intermediates (CIs) are increasingly recognized as important intermediates in atmospheric and combustion chemistry. Modelling in these fields requires reliable characterization of the CI's UV absorption cross sections. Different experimental approaches provided seemingly contradictory results both for the simplest CI as well as for higher analogues. To resolve these discrepancies, we model simultaneously the positions, widths, shapes and absolute intensities of the first absorption bands of CIs using the semiclassical reflection principle approach based on the path integral molecular dynamics. The UV spectra were efficiently processed via the kernel density estimation method. We show that the multireference character complicates the description of the system and the appropriate treatment of the electron correlation is vital. Multi reference methods with dynamical correlation are problematic due to high sensitivity of the results with respect to the active space. Single-reference based methods become reliable once the triple excitations components are included. Interestingly, the very similar CC2 and ADC(2) methods provide highly conflicting results which are, however, reconciled at the CC3 and ADC(3) levels. To calculate the spectra of higher CIs, we introduce composite EOM-CCSD/T and CC2/3 methods providing excellent absorption cross sections at an acceptable computational cost. We provide the first absolute intensities for individual conformers of the CH3CHOO molecule. PMID- 29443345 TI - Disulphide bond exchange inhibited by air - kinetic and thermodynamic products in a library of macrocyclic cysteine derivatives. AB - In this paper we present the synthesis and reactivity of dithiols comprising of two cysteine moieties attached to a dipicolinic acid core. Oxidation of these thiols provides oligomeric macrocycles. Monomers with 13-membered rings are kinetic products which are, however, strained and readily transform into higher oligomers under basic conditions or elevated temperature via a disulphide exchange reaction. Dimers, which are the most stable thermodynamic products, equilibrate only under inert conditions with thiolate as a catalyst. Under aerobic conditions, the thiols are oxidised before the equilibrium is reached. PMID- 29443346 TI - Rational selection of the cation of an ionic liquid to control the reaction outcome of a substitution reaction. AB - A range of ionic liquids was examined as solvents for a substitution reaction. They were chosen through rationally varying the ionic liquid cation in order to enhance the rate constant. Access to charge and electron-withdrawing substituents benefitted rate enhancement, allowing ionic liquids to be rationally selected to control reaction outcome. PMID- 29443347 TI - Patterned tungsten disulfide/graphene heterostructures for efficient multifunctional optoelectronic devices. AB - One of the major issues in graphene-based optoelectronics is to scale-up high performing devices. In this work, we report an original approach for the fabrication of efficient optoelectronic devices from scalable tungsten disulfide (WS2)/graphene heterostructures. Our approach allows for the patterned growth of WS2 on graphene and facilitates the realization of ohmic contacts. Photodetectors fabricated with WS2 on epitaxial graphene on silicon carbide (SiC) present, when illuminated with red light, a maximum responsivity R ~220 A W-1, a detectivity D* ~2.0 * 109 Jones and a -3 dB bandwidth of 250 Hz. The retrieved detectivity is 3 orders of magnitude higher than that obtained with graphene-only devices at the same wavelength. For shorter illumination wavelengths we observe a persistent photocurrent with a nearly complete charge retention, which originates from deep trap levels in the SiC substrate. This work ultimately demonstrates that WS2/graphene optoelectronic devices with promising performances can be obtained in a scalable manner. Furthermore, by combining wavelength-selective memory, enhanced responsivity and fast detection, this system is of interest for the implementation of 2d-based data storage devices. PMID- 29443349 TI - Partitioning-dependent conversion of polyelectrolyte assemblies in an aqueous two phase system. AB - Partitioning refers to the distribution of solute molecules in the two immiscible phases of a mixture of two solutions, such as an aqueous two-phase system (ATPS). The partitioning of RNA and peptide has been adjusted in situ to facilitate their assembly into intracellular membraneless organelles. Despite the immense potential of this approach in artificial systems, a partitioning-dependent assembly of macromolecules has been limited, due to the sophisticated processing associated with their in situ modification. Here we demonstrate an approach to direct the assembly of polyelectrolytes in an ATPS through varying their partitioning via pH changes. Microcapsules can be converted to microgel particles as the polyelectrolytes selectively partition to different emulsion phases when changing pH. Such partitioning-dependence can also be equally applied for complexing hydrophilic nanoparticles with polyelectrolytes in an ATPS. By enabling access of hydrophilic materials across the aqueous interface freely, the ATPS allows modification of their intrinsic properties in situ; this advantage will inspire more versatile control over the partitioning of hydrophilic materials and will create new multi-functional biomaterials. PMID- 29443350 TI - Coronary stent restenosis and the association with allergy to metal content of 316L stainless steel. AB - BACKGROUND: Most intra-coronary stents in use are made of 316 L stainless steel, which contains nickel, chromate and molybdenum. Whether inflammatory and allergic reactions to metals contribute to in-stent restenosis is still a matter of debate. AIM: The aim of this study was to ascertain the relationship between metal allergy and the occurrence of in-stent restenosis. METHODS: Ninety-nine adult patients who underwent two cardiac catheterisations, up to two years apart, were included in the study. Seventy patients had patent stents at the second angiogram (patent stent group) and 29 were found to have in-stent restenosis (restenosis group). All patients underwent patch testing with the relevant metals and the 316L stainless steel plate. RESULTS: Twenty-eight (28.3%) patients were found to have an allergy to at least one metal. There was no significant difference in the prevalence of metal allergy between the patent stent group and the restenosis group (28.6 and 27.6%, respectively; p = 0.921). CONCLUSIONS: Our data do not support the theory that contact allergy plays a role in the pathogenesis of in-stent restenosis. PMID- 29443351 TI - Reinforcement of suture lines with aortic eversion in aortic replacement. AB - BACKGROUND: In this study, we describe the technique of eversion of the native aortic tissue to prevent suture line complications, and report on our results with this technique. METHODS: A total of 42 patients who were operated on due to aortic aneurysm were retrospectively assessed. In all patients, an aortic segment of approximately 2 cm, which was left both distally and proximally, was everted to form a double-layer lumen and the grafts were anastomosed. Postoperative outcomes and long-term follow-up results were assessed. RESULTS: Aortic root replacement was done in 14 cases and eight subjects underwent concurrent coronary artery bypass surgery. Postoperatively, the average volume of the drainage was 375 +/- 75 ml, and there were no re-operations. Twenty-seven patients required blood transfusion. CONCLUSIONS: Reinforcement of the anastomosis line via eversion of the native aortic tissue reduced peri-operative blood loss and pseudo aneurysm and infection, with the advantage of using viable tissue. PMID- 29443352 TI - Levitronix bilateral ventricular assist device, a bridge to recovery in a patient with acute fulminant myocarditis and concomitant cerebellar infarction. AB - We report on the case of a 27-year-old male who presented to our emergency room with chest tightness, dyspnoea and cold sweats. The 12-lead electrocardiogram showed diffuse ventricular tachycardia with wide QRS complexes. Troponin-I level was elevated to 100 ng/ml. The coronary angiogram showed good patency of all three coronary vessels, and acute fulminant myocarditis was suspected. The patient underwent cardiopulmonary resuscitation in the catheter room and high dose inotropic support was initiated to stabilise his haemodynamic status. After resuscitation, the patient was in a coma and acute stroke was highly suspected. In addition, deteriorating cardiogenic shock with acute renal failure and pulmonary oedema were also detected. Due to haemodynamic compromise despite high dose inotropic support, a Levitronix(r) bilateral ventricular assist device (Bi VAD) was implanted on an emergency basis for circulatory support. Postoperative brain computed tomography revealed acute left cerebellar infarction. Because the patient had left cerebellar infarction with right hemiplegia, heart transplantation was contraindicated. Eventually, cardiac systolic function recovered well and the patient underwent successful Bi-VAD removal after a total of 18 days on Levitronix(r) haemodynamic support. He was weaned from the ventilator two weeks later and was discharged 10 days later. PMID- 29443353 TI - Obesity masks the relationship between dietary salt intake and blood pressure in people of African ancestry: the impact of obesity on the relationship between sodium and blood pressure. AB - Previous studies conducted to investigate the relationship between sodium intake and blood pressure in our African population have yielded contradictory results. With the high prevalence of obesity in this population, it is possible that these contradictory findings are due to the masking effects of obesity on this relationship. We measured 24-hour ambulatory blood pressure and 24-hour urine excretion on 547 South Africans of African ancestry. A multivariate regression analysis revealed no independent relationship between 24-hour sodium excretion and blood pressure in the total population sample, but when participants were stratified according to body mass index (BMI) status, there was a significant association between 24-hour sodium excretion and blood pressure in the normal-BMI participants but not in the overweight/obese participants. We concluded that dietary salt intake, indexed by 24-hour urinary sodium excretion, was associated with increased ambulatory blood pressure but this relationship was masked because of a high proportion of overweight/obese individuals in this population. PMID- 29443354 TI - Assessment of myocardial fibrosis by late gadolinium enhancement imaging and biomarkers of collagen metabolism in chronic rheumatic mitral regurgitation. AB - BACKGROUND: In chronic rheumatic mitral regurgitation (CRMR), involvement of the myocardium in the rheumatic process has been controversial. Therefore, we sought to study the presence of fibrosis using late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR) and biomarkers of collagen turnover in CRMR. METHODS: Twenty-two patients with CRMR underwent CMR and echocardiography. Serum concentrations of matrix metalloproteinase- 1 (MMP-1), tissue inhibitor of MMP-1 (TIMP- 1), MMP-1-to-TIMP-1 ratio, procollagen III N-terminal pro-peptide (PIIINP) and procollagen type IC peptide (PIP) were measured. RESULTS: Four patients had fibrosis on LGE-CMR. PICP and PIIINP concentrations were similar to those of the controls, however MMP-1 concentration was increased compared to that of the controls (log MMP-1 3.5 +/- 0.7 vs 2.7 +/- 0.9, p = 0.02). There was increased MMP-1 activity as the MMP-1-to- TIMP-1 ratio was higher in CRMR patients compared to the controls ( -1.2 +/- 0.6 vs -2.1 +/- 0.89, p = 0.002). CONCLUSIONS: Myocardial fibrosis was rare in CRMR patients. CRMR is likely a disease characterised by the predominance of collagen degradation rather than increased synthesis and myocardial fibrosis. PMID- 29443356 TI - Use of Optical Coherence Tomography Angiography in Masqueraders of Wet Age Related Macular Degeneration and Choroidal Neovascularization. PMID- 29443355 TI - Precarious employment and occupational accidents and injuries - a systematic review. AB - Objectives Precarious employment conditions have become more common in many countries over the last decades, and have been linked to various adverse health outcomes. The objective of this review was to collect and summarize existing scientific research of the relationship between dimensions of precarious employment and the rate of occupational injuries. Methods A protocol was developed in accordance with the PRISMA-P checklist for systematic literature reviews. We searched PubMed, Web of Science and Scopus for articles on observational studies from North America, Europe, Australia and New Zealand published in peer-reviewed journals 1990-2017. A minimum of two independent reviewers assessed each article with respect to quality and eligibility criteria. Articles of high/moderate quality meeting all specified inclusion criteria were included in the review. Results The literature search resulted in 471 original titles, of which 17 articles met all the inclusion criteria. The most common exposures were in descending order; temporary employment, multiple jobs, working for a subcontractor at the same worksite/temp agency, part-time, self-employment, hourly pay, union membership, insurance benefits, flexible versus fixed work schedule, wages, job insecurity, work-time control and precarious career trajectories. Ten studies reported a positive association between precarious employment and occupational injuries. Four studies reported a negative association, and three studies did not show any significant association. Conclusions This review supports an association between some of the dimensions of precarious employment and occupational injuries; most notably for multiple jobholders and employees of temp agencies or subcontractors at the same worksite. However, results for temporary employment are inconclusive. There is a need for more prospective studies of high quality, designed to measure effect sizes as well as causality. PMID- 29443357 TI - Low-Energy Stereotactic Radiotherapy for Treatment of Exudative Age-Related Macular Degeneration in a Treat-and-Extend Regimen. AB - BACKGROUND AND OBJECTIVE: To evaluate the effectiveness and safety of low-energy stereotactic radiotherapy (SRT) combined with anti-vascular endothelial growth factor (VEGF) treatment following a treat-and-extend regimen (TER) in wet age related macular degeneration (AMD). PATIENTS AND METHODS: Before/after SRT, the authors compared retrospective consecutive case series of 50 patients requiring frequent anti-VEGF treatment (every 4 or 6 weeks) in wet AMD, treated with a single session of SRT and TER (same manner pre/post-SRT). Outcomes were visual acuity (VA), recurrence-free interval, and central retinal thickness (CRT). RESULTS: After SRT, CRT was reduced from baseline (407.3 MUm +/- 153.2 MUm) to 12 months (320.2 MUm +/- 112.1 MUm; P < .001), with statistical significance from month 2 onward. VA was stable for 12 months (64.0 letters +/- 15.1 letters vs. 63.6 letters +/- 16.2 letters). The mean recurrence-free interval increased from 4.24 weeks +/- 0.66 weeks to 7.52 weeks +/- 3.05 weeks at 12 months (P < .001). No severe side effects were observed. CONCLUSION: Low-energy SRT, combined with anti-VEGF TER, was associated with reduced injection frequency and preserved VA during 12 months of follow-up. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:86 93.]. PMID- 29443358 TI - Microscope-Integrated Intraoperative Ultrahigh-Speed Swept-Source Optical Coherence Tomography for Widefield Retinal and Anterior Segment Imaging. AB - BACKGROUND AND OBJECTIVE: To demonstrate the feasibility of retinal and anterior segment intraoperative widefield imaging using an ultrahigh-speed, swept-source optical coherence tomography (SS-OCT) surgical microscope attachment. PATIENTS AND METHODS: A prototype post-objective SS-OCT using a 1,050-nm wavelength, 400 kHz A-scan rate, vertical cavity surface-emitting laser (VCSEL) light source was integrated to a commercial ophthalmic surgical microscope after the objective. Each widefield OCT data set was acquired in 3 seconds (1,000 * 1,000 A-scans, 12 * 12 mm2 for retina and 10 * 10 mm2 for anterior segment). RESULTS: Intraoperative SS-OCT was performed in 20 eyes of 20 patients. In six of seven membrane peels and five of seven rhegmatogenous retinal detachment repair surgeries, widefield retinal imaging enabled evaluation pre- and postoperatively. In all seven cataract cases, anterior imaging evaluated the integrity of the posterior lens capsule. CONCLUSIONS: Ultrahigh-speed SS-OCT enables widefield intraoperative viewing in the posterior and anterior eye. Widefield imaging visualizes ocular structures and pathology without requiring OCT realignment. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:94-102.]. PMID- 29443359 TI - Validity of the Red Reflex Exam in the Newborn Eye Screening Test Cohort. AB - BACKGROUND AND OBJECTIVE: The validity of the red reflex exam has yet to be tested against new methods of wide-angle imaging that may improve early detection of neonatal ocular pathology. The authors aimed to determine the validity of the pediatrician's red reflex exam using 130 degrees wide-angle external and fundus digital imaging as a gold standard. PATIENTS AND METHODS: This was a prospective cohort study of 194 healthy, term newborns enrolled in the Newborn Eye Screening Test study at Lucile Packard Children's Hospital from July 25, 2013, to July 25, 2014. Red reflex screening was performed by a pediatrician in the newborn nursery and wide-angle fundus digital imaging was performed by a neonatal intensive care unit-certified nurse. The main outcome measure was the validity of the pediatrician's red reflex exam (unweighted kappa [kappa] statistic, sensitivity, specificity). RESULTS: Compared to no subjects with abnormal red reflex exams reported in the pediatrician's notes, 49 subjects demonstrated one or multiple ocular abnormalities on 130 degrees wide-angle fundus imaging (kappa = 0.00). The pediatrician's red reflex exam had a sensitivity of 0.0% (95% CI, 0.0%-7.3%) and specificity of 100.0% (95% CI, 97.5%-100.0%) for the detection of ocular abnormalities. CONCLUSION: This study demonstrates the ability of wide-angle fundus imaging to detect fundus abnormalities not otherwise identified by standard newborn red reflex screening prior to hospital discharge. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:103-110.]. PMID- 29443360 TI - Swept-Source OCT Angiography of Full-Thickness Macular Holes: Appearance and Artifacts. AB - BACKGROUND AND OBJECTIVE: To evaluate swept-source optical coherence tomography angiography (SS-OCTA) images in full-thickness macular holes (FTMHs). PATIENTS AND METHODS: SS-OCTA of FTMHs was performed before or after surgery. Vitrectomy with the temporal inverted internal limiting membrane flap technique was used. The authors measured the diameter and area of the foveal avascular zone (FAZ) in superficial and deep retina vasculature. RESULTS: In 88 patients, two artifact types were observed. First, a hyperreflective circle in the center corresponding to a segmentation failure, as in these cases the segmentation line automatically relocated below the retinal pigment epithelium. Second, in macular holes with cystic spaces around the fovea, detection of blood flow was only partially possible, showing artifacts in the perifoveal vasculature. CONCLUSION: The authors present artifacts occurring during visualization of FTMHs with SS-OCTA and the means to correct them. Eyes with decreased postoperative central retinal thickness have an increased FAZ in the deep retinal layer plexus. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:111-121.]. PMID- 29443361 TI - Optical Coherence Tomography Angiography of the Macula in Adults With a History of Preterm Birth. AB - BACKGROUND AND OBJECTIVE: To evaluate the fovea microvasculature in adult subjects with history of preterm birth using optical coherence angiography (OCTA). PATIENTS AND METHODS: In this retrospective study, macular OCTA images were obtained from adult subjects with a history of preterm birth. The presence of the foveal avascular zone (FAZ) and its size was determined. RESULTS: Ten eyes from six subjects with ages ranging from 26 years old to 65 years old were evaluated. A distinct FAZ was not observed in three eyes (30%). The FAZ was small in other eyes, ranging from 0.07 mm2 to 0.18 mm2. CONCLUSION: Adult subjects with a history of preterm birth may have persistent foveal vasculature in the FAZ. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:122-125.]. PMID- 29443362 TI - Outcomes of Intravitreal Bevacizumab and Diode Laser Photocoagulation for Treatment-Warranted Retinopathy of Prematurity. AB - BACKGROUND AND OBJECTIVE: To investigate the outcomes of infants with treatment warranted retinopathy of prematurity (TW-ROP) who received intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) (IVB) injections as compared to diode laser photocoagulation (DLP). PATIENTS AND METHODS: Data from the Stanford University Network for Diagnosis of Retinopathy of Prematurity database and inpatients at Stanford Children's Hospital were retrospectively reviewed for premature newborns with TW-ROP treated with DLP or 0.625 mg of IVB. Patient characteristics, hospital course, and neurodevelopmental outcomes were compared. RESULTS: In all, 49 eyes from 25 patients were included; 10 infants (20 eyes) received DLP and 15 infants (29 eyes) received IVB. The IVB infants had significantly fewer diagnoses at the time of discharge and fewer readmissions after initial hospital discharge than the DLP infants (four versus six diagnoses, P = .004; zero versus one readmission, P = .038). At an average of 20 months corrected age, there was no significant difference in neurodevelopmental delay (adjusted odds ratio = 0.87; 95% CI, 0.08-9.46). CONCLUSION: Systemic morbidity may be similar among infants treated initially with bevacizumab compared to DLP. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:126-131.]. PMID- 29443363 TI - Sheets Glide-Assisted Intraocular Placement of the Argus II Retinal Prosthesis. AB - BACKGROUND AND OBJECTIVE: As an increasing number of vitreoretinal surgeons are implanting retinal prosthesis devices, the need to share surgical techniques to ease implantation in challenging scenarios grows. The authors share a technique to aide in overcoming a challenge associated with uveal prolapse in a patient undergoing Argus II retinal prosthesis (Second Sight Medical Products, Sylmar, CA) implantation. PATIENTS AND METHODS: A surgical technique is discussed and demonstrated using a video (Video available at www.healio.com/OSLIRetina). RESULTS: A Sheets glide-assisted technique was used to successfully place the electrode array in the vitreous cavity. CONCLUSION: The Sheets glide may be a useful tool in aiding the retinal surgeon to successfully and easily place the electrode array of the Argus II retinal prosthesis. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:132-133.]. PMID- 29443364 TI - Optical Coherence Tomography Microangiography Imaging of Circumscribed Choroidal Hemangioma. AB - Optical coherence tomography angiography (OCTA) is a new imaging technology capable of providing three-dimensional (3-D) retinal and choroidal microvascular maps without a need for exogenous dye. In this study, the authors evaluate the retinal and choroidal microvascular architecture of the macula in a patient with choroidal hemangioma using OCTA. Widefield OCTA with tracking capability and segmentation was performed to provide images with a field of view at 9 * 9 mm2. The en face maximum projection was used to generate 2-D angiograms of different layers with color-coded images. Variable levels of perfusion within the lesion were identified, which correlate well with the known vascular abnormalities of choroidal hemangiomas. OCTA demonstrated an accurate modality to measure the 3-D borders of this lesion. This is the novel utilization of OCTA imaging on choroidal hemangioma. OCTA may provide detailed vascular findings in circumscribed choroidal hemangiomas, which may aid in the diagnosis and evaluation of the treatment response. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:134-137.]. PMID- 29443365 TI - Detection of Choriocapillaris Loss in Alport Syndrome With Swept-Source OCT Angiography. AB - A patient previously diagnosed with Alport Syndrome was evaluated using multimodal imaging. Optical coherence tomography (OCT) demonstrated significant thinning of the inner retina within the macula, and inner retinal cysts were found in the peripheral macula. OCT angiography demonstrated loss of the choriocapillaris. Abnormal collagen appears to have multiple deleterious effects on the retinal and choroidal structure and vasculature. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:138-141.]. PMID- 29443366 TI - Paradoxical Anatomic Response to Topical Carbonic Anhydrase Inhibitor in X-linked Retinoschisis. AB - An 11-year-old boy presented for central vision blurring in each eye. Visual acuity was 20/80 and examination revealed spoke-wheel foveal schisis and peripheral elevated diaphanous inner retina in each eye. Spectral-domain optical coherence tomography showed inner-retinal, flat-topped cysts in each eye. Electrophysiologic testing was refused, but a clinical diagnosis of X-linked retinoschisis was made. Three months after topical dorzolamide (Trusopt; Santen Pharmaceutical, Osaka, Japan) was started, the macular cysts worsened significantly. The medication was stopped and 3 months later, the macular anatomy returned to baseline. Physicians should be aware of this potential paradoxical anatomic response to topical carbonic anhydrase inhibitor therapy in X-linked retinoschisis. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:142-144.]. PMID- 29443367 TI - Swept-Source OCT Angiography of Multiple Evanescent White Dot Syndrome With Inflammatory Retinal Pigment Epithelial Detachment. AB - A 30-year-old woman with photopsias and decreased vision was diagnosed with multiple evanescent white dot syndrome (MEWDS) with an atypical inflammatory subfoveal retinal pigment epithelial detachment (PED) and imaged using swept source optical coherence tomography (SS-OCT) during several visits. SS-OCT imaging revealed a focal area of attenuated choriocapillaris underneath the PED. An attempt to treat the presumed macular inflammatory lesion with corticosteroids resulted in bilateral exudation consistent with central serous chorioretinopathy. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:145-151.]. PMID- 29443368 TI - Active Cone Regeneration Following Autologous Internal Limiting Membrane 'Chunk' Transplantation in Optic Disc Pit-Associated Maculopathy. AB - This case report aims to study active cone regeneration and its functional correlation in optic disc pit maculopathy (ODPM) with a large outer macular defect treated with autologous internal limiting membrane (ILM) "chunk" transplantation. Outcome analysis was done using spectral-domain optical coherence tomography (SD-OCT), adaptive optics, and microperimetry. Visual acuity improved from counting fingers at 2 meters to 6/18 Snellen equivalent postoperatively, whereas SD-OCT demonstrated closure of outer subfoveal defect. Adaptive optics imaging revealed maximum active cone concentration of 14,232/mm2 at the fovea, and fixation stability improved to 61% and 90% (P1 and P2, respectively) on microperimetry. To conclude, autologous ILM "chunk" transplantation provides an additional therapeutic option in treatment of ODPM with large outer macular defect. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:152-155.]. PMID- 29443369 TI - Relation of Renal Dysfunction to Quality of Anticoagulation Control in Patients with Atrial Fibrillation: The FANTASIIA Registry. AB - BACKGROUND: One-third of atrial fibrillation (AF) patients have chronic kidney disease (CKD), a condition that itself increases thromboembolic and major bleeding risks, especially in patients with severe CKD. Bleeding would be accentuated by suboptimal anticoagulation control with vitamin K antagonists (VKA). PURPOSE: This article aimed to investigate the incidence of cardiovascular events, mortality and quality of anticoagulation in relation to CKD in a 'real-world' prospective cohort of AF patients included in the FANTASIIA registry. METHODS: We analysed consecutive AF patients who were prospectively recruited with a year of follow-up. The quality of anticoagulation was estimated by time in therapeutic range (TTR). The annual incidence of events was analysed. RESULTS: We studied 1,936 patients (male: 55.7%, mean: 73.8 +/- 9.4 years): 445 (22.9%) had normal function, 698 (36.1%) had mild CKD, 713 (36.8%) had moderate CKD and 80 (4.2%) had severe CKD. Patients with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (severe CKD) had lower TTR (53.3 +/- 25.6% vs. 61.8 +/- 25.1%, p = 0.007) and higher proportion of poor TTR (67.2 vs. 51.8%; p = 0.014) than patients with eGFR >=30 mL/min/1.73 m2. Severe CKD was significantly associated with cardiovascular mortality (hazard ratio [HR]: 9.33; p = 0.002), major bleeding (HR: 2.94; p = 0.036) and major adverse cardiovascular events (MACE) (HR: 4.93; p = 0.004). Importantly, 375 patients (21.1%) showed a deteriorating eGFR of >=10 mL/min during the follow-up, with significantly higher mortality and cardiovascular events. CONCLUSION: In a prospective and real-world AF registry, approximately 67% of patients with severe CKD had poor anticoagulation control while taking VKA. The presence of severe CKD was an independent factor for cardiovascular mortality, MACE and major bleeding. Worsening eGFR of only >=10 mL/min during follow-up was significantly associated with mortality and major bleeding. PMID- 29443370 TI - Beneficial Effects of High-Density Lipoproteins on Acquired von Willebrand Syndrome in Aortic Valve Stenosis. AB - BACKGROUND: Infusions of apolipoprotein A-I (apoA-I), the major protein component of high-density lipoproteins (HDL), result in aortic valve stenosis (AVS) regression in experimental models. Severe AVS can be complicated by acquired von Willebrand syndrome, a haemorrhagic disorder associated with loss of high-molecular-weight von Willebrand factor (vWF) multimers (HMWM), the latter being a consequence of increased shear stress and enhanced vWF-cleaving protease (ADAMTS-13) activity. Although antithrombotic actions of HDL have been described, its effects on ADAMTS-13 and vWF in AVS are unknown. METHODS AND RESULTS: We assessed ADAMTS-13 activity in plasma derived from a rabbit model of AVS (n = 29) as well as in plasma collected from 64 patients with severe AVS (age 65.0 +/- 10.4 years, 44 males) undergoing aortic valve replacement (AVR). In both human and rabbit AVS plasma, ADAMTS-13 activity was higher than that in controls (p < 0.05). Accordingly, AVS patients had less HMWM than controls (66.3 +/- 27.2% vs. 97.2 +/- 24.1%, p < 0.0001). Both ADAMTS-13 activity and HMWM correlated significantly with aortic transvalvular gradients, thereby showing opposing correlations (r = 0.3, p = 0.018 and r = -0.4, p = 0.003, respectively). Administration of an apoA-I mimetic peptide reduced ADAMTS-13 activity in AVS rabbits as compared with the placebo group (2.0 +/- 0.5 RFU/sec vs. 3.8 +/- 0.4 RFU/sec, p < 0.05). Similarly, a negative correlation was found between ADAMTS-13 activity and HDL cholesterol levels in patients with AVS (r = -0.3, p = 0.045). CONCLUSION: Our data indicate that HDL levels are associated with reduced ADAMTS 13 activity and increased HMWM. HDL-based therapies may reduce the haematologic abnormalities of the acquired von Willebrand syndrome in AVS. PMID- 29443371 TI - Neutrophil Elastase-Derived Fibrin Degradation Products Indicate Presence of Abdominal Aortic Aneurysms and Correlate with Intraluminal Thrombus Volume. AB - BACKGROUND: The intraluminal thrombi (ILT) of abdominal aortic aneurysms (AAA) contain neutrophils, which can secrete elastase. We evaluated whether plasma neutrophil elastase-derived cross-linked fibrin degradation products (E-XDP) could reveal the presence, size and mechanical stress of AAAs and its ILTs. METHODS: E-XDP and D-dimer were measured in plasma from 37 male patients with AAA and 42 male controls. The ILT volumes of the AAAs and any coexisting aneurysms could be measured in 29 patients and finite element analysis was performed to estimate mechanical stress of the ILT. E-XDP, neutrophil elastase and neutrophil marker CD66acd were evaluated in aortic tissue with immunohistochemistry (IHC). The association between ILT volume and E-XDP was validated in a separate cohort (n = 51). RESULTS: E-XDP levels were elevated in patients with AAA compared with controls (p = 5.8e-13), indicated AAA with 98% sensitivity, 86% specificity and increased with presence of coexisting aneurysms. The association between AAA and increased E-XDP was independent of smoking, comorbidities and medication. E-XDP correlated with volume of all ILTs (r = 0.76, p = 4.5e-06), mean ILT stress (r = 0.46, p = 0.013) and the volume of the AAA associated ILT (r = 0.64, p = 0.00017). E-XDP correlated stronger with ILT volume compared with D-dimer (r = 0.76 vs. r = 0.64, p = 0.018). The correlation between E-XDP and ILT volume was validated in the separate cohort (r = 0.53, p = 7.6e 05). IHC revealed E-XDP expression in the ILT, spatially related to neutrophil elastase and neutrophils. CONCLUSION: E-XDP is a marker of the presence of AAA and coexisting aneurysms as well as the volume and mechanical stress of the ILT. PMID- 29443372 TI - Impact of Reticulated Platelets on the Antiplatelet Effect of the Intravenous P2Y12-Receptor Inhibitor Cangrelor. AB - BACKGROUND: Reticulated platelets are associated with impaired antiplatelet response to irreversibly acting P2Y12-receptor inhibitors. However, the impact of reticluated platelets (RP) on the reversibly acting injectable P2Y12-receptor inhibitor cangrelor is unknown. Thus, this study sought to investigate the influence of RP on cangrelor and transitioning strategies to oral P2Y12-receptor inhibitors. METHODS: This study randomized 110 patients undergoing elective percutaneous coronary intervention with use of cangrelor to different oral transitioning strategies loading with prasugrel 60 mg or ticagrelor 180 mg at the start of cangrelor (n = 45 each) or loading with clopidogrel 600 mg after discontinuation of cangrelor (n = 20). ADP-induced platelet reactivity was assessed by impedance aggregometry. Reticulated platelets were analysed by an automated whole blood flow cytometry and described as immature platelet count. RESULTS: There was no correlation of reticulated platelets and ADP-induced platelet reactivity in patients under treatment with cangrelor (r = 0.06, p = 0.47). This finding was consistent in all three transitioning strategies. On day 1 following treatment with cangrelor, the correlation of reticulated platelets and platelet reactivity was detectable again in patients receiving thienopyridines but not ticagrelor (all patients r = 0.37, p < 0.001; clopidogrel: r = 0.59, p = 0.01; prasugrel: r = 0.47, p < 0.001; ticagrelor r = 0.22, p = 0.13). CONCLUSION: Platelet inhibition is not influenced by levels of reticulated platelets during infusion of cangrelor independent of oral P2Y12 receptor inhibitor transitioning strategy. These findings underline the potency of cangrelor as immediate and reversibly acting P2Y12-receptor inhibitor. PMID- 29443373 TI - P2X1 Receptors Amplify FcgammaRIIa-Induced Ca2+ Increases and Functional Responses in Human Platelets. AB - Platelets express key receptors of the innate immune system such as FcgammaRIIa and Toll-like receptors (TLR). P2X1 cation channels amplify the platelet responses to several major platelet stimuli, particularly glycoprotein (GP)VI and TLR2/1, whereas their contribution to Src tyrosine kinase-dependent FcgammaRIIa receptors remains unknown. We investigated the role of P2X1 receptors during activation of FcgammaRIIa in human platelets, following stimulation by cross linking of an anti-FcgammaRIIa monoclonal antibody (mAb) IV.3, or bacterial stimulation with Streptococcus sanguinis. Activation was assessed in washed platelet suspensions via measurement of intracellular Ca2+ ([Ca2+]i) increases, ATP release and aggregation. P2X1 activity was abolished by pre-addition of alpha,beta-meATP, exclusion of apyrase or the antagonist NF449. FcgammaRIIa activation evoked a robust increase in [Ca2+]i (441 +/- 33 nM at 30 MUg/mL mAb), which was reduced to a similar extent (to 66-70% of control) by NF449, pre exposure to alpha,beta-meATP or apyrase omission, demonstrating a significant P2X1 receptor contribution. FcgammaRIIa activation-dependent P2X1 responses were partially resistant to nitric oxide (NO), but abrogated by 500 nM prostacyclin (PGI2). Aggregation responses to bacteria and FcgammaRIIa activation were also inhibited by P2X1 receptor desensitization (to 66 and 42% of control, respectively). However, FcgammaRIIa-mediated tyrosine phosphorylation and ATP release were not significantly altered by the loss of P2X1 activity. In conclusion, we show that P2X1 receptors enhance platelet FcgammaRIIa receptor evoked aggregation through an increase in [Ca2+]i downstream of the initial tyrosine phosphorylation events and early dense granule release. This represents a further route whereby ATP-gated cation channels can contribute to platelet dependent immune responses in vivo. PMID- 29443374 TI - Prognostic Implications of Dual Platelet Reactivity Testing in Acute Coronary Syndrome. AB - Studies on platelet reactivity (PR) testing commonly test PR only after percutaneous coronary intervention (PCI) has been performed. There are few data on pre- and post-PCI testing. Data on simultaneous testing of aspirin and adenosine diphosphate antagonist response are conflicting. We investigated the prognostic value of combined serial assessments of high on-aspirin PR (HASPR) and high on-adenosine diphosphate receptor antagonist PR (HADPR) in patients with acute coronary syndrome (ACS). HASPR and HADPR were assessed in 928 ACS patients before (initial test) and 24 hours after (final test) coronary angiography, with or without revascularization. Patients with HASPR on the initial test, compared with those without, had significantly higher intraprocedural thrombotic events (IPTE) (8.6 vs. 1.2%, p <= 0.001) and higher 30-day major adverse cardiovascular and cerebrovascular events (MACCE; 5.2 vs. 2.3%, p = 0.05), but not 12-month MACCE (13.0 vs. 15.1%, p = 0.50). Patients with initial HADPR, compared with those without, had significantly higher IPTE (4.4 vs. 0.9%, p = 0.004), but not 30-day (3.5 vs. 2.3%, p = 0.32) or 12-month MACCE (14.0 vs. 12.5%, p = 0.54). The c-statistic of the Global Registry of Acute Coronary Events (GRACE) score alone, GRACE score + ASPR test and GRACE score + ADPR test for discriminating 30-day MACCE was 0.649, 0.803 and 0.757, respectively. Final ADPR was associated with 30 day MACCE among patients with intermediate-to-high GRACE score (adjusted odds ratio [OR]: 4.50, 95% confidence interval [CI]: 1.14-17.66), but not low GRACE score (adjusted OR: 1.19, 95% CI: 0.13-10.79). In conclusion, both HASPR and HADPR predict ischaemic events in ACS. This predictive utility is time-dependent and risk-dependent. PMID- 29443375 TI - Ischaemic Events and Stent Thrombosis following Planned Discontinuation of Study Treatment with Ticagrelor or Clopidogrel in the PLATO Study. PMID- 29443376 TI - What is your diagnosis? Subcutaneous mass on a dog. PMID- 29443377 TI - Identification of alpha-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy. AB - : Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T-cell receptors (TCRs) specific for HCC-associated antigens, such as alpha-fetoprotein (AFP), can potentially redirect human T cells to specifically recognize and kill HCC tumor cells to achieve antitumor effects. In this study, using lentivector and peptide immunization, we identified a population of cluster of differentiation 8 (CD8) T cells in human leukocyte antigen (HLA)-A2 transgenic AAD mice that recognized AFP158 epitope on human HCC cells. Adoptive transfer of the AFP158 -specific mouse CD8 T cells eradicated HepG2 tumor xenografts as large as 2 cm in diameter in immunocompromised nonobese diabetic severe combined immunodeficient gamma knockout (NSG) mice. We then established T-cell hybridoma clones from the AFP158 specific mouse CD8 T cells and identified three sets of paired TCR genes out of five hybridomas. Expression of the murine TCR genes redirected primary human T cells to bind HLA-A2/AFP158 tetramer. TCR gene-engineered human T (TCR-T) cells also specifically recognized HLA-A2+ AFP+ HepG2 HCC tumor cells and produced effector cytokines. Importantly, the TCR-T cells could specifically kill HLA-A2+ AFP+ HepG2 tumor cells without significant toxicity to normal primary hepatocytes in vitro. Adoptive transfer of the AFP-specific TCR-T cells could eradicate HepG2 tumors in NSG mice. CONCLUSION: We have identified AFP-specific murine TCR genes that can redirect human T cells to specifically recognize and kill HCC tumor cells, and those AFP158 -specific TCRs have a great potential to engineer a patient's autologous T cells to treat HCC tumors. (Hepatology 2018). PMID- 29443379 TI - What Is Your Diagnosis? Testicular tumor in a horse. PMID- 29443380 TI - Quality of life in Down syndrome: a matter of perspective. PMID- 29443378 TI - Hepatitis C virus E2 envelope glycoprotein induces an immunoregulatory phenotype in macrophages. AB - : A comprehensive strategy to control hepatitis C virus (HCV) infection needs a vaccine. Our phase I study with recombinant HCV E1/E2 envelope glycoprotein (EnvGPs) as a candidate vaccine did not induce a strong immune response in volunteers. We analyzed the interactions of HCV EnvGPs with human monocyte derived macrophages as antigen-presenting cells. HCV E2 induced immune regulatory cytokine interleukin (IL)-10 and soluble CD163 (sCD163) protein expression in macrophages from 7 of 9 blood donors tested. Furthermore, HCV E2 enhanced Stat3 and suppressed Stat1 activation, reflecting macrophage polarization toward M2 phenotype. E2-associated macrophage polarization appeared to be dependent of its interaction with CD81 leading endothelial growth factor receptor (EGFR) activation. Additionally, E2 suppressed the expression of C3 complement, similar to HCV-exposed dendritic cells (DCs), implying potential impairment of immune cell priming. CONCLUSION: Our results suggest that E2 EnvGP may not be an ideal candidate for HCV vaccine development, and discrete domains within E2 may prove to be more capable of elliciting a protective immune response. (Hepatology 2018). PMID- 29443381 TI - Guillain-Barre-like syndrome during pembrolizumab treatment. PMID- 29443382 TI - Reply.